PMID- 21811070 TI - Impact of hemodialysis therapy on anemia of chronic kidney disease: the potential mechanisms. AB - A significant and increasing number of chronic kidney disease (CKD) patients are treated with online hemodiafiltration (OL-HDF), even in the absence of more conclusive survival data. OL-HDF affords several clinical benefits including control of anemia of CKD, a common affliction in dialysis patients. In efforts to understand the underlying mechanisms that contribute to the purported benefits of OL-HDF, we examined the potential role and impact of OL-HDF on key stages of anemia and its correction: erythropoiesis of bone marrow, circulating erythrocytes and on anemia therapy. We review evidence that indicates OL-HDF may modulate key processes of anemia and its therapy, including underlying conditions and responses of uremic toxicity and inflammation that aggravate anemia. Our assessment indicates that OL-HDF favorably impacts anemia by not only eliminating putative uremic inhibitors that suppress erythropoiesis, reducing red cell destruction and increasing iron availability, but also by mechanisms restricting underlying inflammation and endothelial dysfunction that are crucial to both CKD and anemia. PMID- 21811071 TI - An alternative approach for mitral paravalvular leak with Dacron patch curtaining under the guidance of real-time 3-dimensional transesophageal echocardiography. AB - OBJECTIVES: The aim of this study was to evaluate real-time 3-dimensional transesophageal echocardiography (RT-3D TEE) in the assessment of mitral paravalvular leakage curtaining surgery with a Dacron patch. METHODS: RT-3D TEE was used before and after the operation. RESULTS: Repairing a mitral paravalvular leak with Dacron patch curtaining was a useful, simple and new technique with promising feasibility and durability. CONCLUSIONS: In selected patients in whom the mitral paravalvular defect is relatively large, and may thus not be suitable for closing with primary suture, Dacron patch curtaining may be feasible for repair guided with RT-3D TEE; both are described for the first time. PMID- 21811072 TI - Transient left ventricular systolic dysfunction with thrombus and subsequent cardioembolic stroke in short-term overt hypothyroidism. AB - A 57-year-old woman was referred for cardiomegaly on a chest X-ray taken during thyroxine withdrawal for radioiodine therapy after total thyroidectomy. Baseline transthoracic echocardiography showed left ventricular (LV) wall motion abnormalities and an LV apical mural thrombus. Coronary angiography revealed normal epicardial coronary arteries. Despite anticoagulation treatment, the patient developed abrupt aphasia, agraphia and acalculia. The distal branch of the inferior segmental branch on the left middle cerebral artery was not well visualized on magnetic resonance angiography. Three days later, the patient had made a near full neurological recovery. After 4 weeks of anticoagulation therapy, the apical mural thrombus and wall motion abnormalities resolved. This is the first reported case in the medical literature of transient LV systolic dysfunction with thrombus and subsequent cardioembolic stroke in a patient with short-term overt hypothyroidism. PMID- 21811073 TI - A multicenter brain perfusion SPECT study evaluating idiopathic normal-pressure hydrocephalus on neurological improvement. AB - PURPOSE: This study was designed to investigate the specific cerebral blood flow (CBF) pattern in patients with idiopathic normal-pressure hydrocephalus (iNPH) and a predictive value for shunt responsiveness in a multicenter study (Study of Idiopathic Normal-Pressure Hydrocephalus on Neurological Improvement: SINPHONI). METHODS: Eighty-four iNPH patients underwent shunt operations using MRI selection criteria from the SINPHONI and were subjected to CBF single photon emission computed tomography (SPECT). The perfusion patterns on SPECT were classified: anterior-dominant CBF reduction type (A type), posterior-dominant CBF reduction type (P type), and mixed or diffuse CBF reduction type (M type). The predictive value of the CBF pattern for favorable shunt outcome was evaluated. RESULTS: Favorable outcomes were obtained in 76% (64/84) of patients, and shunt responsiveness was achieved in 85% (71/84) of patients. Areas of severely reduced relative CBF were demonstrated around the corpus callosum and in the sylvian fissure area, which included the effects of dilatations of the ventricles and sylvian fissures and relatively increased perfusion in the medial and lateral frontal, parietal, and occipital areas at high convexity. Forty-nine (58%) cases were A type, 25 (30%) cases were M type, and 10 (12%) cases were P type. A, M, and P type cases exhibited 83, 84, and 90% positive predictive values for shunt responsiveness, respectively. Mean modified Rankin scale and Mini-Mental State Examination scores of the A type group were significantly better than those of other groups. CONCLUSION: The iNPH patients showed various patterns of CBF reduction, but there was no significant difference in the predictive value among the three patterns, though CBF reduction patterns may suggest a severe condition of iNPH. PMID- 21811074 TI - Blumgart's technique of pancreaticojejunostomy: an appraisal. AB - BACKGROUND: Although mortality of Whipple's pancreaticoduodenectomy (WPD) is reduced to <5%, morbidity still remains between 30 and 50%. Pancreaticojejunal anastomosis remains the main cause of morbidity. Blumgart anastomosis using transpancreatic U sutures has been proposed to decrease the leak rate and its associated morbidity. We analyzed the results of Blumgart anastomosis applied in consecutive cases of WPD. METHODS: Of 189 patients with periampullary or pancreatic cancer admitted, 100 patients underwent WPD. Except for 2 patients (no duct identified preoperatively), all patients underwent pancreaticojejunostomy by the Blumgart anastomotic technique. The records of 98 patients were analyzed for pancreatic leak and its related complications using the definitions given by the International Study Group for Pancreatic Surgery. RESULTS: Of 98 patients, 63 were men. The mean operative time was 390 min (270-690 min) and blood loss was 275 ml (100-1,000 ml). Overall mortality was 3.06%. The clinically significant pancreatic anastomotic failure leak was seen in only 7 (7.14%) cases (grade B, n = 4; grade C, n = 3) with one patient requiring relaparotomy due to leak. Only one patient died due to a leak-related complication. CONCLUSION: Blumgart pancreaticojejunal anastomosis can be routinely used for reconstruction in WPD. It is a technically simple procedure and is associated with low rates of fistula and its related complications. PMID- 21811075 TI - Relative efficiency of trend tests with misspecified genetic models in stratified analyses of case-control or cohort data. AB - BACKGROUND/AIMS: Genetic single-nucleotide polymorphism (SNP) data are often analyzed using trend tests that rely on a specific assumption about the way that disease frequency varies across genotypes, but the validity of this assumption is not typically known. We explore the relative efficiency of trend tests in which the assumed model may or may not correspond to the true genetic model. METHODS: We derive formulae for the asymptotic relative efficiencies (AREs) comparing tests that assume different genetic models. We consider both unstratified and stratified tests, using both case-control and cohort data. We illustrate these formulae using realistic parameters and compare the calculated AREs to simulated relative efficiencies in finite samples. RESULTS: The AREs are identical for unstratified tests using case-control and cohort data, but differ for stratified tests. Loss of efficiency can be substantial, given specific combinations of high risk allele frequencies, disease frequencies, and assumed versus actual genetic models. Given reasonably large sample sizes, asymptotic calculations align well with finite sample simulations of relative efficiency. CONCLUSIONS: ARE is a useful estimate of the relative efficiency of statistics using different underlying genetic models. ARE calculations reveal that additive gene doses, which are most commonly used, lead to large losses in power in some settings. PMID- 21811076 TI - PSEUDOMARKER: a powerful program for joint linkage and/or linkage disequilibrium analysis on mixtures of singletons and related individuals. AB - A decade ago, there was widespread enthusiasm for the prospects of genome-wide association studies to identify common variants related to common chronic diseases using samples of unrelated individuals from populations. Although technological advancements allow us to query more than a million SNPs across the genome at low cost, a disappointingly small fraction of the genetic portion of common disease etiology has been uncovered. This has led to the hypothesis that less frequent variants might be involved, stimulating a renaissance of the traditional approach of seeking genes using multiplex families from less diverse populations. However, by using the modern genotyping and sequencing technology, we can now look not just at linkage, but jointly at linkage and linkage disequilibrium (LD) in such samples. Software methods that can look simultaneously at linkage and LD in a powerful and robust manner have been lacking. Most algorithms cannot jointly analyze datasets involving families of varying structures in a statistically or computationally efficient manner. We have implemented previously proposed statistical algorithms in a user-friendly software package, PSEUDOMARKER. This paper is an announcement of this software package. We describe the motivation behind the approach, the statistical methods, and software, and we briefly demonstrate PSEUDOMARKER's advantages over other packages by example. PMID- 21811077 TI - An insulin-like growth factor-I receptor defect associated with short stature and impaired carbohydrate homeostasis in an Italian pedigree. AB - BACKGROUND: Mutations in the insulin-like growth factor-I (IGF-I) receptor (IGF1R) have been associated with prenatal and postnatal growth retardation. However, little is known about potential effects of mutations in the IGF1R on carbohydrate homeostasis. METHODS: We investigated clinical, endocrine and metabolic parameters in four family members carrying a novel IGF1R mutation (p.Tyr387X): an 18-year-old male (index case), his sister and two paternal aunts. RESULTS: All family members showed a variable degree of impairment in prenatal growth, with birth weight standard deviation scores (SDS) between -1.65 and -2.37 and birth length SDS between -1.78 and -3.08. Their postnatal growth was also impaired, with height SDS between -1.75 and -4.86. The index case presented high IGF-I levels during childhood and adolescence and delayed bone age. The index case and his two paternal aunts had impaired glucose tolerance (IGT) associated with a variable degree of alterations in insulin sensitivity and secretion. In contrast, the index case's sister, who had had IGT during pregnancy, showed normal glucose metabolism but reduced insulin sensitivity. CONCLUSION: This is the first study showing an association between a novel IGF1R mutation and a variable degree of alterations in prenatal and postnatal growth and in carbohydrate metabolism. PMID- 21811078 TI - Should eGFR and albuminuria be added to the Framingham risk score? Chronic kidney disease and cardiovascular disease risk prediction. AB - Presence of chronic kidney disease (CKD) defined as decreased glomerular filtration rate (GFR) and/or increased urine albumin excretion is associated with heightened risk of cardiovascular disease (CVD) and all-cause as well as CVD mortality. Although CKD is strongly linked with CVD, it remains undetermined whether this strong association is simply due to shared CVD risk factors or unique traits consequential to CKD. The probability of future CVD events can be estimated with reasonable accuracy using the Framingham equation which was derived from the Framingham study, a community-based cohort of 5,209 white adults aged 30-62 years who were first examined in 1948. Efforts to capture excess CVD risk associated with CKD have been evaluated by adding estimated GFR, cystatin C, serum creatinine and measures of urinary albumin excretion to the Framingham equation which is based on traditional cardiovascular risk factors. Although decreased GFR and increased urine albumin excretion are consistently associated with cardiovascular outcomes, the addition of these factors to the Framingham equation has not been shown to substantially improve overall CVD risk prediction in populations not enriched with CKD. Moreover, the Framingham equation itself underpredicts cardiovascular events among adults with stage 3 and 4 CKD without clinical CVD. Given the poor performance of the Framingham equation in adults with CKD, future studies should explore risk equations which include traditional CVD risk factors and the unique comorbidities associated with CKD for prediction of cardiovascular events in adults with CKD. PMID- 21811079 TI - Rate of change in kidney function and the risk of death: the case for incorporating the rate of kidney function decline into the CKD staging system. AB - Chronic kidney disease (CKD) is associated with increased risk of death. A wave of recent studies used longitudinal data to examine the effect of the rate of decline of kidney function on the risk of death. The results from these studies show that there is an independent and graded association between the rate of kidney function decline and the risk of death. There is a need to incorporate the rate of decline in the definition of CKD. This redefinition of CKD will transform a static definition into a dynamic one that more accurately describes the disease state in an individual patient. PMID- 21811080 TI - Most wanted, least found: coarctation. Concerning the article by J.I.E. Hoffman: It is time for routine neonatal screening by pulse oximetry [Neonatology 2011;99:1-9]. PMID- 21811082 TI - Nonpharmacological treatment of affective disorders. Preface. PMID- 21811083 TI - Continuation and maintenance electroconvulsive therapy for mood disorders: review of the literature. AB - BACKGROUND: Electroconvulsive therapy (ECT) is a highly effective treatment for mood disorders. Continuation ECT (C-ECT) and maintenance ECT (M-ECT) are required for many patients suffering from severe and recurrent forms of mood disorders. This is a review of the literature regarding C- and M-ECT. METHODS: We conducted a computerized search using the words continuation ECT, maintenance ECT, depression, mania, bipolar disorder and mood disorders. We report on all articles published in the English language from 1998 to 2009. RESULTS: We identified 32 reports. There were 24 case reports and retrospective reviews on 284 patients. Two of these reports included comparison groups, and 1 had a prospective follow up in a subset of subjects. There were 6 prospective naturalistic studies and 2 randomized controlled trials. CONCLUSIONS: C-ECT and M-ECT are valuable treatment modalities to prevent relapse and recurrence of mood disorders in patients who have responded to an index course of ECT. C-ECT and M-ECT are underused and insufficiently studied despite positive clinical experience of more than 70 years. Studies which are currently under way should allow more definitive recommendations regarding the choice, frequency and duration of C-ECT and M-ECT following acute ECT. PMID- 21811084 TI - Sleep deprivation in mood disorders. AB - Growing clinical evidence in support of the efficacy and safety of sleep deprivation (SD), and its biological mechanisms of action suggest that this technique can now be included among the first-line antidepressant treatment strategies for mood disorders. SD targets the broadly defined depressive syndrome, and can be administered according to several different treatment schedules: total versus partial, single versus repeated, alone or combined with antidepressant drugs, mood stabilizers, or other chronotherapeutic techniques, such as light therapy and sleep phase advance. The present review focuses on clinical evidence about the place of SD in therapy, its indications, dosage and timing of the therapeutic wake, interactions with other treatments, precautions and contraindications, adverse reactions, mechanism of action, and comparative efficacy, with the aim of providing the clinical psychiatrist with an updated, concise guide to its application. PMID- 21811085 TI - Bright-light therapy in the treatment of mood disorders. AB - Bright-light therapy (BLT) is established as the treatment of choice for seasonal affective disorder/winter type (SAD). In the last two decades, the use of BLT has expanded beyond SAD: there is evidence for efficacy in chronic depression, antepartum depression, premenstrual depression, bipolar depression and disturbances of the sleep-wake cycle. Data on the usefulness of BLT in non seasonal depression are promising; however, further systematic studies are still warranted. In this review, the authors present a comprehensive overview of the literature on BLT in mood disorders. The first part elucidates the neurobiology of circadian and seasonal adaptive mechanisms focusing on the suprachiasmatic nucleus (SCN), the indolamines melatonin and serotonin, and the chronobiology of mood disorders. The SCN is the primary oscillator in humans. Indolamines are known to transduce light signals into cells and organisms since early in evolution, and their role in signalling change of season is still preserved in humans: melatonin is synthesized primarily in the pineal gland and is the central hormone for internal clock circuitries. The melatonin precursor serotonin is known to modulate many behaviours that vary with season. The second part discusses the pathophysiology and clinical specifiers of SAD, which can be seen as a model disorder for chronobiological disturbances and the mechanism of action of BLT. In the third part, the mode of action, application, efficacy, tolerability and safety of BLT in SAD and other mood disorders are explored. PMID- 21811086 TI - Transcranial magnetic stimulation in the management of mood disorders. AB - BACKGROUND: Many trials of transcranial magnetic stimulation (TMS) have used small samples and, therefore, lack power. Here we present an up-to-date meta analysis of TMS in the treatment of depression. METHODS: We searched Medline and Embase from 1996 until 2008 for randomized sham-controlled trials, with patients and investigators blinded to treatment, and outcome measured using a version of the Hamilton Depression Rating Scale (or similar). We identified 1,789 studies. Thirty-one were suitable for inclusion, with a cumulative sample of 815 active and 716 sham TMS courses. RESULTS: We found a moderately sized effect in favour of TMS [Random Effects Model Hedges' g = 0.64, 95% confidence interval (95% CI) = 0.50-0.79]. The corresponding Pooled Peto Odds Ratio for treatment response (<=50% reduction in depression scores) was 4.1 (95% CI = 2.9-5.9). There was significant variability between study effect sizes. Meta-regressions with relevant study variables did not reveal any predictors of treatment efficacy. Nine studies included follow-up data with an average follow-up time of 4.3 weeks; there was no mean change in depression severity between the end of treatment and follow-up (Hedges' g = -0.02, 95% CI = -0.22 to +0.18) and no heterogeneity in outcome. DISCUSSION: TMS appears to be an effective treatment; however, at 4 weeks' follow-up after TMS, there had been no further change in depression severity. Problems with finding a suitably blind and ineffective placebo condition may have confounded the published effect sizes. If the TMS effect is specific, only further large double-blind randomized controlled designs with systematic exploration of treatment and patient parameters will help to define optimum treatment indications and regimen. PMID- 21811087 TI - The application of vagus nerve stimulation and deep brain stimulation in depression. AB - Despite the progress in the pharmacotherapy of depression, there is a substantial proportion of treatment-resistant patients. Recently, reversible invasive stimulation methods, i.e. vagus nerve stimulation (VNS) and deep brain stimulation (DBS), have been introduced into the management of treatment resistant depression (TRD). VNS has already received regulatory approval for TRD. This paper reviews the available clinical evidence and neurobiology of VNS and DBS in TRD. The principle of VNS is a stimulation of the left cervical vagus nerve with a programmable neurostimulator. VNS was examined in 4 clinical trials with 355 patients. VNS demonstrated steadily increasing improvement with full benefit after 6-12 months, sustained up to 2 years. Patients who responded best had a low-to-moderate antidepressant resistance. However, the primary results of the only controlled trial were negative. DBS involves stereotactical implantation of electrodes powered by a pulse generator into the specific brain regions. For depression, the targeted areas are the subthalamic nucleus, internal globus pallidus, ventral internal capsule/ventral striatum, the subgenual cingulated region, and the nucleus accumbens. Antidepressant effects of DBS were examined in case series with a total number of 50 TRD patients. Stimulation of different brain regions resulted in a reduction of depressive symptoms. The clinical data on the use of VNS and DBS in TRD are encouraging. The major contribution of the methods is a novel approach that allows for precise targeting of the specific brain areas, nuclei and circuits implicated in the etiopathogenesis of neuropsychiatric disorders. For clinical practice, it is necessary to identify patients who may best benefit from VNS or DBS. PMID- 21811088 TI - Docetaxel plus oxaliplatin in combination with capecitabine as first-line treatment for advanced gastric cancer. AB - OBJECTIVE: In the present phase II study, we evaluated the efficacy and safety of a docetaxel-oxaliplatin-capecitabine combination as a first-line treatment in patients with advanced gastric cancer. PATIENTS AND METHODS: A total of 27 patients (18 males) with histologically confirmed inoperable gastric adenocarcinoma were recruited. Docetaxel was given (50 mg/m(2) i.v.) on day 1 followed by oxaliplatin (75 mg/m(2) i.v.) also on day 1. Capecitabine (2,750 mg/m(2)) was given orally as two daily divided doses from days 1 to 7. Cycles were repeated every 2 weeks. All patients had measurable disease and 18 of them had a performance status (WHO) of 0. RESULTS: A total of 240 treatment cycles were administered. All patients were evaluable for toxicity. Four patients who discontinued treatment early (having received only 3 chemotherapy cycles) were included as non-responders in an intention-to-treat response analysis. Complete response, partial response, stable disease and progressive disease were observed in 4 (15%), 12 (44%), 3 (11%) and 8 (30%) patients, respectively. The observed response rate was 59%, and the disease control rate (complete response + partial response + stable disease) was 70%. At the time of analysis, 6 patients were still alive and the median survival was 18.0 months. The most common grade III/IV toxicities observed were neutropenia (5%), diarrhea (2%), palmar-plantar erythrodysesthesia (2%) and neurotoxicity (1%). All other toxicities were mostly of grade I/II and easily manageable. CONCLUSION: The combination of docetaxel, oxaliplatin and capecitabine in the described mode of administration represents a relatively active and well-tolerated regimen in patients with advanced gastric cancer and warrants further evaluation. PMID- 21811089 TI - Projection from the cochlear nucleus to the peripheral vestibule in Wistar rats. AB - OBJECTIVE: To find morphological evidence of a direct projection from the cochlear nucleus (CN; at the brainstem level) in the auditory system to the peripheral end organs in the vestibular system. METHODS: Experiments were conducted on male Wistar rats (n = 24). Two neuronal tracers were used: (1) 5% molecular probe F-8793 was injected into the unilateral peripheral vestibule and used as a retrograde tracer; (2) PHA-L (Invitrogen L-11270) was injected into the unilateral CN and used as an anterograde tracer. All animals were allowed to recover for 7 days after surgery to facilitate sufficient transportation of the tracers. Subsequently, brainstems in the retrograde group and inner ears in the anterograde group were sliced coronally on a freezing microtome and observed under a fluorescence microscope. RESULTS: After PHA-L injection into the CN, terminal labeling was observed in the peripheral vestibule, especially in the inferior vestibular nerve. The retrograde tracing study showed that the positive cells could be found in the ventral part of the CN. CONCLUSIONS: These results suggest that there is a novel pathway with a consanguineous functional connection between the CN and peripheral vestibule. PMID- 21811090 TI - One target, different effects: a comparison of distinct therapeutic antibodies against the same targets. AB - To date, more than 30 antibodies have been approved worldwide for therapeutic use. While the monoclonal antibody market is rapidly growing, the clinical use of therapeutic antibodies is mostly limited to treatment of cancers and immunological disorders. Moreover, antibodies against only five targets (TNF alpha, HER2, CD20, EGFR, and VEGF) account for more than 80 percent of the worldwide market of therapeutic antibodies. The shortage of novel, clinically proven targets has resulted in the development of many distinct therapeutic antibodies against a small number of proven targets, based on the premise that different antibody molecules against the same target antigen have distinct biological and clinical effects from one another. For example, four antibodies against TNF-alpha have been approved by the FDA -- infliximab, adalimumab, golimumab, and certolizumab pegol -- with many more in clinical and preclinical development. The situation is similar for HER2, CD20, EGFR, and VEGF, each having one or more approved antibodies and many more under development. This review discusses the different binding characteristics, mechanisms of action, and biological and clinical activities of multiple monoclonal antibodies against TNF alpha, HER-2, CD20, and EGFR and provides insights into the development of therapeutic antibodies. PMID- 21811091 TI - Nelfinavir induces radiation sensitization in pituitary adenoma cells. AB - Pituitary adenomas with local invasion and high secretory activity remain a therapeutic challenge. The HIV protease inhibitor nelfinavir is a radiosensitizer in multiple tumor models. We tested nelfinavir as a radiosensitizer in pituitary adenoma cells in vitro and in vivo. We examined the effect of nelfinavir with radiation on in vitro cell viability, clonogenic survival, apoptosis, prolactin secretion, cell cycle distribution, and the PI3K-AKT-mTOR pathway. We evaluated tumor growth delay and confirmed nelfinavir's effect on the PI3K-AKT-mTOR pathway in a hind-flank model. Nelfinavir sensitized pituitary adenoma cells to ionizing radiation as shown by viability assays and clonogenic assay with an enhancement ratio of 1.2 (p < 0.05). There is increased apoptotic cell death, as determined by annexin-V expression and cleaved caspase-3 levels. Nelfinavir does not affect prolactin secretion or cell cycle distribution. In vivo, untreated tumors reached 4-fold volume in 12 days, 17 days with nelfinavir treatment, 27 days with radiation 6 Gy, and 41 days with nelfinavir plus radiation (one-way ANOVA p < 0.001). Decreased phospho-S6 on Western blotting in vitro and immunohistochemistry in vivo demonstrated nelfinavir inhibition of the PI3K-AKT mTOR pathway. Our data suggests a promising combination therapy with nelfinavir plus radiation in pituitary adenomas, which should be investigated in clinical studies. PMID- 21811092 TI - Essential amino acids and glutamine regulate induction of mitochondrial elongation during autophagy. AB - Regulated changes in mitochondrial morphology and ultrastructure regulate several cellular processes, including apoptosis and, as we recently described, autophagy. Elongated mitochondria are spared from autophagic degradation and possess more cristae, where activity of the ATP synthase is increased, maintaining ATP levels in periods of nutrient depletion. Ultimately, mitochondrial elongation is crucial for cell survival during macroautophagy. Whether elongation is a widespread response to the lack of all nutrients, or if mitochondria respond differently to the presence of different ones is unclear. Here we show that mitochondrial shape responds differently to nutrients: elongation is inhibited when cells are starved in the presence of amino acids but not of glucose. Interestingly, starvation induced mitochondrial elongation is a reversible process, but replenishment of amino acids is not sufficient to recover mitochondrial morphology after starvation. Intricate control pathways are likely to be in place to connect shape of the organelle with different energetic sources. PMID- 21811093 TI - Docosahexaenoic acid induces autophagy through p53/AMPK/mTOR signaling and promotes apoptosis in human cancer cells harboring wild-type p53. AB - Docosahexaenoic acid (DHA) has been reported to induce tumor cell death by apoptosis. However, little is known about the effects of DHA on autophagy, another complex well-programmed process characterized by the sequestration of cytoplasmic material within autophagosomes. Here, we show that DHA increased both the level of microtubule-associated protein light-chain 3 and the number of autophagic vacuoles without impairing autophagic vesicle turnover, indicating that DHA induces not only apoptosis but also autophagy. We also observed that DHA induced autophagy was accompanied by p53 loss. Inhibition of p53 increased DHA induced autophagy and prevention of p53 degradation significantly led to the attenuation of DHA-induced autophagy, suggesting that DHA-induced autophagy is mediated by p53. Further experiments showed that the mechanism of DHA-induced autophagy associated with p53 attenuation involved an increase in the active form of AMP-activated protein kinase and a decrease in the activity of mammalian target of rapamycin. In addition, compelling evidence for the interplay between autophagy and apoptosis induced by DHA is supported by the findings that autophagy inhibition suppressed apoptosis and further autophagy induction enhanced apoptosis in response to DHA treatment. Overall, our results demonstrate that autophagy contributes to the cytotoxicity of DHA in cancer cells harboring wild-type p53. PMID- 21811094 TI - Metformin abolishes increased tumor (18)F-2-fluoro-2-deoxy-D-glucose uptake associated with a high energy diet. AB - Insulin regulates glucose uptake by normal tissues. Although there is evidence that certain cancers are growth-stimulated by insulin, the possibility that insulin influences tumor glucose uptake as assessed by ( 18) F-2-Fluoro-2-Deoxy-d Glucose Positron Emission Tomography (FDG-PET) has not been studied in detail. We present a model of diet-induced hyperinsulinemia associated with increased insulin receptor activation in neoplastic tissue and with increased tumor FDG-PET image intensity. Metformin abolished the diet-induced increases in serum insulin level, tumor insulin receptor activation and tumor FDG uptake associated with the high energy diet but had no effect on these measurements in mice on a control diet. These findings provide the first functional imaging correlate of the well known adverse effect of caloric excess on cancer outcome. They demonstrate that, for a subset of neoplasms, diet and insulin are variables that affect tumor FDG uptake and have implications for design of clinical trials of metformin as an antineoplastic agent. PMID- 21811095 TI - Finally, how histone deacetylase inhibitors disrupt mitosis! AB - The disruption of normal mitosis by histone deacetylase inhibitors is a significant contributor to the anticancer effects of these drugs. However, the mechanism by which these drugs affect mitosis is poorly understood. A number of recent papers have now thrown considerable light onto how these drugs elicit this very distinctive cell cycle disruption. PMID- 21811097 TI - Function of ERBB4 is determined by alternative splicing. AB - Alternative splicing is a central tool of evolution that significantly increases the size of transcriptomes and generates functional specification. Within the human ERBB receptor gene family, only ERBB4 is known to produce functionally distinct isoforms as a result of alternative splicing. While ErbB4 signaling has been demonstrated to regulate cellular processes involved in embryogenesis, carcinogenesis and cardiovascular and psychiatric diseases, relatively little is known about the contribution of the individual isoforms in the different biological contexts. Here, we review recent findings as well as provide novel data about the distribution and functions of the ERBB4 splice variants. These observations represent an example of how minor alterations in the transcripts of a single gene can result in even antagonistic cellular responses. The observations also underline the significance of understanding the unique functions of isoforms of a potential drug target gene. PMID- 21811096 TI - Emerging roles of TET proteins and 5-hydroxymethylcytosines in active DNA demethylation and beyond. AB - Cytosine methylation is the major epigenetic modification of metazoan DNA. Although there is strong evidence that active DNA demethylation occurs in animal cells, the molecular details of this process are unknown. The recent discovery of the TET protein family (TET1-3) 5-methylcytosine hydroxylases has provided a new entry point to reveal the identity of the long-sought DNA demethylase. Here, we review the recent progress in understanding the function of TET proteins and 5 hydroxymethylcytosine (5hmC) through various biochemical and genomic approaches, the current evidence for a role of 5hmC as an early intermediate in active DNA demethylation and the potential functions of TET proteins and 5hmC beyond active DNA demethylation. We also discuss how future studies can extend our knowledge of this novel epigenetic modification. PMID- 21811099 TI - Identification of tumorigenic cells and implication of their aberrant differentiation in human hemangioblastomas. AB - The cytological origin of hemangioblastomas (HBs) is controversial possibly owing to limitation in the framework of normal vascular development. Our previous study reported that SSEA1 (stage-specific embryonic antigen-1) cells had the potential of HB-like structure formation in vitro cellular models. Here, we characterized primary proliferating tumor-initiating cells (TICs) and their neoplasmtic transformation. Neural stem cell marker SSEA1 and its lineage-related genes were demonstrated; no embryonic and mesenchymal stem cell markers were detected whereas their lineage-related genes in part were activated. Immunohistochemistry showed that the proliferating marker was preferentially expressed in SSEA1 cells. There was significant difference in the percentage of SSEA1 cells (SSEA1+/Ki67+ cells) between inherited and sporadic HBs although the tumor proliferative index (Ki67+ cells/ all cells) did not reach statistical significance between the two groups. Further, corresponding to the morphological changes of nucleolus in number and size, these highly proliferating SSEA1 cells demonstrated coexpression of either D2-40 or the mesodermal marker Scl (stem cell leukemia), brachyury, and Flk-1 (vascular endothelial growth factor-2), respectively, indicative of the neoplasmtic transformation into the stromal or vascular cells. The present data suggest that HBs might derive from neoplastic transformation of neural stem cells/progenitors. Such findings also provide new insights into the biology of HBs and the definition of TICs in situ, as well as the mechanisms of tumor neovascularization. PMID- 21811098 TI - The sensitive [SWI (+)] prion: new perspectives on yeast prion diversity. AB - Yeast prions are heritable protein-based genetic elements which rely on molecular chaperone proteins for stable transmission to cell progeny. Within the past few years, five new prions have been validated and 18 additional putative prions identified in Saccharomyces cerevisiae. The exploration of the physical and biological properties of these "nouveau prions" has begun to reveal the extent of prion diversity in yeast. We recently reported that one such prion, [SWI(+)], differs from the best studied, archetypal prion [PSI(+)] in several significant ways. ( 1) Notably, [SWI(+)] is highly sensitive to alterations in Hsp70 system chaperone activity and is lost upon growth at elevated temperatures. In that report we briefly noted a correlation amongst prions regarding amino acid composition, seed number and sensitivity to the activity of the Hsp70 chaperone system. Here we extend that analysis and put forth the idea that [SWI(+)] may be representative of a class of asparagine-rich yeast prions which also includes [URE3], [MOT3(+)] and [ISP(+)], distinct from the glutamine-rich prions such as [PSI(+)] and [RNQ(+)]. While much work remains, it is apparent that our understanding of the extent of the diversity of prion characteristics is in its infancy. PMID- 21811100 TI - Detection of apoptotic circulating tumor cells in advanced pancreatic cancer following 5-fluorouracil chemotherapy. AB - The objective of the present study was to evaluate CA19-9 and CK8/18 expression patterns in pancreatic cancer cell lines induced by 5-fluorouracil (5-Fu), and in circulating tumor cells (CTCs) in peripheral blood of patients previously untreated with advanced pancreatic cancer. Furthermore, the goal was to test the relationship of dynamic of CTCs with the effects of the first cycle of chemotherapy. To accomplish this study, CD45 antibody coated beads were used to discard white blood cells in peripheral blood. This was done in combination with CA19-9-Alexa488 and CK8/18-Alexa594 immunofluorescence staining to identify CTCs in circulation from 41 advanced pancreatic cancer patients, before and after chemotherapy. The PL45 pancreatic cancer cell line was incubated with 20 umol/L 5 Fu for 12 and 24 hours to induce apoptosis, and the expression patterns of CA19-9 and CK8/18 were measured, and the extent of apoptosis was evaluated. Subsequently, apoptotic cells and CTCs were measured. Of 41 patients with stage III and IV pancreatic cancer, 80.5% were detected with more than two CTCs in 7.5 mL peripheral blood before any therapy and the median number of CTCs was 16.8+/ 16.0 (0-59). After 7 days by the first cycle of 5-Fu chemotherapy, only 29.3% (12/41) of these patients were detected more than two CTCs in 7.5 mL peripheral blood and the median number of CTCs was 3.8+/-7.8 (0-40) (P=0.000). And no CTCs were detected in 20 healthy donors from 7.5 mL peripheral blood (P=0.000). Apoptotic CTCs were detected after advanced pancreatic patients were administered the first cycle of chemotherapy. Punctate, granular, and bubble-like morphologies with CA19-9 and CK8/18 staining were found and may reflect apoptosis in pancreatic cancer cells and CTCs. Apoptotic CTCs may indicate the efficacy of chemotherapy in pancreatic cancer patients. However, further studies are required to follow up these findings. PMID- 21811102 TI - Snail as a key regulator of PRL-3 gene in colorectal cancer. AB - The regulators of a key metastasis gene PRL-3 in colorectal cancer (CRC) are still largely unknown. We found three potential binding sites of Snail, a key transcriptional factor involved in the epithelial-mesenchymal transition (EMT), in the region of PRL-3 promoter (located at -642 to -383). Moreover, our results showed that one of the Snail binding sites (located at -624 to -619) was the key element to maintain promoter activity of human PRL-3 gene. The transcriptional activity of PRL-3 promoter was abolished after the Snail binding site (located at -624 to -619) was mutated. Both promoter activity and protein expression of PRL-3 in CRC cell lines could be regulated by Snail. In clinical samples of CRC and metastatic lymph node of CRC, expression of PRL-3 protein was correlated with expression of Snail protein. Functional studies using gene over-expression and knockdown methods indicated that Snail promoted proliferation, cell adhesion and migration of human CRC cells. In SW480 cells with PRL-3 stable knockdown, cell proliferation increased after Snail was up-regulated. Our data first reveal transcriptional factor Snail as a key regulator of PRL-3 in CRC. The link between Snail and PRL-3 suggests a new potential mechanism of Snail contributing to progression and metastasis of CRC. PMID- 21811101 TI - Reexamining a proposal: thymidylate synthase 5'-untranslated region as a regulator of translation efficiency. AB - The DNA replicative gene, thymidylate synthase (TYMS), is inhibited upon treatment with the anticancer drug 5-fluorouracil (5FU). TYMS has 28-bp tandem repeat sequences or VNTR (variable numbers of tandem repeats) in the 5' untranslated region (5'-UTR). The number of these repeats is variable in any given population, but the most prevalent are double (2R) and triple (3R) repeat sequences. A single G/C nucleotide polymorphism in the triple repeat sequence gives rise to a 3Rc or a 3Rg triple repeat structure. A widely cited literature used plasmid constructs of the 5'-UTR and proposed that genotyping the TYMS UTRs would predict the efficiency of Tyms protein translation, justifying altered therapeutic dosage of 5FU. Prior studies had unusual features in experimental design, such as using the firefly Kozak sequence in place of the native human TYMS Kozak sequence to determine the ribosomal translational efficiency of TYMS mRNA. Our results using transient transfection, antibiotic-selected pools of transfected cells, and stably transfected clones, while using plasmids having native human Kozak sequence, refute the earlier results. PMID- 21811103 TI - Detailed protocol for evaluation of dynamic perifusion of human islets to assess beta-cell function. AB - The definitive measure of beta-cell quality in an islet is the measurement of beta-cell function, i.e., the ability of the islets to release insulin in a controlled manner in response to minute changes in ambient glucose levels. Continuous flow or dynamic perifusion of the solution containing glucose and secretagogues through the islets is the most accurate assessment of regulated insulin release in vitro. Here, we describe in detail a low cost, mini-perifusion system that can be adapted to any laboratory to assess islet function by examining dynamic insulin release in response to elevated glucose concentrations and addition of secretagogues. Human islets with purity > 80% and viability > 90% were perifused with low glucose (1 mM) and subsequently challenged with high glucose (16.8 mM +/- KCl, 25 mM). A prototypical biphasic response to elevated glucose concentrations was observed with an average 8-fold (above basal) increase in insulin concentration at peak values. Similarly, perifusion with carbachol or exendin-4 (Byetta) with glucose (6 mM) resulted in 1.32- and 1.35-fold increase in insulin secretion above basal. Islets could be maintained in the perifusion apparatus and continued to respond to glucose for up to 3 h. At minimal financial cost and technical expertise, this apparatus can be set-up in any biological laboratory to evaluate regulated hormone release from many cell types in less than 6 h. This will allow other laboratories to measure insulin responses to their drug or modifier of interest in vitro, in a manner that better approximates islet function in vivo. PMID- 21811104 TI - Virus-inhibitory peptide: a natural HIV entry inhibitor in search for a formal target in the viral genome. PMID- 21811105 TI - Liver transplant outcomes in HIV-infected patients: a systematic review and meta analysis with a synthetic cohort. PMID- 21811106 TI - Plasma biomarkers in the prediction and diagnosis of tuberculosis-associated immune reconstitution inflammatory syndrome. PMID- 21811107 TI - Antiretroviral therapy alone resulted in successful resolution of large idiopathic esophageal ulcers in a patient with acute retroviral syndrome. PMID- 21811108 TI - The growing role of epidemiology in drug safety regulation. PMID- 21811109 TI - Epidemiology, comparative effectiveness research, and the National Institutes of Health: forces for health. PMID- 21811110 TI - What can we really learn from observational studies?: the need for empirical assessment of methodology for active drug safety surveillance and comparative effectiveness research. PMID- 21811111 TI - Sharing confidential data for research purposes: a primer. PMID- 21811112 TI - Epidemiologic studies, warts and all, are our best chance. PMID- 21811113 TI - Transportability and causal generalization. PMID- 21811114 TI - DAGitty: a graphical tool for analyzing causal diagrams. PMID- 21811115 TI - Forest Plot Viewer: a new graphing tool. PMID- 21811116 TI - Analgesics during pregnancy and undescended testis. PMID- 21811117 TI - Oral disease and risk of pancreatic cancer. PMID- 21811118 TI - Estimation of population percentiles. PMID- 21811120 TI - Turning a new page in clinical magnetoencephalography: practicing according to the first clinical practice guidelines. PMID- 21811121 TI - American Clinical Magnetoencephalography Society Clinical Practice Guideline 1: recording and analysis of spontaneous cerebral activity. PMID- 21811122 TI - American Clinical Magnetoencephalography Society Clinical Practice Guideline 2: presurgical functional brain mapping using magnetic evoked fields. PMID- 21811123 TI - American Clinical Magnetoencephalography Society Clinical Practice Guideline 3: MEG-EEG reporting. PMID- 21811124 TI - American Clinical Magnetoencephalography Society Clinical Practice Guideline 4: qualifications of MEG-EEG personnel. PMID- 21811125 TI - Generalized periodic epileptiform discharges in critically ill children: a continuum of status epilepticus or an epiphenomenon? AB - PURPOSE: Generalized periodic epileptiform discharges (GPEDs) are a specific periodic EEG pattern, reported with status epilepticus (SE) or a metabolic or an anoxic encephalopathy in critically ill patients. In this study, we examined the clinical course and evolution of EEG findings associated with GPEDs in children with refractory convulsive SE. METHODS: The EEG reports of 279 children with SE diagnosed between 2002 and 2010 were reviewed to detect GPEDs. Ten children were identified with GPEDs on continuous EEG recording. The entire EEG recording was available for review in only six children. In the clinical course, seizure characteristics and evolution of EEG findings were analyzed. RESULTS: Six children (age, 5 to 17 years) were admitted to the intensive care unit with refractory convulsive SE. All had acute symptomatic SE except for one child with a history of epilepsy and developmental delay. Intravenous anesthetic agents were used to treat convulsive SE in five children. After tapering the intravenous anesthetic agents, GPEDs were seen on the continuous EEG recording, nonconvulsive seizures occurred in five, and nonconvulsive SE in four children. None of the children returned to baseline, and three children died. CONCLUSIONS: Generalized periodic epileptiform discharges are seen during the treatment course of convulsive SE in children and heralded seizure recurrence. We found a sequential evolution of the EEG patterns after the control of convulsive SE, with GPEDs occurring in a dynamic fashion in a continuum along with burst suppression and electrographic seizures. Recognizing that GPEDs represent a still active epileptic state after the control of convulsive SE with intravenous anesthetic agents and modifying the treatment regimen to control GPEDs may prevent immediate seizure recurrence. PMID- 21811126 TI - Sphenoidal electrodes significantly change the results of source localization of interictal spikes for a large percentage of patients with temporal lobe epilepsy. AB - Although scalp EEG is a very useful tool for presurgical evaluation in epilepsy, the 10-20 system of electrodes in many cases fails to accurately localize the source of the epileptic seizures. One suggested solution to this problem is to use additional electrodes. Sphenoidal electrodes especially have been suggested to be helpful in identifying the irritative and seizure onset zones in patients with temporal lobe epilepsy. However, the value of these electrodes has been debated, and in many epilepsy centers they are not used. In this study, we investigate the impact of sphenoidal electrodes by comparing the results of EEG source localization with and without sphenoidal recordings. We retrospectively selected patients with temporal lobe epilepsy based on their clinical semiology and electrophysiologic data. For each patient, a prototype spike was used as a template for an automatic pattern search to find similar activities. The identified spikes were then averaged and analyzed by fitting a dipole to the data. The recordings from sphenoidal electrodes were then excluded and the analysis was repeated. It was found that in more than half of the patients inclusion of sphenoidal electrodes resulted in a shift of more than 2 cm in the location of the fitted dipole, and in some cases moved the dipole from the frontal lobe or the insula to the temporal lobe. Our results suggest that sphenoidal electrodes are helpful in the analysis of the EEG recordings of patients suspected of having temporal lobe epilepsy. PMID- 21811127 TI - The correlation between vagus nerve stimulation efficacy and partial onset epilepsies. AB - PURPOSE: To evaluate the correlation between vagus nerve stimulation (VNS) efficacy and partial seizures originating from different brain regions. MATERIALS AND METHODS: The authors retrospectively analyzed the data of 46 subjects with medically intractable epilepsy who had insertion of VNS between April 1999 and July 2005. The clinical outcome was assessed with Engel classification. Subjects were divided into group A (Engel I, II, and III) and group B (Engel IV) for statistical analysis. Group A was referred as a satisfactory outcome. The statistical analysis of the data was assessed whether these parameters such as age, type of seizure, age at insertion of VNS, and lengths of follow-up affect the outcome. RESULTS: Nineteen patients (41.3%) had a satisfactory outcome (Engel II, III). The analysis of VNS efficacy demonstrated that 65% of the patients with frontal lobe epilepsy and only 15% of the patients with temporal lobe epilepsy (TLE) had a satisfactory outcome. There was a statistically significant difference between these types of epilepsyand VNS outcomes (Fisher exact test, P = 0.004). CONCLUSION: VNS is more effective in frontal lobe epilepsy than in temporal lobe epilepsy. Further studies are warranted to verify our findings and the correlation between types of epilepsy and VNS outcome. PMID- 21811128 TI - Relationship between slowing of the EEG and cognitive impairment in Parkinson disease. AB - A previous study using the quantitative EEG technique confirmed that diffuse slowing of the EEG is present in Parkinson disease. The present study was the first to assess the relationship between cognitive impairment and quantitative EEG in Parkinson disease. A total of 100 patients with Parkinson disease with a mean Hoehn-Yahr stage of 2.68 were serially enrolled. Cognitive impairment was assessed using the Mini-Mental State Examination. Lack of ischemic lesions was confirmed in all the patients by MRI. Absolute power values were measured for four frequency bands from delta to beta. The electrodes were divided among six locations as follows: frontal pole and frontal, central, parietal, temporal, and occipital locations. Spectral ratio was calculated as the sum of power values for the alpha- and beta-waves divided by the sum of values for slow waves. The relationship between Mini-Mental State Examination score and spectral ratio was assessed by the Jonckheere-Terpstra trend test. At all electrode locations, spectral ratio significantly decreased with a decline in Mini-Mental State Examination score (frontal pole, P = 0.017; frontal, P = 0.028; central, P = 0.019; parietal, P = 0.004; temporal, P = 0.002; occipital, P = 0.006). The rate of patients with Parkinson disease with slowing of the EEG was more frequent with serious cognitive impairment. PMID- 21811129 TI - EEG observations in elderly with new onset seizures: from developing country perspective. AB - PURPOSE: The authors evaluated the spectra of EEG observations in elderly patients with new onset seizures and correlated it with clinical, laboratory, and imaging findings. METHODOLOGY: This prospective study involved 201 elderly individuals (age: 68.0 +/- 7.5 years; male:female = 1.8:1) who manifested with new onset seizures. Data regarding clinical, laboratory, routine EEG (n = 201), and imaging (computerized tomography = 201; MRI = 43) observations were noted. Details of EEG findings were analyzed and correlated with other parameters. RESULTS: Visual analysis of scalp EEG in 124 patients (61.7%) was abnormal, and the abnormalities included asymmetric background activity (3%) and diffuse slowing (32.8%) and focal slowing (7%) of the background activity. Dominant alpha activity was more common in remote symptomatic group. Higher frequency of alpha waves was observed in patients with cryptogenic epilepsy compared with those with acute symptomatic epilepsy. Diffuse slowing and excess of beta-fast activity were observed more often in acute symptomatic group. Epileptiform activities were evident in one third of patients and were noted in the temporal (38.8%) and frontotemporal (23.9%) regions. In univariate analysis of patients with and without EEG abnormalities, female gender, cluster attacks/status epilepticus, acute symptomatic epilepsy, longer duration of postictal state, lower Glasgow coma scale score, lower Mini-Mental State Examination score, focal deficits, diffuse edema (computerized tomography), and focal lesions (MRI) were significantly associated with abnormal EEG. Presence of epileptiform activity predicted the use of polytherapy (P = 0.004, odds ratio = 3.3). The significant factors associated with an abnormal EEG (multivariate) were female gender (P = 0.03, odds ratio = 2.32), lower Glasgow coma scale score (P = 0.03, odds ratio = 0.70), and lower frequency of alpha-waves (P = 0.04, odds ratio = 0.56). CONCLUSIONS: Scalp EEG was abnormal in approximately two thirds of elderly patients, with the presence of epileptiform activities in one third of patients. Abnormal EEG significantly correlated with lower Glasgow coma scale score, suggesting its role in prognostication. PMID- 21811130 TI - Diazepam-induced changes in EEG oscillations during performance of a sustained attention task. AB - The primary aim of the present study was to test diazepam (DZ) effect, a benzodiazepine (BDZ) usually prescribed to reduce anxiety and to induce sleep, on EEG activity while performing a visual sustained attention task. The EEG activity was recorded in a double-blind placebo experiment, and prestimulus spectral power and inter- and intrahemispheric temporal coupling were assessed during visual sustained attention task performance. A single DZ dose (5 mg) was enough to increase reaction times during visual sustained attention task responses. DZ decreased prestimulus EEG power in the 1- to 6-, 8- to 12-, and 19- to 35-Hz bands and disrupted right intrahemispheric temporal coupling in the alpha frequency range (8-12 Hz). The combined reduction in power and temporal coupling suggests both local and interregional DZ-induced disruption of neuronal synchronicity especially in the right hemisphere in agreement with the prominent attention-related networks in this hemisphere. These data support the notion that the influence of DZ on behavior goes beyond sedative effects and can potentially compromise higher cognitive functions with negative consequences to daily life situations. PMID- 21811131 TI - Watching television: a previously unrecognized powerful trigger of lambda waves. AB - OBJECTIVE: To assess whether lambda waves are elicited by watching television (TV) and their association with demographical and EEG features. METHODS: We retrospectively compared lambda wave occurrence in prolonged EEG monitorings of outpatients who were allowed to watch TV and in standard EEGs recorded in TV-free rooms. All EEGs were interpreted by the same two electroencephalographers. RESULTS: Of 2,072 standard EEG reports, 36 (1.7 %) mentioned lambda waves versus 46 (32.2%) of 143 prolonged EEG monitoring reports (P < 0.001). Multivariable comparison of prolonged EEG monitorings and standard EEGs disclosed that recordings performed in rooms with a TV (odds ratio, 20.6; 95% confidence interval, 4.8-88.0) and normal EEGs (odds ratio, 3.03; 95% confidence interval, 1.5-6.25) were independently associated with lambda waves. In the prolonged EEG monitoring group, all recordings with lambda waves also had positive occipital sharp transients of sleep. CONCLUSIONS: Watching TV likely represents a powerful and previously unrecognized stimulus for lambda waves. Furthermore, this study confirms the benign nature of this EEG variant and its strong association with positive occipital sharp transients of sleep. PMID- 21811132 TI - Isolating visual evoked responses--comparing signal identification algorithms. AB - PURPOSE: To compare signal identification algorithms for recording visual evoked potentials (VEP). METHODS: VEPs were recorded both in the presence and absence of a stimulus. Four algorithms were designed to estimate the probability that a recording contains a stimulus evoked signal, and to assign weights for use in a weighted average to isolate a final VEP. Algorithms were compared on their ability to identify trials containing VEPs; the signal-to-noise (SNR) ratios of the final VEP, and the number of trials required to isolate a VEP that was significantly different from background noise. RESULTS: All the algorithms isolated VEPs that did not differ significantly in timing or amplitude from those extracted using traditional ensemble averaging. All the studied algorithms were capable of identifying and assigning a significantly greater weight to trials containing visually evoked signals compared with trials containing only noise potentials (P < 0.01). The best performing algorithm produced a ninefold increase in the signal-to-noise of the extracted waveform. DISCUSSION: The present investigation provides empirical confirmation that computational signal identification algorithms can improve the detection of VEP signal embedded in noise. When combined with weighted averaging they can reduce the number of trials required for evaluation. PMID- 21811133 TI - Benefit of repeat multiple sleep latency testing in confirming a possible narcolepsy diagnosis. AB - PURPOSE: The clinical diagnosis of narcolepsy is usually uncomplicated in the presence of cataplexy. Objective testing is more important in ambiguous disease. The gold-standard objective test in these cases is the multiple sleep latency test (MSLT). Repeat testing can be burdensome but is reasonable when faced with a diagnostic dilemma. However, there is limited evidence to support this approach. In this study, we assessed the diagnostic utility of a repeat MSLT in patients suspected of narcolepsy whose first MSLT result was nonconfirmatory. METHODS: Of 125 patients who underwent an MSLT between 2004 and 2009, we identified 10 (9.6%) who had undergone repeat studies. We analyzed changes in MSLT parameters while taking account of other relevant differences between testing. RESULTS: Two patients (20%) met narcolepsy criteria during the second MSLT. Nine patients (90%) met sleepiness criteria (mean sleep latency <8 minutes) during the second MSLT while only 5 did during the first (P = 0.05). CONCLUSIONS: We demonstrate that a repeat MSLT confirmed the diagnosis of narcolepsy in 20% of patients whose results had been nonconfirmatory on a first MSLT. This study provides support for a repeat MSLT in cases where clinical suspicion for narcolepsy is high despite an ambiguous first test. PMID- 21811135 TI - Correlation between pupil diameter and angle configuration in the dark room provocative test. AB - PURPOSE: To study the associations between changes in pupil diameter and in the anterior chamber angle configuration during the dark room provocative test. METHODS: The study included 70 suspects of primary angle closure (study group) and 40 normal participants (control group). Using anterior-segment optical coherence tomography (AS-OCT), we measured the anterior chamber angle configuration and pupil diameter at 3 minutes and at 1.5 hours of dark adaptation. RESULTS: In the study group, the mean number of closed angle segments was significantly (P<0.001) higher at 3 minutes of dark adaptation (3.9 +/- 2.3) than at room light conditions (2.6 +/- 2.2) or at 1.5 hours of dark adaptation (3.1 +/- 2.1), with no statistically significant (P>0.05) difference between the 2 latter values. In the study group, the pupil diameter was significantly associated with the number of closed angle segments at 3 minutes of dark adaptation (P<0.01), but not at 1.5 hours of dark adaptation (P=0.13). Defined as an increased number of closed angle segments, the dark room test was positive in a significantly higher number of participants at 3 minutes than at 1.5 hours of dark adaptation [44 (63%) eyes vs. 31 (44%) eyes; P<0.05]. Final interocular pressure was statistically better correlated with the angle configuration segments assessed at 3 minutes (correlation coefficient r2=0.33) than at 1.5 hours of dark adaptation (r2=0.21). CONCLUSIONS: After short-term dark adaptation of 3 minutes, the assessment of the anterior chamber angle configuration by AS OCT is more reliable than as if carried out after a long-term dark adaptation and may be used to identify suspects of primary angle closure. PMID- 21811136 TI - Phase 2 study of cobicistat versus ritonavir each with once-daily atazanavir and fixed-dose emtricitabine/tenofovir df in the initial treatment of HIV infection. AB - OBJECTIVE: To assess efficacy and safety of cobicistat versus ritonavir as pharmacoenhancers for atazanavir when administered with emtricitabine/tenofovir df as initial treatment for HIV-1 infection. DESIGN: Randomized, partially placebo-controlled, double-blind, multicenter study. PARTICIPANTS: Antiretroviral treatment-naive adults, screening HIV-1 RNA of at least 5000 copies/ml and CD4 cell count more than 50 cells/MUl. INTERVENTION: Randomized 2 : 1 (stratified by HIV RNA <= or >100,000 copies/ml) to receive placebo-blinded once-daily cobicistat 150 mg or ritonavir 100 mg with open-label atazanavir and fixed-dose emtricitabine/tenofovir df. MAIN OUTCOME MEASURES: Efficacy and safety at weeks 24 and 48. RESULTS: Eighty-four percent of ATV/co participants and 86% of ATV/r participants suppressed HIV-1 RNA (<50 copies/ ml) at week 24, and 82 and 86% at week 48, respectively, and mean CD4 cell count increased 203 and 199 cells/MUl at week 24 and 208 and 177 cells/MUl at week 48, respectively. Study treatment discontinuation due to adverse events occurred in 4% ATV/co and in 3% ATV/r participants through 48 weeks. Treatment-related adverse events occurred in 36% ATV/co and 48% ATV/r participants; hyperbilirubinemia occurred in 96 and 100%, and ocular icterus or jaundice occurred in 14 and 17%, respectively. Mean estimated glomerular filtration rate (Cockcroft-Gault, ml/min) decrease occurred in both treatment groups and was evident at week 2 (ATV/co -9, ATV/r -4), reached a nadir by week 24 (-15, -14, respectively), and did not progress further through week 48 (-13, -14). CONCLUSION: Using cobicistat and ritonavir as pharmacoenhancers for atazanavir and administered with emtricitabine/tenofovir df achieved comparable rates of virologic suppression and CD4 cell count increase with satisfactory safety profiles. PMID- 21811137 TI - Is expanded HIV treatment preventing new infections? Impact of antiretroviral therapy on sexual risk behaviors in the developing world. AB - There have been dramatic increases in access to antiretroviral therapy (ART) across the developing world, and growing public health attention has focused on the possibility of utilizing ART as a means of slowing the global HIV epidemic. The preventive impact of ART will likely depend on decreasing levels of sexual risk behaviors following treatment initiation. The current review study examines the impact of wider access to ART on sexual risk behaviors among HIV-infected individuals in the developing world. The observational studies to date demonstrate that ART is associated with a significant reduction in unprotected sex following treatment initiation. Although data on the impact of ART on possible risk compensation are rapidly expanding across the developing world, more evidence is still needed before we can safely conclude expanded treatment will result in durable decreases in sexual risk behaviors. PMID- 21811138 TI - Prospective study of the ARCHITECTHIV Ag/Ab Combo fourth generation assay to detect HIV infection in sexually transmitted infection clinics. AB - This prospective, cross-sectional study of HIV testing at two sexually transmitted infection clinics compares testing results from the ARCHITECT HIV Ag/Ab Combo fourth generation assay against the current standard of care in North Carolina (third generation enzyme immunoassay testing with western blot confirmation and reflex nucleic acid amplification testing of pooled seronegative samples). In this setting, the assay reported a sensitivity of 100%, a specificity of 99.9%, and a median turn-around time of 26.1 h. PMID- 21811139 TI - Colorectal microbicide design: triple combinations of reverse transcriptase inhibitors are optimal against HIV-1 in tissue explants. AB - OBJECTIVE: Receptive anal intercourse in both men and women is associated with the highest probability for sexual acquisition of HIV infection. As part of a strategy to develop an effective rectal microbicide, we performed an ex-vivo preclinical evaluation to determine the efficacy and limitation of multiple combinations of reverse transcriptase inhibitors (RTIs). DESIGN: A nucleotide, PMPA (tenofovir), a nucleoside, FTC (emtricitabine), RTIs and two nonnucleoside RTIs, UC781 and TMC120 (dapivirine), were used in double, triple and quadruple combinations against a panel of CCR5-uing and CXCR4-using clade B HIV-1 isolates and against RTI-escape variants. METHODS: Indicator cells and colorectal tissue explants were used to assess antiviral activity of drug combinations. RESULTS: All combinations inhibited the isolates tested in a cellular model and in colorectal explants and produced, for at least one of the compounds, a change in the dose-response curve. Double and triple combinations incrementally augmented activity, even against RTI-escape mutants, whereas quadruple combinations conferred little further advantage. CONCLUSION: The colorectal explant model may be used to identify the best candidate molecules and their combinations at the preclinical stage. Furthermore, this study demonstrates that combinations based on RTIs with different HIV-1 inhibitory mechanisms have potential as colorectal microbicides. PMID- 21811140 TI - Severe food insecurity is associated with elevated unprotected sex among HIV seropositive injection drug users independent of HAART use. AB - OBJECTIVE: Despite emerging evidence of a significant adverse relationship between food insecurity and sexual risk-taking, data have been primarily derived from resource-constrained settings and HIV-negative populations. To our knowledge, this study is the first to longitudinally evaluate the relationship between food insecurity and unprotected sex among HIV-seropositive people who inject drugs [injection drug users (IDUs)] both on and not on HAART. DESIGN: Longitudinal analyses were restricted to HIV-positive IDUs who completed baseline and at least one follow-up visit in a prospective cohort (AIDS Care Cohort to evaluate Exposure to Survival Services, 2005-2009). METHODS: We constructed a multivariate logistic model using generalized estimating equations (GEEs) to assess an independent relationship between severe food insecurity (e.g., hunger due to lack of access or means to acquire food) and unprotected vaginal/anal sex. RESULTS: Among 470 HIV-positive IDUs, the median age was 42 years (interquartile range 36-47) with 61% men and 39% women. The prevalence of severe food insecurity was 71%, with no differences by HAART use. Severe food insecure IDUs were marginally less likely to have a suppressed HIV-1 RNA viral load (31 vs. 39%, P = 0.099). In multivariate GEE analyses, severe food insecurity [adjusted odds ratio = 2.68, 95% confidence interval 1.49-4.82] remained independently correlated with unprotected sex among HIV-positive IDUs, controlling for age, sex/gender, married/cohabitating partner, binge drug use, homelessness, and HAART use. CONCLUSION: These findings highlight a crucial need for structural HIV interventions that incorporate targeted food assistance strategies for IDUs. Given recent evidence of poor virological response among food insecure individuals on HAART, innovative HIV care models should integrate targeted food security programs and early access to HAART. PMID- 21811141 TI - T-cell signalling in antiretroviral-treated, aviraemic HIV-1-positive individuals is present in a raised state of basal activation that contributes to T-cell hyporesponsiveness. AB - OBJECTIVE: Successful antiretroviral therapy (ART) suppresses plasma HIV-1 RNA below detection limits, reducing the chronic insult to the immune systems of infected individuals and supporting a degree of immunological recovery. However, the surface phenotypic profile of T cells in ART-treated patients does not resemble that of healthy, uninfected individuals, but rather shows upregulation of proteins associated with an exhausted immune system. We sought to address whether aviraemic HIV-1 infection, therefore, contributed to long-term alterations in intracellular signalling events within the T cells of infected individuals that contributed to the exhausted phenotype. DESIGN: A flow cytometric approach was employed to assess levels of phosphorylation within T cell signalling proteins in ART-treated HIV-1-positive patients and HIV-negative individuals. METHODS: The relative phosphorylation levels of extracellular signal regulated kinases (ERK), c-Jun N-terminal kinases (JNK), p38, zeta-chain associated protein kinase 70 (ZAP70), linker of activated T cells, SLP76, nuclear factor kappaB were measured within resting and stimulated CD4(+) and CD8(+) T cells from aviraemic HIV-1-positive and healthy individuals by intracellular staining and flow cytometric analysis. RESULTS: Basal levels of phospho-ZAP70, phospho-ERK and phospho-JNK were two-fold to three-fold higher in HIV-1-positive individuals compared with healthy controls, with phospho-p38 also showing a tendency to increase in HIV-1-positive individuals. Interestingly, in contrast to healthy controls, peripheral blood mononuclear cells from aviraemic, infected individuals were refractory to stimulation with IL-2 and CD3/CD28 showing no enhancement of phosphorylation. CONCLUSION: CD4(+) and CD8(+) T cells from HIV-1 positive individuals are poorly responsive to direct stimulation through the T cell receptor due to chronically raised basal activation levels of intracellular signalling molecules. PMID- 21811142 TI - Detection of HIV-1 viruses in tears of patients even under long-term HAART. AB - To determine whether HIV-1 viruses exist in tears of patients under HAART, a cross-sectional study was designed. All participants who underwent long-term HAART with undetectable plasma viral load had detectable HIV-1 viral load in tears (n = 16) and had no difference from the controls (n = 5). Our data suggested that the lacrimal gland and/or other tear-associated tissues could be new reservoirs for HIV-1 and precautions should be taken when doing eye examinations. PMID- 21811143 TI - Memory and naive-like regulatory CD4+ T cells expand during HIV-2 infection in direct association with CD4+ T-cell depletion irrespectively of viremia. AB - OBJECTIVE: The dynamics of CD4(+) regulatory T cells (Treg) during HIV-1 infection remains unclear. To further investigate Treg in this context, we characterized, for the first time, this population in HIV-2-positive individuals. Although both HIV infections are associated with hyperimmune activation and CD4(+) T-cell lymphopenia, most HIV-2-positive individuals display slower disease progression and low-to-undetectable viremia. DESIGN/METHODS: Samples were obtained from cohorts of untreated HIV-2-positive and HIV-1-positive, treated HIV 1-positive and seronegative individuals. The proportion of CD4(+) T cells bearing a Treg phenotype, defined in terms of high-level CD25 or Foxp3 expression, was assessed by flow cytometry and correlated with markers of disease progression. The proportions of naive and memory-like subsets as well as cycling cells were determined. RESULTS: We observed an increased proportion of Treg, associated with disease progression, as well as increased proportions of cycling (Ki67(+)) memory Treg, in untreated HIV-2-positive and HIV-1-positive individuals. We also noted an expansion of Treg that persisted over time in treated, immunologically discordant HIV-1-positive individuals, who, similarly to HIV-2-positive patients, present undetectable viremia and low CD4 T-cell count. CONCLUSION: Overall, we demonstrated that Treg frequency was increased in all lymphopenic HIV-2-positive and HIV-1-positive individuals irrespective of the presence or absence of viremia or antiretroviral treatment. This, in turn, suggests that the observed alterations in Treg frequency in HIV/AIDS are more directly related to the degree of CD4 depletion than to viremia. PMID- 21811144 TI - Increased mortality among publicly insured participants in the HIV Outpatient Study despite HAART treatment. AB - OBJECTIVE: Understanding mortality differences among HIV-infected patients can focus efforts to improve survival. DESIGN: We evaluated death rates, causes, and associated factors among treated patients in the HIV Outpatient Study (HOPS), a large, prospective, multicenter observational cohort of HIV-infected persons seen at a diverse set of US sites of care. METHODS: Among 3754 HOPS participants seen during 1996-2007 with at least 6 months of follow-up after initiating HAART and receiving HAART at least 75% of time under observation ('substantially treated'), we calculated hazard ratios for death using proportional hazards regression models. We also examined death causes and comorbidities among decedents. RESULTS: Substantially treated participants, followed a median 4.7 years (interquartile range, 2.2-8.5), experienced 331 deaths. In multivariable analyses, higher mortality was associated with an index CD4 cell count less than 200 cells/MUl [adjusted hazard ratio (aHR), 2.86; 95% confidence interval (CI) 1.95-4.21], older age (aHR, 1.50 per 10 years; 95% CI 1.33-1.70), log(10)HIV RNA (aHR, 1.67 per log(10); 95% CI 1.51-1.85), but not race/ethnicity (aHR, 0.99 for blacks vs. whites, P = 0.92). Mortality was increased among publicly insured (PUB) vs. privately insured participants (PRV) when index CD4 cell count was at least 200 cells/MUl (aHR, 2.03; 95% CI 1.32-3.14) but not when index CD4 cell count was less than 200 cells/MUl (aHR, 1.3, P = 0.13). By death cause, PUB had significantly more cardiovascular events and hepatic disorders than PRV. Comorbidities more frequent among PUB vs. PRV decedents included cardiovascular disease, renal impairment, and chronic hepatitis. CONCLUSION: Among HAART-treated participants with CD4 cell counts at least 200 cells/MUl, PUB experienced higher death rates than PRV. Non-AIDS death and disease causes predominated among publicly insured decedents, suggesting that treatable comorbidities contributed to survival disparities. PMID- 21811145 TI - Informed choice in infant feeding decisions can be supported for HIV-infected women even in industrialized countries. PMID- 21811147 TI - New method for estimating HIV incidence and time from infection to diagnosis using HIV surveillance data: results for France. AB - OBJECTIVE: To estimate HIV incidence and time between HIV infection and diagnosis of infection. DESIGN: We devised a new model for estimating the incidence of HIV infection and the time between infection and diagnosis from HIV surveillance data. Our approach takes into account temporal changes in HIV test-seeking behaviors and requires few data on individuals newly diagnosed with HIV (i.e. date of diagnosis and clinical status at diagnosis). Using our new approach, we analyzed data for patients newly diagnosed with HIV in France between April 2003 and December 2008. RESULTS: The estimated mean time between infection and diagnosis ranged from 37.0 months among men who have sex with men to approximately 53.0 months among heterosexual men. Intermediate values were obtained for injecting drug users and heterosexual women. We estimated that mean times changed very slightly (<=1.2 months) during the period 2004-2007: it shortened among MSM, remained stable among non-French-national heterosexual men, and lengthened in all the other exposure categories. We estimated that the total number of new infections increased, but not significantly, between 2004 and 2007, reaching 7851 [95% confidence interval 5400-9919] in 2007. MSM accounted for the largest number of new infections (38%). CONCLUSION: HIV continues to spread in France, and the average time between infection and HIV diagnosis remains excessively long. New policies to expand the offer and acceptance of voluntary HIV testing are thus urgently needed. Our method will also be very useful to monitor and evaluate the impact of future HIV testing policies. PMID- 21811146 TI - A prospective study of frequency and correlates of intimate partner violence among African heterosexual HIV serodiscordant couples. AB - BACKGROUND: Intimate partner violence (IPV) is common worldwide and is an important consideration in couples HIV voluntary counseling and testing (CVCT), especially for HIV-serodiscordant couples (i.e. in which only one member is HIV infected). DESIGN: Prospective study of 3408 HIV-serodiscordant couples (2299 in which the HIV-infected partner was female) from seven countries from East and Southern Africa. METHODS: At quarterly visits during up to 2 years of follow-up, participants were asked, separately, about IPV perpetrated against them by their partner during the prior 3 months. Correlates of IPV were determined by generalized estimating equations. RESULTS: The majority of couples were married and living together, with an average duration of partnership of approximately 5 years. More than 39,000 quarterly visits were recorded. IPV was reported in 2.7% of visits by HIV-infected women, 2.2% by HIV-uninfected women, 0.9% by HIV infected men, and 0.7% by HIV-uninfected men. The majority of IPV reports were verbal or a combination of verbal and physical violence. Those who were HIV infected were more likely to report IPV [for women adjusted odds ratio (AOR) 1.33, P = 0.043; for men AOR 2.20, P = 0.001], but IPV was not significantly associated with risk of HIV seroconversion in HIV-uninfected participants. IPV incidence decreased during follow-up (P < 0.001). CONCLUSION: During up to 2 years of prospective follow-up, most persons in stable HIV-serodiscordant partnerships who had undergone CVCT did not report IPV. A modest increased risk of IPV was seen for HIV-infected partners, both female and male. PMID- 21811148 TI - Scene-of-crime analysis by a 3-dimensional optical digitizer: a useful perspective for forensic science. AB - Analysis and detailed registration of the crime scene are of the utmost importance during investigations. However, this phase of activity is often affected by the risk of loss of evidence due to the limits of traditional scene of crime registration methods (ie, photos and videos). This technical note shows the utility of the application of a 3-dimensional optical digitizer on different crime scenes. This study aims in fact at verifying the importance and feasibility of contactless 3-dimensional reconstruction and modeling by optical digitization to achieve an optimal registration of the crime scene. PMID- 21811149 TI - Postoperative pain assessment for upper lid blepharoplasty in Asians. AB - This study was undertaken to investigate the pain intensity, time to peak of pain, bruise, swelling, itching, life limitation, blurred vision, and duration of pain after upper lid blepharoplasty using a survey of pain scale, and to provide objective evidence to aid in education and preoperative counseling of our patients. After upper lid blepharoplasty under local anesthesia, patients were asked to rate their pain on a standardized 11-point pain scale (0-10). After pain assessment of the immediate postoperative period, the evaluation was repeated after 2 to 4 hours, 24 hours, 2 days, 3 days, 7 days, and 1 month. Time to peak of pain, bruise, swelling, itching, life limitation, and blurred vision after surgery were investigated. A total of 60 eyelids (30 patients) were included. Average pain score during the immediate postoperative period was 3.5 in males and 2.2 in females. Pain measurement was maintained up to 7 days after surgery. A significant difference in these pain scores according to gender was observed during the immediate postoperative period and up to 24 hours after surgery. Time to peak after upper lid blepharoplasty was as follows: pain 4.4 hours; swelling 17.3 hours; bruise 33.6 hours; itching 21.1 hours; limitation of life 16.6 hours; and blurred vision 8.7 hours. Most severe pain was observed during the immediate postoperative period and up to 2 to 4 hours after surgery. Pain after upper lid blepharoplasty was mostly mild to moderate and did not exceed a score of 4, which would require reevaluation, and could remain persistent for up to 7 days after surgery. Specific pain-targeted assessment and treatment based on these results are warranted. PMID- 21811150 TI - Asynchronous osteoradionecrosis of the mandible treated with sequential fibula osteoseptocutaneous flaps: a report of two cases. AB - Osteroradionecrosis of the mandible is one of the most serious complications of radiotherapy in head and neck cancer. Once osteoradionecrosis of the mandible has been established, conservative therapy is often useless. Two cases of asynchronous bilateral osteoradionecrosis of the mandible are presented. In both cases, successful reconstruction was performed with 2 free fibula osteoseptocutaneous flap transfers from both legs. We believe that adequate debridement, with removal of dead or hypovascular bone and surrounding soft tissue, followed by vascularized composite bone grafts, is the key for a successful outcome. In our cases, the oral function after 2 reconstructive surgeries with the fibula osteoseptocutaneous flap was acceptable. Furthermore, the patient could walk without difficulty. PMID- 21811151 TI - A new flap design: prefabricated neuro-osseous flap. AB - We hypothesized that an osseous tissue can be prefabricated with a peripheral nerve by vascular induction, and by using a rat model, we tested this hypothesis.Twenty Wistar rats were used in the prefabricated neuro-osseous flap study. Bilateral sciatic nerves were placed linearly within the medullary cavities of the femurs. Left femurs were accepted as the experimental group. The right femurs of all the rats were used as internal control where the sciatic nerves were ligated at the bony entrance of the flap.After 6 weeks, all experimental femur flaps were viable. Radioactivity counts and metabolic activity studies showed viable and functional bone tissue in experimental group compared with control group (P = 0.001). On microangiographic evaluation, significant dilatation of the perineural vasculature was observed in experimental group. Histologic investigations showed viable bone tissue only in the experimental group flaps.Due to its easy applicability, reproducibility, and robust circulation, the prefabricated neuro-osseous flap would be an option in reconstructive surgery. PMID- 21811152 TI - The incidence of and clinical approach to positive allograft cultures in anterior cruciate ligament reconstruction. AB - OBJECTIVE: To define the incidence of positive allograft cultures in anterior cruciate ligament (ACL) reconstruction and to determine a clinical approach to a positive test. DESIGN: Retrospective chart review, cohort series. SETTING: Urban academic hospital. PATIENTS: All patients who underwent anterior cruciate ligament reconstruction using allograft between January 2003 and December 2008. One hundred fifteen patients met the inclusion criteria. INTERVENTIONS: Culture of allograft before surgical implantation. MAIN OUTCOME MEASURES: Positive allograft culture. RESULTS: Positive allograft cultures were obtained in 3 of 115 grafts (2.6%). Two cultures grew coagulase-negative Staphylococcus and 1 grew Escherichia coli, both from the broth only. CONCLUSIONS: Positive cultures in ACL allografts have a reported incidence of 5.7% to 13.25%. Our current series shows an incidence of 2.6%. No patients who had a culture-positive allograft developed a clinical infection postoperatively. Routine preimplantation culture of soft tissue allografts cannot be recommended given the low incidence of positive culture and lack of correlation with clinical infection. In the presence of a positive preimplantation allograft culture without signs of clinical infection, our series and the 4 other published series in the literature demonstrate that antibiotic treatment is not indicated. In contrast, signs and symptoms of septic arthritis should be aggressively treated with irrigation, debridement, and intravenous antibiotics. PMID- 21811153 TI - Absence of altered autophagy after myocardial ischemia in diabetic compared with nondiabetic mice. AB - OBJECTIVES: The extent of autophagy in myocardium following persistent ischemia and the effects of insulin resistance and diabetes on cardiac autophagy following myocardial infarction (MI) have not been well elucidated. It is generally thought that autophagy reflects the nutritional status of cells, presumably alterable by diabetes. It has been conjectured that diminution of autophagy early after the onset of MI may preserve jeopardized myocardium thereby improving prognosis. METHODS: Ten-week-old nondiabetic C57BL6 mice, 20-week-old diabetic and nondiabetic C57BL6 mice were subjected to MI for 4 weeks. Hearts from these mice were harvested and assayed for markers of autophagy. RESULT: Hearts of 10-week old C57BL6 mice subjected to 4 weeks of MI had similar levels of LC3-II, a protein indicator of autophagy, as measured by western blotting compared with hearts from sham operated controls. In 20-week-old C57BL6 mice rendered diabetic by feeding a high-fat diet, the amounts of autophagy were comparable to those in 20-week-old nondiabetic C57BL6 mice on a normal diet. CONCLUSION: The magnitude of autophagy in the heart after infarction is of very modest extent and is not modulated by diabetes. Thus, diminution of autophagy is not likely to reduce infarct size or attenuate late negative remodeling after MI in patients with diabetes. PMID- 21811154 TI - Predictors and importance of prolonged hospital stay after primary PCI for ST elevation myocardial infarction. AB - OBJECTIVE: Although most patients with ST-elevation myocardial infarction treated by primary percutaneous coronary intervention (PCI) have a good prognosis and can be discharged from hospital very soon, some patients must be admitted longer. We performed the current analysis to assess predictors and the prognostic significance of prolonged hospital stay. PATIENTS AND METHODS: In this prospective observational study, individual data from 2323 patients who survived at least 2 days after primary PCI in our hospital were recorded. Patients in the highest tertile of hospital stay were compared with the other patients. Both predictors and prognostic importance of prolonged hospital stay were evaluated. RESULTS: Mean admission duration was 6.7 days (standard deviation=6.6). A total of 797 patients had a hospital stay for more than 6 days (highest tertile). Patients with a longer hospital stay were older, more often female, had more often a history of previous myocardial infarction and signs of heart failure on admission, and had more frequently Thrombolysis in Myocardial Infarction flow 0 before PCI. In addition, a low left ventricular ejection fraction was independently associated with prolonged hospital stay [odds ratio: 2.06 (95% confidence interval: 1.54-2.76)], but with a comparable risk of 1-year mortality [odds ratio: 1.3 (95% confidence interval: 0.8-2.0)]. CONCLUSION: According to this study, a low left ventricular ejection fraction is associated with prolonged hospital stay in patients after primary PCI. Predictors of prolonged hospital stay are age, female sex, previous myocardial infarction, heart failure on admission, and Thrombolysis in Myocardial Infarction flow 0 before PCI. PMID- 21811155 TI - Determination of the cut-off plasma adiponectin level associated with a lower risk of restenosis in patients with stable angina. AB - OBJECTIVE: Hypoadiponectinemia is an independent predictor for the progression of coronary artery disease (CAD); however, the importance of plasma adiponectin levels in the midterm clinical outcome in patients with CAD who underwent percutaneous coronary intervention (PCI) has not been fully elucidated. The purpose of this study was to investigate the association between plasma adiponectin levels and midterm clinical outcome in patients with CAD who underwent PCI. MATERIALS AND METHODS: A total of 112 patients (120 lesions) with stable angina who underwent PCI under intravascular ultrasound guidance, and who underwent follow-up coronary angiography about 8 months after PCI from August 2004 to December 2009 were enrolled in this study. RESULTS: Plasma adiponectin levels were significantly lower in the group with restenosis (n=13) than in the group without restenosis (n=107) (4.2+/-1.5 vs. 6.8+/-4.9 MUg/ml, P<0.0001). A two-graph receiver operating characteristic curve analysis indicated that the cut off point of adiponectin was 6.0 MUg/ml. Although plasma adiponectin levels were independent of well-known risk factors of CAD, a multivariate logistic regression analysis indicated that the higher adiponectin group (patients with hyperadiponectinemia) was independently associated with lower risk of restenosis (odds ratio=0.21, 95% confidence interval=0.03-0.82). CONCLUSION: Hyperadiponectinemia (plasma adiponectin levels >=6.0 MUg/ml) is independently associated with a lower risk of restenosis. Thus, the plasma adiponectin level may be useful as a marker of restenosis independent of preinterventional intravascular ultrasound variables. PMID- 21811156 TI - Acetaldehyde level in spirits from central European countries. AB - Intake of acetaldehyde in alcoholic beverages, in central Europe, might explain the high rate of alcohol-related diseases in these countries. We measured the acetaldehyde level in 30 samples of home-made spirits and 12 samples of industry made spirits from four central European countries, including 35 fruit-based and five grain-based spirits. Acetaldehyde was detected in all fruit-based spirits and in none of the grain-based spirits. Acetaldehyde levels were above 2000 umol/l in 12 samples, 11 of which were home-made. In a multivariate analysis restricted to fruit-based spirits, however, the difference between home-made and industry-based spirits was not statistically significant. These results add evidence to the hypothesis that intake of acetaldehyde in alcoholic beverages, in central Europe, contributes to the burden of alcohol-related disease, especially that of upper digestive tract cancers. The acetaldehyde level should be monitored and high-level exposure should be avoided. PMID- 21811157 TI - Outcomes after symptomatic capsule retention in suspected small bowel obstruction. AB - BACKGROUND AND AIM: Capsule endoscopy (CE) has been proven to be a sensitive and a safe tool for the examination of the small bowel. However, careful patient selection is required to avoid complications, primarily capsule retention. The aims of this study were to evaluate the rate of capsule retention in patients with suspected chronic small bowel obstruction and to analyze the role and the impact of subsequent surgical intervention. METHODOLOGY: Fifteen patients referred for CE with a clinical picture suggestive of chronic small bowel obstruction and with negative imaging studies were retrospectively analyzed. RESULTS: Capsule retention occurred in three (20%) patients who developed symptoms of subacute obstruction and subsequently underwent surgery. Radiation enteritis, Crohn's disease, and an ileal tumor were demonstrated as the causes of the capsule retention in these patients. Surgical removal of the retained capsule was performed and the underlying small bowel disease was treated. CONCLUSION: Capsule retention is a frequent complication of CE in patients with symptoms of chronic small bowel obstruction. Surgery, with the removal of the retained capsule, is proven to be beneficial in identifying the location of, and treating, the underlying disease in these patients. PMID- 21811158 TI - Proton-pump inhibitors in sleep-related breathing disorders: clinical response and predictive factors. AB - BACKGROUND AND AIM: Gastroesophageal reflux is frequently associated with sleep related breathing disorders. We aimed to evaluate the prevalence of acid reflux in patients with sleep-related breathing disorders, their clinical response to proton-pump inhibitor (PPI) treatment, and to identify predictive response factors to this treatment. METHODS: Prospective study among patients attending a sleep clinic. Evaluation of typical and atypical gastroesophageal reflux symptoms, simultaneous 24 h dual-channel pH monitoring and polysomnography were performed in all patients. Patients were treated with pantoprazole. After 3-6 months clinical response was evaluated, and pHmetry and polysomnography repeated. Clinical response was defined in terms of snore, apnea and somnolence grading. Improvement in polysomnography was defined by the Stanford criteria. RESULTS: One hundred and ninety-nine patients were included. Abnormal reflux levels were detected in the distal esophagus in 72% of patients, and in the proximal esophagus in 46%. Clinical or polysomnographic response to PPI treatment was found in 78% of patients. Pretreatment pHmetry was a significant predictor of success: 67% of responders had pathological proximal pHmetry (vs. 33% of nonresponders; P<0.001), and 55% also had pathological distal pHmetry (P<0.05). Age, sex, BMI, alcohol or tobacco abuse, typical or atypical gastroesophageal reflux symptoms, severity of sleeping disorder, and polysomnography were not predictive of outcome. CONCLUSIONS: Patients with sleep-related breathing disorders have an increased prevalence of gastroesophageal reflux disease. They may be successfully treated with PPIs, particularly in patients with an abnormal proximal esophageal pHmetry. PMID- 21811159 TI - Metabolic syndrome is associated with gastric dysplasia. AB - OBJECTIVE: Recent studies have shown an association between metabolic syndrome (MetS) and gastric cancer. This study was carried out to assess the effect of MetS on gastric dysplasia in a Korean population presenting for health check-ups. METHODS: We conducted a retrospective, case-control study on gastric dysplasia between November 2003 and August 2009 at the health screening center. A gastric dysplasia group (N=128) and age-matched, gender-matched control group (N=358) were included. A total of 486 Korean patients aged 20 years or above were assessed for BMI, waist circumference, blood pressure, total cholesterol, low density lipoprotein (LDL)-cholesterol, high density lipoprotein-cholesterol, triglycerides, serum glucose, and HbA1c. RESULTS: In the univariate analysis, fasting glucose, BMI, and the presence of MetS were significant factors associated with the risk of gastric dysplasia. In the multivariate analysis, four of the variables studied (fasting glucose, total cholesterol, LDL-cholesterol, and MetS) had a statistically significant relationship with gastric dysplasia. The risk of gastric dysplasia was associated with modest glucose levels [glucose 100-125 mg/dl; age-adjusted and gender-adjusted relative risk (RR), 2.261; 95% confidence interval (CI), 1.147-4.457; P=0.019], higher total cholesterol levels (total cholesterol >=240 mg/dl; RR, 6.299; 95% CI, 1.277-31.076; P=0.024), modest LDL-cholesterol levels (LDL 130-159 mg/dl; RR, 0.250; 95% CI, 0.069-0.903; P=0.034), and the presence of MetS (MetS >=3 components; RR, 2.177; 95% CI, 1.082 4.379; P=0.029). CONCLUSION: Our findings suggest that MetS is associated with gastric dysplasia in the general Korean population. PMID- 21811160 TI - Stenting of malignant upper oesophageal obstruction: experience in a regional hospital in Singapore. AB - Oesophageal stenting for palliation of malignant obstruction with self-expanding metallic stents is undoubtedly well established. Numerous studies have proven it to be safe and easy to perform with good clinical outcomes. However, stenting of the upper oesophagus is still regarded with apprehension, with many endoscopists concerned about cough, significant throat discomfort or intolerable foreign body sensation. Owing to relatively lack of experience of stenting in the upper oesophagus, many patients ended up with feeding jejunostomy instead. Endoscopic laser boring or dilatation of the upper stenotic oesophageal tumour does not seem to be favoured as it is associated with perforation, bleeding, aspiration pneumonia and the need for several sessions of the procedure to achieve and maintain adequate luminal patency.This study aims to discuss the clinical effectiveness of specially designed cervical oesophageal stents for palliation of malignant upper oesophageal obstruction. PMID- 21811161 TI - A randomized trial of standard-dose versus half-dose rabeprazole, clarithromycin, and amoxicillin in the treatment of Helicobacter pylori infection. AB - OBJECTIVES: To evaluate the efficacy and safety of a standard-dose versus half dose 10-day triple regimen for the eradication of Helicobacter pylori infection. METHODS: A total of 115 consecutive patients with documented infection were enrolled in this open-label trial. Group A (standard dose) received rabeprazole (20 mg), amoxicillin (1 g), and clarithromycin (500 mg), all twice daily for 10 days. Group B (half dose) received rabeprazole (10 mg), amoxicillin (500 mg), and clarithromycin (250 mg), all twice daily for 10 days. (14)C urea breath tests were performed a minimum of 4 weeks after treatment and a minimum of 2 weeks off any acid-suppressive therapy. Compliance and adverse effects were evaluated throughout the treatment period. RESULTS: A total of 115 patients were enrolled (59 women and 56 men; mean age 47.1+/-14.0 years). Eradication occurred in 45 of 58 patients [77.6%; 95% confidence interval (CI): 66.9-88.3%] in the standard dose group versus 44 of 57 in the half-dose group (77.2%; 95% CI: 66.3-88.1%) on an intent-to-treat (ITT) analysis (P=1.00). Per protocol eradication rates were 45 of 57 (78.9%; 95% CI: 68.4-85.9%) and 44 of 54 (81.5%; 95% CI: 71.1-91.8%), respectively (P=0.81). The number of patients reporting any adverse effect was significantly higher in the standard-dose group (64.9 vs. 40.4%; P=0.014). The cost of treatment was significantly less in patients receiving the half-dose regimen (ITT analysis; P<0.05). The number needed to harm to suffer one additional failure in the half-dose over the standard-dose arm was 250 (ITT analysis). CONCLUSION: A half-dose 10-day regimen of rabeprazole, amoxicillin, and clarithromycin is equally effective but cheaper and better tolerated than its standard-dose regimen in the treatment of Helicobacter pylori. Eradication rates of both regimens are, however, suboptimal compared with accepted standards. PMID- 21811162 TI - Helicobacter pylori infection and fundic gastric atrophy are not associated with esophageal squamous cell carcinoma: a case-control study. AB - OBJECTIVE: Recent studies from Asia and Northern Europe suggest that apart from alcohol intake and smoking, fundic gastric atrophy (FGA) may also increase the risk of esophageal squamous cell carcinoma (OSCC). However, because of the wide geographic variation of this cancer and the changing prevalence of the Helicobacter pylori infection, these findings need to be confirmed in other ethnic groups. The aim of this case-control study was to investigate whether H. pylori infection and FGA carry an increased risk for OSCC. PATIENTS AND METHODS: FGA was evaluated, by histology and serology, in 75 patients with OSCC, and 75 sex-matched and age-matched controls. Pepsinogen (PG) I levels 70 MUg/ml or less and PG I/II ratio of 3 or less were indicative for FGA. H. pylori infection was defined as positivity to at least one test among histology, rapid urease test, and serology for both general anti-IgG and anti-CagA. RESULTS: Overall, the prevalence of H. pylori infection was identically high (70.7%) in both patients with OSCC and controls. FGA diagnosed by serology and histology was not associated with an increased risk for OSCC [odds ratio (OR)=1.17; 95% confidence interval (CI)=0.54-2.56 and OR=1.91; 95% CI=0.6-5.99, respectively]. ORs (95% CI) for hazardous alcohol consumption, smoking, and the presence of both risk factors were 5.75 (2.20-15.05), 22.18 (9.41-52.28), and 31.69 (8.39-119.67), respectively. CONCLUSIONS: Hazardous alcohol consumption and smoking increase synergistically the risk for developing OSCC. In our population neither H. pylori infection nor FGA was associated with an increased risk for OSCC. PMID- 21811163 TI - Follow-up of carriers of BRCA1 and BRCA2 variants of unknown significance: variant reclassification and surgical decisions. AB - PURPOSE: : Approximately 5-10% of patients who undergo genetic testing of BRCA1 and BRCA2 receive a variant of unknown significance (VUS) result. The ambiguous nature of a VUS may increase difficulty in patient understanding and decision making regarding risk reduction and surveillance options, including cancer risk reducing surgeries. VUS reclassification to benign or deleterious may occur in time; however, clinical decisions may need to be made expeditiously, and some patients may pursue irreversible treatments before VUS reclassification. METHODS: : We reviewed the surgical decisions of 107 women postdisclosure of a BRCA VUS result counseled at our institute between 1998 and 2009. CONCLUSION: : Among women receiving a BRCA VUS result at our center, 11 of 107 (10.3%) pursued cancer risk-reducing mastectomy and 22 of 107 (20.6%) pursued cancer risk-reducing bilateral salpingo-oophorectomy. Reclassification of VUS occurred up to 9 years after testing, and 5 of 22 (22.7%) women followed up for 8 or more years continue to have a VUS result. We discuss considerations for providers of genetic services to discuss with patients who receive a VUS result. PMID- 21811165 TI - The virtual diagnostic laboratory: a new way of teaching undergraduate medical students about genetic testing. AB - PURPOSE: Medical students often perceive genetics as a discipline focused on rare diseases with relevance only to genetics specialists. Because genetic testing has now infiltrated most if not all medical disciplines, we need new teaching approaches to help trainees incorporate emerging genetic testing strategies appropriately into medical practice. With the ever-increasing number of known disease-associated genes, it is also important to shift from a paradigm of memorization to one of critical evaluation and an awareness of available resources. METHODS: We designed case-based virtual laboratory sessions for first year medical students at Emory University. These sessions emphasize both rare and common health issues and allow the students to practice applying their fundamental genetics knowledge in the diagnostic setting. RESULTS: These sessions proved a valuable approach to presenting the intricacies of diagnostic genetic testing. Students rate the sessions very highly, with 92% of them agreeing or strongly agreeing that the sessions had educational value. The students commented that ours was an effective approach to teaching the material that illustrates well the impact of genetics on patient care. CONCLUSIONS: The virtual diagnostic laboratory approach is an effective, nonlecture-based method of teaching medical students about genetic testing strategies and their application in the clinical setting. PMID- 21811164 TI - Targeted polymerase chain reaction-based enrichment and next generation sequencing for diagnostic testing of congenital disorders of glycosylation. AB - PURPOSE: Congenital disorders of glycosylation are a heterogeneous group of disorders caused by deficient glycosylation, primarily affecting the N-linked pathway. It is estimated that more than 40% of congenital disorders of glycosylation patients lack a confirmatory molecular diagnosis. The purpose of this study was to improve molecular diagnosis for congenital disorders of glycosylation by developing and validating a next generation sequencing panel for comprehensive mutation detection in 24 genes known to cause congenital disorders of glycosylation. METHODS: Next generation sequencing validation was performed on 12 positive control congenital disorders of glycosylation patients. These samples were blinded as to the disease-causing mutations. Both RainDance and Fluidigm platforms were used for sequence enrichment and targeted amplification. The SOLiD platform was used for sequencing the amplified products. Bioinformatic analysis was performed using NextGENe(r) software. RESULTS: The disease-causing mutations were identified by next generation sequencing for all 12 positive controls. Additional variants were also detected in three controls that are known or predicted to impair gene function and may contribute to the clinical phenotype. CONCLUSIONS: We conclude that development of next generation sequencing panels in the diagnostic laboratory where multiple genes are implicated in a disorder is more cost-effective and will result in improved and faster patient diagnosis compared with a gene-by-gene approach. Recommendations are also provided for data analysis from the next generation sequencing-derived data in the clinical laboratory, which will be important for the widespread use of this technology. PMID- 21811166 TI - Principal component analysis: a novel analysis to evaluate the characteristics of osseointegration of different implant surfaces. AB - OBJECTIVE: To apply a new statistical method (principle component analysis; PCA) to evaluate osseointegration. MATERIALS AND METHODS: Two different commercially available implants were selected for the study. Twenty implants, 10 of each type, were placed in the rabbit tibiae (n = 10). The fluorochromes (FLCs) alizarin complexone and calcein green were administered after 20 days and 4 days before sacrifice for labeling. On the day of implantation and retrieval (6 weeks), implant stability was measured with a resonance frequency analyzer (RFA). The retrieved samples were ground sectioned for histomorphometric and FLC quantification. The collected data were analyzed by a PCA software program (Qlucore Omics Explorer, Lund, Sweden) to explore and determine the correlation between different study variables and to analyze the differences between different implants. RESULTS: The RFA presented no significant differences at either time point. The bone-to-implant contact was significantly higher for the TiUnite (NobelBiocare, Gothenburg, Sweden); however, the bone area and FLC quantification showed higher values for the Osseotite (3i Implant Innovation, FL). Consistent with these results, the PCA indicated a strong correlation between TiUnite and high bone-to-implant contact values and between Osseotite and high bone area and FLC values. No correlation between RFA and the biological responses were found. CONCLUSION: The application of the PCA analysis may help interpret and correlate results obtained from numerous evaluations. PMID- 21811167 TI - Osteointegration of autogenous bone graft associated with osteoblastic cells under treatment with caffeine. AB - PURPOSE: The present study investigated osteointegration of autogenous bone (AB) from calvaria graft associated with osteoblastic cells (OC) in bone defects in rats subjected to daily administration of caffeine. MATERIALS AND METHODS: Male rats received daily intraperitoneal injection of 1.5% caffeine (0.2 mL/100 g body weight) or saline solution for 30 days. Then they were anesthetized, submitted to the extraction of the upper right incisor, and implanted with AB only and AB + OC. The animals were killed on 7th, 21st, and 42nd days after surgery, and their maxilla were processed for obtaining semiserial sections (5 MUm) stained with hematoxylin and eosin. Through image analysis system, the bone volume and the quality of graft in adjacent areas were estimated. RESULTS: The results showed that in caffeine treatment, the AB + OC graft showed no foreign body and acute inflammatory reactions inside the defect when compared to AB. The histometric results revealed that the association AB + OC produced significant increase (10% 15%) in bone volume in later experimental period (42 days) when compared with saline solution group (P <= 0.01). CONCLUSIONS: It was concluded that the association of AB from calvaria + OC demonstrated progressive osteointegration and accelerated the repair of bone defects in animals treated with daily caffeine. PMID- 21811168 TI - Risk of lingual plate perforation during implant placement in the posterior mandible: a human cadaver study. AB - AIM: To determine the risk of lingual plate perforations using 2 different implants during implant installation in the posterior mandible, so as to avoid a potentially life-threatening situation and/or a compromise of the success of the surgical procedure. MATERIALS AND METHODS: Nine human cadaver jaws and 16 edentulous sites with missing mandibular posterior teeth were used. Upon flap reflection, 3.7 * 10.0 mm and 3.7 * 13 mm Tapered Screw Vent implants were placed in the edentulous sites parallel to the ridge over the center of the alveolar ridge. The occurrence of lingual plate perforations was assessed visually, and the distance of the fenestration from the alveolar ridge crest, if any, was measured. RESULTS: Nineteen dental implants of each were placed in the second premolar and first molar regions. No lingual concavity perforations were found in all sites, except for a lingual fenestration in 1 first molar site when placing the 3.7 * 10 mm implant (0.053%). CONCLUSION: The risk of a lingual cortical plate fenestration or perforation, due to lingual concavity, in an edentulous posterior mandible in the region of the second premolar or first molar was found to be 0.053% if a regular 3.7-mm diameter tapered implant was used. In the presence of significant lingual concavity in the posterior mandible, a smaller regular diameter implant with a tapered design should be considered to avoid a potential fatal damage of vital structures. PMID- 21811169 TI - 3D finite element analysis of changes in stress levels and distributions for an osseointegrated implant after vertical bone loss. AB - PURPOSE: The effect of stress levels and distributions around the internal nonsubmerged type implants after vertical bone resorption was investigated in this study. MATERIALS AND METHODS: An HSII implant was placed in 4 cylindrical alveolar bone models with differing degrees of thread exposures. The load applied to each implant was von Mises stress and principal stress, 250 N in axial direction and 30 degrees lateral pressure. The difference in the load between the bone and the connective portion of the implant was obtained using ANSYS analysis. RESULTS: Bone loss in the cervical area of the implant was more obvious under lateral pressure. When more threads were exposed, bone level decreased and the maximum load applied on the fixture increased. CONCLUSIONS: It was concluded that higher bone level has a biomechanical advantage with respect to stress concentration. PMID- 21811170 TI - Comparison of 3 luting agents on retention of implant-supported crowns on 2 different abutments. AB - BACKGROUND: For fixed prostheses, retention is one of the most important factors for clinical success. It is unknown whether grooves that increase surface area of implant abutment while retaining the diameter and wall height provide greater uniaxial retention force. The purpose of this study was to determine the retention of 3 different cements on 2 implant abutments with different surface configurations. MATERIALS AND METHODS: Thirty samples on 2 different abutments (a total of 60 crowns) with different margin and axial walls configuration and surface area were used. Metal crowns were fabricated on the abutment and cemented with 3 different (zinc-phosphate [ZP], glass ionomer [GI], or eugenol-free zinc oxide [ZO]) cements. After cementation, implant-abutment-casting assemblies were thermal cycled 1000 times with 1-minute dwell-time between 5 degrees C and 55 degrees C then subjected to tensile test with universal testing machine until decementation occurred. The mean force required to dislodge castings from abutment was determined. RESULTS: The luting agents influenced retention of castings on implant abutments, whereas different surface configurations and total surface area of the abutments did not influence the uniaxial retention forces. Among the cements tested, ZP exhibited higher values of retention, followed by GI and eugenol-free ZO. CONCLUSIONS: The increase in surface area of abutment did not result in improved retention. The present results suggest using ZP rather than GI and eugenol-free ZO in implant-supported crowns to provide higher retention. PMID- 21811171 TI - Tardive Tourette-like syndrome: a systematic review. AB - Tardive Tourette syndrome is characterized by the occurrence of multiple motor and vocal tics in patients on long-term neuroleptic, antiepileptic medication or stimulants, and was first reported by Golden in 1974 and was given its name in 1980 by Steven Stahl who linked it to tardive dyskinesia. The Medline was searched with the combination of the words 'tardive' or 'induced' or 'late' and 'Tourette' or 'Tourettism' and 375 papers were indentified; 42 of them were judged to be relevant. Forty-one cases were identified, caused by antipsychotics, antiepileptics, stimulants and other medication. A number of treatment options are reported in the literature but no systematic study of the syndrome has been done yet. PMID- 21811172 TI - Prevention of poststroke depression with milnacipran in patients with acute ischemic stroke: a double-blind randomized placebo-controlled trial. AB - Poststroke depression (PSD) is one of the most frequent neuropsychiatric consequences of stroke. It has been shown to be associated with both impaired recovery and increased mortality. The purpose of this study is to investigate the prophylactic effect of milnacipran in PSD. Ninety-two patients were enrolled in the 12 months of this double-blind randomized placebo-controlled trial. The assessment was performed at baseline, and at the first, third, sixth, ninth and 12th month after enrollment. The definition of PSD was in accordance with the diagnostic criteria of major depressive episode based on the Diagnostic and Statistical Manual, fourth edition. Forty-six patients were randomized to the treatment group with milnacipran and another 46 patients to the placebo group. No significant differences were found between the two groups in terms of sex (P=0.83), age (P=0.08), marital status (P=0.66), occupation (P=0.22), educational level (P=0.29), and drug side-effects (P=0.73). The incidence of depression in the two groups was 2.22% and 15.22%, respectively. Milnacipran was proved to have a statistically significant advantage in preventing PSD (P<0.05). In conclusion, milnacipran could prevent the development of depression in the first year following a stroke and is safe to use without significant adverse effects in stroke patients. PMID- 21811173 TI - Anomalies of major retroperitoneal vascular structure. AB - OBJECTIVE: To identify anomalies of major retroperitoneal vascular structure (AMRVS) during oncological retroperitoneal surgery and to investigate the effects of these anomalies in surgical procedures. MATERIALS AND METHODS: Two hundred twenty-nine patients who underwent systematic para-aortic and bilateral pelvic lymph node dissection up to the renal vein between September 2006 and December 2008 were included. Normal architecture and structural anomalies of inferior vena cava, abdominal aorta, renal arteries and veins, and common iliac artery and vein were studied. RESULTS: The mean age of the patients was 54.2 years. Anomalies of major retroperitoneal vascular structure were present in 39 patients (17%). Anomalies of renal vessels were identified in 31 patients. Supernumerary renal arteries and veins observed in 11 patients (17%) were the most common renal vessel anomaly. Great vessel injury was present in 19 patients (8.3%). Vascular complication rate was 20.5% in patients with AMRVS. However, in 4 of 8 patients with vascular complication and AMRVS, the complication was not related with anomalous vascular structures. None of the complications was serious and were corrected surgically. There was no difference between patients with AMRVS and those without AMRVS regarding age, body mass index, the extent of upper abdominal dissemination of malignancy and presence of comorbidity for intraoperative bleeding. There was no difference in intraoperative hemorrhage and amount of transfused red blood cell units between the groups. CONCLUSION: Great vessel anomalies, discovered in 1 of 6 patients, were together with increased risk of vascular complications. The probability of presence of vascular anomalies should be taken into account during lymph node dissection. PMID- 21811174 TI - Long-term psychological morbidity, sexual functioning, and relationship outcomes in women with gestational trophoblastic disease. AB - OBJECTIVE: Clinical observation suggests a protracted psychosocial recovery after gestational trophoblastic disease (GTD), although this has not been well studied. We describe long-term psychological morbidity, sexual functioning, and relationship outcomes after GTD. MATERIALS AND METHODS: Cross-sectional analysis was made of 176 Australian women previously diagnosed with GTD recruited from a statewide registry. Participants comprised 149 women (85%) who did not require chemotherapy and 27 women (15%) who required chemotherapy for malignant or persistent GTD/molar disease (gestational trophoblastic tumor [GTT]). Data were collected from medical records and via validated self-report questionnaires. RESULTS: The participants were 94 women (53%) with partial mole, 75 women (43%) with complete mole, 4 women (2%) with choriocarcinoma, and 3 women (2%) with hydatidiform mole not otherwise specified. The mean (SD) age at diagnosis and time since diagnosis were 32.1 (6.3) and 4.7 (3.3) years, respectively. Elevated levels of depression and anxiety were reported by 22% and 26% of the women, respectively. One fifth to half of the women experienced some GTD-related avoidant and intrusive phenomena, the latter being more prominent among women who had not had chemotherapy. Sexual dysfunction was reported by 52% of the women. Most women (81%) felt well supported by their partners during the illness, 19% thought the relationship had changed, and 26% perceived that GTD had negatively affected sex life. This perception was stronger in those who received chemotherapy, although objective measures of sexual morbidity showed no group differences. Socially disadvantaged women and those who did not conceive subsequent to the diagnosis had poorer psychosocial outcomes. CONCLUSIONS: Notwithstanding limitations, this study is the largest of its type to date. Psychological morbidity rates exceeded community norms, but sexual dysfunction rates, although high, are likely consistent with local norms. These findings highlight the long-term burden of GTD and the importance of a supportive care component in management, even among those who do not require chemotherapy. Socially disadvantaged women and those who do not conceive subsequent to GTD diagnosis require greater psychosocial support. PMID- 21811175 TI - Serum HE4 Profile During Primary Chemotherapy of Epithelial Ovarian Cancer. AB - OBJECTIVE: Human epididymis protein 4 (HE4) is a promising novel serum biomarker for the detection of early-stage epithelial ovarian cancer (EOC) and for the differential diagnosis between benign and malignant ovarian tumors. The objective of the present study was to determine the value of HE4 for monitoring the response to primary therapy in patients with advanced disease. METHODS: Serum HE4 and cancer antigen (CA) 125 levels of 10 patients with advanced EOC and one patient with adenocarcinoma of unknown origin were measured preoperatively and during first-line chemotherapy. Seven patients were treated with primary surgery and six cycles of chemotherapy. Response to treatment was evaluated 4 weeks after the completion of chemotherapy using computed tomography. Four patients received neoadjuvant chemotherapy (NACT) before surgery. To evaluate the early response to chemotherapy, changes in serum biomarker levels were compared with metabolic changes of tumors during NACT as detected by positron emission tomography/computed tomography. RESULTS: The profile of HE4 during primary chemotherapy was in line with radiologic and clinical responses. In the neoadjuvant chemotherapy group, HE4 correlated better with the radiologic response than CA 125. CONCLUSION: Assessment of serum HE4 may improve the reliability of response evaluation during chemotherapy for serous epithelial ovarian cancer. PMID- 21811176 TI - Patterns of medication administration from 2001 to 2009 in the treatment of children with acute burn injuries: a multicenter study. AB - Children with burn injuries receive a broad range of medications, from analgesics to antipsychotics, but how utilization of these drugs differs from one pediatric burn center to another is unclear. This study examined utilization patterns of six categories of medication administered acutely to burned children as a first step in creating evidence-based practice guidelines. Six medications administered to pediatric patients enrolled in a multicenter study were recorded from patient charts using a standardized chart review template. The medication categories included opiates, benzodiazepines, antidepressants, beta-blockers, two different anesthetics, and antipsychotics. Data were analyzed by chi and logistical regression analysis. Analysis of data from three sites and 470 patients revealed significant differences in prescription patterns across hospitals for all medication groups except opiates. Differences were significant for benzodiazepines and antidepressants (chi = 7.3; P < .01 for both) controlling for age, gender, race, language, burn size, and length of stay. Differences in prescribing patterns for beta-blockers and the anesthetics ketamine and propofol failed to reach statistical significance; however, the results did trend in that direction (chi = 3.8 and 3.4, respectively; P < .10 for both). The pharmacotherapeutic agents described in this study are an integral part of acute pediatric burn care, and yet there is variation in use of these medications among the centers. The differences in prescribing indicate that, for certain drugs, a range of approaches to pharmacotherapeutics is being used and suggest that evidence-based guidelines for administration of these agents need to be developed. PMID- 21811177 TI - Presenting features of pyometra including an increase in iatrogenic causes. AB - A retrospective case series of 14 patients were diagnosed with pyometra for 10 years at our hospital. We reported iatrogenic causes, such as radiofrequency or uterine artery embolization, and other pyometra causes in our hospital to provide guidance for diagnosis by a gynecologist. PMID- 21811178 TI - Risk factors for persistent cervical intraepithelial neoplasia grades 1 and 2: managed by watchful waiting. AB - OBJECTIVE: : This study examines risk factors for persistent cervical intraepithelial neoplasia (CIN) and examines whether human papillomavirus (HPV) testing predicts persistent lesions. MATERIALS AND METHODS: : Women with histologically diagnosed CIN 1 or CIN 2 (n = 206) were followed up every 3 months without treatment. Human papillomavirus genotyping, plasma levels of ascorbic acid, and red blood cell folate levels were obtained. Cervical biopsy at 12 months determined the presence of CIN. Relative risk (RR) was estimated by log linked binomial regression models. RESULTS: : At 12 months, 70% of CIN 1 versus 54% of CIN 2 lesions spontaneously regressed (p < .001). Levels of folate or ascorbic acid were not associated with persistent CIN at 12 months. Compared with HPV-negative women, those with multiple HPV types (RRs ranged from 1.68 to 2.17 at each follow-up visit) or high-risk types (RRs range = 1.74-2.09) were at increased risk for persistent CIN; women with HPV-16/18 had the highest risk (RRs range = 1.91-2.21). Persistent infection with a high-risk type was also associated with persistent CIN (RRs range = 1.50-2.35). Typing for high-risk HPVs at 6 months only had a sensitivity of 46% in predicting persistence of any lesions at 12 months. CONCLUSIONS: : Spontaneous regression of CIN 1 and 2 occurs frequently within 12 months. Human papillomavirus infection is the major risk factor for persistent CIN. However, HPV testing cannot reliably predict persistence of any lesion. PMID- 21811179 TI - Surgical-pathologic risk factors and immunohistochemical markers of pelvic lymph node metastasis in stage IB1 cervical cancer. AB - OBJECTIVE: : This study aimed to identify the surgical-pathologic risk factors and immunohistochemical markers of pelvic lymph node metastasis in stage IB1 cervical cancer. MATERIALS AND METHODS: : A retrospective review of patients with stage IB1 cervical cancer who underwent radical abdominal hysterectomy, lymph node dissection, and immunohistochemical staining for p53, bcl-2, and Ki-67 was performed. RESULTS: : A total of 29 patients with complete clinical data and pathology tissue blocks are the subjects of this study. Of these patients, 20 (69%) had squamous cell carcinoma, 8 (28%) had adenocarcinoma, and 1 (3%) adenosquamous carcinoma. The median tumor diameter as measured in the pathology laboratory was 2 cm. The median number of lymph nodes removed was 24. Four (14%) patients had positive lymph nodes. Lymphovascular invasion was noted in 10 (34%). None of the 19 patients without lymphovascular invasion had lymph node involvement. Of 29 patients, 2 (7%) had parametrial involvement. There was a statistically significant correlation between tumor diameter and depth of invasion (r = 0.43, p = .02), and between lymphovascular invasion and positive lymph nodes (r = 0.55, p = .0019). The Ki-67 immunostaining index was higher for patients with lymphovascular invasion and/or positive lymph nodes (p = .008 and p = .028, respectively). There was no association between p53 or bcl-2 expression and lymphovascular invasion or lymph node metastasis. CONCLUSIONS: : Lymph node metastasis (14 %) and parametrial involvement (7%) occurred only in patients with lymphovascular invasion and/or large tumor size. The Ki-67 staining index is associated with lymphovascular invasion and lymph node metastasis. PMID- 21811180 TI - Hair in the vagina: a case series. AB - BACKGROUND: : Lack of estrogen after menopause can cause many changes in the lower genital tract of women, including involution of the introitus and collapse of the vestibule into the genital cleft. CASES: : Six cases of hypoestrogenic women are described, with the unusual finding of entrapment of terminal hairs between agglutinated genital folds or in the vagina. In symptomatic cases, there were severe inflammatory changes accompanying these findings. The initial case prompted a lengthy and costly diagnostic process to no avail. A MEDLINE search yielded several cases of pilonidal disease of the clitoris in younger women, but no reports of hair in the vagina of postmenopausal women. CONCLUSIONS: : This report is noteworthy because pilonidal disease in the lower genital tract of postmenopausal women is a less-known clinical entity. A hypothesis is offered based on its clinical similarity to pilonidal disease in the presacral area. PMID- 21811181 TI - Osteonecrosis of femoral head treated with alendronate in a 14-year-old boy: a case report. AB - We describe a 14-year-old adolescent with osteonecrosis of femoral head, who was treated successfully with oral bisphosphonate. To prevent physeal damage by surgical treatment, alendronate was administered weekly for 20 months. A complete resolution was achieved. This report suggests that bisphosphonate may be an effective nonoperative treatment for osteonecrosis of femoral head. PMID- 21811182 TI - A critical review of interventions for clubfoot in low and middle-income countries: effectiveness and contextual influences. AB - Inadequate treatment provision for clubfoot in many low and middle-income countries results in a high prevalence of neglected clubfoot, a condition causing severe impairment. This study critically reviewed evidence on surgical, conservative and mixed (Ponseti) treatment interventions for clubfoot in low and middle-income countries. Intervention effectiveness was analysed by comparing outcomes within International Classification of Functioning groupings. Contextual factors were qualitatively analysed for effect on intervention outcomes. The Ponseti method appeared to be more effective than conservative techniques but was not directly comparable with surgical techniques. Contextual factors were reported to influence outcomes; service providers using the Ponseti technique had made most intentional steps to overcome contextual barriers. PMID- 21811183 TI - Efficacy of novel minimally invasive surgery using spinal microendoscope for treating extraforaminal stenosis at the lumbosacral junction. AB - STUDY DESIGN: A retrospective case study of the spinal microendoscopic surgery for the treatment of extraforaminal stenosis at the lumbosacral junction. OBJECTIVE: To evaluate the efficacy of a minimally invasive technique using spinal microendoscope and to examine the 2-year surgical outcome for this disease. SUMMARY OF BACKGROUND DATA: The paraspinal approach has been the gold standard to expose the extraforaminal space. Although it seems to be ideal, the constricted surgical field of view may compromise the surgeon's ability and increase the risk of complications. This technique can be improved further. METHODS: A total of 32 patients, who completed a minimum follow-up of 2 years after the surgery, were included in this study. The study group consisted of 16 men and 16 women with an average age at surgery of 64 years and a mean follow-up of 37.4 months. Clinical results were evaluated according to the Japanese Orthopaedic Association (JOA) scoring system, visual analog scale, and the North American Spine Society Low Back Outcome Instrument. RESULTS: Two of these patients required revision surgery to correct insufficient decompression in the foramen. In the 30 other patients, the mean JOA score was 15.1 points before surgery and 23.1 points at the final follow-up. The mean recovery rate was 60.1%. The JOA scores improved significantly after surgery and the satisfactory results were maintained until the final follow-up. The visual analog scale scores for low back pain, leg pain, and numbness also significantly improved. Twenty-eight of 32 patients (87.6%) were satisfied with this procedure. CONCLUSIONS: The spinal microendoscopic surgery demonstrated efficacy for treating extraforaminal stenosis at the lumbosacral junction where the lesion is difficult to be exposed. Quick and easy access along with minimal damage to the back muscles and bony structures could be accomplished using the property of its oblique view and angled surgical equipments. This procedure has produced long-lasting favorable outcomes and high patient satisfaction. Novel minimally invasive surgery may replace conventional open methods. PMID- 21811184 TI - A flatter proximal trochlear groove is associated with patella cartilage loss. AB - PURPOSE: The bony articular surface contributes to a joint's congruency, and it might be a determinant of structural change. The aim of this longitudinal study was to determine (i) whether the angle of the trochlear groove is associated with the rate of loss of patella cartilage volume for 2 yr and (ii) whether this association is influenced by particular modifiable and nonmodifiable factors. METHODS: A total of 297 community-based adults with no history of knee pathologic disease were recruited at baseline (2003-2004), and 271 of these subjects were reexamined at follow-up (2006-2007). Magnetic resonance imaging was performed at baseline and follow-up to determine the change in patella cartilage volume, whereas baseline images were used to assess trochlear groove angles. A baseline questionnaire determined participation in vigorous physical activity. RESULTS: For every 1 degrees increase in the proximal trochlear groove angle at baseline, there was an associated 1.12-mm3 (95% confidence interval (CI) = 0.00-2.24 mm3) increase in the annual rate of patella cartilage volume loss. There was a trend for this effect to occur for males, as well as people participating in vigorous physical activity (all P <= 0.07). Males who exercised vigorously were more adversely affected (5.0 mm3 per annum (95% CI = 0.5-9.4 mm3 per annum)) than males who did not exercise vigorously (0.6 mm3 per annum (95% CI = -2.1 to 3.3 mm3 per annum)). CONCLUSIONS: A more flattened proximal trochlear groove is associated with increased patella cartilage volume loss, particularly for physically active men. Our results suggest that lifestyle factors, such as physical activity, may modify the association between joint incongruity and cartilage loss and can be further affected by subjects' characteristics such as gender. Understanding these complex interactions will help optimize strategies to maintain patellofemoral joint health. PMID- 21811185 TI - Effect of warm-up exercise on exercise-induced bronchoconstriction. AB - PURPOSE: Exercise-induced bronchoconstriction (EIB) occurs when vigorous exercise induces bronchoconstriction. Preexercise warm-up routines are frequently used to elicit a refractory period and thus reduce or prevent EIB. This study aimed to conduct a systematic review to evaluate the effectiveness of preexercise routines to attenuate EIB. METHODS: A comprehensive literature search was performed, with steps taken to avoid publication and selection bias. Preexercise warm-up routines were classified into four groups: interval high intensity, continuous low intensity, continuous high intensity, and variable intensity (i.e., a combination of low intensity up to very high intensity). The EIB response was measured by the percent fall in the forced expiratory volume in 1 s (FEV1) after exercise, and the mean differences (MDs) and 95% confidence intervals (CI) are reported. RESULTS: Seven randomized studies met the inclusion criteria. The pooled results showed that high intensity (MD = -10.6%, 95% CI = -14.7% to -6.5%) and variable intensity (MD = -10.9%, 95% CI = -14.37% to -7.5%) exercise warm-up attenuated the fall in FEV1. However, continuous low-intensity warm-up (MD = -12.6%, 95% CI = -26.7% to 1.5%) and continuous high-intensity warm-up (MD = -9.8%, 95% CI = 26.0% to 6.4%) failed to result in a statistically significant reduction in bronchoconstriction. CONCLUSIONS: The most consistent and effective attenuation of EIB was observed with high-intensity interval and variable intensity preexercise warm-ups. These findings indicate that an appropriate warm-up strategy that includes at least some high-intensity exercise may be a short-term nonpharmacological strategy to reducing EIB. PMID- 21811187 TI - Heading in soccer: dangerous play? AB - Soccer is the world's most popular sport and unique in that players use their unprotected heads to intentionally deflect, stop, or redirect the ball for both offensive and defensive strategies. Headed balls travel at high velocity pre- and postimpact. Players, coaches, parents, and physicians are justifiably concerned with soccer heading injury risk. Furthermore, risk of long-term neurocognitive and motor deficits caused by repetitively heading a soccer ball remains unknown. We review the theoretical concerns, the results of biomechanical laboratory experiments, and the available clinical data regarding the effects of chronic, subconcussive head injury during heading in soccer. PMID- 21811188 TI - Repeat gamma knife radiosurgery for trigeminal neuralgia. AB - BACKGROUND: Trigeminal neuralgia (TN) may recur after treatment by gamma knife stereotactic radiosurgery (GKSR). OBJECTIVE: To evaluate management outcomes in patients who underwent repeat GKSR for TN. METHODS: The authors reviewed their experience with repeat GKSR in 119 patients with recurrent TN. The median patient age was 74 years (range, 34-96 years). The median interval between procedures was 26 months. The median target dose for repeat GKSR was 70 Gy (range, 50-90 Gy) and the median cumulative dose was 145 Gy (range, 120-170 Gy). The median follow-up was 48 months (range, 6-187 months) after repeat GKSR. RESULTS: After repeat GKSR, 87% of patients achieved initial pain relief (Barrow Neurological Institute pain score I-IIIb). Pain relief was maintained in 87.8% at 1 year, 69.8% at 3 years, and 44.2% at 5 years. Facial sensory dysfunction occurred in 21% of patients within 18 months after GKSR. Longer pain relief was observed in patients who had recurrent pain in a reduced pain distribution of the face compared with the pain distribution at the time of their initial GKSR, and in those who developed additional trigeminal sensory loss after a repeat procedure. A cumulative edge of brainstem dose >= 44 Gy was more likely to be associated with the development of sensory loss. CONCLUSION: Repeat GKSR provides a similar rate of pain relief as the first procedure. The best responses were observed in patients who had good pain control after the first procedure and those who developed new sensory dysfunction in the affected trigeminal distribution. PMID- 21811189 TI - Accuracy of diffusion tensor magnetic resonance imaging-based tractography for surgery of gliomas near the pyramidal tract: a significant correlation between subcortical electrical stimulation and postoperative tractography. AB - BACKGROUND: Diffusion tensor (DT) imaging-based fiber tracking is a noninvasive magnetic resonance technique that can delineate the course of white matter fibers. OBJECTIVE: To evaluate the accuracy and usefulness of this DT imaging based fiber tracking for surgery in patients with gliomas near the pyramidal tract (PT). METHODS: Subjects comprised 32 patients with gliomas near the PT. DT imaging-based fiber tracks of the PT were generated before and within 3 days after surgery in all patients. A tractography-integrated navigation system was used during the operation. Cortical and subcortical motor-evoked potentials (MEPs) were also monitored during resection to maximize the preservation of motor function. The threshold intensity for subcortical MEPs was examined by searching the stimulus points and changing the stimulus intensity. Minimum distance between the resection border and the illustrated PT was measured on postoperative tractography. RESULTS: In all subjects, DT imaging-based tractography of the PT was successfully performed, preoperatively demonstrating the relationship between tumors and the PT. With the use of the tractography-integrated navigation system and intraoperative MEPs, motor function was preserved postoperatively in all patients. A significant correlation was seen between threshold intensity for subcortical MEPs and the distance between the resection border and PT on postoperative DT imaging. CONCLUSION: DT imaging-based fiber tracking is a reliable and accurate method for mapping the course of subcortical PTs. Fiber tracking and intraoperative MEPs were useful for preserving motor function in patients with gliomas near the PT. PMID- 21811190 TI - Microscope-integrated quantitative analysis of intraoperative indocyanine green fluorescence angiography for blood flow assessment: first experience in 30 patients. AB - BACKGROUND: Intraoperative measurements of cerebral blood flow are of interest during vascular neurosurgery. Near-infrared indocyanine green (ICG) fluorescence angiography was introduced for visualizing vessel patency intraoperatively. However, quantitative information has not been available. OBJECTIVE: To report our experience with a microscope with an integrated dynamic ICG fluorescence analysis system supplying semiquantitative information on blood flow. METHODS: We recorded ICG fluorescence curves of cortex and cerebral vessels using software integrated into the surgical microscope (Flow 800 software; Zeiss Pentero) in 30 patients undergoing surgery for different pathologies. The following hemodynamic parameters were assessed: maximum intensity, rise time, time to peak, time to half-maximal fluorescence, cerebral blood flow index, and transit times from arteries to cortex. RESULTS: For patients without obvious perfusion deficit, maximum fluorescence intensity was 177.7 arbitrary intensity units (AIs; 5-mg ICG bolus), mean rise time was 5.2 seconds (range, 2.9-8.2 seconds; SD, 1.3 seconds), mean time to peak was 9.4 seconds (range, 4.9-15.2 seconds; SD, 2.5 seconds), mean cerebral blood flow index was 38.6 AI/s (range, 13.5-180.6 AI/s; SD, 36.9 seconds), and mean transit time was 1.5 seconds (range, 360 milliseconds-3 seconds; SD, 0.73 seconds). For 3 patients with impaired cerebral perfusion, time to peak, rise time, and transit time between arteries and cortex were markedly prolonged (>20, >9 , and >5 seconds). In single patients, the degree of perfusion impairment could be quantified by the cerebral blood flow index ratios between normal and ischemic tissue. Transit times also reflected blood flow perturbations in arteriovenous fistulas. CONCLUSION: Quantification of ICG-based fluorescence angiography appears to be useful for intraoperative monitoring of arterial patency and regional cerebral blood flow. PMID- 21811191 TI - Association of IL1B polymorphism with left ventricular systolic dysfunction: a relation with the release of interleukin-1beta in stress condition. AB - OBJECTIVE: Proinflammatory cytokines play a major role in the pathomechanisms of heart failure. Besides this, the influence of mental stress on heart failure is poorly documented despite its effects on sympathetic stimulation of interleukin 1beta (IL-1beta) secretion. We examined whether the polymorphisms of proinflammatory cytokines are predictors of left ventricular systolic dysfunction (LVSD) and if so, whether such associations are related to the secretion of these cytokines, in 572 consecutive patients under mental stress produced by coronary angiography. METHODS: We examined IL-1RN (VNTR), IL1A-889 C>T, IL1B-511 C>T, IL6 174 G>C and TNFA-308 G>A, according to LVSD (left ventricular ejection fraction, <40%). Saliva IL-1beta, serum tumour necrosis factor-alpha and C-reactive protein were assayed in basal (T0 and T2, before and after coronary angiography) and stress (T1) conditions. MAIN RESULTS: The 42.1% of patients with LVSD had a 1.5 fold higher frequency of IL1B T allele (P<0.001). IL1B-511TT was associated with LVSD (P=0.008) and with a decrease in IL-1beta level in saliva at T1 (P=0.013). IL-1beta was the highest at T1 (P<0.001) and was associated with left ventricular ejection fraction (P=0.002). The IL1B TT genotype and the C-reactive protein were the two independent predictors of LVSD in multivariate analysis, with an odds ratio of 2.7 (95% confidence interval: 1.3-5.5; P=0.008) and 1.1 (95% confidence interval: 1.1-1.2; P<0.001), respectively. CONCLUSION: IL1B was a predictor of LVSD and of the decreased IL-1beta response to stress. This suggests that IL1B exerts an influence on LVSD through its effect on IL-1beta secretion. PMID- 21811192 TI - Escitalopram versus placebo in the treatment of dysthymic disorder. AB - Numerous studies have assessed the acute efficacy of antidepressants, including selective serotonin reuptake inhibitors, in treating dysthymic disorder; however, escitalopram, the S-enantiomer of citalopram, has not been studied. Thirty-six outpatients with Structured Clinical Interview for DSM-III-R-diagnosed dysthymic disorder, aged 23-65 years (mean+/-SD=44.7+/-11 years), were randomly assigned to double-blind escitalopram (maximum dose 20 mg/day) versus placebo for 12 weeks. Inclusion criteria included age 18-65 years and Hamilton Depression Rating Scale (HDRS) score>=12. We hypothesized that escitalopram would be superior to placebo in the HDRS-24 item total score at week 12. We also hypothesized the superiority of escitalopram over placebo for secondary measures, including the percentage of participants classified as responders and remitters, as well as social functioning (Social Adjustment Scale), clinical global impression-improvement, Global Assessment of Functioning Scale. Participants' baseline HDRS-24 averaged 23.4+/-5.9. Final HDRS-24 scores at last observation carried forward did not differ significantly between escitalopram-treated (mean+/-SD=10.88+/-5.83) and placebo-treated individuals (mean+/-SD=16.4+/-6.34) (F=2.82, degrees of freedom=1,32, P=0.10). Significant differences favoring active medication were found on the Social Adjustment Scale and the Clinical Global Impression Severity and Global Assessment of Functioning Scale, but not in the percentages of responders or remitters. A larger study sample or higher escitalopram dose may show more significant placebo-medication differences. PMID- 21811193 TI - Plasma orexin A, ghrelin, cholecystokinin, visfatin, leptin and agouti-related protein levels during 6-week olanzapine treatment in first-episode male patients with psychosis. AB - The objective of the study was to investigate the change of body mass index (BMI), waist circumference, lipid profile, leptin, ghrelin, orexin, visfatin, agouti-related protein, and cholecystokinin levels during 6 weeks of olanzapine treatment in newly diagnosed first-episode drug naive, young adult, nonobese male patients with psychosis. Twenty male participants who were all first-episode drug naive psychotic patients without prominent affective signs and symptoms and 22 healthy male controls of similar age were included. BMI, waist circumference, fasting glucose, and lipid profiles were measured, and Positive and Negative Syndrome Scale and Brief Psychiatric Rating Scale scores were obtained at baseline, during the second and sixth week of treatment, and the aforementioned neuropeptide levels were measured at baseline and during the sixth week of treatment. Treatment was associated with significant increases in BMI, waist circumference, serum triglyceride, and low-density lipoprotein levels. BMI levels increased more than 7% in over 75% of the patients. Leptin increased, and ghrelin and orexin decreased significantly with olanzapine treatment, whereas cholecystokinin, visfatin, and agouti-related protein levels did not change significantly. In conclusion, consistent with previous studies, we found increased BMI, leptin and lipids during olanzapine treatment. Association of neuropeptide level changes with symptom improvement might be mediated by the dopaminergic and serotonergic systems. PMID- 21811194 TI - The influence of body mass index on the accuracy of ultrasound and computed tomography in diagnosing appendicitis in children. AB - BACKGROUND: Appendicitis is a common pediatric surgical diagnosis that is often guided by radiographic imaging such as ultrasound (US) or computed tomography (CT). Whereas US is preferred because it avoids radiation, data suggest it is less sensitive than CT in diagnosing appendicitis. Body habitus, characterized by body mass index (BMI), may affect the diagnostic value of advanced radiological imaging in children with abdominal pain. OBJECTIVE: The aim of the study was to determine the relationship between BMI and accuracy of US and CT scan for suspected appendicitis. METHODS: We conducted a prospective, observational study of children with suspected appendicitis who presented to the emergency department and underwent radiographic evaluation from June 2007 to July 2008. Patient height and weight were obtained to calculate BMI and correlating z score, zBMI. Patients were grouped into standardized categories: underweight/normal weight, overweight, and obese based on zBMI. Emergency physicians ordered imaging as guided by standard clinical management. Pediatric attending radiologists evaluated all imaging studies; final radiology reports were reviewed and coded by 2 independent reviewers. Appendicitis was defined by pathology. Statistical analysis was performed to evaluate test performance of US and CT in diagnosing appendicitis as related to BMI. RESULTS: Over the study period, 176 patients with suspected appendicitis underwent US and/or CT. Mean age was 11.8 +/- 4.2 years; 42% were male. zBMI ranged from -2.78 to 2.75 (mean, 0.59); 70 children (40%) were overweight or obese; 73 (42%) had appendicitis. Ultrasound was performed on 147 (84%), and CT on 128 children (73%); 99 children (56%) had both studies. The overall sensitivity for US in diagnosing appendicitis was 38% (95% confidence interval [CI], 26%-52%) with a specificity of 97% (95% CI, 90%-99%). In the underweight/normal weight group, the sensitivity of US was 45% (95% CI, 27%-64%); in the overweight group, 35% (95% CI, 15%-61%), and in the obese group, 22% (95% CI, 4%-60%). The sensitivity and specificity of CT were 96% (95% CI, 86%-99%) and 97% (95% CI, 90%-100%) and did not vary by zBMI class. CONCLUSIONS: The sensitivity and specificity of CT for appendicitis are excellent regardless of BMI. Despite a trend of decreasing sensitivity with increasing BMI when using US, no statistically significant difference was found, likely because of type II error. PMID- 21811195 TI - Foreign body aspiration in children: analysis of diagnostic criteria and accurate time for bronchoscopy. AB - OBJECTIVES: The aims of this study were to evaluate the predictive diagnostic value of history, clinical signs and symptoms, and radiological finding and to evaluate whether bronchoscopy is a safe procedure and whether it should be performed in urgent conditions. METHODS: The medical records of 191 children who underwent bronchoscopy for suspected foreign body aspiration (FBA) between 2001 and 2009 were reviewed for demographic data, radiological studies, and bronchoscopic findings retrospectively. RESULTS: There were 117 male and 74 female patients. Their ages ranged from 2 months to 14 years. The major complaints were paroxysmal cough and respiratory insufficiency. Foreign body aspiration was confirmed in 123 patients (65%). Of 106 patients who were admitted in the first 24 hours, FBA was confirmed in 75 patients. Of 116 patients with a definite history of witnessed FBA, 87 patients (75%) were found to have positive bronchoscopic findings. Of 46 patients who had prolonged history of recurrent pulmonary infections, allergic asthma, or bronchiolitis, 31 (67.4%) were found to have FBs. Foreign bodies were frequently organic. Nineteen patients required urgent bronchoscopic evaluation. Sensitivity and specificity for each diagnostic criterion were as follows: clinical history (63% and 32%); symptoms (68% and 53%); physical examination findings (70.5% and 63%); radiological findings (73% and 68%); and the triad of cough, wheezing, and diminished breath sound (88% and 51%), respectively. There was a positive correlation between the presence of wheezing and FB-positive patients. CONCLUSIONS: Although there are no specific symptoms and signs to make a clear-cut diagnosis, history of witnessed FBA, admittance within 24 hours from the beginning of respiratory symptoms, and wheezing are proper indications for bronchoscopy. Bronchoscopy is a safe procedure with few and confined complications. PMID- 21811196 TI - Feasibility of computerized screening for intimate partner violence in a pediatric emergency department. AB - OBJECTIVES: This study aimed to evaluate the feasibility of caregiver-initiated computerized screening in a pediatric emergency department (ED) to identify home safety risks, with a specific emphasis on intimate partner violence (IPV). METHODS: Home safety screening kiosks were developed using information technology as the first step in a plan to decrease family violence. Caregivers self initiated a standard-of-care screening process that included both non-IPV and IPV items. An ED social worker received an automated text page and printed summary of the findings when a caregiver endorsed IPV. System activity was tracked by comparing frequency of completed screens to the daily ED census and by determining the percentage of completed screens that were positive for IPV. The reliability of the technology was evaluated as percentage of days of system downtime. Meetings with ED personnel and direct observations of families were conducted to identify potential barriers and successes to the technology utilization. RESULTS: During a 15-month period, 13,057 computerized screens occurred, with a 4-fold increase in the computerized screening rate after ED triage nurses became champions of these efforts. Fourteen percent of the computerized screens were positive for IPV. The reliability of the technology was considered quite high, with rare system downtime (4.2% of days) reported during the 15 months. There were several themes identified by caregivers and providers regarding barriers to successful use of the safety screening. CONCLUSIONS: A reliable, caregiver-initiated system is possible to offer consistent opportunity to conduct unobtrusive, private screening for IPV and other home safety concerns. PMID- 21811197 TI - Assessing the knowledge of all-terrain vehicle safety for children among Alabama pediatricians. AB - BACKGROUND: Since 1987, the American Academy of Pediatrics (AAP) has had a policy regarding the use of all-terrain vehicles (ATVs) by children, which calls for pediatricians to educate families regarding the dangers of ATV use and to give recommendations for safety. Given the high incidence of ATV-related injuries in Alabama, our objective was to determine if pediatricians in our state are educating patients on ATV hazards and safety. METHODS: All general pediatricians in Alabama who are members of the AAP were asked to complete a survey distributed through e-mail using Survey Monkey(r) (Survey Monkey Palo Alto, Calif). Data were entered into Microsoft(r) Excel (Microsoft Corporation Redmond, Wash). RESULTS: Of the 353 general pediatricians in Alabama, 104 responded. Forty-one percent of the respondents were not aware that there is an AAP policy. Of the 59% who knew of the policy, 36% correctly identified the age limit recommendations. Forty eight percent said that they routinely give anticipatory guidance regarding ATV use. Of them, 63% gave age recommendations younger than stated in the AAP policy. In addition, only 52% of them recommend helmet use, 5% recommend use of reflective clothing, 35% discourage passenger riding, and 8% encourage ATV training classes. Respondents who had patients treated for ATV-related injuries were more likely to give anticipatory guidance than those who had not had patients treated (chi2 = 5.3; P = 0.02; odds ratio, 3.9 [95% confidence interval, 1.2-13.6]). Respondents who practice in rural areas were more likely not to give anticipatory guidance than those who practice in urban areas (chi2 = 2.1; P = 0.14; odds ratio, 2.9 [95% confidence interval, 0.8-5.4]). CONCLUSIONS: Many general pediatricians in a state where ATV use is popular are not familiar with the current AAP policy and do not routinely follow its guidelines. Given the high incidence of ATV-related injuries and the complexities of general practice, exploring multiple methods to modify risk-taking ATV behavior is warranted. PMID- 21811198 TI - Association between upper extremity fractures and weight status in children. AB - OBJECTIVES: Our objective was to determine the odds of having an increased weight status among children with upper extremity fracture (UEF) compared with 3 control groups without fractures. METHODS: This is a secondary analysis of data from the Pediatric Risk of Admission (PRISA and PRISA II) data sets. Patients without chronic illness between the ages of 5 to 14 years were included in the following groups: (1) UEF study group, (2) upper extremity nonfracture injured control group, (3) minor-head-injured control group, and (4) noninjured probability control group. Weight for age/sex percentiles was used to evaluate weight status. The proportions of patients with weight for age/sex greater than the 50th, 85th, and 95th percentiles were determined. Logistic regression was used to generate odds ratios comparing the UEF group with each control group stratified by age. RESULTS: This analysis included 308 patients in the 5- to 9-year age group and 207 patients in the 10- to 14-year age group. The odds of having a weight greater than the 50th percentile for age/sex were significantly increased among children with UEF aged 5 to 9 years compared with all control groups. There were no significant differences in the corresponding odds ratios for children with UEF aged 10 to 14 years compared with controls. CONCLUSIONS: These findings may be related to differential injury mechanisms, mobility patterns, or underlying patient vulnerability to fracture based on weight status and bone qualities in prepubescent versus pubescent populations. Further investigation should explore fracture epidemiology and fracture risk in children stratified by age. PMID- 21811199 TI - Tracking manikin tracheal intubation using motion analysis. AB - OBJECTIVES: This study investigates whether laryngoscope motion-tracking technology can be used to differentiate expert versus novice providers' techniques during endotracheal intubation in infant manikins; this may help improve intubation techniques. METHODS: Each of 11 experts and 11 novices intubated an infant manikin head (Laerdal Corp, Wappinger Falls, NY) 10 times. Laryngoscope motion was tracked using electromagnetic technology during: (1) time from acquisition of laryngoscope to oral insertion, (2) insertion to stabilization of laryngoscope, and (3) stabilization of laryngoscope to insertion of endotracheal tube and withdrawal of laryngoscope. There were 213/220 analyzable data files. Expert versus novice rate of success, laryngoscope blade tip motion path length, handle angle at intubation, time in each phase, and motion of handle relative to manikin were compared. RESULTS: Intubation success rate was greater for experts (105/105 = 100% vs novices 101/108 = 93.5%, P < 0.001). Expert path of motion in phase 2 was longer (mean, 39 vs 29 cm, P < 0.001). The mean difference in the laryngoscope handle angle relative to the manikin occiput was statistically significant (mean angle, -54.42 vs -56.63 degrees; P = 0.001) but within the equipment testing margin of error (2 degrees). Time from insertion to withdrawal of laryngoscope (phases 2 and 3 combined) was greater for experts (16.45 vs 13.15 seconds; P = 0.02). Both experts and novices "rocked" the laryngoscope to achieve laryngeal visualization. CONCLUSIONS: It is feasible to track laryngoscope motion during manikin intubation comparing expert versus novice technique. Experts had a greater success rate, but longer path length, and took longer to achieve manikin intubation. Motion-tracking technology may provide an analytic tool to improve techniques of intubation. PMID- 21811200 TI - Correlation of measures of patient acuity with measures of crowding in a pediatric emergency department. AB - OBJECTIVE: Emergency department (ED) crowding is an increasingly common problem in the United States. Crowding can lead to ED closure and diversion, poor patient satisfaction, and patient safety issues. The purpose of this study was to examine measures of ED census and measures of crowding to determine if a correlation exists in a pediatric ED setting. METHODS: Arkansas Children's Hospital is a major pediatric referral center. Measures of ED acuity (including total census, admission rate, total number of admissions, and proportion of triage category nonurgent patients) and measures of throughput (left-without-being-seen [LWBS] rate and ED length of stay [LOS]) data for 11 years (1996-2006) were plotted, and correlation coefficients were calculated. RESULTS: Annual ED census varied between 35,415 and 40,711 during the 11-year study period. The total number of admissions increased from 4179 in 1996 to 6539 in 2006. When total census was plotted against LWBS rate and ED LOS, a poor correlation was found (R2 = 0.007 for total census vs LWBS rate). However, a strong correlation was found when the relationship between the total number of admissions and LWBS rate was examined (R2 = 0.89). Similarly, a strong relationship between the admission rate and LWBS rate was seen (R2 = 0.75). In addition, a strong correlation was seen between admissions (total and percentage) versus ED LOS. CONCLUSIONS: There is a strong correlation between the number of patients admitted and measures of overcrowding in this pediatric ED, but there is a poor correlation between the total census and overcrowding measures. Targeting process improvement on hospital-wide patient flow may help reduce ED crowding. PMID- 21811201 TI - Point-of-care echocardiography by pediatric emergency physicians. AB - OBJECTIVE: Currently, pediatric emergency medicine (PEM) physicians have limited data on point-of-care echocardiography (POCE). Our goals were to (1) determine the overall accuracy of POCE by PEMs in assessing left ventricular (LV) systolic function visually, presence or absence of pericardial effusion, and cardiac preload by estimating inferior vena cava (IVC) collapsibility, in acutely ill children in the pediatric emergency department; and (2) assess interobserver agreement between the PEM physician and pediatric cardiologist. METHODS: This is a prospective, observational study conducted in an urban, tertiary pediatric facility with an annual census of 67,000 emergency department visits. Patients between the ages of 0 and 18 years meeting 1 or more of the following inclusion criteria were recruited: (1) cardiopulmonary arrest, (2) fluid refractory shock requiring vasoactive infusions, (3) undifferentiated cardiomegaly on chest radiography, and (4) receiving emergent formal echocardiography. All eligible patients underwent POCE by 1 of 2 trained PEM physicians. Dynamic video clips were recorded and reviewed by a pediatric cardiologist who was unaware of the clinical condition of the study patients. RESULTS: For a period of 18 months, we recruited 70 patients. Diminished LV function was noted in 17, pericardial effusion in 16, and abnormal IVC collapsibility in 35 patients. The kappa statistics of agreement between the PEM and the cardiologist for detection of LV function, IVC collapsibility, and effusion were 0.87 (95% confidence interval [CI], 0.73-1.00), 0.73 (95% CI, 0.59-0.88), and 0.77 (95% CI, 0.58-0.95), respectively. The overall sensitivity and specificity of POCE compared with a formal echocardiogram was 95% (95% CI, 82%-99%) and 83% (95% CI, 64%-93%), respectively. CONCLUSIONS: With goal-directed training, PEM physicians may be able to perform POCE and accurately assess for significant LV systolic dysfunction, vascular filling, and the presence of pericardial effusion. The model may be expanded to train physicians to use POCE. PMID- 21811202 TI - Effect of a triage team on length of stay in a pediatric emergency department. AB - OBJECTIVE: This study aimed to determine the impact of a triage team on patient length of stay (LOS) overall and by patient acuity in a pediatric emergency department (ED). METHODS: We conducted a cluster randomized controlled trial in which existing ED staffing was reallocated to include a triage team. The study was conducted in an urban children's ED Monday through Friday, from 6:00 P.M. to 2:00 A.M., for 4 weeks in February 2008. Twenty study periods were randomized according to the absence or presence of a triage team (physician, nurse, and nurse assistant) that initiated evaluations of nonurgent and urgent patients. We compared patient LOS between study periods with and without triage teams, using generalized estimating equations to allow for the clustering of effects by day. RESULTS: Of the 1726 patients, 843 were seen during nontriage team times and 883 during triage team times. Overall, there was a 21-minute decrease in LOS during triage team times compared with nontriage team times, but this was not statistically significant. Stratifying by patient acuity level, LOS was significantly decreased during triage team times for nonurgent (25 minutes, P = 0.001) and urgent patients (50 minutes, P = 0.047) but prolonged for emergent patients (79 minutes, P = 0.019) and unchanged for critically ill patients. CONCLUSIONS: Overall, although we did not find a statistically significant decrease in the LOS with the use of a dedicated triage team, we did find statistically significant decreases in the stratified analysis for urgent, nonurgent patient, and discharged patients. An important reason statistical significance may not have been reached in this study may have been our hospital's current staffing model, and therefore, the use of a triage team as additional staffing versus reallocation of existing staffing may depend on an institution's current level of staffing and its ability to meet patient demand. PMID- 21811203 TI - Out-of-hospital pediatric cardiorespiratory arrest in Galicia: impact of the 2005 resuscitation guidelines. AB - INTRODUCTION: Pediatric out-of-hospital cardiorespiratory arrest (CRA) is a rare event but has a high mortality and morbidity among survivors. In 2005, an international consensus on science and treatment recommendations has been released, with the aim of improving the assistance of patients who had and, eventually, increasing survival without neurologic sequelae. Our objective was to assess the impact of the 2005 guidelines on the initial prehospital assistance of children with out-of-hospital CRA in a community with scattered population. METHODS: This is a prospective observational study following the Utstein-style guidelines of pediatric CRA in 2 periods: group 1 (pre-2005), from July 2002 to February 2005 (32 months); and group 2 (post-2005), from January 2007 to December 2008 (24 months). Patients aged from 0 months to 16 years who had an out-of hospital respiratory or cardiac arrest were included in the study. RESULTS: There were 31 patients (84% cardiac) who had CRA in group 1 and 21 patients (62% cardiac) who had CRA in group 2 (P = 0.073). Both groups were comparable in age, sex, CRA cause, place of CRA incident, management of airway, fluid administrations, and defibrillation attempts. A significant increment in the number of bystander cardiopulmonary resuscitation (CPR) was observed in group 2 (13 [62%] vs 7 [29%], P = 0.004). The intraosseous access was more frequently used in the post-2005 group (8 [38%] vs 5 [16%], P = 0.021). In group 2, a higher percentage of patients received more than 1 adrenaline dose (95% vs 61%, P = 0.006), were treated with bicarbonate (7 [33%] vs 3 [10%], P = 0.045), and were not treated with atropine (5 [24%] vs 17 [55%], P = 0.020). Survival to hospital admission, sustained return of spontaneous circulation, and survival to hospital discharge were comparable in both groups. CONCLUSIONS: In cases of pediatric out of-hospital CRA in a community with scattered population, after the introduction of the 2005 international CPR recommendations, there was an increase in bystander CPR and changes in immediate treatment were detected. However, these changes did not result in a significant outcome improvement. PMID- 21811204 TI - Combining a contact lens and wide-angle viewing system for a wider fundus view. PMID- 21811205 TI - Pars plana vitrectomy without adjuvant procedures for repair of primary rhegmatogenous retinal detachment. AB - PURPOSE: To evaluate the anatomical and functional outcomes of pars plana vitrectomy without adjuvant scleral buckling, prophylactic 360 degrees endolaser photocoagulation, or perfluorocarbon liquid use for the treatment of primary uncomplicated rhegmatogenous retinal detachment. METHODS: Retrospective interventional case series of consecutive patients undergoing vitrectomy for noncomplex rhegmatogenous retinal detachment over a 10-year period. Main outcome measures included primary anatomical success rate, defined as retinal reattachment at final follow-up after a single operation, proportion of eyes achieving a final best-corrected visual acuity <= logarithm of the minimum angle of resolution 0.3 (>= Snellen 20/40), and postoperative complications. RESULTS: With a mean follow-up of 31 months, primary anatomical success was achieved in 95.7% (89 of 93) of eyes. Final anatomical success, defined as retinal attachment at final follow-up without regard to additional procedures, was achieved in 98.9% (92 of 93). Final best-corrected visual acuity of <= logarithm of the minimum angle of resolution 0.3 (>= Snellen 20/40) was achieved in 77.4% of eyes in the cohort. Postoperative proliferative vitreoretinopathy developed in 3.2% of eyes. No new retinal breaks developed postoperatively in the absence of clinically evident proliferative vitreoretinopathy. CONCLUSION: Thorough pars plana vitrectomy alone, without adjuvant scleral buckling, 360 degrees endolaser photocoagulation, or routine perfluorocarbon liquid use, yields high anatomical and functional success rates and low complication rates in the treatment of primary uncomplicated rhegmatogenous retinal detachment. In the absence of observable proliferative vitreoretinopathy, postoperative vitreous base contraction does not appear to be a clinically relevant phenomenon. PMID- 21811206 TI - Mechanical characteristics of the porcine retina in low temperatures. AB - BACKGROUND: We previously observed that the stiffness of the porcine retina was significantly higher when deforming at room temperature than at body temperature. The present study further investigates this phenomenon by examining the mechanical properties of the retina in saline at temperature lower than room temperature. METHODS: Tensile testing was performed on a total of 15 retinal strips dissected from pig eyes. Equal amount of strips from the dissection were tested at 37.0 +/- 0.3 degrees C, 26.1 +/- 0.1 degrees C, and 7.8 +/- 1.2 degrees C. Their transition modulus, stress, and strain were measured for statistical analysis. RESULTS: The transition modulus, the transition stress, and the transition strain of the retinal strips were found to be 11.12 +/- 6.10 kPa, 0.12 +/- 0.07 kPa, and 0.016 +/- 0.001, respectively, at 37.0 degrees C. These values were 111.25 +/- 88.16 kPa, 1.11 +/- 0.85 kPa, and 0.016 +/- 0.001 at 26.1 degrees C, and 125.13 +/- 63.61 kPa, 1.30 +/- 0.50 kPa, and 0.017 +/- 0.003 at 7.8 degrees C, respectively. The differences of the transition modulus and the transition stress at between 37.0 degrees C and 26.1 degrees C and at between 37.0 degrees C and 7.8 degrees C were statistically significant (P < 0.05). There were no significant differences in these values at between 26.1 degrees C and 7.8 degrees C. CONCLUSION: These findings suggest that lowering the temperature of the retina from body temperature is potentially useful to decrease retinal damage in posterior eye surgeries by increasing the resistance of the retina to mechanical deformation. PMID- 21811207 TI - Three treatments for macular edema because of branch retinal vein occlusion: intravitreous bevacizumab or tissue plasminogen activator, and vitrectomy. AB - PURPOSE: To evaluate the effectiveness of intravitreous bevacizumab (Avastin), intravitreous tissue plasminogen activator, and vitrectomy for the macular edema secondary to branch retinal vein occlusion. METHODS: Retrospective, interventional case series. We studied 228 eyes of 228 patients. Forty-one eyes received 1.25 mg of intravitreous bevacizumab, 71 eyes received tissue plasminogen activator, and 116 eyes underwent vitrectomy. A reinjection of 1.25 mg of bevacizumab was based on the morphologic and functional findings. The main outcome measures were the best-corrected visual acuity and optical coherence tomography-determined foveal thickness. RESULTS: The mean postoperative follow-up period was 32.2 months with a range of 12 months to 69 months. The mean number of intravitreous bevacizumab was 2.8 with a range of 1 to 5. The mean best-corrected visual acuity and foveal thickness significantly improved after all 3 treatments, and the differences in the best-corrected visual acuity between the 3 groups were not significant at 12 months. Fourteen eyes (34%) in the intravitreous bevacizumab group and 21 eyes (30%) in the tissue plasminogen activator group required additional surgeries. CONCLUSION: The 3 treatments appear to provide similar visual outcomes at 12 months. However, in some eyes treated with intravitreous bevacizumab or tissue plasminogen activator, additional surgeries were required, and a longer follow-up period was required to determine the final outcome. PMID- 21811208 TI - Macular diseases: moving the battlefield to the patient's home. PMID- 21811209 TI - Overcoming segmentation errors in measurements of macular thickness made by spectral-domain optical coherence tomography. AB - PURPOSE: To assess the frequency and severity of segmentation errors in spectral domain optical coherence tomography, and present an appropriate scan protocol for measuring macular thickness. METHODS: In this study we examined 40 eyes of healthy subjects, 45 eyes with retinal pathology and 31 eyes with subretinal pathology. Patients were prospectively imaged using 12 radial scans and 3 dimensional macular cube scans by spectral-domain optical coherence tomography (3D OCT-1000; Topcon Corp., Japan) at the same sitting. Retinal segmentation errors were noted and graded using a subjective, categoric error scale to generate an error score. We compared the macular thickness measurements with and without error correction, and between the two scan protocols. RESULTS: In this series, 63.8% of eyes (74 of 116 eyes) gave at least 1 segmentation error. Errors were more common in eyes with pathology. There was a significant difference between measurements of macular thickness with and without correcting these errors, regardless of scan protocol (P < 0.05). After error correction of both scan protocols, the macular thickness measurements obtained with the 12 radial scan protocol were equivalent to those obtained with the 3-dimensional macular cube scan protocol. CONCLUSION: Segmentation errors were frequent on scans obtained by spectral-domain optical coherence tomography. We recommend the 12 radial scan protocol with error correction as the standard protocol for measuring macular thickness, particularly in clinical studies. PMID- 21811210 TI - Transscleral albumin diffusion and suprachoroidal albumin concentration in uveal effusion syndrome. AB - PURPOSE: To test the hypothesis that uveal effusion syndrome is caused by reduced transscleral albumin permeability. METHODS: Surgical scleral specimens were obtained from a 55-year-old patient with nanophthalmic uveal effusion syndrome. Specimens were clamped in a modified Ussing chamber, and the rate of transscleral diffusion of fluorescein isothiocyanate-albumin was measured over 12 hours, using a spectrophotometer and predetermined standard curves. The diffusion coefficient was determined at 20 degrees C, and then adjusted to body temperature using Einstein's equation. Results in 3 scleral samples were compared with 10 age matched controls. Albumin and total protein concentration were measured in choroidal fluid and serum. RESULTS: Histologic staining with Alcian blue showed interfibrillary acid mucin deposits. Transmission electron microscopy showed deposits measuring 1 MUm to 10 MUm and collections of expanded, degenerate collagen fibrils. The mean (+/-SD) albumin diffusion coefficient was 12% of that in controls (1.22 +/- 0.67(-8) * 10 vs. 10.3 +/- 7.0 * 10(-8) cm2/second) and below the lower 95% confidence limit of the control group. The diffusion coefficient was calculated to increase 53% to 1.87 +/- 1.03 * 10(-8) cm2/second at 37 degrees C. Choroidal albumin concentration was much higher than physiologic levels, measuring 200 g/L (total protein 321 g/L), 5 times the serum albumin concentration of 42 g/L (total protein 70 g/L). CONCLUSION: Nanophthalmic uveal effusion syndrome can be associated with reduced scleral permeability to albumin, and a very high concentration of retained suprachoroidal albumin. This will lead to an osmotic gradient that retains fluid and may partly explain the pathogenesis of uveal effusion syndrome in some patients. PMID- 21811211 TI - New Jersey's role in stem cell research and the future of modern medicine. PMID- 21811212 TI - Don't say "managed care"; say "patient-centered care". PMID- 21811213 TI - Renewed concern for tort actions based on HIPAA violations. PMID- 21811214 TI - A primer on the uninsured and the healthcare safety net in New Jersey. PMID- 21811215 TI - A cautionary tale: tonsillectomy in modern America. PMID- 21811216 TI - Beware of contracts promising to limit your malpractice liability. PMID- 21811217 TI - Are physicians ready for a terrorist attack? PMID- 21811218 TI - Edward J. Ill: his life, times and the award in his honor. PMID- 21811219 TI - Homeland "medical" security: the prepared physician. PMID- 21811220 TI - Financial planning for professional groups: a formula for success. PMID- 21811221 TI - The perfect storm: when consent practices go wrong. PMID- 21811223 TI - Expeditious entry to novel 2-methylene-2,3-dihydrofuro[3,2-c] chromen-2-ones from 6-chloro-4-hydroxychromen-2-one and propargylic alcohols. AB - A catalytic system consisting of the ruthenium(II) complex [Ru(eta3-2 C3H4Me)(CO)(dppf)][SbF6] (dppf=1,1'-bis(diphenylphosphino)ferrocene) and trifluoroacetic acid has been used to promote the coupling of secondary propargylic alcohols with 6-chloro-4-hydroxychromen-2-one. The reactions afforded unusual 2-methylene-2,3-dihydrofuro[3,2-c]chromen-2-ones in good yields. PMID- 21811225 TI - Expression of p53 in upper urinary tract urothelial carcinoma. AB - The management of upper urinary tract urothelial carcinoma (UUT-UC) is controversial. Radical nephroureterectomy is a major undertaking and has obvious shortcomings in the presence of renal impairment and solitary kidneys, whereas endoscopic management can be associated with a risk of disease progression. There is a pressing need for reliable predictive biomarkers to refine patient selection for renal conservation. p53 is the most frequently investigated molecular marker in UUT-UC. Of the 24 papers published on the subject, expression of p53 is a significant univariate prognostic marker in 12 publications, representing seven unique cohorts. However, multivariate analysis demonstrates that p53 expression is of independent prognostic significance in only five studies, all of which contain potential statistical bias. The currently available data do not, therefore, support a role for p53 in this regard, and suggest a need for prospective large-scale collaborative studies using standardized methods of p53 detection and statistical analysis. PMID- 21811224 TI - Urological aspects of the metabolic syndrome. AB - The metabolic syndrome is common in countries with Western lifestyles. It comprises a number of disorders-including insulin resistance, hypertension and obesity-that all act as risk factors for cardiovascular diseases. Urological diseases have also been linked to the metabolic syndrome. Most established aspects of the metabolic syndrome are linked to benign prostatic hyperplasia (BPH) and prostate cancer. Fasting plasma insulin, in particular, has been linked to BPH and incident, aggressive and lethal prostate cancer. The metabolic syndrome has also been shown to be associated with nonprostatic urological conditions such as male hypogonadism, nephrolithiasis, overactive bladder and erectile dysfunction, although data on these conditions are still sparse. Overall, the results of studies on urological aspects of the metabolic syndrome seem to indicate that BPH and prostate cancer could be regarded as two new aspects of the metabolic syndrome, and that an increased insulin level is a common underlying aberration that promotes both BPH and clinical prostate cancer. Urologists need to be aware of the effect that the metabolic syndrome has on urological disorders and should transfer this knowledge to their patients. PMID- 21811226 TI - Incontinence: what is the learning curve for artificial urinary sphincter surgery? PMID- 21811227 TI - Nonclamping partial nephrectomy: towards improved nephron sparing. AB - Ischemia-reperfusion injury caused by vascular clamping contributes to the decline in glomerular filtration rate following partial nephrectomy. Ischemia is the main modifiable factor that determines postoperative kidney function, and it is likely that a harmless duration of ischemia does not exist. Each additional minute of warm ischemia increases the odds of acute renal failure, severe chronic kidney disease (CKD) and end-stage renal disease. Our experience comparing partial nephrectomy with and without clamping in solitary kidneys suggests that renovascular clamping is the only statistically significant determinant of postoperative renal dysfunction. Studies comparing partial nephrectomy with and without clamping demonstrate that ischemia is associated with a risk of acute renal failure, advanced CKD, and renal replacement therapy. Oncologic outcomes and complications in partial nephrectomy without clamping are similar to those with clamping. Even in complex lesions, partial nephrectomy without vascular clamping is preferable when feasible. PMID- 21811228 TI - Time to stratify? The retinoblastoma protein in castrate-resistant prostate cancer. AB - It is generally held that the retinoblastoma (RB) tumor suppressor functions in multiple tissues to protect against tumor development. However, preclinical studies and analysis of tumor samples of early disease did not support an important role of RB loss in the origin of prostate cancer. By contrast, recent observations in the clinical setting and subsequent modeling of RB function indicate that the tumor suppressor has specialized roles in controlling androgen receptor expression in prostate cancer, and primarily functions to prevent progression to the castration-resistant stage of disease. Furthermore, preclinical models have now shown that loss of RB expression or functional activity decreases the effectiveness of hormone therapy, yet seems to increase sensitivity to a subset of chemotherapeutic agents. Here, the current state of knowledge regarding the implications of RB loss for prostate cancer progression will be reviewed, and potential opportunities for developing RB as a metric to predict therapeutic response will be considered. PMID- 21811229 TI - Metabolic network reconstruction of Chlamydomonas offers insight into light driven algal metabolism. AB - Metabolic network reconstruction encompasses existing knowledge about an organism's metabolism and genome annotation, providing a platform for omics data analysis and phenotype prediction. The model alga Chlamydomonas reinhardtii is employed to study diverse biological processes from photosynthesis to phototaxis. Recent heightened interest in this species results from an international movement to develop algal biofuels. Integrating biological and optical data, we reconstructed a genome-scale metabolic network for this alga and devised a novel light-modeling approach that enables quantitative growth prediction for a given light source, resolving wavelength and photon flux. We experimentally verified transcripts accounted for in the network and physiologically validated model function through simulation and generation of new experimental growth data, providing high confidence in network contents and predictive applications. The network offers insight into algal metabolism and potential for genetic engineering and efficient light source design, a pioneering resource for studying light-driven metabolism and quantitative systems biology. PMID- 21811230 TI - Synthetic incoherent feedforward circuits show adaptation to the amount of their genetic template. AB - Natural and synthetic biological networks must function reliably in the face of fluctuating stoichiometry of their molecular components. These fluctuations are caused in part by changes in relative expression efficiency and the DNA template amount of the network-coding genes. Gene product levels could potentially be decoupled from these changes via built-in adaptation mechanisms, thereby boosting network reliability. Here, we show that a mechanism based on an incoherent feedforward motif enables adaptive gene expression in mammalian cells. We modeled, synthesized, and tested transcriptional and post-transcriptional incoherent loops and found that in all cases the gene product adapts to changes in DNA template abundance. We also observed that the post-transcriptional form results in superior adaptation behavior, higher absolute expression levels, and lower intrinsic fluctuations. Our results support a previously hypothesized endogenous role in gene dosage compensation for such motifs and suggest that their incorporation in synthetic networks will improve their robustness and reliability. PMID- 21811231 TI - Suppressing variation in synthetic circuits. PMID- 21811232 TI - AlleleSeq: analysis of allele-specific expression and binding in a network framework. AB - To study allele-specific expression (ASE) and binding (ASB), that is, differences between the maternally and paternally derived alleles, we have developed a computational pipeline (AlleleSeq). Our pipeline initially constructs a diploid personal genome sequence (and corresponding personalized gene annotation) using genomic sequence variants (SNPs, indels, and structural variants), and then identifies allele-specific events with significant differences in the number of mapped reads between maternal and paternal alleles. There are many technical challenges in the construction and alignment of reads to a personal diploid genome sequence that we address, for example, bias of reads mapping to the reference allele. We have applied AlleleSeq to variation data for NA12878 from the 1000 Genomes Project as well as matched, deeply sequenced RNA-Seq and ChIP Seq data sets generated for this purpose. In addition to observing fairly widespread allele-specific behavior within individual functional genomic data sets (including results consistent with X-chromosome inactivation), we can study the interaction between ASE and ASB. Furthermore, we investigate the coordination between ASE and ASB from multiple transcription factors events using a regulatory network framework. Correlation analyses and network motifs show mostly coordinated ASB and ASE. PMID- 21811233 TI - Jarid2 regulates mouse epidermal stem cell activation and differentiation. AB - Jarid2 is required for the genomic recruitment of the polycomb repressive complex 2 (PRC2) in embryonic stem cells. However, its specific role during late development and adult tissues remains largely uncharacterized. Here, we show that deletion of Jarid2 in mouse epidermis reduces the proliferation and potentiates the differentiation of postnatal epidermal progenitors, without affecting epidermal development. In neonatal epidermis, Jarid2 deficiency reduces H3K27 trimethylation, a chromatin repressive mark, in epidermal differentiation genes previously shown to be targets of the PRC2. However, in adult epidermis Jarid2 depletion does not affect interfollicular epidermal differentiation but results in delayed hair follicle (HF) cycling as a consequence of decreased proliferation of HF stem cells and their progeny. We conclude that Jarid2 is required for the scheduled proliferation of epidermal stem and progenitor cells necessary to maintain epidermal homeostasis. PMID- 21811234 TI - VCIP135 deubiquitinase and its binding protein, WAC, in p97ATPase-mediated membrane fusion. AB - Two distinct p97 membrane fusion pathways are required for Golgi biogenesis: the p97/p47 and p97/p37 pathways. VCIP135 is necessary for both pathways, while its deubiquitinating activity is required only for the p97/p47 pathway. We have now identified a novel VCIP135-binding protein, WAC. WAC localizes to the Golgi as well as the nucleus. In Golgi membranes, WAC is involved in a complex containing VCIP135 and p97. WAC directly binds to VCIP135 and increases its deubiquitinating activity. siRNA experiments revealed that WAC is required for Golgi biogenesis. In an in vitro Golgi reformation assay, WAC was necessary only for p97/p47 mediated Golgi reassembly, but not for p97/p37-mediated reassembly. WAC is hence thought to function in p97/p47-mediated Golgi membrane fusion by activating the deubiquitinating function of VCIP135. We also showed that the two p97 pathways function in ER membrane fusion as well. An in vitro ER reformation assay revealed that both pathways required VCIP135 but not its deubiquitinating activity for their ER membrane fusion. This was consistent with the finding that WAC is unnecessary for p97-mediated ER membrane fusion. PMID- 21811235 TI - LUBAC regulates NF-kappaB activation upon genotoxic stress by promoting linear ubiquitination of NEMO. AB - The transcription factor nuclear factor kappaB (NF-kappaB) regulates various cellular processes such as inflammation and apoptosis. The NF-kappaB essential modulator (NEMO/IKKgamma) is indispensable for NF-kappaB activation by diverse stimuli including genotoxic stress. Here, we show that NEMO linear ubiquitination on K285/309 is critical for genotoxic NF-kappaB activation. The E3 ligase linear ubiquitin chain assembly complex (LUBAC) facilitates NEMO linear ubiquitination upon genotoxic stress. Inhibiting LUBAC function interrupts the genotoxic NF kappaB signalling cascade by attenuating the activation of IKK and TAK1 in response to DNA damage. We further show that the linear ubiquitination of NEMO is a cytoplasmic event, potentially downstream of NEMO nuclear exportation. Moreover, ELKS ubiquitination appears to facilitate linear ubiquitination of NEMO through stabilizing NEMO:LUBAC association upon DNA damage. Deubiquitinating enzyme CYLD inhibits NEMO linear ubiquitination, possibly by disassembling both K63-linked and linear polyubiquitin. We also found that abrogating linear ubiquitination of NEMO significantly increased genotoxin-induced apoptosis, resulting in enhanced sensitivity to chemodrug in cancer cells. Therefore, LUBAC dependent NEMO linear ubiquitination is critical for genotoxic NF-kappaB activation and protects cells from DNA damage-induced apoptosis. PMID- 21811236 TI - A cluster of ribosome synthesis factors regulate pre-rRNA folding and 5.8S rRNA maturation by the Rat1 exonuclease. AB - The 5'-exonuclease Rat1 degrades pre-rRNA spacer fragments and processes the 5' ends of the 5.8S and 25S rRNAs. UV crosslinking revealed multiple Rat1-binding sites across the pre-rRNA, consistent with its known functions. The major 5.8S 5' end is generated by Rat1 digestion of the internal transcribed spacer 1 (ITS1) spacer from cleavage site A(3). Processing from A(3) requires the 'A(3)-cluster' proteins, including Cic1, Erb1, Nop7, Nop12 and Nop15, which show interdependent pre-rRNA binding. Surprisingly, A(3)-cluster factors were not crosslinked close to site A(3), but bound sites around the 5.8S 3'- and 25S 5'-regions, which are base paired in mature ribosomes, and in the ITS2 spacer that separates these rRNAs. In contrast, Nop4, a protein required for endonucleolytic cleavage in ITS1, binds the pre-rRNA near the 5'-end of 5.8S. ITS2 was reported to undergo structural remodelling. In vivo chemical probing indicates that A(3)-cluster binding is required for this reorganization, potentially regulating the timing of processing. We predict that Nop4 and the A(3) cluster establish long-range interactions between the 5.8S and 25S rRNAs, which are subsequently maintained by ribosomal protein binding. PMID- 21811237 TI - Structural mechanisms of DIAP1 auto-inhibition and DIAP1-mediated inhibition of drICE. AB - The Drosophila inhibitor of apoptosis protein DIAP1 exists in an auto-inhibited conformation, unable to suppress the effector caspase drICE. Auto-inhibition is disabled by caspase-mediated cleavage of DIAP1 after Asp20. The cleaved DIAP1 binds to mature drICE, inhibits its protease activity, and, presumably, also targets drICE for ubiquitylation. DIAP1-mediated suppression of drICE is effectively antagonized by the pro-apoptotic proteins Reaper, Hid, and Grim (RHG). Despite rigorous effort, the molecular mechanisms behind these observations are enigmatic. Here we report a 2.4 A crystal structure of uncleaved DIAP1-BIR1, which reveals how the amino-terminal sequences recognize a conserved surface groove in BIR1 to achieve auto-inhibition, and a 3.5 A crystal structure of active drICE bound to cleaved DIAP1-BIR1, which provides a structural explanation to DIAP1-mediated inhibition of drICE. These structures and associated biochemical analyses, together with published reports, define the molecular determinants that govern the interplay among DIAP1, drICE and the RHG proteins. PMID- 21811238 TI - Advantageous grain boundaries in iron pnictide superconductors. AB - High critical temperature superconductors have zero power consumption and could be used to produce ideal electric power lines. The principal obstacle in fabricating superconducting wires and tapes is grain boundaries-the misalignment of crystalline orientations at grain boundaries, which is unavoidable for polycrystals, largely deteriorates critical current density. Here we report that high critical temperature iron pnictide superconductors have advantages over cuprates with respect to these grain boundary issues. The transport properties through well-defined bicrystal grain boundary junctions with various misorientation angles (theta(GB)) were systematically investigated for cobalt doped BaFe(2)As(2) (BaFe(2)As(2):Co) epitaxial films fabricated on bicrystal substrates. The critical current density through bicrystal grain boundary (J(c)(BGB)) remained high (>1 MA cm(-2)) and nearly constant up to a critical angle theta(c) of ~9 degrees , which is substantially larger than the theta(c) of ~5 degrees for YBa(2)Cu(3)O(7-delta). Even at theta(GB)>theta(c), the decay of J(c)(BGB) was much slower than that of YBa(2)Cu(3)O(7-delta). PMID- 21811239 TI - Relative comparisons of call parameters enable auditory grouping in frogs. AB - Whereas many studies on mate choice have measured the relative attractiveness of acoustic sexual signals, there is little understanding of another critical process: grouping and assigning the signals to their sources. For female tungara frogs, assigning the distinct components of male calls to the correct source is a challenge because males sing in aggregations, producing overlapping calls that lead to perceptual errors analogous to those of the 'cocktail party problem'. Here we show that for presentation of >2 call components, however, subjects are more likely to group the two components with the smallest relative differences in call parameters, including relative spatial separation (a primitive acoustic cue) and relative similarity to the species-specific call sequence (a schema-based cue). Thus, like humans, the cognitive rules for the perception of auditory groups amidst multiple sound sources include the use of relative comparisons, a flexible strategy for dynamic acoustic environments. PMID- 21811240 TI - No extension of quantum theory can have improved predictive power. AB - According to quantum theory, measurements generate random outcomes, in stark contrast with classical mechanics. This raises the question of whether there could exist an extension of the theory that removes this indeterminism, as suspected by Einstein, Podolsky and Rosen. Although this has been shown to be impossible, existing results do not imply that the current theory is maximally informative. Here we ask the more general question of whether any improved predictions can be achieved by any extension of quantum theory. Under the assumption that measurements can be chosen freely, we answer this question in the negative: no extension of quantum theory can give more information about the outcomes of future measurements than quantum theory itself. Our result has significance for the foundations of quantum mechanics, as well as applications to tasks that exploit the inherent randomness in quantum theory, such as quantum cryptography. PMID- 21811241 TI - Silver hake tracks changes in Northwest Atlantic circulation. AB - Recent studies documenting shifts in spatial distribution of many organisms in response to a warming climate highlight the need to understand the mechanisms underlying species distribution at large spatial scales. Here we present one noteworthy example of remote oceanographic processes governing the spatial distribution of adult silver hake, Merluccius bilinearis, a commercially important fish in the Northeast US shelf region. Changes in spatial distribution of silver hake over the last 40 years are highly correlated with the position of the Gulf Stream. These changes in distribution are in direct response to local changes in bottom temperature on the continental shelf that are responding to the same large scale circulation change affecting the Gulf Stream path, namely changes in the Atlantic meridional overturning circulation (AMOC). If the AMOC weakens, as is suggested by global climate models, silver hake distribution will remain in a poleward position, the extent to which could be forecast at both decadal and multidecadal scales. PMID- 21811242 TI - Adding control to arbitrary unknown quantum operations. AB - Although quantum computers promise significant advantages, the complexity of quantum algorithms remains a major technological obstacle. We have developed and demonstrated an architecture-independent technique that simplifies adding control qubits to arbitrary quantum operations-a requirement in many quantum algorithms, simulations and metrology. The technique, which is independent of how the operation is done, does not require knowledge of what the operation is, and largely separates the problems of how to implement a quantum operation in the laboratory and how to add a control. Here, we demonstrate an entanglement-based version in a photonic system, realizing a range of different two-qubit gates with high fidelity. PMID- 21811243 TI - Regulation of MITF stability by the USP13 deubiquitinase. AB - The microphthalmia-associated transcription factor (MITF) is essential for melanocyte development. Mutation-induced MAPK pathway activation is common in melanoma and induces MITF phosphorylation, ubiquitination, and proteolysis. Little is known about the enzymes involved in MITF ubiquitination/deubiquitination. Here we report the identification of a deubiquitinating enzyme, named ubiquitin-specific protease 13 (USP13) that appears to be responsible for MITF deubiquitination, utilizing a short hairpin RNA library against known deubiquitinating enzymes. Through deubiquitination, USP13 stabilizes and upregulates MITF protein levels. Conversely, suppression of USP13 (through knockdown) leads to dramatic loss of MITF protein, but not messenger RNA. Through its effects on MITF deubiquitination, USP13 was observed to modulate expression of MITF downstream target genes and, thereby, to be essential for melanoma growth in soft agar and in nude mice. These observations suggest that as a potentially drugable protease, USP13 might be a viable therapeutic target for melanoma. PMID- 21811244 TI - Local BMP receptor activation at adherens junctions in the Drosophila germline stem cell niche. AB - According to the stem cell niche synapse hypothesis postulated for the mammalian haematopoietic system, spatial specificity of niche signals is maximized by subcellularly restricting signalling to cadherin-based adherens junctions between individual niche and stem cells. However, such a synapse has never been observed directly, in part, because tools to detect active growth factor receptors with subcellular resolution were not available. Here we describe a novel fluorescence based reporter that directly visualizes bone morphogenetic protein (BMP) receptor activation and show that in the Drosophila testis a BMP niche signal is transmitted preferentially at adherens junctions between hub and germline stem cells, resembling the proposed synapse organization. Ligand secretion involves the exocyst complex and the Rap activator Gef26, both of which are also required for Cadherin trafficking towards adherens junctions. We, therefore, propose that local generation of the BMP signal is achieved through shared use of the Cadherin transport machinery. PMID- 21811245 TI - Iron-based cathode catalyst with enhanced power density in polymer electrolyte membrane fuel cells. AB - H(2)-air polymer-electrolyte-membrane fuel cells are electrochemical power generators with potential vehicle propulsion applications. To help reduce their cost and encourage widespread use, research has focused on replacing the expensive Pt-based electrocatalysts in polymer-electrolyte-membrane fuel cells with a lower-cost alternative. Fe-based cathode catalysts are promising contenders, but their power density has been low compared with Pt-based cathodes, largely due to poor mass-transport properties. Here we report an iron acetate/phenanthroline/zeolitic-imidazolate-framework-derived electrocatalyst with increased volumetric activity and enhanced mass-transport properties. The zeolitic-imidazolate-framework serves as a microporous host for phenanthroline and ferrous acetate to form a catalyst precursor that is subsequently heat treated. A cathode made with the best electrocatalyst from this work, tested in H(2)-O(2,) has a power density of 0.75 W cm(-2) at 0.6 V, a meaningful voltage for polymer-electrolyte-membrane fuel cells operation, comparable with that of a commercial Pt-based cathode tested under identical conditions. PMID- 21811246 TI - AAV-microdystrophin therapy improves cardiac performance in aged female mdx mice. AB - Dystrophin deficiency leads to lethal dilated Duchenne cardiomyopathy. A promising therapy is to deliver a highly abbreviated microdystrophin gene to the heart using adeno-associated virus (AAV). Microdystrophin has been shown to mitigate dystrophin-deficient skeletal muscle disease. However, it is not clear whether microdystrophin is equally effective in treating Duchenne cardiomyopathy. To evaluate microdystrophin therapy in the heart, we injected 5 * 10(12) viral genome particles/mouse of AAV-9 DeltaR4-23/DeltaC microdystrophin vector via tail vein to ~16-20-month-old (average 18.7-month-old) female mdx mice, a manifesting model of Duchenne cardiomyopathy. Cardiac transduction and heart function were examined at 2-8 months after gene transfer. We observed robust myocardial microdystrophin expression. Electrocardiography (ECG) and left ventricular catheter hemodynamic assays also revealed significant improvement. Furthermore, AAV-microdystrophin therapy prevented dobutamine-stress induced acute cardiac death. We demonstrate for the first time that AAV microdystrophin therapy significantly ameliorates functional deficiency in a phenotypic model of Duchenne cardiomyopathy. Our results support further exploration of microdystrophin therapy to treat Duchenne cardiomyopathy. PMID- 21811247 TI - Systemic gene delivery in large species for targeting spinal cord, brain, and peripheral tissues for pediatric disorders. AB - Adeno-associated virus type 9 (AAV9) is a powerful tool for delivering genes throughout the central nervous system (CNS) following intravenous injection. Preclinical results in pediatric models of spinal muscular atrophy (SMA) and lysosomal storage disorders provide a compelling case for advancing AAV9 to the clinic. An important translational step is to demonstrate efficient CNS targeting in large animals at various ages. In the present study, we tested systemically injected AAV9 in cynomolgus macaques, administered at birth through 3 years of age for targeting CNS and peripheral tissues. We show that AAV9 was efficient at crossing the blood-brain barrier (BBB) at all time points investigated. Transgene expression was detected primarily in glial cells throughout the brain, dorsal root ganglia neurons and motor neurons within the spinal cord, providing confidence for translation to SMA patients. Systemic injection also efficiently targeted skeletal muscle and peripheral organs. To specifically target the CNS, we explored AAV9 delivery to cerebrospinal fluid (CSF). CSF injection efficiently targeted motor neurons, and restricted gene expression to the CNS, providing an alternate delivery route and potentially lower manufacturing requirements for older, larger patients. Our findings support the use of AAV9 for gene transfer to the CNS for disorders in pediatric populations. PMID- 21811248 TI - AAV8-mediated hepatic gene transfer in infant rhesus monkeys (Macaca mulatta). AB - Many genetic metabolic diseases manifest in infancy, therefore, it is important to develop effective treatments that could be implemented at this time. Adeno associated virus serotype 8 (AAV8) gene transfer has been studied in neonatal mouse, cat, and dog models and shown some efficacy with a single hepatic injection at birth. AAV8-mediated liver gene transfer has also generated sustained therapeutic effects in feline and canine models of lysosomal storage disorders. In these models, delaying the age of vector treatment increased gene transfer stability. The growth rate of infant nonhuman primates is more similar to the growth trajectory of humans, thus infant monkeys provide an excellent model to study AAV gene transfer efficiency, stability, and safety. In this study, we report for the first time that AAV8-mediated hepatic gene transfer in infant monkeys is safe and efficient but less stable when compared to adolescent animals. Infant monkeys administered AAV8 intravenously at 1 week postnatal age achieved up to 98% transduction of hepatocytes within 7 days of injection; however, there was significant dilution of genomes and loss of transgene expression 35 days postadministration. Delaying the injection to 1 month postnatal age did not improve stability of transduction but decreased the antibody response to AAV8 capsid. PMID- 21811249 TI - Alternative for anti-TNF antibodies for arthritis treatment. AB - Tumor necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine, plays a key role in the pathogenesis of many inflammatory diseases, including arthritis. Neutralization of this cytokine by anti-TNF-alpha antibodies has shown its efficacy in rheumatoid arthritis (RA) and is now widely used. Nevertheless, some patients currently treated with anti-TNF-alpha remain refractory or become nonresponder to these treatments. In this context, there is a need for new or complementary therapeutic strategies. In this study, we investigated in vitro and in vivo anti-inflammatory potentialities of an anti-TNF-alpha triplex-forming oligonucleotide (TFO), as judged from effects on two rat arthritis models. The inhibitory activity of this TFO on articular cells (synoviocytes and chondrocytes) was verified and compared to that of small interfering RNA (siRNA) in vitro. The use of the anti-TNF-alpha TFO as a preventive and local treatment in both acute and chronic arthritis models significantly reduced disease development. Furthermore, the TFO efficiently blocked synovitis and cartilage and bone destruction in the joints. The results presented here provide the first evidence that gene targeting by anti-TNF-alpha TFO modulates arthritis in vivo, thus providing proof-of-concept that it could be used as therapeutic tool for TNF alpha-dependent inflammatory disorders. PMID- 21811250 TI - Short-time repeat high-risk HPV testing by self-sampling for screening of cervical cancer. AB - BACKGROUND: Testing for high-risk human papillomavirus (HPV) in primary screening for cervical cancer is considered more sensitive, but less specific, in comparison with Pap-smear cytology. Women with persistent HPV infections have a higher risk of developing cervical intraepithelial neoplasia 2+ (CIN2+) lesions. This study was performed to evaluate the gain in specificity for detection of histologically confirmed CIN2+ lesions achieved by short-time repeat testing for high-risk HPV in women aged 30-65 years, with the primary sample for HPV analysis taken by self-sampling. METHODS: A total of 8000 women in Uppsala County, aged 30 65 years, who had not attended organised screening for 6 years or longer, were offered self-sampling of vaginal fluid at home and the samples sent for HPV typing. Of these, 8% (669) were not possible to contact or had performed hysterectomy. Women positive for high-risk HPV in the self-sampling test were invited for a follow-up HPV test and a cervical biopsy on average 3 months after the initial HPV test. RESULTS: In all, 39% (2850/7331) of invited women chose to perform self-sampling of vaginal fluid at home. High-risk HPV infection was found in 6.6% (188) of the women. In all, 89% of the women testing HPV positive performed a follow-up examination, on average 2.7 months, after the first test and 59% of these women were HPV positive in the follow-up test. The prevalence of CIN2+ lesions in women with an initial HPV-positive test was 23% (95% CI 18-30%) and in women with two consecutive HPV-positive tests was 41% (95% CI 31-51%). In women with two positive HPV tests, the prevalence of CIN2+ lesions varied from 49% in women at age 30-39 years to 24% in women at age 50-65 years. Short-time repeat HPV testing increased the specificity for detection of CIN2+ lesions from about 94.2% to 97.8%. The most prevalent HPV types were HPV16 (32%), followed by HPV18/45 (19%) and HPV 33/52/58 (19%). CONCLUSION: The short-time persistence of high-risk HPV infection in this age group was about 60%. Repeat testing for high risk HPV using self-sampling of vaginal fluid can be used to increase the specificity in the screening for cervical cancer in women aged 30-65 years. PMID- 21811251 TI - Dual inhibition of epidermal growth factor and insulin-like 1 growth factor receptors reduce intestinal adenoma burden in the Apc(min/+) mouse. AB - BACKGROUND: Identification of early molecular pathway changes may be useful as biomarkers for tumour response/resistance prediction, and here we provide direct in vivo proof of this concept. The type 1 insulin-like growth factor receptor (IGF1R) has been implicated in various aspects of adenoma development and metastasis. We show here that, in murine intestinal adenomas acutely exposed to a small molecular inhibitor of EGFR (gefitinib), there is concurrent suppression of EGFR downstream signalling and induction of IGF signalling. We therefore tested the hypothesis that blockade of EGFR signalling was being tempered by compensatory activation of the IGF pathway by examining the effect of chronic suppression of IGF1R using AZ12253801, a small molecular tyrosine kinase inhibitor of IGF1R. METHODS: Male Apc(min/+) mice with an intestinal tumour burden were exposed to a single dose of an inhibitor against EGFR (gefitinib), IGF1R (AZ12253801), 0.5% Tween 80 or combined EGFR/IGF1R inhibitor and culled 4 h post dosing. Tumour tissue was analysed to detect the early molecular pathways induced and anti-tumour phenotypic changes. Cohorts of male Apc(min/+) mice (n=15 17) were subsequently treated with gefitinib for a period of 8 weeks and subsequently exposed to single (either gefitinib or AZ12253801) or combined (gefitinib and AZ12253801) therapy. We also included a vehicle-treated cohort, which was never exposed to gefitinib and became symptomatic of the disease by day 150. RESULTS: Both single treatments delayed the onset of disease symptoms. Combined dosing with gefitinib and AZ12253801 similarly delayed the onset of symptoms, and at 200 days suppressed small intestinal tumourigenesis more effectively than either treatment alone (median small intestinal adenoma volume (47 mm(3) (comb) vs 248 mm(3) (AZ12253801), P=0.0003 and 47 mm(3) (comb) vs 123 mm(3) (gefitinib), P=0.0042, Mann-Whitney (two-sided) test). CONCLUSION: Our data provide evidence in support of the use of combinatorial therapy, and establishes the need to further define the precise benefit in vivo. PMID- 21811252 TI - Joint effects of nulliparity and other breast cancer risk factors. AB - BACKGROUND: Pregnancy may reduce breast cancer risk through induction of persistent changes of the mammary gland that make the breast less susceptible to carcinogenic factors. It is not known to what extent the effects of parity are independent of other breast cancer risk factors. METHODS: In a Norwegian cohort of 58 191 women (2890 breast cancers), we assessed whether the effects of parity on postmenopausal breast cancer risk may be modified by menstrual and anthropometric factors. We calculated attributable proportions due to interaction as a measure of synergism. RESULTS: Parity, height, body mass index (BMI), age at menarche and menopause were all associated with breast cancer risk in the expected directions. For BMI, follow-up was stratified into two age groups because of non-proportional hazards. We found that nulliparity and overweight may amplify each other's effect on breast cancer risk among women after 70 years of age (attributable proportion 0.21, 95% confidence interval 0.04-0.39). There was some indication that parity and age at menopause may antagonise each other's effect. Effects of parity were largely unaffected by age at menarche and height. CONCLUSION: Nulliparity and overweight may have a synergistic effect on breast cancer risk in elderly women. If confirmed by others, the findings may help disentangle the interplay of different causes of breast cancer. PMID- 21811253 TI - Prognostic evaluation of febrile neutropenia in apparently stable adult cancer patients. AB - ' BACKGROUND: Predictive models to identify low-risk febrile neutropenia (FN) have been developed with heterogeneous samples, which included stable and unstable patients, solid tumours, acute leukaemia and bone marrow transplantation. These models fail to recognise 5-15% of cases with unexpected complications, and literature specifically addressing apparently stable patients (ASPs) is scarce. METHODS: We reviewed 861 episodes of FN in outpatients with solid tumours, including 692 (80%) episodes with apparent clinical stability. We aimed to investigate the prognosis of this latter group and explore the possibility of stratifying it according to the presenting features. A case control study was performed and the MASCC index was evaluated. RESULTS: The rates of complications and bacteraemia in ASPs were 7.3% and 6.2%, respectively. The MASCC index yielded a low sensitivity to detect complications (36%). Prognostic factors were identified: ECOG performance status >=2, chronic bronchitis, chronic heart failure, stomatitis NCI grade >=2, monocytes <200 mm(-3) and stress hyperglycaemia. CONCLUSION: A very simple assessment is useful to classify the patients with FN according to the risk of complications. A few additional variables may predict the clinical course of the patients. We additionally show that the MASCC index applied to this specific group has a low sensitivity to predict complications. PMID- 21811254 TI - Generation and evaluation of a monoclonal antibody, designated MAdL, as a new specific marker for adenocarcinomas of the lung. AB - BACKGROUND: Different therapy regimens in non-small-cell lung cancer (NSCLC) are of rising clinical importance, and therefore a clear-cut subdifferentiation is mandatory. The common immunohistochemical markers available today are well applicable for subdifferentiation, but a fraction of indistinct cases still remains, demanding upgrades of the panel by new markers. METHODS: We report here the generation and evaluation of a new monoclonal antibody carrying the MAdL designation, which was raised against primary isolated human alveolar epithelial cells type 2. RESULTS: Upon screening, one clone (MAdL) was identified as a marker for alveolar epithelial cell type II, alveolar macrophages and adenocarcinomas of the lung. In a large-scale study, this antibody, with an optimised staining procedure for formalin-fixed tissues, was then evaluated together with the established markers thyroid transcription factor-1, surfactant protein-A, pro-surfactant protein-B and napsin A in a series of 362 lung cancer specimens. The MAdL displays a high specificity (>99%) for adenocarcinomas of the lung, together with a sensitivity of 76.5%, and is capable of delivering independent additional diagnostic information to the established markers. CONCLUSION: We conclude that MAdL is a new specific marker for adenocarcinomas of the lung, which helps to clarify subdifferentiation in a considerable portion of NSCLCs. PMID- 21811255 TI - A two-phase case-control study for colorectal cancer genetic susceptibility: candidate genes from chromosomal regions 9q22 and 3q22. AB - BACKGROUND: Colorectal cancer (CRC) is the second cause of cancer-related death in the Western world. Much of the CRC genetic risk remains unidentified and may be attributable to a large number of common, low-penetrance genetic variants. Genetic linkage studies in CRC families have reported additional association with regions 9q22-31, 3q21-24, 7q31, 11q, 14q and 22q. There are several plausible candidate genes for CRC susceptibility within the aforementioned linkage regions including PTCH1, XPA and TGFBR1 in 9q22-31, and EPHB1 and MRAS in 3q21-q24. METHODS: CRC cases and matched controls were from EPICOLON, a prospective, multicentre, nationwide Spanish initiative, composed of two independent phases. Phase 1 corresponded to 515 CRC cases and 515 controls, whereas phase 2 consisted of 901 CRC cases and 909 controls. Genotyping was performed for 172 single nucleotide polymorphisms (SNPs) in 84 genes located within regions 9q22-31 and 3q21-q24. RESULTS: None of the 172 SNPs analysed in our study could be formally associated with CRC risk. However, rs1444601 (TOPBP1) and rs13088006 (CDV3) in region 3q22 showed interesting results and may have an effect on CRC risk. CONCLUSIONS: TOPBP1 and CDV3 genetic variants on region 3q22 may modulate CRC risk. Further validation and meta-analysis should be undertaken in larger CRC cohorts. PMID- 21811256 TI - Modified primary tumour/vessel tumour/nodal tumour classification for patients with invasive ductal carcinoma of the breast. AB - BACKGROUND: We previously reported that the primary tumour/vessel tumour/nodal tumour (PVN) classification is significantly superior to the UICC pTNM classification and the Nottingham Prognostic Index for accurately predicting the outcome of patients with invasive ductal carcinoma of the breast in a manner that is independent of the nodal status and the hormone receptor status. METHODS: The purpose of the present study was to compare the outcome predictive power of a modified PVN classification to that of the newly devised pathological UICC pTNM classification and the reclassified Nottingham Prognostic Index in a different group of patients with invasive ductal carcinoma (n=1042) using multivariate analyses by the Cox proportional hazard regression model. RESULTS: The modified PVN classification clearly exhibited a superior significant power, compared with the other classifications, for the accurate prediction of tumour recurrence and tumour-related death among patients with invasive ductal carcinoma in a manner that was independent of the nodal status, the hormone receptor status, and adjuvant therapy status. CONCLUSION: The modified PVN classification is a useful classification system for predicting the outcome of invasive ductal carcinoma of the breast. PMID- 21811257 TI - Inhibition of DNA repair with MGMT pseudosubstrates: phase I study of lomeguatrib in combination with dacarbazine in patients with advanced melanoma and other solid tumours. AB - BACKGROUND: The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) reverses the O6-methylguanine (O6-meG) lesion induced by dacarbazine. Depletion of MGMT can be achieved using O6-meG pseudosubstrates. Herein, we report the first phase I experience of the novel O6-meG pseudosubstrate lomeguatrib, combined with dacarbazine. METHODS: This is a phase I dose-escalation study to determine the maximum tolerated dose and recommended phase II dose (RP2D) of lomeguatrib combined with a single dose of dacarbazine on a 21-day schedule. RESULTS: The vast majority of the 41 patients enrolled had metastatic melanoma (36/41) and most had no previous chemotherapy (30/41). The most frequent non hematological adverse events (AEs) were nausea (52%), and fatigue (42%). The most frequent AEs of grade 3-4 severity were neutropaenia (42%), leukopaenia (17%), and thrombocytopaenia (12%). Only 1 patient had a partial response and 10 patients had stable disease. CONCLUSION: The RP2D of lomeguatrib was 40 mg orally twice daily for 10 days combined with 400 mg m(-2) of dacarbazine IV on day 2. Oral administration of lomeguatrib substantially increases the haematological toxicity of dacarbazine consistent with experience with other O6-meG pseudosubstrates. PMID- 21811259 TI - Molecular basis for the actions of Hsp90 inhibitors and cancer therapy. AB - Heat-shock protein 90 (Hsp90) inhibitor downregulates c-Myc expression and upregulates the expression of tumor repressor proteins such as p53 and pRB, inhibiting the G1/S transition and causing G2/M arrest during cell cycle progression. The cycle progression is extensively controlled by the pRB/E2F signaling pathway. E2F is released from the pRB/E2F complex with the phosphorylation of pRB by cyclin-cyclin-dependent kinase (CDK) complexes. The released E2F promotes the transcription of target genes involved in cell cycle progression. The pRB/E2F signaling pathway is controlled by DNA methyltransferase 1 (Dnmt-1). The elevated expression of Dnmt-1 has been reported in carcinomas of the colon, lung and prostate. A defect of pRB expression in Rb -/- cancer cells is caused by the aberrant methylation of CpG in the Rb promoter. The Hsp90 inhibitor disrupts the Dnmt-1/Hsp90 association and upregulates pRB expression. In this review, the Hsp90 inhibitors that show promise for cancer therapy are summarized. PMID- 21811260 TI - Structural characterization of the tobramycin-piperacillin reaction product formed at pH 6.0. AB - Tobramycin is an aminoglycoside antibiotic that loses a significant amount of activity in the presence of Zosyn at pH 6. As part of our investigation into ways to improve the compatibility of tobramycin with Zosyn (which contains piperacillin and tazobactam in an 8:1 ratio buffered at pH 6 by sodium citrate) by lowering the pH, we identified the reaction product of tobramycin and piperacillin at pH 6.0 and the order of the pK(a) values of tobramycin. The structure of the main reaction product of tobramycin and piperacillin at pH 6.0 was determined by 2D NMR to be the product of 3"-NH(2) reacting with the beta lactam of piperacillin. The order of the pK(a) values of the nitrogens of tobramycin was determined by (1)H and (15)N NMR titrations to be 6'-NH(2)>2' NH(2)>1-NH(2)~3"-NH(2)>3-NH(2). At pH 4.0, the reaction between tobramycin and Zosyn was almost negligible for a period of up to 2 h. The pH can be lowered by adding an acid such as HCl or citric acid to Zosyn to make a pH 4.0 buffer. PMID- 21811258 TI - Phase II trial of modified FOLFOX6 and erlotinib in patients with metastatic or advanced adenocarcinoma of the oesophagus and gastro-oesophageal junction. AB - BACKGROUND: There is increased recognition that cancers of the upper GI tract comprise distinct epidemiological and molecular entities. Erlotinib has shown activity in patients with adenocarcinoma of the oesophagus/gastro-oesophageal junction (GEJ), but not in distal gastric cancer. mFOLFOX6 is one of several active regimens used to treat adenocarcinoma of the Eso/GEJ. This study evaluates the efficacy and safety of mFOLFOX6 and erlotinib in patients with metastatic or advanced Eso/GEJ cancers. METHODS: Patients with previously untreated advanced or metastatic Eso/GEJ adenocarcinoma are treated with oxaliplatin 85 mg m(-2), 5-FU 400 mg m(-2), LV 400 mg m(-2) on day 1, 5-FU 2400 mg m(-2) over 48 h and erlotinib 150 mg PO daily. Treatment was repeated every 14 days. The primary objective was response rate (RR), secondary objectives include toxicity, progression-free survival (PFS), overall survival (OS) and to correlate clinical outcome with expression patterns and molecular alterations in the epidermal growth factor receptor-dependent pathways. RESULTS: A total of 33 patients were treated and evaluable: there were two complete responses, 15 partial responses for an objective RR of 51.5% (95% CI, 34.5-68.6%). Median PFS was 5.5 months (95% CI, 3.1-7.5 months) and median OS was 11.0 months (95% CI, 8.0-17.4 months). The most common grade 3-4 toxicities were: diarrhoea (24%), nausea/vomiting (11%), skin rash (8%) and peripheral neuropathy (8%). The frequency of alterations was KRAS mutations (8%), EGFR mutations (0%) and HER2 amplification (19%). CONCLUSION: In patients with Eso/GEJ adenocarcinoma, mFOLFOX6 and erlotinib is active, has an acceptable toxicity profile and FOLFOX +/- erlotinib could be considered for further development. PMID- 21811261 TI - One-step syntheses of nitrofuranyl benzimidazoles that are active against multidrug-resistant bacteria. AB - Nitrofuranyl benzimidazoles can be made in one synthetic step from commercially available starting materials. The compounds displayed unexpected antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci with MICs as low as 1 MUg ml(-1). PMID- 21811262 TI - Flexivirga alba gen. nov., sp. nov., an actinobacterial taxon in the family Dermacoccaceae. AB - A novel actinobacterial strain ST13(T) isolated from soil near wastewater treatment facilities of an electroplating plant was subjected to a polyphasic taxonomic study. Cells of this organism were non-sporulating, and were irregular coccoid to comma shaped. The peptidoglycan of strain ST13(T) contained glutamic acid, serine, alanine, glycine and lysine, and represented the peptidoglycan type A4alpha. The whole-cell sugars contained ribose, glucose, galactose, rhamnose and mannose. The predominant menaquinone was MK-8(H(4)). The major fatty acid was iso C(16:0). The polar lipid contained phosphatidylglycerol. The DNA G+C content was 67.4 mol%. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain ST13(T) fell within the radius of the family Dermacoccaceae, and its closest neighbor was Luteipulveratus mongoliensis MN07-A0370(T) (95.1%). However, strain ST13(T) did not make a coherent clade with members of the recognized organisms. On the basis of the phylogenetic and phenotypic characteristics of this actinobacterium, a novel genus and species, Flexivirga alba gen. nov., sp. nov., is proposed. The type strain of F. alba is ST13(T) (= NBRC 107580(T) = DSM 24460(T)). PMID- 21811263 TI - Khatmiamycin, a motility inhibitor and zoosporicide against the grapevine downy mildew pathogen Plasmopara viticola from Streptomyces sp. ANK313. AB - In the course of our screening for anti-peronosporomycetal agents, we isolated a new compound khatmiamycin (1), together with five known metabolites, GTRI-02 (3), 4-ethyl-5-methyl-heptanamide (4), aloesaponarin II (5), LL-C10037alpha (6) and LL C10037beta (7) from the culture broth of a terrestrial Streptomyces sp. ANK313. The structures of these metabolites were assigned on the basis of their spectroscopic data. Khatmiamycin (1) exhibited potent motility inhibitory (100%) and lytic (83+/-7%) activities against zoospores of the grapevine downy mildew pathogen Plasmopara viticola at 10 MUg ml(-1), followed by compounds 5 (MIC 25 MUg ml(-1)), 7, 6, 3 in the order of decreasing activity. Khatmiamycin (1) also showed potent antibacterial activity against Staphylococcus aureus and Streptomyces viridochromogenes (Tu57) by causing inhibition zones of 11 and 14 mm diameter, respectively, at the dose of 40 MUg per disk. This is the first report on motility inhibitory and lytic activities of metabolites from a terrestrial Streptomyces species against the zoospores of downy mildew pathogen P. viticola. PMID- 21811264 TI - Recent advances in materials for extended-release antibiotic delivery system. AB - To maintain antimicrobial activity, frequent administration of conventional formulations of many antibiotics with short half-life is necessary. Otherwise, concentration under MIC occurs frequently in the course of anti-infective treatment, which induces antibiotic resistance. By maintaining a constant plasma drug concentration over MIC for a prolonged period, extended-release dosage forms maximize the therapeutic effect of antibiotics while minimizing antibiotic resistance. Another undoubted advantage of extended-release formulation is improved patient compliance. For better release properties, many materials have been introduced into the matrix and coating extended-release system in the past few years. Materials that have been widely used in industry are hydrophilic matrix materials such as hydroxypropylmethylcellulose. The excellent biocompatibility and extensive laboratory studies provide biodegradable polymers great potential for industrial applications. In addition, it seems like the researches on tailored materials that are obtained by chemical modification of the existing materials or combination of different carriers in physical mixtures have a long way to go. Meanwhile, with the development of polymers and inorganic porous nanocarriers, nanotechnology is applied increasingly for the extended delivery of antibiotics. This review highlights the development of materials used in extended-release formulation and nanoparticles for antibiotic delivery. We also provide an overview of the antibiotic extended-release products that have provided clinical benefit or are undergoing the clinical trial. PMID- 21811265 TI - Synthesis and in vitro antibacterial activity of new meropenem analogs. PMID- 21811266 TI - Isolation of a novel macrocyclic dilactone-JBIR-101-from Promicromonospora sp. RL26. PMID- 21811269 TI - Observing handoffs and telephone management in GI fellowship training. AB - OBJECTIVES: Gastroenterology (GI) training programs are mandated to teach fellows interpersonal communication and professionalism as basic competencies. We sought to assess important skill sets used by our fellows but not formally observed or measured: handoffs, telephone management, and note writing. We designed an Observed Standardized Clinical Examination (OSCE) form and provided the faculty with checklists to rate fellows' performance on specific criteria. METHODS: We created two new scenarios: a handoff between a tired overnight senior fellow on call and a more junior fellow, and a telephone management case of an ulcerative colitis flare. Fellows wrote a progress notes documenting the encounters. To add educational value, we gave the participants references about handoff communication. Four OSCE stations-handoff communication, telephone management, informed consent, and delivering bad news-were completed by fellows and observed by faculty. RESULTS: Eight faculty members and eight fellows from four GI training programs participated. All the fellows agreed that handoffs can be important learning opportunities and can be improved if they are structured, and that handoff skills can improve with practice. CONCLUSIONS: OSCEs can serve as practicums for assessing complex skill sets such as handoff communication and telephone management. PMID- 21811270 TI - Minimal hepatic encephalopathy and driving: is the genie out of the bottle? PMID- 21811271 TI - Images of the month. PMID- 21811276 TI - Editorial: Celiac disease in Turkey: lessons from the fertile crescent. AB - Celiac disease (CD) is as frequent in Turkey as in Western countries. This finding challenges old theories hypothesizing a selective effect of agriculture spreading on the predisposition to develop CD. Despite the availability of reliable serological tests, e.g., the anti-transglutaminase and antiendomysial antibodies, gray areas of CD diagnosis are increasingly encountered in clinical practice. The diagnostic process must take into consideration the antibody level. The small intestinal biopsy is not the gold standard but one of the important investigations of the diagnostic paraphernalia. New evidence-based guidelines for CD diagnosis are urgently needed for both children and adults. PMID- 21811277 TI - A case for restructuring internal medicine training. PMID- 21811278 TI - Transplant hepatology training for board certification: 6 months during internal medicine residency and 6 months during gastroenterology fellowship? PMID- 21811280 TI - The relevance of reflux monitoring off therapy. PMID- 21811282 TI - Narrow band imaging features and pathological correlations of sessile serrated polyps. PMID- 21811283 TI - Hemoclip-reinforced and EUS-assisted band ligation as an effective and safe technique to treat small GISTs in the gastric fundus. PMID- 21811284 TI - Distribution of FIT results among patients with normal colonoscopy and colorectal neoplasia. PMID- 21811285 TI - Definitive clearance of a chronic hepatitis E virus infection with ribavirin treatment. PMID- 21811288 TI - Partitioning of physiological noise signals in the brain with concurrent near infrared spectroscopy and fMRI. AB - The blood-oxygen level dependent (BOLD) signals measured by functional magnetic resonance imaging (fMRI) are contaminated with noise from various physiological processes, such as spontaneous low-frequency oscillations (LFOs), respiration, and cardiac pulsation. These processes are coupled to the BOLD signal by different mechanisms, and represent variations with very different frequency content; however, because of the low sampling rate of fMRI, these signals are generally not separable by frequency, as the cardiac and respiratory waveforms alias into the LFO band. In this study, we investigated the spatial and temporal characteristics of the individual noise processes by conducting concurrent near infrared spectroscopy (NIRS) and fMRI studies on six subjects during a resting state acquisition. Three time series corresponding to LFO, respiration, and cardiac pulsation were extracted by frequency from the NIRS signal (which has sufficient temporal resolution to critically sample the cardiac waveform) and used as regressors in a BOLD fMRI analysis. Our results suggest that LFO and cardiac signals modulate the BOLD signal independently through the circulatory system. The spatiotemporal evolution of the LFO signal in the BOLD data correlates with the global cerebral blood flow. Near-infrared spectroscopy can be used to partition these contributing factors and independently determine their contribution to the BOLD signal. PMID- 21811289 TI - Image-derived input function for brain PET studies: many challenges and few opportunities. AB - Quantitative positron emission tomography (PET) brain studies often require that the input function be measured, typically via arterial cannulation. Image-derived input function (IDIF) is an elegant and attractive noninvasive alternative to arterial sampling. However, IDIF is also a very challenging technique associated with several problems that must be overcome before it can be successfully implemented in clinical practice. As a result, IDIF is rarely used as a tool to reduce invasiveness in patients. The aim of the present review was to identify the methodological problems that hinder widespread use of IDIF in PET brain studies. We conclude that IDIF can be successfully implemented only with a minority of PET tracers. Even in those cases, it only rarely translates into a less-invasive procedure for the patient. Finally, we discuss some possible alternative methods for obtaining less-invasive input function. PMID- 21811290 TI - Quantification of ligand PET studies using a reference region with a displaceable fraction: application to occupancy studies with [(11)C]-DASB as an example. AB - This paper aims to build novel methodology for the use of a reference region with specific binding for the quantification of brain studies with radioligands and positron emission tomography (PET). In particular: (1) we introduce a definition of binding potential BP(D)=DVR-1 where DVR is the volume of distribution relative to a reference tissue that contains ligand in specifically bound form, (2) we validate a numerical methodology, rank-shaping regularization of exponential spectral analysis (RS-ESA), for the calculation of BP(D) that can cope with a reference region with specific bound ligand, (3) we demonstrate the use of RS-ESA for the accurate estimation of drug occupancies with the use of correction factors to account for the specific binding in the reference. [(11)C]-DASB with cerebellum as a reference was chosen as an example to validate the methodology. Two data sets were used; four normal subjects scanned after infusion of citalopram or placebo and further six test-retest data sets. In the drug occupancy study, the use of RS-ESA with cerebellar input plus corrections produced estimates of occupancy very close the ones obtained with plasma input. Test-retest results demonstrated a tight linear relationship between BP(D) calculated either with plasma or with a reference input and high reproducibility. PMID- 21811291 TI - Circulating inflammatory and atherogenic biomarkers are not increased following single meals of dairy foods. AB - BACKGROUND/OBJECTIVES: Inflammation characterizes obesity and is nutritionally modifiable. The hypothesis of this study is that full-fat dairy foods influence circulating inflammatory and atherogenic biomarkers according to fermentation status. SUBJECTS/METHODS: Thirteen overweight subjects participated in five test meals. Single breakfasts containing control low-fat milk or 45 g fat from butter, cream, yoghurt or cheese were tested over 3 weeks. Plasmas obtained 3 and 6 h were later analyzed for inflammatory markers interleukin (IL)-6, IL-1beta, tumor necrosis factor-alpha and high-sensitive C-reactive protein, and atherogenesis related markers monocyte chemoattractant protein-1, macrophage inflammatory protein-1alpha, intercellular adhesion molecule-1 and vascular cell adhesion molecule-1. A 4-week study in 12 subjects compared the effects on these biomarkers of diets containing ~50 g dairy fat daily as either butter, cream and ice cream (non-fermented) or cheese plus yoghurt (fermented) dairy foods. RESULTS: In single-meal study, one outlier subject showed marked increments in biomarkers, hence the following results apply to 12. Within group analysis includes significant falls at 3 h in four inflammatory markers after cream, butter and low fat, and three atherogenesis-related biomarkers after cream. Changes were few after cheese and yoghurt. By 6 h, most values returned to baseline. However, between group analysis showed no differences between the five meals. The 4-week study showed no significant differences in fasting biomarker concentrations between non-fermented and fermented dairy diets. CONCLUSIONS: Single high-fat meals containing sequentially four different full-fat dairy foods did not increase eight circulating biomarkers related to inflammation or atherogenesis. Among subjects, significant falls occurred at 3 h in inflammatory biomarkers after cream and butter but were not specific for full-fat dairy foods. We could not confirm the reported increments in inflammation after fat meals. PMID- 21811292 TI - Maternal weight misperceptions and smoking are associated with overweight and obesity in low SES preschoolers. AB - OBJECTIVES: To identify modifiable risk factors for obesity among low socioeconomic status (LSES) children. METHODS: Cross-sectional data were obtained from 238 4-7-year-old children and 224 mothers from LSES preschools. Anthropometric measurements were obtained; mothers were interviewed about sociodemographic characteristics, health behaviors, perceptions and beliefs. RESULTS: The combined prevalence of overweight and obesity (OWOB) among children was 29.8% based on the new World Health Organization (WHO) growth standard. Prevalence of OWOB (body mass index >=25) among mothers was 51.8%. Mean age, sleeping hours, gender distribution and poverty level were similar between normal and OWOB children. Over 82% of mothers underestimated their child's weight status. Of the 62 OWOB children, 74.2% were perceived by their mothers as having 'normal weight' (NW) and 8% were perceived as 'thin'. Mothers perceived 67 out of 158 NW children (42.4%) as 'thin' (P<0.001). Mediation analysis indicated that 10% of the effect of maternal underestimation on child's OWOB may be mediated through child's daily sedentary hours (P=0.06). In a multivariable logistic regression analysis controlling for maternal obesity, knowledge regarding breakfast's importance and child's daily sedentary hours, maternal underestimation of the child's weight status (odds ratio=7.33; 95% confidence interval (CI):2.41-22.37; P<0.0001) and parental smoking (odds ratio=3.25; 95% CI: 1.26-8.40; P=0.015) were the only significant factors associated with OWOB in LSES children. CONCLUSIONS: Maternal perception of child's weight status and parental smoking are associated with childhood OWOB among LSES children. These parameters can help identify children at risk for obesity. Maternal perception may be amenable to intervention. PMID- 21811293 TI - Vegetarianism, bone loss, fracture and vitamin D: a longitudinal study in Asian vegans and non-vegans. AB - BACKGROUND/OBJECTIVES: The effect of vegan diet on bone loss has not been studied. The aim of this study was to examine the association between veganism and bone loss in postmenopausal women. SUBJECTS/METHODS: The study was designed as a prospective longitudinal investigation with 210 women, including 105 vegans and 105 omnivores. Femoral neck (FN) bone mineral density (BMD) was measured in 2008 and 2010 by dual-energy X-ray absorptiometry (Hologic QDR4500). The incidence of vertebral fracture was ascertained by X-ray report. Serum levels of C-terminal telopeptide of type I collagen (betaCTX) and N-terminal propeptide of type I procollagen (PINP) were measured by Roche Elecsys assays. Serum concentration of 25-hydroxyvitamin D and parathyroid hormone were measured by electrochemiluminescence. RESULTS: Among the 210 women who initially participated in the study in 2008, 181 women had completed the study and 29 women were lost to follow-up. The rate of loss in FN BMD was -1.91+/-3.45%/year in omnivores and 0.86+/-3.81%/year (P=0.08) in vegans. Lower body weight, higher intakes of animal protein and lipid, and corticosteroid use were associated with greater rate of bone loss. The 2-year incidence of fracture was 5.7% (n=5/88) in vegans, which was not significantly different from omnivores (5.4%, n=6/93). There were no significant differences in betaCTX and PINP between vegans and omnivores. The prevalence of vitamin D insufficiency in vegans was higher than in omnivores (73% versus 46%; P=0.0003). CONCLUSIONS: Vegan diet did not have adverse effect on bone loss and fracture. Corticosteroid use and high intakes of animal protein and animal lipid were negatively associated with bone loss. PMID- 21811294 TI - A vegan or vegetarian diet substantially alters the human colonic faecal microbiota. AB - BACKGROUND/OBJECTIVES: Consisting of ~10(14) microbial cells, the intestinal microbiota represents the largest and the most complex microbial community inhabiting the human body. However, the influence of regular diets on the microbiota is widely unknown. SUBJECTS/METHODS: We examined faecal samples of vegetarians (n=144), vegans (n=105) and an equal number of control subjects consuming ordinary omnivorous diet who were matched for age and gender. We used classical bacteriological isolation, identification and enumeration of the main anaerobic and aerobic bacterial genera and computed absolute and relative numbers that were compared between groups. RESULTS: Total counts of Bacteroides spp., Bifidobacterium spp., Escherichia coli and Enterobacteriaceae spp. were significantly lower (P=0.001, P=0.002, P=0.006 and P=0.008, respectively) in vegan samples than in controls, whereas others (E. coli biovars, Klebsiella spp., Enterobacter spp., other Enterobacteriaceae, Enterococcus spp., Lactobacillus spp., Citrobacter spp. and Clostridium spp.) were not. Subjects on a vegetarian diet ranked between vegans and controls. The total microbial count did not differ between the groups. In addition, subjects on a vegan or vegetarian diet showed significantly (P=0.0001) lower stool pH than did controls, and stool pH and counts of E. coli and Enterobacteriaceae were significantly correlated across all subgroups. CONCLUSIONS: Maintaining a strict vegan or vegetarian diet results in a significant shift in the microbiota while total cell numbers remain unaltered. PMID- 21811297 TI - Neuronal circuits: putting rewards into context. PMID- 21811298 TI - The epithelial contortionists. PMID- 21811295 TI - The neurobiology of gliomas: from cell biology to the development of therapeutic approaches. AB - Gliomas are the most common type of primary brain tumour and are often fast growing with a poor prognosis for the patient. Their complex cellular composition, diffuse invasiveness and capacity to escape therapies has challenged researchers for decades and hampered progress towards an effective treatment. Recent molecular characterization of tumour cells combined with new insights into cellular diversification that occurs during development, and the modelling of these processes in transgenic animals have enabled a more detailed understanding of the events that underlie gliomagenesis. Combining this enhanced understanding of the relationship between neural stem cell biology and the cell lineage relationships of tumour cells with model systems offers new opportunities to develop specific and effective therapies. PMID- 21811299 TI - Healthy ageing through regulated proteostasis. PMID- 21811300 TI - Upward bound: follicular stem cell fate decisions. PMID- 21811301 TI - Signalling gets sorted by retromer. PMID- 21811302 TI - Epistasis, phenotypic disequilibrium and contrasting associations with climate in the land snail Theba pisana. AB - Hotter conditions favour effectively unbanded (EUB) shells in the snail Theba pisana. T. pisana is also polymorphic for colour of the shell's apex, determined by a pair of alleles at a locus linked to the banding locus. Apex colour is epistatic to shell banding, such that banded snails with a dark apex have darker bands. Annual censuses over 22 years across an ecotone between a sheltered Acacia thicket and open dune vegetation showed a persistent association of both EUB shells and pale apex with the Open habitat. The parallel variation was due partly to strong phenotypic disequilibrium, as the combination of EUB with dark apex was rare. Nevertheless, in fully banded shells the frequency of pale apex was also higher in the Open habitat, confirming independent, parallel associations of the two contributors to paleness. Within the Acacia habitat, temporal variation of the frequencies of banding morphs was much greater than for apex colour, and EUB shells were associated with hotter summers. Consistent with its primary effect only on the very small snails, apex colour did not vary with summer conditions, but instead, higher frequencies of pale apices were associated with sunnier winters. The intensity of selection was lower on apex colour than shell banding, due partly to the constraint of phenotypic disequilibrium. The shell traits in T. pisana are an example of complex responses to climatic variation, in which phenotypic disequilibrium constrains evolution of apex colour, but separate mechanisms of selection are evident. PMID- 21811304 TI - Sequencing of high-complexity DNA pools for identification of nucleotide and structural variants in regions associated with complex traits. AB - We have used targeted genomic sequencing of high-complexity DNA pools based on long-range PCR and deep DNA sequencing by the SOLiD technology. The method was used for sequencing of 286 kb from four chromosomal regions with quantitative trait loci (QTL) influencing blood plasma lipid and uric acid levels in DNA pools of 500 individuals from each of five European populations. The method shows very good precision in estimating allele frequencies as compared with individual genotyping of SNPs (r(2) = 0.95, P < 10(-16)). Validation shows that the method is able to identify novel SNPs and estimate their frequency in high-complexity DNA pools. In our five populations, 17% of all SNPs and 61% of structural variants are not available in the public databases. A large fraction of the novel variants show a limited geographic distribution, with 62% of the novel SNPs and 59% of novel structural variants being detected in only one of the populations. The large number of population-specific novel SNPs underscores the need for comprehensive sequencing of local populations in order to identify the causal variants of human traits. PMID- 21811305 TI - A genome-wide study of panic disorder suggests the amiloride-sensitive cation channel 1 as a candidate gene. AB - Panic disorder (PD) is a mental disorder with recurrent panic attacks that occur spontaneously and are not associated to any particular object or situation. There is no consensus on what causes PD. However, it is recognized that PD is influenced by environmental factors, as well as genetic factors. Despite a significant hereditary component, genetic studies have only been modestly successful in identifying genes of importance for the development of PD. In this study, we conducted a genome-wide scan using microsatellite markers and PD patients and control individuals from the isolated population of the Faroe Islands. Subsequently, we conducted a fine mapping, which revealed the amiloride sensitive cation channel 1 (ACCN1) located on chromosome 17q11.2-q12 as a potential candidate gene for PD. The further analyses of the ACCN1 gene using single-nucleotide polymorphisms (SNPs) revealed significant association with PD in an extended Faroese case-control sample. However, analyses of a larger independent Danish case-control sample yielded no substantial significant association. This suggests that the possible risk alleles associated in the isolated population are not those involved in the development of PD in a larger outbred population. PMID- 21811306 TI - Impact of gene patents on diagnostic testing: a new patent landscaping method applied to spinocerebellar ataxia. AB - Recent reports in Europe and the United States raise concern about the potential negative impact of gene patents on the freedom to operate of diagnosticians and on the access of patients to genetic diagnostic services. Patents, historically seen as legal instruments to trigger innovation, could cause undesired side effects in the public health domain. Clear empirical evidence on the alleged hindering effect of gene patents is still scarce. We therefore developed a patent categorization method to determine which gene patents could indeed be problematic. The method is applied to patents relevant for genetic testing of spinocerebellar ataxia (SCA). The SCA test is probably the most widely used DNA test in (adult) neurology, as well as one of the most challenging due to the heterogeneity of the disease. Typically tested as a gene panel covering the five common SCA subtypes, we show that the patenting of SCA genes and testing methods and the associated licensing conditions could have far-reaching consequences on legitimate access to this gene panel. Moreover, with genetic testing being increasingly standardized, simply ignoring patents is unlikely to hold out indefinitely. This paper aims to differentiate among so-called 'gene patents' by lifting out the truly problematic ones. In doing so, awareness is raised among all stakeholders in the genetic diagnostics field who are not necessarily familiar with the ins and outs of patenting and licensing. PMID- 21811307 TI - Pan-ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy: clinical laboratory analysis of >72,400 specimens. AB - Spinal muscular atrophy (SMA) is a leading inherited cause of infant death with a reported incidence of ~1 in 10,000 live births and is second to cystic fibrosis as a common, life-shortening autosomal recessive disorder. The American College of Medical Genetics has recommended population carrier screening for SMA, regardless of race or ethnicity, to facilitate informed reproductive options, although other organizations have cited the need for additional large-scale studies before widespread implementation. We report our data from carrier testing (n = 72,453) and prenatal diagnosis (n = 121) for this condition. Our analysis of large-scale population carrier screening data (n = 68,471) demonstrates the technical feasibility of high throughput testing and provides mutation carrier and allele frequencies at a level of accuracy afforded by large data sets. In our United States pan-ethnic population, the calculated a priori carrier frequency of SMA is 1/54 with a detection rate of 91.2%, and the pan-ethnic disease incidence is calculated to be 1/11,000. Carrier frequency and detection rates provided for six major ethnic groups in the United States range from 1/47 and 94.8% in the Caucasian population to 1/72 and 70.5% in the African American population, respectively. This collective experience can be utilized to facilitate accurate pre- and post-test counseling in the settings of carrier screening and prenatal diagnosis for SMA. PMID- 21811308 TI - Epigenetic regulation of the X-chromosomal macrosatellite repeat encoding for the cancer/testis gene CT47. AB - Macrosatellite repeats (MSRs) present an extreme example of copy number variation, yet their epigenetic regulation in normal and malignant cells is largely understudied. The CT47 cancer/testis antigen located on human Xq24 is organized as an array of 4.8 kb large units. CT47 is expressed in the testis and in certain types of cancer, but not in non-malignant somatic tissue. We used CT47 as a model to study a possible correlation between copy number variation, epigenetic regulation and transcription originating from MSRs in normal and malignant cells. In lymphoblastoid cell lines and primary fibroblasts, CT47 expression was absent, consistent with the observed heterochromatic structure and DNA hypermethylation of the CT47 promoter. Heterochromatinization of CT47 occurs early during development as human embryonic stem cells show high levels of DNA methylation and repressive chromatin modifications in the absence of CT47 expression. In small-cell lung carcinoma cell lines with low levels of CT47 transcripts, we observed reduced levels of histone 3 lysine 9 trimethylation (H3K9me3) and trimethylated lysine 27 of histone H3 (H3K27me3) without concomitant increase in euchromatic histone modifications. DNA methylation levels in the promoter region of CT47 are also significantly reduced in these cells. This supports a model in which during oncogenic transformation, there is a relative loss of repressive chromatin markers resulting in leaky expression of CT47. We conclude that some MSRs, like CT47 and the autosomal MSRs TAF11-Like, PRR20, ZAV and D4Z4, the latter being involved in facioscapulohumeral muscular dystrophy, seem to be governed by common regulatory mechanisms with their abundant expression mostly being restricted to the germ line. PMID- 21811309 TI - Attitudes to reproductive genetic testing in women who had a positive BRCA test before having children: a qualitative analysis. AB - The scope of conditions for which preimplantation genetic diagnosis (PGD) is licensed has recently been expanded in the United Kingdom to include genetic predisposition to adult-onset cancer. This qualitative interview study explores reproductive decision making, knowledge of and attitudes to reproductive genetic testing (prenatal diagnosis and PGD) with 25 women aged 18-45 years who received a positive BRCA test in the United Kingdom before having children. In this cohort of younger women, BRCA testing was motivated by risk management decisions; for some, BRCA status has affected their later decisions about having children. The perceived severity of hereditary breast/ovarian cancer (HBOC) influences thoughts about passing on the mutation to children and willingness to consider reproductive genetic testing, but most participants do not believe HBOC is a condition for which pregnancy termination is justified. PGD is considered more acceptable and advantageous because it would prevent transmission to future generations, but women have concerns about selecting embryos and the fact that they and affected family members would not have been selected. Women would also be deterred by the need to undergo in vitro fertilisation (IVF) and ovarian stimulation for PGD. Awareness of reproductive testing options was very variable among the cohort. The findings highlight the complexities of reproductive decision making for young women who knowingly carry a BRCA mutation, and the dilemmas inherent to reproductive genetic testing when the condition being tested for also affects a prospective parent. Counselling and psychological support for BRCA-positive women and couples concerning reproductive options are strongly indicated. PMID- 21811310 TI - Complexin arrests a neighbor. PMID- 21811311 TI - Conformational flexibility and rotation of the RING domain in activation of cullin-RING ligases. PMID- 21811312 TI - A bottle opener for TBP. PMID- 21811314 TI - Scintillation index of flat-topped Gaussian laser beam in strongly turbulent medium. AB - In a strongly turbulent medium, the scintillation index of flat-topped Gaussian beams is derived and evaluated. In the formulation, unified solution of Rytov method is utilized. Our results correctly reduce to the existing strong turbulence scintillation index of the Gaussian beam, and naturally to spherical and plane wave scintillations. Another checkpoint of our result is the scintillation index of flat-topped Gaussian beams in weak turbulence. Regardless of the order of flatness, scintillations of flat-topped Gaussian beams in strong turbulence are found to be determined mainly by the small-scale effects. For large-sized beams in moderate and strongly turbulent medium, flatter beams exhibit smaller scintillations. PMID- 21811315 TI - Generalized spectral decomposition: a theory and practice to spectral reconstruction. AB - The generalized spectral decomposition (GSD) theorem is introduced, and the generalized fundamental stimulus and metameric black are analyzed to show how they convey the valuable features in terms of color information. The suggestion would be considered as the generalization of Cohen and Kappauf's matrix R theory and its later application in parameric correction by Fairman. The GSD theorem provides a modular model whose arguments can be elaborately set up for high performance spectral recovery. It is also shown that the suggested methods for spectral decomposition and/or spectral reconstruction proposed by different researchers could be considered as special cases of GSD. PMID- 21811316 TI - Deterministic regularization of three-dimensional optical diffraction tomography. AB - In this paper, we discuss a deterministic regularization algorithm to handle the missing cone problem of three-dimensional optical diffraction tomography (ODT). The missing cone problem arises in most practical applications of ODT and is responsible for elongation of the reconstructed shape and underestimation of the value of the refractive index. By applying positivity and piecewise-smoothness constraints in an iterative reconstruction framework, we effectively suppress the missing cone artifact and recover sharp edges rounded out by the missing cone, and we significantly improve the accuracy of the predictions of the refractive index. We also show the noise-handling capability of our algorithm in the reconstruction process. PMID- 21811317 TI - Noninterferometric topography measurements of fast moving surfaces. AB - The topography of moving surfaces is recovered by noninterferometric measurements. The phase reconstruction is derived by measuring the intensities of a backscattered pulsed laser light and solving the transport intensity equation (TIE). The TIE is solved by expanding the phase into a series of Zernike polynomials, leading to a set of appropriate algebraic equations. This technique, which enables us to make a direct connection between experiments and the TIE, has been successfully tested in gas gun experiments. In particular, the topographies of a moving projectile and the free surface of a shocked target were recovered. PMID- 21811318 TI - Bulk wind estimation and prediction for adaptive optics control systems. AB - We present a wind-predictive controller for astronomical adaptive optics (AO) systems that is able to predict the motion of a single windblown layer in the presence of other, more slowly varying phase aberrations. This controller relies on fast, gradient-based optical flow estimation to identify the velocity of the translating layer and a recursive mean estimator to account for turbulence that varies on a time scale much slower than the operating speed of the AO loop. We derive the Cramer-Rao lower bound for the wind estimation problem and show that the proposed estimator is very close to achieving theoretical minimum-variance performance. We also present simulations using on-sky data that show significant Strehl increases from using this controller in realistic atmospheric conditions. PMID- 21811319 TI - Components of purity of a Mueller matrix. AB - The degree of polarimetric purity of a Mueller matrix, also called "depolarization index" [Opt. Acta 33, 185 (1986)] is expressed as a quadratic average of two contributions of different nature. The contribution due to the polarizance and diattenuation properties is given by a unique parameter called "degree of polarizance," and the complementary contribution due to nonpolarizing properties is given by a parameter called "degree of spherical purity." These two intrinsic quantities are useful in order to analyze the sources of the polarimetric purity of a material sample whose Mueller matrix has been measured and provide criteria for the classification of Mueller matrices. PMID- 21811303 TI - Discrepancies in reporting the CAG repeat lengths for Huntington's disease. AB - Huntington's disease results from a CAG repeat expansion within the Huntingtin gene; this is measured routinely in diagnostic laboratories. The European Huntington's Disease Network REGISTRY project centrally measures CAG repeat lengths on fresh samples; these were compared with the original results from 121 laboratories across 15 countries. We report on 1326 duplicate results; a discrepancy in reporting the upper allele occurred in 51% of cases, this reduced to 13.3% and 9.7% when we applied acceptable measurement errors proposed by the American College of Medical Genetics and the Draft European Best Practice Guidelines, respectively. Duplicate results were available for 1250 lower alleles; discrepancies occurred in 40% of cases. Clinically significant discrepancies occurred in 4.0% of cases with a potential unexplained misdiagnosis rate of 0.3%. There was considerable variation in the discrepancy rate among 10 of the countries participating in this study. Out of 1326 samples, 348 were re analysed by an accredited diagnostic laboratory, based in Germany, with concordance rates of 93% and 94% for the upper and lower alleles, respectively. This became 100% if the acceptable measurement errors were applied. The central laboratory correctly reported allele sizes for six standard reference samples, blind to the known result. Our study differs from external quality assessment (EQA) schemes in that these are duplicate results obtained from a large sample of patients across the whole diagnostic range. We strongly recommend that laboratories state an error rate for their measurement on the report, participate in EQA schemes and use reference materials regularly to adjust their own internal standards. PMID- 21811320 TI - Isotropic single-objective microscopy: theory and experiment. AB - Isotropic single-objective (ISO) microscopy is a recently proposed imaging technique that can theoretically exhibit the same axial and transverse resolutions as 4Pi microscopy while using a classical single-objective confocal microscope. This achievement is obtained by placing the sample on a mirror and shaping the illumination beam so that the interference of the incident and mirror reflected fields yields a quasi-spherical spot. In this work, we model the image formation in the ISO fluorescence microscope and simulate its point spread function. Then, we describe the experimental implementation and discuss its practical difficulties. PMID- 21811321 TI - Method for tracing the position of an alien object embedded in a random particulate medium. AB - We have developed a new technique based on light scattering experiments for tracing an alien particle with deterministic potential in a random collection of particles. We have shown that, via a sequence of measurements of light scattered to a far field of a scattering collection, it is possible to locate the center of the alien particle. The analysis of the stability of reconstruction is provided, and it is demonstrated via simulations that the results are stable for sufficiently large wavelength of the incident light and in cases when the size of the alien particle is comparable with the size of the typical particle in the collection. PMID- 21811322 TI - Determination of second-order derivatives of a skew ray with respect to the variables of its source ray in optical prism systems. AB - The second-order derivative of a scalar function with respect to a variable vector is known as the Hessian matrix. We present a computational scheme based on the principles of differential geometry for determining the Hessian matrix of a skew ray as it travels through a prism system. A comparison of the proposed method and the conventional finite difference (FD) method is made at last. It is shown that the proposed method has a greater inherent accuracy than FD methods based on ray-tracing data. The proposed method not only provides a convenient means of investigating the wavefront shape within complex prism systems, but it also provides a potential basis for determining the higher order derivatives of a ray by further taking higher order differentiations. PMID- 21811323 TI - Discrete fractional Fourier transform as a fast algorithm for evaluating the diffraction pattern of pulsed radiation. AB - A technique is proposed for computing the field radiated from a rectangular aperture. This technique, based on the discrete fractional Fourier transform, avoids the complexities of computing the diffraction pattern by the direct evaluation of the Fresnel integral. The advocated approach provides a fast and accurate computational tool, especially in the case of evaluating pulsed fields radiated through two-dimensional screens of complex amplitude. A detailed numerical study that demonstrates the efficacy of this approach is carried out. PMID- 21811324 TI - Improved 2D vector field estimation using probabilistic weights. AB - We consider the application of tomography to the reconstruction of two dimensional vector fields. The most practical sensor configuration in such problems is the regular positioning along the boundary of the reconstruction domain. However, such a configuration does not result in uniform distribution in the Radon parameter space, which is a necessary requirement to achieve accurate reconstruction results. On the other hand, sampling the projection space uniformly imposes serious constraints on space or time. In this paper, we propose to place the sensors regularly along the boundary of the reconstruction domain and employ probabilistic weights with the purpose of compensating for the lack of uniformity in the distribution of projection space parameters. Simulation results demonstrate that, when the proposed probabilistic weights are employed, an average 27% decrease in the reconstruction error may be achieved, over the case that projection measurements are not weighed (e.g., in one case the error reduces from 3.7% to 2.6%). When compared with the case where actual uniform sampling of the projection space is employed, the proposed method achieves a 90 times reduction in the number of the required sensors or 180 times reduction in the total scanning time, with only 7% increase in the error with which the vector field is estimated. PMID- 21811325 TI - Measuring the complex amplitude of wave fields by means of shear interferometry. AB - This paper presents a treatise on the determination of the complex amplitude of a monochromatic wave field from measurements obtained by a lateral shear interferometer. Both amplitude and phase distributions are recovered from the same set of measurements. Special consideration is given to the case of measurements with large shear. Here, the state of the art in the reconstruction of discontinuous wavefronts is extended by introducing a two-step process. In the first step, the phasors of the underlying wavefront are reconstructed across specific subsets of the measurement grid. In the second step, the individual reconstructions are combined by a novel (to the best of the author's knowledge) convolution approach in the Fourier domain, called residual phasor separation. PMID- 21811326 TI - Fourier optics heuristics for diffraction at infinity by an index discontinuity in a one-dimensional slab. AB - We study the far-field reflected diffraction pattern of an index discontinuity in a thin one-dimensional slab illuminated by a plane wave and show that a time saving modeling technique based on plane wave expansion approaches fairly well the Maxwell-based rigorous models. This method is simple to implement, and it furthermore allows a good understanding of the optical phenomena involved in the propagation of light through the slab. PMID- 21811327 TI - Fraunhofer diffraction by a random screen. AB - The stochastic approach is applied to the problem of Fraunhofer diffraction by a random screen. The diffraction pattern is expressed through the random chord distribution. Two cases are considered: the sparse ensemble, where the interference between different obstacles can be neglected, and the densely packed ensemble, where this interference is to be taken into account. The solution is found for the general case and the analytical formulas are obtained for the Switzer model of a random screen, i.e., for the case of Markov statistics. PMID- 21811328 TI - Effects of symmetry breaking on plasmon resonance in a noncoaxial nanotube and nanotube dimer. AB - The effects of symmetry breaking on plasmonic properties of one nanotube and three types of nanotube dimers are numerically investigated. It is found that increasing the coaxial offset can result in redshifting of the transmission spectra and the existence of more peaks in the nanoegglike structures, while the nanocuplike structures present the opposite and more complex behaviors. We also study the combined effects of coaxial offset and gap size. The results show that the nanoegglike spectra redshift with the increase of coaxial offset and the decrease of the gap size, and the nanocuplike spectra display opposite behaviors. The asymmetrical distribution of surface charges demonstrates that the hybridization of dipolar and multipolar plasmon polaritons exist in the cross section of these structures, and the electric field adjacent to the thinner side enhances greatly. The proposed nanostructures may have great potential applications in various near-field optics. PMID- 21811329 TI - Limits on achievable intensity reduction with an optical occulter. AB - Deep shadowing of a normally incident plane wave by an opaque circular disk is partially negated by the formation of a region of strong intensity surrounding the axis passing normally through the disk center. This local intensity enhancement, historically referred to as the Poisson Spot (also known as the Spot of Arago), has been the principal source of difficulties in applications where a significant reduction of the incident intensity is essential. In particular, the NASA Terrestrial Planet Finder's (TPF) mission requires suppression of direct starlight by at least 10 orders of magnitude over the entire visible spectral range. One technique that has been proposed for blocking the direct starlight is to use a rotationally symmetric disk with petallike segments along its boundary. We find that, even though such configurations could, indeed, theoretically provide the desired intensity reduction, they would require unreasonably small radii of curvature at the petals' tips (in the range of micrometers). When the radii of curvature are increased to 3 mm, the intensity reduction drops to a modest 5 to 6 orders of magnitude. Given that for the NASA's TPF mission the proposed occulter radius would be on the order of 25 m, even the 3 mm radius of curvature would be too small for any practical implementation. Further increases of the radius of curvature result in progressively poorer intensity suppression. As an alternative solution we propose an apodized circular disk. We show that with an optimized apodization function, intensity reductions of at least 10 orders of magnitude can be achieved over the entire visible spectral range. Numerical results are presented for parameters appropriate to the NASA TPF mission. PMID- 21811330 TI - Constrained pseudo-Brownian motion and its application to image enhancement. AB - Brownian motion is a random process that finds application in many fields, and its relation to certain color perception phenomena has recently been observed. On this ground, Marini and Rizzi developed a retinex algorithm based on Brownian motion paths. However, while their approach has several advantages and delivers interesting results, it has a high computational complexity. We propose an efficient algorithm that generates pseudo-Brownian paths with a very important constraint: we can guarantee a lower bound to the number of visits to each pixel, as well as its average. Despite these constraints, we show that the paths generated have certain statistical similarities to random walk and Brownian motion. Finally, we present a retinex implementation that exploits the paths generated with our algorithm, and we compare some images it generates with those obtained with the McCann99 and Frankle and McCann's algorithms (two multiscale retinex implementations that have a low computational complexity). We find that our approach causes fewer artifacts and tends to require a smaller number of pixel comparisons to achieve similar results, thus compensating for the slightly higher computational complexity. PMID- 21811331 TI - Coherent transfer function of Fourier transform spectral interferometric coherent anti-Stokes Raman scattering microscopy. AB - We analyze the optical resolution of Fourier transform spectral interferometric coherent anti-Stokes Raman scattering microscopy, which extracts the complex amplitude of an image by using a spectral interferometric effect. Image-formation formulas are presented that describe the properties of the image observed by the apparatus. The image-formation properties represented by the coherent transfer function are different depending on the mode (transmission, reflection, etc.) of the microscopy. PMID- 21811332 TI - Discrete linear canonical transforms based on dilated Hermite functions. AB - Linear canonical transform (LCT) is very useful and powerful in signal processing and optics. In this paper, discrete LCT (DLCT) is proposed to approximate LCT by utilizing the discrete dilated Hermite functions. The Wigner distribution function is also used to investigate DLCT performances in the time-frequency domain. Compared with the existing digital computation of LCT, our proposed DLCT possess additivity and reversibility properties with no oversampling involved. In addition, the length of input/output signals will not be changed before and after the DLCT transformations, which is consistent with the time-frequency area preserving nature of LCT; meanwhile, the proposed DLCT has very good approximation of continuous LCT. PMID- 21811333 TI - Transverse superresolution technique involving rectified Laguerre-Gaussian LG(p)0 beams. AB - A promising technique has been proposed recently [Opt. Commun. 284, 1331 (2011), Opt. Commun. 284, 4107 (2011)] for breaking the diffraction limit of light. This technique consists of transforming a symmetrical Laguerre-Gaussian LG(p)0 beam into a near-Gaussian beam at the focal plane of a thin converging lens thanks to a binary diffractive optical element (DOE) having a transmittance alternatively equal to -1 or +1, transversely. The effect of the DOE is to convert the alternately out-of-phase rings of the LG(p)0 beam into a unified phase front. The benefits of the rectified beam at the lens focal plane are a short Rayleigh range, which is very useful for many laser applications, and a focal volume much smaller than that obtained with a Gaussian beam. In this paper, we demonstrate numerically that the central lobe's radius of the rectified beam at the lens focal plane depends exclusively on the dimensionless radial intensity vanishing factor of the incident beam. Consequently, this value can be easily predicted. PMID- 21811334 TI - Generation of nondiffracting quasi-circular polarization beams using an amplitude modulated phase hologram. AB - We propose an approach to the generation of nondiffracting quasi-circularly polarized beams by a highly focusing azimuthally polarized beam using an amplitude modulated spiral phase hologram. Numerical verifications are implemented in the calculation of the electromagnetic fields and Poynting vector field near the focus based on the vector diffraction theory, and the polarization of the wavefront near the focal plane is analyzed in detail by calculating the Stokes polarization parameters. It is found that the electric field, magnetic field, and Poynting vector field can simultaneously be uniform and nondiverging over a relatively long axial range of ~7.23lambda. In the transverse plane, the ellipticity and azimuthal angle of the local polarization ellipse varies from point to point. No polarization singularity and phase singularity are found at the beam center, which makes the bright spot possible. PMID- 21811335 TI - Orientation gradient detection exhibits variable coupling between first- and second-stage filtering mechanisms. AB - We investigated sensitivity to orientation modulation using visual stimuli with bandpass filtered noise carriers. We characterized the relationship between the spatial parameters of the modulator and the carrier using a 2-AFC detection task. The relationship between these two parameters is potentially informative of the underlying coupling between first- and second-stage filtering mechanisms, which, in turn, may bear on the interrelationship between striate and extrastriate cortical processing. Our previous experiments on analogous motion stimuli found an optimum sensitivity when the ratio of the carrier and modulator spatial frequency parameters (r) was approximately ten. The current results do not exhibit an optimum sensitivity at a given value of the ratio r. Previous experiments involving second-order modulation sensitivity show an inconsistent range of estimates of optimum sensitivity at values of r between 5 and 50. Our results, using a complementary approach, confirm these discrepancies, demonstrating that the coupling between carrier and modulator frequency parameters depends on a number of stimulus-specific factors, such as contrast sensitivity, stimulus eccentricity, and absolute values of the carrier and modulator spatial frequency parameters. We show that these observations are true for a stimulus limited in eccentricity and that this orientation-modulated stimulus does not exhibit scale invariance. Such processing can not be modeled by a generic filter-rectify-filter model. PMID- 21811336 TI - Wavefront propagation in turbulence: an unified approach to the derivation of angular correlation functions. AB - A general expression of the spatial correlation functions of quantities related to the phase fluctuations of a wave that have propagated through the atmospheric turbulence are derived. A generalization of the method to integrand containing the product of an arbitrary number of hypergeometric functions is presented. The formalism is able to give the coefficients of phase-expansion functions orthogonal over an arbitrary circularly symmetric weighting function for an isotropic turbulence spectrum, as well as to describe the effect of the finite outer and inner scales of the turbulence and to describe the spherical propagation or to derive the effects of the analytical operators acting on the phase such as the derivatives of any order. The derivation of the generalized integrals with multiparameters is based on the Mellin transforms integration method. PMID- 21811337 TI - Experimental comparison of autodyne and heterodyne laser interferometry using an Nd:YVO4 microchip laser. AB - Using an Nd:YVO4 microchip laser with a relaxation frequency in the megahertz range, we have experimentally compared a heterodyne interferometer based on a Michelson configuration with an autodyne interferometer based on the laser optical feedback imaging (LOFI) method regarding their signal-to-noise ratios. In the heterodyne configuration, the beating between the reference beam and the signal beam is realized outside the laser cavity, while in the autodyne configuration, the wave beating takes place inside the laser cavity, and the relaxation oscillations of the laser intensity then play an important part. For a given laser output power, object under investigation, and detection noise level, we have determined the amplification gain of the LOFI interferometer compared to the heterodyne interferometer. LOFI interferometry is demonstrated to show higher performance than heterodyne interferometry for a wide range of laser powers and detection levels of noise. The experimental results are in good agreement with the theoretical predictions. PMID- 21811338 TI - Formulation of rigorous coupled-wave theory for gratings in bianisotropic media. AB - A formulation of rigorous coupled-wave theory for diffraction gratings in bianisotropic media that exhibit linear birefringence and/or optical activity is presented. The symmetric constitutive relations for bianisotropic materials are adopted. All of the incident, exiting, and grating materials can be isotropic, uniaxial, or biaxial, with or without optical activity. The principal values of the electric permittivity tensor, the magnetic permeability tensor, and the gyrotropic tensor of the media can take arbitrary values, and the principal axes may be arbitrarily and independently oriented. Procedures for Fourier expansion of Maxwell's equations are described. Distinctive polarization coupling effects due to optical activity are observed in sample calculations. PMID- 21811339 TI - Differential group delay prediction in optical fiber links. AB - We simulate the time evolution of differential group delay (DGD) in a fiber link in the hinge model with time series forecasting procedures, in particular, autoregressive (AR) models with Kalman filter, pattern imitation, and a Taylor expansion. In these studies, the furthest prediction horizon was attained with the AR accompanied by the Kalman filter procedure. We further discuss the influence of measurement noise on the prediction horizon. We also apply these methods to the measured DGD on 40 Gb/s fiber links and discuss the results. PMID- 21811340 TI - Derivation of the scalar radiative transfer equation from energy conservation of Maxwell's equations in the far field. AB - In this paper the expression for the radiative transfer equation (RTE) commonly used when describing light propagation in biological tissues is derived directly from the equation of energy conservation of Maxwell's equations (Poynting's theorem) by making use of a volume-averaged expression for the time-averaged flow of energy. The derivation is presented step by step with Maxwell's equations as the starting point, analyzing all approximations taken in order to arrive at the expression of the scalar RTE employed in biomedical applications, which neglects particle nonsphericity and orientation, depolarization, and coherence effects. PMID- 21811341 TI - Improved near-field calculations using vectorial diffraction integrals in the finite-difference time-domain method. AB - We present an alternative mixed-surface implementation of the Stratton-Chu vectorial diffraction integrals as a means to improve near-field calculations outside the computational domain of the finite-difference time-domain method. This approach, originally derived for far-field calculations, reduces the effect of phase errors and reduces storage costs compared to standard single-surface implementations performed using arithmetic and geometric means. All three methods are applied to a strongly forward-scattering sphere, which is the gold standard for similar simulations with a corresponding analytical Mie series solution. Additionally, the mixed surface is applied to an ensemble of theoretical flow cytometry calibration standards in optical gel. The near-field electromagnetic scattering produced by these or any arbitrary object, such as a cell, could be used to simulate images in a high-numerical-aperture microscope. The results show the mixed-surface implementation outperforms the standard techniques for calculating the near-field electromagnetic fields. PMID- 21811342 TI - Pseudodynamic systems approach based on a quadratic approximation of update equations for diffuse optical tomography. AB - We explore a pseudodynamic form of the quadratic parameter update equation for diffuse optical tomographic reconstruction from noisy data. A few explicit and implicit strategies for obtaining the parameter updates via a semianalytical integration of the pseudodynamic equations are proposed. Despite the ill posedness of the inverse problem associated with diffuse optical tomography, adoption of the quadratic update scheme combined with the pseudotime integration appears not only to yield higher convergence, but also a muted sensitivity to the regularization parameters, which include the pseudotime step size for integration. These observations are validated through reconstructions with both numerically generated and experimentally acquired data. PMID- 21811343 TI - Numerical Simulation of Local Temperature Distortions During Ice Nucleation of Cells in Suspension. AB - Knowledge of intercellular ice formation in cells embedded in an extra-cellular suspension is essential for effective design of freezing protocols. The presence of cell membrane causes super-cooling of the intra-cellular region, which nucleates at much lower temperatures than the surrounding extra-cellular space and is accompanied by the exothermic release of the latent heat. This is a dynamic process and causes thermal distortions in and around the cell where nucleation occurs. In the present study, an attempt has been made to numerically determine the magnitude of thermal distortion (DeltaT) and the time (dt) it takes for this distortion to damp out to the local temperature. A two-dimensional computational model is presented in which the maximum thermal distortions (with an assumed cell diameter of 50 MUm, nucleating at -5 degrees C while being cooled at 5 degrees C/min; denoted as Scenario 1) and the lowest-possible thermal distortions (with an assumed cell diameter of 5 MUm, nucleating at -20 degrees C while being cooled at 100 degrees C/min; denoted as Scenario 2) are determined. Extensive computations have been performed assuming either the presence of a single, dual, or four cells in suspension. It is expected that these representative results would serve the purpose of estimating an effective sampling rate of microscale thermocouples currently being fabricated and of other biomedical devices used to measure intracellular ice formation. PMID- 21811344 TI - Optical Characterization of Optofluidic Waveguides Using Scattered Light Imaging. AB - The use of scattered light images is shown to be an attractive method for the characterization of optofluidic waveguides. The method is shown to be capable of measuring waveguide propagation losses and transmissions between solid and liquid core structures. Measurement uncertainties are considered and characterized and were typically less than 15%. PMID- 21811345 TI - Studies of one-pot double couplings on dibromoquinolines. AB - In a series of studies, the regioselectivity of Suzuki couplings of dibromoquinolines has been investigated. In general, it is much harder to achieve high levels of regioselectivity in these systems compared to many of the other dibromoheteroaromatics that have been studied. Useful levels of selectivity could be achieved for both a 5,7-dibromoquinoline as well as 3,4-dibromoquinoline. Double Suzuki couplings could also be achieved on these two compounds. PMID- 21811346 TI - Phorboxazole Synthetic Studies: Design, Synthesis and Biological Evaluation of Phorboxazole A and Hemi-Phorboxazole A Related Analogues. AB - The design, synthesis and biological evaluation of a new phorboxazole analogue, comprising an acetal replacement for the C-ring tetrahdropyran of the natural product and carrying a potency-enhancing C(45-46) vinyl chloride side chain, is described. In addition, the synthesis of (+)-hemi-phorboxazole A and a series of related hemi-phorboxazole A analogues has been achieved. The new acetal ring replacement analogue displayed activity comparable to that of the parent natural product against HCT-116 (colon) cells (IC(50) 2.25 ng/mL). Equally important, the phorboxazole analogue and two related hemiphorboxazole A congeners exhibited significant antifungal activity when assayed against pathogenic Candida albicans strains. PMID- 21811347 TI - The Columbia University proton-induced soft x-ray microbeam. AB - A soft x-ray microbeam using proton-induced x-ray emission (PIXE) of characteristic titanium (K(alpha) 4.5 keV) as the x-ray source has been developed at the Radiological Research Accelerator Facility (RARAF) at Columbia University. The proton beam is focused to a 120 MUm * 50 MUm spot on the titanium target using an electrostatic quadrupole quadruplet previously used for the charged particle microbeam studies at RARAF. The proton induced x-rays from this spot project a 50 MUm round x-ray generation spot into the vertical direction. The x rays are focused to a spot size of 5 MUm in diameter using a Fresnel zone plate. The x-rays have an attenuation length of (1/e length of ~145 MUm) allowing more consistent dose delivery across the depth of a single cell layer and penetration into tissue samples than previous ultra soft x-ray systems. The irradiation end station is based on our previous design to allow quick comparison to charged particle experiments and for mixed irradiation experiments. PMID- 21811348 TI - Disease, dignity and palliative care. PMID- 21811349 TI - 'BREAKS' Protocol for Breaking Bad News. AB - Information that drastically alters the life world of the patient is termed as bad news. Conveying bad news is a skilled communication, and not at all easy. The amount of truth to be disclosed is subjective. A properly structured and well orchestrated communication has a positive therapeutic effect. This is a process of negotiation between patient and physician, but physicians often find it difficult due to many reasons. They feel incompetent and are afraid of unleashing a negative reaction from the patient or their relatives. The physician is reminded of his or her own vulnerability to terminal illness, and find themselves powerless over emotional distress. Lack of sufficient training in breaking bad news is a handicap to most physicians and health care workers. Adherence to the principles of client-centered counseling is helpful in attaining this skill. Fundamental insight of the patient is exploited and the bad news is delivered in a structured manner, because the patient is the one who knows what is hurting him most and he is the one who knows how to move forward. Six-step SPIKES protocol is widely used for breaking bad news. In this paper, we put forward another six-step protocol, the BREAKS protocol as a systematic and easy communication strategy for breaking bad news. Development of competence in dealing with difficult situations has positive therapeutic outcome and is a professionally satisfying one. PMID- 21811350 TI - Ethics and medico legal aspects of "not for resuscitation". AB - Not for resuscitation in India still remains an abstract concept with no clear guidelines or legal frame work. Cardiopulmonary resuscitation is a complex medical intervention which is often used inappropriately in hospitalized patients and usually guided by medical decision making rather than patient-directed choices. Patient autonomy still remains a weak concept and relatives are expected to make this big decision in a short time and at a time of great emotional distress. This article outlines concepts around ethics and medico legal aspects of not for resuscitation, especially in Indian setting. PMID- 21811351 TI - Preventive palliation in the elderly - organizing health camps for the rural aged. AB - Most of the needs of elders for support and assistance in the later stages of life are fulfilled by informal helpers. The position of a large number of older persons has become vulnerable due to which it cannot be taken for granted that their children will be able to look after them when they need care in old age, specially in view of the longer life span implying an extended period of dependency and higher costs to meet health and other needs. The condition of the rural elderly is even more pitiable, contrary to our beliefs, as availability, affordability and accessibility to medicare facilities are poor. We undertook the task of organizing a health camp in a rural set-up with the idea of implementing our concept of "preventive palliation" in which excellent palliative care was coupled with a pinch of prevention, like routine checks of blood pressure, routine physical check-ups, etc, so that any aberration can be detected early and necessary rectification measures can be implemented. These periods of routine check-ups can also be used to assess the psycho-social, cultural and emotional problems, if any. Such an approach, say every monthly, gives the elderly something to look forward to and ensures a high degree of customer satisfaction and greatly reduces the burden on the current health system. The challenges faced and the data obtained from this study were shocking. The elderly living in rural areas of the tribal state of Jharkhand suffer from poor physical and mental health, a factor which was rather unexpected in the Indian cultural system in the rural setting. Simple strategies like implementing routine health check ups with provision of "nutritious meal program" can go a long way in mitigating these problems in a cost-effective and simple manner. To make the government-based programs accessible and available to the end-users, participation of local bodies like NGOs is mandatory. Preventive palliation, a concept introduced by Kosish, is the way forward for providing palliative care to the rural-based elderly in most parts of India. This concept takes into account the local cultural, social, financial and long term feasibility and sustainability aspects of the care process. PMID- 21811352 TI - The role of dentist in palliative care team. AB - The palliative doctor gives the 'touch of God' as he/she takes care of the terminally ill patient. The oncologist encounters great difficulties in managing oral cavity problems of these patients. A trained dental doctor can help other doctors in dealing with these situations. But the general dental surgeon does not have enough idea about his part in these treatments. The community is also unaware of the role that a nearby dentist can play. Adequate training programs have to be conducted and awareness has to be created. A trained dentist will be a good team mate for the oncologist or radiotherapist or other doctors of the palliative care team. In this paper, a brief attempt is made to list a few areas in which a palliative care dentist can help other members of the palliative care team and also the patient in leading a better life. PMID- 21811353 TI - Occupational care giving conditions and human rights: a study of elderly caregivers in botswana. AB - The article aims to explore and discuss the occupational care giving conditions pitting them against human rights. The article's objective is to initiate discussions and generate literature pertaining to occupational care giving load and assessing the human rights challenge it poses. The article uses analysis of the literature review from an array of eclectic data sources. The following factors were found besetting the caregivers' human rights: (1) Aging; (2) Cultural and community attitudes towards care giving; (3) Risk of contagion; (4) Health hazards and lack of compensation. RECOMMENDATIONS: (1) Adoption of grandparents/grandchildren care symbiosis system; (2) Government remuneration policy for caregivers; (3) Mainstreaming of gender education to encourage men and youth develop an interest in care giving; (4) Institution of laws and policies by countries to provide for the compensation of caregivers' occupational hazards and risks. PMID- 21811354 TI - Care of Terminally Ill Cancer Patients: An Intensivist's Dilemma. AB - BACKGROUND AND CONTEXT: Treatment of terminally ill cancer patients always poses great challenges especially when these critical patients are admitted in intensive care unit (ICU). The severity of their diseases throws a clinical and ethical dilemma to the treating intensivist. AIMS AND OBJECTIVES: To evaluate the benefits of intensive care treatment in terminally ill cancer patients and also to find out whether optimal utilization of critical care resources has got any positive financial, psychological and clinical outcome. MATERIALS AND METHODS: A retrospective evaluation of 53 terminally ill cancer patients, who got admitted to ICU of our department, was carried out. Majority of these patients presented with terminal phase of illness involving multi-organ pathologies with diverse range of symptoms. These patients were provided ventilatory, symptomatic and supportive treatment on patient-to-patient basis. Strict and vigilant monitoring of all vital parameters was carried out. At the end of study, all the data was compiled systematically and was subjected to statistical analysis using non parametric tests. RESULTS: The demographic profile of such patients was highly variable with regard to educational, social and financial status (P<0.05). The most common group of cancer was hematological malignancies (24.53%) followed by lung cancer (18.87%), uteri-ovarian (15.09), colorectal (13.2%) and others. Significant number (P<0.05) of patients (64.15%) required mechanical ventilation and ionotropic support (79.24%). Mortality increased with increasing number of organ system involvement and reaching up to 100% with involvement of 5 or more organ systems. CONCLUSIONS: ICU care is the best form of treatment for terminally ill but resources should be used optimally so that a young deserving patient should not be sacrificed for the scarcity of resources. PMID- 21811355 TI - Caring for dying and meeting death: experiences of Iranian and Swedish nurses. AB - OBJECTIVE: Our world is rapidly becoming a global community, which creates a need to further understand the universal phenomena of death and professional caring for dying persons. This study thus was conducted to describe the meaning of nurses' experiences of caring for dying people in the cultural contexts of Iran and Sweden. MATERIALS AND METHODS: Using a phenomenological approach, phenomenon of caring for dying people was studied. Eight registered nurses who were working in oncology units in Tehran, Iran and eight registered nurses working in hospital and home care in North part of Sweden were interviewed. The interviews were analyzed using the principles of phenomenological hermeneutics. RESULTS: THE FINDINGS WERE FORMULATED BASED ON TWO THEMES INCLUDED: (1) "Sharing space and time to be lost", and (2) "Caring is a learning process. CONCLUSIONS: The results showed that being with dying people raise an ethical demand that calls for personal and professional response, regardless of sex, culture or context. The physical and organizational context must be supportive and enable nurses to stand up to the demands of close relationships. Specific units and teamwork across various personnel seem to be a solution that is missing in Iran. PMID- 21811356 TI - Palliative management of malignant bowel obstruction in terminally ill patient. AB - Mr. P was a 57-year-old man who presented with symptoms of bowel obstruction in the setting of a known metastatic pancreatic cancer. Diagnosis of malignant bowel obstruction was made clinically and radiologically and he was treated conservatively (non-operatively)with octreotide, metoclopromide and dexamethasone, which provided good control over symptoms and allowed him to have quality time with family until he died few weeks later with liver failure. Bowel obstruction in patients with abdominal malignancy requires careful assessment. The patient and family should always be involved in decision making. The ultimate goals of palliative care (symptom management, quality of life and dignity of death) should never be forgotten during decision making for any patient. PMID- 21811357 TI - Aggressive palliative surgery in metastatic phyllodes tumor: impact on quality of life. AB - Metastatic phyllodes tumor has very few treatment options. Phyllodes tumor in metastatic setting has limited role of surgery, radiotherapy and chemotherapy or combined treatment. Most of the patients receive symptomatic management only. We present a case of metastatic phyllodes tumor managed with aggressive margin negative resection of primary tumor leading to palliation of almost all the symptoms, which eventually led to improved quality of life and probably to improved survival. The improved quality of life was objectively assessed with Hamilton depression rating scale. Surgery may be the only mode of palliation in selected patients that provides a better quality of life and directly or indirectly may lead to improved survival. PMID- 21811358 TI - From Editor's Desk. PMID- 21811359 TI - Training programs in communication skills for health care professionals and volunteers. AB - Communication skills are as important as vital needs. Health care professionals have to be aware of their own communication practices and need to undergo periodic appraisal of the same. Training programmes in communication skills are unfortunately not part of our academic curriculum. The article highlights the need and the overview of such training programmes. PMID- 21811360 TI - A timely referral to palliative care team improves quality of life. AB - In the trajectory of disease progress and treatment plan, patients and the family members are confronted with challenging situations like unsurmountable physical distress, inadequate coping patterns, unanswered spiritual issues in the background of serious threat to very existence of life leads to a debilitating Quality of life.The Palliative Care team approach addresses all the issues and also sees the patient to go through the protocols of Palliative care management as well as Oncological treatment plan. Further, this fecilitates a smooth transition from the hospital to home and hospice care. Various studies conducted globally revealed that patients received palliative care intervention along with oncological treatments had higher scores of Quality of life compared to patients received onlyoncology care alone.This article discusses the various factors contributing to late referrals to palliative care team and also care giver's views pertaining to need for early referral. Timely referral to palliative care minimises the patient's and care giver's distress, ensures modest Quality of life and appropriate measures at the end of life care. PMID- 21811361 TI - Team networking in palliative care. AB - "If you want to travel quickly, go alone. But if you want to travel far, you must go together". African proverb. The delivery of palliative care is often complex and always involves a group of people, the team, gathered around the patient and those who are close to them. Effective communication and functional responsive systems of care are essential if palliative care is to be delivered in a timely and competent way. Creating and fostering an effective team is one of the greatest challenges for providers of palliative care. Teams are organic and can be life giving or life sapping for their members. PMID- 21811362 TI - Computerized clinical database development in oncology. AB - In the era of evidence based medicine documentation of clinical data is extremely important. The field of Health informatics is a discipline at the intersection of information science, computer science and health science. Current health informatics field is mainly catering to the general needs of hospital setups. Development of disease / organ/ specialty based computerized clinical data base is still in its infancy and there is a need for clinicians to actively involve in this field to generate authentic and analyzable clinical data. In this article we present our experience of computerized oncology clinical data base development. PMID- 21811363 TI - Networking of palliative care at the corporate level. AB - This article is a story of networking of palliative care at the corporate level. This gives an insight that if you have will and dedication then you can imagine and make it true that networking can start even before the birth of an organization. PMID- 21811364 TI - Teaching palliative care across cultures: the singapore experience. AB - Palliative care is a growing area of practice throughout the world and its promotion relies on adequately trained health care professionals. However, there are only a limited number of postgraduate academic courses or clinical training opportunities available, especially in resource challenged areas of the Asia Pacific region. This article outlines a creative endeavour between Flinders University, Adelaide Australia, the Singapore National Cancer Centre and the Asia Pacific Hospice and Palliative Care Network to provide an educational opportunity for students from the region. The strengths of the programme include its strong theoretical and evidenced-based framework, its multidisciplinary inclusiveness and its innovative and interactive teaching style. The main teaching challenge for the teaching team is to deliver culturally appropriate curricula to students from diverse cultural and linguistic backgrounds. This postgraduate programme is an important initiative for the region and for the development of future leaders and pioneers in the discipline. PMID- 21811365 TI - Back to the future, current trends in breakthrough pain treatments. AB - The importance of effectively managing breakthrough pain for patients on long term background analgesia has recently lead to the development of a range of new products aimed at filling this need. This review article looks at the reasons behind these developments and their implications for clinical practice in resource limited situations. PMID- 21811366 TI - Recent advances in the management of breathlessness. AB - Breathlessness is a frightening symptom to both witness and experience. It is common in many conditions, especially in the palliative setting, profoundly affecting the quality of the person's life. The purpose of this article is to provide an overview of the recent advances in the management of breathlessness in the areas of, knowledge of disease trajectories, assessment, pharmacological and non-pharmacological interventions and the use of oxygen. PMID- 21811367 TI - Networking and training in palliative care: challenging values and changing practice. AB - What make a good doctor is a question posed by the public and profession and is key when designing training programmes. The goal of training is to change practice not simply acquire knowledge yet too often curriculums and assessment focuses on knowledge and skills. Professional practice is underpinned by beliefs and values and therefore training may need to challenge deeply held values in order to result in a change in practice. Palliative care offers an opportunity to challenge values at a deeply personal level as it brings experiences of pain and suffering alongside clinical knowledge and skills. Palliative care is holistic and so real scenarios where physical, psychological, social and spiritual issues are evident can be presented in an interactive, learner centered environment. Training in ethics alongside clinical skills will assist the development of judgment which should also be assessed. Communication skills enable the clinician to hear and understand the needs and wishes of those facing life limiting illness. Training should include aspects of modeling and mentorship to demonstrate and integrate the learning with the realities of clinical practice and include those who lead and influence policy and advocacy. PMID- 21811368 TI - Pain and Opioid Dependence: Is it a Matter of Concern. AB - Opioids are extremely effective in managing cancer pain, and now are utilized for longer periods of time in cancer patients as the treatment for malignancies has become more successful.[1] The goals in cancer pain treatment includes maintaining function in patients with cancer pain (especially in earlier stage disease), and palliation in advanced disease.[1] The perception of the lay public and inexperienced clinicians that addiction is inevitable, often leads to an inappropriate fear to utilize opioids to appropriately manage pain; resulting in persistent under-treatment of cancer pain internationally.[23] There is much confusion about the phenomenon of physical dependence and how this can be differentiated from the maladaptive behaviors that constitute a diagnosis of substance abuse. The burden of cancer and associated cancer pain is projected to continue to rise, and is often at an advanced stage at diagnosis in less developed countries.[4] To be able to provide quality care for this patient population availability of opioids and skilled clinicians in pain management is paramount. In the majority of cases, the main concern is to abate concerns about risks of opioid addiction; to allow adequate pain relief. To understand the infrequent phenomenon of substance abuse in the setting of cancer pain management clear definitions are needed, and review of the epidemiology of occurrence in cancer populations is needed. It is also important to clearly separate the issues of substance abuse at the patient level and diversion of prescribed opioids. There are principles of managing cancer pain in the rare clinical scenario when the risk of substance abuse is high, which can still allow safe management of cancer pain with opioids. PMID- 21811369 TI - Spirituality and palliative care. AB - This paper shows how palliative care developed as a reaction to the compartimentalized technical approach of modern medicine. But what does it mean if we say palliative care wants to treat patients as whole persons? A few pitfalls need to avoided. All disciplines involved in palliative care should act within the limits of their own specific professional role. Physicians and nurses should certainly not force patients into spiritual or religious discussions or practices. They should understand that religion and spirituality also influence the ethical (and thus medical) choices people make, respect their own conscience and worldview too and cultivate conscious compassion. PMID- 21811370 TI - How to plan research in palliative care. AB - Research in palliative care has its challenges. However, research in different aspects of palliative care is important. This paper gives simple methods of planning and conducting a research in the area of palliative care in India. PMID- 21811371 TI - Moving toward a national policy on palliative and end of life care. AB - Indian Palliative Care has developed over the past 17 years but it has also developed disabilities due to lack of a National Policy and hence has compromised its effectiveness. It is true that we have come a long way but we still have many miles to go and we will get there only if we have a proper road map and sign posts. This article attempts to suggest some specific measures in establishing such a National Policy. PMID- 21811372 TI - Gynaecological malignancies from palliative care perspective. AB - Of the approximately 80,000 new cases of all cancers detected every year in India, 10-15% are gynecological malignancies. As per population-based registries under the National Cancer Registry Program, the leading sites of cancer among women are the cervix uteri, breast, and oral cavity. About 50-60% of all cancers among women in India are mainly of the following four organs: cervix uteri, breast, corpus uteri, and ovaries. Over 70% of these women report for diagnostic and treatment services at an advanced stage of disease, resulting in poor survival and high mortality rates. Among all gynecological cancers, ovarian cancer is the deadliest one and, in 2/3(rd) of the cases, is detected in an advanced stage. But, in India and in other developing countries, due to inadequate screening facilities for the preventable cancer cervix, this kills more women than any other cancer in females. Gynecology Oncologist as a sub specialist has an immensely important role in curtailing the menace of gynecological malignancies by providing comprehensive preventive, curative, palliative and follow-up services, with the aim of assuring a good quality of life to women as a cornerstone of cancer management. PMID- 21811373 TI - Paediatric palliative care: theory to practice. AB - Paediatric palliative care is a holistic approach aimed at addressing the complex issues related to the care of children and families facing chronic life limiting illnesses. The needs of children are unique and often quite different from those of adults receiving palliative care. This review article outlines some of the salient features of paediatric palliative care which are relevant to all professionals caring for children with life limiting illnesses in their practice. PMID- 21811374 TI - Incorporating person centred care principles into an ongoing comprehensive cancer management program: an experiential account. AB - Recent research indicates a definite positive impact on treatment outcomes when an integrative approach that focuses on symptom control and quality of life is provided along with the standard therapeutic regimens. However implementation or practice of this approach is not seen widely due to the culture of medical training and practice. This article presents the initial development of a program for incorporating integrative care principles into an ongoing comprehensive cancer care program at a tertiary centre. The key purpose of the program being to develop, facilitate, and establish comprehensive and holistic processes including palliative care principles, that would positively enhance the quantity and quality of life of the person with disease, as well as create an environment that reflects and sustains this approach. The vision, objectives, goals, strategies, activities and results within the 7 months of implementation are documented. The new learnings gained during the process have also been noted in the hope that the model described may be used to conceptualize similar care giving facilities in other centres. PMID- 21811375 TI - Total pain management. AB - We CanSupport provide holistic care to the patients and family. This means, physical, emotional, psychosocial and spiritual care. The objective of this article is to implement a plan for improved high quality care, within a dynamic and complex health care system for palliative care. Twelve years of working experience with palliative care in CanSupport 'India' and 10 years of working palliative care aboard (USA). High level satisfaction of the patient of the patient and families due to the psycho, socio, spiritual model and help for income generation and vocational training. We suggest and encourage, to we this model for all palliative care centre and institutions. PMID- 21811376 TI - Pain in children: neglected, unaddressed and mismanaged. AB - Pain is one of the most misunderstood, under diagnosed, and under treated/untreated medical problems, particularly in children. One of the most challenging roles of medical providers serving children is to appropriately assess and treat their pain. New JCAHO regulations regard pain as "the fifth vital sign" and require caregivers to regularly assess and address pain. Pain being a personal experience, many different terms are used to describe different sensations. Assessment of pain in children is linked to their level of development. Children of the same age vary widely in their perception and tolerance of pain. PMID- 21811377 TI - Hospital-based Palliative care: A Case for Integrating Care with Cure. AB - The reason that probably prompted Dame Cicely Saunders to launch the palliative care movement was the need to move away from the impersonal, technocratic approach to death that had become the norm in hospitals after the Second World War. Palliative care focuses on relieving the suffering of patients and families. Not limited to just management of pain, it includes comprehensive management of any symptom, which affects the quality of life. Care is optimized through early initiation and comprehensive implementation throughout the disease trajectory. Effective palliative care at the outset can help accelerate a positive clinical outcome. At the end of life, it can enhance the opportunity for the patient and family to achieve a sense of growth, resolve differences, and find a comfortable closure. It helps to reduce the suffering and fear associated with dying and prepares the family for bereavement. PMID- 21811378 TI - Research focus in palliative care. AB - This brief article on pre-conference CME topic 'How to plan Research in Palliative Care' is aimed to provide an overview of the background, concept, domains, present research activities and the future prospect for research opportunities. Advances in Palliative Care are made with a focus to address the quality of medical practice and 'quality of death', in those patients who have advanced stage diseases where cure may or may not be possible. The issues which can improve the palliative care delivery and the areas where evidence of practice is still weak can be identified by forming network and collaborative groups for the application of study and research methods in India. PMID- 21811379 TI - The emergence of Clostridium difficile infection among peripartum women: a case control study of a C. difficile outbreak on an obstetrical service. AB - OBJECTIVE: An outbreak of 20 peripartum Clostridium difficile infections (CDI) occurred on the obstetrical service at the University of Washington Medical Center (UWMC) between April 2006 and June 2007. In this report, we characterize the clinical manifestations, describe interventions that appeared to reduce CDI, and determine potential risk factors for peripartum CDI. METHODS: An investigation was initiated after the first three peripartum CDI cases. Based on the findings, enhanced infection control measures and a modified antibiotic regimen were implemented. We conducted a case-control study of peripartum cases and unmatched controls. RESULTS: During the outbreak, there was an overall incidence of 7.5 CDI cases per 1000 deliveries. Peripartum CDI infection compared to controls was significantly associated with cesarean delivery (70% versus 34%; P=0.03), antibiotic use (95% versus 56%; P=0.001), chorioamnionitis (35% versus 5%; P=0.001), and the use of the combination of ampicillin, gentamicin, and clindamycin (50% versus 3%; P<0.001). Use of combination antibiotics remained a significant independent risk factor for CDI in the multivariate analysis. CONCLUSIONS: The outbreak was reduced after the implementation of multiple infection control measures and modification of antibiotic use. However, sporadic CDI continued for 8 months after these measures slowed the outbreak. Peripartum women appear to be another population susceptible to CDI. PMID- 21811381 TI - The use of fuzzy backpropagation neural networks for the early diagnosis of hypoxic ischemic encephalopathy in newborns. AB - OBJECTIVE: To establish an early diagnostic system for hypoxic ischemic encephalopathy (HIE) in newborns based on artificial neural networks and to determine its feasibility. METHODS: Based on published research as well as preliminary studies in our laboratory, multiple noninvasive indicators with high sensitivity and specificity were selected for the early diagnosis of HIE and employed in the present study, which incorporates fuzzy logic with artificial neural networks. RESULTS: The analysis of the diagnostic results from the fuzzy neural network experiments with 140 cases of HIE showed a correct recognition rate of 100% in all training samples and a correct recognition rate of 95% in all the test samples, indicating a misdiagnosis rate of 5%. CONCLUSION: A preliminary model using fuzzy backpropagation neural networks based on a composite index of clinical indicators was established and its accuracy for the early diagnosis of HIE was validated. Therefore, this method provides a convenient tool for the early clinical diagnosis of HIE. PMID- 21811380 TI - Chlamydia trachomatis and Mycoplasma genitalium plasma antibodies in relation to epithelial ovarian tumors. AB - OBJECTIVE: To assess associations of Chlamydia trachomatis and Mycoplasma genitalium antibodies with epithelial ovarian tumors. METHODS: Plasma samples from 291 women, undergoing surgery due to suspected ovarian pathology, were analyzed with respect to C. trachomatis IgG and IgA, chlamydial Heat Shock Protein 60-1 (cHSP60-1) IgG and M. genitalium IgG antibodies. Women with borderline tumors (n=12), ovarian carcinoma (n=45), or other pelvic malignancies (n=11) were matched to four healthy controls each. RESULTS: Overall, there were no associations of antibodies with EOC. However, chlamydial HSP60-1 IgG antibodies were associated with type II ovarian cancer (P=.002) in women with plasma samples obtained >1 year prior to diagnosis (n=7). M. genitalium IgG antibodies were associated with borderline ovarian tumors (P=.01). CONCLUSION: Chlamydial HSP60-1 IgG and M. genitalium IgG antibodies are in this study associated with epithelial ovarian tumors in some subsets, which support the hypothesis linking upper-genital tract infections and ovarian tumor development. PMID- 21811382 TI - In vitro culture conditions for maintaining a complex population of human gastrointestinal tract microbiota. AB - A stable intestinal microbiota is important in maintaining human physiology and health. Although there have been a number of studies using in vitro and in vivo approaches to determine the impact of diet and xenobiotics on intestinal microbiota, there is no consensus for the best in vitro culture conditions for growth of the human gastrointestinal microbiota. To investigate the dynamics and activities of intestinal microbiota, it is important for the culture conditions to support the growth of a wide range of intestinal bacteria and maintain a complex microbial community representative of the human gastrointestinal tract. Here, we compared the bacterial community in three culture media: brain heart infusion broth and high- and low-carbohydrate medium with different growth supplements. The bacterial community was analyzed using denaturing gradient gel electrophoresis (DGGE), pyrosequencing and real-time PCR. Based on the molecular analysis, this study indicated that the 3% fecal inoculum in low-concentration carbohydrate medium with 1% autoclaved fecal supernatant provided enhanced growth conditions to conduct in vitro studies representative of the human intestinal microbiota. PMID- 21811383 TI - Bacterial artificial chromosome libraries of pulse crops: characteristics and applications. AB - Pulse crops are considered minor on a global scale despite their nutritional value for human consumption. Therefore, they are relatively less extensively studied in comparison with the major crops. The need to improve pulse crop production and quality will increase with the increasing global demand for food security and people's awareness of nutritious food. The improvement of pulse crops will require fully utilizing all their genetic resources. Bacterial artificial chromosome (BAC) libraries of pulse crops are essential genomic resources that have the potential to accelerate gene discovery and enhance molecular breeding in these crops. Here, we review the availability, characteristics, applications, and potential applications of the BAC libraries of pulse crops. PMID- 21811384 TI - Multidisciplinary care in pediatric oncology. AB - This paper describes the significant advances in the treatment of childhood cancer and supportive care that have occurred over the last several decades and details how these advances have led to improved survival and quality of life (QOL) for children with cancer through a multidisciplinary approach to care. Advances in the basic sciences, general medicine, cooperative research protocols, and policy guidelines have influenced and guided the multidisciplinary approach in pediatric oncology care across the spectrum from diagnosis through long-term survival. Two case studies are provided to highlight the nature and scope of multidisciplinary care in pediatric oncology care. PMID- 21811385 TI - The relationship between deliberate self-harm behavior, body dissatisfaction, and suicide in adolescents: current concepts. AB - Deliberate self-harm (DSH) is a common though often hidden condition in children and adolescents that may result in suicide. This discussion covers several aspects of DSH including its prevalence, etiology, and management. The relationships of DSH to body dissatisfaction and suicide are specifically considered. Even though most cases of DSH do not end in overt suicide, DSH reflects that potential underlying psychological pathophysiology, and likelihood of eventual death from self-murder, cannot always be predicted or prevented. It is important to take all acts of DSH as serious, and to offer comprehensive management to prevent future acts of DSH and potential suicide. PMID- 21811386 TI - Measuring the impact of allied health research. AB - BACKGROUND: Excellence in Research for Australia (ERA) rankings are given to academic journals in which Australian academics publish. This provides a metric on which Australian institutions and disciplines are ranked for international competitiveness. This paper explores the issues surrounding the ERA rankings of allied health journals in Australia. METHODS: We conducted a broad search to establish a representative list of general allied health and discipline-specific journals for common allied health disciplines. We identified the ERA rankings and impact factors for each journal and tested the congruence between these metrics within the disciplines. RESULTS: Few allied health journals have high ERA rankings (A*/A), and there is variability in the impact factors assigned to journals within the same ERA rank. There is a small group of allied health researchers worldwide, and this group is even smaller when divided by discipline. Current publication metrics may not adequately assess the impact of research, which is largely aimed at clinicians to improve clinical practice. Moreover, many journals are produced by underfunded professional associations, and readership is often constrained by small numbers of clinicians in specific allied health disciplines who are association members. CONCLUSION: Allied health must have a stronger united voice in the next round of ERA rankings. The clinical impact of allied health journals also needs to be better understood and promoted as a research metric. PMID- 21811387 TI - Radioelectric asymmetric brain stimulation and lingual apex repositioning in patients with atypical deglutition. AB - BACKGROUND: Atypical deglutition is exacerbated by stress and anxiety. Several therapeutic approaches have been employed to treat stress and anxiety disorders, ranging from typical psychopharmacological strategies to novel physical protocols, such as transcranial magnetic stimulation and radioelectric asymmetric conveyor (REAC) stimulation. The purpose of the present study was to test the efficacy of REAC brain stimulation in atypical deglutition. METHODS: The position of the lingual apex (Payne method), pattern of free deglutition, and subjective and objective impression of deglutition were evaluated in 128 outpatients suffering from atypical deglutition. Deglutition testing consisted of an operator holding down the lower lip, hence counteracting the strength exerted by the orbicularis muscle. All subjects were treated using two REAC brain stimulation protocols. Patients were assessed before treatment, immediately after treatment, and three months following the last cycle of REAC therapy. RESULTS: REAC stimulation led to an improvement in positioning of the lingual apex and a significant decrease of muscle involvement in all patients immediately after REAC treatment, and the improvement was maintained at three-month follow-up. CONCLUSION: In the present study, the REAC therapeutic protocols led to normalization in lingual apex positioning and significant improvement in swallowing in all participants suffering from atypical deglutition. PMID- 21811388 TI - Health care transition in Germany - standardization of procedures and improvement actions. AB - Previous studies have assessed an increase in the number of people in need and emphasized the advantages of structured discharge management and health care transition. Therefore, our study evaluated the status quo of transition in a major German city after standardization of procedures and implementation of standard forms. Satisfaction with handling of standard forms and improvement of procedures was evaluated. Additionally, patients who had recently been hospitalized were asked about the hospital discharge process. The results show that the recent efforts of standardization helped to improve interface management for health care workers and patients and showed further improvement options. PMID- 21811389 TI - Diclofenac sodium topical solution with dimethyl sulfoxide, a viable alternative to oral nonsteroidal anti-inflammatories in osteoarthritis: review of current evidence. AB - Topical nonsteroidal anti-inflammatory drugs (NSAIDs) may offer a safer alternative to their oral counterparts for the management of osteoarthritis. Diclofenac sodium topical solution with dimethyl sulfoxide (TDiclo) was evaluated in five randomized, controlled trials and is indicated for treatment of the signs and symptoms associated with osteoarthritis of the knee. Three studies showed that TDiclo is superior to placebo and vehicle control with respect to pain, physical function, and perception of osteoarthritis symptoms. Two studies showed that benefits are similar to those of oral diclofenac, with one study demonstrating statistical equivalence. The most common adverse event associated with TDiclo in these studies was dry skin. Incidences of gastrointestinal adverse events and abnormal levels of liver enzymes were lower with TDiclo compared with oral diclofenac in active-controlled studies. Based on these studies, TDiclo represents a practical, evidence-based option for the management of osteoarthritis of the knee. PMID- 21811390 TI - Stability of behavioral estimates of activity-dependent modulation of pain. AB - Temporal sensory summation of pain (TSSP) is a proxy measure of windup in humans and results in increased ratings of pain caused by a repetitive, low-frequency noxious stimulus. Aftersensations (ASs) are pain sensations that remain after TSSP has been induced. We examined the within-session and across-session variability in TSSP and AS estimation in healthy participants and in participants with exercise-induced muscle pain in order to determine whether the presence of pain affected the stability of TSSP and ASs. TSSP was estimated by application of 10 repetitive, low-frequency (<0.33 Hz) thermal pulses and measured by the simple slope of pain ratings between the first and fifth pulses. ASs were measured by the presence of any remaining pain sensations up to 1 minute after TSSP was induced. TSSP estimation remained moderately stable in pain-free participants and in participants with pain within a single testing session but demonstrated low stability across sessions in pain-free participants. AS estimation was stable for all groups. Estimation of TSSP and ASs using these protocols appears to be a reliable single-session outcome measure in studies of interventions for acute muscle pain and in experimental studies with healthy participants. This article evaluates the reliability of a commonly used method of estimating TSSP and ASs in both healthy participants and in a clinically relevant model of acute pain. These protocols have the potential to be used as single-session outcome measures for interventional studies and in experimental studies. PMID- 21811391 TI - Diclofenac topical solution compared with oral diclofenac: a pooled safety analysis. AB - BACKGROUND: Topical nonsteroidal anti-inflammatory drug (NSAID) formulations, which produce less systemic exposure compared with oral formulations, are an option for the management of osteoarthritis (OA). However, the overall safety and efficacy of these agents compared with oral or systemic therapy remains controversial. METHODS: Two 12-week, double-blind, double-dummy, randomized, controlled, multicenter studies compared the safety and efficacy profiles of diclofenac topical solution (TDiclo) with oral diclofenac (ODiclo). Each study independently showed that TDiclo had similar efficacy to ODiclo. To compare the safety profiles of TDiclo and ODiclo, a pooled safety analysis was performed for 927 total patients who had radiologically confirmed symptomatic OA of the knee. This pooled analysis included patients treated with TDiclo, containing 45.5% dimethyl sulfoxide (DMSO), and those treated with ODiclo. Safety assessments included monitoring of adverse events (AEs), recording of vital signs, dermatologic evaluation of the study knee, and clinical laboratory evaluation. RESULTS: AEs occurred in 312 (67.1%) patients using TDiclo versus 298 (64.5%) of those taking ODiclo. The most common AE with TDiclo was dry skin at the application site (24.1% vs 1.9% with ODiclo; P < 0.0001). Fewer gastrointestinal (25.4% vs 39.0%; P < 0.0001) and cardiovascular (1.5% vs 3.5%; P = 0.055) AEs occurred with TDiclo compared with ODiclo. ODiclo was associated with significantly greater increases in liver enzymes and creatinine, and greater decreases in creatinine clearance and hemoglobin (P < 0.001 for all). CONCLUSIONS: These findings suggest that TDiclo represents a useful alternative to oral NSAID therapy in the management of OA, with a more favorable safety profile. PMID- 21811392 TI - High TNF-alpha plasma levels and macrophages iNOS and TNF-alpha expression as risk factors for painful diabetic neuropathy. AB - Painful diabetic neuropathy (PDN) is one of the most common complications of diabetes mellitus. Recently it has become clear that nitric oxide (NO) and proinflammatory cytokines play an important role in the pathogenesis of PDN. We investigated whether the cytokine tumor necrosis factor alpha (TNF-alpha) and NO play a role in PDN pathogenesis by performing a cross-sectional and a case control study in 110 type 2 diabetic patients. Of 110 subjects, 59 patients suffered from PDN (cases) and the remaining were painless DN (controls). Cross sectionally, plasma TNF-alpha levels and immunoreactivity for inducible NO synthase (iNOS) and TNF-alpha were higher in patients with more severe pain on the visual analog scale. There were statistically significant differences between mild and severe pain for TNF-alpha levels, iNOS immunoreactivity, and TNF-alpha immunoreactivity. There were statistically significant differences between mild and severe pain for TNF-alpha levels (mean 15.24 pg/mL +/- 5.42 vs 20.44 +/- 10.34), iNOS immunoreactivity (9.76% +/- 8.60% vs 15.48% +/- 11.56%), and TNF alpha immunoreactivity (13.0% +/- 9.48% vs 20.44% +/- 11.75%). The case-control study showed that TNF-alpha had an odds ratio of 5.053 (P < 0.001), TNF-alpha immunoreactivity of 4.125 (P < 0.001), and iNOS immunoreactivity of 3.546 (P = 0.002). DN patients with high TNF-alpha levels, and high iNOS and TNF-alpha expression in macrophages are at risk of suffering from pain. The higher the TNF alpha level, and iNOS and TNF-alpha immunoreactivity, the more severe the pain. These findings could form the basis of further research into better management of PDN. PMID- 21811393 TI - Nimesulide inhibits protein kinase C epsilon and substance P in sensory neurons - comparison with paracetamol. AB - In this paper we describe new actions of nimesulide and paracetamol in cultured peripheral neurons isolated from rat dorsal root ganglia (DRG). Both drugs were able to decrease in a dose-dependent fashion the number of cultured DRG neurons showing translocation of protein kinase C epsilon (PKCE) caused by exposure to 1 MUM bradykinin or 100 nM thrombin. In addition, the level of substance P (SP) released by DRG neurons and the level of preprotachykinin mRNA expression were measured in basal conditions and after 70 minutes or 36 hours of stimulation with nerve growth factor (NGF) or with an inflammatory soup containing bradykinin, thrombin, endothelin-1, and KCl. Nimesulide (10 MUM) significantly decreased the mRNA levels of the SP precursor preprotachykinin in basal and in stimulated conditions, and decreased the amount of SP released in the medium during stimulation of neurons with NGF or with the inflammatory soup. The effects of paracetamol (10 MUM) on such response was lower. Nimesulide completely inhibited the release of prostaglandin E2 (PGE2) from DRG neurons, either basal or induced by NGF and by inflammatory soup, while paracetamol decreased PGE2 release only partially. Our data demonstrate, for the first time, a direct effect of two drugs largely used as analgesics on DRG neurons. The present results suggest that PKCE might be a target for the effect of nimesulide and paracetamol, while inhibition of SP synthesis and release is clearly more relevant for nimesulide than for paracetamol mechanism of action. PMID- 21811394 TI - DETECTING LOW-LEVEL SYNTHESIS IMPURITIES IN MODIFIED PHOSPHOROTHIOATE OLIGONUCLEOTIDES USING LIQUID CHROMATOGRAPHY - HIGH RESOLUTION MASS SPECTROMETRY. AB - An LC-MS method based on the use of high resolution Fourier transform ion cyclotron resonance mass spectrometry (FTIRCMS) for profiling oligonucleotides synthesis impurities is described.Oligonucleotide phosphorothioatediesters (phosphorothioate oligonucleotides), in which one of the non-bridging oxygen atoms at each phosphorus center is replaced by a sulfur atom, are now one of the most popular oligonucleotide modifications due to their ease of chemical synthesis and advantageous pharmacokinetic properties. Despite significant progress in the solid-phase oligomerization chemistry used in the manufacturing of these oligonucleotides, multiple classes of low-level impurities always accompany synthetic oligonucleotides. Liquid chromatography-mass spectrometry has emerged as a powerful technique for the identification of these synthesis impurities. However, impurity profiling, where the entire complement of low-level synthetic impurities is identified in a single analysis, is more challenging. Here we present an LC-MS method based the use of high resolution-mass spectrometry, specifically Fourier transform ion cyclotron resonance mass spectrometry (FTIRCMS or FTMS). The optimal LC-FTMS conditions, including the stationary phase and mobile phases for the separation and identification of phosphorothioate oligonucleotides, were found. The characteristics of FTMS enable charge state determination from single m/z values of low-level impurities. Charge state information then enables more accurate modeling of the detected isotopic distribution for identification of the chemical composition of the detected impurity. Using this approach, a number of phosphorothioate impurities can be detected by LC-FTMS including failure sequences carrying 3'-terminal phosphate monoester and 3'-terminal phosphorothioate monoester, incomplete backbone sulfurization and desulfurization products, high molecular weight impurities, and chloral, isobutyryl, and N(3) (2-cyanoethyl) adducts of the full length product. When compared with low resolution LC-MS, ~60% more impurities can be identified when charge state and isotopic distribution information is available and used for impurity profiling. PMID- 21811395 TI - Calcium Oxalate Stone Agglomeration Inhibition [tm] Reflects Renal Stone-Forming Activity. AB - Louisiana and other Gulf South states comprise a "Stone Belt" where calcium oxalate stone formers (CaOx SFs) are found at a high rate of approximately 5%. In these patients, the agglomeration of small stone crystals, which are visible in nearly all morning urine collections, forms stones that can become trapped in the renal parenchyma and the renal pelvis. Without therapy, about half of CaOx SFs repeatedly form kidney stones, which can cause excruciating pain that can be relieved by passage, fragmentation (lithotripsy), or surgical removal. The absence of stones in "normal" patients suggests that there are stone inhibitors in "normal" urines.At the Ochsner Renal Stone Clinic, 24-hour urine samples are collected by the patient and sent to the Ochsner Renal Stone Research Program where calcium oxalate stone agglomeration inhibition [tm] measurements are performed. Urine from healthy subjects and inactive stone formers has demonstrated strongly inhibited stone growth [tm] in contrast to urine from recurrent CaOx SFs. [tm] data from 1500 visits of 700 kidney stone patients have been used to evaluate the risk of recurrence in Ochsner's CaOx SF patients. These data have also been used to demonstrate the interactive roles of certain identified urinary stone-growth inhibitors, citrate and Tamm-Horsfall protein (THP), which can be manipulated with medication to diminish recurrent stone formation. Our goal is to offer patients both financial and pain relief by reducing their stones with optimized medication, using medical management to avoid costly treatments. PMID- 21811396 TI - Multiple retinal emboli following a new carotid stenting procedure. AB - This report discusses the observation of multiple retinal emboli following placement of a new carotid stenting device. Especially dense plaques in the carotid artery can shatter into dust-like particles that may be fine enough to penetrate the filter of the new device, thus posing the danger of retinal perfusion. PMID- 21811397 TI - Hyphal development in Candida albicans requires two temporally linked changes in promoter chromatin for initiation and maintenance. AB - Phenotypic plasticity is common in development. For Candida albicans, the most common cause of invasive fungal infections in humans, morphological plasticity is its defining feature and is critical for its pathogenesis. Unlike other fungal pathogens that exist primarily in either yeast or hyphal forms, C. albicans is able to switch reversibly between yeast and hyphal growth forms in response to environmental cues. Although many regulators have been found involved in hyphal development, the mechanisms of regulating hyphal development and plasticity of dimorphism remain unclear. Here we show that hyphal development involves two sequential regulations of the promoter chromatin of hypha-specific genes. Initiation requires a rapid but temporary disappearance of the Nrg1 transcriptional repressor of hyphal morphogenesis via activation of the cAMP-PKA pathway. Maintenance requires promoter recruitment of Hda1 histone deacetylase under reduced Tor1 (target of rapamycin) signaling. Hda1 deacetylates a subunit of the NuA4 histone acetyltransferase module, leading to eviction of the NuA4 acetyltransferase module and blockage of Nrg1 access to promoters of hypha specific genes. Promoter recruitment of Hda1 for hyphal maintenance happens only during the period when Nrg1 is gone. The sequential regulation of hyphal development by the activation of the cAMP-PKA pathway and reduced Tor1 signaling provides a molecular mechanism for plasticity of dimorphism and how C. albicans adapts to the varied host environments in pathogenesis. Such temporally linked regulation of promoter chromatin by different signaling pathways provides a unique mechanism for integrating multiple signals during development and cell fate specification. PMID- 21811398 TI - Coupled evolution of transcription and mRNA degradation. AB - mRNA levels are determined by the balance between transcription and mRNA degradation, and while transcription has been extensively studied, very little is known regarding the regulation of mRNA degradation and its coordination with transcription. Here we examine the evolution of mRNA degradation rates between two closely related yeast species. Surprisingly, we find that around half of the evolutionary changes in mRNA degradation were coupled to transcriptional changes that exert opposite effects on mRNA levels. Analysis of mRNA degradation rates in an interspecific hybrid further suggests that opposite evolutionary changes in transcription and in mRNA degradation are mechanistically coupled and were generated by the same individual mutations. Coupled changes are associated with divergence of two complexes that were previously implicated both in transcription and in mRNA degradation (Rpb4/7 and Ccr4-Not), as well as with sequence divergence of transcription factor binding motifs. These results suggest that an opposite coupling between the regulation of transcription and that of mRNA degradation has shaped the evolution of gene regulation in yeast. PMID- 21811400 TI - Genetic switch underlies C. albicans quick change act. PMID- 21811399 TI - Synaptic transmission from horizontal cells to cones is impaired by loss of connexin hemichannels. AB - In the vertebrate retina, horizontal cells generate the inhibitory surround of bipolar cells, an essential step in contrast enhancement. For the last decades, the mechanism involved in this inhibitory synaptic pathway has been a major controversy in retinal research. One hypothesis suggests that connexin hemichannels mediate this negative feedback signal; another suggests that feedback is mediated by protons. Mutant zebrafish were generated that lack connexin 55.5 hemichannels in horizontal cells. Whole cell voltage clamp recordings were made from isolated horizontal cells and cones in flat mount retinas. Light-induced feedback from horizontal cells to cones was reduced in mutants. A reduction of feedback was also found when horizontal cells were pharmacologically hyperpolarized but was absent when they were pharmacologically depolarized. Hemichannel currents in isolated horizontal cells showed a similar behavior. The hyperpolarization-induced hemichannel current was strongly reduced in the mutants while the depolarization-induced hemichannel current was not. Intracellular recordings were made from horizontal cells. Consistent with impaired feedback in the mutant, spectral opponent responses in horizontal cells were diminished in these animals. A behavioral assay revealed a lower contrast sensitivity, illustrating the role of the horizontal cell to cone feedback pathway in contrast enhancement. Model simulations showed that the observed modifications of feedback can be accounted for by an ephaptic mechanism. A model for feedback, in which the number of connexin hemichannels is reduced to about 40%, fully predicts the specific asymmetric modification of feedback. To our knowledge, this is the first successful genetic interference in the feedback pathway from horizontal cells to cones. It provides direct evidence for an unconventional role of connexin hemichannels in the inhibitory synapse between horizontal cells and cones. This is an important step in resolving a long standing debate about the unusual form of (ephaptic) synaptic transmission between horizontal cells and cones in the vertebrate retina. PMID- 21811401 TI - Darwin in mind: new opportunities for evolutionary psychology. AB - Evolutionary Psychology (EP) views the human mind as organized into many modules, each underpinned by psychological adaptations designed to solve problems faced by our Pleistocene ancestors. We argue that the key tenets of the established EP paradigm require modification in the light of recent findings from a number of disciplines, including human genetics, evolutionary biology, cognitive neuroscience, developmental psychology, and paleoecology. For instance, many human genes have been subject to recent selective sweeps; humans play an active, constructive role in co-directing their own development and evolution; and experimental evidence often favours a general process, rather than a modular account, of cognition. A redefined EP could use the theoretical insights of modern evolutionary biology as a rich source of hypotheses concerning the human mind, and could exploit novel methods from a variety of adjacent research fields. PMID- 21811402 TI - Treatment outcomes and cost-effectiveness of shifting management of stable ART patients to nurses in South Africa: an observational cohort. AB - BACKGROUND: To address human resource and infrastructure shortages, resource constrained countries are being encouraged to shift HIV care to lesser trained care providers and lower level health care facilities. This study evaluated the cost-effectiveness of down-referring stable antiretroviral therapy (ART) patients from a doctor-managed, hospital-based ART clinic to a nurse-managed primary health care facility in Johannesburg, South Africa. METHODS AND FINDINGS: Criteria for down-referral were stable ART (>=11 mo), undetectable viral load within the previous 10 mo, CD4>200 cells/mm(3), <5% weight loss over the last three visits, and no opportunistic infections. All patients down-referred from the treatment-initiation site to the down-referral site between 1 February 2008 and 1 January 2009 were compared to a matched sample of patients eligible for down-referral but not down-referred. Outcomes were assigned based on vital and health status 12 mo after down-referral eligibility and the average cost per outcome estimated from patient medical record data. The down-referral site (n = 712) experienced less death and loss to follow up than the treatment-initiation site (n = 2,136) (1.7% versus 6.2%, relative risk = 0.27, 95% CI 0.15-0.49). The average cost per patient-year for those in care and responding at 12 mo was US$492 for down-referred patients and US$551 for patients remaining at the treatment-initiation site (p<0.0001), a savings of 11%. Down-referral was the cost-effective strategy for eligible patients. CONCLUSIONS: Twelve-month outcomes of stable ART patients who are down-referred to a primary health clinic are as good as, or better than, the outcomes of similar patients who are maintained at a hospital-based ART clinic. The cost of treatment with down-referral is lower across all outcomes and would save 11% for patients who remain in care and respond to treatment. These results suggest that this strategy would increase treatment capacity and conserve resources without compromising patient outcomes. PMID- 21811404 TI - Evidence-based African first aid guidelines and training materials. PMID- 21811403 TI - Retention in HIV care between testing and treatment in sub-Saharan Africa: a systematic review. AB - BACKGROUND: Improving the outcomes of HIV/AIDS treatment programs in resource limited settings requires successful linkage of patients testing positive for HIV to pre-antiretroviral therapy (ART) care and retention in pre-ART care until ART initiation. We conducted a systematic review of pre-ART retention in care in Africa. METHODS AND FINDINGS: We searched PubMed, ISI Web of Knowledge, conference abstracts, and reference lists for reports on the proportion of adult patients retained between any two points between testing positive for HIV and initiating ART in sub-Saharan African HIV/AIDS care programs. Results were categorized as Stage 1 (from HIV testing to receipt of CD4 count results or clinical staging), Stage 2 (from staging to ART eligibility), or Stage 3 (from ART eligibility to ART initiation). Medians (ranges) were reported for the proportions of patients retained in each stage. We identified 28 eligible studies. The median proportion retained in Stage 1 was 59% (35%-88%); Stage 2, 46% (31%-95%); and Stage 3, 68% (14%-84%). Most studies reported on only one stage; none followed a cohort of patients through all three stages. Enrollment criteria, terminology, end points, follow-up, and outcomes varied widely and were often poorly defined, making aggregation of results difficult. Synthesis of findings from multiple studies suggests that fewer than one-third of patients testing positive for HIV and not yet eligible for ART when diagnosed are retained continuously in care, though this estimate should be regarded with caution because of review limitations. CONCLUSIONS: Studies of retention in pre-ART care report substantial loss of patients at every step, starting with patients who do not return for their initial CD4 count results and ending with those who do not initiate ART despite eligibility. Better health information systems that allow patients to be tracked between service delivery points are needed to properly evaluate pre-ART loss to care, and researchers should attempt to standardize the terminology, definitions, and time periods reported. PMID- 21811405 TI - Simplified ART delivery models are needed for the next phase of scale up. PMID- 21811406 TI - The regulation of sulfur metabolism in Mycobacterium tuberculosis. AB - Mycobacterium tuberculosis (Mtb) has evolved into a highly successful human pathogen. It deftly subverts the bactericidal mechanisms of alveolar macrophages, ultimately inducing granuloma formation and establishing long-term residence in the host. These hallmarks of Mtb infection are facilitated by the metabolic adaptation of the pathogen to its surrounding environment and the biosynthesis of molecules that mediate its interactions with host immune cells. The sulfate assimilation pathway of Mtb produces a number of sulfur-containing metabolites with important contributions to pathogenesis and survival. This pathway is regulated by diverse environmental cues and regulatory proteins that mediate sulfur transactions in the cell. Here, we discuss the transcriptional and biochemical mechanisms of sulfur metabolism regulation in Mtb and potential small molecule regulators of the sulfate assimilation pathway that are collectively poised to aid this intracellular pathogen in its expert manipulation of the host. From this global analysis, we have identified a subset of sulfur-metabolizing enzymes that are sensitive to multiple regulatory cues and may be strong candidates for therapeutic intervention. PMID- 21811407 TI - In vivo hypoxia and a fungal alcohol dehydrogenase influence the pathogenesis of invasive pulmonary aspergillosis. AB - Currently, our knowledge of how pathogenic fungi grow in mammalian host environments is limited. Using a chemotherapeutic murine model of invasive pulmonary aspergillosis (IPA) and (1)H-NMR metabolomics, we detected ethanol in the lungs of mice infected with Aspergillus fumigatus. This result suggests that A. fumigatus is exposed to oxygen depleted microenvironments during infection. To test this hypothesis, we utilized a chemical hypoxia detection agent, pimonidazole hydrochloride, in three immunologically distinct murine models of IPA (chemotherapeutic, X-CGD, and corticosteroid). In all three IPA murine models, hypoxia was observed during the course of infection. We next tested the hypothesis that production of ethanol in vivo by the fungus is involved in hypoxia adaptation and fungal pathogenesis. Ethanol deficient A. fumigatus strains showed no growth defects in hypoxia and were able to cause wild type levels of mortality in all 3 murine models. However, lung immunohistopathology and flow cytometry analyses revealed an increase in the inflammatory response in mice infected with an alcohol dehydrogenase null mutant strain that corresponded with a reduction in fungal burden. Consequently, in this study we present the first in vivo observations that hypoxic microenvironments occur during a pulmonary invasive fungal infection and observe that a fungal alcohol dehydrogenase influences fungal pathogenesis in the lung. Thus, environmental conditions encountered by invading pathogenic fungi may result in substantial fungal metabolism changes that influence subsequent host immune responses. PMID- 21811408 TI - Global mRNA degradation during lytic gammaherpesvirus infection contributes to establishment of viral latency. AB - During a lytic gammaherpesvirus infection, host gene expression is severely restricted by the global degradation and altered 3' end processing of mRNA. This host shutoff phenotype is orchestrated by the viral SOX protein, yet its functional significance to the viral lifecycle has not been elucidated, in part due to the multifunctional nature of SOX. Using an unbiased mutagenesis screen of the murine gammaherpesvirus 68 (MHV68) SOX homolog, we isolated a single amino acid point mutant that is selectively defective in host shutoff activity. Incorporation of this mutation into MHV68 yielded a virus with significantly reduced capacity for mRNA turnover. Unexpectedly, the MHV68 mutant showed little defect during the acute replication phase in the mouse lung. Instead, the virus exhibited attenuation at later stages of in vivo infections suggestive of defects in both trafficking and latency establishment. Specifically, mice intranasally infected with the host shutoff mutant accumulated to lower levels at 10 days post infection in the lymph nodes, failed to develop splenomegaly, and exhibited reduced viral DNA levels and a lower frequency of latently infected splenocytes. Decreased latency establishment was also observed upon infection via the intraperitoneal route. These results highlight for the first time the importance of global mRNA degradation during a gammaherpesvirus infection and link an exclusively lytic phenomenon with downstream latency establishment. PMID- 21811409 TI - Crystallography of a Lewis-binding norovirus, elucidation of strain-specificity to the polymorphic human histo-blood group antigens. AB - Noroviruses, an important cause of acute gastroenteritis in humans, recognize the histo-blood group antigens (HBGAs) as host susceptible factors in a strain specific manner. The crystal structures of the HBGA-binding interfaces of two A/B/H-binding noroviruses, the prototype Norwalk virus (GI.1) and a predominant GII.4 strain (VA387), have been elucidated. In this study we determined the crystal structures of the P domain protein of the first Lewis-binding norovirus (VA207, GII.9) that has a distinct binding property from those of Norwalk virus and VA387. Co-crystallization of the VA207 P dimer with Le(y) or sialyl Le(x) tetrasaccharides showed that VA207 interacts with these antigens through a common site found on the VA387 P protein which is highly conserved among most GII noroviruses. However, the HBGA-binding site of VA207 targeted at the Lewis antigens through the alpha-1, 3 fucose (the Lewis epitope) as major and the beta N-acetyl glucosamine of the precursor as minor interacting sites. This completely differs from the binding mode of VA387 and Norwalk virus that target at the secretor epitopes. Binding pocket of VA207 is formed by seven amino acids, of which five residues build up the core structure that is essential for the basic binding function, while the other two are involved in strain-specificity. Our results elucidate for the first time the genetic and structural basis of strain specificity by a direct comparison of two genetically related noroviruses in their interaction with different HBGAs. The results provide insight into the complex interaction between the diverse noroviruses and the polymorphic HBGAs and highlight the role of human HBGA as a critical factor in norovirus evolution. PMID- 21811410 TI - Selection of resistant bacteria at very low antibiotic concentrations. AB - The widespread use of antibiotics is selecting for a variety of resistance mechanisms that seriously challenge our ability to treat bacterial infections. Resistant bacteria can be selected at the high concentrations of antibiotics used therapeutically, but what role the much lower antibiotic concentrations present in many environments plays in selection remains largely unclear. Here we show using highly sensitive competition experiments that selection of resistant bacteria occurs at extremely low antibiotic concentrations. Thus, for three clinically important antibiotics, drug concentrations up to several hundred-fold below the minimal inhibitory concentration of susceptible bacteria could enrich for resistant bacteria, even when present at a very low initial fraction. We also show that de novo mutants can be selected at sub-MIC concentrations of antibiotics, and we provide a mathematical model predicting how rapidly such mutants would take over in a susceptible population. These results add another dimension to the evolution of resistance and suggest that the low antibiotic concentrations found in many natural environments are important for enrichment and maintenance of resistance in bacterial populations. PMID- 21811411 TI - Rare and common regulatory variation in population-scale sequenced human genomes. AB - Population-scale genome sequencing allows the characterization of functional effects of a broad spectrum of genetic variants underlying human phenotypic variation. Here, we investigate the influence of rare and common genetic variants on gene expression patterns, using variants identified from sequencing data from the 1000 genomes project in an African and European population sample and gene expression data from lymphoblastoid cell lines. We detect comparable numbers of expression quantitative trait loci (eQTLs) when compared to genotypes obtained from HapMap 3, but as many as 80% of the top expression quantitative trait variants (eQTVs) discovered from 1000 genomes data are novel. The properties of the newly discovered variants suggest that mapping common causal regulatory variants is challenging even with full resequencing data; however, we observe significant enrichment of regulatory effects in splice-site and nonsense variants. Using RNA sequencing data, we show that 46.2% of nonsynonymous variants are differentially expressed in at least one individual in our sample, creating widespread potential for interactions between functional protein-coding and regulatory variants. We also use allele-specific expression to identify putative rare causal regulatory variants. Furthermore, we demonstrate that outlier expression values can be due to rare variant effects, and we approximate the number of such effects harboured in an individual by effect size. Our results demonstrate that integration of genomic and RNA sequencing analyses allows for the joint assessment of genome sequence and genome function. PMID- 21811412 TI - Expression of arf tumor suppressor in spermatogonia facilitates meiotic progression in male germ cells. AB - The mammalian Cdkn2a (Ink4a-Arf) locus encodes two tumor suppressor proteins (p16(Ink4a) and p19(Arf)) that respectively enforce the anti-proliferative functions of the retinoblastoma protein (Rb) and the p53 transcription factor in response to oncogenic stress. Although p19(Arf) is not normally detected in tissues of young adult mice, a notable exception occurs in the male germ line, where Arf is expressed in spermatogonia, but not in meiotic spermatocytes arising from them. Unlike other contexts in which the induction of Arf potently inhibits cell proliferation, expression of p19(Arf) in spermatogonia does not interfere with mitotic cell division. Instead, inactivation of Arf triggers germ cell autonomous, p53-dependent apoptosis of primary spermatocytes in late meiotic prophase, resulting in reduced sperm production. Arf deficiency also causes premature, elevated, and persistent accumulation of the phosphorylated histone variant H2AX, reduces numbers of chromosome-associated complexes of Rad51 and Dmc1 recombinases during meiotic prophase, and yields incompletely synapsed autosomes during pachynema. Inactivation of Ink4a increases the fraction of spermatogonia in S-phase and restores sperm numbers in Ink4a-Arf doubly deficient mice but does not abrogate gamma-H2AX accumulation in spermatocytes or p53 dependent apoptosis resulting from Arf inactivation. Thus, as opposed to its canonical role as a tumor suppressor in inducing p53-dependent senescence or apoptosis, Arf expression in spermatogonia instead initiates a salutary feed forward program that prevents p53-dependent apoptosis, contributing to the survival of meiotic male germ cells. PMID- 21811413 TI - CHD1 remodels chromatin and influences transient DNA methylation at the clock gene frequency. AB - Circadian-regulated gene expression is predominantly controlled by a transcriptional negative feedback loop, and it is evident that chromatin modifications and chromatin remodeling are integral to this process in eukaryotes. We previously determined that multiple ATP-dependent chromatin remodeling enzymes function at frequency (frq). In this report, we demonstrate that the Neurospora homologue of chd1 is required for normal remodeling of chromatin at frq and is required for normal frq expression and sustained rhythmicity. Surprisingly, our studies of CHD1 also revealed that DNA sequences within the frq promoter are methylated, and deletion of chd1 results in expansion of this methylated domain. DNA methylation of the frq locus is altered in strains bearing mutations in a variety of circadian clock genes, including frq, frh, wc 1, and the gene encoding the frq antisense transcript (qrf). Furthermore, frq methylation depends on the DNA methyltransferase, DIM-2. Phenotypic characterization of Deltadim-2 strains revealed an approximate WT period length and a phase advance of approximately 2 hours, indicating that methylation plays only an ancillary role in clock-regulated gene expression. This suggests that DNA methylation, like the antisense transcript, is necessary to establish proper clock phasing but does not control overt rhythmicity. These data demonstrate that the epigenetic state of clock genes is dependent on normal regulation of clock components. PMID- 21811414 TI - Histone crosstalk directed by H2B ubiquitination is required for chromatin boundary integrity. AB - Genomic maps of chromatin modifications have provided evidence for the partitioning of genomes into domains of distinct chromatin states, which assist coordinated gene regulation. The maintenance of chromatin domain integrity can require the setting of boundaries. The HS4 insulator element marks the 3' boundary of a heterochromatin region located upstream of the chicken beta-globin gene cluster. Here we show that HS4 recruits the E3 ligase RNF20/BRE1A to mediate H2B mono-ubiquitination (H2Bub1) at this insulator. Knockdown experiments show that RNF20 is required for H2Bub1 and processive H3K4 methylation. Depletion of RNF20 results in a collapse of the active histone modification signature at the HS4 chromatin boundary, where H2Bub1, H3K4 methylation, and hyperacetylation of H3, H4, and H2A.Z are rapidly lost. A remarkably similar set of events occurs at the HSA/HSB regulatory elements of the FOLR1 gene, which mark the 5' boundary of the same heterochromatin region. We find that persistent H2Bub1 at the HSA/HSB and HS4 elements is required for chromatin boundary integrity. The loss of boundary function leads to the sequential spreading of H3K9me2, H3K9me3, and H4K20me3 over the entire 50 kb FOLR1 and beta-globin region and silencing of FOLR1 expression. These findings show that the HSA/HSB and HS4 boundary elements direct a cascade of active histone modifications that defend the FOLR1 and beta globin gene loci from the pervasive encroachment of an adjacent heterochromatin domain. We propose that many gene loci employ H2Bub1-dependent boundaries to prevent heterochromatin spreading. PMID- 21811415 TI - Ancestral genes can control the ability of horizontally acquired loci to confer new traits. AB - Horizontally acquired genes typically function as autonomous units conferring new abilities when introduced into different species. However, we reasoned that proteins preexisting in an organism might constrain the functionality of a horizontally acquired gene product if it operates on an ancestral pathway. Here, we determine how the horizontally acquired pmrD gene product activates the ancestral PmrA/PmrB two-component system in Salmonella enterica but not in the closely related bacterium Escherichia coli. The Salmonella PmrD protein binds to the phosphorylated PmrA protein (PmrA-P), protecting it from dephosphorylation by the PmrB protein. This results in transcription of PmrA-dependent genes, including those conferring polymyxin B resistance. We now report that the E. coli PmrD protein can activate the PmrA/PmrB system in Salmonella even though it cannot do it in E. coli, suggesting that these two species differ in an additional component controlling PmrA-P levels. We establish that the E. coli PmrB displays higher phosphatase activity towards PmrA-P than the Salmonella PmrB, and we identified a PmrB subdomain responsible for this property. Replacement of the E. coli pmrB gene with the Salmonella homolog was sufficient to render E. coli resistant to polymyxin B under PmrD-inducing conditions. Our findings provide a singular example whereby quantitative differences in the biochemical activities of orthologous ancestral proteins dictate the ability of a horizontally acquired gene product to confer species-specific traits. And they suggest that horizontally acquired genes can potentiate selection at ancestral loci. PMID- 21811416 TI - Drosophila araucan and caupolican integrate intrinsic and signalling inputs for the acquisition by muscle progenitors of the lateral transverse fate. AB - A central issue of myogenesis is the acquisition of identity by individual muscles. In Drosophila, at the time muscle progenitors are singled out, they already express unique combinations of muscle identity genes. This muscle code results from the integration of positional and temporal signalling inputs. Here we identify, by means of loss-of-function and ectopic expression approaches, the Iroquois Complex homeobox genes araucan and caupolican as novel muscle identity genes that confer lateral transverse muscle identity. The acquisition of this fate requires that Araucan/Caupolican repress other muscle identity genes such as slouch and vestigial. In addition, we show that Caupolican-dependent slouch expression depends on the activation state of the Ras/Mitogen Activated Protein Kinase cascade. This provides a comprehensive insight into the way Iroquois genes integrate in muscle progenitors, signalling inputs that modulate gene expression and protein activity. PMID- 21811417 TI - Adaptations to endosymbiosis in a cnidarian-dinoflagellate association: differential gene expression and specific gene duplications. AB - Trophic endosymbiosis between anthozoans and photosynthetic dinoflagellates forms the key foundation of reef ecosystems. Dysfunction and collapse of symbiosis lead to bleaching (symbiont expulsion), which is responsible for the severe worldwide decline of coral reefs. Molecular signals are central to the stability of this partnership and are therefore closely related to coral health. To decipher inter partner signaling, we developed genomic resources (cDNA library and microarrays) from the symbiotic sea anemone Anemonia viridis. Here we describe differential expression between symbiotic (also called zooxanthellate anemones) or aposymbiotic (also called bleached) A. viridis specimens, using microarray hybridizations and qPCR experiments. We mapped, for the first time, transcript abundance separately in the epidermal cell layer and the gastrodermal cells that host photosynthetic symbionts. Transcriptomic profiles showed large inter individual variability, indicating that aposymbiosis could be induced by different pathways. We defined a restricted subset of 39 common genes that are characteristic of the symbiotic or aposymbiotic states. We demonstrated that transcription of many genes belonging to this set is specifically enhanced in the symbiotic cells (gastroderm). A model is proposed where the aposymbiotic and therefore heterotrophic state triggers vesicular trafficking, whereas the symbiotic and therefore autotrophic state favors metabolic exchanges between host and symbiont. Several genetic pathways were investigated in more detail: i) a key vitamin K-dependant process involved in the dinoflagellate-cnidarian recognition; ii) two cnidarian tissue-specific carbonic anhydrases involved in the carbon transfer from the environment to the intracellular symbionts; iii) host collagen synthesis, mostly supported by the symbiotic tissue. Further, we identified specific gene duplications and showed that the cnidarian-specific isoform was also up-regulated both in the symbiotic state and in the gastroderm. Our results thus offer new insight into the inter-partner signaling required for the physiological mechanisms of the symbiosis that is crucial for coral health. PMID- 21811418 TI - Regulatory cross-talk links Vibrio cholerae chromosome II replication and segregation. AB - There is little knowledge of factors and mechanisms for coordinating bacterial chromosome replication and segregation. Previous studies have revealed that genes (and their products) that surround the origin of replication (oriCII) of Vibrio cholerae chromosome II (chrII) are critical for controlling the replication and segregation of this chromosome. rctB, which flanks one side of oriCII, encodes a protein that initiates chrII replication; rctA, which flanks the other side of oriCII, inhibits rctB activity. The chrII parAB2 operon, which is essential for chrII partitioning, is located immediately downstream of rctA. Here, we explored how rctA exerts negative control over chrII replication. Our observations suggest that RctB has at least two DNA binding domains--one for binding to oriCII and initiating replication and the other for binding to rctA and thereby inhibiting RctB's ability to initiate replication. Notably, the inhibitory effect of rctA could be alleviated by binding of ParB2 to a centromere-like parS site within rctA. Furthermore, by binding to rctA, ParB2 and RctB inversely regulate expression of the parAB2 genes. Together, our findings suggest that fluctuations in binding of the partitioning protein ParB2 and the chrII initiator RctB to rctA underlie a regulatory network controlling both oriCII firing and the production of the essential chrII partitioning proteins. Thus, by binding both RctB and ParB2, rctA serves as a nexus for regulatory cross-talk coordinating chrII replication and segregation. PMID- 21811419 TI - Mechanisms of chromosome number evolution in yeast. AB - The whole-genome duplication (WGD) that occurred during yeast evolution changed the basal number of chromosomes from 8 to 16. However, the number of chromosomes in post-WGD species now ranges between 10 and 16, and the number in non-WGD species (Zygosaccharomyces, Kluyveromyces, Lachancea, and Ashbya) ranges between 6 and 8. To study the mechanism by which chromosome number changes, we traced the ancestry of centromeres and telomeres in each species. We observe only two mechanisms by which the number of chromosomes has decreased, as indicated by the loss of a centromere. The most frequent mechanism, seen 8 times, is telomere-to telomere fusion between two chromosomes with the concomitant death of one centromere. The other mechanism, seen once, involves the breakage of a chromosome at its centromere, followed by the fusion of the two arms to the telomeres of two other chromosomes. The only mechanism by which chromosome number has increased in these species is WGD. Translocations and inversions have cycled telomere locations, internalizing some previously telomeric genes and creating novel telomeric locations. Comparison of centromere structures shows that the length of the CDEII region is variable between species but uniform within species. We trace the complete rearrangement history of the Lachancea kluyveri genome since its common ancestor with Saccharomyces and propose that its exceptionally low level of rearrangement is a consequence of the loss of the non-homologous end joining (NHEJ) DNA repair pathway in this species. PMID- 21811420 TI - SHH1, a homeodomain protein required for DNA methylation, as well as RDR2, RDM4, and chromatin remodeling factors, associate with RNA polymerase IV. AB - DNA methylation is an evolutionarily conserved epigenetic modification that is critical for gene silencing and the maintenance of genome integrity. In Arabidopsis thaliana, the de novo DNA methyltransferase, domains rearranged methyltransferase 2 (DRM2), is targeted to specific genomic loci by 24 nt small interfering RNAs (siRNAs) through a pathway termed RNA-directed DNA methylation (RdDM). Biogenesis of the targeting siRNAs is thought to be initiated by the activity of the plant-specific RNA polymerase IV (Pol-IV). However, the mechanism through which Pol-IV is targeted to specific genomic loci and whether factors other than the core Pol-IV machinery are required for Pol-IV activity remain unknown. Through the affinity purification of nuclear RNA polymerase D1 (NRPD1), the largest subunit of the Pol-IV polymerase, we found that several previously identified RdDM components co-purify with Pol-IV, namely RNA-dependent RNA polymerase 2 (RDR2), CLASSY1 (CLSY1), and RNA-directed DNA methylation 4 (RDM4), suggesting that the upstream siRNA generating portion of the RdDM pathway may be more physically coupled than previously envisioned. A homeodomain protein, SAWADEE homeodomain homolog 1 (SHH1), was also found to co-purify with NRPD1; and we demonstrate that SHH1 is required for de novo and maintenance DNA methylation, as well as for the accumulation of siRNAs at specific loci, confirming it is a bonafide component of the RdDM pathway. PMID- 21811423 TI - Gastric cancer screening in Korea: report on the national cancer screening program in 2008. AB - PURPOSE: The National Cancer Screening Program (NCSP) began in 1999. The objective of this report is to evaluate the results of the NCSP in 2008 and provide essential evidence associated with the gastric cancer screening program in Korea. MATERIALS AND METHODS: Data was obtained from the National Cancer Screening Information System; participation rates in gastric cancer screening were calculated. According to screening modalities, recall rates were estimated with 95% confidence intervals (CIs). RESULTS: The target population of the gastric cancer screening program in 2008 was 7,132,820 Korean men and women aged 40 and over, 2,076,544 of whom underwent upper endoscopy or upper gastrointestinal (UGI) series as screening tools (participation rate, 29.1%). Disparities in participation rates were observed relating to gender and health insurance type. Overall, recall rates of upper endoscopy and UGI series were 3.1% (95% CI, 3.0 to 3.1) and 33.3% (95% CI, 33.3 to 33.4), respectively. CONCLUSION: According to our research, efforts to facilitate participation and to reduce disparities in gastric cancer screening among Korean men and women are needed. These results will provide essential data for evidence-based strategies in gastric cancer control in Korea. PMID- 21811422 TI - The role of stereotactic ablative radiotherapy for early-stage and oligometastatic non-small cell lung cancer: evidence for changing paradigms. AB - A compelling body of non-randomized evidence has established stereotactic ablative lung radiotherapy (SABR) as a standard of care for medically inoperable patients with peripheral early-stage non-small cell lung cancer (NSCLC). This convenient outpatient therapy, which is typically delivered in 3-8 fractions, is also well tolerated by elderly and frail patients, makes efficient use of resources and is feasible using standard commercial equipment. The introduction of lung SABR into large populations has led to an increased utilization of radiotherapy, a reduction in the proportion of untreated patients and an increase in overall survival. In selected patients, the same ablative technology can now achieve durable local control of NSCLC metastases in a variety of common locations including the adrenal glands, bone, brain, and liver. At the same time as this, advances in prognostic molecular markers and targeted systemic therapies mean that there is now a subgroup of patients with stage IV NSCLC and a median survival of around 2 years. This creates opportunities for new trials that incorporate SABR and patient-specific systemic strategies. This selective mini review focuses on the emerging role of SABR in patients with early-stage and oligometastatic NSCLC. PMID- 21811424 TI - Implications of bone-only metastases in breast cancer: favorable preference with excellent outcomes of hormone receptor positive breast cancer. AB - PURPOSE: The aim of the current study was to determine the incidence, clinical presentation, and treatment outcomes of "bone-only metastases" in patients with breast cancer and to analyze the impact of hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status on prognosis. MATERIALS AND METHODS: Between 1994 and 2007, of 968 patients with metastatic breast cancer who underwent palliative management at Samsung Medical Center, 565 (57%) relapsed with distant metastases. Of the 968, 146 (15%) had bone-only metastases during a median follow-up period of 75 months. Among the 146 patients with bone-only metastases, 122 (84%) were relapsed patients after curative surgery and 24 (26%) were initially metastatic cases. RESULTS: The median time from primary surgery to bone-only metastases of the 122 patients was 37 months (95% confidence interval [CI], 27 to 46 months). Bone-only metastases were more common in the HR-positive group than in the other subtypes (85% for HR+; 8.2% for HER2+; 6.8% for triple negative. Among all 146 patients, 75 (51%) were treated with hormone therapy. The median post-relapse progression-free survival was 15 months (95% CI, 13 to 17 months). The median overall survival was much longer in the HR+ patients than the HER2+ and triple negative breast cancer patients with marginal statistical significance (65 vs. 40 vs. 40 months, p=0.077). CONCLUSION: Breast cancer patients with "bone-only metastases" had excellent clinical outcomes. Further study is now warranted to reveal the underlying biology that regulates the behavior of this indolent tumor, as it should identify 'favorable tumor characteristics' in addition to 'favorable preferential metastatic site.' PMID- 21811421 TI - The demoiselle of X-inactivation: 50 years old and as trendy and mesmerising as ever. AB - In humans, sexual dimorphism is associated with the presence of two X chromosomes in the female, whereas males possess only one X and a small and largely degenerate Y chromosome. How do men cope with having only a single X chromosome given that virtually all other chromosomal monosomies are lethal? Ironically, or even typically many might say, women and more generally female mammals contribute most to the job by shutting down one of their two X chromosomes at random. This phenomenon, called X-inactivation, was originally described some 50 years ago by Mary Lyon and has captivated an increasing number of scientists ever since. The fascination arose in part from the realisation that the inactive X corresponded to a dense heterochromatin mass called the "Barr body" whose number varied with the number of Xs within the nucleus and from the many intellectual questions that this raised: How does the cell count the X chromosomes in the nucleus and inactivate all Xs except one? What kind of molecular mechanisms are able to trigger such a profound, chromosome-wide metamorphosis? When is X-inactivation initiated? How is it transmitted to daughter cells and how is it reset during gametogenesis? This review retraces some of the crucial findings, which have led to our current understanding of a biological process that was initially considered as an exception completely distinct from conventional regulatory systems but is now viewed as a paradigm "par excellence" for epigenetic regulation. PMID- 21811425 TI - A retrospective study of first-line combination chemotherapy in advanced colorectal cancer: a Korean single-center experience. AB - PURPOSE: Fluoropyrimidine-based combination chemotherapy, in combination with either oxaliplatin or irinotecan, has demonstrated efficacy and tolerability in treatment of advanced colorectal cancer (ACC). MATERIALS AND METHODS: Between January 2006 and December 2007, a total of 478 ACC patients were treated with combination chemotherapy in first-line settings. Combination therapies included: 5-fluorouracil, folinic acid plus oxaliplatin (FOLFOX, n=172), 5-fluorouracil, folinic acid plus irinotecan (FOLFIRI, n=95), capecitabine plus oxaliplatin (XELOX, n=155), and capecitabine plus irinotecan (XELIRI, n=56). FOLFOX and FOLFIRI were repeated every 2 weeks, whereas XELOX and XELIRI were repeated every 3 weeks until occurrence of disease progression or unacceptable toxicity, or until a patient chose to discontinue treatment. RESULTS: The median age was 58 years (range, 19 to 84 years) and the median chemotherapy durations for FOLFOX, FOLFIRI, XELOX, and XELIRI were 4.9, 4.5, 5.7, and 5.4 months, respectively. Combination chemotherapy regimens were generally well tolerated. The estimated median progression-free-survival (PFS) for all patients was 6.8 months (95% confidence interval, 6.3 to 7.3 months). No statistically significant difference in PFS was found among regimens used as first-line chemotherapy. Sixty percent (n=290) of patients received second or further lines of therapy after failure. CONCLUSION: Fluoropyrimidine-based combination chemotherapy regimens appear to be equally active and tolerable as first-line therapy for ACC. PMID- 21811426 TI - Surgical outcomes of hemorrhagic metastatic brain tumors. AB - PURPOSE: Hemorrhagic metastatic brain tumors are not rare, but little is known about the surgical outcome following treatment. We conducted this study to determine the result of the surgical outcome of hemorrhagic metastatic brain tumors. MATERIALS AND METHODS: From July 2001 to December 2008, 21 patients underwent surgery for hemorrhagic metastatic brain tumors at our institution. 15 patients had lung cancer, 3 had hepatocellular carcinoma, and the rest had rectal cancer, renal cell carcinoma, and sarcoma. 20 patients had macroscopic hemorrhage in the tumors, and one patient had intracerebral hemorrhage surrounding the tumor. A retrospective clinical review was conducted focusing on the patterns of presenting symptoms and signs, as well as local recurrence following surgery. RESULTS: Among 21 hemorrhagic brain metastases, local recurrence developed in two patients. The 12 month progression free survival rate was 86.1%. Mean time to progression was 20.8 months and median survival time after surgery was 11.7 months. CONCLUSION: The results of our study showed that hemorrhagic metastatic brain tumors rarely recurred after surgery. Surgery should be considered as a good treatment option for hemorrhagic brain metastasis, especially in cases with increased intracranial pressure or severe neurologic deficits. PMID- 21811427 TI - An association study of polymorphisms in JAK3 gene with lung cancer in the Korean population. AB - PURPOSE: The genetic alteration of the janus kinases (JAKs), non-receptor tyrosine kinase, is related to the development of human cancers. However, little is known about how the sequence variation of JAK3 contributes to the development of lung cancer. This study investigated whether polymorphisms at the promoter region of the JAK3 gene are associated with the risk of lung cancer in the Korean population. MATERIALS AND METHODS: A total of 819 subjects, including 409 lung cancer patients and 410 healthy controls were recruited. The SNaPshot assay and polymerase chain reaction-restriction fragment length polymorphism analysis were used, and logistic regression analyses were performed to characterize the association between polymorphisms of JAK3 and lung cancer risk. RESULTS: Three polymorphisms (-672 G>A, +64 A>G and +227 G>A) of JAK3 were analyzed for large scale genotyping (n=819). Statistical analyses revealed that polymorphisms and haplotypes in the JAK3 gene were not significantly associated with lung cancer. CONCLUSION: JAK3 gene was not significantly associated with the risk of lung cancer in the Korean population. PMID- 21811428 TI - Predictive value of in vitro adenosine triphosphate-based chemotherapy response assay in advanced gastric cancer patients who received oral 5-Fluorouracil after curative resection. AB - PURPOSE: To assess the usefulness of adenosine triphosphate-based chemotherapy response assay (ATP-CRA) results in advanced gastric cancer patients receiving adjuvant chemotherapy. MATERIALS AND METHODS: Sixty-two patients underwent curative surgical resection between January, 2006 and December, 2008. Their highly purified surgical specimens were evaluated by ATP-CRAs. Of the 62, 49 had successful assay results and they received either oral 5-fluorouracil or other chemotherapies. We retrospectively analyzed data for 24 patients who were treated with oral 5-fluorouracil and whose assays were successful. RESULTS: The median observation time was 24.6 months (range, 10.1 to 40.9 months). The median treatment time was 11.2 months (range, 1.2 to 17.7 months). The median age was 66 years (range, 30 to 81 years). Patients were grouped into sensitive- and resistant-groups according to adenosine triphosphate-based chemotherapy response results for fluorouracil. The sensitive-group showed a significantly longer time to relapse (not reached in the sensitive-group vs. 24.8 months in the resistant group, p=0.043) and longer overall survival compared to the resistant-group (not reached in the sensitive-group vs. 35.7 months in the resistant-group, p=0.16, statistically insignificant). CONCLUSION: Patients who receive curative surgical resection significantly benefit from sensitive adjuvant chemotherapy according to ATP-CRA results for time to relapse. PMID- 21811429 TI - Up-regulation of the DR5 expression by proteasome inhibitor MG132 augments TRAIL induced apoptosis in soft tissue sarcoma cell lines. AB - PURPOSE: Current chemotherapeutics for treating locally advanced or metastatic soft tissue sarcomas (STS) are limited. Accordingly, the present in vitro study was conducted to evaluate the effects of treatment of STS cells with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) applied as a single agent or in combination with a proteasome inhibitor, MG132. MATERIALS AND METHODS: Sensitivity to TRAIL and activity of TRAIL-induced apoptotic pathways were analyzed in four STS cell lines: HTB-82 (rhabdomyosarcoma), HT-1080 (fibrosarcoma), HTB-93 (synovial sarcoma), and HTB-94 (chondrosarcoma). Reduction of the dye dimethylthiazolyl 2,5 diphenyltetrazolium bromide (MTT) was used to evaluate cytotoxic activity; western blots were used to evaluate TRAIL-induced apoptosis. RESULTS: TRAIL induced apoptosis in HTB-93 cells, but had little effect in HTB-82, HT-1080, or HTB-94 cells. Expression of TRAIL receptor-1 and -2 did not correlate with sensitivity to TRAIL. Co-incubation of cells with TRAIL and a proteasome inhibitor, MG132, augmented the apoptotic effect of TRAIL in both TRAIL-sensitive and TRAIL-resistant cells. This effect was due to up regulation of TRAIL receptors and members of the pro-apoptotic BCL-2 family by MG132. CONCLUSION: These data show that combining TRAIL with MG132 enhances apoptosis and overcomes TRAIL resistance. This restoration of TRAIL sensitivity occurs through an increase in the expression of death receptor 5 and of pro apoptotic BCL-2 family members such as BAX. PMID- 21811430 TI - Benign metastasizing leiomyoma with multiple lymph node metastasis: a case report. AB - This is a case report about benign metastasizing leiomyoma with multiple lymph node metastasis. A 34-year-old woman received an abdominal myomectomy for a suspicious leiomyoma. On the pathology report, atypical leiomyoma was suspected. Due to the suspicion of multiple lymph node metastasis on pelvis computed tomography (CT) 1 year after the operation, she was transferred to the Samsung Medical Center on October, 2009 for further work up. According to original slide review, it was determined to be a benign leiomyoma with a mitotic count <5/10 high-power fields, little cytological atypia and no tumor cell necrosis. Additional immunostaining was done. Multiple lymph node metastasis and a small lung nodule were identified on positron emission tomography-CT [corrected] and chest CT. Extensive debulking surgery and diagnostic video-assisted thoracoscopic surgery (VATS) wedge resection were subsequently done. Metastatic lesions were reported to have a histology similar to that of the original mass. VATS right upper lobectomy with mediastinal lymph node dissection was performed because of the pathology result of VATS (adenocarcinoma). She started taking an aromatase inhibitor (Letrozole(r)) and there was no evidence of recurrence of disease on an imaging study and no post-operative complications until recently. PMID- 21811431 TI - Numb chin syndrome with concomitant painful ophthalmoplegia leading to a diagnosis of diffuse large B cell lymphoma. AB - Painful ophthalmoplegia (PO) and concomitant numb chin syndrome (NCS) is a very rare event. There are a few reports in the literature about PO and concomitant NCS that have preceded the diagnosis of a malignancy. In this report, we describe a patient with diffuse large B cell lymphoma who presented with PO and concomitant NCS as the initial symptom of the disease. PMID- 21811433 TI - Combining BMI Stimulation and Mathematical Modeling for Acute Stroke Recovery and Neural Repair. AB - Rehabilitation is a neural plasticity-exploiting approach that forces undamaged neural circuits to undertake the functionality of other circuits damaged by stroke. It aims to partial restoration of the neural functions by circuit remodeling rather than by the regeneration of damaged circuits. The core hypothesis of the present paper is that - in stroke - brain machine interfaces (BMIs) can be designed to target neural repair instead of rehabilitation. To support this hypothesis we first review existing evidence on the role of endogenous or externally applied electric fields on all processes involved in CNS repair. We then describe our own results to illustrate the neuroprotective and neuroregenerative effects of BMI-electrical stimulation on sensory deprivation related degenerative processes of the CNS. Finally, we discuss three of the crucial issues involved in the design of neural repair-oriented BMIs: when to stimulate, where to stimulate and - the particularly important but unsolved issue of - how to stimulate. We argue that optimal parameters for the electrical stimulation can be determined from studying and modeling the dynamics of the electric fields that naturally emerge at the central and peripheral nervous system during spontaneous healing in both, experimental animals and human patients. We conclude that a closed-loop BMI that defines the optimal stimulation parameters from a priori developed experimental models of the dynamics of spontaneous repair and the on-line monitoring of neural activity might place BMIs as an alternative or complement to stem-cell transplantation or pharmacological approaches, intensively pursued nowadays. PMID- 21811434 TI - A protocol for isolation and enriched monolayer cultivation of neural precursor cells from mouse dentate gyrus. AB - In vitro assays are valuable tools to study the characteristics of adult neural precursor cells under controlled conditions with a defined set of parameters. We here present a detailed protocol based on our previous original publication (Babu et al., 2007) to isolate neural precursor cells from the hippocampus of adult mice and maintain and propagate them as adherent monolayer cultures. The strategy is based on the use of Percoll density gradient centrifugation to enrich precursor cells from the micro-dissected dentate gyrus. Based on the expression of Nestin and Sox2, a culture-purity of more than 98% can be achieved. The cultures are expanded under serum-free conditions in Neurobasal A medium with addition of the mitogens Epidermal growth factor and Fibroblast growth factor 2 as well as the supplements Glutamax-1 and B27. Under differentiation conditions, the precursor cells reliably generate approximately 30% neurons with appropriate morphological, molecular, and electrophysiological characteristics that might reflect granule cell properties as their in vivo counterpart. We also highlight potential modifications to the protocol. PMID- 21811435 TI - Estimating the amount of information conveyed by a population of neurons. AB - Recent technological advances have made the simultaneous recording of the activity of many neurons common. However, estimating the amount of information conveyed by the discharge of a neural population remains a significant challenge. Here we describe our recently published analysis method that assists in such estimates. We describe the key concepts and assumptions on which the method is based, illustrate its use with data from both simulated and real neurons recorded from the lateral geniculate nucleus of a monkey, and show how it can be used to calculate redundancy and synergy among neuronal groups. PMID- 21811436 TI - Social facilitation revisited: increase in foraging efforts and synchronization of running in domestic chicks. AB - Social influences on foraging efforts were examined in domestic chicks by investigating the frequency of runs made to feeders and the amount of pecking to gain food. Single or paired chicks foraged in an I-shaped maze equipped with a millet feeder on each end, that distributed one or two grains at variable intervals. Regardless of when the grain(s) were dispensed, chicks ran back and forth between the feeders. Analyses of their movement patterns revealed: (1) running patterns were not directly synchronized with the dispensing of grain(s), (2) running distance was longer in paired chicks than in single chicks, (3) paired chicks partially synchronized their runs between feeders, and (4) social effects were immediate but cumulative after repeated blocks. We further examined the social effects on running by dividing the I-maze into two parallel lanes separated by a transparent wall, so that kleptoparasitic interference of food did not occur. Again, the chicks increased their running speed and were even more synchronized with their partner's movements, indicating that food competition alone was not responsible for increased foraging effort. The number of pecks to get grains was also assessed under conditions where the food tray was gradually replaced, from an easy one to more difficult ones. When tested in the separated I maze, paired chicks pecked more in the difficult food situation without increase in the number of gained grains. Results suggest that (i) social facilitation leads to increased foraging efforts and (ii) the presence of a conspecific is alone may lead to enhanced foraging efforts in chicks. These findings are discussed in terms of possible ecological background of social facilitation. PMID- 21811437 TI - Antisense-mediated RNA targeting: versatile and expedient genetic manipulation in the brain. AB - A limiting factor in brain research still is the difficulty to evaluate in vivo the role of the increasing number of proteins implicated in neuronal processes. We discuss here the potential of antisense-mediated RNA targeting approaches. We mainly focus on those that manipulate splicing (exon skipping and exon inclusion), but will also briefly discuss mRNA targeting. Classic knockdown of expression by mRNA targeting is only one possible application of antisense oligonucleotides (AON) in the control of gene function. Exon skipping and inclusion are based on the interference of AONs with splicing of pre-mRNAs. These are powerful, specific and particularly versatile techniques, which can be used to circumvent pathogenic mutations, shift splice variant expression, knock down proteins, or to create molecular models using in-frame deletions. Pre-mRNA targeting is currently used both as a research tool, e.g., in models for motor neuron disease, and in clinical trials for Duchenne muscular dystrophy and amyotrophic lateral sclerosis. AONs are particularly promising in relation to brain research, as the modified AONs are taken up extremely fast in neurons and glial cells with a long residence, and without the need for viral vectors or other delivery tools, once inside the blood brain barrier. In this review we cover (1). The principles of antisense-mediated techniques, chemistry, and efficacy. (2) The pros and cons of AON approaches in the brain compared to other techniques of interfering with gene function, such as transgenesis and short hairpin RNAs, in terms of specificity of the manipulation, spatial, and temporal control over gene expression, toxicity, and delivery issues. (3) The potential applications for Neuroscience. We conclude that there is good evidence from animal studies that the central nervous system can be successfully targeted, but the potential of the diverse AON-based approaches appears to be under-recognized. PMID- 21811438 TI - Targeting neuronal populations of the striatum. AB - The striatum is critically involved in motor and motivational functions. The dorsal striatum, caudate-putamen, is primarily implicated in motor control and the learning of habits and skills, whereas the ventral striatum, the nucleus accumbens, is essential for motivation and drug reinforcement. The GABA medium sized spiny neurons (MSNs, about 95% of striatal neurons), which are targets of the cerebral cortex and the midbrain dopaminergic neurons, form two pathways. The dopamine D(1) receptor-positive (D(1)R) striatonigral MSNs project to the medial globus pallidus and substantia nigra pars reticulata (direct pathway) and co express D(1)R and substance P, whereas dopamine D(2) receptor-positive (D(2)R) striatopallidal MSNs project to the lateral globus pallidus (indirect pathway) and co-express D(2)R, adenosine A(2A) receptor (A(2A)R) and enkephalin (Enk). The specific role of the two efferent pathways in motor and motivational control remained poorly understood until recently. Indeed, D(1)R striatonigral and D(2)R striatopallidal neurons, are intermingled and morphologically indistinguishable, and, hence, cannot be functionally dissociated with techniques such as chemical lesions or surgery. In view of the still debated respective functions of projection D(2)R striatopallidal and D(1)R striatonigral neurons and striatal interneurons, both in motor control and learning but also in more cognitive processes such as motivation, the present review sum up the development of new models and techniques (bacterial artificial chromosome transgenesis, optogenetic, viral transgenesis) allowing the selective targeting of these striatal neuronal populations in adult animal brain to understand their specific roles. PMID- 21811440 TI - Spinogenesis and Pruning in the Anterior Ventral Inferotemporal Cortex of the Macaque Monkey: An Intracellular Injection Study of Layer III Pyramidal Cells. AB - Pyramidal cells grow and mature at different rates among different cortical areas in the macaque monkey. In particular, differences across the areas have been reported in both the timing and magnitude of growth, branching, spinogenesis, and pruning in the basal dendritic trees of cells in layer III. Presently available data suggest that these different growth profiles reflect the type of functions performed by these cells in the adult brain. However, to date, studies have focused on only a relatively few cortical areas. In the present investigation we quantified the growth of the dendritic trees of layer III pyramidal cells in the anterior ventral portion of cytoarchitectonic area TE (TEav) to better comprehend developmental trends in the cerebral cortex. We quantified the growth and branching of the dendrities, and spinogenesis and pruning of spines, from post natal day 2 (PND2) to four and a half years of age. We found that the dendritic trees increase in size from PND2 to 7 months of age and thereafter became smaller. The dendritic trees became increasingly more branched from PND2 into adulthood. There was a two-fold increase in the number of spines in the basal dendritic trees of pyramidal cells from PND2 to 3.5 months of age and then a 10% net decrease in spine number into adulthood. Thus, the growth profile of layer III pyramidal cells in the anterior ventral portion of the inferotemporal cortex differs to that in other cortical areas associated with visual processing. PMID- 21811439 TI - The striatal balancing act in drug addiction: distinct roles of direct and indirect pathway medium spiny neurons. AB - The striatum plays a key role in mediating the acute and chronic effects of addictive drugs, with drugs of abuse causing long-lasting molecular and cellular alterations in both dorsal striatum and nucleus accumbens (ventral striatum). Despite the wealth of research on the biological actions of abused drugs in striatum, until recently, the distinct roles of the striatum's two major subtypes of medium spiny neurons (MSNs) in drug addiction remained elusive. Recent advances in cell-type-specific technologies, including fluorescent reporter mice, transgenic, or knockout mice, and viral-mediated gene transfer, have advanced the field toward a more comprehensive understanding of the two MSN subtypes in the long-term actions of drugs of abuse. Here we review progress in defining the distinct molecular and functional contributions of the two MSN subtypes in mediating addiction. PMID- 21811442 TI - Goodbye ted (an obituary for edward g. Jones). PMID- 21811441 TI - Mechanisms for the modulation of dopamine d(1) receptor signaling in striatal neurons. AB - In the striatum, dopamine D(1) receptors are preferentially expressed in striatonigral neurons, and increase the neuronal excitability, leading to the increase in GABAergic inhibitory output to substantia nigra pars reticulata. Such roles of D(1) receptors are important for the control of motor functions. In addition, the roles of D(1) receptors are implicated in reward, cognition, and drug addiction. Therefore, elucidation of mechanisms for the regulation of dopamine D(1) receptor signaling is required to identify therapeutic targets for Parkinson's disease and drug addiction. D(1) receptors are coupled to G(s/olf)/adenylyl cyclase/PKA signaling, leading to the phosphorylation of PKA substrates including DARPP-32. Phosphorylated form of DARPP-32 at Thr34 has been shown to inhibit protein phosphatase-1, and thereby controls the phosphorylation states and activity of many downstream physiological effectors. Roles of DARPP-32 and its phosphorylation at Thr34 and other sites in D(1) receptor signaling are extensively studied. In addition, functional roles of the non-canonical D(1) receptor signaling cascades that coupled to G(q)/phospholipase C or Src family kinase become evident. We have recently shown that phosphodiesterases (PDEs), especially PDE10A, play a pivotal role in regulating the tone of D(1) receptor signaling relatively to that of D(2) receptor signaling. We review the current understanding of molecular mechanisms for the modulation of D(1) receptor signaling in the striatum. PMID- 21811443 TI - On the fractal nature of nervous cell system. PMID- 21811444 TI - A high-light sensitivity optical neural silencer: development and application to optogenetic control of non-human primate cortex. AB - Technologies for silencing the electrical activity of genetically targeted neurons in the brain are important for assessing the contribution of specific cell types and pathways toward behaviors and pathologies. Recently we found that archaerhodopsin-3 from Halorubrum sodomense (Arch), a light-driven outward proton pump, when genetically expressed in neurons, enables them to be powerfully, transiently, and repeatedly silenced in response to pulses of light. Because of the impressive characteristics of Arch, we explored the optogenetic utility of opsins with high sequence homology to Arch, from archaea of the Halorubrum genus. We found that the archaerhodopsin from Halorubrum strain TP009, which we named ArchT, could mediate photocurrents of similar maximum amplitude to those of Arch (~900 pA in vitro), but with a >3-fold improvement in light sensitivity over Arch, most notably in the optogenetic range of 1-10 mW/mm(2), equating to >2* increase in brain tissue volume addressed by a typical single optical fiber. Upon expression in mouse or rhesus macaque cortical neurons, ArchT expressed well on neuronal membranes, including excellent trafficking for long distances down neuronal axons. The high light sensitivity prompted us to explore ArchT use in the cortex of the rhesus macaque. Optical perturbation of ArchT-expressing neurons in the brain of an awake rhesus macaque resulted in a rapid and complete (~100%) silencing of most recorded cells, with suppressed cells achieving a median firing rate of 0 spikes/s upon illumination. A small population of neurons showed increased firing rates at long latencies following the onset of light stimulation, suggesting the existence of a mechanism of network-level neural activity balancing. The powerful net suppression of activity suggests that ArchT silencing technology might be of great use not only in the causal analysis of neural circuits, but may have therapeutic applications. PMID- 21811445 TI - The Role of BDNF/TrkB Signaling in Acute Amphetamine-Induced Locomotor Activity and Opioid Peptide Gene Expression in the Rat Dorsal Striatum. AB - Exposure to psychostimulants increases brain-derived neurotrophic factor (BDNF) mRNA and protein levels in the cerebral cortex and subcortical structures. Because BDNF is co-localized with dopamine and glutamate in afferents to the striatum of rats, it may be co-released with those neurotransmitters upon stimulation. Further, there may be an interaction between the intracellular signaling cascades activated by dopamine, glutamate, and TrkB receptors in medium spiny striatal neurons. In the present study, the effect of acute amphetamine administration on TrkB phosphorylation, as an indirect indicator of activation, and striatal gene expression, was evaluated. In Experiment 1, 15 min or 2 h after a single saline or amphetamine (2.5 mg/kg, i.p.) injection, the caudate-putamen (CPu), nucleus accumbens (NAc), and dorsomedial prefrontal cortex (dmPFC) were extracted and processed for phospho (p)-TrkB immunoreactivity. Immunoprecipitation analyses indicated that neither the tyrosine phosphorylation (p-Tyr) or autophosphorylation sites of TrkB (706) were changed in NAc, CPu, or dmPFC 15 min after amphetamine administration. In contrast, p-Tyr and the PLCgamma phosphorylation site of TrkB (816) were increased in the NAc and CPu 2 h after amphetamine. In Experiment 2, intra-striatal infusion of the tyrosine kinase inhibitor, K252a, increased amphetamine-induced vertical activity but not total distance traveled. In addition, K252a inhibited amphetamine-induced preprodynorphin, but not preproenkephalin, mRNA expression in the striatum. These data indicate that acute amphetamine administration induces p-TrkB activation and signaling in a time- and brain region-dependent manner and that TrkB/BDNF signaling plays an important role in amphetamine-induced behavior and striatal gene expression. PMID- 21811446 TI - In vivo Dopamine Efflux is Decreased in Striatum of both Fragment (R6/2) and Full Length (YAC128) Transgenic Mouse Models of Huntington's Disease. AB - Huntington's disease (HD) is characterized by numerous alterations within the corticostriatal circuitry. The striatum is innervated by a dense array of dopaminergic (DA) terminals and these DA synapses are critical to the proper execution of motor functions. As motor disturbances are prevalent in HD we examined DA neurotransmission in the striatum in transgenic (tg) murine models of HD. We used in vivo microdialysis to compare extracellular concentrations of striatal DA in both a fragment (R6/2) model, which displays a rapid and severe phenotype, and a full-length (YAC128) model that expresses a more progressive phenotype. Extracellular striatal DA concentrations were significantly reduced in R6/2 mice and decreased concomitantly with age-dependent increasing motor impairments on the rotarod task (7, 9, and 11 weeks). In a sample of 11-week-old R6/2 mice, we also measured tissue concentrations of striatal DA and found that total levels of DA were significantly depleted. However, the loss of total DA content (<50%) was insufficient to account for the full extent of DA depletion in the extracellular fluid (ECF; ~75%). We also observed a significant reduction in extracellular DA concentrations in the striatum of 7-month-old YAC128 mice. In a separate set of experiments, we applied d-amphetamine (AMPH; 10 MUm) locally into the striatum to stimulate the release of intracellular DA into the ECF. The AMPH induced increase in extracellular DA levels was significantly blunted in 9-week old R6/2 mice. There also was a decrease in AMPH-stimulated DA efflux in 7-month old YAC128 mice in comparison to WT controls, although the effect was milder. In the same cohort of 7-month-old YAC128 mice we observed a significant reduction in the total locomotor activity in response to systemic AMPH (2 mg/kg). Our data demonstrate that extracellular DA release is attenuated in both a fragment and full-length tg mouse model of HD and support the concept of DA involvement in aspects of the syndrome. PMID- 21811447 TI - Statistical analysis of coding for molecular properties in the olfactory bulb. AB - The relationship between molecular properties of odorants and neural activities is arguably one of the most important issues in olfaction and the rules governing this relationship are still not clear. In the olfactory bulb (OB), glomeruli relay olfactory information to second-order neurons which in turn project to cortical areas. We investigate relevance of odorant properties, spatial localization of glomerular coding sites, and size of coding zones in a dataset of [(14)C] 2-deoxyglucose images of glomeruli over the entire OB of the rat. We relate molecular properties to activation of glomeruli in the OB using a non parametric statistical test and a support-vector machine classification study. Our method permits to systematically map the topographic representation of various classes of odorants in the OB. Our results suggest many localized coding sites for particular molecular properties and some molecular properties that could form the basis for a spatial map of olfactory information. We found that alkynes, alkanes, alkenes, and amines affect activation maps very strongly as compared to other properties and that amines, sulfur-containing compounds, and alkynes have small zones and high relevance to activation changes, while aromatics, alkanes, and carboxylics acid recruit very big zones in the dataset. Results suggest a local spatial encoding for molecular properties. PMID- 21811448 TI - Bi-directional effect of increasing doses of baclofen on reinforcement learning. AB - In rodents as well as in humans, efficient reinforcement learning depends on dopamine (DA) released from ventral tegmental area (VTA) neurons. It has been shown that in brain slices of mice, GABA(B)-receptor agonists at low concentrations increase the firing frequency of VTA-DA neurons, while high concentrations reduce the firing frequency. It remains however elusive whether baclofen can modulate reinforcement learning in humans. Here, in a double-blind study in 34 healthy human volunteers, we tested the effects of a low and a high concentration of oral baclofen, a high affinity GABA(B)-receptor agonist, in a gambling task associated with monetary reward. A low (20 mg) dose of baclofen increased the efficiency of reward-associated learning but had no effect on the avoidance of monetary loss. A high (50 mg) dose of baclofen on the other hand did not affect the learning curve. At the end of the task, subjects who received 20 mg baclofen p.o. were more accurate in choosing the symbol linked to the highest probability of earning money compared to the control group (89.55 +/- 1.39 vs. 81.07 +/- 1.55%, p = 0.002). Our results support a model where baclofen, at low concentrations, causes a disinhibition of DA neurons, increases DA levels and thus facilitates reinforcement learning. PMID- 21811449 TI - Recency Effects in the Inferior Parietal Lobe during Verbal Recognition Memory. AB - The most recently encountered information is often most easily remembered in psychological tests of memory. Recent investigations of the neural basis of such "recency effects" have shown that activation in the lateral inferior parietal cortex (LIPC) tracks the recency of a probe item when subjects make recognition memory judgments. A key question regarding recency effects in the LIPC is whether they fundamentally reflect the storage (and strength) of information in memory, or whether such effects are a consequence of task difficulty or an upswing in resting state network activity. Using functional magnetic resonance imaging we show that recency effects in the LIPC are independent of the difficulty of recognition memory decisions, that they are not a by-product of an increase in resting state network activity, and that they appear to dissociate from regions known to be involved in verbal working memory maintenance. We conclude with a discussion of two alternative explanations - the memory strength and "expectancy" hypotheses, respectively - of the parietal lobe recency effect. PMID- 21811450 TI - True and false recognition memories of odors induce distinct neural signatures. AB - Neural bases of human olfactory memory are poorly understood. Very few studies have examined neural substrates associated with correct odor recognition, and none has tackled neural networks associated with incorrect odor recognition. We investigated the neural basis of task performance during a yes-no odor recognition memory paradigm in young and elderly subjects using event-related functional magnetic resonance imaging. We explored four response categories: correct (Hit) and incorrect false alarm (FA) recognition, as well as correct (CR) and incorrect (Miss) rejection, and we characterized corresponding brain responses using multivariate analysis and linear regression analysis. We hypothesized that areas of the medial temporal lobe were differentially involved depending on the accuracy of odor recognition. In young adults, we found that significant activity in the hippocampus and the parahippocampal gyrus was associated with correct (true) recognition of odors, whereas the perirhinal cortex was associated with FAs and Misses. These findings are consistent with literature regarding hypothetical functional organization for memory processing. We also found that for correct recognition and rejection responses, the involvement of the hippocampus decreased when memory performances improved. In contrast to young individuals, elderly subjects were more prone to false memories and exhibited less specific activation patterns for the four response categories. Activation in the hippocampus and the parahippocampal gyrus was positively correlated with response bias scores for true and false recognition, demonstrating that conservative subjects produced an additional search effort leading to more activation of these two medial temporal lobe regions. These findings demonstrate that correct and incorrect recognition and rejection induce distinct neural signatures. PMID- 21811451 TI - Spatiotemporal Dynamics of the Processing of Spoken Inflected and Derived Words: A Combined EEG and MEG Study. AB - The spatiotemporal dynamics of the neural processing of spoken morphologically complex words are still an open issue. In the current study, we investigated the time course and neural sources of spoken inflected and derived words using simultaneously recorded electroencephalography (EEG) and magnetoencephalography (MEG) responses. Ten participants (native speakers) listened to inflected, derived, and monomorphemic Finnish words and judged their acceptability. EEG and MEG responses were time-locked to both the stimulus onset and the critical point (suffix onset for complex words, uniqueness point for monomorphemic words). The ERP results showed that inflected words elicited a larger left-lateralized negativity than derived and monomorphemic words approximately 200 ms after the critical point. Source modeling of MEG responses showed one bilateral source in the superior temporal area ~100 ms after the critical point, with derived words eliciting stronger source amplitudes than inflected and monomorphemic words in the right hemisphere. Source modeling also showed two sources in the temporal cortex approximately 200 ms after the critical point. There, inflected words showed a more systematic pattern in source locations and elicited temporally distinct source activity in comparison to the derived word condition. The current results provide electrophysiological evidence for at least partially distinct cortical processing of spoken inflected and derived words. In general, the results support models of morphological processing stating that during the recognition of inflected words, the constituent morphemes are accessed separately. With regard to derived words, stem and suffix morphemes might be at least initially activated along with the whole word representation. PMID- 21811452 TI - On the Influence of Amplitude on the Connectivity between Phases. AB - In recent studies, functional connectivities have been reported to display characteristics of complex networks that have been suggested to concur with those of the underlying structural, i.e., anatomical, networks. Do functional networks always agree with structural ones? In all generality, this question can be answered with "no": for instance, a fully synchronized state would imply isotropic homogeneous functional connections irrespective of the "real" underlying structure. A proper inference of structure from function and vice versa requires more than a sole focus on phase synchronization. We show that functional connectivity critically depends on amplitude variations, which implies that, in general, phase patterns should be analyzed in conjunction with the corresponding amplitude. We discuss this issue by comparing the phase synchronization patterns of interconnected Wilson-Cowan models vis-a-vis Kuramoto networks of phase oscillators. For the interconnected Wilson-Cowan models we derive analytically how connectivity between phases explicitly depends on the generating oscillators' amplitudes. In consequence, the link between neurophysiological studies and computational models always requires the incorporation of the amplitude dynamics. Supplementing synchronization characteristics by amplitude patterns, as captured by, e.g., spectral power in M/EEG recordings, will certainly aid our understanding of the relation between structural and functional organizations in neural networks at large. PMID- 21811453 TI - Brian hears: online auditory processing using vectorization over channels. AB - The human cochlea includes about 3000 inner hair cells which filter sounds at frequencies between 20 Hz and 20 kHz. This massively parallel frequency analysis is reflected in models of auditory processing, which are often based on banks of filters. However, existing implementations do not exploit this parallelism. Here we propose algorithms to simulate these models by vectorizing computation over frequency channels, which are implemented in "Brian Hears," a library for the spiking neural network simulator package "Brian." This approach allows us to use high-level programming languages such as Python, because with vectorized operations, the computational cost of interpretation represents a small fraction of the total cost. This makes it possible to define and simulate complex models in a simple way, while all previous implementations were model-specific. In addition, we show that these algorithms can be naturally parallelized using graphics processing units, yielding substantial speed improvements. We demonstrate these algorithms with several state-of-the-art cochlear models, and show that they compare favorably with existing, less flexible, implementations. PMID- 21811454 TI - Integrating temporal and spatial scales: human structural network motifs across age and region of interest size. AB - Human brain networks can be characterized at different temporal or spatial scales given by the age of the subject or the spatial resolution of the neuroimaging method. Integration of data across scales can only be successful if the combined networks show a similar architecture. One way to compare networks is to look at spatial features, based on fiber length, and topological features of individual nodes where outlier nodes form single node motifs whose frequency yields a fingerprint of the network. Here, we observe how characteristic single node motifs change over age (12-23 years) and network size (414, 813, and 1615 nodes) for diffusion tensor imaging structural connectivity in healthy human subjects. First, we find the number and diversity of motifs in a network to be strongly correlated. Second, comparing different scales, the number and diversity of motifs varied across the temporal (subject age) and spatial (network resolution) scale: certain motifs might only occur at one spatial scale or for a certain age range. Third, regions of interest which show one motif at a lower resolution may show a range of motifs at a higher resolution which may or may not include the original motif at the lower resolution. Therefore, both the type and localization of motifs differ for different spatial resolutions. Our results also indicate that spatial resolution has a higher effect on topological measures whereas spatial measures, based on fiber lengths, remain more comparable between resolutions. Therefore, spatial resolution is crucial when comparing characteristic node fingerprints given by topological and spatial network features. As node motifs are based on topological and spatial properties of brain connectivity networks, these conclusions are also relevant to other studies using connectome analysis. PMID- 21811455 TI - Wavelet transform for real-time detection of action potentials in neural signals. AB - We present a study on wavelet detection methods of neuronal action potentials (APs). Our final goal is to implement the selected algorithms on custom integrated electronics for on-line processing of neural signals; therefore we take real-time computing as a hard specification and silicon area as a price to pay. Using simulated neural signals including APs, we characterize an efficient wavelet method for AP extraction by evaluating its detection rate and its implementation cost. We compare software implementation for three methods: adaptive threshold, discrete wavelet transform (DWT), and stationary wavelet transform (SWT). We evaluate detection rate and implementation cost for detection functions dynamically comparing a signal with an adaptive threshold proportional to its SD, where the signal is the raw neural signal, respectively: (i) non processed; (ii) processed by a DWT; (iii) processed by a SWT. We also use different mother wavelets and test different data formats to set an optimal compromise between accuracy and silicon cost. Detection accuracy is evaluated together with false negative and false positive detections. Simulation results show that for on-line AP detection implemented on a configurable digital integrated circuit, APs underneath the noise level can be detected using SWT with a well-selected mother wavelet, combined to an adaptive threshold. PMID- 21811457 TI - Combined Imaging Markers Dissociate Alzheimer's Disease and Frontotemporal Lobar Degeneration - An ALE Meta-Analysis. AB - To compare and dissociate the neural correlates of Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD), we combine and synthesize here recent comprehensive meta-analyses. Systematic and quantitative meta-analyses were conducted according to the QUOROM statement by calculating anatomical likelihood estimates (ALE). AD (n = 578) and the three subtypes of FTLD, frontotemporal dementia, semantic dementia (SD), and progressive non-fluent aphasia (n = 229), were compared in conjunction analyses, separately for atrophy and reductions in glucose metabolism. Atrophy coincided in the amygdala and hippocampal head in AD and the FTLD subtype SD. The other brain regions did not show any overlap between AD and FTLD subtypes for both atrophy and changes in glucose metabolism. For AD alone (n = 826), another conjunction analysis revealed a regional dissociation between atrophy and hypoperfusion/hypometabolism, whereby hypoperfusion and hypometabolism coincided in the angular/supramarginal gyrus and inferior precuneus/posterior cingulate gyrus. Our data together with other imaging studies suggest a specific dissociation of AD and FTLD if, beside atrophy, additional imaging markers in AD such as abnormally low parietal glucose utilization and perfusion are taken into account. Results support the incorporation of standardized imaging inclusion criteria into future diagnostic systems, which is crucial for early individual diagnosis and treatment in the future. PMID- 21811456 TI - Expensive Brains: "Brainy" Rodents have Higher Metabolic Rate. AB - Brains are the centers of the nervous system of animals, controlling the organ systems of the body and coordinating responses to changes in the ecological and social environment. The evolution of traits that correlate with cognitive ability, such as relative brain size is thus of broad interest. Brain mass relative to body mass (BM) varies among mammals, and diverse factors have been proposed to explain this variation. A recent study provided evidence that energetics play an important role in brain evolution (Isler and van Schaik, 2006). Using composite phylogenies and data drawn from multiple sources, these authors showed that basal metabolic rate (BMR) correlates with brain mass across mammals. However, no such relationship was found within rodents. Here we re examined the relationship between BMR and brain mass within Rodentia using a novel species-level phylogeny. Our results are sensitive to parameter evaluation; in particular how species mass is estimated. We detect no pattern when applying an approach used by previous studies, where each species BM is represented by two different numbers, one being the individual that happened to be used for BMR estimates of that species. However, this approach may compromise the analysis. When using a single value of BM for each species, whether representing a single individual, or available species mean, our findings provide evidence that brain mass (independent of BM) and BMR are correlated. These findings are thus consistent with the hypothesis that large brains evolve when the payoff for increased brain mass is greater than the energetic cost they incur. PMID- 21811458 TI - Challenges in the pharmacotherapy of urogenital disorders. PMID- 21811459 TI - The grand challenges in cardiovascular drug discovery and development. PMID- 21811460 TI - Risk of Upper Gastrointestinal Bleeding in a Cohort of New Users of Low-Dose ASA for Secondary Prevention of Cardiovascular Outcomes. AB - The Health Improvement Network UK primary care database was used to identify a cohort of 38 077 individuals aged 50-84 years with a first prescription of low dose acetylsalicylic acid (ASA; 75-300 mg/day) for secondary prevention of cardiovascular or cerebrovascular events during 2000-2007. From this cohort, 169 incident cases of upper gastrointestinal bleeding (UGIB) were identified. Controls with no UGIB (n = 2000) were frequency-matched to the cases by age, sex, and follow-up time. A nested case-control analysis was performed to determine risk factors associated with UGIB. The incidence of UGIB was 1.1 per 1000 person years (95% CI, 1.0-1.3). Low-dose ASA users with a history of peptic ulcer disease had an increased risk of UGIB compared with those without (Relative Risk [RR], 4.59; 95% CI, 2.87-7.33). Concomitant use of ASA and clopidogrel (RR, 1.61; 95% CI, 0.85-3.05) or non-steroidal anti-inflammatory drugs (NSAIDs; RR, 2.92; 95% CI, 1.77-4.82) conferred an increased risk of UGIB compared with ASA monotherapy. Discontinuation of ASA therapy (RR: 0.71, 95% CI, 0.42-1.20) and PPI co-treatment given since the start of ASA therapy (RR, 0.56; 95% CI, 0.33-0.96) were associated with a reduced risk of UGIB. In conclusion, in a cohort of individuals receiving low-dose ASA for secondary prevention of cardiovascular or cerebrovascular events, patients with a history of peptic ulcer disease, or who were receiving clopidogrel or NSAIDs had an increased risk of UGIB. The prescription of PPI therapy at the initiation of low-dose ASA reduced the risk of UGIB by almost half. PMID- 21811461 TI - Improvement of Airflow Limitation by Fluticasone Propionate/Salmeterol in Chronic Obstructive Pulmonary Disease: What is the Specific Marker? AB - BACKGROUNDS: Inhaled corticosteroids (ICS)/inhaled long-acting beta(2)-agonists (LABA) combination drugs are widely used for the long-term management of chronic obstructive pulmonary disease (COPD). However, COPD is a heterogeneous condition and treatment with ICS is associated with a higher risk of pneumonia. The identification of a specific marker for predicting the efficacy of ICS/LABA on pulmonary function would be useful in the treatment of COPD. METHODS: Fourteen COPD patients receiving tiotropium therapy participated consecutively. The relationship between the baseline exhaled nitric oxide (FE(NO)) levels as well as serum markers and changes in pulmonary function by fluticasone propionate (FP)/salmeterol (SAL) were analyzed. RESULTS: FP/SAL therapy significantly improved forced vital capacity, forced expiratory volume in 1 s (FEV(1)), and the third phase slope of the single nitrogen washout curve (DeltaN(2)) as well as the FE(NO) level. The baseline FE(NO) levels and positive specific IgE (atopy+) were significantly associated with airway obstructive changes assessed by FEV(1) and DeltaN(2). A baseline FE(NO) level >35 ppb yielded 80.0% sensitivity and 66.7% specificity for identifying the subjects with significant improvement in FEV(1) (greater than 200 mL). An atopy+ yielded 60.0% sensitivity and 88.9% specificity for an improvement in FEV(1). When combined with FE(NO) > 35 ppb and atopy+, it showed 40% sensitivity and 100.0% specificity for FEV(1) improvement. Alternatively, COPD subjects with FE(NO) <= 35 ppb and atopy- did not show significant improvement in FEV(1). CONCLUSION: Combining FE(NO) and specific IgE may be a useful marker for predicting the response to ICS/LABA on airflow limitation in COPD. PMID- 21811462 TI - Drug transport and metabolism in the blood-brain barrier. PMID- 21811463 TI - Potential Clinical Implications of the Urotensin II Receptor Antagonists. AB - Urotensin II (UII) binds to its receptor, UT, playing an important role in the heart, kidneys, pancreas, adrenal gland, and central nervous system. In the vasculature, it acts as a potent endothelium-independent vasoconstrictor and endothelium-dependent vasodilator. In disease states, however, this constriction dilation equilibrium is disrupted. There is an upregulation of the UII system in heart disease, metabolic syndrome, and kidney failure. The increase in UII release and UT expression suggest that UII system may be implicated in the pathology and pathogenesis of these diseases by causing an increase in acyl coenzyme A:cholesterol acyltransferase-1 (ACAT-1) activity leading to smooth muscle cell proliferation and foam cell infiltration, insulin resistance (DMII), as well as inflammation, high blood pressure, and plaque formation. Recently, UT antagonists such as SB-611812, palosuran, and most recently a piperazino isoindolinone based antagonist have been developed in the hope of better understanding the UII system and treating its associated diseases. PMID- 21811464 TI - MicroRNA Involved in Inflammation: Control of Eicosanoid Pathway. AB - MicroRNAs (miRNAs) have emerged as important regulators in human physiological and pathological processes. Recent investigations implicated the involvement of miRNAs in the immune system development and function and demonstrated an unexpected new regulatory level. We summarize the current knowledge about miRNA control in the development of the immune system and discuss their role in the immune and inflammatory responses with a special focus on eicosanoid signaling. PMID- 21811465 TI - Diagnosing GORD in Respiratory Medicine. AB - Gastroesophageal reflux disease (GORD) is increasing in prevalence and is highly associated with several lung diseases such as asthma and COPD. Current diagnostic methods are imperfect, being insensitive, non-specific, expensive, or invasive. An accurate diagnosis of GORD can aid effective treatment and have significant clinical impact. Novel methods such as exhaled breath condensate analysis and electronic nose technology have the potential to improve the accuracy of diagnosing GORD. PMID- 21811466 TI - Acidic Mammalian chitinase and the eye: implications for ocular inflammatory diseases. AB - Chitinases have an important role in the defense of organisms against chitin containing parasites. An acidic mammalian chitinase (AMCase) has been detected in epithelial cells in lung tissue samples taken from patients with asthma as well as in conjunctival epithelium of patients with inflammatory ocular diseases. Particularly, elevated AMCase activity has been observed in ocular tissues of patients with vernal keratoconjunctivitis, seasonal allergic conjunctivitis, and in patients affected by dry eye syndrome. This enzyme is induced via a T(H)2 specific, IL-13-dependent pathway. AMCase may thus be a key mediator of IL-13 induced responses in T(H)2-driven inflammatory ocular diseases. PMID- 21811467 TI - Craniosynostosis of coronal suture in twist1 mice occurs through endochondral ossification recapitulating the physiological closure of posterior frontal suture. AB - Craniosynostosis, the premature closure of cranial suture, is a pathologic condition that affects 1/2000 live births. Saethre-Chotzen syndrome is a genetic condition characterized by craniosynostosis. The Saethre-Chotzen syndrome, which is defined by loss-of-function mutations in the TWIST gene, is the second most prevalent craniosynostosis. Although much of the genetics and phenotypes in craniosynostosis syndromes is understood, less is known about the underlying ossification mechanism during suture closure. We have previously demonstrated that physiological closure of the posterior frontal suture occurs through endochondral ossification. Moreover, we revealed that antagonizing canonical Wnt signaling in the sagittal suture leads to endochondral ossification of the suture mesenchyme and sagittal synostosis, presumably by inhibiting Twist1. Classic Saethre-Chotzen syndrome is characterized by coronal synostosis, and the haploinsufficient Twist1(+/-) mice represents a suitable model for studying this syndrome. Thus, we seeked to understand the underlying ossification process in coronal craniosynostosis in Twist1(+/-) mice. Our data indicate that coronal suture closure in Twist1(+/-) mice occurs between postnatal day 9 and 13 by endochondral ossification, as shown by histology, gene expression analysis, and immunohistochemistry. In conclusion, this study reveals that coronal craniosynostosis in Twist1(+/-) mice occurs through endochondral ossification. Moreover, it suggests that haploinsufficiency of Twist1 gene, a target of canonical Wnt-signaling, and inhibitor of chondrogenesis, mimics conditions of inactive canonical Wnt-signaling leading to craniosynostosis. PMID- 21811468 TI - Frontiers in invertebrate physiology - grand challenge. PMID- 21811469 TI - Aquaporin 1a expression in gill, intestine, and kidney of the euryhaline silver sea bream. AB - This study aimed to investigate the effects of chronic salinity acclimation, abrupt salinity transfer, and cortisol administration on aquaporin 1 (AQP1) expression in gill, intestine, and kidney of silver sea bream (Sparus sarba). An AQP1a cDNA was cloned and found to share 83-96% amino acid sequence identity with AQP1 genes from several fish species. Tissue distribution studies of AQP1a mRNA demonstrated that it was expressed in gill, liver, intestine, rectum, kidney, heart, urinary bladder, and whole blood. Semi-quantitative RT-PCR analysis was used to measure AQP1a transcript abundance in sea bream that were acclimated to salinity conditions of 0, 6, 12, 33, 50, and 70 ppt for 1 month. The abundance of gill AQP1a transcript was highest in sea bream acclimated to 0 ppt whereas no differences were found among 0-50 ppt groups. For intestine, the highest AQP1a transcript amounts were found in sea bream acclimated to 12 and 70 ppt whereas the transcript abundance of kidney AQP1a was found to be unchanged amongst the different salinity groups. To investigate the effects of acute salinity alterations on AQP1a expression, sea bream were abruptly transferred from 33 to 6 ppt. For intestine AQP1a levels were altered at different times, post transfer, but remained unchanged in gill and kidney. To study the effects of cortisol on AQP1a expression, sea bream were administered a single dose of cortisol followed by a 3-day acclimation to either 33 or 6 ppt. The findings from this experiment demonstrated that cortisol administration resulted in alterations of AQP1a transcript in gill and intestine but not in kidney. PMID- 21811470 TI - Angiotensin II Type 1 Receptors and Systemic Hemodynamic and Renal Responses to Stress and Altered Blood Volume in Conscious Rabbits. AB - We examined how systemic blockade of type 1 angiotensin (AT(1)-) receptors affects reflex control of the circulation and the kidney. In conscious rabbits, the effects of candesartan on responses of systemic and renal hemodynamics and renal excretory function to acute hypoxia, mild hemorrhage, and plasma volume expansion were tested. Candesartan reduced resting mean arterial pressure (MAP, 8 +/- 2%) without significantly altering cardiac output (CO), increased renal blood flow (RBF, +38 +/- 9%) and reduced renal vascular resistance (RVR, -32 +/- 6%). Glomerular filtration rate (GFR) was not significantly altered but sodium excretion (U(Na+)V) increased fourfold. After vehicle treatment, hypoxia (10% inspired O(2) for 30 min) did not significantly alter MAP or CO, but reduced heart rate (HR, -17 +/- 6%), increased RVR (+33 +/- 16%) and reduced GFR (-46 +/- 16%) and U(Na+)V (-41 +/- 17%). Candesartan did not significantly alter these responses. After vehicle treatment, plasma volume expansion increased CO (+35 +/- 7%), reduced total peripheral resistance (TPR, -26 +/- 5%), increased RBF (+62 +/ 23%) and reduced RVR (-32 +/- 9%), but did not significantly alter MAP or HR. It also increased U(Na+)V (803 +/- 184%) yet reduced GFR (-47 +/- 9%). Candesartan did not significantly alter these responses. After vehicle treatment, mild hemorrhage did not significantly alter MAP but increased HR (+16 +/- 3%), reduced CO (-16 +/- 4%) and RBF (-18 +/- 6%), increased TPR (+18 +/- 4%) and tended to increase RVR (+18 +/- 9%, P = 0.1), but had little effect on GFR or U(Na+)V. But after candesartan treatment MAP fell during hemorrhage (-19 +/- 1%), while neither TPR nor RVR increased, and GFR (-64 +/- 18%) and U(Na+)V (-83 +/- 10%) fell. AT(1)-receptor activation supports MAP and GFR during hypovolemia. But AT(1)-receptors appear to play little role in the renal vasoconstriction, hypofiltration, and antinatriuresis accompanying hypoxia, or the systemic and renal vasodilatation and natriuresis accompanying plasma volume expansion. PMID- 21811471 TI - Upregulated TRPC3 and Downregulated TRPC1 Channel Expression during Hypertension is Associated with Increased Vascular Contractility in Rat. AB - Transient receptor potential (TRP) C1 and C3 (TRPC1 and TRPC3) are expressed in vascular smooth muscle cells and are thought to be involved in vascular contractility. In the present study, we determined the effect of systemic hypertension on TRPC1/TRPC3 channel expression and vascular contractility in rat carotid artery (CA). CA were studied from male spontaneously hypertensive rats (SHR), Wistar-Kyoto (WKY), and Long Evans (LE) rats. TRPC1/3 expression was determined by RT-PCR and Western blot. TRP channel function was evaluated by whole-cell patch clamp, using UTP (60 MUM) to stimulate TRPC1/3 channels. Contractions of endothelium-denuded CA segments to UTP (1-300 MUM) and phenylephrine (Phe; 0.1 nM-10 MUM) were measured in an isometric tension bath. TRPC1 and TRPC3 mRNA was present in CA of both WKY and SHR. Western blot demonstrated 3.1 +/- 1.2 times greater TRPC3 expression and 0.5 +/- 0.2 times TRPC1 in SHR versus WKY CA. Isolated CA showed potentiated contraction to UTP in the SHR versus WKY. Activation of voltage-dependent Ca(2+) channels (VDCC) in UTP mediated constriction only occurred in SHR CA. Contraction to Phe was unaltered between WKY and SHR CA and involved equal significant VDCC activation in both groups. Patch clamp demonstrated that the UTP-stimulated current (I(utp)) was greater in SHR compared to the normotensive WKY and LE rats with peak I(utp) (at 110 mV) of -63 +/- 24 pA compared to -25 +/- 4 pA, respectively. We demonstrate that UTP-mediated but not Phe-mediated constrictions are potentiated in the CA during hypertension. Expression of TRPC1 is decreased whereas TRPC3 is increased in SHR CA. Interestingly, VDCC activation only contributes to UTP-mediated contraction of SHR CAs whereas it contributes substantially and equally in Phe mediated contraction. We speculate that the alteration of TRPC channel expression in hypertension leads to greater smooth muscle depolarization, VDCC activation, and vascular contractility in the UTP (but not Phe) signaling pathway. PMID- 21811472 TI - When mothers go wrong: likely neural undercurrents related to poor parenting. PMID- 21811473 TI - Using animal models to disentangle the role of genetic, epigenetic, and environmental influences on behavioral outcomes associated with maternal anxiety and depression. AB - The etiology of complex psychiatric disorders results from both genetics and the environment. No definitive environmental factor has been implicated, but studies suggest that deficits in maternal care and bonding may be an important contributing factor in the development of anxiety and depression. Perinatal mood disorders such as postpartum depression occur in approximately 10% of pregnant women and can result in detriments in infant care and bonding. The consequences of impaired maternal-infant attachment during critical early brain development may lead to adverse effects on socioemotional and neurocognitive development in infants resulting in long-term behavioral and emotional problems, including increased vulnerability for mental illness. The exact mechanisms by which environmental stressors such as poor maternal care increase the risk for psychiatric disorders are not known and studies in humans have proven challenging. Two inbred mouse strains may prove useful for studying the interaction between maternal care and mood disorders. BALB/c (BALB) mice are considered an anxious strain in comparison to C57BL/6 (B6) mice in behavioral models of anxiety. These strain differences are most often attributed to genetics but may also be due to environment and gene by environment interactions. For example, BALB mice are described as poor mothers and B6 mice as good mothers and mothering behavior in rodents has been reported to affect both anxiety and stress behaviors in offspring. Changes in gene methylation patterns in response to maternal care have also been reported, providing evidence for epigenetic mechanisms. Characterization of these two mouse inbred strains over the course of pregnancy and in the postpartum period for behavioral and neuroendocrine changes may provide useful information by which to inform human studies, leading to advances in our understanding of the etiology of anxiety and depression and the role of genetics and the environment. PMID- 21811474 TI - Investigating the Role of Current Strength in tDCS Modulation of Working Memory Performance in Healthy Controls. AB - Transcranial direct current stimulation (tDCS) is a brain stimulation technique that has the potential to improve working memory (WM) deficits in many clinical disorders. The aim of this study was to investigate the role of current strength on the ability of anodal tDCS to improve WM, and secondly to investigate the time course of effects. Twelve healthy participants underwent three stimulation sessions consisting of 20 min of either 1 mA anodal tDCS, 2 mA anodal tDCS, or sham tDCS to the left dorsolateral prefrontal cortex (DLPFC) localized via F3, all whilst completing a WM task. Intra-stimulation and post-stimulation WM performances were measured using the n-back and Sternberg tasks respectively. Results revealed no significant improvements in participants' accuracy, but a significant interaction was found with respect to current strength and time for accurate reaction time. The finding provides partial support for the hypothesis, in that it appears current strength may affect aspects of WM performance. However, more research is needed, and a higher difficulty level of WM tasks is one of the suggestions discussed for future research. PMID- 21811476 TI - Data management practices for collaborative research. AB - The success of research in the field of maternal-infant health, or in any scientific field, relies on the adoption of best practices for data and knowledge management. Prior work by our group and others has identified evidence-based solutions to many of the data management challenges that exist, including cost effective practices for ensuring high-quality data entry and proper construction and maintenance of data standards and ontologies. Quality assurance practices for data entry and processing are necessary to ensure that data are not denigrated during processing, but the use of these practices has not been widely adopted in the fields of psychology and biology. Furthermore, collaborative research is becoming more common. Collaborative research often involves multiple laboratories, different scientific disciplines, numerous data sources, large data sets, and data sets from public and commercial sources. These factors present new challenges for data and knowledge management. Data security and privacy concerns are increased as data may be accessed by investigators affiliated with different institutions. Collaborative groups must address the challenges associated with federating data access between the data-collecting sites and a centralized data management site. The merging of ontologies between different data sets can become formidable, especially in fields with evolving ontologies. The increased use of automated data acquisition can yield more data, but it can also increase the risk of introducing error or systematic biases into data. In addition, the integration of data collected from different assay types often requires the development of new tools to analyze the data. All of these challenges act to increase the costs and time spent on data management for a given project, and they increase the likelihood of decreasing the quality of the data. In this paper, we review these issues and discuss theoretical and practical approaches for addressing these issues. PMID- 21811475 TI - Hodological resonance, hodological variance, psychosis, and schizophrenia: a hypothetical model. AB - Schizophrenia is a disorder with a large number of clinical, neurobiological, and cognitive manifestations, none of which is invariably present. However it appears to be a single nosological entity. This article considers the likely characteristics of a pathology capable of such diverse consequences. It is argued that both deficit and psychotic symptoms can be manifestations of a single pathology. A general model of psychosis is proposed in which the informational sensitivity or responsivity of a network ("hodological resonance") becomes so high that it activates spontaneously, to produce a hallucination, if it is in sensory cortex, or another psychotic symptom if it is elsewhere. It is argued that this can come about because of high levels of modulation such as those assumed present in affective psychosis, or because of high levels of baseline resonance, such as those expected in deafferentation syndromes associated with hallucinations, for example, Charles Bonnet. It is further proposed that schizophrenia results from a process (probably neurodevelopmental) causing widespread increases of variance in baseline resonance; consequently some networks possess high baseline resonance and become susceptible to spontaneous activation. Deficit symptoms might result from the presence of networks with increased activation thresholds. This hodological variance model is explored in terms of schizo-affective disorder, transient psychotic symptoms, diathesis stress models, mechanisms of antipsychotic pharmacotherapy and persistence of genes predisposing to schizophrenia. Predictions and implications of the model are discussed. In particular it suggests a need for more research into psychotic states and for more single case-based studies in schizophrenia. PMID- 21811477 TI - Social performance cues induce behavioral flexibility in humans. AB - Behavioral flexibility allows individuals to react to environmental changes, but changing established behavior carries costs, with unknown benefits. Individuals may thus modify their behavioral flexibility according to the prevailing circumstances. Social information provided by the performance level of others provides one possible cue to assess the potential benefits of changing behavior, since out-performance in similar circumstances indicates that novel behaviors (innovations) are potentially useful. We demonstrate that social performance cues, in the form of previous players' scores in a problem-solving computer game, influence behavioral flexibility. Participants viewed only performance indicators, not the innovative behavior of others. While performance cues (high, low, or no scores) had little effect on innovation discovery rates, participants that viewed high scores increased their utilization of innovations, allowing them to exploit the virtual environment more effectively than players viewing low or no scores. Perceived conspecific performance can thus shape human decisions to adopt novel traits, even when the traits employed cannot be copied. This simple mechanism, social performance feedback, could be a driver of both the facultative adoption of innovations and cumulative cultural evolution, processes critical to human success. PMID- 21811478 TI - Interhemispheric Connectivity Influences the Degree of Modulation of TMS-Induced Effects during Auditory Processing. AB - Repetitive transcranial magnetic stimulation (rTMS) has been shown to interfere with many components of language processing, including semantic, syntactic, and phonologic. However, not much is known about its effects on nonlinguistic auditory processing, especially its action on Heschl's gyrus (HG). We aimed to investigate the behavioral and neural basis of rTMS during a melody processing task, while targeting the left HG, the right HG, and the Vertex as a control site. Response times (RT) were normalized relative to the baseline-rTMS (Vertex) and expressed as percentage change from baseline (%RT change). We also looked at sex differences in rTMS-induced response as well as in functional connectivity during melody processing using rTMS and functional magnetic resonance imaging (fMRI). fMRI results showed an increase in the right HG compared with the left HG during the melody task, as well as sex differences in functional connectivity indicating a greater interhemispheric connectivity between left and right HG in females compared with males. TMS results showed that 10 Hz-rTMS targeting the right HG induced differential effects according to sex, with a facilitation of performance in females and an impairment of performance in males. We also found a differential correlation between the %RT change after 10 Hz-rTMS targeting the right HG and the interhemispheric functional connectivity between right and left HG, indicating that an increase in interhemispheric functional connectivity was associated with a facilitation of performance. This is the first study to report a differential rTMS-induced interference with melody processing depending on sex. In addition, we showed a relationship between the interference induced by rTMS on behavioral performance and the neural activity in the network connecting left and right HG, suggesting that the interhemispheric functional connectivity could determine the degree of modulation of behavioral performance. PMID- 21811480 TI - The timing of visual object categorization. AB - AN OBJECT CAN BE CATEGORIZED AT DIFFERENT LEVELS OF ABSTRACTION: as natural or man-made, animal or plant, bird or dog, or as a Northern Cardinal or Pyrrhuloxia. There has been growing interest in understanding how quickly categorizations at different levels are made and how the timing of those perceptual decisions changes with experience. We specifically contrast two perspectives on the timing of object categorization at different levels of abstraction. By one account, the relative timing implies a relative timing of stages of visual processing that are tied to particular levels of object categorization: Fast categorizations are fast because they precede other categorizations within the visual processing hierarchy. By another account, the relative timing reflects when perceptual features are available over time and the quality of perceptual evidence used to drive a perceptual decision process: Fast simply means fast, it does not mean first. Understanding the short-term and long-term temporal dynamics of object categorizations is key to developing computational models of visual object recognition. We briefly review a number of models of object categorization and outline how they explain the timing of visual object categorization at different levels of abstraction. PMID- 21811479 TI - Disorders of pitch production in tone deafness. AB - Singing is as natural as speaking for the majority of people. Yet some individuals (i.e., 10-15%) are poor singers, typically performing or imitating pitches and melodies inaccurately. This condition, commonly referred to as "tone deafness," has been observed both in the presence and absence of deficient pitch perception. In this article we review the existing literature concerning normal singing, poor-pitch singing, and, briefly, the sources of this condition. Considering that pitch plays a prominent role in the structure of both music and speech we also focus on the possibility that speech production (or imitation) is similarly impaired in poor-pitch singers. Preliminary evidence from our laboratory suggests that pitch imitation may be selectively inaccurate in the music domain without being affected in speech. This finding points to separability of mechanisms subserving pitch production in music and language. PMID- 21811481 TI - Two tongues, one brain: imaging bilingual speech production. AB - This review considers speaking in a second language from the perspective of motor sensory control. Previous studies relating brain function to the prior acquisition of two or more languages (neurobilingualism) have investigated the differential demands made on linguistic representations and processes, and the role of domain-general cognitive control systems when speakers switch between languages. In contrast to the detailed discussions on these higher functions, typically articulation is considered only as an underspecified stage of simple motor output. The present review considers speaking in a second language in terms of the accompanying foreign accent, which places demands on the integration of motor and sensory discharges not encountered when articulating in the most fluent language. We consider why there has been so little emphasis on this aspect of bilingualism to date, before turning to the motor and sensory complexities involved in learning to speak a second language as an adult. This must involve retuning the neural circuits involved in the motor control of articulation, to enable rapid unfamiliar sequences of movements to be performed with the goal of approximating, as closely as possible, the speech of a native speaker. Accompanying changes in motor networks is experience-dependent plasticity in auditory and somatosensory cortices to integrate auditory memories of the target sounds, copies of feedforward commands from premotor and primary motor cortex and post-articulatory auditory and somatosensory feedback. Finally, we consider the implications of taking a motor-sensory perspective on speaking a second language, both pedagogical regarding non-native learners and clinical regarding speakers with neurological conditions such as dysarthria. PMID- 21811482 TI - Musical expertise and statistical learning of musical and linguistic structures. AB - Adults and infants can use the statistical properties of syllable sequences to extract words from continuous speech. Here we present a review of a series of electrophysiological studies investigating (1) Speech segmentation resulting from exposure to spoken and sung sequences (2) The extraction of linguistic versus musical information from a sung sequence (3) Differences between musicians and non-musicians in both linguistic and musical dimensions. The results show that segmentation is better after exposure to sung compared to spoken material and moreover, that linguistic structure is better learned than the musical structure when using sung material. In addition, musical expertise facilitates the learning of both linguistic and musical structures. Finally, an electrophysiological approach, which directly measures brain activity, appears to be more sensitive than a behavioral one. PMID- 21811483 TI - Neural processing of repetition and non-repetition grammars in 7- and 9-month-old infants. AB - An essential aspect of infant language development involves the extraction of meaningful information from a continuous stream of auditory input. Studies have identified early abilities to differentiate auditory input along various dimensions, including the presence or absence of structural regularities. In newborn infants, frontal and temporal regions were found to respond differentially to these regularities (Gervain et al., 2008), and in order to examine the development of this abstract rule learning we presented 7- and 9 month-old infants with syllables containing an ABB pattern (e.g., "balolo") or an ABC pattern (e.g., "baloti") and measured activity in left and right lateral brain regions using near-infrared spectroscopy (NIRS). While prior newborn work found increases in oxyhemoglobin (oxyHb) activity in response to ABB blocks as compared to ABC blocks in anterior regions, 7- and 9-month-olds showed no differentiation between grammars in oxyHb. However, changes in deoxyhemoglobin (deoxyHb) pointed to a developmental shift, whereby 7-month-olds showed deoxyHb responding significantly different from zero for ABB blocks, but not ABC blocks, and 9-month-olds showed the opposite pattern, with deoxyHb responding significantly different from zero for the ABC blocks but not the ABB blocks. DeoxyHb responses were more pronounced over anterior regions. A grammar by time interaction also illustrated that during the early blocks, deoxyHb was significantly greater to ABC than in later blocks, but there was no change in ABB activation over time. The shift from stronger activation to ABB in newborns (Gervain et al., 2008) and 7-month-olds in the present study to stronger activation to ABC by 9-month-olds here is discussed in terms of changes in stimulus salience and novelty preference over the first year of life. The present discussion also highlights the importance of future work exploring the coupling between oxyHb and deoxyHb activation in infant NIRS studies. PMID- 21811484 TI - Visual processing in rapid-chase systems: image processing, attention, and awareness. AB - Visual stimuli can be classified so rapidly that their analysis may be based on a single sweep of feedforward processing through the visuomotor system. Behavioral criteria for feedforward processing can be evaluated in response priming tasks where speeded pointing or keypress responses are performed toward target stimuli which are preceded by prime stimuli. We apply this method to several classes of complex stimuli. (1) When participants classify natural images into animals or non-animals, the time course of their pointing responses indicates that prime and target signals remain strictly sequential throughout all processing stages, meeting stringent behavioral criteria for feedforward processing (rapid-chase criteria). (2) Such priming effects are boosted by selective visual attention for positions, shapes, and colors, in a way consistent with bottom-up enhancement of visuomotor processing, even when primes cannot be consciously identified. (3) Speeded processing of phobic images is observed in participants specifically fearful of spiders or snakes, suggesting enhancement of feedforward processing by long-term perceptual learning. (4) When the perceived brightness of primes in complex displays is altered by means of illumination or transparency illusions, priming effects in speeded keypress responses can systematically contradict subjective brightness judgments, such that one prime appears brighter than the other but activates motor responses as if it was darker. We propose that response priming captures the output of the first feedforward pass of visual signals through the visuomotor system, and that this output lacks some characteristic features of more elaborate, recurrent processing. This way, visuomotor measures may become dissociated from several aspects of conscious vision. We argue that "fast" visuomotor measures predominantly driven by feedforward processing should supplement "slow" psychophysical measures predominantly based on visual awareness. PMID- 21811485 TI - Entrainment of perceptually relevant brain oscillations by non-invasive rhythmic stimulation of the human brain. AB - The notion of driving brain oscillations by directly stimulating neuronal elements with rhythmic stimulation protocols has become increasingly popular in research on brain rhythms. Induction of brain oscillations in a controlled and functionally meaningful way would likely prove highly beneficial for the study of brain oscillations, and their therapeutic control. We here review conventional and new non-invasive brain stimulation protocols as to their suitability for controlled intervention into human brain oscillations. We focus on one such type of intervention, the direct entrainment of brain oscillations by a periodic external drive. We review highlights of the literature on entraining brain rhythms linked to perception and attention, and point out controversies. Behaviourally, such entrainment seems to alter specific aspects of perception depending on the frequency of stimulation, informing models on the functional role of oscillatory activity. This indicates that human brain oscillations and function may be promoted in a controlled way by focal entrainment, with great potential for probing into brain oscillations and their causal role. PMID- 21811486 TI - Autotransporters and Their Role in the Virulence of Burkholderia pseudomallei and Burkholderia mallei. AB - Burkholderia pseudomallei and Burkholderia mallei are closely related Gram negative bacteria responsible for the infectious diseases melioidosis and glanders, respectively. Autotransporters (ATs) comprise a large and diverse family of secreted and outer membrane proteins that includes virulence-associated invasins, adhesins, proteases, and actin-nucleating factors. The B. pseudomallei K96243 genome contains 11 predicted ATs, eight of which share homologs in the B. mallei ATCC 23344 genome. This review distils key findings from in silico, in vitro, and in vivo studies on the ATs of B. pseudomallei and B. mallei. To date, the best characterized of the predicted ATs of B. pseudomallei and B. mallei is BimA, a predicted trimeric AT mediating actin-based motility which varies in sequence and mode of action between Burkholderia species. Of the remaining eight predicted B. pseudomallei trimeric autotransporters, five of which are also present in B. mallei, two (BoaA and BoaB), have been implicated in bacterial adhesion to epithelial cells. Several predicted Burkholderia ATs are recognized by human humoral and cell-mediated immunity, indicating that they are expressed during infection and may be useful for diagnosis and vaccine-mediated protection. Further studies on the mode of secretion and functions of Burkholderia ATs will facilitate the rational design of control strategies. PMID- 21811487 TI - B-Cell Gene Therapy for Tolerance Induction: Host but Not Donor B-Cell Derived IL 10 is Necessary for Tolerance. AB - Genetically modified B cells are excellent tolerogenic antigen-presenting cells (APCs) in multiple models of autoimmunity. However, the mechanisms of action are still not completely understood. In our models, we generate antigen-specific tolerogenic B cells by transducing naive or primed B cells with an antigen immunoglobulin G (peptide-IgG) construct. In order to be transduced, B cells require activation with mitogens such as LPS. We and others have found that LPS stimulation of B cells upregulates the production of IL-10, a key cytokine for maintaining immune tolerance. In the current study, we defined the role of B-cell produced IL-10 in tolerance induction by using IL-10 deficient B cells as donor APCs. We found that peptide-IgG transduced IL-10 KO B cells have the same effects as wt B cells in tolerance induction in an experimental autoimmune encephalomyelitis model. Moreover, we demonstrated that the tolerogenic effect of peptide-IgG B cells was completely abrogated in anti-IL-10 receptor antibody treated recipients. Taken together, our results suggest that tolerance induced by peptide-IgG B-cell gene therapy requires IL-10 from the host but not donor B cells. These data shed important insights into the mechanisms of tolerance induction mediated by B-cell gene therapy. PMID- 21811490 TI - Anti-Inflammatory Therapy for Feline Immunodeficiency Virus Infection and Associated AIDS-Like Syndrome. PMID- 21811489 TI - The deep biosphere in terrestrial sediments in the chesapeake bay area, virginia, USA. AB - For the first time quantitative data on the abundance of Bacteria, Archaea, and Eukarya in deep terrestrial sediments are provided using multiple methods (total cell counting, quantitative real-time PCR, Q-PCR and catalyzed reporter deposition-fluorescence in situ hybridization, CARD-FISH). The oligotrophic (organic carbon content of ~0.2%) deep terrestrial sediments in the Chesapeake Bay area at Eyreville, Virginia, USA, were drilled and sampled up to a depth of 140 m in 2006. The possibility of contamination during drilling was checked using fluorescent microspheres. Total cell counts decreased from 10(9) to 10(6) cells/g dry weight within the uppermost 20 m, and did not further decrease with depth below. Within the top 7 m, a significant proportion of the total cell counts could be detected with CARD-FISH. The CARD-FISH numbers for Bacteria were about an order of magnitude higher than those for Archaea. The dominance of Bacteria over Archaea was confirmed by Q-PCR. The down core quantitative distribution of prokaryotic and eukaryotic small subunit ribosomal RNA genes as well as functional genes involved in different biogeochemical processes was revealed by Q PCR for the uppermost 10 m and for 80-140 m depth. Eukarya and the Fe(III)- and Mn(IV)-reducing bacterial group Geobacteriaceae were almost exclusively found in the uppermost meter (arable soil), where reactive iron was detected in higher amounts. The bacterial candidate division JS-1 and the classes Anaerolineae and Caldilineae of the phylum Chloroflexi, highly abundant in marine sediments, were found up to the maximum sampling depth in high copy numbers at this terrestrial site as well. A similar high abundance of the functional gene cbbL encoding for the large subunit of RubisCO suggests that autotrophic microorganisms could be relevant in addition to heterotrophs. The functional gene aprA of sulfate reducing bacteria was found within distinct layers up to ca. 100 m depth in low copy numbers. The gene mcrA of methanogens was not detectable. Cloning and sequencing data of 16S rRNA genes revealed sequences of typical soil Bacteria. The closest relatives of the archaeal sequences were Archaea recovered from terrestrial and marine environments. Phylogenetic analysis of the Crenarchaeota and Euryarchaeota revealed new members of the uncultured South African Gold Mine Group, Deep Sea Hydrothermal Vent Euryarchaeotal Group 6, and Miscellaneous Crenarcheotic Group clusters. PMID- 21811492 TI - Optimal analysis method for dynamic contrast-enhanced diffuse optical tomography. AB - Diffuse Optical Tomography (DOT) is an optical imaging modality that has various clinical applications. However, the spatial resolution and quantitative accuracy of DOT is poor due to strong photon scatting in biological tissue. Structural a priori information from another high spatial resolution imaging modality such as Magnetic Resonance Imaging (MRI) has been demonstrated to significantly improve DOT accuracy. In addition, a contrast agent can be used to obtain differential absorption images of the lesion by using dynamic contrast enhanced DOT (DCE-DOT). This produces a relative absorption map that consists of subtracting a reconstructed baseline image from reconstructed images in which optical contrast is included. In this study, we investigated and compared different reconstruction methods and analysis approaches for regular endogenous DOT and DCE-DOT with and without MR anatomical a priori information for arbitrarily-shaped objects. Our phantom and animal studies have shown that superior image quality and higher accuracy can be achieved using DCE-DOT together with MR structural a priori information. Hence, implementation of a combined MRI-DOT system to image ICG enhancement can potentially be a promising tool for breast cancer imaging. PMID- 21811493 TI - Automatic segmentation of dermoscopic images by iterative classification. AB - Accurate detection of the borders of skin lesions is a vital first step for computer aided diagnostic systems. This paper presents a novel automatic approach to segmentation of skin lesions that is particularly suitable for analysis of dermoscopic images. Assumptions about the image acquisition, in particular, the approximate location and color, are used to derive an automatic rule to select small seed regions, likely to correspond to samples of skin and the lesion of interest. The seed regions are used as initial training samples, and the lesion segmentation problem is treated as binary classification problem. An iterative hybrid classification strategy, based on a weighted combination of estimated posteriors of a linear and quadratic classifier, is used to update both the automatically selected training samples and the segmentation, increasing reliability and final accuracy, especially for those challenging images, where the contrast between the background skin and lesion is low. PMID- 21811491 TI - Extreme antimicrobial Peptide and polymyxin B resistance in the genus burkholderia. AB - Cationic antimicrobial peptides and polymyxins are a group of naturally occurring antibiotics that can also possess immunomodulatory activities. They are considered a new source of antibiotics for treating infections by bacteria that are resistant to conventional antibiotics. Members of the genus Burkholderia, which includes various human pathogens, are inherently resistant to antimicrobial peptides. The resistance is several orders of magnitude higher than that of other Gram-negative bacteria such as Escherichia coli, Salmonella enterica, or Pseudomonas aeruginosa. This review summarizes our current understanding of antimicrobial peptide and polymyxin B resistance in the genus Burkholderia. These bacteria possess major and minor resistance mechanisms that will be described in detail. Recent studies have revealed that many other emerging Gram-negative opportunistic pathogens may also be inherently resistant to antimicrobial peptides and polymyxins and we propose that Burkholderia sp. are a model system to investigate the molecular basis of the resistance in extremely resistant bacteria. Understanding resistance in these types of bacteria will be important if antimicrobial peptides come to be used regularly for the treatment of infections by susceptible bacteria because this may lead to increased resistance in the species that are currently susceptible and may also open up new niches for opportunistic pathogens with high inherent resistance. PMID- 21811488 TI - Protein Secretion Systems in Pseudomonas aeruginosa: An Essay on Diversity, Evolution, and Function. AB - Protein secretion systems are molecular nanomachines used by Gram-negative bacteria to thrive within their environment. They are used to release enzymes that hydrolyze complex carbon sources into usable compounds, or to release proteins that capture essential ions such as iron. They are also used to colonize and survive within eukaryotic hosts, causing acute or chronic infections, subverting the host cell response and escaping the immune system. In this article, the opportunistic human pathogen Pseudomonas aeruginosa is used as a model to review the diversity of secretion systems that bacteria have evolved to achieve these goals. This diversity may result from a progressive transformation of cell envelope complexes that initially may not have been dedicated to secretion. The striking similarities between secretion systems and type IV pili, flagella, bacteriophage tail, or efflux pumps is a nice illustration of this evolution. Differences are also needed since various secretion configurations call for diversity. For example, some proteins are released in the extracellular medium while others are directly injected into the cytosol of eukaryotic cells. Some proteins are folded before being released and transit into the periplasm. Other proteins cross the whole cell envelope at once in an unfolded state. However, the secretion system requires conserved basic elements or features. For example, there is a need for an energy source or for an outer membrane channel. The structure of this review is thus quite unconventional. Instead of listing secretion types one after each other, it presents a melting pot of concepts indicating that secretion types are in constant evolution and use basic principles. In other words, emergence of new secretion systems could be predicted the way Mendeleiev had anticipated characteristics of yet unknown elements. PMID- 21811494 TI - A Comparative Study of Mouse Hepatic and Intestinal Gene Expression Profiles under PPARalpha Knockout by Gene Set Enrichment Analysis. AB - Gene expression profiling of PPARalpha has been used in several studies, but fewer studies went further to identify the tissue-specific pathways or genes involved in PPARalpha activation in genome-wide. Here, we employed and applied gene set enrichment analysis to two microarray datasets both PPARalpha related respectively in mouse liver and intestine. We suggested that the regulatory mechanism of PPARalpha activation by WY14643 in mouse small intestine is more complicated than in liver due to more involved pathways. Several pathways were cancer-related such as pancreatic cancer and small cell lung cancer, which indicated that PPARalpha may have an important role in prevention of cancer development. 12 PPARalpha dependent pathways and 4 PPARalpha independent pathways were identified highly common in both liver and intestine of mice. Most of them were metabolism related, such as fatty acid metabolism, tryptophan metabolism, pyruvate metabolism with regard to PPARalpha regulation but gluconeogenesis and propanoate metabolism independent of PPARalpha regulation. Keratan sulfate biosynthesis, the pathway of regulation of actin cytoskeleton, the pathways associated with prostate cancer and small cell lung cancer were not identified as hepatic PPARalpha independent but as WY14643 dependent ones in intestinal study. We also provided some novel hepatic tissue-specific marker genes. PMID- 21811495 TI - Impact of the number of dissected lymph nodes on survival for gastric cancer after distal subtotal gastrectomy. AB - Objectives. To investigate the prognostic impact of the number of dissected lymph nodes (LNs) in gastric cancer after curative distal gastrectomy. Methods. The survival of 634 patients who underwent curative distal gastrectomy from 1995 to 2004 was retrieved. Long-term surgical outcomes and associations between the number of dissected LNs and the 5-year survival rate were investigated. Results. The number of dissected LNs was one of the most important prognostic indicators. Among patients with comparable T category, the larger the number of dissected LNs was, the better the survival would be (P < 0.05). The linear regression showed that a significant survival improvement based on increasing retrieved LNs for stage II, III and IV (P < 0.05). A cut-point analysis yields the greatest variance of survival rate difference at the levels of 15 LNs (stage I), 25 LNs (stage II) and 30 LNs (stage III). Conclusion. The number of dissected LNs is an independent prognostic factor for gastric cancer. To improve the long-term survival of patients with gastric cancer, removing at least 15 LNs for stage I, 25 LNs for stage II, and 30 LNs for stage III patients during curative distal gastrectomy is recommended. PMID- 21811496 TI - Intrafamilial Genotyping of Helicobacter pylori from Faecal DNA. AB - Helicobacter pylori infection, often acquired in early childhood, is a global cause of undernutrition, gastritis, peptic ulcer disease and gastric carcinoma. This study tested the feasibility of using H. pylori shed in the faeces as a source of DNA for non-invasive epidemiological studies. H. pylori DNA was chemically recovered and isolated using a specific biotinylated oligonucleotide probe with magnetic capture from 28 H. pylori positive faecal samples obtained from children attending hospital for the investigation of suspected H. pylori infection, together with close family members. Random amplification of polymorphic DNA (RAPD) was subsequently used to discriminate each isolate. 93% of stool samples selected were typeable. Parent, child and sibling samples were compared and similarities determined. Phylogenetic analysis showed that H. pylori DNA obtained from the faeces can be used to genotype individual strains, offering a means of studying intrafamilial transfer of this microorganism. PMID- 21811497 TI - Genetically Modified Lactococcus lactis for Delivery of Human Interleukin-10 to Dendritic Cells. AB - Interleukin-10 (IL-10) plays an indispensable role in mucosal tolerance by programming dendritic cells (DCs) to induce suppressor Th-cells. We have tested the modulating effect of L. lactis secreting human IL-10 (L. lactis(IL-10)) on DC function in vitro. Monocyte-derived DC incubated with L. lactis(IL-10) induced effector Th-cells that markedly suppressed the proliferation of allogenic Th-cells as compared to L. lactis. This suppressive effect was only seen when DC showed increased CD83 and CD86 expression. Furthermore, enhanced production of IL 10 was measured in both L. lactis(IL-10)-derived DC and Th-cells compared to L. lactis-derived DC and Th-cells. Neutralizing IL-10 during DC-Th-cell interaction and coculturing L. lactis(IL-10)-derived suppressor Th-cells with allogenic Th cells in a transwell system prevented the induction of suppressor Th-cells. Only 130 pg/mL of bacterial-derived IL-10 and 40 times more exogenously added recombinant human IL-10 were needed during DC priming for the generation of suppressor Th-cells. The spatially restricted delivery of IL-10 by food-grade bacteria is a promising strategy to induce suppressor Th-cells in vivo and to treat inflammatory diseases. PMID- 21811498 TI - Prostate-specific membrane antigen-based therapeutics. AB - Prostate cancer (PC) is the most common noncutaneous malignancy affecting men in the US, leading to significant morbidity and mortality. While significant therapeutic advances have been made, available systemic therapeutic options are lacking. Prostate-specific membrane antigen (PSMA) is a highly-restricted prostate cell-surface antigen that may be targeted. While initial anti-PSMA monoclonal antibodies were suboptimal, the development of monoclonal antibodies such as J591 which are highly specific for the external domain of PSMA has allowed targeting of viable, intact prostate cancer cells. Radiolabeled J591 has demonstrated accurate and selective tumor targeting, safety, and efficacy. Ongoing studies using anti-PSMA radioimmunotherapy with (177)Lu-J591 seek to improve the therapeutic profile, select optimal candidates with biomarkers, combine with chemotherapy, and prevent or delay the onset of metastatic disease for men with biochemical relapse. Anti-PSMA monoclonal antibody-drug conjugates have also been developed with completed and ongoing early-phase clinical trials. As PSMA is a selective antigen that is highly overexpressed in prostate cancer, anti-PSMA-based immunotherapy has also been studied and utilized in clinical trials. PMID- 21811499 TI - An integrated framework to achieve interoperability in person-centric health management. AB - The need for high-quality out-of-hospital healthcare is a known socioeconomic problem. Exploiting ICT's evolution, ad-hoc telemedicine solutions have been proposed in the past. Integrating such ad-hoc solutions in order to cost effectively support the entire healthcare cycle is still a research challenge. In order to handle the heterogeneity of relevant information and to overcome the fragmentation of out-of-hospital instrumentation in person-centric healthcare systems, a shared and open source interoperability component can be adopted, which is ontology driven and based on the semantic web data model. The feasibility and the advantages of the proposed approach are demonstrated by presenting the use case of real-time monitoring of patients' health and their environmental context. PMID- 21811500 TI - The Loss of HIF1alpha Leads to Increased Susceptibility to Cadmium-Chloride Induced Toxicity in Mouse Embryonic Fibroblasts. AB - Wild-type and HIF1alpha -/- MEF cells were used to determine the role of HIF1alpha in cadmium-induced toxicity. Cadmium treatment did not affect HIF1 mediated transcription but led to caspase activation and apoptotic cell death in wild-type and HIF1alpha -/- cells. Cadmium-induced cell death, however, was significantly higher in HIF1alpha -/- cells as compared to their wild-type counterparts. Increased cell death in the HIF1alpha -/- cells was correlated with lower metallothionein protein, elevated levels of reactive oxygen species, and decreased superoxide dismutase enzyme activity. The total and oxidized glutathione levels, and, correspondingly, lipid peroxidation levels were elevated in the null cells compared to wild-type cells, indicating increased antioxidant demand and greater oxidative stress. Overall, the results suggest that basal levels of HIF1alpha play a protective role against cadmium-induced cytotoxicity in mouse embryonic fibroblasts by maintaining metallothionein and antioxidant activity levels. PMID- 21811501 TI - Effect of glycine on lead mobilization, lead-induced oxidative stress, and hepatic toxicity in rats. AB - The effectiveness of glycine in treating experimental lead intoxication was examined in rats. Male Wistar rats were exposed to 3 g/L lead acetate in drinking water for 5 weeks and treated thereafter with glycine (100 and 500 mg/kg, orally) once daily for 5 days or glycine (1000 mg/kg, orally) once daily for 28 days. The effect of these treatments on parameters indicative of oxidative stress (glutathione and malondialdehyde levels), the activity of blood delta aminolevulinic acid dehydratase, and lead concentration in blood, liver, kidney, brain, and bone were investigated. Liver samples were observed for histopathological changes. Glycine was found to be effective in (1) increasing glutathione levels; (2) reducing malondialdehyde levels; (3) decreasing lead levels in bone with the highest dose. However, glycine had no effect on lead mobilization when 100 and 500 mg/kg glycine were administered. In microscopic examination, glycine showed a protective effect against lead intoxication. PMID- 21811502 TI - Self-Assemblies of Single-Walled Carbon Nanotubes through Tunable Tethering of Pyrenes by Dextrin for Rapidly Chiral Sensing. AB - Pyrene-modified dextrin (Py-Dex) was synthesized via the Schiff base reaction between reducing end of dextrins and 1-aminopyrene, and then self-assemblies of single-walled carbon nanotubes (SWNTs) were fabricated through the tunable tethering of pyrene to SWNTs by dextrin chains. The Py-Dex-SWNTs assemblies were found to be significantly water-soluble because of the synergistic effect of dextrin chains and pyrene moieties. Py-Dex and Py-Dex-SWNTs were adequately characterized by NMR, UV-vis, fluorescence spectroscopy, Raman spectroscopy, matrix-assisted laser desorption/ionization-time of flight mass spectroscopy, and transmission electron microscopy. The tethering effect of dextrin toward pyrene moieties was clearly revealed and was found to be tunable by adjusting the length of dextrin chains. The fluorescence of pyrene moieties was sufficiently quenched by SWNTs with the support of dextrin chains. Furthermore, the Py-Dex-SWNTs assemblies were used for chiral selective sensing by introducing cyclodextrins as chiral binding sites. The rapid chiral sensing was successfully tested for different enantiomers. PMID- 21811503 TI - Cellular Reprogramming toward the Erythroid Lineage. AB - Haemoglobinopathies such as thalassaemia and sickle cell disease present a major health burden. Currently, the main forms of treatment for these diseases are packed red blood cell transfusions and the administration of drugs which act to nonspecifically reactivate the production of foetal haemoglobin. These treatments are ongoing throughout the life of the patient and are associated with a number of risks, such as limitations in available blood for transfusion, infections, iron overload, immune rejection, and side effects associated with the drug treatments. The field of cellular reprogramming has advanced significantly in the last few years and has recently culminated in the successful production of erythrocytes in culture. This paper will discuss cellular reprogramming and its potential relevance to the treatment of haemoglobinopathies. PMID- 21811505 TI - Arginine vasopressin-independent mechanism of impaired water excretion in a patient with sarcoidosis complicated by central diabetes insipidus and glucocorticoid deficiency. AB - A 28-year-old man was admitted to our hospital because of reduced livido and increased fatigability. Four months before admission, he noticed polyuria, which was gradually relieved by admission. Magnetic resonance imaging revealed enhancing lesion centrally in the pituitary stalk. Biopsy from the skin revealed noncaseating granuloma composed of epithelioid cells, and a diagnosis of sarcoidosis was made. Although plasma arginine vasopressin (AVP) was undetectable after administration of hypertonic saline, urinary output was within normal range (1.5 to 2.2 L/day). The urine osmolality became above plasma levels during the hypertonic saline test. Hormonal provocative tests revealed partial glucocorticoid deficiency. Soon after the glucocorticoid therapy was begun, moderate polyuria (from 3.5-4.0 liters daily) occurred. At this time, plasma AVP was undetectable, and urine osmolality was consistently below plasma levels during the hypertonic saline test. In conclusion, we showed in human study that masked diabetes insipidus could be mediated by AVP-independent mechanisms. PMID- 21811504 TI - Mutations in epigenetic modifiers in myeloid malignancies and the prospect of novel epigenetic-targeted therapy. AB - In the recent years, the discovery of a series of mutations in patients with myeloid malignancies has provided insight into the pathogenesis of myelodysplastic syndromes (MDSs), myeloproliferative neoplasms (MPNs), and acute myeloid leukemia (AML). Among these alterations have been mutations in genes, such as IDH1/2, TET2, DNMT3A, and EZH2, which appear to affect DNA and/or histone lysine methylation. Large clinical correlative studies are beginning to decipher the clinical importance, prevalence, and potential prognostic significance of these mutations. Additionally, burgeoning insight into the role of epigenetics in the pathogenesis of myeloid malignancies has prompted increased interest in development of novel therapies which target DNA and histone posttranslational modifications. DNA demethylating agents have been demonstrated to be clinically active in a subset of patients with MDS and AML and are used extensively. However, newer, more specific agents which alter DNA and histone modification are under preclinical study and development and are likely to expand our therapeutic options for these diseases in the near future. Here, we review the current understanding of the clinical importance of these newly discovered mutations in AML and MDS patients. We also discuss exciting developments in DNA methyltransferase inhibitor strategies and the prospect of novel histone lysine methyltransferase inhibitors. PMID- 21811506 TI - A 41-Year-Old Man with Two Types of Metachronous Peptic Ulcer Complication due to Zollinger-Ellison Syndrome-Regression of Pancreatic Primary after Chemoembolization of Hepatic Metastases: A Case Report. AB - Introduction. Gastrinoma should be suspected when the peptic ulcer(s) is postbulbar, multiple, refractory, or recurrent, or ulcer is associated with nephrolithiasis, hypocalcaemia, or erosive esophagitis. The majority of gastrinomas are malignant. Case Presentation. The patient is a 41-year-old Iranian man who has been in good health until 36 months ago when duodenal perforation and two bouts of upper GI bleeding (GIB), each two months apart occurred. He also mentioned mild watery diarrhoea and decreased appetite. Serum gastrin level was elevated. Abdominal CT scan revealed pancreatic mass and three enhancing hepatic masses. CT-guided pancreatic biopsy revealed monotonous cells. Chemoembolization of hepatic metastases was done. New ct images 6 months later showed nearly total regressed hepatic and pancreatic lesions. Conclusion. Beside previously defined situations that take gastrinoma into account as the etiology of PUD, accumulation of PUD complications is highly suggestive of Zollinger Ellisone syndrome (ZES). Regression of pancreatic primary after chemoembolization of hepatic metastases is unexplainable at the present time. PMID- 21811507 TI - Abdominal compartment syndrome caused by massive pyonephrosis in an infant with primary obstructive megaureter. AB - The authors report a case of abdominal compartment syndrome caused by massive pyonephrosis in an infant with primary obstructive megaureter successfully treated with emergency surgical decompression. PMID- 21811508 TI - Psoas abscess formation in suboptimally controlled diabetes mellitus. AB - Psoas abscess formation is a rare entity for which diabetes mellitus remains a major predisposing factor. Diabetes has long been associated with a predisposition to unusual and more serious infections. Here we present two cases that demonstrate that chronically suboptimally controlled diabetes remains an important marker for the development of primary psoas abscess. It is important to include psoas abscess in the differential in such patients to ensure early diagnosis and treatment. PMID- 21811509 TI - An unusual case of acute foot drop caused by a pseudoaneurysm. AB - Lower extremity neurologic symptoms are a common presenting problem. Here we report the case of a 73-year-old man who developed acute right foot pain and foot drop. History, physical examination, and electrodiagnostic studies were consistent with a lumbosacral plexopathy. Imaging studies revealed an internal iliac artery pseudoaneurysm, a rare cause of acute foot drop. PMID- 21811510 TI - Toolkit for monitoring and evaluation of indoor residual spraying for visceral leishmaniasis control in the Indian subcontinent: application and results. AB - Background. We field tested and validated a newly developed monitoring and evaluation (M&E) toolkit for indoor residual spraying to be used by the supervisors at different levels of the national kala-azar elimination programs in Bangladesh, India and Nepal. Methods. Methods included document analysis, in depth interviews, direct observation of spraying squads, and entomological chemical assessments (bioassay, susceptibility test, chemical analysis of insecticide residues on sprayed surfaces, vector density measurements at baseline, and three follow-up surveys). Results. We found that the documentation at district offices was fairly complete; important shortcomings included insufficient training of spraying squads and supervisors, deficient spray equipment, poor spraying performance, lack of protective clothing, limited coverage of houses resulting in low bioavailability of the insecticide on sprayed surfaces, and reduced vector susceptibility to DDT in India, which limited the impact on vector densities. Conclusion. The M&E toolkit is a useful instrument for detecting constraints in IRS operations and to trigger timely response. PMID- 21811511 TI - Differential Regulation of the Immune Response in the Spleen and Liver of Mice Infected with Leishmania donovani. AB - Immunity to pathogens requires generation of effective innate and adaptive immune responses. Leishmania donovani evades these host defense mechanisms to survive and persist in the host. A better understanding and identification of mechanisms that L. donovani employs for its survival is critical for developing novel therapeutic interventions that specifically target the parasite. This paper will highlight some of the mechanisms that the parasite utilizes for its persistence and also discuss how the immune response is regulated. PMID- 21811512 TI - Observations on Copy Number Variations in a Kidney-yang Deficiency Syndrome Family. AB - We have performed an analysis of a family with kidney-yang deficiency syndrome (KDS) in order to determine the structural genomic variations through a novel approach designated as "copy number variants" (CNVs). Twelve KDS subjects and three healthy spouses from this family were included in this study. Genomic DNA samples were genotyped utilizing an Affymetrix 100 K single nucleotide polymorphism array, and CNVs were identified by Copy Number Algorithm (CNAT4.0, Affymetrix). Our results demonstrate that 447 deleted and 476 duplicated CNVs are shared among KDS subjects within the family. The homologus ratio of deleted CNVs was as high as 99.78%. One-copy-duplicated CNVs display mid-range homology. For two copies of duplicated CNVs (CNV(4)), a markedly heterologous ratio was observed. Therefore, with the important exception of CNV(4), our data shows that CNVs shared among KDS subjects display typical Mendelian inheritance. A total of 113 genes with established functions were identified from the CNV flanks; significantly enriched genes surrounding CNVs may contribute to certain adaptive benefit. These genes could be classified into categories including: binding and transporter, cell cycle, signal transduction, biogenesis, nerve development, metabolism regulation and immune response. They can also be included into three pathways, that is, signal transduction, metabolic processes and immunological networks. Particularly, the results reported here are consistent with the extensive impairments observed in KDS patients, involving the mass-energy information-carrying network. In conclusion, this article provides the first set of CNVs from KDS patients that will facilitate our further understanding of the genetic basis of KDS and will allow novel strategies for a rational therapy of this disease. PMID- 21811513 TI - Demand for CAM Practice at Hospitals in Japan: A Population Survey in Mie Prefecture. AB - Complementary and alternative medicine (CAM) therapies have been provided at hospitals along with conventional medicine in industrialized nations. Previous studies conducted in Japan revealed high proportion of Japanese had experience of using CAM, but failed to discuss how it should be provided. The present study aims to clarify the demand for CAM practice at hospitals in Japan. A questionnaire consisting of 41 questions was mailed to 10 000 adults randomly selected from the electoral roll of Mie prefecture, Japan in January 2007. The questionnaire asked the subjects about demand for CAM practice at hospitals, types of CAM therapy to be provided and associated reasons. Sociodemographic characteristics, perceived health status, experience and purpose of CAM use, and information resource for CAM were also surveyed. Completed answers were collected from 2824 (28.6%) respondents. Two thousand and nineteen (71.5%) of the respondents demanded CAM practice at hospitals with the most likely reason of "patients can receive treatment under the guidance of a physicians". The three most popular CAM therapies were Kampo, acupressure/massage/Shiatsu and acupuncture/moxibustion. The demand was positively associated with gender, ages of 40-59 years, annual household incomes of 5-7 million yen, occupation of specialist and technical workers and sales workers and poor health status. Higher demand was observed among those who used both CAM and conventional medical therapies for curative purposes. In conclusion, Japanese show a high demand for CAM practice, hoping to use CAM for curative purposes with monitoring by physicians at hospitals. PMID- 21811514 TI - Ameliorative Effect of Active Principle Isolated from Seeds of Eugenia jambolana on Carbohydrate Metabolism in Experimental Diabetes. AB - The aim of this study was to evaluate the antidiabetic activity of LH II purified from ethanolic seed extract of Eugenia jambolana in alloxan-induced mild diabetic (MD) and severely diabetic (SD) rabbits. Ethanolic extract upon chromatographic purification yielded partially purified hypoglycemic principle (SIII) which on further purification by sephadex LH 20 yielded pharmacological active compound LH II. Homogeneity of LH II was tested by HPLC. Phytochemical investigation of LH II by various structural spectra showed the presence of saturated fatty acid, Delta(5) lipid and presence of sterol. LH II was administered orally at a dose of 10 mg kg(-1) body weight to MD and SD. LH II resulted, significant fall in FBG at 90 min (21.2% MD: 28.6% SD), 7th day (35.6% MD) and 15th day (59.6% SD). Glycosylated hemoglobin was significantly decreased (50.5%) in SD after 15 days treatment (Tt). Plasma insulin levels were significantly increased (P < .001). In vitro studies with pancreatic islets showed 3-fold increase in insulin levels as compared to untreated animals. LH II also showed extrapancreatic effect by significantly increasing (P < .001) the activity of key enzymes of glycolysis and significantly decreasing (P < .001) the activity of key enzymes of gluconeogenesis. Liver and muscle glycogen content were increased by 36.6 and 30% for MD, and 52 and 47% for SD, respectively. Thus, the present study demonstrates that LH II possesses potent antidiabetic activity and it is effective in both MD and SD rabbits. PMID- 21811515 TI - Suprasellar hydatid cyst. PMID- 21811516 TI - Sacral myeloradiculitis (Elsberg syndrome) secondary to eosinophilic meningitis caused by Angiostrongylus cantonensis. AB - Elsberg syndrome secondary to eosinophilic meningitis caused by Angiostrongylus cantonensis is uncommon. Clinicians should consider a wide differential diagnosis including tumour, spinal cord infarction, necrosis, vasculitis, drug induced or other sources of infection. In addition, acute urinary retention is a urological emergency and clinicians should keep in mind the prevention of bladder overdistension. The intervention of rehabilitation programmes and clean intermittent catheterisation education for bladder management, in accordance with the patient's condition, is also important. Earlier rehabilitation is important to ensure a speedy recovery and to prevent further complications. PMID- 21811517 TI - Complex alternative splicing of the smarca2 gene suggests the importance of smarca2-B variants. AB - BRM is an ATPase component of the SWI/SNF complex that regulates chromatin remodeling and cell proliferation and is considered a tumor suppressor. In this study we characterized transcripts from the Smarca2 gene that encodes the BRM protein. We found that the human Smarca2 gene (hSmarca2), like its mouse counterpart (mSmarca2), also initiated a short transcript from intron 27 of the long transcript. We name the long and short transcripts as Smarca2-a and Smarca2 b, respectively. Like its human counterpart, mSmarca2-a also underwent alternative splicing at the 54-bp exon 29. The hSmarca2-b had two alternative initiation sites and underwent alternative splicing at three different 3' sites of exon 1 and at exons 2, 3 and/or 5. We identified nine hSmarca2-b mRNA variants that might produce five different proteins. mSmarca2-b also underwent alternative splicing at exon 3 and/or exon 5, besides alternatively retaining part of intron 1 in exon 1. Smarca2-b was expressed more abundantly than Smarca2-a in many cell lines and was more sensitive to serum starvation. Moreover, cyclin D1 also regulated the expression of both Smarca2-a and Smarca2-b in a complex manner. These data suggest that the functions of the Smarca2 gene may be very complex, not just simply inhibiting cell proliferation, and in certain situations may be elicited mainly by expressing the much less known Smarca2-b, not the better studied Smarca2-a and its products BRM proteins. PMID- 21811518 TI - In situ malignant transformation and progenitor-mediated cell budding: two different pathways for breast ductal and lobular tumor invasion. AB - The human breast lobular and ductal structures and the derived tumors from these structures differ substantial in their morphology, microenvironment, biological presentation, functions, and clinical prognosis. Based on these differences, we have proposed that pre-invasive lobular tumors may progress to invasive lesions through "in situ malignant transformation", in which the entire myoepithelial cell layer within a given lobule or lobular clusters undergoes extensive degeneration and disruptions, which allows the entire epithelial cell population associated with these myoepithelial cell layers directly invade the stroma or vascular structures. In contrast, pre-invasive ductal tumors may invade the stroma or vascular structures through "progenitor-mediated cell budding", in which focal myoepithelial cell degeneration-induced aberrant leukocyte infiltration causes focal disruptions in the tumor capsules, which selectively favor monoclonal proliferation of the overlying tumor stem cells or a biologically more aggressive cell clone. Our current study attempted to provide more direct morphological and immunohistochemical data that are consistent with our hypotheses. PMID- 21811519 TI - Malignant transformation and stromal invasion from normal or hyperplastic tissues: true or false? AB - Carcinogenesis is believed to be a multi-step process, progressing sequentially from normal to hyperplastic, to in situ, and to invasive stages. A number of studies, however, have detected malignancy-associated alterations in normal or hyperplastic tissues. As the molecular profile and clinical features of these tissues have not been defined, the authors invited several well-recognized pathologist, oncologists, biologist, surgeons, and molecular biologist to offer their opinion on: (1) whether these tissues belong to a previously unrevealed malignant entity or focal alterations with no significant consequence? (2) whether these alterations are linked to early onset of cancer or cancer of unknown primary site, and (3) how to further define these lesions? PMID- 21811520 TI - Biomarkers predicting progression of human immunodeficiency virus-related disease. AB - Biomarkers in predicting the progression of HIV infected individuals to a state of HIV disease (AIDS) are studied over more than a decade. Use of surrogate markers in the past for tracking clinical progression of the disease was limited, as little knowledge existed about the disease. The aim of this review was to address various changes in biomarker related studies taking place over the last five years, especially the trend towards use of newer biomarkers and experimentation with novel molecules in a quest for halting HIV disease progression. An open search of PUBMED database was made with search key words such as Biomarkers and AIDS (Acquired Immunodeficiency Syndrome).The following were the inclusion criteria for articles: a) all articles published in English language, b) years of publication between 2002-2008 and c) articles limited to adult population. This yielded a total of 417 articles. The criteria used for further judging these studies considered a) type of research design, b) number of biomarkers studied, c) validity of the biomarkers, d) techniques to assess the biomarkers and the impact of the studies in furthering biomarker research, e) sample size for the studies and f) article title or abstracts having the following key words biomarker or biomarkers and predict progression to AIDS. A total of 27 abstracts were reviewed and 12 studies met the above criteria. These 12 different studies consisted of three reviews, four cohort designs, three cross sectional designs, one each of an observational, and an in-vitro design. The various biomarkers emerging as a results were primarily a mix of viral, neural, immunological, HLA (human leukocyte antigen) markers along with lymphocyte counts. Although there have been quite a few advancements in biomarker-related studies, majority of the novel biomarkers discovered need to be further evaluated and replicated in bigger, long-term efficacy trials. Efforts should also be made to discover newer genetic markers of disease progression. Biomarker feedback, a new concept, can be utilized in future studies addressing prevention of HIV infection or halting disease progression. KEYWORDS: Biomarkers; Progression; Designs; HIV; AIDS; Validity. PMID- 21811521 TI - Aortic stiffness in prediabetic adults: relationship to insulin resistance. AB - BACKGROUND: A decrease in the compliance of the arterial system, termed arterial stiffness, results in increased cardiac workload. Several studies have shown that arterial stiffness is increased in individuals with type 2 diabetes. Also, insulin resistance is generally considered to be of major importance in the pathophysiology of type 2 diabetes mellitus given that glucose intolerance and insulin resistance precede the development of overt diabetes, these factors would be associated with arterial stiffness. This study was to evaluate the state of aortic elasticity in prediabetic adults in relation to insulin resistance. METHODS: A case-control study was performed. A total of 113 consecutive adults with prediabetes were enrolled for the study, 32 adults had insulin resistance (group A) and 81 had insulin sensitive (group B). Forty-five healthy (with normal fasting glucose) adults matched for age and gender were considered as control. All were subjected to full medical history and clinical examination including blood pressure and body mass index. Biochemical studies including lipids profile, fasting glucose and homeostasis model assessment of insulin resistance (HOMA IR) test. Echocardiographic studies were done for assessment of the aortic stiffness index. RESULTS: Significant increase in mean aortic stiffness index was seen in group A than group B. Stiffness was correlated with insulin resistance and the correlation appeared to be independent of glucose tolerance status and obesity. Similar correlations were observed with age, triglycerides and waist circumference. CONCLUSIONS: Prediabetic subjects have an aortic stiffness which represent pattern of cardiovascular risk factors. These changes are predominantly observed in prediabetic subjects with increased HOMA IR and visceral obesity independent of glucose levels. KEYWORDS: Prediabetes; Insulin resistance; Aortic stiffness index. PMID- 21811522 TI - Nutritional status of chronic obstructive pulmonary disease patients admitted in hospital with acute exacerbation. AB - BACKGROUND: Patients with Chronic Obstructive Pulmonary Disease (COPD) are frequently hospitalized with an acute exacerbation. Patients with COPD often lose weight. Consequently, deterioration in nutritional status (loss of lean body mass) is a likely repercussion of acute exacerbation in hospitalized COPD patients. The study was carried out to assess the nutritional status of COPD patients with acute exacerbation, during the period of hospital admission, and to evaluate the relationships between the nutritional indices and the pulmonary function parameters. METHODS: A cross sectional observation study constituting 83 COPD patients consecutively hospitalized with acute exacerbation on accrual during a period of one year. Lung function was measured by routine spirometry. Nutritional status was assessed by the measurement of anthropometric parameters. Hospital outcome was also assessed. Statistical analysis was performed using SPSS version 16.0 Independent t-tests and Pearsons correlation coefficient was used. RESULTS: Mean body weight was 50.03 +/- 9.23 kg. Subjects had approximately 5 kg weight loss in previous six months. All the subjects had low BMI (19.38 +/- 3.10) and MUAC (21.18 +/- 2.31) that was significantly below the predicted levels. The correlation between body weight and FEV(1)/FVC% was good (r = 0.648, p = 0.003). BMI was negatively correlated (r = - 0.0103, p= 0.03) with duration of hospital stay. CONCLUSIONS: The high prevalence of malnutrition among hospitalized COPD patients with acute exacerbation is related to their lung function and hospital outcome such as duration of hospital stay. KEYWORDS: Nutritional status; COPD; Acute exacerbation; Hospitalization. PMID- 21811523 TI - Prevalence of thyroid dysfunction among greek type 2 diabetic patients attending an outpatient clinic. AB - BACKGROUND: The aim of the present study was to determine the prevalence of thyroid dysfunction in patients with type 2 diabetes (T2D) attending an outpatient clinic. METHODS: We examined thyroid dysfunction in a total of 1,092 patients with T2D. RESULTS: Prevalence rate of thyroid dysfunction was 12.3%. In the group with thyroid dysfunction there was an excess of females in comparison with the group without thyroid dysfunction (P < 0.001). In addition, patients with thyroid dysfunction had higher values of body mass index (P = 0.03) and HDL cholesterol levels (P = 0.01), and lower values of LDL-cholesterol levels (P = 0.001) in comparison with patients without thyroid dysfunction. Multivariate analysis demonstrated that presence of thyroid dysfunction was related with gender (OR: 0.220, 95% CI: 0.141 - 0.352) and LDL-cholesterol levels (OR: 0.990, 95% CI: 0.985 - 0.995). CONCLUSIONS: The prevalence of thyroid dysfunction among Greek diabetic patients is 12.3%. Diabetic women were more frequently affected than men. Presence of thyroid dysfunction was associated with lower levels of LDL cholesterol concentrations. KEYWORDS: Type 2 diabetes mellitus; Thyroid dysfunction; Hypothyroidism; Gender; LDL-cholesterol; Greece. PMID- 21811524 TI - Role of Adenosine Deaminase Estimation in Differentiation of Tuberculous and Non tuberculous Exudative Pleural Effusions. AB - BACKGROUND: Tuberculosis kills five lakh patients every year in India, commonest being pulmonary tuberculosis and is often associated with effusion. Delay in diagnosis and treatment results in poor prognosis. Several studies have suggested the role of adenosine deaminase (ADA) in the diagnosis of tuberculous pleural effusions, but false-positive results from lymphocytic effusions have also been reported. The purpose of this study is to find out the role of ADA levels in differentiation of tuberculous and non-tuberculous exudative pleural effusions of different etiologies. METHODS: Ninety-six lymphocytic pleural fluid samples were consecutively selected and divided into two groups: tuberculous (n = 56) and non tuberculous (n = 40), depending upon the etiology [Malignancy (n = 16), Infectious diseases (n = 18), Pulmonary embolism (n = 1), Collagen vascular diseases (n = 3) and Sarcoidosis (n = 2)]. ADA was estimated in pleural fluid in all the cases. RESULTS: In all 56 samples, ADA level of tuberculous group was above diagnostic cut-off (40 U/L), while only one sample was above cut-off in non tuberculous group (2.5%). The negative predictive value of ADA for the diagnosis of non-tuberculous etiology was 97.5% (39 of 40) lymphocytic pleural effusion patients. CONCLUSIONS: In this study, ADA levels in nontuberculous exudative pleural effusions rarely exceeded the cut-off; set for tuberculous disease. The pleural fluid ADA levels were significantly higher in tuberculous exudative pleural effusions when compared with non-tuberculous exudative pleural effusions. KEYWORDS: Adenosine deaminase; Tuberculous effusion; Pleural fluid; Exudative pleural effusions. PMID- 21811525 TI - Mycoplasma pneumoniae and Chlamydia pneumoniae seropositivity in patients with age-related macular degeneration. AB - BACKGROUND: To determine a possible relation between Mycoplasma pneumoniae (MP) or Chlamidia pneumoniae (CP) seropositivity and age-related macular degeneration (AMD). METHODS: Sixty patients (20 wet AMD, 20 dry AMD and 20 non-AMD controls) were included in the study. Serum samples were collected for analysis of IgM and IgG antibody seropositivity for CP and MP by enzyme-linked immunosorbent assay (ELISA). Comparison of the distribution of seropositivity of these antibodies among patients with wet and dry AMD, and controls was performed. A prospective comparative clinical trial was applied. RESULTS: There was no major difference in the distribution of IgM and IgG seropositivity to CP and MP in patients with wet and dry AMD, and in controls (p > 0.05). CONCLUSIONS: We found no significant association between MP as well as CP antibody titers and AMD. It seems that MP or CP infection is not a risk factor for AMD. KEYWORDS: Mycoplasma pneumoniae; Chlamydia pneumoniae; Age-related macular degeneration; Serology. PMID- 21811526 TI - Inpatient Oral Anticoagulation Management by Clinical Pharmacists: Safety and Cost effectiveness. AB - BACKGROUND: Warfarin prescription for anticoagulation after cardiac surgery has always been a challenge for junior medical staff. METHODS: A prospective study was carried out to assess the quality of anticoagulation control by junior doctors compared with clinical pharmacists at South Manchester University hospitals NHS Trust. The junior medical staff prescribed warfarin for 50 consecutive patients from April to September 2006 (group A, n = 50) and experienced clinical pharmacists dosed 46 consecutive patients between February and May 2007 (group B, n = 46). RESULTS: In group A, 9 (18%) patients discharge was delayed because of lack of attainment of therapeutic International Normalised Ratio (INR) compared to 3 (6.5%) in group B. The total number of bed days resulting from the delay in group A was 21 compared to 4 in group B. Extrapolated over a year this would amount to approximately 15,750 extra cost incurred in group A opposed to 3000 in group B. CONCLUSIONS: The pharmacists were significantly better than junior doctors in achieving therapeutic INR, resulting in fewer discharge delays. The clinical pharmacists with experience in outpatient anticoagulation clinic can play an important role in inpatient oral anticoagulation management in post cardiac surgery patients thereby providing improved cost effective quality of care. KEYWORDS: Warfarin; Pharmacist; Management. PMID- 21811527 TI - An unusual case of foreign body in the anterior abdominal wall. AB - Accidental or intentional ingestion of sharp metallic foreign bodies is a common clinical occurrence. Predisposing factors include excessive alcohol intake, mental impairment and psychiatric illnesses. Usually, the detection of a migratory foreign body is incidental when patients present with unrelated symptoms. A 50-year-old woman attended the surgical outpatient clinic with a foreign body in the anterior abdominal wall. A foreign body was easily palpable on the right upper quadrant of abdomen. Patient was admitted electively and taken to theatre for removal of foreign body under general anaesthesia. Patient made an uneventful recovery and was discharged with no further follow-up. KEYWORDS: Foreign body; Abdomen; Ingestion; Perforation. PMID- 21811528 TI - A rare tumour of the breast: carcinosarcoma. AB - Carcinosarcoma of the breast, also known as metaplastic carcinoma, is rare with very few cases reported in the literature. A 46-year old female patient presented with a mass in her left breast. Physical examination, ultrasonography and mammography findings were consistent with malignancy. The mass was totally removed. Histopathological examination revealed carcinosarcoma of the breast. Histologic grade of the tumour was III. Ki67 proliferation index was found 40% positive. Tumour cells were positive for p53 (70% positive), c-erb-B2 (5% positive), pancytokeratin and EMA in carcinomatous areas, and vimentin in sarcomatous areas. There was no metastasis in axillary lymph node and distant metastasis. The patient is receiving chemotherapy and is under follow-up in the 54th month. Along with a review of the literature, we present the information regarding the clinical and histological findings and treatment of the patient who was operated due to breast carcinosarcoma. KEYWORDS: Breast; Carcinoma; Carcinosarcoma. PMID- 21811529 TI - Anesthetic management of a pediatric patient with wilsons disease. AB - Wilsons disease, characterized by cirrhosis, extrapyramidal symptoms and Kayser Fleischer corneal rings, is a rare hereditary disease of human copper metabolism. Clinical findings in Wilsons disease are complex and neurological symptoms such as tremor, dysarthria, rigid dystonia, seizures, psychiatric disorders, acute liver failure, chronic hepatitis or cirrhosis may develop. A 4-year-old male patient was operated for traumatic depressed skull fracture and intracerebral hematoma. He was diagnosed with Wilsons disease at the age of 2.5 years and treated with zinc sulphate and D-penicillamine. General anesthesia was induced with propofol, fentanyl, atracurium, and maintained with isoflurane, and oxygen. No complications were encountered during the operation or in the postoperative period. We concluded that general anesthesia can successfully be given to Wilsons disease patients using an anesthetic agent, the metabolism of which is least affected by the liver disease, one that induces least hepatic toxicity. By close follow-up of patients clinically and biochemically, it is possible to reduce the complication rates to a minimum. KEYWORDS: Wilson's Disease; Craniocerebral trauma; Thoracic injuries; General anesthesia; Surgery. PMID- 21811530 TI - Syringomyelia: a complication of an underlying pathology. AB - Patients with syringomyelia may have diverse etiology and experience a variety of symptoms. This report describes two cases of syringomyelia in patients with different profiles, presentations and pathomechanisms. KEYWORDS: Syrigomyelia; Syrinx; Arachnoid cyst; Arnold-Chiari. PMID- 21811531 TI - Measuring treatment outcomes in women with vulvodynia. AB - Vulvodynia or vulvar pain syndrome is a chronic, heterogeneous, and multifactorial gynecological condition with an estimated prevalence of 9 - 12%, broad and substantial effect on quality of life due to physical disabilities, psychological distress and sexual dysfunction. A rationale therapeutic approach for the treatment of vulvodynia is still under investigation. A review of treatment modalities proposed by most of the clinicians involved in managing these patients advocated initially utilizing non-invasive therapies and then to proceed gradually to more aggressive therapies. A multidisciplinary approach that includes behavioral science and neuroimaging is required and recommended. Additionally a team approach should be utilized to test and evaluate therapies including pelvic floor physiotheraphy, psychotherapy, microbiology and pharmacology. It is my hope that this review will assist in the understanding of vulvodynia and its measuring treatment outcomes and will provide a thrust in the right direction to once and for all clarify this complex multifactorial disorder affecting women. KEYWORDS: Treatment; Vulvodynia; Women. PMID- 21811532 TI - Septic shock due to candidemia: outcomes and predictors of shock development. AB - BACKGROUND: The present report describes the outcomes of a cohort of patients with Candida induced septic shock. METHODS: Retrospective analysis of individuals who had at least one positive blood culture for Candida species >= 48 h after ICU admission. Data from patients that developed septic shock within 48 hr of the positive blood culture were compared to non-shock candidemic patients. Patients with a concomitant bacteremia and/or endocarditis were excluded. RESULTS: Fifteen patients with Candida induced septic shock were studied and compared to 35 candidemic patients without shock. Overall mortality was 76% (87 % among those who had shock). A high proportion of non-albicans Candida species causing fungemia (74%) was observed. All patients with shock were receiving antibiotics but not antifungal treatment at the time of shock development, eight were on parenteral nutrition, six on steroids and nine had a cancer history. High dose fluconazole was the most common initial treatment provided. Four patients died before receiving any antifungal treatment. Time in ICU before the development of candidemia was identified as a predictor of shock development (higher chance if fungemia developed < 7 days after ICU admission). CONCLUSIONS: Septic shock due to invasive candidiasis is a near fatal condition. No conventional risk factors were identified to predict shock development other than time (shorter) spent in ICU before the development of candidemia. We encourage clinicians to consider the initiation of appropriate empiric antifungal treatment in high-risk patients who develop septic shock while on antimicrobial treatment. KEYWORDS: Septic shock; Candidemia; Outcome; Predictor. PMID- 21811533 TI - Risk factors for delayed diagnosis of scabies in hospitalized patients from long term care facilities. AB - BACKGROUND: Delayed diagnosis of scabies can cause an institutional outbreak, which causes considerably economic burden to control. This study was to find the risk factors for delayed diagnosis of scabies in hospitalized patients from long term care facilities. METHODS: We conducted a retrospective analysis of the hospitalized patients from long-term care facilities, diagnosed to have scabies between January 2006 and December 2008. A stepwise logistic regression analysis was performed to determine the risk factors for delayed diagnosis of scabies. RESULTS: A total of 706 episodes with scabies were identified retrospectively in 399 hospitalized patients from long-term care facilities. Of these, 44 episodes were considered as delayed diagnosis of scabies. These patients were more associated with chronic usage of steroid (73% vs. 10%, P < 0.001) and had longer duration of hospitalization than the others (30 vs. 13 days, P < 0.001). After logistic regression, steroid therapy was the risk factor of delayed diagnosis of scabies (odds ratio: 23.493). CONCLUSIONS: In the patients from long-term care facilities, clinical physicians should pay more attention to those with chronic usage of steroid to avoid delayed diagnosis of scabies. KEYWORDS: Scabies; Delayed diagnosis; Risk factor; Long-term care facility. PMID- 21811534 TI - Protective effects of L-carnitine on intestinal ischemia/reperfusion injury in a rat model. AB - BACKGROUND: Ischemia/reperfusion (IR) injury of the intestine is a major problem in abdominal pathological condition and is associated with a high morbidity and mortality. The purpose of the study is to determine whether the L-carnitine can prevent the harmful effects of small intestinal IR injury in rats. METHODS: Thirty Sprague-Dawley rats were randomly divided into three groups. Sham operated group (S), for shamoperated, the IR group for rats submitted to 45-minute of intestinal ischemia and 2-hour reperfusion, and IR+L group for those IR group treated with L-carnitine before reperfusion. All the rats were given EmGFP labelled E. coli DH5alpha through gavage 2-hour before the operative procedure. Afterwards the bacterial translocation (BT) from mesenteric lymph nodes (MLN), liver, spleen, lung and portal vein blood were detected. And the colony forming units/g (CFU/g) were counted. The TNF-alpha, IL-1beta, IL-6, and IL-10 in serum were measured by ELISA. The morphometric study was measured by Chius classification. RESULTS: The levels of BT were higher in the IR group than IR+L group (P < 0.05). The E. coli DH5alpha was hardly detected in the S group. The IR+L rats had enhancement of IL-10 and suppressed production of serum TNF-alpha, IL-1beta and IL-6, compared to IR group rats (P < 0.05). The degree of pathological impairment in small intestine was lighter in IR+L than IR group (P < 0.05). CONCLUSIONS: The L-carnitine pretreatment has a positive effect on reducing levels of BT, on inhibiting secretion of proinflammatory cytokines, and on lessening intestinal mucosa injury during small intestinal IR injury. KEYWORDS: L-carnitine; Ischemia/reperfusion injury; Intestine. PMID- 21811536 TI - A case of vogt-koyanagi-harada disease associated with polycystic ovary syndrome. AB - We report a female patient diagnosed as Vogt-Koyanagi-Harada (VKH) and polycystic ovary syndrome (PCOS). She has diagnosed as VKH with diminished vision, bilateral serous retinal detachment, the signs of fundus fluorescein angiography and the findings of optical coherence tomography. The patient was referred to the gynecology clinic for her complaints as weight gain, hirsutismus and amenorrhea. She has also been diagnosed with PCOS. With oral steroid treatment, visual acuity has improved and the detachments have resolved within a month. VKH disease may be associated with polycystic ovary syndrome. The two conditions may have a common autoimmune pathogenesis. KEYWORDS: Autoimmune pathogenesis; Polycystic ovary syndrome; Vogt-Koyanagi-Harada. PMID- 21811535 TI - Atypical teratoid/rhabdoid tumors in adults: a case report and treatment-focused review. AB - Atypical teratoid/rhabdoid tumor is predominantly a childhood tumor and has only been rarely reported in adults; therefore, treatment regimens are often extrapolated from the pediatric experience. Typically, children are treated with craniospinal radiation therapy which is often followed by systemic chemotherapy. Employing pediatric regimens to treat this tumor in adult patients poses a particular risk for myelosuppression, as the prescribed doses in pediatric protocols exceed those tolerated by adults, and conventional craniospinal radiation can be associated with prolonged myelotoxicity and a depletion of the bone marrow reserve in vertebrae of adults. Here we present a case of a woman with a pineal region atypical teratoid/rhabdoid tumor, an unusual adult cancer presenting in an atypical location. This is followed by a review of the disease in adult patients with an emphasis on treatment and suggestions to minimize myelotoxicity. KEYWORDS: Atypical rhabdoid tumor; AT/RT; Pineal tumor; Adult. PMID- 21811537 TI - NSAID-Associated Perforation of a Meckels Diverticulum: A Case Report. AB - Meckels diverticulum is the most frequent congenital malformation of the gastrointestinal tract. The most common ectopic tissue within a Meckels is heterotopic gastric mucosa, with bleeding being the most common presentation. However, perforation of a Meckels diverticulum is a rare presentation. NSAID associated Meckels perforation has been suggested, however has not been documented in the literature. We present a case of a 17-year-old female with acute abdominal pain and tenderness following a 24-hour history of excessive ingestion of NSAIDS for pain related to tooth extraction. Chest radiograph demonstrated free intra-abdominal air and she was subsequently taken for exploratory laparotomy. A perforated Meckels diverticulum was isolated and resected. Though NSAID-associated bleeding of heterotopic gastric mucosa has been described, and perforation of the Meckels diverticulum has been suggested, no clear association between heterotopic gastric mucosa and perforation exists. On the other hand, the relationship between NSAIDS and gastric ulcer perforation is well documented. A similar mechanism may also play a role in NSAID-associated Meckels perforation. With how common NSAID use is, we believe it is important to document NSAID-associated perforation of a Meckels diverticulum. KEYWORDS: Meckels diverticulum; NSAIDS; Perforation; Heterotopic gastric mucosa. PMID- 21811538 TI - An adolescent patient with hip pain: slipped capital femoral epiphysis. PMID- 21811539 TI - Does open access improve the process and outcome of podiatric care? AB - BACKGROUND: Open access to clinics is a management strategy to improve healthcare delivery. Providers are sometimes hesitant to adopt open access because of fear of increased visits for potentially trivial complaints. We hypothesized open access clinics would result in decreased wait times, increased number of podiatry visits, fewer no shows, higher rates of acute care visits, and lower minor amputation rates over control clinics without open access. METHODS: This study was a national retrospective case-control study of VHA (Veterans Hospital Administration) podiatry clinics in 2008. Eight case facilities reported to have open podiatry clinic access for at least one year were identified from an email survey. Sixteen control facilities with similar structural features (e.g., full time podiatrists, health tech, residency program, reconstructive foot surgery, vascular, and orthopedic surgery) were identified in the same geographic region as the case facilities. RESULTS: Twenty-two percent of facilities responded to the survey. Fifty-four percent reported open access and 46% did not. There were no differences in facility or podiatry panel size, podiatry visits, or visit frequency between the cases and controls. Podiatry visits trended higher for control facilities but didn't reach statistical significance. Case facilities had more new consults seen within 30 days (96%, 89%; P = 0.050) and lower minor amputation rates (0.62/1,000, 1.0/1,000; P = 0.041). CONCLUSIONS: The VHA is the worlds largest managed care organization and it relies on clinical efficiencies as one mechanism to improve the quality of care. Open access clinics had more timely access for new patients and lower rates of minor amputations. PMID- 21811540 TI - In vitro activity of carbapenems alone and in combination with amikacin against KPC-producing Klebsiella pneumoniae. AB - BACKGROUND: Although carbapenems are the primary treatment strategy for invasive infections caused by ESBL bacteria, case reports of these pathogens with reduced carbapenem susceptibility have emerged. One potential treatment modality is to optimize the use of anti-infectives with combination therapy. We evaluated the activity of carbapenems alone and in combination with amikacin against these clinical isolates. METHODS: Time-kill studies evaluated ertapenem (ETP), imipenem (IPM), meropenem (MEM), and amikacin (AMK) against 4 non-duplicate clinical isolates of Klebsiella pneumoniae that were resistant to these antibiotics. Synergy was defined as >= 2 log(10) decrease CFU/mL at 24 h for the combination when compared with the most active single agent of the combination, plus the number of surviving organisms for the antimicrobial combination was >= 2 log(10) less than the initial inoculum. RESULTS: All isolates carried bla(KPC-3) and genes encoding TEM-1 and SHV-11/-36; and were resistant to carbapenems (MIC at >= 8 g/mL for ETP, MEM and IPM) and AMK (MIC 32 g/mL) using broth microdilution. As monotherapy, none of the carbapenems nor AMK achieved and maintained bactericidal activity defined as >= 99.9% or > 3 log(10) killing. From time-kill studies, synergy was demonstrated for MEM and IPM in combination with AMK over the entire 24 h against all isolates. In addition, MEM and IPM with AMK achieved and maintained bactericidal activity (>= 99.9% killing) at 24 h against 2 and 1 isolate(s), respectively. Bactericidal activity and synergy were not observed for ETP combinations. CONCLUSIONS: The combination of MEM or IPM with AMK displayed synergistic activity against KPC-3-producing K. pneumoniae isolates. KEYWORDS: ESBL; Klebsiella pneumoniae; KPC; Carbapenemase; Time-kill; Meropenem; Amikacin; Imipenem; Ertapenem; Carbapenem; Synergy. PMID- 21811541 TI - Spontaneous pneumothorax: a 5-year experience. AB - BACKGROUND: Spontaneous pneumothorax (SP) is defined by the presence of air in the pleural space without history of trauma. It is classified as secondary if coexisting with underlying pulmonary disease. Its an entity with considerable incidence and treatment particularities which give reason for a reflection on the subject. We present a 5-year casuistry, characterizing the SP epidemiology, clinical presentation, investigation and therapeutic choices. METHODS: Sixty-six patients were included in the study, corresponding to 93 episodes of SP. RESULTS: We have found male predominance and the mean age was 34.5 years old. In 60.6% of cases there was history of tobacco use; 36.4% of cases were classified as secondary; 30.1% of patients with secondary SP and 21.7% with primary SP recurred; 89.2% had an acute presentation. The most frequent initial symptom was chest pain (90.3%) and 81.7% had diminished breath sounds. In 17.3% it was documented a physical strain associated. We did not identify statistically significant association between the SP occurrence and the variation of the atmospheric pressure, on the first day of symptoms. In 12.9% of episodes the initial treatment option was observation. In most of the episodes the lung totally expanded. However, in 29.1% of the episodes surgical treatment was needed. CONCLUSIONS: Our results are similar to the literature. Some clinical records are incomplete, demanding the implementation of rules to improve knowledge about this matter. KEYWORDS: Spontaneous pneumothorax; Primary spontaneous pneumothorax; Secondary spontaneous pneumothorax; Epidemiology. PMID- 21811542 TI - Association between tooth loss and bone mineral density in Brazilian postmenopausal women. AB - BACKGROUND: To evaluate oral health in postmenopausal women and verify whether there is a correlation between tooth loss according to index of decayed, missing, filled teeth (DMFT) and bone mineral density (BMD). METHODS: A cross-sectional study was conducted with 100 women. The DMFT and its associations with lumbar and femoral BMD (T-score and g/cm) were assessed. Analysis of covariance and multiple logistic regression were applied and the mean and standard deviation, absolute and relative frequencies (percentages) were obtained. RESULTS: The analysis of covariance (ANCOVA) revealed significant association between the DMFT index and bone mass (T-score), compared to the young adult in L2-L4 (P = 0.0252) and in bone mass in L2-L4 (below average) in g/cm(2) and in the DMFT index (P = 0.0332), and for women with bone mass below the average index DMFT was higher. Between L2 L4 below average (g/cm(2)) and extracted component (P = 0.0483) association was also significant because women with bone mass below the average had a greater extracted component. CONCLUSIONS: Postmenopausal women with poor oral health may present reduced bone mass. There was significant association between BMD and DMFT at the L2-L4 site. Women must be advised that their good oral health, amount and quality of bone mass should also be matters of concern. PMID- 21811543 TI - Clinical comparison of conventional testicular sperm extraction and microdissection techniques for non-obstructive azoospermia. AB - BACKGROUND: We compared the efficacy of microdissection testicular sperm extraction (microdissection TESE) and conventional TESE in patients with non obstructive azoospermia (NOA) and related the positive sperm recovery to certain variables: follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels, testicular volume and histology. METHODS: Sperm retrieval rates (SRR) in patients with NOA who underwent microdissection TESE (n = 65) or conventional TESE (n = 68) were compared and related to the different variables. RESULTS: SRR by microdissection TESE (56.9%) was significantly higher than conventional TESE (38.2%). There was a positive relation between the SRR and increased testicular volume or decreased FSH levels. No effect of Testosterone or Prolactin levels on SRR by using either technique was observed. Sperm were recovered from those with hypospermatogenesis in 84% and 92.9% by conventional and microdissection TESE, respectively (P = 0.3). In cases of maturation arrest the SRR was 27.3% and 36.4%, respectively (P = 0.6). In cases of Sertoli-cell-only syndrome (SCOS) the SRR was 6.2% and 26.9%, respectively (P = 0.03). No major operative complications occurred in any patient in either group, and no patient required post-operative hormone replacement to treat hypogonadism. CONCLUSIONS: Microdissection TESE significantly had twice better probability of success of SRR when compared to conventional TESE. No secure pre-operative prognostic elements of sperm recovery exist for NOA patients. Microdissection TESE appears to be recommendable in cases of atrophied testicles, high FSH concentration, or when SCOS with high FSH concentration can be predicted. PMID- 21811544 TI - Quality of life in patients undergoing hemodialysis or peritoneal dialysis treatment. AB - BACKGROUND: Does the type of dialysis treatment make a difference to the quality of life (QoL) and mental health of renal patients in Athens? The study investigated the differences in 84 in-center hemodialysis (HD) and 60 continuous ambulatory peritoneal dialysis (CAPD/PD) patients. METHODS: Patient-reported assessments included: WHOQOL-BREF inventory of World Health Organization, General Health Questionnaire (GHQ-28) of Goldberg, State-Trait Anxiety Innuentory, Center for Epidemiologic Studies Depression Scale (CES-D) and Multidimensional Health Locus of Control (MHLC). RESULTS: Results indicated that HD patients reported lower QoL in the environment and social relationships domains. More symptoms were also reported in the GHQ-28 subscales of anxiety/insomnia and severe depression. This measurement includes sleep problems and suicidal thoughts. CONCLUSIONS: The findings confirm the differences between the two treatment modalities, indicating that HD patients have poorer QoL in several aspects of their environment and their social relationships. Both groups reported elevated depression. However, HD patients reported more suicidal thoughts and sleep problems compared to PD patients. PMID- 21811545 TI - Epidemiological aspects of exotic malaria and dengue fever in travelers in Korea. AB - In order to compare the epidemiological aspects of exotic malaria (EM) and dengue fever (DF) imported by travelers in Korea, we have analyzed the current state both of the disease incidence and related risk factors. A total of 345 cases of EM occurred between 2001 and 2008 in Korea, and the average incidence rate per 100,000 population was 0.091. A total of 252 of DF cases occurred during the same period, and its rate was 0.063. While most of the EM and DF prevalence occurred in summer, prevalence in spring and winter was more prominent for EM (P < 0.05 ~ P < 0.01), while outbreaks in summer were more frequent for DF (P < 0.01). In Korea, more males were infected with EM and DF than females (P < 0.01). The remarkable difference between gender distributions in Korea is believed to reflect cultural differences in terms of work and travel. In both diseases, the manhood age bracket (20 - 39 years old) is possible due to increased oversea activities and travel. Moreover, reported EM cases in several prefectures in the regions of Asia and Africa were widely spread by the appropriate vector of mosquitoes, while the vectors of DF in the region of Asia are limited. PMID- 21811546 TI - Myocardial infarction thought to be provoked by local epinephrine injection during endoscopic submucosal dissection. AB - Due to its hemostatic effect, local epinephrine has been used to minimize mucosal bleeding during endoscopic submucosal dissection (ESD), but its clinical benefit remains unclear. On the other hand, several adverse events deemed to be caused by epinephrine have been observed during ESD. A 73-year-old woman developed myocardial infarction after ESD for a large rectal adenoma, and an 80-year-old woman developed abrupt chest tightness during ESD. In both patients, changes on electrocardiogram and elevated cardiac markers provided evidence of myocardial ischemia. The patients were transferred to the cardiac care unit and recovered completely. Up to our knowledge this is the first report of myocardial infarction thought to be provoked by submucosal epinephrine injection during ESD. PMID- 21811550 TI - Effects of engineered nanoparticles on the assembly of exopolymeric substances from phytoplankton. AB - The unique properties of engineered nanoparticles (ENs) that make their industrial applications so attractive simultaneously raise questions regarding their environmental safety. ENs exhibit behaviors different from bulk materials with identical chemical compositions. Though the nanotoxicity of ENs has been studied intensively, their unintended environmental impacts remain largely unknown. Herein we report experimental results of EN interactions with exopolymeric substances (EPS) from three marine phytoplankton species: Amphora sp., Ankistrodesmus angustus and Phaeodactylum tricornutum. EPS are polysaccharide-rich anionic colloid polymers released by various microorganisms that can assemble into microgels, possibly by means of hydrophobic and ionic mechanisms. Polystyrene nanoparticles (23 nm) were used in our study as model ENs. The effects of ENs on EPS assembly were monitored with dynamic laser scattering (DLS). We found that ENs can induce significant acceleration in Amphora sp. EPS assembly; after 72 hours EN-EPS aggregation reached equilibrium, forming microscopic gels of ~4-6 um in size. In contrast, ENs only cause moderate assembly kinetic acceleration for A. angustus and P. tricornutum EPS samples. Our results indicate that the effects of ENs on EPS assembly kinetics mainly depend on the hydrophobic interactions of ENs with EPS polymers. The cycling mechanism of EPS is complex. Nonetheless, the change of EPS assembly kinetics induced by ENs can be considered as one potential disturbance to the marine carbon cycle. PMID- 21811551 TI - Perfluorocarbon particle size influences magnetic resonance signal and immunological properties of dendritic cells. AB - The development of cellular tracking by fluorine ((19)F) magnetic resonance imaging (MRI) has introduced a number of advantages for following immune cell therapies in vivo. These include improved signal selectivity and a possibility to correlate cells labeled with fluorine-rich particles with conventional anatomic proton ((1)H) imaging. While the optimization of the cellular labeling method is clearly important, the impact of labeling on cellular dynamics should be kept in mind. We show by (19)F MR spectroscopy (MRS) that the efficiency in labeling cells of the murine immune system (dendritic cells) by perfluoro-15-crown-5-ether (PFCE) particles increases with increasing particle size (560>365>245>130 nm). Dendritic cells (DC) are professional antigen presenting cells and with respect to impact of PFCE particles on DC function, we observed that markers of maturation for these cells (CD80, CD86) were also significantly elevated following labeling with larger PFCE particles (560 nm). When labeled with these larger particles that also gave an optimal signal in MRS, DC presented whole antigen more robustly to CD8+ T cells than control cells. Our data suggest that increasing particle size is one important feature for optimizing cell labeling by PFCE particles, but may also present possible pitfalls such as alteration of the immunological status of these cells. Therefore depending on the clinical scenario in which the (19)F-labeled cellular vaccines will be applied (cancer, autoimmune disease, transplantation), it will be interesting to monitor the fate of these cells in vivo in the relevant preclinical mouse models. PMID- 21811552 TI - Experimental gastric carcinogenesis in Cebus apella nonhuman primates. AB - The evolution of gastric carcinogenesis remains largely unknown. We established two gastric carcinogenesis models in New-World nonhuman primates. In the first model, ACP03 gastric cancer cell line was inoculated in 18 animals. In the second model, we treated 6 animals with N-methyl-nitrosourea (MNU). Animals with gastric cancer were also treated with Canova immunomodulator. Clinical, hematologic, and biochemical, including C-reactive protein, folic acid, and homocysteine, analyses were performed in this study. MYC expression and copy number was also evaluated. We observed that all animals inoculated with ACP03 developed gastric cancer on the 9(th) day though on the 14(th) day presented total tumor remission. In the second model, all animals developed pre-neoplastic lesions and five died of drug intoxication before the development of cancer. The last surviving MNU-treated animal developed intestinal-type gastric adenocarcinoma observed by endoscopy on the 940(th) day. The level of C-reactive protein level and homocysteine concentration increased while the level of folic acid decreased with the presence of tumors in ACP03-inoculated animals and MNU treatment. ACP03 inoculation also led to anemia and leukocytosis. The hematologic and biochemical results corroborate those observed in patients with gastric cancer, supporting that our in vivo models are potentially useful to study this neoplasia. In cell line inoculated animals, we detected MYC immunoreactivity, mRNA overexpression, and amplification, as previously observed in vitro. In MNU-treated animals, mRNA expression and MYC copy number increased during the sequential steps of intestinal-type gastric carcinogenesis and immunoreactivity was only observed in intestinal metaplasia and gastric cancer. Thus, MYC deregulation supports the gastric carcinogenesis process. Canova immunomodulator restored several hematologic measurements and therefore, can be applied during/after chemotherapy to increase the tolerability and duration of anticancer treatments. PMID- 21811553 TI - Impact of health facility-based insecticide treated bednet distribution in Malawi: progress and challenges towards achieving universal coverage. AB - BACKGROUND: High levels of insecticide treated bednet (ITN) use reduce malaria burden in countries with intense transmission such as Malawi. Since 2007 Malawi has implemented free health facility-based ITN distribution for pregnant women and children <5 years old (under-5s). We evaluated the progress of this targeted approach toward achieving universal ITN coverage. METHODS: We conducted a cross sectional household survey in eight districts in April 2009. We assessed household ITN possession, ITN use by all household members, and P. falciparum asexual parasitemia and anemia (hemoglobin <11 grams/deciliter) in under-5s. RESULTS: We surveyed 7,407 households containing 29,806 persons. Fifty-nine percent of all households (95% confidence interval [95% CI]: 56-62), 67% (95% CI: 64-70) of eligible households (i.e., households with pregnant women or under-5s), and 40% (95% CI: 36-45) of ineligible households owned an ITN. In households with at least one ITN, 76% (95% CI: 74-78) of all household members, 88% (95% CI: 87 90) of under-5s and 90% (95% CI: 85-94) of pregnant women used an ITN the previous night. Of 6,677 ITNs, 92% (95% CI: 90-94) were used the previous night with a mean of 2.4 persons sleeping under each ITN. In multivariable models adjusting for district, socioeconomic status and indoor residual spraying use, ITN use by under-5s was associated with a significant reduction in asexual parasitemia (adjusted odds ratio (aOR) 0.79; 95% CI: 0.64-0.98; p-value 0.03) and anemia (aOR 0.79; 95% CI 0.62-0.99; p-value 0.04). Of potential targeted and non targeted mass distribution strategies, a campaign distributing 1 ITN per household might increase coverage to 2.1 household members per ITN, and thus achieve near universal coverage often defined as 2 household members per ITN. CONCLUSIONS: Malawi has substantially increased ITN coverage using health facility-based distribution targeting pregnant women and under-5s, but needs to supplement these activities with non-targeted mass distribution campaigns to achieve universal coverage and maximum public health impact. PMID- 21811554 TI - Effectiveness of protease inhibitor monotherapy versus combination antiretroviral maintenance therapy: a meta-analysis. AB - BACKGROUND: The unparalleled success of combination antiretroviral therapy (cART) is based on the combination of three drugs from two classes. There is insufficient evidence whether simplification to ritonavir boosted protease inhibitor (PI/r) monotherapy in virologically suppressed HIV-infected patients is effective and safe to reduce cART side effects and costs. METHODS: We systematically searched Medline, Embase, the Cochrane Library, conference proceedings and trial registries to identify all randomised controlled trials comparing PI/r monotherapy to cART in suppressed patients. We calculated in an intention to treat (loss-of follow-up, discontinuation of assigned drugs equals failure) and per-protocol analysis (exclusion of protocol violators following randomisation) and based on three different definitions for virological failure pooled risk ratios for remaining virologically suppressed. FINDINGS: We identified 10 trials comparing 3 different PIs with cART based on a PI/r plus 2 reverse transcriptase inhibitors in 1189 patients. With the most conservative approach (viral load <50 copies/ml on two consecutive measurements), the risk ratios for viral suppression at 48 weeks of PI/r monotherapy compared to cART were in the ITT analysis 0.94 8 (95% CI 0.89 to 1.00) p = 0.06; risk difference 0.06 (95%CI -0.11 to 0) p = 0.05, p for heterogeneity = 0.08, I(2) = 43.1%) and in the PP analysis 0.93 ((95%CI 0.90 to 0.97) p<0.001; risk difference -0.07 (95%CI -0.10 to -0.03) p<0.001, p for heterogeneity = 0.44, I(2) = 0%). Reintroduction of cART in 44 patients with virological failure led in 93% to de novo viral suppression. INTERPRETATION: Virologically well suppressed HIV infected patients have a lower chance to maintain viral suppression when switching from cART to PI/r monotherapy. Failing patients achieve high rates of de-novo viral suppression following reintroduction of reverse transcriptase inhibitors. PMID- 21811555 TI - Monoterpene variation mediated attack preference evolution of the bark beetle Dendroctonus valens. AB - Several studies suggest that some bark beetle like to attack large trees. The invasive red turpentine beetle (RTB), Dendroctonus valens LeConte, one of the most destructive forest pests in China, is known to exhibit this behavior. Our previous study demonstrated that RTBs preferred to attack large-diameter trees (diameter at breast height, DBH >=30 cm) over small-diameter trees (DBH <=10 cm) in the field. In the current study, we studied the attacking behavior and the underlying mechanisms in the laboratory. Behavioral assays showed that RTBs preferred the bark of large-DBH trees and had a higher attack rate on the bolts of these trees. Y-tube assays showed that RTBs preferred the volatiles released by large-DBH trees to those released by small-DBH trees. Subsequent analysis revealed that both large- and small-DBH trees had the same composition of monoterpenes, but the concentration of each component differed; thus it appeared that the concentrations acted as cues for RTBs to locate the right-sized host which was confirmed by further behavioral assays. Moreover, large-DBH pine trees provided more spacious habitat and contained more nutrients, such as nitrogen, than did small-DBH pine trees, which benefited RTBs' fecundity and larval development. RTBs seem to have evolved mechanisms to locate those large hosts that will allow them to maximize their fitness. Monoterpene variation mediated attack preference implies the potential for the management of RTB. PMID- 21811557 TI - Local enhancement promotes cockroach feeding aggregations. AB - Communication and learning from each other are part of the success of animal societies. Social insects invest considerable effort into signalling to their nestmates the locations of the most profitable resources in their environment. Growing evidence also indicates that insects glean such information through cues inadvertently provided by their conspecifics. Here, we investigate social information use in the foraging decisions by gregarious cockroaches (Blattella germanica L.). Individual cockroaches given a simultaneous choice in a Y olfactometer between the odour of feeding conspecifics and the mixed odour of food plus non-feeding conspecifics showed a preference for the arm scented with the odour of feeding conspecifics. Social information (the presence of feeding conspecifics) was produced by cockroaches of all age classes and perceived at short distance in the olfactometer arms, suggesting the use of inadvertently provided cues rather than signals. We discuss the nature of these cues and the role of local enhancement (the selection of a location based on cues associated with the presence of conspecifics) in the formation of feeding aggregations in B. germanica. Similar cue-mediated recruitments could underpin a wide range of collective behaviours in group-living insects. PMID- 21811556 TI - Eosinophils increase neuron branching in human and murine skin and in vitro. AB - Cutaneous nerves are increased in atopic dermatitis, and itch is a prominent symptom. We studied the functional interactions between eosinophils and nerves in human and mouse skin and in culture. We demonstrated that human atopic dermatitis skin has eosinophil granule proteins present in the same region as increased nerves. Transgenic mice in which interleukin-5 (IL-5) expression is driven by a keratin-14 (K14) promoter had many eosinophils in the epidermis, and the number of nerves was also significantly increased in the epidermis. In co-cultures, eosinophils dramatically increased branching of sensory neurons isolated from the dorsal root ganglia (DRG) of mice. This effect did not occur in DRG neurons co cultured with mast cells or with dead eosinophils. Physical contact of the eosinophils with the neurons was not required, and the effect was not blocked by an antibody to nerve growth factor. DRG neurons express eotaxin-1, ICAM-1 and VCAM-1, which may be important in the recruitment, binding, and activation of eosinophils in the region of cutaneous nerves. These data indicate a pathophysiological role for eosinophils in cutaneous nerve growth in atopic dermatitis, and suggest they may present a therapeutic target in atopic dermatitis and other eosinophilic skin conditions with neuronal symptoms such as itch. PMID- 21811558 TI - Differential cathelicidin expression in duodenal and gastric biopsies from Tanzanian and German patients. AB - BACKGROUND: Epithelial surfaces such as the gastrointestinal mucosa depend on expression of antimicrobial peptides like cathelicidin for immune defence against pathogens. The mechanisms behind mucosal cathelicidin regulation are incompletely understood. METHODS: Cathelicidin expression was analysed in duodenal, antral and corpus/fundic mucosal biopsies from African and German patients. Additionally, cathelicidin expression was correlated with Helicobacter pylori (HP) infection and the inflammatory status of the mucosa. RESULTS: High cathelicidin transcript abundance was detected in duodenal biopsies from African subjects. On the contrary, cathelicidin mRNA expression was either undetectable or very low in tissue specimens from German patients. Also, in the antrum and corpus/fundus regions of the stomach significantly higher cathelicidin transcript levels were measured in Tanzanian compared to German patients. In gastric biopsies from African patients cathelicidin expression was increased in HP positive compared to HP negative subjects. Additionally, the inflammatory status measured by IL-8 expression correlated well with the HP infection status. CONCLUSIONS: A higher duodenal and gastric cathelicidin expression in African (compared with European) individuals may be due to upregulation by antigenic stimulation and may confer a higher resistance against enteric infections. PMID- 21811559 TI - Why birds with deferred sexual maturity are sedentary on islands: a systematic review. AB - BACKGROUND: Island faunas have played central roles in the development of evolutionary biology and ecology. Birds are among the most studied organisms on islands, in part because of their dispersal powers linked to migration. Even so, we lack of information about differences in the movement ecology of island versus mainland populations of birds. METHODOLOGY/PRINCIPAL FINDINGS: Here we present a new general pattern indicating that large birds with deferred sexual maturity are sedentary on islands, and that they become so even when they are migratory on the mainland. Density-dependent variation in the age at first breeding affects the survivorship of insular populations and this, in turn, affects the movement ecology of large birds. Because density-dependent variation in the age of first breeding is critical to the long-term survival of small isolated populations of long-lived species, migratory forms can successfully colonize islands only if they become sedentary once there. Analyses of the movement ecology of continental and insular populations of 314 species of raptors, 113 species of Ciconiiformes and 136 species of passerines, along with individual-based population simulations confirm this prediction. CONCLUSIONS: This finding has several consequences for speciation, colonization and survival of small isolated population of species with deferred sexual maturity. PMID- 21811560 TI - Principal component analysis of dynamic relative displacement fields estimated from MR images. AB - Non-destructive measurement of acceleration-induced displacement fields within a closed object is a fundamental challenge. Inferences of how the brain deforms following skull impact have thus relied largely on indirect estimates and course resolution cadaver studies. We developed a magnetic resonance technique to quantitatively identify the modes of displacement of an accelerating soft object relative to an object enclosing it, and applied it to study acceleration-induced brain deformation in human volunteers. We show that, contrary to the prevailing hypotheses of the field, the dominant mode of interaction between the brain and skull in mild head acceleration is one of sliding arrested by meninges. PMID- 21811561 TI - Cell arrest and cell death in mammalian preimplantation development: lessons from the bovine model. AB - BACKGROUND: The causes, modes, biological role and prospective significance of cell death in preimplantation development in humans and other mammals are still poorly understood. Early bovine embryos represent a very attractive experimental model for the investigation of this fundamental and important issue. METHODS AND FINDINGS: To obtain reference data on the temporal and spatial occurrence of cell death in early bovine embryogenesis, three-dimensionally preserved embryos of different ages and stages of development up to hatched blastocysts were examined in toto by confocal laser scanning microscopy. In parallel, transcript abundance profiles for selected apoptosis-related genes were analyzed by real-time reverse transcriptase-polymerase chain reaction. Our study documents that in vitro as well as in vivo, the first four cleavage cycles are prone to a high failure rate including different types of permanent cell cycle arrest and subsequent non apoptotic blastomere death. In vitro produced and in vivo derived blastocysts showed a significant incidence of cell death in the inner cell mass (ICM), but only in part with morphological features of apoptosis. Importantly, transcripts for CASP3, CASP9, CASP8 and FAS/FASLG were not detectable or found at very low abundances. CONCLUSIONS: In vitro and in vivo, errors and failures of the first and the next three cleavage divisions frequently cause immediate embryo death or lead to aberrant subsequent development, and are the main source of developmental heterogeneity. A substantial occurrence of cell death in the ICM even in fast developing blastocysts strongly suggests a regular developmentally controlled elimination of cells, while the nature and mechanisms of ICM cell death are unclear. Morphological findings as well as transcript levels measured for important apoptosis-related genes are in conflict with the view that classical caspase-mediated apoptosis is the major cause of cell death in early bovine development. PMID- 21811562 TI - GATA6 activates Wnt signaling in pancreatic cancer by negatively regulating the Wnt antagonist Dickkopf-1. AB - Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease characterized by late diagnosis and treatment resistance. Recurrent genetic alterations in defined genes in association with perturbations of developmental cell signaling pathways have been associated with PDAC development and progression. Here, we show that GATA6 contributes to pancreatic carcinogenesis during the temporal progression of pancreatic intraepithelial neoplasia by virtue of Wnt pathway activation. GATA6 is recurrently amplified by both quantitative-PCR and fluorescent in-situ hybridization in human pancreatic intraepithelial neoplasia and in PDAC tissues, and GATA6 copy number is significantly correlated with overall patient survival. Forced overexpression of GATA6 in cancer cell lines enhanced cell proliferation and colony formation in soft agar in vitro and growth in vivo, as well as increased Wnt signaling. By contrast siRNA mediated knockdown of GATA6 led to corresponding decreases in these same parameters. The effects of GATA6 were found to be due to its ability to bind DNA, as forced overexpression of a DNA-binding mutant of GATA6 had no effects on cell growth in vitro or in vivo, nor did they affect Wnt signaling levels in these same cells. A microarray analysis revealed the Wnt antagonist Dickopf-1 (DKK1) as a dysregulated gene in association with GATA6 knockdown, and direct binding of GATA6 to the DKK1 promoter was confirmed by chromatin immunoprecipitation and electrophoretic mobility shift assays. Transient transfection of GATA6, but not mutant GATA6, into cancer cell lines led to decreased DKK1 mRNA expression and secretion of DKK1 protein into culture media. Forced overexpression of DKK1 antagonized the effects of GATA6 on Wnt signaling in pancreatic cancer cells. These findings illustrate that one mechanism by which GATA6 promotes pancreatic carcinogenesis is by virtue of its activation of canonical Wnt signaling via regulation of DKK1. PMID- 21811563 TI - The LSD1-type zinc finger motifs of Pisum sativa LSD1 are a novel nuclear localization signal and interact with importin alpha. AB - BACKGROUND: Genetic studies of the Arabidopsis mutant lsd1 highlight the important role of LSD1 in the negative regulation of plant programmed cell death (PCD). Arabidopsis thaliana LSD1 (AtLSD1) contains three LSD1-type zinc finger motifs, which are involved in the protein-protein interaction. METHODOLOGY/PRINCIPAL FINDINGS: To further understand the function of LSD1, we have analyzed cellular localization and functional localization domains of Pisum sativa LSD1 (PsLSD1), which is a homolog of AtLSD1. Subcellular localization analysis of green fluorescent protein (GFP)-tagged PsLSD1 indicates that PsLSD1 is localized in the nucleus. Using a series of GFP-tagged PsLSD1 deletion mutants, we found that the three LSD1-type zinc finger motifs of PsLSD1 alone can target GFP to the nucleus, whereas deletion of the three zinc finger motifs or any individual zinc finger motif causes PsLSD1 to lose its nuclear localization, indicating that the three zinc finger motifs are necessary and sufficient for its nuclear localization. Moreover, site-directed mutagenesis analysis of GFP-tagged PsLSD1 indicates that tertiary structure and basic amino acids of each zinc finger motif are necessary for PsLSD1 nuclear localization. In addition, yeast two-hybrid, pull-down, and BiFC assays demonstrate that the three zinc finger motifs of PsLSD1 directly bind to importin alpha in vitro and in vivo. CONCLUSIONS/SIGNIFICANCE: Our data demonstrate that the LSD1-type zinc finger motifs of PsLSD1 are a novel nuclear localization signal and directly bind to importin alpha, and suggest that the nuclear import of LSD1 may rely on the interaction between its zinc finger motifs and importin alpha. Moreover, the nuclear localization of PsLSD1 suggests that LSD1 may function as a transcription regulator involved in negatively regulating PCD. PMID- 21811564 TI - Trichostatin A selectively suppresses the cold-induced transcription of the ZmDREB1 gene in maize. AB - Post-translational modifications of histone proteins play a crucial role in responding to environmental stresses. Histone deacetylases (HDACs) catalyze the removal of an acetyl group from histones and are generally believed to be a transcriptional repressor. In this paper, we report that cold treatment highly induces the up-regulation of HDACs, leading to global deacetylation of histones H3 and H4. Treatment of maize with the HDAC inhibitor trichostatin A (TSA) under cold stress conditions strongly inhibits induction of the maize cold-responsive genes ZmDREB1 and ZmCOR413. However, up-regulation of the ZmICE1 gene in response to cold stress is less affected. The expression of drought and salt induced genes, ZmDBF1 and rab17, is almost unaffected by TSA treatment. Thus, these observations show that HDACs may selectively activate transcription. The time course of TSA effects on the expression of ZmDREB1 and ZmCOR413 genes indicates that HDACs appear to directly activate the ZmDREB1 gene, which in turn modulates ZmCOR413 expression. After cold treatment, histone hyperacetylation and DNA demethylation occurs in the ICE1 binding region, accompanied by an increase in accessibility to micrococcal nuclease (MNase). The two regions adjacent to the ICE1 binding site remain hypoacetylated and methylated. However, during cold acclimation, TSA treatment increases the acetylation status and accessibility of MNase and decreases DNA methylation at these two regions. However, TSA treatment does not affect histone hyperacetylation and DNA methylation levels at the ICE1 binding regions of the ZmDREB1 gene. Altogether, our findings indicate that HDACs positively regulate the expression of the cold-induced ZmDREB1 gene through histone modification and chromatin conformational changes and that this activation is both gene and site selective. PMID- 21811565 TI - Characterization of the channel constriction allowing the access of the substrate to the active site of yeast oxidosqualene cyclase. AB - In oxidosqualene cyclases (OSCs), an enzyme which has been extensively studied as a target for hypocholesterolemic or antifungal drugs, a lipophilic channel connects the surface of the protein with the active site cavity. Active site and channel are separated by a narrow constriction operating as a mobile gate for the substrate passage. In Saccharomyces cerevisiae OSC, two aminoacidic residues of the channel/constriction apparatus, Ala525 and Glu526, were previously showed as critical for maintaining the enzyme functionality. In this work sixteen novel mutants, each bearing a substitution at or around the channel constrictions, were tested for their enzymatic activity. Modelling studies showed that the most functionality-lowering substitutions deeply alter the H-bond network involving the channel/constriction apparatus. A rotation of Tyr239 is proposed as part of the mechanism permitting the access of the substrate to the active site. The inhibition of OSC by squalene was used as a tool for understanding whether the residues under study are involved in a pre-catalytic selection and docking of the substrate oxidosqualene. PMID- 21811566 TI - Establishment of a knock-in mouse model with the SLC26A4 c.919-2A>G mutation and characterization of its pathology. AB - Recessive mutations in the SLC26A4 gene are a common cause of hereditary hearing impairment worldwide. Previous studies have demonstrated that different SLC26A4 mutations may have different pathogenetic mechanisms. In the present study, we established a knock-in mouse model (i.e., Slc26a4(tm1Dontuh/tm1Dontuh) mice) homozygous for the c.919-2A>G mutation, which is a common mutation in East Asians. Mice were then subjected to audiologic assessment, a battery of vestibular evaluations, and inner ear morphological studies. All Slc26a4(tm1Dontuh/tm1Dontuh) mice revealed profound hearing loss, whereas 46% mice demonstrated pronounced head tilting and circling behaviors. There was a significant difference in the vestibular performance between wild-type and Slc26a4(tm1Dontuh/tm1Dontuh) mice, especially those exhibiting circling behavior. Inner ear morphological examination of Slc26a4(tm1Dontuh/tm1Dontuh) mice revealed an enlarged endolymphatic duct, vestibular aqueduct and sac, atrophy of stria vascularis, deformity of otoconia in the vestibular organs, consistent degeneration of cochlear hair cells, and variable degeneration of vestibular hair cells. Audiologic and inner ear morphological features of Slc26a4(tm1Dontuh/tm1Dontuh) mice were reminiscent of those observed in humans. These features were also similar to those previously reported in both knock-out Slc26a4(-/-) mice and Slc26a4(loop/loop) mice with the Slc26a4 p.S408F mutation, albeit the severity of vestibular hair cell degeneration appeared different among the three mouse strains. PMID- 21811567 TI - Prognostic factors for esophageal squamous cell carcinoma--a population-based study in Golestan Province, Iran, a high incidence area. AB - Golestan Province in northern Iran is an area with a high incidence of esophageal squamous cell carcinoma (ESCC). We aimed to investigate prognostic factors for ESCC and survival of cases in Golestan, on which little data were available. We followed-up 426 ESCC cases participating in a population-based case-control study. Data were analyzed using the Kaplan-Meier method and the Cox proportional hazard models. Median survival was 7 months. Age at diagnosis was inversely associated with survival, but the association was disappeared with adjustment for treatment. Residing in urban areas (hazard ratio, HR = 0.70; 95% CI 0.54-0.90) and being of non-Turkmen ethnic groups (HR = 0.76; 95% CI 0.61-0.96) were associated with better prognosis. In contrast to other types of tobacco use, nass (a smokeless tobacco product) chewing was associated with a slightly poorer prognosis even in models adjusted for other factors including stage of disease and treatment (HR = 1.38; 95% CI 0.99-1.92). Opium use was associated with poorer prognosis in crude analyses but not in adjusted models. Almost all of potentially curative treatments were associated with longer survival. Prognosis of ESCC in Golestan is very poor. Easier access to treatment facilities may improve the prognosis of ESCC in Golestan. The observed association between nass chewing and poorer prognosis needs further investigations; this association may suggest a possible role for ingestion of nass constituents in prognosis of ESCC. PMID- 21811568 TI - Functional disconnection and compensation in mild cognitive impairment: evidence from DLPFC connectivity using resting-state fMRI. AB - The known regional abnormality of the dorsolateral prefrontal cortex (DLPFC) and its role in various neural circuits in mild cognitive impairment (MCI) has given prominence to its importance in studies on the disconnection associated with MCI. The purpose of the current study was to examine the DLPFC functional connectivity patterns during rest in MCI patients and the impact of regional grey matter (GM) atrophy on the functional results. Structural and functional MRI data were collected from 14 MCI patients and 14 age, gender-matched healthy controls. We found that both the bilateral DLPFC showed reduced functional connectivity with the inferior parietal lobule (IPL), superior/medial frontal gyrus and sub cortical regions (e.g., thalamus, putamen) in MCI patients when compared with healthy controls. Moreover, the DLPFC connectivity with the IPL and thalamus significantly correlated with the cognitive performance of patients as measured by mini-mental state examination (MMSE), clock drawing test (CDT), and California verbal learning test (CVLT) scores. When taking GM atrophy as covariates, these results were approximately consistent with those without correction, although there may be a decrease in the statistical power. These results suggest that the DLPFC disconnections may be the substrates of cognitive impairments in MCI patients. In addition, we also found enhanced functional connectivity between the left DLPFC and the right prefrontal cortex in MCI patients. This is consistent with previous findings of MCI-related increased activation during cognitive tasks, and may represent a compensatory mechanism in MCI patients. Together, the present study demonstrated the coexistence of functional disconnection and compensation in MCI patients using DLPFC functional connectivity analysis, and thus might provide insights into biological mechanism of the disease. PMID- 21811569 TI - Differential gene expression by RamA in ciprofloxacin-resistant Salmonella Typhimurium. AB - Overexpression of ramA has been implicated in resistance to multiple drugs in several enterobacterial pathogens. In the present study, Salmonella Typhimurium strain LTL with constitutive expression of ramA was compared to its ramA-deletion mutant by employing both DNA microarrays and phenotype microarrays (PM). The mutant strain with the disruption of ramA showed differential expression of at least 33 genes involved in 11 functional groups. The study confirmed at the transcriptional level that the constitutive expression of ramA was directly associated with increased expression of multidrug efflux pump AcrAB-TolC and decreased expression of porin protein OmpF, thereby conferring multiple drug resistance phenotype. Compared to the parent strain constitutively expressing ramA, the ramA mutant had increased susceptibility to over 70 antimicrobials and toxic compounds. The PM analysis also uncovered that the ramA mutant was better in utilization of 10 carbon sources and 5 phosphorus sources. This study suggested that the constitutive expression of ramA locus regulate not only multidrug efflux pump and accessory genes but also genes involved in carbon metabolic pathways. PMID- 21811570 TI - Experimentally guided computational model discovers important elements for social behavior in myxobacteria. AB - Identifying essential factors in cellular interactions and organized movement of cells is important in predicting behavioral phenotypes exhibited by many bacterial cells. We chose to study Myxococcus xanthus, a soil bacterium whose individual cell behavior changes while in groups, leading to spontaneous formation of aggregation center during the early stage of fruiting body development. In this paper, we develop a cell-based computational model that solely relies on experimentally determined parameters to investigate minimal elements required to produce the observed social behaviors in M. xanthus. The model verifies previously known essential parameters and identifies one novel parameter, the active turning, which we define as the ability and tendency of a cell to turn to a certain angle without the presence of any obvious external factors. The simulation is able to produce both gliding pattern and spontaneous aggregation center formation as observed in experiments. The model is tested against several known M. xanthus mutants and our modification of parameter values relevant for the individual mutants produces good phenotypic agreements. This outcome indicates the strong predictive potential of our model for the social behaviors of uncharacterized mutants and their expected phenotypes during development. PMID- 21811571 TI - Coexistence of trichome variation in a natural plant population: a combined study using ecological and candidate gene approaches. AB - The coexistence of distinct phenotypes within populations has long been investigated in evolutionary ecology. Recent studies have identified the genetic basis of distinct phenotypes, but it is poorly understood how the variation in candidate loci is maintained in natural environments. In this study, we examined fitness consequences and genetic basis of variation in trichome production in a natural population of Arabidopsis halleri subsp. gemmifera. Half of the individuals in the study population produced trichomes while the other half were glabrous, and the leaf beetle Phaedon brassicae imposed intensive damage to both phenotypes. The fitness of hairy and glabrous plants showed no significant differences in the field during two years. A similar result was obtained when sibling hairy and glabrous plants were transplanted at the same field site, whereas a fitness cost of trichome production was detected under a weak herbivory condition. Thus, equivalent fitness of hairy and glabrous plants under natural herbivory allows their coexistence in the contemporary population. The pattern of polymorphism of the candidate trichome gene GLABROUS1 (GL1) showed no evidence of long-term maintenance of trichome variation within the population. Although balancing selection under fluctuating biotic environments is often proposed to explain the maintenance of defense variation, the lack of clear evidence of balancing selection in the study population suggests that other factors such as gene flow and neutral process may have played relatively large roles in shaping trichome variation at least for the single population level. PMID- 21811572 TI - The impact of Contact Isolation on the quality of inpatient hospital care. AB - BACKGROUND: Contact Isolation is a common hospital infection prevention method that may improve infectious outcomes but may also hinder healthcare delivery. METHODS: To evaluate the impact of Contact Isolation on compliance with individual and composite process of care quality measures, we formed four retrospective diagnosis-based cohorts from a 662-bed tertiary-care medical center. Each cohort contained patients evaluated for one of four Centers for Medicare and Medicaid Services (CMS) Hospital Compare process measures including Acute Myocardial Infarction (AMI), Congestive Heart Failure (CHF), Pneumonia (PNA) and Surgical Care Improvement Project (SCIP) from January 1, 2007 through May 30, 2009. RESULTS: The 6716-admission cohort included 1259 with AMI, 834 with CHF, 1377 with PNA and 3246 in SCIP. Contact Isolation was associated with not meeting 4 of 23 individual hospital measures (4 of 10 measures were not met for care provided while patients are typically isolated). Contact Isolation was independently associated with lower compliance with the composite pneumonia process-of-care measure (OR 0.3, 95% CI 0.1-0.7). AMI, CHF and SCIP composite measures were not impacted by Contact Isolation. CONCLUSIONS: Contact Isolation was associated with lower adherence to some pneumonia quality of care process measures of care on inpatient wards but did not impact CHF, AMI or SCIP measures. PMID- 21811573 TI - The spatial heterogeneity between Japanese encephalitis incidence distribution and environmental variables in Nepal. AB - BACKGROUND: To identify potential environmental drivers of Japanese Encephalitis virus (JE) transmission in Nepal, we conducted an ecological study to determine the spatial association between 2005 Nepal JE incidence, and climate, agricultural, and land-cover variables at district level. METHODS: District-level data on JE cases were examined using Local Indicators of Spatial Association (LISA) analysis to identify spatial clusters from 2004 to 2008 and 2005 data was used to fit a spatial lag regression model with climate, agriculture and land cover variables. RESULTS: Prior to 2006, there was a single large cluster of JE cases located in the Far-West and Mid-West terai regions of Nepal. After 2005, the distribution of JE cases in Nepal shifted with clusters found in the central hill areas. JE incidence during the 2005 epidemic had a stronger association with May mean monthly temperature and April mean monthly total precipitation compared to mean annual temperature and precipitation. A parsimonious spatial lag regression model revealed, 1) a significant negative relationship between JE incidence and April precipitation, 2) a significant positive relationship between JE incidence and percentage of irrigated land 3) a non-significant negative relationship between JE incidence and percentage of grassland cover, and 4) a unimodal non-significant relationship between JE Incidence and pig-to-human ratio. CONCLUSION: JE cases clustered in the terai prior to 2006 where it seemed to shift to the Kathmandu region in subsequent years. The spatial pattern of JE cases during the 2005 epidemic in Nepal was significantly associated with low precipitation and the percentage of irrigated land. Despite the availability of an effective vaccine, it is still important to understand environmental drivers of JEV transmission since the enzootic cycle of JEV transmission is not likely to be totally interrupted. Understanding the spatial dynamics of JE risk factors may be useful in providing important information to the Nepal immunization program. PMID- 21811574 TI - Genome-wide association scan in HIV-1-infected individuals identifying variants influencing disease course. AB - BACKGROUND: AIDS develops typically after 7-11 years of untreated HIV-1 infection, with extremes of very rapid disease progression (<2 years) and long term non-progression (>15 years). To reveal additional host genetic factors that may impact on the clinical course of HIV-1 infection, we designed a genome-wide association study (GWAS) in 404 participants of the Amsterdam Cohort Studies on HIV-1 infection and AIDS. METHODS: The association of SNP genotypes with the clinical course of HIV-1 infection was tested in Cox regression survival analyses using AIDS-diagnosis and AIDS-related death as endpoints. RESULTS: Multiple, not previously identified SNPs, were identified to be strongly associated with disease progression after HIV-1 infection, albeit not genome-wide significant. However, three independent SNPs in the top ten associations between SNP genotypes and time between seroconversion and AIDS-diagnosis, and one from the top ten associations between SNP genotypes and time between seroconversion and AIDS related death, had P-values smaller than 0.05 in the French Genomics of Resistance to Immunodeficiency Virus cohort on disease progression. CONCLUSIONS: Our study emphasizes that the use of different phenotypes in GWAS may be useful to unravel the full spectrum of host genetic factors that may be associated with the clinical course of HIV-1 infection. PMID- 21811575 TI - Experimental meningococcal sepsis in congenic transgenic mice expressing human transferrin. AB - Severe meningococcal sepsis is still of high morbidity and mortality. Its management may be improved by an experimental model allowing better understanding of its pathophysiology. We developed an animal model of meningococcal sepsis in transgenic BALB/c mice expressing human transferrin. We studied experimental meningococcal sepsis in congenic transgenic BALB/c mice expressing human transferrin by transcriptional profiling using microarray analysis of blood and brain samples. Genes encoding acute phase proteins, chemokines and cytokines constituted the largest strongly regulated groups. Dynamic bioluminescence imaging further showed high blood bacterial loads that were further enhanced after a primary viral infection by influenza A virus. Moreover, IL-1 receptor associated kinase-3 (IRAK-3) was induced in infected mice. IRAK-3 is a negative regulator of Toll-dependant signaling and its induction may impair innate immunity and hence result in an immunocompromised state allowing bacterial survival and systemic spread during sepsis. This new approach should enable detailed analysis of the pathophysiology of meningococcal sepsis and its relationships with flu infection. PMID- 21811576 TI - Do frogs get their kicks on Route 66? Continental U.S. transect reveals spatial and temporal patterns of Batrachochytrium dendrobatidis infection. AB - The chytrid fungus Batrachochytrium dendrobatidis (Bd) has been devastating amphibians globally. Two general scenarios have been proposed for the nature and spread of this pathogen: Bd is an epidemic, spreading as a wave and wiping out individuals, populations, and species in its path; and Bd is endemic, widespread throughout many geographic regions on every continent except Antarctica. To explore these hypotheses, we conducted a transcontinental transect of United States Department of Defense (DoD) installations along U.S. Highway 66 from California to central Illinois, and continuing eastward to the Atlantic Seaboard along U.S. Interstate 64 (in sum from Marine Corps Base Camp Pendleton in California to Naval Air Station Oceana in Virginia). We addressed the following questions: 1) Does Bd occur in amphibian populations on protected DoD environments? 2) Is there a temporal pattern to the presence of Bd? 3) Is there a spatial pattern to the presence of Bd? and 4) In these limited human-traffic areas, is Bd acting as an epidemic (i.e., with evidence of recent introduction and/or die-offs due to chytridiomycosis), or as an endemic (present without clinical signs of disease)? Bd was detected on 13 of the 15 bases sampled. Samples from 30 amphibian species were collected (10% of known United States' species); half (15) tested Bd positive. There was a strong temporal (seasonal) component; in total, 78.5% of all positive samples came in the first (spring/early-summer) sampling period. There was also a strong spatial component- the eleven temperate DoD installations had higher prevalences of Bd infection (20.8%) than the four arid (<60 mm annual precipitation) bases (8.5%). These data support the conclusion that Bd is now widespread, and promote the idea that Bd can today be considered endemic across much of North America, extending from coast-to-coast, with the exception of remote pockets of naive populations. PMID- 21811577 TI - Defective CFTR expression and function are detectable in blood monocytes: development of a new blood test for cystic fibrosis. AB - BACKGROUND: Evaluation of cystic fibrosis transmembrane conductance regulator (CFTR) functional activity to assess new therapies and define diagnosis of cystic fibrosis (CF) is cumbersome. It is known that leukocytes express detectable levels of CFTR but the molecule has not been characterized in these cells. In this study we aim at setting up and validating a blood test to evaluate CFTR expression and function in leukocytes. DESCRIPTION: Western blot, PCR, immunofluorescence and cell membrane depolarization analysis by single-cell fluorescence imaging, using the potential-sensitive DiSBAC(2)(3) probe were utilized. Expression of PKA phosphorylated, cell membrane-localized CFTR was detected in non-CF monocytes, being undetectable or present in truncated form in monocytes derived from CF patients presenting with nonsense mutations. CFTR agonist administration induced membrane depolarization in monocytes isolated from non-CF donors (31 subjects) and, to a lesser extent, obligate CFTR heterozygous carriers (HTZ: 15 subjects), but it failed in monocytes from CF patients (44 subjects). We propose an index, which values in CF patients are significantly (p<0.001) lower than in the other two groups. Nasal Potential Difference, measured in selected subjects had concordant results with monocytes assay (Kappa statistic 0.93, 95%CI: 0.80-1.00). RESULTS AND SIGNIFICANCE: CFTR is detectable and is functional in human monocytes. We also showed that CFTR-associated activity can be evaluated in 5 ml of peripheral blood and devise an index potentially applicable for diagnostic purposes and both basic and translational research: from drug development to evaluation of functional outcomes in clinical trials. PMID- 21811578 TI - Analysis of micro- and nano-structures of the corneal surface of Drosophila and its mutants by atomic force microscopy and optical diffraction. AB - Drosophila melanogaster is a model organism instrumental for numerous biological studies. The compound eye of this insect consists of some eight hundred individual ommatidia or facets, ca. 15 um in cross-section. Each ommatidium contains eighteen cells including four cone cells secreting the lens material (cornea). High-resolution imaging of the cornea of different insects has demonstrated that each lens is covered by the nipple arrays--small outgrowths of ca. 200 nm in diameter. Here we for the first time utilize atomic force microscopy (AFM) to investigate nipple arrays of the Drosophila lens, achieving an unprecedented visualization of the architecture of these nanostructures. We find by Fourier analysis that the nipple arrays of Drosophila are disordered, and that the seemingly ordered appearance is a consequence of dense packing of the nipples. In contrast, Fourier analysis confirms the visibly ordered nature of the eye microstructures--the individual lenses. This is different in the frizzled mutants of Drosophila, where both Fourier analysis and optical imaging detect disorder in lens packing. AFM reveals intercalations of the lens material between individual lenses in frizzled mutants, providing explanation for this disorder. In contrast, nanostructures of the mutant lens show the same organization as in wild-type flies. Thus, frizzled mutants display abnormal organization of the corneal micro-, but not nano-structures. At the same time, nipples of the mutant flies are shorter than those of the wild-type. We also analyze corneal surface of glossy-appearing eyes overexpressing Wingless--the lipoprotein ligand of Frizzled receptors, and find the catastrophic aberration in nipple arrays, providing experimental evidence in favor of the major anti-reflective function of these insect eye nanostructures. The combination of the easily tractable genetic model organism and robust AFM analysis represents a novel methodology to analyze development and architecture of these surface formations. PMID- 21811579 TI - Identification of changes in wheat (Triticum aestivum L.) seeds proteome in response to anti-trx s gene. AB - BACKGROUND: Thioredoxin h (trx h) is closely related to germination of cereal seeds. The cDNA sequences of the thioredoxin s (trx s) gene from Phalaris coerulescens and the thioredoxin h (trx h) gene from wheat are highly homologous, and their expression products have similar biological functions. Transgenic wheat had been formed after the antisense trx s was transferred into wheat, and it had been certified that the expression of trx h decreased in transgenic wheat, and transgenic wheat has high resistance to pre-harvest sprouting. METHODOLOGY/PRINCIPAL FINDINGS: Through analyzing the differential proteome of wheat seeds between transgenic wheat and wild type wheat, the mechanism of transgenic wheat seeds having high resistance to pre-harvest sprouting was studied in the present work. There were 36 differential proteins which had been identified by matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF-MS). All these differential proteins are involved in regulation of carbohydrates, esters, nucleic acid, proteins and energy metabolism, and biological stress. The quantitative real time PCR results of some differential proteins, such as trx h, heat shock protein 70, alpha-amylase, beta amylase, glucose-6-phosphate isomerase, 14-3-3 protein, S3-RNase, glyceraldehyde 3-phosphate dehydrogenase, and WRKY transcription factor 6, represented good correlation between transcripts and proteins. The biological functions of many differential proteins are consistent with the proposed role of trx h in wheat seeds. CONCLUSIONS/SIGNIFICANCE: A possible model for the role of trx h in wheat seeds germination was proposed in this paper. These results will not only play an important role in clarifying the mechanism that transgenic wheat has high resistance to pre-harvest sprouting, but also provide further evidence for the role of trx h in germination of wheat seeds. PMID- 21811580 TI - Yki/YAP, Sd/TEAD and Hth/MEIS control tissue specification in the Drosophila eye disc epithelium. AB - During animal development, accurate control of tissue specification and growth are critical to generate organisms of reproducible shape and size. The eye antennal disc epithelium of Drosophila is a powerful model system to identify the signaling pathway and transcription factors that mediate and coordinate these processes. We show here that the Yorkie (Yki) pathway plays a major role in tissue specification within the developing fly eye disc epithelium at a time when organ primordia and regional identity domains are specified. RNAi-mediated inactivation of Yki, or its partner Scalloped (Sd), or increased activity of the upstream negative regulators of Yki cause a dramatic reorganization of the eye disc fate map leading to specification of the entire disc epithelium into retina. On the contrary, constitutive expression of Yki suppresses eye formation in a Sd dependent fashion. We also show that knockdown of the transcription factor Homothorax (Hth), known to partner Yki in some developmental contexts, also induces an ectopic retina domain, that Yki and Scalloped regulate Hth expression, and that the gain-of-function activity of Yki is partially dependent on Hth. Our results support a critical role for Yki- and its partners Sd and Hth--in shaping the fate map of the eye epithelium independently of its universal role as a regulator of proliferation and survival. PMID- 21811581 TI - The action mechanism of the Myc inhibitor termed Omomyc may give clues on how to target Myc for cancer therapy. AB - Recent evidence points to Myc--a multifaceted bHLHZip transcription factor deregulated in the majority of human cancers--as a priority target for therapy. How to target Myc is less clear, given its involvement in a variety of key functions in healthy cells. Here we report on the action mechanism of the Myc interfering molecule termed Omomyc, which demonstrated astounding therapeutic efficacy in transgenic mouse cancer models in vivo. Omomyc action is different from the one that can be obtained by gene knockout or RNA interference, approaches designed to block all functions of a gene product. This molecule- instead--appears to cause an edge-specific perturbation that destroys some protein interactions of the Myc node and keeps others intact, with the result of reshaping the Myc transcriptome. Omomyc selectively targets Myc protein interactions: it binds c- and N-Myc, Max and Miz-1, but does not bind Mad or select HLH proteins. Specifically, it prevents Myc binding to promoter E-boxes and transactivation of target genes while retaining Miz-1 dependent binding to promoters and transrepression. This is accompanied by broad epigenetic changes such as decreased acetylation and increased methylation at H3 lysine 9. In the presence of Omomyc, the Myc interactome is channeled to repression and its activity appears to switch from a pro-oncogenic to a tumor suppressive one. Given the extraordinary therapeutic impact of Omomyc in animal models, these data suggest that successfully targeting Myc for cancer therapy might require a similar twofold action, in order to prevent Myc/Max binding to E-boxes and, at the same time, keep repressing genes that would be repressed by Myc. PMID- 21811582 TI - L-Ilf3 and L-NF90 traffic to the nucleolus granular component: alternatively spliced exon 3 encodes a nucleolar localization motif. AB - Ilf3 and NF90, two proteins containing double-stranded RNA-binding domains, are generated by alternative splicing and involved in several functions. Their heterogeneity results from posttranscriptional and posttranslational modifications. Alternative splicing of exon 3, coding for a 13 aa N-terminal motif, generates for each protein a long and short isoforms. Subcellular fractionation and localization of recombinant proteins showed that this motif acts as a nucleolar localization signal. Deletion and substitution mutants identified four arginines, essential for nucleolar targeting, and three histidines to stabilize the proteins within the nucleolus. The short isoforms are never found in the nucleoli, whereas the long isoforms are present in the nucleoplasm and the nucleoli. For Ilf3, only the posttranslationally-unmodified long isoform is nucleolar, suggesting that this nucleolar targeting is abrogated by posttranslational modifications. Confocal microscopy and FRAP experiments have shown that the long Ilf3 isoform localizes to the granular component of the nucleolus, and that L-Ilf3 and L-NF90 exchange rapidly between nucleoli. The presence of this 13 aminoacid motif, combined with posttranslational modifications, is responsible for the differences in Ilf3 and NF90 isoforms subcellular localizations. The protein polymorphism of Ilf3/NF90 and the various subcellular localizations of their isoforms may partially explain the various functions previously reported for these proteins. PMID- 21811583 TI - Lgt processing is an essential step in Streptococcus suis lipoprotein mediated innate immune activation. AB - BACKGROUND: Streptococcus suis causes invasive infections in pigs and occasionally in humans. The host innate immune system plays a major role in counteracting S. suis infections. The main components of S. suis able to activate the innate immune system likely include cell wall constituents that may be released during growth or after cell wall integrity loss, however characterization of these components is still limited. METHODOLOGY/PRINCIPAL FINDINGS: [corrected] A concentrated very potent innate immunity activating supernatant of penicillin-treated S. suis was SDS-PAGE fractionated and tested for porcine peripheral blood mononucleated cell (PBMC) stimulating activity using cytokine gene transcript analysis. More than half of the 24 tested fractions increased IL-1beta and IL-8 cytokine gene transcript levels in porcine PBMCs. Mass spectrometry of the active fractions indicated 24 proteins including 9 lipoproteins. Genetic inactivation of a putative prolipoprotein diacylglyceryl transferase (Lgt) gene resulted in deficient lipoprotein synthesis as evidenced by palmitate labeling. The Lgt mutant showed strongly reduced activation of porcine PBMCs, indicating that lipoproteins are dominant porcine PBMC activating molecules of S. suis. CONCLUSION/SIGNIFICANCE: This study for the first time identifies and characterizes lipoproteins of S. suis as major activators of the innate immune system of the pig. In addition, we provide evidence that Lgt processing of lipoproteins is required for lipoprotein mediated innate immune activation. PMID- 21811584 TI - Regulation of oxidative stress response by CosR, an essential response regulator in Campylobacter jejuni. AB - CosR (Campylobacter oxidative stress regulator; Cj0355c) is an OmpR-type response regulator essential for the viability of Campylobacter jejuni, a leading foodborne pathogen causing human gastroenteritis worldwide. Despite importance, the function of CosR remains completely unknown mainly because of cell death caused by its knockout mutation. To overcome this technical limitation, in this study, antisense technology was used to investigate the regulatory function of CosR by modulating the level of CosR expression. Two-dimensional gel electrophoresis (2DGE) was performed to identify the CosR regulon either by suppressing CosR expression with antisense peptide nucleic acid (PNA) or by overexpressing CosR in C. jejuni. According to the results of 2DGE, CosR regulated 32 proteins involved in various cellular processes. Notably, CosR negatively regulated a few key proteins of the oxidative stress response of C. jejuni, such as SodB, Dps, Rrc and LuxS, whereas CosR positively controlled AhpC. Electrophoretic mobility shift assay showed that CosR directly bound to the promoter region of the oxidative stress genes. DNase I footprinting assays identified 21-bp CosR binding sequences in the sodB and ahpC promoters, suggesting CosR specifically recognizes and binds to the regulated genes. Interestingly, the level of CosR protein was significantly reduced by paraquat (a superoxide generator) but not by hydrogen peroxide. Consistent with the overall negative regulation of oxidative stress defense proteins by CosR, the CosR knockdown by antisense rendered C. jejuni more resistant to oxidative stress compared to the wild type. Overall, this study reveals the important role played by the essential response regulator CosR in the oxidative stress defense of C. jejuni. PMID- 21811585 TI - Genomic profiling of submucosal-invasive gastric cancer by array-based comparative genomic hybridization. AB - Genomic copy number aberrations (CNAs) in gastric cancer have already been extensively characterized by array comparative genomic hybridization (array CGH) analysis. However, involvement of genomic CNAs in the process of submucosal invasion and lymph node metastasis in early gastric cancer is still poorly understood. In this study, to address this issue, we collected a total of 59 tumor samples from 27 patients with submucosal-invasive gastric cancers (SMGC), analyzed their genomic profiles by array CGH, and compared them between paired samples of mucosal (MU) and submucosal (SM) invasion (23 pairs), and SM invasion and lymph node (LN) metastasis (9 pairs). Initially, we hypothesized that acquisition of specific CNA(s) is important for these processes. However, we observed no significant difference in the number of genomic CNAs between paired MU and SM, and between paired SM and LN. Furthermore, we were unable to find any CNAs specifically associated with SM invasion or LN metastasis. Among the 23 cases analyzed, 15 had some similar pattern of genomic profiling between SM and MU. Interestingly, 13 of the 15 cases also showed some differences in genomic profiles. These results suggest that the majority of SMGCs are composed of heterogeneous subpopulations derived from the same clonal origin. Comparison of genomic CNAs between SMGCs with and without LN metastasis revealed that gain of 11q13, 11q14, 11q22, 14q32 and amplification of 17q21 were more frequent in metastatic SMGCs, suggesting that these CNAs are related to LN metastasis of early gastric cancer. In conclusion, our data suggest that generation of genetically distinct subclones, rather than acquisition of specific CNA at MU, is integral to the process of submucosal invasion, and that subclones that acquire gain of 11q13, 11q14, 11q22, 14q32 or amplification of 17q21 are likely to become metastatic. PMID- 21811586 TI - Newborn genetic screening for hearing impairment: a preliminary study at a tertiary center. AB - Universal newborn hearing screening (UNHS) is of paramount importance for early identification and management of hearing impairment in children. However, infants with slight/mild, progressive, or late-onset hearing impairment might be missed in conventional UNHS. To investigate whether genetic screening for common deafness-associated mutations could assist in identifying these infants, 1017 consecutive newborns in a tertiary hospital were subjected to both newborn hearing screening using a two-step distortion-product otoacoustic emissions (DPOAE) screening and newborn genetic screening (NGS) for deafness. The NGS targeted 4 deafness-associated mutations commonly found in the Taiwanese population, including p.V37I (c.109G>A) and c.235delC of the GJB2 gene, c.919 2A>G of the SLC26A4 gene, and mitochondrial m.1555A>G of the 12S rRNA gene. The results of the NGS were then correlated to the results of the NHS. Of the 1017 newborns, 16 (1.6%) had unilateral DPOAE screening failure, and 22 (2.2%) had bilateral DPOAE screening failure. A total of 199 (19.6%) babies were found to have at least 1 mutated allele on the NGS for deafness, 11 (1.1%) of whom were homozygous for GJB2 p.V37I, 6 (0.6%) compound heterozygous for GJB2 p.V37I and c.235delC, and 1 (0.1%) homoplasmic for m.1555A>G, who may potentially have hearing loss. Among them, 3 babies, 5 babies, and 1 baby, respectively, passed the NHS at birth. Comprehensive audiological assessments in the 9 babies at 3 months identified 1 with slight hearing loss and 2 with mild hearing loss. NGS for common deafness-associated mutations may identify infants with slight/mild or potentially progressive hearing impairment, thus compensating for the inherent limitations of the conventional UNHS. PMID- 21811587 TI - Association between genetic subgroups of pancreatic ductal adenocarcinoma defined by high density 500 K SNP-arrays and tumor histopathology. AB - The specific genes and genetic pathways associated with pancreatic ductal adenocarcinoma are still largely unknown partially due to the low resolution of the techniques applied so far to their study. Here we used high-density 500 K single nucleotide polymorphism (SNP)-arrays to define those chromosomal regions which most commonly harbour copy number (CN) alterations and loss of heterozygozity (LOH) in a series of 20 PDAC tumors and we correlated the corresponding genetic profiles with the most relevant clinical and histopathological features of the disease. Overall our results showed that primary PDAC frequently display (>70%) extensive gains of chromosomes 1q, 7q, 8q and 20q, together with losses of chromosomes 1p, 9p, 12q, 17p and 18q, such chromosomal regions harboring multiple cancer- and PDAC-associated genes. Interestingly, these alterations clustered into two distinct genetic profiles characterized by gains of the 2q14.2, 3q22.1, 5q32, 10q26.13, 10q26.3, 11q13.1, 11q13.3, 11q13.4, 16q24.1, 16q24.3, 22q13.1, 22q13.31 and 22q13.32 chromosomal regions (group 1; n = 9) versus gains at 1q21.1 and losses of the 1p36.11, 6q25.2, 9p22.1, 9p24.3, 17p13.3 and Xp22.33 chromosomal regions (group 2; n = 11). From the clinical and histopathological point of view, group 1 cases were associated with smaller and well/moderately-differentiated grade I/II PDAC tumors, whereas and group 2 PDAC displayed a larger size and they mainly consisted of poorly-differentiated grade III carcinomas. These findings confirm the cytogenetic complexity and heterozygozity of PDAC and provide evidence for the association between tumor cytogenetics and its histopathological features. In addition, we also show that the altered regions identified harbor multiple cancer associate genes that deserve further investigation to determine their relevance in the pathogenesis of PDAC. PMID- 21811588 TI - RIG-I is required for the inhibition of measles virus by retinoids. AB - Vitamin A can significantly decrease measles-associated morbidity and mortality. Vitamin A can inhibit the replication of measles virus (MeV) in vitro through an RARalpha- and type I interferon (IFN)-dependent mechanism. Retinoid-induced gene I (RIG-I) expression is induced by retinoids, activated by MeV RNA and is important for IFN signaling. We hypothesized that RIG-I is central to retinoid mediated inhibition of MeV in vitro. We demonstrate that RIG-I expression is increased in cells treated with retinoids and infected with MeV. The central role of RIG-I in the retinoid-anti-MeV effect was demonstrated in the Huh-7/7.5 model; the latter cells having non-functional RIG-I. RAR-dependent retinoid signaling was required for the induction of RIG-I by retinoids and MeV. Retinoid signaling was also found to act in combination with IFN to induce high levels of RIG-I expression. RIG-I promoter activation required both retinoids and MeV, as indicated by markers of active chromatin. IRF-1 is known to be regulated by retinoids and MeV, but we found recruitment of IRF-1 to the RIG-I promoter by retinoids alone. Using luciferase expression constructs, we further demonstrated that the IRF-1 response element of RIG-I was required for RIG-I activation by retinoids or IFN. These results reveal that retinoid treatment and MeV infection induces significant RIG-I. RIG-I is required for the retinoid-MeV antiviral response. The induction is dependent on IFN, retinoids and IRF-1. PMID- 21811589 TI - NTPase and 5'-RNA triphosphatase activities of Chikungunya virus nsP2 protein. AB - Chikungunya virus (CHIKV) is an insect borne virus (genus: Alphavirus) which causes acute febrile illness in humans followed by a prolonged arthralgic disease that affects the joints of the extremities. Re-emergence of the virus in the form of outbreaks in last 6-7 years has posed a serious public health problem. CHIKV has a positive sense single stranded RNA genome of about 12,000 nt. Open reading frame 1 of the viral genome encodes a polyprotein precursor, nsP1234, which is processed further into different non structural proteins (nsP1, nsP2, nsP3 and nsP4). Sequence based analyses have shown helicase domain at the N-terminus and protease domain at C-terminus of nsP2. A detailed biochemical analysis of NTPase/RNA helicase and 5'-RNA phosphatase activities of recombinant CHIKV-nsP2T protein (containing conserved NTPase/helicase motifs in the N-terminus and partial papain like protease domain at the C-terminus) was carried out. The protein could hydrolyze all NTPs except dTTP and showed better efficiency for ATP, dATP, GTP and dGTP hydrolysis. ATP was the most preferred substrate by the enzyme. CHIKV-nsP2T also showed 5'-triphosphatase (RTPase) activity that specifically removes the gamma-phosphate from the 5' end of RNA. Both NTPase and RTPase activities of the protein were completely dependent on Mg(2+) ions. RTPase activity was inhibited by ATP showing sharing of the binding motif by NTP and RNA. Both enzymatic activities were drastically reduced by mutations in the NTP binding motif (GKT) and co-factor, Mg(2+) ion binding motif (DEXX) suggesting that they have a common catalytic site. PMID- 21811590 TI - Cloacal bacterial diversity increases with multiple mates: evidence of sexual transmission in female common lizards. AB - Sexually transmitted diseases have often been suggested as a potential cost of multiple mating and as playing a major role in the evolution of mating systems. Yet there is little empirical data relating mating strategies to sexually transmitted microorganisms in wild populations. We investigated whether mating behaviour influences the diversity and composition of cloacal assemblages by comparing bacterial communities in the cloaca of monandrous and polyandrous female common lizards Zootoca vivipara sampled after the mating period. We found that polyandrous females harboured more diverse communities and differed more in community composition than did monandrous females. Furthermore, cloacal diversity and variability were found to decrease with age in polyandrous females. Our results suggest that the higher bacterial diversity found in polyandrous females is due to the sexual transmission of bacteria by multiple mates. The impact of mating behaviour on the cloacal microbiota may have fitness consequences for females and may comprise a selective pressure shaping the evolution of mating systems. PMID- 21811591 TI - Disproportionate alterations in the anterior and posterior insular cortices in obsessive-compulsive disorder. AB - BACKGROUND: Recent studies have reported that the insular cortex is involved in the pathophysiology of obsessive-compulsive disorder (OCD). However, specific morphometric abnormalities of the insular subregions remain unclear. In this study, we examined insular cortical volume to determine whether the volume of the anterior and posterior insular cortices of unmedicated OCD patients differed according to different symptom dimensions. METHODS/PRINCIPAL FINDINGS: Using magnetic resonance imaging, we measured the gray matter volumes of the insular cortex and its subregions (anterior and posterior divisions) in 41 patients with OCD (31 drug-naive and 10 non-medicated) and 53 healthy controls. Volumetric measures of the insular cortex were compared according to different OC symptoms. Enlarged anterior and reduced posterior insular cortices were observed in OCD patients. The insular volumetric alterations were more significant in OCD patients with predominant checking rather than cleaning symptoms when compared with healthy controls. CONCLUSIONS/SIGNIFICANCE: Our results suggest the presence of unbalanced anterior and posterior insular volumetric abnormalities in unmedicated OCD patients and emphasize the distinct role of the insular cortex in different OC symptoms. We propose that the insular morphometric alterations may influence the modulation of interoceptive processing, the insular functional role, in OCD patients with different symptoms. PMID- 21811593 TI - Prediction of inhibitory activity of epidermal growth factor receptor inhibitors using grid search-projection pursuit regression method. AB - The epidermal growth factor receptor (EGFR) protein tyrosine kinase (PTK) is an important protein target for anti-tumor drug discovery. To identify potential EGFR inhibitors, we conducted a quantitative structure-activity relationship (QSAR) study on the inhibitory activity of a series of quinazoline derivatives against EGFR tyrosine kinase. Two 2D-QSAR models were developed based on the best multi-linear regression (BMLR) and grid-search assisted projection pursuit regression (GS-PPR) methods. The results demonstrate that the inhibitory activity of quinazoline derivatives is strongly correlated with their polarizability, activation energy, mass distribution, connectivity, and branching information. Although the present investigation focused on EGFR, the approach provides a general avenue in the structure-based drug development of different protein receptor inhibitors. PMID- 21811592 TI - Exercise-induced splanchnic hypoperfusion results in gut dysfunction in healthy men. AB - BACKGROUND: Splanchnic hypoperfusion is common in various pathophysiological conditions and often considered to lead to gut dysfunction. While it is known that physiological situations such as physical exercise also result in splanchnic hypoperfusion, the consequences of flow redistribution at the expense of abdominal organs remained to be determined. This study focuses on the effects of splanchnic hypoperfusion on the gut, and the relationship between hypoperfusion, intestinal injury and permeability during physical exercise in healthy men. METHODS AND FINDINGS: Healthy men cycled for 60 minutes at 70% of maximum workload capacity. Splanchnic hypoperfusion was assessed using gastric tonometry. Blood, sampled every 10 minutes, was analyzed for enterocyte damage parameters (intestinal fatty acid binding protein (I-FABP) and ileal bile acid binding protein (I-BABP)). Changes in intestinal permeability were assessed using sugar probes. Furthermore, liver and renal parameters were assessed. Splanchnic perfusion rapidly decreased during exercise, reflected by increased gap(g a)pCO(2) from -0.85+/-0.15 to 0.85+/-0.42 kPa (p<0.001). Hypoperfusion increased plasma I-FABP (615+/-118 vs. 309+/-46 pg/ml, p<0.001) and I-BABP (14.30+/-2.20 vs. 5.06+/-1.27 ng/ml, p<0.001), and hypoperfusion correlated significantly with this small intestinal damage (r(S) = 0.59; p<0.001). Last of all, plasma analysis revealed an increase in small intestinal permeability after exercise (p<0.001), which correlated with intestinal injury (r(S) = 0.50; p<0.001). Liver parameters, but not renal parameters were elevated. CONCLUSIONS: Exercise-induced splanchnic hypoperfusion results in quantifiable small intestinal injury. Importantly, the extent of intestinal injury correlates with transiently increased small intestinal permeability, indicating gut barrier dysfunction in healthy individuals. These physiological observations increase our knowledge of splanchnic hypoperfusion sequelae, and may help to understand and prevent these phenomena in patients. PMID- 21811594 TI - Ecosystem resilience and threshold response in the Galapagos coastal zone. AB - BACKGROUND: The Intergovernmental Panel on Climate Change (IPCC) provides a conservative estimate on rates of sea-level rise of 3.8 mm yr(-1) at the end of the 21(st) century, which may have a detrimental effect on ecologically important mangrove ecosystems. Understanding factors influencing the long-term resilience of these communities is critical but poorly understood. We investigate ecological resilience in a coastal mangrove community from the Galapagos Islands over the last 2700 years using three research questions: What are the 'fast and slow' processes operating in the coastal zone? Is there evidence for a threshold response? How can the past inform us about the resilience of the modern system? METHODOLOGY/PRINCIPAL FINDINGS: Palaeoecological methods (AMS radiocarbon dating, stable carbon isotopes (delta(13)C)) were used to reconstruct sedimentation rates and ecological change over the past 2,700 years at Diablas lagoon, Isabela, Galapagos. Bulk geochemical analysis was also used to determine local environmental changes, and salinity was reconstructed using a diatom transfer function. Changes in relative sea level (RSL) were estimated using a glacio isostatic adjustment model. Non-linear behaviour was observed in the Diablas mangrove ecosystem as it responded to increased salinities following exposure to tidal inundations. A negative feedback was observed which enabled the mangrove canopy to accrete vertically, but disturbances may have opened up the canopy and contributed to an erosion of resilience over time. A combination of drier climatic conditions and a slight fall in RSL then resulted in a threshold response, from a mangrove community to a microbial mat. CONCLUSIONS/SIGNIFICANCE: Palaeoecological records can provide important information on the nature of non linear behaviour by identifying thresholds within ecological systems, and in outlining responses to 'fast' and 'slow' environmental change between alternative stable states. This study highlights the need to incorporate a long-term ecological perspective when designing strategies for maximizing coastal resilience. PMID- 21811595 TI - Adaptive group coordination and role differentiation. AB - Many real world situations (potluck dinners, academic departments, sports teams, corporate divisions, committees, seminar classes, etc.) involve actors adjusting their contributions in order to achieve a mutually satisfactory group goal, a win win result. However, the majority of human group research has involved situations where groups perform poorly because task constraints promote either individual maximization behavior or diffusion of responsibility, and even successful tasks generally involve the propagation of one correct solution through a group. Here we introduce a group task that requires complementary actions among participants in order to reach a shared goal. Without communication, group members submit numbers in an attempt to collectively sum to a randomly selected target number. After receiving group feedback, members adjust their submitted numbers until the target number is reached. For all groups, performance improves with task experience, and group reactivity decreases over rounds. Our empirical results provide evidence for adaptive coordination in human groups, and as the coordination costs increase with group size, large groups adapt through spontaneous role differentiation and self-consistency among members. We suggest several agent-based models with different rules for agent reactions, and we show that the empirical results are best fit by a flexible, adaptive agent strategy in which agents decrease their reactions when the group feedback changes. The task offers a simple experimental platform for studying the general problem of group coordination while maximizing group returns, and we distinguish the task from several games in behavioral game theory. PMID- 21811596 TI - Expression of the lantibiotic mersacidin in Bacillus amyloliquefaciens FZB42. AB - Lantibiotics are small peptide antibiotics that contain the characteristic thioether amino acids lanthionine and methyllanthionine. As ribosomally synthesized peptides, lantibiotics possess biosynthetic gene clusters which contain the structural gene (lanA) as well as the other genes which are involved in lantibiotic modification (lanM, lanB, lanC, lanP), regulation (lanR, lanK), export (lanT(P)) and immunity (lanEFG). The lantibiotic mersacidin is produced by Bacillus sp. HIL Y-85,54728, which is not naturally competent. METHODOLOGY/PRINCIPAL FINDINGS: The aim of these studies was to test if the production of mersacidin could be transferred to a naturally competent Bacillus strain employing genomic DNA of the producer strain. Bacillus amyloliquefaciens FZB42 was chosen for these experiments because it already harbors the mersacidin immunity genes. After transfer of the biosynthetic part of the gene cluster by competence transformation, production of active mersacidin was obtained from a plasmid in trans. Furthermore, comparison of several DNA sequences and biochemical testing of B. amyloliquefaciens FZB42 and B. sp. HIL Y-85,54728 showed that the producer strain of mersacidin is a member of the species B. amyloliquefaciens. CONCLUSIONS/SIGNIFICANCE: The lantibiotic mersacidin can be produced in B. amyloliquefaciens FZB42, which is closely related to the wild type producer strain of mersacidin. The new mersacidin producer strain enables us to use the full potential of the biosynthetic gene cluster for genetic manipulation and downstream modification approaches. PMID- 21811597 TI - Widespread expression of BORIS/CTCFL in normal and cancer cells. AB - BORIS (CTCFL) is the paralog of CTCF (CCCTC-binding factor; NM_006565), a ubiquitously expressed DNA-binding protein with diverse roles in gene expression and chromatin organisation. BORIS and CTCF have virtually identical zinc finger domains, yet display major differences in their respective C- and N-terminal regions. Unlike CTCF, BORIS expression has been reported only in the testis and certain malignancies, leading to its classification as a "cancer-testis" antigen. However, the expression pattern of BORIS is both a significant and unresolved question in the field of DNA binding proteins. Here, we identify BORIS in the cytoplasm and nucleus of a wide range of normal and cancer cells. We compare the localization of CTCF and BORIS in the nucleus and demonstrate enrichment of BORIS within the nucleolus, inside the nucleolin core structure and adjacent to fibrillarin in the dense fibrillar component. In contrast, CTCF is not enriched in the nucleolus. Live imaging of cells transiently transfected with GFP tagged BORIS confirmed the nucleolar accumulation of BORIS. While BORIS transcript levels are low compared to CTCF, its protein levels are readily detectable. These findings show that BORIS expression is more widespread than previously believed, and suggest a role for BORIS in nucleolar function. PMID- 21811598 TI - Allorecognition in the Tasmanian devil (Sarcophilus harrisii), an endangered marsupial species with limited genetic diversity. AB - Tasmanian devils (Sarcophilus harrisii) are on the verge of extinction due to a transmissible cancer, devil facial tumour disease (DFTD). This tumour is an allograft that is transmitted between individuals without immune recognition of the tumour cells. The mechanism to explain this lack of immune recognition and acceptance is not well understood. It has been hypothesized that lack of genetic diversity at the Major Histocompatibility Complex (MHC) allowed the tumour cells to grow in genetically similar hosts without evoking an immune response to alloantigens. We conducted mixed lymphocyte reactions and skin grafts to measure functional MHC diversity in the Tasmanian devil population. The limited MHC diversity was sufficient to produce measurable mixed lymphocyte reactions. There was a wide range of responses, from low or no reaction to relatively strong responses. The highest responses occurred when lymphocytes from devils from the east of Tasmania were mixed with lymphocytes from devils from the west of Tasmania. All of the five successful skin allografts were rejected within 14 days after surgery, even though little or no MHC I and II mismatches were found. Extensive T-cell infiltration characterised the immune rejection. We conclude that Tasmanian devils are capable of allogeneic rejection. Consequently, a lack of functional allorecognition mechanisms in the devil population does not explain the transmission of a contagious cancer. PMID- 21811599 TI - Revolutionizing clinical microbiology laboratory organization in hospitals with in situ point-of-care. AB - BACKGROUND: Clinical microbiology may direct decisions regarding hospitalization, isolation and anti-infective therapy, but it is not effective at the time of early care. Point-of-care (POC) tests have been developed for this purpose. METHODS AND FINDINGS: One pilot POC-lab was located close to the core laboratory and emergency ward to test the proof of concept. A second POC-lab was located inside the emergency ward of a distant hospital without a microbiology laboratory. Twenty-three molecular and immuno-detection tests, which were technically undemanding, were progressively implemented, with results obtained in less than four hours. From 2008 to 2010, 51,179 tests yielded 6,244 diagnoses. The second POC-lab detected contagious pathogens in 982 patients who benefited from targeted isolation measures, including those undertaken during the influenza outbreak. POC tests prevented unnecessary treatment of patients with non streptococcal tonsillitis (n = 1,844) and pregnant women negative for Streptococcus agalactiae carriage (n = 763). The cerebrospinal fluid culture remained sterile in 50% of the 49 patients with bacterial meningitis, therefore antibiotic treatment was guided by the molecular tests performed in the POC-labs. With regard to enterovirus meningitis, the mean length-of-stay of infected patients over 15 years old significantly decreased from 2008 to 2010 compared with 2005 when the POC was not in place (1.43+/-1.09 versus 2.91+/-2.31 days; p = 0.0009). Altogether, patients who received POC tests were immediately discharged nearly thrice as often as patients who underwent a conventional diagnostic procedure. CONCLUSIONS: The on-site POC-lab met physicians' needs and influenced the management of 8% of the patients that presented to emergency wards. This strategy might represent a major evolution of decision-making regarding the management of infectious diseases and patient care. PMID- 21811600 TI - A star in the brainstem reveals the first step of cortical magnification. AB - A fundamental question in the neurosciences is how central nervous system (CNS) space is allocated to different sensory inputs. Yet it is difficult to measure innervation density and corresponding representational areas in the CNS of most species. These measurements can be made in star-nosed moles (Condylura cristata) because the cortical representation of nasal rays is visible in flattened sections and afferents from each ray can be counted. Here we used electrophysiological recordings combined with sections of the brainstem to identify a large, visible star representation in the principal sensory nucleus (PrV). PrV was greatly expanded and bulged out of the brainstem rostrally to partially invade the trigeminal nerve. The star representation was a distinct PrV subnucleus containing 11 modules, each representing one of the nasal rays. The 11 PrV ray representations were reconstructed to obtain volumes and the largest module corresponded to ray 11, the mole's tactile fovea. These measures were compared to fiber counts and primary cortical areas from a previous investigation. PrV ray volumes were closely correlated with the number of afferents from each ray, but afferents from the behaviorally most important, 11(th) ray were preferentially over-represented. This over-representation at the brainstem level was much less than at the cortical level. Our results indicate that PrV provides the first step in magnifying CNS representations of important afferents, but additional magnification occurs at higher levels. The early development of the 11(th), foveal appendage could provide a mechanism for the most important afferents to capture the most CNS space. PMID- 21811601 TI - Characterization of a novel cutaneous human papillomavirus genotype HPV-125. AB - The DNA genome of a novel HPV genotype, HPV-125, isolated from a hand wart of an immuno-competent 19-year old male was fully cloned, sequenced and characterized. The full genome of HPV-125 is 7,809-bp in length with a GC content of 46.4%. By comparing the nucleotide sequence of the complete L1 gene, HPV-125 is phylogenetically placed within cutaneotrophic species 2 of Alphapapillomaviruses, and is most closely related to HPV-3 and HPV-28. HPV-125 has a typical genomic organization of Alphapapillomaviruses and contains genes coding for five early proteins, E6, E7, E1, E2 and E4 and two late capsid proteins, L1 and L2. The genome contains two non-coding regions: the first located between the L1 and E6 genes (nucleotide positions 7,137-7,809, length 673-bp) and the second between genes E2 and L2 (nucleotide positions 3,757-4,216, length 460-bp). The E6 protein of HPV-125 contains two regular zinc-binding domains at amino acid positions 29 and 102, whereas the E7 protein exhibits one such domain at position 50. HPV-125 lacks the regular pRb-binding core sequence within its E7 protein. In order to assess the tissue predilection and clinical significance of HPV-125, a quantitative type-specific real-time PCR was developed. The 95% limit-of detection of the assay was 2.5 copies per reaction (range 1.7-5.7) and the intra- and inter-assay coefficients of variation were 0.47 and 2.00 for 100 copies per reaction, and 1.15 and 2.15 for 10 copies per reaction, respectively. Testing of a representative collection of HPV-associated mucosal and cutaneous benign and malignant neoplasms and hair follicles (a total of 601 samples) showed that HPV 125 is a relatively rare HPV genotype, with cutaneous tropism etiologically linked with sporadic cases of common warts. PMID- 21811602 TI - Interferon impedes an early step of hepatitis delta virus infection. AB - Hepatitis delta virus (HDV) infects hepatocytes, the major cell type of the liver. Infection of the liver may be either transient or chronic. The prognosis for patients with chronic HDV infection is poor, with a high risk of cirrhosis and hepatocellular carcinoma. The best antiviral therapy is weekly administration for at least one year of high doses of interferon alpha. This efficacy of interferon therapy has been puzzling in that HDV replication in transfected cell lines is reported as insensitive to administration of interferon alpha or gamma. Similarly, this study shows that even when an interferon response was induced by transfection of poly(IC) into a cell line, HDV RNA accumulation was only modestly inhibited. However, when the HDV replication was initiated by infection of primary human hepatocytes, simultaneous addition of interferons alpha or gamma at 600 units/ml, a concentration comparable to that achieved in treated patients, the subsequent HDV RNA accumulation was inhibited by at least 80%. These interferon treatments were shown to produce significant time-dependent increases of host response proteins such as for Stat-1, phosphoStat-1, Mx1/2/3 and PKR, and yet interferon pretreatment of hepatocytes did not confer an increased inhibition of HDV replication over interferon treatment at the time of (or after) infection. These and other data support the interpretation that interferon action against HDV replication can occur and is largely mediated at the level of entry into primary human hepatocytes. Thus in vivo, the success of long-term interferon therapy for chronic HDV, may likewise involve blocking HDV spread by interfering with the initiation of productive infection of naive hepatocytes. PMID- 21811603 TI - Genetic characterization of conserved charged residues in the bacterial flagellar type III export protein FlhA. AB - For assembly of the bacterial flagellum, most of flagellar proteins are transported to the distal end of the flagellum by the flagellar type III protein export apparatus powered by proton motive force (PMF) across the cytoplasmic membrane. FlhA is an integral membrane protein of the export apparatus and is involved in an early stage of the export process along with three soluble proteins, FliH, FliI, and FliJ, but the energy coupling mechanism remains unknown. Here, we carried out site-directed mutagenesis of eight, highly conserved charged residues in putative juxta- and trans-membrane helices of FlhA. Only Asp-208 was an essential acidic residue. Most of the FlhA substitutions were tolerated, but resulted in loss-of-function in the DeltafliH-fliI mutant background, even with the second-site flhB(P28T) mutation that increases the probability of flagellar protein export in the absence of FliH and FliI. The addition of FliH and FliI allowed the D45A, R85A, R94K and R270A mutant proteins to work even in the presence of the flhB(P28T) mutation. Suppressor analysis of a flhA(K203W) mutation showed an interaction between FlhA and FliR. Taken all together, we suggest that Asp-208 is directly involved in PMF-driven protein export and that the cooperative interactions of FlhA with FlhB, FliH, FliI, and FliR drive the translocation of export substrate. PMID- 21811604 TI - Synthesis and investigation of a radioiodinated F3 peptide analog as a SPECT tumor imaging radioligand. AB - A radioiodinated derivative of the tumor-homing F3 peptide, (N-(2-{3 [(125)I]Iodobenzoyl}aminoethyl)maleimide-F3Cys peptide, [(125)I]IBMF3 was developed for investigation as a SPECT tumor imaging radioligand. For this purpose, we custom synthesized a modified F3 peptide analog (F3Cys) incorporating a C-terminal cysteine residue for site-specific attachment of a radioiodinated maleimide conjugating group. Initial proof-of-concept Fluorescence studies conducted with AlexaFluor 532 C(5) maleimide-labeled F3Cys showed distinct membrane and nuclear localization of F3Cys in MDA-MB-435 cells. Additionally, F3Cys conjugated with NIR fluorochrome AlexaFluor 647 C(2) maleimide demonstrated high tumor specific uptake in melanoma cancer MDA-MB-435 and lung cancer A549 xenografts in nude mice whereas a similarly labeled control peptide did not show any tumor uptake. These results were also confirmed by ex vivo tissue analysis. No-carrier-added [(125)I]IBMF3 was synthesized by a radioiododestannylation approach in 73% overall radiochemical yield. In vitro cell uptake studies conducted with [(125)I]IBMF3 displayed a 5-fold increase in its cell uptake at 4 h when compared to controls. SPECT imaging studies with [(125)I]IBMF3 in tumor bearing nude mice showed clear visualization of MDA-MB-435 xenografts on systemic administration. These studies demonstrate a potential utility of F3 peptide-based radioligands for tumor imaging with PET or SPECT techniques. PMID- 21811605 TI - Glucocorticoid regulation of astrocytic fate and function. AB - Glial loss in the hippocampus has been suggested as a factor in the pathogenesis of stress-related brain disorders that are characterized by dysregulated glucocorticoid (GC) secretion. However, little is known about the regulation of astrocytic fate by GC. Here, we show that astrocytes derived from the rat hippocampus undergo growth inhibition and display moderate activation of caspase 3 after exposure to GC. Importantly, the latter event, observed both in situ and in primary astrocytic cultures is not followed by either early- or late-stage apoptosis, as monitored by stage I or stage II DNA fragmentation. Thus, unlike hippocampal granule neurons, astrocytes are resistant to GC-induced apoptosis; this resistance is due to lower production of reactive oxygen species (ROS) and a greater buffering capacity against the cytotoxic actions of ROS. We also show that GC influence hippocampal cell fate by inducing the expression of astrocyte derived growth factors implicated in the control of neural precursor cell proliferation. Together, our results suggest that GC instigate a hitherto unknown dialog between astrocytes and neural progenitors, adding a new facet to understanding how GC influence the cytoarchitecture of the hippocampus. PMID- 21811606 TI - Identification of the pangenome and its components in 14 distinct Aggregatibacter actinomycetemcomitans strains by comparative genomic analysis. AB - BACKGROUND: Aggregatibacter actinomycetemcomitans is genetically heterogeneous and comprises distinct clonal lineages that may have different virulence potentials. However, limited information of the strain-to-strain genomic variations is available. METHODOLOGY/PRINCIPAL FINDINGS: The genome sequences of 11 A. actinomycetemcomitans strains (serotypes a-f) were generated de novo, annotated and combined with three previously sequenced genomes (serotypes a-c) for comparative genomic analysis. Two major groups were identified; serotypes a, d, e, and f, and serotypes b and c. A serotype e strain was found to be distinct from both groups. The size of the pangenome was 3,301 genes, which included 2,034 core genes and 1,267 flexible genes. The number of core genes is estimated to stabilize at 2,060, while the size of the pangenome is estimated to increase by 16 genes with every additional strain sequenced in the future. Within each strain 16.7-29.4% of the genome belonged to the flexible gene pool. Between any two strains 0.4-19.5% of the genomes were different. The genomic differences were occasionally greater for strains of the same serotypes than strains of different serotypes. Furthermore, 171 genomic islands were identified. Cumulatively, 777 strain-specific genes were found on these islands and represented 61% of the flexible gene pool. CONCLUSIONS/SIGNIFICANCE: Substantial genomic differences were detected among A. actinomycetemcomitans strains. Genomic islands account for more than half of the flexible genes. The phenotype and virulence of A. actinomycetemcomitans may not be defined by any single strain. Moreover, the genomic variation within each clonal lineage of A. actinomycetemcomitans (as defined by serotype grouping) may be greater than between clonal lineages. The large genomic data set in this study will be useful to further examine the molecular basis of variable virulence among A. actinomycetemcomitans strains. PMID- 21811607 TI - Transient receptor potential (TRP) and Cch1-Yam8 channels play key roles in the regulation of cytoplasmic Ca2+ in fission yeast. AB - The regulation of cytoplasmic Ca(2+) is crucial for various cellular processes. Here, we examined the cytoplasmic Ca(2+) levels in living fission yeast cells by a highly sensitive bioluminescence resonance energy transfer-based assay using GFP-aequorin fusion protein linked by 19 amino acid. We monitored the cytoplasmic Ca(2+) level and its change caused by extracellular stimulants such as CaCl(2) or NaCl plus FK506 (calcineurin inhibitor). We found that the extracellularly added Ca(2+) caused a dose-dependent increase in the cytoplasmic Ca(2+) level and resulted in a burst-like peak. The overexpression of two transient receptor potential (TRP) channel homologues, Trp1322 or Pkd2, markedly enhanced this response. Interestingly, the burst-like peak upon TRP overexpression was completely abolished by gene deletion of calcineurin and was dramatically decreased by gene deletion of Prz1, a downstream transcription factor activated by calcineurin. Furthermore, 1 hour treatment with FK506 failed to suppress the burst-like peak. These results suggest that the burst-like Ca(2+) peak is dependent on the transcriptional activity of Prz1, but not on the direct TRP dephosphorylation. We also found that extracellularly added NaCl plus FK506 caused a synergistic cytosolic Ca(2+) increase that is dependent on the inhibition of calcineurin activity, but not on the inhibition of Prz1. The synergistic Ca(2+) increase is abolished by the addition of the Ca(2+) chelator BAPTA into the media, and is also abolished by deletion of the gene encoding a subunit of the Cch1-Yam8 Ca(2+) channel complex, indicating that the synergistic increase is caused by the Ca(2+) influx from the extracellular medium via the Cch1-Yam8 complex. Furthermore, deletion of Pmk1 MAPK abolished the Ca(2+) influx, and overexpression of the constitutively active Pek1 MAPKK enhanced the influx. These results suggest that Pmk1 MAPK and calcineurin positively and negatively regulate the Cch1-Yam8 complex, respectively, via modulating the balance between phosphorylation and dyphosphorylation state. PMID- 21811608 TI - Silencing nuclear pore protein Tpr elicits a senescent-like phenotype in cancer cells. AB - BACKGROUND: Tpr is a large coiled-coil protein located in the nuclear basket of the nuclear pore complex for which many different functions were proposed from yeast to human. METHODOLOGY/PRINCIPAL FINDINGS: Here we show that depletion of Tpr by RNA interference triggers G0-G1 arrest and ultimately induces a senescent like phenotype dependent on the presence of p53. We also found that Tpr depletion impairs the NES [nuclear export sequence]-dependent nuclear export of proteins and causes partial co-depletion of Nup153. In addition Tpr depletion impacts on level and function of the SUMO-protease SENP2 thus affecting SUMOylation regulation at the nuclear pore and overall SUMOylation in the cell. CONCLUSIONS: Our data for the first time provide evidence that a nuclear pore component plays a role in controlling cellular senescence. Our findings also point to new roles for Tpr in the regulation of SUMO-1 conjugation at the nuclear pore and directly confirm Tpr involvement in the nuclear export of NES-proteins. PMID- 21811609 TI - Household tobacco smoke and admission weight predict severe bronchiolitis in infants independent of deprivation: prospective cohort study. AB - OBJECTIVES: To examine demographic, environmental and clinical factors associated with severe bronchiolitis in infants admitted to hospital and quantify the independent effects of these factors. DESIGN: Prospective cohort study. SETTING: Alder Hey Children's Hospital, Liverpool, United Kingdom. PARTICIPANTS: 378 infants admitted to hospital with a diagnosis of bronchiolitis, of whom 299 (79%) were antigen positive to respiratory syncytial virus (RSV). OUTCOME: Severity of disease during admission, defined as "no need for supplemental oxygen" (reference group), "any need for supplemental oxygen" and "any need for mechanical ventilation". RESULTS: Univariate analysis found male sex (p = 0.035) and tobacco smoking by a household member (p<0.001) were associated with need for both supplemental oxygen and mechanical ventilation. Premature birth, low gestation, low birth weight, low admission weight and low corrected age on admission were also associated with need for mechanical ventilation (all p<=0.002). Deprivation scores (IMD 2004) were significantly higher in households where a member smoked compared to non-smoking households (p<0.001). The odds of smoking predicted by deprivation were 7 times higher (95%CI (3.59, 14.03)), when comparing the least and most deprived quintiles of the study population. Family history of atopic disease and deprivation score were not associated with severe disease. Multivariate multinomial logistic regression which initially included all covariates, found household tobacco smoking (adjusted OR = 2.45, 95%CI (1.60, 3.74) predicted need for oxygen supplementation. Household tobacco smoking (adjusted OR = 5.49, (2.78, 10.83)) and weight (kg) on admission (adjusted OR = 0.51, (0.40, 0.65)) were both significant predictors in the final model for mechanical ventilation. The same associations and similar size of effects were found when only children with proven RSV infection were included in analysis. CONCLUSIONS: Low admission weight and householder tobacco smoking increased the risk of severe bronchiolitis in infants admitted to hospital. These effects were independent of a standard deprivation measure. NIHR Study Ref. DHCS/G121/10. PMID- 21811610 TI - Differentiation-dependent interpentameric disulfide bond stabilizes native human papillomavirus type 16. AB - Genetic and biochemical analyses of human papillomavirus type 16 (HPV16) capsids have shown that certain conserved L1 cysteine residues are critical for capsid assembly, integrity, and maturation. Since previous studies utilized HPV capsids produced in monolayer culture-based protein expression systems, the ascribed roles for these cysteine residues were not placed in the temporal context of the natural host environment for HPV, stratifying and differentiating human tissue. Here we extend upon previous observation, that HPV16 capsids mature and become stabilized over time (10-day to 20-day) in a naturally occurring tissue-spanning redox gradient, by identifying temporal roles for individual L1 cysteine residues. Specifically, the C175S substitution severely undermined wild-type titers of the virus within both 10 and 20-day tissue, while C428S, C185S, and C175,185S substitutions severely undermined wild-type titers only within 20-day tissue. All mutations led to 20-day virions that were less stable than wild-type and failed to form L1 multimers via nonreducing SDS-PAGE. Furthermore, Optiprep fractionated 20-day C428S, C175S, and C175,185S capsids appeared permeable to endonucleases in comparison to wild-type and C185S capsids. Exposure to an oxidizing environment failed to enhance infectious titers of any of the cysteine mutants over time as with wild-type. Introduction of these cys mutants results in failure of the virus to mature. PMID- 21811611 TI - Cable pili and the associated 22 kDa adhesin contribute to Burkholderia cenocepacia persistence in vivo. AB - BACKGROUND: Infection by Burkholderia cenocepacia in cystic fibrosis (CF) patients is associated with poor clinical prognosis. Previously, we demonstrated that one of the highly transmissible strains, BC7, expresses cable pili and the associated 22 kDa adhesin, both of which contribute to BC7 binding to airway epithelial cells. However, the contribution of these factors to induce inflammation and bacterial persistence in vivo is not known. METHODOLOGY/PRINCIPAL FINDINGS: Wild-type BC7 stimulated higher IL-8 responses than the BC7 cbl and BC7 adhA mutants in both CF and normal bronchial epithelial cells. To determine the role of cable pili and the associated adhesin, we characterized a mouse model of B. cenocepacia, where BC7 are suspended in Pseudomonas aeruginosa alginate. C57BL/6 mice were infected intratracheally with wild-type BC7 suspended in either alginate or PBS and were monitored for lung bacterial load and inflammation. Mice infected with BC7 suspended in PBS completely cleared the bacteria by 3 days and resolved the inflammation. In contrast, mice infected with BC7 suspended in alginate showed persistence of bacteria and moderate lung inflammation up to 5 days post-infection. Using this model, mice infected with the BC7 cbl and BC7 adhA mutants showed lower bacterial loads and mild inflammation compared to mice infected with wild-type BC7. Complementation of the BC7 cblS mutation in trans restored the capacity of this strain to persist in vivo. Immunolocalization of bacteria revealed wild-type BC7 in both airway lumen and alveoli, while the BC7 cbl and BC7 adhA mutants were found mainly in airway lumen and peribronchiolar region. CONCLUSIONS AND SIGNIFICANCE: B. cenocepacia suspended in alginate can be used to determine the capacity of bacteria to persist and cause lung inflammation in normal mice. Both cable pili and adhesin contribute to BC7-stimulated IL-8 response in vitro, and BC7 persistence and resultant inflammation in vivo. PMID- 21811612 TI - An integrative view of mechanisms underlying generalized spike-and-wave epileptic seizures and its implication on optimal therapeutic treatments. AB - Many types of epileptic seizures are characterized by generalized spike-and-wave discharges. In the past, notable effort has been devoted to understanding seizure dynamics and various hypotheses have been proposed to explain the underlying mechanisms. In this paper, by taking an integrative view of the underlying mechanisms, we demonstrate that epileptic seizures can be generated by many different combinations of synaptic strengths and intrinsic membrane properties. This integrative view has important medical implications: the specific state of a patient characterized by a set of biophysical characteristics ultimately determines the optimal therapeutic treatment. Through the same view, we further demonstrate the potentiation effect of rational polypharmacy in the treatment of epilepsy and provide a new angle to resolve the debate on polypharmacy. Our results underscore the need for personalized medicine and demonstrate that computer modeling and simulation may play an important role in assisting the clinicians in selecting the optimal treatment on an individual basis. PMID- 21811613 TI - Dogs leaving the ICU carry a very large multi-drug resistant enterococcal population with capacity for biofilm formation and horizontal gene transfer. AB - The enterococcal community from feces of seven dogs treated with antibiotics for 2-9 days in the veterinary intensive care unit (ICU) was characterized. Both, culture-based approach and culture-independent 16S rDNA amplicon 454 pyrosequencing, revealed an abnormally large enterococcal community: 1.4+/ 0.8*10(8) CFU gram(-1) of feces and 48.9+/-11.5% of the total 16,228 sequences, respectively. The diversity of the overall microbial community was very low which likely reflects a high selective antibiotic pressure. The enterococcal diversity based on 210 isolates was also low as represented by Enterococcus faecium (54.6%) and Enterococcus faecalis (45.4%). E. faecium was frequently resistant to enrofloxacin (97.3%), ampicillin (96.5%), tetracycline (84.1%), doxycycline (60.2%), erythromycin (53.1%), gentamicin (48.7%), streptomycin (42.5%), and nitrofurantoin (26.5%). In E. faecalis, resistance was common to tetracycline (59.6%), erythromycin (56.4%), doxycycline (53.2%), and enrofloxacin (31.9%). No resistance was detected to vancomycin, tigecycline, linezolid, and quinupristin/dalfopristin in either species. Many isolates carried virulence traits including gelatinase, aggregation substance, cytolysin, and enterococcal surface protein. All E. faecalis strains were biofilm formers in vitro and this phenotype correlated with the presence of gelE and/or esp. In vitro intra-species conjugation assays demonstrated that E. faecium were capable of transferring tetracycline, doxycycline, streptomycin, gentamicin, and erythromycin resistance traits to human clinical strains. Multi-locus variable number tandem repeat analysis (MLVA) and pulsed-field gel electrophoresis (PFGE) of E. faecium strains showed very low genotypic diversity. Interestingly, three E. faecium clones were shared among four dogs suggesting their nosocomial origin. Furthermore, multi locus sequence typing (MLST) of nine representative MLVA types revealed that six sequence types (STs) originating from five dogs were identical or closely related to STs of human clinical isolates and isolates from hospital outbreaks. It is recommended to restrict close physical contact between pets released from the ICU and their owners to avoid potential health risks. PMID- 21811614 TI - Poly-thymidine oligonucleotides mediate activation of murine glial cells primarily through TLR7, not TLR8. AB - The functional role of murine TLR8 in the inflammatory response of the central nervous system (CNS) remains unclear. Murine TLR8 does not appear to respond to human TLR7/8 agonists, due to a five amino acid deletion in the ectodomain. However, recent studies have suggested that murine TLR8 may be stimulated by alternate ligands, which include vaccinia virus DNA, phosphothioate oligodeoxynucleotides (ODNs) or the combination of phosphothioate poly-thymidine oligonucleotides (pT-ODNs) with TLR7/8 agonists. In the current study, we analyzed the ability of pT-ODNs to induce activation of murine glial cells in the presence or absence of TLR7/8 agonists. We found that TLR7/8 agonists induced the expression of glial cell activation markers and induced the production of multiple proinflammatory cytokines and chemokines in mixed glial cultures. In contrast, pT-ODNs alone induced only low level expression of two cytokines, CCL2 and CXCL10. The combination of pT-ODNs along with TLR7/8 agonists induced a synergistic response with substantially higher levels of proinflammatory cytokines and chemokines compared to CL075. This enhancement was not due to cellular uptake of the agonist, indicating that the pT-ODN enhancement of cytokine responses was due to effects on an intracellular process. Interestingly, this response was also not due to synergistic stimulation of both TLR7 and TLR8, as the loss of TLR7 abolished the activation of glial cells and cytokine production. Thus, pT-ODNs act in synergy with TLR7/8 agonists to induce strong TLR7-dependent cytokine production in glial cells, suggesting that the combination of pT-ODNs with TLR7 agonists may be a useful mechanism to induce pronounced glial activation in the CNS. PMID- 21811615 TI - Arginase 2 deletion reduces neuro-glial injury and improves retinal function in a model of retinopathy of prematurity. AB - BACKGROUND: Retinopathy of prematurity (ROP) is a major cause of vision impairment in low birth weight infants. While previous work has focused on defining the mechanisms of vascular injury leading to retinal neovascularization, recent studies show that neurons are also affected. This study was undertaken to determine the role of the mitochondrial arginine/ornithine regulating enzyme arginase 2 (A2) in retinal neuro-glial cell injury in the mouse model of ROP. METHODS AND FINDINGS: Studies were performed using wild type (WT) and A2 knockout (A2-/-) mice exposed to Oxygen Induced Retinopathy (OIR). Neuronal injury and apoptosis were assessed using immunohistochemistry, TUNEL (terminal deoxynucleotidyl transferase dUTP nick end) labeling and Western blotting. Electroretinography (ERG) was used to assess retinal function. Neuro-glial injury in WT ROP mice was evident by TUNEL labeling, retinal thinning, decreases in number of rod bipolar cells and glial cell activation as compared with room air controls. Significant reduction in numbers of TUNEL positive cells, inhibition of retinal thinning, preservation of the rod bipolar cells and prevention of glial activation were observed in the A2-/- retinas. Retinal function was markedly impaired in the WT OIR mice as shown by decreases in amplitude of the b-wave of the ERG. This defect was significantly reduced in A2-/- mice. Levels of the pro apoptotic proteins p53, cleaved caspase 9, cytochrome C and the mitochondrial protein Bim were markedly increased in WT OIR retinas compared to controls, whereas the pro-survival Mitochondrial protein BCL-xl was reduced. These alterations were largely blocked in the A2-/- OIR retina. CONCLUSIONS: Our data implicate A2 in neurodegeneration during ROP. Deletion of A2 significantly improves neuronal survival and function, possibly through the regulation of mitochondrial membrane permeability mediated apoptosis during retinal ischemia. These molecular events are associated with decreased activation of glial cells, suggesting a rescue effect on macroglia as well. PMID- 21811616 TI - Alba-domain proteins of Trypanosoma brucei are cytoplasmic RNA-binding proteins that interact with the translation machinery. AB - Trypanosoma brucei and related pathogens transcribe most genes as polycistronic arrays that are subsequently processed into monocistronic mRNAs. Expression is frequently regulated post-transcriptionally by cis-acting elements in the untranslated regions (UTRs). GPEET and EP procyclins are the major surface proteins of procyclic (insect midgut) forms of T. brucei. Three regulatory elements common to the 3' UTRs of both mRNAs regulate mRNA turnover and translation. The glycerol-responsive element (GRE) is unique to the GPEET 3' UTR and regulates its expression independently from EP. A synthetic RNA encompassing the GRE showed robust sequence-specific interactions with cytoplasmic proteins in electromobility shift assays. This, combined with column chromatography, led to the identification of 3 Alba-domain proteins. RNAi against Alba3 caused a growth phenotype and reduced the levels of Alba1 and Alba2 proteins, indicative of interactions between family members. Tandem-affinity purification and co immunoprecipitation verified these interactions and also identified Alba4 in sub stoichiometric amounts. Alba proteins are cytoplasmic and are recruited to starvation granules together with poly(A) RNA. Concomitant depletion of all four Alba proteins by RNAi specifically reduced translation of a reporter transcript flanked by the GPEET 3' UTR. Pulldown of tagged Alba proteins confirmed interactions with poly(A) binding proteins, ribosomal protein P0 and, in the case of Alba3, the cap-binding protein eIF4E4. In addition, Alba2 and Alba3 partially cosediment with polyribosomes in sucrose gradients. Alba-domain proteins seem to have exhibited great functional plasticity in the course of evolution. First identified as DNA-binding proteins in Archaea, then in association with nuclear RNase MRP/P in yeast and mammalian cells, they were recently described as components of a translationally silent complex containing stage-regulated mRNAs in Plasmodium. Our results are also consistent with stage-specific regulation of translation in trypanosomes, but most likely in the context of initiation. PMID- 21811617 TI - Gender differences and effect of air pollution on asthma in children with and without allergic predisposition: northeast Chinese children health study. AB - BACKGROUND: Males and females exhibit different health responses to air pollution, but little is known about how exposure to air pollution affects juvenile respiratory health after analysis stratified by allergic predisposition. The aim of the present study was to assess the relationship between air pollutants and asthmatic symptoms in Chinese children selected from multiple sites in a heavily industrialized province of China, and investigate whether allergic predisposition modifies this relationship. METHODOLOGY/PRINCIPAL FINDINGS: 30139 Chinese children aged 3-to-12 years were selected from 25 districts of seven cities in northeast China in 2009. Information on respiratory health was obtained using a standard questionnaire from the American Thoracic Society. Routine air-pollution monitoring data was used for particles with an aerodynamic diameter <=10 um (PM(10)), sulfur dioxide (SO(2)), nitrogen dioxides (NO(2)), ozone (O(3)) and carbon monoxide (CO). A two-stage regression approach was applied in data analyses. The effect estimates were presented as odds ratios (ORs) per interquartile changes for PM(10), SO(2), NO(2), O(3), and CO. The results showed that children with allergic predisposition were more susceptible to air pollutants than children without allergic predisposition. Amongst children without an allergic predisposition, air pollution effects on asthma were stronger in males compared to females; Current asthma prevalence was related to PM(10) (ORs = 1.36 per 31 ug/m(3); 95% CI, 1.08-1.72), SO(2) (ORs = 1.38 per 21 ug/m(3); 95%CI, 1.12-1.69) only among males. However, among children with allergic predisposition, more positively associations between air pollutants and respiratory symptoms and diseases were detected in females; An increased prevalence of doctor-diagnosed asthma was significantly associated with SO(2) (ORs = 1.48 per 21 ug/m(3); 95%CI, 1.21-1.80), NO(2) (ORs = 1.26 per 10 ug/m(3); 95%CI, 1.01-1.56), and current asthma with O(3) (ORs = 1.55 per 23 ug/m(3); 95%CI, 1.18-2.04) only among females. CONCLUSION/SIGNIFICANCE: Ambient air pollutions were more evident in males without an allergic predisposition and more associations were detected in females with allergic predisposition. PMID- 21811618 TI - A functional proteomic method for biomarker discovery. AB - The sequencing of the human genome holds out the hope for personalized medicine, but it is clear that analysis of DNA or RNA content alone is not sufficient to understand most disease processes. Proteomic strategies that allow unbiased identification of proteins and their post-transcriptional and -translation modifications are an essential complement to genomic strategies. However, the enormity of the proteome and limitations in proteomic methods make it difficult to determine the targets that are particularly relevant to human disease. Methods are therefore needed that allow rational identification of targets based on function and relevance to disease. Screening methodologies such as phage display, SELEX, and small-molecule combinatorial chemistry have been widely used to discover specific ligands for cells or tissues of interest, such as tumors. Those ligands can be used in turn as affinity probes to identify their cognate molecular targets when they are not known in advance. Here we report an easy, robust and generally applicable approach in which phage particles bearing cell- or tissue-specific peptides serve directly as the affinity probes for their molecular targets. For proof of principle, the method successfully identified molecular binding partners, three of them novel, for 15 peptides specific for pancreatic cancer. PMID- 21811619 TI - EphB6 receptor modulates micro RNA profile of breast carcinoma cells. AB - Breast carcinoma cells have a specific pattern of expression for Eph receptors and ephrin ligands. EphB6 has previously been characterized as a signature molecule for invasive breast carcinoma cells. The transcription of EphB6 is silenced in breast carcinoma cells and its re-expression leads to decreased invasiveness of MDA-MB-231 cells. Such differences in phenotypes of native and EphB6 expressing MDA-MB-231 cells relate to an altered profile of micro RNAs. Comparative hybridization of total RNA to slides containing all known miRNAs by using locked nucleic acid (LNA) miRCURY platform yielded a significantly altered profile of miRNAs in MDA-MB-231 cells stably transfected with EphB6. After applying a threshold of change and a p-value of <0.001, the list of significantly altered miRNAs included miR-16, miR-23a, miR-24, miR-26a, miR-29a, miR-100, miRPlus-E1172 and miRPlus-E1258. The array-based changes were validated by real time qPCR of miR-16, miR-23a, miR-24 and miR-100. Except miRPlus-E1172 and miRPlus-E1258, the remaining six miRNAs have been observed in a variety of cancers. The biological relevance of target mRNAs was predicted by using a common target selection approach that allowed the identification of SMARCA5, SMARCC1, eIF2C2, eIF2C4, eIF4EBP2, FKABP5, FKBP1A, TRIB1, TRIB2, TRIB3, BMPR2, BMPR1A and BMPR1B as important targets of a subset of significantly altered miRNAs. Quantitative PCR revealed that the levels of SMARCC1, eIFC4, eIF4EB2, FKBP1a, FKBP5, TRIB1, TRIB3, BMPR1a and BMPR2 transcripts were significantly decreased in MDA-MB-231 cells transfected with EphB6. These observations confirm targeting of specific mRNAs by miR-100, miR-23a, miR-16 and miR-24, and suggest that the kinase-deficient EphB6 receptor is capable of initiating signal transduction from the cell surface to the nucleus resulting in the altered expression of a variety of genes involved in tumorigenesis and invasion. The alterations in miRNAs and their target mRNAs also suggest indirect involvement of EphB6 in PI3K/Akt/mTOR pathways. PMID- 21811620 TI - Interferon production and signaling pathways are antagonized during henipavirus infection of fruit bat cell lines. AB - Bats are natural reservoirs for a spectrum of infectious zoonotic diseases including the recently emerged henipaviruses (Hendra and Nipah viruses). Henipaviruses have been observed both naturally and experimentally to cause serious and often fatal disease in many different mammal species, including humans. Interestingly, infection of the flying fox with henipaviruses occurs in the absence of clinical disease. The extreme variation in the disease pattern between humans and bats has led to an investigation into the effects of henipavirus infection on the innate immune response in bat cell lines. We report that henipavirus infection does not result in the induction of interferon expression, and the viruses also inhibit interferon signaling. We also confirm that the interferon production and signaling block in bat cells is not due to differing viral protein expression levels between human and bat hosts. This information, in addition to the known lack of clinical signs in bats following henipavirus infection, suggests that bats control henipavirus infection by an as yet unidentified mechanism, not via the interferon response. This is the first report of henipavirus infection in bat cells specifically investigating aspects of the innate immune system. PMID- 21811621 TI - Antibodies that induce phagocytosis of malaria infected erythrocytes: effect of HIV infection and correlation with clinical outcomes. AB - HIV infection increases the burden of disease of malaria in pregnancy, in part by impairing the development of immunity. We measured total IgG and phagocytic antibodies against variant surface antigens of placental-type CS2 parasites in 187 secundigravidae (65% HIV infected). In women with placental malaria infection, phagocytic antibodies to CS2(VSA) were decreased in the presence of HIV (p = 0.011) and correlated positively with infant birth weight (coef = 3.57, p = 0.025), whereas total IgG to CS2(VSA) did not. Phagocytic antibodies to CS2(VSA) are valuable tools to study acquired immunity to malaria in the context of HIV co-infection. Secundigravidae may be an informative group for identification of correlates of immunity. PMID- 21811622 TI - Comparison of LED and conventional fluorescence microscopy for detection of acid fast bacilli in a low-incidence setting. AB - INTRODUCTION: Light emitting diode fluorescence microscopes have many practical advantages over conventional mercury vapour fluorescence microscopes, which would make them the preferred choice for laboratories in both low- and high-resource settings, provided performance is equivalent. METHODS: In a nested case-control study, we compared diagnostic accuracy and time required to read slides with the Zeiss PrimoStar iLED, LW Scientific Lumin, and a conventional fluorescence microscope (Leica DMLS). Mycobacterial culture was used as the reference standard, and subgroup analysis by specimen source and organism isolated were performed. RESULTS: There was no difference in sensitivity or specificity between the three microscopes, and agreement was high for all comparisons and subgroups. The Lumin and the conventional fluorescence microscope were equivalent with respect to time required to read smears, but the Zeiss iLED was significantly time saving compared to both. CONCLUSIONS: Light emitting diode microscopy should be considered by all tuberculosis diagnostic laboratories, including those in high income countries, as a replacement for conventional fluorescence microscopes. Our findings provide support to the recent World Health Organization policy recommending that conventional fluorescence microscopy be replaced by light emitting diode microscopy using auramine staining in all settings where fluorescence microscopy is currently used. PMID- 21811623 TI - Distinct lineages of Schistocephalus parasites in threespine and ninespine stickleback hosts revealed by DNA sequence analysis. AB - Parasitic interactions are often part of complex networks of interspecific relationships that have evolved in biological communities. Despite many years of work on the evolution of parasitism, the likelihood that sister taxa of parasites can co-evolve with their hosts to specifically infect two related lineages, even when those hosts occur sympatrically, is still unclear. Furthermore, when these specific interactions occur, the molecular and physiological basis of this specificity is still largely unknown. The presence of these specific parasitic relationships can now be tested using molecular markers such as DNA sequence variation. Here we test for specific parasitic relationships in an emerging host parasite model, the stickleback-Schistocephalus system. Threespine and ninespine stickleback fish are intermediate hosts for Schistocephalus cestode parasites that are phenotypically very similar and have nearly identical life cycles through plankton, stickleback, and avian hosts. We analyzed over 2000 base pairs of COX1 and NADH1 mitochondrial DNA sequences in 48 Schistocephalus individuals collected from threespine and ninespine stickleback hosts from disparate geographic regions distributed across the Northern Hemisphere. Our data strongly support the presence of two distinct clades of Schistocephalus, each of which exclusively infects either threespine or ninespine stickleback. These clades most likely represent different species that diverged soon after the speciation of their stickleback hosts. In addition, genetic structuring exists among Schistocephalus taken from threespine stickleback hosts from Alaska, Oregon and Wales, although it is much less than the divergence between hosts. Our findings emphasize that biological communities may be even more complex than they first appear, and beg the question of what are the ecological, physiological, and genetic factors that maintain the specificity of the Schistocephalus parasites and their stickleback hosts. PMID- 21811624 TI - Sensitivity and specificity of medial temporal lobe visual ratings and multivariate regional MRI classification in Alzheimer's disease. AB - BACKGROUND: Visual assessment rating scales for medial temporal lobe (MTL) atrophy have been used by neuroradiologists in clinical practice to aid the diagnosis of Alzheimer's disease (AD). Recently multivariate classification methods for magnetic resonance imaging (MRI) data have been suggested as alternative tools. If computerized methods are to be implemented in clinical practice they need to be as good as, or better than experienced neuroradiologists and carefully validated. The aims of this study were: (1) To compare the ability of MTL atrophy visual assessment rating scales, a multivariate MRI classification method and manually measured hippocampal volumes to distinguish between subjects with AD and healthy elderly controls (CTL). (2) To assess how well the three techniques perform when predicting future conversion from mild cognitive impairment (MCI) to AD. METHODS: High resolution sagittal 3D T1w MP-RAGE datasets were acquired from 75 AD patients, 101 subjects with MCI and 81 CTL from the multi-centre AddNeuroMed study. An automated analysis method was used to generate regional volume and regional cortical thickness measures, providing 57 variables for multivariate analysis (orthogonal partial least squares to latent structures using seven-fold cross-validation). Manual hippocampal measurements were also determined for each subject. Visual rating assessment of MTL atrophy was performed by an experienced neuroradiologist according to the approach of Scheltens et al. RESULTS: We found prediction accuracies for distinguishing between AD and CTL of 83% for multivariate classification, 81% for the visual rating assessments and 89% for manual measurements of total hippocampal volume. The three different techniques showed similar accuracy in predicting conversion from MCI to AD at one year follow-up. CONCLUSION: Visual rating assessment of the MTL gave similar prediction accuracy to multivariate classification and manual hippocampal volumes. This suggests a potential future role for computerized methods as a complement to clinical assessment of AD. PMID- 21811625 TI - Evidence for the complexity of microRNA-mediated regulation in ovarian cancer: a systems approach. AB - MicroRNAs (miRNAs) are short (~22 nucleotides) regulatory RNAs that can modulate gene expression and are aberrantly expressed in many diseases including cancer. Previous studies have shown that miRNAs inhibit the translation and facilitate the degradation of their targeted messenger RNAs (mRNAs) making them attractive candidates for use in cancer therapy. However, the potential clinical utility of miRNAs in cancer therapy rests heavily upon our ability to understand and accurately predict the consequences of fluctuations in levels of miRNAs within the context of complex tumor cells. To evaluate the predictive power of current models, levels of miRNAs and their targeted mRNAs were measured in laser captured micro-dissected (LCM) ovarian cancer epithelial cells (CEPI) and compared with levels present in ovarian surface epithelial cells (OSE). We found that the predicted inverse correlation between changes in levels of miRNAs and levels of their mRNA targets held for only ~11% of predicted target mRNAs. We demonstrate that this low inverse correlation between changes in levels of miRNAs and their target mRNAs in vivo is not merely an artifact of inaccurate miRNA target predictions but the likely consequence of indirect cellular processes that modulate the regulatory effects of miRNAs in vivo. Our findings underscore the complexities of miRNA-mediated regulation in vivo and the necessity of understanding the basis of these complexities in cancer cells before the therapeutic potential of miRNAs can be fully realized. PMID- 21811626 TI - The effect of pulmonary artery catheter use on costs and long-term outcomes of acute lung injury. AB - BACKGROUND: The pulmonary artery catheter (PAC) remains widely used in acute lung injury (ALI) despite known complications and little evidence of improved short term mortality. Concurrent with NHLBI ARDS Clinical Trials Network Fluid and Catheters Treatment Trial (FACTT), we conducted a prospectively-defined comparison of healthcare costs and long-term outcomes for care with a PAC vs. central venous catheter (CVC). We explored if use of the PAC in ALI is justified by a beneficial cost-effectiveness profile. METHODS: We obtained detailed bills for the initial hospitalization. We interviewed survivors using the Health Utilities Index Mark 2 questionnaire at 2, 6, 9 and 12 m to determine quality of life (QOL) and post-discharge resource use. Outcomes beyond 12 m were estimated from federal databases. Incremental costs and outcomes were generated using MonteCarlo simulation. RESULTS: Of 1001 subjects enrolled in FACTT, 774 (86%) were eligible for long-term follow-up and 655 (85%) consented. Hospital costs were similar for the PAC and CVC groups ($96.8k vs. $89.2k, p = 0.38). Post discharge to 12 m costs were higher for PAC subjects ($61.1k vs. 45.4k, p = 0.03). One-year mortality and QOL among survivors were similar in PAC and CVC groups (mortality: 35.6% vs. 31.9%, p = 0.33; QOL [scale: 0-1]: 0.61 vs. 0.66, p = 0.49). MonteCarlo simulation showed PAC use had a 75.2% probability of being more expensive and less effective (mean cost increase of $14.4k and mean loss of 0.3 quality-adjusted life years (QALYs)) and a 94.2% probability of being higher than the $100k/QALY willingness-to-pay threshold. CONCLUSION: PAC use increased costs with no patient benefit and thus appears unjustified for routine use in ALI. TRIAL REGISTRATION: www.clinicaltrials.gov NCT00234767. PMID- 21811628 TI - A novel redox method for rapid production of functional bi-specific antibodies for use in early pilot studies. AB - We demonstrate here a rapid alternative method for the production of functional bi-specific antibodies using the mild reducing agent 2-mercaptoethanesulfonic acid sodium salt (MESNA). Following reduction of a mixture of two monoclonal antibodies with MESNA to break inter heavy chain bonds, this solution is dialysed under oxidising conditions and antibodies are allowed to reform. During this reaction a mixture of antibodies is formed, including parental antibodies and bi specific antibody. Bi-specific antibodies are purified over two sequential affinity columns. Following purification, bi-specificity of antibodies is determined in enzyme-linked immunosorbent assays and by flow cytometry. Using this redox method we have been successful in producing hybrid and same-species bi specific antibodies in a time frame of 6-10 working days, making this production method a time saving alternative to the time-consuming traditional heterohybridoma technology for the production of bi-specific antibodies for use in early pilot studies. The use of both rat and mouse IgG antibodies forming a rat/mouse bi-specific antibody as well as producing a pure mouse bi-specific antibody and a pure rat bi-specific antibody demonstrates the flexibility of this production method. PMID- 21811627 TI - Human apolipoprotein A-I-derived amyloid: its association with atherosclerosis. AB - Amyloidoses constitute a group of diseases in which soluble proteins aggregate and deposit extracellularly in tissues. Nonhereditary apolipoprotein A-I (apoA-I) amyloid is characterized by deposits of nonvariant protein in atherosclerotic arteries. Despite being common, little is known about the pathogenesis and significance of apoA-I deposition. In this work we investigated by fluorescence and biochemical approaches the impact of a cellular microenvironment associated with chronic inflammation on the folding and pro-amyloidogenic processing of apoA I. Results showed that mildly acidic pH promotes misfolding, aggregation, and increased binding of apoA-I to extracellular matrix elements, thus favoring protein deposition as amyloid like-complexes. In addition, activated neutrophils and oxidative/proteolytic cleavage of the protein give rise to pro amyloidogenic products. We conclude that, even though apoA-I is not inherently amyloidogenic, it may produce non hereditary amyloidosis as a consequence of the pro inflammatory microenvironment associated to atherogenesis. PMID- 21811629 TI - Sulindac sulfide reverses aberrant self-renewal of progenitor cells induced by the AML-associated fusion proteins PML/RARalpha and PLZF/RARalpha. AB - Chromosomal translocations can lead to the formation of chimeric genes encoding fusion proteins such as PML/RARalpha, PLZF/RARalpha, and AML-1/ETO, which are able to induce and maintain acute myeloid leukemia (AML). One key mechanism in leukemogenesis is increased self renewal of leukemic stem cells via aberrant activation of the Wnt signaling pathway. Either X-RAR, PML/RARalpha and PLZF/RARalpha or AML-1/ETO activate Wnt signaling by upregulating gamma-catenin and beta-catenin. In a prospective study, a lower risk of leukemia was observed with aspirin use, which is consistent with numerous studies reporting an inverse association of aspirin with other cancers. Furthermore, a reduction in leukemia risk was associated with use of non-steroidal anti-inflammatory drug (NSAID), where the effects on AML risk was FAB subtype-specific. To better investigate whether NSAID treatment is effective, we used Sulindac Sulfide in X-RARalpha positive progenitor cell models. Sulindac Sulfide (SSi) is a derivative of Sulindac, a NSAID known to inactivate Wnt signaling. We found that SSi downregulated both beta-catenin and gamma-catenin in X-RARalpha-expressing cells and reversed the leukemic phenotype by reducing stem cell capacity and increasing differentiation potential in X-RARalpha-positive HSCs. The data presented herein show that SSi inhibits the leukemic cell growth as well as hematopoietic progenitors cells (HPCs) expressing PML/RARalpha, and it indicates that Sulindac is a valid molecular therapeutic approach that should be further validated using in vivo leukemia models and in clinical settings. PMID- 21811630 TI - Axonal varicosity density as an index of local neuronal interactions. AB - Diffuse transmission is an important non-synaptic communication mode in the cerebral neocortex, in which neurotransmitters released from en passant varicosities interact with surrounding cells. In a previous study we have shown that the cholinergic axonal segments which were in the microproximity with dopaminergic fibers possessed a greater density of en passant varicosities compared to more distant segments, suggesting an activity-dependent level of en passant varicosities in the axonal zone of interaction. To further evaluate this plastic relationship, the density of cholinergic varicosities was quantified on fiber segments within the microproximity of activated or non-activated pyramidal cells of the prefrontal cortex (mPFC). Repetitive 14 days patterned visual stimulation paired with an electrical stimulation of the cholinergic fibers projecting to the mPFC from the HDB was performed to induce persistent axonal plastic changes. The c-Fos early gene immunoreactivity was used as a neuronal activity marker of layer V pyramidal cells, labelled with anti-glutamate transporter EAAC1. Cholinergic fibers were labeled with anti-ChAT (choline acetyltransferase) immunostaining. The density of ChAT+ varicosities on and the length of fiber segments within the 3 um microproximity of c-Fos positive/negative pyramidal cells were evaluated on confocal images. More than 50% of the pyramidal cells in the mPFC were c-Fos immunoreactive. Density of ChAT+ varicosities was significantly increased within 3 um vicinity of activated pyramidal cells (0.50+/-0.01 per um of ChAT+ fiber length) compared to non activated cells in this group (0.34+/-0.001; p<=0.05) or control rats (0.32+/ 0.02; p<=0.05). Different types of stimulation (visual, HDB or visual/HDB) induced similar increase of the density of ChAT+ varicosities within microproximity of activated pyramidal cells. This study demonstrated at the subcellular level an activity-dependent enrichment of ChAT+ varicosities in the axonal zone of interaction with other neuronal elements. PMID- 21811632 TI - Frequent use of paracetamol and risk of allergic disease among women in an Ethiopian population. AB - INTRODUCTION: The hypothesis that paracetamol might increase the risk of asthma and other allergic diseases have gained support from a range of independent studies. However, in studies based in developed countries, the possibility that paracetamol and asthma are associated through aspirin avoidance is difficult to exclude. OBJECTIVES: To explore this hypothesis among women in a developing country, where we have previously reported aspirin avoidance to be rare. METHODS: In 2005/6 a population based cohort of 1065 pregnant women was established in Butajira, Ethiopia and baseline demographic data collected. At 3 years post birth, an interview-based questionnaire administered to 945 (94%) of these women collected data on asthma, eczema, and hay fever in the past 12 month, frequency of paracetamol use and potential confounders. Allergen skin tests to Dermatophagoides pteronyssinus and cockroach were also performed. The independent effects of paracetamol use on allergic outcomes were determined using multiple logistic regression analysis. FINDINGS: The prevalence of asthma, eczema and hay fever was 1.7%, 0.9% and 3.8% respectively; of any one of these conditions 5.5%, and of allergen sensitization 7.8%. Paracetamol use in the past month was reported by 29%, and associations of borderline significance were seen for eczema (adjusted OR (95% CI) = 8.51 (1.68 to 43.19) for 1-3 tablets and 2.19 (0.36 to 13.38) for >=4 tablets, compared to no tablets in the past month; overall p = 0.055) and for 'any allergic condition' (adjusted OR (95% CI) = 2.73 (1.22 to 6.11) for 1-3 tablets and 1.35 (0.67 to 2.70) for >=4 tablets compared to 0 in the past month; overall p = 0.071). CONCLUSIONS: This study provides further cross-sectional evidence that paracetamol use increases the risk of allergic disease. PMID- 21811631 TI - Integrated expression profiling and genome-wide analysis of ChREBP targets reveals the dual role for ChREBP in glucose-regulated gene expression. AB - The carbohydrate response element binding protein (ChREBP), a basic helix-loop helix/leucine zipper transcription factor, plays a critical role in the control of lipogenesis in the liver. To identify the direct targets of ChREBP on a genome wide scale and provide more insight into the mechanism by which ChREBP regulates glucose-responsive gene expression, we performed chromatin immunoprecipitation sequencing and gene expression analysis. We identified 1153 ChREBP binding sites and 783 target genes using the chromatin from HepG2, a human hepatocellular carcinoma cell line. A motif search revealed a refined consensus sequence (CABGTG nnCnG-nGnSTG) to better represent critical elements of a functional ChREBP binding sequence. Gene ontology analysis shows that ChREBP target genes are particularly associated with lipid, fatty acid and steroid metabolism. In addition, other functional gene clusters related to transport, development and cell motility are significantly enriched. Gene set enrichment analysis reveals that ChREBP target genes are highly correlated with genes regulated by high glucose, providing a functional relevance to the genome-wide binding study. Furthermore, we have demonstrated that ChREBP may function as a transcriptional repressor as well as an activator. PMID- 21811633 TI - Multidimensional recording (MDR) and data sharing: an ecological open research and educational platform for neuroscience. AB - Primate neurophysiology has revealed various neural mechanisms at the single-cell level and population level. However, because recording techniques have not been updated for several decades, the types of experimental design that can be applied in the emerging field of social neuroscience are limited, in particular those involving interactions within a realistic social environment. To address these limitations and allow more freedom in experimental design to understand dynamic adaptive neural functions, multidimensional recording (MDR) was developed. MDR obtains behavioral, neural, eye position, and other biological data simultaneously by using integrated multiple recording systems. MDR gives a wide degree of freedom in experimental design because the level of behavioral restraint is adjustable depending on the experimental requirements while still maintaining the signal quality. The biggest advantage of MDR is that it can provide a stable neural signal at higher temporal resolution at the network level from multiple subjects for months, which no other method can provide. Conventional event-related analysis of MDR data shows results consistent with previous findings, whereas new methods of analysis can reveal network mechanisms that could not have been investigated previously. MDR data are now shared in the public server Neurotycho.org. These recording and sharing methods support an ecological system that is open to everyone and will be a valuable and powerful research/educational platform for understanding the dynamic mechanisms of neural networks. PMID- 21811634 TI - Tumor-associated macrophages (TAMs) form an interconnected cellular supportive network in anaplastic thyroid carcinoma. AB - BACKGROUND: A relationship between the increased density of tumor-associated macrophages (TAMs) and decreased survival was recently reported in thyroid cancer patients. Among these tumors, anaplastic thyroid cancer (ATC) is one of the most aggressive solid tumors in humans. TAMs (type M2) have been recognized as promoting tumor growth. The purpose of our study was to analyze with immunohistochemistry the presence of TAMs in a series of 27 ATC. METHODOLOGY/PRINCIPAL FINDINGS: Several macrophages markers such as NADPH oxidase complex NOX2-p22phox, CD163 and CD 68 were used. Immunostainings showed that TAMs represent more than 50% of nucleated cells in all ATCs. Moreover, these markers allowed the identification of elongated thin ramified cytoplasmic extensions, bestowing a "microglia-like" appearance on these cells which we termed "Ramified TAMs" (RTAMs). In contrast, cancer cells were totally negative. Cellular stroma was highly simplified since apart from cancer cells and blood vessels, RTAMs were the only other cellular component. RTAMs were evenly distributed and intermingled with cancer cells, and were in direct contact with other RTAMs via their ramifications. Moreover, RTAMs displayed strong immunostaining for connexin Cx43. Long chains of interconnected RTAMs arose from perivascular clusters and were dispersed within the tumor parenchyma. When expressed, the glucose transporter Glut1 was found in RTAMs and blood vessels, but rarely in cancer cells. CONCLUSION: ATCs display a very dense network of interconnected RTAMs in direct contact with intermingled cancer cells. To our knowledge this is the first time that such a network is described in a malignant tumor. This network was found in all our studied cases and appeared specific to ATC, since it was not found in differentiated thyroid cancers specimens. Taken together, these results suggest that RTAMs network is directly related to the aggressiveness of the disease via metabolic and trophic functions which remain to be determined. PMID- 21811635 TI - Adipose tissue fatty acid patterns and changes in anthropometry: a cohort study. AB - INTRODUCTION: Diets rich in n-3 long chain polyunsaturated fatty acids (LC-PUFA), but low in n-6 LC-PUFA and 18:1 trans-fatty acids (TFA), may lower the risk of overweight and obesity. These fatty acids have often been investigated individually. We explored associations between global patterns in adipose tissue fatty acids and changes in anthropometry. METHODS: 34 fatty acid species from adipose tissue biopsies were determined in a random sample of 1100 men and women from a Danish cohort study. We used sex-specific principal component analysis and multiple linear regression to investigate the associations of adipose tissue fatty acid patterns with changes in weight, waist circumference (WC), and WC controlled for changes in body mass index (WC(BMI)), adjusting for confounders. RESULTS: 7 principal components were extracted for each sex, explaining 77.6% and 78.3% of fatty acid variation in men and women, respectively. Fatty acid patterns with high levels of TFA tended to be positively associated with changes in weight and WC for both sexes. Patterns with high levels of n-6 LC-PUFA tended to be negatively associated with changes in weight and WC in men, and positively associated in women. Associations with patterns with high levels of n-3 LC-PUFA were dependent on the context of the rest of the fatty acid pattern. CONCLUSIONS: Adipose tissue fatty acid patterns with high levels of TFA may be linked to weight gain, but patterns with high n-3 LC-PUFA did not appear to be linked to weight loss. Associations depended on characteristics of the rest of the pattern. PMID- 21811637 TI - Food-web structure of seagrass communities across different spatial scales and human impacts. AB - Seagrass beds provide important habitat for a wide range of marine species but are threatened by multiple human impacts in coastal waters. Although seagrass communities have been well-studied in the field, a quantification of their food web structure and functioning, and how these change across space and human impacts has been lacking. Motivated by extensive field surveys and literature information, we analyzed the structural features of food webs associated with Zostera marina across 16 study sites in 3 provinces in Atlantic Canada. Our goals were to (i) quantify differences in food-web structure across local and regional scales and human impacts, (ii) assess the robustness of seagrass webs to simulated species loss, and (iii) compare food-web structure in temperate Atlantic seagrass beds with those of other aquatic ecosystems. We constructed individual food webs for each study site and cumulative webs for each province and the entire region based on presence/absence of species, and calculated 16 structural properties for each web. Our results indicate that food-web structure was similar among low impact sites across regions. With increasing human impacts associated with eutrophication, however, food-web structure show evidence of degradation as indicated by fewer trophic groups, lower maximum trophic level of the highest top predator, fewer trophic links connecting top to basal species, higher fractions of herbivores and intermediate consumers, and higher number of prey per species. These structural changes translate into functional changes with impacted sites being less robust to simulated species loss. Temperate Atlantic seagrass webs are similar to a tropical seagrass web, yet differed from other aquatic webs, suggesting consistent food-web characteristics across seagrass ecosystems in different regions. Our study illustrates that food-web structure and functioning of seagrass habitats change with human impacts and that the spatial scale of food-web analysis is critical for determining results. PMID- 21811636 TI - Acute Vhl gene inactivation induces cardiac HIF-dependent erythropoietin gene expression. AB - Von Hippel Lindau (Vhl) gene inactivation results in embryonic lethality. The consequences of its inactivation in adult mice, and of the ensuing activation of the hypoxia-inducible factors (HIFs), have been explored mainly in a tissue specific manner. This mid-gestation lethality can be also circumvented by using a floxed Vhl allele in combination with an ubiquitous tamoxifen-inducible recombinase Cre-ER(T2). Here, we characterize a widespread reduction in Vhl gene expression in Vhl(floxed)-UBC-Cre-ER(T2) adult mice after dietary tamoxifen administration, a convenient route of administration that has yet to be fully characterized for global gene inactivation. Vhl gene inactivation rapidly resulted in a marked splenomegaly and skin erythema, accompanied by renal and hepatic induction of the erythropoietin (Epo) gene, indicative of the in vivo activation of the oxygen sensing HIF pathway. We show that acute Vhl gene inactivation also induced Epo gene expression in the heart, revealing cardiac tissue to be an extra-renal source of EPO. Indeed, primary cardiomyocytes and HL 1 cardiac cells both induce Epo gene expression when exposed to low O(2) tension in a HIF-dependent manner. Thus, as well as demonstrating the potential of dietary tamoxifen administration for gene inactivation studies in UBC-Cre-ER(T2) mouse lines, this data provides evidence of a cardiac oxygen-sensing VHL/HIF/EPO pathway in adult mice. PMID- 21811638 TI - Neurophysiological correlates of laboratory-induced aggression in young men with and without a history of violence. AB - In order to further understand the mechanisms involved in planning an aggressive act, we conducted an event-related potential (ERP) study of young men with and without a history of violence. Participants completed a competitive reaction time task (based on the Taylor aggression paradigm) against a virtual opponent. In "passive" blocks, participants were punished by the opponent when losing the trial but could not punish, when winning, whereas in "active" blocks, participants were able to punish the opponent when winning, but were not punished when losing. Participants selected punishment strength in a decision phase prior to each reaction time task and were informed whether they had won or lost in the outcome phase. Additionally, a flanker task was conducted to assess basic performance monitoring. Violent participants selected stronger punishments, especially in "active" blocks. During the decision phase, a frontal P200 was more pronounced for violent participants, whereas non-violent participants showed an enhanced frontal negativity around 300 ms. The P200 might reflect the decision to approach the opponent at a very early state, the latter negativity could reflect inhibition processes, leading to a more considerate reaction in non-violent participants. During the outcome phase, a Feedback-Related Negativity was seen in both groups. This effect was most pronounced when losing entailed a subsequent inability to retaliate. The groups did not differ in the flanker task, indicating intact basic performance monitoring. Our data suggest that the planning of an aggressive act is associated with distinct brain activity and that such activity is differentially represented in violent and non-violent individuals. PMID- 21811639 TI - Turtle functions downstream of Cut in differentially regulating class specific dendrite morphogenesis in Drosophila. AB - BACKGROUND: Dendritic morphology largely determines patterns of synaptic connectivity and electrochemical properties of a neuron. Neurons display a myriad diversity of dendritic geometries which serve as a basis for functional classification. Several types of molecules have recently been identified which regulate dendrite morphology by acting at the levels of transcriptional regulation, direct interactions with the cytoskeleton and organelles, and cell surface interactions. Although there has been substantial progress in understanding the molecular mechanisms of dendrite morphogenesis, the specification of class-specific dendritic arbors remains largely unexplained. Furthermore, the presence of numerous regulators suggests that they must work in concert. However, presently, few genetic pathways regulating dendrite development have been defined. METHODOLOGY/PRINCIPAL FINDINGS: The Drosophila gene turtle belongs to an evolutionarily conserved class of immunoglobulin superfamily members found in the nervous systems of diverse organisms. We demonstrate that Turtle is differentially expressed in Drosophila da neurons. Moreover, MARCM analyses reveal Turtle acts cell autonomously to exert class specific effects on dendritic growth and/or branching in da neuron subclasses. Using transgenic overexpression of different Turtle isoforms, we find context-dependent, isoform specific effects on mediating dendritic branching in class II, III and IV da neurons. Finally, we demonstrate via chromatin immunoprecipitation, qPCR, and immunohistochemistry analyses that Turtle expression is positively regulated by the Cut homeodomain transcription factor and via genetic interaction studies that Turtle is downstream effector of Cut-mediated regulation of da neuron dendrite morphology. CONCLUSIONS/SIGNIFICANCE: Our findings reveal that Turtle proteins differentially regulate the acquisition of class-specific dendrite morphologies. In addition, we have established a transcriptional regulatory interaction between Cut and Turtle, representing a novel pathway for mediating class specific dendrite development. PMID- 21811640 TI - Disrupted lymph node and splenic stroma in mice with induced inflammatory melanomas is associated with impaired recruitment of T and dendritic cells. AB - Migration of dendritic cells (DC) from the tumor environment to the T cell cortex in tumor-draining lymph nodes (TDLN) is essential for priming naive T lymphocytes (TL) to tumor antigen (Ag). We used a mouse model of induced melanoma in which similar oncogenic events generate two phenotypically distinct melanomas to study the influence of tumor-associated inflammation on secondary lymphoid organ (SLO) organization. One tumor promotes inflammatory cytokines, leading to mobilization of immature myeloid cells (iMC) to the tumor and SLO; the other does not. We report that inflammatory tumors induced alterations of the stromal cell network of SLO, profoundly altering the distribution of TL and the capacity of skin derived DC and TL to migrate or home to TDLN. These defects, which did not require tumor invasion, correlated with loss of fibroblastic reticular cells in T cell zones and in impaired production of CCL21. Infiltrating iMC accumulated in the TDLN medulla and the splenic red pulp. We propose that impaired function of the stromal cell network during chronic inflammation induced by some tumors renders spleens non-receptive to TL and TDLN non-receptive to TL and migratory DC, while the entry of iMC into these perturbed SLO is enhanced. This could constitute a mechanism by which inflammatory tumors escape immune control. If our results apply to inflammatory tumors in general, the demonstration that SLO are poorly receptive to CCR7-dependent migration of skin-derived DC and naive TL may constitute an obstacle for proposed vaccination or adoptive TL therapies of their hosts. PMID- 21811641 TI - Laboratory confirmation of Buruli ulcer disease in Togo, 2007-2010. AB - BACKGROUND: Since the early 1990s more than 1,800 patients with lesions suspicious for Buruli ulcer disease (BUD) have been reported from Togo. However, less than five percent of these were laboratory confirmed. Since 2007, the Togolese National Buruli Ulcer Control Program has been supported by the German Leprosy and Tuberculosis Relief Association (DAHW). Collaboration with the Department for Infectious Diseases and Tropical Medicine (DITM), University Hospital, Munich, Germany, allowed IS2404 PCR analysis of diagnostic samples from patients with suspected BUD during a study period of three years. METHODOLOGY/PRINCIPAL FINDINGS: The DAHW integrated active BUD case finding in the existing network of TB/Leprosy Controllers and organized regular training and outreach activities to identify BUD cases at community level. Clinically suspected cases were referred to health facilities for diagnosis and treatment. Microscopy was carried out locally, external quality assurance (EQA) at DITM. Diagnostic samples from 202 patients with suspected BUD were shipped to DITM, 109 BUD patients (54%) were confirmed by PCR, 43 (29.9%) by microscopy. All patients originated from Maritime Region. EQA for microscopy resulted in 62% concordant results. CONCLUSIONS/SIGNIFICANCE: This study presents a retrospective analysis of the first cohort of clinically suspected BUD cases from Togo subjected to systematic laboratory analysis over a period of three years and confirms the prevalence of BUD in Maritime Region. Intensified training in the field of case finding and sample collection increased the PCR case confirmation rate from initially less than 50% to 70%. With a PCR case confirmation rate of 54% for the entire study period the WHO standards (case confirmation rate >=50%) have been met. EQA for microscopy suggests the need for intensified supervision and training. In January 2011 the National Hygiene Institute, Lome, has assumed the role of a National Reference Laboratory for PCR confirmation and microscopy. PMID- 21811642 TI - Mycolactone diffuses into the peripheral blood of Buruli ulcer patients- implications for diagnosis and disease monitoring. AB - BACKGROUND: Mycobacterium ulcerans, the causative agent of Buruli ulcer (BU), is unique among human pathogens in its capacity to produce a polyketide-derived macrolide called mycolactone, making this molecule an attractive candidate target for diagnosis and disease monitoring. Whether mycolactone diffuses from ulcerated lesions in clinically accessible samples and is modulated by antibiotic therapy remained to be established. METHODOLOGY/PRINCIPAL FINDING: Peripheral blood and ulcer exudates were sampled from patients at various stages of antibiotic therapy in Ghana and Ivory Coast. Total lipids were extracted from serum, white cell pellets and ulcer exudates with organic solvents. The presence of mycolactone in these extracts was then analyzed by a recently published, field-friendly method using thin layer chromatography and fluorescence detection. This approach did not allow us to detect mycolactone accurately, because of a high background due to co extracted human lipids. We thus used a previously established approach based on high performance liquid chromatography coupled to mass spectrometry. By this means, we could identify structurally intact mycolactone in ulcer exudates and serum of patients, and evaluate the impact of antibiotic treatment on the concentration of mycolactone. CONCLUSIONS/SIGNIFICANCE: Our study provides the proof of concept that assays based on mycolactone detection in serum and ulcer exudates can form the basis of BU diagnostic tests. However, the identification of mycolactone required a technology that is not compatible with field conditions and point-of-care assays for mycolactone detection remain to be worked out. Notably, we found mycolactone in ulcer exudates harvested at the end of antibiotic therapy, suggesting that the toxin is eliminated by BU patients at a slow rate. Our results also indicated that mycolactone titres in the serum may reflect a positive response to antibiotics, a possibility that it will be interesting to examine further through longitudinal studies. PMID- 21811644 TI - Lymphatic filariasis: a method to identify subclinical lower limb change in PNG adolescents. AB - Lymphedema related to lymphatic filariasis (LF) is a disabling condition that commonly manifests in adolescence. Fifty-three adolescents, 25 LF infected and 28 LF non-infected, in age and sex-matched groups, using the Binax ICT rapid card test for filarial antigen were recruited to the study. None of the participants had overt signs of lymphedema. Lymphedema assessment measures were used to assess lower limb tissue compressibility (tonometry), limb circumference (tape measure), intra- and extra-cellular fluid distribution (bioimpedance) and joint range of motion (goniometry). The mean tonometric measurements from the left, right, and dominant posterior thighs were significantly larger in participants with LF compared to participants who had tested negative for LF (p = 0.005, p = 0.004, and p = 0.003, respectively) indicating increased tissue compressibility in those adolescents with LF. ROC curve analysis to define optimal cut-off of the tonometry measurements indicated that at 3.5, sensitivity of this potential screening test is 100% (95%-CI = 86.3%, 100%) and specificity is 21.4% (95%-CI = 8.3%, 41.0%). It is proposed that this cut-off can be used to indicate tissue change characteristic of LF in an at-risk population of PNG adolescents. Further longitudinal research is required to establish if all those with tissue change subsequently develop lymphedema. However, thigh tonometry to identify early tissue change in LF positive adolescents may enable early intervention to minimize progression of lymphedema and prioritization of limited resources to those at greatest risk of developing lifetime morbidity. PMID- 21811643 TI - Effect of schistosomiasis and soil-transmitted helminth infections on physical fitness of school children in Cote d'Ivoire. AB - BACKGROUND: Schistosomiasis and soil-transmitted helminthiasis are important public health problems in sub-Saharan Africa causing malnutrition, anemia, and retardation of physical and cognitive development. However, the effect of these diseases on physical fitness remains to be determined. METHODOLOGY: We investigated the relationship between schistosomiasis, soil-transmitted helminthiasis and physical performance of children, controlling for potential confounding of Plasmodium spp. infections and environmental parameters (i.e., ambient air temperature and humidity). A cross-sectional survey was carried out among 156 school children aged 7-15 years from Cote d'Ivoire. Each child had two stool and two urine samples examined for helminth eggs by microscopy. Additionally, children underwent a clinical examination, were tested for Plasmodium spp. infection with a rapid diagnostic test, and performed a maximal multistage 20 m shuttle run test to assess their maximal oxygen uptake (VO(2) max) as a proxy for physical fitness. PRINCIPAL FINDINGS: The prevalence of Schistosoma haematobium, Plasmodium spp., Schistosoma mansoni, hookworm and Ascaris lumbricoides infections was 85.3%, 71.2%, 53.8%, 13.5% and 1.3%, respectively. Children with single, dual, triple, quadruple and quintuple species infections showed VO(2) max of 52.7, 53.1, 52.2, 52.6 and 55.6 ml kg(-1) min(-1), respectively. The VO(2) max of children with no parasite infections was 53.5 ml kg(-1) min(-1). No statistically significant difference was detected between any groups. Multivariable analysis revealed that VO(2) max was influenced by sex (reference: female, coef. = 4.02, p<0.001) and age (years, coef. = -1.23, p<0.001), but not by helminth infection and intensity, Plasmodium spp. infection, and environmental parameters. CONCLUSION/SIGNIFICANCE: School-aged children in Cote d'Ivoire showed good physical fitness, irrespective of their helminth infection status. Future studies on children's physical fitness in settings where helminthiasis and malaria co-exist should include pre- and post-intervention evaluations and the measurement of hemoglobin and hematocrit levels and nutritional parameters as potential co-factors to determine whether interventions further improve upon fitness. PMID- 21811645 TI - Clinical and virological factors influencing the performance of a NS1 antigen capture assay and potential use as a marker of dengue disease severity. AB - BACKGROUND: Detection of dengue NS1 antigen in acute infection has been proposed for early diagnosis of dengue disease. The aim of this study was to evaluate the clinical and virological factors influencing the performance of the Platelia NS1 Ag kit (BioRad) and to assess the potential use of NS1 antigen and dengue viral loads as markers of dengue disease severity. METHODOLOGY/PRINCIPAL FINDINGS: Blood specimens were collected from patients hospitalized at the Kampong Cham hospital during the 2006 and 2007 dengue epidemics in Cambodia. Dengue infection was confirmed in 243/339 symptomatic patients and in 17 asymptomatic individuals out of 214 household members tested. Overall sensitivity and specificity of Platelia NS1 Ag kit were 57.5% and 100% respectively. NS1 Ag assay combined with IgM antibody capture ELISA significantly increased the sensitivity for dengue diagnosis. NS1 Ag positivity rate was found significantly higher in DF than in DHF/DSS, in primary than in secondary infections, in patients with a high viremia (>5 log/mL) and in patients infected with DENV-1. In asymptomatic individuals, the NS1 Ag capture sensitivity tends to be lower than that in symptomatic patients. Milder disease severity was observed independently in patients with RNA copy number >5 log10 cDNA equivalents/mL or in high level of NS1 antigen ratio or in DENV-1 infection. CONCLUSIONS: Overall sensitivity of NS1 Ag detection kit varied widely across the various forms of dengue infection or disease. Sensitivity was highest in patients sampled during the first 3 days after onset of fever, in patients with primary infection, DENV-1 infection, with high level of viremia and in DF rather than DHF/DSS. In asymptomatic patients, RT-PCR assay has proved to be more sensitive than NS1 antigen detection. The NS1 antigen level correlated significantly with viremia and a low NS1 antigen ratio was associated with more severe disease. PMID- 21811646 TI - Emergence of a globally dominant IncHI1 plasmid type associated with multiple drug resistant typhoid. AB - Typhoid fever, caused by Salmonella enterica serovar Typhi (S. Typhi), remains a serious global health concern. Since their emergence in the mid-1970s multi-drug resistant (MDR) S. Typhi now dominate drug sensitive equivalents in many regions. MDR in S. Typhi is almost exclusively conferred by self-transmissible IncHI1 plasmids carrying a suite of antimicrobial resistance genes. We identified over 300 single nucleotide polymorphisms (SNPs) within conserved regions of the IncHI1 plasmid, and genotyped both plasmid and chromosomal SNPs in over 450 S. Typhi dating back to 1958. Prior to 1995, a variety of IncHI1 plasmid types were detected in distinct S. Typhi haplotypes. Highly similar plasmids were detected in co-circulating S. Typhi haplotypes, indicative of plasmid transfer. In contrast, from 1995 onwards, 98% of MDR S. Typhi were plasmid sequence type 6 (PST6) and S. Typhi haplotype H58, indicating recent global spread of a dominant MDR clone. To investigate whether PST6 conferred a selective advantage compared to other IncHI1 plasmids, we used a phenotyping array to compare the impact of IncHI1 PST6 and PST1 plasmids in a common S. Typhi host. The PST6 plasmid conferred the ability to grow in high salt medium (4.7% NaCl), which we demonstrate is due to the presence in PST6 of the Tn6062 transposon encoding BetU. PMID- 21811647 TI - Multi-locus sequence analysis reveals profound genetic diversity among isolates of the human pathogen Bartonella bacilliformis. AB - Bartonella bacilliformis is the aetiological agent of human bartonellosis, a potentially life threatening infection of significant public health concern in the Andean region of South America. Human bartonellosis has long been recognised in the region but a recent upsurge in the number of cases of the disease and an apparent expansion of its geographical distribution have re-emphasized its contemporary medical importance. Here, we describe the development of a multi locus sequence typing (MLST) scheme for B. bacilliformis and its application to an archive of 43 isolates collected from patients across Peru. MLST identified eight sequence types among these isolates and the delineation of these was generally congruent with those of the previously described typing scheme. Phylogenetic analysis based on concatenated sequence data derived from MLST loci revealed that seven of the eight sequence types were closely related to one another; however, one sequence type, ST8, exhibited profound evolutionary divergence from the others. The extent of this divergence was akin to that observed between other members of the Bartonella genus, suggesting that ST8 strains may be better considered as members of a novel Bartonella genospecies. PMID- 21811648 TI - A screen against Leishmania intracellular amastigotes: comparison to a promastigote screen and identification of a host cell-specific hit. AB - The ability to screen compounds in a high-throughput manner is essential in the process of small molecule drug discovery. Critical to the success of screening strategies is the proper design of the assay, often implying a compromise between ease/speed and a biologically relevant setting. Leishmaniasis is a major neglected disease with limited therapeutic options. In order to streamline efforts for the design of productive drug screens against Leishmania, we compared the efficiency of two screening methods, one targeting the free living and easily cultured promastigote (insect-infective) stage, the other targeting the clinically relevant but more difficult to culture intra-macrophage amastigote (mammal-infective) stage. Screening of a 909-member library of bioactive compounds against Leishmania donovani revealed 59 hits in the promastigote primary screen and 27 in the intracellular amastigote screen, with 26 hits shared by both screens. This suggested that screening against the promastigote stage, although more suitable for automation, fails to identify all active compounds and leads to numerous false positive hits. Of particular interest was the identification of one compound specific to the infective amastigote stage of the parasite. This compound affects intracellular but not axenic parasites, suggesting a host cell-dependent mechanism of action, opening new avenues for anti-leishmanial chemotherapy. PMID- 21811649 TI - CFH, VEGF, and PEDF genotypes and the response to intravitreous injection of bevacizumab for the treatment of age-related macular degeneration. AB - We determined whether there is an association between complement factor H (CFH), high-temperature requirement A-1 (HTRA1), vascular endothelial growth factor (VEGF), and pigment epithelium-derived factor (PEDF) genotypes and the response to treatment with a single intravitreous injection of bevacizumab for age-related macular degeneration (AMD). Eighty-three patients with exudative AMD treated by bevacizumab injection were genotyped for three single nucleotide polymorphisms (SNPs; rs800292, rs1061170, rs1410996) in the CFH gene, a rs11200638-SNP in the HTRA1 gene, three SNPs (rs699947, rs1570360, rs2010963) in the VEGF gene, and four SNPs (rs12150053, rs12948385, rs9913583, rs1136287) in the PEDF gene using a TaqMan assay. The CT genotype (heterozygous) of CFH-rs1061170 was more frequently represented in nonresponders in vision than TT genotypes (nonrisk allele homozygous) at the time points of 1 and 3 months, while there was no CC genotype (risk allele homozygous) in our study cohort (p = 7.66 * 10(-3), 7.83 * 10(-3), respectively). VEGF-rs699947 was also associated with vision changes at 1 month and PEDF-rs1136287 at 3 months (p = 5.11 * 10(-3), 2.05 * 10(-2), respectively). These variants may be utilized for genetic biomarkers to estimate visual outcomes in the response to intravitreal bevacizumab treatment for AMD. PMID- 21811650 TI - Can we slow down the global increase of adiposity? PMID- 21811651 TI - Determinants of health disparities: the perennial struggle against polio in Nigeria. AB - Polio remains a global public health issue, and even though it has been eradicated from most countries of the world, countries like Nigeria, the largest black nation on earth, threatens the dream of total eradication of polio from the surface of the earth. Transmission of wild polio virus has never been eliminated in Nigeria, but even worse is the number of countries, both in Sub-Saharan Africa and all over the world that has become re-infected by polio virus strains from Northern Nigeria in recent past. Although a lot has been documented about the Nigerian polio struggle, one aspect that has received little attention on this issue is ethnic and geographic disparities between the Southern and the Northern parts of Nigeria. Understanding these disparities involved in polio virus transmission in Nigeria, as well as the social determinants of health prevalent in Northern Nigeria will help government and other stakeholders and policy makers to synergize their efforts in the fight against this perennial scourge. PMID- 21811652 TI - Construction of national standards of weight and height and growth charts of Iranian children: a review article. AB - OBJECTIVES: Growth charts are the most important evaluation tools for the assessment of growth and development of children which could be further used to develop preventive interventions. This study was undertaken with the aim of reviewing different current growth curves, their advantages and disadvantages, and performing a review of the studies conducted in Iran and other countries on determination of weight and height standards. METHODS: In order to collect materials for this review, a detailed search of Scientific Information Database (SID), Iran Medex, MEDLINE, PubMed, and Web of Science was carried out for the time period 2005-2010. RESULTS: The results of performed studies in European and Asian countries showed that the height and weight curves of these children were different from WHO and NCHS growth standards. The finding of growth trend study of Iranian children showed that the mean height and weight of girls and boys were increased. In spite of these increases, the median height and weight of Iranian girls and boys under 15 years was under 20(th) percentile of the United States National Center for the Health Statistics. CONCLUSIONS: Considering the epidemiological changes and existing genetic differences and different children's weight and height growth patterns, it seems that the global standard for the children's growth, including the WHO standards, are not applicable to all the populations and each country should construct a separate national standard. PMID- 21811653 TI - Hospital acquired antibiotic-resistant acinetobacter baumannii infections in a 400-bed hospital in Tehran, Iran. AB - OBJECTIVES: Acinetobacter baumannii is an omnipresent pathogen known as a major agent in healthcare and nosocomoal-associated infections. Its ability to develop resistant pattern to the major and broad spectrum antibiotics is an important issue to be studied. METHODS: In this study, 101 strains of Acinetobacter baumannii were isolated from the hospitalized patients during July 2007 to June 2009 in one teaching hospital in the southern Tehran. The identification of Acinetobacter baumannii and resistant pattern was performed by using conventional bacteriological methods and Clinical Laboratory and Standards Institute (CLSI). RESULTS: Respiratory tract specimens were the most common place of Acinetobacter isolation. The organism was resistant to ceftazidime (96%), ceftizoxime (95%), ceftriaxone (93%), amikacin (58%), gentamicin (68%), co-terimoxazole (85%), and ciprofloxacin (85%). This pattern also pointed that imipenem had the lowest resistance rate (9%). CONCLUSIONS: Susceptibility rates of Acinetobacter baumannii isolates to third-generation cephalosporins, fluoroquinolones, amikacin, gentamicin, and trimethoprim/sulfamethoxazole (SXT) were very low and the rate of resistant Acinetobacter baumannii to imipenem was significant. It would be a good idea to consider surveillance of antibiotic usage and restriction of using broad spectrum antibiotics before development of resistance to these agents. PMID- 21811654 TI - Factors affecting survival of women diagnosed with breast cancer in El-Minia Governorate, Egypt. AB - OBJECTIVES: This study was conducted to determine breast cancer survival time and the association between breast cancer survival and socio-demographic and pathologic factors among women, in El-Minia, Egypt. While there has been much researches regarding prognostic factors for breast cancer but the majority of these studies were from developed countries. El-Minia has a population of approximately 4 million. To date, no research has been performed to determine breast cancer survival and the factors affecting it in El-minia. METHODS: This retrospective study used data obtained from the cancer registry in the National Institute of Oncology in El-Minia and included 1207 women diagnosed with first primary breast cancer between 1(st) January 2005 and 31(st) December 2009 and followed to 30(th) June 2010. The association between survival and sociodemographic and pathological factors and distant metastasis at diagnosis, and treatment options was investigated using unifactorial chi-square test and multi-factorial (Cox regression) analyses. Kaplan-Meier analysis was used to compare survival time among different groups. RESULTS: Median survival time was 83.8 +/- 3.2. Cox regression showed that high vs low educational level (Hazard ratio (HR)= 0.35, 95% CI; 0.27-0.46), metastases to bone (HR = 3.22, 95% CI: 1.71 6.05), metastases to lung (HR= 2.314, 95% CI: 1.225-4.373), tumor size (<= 2 cm vs >= 5 cm: HR = 1.4, 95% CI: 1.1-1.8) and number of involved nodes (1 vs > 10 HR = 5.21, 95%CI: 3.1-9.01) were significantly related to survival. CONCLUSIONS: The results showed the need to develop screening programs and standardized treatment regimens in a tax-funded health care system. PMID- 21811655 TI - Comparison of the knowledge, attitude and practice of Iranian college students about tobacco use in comparison to their American and Chinese counterparts. AB - OBJECTIVES: The purpose of this survey was to compare the knowledge, attitude and practice of Iranian, American and Chinese college students about tobacco use. METHODS: In this cross-sectional study, a questionnaire that was designed for the first time in comparative studies for the purpose of gathering information from American and Chinese college students was used. The students were selected by convenience sampling. RESULTS: In Iran, 958 participants (456 male and 485 female) enrolled in the study. In addition, 1534 Chinese participants (39.7% female and 60.3% male) and 597 American participants (62.1% female and 37.9% male) were included in the study. Comparing the consumption of tobacco among college students of the three mentioned countries, it is shown that American women have more experiences in smoking cigarettes, cigars, pipes and chewing tobacco. CONCLUSIONS: This survey determined the tendency toward smoking among the students and their perception of this behavior and its outcome among the students from Iran, USA and China. It provided significant differences, however the culture dissimilarities in responding to such type of surveys should be taken into account. PMID- 21811656 TI - Effects of exercise in polluted air on the aerobic power, serum lactate level and cell blood count of active individuals. AB - OBJECTIVES: The purpose of this study was to assess the effects of exercise on the aerobic power, serum lactate level, and cell blood count among active individuals in the environments with similar climatic characteristics differing in their level of air pollution. METHODS: This trial comprised 20 volunteer students of Physical education in The University of Isfahan, Iran. Two places with the same climate (altitude, temperature, and humidity), but low and high level of air pollutants air were selected in Isfahan, Iran. Participants underwent a field Cooper test with a 12-minute run for fitness assessment. Then the aerobic power, serum lactate, and cell blood counts were measured and compared between the two areas. RESULTS: The study participants had a mean (SD) age of 21.70 (2.10) years and body mass index (BMI) of 24.44 (2.32) Kg/m2. We found a significant decrease in mean Vo2 max, red blood cell count, hemoglobin, hematocrit, and mean corpuscular hemoglobin, as well as significant increase in mean lactate level, white blood cell count and mean corpuscular volume in the higher-polluted than in the lower-polluted area. No significant difference was documented for other parameters as platelet counts or maximum heart rate. CONCLUSIONS: Exercise in high-polluted air resulted in a significant reduction in the performance at submaximal levels of physical exertion. Therefore, the acute exposure to polluted air may cause a significant reduction in the performance of active individuals. The clinical importance of these findings should be assessed in longitudinal studies. PMID- 21811657 TI - Parental atopy and exposure to pets on asthma: a hospital-based case-control study. AB - OBJECTIVES: Studies of parental atopy, exposure to pets, and the risk of asthma have provided conflicting results. We aimed to assess the relationship between asthma among adults with parental atopy, pet keeping inside, and pet keeping outside the home. This study involved a total of 159 adults. The clinically diagnosed cases were 53 adults with asthma as per Global Initiative for Asthma (GINA) guidelines and 106 controls without asthma. METHODS: The study design was a hospital based case-control study. Information on parental atopy and exposure to pets was collected by using a self-administrated questionnaire. We used the exposure odds ratio and 95% confidence interval (CI) to quantify the relation between determinants of interest and the risk of asthma. These were estimated using logistic regression analysis with SPSS version 11.5. RESULTS: The paternal and maternal history of asthma were found to have significant effect on asthma among adults with adjusted odds ratio (OR) of 6.70 (1.92-23.33 95%CI) and 3.33 (1.25-8.89 95% CI) respectively. Parental history and parental atopy significantly increased risk of asthma among adults with adjusted odds ratios of 5.78 (2.38-14.05 95% CI) and 3.65 (1.58-8.43 95% CI) respectively. There was no significant association between asthma and exposure to pets. The adjusted odds ratios for pet keeping inside and outside the house were 1.61 (0.55-4.7395%CI) and 1.32 (0.61-2.87 95%CI) respectively. CONCLUSIONS: Our results support the hypothesis that both parental history and parental atopy increase the risk of asthma among adults whereas pet keeping inside and outside the house during the previous 12-month period were not significantly associated with asthma among adults. PMID- 21811658 TI - Does lipoprotein (a) level have a predictive value in restenosis after coronary stenting? AB - OBJECTIVES: Lipid disorders, lipoproteins, diabetes mellitus, and hypertension are the known risk factors for coronary artery diseases; however, their role is unknown in restenosis after coronary stenting. This study aimed to review the role of these factors, particularly lipoprotein (a) or Lp (a), as a predictive factor for restenosis after coronary stenting with Bare Metal Stent. METHODS: In this study, coronary artery stenting was performed on 170 patients. Follow-up was done using coronary angiography in 128 patients, 6 months after conducting angioplasty. Clinical and biochemical characteristics of the patients were collected as prospective method and were compared between the patients with and without restenosis. RESULTS: Restenosis was seen in 46 patients (35.9%). Fasting blood glucose level (FBG) in patients with restenosis was significantly higher than patients without restenosis (102.3 +/- 39 mg/dl vs. 84.5 +/- 28.9 [OR: 1.02, 95% CI: 1.00-1.04]). Lp (a) levels (OR: 0.54, 95% CI: 0.26-1.10) and other biochemical markers and clinical variables had no correlation with restenosis. CONCLUSIONS: Lipoproteins and lipids may not be the underlying cause of restenosis but accurate control of diabetes may improve prognosis after elective coronary stenting. PMID- 21811659 TI - Knowledge, attitudes and proposals of medical students concerning transplantations in Greece. AB - OBJECTIVES: In Greece, there is limited research on issues related to organ donation. We aimed to study the attitudes, knowledge, and actions of local medical students regard to organ donation and transplantations of tissues and organs in Greece. METHODS: This cross-sectional questionnaire based survey was done in Laboratory of Hygiene and Social Medicine, School of Medicine, Aristotle University of Thessaloniki, Greece on medical students in years 1 to 6. In a sample of 600 medical students, a special anonymous questionnaire, which included data as sex, age, and semester of studies, as well as questions regarding certain aspects of transplantation, was distributed. 558 valid questionnaires were completed (men 52.3% and women 47.7%). RESULTS: The vast majority of the sample (93.6%) were in favor of transplantations whereas 32 (5.7%) of the students claimed to be organ donors. 78.9% claimed ignorance of the existing legislation concerning transplantations and organ donation in our country. 81.2% believed that the voting of law, which would consider all Greek organ donors after death will cause strong reactions. As the main causes, responsible for the shortage of transplants in our country were stated to be the inadequate public information, Greek mentality, and the lack of organized transplant centers. Public information through Media, a lifelong free health check-up for organ donors and activation of voluntary organizations that promote organ donation were proposed as the most important actions that could increase organ donation and transplantations in Greece. CONCLUSIONS: The need for further informative actions stressing the importance of organ donations appears to be the only way to increase transplantations in our country and towards this direction medical students could also be activated. A new medical curriculum should increase medical students' awareness of the organ shortage problem. Public education is recommended to correct misconceptions. PMID- 21811660 TI - Polymerase chain reaction (PCR) assay for rapid diagnosis and its role in prevention of human brucellosis in Punjab, India. AB - OBJECTIVES: Brucellosis is the most common zoonotic disease that has been diagnosed mainly by serological tests and blood culture to some extent. This study was designed to establish a PCR technique for rapid diagnosis to be used in surveillance activities. METHODS: The purpose of this study was firstly explained to the study population and verbal consent was obtained before sample collection. Peripheral blood was collected from 116 occupationally exposed groups with and without pyrexia of unknown origin from various districts of Punjab. Samples were subjected to blood culture, serological tests and DNA extraction was done using conventional laboratory extraction procedure. A primer pair B4/B5 that amplifies a gene encoding a 31 kDa immunogenic outer membrane protein (bcsp31) of Brucella species was used for PCR amplification. RESULTS: The results showed that 8 (7%) of the cases had positive PCR and the detection threshold of primers used in this study were 715 cfu/ml. PCR results were 51.3% accurate for sensitivity of 12.6% and specificity of 100% using STAT as gold standard. CONCLUSIONS: Early-case reporting is possible by rapid tests like PCR. Thus, PCR is a promising diagnostic tool for routine investigation and surveillance of brucellosis which is the key element for management of prevention and control programmes. But patient condition before testing, optimal clinical specimen, sample volume used, simple and efficient DNA extraction protocol are the points of concern for PCR to be used as a routine test in clinical laboratory practice. PMID- 21811661 TI - Intrinsic third ventricular craniopharyngioma: A case report. AB - Craniopharyngioma accounts for 2.5-4 percent of all intracranial tumors. The tumor is more observed in the chiasmatic region in adults and the intraventricular subtype is rare. We report an intraventricular craniopharyngioma in a 22-year-old woman presented with chronic headache. Magnetic Resonance Imaging showed hyperintense large mass on T(1)-weighted images and hypointense mass on T(2)-weighted images in third ventricle with pressure effect on both lateral ventricles and foramen of Monro. The diagnosis of craniopharyngioma was confirmed through histopathological examination of the resected tumor after surgery. After a follow-up period of nine months, neither tumor recurrence nor regrowth occurred. The early diagnosis of this relatively frequent tumor would help to prevent related sequelae. PMID- 21811662 TI - Why coverage of influenza vaccine is not enough in patients receiving chemotherapy? PMID- 21811663 TI - "Epigenetically reprogramming of human embryonic stem cells by 3-deazaneplanocin A and sodium butyrate", Int J Prev Med. 2011 Apr;2(2):73-8 is retracted. AB - [This corrects the article on p. 73 in vol. 2, PMID: 21603011.]. PMID- 21811664 TI - More risk factors of hepatitis C transmission should be considered in Pakistan. PMID- 21811665 TI - Clinical Significance of MicroRNA Expression Profiles and Polymorphisms in Lung Cancer Development and Management. AB - Lung cancers account for a huge percentage of death in industrialized countries, and hence there is an increasing call for the development of novel treatments. These malignancies are caused by a combination of environmental factors, principally cigarette smoking and genetic alterations. MicroRNAs (miRNAs) are a recently discovered class of regulatory noncoding small RNAs with a significance in numerous biological processes. Strong evidence links miRNA impaired expression profiles and pathways to the etiology of several diseases, including neoplasia. This paper focuses on the emerging role of miRNA function in lung cancer development with particular highlighting on the use of miRNA profiles and polymorphisms for the molecular and biological characterization of tumor pulmonary growth and progression. Furthermore, we underline the potential utility of lung cancer-associated miRNAs as clinical biomarkers with a diagnostic, prognostic, and therapeutic significance and give emphasis to the promising novel miRNA-based curative strategies. PMID- 21811666 TI - Prognosis of thyroid cancer related to pregnancy: a systematic review. AB - Differentiated thyroid cancer (DTC) is the second most common cancer in pregnancy. Its management is a challenge for both doctors and patients, and the best timing for surgery is unclear. A systematic review evaluating the prognosis of DTC in pregnant patients was conducted. After reviewing 401 unique citations and 54 full texts, 4 studies that compared the prognosis of patients with DTC related to pregnancy (DTC diagnosed during pregnancy or within 12 months after childbirth) or not were included. In two studies the primary outcome was overall survival, in one study the primary outcomes were recurrent disease and death related to thyroid cancer, and in one study the primary outcome was recurrent or persistent disease. In the first two studies, there was no difference in overall survival in patients with pregnancy-related DTC, when compared with matched controls; in one study, there was no difference in death caused by DTC nor recurrence in DTC related to pregnancy. Nevertheless, in a recent retrospective study, a higher rate of recurrent or persistent DTC was observed in patients with DTC related to pregnancy. There are not many studies on which to base treatment decisions in pregnant patients with DTC. PMID- 21811667 TI - Optical coherence tomography of retinal and choroidal tumors. AB - Optical coherence tomography (OCT) has revolutionized the field of ophthalmology since its introduction 20 years ago. Originally intended primarily for retina specialists to image the macula, it has found its role in other subspecialties that include glaucoma, cornea, and ocular oncology. In ocular oncology, OCT provides axial resolution to approximately 7 microns with cross-sectional images of the retina, delivering valuable information on the effects of intraocular tumors on the retinal architecture. Some effects include retinal edema, subretinal fluid, retinal atrophy, photoreceptor loss, outer retinal thinning, and retinal pigment epithelial detachment. With more advanced technology, OCT now provides imaging deeper into the choroid using a technique called enhanced depth imaging. This allows characterization of the thickness and reflective quality of small (<3 mm thick) choroidal lesions including choroidal nevus and melanoma. Future improvements in image resolution and depth will allow better understanding of the mechanisms of visual loss, tumor growth, and tumor management. PMID- 21811669 TI - Optical coherence tomography findings in idiopathic macular holes. AB - Purpose. To describe the characteristics of idiopathic macular holes (MH) on optical coherence tomography (OCT) and correlate OCT with clinical assessment. Design. Cross-sectional chart review and OCT assessment. Participants. Sixty seven eyes with a clinically diagnosed idiopathic MH with available OCT data. Methods. A retrospective chart review and OCT assessment. Results. Based on OCT grading, 40 eyes had a full-thickness macular hole (FTMH) and 21 eyes had a lamellar macular hole (LMH). Clinical exam and OCT assessment agreed in 53 (87%) eyes when assessing the extent of MH. Six eyes (14.6%) in the FTMH group, and 3 eyes in the LMH group (14.3%) had persistent vitreomacular traction. Thirty-seven eyes (92.5%) in the FTMH group and 11 eyes (52.4%) in the LMH group had associated intraretinal cysts. Two eyes (5.0%) in the FTMH group and zero eyes in the LMH group had subretinal fluid. Intraretinal cysts were found to be more frequently associated with FTMH than with LMH (P < 0.001). Conclusion. This paper described OCT findings in a group of patients with clinically diagnosed MH. A high level of correlation between clinical assessment and OCT findings of LMH and FTMH was observed, and intraretinal cysts were often present in FTMH. PMID- 21811668 TI - Current approaches for management of postpenetrating keratoplasty astigmatism. AB - A successful corneal graft requires both clarity and an acceptable refraction. A clear corneal graft may be an optical failure if high astigmatism limits visual acuity. Intraoperative measures to reduce postkeratoplasty astigmatism include round and central trephination of cornea with an adequate size, appropriate sutures with evenly distributed tension, and perfect graft-host apposition. Suture manipulation has been described for minimising early postoperative astigmatism. If significant astigmatism remains after suture removal, which cannot be corrected by optical means, then further surgical procedures containing relaxing incisions, compression sutures, laser refractive surgery, insertion of intrastromal corneal ring segments, wedge resection, and toric intraocular lens implantation can be performed. When astigmatism cannot be reduced using one or more abovementioned approaches, repeat penetrating keratoplasty should inevitably be considered. However, none of these techniques has emerged as an ideal one, and corneal surgeons may require combining two or more approaches to exploit the maximum advantages. PMID- 21811671 TI - Bioconversion of Agricultural Waste to Ethanol by SSF Using Recombinant Cellulase from Clostridium thermocellum. AB - The effect of different pretreatment methods, temperature, and enzyme concentration on ethanol production from 8 lignocellulosic agrowaste by simultaneous saccharification and fermentation (SSF) using recombinant cellulase and Saccharomyces cerevisiae were studied. Recombinant cellulase was isolated from E. coli BL21 cells transformed with CtLic26A-Cel5-CBM11 full-length gene from Clostridium thermocellum and produced in both batch and fed-batch processes. The maximum cell OD and specific activity in batch mode were 1.6 and 1.91 U/mg, respectively, whereas in the fed-batch mode, maximum cell OD and specific activity were 3.8 and 3.5 U/mg, respectively, displaying a 2-fold increase. Eight substrates, Syzygium cumini (jamun), Azadirachta indica (neem), Saracens indica (asoka), bambusa dendrocalmus (bamboo), Populas nigra (poplar), Achnatherum hymenoides (wild grass), Eucalyptus marginata (eucalyptus), and Mangifera indica (mango), were subjected to SSF. Of three pretreatments, acid, alkali, and steam explosion, acid pretreatment Syzygium cumini (Jamun) at 30 degrees C gave maximum ethanol yield of 1.42 g/L. PMID- 21811670 TI - Associations between Ambulatory Blood Pressure Parameters and Cerebral White Matter Lesions. AB - Silent cerebral white matter lesions (WMLs) are a common finding on magnetic resonance imaging of the brain in the elderly. However, in patients with hypertension, WMLs tend to occur earlier in life and appear to be more severe. There is a body of evidence that supports the idea that WMLs in asymptomatic hypertensive patients should be considered a silent early marker of brain damage. It is known that ambulatory blood pressure monitoring (ABPM) correlates more closely with hypertension-related organ damage than office blood pressure. This paper focuses on the associations between blood pressure parameters obtained by 24-hour ABMP and cerebral WMLs. PMID- 21811672 TI - Laccase-Based CLEAs: Chitosan as a Novel Cross-Linking Agent. AB - Laccase from Coriolopsis Polyzona was insolubilized as cross-linked enzyme aggregates (CLEAs) for the first time with chitosan as the cross-linking agent. Concentrations between 0.01 and 1.867 g/L of chitosan were used and between 0.05 and 600 mM of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride. The laccase was precipitated using ammonium sulphate and cross-linked simultaneously. Specific activity and thermal stability of these biocatalysts were measured. Activities of up to 737 U/g were obtained when 2,2-azino-bis-(3 ethylbenzthiazoline-6-sulfonic acid) (ABTS) was used as a substrate. Moreover, the stability of these biocatalysts was improved with regards to thermal degradation compared to free laccase when exposed to denaturing conditions of high temperature and low pH. The CLEAs stability against chemical denaturants was also tested but no significant improvement was detected. The total amount of ABTS to be oxidized during thermal degradation by CLEAs and free laccase was calculated and the insolubilized enzymes were reported to oxidize more substrate than free laccase. The formation conditions were analyzed by response surface methodology in order to determine an optimal environment for the production of efficient laccase-based CLEAs using chitosan as the cross-linking agent. After 24 hours of formation at pH 3 and at 4 degrees C without agitation, the CLEAs exhibit the best specific activity. PMID- 21811673 TI - Petroleum-degrading enzymes: bioremediation and new prospects. AB - Anthropogenic forces, such as petroleum spills and the incomplete combustion of fossil fuels, have caused an accumulation of petroleum hydrocarbons in the environment. The accumulation of petroleum and its derivatives now constitutes an important environmental problem. Biocatalysis introduces new ways to improve the development of bioremediation strategies. The recent application of molecular tools to biocatalysis may improve bioprospecting research, enzyme yield recovery, and enzyme specificity, thus increasing cost-benefit ratios. Enzymatic remediation is a valuable alternative as it can be easier to work with than whole organisms, especially in extreme environments. Furthermore, the use of free enzymes avoids the release of exotic or genetically modified organisms (GMO) in the environment. PMID- 21811674 TI - Immobilization of a Commercial Lipase from Penicillium camembertii (Lipase G) by Different Strategies. AB - The objective of this work was to select the most suitable procedure to immobilize lipase from Penicillium camembertii (Lipase G). Different techniques and supports were evaluated, including physical adsorption on hydrophobic supports octyl-agarose, poly(hydroxybutyrate) and Amberlite resin XAD-4; ionic adsorption on the anionic exchange resin MANAE-agarose and covalent attachment on glyoxyl-agarose, MANAE-agarose cross-linked with glutaraldehyde, MANAE-agarose glutaraldehyde, and epoxy-silica-polyvinyl alcohol composite. Among the tested protocols, the highest hydrolytic activity (128.2 +/- 8.10 IU.g(-1) of support) was achieved when the lipase was immobilized on epoxy-SiO(2)-PVA using hexane as coupling medium. Lipase immobilized by ionic adsorption on MANAE-agarose also gave satisfactory result, attaining 55.6 +/- 2.60 IU.g(-1) of support. In this procedure, the maximum loading of immobilized enzyme was 9.3 mg.g(-1) of gel, and the highest activity (68.8 +/- 2.70 IU.g(-1) of support) was obtained when 20 mg of protein.g(-1) was offered. Immobilization carried out in aqueous medium by physical adsorption on hydrophobic supports and covalent attachment on MANAE agarose-glutaraldehyde and glyoxyl-agarose was shown to be unfeasible for Lipase G. Thermal stability tests revealed that the immobilized derivative on epoxy SiO(2)-PVA composite using hexane as coupling medium had a slight higher thermal stability than the free lipase. PMID- 21811675 TI - Elevated Evolutionary Rates among Functionally Diverged Reproductive Genes across Deep Vertebrate Lineages. AB - Among closely related taxa, proteins involved in reproduction generally evolve more rapidly than other proteins. Here, we apply a functional and comparative genomics approach to compare functional divergence across a deep phylogenetic array of egg-laying and live-bearing vertebrate taxa. We aligned and annotated a set of 4,986 1 : 1 : 1 : 1 : 1 orthologs in Anolis carolinensis (green lizard), Danio rerio (zebrafish), Xenopus tropicalis (frog), Gallus gallus (chicken), and Mus musculus (mouse) according to function using ESTs from available reproductive (including testis and ovary) and non-reproductive tissues as well as Gene Ontology. For each species lineage, genes were further classified as tissue specific (found in a single tissue) or tissue-expressed (found in multiple tissues). Within independent vertebrate lineages, we generally find that gonadal specific genes evolve at a faster rate than gonadal-expressed genes and significantly faster than non-reproductive genes. Among the gonadal set, testis genes are generally more diverged than ovary genes. Surprisingly, an opposite but nonsignificant pattern is found among the subset of orthologs that remained functionally conserved across all five lineages. These contrasting evolutionary patterns found between functionally diverged and functionally conserved reproductive orthologs provide evidence for pervasive and potentially cryptic lineage-specific selective processes on ancestral reproductive systems in vertebrates. PMID- 21811676 TI - A molecular perspective on systematics, taxonomy and classification amazonian discus fishes of the genus symphysodon. AB - With the goal of contributing to the taxonomy and systematics of the Neotropical cichlid fishes of the genus Symphysodon, we analyzed 336 individuals from 24 localities throughout the entire distributional range of the genus. We analyzed variation at 13 nuclear microsatellite markers, and subjected the data to Bayesian analysis of genetic structure. The results indicate that Symphysodon is composed of four genetic groups: group PURPLE-phenotype Heckel and abacaxi; group GREEN-phenotype green; group RED-phenotype blue and brown; and group PINK populations of Xingu and Cameta. Although the phenotypes blue and brown are predominantly biological group RED, they also have substantial contributions from other biological groups, and the patterns of admixture of the two phenotypes are different. The two phenotypes are further characterized by distinct and divergent mtDNA haplotype groups, and show differences in mean habitat use measured as pH and conductivity. Differences in mean habitat use is also observed between most other biological groups. We therefore conclude that Symphysodon comprises five evolutionary significant units: Symphysodon discus (Heckel and abacaxi phenotypes), S. aequifasciatus (brown phenotype), S. tarzoo (green phenotype), Symphysodon sp. 1 (blue phenotype) and Symphysodon sp. 2 (Xingu group). PMID- 21811677 TI - A brief journey into the history of the arterial pulse. AB - Objective. This paper illustrates the evolution of our knowledge of the arterial pulse from ancient times to the present. Several techniques for arterial pulse evaluation throughout history are discussed. Methods. Using databases including Worldcat, Pubmed, and Emory University Libraries' Catalogue, the significance of the arterial pulse is discussed in three historical eras of medicine: ancient, medieval, and modern. Summary. Techniques used over time to analyze arterial pulse and its characteristics have advanced from simple evaluation by touch to complex methodologies such as ultrasonography and plethysmography. Today's understanding of the various characteristics of the arterial pulse relies on our ancestors' observations and experiments. The pursuit of science continues to lead to major advancements in our knowledge of the arterial pulse and its application in diagnosis of atherosclerotic disease. PMID- 21811678 TI - A review of different behavior modification strategies designed to reduce sedentary screen behaviors in children. AB - Previous research suggests that reducing sedentary screen behaviors may be a strategy for preventing and treating obesity in children. This systematic review describes strategies used in interventions designed to either solely target sedentary screen behaviors or multiple health behaviors, including sedentary screen behaviors. Eighteen studies were included in this paper; eight targeting sedentary screen behaviors only, and ten targeting multiple health behaviors. All studies used behavior modification strategies for reducing sedentary screen behaviors in children (aged 1-12 years). Nine studies only used behavior modification strategies, and nine studies supplemented behavior modification strategies with an electronic device to enhance sedentary screen behaviors reductions. Many interventions (50%) significantly reduced sedentary screen behaviors; however the magnitude of the significant reductions varied greatly ( 0.44 to -3.1 h/day) and may have been influenced by the primary focus of the intervention, number of behavior modification strategies used, and other tools used to limit sedentary screen behaviors. PMID- 21811679 TI - Selective Glucocorticoid Receptor (GR-II) Antagonist Reduces Body Weight Gain in Mice. AB - Previous research has shown that mifepristone can prevent and reverse weight gain in animals and human subjects taking antipsychotic medications. This proof-of concept study tested whether a more potent and selective glucocorticoid receptor antagonist could block dietary-induced weight gain and increase insulin sensitivity in mice. Ten-week-old, male, C57BL/6J mice were fed a diet containing 60% fat calories and water supplemented with 11% sucrose for 4 weeks. Groups (n = 8) received one of the following: CORT 108297 (80 mg/kg QD), CORT 108297 (40 mg/kg BID), mifepristone (30 mg/kg BID), rosiglitazone (10 mg/kg QD), or vehicle. Compared to mice receiving a high-fat, high-sugar diet plus vehicle, mice receiving a high-fat, high-sugar diet plus either mifepristone or CORT 108297 gained significantly less weight. At the end of the four week treatment period, mice receiving CORT 108297 40 mg/kg BID or CORT 108297 80 mg/kg QD also had significantly lower steady plasma glucose than mice receiving vehicle. However, steady state plasma glucose after treatment was not highly correlated with reduced weight gain, suggesting that the effect of the glucocorticoid receptor antagonist on insulin sensitivity may be independent of its mitigating effect on weight gain. PMID- 21811680 TI - Renal mitochondrial cytopathies. AB - Renal diseases in mitochondrial cytopathies are a group of rare diseases that are characterized by frequent multisystemic involvement and extreme variability of phenotype. Most frequently patients present a tubular defect that is consistent with complete De Toni-Debre-Fanconi syndrome in most severe forms. More rarely, patients present with chronic tubulointerstitial nephritis, cystic renal diseases, or primary glomerular involvement. In recent years, two clearly defined entities, namely 3243 A > G tRNA(LEU) mutations and coenzyme Q10 biosynthesis defects, have been described. The latter group is particularly important because it represents the only treatable renal mitochondrial defect. In this paper, the physiopathologic bases of mitochondrial cytopathies, the diagnostic approaches, and main characteristics of related renal diseases are summarized. PMID- 21811681 TI - Acute Kidney Injury in ADPKD Patients with Pneumonia. AB - Background. In animal models, polycystic kidneys are susceptible to acute kidney injury (AKI). We examined the occurrence of AKI in a cohort of autosomal dominant polycystic kidney disease (ADPKD) and non-ADPKD patients with acute pneumonia. Design. All ADPKD patients admitted to Mayo Clinic Rochester for pneumonia from January 1990 to April 2010 were examined. Sixty-three patients had lobar infiltration and consolidation on chest X-ray. After excluding patients on dialysis, with organ transplantation, and on chronic immunosuppression, 24 remaining ADPKD patients were enrolled. Twenty-three of the 24 were matched with 92 (1 : 4 ratio) non-ADPKD pneumonia patients based on their baseline eGFR. AKI was defined as serum creatinine elevation >=0.3 mg/dL. Results. Sixteen of the 23 ADPKD patients (69.6%) and 36 of the 92 (39.1%) non-ADPKD patients developed AKI, P = 0.008. In both groups, those who developed AKI had a lower baseline eGFR (41.1 +/- 5.00 versus 58.7 +/- 11.8 in ADPKD and 40.2 +/- 3.65 versus 51.8 +/- 2.24 mL/min/1.73 m(2) in the non-ADPKD group), more intensive care unit admissions, and longer hospital stays. AKI was associated with a reduced survival in both groups. Conclusions. Patients with ADPKD admitted for acute pneumonia had more frequent episodes of AKI than non-ADPKD patients with comparable kidney function. PMID- 21811682 TI - Review of the recent literature on the mode of delivery for singleton vertex preterm babies. AB - Choosing the safest method of delivery and preventing preterm labour are obstetric challenges in reducing the number of preterm births and improving outcomes for mother and baby. Optimal route of delivery for preterm vertex neonates has been a controversial topic in the obstetric and neonatal community for decades and continues to be debated. We reviewed 22 studies, most of which have been published over the last five years with an aim to find answers to the clinical questions relevant to deciding the mode of delivery. Findings suggested that the neonatal outcome does not depend on the mode of delivery. Though Caesarean section rates are increasing for preterm births, it does not prevent neurodisability and cannot be recommended unless there are other obstetric indications to justify it. Therefore, clinical judgement of the obstetrician depending on the individual case still remains important in deciding the mode of delivery. PMID- 21811684 TI - Cool dentists. PMID- 21811683 TI - Obesity, metabolic syndrome, and adipocytes. AB - Obesity and metabolic syndromes are examples whereby excess energy consumption and energy flux disruptions are causative agents of increased fatness. Because other, as yet elucidated, cellular factors may be involved and because potential treatments of these metabolic problems involve systemic agents that are not adipose depot-specific in their actions, should we be thinking of adipose depot specific (cellular) treatments for these problems? For sure, whether treating obesity or metabolic syndrome, the characteristics of all adipose depot-specific adipocytes and stromal vascular cells should be considered. The focus of this paper is to begin to align metabolic dysfunctions with specific characteristics of adipocytes. PMID- 21811685 TI - The influence of type 2 diabetes mellitus on the expression of inflammatory mediators and tissue inhibitor of metalloproteinases-2 in human chronic periodontitis. AB - PURPOSE: The purpose of this study was to compare and quantify the expression of C-reactive protein (CRP), matrix metalloproteinase (MMP)-14, and tissue inhibitor of metalloproteinases (TIMP)-2 in gingival tissues of patients with chronic periodontitis accompanied with inflammatory reaction related to alveolar bone resorption with or without type 2 diabetes mellitus (DM). METHODS: Twelve patients with type 2 DM and chronic periodontitis (group 3), twelve patients with chronic periodontitis (group 2), and twelve healthy individuals (group 1) were included in the study. Gingival tissue biopsies were collected from each patient and from healthy individuals at the time of periodontal surgery (including surgical crown lengthening) or tooth extraction. The concentrations of cytokines were determined by a western blot analysis. RESULTS: The expression levels of CRP and MMP-14 increased in group 2 and 3, and they were highest in group 3. The expressions of TIMP-2 also increased in group 2 and 3. CONCLUSIONS: This study demonstrated that the expression levels of CRP, MMP-14, and TIMP-2 might be inflammatory markers in periodontal inflamed tissue. It can be assumed that CRP, MMP-14, and TIMP-2 may be partly involved in the progression of periodontal inflammation associated to type 2 DM. PMID- 21811686 TI - Efficacy of electrical neuromuscular stimulation in the treatment of chronic periodontitis. AB - PURPOSE: The purpose of the present randomized controlled clinical study was to evaluate the short-term outcomes of microcurrent electrical neuromuscular stimulation (MENS) as an adjunct method to nonsurgical periodontal therapy. METHODS: Twenty patients with moderate to severe chronic periodontitis were recruited into the study and randomly treated with either nonsurgical periodontal therapy followed by 5 MENS treatments with a microcurrent device or by nonsurgical periodontal therapy alone. Periodontal parameters were measured at baseline and 6 weeks following therapy, and included the plaque index, bleeding on probing, probing depth, and clinical attachment level (CAL). RESULTS: All measured values were reduced at the time of re-evaluation. The amount of inflammation was significantly reduced in both the test (P=0.002) and control group (P=0.015). The test group demonstrated a significant CAL gain at 6 weeks following therapy, including non-molar (P=0.009) and molar teeth (P=0.028). In comparison with the control group, the test group showed statistically significant differences in the CAL on both molar (P=0.027) and non-molar teeth (P=0.031). CONCLUSIONS: In conclusion, the short-term results of the study indicate that MENS could be a suitable adjunctive method in the treatment of chronic periodontitis. PMID- 21811687 TI - The biological effect of cyanoacrylate-combined calcium phosphate in rabbit calvarial defects. AB - PURPOSE: The purpose of this study was to determine the biological effects of cyanoacrylate-combined calcium phosphate (CCP), in particular its potential to act as a physical barrier - functioning like a membrane - in rabbit calvarial defects. METHODS: In each animal, four circular calvarial defects with a diameter of 8 mm were prepared and then filled with either nothing (control group) or one of three different experimental materials. In the experimental conditions, they were filled with CCP alone (CCP group), filled with biphasic calcium phosphate (BCP) and then covered with an absorbable collagen sponge (ACS; BCP/ACS group), or filled with BCP and then covered by CCP (BCP/CCP group). RESULTS: After 4 and 8 weeks of healing, new bone formation appeared to be lower in the CCP group than in the control group, but the difference was not statistically significant. In both the CCP and BCP/CCP groups, inflammatory cells could be seen after 4 and 8 weeks of healing. CONCLUSIONS: Within the limits of this study, CCP exhibited limited osteoconductivity in rabbit calvarial defects and was histologically associated with the presence of inflammatory cells. However, CCP demonstrated its ability to stabilize graft particles and its potential as an effective defect filler in bone augmentation, if the biocompatibility and osteoconductivity of CCP were improved. PMID- 21811688 TI - The plaque-removing efficacy of a single-tufted brush on the lingual and buccal surfaces of the molars. AB - PURPOSE: To test the plaque-removal efficacy of a single-tufted toothbrush on the posterior molars compared with a flat-trimmed toothbrush. METHODS: Forty-nine subjects were selected. Professional instruction and written brushing instructions were given. After thorough supra-gingival scaling and polishing, all subjects were asked to abstain from oral hygiene procedures for 24 hours prior to the first experiment. The subjects were randomized to a treatment sequence. The modified Quigley and Hein plaque index was recorded pre- and post-tooth brushing, at 6 surfaces of the posterior molars. After a wash-out period, all the remaining plaque was removed professionally. Twenty-four hours of brushing abstinence was again performed. The plaque index was recorded pre- and post-tooth brushing after the subjects were given the second toothbrush in the cross-over sequence. RESULTS: The percentage reductions in plaque scores achieved with the single tufted brushes were significantly higher than those of the flat-trimmed brush at the maxillary buccal interproximal, marginal and mandibular lingual interproximal site. The other locations showed no significant difference. CONCLUSIONS: The results of the present study implied that the single-tufted brush could be an effective tool for the removal of plaque at some, but not all, sites of the posterior molars. PMID- 21811689 TI - Effect of erbium-doped: yttrium, aluminium and garnet laser irradiation on the surface microstructure and roughness of sand-blasted, large grit, acid-etched implants. AB - PURPOSE: The present study was performed to evaluate the effect of erbium-doped: yttrium, aluminium and garnet (Er:YAG) laser irradiation on sand-blasted, large grit, acid-etched (SLA) implant surface microstructure according to varying energy levels and application times of the laser. METHODS: The implant surface was irradiated by the Er:YAG laser under combined conditions of 100, 140, or 180 mJ/pulse and an application time of 1 minute, 1.5 minutes, or 2 minutes. Scanning electron microscopy (SEM) was used to examine the surface roughness of the specimens. RESULTS: All experimental conditions of Er:YAG laser irradiation, except the power setting of 100 mJ/pulse for 1 minute and 1.5 minutes, led to an alteration in the implant surface. SEM evaluation showed a decrease in the surface roughness of the implants. However, the difference was not statistically significant. Alterations of implant surfaces included meltdown and flattening. More extensive alterations were present with increasing laser energy and application time. CONCLUSIONS: To ensure no damage to their surfaces, it is recommended that SLA implants be irradiated with an Er:YAG laser below 100 mJ/pulse and 1.5 minutes for detoxifying the implant surfaces. PMID- 21811690 TI - The clinical assessment of aggressive periodontitis patients. AB - PURPOSE: Few epidemiologic studies have investigated aggressive periodontitis in Koreans, but such studies of disease prevalence and other clinical characteristics would be invaluable in providing proper treatment. The aim of this study was to assess the prevalence of aggressive periodontitis and to measure the extent of associated periodontal breakdown. METHODS: The study population consisted of 1,692 patients who visited the Department of Periodontology, Wonkwang Daejeon Dental Hospital from January to December, 2010. Clinical parameters (probing depth, gingival recession, periodontal attachment loss) were measured by a single examiner, and radiographic examination was performed at the baseline. RESULTS: Twenty-eight (1.65%) patients showed clinical features of aggressive periodontitis, of which 27 patients exhibited the generalized form, and 1 exhibited the localized form. There was no significant difference between the percentage of male and female patients. The probing pocket depth of the maxillary first molar was deeper than that of the other teeth and gingival recession was also the most serious at the maxillary first molar. The periodontal attachment loss was the highest at the maxillary first molar. The average number of missing teeth was 1.29 per subject. Loss of the second molar was prominent. CONCLUSIONS: Within the limitations of this study, the periodontal breakdown evaluated by attachment loss was found to be most severe at the first molars of aggressive periodontitis patients. However, further large scale multicenter studies are necessary to access more precise data, including prevalence. PMID- 21811691 TI - Effect of globular adiponectin on interleukin-6 and interleukin-8 expression in periodontal ligament and gingival fibroblasts. AB - PURPOSE: Globular adiponectin (gAd) is a type of adipocytokine, which is mainly produced by adipose tissue. It has been reported that gAd acts as a pro- as well as an anti-inflammatory factor. Interleukin (IL)-6 and IL-8 are pro-inflammatory cytokines. To investigate the role of gAd on periodontal tissues, the expression of adiponectin receptor 1 (AdipoR1) and the effect of gAd on the expression of IL 6 and IL-8 were investigated in periodontal ligament (PDL) and gingival fibroblasts. METHODS: PDL and gingival fibroblasts were cultured from human periodontal tissues. gAd derived from Escherichia coli and murine myeloma cells were used. The expression of AdipoR1 was estimated by reverse transcription polymerase chain reaction and western blot. The expression of cytokines was measured by enzyme-linked immunosorbent assay. RESULTS: PDL and gingival fibroblasts expressed both mRNA and protein of AdipoR1. gAd derived from E. coli increased the production of IL-6 and IL-8, but polymyxin B, an inhibitor of lipopolysaccharide (LPS), inhibited IL-6 and IL-8 production induced by gAd in both types of cells. gAd derived from murine myeloma cells did not induce IL-6 and IL-8 production in those cells. gAd derived from E. coli contained higher levels of LPS than gAd derived from murine myeloma cells. LPS increased production of IL-6 and IL-8 in PDL and gingival fibroblasts, but pretreatment of cells with gAd derived from murine myeloma cells did not inhibit LPS-induced IL-6 and IL-8 expression. CONCLUSIONS: Our results suggest that PDL and gingival fibroblasts express AdipoR1 and that gAd does not act as a modulator of IL-6 and IL-8 expression in PDL and gingival fibroblasts. PMID- 21811693 TI - New insights into the mechanism of the down-regulation of mast cells in the treatment of interstitial cystitis: possible role of siglecs. PMID- 21811692 TI - Curcumin suppresses the production of interleukin-6 in Prevotella intermedia lipopolysaccharide-activated RAW 264.7 cells. AB - PURPOSE: Curcumin is known to exert numerous biological effects including anti inflammatory activity. In this study, we investigated the effects of curcumin on the production of interleukin-6 (IL-6) by murine macrophage-like RAW 264.7 cells stimulated with lipopolysaccharide (LPS) from Prevotella intermedia, a major cause of inflammatory periodontal disease, and sought to determine the underlying mechanisms of action. METHODS: LPS was prepared from lyophilized P. intermedia ATCC 25611 cells by the standard hot phenol-water method. Culture supernatants were collected and assayed for IL-6. We used real-time polymerase chain reaction to detect IL-6 mRNA expression. IkappaB-alpha degradation, nuclear translocation of NF-kappaB subunits, and STAT1 phosphorylation were characterized via immunoblotting. DNA-binding of NF-kappaB was also analyzed. RESULTS: Curcumin strongly suppressed the production of IL-6 at both gene transcription and translation levels in P. intermedia LPS-activated RAW 264.7 cells. Curcumin did not inhibit the degradation of IkappaB-alpha induced by P. intermedia LPS. Curcumin blocked NF-kappaB signaling through the inhibition of nuclear translocation of NF-kappaB p50 subunit. Curcumin also attenuated DNA binding activity of p50 and p65 subunits and suppressed STAT1 phosphorylation. CONCLUSIONS: Although further study is required to explore the detailed mechanism of action, curcumin may contribute to blockade of the host-destructive processes mediated by IL-6 and appears to have potential therapeutic values in the treatment of inflammatory periodontal disease. PMID- 21811694 TI - Potential targeting of siglecs, mast cell inhibitory receptors, in interstitial cystitis. AB - Mast cell increases and activation are detected in the chronic inflammatory bladder disease interstitial cystitis (IC), and their proinflammatory mediators are felt to contribute to regional pelvic pain and inflammatory pathophysiology. The immunoreceptor tyrosine-based inhibition motif-containing sialic acid-binding immunoglobulin-like lectins (Siglecs) expressed in mast cells could be evaluated as in vivo signaling regulators capable of inhibiting IC-related mast cell activation. PMID- 21811695 TI - Circadian rhythms in urinary functions: possible roles of circadian clocks? AB - Circadian clocks are the endogenous oscillators that harmonize a variety of physiological processes within the body. Although many urinary functions exhibit clear daily or circadian variation in diurnal humans and nocturnal rodents, the precise mechanisms of these variations are as yet unclear. In this review, we briefly introduce circadian clocks and their organization in mammals. We then summarize known daily or circadian variations in urinary function. Importantly, recent findings by others as well as results obtained by us suggest an active role of circadian clock genes in various urinary functions. Finally, we discuss possible research avenues for the circadian control of urinary function. PMID- 21811696 TI - Swimming: effects on stress urinary incontinence and the expression of nerve growth factor in rats following transabdominal urethrolysis. AB - PURPOSE: Stress urinary incontinence (SUI) commonly occurs in women, and it has an enormous impact on quality of life. Surgery, drugs, and exercise have been recommended for the treatment of this disease. Among these, exercise is known to be effective for the relief of symptoms of SUI; however, the efficacy and underlying mechanisms of the effect of exercise on SUI are poorly understood. We investigated the effect of swimming the symptom of SUI in relation to the expression of nerve growth factor (NGF) in rats. METHODS: Transabdominal urethrolysis was used to induce SUI, in Sprague-Dawley rats. The experimental groups were divided into the following three groups: sham-operation group, transabdominal urethrolysis-induced group, and transabdominal urethrolysis induced and swimming group. The rats in the swimming group were forced to swim for 30 minutes once daily starting 2 weeks after SUI induction and continuing for 4 weeks. For this study, determination of abdominal leak point pressure and immunohistochemistry for NGF in the urethra and in the neuronal voiding centers (medial preoptic nucleus [MPA], ventrolateral periaqueductal gray [vlPAG], pontine micturition center [PMC], and spinal cord [L4-L5]) were performed. RESULTS: Transabdominal urethrolysis significantly reduced the abdominal leak point pressure, thereby contributing to the induction of SUI. Abdominal leak point pressure, however, was significantly improved by swimming. The expression of NGF in the urethra and in the neuronal voiding centers (MPA, vlPAG, PMC, and L4-L5) relating to micturition was enhanced by the induction of SUI. Swimming, however, significantly suppressed SUI-induced NGF expression. CONCLUSIONS: Swimming alleviated symptoms of transabdominal urethrolysis-induced SUI, as assessed by an increase in abdominal leak point pressure. The underlying mechanisms of these effects of swimming might be ascribed to the inhibitory effect of swimming on NGF expression. PMID- 21811698 TI - Heart Rate Variability in Men with Erectile dysfunction. AB - PURPOSE: The objective of this study is to investigate alteration of autonomic nervous system (ANS) activity in patients suffering from erectile dysfunction (ED) by comparing parameters of heart rate variability (HRV) between men with ED and healthy subjects. METHODS: A retrospective review was performed on 40 ED patients (mean age, 46.0+/-8.49 years) without any disease and 180 healthy control people (mean age, 44.4+/-7.83 years) without ED in our institution from June 2008 to July 2010. And electrocardiographic signals were obtained to measure HRV parameters for both patients and controls in a resting state. RESULTS: For the time domain analysis, square root of the mean differences between successive RR intervals (RMSSD) representing parasympathetic activity was lower in patients than controls although P-value was not statistically significant (P=0.060). For the frequency domain analysis, high frequency (HF) representing parasympathetic activity was lower in patients than controls (P=0.232) and low frequency (LF) representing mainly sympathetic activity was higher in patients than controls (P=0.416). Lastly, LF/HF ratio reflecting sympathetic/parasympathetic activity ratio was statistically higher in patients than controls (P=0.027). CONCLUSIONS: Patients with ED exhibited different HRV parameters compared with normal controls. This suggests that the patients with ED may have some kind of imbalance in the ANS and it may be possible that general imbalance of the ANS is one of the causes of ED. Thus, HRV analysis may give valuable diagnostic information and serve as a rapid screening tool to evaluate altered ANS activity in patients with ED. PMID- 21811697 TI - Impact of nocturia on health-related quality of life and medical outcomes study sleep score in men. AB - PURPOSE: To evaluate the impact of nocturia on health-related quality of life and sleep in men. METHODS: From January 2008 to December 2008, 284 patients with lower urinary tract symptoms were selected for this study. The participants completed a series of questionnaires on health-related quality of life (the overactive bladder questionnaire, or OAB-q), the Medical Outcomes Study (MOS) sleep scale, and the frequency volume chart. RESULTS: The patient population had a mean age of 60.0+/-13.4 years (range, 40 to 79 years). The mean duration of symptoms was 28.8+/-34.6 months. The mean number of voiding episodes per night was measured as follows: 88 patients (31.0%) reported no nocturia, 60 patients (21.1%) reported 2>voids/night >=1, 56 patients (19.7%) reported 3>voids/night >=2, and 80 patients (28.2%) reported >=3 voids/night. The mean number of nocturia episodes increased with age (P=0.001), and the number of nocturia episodes was significantly associated with the OAB-q symptom score (P=0.001) and symptom bother (P=0.001). Among the categories of the MOS sleep scale, sleep index I (P=0.020), sleep disturbance (P=0.010), adequacy of sleep (P=0.005), and somnolence (P=0.041) were significantly associated with an increased number of nocturia episodes. CONCLUSIONS: The number of nocturia episodes increased with age in men. Nocturia appeared to be associated with further negative effects on sleep quality, health-related quality of life, and symptom bother. PMID- 21811699 TI - Tamsulosin Monotherapy versus Combination Therapy with Antibiotics or Anti Inflammatory Agents in the Treatment of Chronic Pelvic Pain Syndrome. AB - PURPOSE: Chronic pelvic pain syndrome (CPPS) is treated by use of various protocols. We compared tamsulosin monotherapy with tamsulosin in combination with antibiotics or anti-inflammatory agents and evaluated the efficacy of these treatments in patients with CPPS. METHODS: Patients (n=107) who were younger than 55 years and diagnosed with CPPS were randomly assigned to treatment with tamsulosin at 0.2 mg (group A), tamsulosin at 0.2 mg plus anti-inflammatory drugs (group B) or tamsulosin at 0.2 mg plus antibiotics (group C) daily. We applied the National Institutes of Health-Chronic Prostatitis Symptom Index (NIH-CPSI) and the International Prostate Symptom Score (IPSS) to evaluate 100 patients who were treated for 12 weeks (7 withdrew). Scores of the three groups were compared by analysis of variance and we also evaluated subscores, which included pain, voiding and quality of life (QoL). RESULTS: All three groups showed statistically significant decreases in NIH-CPSI score, IPSS and subscore scores (P<0.05). There were no statistically significant differences between the groups except for the QoL domain of the IPSS (group A vs. C; P<0.01). CONCLUSIONS: Tamsulosin monotherapy for 12 weeks was effective for treating patients with CPPS, compared with combination therapy with antibiotics or anti-inflammatory drugs. PMID- 21811700 TI - Bicycle riding: impact on lower urinary tract symptoms and erectile function in healthy men. AB - PURPOSE: Recently, reports in the mass media have implicated that bicycle riding increases the risk of erectile dysfunction and prostatic diseases. So, we evaluate the impact of bicycle riding on erectile function and lower urinary tract symptoms (LUTS) in healthy general men. METHODS: From 26 June 2010 to 20 July 2010, we investigate degree of LUTS (voiding and storage symptoms), using International Continence Society-male Questionnaire (ICS-mQ) and erectile function using International Index of Erectile Function-5 Questionnaire (IIEF-5) in 5 work places (personnel of public office, hospital, university, etc.) of which bicycle riding club members were doing active club activities. Respondents, who participated in club activities for 6 months and longer, were classified as the bicycle club (142 men; age, 44.02+/-8.56). Ones who do not ride bicycles were classified as the control group (83 men; age, 42.13+/-7.85). People who were having the history of urological and other chronic diseases (diabetes, vascular disease, heart disease, etc) were excluded from both groups. RESULTS: Bicycle club is not significantly associated with increased prevalence of LUTS (bicycle club, 2.1 to 57.7% control, 4.8 to 73.5%) and erectile dysfunction (bicycle club, 46.1% control, 55.4%). The total mean score (storage/voiding/erectile function) of bicycle club (13.93+/-1.95/11.14+/-3.49/20.46+/-5.30) were not significantly different from control (14.35+/-2.49/11.52+/-3.38/20.40+/-4.07) (P=0.190 to 0.968). CONCLUSIONS: These results suggested that bicycle riding as exercise or hobby has no negative effect on LUTS and erectile function in healthy general men, although this research data were limited to the questionnaire analysis. PMID- 21811701 TI - Urethral erosion and perineal cellulitis after midurethral sling procedure. AB - Midurethral tension-free sling procedure has become one of the most popular techniques for the treatment of stress urinary incontinence. As the time elapsed, however, complications associated with a synthetic tape have been reported to occur. Recently, we experienced a rare case of urethral erosion with perineal cellulitis at anterior wall of vagina after midurethral sling procedure. So our experience was presented with a review of literature. PMID- 21811702 TI - Paraganglioma of the cauda equina region: A report of three cases. AB - BACKGROUND: Cauda equina paragangliomas (CEP) are rare tumors. Low back pain and sciatica are the main presenting symptoms. Magnetic resonance imaging (MRI) is the study of choice and treatment consists of total excision when feasible. Definitive diagnosis can only be made after immunohistochemical investigation. CEP is classified as grade I WHO and after total removal the prognosis is excellent. Nonetheless, after subtotal removal, tumor recurrence can occur. CASE DESCRIPTION: We present 3 cases of CEP, preoperatively diagnosed as an intradural mass on MRI and suspected to be ependymoma. All 3 patients presented with low back pain and variable sciatic pain. Total resection of the tumor was performed after which all patients fully recovered. There is no recurrence after 13, 11, and 5 years, respectively. CONCLUSION: CEP is a rare tumor. We diagnosed 3 paragangliomas out of a series of 105 intradural extramedullary tumors in adults (1994-2005). No recurrence was seen after total resection. In retrospect, both the intraoperative appearance and the MR image were not completely typical for schwannoma or ependymoma, but final diagnosis can only be made histologically. PMID- 21811703 TI - Spinal dural attachments to the vertebral column: An anatomic report and review of the literature. AB - BACKGROUND: The spinal dura is anchored within the vertebral canal by connective tissue in the epidural space as well as the spinal roots. Inadvertent disruption of these dural attachments may lead to durotomy and cerebrospinal fluid (CSF) leaks. We observed well-developed connective tissue ligaments connecting the lumbar dura to the spinal column and examined these tissues microscopically. METHODS: Intraoperative images were obtained during lumbar laminectomy procedures. They demonstrated connective tissue attachments, linking the lumbar dura to the spinal column in the dorsal midline and dorsolaterally. Tissue samples were obtained and examined microscopically. We then conducted a search of the literature to find references to dural attachments to the spinal column. RESULTS: Histological examination of the samples showed minimal cellular fibrous tissue. To date no references to these attachments have been made in neurosurgical literature. Previous studies, including live, cadaveric, and radiographic examinations, have demonstrated a dorsomedian fold of dura attached to the junction of the ligamentum flavum, and dorsolateral ligaments that divide the dorsal epidural space into an anterior and posterior compartment. CONCLUSIONS: Epidural fibrous connections or ligaments between the dura and the lumbar spinal column may be of clinical importance to the neurosurgeon. Care should be taken during lumbar procedures not to disrupt or tear these ligaments as this may cause dural tears and CSF leaks. Identifying these ligaments and cutting them sharply may prevent inadvertent durotomies. PMID- 21811704 TI - A short segment intracranial-intracranial jump graft bypass followed by proximal arterial occlusion for a distal MCA aneurysm. AB - BACKGROUND: To describe the use of a short segment cortical intracranial intracranial (IC-IC) bypass for the treatment of a distal middle cerebral artery (MCA) aneurysm. CASE DESCRIPTION: A 54-year-old woman presented with a loss of consciousness followed by multiple seizures and was found to have a partially thrombosed distal MCA aneurysm. This possibly mycotic aneurysm was treated by creating a short segment jump graft between a normal cortical artery and a nearby cortical branch arising from the aneurysmal M3 arterial segment. The bypass allowed for subsequent occlusion of the aneurysmal vessel without ischemic consequence. At surgery, the anterior division of the superficial temporal artery (STA) was exposed and dissected. Intraoperative angiography was utilized to localize a cortical artery arising from the involved segment as well as a nearby cortical artery arising from a distinct, uninvolved MCA branch. A segment of the STA was harvested, and then 10-0 suture was utilized to anastomose this short segment, to both the involved and normal cortical arteries. This created a short jump graft allowing for subsequent sacrifice of the diseased artery. Following surgery, the patient immediately underwent coil embolization of the aneurysm back into the parent artery resulting in local vascular sacrifice. The remainder of the patient's hospital course was uneventful. She was discharged home in good condition. CONCLUSIONS: We suggest that cortical IC-IC bypass followed by endovascular arterial sacrifice as performed in our case represents a simple and safe option for treating unclippable distal MCA aneurysms including mycotic lesions. PMID- 21811705 TI - A minimally-invasive rat model of subarachnoid hemorrhage and delayed ischemic injury. AB - BACKGROUND: Double-injection models of subarachnoid hemorrhage (SAH) in rats are the most effective in producing vasospasm, delayed neurological deficits and infarctions. However, they require two large surgeries to expose the femoral artery and the atlanto-occipital membrane. We have developed a minimally-invasive modification that prevents confounding effects of surgical procedures, leakage of blood from the subarachnoid space and minimizes risk of infection. METHODS: Rats are anesthetized and the ventral tail artery is exposed through a small (5 mm), midline incision, 0.2 mL of blood is taken from the artery and gentle pressure is applied for hemostasis. The rat is flipped prone, and with the head flexed to 90 degrees in a stereotactic frame, a 27G angiocath is advanced in a vertical trajectory, level with the external auditory canals. Upon puncturing the atlanto occipital membrane, the needle is slowly advanced and observed for cerebrospinal fluid (CSF). A syringe withdraws 0.1 mL of CSF and the blood is injected into the subarachnoid space. The procedure is repeated 24 hours later by re-opening the tail incision. At 8 days, the rats are euthanized and their brains harvested, sectioned, and incubated with triphenyltetrazolium chloride (TTC). RESULTS: Rats develop neurological deficits consistent with vasospasm and infarction as previously described in double-injection models. Cortical and deep infarctions were demonstrated by TTC staining and on histopathology. CONCLUSIONS: A minimally invasive, double-injection rat model of SAH and vasospasm is feasible and produces neurological deficits and infarction. This model can be used to study neuroprotective treatments for vasospasm and delayed neurological deficits following SAH, reducing the confounding effects of surgical interventions. PMID- 21811706 TI - From the bench to the bedside: Sleeping when you're awake, lasers and the blood brain barrier, neurons with a taste for lactate, and more.... PMID- 21811707 TI - Tectal plate glioblastoma multiforme. AB - BACKGROUND: Tectal plate tumors have traditionally been considered low-grade, indolent lesions. We report a patient who presented with a tectal region glioblastoma multiforme (GBM), a rare pathology in this anatomic location. CASE DESCRIPTION: This is a case report of a 45-year-old female that presented with worsening confusion, memory loss, and loss of bladder control for 3 days. There was no family history of brain malignancy. The patient presented with Parinaud's phenomenon. Pronator drift was not present. The patient had dysarthric speech. An elevated white blood cell count was also noted. Non-contrast CT scan of the head showed the presence of a tectal region mass and hydrocephalus. A follow-up MRI with and without contrast confirmed the presence of a 4.2 * 3.3 * 4.6 cm(3) mass. Magnetic Resonance Spectroscopy (MRS) demonstrated an elevated choline/N acetylaspartate ratio and an increase in lactate suggesting an aggressive neoplasm. A ventriculoperitoneal shunt was initially placed to relieve the hydrocephalus. The patient subsequently underwent a suboccipital craniotomy for debulking of tumor and for tissue diagnosis. Pathology of the lesion was consistent with GBM. The patient declined postoperative treatment with chemotherapy and radiation. CONCLUSION: Although tectal region masses are predominantly low-grade lesions, high-grade lesions can present in this anatomical location. Furthermore, MRS can help to differentiate benign lesions from more aggressive lesions in the tectal plate. Biopsy of tectal plate lesions should be considered in select cases to establish diagnosis and prognosis in order to optimize treatment. PMID- 21811709 TI - Attenuating surface plasmon resonance via core/alloy architectures. AB - The layer-by-layer processing of Au/Au(x)Pd(1-x) core/alloy nanoparticles via microwave irradiation (MWI) based hydrothermal heating is described. Alloy shell growth was monitored by the attenuation of surface plasmon resonance (SPR) as a function of shell thickness and composition. Discrete dipole approximation (DDA) correlated the SPR to particle morphology. PMID- 21811708 TI - Effects of Biomolecular Flexibility on Alchemical Calculations of Absolute Binding Free Energies. AB - The independent trajectory thermodynamic integration (IT-TI) approach (Lawrenz et. al J. Chem. Theory. Comput. 2009, 5:1106-1116(1)) for free energy calculations with distributed computing is employed to study two distinct cases of protein-ligand binding: first, the influenza surface protein N1 neuraminidase bound to the inhibitor oseltamivir, and second, the M. tuberculosis enzyme RmlC complexed with the molecule CID 77074. For both systems, finite molecular dynamics (MD) sampling and varied molecular flexibility give rise to IT-TI free energy distributions that are remarkably centered on the target experimental values, with a spread directly related to protein, ligand, and solvent dynamics. Using over 2 MUs of total MD simulation, alternative protocols for the practical, general implementation of IT-TI are investigated, including the optimal use of distributed computing, the total number of alchemical intermediates, and the procedure to perturb electrostatics and van der Waals interactions. A protocol that maximizes predictive power and computational efficiency is proposed. IT-TI outperforms traditional TI predictions and allows a straightforward evaluation of the reliability of free energy estimates. Our study has broad implications for the use of distributed computing in free energy calculations of macromolecular systems. PMID- 21811710 TI - Double-emulsion drops with ultra-thin shells for capsule templates. AB - We introduce an emulsification technique that creates monodisperse double emulsion drops with a core-shell geometry having an ultra-thin wall as a middle layer. We create a biphasic flow in a microfluidic capillary device by forming a sheath flow consisting of a thin layer of a fluid with high affinity to the capillary wall flowing along the inner wall of the capillary, surrounding the innermost fluid. This creates double-emulsion drops, using a single-step emulsification, having a very thin fluid shell. If the shell is solidified, its thickness can be small as a hundred nanometres or even less. Despite the small thickness of this shell, these structures are nevertheless very stable, giving them great potential for encapsulation. We demonstrate this by creating biodegradable microcapsules of poly(lactic acid) with a shell thickness of a few tens of nanometres, which are potentially useful for encapsulation and delivery of drugs, cosmetics, and nutrients. PMID- 21811711 TI - Rational design of aminoanthraquinones for colorimetric detection of heavy metal ions in aqueous solution. AB - A family of water-soluble colorimetric chemosensors incorporating an anthraquinone signalling subunit functionalized with a polyamine chain that bears hydrophilic diethoxyphosphoryl moieties was prepared with the aim of assaying metal cations. The outstanding UV-Vis absorption properties of the 1 aminoanthraquinone chromophore allowed the efficient visual detection and quantification of copper(II) ions by chelators L(1)-L(3) in buffered aqueous solution. Moreover, the visible response of L(2) is not interfered by addition of large excesses of 13 common metal ions, whereas chemosensor L(3) produces also a color change in the presence of equimolar amounts of lead(II). Considering the 134 nm gap between both absorption maxima, simultaneous colorimetric quantification of lead and copper can be envisaged. Detailed potentiometric and spectrophotometric analysis of Cu(2+) complexation by L(2) and L(3), as well as Pb(2+) and Cd(2+) by L(3) was undertaken in order to gain a deeper insight into the pH-dependent speciation and understanding the color changing process. Furthermore, the inner coordination sphere of the [PbL(3)](2+) complex was probed by NMR spectroscopy. PMID- 21811712 TI - 35 years of palladium-catalyzed cross-coupling with Grignard reagents: how far have we come? AB - This tutorial review is intended to provide the reader with a timely review of major developments and the current state-of-the-art of palladium-catalyzed cross coupling reactions with Grignard reagents. Organomagnesium reagents, the most reactive and most easily accessible nucleophiles for carbon-carbon bond forming cross-coupling reactions, were the first nucleophiles ever employed in cross coupling reactions, but have only recently been re-discovered for highly efficient and (stereo)selective coupling reactions. This is mostly a consequence of improved catalyst systems with bulky phosphine, phosphonate or carbene ligands and new metal-halogen exchange procedures for the generation of functionalized Grignard reagents. PMID- 21811713 TI - Advances on structuring, integration and magnetic characterization of molecular nanomagnets on surfaces and devices. AB - This critical review represents a concise revision of the different experimental approaches so far followed for the structuration of molecular nanomagnets on surfaces, since the first reports on the field more than ten years ago. Afterwards, a presentation of the different experimental approaches followed for their integration in sensors is described. Such work involves mainly two families of sensors and devices, microSQUIDs sensors and three-terminal devices for single molecule detection. Finally the last section is devoted to a detailed revision of the different experimental techniques that can be used for the magnetic characterization of these systems on surfaces, ranging from magnetic circular dichroism to magnetic force microscopy. The use of these techniques to characterize other nanostructured magnetic materials, such as nanoparticles, is also revised. The aim is to give a broad overview of the last advances achieved with these techniques and their potential and evolution over the next years. PMID- 21811714 TI - Surface tension of ionic liquids and ionic liquid solutions. AB - Some of the most active scientific research fronts of the past decade are centered on ionic liquids. These fluids present characteristic surface behavior and distinctive trends of their surface tension versus temperature. One way to explore and understand their unique nature is to study their surface properties. This critical review analyses most of the surface tension data reported between 2001 and 2010 (187 references). PMID- 21811715 TI - Benchtop micromolding of polystyrene by soft lithography. AB - Polystyrene (PS), a standard material for cell culture consumable labware, was molded into microstructures with high fidelity of replication by an elastomeric polydimethylsiloxane (PDMS) mold. The process was a simple, benchtop method based on soft lithography using readily available materials. The key to successful replica molding by this simple procedure relies on the use of a solvent, for example, gamma-butyrolactone, which dissolves PS without swelling the PDMS mold. PS solution was added to the PDMS mold, and evaporation of the solvent was accomplished by baking the mold on a hotplate. Microstructures with feature sizes as small as 3 MUm and aspect ratios as large as 7 were readily molded. Prototypes of microfluidic chips made from PS were prepared by thermal bonding of a microchannel molded in PS with a flat PS substrate. The PS microfluidic chip displayed much lower adsorption and absorption of hydrophobic molecules (e.g. rhodamine B) compared to a comparable chip created from PDMS. The molded PS surface exhibited stable surface properties after plasma oxidation as assessed by contact angle measurement. The molded, oxidized PS surface remained an excellent surface for cell culture based on cell adhesion and proliferation. To demonstrate the application of this process for cell biology research, PS was micromolded into two different microarray formats, microwells and microposts, for segregation and tracking of non-adherent and adherent cells, respectively. The micromolded PS possessed properties that were ideal for biological and bioanalytical needs, thus making it an alternative material to PDMS and suitable for building lab-on-a-chip devices by soft lithography methods. PMID- 21811716 TI - Pyroelectric Adaptive Nanodispenser (PYRANA) microrobot for liquid delivery on a target. AB - Manipulation of micro-sized objects in lab-on-a-chip and microfluidic environments is essential for different experiments and procedures ranging from chemical to biological applications and for experimental biotechnologies. For example polymeric particles, useful as targets for encapsulating or for being covered by drug vaccines, can be manipulated and controlled with the aim of releasing them to specific sites. Here we show a novel ElectroHydroDynamic tool able to control and manipulate dielectric micro-targets by a touch-less approach. This approach allows one to manipulate liquids and nano-particles simultaneously for specific delivery applications (i.e. decoration and coating). Thus a sort of EHD micro-robot is proposed. This flexible tool provides a new and powerful way to operate various tasks as demonstrated by the experiments reported here. PMID- 21811717 TI - Lab on a chip technologies for bioenergy and biosustainability research. PMID- 21811726 TI - Pressure-enhanced dehydrogenation reaction of the LiBH4-YH3 composite. AB - The increase in hydrogen back pressure unexpectedly enhances the overall dehydrogenation reaction rate of the 4LiBH(4) + YH(3) composite significantly. Also, argon back pressure has a similar influence on the composite. Gas back pressure seems to enhance the dehydrogenation reaction by kinetically suppressing the formation of the diborane by-product. PMID- 21811727 TI - The morphology of aerosol particles consisting of hydrophobic and hydrophilic phases: hydrocarbons, alcohols and fatty acids as the hydrophobic component. AB - The morphology of bi-phase aerosol particles containing phase separated hydrophobic and hydrophilic components is considered, comparing simulations based on surface and interfacial tensions with measurements made by aerosol optical tweezers. The competition between the liquid phases adopting core-shell and partially engulfed configurations is considered for a range of organic compounds including saturated and unsaturated hydrocarbons, aromatics, alcohols, ketones, carboxylic acids, esters and amines. When the solubility of the organic component and the salting-out of the organic component to the surface by the presence of concentrated inorganic solutes in the aqueous phase are considered, it is concluded that the adoption of a partially engulfed structure predominates, with the organic component forming a surface lens. The aqueous surface can be assumed to be stabilised by a surface enriched in the organic component. The existence of acid-base equilibria can lead to the dissociation of organic surfactants and to significant lowering of the surface tension of the aqueous phase, further supporting the predominance of partially engulfed structures. Trends in morphology from experimental measurements and simulations are compared for mixed phased droplets in which the organic component is decane, 1-octanol or oleic acid with varying relative humidity. The consequences of partially engulfed structures for aerosol properties are considered. PMID- 21811728 TI - Visible and ultraviolet spectroscopy of gas phase protein ions. AB - Optical spectroscopy has contributed enormously to our knowledge of the structure and dynamics of atoms and molecules and is now emerging as a cornerstone of the gas phase methods available for investigating biomolecular ions. This article focuses on the UV and visible spectroscopy of peptide and protein ions stored in ion traps, with emphasis placed on recent results obtained on protein polyanions, by electron photodetachment experiments. We show that among a large number of possible de-excitation pathways, the relaxation of biomolecular polyanions is mainly achieved by electron emission following photo-excitation in electronically excited states. Electron photodetachment is a fast process that occurs prior to relaxation on vibrational degrees of freedom. Electron photodetachment yield can then be used to record gas phase action spectra for systems as large as entire proteins, without the limitation of system size that would arise from energy redistribution on numerous modes and prevent fragmentation after the absorption of a photon. The optical activity of proteins in the near UV is directly related to the electronic structure and optical absorption of aromatic amino acids (Trp, Phe and Tyr). UV spectra for peptides and proteins containing neutral, deprotonated and radical aromatic amino acids were recorded. They displayed strong bathochromic shifts. In particular, the results outline the privileged role played by open shell ions in molecular spectroscopy which, in the case of biomolecules, is directly related to their reactivity and biological functions. The optical shifts observed are sufficient to provide unambiguous fingerprints of the electronic structure of chromophores without the requirement of theoretical calculations. They constitute benchmarks for calculating the absorption spectra of chromophores embedded in entire proteins and could be used in the future to study biochemical processes in the gas phase involving charge transfer in aromatic amino acids, such as in the mediation of electron transfer or redox reactions. We then addressed the important question of the sensitivity of protein optical spectra to the intrinsic properties of protein ions, including conformation, charge state, etc., and to environmental factors. We report optical spectra for different charge states of insulin, for ubiquitin starting from native and denaturated solutions, and for apo-myoglobin protein. All these spectra are compared critically to spectra recorded in solution, in order to assess solvent effects. We also report the spectra of peptides complexed with metal cations and show that complexation gives rise to new optical transitions related to charge transfer types of excitation. The perspectives of this work include integrative approaches where UV-Vis spectroscopy could, for example, be combined with ion mobility spectrometry and high level calculations for protein structural characterization. It could also be used in spectroscopy to probe biological processes in the gas phase, with different light sources including VUV radiation (to probe different types of excitations) and ultra short pulses with time and phase modulation (to probe and control the dynamics of de-excitation or charge transfer events), and with the derivatization of proteins with chromophores to modulate their optical properties. We also envision that photo excitation will play an important role in the future to produce intermediates with new chemical and reactive properties. Another promising route is to conduct activated electron photodetachment dissociation experiments. PMID- 21811729 TI - Determination of atrazine in surface waters by combination of POCIS passive sampling and ELISA detection. AB - Polar organic compound integrative samplers (POCIS) in combination with instrumental techniques such as LC-MS-MS were previously used to monitor environmental pollutants but the performance of alternative immunochemical methods such as ELISA (enzyme-linked immunosorbent assay) has been explored less. In the present study, POCIS technology was applied to surface water sampling in the Czech Republic, and ELISA was used as a detection technique for the herbicide atrazine. In the first study, 28 samples from streams around small municipal waste water treatment plants (WWTPs) were collected using two different devices (POCISpest and POCISpharm) over the course of 21 days. Elevated atrazine concentrations (up to 25 ng per POCIS) were found in samples down-stream of WWTPs. This observation was also confirmed in another two year study (4 sampling periods) investigating 7 river sites around a major city of Brno as well as the inlet and outlet of the city's WWTP. High atrazine levels were systematically determined at the outlet from the WWTPs (120-605 ng per POCIS). A decreasing trend in the atrazine concentrations in rivers around the city of Brno has been observed, with the highest levels observed within the first sampling period in spring 2007 (100-600 ng per POCIS, with an extreme value of 2760 ng per POCIS). Results of the atrazine ELISA were closely correlated with LC-MS/MS, which confirmed good applicability of ELISA as a cost-effective screening tool. PMID- 21811730 TI - UVA/Vis-induced nitrous acid formation on polyphenolic films exposed to gaseous NO2. AB - Photochemical processes on ground and airborne surfaces have been suspected to lead to production of HONO in the sunlit lower troposphere, e.g. upon light activation of humic acids followed by reaction with adsorbed NO(2). Here, we used tannic and gentisic acids as proxies for atmospheric polyphenolic compounds to obtain further insights into the photoenhanced NO(2) conversion to HONO, which is a significant tropospheric hydroxyl radical (OH) source. The coated wall flow tube technique was used in combination with online detection of gas-phase HONO and NO(x) under different irradiation conditions. Photoenhanced HONO formation rates of 0.1 to 2 ppbv s(-1) were measured upon NO(2) (0-400 ppbv) uptake on tannic and gentisic acid coatings under irradiation with UV light. The data allow identification of three pathways of light-induced HONO formation: (I) photolysis of a nitroaromatic intermediate formed by a non-photochemical process in the dark, with a photolysis frequency of 10(4) s(-1) at 2 * 10(20) photons m(-2) photon flux; (II) direct photo-oxidation, presumably through electron or hydrogen transfer of the excited substrate; and (III) sensitized electron or hydrogen transfer as suggested before but also demonstrated for visible irradiation here. Aging of tannic acid under oxygen in the dark led to products which promoted light-induced HONO formation in the visible. PMID- 21811731 TI - Highly sensitive and selective colorimetric visualization of streptomycin in raw milk using Au nanoparticles supramolecular assembly. AB - Electrostatic interaction between streptomycin and mercaptoacetic acid modified gold nanoparticles can be used for a facile and reliable probe for streptomycin with high sensitivity and selectivity. PMID- 21811732 TI - First substoichiometric version of the catalytic enantioselective addition of an alkyllithium to an aldehyde. AB - A substoichiometric enantioselective version of the extremely fast nucleophilic addition of Alk-Li to RCHO is made possible thanks to a thorough analysis of the aggregation phenomena involved in the reaction: calculated quantities of LiCl must be added to the medium at the right time to keep the catalytic cycle running. PMID- 21811733 TI - A simple chemical model for clathrate hydrate inhibition by polyvinylcaprolactam. AB - A dimeric model compound gives structural insight into the mode of interaction of low dosage hydrate inhibitors with water. PMID- 21811734 TI - A general model of metal underpotential deposition in the presence of thiol-based additives based on an in situ STM study. AB - Bis(3-sulfopropyl)disulfide (SPS) is a common additive in commercial copper electroplating baths. We have studied the influence of SPS on Cu underpotential deposition (UPD) on a Au(111) single crystal surface by means of cyclic voltammetry (CV) and electrochemical scanning tunneling microscopy (EC-STM). By combining our results with the results from the literature we propose a model that describes different stages of Cu UPD in the presence of SPS. Further analysis shows that our model is also applicable to a more general case of UPD of different metals, e.g. Cu and Ag, on a thiol-modified single-crystal surface, where the bond between the substrate and the thiol is adatom mediated. In addition, we have verified our model by in situ observation of the lifting of the Herringbone reconstruction on the Au(111) surface by Cu UPD. PMID- 21811735 TI - Effect of nitrogen and intrinsic defect complexes on conversion efficiency of ZnO for hydrogen generation from water. AB - Band gap narrowing is important for applications of ZnO, especially for photoelectrochemical water splitting. In this work, we carried out first principles electronic structure calculations with a hybrid density functional on defected ZnO. It is found that nitrogen substitutional doping alone cannot explain the largely enhanced conversion efficiency observed in nitrogen doped ZnO. Instead, complex defects formed by substitutional nitrogen and intrinsic defects play an important role in the band gap narrowing, in agreement with recent experimental results. We propose ZnO fabricated in a Zn-rich environment with heavy nitrogen doping as a photocatalyst for hydrogen generation from water splitting. A method for controlling the band gap of ZnO is also proposed. PMID- 21811736 TI - Reduction of copper(II) complexes of tridentate ligands by nitric oxide and fluorescent detection of NO in methanol and water media. AB - Two copper complexes, 1 and 2, with tridentate N-donor ligands, L(1) and L(2) [L(1)= (1-methyl-1H-imidazol-2-ylmethyl)-(2-pyridin-2-yl-ethyl)amine, L(2) = (2 pyridin-2-yl-ethyl)-pyridin-2 yl-methylamine] respectively, have been synthesized and characterized. On exposure to nitric oxide, the copper(II) centers in complexes 1 and 2 were found to undergo reduction in various solvents. In acetonitrile solvent the reduction was accompanied by a simultaneous N nitrosation on the secondary amine center on the ligand frameworks. Complexes 3 and 4 were prepared with ligands L(3) and L(4), respectively. L(3) and L(4) [L(3) = 5-dimethylamino-naphthalene-1-sulfonic acid (1-methyl-1H-imidazol-2-ylmethyl) (2-pyridin-2-yl-ethyl)-amide; L(4) = 5-dimethylamino-naphthalene-1-sulfonic acid(2-pyridin-2-yl-ethyl)-pyridin-2-ylmethyl-amide] are the dansyl derivatives of L(1) and L(2), respectively. Complex 4, due to paramagnetic quenching, does not display any fluorescence; however, on addition of nitric oxide to a methanol or water solution of complex 4, the fluorescence intensity of the fluorophore has been found to be restored. This is attributed to the reduction of the Cu(II) center by nitric oxide to diamagnetic Cu(I). The turn-on of quenched fluorescence intensity has been observed both in methanol and water media. PMID- 21811737 TI - Binuclear half-metallocene chromium(III) complexes mediated ethylene polymerization with alkylaluminium as cocatalyst. AB - Binuclear half-metallocene chromium complexes {Cp*[3-(CH==NR)-2-O C(10)H(5)]CrCl}(2) [Cp* = C(5)Me(5); R = (i)Pr (1), Ph (2), 2,6-(i)Pr(2)C(6)H(3) (3)] based on 1,1'-binaphthyl ligands, as well as their mononuclear analogues Cp*[3-(CH==NR)-2'-R'-2-O-C(20)H(11)]CrCl [R = (i)Pr, R' = (n)BuO (4), R = Ph, R' = (n)BuO (5), R = 2,6-(i)Pr(2)C(6)H(3), R' = (n)BuO (6), R = (i)Pr, R' = H (7)], were synthesized and characterized by mass spectrometry, elemental analysis, magnetic measurement, and UV-vis spectroscopy. The molecular structures of complexes 1, 3, 5 and 6 were further confirmed by single-crystal X-ray crystallographic analysis. When activated with a small amount of AlMe(3), these binuclear complexes exhibited higher activities in catalyzing ethylene polymerization in comparison with their mononuclear analogues, affording high molecular weight polymers with unimodal molecular weight distributions. The highest activity up to 2.87 * 10(6) g PE (mol Cr)(-1) h(-1) was achieved in the catalyst system of complex 3 bearing a bulky 2,6-(i)Pr(2)C(6)H(3) group on the imine nitrogen atom in the presence of 25 equiv. AlMe(3) as activator at 20 degrees C. (13)C NMR analysis indicates the resultant polymers are linear and no evidence on branch was found. PMID- 21811738 TI - Predicting and rationalizing the effect of surface charge distribution and orientation on nano-wire based FET bio-sensors. AB - A single charge screening model of surface charge sensors in liquids (De Vico et al., Nanoscale, 2011, 3, 706-717) is extended to multiple charges to model the effect of the charge distributions of analyte proteins on FET sensor response. With this model we show that counter-intuitive signal changes (e.g. a positive signal change due to a net positive protein binding to a p-type conductor) can occur for certain combinations of charge distributions and Debye lengths. The new method is applied to interpret published experimental data on Streptavidin (Ishikawa et al., ACS Nano, 2009, 3, 3969-3976) and Nucleocapsid protein (Ishikawa et al., ACS Nano, 2009, 3, 1219-1224). PMID- 21811739 TI - Growth of immobilized DNA by polymerase: bridging nanoelectrodes with individual dsDNA molecules. AB - We present a method for controlled connection of gold electrodes with dsDNA molecules (locally on a chip) by utilizing polymerase to elongate single-stranded DNA primers attached to the electrodes. Thiol-modified oligonucleotides are directed and immobilized to nanoscale electrodes by means of dielectrophoretic trapping, and extended in a procedure mimicking PCR, finally forming a complete dsDNA molecule bridging the gap between the electrodes. The technique opens up opportunities for building from the bottom-up, for detection and sensing applications, and also for molecular electronics. PMID- 21811740 TI - SnO2 nanosheet hollow spheres with improved lithium storage capabilities. AB - In this work, we employ new chemistry to grow tin oxide nanosheets in the gel matrix of sulfonated polystyrene hollow spheres. After calcination in air, hierarchical hollow spheres assembled from SnO(2) nanosheets can be obtained. In virtue of the porous shell structure and internal voids, these SnO(2) hierarchical nanosheet hollow spheres exhibit improved lithium storage capability. PMID- 21811741 TI - Local structure of Mn4+ and Fe3+ spin probes in layered LiAlO2 oxide by modelling of zero-field splitting parameters. AB - The zero-field splitting parameters (ZFS) of Mn(4+) and Fe(3+) ions in LiAlO(2) with a layered structure are analyzed experimentally and theoretically by using high-frequency electron paramagnetic resonance spectroscopy, Neuman superposition model (NSM), DFT and multiconfigurational calculations. The interpretation of ZFS is based on the comparison of the experimentally determined values with the calculated ones. This approach allows assessing the performance of different methods for computation of ZFS of Fe(3+) and Mn(4+) in layered oxide matrices. DFT and multiconfigurational calculations are used to analyze the effect of oxygen, aluminium, and lithium neighbours on ZFS of Fe(3+) and Mn(4+). These calculations are based on a cluster comprising Fe(3+) or Mn(4+) ions in a trigonally compressed octahedron with 6 metal ions (Al(3+) or Co(3+)) as first metal neighbours and 6 O(2-) and 2 Li(+) (above and below the layer) as second neighbours. A satisfactory agreement with the experimental data is achieved when the local structure of Mn(4+) and Fe(3+) deviates from the trigonal host-site geometry. The local structure of Fe(3+) comprises an axial distortion, while trigonal environment with reduced extent of distortion appears around Mn(4+). PMID- 21811742 TI - Au@Ag core-shell nanoparticles: efficient all-plasmonic Fano-resonance generators. AB - Fano resonances (FR) in strongly coupled systems like a metallic dimer arise due to the coupling between the spectrally localized surface plasmon resonance (SPR) of a noble metal nanoparticle and the continuum of interband transitions of the other. Since its discovery in Au-Ag dimers, several plasmonic structures have been proposed as candidates for obtaining Fano resonances. However, most of them either are difficult to synthesize or do not generate FR signal of adequate intensity. In this paper we demonstrate that simple Au@Ag core-shell nanoparticles with typical shell thickness below 5.0 nm, which can be synthesized through a common citrate reduction method, have a Fano resonance easily detectable in the far-field. PMID- 21811743 TI - Kinked gold nanowires and their SPR/SERS properties. AB - We report a facile chemical synthesis of kinked gold nanowires through anisotropic growth along the (111) direction with a high density of twin-plane defects. The resulting kinked gold nanowires exhibited pronounced near-IR absorption and were demonstrated as good SERS substrates. PMID- 21811744 TI - Management of human cytomegalovirus infection in transplantation: validation of virologic cut-offs for preemptive therapy and immunological cut-offs for protection. AB - Human cytomegalovirus (HCMV) still causes major viral complications in the post transplant period of both solid-organ (SO) and hematopoietic stem cell (HSC) transplant (T) recipients (R). Diagnosis of HCMV infection is mostly made by real time PCR-based methodologies, which allow quantification of viral DNA in both blood and, if required, organ tissues or local secretions. HCMV infection/disease can be prevented by either universal prophylaxis or preemptive therapy. The latter approach has mostly been used in European Transplantation Centers upon reaching predetermined cut-off levels of viral load, predictive of high risk for HCMV disease. In our Department, these cut-offs are higher for SOTR (3x105 DNA copies/ml whole blood) and lower for HSCTR (3x104 DNA copies/ml). Antiviral therapy is continued until viral DNA disappearance from blood or tissues. However, the authentic long-term control of HCMV infection is achieved when HCMV specific CD4+ and CD8+ T-cells are detected in blood or tissues. Proposed immunological cut-off levels conferring protection are: one HCMV-specific CD4+ and three CD8+ T-cells/ml blood for HSCTR, and 0.4 HCMV-specific T-cells/ml for both CD4+ and CD8+ in SOTR. However, anti-rejection in SOTR and anti- GvHD in HSCTR steroid therapies make patients susceptible to HCMV infection, even in the presence of protective levels of specific T-cells. PMID- 21811745 TI - Synergy of molecular and serological methods in minimally invasive diagnosis of enteroviral cardiac infection. AB - Treatment of myocarditis and pericarditis can differ on the basis of aetiology: systemic or auto-immune disease can be positively influenced by corticoid therapy, whereas this kind of treatment can worsen the course of virus-induced disease. Therefore, the aetiological diagnosis is extremely important. The synergistic use of minimally invasive serological, IgG, IgM, IgA, and neutralizing titres, and RNA detection was evaluated on representative patients out of 238 suffering from cardiopathies. The results obtained for each case can yield reliable guidelines that rapidly highlight the presence of a viral aetiology so that an endomyocardial biopsy can be performed thus eliminating incorrect therapies. Thus, not only is this technique rapid, minimally invasive providing the clinician with decisive data, but it is cost effective for the health system. PMID- 21811746 TI - Prevalence of cytomegalovirus infection and its role in total immunoglobulin pattern in Iranian patients with different subtypes of multiple sclerosis. AB - Multiple sclerosis (MS) is the most common autoimmune disease characterized by multifocal areas of inflammatory demyelination within the central nervous system. Cytomegalovirus (CMV) has a complex pathobiology and in most cases is simply asymptomatic. There is some recent controversy over the role of CMV in the pathology of MS. The aim of this study was to evaluate active CMV infection and its effect on the humoral immunity in patients with MS. Serum, plasma, peripheral blood mononuclear cells (PBMCs), saliva and urine collected from MS patients (n=78) and healthy subjects (n=123) were screened for the presence of anti-CMV antibodies and CMV-DNA by nephelometric and PCR methods. Concentrations of total antibodies in MS subtypes were measured using both nephelometric and enzyme linked fluorescent assay (ELFA) techniques. The results extend the observation of an increased frequency of CMV-DNA in patients, in contrast with controls (p<0.001). Furthermore, systemic CMV infections were found in 25.5% of patients and only 3.2% of controls (p<0.001). There was significant difference in the titers of anti-CMV IgG and total IgE in patient and controls (P<0.001). These results support the hypothesis that CMV may contribute to MS thought to establish systemic infection process and induce immune response. PMID- 21811747 TI - Quantitative detection of HHV-6 and HHV-7 in transbronchial biopsies from lung transplant recipients. AB - The occurrence and significance of HHV-6 and HHV-7 were investigated in pulmonary tissue from lung transplant recipients. Eighty-seven transbronchial biopsies from 30 patients were studied by quantitative real-time PCR; the association with histopathological features was investigated. HHV-6 and HHV-7-DNA were detected in 6.9% and 9.2% transbronchial biopsies, respectively. A significant association between HHV-6 detection on transbronchial biopsies and interstitial pneumonia was found, in contrast to the lack of association between viral detection on bronchoalveolar lavage and any histopathological feature. No association was evidenced in terms of acute and chronic rejection. The finding of HHV-6 and/or HHV-7-DNA positivity in all the cases with ischemia-reperfusion injury suggests a possible role in favouring ?-herpesviruses reactivation, as previously described for HCMV in renal transplantation. PMID- 21811748 TI - Effective use of nitrocellulose-blotted antigens for phage display monoclonal antibody selection. AB - The combinatorial phage display library approach to antibody repertoire cloning offers a powerful tool for the isolation of specific antibodies to defined target antigens. Panning strategy is often a very critical point for selecting antibody displayed on the surface of bacteriophages. Most selection strategies described to date have relied on the availability of purified and often recombinant antigen, providing the possibility to perform selections on a well defined antigen source. However, when the antigen is difficult to purify by means of laborious and time-consuming chromatography procedures, panning of phage antibody libraries has to be performed on complex antigen sources such as cell surfaces or tissue sections, or even by in vivo selection methods. This provides a series of technical and experimental complications. In the present work, we successfully generated a mouse monoclonal antibody fragment from a phage display library directed against protein E7 of HPV18 avoiding antigen purification as for immunizing mice as for antibody library selection. Our work demonstrates the feasibility of phage antibody selections on antigens transferred to a nitrocellulose membrane as solid support, using one-dimensional polyacrylamide gel electrophoresis system as the only practice to separate a given antigen present in bacterial crude cell lysate. PMID- 21811749 TI - Two unlinked cases of foodborne botulism in Italy at the beginning of 2010. AB - The study provides data on two cases of foodborne botulism caused by consumption of commercial vegetable products: artichoke preserve and cream of vegetable soup. By mouse bioassay, Clostridium botulinum toxin in both the suspected food samples was detected and identified as type B toxin. The detection of C. botulinum toxin in the artichoke preserve indicates an inadequate food production technology while the presence of C. botulinum toxin in the vegetable soup appeared to be related to wrong behavior on the part of the consumer and to faulty food preservation. The study confirms that an early identification and reporting of suspected botulism cases is vital in the prevention of accidental widespread outbreaks. PMID- 21811750 TI - Antibiotic utilization and Pseudomonas aeruginosa resistance in intensive care units. AB - Pseudomonas aeruginosa is one of the most frequent and dangerous pathogens involved in the etiology of severe nosocomial infections. A retrospective observational study was conducted at all intensive care units of the University Hospital in Olomouc, Czech Republic (155 ICU beds). Complete antibiotic utilization data of the ICUs in the period of 1999 to 2008 were processed according to ATC/DDD system and expressed in defined daily doses per 100 bed-days (DBD). Utilization of meropenem, imipenem, ciprofloxacin, ofloxacin, pefloxacin, gentamicin, amikacin, ceftazidime, cefoperazone, cefoperazone/sulbactam and piperacillin/tazobactam was measured. Pseudomonas aeruginosa strains were isolated from clinical material obtained from patients hospitalized in ICUs. During the ten-year period, utilization of the entire group of antibiotics monitored grew. It increased from 23.52 DBD in 1999 to 27.48 DBD in 2008 with a peak of 33.04 DBD in 2007. P. aeruginosa accounted for as much as 42% of pneumonias and 23% of surgical wound infections. Our results show that P. aeruginosa strains became gradually resistant to all antibiotics used in the treatment of the infections caused by them, with the exception of amikacin and piperacillin/tazobactam. PMID- 21811751 TI - Comparison between two standardized cultural methods and 24 hour duplex SYBR green real-time PCR assay for Salmonella detectionin meat samples. AB - Food-borne diseases caused by Salmonella represent a worldwide public health problem. Salmonella must be absent in an established amount depending on the kind of the product and usually cultural methods have to be applied to evaluate the compliance of the products. ISO 6579:2002 in Europe and FSIS MLG 4.04.:2008 in the USA have usually been employed to detect Salmonella in meat, poultry and egg products. A Real Time PCR method using probes has recently been validated against the NMKL (Nordic Committee on Food Analysis) standard method. This method has been modified using the less expensive Sybr Green Real Time PCR approach and applied directly in the 18 hours preenrichment broth for the purpose of detecting Salmonella in meat products in less than 24 hours. The purpose of this study was to: - compare the effectiveness of ISO and FSIS cultural methods; - develop a new 24 hour duplex Sybr Green Real Time PCR-melting curve analysis; - evaluate the performance of Salmonella, Standard Method, Rapid Method, SYBR Green Real Time PCR. The equivalence between ISO and FSIS methods was demonstrated and the use of SYBR Green Real Time PCR as a screening tool for negative results seems appealing especially to evaluate compliance with the HACCP systems. PMID- 21811752 TI - The protein "mycoarray": a novel serological assay for the laboratory diagnosis of primitive endemic mycoses. AB - A protein microarray containing fungal antigens (the "mycoarray") has been set up to provide rapid and appropriate serodiagnosis of primitive endemic mycoses, an important cause of morbidity and mortality in an increasingly high number of patients. The mycoarray consists of three antigen extracts (histoplasmin, coccidioidin and Coccidioides "TP") and antibody dilution curves were spotted on microarray slides. The arrays were processed with coccidioidomycosis and histoplasmosis patients? sera or with control sera and the occurring immunocomplexes were detected by indirect immunofluorescence. In agreement with clinical and microbiological diagnosis, the results distinguished between histoplasmosis and coccidioidomycosis patients. In addition, the assay could clearly discriminate between IgM and IgG antibody reactivity. No reactivity was ever observed in the arrays processed with negative control sera. Therefore, this pilot study demonstrates that the "mycoarray" is sensitive and specific enough to discriminate between healthy individuals and patients with histoplasmosis or coccidioidomycosis. Because of miniaturization and multiparametricity, the new assay cuts costs and processing time. Thus, once clinically validated and implemented as a large-scale array, the "mycoarray" will be ready to be applied to the daily clinical practice. PMID- 21811753 TI - Hepatic safety profile of darunavir with low-dose ritonavir (DRV/r) in HIV/HCV coinfected and HIV monoinfected patients. AB - The hepatic safety profile of ART including DRV/r was retrospectively evaluated in antiretroviral-experienced HIV-infected patients (18 HIV/HCV coinfected, group A and 29 infected with HIV alone, group B) during a 72 week study. During the study, liver enzyme values were higher in group A, but in the case of abnormal transaminase levels, the median values did not exceed 1.6xULN. This study showed evidence of long-lasting hepatic safety of ART including PI DRV/r in HIV/HCV coinfected and in HIV monoinfected persons. PMID- 21811754 TI - Preliminary data of different methods for the indirect diagnosis of Mycobacterium bovis infection. AB - We compared the response induced by QuantiFERON-TB Gold antigens to that obtained with the Intradermal Comparative Tuberculin Test and BOVIGAM assay. Our results showed that the QuantiFERON-TB Gold technique used in humans could also be applied for the diagnosis of TB infection in cattle. PMID- 21811755 TI - Diagnosing tuberculosis in pregnancy: a case report. AB - A case of miliary tuberculosis complicated by deciduitis and sub-chorionitis in a pregnant woman manifesting also influenza A/H1N1v infection and urinary tract infection is reported. Diagnosis of tuberculosis was obtained before delivery by examining amniotic fluid for Mycobacterium tuberculosis. Even though maternal symptoms did not suggest TB, diagnosis was early enough to start effective treatment in both the mother and the neonate and prevent in-hospital M.tuberculosis diffusion. A high index of suspicion by health professionals is required to detect and manage tuberculosis in pregnancy and newborns in both the developed and developing word. PMID- 21811756 TI - Recurrence of erythema induratum of Bazin in a patient under chemotherapy for breast cancer. AB - Erythema induratum of Bazin (EIB) is a chronic nodular eruption occurring on the lower legs of young and middleaged women which is considered the most common tuberculid. A 54-year-old woman, in treatment with chemotherapy for breast cancer, presented subcutaneous erythematous plaques and nodules on the lower limbs. She had been diagnosed with EIB 3 years earlier and diagnostic work-up showed at that time signs suggestive of latent tuberculosis. The suspect of a recurrent form of EIB was confirmed by histopathological examination. A peculiar feature of our report consists in the recurrence of EIB, which is regarded as a hyperergic response against M. tuberculosis antigens, in a patient who was receiving chemotherapy with well-known immunosuppressive effects. PMID- 21811757 TI - Intestinal myiasis due to Eristalis tenax: report of a new case in Spain. AB - We describe a new case of accidental intestinal myiasis by Eristalis tenax in Spain. Only about 20 cases have been reported worldwide, two of them occurring in Spain. A 51-year-old patient with nonspecific abdominal pain and occasional diarrhoea expelled larvae in her stool. Macroscopic analysis of these larvae revealed morphology compatible with that of Eristalis tenax. The larva analysis showed its autofluorescence as parasitological feature described for the first time. PMID- 21811758 TI - Role of HSP27 in tumor necrosis factor-alpha-stimulated interleukin-6 synthesis in osteoblasts. AB - Heat shock protein 27 (HSP27) is known to act as a molecular chaperone. We have recently reported that HSP27 regulates osteocalcin synthesis in osteoblast-like MC3T3-E1 cells. In the present study, we investigated the role of HSP27 in tumor necrosis factor-alpha (TNF-alpha)-stimulated interleukin-6 (IL-6) synthesis in MC3T3-E1 cells. The levels of IL-6 release and IL-6 mRNA stimulated by TNF-alpha in MC3T3-E1 cells transfected with HSP27 was significantly higher than those in the control cells. In addition, the levels of secreted IL-6 and IL-6 mRNA in the phospho-mimic HSP27-overexpressing cells were significantly higher than those in the non-phosphoryl-atable HSP27-overexpressing cells. Furthermore, we observed no significant differences in the phosphorylation levels of IkappaB/NFkappaB, Akt, and p44/p42 mitogen-activated protein kinase among the 4 types of transfected cells. Therefore, these results strongly suggest that HSP27 enhances TNF-alpha stimulated IL-6 synthesis, and that the phosphorylation status of HSP27 is related to IL-6 synthesis in osteoblasts. PMID- 21811759 TI - Alleviation of atopic dermatitis-related symptoms by Perilla frutescens Britton. AB - To ascertain whether an aqueous fraction of Perilla frutescens Britton (PfB/af) has advantageous anti-atopic dermatitis activity, we used a 2,4 dinitrofluorobenzene (DNFB)-induced animal model of atopic dermatitis symptoms to investigate the effects of the extract. We performed an ear swelling assay by comparing thickness of the DNFB-induced ear, and measured the numbers of eosinophils as well as total immune cells. We analyzed the expression levels of matrix metalloproteinase (MMP)-9, interleukin (IL)-31 and of the T-bet transcription factor. The results revealed that PfB/af (100 ug/ml) exhibited strong anti-atopic dermatitis activity, interceding drastic reduction (35%) of the immune response, as measured by the thickness of ear epidermis swelling, and resulting in decreased eosinophil levels (73.7%) in adjacent skin tissues. Collectively, the present results suggest that PfB/af has potential for mitigation of atopic dermatitis-like symptoms induced by DNFB in the mouse. PMID- 21811760 TI - Different patterns of nigrostriatal degeneration in tremor type versus the akinetic-rigid and mixed types of Parkinson's disease at the early stages: molecular imaging with 123I-FP-CIT SPECT. AB - The various associations of motor and non-motor symptoms, the onset of motor complications, the cognitive disorder's appearance and other factors make Parkinson's disease (PD) a heterogeneous syndrome with multiple phenotypes. The necessity of discriminating between different forms of PD could have a role in understanding the pathophysiology of extrapyramidal signs with clinical implications. The aim of this study was to evaluate if there is a relationship between the clinical motor phenotypes of PD and the scintigraphic pattern of 123I FP-CIT single photon emission computed tomography (SPECT). We examined 47 patients with early idiopathic PD (25 males; 22 females; mean age 58+/-2 years) and subdivided them in different clinical forms on the basis of dominance of resting tremor (n=20), bradykinesia plus rigidity (n=20) and the presence of both clinical signs [mixed type (MT, n=7)]. We correlated this status with the semi quantitative analysis of SPECT with 123I-FP-CIT. Tremor type patients showed a lower reduction of 123I-FP-CIT uptake compared to akinetic-rigid type patients in contralateral caudate (P=0.0139) and putamen (P=0.0028) nuclei. 123I-FP-CIT uptake was higher in the ipsilateral caudate (P=0.0050) and putamen (P=0.0012) of tremor type patients compared to akinetic-rigid type patients. Comparisons of the striatal uptake in the tremor type and akinetic-rigid type patients with the MT patients revealed significant differences only in the ipsilateral and contralateral caudate. Our data indicate that in akinetic-rigid patients the dopaminergic system is more involved compared to that in the tremor type patients and that this difference is present from the initial stage of the disease. Moreover, our results suggest that PD phenotypes could be related not only to the dopaminergic involvement but also to other systems. PMID- 21811761 TI - Podoplanin and SOX2 expression in esophageal squamous cell carcinoma after neoadjuvant chemo-radiotherapy. AB - Neoadjuvant chemo-radiotherapy (CRT) followed by surgery are the standard approaches for locally advanced esophageal cancer. However, the overall cure rate is very low. The aim of this preliminary study was to evaluate the expression of podoplanin and SOX2 known as stemness markers for esophageal squamous cell carcinoma (ESCC) and their association with clinical outcome. We obtained a total of 20 specimens from patients with ESCC who underwent neoadjuvant CRT (30-40 Gy; 5-fluorouracil plus cisplatin) followed by surgery. Podoplanin and SOX2 expression was evaluated using immunohistochemistry and the association of their expressions with clinicopathological variables was investigated. Podoplanin and SOX2 staining was detected not only in residual cancer cells, but also in the basal layer of adjacent normal mucosa after neoadjuvant CRT. High expression of podoplanin was correlated with lymph node metastasis, advanced postoperative stage and vascular invasion (P<0.05), while, high expression of SOX2 was correlated with lymphatic, vascular invasion, poor differentiated tumor and incomplete resection (P<0.05). High expression of podoplanin was significantly associated with poor overall survival (P<0.05). In conclusion, the expression levels of podoplanin and SOX2 expression may be useful prognostic markers for ESCC treated with neoadjuvant CRT. PMID- 21811762 TI - Protein expression of the Ets transcription factor Elf-1 in breast cancer cells is negatively correlated with histological grading, but not with clinical outcome. AB - Several members of the Ets (E26 transformation specific) transcription factor family are involved in tumor progression, e.g. by activating matrix metalloproteases. Ets proteins share a unique DNA-binding domain, the Ets domain, which specifically recognizes GGAA/T-containing sequences common in many promoters. While the roles of quite a number of Ets proteins in carcinogenesis have been well established, little is known about the importance of the Ets protein Elf-1 (E74-like factor 1) in cancer. Herein, we analyzed the expression of Elf-1 in breast cancer. We found that, like T-cells, breast cancer cells express both the 80 and 98 kDa isoforms of the Elf-1 protein with the 98 kDa isoform only be present in the nucleus. Immunohistochemical analysis of 119 breast cancer biopsies showed anti-Elf-1 immunoreactivity exclusively in the nucleus. Elf-1 expression varied largely among the breast cancer samples showing a negative correlation with histological grading. However, no association of Elf 1 expression with clinical outcome was observed, even when sub-cohorts of patients who received either only adjuvant endocrine treatment or only chemotherapy were separately analyzed. These data suggest that Elf-1 may modulate breast cancer progression to some extent without having an impact on survival of breast cancer patients. PMID- 21811763 TI - Curcumin reverses chemoresistance of human gastric cancer cells by downregulating the NF-kappaB transcription factor. AB - Gastric cancer remains one of the major health problems worldwide. Chemotherapy is an important therapeutic modality for gastric cancer, but the success rate of this treatment is limited because of chemoresistance. The ubiquitously expressed transcription factor NF-kappaB has been suggested to be associated with chemoresistance of gastric cancer. Agents that can either enhance the effects of chemotherapeutics or overcome chemoresistance to chemotherapeutics are needed for the treatment of gastric cancer. Curcumin, a component of turmeric, is one such agent that has been shown to suppress NF-kappaB and increase the efficacy of chemotherapy. In this study, we investigated whether curcumin can reverse chemoresistance by downregulating NF-kappaB in human gastric cancer cells. SGC 7901 human gastric cancer cells was treated with chemotherapeutics (etoposide and doxorubicin) or by combined application of curcumin and chemotherapeutics. The viability of SGC-7901 cells was measured by MTT assay. Apoptosis of SGC-7901 cells was detected using the TUNEL and Annexin V/PI methods. The protein levels of NF-kappaB were analyzed by immunocytochemical staining. EMSA was used to confirm the increased nuclear translocation of RelA. The protein levels of p IkappaBalpha, Bcl-2 and Bcl-xL were analyzed by Western blotting. The chemotherapeutics (etoposide and doxorubicin) suppressed the growth of SGC-7901 cells, in a time-dose-dependent manner. Use of curcumin in addition to these agents can suppress cell growth further (inhibitory rate: doxorubicin vs. doxorubicin + curcumin, 33% vs. 45%, p<0.05; etoposide vs. etoposide + curcumin, 35% vs. 48%, p<0.05). Furthermore, chemotherapeutics induced apoptosis of SGC 7901 cells and activated NF-kappaB. The combination of curcumin and chemotherapeutics induced apoptosis of SGC-7901 cells further, attenuated the activation of NF-kappaB, and reduced expression of the NF-kappaB-regulated anti apoptotic gene products Bcl-2 and Bcl-xL. Curcumin potentiates the antitumor effects of chemotherapeutics in gastric cancer by suppressing NF-kappaB and NF kappaB-regulated anti-apoptotic genes. PMID- 21811764 TI - Acetylbritannilactone suppresses growth via upregulation of kruppel-like transcription factor 4 expression in HT-29 colorectal cancer cells. AB - Acetylbritannilactone (ABL) is a new active compound isolated from Inula Britannica L, a traditional Chinese medicinal herb. It has been reported that ABL can inhibit the proliferation of vascular smooth muscle cells (VSMCs) and neointima formation after balloon injury in rats. ABL also shows chemopreventive properties by inducing cell apoptosis in breast and ovarian cancers, but the antitumor activity and the molecular targets of ABL in colon cancer cells have not been determined. In this study, we showed that ABL inhibits the growth in dose- and time-dependent manners by inducing cell cycle arrest in G0/G1 phase of HT-29 human colon cancer cells. This suppression was accompanied by a strong decrease of cyclin E and CDK4 protein levels, and an increase in p21 protein expression in HT-29 cells. We also show that ABL-induced growth inhibition is associated with the upregulation of KLF4 expression. The overexpression of KLF4 by infection with pAd-KLF4 resulted in growth inhibition, with decrease in the protein levels of cyclin E and CDK4, and increase in the expression of p21, similarly to the effects of ABL. Conversely, knockdown of KLF4 using a specific siRNA impaired the ABL-induced growth inhibition in HT-29 cells. These results suggest that KLF4 as an important cellular target of ABL mediates the growth inhibition of HT-29 cells induced by ABL via upregulation of p21 expression. PMID- 21811765 TI - Correlation between computed tomography findings and epidermal growth factor receptor and KRAS gene mutations in patients with pulmonary adenocarcinoma. AB - We examined the correlation between computed tomography (CT) findings and the incidence of epidermal growth factor receptor (EGFR) and KRAS mutations in lung adenocarcinoma. We analyzed the tumors of 136 patients with surgically resected primary lung adenocarcinoma. CT scans were evaluated for the presence of ground grass opacity (GGO), spiculation and the maximum diameter of the tumor was measured. SMart Amplification Process (ver. 2) was used to detect the presence of EGFR and KRAS mutations. EGFR and KRAS mutations were found in 56 (41.1%) and 25 (18.4%) of the 136 cases, respectively. Although no significant association was found between GGO and EGFR mutations (p=0.07), the EGFR mutation occurred more frequently in male patients with GGO than in those without GGO (p=0.04). The KRAS mutation occurred more frequently in patients whose tumor diameter was >= 31 mm than in those whose tumor diameter was <30 mm (p=0.003). Evaluation of CT findings may be helpful for determining the presence of EGFR and KRAS mutations, particularly when it is not possible to obtain a tumor specimen. PMID- 21811766 TI - Increased fall risk is associated with elevated co-contraction about the ankle during static balance challenges in older adults. AB - Falls are a leading contributor to disability in older adults. Increased muscle co-contraction in the lower extremities during static and dynamic balance challenges has been associated with aging, and also with a history of falling. Co contraction during static balance challenges has not been previously linked with performance on clinical tests designed to ascertain fall risk. The purpose of this study was to investigate the relationship between co-contraction about the ankle during static balance challenges with fall risk on a commonly used dynamic balance assessment, the Four Square Step Test (FSST). Twenty-three volunteers (mean age 73 years) performed a series of five static balance challenges (Romberg eyes open/closed, Sharpened Romberg eyes open/closed, and Single Leg Standing) with continuous electromyography (EMG) of bilateral tibialis anterior and gastrocnemius muscles. Participants then completed the FSST and were categorized as 'at-risk' or 'not-at-risk' to fall based on a cutoff time of 12 s. Co contraction was quantified with co-contraction index (CCI). CCI during narrow base conditions was positively correlated with time to complete FSST. High CCIs during all static balance challenges with the exception of Romberg stance with eyes closed were predictive of being at-risk to fall based on FSST time, odds ratio 19.3. The authors conclude that co-contraction about the ankle during static balance challenges can be predictive of performance on a dynamic balance test. PMID- 21811767 TI - Muscle damage induced by electrical stimulation. AB - Electrical stimulation (ES) induces muscle damage that is characterised by histological alterations of muscle fibres and connective tissue, increases in circulating creatine kinase (CK) activity, decreases in muscle strength and development of delayed onset muscle soreness (DOMS). Muscle damage is induced not only by eccentric contractions with ES but also by isometric contractions evoked by ES. Muscle damage profile following 40 isometric contractions of the knee extensors is similar between pulsed current (75 Hz, 400 MUs) and alternating current (2.5 kHz delivered at 75 Hz, 400 MUs) ES for similar force output. When comparing maximal voluntary and ES-evoked (75 Hz, 200 MUs) 50 isometric contractions of the elbow flexors, ES results in greater decreases in maximal voluntary contraction strength, increases in plasma CK activity and DOMS. It appears that the magnitude of muscle damage induced by ES-evoked isometric contractions is comparable to that induced by maximal voluntary eccentric contractions, although the volume of affected muscles in ES is not as large as that of eccentric exercise-induced muscle damage. It seems likely that the muscle damage in ES is associated with high mechanical stress on the activated muscle fibres due to the specificity of motor unit recruitment (i.e., non-selective, synchronous and spatially fixed manner). The magnitude of muscle damage induced by ES is significantly reduced when the second ES bout is performed 2-4 weeks later. It is possible to attenuate the magnitude of muscle damage by "pre conditioning" muscles, so that muscle damage should not limit the use of ES in training and rehabilitation. PMID- 21811768 TI - Pelvic organ prolapse and collagen-associated disorders. AB - INTRODUCTION AND HYPOTHESIS: Pelvic organ prolapse (POP) and other disorders, such as varicose veins and joint hypermobility, have been associated with changes in collagen strength and metabolism. We hypothesized that these various disorders were more prevalent in both POP patients and their family members. METHODS: In this study, the prevalence of various collagen-associated disorders, including POP, was compared between POP patients (n = 110) and control patients (n = 100) and their first and second degree family members. RESULTS: POP patients reported a higher prevalence of varicose veins, joint hypermobility and rectal prolapse and were more likely to have family members with POP as compared to the control group (p < 0.01). In contrast, the family members of the POP group did not report a higher prevalence of collagen-associated disorders compared to the family members of the control group (p = 0.82). CONCLUSIONS: POP and other collagen associated disorders may have a common aetiology, originating at the molecular level of the collagens. PMID- 21811769 TI - Sexual function following retropubic TVT and transobturator Monarc sling in women with intrinsic sphincter deficiency: a multicentre prospective study. AB - INTRODUCTION AND HYPOTHESIS: A prospective study comparing the effect of the tension-free vaginal tape (TVT) to the Monarc sling on sexual function in women with urodynamic stress incontinence (USI) and intrinsic sphincter deficiency (ISD) is presented. METHODS: Eighty-seven sexually active women with USI and ISD were enrolled. Sexual function was assessed pre-operatively and at 6 and 12 months post-operatively by history, PISQ-12, UDI-6 and IIQ-7 questionnaires. RESULTS: A significant increase was detected in PISQ-12 score following both TVT and Monarc insertion. This score was greater in the TVT group at 6 months but not at 12 months when compared to the Monarc group. A significant decrease in UDI-6 and IIQ-7 score was detected. Specifically, coital incontinence and fear of leakage were reduced in both groups, and no change in dyspareunia or orgasm intensity was found. CONCLUSIONS: Sexual function improves 6 months after TVT or Monarc sling, and this benefit is maintained at 12 months. PMID- 21811770 TI - Assessment of flubendiamide residues in pigeon pea in different agro-climatic zones of India. AB - Supervised field trials were conducted at the research farms of four agricultural universities located at different agro-climatic zones of India to find out the harvest time residues of flubendiamide and its des-iodo metabolite on pigeon pea (Cajanus cajan) during the year 2006-2007. Two spray applications of flubendiamide 20 WDG at 50 g (T(1)) and 100 g (T(2)) a.i./ha were given to the crop at 15-days interval. The foliage samples at different time intervals were drawn at only one location, however, the harvest time samples of pigeon pea grain, shell, and straw were drawn at all the four locations. The residues were estimated by HPLC coupled with UV-VIS variable detector. No residues of flubendiamide and its des-iodo metabolite were found at harvest of the crop at or above the LOQ level of 0.05 MUg/g. On the basis of the data generated, a pre harvest interval (PHI) of 28 days has been recommended and the flubendiamide 20 WDG has been registered for use on pigeon pea by Central Insecticide Board and Registration Committee, Ministry of Agriculture, Government of India and the MRL has been fixed by Ministry of Health and Family Welfare, Government of India under Prevention of Food and Adulteration as 0.05 MUg/g on pigeon pea grains. PMID- 21811771 TI - The variability of surface water quality indicators in relation to watercourse typology, Czech Republic. AB - This paper examines the relationships between watercourse typology and selected indicators of long-term surface water quality for rivers in the Czech Republic. The parameters used to define watercourse typology are in accord with the Water Framework Directive 2000/60/EC outlined by the European Commission. The relationships were tested using descriptive and multivariate statistical analysis, namely cluster analysis and canonical correspondence analysis. It was found that only some of the typological parameters have a close association with indicators of surface water quality. Specifically, the parameters of altitude and geology show clear relationships with pH, calcium content, and the saprobity index of macroinvertebrates. Conversely, parameters that are strongly influenced by anthropogenic pollution show weak relationships with indicators of surface water quality. These depend instead on the presence of pollution sources rather than on natural environmental conditions. PMID- 21811772 TI - A simple method to identify areas of environmental risk due to manure application. AB - The management of swine manure is becoming an important environmental issue in Chile. One option for the final disposal of manure is to use it as a biofertilizer, but this practice could impact the surrounding environment. To assess the potential environmental impacts of the use of swine manure as a biofertilizer, we propose a method to identify zones of environmental risk through indices. The method considers two processes: nutrient runoff and solute leaching, and uses available information about soils, crops and management practices (irrigation, fertilization, and rotation). We applied the method to qualitatively assess the environmental risk associated with the use of swine manure as a biofertilizer in an 8,000-pig farm located in Central Chile. Results showed that the farm has a moderate environmental risk, but some specific locations have high environmental risks, especially those associated with impacts on areas surrounding water resources. This information could assist the definition of better farm-level management practices, as well as the preservation of riparian vegetation acting as buffer strips. The main advantage of our approach is that it combines qualitative and quantitative information, including particular situations or field features based on expert knowledge. The method is flexible, simple, and can be easily extended or adapted to other processes. PMID- 21811773 TI - Lenalidomide in combination with dexamethasone induced rhabdomyolysis in a multiple myeloma patient treated with pravastatin. PMID- 21811775 TI - Conformational flexibility, binding energy, role of salt bridge and alanine mutagenesis for c-Abl kinase complex. AB - Abl kinase plays a decisive role in the mechanism of the most fatal human pathogen chronic mylogenous leukemia (CML). Here, we have carried out a comprehensive study about the conformational flexibility, role of salt bridge and the protein- ligand interaction for this kinase with its well-known inhibitor, Imatinib. We have performed molecular dynamics simulations for conformational behavior, investigated the salt bridges and calculated the binding free energy of Imatinib with MM-PB/SA method for Abl kinase complex. We also explored the role of salt-bridge in the kinase complex and its effect on binding activity of inhibitors. Furthermore, to investigate the importance of those residues which form salt bridges, we mutated them by Alanine with the help of Alanine scanning program. We noticed significant variations in total free energy of Imatinib in all possible mutations. The binding free energy of ligand for kinase receptor was analyzed by molecular mechanics Poission Boltzmann surface area (MM-PB/SA) method. These results suggest that conserved glutamic acid and lysine are necessary for stability of complex. PMID- 21811774 TI - Genetic analysis of patients with deep vein thrombosis during pregnancy and postpartum. AB - Deep vein thrombosis (DVT) is a serious pregnancy-related complication. Recent studies indicate that the genetic background for DVT differs with ethnicity. In our study, we enrolled 18 consecutive Japanese patients who had developed DVT during pregnancy and postpartum. We performed a genetic analysis of three candidate genes for DVT, protein S, protein C and antithrombin, in these patients. We found that four patients had missense mutations in the protein S gene, including the K196E mutation in two patients, the L446P mutation in one patient, and the D79Y and T630I mutations in one patient, as well as one patient with the C147Y mutation in the protein C gene. All five patients with genetic mutations had DVT in their first two trimesters. Nine of the patients without genetic mutations developed DVT in the first two trimesters, and four in the postpartum period. Thus, genetic mutations in the protein S gene were predominant in pregnant Japanese DVT women, and DVT in pregnant women with genetic mutations occurred more frequently at the early stage of pregnancy than postpartum. Considering the rapid decrease in protein S activity during pregnancy, we may need to assess thrombophilia in women before pregnancy. PMID- 21811776 TI - BON-BONs: cyclic molecules with a boron-oxygen-nitrogen backbone. Computational studies of their thermodynamic properties. AB - Although they were first reported in 1963, molecules with a boron-oxygen-nitrogen dimeric backbone do not seem to have been investigated seriously in terms of thermodynamic properties. Here we report on the calculated structures and properties, including thermodynamics, of several so-called "BON-BON" molecules. With the popularity of nitrogen-containing substituents on new high-energy materials, nitro-substituted BON-BONs were a focus of our investigation. A total of 42 BON-BON molecules were evaluated, and thermochemical analysis shows a decrease in the specific enthalpy of combustion or decomposition with increasing NO(2) content, consistent with other systems. PMID- 21811777 TI - Structural and electronic properties of Z isomers of (4alpha->6'',2alpha->O->1'') phenylflavans substituted with R = H, OH and OCH3 calculated in aqueous solution with PCM solvation model. AB - In the search for new antioxidants, flavan structures called our attention, as substructures of many important natural compounds, including catechins (flavan-3 ols), simple and dimeric proanthocyanidins, and condensed tannins. In this work the conformational space of the Z-isomers of (4alpha->6'', 2alpha->O->1'') phenylflavans substituted with R = H, OH and OCH(3) was scanned in aqueous solution, simulating the solvent by the polarizable continuum model (PCM). Geometry optimizations were performed at B3LYP/6-31 G level. Electronic distributions were analyzed at a better calculation level, thus improving the basis set (6-311++G). A topological study based on Bader's theory (atoms in molecules) and natural bond orbital (NBO) framework was performed. Furthermore, molecular electrostatic potential maps (MEPs) were obtained and thoroughly analyzed. The stereochemistry was discussed, and the effect of the solvent was addressed. Moreover, intrinsic properties were identified, focusing on factors that may be related to their antioxidant properties. Hyperconjugative and inductive effects were described. The coordinated NBO/AIM analysis allowed us to rationalize the changes of MEPs in a polar solvent. To investigate the molecular and structural properties of these compounds in biological media, the polarizabilities and dipolar moments were predicted which were further used to enlighten stability and reactivity properties. All conformers were taken into account. Relevant stereoelectronic aspects were described for understanding the stabilization and antioxidant function of these structures. PMID- 21811778 TI - Theoretical studies on models of lysine-arginine cross-links derived from alpha oxoaldehydes: a new mechanism for glucosepane formation. AB - Availability and high reactivity of alpha-oxoaldehydes have been approved by experimental techniques not only in vivo systems but also in foodstuffs. In this article we re-examine the mechanism of glucosepane formation by using computational model chemistry. Density functional theory has been applied to propose a new mechanism for glucosepane formation through reaction of alpha oxoaldehydes with methyl amine (MA) and methyl guanidine (MGU) models of lysine and arginine residues respectively. This non enzymatic process can be described in three main steps: (1) Schiff base formation from methyl amine, methyl glyoxal (MGO) (2) addition of methyl guanidine and (3) addition of glyceraldehyde. We show that this process is thermodynamically possible and presents a rate determining step with a reasonable free energy barrier equal to 37.8 kcal mol(-1) in water solvent. Comparisons were done with the mechanism formation of GODIC (glyoxal-derived imidazolium cross-link) and MODIC (methyl glyoxal-derived imidazolium cross-link), two other important cross-links in vivo. PMID- 21811779 TI - Fresh-frozen human bone allograft in vertical ridge augmentation: clinical and tomographic evaluation of bone formation and resorption. AB - The aim of the current study is to evaluate fresh-frozen human bone allografts (FHBAs) used in vertical ridge augmentation clinically and by computed tomography, and to analyze the resulting bone formation and graft resorption. Sixteen FHBAs were grafted in the maxillae and mandibles of 9 patients. The FHBAs, which were provided by the Musculoskeletal Tissue Bank of Marilia Hospital (Unioss), were frozen at -80 degrees C. After 7 months, dental implants were placed and bone parameters were evaluated. Vertical bone formation was measured by computerized tomography before (T0) and at 7 months (T1) after the surgical procedure. Bone graft resorption was measured clinically from a landmark screw head using a periodontal probe. The results were analyzed by Student's t-test. Significant differences existed in the bone formation values at T0 and T1, with an average change of 4.03 +/- 1.69 mm. Bone graft resorption values were 1.0 +/- 0.82 mm (20%). Implants were placed with varying insertion torque values (35-45 Ncm), and achieved primary stability. This study demonstrates that FHBAs promote satisfactory vertical bone formation with a low resorption rates, good density, and primary implant stability. PMID- 21811780 TI - Innate humoural immunity is related to eggshell bacterial load of European birds: a comparative analysis. AB - Fitness benefits associated with the development of a costly immune system would include not only self-protection against pathogenic microorganisms but also protection of host offspring if it reduces the probability and the rate of vertical transmission of microorganisms. This possibility predicts a negative relationship between probabilities of vertical transmission of symbionts and level of immune response that we here explore inter-specifically. We estimated eggshell bacterial loads by culturing heterotrophic bacteria, Enterococcus, Staphylococcus and Enterobacteriaceae on the eggshells of 29 species of birds as a proxy of vertical transmission of bacteria from mother to offspring. For this pool of species, we also estimated innate immune response (natural antibody and complement (lysis)) of adults, which constitute the main defence against bacterial infection. Multivariate general linear models revealed the predicted negative association between natural antibodies and density of bacteria on the eggshell of 19 species of birds for which we sampled the eggs in more than one nest. Univariate analyses revealed significant associations for heterotrophic bacteria and for Enterobacteriaceae, a group of bacteria that includes important pathogens of avian embryos. Therefore, these results suggest a possible trans generational benefit of developing a strong immune system by reducing vertical transmission of pathogens. PMID- 21811782 TI - Severe CMV reactivation and gastritis during treatment of follicular lymphoma with bendamustine. PMID- 21811781 TI - Transcriptional regulation of defence genes and involvement of the WRKY transcription factor in arbuscular mycorrhizal potato root colonization. AB - The establishment of arbuscular mycorrhizal associations causes major changes in plant roots and affects significantly the host in term of plant nutrition and resistance against biotic and abiotic stresses. As a consequence, major changes in root transcriptome, especially in plant genes related to biotic stresses, are expected. Potato microarray analysis, followed by real-time quantitative PCR, was performed to detect the wide transcriptome changes induced during the pre-, early and late stages of potato root colonization by Glomus sp. MUCL 41833. The microarray analysis revealed 526 up-regulated and 132 down-regulated genes during the pre-stage, 272 up-regulated and 109 down-regulated genes during the early stage and 734 up-regulated and 122 down-regulated genes during the late stage of root colonization. The most important class of regulated genes was associated to plant stress and in particular to the WRKY transcription factors genes during the pre-stage of root colonization. The expression profiling clearly demonstrated a wide transcriptional change during the pre-, early and late stages of root colonization. It further suggested that the WRKY transcription factor genes are involved in the mechanisms controlling the arbuscular mycorrhizal establishment by the regulation of plant defence genes. PMID- 21811783 TI - Lymphopenia following the completion of first-line therapy predicts early relapse in patients with diffuse large B cell lymphoma. AB - Early relapse is a parameter that affects clinical outcomes in relapsed diffuse large B cell lymphoma (DLBCL). The prognostic value of lymphopenia following the completion of first-line therapy and the relationship between lymphopenia and early relapse are unknown. Therefore, we studied the role of absolute lymphocyte count (ALC) on early relapse. We retrospectively analyzed de novo DLBCL patients who were treated with rituximab-containing treatment between 2003 and 2010. The median age at the time of diagnosis of 59 DLBCL patients was 71 years. We identified no association between ALC at diagnosis and ALC following the completion of first-line therapy. Among all patients analyzed, 13 (22%) patients were confirmed to exhibit early relapse. Low ALC following the completion of first-line therapy was significantly associated with early relapse by univariate analysis [hazard ratio (HR) = 4.05; 95% confidence interval (CI), 1.11-14.73; P = 0.02] and multivariate analysis (HR = 4.66; 95% CI, 1.24-17.48; P = 0.023). The low ALC group tended to have worse outcomes than the high ALC group with lower rates of progression-free survival (66% and 74%, respectively; P = 0.13) and overall survival (74% and 86%, respectively; P = 0.09), but these differences did not reach statistically. Lymphopenia following the completion of first-line therapy can be used as a marker to predict early relapse. PMID- 21811784 TI - Investigating ANKH and ENPP1 in Slovakian families with chondrocalcinosis. AB - Familial articular chondrocalcinosis (CC) was first reported in 1963. It is characterised by multiple calcifications of hyaline and fibrous cartilage in the joints and intervertebral discs. Mutations in ANKH have been identified in several pedigrees as a monogenic cause for this disorder. ANKH is a key protein in pyrophosphate metabolism and is involved in pyrophosphate transport across the cell membrane. The objective of this work was to screen ANKH and ENPP1, two key genes in pyrophosphate metabolism, in Slovakian kindreds with familial CC. DNA samples from 25 individuals (10 affected, 15 unaffected) from 8 families were obtained. The promoter, coding regions and intron-exon boundaries of ANKH and ENPP1 were sequenced. Twelve DNA sequence variants, six in each gene, were identified. All the variants had been previously identified. None segregated with the disease. Our results suggest that neither ANKH nor ENPP1 mutations are the cause of CC in these families, indicating that possibly other major genes are involved in the aethiopathogenesis of this condition in these families. PMID- 21811785 TI - Immunization with N-propionyl polysialic acid-KLH conjugate in patients with small cell lung cancer is safe and induces IgM antibodies reactive with SCLC cells and bactericidal against group B meningococci. AB - PURPOSE: Polysialic acid (polySA) is a polymer side chain bound to the neural cell adhesion molecule that is extensively expressed on the surface of small cell lung cancer (SCLC) cells. In our previous study, a robust antibody response was noted in patients with SCLC after vaccination with 30 MUg of keyhole limpet hemocyanin (KLH)-conjugated N-propionylated (NP-) polySA, but peripheral neuropathy and ataxia were detected in several vaccinated patients. The objectives of the current trial were to establish the lowest optimal dose and to confirm the safety of the induction of antibodies against polySA with the NP polySA vaccine. EXPERIMENTAL DESIGN: Patients with SCLC who completed initial treatment and had no evidence of disease progression were injected with either 10 or 3 MUg of NP-polySA conjugated to KLH and mixed with 100 MUg of immunologic adjuvant (QS-21) at weeks 1, 2, 3, 4, 8, and 16. RESULTS: Nine patients were enrolled at each of the two dose levels. Prior to vaccination, one patient in each group had low-titer antibodies against polysialic acid. All patients at the 10 MUg vaccine dose level responded to vaccination with IgM antibody titers against polysialic acid (median titer 1/1,280 by ELISA), and all but one patient made IgM and IgG antibodies against the artificial vaccine immunogen, NP polysialic acid (median titer 1/10,240). The antibody responses at the 3 MUg vaccine dose level were lower; six of nine patients developed antibodies against polysialic acid (median titer 1/160). Post-vaccination sera from 6/9 and 3/9 patients in the 10 and 3 MUg groups reacted strongly with human SCLC cells by fluorescent-activated cell sorting (FACS). Sera from all patients in the 10 MUg dose group also had bactericidal activity against group B meningococci with rabbit complement. Self-limited grade 3 ataxia of unclear etiology was seen in 1 of 18 patients. CONCLUSIONS: Vaccination with NP-polySA-KLH resulted in consistent high-titer antibody responses, with the 10 MUg dose significantly more immunogenic than the 3 MUg dose. This study establishes the lowest optimally immunogenic dose of NP-polysialic acid in this NP-polysialic acid-KLH conjugate vaccine to be at least 10 MUg, and it establishes the vaccine's safety. We plan to incorporate NP-polySA into a polyvalent vaccine against SCLC with four glycolipid antigens also widely expressed in SCLC-GD2, GD3, fucosylated GM1, and globo H. PMID- 21811786 TI - H2O2 production within tumor microenvironment inversely correlated with infiltration of CD56(dim) NK cells in gastric and esophageal cancer: possible mechanisms of NK cell dysfunction. AB - Human NK cells can be divided into two subsets, CD56(dim)CD16(+)NK and CD56(bright)CD16(-)NK cells, based on their expression of CD56 and CD16. In the present study, we analyzed the relationship between CD56(dim)/CD56(bright) NK cells and H2O2 in tumor-infiltrating NK cells in patients with gastric (n = 50) and esophageal (n = 35) cancer. The ratio of CD56(dim) NK cells infiltrating tumors gradually decreased according to disease progression. H2O2 was abundantly produced within tumor microenvironments, and there was an inverse correlation between CD56(dim) NK cell infiltration and H2O2 production. CD56(dim) NK cells are more sensitive to apoptosis induced by physiological levels of H2O2 than CD56(bright) NK cells. Furthermore, the exposure of NK cells to H2O2 resulted in the impairment of ADCC activity. In conclusion, H2O2 produced within tumor microenvironments inversely correlated with the infiltration of CD56(dim) NK cells, possibly due to their preferentially induced cell death. These observations may explain one of the mechanisms behind NK cell dysfunction frequently observed in tumor microenvironments. PMID- 21811787 TI - [Preventive strategies in prosthetic dentistry]. AB - Despite the success in preventing oral diseases, the prevalence of tooth loss in the German population remains high and increases with age. Today, the advances in prosthetic dentistry allow necessary tooth replacement following preventive strategies-after considering benefits and risks. Modern treatment options improve the overall prognosis of the stomatognathic system and the quality of life of the affected patients significantly. Hereby, adverse iatrogenic effects can be minimized or even completely avoided by extending the traditional treatment spectrum, e.g., using adhesively fixed restorations and implant-supported restorations, and refraining from placing restorations that are unnecessary from the medical point of view. Generally, patients benefit greatly from prosthetic treatment and the achieved health gain is remarkably high. It encompasses not only the recovery of the impaired oral functions but also extends to the whole human organism, including nutrition, digestion, musculoskeletal system, as well as mental and social well-being. PMID- 21811788 TI - Responses of HSC70 expression in diencephalon to iron deficiency anemia in rats. AB - A powdered diet containing 100 or 3 ppm Fe was fed to rats starting at the age of 3 weeks. The voluntary activity level was checked using a wheel in the cage during the 17th week after the beginning of supplementation. Significantly less activity was seen in the 3 ppm Fe group during both light and dark periods. After 20 weeks, the blood and diencephalon were sampled from both groups. Lower hematocrit and blood hemoglobin content was observed in the 3 ppm Fe group. The level of 70 kDa heat shock cognate (HSC70) expression was greater in the diencephalon of the 3 ppm Fe group. In addition, the distribution of HSC70 was determined by proximity ligation assay. More HSC70-positive as well as total cells were noted in several areas of the diencephalon of the iron-deficient rats. The altered expression and distribution of HSC70 might play some role in the neurological changes. PMID- 21811789 TI - Chronic sympathetic activation promotes downregulation of beta-adrenoceptor mediated effects in the guinea pig heart independently of structural remodeling and systolic dysfunction. AB - It is uncertain if downregulation of beta-adrenoceptor signaling pathway is promoted by an enhanced adrenergic tone at an early stage of cardiac disease, or it develops secondary to detrimental local myocardial changes in advanced heart failure. We examined the integrity of beta-adrenoceptor signaling pathway upon chronic infusion of isoproterenol, a beta-adrenoceptor agonist, at a dose producing no structural left ventricular (LV) remodeling and systolic dysfunction. Subcutaneous isoproterenol infusion (400 MUg kg(-1) h(-1) over 16 days) to guinea pigs using osmotic minipumps produced no change in cardiac weights, LV internal dimensions, myocyte cross-sectional area, extent of interstitial fibrosis, and basal contractile function. Isolated, perfused heart preparations from isoproterenol-treated guinea pigs exhibited attenuated responsiveness to acute beta-adrenoceptor stimulation, as evidenced by reduced LV developed pressure increase, less shortening of LV epicardial monophasic action potential and effective refractory period, and less myocardial cyclic adenosine monophosphate elevation, in response to isoproterenol exposure, when compared to saline-treated controls. Pharmacological responses to forskolin, an activator of the adenylate cyclase catalytic subunit, were well preserved in isoproterenol treated hearts. Downregulation of beta-adrenoceptor-mediated effects upon chronic isoproterenol infusion was associated with markedly reduced stimulatory G-protein alpha-subunit (G(salpha)) myocardial expression levels. No change in expression levels of beta-adrenoceptors, G-protein-coupled receptor kinase 2, inhibitory G protein alpha-subunit (G(ialpha2)), and Ca(v)1.2 and K(v)7.1 ion channels was determined in isoproterenol-treated hearts. We therefore conclude that sustained adrenergic overstimulation may promote downregulation of myocardial beta adrenoceptor-mediated effects independently of structural LV remodeling and systolic failure, an effect attributed to beta-adrenoceptor uncoupling from adenylate cyclase due to reduced G(salpha)-protein expression. PMID- 21811790 TI - Trisk 32 regulates IP(3) receptors in rat skeletal myoblasts. AB - To date, four isoforms of triadins have been identified in rat skeletal muscle. While the function of the 95-kDa isoform in excitation-contraction coupling has been studied in detail, the role of the 32-kDa isoform (Trisk 32) remains elusive. Here, Trisk 32 overexpression was carried out by stable transfection in L6.G8 myoblasts. Co-localization of Trisk 32 and IP(3) receptors (IP(3)R) was demonstrated by immunocytochemistry, and their association was shown by co immunoprecipitation. Functional effects of Trisk 32 on IP(3)-mediated Ca(2+) release were assessed by measuring changes in [Ca(2+)](i) following the stimulation by bradykinin or vasopressin. The amplitude of the Ca(2+) transients evoked by 20 MUM bradykinin was significantly higher in Trisk 32-overexpressing (p < 0.01; 426 +/- 84 nM, n = 27) as compared to control cells (76 +/- 12 nM, n = 23). The difference remained significant (p < 0.02; 217 +/- 41 nM, n = 21, and 97 +/- 29 nM, n = 31, respectively) in the absence of extracellular Ca(2+). Similar observations were made when 0.1 MUM vasopressin was used to initiate Ca(2+) release. Possible involvement of the ryanodine receptors (RyR) in these processes was excluded, after functional and biochemical experiments. Furthermore, Trisk 32 overexpression had no effect on store-operated Ca(2+) entry, despite a decrease in the expression of STIM1. These results suggest that neither the increased activity of RyR, nor the amplification of SOCE, is responsible for the differences observed in bradykinin- or vasopressin-evoked Ca(2+) transients; rather, they were due to the enhanced activity of IP(3)R. Thus, Trisk 32 not only co-localizes with, but directly contributes to, the regulation of Ca(2+) release via IP(3)R. PMID- 21811791 TI - Light, temperature, and desiccation effects on photosynthetic activity, and drought-induced ultrastructural changes in the green alga Klebsormidium dissectum (Streptophyta) from a high alpine soil crust. AB - Members of the cosmopolitan green algal genus Klebsormidium (Klebsormidiales, Streptophyta) are typical components of terrestrial microbiotic communities such as biological soil crusts, which have many important ecological functions. In the present study, Klebsormidium dissectum (Gay) Ettl & Gartner was isolated from a high alpine soil crust in the Tyrolean Alps, Austria. Physiological performance in terms of growth and photosynthesis was investigated under different controlled abiotic conditions and compared with ultrastructural changes under the treatments applied. K. dissectum showed very low light requirements as reflected in growth patterns and photosynthetic efficiency. Increasing temperatures from 5 degrees C to 40 degrees C led to different effects on respiratory oxygen consumption and photosynthetic oxygen evolution. While at low temperatures (5-10 degrees C), respiration was not detectable or on a very low level, photosynthesis was relatively high, Reversely, at the highest temperature, respiration was unaffected, and photosynthesis strongly inhibited pointing to strong differences in temperature sensitivity between both physiological processes. Although photosynthetic performance of K. dissectum was strongly affected under short-term desiccation and recovered only partly after rehydration, this species was capable to survive even 3 weeks at 5% relative air humidity. K. dissectum cells have a cell width of 5.6 +/- 0.3 MUm and a cell length of 8.4 +/- 2.0 MUm. Desiccated cells showed a strongly reduced cell width (46% of control) and cell length (65% of control). In addition, in desiccated cells, fewer mitochondria were stained by DIOC(6), and damaged plasma membranes were detected by FM 1-43 staining. High pressure freeze fixation as well as chemical fixation allowed visualizing ultrastructural changes caused by desiccation. In such cells, the nucleus and chloroplast were still visibly intact, but the extremely thin cell walls (75-180 nm) were substantially deformed. The cytoplasm appeared electron dense and mitochondria were altered. Although K. dissectum can be characterized as euryoecious species, all ecophysiological and ultrastructural data indicate susceptibility to desiccation. However, the steadily occurring fragmentation of filaments into smaller units leads to improved self protection and thus may represent a life strategy to better survive longer periods of drought in exposed alpine soil crusts. PMID- 21811792 TI - Genomic analysis reveals multiple [FeFe] hydrogenases and hydrogen sensors encoded by treponemes from the H(2)-rich termite gut. AB - We have completed a bioinformatic analysis of the hydrogenases encoded in the genomes of three termite gut treponeme isolates: hydrogenotrophic, homoacetogenic Treponema primitia strains ZAS-1 and ZAS-2, and the hydrogen-producing, sugar fermenting Treponema azotonutricium ZAS-9. H(2) is an important free intermediate in the breakdown of wood by termite gut microbial communities, reaching concentrations in some species exceeding those measured for any other biological system. The spirochetes encoded 4, 8, and 5 [FeFe] hydrogenase-like proteins, identified by their H domains, respectively, but no other recognizable hydrogenases. The [FeFe] hydrogenases represented many sequence families previously proposed in an analysis of termite gut metagenomic data. Each strain encoded both putative [FeFe] hydrogenase enzymes and evolutionarily related hydrogen sensor/transducer proteins likely involved in phosphorelay or methylation pathways, and possibly even chemotaxis. A new family of [FeFe] hydrogenases (FDH-Linked) is proposed that may form a multimeric complex with formate dehydrogenase to provide reducing equivalents for reductive acetogenesis in T. primitia. The many and diverse [FeFe] hydrogenase-like proteins encoded within the sequenced genomes of the termite gut treponemes has enabled the discovery of a putative new class of [FeFe] hydrogenase proteins potentially involved in acetogenesis and furthered present understanding of many families, including sensory, of H domain proteins beyond what was possible through the use of fragmentary termite gut metagenome sequence data alone, from which they were initially defined. PMID- 21811793 TI - Persistence of resistance to erythromycin and tetracycline in swine manure during simulated composting and lagoon treatments. AB - The use of antimicrobials in food animal production leads to the development of antimicrobial resistance (AMR), and animal manure constitutes the largest reservoir of such AMR. In previous studies, composted swine manure was found to contain substantially lower abundance of AMR genes that encode resistance to tetracyclines (tet genes) and macrolide-lincosamide-streptogramin B (MLS(B)) superfamily (erm genes), than manures that were treated by lagoons or biofilters. In this study, temporal changes in AMR carried by both cultivated and uncultivated bacteria present in swine manure during simulated composting and lagoon storage were analyzed. Treatments were designed to simulate the environmental conditions of composting (55 degrees C with modest aeration) and lagoon storage (ambient temperature with modest aeration). As determined by selective plate counting, over a 48-day period, cultivated aerobic heterotrophic erythromycin-resistant bacteria and tetracycline-resistant bacteria decreased by more than 4 and 7 logs, respectively, in the simulated composting treatment while only 1 to 2 logs for both resistant bacterial groups in the simulated lagoon treatment. Among six classes each of erm and tet genes quantified by class specific real-time PCR assays, the abundance of erm(A), erm(C), erm(F), erm(T), erm(X), tet(G), tet(M), tet(O), tet(T), and tet(W) declined marginally during the first 17 days, but dramatically thereafter within 31 days of the composting treatment. No appreciable reduction of any of the erm or tet genes analyzed was observed during the simulated lagoon treatment. Correlation analysis showed that most of the AMR gene classes had similar persistence pattern over the course of the treatments, though not all AMR genes were destructed at the same rate during the treatments. PMID- 21811794 TI - Can hydrodynamics change phosphorus strategies of diatoms?-Nutrient levels and diatom blooms in lotic and lentic ecosystems. AB - Diatom blooms occur in many water bodies worldwide, causing significant ecological and social concerns. In order to understand the mechanisms of diatom blooms formation, the effects of varying phosphorus (P) concentration and hydrodynamics on the growth of diatoms were studied by combining results from field observations and laboratory experiments. The field investigation showed that spring diatom blooms (Cyclotella meneghiniana and Stephanodiscus hantzschii) occurred in Lake Taihu and Hanjiang River with similar environmental factors such as water temperature, pH, and dissolved oxygen in 2008. Concentrations of total phosphorus (TP), total nitrogen, and ammonia nitrogen (NH(4)-N) in Lake Taihu were significantly higher than the concentrations in the Hanjiang River. Laboratory experiments were conducted to evaluate growth and physiological responses of four lotic diatoms (Cyclotella atomus, Fragilaria crotonensis, Nitzschia palea, and S. hantzschii, isolated from the Hanjiang River) and three lentic diatoms (C. meneghiniana, Melosira varians, and Stephanodiscus minutulus, isolated from Lake Taihu, Lake Donghu, and Guanqiao Pond, respectively) to various P concentrations under small-scale turbulent and standing conditions. Our results showed that, with turbulence, lotic diatoms C. atomus, F. crotonensis, N. palea, and S. hantzschii demonstrated a significant increase in affinity for P compared with lentic diatoms C. meneghiniana, M. varians, and S. minutulus. Moreover, lotic diatoms C. atomus, F. crotonensis, and N. palea had higher growth rates and photosynthetic efficiencies with small-scale turbulence than with standing conditions both in P-limited and P-replete conditions. Lotic species S. hantzschii and three lentic diatoms (C. meneghiniana, M. varians, and S. minutulus) grew well under standing conditions. Our results may explain our field observation that the occurrence of diatom blooms in lakes is often associated with higher TP concentrations whereas in rivers, diatom blooms occur at a wide range of TP concentrations under flows. Therefore, different hydrodynamics and nutrient concentrations determined the dominant diatom species, according to their habitat-dependent physiological characteristics. PMID- 21811795 TI - Defining the Pseudomonas genus: where do we draw the line with Azotobacter? AB - The genus Pseudomonas has gone through many taxonomic revisions over the past 100 years, going from a very large and diverse group of bacteria to a smaller, more refined and ordered list having specific properties. The relationship of the Pseudomonas genus to Azotobacter vinelandii is examined using three genomic sequence-based methods. First, using 16S rRNA trees, it is shown that A. vinelandii groups within the Pseudomonas close to Pseudomonas aeruginosa. Genomes from other related organisms (Acinetobacter, Psychrobacter, and Cellvibrio) are outside the Pseudomonas cluster. Second, pan genome family trees based on conserved gene families also show A. vinelandii to be more closely related to Pseudomonas than other related organisms. Third, exhaustive BLAST comparisons demonstrate that the fraction of shared genes between A. vinelandii and Pseudomonas genomes is similar to that of Pseudomonas species with each other. The results of these different methods point to a high similarity between A. vinelandii and the Pseudomonas genus, suggesting that Azotobacter might actually be a Pseudomonas. PMID- 21811797 TI - The efficacy of tramadol/acetaminophen combination tablets (Ultracet(r)) as add on and maintenance therapy in knee osteoarthritis pain inadequately controlled by nonsteroidal anti-inflammatory drug (NSAID). AB - The purpose of this study is to compare the efficacy of tramadol 37.5 mg/acetaminophen 325 mg combination tablets (tramadol/APAP) with that of nonsteroidal anti-inflammatory drugs (NSAIDs) as maintenance therapy following tramadol/APAP and NSAID combination therapy in knee osteoarthritis (OA) pain which was inadequately controlled by NSAIDs. Subjects with knee OA for over 1 year and moderate pain (numerical rating scale [NRS] >=5) despite at least 4 weeks' NSAID therapy (meloxicam 7.5 mg or 15 mg qd or aceclofenac 100 mg bid) received tramadol/APAP add-on (combination with NSAID) for 4 weeks. Thereafter, subjects with significant pain improvement (NRS <4) were randomized to receive either tramadol/APAP or NSAID for 8 weeks. On days 29 and 57, Western Ontario and McMaster Universities (WOMAC) OA index score was measured. Secondary measures included pain intensity (NRS), pain relief score, and subjects' and investigators' overall medication assessments. Of 143 subjects enrolled, 112 completed the 4-week tramadol/APAP and NSAID combination phase and 97 (67.8%) experienced significant pain improvement. Of the 97 subjects randomized, 36 in tramadol/APAP group and 47 in NSAID group completed the 8-week comparator study. On days 29 and 57, WOMAC scores and pain intensities did not increase in both groups compared to measurements immediately after the combination therapy. At these two time points, there were no significant differences in WOMAC scores, pain intensities, and other secondary measures between the two groups. Overall adverse event rates were similar in both groups. Tramadol/APAP add-on significantly improved knee OA pain which had been inadequately controlled by NSAIDs. In those subjects who showed favorable response to tramadol/APAP and NSAID combination therapy, both tramadol/APAP and NSAIDs were effective at maintaining the pain-reduced state and there was no significant difference in efficacy between tramadol/APAP and NSAIDs. PMID- 21811796 TI - Differentiated response of denitrifying communities to fertilization regime in paddy soil. AB - The impact of fertilization regimes on sequential denitrifying communities was investigated in a rice paddy field with 17 years continuous fertilization, located in Taoyuan Agro-ecosystem Research Station (110 degrees 72" E, 28 degrees 52" N), China. The diversity, community composition, and size of denitrifying genes of narG, qnorB, and nosZ were determined using molecular tools including terminal restriction fragment length polymorphism, quantitative polymerase chain reaction (qPCR), cloning, and sequencing analysis. Soil samples were collected from the plots with no fertilizer (NF), urea (UR), balanced mineral fertilizers (BM), and BM combined with rice straw (BMR). UR and BM caused marked increase in the community size of the denitrifying genes; however, BMR resulted in the highest abundance. The community size of narG was the most affected by the fertilization regimes, while qnorB was the least. Fertilization also induced some shifts in the composition of denitrifying genes, but the responses of different genes varied. However, fertilization regimes caused no significant changes to the diversity of the denitrifying genes. Potential denitrification activity (PDA) was significantly correlated with the abundance of narG and nosZ rather than qnorB, but there were no such correlations between PDA and the composition and diversity of denitrifying communities. Conclusively, long-term fertilization significantly affected denitrifying community size and composition, but not diversity. Among the sequential denitrifying genes, narG was the most, while qnorB was the least sensitive communities to fertilization regimes. PMID- 21811798 TI - Peripheral artery disease (PAD) screening in the asymptomatic population: why, how, and who? AB - Measurement of ankle-brachial index (ABI) was developed to assess peripheral artery disease (PAD) in patients with symptoms of peripheral ischemia being present at rest or only functionally dependent (intermittent claudication). Reduced ABI is caused by arterial obstruction between the aortic arch and feet (lower limb), which in the Western world is caused by atherosclerosis if not previous trauma. Whereas severity of intermittent claudication is only poorly related to ABI, cardiovascular outcomes are as follows: the lower the ABI the higher the incidence of cardiovascular events and death. Measuring ABI identifies asymptomatic persons at increased risk of cardiovascular morbidity and mortality: an ABI <0.9 doubles the risk of death of any cause. Reduced ABI is highly prevalent in the elderly population; 3% to 5% among people 60 years of age and >25% in people between 80 and 90 years of age. The majority of persons with reduced ABI are asymptomatic and therefore unaware of the increased risk they are living with, thus, screening by measuring ABI offers the opportunity for identifying persons at high risk. Unfortunately, most primary care physicians are not performing ABI in their office. Reimbursement issues along with inadequate knowledge of ABI are barriers for adoption and must be addressed. PMID- 21811800 TI - Using RFID yoking proof protocol to enhance inpatient medication safety. AB - The low birth rate has led to an aging society; the burgeoning number of elderly patients may affect the medical quality and result in negative medical incidents. There are many factors that lead to medical errors, such as similar medication names, erroneous labels and packaging, as well as staff shortages, fatigue and carelessness. Determining how to reduce medical errors has become an important issue. As RFID exhibits powerful identification characteristics, it can help nurses to quickly identify patients and their corresponding medicine. Currently, there are numerous practical applications for improving the efficiency of Radio Frequency Identification (RFID) systems. In this paper, we use an RFID yoking proof mechanism which conforms to EPCglobal Class 1 Generation 2 standards to improve patient safety and reduce medical errors. Our scheme can achieve different goals such as resist numerous known attacks, achieve mutual authentication, anonymity and non-repudiation. It also provides a practical medical care and offer higher quality of medical care. The pharmacist cannot deny that this prescription was confirmed for the patient and the nurse cannot also deny he or she dispensed this medicine to the patient for protecting the patients' interests. PMID- 21811801 TI - Design ensemble machine learning model for breast cancer diagnosis. AB - In this paper, we classify the breast cancer of medical diagnostic data. Information gain has been adapted for feature selections. Neural fuzzy (NF), k nearest neighbor (KNN), quadratic classifier (QC), each single model scheme as well as their associated, ensemble ones have been developed for classifications. In addition, a combined ensemble model with these three schemes has been constructed for further validations. The experimental results indicate that the ensemble learning performs better than individual single ones. Moreover, the combined ensemble model illustrates the highest accuracy of classifications for the breast cancer among all models. PMID- 21811799 TI - The SHAPE guideline: ahead of its time or just in time? AB - In 2006, a grass roots movement called SHAPE (Screening for Heart Attack Prevention and Education) published a novel practice guideline for cardiovascular screening in the asymptomatic at-risk population. It suggested the use of noninvasive tests for subclinical atherosclerosis in cardiovascular risk assessment to target intensified preventive care to those at highest risk. The SHAPE guideline received much attention but not as much support from the "official" medical societies. However, subsequent studies published since 2006 have now provided strong supportive evidence for the strategy spearheaded by the SHAPE guideline. Indeed, the latest guidelines issued jointly by the American Heart Association and the American College of Cardiology have elevated recommendation levels for noninvasive imaging of subclinical atherosclerosis. This change is widely viewed as a significant step toward the SHAPE guidelines. The background for SHAPE and the evidence behind the recommendation to use coronary artery calcium score measured by computed tomography, carotid intima media thickness and plaque measured by ultrasound, and ankle-brachial index in cardiovascular risk assessment is reviewed in this article. PMID- 21811802 TI - Simple database to select promoters for plant transgenesis. AB - The experiments with transgenic plants frequently demand selection of promoters providing appropriate transcription patterns. The set of promoters commonly used in vectors and genetic constructs is very limited, and these promoters provide only a few variants of gene expression patterns. Moreover, identical promoters in a complex construct can induce transgene silencing. This problem can be solved using a variety of plant gene promoters with experimentally verified characteristics. However, this requires a time-consuming analysis of literature data. Here, we describe a database of plant promoters (TransGene Promoters, TGP; http://wwwmgs.bionet.nsc.ru/mgs/dbases/tgp/home.html ). TGP contains the information on genomic DNA segments providing certain expression patterns of reporter genes in experiments with transgenic plants. TGP was constructed on the SRS platform, and its interface allows users to search for the promoters with particular characteristics. PMID- 21811803 TI - The association of receptor of advanced glycated end products and inflammatory mediators contributes to endothelial dysfunction in a prospective study of acute kidney injury patients with sepsis. AB - The pathogenesis of acute kidney injury (AKI) occurring due to sepsis is incompletely understood. Endothelial activation, defined as up-regulation of adhesion molecules by proinflammatory cytokines, may be central to the development of sepsis-induced AKI. Our aim was to determine levels of circulating adhesion molecules endothelial (E)-selectin, intercellular adhesion molecule (ICAM), and vascular cell adhesion molecule (VCAM), inflammatory mediators; tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta (TGF-beta), vasoactive mediators; endothelin-1 (ET-1) and nitric oxide (NO), soluble receptor for advanced glycated end products (sRAGE) and serum fetuin-A in septic AKI patients before and after antibiotic therapy. Nineteen AKI patients with sepsis and fifteen healthy controls were enrolled in this prospective study. Results revealed that 12 weeks of therapy caused amelioration of endothelial and inflammatory injuries as well as renal function markers. Moreover, the positive correlations between levels of RAGE and E-selectin (r=0.88), ET-1 (r=0.90), and TNF-alpha (r=0.94) and negative with NO (r=-0.75-0.95) suggest that possible interaction of RAGE and inflammation may contribute to endothelial dysfunction in septic AKI patients. PMID- 21811804 TI - A meta-analytic approach to estimating nocebo effects in neuropathic pain trials. AB - The development of non-specific adverse effects following the administration of an active or inert substance is referred to as nocebo phenomenon. We aimed to estimate the frequency and severity of nocebo responses in clinical trials of pharmacological treatments for neuropathic pain. A systematic Medline search for all randomized, placebo-controlled neuropathic pain trials published between 2000 and 2010 was carried out. Meta-analysis of the frequency of nocebo responses was performed by pooling the percentage of placebo-treated patients that exhibited drug-related adverse events. Nocebo severity was calculated from the percentage of placebo-treated patients that dropped out due to drug-related adverse events. The pooled frequency of nocebo responses in neuropathic pain trials was 52.0% (95% CI: 35.7-67.9) and the pooled nocebo severity was 6.0% (95% CI: 4.5-8.0). Meta-regression analysis revealed an association between the frequency of nocebo responses and the percentage of females in the placebo-treated group (p = 0.0028). Furthermore, nocebo severity displayed a significant association with the study population (p = 0.0386). Our data indicates a powerful nocebo effect in neuropathic pain trials that may be influenced by gender- and population-related factors. A strong nocebo effect may be adversely affecting adherence and efficacy of current treatments for neuropathic pain in clinical practice. PMID- 21811805 TI - Pregnancy in multiple sclerosis: clinical and self-report scales. AB - Relapse rate is decreased during pregnancy in multiple sclerosis (MS). Risk for postpartum relapse is increased in the first 3 months after delivery. We aimed to study clinical course of MS around pregnancy, using clinical as well as self report scales, including data on quality of life (QoL), and to identify clinical factors predisposing for postpartum relapse. We performed a prospective, longitudinal study among 35 MS patients and 20 controls. In patients we assessed expanded disability status scale (EDSS), the Guy's neurological disability scale (GNDS) and the multiple sclerosis impact scale 29 (MSIS-29). In patients and controls we assessed the MOS 36 item short form health survey questionnaire (SF36), consisting of eight domains. The previously described surge in relapses after delivery was also obvious in this study (p = 0.005). At group level EDSS and MSIS-29 did not show overt fluctuations over time. The GNDS, however, improved during the third trimester, compared to the first trimester (p = 0.003). A concomitant improvement in the SF36 domains vitality (p < 0.001) and general health (p = 0.001) was found in patients. At the final visit, at least 9 months after delivery, no worsening of EDSS, GNDS, MSIS-29 or SF36 was observed compared with the (for MS, beneficial) third trimester. Duration of disease, relapses in the year preceding pregnancy or relapses during pregnancy were not associated with postpartum relapse. QoL is improved during pregnancy. Although relapse rate was increased directly after delivery, in the mid long term after delivery no adverse effects of pregnancy on MS were found. PMID- 21811806 TI - Second-half-of-the-day headache as a manifestation of spontaneous CSF leak. AB - Orthostatic headache related to spontaneous cerebrospinal fluid leak (CSF) appears within 2 h of sitting or standing in most patients. However, longer delays to headache onset have been observed, including some patients who have headaches only in the afternoon. The objective of this study is to describe second-half-of-the-day headache as a manifestation of spontaneous CSF leak and propose potential mechanisms. From 142 patients evaluated by one of us (B.M.) during a 10-year period for spontaneous intracranial hypotension, those describing headache occurring exclusively in the afternoon accompanied by typical changes of intracranial hypotension on head MRI were retrospectively identified and their medical records reviewed. Five patients met our pre-defined inclusion criteria (5/142, 3.5%; three women; mean age 50 years). Second-half-of-the-day headache was an initial symptom of intracranial hypotension in one patient, spontaneously evolved from prior all-day orthostatic headache in one patient, and was a residual or recurrent symptom after epidural blood patch in three patients. Head MRI changes due to intracranial hypotension were decreased during second half-of-the-day-headache compared to typical all-day orthostatic headache in three out of four patients. The timing of second-half-of-the-day headache and orthostatic headache in the clinical course of patients with spontaneous CSF leaks and related MRI findings suggest that second-half-of-the-day headache is likely a manifestation of a slowed or slow-flow CSF leak. PMID- 21811807 TI - Review of the randomized evaluation of long-term anticoagulation therapy (RE-LY) trial: warfarin versus dabigatran. PMID- 21811808 TI - Prenatal counseling on seat belt use and crash-related medical care. AB - Describe the prevalence of and characteristics associated with being hurt in a car accident during pregnancy; the resulting medical care needed; and the association between counseling and the medical care needed after a car accident. Secondary data analysis of PRAMS (Pregnancy Risk Assessment Monitoring System) data, a population based survey of women with a recent live birth. Two percent of women were hurt in a car accident during their pregnancy. Only 57% of them had received counseling on seat belt use. Most women (87%) who were hurt in an accident needed medical care. Being counseled on seat belt use was not associated with the level of care needed. Most pregnant women who are hurt in a car accident require medical care or bed rest. Public health action and research is needed to reduce the burden of motor-vehicle related injuries among pregnant women. PMID- 21811809 TI - A preliminary study of the neural correlates of the intensities of self-reported gambling urges and emotions in men with pathological gambling. AB - Although self-reported gambling urge intensities have clinical utility in the treatment of pathological gambling (PG), prior studies have not investigated their neural correlates. Functional magnetic resonance imaging (fMRI) was conducted while 10 men with PG and 11 control comparison (CON) men viewed videotaped scenarios of gambling, happy or sad content. Participants rated the intensity of their emotions and motivations and reported the qualities of their responses. Relative to the CON group, the PG group reported similar responses to sad and happy scenarios, but stronger emotional responses and gambling urges when viewing the gambling scenarios. Correlations between self-reported responses and brain activations were typically strongest during the period of reported onset of emotional/motivational response and more robust in PG than in CON subjects for all conditions. During this epoch, corresponding with conscious awareness of an emotional/motivational response, subjective ratings of gambling urges in the PG group were negatively correlated with medial prefrontal cortex activation and positively correlated with middle temporal gyrus and temporal pole activations. Sadness ratings in the PG group correlated positively with activation of the medial orbitofrontal cortex, middle temporal gyrus, and retrosplenial cortex, while self-reported happiness during the happy videos demonstrated largely inverse correlations with activations in the temporal poles. Brain areas identified in the PG subjects have been implicated in explicit, self-referential processing and episodic memory. The findings demonstrate different patterns of correlations between subjective measures of emotions and motivations in PG and CON subjects when viewing material of corresponding content, suggesting in PG alterations in the neural correlates underlying experiential aspects of affective processing. PMID- 21811810 TI - Surgical treatment of displaced medial clavicle fractures using a small T-shaped plate and tension band sutures. AB - The surgical treatment of medial clavicle nonunion is associated with high complication and failure rates, particularly with regard to metal work migration. Therefore, we describe a simple surgical procedure for displaced medial clavicle fractures using a small T-shaped plate and multiple tension band sutures. After stabilizing the medial clavicle fracture using a small nonunion for the distal radius, our simple technique for preventing high complication and failure rates is performed easily and effectively, with sufficient tension band sutures. PMID- 21811812 TI - Molecular mass spectrometric identification of superoxide dismutase in the liver of mice Mus musculus and Mus spretus using a metallomics analytical approach. AB - This paper reports the identification and quantification of superoxide dismutase in the liver of Mus musculus and Mus spretus mice using a metallomics analytical approach. The approach consisted of using orthogonal chromatographic systems coupled to ICP-MS and UV detectors. Size-exclusion fractionation of the cytosolic extracts was followed by anion-exchange chromatographic separation of Cu- and Zn containing species. After purification then tryptic digestion, Cu- and Zn containing superoxide dismutase was identified by nESI-QqTOF. The MS-MS spectra of doubly charged peptides, with the Mascot searching engine, were used to obtain the sequence of the protein. PMID- 21811813 TI - Novel electrocardiogram manifestations of a tension pneumothorax. PMID- 21811814 TI - Radiation exposure in children during the current era of pediatric cardiac intervention. AB - Cardiac catheterizations are among the X-ray procedures with the highest patient radiation dose and therefore are of great concern in pediatric settings. This study aimed to evaluate factors that influence variability of X-ray exposure in children with congenital heart diseases during cardiac catheterization. The study included 107 children who underwent either diagnostic (n = 46) or interventional (n = 61) procedures. A custom-made sheet for patient and procedural characteristics was designed. Data were collected, and different correlations were applied to determine factors that influence variability of X-ray exposure. The fluoroscopy time (FT) differed significantly between the diagnostic (8.9 +/- 6.3 min) and intervention (12.8 +/- 9.98 min) groups (P = 0.032). The mean dose area product (DAP) differed significantly between the two groups (3.775 +/- 2.5 Gy/cm(2) vs. 13.239 +/- 15.4 Gy/cm(2); P = 0.003). The highest DAP was during left anterior oblique (LAO) cranial 30 degrees angulation (2.8 Gy/cm(2)/4 s cine). The mean cumulative dose (CD) was 0.053 Gy in diagnostic cases and 0.48 Gy in intervention cases. The effective dose was 5.97 +/- 7.05 mSv for therapeutic procedures compared with 3.42 +/- 3.64 mSv for diagnostic procedures. The FT correlated significantly with both the DAP (r = 0.718; P < 0.001) and the CD (r = 0.701; P < 0.001). Other correlations were reported. An increasing number of therapeutic catheterization procedures are being performed for children. The justification for these procedures is evident because they avoid complicated surgery. However, the complexity of these procedures results in higher radiation exposures. PMID- 21811811 TI - Rodent models of TDP-43 proteinopathy: investigating the mechanisms of TDP-43 mediated neurodegeneration. AB - Since the identification of phosphorylated and truncated transactive response DNA binding protein 43 (TDP-43) as a primary component of ubiquitinated inclusions in amyotrophic lateral sclerosis and frontotemporal lobar degeneration with ubiquitin-positive inclusions, much effort has been directed towards ascertaining how TDP-43 contributes to the pathogenesis of disease. As with other protein misfolding disorders, TDP-43-mediated neuronal death is likely caused by both a toxic gain and loss of TDP-43 function. Indeed, the presence of cytoplasmic TDP 43 inclusions is associated with loss of nuclear TDP-43. Moreover, post translational modifications of TDP-43, including phosphorylation, ubiquitination, and cleavage into C-terminal fragments, may bestow toxic properties upon TDP-43 and cause TDP-43 dysfunction. However, the exact neurotoxic TDP-43 species remain unclear, as do the mechanism(s) by which they cause neurotoxicity. Additionally, given our incomplete understanding of the roles of TDP-43, both in the nucleus and the cytoplasm, it is difficult to truly appreciate the detrimental consequences of aberrant TDP-43 function. The development of TDP-43 transgenic animal models is expected to narrow these gaps in our knowledge. The aim of this review is to highlight the key findings emerging from TDP-43 transgenic animal models and the insight they provide into the mechanisms driving TDP-43-mediated neurodegeneration. PMID- 21811815 TI - RAD50 and NBS1 are not likely to be susceptibility genes in Chinese non-BRCA1/2 hereditary breast cancer. AB - Deleterious mutations in several genes that are involved in repair of damage to DNA have been associated with an increased risk of breast cancer. Recent studies have shown sequence variants in two such genes, RAD50 and NBS1, which can be predisposed to breast cancer. The aim of this study is to elucidate the contribution of RAD50 and NBS1 germline mutations to the etiology of non-BRCA1/2 hereditary breast cancer in China. We conducted a mutational analysis of RAD50 and NBS1 in genomic DNA from 384 Chinese women with early-onset breast cancer and/or affected relatives. All the coding exons and adjacent intronic splice junction rejoins of RAD50 and NBS1 were screened using PCR-DHPLC and DNA sequencing analysis. Among all cases, no obviously deleterious mutations were observed in RAD50; one synonymous change c.102G>A at codon 34 and one single nucleotide polymorphism IVS9 + 19C>T were identified in NBS1. Furthermore, there was no remarkable difference in the allele frequency of NBS1 c.553G>C (E185Q) between cases (172/384) and controls (182/420). Our results exclude the possible role of RAD50 and NBS1 in familial breast cancer predisposition in Chinese women, and there is no evidence for the recommendation of RAD50 and NBS1 for genetic testing in China. PMID- 21811816 TI - Oxidative stress and hematological profiles of advanced breast cancer patients subjected to paclitaxel or doxorubicin chemotherapy. AB - Several adverse effects of chemotherapy treatments have been described, and most of these effects are associated with direct interactions between blood cells and indirect effects generated during the oxidative metabolism of antineoplastic drugs. In this study we evaluated the oxidative systemic status and hematological profiles of breast cancer patients with advanced ductal infiltrative carcinoma treated with doxorubicin (DOX) or paclitaxel (PTX) within 1 h after chemotherapy. Blood analyses included evaluation of hemogram, pro-oxidative markers, and antioxidant status. The results showed that advanced breast cancer diseased (AD) patients without previous chemotherapy presented anemia and high oxidative stress status characterized by elevated levels of lipid peroxidation and nitric oxide, and reduced catalase activity when compared with controls. DOX-treated patients exhibited increased anemia and reduced antioxidant status, which was revealed by decreases in reduced glutathione levels and the total antioxidant capacity of plasma; however, these changes did not lead to further increases in lipid peroxidation or carbonyl proteins when compared with the AD group. PTX-treated patients also showed increased anemia, lactate dehydrogenase leakage, and enhanced lipid peroxidation. These data reveal for the first time that patients subjected to chemotherapy with DOX or PTX present immediate systemic oxidative stress and red blood cell oxidative injury with anemia development. These findings provide a new perspective on the systemic redox state of AD and patients subjected to chemotherapy regarding oxidative stress enhancement and its possible involvement in the aggravation of chronic anemia. PMID- 21811817 TI - Gene stacking strategies with doubled haploids derived from biparental crosses: theory and simulations assuming a finite number of loci. AB - Recent progress in genotyping and doubled haploid (DH) techniques has created new opportunities for development of improved selection methods in numerous crops. Assuming a finite number of unlinked loci (l) and a given total number (n) of individuals to be genotyped, we compared, by theory and simulations, three methods of marker-assisted selection (MAS) for gene stacking in DH lines derived from biparental crosses: (1) MAS for high values of the marker score (T, corresponding to the total number of target alleles) in the F(2) generation and subsequently among DH lines derived from the selected F(2) individual (Method 1), (2) MAS for augmented F(2) enrichment and subsequently for T among DH lines from the best carrier F(2) individual (Method 2), and (3) MAS for T among DH lines derived from the F(1) generation (Method 3). Our objectives were to (a) determine the optimum allocation of resources to the F(2) ([Formula: see text]) and DH generations [Formula: see text] for Methods 1 and 2 by simulations, (b) compare the efficiency of all three methods for gene stacking by simulations, and (c) develop theory to explain the general effect of selection on the segregation variance and interpret our simulation results. By theory, we proved that for smaller values of l, the segregation variance of T among DH lines derived from F(2) individuals, selected for high values of T, can be much smaller than expected in the absence of selection. This explained our simulation results, showing that for Method 1, it is best to genotype more F(2) individuals than DH lines ([Formula: see text]), whereas under Method 2, the optimal ratio [Formula: see text] was close to 0.5. However, for ratios deviating moderately from the optimum, the mean [Formula: see text] of T in the finally selected DH line ([Formula: see text]) was hardly reduced. Method 3 had always the lowest mean [Formula: see text] of [Formula: see text] except for small numbers of loci (l = 4) and is favorable only if a small number of loci are to be stacked in one genotype and/or saving one generation is of crucial importance in cultivar development. Method 2 is under most circumstances the superior method, because it generally showed the highest mean [Formula: see text] and lowest SD of [Formula: see text] for the finally selected DH. PMID- 21811818 TI - Association mapping and gene-gene interaction for stem rust resistance in CIMMYT spring wheat germplasm. AB - The recent emergence of wheat stem rust Ug99 and evolution of new races within the lineage threatens global wheat production because they overcome widely deployed stem rust resistance (Sr) genes that had been effective for many years. To identify loci conferring adult plant resistance to races of Ug99 in wheat, we employed an association mapping approach for 276 current spring wheat breeding lines from the International Maize and Wheat Improvement Center (CIMMYT). Breeding lines were genotyped with Diversity Array Technology (DArT) and microsatellite markers. Phenotypic data was collected on these lines for stem rust race Ug99 resistance at the adult plant stage in the stem rust resistance screening nursery in Njoro, Kenya in seasons 2008, 2009 and 2010. Fifteen marker loci were found to be significantly associated with stem rust resistance. Several markers appeared to be linked to known Sr genes, while other significant markers were located in chromosome regions where no Sr genes have been previously reported. Most of these new loci colocalized with QTLs identified recently in different biparental populations. Using the same data and Q + K covariate matrices, we investigated the interactions among marker loci using linear regression models to calculate P values for pairwise marker interactions. Resistance marker loci including the Sr2 locus on 3BS and the wPt1859 locus on 7DL had significant interaction effects with other loci in the same chromosome arm and with markers on chromosome 6B. Other resistance marker loci had significant pairwise interactions with markers on different chromosomes. Based on these results, we propose that a complex network of gene-gene interactions is, in part, responsible for resistance to Ug99. Further investigation may provide insight for understanding mechanisms that contribute to this resistance gene network. PMID- 21811819 TI - Genetic diversity, structure, gene flow and evolutionary relationships within the Sorghum bicolor wild-weedy-crop complex in a western African region. AB - Gene flow between domesticated plants and their wild relatives is one of the major evolutionary processes acting to shape their structure of genetic diversity. Earlier literature, in the 1970s, reported on the interfertility and the sympatry of wild, weedy and cultivated sorghum belonging to the species Sorghum bicolor in most regions of sub-Saharan Africa. However, only a few recent surveys have addressed the geographical and ecological distribution of sorghum wild relatives and their genetic structure. These features are poorly documented, especially in western Africa, a centre of diversity for this crop. We report here on an exhaustive in situ collection of wild, weedy and cultivated sorghum assembled in Mali and in Guinea. The extent and pattern of genetic diversity were assessed with 15 SSRs within the cultivated pool (455 accessions), the wild pool (91 wild and weedy forms) and between them. F (ST) and R (ST) statistics, distance-based trees, Bayesian clustering methods, as well as isolation by distance models, were used to infer evolutionary relationships within the wild weedy-crop complex. Firstly, our analyses highlighted a strong racial structure of genetic diversity within cultivated sorghum (F (ST) = 0.40). Secondly, clustering analyses highlighted the introgressed nature of most of the wild and weedy sorghum and grouped them into two eco-geographical groups. Such closeness between wild and crop sorghum could be the result of both sorghum's domestication history and preferential post-domestication crop-to-wild gene flow enhanced by farmers' practices. Finally, isolation by distance analyses showed strong spatial genetic structure within each pool, due to spatially limited dispersal, and suggested consequent gene flow between the wild and the crop pools, also supported by R (ST) analyses. Our findings thus revealed important features for the collection, conservation and biosafety of domesticated and wild sorghum in their centre of diversity. PMID- 21811820 TI - Simple sequence repeat markers linked to QTL for resistance to Watermelon mosaic virus in melon. AB - A population of recombinant inbred lines (RIL) derived from a cross between the Watermelon mosaic virus (WMV) resistant genotype TGR-1551 and the susceptible Spanish cultivar 'Bola de Oro' has been evaluated for WMV resistance in spring, fall and growth chamber conditions. The quantitative trait loci (QTL) analyses detected one major QTL (wmv) on linkage group (LG) XI close to the microsatellite marker CMN04_35. This QTL controls the resistance to WMV in the three environmental conditions evaluated. Other minor QTLs affecting the severity of viral symptoms were identified, but they were not detected in all the assayed environments. The screening of the marker CMN04_35 in an F(2) progeny, derived from the same cross, confirmed the effect of this QTL on the expression of WMV resistance also in early generations, which evidences the usefulness of this marker for a marker assisted selection program. PMID- 21811822 TI - Sagittal spino-pelvic balance is a crucial analysis for normal and degenerative spine. PMID- 21811821 TI - Evaluation of the in vitro cell-material interactions and in vivo osteo integration of a spinal acrylic bone cement. AB - INTRODUCTION: Polymethylmethacrylate bone cements have proven performance in arthroplasty and represent a common bone filler, e.g. in vertebroplasty. However, acrylic cements are still subject to controversy concerning their exothermic reaction and osteo-integration potential. Therefore, we submitted a highly filled acrylic cement to a systematic investigation on the cell-material and tissue implant response in vitro and in vivo. MATERIALS AND METHODS: Cured Vertecem V+ Cements were characterized by electron microscopy. Human bone marrow-derived mesenchymal stem cell morphology, growth and differentiation on the cured cement were followed for 28 days in vitro. The uncured cement was injected in an ovine cancellous bone defect and analysed 4 and 26 weeks post-implantation. RESULTS: The rough surface of the cement allowed for good stem cells adhesion in vitro. Up regulation of alkaline phosphatase was detected after 8 days of incubation. No adverse local effects were observed macroscopically and microscopically following 4 and 26 weeks of implantation of the cement into drill-hole defects in ovine distal femoral epiphysis. Direct bone apposition onto the implant surface was observed resulting in extended signs of osteo-integration over time (35.2 +/- 24.2% and 88.8 +/- 8.8% at week 4 and 26, respectively). CONCLUSION: Contrary to the established opinion concerning bony tissue response to implanted acrylic bone cements, we observed an early cell-implant in vitro interaction leading to cell growth and differentiation and significant signs of osteo-integration for this acrylic cement using standardized methods. Few outlined limitations, such as the use of low cement volumes, have to be considered in the interpretation of the study results. PMID- 21811823 TI - Sagittal imbalance cascade for simple degenerative spine and consequences: algorithm of decision for appropriate treatment. AB - INTRODUCTION: The main objective of all the sagittal compensating mechanisms is to allow a subject to stand and keep an erect position. MATERIALS AND METHODS: The cascade of compensating mechanisms appears progressively with the increasing amount of imbalance of the spine until compensation is no longer possible. The loss of lumbar lordosis can be considered as the initiating event of sagittal imbalance. This loss of the normal lordosis pushes the C7 plumb line forward. RESULTS: The assessment of sagittal balance has to include to be complete: a parameter measuring the global balance of the trunk, either C7 plumb line and sacral plateau, the position of the pelvis rotation by the pelvic tilt, and a description of the position of the lower limbs. Those three parameters have been taken into account by the newly described method called full balance integrated (FBI). This evaluation is easily done on a sagittal full spine standing X-ray from C2 to the pelvis, including the first 10 cm of the femur. CONCLUSION: Three questions to answer: What is the value of the pelvis incidence? Is the patient balanced? Are there compensatory mechanisms? PMID- 21811824 TI - Pediatric sagittal alignment. AB - There is a wide variation in the regional parameters used to describe the spine and sacro-pelvis in children and adolescents. There is a slight tendency for thoracic kyphosis and lumbar lordosis to increase with age. Pelvic incidence and pelvic tilt also tend to increase during growth, while sacral slope remains relatively stable. Strong knowledge of the close relationships between adjacent anatomical regions of the spine and sacro-pelvis is the key when evaluating and interpreting sagittal spino-pelvic alignment. The scheme of correlations between adjacent regional parameters needs to be preserved in order to maintain a balanced posture. The net resultant from these relationships between adjacent anatomical regions is best represented by parameters of sagittal global balance. C7 plumbline tends to move backwards from childhood to adulthood, where it stabilizes or slightly moves forward secondary to degenerative changes. C7 plumbline in front of both hip axis and center of the upper sacral endplate occurs in 29% of subjects aged 3-10 years, 12% of subjects aged between 10 and 18 years, and 14% of subjects aged 18 years or older. Therefore, although most normal subjects stand with a C7 plumbline behind the hip axis, a C7 plumbline in front of both hip axis and sacrum can be seen in normal individuals. However, progressive forward displacement of C7 plumbline should raise a suspicion for the risk of developing spinal pathology. PMID- 21811825 TI - Regulation of polyamine metabolism by translational control. AB - Polyamines are low molecular weight, positively charged compounds that are ubiquitous in all living cells. They play a crucial role in many biochemical processes including regulation of transcription and translation, modulation of enzyme activities, regulation of ion channels and apoptosis. A strict balance between synthesis, catabolism and excretion tightly controls the cellular concentration of polyamines. The concentrations of rate-limiting enzymes in the polyamine synthesis and degradation pathways are regulated at different levels, including transcription, translation and degradation. Polyamines can modulate the translation of most of the enzymes required for their synthesis and catabolism through feedback mechanisms that are unique for each enzyme. Translational control is associated with cis-acting and trans-acting factors that can be influenced by the concentration of polyamines through mechanisms that are not completely understood. In this review, we present an overview of the translational control mechanisms of the proteins in the polyamine pathway, including ornithine decarboxylase (ODC), ODC antizyme, S-adenosylmethionine decarboxylase and spermidine/spermine N(1) acetyltransferase, highlighting the areas where more research is needed. A better understanding of the translational control of these enzymes would offer the possibility of a novel pharmacological intervention against cancer and other diseases. PMID- 21811826 TI - Mutual adaptation between mouse transglutaminase 4 and its native substrates in the formation of copulatory plug. AB - Formation of copulatory plugs by male animals is a common means of reducing competition with rival males. In mice, copulatory plugs are formed by the coagulation of seminal vesicle secretion (SVS), which is a very viscous and self clotting fluid containing high concentration of proteins. In its native state, mouse SVS contains a variety of disulfide-linked high-molecular-weight complexes (HMWCs) composed of mouse SVS I-III, which are the major components of mouse SVS. Further, mouse SVS I-III are the substrates for transglutaminase 4 (TGM4), a cross-linking enzyme secreted from the anterior prostate. According to activity assays, mouse TGM4 prefers a mild reducing and alkaline environment. However, under these conditions, the activity of mouse TGM4 toward SVS I-III was much lower than that of a common tissue-type TGM, TGM2. On the other hand, mouse TGM4 exhibited much higher cross-linking activity than TGM2 when native HMWCs containing SVS I-III were used as substrates under non-reducing condition. By the action of TGM4, the clot of SVS became more resistant to proteolysis. This indicates that the activity of TGM4 can further rigidify the copulatory plug and extend its presence in the female reproductive tract. Together with the properties of TGM4 and the nature of its disulfide-linked SVS protein substrates, male mice can easily transform the semen into a rigid and durable copulatory plug, which is an important advantage in sperm competition. PMID- 21811827 TI - Movement of protein and macromolecules between host plants and the parasitic weed Phelipanche aegyptiaca Pers. AB - Little is known about the translocation of proteins and other macromolecules from a host plant to the parasitic weed Phelipanche spp. Long-distance movement of proteins between host and parasite was explored using transgenic tomato plants expressing green fluorescent protein (GFP) in their companion cells. We further used fluorescent probes of differing molecular weights to trace vascular continuity between the host plant and the parasite. Accumulation of GFP was observed in the central vascular bundle of leaves and in the root phloem of transgenic tomato plants expressing GFP under the regulation of AtSUC2 promoter. When transgenic tomato plants expressing GFP were parasitized with P. aegyptiaca, extensive GFP was translocated from the host phloem to the parasite phloem and accumulated in both Phelipanche tubercles and shoots. No movement of GFP to the parasite was observed when tobacco plants expressing GFP targeted to the ER were parasitized with P. aegyptiaca. Experiments using fluorescent probes of differing molecular weights to trace vascular continuity between the host plant and the parasite demonstrated that Phelipanche absorbs dextrans up to 70 kDa in size from the host and that this movement can be bi-directional. In the present study, we prove for the first time delivery of proteins from host to the parasitic weed P. aegyptiaca via phloem connections, providing information for developing parasite resistance strategies. PMID- 21811828 TI - ZmCBF3 overexpression improves tolerance to abiotic stress in transgenic rice (Oryza sativa) without yield penalty. AB - Plant productivity is greatly affected by environmental stresses such as drought, salt, and freezing. We previously described a C-repeat binding transcription factor from maize (ZmCBF3) that was upregulated by both abscisic acid and low temperature and actively expressed during embryogenesis. To understand the stress response in rice, transgenic ZmCBF3 rice with ubiquitin promoter was developed. T3 generation was planted and analyzed. The results showed that overexpression of ZmCBF3 in rice did not cause growth retardation under normal growth conditions with improved tolerance to drought, high-salt, and low-temperature stresses. Moreover, the transgenic rice grain yield was similar to wild type plants under normal conditions. The transgenic plants showed enhanced survival rate and reduced malondialdehyde content and relative conductivity under drought, salt, and low-temperature stresses. ZmCBF3 overexpression in transgenic rice increased the transcript levels of stress-induced genes and enhanced the tolerance to drought, salt, and low-temperature stresses. PMID- 21811829 TI - An effective instillation method for water-assisted colonoscopy as performed by in-training endoscopists in terms of volume and temperature. AB - BACKGROUND AND STUDY AIMS: There is general consensus that water instillation helps insert a colonoscope. However, the most effective method for water instillation has not yet been established, especially for endoscopists-in training. The aim of this study was to determine volume and temperature for effective water instillation colonoscopy. PATIENTS AND METHODS: This is a prospective, randomized, controlled trial that was carried out at a single center, and a total of 207 consecutive subjects who underwent colonoscopic examination for health checkup were included in the study. Water instillation of supplied water was conducted under four different conditions: 100 and 300 ml at room temperature, 300 ml at 30 degrees C and no use of water instillation. The following parameters were recorded and analyzed: intubation success rate, independent predictors of successful intubation and intubation time to reach the cecum. RESULTS: The intubation success rate was not significantly different between individual groups. Independent predictors of successful intubation were younger age (P = 0.004) and later examined subjects (P = 0.016). The 300-ml warm water instillation during colonoscopy significantly reduced intubation time over the conventional method without water instillation (P = 0.034). CONCLUSIONS: Instillation of 300-ml warm (30 degrees C) water during colonoscopy can reduce cecal intubation time for in-training endoscopists without improving the intubation success rate. PMID- 21811830 TI - Validity and reliability of the Fear-Avoidance Beliefs Questionnaire (FABQ) in workers with upper extremity injuries. AB - INTRODUCTION: Fear Avoidance Beliefs (FAB) have been associated with increased pain, dysfunction and difficulty returning to work in Upper Extremity (UE) injures. The FABQ is used to assess FAB, but its measurement properties have not been established in UE. The purpose of this study is to evaluate the reliability and validity of the FABQ to screen UE compensated injured workers for FAB. METHODS: Consenting workers attending a specialty clinic completed a modified FABQ, QuickDASH (Disability), SPADI Pain Score and von Korff Chronic Pain Grade (Pain), SF-36v2 (General Health), and Work Instability Scale (Job Instability). A sub-sample of workers (n = 48) completed the FABQ 2 weeks later for test-retest reliability. RESULTS: 187 workers; 54.0% male; mean age 45.2 (sd 9.68); 56% were currently working. Mean subscale scores (FABQ-Work [FABQ-W]/FABQ-Physical Activity [FABQ-PA]) were 35/42 and 20/24. Ceiling effects (23%/38%) existed in both subscales. Cronbach's alphas were 0.75/0.78. Test-retest analysis (ICC(2,1)) was lower than desired (0.52/0.59). Construct validation was supported by a moderate correlation between FABQ-W/FABQ-PA and QuickDASH Work Module (0.51/0.42) and WIS (0.46/0.38) in those currently working. Low correlations were found between the subscales measures of pain (SPADI: 0.24/0.23; Chronic Pain Grade: 0.25/0.25), and SF-36 MCS (-0.25/-0.30). CONCLUSIONS: Although FAB is an important concept to measure in compensated UE injured workers, the FABQ had limitations in this population as there was a high ceiling effect, and lower than desired reliability for individual discrimination. A priori hypotheses around construct validity were rejected for 16/22 concepts tested. PMID- 21811831 TI - Drug-related problems in diabetes and transplant patients: an observational study with home visits. AB - OBJECTIVES: To get insight into the medication management of diabetes type 2 (DM) as well as solid organ transplant (Tx) patients and to analyse drug-related problems (DRPs) in order to explore opportunities for the provision of pharmaceutical care. SETTING: Seventy-nine Swiss community pharmacies offering internships for pharmacy students. METHODS: Diabetes and transplant patients were recruited in community pharmacies and were interviewed at home by fifth-year pharmacy students who were supervised by a trained investigator, using a specific interview guide developed for this study. MAIN OUTCOME MEASURE: Pattern and frequency of DRPs and pattern of medication management. RESULTS: In total, 22 (Tx patients) and 54 (DM patients) home visits were carried out. Mean age of visited patients was 71.4 +/- 8.1 years (DM) and 52.6 +/- 13.8 years (Tx). Overall, 37.0% (DM) and 50.0% (Tx) of participants were female. We identified 7.4 +/- 2.4 (mean +/- SD) DRPs per visited patient, with considerable differences between Tx and DM patients (6.3 +/- 1.7 vs. 7.8 +/- 2.5). The most frequent DRPs were risk for non adherence (DM: 61.1%; Tx: 77.3%), confusion of generic and trade names (DM: 74.1%; Tx: 27.3%), hoarding of over-the-counter medicines (DM: 48.1%; Tx: 4.5%) and prescription-only medicines (DM: 37.0%; Tx: 36.4%), gaps in knowledge about potential interactions (DM: 61.1%; Tx: 18.2%) and purpose of drugs (DM: 48.1%; Tx: 36.4%). Mean (SD) duration of the visits was 51.7 +/- 21.4 min. CONCLUSION: Visiting Tx and DM patients in their homes allowed the identification of a wide range of opportunities for pharmaceutical care as well as specific DRPs which most probably would have escaped a medication review in the pharmacy. PMID- 21811832 TI - Self-medication practices among adult population attending community pharmacies in Malaysia: an exploratory study. AB - OBJECTIVE: To assess the prevalence of self-medication among adults in an urban setting and to identify any factors contributing to self-medication in relation to consumer characteristics. SETTING: The study was carried out in Kuala Lumpur, the capital of Malaysia. METHODS: A cross-sectional study using a self administered questionnaire including adults above 21 years old as an exit survey was conducted in Kuala Lumpur. MAIN OUTCOME MEASURES: Number of medications taken in a day by participants, source of medication for the treatment of minor illnesses among participants, common illnesses chosen for self-medication by participants, and the sources of information of participants. RESULTS: Of 314 participants, 62.7% had taken at least one medication in the past week without prescription and 62.7% believed that over the counter medicines were just as effective as those prescribed by doctors. 69.4% would seek a healthcare professional's advice before purchasing any medication and 86.9% would consult a pharmacist prior to buying medication from the pharmacy. Only 86% checked the expiry dates on medications and 54.5% reported keeping leftover medication. CONCLUSIONS: Self-medication practice is prevalent in Kuala Lumpur but some practice might be harmful. Education on appropriate use of self-medication need to be emphasized in order to ensure quality use of medicines. PMID- 21811833 TI - A phase I pharmacokinetic and safety evaluation of oral pazopanib dosing administered as crushed tablet or oral suspension in patients with advanced solid tumors. AB - Because cancer patients may have difficulty swallowing whole tablets, crushing tablets or ingesting an oral suspension is a practical alternative. This open label, 2-part, randomized crossover, phase I study evaluated the pharmacokinetics and tolerability of pazopanib administered as a crushed tablet or an oral suspension relative to whole tablet in patients with advanced cancer (Part 1). Patients completing Part 1 were eligible for continuous daily pazopanib 800 mg (Part 2). Administration of a single pazopanib 400 mg crushed tablet increased the area under the curve from 0 to 72 h (AUC((0-72)); 46%) and maximum observed plasma concentration (C(max); ~2-fold), and decreased time to achieve maximum plasma concentration (T(max); ~2 h), indicating increased rate and extent of oral absorption relative to whole-tablet administration. Similarly, a single dose of pazopanib 400 mg suspension increased AUC((0-72)) (33%) and C(max) (29%), and decreased T(max) (1 h). These changes in pharmacokinetic parameters were not associated with increases in the magnitude or duration of short-term (ie, up to 72 h) blood pressure elevation compared with whole-tablet administration. PMID- 21811834 TI - Effects of club soda and ginger brew on linguapalatal pressures in healthy swallowing. AB - Oral chemesthesis is the detection of chemicals that activate temperature and pain receptors in the oral mucosa. Presentation of orally chemesthetic input has been theorized to stimulate a faster, stronger swallow. We measured differences in peak linguapalatal swallowing pressures, pressure durations, and pressure adjustments in response to two volumes of water and carbonation (in Schweppes(r) Club Soda) and carbonation + gingerol (in Reed's Extra Ginger Brew) in 20 young adult women. There was a main effect of stimulus on linguapalatal swallowing pressure, F(6,74) = 6.247, p = 0.000, hp(2) = 0.536 (Reed's Extra Ginger Brew > Schweppes Club Soda > water). Rising and releasing linguapalatal pressure durations were greater for carbonation + gingerol and carbonation than for water. Our results add to the evidence that orally chemesthetic beverages influence greater neuromotor activity compared to water during the oral stage of swallowing. Our findings also suggest that there may be some benefit to the cumulative addition of chemosensory agents in a beverage. Clinically, this provides a theoretical basis for considering the use of these or chemically similar beverages as facilitating stimuli in patients who aspirate thin liquids. PMID- 21811835 TI - Racial differences among supported housing clients in outcomes and therapeutic relationships. AB - This study examined racial differences between African American and White supported housing clients in clinical outcomes and in their relationships with their landlords, medical and mental health care providers, and religious faith. Housing, mental health, and substance abuse outcomes of 204 White clients and 269 Black clients participating in a national homeless initiative were examined, along with their ratings of their relationships with landlords, health care providers, and religious participation. There were no significant racial differences found on outcomes or on client ratings of the helpfulness of relationships with landlords and health care providers. However, Black participants reported significantly stronger religious faith and religious participation than White participants. Together, these results suggest the religious faith of Black clients should be appreciated as a potential asset in supported housing services and that efforts to maintain racial equality should be continued in the delivery of health services. PMID- 21811837 TI - Interference effects of stimulus-response modality pairings in dual tasks and their robustness. AB - Recent evidence suggests that the degree of interference in dual-task situations depends crucially on the pairings of input- and output modalities of the two component tasks with increased dual-task costs for modality incompatible (i.e., visual-vocal and auditory-manual) compared to modality compatible (i.e., visual manual and auditory-vocal) dual tasks. These effects of modality pairings in dual tasks have been related to the overlap of non-preferred processing pathways in modality incompatible tasks. Until now, modality compatibility has not yet been related to other sources of interference in a dual-task context, such as stimulus response (S-R) compatibility or crosstalk. In the present study, we conducted two experiments using the paradigm of the psychological refractory period (PRP) to test the effects of S-R compatibility and crosstalk on the effects of modality compatibility in temporally overlapping task situations. Experiment 1 revealed an overadditive interaction between stimulus onset asynchrony and modality compatibility for tasks with S-R compatible mappings, indicating that modality compatibility effects are present in different task situations, even when S-R mappings are otherwise compatible. In Experiment 2, we aimed at pinpointing the boundaries of the effects of modality compatibility in dual-task situations. We showed that additional sources of dual-task interference in a modality compatible dual task could overwrite the pronounced PRP effect previously shown for modality incompatible tasks. Taken together, these data provide new evidence that the specific types of stimulus-response modality pairings are an additional factor that might interact with other sources of interference in dual-task situations. PMID- 21811838 TI - [Urethro-crural fistula to the adductor canal. Late complication following radiotherapy for recurrent prostate cancer]. AB - Urinary fistulas are rare (late) complications following radiotherapy for prostate cancer. We present the case of a urethro-crural fistula to the adductor canal 7 years after radiotherapy in a man who had previously undergone radical prostatectomy. PMID- 21811836 TI - Significance of heparanase in cancer and inflammation. AB - Heparan sulfate proteoglycans (HSPGs) are primary components at the interface between virtually every eukaryotic cell and its extracellular matrix. HSPGs not only provide a storage depot for heparin-binding molecules in the cell microenvironment, but also decisively regulate their accessibility, function and mode of action. As such, they are intimately involved in modulating cell invasion and signaling loops that are critical for tumor growth, inflammation and kidney function. In a series of studies performed since the cloning of the human heparanase gene, we and others have demonstrated that heparanase, the sole heparan sulfate degrading endoglycosidase, is causally involved in cancer progression, inflammation and diabetic nephropathy and hence is a valid target for drug development. Heparanase is causally involved in inflammation and accelerates colon tumorigenesis associated with inflammatory bowel disease. Notably, heparanase stimulates macrophage activation, while macrophages induce production and activation of latent heparanase contributed by the colon epithelium, together generating a vicious cycle that powers colitis and the associated tumorigenesis. Heparanase also plays a decisive role in the pathogenesis of diabetic nephropathy, degrading heparan sulfate in the glomerular basement membrane and ultimately leading to proteinuria and kidney dysfunction. Notably, clinically relevant doses of ionizing radiation (IR) upregulate heparanase expression and thereby augment the metastatic potential of pancreatic carcinoma. Thus, combining radiotherapy with heparanase inhibition is an effective strategy to prevent tumor resistance and dissemination in IR-treated pancreatic cancer patients. Also, accumulating evidence indicate that peptides derived from human heparanase elicit a potent anti-tumor immune response, suggesting that heparanase represents a promising target antigen for immunotherapeutic approaches against a broad variety of tumours. Oligosaccharide based compounds that inhibit heparanase enzymatic activity were developed, aiming primarily at halting tumor growth, metastasis and angiogenesis. Some of these compounds are being evaluated in clinical trials, targeting both the tumor and tumor microenvironment. PMID- 21811839 TI - [Recto-vesico-cutaneous fistula following salvage cryotherapy of the prostate due to recurrent localized prostate cancer]. AB - For patients with recurrent prostate cancer after initial external beam radiation salvage cryotherapy is considered as an alternative to salvage prostatectomy. We report a serious complication of salvage cryotherapy in a 72-year-old man suffering from a severe recto-vesico-cutaneous fistula 6 weeks after salvage cryotherapy. To manage this situation salvage cystoprostatectomy and continent urinary diversion with creation of an ileocaecal pouch with cutaneous stoma had to be performed. PMID- 21811840 TI - Polling booth surveys: a novel approach for reducing social desirability bias in HIV-related behavioural surveys in resource-poor settings. AB - This study compared rates of HIV-related sexual risk behaviours reported in individual face-to-face (FTFI) and group anonymous polling booth (PBS) interviews in India. In PBS, respondents grouped by gender and marital status answered yes/no questions by putting tokens with question numbers in colour-coded containers. Data were subsequently collated for each group as a whole, so responses were not traceable back to individuals. Male and female PBS participants reported substantially higher rates of pre-marital, extra-marital, commercial and anal sex than FTFI participants; e.g. 11 vs. 2% married males reported paying for sex; 6 vs. 1% unmarried males reported homosexual anal sex. PMID- 21811841 TI - Male migration/mobility and HIV among married couples: cross-sectional analysis of nationally representative data from India. AB - This paper examines the associations between male migration and mobility with HIV among married couples in India. Cross-sectional analyses of a nationally representative household survey conducted across all 29 states of India from 2005 to 2006 via the National Family Health Survey-3 (NFHS-3) included a subsample of 27,771 married couples who were tested for HIV as a part of their participation. Both bi-variate and multi-variate analyses were conducted. About 0.5% of the total married couples in the current study included an HIV-infected partner; 0.11% were HIV concordant and 0.38% were HIV serodiscordant couples. Adjusted logistic regression analyses demonstrated that HIV infection in couples (seroconcordant or serodiscordant) was significantly more likely among those couples where the man was migrant but not mobile and those couples where the man was migrant as well as mobile, relative to those couples where the man was neither migrant nor mobile. Male migration increases the risk for HIV among married couples in India, largely in the form of serodiscordance in which men are HIV infected. These findings document the need for not only primary prevention efforts to reduce HIV acquisition among migrant male workers, particularly more mobile migrants, but also efforts are needed to reduce subsequent transmission to their wives. PMID- 21811842 TI - Primary relationships, HIV treatment adherence, and virologic control. AB - To identify factors associated with antiretroviral therapy (ART) adherence and virologic control among HIV-positive men on ART in primary relationships, data were collected from 210 male couples (420 men). Dyadic actor-partner analyses investigated associations with three levels of adherence-related dependent variables: self-efficacy (ASE), self-reported adherence, and virologic control. Results indicated that higher patient ASE was related to his own positive beliefs about medications, higher relationship autonomy and intimacy, and fewer depressive symptoms. Fewer depressive symptoms and less relationship satisfaction in the partner were linked to higher ASE in the patient. Better self-reported adherence was related to the patient's positive appraisal of the relationship and the partner's positive treatment efficacy beliefs. Greater medication concerns of both patient and partner were associated with less adherence. The partner's higher relationship commitment was associated with lower viral load in the patient. Findings suggest that depressive symptoms, treatment beliefs, and relationship quality factors of both partners may influence adherence-related outcomes. PMID- 21811843 TI - Social network-based interventions to promote condom use: a systematic review. AB - Effective sexually transmitted infection (STIs)/HIV prevention programs are urgently needed, but translating evidence-based methods of STI/HIV prevention into sustainable programs has been difficult. Social influences are critical for establishing condom use norms. This study systematically reviewed social network based interventions focused on condom promotion. Social networks were defined as groups who self-identified prior to the research study. Eleven eligible research studies were identified and included in this review. Only three studies measured biological endpoints and five studies used validated measures of condom use. Among the nine studies with control groups, eight showed significant improvements in at least one measure of condom use. There were large differences in how social network members were identified and involved in the interventions. This systematic review highlights the potential utility of social network-based condom promotion programs. More research is needed to show how these promising studies can be expanded. PMID- 21811844 TI - Social network predictors of disclosure of MSM behavior and HIV-positive serostatus among African American MSM in Baltimore, Maryland. AB - This study examined correlates of disclosure of MSM behavior and seropositive HIV status to social network members among 187 African American MSM in Baltimore, MD. 49.7% of participants were HIV-positive, 64% of their social network members (excluding male sex partners) were aware of their MSM behavior, and 71.3% were aware of their HIV-positive status. Disclosure of MSM behavior to network members was more frequent among participants who were younger, had a higher level of education, and were HIV-positive. Attributes of the social network members associated with MSM disclosure included the network member being HIV-positive, providing emotional support, socializing with the participant, and not being a female sex partner. Participants who were younger were more likely to disclose their positive HIV status. Attributes of social network members associated with disclosure of positive serostatus included the network member being older, HIV positive, providing emotional support, loaning money, and not being a male sex partner. PMID- 21811845 TI - Syringe coverage in an Australian setting: does a high level of syringe coverage moderate syringe sharing behaviour? AB - We examined individual-level syringe coverage among 417 people who inject drugs who were recruited from pharmacies in New South Wales in 2009. There was a U shaped distribution of syringe coverage with many people having very high (51%) or very low (23%) coverage. Overall, two-thirds of respondents (63%) reported adequate coverage (>= 100%). Respondents who had not used a needle and syringe program in the previous month were more likely to report inadequate coverage (AOR 2.25, 95% CI 1.25-4.05) as were those who reported daily or more frequent injecting (AOR 3.69, 95% CI 2.00-6.81). Inadequate syringe coverage was not independently associated with receptive needle sharing. The level of syringe coverage was high among this sample, and met targets set out by UNAIDS and other organisations. We found that inadequate syringe coverage was not independently correlated with receptive needle sharing, possibly because coverage is sufficient to diminish the relationship between syringe availability and sharing behaviours. PMID- 21811846 TI - [The psychocardiologic side of implantation, wearing and psychological adjustment to the activity of an implanted cardioverter/defibrillator]. PMID- 21811847 TI - Effects of everolimus in combination with sildenafil in monocrotaline-induced pulmonary hypertension in rats. AB - In our study, we investigated the efficacy of everolimus in combination with sildenafil on hemodynamic and morphological parameters in rats with monocrotaline induced pulmonary hypertension (PH). Right ventricular pressure (RVP), right ventricular hypertrophy, and the response to vasoconstrictor and vasodilator agents in pulmonary arteries as evaluated by myography and histopathological changes were compared among the groups. RVP and right ventricle/body weight ratios were increased in non-treated monocrotaline groups versus the controls; these increased ratios were decreased in the treated groups and were similar to control values. The contractile responses to endothelin-1 in the pulmonary arteries were decreased in the non-treated monocrotaline groups versus the control. In the treatment groups, contractile responses were similar to those in the controls. Responses to acetylcholine and sodium nitroprusside relaxation were decreased in non-treated monocrotaline groups but were improved significantly in the everolimus groups. Upon histopathological examination, the vascular hypertrophy and cardiac hypertrophy observed in monocrotaline groups were improved by the sildenafil and everolimus treatment. In particular, these improvements became remarkable, including the inflammatory changes, in the everolimus treatment groups. In the light of these results, sildenafil and everolimus in combination were more effective than sildenafil treatment alone in reversing the remodelling process without any cardiovascular toxic effects in the monocrotaline-induced PH model. PMID- 21811848 TI - Ginsenoside Rd protects neurons against glutamate-induced excitotoxicity by inhibiting ca(2+) influx. AB - Our previous studies have demonstrated that ginsenoside Rd (GSRd), one of the principal ingredients of Pana notoginseng, has neuroprotective effects against ischemic stroke. However, the possible mechanism(s) underlying the neuroprotection of GSRd is/are still largely unknown. In this study, we treated glutamate-injured cultured rat hippocampal neurons with different concentrations of GSRd, and then examined the changes in neuronal apoptosis and intracellular free Ca(2+) concentration. Our MTT assay showed that GSRd significantly increased the survival of neurons injured by glutamate in a dose-dependent manner. Consistently, TUNEL and Caspase-3 staining showed that GSRd attenuated glutamate induced cell death. Furthermore, calcium imaging assay revealed that GSRd significantly attenuated the glutamate-induced increase of intracellular free Ca(2+) and also inhibited NMDA-triggered Ca(2+) influx. Thus, the present study demonstrates that GSRd protects the cultured hippocampal neurons against glutamate-induced excitotoxicity, and that this neuroprotective effect may result from the inhibitory effects of GSRd on Ca(2+) influx. PMID- 21811849 TI - Characterization of a novel flooding stress-responsive alcohol dehydrogenase expressed in soybean roots. AB - Alcohol dehydrogenase (Adh) is the key enzyme in alcohol fermentation. We analyzed Adh expression in order to clarify the role of Adh of soybeans (Glycine max) to flooding stress. Proteome analysis confirmed that expression of Adh is significantly upregulated in 4-day-old soybean seedlings subjected to 2 days of flooding. Southern hybridization analysis and soybean genome database search revealed that soybean has at least 6 Adh genes. The GmAdh2 gene that responded to flooding was isolated from soybean cultivar Enrei. Adh2 expression was markedly increased 6 h after flooding and decreased 24 h after floodwater drainage. In situ hybridization and Western blot indicated that flooding strongly induces Adh2 expression in RNA and protein levels in the root apical meristem. Osmotic, cold, or drought stress did not induce expression of Adh2. These results indicate that Adh2 is a flooding-response specific soybean gene expressed in root tissue. PMID- 21811850 TI - RNA-Seq analysis and de novo transcriptome assembly of Hevea brasiliensis. AB - Hevea brasiliensis, being the only source of commercial natural rubber, is an extremely economically important crop. In an effort to facilitate biological, biochemical and molecular research in rubber biosynthesis, here we report the use of next-generation massively parallel sequencing technologies and de novo transcriptome assembly to gain a comprehensive overview of the H. brasiliensis transcriptome. The sequencing output generated more than 12 million reads with an average length of 90 nt. In total 48,768 unigenes (mean size = 436 bp, median size = 328 bp) were assembled through de novo transcriptome assembly. Out of 13,807 H. brasiliensis cDNA sequences deposited in Genbank of the National Center for Biotechnology Information (NCBI) (as of Feb 2011), 11,746 sequences (84.5%) could be matched with the assembled unigenes through nucleotide BLAST. The assembled sequences were annotated with gene descriptions, Gene Ontology (GO) and Clusters of Orthologous Group (COG) terms. In all, 37,432 unigenes were successfully annotated, of which 24,545 (65.5%) aligned to Ricinus communis proteins. Furthermore, the annotated uingenes were functionally classified according to the GO, COG and Kyoto Encyclopedia of Genes and Genomes databases. Our data provides the most comprehensive sequence resource available for the study of rubber trees as well as demonstrates effective use of Illumina sequencing and de novo transcriptome assembly in a species lacking genomic information. PMID- 21811851 TI - Tissue perfusion in pathologies of the pancreas: assessment using 128-slice computed tomography. AB - PURPOSE: Perfusion CT can provide information regarding blood perfusion and permeability in (tumor) tissues in a non-invasive manner. In this study, values of CT perfusion parameters in several pancreas pathologies were determined and compared to a control population. MATERIALS AND METHODS: Dynamic 128-slice perfusion CT was performed in patients admitted to the radiology department between June 2010 and March 2011. Included pathologies were pancreatic adenocarcinoma, acute and chronic pancreatitis, neuroendocrine tumors, and (pseudo)cystic lesions. Parametric mappings of blood flow, blood volume, and permeability surface area product were generated. RESULTS: Blood flow and blood volume were significantly lower in acute and chronic pancreatitis compared to the control group. In the center of adenocarcinoma tumors, low blood flow and blood volume was observed, gradually increasing toward the tumor rim; perfusion values in pancreatic parenchyma adjacent to the tumor were not significantly different from the control population. In neuroendocrine tumors, significantly increased perfusion values were observed. CONCLUSION: Compared to the control population, significant decreases in perfusion values were observed in all pancreatic pathologies under study, except in neuroendocrine tumors. Perfusion CT values can be used as an additional parameter to differentiate pancreatic pathologies. PMID- 21811852 TI - Identification of the core sequence elements in Penaeus stylirostris densovirus promoters. AB - In silico analysis of three Penaeus stylirostris densovirus (PstDNV) promoters, designated P2, P11, and P61, revealed sequence motifs including the TATA box, downstream promoter element (DPE), GC- and A-rich regions, inverted repeat, activation sequence-1 like (ASL) box, and a conserved guanosine (G) at +24. To delineate the regulatory role of these motifs on promoter activity, deletion constructs were made in a promoter assay vector, pGL3 Basic, that contains a luciferase reporter gene. Luciferase assay showed that P2 had the highest promoter activity followed by P11 and P61 in Sf9 cells. The deletions of inverted repeat, DPE, and GC-rich regions in P2 had the highest negative impact on this promoter. Deletions of DPE, G at the +24, and ASL box in P11 had the highest negative impact on this promoter activity. In P61, DPE and G at +24 are the two key regulators of transcriptional activity. Identification of the key transcriptional regulators is important in understanding the PstDNV pathogenesis in shrimp. This information is also valuable in constructing shrimp viral promoter-based vectors for protein expression in insect cell culture system as well as in shrimp. PMID- 21811853 TI - Static rotational and sagittal knee laxity measurements after reconstruction of the anterior cruciate ligament. AB - PURPOSE: The goal of the present study was to evaluate static anteroposterior and rotational knee laxity after ACL reconstructions with two noninvasive measurement devices by comparing the measured results of the operated with the contralateral healthy knees of the patients. METHODS: Fifty-two consecutive patients were reviewed after isolated single-bundle transtibial ACL reconstruction using a BPTB graft. At a mean follow-up of 27 months, sagittal AP laxity was tested using a noninvasive knee measurement system (Genourob) with an applied pressure of 67 N, 89 N and 134 N. Rotational laxity was measured using a noninvasive rotational knee laxity device (Rotameter) with an applied torque of 5, 8 and 10 Nm. The results were compared with the measurements of the patients' healthy contralateral knees. Tegner, Lysholm and IKDC score were used in order to evaluate the clinical outcome. RESULTS: Pivot shift was negative (33) or glide (16) in 49 patients with 12 of 16 (75%) patients having also a pivot glide on the healthy contralateral side; Lachman tests were negative in 50 cases. Subjective assessment of the IKDC score was classified according to category A in 44 patients, B in 5 patients and C in 3 patients. Mean Lysholm score was 94.5 +/- 9.5, median Tegner score was 7 (3-9) preoperative and 6 (3-9) at follow-up (n.s.). Anteroposterior knee laxity measurements revealed mean side-to-side differences of 0.6-1.3 mm (P < 0.0001). Rotational laxity measurements revealed no statistical significant differences between the operated and the contralateral knee (n.s.). The measured differences in the entire rotational range varied from 0.2 degrees to 1 degrees depending on the applied torque. In those 3 patients with a positive pivot shift, differences in the entire rotational range of 4.5 degrees at 5 N, 4.6 degrees at 8 N and 4.1 degrees at 10 N were found. CONCLUSION: Static knee laxity was quantified after ACL surgery using the introduced noninvasive measurement systems by comparing the measured results of the operated with the contralateral healthy knees. Significant differences were found in AP laxity although they were defined as clinically successful according to the IKDC classification. No significant differences were found in rotational knee laxity measurements. Therefore, the used noninvasive masurement devices might offer a high potential for objective quality control in knee ligament injuries and their treatment. LEVEL OF EVIDENCE: Retrospective case series, Level IV. PMID- 21811854 TI - Age as a predictor of residual muscle weakness after anterior cruciate ligament reconstruction. AB - PURPOSE: The objective of this study was to reveal the predicting factors for muscle recovery in the lower extremity after anterior cruciate ligament (ACL) reconstruction. METHODS: One hundred and thirty-five (135) patients who underwent ACL reconstruction using hamstring autograft were evaluated. Exclusion criteria were bilateral ACL injury, chondral treatment and multiple ligament injury. Nonanatomical single-bundle reconstruction (SB) was performed in 79 patients, and anatomical double-bundle reconstruction (DB) was performed in 56 patients. Strength of quadriceps and knee flexion muscles were assessed at 60 degrees /s using a Cybex II dynamometer (Lumex, Ronkonkoma, NY) at 3, 6 and 9 months after ACL reconstruction. Anterior tibial translation and pivot shift test were also evaluated. The medical records were reviewed to extract the following information: age, gender, the amount of pre and postoperative KT 1000, technique of reconstruction (SB or DB) and postoperative knee rotation. RESULTS: No significant difference of muscle recovery in the lower extremity was observed at any time point after ACL reconstruction between the SB and DB groups. The DB group showed significantly better postoperative antero-posterior and rotational knee laxity than the SB group. Logistic regression analysis showed significant correlation with only age and muscle recovery. CONCLUSION: For clinical relevance, there is a risk of muscle recovery delay when ACL reconstruction is performed in elderly patients. Anatomical DB reconstruction resulted in significantly better knee stability, but had no positive effect on muscle recovery. LEVEL OF EVIDENCE: Retrospective study, Level II. PMID- 21811855 TI - The effect of knee position on blood loss and range of motion following total knee arthroplasty. AB - PURPOSE: This study prospectively assessed the effects of knee position on blood loss and range of motion after primary total knee arthroplasty (TKA). METHODS: One hundred and ten consecutive TKA patients were randomized into flexion group and extension group. Both groups had the leg elevated 30 degrees at the hip over an inactive CPM for 72 h postoperatively. The flexion group had the knee flexed to 30 degrees during this period. The extension group had the knee extended fully. Perioperative blood loss, hidden blood loss, knee swelling, ecchymosis, analgesia requirements, range of motion (ROM), fixed flexion deformity (FFD), straight-leg raising action, and postoperative complications within 6 weeks of surgery were measured for evaluation and comparison. RESULTS: The postoperative hidden blood loss, knee swelling, and scope of ecchymosis were significantly lower in the flexion group than in the extension group, and ROM and straight-leg raising action were significantly higher during the early period after operation. No significant difference was observed in perioperative blood loss, the amount of morphine used, or FFD in the early postoperative period or in ROM and FFD at 6 weeks postoperatively. CONCLUSIONS: The findings of this study indicate that flexion of the knee to 30 degrees with the leg elevated 30 degrees at the hip after total knee arthroplasty may mitigate knee swelling and provide other beneficial results during the early rehabilitation following TKA. LEVEL OF EVIDENCE: Prospective comparative study, Level I. PMID- 21811856 TI - Acromioclavicular motion after surgical reconstruction. AB - PURPOSE: A retrospective long-term study was carried out to determine whether there was any correlation between the clinical motion of the acromioclavicular joint evaluated by a test we set up using 90 degrees of abduction and 0 degrees of external rotation against resistance [90 degrees /0 degrees RTest] and the cross arm test (compared to the healthy side) and full return to everyday activities after surgical repair. METHODS: A clinical and radiographic evaluation was carried out on 51/80 subjects at a 5.4-year mean follow-up, treated for acromioclavicular joint dislocation with an extra-articular artificial loop, between 2000 and 2006. RESULTS: The 25 subjects with ossifications obtained a normal acromioclavicular joint motion, on both the horizontal and vertical planes. There was a correlation between the normal motion of the reconstructed acromioclavicular joint (compared to the healthy side) in these 25 patients and full clinical recovery, whilst there was no correlation between the Constant score, the simple shoulder test, the radiographic evaluation on one hand and the clinical motion of the joint on the other. Two patients had recurrent dislocation. Three had mobilization of the screws without reduction loss, or negative clinical outcome. CONCLUSIONS: A postoperative radiographic evaluation should be correlated with a clinical evaluation of the acromioclavicular joint motion (normal, hypermobile, unstable). Normal acromioclavicular joint motion was observed in subjects who developed significant ossifications. The study shows that the clinical evaluation of acromioclavicular joint motion is a simple and trustworthy method to assess the clinical result of a surgical repair. LEVEL OF EVIDENCE: Diagnostic study investigating a diagnostic test, Level III. PMID- 21811857 TI - Expectation, satisfaction and clinical outcome of patients after total knee arthroplasty. AB - PURPOSE: There is a well-known difference between patients expectation, satisfaction and the measured clinical outcome in total knee arthroplasty (TKA). It has been hypothesized that higher expectation prior to surgery and higher satisfaction will show better clinical outcome according to well-established scoring systems, frequently used for assessment after TKA. METHODS: A consecutive group of 102 patients was included who received TKA for degenerative osteoarthritis. A modified patients expectation form was used prior and 8 months after surgery. Furthermore, the KSS, WOMAC and SF-36 served for patient assessment. Patients were grouped in responder and non-responder according to their level of expectation and fulfilment of expectation after surgery using a Likert scale. RESULTS: A total of 54 patients (53%) showed expectation prior to surgery of 1 or 2 and a satisfaction after surgery of 1 or 2 according to the Likert scales. These patients were classified as responders. Considering the continuous parameters of KSS, SF-36 and WOMAC, a few statistically significant differences were found between the responders and non-responders at baseline (pre surgery) and at the fulfilment of their expectation after surgery. Patient expectation prior to surgery did not differ between both groups. The more satisfied patients showed significant better results in the KSS, WOMAC and SF-36 after surgery. The parameters general health (SF-36) and role emotional (SF-36) measured prior to surgery dominate the predictive potential to get a responder with sensitivity of 74%, specificity of 81% and a rate of correct classification of 78%. CONCLUSION: This study has shown that patient satisfaction correlates well with the clinical outcome according to the KSS, WOMAC and SF-36. The indication for TKA should consider the general health, emotional role and knee function of the patients as well in order to predict patient's outcome. PMID- 21811858 TI - Complete genomic sequence of the Lactobacillus temperate phage LF1. AB - Bacteriophage LF1, a newly isolated temperate phage from a mitomycin-C-induced lysate of wild type Lactobacillus fermentum, was found to contain a double-strand DNA of 42,606 base pairs (bp) with a G+C content of 45%. Bioinformatic analysis of the phage genome revealed 57 putative open reading frames (ORFs). The predicted protein products of ORFs were determined and described. According to morphological analysis by transmission electron microscopy (TEM), LF1 has an isometric head and a non-contractile tail, indicating that it belongs to the family Siphoviridae. The temperate phage LF1 has a good genetic mosaic relationship with PhiPYB5 in the packaging module. To our knowledge, this is first report of genomic sequencing and characterization of temperate phage LF1 from wild-type L. fermentum isolated from Kimchi in Korea. PMID- 21811859 TI - Perceptions of personal risk about smoking and health among Bosnian refugees living in the United States. AB - More than 60% of Bosnian refugees in the United States may be current smokers. Examining health beliefs can provide insight into smoking behaviors in this community. Four hundred ninety-nine Bosnians were interviewed about health beliefs and personal health risks related to smoking. ANOVA was used to compare current, former, and never smokers. General health beliefs were significantly different by smoking status with medium effect sizes (P < .001; eta(2) = 0.04 0.06); current smokers were less likely to agree that smokers live shorter lives and that smokers are more likely to get heart disease. Significant differences with large effect sizes (P < .001; eta(2) = 0.11-0.29) were found in perception of personal risk of lung cancer and heart disease among current, former, and never smokers. Current smokers perceived their own health risks as less severe than those of other smokers. High smoking rates and smokers' optimism related to health indicate that culturally tailored educational and cessation interventions are needed for Bosnian refugee communities. PMID- 21811860 TI - Positive Darwinian selection drives the evolution of the morphology-related gene, EPCAM, in particularly species-rich lineages of African cichlid fishes. AB - The study of genetic evolution within the context of adaptive radiations offers insights to genes and selection pressures that result in rapid morphological change. Cichlid fishes are very species-rich and variable in coloration, behavior, and morphology, and so provide a classical model system for studying the genetics of adaptive radiation. In this study, we researched the evolution of the epithelial cell adhesion molecule (EPCAM), a candidate gene for the adaptive evolution of morphology broadly, and skin development specifically, in fishes. We compared EPCAM gene sequences from a rapidly speciating African cichlid lineage (the haplochromines), a species-poor African lineage (Nile tilapia Oreochromis niloticus), and a very young adaptive radiation in the Neotropics (sympatric crater lake Midas cichlids, Amphilophus sp.). Our results, based on a hierarchy of evolutionary analyses of nucleotide substitution, demonstrate that there are different selection pressures on the EPCAM gene among the cichlid lineages. Several waves of positive natural selection were identified not only on the terminal branches, but also on ancestral branches. Interestingly, significant positive or directional selection was found in the haplochromine cichlids only but not the comparatively species-poor tilapia lineage. We hypothesize that the strong signal of selection in the ancestral African cichlid lineage coincided with the transition from riverine to lacustrine habitat. The two neotropical species for which we collected new sequence data were invariant in the EPCAM locus. Our results suggest that functional changes promoted by positive Darwinian selection are widespread in the EPCAM gene during African cichlid evolution. PMID- 21811861 TI - Cross-validation of input functions obtained by H2 15O PET imaging of rat heart and a blood flow-through detector. AB - PURPOSE: Positron emission tomography (PET) with 15O-labeled water (H2 15O) facilitates the visualization and quantification of blood flow in clinical investigations and also in small animals. The quantification of blood flow requires an input function, which is generally obtained by measuring radioactivity in arterial blood withdrawn during PET scanning. However, this approach is not always feasible, because abundant blood sampling may affect the physiological process being measured. The purpose of the present study was to develop and cross-validate two methods, namely, a blood- and an image-based method for obtaining the input function for blood flow studies from rat H2 15O PET. METHODS: The study material consisted of two separate groups of rats. Group 1 rats were imaged twice by a high-resolution research tomograph PET camera at resting condition for a test-retest study (n = 4), and group 2 rats were imaged with and without adenosine infusion for a rest-stress study (n = 4). In group 1, radioactivity concentration in arterial blood was measured with a new flow through detector during imaging and a blood-based input function was obtained. The image-based input function was estimated using time-activity curves from the left ventricle and myocardial regions. To validate the two input function methods, myocardial blood flow (MBF) and cerebral blood flow (CBF) were computed, and the methods were tested for reproducibility (test-retest study) and changes (rest-stress study). RESULTS: The blood- and image-based input functions were similar, and the corresponding CBF values differed only by -6.9 +/- 8.1%. In the test-retest study, both MBF and CBF showed good reproducibility, and in the rest stress study, adenosine significantly increased both MBF (P = 0.035) and CBF (P = 0.029), compared with the resting condition. CONCLUSION: It is possible both to measure the input function from rat arteria femoralis during H2 15O PET imaging and to estimate the input function from rat H2 15O PET images, thereby facilitating the assessment of blood flow in organs visible in PET images. PMID- 21811863 TI - A case of posterior element fracture in Kummell's disease. AB - Kummell's disease is a rare, delayed posttraumatic collapse of a vertebral body that can occur several months or even years after an osteoporotic compression fracture. However, there are few reports of posterior element fractures associated with Kummell's disease. A 72-year-old man who had sustained an L1 osteoporotic compression fracture 14 months prior was admitted to our institution with incapacitating back pain. Plain radiographs showed progressive collapse of the L1 vertebral body and severe kyphosis at the thoracolumbar junction. Magnetic resonance imaging revealed a posterior element fracture as well as osteonecrosis of the L1 vertebral body. An L1 percutaneous vertebroplasty was performed, followed by bone cement-augmented screw fixation to maintain stability and correct the kyphotic deformity. After surgery, pain relief was immediate, and the patient was able to walk unassisted. This case illustrates that continuous axial distraction stress caused by aggravated kyphosis secondary to Kummell's disease may result in posterior element fractures. Our discussion concludes with a literature review. PMID- 21811864 TI - The effect of exercise on pQCT parameters of bone structure and strength in postmenopausal women--a systematic review and meta-analysis of randomized controlled trials. AB - Inconsistent study findings of exercise on areal bone density highlight the need to include parameters of bone geometry and volumetric bone density measurements. Using a systematic review and meta-analysis, we found a decrease in bone loss through the maintenance of cortical and trabecular volumetric bone mineral density (BMD). Studies with longer exercise durations and larger sample sizes are needed. INTRODUCTION: Exercise has long been recommended to prevent age-related loss of bone mass in postmenopausal women. However, inconsistent study findings on the effect of exercise on BMD preservation have highlighted the importance of extending the evaluation of bone to include the parameters of bone geometry. We conducted both a systematic review and meta-analysis of the effects of exercise on bone geometry and volumetric BMD in postmenopausal women. METHODS: We searched MEDLINE, PubMed, and EMBASE from 1950 to April 2009 and included prospective, randomized controlled trials of healthy postmenopausal women where the intervention involved exercise or sport and outcomes included quantitative or peripheral quantitative computed tomography bone parameters. Outcome variables included: total volumetric BMD, cortical volumetric BMD (CvBMD), trabecular volumetric BMD (TrvBMD), total bone mineral content, cortical BMC, total bone area, cortical area, polar stress-strain index, and bone strength index. RESULTS: Six studies satisfied our inclusion and exclusion criteria. Lower extremity exercises resulted in small (~0.9%) but significant improvements in TrvBMD of the distal tibia (p = 0.0006) and in CvBMD of the tibial shaft (p = 0.0007). Studies with longer durations of exercise (12 months) and those in early postmenopausal women showed significant changes in CvBMD at the tibial shaft. CONCLUSIONS: We conclude that exercise in postmenopausal women may decrease bone loss by maintaining cortical and trabecular volumetric BMD. To better understand the effect of exercise on bone geometric structure and strength, more studies of longer duration and larger sample sizes are needed. PMID- 21811862 TI - Socioeconomic status, race, and bone turnover in the Midlife in the US Study. AB - Among a group of 940 US adults, economic adversity and minority race status were associated with higher serum levels of markers of bone turnover. These results suggest that higher levels of social stress may increase bone turnover. INTRODUCTION: To determine socioeconomic status (SES) and race differences in levels of bone turnover. METHODS: Using data from the Biomarker Substudy of the Midlife in the US (MIDUS) study (491 men, 449 women), we examined cross-sectional associations of SES and race with serum levels of bone turnover markers (bone specific alkaline phosphatase [BSAP], procollagen type I N-terminal propeptide [PINP], and N-telopeptide [Ntx]) separately in men and women. Linear multivariable regression was used to control for body weight, menopausal transition stage, and age. RESULTS: Among men, low family poverty-to-income ratio (FPIR) was associated with higher turnover, but neither education nor race was associated with turnover. Men with FPIR <3 had 1.808 nM BCE higher Ntx (P = 0.05), 3.366 U/L higher BSAP (P = 0.02), and 7.066 higher PINP (P = 0.02). Among women, neither education nor FPIR was associated with bone turnover, but Black women had 3.688 nM BCE higher Ntx (P = 0.001), 5.267 U/L higher BSAP (P = 0.005), and 11.906 MUg/L higher PINP (P = 0.008) compared with non-Black women. CONCLUSIONS: Economic adversity was associated with higher bone turnover in men, and minority race status was associated with higher bone turnover in women, consistent with the hypothesis that higher levels of social stresses cause increased bone turnover. The magnitude of these associations was comparable to the effects of some osteoporosis medications on levels of turnover. PMID- 21811865 TI - Association between weight changes and changes in hip geometric indices in the Japanese female population during 10-year follow-up: Japanese Population-based Osteoporosis (JPOS) Cohort Study. AB - During a 10-year follow-up of 893 women of various ages from the Japanese Population-based Osteoporosis Cohort Study, we evaluated the relationship between weight changes and hip geometric strength assessed by hip structure analysis. Our findings suggest that maintaining weight may help retain geometric strength and reduce hip fracture risk. INTRODUCTION: The effects of changes in anthropometric indices on hip geometry in women of various ages are unclear. We evaluated these effects by analyzing 10-year longitudinal data from a representative sample of Japanese women. METHODS: Dual-energy X-ray absorptiometry scans of the proximal femur were performed at baseline and at the 10-year follow-up. Data were analyzed with the Hip Structure Analysis (HSA) program, which yields geometric strength indices including cross-sectional area (CSA), section modulus (SM) and subperiosteal diameter (PD) at regions of interest (ROIs) in the narrow neck (NN), intertrochanter, and femoral shaft (FS) regions. Annual percent change of each HSA index was determined. Height and weight were measured at baseline and follow-up. RESULTS: After excluding subjects with factors affecting bone metabolism, we evaluated 893 women (18-79 years old at baseline). The greatest changes in most HSA indices during the follow-up were observed in subjects aged >= 70 years at all ROIs. PD modestly but significantly expanded with age, but this change was not significant in subjects aged >= 70 years or those who had entered menopause >= 20 years before baseline. An increasing trend in weight was associated with an increase or smaller decline in CSA and SM at the NN and FS regions regardless of menopausal status after adjusting for age, height, and weight at baseline and change of estimated volumetric bone mineral density. Changes in height showed a much weaker association with HSA indices. CONCLUSIONS: Maintaining weight may help retain hip geometric strength and reduce the risk of hip fracture. PMID- 21811866 TI - Effect of monthly ibandronate on hip structural geometry in men with low bone density. AB - Hip structural analysis (HSA) performed in a subset of participants from the STudy Researching Osteoporosis iN Guys (STRONG) demonstrated that 1 year of ibandronate treatment was associated with a significant improvement in some but not all parameters of hip geometry relative to placebo in men with low bone density. INTRODUCTION: HSA was performed on dual-energy X-ray absorptiometry (DXA) images in a subset of participants from the STRONG to examine the impact of monthly ibandronate on geometric properties of the hip in men with low bone density. METHODS: This prespecified subgroup analysis evaluated men in the intent to-treat population of STRONG with baseline and 12-month DXA data. Cross sectional geometric parameters of the femoral shaft (FS), intertrochanter region (IT), and narrow neck (NN) were calculated from femoral DXA scans. All analyses were exploratory. Treatment differences were evaluated using analysis of covariance, which adjusted for baseline parameter value, testosterone level, and treatment. RESULTS: HSA was performed on DXA scans from 89 men (34 placebo; 55 monthly ibandronate). Significant increases in average cortical thickness and cross-sectional area and decreases (i.e., improvements) in the buckling ratio were observed at the FS and IT at 12 months for ibandronate-treated men compared with placebo-treated men. No significant differences were observed between ibandronate and placebo for any NN HSA parameters. CONCLUSIONS: One year of ibandronate treatment was associated with a significant improvement in some but not all parameters of hip geometry relative to placebo in men with low bone density, suggesting that ibandronate may improve resistance to axial compressive forces and bending forces at the hip. PMID- 21811867 TI - Treatment for older men with fractures. AB - Less than 10% of men receive osteoporosis treatment, even after a fracture. A study of 17,683 men revealed that older men, those with spinal fractures, and those taking steroids or antidepressants are more likely to receive treatment after a fracture. Seeing a primary care physician also increases osteoporosis treatment rates. INTRODUCTION: In 2000, the FDA approved bisphosphonates for the treatment of osteoporosis in men. The purpose of this study is to estimate the frequency of bisphosphonate therapy within 12 months following a fracture and describe patient/physician factors associated with treatment. METHODS: Health insurance claims for 17,683 men >= 65 years of age, who had a claim for an incident fracture from 2000 to 2005, were followed for at least 6 months post fracture for the initiation of treatment with a bisphosphonate. Patient characteristics, diagnostic procedures, therapies, co-morbidities, and provider characteristics were compared for men who received treatment with those who did not. RESULTS: Eight percent of men (n = 1,434) received bisphosphonate therapy. Overall treatment increased from 7% in 2001 to 9% in 2005 (p < 0.001). Treatment for hip fractures remained at 7% (p = 0.747). Treatment increased with age: 6% in men aged 65-69 compared to 11.6% in men aged 85-89 (p < 0.001). Factors associated with treatment included: diagnosis of osteoporosis (OR = 8.8; 95% CI, 7.7, 10.4), glucocorticoid therapy (OR = 3.2; 95% CI, 2.4, 4.3), bone mineral density measurement (OR = 3.4; 95% CI, 2.9, 4.0), and antidepressant therapy with tricyclics (OR = 2.0; 95% CI, 1.2, 3.5) or selective serotonin reuptake inhibitors (OR = 1.7; 95% CI, 1.3, 2.4). Men with vertebral fractures (OR = 2.2; 95% CI, 1.8, 2.6) and men seen by primary physicians (OR = 2.6; 95% CI, 2.3, 3.1) were more likely to receive treatment. CONCLUSIONS: Less than 10% of men received bisphosphonate therapy following a low-impact fracture. Men with a primary physician were more likely to receive bisphosphonate therapy; however, <25% of men were seen by a primary physician. PMID- 21811868 TI - Prospective study in critically ill non-neutropenic patients: diagnostic potential of (1,3)-beta-D-glucan assay and circulating galactomannan for the diagnosis of invasive fungal disease. AB - Diagnosis of invasive fungal disease (IFD) in patients under intensive care is challenging. Circulating biomarkers, (1,3)-beta-D-glucan (BG) and galactomannan (GM), were prospectively assessed in 98 critically ill patients at risk of IFD. There were 11 cases of invasive aspergillosis (IA; 4 proven and 7 probable), 9 cases of proven invasive candidiasis (IC), 1 case of mixed proven IC and probable IA, 1 case of proven zygomycosis, and 1 case of mixed mycelial proven IFD. In all IA cases there was no significant difference when the area under the receiver operating characteristic curve (AUC) of GM (0.873 [95%CI, 0.75-0.99]) and BG (0.856 [95% CI, 0.71-0.99]) were compared (p = 0.871). The AUC for BG in IC and for the rest of the IFD cases was 0.605 (95% CI, 0.39-0.82) and 0.768 (95% CI, 0.63-0.90) respectively. Positive BG (40%) predated blood culture (n = 3) and abdominal pus (n = 1) a mean of 3.25 days before Candida was grown. In patients with IFD caused by molds, BG appeared a mean of 5.65 days before culture results. For the diagnosis of patients at risk of IC, BG has shown a high NPV (94.5%), with positive results also predating blood cultures in 30% of patients. In conclusion, early BG results permit a timely initiation of antifungal therapy in patients at risk of IFD. PMID- 21811869 TI - Staphylococcus aureus nasal carriage is associated with serum 25-hydroxyvitamin D levels, gender and smoking status. The Tromso Staph and Skin Study. AB - Vitamin D induces the expression of antimicrobial peptides with activity against Staphylococcus aureus. Thus, we studied the association between serum 25 hydroxyvitamin D (25(OH)D) and S. aureus nasal colonization and carriage. Nasal swabs, blood samples and clinical data from 2,115 women and 1,674 men, aged 30-87 years, were collected in the Tromso Staph and Skin Study 2007-08, as part of the population-based sixth Tromso Study. Multivariate logistic regression analyses were stratified by recognized risk factors for S. aureus carriage: sex, age and smoking. In non-smoking men, we observed a 6.6% and 6.7% decrease in the probability of S. aureus colonization and carriage, respectively, by each 5 nmol/l increase in serum 25(OH)D concentration (P < 0.001 and P = 0.001), and serum 25(OH)D > 59 nmol/l and >=75 nmol/l as thresholds for ~30% and ~50% reduction in S. aureus colonization and carriage. In non-smoking men aged 44-60 years, the odds ratio for S. aureus colonization was 0.44 (95% confidence interval, 0.28-0.69) in the top tertile of serum 25(OH)D versus the bottom tertile. In women and smokers there were no such associations. Our study supports that serum vitamin D is a determinant of S. aureus colonization and carriage. PMID- 21811870 TI - Development of an endothelial-smooth muscle cell coculture model using phenotype controlled smooth muscle cells. AB - A coculture of endothelial cells (ECs) and smooth muscle cells (SMCs), which mimics cellular interactions appearing in vivo, has been performed in studies on the relationship between atherogenesis and fluid shear stress conditions. Although healthy arteries in vivo consist of contractile phenotype SMCs, cultured cells used in many studies normally exhibit a synthetic phenotype. Here, we developed an EC-SMC coculture model to investigate the interactions between ECs and contractile SMCs, and examined the effect of shear stress applied to ECs on SMC phenotypes. Cultured human umbilical artery SMCs were differentiated into contractile states by arresting cell growth using a serum-free medium. Western blotting confirmed that SMC expression of contractile protein markers, alpha smooth muscle actin (SMA) and calponin, increased to levels similar to those observed in arterial cells. After coculturing contractile SMCs with ECs separated by a collagen gel layer, the expression of alpha-SMA decreased under static conditions, indicating that the SMC phenotype tended to be synthetic by coculturing with ECs, but shear stress applied to cocultured ECs maintained the level of alpha-SMA expression in SMCs. The coculture model constructed in the present study will be a useful tool to investigate interactions between ECs and contractile SMCs under shear conditions. PMID- 21811871 TI - Use of antidepressant medication and risk of type 2 diabetes: results from three cohorts of US adults. AB - AIMS/HYPOTHESIS: The results of several studies have suggested a potential positive association between use of antidepressant medication (ADM) and incident type 2 diabetes mellitus. We examined this association in three cohorts of US adults. METHODS: We followed 29,776 men in the Health Professionals Follow-up Study (HPFS, 1990-2006), 61,791 women in the Nurses' Health Study I (NHS I, 1996 2008) and 76,868 women in NHS II (1993-2005), who were free of diabetes mellitus, cardiovascular disease or cancer at baseline. The mean baseline ages for participants from the HPFS and NHS I and II were 56.4, 61.3 and 38.1 years, respectively. ADM use and other covariates were assessed at baseline and updated every 2 years. A time-dependent Cox proportional hazards model was used, and HRs were pooled together across the three cohorts. RESULTS: During 1,644,679 person years of follow-up, we documented 6,641 new cases of type 2 diabetes. ADM use was associated with an increased risk of diabetes in all three cohorts in age adjusted models (pooled HR 1.68 [95% CI 1.27, 2.23]). The association was attenuated after adjustment for diabetes risk factors and histories of high cholesterol and hypertension (1.30 [1.14, 1.49]), and further attenuated by controlling for updated BMI (1.17 [1.09, 1.25]). Use of selective serotonin reuptake inhibitors and other antidepressants (mainly tricyclic antidepressants) were both associated with an elevated risk of diabetes, with pooled multivariate adjusted HRs of 1.10 (1.00, 1.22) and 1.26 (1.11, 1.42), respectively. CONCLUSIONS/INTERPRETATION: The results suggest that ADM users had a moderately elevated risk of type 2 diabetes mellitus compared with non-users, even after adjustment for BMI. PMID- 21811872 TI - Trends in population attributable fraction of acute coronary syndrome and ischaemic stroke due to diabetes in Finland. AB - AIMS/HYPOTHESIS: Cardiovascular disease (CVD) event rates are decreasing, but the prevalence of diabetes is increasing. The effect of these developments on the population attributable fraction (PAF) of CVD events due to diabetes is not known. METHODS: We used country-wide healthcare registers to identify all persons aged 25-80 years treated for diabetes in Finland during 1992-2002. These data were further linked to the National Cardiovascular Disease Register to identify the first CVD events (acute coronary syndrome and ischaemic stroke) among the individuals with and without diabetes. We calculated the annual PAF of the first CVD events due to diabetes separately for men and women. RESULTS: The number of men treated for diabetes each year almost doubled during the study period from 37,073 to 69,158 between 1992 and 2002. Among women, the number increased from 42,485 to 57,372. The annual number of first CVD events in the country declined among men with diabetes from 13,436 to 12,678 and among women with diabetes from 8,658 to 7,521 between 1992 and 2002. During the same period, the PAF due to diabetes of the first CVD events increased among men from 11.4% (95% CI 10.8, 12.0%) to 13.8% (95% CI 13.2, 14.5%) and decreased among women from 20.1% (95% CI 19.2, 21.0%) to 16.9% (95% CI 15.9, 17.8%). The trends in PAF were different between the sexes (p < 0.001 for the interaction year * sex). CONCLUSIONS/INTERPRETATION: Despite the very large increase in the prevalence of diabetes, the PAF of the first CVD events due to diabetes decreased in women and increased only slightly in men. PMID- 21811874 TI - Bird predation enhances tree seedling resistance to insect herbivores in contrasting forest habitats. AB - According to the associational resistance hypothesis, neighbouring plants are expected to influence both the insect herbivore communities and their natural enemies. However, this has rarely been tested for the effects of canopy trees on herbivory of seedlings. One possible mechanism responsible for associational resistance is the indirect impact of natural enemies on insect herbivory, such as insectivorous birds. But it remains unclear to what extent such trophic cascades are influenced by the composition of plant associations (i.e. identity of 'associated' plants). Here, we compared the effect of bird exclusion on insect leaf damage for seedlings of three broadleaved tree species in three different forest habitats. Exclusion of insectivorous birds affected insect herbivory in a species-specific manner: leaf damage increased on Betula pendula seedlings whereas bird exclusion had no effect for two oaks (Quercus robur and Q. ilex). Forest habitat influenced both the extent of insect herbivory and the effect of bird exclusion. Broadleaved seedlings had lower overall leaf damage within pine plantations than within broadleaved stands, consistent with the resource concentration hypothesis. The indirect effect of bird exclusion on leaf damage was only significant in pine plantations, but not in exotic and native broadleaved woodlands. Our results support the enemies hypothesis, which predicts that the effects of insectivorous birds on insect herbivory on seedlings are greater beneath non-congeneric canopy trees. Although bird species richness and abundance were greater in broadleaved woodlands, birds were unable to regulate insect herbivory on seedlings in forests of more closely related tree species. PMID- 21811873 TI - Restoration of hepatic glycogen deposition reduces hyperglycaemia, hyperphagia and gluconeogenic enzymes in a streptozotocin-induced model of diabetes in rats. AB - AIMS/HYPOTHESIS: Glycogen deposition is impaired in diabetes, thus contributing to the development of hyperglycaemia. Several glucose-lowering strategies have attempted to increase liver glycogen deposition by modulating targets, which eventually trigger the activation of liver glycogen synthase (LGS). However, these targets also alter several other biological processes, and therefore their therapeutic use may be limited. Here we tested the approach of directly activating LGS and evaluated the potential of this strategy as a possible treatment for diabetes. METHODS: In this study, we examined the efficacy of directly overproducing a constitutively active form of LGS in the liver to ameliorate streptozotocin-induced diabetes in rats. RESULTS: Activated mutant LGS overproduction in the liver of streptozotocin-induced diabetic rats normalised liver glycogen content, despite low levels of glucokinase and circulating insulin. Moreover, this overproduction led to a decrease in food intake and in the production of the main gluconeogenic enzymes, glucose-6-phosphatase, fructose 1,6-bisphosphatase and phosphoenolpyruvate carboxykinase. The resulting combined effect was a reduction in hyperglycaemia. CONCLUSIONS/INTERPRETATION: The restoration of liver glycogen ameliorated diabetes and therefore is considered a potential strategy for the treatment of this disease. PMID- 21811875 TI - The association between non-Hodgkin lymphoma and methylation of p73. AB - To investigate the effects of methylation of the p73 gene on the pathogenesis of non-Hodgkin lymphoma (NHL), the methylation status of the p73 gene promoter and the expression of p73 mRNA were examined in NHLs by methylation-specific polymerase chain reaction (MSP) and reverse transcription-polymerase chain reaction, respectively; p73 protein was detected by Western blotting analysis. Furthermore, the expression of p73 mRNA in NHL cells treated with 5-Aza-2' deoxycytidine was analyzed. MSP results revealed that the promoter of p73 was methylated in 87.5% of NHLs but was not methylated in reactive hyperplasia lymph node samples. The expression of p73 mRNA was not detected in 83.33% of NHLs but was detected in all of the reactive hyperplasia lymph node samples. The p73 protein was not detected in 91.67% of NHLs but was detected in all of the reactive hyperplasia lymph node samples. The expression of p73 mRNA was detected in NHL cells treated with 5-Aza-2'-deoxycytidine. The inactivation of p73, predominantly by methylation, may be involved in the pathogenesis of NHLs. PMID- 21811877 TI - Targeted cardiac post-mortem computed tomography angiography: a pictorial review. AB - With the introduction of targeted coronary artery angiography to post-mortem computed tomography (PMCT) it is now possible to assess the coronary arteries and left ventricle after death without, case dependent, the necessity to undertake an invasive autopsy. The purpose of this pictorial review is to act as a walk through aid memoire and educational learning document for radiologists and pathologists alike who may be new to the use and interpretation of targeted PMCT angiography. By using an example scanning protocol, which uses both positive and negative (air) contrast mediums, this pictorial review provides a systematic approach to vessel and ventricular assessment that is based upon clinical cardiac angiography but adapted to PMCT. PMID- 21811878 TI - Syphilitic aortic aneurysm rupture as cause of sudden death. PMID- 21811879 TI - Oxidative stress and inflammatory markers in the exhaled breath condensate of children with OSA. AB - INTRODUCTION: Obstructive sleep apnea (OSA) in children has been associated with systemic inflammation and oxidative stress. Limited evidence indicates that pediatric OSA is associated with oxidative stress and inflammation in the airway. OBJECTIVE: The objective of this study is to assess the hypothesis that levels of oxidative stress and inflammatory markers in the exhaled breath condensate (EBC) of children with OSA are higher than those of control subjects. METHODS: Participants were children with OSA and control subjects who underwent overnight polysomnography. Morning levels of hydrogen peroxide (H(2)O(2)) and sum of nitrite and nitrate (NO(x)) in EBC of participants were measured. RESULTS: Twelve subjects with moderate-to-severe OSA (mean age +/- standard deviation: 6.3 +/- 1.7 years; apnea-hypopnea index--AHI, 13.6 +/- 10.1 episodes/h), 22 subjects with mild OSA (6.7 +/- 2.1 years; AHI, 2.8 +/- 1 episodes/h) and 16 control participants (7.7 +/- 2.4 years; AHI, 0.6 +/- 0.3 episodes/h) were recruited. Children with moderate-to severe OSA had higher log-transformed H(2)O(2) concentrations in EBC compared to subjects with mild OSA, or to control participants: 0.4 +/- 1.1 versus -0.9 +/- 1.3 (p = 0.015), or versus -1.2 +/- 1.2 (p = 0.003), respectively. AHI and % sleep time with oxygen saturation of hemoglobin <95% were significant predictors of log-transformed H(2)O(2) after adjustment by age and body mass index z score (p < 0.05). No significant differences were demonstrated between the three study groups in terms of EBC NO(x) levels. CONCLUSIONS: Children with moderate-to-severe OSA have increased H(2)O(2) levels in morning EBC, an indirect index of altered redox status in the respiratory tract. PMID- 21811880 TI - Health care practices of the foreign born Asian Indians in the United States. A community based survey. AB - Although successful utilization of medical and preventive care by members of the non-US born communities is an important public health concern, our knowledge regarding health practices of different ethnic subgroups is limited. In the present study, participants of the health fairs organized during South Asian cultural and religions events were asked anonymously to complete the South Asian Total Health Initiative (SATHI) health survey questionnaire to evaluate their health-related practices, self-health perception, and satisfaction with medical care. Among 1,250 surveyed, 1,016 foreign born Asian Indians adults that represented the fastest growing subgroups of the South Asian born nationals in the US were included in the analysis. We found that the majority reported healthy behavior (exercise activities and abstinence from alcohol or tobacco), high self health perception, satisfaction with medical care, and compliance with annual routine medical examinations that was directly associated with the annual house income. Approximately 40% of women complied with breast and cervical cancer screenings and less than 20% of men complied with prostate cancer screening guidelines. Presence of chronic conditions (mostly cardiovascular pathology and/or diabetes) that were reported by approximately half of the participants negatively impacted their self-health perception. In conclusion, positive self reported health perception and compliance with routine health examinations of the surveyed foreign born Asian Indians was reported along with an increased rate of chronic morbidity and underutilization of specific preventive services. Observed discrepancy between self-health perception and health status highlights the need to enhance utilization of preventive services among the non-US born Asian Indian community. PMID- 21811881 TI - Enacting remembrance: turning toward memorializing September 11th. AB - The memorial at the site of the former World Trade Center will open on the tenth anniversary of 9/11 to help us commemorate, honor, educate, and mourn. Memorializing is an act that involves shared memory and collective grieving aiming also to restore severed communal bonds and dismantled cultural ideals. As such, it is a form of cultural renewal that can transform traumatized mourners into an ethical community of memory. The active rituals of memorial activity utilize both inscribed and non-inscribed practices to help survivors of mass trauma manage fear, disorganization, and helplessness as well as sorrow. To bear witness to horrific events and the suffering they induced is a moral act. To do so together with people who may have seen the events of 9/11 from other perspectives, while also remembering one's own vision of what mattered, may mean learning to tolerate multiple conflicting narratives about the events' meanings. It is time to turn our attention from the memorial to memorializing. PMID- 21811884 TI - Acute toxicity of zinc to several aquatic species native to the Rocky Mountains. AB - National water-quality criteria for the protection of aquatic life are based on toxicity tests, often using organisms that are easy to culture in the laboratory. Species native to the Rocky Mountains are poorly represented in data sets used to derive national water-quality criteria. To provide additional data on the toxicity of zinc, several laboratory acute-toxicity tests were conducted with a diverse assortment of fish, benthic invertebrates, and an amphibian native to the Rocky Mountains. Tests with fish were conducted using three subspecies of cutthroat trout (Colorado River cutthroat trout Oncorhynchus clarkii pleuriticus, greenback cutthroat trout O. clarkii stomias, and Rio Grande cutthroat trout O. clarkii virginalis), mountain whitefish (Prosopium williamsoni), mottled sculpin (Cottus bairdi), longnose dace (Rhinichthys cataractae), and flathead chub (Platygobio gracilis). Aquatic invertebrate tests were conducted with mayflies (Baetis tricaudatus, Drunella doddsi, Cinygmula sp. and Ephemerella sp.), a stonefly (Chloroperlidae), and a caddis fly (Lepidostoma sp.). The amphibian test was conducted with tadpoles of the boreal toad (Bufo boreas). Median lethal concentrations (LC(50)s) ranged more than three orders of magnitude from 166 MUg/L for Rio Grande cutthroat trout to >67,000 MUg/L for several benthic invertebrates. Of the organisms tested, vertebrates were the most sensitive, and benthic invertebrates were the most tolerant. PMID- 21811882 TI - The amount of neoadjuvant chemotherapy for Barrett's carcinoma does not correlate with long-term survival. AB - INTRODUCTION: Several studies have proven an ameliorated prognosis after a neoadjuvant therapy for locally advanced Barrett's carcinoma in case of response. The necessary amount of neoadjuvant chemotherapy within a multimodal therapy concept with following oesophageal resection has never been evaluated so far. METHODS: The clinical course of 122 patients with Barrett's carcinoma, who all underwent a neoadjuvant chemotherapy with cisplatin, five fluorouracil and leucovorin and following oesophagectomy, was reviewed. The pretherapeutic clinical and postoperative histopathological staging, histopathological response, clinical course, recurrence rates and long-term survival were retrospectively analysed and compared to the data of 30 patients, who were included in the same multimodal therapy concept, but who had to cease the chemotherapy early because of toxicity. RESULTS: Postoperative pathological staging showed that the response rate correlates with the N and R status. The responding patients benefit from longer survival. Comparing the two subgroups, we could not find a significant difference in response rate, tumour staging, resection rate, long-term survival or pattern of recurrent disease. However, postoperative morbidity and mortality did not correlate with severe chemotherapy-induced toxicity. CONCLUSIONS: This is the first study on the necessary number of chemotherapy cycles in terms of a neoadjuvant therapy for Barrett's carcinoma. We could show a similar downstaging effect, a good histopathological response and a comparable ameliorated long-term survival of patients with one compared to patients with three chemotherapy cycles. A biological selection seems to determine the course of the disease already at this early stage. PMID- 21811883 TI - Endoscopic management of early esophageal neoplasia: an emerging standard. AB - INTRODUCTION: Endoscopic mucosal resection (EMR) and ablation technologies have markedly changed the treatment of early esophageal neoplasia. We analyzed treatment and outcomes of patients undergoing multimodal endoscopic treatment of early esophageal neoplasia at our institution. METHODS: Records of patients undergoing endoscopic treatment for esophageal low-grade intraepithelial neoplasia (LGIN, n = 11), high-grade intraepithelial neoplasia (HGIN, n = 24), or T1N0M0 neoplasia (n = 10), presenting between 2007 and 2009, were reviewed. Outcomes included eradication of neoplasia/intestinal metaplasia, development of metachronous neoplasia, and progression to surgical resection. RESULTS: There were 45 patients, 96% male, with a mean age 67 years. The degree of neoplasia prior to intervention was intramucosal (8) or submucosal (2) carcinoma in 10, HGIN in 24, and LGIN in 11. Patients underwent a total of 166 procedures (median 3/patient, range 1-9). These included 120 radiofrequency ablation sessions, 38 EMRs, and 8 cryoablations. Mean follow-up was 21.3 months. Neoplasia and intestinal metaplasia were eradicated in 87.2% and 56.4% of patients, respectively, while 15.4% developed metachronous neoplasia. Three patients underwent esophagectomy. No patient developed unresectable disease or died. CONCLUSION: Endoscopic treatment of early esophageal neoplasia is safe and effective in the short term. A minority of treated patients developed recurrent neoplasia, which is usually amenable to further endoscopic therapy. Complications are relatively minor and uncommon. Endoscopic therapy as the initial treatment for early esophageal neoplasia is an emerging standard of care. PMID- 21811885 TI - Development of the PICMIN (picture of mental illness in newspapers): instrument to assess mental illness stigma in print media. AB - PURPOSE: The aim of this paper is to report on the development and applicability of a standardised and objective measure of stigma of mental illness in print media. Picture of mental illness in newspapers (PICMIN) instrument consists of eleven descriptive and five analytical categories. It is intended to allow comparison among countries and different studies over time. METHODS: The research team conducted a three-phase study to develop the instrument based on the principles of content analysis and test its inter-coder reliability (ICR). In the first phase, keyword search and ICR assessment was performed on articles from Croatia (75), Czech Republic (203), and Slovakia (172). The second phase consisted of instrument revision and training, along with ICR reassessment on 40 articles from USA and UK. In the third, main phase articles from Croatia (238), Czech Republic (226), and Slovakia (158) were analysed with the final version of the PICMIN instrument. RESULTS: Across three countries, ICR was found acceptable to assess mental illness representations related to stigma in print media. Print media representations of the mental illness in Croatia, Czech Republic, and Slovakia significantly differed in the type of media distribution, whether headline of the article was positioned on the media cover, in the use of a sensationalistic style of writing, in the association of aggressive behaviour with persons with mental illness and in the distribution of the global impression of the headline. CONCLUSIONS: PICMIN instrument allows comparison among countries and different studies over time. PMID- 21811886 TI - Marital conflict and early adolescents' self-evaluation: the role of parenting quality and early adolescents' appraisals. AB - Cognitive appraisals and family dynamics have been identified as mediators of the relationship between marital conflict and children's adjustment. Surprisingly little research has investigated both meditational processes in the same study. Guided by the cognitive-contextual framework and the spillover hypothesis, the present study integrated factors from both theories early adolescents' appraisals of threat and self-blame, as well as perceived parenting quality as mediators of the link between early adolescents' perception of marital conflict and their self evaluations (self-esteem and scholastic competence). Analyses were based on the first two waves of an ongoing longitudinal study. Participants were 176 two parent families, and their early adolescents (50.5% girls) whose mean age was 10.61 years at Time 1 (SD =0.40) and 11.63 years at Time 2 (SD=0.39). Structural equation modeling analyses indicated that parenting quality and early adolescents' perceived threat provided indirect pathways between marital conflict and early adolescents' self-esteem 1 year later when controlling for their initial level of self-esteem. With respect to scholastic competence, only fathers' parenting was an indirect link. Self-blame did not play a role. Implications for understanding the mechanisms by which exposure to marital conflict predicts early adolescents' maladjustment are discussed. PMID- 21811887 TI - Reactivation of protein aggregates by mortalin and Tid1--the human mitochondrial Hsp70 chaperone system. AB - The mitochondrial 70-kDa heat shock protein (mtHsp70), also known in humans as mortalin, is a central component of the mitochondrial protein import motor and plays a key role in the folding of matrix-localized mitochondrial proteins. MtHsp70 is assisted by a member of the 40-kDa heat shock protein co-chaperone family named Tid1 and a nucleotide exchange factor. Whereas, yeast mtHsp70 has been extensively studied in the context of protein import in the mitochondria, and the bacterial 70-kDa heat shock protein was recently shown to act as an ATP fuelled unfolding enzyme capable of detoxifying stably misfolded polypeptides into harmless natively refolded proteins, little is known about the molecular functions of the human mortalin in protein homeostasis. Here, we developed novel and efficient purification protocols for mortalin and the two spliced versions of Tid1, Tid1-S, and Tid1-L and showed that mortalin can mediate the in vitro ATP dependent reactivation of stable-preformed heat-denatured model aggregates, with the assistance of Mge1 and either Tid1-L or Tid1-S co-chaperones or yeast Mdj1. Thus, in addition of being a central component of the protein import machinery, human mortalin together with Tid1, may serve as a protein disaggregating machine which, for lack of Hsp100/ClpB disaggregating co-chaperones, may carry alone the scavenging of toxic protein aggregates in stressed, diseased, or aging human mitochondria. PMID- 21811888 TI - Retrieval-induced forgetting without competition: testing the retrieval specificity assumption of the inhibition theory. AB - According to the inhibition theory of forgetting (Anderson, Journal of Memory and Language 49:415-445, 2003; Anderson, Bjork, & Bjork, Psychonomic Bulletin & Review 7:522-530, 2000), retrieval practice on a subset of target items leads to forgetting for the other, nontarget items, due to the fact that these other items interfere during the retrieval process and have to be inhibited in order to resolve the interference. In this account, retrieval-induced forgetting occurs only when competition takes place between target and nontarget items during target item practice, since only in such a case is inhibition of the nontarget items necessary. Strengthening of the target item without active retrieval should not lead to such an impairment. In two experiments, we investigated this assumption by using noncompetitive retrieval during the practice phase. We strengthened the cue-target item association during practice by recall of the category name instead of the target item, and thus eliminated competition between the different item types (as in Anderson et al., Psychonomic Bulletin & Review 7:522-530 2000). In contrast to the expectations of the inhibition theory, retrieval-induced forgetting occurred even without competition, and thus the present study does not support the retrieval specificity assumption. PMID- 21811889 TI - Preparation, characterization, pharmacokinetics and tissue distribution of solid lipid nanoparticles loaded with tetrandrine. AB - Tetrandrine (TET) is a poorly water-soluble bisbenzylisoquinoline alkaloid. In this study, TET solid lipid nanoparticles (SLNs) were prepared by a melt emulsification and ultrasonication technique. Precirol((r)) ATO 5, glyceryl monostearate, and stearic acid were used as the lipid matrix for the SLNs, while Lipoid E80, Pluronic F68, and sodium deoxycholate were used as emulsifying and stabilizing agents. The physicochemical characteristics of the TET-SLNs were investigated when it was found that the mean particle size and zeta potential of the TET-SLNs were 134 +/- 1.3 nm and -53.8 +/- 1.7 mV, respectively, and the entrapment efficiency (EE) was 89.57% +/- 0.39%. Differential scanning calorimetry indicated that TET was in an amorphous state in SLNs. TET-SLNs exhibited a higher release rate at a lower pH and a lower release rate at a higher pH. The release pattern of the TET-SLNs followed the Weibull model. The pharmacokinetics of TET-SLNs after intravenous administration to male rats was studied. TET-SLN resulted in a higher plasma concentration and lower clearance. The biodistribution study indicated that TET-SLN showed a high uptake in reticuloendothelial system organs. In conclusion, TET-SLNs with a small particle size, and high EE, can be produced by the method described in this study. The SLN system is a promising approach for the intravenous delivery of tetrandrine. PMID- 21811890 TI - Respiratory involvement in IgG4-related Mikulicz's disease. AB - 'Immunoglobulin G4 (IgG4)-related disease' is a new clinical concept of multi organ diseases, with Mikulicz's disease (MD) being a clinical phenotype of IgG4 related disease. To clarify the clinical characteristics of respiratory involvement associated with IgG4-related MD, we retrospectively assessed 25 patients with MD, 11 (44%) of whom had allergic symptoms, and 7 (28%) of whom complained of respiratory problems. Thirteen patients (52%) presented with pulmonary and/or mediastinal lesions (P-MD) on chest computed tomography (CT), and 11 (44%) had lesions limited to the lacrimal and/or salivary glands (L-MD). Mean serum total protein, IgG, and IgG4 concentrations were significantly higher and CH50 was significantly lower in the P-MD than in the L-MD group. Immune complex was present only in the P-MD group. Chest CT images showed bronchial wall thickening, consolidation, nodule(s), interlobular thickening, ground glass opacity, pleural thickening/effusion, and mediastinal lymphadenopathy. Five of seven patients who underwent histological examination of the lungs had abundant IgG4-positive plasma cell infiltrates (IgG4/IgG-positive plasma cells >40%), but the other two did not. These findings suggest that respiratory lesions are not rare in patients with IgG4-related MD, and that they present with various manifestations. IgG4-related MD should be differentiated from similar diseases, such as sarcoidosis, bronchial asthma, Sjogren's syndrome, and malignant lymphoma. PMID- 21811891 TI - [Forequarter amputation of the right upper chest: limitations of ultra radical interdisciplinary oncological surgery]. AB - Total forearm free flap procedures after forequarter amputations have been sparsely described in the literature. Using the amputated arm as a "free filet flap" remains a viable surgical option after radical forequarter amputations performed for the resection of large, invasive tumors of the shoulder or thoracic wall region. Using the forequarter specimen as a donor site seems favorable in that it eliminates the usual donor site morbidity. Nevertheless, in our patient with invasive ductal carcinoma of the breast and a fibrosarcoma suffering from severe pain and septic conditions - which failed to respond properly to conservative therapy - as well as rapidly progressive tumor ulceration despite repeated radiation therapy, we decided to attempt complete tumor removal by hemithoracectomy as a last resort. This decision was taken following multiple interdisciplinary consultations and thorough patient information. Although technically feasible with complete tumor removal and safe soft tissue free flap coverage, the postoperative course raises questions about the advisability of such ultra radical surgical procedures, as well as about the limitations of respiratory recovery after hemithoracectomy with removal of the sternum. Hence, based on our experience with such radical tumor surgery, we discuss the issues of diminished postoperative pulmonary function, intensive care possibilities and ethical issues. The English full-text version of this article is available at SpringerLink (under "Supplemental"). PMID- 21811893 TI - A clinicopathological study of diagnostically challenging meningioma mimics. AB - The occurrence of neoplastic and nonneoplastic dural based masses that mimic meningiomas is infrequent and may not be considered during radiological and intraoperative analysis. We describe single institute study of 20 such rare cases. This study included total of 20 cases of meningioma mimics. The clinical, radiological and histopathological findings were evaluated. Tissue fixed in 10% formalin was routinely processed and 5 MU thick sections were cut and stained with hematoxylin & eosin. Histochemistry and immunohistochemistry using avidin biotin complex immunoperoxidase method was done wherever indicated. In the present study group, 15 were male and 5 female with a male: female ratio of 3:1. The age ranged from 14 to 78 years. Radiologically all these lesions were extra axial in location, predominantly hypointense on T2W, isointense on T1W images and showed intense homogenous enhancement on contrast administration. Four cases were in pediatric age group with histopathological diagnosis of Rosai Dorfman disease, medulloblastoma, hemangiopericytoma and malignant melanoma. In the adult population, the histopathological diagnoses were hemangiopericytoma, undifferentiated sarcoma, extraskeletal osteosarcoma, Rosai Dorfman disease, medulloblastoma, and metastases from systemic malignancies. Of the total 6 cases of metastases 1 was nonseminomatous germ cell tumor from a primary in testis, 1 was adenocarcinoma from an unknown primary, and 4 were adenocarcinoma from lung. There was a single case of dural based frontal lobe malignant melanoma with congenital hairy nevi on anterior chest wall, scalp, anterior abdominal wall and inguinal region. As the management and biologic behaviour of many of the MM are different, it is essential to familiarize ourselves to them. PMID- 21811892 TI - Gemcitabine induced myositis in patients with pancreatic cancer: case reports and topic review. AB - Gemcitabine potential myotoxicity has been described in several cases of radiation recall and in patients treated with gemcitabine alone or in combination with other chemotherapy agents. We report two cases of gemcitabine related myositis identified at our institution, and perform a literature review of cases which meet the criteria for gemcitabine induced myositis associated to either radiation therapy or chemotherapy alone. PMID- 21811894 TI - Acenocoumarol sensitivity and pharmacokinetic characterization of CYP2C9 *5/*8,*8/*11,*9/*11 and VKORC1*2 in black African healthy Beninese subjects. AB - This study aimed at investigating the contribution of CYP2C9 and VKORC1 genetic polymorphisms to inter-individual variability of acenocoumarol pharmacokinetics and pharmacodynamics in Black Africans from Benin. Fifty-one healthy volunteers were genotyped for VKORC1 1173C>T polymorphism. All of the subjects had previously been genotyped for CYP2C9*5, CYP2C9*6, CYP2C9*8, CYP2C9*9 and CYP2C9*11 alleles. Thirty-six subjects were phenotyped with a single 8 mg oral dose of acenocoumarol by measuring plasma concentrations of (R)- and (S) acenocoumarol 8 and 24 h after the administration using chiral liquid chromatography tandem mass-spectrometry. International normalized ratio (INR) values were determined prior to and 24 h after the drug intake. The allele frequency of VKORC1 variant (1173C>T) was 1.96% (95% CI 0.0-4.65%). The INR values did not show statistically significant difference between the CYP2C9 genotypes, but were correlated with body mass index and age at 24 h post-dosing (P < 0.05). At 8 h post dose, the (S)-acenocoumarol concentrations in the CYP2C9*5/*8 and CYP2C9*9/*11 genotypes were about 1.9 and 5.1 fold higher compared with the CYP2C9*1/*1 genotype and 2.2- and 6.0-fold higher compared with the CYP2C9*1/*9 group, respectively. The results indicated that pharmacodynamic response to acenocoumarol is highly variable between the subjects. This variability seems to be associated with CYP2C9*5/*8 and *9/*11 variant and demographic factors (age and weight) in Beninese subjects. Significant association between plasma (S)-acenocoumarol concentration and CYP2C9 genotypes suggested the use of (S)-acenocoumarol for the phenotyping purpose. Larger number of subjects is needed to study the effect of VKORC1 1173C>T variant due to its low frequency in Beninese population. PMID- 21811896 TI - Retrieval-induced forgetting in recognition is absent under time pressure. AB - We examined retrieval-induced forgetting (RIF) in recognition from a dual-process perspective, which suggests that recognition depends on the outputs of a fast familiarity process and a slower recollection process. In order to determine the locus of the RIF effect, we manipulated the availability of recollection at retrieval via response deadlines. The standard RIF effect was observed in a self paced test but was absent in a speeded test, in which judgments presumably depended on familiarity more than recollection. The findings suggested that RIF specifically affects recollection. This may be consistent with a context-specific view of retrieval inhibition. PMID- 21811897 TI - Repetition blindness: the survival of the grouped. AB - The repetition blindness (RB) effect demonstrates that people often fail to detect the second presentation of an identical object (e.g., Kanwisher, 1987). Grouping of identical items is a well-documented perceptual phenomenon, and this grouping generally facilitates perception. These two effects pose a puzzle: RB impairs perception, while perceptual grouping improves it. Here, we combined these two effects and studied how they interact. In a series of three experiments, we presented repeated items in a simultaneous string, while manipulating the organization of the repeated items in groups within a string. We observed an interaction between RB and grouping that we summarize with a rule that we call "the survival of the grouped": In essence, the ability to group repeated elements protects them from RB. These findings are discussed within the framework of the object file theory. PMID- 21811898 TI - Is selective arthroscopic revision beneficial for treating recurrent anterior shoulder instability? AB - BACKGROUND: Surgeons have traditionally treated recurrent shoulder dislocation by open methods. With the advent of arthroscopic repair techniques some surgeons reported higher recurrence rates than with open methods but some of those reports included patients with a variety of problems, including bone loss and those continuing in contact sports. It is unclear whether recurrence rates would be higher in patients without bone loss and those willing to forego contact sports. QUESTIONS/PURPOSES: We therefore determined recurrence rates and functional scores after arthroscopic revision shoulder stabilization in patients without bone loss and those not subsequently participating in contact sports. PATIENTS AND METHODS: We retrospectively reviewed 16 patients who underwent a revision arthroscopic Bankart repair using suture anchors. An arthroscopic approach was selected in patients with a unilateral traumatic injury and mild to moderate bone loss. Arthroscopic stabilization was contraindicated in patients with (1) multidirectional shoulder instability; (2) greater than 25% glenoid bone loss; (3) a Hill Sachs lesion involving more than one-third of the articular surface of the humeral head; and (4) patients electing to continue pursuing contact sports. At followup, physical examination of both shoulders was conducted. Several functional scores (Rowe, UCLA, and Constant & Murley) were compiled. The minimum followup was 24 months (mean, 31 months; range, 24-46 months). RESULTS: The UCLA score (22-31), Constant & Murley score (69-80), and Rowe score (33-80) all improved. Shoulder instability recurred in three of the 16 patients, two sustaining dislocations and one a subluxation. One recurrence was the result of new trauma and this patient underwent an open Latarjet procedure; the other two patients refused further surgery. CONCLUSIONS: Revision arthroscopic Bankart repair using suture anchors was associated with a low recurrence rate and restoration of acceptable function in patients without bone loss and not participating in contact sports. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 21811895 TI - Interactions between coagulation and complement--their role in inflammation. AB - The parallel expression of activation products of the coagulation, fibrinolysis, and complement systems has long been observed in both clinical and experimental settings. Several interconnections between the individual components of these cascades have also been described, and the list of shared regulators is expanding. The co-existence and interplay of hemostatic and inflammatory mediators in the same microenvironment typically ensures a successful host immune defense in compromised barrier settings. However, dysregulation of the cascade activities or functions of inhibitors in one or both systems can result in clinical manifestations of disease, such as sepsis, systemic lupus erythematosus, or ischemia-reperfusion injury, with critical thrombotic and/or inflammatory complications. An appreciation of the precise relationship between complement activation and thrombosis may facilitate the development of novel therapeutics, as well as improve the clinical management of patients with thrombotic conditions that are characterized by complement-associated inflammatory responses. PMID- 21811899 TI - Restoration of the distal femur impacts patellar height in revision TKA. AB - BACKGROUND: Restoring patellar height is important in revision TKA for normal knee function and kinematics. Alteration in patellar height after revision TKA is associated with inferior extensor mechanism function. QUESTIONS/PURPOSES: We determined whether gap balancing with bone preservation and distal femoral augmentation would restore patellar height and patellar height changed in patients undergoing septic and aseptic revision TKA. PATIENTS AND METHODS: We retrospectively reviewed 76 patients who had revision TKA between 2006 and 2009; 12 had two-stage revisions for infected TKA, and 64 had revision for aseptic failure. We compared preoperative and postoperative radiographs and measured the patellar height using the Insall-Salvati ratio in both groups. We reviewed operative records to determine type of exposure and amount of distal femoral augmentation used to restore the joint line. RESULTS: Overall mean preoperative and postoperative Insall-Salvati ratios were 1.02 and 1.04, respectively. In the septic group, mean preoperative and postoperative Insall-Salvati ratios were 1.07 and 0.99, respectively. In the aseptic group, mean preoperative and postoperative Insall-Salvati ratios were 1.01 and 1.05, respectively. Overall, nine patients had preoperative patella baja; seven of these had an improvement to normal height. There was little difference in preoperative and postoperative Insall Salvati ratios in patients with patella alta. Distal augmentation was used in 10 of 12 patients in the septic group and 48 of 64 patients in the aseptic group. CONCLUSIONS: Surgeons can maintain normal patellar height and improve patella baja by preserving bone stock and using distal femoral augments to restore the distal joint line during revision TKA. PMID- 21811900 TI - Does open reduction and pinning affect outcome in severely displaced supracondylar humeral fractures in children? A systematic review. AB - Supracondylar fracture of the humerus is the second most common fracture in children (16.6%) and the most common elbow fracture. These fractures are classified using the modified Gartland classification. Type III and type IV are considered to be totally displaced. A totally displaced fracture is one of the most difficult fractures to manage and may lead to proceeding to open procedures to achieve acceptable reductions. Many surgeons are concerned about its outcome compared to closed procedures. We therefore performed a systematic review of the literature to investigate the existing evidence regarding functional and radiological outcomes as well as postsurgical complications of primary open compared to primary closed reduction. PMID- 21811901 TI - Peak incidence of distal radius fractures due to ice skating on natural ice in The Netherlands. AB - An increase of distal radius fractures was seen in 2009 when an extended cold spell allowed natural ice skating in Amsterdam. This resulted in overload of our Emergency Departments and operating rooms. This study reports patient and fracture characteristics of these injuries. We also determined potential skating related risk factors. All patients who sustained a distal radius fracture during natural ice skating between January 3 and January 12, 2009 were included. Patient and fracture characteristics, treatment, validated outcome (Quick DASH) at 3 months after injury were determined. Natural ice skating accounted for a 5.5-fold increase of distal radius fractures (92 fractures) compared to a similar time period without natural ice skating in 2008. Fracture types were AO-type A, n = 50, type B, n = 11 and type C, n = 31. Twenty-eight patients were casted without reduction. Fifty-four patients underwent at least one reduction before casting. The non-operative group consisted of 67 patients (68 fractures, male/female 18/49) with an average age of 55.5 years. Twenty-three patients (24 fractures) underwent internal fixation. Quick DASH for the whole group was a mean of 23.1 points (range 0-95). The mean Quick DASH for the non-operatively treated group was 19.9 points (range 0-95), for the operatively treated group 31.7 points (range 2-65). Distal radius fractures increased 5.5-fold during a period with natural ice skating. Women aged 50 and over were predominantly affected. Most fractures were extra-articular, and the vast majority was treated non operatively. Utilization of wrist-protecting devices should be considered during future natural ice periods. PMID- 21811902 TI - Bone lengthening osteogenesis, a combination of intramembranous and endochondral ossification: an experimental study in sheep. AB - We evaluated the morphological features of the newly formed tissue in an experimental model of tibial callotasis lengthening on 24 lambs, aged from 2 to 3 months at the time of operation. A unilateral external fixator prototype Monotube Triax((r)) (Stryker Howmedica Osteonics, New Jersey) was applied to the left tibia. A percutaneous osteotomy was performed in a minimally traumatic manner using a chisel. Lengthening was started 7 days after surgery and was continued to 30 mm. The 24 animals were randomly divided into three groups of 8 animals each: in Group 1, lengthening took place at a rate of 1 mm/day for 30 days; in Group 2, at a rate of 2 mm/day for 15 days; in Group 3, at a rate of 3 mm/day for 10 days. In each group, 4 animals were killed 2 weeks after end of lengthening, and the other 4 animals at 4 weeks after end of lengthening. To assess bony formation in the distraction area, radiographs were taken every 2 weeks from the day of surgery. To study the process of vascularization, we used Spalteholz's technique. After killing, the tibia of each animal was harvested, and sections were stained with hematoxylin and eosin, Masson's trichrome, and Safranin-O. Immunohistochemistry was performed, using specific antibodies to detect collagens I and II, S100 protein, and fibronectin. A combination of intramembranous and endochondral ossification occurred together at the site of distraction. Our study provides a detailed structural characterization of the newly formed tissue in an experimental model of tibial lengthening in sheep and may be useful for further investigations on callotasis. PMID- 21811903 TI - A safer technique for the double elevation osteotomy in severe infantile tibia vara. AB - Infantile tibia vara is a deformity of abrupt angulation into varus due to an affection of the postromedial aspect of the proximal tibial physis. The deformity often includes internal tibial torsion and limb length discrepancy. Gradual correction of the deformity is currently the treatment of choice for these challenging cases as it requires less invasive surgery, allows progressive and adjustable correction, permits bone lengthening if needed and achieves a more accurate correction compared to acute correction. Elevation of the depressed medial tibial condyle allows restoration of the joint architecture. Different techniques described to elevate the depressed medial tibial plateau are all technically demanding and carry potential risks of unsalvageable intra-operative complications. The aim of this study is to report the results of a safer technique for the double elevation osteotomy combined with gradual correction using the Ilizarov frame, allowing it to be more reproducible, less technically demanding and avoid those potential complications. This study included 12 limbs in 8 patients (mean age 9 years), all were classified as stage V or VI according to the Langenskiold classification. All osteotomies healed completely in all patients. The mean time in the frame was 23 weeks. The mean preoperative femoral shaft-tibial shaft angle was 36 degrees of varus. This improved to 5 degrees of varus. The mean preoperative femoral condyle-tibial shaft angle was 58 degrees . This improved to 84 degrees . The mean preoperative angle of depressed medial tibial plateau was 63 degrees . This improved to 8 degrees . All patients were maintaining full extension of the knee at the final follow-up, and all patients noticed a significant improvement in their gait pattern. We believe that this technique is safer and less invasive compared to traditional and even newly described techniques for elevating the depressed medial tibial plateau and correcting the deformity in severe infantile tibia vara, which will allow it to be more reproducible. PMID- 21811904 TI - Surgical treatment of displaced intra-articular calcaneal fracture using a single small lateral approach. AB - The objective of this study was to evaluate the outcome of semi-open reduction and minimal internal fixation through a single small lateral approach as a minimally invasive technique for treatment of displaced intra-articular calcaneal fractures. This prospective study was conducted on eighteen patients (16 men and 2 women). The average age was 37.7 (22-55). The most common cause of injury was a fall from height in fourteen patients. Patients were operated on within a mean time of 4.8 days of admission (1-11 days) and were followed up for an average period of 24.1 months (6-39 months). Patients were evaluated clinically using the Creighton-Nebraska Heath Foundation Assessment score of Crosby and Fitzgibbons (J Bone Joint Surg (Am) 72-A:852-859, 1990). The scoring system proposed by Knirk and Jupiter was used for radiological assessment of the posterior subtalar joint (Knirk and Jupiter in J Bone Joint Surg (Am) 68-A: 647-659, 1986). The skin incision healed in all cases without necrosis, infection, or sural nerve injury. All fractures healed after an average of 8 weeks (7-10 weeks), and patients returned to the routine daily activities after an average time of 4.3 months (3-7 months). In conclusion, semi-open reduction and minimal internal fixation through a small lateral approach is an effective treatment for carefully selected cases of displaced intra-articular calcaneal fractures. PMID- 21811905 TI - Subtalar versus triple arthrodesis after intra-articular calcaneal fractures. AB - Depending upon initial treatment, between 2 and 30% of patients with a displaced intra-articular calcaneal fracture require a secondary arthrodesis. The aim of this study was to investigate the effect of subtalar versus triple arthrodesis on functional outcome. A total of 33 patients with 37 secondary arthrodeses (17 subtalar and 20 triple) with a median follow-up of 116 months were asked to complete questionnaires regarding disease-specific functional outcome (Maryland Foot Score, MFS), quality of life (SF-36) and overall satisfaction with the treatment (Visual Analogue Scale, VAS). Patient groups were comparable considering median age at fracture, initial treatment (conservative or operative), time to arthrodesis, median follow-up, and post-arthrodesis radiographic angles. The MFS score was similar after subtalar versus triple arthrodesis (59 vs. 56 points; P = 0.79). No statistically significant difference was found for the SF-36 (84 vs. 83 points; P = 0.67) and the VAS (5 vs. 6; P = 0.21). Smoking was statistically significantly associated with a non-union (chi(2) = 6.60, P = 0.017). The current study suggests that there is no significant difference in functional outcome between an in situ subtalar or triple arthrodesis as a salvage technique for symptomatic arthrosis after an intra-articular calcaneal fracture. Smoking is a risk factor for non-union. PMID- 21811906 TI - Reconstruction of isolated scaphoid dislocation with carpal dissociation, associated with a carpal anomaly. AB - A case is presented of isolated scaphoid dislocation with carpal dissociation in the presence of a lunato-triquetral coalition. We present the treatment and follow-up of this case. In addition, the literature on scaphoid dislocation and its treatment is reviewed. We emphasize the need to reconstruct the carpal alignment and scapho-lunate linkage. PMID- 21811907 TI - Preservation of the shoulder joint by the use of a hybrid-spacer after septic loosening of a reversed total shoulder joint arthroplasty: a case report. AB - Infections of a total joint replacement (TJR) of the shoulder are rare complications. After revision surgery, the incidence rises dramatically. If infection occurs, it leads to a loss of function and may be devastating to the joint. Treatment options range from single- to multiple-staged revision programs, permanent resection arthroplasty or exarticulation. In this case, a reversed shoulder endoprosthesis, which was implanted after multiple revisions of a TJR due to a posttraumatic omarthrosis and rotator cuff insufficiency, got infected. A hybrid-spacer, made of a humeral nail and a custom-made PMMA spacer forming the humeral head, was used during the revision program. After two operations, clinical and paraclinical signs turned back to normal. The patient felt well and was satisfied with the result of the therapy. The hybrid-spacer was then left in situ as a definitive solution with a satisfying range of motion. This case report shows that a hybrid-spacer can be helpful in the treatment of an infected shoulder TJR. PMID- 21811908 TI - AMP-activated protein kinase: a potential target for ginsenosides? AB - Panax ginseng is a best-selling medicinal plant showing an antidiabetic activity via human, animal and in vitro studies. Among bioactive constituents found in ginseng, ginsenosides are known to be responsible for antidiabetic activity of ginseng. Ginsenoside Rb2, one of the major ginsenosides found in Asian ginseng, is shown to inhibit palmitate-induced gluconeogenesis in H4IIE rat hepatocytes via AMP-activated protein kinase (AMPK)-induced up-regulation of orphan nuclear receptor small heterodimer partner (SHP). Up to now, about thirteen articles were published to demonstrate that the pharmacological or physiological activities of ginsenosides are associated with AMPK, and only protopanaxatriol-type ginsenosides such as Re, Rg1 and Rg2, have been shown to suppress the hepatic glucose production. Therefore, Rb2 is the first protopanaxadiol-type ginsenoside shown to inhibit hepatic gluconeogenesis through AMPK activation. Further work will reveal whether activation of AMPK pathway by Rb2 would be beneficial to diabetic animals or type 2 diabetic patients. PMID- 21811909 TI - The development of non-peptide glucagon-like peptide-1 receptor agonist for the treatment of type 2 diabetes. AB - Glucagon-like peptide-1 (GLP-1) is the main member of the incretin family and stimulates insulin secretion by binding with its specific receptor on pancreatic beta-cells. In addition, GLP-1 exerts broad beneficial effects on the glucose regulation by suppressing food intake and delaying stomach emptying. Now, long acting GLP-1 analogs including exenatide and liraglutide have been approved for the treatment of diabetes mellitus type 2, however long-term injection can limit their use for these chronic patients. In this report, the authors provide a review on the development of non-peptide GLP-1 receptor agonists and introduce a novel agonist DA-15864. PMID- 21811910 TI - Antiretroviral therapy 2010 update: current practices and controversies. AB - Over the past four years, significant advances have been made in human immunodeficiency virus (HIV) therapy. In addition to the release of two new classes of antiretrovirals, our understanding of the older antiretrovirals continues to improve. Multiple combination pills have been brought to market, simplifying the regimens for patient ease. New controversies have arisen, notably the role of antiretrovirals in the chronic inflammatory state that HIV infection produces, which may lead to excess cardiac, renal, and hepatic mortality. The optimum time to initiate antiretroviral therapy remains unknown but clinicians are treating HIV infection earlier in its course. In this article, we review these and other new issues relating to the care of the HIV patient. PMID- 21811911 TI - Synthesis, antiproliferative activity, acute toxicity and assessment of the antiandrogenic activities of new androstane derivatives. AB - A number of 17-oxo-5-androsten-3beta-yl esters (9a-9f) and 3beta-alkoxy-5 androsten-17-ones (11a-11e) were synthesized from commercially available (25R)-5 spirosten-3beta-ol (Diosgenin) (4) as starting material. The synthesized compounds were evaluated for their antiproliferative activity against the prostate-specific cancer cell line DU-145, acute toxicity and effect on serum androgen levels, and compared with finasteride as positive control. Some of the compounds exhibited better cytotoxicity and antiandrogenic activity than the reference control. The detailed synthesis, spectroscopic data and biological activity of the synthesized compounds are reported. PMID- 21811912 TI - Synthesis and evaluation of C-ring aromatized analogues of phenanthridone alkaloids. AB - Phenanthridone alkaloids are envisaged as an attractive lead for the development of anticancer agents. We have prepared a series of aromatized analogues on the basis of the structure of this class of alkaloids with the hope of finding the simplified compounds with comparable activities. The obtained analogues were evaluated for their cytotoxic effect against several cancer cell lines and found to be virtually inactive. These observations together with molecular modeling studies strongly suggest that the stereochemistries of hydroxyl groups in C-ring of phenanthridone alkaloids are crucial to biological effects. PMID- 21811913 TI - Synthesis and antiproliferative activity of 1,4-bis(dimethylamino)-9,10 anthraquinone derivatives against P388 mouse leukemic tumor cells. AB - A series of 2-substituted-1,4-bis(dimethylamino)-9,10-anthraquinone derivatives were synthesized and their in vitro antiproliferative activities against p388 mouse leukemic tumor cells were evaluated. In addition, the effect of substituents on the phenyl ring was investigated. Among the derivatives tested, seven showed a high antiproliferative effect and three showed a moderate effect. In addition, introduction of a series of substituted phenyl groups into 1,4 bis(dimethylamino)-9,10-anthraquinone at 2-position were shown to enhance its antiproliferative activity. The antiproliferative activity also increased upon substitution of the benzene ring by an electron donating group such as an amine or methoxyl group. PMID- 21811914 TI - Synthesis of mono, bis-2-(2-arylideneaminophenyl) indole azomethines as potential antimicrobial agents. AB - A series of mono and bis 2-2-(arylidineaminophenyl)indole azomethines have been synthesized by a condensation reaction of 2-(2-amino phenyl) indole with various mono and diketones R-CO-R(l) /R-CO-X-CO-R(l) (1:1/2:1 ratio) in ethanol media. The synthesized azomethines were characterized via IR, (1)H-NMR, (13)C-NMR, MS and elemental analysis. The antimicrobial activity of these compounds against different bacteria and fungi was also evaluated. PMID- 21811915 TI - Synthesis and antimicrobial activity of new 1-[(tetrazol-5-yl)methyl] indole derivatives, their 1,2,4-triazole thioglycosides and acyclic analogs. AB - New 1-[(tetrazol-5-yl)methyl]indole derivatives, their acyclic nucleoside analogs and the corresponding glycoside derivatives were synthesized. Furthermore, the [)(1,2,4-triazol-3-yl)methyl])-2H-tetrazole derivative as well as the corresponding thioglucoside were prepared. The synthesized compounds were tested for their antimicrobial activity against Aspergillus Niger, Penicillium sp, Candida albican, Bacillus subtilis, Streptococcus lacti, Escherichia coli, Pseudomonas sp., and streptomyces sp. Compounds 3, 5 and 19b exhibited potent antibacterial activity and compounds 4, 5 and 10 exhibited high activities against the tested fungi compared with fusidic acid. PMID- 21811916 TI - Constituents of the root of Anemone tomentosa. AB - A new diterpene glycoside, tomentoside I (1), along with eleven known compounds, including the four coumarins, 4,5-dimethoxyl-7-methylcoumarin (2), 4,7-dimethoxyl 5-methylcoumarin (3), isofraxidin (4) and fraxidin (5) as well as the seven triterpenoids, oleanolic acid (6), oleanolic acid 3-O-alpha-L-arabinopyranoside (7), oleanolic acid 3-O-beta-D-galactopyranosyl-(1->3)-beta-D-glucopyranoside (8), hederagenin 3-O-alpha-L-arabinopyranoside (9), betulinic acid (10), 18 hydroxyursolic acid (11) and 2alpha,3beta,23-trihydroxyurs-12-en-28-oic acid (12) were isolated from the ethanolic extract of the root of Anemone tomentosa and their chemical structures were elucidated by spectroscopic methods. The antimicrobial activities of compounds 1-12 were measured using the agar disc diffusion method. Also, their antioxidant activities against 1,1-diphenyl-2 picrylhydrazyl (DPPH) were evaluated. PMID- 21811917 TI - Synthesis and anti-platelet activity of obovatol derivatives. AB - Obovatol derivatives were synthesized and evaluated for anti-platelet activity. Three derivatives (1, 2, 4i) displayed equipotent activity to obovatol in arachidonic acid-induced platelet aggregation. An initial SAR study revealed that the introduction of alkoxy group in B ring could enhance inhibitory activity. PMID- 21811918 TI - Self-microemulsifying drug delivery system for improved oral bioavailability of dipyridamole: preparation and evaluation. AB - Dipyridamole shows poor and variable bioavailability after oral administration due to pHdependent solubility, low biomembrane permeability as well as being a substrate of P-glycoprotein. In order to improve the oral absorption of dipyridamole, a self-microemulsifying drug delivery system (SMEDDS) for dipyridamole was prepared and evaluated in vitro and in vivo. The optimum formulation was 18% oleic acid, 12% Labrafac lipophile WL 1349, 42% Solutol HS 15 and 28% isopropyl alcohol. It was found that the performance of self microemulsification with the combination of oleic acid and Labrafac lipophile WL 1349 increased compared with just one oil. The results obtained from an in vitro dissolution assay indicated that dipyridamole in SMEDDS dissolved rapidly and completely in pH 6.8 aqueous media, while the commercial drug tablet was less soluble. An oral bioavailability study in rats showed that dipyridamole in the SMEDDS formulation had a 2.06-fold increased absorption compared with the simple drug suspension. It was evident that SMEDDS may be an effective approach to improve the oral absorption for drugs having pH-dependent solubility. PMID- 21811919 TI - Taguchi approach for anti-heat stress prescription compatibility in mice spleen lymphocytes in vitro. AB - Heat stress (HS) may induce immunosuppression as well as inhibit the proliferation of lymphocytes. This study evaluated the effects on immune function of our prescription on splenic lymphocytes under HS as well as its compatibility. The effects of four herbal extracts from Agastache rugosa, Atractylodes lancea, Cortex Phellodendri, and Gypsum Fibrosum on heat treated splenic lymphocytes were investigated and the compatibility of the prescription was also explored by using the Taguchi method. This study revealed changes in proliferation by traditional Chinese medicines of splenic lymphocytes after HS. Proliferation in the HS group was significantly lower than the control group. Under HS, the effects of higher concentrations of Agastache rugosa (100 and 200 MUg/mL), Atractylodes lancea (100 and 200 MUg/mL), Cortex Phellodendri (50 and 100 MUg/mL) and Gypsum Fibrosum (100 and 200 MUg/mL) caused a significant increase on ConA/LPS-induced proliferation of lymphocytes than lower concentrations. We, therefore, conclude that the prescription of traditional Chinese medicines may recover splenic lymphocytes from the immunosuppression induced by HS. The Taguchi design, which allows rapid and high efficiency for the selection of the best conditions for our prescription on HS-treated splenic lymphocytes, demonstrated that Agastache rugosa (200 MUg/mL), Atractylodes lancea (200 MUg/mL), Cortex Phellodendri (100 MUg/mL) and Gypsum Fibrosum (100 MUg/mL) were the optimal conditions for the prescription. The validation experiment confirmed that our composition in optimum extraction conditions enhanced effects on ConA or LPS-stimulated lymphocytes under HS. The results showed that the Taguchi optimization approach is a suitable method for optimization of the composition of prescription. PMID- 21811920 TI - In vitro and in vivo evaluations of ketoprofen extended release pellets prepared using powder layering technique in a rotary centrifugal granulator. AB - In the present study, an extended release pellet dosage form of ketoprofen was prepared using powder layering technique. A combination of ethyl cellulose (45 cps) and shellac polymers was used as a binder (12% w/w polymer) during drug layering and an extended release coating (1:3 ratio at 2%, 4% and 7% w/w polymer) within the same apparatus. The coated pellets were characterized for sphericity, Hardness-Friability Index, and drug content, and also underwent scanning electron microscopy. In vitro dissolution was performed in 900 mL of phosphate buffer (pH 6.8) using paddle apparatus at 100 rpm. Ethyl cellulose and shellac when used as binders during drug loading did not extend ketoprofen release beyond 3 h. However, coating of the drug loaded pellets using ethyl cellulose and shellac resulted in an extended release profile of about 10 h. Using Higuchi's model and the Korsmeyer equation, the drug release mechanism from the pellets was found to be an anomalous type involving diffusion and erosion. Scanning electron microscopy was used to visualize the pellet morphology and drug release mechanism during dissolution testing. In vivo evaluations of the extended release pellets in rats indicated a significant increase in the time to reach maximum concentration (t(max)) and extent of absorption (AUC(0-infinity)) compared to the ketoprofen immediate release tablet blend dispersed and dosed. In conclusion, extended release pellets of ketoprofen could perform therapeutically better than conventional dosage forms, leading to improved efficacy for a prolonged period. PMID- 21811921 TI - Determining the difference in medication compliance between the general patient population and patients receiving antihypertensive therapy: a case study. AB - This study addressed the issue of medication compliance in general, compliance with antihypertensive therapy, and the relationship between these two groups. In addition to determining the reasons for noncompliance with therapy prescription, the aim of this study was to also establish whether it was considered feasible by the patients to comply with their physician's instructions and whether the patients believed that the prescribed therapy was beneficial to their health. Hypertensive patients were compared to the total study population according to age groups. The study was designed as a cross-sectional survey with the use of a 33-item self-administered questionnaire. The study included 635 individuals who were collecting or buying drugs for the treatment of chronic diseases, with special reference to subjects taking antihypertensive agents (n = 361). More than half (n = 361; 56.9%) of the 635 study subjects were on therapy for arterial hypertension and possibly for some other diseases. The great majority of study subjects reported forgetfulness as the main reason for skipping drug doses. Comparison between the total study population and the subjects treated for arterial hypertension according to age groups (compliant, noncompliant and all together) yielded no statistically significant difference. We concluded that there was no difference in medication compliance between the general patient population and patients receiving antihypertensive therapy and there was no correlation between medication compliance and age. PMID- 21811922 TI - Plasma membrane as the target site of cholic acid analogs. AB - Although the mechanism is unknown, Calculus Bovis and its active components, cholic acid analogs (CAAs), have been used in China to treat a wide range of diseases. Based on the previous finding that the potency of CAA is strongly dependent on the intrinsic surface activity, this paper aimed to investigate the role of the plasma membrane in the pharmacological activity of CAAs. First, CAAs (0.1 mM) caused a surface activity-dependent depression on ATPase activity in the cell membrane extract, but it had no effects on other cellular extracts, suggesting an indispensable role of the membrane environment for pharmacological activity. Second, CAAs lowered the membrane fluidity of cultured Caco-2 cells with the same rank-order of potency sequence. Third, the hypothesis that any functional protein located on the membrane is influenced by changes in cellular membrane fluidity was supported by: ileal contraction that was induced by acetylcholine and mediated by the muscarinic receptor (M-receptor) or the relaxation induced by adrenaline and mediated by the beta-adrenergic receptor (beta-receptor) was inhibited by CAAs. They also had similar rank-order of potency and the effects on the plasma membrane. Collectively, the plasma membrane may be a target for the CAAs to exert the multiple pharmacological effects which are mediated by the alteration of the membrane mobility and the function of integral membrane proteins. PMID- 21811924 TI - Influence of dihydropyridine calcium antagonist nitrendipine on benzo(a)pyrene induced oxidative stress. AB - The aim of this study was to investigate the influence of nitrendipine (NIT), a dihydropyridine derived calcium channel antagonist, on polycyclic aromatic hydrocarbon benzo(a)pyrene (BAP)-induced oxidative stress. Male Sprague Dawley rats (155-220 g) were divided into four groups: Control (corn oil, i.p.); BAP (200 mg/kg, i.p.), BAP + NIT (200 mg/kg, i.p. + 50 mg/kg, i.p.), and NIT (50 mg/kg, i.p.) groups. Twenty-four hours after the injection of BAP, the rats were sacrificed and blood samples, liver, lung, and brain tissues were removed to determine serum alanine transaminase (ALT), aspartate transferase (AST), and gamma-glutamyltransferase (GGT) activities and tissue thiobarbituric acid reactive substances (TBARS), glutathione (GSH), and superoxide dismutase (SOD) levels. BAP significantly elevated serum ALT and TBARS levels in all tissues. However, NIT pre-treatment protected against increasing TBARS levels in lung and brain tissues. In addition, NIT pre-treatment significantly increased SOD levels in lung and liver tissues, as well as GSH levels in the lungs, compared to the BAP group. Thus, in conclusion, further studies are required to confirm the protective effects of calcium channel blockers, especially in liver tissue. PMID- 21811923 TI - Effects of borneol on the intestinal transport and absorption of two P glycoprotein substrates in rats. AB - As the most prevalent route of delivery, oral administration has the challenge of potentially low bioavailability in part because P-glycoprotein (P-gp) in the intestinal tract affects absorption. Therefore, absorption enhancers or P-gp inhibitors are strategies to solve this problem. The aim of the present study was to investigate the effects of borneol on transportation of colchicine and rhodamine123, two P-gp substrates, in rats. In vitro transportation was assessed with a diffusion chamber system with isolated rat intestines. Different concentrations of borneol (10, 40 and 80 MUg/mL) were prepared in solutions with two P-gp substrates compared with blank solutions. The in vivo effects on colchicine were assessed by a pharmacokinetic study. Borneol enhanced the absorptive transport of two P-gp substrates, which was relevant to the concentration. A pharmacokinetic study showed that in the presence of borneol, a significant increase in C(max) and AUC(0->8) of colchicine occurred when compared to colchicine alone. The study showed that borneol affected two P-gp substrates in the intestine, possibly by inhibiting the effects of P-gp and enhancing intestinal absorption of drugs. Therefore, borneol could be developed as a P-gp inhibitor and absorptive enhancer. PMID- 21811925 TI - Antimycobacterial activity of fusaric acid from a mangrove endophyte and its metal complexes. AB - Due to the increasing prevalence of multidrug-resistant Mycobacterium tuberculosis, there is an urgent need for new antituberculosis drugs that have novel mechanisms of action. As part of our ongoing search for antimycobacterial metabolites from mangrove endophytes, chemical analysis of the active extract of a strain of Fusarium sp. was performed, which led to the isolation of fusaric acid as the predominant constituent. A variety of metal complexes of fusaric acid were prepared. Antimycobacterial assays showed that Cadmium (II) and Copper (II) complexes exhibited potent inhibitory activity against the M. bovis BCG strain [minimum inhibitory concentration (MIC) = 4 MUg/mL] and the M. tuberculosis H37Rv strain (MIC = 10 MUg/mL), respectively. This is the first report of the antimycobacterial activity of the mangrove Fusarium metabolite and its coordinating metal complexes. PMID- 21811926 TI - Compliance of scored tablet halves produced by Palestinian Pharmaceutical Companies with the new European Pharmacopoeia requirements. AB - The aim of this study was to evaluate the weight uniformity of commonly divided tablets produced by Palestinian Pharmaceutical Companies and to evaluate the importance of both patient- and formulation-related variables on the splitting results. Eighty-four volunteers were enrolled in this study; their age, gender and occupation were documented in order, and the effect of these variables on the tablet splitting results was evaluated. Each volunteer was asked to divide six scored tablets of each product tested and was given clear instructions on how to conduct the splitting process. The split units were individually weighed and the RSD for each product was calculated as instructed in the European Pharmacopoeia (Ph. Eur. 5.5). Only one scored tablet product passed the Ph. Eur. test of mass uniformity, while the remaining 13 products failed; this indicates that the splitting of these tablet products is not a reliable means for the provision of accurate doses to patients. Age, gender and occupation of volunteers were not found to be predictive of any variability noted in the splitting results. The only factors that were suspected to be linked to passing the splitting test, as per the European Pharmacopoeia, were the shape, friability and hardness of the tablets. As a result of this study, we believe that the practice of dividing tablets, which should provide therapeutic and economic benefits for the patient, may potentially cause significant problems, especially in drugs with low therapeutic indices. Tablets produced by Palestinian Pharmaceutical Companies should comply with the new Ph. Eur. splitting regulations to reduce this potential for complications. PMID- 21811927 TI - Inhibitory effects of OD 78 [3-(4-bromo-phenoxy)-4,5-dihydroxybenzoic acid-methyl ester] on the proliferation and migration of TNF-alpha-induced rat aortic smooth muscle cells. AB - The proliferation and migration of vascular smooth muscle cells (VSMCs) play important roles in the formation and progression of intimal thickening in early phase atherosclerosis and in restenosis after vascular injury. Tumor necrosis factor-alpha (TNF-alpha) is released from macrophages in atherosclerotic lesions and from neointimal vascular smooth muscle cells after balloon-injury. Obovatol, a major biphenolic component isolated from the Magnolia obovata leaf, is known to have anti-inflammatory and antitumor activities. The goal of this study was to examine the cardioprotective effects of the obovatol derivative OD 78 on the TNF alpha-induced proliferation and migration of rat aortic smooth muscle cells (RASMCs). The antiproliferative effects of OD 78 on RASMCs were examined by cell counting and [(3)H]-thymidine incorporation assays. Treatment of cells with 1-4 MUM OD 78 inhibited the proliferation and DNA synthesis of TNF-alpha-stimulated RASMCs in a concentration-dependent manner, without cytotoxicity. Treatment with OD 78 inhibited TNF-alpha-mediated p38 phosphorylation, but did not change the activation of extracellular signal-regulated kinase or c-Jun N-terminal kinase. Furthermore, treatment with OD 78 decreased TNF-alpha-induced levels of cyclin E, cyclin D1, CDK2, proliferating cell nuclear antigen, and phosphorylated retinoblastoma protein, but not the CDK4 expression level. Also, OD 78 inhibits the migration of TNF-alpha-induced RASMC in transwells. OD 78 treatment strongly decreased matrix metalloproteinase-9 (MMP-9) expression in a dose-dependent manner, but the MMP-2 expression was unchanged. These results show that OD 78 may be developed as a potential antiproliferative agent for the treatment of angioplasty restenosis and atherosclerosis. PMID- 21811928 TI - The antidiabetic effect of ginsenoside Rb2 via activation of AMPK. AB - Ginsenosides, which are active compounds found in ginseng (Panax ginseng), are used as antidiabetic treatments. The aim of this study was to determine whether Rb2, a type of ginsenoside, regulates hepatic gluconeogenesis through AMP activated protein kinase (AMPK) and the orphan nuclear receptor small heterodimer partner (SHP) in hyperlipidemic conditions used as an in vitro model of type 2 diabetes. Considering these results, we concluded that Rb2 may inhibit palmitate induced gluconeogenesis via AMPK-induced SHP by relieving ER stress, a cause of gluconeogenesis. PMID- 21811929 TI - Involvement of T-cell immunoregulation by ochnaflavone in therapeutic effect on fungal arthritis due to Candida albicans. AB - Arthritis due to pathogenic fungi is a serious disease causing rapid destruction of the joint. In the pathogenesis of arthritis, T lymphocytes are considered to be one of the major immune cells. In present study, we examined the T cell immunoregulatory effect by ochnaflavone (Och), a biflavonoid, on arthritis caused by Candida albicans that is the most commonly associated with fungal arthritis. To examine the effects of ochnaflavonon Candida albicans-caused septic arthritis, an emulsified mixture of C. albicans cell wall and complete Freund's adjuvant (CACW/CFA) was injected into BALB/c mice via hind footpad route on days -3, -2, and -1. On Day 0, Och at 1 or 2 mg/dose/time was intratraperitoneally given to mice with the swollen footpad every other day for 3 times. The footpad-edema was measured for 20 days. Results revealed that Och reduced the edema at all dose levels and furthermore, there was app. 45% reduction of the edema in animals given 2 mg-dose at the peak of septic arthritis (p < 0.05). This anti-arthritic effect was accompanied by the diminishing of the DTH (delayed type hypersensitivity) activity against the CACW and by the provoking of the dominant T helper 2 (Th2) type cytokines production (IL-4 and Il-10), which appeared to result in a suppression of T helper 1 cytokines (IFN-gamma and IL-2). Besides the T cell immunoregulatory activity, Och inhibited T cells activation as evidenced by the IL-2 reduction from PMA/ionomycin-stimulated Jurkat cell line and in addition, the compound killed macrophages in a dose-dependent manner (p < 0.05). However, Och caused no hemolysis (p < 0.05). These data implicate that Och, which has anti-arthritic activity based on the Th2 dominance as well as macrophage removal, can be safely administered into the blood circulation for treatment of the arthritis caused by C. albicans. Thus, it can be concluded that Och would be an ideal immunologically evaluated agent for treating of Candida arthritis. PMID- 21811930 TI - Plant-derived antigens as mucosal vaccines. AB - During the last two decades, researchers have developed robust systems for recombinant subunit vaccine production in plants. Stably and transiently transformed plants have particular advantages that enable immunization of humans and animals via mucosal delivery. The initial goal to immunize orally by ingestion of plant-derived antigens has proven difficult to attain, although many studies have demonstrated antibody production in both humans and animals, and in a few cases, protection against pathogen challenge. Substantial hurdles for this strategy are low-antigen content in crudely processed plant material and limited antigen stability in the gut. An alternative is intranasal delivery of purified plant-derived antigens expressed with robust viral vectors, especially virus-like particles. The use of pattern recognition receptor agonists as adjuvants for mucosal delivery of plant-derived antigens can substantially enhance serum and mucosal antibody responses. In this chapter, we briefly review the methods for recombinant protein expression in plants, and describe progress with human and animal vaccines that use mucosal delivery routes. We do not attempt to compile a comprehensive list, but focus on studies that progressed to clinical trials or those that showed strong indications of efficacy in animals. Finally, we discuss some regulatory concerns regarding plant-based vaccines. PMID- 21811931 TI - [Changes in urology - appeal by the presidents of the German Society of Urology and Association of German Urologists: fair cooperation instead of more competition]. PMID- 21811932 TI - [Testosterone substitution therapy in prostate cancer]. AB - After the fourth decade of life the total testosterone level in men decreases continually. If clinical symptoms, such as decreased libido or erectile dysfunction are combined with a decreased serum testosterone level this is known as late onset hypogonadism (LOH) or partial androgen deficiency in the aging male (PADAM). In such cases testosterone substitution therapy is indicated. One important question is how to treat patients suffering from LOH but also have prostate cancer which was treated curatively in the past? Only relatively little data are available with small numbers of patients which show that testosterone substitution therapy is possible without an increased risk of a relapse in cases of cured prostate cancer. If the patient was cured it does not matter if radical prostatectomy or radiation therapy was used. It is mandatory that patients are well-informed about substitution therapy and that regular surveillance and controls are carried out during the therapy. For patients who still have prostate cancer which has not yet been treated or not yet cured decisions on whether the benefit of the testosterone replacement is greater than the potential risk of a progress of the disease have to be made on an individual case-specific basis. PMID- 21811937 TI - Determination of rivaroxaban by different factor Xa specific chromogenic substrate assays: reduction of interassay variability. AB - Rivaroxaban and other oral direct factor Xa inhibitors (ODiXa) are currently developed for prophylaxis and treatment of thromboembolic diseases using fixed doses. Although routine monitoring is not required, assessing the intensity of anticoagulation may be useful under certain clinical conditions. ODiXa prolong coagulation times of several clotting assays and, thus, their concentration may be determined in factor Xa specific chromogenic substrate assays. So far, no standardized and validated assay is commercially available. Here, five methods (A through E) are studied and optimized to reduce interassay variability. Human pooled plasma was spiked by a serial dilution of rivaroxaban (25-900 ng/ml). The release of para-nitroaniline from the chromogenic substrates was measured by the optical density (OD) at 405 nm. Method B was identified to yield the lowest sum of deviations from the mean value of the OD concentration curve calculated from all assays. Spline functions were developed for OD versus concentration curves for all methods. The calculated OD versus concentration curves overlapped for all methods. The coefficient of variation for all assays and concentrations of rivaroxaban decreased from 25.3 +/- 11.4% using the original data to 3.8 +/- 2.2% using the calculated data (P < 0.0001). The robustness of the chromogenic assay (method B) remains to be corroborated in interlaboratory comparisons. PMID- 21811938 TI - Sensitizing the teachers towards school mental health issues: an Indian experience. AB - The School Mental Health (SMH) services play critical roles fostering positive mental health and helping children with psychological problems. Despite its proven value, SMH services remain less developed in India. In this context, sensitizing teachers about child mental health issues could be considered as an important step in SMH promotion. Towards this goal, a large scale sensitization program for school teachers on SMH issues was carried out in an Indian city. This paper reports the process and the outcome of this sensitization program. PMID- 21811939 TI - Increased polyp detection using narrow band imaging compared with high resolution endoscopy in patients with hyperplastic polyposis syndrome. AB - BACKGROUND AND STUDY AIMS: Hyperplastic polyposis syndrome (HPS) is associated with colorectal cancer and is characterized by multiple hyperplastic polyps, sessile serrated adenomas (SSAs) and adenomas. Narrow band imaging (NBI) may improve the detection of polyps in HPS. We aimed to compare polyp miss rates with NBI with those of high resolution endoscopy (HRE). PATIENTS AND METHODS: In a single center, randomized crossover study consecutive HPS patients underwent tandem colonoscopy with HRE and NBI, in randomized order with removal of all detected polyps. RESULTS: In 22 patients with HPS, 209 polyps were detected, including 27 with normal histology, 116 hyperplastic polyps, 42 SSAs, and 24 adenomas. Among patients assigned to HRE first (n = 11) a total of 78 polyps was detected; subsequent NBI added 44 polyps. In patients examined with NBI first, 78 polyps were detected and subsequent HRE added 9. Polyp miss rates of HRE and NBI were 36% and 10% (OR 0.21; 0.09-0.45). Flat polyp shape was independently associated with increased miss rate. CONCLUSION: NBI significantly reduces polyp miss rates in HPS patients. We recommend using either NBI or chromoendoscopy for colonoscopic surveillance of HPS patients with removal of all detected polyps. PMID- 21811940 TI - Nurse-administered propofol sedation for endoscopy: a risk analysis during an implementation phase. AB - BACKGROUND AND STUDY AIMS: The aim of the present study was to perform a risk analysis during the implementation phase of nurse-administered propofol sedation (NAPS) and to validate our structured training program. PATIENTS AND METHODS: A structured training program was developed both for endoscopists and for endoscopy nurses who were administering propofol sedation. The nurses' program comprised a 6-week course including theoretical and practical training in airway management, and the endoscopists' program consisted of 2.5 h of theory and a short course in practical airway management. In the implementation phase, data from 1822 endoscopic procedures in 1764 patients were prospectively collected. All adverse events related to sedation were recorded (defined as oxygen saturation < 92%, airway handling, assisted ventilation, need for intubation, change in blood pressure > 20 mmHg). RESULTS: 78 cases of hypoxemia were documented in 1764 patients (4.4%), in 56/983 upper endoscopies (5.7%) and 22/754 lower endoscopies (2.9%) (P = 0.007). Assisted ventilation was necessary in 19 cases (1.1%) and anesthesiologic assistance was requested 10 times. Two patients required endotracheal intubation. A change in blood pressure was recorded in 451 patients (26%). Independent risk factors were type of intervention and level of experience of the staff performing the sedation. CONCLUSION: These results were obtained after development of a structured training program both for endoscopists and nurses using propofol for sedation, and can be used as basis for further comparison. NAPS for endoscopic procedures is safe when performed by personnel properly trained in airway handling and sedation with propofol, and has considerable advantages compared with conventional sedation for endoscopy. PMID- 21811941 TI - Jejunal gastrointestinal stromal tumor missed by three capsule endoscopies. PMID- 21811943 TI - Contrast enhancement during endosonography to diagnose autoimmune pancreatitis. PMID- 21811945 TI - Terminal ileum images for verification of colonoscopy completion. PMID- 21811947 TI - [Progress in undergraduate and postgraduate education in abdominal ultrasonography at German university hospitals in 1999-2009]. AB - AIM: The aim of this study was to assess the current state of undergraduate and postgraduate education in abdominal ultrasonography at German university hospitals and to compare these findings with data from 1999. METHODS: A survey, encompassing questions related to technical equipment, undergraduate education, graduate education and quality assurance, was conducted at all 36 gastroenterological departments of university hospitals in Germany. The response rate was 86 %. RESULTS: Currently, there is an average of four dedicated ultrasound units for abdominal ultrasonography per department. Two percent are basic units, 12 % are middle-class and 86 % are high-end units. Compared to 1999 there has been an improvement in the quality of ultrasound units but no increase in number; the percentage of high-end units has considerably increased. All departments offer undergraduate training in abdominal ultrasonography. On average, about 100 students per semester take part in training programmes. Ten years ago only 86 % of hospitals provided undergraduate training, for an average of 55 students per semester. Postgraduate training is offered full-time in 94 % of hospitals (1999: 77 %) over a mean time span of 6.1 months (1999: 4.3 months). In 2009a mean of 4.7 physicians per department underwent ultrasonography training, down from 5.6 physicians per department in 1999. CONCLUSION: Over the ten-year observation period, the quality of dedicated ultrasonography equipment for abdominal ultrasonography in the gastroenterological departments of German university hospitals has improved considerably, while the quality of postgraduate education has improved only slightly. In addition, there was improvement in undergraduate ultrasonography training. PMID- 21811948 TI - Excessive bilirubin elevation in a patient with hereditary spherocytosis and intrahepatic cholestasis. AB - Hereditary spherocytosis is a common hemolytic anemia with an estimated incidence of 1 / 2500 births. It is caused by a molecular defect in one or more of the proteins of the red blood cell cytoskeleton. Mutations in the ABCB11 gene, encoding the bile salt export pump, can entail progressive familial intrahepatic cholestasis and benign recurred intrahepatic cholestasis. A 18 year old Turkish patient with hereditary spherocytosis was admitted to hospital with pruritus and severe jaundice. Ultrasound examination presented stones in gallbladder and bile duct. After endoscopic retrograde cholangiography with extraction of small bile duct stones abdominal pain resolved and liver enzymes normalized within a few days, but bilirubin and bile acids remained highly elevated. Liver biopsy revealed a severe canalicular cholestasis. Genetic analysis showed the compound heterozygous variants ABCB11 A 444V and 3084A > G. Treatment with ursodesoxycholic acid and intermittent therapy with prednisone reduced pruritus and jaundice with concomitant improvement of blood test. Here we report the first case of a patient with combined hereditary spherocytosis and compound heterozygous ABCB11 gene variants predisposing to intrahepatic cholestasis. Therefore, patients with hemolytic disorders should be investigated for bile acid transporter diseases in case of hyperbilirubinemia and severe cholestasis. PMID- 21811949 TI - Application of the OTSC system for the closure of fistulas, anastomosal leakages and perforations within the gastrointestinal tract. AB - Until recently there has been no technique available which reproducibly and safely allowed endoscopic closures of penetrating defects within the digestive tract. With the new "over the scope clipping system" (OTSC system(r)), which regarding design and function is similar to a bear-trap, a method is available for the endoscopic closure of fistulas and perforations. Here, we present a series of 10 patients, in whom different penetrating defects within the digestive tract could be closed in 9 of 10 cases successfully by the OTSC system(r): fistulas (esophagotracheal, esophagopleural, gastrocutaneous and colovesical), perforations (after mucosectomy, after papillotomy and PEG misplacement) and anastomosal leakages (after gastrotomy and gastrectomy). In another case we demonstrate our first experience with the OTSC system(r) for the prevention of perforations during deep endoscopic R 0 resection of a T 1(sm1)G1 sigmoideal cancer after initial R 1 resection. PMID- 21811950 TI - Large-bowel obstruction as a late sequela of retrosternal diaphragmatic hernia. AB - A 37-year-old man with a past history of a fall from height 16 years previously was admitted with acute abdomen. Investigations revealed intestinal obstruction caused by a diaphragmatic hernia. He had an incarcerated omentum and Richter's hernia of the transverse colon secondary to left diaphragmatic hernia leading to colonic ileus. Following resection of the strangulated omentum and reduction of the colon intraabdominally, a surgical repair of the hernia was performed using an abdominal and transthoracic approach. The relatively rare late complication of a left-sided enterothorax with ileus makes this a remarkable case and underlines the need for early surgery to avoid late complications. PMID- 21811951 TI - [Current value of quinolones in Helicobacter pylori therapy]. AB - Eradication rates in first-line Helicobacter pylori therapy have been declining over the last decades, mainly due to increasing resistance against the recommended antibiotics clarithromycin and metronidazole. Thus, there is a need to evaluate novel regimens and substances to offer effective alternative treatment strategies. New generation quinolones, like levofloxacin and moxifloxacin, exhibit a broad-spectrum activity against various Gram-positive and Gram-negative strains and are mostly well tolerated. Based on a large number of studies, quinolones have been introduced in second-line and rescue treatment and are recommended for these indications in current guidelines. Various studies have investigated alternative strategies for first-line treatment including quinolone based regimens. In the context of increasing resistance rates of Helicobacter pylori against quinolones some risks and benefits have to be considered when using quinolones as a first-line strategy. Besides numerous studies investigating levofloxacin and moxifloxacin there are some promising results for the new substance sitafloxacin, which might overcome primary resistance of Helicobacter pylori against conventional quinolones. PMID- 21811952 TI - Post-infectious irritable bowel syndrome--a review of the literature. AB - INTRODUCTION: Despite considerable research efforts, the epidemiological characteristics of post-infectious symptoms of the irritable bowel syndrome-type (PI-IBS) are not yet well defined. Estimates of its incidence after gastrointestinal (GI) infection show considerable variation and the number of patients with a history of a GI infection among all patients with IBS is practically unknown. This review aims at summarizing published estimates (i) on the prevalence of PI-IBS among all IBS patients and (ii) on PI-IBS incidence after GI infection, critically discusses methodological differences that may explain the variation of the presented findings and gives an overview on currently identified risk factors for the development of PI-IBS. METHODS: A systematic literature review was perfomed of studies indexed in PUBMED that assessed the epidemiology and risk factors of PI-IBS. RESULTS: The reported incidence of PI-IBS ranges for epidemic infections between 7 and 36 %, for individual infections between 4 and 36 % and for traveller's diarrhea from 4 to 14 %. Estimates of the prevalence of PI-IBS range from as low as 7 % to more than 1/3 of all IBS patients, depending on the study design. The predictors and biomarkers are varying among the studies. CONCLUSION: PI-IBS appears to be common following infectious enteritis and among all IBS patients, but precise estimates are still lacking. PMID- 21811953 TI - [A dogma changes! Barrett's mucosa without goblet cells?]. PMID- 21811954 TI - [Factors influencing the decision of future psychiatrists to practice establishment. Results from a survey of young physicians in Germany]. AB - OBJECTIVE: Office based psychiatrists are playing a decisive role regarding the provision and coordination of community based, continuous mental health care. Although the estimated need for office based psychiatrists and neurologists is covered to 125 % in Germany, a physician shortage is emerging in some regions. Therefore, the present study aimed to investigate factors influencing the decision of future psychiatrists to a practice establishment. METHODS: 14,939 young physicians aged under 40 without completed specialist medical training were contacted by mail using databases of five state chambers of physicians (Lower Saxony, Westfalen-Lippe, Saxony, Saxony-Anhalt, Mecklenburg-Western Pomerania). The physicians were asked to answer questions regarding socio-demographic characteristics, the aspired medical speciality, their purpose to establish a practice, and an 18-items questionniare regarding important aspects for the latter decision. As revealed in a former study, the 18 items are related to six factors for practice establishment. The answers of 5,053 respondents were eligible for data analysis. RESULTS: 4.3 % of the examined physicians aspired a medical specialist training in psychiatry, 44 % of them plan to establish a practice. Future psychiatrists as well as other physicians valued the surrounding conditions for family as most important factor regarding a practice establishment, followed by professional duties (e. g. on-call duty) and financial conditions. The quality of life in the surrounding area had least importance. CONCLUSIONS: The results point on measures which could be suited making a practice establishment for young physicians attractive. PMID- 21811955 TI - [Needs of clients cared for by community mental health nurses]. AB - OBJECTIVE: To assess needs for care rated by clients and their community mental health nurses and their agreement on needs. METHODS: 47 randomly selected clients and their care professionals completed the Camberwell Assessment of Need. RESULTS: Psychiatric nurses indicate a higher number of total and met need than their clients. Unmet need was rated most highly in the domains of psychological distress, company of others and intimate relationships. Professionals underrated their clients' needs in the areas physical health, information about condition and treatment and psychological distress and indicated a higher level of need than their clients in the domains of daily activities and psychological distress. CONCLUSIONS: Care planning and care targeting should respond to the unmet needs of the clients in order to prevent care deficiencies. Differences in the evaluations indicate the importance to include client's viewpoints into the needs assessment. PMID- 21811956 TI - [Cyberstalking: prevalence and impact on victims]. AB - OBJECTIVE: The present study was designed to investigate prevalence and types of cyberstalking and its impact on mental health. METHOD: Internet survey of 6379 participants in the Web-based social network Studi-VZ. RESULTS: The prevalence of cyberstalking was 6.3 %. Cyberstalking appears to be a frequently occurring phenomenon. Contrary to earlier assumptions, not based on empirical studies, there are striking similarities of cyberstalking and stalking in the real world. The gender distribution is comparable to real life stalking: Most of the victims are female and most of the perpetrators are male. Like other forms of stalking in the real world, cyberstalking occurs most often in the context of ex-partner relationships and contacts with friends, acquaintances and work colleagues. Compared to non-victims, victims of cyberstalking scored significantly poorer on the WHO-5 well-being index. CONCLUSION: Due to the increasing use of web-based social networks psychiatrists and psychotherapists have to become experts in the issue of cyberstalking since victims will frequently ask them for help. As cyberstalking does not appear to be a separate diagnostic entity, similar counselling techniques that are applied for other forms of stalking should be provided. PMID- 21811957 TI - [After 200 years of psychiatry: are mechanical restraints in Germany still inevitable?]. AB - BACKGROUND: Mechanical restraint and seclusion are not therapeutic interventions but procedures to safeguard patients or staff representing a failure of therapeutic approaches. Quality management including benchmarkings yields considerable variations between different hospitals. However, an enduring and significant decrease in the frequency and duration of such coercive measures so far has not been achieved by means of quality management. A new set of approaches is therefore required. RESULTS: Amending the British practice of "physical restraint" for German conditions, a technique of holding the patient was developed accompanied by manualised interventions of verbal de-escalation. In contrast to mechanical restraint, the technique represents a therapeutic intervention and is usually of short duration. An implementation is planned in a group of hospitals collaborating in the prevention of violence and coercion in psychiatry. CONCLUSIONS: This new technique appears a promising approach to fundamentally change the practice of mechanical restraint in Germany. Evidence of the effect of this technique on frequency and duration of mechanical restraints needs to be gathered. PMID- 21811958 TI - [Fatal aspiration following polydipsia in schizophrenia]. AB - OBJECTIVE AND METHODS: Polydipsia with hyponatraemia commonly occurs with chronic psychosis and is associated with a reduced life expectancy for individuals diagnosed with schizophrenia. We describe a 51 years old man who presented with polydipsia during a relapse of paranoid schizophrenia. While treated with Clozapine, and despite regular observation and daily control of creatinine and electrolytes, the man suddenly collapsed and died after drinking huge amounts of water. No sedation from psychotropic medication or drugs and alcohol was present in this case. Sodium levels on the day of death and the day before were within normal range. A post-mortem revealed aspiration of water and gastric content as the cause of asphyxiation and death. A literature search in Medline and Embase did not yield a description of a similar case. RESULTS AND CONCLUSIONS: This case highlights the risk of aspiration associated with polydipsia in chronic schizophrenia. Daily control of electrolytes to identify hyponatremia and regular observation are recommended but may not be sufficient to prevent sudden death from drinking huge amounts of water. PMID- 21811959 TI - Do persons that changed health insurance differ from those who did not? The case of diabetes. AB - AIMS: We aimed to compare German adults that changed health insurance since 1996 with those who did not with special emphasis on diabetes. METHODS: 8 representative surveys (conducted 2005-2008) of the 'Bertelsmann Healthcare Monitor' comprising 12,362 participants aged 18-79 years were analysed. We compared participants that changed their health insurance fund with those who did not. To study if diabetes is associated with switching, we fitted logistic regression models and stepwise adjusted for age, sex, cardiovascular comorbidities, anthropometric measures and health-related factors. RESULTS: About one third (32.0%) changed their health insurance fund since 1996. Compared to persons that did not change, those who did were younger, higher educated, assessed their health status better and had less cardiovascular diseases. The prevalence of diabetes was much lower in persons that changed their fund than in those who did not (3.6% vs. 8.9%; Odds Ratio [OR]: 0.38; 95% confidence interval [CI]: 0.31-0.47). Adjusting for age and sex leads to a non-significant OR of 0.81 (95% CI: 0.64-1.02), which remained in the fully adjusted model (OR: 0.88; 95% CI: 0.69-1.12). CONCLUSIONS: Persons that changed their fund had a much lower prevalence of diabetes than those who did not. Most of this difference could be explained by age. We found quite similar figures for hypertension, a more prevalent disease. However, ORs were significant in all described models, probably due to a higher statistical power. PMID- 21811960 TI - The evidence for the use of growth factors and active skin substitutes for the treatment of non-infected diabetic foot ulcers (DFU): a health technology assessment (HTA). AB - AIMS: Assessment of the safety, efficacy and effectiveness of growth factors alone or in combination with other technologies in the treatment of DFU including medical, economical, social, ethical and juridical aspects. METHODS: We systematically searched relevant data bases limited to English and German language and publications since 1990. Review and assessment of the quality of publications followed methods conforming to widely accepted standards for evidence-based medicine and health economics. RESULTS: We identified 25 studies comparing becaplermin, rhEGF, bFGF and the metabolically active skin grafts Dermagraft and Apligraf with standard wound care (SWC) alone or extracellular wound matrix. Study duration ranged from 12 to 20 weeks and the study population comprised between 17 and 382 patients. Treatment with becaplermin, rhEGF, Dermagraft and Apligraf resulted in a higher incidence of complete wound closure and shorter time to complete wound healing with statistically significant differences. Regarding the proportion of adverse events there was no difference between treatment groups. The methodological quality of the studies was affected by significant deficiencies. Economic evaluations showed becaplermin being cost effective. CONCLUSIONS: Add-on therapy with growth factors and active skin substitutes for treating uncomplicated DFU could be an alternative to SWC alone. For explicit recommendations further studies with stronger evidence are necessary. PMID- 21811961 TI - Skeletal muscle insulin resistance in morbid obesity: the role of interleukin-6 and leptin. AB - BACKGROUND: Although insulin resistance in obesity is established, the link between excess body fat and skeletal muscle insulin resistance is obscure. The aim of this study was to investigate whether cytokines secreted from the subcutaneous adipose tissue are related to the sensitivity of glucose metabolism to insulin in skeletal muscle. METHODS: A meal was given to 14 obese and 10 non obese women. Plasma samples were taken for 360 min from a forearm vein and from the radial artery for glucose and insulin measurements. Interleukin-6, leptin, TNFalpha, resistin and adiponectin were measured preprandially from the radial artery and from the superficial epigastric vein. Forearm blood flow was measured with plethysmography. RESULTS: (1) In obese vs non-obese: (a) Glucose uptake by skeletal muscle was decreased (AUC (0-360)369 +/- 55 vs. 877 +/- 146 MUmol/100 g tissue, p=0.001) (b) arterial interleukin-6 (2.5 +/- 0.5 vs. 1 +/- 0.1 pg/ml, p=0.013) and subcutaneous venous interleukin-6 (5 +/- 0.5 vs. 3.4 +/- 0.5 pg/ml, p=0.027) were increased (c) arterial leptin (63 +/- 7 vs. 5 +/- 0.6 ng/ml, p<0.0001) and subcutaneous venous leptin 80 +/- 8 vs. 6.5 +/- 0.7 ng/ml, p<0.0001) were increased. (2) Arterial interleukin-6 (p=0.002) and subcutaneous venous interleukin-6 (p=0.014) were negatively associated with forearm glucose uptake in obese. (3) No association was found between leptin and forearm glucose uptake, after correcting with fat mass. CONCLUSIONS: In morbid obesity: (1) Subcutaneous adipose tissue releases interleukin-6 which could then mediate insulin resistance in skeletal muscle. (2) Although there is increased secretion of leptin by the subcutaneous adipose tissue, leptin levels are not correlated to the sensitivity of glucose metabolism to insulin in muscle. PMID- 21811962 TI - Paget's disease of bone and calcium homeostasis: focus on bisphosphonate treatment. AB - Paget's disease of bone (PDB) is the second most common metabolic bone disease. Bisphosphonates (BPs) are currently the drugs of choice for PDB. PDB and osteomalacia are both common in the elderly. The concept of relative vitamin D deficiency in patients with PDB was suggested long ago, but it has not yet elucidated. Both diseases predispose to fractures, but their combined action to fragility has not been studied yet. The older BPs, mainly etidronate, further inhibit bone mineralization. Mineralization defects have also been described in patients with PDB treated with pamidronate. Moreover, hypocalcemia and secondary hyperparathyroidism after treatment with BPs have been described in PDB. Hypocalcemia seems to be more severe after treatment with the more potent, intravenous zoledronic acid, which is currently the treatment of choice for PDB. The counteracting hyperparathyroidism pathophysiologically intends to increase renal reabsorption of calcium and 1.25-dihydroxy vitamin D production and to stimulate osteoclasts in order to prevent long-term hypocalcemia. However, the effect of PTH on osteoclasts is, at least partly, restricted in patients taking BPs. Secondary hyperparathyroidism is a potentially detrimental condition, especially in patients already suffering from another bone disease. Serum calcium and vitamin D deficiency should be restored before BP treatment and calcium and vitamin D administration should be possibly continued for longer after achieving normocalcemia, which may shorten the duration of secondary hyperparathyroidism. QUICK SUMMARY: Mineralization defects and hypocalcemia with secondary hyperparathyroidism have been described in patients with Paget's disease of bone treated with bisphosphonates. Secondary hyperparathyroidism may be a potentially detrimental condition for patients with Paget's disease of bone. PMID- 21811963 TI - Apelin, prediabetes and atherosclerosis. PMID- 21811964 TI - High estradiol levels are associated with increased mortality in older men referred to coronary angiography. AB - There is evidence showing an important role of estrogens in men's health. We aimed to evaluate whether estradiol levels are associated with overall mortality and specific fatal events.We measured estradiol levels in 2,078 men who were routinely referred for coronary angiography (1997-2000).The main outcome measures were Cox proportional hazard ratios (HRs) for mortality from all causes, from cardiovascular and non-cardiovascular causes including cancer according to estradiol levels.Multivariable HRs (with 95% confidence intervals) for all-cause, non-cardiovascular, and cancer mortality were 1.43 (1.08-1.91), 2.11 (1.34-3.34), and 2.27 (1.00-5.19), respectively, in the fourth estradiol quartile as compared to the first. There was no significant association of estradiol levels with cardiovascular mortality. In multivariate adjusted analyses, higher estradiol levels in men were significantly associated with prevalent strokes, peripheral vascular disease, and carotid artery stenosis compared to lower estradiol levels.High levels of estradiol are associated with all-cause and non cardiovascular mortality in a large cohort of older men referred to coronary angiography. Further studies are warranted to confirm our results and to elucidate the underlying mechanisms. PMID- 21811966 TI - Establishing a composite tissue allotransplantation program. AB - Composite tissue allotransplantation (CTA) has emerged as a promising surgical option to restore the form and function of missing or severely damaged structures such as the face, hands, or trachea. Currently, there are four active CTA programs in the United States and numerous others under development. The process of development of a CTA program in the United States involves successful collaboration between a strong project leader with vested clinical research interest, a multidisciplinary team of investigators, an Institutional Review Board, a regional Organ Processing Organization (PO), and the hospital's administration. The process of establishment of a CTA program can be slow and lengthy, therefore the project leader must strive to maintain the enthusiasm alive and drive the project forward. At all phases of development, the project must remain focused on the patients, must recognize and address all potential patient safety issues, must take into account the concerns, issues and logistic hurdles faced by the OPO, and must be financially responsible by ensuring that postoperative costs related to medical care and life-long immunosuppression are covered by medical insurance. This article describes the process of establishment of a CTA program at Brigham and Women's Hospital, Boston, MA with special emphasis on strategy and planning. PMID- 21811967 TI - Free tissue transfer in acute burns. AB - Major burn injuries can be devastating for the patients and their carers both in terms of morbidity and mortality. Therefore, it is important to optimize the treatment of the injured patient. After initial resuscitation and physiological stabilization, thorough surgical debridement of the burn is necessary. Often resultant defects can be resurfaced with split skin grafting or local flaps. However, in a small percentage of cases free flap surgery is necessary. Free tissue transfer in burns surgery is rare, but is indicated in those patients in which there is loss of a vascularized surface suitable for grafting such as exposed tendon, or bone following surgical debridement, and in extreme cases for limb salvage. This review article discusses the rationale for free flap surgery in terms of types of burn injuries, perioperative considerations, and summarizes the literature in free tissue transfer in acute burns. PMID- 21811965 TI - Low prevalence of clinically high-risk women and pathological thyroid ultrasound among pregnant women positive in universal screening for thyroid disorders. AB - BACKGROUND: It is controversial whether screening program for thyroid disorders in pregnancy should be universal or targeted case-finding. To evaluate the relationship between history, laboratory parameters and thyroid ultrasound (TUS) in pregnant women positive in universal screening. SUBJECTS AND METHODS: The screening included investigation of serum TSH (thyroid stimulating hormone) and TPOAb (antithyroperoxidase antibodies) in 5,520 unselected pregnant women in the 9-11th gestational week. In 822 the screening was positive: abnormal TSH (> 3.67 or < 0.06 mIU/l) and/or positive TPOAb (> 143 kIU/l). 200 consecutive women with positive screening were included it the study. RESULTS: 41 women (21%) had transient gestational hyperthyroidism (TGH) and 159 (79%) had a thyroid pathology: 10 (5%) overt hypothyroidism; 76 (38%) subclinical hypothyroidism, 7 (3.5%) overt hyperthyroidism and 66 (33%) euthyroid TPOAb positivity. After exclusion of TGH, only 74/159 (47%) women were classified as high-risk for thyroid disease according to their history. There were no significant clinical and laboratory differences between the high- vs. low-risk women, except for higher proportion of FT4<75th percentile (P=0.008) and larger thyroid volume in the high-risk group (P=0.04). Finally, only 66/126 (52%) of TPOAb-positive pregnant women had autoimmune pattern in TUS in comparison with 41/49 (84%) TPOAb positive non-pregnant control women of comparable age (P<0.001). CONCLUSIONS: Less than half of the positively screened pregnant women can be classified as high-risk and almost half of them had not autoimmune pattern in TUS. High- and low-risk pregnant women have similar clinical and laboratory characteristics. PMID- 21811968 TI - Descending geniculate artery: the ideal recipient vessel for free tissue transfer coverage of below-the-knee amputation wounds. AB - The descending geniculate artery has received notoriety as the source vessel of the medial femoral condyle vascularized bone flap in recent years. Its size and location enable it to serve as a useful recipient vessel in free flap reconstruction about the knee. It is particularly useful in coverage of unstable below-the-knee amputation stumps when recipient vessels are limited. It provides the ease and convenience of two-team surgery in the supine position and its distal position permits convenient and distal insetting of the transferred flap of choice. A discussion of its use in this setting and exemplary cases are provided. PMID- 21811969 TI - Technical aspects of the recipient operation in hand transplantation. AB - The goal of hand allotransplantation is to achieve graft survival and useful long term function. To achieve these goals, precise surgical technique is of critical importance. The key surgical steps and sequence of events in hand allotransplantation are similar to major upper extremity replantations, but are modified to accommodate major conceptual differences that exist between the two procedures. PMID- 21811970 TI - [Increased liver enzymes and metabolic risk - case 7/2011]. PMID- 21811971 TI - [Mutation screening and prenatal diagnosis of tuberous sclerosis complex]. AB - OBJECTIVE: To screen mutations of tuberous sclerosis complex (TSC) patients to confirm a clinical diagnosis of TSC, and to perform prenatal diagnosis for families with mutations. METHODS: In this study, PCR-denaturing high-performance liquid chromatography(DHPLC), supplemented with sequencing when necessary, was used to screen TSC1 and TSC2 mutations in 21 patients from 19 pedigrees visited author's hospital in the last five years. For novel mutations, one hundred unrelated healthy individuals were screened to exclude the possibility of polymorphism. RESULTS: Seventeen different mutations were found in 21 patients of 19 pedigrees with 13 being novel mutations, including c. 2672delA, c. 2672insA of TSC1 gene and c.4918insCGCC, c.1143delG, Intron27+1 G>A, c.1957-1958delAG, Intron5+1 G>A, c.910insCT, c.2753 C>G, c.4078dupAGCAAGTCCAGCTCCTC, Intron 11 -1 G>A, Intron 14+1 G>A, c.684 C>A of TSC2 gene, indicating a high frequency of de novo mutations in TSC. Three of these mutations were in the TSC1 gene (N762S, c.2672insA and c. 2672delA), while all remaining 14 were in the TSC2 gene. Prenatal diagnosis for TSC was performed for 7 fetuses from these pedigrees. The six fetuses that tested negative for TSC mutations were carried to term and, to date, none of these children has shown symptoms of TSC. CONCLUSION: Author's data showed that a mutation detection rate of tuberous sclerosis was 89.5%(17/19) among patients in author's hospital. The ratio of TSC2 and TSC1 mutations was about 1:1 in the familial cases, but TSC2 mutation was more common than TSC1 mutation in sporadic cases. Author's data demonstrated that birth of TSC children for those with familial history of TSC could be prevented through prenatal diagnosis. PMID- 21811972 TI - [Maternally inherited aminoglycoside-induced and nonsyndromic hearing loss in five Han Chinese pedigrees]. AB - OBJECTIVE: To study the effect of the mitochondrial 12S rRNA mutations on aminoglycoside-induced and nonsyndromic hearing loss, to carry out the clinical and molecular characterization of five Han Chinese pedigrees with maternally transmitted aminoglycoside-induced and nonsyndromic hearing loss. METHODS: Five pedigrees of maternally transmitted aminoglycoside-induced and nonsyndromic hearing loss were collected, genomic DNA was extracted, and complete mitochondrial genomes and the gap junction protein beta 2 (GJB2) gene were amplified and sequenced. RESULTS: Clinical evaluation revealed a wide range of severity, age-at-onset and audiometric configuration of hearing impairment in the matrilineal relatives in these families. The penetrance rates of hearing loss in these pedigrees were 17.6%, 50.0%, 66.7%, 31.3% and 23.1%, with an average of 37.7%, when aminoglycoside-induced deafness was included. Sequence analysis of the complete mitochondrial genomes in these pedigrees identified the known 1555A>G mutation and distinct sets of mitochondrial DNA(mtDNA) polymorphisms belonging to Eastern Asian haplogroups D4b2b, B4c1b1, F3, C1 and D5a, respectively. Of these variants, ND1 L89T and CO3 A200T mutations resided at the highly conservative regions. However, there were no functionally significant mutations in tRNAs and rRNAs or secondary known mutations. No hearing loss related GJB2 gene mutation was observed. CONCLUSION: The lack of significant mutation in the ruled out the possible involvement of GJB2 in the phenotypic expression of the 1555A>G mutation in those affected subjects. However, aminoglycosides, mtDNA variations and other nuclear modifier genes may play an important role in the phenotypic manifestation of the 1555A>G mutation in these Chinese families. PMID- 21811973 TI - [Mutation analysis of GCDH gene in eight patients with glutaric aciduria type I]. AB - OBJECTIVE: To investigate the mutations of glutaryl-CoA dehydrogenase (GCDH) gene in patients with glutaric aciduria type I(GA-1). METHODS: Genomic DNA was extracted from peripheral blood cells of the eight probands with GA-1 who were diagnosed by urine and blood analyses. By PCR and direct sequencing, all 11 exons and their flanking sequences of the GCDH gene were examined. Mutation search was also performed in some of their family members. RESULTS: Among the eight patients diagnosed by metabolic screening, seven patients belonged to classical infantile onset. One patient, however, was adult-onset, who was admitted to the hospital because of suffering from ischemic cerebral stroke. The GCDH gene mutations were identified in all the eight probands with GA-1: five of them had compound heterozygous mutations, while the other three harbored only one heterozygous mutation. Totally, nine different mutations of the GCDH gene were identified in the eight probands, four of them were novel, i.e., c.148T>C, c.371G>A, 909delC and c.263G>A. CONCLUSION: GCDH gene mutations are identified in 8 patients with GA-1 in mainland China, including one adult patient with late onset. Four novel mutations of GCDH gene are found which expanded the mutational spectrum of the GCDH gene. PMID- 21811974 TI - [Genotype-phenotype analysis of a Chinese family with split hand/split foot and syndactyly]. AB - OBJECTIVE: To determine the causative gene mutation in a Chinese family with split hand/split foot malformation (SHFM) and explore the genotype-phenotype relationship. METHODS: Genomic DNA was extracted from peripheral blood samples of the patients and their family members. Polymerase chain reaction (PCR) was performed to amplify all the exons of P63 gene and HOXD13 gene. Then the PCR products were sequenced bidirectionally to screen mutations. RESULTS: A heterozygous 956G>A transversion in exon 7 of P63 gene was identified in all patients, which resulted in the substitution of histidine residue for arginine at position 280 of P63 protein (R280H). This mutation was not found in the unaffected family members. CONCLUSION: Patients in this pedigree are characterized by symmetrical split hand and split foot with syndactyly. This condition is caused by the R280H mutation in P63 gene. PMID- 21811975 TI - [Genetic screening of mutation hot-spots for nonsyndromic hearing loss in southern Jiangsu province with SNaPshot]. AB - OBJECTIVE: To investigate the mutation frequency in 7 mutation hot-spots of deafness gene in southern Jiangsu province and verify the performance of the SNaPshot technology platform, designed for genetic screening of non-syndromic hearing loss (NSHL) in Chinese. METHODS: One hundred and twenty-five NSHL patients were enrolled. Amplification of 235delC, 299-300delAT in GJB2 gene, IVS7 2A>G, 2168 A>G in SLC26A4 gene, and 1555A>G, 7445 A>G and 3243 A>G in mitochondrial DNA (mtDNA) was performed using multiplex polymerase chain reaction (PCR) technology. Afterwards, the sequence-specific probe interrogated each locus and labeled it at the 3' end using fluorescent dideoxynucleotide chemistry by the SNaPshot Multiplex Kit, the resulting products were then separated electrophoretically in ABI PRISM R 3130 Genetic Analyzer and analyzed in the presence of a fifth-dye-labeled size standard. Finally, the genotyping results were verified by direct sequencing or PCR-restriction fragment length polymorphism (PCR-RFLP). RESULTS: (1) The total mutation frequency for the 7 mutation hot-spots was 53.6%. The mutation frequency of 235delC was 24.0%, 299 300delAT was 5.6% in the GJB2 gene, IVS7-2A>G was 15.2%, 2168A>G was 3.2% in the SLC26A4 gene. The mutation frequency of 1555A>G and 7445 A>G in mtDNA was 4.8% and 0.8% respectively. The mutation 3243 A>G was not detected. (2) The SNaPshot results were consistent with that from direct sequencing or PCR-RFLP, and the specificity and sensitivity of detection were 100%. CONCLUSION: (1) More than half of the patients with deafness in southern Jiangsu province carry the mutations of the seven hot-spots. (2) The genetic screening technology platform based on SNaPshot can detect 7 mutations in one reaction, and is efficient and suitable for clinical practice. PMID- 21811976 TI - [Mutation analysis of beta myosin heavy chain gene in hypertrophic cardiomyopathy families]. AB - OBJECTIVE: To detect the gene mutations of beta-myosin heavy chain gene (MYH7) in Chinese pedigrees with hypertrophic cardiomyopathy (HCM), and to analyze the correlation between the genotype and phenotype. METHODS: Exons 3, 5, 7-9, 11-16 and 18-23 of the MYH7 gene were amplified with PCR in three Chinese pedigrees with HCM. The products were sequenced. Sequence alignment between the detected and the standard sequences was performed. RESULTS: A missense mutation of Thr441Met in exon 14 was identified in a pedigree, which was not detected in the controls. Several synonymous mutations of MYH7 gene were detected in the three pedigrees. CONCLUSION: The mutation of Thr441Met, located in the actin binding domain of the globular head, was first identified in Chinese. It probably caused HCM. HCM is a heterogeneous disease. Many factors are involved in the process of its occurrence and development. PMID- 21811977 TI - [Study on the mutations of phenylalanine hydroxylase gene in patients with phenylketonuria in Shanxi province]. AB - OBJECTIVE: To study the mutations in exons 3, 6, 7, 11 and 12 of the phenylalanine hydroxylase gene (PAH) in Shanxi population. METHODS: The mutations in exons 3, 6, 7, 11 and 12 and flanking sequences of PAH gene were detected by PCR-DNA sequencing, in 59 patients with phynelketonuria(PKU) and 100 healthy children from Shanxi province. RESULTS: By sequence analysis, three single nucleotide polymorphism (SNP) Q232Q (CAA>CAG), V245V (GTG>GTA) and L385L (CTG>CTC) were detected in both the patients and healthy children, with the frequencies of nt 696, 735 and 1155 of the PAH cDNA up to 96.2%, 76.1% and 7.6% in patients respectively, and 97.0%, 77.3% and 8.3% respectively in the healthy controls. In addition, 72 different mutations accounting for 61.0% of mutant alleles were identified in the patients only. In exon 3, R111X, H64>TfsX9 and S70 del were found accounting for 5.1%, 0.8% and 0.8%; EX6-96A>G in exon 6 was found accounting for 10.2%. In exon 7, R243Q was the highest incidence accounting for 12.7%, followed by Ivs7+2 T>A(5.1%) and T278I(2.5%); the lowest incidences were G247V, R252Q, L255S, R261Q and E280K accounting for 0.8 %, respectively. In exon 11, Y356X (5.9%) and V399V (5.1%) were found; in exon 12, R413P and A434D were found accounting for 5.9% and 2.5%. In total, 9 missense mutations, 3 splice site mutations, 2 nonsense mutations and 2 deletions were included in 16 kinds of different mutations. CONCLUSION: The mutation characteristics and distribution in exons 3, 6, 7, 11 and 12 of the PAH gene have been identified, and it suggested that the EX6-96A>G and R243Q were the hot spots of PAH gene mutations in Shanxi PKU population. PMID- 21811978 TI - [Molecular mechanism of an individual with weaken B phenotype in ABO blood group]. AB - OBJECTIVE: To elucidate the serological characteristics and molecular mechanism of a blood donor with weaken B antigen. METHODS: The ABO blood group antigens on red blood cells were identified by monoclonal antibodies, the ABO antibodies in serum were detected by standard A, B, O cells and the activity of the B glycosyltransferase was analyzed. The full-length sequence and 5'-untranslated region (5'-UTR) sequence of ABO gene were amplified by polymerase chain reaction (PCR) respectively and direct sequencing. The alternative splicing isoforms of ABO cDNA were obtained by reverse transcription-PCR(RT-PCR) and analyzed with cloning and sequencing techniques. The level of methylation of the CpG island in ABO gene promoter was analyzed by bisulfite sequencing method. RESULTS: The serological characteristic of the donor showed that the B antigen was decreased obviously without anti-B antibodies in serum and the B glycosyltransferase activity was decreased as well. The genotype of the donor was B101/O01 without any other mutations in the full-length coding sequences and splice receptor sites. The nucleotide characteristics of the 5'-UTR was consistent with B101/O01 and no any abnormity was identified in the promoter, enhancer and the negative regulatory sequence regions. The integrative cDNA transcript of ABO gene was obtained and no new splicing isoform was found. Compared with the normal B phenotype, a number of methylated CpG sites were found near the promoter of ABO gene in this sample. CONCLUSION: The methylation in the CpG island of ABO gene promoter region may cause weak expression of the B antigen. PMID- 21811979 TI - [Optimization of polymerase chain reaction assay combined with capillary electrophoresis to detect the pre- and full mutation of FMR1 gene]. AB - OBJECTIVE: To develop an efficient, high resolution PCR assay suitable for detection of the (CGG)n repeats of the fragile X mental retardation 1 (FMR1) gene by optimizing the PCR system in combination with capillary electrophoresis. METHODS: Three standard samples and twelve samples that were verified by Southern blot analysis including both male and female in the normal, pre- and full mutation range were used in this study to evaluate the enhanced PCR system. All amplicons were electrophoresed by agarose, polyacrylamide and capillary electrophoresis to compare the results. RESULTS: The enhanced PCR assay developed in this study was able to detect a full mutation with (CGG)n being larger than 260 repeats in a male. An expanded pre-mutation allele with (CGG)n as large as 183 repeats in a female was also amplified. The capillary electrophoresis method used in this study was able to distinguish two alleles with 1 CGG repeat difference and the results were reproducible. CONCLUSION: A high resolution PCR assay is developed, which is much more efficient than the general PCR systems. It is suitable for the clinical screening of FMR1 gene and will greatly reduce the number of Southern blot analysis needed in clinical application. PMID- 21811980 TI - [Advances of treatment for Duchenne muscular dystrophy with exon skipping]. AB - Duchenne muscular dystrophy (DMD) is a lethal muscular disorder caused by mutations in the dystrophin gene for which no mutation targeted therapy has been available so far. However, a new method named exon-skipping mediated by antisense oligonucleotides has considerable potential for DMD therapy. In this review, the principle, basic research and clinical research of exon-skipping are mainly summarized. PMID- 21811981 TI - [Analysis of GJB2 gene coding sequence in patients with nonsyndromic hearing loss]. AB - OBJECTIVE: To analyze the coding sequence of GJB2 gene in six pedigrees with nonsyndromic hearing loss in order to find deafness-causing mutations in the GJB2 gene, and to explore the inherent pattern of deafness-causing mutations in the GJB2 gene. METHODS: Genomic DNA was extracted from peripheral blood for the probands and their family members. Coding sequence of the GJB2 gene was amplified by polymerase chain reaction, sequence variations were determined by DNA sequencing. Amplified fragments with overlapping peaks on sequencing chromatogram were sequenced by TA cloning in order to determine whether the mutations originated from the same allele. RESULTS: Mutations in the GJB2 gene were found in 4 out of the 6 pedigrees with nonsyndromic hearing loss. Four types of mutations were detected in the GJB2 gene, which were 235delC, 299-300delAT, 79G>A+341A>G, and 109G>A. Compound heterozygous polymorphisms 79G>A and 341A>G, and mutations 109G>A and 235delC had deafness-causing effects. CONCLUSION: Heterogeneous mutations of the GJB2 gene are frequently seen in patients with nonsyndromic hearing loss. Sometimes, polymorphisms may cause deafness when they are combined. Environmental factors and other genes may contribute to hearing loss caused by the GJB2 gene mutations. PMID- 21811982 TI - [Clinical significance of large-scale screening of A1555G mutation of mitochondria DNA for neonates]. AB - OBJECTIVE: To explore the necessity of large-scale screening of mitochondria DNA (mtDNA) A1555G mutation for prevention of aminoglycoside antibiotic induced deafness in newborns. METHODS: One thousand blood filter samples were collected from neonates born in July 2008 in Shenzhen. DNA was extracted with Chelex-100 Resin and amplified by PCR. The mtDNA A1555G mutation was determined by denaturing high-performance liquid chromatography(DHPLC) for PCR products. The positive frequency was calculated. RESULTS: The mitochondrial DNA A1555G mutation was detected in 2 cases of 1000 neonates. The frequency of mutation was 0.2%. CONCLUSION: There is a high frequency of mtDNA A1555G mutation in neonates, the large-scale screening of mtDNAA1555G mutation in newborns might detect the individuals sensitive to aminoglycoside antibiotic, which is helpful to guide a rational medication for newborns and the maternal relatives at high-risk. Furthermore, it might be useful to prevent aminoglycoside antibiotic induced deafness. PMID- 21811983 TI - [Recombination between human leukocyte antigen -A and -C loci within two Chinese Han families]. AB - OBJECTIVE: To investigate the recombination events between human leukocyte antigen (HLA) loci within two families. METHODS: Identification of HLA-A, -C, -B, -DRB1 and -DQB1 loci was firstly carried out using polymerase chain reaction sequence specific oligonucleotide. Then HLA high resolution typing was performed using polymerase chain reaction sequencing-based typing. The recombination between HLA loci was identified by family genetic analysis. The parentage possibility was analyzed by short tandom repeat technique. RESULTS: Recombination between the HLA-A and C loci was identified within two families. One individual inherited a paternal haplotype that was the result of a recombination event between the father's HLA-A and -C loci on his chromosomes. The other individual inherited a maternal haplotype that was the result of a recombination event between the mother's HLA-A and -C loci. The high parentage possibilities were obtained in the family members. CONCLUSION: The recombination events of HLA-A and -C have been found in two Chinese families, which may help further study on the mechanism of HLA recombination. PMID- 21811984 TI - [Mutation analysis of KRT10 gene in a patient with bullous congenital ichthyosiform erythroderma]. AB - OBJECTIVE: To investigate the gene mutation in one sporadic case of bullous congenital ichthyosiform erythroderma (BCIE), and to explore the relationship between the genotype and phenotype. METHODS: DNA was extracted from the blood samples of the patient with BCIE, unaffected members of the pedigree, and 50 unrelated healthy controls. PCR was used to amplify the hot spot fragment of keratin 1 (KRT1) and keratin 10 (KRT10) gene. The PCR products were directly sequenced to detect the mutations. RESULTS: A heterozygous 467G>A mutation was found in the patient, resulting in the substitution of arginine (R) by histidine (H) in codon 156 (R156H) in the 1A domain of the KRT10 protein but not in the healthy individuals from the family and the 50 unrelated individuals. CONCLUSION: The mutation of 467G>A in exon 1 of KRT10 gene identified may play a major role in the pathogenic mechanism of this case of BCIE. PMID- 21811985 TI - [Cytogenetics and genome-wide copy number variation analysis of a suspect patient with Prader-Willi syndrome]. AB - OBJECTIVE: To definite the etiopathogenisis by carrying out the genome-wide copy number variation analysis for a suspect patient with Prader-Willi syndrome. METHODS: The peripheral blood was collected from the patient who was diagnosed as having Prader-Willi syndrome, as well as his parents for conventional cytogenetic G-banding and high resolution chromosome assay. Genomic DNA of the child patient was extracted from the blood to perform the genome-wide copy number variation analysis. RESULTS: There was a heterozygosis deletion of a 5Mb region in chromosome 15q11.2-q13.1 by the genome-wide copy number variation analysis, but no abnormality was observed in high resolution chromosome assay in the child patient and his parents. Baylay and Gesell developmental scale was assessed regularly; the results suggested that the IQ of the child patient was 60-70, according with the clinical feature of Prader-Willi syndrome. CONCLUSION: The heterozygosis deletion in chromosome 15q11.2-q13.1 is the cause of Prader-Willi syndrome in this family. Further molecular genetics detection can make up for the insufficiency in cytogenetics methods, when no abnormality is observed at the level of cytogenetics in patients with Prader-Willi syndrome. PMID- 21811986 TI - [Association of the polymorphisms in the promoter region of tumor necrosis factor alpha and interleukin 6 genes with schizophrenia]. AB - OBJECTIVE: To investigate the relationship between the -308G/A, -857C/T and 1031T/C of tumor necrosis factor alpha gene (TNF- alpha), -174G/C and -572C/G of interleukin-6 gene (IL-6) polymorphisms and schizophrenia. METHODS: Genomic DNA was isolated from the venous blood leukocytes of 346 unrelated patients with schizophrenia and 323 healthy unrelated individuals (control group). All of the polymorphisms were genotyped by PCR-restriction fragment length polymorphisms (PCR-RFLP). Genotype and allele frequencies were analyzed by SPSS13.0 software. RESULTS: There were significant differences in both allele and genotype frequencies of -857C/T of TNF-alpha gene between the schizophrenia and control groups (P< 0.05). The allele T of -857C/T in schizophrenia group was significantly higher than that in control group (chi-square was 9.414, P=0.002, OR=1.511, 95%CI:1.160-1.969). In addition, there were significant differences in the positive and negative syndrome scale (PANSS) total score and negative symptoms between the patients with different -857C/T genotypes, and the negative symptom score of TT genotype was significantly higher than that of CC genotype (P<0.05). CONCLUSION: There is an association between -857C/T of TNF-alpha gene and schizophrenia, individuals with T allele of -857C/T are susceptible to schizophrenia, and there is an association between -857C/T and negative symptom score. PMID- 21811987 TI - [A study on correlation between sperm DNA fragmentation index and age of male, various parameters of sperm and in vitro fertilization outcome]. AB - OBJECTIVE: To study the correlation between sperm DNA fragmentation index (DFI), age of male, various parameters of sperm, rates of fertilization, high quality embryo and pregnancy and implantation rates. METHODS: One hundred and eleven infertile couples were selected randomly, and DFI was tested by flow cytometry for the sperm used for IVF. The patients were divided into different groups according to the DFI scores. The results of each group were analyzed. RESULTS: The IVF normal fertilization was significantly lower in couples with sperm DFI over 10% (60.5%) than that in couples with DFI below 10% (70.1%) (P<0.05). Significantly positive correlation was found between DFI and the age of male (r=0.624, P<0.05). DFI was also significantly negatively correlated with the percentage of linearly progressive sperm (r=-0.360, P<0.05). There was no significant correlation between the rates of high quality cleaved embryos, pregnancy and implantation rate and sperm DFI. CONCLUSION: DFI scores are increased with male's age, and it can influence the sperm motility. DFI=10% can be considered as a critical point which can be used to estimate the clinical fertility rate of IVF. But it could not provide relative information about the rates of high quality embryos and pregnancy for infertile couples undergoing IVF procedure. PMID- 21811988 TI - [Association of rs1805127 polymorphism of KCNE1 gene with atrial fibrillation in Uigur population of Xinjiang]. AB - OBJECTIVE: To investigate the association between the polymorphism of potassium voltage-gated channel, Isk-related family, member 1 (KCNE1) gene and atrial fibrillation (AF) in Uigur patients of Xinjiang. METHODS: Three hundred and three patients with atrial fibrillation and 328 healthy controls were tested for the genotype for the KCNE1 gene SNP in the rs1805127 locus by polymerase chain reaction-restriction fragment length polymorphism. The risk factors were also included. RESULTS: The genotype frequencies of AA, AG and GG were 0.092 (28/303), 0.386 (117/303) and 0.522 (158/303) in the AF patients while they were 0.122(40/328), 0.485 (159/328) and 0.393 (129/328) in controls. There was significant difference in frequencies of the three genotypes (chi-square was 10.465, P=0.005) and G allele (0.715 vs. 0.636, chi-square was 8.907, P=0.003) between the AF and control groups. Logistic regression analysis showed that the KCNE1 polymorphism was the main risk factor of AF in Uigur population. The OR value of genotype GG was 1.55, the 95% CI: 0.73-3.27. CONCLUSION: For Uigur population, genetic polymorphism of rs1805127 locus of the KCNE1 gene may increase the risk of atrial fibrillation. PMID- 21811989 TI - [Clinical and laboratory investigation of patients with hematologic malignancies harboring der(1;7)(q10;p10)]. AB - OBJECTIVE: To investigate the clinical and laboratory characteristics of patients with various hematological malignancies harboring der(1;7)(q10;p10). METHODS: Bone marrow samples were collected and undergone short-time unstimulated culture and R-banding, and karyotyped by conventional cytogenetic assay (CCA). Megalokaryocytes were detected by streptavidin-AKP (SAP). Retrospective analyses including the clinical and laboratory data were performed. RESULTS: Nineteen of the 21 patients were male. Most of the patients are of older age. Thirteen cases (61.9%) were der(1;7)(q10;p10) without additional aberrations, 8(38.1%) patients had additional aberrations. Sixteen out of the 18 cases (88.9%) who underwent SAP analysis had diminutive megalokaryocyte, and lymphoid megalokaryocyte was found in 10 cases (55.6%). The der(1;7) patients manifested poor response to treatment. CONCLUSION: The der(1;7) patients demonstrated distinct male predominance, older age at diagnosis, and some clinically distinctive features. These patients showed poor prognosis. The cytogenetic abnormality, i.e., der(1;7)(q10;p10), can be used as a prognostic indicator. PMID- 21811990 TI - [Association of single nucleotide polymorphism of reduced folate carrier gene with susceptibility to acute leukemia]. AB - OBJECTIVE: To investigate the allele and genotype frequencies of reduced folate carrier gene (RFC) 80G/A polymorphism in Chinese patients with acute leukemia (AL) and healthy control children, and to provide clue for association between the single nucleotide polymorphism (SNP) of RFC and the occurrence of AL. METHODS: Bone marrow samples from 98 childhood patients with AL and peripheral blood samples from 135 healthy children were obtained to prepare complementary DNAs (cDNAs). The cDNAs were analyzed for the polymorphisms in RFC 80G/A by reverse transcriptase-polymerase chain reaction-denaturing gradient gel electrophoresis (RT-PCR-DGGE) and direct sequencing. RESULTS: The A allele frequencies of the AL patients and control children were 0.515 and 0.415, respectively (P< 0.05). Chi-square test confirmed a statistical significance of the association between RFC80 G/A and AL. CONCLUSION: RFC 80AA or GA genotype may contribute to increasing the susceptibility to AL. PMID- 21811991 TI - [Study on HLA nucleotide sequence matching in epitope positions among recipient donor pairs for allogenic hematopoietic stem-cell transplantation]. AB - OBJECTIVE: To analyze the human leukocyte antigens(HLA)-A, -B, -Cw, -DRB1 and DQB1 nucleotide sequences between patients waiting for allogenic hematopoietic stem-cell transplantation (HSCT) and donors in Chinese population, and to establish strategy for maximizing optimal donor selection. METHODS: HLA high resolution typing in a total of 537 recipient-donor pairs was determined by sequence based typing (SBT) method. The nucleotide BLAST tool was used to compare the nucleotide sequences among recipient-donor pairs. RESULTS: Only 16.20% (88/537) of recipient-donor pairs were found to fully match for nucleotide sequences of all HLA-A,-B,-Cw, -DRB1 and -DQB1 loci. Mismatch rate in single locus were 8.38% in HLA-A, 0.74% in HLA-B, 12.29% in HLA-C, 2.42% in HLA-DRB1, and 2.79% in HLA-DQB1, respectively. Mismatch rate in two or multiple HLA loci was 42.65%. Nonpermissive allele mismatch combinations (A 02:01-A 02:06, A 02:06 A 02:07, Cw 03:04-Cw 15:02, Cw 03:03-Cw 04:01, Cw 03:04-Cw 14:02, Cw 03:03-Cw 08:01, DRB1 04:03:01-DRB1 04:05) were detected in single mismatch HLA locus of recipient-donor pairs, mismatches of B 07:05:01-B 07:06, Cw 07:01:01-Cw 07:06 combinations outside of epitope positions were detected in two recipient-donor pairs. CONCLUSION: Our data suggested that attention should be paid in comparing nucleotide sequences between recipient and donor, and in distinguishing nucleotide sequence mismatches within and outside of the epitope positions. These results could serve as guidelines for donor selection. PMID- 21811992 TI - [Association of single nucleotide polymorphism on chromosome 12q24.31 with susceptibility to coronary artery disease]. AB - OBJECTIVE: To determine whether the single nucleotide polymorphism (SNP) on chromosome 12q24.31(rs2259816) is associated with coronary artery disease (CAD) in Han population of southwest China. METHODS: A case-control association study with 592 unrelated patients with coronary artery disease and 463 normal controls from Chinese Han population was performed. Genotype for the SNP on chromosome 12q24.31 (rs2259816) was determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: The genotypes of AA, AC, CC were both detected in the coronary artery disease group and the control group. The frequencies of A allele were 49.5% in case group and 43.8% in control group, showing statistically significant difference(OR=1.129, 95%CI:1.029-1.239, P=0.010). CONCLUSION: The replication study showed that the genetic polymorphism in rs2259816 is associated with coronary artery disease in Han population of southwest China. PMID- 21811994 TI - Variation in joint shape of osteoarthritic knees. AB - OBJECTIVE: To investigate the role of joint shape in knee osteoarthritis (OA) by determining which aspects of bone shape are different in OA knees compared with control knees. METHODS: Using a statistical shape model, we compared radiographs showing the shape of OA knees with radiographs showing the shape of control knees in a population of 609 women (1,218 knees) extracted from the Rotterdam Study. Furthermore, we used magnetic resonance imaging to compare the shape of knees with cartilage defects with the shape of knees without cartilage defects. RESULTS: Three statistical shape modes, referring to 3 distinct aspects of the shape of the knee, were significantly associated with the presence of radiographic OA (modes 2, 4, and 15). Mode 2 reflected the width of the femoral and tibial bones, which was increased in patients with OA. Knees with cartilage defects also had wider femoral and tibial bones compared with knees without cartilage defects. Mode 4 reflected the variation in flexion of the knee during radiography. OA knees were more extended compared with control knees. Mode 15 showed that patients with OA had an elevated lateral tibial plateau, which was associated with pain. CONCLUSION: In women, knees with OA were wider, more extended during radiography, and had an elevated lateral tibial plateau. These results show that the shape of the knee is involved in OA, which might lead to novel imaging biomarkers to monitor or predict knee OA. PMID- 21811993 TI - CXCL10 and its receptor CXCR3 regulate synovial fibroblast invasion in rheumatoid arthritis. AB - OBJECTIVE: CXCL10 is expressed in increased levels in highly invasive fibroblast like synoviocytes (FLS) from arthritic DA rats and from patients with rheumatoid arthritis (RA). This study was undertaken to analyze the role of CXCL10 and its receptor CXCR3 in regulation of the invasive properties of FLS. METHODS: FLS were isolated from synovial tissue of RA patients and from DA rats and arthritis resistant DA.F344(Cia5d) rats with pristane-induced arthritis. We used an in vitro model of invasion through Matrigel, which has been shown to correlate with articular damage in RA and in rat arthritis. FLS were cultured in the presence or absence of CXCL10, anti-CXCR3 antibody, or the CXCR3 inhibitor AMG487 and then studied for invasion, matrix metalloproteinase (MMP) production (MMPs 1-3), intracellular calcium influx, and cell morphology. RESULTS: DA rat FLS produced higher levels of CXCL10 compared with minimally invasive FLS from DA.F344(Cia5d) rats. CXCL10 treatment increased the invasiveness of FLS from DA.F344(Cia5d) rats by 2-fold, and this increase was blocked by anti-CXCR3. Both anti-CXCR3 and AMG487 reduced invasiveness of FLS from DA rats, by as much as 77%. AMG487 significantly reduced invasiveness of RA FLS (by 58%). CXCR3 blockade reduced levels of MMP-1 by 65%, inhibited receptor signaling (64-100% reduction in intracellular calcium influx), and interfered with actin cytoskeleton reorganization and lamellipodia formation in FLS from rats and RA patients. CONCLUSION: We describe and characterize a new autocrine/paracrine role of CXCL10/CXCR3 in the regulation of FLS invasion in rats with arthritis and in RA patients. These observations suggest that the CXCL10/CXCR3 axis is a potential new target for therapies aimed at reducing FLS invasion and its associated joint damage and pannus invasion and destruction in RA. PMID- 21811995 TI - Impaired dendritic cell proinflammatory cytokine production in psoriatic arthritis. AB - OBJECTIVE: The pathogenesis of psoriatic arthritis (PsA) remains poorly understood. The underlying chronic inflammatory immune response is thought to be triggered by unknown environmental factors potentially arising from a defective immune function. We undertook this study to determine whether an impaired acute inflammatory response by dendritic cells (DCs) might compromise the clearance of bacteria and predispose to chronic inflammation. METHODS: We determined cytokine production by DCs from healthy controls and from patients with rheumatoid arthritis, PsA, and psoriasis in response to Mycobacterium tuberculosis, Mycobacterium avium paratuberculosis, and a range of other bacteria and Toll-like receptor (TLR) ligands. Phenotypic differences involved in cellular responses against (myco)bacteria were determined by quantitative polymerase chain reaction and flow cytometry. RESULTS: The secretion of proinflammatory cytokines by PsA DCs was impaired upon in vitro challenge with mycobacteria and TLR-2 ligands. This impairment was associated with elevated serum levels of C-reactive protein. The expression of TLR-2 and other receptors known to mediate mycobacterial recognition was unaltered. In contrast, the intracellular TLR inhibitors suppressor of cytokine signaling 3 and A20 were more highly expressed in DCs from PsA patients. PsA DCs further demonstrated up-regulated levels of ATG16L1, NADPH oxidase 2, and LL37, which are molecules implicated in the immune response against intracellular bacteria. CONCLUSION: Our findings indicate that DCs from PsA patients have a disordered immune response toward some species of (myco)bacteria. This might predispose to impaired immune responses to, and in turn impaired clearance of, these bacteria, setting the stage for the chronic inflammation of joints, entheses, skin, and the gut. PMID- 21811996 TI - Factors influencing the efficacy of two injections of a pandemic 2009 influenza A (H1N1) nonadjuvanted vaccine in systemic lupus erythematosus. AB - OBJECTIVE: To assess the factors influencing the efficacy of 2 injections of a pandemic 2009 influenza A (H1N1) vaccine in patients with systemic lupus erythematosus (SLE). METHODS: We conducted a single-center, observational prospective study of 111 patients who were vaccinated with a monovalent, inactivated, nonadjuvanted, split-virus vaccine during December 2009 and January 2010 and received a second dose of vaccine 3 weeks later. The antibody response was evaluated using the hemagglutination inhibition assay according to the guidelines recommended for the pandemic vaccine, consisting of 3 immunogenicity criteria (i.e., a seroprotection rate of 70%, a seroconversion rate of 40%, and a geometric mean ratio [GMR] of 2.5). RESULTS: The 3 immunogenicity criteria were met on day 42 (seroprotection rate 80.0% [95% confidence interval (95% CI) 72.5 87.5%], seroconversion rate 71.8% [95% CI 63.4-80.2%], and GMR 10.3 [95% CI 2.9 14.2]), while only 2 criteria were met on day 21 (seroprotection rate 66.7% [95% CI 57.9-75.4%], seroconversion rate 60.4% [95% CI 51.3-69.5%], and GMR 8.5 [95% CI 3.2-12.0]). The vaccine was well tolerated. Disease activity, assessed by the Safety of Estrogens in Lupus Erythematosus National Assessment version of the SLE Disease Activity Index, the British Isles Lupus Assessment Group score, and the Systemic Lupus Activity Questionnaire, did not increase. In the multivariate analysis, vaccination failure was significantly associated with immunosuppressive treatment or a lymphocyte count of <= 1.0 * 109/liter. The second injection significantly increased the immunogenicity in these subgroups, but not high enough to fulfill the seroprotection criterion in patients receiving immunosuppressive treatment. CONCLUSION: Our findings indicate that the efficacy of the vaccine was impaired in patients who were receiving immunosuppressive drugs or who had lymphopenia. A second injection increased vaccine immunogenicity without reaching all efficacy criteria for a pandemic vaccine in patients receiving an immunosuppressive agent. These results open possibilities for improving anti-influenza vaccination in SLE. PMID- 21811997 TI - Effect of type of alcoholic beverage in causing acute pancreatitis. AB - BACKGROUND: The effect of different alcoholic beverages and drinking behaviour on the risk of acute pancreatitis has rarely been studied. The aim of this study was to investigate the effect of different types of alcoholic beverage in causing acute pancreatitis. METHODS: A follow-up study was conducted, using the Swedish Mammography Cohort and Cohort of Swedish Men, to study the association between consumption of spirits, wine and beer and the risk of acute pancreatitis. No patient with a history of chronic pancreatitis was included and those who developed pancreatic cancer during follow-up were excluded. Multivariable Cox proportional hazards models were used to estimate rate ratios. RESULTS: In total, 84,601 individuals, aged 46-84 years, were followed for a median of 10 years, of whom 513 developed acute pancreatitis. There was a dose-response association between the amount of spirits consumed on a single occasion and the risk of acute pancreatitis. After multivariable adjustments, there was a 52 per cent (risk ratio 1.52, 95 per cent confidence interval 1.12 to 2.06) increased risk of acute pancreatitis for every increment of five standard drinks of spirits consumed on a single occasion. The association weakened slightly when those with gallstone related pancreatitis were excluded. There was no association between consumption of wine or beer, frequency of alcoholic beverage consumption including spirits, or average total monthly consumption of alcohol (ethanol) and the risk of acute pancreatitis. CONCLUSION: The risk of acute pancreatitis was associated with the amount of spirits consumed on a single occasion but not with wine or beer consumption. PMID- 21811998 TI - Fetal transverse limb defects: case series and literature review. AB - PURPOSE: To investigate the incidence and outcome of antenatally diagnosed isolated transverse limb defects at a major tertiary center and to review the literature relevant to this rare condition. METHODS: This was a retrospective review of all cases (2000-2009) diagnosed with an isolated transverse limb defect referred to a tertiary fetal medicine center. Isolated transverse limb defects were defined as partial or complete absence of a part of one or more limbs in the absence of other abnormalities. RESULTS: Nine cases were identified. The upper limbs were affected in seven cases. The median gestational age at diagnosis was 22+5 weeks (range 21-29 weeks). The defects ranged from absence of digits to the absence of three limbs in one case. Four women opted to have termination of pregnancy. Postnatal and postmortem examination confirmed the ultrasound findings. No obvious risk factors could be identified in the majority of cases. CONCLUSIONS: Most cases of limb defects are believed to be secondary to a vascular insult occurring early in embryonic life. The reason for upper limb predominance remains unclear. Perinatal outcome in this series was poor with the majority of pregnancies terminated. Long-term functional outcome depends on the severity of the limb reduction defect. PMID- 21811999 TI - Prenatal 3D sonographic diagnosis of an isolated lateral facial cleft. AB - We report a case of lateral facial cleft (Tessier 7) diagnosed by sonography at a gestational age of 24 weeks. Two-dimensional sonography revealed a fetus appropriate for gestational age without obvious anomaly, but a three-dimensional sonogram with surface mode rendering showed asymmetrical macrostomia as a result of a left lateral facial cleft. Our case highlights the advantage of using three dimensional sonography in the prenatal diagnosis of lateral facial clefts. PMID- 21812000 TI - A case of pyruvate dehydrogenase E1alpha subunit deficiency with antenatal brain dysgenesis demonstrated by prenatal sonography and magnetic resonance imaging. AB - Prenatal depiction of brain dysgenesis in patients with pyruvate dehydrogenase complex (PDHc) deficiencies has been infrequently reported. As PDHc plays a critical role in the brain that obtains all of the energy from the aerobic oxidation of glucose, its deficiency is a severe inborn disorder of metabolism, which predominantly affects the nervous system. This report describes a case of PDHc deficiency with antenatal brain dysgenesis depicted in detail by fetal ultrasound and magnetic resonance imaging. This is the first case report clearly demonstrating the developing mechanism and time course of antenatal brain lesions in a patient with PDHc deficiency. PMID- 21812001 TI - Soft tissue chondromyxoid fibroma of the foot: sonographic findings. AB - Chondromyxoid fibroma is a rare benign bone tumor, which represents less than 1% of primary bone tumors. However, chondromyxoid fibroma developing in the soft tissue is extremely rare. We report the sonographic findings in a case of soft tissue chondromyxoid fibroma in the foot confirmed pathologically. PMID- 21812002 TI - Prenatal diagnosis of aortopulmonary window. AB - Aortopulmonary window (APW) is a rare congenital heart malformation. It refers to a connection between the ascending aorta and the pulmonary trunk before bifurcation. We report a case of APW that was detected by prenatal fetal echocardiography. The diagnosis was confirmed postnatally with an additional partial anomalous pulmonary venous connection. Corrective surgery was performed at the age of 1 week. Prenatal diagnosis of APW is important because an operation early after birth is required to prevent congestive heart failure due to high pulmonary blood flow. It is essential to visualize the aortopulmonary septum during fetal echocardiographic examination. PMID- 21812004 TI - Distribution characteristics of clarithromycin and azithromycin, macrolide antimicrobial agents used for treatment of respiratory infections, in lung epithelial lining fluid and alveolar macrophages. AB - The distribution characteristics of clarithromycin (CAM) and azithromycin (AZM), macrolide antimicrobial agents, in lung epithelial lining fluid (ELF) and alveolar macrophages (AMs) were evaluated. In the in vivo animal experiments, the time-courses of the concentrations of CAM and AZM in ELF and AMs following oral administration (50 mg/kg) to rats were markedly higher than those in plasma, and the area under the drug concentration-time curve (AUC) ratios of ELF/plasma of CAM and AZM were 12 and 2.2, and the AUC ratios of AMs/ELF were 37 and 291, respectively. In the in vitro transport experiments, the basolateral-to-apical transport of CAM and AZM through model lung epithelial cell (Calu-3) monolayers were greater than the apical-to-basolateral transport. MDR1 substrates reduced the basolateral-to-apical transport of CAM and AZM. In the in vitro uptake experiments, the intracellular concentrations of CAM and AZM in cultured AMs (NR8383) were greater than the extracellular concentrations. The uptake of CAM and AZM by NR8383 was inhibited by ATP depletors. These data suggest that the high distribution of CAM and AZM to AMs is due to the sustained distribution to ELF via MDR1 as well as the high uptake by the AMs themselves via active transport mechanisms. PMID- 21812003 TI - Tissue disposition of the insect repellent DEET and the sunscreen oxybenzone following intravenous and topical administration in rats. AB - The insect repellent N,N-diethyl-m-toluamide (DEET) and sunscreen oxybenzone (OBZ) have been shown to produce synergistic permeation enhancement when applied concurrently in vitro and in vivo. The disposition of both compounds following intravenous administration (2 mg/kg of DEET or OBZ) and topical skin application (100 mg/kg of DEET and 40 mg/kg of OBZ) was determined in male Sprague-Dawley rats. Pharmacokinetic analysis was also conducted using compartmental and non compartmental methods. A two-compartment model was deemed the best fit for intravenous administration. The DEET and oxybenzone permeated across the skin to accumulate in blood, liver and kidney following topical skin application. Combined use of DEET and oxybenzone accelerated the disappearance of both compounds from the application site, increased their distribution in the liver and significantly decreased the apparent elimination half-lives of both compounds (p < 0.05). Hepatoma cell studies revealed toxicity from exposure to all treatment concentrations, most notably at 72 h. Although DEET and oxybenzone were capable of mutually enhancing their percutaneous permeation and systemic distribution from topical skin application, there was no evidence of increased hepatotoxic deficits from concurrent application. PMID- 21812005 TI - Collection and storage of human blood and adipose for genomic analysis of clinical samples. AB - In this methods article, we describe collection and storage of clinically acquired blood and adipose samples for transcript analysis in an ongoing study exploring obesity in renal transplant recipients. Total ribonucleic acid (RNA) was isolated from whole blood using the LeukoLOCKTM Total RNA Isolation System (n = 4), and comparisons between fresh and frozen samples were made. Abdominal subcutaneous adipose samples (n = 4) were obtained during kidney transplantation, flash frozen, and stored at -80 degrees C. Adipose RNA was extracted using either the STAT-60 method modified for lipids or Trizol plus RNeasy extraction. Affymetrix HG-U133 plus 2.0 arrays and Affymetrix Human Gene 1.0 ST arrays were used for both blood and adipose transcriptome analysis. Purity, quality, and quantity of RNA were high with comparable results using both array platforms. PMID- 21812007 TI - Intravenous morphine and chest pain. PMID- 21812006 TI - Depressive symptoms and occupational stress among Chinese female nurses: the mediating effects of social support and rational coping. AB - The study reported here was designed to investigate the relationship between depressive symptoms and occupational stress in female nurses in China during the period June-July 2008. The hypothesis tested was that social support and rational coping would mediate the effects of occupational stress on depressive symptoms. Our structural equation modeling revealed that social support and rational coping were negatively correlated with depressive symptoms. Social support and rational coping mediated the effects of occupational stress on depressive symptoms. Role overload, role insufficiency, and role boundary were predictive of depressive symptoms. These results indicated that lessening occupational stress and strengthening social support and rational coping could decrease depressive symptoms among Chinese female nurses. PMID- 21812008 TI - Direct access midwifery booking for prenatal care and its role in Down syndrome screening. AB - OBJECTIVE: To compare the uptake of Down syndrome screening by women following referral by direct access and general practitioner (GP) modes. METHODS: The method of referral by either GP or direct access, for women who booked into prenatal care in Hull and East Yorkshire in 2010, was analysed using data collected from the Protos database at the Women and Children's Hospital, Hull. Subsequently, the uptake of first and second trimester screening for Down syndrome was reviewed by combining the Protos database to the screening data collected by the Clinical Biochemistry Laboratory at Hull Royal Infirmary, Hull. RESULTS: Women booked into prenatal care significantly earlier when referred by GP in comparison to direct access with a significant difference in screening uptake of 49.5 and 42.7%, respectively. The ratio of uptake between first and second trimester screening was not significantly different. CONCLUSIONS: Further research on the new direct access method of referral is required, as it may have a role in the uptake of prenatal screening for Down syndrome. More time is needed to show a definitive effect. PMID- 21812009 TI - Individual differences in the effects of mobile phone exposure on human sleep: rethinking the problem. AB - Mobile phone exposure-related effects on the human electroencephalogram (EEG) have been shown during both waking and sleep states, albeit with slight differences in the frequency affected. This discrepancy, combined with studies that failed to find effects, has led many to conclude that no consistent effects exist. We hypothesised that these differences might partly be due to individual variability in response, and that mobile phone emissions may in fact have large but differential effects on human brain activity. Twenty volunteers from our previous study underwent an adaptation night followed by two experimental nights in which they were randomly exposed to two conditions (Active and Sham), followed by a full-night sleep episode. The EEG spectral power was increased in the sleep spindle frequency range in the first 30 min of non-rapid eye movement (non-REM) sleep following Active exposure. This increase was more prominent in the participants that showed an increase in the original study. These results confirm previous findings of mobile phone-like emissions affecting the EEG during non-REM sleep. Importantly, this low-level effect was also shown to be sensitive to individual variability. Furthermore, this indicates that previous negative results are not strong evidence for a lack of an effect and, given the far reaching implications of mobile phone research, we may need to rethink the interpretation of results and the manner in which research is conducted in this field. PMID- 21812010 TI - Whole-genome expression analysis in primary human keratinocyte cell cultures exposed to 60 GHz radiation. AB - The main purpose of this study is to investigate potential responses of skin cells to millimeter wave (MMW) radiation increasingly used in the wireless technologies. Primary human skin cells were exposed for 1, 6, or 24 h to 60.4 GHz with an average incident power density of 1.8 mW/cm(2) and an average specific absorption rate of 42.4 W/kg. A large-scale analysis was performed to determine whether these exposures could affect the gene expression. Gene expression microarrays containing over 41,000 unique human transcript probe sets were used, and data obtained for sham and exposed cells were compared. No significant difference in gene expression was observed when gene expression values were subjected to a stringent statistical analysis such as the Benjamini-Hochberg procedure. However, when a t-test was employed to analyze microarray data, 130 transcripts were found to be potentially modulated after exposure. To further quantitatively analyze these preselected transcripts, real-time PCR was performed on 24 genes with the best combination of high fold change and low P-value. Five of them, namely CRIP2, PLXND1, PTX3, SERPINF1, and TRPV2, were confirmed as differentially expressed after 6 h of exposure. To the best of our knowledge, this is the first large-scale study reporting on potential gene expression modification associated with MMW radiation used in wireless communication applications. PMID- 21812011 TI - Microsecond and nanosecond electric pulses in cancer treatments. AB - New local treatments based on electromagnetic fields have been developed as non surgical and minimally invasive treatments of tumors. In particular, short electric pulses can induce important non-thermal changes in cell physiology, especially the permeabilization of the cell membrane. The aim of this review is to summarize the present data on the electroporation-based techniques: electrochemotherapy (ECT), nanosecond pulsed electric fields (nsPEFs), and irreversible electroporation (IRE). ECT is a safe, easy, and efficient technique for the treatment of solid tumors that uses cell-permeabilizing electrical pulses to enhance the activity of a non-permeant (bleomycin) or low permeant (cisplatin) anticancer drug with a very high intrinsic cytotoxicity. The most interesting feature of ECT is its unique ability to selectively kill tumor cells without harming normal surrounding tissue. ECT is already used widely in the clinics in Europe. nsPEFs could represent a drug free, purely electrical cancer therapy. They allow the inhibition of tumor growth, and interestingly, nsPEF can target intracellular organelles. However, many questions remain on the mechanism of action of these pulses. Finally, IRE is a new ablation procedure using pulses that provoke the permanent permeabilization of the cells resulting in their death. This technique does not result in any thermal effect, which is its main advantage in current physical ablation technologies. For both the nsPEF and the IRE, the preservation of the normal tissue, which is characteristic of ECT, has not yet been shown and their safety and efficacy still have to be investigated thoroughly in vivo and in the clinics. PMID- 21812012 TI - Extracellular ATP induces CD44 shedding from macrophage-like P388D1 cells via the P2X7 receptor. AB - The P2X7 receptor (P2X7R) is a nucleotide receptor expressed predominantly on hemopoietic, bone, and epithelial cells. The P2X7R can be activated by extracellular ATP and induces the influx of calcium, releases cytokines, and participates in cell proliferation and apoptosis. CD44 is an adhesion molecule. The effects of CD44 include cell-cell and cell-matrix adhesion interactions, lymphocyte activation, and cell migration. Many studies have shown that P2X7R and CD44 play important roles in hematological malignancies, but no study exists regarding the relationship between P2X7R and CD44. In the present study, we characterized P388D1 cells for the surface expression of CD44 and analyzed ATP induced shedding. The data showed that P388D1 cells express CD44. Incubation of P388D1 cells with ATP induced a rapid loss of CD44 from the P388D1 cell surface. In addition, using a receptor inhibitor and P2X7R short hairpin RNA, we showed that the loss of CD44 is mediated via the P2X7R. Finally, we demonstrated that activation of P2X7R by ATP induces CD44 shedding. PMID- 21812013 TI - Overexpression of apoptosis-associated speck-like protein in P388D1 murine lymphoma cells affects metastatic properties. AB - Apoptosis-associated speck-like protein (ASC) is a bipartite adaptor molecule that participates in inflammation and apoptosis. ASC silencing has been observed in a significant proportion of human cancers. Here, we examined the role of ASC overexpression in the metastasis of the P388D1 murine lymphoma cell line to the liver, lung, spleen and kidney. First, we determined that the P388D1 cells express ASC. Then, ASC overexpression in P388D1 was achieved by transfecting pEGFP-ASC-C2 into the P388D1 cells. Furthermore, after the ASC-overexpressing P388D1 cells were injected into DBA/2 mice through the vena caudalis, their metastasis to the lung and the liver was significantly reduced in the pEGFP-ASC C2-transfected group. These data indicate that ASC overexpression affects the in vivo metastatic properties of P388D1 cells. PMID- 21812014 TI - Immunophenotype distinction between acute promyelocytic leukaemia and CD15- CD34- HLA-DR- acute myeloid leukaemia with nucleophosmin mutations. AB - Acute promyelocytic leukaemia (APL) is a unique clinicobiologic entity that can be successfully treated with All-trans Retinoic Acid ATRA-based regimens. Some cases of acute myeloid leukaemia (AML) with nucleophosmin (NPM) mutations have an immunophenotype that is similar to APL. The objective of the study is to compare antigenic expression in a group of APL patients with that in AML patients with NPM mutations and an APL-like immunophenotype (CD15- CD34- HLA-DR-). A consecutive series of 40 APL and 12 NPM patients with an APL-like phenotype were included in the study. Immunophenotypic patterns were investigated by multiparametric flow cytometry. Promyelocytic leukaemia-retinoic acid receptor alpha transcript type, NPM and FLT3 mutations were investigated using conventional methods. Statistically significant differences were found between APL and NPM-mutated AML in CD33, CD13, CD2 and CD110 reactivity. CD2 expression was absent in every patient with NPM-mutated AML. In addition, mean fluorescence intensity and the coefficient of variation (cv) of CD33 and CD13 showed statistical differences between the two groups for CD33 (p = 0.007) and a trend to significance for CD13 (p = 0.05). Furthermore, among 45 evaluable patients, CD110 expression statistically differentiates between the two groups: [2/33 (6%) in the APL group and 8/12 (66.6%) in the NPM-mutated AML (p = 0.014)]. However, these traits were subtle, raising the possibility of practical diagnostic challenges. In conclusion, CD110 and CD33 reactivity may be useful to distinguish APL from NPM-mutated AML with CD15, CD34 and HLA-DR negativity. Nevertheless, cytogenetic and molecular characterization is necessary to establish the accurate diagnosis of AML. PMID- 21812015 TI - Antiallodynic effects of propentofylline Elicited by interrupting spinal glial function in a rat model of bone cancer pain. AB - The activation of microglia and astrocytes in the spinal cord is involved in the progress of cancer pain. Propentofylline (PPF), a glial modulating agent, alleviates pain hypersensitivity in neuropathic pain models. The present study investigated the potential roles of PPF in a preclinical rat model of bone caner pain established by inoculating Walker 256 cells into the left tibia. At day 9 postinoculation, single administration of PPF (10 MUg/10 MUl, i.t.) significantly but transiently suppressed mechanical allodynia induced by bone cancer. Repeated application of PPF (10 MUg/10 MUl, i.t., once daily from days 9 to 12) persistently relieved mechanical allodynia on the side ipsilateral to surgery. Immunohistochemistry and ELISA showed that microglia and astrocytes in the spinal cord were activated, and the production of glia-derived proinflammatory cytokines interleukin-1beta (IL-1beta), IL-6, and tumor necrosis factor-alpha (TNF-alpha) markedly increased at day 12 postinoculation in the cancer group. Intrathecal injection of PPF (10 MUg/10 MUl) significantly inhibited the activation of spinal glial cells and the expression of proinflammatory cytokines. These results suggest that the glial modulating agent PPF has antiallodynic effects on bone cancer pain and has potential utility for clinical treatment of cancer pain. PMID- 21812017 TI - Improved differential diagnosis of anemia of chronic disease and iron deficiency anemia: a prospective multicenter evaluation of soluble transferrin receptor and the sTfR/log ferritin index. AB - Anemia of chronic disease (ACD) and iron deficiency anemia (IDA) are the most prevalent forms of anemia and often occur concurrently. Standard tests of iron status used in differential diagnosis are affected by inflammation, hindering clinical interpretation. In contrast, soluble transferrin receptor (sTfR) indicates iron deficiency and is unaffected by inflammation. Objectives of this prospective multicenter clinical trial were to evaluate and compare the diagnostic accuracy of sTfR and the sTfR/log ferritin index (sTfR Index) for differential diagnosis using the automated Access((r)) sTfR assay (Beckman Coulter) and sTfR Index. We consecutively enrolled 145 anemic patients with common disorders associated with IDA and ACD. Subjects with IDA or ACD + IDA had significantly higher sTfR and sTfR Index values than subjects with ACD (P < 0.0001). ROC curves produced the following cutoffs for sTfR: 21 nmol/L (or 1.55 mg/L), and the sTfR Index: 14 (using nmol/L) (or 1.03 using mg/L). The sTfR Index was superior to sTfR (AUC 0.87 vs. 0.74, P < 0.0001). Use of all three parameters in combination more than doubled the detection of IDA, from 41% (ferritin alone) to 92% (ferritin, sTfR, sTfR Index). Use of sTfR and the sTfR Index improves detection of IDA, particularly in situations where routine markers provide equivocal results. Findings demonstrate a significant advantage in the simultaneous determination of ferritin, sTfR and sTfR Index. Obtaining a ferritin level alone may delay diagnosis of combined IDA and ACD. PMID- 21812018 TI - Rapid response of plasmacytomas to lenalidomide plus low-dose dexamethasone therapy in a patient with relapsed multiple myeloma. PMID- 21812016 TI - Axon-glia synapses are highly vulnerable to white matter injury in the developing brain. AB - The biology of cerebral white matter injury has been woefully understudied, in part because of the difficulty of reliably modeling this type of injury in rodents. Periventricular leukomalacia (PVL) is the predominant form of brain injury and the most common cause of cerebral palsy in premature infants. PVL is characterized by predominant white matter injury. No specific therapy for PVL is presently available, because the pathogenesis is not well understood. Here we report that two types of mouse PVL models have been created by hypoxia-ischemia with or without systemic coadministration of lipopolysaccharide (LPS). LPS coadministration exacerbated hypoxic-ischemic white matter injury and led to enhanced microglial activation and astrogliosis. Drug trials with the antiinflammatory agent minocycline, the antiexcitotoxic agent NBQX, and the antioxidant agent edaravone showed various degrees of protection in the two models, indicating that excitotoxic, oxidative, and inflammatory forms of injury are involved in the pathogenesis of injury to immature white matter. We then applied immunoelectron microscopy to reveal fine structural changes in the injured white matter and found that synapses between axons and oligodendroglial precursor cells (OPCs) are quickly and profoundly damaged. Hypoxia-ischemia caused a drastic decrease in the number of postsynaptic densities associated with the glutamatergic axon-OPC synapses defined by the expression of vesicular glutamate transporters, vGluT1 and vGluT2, on axon terminals that formed contacts with OPCs in the periventricular white matter, resulted in selective shrinkage of the postsynaptic OPCs contacted by vGluT2 labeled synapses, and led to excitotoxicity mediated by GluR2-lacking, Ca(2+) -permeable AMPA receptors. Overall, the present study provides novel mechanistic insights into the pathogenesis of PVL and reveals that axon-glia synapses are highly vulnerable to white matter injury in the developing brain. More broadly, the study of white matter development and injury has general implications for a variety of neurological diseases, including PVL, stroke, spinal cord injury, and multiple sclerosis. PMID- 21812019 TI - Inflammation, TNFalpha and endothelial dysfunction link lenalidomide to venous thrombosis in chronic lymphocytic leukemia. AB - Patients receiving lenalidomide are at an increased risk for deep venous thrombosis (DVT). Here, we prospectively investigated the DVT risk in patients with relapsed chronic lymphocytic leukemia (CLL) treated with lenalidomide (n = 32). Five patients developed six incidents of DVT over 1 year for an annual incidence of 16%. Three of these were considered drug-related. Median time to DVT was 105 days (range 56-259 days). No pulmonary embolism was detected. Hypercoagulability screen before study entry was negative in all patients who subsequently developed DVTs. Compared to normal volunteers CLL patients had increased baseline levels of D-dimer, thrombin-antithrombin, soluble vascular endothelial adhesion molecule 1 (sVCAM-1), and thrombomodulin (p < 0.001). After 1 week on lenalidomide D-dimer, thrombomodulin, sVCAM-1, factor VIII, TNFalpha, and C-reactive protein were significantly increased while protein C was decreased (p < 0.001). In patients with lenalidomide-related DVTs, TNFalpha, and sVCAM-1 were more strongly upregulated than in all other patients (p < 0.05) and TNFalpha and sVCAM-1 levels were significantly correlated (r = 0.65, p < 0.001). These data link lenalidomide associated DVTs with TNFalpha upregulation and endothelial cell dysfunction and suggest that aspirin may have a role for DVT prophylaxis in these patients. PMID- 21812020 TI - Laboratory evaluation of clopidogrel responsiveness by platelet function and genetic methods. AB - Clopidogrel is a widely used antiplatelet agent that irreversibly inhibits platelet P2Y12 ADP receptors after conversion to an active metabolite. There are a number of laboratory tests capable of detecting clopidogrel-induced platelet inhibition and published literature correlates suboptimal clopidogrel response to adverse cardiovascular outcomes. Genetic polymorphisms are thought to affect conversion of the prodrug to the active metabolite, and the FDA has recently added a black-box warning to clopidogrel to highlight the effects of these polymorphisms on drug bioavailability and to inform prescribers about the availability of genetic testing. For these reasons, there is growing interest in the use of laboratory tests to monitor patients treated with clopidogrel. This article summarizes the currently available laboratory testing, including platelet function tests and genotyping for CYP2C19 variants. PMID- 21812021 TI - Increasing breeding behaviors in a captive colony of Northern Bald Ibis through conspecific acoustic enrichment. AB - The goal of this study was to increase reproductive behaviors in a captive colony of Northern Bald Ibis (Geronticus eremita) at the Bronx Zoo. The Northern Bald Ibis is classified as critically endangered by the IUCN, with only about 100 known breeding pairs in the wild. Our analysis of zoo breeding and colony size data confirmed earlier observations that small captive colonies of this species do not breed as well as larger colonies, possibly because of insufficient social cues. Using principles from social facilitation theory, we attempted to provide such social cues by presenting acoustic enrichment in the form of conspecific breeding vocalization playbacks. In May 2009, we tracked multiple breeding behaviors during playbacks and control periods. Although breeding behaviors increased in response to playbacks, the colony produced no eggs. We repeated this experiment in April 2010 using playbacks of higher quality recordings acquired from a semi-wild breeding colony of Northern Bald Ibis in Austria. Breeding behaviors again increased during playbacks. In addition, five pairs in this colony of 15 birds produced 13 eggs, and six chicks successfully fledged--the first reproductive success in this colony since 2007. The acoustic enrichment techniques we employed may encourage increased breeding activity in captive populations of colonial species as well as wild colonies with small populations. PMID- 21812022 TI - Secretory pattern of inhibin during estrous cycle and pregnancy in African (Loxodonta africana) and Asian (Elephas maximus) elephants. AB - The ovary of female elephants has multiple corpora lutea (CL) during the estrous cycle and gestation. The previous reports clearly demonstrated that inhibin was secreted from lutein cells as well as granulosa cells of antral follicles in cyclic Asian elephants. The aim of this study is to investigate the inhibin secretion during the pregnancy in African and Asian elephants. Two African elephants and two Asian elephants were subjected to this study. Circulating levels of immunoreactive (ir-) inhibin and progesterone were measured by radioimmunoassay. Four pregnant periods of an African elephant and three pregnant periods of an Asian elephant were analyzed in this study. Circulating levels of ir-inhibin started to increase at 1 or 2 week before the ovulation and reached the peak level 3 or 4 weeks earlier than progesterone during the estrous cycle in both African and Asian elephants. After last luteal phase, the serum levels of ir inhibin remained low throughout pregnancy in both an African and an Asian elephant. The mean levels of ir-inhibin during the pregnancy were lower than the luteal phase in the estrous cycle despite high progesterone levels were maintained throughout the pregnancy. These results strongly suggest that CL secrete a large amount of progesterone but not inhibin during the pregnancy in elephants. PMID- 21812023 TI - Morphology of the human vertebral endplate. AB - It is presumed that poor intervertebral disc cell nutrition is a contributing factor in degeneration, and is exacerbated by vertebral endplate sclerosis. Yet, quantitative relationships between endplate morphology and degeneration are unavailable. We investigated how endplate bone microstructure relates to indices of disc degeneration, such as morphologic grade, proteoglycan content, and cell density. Intervertebral core samples [n = 96, 14 subjects, L1-L5 level, ages 35 85 (64 +/- 16 years), degeneration grade 1 (n = 4), grade 2 (n = 32), grade 3 (n = 44), grade 4 (n = 10), grade 5 (n = 6)] that included subchondral bone, cartilage endplate, and adjacent nucleus were harvested from human cadaveric lumbar spines. The morphology of the vertebral endplate was analyzed using uCT and the adjacent nucleus tissue was collected for biochemical and cellular analyses. Relationships between vertebral endplate morphology and adjacent disc degeneration were analyzed. Contrary to the prevailing notion, vertebral endplate porosity increased between 50% and 130% and trabecular thickness decreased by between 20% and 50% with advancing disc degeneration (p < 0.05). We also observed that nucleus cell density increased (R(2) = 0.33, p < 0.05) and proteoglycan content decreased (R(2) = 0.47, p < 0.05) as the endplate became more porous. Our data suggest that endplate sclerosis is not a fundamental factor contributing to disc degeneration. Rather, the opposite was observed in our samples, as the endplate became progressively more porous with age and degeneration. Since ischemic disc cell behavior is commonly associated with degenerative change, this may be related to other factors such as the quality of vertebral capillaries, as opposed to decreased permeability of intervening tissues. PMID- 21812024 TI - Patients with patellofemoral pain exhibit elevated bone metabolic activity at the patellofemoral joint. AB - Patellofemoral pain is characterized by pain behind the kneecap and is often thought to be due to high stress at the patellofemoral joint. While we cannot measure bone stress in vivo, we can visualize bone metabolic activity using (18) F NaF PET/CT, which may be related to bone stress. Our goals were to use (18) F NaF PET/CT to evaluate whether subjects with patellofemoral pain exhibit elevated bone metabolic activity and to determine whether bone metabolic activity correlates with pain intensity. We examined 20 subjects diagnosed with patellofemoral pain. All subjects received an (18) F NaF PET/CT scan of their knees. Uptake of (18) F NaF in the patella and trochlea was quantified by computing the standardized uptake value and normalizing by the background tracer uptake in bone. We detected increased tracer uptake in 85% of the painful knees examined. We found that the painful knees exhibited increased tracer uptake compared to the pain-free knees of four subjects with unilateral pain (P = 0.0006). We also found a correlation between increasing tracer uptake and increasing pain intensity (r(2) = 0.55; P = 0.0005). The implication of these results is that patellofemoral pain may be related to bone metabolic activity at the patellofemoral joint. PMID- 21812025 TI - Edge-loading severity as a function of cup lip radius in metal-on-metal total hips--a finite element analysis. AB - While favorable tribological properties and allowance for larger femoral head sizes have made metal-on-metal (MoM) bearings an increasingly popular choice for total hip arthroplasty, concerns have mounted regarding adverse reactions to metal wear debris and ions. MoM cups differ from conventional polyethylene cups in terms of edge profile design and reductions from full hemisphericity, suggesting differences in loading at or near the cup edge, especially during subluxation events. Finite element analysis was used to investigate the effects of cup orientation and lip edge curvature on damage propensity for edge or near edge loading during subluxation. Increased cup lip radius (resulting in reduced articular arc) had a detrimental effect upon subluxation-free hip range of motion and upon dislocation resistance. Contact stresses near the cup edge demonstrated complex relationships between edge radius and cup orientation, with peak stresses being influenced by both variables. The tendency for scraping wear at the egress site demonstrated similarly complex dependencies. These data indicate that acetabular cup design is an important determinant of edge and near-edge loading damage propensity. PMID- 21812026 TI - FGF receptors control vitamin D and phosphate homeostasis by mediating renal FGF 23 signaling and regulating FGF-23 expression in bone. AB - The functional interaction between fibroblast growth factor 23 (FGF-23) and Klotho in the control of vitamin D and phosphate homeostasis is manifested by the largely overlapping phenotypes of Fgf23- and Klotho-deficient mouse models. However, to date, targeted inactivation of FGF receptors (FGFRs) has not provided clear evidence for an analogous function of FGFRs in this process. Here, by means of pharmacologic inhibition of FGFRs, we demonstrate their involvement in renal FGF-23/Klotho signaling and elicit their role in the control of phosphate and vitamin D homeostasis. Specifically, FGFR loss of function counteracts renal FGF 23/Klotho signaling, leading to deregulation of Cyp27b1 and Cyp24a1 and the induction of hypervitaminosis D and hyperphosphatemia. In turn, this initiates a feedback response leading to high serum levels of FGF-23. Further, we show that FGFR inhibition blocks Fgf23 transcription in bone and that this is dominant over vitamin D-induced Fgf23 expression, ultimately impinging on systemic FGF-23 protein levels. Additionally, we identify Fgf23 as a specific target gene of FGF signaling in vitro. Thus, in line with Fgf23- and Klotho-deficient mouse models, our study illustrates the essential function of FGFRs in the regulation of vitamin D and phosphate levels. Further, we reveal FGFR signaling as a novel in vivo control mechanism for Fgf23 expression in bone, suggesting a dual function of FGFRs in the FGF-23/Klotho pathway leading to vitamin D and phosphate homeostasis. PMID- 21812027 TI - Determinants of serum sclerostin in healthy pre- and postmenopausal women. AB - Sclerostin is a secreted Wnt antagonist produced almost exclusively by osteocytes that regulates bone mass. However, there is currently limited information on the determinants of sclerostin in a large population-based study. The main objectives of the present study were to: (1) establish reference normative interval values for serum sclerostin in randomly selected healthy premenopausal women; (2) study the changes in serum sclerostin in relation to age in premenopausal and postmenopausal women and the factors that may influence bone turnover; and (3) determine the effect of menopausal status on serum sclerostin. A total of 1803 women were studied (including [n = 1235] premenopausal, and [n = 568] postmenopausal women, respectively, aged 20 to 79 years). A total of 443 healthy premenopausal women (aged 35 to 45 years) were used to establish reference normative intervals for serum sclerostin. All women studied were medically examined and had their bone mineral density values obtained for the lumbar spine (L(1) -L(4) ) and femoral neck according to a detailed inclusion criteria. In all women, values of serum sclerostin increased with increasing age up to the age of 45 years, and remained increased in postmenopausal women. Significant increases were evident in serum sclerostin in postmenopausal women with increasing years since menopause. Using stepwise multiple linear regression analysis, several variables were identified as determinants of serum sclerostin, including age, parathyroid hormone, estradiol (E(2)), and follicle-stimulating hormone (FSH) for premenopausal women; age, FSH, and E(2) for postmenopausal women; and age, serum osteocalcin, FSH, and E(2) in the entire sample studied. Further studies are needed to establish the potential role of this increase in mediating the known age-related impairment in bone formation. PMID- 21812028 TI - Nicotinamide phosphoribosyltransferase (Nampt) affects the lineage fate determination of mesenchymal stem cells: a possible cause for reduced osteogenesis and increased adipogenesis in older individuals. AB - Human aging is associated with a progressive decline in bone mass and an accumulation of marrow fat. We found that osteoblast differentiation was reduced and adipocyte formation increased in bone marrow stromal cells derived from aged mice compared with young controls. The increased adipogenesis correlated with a relatively lower Sirt1 activity and a lower intracellular NAD(+) concentration. We suppose that these effects were caused by age-related reduction of nicotinamide phosphoribosyltransferase (Nampt), the enzyme catalyzing NAD resynthesis from nicotinamide (NAM). In support of this hypothesis, treatment with Nampt inhibitor FK866 increased adipocyte formation and reduced mineralization in primary cultured bone marrow stromal cells. In addition, knockdown of Nampt in the mouse mesenchymal cell line C3H10T1/2 cells resulted in decreased Sirt1 activity and enhanced adipogenesis. Interestingly, although Nampt deficiency resulted in both decreased intracellular NAD(+) and increased NAM, the cell differentiation could be controlled only by regulation of NAM. These results indicate that the lineage fate determination of mesenchymal stem cells (MSCs) is influenced by cell energy metabolism and points to a possible mechanism for the development of senile osteoporosis. Furthermore, we suggest that side effects on bone should be considered when evaluating the long-term safety of NAD-interfering pharmaceuticals. PMID- 21812029 TI - Heterozygous inactivation of Gnas in adipose-derived mesenchymal progenitor cells enhances osteoblast differentiation and promotes heterotopic ossification. AB - Human genetic disorders sharing the common feature of subcutaneous heterotopic ossification (HO) are caused by heterozygous inactivating mutations in GNAS, a gene encoding multiple transcripts including two stimulatory G proteins, the alpha subunit of the stimulatory G protein (G(s)alpha) of adenylyl cyclase, and the extralong form of G(s)alpha, XLalphas. In one such disorder, progressive osseous heteroplasia (POH), bone formation initiates within subcutaneous fat before progressing to deeper tissues, suggesting that osteogenesis may involve abnormal differentiation of mesenchymal precursors that are present in adipose tissues. We determined by immunohistochemical analysis that GNAS protein expression is limited to G(s)alpha in bone-lining cells and to G(s)alpha and XLalphas in osteocytes. By contrast, the GNAS proteins G(s)alpha, XLalphas, and NESP55 are detected in adipocytes and in adipose stroma. Although Gnas transcripts, as assessed by quantitative RT-PCR, show no significant changes on osteoblast differentiation of bone-derived precursor cells, the abundance of these transcripts is enhanced by osteoblast differentiation of adipose-derived mesenchymal progenitors. Using a mouse knockout model, we determined that heterozygous inactivation of Gnas (by disruption of the G(s)alpha-specific exon 1) abrogates upregulation of multiple Gnas transcripts that normally occurs with osteoblast differentiation in wild-type adipose stromal cells. These transcriptional changes in Gnas(+/-) mice are accompanied by accelerated osteoblast differentiation of adipose stromal cells in vitro. In vivo, altered osteoblast differentiation in Gnas(+/-) mice manifests as subcutaneous HO by an intramembranous process. Taken together, these data suggest that Gnas is a key regulator of fate decisions in adipose-derived mesenchymal progenitor cells, specifically those which are involved in bone formation. PMID- 21812030 TI - Trabecular and cortical bone density and architecture in women after 60 days of bed rest using high-resolution pQCT: WISE 2005. AB - Prolonged bed rest is used to simulate the effects of spaceflight and causes disuse-related loss of bone. While bone density changes during bed rest have been described, there are no data on changes in bone microstructure. Twenty-four healthy women aged 25 to 40 years participated in 60 days of strict 6-degree head down tilt bed rest (WISE 2005). Subjects were assigned to either a control group (CON, n = 8), which performed no countermeasures; an exercise group (EXE, n = 8), which undertook a combination of resistive and endurance training; or a nutrition group (NUT, n = 8), which received a high-protein diet. Density and structural parameters of the distal tibia and radius were measured at baseline, during, and up to 1 year after bed rest by high-resolution peripheral quantitative computed tomography (HR-pQCT). Bed rest was associated with reductions in all distal tibial density parameters (p < 0.001), whereas only distal radius trabecular density decreased. Trabecular separation increased at both the distal tibia and distal radius (p < 0.001), but these effects were first significant after bed rest. Reduction in trabecular number was similar in magnitude at the distal radius (p = 0.021) and distal tibia (p < 0.001). Cortical thickness decreased at the distal tibia only (p < 0.001). There were no significant effects on bone structure or density of the countermeasures (p >= 0.057). As measured with HR pQCT, it is concluded that deterioration in bone microstructure and density occur in women during and after prolonged bed rest. The exercise and nutrition countermeasures were ineffective in preventing these changes. PMID- 21812032 TI - Hereditary vitamin D-resistant rickets (HVDRR) owing to a heterozygous mutation in the vitamin D receptor. AB - Hereditary vitamin D-resistant rickets (HVDRR) is a rare autosomal recessive disease caused by mutations in the vitamin D receptor (VDR). Patients exhibit severe rickets and hypocalcemia. Heterozygous parents and siblings appear normal and exhibit no symptoms of the disease. We analyzed the VDR gene of a young girl who exhibited the clinical features of HVDRR without alopecia. The patient had clinical and radiographic features of rickets, hypocalcemia, and elevated serum concentrations of 1,25-dihydroxyvitamin D [1,25(OH)(2)D]. A single heterozygous missense mutation was found in the VDR gene that substituted glutamic acid with alanine at amino acid 420 (E420A). Sequencing of the girl's VDR cDNAs showed that the f/M1 allele contained the E420A mutation, whereas the F/M4 allele was completely normal. The girl's father, who was also heterozygous for the E420A mutation on the f/M1 allele, exhibited minor symptoms of vitamin D resistance. In contrast, the mother had no signs of the disease and had no mutations in her VDR gene. Both the girl and the father's skin fibroblasts showed resistance to 1,25(OH)(2)D(3) by their severely reduced induction of CYP24A1 gene expression. In transactivation assays, the E420A mutant VDR showed dominant-negative activity towards the wild-type VDR. This is the first report that we are aware of describing a patient with HVDRR caused by a single heterozygous missense mutation in the VDR gene. The E420A mutant appears to act in a dominant-negative fashion, silencing the wild-type VDR and resulting in an attenuated response to 1,25(OH)(2)D(3). PMID- 21812033 TI - An anatomic study of the quadratus plantae in relation to tendinous slips of the flexor hallucis longus for gait analysis. AB - The aim of this study was to demonstrate the morphology of the quadratus plantae (QP) in relation to the tendinous slips of the flexor hallucis longus (FHL) and their surrounding structures, thereby providing data to understand function of the QP during gait, and for analyzing the movements of the foot and designing postoperative rehabilitation programs. The QP was investigated in 50 specimens of embalmed adult cadavers. The QP inserted into the tendon of the flexor digitorum longus (FDL) and the tendinous slips of the FHL in 96%, and only to the tendon of the FDL in 4%. The tendinous slip of the FHL targeted the tendon for the second toe in 4 of the 50 specimens (8%). The tendinous slip divided into two separate slips to the tendons for the second and third toes in 32 specimens (64%), and for the second, third, and fourth toes in 14 specimens (28%). Thus, the tendon and tendinous slips of the FHL may distribute the load of the great toe to the second toe to the third or fourth toe in the forefoot, especially during toe-off. In addition, the main attachment of the QP to the tendinous slips of the FHL may provide more efficient control of the long flexor tendons in comparison with that of the QP to the tendon of the FDL. PMID- 21812034 TI - The PLA2G6 gene in early-onset Parkinson's disease. AB - BACKGROUND: The definite etiology of neurodegenerative disorders such as Parkinson's disease (PD) is still unknown. Because of its role in the generation of reactive oxygen species and its association with neurodegeneration with brain iron accumulation, a possible involvement of calcium-independent group VI phospholipase A(2) (iPLA(2)-VI) in the pathogenesis of PD has been proposed. METHODS: In this study we analyzed all 17 exons of the PLA2G6 gene encoding iPLA(2)-VI in a group of 102 discordant pairs with early-onset Parkinson's disease (EOPD) and an additional sample of 166 EOPD patients and 155 unrelated controls. RESULTS: The nonsynonymous single-nucleotide polymorphisms (SNPs) 2339A>G (n = 2) and 2341G>A (n = 1) in 2 neighboring codons were found in 3 patients with typical L-dopa-responsive sporadic EOPD and in none of our controls, indicating a possible role of PLA2G6 in the pathogenesis of EOPD in rare cases. CONCLUSIONS: Future studies should investigate the prevalence of these SNPs in other PD populations and larger control groups and also address possible genetic alterations in the remaining parts of the PLA2G6 gene. PMID- 21812035 TI - Parkinson's disease: What remains of the "missing heritability"? PMID- 21812031 TI - Hypoparathyroidism in the adult: epidemiology, diagnosis, pathophysiology, target organ involvement, treatment, and challenges for future research. AB - Recent advances in understanding the epidemiology, genetics, diagnosis, clinical presentations, skeletal involvement, and therapeutic approaches to hypoparathyroidism led to the First International Workshop on Hypoparathyroidism that was held in 2009. At this conference, a group of experts convened to discuss these issues with a view towards a future research agenda for this disease. This review, which focuses primarily on hypoparathyroidism in the adult, provides a comprehensive summary of the latest information on this disease. PMID- 21812036 TI - Disruption of astrocytic glutamine turnover by manganese is mediated by the protein kinase C pathway. AB - Manganese (Mn) is a trace element essential for normal human development and is required for the proper functioning of a variety of physiological processes. Chronic exposure to Mn can cause manganism, a neurodegenerative disorder resembling idiopathic Parkinson's disease (PD). Mn(II) neurotoxicity is characterized by astrocytic impairment both in the expression and activity of glutamine (Gln) transporters. Because protein kinase C (PKC) activation leads to the downregulation of a number of neurotransmitter transporters and Mn(II) increases PKC activity, we hypothesized that the PKC signaling pathway contributes to the Mn(II)-mediated disruption of Gln turnover. Our results have shown that Mn exposure increases the phosphorylation of both the PKCalpha and PKCdelta isoforms. PKC activity was also shown to be increased in response to Mn(II) treatment. Corroborating our earlier observations, Mn(II) also caused a decrease in Gln uptake. This effect was blocked by PKC inhibitors. Notably, PKC activation caused a decrease in Gln uptake mediated by systems ASC and N, but had no effect on the activities of systems A and L. Exposure to alpha-phorbol 12 myristate 13-acetate significantly decreased SNAT3 (system N) and ASCT2 (system ASC) protein levels. Additionally, a co-immunoprecipitation study demonstrated the association of SNAT3 and ASCT2 with the PKCdelta isoform, and Western blotting revealed the Mn(II)-mediated activation of PKCdelta by proteolytic cleavage. PKC activation was also found to increase SNAT3 and ubiquitin ligase Nedd4-2 binding and to induce hyperubiquitination. Taken together, these findings demonstrate that the Mn(II)-induced dysregulation of Gln homeostasis in astrocytes involves PKCdelta signaling accompanied by an increase in ubiquitin mediated proteolysis. PMID- 21812037 TI - Predicting pediatric posttraumatic stress disorder after road traffic accidents: the role of parental psychopathology. AB - This study examined prospectively the role of parental psychopathology among other predictors in the development and persistence of posttraumatic stress disorder (PTSD) in 57 hospitalized youths aged 7-18 years immediately after a road traffic accident and 1 and 6 months later. Self report questionnaires and semistructured diagnostic interviews were used in all 3 assessments. Neuroendocrine evaluation was performed at the initial assessment. Maternal PTSD symptomatology predicted the development of children's PTSD 1 month after the event, OR = 6.99, 95% CI [1.049, 45.725]; the persistence of PTSD 6 months later was predicted by the child's increased evening salivary cortisol concentrations within 24 hours of the accident, OR = 1.006, 95% CI [1.001, 1.011]. Evaluation of both biological and psychosocial predictors that increase the risk for later development and maintenance of PTSD is important for appropriate early prevention and treatment. PMID- 21812038 TI - A nanogenerator for energy harvesting from a rotating tire and its application as a self-powered pressure/speed sensor. PMID- 21812039 TI - ZnO-microrod/p-GaN heterostructured whispering-gallery-mode microlaser diodes. PMID- 21812040 TI - Syntheses of Group 4 ansa-trovacene complexes and conversion of [1]silatrovacenophanes into paramagnetic metallopolymers by ring-opening polymerization. AB - An improved protocol for the selective dilithiation of [V(eta(5)-C(5)H(5))(eta(7) C(7)H(7))] has been developed, which afforded [V(eta(5)-C(5)H(4)Li)(eta(7) C(7)H(6)Li)].PMDTA (5; PMDTA=N,N,N',N'',N''-pentamethyldiethylenetriamine) in almost quantitative yield (98%). In the solid state, the species features a dimeric structure with two terminal and two bridging lithium atoms, with the latter connecting both sandwich subunits. Reaction with suitable Group 4 dihalide compounds enabled the isolation of highly strained silicon- and germanium-bridged [1]trovacenophanes 6 and 7. Similarly, reaction of 5 with Cl(2)Sn(2)tBu(4) afforded the rather unstrained complex [V(eta(5)-C(5)H(4))(eta(7) C(7)H(6))Sn(2)tBu(4)] (8), which together with 7 represent the first trovacenophanes to incorporate heavier analogues of silicon in the ansa-bridge. Ring-opening polymerization reactions of [V(eta(5)-C(5)H(4))(eta(7) C(7)H(6))SiRR'] (2a: R=R'=Me; 6: R=Me, R'=iPr) were performed by heating in a solution of toluene in the presence of the Karstedt catalyst, which resulted in the formation of the corresponding soluble poly(trovacenylsilanes) in yields of 41 and 33%, respectively. As estimated by gel permeation chromatography (GPC), the macromolecules possess molecular weights of M(n)=10,010 and 5580 g mol(-1) with polydispersity indices of 2.31 and 1.64 for 9 and 10, respectively. ESR spectroscopic studies on 9 and 10 revealed only a single broad resonance in each case without any identifiable (51)V hyperfine coupling. PMID- 21812041 TI - New molecular markers for prostate tumor imaging: a study on 2-methylene substituted fatty acids as new AMACR inhibitors. AB - The development of prostate carcinoma is associated with alterations in fatty acid metabolism. alpha-Methylacyl-CoA racemase (AMACR) is a peroxisomal and mitochondrial enzyme that catalyses interconversion between the (S)/(R)-isomers of a range of alpha-methylacyl-CoA thioesters. AMACR is involved in the beta oxidation of the dietary branched-chain fatty acids and bile acid intermediates. It is highly expressed in prostate (more than 95 %), colon (92 %), and breast cancers (44 %) but not in the respective normal or hyperplastic tissues. Thus, targeting of AMACR could be a new strategy for molecular imaging and therapy of prostate and some other cancers. Unlabeled 2-methylenacyl-CoA thioesters (12 a-c) were designed as AMACR binding ligands. The thioesters were tested for their ability to inhibit the AMACR-mediated epimerization of (25R)-THC-CoA and were found to be strong AMACR inhibitors. Radioiodinated (E)-(131) I-13-iodo-2 methylentridec-12-enoic acid ((131) I-7 c) demonstrated preferential retention in AMACR-positive prostate tumor cells (LNCaP, LNCaP C4-2wt and DU145) compared with both AMACR-knockout LNCaP C4-2 AMACR-siRNA and benign BPH1 prostate cell lines. A significant protein-bound radioactive fraction with main bands at 47 (sum of molecular weights of AMACR plus 12 c), 70, and 75 kDa was detected in LNCaP C4-2 wt cells. In contrast, only negligible amounts of protein-bound radioactivity were found in LNCaP C4-2 AMACR-siRNA cells. PMID- 21812042 TI - Inorganic Sn-X-complex-induced 1D, 2D, and 3D copper sulfide superstructures from anisotropic hexagonal nanoplate building blocks. AB - A facile route was demonstrated for inorganic Sn-X-complex-induced syntheses of self-assembled 1D columnar, 2D raftlike, and 3D stratiform anisotropic Cu(2)S hexagonal nanoplates. The factors (reaction time, temperature, the concentration of Sn-X complex, and so on) that influence the size, phase, monodispersity, and self-assembly ability of the Cu(2)S hexagonal nanoplates were studied in detail. It was found that the Sn-X complex could inhibit the growth of the <001> direction of monoclinic Cu(2)S nanocrystals, which further induced the formation of the hexagonal lamellar structure. Furthermore, it revealed that the formation of the 1D arrangement was preferred as particles stacked in a face-to-face configuration by maximizing ligand-surface interactions. Then, high ligand density along the side of the 1D columnar arrangement induced well-defined 2D raftlike and 3D stratiform self-assembly. PMID- 21812043 TI - Pd-catalyzed orthogonal Knoevenagel/Perkin condensation-decarboxylation Heck/Suzuki sequences: tandem transformations of benzaldehydes into hydroxy functionalized antidiabetic stilbene-cinnamoyl hybrids and asymmetric distyrylbenzenes. AB - Tandem reactions that involve chemoselective Knoevenagel/Perkin condensation decarboxylation-Heck/Suzuki coupling or Heck-aldol sequences have been achieved. This enabled the first concise and efficient synthesis of several important hydroxy-functionalized compound classes, such as stilbene-cinnamoyl hybrids (potent protein tyrosine phosphatase1B inhibitors), cinnamoyl-cinnamic acid hybrids, asymmetric distyrylbenzenes, and biarylstyrenes. Previously reported synthesis require multiple steps and protection/deprotection manipulations. PMID- 21812044 TI - Bifunctional hydrogen-bond donors that bear a quinazoline or benzothiadiazine skeleton for asymmetric organocatalysis. AB - Hydrogen-bond (HB)-donor catalysts that bear a 2-aminoquinazolin-4-(1H)-one or a 3-aminobenzothiadiazine-1,1-dioxide skeleton have been developed, and it has been shown that these catalyst motifs act similarly to other HB-donor catalysts such as thioureas. The highly enantioselective hydrazination of 1,3-dicarbonyl compounds was realized even at room temperature with up to 96% ee for 2 aminoquinazolin-4-(1H)-one-type catalysts, which were more effective than the corresponding urea and thiourea catalysts. In addition, benzothiadiazine-1,1 dioxide-type catalysts were shown to promote the isomerization of alkynoates to allenoates with high enantioselectivity. To overcome the problem that the products were obtained as mixtures with the starting alkynoates, we developed the tandem isomerization and cycloaddition of alkynoates for the synthesis of advanced chiral compounds such as bicyclo[2.2.1]heptenes and 3-alkylidene pyrrolidine without a significant loss of enantioselectivity. PMID- 21812045 TI - Concise construction of sarain A core according to a biosynthetic proposal: cyclization through an intramolecular Mannich-type reaction involving an endocyclic N-acyliminium ion. PMID- 21812046 TI - Intermolecular twofold carbopalladation/cyclization sequence to access chromans and isochromans from carbohydrates. PMID- 21812047 TI - Imaging pH with hyperpolarized 13C. AB - pH is a fundamental physiological parameter that is tightly controlled by endogenous buffers. The acid-base balance is altered in many disease states, such as inflammation, ischemia and cancer. Despite the importance of pH, there are currently no routine methods for imaging the spatial distribution of pH in humans. The enormous gain in sensitivity afforded by dynamic nuclear polarization (DNP) has provided a novel way in which to image tissue pH using MR, which has the potential to be translated into the clinic. This review explores the advantages and disadvantages of current pH imaging techniques and how they compare with DNP-based approaches for the measurement and imaging of pH with hyperpolarized (13)C. Intravenous injection of hyperpolarized (13)C-labeled bicarbonate results in the rapid production of hyperpolarized (13)CO(2) in the reaction catalyzed by carbonic anhydrase. As this reaction is close to equilibrium in the body and is pH dependent, the ratio of the (13)C signal intensities from H(13)CO(3)(-) and (13)CO(2), measured using MRS, can be used to calculate pH in vivo. The application of this technique to a murine tumor model demonstrated that it measured predominantly extracellular pH and could be mapped in the animal using spectroscopic imaging techniques. A second approach has been to use the production of hyperpolarized (13)CO(2) from hyperpolarized [1 (13)C]pyruvate to measure predominantly intracellular pH. In tissues with a high aerobic capacity, such as the heart, the hyperpolarized [1-(13)C]pyruvate undergoes rapid oxidative decarboxylation, catalyzed by intramitochondrial pyruvate dehydrogenase. Provided that there is sufficient carbonic anhydrase present to catalyze the rapid equilibration of the hyperpolarized (13)C label between CO(2) and bicarbonate, the ratio of their resonance intensities may again be used to estimate pH, which, in this case, is predominantly intracellular. As both pyruvate and bicarbonate are endogenous molecules they have the potential to image tissue pH in the clinic. PMID- 21812048 TI - Two-step anomalous diffusion tensor imaging. AB - We extend the formalism of anomalous diffusion imaging to include directional anisotropy of fitted parameters. The resulting technique is termed anomalous diffusion tensor imaging (aDTI), and allows the directional properties of the distributed diffusion coefficient (alpha) and the anomalous diffusion exponent, (gamma) to be analysed using the same analytical techniques as regular diffusion tensor imaging (DTI). Together, these parameters quantify the rate of diffusion (alpha) and the complexity of the diffusion environment (gamma). We generated tensor images for the anomalous exponent tensor (Gamma) and distributed diffusivity tensor (A) from in vivo human brain data and present images of eigenvalues, eigenvectors, Trace/3 (Tr), fractional anisotropy (FA) and tensor shape measures. In white matter, A is found to have a median Tr = 0.56 * 10(- 3) mm(2) s(- 1), FA = 0.58 and Gamma Tr = 0.69, FA = 0.13. We observed that white matter shows a similar anisotropic geometry for the distributed diffusion tensor as for the regular diffusion tensor, whereas the anomalous exponent tensor exhibits a different shape characteristic which may be informative of tissue microstructure. PMID- 21812050 TI - Limitations to the structure-based design of HIV-1 vaccine immunogens. AB - In spite of 25 years of intensive research, no effective human immunodeficiency virus type 1 (HIV-1) vaccine has yet been developed. One reason for this is that investigators have concentrated mainly on the structural analysis of HIV-1 antigens because they assumed that it should be possible to deduce vaccine relevant immunogens from the structure of viral antigens bound to neutralizing monoclonal antibodies. This unwarranted assumption arises from misconceptions regarding the nature of protein epitopes and from the belief that it is justified to extrapolate from the antigenicity to the immunogenicity of proteins. Although the structure of the major HIV-1 antigenic sites has been elucidated, this knowledge has been of little use for designing an HIV-1 vaccine. Little attention has been given to the fact that protective immune responses tend to be polyclonal and involve antibodies directed to several different epitopes. It is concluded that only trial and error, empirical investigations using numerous immunization protocols may eventually allow us to identify which mixtures of immunogens are likely to be the best candidates for an HIV-1 vaccine. PMID- 21812051 TI - A survey of the 2006-2009 quartz crystal microbalance biosensor literature. AB - Since the publication of the original review of piezoelectric acoustic sensors in this series there has been a consistent, gradual expansion in the number of published papers using 'quartz crystal microbalances' (QCM). Between 2001 and 2009, the number of QCM publications per annum has increased from 49 to 273, with a two-fold increase in papers per annum between 2004 and 2008. Within the field, comparing the time covered by the current to the previous review, there are trends towards increasing use of QCM in the study of protein adsorption to surfaces (93% increase), homeostasis (67% increase), protein-protein interactions (40% increase) and carbohydrates (43% increase). New commercial systems have been released that are driving the uptake of the technology for characterization of binding specificities, affinities, kinetics and conformational changes associated with a molecular recognition event. This paper highlights theoretical and practical aspects of the principles that underpin acoustic analysis, then reviews exemplary papers in key application areas involving small molecular weight ligands, carbohydrates, proteins, nucleic acids, viruses, bacteria, cells and membrane interfaces. PMID- 21812052 TI - Simultaneous topography and recognition imaging on endothelial cells. AB - Determining the landscape of specific binding sites on biological samples with high spatial accuracy (in the order of several nanometres) is an important task in many fields of biological science. During the past five years, dynamic recognition imaging (e.g. simultaneous topography and recognition (TREC) imaging) has proven to be a powerful technique in biophysical research. This technique becomes an indispensable tool for high-resolution receptor mapping as it has been successfully demonstrated on different biomolecular model systems. In these studies, the topographical imaging of receptor molecules is combined with molecular recognition by their cognate ligands bound to the atomic force microscope (AFM) tip via a flexible and distensible tether. In this review, we describe the principles of TREC imaging and provide a flavour of its recent application on endothelial cells. PMID- 21812053 TI - The PINIT domain of PIAS3: structure-function analysis of its interaction with STAT3. AB - The protein inhibitor of activated signal transducer and activator of transcription 3 (PIAS3) regulates the transcriptional activity of signal transducer and activator of transcription 3 (STAT3) which regulates transcription of genes involved in cell growth, proliferation and apoptosis. The conserved proline, isoleucine, asparagine, isoleucine, threonine (PINIT) domain of PIAS3 is thought to promote STAT3-PIAS3 interaction. The (His)(7) -PINIT domain (PIAS3(85 272) ) was heterologously expressed and purified to homogeneity by nickel affinity and size exclusion chromatography, and shown to be a folded monomer in solution. Using surface plasmon resonance spectroscopy (SPR) the PINIT domain (PIAS3(85-272) ) alone was shown to specifically bind to STAT3 in a concentration dependent manner. L97A, R99N and R99Q mutations of the PINIT domain were found to abrogate binding to STAT3, suggesting that these residues were part of a potential binding surface. An homology model for the PINIT domain was calculated to analyse the potential locations of L97 and R99 in the structure, and to evaluate the potential role of these residues in interactions with STAT3. PMID- 21812054 TI - Human dipeptidyl peptidase III: insights into ligand binding from a combined experimental and computational approach. AB - Human dipeptidyl peptidase III (DPP III) is a zinc-exopeptidase with implied roles in protein catabolism, pain modulation, and defense against oxidative stress. To understand the mode of ligand binding into its active site, we performed molecular modeling, site-directed mutagenesis, and biochemical analyses. Using the recently determined crystal structure of the human DPP III we built complexes between both, the wild-type (WT) protein and its mutant H568N with the preferred substrate Arg-Arg-2-naphthylamide (RRNA) and a competitive inhibitor Tyr-Phe-hydroxamate (Tyr-Phe-NHOH). The mutation of the conserved His568, structurally equivalent to catalytically important His231 in thermolysin, to Asn, resulted in a 1300-fold decrease of k(cat) for RRNA hydrolysis and in significantly lowered affinity for the inhibitor. Molecular dynamics simulations revealed the key protein-ligand interactions as well as the ligand-induced reorganization of the binding site and its partial closure. Simultaneously, the non-catalytic domain was observed to stretch and the opening at the wide side of the inter-domain cleft became enhanced. The driving force for these changes was the formation of the hydrogen bond between Asp372 and the bound ligand. The structural and dynamical differences, found for the ligand binding to the WT enzyme and the H568N mutant, and the calculated binding free energies, agree well with the measured affinities. On the basis of the obtained results we suggest a possible reaction mechanism. In addition, this work provides a foundation for further site-directed mutagenesis experiments, as well as for modeling the reaction itself. PMID- 21812055 TI - Hapten-antibody recognition studies in competitive immunoassay of alpha zearalanol analogs by computational chemistry and Pearson Correlation analysis. AB - The molecular recognition of hapten-antibody is a fundamental event in competitive immunoassay, which guarantees the sensitivity and specificity of immunoassay for the detection of haptens. The aim of this study is to investigate the correlation between binding ability of one monoclonal antibody, 1H9B4, recognizing and the molecular aspects of alpha-zearalanol analogs. The mouse derived monoclonal antibody was produced by using alpha-zearalanol conjugated to bovine serum albumin as an immunogen. The antibody recognition abilities, expressed as IC(50) values, were determined by a competitive ELISA. All of the hapten molecules were optimized by Density Function Theory (DFT) at B3LYP/ 6-31G* level and the conformation and electrostatic molecular isosurface were employed to explain the molecular recognition between alpha-zearalanol analogs and antibody 1H9B4. Pearson Correlation analysis between molecular descriptors and IC(50) values was qualitatively undertaken and the results showed that one molecular descriptor, surface of the hapten molecule, clearly demonstrated linear relationship with antibody recognition ability, where the relationship coefficient was 0.88 and the correlation was significant at p < 0.05 level. The study shows that computational chemistry and Pearson Correlation analysis can be used as tool to help the immunochemistries better understand the processing of antibody recognition of hapten molecules in competitive immunoassay. PMID- 21812056 TI - Identification of selective ligands for human fibrin recognition using high throughput docking. AB - The ultimate aim of this study is to identify new molecules that are able to recognize polymerized fibrin, which is the main component of a thrombus. These selective ligands can be exposed on the surface of particular nanoparticles used for the targeted delivery of fibrinolytic drugs. The targeted delivery of these drugs is expected to help to keep under control the severe side effects which can occur if the drugs are administered systemically. The study focuses on the application of high-throughput docking methods used to screen a library of thousands of commercial compounds. The aim was to identify molecules that are potentially capable of interacting with the human fibrin gamma(312-324) epitope. The best scoring compounds were purchased and tested through fluorimetric assays in order to estimate their affinity toward fibrin. The results show that the protocol proposed here for identifying new compounds of interest may provide a valuable contribution to the discovery of lead molecules for human fibrin recognition. PMID- 21812057 TI - Characterization of N-cadherin unbinding properties in non-malignant (HCV29) and malignant (T24) bladder cells. AB - The expression of N-cadherin, characteristic of various cancers, very often leads to changes in the cells' adhesive properties. Thus, we sought to find out if N cadherin expressed in various, but cancer-related cells, differs in its functional properties that could contribute to variations in cells' phenotypes. In our work, measurements of an unbinding force of a single N-cadherin molecule, probed with the same antibody both on a surface of living non-malignant (HCV29) and malignant cells (T24) of bladder cancer, were carried out with the use of an atomic force microscopy. The results show the enhanced N-cadherin level in T24 malignant cells (8.7% vs. 3.6% obtained for non-malignant one), confirmed by the Western blot and the immunohistochemical staining. The effect was accompanied by changes in unbinding properties of an individual N-cadherin molecule. Lower unbinding force values (26.1 +/- 7.1 pN) in non-malignant cells reveal less stable N-cadherin complexes, as compared to malignant cells (61.7 +/- 14.6 pN). This suggests the cancer-related changes in a structure of the binding site of the antibody, located at the extracellular domain of N-cadherin. PMID- 21812058 TI - Reassessment of the size of the supermolecular state of Dishevelled-3. AB - Amendment of the interpretation of recently published size-exclusion chromatography data for Dishevelled-3 on Superdex 200 and Sephacryl S-400 has led to an increase in the estimated size of the supermolecular state from 2000 to 35 000 kDa, a value that essentially duplicates the redetermined and reported estimates obtained by fluorescence correlation spectroscopy on live cells. The earlier discrepancy between the sizes of the extensively aggregated form of this scaffold protein in vivo and in vitro is thereby eliminated. PMID- 21812059 TI - P-selectin/ligand unbinding force measured with atomic force microscopy: comparison of two chemical protocols for the tethering of single molecules. AB - Leukocytes, as an indispensable arm of the immune system, need to be recruited from the flowing blood and transferred to the sites of infection. Their extravasation is feasible due to their ability to tether and roll over the activated endothelium, which is much dependent on the association of their selectin molecules with ligands on the activated endothelial cells. In view of the importance of this interaction for the physiological immune functions as well as for autoimmune diseases, specifying the affinity of selectins to their ligands at the single molecule level appears a challenging task to gain insight into the mechanisms that control leukocyte-endothelial avidity. To this end we functionalized substrates with P-selectin and cantilever probes with its major ligand, the P-selectin glycoprotein ligand-1, and used atomic force microscopy to measure their unbinding force. Two different chemical protocols were used for the tethering of the molecules on the substrates, one based on a homobifunctional poly(ethylene glycol) linker and the other on the use of antibody-specific binding. The unbinding forces measured with the two methods were 312 +/- 149 and 230 +/- 57 pN, respectively. Measurements on activated endothelials, declaratory of single molecule interactions, gave comparable results. PMID- 21812060 TI - Mechanism and thermodynamics of ligand binding to auxin amidohydrolase. AB - BrILL2 is catalytically the most efficient auxin amidohydrolase from Brassica rapa, playing a key role in auxin metabolism by catalyzing its release from amino acid conjugates. Auxins, with the most abundant representative indole-acetic acid ([1H-indol-3-yl]-acetic acid, IAA), are a group of plant hormones that in very small concentrations regulate ubiquitin-mediated degradation of transcription regulators. Kinetic studies on BrILL2 showed that it hydrolyzes alanine conjugates of IAA and of its larger analogues, indole-propionic acid (3-[1H-indol 3-yl]-propionic acid, IPA) and indole-butyric acid (4-[1H-indol-3-yl]-butyric acid, IBA). Structurally, BrILL2 belongs to the largest known family of metallopeptidases (M20) that share a recognizable 3D structure, characterized by two perpendicular domains. Its members have been implicated in numerous biochemical processes and have been found across all species sequenced to date. Here, molecular dynamics simulations were carried out to study structural and thermodynamic properties of ligand binding to BrILL2. A conformational change was captured in multiple copies of 10 ns long simulations, described by a rigid body movement of the two domains, and its associated key interactions between residues were examined. For the three substrates, complexes in two possible binding modes were recreated, along with a single binding mode for the putative substrate tryptophanyl-alanine (Trp-Ala), which were subsequently simulated in multiple copies of 10 ns long simulations. Thermodynamic calculations were used to assess their binding affinities and explain the selectivity toward the longer ligands. Based on the results, a possible route for the reaction is proposed. PMID- 21812061 TI - Generation, characterization, and docking studies of DNA-hydrolyzing recombinant F(ab) antibodies. AB - Previously we established a series of catalytic antibodies (catAbs) capable of hydrolyzing DNA prepared by hybridoma technology. A group of these catAbs exhibited high reactivity and substrate specificity. To determine the molecular basis for these catAbs, we cloned, sequenced, and expressed the variable regions of this group of antibodies as functional F(ab) fragments. The nucleotide and deduced amino acid sequences of the expressed light chain (Vkappa) germline gene assignments confidently belonged to germline family Vkappa1A, gene bb1.1 and GenBank accession number EF672207 while heavy chain variable region V(H) genes belonged to V(H) 1/V(H) J558, gene V130.3 and GenBank accession number EF672221. A well-established expression system based on the pARA7 vector was examined for its ability to produce catalytically active antibodies. Recombinant F(ab) (rF(ab) ) fragments were purified and their hydrolyzing activity was analyzed against supercoiled pUC19 plasmid DNA (scDNA). The study of rF(ab) provides important information about the potential catalytic activities of antibodies whose structure allows us to understand their basis of catalysis. Molecular surface analysis and docking studies were performed on the molecular interactions between the antibodies and poly(dA9), poly(dG9), poly(dT9), and poly(dC9) oligomers. Surface analysis identified the important sequence motifs at the binding sites, and different effects exerted by arginine and tyrosine residues at different positions in the light and heavy chains. This study demonstrates the potential usefulness of the protein DNA surrogate in the investigation of the origin of anti-DNA antibodies. These studies may define important features of DNA catAbs. PMID- 21812062 TI - Constitutive activity and ligand-dependent activation of the nuclear receptor CAR insights from molecular dynamics simulations. AB - The constitutive androstane receptor (CAR) possesses, unlike most other nuclear receptors, a pronounced basal activity in vitro whose structural basis is still not fully understood. Using comparative molecular dynamics simulations of CAR X ray crystal structures, we evaluated the molecular basis for constitutive activity and ligand-dependent receptor activation. Our results suggest that a combination of van der Waals interactions and hydrogen bonds is required to maintain the activation helix in the active conformation also in absence of a ligand. Furthermore, we identified conformational rearrangements within the ligand-binding pocket upon agonist binding and an influence of CAR inducers pregnanedione and CITCO on the helical conformation of the activation helix. Based on the results a model for ligand-dependent CAR activation is suggested. PMID- 21812063 TI - Combining resources to obtain a comprehensive survey of the bovine embryo transcriptome through deep sequencing and microarrays. AB - While most assisted reproductive technologies (ART) are considered routine for the reproduction of species of economical importance, such as the bovine, the impact of these manipulations on the developing embryo remains largely unknown. In an effort to obtain a comprehensive survey of the bovine embryo transcriptome and how it is modified by ART, resources were combined to design an embryo specific microarray. Close to one million high-quality reads were produced from subtracted bovine embryo libraries using Roche 454 Titanium deep sequencing technology, which enabled the creation of an augmented bovine genome catalog. This catalog was enriched with bovine embryo transcripts, and included newly discovered indel type and 3'UTR variants. Using this augmented bovine genome catalog, the EmbryoGENE Bovine Microarray was designed and is composed of a total of 42,242 probes, including 21,139 known reference genes; 9,322 probes for novel transcribed regions (NTRs); 3,677 alternatively spliced exons; 3,353 3'-tiling probes; and 3,723 controls. A suite of bioinformatics tools was also developed to facilitate microrarray data analysis and database creation; it includes a quality control module, a Laboratory Information Management System (LIMS) and microarray analysis software. Results obtained during this study have already led to the identification of differentially expressed blastocyst targets, NTRs, splice variants of the indel type, and 3'UTR variants. We were able to confirm microarray results by real-time PCR, indicating that the EmbryoGENE bovine microarray has the power to detect physiologically relevant changes in gene expression. PMID- 21812064 TI - A NEO-PI-R short form for older adults. AB - This article reports on the construction and examination of a 120 item version (NEO-PI-R-SF) of the Dutch/Belgian NEO-Personality Inventory-Revised (NEO-PI-R). The item selection was based on criteria of appropriateness for older adults and psychometric contribution. The factor structure of the NEO-PI-R-SF proved highly equivalent to the parent instrument, indicating concordant validity. Coefficients alpha were generally lower due to the reduction of items. When assessed in a new sample of older adults (N=794), the factor structure of the NEO-PI-R-SF proved replicable, except for the facet scales A1: Trust and A3: Altruism. Coefficients alpha for the domain scales were satisfactory, while the coefficients alpha for the facet scales were marginal to satisfactory and below those found in two adult samples (N=1305 and N=682). It was concluded that the NEO-PI-R-SF may be a time saving alternative for research when a fine-grained description of personality among older adults is required. PMID- 21812065 TI - A study of the dimensionality and measurement precision of the SCL-90-R using item response theory. AB - We used item response theory (IRT) to (a) investigate the dimensionality of the Symptom Checklist-90-Revised (SCL-90-R) in a severely disturbed patient group, (b) improve the subscales in a meaningful way and (c) investigate the measurement precision of the improved scales. The total sample comprised 3078 patients (72% women, mean age=35+/-9) admitted to 14 different day hospitals participating in the Norwegian Network of Personality-focused Treatment Programmes. Mokken Scale Analysis was used to investigate the dimensionality of the SCL-90-R and improve the subscales. This analysis was theory-driven: the scales were built on two start items that reflected the content of the disorder that corresponds with the specific scale. The Graded Response Model was employed to determine measurement precision. Our theory-driven IRT approach resulted in a new seven-factor solution including 60 of the 90 items clustered in seven scales: depression, agoraphobia, physical complaints, obsessive-compulsive, hostility (unchanged), distrust and psychoticism. Most of the new scales discriminated reliably between patients with moderately low scores to moderately high scores. In conclusion, we found support for the multidimensionality of the SCL-90-R in a large sample of severely disturbed patients. PMID- 21812066 TI - More potential in statistical analyses of event-related potentials: a mixed regression approach. AB - Despite many developments in the methods of event-related potentials (ERPs), little attention has gone out to the statistical handling of ERP data. Trials are often averaged, and univariate or repeated measures of analysis of variance (ANOVA) are used to test hypotheses. The aim of this study was to introduce mixed regression to ERP research and to demonstrate advantages associated with this method. Eighty-five healthy subjects received electrical pain stimuli with simultaneous electroencephalography (EEG) registration. Analyses first showed that results obtained with mixed regression analyses are highly comparable to those using repeated measures of ANOVA. Second, important advantages of the mixed regression technique were demonstrated by allowing the inclusion of persons with missing data, single trial analysis, non-linear time effects, time*person effects (random slope effects) and a within-subject covariate. Among others, the results showed a strong trial (habituation) effect, which contraindicates the common procedure of averaging of trials. Furthermore, the regression coefficients for intensity and trial varied significantly between persons, indicating individual differences in the effect of intensity and trial on the ERP amplitude. In conclusion, using mixed regression analysis as a statistical technique in ERP research will advance the science of unravelling mechanisms underlying ERP data. PMID- 21812067 TI - Record linkage for pharmacoepidemiological studies in cancer patients. AB - BACKGROUND: An increasing need has developed for the post-approval surveillance of (new) anti-cancer drugs by means of pharmacoepidemiology and outcomes research in the area of oncology. OBJECTIVES: To create an overview that makes researchers aware of the available database linkages in Northern America and Europe which facilitate pharmacoepidemiology and outcomes research in cancer patients. METHODS: In addition to our own database, i.e. the Eindhoven Cancer Registry (ECR) linked to the PHARMO Record Linkage System, we considered database linkages between a population-based cancer registry and an administrative healthcare database that at least contains information on drug use and offers a longitudinal perspective on healthcare utilization. Eligible database linkages were limited to those that had been used in multiple published articles in English language included in Pubmed. The HMO Cancer Research Network (CRN) in the US was excluded from this review, as an overview of the linked databases participating in the CRN is already provided elsewhere. Researchers who had worked with the data resources included in our review were contacted for additional information and verification of the data presented in the overview. RESULTS: The following database linkages were included: the Surveillance, Epidemiology, and End-Results-Medicare; cancer registry data linked to Medicaid; Canadian cancer registries linked to population based drug databases; the Scottish cancer registry linked to the Tayside drug dispensing data; linked databases in the Nordic Countries of Europe: Norway, Sweden, Finland and Denmark; and the ECR-PHARMO linkage in the Netherlands. Descriptives of the included database linkages comprise population size, generalizability of the population, year of first data availability, contents of the cancer registry, contents of the administrative healthcare database, the possibility to select a cancer-free control cohort, and linkage to other healthcare databases. CONCLUSIONS: The linked databases offer a longitudinal perspective, allowing for observations of health care utilization before, during, and after cancer diagnosis. They create new powerful data resources for the monitoring of post-approval drug utilization, as well as a framework to explore the (cost-)effectiveness of new, often expensive, anti-cancer drugs as used in everyday practice. PMID- 21812068 TI - Reliability of the reported ingested dose of acetaminophen for predicting the risk of toxicity in acetaminophen overdose patients. AB - PURPOSE: The present study examines the relationship between the dose of acetaminophen reported to have been ingested by patients and the occurrence of serum acetaminophen levels above the 'possible toxicity' line in patients presenting at the hospital after acetaminophen overdose. The prognostic value of patient-reported dosage cut-offs of 8, 10 and 12 g was determined. METHODS: This retrospective cohort study included patients admitted to the emergency department or hospital within 24 hours of acetaminophen ingestion. Serum acetaminophen concentrations were considered to be the gold standard, and specificity, sensitivity and positive/negative predictive values were calculated from the reported ingested dose, to predict toxicity using the Rumack-Matthew nomogram (i.e. the 'possible toxicity' treatment line) and standard equations. RESULTS: Of 305 patients identified, 291 met the study inclusion criteria, and 121 (41.6%) had serum acetaminophen concentrations above the 'possible toxicity' treatment line. The range of patient-reported acetaminophen ingested was 1-75 g, with 185 patients (63.6%) reporting >=8 g. One hundred eighteen patients (97.5%) who reported ingesting >=8 g had serum acetaminophen concentrations above the '150 line', compared with only three patients (2.5%) who reported ingesting <8 g (p < 0.001). The positive predictive value of a patient-reported dose >=8 g for predicting serum acetaminophen concentrations above the 'possible toxicity' treatment line was 63.78%, with a negative predictive value of 97.17%. The sensitivity of patient-reported doses >=8 g was high (97.52%) but with low specificity (60.59%). The sensitivity of patient-reported doses >=10 g also was high (89.26%) with low specificity (65.29%), whereas the sensitivity of >=12 g dose was low (61.16%) with high specificity (86.47%). CONCLUSIONS: Patient reported doses of acetaminophen are good risk indicators for acetaminophen overdose patients in Malaysia. Patient-reported ingestion of >=8 g (as a cut-off dose) had a higher sensitivity than >=10 g or >=12 g. The results of this study have important implications for toxicity risk evaluations in areas with poor serum acetaminophen assay availability. PMID- 21812069 TI - Anxiety and specific distress in women at intermediate and high risk of breast cancer before and after surveillance by magnetic resonance imaging and mammography versus standard mammography. AB - BACKGROUND: Intensive surveillance in women at intermediate and high breast cancer risk is currently investigated in a French prospective, non-randomized, multicentre study. Two surveillance modalities, standard imaging-mammography +/- ultrasound ('Mx')-or standard imaging with magnetic resonance imaging ('MRI'), provided according to the level of breast cancer risk, are compared on psychological distress. METHODS: A total of 1561 women were invited to complete the State-Trait Anxiety Inventory (STAI), Impact of Event Scale (IES) Intrusion and Avoidance subscales and breast cancer-risk perception items at T0 (before examination) and T2 (1 to 3 months later) and the STAI-State anxiety at T1 (just after examination). Multiple regression analyses were performed. RESULTS: Baseline compliance was high (>91%). Between surveillance modalities, women differed significantly for age, education level, breast cancer-risk objective estimates and subjective perception. Mean STAI-State anxiety scores reflected low to moderate distress in both surveillance modalities. At baseline, MRI was associated with lower STAI-State anxiety (p <= 0.001) and Avoidance scores (p = 0.02), but at T1 and T2, no difference between surveillance modalities was observed on psychological outcomes. Abnormal surveillance result was associated with a higher STAI-State anxiety (p <= 0.01) and IES-Intrusion (p <= 0.01) scores; a personal history of breast cancer and higher risk perception was associated with higher psychological distress at T1 and T2. CONCLUSION: Standard breast imaging including MRI does not seem to convey more harmful psychological effects than standard imaging alone. Higher psychological distress observed in the case of history of breast cancer or higher breast cancer-risk perception evidences women with needs for specific support and information. PMID- 21812070 TI - Toxicity induced by cumene hydroperoxide in PC12 cells: protective role of thiol donors. AB - Oxidative shock and production of reactive oxygen species are known to play a major role in situations leading to neuron degeneration, but the precise mechanisms responsible for cell degeneration remain uncertain. In the present article, we have studied in PC 12 cells the effect of cumene hydroxyperoxide on both cell metabolism and morphology. We observed that relatively low concentrations of the drug (100 MUM) led to a significant decrease in the cellular content of ATP and reduced glutathione as well as to a decreased mitochondrial potential. These metabolic alterations were followed by an important increase in intracellular free calcium and membrane disruption and death. In parallel, we observed profound changes in cell morphology with a shortening of cell extensions, the formation of ruffles and blebs at the cell surface, and a progressive detachment of the cells from the surface of the culture flasks. We also showed that addition of thiol donors such as N acetylcysteine or beta-mercaptoethanol, which were able to enhance cell glutathione content, almost completely protected PC 12 cells from the toxic action of cumene hydroperoxide whereas pretreatment by buthionine sulfoximine, a selective inhibitor of GSH synthesis, enhanced its action. PMID- 21812071 TI - Comparison of antioxidant effectiveness of lipoic acid and dihydrolipoic acid. AB - The abilities of dihydrolipoic acid (DHLA) to scavenge peroxynitrite (ONOO(-) ), galvinoxyl radical, 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonate) cation radical (ABTS(+*) ), and 2,2'-diphenyl-1-picrylhydrazyl radical (DPPH) were higher than those of lipoic acid (LA). The effectiveness of DHLA to protect methyl linoleate against 2,2'-azobis(2-amidinopropane hydrochloride) (AAPH) induced oxidation was about 2.2-fold higher than that of LA, and DHLA can retard the autoxidation of linoleic acid (LH) in the beta-carotene-bleaching test. DHLA can also trap ~0.6 radicals in AAPH-induced oxidation of LH. Moreover, DHLA can scavenge ~2.0 radicals in AAPH-induced oxidation of DNA and AAPH-induced hemolysis of erythrocytes, whereas LA can scavenge ~1.5 radicals at the same experimental conditions. DHLA can protect erythrocytes against hemin-induced hemolysis, but accelerate the degradation of DNA in the presence of Cu(2+) . Therefore, the antioxidant capacity of -SH in DHLA is higher than S-S in LA. PMID- 21812073 TI - Effect of tin and lead chlorotriphenyl analogues on selected living cells. AB - Three kinds of living cells, human embryonic kidney cells, Saccharomyces cerevisiae, and Escherichia coli, were tested for their sensitivity to chlorotriphenyltin and chlorotriphenyllead. The tin compound proved definitely more toxic than the lead derivative, particularly in the case of the human embryonic kidney cells devoid of any protective cell wall. Electron paramagnetic resonance (EPR) comparative studies carried out by using a natural model liposome system (egg yolk lecithin) confirmed considerable changes within the lipid bilayer upon doping by the aforementioned additives, which may be crucial to the mechanism of the observed cell cleavage. The individual dopants revealed diverse impact upon the membrane's condition, chlorotriphenyltin distinctly fluidized the lipid system, whereas chlorotriphenyllead stiffened the medium within the membrane. A theoretical approach concerning such different behaviors of studied tin and lead analogues because of their high toxicity in living cells has been presented. PMID- 21812072 TI - Ethanol-induced redox imbalance in rat kidneys. AB - This study reports the effects of long-term ethanol consumption on kidney redox status, in terms of enzymatic mechanisms involved in regulating the cytosolic [NADH]/[NAD(+) ] balance. Wistar rats were treated with ethanol (2 g/kg body weight/24 h) via intragastric intubation for 10 and 30 weeks, respectively. Ethanol administration induced an enhancement of alcohol dehydrogenase activities and affected the capacity of the kidney to prevent NADH accumulation in the cytosol. After 10 weeks, the excess of NADH was balanced by increased activities of malate dehydrogenase and aspartate transaminase. In the event of a longer period of ethanol intake, the kidney was not able to balance the NADH excess, even though an increase in malate dehydrogenase, lactate dehydrogenase, aspartate transaminase, and alanine transaminase activities was noted. The electrophoretic analysis of alcohol dehydrogenase, lactate dehydrogenase, and malate dehydrogenase isoforms revealed differences between control and ethanol-treated animals. The results suggest that rat kidneys have a multicomponent metabolic response to the same daily dose of ethanol that functions to maintain the redox status and which varies with the length of the administration period. PMID- 21812075 TI - Observation of in vivo cytochrome-based electron-transport dynamics using time resolved evanescent wave electroabsorption spectroscopy. PMID- 21812074 TI - Silk fibroin has a protective effect against high glucose induced apoptosis in HIT-T15 cells. AB - High glucose levels induce cell death in many cell types, including pancreatic beta-cells. Although protective agents against glucotoxicity have been searched for extensively, so far none have been found. In this report, we tested silk fibroin (SF) as a candidate material for antiglucotoxicity in the pancreatic beta cell (HIT-T15 cell) line. Approximately 50% of cells were killed after treatment with 80 mg/mL glucose. This reduction of cell number was recovered by the addition of SF at 50 mg/mL. SF treatment also decreased cellular reactive oxygen species (ROS) and increased proliferating cellular nuclear antigen (PCNA) immunoreactivity. In addition, TUNEL assays demonstrated that SF protects against glucose-induced apoptosis of HIT-T15 cells, suggesting that SF might protect cells from cell death by lowering cellular ROS levels. SF also induced expression of the insulin-like growth factor-1 (IGF-1) gene, and IGF-1 expression may be the cause of SF-induced protection against glucose toxicity. Taken together, these results suggest that SF could serve as a potential therapeutic agent to treat the hyperglycemia-induced death of pancreatic beta-cells. PMID- 21812076 TI - Introducing lasso peptides as molecular scaffolds for drug design: engineering of an integrin antagonist. PMID- 21812077 TI - Atomic-distribution-dependent electrocatalytic activity of Au-Pd bimetallic nanocrystals. PMID- 21812080 TI - Resveratrol--current status and outlook. PMID- 21812078 TI - Palladium(0)-catalyzed intermolecular amination of unactivated C(sp3)-H bonds. PMID- 21812081 TI - Dehydrative cyclization of alkynals: vinylidene complexes with the Cbeta incorporated into unsaturated five- or six-membered rings. PMID- 21812082 TI - Impact of strand length on the stability of parallel-beta-sheet secondary structure. PMID- 21812083 TI - An acyclic oligoheteroaryle that discriminates strongly between diverse G quadruplex topologies. PMID- 21812084 TI - Spin-crossover Fe(II)4 squares: two-step complete spin transition and reversible single-crystal-to-single-crystal transformation. PMID- 21812085 TI - Nanoparticle netpoints for shape-memory polymers. PMID- 21812086 TI - Rb4Sn5P4Se20: a semimetallic selenophosphate. PMID- 21812087 TI - Iridium-catalyzed reactions of omega-arylalkanols to alpha,omega-diarylalkanes. PMID- 21812089 TI - Single coronary artery syndrome: cardiac computed tomography angiography as a leading imaging modality. AB - Single coronary artery syndrome is usually an asymptomatic condition in most patients; thus most patients are diagnosed when noninvasive imaging (cardiac computed tomography angiography, cardiac magnetic resonance) or invasive coronary angiography is done for evaluation for other cardiac conditions. With advances using cardiovascular imaging in the evaluation and management of single coronary artery syndrome; Cardiac Computed Tomography Angiography (CCTA) has emerged as a very essential and leading imaging modality. CCTA has the best resolution (spatial and temporal) among the imaging modalities available for analyzing the cardiovascular system for the diagnosis and management of single coronary artery syndrome. We are presenting cases of patients with single coronary artery syndrome with 3 different courses (anterior, septal, inter-arterial), illustrating how CCTA gives a detailed anatomic/structural evaluation of the origin and course of the coronary arteries, and other cardiac structures. Thus in patients diagnosed with single coronary artery syndrome, CCTA can provide vital information on the not only the course, but the associated narrowing of coronary vessels. PMID- 21812090 TI - Feasibility of transcatheter closure in unselected patients with secundum atrial septal defect, using Amplatzer devices and a modified sizing balloon technique. AB - OBJECTIVES: We aimed to assess (1) the role of surgical versus transcatheter closure techniques and (2) the impact of a modified implantation technique to optimize closure of secundum septal defects with the Amplatzer device. BACKGROUND: Despite several comparative studies, the respective roles of surgical and transcatheter closure are not clarified. Additionally, the impact of modified method of implantation on device closure remains unknown. METHODS: Fifty-seven unselected patients were referred for secundum atrial septal defect closure in 2009, at a median age and weight of 27.5 (0.8-88) years and 40.6 (5.6-97) kg, respectively. Transcatheter closure was attempted in 53 cases under transesophagal echocardiography guidance in children (n = 28) and intracardiac echocardiography guidance in adults. If standard closure failed, a sizing balloon catheter inflated in the left atrium was used as a support to secure the position of the device upon deployment. RESULTS: Fifty of the 57 cases (88%) were successfully closed with a median Amplatzer Septal Occluder size of 20 (10-40) mm, using the sizing balloon technique in eight (16%) cases. No major complication occurred. A trivial residual shunt remained in two patients (4%) whereas a mild mitral regurgitation appeared in one. By univariate analysis, a deficient superior-posterior rim and a large defect (>15 mm(2) /m(2) ) were associated with the use of the sizing balloon technique (P = 0.04 and 0.03, respectively). A deficient superior-posterior rim and pulmonary hypertension were associated with failure to close the defect (P = 0.02 and 0.03, respectively). CONCLUSION: The majority of secundum atrial septal defect is amenable to transcatheter closure, using a modified implantation technique in 16% of cases. PMID- 21812091 TI - A case of successful angioplasty by the "double retrograde" approach for chronic total occlusion in the left circumflex artery. AB - Currently introduced retrograde approach may increase the success rate of percutaneous coronary interventions on chronic total occlusion (CTO) lesion. This article describes a case of CTO in the left circumflex artery (LCX), which did not allow the regular retrograde approach to deliver a guide wire. At first, a guide wire was attempted to advance from the apical collateral channel, which supplied the distal LCX. However, wiring was extremely difficult because the collateral channel was headed reversely against the direction that the wire was going. Different angle angiogram revealed the existence of another collateral artery, which supplied the distal RCA (posterior descending branch). A guide wire was successfully advanced from the distal RCA, through apical collateral channel, and reached the distal LCX. After the wire was retrieved from the guiding catheter engaged in the left main trunk, antegrade access for balloon and stent delivery was obtained. This method, a sort of "double retrograde" approach, would be worthy to consider when recanalization is failed by other approaches. PMID- 21812092 TI - Electric polarization and mechanism of B-type carbonated apatite ceramics. AB - B-type carbonated apatite (CAp) ceramics, nonstoichiometric hydroxyapatites (HAp) with carbonate ions (CO(3)(2-) substituting for phosphate ions, are the major inorganic components of vertebrate bones. Due to the carbonate substitution, CAp is more biodegradable than HAp and has been expected a next generation biomaterial. We have reported the electric polarization of HAp, and induced stored electric charges and electric fields in poling HAp could promote bone healing. Here, we applied electric polarization to CAp and showed the role of substituted CO(3)(2-) concentrations in CAp in its electric polarization and polarization mechanisms. We found that the electrical conductivities (sigma) and stored charges (Q) of poling CAp dramatically increased with carbonate ion contents. We also found that CAp showed higher activation energy both for conduction and for depolarization than HAp, even though the values of sigma and Q are much higher than those of HAp. These results suggested that the substitution of a small amount of CO(3)(2-) for PO(4)(3-) resulted in a change in the conduction and polarization mechanisms in CAp compared with HAp. Our study showed that the poling CAp has the potential to be a new functional biomaterial with biodegradation and large stored electric charges. PMID- 21812093 TI - Regulation on the biocompatibility of bioactive titanium metals by type I collagen. AB - To study the regulation on the biocompatibility of titanium metal surface structure, the interaction between the collagen and the titanium surface structure were studied with titanium surfaces subjected to anodic oxidation and acid-alkali treatment. The cell response on the treated surfaces was studied in vitro experiments of MG63 osteoblasts. The effects of different collagen adsorption ability on the biomineralization were investigated with simulated body fluid (SBF) experiment and osteoblasts culture experiments in a mineralization culture medium. It was found that the collagen adsorption ability was controlled by the wettability. The acid-alkali treated titanium could adsorb much more collagen on its surface. The abilities of cell attachment and proliferation were improved after collagen soaking. The apatite formation ability was inhibited in SBF after collagen adsorption on the surfaces, but improved in cell-involved situation. The ALP and OCN activity of MG63 cells assay showed the collagen on the titanium surface could enhance the bioactivity of the cells, which could accelerate the biomineralization process in cell culture experiments. The result indicated that the different adsorption ability of type I collagen could regulate the biocompatibility of titanium metal surface. It is possible to optimize the biocompatibility of the titanium metals by using suitable surface modification method. PMID- 21812094 TI - BV-2 microglial cells sense micro-nanotextured silicon surface topology. AB - Artificial biomimetic substrates provide useful models for studying cell adhesion, signaling, and differentiation. This article describes biological interactions with a new type of tunable, micro-nanotextured silicon substrate, generated by irradiation of a hydrogenated amorphous silicon film with a large beam, excimer laser (248 nm). In this study, we demonstrate that BV-2 microglial cells can sense differences in laser processed silicon surface topology over the range of 30 nm to 2 MUm, where they undergo marked morphogenic changes with increasing feature size. The cells adopt a more elongated shape in the presence of the modified surface structure and exhibit increased levels of actin-rich microdomains, suggesting enhanced adhesion. The excimer laser modification of hydrogenated amorphous silicon to generate micro-nanostructures realizes large area benefits as well as providing a biomaterial where the external and internal structure can be altered and tuned for various applications. PMID- 21812095 TI - Characterization of astrocyte reactivity and gene expression on biomaterials for neural electrodes. AB - Neural electrode devices hold great promise to help people with the restoration of lost functions. However, research is lacking in the biomaterial design of a stable, long-term device. Glial scarring is initiated when a device is inserted into brain tissue and an inflammatory response ensues. Astrocytes become hypertrophic, hyperplastic, and upregulate glial-fibrillary acidic protein. This study was designed to investigate the astrocyte proliferation, viability, morphology, and gene expression to assess the reactive state of the cells on different material surfaces. Although platinum and silicon have been extensively characterized both in vivo and in vitro for their biocompatibility with neuronal cells, this study used the novel usage of PMMA and SU-8 in neural electrodes by comparative analysis of materials' biocompatibility. This study has shown evidence of noncytotoxicity of SU-8. We have also confirmed the biocompatibility of PMMA with astrocytes. Moreover, we have established sound guidelines of which neural implant materials should meet to be depicted biocompatible. PMID- 21812096 TI - No evidence that extended tracts of homozygosity are associated with Alzheimer's disease. AB - We sought to investigate the contribution of extended runs of homozygosity in a genome-wide association dataset of 1,955 Alzheimer's disease cases and 955 elderly screened controls genotyped for 529,205 autosomal single nucleotide polymorphisms. Tracts of homozygosity may mark regions inherited from a common ancestor and could reflect disease loci if observed more frequently in cases than controls. We found no excess of homozygous tracts in Alzheimer's disease cases compared to controls and no individual run of homozygosity showed association to Alzheimer's disease. PMID- 21812097 TI - Linkage analyses of stimulant dependence, craving, and heavy use in American Indians. AB - Amphetamine-type substances are the second most widely used illicit drugs in the United States. There is evidence to suggest that stimulant use (cocaine and methamphetamine) has a heritable component, yet the areas of the genome underlying these use disorders are yet to be identified. This study's aims were to map loci linked to stimulant dependence, heavy use, and craving in an American Indian community at high risk for substance dependence. DSM diagnosis of stimulant dependence, as well as indices of stimulant "craving," and "heavy use," were obtained using the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA). Genotypes were determined for a panel of 791 microsatellite polymorphisms in 381 members of multiplex families using SOLAR. Stimulant dependence, stimulant "craving," and "heavy stimulant use," were all found to be heritable. Analyses of multipoint variance component LOD scores, failed to yield evidence of linkage for stimulant dependence. For the stimulant "craving" phenotype, linkage analysis revealed a locus that had a LOD score of 3.02 on chromosome 15q25.3-26.1 near the nicotinic receptor gene cluster. A LOD score of 2.05 was found at this same site for "heavy stimulant use." Additional loci with LOD scores above 2.00 were found for stimulant "craving" on chromosomes 12p13.33 13.32 and 18q22.3. These results corroborate the importance of "craving" as an important phenotype that is associated with regions on chromosome 12, 15, and 18, that have been highlighted in prior segregation studies in this and other populations for substance dependence-related phenotypes. PMID- 21812098 TI - Association between TCF4 and schizophrenia does not exert its effect by common nonsynonymous variation or by influencing cis-acting regulation of mRNA expression in adult human brain. AB - Large collaborative Genome-wide Association studies of schizophrenia have identified genes and genomic regions that are associated with the disorder at highly stringent levels of statistical significance. Among these, transcription factor 4 (TCF4) is one of the best supported although the associated SNP (rs9960767) is located within intron 3 and has no obvious function. Seeking the mechanism at TCF responsible for the association, we examined TCF4 for coding variants, and for cis regulated variation in TCF4 gene expression correlated with the associated SNP using an assay to detect differential allelic expression. Using data from the 1000 genomes project, we were unable to identify any nonsynonymous coding variants at the locus. Allele specific expression analysis using human post mortem brain samples revealed no evidence for cis-regulated mRNA expression related to genotype at the schizophrenia associated SNP. We conclude that association between schizophrenia and TCF4 is not mediated by a relatively common non-synonymous variant, or by a variant that alters mRNA expression as measured in adult human brain. It remains possible that the risk allele at this locus exerts effects on expression exclusively in a developmental context, in cell types or brain regions not adequately represented in our analysis, or through post-transcriptional effects, for example in the abundance of the protein or its sub-cellular distribution. PMID- 21812100 TI - A loss-of-function mutation in the SLC9A6 gene causes X-linked mental retardation resembling Angelman syndrome. AB - SLC9A6 mutations have been reported in families in whom X-linked mental retardation (XMR) mimics Angelman syndrome (AS). However, the relative importance of SLC9A6 mutations in patients with an AS-like phenotype or XMR has not been fully investigated. Here, the involvement of SLC9A6 mutations in 22 males initially suspected to have AS but found on genetic testing not to have AS (AS like cohort), and 104 male patients with XMR (XMR cohort), was investigated. A novel SLC9A6 mutation (c.441delG, p.S147fs) was identified in one patient in the AS-like cohort, but no mutation was identified in XMR cohort, suggesting mutations in SLC9A6 are not a major cause of the AS-like phenotype or XMR. The patient with the SLC9A6 mutation showed the typical AS phenotype, further demonstrating the similarity between patients with AS and those with SLC9A6 mutations. To clarify the effect of the SLC9A6 mutation, we performed RT-PCR and Western blot analysis on lymphoblastoid cells from the patient. Expression of the mutated transcript was significantly reduced, but was restored by cycloheximide treatment, indicating the presence of nonsense mediated mRNA decay. Western blot analysis demonstrated absence of the normal NHE6 protein encoded for by SLC9A6. Taken together, these findings indicate a loss-of-function mutation in SLC9A6 caused the phenotype in our patient. PMID- 21812101 TI - Distinct de novo deletions in a brother-sister pair with RTT: a case report. AB - Rett syndrome (RTT), a neurodevelopmental disorder caused by mutations in the X linked gene encoding methyl-CpG-binding protein2 (MeCP2), is a leading cause of mental retardation in females. Majority of cases are sporadic (99%) but some familial cases have also been observed. We describe a familial study with a brother-sister pair with symptoms of RTT and exhibiting distinct deletions in the MECP2. The non-shared de novo deletion in the two sibs provides important insights into the disease etiology, especially for male sibs showing varied phenotypes as compared to the classical ones seen in the females. PMID- 21812099 TI - Genome scan of age-at-onset in the NIMH Alzheimer disease sample uncovers multiple loci, along with evidence of both genetic and sample heterogeneity. AB - Alzheimer's disease (AD) is a common neurodegenerative disorder of late life with a complex genetic basis. Although several genes are known to play a role in rare early onset AD, only the APOE gene is known to have a high contribution to risk of the common late-onset form of the disease (LOAD, onset >60 years). APOE genotypes vary in their AD risk as well as age-at-onset distributions, and it is likely that other loci will similarly affect AD age-at-onset. Here we present the first analysis of age-at-onset in the NIMH LOAD sample that allows for both a multilocus trait model and genetic heterogeneity among the contributing sites, while at the same time accommodating age censoring, effects of known genetic covariates, and full pedigree and marker information. The results provide evidence for genomic regions not previously implicated in this data set, including regions on chromosomes 7q, 15, and 19p. They also affirm evidence for loci on chromosomes 1q, 6p, 9q, 11, and, of course, the APOE locus on 19q, all of which have been reported previously in the same sample. The analyses failed to find evidence for linkage to chromosome 10 with inclusion of unaffected subjects and extended pedigrees. Several regions implicated in these analyses in the NIMH sample have been previously reported in genome scans of other AD samples. These results, therefore, provide independent confirmation of AD loci in family-based samples on chromosomes 1q, 7q, 19p, and suggest that further efforts towards identifying the underlying causal loci are warranted. PMID- 21812102 TI - Genomic architecture of aggression: rare copy number variants in intermittent explosive disorder. AB - Copy number variants (CNVs) are known to be associated with complex neuropsychiatric disorders (e.g., schizophrenia and autism) but have not been explored in the isolated features of aggressive behaviors such as intermittent explosive disorder (IED). IED is characterized by recurrent episodes of aggression in which individuals act impulsively and grossly out of proportion from the involved stressors. Previous studies have identified genetic variants in the serotonergic pathway that play a role in susceptibility to this behavior, but additional contributors have not been identified. Therefore, to further delineate possible genetic influences, we investigated CNVs in individuals diagnosed with IED and/or personality disorder (PD). We carried out array comparative genomic hybridization on 113 samples of individuals with isolated features of IED (n = 90) or PD (n = 23). We detected a recurrent 1.35-Mbp deletion on chromosome 1q21.1 in one IED subject and a novel ~350-kbp deletion on chromosome 16q22.3q23.1 in another IED subject. While five recent reports have suggested the involvement of an ~1.6-Mbp 15q13.3 deletion in individuals with behavioral problems, particularly aggression, we report an absence of such events in our study of individuals specifically selected for aggression. We did, however, detect a smaller ~430-kbp 15q13.3 duplication containing CHRNA7 in one individual with PD. While these results suggest a possible role for rare CNVs in identifying genes underlying IED or PD, further studies on a large number of well characterized individuals are necessary. PMID- 21812103 TI - Borderline personality traits and adult attention-deficit hyperactivity disorder symptoms: a genetic analysis of comorbidity. AB - Previous research has established the comorbidity of adult Attention-Deficit Hyperactivity Disorder (ADHD) with different personality disorders including Borderline Personality Disorder (BPD). The association between adult ADHD and BPD has primarily been investigated at the phenotypic level and not yet at the genetic level. The present study investigates the genetic and environmental contributions to the association between borderline personality traits (BPT) and ADHD symptoms in a sample of 7,233 twins and siblings (aged 18-90 years) registered with the Netherlands Twin Register and the East Flanders Prospective Twin Survey (EFPTS) . Participants completed the Conners' Adult ADHD Rating Scales (CAARS-S:SV) and the Personality Assessment Inventory-Borderline Features Scale (PAI-BOR). A bivariate genetic analysis was performed to determine the extent to which genetic and environmental factors influence variation in BPT and ADHD symptoms and the covariance between them. The heritability of BPT and ADHD symptoms was estimated at 45 and 36%, respectively. The remaining variance in BPT and ADHD symptoms was explained by unique environmental influences. The phenotypic correlation between BPT and ADHD symptoms was estimated at r = 0.59, and could be explained for 49% by genetic factors and 51% by environmental factors. The genetic and environmental correlations between BPT and ADHD symptoms were 0.72 and 0.51, respectively. The shared etiology between BPT and ADHD symptoms is thus a likely cause for the comorbidity of the two disorders. PMID- 21812104 TI - Phenotypical spectrum of cerebellar ataxia associated with a novel mutation in the CA8 gene, encoding carbonic anhydrase (CA) VIII. AB - We define the neurological characteristics of familial cases from multiple branches of a large consanguineous family with cerebellar ataxia, mental retardation (MR), and dysequilibrium syndrome type 3 caused by a mutation in the recently cloned CA8 gene. The linkage analysis revealed a high logarithm of the odds (LOD) score region on 8q that harbors the CA8 in which a novel homozygous c.484G>A (p.G162R) mutation was identified in all seven affected members. The patients had variable cerebellar ataxia and mild cognitive impairment without quadrupedal gait. The brain MRI showed variable cerebellar volume loss and ill defined peritrigonal white matter abnormalities. The Fluorodeoxyglucose Positron Emission Tomography (FDG PET) revealed hypometabolic cerebellar hemispheres, temporal lobes, and mesial cortex. This report expands the neurological and radiological phenotype associated with CA8 mutations. CA8 involvement should be considered in the differential diagnosis of other genetically unresolved autosomal recessive cerebellar ataxias. PMID- 21812105 TI - Differential modulation of cord blood and peripheral blood monocytes by intravenous immunoglobulin. AB - BACKGROUND: Immunoglobulins (IVIG) have been shown to be useful in adults suffering from sepsis. In contrast, prophylactic and curative IVIG trials failed to show beneficial effects in neonates. We tested the hypothesis that IVIG, have different effects on monocytes from cord blood (CBMO) and peripheral blood monocytes from adults (PBMO) with respect to survival, phenotype, and function. METHODS: Mononuclear cells, or purified monocytes, were cultured in 5% human serum, incubated with polyvalent IVIG (1 mg/ml), stimulated with green fluorescent protein (GFP)-labeled Escherichia coli (E. Coli-GFP), Interferon gamma (IFN-gamma, 50 U/ml), or the T cell mitogen anti-CD3 monoclonal antibody, alphaCD3-mAb, (5 MUg/ml). Phagocytosis, phenotype, T cell proliferation, and apoptosis were assessed by flow cytometry. RESULTS: IVIG enhanced phagocytosis in PBMO or CBMO when infected directly after isolation, while IVIG had no effect on monocytes cultured 48 h prior to infection. In contrast to PBMO, IVIG inhibited the IFN-gamma mediated up-regulation of CD80, CD86, and HLA-DR on CBMO. In the presence of IVIG, stimulation with alphaCD3 in cord blood enhanced deletion, inhibited blast formation and CD28 up-regulation of T cells (P < 0.05 vs. T cells from adults). IVIG induced monocyte apoptosis, associated with up-regulation of Annexin V and loss of nuclear DNA, which was more pronounced in CBMO. Although phagocytosis induced cell death (PICD) was lower in CBMO (P < 0.05 vs. PBMO), the addition of IVIG enhanced PICD levels of CBMO to the extent of PBMO. CONCLUSIONS: IVIG inhibits co-stimulatory receptors and functions of CBMO and induces apoptosis. These findings may be of clinical relevance for the failure of IVIG benefit in neonatal sepsis. PMID- 21812106 TI - Basal levels of CD34 positive cells in peripheral blood differ between individuals and are stable for 18 months. AB - BACKGROUND: Detection of basal levels of CD34 progenitor cells is a rare event analysis enumerating cells down to 1 cell/MUl. A reproducible analytic approach was used in three independent clinical trials in which multiple sequential assays were obtained from the same individual. METHODS: A 4 color panel combining, HLA DR, CD34, CD45, and CD11b was used in a dual platform analysis to quantify CD34 progenitor cells in peripheral blood, with quality control focused at the lowest measurements (i.e., basal levels), where assay error is greatest. RESULTS: Repeat testing of individuals every 4 h over the course of 6 days provided a unique opportunity to assess the precision of the analytic technique and identified basal differences between individuals. In a second study, the basal levels were stable for 10 weeks while in a third study the individual differences were maintained for 18 months. This approach was then used to monitor the kinetics of mobilization of CD34 cells following G-CSF stimulation every 4 h. CONCLUSIONS: The differences between individuals in basal levels of CD34 were shown to be a biologic constant, stable for 18 months and not a result of the variability of the assay, shown by low coefficients of variation for each individual. These results can be used to augment a quality control program by monitoring individuals over time to establish intra and inter-laboratory assay precision. In addition, the response of six individuals to G-CSF demonstrated differences in absolute numbers of mobilized CD34 progenitor cells but showed identical kinetics, peaking at 80-110 h. PMID- 21812107 TI - Coenzyme Q10 suppresses oxLDL-induced endothelial oxidative injuries by the modulation of LOX-1-mediated ROS generation via the AMPK/PKC/NADPH oxidase signaling pathway. AB - SCOPE: The lectin-like oxidized low-density lipoprotein receptor (LOX-1) is one pivot receptor for oxidized low-density lipoprotein (oxLDL) in human endothelial cells. Co-enzyme Q10 (Co Q10) has been widely used in clinical intervention. However, the molecular mechanisms underlying its protective effects against oxidative stress in endothelial cells are still largely unknown. This study was designed to test the hypothesis that Co Q10 mitigates oxLDL-induced endothelial oxidative injuries via modulation of LOX-1-mediated reactive oxygen species (ROS) generation and explored the role of AMP-activated protein kinase (AMPK), a negative regulator of NADPH oxidase. METHODS AND RESULTS: Human umbilical vein endothelial cells (HUVECs) were pretreated with Co Q10 and then incubated with oxLDL for 24 h. Co Q10 attenuated oxLDL-elicited LOX-1 expression and ROS generation by suppression of NADPH oxidase activation. Co Q10 rescued dephosphorylation of AMPK caused by oxLDL that in turn led to an activation of NADPH oxidase by PKC. The results were confirmed using AMPK siRNA. Moreover, oxLDL-suppressed Akt/eNOS and enhanced p38 phosphorylation, which in turn activated NF-kappaB pathway. These detrimental events were ameliorated by Co Q10. CONCLUSION: These results provide new highlight onto the possible molecular mechanisms of how Q10 suppresses oxLDL-induced endothelial oxidative injuries by the modulation of LOX-1-mediated ROS generation via the AMPK/PKC/NADPH oxidase signaling pathway. PMID- 21812111 TI - Evaluation of copper-1,3,5-benzenetricarboxylate metal-organic framework (Cu-MOF) as a selective sorbent for Lewis-base analytes. AB - The metal-organic framework copper-1,3,5-benzenetricarboxylate (Cu-BTC) was evaluated for its ability to selectively interact with Lewis-base analytes by examining retention on gas-chromatographic columns packed with Chromosorb W HP that contained 3.0% SE-30 along with various loadings of Cu-BTC. Scanning electron microscopy images of the support material showed the characteristic Cu BTC crystals embedded in the SE-30 coating on the diatomaceous support. The results indicated that the Cu-BTC-containing stationary phase had limited thermal stability (220 degrees C) and strong general retention for analytes. Kovats index calculations showed selective retention (amounting to about 300 Kovats units) relative to n-alkanes for many small Lewis-base analytes on a column that contained 0.75% Cu-BTC compared with an SE-30 control. Short columns that contained lower loadings of Cu-BTC (0.10%) allowed elution of nitroaromatics; however, selectivity was not observed for aromatic compounds (including nitroaromatics) or nitroalkanes. Observed retention characteristics are discussed. PMID- 21812109 TI - Acrolein-induced dyslipidemia and acute-phase response are independent of HMG-CoA reductase. AB - SCOPE: Aldehydes are ubiquitous natural constituents of foods, water and beverages. Dietary intake represents the greatest source of exposure to acrolein and related aldehydes. Oral acrolein induces dyslipidemia acutely and chronically increases atherosclerosis in mice, yet the mechanisms are unknown. Because lipid synthesis and trafficking are largely under hepatic control, we examined hepatic genes in murine models of acute and chronic oral acrolein exposure. METHODS AND RESULTS: Changes in hepatic gene expression were examined using a Steroltalk microarray. Acute acrolein feeding modified plasma and hepatic proteins and increased plasma triglycerides within 15 min. By 6 h, acrolein altered hepatic gene expression including Insig1, Insig2 and Hmgcr genes and stimulated an acute phase response (APR) with up-regulation of serum amyloid A genes (Saa) and systemic hypoalbuminemia. To test if decreased HMG-CoA reductase activity could modify acrolein-induced dyslipidemia or the APR, mice were pretreated with simvastatin. Statin treatment, however, did not alter acrolein-induced dyslipidemia or hypoalbuminemia associated with an APR. Few hepatic genes were dysregulated by chronic acrolein feeding in apoE-null mice. These studies confirmed that acute acrolein exposure altered expression of hepatic genes involved with lipid synthesis and trafficking and APR, and thus, indicated a hepatic locus of acrolein-induced dyslipidemia and APR that was independent of HMG CoA-reductase. CONCLUSION: Dietary intake of acrolein could contribute to cardiovascular disease risk by disturbing hepatic function. PMID- 21812108 TI - The effects of acrolein on the thioredoxin system: implications for redox sensitive signaling. AB - The reactive aldehyde acrolein is a ubiquitous environmental pollutant and is also generated endogenously. It is a strong electrophile and reacts rapidly with nucleophiles including thiolates. This review focuses on the effects of acrolein on thioredoxin reductase (TrxR) and thioredoxin (Trx), which are major regulators of intracellular protein thiol redox balance. Acrolein causes irreversible effects on TrxR and Trx, which are consistent with the formation of covalent adducts to selenocysteine and cysteine residues that are key to their activity. TrxR and Trx are more sensitive than some other redox-sensitive proteins, and their prolonged inhibition could disrupt a number of redox-sensitive functions in cells. Among these effects are the oxidation of peroxiredoxins and the activation of apoptosis signal regulating kinase (ASK1). ASK1 promotes MAP kinase activation, and p38 activation contributes to apoptosis and a number of other acrolein-induced stress responses. Overall, the disruption of the TrxR/Trx system by acrolein could be significant early and prolonged events that affect many aspects of redox-sensitive signaling and oxidant stress. PMID- 21812112 TI - Preparative separation of minor saponins from Platycodi Radix by high-speed counter-current chromatography. AB - Platycosides (PSs), the saponins found in the root of Platycodon grandiflorum (Jacq.) A. DC. (Platycodi Radix), are typically composed of oleanene backbones with two side chains; one is a 3-O-glucose linked by a glycosidic bond, and the other is a 28-O-arabinose-rhamnose-xylose-apiose linked by an ester bond. Minor saponins, acetylated isomers of the major saponin on either the 2'' or 3'' position of rhamnose, were isolated from Platycodi Radix using a multi-step process including high-speed counter-current chromatography (HSCCC) and preparative reversed-phase high-performance liquid chromatography (RP-HPLC). After the separation of the major components, the enriched minor saponin fraction was used for this study. A two-phase solvent system consisting of chloroform methanol-isopropanol-water (3:2:2:3, v/v) was used for HSCCC. HSCCC separation of the enriched minor saponin fraction yielded 2''-O-acetylplatycodin D, 3''-O acetylpolygalacin D, 2''-O-acetylpolygalacin and a mixture of 3''-O acetylplatycodin D and polygalacin D. The mixture fraction from HSCCC separation was further purified by preparative RP-HPLC, giving 3''-O-acetylplatycodin D and polygalacin D at a purity of over 98.9%. The developed method provides the preparative and rapid separation of minor saponins in the crude extract of Platycodi Radix. To the best of our knowledge, this is the first on the separation of acetylated PSs by HSCCC. PMID- 21812113 TI - An improved liquid chromatographic method for the analysis of tylosin and its impurities. AB - A selective reversed-phase (RP) liquid chromatographic (LC) method coupled with UV for the determination of tylosin and its related substances is described. The gradient method uses a Capcell pak C18 ACR column (25 cm*4.6 mm id, 5 MUm) maintained at a temperature of 60 degrees C. The mobile phases consist of acetonitrile, phosphate buffer pH 5.5 and water: (A; 27.5:10:62.5 v/v/v) and (B; 50:10:40 v/v/v). The flow rate is 1.0 mL/min and UV detection is performed at 280 nm. It allows the separation of all known and 22 other unknown related substances (>=0.02%) from the main compound and from one another. The method shows good precision, sensitivity, linearity (between 0.2 MUg/mL and 1.25 mg/mL) and robustness. The limit of quantification is 0.2 MUg/mL, corresponding to 0.020%. Seven bulk tylosin samples containing a large number of impurities were examined using this method. PMID- 21812114 TI - Chromatography of bis-(3-sulfopropyl) disulfide and its breakdown products by HPLC coupled with electrochemical detection. AB - A chromatographic method for the detection of bis-(3-sulfopropyl) disulfide (SPS), a common additive in acidic copper plating baths, and its breakdown products is demonstrated. The detection scheme involves a combination of solid phase extraction for sample pre-treatment, C(18) reversed-phase high-performance liquid chromatography column for separation, and electrochemical sensor for detection of all non-fully oxidized sulfur-containing compounds. We were able to achieve an effective separation and accurately assign chromatographic peaks to all detectable species. Owing to a high sensitivity of the utilized electrochemical detector, detection in low parts per billion range was possible. This can prove crucial for plating bath control, since minute amounts of certain by-products significantly affect the bath performance. PMID- 21812115 TI - Estimation of molecular diffusivity in aqueous solution of acetonitrile by the Wilke-Chang equation. AB - It was tried to estimate the molecular diffusivity (D(m)) of solutes in the mixtures of acetonitrile (ACN) and water by the Wilke-Chang equation. Although the information about association coefficient (alpha) is necessary for the calculation, it has never been proposed for ACN. The value of alpha was estimated as 1.37 from D(m) of benzene in ACN at 303 K experimentally measured by the peak parking method. The values of alpha, i.e. 2.6, 1.9, 1.5, and 1.0, which have respectively been proposed for four solvents, i.e. water, methanol, ethanol, and benzene, were correlated with two physico-chemical parameters of the solvents, i.e. solubility parameter and E(T) value. The alpha value for ACN was plotted around the two correlations, indicating its appropriateness. The values of D(m) calculated by the Wilke-Chang equation using the alpha value for ACN were compared with those measured by the peak parking method and the Aris-Taylor method in aqueous solutions of ACN. The mean square deviation of the estimation of D(m) was calculated as 8.8 and 14%. It was demonstrated that the Wilke-Chang equation can be used for estimating D(m) with a reasonable accuracy in the mixtures consisting of ACN and water. PMID- 21812116 TI - The human variome: genomic and epigenomic diversity. PMID- 21812117 TI - Evaluation of a multilayered chitosan-hydroxy-apatite porous composite enriched with fibronectin or an in vitro-generated bone-like extracellular matrix on proliferation and diferentiation of osteoblasts. AB - The use of extracellular matrix (ECM) molecules from tissues is an interesting way to induce specific responses of cells grown onto composite scaffolds to promote adhesion, proliferation and differentiation. There have been several studies on the effects on cell proliferation and differentiation of osteoprogenitor cells cultured onto composites, either adding some ECM molecules or grown in the presence of growth factors. Other studies involve the use of osteoblasts cultured on a three-dimensional (3D) matrix, enriched with ECM molecules produced by the same cells grown previously inside the composite. Here, the effect of enrichment of a novel multilayered chitosan-hydroxyapatite composite with ECM molecules produced by osteoblasts, or the addition of 25 or 50 ug/ml fibronectin to the composite, on proliferation and differentiation of osteoblasts cultured on these composites was studied. The results showed an increase in the number of osteoblasts from day 1 of culture, which was higher in the group grown onto composites enriched with the highest concentration of fibronectin or with ECM molecules produced naturally by osteoblasts cultured previously on them, when compared with the control group. However, this increment tended to decline in all groups after day 7 of culture, the day when they reached the highest peak of proliferation. Differentiation expressed as alkaline phosphatase activity followed the proliferation pattern of the cells cultivated on the scaffolds. The results demonstrate the potential offered by these enriched 3D multilayered composites for improving their ability as bone grafting material. PMID- 21812118 TI - Particle morphology characterization and manipulation in biomass slurries and the effect on rheological properties and enzymatic conversion. AB - An improved understanding of how particle size distribution relates to enzymatic hydrolysis performance and rheological properties could enable enhanced biochemical conversion of lignocellulosic feedstocks. Particle size distribution can change as a result of either physical or chemical manipulation of a biomass sample. In this study, we employed image processing techniques to measure slurry particle size distribution and validated the results by showing that they are comparable to those from laser diffraction and sieving. Particle size and chemical changes of biomass slurries were manipulated independently and the resulting yield stress and enzymatic digestibility of slurries with different size distributions were measured. Interestingly, reducing particle size by mechanical means from about 1 mm to 100 MUm did not reduce the yield stress of the slurries over a broad range of concentrations or increase the digestibility of the biomass over the range of size reduction studied here. This is in stark contrast to the increase in digestibility and decrease in yield stress when particle size is reduced by dilute-acid pretreatment over similar size ranges. PMID- 21812119 TI - Festschrift in honor of the 100th birthday of Theodore Forster. PMID- 21812120 TI - Proceedings of a workshop on Klinefelter Syndrome. May 6-8, 2010, Copenhagen, Denmark. PMID- 21812121 TI - Proceedings of the 2011 ASCO Gastrointestinal Cancers Symposium. January 20-22, 2011,San Francisco, CA, USA. PMID- 21812122 TI - Special issue dedicated to the memory of Oleg Abramov and Anne-Marie Wilhelm. PMID- 21812123 TI - Proceedings of the 17th International Symposium on Electro- and Liquid Phase separation Techniques. August 29 - September 1, 2010, Baltimore, Maryland, USA. PMID- 21812124 TI - N-type Ca2+ channels as scaffold proteins in the assembly of signaling molecules for GABAB receptor effects. PMID- 21812125 TI - G protein-induced trafficking of voltage-dependent calcium channels. PMID- 21812126 TI - Arrestin is required for agonist-induced trafficking of voltage-dependent calcium channels. PMID- 21812127 TI - beta-Adrenergic receptor activation induces internalization of cardiac Cav1.2 channel complexes through a beta-arrestin 1-mediated pathway. PMID- 21812129 TI - Selected Papers of the 4th Summer School of Monolith Technology for Biochromatography, Bioconversion and Phase State Synthesis. May 30- June 2, 2010, Portoroz, Slovenia. PMID- 21812128 TI - Strengthening our soldiers SOS and their families: contemporary psychological advances applied to wartime problems. Why now? Why us? What next? PMID- 21812132 TI - Abstracts of the Annual Symposium of the Society for the Study of Inborn Errors of Metabolism. Geneva, Switzerland. August 30-September 2, 2011. PMID- 21812133 TI - Abstracts of the Thirty-fourth Meeting of the American Society of Primatologists. September 16-19, 2011. Austin, Texas, USA. PMID- 21812131 TI - [To the Editor: Homeopathy]. PMID- 21812134 TI - Proceedings of the 34th Scientific Meeting of the Association of Marine Laboratories of the Caribbean. May 25-28, 2009, Roseau, Dominica. PMID- 21812135 TI - Abstracts of the 15th Congress of the International Headache Society. June 23-26, 2011. Berlin, Germany. PMID- 21812136 TI - Proceedings and abstracts of the 6th World Workshop on Oral Health and Disease in AIDS, April 21-24, 2009, Beijing, China. PMID- 21812137 TI - Guest editors' introduction to the special section on bioinformatics research and applications. PMID- 21812138 TI - [Genetic characterization of Vibrio cholerae strains emerging in Russian Federation during 7th cholera pandemic]. AB - AIM: Comparative molecular-genetic analysis of clinical Vibrio cholerae eltor biovariant strains isolated in Russia during various years. MATERIALS AND METHODS: Microbiological and biochemical methods were used for studies of 25 clinical strains of classic and eltor biovariant cholera, PCR testing and sequencing of various genes was also performed. RESULTS: Phenotypic and genetic analysis of clinical V. cholerae strains isolated in Russia during 7th cholera pandemic has confirmed that they belong to biovariant eltor. PCR testing of 21 isolates obtained from patients in 1970 - 2010 has shown that epidemic complications in Russia from 1993 were caused by altered V. cholerae biovariant eltor. Presence of classic cholera biovariant ctxB coding gene in cholera toxin coding CTX prophage is the genetic alteration of these variants, ctxB sequencing in altered variants has confirmed PCR data and shown 2 ctxB gene alleles (ctxB1 and ctxB7). Altered variants produced significantly more cholera toxin than typical strains. CONCLUSION: In 1970 - 2010 67.6% of clinical isolates were altered V. cholera biovariant eltor variants. These new variants were genetically diverse. Alteration of cholera eltor biovariant genome caused toxigenicity increase. PMID- 21812139 TI - [Epidemiology of influenza A/California/07/09 (H1N1) in population of 49 cities in Russia in 2009 - 2010]. AB - AIM: Comparison of influenza A(H1N1) epidemic in Russia caused by pandemic virus A/ California/07/09 (H1N1) in 2009 with previous epidemics of influenza A of this subtype. MATERIALS AND METHODS: Analysis of A/California/07/09 (H1N1) epidemic was carried out in 49 cities--bases of Federal center of influenza. Parameters of this epidemic by duration, influenza and acute respiratory viral illness morbidity, hospitalization and mortality rates from laboratory confirmed influenza in the population in general and in age groups (0 - 2 years, 3 - 6 years, 7 - 14 years, 15 - 64 years, 65 years and older) were studied. RESULTS: A/California/07/09 (H1N1) epidemic differed from the seasonal epidemics by unusually early onset, monoetiology, wide coverage of the population of cities, longer duration and higher morbidity in the population from 7 to 64 years of age, higher rate of hospitalizations and number of lethal outcomes in the population from 15 to 64 years of age. Lower morbidity, rate of hospitalizations and number of lethal outcomes was notable in individuals older than 65 years, that is an indication of the presence of an anamnestic immunity. CONCLUSION: Comparative analysis of A/ California/07/09 (H1N1) epidemic with 3 previous influenza pandemics in Russia has shown, that during this epidemic population morbidity was 2 times lower than during 1957 and 1968 pandemics, and the rate approached that of the 1977 pandemic. This epidemic differed from previous pandemics by a delay of city-megapolis and preschool aged children involvement, early onset and lower intensity of peak; lower relative rate of morbidity among adult population and higher--among school children; higher multiplicity of excessive morbidity of children compared with morbidity of people older than 15 years. PMID- 21812140 TI - [Cancer molecular epidemiology: new horizons of prophylaxis]. AB - Perspectives of malignant neoplasm prophylaxis based on molecular biology achievements are discussed. Gene variants critical to development of hereditary cancer syndromes, genes modulating malignant neoplasm development risk without hereditary cancer syndrome development, and genes determining tendency of individuals for different malignant neoplasm progress risk increasing lifestyle factors are examined. Molecular epidemiology by using large scale population analysis of cancerogenesis linked genetic polymorphisms prevalence allows determination of risk groups at the most earlier stages of cell transformation or even before the onset of cell malignization and development of goal-based prophylaxis measures based on polymorphism and corresponding cancer type. Epidemiologic analysis of this type allows for earlier diagnostics in risk groups, therapy efficacy increase, disability decrease. Specific therapy on molecular level may be possible in the future. PMID- 21812141 TI - [Immunogenicity of influenza virus H5N2 vaccine strain samples produced by roller cultivation in media with plant derived components]. AB - AIM: Study in CBA line mice of immunogenicity of cold adapted reassortant influenza virus H5N2 vaccine strain samples produced in rollers in MDCK and Vero cell cultures by using plant derived components. MATERIALS AND METHODS: Antibody levels in blood sera and nasal swabs, lungs and small intestine of experimental vaccine strain sample immunized mice were evaluated by using HI reaction in accordance with WHO recommendations. RESULT: Reassortant vaccine strain A/17/duck/Potsdam/86/92 (H5N2) produced in MDCK and Vero cells by using plant derived components (rice and soy flour hydrolyzate and plant protease based nutrient medium) after intranasal immunization of mice induced local and humoral antibodies, and the latter not only against homologous virus, but also against highly pathogenic avian influenza virus strains A/ Chicken/Suzdalka/Nov-11/2005 and A/Chicken/Kurgan/05/2005. CONCLUSION: Immunogenicity studies of reassortant influenza virus A/17/duck/Potsdam/86/92 (H5N2) vaccine strain samples cultivated in MDCK and Vero cells by using media with plant derived components in mice show high levels of humoral and secretory immunity. PMID- 21812142 TI - [Modification of infrastructure of Candida albicans under the influence of associative microbiota exometabolites]. AB - AIM: Evaluation of the influence of bacterial microbiota exometabolites on temporal organization of biological features of Candida albicans. MATERIALS AND METHODS; Experiments were carried out on the model of C. albicans 24433 ATCC for 24 hours with 4 hour intervals. Biorythms of proliferative, phospholipase and adhesive activity of fungi were studied. Influence of exometabolites of Staphylococcus aureus 25923 ATCC, Escherichia coli 35218 ATCC, Pseudomonas aeruginosa 27853 ATCC on biological properties of C. albicans were examined. The results were statistically analyzed by using Student's t-test. RESULTS: Circadian biological rhythms were detected for all investigated parameters of C. albicans 24433 ATCC. In the presence of exometabolites of S. aureus and P. aeruginosa, rhythm profile and amplitude oscillation of the fungi changes, and phase synchronism is disrupted. Under the influence of exometabolites of Gram-negative microbiota a marked desynchrony of fungi adhesive activity was observed. CONCLUSION: The results obtained confirm the key role of microorganisms in the formation and regulation of pathogenic microsymbiocenosis, and determine the necessity to study mechanisms of symbiotic interaction of bacteria and fungi. PMID- 21812143 TI - [Prevalence of latent (HBs negative) chronic hepatitis B among patients of infectious disease cabinets in St. Petersburg outpatients clinics]. AB - AIM: Evaluation of prevalence of latent form (HBsAg negative) of chronic viral hepatitis B (HVHB) among patients being examined in cabinets of St. Petersburg infectious disease polyclinics with chronic viral hepatitis diagnosis. MATERIALS AND METHODS: Laboratory investigation included HVHB markers determination: HBsAg, anti-HBs, anti-HBcor IgM, anti-HBcor, HBeAg, anti-HBe, hepatitis B virus (HBV) DNA in blood sera and plasma of patients. A total of 705 individuals were examined. RESULTS: In 25.4% of patients laboratory markers of hepatitis B virus were not present, 20.1% of patients were reconvalescent with anti-HBs antibodies in titers greater than 10 IU/ml and HBV DNA not present. Laboratory HVHB diagnosis was confirmed only in 384 (54.5%) of examined patients, most of these had HBsAg positive form of infection (69.0%) with HBV DNA in blood sera (60%). Only anti-HBcor or anti-HBe antibodies were detected and HBsAg and anti-HBs were not detected in 119 (31.0%) of cases. 6 patients of this group had HBV DNA in blood plasma higher than 20 IU/ml (1.6% of total number of patients with laboratory confirmed HVHB). CONCLUSION: Standard laboratory examination of patients from hepatitis B infection (including HVHB) high risk groups should include a full list of markers (serological and DNA), thus allowing latent HVHB diagnostics, that, based on our data, amounts to 1.6% of examined patients with HVHB. PMID- 21812144 TI - A report of suicide trends and overall suicide prevention measures in Germany: opinion on prevention measures is important. PMID- 21812145 TI - A report on the importance of further liaison between relevant organizations in implementing suicide prevention measures in Japan: a summary along with a look at areas of future study. PMID- 21812146 TI - A triumvirate of leaders in HIV vaccine field depart posts. PMID- 21812147 TI - Addendum to "The cytotoxicity and genotoxicity of hexavalent chromium in Steller sea lion lung fibroblasts compared to human lung fibroblasts" [Comp Biochem Physiol C Toxicol Pharmacol. 152(1)91-8. PMID- 21812148 TI - [Comparison between conventional radiotherapy and intensity modulated radiotherapy for head and neck cancer-effectiveness and adverse effect-]. PMID- 21812149 TI - [Problems of salvage therapy following concurrent chemoradiotherapy]. PMID- 21812150 TI - [Q & A in imaging diagnosis]. PMID- 21812151 TI - White-spot lesions. PMID- 21812152 TI - Group health plans and health insurance issuers relating to coverage of preventive services under the Patient Protection and Affordable Care Act. Interim final rules with request for comments. AB - This document contains amendments to the interim final regulations implementing the rules for group health plans and health insurance coverage in the group and individual markets under provisions of the Patient Protection and Affordable Care Act regarding preventive health services. PMID- 21812153 TI - Dialysis in the kingdom of Saudi Arabia. PMID- 21812154 TI - Leaving a person behind: history, personhood, and struggles over forest resources in the Sangha Basin of Equatorial Africa. PMID- 21812155 TI - "Enkurma sikitoi": commoditization, drink, and power among the Maasai. PMID- 21812156 TI - The anatomy of a demographic explosion: Luanda, 1844-1850. PMID- 21812158 TI - Global fascism and the male body: ambitions, similarities and dissimilarities. PMID- 21812159 TI - Miracles of war. PMID- 21812160 TI - Model of masculinity: Mussolini, the "new Italian" of the Fascist era. PMID- 21812161 TI - The use of computer image analyses in the assessment of chosen histoclinical features of nephroblastoma cells in children. AB - The goal of the research was to assess the nuclear morphometric discriminant function (MV(f)) in the analyzed group of nephroblastomas and to evaluate its potential prognostic value. We found a statistically important correlation between favourable histology of Wilms' tumours (according to SIOP 93-01 and SIOP 2001 classifications of kidney tumours of childhood) and low values of MV(f) discriminant function, which was also associated with the best prognosis for the patients. We believe that MV(f) assessment may be a helpful tool in making prognosis in doubtful cases of nephroblastomas in children. PMID- 21812162 TI - Muscular "Anschluss": German bodies and Austrian imitators. PMID- 21812163 TI - [Coping with ubiquitous DNA testing]. PMID- 21812164 TI - [5th Janske Lazne Symposium. 13-15 January 2011]. PMID- 21812165 TI - Pediatricians' experience with and response to parental vaccine safety concerns and vaccine refusals: a survey of Connecticut pediatricians. AB - OBJECTIVES: Physicians are seeing increasing numbers of parents who question the safety of vaccines or refuse to vaccinate their children. This study examined how frequently pediatricians in one New England state encounter parental vaccine safety concerns and vaccine refusals, how often physicians dismiss families from their practices for vaccine refusal, and how parental vaccine refusal impacts pediatricians personally. METHODS: The study consisted of a quantitative survey of primary care pediatricians in one New England state; 133 pediatricians completed the questionnaire. Variables examined included number of parental vaccine concerns and refusals seen by each physician, physicians' response to parental vaccine concerns and refusals, the personal impact of parental vaccine safety refusals on pediatricians, and respondent estimates of socioeconomic characteristics of families seen in their practices. RESULTS: The majority of responding pediatricians reported an increase in parental vaccine safety concerns and refusals. More than 30% of responding pediatricians have dismissed families because of their refusal to immunize. Suburban physicians caring for wealthier, better educated families experience more vaccine concerns and/or refusals and are more likely to dismiss families for vaccine refusal. Vaccine refusals have a negative personal impact on one-third of physician respondents. CONCLUSIONS: Pediatricians in Connecticut are reporting increased levels of parental vaccine safety concerns and refusals. Physicians who report more parental vaccine safety concerns and refusals and who care for wealthier, better educated families are more likely to dismiss families who refuse vaccines and to be negatively affected by parental vaccine refusals, which may adversely impact childhood vaccination rates. PMID- 21812166 TI - How parents' negative experiences at immunization visits affect child immunization status in a community in New York City. AB - OBJECTIVE: Little is known about how families' experiences with immunization visits within the medical home may affect children's immunization status. We assessed the association between families' negative immunization experiences within the medical home and underimmunization. METHODS: We surveyed parents (n = 392) of children aged 2-36 months about immunization experiences at community health centers, hospital-based clinics, private practices, and community-based organizations in New York City. We used Chi-square tests and odds ratios (ORs) to assess the relationship between medical home elements and parental immunization experience ratings. We used multivariable analysis to determine the association between negative experiences during immunization visits and underimmunization, controlling for insurance, maternal education, and receipt of benefits from the Special Supplemental Nutrition Program for Women, Infants, and Children. RESULTS: The majority of children were of Latino race/ethnicity and had Medicaid and a medical home. One-sixth (16.9%) of families reported a previous negative immunization experience, primarily related to the child's reaction, waiting time, and attitudes of medical and office staff. Parents' negative immunization experiences were associated with the absence of four components of the medical home: continuity of care, family-centered care, compassionate care, and comprehensive care. In addition, children in families who reported a negative experience were more likely to have been underimmunized (adjusted OR = 2.00; 95% confidence interval 1.12, 3.58). CONCLUSIONS: In a community in New York City, underimmunization of young children was associated with negative immunization experiences. Strategies to improve family experiences with immunization visits within the medical home (particularly around support for the family), medical and ancillary staff attitudes, and reduced waiting time may lead to improved immunization delivery. PMID- 21812167 TI - Improving immunization rates at 18 months of age: implications for individual practices. AB - OBJECTIVE: We sought to model the effect that a targeted immunization visit at 18 months of age could have on immunization rates of preschool-aged children in a sample of pediatric practices. METHODS: We conducted retrospective chart reviews in six practices of all active patients aged 18-30 months. Up-to-date (UTD) status was defined as receipt of four diphtheria-tetanus-acellular pertussis, three polio, one measles-mumps-rubella, three hepatitis B, and one varicella vaccines. Haemophilus influenza tybe b vaccine was not included due to a shortage in vaccine supply during the time of the study. Practice vaccination rates were determined at 17 months, 18 months, and the age at assessment. Of those not UTD at 17 months, the percentage of children who could be brought UTD with one visit was calculated for each practice. This calculated rate was compared with the measured rate at 18 months of age and at the age of assessment. RESULTS: At each practice, we reviewed 183-616 charts (median = 382). Observed UTD immunization rates at 17 months ranged from 26% to 64% (median = 38%) and increased 3 to 27 percentage points (median = 6) from age 17 months to 18 months and 9 to 39 percentage points (median = 17) from age 17 months to the age at assessment. A simulated vaccination visit at 18 months of age could improve the UTD rates from 27 to 61 percentage points (median = 44). CONCLUSION: Practice-based interventions aimed at encouraging an 18-month well-child visit that emphasizes delivery of vaccines have the potential to substantially increase timely vaccination rates among individual practices. PMID- 21812168 TI - Increasing inner-city adult influenza vaccination rates: a randomized controlled trial. AB - OBJECTIVES: In a population of seniors served by urban primary care centers, we evaluated the effect of the practice-based intervention on influenza immunization rates and disparities in vaccination rates by race/ethnicity and insurance status. METHODS: A randomized controlled trial during 2003-2004 tested patient tracking/recall/outreach and provider prompts on improving influenza immunization rates. Patients aged > or = 65 years in six large inner-city primary care practices were randomly allocated to study or control group. Influenza immunization coverage was measured prior to enrollment and on the end date. RESULTS: At study end, immunization rates were greater for the intervention group than for the control group (64% vs. 22%, p < 0.0001). When controlling for other factors, the intervention group was more than six times as likely to receive influenza vaccine. The intervention was effective across gender, race/ ethnicity, age, and insurance subgroups. Among the intervention group, 3.5% of African Americans and 3.2% of white people refused influenza immunization. CONCLUSIONS: Patient tracking/recall/outreach and provider prompts were intensive but successful approaches to increasing seasonal influenza immunization rates among this group of inner-city seniors. PMID- 21812169 TI - Extra-immunization as a clinical indicator for fragmentation of care. AB - OBJECTIVES: We assessed whether extra-immunization can serve as a clinical indicator for fragmentation of care. METHODS: Using public-use files of the 1999 2003 National Immunization Survey, we classified children 19-35 months of age by their vaccination providers for the degree of fragmentation of care as ordered from lowest with one vaccine provider, to increasing fragmentation with multiple providers in one facility type, to multiple providers in more than one facility type. Extra-immunization was defined conservatively based on the year-specific recommendations of the Advisory Committee on Immunization Practices (ACIP) for immunizations due before 18 months of age. Of note, 1999-2003 transitioned from oral to inactivated poliovirus vaccines. RESULTS: The rate for extra-immunization was 9.4% (95% confidence interval [CI] 9.2, 9.7). Of single vaccines, the rate for polio vaccine was highest (5.7%, 95% CI 5.5, 6.0). Extra-immunization was lowest for the 69% of children with only one vaccination provider (6.4%, 95% CI 6.1, 6.7), was higher in children who had more than one vaccination provider with one vaccination facility type (13.9%, 95% CI 13.2, 14.6), and highest with more than one facility type (24.1%, 95% CI 22.5, 25.6). Logistic regression (including race/ethnicity, language, provider type, survey year, and a parent-held immunization record) confirmed that multiple providers (adjusted odds ratio [AOR] = 2.30), multipl facility types (AOR = 4.67), Spanish language (AOR = 1.29), and race/ethnicity (black AOR = 1.16, Hispanic AOR = 1.31) were each associated with extra-immunization. Excluding poliovirus vaccine from the analysis, AORs for multiple providers and multiple facility types increased to 3.64 and 8.95, respectively. CONCLUSIONS: Extra-immunization is associated with receiving immunizations from multiple providers and multiple facility types. PMID- 21812170 TI - Validity of parent-reported vaccination status for adolescents aged 13-17 years: National Immunization Survey-Teen, 2008. AB - OBJECTIVE: The validity of parent-reported adolescent vaccination histories has not been assessed. This study evaluated the validity of parent-reported adolescent vaccination histories by a combination of immunization card and recall, and by recall only, compared with medical provider records. METHODS: We analyzed data from the 2008 National Immunization Survey-Teen. Parents of adolescents aged 13-17 years reported their child's vaccination history either by immunization card and recall (n = 3,661) or by recall only (n = 12,822) for the hepatitis B (Hep B), measles-mumps-rubella (MMR), varicella (VAR), tetanus diphtheria/tetanus-diphtheria-acellular pertussis (Td/ Tdap), meningococcal conjugate (MCV4), and quadrivalent human papillomavirus (HPV4) (for girls only) vaccines. We validated parental report with medical records. RESULTS: Among the immunization card/recall group, vaccines with > 20% false-positive reports included MMR (32.3%) and Td/Tdap (36.9%); vaccines with > 20% false-negative reports included VAR (35.2%), MCV4 (36.0%), and Tdap (41.9%). Net bias ranged from -25.0 to -0.1 percentage points. Kappa values ranged from 0.22 to 0.92. Among the recall-only group, vaccines with > 20% false-positive reports included Hep B (33.9%), MMR (61.4%), VAR (26.2%), and Td/Tdap (60.6%); vaccines with > 20% false-negative reports included Hep B (58.9%), MMR (33.7%), VAR (51.6%), Td/Tdap (25.5%), Tdap (50.3%) MCV4 (63.0%), and HPV4 (20.5%). Net bias ranged from -46.0 to 0.5 percentage points. Kappa values ranged from 0.03 to 0.76. CONCLUSIONS: Validity of parent-reported vaccination histories varies by type of report and vaccine. For recently recommended vaccines, false-negative rates were substantial and higher than false-positive rates, resulting in net underreporting of vaccination rates by both the immunization card/recall and recall-only groups. Provider validation of parent-reported vaccinations is needed for valid surveillance of adolescent vaccination coverage. PMID- 21812171 TI - Assessing the relationship between seasonal and H1N1 influenza vaccination status in Michigan children, 2009-2010. AB - OBJECTIVES To examine the relationship between the outcome of vaccination for H1N1 influenza and receipt of seasonal influenza vaccine in Michigan children during the 2009-2010 season, we examined the influenza vaccination status of all Michigan residents aged six months to 18 years who were enrolled in the Michigan Care Improvement Registry. METHODS: We calculated descriptive statistics for dichotomous and categorical variables, including numbers of children vaccinated with either influenza (H1N1) monovalent vaccine and/or seasonal influenza vaccine, gender, race! / ethnicity, provider type, moved-or-gone-elsewhere (MOGE) status, and vaccin type. We used logistic regression, adjusting for potential confounders and effect modifiers (age and MOGE status), to calculate odds ratios associate with H1N1 vaccine status (vaccinated vs. unvaccinated). RESULTS. Michigan children who were vaccinated for seasonal influenza from August 1, 2009, to February 27, 2010, were 6.26 (95% confidence interval 6.18, 6.34) times as likely as children who were unvaccinated for seasonal influenza to be vaccinated with H1N1 2009 monovalent vaccine. Private health-care providers administered 91% of the seasonal influenza vaccine and 59% of the H1N1 vaccine. CONCLUSIONS. Increasing seasonal influenza vaccination campaign efforts could also benefit pandemic influenza vaccination efforts. Special educational outreach to parents regarding the importance of influenza vaccination for all children, regardless of age, may be needed. Stocking and offering traditional seasonal vaccine with pandemic-specific vaccine may aid in increasing immunization uptake. Efforts should be made to ensure that private providers are supplied with adequate pandemic vaccine as part of preparedness planning. PMID- 21812172 TI - Using the North Dakota Immunization Information System to determine adolescent vaccination rates and uptake. AB - OBJECTIVES: We described the uptake and coverage rates of meningococcal conjugate vaccine (MCV4); tetanus-diphtheria-acellular pertussis vaccine (Tdap); and quadrivalent human papillomavirus vaccine (HPV4) in North Dakota using the North Dakota Immunization Information System (NDIIS). METHODS: We analyzed all available MCV4, Tdap, and HPV4 doses given after vaccine licensure and through December 31, 2009, obtained from the NDIIS to identify trends and patterns in vaccine administration. We analyzed all data by administration date, age group, and health-care provider type. We also calculated missed opportunities to complete all recommended vaccines among vaccinated adolescents. RESULTS: For adolescents aged 13-17 years, 69.2% had > or = 1 dose of Tdap and 62.8% had > or = 1 dose of MCV4. Of females aged 13-17 years, 42.8% initiated the HPV4 vaccination series and 24.9% received > or = 3 HPV4 doses. Only 48.7% of males aged 13-17 years received both Tdap and MCV4 at the same visit, and only 11.5% of females aged 13-17 years received Tdap, MCV4, and HPV4 doses at the first visit. CONCLUSIONS: The NDIIS is useful in tracking adolescent vaccine uptake. The immunization rates for all three routinely recommended adolescent vaccines are rising in North Dakota, although at different paces. Providers should be educated about the importance of not missing opportunities to vaccinate, and school-based vaccination clinics should be used to reach adolescents who are less likely to have preventive care visits. PMID- 21812173 TI - The effect of policy changes on hepatitis A vaccine uptake in Arizona children, 1995-2008. AB - OBJECTIVE: In 1995, the first hepatitis A vaccines became available for use. At that time, Arizona had the highest hepatitis A incidence of all 50 states. During that same time period, the Arizona State Immunization Information System (ASIIS) was created to collect information on all immunizations given in the state. Four state-level hepatitis A vaccination policies were enacted according to Centers for Disease Control and Prevention recommendations and local initiatives from 1996 to 2005. Our primary objective was to assess the impact of these policies on vaccine uptake in children. METHODS: Immunization records from ASIIS were used to calculate yearly coverage of children with at least one reported hepatitis A vaccination between 1995 and 2008. Proportions vaccinated were calculated by age group (12-23 months, 24-59 months, 5-9 years, 10-14 years, and 15-19 years) for three regions: Maricopa County; Apache and Navajo counties; and the remaining 12 Arizona counties, which were grouped as one to reflect different target groups for the four policies examined. We calculated percent changes from before and after each policy implementation. RESULTS: Significantly different percent changes were detected among the three regions that related to the four policies implemented. Percent change in uptake was consistently higher in the regions that were targeted for that specific policy. CONCLUSIONS: Analysis of ASIIS data revealed a major effect of hepatitis A policy recommendations on vaccine uptake in Arizona. Targeting high-risk populations through vaccine recommendations and child care entry requirements was highly successful in achieving higher vaccination coverage. PMID- 21812174 TI - The Swiss National Vaccination Coverage Survey, 2005-2007. AB - OBJECTIVES: We described the results from the Swiss National Vaccination Coverage Survey (SNVCS) 2005-2007, a survey designed to monitor immunization coverage of children and adolescents residing in Switzerland in each canton within a three year period. METHODS: The SNVCS is a cross-sectional survey using a two-stage sampling design targeting children aged 2, 8, and 16 years. Families of selected children were contacted by mail and telephone. Coverage was determined via vaccination cards or vaccination summary forms. RESULTS: A total of 25 out of 26 cantons participated in the survey, with 8,286 respondents for children aged 24 35 months, 10,314 respondents for children aged 8 years, and 9,301 respondents for teenagers aged 16 years. Compared with data from 1999-2003, coverage estimates for toddlers remained unchanged for diphtheria, tetanus, pertussis, poliomyelitis, and Haemophilus influenzae type b vaccines at three doses, but increased five percentage points to 86%-87% for measles-mumps-rubella at one dose and was 71% at two doses. Coverage for measles, mumps, and rubella were 89%-90% at one dose and 75% at two doses for 8-year-olds, and 94% and 76% for the two dosages, respectively, for 16-year-olds. Linguistic region and nationality were highly correlated with being vaccinated against measles for the two younger age groups. CONCLUSION: Despite the increase in vaccine coverage, measles vaccination is still low, and the World Health Organization goal to eliminate measles by 2010 was not achieved in Switzerland. More efforts are needed by the cantons and the central government to increase vaccination coverage. PMID- 21812175 TI - Vaccination coverage among U.S. children aged 19-35 months entitled by the Vaccines for Children program, 2009. AB - OBJECTIVES: Following the measles outbreaks of the late 1980s and early 1990s, vaccination coverage was found to be low nationally, and there were pockets of underimmunized children primarily in inner cities. We described the percentage and demographics of children who were entitled to the Vaccines for Children (VFC) program in 2009 and evaluated whether Healthy People 2010 (HP 2010) vaccination coverage objectives of 90% were achieved among these children. METHODS: We analyzed data from 16,967 children aged 19-35 months sampled by the National Immunization Survey in 2009. VFC-entitled children included children who were (1) on Medicaid, (2) not covered by health insurance, (3) of American Indian/Alaska Native race/ethnicity, or (4) covered by private health insurance that did not pay all of the costs of vaccines, but who were vaccinated at a Federally Qualified Health Center or a Rural Health Center. RESULTS: An estimated 49.7% of all children aged 19-35 months were entitled to VFC vaccines. Compared with children who did not qualify for VFC, the VFC-entitled children were significantly more likely to be Hispanic or non-Hispanic black; to have a mother who was widowed, divorced, separated, or never married; and to live in a household with an annual income below the federal poverty level. Mothers of VFC entitled children were significantly less likely to have some college experience or to be college graduates. Of nine vaccines analyzed, two vaccines--polio at 91.7% and hepatitis B at 92.2%--achieved the HP 2010 90% coverage objective for VFC-entitled children, and four others, including measles-mumps-rubella at 88.8%, achieved greater than 80% coverage. Conclusions. Today, children with demographic characteristics like those of children who were at the epicenter of the measles outbreaks two decades ago are entitled to VFC vaccines at no cost, and have achieved high vaccination coverage levels. PMID- 21812177 TI - [Celine Doray. Doing things differently]. PMID- 21812176 TI - Parental delay or refusal of vaccine doses, childhood vaccination coverage at 24 months of age, and the Health Belief Model. AB - OBJECTIVE: We evaluated the association between parents' beliefs about vaccines, their decision to delay or refuse vaccines for their children, and vaccination coverage of children at aged 24 months. METHODS: We used data from 11,206 parents of children aged 24-35 months at the time of the 2009 National Immunization Survey interview and determined their vaccination status at aged 24 months. Data included parents' reports of delay and/or refusal of vaccine doses, psychosocial factors suggested by the Health Belief Model, and provider-reported up-to-date vaccination status. RESULTS: In 2009, approximately 60.2% of parents with children aged 24-35 months neither delayed nor refused vaccines, 25.8% only delayed, 8.2% only refused, and 5.8% both delayed and refused vaccines. Compared with parents who neither delayed nor refused vaccines, parents who delayed and refused vaccines were significantly less likely to believe that vaccines are necessary to protect the health of children (70.1% vs. 96.2%), that their child might get a disease if they aren't vaccinated (71.0% vs. 90.0%), and that vaccines are safe (50.4% vs. 84.9%). Children of parents who delayed and refused also had significantly lower vaccination coverage for nine of the 10 recommended childhood vaccines including diphtheria-tetanus-acellular pertussis (65.3% vs. 85.2%), polio (76.9% vs. 93.8%), and measles-mumps-rubella (68.4% vs. 92.5%). After adjusting for sociodemographic differences, we found that parents who were less likely to agree that vaccines are necessary to protect the health of children, to believe that their child might get a disease if they aren't vaccinated, or to believe that vaccines are safe had significantly lower coverage for all 10 childhood vaccines. CONCLUSIONS: Parents who delayed and refused vaccine doses were more likely to have vaccine safety concerns and perceive fewer benefits associated with vaccines. Guidelines published by the American Academy of Pediatrics may assist providers in responding to parents who may delay or refuse vaccines. PMID- 21812178 TI - [Cancer registries]. PMID- 21812179 TI - [How to choose your sunglasses]. PMID- 21812180 TI - [Mental health: an entire world in action]. PMID- 21812181 TI - [Replacement caregiver for alzheimer patients]. PMID- 21812182 TI - [Lower extremity edema]. PMID- 21812183 TI - [Teamwork, yes!]. PMID- 21812184 TI - [When patients support each other]. PMID- 21812186 TI - [Sunburn]. PMID- 21812185 TI - [Organ donation and ethnic groups]. PMID- 21812187 TI - [The QT interval. An indicator of danger. Do you know how to calculate it?]. PMID- 21812188 TI - [Nausea and vomiting in pregnancy]. PMID- 21812189 TI - [Ragweed: a fight]. PMID- 21812191 TI - [Systematic investing. An efficient way of growing wealth]. PMID- 21812190 TI - [Making antibiotic therapy easier to use. A welcome advance for those with cystic fibrosis]. PMID- 21812192 TI - Advancing family planning research in Africa. PMID- 21812193 TI - The global roadmap to universal access to family planning: from Cairo to Kampala. PMID- 21812194 TI - Contraceptive use: knowledge, perceptions and attitudes of refugee youths in Oru Refugee Camp, Nigeria. AB - Refugee youths are vulnerable persons who have a need for contraception, yet face challenges that limit its use. Data on perceptions, knowledge, access and attitudes toward contraceptive use were collected from 208 refugee youths living in Oru refugee camp, Nigeria. Findings revealed that respondents experience difficulty gaining access to family planning services, which are not available in the camp. Most respondents had little correct information about contraceptives; 42.9% had misperceptions about its safety, believing that contraceptives are dangerous and that chemicals in contraceptives can damage their reproductive system. Such beliefs have resulted in the low use of contraceptives (31.6% use last sex) and many unintended pregnancies, which have caused some refugee girls to drop out of school. Findings may aid in the development of targeted interventions to educate refugee youths in order to dispel misperceptions about the safety of contraceptives and ensure adequate access to family planning services. PMID- 21812195 TI - Knowledge, perceptions and ever use of modern contraception among women in the Ga East District, Ghana. AB - A survey of 332 women, ages 15-49 years, was carried out in the Ga East district of Ghana to identify community knowledge, perceptions, and factors associated with ever using modern family planning (FP). Knowledge of modern FP was almost universal (97 percent) although knowledge of more than three methods was 56 percent. About 60 percent of all and 65 percent of married respondents reported ever use of a modern method. Among ever users, 82 percent thought contraceptives were effective for birth control. However, one-third did not consider modern FP safe. About 20 percent indicated their male partner as a barrier, and 65 percent of users reported at least one side effect. In a multivariate model that controlled for age, education, religion, and occupation, being married remained significantly associated (OR = 2.14; p=0.01) with ever use of a modern contraceptive method. Interventions are needed to address service- and knowledge related barriers to use. PMID- 21812196 TI - Factors that influence male involvement in sexual and reproductive health in western Kenya: a qualitative study. AB - This study explored factors that influence male involvement in reproductive health in western Kenya. Qualitative study design was used. From December 2008 to February 2009, data were collected via in-depth interviews and focus group discussions (FGDs) at three provinces of western Kenya. Twelve in-depth interviews and eight FGDs were conducted. Five participants in in-depth interviews were female, seven were male. Four of the FGDs had all-male participants, four all-female. The factors that influence male involvement in reproductive health emerged in two themes, namely gender norms and the traditional approaches used to implement reproductive health and family planning programs. Any strategy taken to involve men in reproductive health must therefore consider addressing these two factors. A review of the traditional approaches of implementing reproductive health is necessary to make them more male-friendly. PMID- 21812197 TI - Male involvement in family planning decision making in Ile-Ife, Osun State, Nigeria. AB - This study assessed men's awareness, attitude, and practice of modern contraceptive methods, determined the level of spousal communication, and investigated the correlates of men's opinion in family planning decision making in Ile-Ife, Nigeria. Quantitative methodology was employed in this cross sectional descriptive design using a structured household questionnaire to collect information from 402 male study participants. A multistage sampling procedure was employed. Eighty-nine percent of men approved of the use of family planning while only about 11 percent disapproved of it. Eighty percent of men had ever used contraception while 56 percent of them were current users. Spousal communication about family planning and other family reproductive goals was quite poor. The socio-demographic correlates of men's opinions included religion, marriage type, educational attainment, and occupation (p < 0.05). The study concluded that male involvement in family planning decision making was poor and their patronage of family planning services was low. PMID- 21812198 TI - Influence of independent and proximate variables on condom use in selected states in Nigeria. AB - The study examined the influence of individual and proximate factors in determining condom use. Current use of condom and condom use during last sex were used as proxies for consistent condom use. Data on 3,797 sexually active respondents of reproductive age were analyzed from the 2007 USAID-COMPASS midline evaluation on basic family planning and reproductive health outcomes in five Nigerian states. About 9% of respondents were current users, while 11% used a condom during last sex. Younger and more educated respondents were more likely to report condom use. Of the 23 variables, four were statistically significant (p < 0.05) in predicting current use for females, and five for males; six were statistically significant in predicting condom use during last sex for females and seven for males. The paper concluded that understanding the determinants and predictors of condom use is critical to improving family planning and reproductive health indicators in Nigeria. PMID- 21812199 TI - Assessing the importance of gender roles in couples' home-based sexual health services in Malawi. AB - To more effectively address individuals' and couples' sexual and reproductive health needs, innovative service delivery strategies are being explored. These strategies are logistically and ethically complicated, considering prevailing gender inequalities in many contexts. We conducted an exploratory study to assess the acceptability of couples' home-based sexual health services in Malawi. We collected qualitative data from six focus group discussions and 10 husband-wife indepth interviews to gain a more thorough understanding of how gender norms influence acceptability of couples' sexual health services. Findings reveal that women are expected to defer to their husbands and may avoid conflict through covert contraceptive use and non-disclosure of HIV status. Many men felt that accessing sexual health services is stigmatizing, causing some to avoid services or to rely on informal information sources. Gender norms and attitudes toward existing services differentially impact men and women in this setting, influencing the perceived benefits of couples' sexual health services. PMID- 21812200 TI - Return to sexual activity and modern family planning use in the extended postpartum period: an analysis of findings from seventeen countries. AB - Unintended pregnancies can lead to poor maternal and child health outcomes. Family planning use during the first year postpartum has the potential to significantly reduce at least some of these unintended pregnancies. This paper examines the relationship of menses return, breastfeeding status, and postpartum duration on return to sexual activity and use of modern family planning among postpartum women. This paper presents results from a secondary data analysis of Demographic and Health Surveys from 17 countries. For postpartum women, the return of menses, breastfeeding status, and postpartum duration are significantly associated with return to sexual activity in at least 10 out of the 17 countries but not consistently associated with family planning use. Only menses return had a significant association with use of modern family planning in the majority of countries. These findings point to the importance of education about pregnancy risk prior to menses return. PMID- 21812201 TI - Family planning, abortion, and HIV in Ghanaian print media: a 15-month content analysis of a national Ghanaian newspaper. AB - This study assessed coverage of reproductive health (RH) issues--family planning (FP), abortion, and HIV--in the Ghanaian Daily Graphic newspaper. Using the composite week sampling technique, the researcher analyzed the contents of 62 editions of the paper. Prominence was measured using various attributes, and differences in mean coverage over time were assessed using analysis of variance. This review shows that coverage of RH issues was extraordinarily poor, less than 1 percent each for FP, abortion, and HIV. RH news that was covered was given little prominence. These findings support the popular impression that the Daily Graphic does not give priority to reproductive health issues in its coverage. RH advocates need to develop innovative means of integrating RH content into existing media outlets. PMID- 21812202 TI - Use of HIV-related services and modern contraception among women of reproductive age, Rakai Uganda. AB - Voluntary counseling and testing (VCT) and HIV care (HIVC) can be an opportunity for reproductive health messages and services integration. The objective of this study is to assess the association between uptake of HIV-related services and use of modern contraception among reproductive-age women. Data are derived from community cohort data, where HIV+ respondents were referred to the Rakai Health Sciences program's HIVC clinic. Use of modern contraceptive and VCT receipt were by self-report. Multinomial logistic regression was used to estimate relative risk ratios (RRR) of contraception use by HIVC and VCT. Receipt of VCT was significantly associated with higher use of condoms for FP, adj.RRR 1.78 (1.07, 2.95), and other modern contraceptives, adj.RRR = 1.56(1.15, 2.11). Increasing level of HIVC was associated with decreasing level of unmet need for contraception. Use of condoms for family planning is common among HIV-related services attendees. Utilization of other modern contraceptive methods needs to be increased. PMID- 21812203 TI - Factors influencing contraceptive choice and discontinuation among HIV-positive women in Kericho, Kenya. AB - This study explored perceptions towards and utilization of contraception among HIV-positive, reproduction-age women in Kericho, Kenya, an area with high HIV and low contraceptive prevalence rates. Qualitative methods were used in three focus group discussions and 15 in-depth interviews to gather data from 46 HIV-positive women ages 18 to 45, purposively selected by age strata. Analysis was performed using ATLAS-ti (ATLAS-ti Center, Berlin). Most participants reported familiarity with modern contraceptives. Participants generally perceived that men opposed contraception. Some women indicated that their HIV status dictated contraceptive decisions, particularly with regard to abstinence. Women reported method discontinuation because of side effects, having met desired parity, and menstrual changes. Findings suggested that perceptions about side effects, opinions of the male partner, and HIV disease progression play important roles in contraceptive decisions. Counseling can dispel incorrect information and optimize contraceptive practice in this setting. PMID- 21812204 TI - Factors associated with induced abortion among women in Hohoe, Ghana. AB - In Hohoe, Ghana, induced abortion is the second highest cause of hospital admissions. We aimed to describe factors influencing induced abortion among 408 randomly selected women aged 15-49 years. 21% of the women had had an abortion; of those, 36% said they did not want to disrupt their education or employment; 66% of the abortions were performed by doctors. Bivariate logistic regression showed that compared with women with secondary education, women with basic education (OR = 0.31, 95% CI: 0.18-0.54) and uneducated women (OR = 0.24, 95% CI: 0.07-0.70) were significantly less likely to have had an abortion. Women who were married (OR = 1.83, 95% CI: 1.10-3.04), peri-urban residents (OR = 1.88, 95% CI: 0.95-3.94), and women with formal employment (OR = 2.22, 95% CI: 0.86-5.45) were more likely to have had an abortion. Stakeholders should improve access to effective contraception to lower the chance of needing an abortion and target education programmes at those with unmet need for contraception. PMID- 21812205 TI - Influence of family size, household food security status, and child care practices on the nutritional status of under-five children in Ile-Ife, Nigeria. AB - Fertility pattern and reproductive behaviours affect infant death in Nigeria. Household food insecurity and poor care practices also place children at risk of morbidity and mortality. The objectives of this study were to assess the influence of family size, household food security status, and child care practices on the nutritional status of under-five children in Ile-Ife, Nigeria. The study employed a descriptive cross-sectional design. A semi-structured questionnaire was used to collect data from 423 mothers of under-five children and their children in the households selected through multistage sampling methods. Food-insecure households were five times more likely than secure households to have wasted children (crude OR = 5.707, 95 percent CI = 1.31 24.85). Children with less educated mothers were significantly more likely to be stunted. The prevalence of food insecurity among households in Ile-Ife was high. Households with food insecurity and less educated mothers were more likely to have malnourished children. PMID- 21812206 TI - Population and reproductive health in National Adaptation Programmes of Action (NAPAs) for climate change in Africa. AB - This paper reviews 44 National Adaptation Programmes of Action (NAPAs) to assess the NAPA process and identify the range of interventions included in countries' priority adaptation actions and highlight how population issues and reproductive health/family planning (RH/FP) are addressed as part of the adaptation agenda. A majority of the 44 NAPAs identify rapid population growth as a key component of vulnerability to climate change impacts. However, few chose to prioritise NAPA funds for family planning/reproductive health programmes. The paper emphasizes the need to translate the recognition of population pressure as a factor related to countries' ability to adapt to climate change into relevant project activities. Such projects should include access to RH/FP, in addition to other strategies such as girls' education and women's empowerment that lead to lower fertility. Attention to population and integrated strategies should be central and aligned to longer-term national adaptation plans and strategies. PMID- 21812207 TI - A holistic approach to reproductive health interventions: Talk 2 Me case study. AB - The Talk 2 Me project is a good example of putting knowledge into action and trying out best practices gained from conferences. The design of this project was based on knowledge shared by Straight Talk Foundation of Uganda during the 2008 "Investing in Young People's Health and Development: Research that Improves Policies and Programs" in Abuja, Nigeria. The idea was to use peer educators in secondary schools to facilitate discussions on sexuality, HIV/AIDS, STIs, and other reproductive health issues. The innovative strategy was to record the stories of students as they were discussed and to publish them in a monthly newsletter (Talk2Me). The newsletters were shared among young people in and out of school, so they could learn from the discussions in the different school groups. PMID- 21812208 TI - Strategies used by facilities in Uganda to integrate family planning into HIV care: what works and what doesn't. PMID- 21812209 TI - Without strong integration of family planning into PMTCT services in Rwanda, clients remain with a high unmet need for effective family planning. PMID- 21812210 TI - [Pediatric diabetology at the University Children's Hospital Queen Fabiola in Brussels is 40 years old]. AB - By the end of medical school at the Free University of Brussels (ULB) in 1969, I began my specialization in pediatrics. Immediately, my mentor, Professor Helmut Loeb led me into pediatric diabetes which was non-existent in Belgium. Forty years later, the diabetes clinic for children and adolescents at the University Children's Hospital Queen Fabiola in Brussels has the largest number of young patients in Belgium, social medical activities and clinical research, with the best protective glycated hemoglobin levels (proven in international comparisons from Hvidore Study Group on Childhood Diabetes) in relation to potentially invalidating complications in the short and long term. Nevertheless, this wasn't obvious, because to stay humanistic, the fight was very hard. Over four decades, hospital life changed: balkanisation of pediatrics at ULB and competition in the same field; overrun by administrative and political power at the expense of medical freedom; weakening of the medical status at university hospitals in order to dominate and break solidarity; emphasis of financial gain instead of better quality of care and treatment. Fortunately, despite all of these pitfalls, some doctors and administrators are still able to maintain non-profit quality care for all and in our interests as a whole. Moreover, Belgian Social Security has recognized pediatric diabetic centers and subsidizes the pluridisciplinary teams of which the standards have been fairly defined. If type 1 diabetes occurs in younger and younger children, the future of pediatric diabetology will also include type 2 diabetes whose rates are exponential in countries where "fast food" reigns along with little physical exercise. Belgium is about 10 years behind what's happening in the United States.... PMID- 21812211 TI - [(R)evolution in pediatric diabetology]. AB - Before the discovery of insulin 87 years ago, all diabetic children died within a few weeks or months following diagnosis. Since then, improvements in the treatment and live of young diabetics have sometimes occurred in (r)evolutions that have caused debate among physicians. They are briefly reviewed in this paper. Today's young diabetics, properly trained in self-monitoring and self treatment, are as competitive physically and intellectually as their non-diabetic peers provided their glycemic control (i.e., their glycated hemoglobin levels) is kept close to normal. They escape the potentially incapacitating complications associated with chronic hyperglycemia of several decades' duration: blindness, renal failure, amputations, excess cardiovascular mortality, etc. To achieve this favourable outcome, diabetic children should be followed by multidisciplinary teams that include pediatric diabetologists and have a large enough case load to acquire a high level of expertise. Quality of care and patient well-being should be compared across teams with the goal of optimizing both these parameters. Any dogmatism must be avoided. The international comparisons of the Hvidore Study Group on Childhood Diabetes have shown that diabetic children and adolescents on twice-daily free-mix regimens have significantly lower HbA1c than those on basal bolus, pumps or twice-daily premixed/insulin regimens. Attempts to prevent type 1 diabetes are under way: vitamin D supplementation, avoidance of beta-casein (cow's milk hypothesis), etc. A definitive cure for type 1 diabetes mellitus is difficult to foresee. PMID- 21812212 TI - [Fight for the development of pediatric diabetology in Belgium]. AB - In Belgium, the first educative vacation camp for diabetic children was organized in 1969 by Helmut Loeb, using as a model the French camps of Henri Lestradet which existed since 1953. Diabetic children were trained in self-monitoring and self-treatment, with a normal diet. From that moment specialized pediatricians having acquired their experience in the vacation camps, surrounded by a multidisciplinary team, began to manage diabetic children instead of internists. However this fight was difficult and, in 1977, an organization especially devoted to diabetic children was created. Finally, in 1997, the Social Security recognized the specificity of pediatric centers for diabetic children and adolescents. PMID- 21812213 TI - [The development of international pediatric diabetes organizations]. AB - Around 1960, it became clear that, with very few exceptions, the treatment of children with diabetes was not in the hands of paediatricians but in those of adult diabetologists. In 1972, Zvi Laron (Tel Aviv), Henri Lestradet (Paris) and Helmut Loeb (Bruxelles) decided that a separate paediatric association for the care and education of children and adolescents with diabetes was needed. The "International Study Group on Diabetes in Children and Adolescents (ISGD)" was born. In 1993, the name was changed to the "International Society for Pediatric and Adolescent Diabetes (ISPAD)". In 2009, a total of 891 members, from 89 countries, was counted. "Pediatric Diabetes" is the scientific membership journal with an impact factor of 2.424. PMID- 21812214 TI - [Harry Dorchy and pediatric diabetology]. AB - "Monsieur Le Professor Harry Dorchy is retiring". He has had a brilliant 40 year career since receiving his medical degree from the Free University of Brussels in 1969 and his PhD--entitled " Contribution a l'etude du diabete de l'enfant et de l'adolescent "--in 1981 from the same illustrious university. He had the great fortune to connect with his mentor, Professor Helmut Jean Loeb, and for many years, the two of them cared for young people with diabetes in Brussels and worked closely to establish a remarkable legacy of clinical care, research and innovative thinking about how young children in Belgium--in fact, around the world--, ought to be considered and treated. At the moment of his official retirement, he has an active patient census of 792 patients, 442 under the age of 18 years, at the Queen Fabiola University Children's Hospital in Brussels. As a member of the Hvidoere International Study Group on Childhood Diabetes, Dr Dorchy's patients have the great honor of being the most successful study cohort: those with the lowest (ie. best) levels of hemoglobin A1c. And they do so without excessive hypoglycemia! Dr Dorchy has had 490 publications as an author in his scientific career, 335 as first author. Dr Dorchy's research has complemented his superb work as a clinician : screening for subclinical complications, normal and flexible diet, physical activity, glycemic control and insulin treatment, quality of life, genetics and immunology, specific types of diabetes, etc. Since 1996, with his pediatric diabetologist comrade, Professor Stuart Brink from Boston, he has traveled annually to Romania to help organize, administer and teach at an annual ISPAD-Timisoara Pediatric and Adolescent Diabetes Post-Graduate Course with Professor Viorel Serban. PMID- 21812215 TI - [Management of type 1 diabetes (insulin, diet, sport): "Dorchy's recipes"]. AB - The principal aims of therapeutic management of the child, adolescent and adult with type 1 diabetes are to allow good quality of life and to avoid long-term complications by maintaining blood glucose concentrations close to the normal range and an HbA1c level under 7%. The number of daily insulin injections, 2 or > or = 4, by itself does not necessarily give better results, but the 4-injection regimen allows greater freedom, taking into account that the proper insulin adjustment is difficult before adolescence. Successful glycemic control in young patients depends mainly on the quality and intensity of diabetes education. Any dogmatism must be avoided. Due to their pharmakokinetic characteristics, fast acting and long-acting insulin analogues have specific indications in both the twice-daily injection regimen and the basal-bolus insulin therapy. They improve quality of life, without necessarily reducing HbA1c. Dietary recommendations issued over the last few years are the same for diabetic and non-diabetic individuals in order to avoid degenerative diseases. In the twice-daily free-mix regimen, the allocation of carbohydrates throughout the day is essential. There is no linear correlation between the metabolization of x grams of glucose by y units of insulin and carbohydrate counting is a piece of nonsense. Glycamic changes during exercise depend largely on blood insulin levels. In the young diabetic, during insulin deficiency, and therefore in a poor degree of metabolic control, i.e. hyperglycemic and ketotic, exercise accentuates hyperglycemia and ketosis, leading to extreme fatigue. If the insulin dosage is too high, the increase in muscular assimilation, combined with the shutdown of liver glucose production, may result in a severe hypoglycemia. During the recovery period, the repletion of muscular and hepatic glycogen stores may also provoke an hypoglycemia during hours after the cessation of muscular work. PMID- 21812216 TI - [Biological variation of glycation and mean blood glucose have greater influence on Hba1c levels in type 1 young diabetic patients than glucose instability]. AB - The aim of the study was to assess the relative influence of mean blood glucose (MBG), glucose instability (GI) and biological variation of glycohemoglobin (BVG) on HbA1c. The study included 378 unselected young type 1 diabetic patients with a diabetes duration > 1 year. There were 1,409 visits with simultaneous HbA1c determinations and self-monitoring of BG meter downloads. GI was quantified by measuring the standard deviation (SD) of the recorded BG values. A statistical model was developed to predict HbA1c from MBG. Hemoglobin glycation index (HGI) was calculated (HGI = observed HbA1c--predicted HbA1c) for each visit to assess BVG based on the directional deviation of observed HbA1c from that predicted by MBG in the model. Afterwards, the population was divided by thirds into high-, moderate-, and low-HGI groups, i.e. high-, moderate-, and low-glycators, reflecting BVG. A total of 246,000 preprandial BG measurements were analysed, with a mean of 177 per visit. Grand MBG +/- SD was 171 +/- 40 mg/dl. Predicted HbA1c was calculated from the equation: 3.8399 + 0.0242 x MBG (r = 0.66; p < 0.0001). A MBG change of 40 mg/dl corresponded to 1% change in HbA1c, within the range 6-12%. Multiple regression analysis showed no significant relationship between SD and HbA1c, after adjustment for MBG. MBG was 10 times more important than SD to predict HbA1c. MBG was not statistically different between the high- and low glycators, but HbA1c was significantly different. Multiple linear regression was used to predict HbA1c from MBG, SD and BVG (measured by HGI), adjusted for age, duration, gender and ethnic origin. BVG and MBG had large influences on HbA1c, the impact of BVG being 84% of the impact of MBG. On the other hand, GI had only 17% of the impact of MBG. In conclusion the effect of BVG on HbA1c is independent and much greater that the influence attributable to GI. Hemoglobin glycation phenotype, responsible for BVG, may be important for the clinical assessment of diabetic patients in order to avoid complications. PMID- 21812217 TI - [Severe hypoglycemia in children and adolescents with type 1 diabetes: risks factors and management]. AB - Hypoglycemia is one of the most common acute complications in the treatment of type 1 diabetes. It is the result of a mismatch between insulin dose, food consumed, and recent exercise. Hypoglycemia occurs more frequently in younger children and with lower HbA1c levels. Symptoms of hypoglycemia result from autonomic (adrenergic) activation and/or neurological dysfunction (neuroglycopenia). Severe hypoglycemia means that the child is having altered mental status and cannot assist in his care, is semiconscious or unconscious, or in coma--convulsions and may require parenteral therapy (glucagon or i.v. glucose). The blood glucose threshold for symptoms may be affected by antecedent hypoglycemia, duration of diabetes with decrease in neurohormonal counterregulatory responses. This phenomenon is termed hypoglycemia unawareness and is an important cause of severe hypoglycemia. Fortunately, there is absence of adverse effects of severe hypoglycemia on cognitive function in children with diabetes over 18 months, even if some controversies exist. Severe hypoglycemia is rapidly reversed by injection of glucagon 0.5 mg if < 25 kg, 1.0 mg if > 25 kg. In the hospital, intravenous infusion of glucose should be administered, e.g. glucose 10%, 2-5 mg/kg/min (1.2-3.0 ml/kg). PMID- 21812218 TI - [Diabetic ketoacidosis: diagnosis, management, prevention]. AB - Diabetic ketoacidosis results from relative or absolute deficiency of insulin and is a frequent metabolic emergency. It occurs in previously undiagnosed diabetes, in half of the cases in Europe, or is the consequence of a severe unbalance in a well-known diabetic patient, who, deliberately or not, does not take enough or not at all insulin. In population studies, the mortality rate in children ranges from 0,15% to 0,30%, cerebral edema accounts for 60% to 90%. Three stages are described: ketosis, ketoacidosis, ketoacidotic coma. This paper summarizes the physiopathology as well as the clinical and biological signs. It opens up an algorithm for the management of diabetic ketoacidosis and its complications and indicates prevention methods. PMID- 21812219 TI - [Growth in type 1 diabetic children]. AB - Despite the fact that height in diabetic children has extensively been studied, many controversies remain. The aim of this study is to review growth in type 1 diabetes. Height at diagnosis is probably not increased compared with appropriate reference data. Later loss of height is observed due to a reduced peak height velocity during puberty. The poor pubertal growth can be linked to abnormalities of the growth hormone--insulinlike growth factor-I axis. It has also been showed that good metabolic control is necessary to allow normal growth in diabetic children. Metabolic control and the age at onset of type 1 diabetes are reported to be significant factors influencing final height. Careful monitoring of height and weight in diabetic patients must be made and good glycemic control has to be maintained to allow normal growth and development in diabetic patients. PMID- 21812220 TI - [From adolescence to pregnancy: a model of multidisciplinary team support for future pregnant women]. AB - The frequency and severity of maternal and neonatal complications of diabetes are strongly related to the degree of metabolic control. The major goal of therapeutic management of the diabetic mother requires the achievement of euglycaemia during the pre- and peri-conceptional periods, during pregnancy until delivery. Besides the need for frequent and individualized insulin dose adjustment, the patient's adhesion to the treatment, with the constraints it implies, is directly related to the prognosis of pregnancy for the mother and the newborn. An extended longitudinal follow-up allows the patient to become familiar with the multidisciplinary specialist team who will be in charge of her pregnancy. This condition seems a prerequisite to the completion of a form of reciprocal "contract of confidence" in order to strengthen the motivation of the mother and make more efficient the conditions of her supervision. The quality of metabolic control has been studied by retrospective analysis of the evolution of 32 pregnancies in 21 diabetic patients who received this form of longitudinal follow-up. The mean and median HbA1c measurements at childbirth, respectively 6.2 and 6.3%, seem to confirm the relevance of this model of longitudinal follow-up. PMID- 21812221 TI - [Screening for subclinical complications in children and adolescents with type 1 diabetes: experience acquired in Brussels]. AB - Clinical studies conducted since the 1970s by the pediatric diabetology group of the Free University of Brussels have demonstrated that screening for subclinical retinopathy, neuropathy, and nephropathy should be started at puberty and at least 3 years after the diabetes diagnosis with the goal of detecting early abnormalities responsible for subclinical disorders that can be reversed by improved metabolic control, thus preventing the occurrence of irreversible potentially incapacitating lesions. A 1974 retinal fluorescein angiography study showed that the development of microaneurysms, which are irreversible lesions, could be preceded by fluorescein leakage due to disruption of the blood-retinal barrier. Risk factors for early retinopathy include: duration of diabetes, age at diagnosis (with younger children having longer times to retinopathy), puberty and sex (with onset one year earlier in girls than in boys), long-term bad metabolic control over several years, high cholesterol levels and excessive body mass index (2002). On the other hand, rapid improvement of diabetic control may worsen diabetic retinopathy (1985). Minimal EEG abnormalities were found in relationship with frequent and severe hypoglycemic comas and/or convulsions, and retinopathy (1979). Desynchronization of action potentials in distal nerve fibers preceded conduction velocity slowing (1981). A single high glycated hemoglobin value was associated with peroneal motor nerve conduction slowing (1985), which was not observed in the femoral nerve (1987). Sympathetic skin response (1996) and statistical analysis of heart rate variability (2001) could have some interest for the diagnosis of early diabetic autonomic neuropathy. Early microproteinuria is of mixed origin, being both glomerular (microalbumin) and tubular (beta2 microglobulin). Exercise testing to exhaustion did not provide additional information than the basal excretion (1976). Microtransferrinuria (1984) and urinary acid glycosaminoglycans output (2001) could also be predictive markers of glomerular dysfunction. Physical training reduced exercise-related proteinuria by half (1988). High levels of serum lipoprotein (a) were not associated with the presence of subclinical complications (1996). On the other hand, ultra sensitive C-reactive protein could be an interesting indicator for the risk of developing early complications (2005). Poor metabolic control was associated with higher levels of triglycerides, total cholesterol, LDL cholesterol, and apolipoprotein B (1990). Decreased gluthatione peroxidase, gluthatione reductase, and of vitamin C levels, denoting moderate oxidative stress, were found (1996), although there was no evidence of increased LDL cholesterol peroxidation (1998). Erythrocytes exhibited increased glycolytic activity, and neutrophils decreased migration, in relationship with metabolic control (1992). The degree of metabolic control influenced serum triiodothyronine levels (1985), magnesium concentrations (1999). Helicobacter pylori infection and eradication are not related to HbA1c levels (2007). Insulin therapy could activate the complement pathway if intermediate and long-acting insulin preparations without protamine sulphate are used (1992), and provoke higher BMI in adolescents on 4 insulin injections (1988). Well-being was inversely related to glycated hemoglobin levels (1997). Family cohesiveness and parental alexithymia predict glycemic control (2008). Alexithymia factor explains 11.5% of the HbA1c total variance (2010). PMID- 21812222 TI - [Neonatal diabetes: a case of pancreatic beta cell agenesis and a 38-year follow up of a permanent neonatal diabetes mellitus]. AB - Neonatal diabetes, transient (TND) or permanent (PND) is a rare disease, with a reported frequency of 1/300,000. If establishing a diagnosis is quite easy, treatment remains challenging during childhood. Understanding of physiopathology increased this last decade, as many mutations in genes playing critical roles in the development of pancreas, have been described: the most common are chromosome 6q anomalies in the case of TND, and mutations in KCNJ11 and ABCC8 genes encoding the subunit of the insulin cell potassium channel in the case of PND. We report on 2 peculiar stories: the first one is the unique case of a newborn with isodisomy of chromosome 6, methylmalonic acidemia and pancreatic beta cell agenesis, who died on the 16th day of life. The second one is the longest follow up ever described, 38-year, of a permanent neonatal diabetes mellitus without complications, except for rare micro-aneurysms, in spite of insufficient metabolic control. PMID- 21812223 TI - [(Pre)type 2 diabetes and MODY: pediatric diabetology future]. AB - Type 2 diabetes mellitus (T2D) is no longer a disease only of adults. In some American locations and populations, incidence and prevalence of T2D are much higher than those of type 1 diabetes, because of increased calorie and fat intake, and decreased exercise. The increasing prevalence of T2D in the United States has closely paralleled the increase in childhood obesity noted there, but now across the Western world. Besides obesity, the other youth risk factors for T2D are: ethnicity, family history, puberty, female, metabolic syndrome, acanthosis nigricans and polycystic ovary syndrome. Any feature or condition associated with insulin resistance/hyperinsulinemia should alert to screen youth at increased risk for (pre)T2D. T2D should be differenciated from monogenic diabetes (Maturity Onset Diabetes of the Young or MODY). Treatment goals are to decrease weight and increase exercise, to normalize insulinemia, glycemia and HbA1c, to control hypertension and hyperlipidemia. The aim of the pharmacological therapy is to decrease insulin resistance, namely by metformin. Sometimes, insulin therapy is necessary. PMID- 21812224 TI - [Felicien Rops and phosphatous diabetes in the 19th century]. AB - Felicien Rops was among the 19th century's finest draughtsmen and Belgium's most sulphurous artist. Rops was also a prolific letter-writer. In his correspondence, he complained of real or imaginary diseases among which phosphatous diabetes. Causes and treatments of diabetes at that time are described. PMID- 21812225 TI - [Use of computerized neuropsychological tests and of nuclear magnetic resonance spectroscopy in clinical assessment of adult patients with phenylketonuria]. AB - Phenylketonuria is the most common inborn error of metabolism. Adult patients often discontinue dietary treatment and can subsequently develop serious brain dysfunction. Some of them, however, do not present any symptoms, despite long term exposition to high blood phenylalanine concentration. As the extent of brain toxicity of hyperphenylalaninemia is not clear in adults, new diagnostic methods are needed to assess brain effects of hyperphenylalaninemia. The aim of the study was to evaluate the usefulness of magnetic resonance spectroscopy and of computerized neuropsychological tests for measurement of brain phenylalanine concentration and for early detection of hyperphenylalaninemia-related brain dysfunction. Assessment of sustained attention, working memory and inhibitive control was performed in a group of 50 adults with phenylketonuria by means of computerized CANTAB system. Additionally, in 40 patients, measurement of brain phenylalanine signal was done by means of magnetic resonance spectroscopy. The results were correlated with plasma phenylalanine concentrations. Worsening of neuropsychological efficiency as well as increase of brain phenylalanine concentration correlated with high levels of plasma phenylalanine. Interestingly, in two cases, despite high plasma phenylalanine concentration, low brain phenylalanine concentration was observed accompanied by good results of neuropsychological tests. This finding suggests presence of mechanisms limiting brain toxicity of hyperphenylalaninemia in some patients. It should be stressed, however, that such situation can be expected rarely, and is probably restricted to cases with moderate hyperphenylalaninemia. Combination of computerized neu- ropsychological tests and of magnetic resonance spectroscopy is a useful diagnostic method which could allow for careful individualization of dietary recommendations in selected patients with phenylketonuria. PMID- 21812226 TI - [The risk assessment of lungs' apices injury in patients after radioactive iodine therapy due to hyperthyroidism]. AB - In the light of recent research data hypothesis on radioactive iodine therapy leading to inflammatory reaction in lungs' apices has lately gained wider acceptance among pulmonologists. The study published of late showed that in one female patient previously treated with radioiodine due to toxic multinodular goiter 99mTc-Tectreotide uptake was found in the lung apex. The aim of study was evaluation of the risk assessment of inflammatory reaction in lungs' apices among patients treated with radioactive iodine due to hyperthyroidism. The study was carried out in 15 female patients (mean age 75 years +/-10 years) with large toxic multinodular goiter and fine needle aspiration biopsy negative for malignancy and who did not qualify for thyreoidectomy. Mean radioactive iodine therapeutic dose used in the study was 940 MBq. Chest SPECT scan (99mTc Tectreotide) was performed one year after radioiodine therapy. Trace uptake in lung apex has been noted only in one patient. In 14 out of 15 patients in the study tectreotide uptake has not been found in any lungs' apices. All of 15 patients became euthyroid six months after radioactive iodine therapy and had their thyroid gland shrinked. No significant correlation between inflammatory reaction in lung apices and radioiodine therapy in patients with hyperthyroidism and large multinodular goiter was found in conducted study. PMID- 21812227 TI - [Elevated blood glucose level as a risk factor of hospital-acquired pneumonia among patients treated in the intensiv care unit (ICU)]. AB - Hospital acquired-pneumonia is the most frequently occurring hospital-acquired infection in intensive care units (ICU). The study group consisted of 233 patients treated over 12 months in the ICU of the 1st Department of General Surgery and Gastroenterological Surgery Clinics, University Hospital in Krakow. Patients were divided in two groups: experimental--consisting of 92 patients with hospital-acquired pneumonia, and control--consisting of 141 patients without the disease. The following risk factors of hospital-acquired pneumonia risk were analysed for both groups: length of stay in the ICU, duration of mechanical ventilation, kind of treatment applied, presence of a gastrointestinal tube, blood glucose levels. Significantly more patients with hospital-acquired pneumonia than controls had blood glucose level above 6 mmol/l (OR = 2.23). Monitoring and maintainment of glucose level within the normal ranges is an important element of successful treatment. In fact, glucose level is the only risk factor that can be easily modified compared with other analyzed factors. PMID- 21812228 TI - [Serum level of sL-selectin and leukocyte surface expression of L-selectin in patients with type 2 diabetes]. AB - The aims of the study were assessment of serum level of sL-selectin and leukocyte (neutrophil and monocyte) surface expression of L-selectin in peripheral blood. Subjects and methods. Eighty patients with type 2 diabetes were enrolled in the study. The diabetic patients were divided into three groups: group A--diabetic micro-angiopathy, group B--diabetic macroangiopathy and group C--patients without vascular complications. The control group included 20 healthy volunteers. Serum level of sL-selectin was determined by immunoenzymatic assay. Flow cytometry was used to analyse surface expresion of L-selectin. Results. In patients with type 2 diabetes sL-selectin level was significantly decreased in comparison with control group. Serum level of sL-selectin did not significantly vary between diabetic groups. In patients with diabetic microangiopathy and macroangiopathy leukocyte expression of L-selectin was significantly lower in comparison with the healthy control and patients without vascular complications. CONCLUSIONS: Serum level of sL-selectin is decreased in patients with type 2 diabetes. The development of chronic vascular complications, diabetic micro- and macroangiopathy, is accompanied by decrease of leukocyte surface expression of L-selectin. PMID- 21812229 TI - [Urinary tract infection in patient after brain injury]. AB - INTRUDUCTION: One of the most important problems in treating patients after head injury is urinary complication. The first place take urinary infections, which disturb rehabilitation process. Clean intermittent catherization, bladder training and good care do not preserve infection. The purpose of our study was to present the frequency of urinary infections and main pathogens involved in these infections among patients treated in The Department of Rehabilitation after head injury. MATERIAL AND METHODS: We gathered microbiological tests and observations from 398 patients (from 2 to 73 years old) after head injury treated in years 2003-2005. Some of them survived head injury and some of them had also multiorgan injury. RESULTS: In 133 of them we found bladder and urethra infections, vesical calculus in 11 cases. In one case we found prostatic abscessus and in one case urethroscrotal fistula. Each patient had microbiological test of urine after he was admitted to the Department. If the test was positive he had pharmacological treatment. In 157 urinary infections we selected Proteus sp., Pseudomonas aeruginosa, Escherichia coli, Klebsiella sp., Enterococcus sp., Acinetobacter sp. Serratia marcescens, Morganella morganii, Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus agalactiae and Candida albicans was represented not so often. CONCLUSIONS: The most frequent pathogens were: Proteus mirabilis, Pseudomonas aeruginosa, E. coli. Most of patients had positive microbiological tests at the admittance to our Department. These complications extend the rehabilitation process and generate high costs. It is necessary to create standards of care of neuropathic bladder in patients after head injury. PMID- 21812230 TI - [Neurophysiological evaluation of cognitive functions in patients with anorexia nervosa--preliminary report]. AB - INTRODUCTION: Anorexia nervosa (AN) is a disease with multi factorial etiology. Recent studies search the cause of its origin in impairments in neuroendocrinal transmission, genetics, psychological and socio-cultural factors. This disturbance affects the patient's attitude to eating. Many complex physical and psychiatric symptoms of AN require wide approach to the patient on the biological, psychiatric and psychological level. AIM: The purpose of this studies was to determine implications in cognitive functioning in patients with AN. MATERIAL AND METHODS: 10 patients with AN and 20 healthy as a control group were recruited. Cognitive functioning was evaluated using P300 wave component of event related potentials (ERP) and Wisconsin Card Sorting Test. International Federation of Clinical Neurophysiology (IFCN) recommendations for recording and analyzing of ERP were used. These studies were performed using Viking Quest (Nicolet ViaSys Healthcare, U.S.A.). They were recorded using the "oddball paradigm" procedure. The reception of potentials was completed by unipolar method with far-field recording (Fz, Cz, Pz and 10, EOG, 10-20 system). The latencies of the first negative wave N1, next positive P2, the following N2 negative and positive component P300 were evaluated. Moreover, the amplitude differences N1 P2, P2-N2, N2-P3 were analyzed. RESULTS: It was found that both latencies of P300 potential components and WCST results were quite normal. However, reduction of P300 amplitude was observed in patients with AN compared to control group, what can be the result of diminished absorption of cognitive structures during analyzing the stimuli. CONCLUSIONS: The results did not show significant differences in cognitive functioning in patients. Changes in the components of P300 wave indicate the need for further neurophysiological research on larger group to determine the degree of impairments in cognitive functioning in patients with AN. PMID- 21812231 TI - [Tension-free technique for the repair of strangulated abdominal hernias]. AB - There are just few studies regarding the use of tension-free techniques during the emergency operations of strangulated hernias among all the articles on the subject of surgical herniorrhaphy. Assessment of safety of the use of mono- or double-filament polypropylene mesh for the repair of strangulated hernia constituted the aim of the study. There were 81 inguinal and 34 other hernias (mostly incisional) in the group of 115 surgically treated patients with strangulated abdominal wall hernias. During the surgical operation in 84 patients strangulated bowel loop was reduced, 22 patients were treated with reduction of larger omentum, 7 patients required bowel resection (including 2 resections of Meckel diverticulum) and 2 resections of the omentum. All patients received prophylactic dose of broad-spectrum antibiotic during the surgical procedure and for 2-4 days after the operation. There were 15 cases of surgical site complications noted. Only two such cases (purulent infection in two patients and necrosis of wound margins in one) constituted potential threat to the implant. The incidence of local surgical complications was somewhat lower in the group of inguinal hernias as compared to the others (11.1% vs. 17.6%). The data from our study confirm the fact that mono- or double-filament polypropylene mesh can be safely used for the repair of strangulated hernia and the risk of local surgical complications is scant. PMID- 21812232 TI - [The assessment of patient's satisfaction with nursing care on the surgical and non-surgical units with the use of The Newcastle Satisfaction with Nursing Scale (NSNS)]. AB - The article presents research of which the aim was to assess patients' satisfaction with nursing care during the hospitalization in the cardiological deparment (non-surgical department) and the urological department (surgical department) of the 111th Military Hospital (111 Szpital Wojskowy) in Poznar. The questionnaire based on The Newcastle Satisfaction with Nursing Scale (NSNS) was carried out among 200 patients during a period of six months. The results of the questionnaire showed (among other things) that the patients expressed positive opinions about nursing care and had positive experiences connected with their hospital stay. PMID- 21812233 TI - [The analyze of recurrent varicose veins development after surgical treatment of lower limbs varicose veins]. AB - Possible development of recurrent varicose veins (RVV) is one of the main reasons for abandonment of patients to undergo varicose veins surgical treatment. Regardless of the increase in the number of the treatment the primary method of improving the surgical technique is to identify the causes of earlier failures. The aim of this study was to determine the mechanisms responsible for the development of recurrent varicose veins after surgical treatment of primary varicose veins. We studied 507 patients (680 limbs) with primary varicose veins of the lower limbs operated in the years 1996-2007 using the classical technique. The results of pre-and postoperative signs, duplex studies and operational protocols were analyzed. Follow-up was 36-156 months (mean 89.7 +/- 31.2 months). RVV development was observed in 36.9% of operated limbs. Irregularities of surgical techniques and neovascularization were responsible for the development of changes to 87.6% and disease progression in the development of changes in 27.4% of limbs with RVV. At 15.5% of limbs with RVV occurred more than one cause of relapse. In logistic regression combined effects of several factors shown to exist only significant relationship between development and the presence of RVV stumps in sapheno-femoral junction (SFJ) and the presence of inefficient SFJ tributaries of the stumps. The risk of development of new varicose veins was independent on the correctness of the implementation of the first treatment. The most common cause of development of RW were imperfections of surgical treatment, principally in the form of leaving the stumps with insufficient SFJ tributaries, or the development of neovascularization. It appears that improving the quality of treatment may favorably affect the development of a decreased incidence of recurrent varicose veins. PMID- 21812234 TI - [Functionalization of carbon nanotubes for multimodal drug delivery]. AB - Nanotechnology is a very promising technology with a potential that can revolutionise the pharmaceutical industry. One interesting nanostructure are carbon nanotubes whose application possibilities are restricted by their solubility. Their solubility can be improved by applying endo- and exohedral modifications. The paper offers a review of the hitherto applied methods of functionalisation permitting the use of carbon nanotubes for biomedical purposes. PMID- 21812235 TI - [Role of mast cells in the pathogenesis of atherosclerosis]. AB - Atherosclerosis is chronic, inflammatory disease. In artery inflammation main role play cells of the immune system, including lymphocytes and macrophages. This circle of the cells modulating atherogenesis enclose also mast cells. Activated mast cell degranulate and release many types of mediators, including cytokines, chemokins, growth factors, vasoactive substances and proteolytic enzymes. This mediators can modulate inflammatory reaction in artery wall directly, by releasing proinflammatory cytokines or indirectly, influencing the activity of the other cells of the immune system, taking a part in the process of atherogenesis. Due to the ability of secretion and activation of proteolytic enzymes (chymase, tryptase, metalloproteinases), mast cells are prone to degrade various components of pericellular and extracellular matrices, including collagen, main protein of the fibrous cap of atherosclerotic plaque, rendering to plaque destabilization, increasing the onset of the atherothrombotic complications. Mast cell proteases can also modulate proliferation and apoptosis of the endothelial and smooth muscle cells of the artery wall. In spite of the fact, that most of the studies about mast cells are performed ex vivo on human tissues or cell cultures and rodents, this findings lead to recognize mechanisms by which mast cell can intervene in atherogenesis process. Moreover, there are some trials of using some of the mast cell mediators in differentiation of cardiovascular diseases and prediction the clinical condition of the patients. PMID- 21812236 TI - [Electrophysiological testing of carpal tunnel syndrome complex treatment results at patients with increased risk of median nerve entrapment mononeuropathy at the wrist]. AB - Electrophysiological testing of sensory and motor fibers of entrapped median nerve allows to assess objectively the degree of median nerve impairment in carpal tunnel syndrome. The median nerve conduction study confirms the clinical diagnosis, especially in patients where symptoms are not obvious. Carpal tunnel syndrome is caused by compression of the median nerve at the wrist. Due to the fact that there are many predisposing factors increasing risk of median nerve mononeuropathy at the wrist, this syndrome is very common. Treatment of carpal tunnel syndrome may be long-lasting. In order to be curative, it needs to be complex, both in mild and advanced cases and requires medical personnel to take an individual approach to the patient. PMID- 21812237 TI - [Assessment of chemoreflex involved in reflex cardio-respiratory control]. AB - Impaired chemosensitivity is an important element of the pathogenesis and the course of various cardiovascular diseases. Our paper presents the assessment of the sensitivity of the central (located on the ventrolateral medullary surface, sensitive to hypercapnea and acidosis) and peripheral (located in the carotid and aortic bodies, sensitive to hypoxia) chemoreceptors, pointing out a physiological and clinical aspects of their application. PMID- 21812238 TI - [Withdrawal of life support care is an ethical decision]. PMID- 21812239 TI - [A letter requesting lung scintigraphy. Clinical follow up or rough marketing?]. PMID- 21812240 TI - [Difficult ot evaluate new surgical methods. IDEAL gives better control of surgical innovation and development]. PMID- 21812241 TI - [Education of specialists in emergency medicine according to a current pedagogical model. The basis is scenario training and clinical practice under supervision]. PMID- 21812242 TI - [A study of laryngeal papilloma in northern Sweden. Two cases of oncogenic HPV among 26 patients]. PMID- 21812243 TI - [Better gas anesthesia technique better for environment, economics and patients. Systematic improvement work gave results]. PMID- 21812244 TI - [Popliteal artery--a quite special vessel with specific problems]. PMID- 21812245 TI - [Physicians defend Scandlab: "Salivary cortisol test can determine adrenal fatigue"]. PMID- 21812246 TI - [The medical profession delegitimized]. PMID- 21812247 TI - [Power, exhaustion, illness--and disastrous decisions]. PMID- 21812248 TI - [HIV and AIDS - a global challenge]. PMID- 21812249 TI - [Infections with human immunodeficiency viruses. Part I: pathogens, epidemiology, and clinical presentation]. AB - Human immunodeficiency viruses 1 (HIV-1) and 2 (HIV-2) are single-stranded, enveloped ribonucleic acid viruses of the retrovirus family (retroviridae). They are transmitted by unprotected sexual intercourse, the inoculation of HIV contaminated blood into the bloodstream and from mother to child via the prenatal, perinatal and postnatal route (in breast-feeding women). In contrast to infections with HIV-2, HIV-1 infections are frequently distributed worldwide and belong to the most common severe infections in humans. 90% of all HIV-1 infected people, however, live in less developed countries, e.g., numerous areas in South and Eastern Africa. Without an appropriate antiretroviral treatment, HIV-1 infections lead after a perennial, individual-dependent period to a state of generalized low immunity (acquired immunodeficiency syndrome, AIDS), resulting in the establishment of several illnesses due to a wide range of opportunistic pathogens. In several less developed regions, these so-called AIDS-defining diseases still represent one of the most frequent causes of death. PMID- 21812250 TI - [Pneumococcal vaccine: protection of adults and reduction of antibiotic resistence by vaccination of children with a conjugated vaccine]. AB - Pneumococcal infections (pneumonia, otitis media, sinusitis, meningitis) are common and usually involve toddlers, immunocompromised and the elderly. Main reservoir of pneumococci is the nasopharyngeal zone of healthy carriers, especially of toddlers. Currently, two types of pneumococcal vaccines are in clinical use, which induce production of antibodies against capsular polysaccharides. The older vaccine consists of pure capsular polysaccharides. It induces a limited immunity, because polysaccharides are poor antigens that stimulate mainly B-cells. In children under two years of age this vaccine is not used, because it does not induce a sufficient immunologic response, presumably because of the immaturity of their immune system. In 2000, a vaccination program with a novel pneumococcal vaccine was launched in the USA. This vaccine contains capsular polysaccharides, that are conjugated with a highly immunogenic protein. It induces both a T cell and B cell response that results in specific humoral and mucosal immunity. U.S. data demonstrate, that serotypes covered by the conjugated vaccine can be reduced in the whole population by vaccination of children being the main reservoir of pneumococci. This so called ,,herd protection" results in a decrease in invasive pneumococcal diseases in vaccinees and non-vaccinees as well as in a reduction of antibiotic resistance rates by reducing resistant pneumococcal cones. PMID- 21812251 TI - [Mast cells - more than allergy mediators. News from mast cell research]. PMID- 21812252 TI - [Is the era from the end of warfarin?]. PMID- 21812253 TI - [Individualized medicine between expectations and reality]. PMID- 21812254 TI - [Modality of combined methods of quantitative and qualitative research in evaluation of therapeutic effects of Chinese medicine]. AB - The core of evidence-based medicine lies in implementing the current best available evidence of clinical research to direct the decision making in clinical practice, incorporation of individual experience and value and preference of patients. However, the current evaluation method for clinical therapeutic effect cannot reflect the humanity and wholesomeness as well as individualized tailored treatment of Chinese medicine (CM) by using randomized controlled trials. This assay addressed the complex intervention of highly individualized treatment of CM and its societal characteristics, and the author proposes a model for the evaluation of therapeutic effects of CM in which quantitative and qualitative methods are combined, embodying the characteristics of the social and natural sciences in CM. The model can show the dynamic process of CM diagnosis and treatment from a perspective of the whole system and can be used for the evaluation of complex intervention of CM. We hope to raise a different thinking and method from the new drug development in the therapeutic effect evaluation. PMID- 21812255 TI - [Consensus on irritable bowel syndrome by integrative medicine]. PMID- 21812256 TI - [The interior-exterior correlation between fei and dachang from the lung function injury in ulcerative colitis patients]. AB - OBJECTIVE: To observe the probability of the lung injury and the features of the lung function injury in ulcerative colitis patients, and to preliminarily study the correlation with its severity, and further to analyze the interior-exterior correlation between Fei and Dachang. METHODS: Seventy patients with UC were assigned to the mild group and the moderate-severe group by the severity, 35 cases in each group. Another thirty healthy subjects were recruited as the control group. Relative indices of the lung function in each group were observed and compared. RESULTS: The lung injury occurred in 67. 14% of the UC patients (47 cases). Forced expiratory volume at 1st s/forced volume capacity (FEV1/FVC), maximal expiratory flow in 75% vital capacity (FEF75), total lung capacity (TLC), diffusion capacity for carbon monoxide of lung (DLCO), and diffusion capacity for carbon monoxide of lung/alveolar ventilation (DLCO/VA) were lower compared with those of the control group, showing statistical significance (P < 0.05). The ratio of residual volume/total lung capacity (RV/TLC) was lower in the mild group than in the moderate-severe group (P < 0.01). The DLCO was higher in the mild group than in the moderate-severe group (P < 0.05). CONCLUSIONS: Most UC patients were complicated with the lung function injury, mainly featured as middle and small airway obstruction and decreasing diffusing capacity. Besides, along with the aggravation of the disease, the decreasing diffusing capacity and increasing RV/TLC occurred. They provided objective reliance for Fei and Dachang interior exteriorly correlated. PMID- 21812257 TI - [Basic pathogenesis of asthenia of healthy energy and blood stasis in liver cirrhosis studied by serum proteomics]. AB - OBJECTIVE: To study the basic pathogenesis of "asthenia of healthy energy and blood stasis" in liver cirrhosis studied by Chinese syndromes and serum proteomics. METHODS: The information of four methods of examinations and serum samples were collected from 44 cases of male cirrhotic patients and 17 cases of healthy male volunteers. The different syndrome groups were summarized according to syndrome differentiation and frequency analysis using the patient's information of four methods of examinations. The serum proteins were isolated by magnetic beads and detected by matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF-MS). The proteins expressed differently between cirrhotic patients of different syndrome types and healthy volunteers were analyzed by statistical analysis software (product of Bruker Corporation ClinProTools 2.1 software). The diagnosis model was established by QC algorithm. RESULTS: The liver cirrhosis syndrome with the appearance frequency of more than 30% was sequenced from high to low as fatigue, listlessness, spider telangiectasia, liver palms, anorexia, bleeding from the nose, the gum or the subcutaneous tissue, the abdominal distention, shortness of breath while moving, dim facial complexion, pricking pain of the flank, weak waist and knees, dull pain in the flank, burning sensation of five centers, or low fever, hectic fever, and night sweat. The cases belonging to Child-Pugh A in the seventeen patients of the Pi-qi asthenia syndrome group accounted for 64.7%. The cases belonging to Child-Pugh C in the twelve patients of the Gan-Shen yin deficiency syndrome group accounted for 66.7%. The cases belonging to Child-Pugh A were similar to the cases belonging to Child-Pugh C in the fifteen patients of the blood stasis syndrome group, being more than 40%. Such syndromes as spider telangiectasia, liver palms, shortness of breath while moving, burning sensation of five centers, or low fever, hectic fever, and night sweat, varicose vein of the abdominal wall, and edema of lower extremities appeared more frequently in Child-Pugh C than in Child-Pugh A (all P < 0.05). The characteristic protein expression peak with mass to-charge ratio of 4642.81, 4963.91, 5247.8, 5805.95, 6305.27, and 12447.7 in the Pi-qi asthenia syndrome diagnosis model were chosen. The former five peaks could be found in Child-Pugh A and Child-Pugh C. The protein expression peak with mass to-charge ratio of 9 290. 3 was the characteristic protein expression peak in the Gan-Shen yin deficiency syndrome diagnosis model. The protein expression peak with mass-to-charge ratio of 9290.06 and 7 768. 29 were down-regulated in the Gan Shen yin deficiency syndrome group compared with the other two syndromes groups. The protein expression peaks 9290.3 and 7768.29 were included in the diagnosis model of hepatitis B cirrhosis. They did not appear in Child-Pugh A, while they were gradually down-regulated in Child-Pugh B and Child-Pugh C. Of the other seventeen protein expression peaks in patients of the Gan-Shen yin deficiency syndrome, eight expressed in Child-Pugh A. The protein expression peaks 4964.55 and 5806.83 that expressed both in Child-Pugh A and Child-Pugh C constituted the characteristic protein peaks of the hepatitis B cirrhosis blood stasis diagnosis model. The diagnosis model of the Pi-qi asthenia syndrome was established with the sensitivity of 100% and the specificity of 82.35%. The diagnosis model of the Gan-Shen yin deficiency syndrome was established with the sensitivity of 100% and the specificity of 94.12%. The diagnosis model of the blood stasis syndrome was established with the sensitivity of 100% and the specificity of 100%. CONCLUSIONS: Asthenia of healthy energy and blood stasis was the basic pathogenesis during the whole process of liver cirrhosis. Asthenia of healthy energy covers Pi-qi asthenia and Gan-Shen yin deficiency. Gan-Shen yin deficiency was obvious in the compensation stage of liver cirrhosis, but it has manifested in this stage. So early treatment was necessary. PMID- 21812258 TI - [Study on ribosomal protein gene expression in patients with ulcerative colitis of Pi-asthenic syndrome and Pi-asthenic syndrome]. AB - OBJECTIVE: To study differential expression profiles of ribosomal protein (RP) genes in healthy subjects and ulcerative colitis (UC) patients of Pi-asthenic syndrome (PAS) and of dampness-heat syndrome (DHS), thus providing experimental bases for " Pi as the source of qi and blood" theory from the view of protein synthesis. METHODS: RP genes arrays were made. The mucous membrane of colon was detected in four UC patients of PAS (UC-PAS), four UC patients of DHS (UC-DHS), and four healthy subjects (N), and data analyzed using BRB-TOOL Software Package (3.9). Bioinformatics analyses were conducted in differential genes. RESULTS: Low density RP gene chips were successfully produced, including 77 RP genes and two RP like genes (RPL26-like1 and RPL7-like1). There were twelve differential genes between UC (PAS+DHS) and N, all of which were down-regulated genes. There were nineteen differential genes between UC-DHS and N, all of which showed down regulating tendency. There were three differential genes between UC-PAS and N, all of which were down-regulated genes. There were six differential genes between UC-PAS and UC-DHS, all of which were up-regulated genes. Cluster analysis showed that normal and UC samples of this chip can be classified according to gene expression profiles, and UC-PAS and UC-DHS can be classified by clustering. Various differential genes had a common transcription regulatory factor. CONCLUSIONS: RP genes arrays were successfully produced. RP gene expressions were down-regulated in UC-PAS and UC-DHS. Corresponding gene expression profiles were shown in N, UC-PAS and UC-DHS. PMID- 21812259 TI - [Therapeutic efficacy assessment of Chinese medicine on mild cognitive impairment]. AB - OBJECTIVE: To systematically analyze the therapeutic efficacy and safety of Chinese medicine on aged patients with mild cognitive impairment (MCI). METHODS: The PubMed, EMbase, Cochrane Library, CNKI, VIP, Wanfang Database, and CBM database were retrieved by computer. On the basis of strictly assessing the quality of literatures, the evidence quality was assessed using GRADE Software. RESULTS: Totally 680 papers were primarily retrieved and analyses were conducted in the finally selected 22 RCT articles. Descriptive analyses were conduced due to different interventions in each study. The therapeutic efficacy was assessed as follows. (1) As to the conversion of MCI to Alzheimer's disease (AD), no case conversed to MCI in Jiawei Wuzi Yanzong Granule Group and Shenyin Oral Liquid Group. But there was no statistical difference when compared with that in the placebo group and the vitamin E group. Significant difference was shown between Tiantai No. 1 and the placebo. (2) As for the improvement of cognitive functions, relative therapeutic efficacies of Chinese herbs were different. (3) The improvement of the activities of daily life, serum SOD and MDA contents, and P amyloid concentration in MCI patients was different due to the application of different therapeutic drugs. CONCLUSION: Chinese herbs showed certain therapeutic efficacy in improving MCI. But clinical application could not be recommended due to poor qualities of literatures and evidence. PMID- 21812260 TI - [Intervention of tianwang buxin decoction combined with dormancy hygiene education for treatment of sub-healthy insomnia patients of yin deficiency fire excess syndrome]. AB - OBJECTIVE: To assess the clinical efficacy, safety and compliance of tianwang buxin decoction (TWBXD) combined with dormancy hygiene education (DHE) and TWBXD alone in treatment of sub-healthy insomnia patients of yin deficiency fire excess syndrome. METHODS: The multi-centered, single blinded randomized clinical trial design was adopted. One hundred and one sub-healthy insomnia subjects of yin deficiency fire excess syndrome were randomly assigned to two groups. The 50 in the treatment group were treated by combined treatment with TWBXD and DHE, while the 51 in the control group were treated with TWBXD alone. The therapeutic efficacy, Pittsburgh sleep quality index (PSQI) score, clinical global impression improvement (CGI) score, quality of life made by WHO (WHOQOL-BREF) score, and safety in the two groups were compared. RESULTS: The effective rate in the treatment group was 68.08%, lower than that in the control group (75.00%), but the difference between them was statistically insignificant. The PSQI score in the treatment group were reduced from 12.00 +/- 2.25 to 7.55 +/- 2.91 (P < 0.01). It was reduced from 11.68 +/- 2.21 to 7.16 +/- 3.13 in the control group (P < 0.01). The improvement of CGI score and WHOQOL-BREF score was also shown in the two groups after treatment (P < 0.01). No significant difference was shown in each index between the two groups. There was no significant difference in CGI between two weeks after drug withdrawal and by the end of the therapeutic course in the same group (P > 0.05). There was no statistical significance in inter group comparison (P > 0.05). CONCLUSION: Significant effect was achieved by TWBXD combined with DHE and by TWBXD alone. Their efficacies were equivalent, with high compliance and safety. PMID- 21812261 TI - [Effect of bushen huoxue granule on dopamine neurotransmitter and dopamine transporter in the brain of patients with Parkinson's disease]. AB - OBJECTIVE: To observe the effect of Bushen Huoxue Granule (BHG) on dopamine (DA) neurotransmitter and dopamine transporter (DAT) in the brain of patients with Parkinson's disease (PD) as an adjunctive therapy. METHODS: Ninety-four PD patients were randomly assigned to two groups, 47 in each group. Madopar was given to all as the basic treatment group. The placebo was given to those in the control group while BHG was given to those in the treatment. The therapeutic course for all was three months. Before and after treatment DA levels in the brain of patients were detected by encephalofluctuograph (EFG) technique. Changes of DAT in the striatum of patients in the treatment group were detected by positron emission tomography (PET) and region of interest (ROI) analysis. RESULTS: (1) Before treatment the DA level was lower in the two groups than the normal value, showing significant difference (P < 0.01), but with no significant difference between the two groups (P > 0.05). After treatment the DA level obviously increased in the two groups, showing significant difference from that before treatment (P < 0.01). No significant difference existed in the DA level in the two groups when compared with the normal value (P > 0.05), but with significant difference between the two groups (P < 0.05). Better results were obtained in the treatment group than in the control group. (2) The DAT radioactive accumulation inside the striatum increased obviously in the treatment group after treatment. ROI analysis showed the total ratio of striatum/cerebellum before and after treatment was 1.86 +/- 0.32 and 2.61 +/- 0.53 respectively, showing statistical difference (P < 0.05). CONCLUSION: BHG could improve the DA level of PD patients, and increasing DAT contents in the striatum, thus playing a role in effectively treating PD. PMID- 21812262 TI - [Treatment of hematopathy by tiaohe ganpi recipe in assisting the hematopoietic stem cell transplantation]. AB - OBJECTIVE: To observe the clinical efficacy and the survival of hematopathy patients by Tiaohe Ganpi Recipe (TGR) in assisting the hematopoietic stem cell transplantation (HSCT), thus finding out new thinking ways and methods for Chinese medicine in intervening HSCT. METHODS: Twenty-seven hematopathy patients scheduled to receive HSCT were randomly assigned to two groups, thirteen in the control group and fourteen in the treatment group. They were treated with the conventional treatment of HSCT, but TGR was additionally given to patients in the treatment group during the whole course. All patients were followed up till December 31, 2009 (with the median follow-up time of twenty-five months). The hemopoietic rebuilding time, the implantation state, the therapy correlated mortality, the recurrence rate, preconditioning correlated complications, and graft-versus-host disease (GVHD), the survival time, the survival probability, and so on in the two groups were observed and compared. RESULTS: Better results were obtained in the treatment group in the survival time (41.6 +/- 6.5 months vs. 21.0 +/- 5.9 months), the survival probability (78.6% vs. 30.8%), the 1-3 year cumulative interval survival rate (80.8% vs. 46.2%, 69.3% vs. 34.6%, and 69.3% vs. 34.6%, respectively), the therapy correlated mortality (0 vs. 30.8%), and the death risk (all P < 0.05). As time went by, the cumulative survival rate decreased and the death risk increased gradually in both groups. There was insignificant difference in the hemopoietic rebuilding time (17.9 +/- 7. 9 days vs. 18.1 +/- 6.8 days), the implantation state, the occurrence rate of preconditioning correlated complications (14.3% vs. 23.1%), GVHD occurrence, and the recurrence rate (21.4% vs. 23.1%, P > 0.05). CONCLUSION: TGR could lower the therapy correlated mortality, prolong the survival time, and improve the cumulative survival rate in the HSCT treatment of hematopathy patients, playing efficacy enhancing and toxicity reducing effect. PMID- 21812263 TI - [Intervention of astragalus injection on the kidney injury after cardiopulmonary bypass of infants with congenital heart disease]. AB - OBJECTIVE: To study the intervention of astragalus injection in the kidney injury of infants with congenital heart disease after cardiopulmonary bypass, thus providing a new method for protection of the kidney injury in them. METHODS: Forty infants undergoing cardiac surgery with cardiopulmonary bypass were randomly assigned to the test group and the control group, twenty in each group. Astragalus Injection (at the dose of 2 mL/kg) was added in the perfusion fluid before giving to infants in the test group before bypass, while the normal saline of the same volume was added in the perfusion fluid before giving to infants in the control group (P < 0.01). The concentrations of serum tumor necrosis factor alpha (TNF)-alpha, interleukin-6 (IL-6), cystatin C (CysC), and N-acetyl-beta-D glucosaminidase (NAG) were detected with ELISA at the following time points, i.e., before bypass (T1), by the end of the surgery (T2), 2 h after surgery (T3), 6 h after surgery (T4), and 24 h after surgery (T5). RESULTS: The serum CysC concentrations were not significantly higher after CPB (P > 0.05). The urinary NAG level increased significantly in the control group after surgery (P < 0.05), but no obvious increase of the urinary NAG level was found in the test group after surgery (P > 0.05). It was obviously lower than that of the control group (P < 0.05). After CPB serum TNF-alpha and IL-6 levels increased significantly in the control group (P < 0.05), while they were lower in the test group than in the control group (P < 0.01). CONCLUSIONS: CPB may result in the renal tubular injury in infants with congenital heart disease. The application of Astragalus Injection before the CPB plays a role in protecting renal tubular functions. PMID- 21812264 TI - [Predisposing factors of hysteromyoma and effect of hualiu recipe on it]. AB - OBJECTIVE: To observe the clinical efficacy of hualiu recipe (HLR) in treating hysteromyoma, and to explore the correlation between the predisposing factors and the tumor volume as well as the therapeutic efficacy. METHODS: One hundred and ten outpatients with hysteromyoma of qi deficiency blood stasis syndrome were enrolled, who were outpatients of Department of Gynecology, Shanghai Yueyang Hospital of Integrative Medicine from September 2005 to September 2007. Their predisposing factors were collected by questionnaire. They were randomly assigned to two groups. The eighty patients in the treatment group were treated with HLR, while the thirty patients in the control group were treated with Guizhi Fuling Capsule. The clinical efficacy and changes of uterus and tumor volumes before and after treatment, improvement of Chinese syndrome, and the correlation between the therapeutic efficacy and predisposing factors were observed. RESULTS: The total effective rate in the treatment group was 85.0% (68/80), while that in the control group was 66.7% (20/30), showing statistical significance (P < 0.05). The therapeutic efficacy of patients with predisposing factors was better in the treatment group than in the control group, showing significant difference (P < 0.05). The tumor volume was observed to be positively correlated with the delivery age, the disease course, and the emotional stress. The clinical efficacy was negatively correlated with the disease course, the emotional stress, and the hyperplasia of mammary glands. CONCLUSION: HLR could effectively reduce the tumor volume of hysteromyoma, and obviously improve clinical symptoms and accompanied disease. The therapeutic efficacy could be improved by prevention and treatment of predisposing factors. PMID- 21812265 TI - [Clinical efficacy of Chinese herbal retention enema combined with intrauterine douching for patients with endometritis]. AB - OBJECTIVE: To study the clinical efficacy of Chinese herbal retention enema combined with intrauterine douching for patients with endometritis diagnosed by hysteroscopy. They failed in in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI)-embryo transfer (ET) treatment. METHODS: 131 patients received hysteroscopy after they failed in routine IVF/ICSI-ET treatment. Of them, 66 patients diagnosed as endometritis were enrolled as the test group and 65 patients without endometritis were enrolled as the control group. Chinese herbal retention enema combined with intrauterine douching was performed on patients in the test group before the next IVF/ICSI, while direct IVF/ICSI was performed on those in the control group. The embryo implantation rate and the clinical pregnancy rate were compared between the two groups. RESULTS: The clinical pregnancy rate and the embryo implantation rate were 48.5% and 24.2% respectively, while they were 29.2% and 14.9% respectively in the control group, showing significant difference (P < 0.05). CONCLUSION: Chinese herbal retention enema combined with intrauterine douching could improve the embryo implantation rate and the clinical pregnancy in patients with endometritis. PMID- 21812266 TI - [Clinical study of curing patients with perennial allergic rhinitis by qumin tongbi nasal spraying agent]. AB - OBJECTIVE: To study the mechanism of action and the therapeutic efficacy of treating patients with perennial allergic rhinitis by Qumin Tongbi Nasal Spraying Agent (QTNSA). METHODS: One hundred and three patients with perennial allergic rhinitis were randomly assigned to two groups. Of them, 57 patients in the treatment group were treated with QTNSA and 46 patients in the control group were treated with Veconase. Seven days were taken as one therapeutic course, two courses in total. The therapeutic efficacy and the serum levels of interleukin-4 (IL-4), IL-8, immunoglobulin E (IgE) and nasal airway resistance (NAR), symptoms and signs integrals before and after treatment were observed in the two groups. RESULTS: There was no statistical significance between the treatment group and the control group in the markedly effective rate (61.40% vs. 63. 04%) and the total effective rate (87.72% vs. 89.13%). After treatment symptoms and signs integrals of the two groups were significantly improved when compared with before treatment (P < 0.01). There was no significant difference between the two groups after treatment (P > 0.05). The serum levels of IL-4, IL-8, IgE, and NAR were significantly higher in the two groups than those of the normal group. They significantly decreased after treatment in the two groups, showing statistical difference (P < 0.01). There was no statistical difference between the treatment group and the control group (P > 0.05). CONCLUSIONS: QTNSA could effectively treat perennial allergic rhinitis. It could obviously lower serum levels of IL-4, IL-8, IgE, and NAR in patients with perennial allergic rhinitis. PMID- 21812267 TI - [Effect of jianpi jiedu recipe on microvessel density and cyclooxygenase-2 expression in Heliobacter pylori induced gastric cancer]. AB - OBJECTIVE: To investigate the regulatory effect of jianpi jiedu Recipe (JJR) on the microvessel density (MVD) and cyclooxygenase-2 (COX-2) in long-term infection of Helicobacter pylori induced gastric cancer of C57BL/6 mice, thus providing experimental bases for its treatment of the H. pylori correlated gastropathy. METHODS: C57BL/6 mouse gastric cancer model induced by H. pylori infection was established by gastrogavage of H. pylori standard strain SS1. Mice were divided into the control group, the model group, low dose JJR group, and the high dose JJR group, 40 in each group. Mice were sacrificed after 72-week medication. Changes of the gastric mucosa MVD of mice in each group were detected by immunohistochemical method. Expressions of COX-2 mRNA and protein were detected by Real-time fluorescent quantitative polymerase chain reaction and immunohistochemical method. RESULTS: The occurrence rate of gastric cancer in the control group, the model group, the low dose JJR group, and the high dose JJR group was 0, 22.2%, 11.1%, and 10.0%, respectively. The gastric mucosa MVD (number/cm2) of mice in each group was 2.50 +/- 1.54, 18.56 +/- 2.62, 14.61 +/- 3.60, and 7.39 +/- 1.75, respectively. The gastric mucosa MVD in the model group increased more obviously than that in the control group (P < 0.01). The gastric mucosa MVD significantly decreased in the low dose JJR group and the high dose JJR group (P < 0.01). Expressions of COX-2 mRNA and protein in the model group increased more obviously than those in the control group (P < 0.01). Low dose JJR and high dose JJR could decrease their expressions in a dose dependent manner. CONCLUSIONS: H. pylori infection could increase the gastric mucosa MVD of C57BL/6 mice and promote COX-2 expressions, which might play a promoting effect in the incidence of H. pylori induced gastric cancer. JJR could decrease the gastric mucosa MVD and inhibit COX-2 expressions, which might be one of its important mechanisms of preventing and treating gastric cancer. PMID- 21812269 TI - [Discussion of Chinese syndrome typing in acute hepatic failure model]. AB - OBJECTIVE: To study Chinese syndrome typing of acute hepatic failure (AHF) mice model by screening effective formulae. METHODS: Lipoplysaccharides (LPS)/D galactosamine (D-GaIN) was intraperitoneally injected to mice to establish the AHF mice model. Yinchenhao Decoction, Huanglian Jiedu Decoction, Buzhong Yiqi Decoction, and Xijiao Dihuang Decoction were administered to model mice respectively by gastrogavage. The behavior and the survival rate were monitored. The liver function and pathological changes of liver tissues were detected. RESULTS: In all the tested classic recipes, the survival rate was elevated from 10% to 60% by administration of Xijiao Dihuang Decoction. Five h after modeling, the serum alanine aminotransferase (ALT) level was (183.95 +/- 52.00) U/L, and aspartate aminotransferase (AST) (235.70 +/- 34.03) U/L in Xijiao Di-huang Decoction Group, lower than those of the model control group, but with insignificant difference (ALT: 213.32 +/- 71.93 U/L; AST: 299.48 +/- 70.56 U/L, both P > 0.05). Xijiao Dihuang Decoction could obviously alleviate the liver injury. CONCLUSIONS: Xijiao Dihuang Decoction was an effective formula for LPS/D GaIN induced AHF model. According to syndrome typing through formula effect, heat toxin and blood stasis syndrome dominated in the LPS/D-GalN induced AHF mice model. PMID- 21812268 TI - [Attenuation and mechanism of endoplasmic reticulum stress-mediated hepatocyte apoptosis in rats with alcohol-induced liver injury by qinggan huoxue recipe and its disassembled formulas]. AB - OBJECTIVE: To explore attenuation and mechanism of endoplasmic reticulum stress (ERS)-mediated hepatocyte apoptosis in rats with alcohol-induced liver injury by Qinggan Huoxue Recipe (QGHXR) and its disassembled formulas (Qinggan Recipe and Huoxue Recipe respectively). METHODS: A rat model of chronic alcoholic liver injury was successfully established using a compound reagent of alcohol, corn oil, and pyrazol. The modeled rats were randomly divided into the model group, the QGHXR group, the Qinggan Recipe (QGR) group, and the Huoxue Recipe group (HXR). The CCl4 control group and the normal control group were also set up. There were ten rats in each group. All rats of modeled groups were gastrogavaged with alcohol compound reagent every morning. Rats in the QGHXR group (at the daily dose of 9. 5 g/kg, QGR group (at the daily dose of 3.0 g/kg), and HXR group (at the daily dose of 6.5 g/kg) were administered with corresponding medicines by gastrogavage every afternoon. Equal volume of normal saline was given to rats of the model group by gastrogavage. CCl4 was intraperitoneally injected at the dose of 0.3 mL/kg to rats in the CCl4 control group, once per week. Normal saline was given to rats in the normal control group by gastrogavage. The treatment was lasted for two weeks. Pathological changes of the liver were observed by histopathology. Serum total homocysteine (tHCY) level was detected by ELISA. The hepatocyte apoptosis rate was detected using flow cytometry. The gene and protein expressions of eukaryotic translation initiation factor 2 alpha (elF-2alpha), phosphorylation elF-2alpha (pelF-2alpha), glucose-regulated protein 78 (GRP78), and Caspase-3 in the liver were examined using Real-time PCR and Westen blot respectively. RESULTS: Compared with the normal control group, typical pathological changes of chronic alcoholic liver injury such as steatosis, inflammation, and even fibrosis occurred in model rats. The hepatocyte apoptosis obviously increased, with the apoptosis rate reaching the five-fold of that in normal rats. Besides, early apoptosis dominated. The serum tHCY level significantly increased. The expressions of p-elF-2alpha, GRP78, and Caspase-3 protein obviously increased (P < 0.01). Expressions of GRP78 and Caspase-3 mRNA significantly increased (P < 0.05, P < 0.01). Compared with the model group, the degrees of the liver injury and the hepatocyte apoptosis in the QGHXR group, the QGR group, and the HXR group were significantly alleviated. The serum tHCY level was significantly lowered. The protein expressions of p-elF-2a, GRP78, and Caspase-3 obviously decreased (P < 0.01). mRNA expressions of GRP78 and Caspase-3 obviously decreased in the QGHXR group (P < 0.05, P < 0.01). Only GRP78 mRNA expression obviously decreased in the QGR group (P < 0.05). CONCLUSION: QGHXR and its disassembled formulas could attenuate ERS-mediated hepatocyte apoptosis in alcohol-induced liver injury rats by lowering the serum tHCY level and expressions of ERS apoptosis correlated factors. PMID- 21812270 TI - [Regulatory effect of lipo tiaozhi capsule on the expression of peroxisome proliferator-activated receptors mRNA in dyslipidemia rats and ApoE(-/-) mice]. AB - OBJECTIVE: To study the regulatory effect of lipi tiaozhi capsule (LTC) on the expression of peroxisome proliferator-activated receptor (PPAR) alpha and gamma mRNA in dyslipidemia rats and ApoE(-/-) mice, and to explore its mechanisms for regulating lipid metabolism. Methods 48 Wistar rats were randomly divided into the blank group, the model group, the treatment group (treated by LTC), and the control group (treated by Xuezhi-kang Capsule). After four-week modeling (except the blank group) 30 ApoE(-/-) mice were randomly divided into the blank group, the treatment group, and the control group. LTC was given by gastrogavage to rats and ApoE(-/-) mice in LTC groups while XZKC was given to XZKC groups. The medication was conducted once daily for eight weeks. The serum TC and TG contents of rats and mice were determined by enzymic method. The serum high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) were detected by precipitation method. PPARalpha and gamma mRNA expressions were detected in the liver tissue of the rats and mice by fluorescent PCR. RESULTS: Compared with the model group and the blank group, the serum contents of TC, TG, and LDL-C of rats or mice in the treatment group decreased significantly (P < 0.01). The serum content of HDL-C increased significantly (P < 0.01). PPARalpha and gamma mRNA expressions of rats or mice increased significantly (P < 0.01). Compared with the control group, the serum contents of TC, TG, and LDL-C of mice and rats in the treatment group decreased (all P < 0.05), the serum content of HDL-C increased significantly (P < 0.05, P < 0.01). And PPARalpha and gamma mRNA expressions of rats or mice increased significantly (P < 0.05). CONCLUSION: LTC could significantly increase PPARa and y mRNA expressions of experimental dyslipidemia rats and ApoE(-/-) mice, playing roles in regulating nuclear factors and further effecting lipid metabolism. PMID- 21812271 TI - [Effect of triangle drugs as ginseng, Trichosanthes kirilowii maxim and rhubarb on the level of blood lipids and related pro-inflammatory cytokines during the process of treating atherosclerosis]. AB - OBJECTIVE: To study the effect of triangle drugs as ginseng, Trichosanthes kirilowii Maxim, and rhubarb on the levels of blood lipids as [total cholesterol (TC), triglyeride (TG), high-density lipoprotein cholesterol (HDL-C), and low density lipoprotein cholesterol (LDL-C)] and pro-inflammatory cytokines as intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and high sensitive C reactive protein (hs-CRP) during the process of treating atherosclerosis. METHODS: Twenty New Zealand rabbits were randomly divided into three groups after one-week adaptive feeding, i.e., the normal control group (n=6), the model group (n=6), and the triangle drugs group (n=8). High fat diet was fed to rabbits in the triangle drugs group and the model group at the daily dose of 100 g for six weeks. Iliac artery was injured in the model group and the triangle drugs group at the seventh week using balloon injury. High fat diet was successively fed to those after surgery for six weeks. At the same time of modeling, preventive medication (at the daily dose of dry ginseng 0.64 g/kg, Trichosanthes kirilowii Maxim 2.14 g/kg, and prepared Radix et Rhizoma Rhei with wine 0.43 g/kg, with the volume of 2 mL/kg) was administered by gastrogavage to rabbits in the triangle drugs group. Changes of blood lipids levels and related pro-inflammatory cytokines were dynamically observed. RESULTS: On the 7th week (before surgery), the levels of TC, TG, HDL-C, and LDL-C in the model group, TC, HDL-C, and LDL-C in the triangle drugs group significantly increased, showing significant difference when compared with those of the normal control group (P < 0.05). The levels of pro-inflammatory cytokines in the model group and the triangle drugs group were significantly higher than those in the normal control group (P < 0.05). Levels of TC, TG, and LDL-C were lower in the triangle drugs group than in the model group, showing statistical difference (P < 0.05). After the 8th week the levels of blood lipids and ICAM-1 in the model group, and levels of TC, LDL-C, HDL-C, and ICAM-1 in the triangle drugs group were significantly higher than those of the normal control group, showing statistical difference (P < 0.05). After the 12th week levels of blood lipids in the model group, LDL-C and HDL-C in the triangle drugs group were significantly higher than those of the normal control group, showing statistical difference (P < 0.05). The LDL-C level was lower in the triangle drugs group than in the model group, showing statistical difference (P < 0.05). The levels of VCAM-1, ICAM-1, and hs-CRP in the model group were obviously higher than those in the triangle drugs group and the normal control group, showing statistical significance (P < 0.05). The hs-CRP level was higher in the triangle drugs group than in the normal control group, showing statistical difference (P < 0.05). CONCLUSIONS: The triangle drugs may postpone the process of atherosclerosis by lowering blood lipids levels, especially by lowering the elevating levels of TC and LDL-C. Its roles in decreasing the level of pro-inflammatory cytokines might be associated with lipids lowering and anti-inflammation. Its roles may also be associated with improvement of the endothelial function and inhibition of the smooth muscle proliferation. PMID- 21812272 TI - [Effect of epigallocatechin gallate on lactacystin-induced PC12 cell injury]. AB - OBJECTIVE: To study the effect of epigallocatechin gallate (EGCG) against lactacystin induced PC12 cell injury. METHODS: The inoculated rat PC12 cells were cultured for 24 h, followed by intervention. The cells were divided into 5 groups, i.e., the normal control group, 10 micromol/L lactacystin injury group, and the EGCG pretreated groups (at the final concentration of 5, 10, and 50 micromol/L, respectively). The cytoactive was detected by MTT colorimetry. Morphological changes of the cell nucleus were observed by Hoechst 33,258 staining, and the apoptosis ratio was detected by flow cytometry (FCM). RESULTS: EGCG at different doses showed protective effect on lactacystin-induced PC12 cell injury. Compared with the lactacystin injury group [(61.22 +/- 1.02)%], the cytoactive in EGCG pretreated groups at the final concentration of 5, 10, and 50 micromol/L, respectively increased obviously to (66.99 +/- 1.30)%, (66.67 +/- 0.65)%, and (73.4 +/- 0.67)%, respectively. Hoechst 33 258 staining found that more nuclear pyknosis and aggregation occurred in the lactacystin injury group, but less occurred in EGCG pretreated groups. FCM indicated that the apoptosis ratio was reduced by EGCG pretreatment. It was 3.0%, 60.4%, 59.8%, 57.5%, and 38.6%, respectively in the normal control group, the lactacystin injury group, and EGCG pretreated groups (at the final concentration of 5, 10, and 50 micromol/L, respectively). CONCLUSION: EGCG could attenuate lactacystin induced PC 12 cell injury. PMID- 21812273 TI - [Baicalin suppresses beta-amyloid protein induced hippocampal cyclooxygenase-2 expression]. AB - OBJECTIVE: To study the brain protection of baicalin on rats with Alzheimer's disease (AD) and its probable mechanism of action. METHODS: Thirty-six male healthy Wistar rats were randomly divided into the sham-operative group, the AD group, and the baicalin group, twelve in each. beta-amyloid protein 1-40 was injected to the bilateral hippocampus of rats in the AD group and the baicalin group to establish the AD rat model. The sham operation was performed to rats of the sham-operative group in the same way. Equal volume of 0.9% sodium chloride solution was injected to the bilateral hippocampus of rats in the sham-operative group. Baicalin was intraperitoneally injected at the daily dose of 40 mg/kg to rats in the baicalin group before and after operation, once daily for 7 successive days. Equal volume of buffer solution was intraperitoneally injected to rats in the sham-operative group and the AD group in the same procedures at the same time points. The expression of hippocampal cyclooxygenase-2 (COX-2) was determined by Western blot. The spatial learning memory capacities was observed using T-morris test. Histological changes were observed using hematoxylin-eosin (HE) staining. RESULTS: Results of the T-morris test showed the spontaneous alternation selective ratio decreased in the AD group (28.33% +/- 7.50%) and the baicalin group (38.33% +/- 7.50%) (both P < 0.05) when compared with the sham operative group (61.67% +/- 7.50%). There was significant difference between the AD group and the baicalin group (P < 0.05). Results of HE staining showed degeneration and necrosis of cortical and hippocampal neurons in the AD group and the baicalin group. Changes in the AD group were more obvious. Results of Western blot showed the expression of hippocampal cyclooxygenase (COX-2) obviously increased in the AD group, while it obviously decreased in the baicalin group (P < 0.05). CONCLUSION: Baicalin could alleviate beta-amyloid protein induced brain injury, which might be associated with its inhibition on the COX-2 expression. PMID- 21812274 TI - [Effect of chronic psychological stress on vascular endothelial dysfunction rats and intervention tongxinluo on it]. AB - OBJECTIVE: To observe the effect of chronic psychological stress on vascular endothelial dysfunction rats and to explore the intervention and mechanism of Tongxinluo (TXL) on it. METHODS: Forty male Wistar rats were randomly divided into the normal control group (with no modeling), the endothelial dysfunction group (the HCY group), the psychological stress group (the model group), and TXL group, ten in each group. Rats in the latter three groups were fed with 3% high methionine diet to duplicate vascular endothelial dysfunction (VED) model. In addition, chronic psychological stress was applied in VED rats using repeated binding method. TXL at the dose of 1.2 g/kg body weight was given by gastrogavage. The plasma endothelin (ET) and angiotensin II (Ang II), serum cortisone (CORT) were detected by radioimmunoassay. The serum nitric oxide (NO) was detected by nitrate reductase. Ultrastructural changes of aortic endothelial cells were observed by transmission electron microscope. Serum levels of norepinephrine (NE) and epinephrine (E) were detected by enzyme linked immunosorbent assay (ELISA). RESULTS: Compared with the plasma ET level and the serum NO level in the HCY group (161.70 +/- 13.96 pg/mL and 26.82 +/- 13.03 micromol/L), the plasma ET level obviously increased (178.25 +/- 21.85 pg/mL) (P < 0.05) and the serum NO level decreased (24.91 +/- 9.95 micromol/L, P > 0.05), levels of CORT, NE, and E obviously increased in the model group (all P < 0.05). Ultrastructural changes of aortic endothelial cells were obviously injured. Compared with the model group, the plasma ET level (154.74 +/- 13.27 pg/mL), Ang II, CORT, NE, and E obviously decreased (P < 0.05, P < 0.01), the serum NO level obviously increased (34.44 +/- 18.35 micromol/L, P < 0.05). Ultrastructural changes of aortic endothelial cells were obviously improved. CONCLUSIONS: Chronic psychological stress could obviously aggravate endothelial injury in VED rats. TXL showed protection on the vascular endothelial structure and function. PMID- 21812275 TI - [Inhibitory acting mechanism of psoralen-osthole on bone metastasis of breast cancer--an expatiation viewing from OPG/RANKL/RANK system]. AB - OBJECTIVE: To find the optimal proportion of Composite Fructus Psoralea and Fructus Cnidii (CFPC) for inhibiting the bone metastasis of breast cancer by way of exploring its acting mechanism viewing from OPG/RANKL/RANK system. METHODS: The human bone metastasis of breast cancer model was established by injecting tumor cells of MDA-MB-231BO cell line into the left cardiac ventricle of nude mice. The modeled mice were randomly divided into seven groups: the blank group administered with normal saline by gastrogavage, the positive control group with zoledronic acid via peritoneal injection, and the 5 tested group with CFPC in different proportions of Fructus Psoralea and Fructus Cnidii, i.e., (A, 4:0; B, 3:1; C, 1:1; D, 1:3, and E 0:4), given by gastric infusion. The treatment started from 1 week after modeling and lasted for six weeks. By the end of the experiment, the metastatic foci in bone were imaged by radionuclide tracing method and X-ray photograph, and separated for detecting gene and protein expressions of osteoprotegerin (OPG), receptor activator of nuclear factor-kappaB ligand (RANKL), interleukin-8 (IL-8), parathyroid hormone-related protein (PTHrP), macrophage colony stimulating factor (MCSF) by Real-time PCR and Western blot respectively. RESULTS: Inhibition of bone metastasis gene was displayed to some extent in all the tested groups treated with CFPC, showing an increased level of OPG mRNA expression (It was 60.343 +/- 6.274 in the tested group C), and decreased mRNA expressions of IL-8, PTHrP, MCSF, RANKL (218.010 +/- 12.802, 232.399 +/- 14.354, 319.831 +/- 5.322, and 195.701 +/- 4. 862, respectively in the tested group C). The optimal effect was shown in the tested group C, showing significant difference to that in the blank group (P < 0.01). Meanwhile, the OPG in the bone metastatic foci could be up-regulated and protein expressions of RANKL/IL-8/PTHrP/MCSF down-regulated in all the tested groups. The optimal effect was shown in the tested group C, with significant difference from those of the normal saline group. CONCLUSION: CFPC could inhibit the bone metastasis of breast cancer through activating OPG/RANKL/RANK pathway. Among different proportions of Fructus Psoralea and Fructus Cnidii, 1:1 was the best one. PMID- 21812276 TI - [The renal protective effect of xinganbao capsule in adriamycin induced nephropathy rats]. AB - OBJECTIVE: To study the renal protective effect of Xinganbao Capsule on rats with adriamycin induced nephropathy (AIN). METHODS: Forty male SD rats were randomly divided into four groups, i.e., the normal control group (N), the AIN model group (M), the Benazepril group (B),and the Xinganbao Capsule group (X). AIN rat model was established by left unilateral nephrectomy and repeated caudal vein injection of adriamycin. Gastric perfusion of xinganbao Capsule (at the dose of 500 mg/kg per day) and Benazepril (at the dose of 4 mg/kg per day) was given to rats in the X group and the B group respectively one week after nephrectomy. Rats were sacrificed at the 8th week after medication. The 24-h urinary protein excretion (24 h-UP) and blood biochemical indices were determined. Renal tissues were collected for pathological changes under light and electron microscopes. Expressions of fibronection (FN), collagen IV (COL-IV), and osteopontin (OPN) in renal tissues were detected by immunohistochemistry. mRNA levels of transforming growth factor-beta 1 (TGF-beta1), tissue inhibitor of metalloproteinase-1 (TIMP 1), and plasminogen activator inhibitor-1 (PAI-1) were measured by fluorescent Real-time PCR. RESULTS: When compared with the model group, 24 h-UP, blood urea nitrogen (BUN), and serum creatinine (SCr), and blood lipids levels were significantly lowered in the X group. The mesangial matrix percentage was less in the X group than in the M group. Renal FN, COL-IV, and OPN expressions more significantly decreased in the X group than in the M group. Similarly mRNA expressions of TGF-beta1,, TIMP-1, PAl-1 in renal tissues obviously decreased. CONCLUSION: Xinganbao Capsule could exert its renal protective action possibly through reducing the urinary protein excretion, correcting lipid metabolic disturbance, inhibiting excessive accumulation of extracellular matrix, decreasing the expression of fibrosis factors, and improving the pathological damage of kidneys in the AIN rat model. PMID- 21812277 TI - [Studies on the vascular endothelial cell injury model of blood stasis syndrome from the angle of combination of disease identification and syndrome differentiation]. AB - To study and analyze the model types, methods, and prospective of the vascular endothelial cell injury model of blood stasis syndrome from the angle of combination of disease identification and syndrome differentiation. We believe that studies on the vascular endothelial cell injury model of blood stasis syndrome should manifest the features of the combination of disease identification and syndrome differentiation. Following microscopic path and applying macroscopic theory could become an important technological platform for screening drugs of activating blood stasis and removing stasis, and providing beneficial clues for studies of Chinese medicine syndrome modeling. PMID- 21812278 TI - [Progress of Chinese syndrome distribution features for coronary heart disease and its different subtypes]. PMID- 21812279 TI - [Progress of gold theragran's effect on learning and memory and its mechanism on anti-brain tissue injury]. PMID- 21812280 TI - [Features of extra-esophageal symptoms of gastroesophageal reflux disease and Chinese medicine treatment for it]. PMID- 21812281 TI - [Effects of topographic factors on the distribution patterns of ground plants with different growth forms in montane forests in North Guangdong, China]. AB - By using canonical correspondence analysis (CCA), this paper studied the effects of small-scale topographic changes on the distribution patterns of ground plants with different growth forms in the montane evergreen broad-leaved forest in Chebaling National Nature Reserve of North Guangdong, China. It was observed that slope aspect, slope grade, and slope position had significantly integrative effects on the distribution patterns of four growth form ground plants (fern, liana, herb, and shrub). Slope aspect had significant effects on the distribution patterns of all four ground plants but slope position didn't have, whereas slope grade only affected the distribution pattern of shrub significantly. From shady slope to semi-shady slope, and to semi-sunny slope, the abundance of the four growth form ground plants decreased gradually, indicating that shade plants were dominant in the ground vegetation of subtropical montane evergreen broad-leaved forest. Most shrubs were shade-tolerant species, and their change patterns of richness and diversity with slope aspect were the same as the change pattern of abundance. Shrubs were sensitive to the change of slope grade, and richer on gentle slopes. In hilly and low mountains, slope position changed little, and had less effects on the distribution patterns of ground plants. At stand-level, horizontal topographic factor (slope grade aspect) had much greater effects on the distribution patterns of ground plants, as compared with vertical topographic factors (slope grade and slope position), which suggested that slope aspect was the major factor affecting the water and heat conditions in subtropical montane forest. PMID- 21812282 TI - [Effects of highway on the vegetation species composition along a distance gradient from road edge in southeastern margin of Tengeer Desert]. AB - Aimed to examine the effects of highway on the vegetation species composition in arid desert area, forty-eight transects perpendicular to the provincial highway 201 from Shapotou to Jing-tai in the southeastern margin of Tengger Desert were installed, with the vegetation species distribution along a distance gradient from the road edge investigated. The results showed that with increasing distance from the road edge, the species number, coverage, biomass, and alpha-diversity of herbaceous plants declined, but had no significant differences with the control beyond 5 m. Within 0-6 m to the road edge, the herbaceous plant height was greater than that of the control, but their density had less change. Within 0-2 m to the road edge, the species turnover rate of herbaceous plants was lower; at 2 5m, this rate was the highest; while beyond 10 m, the species composition of herbaceous plants was similar to that of the control. The herbaceous plant community at the road edge was dominated by gramineous plants, with the disturbance-tolerant species Pennisetum centrasiaticum, Chloris virgata, and Agropyron cristatum accounting for 68.6% of the total. C. virgata beyond 1 m to the road edge had a rapid decrease in its individual number and presence frequency, P. centrasiaticum and A. cristatum beyond 2 m also showed a similar trend, while the composite plants Artemisia capillaris and A. frigida beyond 2 m from the road edge had a rapid increase in its individual number, accounting for 70% of the herbaceous plants. At the road edge, the coverage and density of shrubs were significantly lower than those of the control, but the species composition had no significant difference. PMID- 21812283 TI - [Structural characteristics of Sophora moorcroftiana community on wind-sandy land in middle reaches of Yaluzangbu River]. AB - Based on quadrat investigation and hierarchical cluster analysis, this paper studied the structural characteristics of Sophora moorcroftiana community at its different restoration succession stages on the wind-sandy land in middle reaches of Yaluzangbu River. The plant community on the wind-sandy land could be divided into 6 types, i.e., S. moorcroftiana community, Orinus thoroldii community, S. moorcroftiana < O. thoroldii community, S. moorcroftiana-O. thoroldii community, Artemisia weiibyii+S. moorcroftiana community, and S. moorcroftiana+A. weiibyii community. The restoration succession began with the sand-fixing S. moorcroftiana distributed on moving dune, followed by O. thoroldii invasion, and then, S. moorcroftiana-O. thoroldii community formed gradually. Another restoration succession approach began with O. thoroldii community, S. moorcroftiana occurred then, and finally, S. moorcroftiana-O, thoroldii community formed. On semi-fixed dune, A. weiibyi could invade the community, and S. moorcroftiana+A. weiibyi community formed. The climax community on the wind-sandy land was the shrub community dominated by S. moorcroftiana. With increasing slope grade, the coverage and height of S. moorcroftiana community tended to decrease. Biological crust had definite improvement effect on the soil physical and chemical properties. At the places with biological crust, surface soil water content was significantly higher, compared with that at the places with other restoration succession stages of S. moorcroftiana community. The crown diameter, plant height, and the sprouting branch number of S. moorcroftiana community were the highest on moving dune, followed by on fixed dune, and on semi-fixed dune. The dead branch number at different restoration succession stages indicated that S. moorcroftiana population had a declining trend after the sand was fixed. PMID- 21812284 TI - [Effects of extreme drought on plant species in Karst area of Guizhou Province, Southwest China]. AB - Based on the investigation data of damaged vegetations in Karst areas of Guizhou Province during the extreme drought in 2010, an investigation was made on the species composition, floristic composition, life form, leaf characteristics, and environmental conditions of drought-damaged plants at six sampling plots. At these plots, there were 31 plant species drought-damaged, among which, Cunninghamia lanceolata, Celastrus orbiculatus, Rapanea neriifolia, Myrsine semiserrata, Cyclobalanopsis glauca, and Cinnamomum glanduliferum damaged most, and the tropical evergreen arbors with mesophyllous, leathery, and simple leaf suffered more seriously. The damaged plants mainly located on the middle or upper part of steep slopes, and on the thin limestone soils originated from horizontal attitude carbonate rocks. The plants in the microhabitats with soil layer < 30 cm and rock-soil were damaged most, accounting for 87.4% and 40.0% of the total, respectively. It was suggested that the temperate deciduous trees with microphyll could be more planted in Karst areas, and that the microhabitat for the afforestation could be in gully and with thicker soil layer and good site condition. PMID- 21812285 TI - [Point pattern analysis of Phyllostachys bissetti ramet population in West China Rainy Area]. AB - In this paper, point pattern analysis was conducted to study the spatial distribution of Phyllostachys bissetii ramet population and the spatial association between different age-class P. bissetii ramet populations in West China Rainy Area. The ramet population had a clumped distribution at the scale 0 0.32 m, a regular distribution at the scale 0.64-4.48 m, and a random distribution at the scale > 4.48 m. Different age-class ramet populations mainly had a random distribution at the scale 0-8.00 m, though a slight difference was observed among different age-classes. The spatial association between age-class I and age-classes II and III at the scale 1.76 - 4.16 m and 0.32-4.16 m approached to or reached to negative, respectively, while the spatial association between age-classes I and IV at the scale 0.32-3.04 m was significantly negative, indicating that the spatial negative association between younger and elder ramet populations increased with enlarged age-class difference. The spatial pattern of P. bissetii ramet population and the spatial association between different age class ramet populations were depended on spatial scale, ramet age, and environmental factors. PMID- 21812286 TI - [Cold resistance of Pistacia chinensis and Koelreuteria integrifoliola]. AB - Taking one-year-old dormant shoots of Pistacia chinensis and Koelreuteria integrifoliola as test materials and the shoots of northern indigenous tree species K. paniculata as the control, the changes of their membrane-lipid peroxidation, antioxidative enzyme activity, and organic osmoregulatory substance content under artificial cooling were studied, aimed to analyze the differences of the three tree species in cold resistance. With the decrease of temperature, the ion leakage percentage of the three tree species increased in S-shape, and the SOD and POD activities decreased after an initial increase. The MDA, soluble protein, and soluble sugar contents of K. integrifoliola and K. paniculata under decreasing temperature decreased after an initial increase, while those of P. chinensis had an increasing trend. The semi-lethal temperature (LT50 ) of K. paniculata, K. integrifoliola, and P. chinensis calculated by the Logistic equation of ion leakage percentage was -27.2 degrees C, -23.7 degrees C, and 27.0 degrees C, respectively. Among the three tree species, K. paniculata had the strongest cold resistance, followed by P. chinensis, and K. integrifoliola. PMID- 21812287 TI - [Effects of short-term enhanced UV-B radiation on the PS II photochemical efficiency of alpine plant Saussurea superba]. AB - A simulation experiment of short-term supplementation of UV-B was conducted to study the changes of chlorophyll fluorescence coefficients of alpine plant Saussurea superba under three typical weather conditions (sunny, cloudy, and shady) in Qinghai-Tibet Plateau. When the weather changed from sunny to shady, the maximal quantum efficiency of PS II photochemistry (F(v)/F(m)) after 3 minutes of dark adaptation increased significantly, the actual photochemical efficiency of PS II (phi(PS II)) and photochemical quenching (q(P)) also increased, but the non-photochemical quenching (NPQ) decreased, demonstrating that PAR was the main factor affecting the PS II photochemical efficiency of S. superba. After the short-term supplementation of UV-B, the F(v)/F(m) and NPQ under the three typical weather conditions had a slight decrease but the phi(PS II) and q(P) had a slight increase, while the photosynthetic gas exchange had less change. The increasing trend of net photosynthetic rate P(n) and psi(PS II) under enhanced UV-B radiation could be related to the existence of more UV-A component, and also, benefited from the increased leaf thickness. UV-B radiation had potential negative effects on leaf photosynthetic components. PMID- 21812288 TI - [Effects of NaCl stress on the seedling growth and K(+)- and Na(+) -allocation of four leguminous tree species]. AB - Taking the pot-cultured seedlings of four leguminous tree species (Albizia julibrissin, Robinia pseudoacacia, Sophora japonica, and Gleditsia sinensis) as test materials, this paper studied their growth indices, critical salt concentration (C50), and K+ and Na+ allocation under different levels of NaCl stress, aimed to understand the difference of test tree species in salt tolerance. NaCl stress inhibited the seedling growth of the tree species. Under NaCl stress, the dry matter accumulation decreased, while the root/shoot ratio increased, especially for A. julibrissin and G. sinensis. Quadratic regression analysis showed that the C50 of A. julibrissin, R. pseudoacacia, S. japonica, and G. sinensis was 3.0 per thousand, 5.0 per thousand, 4.5 per thousand, and 3.9 per thousand, respectively, i.e., the salt tolerance of the four tree species was in the order of R. pseudoacacia > S. japonica > G. sinensis > A. julibrissin. In the root, stem, and leaf of the four tree species seedlings, the Na+ content increased with the increase of NaCl stress, while the K+ content (except in the root of A. julibrissin) decreased after an initial increase, resulting in a larger difference in the K+/Na+ ratio in the organs. Under the same NaCl stress, the allocation of Na+ in different organs of the four tree species seedlings decreased in the order of root>stem>leaf, while that of K+ differed with tree species and NaCl stress, and leaf was the main storage organ for K+. The K+/Na+ ratio in different organs decreased in the sequence of leaf>stem>root. R. pseudoacacia under NaCl stress accumulated more K+ and less Na+ in stem and leaf, and had higher K+/Na+ ratio in all organs and higher dry mass, being assessed to be more salt-tolerant. In contrast, A. julibrissin under high NaCl stress accumulated more Na+ in stem and leaf, and had a lower K+/Na+ ratio in all organs and lower dry mass, being evaluated to be lesser salt-tolerant. The K+ accumulation in seedling stem and leaf and the Na+ retention in seedling root could be the main reasons for the salt tolerance of leguminous tree species under NaCl stress. PMID- 21812289 TI - [Soil hydrolase characteristics in late soil-thawing period in subalpine/alpine forests of west Sichuan]. AB - Late soil-thawing period is a critical stage connecting winter and growth season. The significant temperature fluctuation at this stage might have strong effects on soil ecological processes. In order to understand the soil biochemical processes at this stage in the subalpine/alpine forests of west Sichuan, soil samples were collected from the representative forests including primary fir forest, fir and birch mixed forest, and secondary fir forest in March 5-April 25, 2009, with the activities of soil invertase, urease, and phosphatase (neutral, acid and alkaline phosphatases) measured. In soil frozen period, the activities of the three enzymes in test forests still kept relatively higher. With the increase of soil temperature, the activities of hydrolases at the early stage of soil-thawing decreased rapidly after a sharp increase, except for neutral phosphatease. Thereafter, there was an increase in the activities of urease and phosphatase. Relative to soil mineral layer, soil organic layer had higher hydrolase activity in late soil-thawing period, and showed more obvious responses to the variation of soil temperature. PMID- 21812290 TI - [Low-phosphorus tolerance and related physiological mechanism of Xieqingzao B//Xieqingzao B/Dongxiang wild rice BC1F9 populations]. AB - By the method of water culture, the low-phosphorus tolerance of 221 lines of Xieqingzao B//Xieqingzao B/Dongxiang wild rice BC1 F9 populations was indentified. The morphological indices including plant height, leaf age, yellow leaf number, and shoot dry mass as well as the physiological indices including MDA, soluble sugar, and shoot phosphorus content were measured, also, the phosphorus efficiency was calculated, and the correlations among the indices were analyzed. All the 221 lines had differences in the seven test indices, and the low-phosphorus tolerance lines under low-phosphorus stress had higher values of relative leaf age, relative plant height, relative shoot dry mass, and relative soluble sugar content, but lower values of relative yellow leaf number and relative malondialdehyde content. The relative shoot phosphorus content had less difference. Phosphorus efficiency was positively correlated with phosphorus utilization efficiency and phosphorus uptake efficiency, and the correlation between phosphorus efficiency and phosphorus utilization efficiency was at significant level (P < 0.01), suggesting that the low-phosphorus tolerance capability of the low-phosphorus tolerance lines was mainly attributed to the high phosphorus utilization efficiency of the lines, namely, low-phosphorus tolerance lines had stronger capability in synthesizing dry mass with per unit phosphorus uptake. PMID- 21812291 TI - [Effects of sulfur plus resin-coated controlled release urea fertilizer on winter wheat dry matter accumulation and allocation and grain yield]. AB - A field experiment was conducted to study the effects of sulfur plus resin-coated urea fertilizer on the winter wheat dry matter accumulation and allocation and grain yield. Four treatments were installed, i.e., sulfur plus resin-coated urea (SRCU), resin-coated urea (RCU), sulfur-amended conventional urea (SU), and conventional urea (U). The coated urea fertilizers were applied as basal, and the conventional urea fertilizers were 50% applied as basal and 50% applied as topdressing. There were no significant differences in the plant dry matter accumulation and grain yield between treatments RCU and U. Under the conditions the available S content in 0-20 cm soil layer was 43.2 mg x kg(-1) and the S application rate was 91.4 kg x hm(-2), treatments SRCU and SU had no significant differences in the dry matter accumulation and allocation after anthesis and the grain yield, but the amount of the assimilates after anthesis allocated in grain, the grain-filling rate at mid grain-filling stage, the 1000-grain weight, and the grain yield in the two treatments were significantly higher than those in treatment RCU. When the available S content in 0-20 cm soil layer was 105.1 mg x kg(-1) and the S application rate was 120 kg x hm(-2), the grain yield in treatment SRCU was significantly higher than that in treatment SU, but had no significant difference with that in treatments RCU and U. These results suggested that from the viewpoints of dry matter accumulation and allocation and grain yield, the nitrogen released from SRCU had the same regulation effect as the conventional urea 50% applied as basal and 50% applied as topdressing, while the regulation effect of the sulfur released from SRCU was controlled by the available S content in 0-20 cm soil layer. When the soil available S content was 43.2 mg x kg(-1), the released sulfur could promote the dry matter accumulation after anthesis and the grain-filling, and increase the grain yield significantly; when the soil available S content was 105.1 mg x kg(-1), the released sulfur from SRCU had no significant effect in increasing grain yield. Excessive S-amendment could even induce the decrease of grain yield. PMID- 21812292 TI - [Effects of conservation tillage and weed control on soil water and organic carbon contents in winter wheat field]. AB - Taking a long-term (since 2004) straw-returning winter wheat field as the object, an investigation was made in the wheat growth seasons of 2008-2009 and 2009-2010 to study the effects of different tillage methods (rotary tillage, harrow tillage, no-tillage, subsoil tillage, and conventional tillage) and weed management on the soil water and organic carbon contents. No matter retaining or removing weeds, the weed density under subsoil tillage and no-tillage was much higher than that under rotary tillage, harrow tillage, and conventional tillage. From the jointing to the milking stage of winter wheat, retaining definite amounts of weeds, no matter which tillage method was adopted, could significantly increase the 0-20 cm soil water content, suggesting the soil water conservation effect of retaining weeds. Retaining weeds only increased the soil organic carbon content in 0-20 cm layer at jointing stage. At heading and milking stages, the soil organic carbon contents in 0-20, 20-40, and 40-60 cm layers were lower under weed retaining than under weed removal. Under the conditions of weed removal, the grain yield under subsoil tillage increased significantly, compared with that under the other four tillage methods. Under the conditions of weed retaining, the grain yield was the highest under rotary tillage, and the lowest under conventional tillage. PMID- 21812293 TI - [Effects of combined fertilization of N, P, and K on nicotine content of filling type flue-cured tobacco]. AB - An orthogonal regression field experiment was conducted to study the effects of combined fertilization of N, P, and K on the nicotine content in the upper leaves of filling type flue-cured tobacco (Nicotiana tobacum) variety "Longjiang 911" from Northeast China. The regression effect models of N, P, and K fertilization rates and upper leaf nicotine content were established, and the effects of the fertilization rates and their interactions were analyzed. Based on these, an optimized NPK fertilization scheme was drawn up to reduce the nicotine content in the upper leaves of "Longjiang 911". The model analyses showed that the nicotine content in the upper leaves of "Longjiang 911" decreased after an initial increase with the increasing fertilization rate of N, increased with the increasing fertilization rate of P, and had a sharp decrease with the increasing fertilization rate of K. The two-factor effects of NKP on the nicotine content were in the order of NK >PK>NP. Within a certain range of fertilization rates, NP and PK had negative correlations with the nicotine content, suggesting the antagonistic effects between N and P and between P and K, while NK was on the contrary, suggesting the synergistic effects between N and K. A comprehensive analysis on the regression effect models of N, P, and K fertilization rates and upper leaf nicotine content showed that the basal fertilization rates of N, P, and K for the tobacco production on warp soil were recommended as 33.5-47.8 kg x hm(-2), 40.2-63.6 kg x hm(-2), and 78.0-119.6 kg x hm(-2), respectively. PMID- 21812294 TI - [Effects of exogenous CaCl2 on the functions of flue-cured tobacco seedlings leaf photosystem II under drought stress]. AB - Taking chlorophyll a fluorescence transient OJIP as the probe, this paper studied the effects of foliar spraying 10 mmol x L(-1) of CaCl2 on the functions of photosystem II (PS II) in tobacco seedling leaves under drought stress. Drought stress decreased the conversion efficiency of PS II primary light energy (F(v)/F(m)) and electron transport rate (ETR), and inhibited the primal process of photosynthesis, resulting in an obvious photoinhibition. After the spraying of CaCl2, the decrement of quantum yield for electron transport (phiE(o)) under drought stress was obviously lower, and the increment of electron transport efficiency of per reaction center (ET(o)/RC) was obviously higher, compared with those after the spraying of water. Foliar spraying CaCl2 increased the amount of PS II -captured light energy used for photosynthesis electron transport, the efficiency of surplus active reaction center, as well as the energy transport in electron transport chain, making the PS II remain relatively high activity under drought stress, and accordingly, the drought resistance of the tobacco seedlings was improved. PMID- 21812295 TI - [Estimation model for water requirement of greenhouse tomato under drip irrigation]. AB - Based on the modified Penman-Monteith equation, and through the analysis of the relationships between crop coefficient and cumulative temperature, a new model for estimating the water requirement of greenhouse tomato under drip irrigation was built. The model was validated with the measured data of plant transpiration and soil evaporation in May 2-13 (flowering-fruit-developing stage) and June 9-20 (fruit-maturing stage) , 2009. This model was suitable for the estimation of reference evapotranspiration (ET(0)) in greenhouse. The crop coefficient of greenhouse tomato was correlated as a quadratic function of cumulative temperature. The mean relative error between measured and estimated values was less than 10%, being able to estimate the water requirement of greenhouse tomato under drip irrigation. PMID- 21812296 TI - [Effects of spent mushroom compost on greenhouse cabbage growth under soil salt stress]. AB - A pot experiment was conducted to study the effect of spent mushroom compost (SMC) in alleviating greenhouse soil secondary salinization and cabbage salt stress. With the amendment of SMC, the salinized soil after 60 day cabbage cultivation had a pH value close to 7.0, its organic matter and available phosphorous contents increased significantly, and the increment of total water soluble salt content reduced, compared with the control. When the amendment amount of SMC was 10 g x kg(-1), the increment of soil water soluble salt content was the least, suggesting that appropriate amendment with SMC could reduce the salt accumulation in greenhouse soil. Amendment with SMC increased the cabbage seed germination rate, plant height, plant fresh mass, chlorophyll SPAD value, and vitamin C content, and decreased the proline content significantly. All the results indicated that SMC could improve the growth environment of greenhouse cabbage, and effectively alleviate the detrimental effect of salt stress. PMID- 21812297 TI - [Characteristics of soil respiration in Phyllostachys edulis forest in Wanmulin Natural Reserve and related affecting factors]. AB - By using Li-Cor 8100 open soil carbon flux system, the dynamic changes of soil respiration rate in Phyllostachys edulis forest in Wanmulin Natural Reserve in Fujian Province of China were measured from January 2009 to December 2009, with the relationships between the dynamic changes and related affecting factors analyzed. The monthly variation of soil respiration rate in the forest presented a double peak curve, with the peaks appeared in June 2009 (6. 83 micromol x m(-2) x s(-1)) and September 2009 (5.59 micromol x m(-2) x s(-1)), and the seasonal variation of the soil respiration rate was significant, with the maximum in summer and the minimum in winter. The soil respiration rate had significant correlation with the soil temperature at depth 5 cm (P < 0.05), but no significant correlation with soil moisture (P > 0.05). The monthly variation of litter fall mass in the forest was in single peak shape, and there was a significantly positive correlation between the monthly litter fall mass and soil respiration rate (P < 0.05). Two-factor model of soil temperature and litter fall mass could explain 93.2% variation of the soil respiration rate. PMID- 21812298 TI - [Methane emission flux of Zhalong Phragmites australis wetlands in growth season]. AB - Static chamber/gas chromatogram method was adopted to measure the methane emission flux of Zhalong Phragmites australis wetlands with different water levels in a growth season from May to October, 2009, aimed to understand the methane emission pattern in natural freshwater P. australis wetland in frigid region. During the observation period, the average methane emission flux of test wetlands ranged from -21.18 to 46.15 mg x m(-2) x h(-1), with a mean of 7.67 mg x m(-2) x h(-1). In deep water zone (average water level 100 cm) and shallow water zone (average water level 25 cm), the average methane emission flux was 5.81 and 9.52 mg x m(-2) x h(-1), with a peak in August and July, respectively, and the minimum in October. In summer (from June to July), the methane emission flux in deep water zone was significantly lower than that in shallow water zone; while in spring (May) and autumn (from August to October), a reversed trend was observed. The methane emission flux had a seasonal pattern of summer > autumn > spring, and a diurnal pattern of being the highest at 12:00 and 14:00 and the lowest at 0:00. Temperature and water level were the major factors affecting the methane emission flux in freshwater P. australis wetlands in frigid region. PMID- 21812299 TI - [Main interspecific competition and land productivity of fruit-crop intercropping in Loess Region of West Shauxi]. AB - Taking the four typical fruit-crop intercropping models, i.e., walnut-peanut, walnut-soybean, apple-peanut, and apple-soybean, in the Loess Region of western Shanxi Province as the objects, this paper analyzed the crop (peanut and soybean) photosynthetic active radiation (PAR), net photosynthetic rate (P(n)), yield, and soil moisture content. Comparing with crop monoculture, fruit-crop intercropping decreased the crop PAR and P(n). The smaller the distance from tree rows, the smaller the crop PAR and P(n). There was a significantly positive correlation between the P(n) and crop yield, suggesting that illumination was one of the key factors affecting crop yield. From the whole trend, the 0-100 cm soil moisture content had no significant differences between walnut-crop intercropping systems and corresponding monoculture cropping systems, but had significant differences between apple-crop intercropping systems and corresponding monoculture cropping systems, indicating that the competition for soil moisture was more intense in apple-crop intercropping systems than in walnut-crop intercropping systems. Comparing with monoculture, fruit-crop intercropping increased the land use efficiency and economic benefit averagely by 70% and 14%, respectively, and walnut-crop intercropping was much better than apple-crop intercropping. To increase the crop yield in fruit-crop intercropping systems, the following strategies should be taken: strengthening the management of irrigation and fertilization, increasing the distances or setting root barriers between crop and tree rows, regularly and properly pruning, and planting shade-tolerant crops in intercropping. PMID- 21812300 TI - [Physiological mechanisms of growth regulators 6-BA and ABA in mitigating low temperature stress of cotton fiber development]. AB - A field trial with high fiher quality cotton cultivar Kemian 1 was conducted in Nanjing (lower reaches of Yangtze River) in 2006-2007 to study the effects of growth regulators 6-BA and ABA on the boll and fiber development and related physiological mechanisms under low temperature stress. The cotton seeds were sown on April 25 and May 25, respectively, which could result in different temperature for the bolls on the same positions, and the growth regulators were sprayed at flowering stage. Spraying 6-BA increased the boll weight and fiber quality under both normal and low temperature conditions; whereas spraying ABA induced the decrease of fiber quality under normal temperature but decreased the reduction magnitude of fiber quality under low temperature condition. 6-BA increased significantly the boll sucrose content and sucrose synthase and sucrose phosphate synthase activities, while ABA only increased boll beta-1, 3-glucanase activity. Both 6-BA and ABA had less effects on the activity of sucrose invertase, a key enzyme for fiber development. Under low temperature condition, spraying 6-BA or ABA improved fiber quality, but the action mechanisms were different. 6-BA improved fiber quality via enhancing the activities of relevant enzymes; while ABA improved fiber quality via increasing the stress resistance of cotton plants. PMID- 21812301 TI - [Dynamics of forest fire weather indices in Tahe County of Great Xing' an Mountains region, Heilongjiang Province]. AB - Based on the 1974-2008 forest fire and meteorological data in Tahe County of Great Xing' an Mountains region, and with the help of Canadian Forest Fire Weather Index System (CFFWIS), this paper qualitatively and quantitatively analyzed the dynamics of forest fire weather indices in the region. In 1974-2008, the mean annual fire occurrence in the region showed an increasing trend, and the increment in 2000-2008 was 72.2%, compared with that in 1974-1999. The fuel moisture codes, fire behavior indices, and fire severity indices in 1974-2008 had an overall increasing trend, which was more evident with time extended. In the future, the probability of forest fire occurrence in the region would be increasing, fuels would be getting drier, fire intensity would be increased, fire weather would be more serious, and fire control would be more difficult. Therefore, more efforts should be made to improve the capability of forest fire control, especially in summer. As a fundamental technique, prescribed burning should be applied to reduce the fuel load. From this doing, the probability of fire occurrence and the fire potential intensity could be reduced. PMID- 21812302 TI - [Changes of China agricultural climate resources under the background of climate change. V. Change characteristics of agricultural climate resources in Ningxia]. AB - Based on the 1961-2009 weather data from 21 meteorological stations in Ningxia, this paper analyzed the spatiotemporal variation trend of regional agricultural climate resources in Ningxia, Northwest China. In 1961-2009, the air temperature in Ningxia increased gradually from south to north, with the mean annual temperature increased by 0.4 degrees C x (10 a)(-1) , while the annual precipitation in most regions decreased gradually, with a decrement 4.26 mm x (10 a)(-1). Both the frost-free period and the duration of crop growth season prolonged. The regions with > or = 10 degrees C accumulated temperature being > or = 3200 degrees C x d extended southwardly, and thereby, the regions adaptive for planting mid and late rice increased. In 2001-2009, most regions were adaptive for plating winter wheat, and the whole Ningxia was adaptive for plating spring wheat. In the southern mountain regions, the region with mean temperature in July being < or = 20 degrees C decreased gradually, and accordingly, the regions adaptive for planting potato decreased. PMID- 21812303 TI - [Relationships between urban green belt structure and temperature-humidity effect]. AB - Taking four green belts with different internal constitutions and five green belts with different canopy densities along the west fourth ring road of Beijing as test objects, and by using small-scale quantitative measurement method, this paper studied the relationships between different structure urban green belts (width 42 m) and temperature-humidity effect in Beijing. Comparing with the control, lawn had no obvious effect on the decrease of air temperature and the increase of relative humidity, while shrub-herbage, tree-shrub-herbage, and tree herbage had significant effect. When the canopy density was 10%-31%, green belts had definite effect on the decrease of air temperature and the increase of relative humidity; when the canopy density reached 44%, the effect became significant; and when the canopy density exceeded 67%, the effect was significant and stable. PMID- 21812304 TI - [Regulation effects of reverse-slope level terrace on the runoff and sediment yield in sloping farmland]. AB - A dynamic monitoring on the rainfall-runoff process and the surface runoff and sediment yield in a sloping farmland was conducted at a natural rainfall runoff plot in the watershed of Jianshan River, the first tributary of Fuxian Lake, Chengjiang, aimed to study the regulation effects of reverse-slope level terrace on the runoff and sediment yield in red soil sloping farmlands of Yunnan. The regulation rates of runoff and sediment yield by the reverse-slope level terrace were 49.5%-87.7% and 56.7%-96.1%, averagely 65.3% and 80.7%, respectively, showing that the regulation effects of reverse-slope level terrace on the runoff and sediment yield, especially the latter in sloping farmland were prominent. The variation coefficients of the test parameters for undisturbed sloping farmland and reverse-slope level terrace were in the order of sediment yield > runoff > rainfall. Comparing with undisturbed sloping farmland, reverse-slope level terrace had smaller surface runoff and smaller relative deviation degree of sediment yield, demonstrating its remarkable effect in controlling runoff and sediment yield in sloping farmland. PMID- 21812305 TI - [Regional land main-function division of Guangdong Province based on gravity center and central place theory]. AB - In this paper, the regional land main-function division of Guangdong Province was studied, based on the statistical indices of 21 cities in the Province in 2008 and the central place theory, and by the methods of spatial gravity center and fuzzy clustering. In 2008, cities Guangzhou, Shenzhen, Shantou, Foshan, Dongguan, and Chaozhou were the prior developed zones, lying in gravity center region and well exerted their radiating role in developed economy, being the central region for the development of economy in the Province. Cities Heyuan, Shanwei, Jiangmen, Yangjiang, Zhanjiang, Maoming, and Zhaoqing were the restrictively developed zones. These cities had lower centrality index and worse economic base, and thereby, their ecological restoration and protection should be strengthened to make these cities be established into an eco-benefit ensured region. Cities Zhuhai, Shaoguan, Meizhou, Huizhou, Zhongshan, Qingyuan, Jieyang and Yunfu were the key developed zones, which should undertake the transfer of the industries from prior developed zones of Guangdong and limit the transfer of population from restrictively developed zones of the Province, gradually becoming the main supporting region for the economic development and population agglomeration of Guangdong. PMID- 21812306 TI - [Niche comparison of dominant entomopathogenic fungi in three forest ecosystems]. AB - An investigation was made on the quantitative composition, niche width, and niche overlap of dominant entomopathogenic fungi in three different forest ecosystems, i.e., natural broad-leaved forest, natural secondary broad-leaved forest, and pure Masson' s pine plantation. In the three forest ecosystems, Beauveria bassiana was the first dominant species in natural secondary broad-leaved forest, the second in pure Masson's pine plantation, and the third in natural broad leaved forest. B. bassiana had the broadest temporal niche width and nutritional niche width, whereas the dominant species Isaria cateinannulata, L. farinose, and I. tenuipes had much smaller niche widths. Meanwhile, B. bassiana had larger temporal niche overlaps but smaller nutritional niche overlaps with other dominant entomopathogenic fungi. It was suggested that in the three forest ecosystems, B. bassiana had the longest occurrence duration, widest host range, and strongest environmental adaptability. PMID- 21812307 TI - [Biodegradation of o-chlorophenol by photosynthetic bacteria under co metabolism]. AB - Photosynthetic bacterial strain PSB-1D cannot utilize o-chlorophenol (2-CP) as the sole carbon source for energy. In this paper, different carbon sources (malic acid, sodium propionate, sodium acetate, sodium citrate, phenol, glucose, and soluble starch) were taken as the co-metabolism substrates to study their effects on PSB-1D growth and 2-CP degradation under the condition of aerobic culture in darkness. Among the substrates, glucose was most efficient, which promoted the reproduction of PSB-1D, enhanced the 2-CP degradation efficiency, and shortened the degradation period. The optimization experiment of added concentration of glucose showed that when the added glucose concentration was 3 g x L(-1), the PSB 1D cell concentration deltaD560 after 168 h culture was 1.749, the half-time of 2 CP was shortened to 3.9 d, and the degradation rate constant was increased to 0.00864 h(-1). The SDS-PAGE analysis on the total microbial cellular protein showed that taking glucose as the co-metabolism substrate, PSB-1D could induce a specific 2-CP-degrading enzyme. PMID- 21812308 TI - [Effects of temperature on Keratella quadrata life table demography and morphometric characteristics]. AB - By the method of individual culture, this paper studied the effects of temperature (10 degrees C, 15 degrees C, 20 degrees C, and 25 degrees C) on the life table demography (net reproductive rate, intrinsic rate of population increase, generation time, average lifespan, and proportion of mictic offspring) and the offspring morphometric characteristics (body length, body width, antero median spine length, left and right antero-lateral spine lengths, left and right posterior-spine lengths, and posterior spine number) of two posterior-spined, single posterior-spined, and zero posterior-spined morphotypes of Keratella quadrata. All the test life table demographic parameters and offspring morphometric parameters differed with morphotype and temperature, and their responses to elevated temperature differed with morphotype. Temperature had significant effects on the intrinsic rate of population increase, generation time, average lifespan, and the offspring morphometric parameters (P < 0.05); morphotype had significant effects on the offspring body length, antero-median spine length, and left and right posterior-spine lengths (P < 0.05) but less effects on the life table demography (P > 0.05); and the interaction of temperature and morphotype had significant effects on the generation time and all the offspring morphometric parameters (P < 0.05). Among the three morphotypes, the two posterior-spined morphotype had shorter offspring body length (122.1+/- 0.6 microm) than the zero and single posterior-spined morphotypes (126.3 +/- 0.7 microm and 125.1 +/- 0.7 microm, respectively). The offspring antero-median spine length (32.5 +/- 0.3 microm) of the two posterior-spined morphotype was longer than that of the zero and single posterior-spined morphotypes (31.1 +/- 0.3 microm and 30.8 +/- 0.3 microm, respectively). The offspring left and right posterior-spine lengths of the two posterior-spined morphotype (31.2 +/- 1.0 microm and 32.3 +/- 0.9 microm, respectively) were similar to those of the single posterior-spined morphotype (29.5 +/-0.8 microm and 31.5 +/- 0.6 microm, respectively), but shorter than those of the zero posterior-spin ed morphotype (36.7 +/- 1.5 microm and 37.3 +/- 1.6 microm, respectively). The relationships between the offspring spine length, body width, and body length were also affected by temperature and morphotype. PMID- 21812309 TI - [Dynamics of soil arthropod community structure and its responses to forest fragmentation during the decomposition of Castanopsis eyrei leaf litter]. AB - Five evergreen broad-leaved forests (one continuous forest and four fragmented forests) in the mountain areas in the juncture of Zhejiang, Fujian, and Jiangxi Provinces, East China were selected as test objects to study the dynamics of soil arthropod community structure and its responses to forest fragmentation during the decomposition of dominant tree species Castanopsis eyrei leaf litter. A total of 899 soil arthropods were collected, belonging to 9 classes and 25 orders. Lepidoptera was the dominant taxon, accounting for 10% of the individual, while Hymenoptera, Collembola, Diptera, Prostigmata, and Geophilomorpha were the common taxa. The decomposition rate of C. eyrei leaf litter was the highest in August and lower in April-June and December, which was in accordance with the seasonal dynamics of the taxa number and individual number of soil arthropods. Meanwhile, the taxa number, individual number, and species diversity of soil arthropods differed between continuous forest and fragmented forests, suggesting that both area effect and edge effect affected the dynamics of soil arthropod community structure during the decomposition of C. eyrei leaf litter. PMID- 21812310 TI - [Adult oviposition and larvae feeding behavior of Spodoptera litura (Lepidoptera: Noctuidae) on tobacco plants after infested by B-biotype Bemisia tabaci (Homoptera: Aleyrodidae)]. AB - To understand the effects of the defense responses of tobacco plants induced by the infesting of B-biotype Bemisia tabaci to Spodoptera litura, and to explore the mechanisms of the interspecific interactions between B-biotype B. tabaci and S. litura, a laboratory experiment was conducted to study the effects of tobacco plants after infested by B-biotype B. tabaci on the adult oviposition selection and the larvae feeding, anti-feeding, and other feeding behaviors of S. litura. Comparing with that on control plants, the egg number oviposited by adult S. litura on the infested plants decreased by 40.9%. The plant leaves infested had great repellent effect to the newly-hatched S. litura larvae, while the middle leaves and the leaves with systemic damage symptom (white-vein) had definite attractive effect. Unexpanded terminal leaves had no effects on the host selection of S. litura larvae. The S. litura larvae had significant anti-feeding behavior on the leaves infested, being more notable than that on the leaves with white-vein. On the leaves infested and with white-vein, the feeding times per unit duration or the feeding percentage of S. litura larvae decreased, the time of initiating feeding prolonged, and the total feeding area declined significantly, compared with the control. In conclusion, the tobacco plants after infested by B-biotype B. tabaci had negative effects on the adult oviposition and larvae feeding of S. litura, and the results of the study would be useful in understanding the population dynamics of tobacco pests and their management. PMID- 21812311 TI - [Annual change of phytoplankton ecological features in Fangchenggang Bay of Guangxi, South China]. AB - In March, June, September, and December 2007, investigations were conducted on the species composition, dominant species, community structure, and abundance distribution of phytoplankton in the Fangchenggang Bay of Guangxi. Based on the investigation data, the phytoplankton abundance, biotic index, and their correlations with environmental factors were analyzed. A total of 138 species of 54 genera were identified, among which, 112 species belonged to 37 genera of diatoms, 21 species belonged to 12 genera of dinoflagellates, 2 species belonged to chrysophyta, 2 species belonged to chlorophyta, and 1 species belonged to cyanophyta. In whole year, the dominant species was Skeletonema costatum. The species number had a trend decreasing from the outer to the inner of the Bay and from spring to winter, while the cell abundance was decreased from the inner to the outer of the Bay. There was an obvious annual change in the cell abundance, being the highest (151.39 x 10(4) cells x dm(-3)) in summer (June) and the lowest (0.35 x 10(4) cells x dm(-3)) in winter (December). In spring, both the diversity and the species number were higher. Correlation analysis demonstrated that the distribution of phytoplankton community had definite correlations with water nutrient content, temperature and salinity. At the observation stations 1 and 2 in west Bay, due to the effects of Fangcheng River runoff and hydrodynamic forces such as tide, water salinity was lower and nutrient content was higher, and accordingly, S. costatum cells in summer could greatly reproduce, even result in high probability of red tide. PMID- 21812312 TI - [Spatial distribution patterns of heterotrophic, nitrogen, and phosphate bacteria in hypoxic zone of Yangtze River Estuary]. AB - In August 15-28, 2009, a preliminary study was conducted on the spatial distribution characteristics of heterotrophic bacteria (HB), inorganic phosphate bacteria (IPB), organic phosphate bacteria (OPB), denitrifying bacteria (DB), and ammonifying bacteria (AB) in the hypoxic zone of Yangtze River Estuary. In the water surface, water bottom, and sediment surface of the zone, the average quantity of AB was the largest, being 307.52 x 10(4) cells x L(-1), 184.50 x 10(4) cells x L(-1), 199.97 x 10(2) cells x g(-1), followed by that of HB (87.35 x 10(4) cfu x L(-1), 86.85 x 10(4) cfu x L(-1), and 19.56 x 10(2) cfu x g(-1)), and of OPB (19.26 x 10(4) cfu x L(-1), 18.82 x 10(4) cfu x L(-1), and 19.56 x10(2) cfu x g(-1), respectively). IPB was only observed within the Yangtze Estuary, south passage of the Estuary, and Zhoushan inshore, and its average quantity in the water surface, water bottom, and sediment surface was 18.50 x 10(4) cfu x L(-1), 31.00 x 10(4) cfu x L(-1), and 7.17 x 10(2) cfu x g(-1) respectively. DB had a wide distribution, but its average quantity was low, being 3.94 x 10(4) cells x L(-1), 23.08 x 10(4) cells x L(-1), and 6.22 x 10(2) cells x g(-1) in the water surface, water bottom, and sediment surface, respectively. Salinity, NO3(-)-N, PO4(3-)-P, SiO3(2)-Si, and pH were the main factors affecting the distribution of HB, IPB, OPB, and DB in water body and sediment surface. The HB, IPB, and OPB in water bottom and sediment surface had significant positive correlation with water temperature; the HB and OPB in water bottom and the IPB in sediment surface were significantly positively correlated with dissolved oxygen (DO); while the AB in sediment surface was significantly negatively correlated with DO. Cluster analysis showed that hypoxia affected the bacterial community structure in sediment surface. PMID- 21812313 TI - [Ecological characteristics of different Pseudosciaena crocea culture models]. AB - A comparative study was conducted on the ecological characteristics of different Pseudosciaena crocea culture models including monoculture P. crocea (F) and polyculture P. crocea with seaweed Gracilaria lichevoides (FG), benthos Perinereis aibuhitensis (FP), and G. lichevoides plus P. aibuhitensis (FGP) in land-based enclosures, with the sediment and water environment condition, culture benefit, and nitrogen (N) and phosphorus (P) reclaim efficiency analyzed. G. lichevoides could effectively remove the N and P in the water body. The water N and P concentrations in FG and FGP were significantly lower than those in F and FP, and the P utilization efficiency reached 33.8% - 34.0% of the total P input. P. aibuhitensis improved sediment environment condition. The sediment N and P concentrations in FP and FGP were lower than those in F and FG, and had significant differences between surface sediment (1-2 cm) and subsurface sediment (2-4 cm). Comparing with those in F, the total N, total P, and inorganic P in FP and FGP reduced by 8.9% -9.2% , 6.1% -6.3% and 8.0% -8.1%, respectively. P. aibuhitensis had a higher efficiency in reclaiming sediment P (7.5% -7.8% of the total P input), being able to effectively mitigate the P accumulation in sediment. Among the test models, FGP had the best material utilization efficiency and optimal resource benefit. PMID- 21812314 TI - [Fish community structure and its seasonal change in subtidal sandy beach habitat off southern Gouqi Island]. AB - To understand the characteristics of fish community structure in sandy beach habitats of island reef water areas, and to evaluate the potential capacity of these habitats in local fish stock maintenance, fishes were monthly collected with multi-mesh trammel nets in 2009 from the subtidal sandy beach habitat off southern Gouqi Island, taking the adjacent rocky reef habitat as the control. alpha and beta species diversity indices, index of relative importance (IRI), relative catch rate, and dominance curve for abundance and biomass (ABC curve) were adopted to compare the fish species composition, diversity, and community pattern between the two habitats, and multivariate statistical analyses such as non-metric multidimensional scaling (nMDS) and cluster were conducted to discuss the fish assemblage patterns. A total of 63 fish species belonging to 11 orders, 38 families, and 56 genera were collected, of which, 46 fish species were appeared in the two habitats. Due to the appearance of more warm water species in sandy bottom, the fishes in subtidal sandy beach habitat showed much higher richness, and the abundance catch rate (ACR) from May to July was higher than that in rocky reef habitat. In most rest months, the ACR in subtidal sandy beach habitat also showed the similar trend. However, the species richness and diversity in spring and summer were significantly lower in subtidal sandy beach habitat than in rocky reef habitat, because of the high species dominance and low evenness in the sandy beach habitat. Japanese tonguefish (Paraplagusia japonica) was the indicator species in the sandy beach habitat, and dominated in early spring, later summer, autumn, and winter when the fishing pressure was not strong. In sandy bottom, a unique community structure was formed and kept in dynamic, due to the nursery use of sandy beach by Japanese anchovy (Engraulis japonicus) from May to July, the gathering of gray mullet (Mugil cephalus) in most months for feeding, and the large quantity appearance of plotosid catfish (Plotosus anguillaris) in early Autumn, which was quite different from the community structure pattern dominated by reef fishes in rocky-algae habitat. The subtidal sandy bottom off Gouqi Island was serving as both nursery and feeding grounds for many fish species, being a suitable habitat for flatfishes. It was concluded that the sandy beaches around Gouqi Island could be a very important habitat for economic fish species, especially as a nursery ground for juvenile fishes, contributing to the fish stock maintenance in specific area. PMID- 21812315 TI - [Soil seed bank research of China mining areas: necessity and challenges]. AB - Soil seed bank consists of all living seeds existed in soil and its surface litter, especially in topsoil, and can reflect the characteristics of regional biodiversity. As the base of vegetation restoration and potential greening material, topsoil and its seed bank are the limited and non-renewable resources in mining areas. The study of soil seed bank has become one of the hotspots in the research field of vegetation restoration and land reclamation in China mining areas. Owing to the special characteristics of mining industry, the soil seed bank study of mining areas should not only concern with the seed species, quantities, and their relations with ground surface vegetation, but also make use of the research results on the soil seed bank of other fragile habitats. Besides, a breakthrough should be sought in the thinking ways and research approach. This paper analyzed the particularity of mining area's soil seek bank research, summarized the research progress in the soil seed bank of mining areas and other fragile habitats, and put forward the challenges we are facing with. It was expected that this paper could help to reinforce the soil seed bank research of China mining areas, and provide scientific guidelines for taking great advantage of the significant roles of soil seed bank in land reclamation and vegetation restoration in the future. PMID- 21812316 TI - [Fractal theory and its application in the analysis of soil spatial variability: a review]. AB - Soil has spatial variability in its attributes. The analysis of soil spatial variability is of significance for soil management. This paper summarized the fractal theory and its application in spatial analysis of soil variability, with the focus on the utilization of moment method in calculating the fractal dimension of soil attributes, the multi-fractal analysis of soil spatial variability, and the scaling up of soil attributes based on multi-fractal parameters. The studies on the application of fractal theory and multi-fractal method in the analysis of soil spatial variability were also reviewed. Fractal theory could be an important tool in quantifying the spatial variability and scaling up of soil attributes. PMID- 21812317 TI - [Impacts of hydroelectric cascade exploitation on river ecosystem and landscape: a review]. AB - Hydroelectric cascade exploitation, one of the major ways for exploiting water resources and developing hydropower, not only satisfies the needs of various national economic sectors, but also promotes the socio-economic sustainable development of river basin. unavoidable anthropogenic impacts on the entire basin ecosystem. Based on the process of hydroelectric cascade exploitation and the ecological characteristics of river basins, this paper reviewed the major impacts of hydroelectric cascade exploitation on dam-area ecosystems, river reservoirs micro-climate, riparian ecosystems, river aquatic ecosystems, wetlands, and river landscapes. Some prospects for future research were offered, e.g., strengthening the research of chain reactions and cumulative effects of ecological factors affected by hydroelectric cascade exploitation, intensifying the study of positive and negative ecological effects under the dam networks and their joint operations, and improving the research of successional development and stability of basin ecosystems at different temporal and spatial scales. PMID- 21812318 TI - [Allelopathy of garlic root exudates]. AB - By the method of water culture, the root exudates of Cangshan garlic and Caijiapo garlic were collected to study their allelopathic effects on the seed germination and seedling growth of lettuce, and on the development of pathogens Fusarium oxysporum f. sp. cucumerinum and F. oxysporium f. sp. niveum. The root exudates of the two garlic cultivars promoted the lettuce seed germination and seedling growth at low concentrations (0.1 and 0.2 g x mL(-1)), but showed inhibitory effects at high concentrations (0.4 and 0.6 g x mL(-1)), with the inhibitory effects being stronger for the root exudates of Caijiapo garlic. The two garlic cultivars' root exudates also had inhibitory effects on the mycelia growth and spore germination of the pathogens, and the effects increased with increasing concentration of the exudates, being stronger for Caijiapo garlic than for Cangshan garlic. F. oxysporum f. sp. cucumerinum was more sensitive to the inhibitory effects of the root exudates of the two garlic cultivars, as compared to F. oxysporium f. sp. niveum. PMID- 21812319 TI - [Allelopathic interactions between invasive plant Solidago canadensis and native plant Phragmites australis]. AB - Taking the seeds of invasive plant Solidago canadensis and native plant Phragmites australis from their mono- and co-dominant communities as allelopathic acceptors, this paper analyzed the differences in the seed germination rate and sprout length after treated with five level (12.5, 25, 50, 100, and 200 mg x mL( 1)) S. canadensis and P. australis extracts, aimed to understand the allelopathic interactions between the two species. The 1000-grain weight and seed germination rate under distilled water treatment of the two species in co-dominated community were greater than those in mono-dominant community. Low level (12.5 and 25 mg x mL(-1)) S. canadensi extracts slightly promoted the seed germination rates of S. canadensis in both mono- and co-dominant communities, but high level (50, 100, and 200 mg x mL(-1)) S. canadensi extracts had strong inhibition effect, especially for the S. canadensis in co-dominated community. No significant patterns were observed about the effects of P. australis extract on S. canadensis seed germination. The sprout length of S. canadensis seeds in both mono- and co dominant communities decreased with increasing level of S. canadensis extract, but decreased in a fluctuation way with increasing level of P. australis extract. After treated with the extracts of P. australis or S. canadensis, the seed germination rate of P. australis in mono-dominant community was significantly greater than that in co-dominant community (P < 0.05), but there was no significant difference between these two extracts. PMID- 21812320 TI - Lipid nanoemulsions for anti-cancer drug therapy. AB - Multifunctional lipid nanoemulsions have shown to combine several advantages e.g. tissue targeting, cell targeting, imaging analysis, barrier permeability enhancement, and therapeutic purposes. Depending on the choice of lipid composition, surfactants and additional surface modifiers ratio, different drug loadings may be achieved and exploited for drug delivery in cancer chemotherapy. However, a safe and effective delivery system for cancer therapy should also be able to overcome the major impediment of multidrug resistance. Several strategies have been tested in nanoemulsions including P-glycoprotein-mediated drug resistance. The present review focuses on a comprehensive discussion of the use of nanoemulsions in anti-cancer therapy, reporting the technological aspects of pharmaceutical formulation of these carriers, and exploiting their advantages in siRNA therapy. PMID- 21812321 TI - Highly efficient and lowly toxic docetaxel nanoemulsions for intravenous injection to animals. AB - Hypersensitivity many occur with commercial docetaxel injections containing Tween 80 and ethanol. An alternative formulation of docetaxel, an oil-in-water nanoemulsion was prepared using the high-pressure homogenization method. It was composed of medium-chain triglyceride, oleic acid, egg lecithin, and poloxamer. These ingredients are known as safe agents for intravenous (i.v.) injection. The nanoemulsion had a small size of 169 nm, and a high surface charge with the zeta potential of -33.9 mV. It maintained well stable even under high centrifugation. Acute toxicity of i.v. injection, erythrocyte hemolysis experiment, and rabbit ear vein irritation test showed no toxicity for the docetaxel nanoemulsion. The docetaxel nanoemulsion led to a larger apparent distribution volume and area under curve than the docetaxel injection after i.v. administration to rats. The histopathological test of tumor further demonstrated the highly anticancer efficiency of the docetaxel nanoemulsion. Thus, the nanoemulsion is a promising delivery system for docetaxel with highly anticancer efficiency and low toxicity. PMID- 21812322 TI - Optimization of preparation and property studies on glycosylated albumin as drug carrier for nanoparticles. AB - Glycosylated BSA was prepared via Maillard reaction and central composite design (CCD) technique was applied to study the effects of reaction time, temperature, the pH value of the buffer solution on the degree of graft (DG), content of the melanoid (A420) and emulsifying stability (ES) of the resultant product. Fluorescence spectra as well as several other techniques including sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), infrared spectrum (IR) and differential scanning calorimetry (DSC) were employed to study the possible differences between the glycosylated BSA and BSA. Glycosylated albumin possessed distinct properties from BSA and had the great potential to be used as the drug carrier for nanoparticles. PMID- 21812323 TI - Development of a novel ophthalmic ciclosporin A-loaded nanosuspension using top down media milling methods. AB - To develop a novel ciclosporin A (CsA)-loaded nanosuspension causing less ocular irritation, a range of nanosuspensions was prepared with various polymers using a media milling method. The effects of polymer, milling time, milling speed and bead material on the particle size of the nanosuspension were investigated. Stability and irritation tests in rabbits' eyes were then performed comparing the nanosuspension with a commercial product. Of the nanosuspensions prepared with various polymers, that with PVA showed no creaming or sedimentation phenomena and gave the smallest particles of about 530 nm. The particle size decreased abruptly as the milling time increased to 2 h and then hardly decreased further. As the milling speed was increased, the particle size of CsA in the nanosuspension also increased. Nanosuspensions prepared with zirconia beads gave significantly finer particles than those with polystyrene beads. In particular, the CsA-loaded nanosuspension with a CsA/PVA/water weight ratio of 0.5/1/100 prepared using the top-down media milling method with zirconia beads of 300 microm diameter at 1000 rpm for 2 h gave a minimum particle size of about 530 nm. This nansuspension was physcally and chemically stable for at least two months. In the Draize test, both this nanosuspension and the commercial product gave very slight ocular irritation. However, in the Schirmer tear test, this nanosuspension caused less irritation to the rabbits' eyes compared to the commercial product. Thus, the CsA loaded nanosuspension prepared with PVA and water using the top-down media milling method could be a promising candidate for causing less ocular irritation. PMID- 21812324 TI - Lipid nanoemulsions loaded with doxorubicin-oleic acid ionic complex: characterization, in vitro and in vivo studies. AB - This study aimed at developing a novel lipid nanoemulsion formulation of doxorubicin (DOX) which is feasible for scale-up production, exhibits good parenteral acceptability, and further improves the therapeutic index of the drug. Oleic acid was used to form ionic complex with DOX in order to enhance its lipophilicity. The lipid nanoemulsions loaded with doxorubicin-oleic acid complex (DOX-OA-LNs) were prepared using a simple high-pressure homogenization method and fully characterized from physicochemical and in vitro release standpoint. Afterwards, the DOX-OA-LNs and free DOX were compared with respect to their in vitro cellular uptake and cytotoxicity, and their in vivo pharmacokinetics and biodistribution behavior in mice were also investigated. The obtained DOX-OA-LNs could achieve high encapsulation efficiency of 93.7 +/- 1.2% under optimal conditions. The in vitro release behavior displayed biphasic drug release pattern with rapid release at the initial stage and prolonged release afterwards. The DOX OA-LNs exhibited higher growth inhibitory effect than free DOX by MTT assay. Flow cytometry and confocal microscopy studies showed that the cellular uptake of free DOX and DOX-OA-LNs were comparable. Pharmacokinetics and in vivo distribution studies in mice showed that DOX-OA-LNs demonstrated significantly higher DOX level in blood and longer circulation time than free DOX. Moreover, DOX-OA-LNs significantly decreased DOX concentration in heart, lung and kidney. These results suggested that DOX-OA-LNs could be a promising formulation for the delivery of DOX in tumor chemotherapy. PMID- 21812325 TI - Preparation and in vitro anticancer activity of oxymatrine mixed micellar nanoparticles. AB - The aim of this study was to prepare oxymatrine (OMT) mixed micellar nanoparticles to delay release of the drug and enhance its cytotoxicity against cancer cells. A co-solvent evaporation method using lipoid E80, lipoid S75, MPEG PLA and Poloxamer 188 was chosen to prepare the OMT formulation, and its release characteristics, cytotoxic activity in vitro and physical characteristics were evaluated. The results showed that OMT mixed micellar nanoparticles have sustained release and cytotoxic activity in vitro to the SMMC-7721 cell line. PMID- 21812326 TI - Valproate release from polycaprolactone implants prepared by 3D-bioplotting. AB - In this study we examined the release kinetics of valproate from polycaprolactone (PCL) implants constructed for local antiepileptic therapy. The PCL implants were produced with a novel 3D-Bioplotting technology. Release kinetics were determined by superfusion of these implants. Valproate was measured in the superfusate fractions with high pressure liquid chromatography (HPLC). The HPLC measurements were linear over a concentration range of 10-500 microg/mL for valproate and the limit of quantification was found to be 9 microg/mL. The HPLC method used is simple, accurate and sensitive. Within the first day, valproate (10% w/w)-PCL implants released already 77% of the maximum possible liberated amount whereas (5% w/w)-PCL implants released only 53%. After four days, 88% of valproate was released from (10% w/w)-PCL implants and 94% valproate from (5% w/w)-PCL implants. When valproate was ground before the 3D-Bioplotting process, only 63% from (10% w/w)-PCL implants was released within the first day. This released amount of ground valproate was significantly lower compared to that which was not ground from the (10% w/w)-PCL implants. After three days of superfusion a total amount of 89% of ground valproate within the implants was released, corresponding to 88% of non-ground valproate after four days. The fast releasing PCL implants can be used to study acute effects of locally applied valproate on epileptogenesis in vivo after initiation of an epileptic focus in an animal model. The corresponding biocompatibility may also be analysed. PMID- 21812327 TI - Tanshinone IIA prevents cardiac remodeling through attenuating NAD (P)H oxidase derived reactive oxygen species production in hypertensive rats. AB - Tanshinone IIA is one of major constituents of Salvia miltiorrhiza Bunge known as Danshen. Our and others' studies have shown that Tan IIA could protect cardimyocyte against apoptosis; however the effect of Tan IIA on cardiac remodeling disease is still unknown. In this study, we investigated the effects of Tan IIA on cardiac hypertrophy and fibrosis in two-kidney, two-clip (2K2C) hypertensive rats and by which, if any, mechanisms. Administration of 2K2C hypertensive rats with Tan IIA attenuated cardiac dysfunction and fibrosis. However Tan IIA treatment had no effects on BP control. Further studies revealed that Tan IIA inhibited the increased NAD(P)H oxidase activity and expression as well as O2*- production in 2K2C hypertensive rats. Our results indicated that Tan IIA significantly improved cardiac function and attenuated fibrosis in 2K2C hypertensive rats. The protective action of Tan IIA is likely mediated by its antioxidant effect, independent of BP control, partially via inhibiting NADPH oxidase. PMID- 21812328 TI - Construction of a model to estimate the CYP3A inhibitory effect of grapefruit juice. AB - Grapefruit juice (GFJ) is known to affect the pharmacokinetics of a variety of drugs administered concomitantly and this is due to inhibition of intestinal CYP3A, a barrier protein for drug absorption. Some compounds such as furanocoumarin derivatives have been reported as inhibitors of the enzyme. On the other hand, inhibitory potentials of GFJ on CYP3A-oxidation activities differ widely between brands of juices. Information on the percentage contributed by ingredients in GFJ is also limited. Therefore, construction of prediction models for the CYP3A inhibitory potentials of GFJ brands was attempted by using concentrations of ingredients in GFJ. Concentrations of bergaptol, bergamottin, 6', 7'-dihydroxybergamottin, naringin, and naringenin in 23 kinds of GFJ were determined with high-performance liquid chromatography (HPLC). Furthermore, inhibitory effects on CYP3A activity were measured based on the initial rate for testosterone 6beta-hydroxylation in the presence of each GFJ. Results of multi regression analyses between the ingredients and the enzymatic inhibitory effects revealed that concentrations of bergamottin, 6',7'-dihydroxybergamottin, and naringin were significant variables for CYP3A inhibition of GFJ. According to the standard partial regression coefficient for each explanatory variable, bergamottin and 6',7'-dihydroxybergamottin are the most important factors for inhibition. The multiple correlation coefficient (R) and the multiple correlation coefficient with leave-one-out cross validation (Q) of the model equation were 0.94 and 0.91, respectively. These results suggest that the concentrations of ingredients can explain most variances of inhibitory effects among brands. This model may be a useful method for the prediction of the GFJ interaction potential. PMID- 21812329 TI - Protein L-isoaspartyl O-methyltransferase inhibits amyloid beta fibrillogenesis in vitro. AB - Fibrillar aggregates of beta-amyloid peptide (Abeta) are major constituents of the senile plaques found in the brains of patients suffering from Alzheimer's disease (AD). Previous studies have shown that spontaneous isomerization or racemization of aspartyl residues in Abeta peptides leads to conformational changes in the secondary structure and increased aggregative ability of the peptides. Protein L-isoaspartyl O-methyltransferase (PIMT, EC 2.1.1.77) is a repairing enzyme converting L-isoaspartyl/D-aspartyl residues in damaged proteins to normal L-aspartyl residues. In this study it was investigated, whether PIMT is able to modulate Abeta fibrillogenesis in vitro by methylation of isoaspartyl residue using purified 5Abeta and PIMT. A Thioflavin-T (Th-T) binding assay conducted after aging Abeta in vitro (37 degrees C, pH 7.4 in PBS) revealed that PIMT inhibited the increase of fluorescence caused by amyloid fibrillogenesis. Western blot analysis revealed that high molecular Abeta aggregates (> 200 kDa) only occurred during Abeta incubation, while they were reduced in response to incubation with PIMT and AdoMet. Additionally, circular dichroism (CD) showed that the beta-sheet structure was increased in Abeta peptides in a time-dependent fashion, while PIMT suppressed the beta-sheet transition after 24 h. Finally, transmission electron microscopy (TEM) revealed that PIMT reduced the size of the Abeta aggregates and induced a different pathway, leading to the formation of amorphous structures. Taken together, these findings indicate that isoaspartyl methylation leads to partial blockade of fibrillogenesis of Abeta by inhibiting the beta transition in the Abeta peptide. PMID- 21812330 TI - Effects of atorvastatin on bone metabolism and bone mineral density in Wistar rats. AB - OBJECTIVE: To investigate the effects of atorvastatin on bone formation, bone resorption and bone mineral density in Wistar rats. METHODS: Sixty healthy male Wistar rats were randomly divided into one control group treated with vehicle alone and three drug treatment groups, which were treated with atorvastatin at 5 mg/kg x d, 25 mg/kg x d and 50 mg/kg x d respectively. Left femur BMD and bone metabolic parameters were measured after 8 weeks of treatment. In high dose of atorvastatin group, 20 rats were randomly allocated into persistent treatment group or atorvastatin washout group for another 4 weeks; bone metabolic parameters were retested. RESULTS: Compared with vehicle alone, atorvastatin treatment significantly increased serum levels of ALP and BGP, but had no effects on serum Ca or P levels. Moreover, atorvastatin significantly decreased bone resorption markers including 24 h urinary Ca/Cr ratio, P/Cr ratio and serum IL-6 level. There was no significant difference among atorvastatin treatment groups. After 4 weeks of washout period, the effects of atorvastatin on bone formation and resorption markers decreased. Atorvastatin treatment did not alter BMD compared with the control group, even in the highest dose of atorvastatin group. CONCLUSION: Atorvastatin treatment in a certain extent inhibits bone resorption and promotes bone formation, but has no significant effects on bone mineral density in healthy rats. PMID- 21812331 TI - Analgesic activity of the aqueous fraction from the ethanolic extract of Chrysanthemum indicum in mice. AB - The aqueous fraction (AF) of an ethanolic extract from Chrysanthemum indicum was evaluated for analgesic activity in mice using chemical and thermal models of nociception. Given orally, AF at doses of 300 and 600 mg/kg produced significant inhibitions on chemical nociception induced by intraperitoneal acetic acid, subplantar formalin/capsaicin injections and on thermal nociception in the tail flick test and in the hot plate test. In the pentobarbital sodium-induced sleeping time test and the open-field test, AF neither significantly enhanced the pentobarbital sodium-induced sleeping time nor impaired the motor performance, indicating that the observed analgesic activity was unlikely due to sedation or motor abnormality. In a measurement of core body temperature, AF did not affect temperature within 80 min. Moreover, the effective dose (600 mg/kg) also showed no toxicity within 7 days. These results suggested further that AF produced analgesic activity possibly related to the flavonoid glycosides and phenolic glycosides in this fraction. PMID- 21812332 TI - A toxicological evaluation of a claudin modulator, the C-terminal fragment of Clostridium perfringens enterotoxin, in mice. AB - Tight junctions (TJs) maintain cellular polarity between the apical and basolateral region of epithelial cells. Claudin, a tetra-transmembrane protein, plays a pivotal role in the barrier function of TJs. We previously found that a claudin modulator, the C-terminal fragment of Clostridium perfringens enterotoxin (C-CPE), may be a promising candidate for improving the mucosal absorption of drugs. C-CPE is a fragment of enterotoxin, and putative CPE claudin receptors are highly expressed in liver and kidney. The safety and antigenicity of C-CPE must be evaluated for future clinical application. Therefore, we evaluated whether C CPE administration in mice leads to tissue injury or production of antibodies. Intravenous administration of C-CPE at 5 mg/kg, which is a more than 25-fold higher dose than that used in a murine mucosal absorption model, did not increase biochemical markers of liver and kidney injury even after 11 injections once a week. Nasal C-CPE administration (2 mg/kg) once a week for 11 administrations also did not increase these biochemical markers, but 6 administrations of C-CPE resulted in elevation of C-CPE-specific serum IgG. These results indicate that development of a less antigenic claudin modulator will be essential for future clinical application of a C-CPE-based mucosal absorption enhancer. PMID- 21812333 TI - Pharmacokinetics of hydroxycamptothecin nanosuspensions in rats. AB - The purpose of the present study was to investigate the pharmacokinetics of hydroxycamptothecin nanosuspensions after intravenous administration in rats. Hydroxycamptothecin injection was studied parallelly. The results showed that AUC(0 --> infinity), MRT, t1/2(alpha) and t1/2(beta) of hydroxycamptothecin nanosuspensions was significantly higher, while their total body clearance was lower than those of hydroxycamptothecin injections. The results indicate that hydroxycamptothecin nanosuspensions significantly increase hydroxycamptothecin blood concentrations and retention within the systemic circulation. PMID- 21812334 TI - Cytotoxicity testing of carrier-based microcomposites for DPI application. AB - Inhalation is an attractive delivery route for systemic and local therapy. High local drug concentrations may permit non-invasive delivery, lower therapeutic doses, reduced systemic side-effects, and reduced metabolic degradation of the drug in the liver. In our earlier study, carrier-based microcomposites were prepared and investigated. The present study introduces studies of the cytotoxicity of meloxicam-containing microcomposites on monolayers of Calu-3 cells, in order to acquire information on its availability in pulmonary formulations. By relating cytotoxicity and drug dissolution, the appropriate amount of meloxicam for dry powder inhalation could be determined. PMID- 21812335 TI - Synthesis and cytotoxic activities of new fatty acid esters of 20(S) protopanaxadiol. AB - In order to find new lead compounds with antitumour activies, thirteen new fatty acid esters of 20(S)-protopanaxadiol (PPD) were synthesized using oleoyl chloride or fatty acids and N,N'-dicyclohexylcarbodiimide (DCC). Their cytotoxic activities were tested using the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide] method, and the structure-activity relationships between the fatty acid esters of PPD and their cytotoxic activities are discussed. PMID- 21812336 TI - A new bibenzyl from Dendrobium secundum. AB - From the aerial parts of Dendrobium secundum, a new bibenzyl, namely 4,5,4' trihydroxy-3,3'-dimethoxybibenzyl, was isolated, along with four known compounds which included brittonin A, moscatilin, syringaresinol, and ferulic acid. All of these isolates showed appreciable DPPH free radical scavenging potential, except for brittonin A, which was devoid of activity. PMID- 21812337 TI - Melanin biosynthesis inhibitory and antioxidant activities of quercetin-3'-O-beta D-glucoside isolated from Allium cepa. AB - In the course of searching for new whitening agents, we have found that the methanol extract of dried skin of Allium cepa shows potent melanin biosynthesis inhibitory activity in B16 melanoma cells. Bioassay-guided fractionation led to the isolation of quercetin-3'-O-beta-D-glucoside (1) from the methanol extract of dried skin of A. cepa, which inhibited melanin formation in B16 melanoma cells with an IC50 value of 38.8 microM and mushroom tyrosinase with an IC50 value of 6.5 microM using L-tyrosine and 48.5 microM using L-dihydroxyphenylalanine as substrates, respectively. In addition, the antioxidant activity of 1 was evaluated in the oxygen radical absorbance capacity assay; it showed 3.04 micromol Trolox equivalents/mmol. 1 was shown to be a promising ingredient that could be useful for treating hyperpigmentation and for protecting against oxidative stress. PMID- 21812338 TI - Phytoecdysteroids of Silene guntensis and their in vitro cytotoxic and antioxidant activity. AB - Phytoecdysteroids from aerial parts of Silene guntensis B. Fedtsch were investigated and three phytoecdysteroids were isolated: 2,3-diacetate-22-benzoate 20-hydroxyecdysone (1), 2-deoxy-20-hydroxyecdysone (2), and 20-hydroxyecdysone (3). Their chemical structures were elucidated by DEPT, COSY, 1H and 13C NMR spectroscopy. The isolated compounds 1-3 and crude extracts were evaluated for their antiproliferative and antioxidant activities. They exhibited substantial inhibition of cell growth against human cervix adenocarcinoma (HeLa), hepatocellular carcinoma (HepG-2), and breast adenocarcinoma (MCF-7) cells. The chloroform extract showed potent cytotoxic effects [IC50 values (26.58 +/- 1.88) microg/mL, (20.99 +/- 1.64) microg/mL, and (18.89 +/- 2.36) microg/mL, respectively]. The new compound 1 was mildly cytotoxic compared to extracts [(127.97 +/- 11.34), (106.76 +/- 7.81), and (203.10 +/- 19.56) microg/mL, respectively]. Water and n-butanol extracts exhibited good antioxidant activities [IC50 values of (68.90 +/- 6.45) microg/mL and (69.12 +/- 5.85) microg/mL, respectively]. PMID- 21812339 TI - Indole alkaloids from Aspidosperma rigidum and A. schultesii and their antiparasitic effects. AB - Five oxindole alkaloids, three plumerane-type alkaloids, subtype haplophitine, and one aspidospermatane-type alkaloid, subtype tubotaiwine, were isolated from the medicinal plants Aspidosperma rigidum and A. schultesii. One compound was identified as the transoid conformer of 18-oxo-O-methylaspidoalbine which was not previously described. The antiparasitic activity of all compounds against Trypanosoma cruzi and Leishmania infantum and their non-specific cytotoxicity against mammalian cells were also determined. PMID- 21812340 TI - Bioactivities of triterpenes and a sterol from Syzygium samarangense. AB - Cycloartenyl stearate (1a), lupenyl stearate (1b), sitosteryl stearate (1c), and 24-methylenecycloartanyl stearate (1d) (sample 1) from the air-dried leaves of Syzygium samarangense exhibited potent analgesic and anti-inflammatory activities at effective doses of 6.25 mg/kg body weight and 12.5 mg/kg body weight, respectively. Sample 1 also exhibited negligible toxicity on zebrafish embryonic tissues. There were incidences of mortality upon direct exposure of sample 1 to dechorionated embryos, but higher mortality and aberration were observed during intact chorion treatment. PMID- 21812341 TI - Effect of triterpenoids and limonoids isolated from Cabralea canjerana and Carapa guianensis (Meliaceae) against Spodoptera frugiperda (J. E. Smith). AB - The activities of two triterpenoids, ocotillone and cabraleadiol, and four limonoids, methyl angolensate, 3-beta-deacetylfissinolide, 7-deacetoxy-7 oxogedunin, and beta-photogedunin, isolated from arillus of Carapa guianensis and fruits and seeds of Cabralea canjerana (Meliaceae), were evaluated against the fall armyworm Spodoptera frugiperda. Gedunin was used as a positive control. 7 Deacetoxy-7-oxogedunin and beta-photogedunin reduced the pupal weight as occurred with gedunin. Cabraleadiol, 3-beta-deacetylfissinolide, and 7-deacetoxy-7 oxogedunin prolonged the larval phase similar to the control (gedunin) of approximately 1.2 days at 50.0 mg kg(-1). The highest insecticidal activity was obtained for beta-photogedunin. PMID- 21812342 TI - A new hepatoprotective flavone glycoside from the flowers of Onopordum alexandrinum growing in Egypt. AB - A bioactivity-guided fractionation of the ethyl acetate fraction of the flowers of Onopordum alexandrinum L. (Asteraceae) yielded a new flavonoidal glycoside designated as acacetin-7-O-galacturonide (9), alongside with nine known flavonoids; 6-methoxy-apigenin (hispidulin) (1), acacetin (2), apigenin (3), luteolin (4), kaempferol (5), eriodictyol (6), apigenin-7-O-glucoside (7), luteolin-7-O-glucoside (8), and kaempferol-3-O-rutinoside (10). The compounds were assayed for their hepatoprotective activity against CCl4-induced hepatic cell damage in rats and free radical scavenging activity using 2,2-diphenyl-1 picrylhydrazyl (DPPH). Compounds 4, 6, 9, and 10 have not been previously reported from flowers of O. alexandrinum L., and this is the first report of acacetin-7-O-galacturonide (9) in nature which has also shown significant hepatoprotective and free radical scavenging effects. The isolated compounds were identified using different spectroscopic methods (UV, 1H NMR, 13C NMR, HMQC, HMBC, and COSY). PMID- 21812343 TI - Citronellol disrupts membrane integrity by inducing free radical generation. AB - Citronellol, an oxygenated monoterpene, is found naturally in the essential oils of several aromatic plants and has been reported to exhibit growth inhibitory and pesticidal activities. However, its mechanism of action is largely unexplored. We investigated the effect of citronellol, which is lipophilic in nature on membrane integrity in terms of lipid peroxidation, conjugated dienes content, membrane permeability, cell death, and activity of the enzyme lipoxygenase in roots of hydroponically grown wheat. Citronellol (50-250 microM) caused a significant inhibition of root and shoot growth. Furthermore, exposure to citronellol enhanced the solute leakage, increased the malondialdehyde content and lipoxygenase activity, and decreased the conjugated diene content. This indicates that citronellol induces generation of reactive oxygen species (ROS) resulting in lipid peroxidation and membrane damage. This was confirmed by in situ histochemical studies indicating cell death and disruption of membrane integrity. We conclude from this study that citronellol inhibits the root growth by ROS mediated membrane disruption. PMID- 21812344 TI - Do cyanobacterial lipids contain fatty acids longer than 18 carbon atoms? AB - Fatty acids of twelve species of cyanobacteria grown under different photoautotrophic conditions were studied and their composition was compared with literature data of many other species. We have come to the conclusion that the lipids of cyanobacteria do not contain fatty acids with a chain longer than 18 carbon atoms. In our opinion, omission of an analytical procedure, i.e. purification of fatty acid methyl esters before gas chromatography, leads to incorrect interpretation of the results. Absence or presence of fatty acids was suggested as a useful taxonomic marker and a proper diagnostic indicator in the commercial application of cyanobacterial biomass. PMID- 21812345 TI - Preparation, characterization, and biotransformation of the inclusion complex of phytosterols and hydroxypropyl-beta-cyclodextrin by Mycobacterium neoaurum. AB - The inclusion complex of hydroxypropyl-beta-cyclodextrin (HBbetaCD) and phytosterols (PSs) was prepared and characterized by thermogravimetric analysis (TGA) and infrared (IR) spectroscopy. Biotransformation of the inclusion complex of phytosterols and hydroxypropyl-beta-cyclodextrin (PSs-HBbetaCD) by Mycobacterium neoaurum to 1,4-androstadiene-3,17-dione and 4-androstene-3,17 dione [AD(D)] was studied. The TGA and IR results indicated that the thermal stability of PSs was improved in the complex with HBbetaCD. Biotransformation improved the solubility of PSs in the aqueous medium a lot because the AD(D) production was increased remarkably compared with the control, but growth of the bacteria was inhibited in the presence of HBbetaCD. The optimal inclusion ratio, ultrasonic treating time, dosage, and time of addition of PSs-HBbetaCD complexe were found to be 2:1, 10 min, 1.5 g/30 ml medium, and 48 h after incubation, respectively. This inclusion technique not only increased the availability of the substrates for the microorganisms, but also the capability of these microorganisms to produce AD(D) from PSs. PMID- 21812346 TI - Expression of carotenogenic genes and astaxanthin production in Xanthophyllomyces dendrorhous as a function of oxygen tension. AB - This report gives an insight into the specific changes in the transcription of four key carotenogenic genes [encoding geranylgeranyl diphosphate synthase (crtE), phytoene desaturase (crtI), phytoene synthase lycopene cyclase (crtYB), and astaxanthin synthase (ast), respectively] in Xanthophyllomyces dendrorhous cultures, with regard to dissolved oxygen (DO) contents of 10%, 25%, and 40% air saturation, respectively. 25% DO proved to be the most beneficial for yeast growth, transcription of carotenogenic genes, and astaxanthin content. PMID- 21812347 TI - Purification of a toxic metalloprotease produced by the pathogenic Photobacterium damselae subsp. piscicida isolated from cobia (Rachycentron canadum). AB - The aim of the present study was to purify and characterize a toxic protease secreted by the pathogenic Photobacterium damselae subsp. piscicida strain CP1 originally isolated from diseased cobia (Rachycentron canadum). The toxin isolated by anion exchange chromatography, was a metalloprotease, inhibited by L cysteine, ethylenediaminetetraacetic acid (EDTA), ethylene glycol-bis(beta aminoethyl ether)N,N,N',N'-tetraacetic acid (EGTA), 1,10-phenanthroline, N-tosyl L-phenylalanine-chloromethyl ketone (TPCK), and N-alpha-p-tosyl-L-lysine chloromethyl ketone (TLCK), and showed maximal activity at pH 6.0-8.0 and an apparent molecular mass of about 34.3 kDa. The toxin was also completely inhibited by HgCl2, and partially by sodium dodecyl sulfate (SDS) and CuCl2. The extracellular products and the partially purified protease were lethal to cobia with LD50 values of 1.26 and 6.8 microg protein/g body weight, respectively. The addition of EDTA completely inhibited the lethal toxicity of the purified protease, indicating that this metalloprotease was a lethal toxin produced by the bacterium. PMID- 21812348 TI - Linker histone H1.b is polymorphic in grey partridge (Perdix perdix). AB - This study was aimed at characterizing allelic variations of erythrocyte histone H1.b by comparing the electrophoretic patterns of histone H1.b from individuals of grey partridge (Perdix perdix) population. As two alloforms, H1.b1 and H1.b2, were discerned in the screening gels, the histone H1.b was regarded to be a polymorphic protein encoded by a gene with two codominant alleles, b1 and b2, at a locus. The tested population was found to be at Hardy-Weinberg equilibrium (chi2 = 0.834, p = 0.361), with only a minor heterozygote deficiency (fixation index F = 0.136). Since the histone H1.b alloforms were identified in a two dimensional gel containing sodium dodecyl sulfate, with no significant differences in their migration pattern in an one-dimensional acetic acid polyacrylamide gel, we assumed that the H1.b alloforms possessed a similar net charge and differed in their apparent molecular weights. A comparison of N bromosuccinimide-cleaved and alpha-chymotrypsin-digested products of histone H1.b alloforms revealed slight differences in the velocity of C-terminal peptides and a similarity in migration of their N-terminal peptides in one-dimensional sodium dodecyl sulfate-polyacrylamide gel. Therefore, it seemed that the histone H1.b alloforms might differ in this amino acid sequence in a protein segment between N bromosuccinimide cleavage site and the very C-terminus. PMID- 21812349 TI - Three-dimensional modelling of honeybee venom allergenic proteases: relation to allergenicity. AB - Api SI and Api SII are serine proteases of the honeybee venom containing allergenic determinants. Each protease consists of two structural modules: an N terminal CUB (Api SI) or a clip domain (Api SII) and a C-terminal serine protease like (SPL) domain. Both domains are connected with a linker peptide. The knowledge about the structure and function of Api SI and Api SII is limited mainly to their amino acid sequences. We constructed 3-D models of the two proteases using their amino acid sequences and crystallographic coordinates of related proteins. The models of the SPL domains were built using the structure of the prophenoloxidase-activating factor (PPAF)-II as a template. For modelling of the Api SI CUB domain the coordinates of porcine spermadhesin PSP-I were used. The models revealed the catalytic and substrate-binding sites and the negatively charged residue responsible for the trypsin-like activity. IgE-binding and antigenic sites in the two allergens were predicted using the models and programs based on the structure of known epitopes. Api SI and Api SII show structural and functional similarity to the members of the PPAF-II family. Most probably, they are part of the defence system of Apis mellifera. PMID- 21812350 TI - Biofixation of CO2 from synthetic combustion gas using cultivated microalgae in three-stage serial tubular photobioreactors. AB - Coal is the most abundant of the fossil fuels, with reserves estimated at 102 billions of tons. The feasibility of using coal as a fuel depends upon reducing emissions of gas when it is burnt, such as carbon dioxide (CO2), sulfur oxides (SO(x)), and nitrogen oxides (NO(x)). The removal of CO2 with microalgae may be one of the most efficient ways of reducing this gas, without the need for radical changes in the world's energy supply and production methods. Spirulina sp. LEB-18 and Scenedesmus obliquus LEB-22 were cultivated in serial tubular photobioreactors, with the aim of measuring the potential of CO2 biofixation and the resistance of the microalgae to SO2 and NO. Spirulina sp. and S. obliquus had CO2 biofixation scores of 0.27 and 0.22 g L(-1) d(-1), respectively. Both microalgae were resistant to SO2 and NO, and grew during the 15 d they were cultivated, which proves that using microalgae is an efficient method of biofixation of CO2 emitted when fossil fuels are burnt. PMID- 21812351 TI - Do hospital chief executive officers extract rents from Certificate of Need laws? AB - Prior research suggests that Certificate of Need (CON) laws reduce competition in the hospital services industry. As a result, this study empirically investigates if not-for-profit hospital chief executive officers (CEOs) are able to extract rents from CON laws in the form of higher compensation. A sample of 256 not-for profit hospital CEOs in states with and without CON laws and data for 2007 are used in the empirical analysis. The study considers the endogenous nature of a CON law and allows such a law to indirectly affect CEO compensation through its impact on the number of hospitals and beds. The multiple regression results indicate that special and public interests both motivate the decision of a state to maintain a CON law. CON laws are shown to reduce the number of beds at the typical hospital by 12 percent, on average, and the number of hospitals per 100,000 persons by 48 percent. These reductions ultimately lead urban hospital CEOs in states with CON laws to extract economic rents of $91,000 annually. PMID- 21812352 TI - Economic factors converge: force hospitals to review pricing strategies. AB - The US hospital service price structures are complex and tend to be significantly higher than the actual cost to provide the service. Health care consumers have been given more authority to drive health care decisions. Transparency in health care is forcing hospitals to critically review and substantiate service prices. It is vital that US hospitals review their pricing strategies in order to continue as strong leaders in the health care market. PMID- 21812353 TI - Measuring the profitability of a hospital pulmonary function laboratory: a case study. AB - The primary purpose of this article is to evaluate a proposal for a regional hospital to create a second Pulmonary Function Test laboratory (PFT lab) for outpatients. We separated the PFT lab from its departmental budget, thereby allowing a unique determination of the lab's profitability. The lab's separate financial analysis helped us to gain an understanding of the revenues and expenses of the PFT lab, providing information needed to comment on the proposed second lab. Additionally, we recommend a means for maintaining separate control over the PFT lab's revenues and costs and ascertain the efficacy of instituting a separate budget for the PFT lab. PMID- 21812354 TI - The courthouse doors do not close: constitutional challenges to non-economic damage caps. AB - Following efforts at addressing health care reform that spanned decades, the US Congress passed massive health reform legislation in 2010, with key provisions to be implemented over the next few years. This legislation has been heralded as the ultimate legislative response to the spiraling cost of care and inequity of access to care. Yet, these reforms have left many unanswered questions about the perennial issue of tort reform, in particular, caps on non-economic damages. This article begins with a broad perspective on tort reform and the debate surrounding the issue, and ends with a search for common ground where the threat of litigation may be reduced while the constitutional rights of citizens remain safeguarded. PMID- 21812355 TI - Teleradiology: friend or foe? What imaging's now indispensable partner means for radiology's future and for the quality of care. AB - Over the past half decade, teleradiology companies have served as invaluable business partners to local radiology providers grappling with declining reimbursements, shrinking budgets, and an imaging utilization explosion that has rendered workloads unmanageable. The teleradiology business model has helped to stabilize local imaging groups through economies of scale to control costs, by facilitating rapid workflow and report turnaround times, and offering a broad range of subspecialty expertise. Teleradiology has landed radiology at an important crossroads and market forces are actively shaping its future. This article examines the role of technological innovation in teleradiology's success, and suggests that persistent technological and operational limitations raise important questions regarding quality of care. This article also joins the imaging industry's discussion as to whether radiology can be (or has been) commoditized, and explores the feasibility of the commoditization of imaging and its impact on traditional radiology practice. There appears to be an important role for teleradiology in the provision of radiology services going forward, and yet boundaries must be thoughtfully drawn in order to achieve best practices for the specialty's future. tion, commoditization. PMID- 21812356 TI - [Gastric non-Hodgkin's lymphoma--clinical symptoms and diagnostic problems]. AB - INTRODUCTION: Gastric lymphoma takes 70% of lymphomas in gastric tract. Lack of characteristic symptoms and histological changes makes these disease difficult to recognize. The aim of the study was to search for specific constellation of the symptoms due to validation of diagnostic standards. MATERIAL AND METHODS: Retrospective analysis of clinical data for the group of 64 patients treated during 10 years in Hematology Department of Pomeranian Medical University in Szczecin. RESULTS: Recognition of gastric lymphoma in 80% was based on gastrocopy and histopatology examination. Gastrectomy was useful in 14 cases. Classic Ultrasound Abdomen Examination confirmed changes in 40%. Epigastic pain was raported as the most common symptom (54 from 64 patients). Systemic symptom appears in 34/64 patients (usually the loss of the body mass). CONCLUSIONS: 1. Clinical symptoms of non-Hodgkin's lymphoma in gastric localization are not specific. Epigastric pain, nausea and body mass lost are the symptoms the most often reported and physical symptoms do not reflect in systemic disease. 2. The standard of examination should consist of the transesophageal sonography (EUS) completed with multiple biopsy of gastric membrane and Hp tests. PMID- 21812357 TI - [The influence of short-term magnesium carbonate treatment on calcium-phosphorus balance in dialysis patients]. AB - INTRODUCTION: The phosphate-binders presently used in the treatment of calcium phosphorus disorders in dialysis patients remain a crucial element of cardio vascular protection. The aim of the study was to assess short-time magnesium carbonate treatment efficacy in hemodialysis patients with hyperphosphatemia. MATERIAL AND METHODS: The study involved 64 participants (32 male and 32 female) aged 29-84 years, with end-stage renal disease, hyperphosphatemia (> 1.78 mmol/l), dialysis 3 times a week, mean session time 4 hours 15 minutes. All the patients were divided into three groups: I--30 patients treated with magnesium carbonate 3 x 1 g; group II--10 patients treated with sevelamer hydrochloride 0.8 g--3 x 2 tabl (3 x 1.6 g); group III--24 patients treated with calcium carbonate 3 x 2 g. Participants were categorized randomly to groups I and II and to group III only patients with decreased serum calcium concentration (< 2.1 mmol/1) were assigned. The doses stayed constant within 12 weeks of therapy. RESULTS: In group treated with magnesium carbonate after 3 months of the treatment the decrease of plasma parathormon (iPTH) from 526.1 +/- 463.3 to 443.2 +/- 223.1 (pg/ml), calcium (Ca) from 2.4 +/- 0.2 to 2.3 +/- 0.1 (mmol/1); the highest reduction of phosphate (P) 2.1 +/- 0.5 to 1.6 +/- 0.4 (mmol/1) and calcium phosphate product (Cax P) from 4.6 +/- 2.3 to 3.5 +/- 1.1 (mmol2/ l2) were observed. In group II, iPTH slightly increased from initial 425.26 +/- 192.5 to 445.6 +/- 222.3 (pg/ml); serum calcium decreased from 2.23 +/- 0.17 to 2.0 +/- 0.2 (mmol/l); phosphates dropped from 2.35 +/- 0.43 to 2.0 +/- 0.3 (mmol/l) and Ca x P index from 5.1 +/- 1.2 to 4.1 +/- 0.7 (mmol2/l2). In group treated with calcium carbonate iPTH decreased from 308.2 +/- 196.6 to 301.9 +/- 188.5 (pg/ml). Calcium, phosphate and Ca x P dropped during the treatment from 2.06 +/- 0.23 to 2.05 +/- 0.2 (mmol/l), 2.17 +/- 0.36 to 1.86 +/- 0.45 (mmol/l) and from 4.7 +/- 0.8 to 3.7 +/- 0.9 (mmol2/l2), respectively. Calcium-phosphorus disorders were normalized to actual guidelines only in participants treated with magnesium carbonate. CONCLUSIONS: Magnesium carbonate seems to be the effective treatment of calcium-phosphorus disorders in hemodialysis patients. However its administration, similarly to other non-calcium phosphate-binders, is limited and dedicated to patients with normal serum calcium concentration. PMID- 21812359 TI - [Colopleural fistula complicating laparotomy for perforated gastric ulcer]. AB - Colopleural fistula is a very rare clinical problem which was described barely in a few articles. Common causes of this kind of fistula are strangulated diaphragm hernias and neoplasms of the splenic flexure of the colon. We report a case of 58 years old male with colopleural fistula. Symptoms of left sided pyo and pneumothorax appeared two weeks after laparotomy for perforated peptic gastric ulcer. Chest tube was inserted and antibiotics was used. The pyothorax was evacuated almost entirely. Left sided recurrent purulent thoracic wall fistulas complicated the latter two and a half year course. Finnaly the reccurence of left sided pyothorax leaded to surgical treatment. During thoracotomy decortication and resection of cirrhotic lover lobe of the left lung was performed. In the postoperative course faecal fluid appeared in the left pleural cavity. The patient was transfer to The Surgical Department where fistula between colon and pleural cavity was confirmed by colonoscopy. During laparotomy fistula between splenic flexure of the colon penetrating through diaphragm was confirmed and excised. The patient was cured. On the basis of reviewed literature we discuss possible pathological mechanisms of creating colopleural fistula, diagnostic workup and treatment. We conclude that colonoscopic examination may be helpful in diagnosis and localization of fistula site when radiological examination fails. Colopleural fistula course may lasts with few symptoms for years. PMID- 21812358 TI - [The "heart-hand" syndrome in a 8-year-old-boy with short stature]. AB - "Heart-hand" syndrome is a broad category of diseases. The most common form is Holt-Oram syndrome (HOS) that occurs in approximately 1:100 000 live births. It is characterized by upper limb defects (carpal bone defects, triphalangeal thumbs, hypoplasia or absence of the thumb and the radial ray) and cardiac septal defects (atrial septal defects or ventricular septal defects). There are three main types of "heart-hand" syndromes. "Heart-hand" syndrome type I--HOS is characterised by atrial septal defect and thumb anomaly, type II (Tabatznik syndrome) by short distal phalanx of the thumb, upper limb abnormalities and cardiac arrhythmias, type III by cardiac conduction diseases and shortening of the middle phalanges. The aim of this report is to present a new case of the "heart-hand" syndrome in the family. This diagnosis was established on the base of clinical examination, radiological findings, and echocardiography. Our patient demonstrates congenital bilateral absence of a radial bone and thumbs, dextrocardia and patent foramen ovale. PMID- 21812360 TI - [The importance of rehabilitation after operative treatment of Dupuytren's disease]. AB - Postoperative hand therapy in patients after surgery for Dupuytren's contracture is common in medical practice. Through an effective splinting and exercise program, the surgical outcome can be enhanced. The treatment plan must take into account the wide range of reactions to surgery. The management plan must be flexible, more than in most areas of hand surgery. The most important points in hand therapy after surgery for Dupuytren's disease include: 1) early detection of potential postoperative complications--including disturbances in wound healing; 2) edema control; 3) scar management; 4) maintenance of surgical correction; 5) restoration of finger flexion to the degree of preoperative range of motion. The postoperative program of hand rehabilitation depends on type of surgery, and therapist's education. The hand therapist should see all patients initially on removal of the operative dressing and provide advice on a program of active mobilization. Thereafter, patients should be seen routinely at weekly intervals to ensure that recovery of motion is progressing. PMID- 21812361 TI - [Processes of free radical lipid peroxidation with a particular regard to the role of paraoxonase-1 in the pathogenesis of multiple sclerosis]. AB - Oxidative stress is an imbalance between free radicals production and antioxidant defences. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) can attact and demage a variety of critical biological molecules, including lipids, essential cellular proteins and DNA and may be exert in pathogenesis of many disorders. Products of lipid peroxidation can be easily reliably detected in biological fluids and tissues, yielding sensitive and specific signals of lipid peroxidation occurred in vivo. Those products are: isoprostanes (isoP) dimalonealdehyde (MDA), 4-hydroxynonenal (4-HNE). Paraoxonase-1 (PON-1) play a key role in defence of lipid peroxidation. PON-1 is an serum enzyme bound up with high density lipoproteins (HDL). The aim of this work is to discuss the role of oxidative stress in the pathogenesis of multiple sclerosis. PMID- 21812362 TI - [Diagnostic value of antineutophil cytoplasmic antibodies]. AB - Antineutrophil cytoplasmic antibodies (ANCA) constitute a family of auto antibodies directed against various components of the neutrophil cytoplasm. The indirect immunofluorecence assays detected three fluorescent staining patterns: cANCA--cytoplasmic; pANCA--perinuclear and aANCA--atypical. Occurence ANCA is mainly associated with Wegener's granulomatosis and vasculitis, but they are also detected in autoimmune diseases (eg. in systemic lupus erythematosus, in rheumathoid arthritis, Sjogren's syndrome, in dermatomyositis) and in inflamatory bowel diseases (Crohn disease, colitis ulcerosa). Presence of ANCA was found also in primary sclerosing cholangitis, in chronic infections and in person using some kinds of drugs. The aim of the study was to review recent investigations concerning prevalence of ANCA and their diagnostic value not only for vasculitis but also for the other disease in which they are detected. PMID- 21812363 TI - [Dementia--distribution and diagnostic criteria]. AB - The ageing of the population makes the health problems of elderly people a major issue in the work of various specialists. More and more people show cognitive functions disorders from minor to considerable ones. The most common cause of dementia is Alzheimer's disease. The diagnostic criteria of dementia in the course of Alzheimer's disease or the criteria of vascular dementia are described in this article. Although we mention the scales focused on cognitive functions disorders. PMID- 21812365 TI - [The importance of resting ECG in diagnosis of coronary heart disease exacerbation and in heart rate disregulations in patients under home palliative care]. AB - There are large numbers of people suffering from simultaneous coronary heart disease and ischaemic heart disease who remain under home palliative care. When concentrating on oencological palliative treatment, there exists sometimes a tendency to forget about the possibility of deterioration in the general condition of a patient with cardio-vascular system dysfunctions. Deterioration in the patient's condition and persistent somatic complaints are frequently interpreted as progress in neoplastic disease or side effects of the employed therapy. It frequently leads to unnecessary discontinuation of palliative oencological treatment. Severe general condition of most patients limits the possibility of ischaemic heart disease diagnosis. It is also impossible to perform stress tests. Resting ECG is a simple and relatively inexpensive diagnostic method, possible to be performed at home by the patient's bed. Basing on a medical survey and an analysis of ECG record, diagnosis of deterioration in CHNS is very successful. The management of a patient with advanced neoplastic disease coexistent with ischaemic heart disease demands careful oencological and cardiologic treatment. ECG examinations carried in the patient's bed constitutes a crucial element of diagnostics in deteriorating coronary heart disease and in heart rate disregulations in patients under home palliative care. PMID- 21812364 TI - [Dry eye syndrom--multispecialistic disease. Part two: diagnostic procedure and treatment]. AB - The authors present the review of the literature concerning on the diagnostic procedure and current treatment of the dry eye, including anti-inflammatory treatment. To diagnosis of the dry eye syndrome is based on the combination of clinical symptoms and clinical tests. These clinical tests evaluate tear clearance, tear stability, ocular surface integrity, tear osmolarity and conjunctival cytology. Measurement of tear osmolarity might provide a "gold standard" of diagnosis, but a practical tear osmolarity test is not yet widely available. Measurement of tear film instability by means of a TBUT test has good overall accuracy and may be more repeatable than many other diagnostic tests. The first step in managing the disease is to identify the underlying etiology and to try to eliminate it and/or treat it. Inflammation and the interruption of the inflammatory cascade seem to be the main focus in the treatment of dry eye, giving the anti-inflammatory therapy a new critical role. PMID- 21812367 TI - Fats and fatty acids in human nutrition. Report of an expert consultation. PMID- 21812366 TI - [20th anniversary of Association Doctors of Hope. Experience resulting from the cooperation with Polish medical communities in the Polish Borderlands (Kresy)]. AB - 20th Anniversary of Association Doctors of Hope (ADH) is an opportunity for presentation of the conclusions resulting from the realization of our tasks, especially those related to the Polish medical communities in the Borderlands. Maintaining the contacts with the Polish minorities in Lithuania, Latria, Byelorussia, Ukraine, Romania, Moldavia and Georgia are the priority tasks of ADH. Those communities differ in the extent of their needs and the relations with the local authorities in the context of the aid provided by our Association and the cooperation with us. The programme of our medical missions in the Borderlands included: a) rendering immediate aid by supplying medicines, medical materials; b) physical examination of groups of Poles (including the youths); c) organizing joint medical and pedagogical conferences concerning heath problems and healthy lifestyle. The article refers to the need for coordination of the cooperation among Polish organizations, the organizations in the Borderlands and consulates, in order to facilitate studying of the Poles in Poland, as well as to arrange for specialization residencies in Poland for doctor of Polish descent. Perfecting of the professional qualifications is a vital factor in strengthening the respect for the Polish communities, which, as minorities, are continuously expose to breaking the law by the local authorities. PMID- 21812369 TI - Initial reaction raises criticism. PMID- 21812368 TI - Integrating health care: wave of the future. PMID- 21812370 TI - Halting hospitalizations. PMID- 21812371 TI - On the road: rural long-term care facilities underpin economies. PMID- 21812372 TI - [Pest and cholera again?]. PMID- 21812373 TI - [Informed consent for treatment in child and adolescent medicine in Germany and Austria]. PMID- 21812374 TI - [Intensive care diary for premature infants. A project report]. PMID- 21812375 TI - [Diarrhea due to EHEC pathogens: characteristics in childhood]. PMID- 21812377 TI - [Great hopes, bitter loss]. PMID- 21812376 TI - [New Basel pediatric hospital]. PMID- 21812378 TI - ["Starting life with good health - young family network" introduced]. PMID- 21812380 TI - [Can one - should one learn parenthood?]. PMID- 21812379 TI - [Indications for growth hormone therapy]. PMID- 21812381 TI - A complication in pregnancy. Blood glucose control is key to having a healthy baby. PMID- 21812382 TI - Farm fresh. The ins and outs of community-supported agriculture. PMID- 21812383 TI - For love of the game. Golfer Carling Coffing's life on the links. Interview by Carolyn Butler. PMID- 21812384 TI - Rising stars. Three young athletes with diabetes at the top of their sports. PMID- 21812385 TI - Aging. Secrets of staying fit and functional while getting older. PMID- 21812386 TI - The 3-in 1 plan. PMID- 21812387 TI - The clock is ticking. For people with diabetes, body rhythms may govern more than sleep. PMID- 21812388 TI - Genome-wide profiling of responses to cadmium in the diatom Phaeodactylum tricornutum. AB - The only group of organisms in which a biological function for cadmium has been shown is the diatoms, which are unicellular phytoplankton. Yet diatoms exhibit similar sensitivity to Cd as other groups of phytoplankton. We have investigated responses of Cd on molecular, metabolic, and physiological levels in the diatom Phaeodactylum tricornutum. P. tricornutum apparently has a high tolerance to Cd; only minor responses were observed on growth, pigment, and transcriptional changes at cadmium concentrations of 123 MUg/L. No significant changes in chlorophyll and xanthophyll levels were observed, and the very few transcripts affected strongly indicate that the cells were able to respond to the increased Cd(2+) levels without changing proteins levels. At 10 times this concentration, 1230 MUg/L, a much clearer response was observed, including transcripts encoding proteins involved in metal transport, cell signaling, and detoxification processes. Our results point toward putative pathways for the removal or detoxification of Cd and its metabolites as well as a possible Cd uptake mechanism. We predict that ATPase5-1B is involved in removal of Cd by pumping Cd(2+) ions out of the cell, whereas VIT1/CCC1 sequesters Cd(2+) in the vacuole. PMID- 21812391 TI - Assignment and stereocontrol of hibarimicin atropoisomers. AB - A stereochemical feature of the hibarimicins is a central biaryl (HMP-Y6) or aryl quinone (hibarimicinone) incorporated as a single atropodiastereomer. Herein, a chiral resolution and deracemization process to access optically enriched biaryls aR-3 and aS-3 is described. From these atropoenantiomers the BCD-EFG ring system of HMP-Y6 is constructed [(+)-aR-7]. Comparison of CD spectra of aR-7 to HMP-Y6 leads to the assignment of HMP-Y6 and hibarimicin B atropoisomers as aR and aS, respectively. PMID- 21812393 TI - Ir(I)-catalyzed enantioselective secondary sp3 C-H bond activation of 2 (alkylamino)pyridines with alkenes. AB - A cationic Ir(I)-tolBINAP complex catalyzed an enantioselective C-C bond formation initiated by secondary sp(3) C-H bond cleavage adjacent to a nitrogen atom. The reaction of 2-(alkylamino)pyridines with various alkenes gave chiral amines in good yields with high enantiomeric excesses. PMID- 21812392 TI - Enantioselective synthesis of (-)-jiadifenin, a potent neurotrophic modulator. AB - The first enantioselective synthesis of (-)-jiadifenin (1), a potent neurite outgrowth promoter isolated from the Illicium species, is described. The synthetic strategy builds upon bicyclic motif 6, which represents the AB ring of the natural product and proceeds in 19 steps and 1.1% overall yield. Key to our approach is a Mn(III)-mediated oxidation reaction of A ring that, following a regio- and diastereoselective alpha-hydroxylation and methylation sequence, produces the desired functionalities of (-)-jiadifenin. The effect of synthetic 1 in NGF-mediated neurite outgrowth was also measured in PC-12 cells. PMID- 21812395 TI - Eight-coordinated arsenic in the Zintl phases RbCd4As3 and RbZn4As3: synthesis and structural characterization. AB - Reported are two new series of Zintl phases, ACd(4)Pn(3) and AZn(4)Pn(3) (A = Na, K, Rb, Cs; Pn = As, P), whose structures feature complex atomic arrangements based on four- and eight-coordinated arsenic and phosphorus. A total of 12 compounds have been synthesized from the corresponding elements via high temperature reactions, and their structures have been established by X-ray diffraction. RbCd(4)As(3), KCd(4)As(3), NaCd(4)As(3), NaZn(4)As(3), KCd(4)P(3), and KZn(4)P(3) crystallize with a new rhombohedral structure (space group R3m, Z = 3, Pearson symbol hR24), while the isoelectronic RbZn(4)As(3), CsCd(4)As(3), CsZn(4)As(3), KZn(4)As(3), CsZn(4)P(3), and RbZn(4)P(3) adopt the tetragonal KCu(4)S(3)-type structure (space group P4/mmm, Z = 1, Pearson symbol tP8). Both structures are very closely related to the ubiquitous CaAl(2)Si(2) and ThCr(2)Si(2) structure types, and the corresponding relationships are discussed. The experimental results have been complemented by linear muffin-tin orbital (LMTO) tight-binding band structure calculations. Preliminary transport properties measurements on polycrystalline samples suggest that the compounds of these families could be promising thermoelectric materials. PMID- 21812394 TI - A turn-on fluorescent iron complex and its cellular uptake. AB - In the treatment of chronic iron overload disorders, ligands capable of complexing so-called "labile" (nonprotein bound) Fe are required to enter iron loaded cells, sequester excess Fe, and then exit the cell (and the body) as an intact Fe complex. Despite the emergence of several ligand families that show high activity in mobilizing intracellular Fe, the mechanism and the locations of these subcellular labile Fe pools are still poorly understood. Our previous studies have unearthed a class of heterocyclic hydrazine-based chelators (e.g., benzoyl picolinoyl hydrazine, H(2)BPH) that show excellent activity at mobilizing Fe from Fe-loaded cells. Herein, we have grafted a fluorescent tag (rhodamine B) onto H(2)BPH to generate a ligand (L(1)) that is nonfluorescent in its uncomplexed form but becomes strongly fluorescent in complex with Fe(III). The free ligand and its 1:2 Fe complex [Fe(III)(L(1))(2)](3+) have both been fully characterized spectroscopically and with X-ray crystallography. Confocal fluorescent microscopy of HeLa cells incubated with [Fe(III)(L(1))(2)](3+) shows that the complex rapidly enters HeLa cells and localizes within endosomes/lysosomes. PMID- 21812396 TI - Mechanochromic luminescence switch of platinum(II) complexes with 5 trimethylsilylethynyl-2,2'-bipyridine. AB - Planar platinum(II) complexes Pt(bpyC=CSiMe(3))(C=CC(6)H(4)R-4)(2) (R = H (1), Bu(t) (2)) with 5-trimethylsilylethynyl-22'-bipyridine show an unusual, reversible, and reproducible mechanical stimuli-responsive color and luminescence switch. When crystalline 1 or 2 is ground, bright yellow-green emitting is immediately converted to red luminescence with an emission red shift of 121-155 nm for 1 or 53-89 nm for 2. Meanwhile, the crystalline state is transformed to an amorphous phase that can be reverted to the original crystalline state by organic vapor adsorbing or heating, along with red luminescence turning back to yellow green emitting. The reversibility and reproducibility of luminescence mechanochromic properties have been dynamically monitored by the variations in emission spectra and X-ray diffraction patterns. The drastic grinding-triggered emission red shift is likely involved in the formation of a dimer or an aggregate through Pt-Pt interaction, resulting in a conversion of the (3)MLCT/(3)LLCT emissive state in the crystalline state into the (3)MMLCT triplet state in the amorphous phase. Compared with the drastic grinding-triggered emission red shift in 1 (121-155 nm), the corresponding response shift in 2 (53-89 nm) is much smaller since a bulky tert-butyl in C=CC(6)H(4)bu(t)-4 induces the planar platinum(II) molecules to stack through a longer Pt-Pt distance and less intermetallic contact compared with that in 1, as suggested from EXAFS studies. PMID- 21812397 TI - Sequential extraction study of stability of adsorbed mercury in chemically modified activated carbons. AB - Activated carbons chemically modified with sulfur and bromine are known for their greater effectiveness in capturing vapor Hg from coal combustion and other industrial flue gases. The stability of captured Hg in spent activated carbons determines the final fate of Hg and is critical to devising Hg control strategy. However, it remains a subject that is largely unknown, particularly for Br treated activated carbons. Using a six-step sequential extraction procedure, this work evaluated the leaching potential of Hg captured with four activated carbons, one lignite-derived activated carbon, and three chemically treated with Br(2), KClO(3), and SO(2). The results demonstrated clearly the positive effect of Br- and SO(2)-treatment on the stability of captured Hg. The Hg captured with brominated activated carbon was very stable and likely in the form of mercurous bromide complex. Sulfur added at high temperature with SO(2) was able to stabilize a majority of Hg by forming sulfide and possibly sulfonate chelate. The presence of sulfate however made a small fraction of captured Hg (<10%) labile under mild conditions. Treating activated carbon with KClO(3) lowered the overall stability of captured Hg. A positive dependence of Hg stability on Hg loading temperature was observed for the first time. PMID- 21812398 TI - Comprehensive structural analysis of mutant nucleosomes containing lysine to glutamine (KQ) substitutions in the H3 and H4 histone-fold domains. AB - Post-translational modifications (PTMs) of histones play important roles in regulating the structure and function of chromatin in eukaryotes. Although histone PTMs were considered to mainly occur at the N-terminal tails of histones, recent studies have revealed that PTMs also exist in the histone-fold domains, which are commonly shared among the core histones H2A, H2B, H3, and H4. The lysine residue is a major target for histone PTM, and the lysine to glutamine (KQ) substitution is known to mimic the acetylated states of specific histone lysine residues in vivo. Human histones H3 and H4 contain 11 lysine residues in their histone-fold domains (five for H3 and six for H4), and eight of these lysine residues are known to be targets for acetylation. In the present study, we prepared 11 mutant nucleosomes, in which each of the lysine residues of the H3 and H4 histone-fold domains was replaced by glutamine: H3 K56Q, H3 K64Q, H3 K79Q, H3 K115Q, H3 K122Q, H4 K31Q, H4 K44Q, H4 K59Q, H4 K77Q, H4 K79Q, and H4 K91Q. The crystal structures of these mutant nucleosomes were determined at 2.4-3.5 A resolutions. Some of these amino acid substitutions altered the local protein-DNA interactions and the interactions between amino acid residues within the nucleosome. Interestingly, the C-terminal region of H2A was significantly disordered in the nucleosome containing H4 K44Q. These results provide an important structural basis for understanding how histone modifications and mutations affect chromatin structure and function. PMID- 21812399 TI - Total synthesis of aeruginazole A. AB - The first total synthesis of Aeruginazole A, prepared via a convergent strategy that involved both solid-phase peptide synthesis and solution phase chemistry and that enabled conservation of the stereochemistry of the intermediates, is reported. PMID- 21812400 TI - Using synthetically modified proteins to make new materials. AB - The uniquely diverse structures and functions of proteins offer many exciting opportunities for creating new materials with advanced properties. Exploiting these capabilities requires a set of versatile chemical reactions that can attach nonnatural groups to specific locations on protein surfaces. Over the years, we and others have developed a series of new techniques for protein bioconjugation, with a particular emphasis on achieving high site selectivity and yield. Using these reactions, we have been able to prepare a number of new materials with functions that depend on both the natural and the synthetic components. In this Account, we discuss our progress in protein bioconjugation over the past decade, focusing on three distinct projects. We first consider our work to harness sunlight artificially by mimicking features of the photosynthetic apparatus, with its beautifully integrated system of chromophores, electron transfer groups, and catalytic centers. Central to these photosystems are light-harvesting antennae having hundreds of precisely aligned chromophores with positions that are dictated by the proteins within the arrays. Our approach to generating similar arrangements involves the self-assembly of tobacco mosaic virus coat proteins bearing synthetic chromophore groups. These systems offer efficient light collection, are easy to prepare, and can be used to build complex photocatalytic systems through the modification of multiple sites on the protein surfaces. We then discuss protein-based carriers that can deliver drugs and imaging agents to diseased tissues. The nanoscale agents we have built for this purpose are based on the hollow protein shell of bacteriophage MS2. These 27 nm capsids have 32 pores, which allow the entry of relatively large organic molecules into the protein shell without requiring disassembly. Our group has developed a series of chemical strategies that can install dyes, radiolabels, MRI contrast agents, and anticancer drugs on the inside surface of these capsids. We have also developed methods to decorate the external surfaces with binders for specific proteins on cancer cells. As a third research area, our group has developed protein-polymer hybrid materials for water remediation. To reduce the toxicity of heavy metals in living cells, Nature has evolved metallothioneins, which are sulfur-rich polypeptides that bind mercury, cadmium, and other toxic ions at sub-parts-per billion concentrations. Unfortunately, these proteins are very difficult to incorporate into polymers, largely because typical protein modification reactions target the very cysteine, lysine, and carboxylate-containing residues that are required for their proper function. To address this challenge, we developed a new way to attach these (and many other) proteins to polymer chains by expressing them as part of an N- and C-terminal modification "cassette". The resulting materials retain their selectivity and can remove trace amounts of toxic metal ions from ocean water. Each of these examples has presented a new set of protein bioconjugation challenges that have been met through the development of new reaction methodology. Future progress in the generation of protein-based materials will require scalable synthetic techniques with improved yields and selectivities, inexpensive purification methods for bioconjugates, and theoretical and dynamical treatments for designing new materials through protein self-assembly. PMID- 21812402 TI - Unexpected alkyl group migration in palladium(II) benzocarbaporphyrins. AB - Reaction of a benzocarbaporphyrin with methyl or ethyl iodide and potassium carbonate in refluxing acetone primarily afforded the 22-alkylation products. Subsequent metalation with palladium(II) acetate in refluxing acetonitrile gave the palladium(II) organometallic derivatives where the alkyl group had migrated to the 21-position. PMID- 21812401 TI - Synthesis and characterization of [1,2,5]chalcogenazolo[3,4 f]benzo[1,2,3]triazole and [1,2,3]triazolo[3,4-g]quinoxaline derivatives. AB - The synthesis and characterization is reported of low bandgap [1,2,5]chalcogenazolo[3,4-f]benzo[1,2,3]triazole and [1,2,3]triazolo[3,4 g]quinoxaline derivatives that display higher solubility and stability then their thiadiazole counterparts, [1,2,5]chalcogenazolo[3,4-f]benzo[2,1,3]thiadiazole and [1,2,5]thiadiazolo[3,4-g]quinoxaline, respectively. PMID- 21812403 TI - Charge-induced conformational changes of PEG-(Na(+))(n) in a vacuum and aqueous nanodroplets. AB - Charged-induced conformational changes of sodiated poly(ethylene glycol) (PEG (Na(+))(n)) in a vacuum and water droplets were studied using molecular simulations. In a vacuum, compact and partially unwound conformations were identified by analyzing occupation probabilities on reaction surfaces defined by the accessible surface area of the macroion, the distance between the centers of mass of the PEG molecule and of the cations and radius of gyration of the macromolecule. The critical charge of the macromolecule for which there is coexistence of various conformations was estimated using the Rayleigh criterion for the breakdown of highly charged droplets and compared with that observed in the simulations. The simulation findings agreed well with the Rayleigh prediction. The properties of sodiated PEG macromolecules in the presence of solvent and ions were also investigated. It was found that the macroion becomes saturated with charge. The highly charged state leads to an extended conformation that is partially expelled by the droplet. However, a portion of the chain is still in contact with the solvent. Drying-out of the solvent leaves the macroion in a stretched necklace-like conformation. The mechanism of release of sodiated PEG from an aqueous droplet was shown to be distinctly different from that of a protonated polyhistidine in a water nanodroplet, demonstrating sensitivity of the disintegration mechanism of the nanodroplet to the degree of hydrophilicity of the macroion. PMID- 21812404 TI - Proton-coupled electron transfer from tyrosine: a strong rate dependence on intramolecular proton transfer distance. AB - Proton-coupled electron transfer (PCET) was examined in a series of biomimetic, covalently linked Ru(II)(bpy)(3)-tyrosine complexes where the phenolic proton was H-bonded to an internal base (a benzimidazyl or pyridyl group). Photooxidation in laser flash/quench experiments generated the Ru(III) species, which triggered long-range electron transfer from the tyrosine group concerted with short-range proton transfer to the base. The results give an experimental demonstration of the strong dependence of the rate constant and kinetic isotope effect for this intramolecular PCET reaction on the effective proton transfer distance, as reflected by the experimentally determined proton donor-acceptor distance. PMID- 21812405 TI - Effect of pore size on the condensation/evaporation transition of confined water in equilibrium with saturated bulk water. AB - The effect of pore size on the condensation/evaporation transition of confined water upon varying the strength of the water-surface interaction is studied under conditions of equilibrium with saturated bulk. Monte Carlo simulations in the grand canonical ensemble were used to determine water density in spherical pores of radius R(p) = 9, 12, 15, 20, and 25 A in the temperature range from T = 270 K to the bulk critical temperature. The critical values of the well depth of the water-surface interaction potential, which mark the limits of the metastability of vapor and liquid phases in pores (U(0)(cond) and U(0)(evap), respectively), were determined. U(0)(cond) strongly depends on temperature, practically does not depend on the pore size, and corresponds to some particular density of water vapor near a surface. In contrast, U(0)(evap) only slightly depends on temperature, depends strongly on pore size, and corresponds to the density in the pore interior by about 2% below the bulk value. The critical water-pore interaction U(0)(c), which separates regimes of capillary condensation and capillary evaporation, is found to be changed from -1.75 to -0.94 kcal/mol when the pore radius R(p) increases from 9 to 25 A. The size dependence of U(0)(c) is attributed to the change of the contact angle due to the line tension effect. Extrapolation of the dependence U(0)(c)(R(p)) to the flat surface gives the critical value U(0)(c)(infinity) ~ -0.61 kcal/mol. PMID- 21812406 TI - Metabolomics and food processing: from semolina to pasta. AB - The objective of this study was to investigate the metabolite variations during industrial pasta processing (from semolina to dried pasta) for five different commercial products. Up to 76 metabolites were detected. Significant differences were observed between wholemeal and refined pasta samples, with the wholemeal pasta richer in many classes of compounds such as phytosterols, policosanols, unsaturated fatty acids, amino acids, carotenoids, minerals, and so on. Significant differences were also observed between samples of refined pasta apparently similar for the actual parameters used for the assessment of pasta quality. The results indicated that a number of metabolites undergo a transformation during the pasta-making process depending on the processing conditions adopted. The approach used in this work shows the high potential of metabolite profiling for food investigations with regard to process-related transformation, safety, and nutrition. PMID- 21812407 TI - Synthesis of 1-aminoisoquinolines via Rh(III)-catalyzed oxidative coupling. AB - [RhCp*Cl(2)](2) can catalyze the oxidative coupling of N-aryl and N-alkyl benzamidines with alkynes to give N-substituted 1-aminoisoquinolines in high selectivity. PMID- 21812409 TI - Ambient isobaric heat capacities, C(p,m), for ionic solids and liquids: an application of volume-based thermodynamics (VBT). AB - Thermodynamic properties, such as standard entropy, among others, have been shown to correlate well with formula volume, V(m), thus permitting prediction of these properties on the basis of chemical formula and density alone, with no structural detail required. We have termed these procedures "volume-based thermodynamics" (VBT). We here extend these studies to ambient isobaric heat capacities, C(p,m), of a wide range of materials. We show that heat capacity is strongly linearly correlated with formula volume for large sets of minerals, for ionic solids in general, and for ionic liquids and that the results demonstrate that the Neumann Kopp rule (additivity of heat capacity contributions per atom) is widely valid for ionic materials, but the smaller heat capacity contribution per unit volume for ionic liquids is noted and discussed. Using these correlations, it is possible to predict values of ambient (298 K) heat capacities quite simply. We also show that the heat capacity contribution of water molecules of crystallization is remarkably constant, at 41.3 +/- 4.7 J K(-1) (mol of water)( 1), so that the heat capacities of various hydrates may be reliably estimated from the values of their chemical formula neighbors. This result complements similar observations that we have reported for other thermodynamic differences of hydrates. PMID- 21812408 TI - Rare cell separation and analysis by magnetic sorting. AB - The separation and or isolation of rare cells using magnetic forces are commonly used and growing in use ranging from simple sample prep for further studies to a FDA approved, clinical diagnostic test. This growth is the result of both the demand to obtain homogeneous rare cells for molecular analysis and the dramatic increases in the power of permanent magnets that even allow the separation of some unlabeled cells based on intrinsic magnetic moments, such as malaria parasite-infected red blood cells. PMID- 21812410 TI - Isolation and characterization of aphidicolin and chlamydosporol derivatives from Tolypocladium inflatum. AB - Six new secondary metabolites including two aphidicolin analogues, inflatins A (1) and B (2), and four chlamydosporol derivatives, inflatins C-F (3-6), have been isolated from the crude extract of Tolypocladium inflatum. The structures of 1-6 were determined mainly by NMR experiments, and 4 and 5 were further confirmed by X-ray crystallography. The absolute configurations of C-16 in 1 and C-5 in 3 were deduced via the circular dichroism data of the in situ formed [Rh2(OCOCF3)4] complexes, whereas that of 4 was assigned by X-ray crystallography using Cu Kalpha radiation. Compounds 1 and 2 showed modest cytotoxicity against a panel of eight human tumor cell lines. PMID- 21812411 TI - In situ curing of sliding SU-8 droplet over a microcontact printed pattern for tunable fabrication of a polydimethylsiloxane nanoslit. AB - A tunable process for polydimethylsiloxane (PDMS) nanoslit fabrication is developed for nanofluidic applications. A microcontact printing (MUCP) of a laterally spreading self-assembled hexadecanethiol (HDT) layer, combined with in situ curing of a sliding SU-8 droplet, enables precise and independent tuning of a nanoslit-mold width and height using a single MUCP master mold. The SU-8 nanoslit-mold is replicated using a hard-soft composite PDMS to prevent channel collapse at low (<0.2) aspect ratio (height over width). The fluidic characteristics as well as dimensions of nanoslits fabricated with various conditions are analyzed using a fluorescein sample and AFM images. Finally, concentration polarization-based sample preconcentration is successfully demonstrated at the nanoslit boundary where an electric double-layer is overlapped. PMID- 21812412 TI - Coupled electron and proton transfer processes in 4-dimethylamino-2-hydroxy benzaldehyde. AB - TDDFT calculations, picosecond transient absorption, and time-resolved fluorescence studies of 4-dimethylamino-2-hydroxy-benzaldehyde (DMAHBA) have been carried out to study the electron and proton transfer processes in polar (acetonitrile) and nonpolar (n-hexane) solvents. In n-hexane, the transient absorption (TA) as well as the fluorescence originate from the pipi* state of the keto form (with the carbonyl group in the benzaldehyde ring), which is produced by an intramolecular proton transfer from the initially excited pipi* state of the enol form (OH group in the ring). The decay rate of TA and fluorescence are essentially identical in n-hexane. In acetonitrile, on the other hand, the TA exhibits features that can be assigned to the highly polar twisted intramolecular charge transfer (TICT) states of enol forms, as evidenced by the similarity of the absorption to the TICT-state absorption spectra of the closely related 4 dimethylaminobenzaldehyde (DMABA). As expected, the decay rate of the TICT-state of DMAHBA is different from the fluorescence lifetime of the pipi* state of the keto form. The occurrence of the proton and electron transfers in acetonitrile is in good agreement with the predictions of the TDDFT calculations. The very short lived (~1 ps) fluorescence from the pipi* state of the enol form has been observed at about 380 nm in n-hexane and at about 400 nm in acetonitrile. PMID- 21812413 TI - Density-dependent liquid nitromethane decomposition: molecular dynamics simulations based on ReaxFF. AB - The decomposition mechanism of hot liquid nitromethane at various compressions was studied using reactive force field (ReaxFF) molecular dynamics simulations. A competition between two different initial thermal decomposition schemes is observed, depending on compression. At low densities, unimolecular C-N bond cleavage is the dominant route, producing CH(3) and NO(2) fragments. As density and pressure rise approaching the Chapman-Jouget detonation conditions (~30% compression, >2500 K) the dominant mechanism switches to the formation of the CH(3)NO fragment via H-transfer and/or N-O bond rupture. The change in the decomposition mechanism of hot liquid NM leads to a different kinetic and energetic behavior, as well as products distribution. The calculated density dependence of the enthalpy change correlates with the change in initial decomposition reaction mechanism. It can be used as a convenient and useful global parameter for the detection of reaction dynamics. Atomic averaged local diffusion coefficients are shown to be sensitive to the reactions dynamics, and can be used to distinguish between time periods where chemical reactions occur and diffusion-dominated, nonreactive time periods. PMID- 21812414 TI - Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK). AB - Because of the critical roles of aberrant signaling in cancer, both c-MET and ALK receptor tyrosine kinases are attractive oncology targets for therapeutic intervention. The cocrystal structure of 3 (PHA-665752), bound to c-MET kinase domain, revealed a novel ATP site environment, which served as the target to guide parallel, multiattribute drug design. A novel 2-amino-5-aryl-3 benzyloxypyridine series was created to more effectively make the key interactions achieved with 3. In the novel series, the 2-aminopyridine core allowed a 3-benzyloxy group to reach into the same pocket as the 2,6 dichlorophenyl group of 3 via a more direct vector and thus with a better ligand efficiency (LE). Further optimization of the lead series generated the clinical candidate crizotinib (PF-02341066), which demonstrated potent in vitro and in vivo c-MET kinase and ALK inhibition, effective tumor growth inhibition, and good pharmaceutical properties. PMID- 21812415 TI - Liposomes: from a clinically established drug delivery system to a nanoparticle platform for theranostic nanomedicine. AB - For decades, clinicians have used liposomes, self-assembled lipid vesicles, as nanoscale systems to deliver encapsulated anthracycline molecules for cancer treatment. The more recent proposition to combine liposomes with nanoparticles remains at the preclinical development stages; however, such hybrid constructs present great opportunities to engineer theranostic nanoscale delivery systems, which can combine simultaneous therapeutic and imaging functions. Many novel nanoparticles of varying chemical compositions are being developed in nanotechnology laboratories, but further chemical modification is often required to make these structures compatible with the biological milieu in vitro and in vivo. Such nanoparticles have shown promise as diagnostic and therapeutic tools and generally offer a large surface area that allows covalent and non-covalent surface functionalization with hydrophilic polymers, therapeutic moieties, and targeting ligands. In most cases, such surface manipulation diminishes the theranostic properties of nanoparticles and makes them less stable. From our perspective, liposomes offer structural features that can make nanoparticles biocompatible and present a clinically proven, versatile platform for further enhancement of the pharmacological and diagnostic efficacy of nanoparticles. In this Account, we describe two examples of liposome-nanoparticle hybrids developed as theranostics: liposome-quantum dot hybrids loaded with a cytotoxic drug (doxorubicin) and artificially enveloped adenoviruses. We incorporated quantum dots into lipid bilayers, which rendered them dispersible in physiological conditions. This overall vesicular structure allowed them to be loaded with doxorubicin molecules. These structures exhibited cytotoxic activity and labeled cells both in vitro and in vivo. In an alternative design, lipid bilayers assembled around non-enveloped viral nanoparticles and altered their infection tropism in vitro and in vivo with no chemical or genetic capsid modifications. Overall, we have attempted to illustrate how alternative strategies to incorporate nanoparticles into liposomal nanostructures can overcome some of the shortcomings of nanoparticles. Such hybrid structures could offer diagnostic and therapeutic combinations suitable for biomedical and even clinical applications. PMID- 21812416 TI - Staphylococcus aureus sortase A contributes to the Trojan horse mechanism of immune defense evasion with its intrinsic resistance to Cys184 oxidation. AB - Staphylococcus aureus is a Gram-positive bacterial pathogen that causes serious infections which have become increasingly difficult to treat due to antimicrobial resistance and natural virulence strategies. Bacterial sortase enzymes are important virulence factors and good targets for future antibiotic development. It has recently been shown that sortase enzymes are integral to bacterial survival of phagocytosis, an underappreciated, but vital, step in S. aureus pathogenesis. Of note, the reaction mechanism of sortases relies on a solvent accessible cysteine for transpeptidation. Because of the common strategy of oxidative damage employed by professional phagocytes to kill pathogens, it is possible that this cysteine may be oxidized inside the phagosome, thereby inhibiting the enzyme. This study addresses this apparent paradox by assessing the ability of physiological reactive oxygen species, hydrogen peroxide and hypochlorite, to inhibit sortase A (SrtA) from S. aureus. Surprisingly, we found that SrtA is highly resistant to oxidative inhibition, both in vitro and in vivo. The mechanism of resistance to oxidative damage is likely mediated by maintaining a high reduction potential of the catalytic cysteine residue, Cys184. This is due to the unusual active site utilized by S. aureus SrtA, which employs a reverse protonation mechanism for transpeptidation, resulting in a high pK(a) as well as reduction potential for Cys184. The results of this study suggest that S. aureus SrtA is able to withstand the extreme conditions encountered in the phagosome and maintain function, contributing to survival of phagocytotic killing. PMID- 21812417 TI - Effects of molecular adsorption on the electronic structure of single-layer graphene. AB - The interaction of small molecules (CCl(4), CS(2), H(2)O, and acetone) with single-layer graphene (SLG) has been studied under steady-state conditions using infrared multiple-internal-reflection spectroscopy. Adsorption results in a broad and intense absorption band, spanning the ~200 to 500 meV range, which is attributed to electronic excitation. This effect, which has not previously been reported for SLG, has been further investigated using dispersion-corrected density functional theory to model the adsorption of H(2)O on SLG supported on an SiO(2) substrate. However, the ideal and defect-free model does not reproduce the observed adsorption-induced electronic transition. This and other observations suggest that the effect is extrinsic, possibly the result of an adsorption induced change in the in-plane strain, with important differences arising between species that form liquid-like layers under steady-state conditions and those that do not. Furthermore, the C-H stretching modes of CH(2) groups, incorporated in the SLG as defects, undergo nonadiabatic coupling to the electronic transition. This leads to pronounced antiresonance effects in the line shapes, which are analyzed quantitatively. These results are useful in understanding environmental effects on graphene electronic structure and in demonstrating the use of the vibrational spectroscopy of H-containing defects in characterizing SLG structure. PMID- 21812418 TI - Chemoproteomics-based design of potent LRRK2-selective lead compounds that attenuate Parkinson's disease-related toxicity in human neurons. AB - Leucine-rich repeat kinase-2 (LRRK2) mutations are the most important cause of familial Parkinson's disease, and non-selective inhibitors are protective in rodent disease models. Because of their poor potency and selectivity, the neuroprotective mechanism of these tool compounds has remained elusive so far, and it is still unknown whether selective LRRK2 inhibition can attenuate mutant LRRK2-dependent toxicity in human neurons. Here, we employ a chemoproteomics strategy to identify potent, selective, and metabolically stable LRRK2 inhibitors. We demonstrate that CZC-25146 prevents mutant LRRK2-induced injury of cultured rodent and human neurons with mid-nanomolar potency. These precise chemical probes further validate this emerging therapeutic strategy. They will enable more detailed studies of LRRK2-dependent signaling and pathogenesis and accelerate drug discovery. PMID- 21812419 TI - Photodegradation of azobenzene-based self-assembled monolayers characterized by in-plane birefringence. AB - Azobenzene-based self-assembled monolayers (azo-SAMs) are photoactive and become orientationally ordered when illuminated with linearly polarized light (LPL), making them attractive as dynamic alignment layers in liquid crystal cells. Azo SAMs, however, are chemically unstable when exposed to both air and light. We have characterized the photodegradation of a methyl red-based SAM by measuring with a high-sensitivity polarimeter the optical anisotropy induced by illumination with linearly polarized actinic light after the sample is irradiated with circularly polarized light (CPL) in air. The number of unbleached, photoactive molecules in the SAM decays exponentially with CPL exposure time, lowering the reorientation rate during photowriting with LPL. Azo-SAMs in an argon atmosphere, in contrast, are chemically stable and remain photoactive even after exposure to CPL. PMID- 21812420 TI - Tyrosine-based 1-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]cytosine and -adenine ((S)-HPMPC and (S)-HPMPA) prodrugs: synthesis, stability, antiviral activity, and in vivo transport studies. AB - Eight novel single amino acid (6-11) and dipeptide (12, 13) tyrosine P-O esters of cyclic cidofovir ((S)-cHPMPC, 4) and its cyclic adenine analogue ((S)-cHPMPA, 3) were synthesized and evaluated as prodrugs. In vitro IC(50) values for the prodrugs (<0.1-50 MUM) vs vaccinia, cowpox, human cytomegalovirus, and herpes simplex type 1 virus were compared to those for the parent drugs ((S)-HPMPC, 2; (S)-HPMPA, 1; IC(50) 0.3-35 MUM); there was no cytoxicity with KB or HFF cells at <=100 MUM. The prodrugs exhibited a wide range of half-lives in rat intestinal homogenate at pH 6.5 (<30-1732 min) with differences of 3-10* between phostonate diastereomers. The tyrosine alkylamide derivatives of 3 and 4 were the most stable. (l)-Tyr-NH-i-Bu cHPMPA (11) was converted in rat or mouse plasma solely to two active metabolites and had significantly enhanced oral bioavailability vs parent drug 1 in a mouse model (39% vs <5%). PMID- 21812421 TI - Discovery of a clinical stage multi-kinase inhibitor sodium (E)-2-{2-methoxy-5 [(2',4',6'-trimethoxystyrylsulfonyl)methyl]phenylamino}acetate (ON 01910.Na): synthesis, structure-activity relationship, and biological activity. AB - Cyclin D proteins are elevated in many cancer cells, and targeted deletion of cyclin D1 gene in the mammary tissues protects mice from breast cancer. Accordingly, there is an increasing awareness of this novel nonenzymatic target for cancer therapeutics. We have developed novel, nonalkylating styrylbenzylsulfones that induce cell death in wide variety of cancer cells without affecting the proliferation and survival of normal cells. The development of derivatized styrylbenzylsulfones followed logically from a tumor cell cytotoxicity screen performed in our laboratory that did not have an a priori target profile. Modifications of some of the precursor molecules led to lead optimization with regard to tumor cell cytotoxicity. In this report we describe the synthesis and structure-activity relationships of novel, nonalkylating (E) styrylbenzylsulfones and the development of the novel anticancer agent sodium (E) 2-{2-methoxy-5-[(2',4',6'-trimethoxystyrylsulfonyl)methyl]phenylamino}acetate (ON 01910.Na), which is in phase III trials for myelodysplastic syndromes (MDS) associated with aberrant expression of cyclin D proteins. PMID- 21812422 TI - Competition between reaction and intramolecular energy redistribution in solution: observation and nature of nonstatistical dynamics in the ozonolysis of vinyl ethers. AB - Experimental product ratios in ozonolyses of alkyl vinyl ethers in solution do not fit with expectations based on statistical rate theories. The selectivity among cleavage pathways increases with the size of the alkyl group but to an extent that is far less than RRKM theory would predict. Trajectory studies account for the observed selectivities and support a mechanism involving a competition between cleavage of the primary ozonide and intramolecular vibrational energy redistribution. A statistical model is presented that assumes that RRKM theory holds for a molecular subset of the primary ozonides, allowing the rates of energy loss from the ozonides to be estimated from the observed product ratios. PMID- 21812424 TI - Application of a tandem mass spectrometer and core-shell particle column for the determination of 151 pesticides in grains. AB - A comparison of ultrahigh performance liquid chromatography (UHPLC) with a 2.6 MUm core-shell particle column (Kinetex C(18)) and conventional liquid chromatography (LC) with a 3 MUm porous particle column (Atlantis dC(18)), coupled with electrospray ionization tandem mass spectrometry (ESI-MS/MS), for the determination of 151 pesticides in grains is presented in this study. Pesticides were extracted from grain samples using a procedure known as QuEChERS (quick, easy, cheap, effective, rugged, and safe). Quantification, with an analytical range from 5 to 500 MUg/kg, was achieved using matrix-matched standard calibration curves with isotopically labeled standards or a chemical analogue as internal standards. The method performance parameters that included overall recovery, intermediate precision, and measurement uncertainty were evaluated using a designed experiment, that is, the nested design. The UHPLC (Kinetex C(18)) was superior to conventional LC (Atlantis dC(18)) as it yielded a shorter analytical run time, increased method sensitivity, and improved method performance. For UHPLC/ESI-MS/MS (Kinetex C(18)), 90% of the pesticides studied had recoveries between 81 and 110%, 88% of the pesticides had intermediate precision <=20%, and 84% of the pesticides showed measurement uncertainty <=40%. As compared to UHPLC/ESI-MS/MS (Kinetex dC(18)), the LC/ESI-MS/MS (Atlantis dC(18)) showed a relatively lower sensitivity, less repeatability, and larger measurement uncertainty. UHPLC/ESI-MS/MS with 2.6 MUm core-shell particle column and scheduled MRM proved to be a good choice for quantification or determination of pesticides in grains. PMID- 21812425 TI - Synthesis and stereospecificity of 4,5-disubstituted oxazolidinone ligands binding to T-box riboswitch RNA. AB - The enantiomers and the cis isomers of two previously studied 4,5-disubstituted oxazolidinones have been synthesized, and their binding to the T-box riboswitch antiterminator model RNA has been investigated in detail. Characterization of ligand affinities and binding site localization indicates that there is little stereospecific discrimination for binding antiterminator RNA alone. This binding similarity between enantiomers is likely due to surface binding, which accommodates ligand conformations that result in comparable ligand-antiterminator contacts. These results have significant implications for T-box antiterminator targeted drug discovery and, in general, for targeting other medicinally relevant RNA that do not present deep binding pockets. PMID- 21812426 TI - Blockade of Her2/neu binding to Hsp90 by emodin azide methyl anthraquinone derivative induces proteasomal degradation of Her2/neu. AB - Overexpression of HER2/neu, a transmembrane tyrosine kinase acting as a coreceptor for other EGFR family members, is well-known to be associated with a poor prognosis in cancer. In the present study, we observed that emodin AMAD, a novel emodin azide methyl anthraquinone derivative, extracted from nature's giant knotweed rhizome of traditional Chinese herbs, potently decreased Her2/neu protein in dose- and time-dependent manners and also inhibited the downstream MAPK and PI3K-Akt signaling pathway. Intriguingly, reverse transcription-PCR and protein turnover assay revealed that the decrease of Her2/neu was independent of mRNA level but primarily owing to its protein stability. Meanwhile, proteasome inhibitor MG132 but not lysosome inhibitor chloroquine could restore Her2/neu and polyubiquitination of Her2/neu was augmented during emodin AMAD treatment. Furthermore, immunofluorescence study with anti-Her2/neu antibody showed that emodin AMAD disturbed the subcellular distribution of Her2/neu, with decreased location in the plasma membrane. Molecular docking studies predicted that AMAD can interact with the ATP-binding pocket of both Hsp90 and Her2/neu. Importantly, coimmunoprecipitation and immunofluorescence study revealed that emodin AMAD markedly impaired the binding between Hsp90 and Her2/neu and could bind to both Hsp90 and Her2/neu as reinforced by molecular modeling studies. In addition, combination of emodin AMAD treatment and siRNA against Her2 synergistically inhibited proliferation and induced apoptosis. Taken together, these data suggest that blockade of Her2/neu binding to Hsp90 and following proteasomal degradation of Her2/neu were involved in emodin AMAD-induced apoptosis in Her2/neu overexpressing cancer cells. Our results provide suggestions that emodin AMAD could be promising as a new targeting therapeutic strategy in the treatment of Her2/neu-overexpressing cancers. PMID- 21812427 TI - Do invasive mussels restrict offshore phosphorus transport in Lake Huron? AB - Dreissenid mussels were first documented in the Laurentian Great Lakes in the late 1980s. Zebra mussels (Dreissena polymorpha) spread quickly into shallow, hard-substrate areas; quagga mussels (Dreissena rostriformis bugensis) spread more slowly and are currently colonizing deep, offshore areas. These mussels occur at high densities, filter large water volumes while feeding on suspended materials, and deposit particulate waste on the lake bottom. This filtering activity has been hypothesized to sequester tributary phosphorus in nearshore regions reducing offshore primary productivity. We used a mass balance model to estimate the phosphorus sedimentation rate in Saginaw Bay, a shallow embayment of Lake Huron, before and after the mussel invasion. Our results indicate that the proportion of tributary phosphorus retained in Saginaw Bay increased from approximately 46-70% when dreissenids appeared, reducing phosphorus export to the main body of Lake Huron. The combined effects of increased phosphorus retention and decreased phosphorus loading have caused an approximate 60% decrease in phosphorus export from Saginaw Bay to Lake Huron. Our results support the hypothesis that the ongoing decline of preyfish and secondary producers including diporeia (Diporeia spp.) in Lake Huron is a bottom-up phenomenon associated with decreased phosphorus availability in the offshore to support primary production. PMID- 21812428 TI - Blue-light emission of Cu(I) complexes and singlet harvesting. AB - Strongly luminescent neutral copper(I) complexes of the type Cu(pop)(NN), with pop = bis(2-(diphenylphosphanyl)phenyl)ether and NN = bis(pyrazol-1 yl)borohydrate (pz(2)BH(2)), tetrakis(pyrazol-1-yl)borate (pz(4)B), or bis(pyrazol-1-yl)-biphenyl-borate (pz(2)Bph(2)), are readily accessible in reactions of Cu(acetonitrile)(4)(+) with equimolar amounts of the pop and NN ligands at ambient temperature. All products were characterized by means of single crystal X-ray diffractometry. The compounds exhibit very strong blue/white luminescence with emission quantum yields of up to 90%. Investigations of spectroscopic properties and the emission decay behavior in the temperature range between 1.6 K and ambient temperature allow us to assign the emitting electronic states. Below 100 K, the emission decay times are in the order of many hundreds of microseconds. Therefore, it is concluded that the emission stems from the lowest triplet state. This state is assigned to a metal-to-ligand charge-transfer state (3MLCT) involving Cu-3dand pop-pi* orbitals. With temperature increase, the emission decay time is drastically reduced, e.g. to 13 MUs [corrected] (Cu(pop) (pz(2)Bph(2))), at ambient temperature. At this temperature, the complexes exhibit high emission quantum yields, as neat material or doped into poly(methyl methacrylate) (PMMA). This behavior is assigned to an efficient thermal population of a singlet state (being classified as (1)MLCT), which lies only 800 to 1300 cm(-1) above the triplet state, depending on the individual complex. Thus, the resulting emission at ambient temperature largely represents a fluorescence. For applications in OLEDs and LEECs, for example, this type of thermally activated delayed fluorescence (TADF) creates a new mechanism that allows to harvest both singlet and triplet excitons (excitations) in the lowest singlet state. This effect of singlet harvesting leads to drastically higher radiative rates than obtainable for emissions from triplet states of Cu(I) complexes. PMID- 21812429 TI - Effect of thioethers on DNA platination by trans-platinum complexes. AB - Increasing evidence indicates that sulfur-containing molecules can play important roles in the activity of platinum anticancer drugs. Although nuclear DNA is retained to be the ultimate target, these platinum compounds can readily react with a variety of other substrates containing a soft donor atom, such as proteins, peptides, and low molecular weight biomolecules, before reaching DNA. In a recent study it was demonstrated that the DNA platination rate of a trans geometry antitumor drug was dramatically enhanced by methionine binding, thus suggesting that the thioether could serve as a catalyst for DNA platination. In this work we performed detailed studies on the reactions of a widely investigated and very promising trans-platinum complex having two iminoethers and two chlorido ligands, trans-EE, with methionine (Met) and guanosine 5'-monophosphate (GMP). The results show that in the reaction of trans-EE with methionine the bisadduct is the dominant species in the early stage of the reaction. The reaction is also influenced by chloride concentration: at low NaCl the bis-methionine adduct is formed in preference, whereas the monoadduct is favored at high NaCl concentration. Not only the monomethionine complex, trans-PtCl(E iminoether)(2)(AcMet), but also the bis-methionine adduct, trans-Pt(E iminoether)(2)(AcMet)(2), which has already lost both leaving chlorides, can react with GMP to form the ternary platinum complex trans-Pt(E iminoether)(2)(AcMet)(GMP). The latter reaction discloses the possibility of direct coordination to DNA of a platinum-protein adduct, in which the two carrier ligands remain intact; this is not the case of cis-oriented platinum complexes, like cisplatin, for which formation of a ternary complex is usually accompanied by loss of at least one carrier ligand. Interestingly, isomerization from S to N coordination of one methionine takes place in the bis-methionine complex at neutral pH, while the monoadduct appears to be stable. The shift from S to N coordination of one methionine in the trans-bis-methionine adduct can easily account for the obtainment of the cis isomer in the bis-chelated Pt(Met-S,N)(2) end product. PMID- 21812430 TI - Layer-by-layer assembled Fe3O4@C@CdTe core/shell microspheres as separable luminescent probe for sensitive sensing of Cu2+ ions. AB - A novel multifunctional microsphere with a fluorescent CdTe quantum dots (QDs) shell and a magnetic core (Fe(3)O(4)) has been successfully developed and prepared by a combination of the hydrothermal method and layer-by-layer (LBL) self-assembly technique. The resulting fluorescent Fe(3)O(4)@C@CdTe core/shell microspheres are utilized as a chemosensor for ultrasensitive Cu(2+) ion detection. The fluorescence of the obtained chemosensor could be quenched effectively by Cu(2+) ions. The quenching mechanism was studied and the results showed the existence of both static and dynamic quenching processes. However, static quenching is the more prominent of the two. The modified Stern-Volmer equation showed a good linear response (R(2) = 0.9957) in the range 1-10 MUM with a quenching constant (K(sv)) of 4.9 * 10(4) M(-1). Most importantly, magnetic measurements showed that the Fe(3)O(4)@C@CdTe core/shell microspheres were superparamagnetic and they could be separated and collected easily using a commercial magnet in 10 s. These results obtained not only provide a way to solve the embarrassments in practical sensing applications of QDs, but also enable the fabrication of other multifunctional nanostructure-based hybrid nanomaterials. PMID- 21812432 TI - High performance organic thin film transistors with solution processed TTF-TCNQ charge transfer salt as electrodes. AB - Fabrication of high-performance organic thin film transistors (OTFTs) with solution processed organic charge transfer complex (TTF-TCNQ) film as bottom contact source-drain electrodes is reported. A novel capillary based method was used to deposit the source-drain electrodes from solution and to create the channel between the electrodes. Both p- and n-type OTFTs have been fabricated with solution deposited organic charge transfer film as contact electrodes. Comparison of the device performances between OTFTs with TTF-TCNQ as source-drain electrodes and those with Au electrodes (both top and bottom contact) indicate that better results have been obtained in organic complex film contacted OTFT. The high mobility, low threshold voltage, and efficient carrier injection in both types of OTFTs implies the potential use of the TTF-TCNQ based complex material as low-cost contact electrodes. The lower work function of the TTF-TCNQ electrode and better contact of the complex film with the organic thin film owing to the organic-organic interface results in efficient charge transfer into the semiconductor yielding high device performance. The present method having organic metal as contact materials promises great potential for the fabrication of all organics and plastic electronics devices with high throughput and low-cost processing. PMID- 21812434 TI - Density functional theory studies of interactions of ruthenium-arene complexes with base pair steps. AB - Density functional theory (DFT) calculations have been performed to determine the strength and geometry of intermolecular interactions of "piano-stool" ruthenium arene complexes, which show potential as anticancer treatments. Model complexes with methane and benzene indicate that the coordinated arene has C-H...pi acceptor ability similar to that of free benzene, whereas this arene acts as a much stronger C-H donor or partner in pi-stacking than free benzene. The source of these enhanced interactions is identified as a combination of electrostatic and dispersion effects. Complexes of Ru-arene complexes with base-pair step fragments of DNA, in which the arene has the potential to act as an intercalator, have also been investigated. Binding energies are found to be sensitive to the size and nature of the arene, with larger and more flexible arenes having stronger binding. pi-stacking and C-H...pi interactions between arene and DNA bases and hydrogen bonds from coordinated N-H to DNA oxygen atoms, as well as covalent Ru-N bonding, contribute to the overall binding. The effect of complexation on DNA structure is also examined, with larger rise and more negative slide values than canonical B-DNA observed in all cases. PMID- 21812433 TI - Exploring the biology of lipid peroxidation-derived protein carbonylation. AB - The sustained overproduction of reactive oxygen and nitrogen species results in an imbalance of cellular prooxidant-antioxidant systems and is implicated in numerous disease states, including alcoholic liver disease, cancer, neurological disorders, inflammation, and cardiovascular disease. The accumulation of reactive aldehydes resulting from sustained oxidative stress and lipid peroxidation is an underlying factor in the development of these pathologies. Determining the biochemical factors that elicit cellular responses resulting from protein carbonylation remains a key element to developing therapeutic approaches and ameliorating disease pathologies. This review details our current understanding of the generation of reactive aldehydes via lipid peroxidation resulting in protein carbonylation, focusing on pathophysiologic factors associated with 4 hydroxynonenal-protein modification. Additionally, an overview of in vitro and in vivo model systems used to study the physiologic impact of protein carbonylation is presented. Finally, an update of the methods commonly used in characterizing protein modification by reactive aldehydes provides an overview of isolation techniques, mass spectrometry, and computational biology. It is apparent that research in this area employing state-of-the-art proteomics, mass spectrometry, and computational biology is rapidly evolving, yielding foundational knowledge concerning the molecular mechanisms of protein carbonylation and its relation to a spectrum of diseases associated with oxidative stress. PMID- 21812435 TI - Bioelectrochemical interface engineering: toward the fabrication of electrochemical biosensors, biofuel cells, and self-powered logic biosensors. AB - Over the past decade, researchers have devoted considerable attention to the integration of living organisms with electronic elements to yield bioelectronic devices. Not only is the integration of DNA, enzymes, or whole cells with electronics of scientific interest, but it has many versatile potential applications. Researchers are using these ideas to fabricate biosensors for analytical applications and to assemble biofuel cells (BFCs) and biomolecule based devices. Other research efforts include the development of biocomputing systems for information processing. In this Account, we focus on our recent progress in engineering at the bioelectrochemical interface (BECI) for the rational design and construction of important bioelectronic devices, ranging from electrochemical (EC-) biosensors to BFCs, and self-powered logic biosensors. Hydrogels and sol-gels provide attractive materials for the immobilization of enzymes because they make EC-enzyme biosensors stable and even functional in extreme environments. We use a layer-by-layer (LBL) self-assembly technique to fabricate multicomponent thin films on the BECI at the nanometer scale. Additionally, we demonstrate how carbon nanomaterials have paved the way for new and improved EC-enzyme biosensors. In addition to the widely reported BECI-based electrochemical impedance spectroscopy (EIS)-type aptasensors, we integrate the LBL technique with our previously developed "solid-state probe" technique for redox probes immobilization on electrode surfaces to design and fabricate BECI based differential pulse voltammetry (DPV)-type aptasensors. BFCs can directly harvest energy from ambient biofuels as green energy sources, which could lead to their application as simple, flexible, and portable power sources. Porous materials provide favorable microenvironments for enzyme immobilization, which can enhance BFC power output. Furthermore, by introducing aptamer-based logic systems to BFCs, such systems could be applied as self-powered and intelligent aptasensors for the logic detection. We have developed biocomputing keypad lock security systems which can be also used for intelligent medical diagnostics. BECI engineering provides a simple but effective approach toward the design and fabrication of EC-biosensors, BFCs, and self-powered logic biosensors, which will make essential contributions in the development of creative and practical bioelectronic devices. The exploration of novel interface engineering applications and the creation of new fabrication concepts or methods merit further attention. PMID- 21812436 TI - A model for the stability of films stabilized by randomly packed spherical particles. AB - Particle stabilized thin films occur in a range of industrial applications where their properties affect the efficiency of the process concerned. However, due to their dynamic and unstable nature they are difficult to observe experimentally. As such, a tractable way of gaining insight into the fundamental aspects of this complicated system is to use computer simulations of particles at interfaces. This paper presents modeling results of the effect of nonuniform packing of spherical particles on the stability of thin liquid films. Surface Evolver was used to model cells containing up to 20 particles, randomly packed in a thin liquid film. The capillary pressure required to rupture the film for a specific combination of particle arrangement, packing density, and contact angle was identified. The data from the periodic, randomly packed models has been used to find a relationship between particle packing density, contact angle, and critical capillary pressure which is refined to a simple equation that depends on the film loading and contact angle of the particles it contains. The critical capillary pressure for film rupture obeys the same trends observed for particles in regular 2D and 3D packing arrangements. The absolute values of P*(crit), however, are consistently lower than those for regular packing. This is due to the irregular arrangement of the particles, which allows for larger areas of free film to exist, lowering the critical capillary pressure required to rupture the film. PMID- 21812437 TI - Anion recognition in water with use of a neutral uranyl-salophen receptor. AB - A new water-soluble uranyl-salophen complex incorporating two glucose units has been synthesized. This neutral derivative shows noteworthy binding affinity for fluoride in water thanks to the Lewis acid-base interaction occurring between the metal and the anion. Such interaction is strong enough to overcome the high hydration enthalpy of fluoride. Moreover this complex effectively binds hydrogen phosphate and exhibits remarkably strong association for nucleotide polyanions ADP(3-) and ATP(4-). PMID- 21812438 TI - Analysis of the equilibrium droplet shape based on an ellipsoidal droplet model. AB - The extent of a droplet's spreading over a flat, smooth solid substrate and its equilibrium height in the presence of gravity are determined approximately, without a numerical solution of the governing nonlinear differential equation, by assuming that the droplet takes on the shape of an oblate spheroidal cap and by minimizing the corresponding free energy. The comparison with the full numerical evaluations confirms that the introduced approximation and the obtained results are accurate for contact angles below about 120 degrees and for droplet sizes on the order of the capillary length of the liquid. The flattening effect of gravity is to increase the contact radius and decrease the height of the droplet, with these being more pronounced for higher values of the Bond number. PMID- 21812439 TI - Hybrid nanocrystals: achieving concurrent therapeutic and bioimaging functionalities toward solid tumors. AB - Bioimaging and therapeutic agents accumulated in ectopic tumors following intravenous administration of hybrid nanocrystals to tumor-bearing mice. Solid, nanosized paclitaxel crystals physically incorporated fluorescent molecules throughout the crystal lattice and retained fluorescent properties in the solid state. Hybrid nanocrystals were significantly localized in solid tumors and remained in the tumor for several days. An anticancer effect is expected of these hybrid nanocrystals. PMID- 21812440 TI - Phthalimido-boronsubphthalocyanines: new derivatives of boronsubphthalocyanine with bipolar electrochemistry and functionality in OLEDs. AB - Phthalimides have been found to react with Cl-BsubPc to produce a new class of BsubPc derivatives, phthalimido-boronsubphthalocyanines (Phth-BsubPcs). They exhibit a high quantum yield for photoluminescence (Phi), maintain a high molar extinction coefficient (epsilon) and have bipolar electrochemical stability previously unseen in simple BsubPc derivatives. Their bipolar electrochemical characteristics have been extended into simple organic electronic devices: in OLEDs as charge transporters and emitters. PMID- 21812441 TI - Potential induced changes in neuromedin B adsorption on Ag, Au, and Cu electrodes monitored by surface-enhanced Raman scattering. AB - Surface-enhanced Raman scattering (SERS), electrochemistry, and generalized two dimensional correlation analysis (G2DCA) methods were used to define neuromedin B (NMB) ordered superstructures on Ag, Au, and Cu electrode surfaces at different applied electrode potentials in an aqueous solution at physiological pH. The orientation of NMB and the adsorption mechanism were determined based on the analysis of enhancement, broadness, and shift in wavenumber of particular bands, which allow drawing some conclusions about NMB geometry and changes in this geometry upon change of the electrode type and applied electrode potential. The presented data demonstrated that NMB deposited onto the Ag, Au, and Cu electrode surfaces showed bands due to vibrations of the moieties that were in contact/close proximity to the electrode surfaces and thus were located on the same side of the polypeptide backbone. These included the Phe(9) and Trp(4) rings, the sulfur atom of Met(10), and the -CCN- and -C?O units of Asn(2). However, some subtle variations in the arrangement of these fragments upon changes in the applied electrode potential were distinguished. The Amide-III vibrations exhibited an electrochemical Stark effect (potential dependent frequencies) with Stark tuning slope sensitive to the electrode material. Potential-difference spectrum revealed that the imidazole ring of His(8) was bonded to the Cu electrode surface at relatively positive potentials. PMID- 21812442 TI - Ultrasensitive multiplexed microRNA quantification on encoded gel microparticles using rolling circle amplification. AB - There is great demand for flexible biomolecule analysis platforms that can precisely quantify very low levels of multiple targets directly in complex biological samples. Herein we demonstrate multiplexed quantification of microRNAs (miRNAs) on encoded hydrogel microparticles with subfemtomolar sensitivity and single-molecule reporting resolution. Rolling circle amplification (RCA) of a universal adapter sequence that is ligated to all miRNA targets captured on gel embedded probes provides the ability to label each target with multiple fluorescent reporters and eliminates the possibility of amplification bias. The high degree of sensitivity achieved by the RCA scheme and the resistance to fouling afforded by the use of gel particles are leveraged to directly detect miRNA in small quantities of unprocessed human serum samples without the need for RNA extraction or target-amplification steps. This versatility has powerful implications for the development of rapid, noninvasive diagnostic assays. PMID- 21812443 TI - The involvement of organic anion transporting polypeptide in the hepatic uptake of telmisartan in rats: PET studies with [11C]telmisartan. AB - Telmisartan, a selective angiotensin II receptor antagonist, is primarily excreted via hepatobiliary transport. The predominant contribution of organic anion transporting polypeptide (OATP) 1B3 in its hepatic uptake of telmisartan has been demonstrated by in vitro transport studies. In the present study, a quantitative positron emission tomography (PET) methodology was developed for in vivo kinetic assessment of hepatobiliary transport of telmisartan. Serial abdominal PET scans were performed in rats following intravenous administration of [(11)C]telmisartan as a radiotracer. PET scans revealed that [(11)C]telmisartan was localized primarily in the liver and some of the radioactivity moved to the intestine, which corresponds to biliary excretion. Radiometabolite analysis by radiometric HPLC showed that [(11)C]telmisartan was converted to its acylglucuronide, which was mainly detected in bile, but little in plasma and liver. Integration plot analysis revealed that [(11)C]telmisartan was taken up into the liver as rapidly as the hepatic blood flow rate, and the radiometabolite was subsequently excreted into the bile. When rifampicin, a typical Oatp inhibitor, was coadministered with [(11)C]telmisartan in rats, hepatic uptake clearance of [(11)C]telmisartan was significantly decreased, whereas biliary efflux clearance was not changed. Coinjection with unlabeled telmisartan (4 and 10 mg/kg) also decreased hepatic uptake clearance of [(11)C]telmisartan. On the other hand, PET imaging analysis revealed a significant increase of biliary efflux when telmisartan dose was increased to more than 4 mg/kg. These results suggested that the hepatic uptake of [(11)C]telmisartan mainly consists of a saturable process mediated by Oatps in rats, according to noninvasive real-time measurement of tissue radioactivity with the use of PET. The present study with rats is expected to provide the feasibility of PET imaging study to quantitatively estimate OATP1B3 function in humans. PMID- 21812444 TI - Synthesis and structure of a bismuth(III)/chromium(VI) oxo cluster containing a Bi4Cr4O12 core. AB - Bismuth(III) compounds containing the Klaui's oxygen tripodal ligand [CpCo{P(O)(OEt)(2)}(3)](-) (L(OEt)(-)) have been synthesized, and their interactions with dichromate in aqueous media were studied. The treatment of Bi(5)O(OH)(9)(NO(3))(4) with NaL(OEt) in water afforded [L(OEt)Bi(NO(3))(2)](2) (1), whereas that of BiCl(3) with NaL(OEt) in CH(2)Cl(2) yielded L(OEt)BiCl(2) (2). Chloride abstraction of 2 with AgX afforded [L(OEt)BiX(2)](2) [X(-) = triflate (OTf(-)) (3), tosylate (OTs(-)) (4)]. In aqueous solutions at pH > 4, 4 underwent ligand redistribution to give the bis(tripod) complex [(L(OEt))(2)Bi(H(2)O)][OTs] (5). The treatment of 4 with Na(2)Cr(2)O(7) in acetone/water afforded the Bi(III)/Cr(VI) oxo cluster [(L(OEt))(4)Bi(4)(MU(3) CrO(4))(2)(MU(3)-Cr(2)O(7))(2)] (6) containing a unique Bi(4)Cr(4)O(12) oxometallic core. Compound 6 oxidized benzyl alcohol to give ca. 6 equiv of benzaldehyde. The reaction between 2 and CrO(3) yielded [L(OEt)Bi(OCrO(2)Cl)](2)(MU-Cl)(2) (7). The crystal structures of complexes 4-7 have been determined. PMID- 21812445 TI - Multireversible redox processes in pentanuclear bis(triple-helical) manganese complexes featuring an oxo-centered triangular {Mn(II)2Mn(III)(MU3-O)}5+ or {Mn(II)Mn(III)2(MU3-O)}6+ core wrapped by two {Mn(II)2(bpp)3}-. AB - A new pentanuclear bis(triple-helical) manganese complex has been isolated and characterized by X-ray diffraction in two oxidation states: [{Mn(II)(MU bpp)(3)}(2)Mn(II)(2)Mn(III)(MU-O)](3+) (1(3+)) and [{Mn(II)(MU bpp)(3)}(2)Mn(II)Mn(III)(2)(MU-O)](4+) (1(4+)). The structure consists of a central {Mn(3)(MU(3)-O)} core of Mn(II)(2)Mn(III) (1(3+)) or Mn(II)Mn(III)(2) ions (1(4+)) which is connected to two apical Mn(II) ions through six bpp(-) ligands. Both cations have a triple-stranded helicate configuration, and a pair of enantiomers is present in each crystal. The redox properties of 1(3+) have been investigated in CH(3)CN. A series of five distinct and reversible one electron waves is observed in the -1.0 and +1.50 V potential range, assigned to the Mn(II)(4)Mn(III)/Mn(II)(5), Mn(II)(3)Mn(III)(2)/Mn(II)(4)Mn(III), Mn(II)(2)Mn(III)(3)/Mn(II)(3)Mn(III)(2), Mn(II)Mn(III)(4)/Mn(II)(2)Mn(III)(3), and Mn(III)(5)/Mn(II)Mn(III)(4) redox couples. The two first oxidation processes leading to Mn(II)(3)Mn(III)(2) (1(4+)) and Mn(II)(2)Mn(III)(3) (1(5+)) are related to the oxidation of the Mn(II) ions of the central core and the two higher oxidation waves, close in potential, are thus assigned to the oxidation of the two apical Mn(II) ions. The 1(4+) and 1(5+) oxidized species and the reduced Mn(4)(II) (1(2+)) species are quantitatively generated by bulk electrolyses demonstrating the high stability of the pentanuclear structure in four oxidation states (1(2+) to 1(5+)). The spectroscopic characteristics (X-band electron paramagnetic resonance, EPR, and UV-visible) of these species are also described as well as the magnetic properties of 1(3+) and 1(4+) in solid state. The powder X- and Q-band EPR signature of 1(3+) corresponds to an S = 5/2 spin state characterized by a small zero-field splitting parameter (|D| = 0.071 cm(-1)) attributed to the two apical Mn(II) ions. At 40 K, the magnetic behavior is consistent for 1(3+) with two apical S = 5/2 {Mn(II)(bpp)(3)}(-) and one S = 2 noninteracting spins (11.75 cm(3) K mol(-1)), and for 1(4+) with three S = 5/2 noninteracting spins (13.125 cm(3) K mol(-1)) suggesting that the {Mn(II)(2)Mn(III)(MU(3)-O)}(5+) and {Mn(II)Mn(III)(2)(MU(3)-O)}(6+) cores behave at low temperature like S = 2 and S = 5/2 spin centers, respectively. The thermal behavior below 40 K highlights the presence of intracomplex magnetic interactions between the two apical spins and the central core, which is antiferromagnetic for 1(3+) leading to an S(T) = 3 and ferromagnetic for 1(4+) giving thus an S(T) = 15/2 ground state. PMID- 21812446 TI - Existence of two concomitant magnetic structures below T(Neel) for the natrochalcite, NaFe(II)2(H3O2)(MoO4)2. AB - A comparative study of the magnetic properties and magnetic structures of the natrochalcite, NaFe(2)(D(3)O(2))(MoO(4))(2) (FeD) to those of the isostructural NaCo(2)(D(3)O(2))(MoO(4))(2) (CoD) and NaNi(2)(D(3)O(2))(MoO(4))(2) (NiD) is presented. The structural change is a shrinking of the unit cell in the order of the ionic radii of the transition metal, FeD > CoD > NiD. While NiD and CoD are canted-antiferromagnets with T(N) = 28 and 21 K, respectively, FeD is an anisotropic 2D-Ising antiferromagnet (T(N) = 17 K) with a spin-flop field of 14 kOe at 2 K and the presence of a hysteresis loop reaching only (1)/(4) of the saturation magnetization in 70 kOe. The critical field decreases almost linearly on warming to T(N). The neutron diffraction patterns of FeD below T(N) display numerous magnetic Bragg peaks which cannot be assigned to any one magnetic structure but fits well to two superposed sets, one with a temperature independent line width and has a propagation vector k(1) = (0, 0, 0) while for the other there is a clear dependence and k(2) = (0, 0, 1/2). In the k(1) = (0, 0, 0) magnetic structure the moments are parallel to each other within one chain and lie along the a-axis but are antiparallel to those in neighboring chains. In contrast CoD and NiD, for which k = (0, 0, 0), have their moments aligned along the b-axis and ac-plane, respectively. The second magnetic structure, k(2) = (0, 0, 1/2), is characterized by four sublattices, two per layer, where the moments are in the ab-plane and canted with a resultant along the a-axis which is compensated by those of the adjacent layers. For the k(2) = (0, 0, 1/2) structure, the scattering coherent length decreases, and the moments tend progressively toward the a-axis upon increasing temperature. The coexistence of two concomitant magnetic structures is unprecedented for compounds containing transition metal moment carriers. PMID- 21812447 TI - Computational investigation of amine-oxygen exciplex formation. AB - It has been suggested that fluorescence from amine-containing dendrimer compounds could be the result of a charge transfer between amine groups and molecular oxygen [Chu, C.-C.; Imae, T. Macromol. Rapid Commun. 2009, 30, 89.]. In this paper we employ equation-of-motion coupled cluster computational methods to study the electronic structure of an ammonia-oxygen model complex to examine this possibility. The results reveal several bound electronic states with charge transfer character with emission energies generally consistent with previous observations. However, further work involving confinement, solvent, and amine structure effects will be necessary for more rigorous examination of the charge transfer fluorescence hypothesis. PMID- 21812449 TI - Synthesis of gamma-benzopyranone by TfOH-promoted regioselective cyclization of o alkynoylphenols. AB - Regioselective cyclization of o-alkynoylphenols forming gamma-benzopyranones has been demonstrated. Trifluoromethanesulfonic acid (TfOH) induced 6-endo cyclization of o-alkynoylphenols without forming 5-exo cyclized benzofuranone derivatives to provide the corresponding gamma-benzopyranones in high yields. PMID- 21812448 TI - Phosphine-catalyzed annulations of azomethine imines: allene-dependent [3 + 2], [3 + 3], [4 + 3], and [3 + 2 + 3] pathways. AB - In this paper we describe the phosphine-catalyzed [3 + 2], [3 + 3], [4 + 3], and [3 + 2 + 3] annulations of azomethine imines and allenoates. These processes mark the first use of azomethine imines in nucleophilic phosphine catalysis, producing dinitrogen-fused heterocycles, including tetrahydropyrazolo-pyrazolones, pyridazinones, -diazepinones, and -diazocinones. Counting the two different reaction modes in the [3 + 3] cyclizations, there are five distinct reaction pathways-the choice of which depends on the structure and chemical properties of the allenoate. All reactions are operationally simple and proceed smoothly under mild reaction conditions, affording a broad range of 1,2-dinitrogen-containing heterocycles in moderate to excellent yields. A zwitterionic intermediate formed from a phosphine and two molecules of ethyl 2,3-butadienoate acted as a 1,5 dipole in the annulations of azomethine imines, leading to the [3 + 2 + 3] tetrahydropyrazolo-diazocinone products. The incorporation of two molecules of an allenoate into an eight-membered-ring product represents a new application of this versatile class of molecules in nucleophilic phosphine catalysis. The salient features of this protocol--the facile access to a diverse range of nitrogen-containing heterocycles and the simple preparation of azomethine imine substrates--suggest that it might find extensive applications in heterocycle synthesis. PMID- 21812450 TI - Stereoselective synthesis of substituted 1,3-oxazolidines via Pd-catalyzed carboamination reactions of O-vinyl-1,2-amino alcohols. AB - The stereoselective synthesis of 2,4- and 2,5-disubstituted 1,3-oxazolidines is accomplished via Pd-catalyzed carboamination of O-vinyl-1,2-amino alcohol derivatives. The transformations generate cis-disubstituted products with good to excellent diastereoselectivity, and enantiomerically enriched substrates are converted without loss of optical purity. In addition to yielding synthetically useful products that are difficult to generate with existing methods, these transformations illustrate that electron-rich enol ethers are viable substrates for alkene carboamination processes. PMID- 21812452 TI - Total synthesis of (-)-leuconicine A and B. AB - Concise asymmetric total syntheses of Strychnos alkaloids (-)-leuconicine A (14 steps, 9% overall yield) and B (13 steps, 10% overall yield) have been accomplished. Key steps include (1) our sequential one-pot spiro cyclization/intramolecular aza-Baylis-Hillman method to prepare the ABCE framework; (2) a novel domino acylation/Knoevenagel cyclization to prepare the F ring; and (3) a Heck cyclization to access the D-ring. PMID- 21812451 TI - Enzymatic timing and tailoring of macrolactamization in syringolin biosynthesis. AB - The enzymatic activation of 3,4-dehydrolysine and subsequent formation of the 12 membered syringolin macrolactam were investigated. The timing of the desaturation was elucidated through the analysis of the initial adenylation domain of SylD. The SylD-TTE didomain was characterized and demonstrated to be the catalyst for formation of 12-membered macrocycles. When the SylD thioesterase domain was reacted with a family of acyclic CoA both natural and unnatural macrocycles were generated. PMID- 21812453 TI - Synthesis and reactivity of sulfamoyl azides and 1-sulfamoyl-1,2,3-triazoles. AB - Sulfamoyl azides are readily generated from secondary amines and a novel sulfonyl azide transfer agent, 2,3-dimethyl-1H-imidazolium triflate. They react with alkynes in the presence of a CuTC catalyst forming 1-sulfamoyl-1,2,3-triazoles. The latter are shelf-stable progenitors of rhodium azavinyl carbenes, versatile reactive intermediates that, among other reactions, readily and asymmetrically add to olefins. PMID- 21812454 TI - Pseudocryptand-type [3]pseudorotaxane and "hook-ring" polypseudo[2]catenane based on a bis(m-phenylene)-32-crown-10 derivative and bisparaquat derivatives. AB - The first pseudocryptand-type supramolecular [3]pseudorotaxane was designed and prepared via the self-assembly of a bispicolinate BMP32C10 derivative and a bisparaquat. The complexation behavior was cooperative. In addition, the complex comprised of the BMP32C10 derivative and a cyclic bisparaquat demonstrated strong binding; interestingly, a poly[2]pseudocatenane structure was formed in the solid state for the first time. PMID- 21812455 TI - General and expedient synthesis of 1,4-dioxygenated xanthones. AB - A facile entry to 1,4-dioxygenated xanthones having a variety of substitution patterns and substituents was developed that features a novel application of the Moore cyclization using substrates that were readily assembled in a highly convergent fashion by an acetylide stitching process. The practical utility of the methodology was demonstrated by an efficient synthesis of a naturally occurring xanthone and correction of the structure of dulcisxanthone C. PMID- 21812456 TI - Exploiting topological constraints to reveal buried sequence motifs in the membrane-bound N-linked oligosaccharyl transferases. AB - The central enzyme in N-linked glycosylation is the oligosaccharyl transferase (OTase), which catalyzes glycan transfer from a polyprenyldiphosphate-linked carrier to select asparagines within acceptor proteins. PglB from Campylobacter jejuni is a single-subunit OTase with homology to the Stt3 subunit of the complex multimeric yeast OTase. Sequence identity between PglB and Stt3 is low (17.9%); however, both have a similar predicted architecture and contain the conserved WWDxG motif. To investigate the relationship between PglB and other Stt3 proteins, sequence analysis was performed using 28 homologues from evolutionarily distant organisms. Since detection of small conserved motifs within large membrane-associated proteins is complicated by divergent sequences surrounding the motifs, we developed a program to parse sequences according to predicted topology and then analyze topologically related regions. This approach identified three conserved motifs that served as the basis for subsequent mutagenesis and functional studies. This work reveals that several inter-transmembrane loop regions of PglB/Stt3 contain strictly conserved motifs that are essential for PglB function. The recent publication of a 3.4 A resolution structure of full length C. lari OTase provides clear structural evidence that these loops play a fundamental role in catalysis [ Lizak , C. ; ( 2011 ) Nature 474 , 350 - 355 ]. The current study provides biochemical support for the role of the inter transmembrane domain loops in OTase catalysis and demonstrates the utility of combining topology prediction and sequence analysis for exposing buried pockets of homology in large membrane proteins. The described approach allowed detection of the catalytic motifs prior to availability of structural data and reveals additional catalytically relevant residues that are not predicted by structural data alone. PMID- 21812458 TI - Highly active iridium/iridium-tin/tin oxide heterogeneous nanoparticles as alternative electrocatalysts for the ethanol oxidation reaction. AB - Ethanol is a promising fuel for low-temperature direct fuel cell reactions due to its low toxicity, ease of storage and transportation, high-energy density, and availability from biomass. However, the implementation of ethanol fuel cell technology has been hindered by the lack of low-cost, highly active anode catalysts. In this paper, we have studied Iridium (Ir)-based binary catalysts as low-cost alternative electrocatalysts replacing platinum (Pt)-based catalysts for the direct ethanol fuel cell (DEFC) reaction. We report the synthesis of carbon supported Ir(71)Sn(29) catalysts with an average diameter of 2.7 +/- 0.6 nm through a "surfactant-free" wet chemistry approach. The complementary characterization techniques, including aberration-corrected scanning transmission electron microscopy equipped with electron energy loss spectroscopy, X-ray diffraction, X-ray photoelectron spectroscopy, and X-ray absorption spectroscopy, are used to identify the "real" heterogeneous structure of Ir(71)Sn(29)/C particles as Ir/Ir-Sn/SnO(2), which consists of an Ir-rich core and an Ir-Sn alloy shell with SnO(2) present on the surface. The Ir(71)Sn(29)/C heterogeneous catalyst exhibited high electrochemical activity toward the ethanol oxidation reaction compared to the commercial Pt/C (ETEK), PtRu/C (Johnson Matthey) as well as PtSn/C catalysts. Electrochemical measurements and density functional theory calculations demonstrate that the superior electro-activity is directly related to the high degree of Ir-Sn alloy formation as well as the existence of nonalloyed SnO(2) on surface. Our cross-disciplinary work, from novel "surfactant free" synthesis of Ir-Sn catalysts, theoretical simulations, and catalytic measurements to the characterizations of "real" heterogeneous nanostructures, will not only highlight the intriguing structure-property correlations in nanosized catalysts but also have a transformative impact on the commercialization of DEFC technology by replacing Pt with low-cost, highly active Ir-based catalysts. PMID- 21812457 TI - Strategy for increasing drug solubility and efficacy through covalent attachment to polyvalent DNA-nanoparticle conjugates. AB - Paclitaxel, a potent chemotherapeutic utilized in a variety of cancers, can be limited in its effectiveness due to inherent insolubility in aqueous media and acquired chemoresistance within certain cells. An approach has been developed for increasing Paclitaxel solubility and effectiveness by covalent attachment to gold nanoparticles via DNA linkers. The resulting conjugates are highly soluble in aqueous buffer, exhibiting greater than a 50-fold increase in solubility over the unconjugated drug. DNA linkers are labeled with a fluorophore, which affords a convenient means of visualizing resultant conjugates within cells. Internalized conjugates demonstrate increased activity as compared with free drug across a variety of cell types, including a Paclitaxel-resistant cell line. Attachment to DNA-nanoparticle conjugates may become a general strategy for solubilizing and enhancing a wide variety of therapeutic agents in aqueous media. PMID- 21812459 TI - Subdiffraction-limited milling by an optically driven single gold nanoparticle. AB - We propose and demonstrate a hybrid lithographic technique capable of nanopatterning surfaces by optothermal decomposition of a polymeric film induced by a single metal nanoparticle. A tightly focused laser beam exerting a strong optical force onto the nanoparticle is used to move it inside the polymer film. Due to efficient plasmonic absorption of the laser light, the nanoparticle is heated up to temperatures of several hundred degrees, causing melting or even thermal decomposition of the polymer film. By this method, grooves less than 100 nm wide and tens of micrometers long can be directly milled in a polymer layer. PMID- 21812460 TI - Controlling the stereospecificity of a volume-conserving adiabatic photoisomerization within a nanotubular self-assembled cage: a reversible light heat torque converter. AB - We present herein a host-guest supramolecular system by which we were able to obtain precise control of the stereospecificity of a new and unusual adiabatic photoisomerization reaction capable of restoring reversibly the original configuration. The host-guest system is composed of (a) a naphthalene ring linked centrosymmetrically-via sp(2) hybridized oxygen atoms-with methoxytriethyleneglycol chains (1) and (b) a nanotubular cage formed by four self-assembled face-to-face beta-cyclodextrins threaded onto the long "axle" of 1. The compound 1 can exist in distinct cis,cis, cis,trans, and trans,trans conformations that are spectrally distinguishable (see Scheme 1 ). Spectroscopic and kinetic manifestations of the torsional isomerization of 1 in the lowest excited singlet state both in solution and within the tubular cage were investigated. The results provide clear evidence that the compact cavity completely blocks the photoisomerization pathway manifested in common solution (cis,cis* -> cis,trans*), allowing observation of stereospecific, volume conserving turning of the naphthalene ring about the two "quasidouble" bonds C(Naph)-O by phi ~ 180 degrees (cis,cis* -> trans,trans*). The photoisomerization is purely adiabatic, and the encaged molecule restores its original configuration by generating torque thermally, when relaxing to the ground state. PMID- 21812461 TI - Experimental investigation of the absolute enthalpies of formation of 2,3-, 2,4-, and 3,4-pyridynes. AB - The absolute enthalpies of formation of 3,4-, 2,3-, and/or 2,4-didehydropyridines (3,4-, 2,3- and 2,4-pyridynes) have been determined by using energy-resolved collision-induced dissociation of deprotonated 2- and 3-chloropyridines. Bracketing experiments find the gas-phase acidities of 2- and 3-chloropyridines to be 383 +/- 2 and 378 +/- 2 kcal/mol, respectively. Whereas deprotonation of 3 chloropyridine leads to formation of a single ion isomer, deprotonation of the 2 chloro isomer results in a nearly 60:40 mixture of regioisomers. The enthalpy of formation of 3,4-pyridyne is measured to be 121 +/- 3 kcal/mol by using the chloride dissociation energy for deprotonated 3-chloropyridine. The structure of the product formed upon dissociation of the ion from 2-chloropyridine cannot be unequivocally assigned because of the isomeric mixture of reactant ions and the fact that the potential neutral products (2,3-pyridyne and 2,4-pyridyne) are predicted by high level spin-flip coupled-cluster calculations to be nearly the same in energy. Consequently, the enthalpies of formation for both neutral products are assigned to be 130 +/- 3 kcal/mol. Comparison of the enthalpies of dehydrogenation of benzene and pyridine indicates that the nitrogen in the pyridine ring does not have any effect on the stability of the aryne triple bond in 3,4-pyridyne, destabilizes the aryne triple bond in 2,3-pyridyne, and stabilizes the 1,3-interaction in 2,4-pyridyne compared to that in m-benzyne. Natural bond order calculations show that the effects on the 2,3- and 2,4 pyridynes result from polarization of the electrons caused by interaction with the lone pair. The polarization in 2,4-pyridyne is stabilizing because it creates a 1,2-interaction between the nitrogen and dehydrocarbons that is stronger than the 1,3-interaction between the dehydrocarbons. PMID- 21812463 TI - Catalytic chameleon dendrimers. AB - Dendrimers with boronic ester end-groups and an iron porphyrin core were synthesized and characterized. The dendrimer termini were reversibly exchanged by the addition of appropriate diol molecules. According to molecular dynamics (MD) simulations, the exchange of termini may lead to changes in the conformational behavior of the dendrimer, specifically regarding the average position of the end groups relative to the core. The spatial steric disposition attained with different termini was shown to significantly affect epoxidation reaction activity and selectivity with various alkenes, thus allowing for an original way to control and adjust catalytic behavior under alternating environments. PMID- 21812462 TI - Chemoenzymatic labeling of protein C-termini for positive selection of C-terminal peptides. AB - Many proteomic experiments require selective labeling of either N- or C-termini of proteins and recovery of terminal peptides. Although N-termini can be selectively labeled, selective labeling of protein C-termini has not been possible due to the difficulty in discriminating between the carboxyl group on the C-terminus versus that on aspartate and glutamate residues. Here we describe the first simple proteomic approach for positive selection of protein C-termini, Profiling Protein C-Termini by Enzymatic Labeling (ProC-TEL). ProC-TEL uses carboxypeptidase Y and other readily available reagents to selectively add an affinity tag to protein C-termini and to capture C-terminal peptides from complex cell lysates for mass spectrometry (MS) identification. Using ProC-TEL, we identify novel C-terminal processing and internal proteolytic cleavage events. These results indicate that ProC-TEL provides a straightforward approach for profiling C-terminal peptides and identifying protein processing in complex biological samples. PMID- 21812464 TI - Coupled concentration polarization and electroosmotic circulation near micro/nanointerfaces: Taylor-Aris model of hydrodynamic dispersion and limits of its applicability. AB - Mismatches in electrokinetic properties between micro- and nanochannels give rise to superposition of electroosmotic and pressure-driven flows in the microchannels. Parabolic or similar flow profiles are known to cause the so called hydrodynamic dispersion, which under certain conditions can be formally assimilated to an increase in the solute diffusivity (Taylor-Aris model). It is demonstrated theoretically that taking into account these phenomena modifies considerably the pattern of current-induced concentration polarization of micro/nanointerfaces as compared to the classical model of unstirred boundary layer. In particular, the hydrodynamic dispersion leads to disappearance of limiting current. At essentially "over-limiting" current densities, the time dependent profiles of salt concentration in microchannels behave like sharp concentration "fronts" moving away from the interface until they reach the reservoir end of the microchannel. Under galvanostatic conditions postulated in this study, these "fronts" move with practically constant speed directly proportional to the current density. The sharp transition from a low concentration to a high-concentration zone can be useful for the analyte preconcentration via stacking. The pattern of moving sharp concentration "fronts" has been predicted for the first time for relatively broad microchannels with negligible surface conductance. The Taylor-Aris approach to the description of hydrodynamic dispersion is quantitatively applicable only to the analysis of sufficiently "slow" processes (as compared to the characteristic time of diffusion relaxation in the transversal direction). A posteriori estimates reveal that the condition of "slow" processes is typically not satisfied close to current-polarized micro/nanointerfaces. Accordingly, to make the description quantitative, one needs to go beyond the Taylor-Aris approximation, which will be attempted in future studies. It is argued that doing so would make even stronger the dampening impact of hydrodynamic dispersion on the current-induced concentration polarization of micro/nanointerfaces. PMID- 21812465 TI - Immuno-hybridization chain reaction for enhancing detection of individual cytokine-secreting human peripheral mononuclear cells. AB - We present here a new method to enhance the detection of secreted cytokines and chemokines from single human mononuclear cells. The technique uses a hybridization chain reaction (HCR) to amplify signals resulting from sandwich immunoassays. This immuno-HCR employs oligonucleotide-based initiators covalently linked to antibodies to propagate a chain reaction of hybridization events involving a pair of complementary hairpin oligomers bearing fluorescent labels. Integrating this strategy for signal amplification with microengraving (a soft lithographic method for printing arrays of secreted proteins from thousands of single cells) improves both the limits of detection and sensitivity for cytokines and chemokines captured from individual cells by an average of 200-fold relative to methods for direct detection by fluoresence. This approach should enhance the utility of microengraving for defining the immunological signatures of diseases and responses to interventional therapies based on multiplexed single-cell analysis. PMID- 21812466 TI - Synthesis and characterization of thorium(IV) sulfates. AB - Three Th(IV) sulfates, two new and one previously reported, have been synthesized from aqueous solution. In all of the compounds, the sulfate anions coordinate the Th(4+) metal center(s) in a monodentate manner with Th-S distances of 3.7-3.8 A. Th(SO(4))(2)(H(2)O)(7).2(H(2)O) (1; P2(1)/m, a = 7.224(1) A, b = 12.151(1) A, c = 7.989(1) A, ss =98.289(2) degrees ) and Th(4)(SO(4))(7)(H(2)O)(7)(OH)(2).H(2)O (2; Pnma, a = 18.139(2) A, b = 11.173(1) A, c = 14.391(2) A) each contain 9 coordinate monomeric (1,2) and dimeric (2) Th(IV) cations in monocapped square antiprism geometry. Alternatively, Th(OH)(2)SO(4) (3; Pnma, a = 11.684(1) A, b = 6.047(1) A, c = 7.047(1) A) is built from chains of hydroxo-bridged, 8-coordinate Th(4+) centers. Whereas 1 adopts a molecular structure, 2 and 3 both exhibit 3D architectures. Differences in the dimensionality and the topology of 1-3 are manifested in the local coordination environment about the Th(IV) centers, the formation of oligomeric Th(4+) species, and the extended connectivity of the sulfate ligands. Herein, we report the syntheses and characterization of 1-3 as well as the atomic correlations of 1 in solution, as determined by high-energy X ray scattering (HEXS). PMID- 21812467 TI - Reduction of amine N-oxides by diboron reagents. AB - Facile reduction of alkylamino-, anilino-, and pyridyl-N-oxides can be achieved via the use of diboron reagents, predominantly bis(pinacolato)- and in some cases bis(catecholato)diboron [(pinB)(2) and (catB)(2), respectively]. Reductions occur upon simply mixing the amine N-oxide and the diboron reagent in a suitable solvent, at a suitable temperature. Extremely fast reductions of alkylamino- and anilino-N-oxides occur, whereas pyridyl-N-oxides undergo slower reduction. The reaction is tolerant of a variety of functionalities such as hydroxyl, thiol, and cyano groups, as well as halogens. Notably, a sensitive nucleoside N-oxide has also been reduced efficiently. The different rates with which alkylamino- and pyridyl-N-oxides are reduced has been used to perform stepwise reduction of the N,N'-dioxide of (S)-(-)-nicotine. Because it was observed that (pinB)(2) was unaffected by the water of hydration in amine oxides, the feasibility of using water as solvent was evaluated. These reactions also proceeded exceptionally well, giving high product yields. In constrast to the reactions with (pinB)(2), triethylborane reduced alkylamino-N-oxides, but pyridine N-oxide did not undergo efficient reduction even at elevated temperature. Finally, the mechanism of the reductive process by (pinB)(2) has been probed by (1)H and (11)B NMR. PMID- 21812469 TI - Magnitude and nature of carbohydrate-aromatic interactions in fucose-phenol and fucose-indole complexes: CCSD(T) level interaction energy calculations. AB - The CH/pi contact structures of the fucose-phenol and fucose-indole complexes and the stabilization energies by formation of the complexes (E(form)) were studied by ab initio molecular orbital calculations. The three types of interactions (CH/pi and OH/pi interactions and OH/O hydrogen bonds) were compared and evaluated in a single molecular system and at the same level of theory. The E(form) calculated for the most stable CH/pi contact structure of the fucose phenol complex at the CCSD(T) level (-4.9 kcal/mol) is close to that for the most stable CH/pi contact structure of the fucose-benzene complex (-4.5 kcal/mol). On the other hand the most stable CH/pi contact structure of the fucose-indole complex has substantially larger E(form) (-6.5 kcal/mol). The dispersion interaction is the major source of the attraction in the CH/pi contact structures of the fucose-phenol and fucose-indole complexes as in the case of the fucose benzene complex. The electrostatic interactions in the CH/pi contact structures are small (less than 1.5 kcal/mol). The nature of the interactions between the nonpolar surface of the carbohydrate and aromatic rings is completely different from that of the conventional hydrogen bonds where the electrostatic interaction is the major source of the attraction. The distributed multipole analysis and DFT SATP analysis show that the dispersion interactions in the CH/pi contact structure of fucose-indole complex are substantially larger than those in the CH/pi contact structures of fucose-benzene and fucose-phenol complexes. The large dispersion interactions are responsible for the large E(form) for the fucose indole complex. PMID- 21812468 TI - Metal-free chlorodeboronation of organotrifluoroborates. AB - A mild and metal-free method for the chlorodeboronation of organotrifluoroborates using trichloroisocyanuric acid (TCICA) was developed. Aryl-, heteroaryl-, alkenyl-, alkynyl-, and alkyltrifluoroborates were converted into the corresponding chlorinated products in good yields. This method proved to be tolerant of a broad range of functional groups. PMID- 21812470 TI - Organocatalytic asymmetric Michael addition of 1-acetylindolin-3-ones to alpha,beta-unsaturated aldehydes: synthesis of 2-substituted indolin-3-ones. AB - A highly efficient asymmetric Michael addition of 1-acetylindolin-3-ones to alpha,beta-unsaturated aldehydes is developed to afford 2-substituted indolin-3 one derivatives in high yields (up to 94%) with good stereoselectivities (up to 11:1 dr and 96% ee). The Michael adducts can be transformed into substituted cyclopentyl[b]indoline compounds conveniently without racemization. PMID- 21812471 TI - Bifunctional trehalose anode incorporating two covalently linked enzymes acting in series. AB - A bienzymatic electrode incorporating trehalase (Tre) and glucose oxidase (GOx) covalently bound to the surface of Pt through a functionalized thiol linker (Tre|GOx|Pt) has been designed and assembled and its catalytic properties examined by chemical and electrochemical methods in aqueous phosphate buffer solutions (PBS, pH 7.4). Exposure of Tre|GOx|Pt to PBS containing trehalose (Tr) and subsequent polarization at 0.6 V versus Ag/AgCl yielded after a few minutes well-defined steady-state currents ascribed to the oxidation of hydrogen peroxide generated by the GOx-mediated oxidation of glucose (Gl) produced by the Tre mediated dissociation of Tr. Plots of the steady-state currents versus [Tr] over the range examined, i.e., 5-25 mM, were found to be linear. Implications of these results toward the development of an implantable biofuel cell as an autonomous energy conversion device for insects are discussed. PMID- 21812472 TI - Formation of defect-free latex films on porous fiber supports. AB - We present here the creation of a defect-free polyvinylidene chloride barrier layer on the lumen-side of a hollow fiber sorbent. Hollow fiber sorbents have previously been shown to be promising materials for enabling low-cost CO(2) capture, provided a defect-free lumen-side barrier layer can be created. Film experiments examined the effect of drying rate, latex age, substrate porosity (porous vs nonporous), and substrate hydrophobicity/hydrophilicity. Film studies show that in ideal conditions (i.e., slow drying, fresh latex, and smooth nonporous substrate), a defect-free film can be formed, whereas the other permutations of the variables investigated led to defective films. These results were extended to hollow fiber sorbents, and despite using fresh latex and relatively slow drying conditions, a defective lumen-side layer resulted. XRD and DSC indicate that polyvinylidene chloride latex develops crystallinity over time, thereby inhibiting proper film formation as confirmed by SEM and gas permeation. This and other key additional challenges associated with the porous hollow fiber substrate vs the nonporous flat substrate were overcome. By employing a toluene vapor saturated drying gas (a swelling solvent for polyvinylidene chloride) a defect-free lumen-side barrier layer was created, as investigated by gas and water vapor permeation. PMID- 21812473 TI - Asymmetric organocatalytic allylic substitution of Morita-Baylis-Hillman carbonates with allylamines for the synthesis of 2,5-dihydropyrroles. AB - The asymmetric allylic substitution reaction of MBH carbonates with allylamines has been developed, which affords N-allyl-beta-amino-alpha-methylene esters in high yields and enantioselectivities. After a subsequent ring-closure metathesis of the products, a series of optically active 2,5-dihydropyrroles could be obtained smoothly in high yields without any loss of enantioselectivity. Finally, a tentative mechanism for rationalization of the reaction has been proposed. PMID- 21812474 TI - Heterogeneous ligand-nanoparticle distributions: a major obstacle to scientific understanding and commercial translation. AB - Nanoparticles conjugated with functional ligands are expected to have a major impact in medicine, photonics, sensing, and nanoarchitecture design. One major obstacle to realizing the promise of these materials, however, is the difficulty in controlling the ligand/nanoparticle ratio. This obstacle can be segmented into three key areas: First, many designs of these systems have failed to account for the true heterogeneity of ligand/nanoparticle ratios that compose each material. Second, studies in the field often use the mean ligand/nanoparticle ratio as the accepted level of characterization of these materials. This measure is insufficient because it does not provide information about the distribution of ligand/nanoparticle species within a sample or the number and relative amount of the different species that compose a material. Without these data, researchers do not have an accurate definition of material composition necessary both to understand the material-property relationships and to monitor the consistency of the material. Third, some synthetic approaches now in use may not produce consistent materials because of their sensitivity to reaction kinetics and to the synthetic history of the nanoparticle. In this Account, we describe recent advances that we have made in under standing the material composition of ligand nanoparticle systems. Our work has been enabled by a model system using poly(amidoamine) dendrimers and two small molecule ligands. Using reverse phase high-pressure liquid chromatography (HPLC), we have successfully resolved and quantified the relative amounts and ratios of each ligand/dendrimer combination. This type of information is rare within the field of ligand-nanoparticle materials because most analytical techniques have been unable to identify the components in the distribution. Our experimental data indicate that the actual distribution of ligand-nanoparticle components is much more heterogeneous than is commonly assumed. The mean ligand/nanoparticle ratio that is typically the only information known about a material is insufficient because the mean does not provide information on the diversity of components in the material and often does not describe the most common component (the mode). Additionally, our experimental data has provided examples of material batches with the same mean ligand/nanoparticle ratio and very different distributions. This discrepancy indicates that the mean cannot be used as the sole metric to assess the reproducibility of a system. We further found that distribution profiles can be highly sensitive to the synthetic history of the starting material as well as slight changes in reaction conditions. We have incorporated the lessons from our experimental data into the design of new ligand-nanoparticle systems to provide improved control over these ratios. PMID- 21812475 TI - Toward the growth of an aligned single-layer MoS2 film. AB - Molybdenum disulfide (molybdenite) monolayer islands and flakes have been grown on a copper surface at comparatively low temperature and mild conditions through sulfur loading of the substrate using thiophenol (benzenethiol) followed by the evaporation of Mo atoms and annealing. The MoS(2) islands show a regular Moire pattern in scanning tunneling microscopy, attesting to their atomic ordering and high quality. They are all aligned with the substrate high-symmetry directions providing for rotational-domain-free monolayer growth. PMID- 21812476 TI - Planar chirality of twisted trans-azobenzene structure induced by chiral transfer from binaphthyls. AB - The absolute configuration of a binaphthyl-azobenzene dyad 2b, which has a chiral axis and a chiral plane, was determined by comparing the experimental circular dichroism (CD) spectra with the theoretical CD spectra calculated by the time dependent (TD)-DFT method. The CD signals of the trans-azobenzene moiety indicated that the two benzene rings of this moiety are twisted unidirectionally. It is suggested that these dyads with shorter linkers may be suitable for use as chiroptical switches. PMID- 21812477 TI - Enhanced toxicity of the protein cross-linkers divinyl sulfone and diethyl acetylenedicarboxylate in comparison to related monofunctional electrophiles. AB - Previously, we determined that diethyl acetylenedicarboxylate (DAD), a protein cross-linker, was significantly more toxic than analogous monofunctional electrophiles. We hypothesized that other protein cross-linkers enhance toxicity similarly. In agreement with this hypothesis, the bifunctional electrophile divinyl sulfone (DVSF) was 6-fold more toxic than ethyl vinyl sulfone (EVSF) in colorectal carcinoma cells and greater than 10-fold more toxic in Saccharomyces cerevisiae. DVSF and DAD caused oligomerization of yeast thioredoxin 2 (Trx2p) in vitro and promoted Trx2p cross-linking to other proteins in yeast at cytotoxic doses. Our results suggest that protein cross-linking is considerably more detrimental to cellular homeostasis than simple alkylation. PMID- 21812478 TI - CuI/TMEDA-catalyzed annulation of 2-bromo alkynylbenzenes with Na2S: synthesis of benzo[b]thiophenes. AB - A copper-catalyzed thiolation annulation reaction of 2-bromo alkynylbenzenes with sodium sulfide has been developed. In the presence of CuI and TMEDA, a variety of 2-substituted benzo[b]thiophenes were readily prepared in moderate to good yields by the reaction of 2-bromo alkynylbenzenes and Na(2)S.9H(2)O. PMID- 21812479 TI - Cytotoxic origin of copper(II) oxide nanoparticles: comparative studies with micron-sized particles, leachate, and metal salts. AB - The work investigates the source of toxicity of copper oxide nanoparticles (CuO NPs) with respect to its leaching characteristic and speciation. Complexation mediated leaching of CuO NPs by amino acids was identified as the source of toxicity toward Escherichia coli, the model microorganism used in the current study. The leached copper-peptide complex induces a multiple-fold increase in intracellular reactive oxygen species generation and reduces the fractions of viable cells, resulting in the overall inhibition of biomass growth. The cytotoxicity of the complex leachate is however different from that of equivalent soluble copper salts (nitrates and sulfates). A pH-dependent copper speciation during the addition of copper salts gives rise to uncoordinated copper ions, which in turn result in greater toxicity and cell lysis, the latter of which was not observed for CuO NPs even at comparable pH. Since leaching did not occur with micrometer-sized CuO, no cytotoxicty effect was observed, thus highlighting the prominence of materials toxicity at the nanoscale. PMID- 21812480 TI - Intrinsic Tween 20 improves release and antilisterial properties of co encapsulated nisin and thymol. AB - Antimicrobial delivery systems have been proposed as potential solutions to improve effectiveness of antimicrobials in food matrixes by shielding antimicrobials from contacting food matrix components and releasing them continuously. In this work, spray-dried capsules were produced from zein solutions with the same concentrations of nisin and thymol but with varying Tween 20 contents for characterization of release kinetics of antimicrobials and antilisterial properties. At intermediate levels of Tween 20, sustained and more complete release of antimicrobials was observed at pH 6.0 and 8.0. Most capsule samples were more effective than free antimicrobials against Listeria monocytogenes in 2% reduced fat milk, and the best capsule treatment reduced the bacterial population by 2 log CFU/mL more than comparable free antimicrobials after 4 h incubation at 25 degrees C. Our work demonstrated that nonionic surfactant can be conveniently used to modulate characteristics of delivery systems to effectively improve antimicrobial functions in food systems. PMID- 21812481 TI - Identification of (poly)phenolic compounds in concord grape juice and their metabolites in human plasma and urine after juice consumption. AB - Analysis of Concord grape juice by HPLC with ESI-MS(n), PDA, and fluorescence detection resulted in the identification and quantification of 60 flavonoids and related phenolic compounds, which were present at an overall concentration of 1508 +/- 31 MUmol/L. A total of 25 anthocyanins were detected, which were mono- and di-O-glucosides, O-acetylglucosides, O-p-coumaroyl-O-diglucosides, and O-p coumaroylglucosides of delphinidin, cyanidin, petunidin, peonidin, and malvidin. The anthocyanins represented 46% of the total phenolic content of the juice (680 MUmol/L). Tartaric esters of hydroxycinnamic acids, namely, trans-caftaric and trans-coutaric acids, and to a lesser extent trans-fertaric acid accounted for 29% of the phenolic content, with a total concentration of 444 MUmol/L, of which 85% comprised trans-caftaric acid. Free hydroxycinnamic acids were also quantified but contributed to <1% of the total phenolic content (8.4 MUmol/L). The other groups of polyphenolic compounds present in the juice, accounting for 24% of the total, comprised monomeric and oligomeric units of (epi)catechin and (epi)gallocatechin (248 MUmol/L), flavonols (76 MUmol/L), gallic acid (51 MUmol/L), and trans-resveratrol (1.5 MUmol/L). The bioavailability of the (poly)phenolic compounds in 350 mL of juice was investigated following acute intake by healthy volunteers. Plasma and urine were collected over 0-24 h and analyzed for parent compounds and metabolites. In total, 41 compounds, principally metabolites, were identified. PMID- 21812482 TI - Unique structural and electronic features of perferryl-oxo oxidant in Cytochrome P450. AB - We have performed hybrid density functional theory (DFT) calculations on the geometric and electronic structures of low-lying doublet and quartet ferryl-oxo [Fe(IV)?O] oxidants and a doublet perferryl-oxo [Fe(V)?O] oxidant in Cytochrome P450. Fully optimized structures of compound I models have been determined, and the proper symmetry of wave functions has been restored by the spin-projection technique. The results show that the perferryl-oxo species is relatively low lying, as compared with the excited state of the ferryl-oxo species, if the iron oxo bond is properly described as the mixing of several appropriate excited electronic configurations to minimize electron repulsion. This means that the perferryl-oxo species is virtually in a mixed-valent resonance state, ?Fe(V)?O < > ?Fe(IV)*?-?*O, containing a highly reactive ppi atomic oxygen radical. The anionic thiolate ligand acts as a Lewis sigma base and functions to achieve the stability of the perferryl-oxo complex and to activate the oxo ligand trans to it by asymmetric bond distortion along the O-Fe-S axis by lengthening the Fe-O bond and shortening the Fe-S bond, prior to the hydrogen-atom abstraction from the substrate. PMID- 21812483 TI - Influence of (2,3,4,5,6-pentamethyl/phenyl)phenyl scaffold: stereoelectronic control of the persistence of o-quinonoid reactive intermediates of photochromic chromenes. AB - Regioisomeric photochromic chromenes 1Ch-6Ch substituted with the (2,3,4,5,6 pentamethyl/phenyl)phenyl scaffold were designed to delve into stereoelectronic effects on the spectrokinetic properties of photogenerated o-quinonoid reactive intermediates. While the latter derived from 1Ch, 2Ch, 4Ch, and 5Ch were found to exhibit notable persistence, those from 3Ch and 6Ch were found to revert rapidly at room temperature to preclude visible coloration. The intermediates of 1Ch and 2Ch were found to be marginally more stable than those of 4Ch and 5Ch, respectively, attesting to the possibility of toroidal conjugation via C(ipso)-pi orbitals in the former. The rapid reversion of the intermediates of 3Ch and 6Ch is attributed to unfavorable electronic repulsion between the phenyl ring of the (pentamethyl/phenyl)phenyl scaffold and one of the lone-pairs of the o-quinonoid oxygen. Thus, the regioisomerically substituted photochromic chromenes are shown to permit control of the reversion, very rapidly as well as slowly, of the colored o-quinonoid intermediates through operation of stereoelectronic effects differently. PMID- 21812484 TI - Comparative height measurements of dip-pen nanolithography-produced lipid membrane stacks with atomic force, fluorescence, and surface-enhanced ellipsometric contrast microscopy. AB - Dip-pen nanolithography (DPN) with phospholipids has been shown to be a powerful tool for the generation of biologically active surface patterns, but screening of the obtained lithographic structures is still a bottleneck in the quality control of the prepared samples. Here we performed a comparative study with atomic force microscopy (AFM), fluorescence microscopy (FM), and surface-enhanced ellipsometric contrast (SEEC) microscopy of phospholipid membrane stacks consisting of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) with high admixing of 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-[6-[(2,4 dinitrophenyl)amino]hexanoyl] (DNP Cap PE) produced by DPN. We present a structural model of membrane stacking based on the combined information gained from the three microscopic techniques. Domains of phase-separated DNP Cap PE can be detected at high DNP Cap PE admixing that are not present at medium or low admixings. While the optical methods allow for a high-throughput screening of lithographic structures (compared to AFM), it was found that, when relying on FM alone, artifacts due to phase-separation phenomena can be introduced in the case of thin membrane stacks. PMID- 21812485 TI - Molecular dynamics simulation studies of caffeine aggregation in aqueous solution. AB - Molecular dynamics simulations were carried out on a system of eight independent caffeine molecules in a periodic box of water at 300 K, representing a solution near the solubility limit for caffeine at room temperature, using a newly developed CHARMM-type force field for caffeine in water. Simulations were also conducted for single caffeine molecules in water using two different water models (TIP3P and TIP4P). Water was found to structure in a complex fashion around the planar caffeine molecules, which was not sensitive to the water model used. As expected, extensive aggregation of the caffeine molecules was observed, with the molecules stacking their flat faces against one another like coins, with their methylene groups staggered to avoid steric clashes. A dynamic equilibrum was observed between large n-mers, including stacks with all eight solute molecules, and smaller clusters, with the calculated osmotic coefficient being in acceptable agreement with the experimental value. The insensitivity of the results to water model and the congruence with experimental thermodynamic data suggest that the observed stacking interactions are a realistic representation of the actual association mechanism in aqueous caffeine solutions. PMID- 21812486 TI - Synthetic, structural, and biosynthetic studies of an unusual phospho glycopeptide derived from alpha-dystroglycan. AB - Aberrant glycosylation of alpha-dystroglycan (alpha-DG) results in loss of interactions with the extracellular matrix and is central to the pathogenesis of several disorders. To examine protein glycosylation of alpha-DG, a facile synthetic approach has been developed for the preparation of unusual phosphorylated O-mannosyl glycopeptides derived from alpha-DG by a strategy in which properly protected phospho-mannosides are coupled with a Fmoc protected threonine derivative, followed by the use of the resulting derivatives in automated solid-phase glycopeptide synthesis using hyper-acid-sensitive Sieber amide resin. Synthetic efforts also provided a reduced phospho-trisaccharide, and the NMR data of this derivative confirmed the proper structural assignment of the unusual phospho-glycan structure. The glycopeptides made it possible to explore factors that regulate the elaboration of critical glycans. It was established that a glycopeptide having a 6-phospho-O-mannosyl residue is not an acceptor for action by the enzyme POMGnT1, which attaches beta(1,2)-GlcNAc to O-mannosyl moietes, whereas the unphosphorylated derivate was readily extended by the enzyme. This finding implies a specific sequence of events in determining the structural fate of the O-glycan. It has also been found that the activity of POMGnT1 is dependent on the location of the acceptor site in the context of the underlying polypeptide/glycopeptide sequence. Conformational analysis by NMR has shown that the O-mannosyl modification does not exert major conformational effect on the peptide backbone. It is, however, proposed that these residues, introduced at the early stages of glycoprotein glycosylation, have an ability to regulate the loci of subsequent O-GalNAc additions, which do exert conformational effects. The studies show that through access to discrete glycopeptide structures, it is possible to reveal complex regulation of O-glycan processing on alpha-DG that has significant implications both for its normal post-translational maturation, and the mechanisms of the pathologies associated with hypoglycosylated alpha-DG. PMID- 21812487 TI - Preparation and characterization of monodispersed microfloccules of TiO2 nanoparticles with immobilized multienzymes. AB - Microfloccules of TiO(2) nanoparticles, on which glycerol-dehydrogenase (GDH), 1,3-propanediol-oxidoreductase (PDOR), and glycerol-dehydratase (GDHt) were coimmobilized, were prepared by adsorption-flocculation with polyacrylamide (PAM). The catalytic activity of immobilized enzyme in the glycerol redox reaction system, the enzyme leakage, stabilities of pH and temperature, as well as catalytic kinetics of immobilized enzymes relative to the free enzymes were evaluated. Enzyme loading on the microfloccules as much as 104.1 mg/g TiO(2) (>90% loading efficiency) was obtained under the optimal conditions. PAM played a key role for the formation of microfloccules with relatively homogeneous distribution of size and reducing the enzyme leakage from the microfloccules during the catalysis reaction. The stabilities of GDH against pH and temperature was significantly higher than that those of free GDH. Kinetic study demonstrated that simultaneous NAD(H) regeneration was feasible in glycerol redox system catalysted by these multienzyme microfloccules and the yield of 1, 3-popanediol (1, 3-PD) was up to 11.62 g/L. These results indicated that the porous and easy separation microfloccules of TiO(2) nanoparticles with immobilized multienzymes were efficient in term of catalytic activity as much as the free enzymes. Moreover, compared with free enzyme, the immobilized multienzymes system exhibited the broader pH, higher temperature stability. PMID- 21812488 TI - Aziridines from intramolecular alkene aziridination of sulfamates: reactivity toward carbon nucleophiles. application to the synthesis of spisulosine and its fluoro analogue. AB - Catalytic intramolecular alkene aziridination of sulfamate is an emerging methodology for the asymmetric synthesis of chiral functionalized amines involving the formation of bicyclic aziridines. This study demonstrates the ability of the latter to undergo ring-opening with various carbon nucleophiles: Grignard reagents, lithium salts of terminal alkynes, dithiane, malonate. These S(N)2-type reactions occur with high levels of regio- and chemoselectivity to generally afford seven-membered cyclic sulfamidates in good yields. Carbon nucleophiles have also been found to react with these sulfamidates provided that the sulfamate ester has been previously activated by introduction of a tosyl substituent on the NH group. The versatility of this strategy has been illustrated with the syntheses of spisulosine and its fluoro analogue. PMID- 21812489 TI - Biocatalytic deacylation studies on tetra-O-acyl-beta-D-xylofuranosyl nucleosides: synthesis of xylo-LNA monomers. AB - A Novozyme-435 catalytic methodology has been developed for selective deacylation of one of the acyloxy functions involving a primary -OH group over the other acyloxy functions involving primary and secondary -OH groups in 4'-C acyloxymethyl-2',3',5'-tri-O-acyl-beta-D-xylofuranosyl nucleosides. Optimization of the biocatalytic reaction revealed that tetra-O-butanoyl-beta-D-xylofuranosyl nucleosides are the best substrates for the enzyme. The possibility of acyl migration during enzymatic deacylation reactions has been ruled out by carrying out biocatalytic deacylation reactions on mixed esters of 4'-C-hydroxymethyl 2',3',5'-tri-O-acetyl-beta-D-xylofuranosyl nucleosides. The developed methodology has been used for the efficient synthesis of xylo-LNA monomers T, U, A, and C in good yields. PMID- 21812490 TI - Palladium-catalyzed stereoconvergent formylation of (E/Z)-beta-bromo-beta fluorostyrenes: straightforward access to (Z)-alpha-fluorocinnamic aldehydes and (Z)-beta-fluorocinnamic alcohols. AB - We report here the stereoconvergent formylation of (E/Z)-beta-bromo-beta fluorostyrene mixtures with carbon monoxide and sodium formate catalyzed by palladium. Optimization of reaction conditions leads to the corresponding pure (Z)-alpha-fluorocinnamaldehydes in good yields. The reaction was extended to styrenes bearing electro-attracting or electro-donating groups. The obtained alpha-fluoroaldehydes were smoothly reduced to the corresponding (Z)-beta fluorocinnamic alcohol by NaBH(4). The reaction could be performed on functionalized substrates as demonstrated by the access to the glucoside of beta fluoroconiferyl alcohol, (Z)-beta-fluoroconiferin, a strong inhibitor of lignin polymerization. PMID- 21812492 TI - Computational study on the mechanism and selectivity of C-H bond activation and dehydrogenative functionalization in the synthesis of rhazinilam. AB - The key platinum mediated C-H bond activation and functionalization steps in the synthesis of (-)-rhazinilam (Johnson, J. A.; Li, N.; Sames, D. J. Am. Chem. Soc. 2002, 124, 6900) were investigated using the M06 and B3LYP density functional approximation methods. This computational study reveals that ethyl group dehydrogenation begins with activation of a primary C-H bond in preference to a secondary C-H bond in an insertion/methane elimination pathway. The C-H activation step is found to be reversible while the methane elimination (reductive elimination) transition state controls rate and diastereoselectivity. The chiral oxazolinyl ligand induces ethyl group selectivity through stabilizing weak interactions between its phenyl group (or cyclohexyl group) and the carboxylate group. After C-H activation and methane elimination steps, Pt-C bond functionalization occurs through beta-hydride elimination to give the alkene platinum hydride complex. PMID- 21812493 TI - Electronic energy transfer in highly aligned MEH-PPV single chains. AB - This paper describes the simultaneous measurement of excitation and emission anisotropy to visualize energy transfer in single chains of the prototypical conjugated polymer MEH-PPV, for samples with >70% of the single chains organized into extended, rod-like conformations. The uniformity and high degree of order of the single molecules in these experiments has allowed direct comparison of our experimental data to energy-transfer simulations in model polymer chains. Increases in average anisotropy from 0.62 to 0.74 from excitation to emission and average changes of <15 degrees to the in-plane dipole principal orientation axis confirmed that energy was transferred to a relatively small number of sites in these highly ordered chains. This organization persisted even at large molecular weights (M(n) = 850 kDa). Electronic energy transfer in highly anisotropic model chains was simulated using an incoherent Forster-type mechanism to generate modulation depth histograms in good agreement with the observed data, as well as ensemble emission energies consistent with previously reported results. In these ordered model chains, excitons migrated an average of 6 nm before emission. This distance, far larger than the radius for single-step FRET, implies that energy transfer in MEH-PPV is a multistep funneling process. PMID- 21812494 TI - Dual fluorescence of ellipticine: excited state proton transfer from solvent versus solvent mediated intramolecular proton transfer. AB - Photophysical properties of a natural plant alkaloid, ellipticine (5,11-dimethyl 6H-pyrido[4,3-b]carbazole), which comprises both proton donating and accepting sites, have been studied in different solvents using steady state and time resolved fluorescence techniques primarily to understand the origin of dual fluorescence that this molecule exhibits in some specific alcoholic solvents. Ground and excited state calculations based on density functional theory have also been carried out to help interpretation of the experimental data. It is shown that the long-wavelength emission of the molecule is dependent on the hydrogen bond donating ability of the solvent, and in methanol, this emission band arises solely from an excited state reaction. However, in ethylene glycol, both ground and excited state reactions contribute to the long wavelength emission. The time-resolved fluorescence data of the system in methanol and ethylene glycol indicates the presence of two different hydrogen bonded species of ellipticine of which only one participates in the excited state reaction. The rate constant of the excited state reaction in these solvents is estimated to be around 4.2-8.0 * 10(8) s(-1). It appears that the present results are better understood in terms of solvent-mediated excited state intramolecular proton transfer reaction from the pyrrole nitrogen to the pyridine nitrogen leading to the formation of the tautomeric form of the molecule rather than excited state proton transfer from the solvents leading to the formation of the protonated form of ellipticine. PMID- 21812495 TI - Biomimetic organocatalytic asymmetric synthesis of 2-substituted piperidine-type alkaloids and their analogues. AB - Natural substances such as pelletierine and its analogues have been prepared in up to 97% ee and good yield by a protective-group-free, biomimetic approach. Usage of benzonitrile or acetonitrile as solvents effectively prevents product racemization. PMID- 21812496 TI - The challenges of gout management in the elderly. AB - Gout is common in the elderly and its management is frequently complicated by the presence of co-morbid conditions and medications prescribed for other conditions. The management of gout is 2-fold: (i) treatment of the acute attack to rapidly resolve the pain and inflammation; and (ii) long-term urate-lowering therapy (ULT) to prevent further gouty episodes. NSAIDs, colchicine, corticosteroids and more recently interleukin (IL)-1 inhibitors are effective treatments for acute gout. The choice of agent is determined by the patient's age, co-morbidities and concomitant medications. Renal impairment is of particular concern in the elderly and may preclude the use of NSAIDs and colchicine. The IL-1 inhibitors are rapidly effective but data in the elderly are limited. ULT aiming for a serum urate <0.36 mmol/L, or lower in severe tophaceous gout, is critical for the long term management of gout. Urate lowering can be achieved by inhibiting the production of uric acid through xanthine oxidase inhibition (allopurinol, febuxostat), increasing uric acid excretion via the kidneys (uricosuric agents: probenecid, benzbromarone) or dissolving uric acid to the more water soluble allantoin (recombinant uricases: pegloticase, rasburicase). Allopurinol is the most commonly used ULT, but there is no consensus on dosing in renal impairment. Febuxostat is effective at lowering serum urate, but there are limited data in the elderly and patients with renal impairment. Furthermore, there are concerns about cardiovascular safety. Probenecid is ineffective in patients with renal impairment (creatinine clearance <60 mL/min) and the availability of benzbromarone is limited because of concerns about its hepatotoxicity. The recombinant uricases provide an exciting new therapeutic option, but there are limited data for their use in the elderly. These agents may be particularly useful in patients with a high urate burden (e.g. those with tophi); however, they may precipitate a severe flare of gout and this will require treatment in its own right. Careful consideration of the patient's concomitant medications is required as many drugs increase serum urate. Successful urate lowering will ultimately reduce gout flares and thereby improve patient quality of life. PMID- 21812497 TI - Disease modification in Parkinson's disease. AB - Parkinson's disease (PD) is an age-related, progressive, multisystem neurodegenerative disorder resulting in significant morbidity and mortality, as well as a growing social and financial burden in an aging population. The hallmark of PD is loss of dopaminergic neurons of the substantia nigra pars compacta, leading to bradykinesia, rigidity and tremor. Current pharmacological treatment is therefore centred upon dopamine replacement to alleviate symptoms. However, two major problems complicate this approach: (i) motor symptoms continue to progress, requiring increasing doses of medication, which result in both short term adverse effects and intermediate- to long-term motor complications; (ii) dopamine replacement does little to treat non-dopaminergic motor and non-motor symptoms, which are an important source of morbidity, including dementia, sleep disturbances, depression, orthostatic hypotension, and postural instability leading to falls. It is critical, therefore, to develop a broader and more fundamental therapeutic approach to PD, and major research efforts have focused upon developing neuroprotective interventions. Despite many encouraging preclinical data suggesting the possibility of addressing the underlying pathophysiology by slowing cell loss, efforts to translate this into the clinical realm have largely proved disappointing in the past. Barriers to finding neuroprotective or disease-modifying drugs in PD include a lack of validated biomarkers of progression, which hampers clinical trial design and interpretation; difficulties separating symptomatic and neuroprotective effects of candidate neuroprotective therapies; and possibly fundamental flaws in some of the basic preclinical models and testing. However, three recent clinical trials have used a novel delayed-start design in an attempt to overcome some of these roadblocks. While not examining markers of cell loss and function, which would determine neuroprotective effects, this trial design pragmatically tests whether earlier versus later intervention is beneficial. If positive (i.e. if an earlier intervention proves more effective), this demonstrates disease modification, which could result from neuroprotection or from other mechanisms. This strategy therefore provides a first step towards supporting neuroprotection in PD. Of the three delayed-start design clinical trials, two have investigated early versus later start of rasagiline, a specific irreversible monoamine oxidase B inhibitor. Each trial has supported, although not proven, disease-modifying effects. A third delayed-start-design clinical trial examining potential disease-modifying effects of pramipexole has unfortunately reportedly been negative according to preliminary presentations. The suggestion that rasagiline is disease modifying is made all the more compelling by in vitro and PD animal-model studies in which rasagiline was shown to have neuroprotective effects. In this review, we examine efforts to demonstrate neuroprotection in PD to date, describe ongoing neuroprotection trials, and critically discuss the results of the most recent delayed-start clinical trials that test possible disease-modifying activities of rasagiline and pramipexole in PD. PMID- 21812498 TI - Is antiarrhythmic treatment in the elderly different? a review of the specific changes. AB - Aging is associated with electrical and structural changes of the myocardium. The response to catecholamines is also reduced and the baroreceptor reflex activity is blunted. These aspects conceivably affect the response to antiarrhythmic drugs in the elderly. Furthermore, physiological parameters change in older age, affecting the pharmacokinetics of drugs. In this article, the literature on the pharmacokinetics and pharmacodynamics of antiarrhythmic drugs in elderly subjects is reviewed with the purpose of improving their optimal and safe prescription. Pharmacokinetic studies of antiarrhythmic drugs in the elderly are sparse, and there are no data available for procainamide and propafenone. Mean dose reductions calculated for elderly patients relative to younger patients are 60% for digoxin, 19% for diltiazem, 32% for disopyramide, 31% for flecainide, 40% for metoprolol, 35% for quinidine, 29% for sotalol and 26% for verapamil. No dose reductions are required for dofetilide or dronedarone. The clearance of dofetilide is not affected by age after correction for renal function. The dosage of dofetilide is individualized according to an algorithm based on the corrected QT (QTc) interval and renal function. Although the area under the plasma concentration-time curve (AUC) for dronedarone is larger in elderly patients, the dose should not be reduced because the registered dose has specifically been studied in an elderly population. In elderly patients with renal insufficiency, hepatic impairment, heart failure or certain genetic variants, the pharmacokinetics of antiarrhythmic drugs might be affected to an even greater extent, meaning additional dosage adjustments are necessary. With increasing age, the number of prescribed drugs increases because of co-morbidity, making interactions between drugs more likely. Several drugs interact with antiarrhythmic drugs, leading to clinically relevant changes in drug concentrations or AUC values. Furthermore, several drugs with non-cardiovascular indications appear to have QTc prolonging effects. The combination of these drugs with antiarrhythmic drugs that affect the QTc interval increases the risk of developing torsades de pointes and should therefore be avoided. Altered effects of drugs in the elderly can also be the result of age-related changes in the cardiovascular system. For example, atenolol and sotalol show greater effects, i.e. reductions in heart rate and increased probability of adverse effects, at a given plasma concentration in older subjects compared with younger subjects. It remains unclear whether old age as such is a determinant for reduced or modified efficacy of antiarrhythmic drugs. In a randomized study it was found that patients aged >=65 years with atrial fibrillation had better survival with rate control than with rhythm control. However, different treatment strategies were compared and the results cannot be extrapolated to indicate better survival with a specific antiarrhythmic drug. Antiarrhythmic drugs will remain the first-line approach in most patients for the prevention or suppression of atrial and ventricular arrhythmias. As a rule of thumb, a 50% reduction in the starting dose of antiarrhythmic drugs compared with younger patients appears a wise approach in elderly patients. However, this does not apply to dofetilide and dronedarone. The selection of antiarrhythmic drugs in the elderly is predominantly determined by factors such as the treatment target, assumed patient compliance, possible drug interactions, co-morbidity, and renal and liver function. Efficacy and safety monitoring should take into account symptoms, ECG findings, rhythm recordings, plasma drug concentrations and other laboratory parameters. PMID- 21812499 TI - Systemic therapies for metastatic renal cell carcinoma in older adults. AB - The introduction of targeted therapies has radically changed the treatment paradigm for metastatic renal cell carcinoma (mRCC). However, multiple clinical dilemmas have emerged. For instance, limited data are available to juxtapose the safety and efficacy profile of targeted therapies between older and younger adults. Herein, pivotal trials of vascular endothelial growth factor (VEGF)- and mammalian target of rapamycin (mTOR)-directed therapies are assessed in the context of their implications in treating older adults with mRCC. In general, subset analyses from these pivotal studies suggest similar efficacy of targeted therapies amongst older adults. Aging is accompanied by a multitude of physiological changes, as well as an increased prevalence of co-morbidities. The age-related toxicity profiles of targeted agents for mRCC are detailed to provide a framework for the risks and benefits of these therapies in older adults. Ultimately, tools such as the Comprehensive Geriatric Assessment (CGA) that account for physiological (as opposed to chronological) age may prove useful in the evaluation and treatment of older adults with mRCC. PMID- 21812501 TI - Exclusion of older people from clinical trials: professional views from nine European countries participating in the PREDICT study. AB - BACKGROUND: There has been concern about under-representation of older people in clinical trials. The PREDICT study reported that older people and those with co morbidity continue to be excluded unjustifiably from clinical trials. However, there is no information about differences of opinion on these issues between EU countries. The results of a survey of health-related professionals from nine EU countries that participated in the PREDICT study are presented in this study. OBJECTIVE: The aim of the study was to identify and examine any differences of opinion between EU countries on the inclusion of older patients in clinical trials. METHODS: A questionnaire using a Likert scale and free text was completed by 521 general practitioners, geriatricians, clinical researchers, ethicists, nurses and industry pharmacologists/pharmacists. The questions explored the impact of the present situation, possible reasons for under-representation and potential methods of improving participation. Countries participating were the Czech Republic, Israel, Italy, Lithuania, the Netherlands, Poland, Romania, Spain and the UK. RESULTS: There was agreement that exclusion from clinical trials on age grounds alone was unjustified (87%) and that under-representation of older people in trials caused difficulties for prescribers (79%) and patients (73%). There were national differences between professionals. All but the Lithuanians believed that older people were disadvantaged because of under-representation. The Czech, Lithuanian and Romanian professionals felt that it was justified to have age limits based on co-morbidity (61-83%) and polypharmacy (63-85%). Romanians also thought that having age limits on trial participation was justified because of reduced life expectancy (62%) and physical disability (58%) in older people. All but the Romanian professionals felt that the present arrangements for clinical trials were satisfactory (62%). All but the Israelis (56%) and Lithuanians (70%) agreed that regulation of clinical trials needed alteration. CONCLUSIONS: Although respondent selection bias cannot be excluded, the differences that emerged between countries may be the result of the political and healthcare-system differences between older and newer members of the EU. These differences may influence decision making about clinical trial regulations and practice in older people. PMID- 21812500 TI - Polymyalgia rheumatica and giant cell arteritis in older patients: diagnosis and pharmacological management. AB - Giant cell arteritis (GCA) is an inflammatory vasculopathy that involves large- and medium-sized arteries and can cause vision loss, stroke and aneurysms. GCA occurs in people aged >50 years and is more common in women. A higher incidence of the disease is observed in populations from Northern European countries. Polymyalgia rheumatica (PMR) is a periarticular inflammatory process manifesting as pain and stiffness in the neck, shoulders and pelvic girdle. PMR shares the same pattern of age and sex distribution as GCA. The pathophysiology of PMR and GCA is not completely understood, but the two conditions may be related and often occur concurrently. A delay in the diagnosis should be avoided because of the risk of vascular ischaemic complications due to GCA. The diagnosis should be considered in patients aged >50 years presenting with symptoms such as new headache, visual disturbances, jaw claudication or symptoms of PMR. GCA can also present as a systemic inflammatory syndrome with fever of unknown origin. Marked elevation of acute-phase reactants, recognizable in higher erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels, is often seen in both PMR and GCA. However, some patients can present with a normal ESR. Confirmation of the diagnosis of GCA by temporal artery biopsy is important because clinical findings and laboratory tests are not specific, and because a diagnosis of GCA commits patients to long-term treatment with corticosteroids. The role of imaging techniques for the diagnosis of GCA remains unclear, but these modalities can be helpful in assessing the extent of vascular involvement, especially when extra-cranial disease is present. In PMR, subdeltoid and subacromial bursitis can be identified by imaging techniques, especially ultrasound or MRI. The clinical manifestations of GCA and PMR respond dramatically within 12-48 hours of starting corticosteroid treatment. The initial corticosteroid dosage commonly used in GCA is oral prednisone 40-60 mg/day, and for patients with PMR a dosage of 15-20 mg/day is often sufficient. A prolonged course of treatment is necessary, and corticosteroids are gradually tapered, guided by regular clinical evaluation and ESR (and/or CRP) measurement. Methotrexate is the best studied corticosteroid-sparing agent in GCA, and may be useful for patients with frequent disease relapses and/or corticosteroid-related toxicity. Retrospective studies favour aspirin (acetylsalicylic acid) as an effective adjuvant treatment for reducing the ischaemic complications of GCA. The long-term course of corticosteroid therapy frequently exposes elderly patients with PMR/GCA to various adverse effects, which can be attenuated with appropriate prophylactic measures. Co-morbid diseases and polypharmacy can pose particular challenges in the geriatric population. In general, the life expectancy of patients with GCA does not appear to be shortened, whereas the morbidity associated with the disease and its treatment is well recognized. PMID- 21812502 TI - Drug trials and older people: time to embrace the complexity of age. PMID- 21812504 TI - Cellular redox pathways as a therapeutic target in the treatment of cancer. AB - The vulnerability of some cancer cells to oxidative signals is a therapeutic target for the rational design of new anticancer agents. In addition to their well characterized effects on cell division, many cytotoxic anticancer agents can induce oxidative stress by modulating levels of reactive oxygen species (ROS) such as the superoxide anion radical, hydrogen peroxide and hydroxyl radicals. Tumour cells are particularly sensitive to oxidative stress as they typically have persistently higher levels of ROS than normal cells due to the dysregulation of redox balance that develops in cancer cells in response to increased intracellular production of ROS or depletion of antioxidant proteins. In addition, excess ROS levels potentially contribute to oncogenesis by the mediation of oxidative DNA damage. There are several anticancer agents in development that target cellular redox regulation. The overall cellular redox state is regulated by three systems that modulate cellular redox status by counteracting free radicals and ROS, or by reversing the formation of disulfides; two of these are dependent on glutathione and the third on thioredoxin. Drugs targeting S-glutathionylation have direct anticancer effects via cell signalling pathways and inhibition of DNA repair, and have an impact on a wide range of signalling pathways. Of these agents, NOV-002 and canfosfamide have been assessed in phase III trials, while a number of others are undergoing evaluation in early phase clinical trials. Alternatively, agents including PX-12, dimesna and motexafin gadolinium are being developed to target thioredoxin, which is overexpressed in many human tumours, and this overexpression is associated with aggressive tumour growth and poorer clinical outcomes. Finally, arsenic derivatives have demonstrated antitumour activity including antiproliferative and apoptogenic effects on cancer cells by pro-oxidant mechanisms, and the induction of high levels of oxidative stress and apoptosis by an as yet undefined mechanism. In this article we review anticancer drugs currently in development that target cellular redox activity to treat cancer. PMID- 21812503 TI - Targeted therapies for gastric cancer: current status. AB - Gastric cancer represents one of the most common cancers internationally. Unfortunately the majority of patients still present at an advanced stage, and despite advances in diagnostic and treatment strategies, outcomes still remain poor with high mortality rates despite a decline in incidence. Whilst the utility of classical chemotherapy agents has been explored thoroughly (and continues to be investigated, alone or in various combinations), advances have been slow and the efficacy of these agents has reached a plateau. As such, the focus of recent study has shifted toward developing a greater understanding of the molecular biology of carcinogenesis and the cancer cell phenotype, and, in turn, the development of rationally designed drugs that target molecular aberrancies in signal transduction pathways specific to gastric cancer. These targets include circulating growth and angiogenic factors, cell surface receptors, and other molecules that comprise downstream intracellular signalling pathways, including receptor tyrosine kinases. Therapeutic advances in this area significantly lag behind other solid organ malignancies such as breast and colorectal cancer. This article reviews the role of targeted therapies in gastric cancer, including rationale and mechanism of action, current and emerging data, as single-agent therapy or in combination regimens. A recently published randomized phaseIII trial supporting the use of trastuzumab, an anti-human epidermal growth factor receptor 2 (HER2)/neu monoclonal antibody, in a selected population of patients is discussed. Therapies that have been evaluated in phase II trials are also reviewed, as well as promising new therapies currently being investigated in preclinical or phase I studies. There is optimism that targeted therapies, whether as single-agent therapy or in combination with traditional therapies, including chemotherapy, radiotherapy and surgery, may yet have an impact on improvement of the overall prognosis of gastric cancer. PMID- 21812505 TI - Management strategies for recurrent platinum-resistant ovarian cancer. AB - Although ovarian cancer is often a chemosensitive malignancy, patients who are resistant to platinum-based chemotherapy represent a therapeutic challenge. Currently, the only drugs that are US FDA approved to treat this subset of patients are paclitaxel, pegylated liposomal doxorubicin (PLD) and topotecan. The response rates with these agents is in the 10-15% range and overall survival is around 12 months. Other drugs that have shown some activity in platinum-resistant ovarian cancer include the taxane analogues, oral etoposide, pemetrexed and bevacizumab. Unfortunately, randomized phase III trials of second-line chemotherapy in patients with platinum-resistant ovarian cancer have not shown an advantage over existing therapy with respect to progression-free survival or overall survival. The only trial that has reported a significant progression-free survival advantage over standard therapy is a randomized phase II trial of PLD with or without EC145, a folate-linked vinca alkaloid. Final survival results of this trial are pending. PMID- 21812506 TI - Difficult-to-treat gouty arthritis: a disease warranting better management. AB - Gouty arthritis is the most common inflammatory arthritis in adults and is characterized by very painful flares. Gouty arthritis results from an elevated body uric acid pool, which leads to deposition of monosodium urate crystals, mainly in the joints. These crystals trigger the release of proinflammatory cytokines, in particular interleukin (IL)-1beta, which stimulates inflammation. Gouty arthritis can progress to a chronic, deforming and physically disabling disease through the development of disfiguring tophi, joint destruction and persistent pain. Standard treatments are effective in most patients. Acutely, anti-inflammatory therapies provide rapid pain relief and resolution of flares. Chronically, urate-lowering therapies reduce serum urate levels and, in combination with anti-inflammatory prophylaxis, reduce the risk of flares. However, for a growing number of patients, current standard treatments are ineffective or are contraindicated, largely due to the presence of co morbidities. Indeed, metabolic syndrome, hypertension, dyslipidaemia, cardiovascular disease, diabetes mellitus and renal impairment are all highly prevalent in individuals with gouty arthritis, and may lead to standard treatments being ineffective or inappropriate. Such patients with difficult-to treat disease require alternative therapies. Gouty arthritis can have a major impact on health-related quality of life (HR-QOL), especially in patients with difficult-to-treat disease, as revealed by recent studies comparing HR-QOL for patients with gouty arthritis with that of the general population. All studies revealed clinically significant reductions in physical functioning for individuals with gouty arthritis compared with the general population. The difference was particularly marked for patients with difficult-to-treat disease. Gouty arthritis also constitutes an important economic burden through absence from work and medical costs. Again, the burden is greater in patients with difficult-to-treat disease. The development of difficult-to-treat disease reflects the short-comings of current standard treatments in a growing number of gouty arthritis patients. This has been recognized by the pharmaceutical industry and has promoted the development of innovative therapies. An appreciation of the key role of IL-1beta in inflammation in gouty arthritis has led to the development of a new class of anti-inflammatory agents that block IL-1beta signal transduction. The current IL-1beta blockers in trials are rilonacept and canakinumab. Canakinumab, a fully human anti-IL-1beta monoclonal antibody, has been shown to produce rapid and sustained pain relief from acute flares in patients with difficult-to-treat disease, and both rilonacept and canakinumab have been shown to reduce the risk of recurrent flares. Promising new therapies for reducing serum urate levels are also being developed. These include the recently approved therapies pegloticase (a pegylated form of the enzyme uricase that converts urate to allantoin), inhibitors of renal urate transporter proteins, and inhibitors of purine nucleotide phosphorylase, an enzyme involved in purine metabolism. Further studies are warranted to establish the value and role of these new therapies in the management of gouty arthritis. These new options should help reduce the growing human burden associated with gouty arthritis, lowering the tophaceous burden, minimizing the risk of flares, and enabling patients to achieve rapid and effective pain relief when flares do occur. PMID- 21812508 TI - Romidepsin: in the treatment of T-cell lymphoma. AB - Romidepsin is a histone deacetylase inhibitor with high inhibitory activity for class I histone deacetylases. Intravenous romidepsin is indicated in the US for the treatment of adult patients with cutaneous T-cell lymphoma (CTCL) or peripheral T-cell lymphoma (PTCL) who have received at least one prior systemic therapy. The clinical efficacy of romidepsin has been demonstrated in two noncomparative, multicentre, phase II trials in patients with relapsed, refractory or advanced CTCL. In both trials, therapy with intravenous romidepsin was associated with an overall response (i.e. both complete response and partial response) rate of 34% and a complete response rate of 6%. The efficacy of romidepsin was also evaluated in patients with relapsed or refractory PTCL in two noncomparative, multicentre, phase II trials. Intravenous romidepsin therapy was associated with overall response rates of 38% and 26% and a complete response rate of 18% and 13% in these trials. Romidepsin had an acceptable tolerability profile in clinical trials in patients with CTCL or PTCL. The most common adverse events of grade 3 or 4 severity considered at least possibly related to romidepsin were haematological or asthenic in nature, and included leukopenia, lymphopenia, granulocytopenia, thrombocytopenia, fatigue and anaemia. PMID- 21812509 TI - Dexmedetomidine: a review of its use for sedation in mechanically ventilated patients in an intensive care setting and for procedural sedation. AB - Dexmedetomidine (Precedex(r)), a pharmacologically active dextroisomer of medetomidine, is a selective alpha(2)-adrenergic receptor agonist. It is indicated in the US for the sedation of mechanically ventilated adult patients in an intensive care setting and in non-intubated adult patients prior to and/or during surgical and other procedures. This article reviews the pharmacological properties, therapeutic efficacy and tolerability of dexmedetomidine in randomized, double-blind, placebo-controlled, multicentre studies in these indications. Post-surgical patients in an intensive care setting receiving dexmedetomidine required less rescue sedation with intravenous propofol or intravenous midazolam to achieve and/or maintain optimal sedation during the assisted ventilation period than placebo recipients, according to two randomized, double-blind, multinational studies. Moreover, significantly more dexmedetomidine than placebo recipients acquired and/or maintained optimal sedation without rescue sedation. Sedation with dexmedetomidine was also effective in terms of the total dose of morphine administered, with dexmedetomidine recipients requiring less morphine than placebo recipients; with regard to patient management, dexmedetomidine recipients were calmer and easier to arouse and manage than placebo recipients. Intravenous dexmedetomidine was effective as a primary sedative in two randomized, double-blind, placebo-controlled, multicentre studies in adult patients undergoing awake fibre-optic intubation or a variety of diagnostic or surgical procedures requiring monitored anaesthesia care. In one study, significantly fewer dexmedetomidine than placebo recipients required rescue sedation with intravenous midazolam to achieve and/or maintain optimal sedation; conversely, in another study, rescue sedation with intravenous midazolam was not required by significantly more dexmedetomidine than placebo recipients. Primary sedation with intravenous dexmedetomidine was also effective in terms of the secondary efficacy endpoints, including the mean total dose of midazolam and fentanyl administered and the percentage of patients requiring further sedation (in addition to dexmedetomidine or placebo and midazolam), with, for the most part, significant between-group differences observed in favour of dexmedetomidine over placebo. In general, no significant differences were observed between the dexmedetomidine and placebo treatment groups in the anaesthesiologists' assessment of ease of intubation, haemodynamic stability, patient cooperation and/or respiratory stability. Intravenous dexmedetomidine is generally well tolerated when utilized in mechanically ventilated patients in an intensive care setting and for procedural sedation in non-intubated patients. Dexmedetomidine is associated with a lower rate of postoperative delirium than midazolam or propofol; it is not associated with respiratory depression. While dexmedetomidine is associated with hypotension and bradycardia, both usually resolve without intervention. Thus, intravenous dexmedetomidine provides a further option as a short-term (<24 hours) primary sedative in mechanically ventilated adult patients in an intensive care setting and in non-intubated adult patients prior to and/or during surgical and other procedures. PMID- 21812510 TI - Pathophysiology and therapy of cardiac dysfunction in Duchenne muscular dystrophy. AB - Cardiac dysfunction is a frequent manifestation of Duchenne muscular dystrophy (DMD) and a common cause of death for individuals with this condition. Early diastolic dysfunction and focal fibrosis proceed to dilated cardiomyopathy (DCM), complicated by heart failure and arrhythmia in most patients. Improvements in the management of respiratory insufficiency in DMD have improved lifespan and overall prognosis, but heart failure and sudden death continue to impact survival and quality of life for people with DMD. Since the specific mechanisms resulting in heart failure for people with DMD are poorly understood, current treatments are not targeted, but rely on approaches that are considered standard for DCM. These approaches include angiotensin-converting enzyme (ACE) inhibitors and beta adrenoceptor antagonists. Data from one trial in DMD support the use of ACE inhibitors before the onset of left ventricular dysfunction. Angiotensin receptor blockers have shown similar efficacy to ACE inhibitors in numerous studies of dilated cardiomyopathy, and are a good choice for patients who cannot tolerate ACE inhibition. The pathogenesis of DMD-associated cardiomyopathy may be similar to other genetic disorders of the cytoskeletal complex of ventricular myocytes, though unique features offer targeted opportunities to impact treatment. Novel areas of investigation are focused on the regulatory role of dystrophin in relation to neuronal nitric oxide synthase (nNOS) and transient receptor potential canonical channels (TRPC). Inhibition of phosphodiesterase-5 (PDE5) addresses several aspects of regulatory dysfunction induced by dystrophin deficiency, and studies with PDE5-inhibitors have shown benefits in murine models of DMD. PDE5-inhibitors are currently under investigation in at least one study in humans. This article focuses on mechanisms of cardiac dysfunction, as well as potential targets for pharmacologic manipulation to prevent or improve cardiomyopathy in DMD. PMID- 21812507 TI - Pharmacology of dipeptidyl peptidase-4 inhibitors: similarities and differences. AB - The dipeptidyl peptidase (DPP)-4 inhibitors, which enhance glucose-dependent insulin secretion from pancreatic beta cells by preventing DPP-4-mediated degradation of endogenously released incretin hormones, represent a new therapeutic approach to the management of type 2 diabetes mellitus. The 'first-in class' DPP-4 inhibitor, sitagliptin, was approved in 2006; it was followed by vildagliptin (available in the EU and many other countries since 2007, although approval in the US is still pending), saxagliptin (in 2009), alogliptin (in 2010, presently only in Japan) and linagliptin, which was approved in the US in May 2011 and is undergoing regulatory review in Japan and the EU. As the number of DPP-4 inhibitors on the market increases, potential differences among the different members of the class become important when deciding which agent is best suited for an individual patient. The aim of this review is to provide a comprehensive and updated comparison of the pharmacodynamic and pharmacokinetic properties of DPP-4 inhibitors, and to pinpoint pharmacological differences of potential interest for their use in therapy. Despite their common mechanism of action, these agents show significant structural heterogeneity that could translate into different pharmacological properties. At the pharmacokinetic level, DPP-4 inhibitors have important differences, including half-life, systemic exposure, bioavailability, protein binding, metabolism, presence of active metabolites and excretion routes. These differences could be relevant, especially in patients with renal or hepatic impairment, and when considering combination therapy. At the pharmacodynamic level, the data available so far indicate a similar glucose-lowering efficacy of DPP-4 inhibitors, either as monotherapy or in combination with other hypoglycaemic drugs, a similar weight-neutral effect, and a comparable safety and tolerability profile. Data on nonglycaemic parameters are scant at present and do not allow a comparison among DPP-4 inhibitors. Several phase III trials of DPP-4 inhibitors are currently ongoing; these trials, along with post-marketing surveillance data, will hopefully increase our knowledge about the long-term efficacy and safety of DPP-4 inhibitor therapy, the effect on pancreatic cell function and peripheral glucose metabolism, and the effect on cardiovascular outcomes in patients with type 2 diabetes. PMID- 21812511 TI - Reply to Comment on: Patterns of transfer in labour and birth in rural New Zealand. PMID- 21812512 TI - Sudden cardiac death thirty years ago and at present. The role of autonomic disturbances in acute myocardial infarction revisited. AB - The most common cause of sudden cardiac death is ventricular fibrillation (VF). In addition to the status, size and location of the ventricular focus, a major pathogenic mechanism triggering VF is autonomic dysbalance (disturbance). This term refers to a wide range of reflex changes in the ratio of sympathetic to vagal ventricular activation over time, occurring immediately after coronary artery occlusion at the onset of acute myocardial infarction (AMI). Another trigger of VF is autonomic disturbance due to emotional stress. Experimental and clinical research into autonomic disturbances associated with coronary artery occlusion and emotional stress was given considerable attention as early as some 30 years ago when researchers were already searching for ways of inhibiting autonomic disturbances using predominant sympathetic and vagal activation by beta blockers (BB) and atropine, respectively. The aim of our paper is to compare results obtained 30 years ago with current status of experimental and clinical research into SCD prevention. Another aim is to identify questions that have remained unanswered to date; answers to these outstanding questions could help further reduce the risk of SCD. PMID- 21812513 TI - The opposite polarity of the PQ segment compared to the P wave isointegral maps. AB - The aim of our work was to study the opposite polarity of the PQ segment to the P wave body surface potential maps in different groups of patients. We constructed isointegral maps (IIM) in 26 healthy controls (C), 16 hypertensives (HT), 26 patients with arterial hypertension and left ventricular hypertrophy (LVH) and 15 patients with myocardial infarction (MI). We analyzed values and positions of map extrema and compared the polarity of maps using the correlation coefficient. The IIM P maxima appeared mainly over the precordium, the minima mainly in the right subclavicular area. The highest maxima were in the MI group, being significantly higher than in the HT and LVH groups. No differences concerning any values of other extrema were significant. The IIM PQ maxima were distributed over the upper half of the chest; the minima mainly over the middle sternum. A statistically significant opposite polarity between the IIM P and IIM PQ was found in 80 % of cases. The opposite polarity of the P wave and the PQ segment was proved in isointegral body surface maps. The extrema occurred in areas not examined by the standard chest leads. This has to be considered for diagnostic purposes. PMID- 21812514 TI - The cardiovascular effects of central hydrogen sulfide are related to K(ATP) channels activation. AB - Hydrogen sulfide (H(2)S), an endogenous "gasotransmitter", exists in the central nervous system. However, the central cardiovascular effects of endogenous H(2)S are not fully determined. The present study was designed to investigate the central cardiovascular effects and its possible mechanism in anesthetized rats. Intracerebroventricular (icv) injection of NaHS (0.17~17 microg) produced a significant and dose-dependent decrease in blood pressure (BP) and heart rate (HR) (P < 0.05) compared to control. The higher dose of NaHS (17 microg, n = 6) decreased BP and HR quickly of rats and 2 of them died of respiratory paralyse. Icv injection of the cystathionine beta-synthetase (CBS) activator s-adenosyl-L methionine (SAM, 26 microg) also produced a significant hypotension and bradycardia, which were similar to the results of icv injection of NaHS. Furthermore, the hypotension and bradycardia induced by icv NaHS were effectively attenuated by pretreatment with the K(ATP) channel blocker glibenclamide but not with the CBS inhibitor hydroxylamine. The present study suggests that icv injection of NaHS produces hypotension and bradycardia, which is dependent on the K(ATP) channel activation. PMID- 21812515 TI - Voltage-dependent P/Q-type calcium channels at the frog neuromuscular junction. AB - It is well known that antagonists of N-type voltage-gated calcium channels inhibit the evoked quantal release of acetylcholine in amphibian neuromuscular synapses. This, however, does not exclude the functional expression of other types of voltage-gated calcium channels in these nerve terminals. Using immunocytochemistry, we detected the expression of the alpha1A subunit of P/Q type calcium channels (that is otherwise typical of mammalian motor nerve endings) in the frog neuromuscular junction. In addition, we demonstrated that the P/Q-type channel blocker omega-agatoxin IVA (20 nM) reduced the action potential-induced calcium transient and significantly decreased both spontaneous and evoked mediator release. Our data indicates the functional expression of P/Q type calcium channels in the frog motor nerve ending which participate in acetylcholine release. PMID- 21812516 TI - Inhibitory effect of metformin on oxidation of NADH-dependent substrates in rat liver homogenate. AB - Metformin is widely used in the treatment of Type 2 diabetes, however, mechanisms of its antihyperglycemic effect were not yet fully elucidated. Complex I of mitochondrial respiration chain is considered as one of the possible targets of metformin action. In this paper, we present data indicating that the inhibitory effect of metformin can be tested also in liver homogenate. Contrary to previous findings on hepatocytes or mitochondria under our experimental conditions, lower metformin concentrations and shorter time of preincubation give significant inhibitory effects. These conditions enable to study the mechanism of the inhibitory effect of metformin in small samples of biological material (50-100 mg wet weight) and compare more experimental groups of animals because isolation of mitochonria is unnecessary. PMID- 21812517 TI - Eye tracking using artificial neural networks for human computer interaction. AB - This paper describes an ongoing project that has the aim to develop a low cost application to replace a computer mouse for people with physical impairment. The application is based on an eye tracking algorithm and assumes that the camera and the head position are fixed. Color tracking and template matching methods are used for pupil detection. Calibration is provided by neural networks as well as by parametric interpolation methods. Neural networks use back-propagation for learning and bipolar sigmoid function is chosen as the activation function. The user's eye is scanned with a simple web camera with backlight compensation which is attached to a head fixation device. Neural networks significantly outperform parametric interpolation techniques: 1) the calibration procedure is faster as they require less calibration marks and 2) cursor control is more precise. The system in its current stage of development is able to distinguish regions at least on the level of desktop icons. The main limitation of the proposed method is the lack of head-pose invariance and its relative sensitivity to illumination (especially to incidental pupil reflections). PMID- 21812518 TI - Notch signaling may negatively regulate neonatal rat cardiac fibroblast myofibroblast transformation. AB - Cardiac fibroblast-myofibroblast transformation (CMT) is a critical event in the initiation of myocardial fibrosis. Notch signaling has been shown to regulate myofibroblast transformation from other kinds of cells. However, whether Notch signaling is also involved in CMT remains unclear. In the present study, expressions of Notch receptors in cardiac fibroblasts (CFs) were examined, effects of Notch signaling inhibitor N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S phenylglycine t-butyl ester (DAPT) and transforming growth factor-beta1 (TGF beta1) on CMT were determined by increasing alpha-smooth muscle actin (alpha-SMA) expression and collagen synthesis, and Notch signaling was examined by analyzing expressions of Notch receptors. The results showed that: (1) Notch receptor 1, 2, 3 and 4 were all expressed in CFs; (2) DAPT promoted CMT in a time-dependent manner; (3) During the period of CMT induced by TGF-beta1, expressions of Notch receptor 1, 3 and 4 in CFs were down-regulated, whereas there was no change for Notch receptor 2. Moreover, the downtrends of Notch 1, 3 and 4 were corresponding to the trend growth of alpha-SMA expression and collagen synthesis. These results suggested that inhibiting of Notch signaling might promote CMT. The down regulations of Notch receptor 1, 3 and 4 induced by TGF-beta1 may facilitate CMT. In conclusion, inhibition of Notch signaling might be a novel mechanism of CMT in myocardial fibrosis. PMID- 21812519 TI - Influence of collagen and chondroitin sulfate (CS) coatings on poly-(lactide-co glycolide) (PLGA) on MG 63 osteoblast-like cells. AB - Poly-(lactide-co-glycolide) (PLGA) is an FDA-approved biodegradable polymer which has been widely used as a scaffold for tissue engineering applications. Collagen has been used as a coating material for bone contact materials, but relatively little interest has focused on biomimetic coating of PLGA with extracellular matrix components such as collagen and the glycosaminoglycan chondroitin sulfate (CS). In this study, PLGA films were coated with collagen type I or collagen I with CS (collagen I/CS) to investigate the effect of CS on the behaviour of the osteoblastic cell line MG 63. Collagen I/CS coatings promoted a significant increase in cell number after 3 days (in comparison to PLGA) and after 7 days (in comparison to PLGA and collagen-coated PLGA). No influence of collagen I or collagen I/CS coatings on the spreading area after 1 day of culture was observed. However, the cells on collagen I/CS formed numerous filopodia and displayed well developed vinculin-containing focal adhesion plaques. Moreover, these cells contained a significantly higher concentration of osteocalcin, measured per mg of protein, than the cells on the pure collagen coating. Thus, it can be concluded that collagen I/CS coatings promote MG 63 cell proliferation, improve cell adhesion and enhance osteogenic cell differentiation. PMID- 21812520 TI - Is severe pulmonary hypertension a contraindication for orthotopic heart transplantation? Not any more. AB - Pulmonary hypertension (PH) unresponsive to pharmacological intervention is considered a contraindication for orthotopic heart transplantation (OHTX) due to risk of postoperative right-heart failure. In this prospective study, we describe our experience with a treatment strategy of improving severe PH in heart transplant candidates by means of ventricular assist device (VAD) implantation and subsequent OHTX. In 11 heart transplantation candidates with severe PH unresponsive to pharmacological intervention we implanted VAD with the aim of achieving PH to values acceptable for OHTX. In all patients we observed significant drop in pulmonary pressures, PVR and TPG (p < 0.001 for all) 3 months after VAD implantation to values sufficient to allow OHTX. Seven patients underwent transplantation (mean duration of support 216 days) while none of patients suffered right-side heart failure in postoperative period. Two patients died after transplantation and five patients are living in very good condition with a mean duration of 286 days after OHTX. In our opinion, severe PH is not a contraindication for orthotopic heart transplantation any more. PMID- 21812521 TI - Increased circulating and epicardial adipose tissue mRNA expression of fibroblast growth factor-21 after cardiac surgery: possible role in postoperative inflammatory response and insulin resistance. AB - We studied the changes in serum fibroblast growth factor-21 (FGF-21) concentrations, its mRNA, and protein expression in skeletal muscle and adipose tissue of 15 patients undergoing cardiac surgery. Blood samples were obtained: prior to initiation of anesthesia, prior to the start of extracorporeal circulation, upon completion of the surgery, and 6, 24, 48, and 96 hours after the end of the surgery. Tissue sampling was performed at the start and end of surgery. The mean baseline serum FGF-21 concentration was 63.1 (43.03-113.95) pg/ml and it increased during surgery with peak 6 hours after its end [385.5 (274.55-761.65) pg/ml, p < 0.001], and returned to baseline value [41.4 (29.15 142.83) pg/ml] 96 hours after the end of the surgery. Serum glucose, insulin, CRP, IL-6, IL-8, MCP-1, and TNF-alpha concentrations significantly increased during the surgery. Baseline FGF-21 mRNA expression in skeletal muscle was higher than in both adipose tissue depots and it was not affected by the surgery. Epicardial fat FGF-21 mRNA increased after surgery. Muscle FGF-21 mRNA positively correlated with blood glucose levels at the end of the surgery. Our data suggest a possible role of FGF-21 in the regulation of glucose metabolism and insulin sensitivity in surgery-related stress. PMID- 21812522 TI - Association of metabolic and genetic factors with cholesterol esterification rate in HDL plasma and atherogenic index of plasma in a 40 years old Slovak population. AB - We assessed association between novel biomarkers of cardiovascular disease and conventional factors in 40 years old subjects (208 men and 266 women) from the general population of Slovakia. FER(HDL) (cholesterol esterification rate in HDL plasma), AIP--Atherogenic Index of Plasma [Log(TG/HDL-C)] as markers of lipoprotein particle size, and CILP2, FTO and MLXIPL polymorphisms, were examined in relation to biomarkers and conventional risk factors. Univariate analyses confirmed correlation between AIP, FER(HDL) and the most of measured parameters. Relations between AIP and CILP2, FTO and MLXIPL were not significant. However, CILP2 was significantly related to FER(HDL) in both genders. In multivariate analysis BMI was the strongest correlate of AIP levels. In multivariate model variability of FER(HDL) was best explained by AIP (R(2) = 0.55) in both genders with still significant effect of CILP2 SNP in men. In a model where AIP was omitted, TG levels explained 43 % of the FER(HDL) variability in men, while in women HDL-C was the major determinant (42 %). In conclusions, FER(HDL) and AIP related to the known markers of cardiovascular risk provide means to express their subtle interactions by one number. Our novel finding of association between CILP2 polymorphism and FER(HDL) supports its role in lipid metabolism. PMID- 21812523 TI - Normocapnic high frequency oscillatory hyperventilation increases oxygenation in pigs. AB - High frequency oscillatory ventilation (HFOV), contrary to conventional ventilation, enables a safe increase in tidal volume (V(T)) without endangering alveoli by volutrauma or barotrauma. The aim of the study is to introduce the concept of normocapnic high frequency oscillatory hyperventilation and to assess its effect upon oxygen gain under experimental conditions. Laboratory pigs (n = 9) were investigated under total intravenous anesthesia in three phases. Phase 1: Initial volume controlled HFOV period. Phase 2: Hyperventilation--V(T) was increased by (46 +/- 12) % when compared to normocapnic V(T) during phase 1. All other ventilatory parameters were unchanged. A significant increase in PaO(2) (by 3.75 +/- 0.52 kPa, p < 0.001) and decrease in PaCO(2) (by -2.05 +/- 0.31 kPa, p < 0.001) were obtained. Phase 3: Normocapnia during hyperventilation was achieved by an iterative increase in the CO(2) fraction in the inspiratory gas by a CO(2) admixture. All ventilatory parameters were unchanged. A significant increase in PaO(2) (by 3.79 +/- 0.73 kPa, p < 0.001), similar to that which was observed in phase 2, was preserved in phase 3 whereas normocapnia was fully re-established. The concept of high frequency normocapnic hyperventilation offers a lung protective strategy that significantly improves oxygenation whilst preserving normocapnia. PMID- 21812524 TI - Preparation and characterization of tablet formulation based on solid dispersion of glimepiride and poly(ester amide) hyperbranched polymer. AB - The feasibility of incorporating a solid dispersion containing poorly soluble antidiabetic drug glimepiride and poly(ester amide) hyperbranched polymer into a tablet using a direct-compression tabletting technique was investigated. Tablet cores were additionally coated with hydroxypropyl methylcellulose phthalate in order to protect the extremely hygroscopic solid dispersion from atmospheric moisture. Preliminary stability studies show that glimepiride, which is in amorphous form within solid dispersion, is chemically stable, even if tablets are exposed to elevated temperature and/or moisture. In-vitro dissolution studies show some impact of storage conditions on the tablet cores disintegration time and, consequently, drug release rate. Glimepiride solubility also deteriorates somewhat, most probably due to its partial recrystallization. Storage conditions much less affect the physical stability of coated tablets, which was ascribed to reduced tablet hygroscopicity due to the presence of protecting coating. The hyperbranched polymers are rather new and complex macromolecules. Therefore, we addressed also the biocompatibility of hyperbranched polymer, i.e., its impact on haemolysis of the red blood cells. The concentration required for the haemolytic effect on the red blood cells is around 100-times higher than its expected gastrointestinal luminal concentration, which makes the occurrence of hyperbranched polymer mediated cytotoxicity very unlikely. PMID- 21812526 TI - Mitochondrial and cytosolic calcium in rat hearts under high-K(+) cardioplegia and pyruvate: mechano-energetic performance. AB - High-K(+)-cardioplegia (CPG) and pyruvate (Pyr) are used as cardioprotective agents. Considering that mitochondria play a critical role in cardiac dysfunction, we investigated the effect of CPG on mitochondrial Ca(2+) uptake and sarcorreticular (SR) calcium handling. Cytosolic and mitochondrial Ca(2+), as well as mitochondrial membrane potential (DeltaPsim) were assessed in rat cardiomyocytes by confocal microscopy. Mechano-calorimetrical correlation was studied in perfused hearts. CPG did not modify JC-1 (DeltaPsim), but transiently increased, by up to 1.8 times, the Fura-2 (intracellular Ca concentration, [Ca(2+)]i) and Rhod-2 (mitochondrial free Ca concentration [Ca(2+)]m) fluorescence of resting cells, with exponential decays. The addition of 5 umol.L( 1) thapsigargin (Tpg) increased the Rhod-2 fluorescence in a group of cells without any effect on the Fura-2 signal. In rat hearts perfused with CPG, 1 umol.L(-1) Tpg decreased resting heat rate (DeltaH(r): -0.44 +/- 0.07 mW.g(-1)), while the addition of 5 umol.L(-1) KB-R7943 increased resting pressure (DeltarLVP by +5.26 +/- 1.10 mm Hg; 1 mm Hg = 133.322 Pa). The addition of 10 mmol.L(-1) Pyr to CPG increased H(r) (+3.30 +/- 0.24 mW.g(-1)) and DeltarLVP (+2.2 +/- 0.4 mm Hg), which are effects potentiated by KB-R7943. The results suggest that under CPG, (i) there was an increase in [Ca(2+)]i and [Ca(2+)]m (without changing DeltaPsim) that decayed by exothermic removal mechanisms; (ii) mitochondrial Ca(2+) uptake contributed to the removal of cytosolic Ca(2+), in a process that was potentiated by inhibition of sarco-endoplasmic reticulum Ca(2+)-ATPase (SERCA), and reduced by KB-R7943; (iii) under these conditions, SERCA represents the main energetic consumer; (iv) Pyr increased the energetic performance of hearts,mainly by inducing mitochondrial metabolism. PMID- 21812525 TI - Levobupivacaine-induced contraction of isolated rat aorta is calcium dependent. AB - Levobupivacaine is a long-acting local anesthetic that intrinsically produces vasoconstriction in isolated vessels. The goals of this study were to investigate the calcium-dependent mechanism underlying levobupivacaine-induced contraction of isolated rat aorta in vitro and to elucidate the pathway responsible for the endothelium-dependent attenuation of levobupivacaine-induced contraction. Isolated rat aortic rings were suspended to record isometric tension. Cumulative levobupivacaine concentration-response curves were generated in either the presence or absence of the antagonists verapamil, nifedipine, SKF-96365, 2 aminoethoxydiphenylborate, Gd(3+), N(W)-nitro-l-arginine methyl ester (L-NAME), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), and methylene blue, either alone or in combination. Verapamil, nifedipine, SKF-96365, 2 aminoethoxydiphenylborate, low calcium concentrations, and calcium-free Krebs solution attenuated levobupivacaine-induced contraction. Gd(3+) had no effect on levobupivacaine-induced contraction. Levobupivacaine increased intracellular calcium levels in vascular smooth muscle cells. L-NAME, ODQ, and methylene blue increased levobupivacaine-induced contraction in endothelium-intact aorta. SKF 96365 attenuated calcium-induced contraction in a previously calcium-free isotonic depolarizing solution containing 100 mmol/L KCl. Levobupivacaine-induced contraction of rat aortic smooth muscle is mediated primarily by calcium influx from the extracellular space mainly via voltage-operated calcium channels and, in part, by inositol 1,4,5-trisphosphate receptor-mediated release of calcium from the sarcoplasmic reticulum. The nitric oxide - cyclic guanosine monophosphate pathway is involved in the endothelium-dependent attenuation of levobupivacaine induced contraction. PMID- 21812527 TI - Effects of 17beta-estradiol and antioxidant administration on oxidative stress and insulin resistance in ovariectomized rats. AB - The prevalence of insulin resistance syndrome increases during menopause with the overproduction of reactive oxygen species and impairment of the free radical scavenger function. Therefore, we investigated the effects of 17beta-estradiol (E(2)) and vitamin E, as an antioxidant, on lipid peroxidation and antioxidant levels in the brain cortex and liver of ovariectomized rats as well as on insulin resistance in those rats. Forty female Sprague-Dawley rats, 3 months of age and weighing 231.5 +/- 9.4 g, were divided into 4 groups: sham, ovariectomized (OVX), OVX treated with E(2) (40 ug/kg subcutaneously), and OVX treated with E(2) and vitamin E (100 mg/kg intraperitoneally). The 4 groups received the appropriate treatment every day for 8 weeks. Levels of glutathione, glutathione peroxidase, superoxide dismutase , catalase, and malondialdehyde in the brain cortex and liver of ovariectomized rats were measured. Also, fasting plasma insulin, glucose, and homeostatis model assessment of insulin resistance (HOMA-IR) were determined. Malondialdehyde increased and antioxidants (glutathione, glutathione peroxidase, catalase, superoxide dismutase) decreased in the brain cortex and liver of OVX rats. Also, fasting glucose, insulin, and HOMA-IR increased in OVX rats. E(2) and E(2) plus vitamin E decreased malondialdehyde and increased antioxidants in the brain cortex and liver of OVX rats. Moreover, they decreased fasting glucose, insulin, and HOMA-IR in ovariectomized rats. This study demonstrates that E(2) and E(2) plus vitamin E supplementation to OVX rats may improve insulin resistance, strengthen the antioxidant system, and reduce lipid peroxidation. PMID- 21812528 TI - Dissociation of the vacuolar and macroautophagic cytopathology from the cytotoxicity induced by the lipophilic local anesthetic bupivacaine. AB - Local anesthetics, like many other cationic drugs, induce a vacuolar and macroautophagic cytopathology that has been observed in vivo and in various cell types; some also induce cytotoxicity of mitochondrial origin (apoptosis and necrosis) and it is not known whether the 2 types of toxicity overlap or interact. We compared bupivacaine with a more hydrophilic agent, lidocaine, for morphological, functional, and toxicological responses in a previously exploited nonneuronal system, primary smooth muscle cells. Bupivacaine induced little vacuolization (>=2.5 mmol/L, 4 h), but elicited autophagic accumulation (>=0.5 mmol/L, 4 h) and was massively cytotoxic at 2.5-5 mmol/L (4-24 h), the latter effect being unabated by the V-ATPase inhibitor bafilomycin A1. Lidocaine exerted little cytotoxicity at and below 5 mmol/L for 24 h, but intensely induced the V ATPase-dependent vacuolar and autophagic cytopathology. Bupivacaine was more potent than lidocaine in disrupting mitochondrial potential, as judged by Mitotracker staining (significant proportions of cells affected in the 1-5 and 5 10 mmol/L concentration ranges, respectively). The addition of mitochondrial inactivating toxins antimycin A and oligomycin to lidocaine (2.5 mmol/L) reproduced the profile of bupivacaine action (low intensity of vacuolization and retained autophagic accumulation). The high potency of bupivacaine as a mitochondrial toxicant eclipses the benign vacuolar and autophagic response seen with more hydrophilic local anesthetics. PMID- 21812529 TI - Carbon dioxide enhances substance P-induced epithelium-dependent bronchial smooth muscle relaxation in Sprague-Dawley rats. AB - Hypocapnia and hypercapnia constrict and relax airway smooth muscle, respectively, through pH- and calcium (Ca(2+))-mediated mechanisms. In this study we explore a potential role for the airway epithelium in these responses to carbon dioxide (CO(2)). Contractile and relaxant responses of isolated rat bronchial rings were measured under hypocapnic, eucapnic, and hypercapnic conditions. Substance P was added to methacholine precontracted bronchial rings with and without epithelium. The role of Ca(2+) was assessed using Ca(2+)-free solutions and a Ca(2+) channel blocker, nifedipine. The effects of pH were assessed in solutions with HEPES buffer. Hypocapnic challenge increased the organ bath's pH and increased bronchial smooth muscle resting tension. This effect was abolished with HEPES buffer and partially inhibited by nifedipine. Hypocapnic conditions suppressed substance P-induced epithelium-dependent relaxation, whereas hypercapnia augmented the response. The epithelial hypocapnic effect was pH dependent, whereas the hypercapnic effect was pH independent. CO(2) had no effect on the epithelial independent smooth muscle agonists methacholine and isoproterenol. In conclusion our data indicate that, in addition to the effects of pH and Ca(2+), CO(2) affects airway smooth muscle by a pH-independent, epithelium-mediated mechanism. These findings could potentially lead to new treatments for asthma involving CO(2)-sensing receptors in the airways. PMID- 21812530 TI - The effect of alphaxalone-alphadolone, propofol, and pentobarbitone anaesthesia on the beta-endorphin and ACTH response to haemorrhage in the pig. AB - In the literature there appears to be variability in reported levels of certain hormones during haemorrhage, specifically adrenocorticotrophic hormone (ACTH) and beta-endorphin. It is possible that this variability may be due to the choice of anaesthetic. Therefore, the effect of 3 common research-only anaesthetic agents (alphaxalone-alphadolone, propofol, and pentobarbitone) on ACTH and beta endorphin levels during haemorrhage was assessed in pigs. Animals were divided into 3 groups: group I received alphaxalone-alphadolone (n = 5), group II received propofol (n = 6), and group III received pentobarbitone (n = 6). Pigs were subjected to a continuous fixed-volume haemorrhage under one of the above anaesthetics while being mechanically ventilated. ACTH and beta-endorphin levels increased significantly during haemorrhage under propofol and pentobarbitone anaesthesia but not with alphaxalone-alphadolone. For ACTH there was no significant difference between the groups, whereas for beta-endorphin there was a significant difference between the propofol- and pentobarbitone-anaesthetized pigs. The increase in heart rate during haemorrhage was significantly different between the alphaxalone-alphadolone and propofol as well as between the propofol and pentobarbitone groups. The drop in blood pressure was only significantly different between the alphaxalone-alphadolone- and propofol-anaesthetized pigs. These results indicate that the choice of anaesthetic agent can affect the hormone response to haemorrhage and may account for the variable hormone levels reported in the published literature to date. PMID- 21812531 TI - Morphometric and geometric anatomy of the caucasian orbital floor. AB - INTRODUCTION: To describe the morphometric and geometric relationships of the orbital floor in a Caucasian population. MATERIALS AND METHODS: Exenterations of 47 orbits from 24 formalin fixed cadavers were performed. Morphometric measurements were taken between anatomical landmarks located along the orbital floor and the orbital apex. The mean measurements were used to calculate geometric data. These results were analysed according to sex and side and compared to results from other ethnic populations. RESULTS: The average distances from the infraorbital foramen to the nasolacrimal fossa, inferior orbital fissure, optic canal and inferior orbital rim were 20.67 mm (+/- 2.42), 25.40 mm (+/-2.70), 43.23 mm (+/-3.35) and 8.95 mm (+/- 1.53), respectively. The average distances from the tip of the infraorbital groove to the tip of the inferior orbital fissure, lateral aspect of the inferomedial strut, optic canal and the intersection with the inferior orbital fissure were 14.08 mm (+/-2.41), 12.12 mm (+/-2.42), 35.02 mm (+/-3.17) and 20.05 mm (+/- 2.87), respectively. The distances from the tip of the inferior orbital fissure to the optic canal and the intersection with the inferior orbital groove were 29.56 mm (+/-2.73) and 13.37 mm (+/-2.76), respectively. DISCUSSION: Orbital surgeons should be aware of the morphometric relationships of the orbital floor due to the degree of variation that exists between different ethnic groups. Geometric data may be used to provide orbital surgeons with a navigational template that can be used to plan surgery and as a guide intraoperatively. PMID- 21812532 TI - Spinal cord excitability is not influenced by elevated blood lactate levels. AB - The aim of the present study was to examine the association of high blood lactate levels, induced with a maximal cycling or with an intravenous infusion, with spinal cord excitability. The study was carried out on 17 male athletes; all the subjects performed a maximal cycling test on a mechanically braked cycloergometer, while 6 of them were submitted to the intravenous infusion of a lactate solution (3 mg/kg in 1 min). Before the exercise or the injection, also at the end as well as 5 and 10 min after the conclusion, venous blood lactate was measured and excitability of the spinal alpha-motoneurons was evaluated by using the H reflex technique. In both experimental conditions, it has been observed that an exhaustive exercise is associated with a strong increase of blood lactate (but not of blood glucose) and with a significant reduction of spinal excitability. Since a similar augment of blood lactate induced by an intravenous infusion, in subjects not performing any exercise, is not associated with significant changes of spinal excitability, it can be concluded that the increase of blood lactate levels during a maximal exercise is not per se capable of modifying the excitability of spinal alpha-motoneurons. PMID- 21812533 TI - A phase I study evaluating ibritumomab tiuxetan (Zevalin(r)) in combination with bortezomib (Velcade(r)) in relapsed/refractory mantle cell and low grade B-cell non-Hodgkin lymphoma. AB - Proteasome inhibitors may inhibit DNA repair of radiation-induced strand breaks and adducts thereby making the combination of radioimmunotherapy and bortezomib a promising approach. Preclinical models demonstrate additive/synergistic effects from combining DNA damaging agents with proteasome inhibitors. This phase I trial combines ibritumomab tiuxetan with bortezomib. Twelve patients with relapsed/refractory mantle cell and low grade B-cell non-Hodgkin lymphoma were enrolled. Patients with prior radioimmunotherapy were prohibited. The maximum tolerated dose (MTD) was not reached. No dose limiting toxicities (DLTs) occurred in cohort 1 or 2. One of six patients on cohort 3 had DLTs of asthenia, dizziness and neuropathy. Grade 3/4 thrombocytopenia occurred in two patients (16%) and grade 3/4 neutropenia in three patients (25%). Five subjects (41.7%) had complete responses (CRs) and one patient had a partial response (8.3%) for an overall response rate (ORR) of 50%. The combination of standard dose ibritumomab tiuxetan and bortezomib at 1.5 mg/m(2) is well tolerated with a promising response rate. PMID- 21812534 TI - Large B-cell lymphomas with plasmablastic differentiation: a biological and therapeutic challenge. AB - Plasmablastic differentiation can be found in a variety of large B-cell lymphomas, including plasmablastic lymphoma, ALK-positive large B-cell lymphoma, primary effusion lymphoma, large B-cell lymphoma arising in human herpesvirus-8 (HHV-8)-associated multicentric Castleman disease and diffuse large B-cell lymphoma (DLBCL) with partial plasmablastic phenotype. These tumors are characterized by acquisition of the transcriptional profile of plasma cells (with overexpression of PRDM1/Blimp1 and XBP1s, in concert with extinction of the B cell differentiation program) by proliferating immunoblasts. This particular biological entity, i.e. large B-cell lymphoma with plasmablastic differentiation, is almost always associated with an aggressive clinical behavior. This review summarizes the current knowledge of the biological basis of plasmablastic differentiation in large B-cell lymphomas, the diagnostic borders with DLBCL and multiple myeloma, the associated adverse molecular events (with concomitant MYC, p53 and ALK alterations) and the potential therapeutic targets so far identified (including the unfolded protein response pathway). The highly aggressive nature of these lymphomas and the relative paucity of molecular data available highlight the need for deeper insights into the molecular pathogenesis of large B-cell lymphomas with plasmablastic differentiation in order to identify new and effective alternative treatments. PMID- 21812535 TI - Progressive multifocal leukoencephalopathy after treatment with rituximab, fludarabine and cyclophosphamide in a patient with chronic lymphocytic leukemia. PMID- 21812536 TI - Phase I clinical trial of CpG oligonucleotide 7909 (PF-03512676) in patients with previously treated chronic lymphocytic leukemia. AB - CpG oligonucleotide 7909 (CpG 7909, PF-03512676), a synthetic 24mer single stranded agonist of TLR9 expressed by B cells and plasmacytoid dendritic cells, is immunomodulatory and can cause activation-induced death of chronic lymphocytic leukemia (CLL) cells. We report a phase I study of CpG 7909 in 41 patients with early relapsed CLL. A single intravenous dose of CpG 7909 was well tolerated with no clinical effects and no significant toxicity up to 1.05 mg/kg. Single dose subcutaneous CpG 7909 had a maximum tolerated dose (MTD) of 0.45 mg/kg with dose limiting toxicity of myalgia and constitutional effects. Multiple weekly subcutaneous doses at the MTD were well tolerated. CpG 7909 administration induced immunologic changes in CLL and non-malignant cells that were dose and route dependent. We conclude that multidose therapy with subcutaneous CpG 7909 (0.45 mg/kg) could be used in future phase II combination clinical trials for CLL. PMID- 21812537 TI - Bone involvement in patients with stage IV diffuse large B-cell lymphoma: does it have a prognostic value? PMID- 21812538 TI - The unique entity of nodular lymphocyte-predominant Hodgkin lymphoma: current approaches to diagnosis and management. AB - Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare disease constituting only 3-8% of all Hodgkin lymphoma. It has a distinct histological and clinical presentation as well as significantly different natural history compared to the classical form of Hodgkin lymphoma. Presenting most often as early-stage disease, NLPHL is characterized by frequent relapses, but paradoxically an overall good prognosis. The approach to management should therefore reflect this pattern and focus on attaining prolonged remissions, with long-term follow-up paramount. Due to the rarity of the disease, few prospective data exist. Options for treatment include radiotherapy, chemotherapy or combined chemotherapy plus radiotherapy and targeted anti-CD20 antibody therapy, as well as observation in selected patients. PMID- 21812539 TI - Treatment of chronic lymphocytic leukemia requires targeting of the protective lymph node environment with novel therapeutic approaches. AB - Chronic lymphocytic leukemia (CLL) remains associated with low complete response rates and high relapse rates. This is in part due to poor understanding of CLL biology and thus inadequate targeting of therapy. For years CLL has been proposed as bi-compartmental: the quiescent tumor in the periphery and the proliferating cells within specific microenvironments. Historically the bone marrow was considered the major tissue of the CLL microenvironment. However, many recent innovative studies have categorically shown that peripheral CLL cells are derived from the lymph nodes (LN). Proliferation here is largely driven by helper T cells via CD40-CD40L engagement. Critically, in vitro studies have shown that such engagement additionally protects LN CLLs from apoptosis. Agents inducing apoptosis in non-CD40 engaged CLL cells are frequently ineffective against those continually engaged with CD40L. This emphasizes that, in order to improve responses and prevent relapse, novel therapies must be assessed against CD40L engaged CLL cells to show effective targeting against the LN. This review discusses the evidence supporting the superior involvement of the LN in CLL, how CD40L engaged CLL studies should be conducted, and the novel therapies studied in vitro and in vivo that have been proposed to be effective in this setting. PMID- 21812540 TI - A mathematical model for calculating the shelf life of ascorbic acid solution under given conditions. AB - The objective of this paper is to calculate the shelf life of ascorbic acid solution under given conditions by using a mathematical model. An antioxidant, sodium metabisulfite, was added to the ascorbic acid solution. The kinetic parameters of the degradation reaction of ascorbic acid and sodium metabisulfite, were investigated, respectively, and then a mathematical model was developed. According to the mathematical model, the calculated shelf lives of ascorbic acid solution were 783, 835, 873, and 885 days for specifications 2, 5, 10, and 20 mL, respectively. The results showed that the obtained mathematical model can be used to calculate the shelf life of ascorbic acid solution under given conditions. PMID- 21812541 TI - Physical abuse in early childhood and transition to first sexual intercourse among youth in Cape Town, South Africa. AB - This study examined the relationship of physical abuse in early childhood and timing of first sexual intercourse among young South Africans aged 14 to 22 in Cape Town. Using the Cape area panel survey and applying log-normal models, time ratios were estimated to show how rapidly or slowly youth experience first sexual intercourse. Results indicated that boys who experienced physical abuse in early childhood had faster timing to first sex. Boys and girls with violent school environments had faster timing to first sex. Race moderated the effects of physical abuse. Compared to Blacks, Coloreds who experienced higher levels of physical abuse in early childhood had faster timing to first sex. Youth with greater knowledge about HIV/AIDS and those with greater risk perception of contracting HIV/AIDS delayed first sex. On the basis of these findings, policy makers are encouraged to consider the early childhood experiences of youth when designing policies toward HIV/AIDS prevention in South Africa. PMID- 21812542 TI - Sibling sexual abuse: an empirical analysis of offender, victim, and event characteristics in National Incident-Based Reporting System (NIBRS) data, 2000 2007. AB - Sibling sexual abuse is identified as the most common form of familial sexual abuse. Extant literature is plagued by definitional inconsistencies, data limitations, and inadequate research methodology. Trivialized as "normal" sexual exploration, sibling sexual abuse has been linked to psychosocial/psychosexual dysfunction. Research has relied on retrospective, convenience, and/or homogenous samples. This work drew on eight years of National Incident-Based Reporting System data (2000-2007) to provide aggregate level baseline information. This work extended prior research exploring victim-, offender-, and incident-based characteristics. Results highlight the need for expanded definitional criteria relating to both age and gender to better inform risk assessment and prevention. Findings both corroborate and contrast prior work and suggest victim- and offender-based gender differences. PMID- 21812543 TI - Childhood sexual abuse severity reconsidered: a factor structure of CSA characteristics. AB - To address the lack of empirically grounded measures of childhood sexual abuse severity, a survey of self-report items was developed following a thorough review of the childhood sexual abuse literature. An exploratory factor analysis was conducted using data collected from a convenience sample of college students that included 275 females and males with a history of childhood sexual abuse. The solution produced seven factors interpreted as the following: (a) less intrusive forms of childhood sexual abuse (e.g., sexual invitations, kissing), (b) more intrusive forms of childhood sexual abuse (e.g., oral sex, intercourse), (c) humiliation/fear, (d) childhood sexual abuse involving photography, (e) familiarity with the perpetrator, (f) physical force/rape, and (g) active digital penetration. Correlations among these factors further suggested the existence of two relatively independent second-order factors, one based on the levels of physical intrusiveness and the other composed of the psychological/emotional factors. While arguably the most common measurement of severity, physical intrusiveness had little association with critical factors such as humiliation, fear, and association with the perpetrator. Consequently, physical intrusiveness appears to be an inadequate stand-alone measure of childhood sexual abuse severity. These results are proposed to lay the groundwork for an improved, more comprehensive measure of childhood sexual abuse severity. PMID- 21812544 TI - Differences in perceptions of child sexual abuse based on perpetrator age and respondent gender. AB - Child sexual abuse changes the lives of countless children. Child sexual abuse victims experience short and long term negative outcomes that affect their daily functioning. In this study, undergraduate students' perceptions of CSA were obtained using vignettes with an adult or child perpetrator and a general questionnaire. Results indicated participants receiving the child-on-child vignette were less likely to rate the vignette as abuse, saw the abuse as less severe, and assigned less blame to the perpetrator than participants reading the adult-on-child vignette. On a general questionnaire, male participants saw child on-child abuse as less severe and more encouraged by society than did female participants. The information can be utilized by professionals in treatment planning and preventing revictimization at disclosure. PMID- 21812545 TI - Growing up at centrepoint: retrospective accounts of childhood spent at an intentional community. AB - A qualitative analysis of the accounts of 29 adults who grew up in a controversial New Zealand community identified positive and negative experiences and their psychological implications. In addition to highly publicized child sexual abuse that occurred at Centrepoint, children also experienced parental neglect, psychological manipulation, illegal drug use and stigma from the broader society. These factors created an adverse matrix that facilitated sexual abuse. Positive experiences included support for vulnerable families and children, recreational activities, and the opportunity to develop communication skills. While there may be positive experiences for children living in intentional communities such as this one, it is important to be aware of the potential for psychological harm to children in communities with powerful, shared systems of belief, skepticism about the broader society, and strong dynamics of dependence. These findings may have implications for other similar communities operating elsewhere in the world. PMID- 21812547 TI - The association of maternal depressive symptoms with child externalizing problems: the role of maternal support following child sexual abuse. AB - This study examines the role of abuse-specific maternal support in the association between parent depressive symptoms and child externalizing problems in a sample of children with a history of sexual abuse. In total, 106 mother child dyads were studied. The association between maternal depressive symptoms and child delinquency behaviors was found to partially operate through abuse specific maternal support, which was assessed via parent report. Implications of the findings for parenting programs are discussed, and future research directions are considered. PMID- 21812546 TI - Healing from childhood sexual abuse: a theoretical model. AB - Childhood sexual abuse is a prevalent social and health care problem. The processes by which individuals heal from childhood sexual abuse are not clearly understood. The purpose of this study was to develop a theoretical model to describe how adults heal from childhood sexual abuse. Community recruitment for an ongoing broader project on sexual violence throughout the lifespan, referred to as the Sexual Violence Study, yielded a subsample of 48 women and 47 men who had experienced childhood sexual abuse. During semistructured, open-ended interviews, they were asked to describe their experiences with healing from childhood sexual abuse and other victimization throughout their lives. Constructivist grounded theory methods were used with these data to develop constructs and hypotheses about healing. For the Sexual Violence Study, frameworks were developed to describe the participants' life patterns, parenting experiences, disclosures about sexual violence, spirituality, and altruism. Several analytic techniques were used to synthesize the findings of these frameworks to develop an overarching theoretical model that describes healing from childhood sexual abuse. The model includes four stages of healing, five domains of functioning, and six enabling factors that facilitate movement from one stage to the next. The findings indicate that healing is a complex and dynamic trajectory. The model can be used to alert clinicians to a variety of processes and enabling factors that facilitate healing in several domains and to guide discussions on important issues related to healing from childhood sexual abuse. PMID- 21812548 TI - M-CAT element mediates mechanical stretch-activated transcription of B-type natriuretic peptide via ERK activation. AB - The muscle-CAT (M-CAT) promoter element is found on promoters of most muscle specific cardiac genes, but its role in cardiac pathology is poorly understood. Here we studied whether the M-CAT element is involved in hypertrophic process activated by mechanical stretch, and identified the intracellular pathways mediating the response. When an in vitro stretch model of cultured neonatal rat cardiomyocytes and luciferase reporter construct driven by rat B-type natriuretic peptide (BNP) promoter were used, mutation of M-CAT element inhibited not only the basal reporter activity (88%), but also the stretch-activated BNP transcription (58%, p < 0.001). Stretch-induced BNP promoter activation was associated with an increase in transcriptional enhancer factor-1 (TEF-1) binding activity after 24 h mechanical stretch (p < 0.05). Inhibition of mitogen activated protein kinases ERK, JNK, or p38 attenuated stretch-induced BNP activation. Interestingly, as opposed to p38 and JNK, inhibition of ERK had no additional effect on transcriptional activity of BNP promoter harboring the M-CAT mutation, suggesting a pivotal role for ERK in regulating stretch-induced BNP transcription via M-CAT binding site. Finally, immunoprecipitation studies showed that mechanical stretch induced myocyte enhancer factor-2 (MEF-2) binding to TEF 1. These data suggest a central role for M-CAT element in regulation of mechanical stretch-induced hypertrophic response via ERK activation. PMID- 21812549 TI - Bioanalysis young investigator: Meenakshi Tripathi. PMID- 21812550 TI - Interview with Niyaz Ahmad. PMID- 21812551 TI - Bioanalysis young investigator: Halil Tekin. Interview by Ali Khademhosseini and Robert S Langer. PMID- 21812552 TI - Bioanalysis young investigator: Filippos Michopoulos. PMID- 21812553 TI - Interview with Despina Kalogianni. PMID- 21812554 TI - TMS to the lateral occipital cortex disrupts object processing but facilitates scene processing. AB - The study of brain-damaged patients and advancements in neuroimaging have lead to the discovery of discrete brain regions that process visual image categories, such as objects and scenes. However, how these visual image categories interact remains unclear. For example, is scene perception simply an extension of object perception, or can global scene "gist" be processed independently of its component objects? Specifically, when recognizing a scene such as an "office," does one need to first recognize its individual objects, such as the desk, chair, lamp, pens, and paper to build up the representation of an "office" scene? Here, we show that temporary interruption of object processing through repetitive TMS to the left lateral occipital cortex (LO), an area known to selectively process objects, impairs object categorization but surprisingly facilitates scene categorization. This result was replicated in a second experiment, which assessed the temporal dynamics of this disruption and facilitation. We further showed that repetitive TMS to left LO significantly disrupted object processing but facilitated scene processing when stimulation was administered during the first 180 msec of the task. This demonstrates that the visual system retains the ability to process scenes during disruption to object processing. Moreover, the facilitation of scene processing indicates disinhibition of areas involved in global scene processing, likely caused by disrupting inhibitory contributions from the LO. These findings indicate separate but interactive pathways for object and scene processing and further reveal a network of inhibitory connections between these visual brain regions. PMID- 21812555 TI - Increased alpha (8-12 Hz) activity during slow wave sleep as a marker for the transition from implicit knowledge to explicit insight. AB - The number reduction task (NRT) allows us to study the transition from implicit knowledge of hidden task regularities to explicit insight into these regularities. To identify sleep-associated neurophysiological indicators of this restructuring of knowledge representations, we measured frequency-specific power of EEG while participants slept during the night between two sessions of the NRT. Alpha (8-12 Hz) EEG power during slow wave sleep (SWS) emerged as a specific marker of the transformation of presleep implicit knowledge to postsleep explicit knowledge (ExK). Beta power during SWS was increased whenever ExK was attained after sleep, irrespective of presleep knowledge. No such EEG predictors of insight were found during Sleep Stage 2 and rapid eye movement sleep. These results support the view that it is neuronal memory reprocessing during sleep, in particular during SWS, that lays the foundations for restructuring those task related representations in the brain that are necessary for promoting the gain of ExK. PMID- 21812556 TI - Different brain activities predict retrieval success during emotional and semantic encoding. AB - There is an increasing line of evidence supporting the idea that the formation of lasting memories involves neural activity preceding stimulus presentation. Following this line, we presented words in an incidental learning setting and manipulated the prestimulus state by asking the participants to perform either an emotional (neutral or emotional) or a semantic (animate or inanimate) decision task. Later, we tested the retrieval of each previously presented word with a recognition memory test. For both conditions, the subsequent memory effect (SME) was defined as ERP difference between subsequently remembered and forgotten words. Comparing the prestimulus SME between and within the two conditions yielded topographic differences in the time interval from -1300 to -700 msec before stimulus onset. This indicates that the activity of brain areas involved in incidental encoding of semantic information varied in the spatial distribution of ERPs, depending on the emotional and semantic requirements of the task. These findings provide evidence that there is a difference in semantic and emotional preparatory processes, which modulates successful encoding into episodic memory. This difference suggests that there are multiple task-specific functional neural systems that support memory formation. These systems differ in location and/or relative contribution of some of the brain structures that generate the measured scalp electric fields. Consequently, the cognitive processes that enable memory formation depend on the differential semantic nature of the study task and reflect differences in the preparatory processing of the multiple semantic components of a word's meaning. PMID- 21812558 TI - Neural measures of dynamic changes in attentive tracking load. AB - In everyday life, we often need to track several objects simultaneously, a task modeled in the laboratory using the multiple-object tracking (MOT) task [Pylyshyn, Z., & Storm, R. W. Tracking multiple independent targets: Evidence for a parallel tracking mechanism. Spatial Vision, 3, 179-197, 1988]. Unlike MOT, however, in life, the set of relevant targets tends to be fluid and change over time. Humans are quite adept at "juggling" targets in and out of the target set [Wolfe, J. M., Place, S. S., & Horowitz, T. S. Multiple object juggling: Changing what is tracked during extended MOT. Psychonomic Bulletin & Review, 14, 344-349, 2007]. Here, we measured the neural underpinnings of this process using electrophysiological methods. Vogel and colleagues [McCollough, A. W., Machizawa, M. G., & Vogel, E. K. Electrophysiological measures of maintaining representations in visual working memory. Cortex, 43, 77-94, 2007; Vogel, E. K., McCollough, A. W., & Machizawa, M. G. Neural measures reveal individual differences in controlling access to working memory. Nature, 438, 500-503, 2005; Vogel, E. K., & Machizawa, M. G. Neural activity predicts individual differences in visual working memory capacity. Nature, 428, 748-751, 2004] have shown that the amplitude of a sustained lateralized negativity, contralateral delay activity (CDA) indexes the number of items held in visual working memory. Drew and Vogel [Drew, T., & Vogel, E. K. Neural measures of individual differences in selecting and tracking multiple moving objects. Journal of Neuroscience, 28, 4183-4191, 2008] showed that the CDA also indexes the number of items being tracking a standard MOT task. In the current study, we set out to determine whether the CDA is a signal that merely represents the number of objects that are attended during a trial or a dynamic signal capable of reflecting on-line changes in tracking load during a single trial. By measuring the response to add or drop cues, we were able to observe dynamic changes in CDA amplitude. The CDA appears to rapidly represent the current number of objects being tracked. In addition, we were able to generate some initial estimates of the time course of this dynamic process. PMID- 21812557 TI - Discriminating between auditory and motor cortical responses to speech and nonspeech mouth sounds. AB - Several perspectives on speech perception posit a central role for the representation of articulations in speech comprehension, supported by evidence for premotor activation when participants listen to speech. However, no experiments have directly tested whether motor responses mirror the profile of selective auditory cortical responses to native speech sounds or whether motor and auditory areas respond in different ways to sounds. We used fMRI to investigate cortical responses to speech and nonspeech mouth (ingressive click) sounds. Speech sounds activated bilateral superior temporal gyri more than other sounds, a profile not seen in motor and premotor cortices. These results suggest that there are qualitative differences in the ways that temporal and motor areas are activated by speech and click sounds: Anterior temporal lobe areas are sensitive to the acoustic or phonetic properties, whereas motor responses may show more generalized responses to the acoustic stimuli. PMID- 21812559 TI - Two hemispheres for better memory in old age: role of executive functioning. AB - This experiment explored the functional significance of age-related hemispheric asymmetry reduction associated with episodic memory and the cognitive mechanisms that mediate this brain pattern. ERPs were recorded while young and older adults performed a word-stem cued-recall task. Results confirmed that the parietal old/new effect was of larger latency and reduced magnitude and less lateralized in the older group than the young group. Correlational and regression analyses indicated that the degree of laterality of brain activity determines the accuracy of memory performance and mediates age-related differences in memory performance among older participants. They also confirmed a cascade model in which the individual level of executive functioning of older adults mediates age-related differences in the degree of lateralization of brain activity, which in turn mediates age-related differences in memory performance. PMID- 21812560 TI - The bimusical brain is not two monomusical brains in one: evidence from musical affective processing. AB - Complex auditory exposures in ambient environments include systems of not only linguistic but also musical sounds. Because musical exposure is often passive, consisting of listening rather than performing, examining listeners without formal musical training allows for the investigation of the effects of passive exposure on our nervous system without active use. Additionally, studying listeners who have exposure to more than one musical system allows for an evaluation of how the brain acquires multiple symbolic and communicative systems. In the present fMRI study, listeners who had been exposed to Western-only (monomusicals) and both Indian and Western musical systems (bimusicals) since childhood and did not have significant formal musical training made tension judgments on Western and Indian music. Significant group by music interactions in temporal and limbic regions were found, with effects predominantly driven by between-music differences in temporal regions in the monomusicals and by between music differences in limbic regions in the bimusicals. Effective connectivity analysis of this network via structural equation modeling (SEM) showed significant path differences across groups and music conditions, most notably a higher degree of connectivity and larger differentiation between the music conditions within the bimusicals. SEM was also used to examine the relationships among the degree of music exposure, affective responses, and activation in various brain regions. Results revealed a more complex behavioral-neural relationship in the bimusicals, suggesting that affective responses in this group are shaped by multiple behavioral and neural factors. These three lines of evidence suggest a clear differentiation of the effects of the exposure of one versus multiple musical systems. PMID- 21812561 TI - Visual processing of contour patterns under conditions of inattentional blindness. AB - An inattentional blindness paradigm was adapted to measure ERPs elicited by visual contour patterns that were or were not consciously perceived. In the first phase of the experiment, subjects performed an attentionally demanding task while task-irrelevant line segments formed square-shaped patterns or random configurations. After the square patterns had been presented 240 times, subjects' awareness of these patterns was assessed. More than half of all subjects, when queried, failed to notice the square patterns and were thus considered inattentionally blind during this first phase. In the second phase of the experiment, the task and stimuli were the same, but following this phase, all of the subjects reported having seen the patterns. ERPs recorded over the occipital pole differed in amplitude from 220 to 260 msec for the pattern stimuli compared with the random arrays regardless of whether subjects were aware of the patterns. At subsequent latencies (300-340 msec) however, ERPs over bilateral occipital parietal areas differed between patterns and random arrays only when subjects were aware of the patterns. Finally, in a third phase of the experiment, subjects viewed the same stimuli, but the task was altered so that the patterns became task relevant. Here, the same two difference components were evident but were followed by a series of additional components that were absent in the first two phases of the experiment. We hypothesize that the ERP difference at 220-260 msec reflects neural activity associated with automatic contour integration whereas the difference at 300-340 msec reflects visual awareness, both of which are dissociable from task-related postperceptual processing. PMID- 21812563 TI - Recoding between two types of STM representation revealed by the dynamics of memory search. AB - Visual STM (VSTM) is thought to be related to visual attention in several ways. Attention controls access to VSTM during memory encoding and plays a role in the maintenance of stored information by strengthening memorized content. We investigated the involvement of visual attention in recall from VSTM. In two experiments, we measured electrophysiological markers of attention in a memory search task with varying intervals between VSTM encoding and recall, and so we were able to track recoding of representations in memory. Results confirmed the involvement of attention in VSTM recall. However, the amplitude of the N2pc and N3rs components, which mark orienting of attention and search within VSTM, decreased as a function of delay. Conversely, the amplitude of the P3 and sustained posterior contralateral negativity components increased as a function of delay, effectively the opposite of the N2pc and N3rs modulations. These effects were only observed when verbal memory was not taxed. Thus, the results suggested that gradual recoding from visuospatial orienting of attention into verbal recall mechanisms takes place from short to long retention intervals. Interestingly, recall at longer delays was faster than at short delays, indicating that verbal representation is coupled with faster responses. These results extend the orienting-of-attention hypothesis by including an account of representational recoding during short-term consolidation and its consequences for recall from VSTM. PMID- 21812564 TI - Development of functional connectivity during adolescence: a longitudinal study using an action-observation paradigm. AB - Successful interpersonal interactions rely on an ability to read the emotional states of others and to modulate one's own behavior in response. The actions of others serve as valuable social stimuli in this respect, offering the observer an insight into the actor's emotional state. Social cognition continues to mature throughout adolescence. Here we assess longitudinally the development of functional connectivity during early adolescence within two neural networks implicated in social cognition: one network of brain regions consistently engaged during action observation and another one associated with mentalizing. Using fMRI, we reveal a greater recruitment of the social-emotional network during the observation of angry hand actions in male relative to female adolescents. These findings are discussed in terms of known sex differences in adolescent social behavior. PMID- 21812562 TI - Contribution of subregions of human frontal cortex to novelty processing. AB - Novelty processing was studied in patients with lesions centered in either OFC or lateral pFC (LPFC). An auditory novelty oddball ERP paradigm was applied with environmental sounds serving as task irrelevant novel stimuli. Lesions to the LPFC as well as the OFC resulted in a reduction of the frontal Novelty P3 response, supporting a key role of both frontal subdivisions in novelty processing. The posterior P3b to target sounds was unaffected in patients with frontal lobe lesions in either location, indicating intact posterior cortical target detection mechanisms. LPFC patients displayed an enhanced sustained negative slow wave (NSW) to novel sounds not observed in OFC patients, indicating prolonged resource allocation to task-irrelevant stimuli after LPFC damage. Both patient groups displayed an enhanced NSW to targets relative to controls. However, there was no difference in behavior between patients and controls suggesting that the enhanced NSW to targets may index an increased resource allocation to response requirements enabling comparable performance in the frontal lesioned patients. The current findings indicate that the LPFC and OFC have partly shared and partly differential contributions to the cognitive subcomponents of novelty processing. PMID- 21812565 TI - When one person's mistake is another's standard usage: the effect of foreign accent on syntactic processing. AB - How do native listeners process grammatical errors that are frequent in non native speech? We investigated whether the neural correlates of syntactic processing are modulated by speaker identity. ERPs to gender agreement errors in sentences spoken by a native speaker were compared with the same errors spoken by a non-native speaker. In line with previous research, gender violations in native speech resulted in a P600 effect (larger P600 for violations in comparison with correct sentences), but when the same violations were produced by the non-native speaker with a foreign accent, no P600 effect was observed. Control sentences with semantic violations elicited comparable N400 effects for both the native and the non-native speaker, confirming no general integration problem in foreign accented speech. The results demonstrate that the P600 is modulated by speaker identity, extending our knowledge about the role of speaker's characteristics on neural correlates of speech processing. PMID- 21812567 TI - The rapid extraction of gist-early neural correlates of high-level visual processing. AB - The human cognitive system is highly efficient in extracting information from our visual environment. This efficiency is based on acquired knowledge that guides our attention toward relevant events and promotes the recognition of individual objects as they appear in visual scenes. The experience-based representation of such knowledge contains not only information about the individual objects but also about relations between them, such as the typical context in which individual objects co-occur. The present EEG study aimed at exploring the availability of such relational knowledge in the time course of visual scene processing, using oscillatory evoked gamma-band responses as a neural correlate for a currently activated cortical stimulus representation. Participants decided whether two simultaneously presented objects were conceptually coherent (e.g., mouse-cheese) or not (e.g., crown-mushroom). We obtained increased evoked gamma band responses for coherent scenes compared with incoherent scenes beginning as early as 70 msec after stimulus onset within a distributed cortical network, including the right temporal, the right frontal, and the bilateral occipital cortex. This finding provides empirical evidence for the functional importance of evoked oscillatory activity in high-level vision beyond the visual cortex and, thus, gives new insights into the functional relevance of neuronal interactions. It also indicates the very early availability of experience-based knowledge that might be regarded as a fundamental mechanism for the rapid extraction of the gist of a scene. PMID- 21812566 TI - Reduced specificity of hippocampal and posterior ventrolateral prefrontal activity during relational retrieval in normal aging. AB - Neuroimaging studies of episodic memory in young adults demonstrate greater functional neural activity in ventrolateral pFC and hippocampus during retrieval of relational information as compared with item information. We tested the hypothesis that healthy older adults--individuals who exhibit behavioral declines in relational memory--would show reduced specificity of ventrolateral prefrontal and hippocampal regions during relational retrieval. At study, participants viewed two nouns and were instructed to covertly generate a sentence that related the words. At retrieval, fMRIs were acquired during item and relational memory tasks. In the relational task, participants indicated whether the two words were previously seen together. In the item task, participants indicated whether both items of a pair were previously seen. In young adults, left posterior ventrolateral pFC and bilateral hippocampal activity was modulated by the extent to which the retrieval task elicited relational processing. In older adults, activity in these regions was equivalent for item and relational memory conditions, suggesting a reduction in ventrolateral pFC and hippocampal specificity with normal aging. PMID- 21812568 TI - Human dorsal striatum encodes prediction errors during observational learning of instrumental actions. AB - The dorsal striatum plays a key role in the learning and expression of instrumental reward associations that are acquired through direct experience. However, not all learning about instrumental actions require direct experience. Instead, humans and other animals are also capable of acquiring instrumental actions by observing the experiences of others. In this study, we investigated the extent to which human dorsal striatum is involved in observational as well as experiential instrumental reward learning. Human participants were scanned with fMRI while they observed a confederate over a live video performing an instrumental conditioning task to obtain liquid juice rewards. Participants also performed a similar instrumental task for their own rewards. Using a computational model-based analysis, we found reward prediction errors in the dorsal striatum not only during the experiential learning condition but also during observational learning. These results suggest a key role for the dorsal striatum in learning instrumental associations, even when those associations are acquired purely by observing others. PMID- 21812569 TI - When "it" becomes "mine": attentional biases triggered by object ownership. AB - Previous research has demonstrated that higher-order cognitive processes associated with the allocation of selective attention are engaged when highly familiar self-relevant items are encountered, such as one's name, face, personal possessions and the like. The goal of our study was to determine whether these effects on attentional processing are triggered on-line at the moment self relevance is established. In a pair of experiments, we recorded ERPs as participants viewed common objects (e.g., apple, socks, and ketchup) in the context of an "ownership" paradigm, where the presentation of each object was followed by a cue indicating whether the object nominally belonged either to the participant (a "self" cue) or the experimenter (an "other" cue). In Experiment 1, we found that "self" ownership cues were associated with increased attentional processing, as measured via the P300 component. In Experiment 2, we replicated this effect while demonstrating that at a visual-perceptual level, spatial attention became more narrowly focused on objects owned by self, as measured via the lateral occipital P1 ERP component. Taken together, our findings indicate that self-relevant attention effects are triggered by the act of taking ownership of objects associated with both perceptual and postperceptual processing in cortex. PMID- 21812570 TI - Frontal oscillatory dynamics predict feedback learning and action adjustment. AB - Frontal oscillatory dynamics in the theta (4-8 Hz) and beta (20-30 Hz) frequency bands have been implicated in cognitive control processes. Here we investigated the changes in coordinated activity within and between frontal brain areas during feedback-based response learning. In a time estimation task, participants learned to press a button after specific, randomly selected time intervals (300-2000 msec) using the feedback after each button press (correct, too fast, too slow). Consistent with previous findings, theta-band activity over medial frontal scalp sites (presumably reflecting medial frontal cortex activity) was stronger after negative feedback, whereas beta-band activity was stronger after positive feedback. Theta-band power predicted learning only after negative feedback, and beta-band power predicted learning after positive and negative feedback. Furthermore, negative feedback increased theta-band intersite phase synchrony (a millisecond resolution measure of functional connectivity) among right lateral prefrontal, medial frontal, and sensorimotor sites. These results demonstrate the importance of frontal theta- and beta-band oscillations and intersite communication in the realization of reinforcement learning. PMID- 21812571 TI - The neurotopography of written word production: an fMRI investigation of the distribution of sensitivity to length and frequency. AB - This research is directed at charting the neurotopography of the component processes of the spelling system by using fMRI to identify the neural substrates that are sensitive to the factors of lexical frequency and word length. In spelling, word frequency effects index orthographic long-term memory whereas length effects, as measured by the number of letters, index orthographic working memory (grapheme buffering). Using the task of spelling to dictation in the scanner, we found a highly differentiated neural distribution of sensitivity to the factors of length and lexical frequency, with areas exhibiting sensitivity to length but not frequency and vice versa. In addition, a direct comparison with the results of a previous study [Rapp, B., & Lipka, K. The literate brain: The relationship between spelling and reading. Journal of Cognitive Neuroscience, 23, 1180-1197, 2011] that used a very different spelling task yielded a converging pattern of findings regarding the neural substrates of the central components of spelling. Also, with regard to relationship between reading and spelling, we replicated previous functional neuroimaging studies that have shown overlapping regions of activation in the left posterior inferior frontal gyrus and midfusiform gyrus for word reading and spelling. PMID- 21812572 TI - Role of Broca's area in implicit motor skill learning: evidence from continuous theta-burst magnetic stimulation. AB - Complex actions can be regarded as a concatenation of simple motor acts, arranged according to specific rules. Because the caudal part of the Broca's region (left Brodmann's area 44, BA 44) is involved in processing hierarchically organized behaviors, we aimed to test the hypothesis that this area may also play a role in learning structured motor sequences. To address this issue, we investigated the inhibitory effects of a continuous theta-burst TMS (cTBS) applied over left BA 44 in healthy subjects, just before they performed a serial RT task (SRTT). SRTT has been widely used to study motor skill learning and is also of interest because, for complex structured sequences, subjects spontaneously organize them into smaller subsequences, referred to as chunks. As a control, cTBS was applied over the vertex in another group, which underwent the same experiment. Control subjects showed both a general practice learning effect, evidenced by a progressive decrease in RT across blocks and a sequence-specific learning effect, demonstrated by a significant RT increase in a pseudorandom sequence. In contrast, when cTBS was applied over left BA 44, subjects lacked both the general practice and sequence-specific learning effects. However, surprisingly, their chunking pattern was preserved and remained indistinguishable from controls. The present study indicates that left BA 44 plays a role in motor sequence learning, but without being involved in elementary chunking. This dissociation between chunking and sequence learning could be explained if we postulate that left BA 44 intervenes in high hierarchical level processing, possibly to integrate elementary chunks together. PMID- 21812573 TI - Measurement of the midpalatal suture width. AB - OBJECTIVE: To conduct a pilot study to investigate the potentiality to determine the midpalatal sutural width radiographically with a flat-panel volume computed tomography (fpVCT) in a porcine model. MATERIALS AND METHODS: Bone samples from the midpalatal suture of five young (16 weeks) and five old (200 weeks) sus scrofa domestica were gathered. The midpalatal suture width was measured via fpVCT and compared to respective histological preparations. Results with P < .05 were considered significant. RESULTS: The data obtained by fpVCT and by histomorphometric analysis reveal a highly significant age dependency of the measured suture width (both P < .0001), with lower suture width values in older subjects compared to the younger group. The averaged suture widths measured in the fpVCT images shows a distinctively higher mean compared to the histomorphometric data with high statistical significance (P < .0001). The evaluated difference between both methods was almost constant. CONCLUSION: fpVCT is a powerful tool for determining midpalatal sutural width. PMID- 21812574 TI - Effects of washer on the stress distribution of mini-implant. AB - OBJECTIVE: To investigate the biomechanical effects of 'washer' designed for improving mini-implant stability. MATERIALS AND METHODS: Four three-dimensional finite element models of the mini-implant and surrounding bone were constructed with washers in different spike lengths (1.5 mm, 2.0 mm, and 2.5 mm). The force was applied in two directions (45 degrees and 90 degrees ). The stress distribution on surrounding bone and the displacement of the mini-implant were analyzed. Plots of tensile stress, compression stress, and displacement were calculated, and maximum values in each category were analyzed. RESULTS: The stress distribution was different between the models with washer and without washer. However, no remarkable differences in stress distribution were observed among the models with washer, regardless of spike length. A significantly greater displacement value was observed in the model without washer compared to the models with washer, but no notable difference in displacement value was found among the models with washer. The plots of the displacement distribution of the models with washer presented notable pattern differences as compared with that of the model without washer. CONCLUSION: With the use of the washer, a more homogeneous distribution of bone stress and less displacement of the mini-implant can be achieved. PMID- 21812575 TI - New details on the clefted uvular muscle: analyzing its role at histological scale by model-based deformation analyses. AB - OBJECTIVE: As an initial step to a complex reconstruction model for virtual surgery, the present study was carried out to provide data on the prenatal cleft lip and palate uvular muscle in eight specimens. METHOD: Serial sections of viscerocrania of 18 aborted embryos and fetuses were studied microscopically and segmented manually. Registration, three-dimensional reconstruction, and finite element analyses were conducted. RESULTS: Incompletely clefted uvulae showed anterior fusion and dorsal fission of the bilateral uvular muscle bodies. A complete cleft lip and palate specimen evidenced single bilateral uvular muscle bodies lying medially and orally below the cleft shelf, its central longitudinal fibers running beneath the oral-median mucosa. In incompletely clefted uvulae, 10% to 50% of circular peripheral fibers crossed the midline within the central third of the anterioposterior muscle, behind the levator loop. Of the fibers, 30% to 60% crossed to the ipsilateral palatopharyngeus muscle. Fibers inserted into the uvular basal membrane in a 60% nasal and 40% oral distribution at the middle third of the macroscopically clefted uvula. The macroscopic uvula itself consisted of loose connective tissue and salivary glands. Deformation analysis did disclose local stress, suggesting the uvular muscle contributes to velopharyngeal closure in normal anatomy and extends the cleft edges in cleft palate. CONCLUSION: Cleft lip and palate reconstruction should reasonably use the uvular muscle to augment the velar midline bulk. Uvular muscle deformation calculation was successful, permitting functional insight on the basis of microanatomical specimens, so far a bigger complete velar model can be ventured. PMID- 21812577 TI - Computational and mathematical methods in medicine. PMID- 21812576 TI - Growth hormone and outcome in patients with intracerebral hemorrhage: a pilot study. AB - BACKGROUND: Endocrine alterations of the hypothalamic-pituitary-axis are one of the first measurable physiological changes in cerebral insults. During acute stress, human growth hormone (GH) is stimulated and has shown to have a prognostic value in various diseases. Within this pilot study, we evaluated the prognostic value of GH in patients with acute intracerebral hemorrhage (ICH). METHODS: In a prospective observational study in 40 consecutive patients with ICH, GH was measured on admission. The prognostic value of GH to predict 30-day mortality and 90-day functional outcome was assessed. Favorable functional outcome was defined as Barthel Index score >85 points and Modified Rankin Scale <3 points. RESULTS: GH levels were increased in patients who died within 30 days as compared to survivors (0.45 (IQR 0.20-1.51) vs. 1.51 (IQR 0.91-4.08) p = 0.03), and in patients with an unfavorable functional outcome as compared to patients with a favorable functional outcome after 90 days 0.28 (IQR 0.16-0.61) vs. 0.78 (IQR 0.31-1.99) p = 0.03). For mortality prediction, receiver-operating characteristics revealed an area under the curve (AUC) on admission for GH of 0.78 (95% CI 0.60-0.96), which was in the range of the Glasgow Coma Score (GCS) (AUC 0.82 (95% CI 0.59-1.00) p = 0.80). For functional outcome prediction, GH had an AUC of 0.71 (95% CI 0.54-0.87), which was statistically not different from the GCS (AUC 0.81 (95% CI 0.68-0.94) p = 0.36). CONCLUSIONS: In our small cohort of patients with acute ICH, elevated GH level were associated with increased mortality and worse outcome. If confirmed in a larger study, GH levels may be used as an additional prognostic factor in ICH patients. (ClincalTrials.gov number NCT00390962). PMID- 21812578 TI - Modelling the hepatitis C with different types of virus genome. AB - Hepatitis C virus (HCV) is one of the leading known causes of liver disease in the world. The HCV is a single-stranded RNA virus. The genomes of HCV display significant sequence heterogeneity and have been classified into types and subtypes. Types from 1 to 11 have so far been recognized, each type having a variable number of subtypes. It has been confirmed that 90% approximately of the isolates HCV infections in Egypt belong to a single subtype (4a) [10]. In this paper, we construct a mathematical model to study the spread of HCV-subtype 4a amongst the Egyptian population. The relation between HCV-subtype 4a and the other subtypes has also been studied. The values of reproduction numbers R (01), R (02) have been derived [5]. Also, threshold conditions for the value of the transmission rates k (1) and k (02), in terms of R (01), R (02) and the mutation factor MU have been determined to insure that the disease will die out. If the conditions fail to happen the disease takes off and becomes endemic. PMID- 21812579 TI - A mathematical model for the dynamics of HIV/AIDS with gradual behaviour change. AB - An HIV/AIDS model that incorporates gradual behaviour change is formulated with a variable force of infection for the adult population. The variability is modelled using a general function of time since introduction of the initial infective and exemplified for three specific functions. Expressions for the time taken for the reproductive number to reduce to unity and expressions for the time taken to attain a stationary steady state are deduced and discussed. Model projections for urban, peri-urban and rural Uganda are compared with corresponding antenatal clinic sites prevalence trends. The analysis shows that the dramatic decline in HIV prevalence in Uganda in the early 1990s was only possible through drastic declines in the force of infection. Since prevalence was high and reductions in frequency of sexual acts was minimal, the huge reduction could be attributed to reductions in probability of transmission per sexual act probably due to increased selective condom use among high risk sexual partnerships since overall condom use was low. PMID- 21812580 TI - Mathematical model for HIV/AIDS with complacency in a population with declining prevalence. AB - An HIV/AIDS model incorporating complacency for the adult population is formulated. Complacency is assumed a function of number of AIDS cases in a community with an inverse relation. A method to find the equilibrium state of the model is given by proving a stated theorem. An example to illustrate use of the theorem is also given. Model analysis and simulations show that complacency resulting from dependence of HIV transmission on number of AIDS cases in a community leads to damped periodic oscillations in the number of infectives with oscillations more marked at lower rates of progression to AIDS. The implications of these results to public health with respect to monitoring the HIV/AIDS epidemic and widespread use of antiretroviral (ARV) drugs is discussed. PMID- 21812581 TI - Mathematical and biological modelling of RNA secondary structure and its effects on gene expression. AB - Secondary structures within the 5' untranslated regions of messenger RNAs can have profound effects on the efficiency of translation of their messages and thereby on gene expression. Consequently they can act as important regulatory motifs in both physiological and pathological settings. Current approaches to predicting the secondary structure of these RNA sequences find the structure with the global-minimum free energy. However, since RNA folds progressively from the 5' end when synthesised or released from the translational machinery, this may not be the most probable structure. We discuss secondary structure prediction based on local-minimisation of free energy with thermodynamic fluctuations as nucleotides are added to the 3' end and show that these can result in different secondary structures. We also discuss approaches for studying the extent of the translational inhibition specified by structures within the 5' untranslated region. PMID- 21812582 TI - Effect of allocated radiotherapy after breast surgeries over death risk in early breast cancer patients: a meta-analysis. AB - Meta-analysis is a widely used tool to synthesize the results of a set of primary studies leading to more powerful conclusions than those provided by isolated ones. To evaluate the effect of allocated radiotherapy, types of breast surgery and other risk factors over death risk in early breast cancer patients, we carried out a meta-analysis using logistic regression attending to the dichotomous character of the outcome. Our findings suggest that the type of breast surgery is an effect modifier of the risk factors over death in early breast cancer patients. The effect of allocated radiotherapy is associated with a less risk of death only for patients who had mastectomy plus axillary sampling. The effect of a systemic treatment is not associated with death risk for patients who had breast conservation, on the contrary it is associated for those patients with mastectomy alone and with mastectomy with axillary clearance. PMID- 21812583 TI - Amplitude suppression and chaos control in epileptic EEG signals. AB - In this paper we have proposed a novel amplitude suppression algorithm for EEG signals collected during epileptic seizure. Then we have proposed a measure of chaoticity for a chaotic signal, which is somewhat similar to measuring sensitive dependence on initial conditions by measuring Lyapunov exponent in a chaotic dynamical system. We have shown that with respect to this measure the amplitude suppression algorithm reduces chaoticity in a chaotic signal (EEG signal is chaotic). We have compared our measure with the estimated largest Lyapunov exponent measure by the largelyap function, which is similar to Wolf's algorithm. They fit closely for all but one of the cases. How the algorithm can help to improve patient specific dosage titration during vagus nerve stimulation therapy has been outlined. PMID- 21812584 TI - Paroxysmal sympathetic hyperactivity after acquired brain injury: a review of diagnostic criteria. AB - PRIMARY OBJECTIVE: To evaluate the development and usage of diagnostic criteria for paroxysmal sympathetic hyperactivity (PSH) following acquired brain injury (ABI), then comparatively analyse published criteria. RESEARCH DESIGN: Systematic literature review. METHODS AND PROCEDURES: Literature published in English language prior to 30 November 2008 was reviewed for dysautonomic syndromes following ABI, characterized by simultaneous paroxysmal autonomic hyperactivity and motor over-activity. MAIN OUTCOME AND RESULTS: Sixty papers presenting 349 cases of PSH were identified, with a further 21 papers providing additional information regarding the condition. Only 27 of these 81 papers (33%) utilized diagnostic criteria. There were nine novel or substantially modified diagnostic criteria sets, which were analysed further. Criteria showed strong agreement on core clinical features of PSH-heart rate (HR), blood pressure, respiratory rate, temperature, sweating, and motor hyperactivity. Most criteria sets utilized a polythetic diagnostic system and all but one indicated severity thresholds, e.g. HR >120 beats per minute. Two papers specified a minimum episode frequency and four papers required a minimum syndrome duration. CONCLUSIONS: Of necessity, diagnostic criteria have been developed ad hoc. The differences between criteria complicate both clinical diagnosis and the process of comparing research cohorts. These findings demarcate the need for a single set of PSH diagnostic criteria and provide the substrate for scientific consensus. PMID- 21812585 TI - Incidence and risk factors of early post-traumatic seizures in Nigerians. AB - OBJECTIVES: To determine the incidence and risk factors of early post-traumatic seizures (PTS) in Nigerian subjects. METHODS: Subjects were recruited consecutively, classified as mild, moderate or severe traumatic brain injury (TBI), and followed for 168 hrs for development of seizures. RESULTS: There were 266 subjects, 213 (80%) males and 53 (20%) females, with mean age 31 years (sd 18, range 1-80, median 30). Causes of TBI were motor traffic accident (MTA) related in 217 (82%), falls in 25 (9%), struck by objects in 15 (5%), firearms in 4 (2%), sports and recreation in 3 (1%), and failed suicide in 2 (1%). Cumulative incidence of early PTS was 1190/00 (95% CI 80-156). Risk factors were age <=12 years, severity of TBI, history of seizures, and TBI at weekend, but gender and GCS were not. Skeletomotor palsy was independently associated with early PTS. CONCLUSIONS: Incidence of early PTS is high in this population, probably due to the relatively high proportion of severe TBI. Risk factors are TBI severity, young age, history of seizures, and TBI at weekends. The best preventive strategy is reduction of MTA, which causes over 80% of TBI. Prophylactic anti-seizure therapy may benefit subjects with severe TBI and skeletomotor deficits. PMID- 21812586 TI - Clinical usefulness of diffusion tensor imaging in patients with transtentorial herniation following traumatic brain injury. AB - PRIMARY OBJECTIVE: This study investigated the clinical usefulness of diffusion tensor tractography (DTT) for elucidation of the corticospinal tract (CST) state in patients with transtentorial herniation (TH) following traumatic brain injury (TBI). METHODS AND PROCEDURES: Eleven consecutive patients with TH were recruited among 175 patients with TBI. Patients who showed TH were classified into two groups according to DTT findings: Group 1: the integrity of CST was preserved, Group 2: the integrity of CST was disrupted at the cerebral peduncle (CP) or pons. OUTCOMES AND RESULTS: Five patients belonged to Group 1 of TH, six patients to Group 2 of TH. On DTT of Group 1, fractional anisotropy values of the CP and pons along the CST in the affected hemisphere were lower than those of the unaffected hemisphere; however, the difference was not significant (p > 0.05). In Group 2, fractional anisotropy values of the CP and pons in the affected hemisphere were significantly lower than those of the unaffected hemisphere (p < 0.05). CONCLUSIONS: It was found that DTT is useful in evaluation of the presence and the severity of CST injury in patients with TH following TBI. PMID- 21812587 TI - Discourse information content in non-aphasic adults with brain injury: a pilot study. AB - BACKGROUND: The functional evaluation of discourse informativeness is widely used in both clinical practice and research, and impoverished and confused discourse has been described in individuals with traumatic brain injury (TBI). These symptoms have been related to language processing deficits at the macrolinguistic level. However, the functional counterpart of these deficits, i.e. poor informativeness in standardized analysis of elicited speech samples, has been less explored. METHODS AND PROCEDURES: In this pilot study, samples of narrative discourse from 10 non-aphasic TBI adults and 28 healthy adults were examined to study the relationship between standardized measures of informativeness (i.e. Correct Information Unit analysis) and language processing errors at the macrolinguistic level and to compare performance of the two groups. MAIN OUTCOMES AND RESULTS: The participants with TBI did not produce relevant within-sentence errors and information content of their narratives was not different from that of the healthy participants. However, their production of errors of cohesion, local coherence and global coherence was significantly greater. These macrolinguistic errors corresponded to reduced levels of information efficiency (% CIUs score). CONCLUSIONS: Functional measures of speech informativeness such as the CIU scores may be useful for the clinical assessment of discourse processing deficits in TBI individuals without aphasic symptoms. PMID- 21812588 TI - Interdisciplinary rehabilitation of mild TBI and PTSD: a case report. AB - BACKGROUND: Prevalence of mild traumatic brain injury (mTBI) or concussion on the battlefield in Iraq/Afghanistan has resulted in its designation as a 'signature injury'. Civilian studies have shown that negative expectations for recovery may lead to worse outcomes. While there is concern that concussion screening procedures in the Veteran's Affairs Healthcare System and the Department of Defence could fuel negative expectations, leading to negative iatrogenic effects, it has been difficult to document this in clinical settings. The aim of this report is to describe the case of a veteran with comorbid mTBI/PTSD with persistent symptoms of unknown aetiology and the effects of provider communications on the patient's recovery. METHODS: Case report of a veteran with reported mTBI, including provider communications, neuropsychological test results and report of functioning after changes in provider messages. RESULTS: Two-years post-mTBI, the patient attributed cognitive difficulties to his brain injury, but neuropsychological assessment found that his cognitive profile was consistent with psychological rather than neurological dysfunction. After providers systematically emphasized expectations of recovery, the patient's daily functioning improved. CONCLUSIONS: This case illustrates difficulties in mass screening for and treating mTBI. Recommendations for improvement include clinician training in effectively communicating positive expectations of recovery after concussion. PMID- 21812589 TI - Letter to the editor. Traumatic brain injury--in prisoners and in the community. PMID- 21812593 TI - Can you see me in the snow? Action simulation aids the detection of visually degraded human motion. AB - Using a novel paradigm, we demonstrate that action simulation can directly facilitate ongoing perception of people's movements. Point-light actors (PLAs) representing common human motions were shown embedded in a visual noise reminiscent of "TV snow". At first, the PLAs were perceived clearly, then occluded from view for a short duration, during which it was hypothesized that a real-time action simulation was generated tracking the motion's course. The PLA then reappeared in motion at variable visibility against the noise, whilst detection thresholds for the reappearance were measured. In the crucial manipulation, the test motion was either temporally congruent with the motion as it would have continued during occlusion, and thus temporally matching the simulation, or temporally incongruent. Detection thresholds were lower for congruent than for incongruent reappearing motions, suggesting that reappearing motion that temporally matched the internal action simulation was more likely to be detected. PMID- 21812592 TI - The ratio of a urinary tobacco-specific lung carcinogen metabolite to cotinine is significantly higher in passive than in active smokers. AB - 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol plus its glucuronides (total NNAL), metabolites of the lung carcinogen NNK, and total cotinine, metabolites of nicotine, are biomarkers of active and passive cigarette smoking. We calculated the total NNAL:total cotinine (*10(3)) ratio in 408 passive (infants, children, and adults) and 1088 active smokers. The weighted averages were 0.73 (95% confidence interval 0.71, 0.76) for passive smokers and 0.07 (0.06, 0.08) for active smokers (p < 0.0001). These results demonstrate that cotinine measurements may underestimate exposure of passive smokers to the lung carcinogen NNK in second-hand cigarette smoke. The total NNAL:total cotinine (*10(3)) ratio may provide an improved biomarker for evaluating the health effects of passive smoking. PMID- 21812594 TI - The other-race effect does not rely on memory: Evidence from a matching task. AB - Viewers are typically better at remembering faces from their own race than from other races; however, it is not yet established whether this effect is due to memorial or perceptual processes. In this study, UK and Egyptian viewers were given a simultaneous face-matching task, in which the target faces were presented upright or upside down. As with previous research using face memory tasks, participants were worse at matching other-race faces than own-race faces and showed a stronger face inversion effect for own-race faces. However, subjects' performance on own and other-race faces was highly correlated. These data provide strong evidence that difficulty in perceptual encoding of unfamiliar faces contributes substantially to the other-race effect and that accounts based entirely on memory cannot capture the full data. Implications for forensic settings are also discussed. PMID- 21812591 TI - Biomaterials for the development of peripheral nerve guidance conduits. AB - Currently, surgical treatments for peripheral nerve injury are less than satisfactory. The gold standard of treatment for peripheral nerve gaps >5 mm is the autologous nerve graft; however, this treatment is associated with a variety of clinical complications, such as donor site morbidity, limited availability, nerve site mismatch, and the formation of neuromas. Despite many recent advances in the field, clinical studies implementing the use of artificial nerve guides have yielded results that are yet to surpass those of autografts. Thus, the development of a nerve guidance conduit, which could match the effectiveness of the autologous nerve graft, would be beneficial to the field of peripheral nerve surgery. Design strategies to improve surgical outcomes have included the development of biopolymers and synthetic polymers as primary scaffolds with tailored mechanical and physical properties, luminal "fillers" such as laminin and fibronectin as secondary internal scaffolds, surface micropatterning, stem cell inclusion, and controlled release of neurotrophic factors. The current article highlights approaches to peripheral nerve repair through a channel or conduit, implementing chemical and physical growth and guidance cues to direct that repair process. PMID- 21812595 TI - The intake of grain fibers modulates cytokine levels in blood. AB - Dietary fiber may modulate the environment of the intestinal lumen, alter the intestinal microflora populations, and influence the immune response and disease risk. Epidemiological investigations have suggested that higher fiber intake is associated with lower overall mortality, in particular from cardiovascular and digestive tract diseases. Here a panel of 17 cytokines and chemokines were measured in plasma of 88 cancer-free subjects sampled within the Italian EPIC Italy cohort. A statistically significant inverse association (p-trend = 0.01) was observed for cereal fiber and cytokines included in the main factor in factor analysis (IL-1beta, IL-4, IL-5, IL-6, IL-13, and TNF-alpha), which alone explained 35.5% of variance. Our study suggests that fiber intake, especially cereal fiber, may be associated with a decreased level of pro-inflammatory cytokines. PMID- 21812599 TI - Ask George. PMID- 21812600 TI - Counterfeits threaten patient safety. PMID- 21812601 TI - Education 101: how to improve your department's training program. PMID- 21812602 TI - Departments may find money in outside services. PMID- 21812603 TI - A human factors perspective: auditory alarm signals. PMID- 21812604 TI - Designing effective alarm sounds. PMID- 21812605 TI - Guidelines from 80001: maintaining a medical IT network. PMID- 21812606 TI - How to manage effectively as you climb the ladder. PMID- 21812607 TI - Working together: manufacturers' instructions crucial to sterilization. PMID- 21812608 TI - Medtronic executive cites challenge of technology access. PMID- 21812609 TI - Automated system tracks clinician support calls. PMID- 21812610 TI - Don't be shy and retiring with old equipment. PMID- 21812611 TI - Tissue processors. PMID- 21812612 TI - Staffing metrics: a case study. PMID- 21812614 TI - Security concerns offer opportunities. PMID- 21812615 TI - Questions, as well as answers, are worth sharing. PMID- 21812616 TI - Surgical beds and hyper/hypothermia units. PMID- 21812617 TI - Blood trauma testing for mechanical circulatory support devices. AB - Preclinical hemolysis testing is a critical requirement toward demonstrating device safety for U.S. Food and Drug Administration (FDA) 510(k) approval of mechanical circulatory support devices (MCSD). FDA and ASTM (formerly known as the American Society for Testing and Materials) have published guidelines to assist industry with developing study protocols. However, there can be significant variability in experimental procedures, study design, and reporting of data that makes comparison of test and predicate devices a challenge. To overcome these limitations, we present a hemolysis testing protocol developed to enable standardization of hemolysis testing while adhering to FDA and ASTM guidelines. Static mock flow loops primed with fresh bovine blood (600 mL, Hematocrit = 27+/-5%, heparin titrated for ACT >300 sec) from a single-source donor were created as a platform for investigating test and predicate devices. MCSD differential pressure and temperature were maintained at 80 mmHg and 25 degrees +/-2 degrees C. Blood samples (3 ml) were collected at 0, 5, 90, 180, 270, 360 minutes to measure CBC and plasma free hemoglobin. This protocol led to 510(k) approval of two adult MCSD and has been used to test novel cannulae and a pediatric MCSD. Standardization of hemolysis testing procedures and transparency of results may enable better blood trauma characterization of MCS devices to facilitate the FDA 510(k) and PMA submission processes and improve clinical outcomes. PMID- 21812618 TI - Should CBET stand for computing and biomedical equipment technician? PMID- 21812619 TI - Tailored therapy for heart failure: neurohormones. AB - Plasma B type cardiac natriuretic peptides reflect cardiac structure and function and have proven roles in assisting in the diagnosis of acute heart failure. They are also powerful independent prognostic indicators across the full spectrum of cardiovascular disease. The efficacy of serial measurements of plasma B type peptides in guiding titration of therapy for chronic heart failure has been the subject of a number of randomized controlled trials. These are summarized in the following brief review. In the decade 2000-2010, 8 trials have been completed. Study design, the characteristics of the heart failure population studied, duration of follow-up, the exact end points recorded, and target peptide levels pursued all differ somewhat between trials. However, an overall consistency is emerging, supported by 2 metaanalyses. In aggregate, the existing trial data suggest that adjustment of treatment in chronic heart failure according to serial B type peptide measurements used in conjunction with established clinical methods is likely to reduce cardiac mortality and admissions with heart failure, at least in those patients aged under 75 years with impaired left ventricular systolic function. PMID- 21812620 TI - Modified magnesium and lipoproteins in children with attention deficit hyperactivity disorder (ADHD). AB - OBJECTIVE: Polyunsaturated fatty acids (PUFAs) have shown to be helpful in the therapy of ADHD. Various stabilizing co-factors may contribute to this effect, as like magnesium (Mg). Mg supports fatty acid enzyme activity and is essential for the neuronal activity. However, the way of Mg to influence psychic processes, particularly in ADHS, is not yet known precisely. Therefore, in this study the concentrations of further lipid parameters were assessed. We intended to prove, if there is a lack of Mg and someone different lipoprotein concentration in ADHD patients compared to controls. METHODS: In nine boys with ADHD (8.2 +/- 0.6 years) and 11 controls (7.9 +/- 0.87 years), blood serum Mg, total cholesterol, triglycerides, Lipoprotein Lipase, total Phospholipids, Apolipoproteins a and b, HDL- and LDL-cholesterol were measured, under two different stressful conditions. RESULTS: In ADHD, Mg and HDL concentrations were significantly higher and Apob lower than in controls. CONCLUSIONS: Contrary to our supposition, in ADHD was no lack, but an excess of Mg. HDL was hightened and Apob lowered. Lipoprotein metabolism seems to be modified in ADHD. PMID- 21812621 TI - Increased familiarity of intellectual deficits in early-onset schizophrenia spectrum disorders. AB - OBJECTIVES: Early-onset schizophrenia is considered to be neurobiologically similar to adult-onset forms, although it represents a more severe expression of the disorder. In the present study, we explored putative larger familial vulnerability of intellectual impairments in early-onset schizophrenia spectrum disorders (EOS) when compared to adult-onset (AOS) families. METHODS: A sample of 340 subjects including schizophrenia spectrum disorder patients, their first degree relatives and age-matched healthy controls was assessed on intelligence quotient (IQ). We used linear regression analysis and intraclass correlation coefficients (ICC) to explore familial aggregation of IQ across age at onset groups. RESULTS: The relationship between IQ level of patients and their first degree relatives showed positive linear association (beta = 0.43, P < 0.01). High significant familial aggregation was found for intelligence quotient in EOS families (ICC = 0.618, P < 0.01), while AOS families responded to lower estimates (ICC = 0.204, P = 0.26; between ICC comparison z = 1.993, P < 0.05). CONCLUSIONS: High aggregation of intellectual performance in the EOS group suggests larger familial vulnerability in early-onset forms of the disease when cognitive functions are considered. Within a continuum of psychopathology in schizophrenia spectrum disorders, specific genetic effects are discussed for distinct onset forms that might be in line with a neurodevelopmental model of the disease. PMID- 21812622 TI - Frontopolar cortical inefficiency may underpin reward and working memory dysfunction in bipolar disorder. AB - OBJECTIVES: Emotional dysregulation in bipolar disorder is thought to arise from dysfunction within prefrontal cortical regions involved in cognitive control coupled with increased or aberrant activation within regions engaged in emotional processing. The aim of this study was to determine the common and distinct patterns of functional brain abnormalities during reward and working memory processing in patients with bipolar disorder. METHODS: Participants were 36 euthymic bipolar disorder patients and 37 healthy comparison subjects matched for age, sex and IQ. Functional magnetic resonance imaging (fMRI) was conducted during the Iowa Gambling Task (IGT) and the n-back working memory task. RESULTS: During both tasks, patients with bipolar disorder demonstrated a pattern of inefficient engagement within the ventral frontopolar prefrontal cortex with evidence of segregation along the medial-lateral dimension for reward and working memory processing, respectively. Moreover, patients also showed greater activation in the anterior cingulate cortex during the Iowa Gambling Task and in the insula during the n-back task. CONCLUSIONS: Our data implicate ventral frontopolar dysfunction as a core abnormality underpinning bipolar disorder and confirm that overactivation in regions involved in emotional arousal is present even in tasks that do not typically engage emotional systems. PMID- 21812624 TI - Has equity in relative survival improved over time in Finland - a methodological exercise. AB - BACKGROUND: Population-based relative survival is widely used as a method of monitoring the success of cancer control. This success may not be relevant only for an entire country but also regional developments over time are of interest. It would not only be important that the relative survival improved but also that the differences between regions decreased over time. METHODS: In this paper the authors show how relative survival methods can be used to study such differences. In addition to standard methods, some more recently introduced approaches are used, most notably a method for checking the goodness of fit of the relative survival model. This gives confidence in the obtained results and provides additional insight when assumptions are not met. RESULTS: An analysis of cancers of the colon and ovary by cancer control region in Finland in 1953-2003 shows an overall improvement in relative survival, accompanied in colon cancer also by a decrease of differences in relative survival between the regions. Thus, the desired course was observed in colon cancer but not in cancer of the ovary. CONCLUSIONS: These results, applied to further sites, should lead to investigation of differences in cancer control policies between regions. PMID- 21812623 TI - Antidepressant-like effect of sodium butyrate (HDAC inhibitor) and its molecular mechanism of action in the rat hippocampus. AB - OBJECTIVES: Epigenetic mechanisms, such as changes in gene expression resulting from chromatin remodeling through histone acetylation, have been implicated in the pathophysiology of depression. However, the antidepressant-like effect of the histone deacetylase inhibitor sodium butyrate (SB) has been inconclusive. The aim of this study was to examine the antidepressant-like effect of SB and elucidate its molecular mechanisms. METHODS: We examined the antidepressant-like effect of SB in a forced swim test (FST) and a tail suspension test (TST). Hippocampal gene expression analyses using DNA microarray and real-time PCR were undertaken. Western blotting and ChIP assay were undertaken to examine whether histone acetylation was associated with changes in gene expression by SB. RESULTS: Repeated administration of SB significantly reduced immobility on the FST and the TST, and significantly altered the levels of mRNA for several genes; e.g., upregulation of transthyretin (Ttr) and downregulation of serotonin 2A receptor (Htr2a). Western blotting and ChIP assay revealed selective increases in histone H4 acetylation at the promoter of the Ttr gene with a significant increase in Ttr immunoreactivity 24 h after the final administration of SB. CONCLUSION: These findings suggest the possibility that alterations in gene expression, including upregulation of Ttr and downregulation of several other genes, including Htr2a, may be involved in antidepressant-like effect of SB. PMID- 21812625 TI - A rare occurrence of primary T-cell lymphoma of the breast in pregnancy. PMID- 21812626 TI - Pancreatic cancer; reporting and long-term survival in Sweden. AB - BACKGROUND: The overall completeness of the Swedish Cancer Register is high, although underreporting for certain sites must be acknowledged. The aims of the present study were twofold. Firstly to assess the completeness of reporting of pancreatic cancer to the Swedish Cancer Register, and secondly to identify and characterise long-term survivors based on information from two separate population-based register resources. MATERIAL AND METHODS: To assess the completeness of the Cancer Register, pancreatic cancer cases registered in the National Patient Register between 1987 and 1999 were compared to cases reported to the Cancer Register. For estimations of long-term survival, the study population was restricted to 4321 cases identified both in the Cancer Register and the Patient Register with a histopathologically confirmed diagnosis of pancreatic ductal adenocarcinoma. A complete follow-up of survival in this group was performed till December 31, 2004. RESULTS: There was a considerable underreporting of pancreatic cancer to the Cancer Register. During the period under study, a total of 19 745 patients were identified with a diagnosis of pancreatic cancer. Of these, only 73% had been reported to the Cancer Register. The underreporting increased markedly with age at diagnosis and was more pronounced during the second period under study. Only 2.8% of patients with a histopathologically confirmed diagnosis of pancreatic ductal adenocarcinoma survived five years or longer. The likelihood of long-term survival was strongly associated with younger age and surgery. Pancreatic resection was reported in 20.4% of all patients. Median survival among those operated on was 12 months compared to 4.6 months in all patients. CONCLUSIONS: Underreporting of pancreatic cancer to the Swedish Cancer Register was pronounced and increased with older age. Less than 3% of patients with a record of pancreatic cancer both in the Cancer Register and the Patient Register survived five years or longer. PMID- 21812627 TI - Meeting report of the International Consortium of Stem Cell Networks' Workshop Towards Clinical Trials Using Stem Cells for Amyotrophic Lateral Sclerosis/Motor Neuron Disease. AB - The International Consortium of Stem Cell Networks' (ICSCN) Workshop Towards Clinical Trials Using Stem Cells for Amyotrophic Lateral Sclerosis (ALS)/Motor Neuron Disease (MND) was held on 24-25 January 2011. Twenty scientific talks addressed aspects of cell derivation and characterization; preclinical research and phased clinical trials involving stem cells; latest developments in induced pluripotent (iPS) cell technology; industry involvement and investment. Three moderated panel discussions focused on unregulated ALS/MND treatments, and the state of the art and barriers to future progress in using stem cells for ALS/MND. This review highlights the major insights that emanated from the workshop around the lessons learned and barriers to progress for using stem cells for understanding disease mechanism, drug discovery, and as therapy for ALS/MND. The full meeting report is only available in the online version of the journal. Please find this material with the following direct link to the article: http://www.informahealthcare.com/als/doi/10.3109/17482968.2011.590992 . PMID- 21812628 TI - Intramedullary spinal cord implantation of human CD34+ umbilical cord-derived cells in ALS. AB - Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder with marginal therapeutic options. Degeneration of motor neurons in the primary motor cortex, brainstem and spinal cord lead to rapidly progressive paralysis and finally to death due to respiratory failure. As pharmacological therapies have failed to provide sufficient neuroprotective effects in ALS, transplantation of stem or progenitor cells is considered a promising treatment strategy. Cell transplantation approaches in ALS mainly aim to generate a neuroprotective environment for degenerating motor neurons by transplantation of non-neuronal cells, rather than to replace lost motor neurons. We present a 63-year-old male patient suffering from ALS who underwent intramedullary thoracic spinal cord implantation of human CD34(+) umbilical cord-derived haematopoietic progenitor cells with a three-year follow up after transplantation. PMID- 21812629 TI - Value of quantitative analysis of routine clinical MRI sequences in ALS. AB - Simple morphological assessment of conventional MRI used in routine neurological diagnostic work-up lacks sensitivity and specificity for amyotrophic lateral sclerosis (ALS). Quantitative analysis of routine MRI sequences might, however, be more suitable to reveal ALS-related pathological cerebral alterations. We investigated 10 ALS patients and 10 age- and sex-matched healthy controls by MRI. Brain maps of T2 relaxation time (T2), relative proton density (PD), and apparent diffusion coefficient (ADC) were obtained. Values of these parameters were measured in 22 selected brain regions, and compared among the patients and the controls by using paired t-test with Bonferroni corrected alpha level (= 0.002). In ALS patients, increased PD was found in the pyramidal tract, corpus callosum, and white and grey matter. T2 elongation was found at the genu of corpus callosum, and at the posterior limb of the internal capsule (ICP). ADC values showed a tendency towards an increase in patients, which was only significant at the ICP. PD therefore appeared to be the most sensitive parameter for the detection of degenerative changes not only in the motor system but also in extramotor brain regions. PMID- 21812630 TI - Severe difficulties with word recognition in noise after platinum chemotherapy in childhood, and improvements with open-fitting hearing-aids. AB - OBJECTIVE: To investigate word recognition in noise in subjects treated in childhood with chemotherapy, study benefits of open-fitting hearing-aids for word recognition, and investigate whether self-reported hearing-handicap corresponded to subjects' word recognition ability. DESIGN: Subjects diagnosed with cancer and treated with platinum-based chemotherapy in childhood underwent audiometric evaluations. STUDY SAMPLE: Fifteen subjects (eight females and seven males) fulfilled the criteria set for the study, and four of those received customized open-fitting hearing-aids. RESULTS: Subjects with cisplatin-induced ototoxicity had severe difficulties recognizing words in noise, and scored as low as 54% below reference scores standardized for age and degree of hearing loss. Hearing impaired subjects' self-reported hearing-handicap correlated significantly with word recognition in a quiet environment but not in noise. Word recognition in noise improved markedly (up to 46%) with hearing-aids, and the self-reported hearing-handicap and disability score were reduced by more than 50%. CONCLUSIONS: This study demonstrates the importance of testing word recognition in noise in subjects treated with platinum-based chemotherapy in childhood, and to use specific custom-made questionnaires to evaluate the experienced hearing-handicap. Open-fitting hearing-aids are a good alternative for subjects suffering from poor word recognition in noise. PMID- 21812631 TI - A study of recorded versus live voice word recognition. AB - OBJECTIVE: To determine administration times for word recognition presented via monitored live voice (MLV) and compact disc (CD) recordings. DESIGN: A quasi experimental design was used. Fifty-word NU-6 lists were presented in three conditions: (1) MLV, (2) short ISI CD recording, and (3) long ISI CD recording. STUDY SAMPLE: Listeners with normal hearing (NH) and hearing impairment (HI) participated in this study. RESULTS: Average administration time using MLV was significantly shorter than using recorded word lists for both groups of listeners. MLV presentation to the NH listeners was significantly faster than the MLV presentation to the HI listeners. There were no significant differences between groups in the administration times for any of the recorded lists (long or short ISI). Considerably more variability in administration time was observed for MLV presentation compared to recorded presentations. CONCLUSIONS: MLV presentation was about one minute faster than the shortest CD recording of the NU 6 fifty-item word lists, but it was only 49 seconds quicker when administering tests to individuals with hearing loss. Because the majority of our patients are hearing impaired, the difference of 49 seconds is not clinically significant. This difference is even less when 25-item word lists are used. PMID- 21812632 TI - Is mother-child transmission a possible vehicle for xylitol prophylaxis in acute otitis media? AB - OBJECTIVE: Xylitol can be a prophylaxis for acute otitis media (AOM), especially when administered via chewing gum, but that vehicle has limitations for children. This review sought evidence for links of mother-child transmission of bacteria and as a vehicle for xylitol as a prophylaxis for dental caries and its translation to AOM in infants and young children. DESIGN: Qualitative systematic review. METHOD: Combining output from 43 search strings used earlier and submitting 20 new strings to PubMed resulted in 14 studies (six were excluded; eight were included). Included studies had to be published in English-language, peer-reviewed journals; involve mothers using xylitol; and assess bacteria or caries in their children. Evaluation forms were completed for search, retrieval, and quality assessment of included studies. RESULTS: The studies showed that mothers' chewing xylitol gum was a prophylaxis against bacteria and caries in their children. A mother-child transmission model was presented as a possible vehicle for use in comprehensive prevention programs for AOM. CONCLUSIONS: Potential for xylitol use to prevent AOM warrants further study. A mother-child model may apply to AOM for transmission of bacteria and as a prophylaxis, but alternative vehicles like nasal sprays should be investigated for ease of use and effectiveness. PMID- 21812633 TI - Factors that influence disclosure of hearing loss in the workplace. AB - OBJECTIVE: The objective of the study was to identify factors that lead individuals to conceal or disclose their hearing loss in the workplace. DESIGN: A qualitative research paradigm called qualitative description was selected to address this issue. STUDY SAMPLE: Twelve people who had an adult onset hearing loss, and were gainfully employed, participated in audio-recorded semi-structured interviews designed to probe issues related to disclosure of hearing loss. A photo elicitation interview technique was employed during the interviews. Content analyses were used to extract pertinent information from verbatim transcripts. RESULTS: Five recurring themes emerged as important considerations in relation to this topic: (1) perceived importance of the situation; (2) perceived sense of control; (3) community affiliation; (4) burden of communication; and (5) coexisting issues related to hearing loss. CONCLUSIONS: The findings are discussed in relation to other concealable stigmatizing traits, stigma-theory, and social-cognitive theory. The clinical implications of these findings are discussed, with particular emphasis placed on worker self-efficacy. PMID- 21812634 TI - Parental perspectives on decision-making and outcomes in pediatric bilateral cochlear implantation. AB - OBJECTIVE: Bilateral cochlear implantation is becoming standard care to improve outcomes for children with profound or severe to profound hearing loss. This study examined parents' perceptions of the decision process and of the benefits of two implants. DESIGN: The study adopted a qualitative approach, examining parents' views through individual semi-structured interviews. STUDY SAMPLE: The participants consisted of the parents of 15 children at one centre in Ontario, Canada, where 26 children had received bilateral implants. Children ranged in age from 1.8 to 11.9 years and their experience with two implants ranged from 0.3 to 4.2 years. RESULTS: Parents described decision-making as relatively straightforward. However, many parents shared concerns related to surgery. Primary reasons for choosing two implants were neuroplasticity, preference for a backup device, and maximizing potential through technology. Expected outcomes included better speech understanding in noise and the ability to locate the source of sounds. Perceived benefits of bilateral implantation included improved speech understanding in noise, the availability of a backup implant, and parents' assurance that they had provided their children with the best possible access to hearing. CONCLUSIONS: Overall, parents were satisfied with the second implant and identified benefits that are not easily quantifiable through traditional clinical measures. PMID- 21812635 TI - A multicenter study on the audiometric findings of styrene-exposed workers. AB - OBJECTIVE: The objective of this study was to evaluate hearing loss among workers exposed to styrene, alone or with noise. DESIGN: This cross-sectional study was conducted as part of NoiseChem, a European Commission 5th Framework Programme research project, by occupational health institutes in Finland, Sweden, and Poland. STUDY SAMPLE: Participants' ages ranged from 18-72 years (n = 1620 workers). Participants exposed to styrene, alone or with noise, were from reinforced fiberglass products manufacturing plants (n = 862). Comparison groups were comprised of workers noise-exposed (n = 400) or controls (n = 358). Current styrene exposures ranged from 0 to 309 mg/m(3), while mean current noise levels ranged from 70-84 dB(A). Hearing thresholds of styrene-exposed participants were compared with Annexes A and B from ANSI S3.44, 1996. RESULTS: The audiometric thresholds of styrene exposed workers were significantly poorer than those in published standards. Age, gender, and styrene exposure met the significance level criterion in the multiple logistic regression for the binary outcome 'hearing loss' (P = 0.0000). Exposure to noise (<85 dBA p = 0.0001; >=85 dB(A) p = 0.0192) interacted significantly with styrene exposure. CONCLUSIONS: Occupational exposure to styrene is a risk factor for hearing loss, and styrene-exposed workers should be included in hearing loss prevention programs. PMID- 21812636 TI - Otological diagnoses and probable age-related auditory neuropathy in "younger" and "older" elderly persons. AB - OBJECTIVE: Audiological data from a population based epidemiological investigation were studied on elderly persons. Specific diagnoses of otological and audiological disorders, which can result in hearing loss, were searched for. DESIGN: A retrospective register study. STUDY SAMPLE: Three age cohorts, 474 70- and 75-year olds ("younger"), and 252 85-year olds ("older"), were studied. Clinical pure tone and speech audiometry was used. Data from medical files were included. RESULTS: Conductive hearing loss was diagnosed in 6.1% of the "younger" elderly persons, and in 10.3% of the "older" ones. Specific diagnoses (chronic otitis media and otosclerosis) were established in about half of the cases. Sensorineural hearing loss, other than age-related hearing loss and noise induced hearing loss, was diagnosed in 3.4 % and 5.2% respectively. Severely impaired speech recognition, possibly reflecting age-related auditory neuropathy, was found in 0.4% in the "younger" group, and in 10% in the "older" group. Bilateral functional deafness was present in 3.2% of the 85-year-old persons, but was not present in the 70-75-year group. CONCLUSION: The incidence of probable age related auditory neuropathy increases considerably from 70-75 to 85 years. There are marked differences between "younger" and "older" elderly persons regarding hearing loss that severely affects oral communication. PMID- 21812637 TI - The blind spot issue. PMID- 21812638 TI - High serum ACE activity predicts severe hypoglycaemia over time in patients with type 1 diabetes. AB - AIMS/HYPOTHESIS: High serum angiotensin-converting enzyme (ACE) activity is associated with increased risk of severe hypoglycaemia (SH) within 1 year in type 1 diabetes. We wanted to find out whether ACE activity is stable over time and predicts SH beyond 1 year, and if gender differences exist in the association between ACE activity and risk of SH. METHODS: A follow-up study of 128 adult patients with type 1 diabetes was conducted. At entry, ACE activity was measured. For 12 months, patients prospectively recorded events of severe hypoglycaemia (SH). At a median of 40 months, ACE activity was measured again and participants recalled the number of SH in the last year. RESULTS: ACE activity is reproducible over 40 months (p < 0.00001). Patients with SH during the baseline study also had SH during follow-up (p < 0.00001). Serum ACE activity measured at baseline was positively associated with the rate of SH at follow-up (p = 0.0003) with a 3.2 fold increased rate of SH in subjects belonging to the upper ACE quartile compared to subjects in the three lowest quartiles (p < 0.00001). The association between high serum ACE activity and increased risk of SH did not differ significantly in women and men. CONCLUSION: In type 1 diabetes individual serum ACE activity is reproducible over time. High ACE activity predicts recurrent SH over at least 40 months with no differences between genders. PMID- 21812639 TI - Brain oscillatory activity during spatial navigation: theta and gamma activity link medial temporal and parietal regions. AB - Brain oscillatory correlates of spatial navigation were investigated using blind source separation (BSS) and standardized low resolution electromagnetic tomography (sLORETA) analyses of 62-channel EEG recordings. Twenty-five participants were instructed to navigate to distinct landmark buildings in a previously learned virtual reality town environment. Data from periods of navigation between landmarks were subject to BSS analyses to obtain source components. Two of these cortical sources were found to exhibit significant spectral power differences during navigation with respect to a resting eyes open condition and were subject to source localization using sLORETA. These two sources were localized as a right parietal component with gamma activation and a right medial-temporal-parietal component with activation in theta and gamma bandwidths. The parietal gamma activity was thought to reflect visuospatial processing associated with the task. The medial-temporal-parietal activity was thought to be more specific to the navigational processing, representing the integration of ego- and allo-centric representations of space required for successful navigation, suggesting theta and gamma oscillations may have a role in integrating information from parietal and medial-temporal regions. Theta activity on this medial-temporal-parietal source was positively correlated with more efficient navigation performance. Results are discussed in light of the depth and proposed closed field structure of the hippocampus and potential implications for scalp EEG data. The findings of the present study suggest that appropriate BSS methods are ideally suited to minimizing the effects of volume conduction in noninvasive recordings, allowing more accurate exploration of deep brain processes. PMID- 21812640 TI - Craniorachischisis with a variant of pentalogy of Cantrell, with lung extrophy. AB - A case of cranioraschischisis including incomplete pentalogy of Cantrell (PC) is described. The female fetus had a large omphalocele with evisceration of the heart, left lung, liver, stomach, and intestines accompanying anencephaly, cervical, thoracal lumbar, spina bifida. The fetus had ectopia cordis and diaphragmatic agenesia with an intact sternum. We present a case of a neonate with the stigmata for PC with the exception of a sternal defect. A literature review is also included. Sonographers should check for ventral and dorsal anomalies with PC because they may occur simultaneously. PMID- 21812641 TI - A new species of Rhabdias (Nematoda: Rhabdiasidae) in Calotes versicolor (Squamata: Agamidae) from Singapore. AB - Rhabdias singaporensis n. sp. (Rhabditida: Rhabdiasidae) from the lungs of Calotes versicolor (Squamata: Agamidae) from Singapore is described and illustrated. Rhabdias singaporensis n. sp. represents the 77th species assigned to the genus, the eighth of the Asian region, and the second from Singapore. The distinguishing characteristic of the new species is the location of the excretory pore. In all species of Rhabdias for which excretory pore location data are available, the excretory pore is situated just posterior to the level of the nerve ring; in R. singaporensis , it lies near the esophageointestinal junction. PMID- 21812642 TI - The role of alternate hosts in the ecology and life history of Hematodinium sp., a parasitic dinoflagellate of the blue crab (Callinectes sapidus). AB - Hematodinium sp. infections are relatively common in some American blue crab (Callinectes sapidus) populations in estuaries of the western Atlantic Ocean. Outbreaks of disease caused by Hematodinium sp. can be extensive and can cause substantial mortalities in blue crab populations in high salinities. We examined several species of crustaceans to determine if the same species of Hematodinium that infects C. sapidus is found in other crustaceans from the same localities. Over a 2-yr period, 1,829 crustaceans were collected from the Delmarva Peninsula, Virginia, examined for the presence of infections. A portion of the first internal transcribed spacer (ITS1) region of the ribosomal RNA (rRNA) gene complex from Hematodinium sp. was amplified and sequences were compared among 35 individual crustaceans putatively infected with the parasite, as determined by microscopic examination, and 4 crustaceans putatively infected based only on PCR analysis. Of the 18 crustacean species examined, 5 were infected with Hematodinium sp. after microscopic examination and PCR analysis, including 3 new host records, and an additional species was positive only via PCR analysis. The ITS1 rRNA sequences of Hematodinium sp. from the infected crustaceans were highly similar to each other and to that reported from C. sapidus (>98%). The similarity among these ITS1 sequences and similarities in the histopathology of infected hosts is evidence that the same species of Hematodinium found in C. sapidus infects a broad range of crustaceans along the Delmarva Peninsula. Our data indicate that the species of Hematodinium found in blue crabs from estuaries along the east coast of North America is a host generalist, capable of infecting hosts in different families within the Order Decapoda. Additionally, evidence indicates that it may be capable of infecting crustaceans within the Order Amphipoda. PMID- 21812643 TI - Helminth parasites of the western willet, Tringa semipalmata inornata, from Montana and Texas with a checklist of helminth parasites. AB - In total, 26 western willets, Tringa semipalmata inornata , were examined for helminth parasites, including 8 spring migrating hosts from the Chihuahua Desert, Rio Grande Valley, Texas, and 18 post-breeding hosts from east central Montana. Sixteen species of helminth parasites were present in component communities for both spring migrants and post-breeding birds. There were 9 species of trematodes, 2 cestodes, and 5 of nematodes, with a total of 1,593 individual specimens (X = 99.6, +/-SE = 57.9, M = 9) present in migrating willets, and 5 species of trematodes, 8 cestodes, and 3 nematodes for a total of 1,148 individual specimens (X = 71.8, +/-SE = 34.4, M = 12) present in post-breeding hosts. Species richness in infracommunities ranged from 2 to 10 (X = 5.1, +/-SE = 0.95, M = 5.3) for spring migrants, and from 1 to 4 (X = 2.8, +/-SE = 0.26, M = 3) for post-breeding birds. Diversity and evenness were 0.72 and 0.23 for spring migrants and. 0.62 and 0.17 for post-breeding hosts. Trematodes were the dominant taxa in spring migrants and cestode taxa in post-breeding hosts. Helminths with marine associated life cycles were present in larger numbers in spring migrants from the Rio Grande Valley (11 of 16 species) than in post-breeding hosts from Montana hosts (4 of 16 species). The higher number of marine species in spring migrants was probably related to their more recent association with a marine habitat. Several species of Anomotaenia were major contributors to the component communities in both localities. Four species of nematodes with large prevalence, i.e., Schistorophus skrjabini, Sciadiocara umbellifera, Skrjabinoclava inornatae, and Sobolivicephalus lichtensfelsi, observed in spring migrants from the Rio Grande Valley were absent from Montana hosts. There was only a 2% similarity between the Rio Grande Valley and Montana. All helminth species, except for the possibility of Anomotaenia spp., were generalists. A checklist of helminth parasites of the willet is included. PMID- 21812644 TI - Effects of oolong tea on gene expression of gluconeogenic enzymes in the mouse liver and in rat hepatoma H4IIE cells. AB - Tea has many beneficial effects. We have previously reported that green tea and a catechin-rich green tea beverage modulated the gene expression of the gluconeogenic enzymes glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) in the normal murine liver. In the present study, we examined the effects of oral administration of oolong tea on the hepatic expression of gluconeogenesis-related genes in the mouse. The intake of oolong tea for 4 weeks reduced the hepatic expression of G6Pase and PEPCK together with that of the transcription factor hepatocyte nuclear factor (HNF) 4alpha. When rat hepatoma H4IIE cells were incubated in the presence of oolong tea, the expression of these genes was repressed in accordance with the findings in vivo. The reduced protein expression of PEPCK and HNF4alpha was also demonstrated. We then fractionated oolong tea by sequential extraction with three organic solvents to give three fractions and the residual fraction (Fraction IV). In addition to organic fractions, Fraction IV, which was devoid of low-molecular-weight catechins such as (-)-epigallocatechin gallate (EGCG), had effects similar to those of oolong tea on H4IIE cells. Fraction IV repressed the gene expression of insulin-like growth factor binding protein 1, as insulin did. This activity was different from that of EGCG. The present findings suggest that drinking oolong tea may help to prevent diabetes and that oolong tea contains a component or components with insulin-like activity distinguishable from EGCG. Identification of such component(s) may open the way to developing a new drug for diabetes. PMID- 21812645 TI - Royal jelly protects against ultraviolet B-induced photoaging in human skin fibroblasts via enhancing collagen production. AB - Royal jelly (RJ) is a honeybee product containing proteins, carbohydrates, fats, free amino acids, vitamins, and minerals. As its principal unsaturated fatty acid, RJ contains 10-hydroxy-2-decenoic acid (10-HDA), which may have antitumor and antibacterial activity and a capacity to stimulate collagen production. RJ has attracted interest in various parts of the world for its pharmacological properties. However, the effects of RJ on ultraviolet (UV)-induced photoaging of the skin have not been reported. In this study we measured the 10-HDA content of RJ by high-performance liquid chromatography and tested the effects of RJ on UVB induced skin photoaging in normal human dermal fibroblasts. The effects of RJ and 10-HDA on UVB-induced photoaging were tested by measuring procollagen type I, transforming growth factor (TGF)-beta1, and matrix metalloproteinase (MMP)-1 after UVB irradiation. The RJ contained about 0.211% 10-HDA. The UVB-irradiated human skin fibroblasts treated with RJ and 10-HDA had increased procollagen type I and TGF-beta1 productions, but the level of MMP-1 was not changed. Thus RJ may potentially protect the skin from UVB-induced photoaging by enhancing collagen production. PMID- 21812646 TI - Antioxidant and anticarcinogenic effects of methanolic extract and volatile oil of fennel seeds (Foeniculum vulgare). AB - The present study evaluated the efficacy of fennel seed methanolic extract (FSME) for its antioxidant, cytotoxic, and antitumor activities and for its capacity to serve as a nontoxic radioprotector in Swiss albino mice. We also assessed the natural antioxidant compounds of FSME for use in industrial application. Cytotoxic activity of FSME was evaluated in a mouse model of Ehrlich ascites carcinoma (EAC) and on different types of human cell lines in vitro. The safety and optimum dose of FSME were determined. FSME, 100 mg/kg, was injected intraperitoneally into mice bearing EAC before the mice were exposed to three 2 Gy doses of gamma irradiation. After 30 days, mice were fasted for 18 hours and then sacrificed to observe the lifespan of EAC-bearing hosts. Malondialdehyde (MDA), catalase activity, glutathione content, and total protein in serum, liver tissue, and ascitic fluid were determined. Iron, total iron-binding capacity, transferrin, and ferritin were also evaluated in serum. The data showed the presence of different types of compounds in FSME, such as flavonoids, terpenoids, alkaloids, phenols, and sterols; estragole (71.099%) was the predominant alcohol, gallic acid was the phenolic compound (18.895%), and L-limonene was the most prevalent monoterpene hydrocarbon (11.967%). The mean+/-standard deviation 50% inhibitory concentrations were 50+/-0.03 MUg/mL for the MCF7 breast cancer cell line and 48+/-022 MUg/mL for the Hepg-2 liver cancer cell line. The significant increase in MDA levels and the significant decrease in catalase activity and glutathione content in liver and tumor tissue in mice bearing EAC were ameliorated after FSME administration. In contrast, total protein content was increased in ascitic fluid. Serum iron was inversely proportional to the levels of ferritin and transferrin and total iron-binding capacity. Administration of FSME before irradiation exerted a cytoprotective effect against gamma irradiation, as manifested by a restoration of the MDA level, catalase activity, and GSH content to near-normal levels. In conclusion, FSME may have remarkable anticancer potential against a breast cancer cell line (MCF7) and liver cancer cell line (Hepg-2). It also showed strong free radical-scavenging activity (100%). Thus, FSME may reduce oxidative stress and protect mouse cells from damage caused by reactive oxygen species. In addition, it could be used as a safe, effective, and easily accessible source of natural antioxidants to improve the oxidative stability of fatty foods during storage. FSME also exhibited an antitumor effect by modulating lipid peroxidation and augmenting the antioxidant defense system in EAC-bearing mice with or without exposure to radiation. PMID- 21812647 TI - Leukocyte-stimulating effect and phytochemical screening of Trichilia hirta extracts. AB - Trichilia hirta (Family Meliaceae) is a tree traditionally used in the folk medicine of Cuba to treat asthma, cancer, and ulcers. The objective of this study was to determine the phytochemical composition of ethanol extracts obtained from leaves, roots, and stem bark and to evaluate the leukocyte-stimulating effect of T. hirta root extracts on BALB/c mice. The chemical composition of the extracts was determined by phytochemical screening. Saponins, tannins, flavonoids, and coumarins were detected in extracts of T. hirta. The leukocyte-stimulating effect was evaluated by oral application of ethanol extracts (81.8 and 976 mg/kg) in BALB/c mice for 7 days. The application of 976 mg of extract/kg increased the total leukocyte count up to 15-33%; this effect was significant for neutrophil counts compared with control animals (P<.05). In addition, a dose of 82 mg/kg significantly increased total leukocytes at day 4 of the study (P<.05). The results indicated that T. hirta extracts contain phytochemicals reported as immunostimulants. The administration of these extracts to BALB/c mice indicated that ethanol extract could exhibit leukocyte-stimulating properties and makes it a promising alternative for the development of an immunoprotective agent. PMID- 21812648 TI - Abietic acid has an anti-obesity effect in mice fed a high-fat diet. AB - We investigated the anti-obesity effect of abietic acid in mice fed a high-fat diet with emphasis on changes in adipogenesis in epididymal adipose tissues. Male C57BL/6J mice were divided into four groups and fed a normal diet, a high-fat diet (HFD), or HFD plus oral administration of abietic acid (20 mg/kg of body weight/day [LA] or 40 mg/kg of body weight/day [HA]) for 8 weeks. Compared with the HFD group, mice orally administered 40 mg of abietic acid/kg of body weight/day exhibited significantly decreased body weight and adipose tissue weights. Serum triglyceride concentrations in the HA group were significantly lower than those in the HFD group, as were the levels of serum insulin and leptin. Hematoxylin and eosin staining revealed that epididymal adipose tissue mass was decreased by abietic acid administration. Abietic acid also inhibited the protein expression of sterol regulatory element-binding protein-1c, CCAAT/enhancer-binding protein alpha, and CD36 in epididymal adipose tissues, which are up-regulated by HFDs. These data demonstrate that abietic acid has an anti-obesity effect in mice mediated by the regulation of adipogenesis. PMID- 21812649 TI - A novel herbal formulation "LiverCare" differentially regulates primary rat hepatocyte and hepatocarcinoma cell proliferation in vitro. AB - Hepatocyte growth factor (HGF) plays an important role in hepatocyte proliferation. HGF expression is regulated by various signaling molecules and nuclear receptors. In the present study, LiverCare((r)) (LC), a novel polyherbal formulation (The Himalaya Drug Company, Bangalore, India), was evaluated for its efficacy, using co-cultures of primary rat hepatocytes-non-parenchymal cells (NPCs) and human hepatocellular carcinoma cells (HepG2). The rate of primary hepatocyte co-culture proliferation was significantly and dose-dependently increased by LC as determined by [(3)H]thymidine incorporation into newly synthesized DNA and cell proliferation assay. LC also increased HGF expression in primary hepatocyte co-culture. Albumin and urea content remained constant during proliferation of hepatocyte co-cultures in the presence of LC with decreased activity of alanine aminotransferase. It is interesting that LC inhibited incorporation of [(3)H]thymidine into DNA in HepG2 cells. LC enhanced peroxisome proliferator-activated receptor-alpha expression during hepatocyte proliferation, whereas tumor necrosis factor-alpha expression remained unaffected. In conclusion, our study clearly showed that LC differentially regulates primary rat hepatocytes and human hepatocarcinoma cell proliferation. LC may be a promising candidate for treating degenerative liver diseases by enhancing liver regeneration. PMID- 21812650 TI - Correlation between antioxidant activity of garlic extracts and WEHI-164 fibrosarcoma tumor growth in BALB/c mice. AB - The biological activities of garlic may be affected by different processing methods. This study, therefore, aimed to evaluate potential anticancer effects of different type of processed garlic extracts on WEHI-164 tumor cells in inbred BALB/c mice and correlate the tumor growth rates with some garlic constituents. In a preclinical trial 60 BALB/c mice were injected with WEHI-164 tumor cells and divided into six groups of 10 animals. Group 1 mice received 200 MUL of saline, and groups 2-6 were injected intraperitoneally with fresh, microwaved, 3-month old, leaves, and boiled garlic extracts, respectively, at 20 mg/kg/0.2 mL. Three weeks following tumor inoculation, the mean tumor size in garlic extract-treated groups was reduced with significant reductions observed in the fresh and microwaved extract groups compared with the control group (P<.05). The antioxidant capacity and the amounts of allicin, flavonoids, and phenolic compounds in differentially processed garlic were evaluated and correlated with their anticancer activities. There was a linear correlation between the amounts of allicin, flavonoids, or phenolic components derived from fresh, microwaved, 3 month-old, leaves, and boiled garlic and cancer growth prevention. In conclusion, garlic has anticancer activity against WEHI-164 tumor cells, and processing such as heating reduces its effect dramatically. The anticancer activities of different kinds of garlic are related to the level of allicin, flavonoids, and phenolic components. Therefore, fresh garlic has the highest content of bioactive components and the greatest anticancer efficacy. PMID- 21812651 TI - Ocimum sanctum Linn. leaf extracts inhibit acetylcholinesterase and improve cognition in rats with experimentally induced dementia. AB - Cognitive disorders such as dementia, attention deficits, and Alzheimer's disease (AD) have been well investigated. However, effective interventions for the promotion and progression of AD are unavailable to date. The present work was undertaken to investigate the effects of the aqueous (300 and 500 mg/kg) and alcoholic (300 and 500 mg/kg) extracts of Ocimum sanctum Linn. leaves as an antidementic and anticholinesterase agent and also as an immunostimulant in rats. Maximal electroshock, atropine, and cyclosporine were used to induce dementia. The passive avoidance task was used for assessing memory. Acetylcholinesterase (AChE) activity was estimated in different parts of the brain, and immune status was studied using dinitrochlorobenzene (DNCB) skin sensitivity tests. In all the three models both aqueous and alcoholic O. sanctum extracts decreased the time taken to reach the shock-free zone and the number of mistakes and significantly decreased the AChE activity in rats. O. sanctum treatment significantly increased the induration in the DNCB skin test. Therefore, O. sanctum was shown to be useful for the management of experimentally induced cognitive dysfunctions in rats. PMID- 21812652 TI - Efficacy of large doses of IL-2-activated human leukocyte antigen haploidentical peripheral blood stem cells on refractory metastatic renal cell carcinoma. AB - Traditional immunotherapy for patients with refractory metastatic renal cell carcinoma (RCC) is limited because the tumors themselves induce immunosuppression. The aim of this article was to evaluate the clinical efficacy of the infusion of a high dose of interleukin (IL)-2-activated allogeneic haploidentical peripheral blood stem cells (haplo-PBSCs) in patients with advanced intractable RCC. Ten advanced RCC patients and their haploidentical relatives, who were haplo-PBSC donors, were enrolled in this study. All patients accepted one cycle of activated haplo-PBSCs. The clinical and immunologic responses were evaluated. A range from 2.3 to 5.5*10(10) of activated haplo-PBSCs were harvested after exposure to recombinant human IL-2 (rhIL-2), along with a significant increase in the proportion of natural killer cells and activated lymphocytes (CD69+ and CD25+). Enhanced cytotoxicity of haplo-PBSCs for RCC was also observed. After treatment, 2 (2/10) cases of partial remission, 6 (6/10) cases of stable disease, and 2 (2/10) cases of progressive disease were identified in these 10 patients. The median progression-free survival of the 10 patients was 5.5 months (3-14 months). The adoptive transfusion of IL-2-activated haplo-PBSCs can induce sustained antitumor effects for advanced intractable RCC patients who have had no response to conventional immunotherapy. PMID- 21812653 TI - Features associated with survival in metastatic melanoma patients treated with patient-specific dendritic cell vaccines. AB - Previously, a 54% 5-year survival was reported for metastatic melanoma patients treated with patient-specific vaccines consisting of autologous dendritic cells loaded with antigens from autologous proliferating tumor cells. This study attempted to determine which clinical and laboratory factors best explained long term survival in this group of patients. Univariate analyses were used to identify factors associated with continuous survival after initiating vaccine therapy. Multivariate logistic regression was used to identify independent factors to classify survival at 3.5 years. Survivors were followed a minimum of 3.7 years (median: 5.7). Univariate analyses identified eight features associated with improved survival: Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, no measurable disease at study entry, receiving 8 vaccinations, age <50 years, normal baseline lactate dehydrogenase, no history of visceral metastases, anergy to standard skin tests, and failure of interferon-gamma (IFN gamma) to induce apoptosis in autologous tumor cells. After examining 54 variables for which complete information was available over all patients, the best multivariate regression for survival at 3.5 years utilized six features: prior radiation therapy, younger age, male gender, ECOG PS 0, higher numbers of cells administered during the first 3 injections, and lower numbers of viable cells administered during the first 3 injections. This model correctly classified survival for 28 of 32 patients (87%) and death for 20 of 22 (91%). When features with incomplete information were included in the analysis, addition of IFN-gamma induced apoptosis (n=49) improved predictive accuracy to 27 of 29 (93%) for survival and 19 of 20 (95%) for death. Dependencies between variables were common, but these multivariate linear models yielded high classification accuracy for survival at 3.5 years and identified two features of the vaccine itself as being of independent significance. PMID- 21812654 TI - Efficient in vitro labeling of human prostate cancer cells with superparamagnetic iron oxide nanoparticles. AB - The purpose of this study was to investigate the feasibility and optimization of protocols using superparamagnetic iron oxide (SPIO) nanoparticles to label human prostate cancer cell lines PC3 in vitro. The PC3 cells were labeled with different concentrations (28-252 MUg Fe/mL) of SPIO and increasing incubation time (6-24 hours), in the presence or absence of a transfection agent poly-l lysine (PLL). The cell labeling efficiency was analyzed by Prussian blue stain method. The cellular viability was evaluated using trypan blue dye exclusion test. The signal intensity change of the labeled cells was assessed with magnetic resonance imaging (MRI). The results demonstrated that the iron oxide uptake by PC3 cells was dependent on dose and time. The PLL significantly increased the iron load of cells (p<0.01). A final concentration of SPIO nanoparticles of 42 126 MUg/mL with 12-24 hours incubation times could be sufficient to label PC3 cells for cellular MRI without impairment of cell viability. This technology may allow for further study into the mechanisms underlying prostate cancer progression as well as permit the real-time imaging of the effectiveness of cancer therapies in vivo. PMID- 21812656 TI - SCIP to the Loo? PMID- 21812657 TI - The changing face of Staphylococcus aureus: a continuing surgical challenge. AB - BACKGROUND: Staphylococcus aureus continues to be an important pathogen for surgeons. Surgical infections of interest caused by this pathogen include community-acquired infections, especially of skin and soft tissue; surgical site infections; and nosocomial infections during the post-operative period. METHODS: A literature review was conducted to detail the history of S. aureus in surgical care; to identify the structural elements of the pathogen, the secreted exotoxins and enzymes, and the changing resistance patterns that make S. aureus an ever formidable clinical foe; to consider whether screening for the pathogen and directed antimicrobial prophylaxis are useful; and to identify antimicrobial agents employed currently in treatment of established infections. RESULTS: Staphylococcus aureus has shown a pattern of increasing prevalence of infections among hospitalized patients and a pattern of increasing resistance. A broad array of virulence factors account for its continued pathogenicity, and new virulence characteristics continue to be acquired. Staphylococcus aureus has an uncanny ability to adapt and develop resistance to each new antibiotic as it is introduced into clinical care. Although screening and directed surgical prophylaxis against methicillin- (now sometimes referred to as meticillin-) resistant S. aureus (MRSA) is controversial, effective efforts to decrease the incidence of nosocomial infections may be decreasing the numbers of MRSA infections encountered, and current agents remain effective for therapy. CONCLUSIONS: Staphylococcus aureus continues to be a major pathogen for surgical patients. The scope of infections has expanded recently to include toxic shock syndrome, severe community-acquired soft tissue infections with unique virulence characteristics, and highly resistant pathogens. The adaptability of the organism requires that new prevention and treatment strategies be developed continuously to meet the challenge of future infections. PMID- 21812658 TI - An Interview with Stefan Duhr, PhD, and Moran Jerabek-Willemsen, PhD. PMID- 21812660 TI - Molecular interaction studies using microscale thermophoresis. AB - Abstract The use of infrared laser sources for creation of localized temperature fields has opened new possibilities for basic research and drug discovery. A recently developed technology, Microscale Thermophoresis (MST), uses this temperature field to perform biomolecular interaction studies. Thermophoresis, the motion of molecules in temperature fields, is very sensitive to changes in size, charge, and solvation shell of a molecule and thus suited for bioanalytics. This review focuses on the theoretical background of MST and gives a detailed overview on various applications to demonstrate the broad applicability. Experiments range from the quantification of the affinity of low-molecular-weight binders using fluorescently labeled proteins, to interactions between macromolecules and multi-component complexes like receptor containing liposomes. Information regarding experiment and experimental setup is based on the Monolith NT.115 instrument (NanoTemper Technologies GmbH). PMID- 21812661 TI - The use of topical honey in the treatment of corneal abrasions and endotoxin induced keratitis in an animal model. AB - PURPOSE: To investigate the effect of topically applied honey on intact corneas, surgically induced corneal abrasions and endotoxin induced keratitis. MATERIALS AND METHODS: The effect of honey on the cornea was investigated by application of honey on intact corneas, wounded corneas and endotoxin-induced keratitis in Lewis rats. The corneas were wounded by creating an epithelial defect using a surgical blade, and the keratitis was induced by topically applying Pseudomonas aeruginosa endotoxin to scarified corneas. After treatment rats were sacrificed and cornea harvested in each case. Corneas were processed for paraffin embedding for histological and immuno-fluorescence staining. Corneas were also harvested and processed for total ribonucleic acid (RNA) isolation for reverse transcriptase polymerase chain reaction (RT-PCR) analysis for various growth factors and inflammatory chemokines/cytokines). RESULTS: Histological analysis revealed that no inflammation or morphological changes occurred after honey treatment in naive intact corneas. Vascular endothelial growth factor (VEGF) levels were also not altered after honey treatment. Topical application of honey to injured corneas resulted in faster epithelial healing and decreased expression of VEGF, transforming growth factor beta (TGF-beta), interferon gamma (IFN-gamma), interleukin 12 (IL-12) and tumor necrosis factor alpha (TNF-alpha) in injured corneas. Our results also established that honey treatment reduced the inflammation in endotoxin-induced keratitis by reducing the levels of angiogenic factors (VEGF and TGF-beta), inflammatory cytokines (IL-12) and chemokines (CC chemokine receptor 5(CCR-5)). CONCLUSION: Short term use of honey on intact corneas can be safe. Honey has anti-angiogenic and anti-inflammatory properties that can be explored in several corneal inflammatory and infectious conditions. PMID- 21812662 TI - Putative rabbit conjunctival epithelial stem/progenitor cells preferentially reside in palpebral conjunctiva. AB - PURPOSE: Conjunctival epithelia play an important role in forming a physical protective barrier of the ocular surface. To protect the integrity of the ocular surface, the conjunctival epithelial cells (CECs) must be self-renewing from local stem cells. In this study, the distribution of conjunctival epithelial stem/progenitor cells was determined. METHODS: In a long-term bromodeoxyuridine (BrdU) label-retaining study, adult New Zealand white rabbits were injected intraperitoneally with BrdU 50 mg/kg/d for 7 days and follow-up for 6 weeks. In the short-term BrdU label-retaining study, rabbits were injected intraperitoneally with BrdU 50 mg/kg once and BrdU-labeled CECs were detected after 1, 3, 5, and 7 days, respectively. In vitro, growth kinetics, proliferating cell nuclear antigen (PCNA) immunocytochemical staining and colony-forming abilities of rabbit palpebral, fornical and bulbar CECs cultured in an identical environment were investigated and compared between different parts. RESULTS: In the long-term BrdU label-retaining study, BrdU-labeled cells concentrated at the mucocutaneous junction. In the short-term BrdU label-retaining study, the peak concentration of BrdU label-retaining conjunctival epithelial cells progressively migrated from the mucocutaneous junction to the fornix in rabbits 1, 3, 5 and 7 days postinjection respectively, but a focus of BrdU-labeled cells remained in the mucocutaneous junction at all postinjection intervals. Rabbit palpebral CECs grew faster and assigned more PCNA-positive cells and higher colony-forming abilities than the other two parts in vitro. CONCLUSIONS: Long-term retention of BrdU-labeled cells at the mucocutaneous junction indicated that slow-cycling stem cells may locate at this position. The epithelial stem/progenitor cells at the mucocutaneous junction may serve as an origination of transient amplifying cells that migrate towards the fornix. Rabbit palpebral CECs (including mucocutaneous junction epithelial cells) possess higher self-renewing ability in vitro. Collectively, conjunctival epithelial stem/progenitor cells in the rabbit may preferentially reside in palpebral conjunctiva, especially the mucocutaneous junction. PMID- 21812664 TI - Restrictions on the use of prescribing data for drug promotion. PMID- 21812663 TI - Lebrikizumab treatment in adults with asthma. AB - BACKGROUND: Many patients with asthma have uncontrolled disease despite treatment with inhaled glucocorticoids. One potential cause of the variability in response to treatment is heterogeneity in the role of interleukin-13 expression in the clinical asthma phenotype. We hypothesized that anti-interleukin-13 therapy would benefit patients with asthma who had a pretreatment profile consistent with interleukin-13 activity. METHODS: We conducted a randomized, double-blind, placebo-controlled study of lebrikizumab, a monoclonal antibody to interleukin 13, in 219 adults who had asthma that was inadequately controlled despite inhaled glucocorticoid therapy. The primary efficacy outcome was the relative change in prebronchodilator forced expiratory volume in 1 second (FEV(1)) from baseline to week 12. Among the secondary outcomes was the rate of asthma exacerbations through 24 weeks. Patient subgroups were prespecified according to baseline type 2 helper T-cell (Th2) status (assessed on the basis of total IgE level and blood eosinophil count) and serum periostin level. RESULTS: At baseline, patients had a mean FEV(1) that was 65% of the predicted value and were taking a mean dose of inhaled glucocorticoids of 580 MUg per day; 80% were also taking a long-acting beta-agonist. At week 12, the mean increase in FEV(1) was 5.5 percentage points higher in the lebrikizumab group than in the placebo group (P = 0.02). Among patients in the high-periostin subgroup, the increase from baseline FEV(1) was 8.2 percentage points higher in the lebrikizumab group than in the placebo group (P = 0.03). Among patients in the low-periostin subgroup, the increase from baseline FEV(1) was 1.6 percentage points higher in the lebrikizumab group than in the placebo group (P = 0.61). Musculoskeletal side effects were more common with lebrikizumab than with placebo (13.2% vs. 5.4%, P = 0.045). CONCLUSIONS: Lebrikizumab treatment was associated with improved lung function. Patients with high pretreatment levels of serum periostin had greater improvement in lung function with lebrikizumab than did patients with low periostin levels. (Funded by Genentech; ClinicalTrials.gov number, NCT00930163 .). PMID- 21812665 TI - Higher First Amendment hurdles for public health regulation. PMID- 21812666 TI - Graphic warnings for cigarette labels. PMID- 21812667 TI - Images in clinical medicine. Syphilitic chancre of the tongue. PMID- 21812668 TI - Developing the nation's biosimilars program. PMID- 21812669 TI - Redesigning employee health incentives--lessons from behavioral economics. PMID- 21812670 TI - A differentiation diagnosis--specialization and the medical student. PMID- 21812671 TI - Emergence of a new pathogenic Ehrlichia species, Wisconsin and Minnesota, 2009. AB - BACKGROUND: Ehrlichiosis is a clinically important, emerging zoonosis. Only Ehrlichia chaffeensis and E. ewingii have been thought to cause ehrlichiosis in humans in the United States. Patients with suspected ehrlichiosis routinely undergo testing to ensure proper diagnosis and to ascertain the cause. METHODS: We used molecular methods, culturing, and serologic testing to diagnose and ascertain the cause of cases of ehrlichiosis. RESULTS: On testing, four cases of ehrlichiosis in Minnesota or Wisconsin were found not to be from E. chaffeensis or E. ewingii and instead to be caused by a newly discovered ehrlichia species. All patients had fever, malaise, headache, and lymphopenia; three had thrombocytopenia; and two had elevated liver-enzyme levels. All recovered after receiving doxycycline treatment. At least 17 of 697 Ixodes scapularis ticks collected in Minnesota or Wisconsin were positive for the same ehrlichia species on polymerase-chain-reaction testing. Genetic analyses revealed that this new ehrlichia species is closely related to E. muris. CONCLUSIONS: We report a new ehrlichia species in Minnesota and Wisconsin and provide supportive clinical, epidemiologic, culture, DNA-sequence, and vector data. Physicians need to be aware of this newly discovered close relative of E. muris to ensure appropriate testing, treatment, and regional surveillance. (Funded by the National Institutes of Health and the Centers for Disease Control and Prevention.). PMID- 21812672 TI - Horse versus rabbit antithymocyte globulin in acquired aplastic anemia. AB - BACKGROUND: In severe acquired aplastic anemia, hematopoietic failure is the result of immune-mediated destruction of bone marrow stem and progenitor cells. Immunosuppressive therapy with antithymocyte globulin (ATG) plus cyclosporine is an effective alternative to stem-cell transplantation and improves blood counts and survival. Although horse ATG is the standard therapy, rabbit ATG is more potent in depleting peripheral-blood lymphocytes and is preferred in other clinical circumstances. METHODS: From December 2005 through July 2010, we performed a randomized trial comparing these two ATG formulations in conventional regimens. Patients were treated at a single facility. The primary outcome was hematologic response at 6 months, as determined by blood counts. The study was designed to enroll 60 patients each for the rabbit-ATG and horse-ATG groups and was powered to detect a difference of 25 percentage points in the response rate. RESULTS: A large, unexpected difference was observed in the rate of hematologic response at 6 months in favor of horse ATG (68%; 95% confidence interval [CI], 56 to 80) as compared with rabbit ATG (37%; 95% CI, 24 to 49; P<0.001). Overall survival at 3 years also differed, with a survival rate of 96% (95% CI, 90 to 100) in the horse-ATG group as compared with 76% (95% CI, 61 to 95) in the rabbit ATG group (P=0.04) when data were censored at the time of stem-cell transplantation, and 94% (95% CI, 88 to 100) as compared with 70% (95% CI, 56 to 86; P=0.008) in the respective groups when stem-cell-transplantation events were not censored. CONCLUSIONS: In a randomized study, rabbit ATG was inferior to horse ATG as a first treatment for severe aplastic anemia, as indicated by hematologic response and survival. (Funded by the Intramural Research Program of the National Institutes of Health; ClinicalTrials.gov number, NCT00260689.). PMID- 21812673 TI - Clinical practice. Chronic hypertension in pregnancy. PMID- 21812674 TI - Images in clinical medicine. "Thumb sign" of epiglottitis. PMID- 21812675 TI - Clinical problem-solving. Looking at the whole picture. PMID- 21812677 TI - Assisted reproduction--Canada's Supreme Court and the "global baby". PMID- 21812678 TI - Evidence for human lung stem cells. PMID- 21812679 TI - Evidence for human lung stem cells. PMID- 21812680 TI - Evidence for human lung stem cells. PMID- 21812682 TI - Pneumodilation versus laparoscopic Heller's myotomy for achalasia. PMID- 21812683 TI - Pneumodilation versus laparoscopic Heller's myotomy for achalasia. PMID- 21812685 TI - CABG in patients with left ventricular dysfunction. PMID- 21812686 TI - CABG in patients with left ventricular dysfunction. PMID- 21812687 TI - CABG in patients with left ventricular dysfunction. PMID- 21812688 TI - CABG in patients with left ventricular dysfunction. PMID- 21812689 TI - CABG in patients with left ventricular dysfunction. PMID- 21812691 TI - Myocardial viability in ischemic left ventricular dysfunction. PMID- 21812692 TI - Myocardial viability in ischemic left ventricular dysfunction. PMID- 21812693 TI - Myocardial viability in ischemic left ventricular dysfunction. PMID- 21812695 TI - Prescriptions, privacy, and the first amendment. PMID- 21812696 TI - Prescriptions, privacy, and the first amendment. PMID- 21812697 TI - Prescriptions, privacy, and the First Amendment. PMID- 21812699 TI - Diagnosis of smoldering multiple myeloma. PMID- 21812700 TI - The TEMPI syndrome--a novel multisystem disease. PMID- 21812703 TI - Cervical vertebral maturation of children with orofacial clefts. AB - OBJECTIVE: To evaluate the skeletal maturation of male children with orofacial clefts using the cervical vertebral maturation (CVM) method. DESIGN: Case-control study. SETTING: The School of Stomatology, Peking University. PATIENTS: Subjects were 443 boys with cleft lip and/or cleft palate (CL/P) aged 8 to 16 years who were compared with 1772 boys without clefts in an age-matched control group. RESULTS: The 8- to 10-year-old boys of both groups were in CS1. Most of the 11- to 14-year-old boys without CL/P were in CS3 and CS4, though it was not so obvious in boys with CL/P. Most 15- to 16-year-old boys without CL/P were in CS5 and CS6, while there were a lot of boys with CL/P who were still in cervical stages before CS5. Clefts had a significant effect on growth, and boys without CL/P were 1.737 times more likely to have achieved higher cervical stages. From Mann-Whitney test of every age phase, the difference existed in each year of the age range of 11 to 16 years, except from 12 to 13 years (p = .100). In these age phases, the cervical stages of boys with CL/P were lower than those for boys without CL/P. By the age of 14, children with CL/P had a 4.679 times higher risk of delayed CS3, and the 95% confidence interval for the odds ratio was 2.129 to 10.286. CONCLUSIONS: Boys with CL/P are at a higher risk of delayed growth period and retarded pubertal growth peak. PMID- 21812704 TI - Smoking is ok as long as I eat healthily: Compensatory Health Beliefs and their role for intentions and smoking within the Health Action Process Approach. AB - Compensatory Health Beliefs (CHBs) are defined as beliefs that the negative consequences of unhealthy behaviours can be compensated for by engaging in healthy behaviours. CHBs have not yet been investigated within a framework of a behaviour change model, nor have they been investigated in detail regarding smoking. Thus, the aim of this study was to investigate on a theoretical basis whether smoking-specific CHBs, as a cognitive construct, add especially to the prediction of intention formation but also to changes in smoking behaviour over and above predictors specified by the Health Action Process Approach (HAPA). The sample comprised 385 adolescent smokers (mean age: 17.80). All HAPA-specific variables and a smoking-specific CHB scale were assessed twice, 4 months apart. Data were analysed using structural equation modelling. Smoking-specific CHBs were significantly negatively related to the intention to stop smoking over and above HAPA-specific predictors. Overall, 39% of variance in the intention to quit smoking was explained. For the prediction of smoking, CHBs were not able to explain variance over and above planning and self-efficacy. Thus, smoking specific CHBs seem mainly important in predicting intentions but not behaviour. Overall, the findings contribute to the understanding of the role of smoking specific CHBs within a health-behaviour change model. PMID- 21812705 TI - The locus of the benefits of repetition-lag memory training. AB - The repetition-lag training procedure developed by Jennings and Jacoby (2003 , Neuropsychological Rehabilitation, 14, 417) has been shown to improve older adults' performance in the recognition memory task used for training, and to improve performance in a variety of other memory and executive function tasks ( Jennings, Webster, Kleykamp, & Dagenbach, 2005 , Aging, Neuropsychology, and Cognition, 12, 278). The present study examined the effects of concurrent interference tasks during the study or test phases of training to localize the source of gains. Overall, the results suggest that training is resilient and resistant to interference, but also that the processes used during the test phases of training are more important to the gains seen in the primary task and in the transfer tasks than those used in the study phases. PMID- 21812706 TI - Last Call: decreasing drunk driving among 21-34-year-old bar patrons. AB - Any effort to decrease the toll of drunk driving must include efforts directed at people who drink in bars, particularly young adults who use motor vehicles after drinking. We designed a multifaceted social marketing campaign, Last Call, to increase the use of designated drivers and safe rides homes among 21-34-year olds. There were three components to the intervention: (1) use of taxi stands to promote taxi use; (2) point-of-sale information to patrons at partner bars and (3) a mass media campaign to support the designated driver/safe ride home message. Among the heaviest drinkers, the programme significantly increased the use of designated drivers and increased the use of taxis by 63%. PMID- 21812707 TI - Profile of injury cases admitted to a tertiary level hospital in south India. AB - Injuries now rank among the leading causes of morbidity and mortality the world over. Injuries are steadily increasing in developing countries like India. Systematic and scientific efforts in injury prevention and control are yet to begin in India. Data on injuries are very essential to plan preventive and control measures. The objective of this study is to know the profile of the injury cases admitted to M S Ramaiah hospital, Bangalore, India, using a cross sectional study design for six months, i.e. from Oct 2008 to April 2009. The mean age of the study population was 35.3 years (SD = 15.38), 69.1% were injured in road traffic accidents (RTA), 28.7% due to falls and 2.2% due to burns. Nearly 14.4% were under the influence of alcohol. Nearly 73.6% of RTA cases were two wheeler users, 48.5% had not followed sign boards and 56.5% had not obeyed the one-way rules, 63.5% of the two-wheeler users did not use helmets. Also, 38% of two wheelers had two pillion riders, whereas 57% of four-wheeler users had not used a seat belt. Among falls, 58% occurred at home, 49% occurred due to slippery surface. Road traffic accidents were the most common cause for injuries, in which two wheelers were most commonly involved. Strict enforcement of traffic rules and education on road safety are very essential to prevent injuries. PMID- 21812708 TI - Supervised versus unsupervised categorization: two sides of the same coin? AB - Supervised and unsupervised categorization have been studied in separate research traditions. A handful of studies have attempted to explore a possible convergence between the two. The present research builds on these studies, by comparing the unsupervised categorization results of Pothos et al. ( 2011 ; Pothos et al., 2008 ) with the results from two procedures of supervised categorization. In two experiments, we tested 375 participants with nine different stimulus sets and examined the relation between ease of learning of a classification, memory for a classification, and spontaneous preference for a classification. After taking into account the role of the number of category labels (clusters) in supervised learning, we found the three variables to be closely associated with each other. Our results provide encouragement for researchers seeking unified theoretical explanations for supervised and unsupervised categorization, but raise a range of challenging theoretical questions. PMID- 21812709 TI - Toddlers' language-mediated visual search: they need not have the words for it. AB - Eye movements made by listeners during language-mediated visual search reveal a strong link between visual processing and conceptual processing. For example, upon hearing the word for a missing referent with a characteristic colour (e.g., "strawberry"), listeners tend to fixate a colour-matched distractor (e.g., a red plane) more than a colour-mismatched distractor (e.g., a yellow plane). We ask whether these shifts in visual attention are mediated by the retrieval of lexically stored colour labels. Do children who do not yet possess verbal labels for the colour attribute that spoken and viewed objects have in common exhibit language-mediated eye movements like those made by older children and adults? That is, do toddlers look at a red plane when hearing "strawberry"? We observed that 24-month-olds lacking colour term knowledge nonetheless recognized the perceptual-conceptual commonality between named and seen objects. This indicates that language-mediated visual search need not depend on stored labels for concepts. PMID- 21812710 TI - Face processing as a brain adaptation at multiple timescales. AB - I consider face processing as the brain's adaptive response to phylogenetic, ontogenetic, and task-specific factors. Focusing on wide-ranging evidence from both my own laboratory and others, evidence for a primitive "quick and dirty" route for face processing that exists prior to postnatal experience is reviewed. Next, I trace the emergence of cortical specialization for face processing influenced by individual developmental experience (ontogenetic adaptation) and suggest that this ontogenetic adaptation is also heavily constrained by the phylogenetic system. Finally, I turn to recent evidence on task-specific modulation of activity in the core face network that illustrates brain adaptation at a finer timescale than that for the other systems. Current evidence indicates that task-specific modulation of the cortical face network does not emerge until the teenage years. As previously proposed for other components of cognition, I propose that these systems are complementary to each other, each compensating for the others' weaknesses. Different face-related systems are adapted to respond to survival pressures at different timescales, from millennia, to months, to microseconds. PMID- 21812711 TI - Necrotic enteritis in broilers: an updated review on the pathogenesis. AB - Clostridium perfringens-induced necrotic enteritis and related subclinical disease have become economically significant problems for the broiler industry. Fortunately, scientific interest in this topic has grown: new C. perfringens virulence factors have been discovered and new insight gained about the pathogenesis of necrotic enteritis. It has been shown that alpha toxin, for a long time thought to be the key virulence factor, is not essential for the development of the disease. Moreover, it is now clearly established that only certain C. perfringens strains are capable of inducing necrotic enteritis under specific conditions that predispose to the disease and they constitute only a minority in the intestinal tract of healthy chickens. A novel pore-forming toxin, NetB, has been identified in these virulent avian C. perfringens strains. Using a gene knockout mutant, it has been shown that NetB is a critical virulence factor in the pathogenesis of necrotic enteritis in broilers. In addition to toxin production, other factors have been described that contribute to the ability of certain C. perfringens strains to cause necrotic enteritis in broilers. It has been suggested that proteolytic enzymes play an important role in the initial stages of necrotic enteritis since the villi are first affected at the level of the basement membrane and the lateral domain of the enterocytes. In field outbreaks of necrotic enteritis, a single clone of C. perfringens is dominant in intestines of all affected birds, as opposed to the mixture of different C. perfringens strains that can be isolated from healthy bird intestines. It has been proposed that bacteriocin production is responsible for the dominance of a single strain in necrotic enteritis cases. Furthermore, it has been shown that virulent strains are more able to adhere to extracellular matrix molecules than non-virulent strains. The current knowledge on the pathogenesis of the disease has been summarized in this short review. PMID- 21812712 TI - Mycoplasma gallisepticum experimental infection and tissue distribution in chickens, sparrows and pigeons. AB - The most effective approaches to control the spread of Mycoplasma gallisepticum include strict biosecurity measures, continuous surveillance and eradication of infected flocks. The rapid expansion of the poultry industry worldwide in restricted geographical areas and severe economic losses due to M. gallisepticum outbreaks make it crucial to identify and better control the vectors responsible for the transmission of the disease. In the present study we evaluated the susceptibility of sparrows and pigeons to M. gallisepticum and the tissue distribution of M. gallisepticum in these species as compared with chickens. This information will further define the role of these common avian species in M. gallisepticum transmission. Twenty-six chickens, pigeons, and sparrows were experimentally inoculated with a field strain of M. gallisepticum and were monitored for the development of clinical signs, seroconversion, productive infection by culture, and M. gallisepticum distribution in their tissues by immunohistochemistry. All M. gallisepticum-inoculated chickens showed mild respiratory signs, seroconverted (haemagglutination inhibition geometric mean titre = 494) and shed M. gallisepticum in their tracheas. M. gallisepticum antigens were observed at high levels by immunohistochemistry in their tracheas, conjunctivas, nasal turbinates, and air sacs. The pigeons and sparrows did not show clinical signs or seroconvert but M. gallisepticum was reisolated up to 7 days post inoculation from pigeons and intermittently from sparrows. M. gallisepticum antigens were observed at low level in the conjunctiva of some pigeons and sparrows, as well as in the trachea of some sparrows. We conclude that pigeons and sparrows are partially susceptible to M. gallisepticum infection but do not seroconvert or maintain a steady carrier state similar to chickens and that these species may play a role in M. gallisepticum transmission between poultry farms as mechanical vectors. PMID- 21812713 TI - Pathological and epidemiological significance of goose haemorrhagic polyomavirus infection in ducks. AB - Goose haemorrhagic polyomavirus (GHPV) is the viral agent of haemorrhagic nephritis enteritis of geese, a lethal disease of goslings. It was recently shown that GHPV can also be detected in Muscovy and mule ducks. The goal of the present study was to investigate the pathobiology of GHPV in ducks. In the first experiment, field isolates of GHPV from Muscovy or mule ducks were fully sequenced and compared with goose GHPV. These duck isolates were then used to inoculate 1-day-old goslings. Typical clinical signs and lesions of haemorrhagic nephritis enteritis of geese were reproduced, indicating that "duck-GHPV" isolates are virulent in geese. In the second experiment, 1-day-old and 21-day old Muscovy ducklings were infected by a reference GHPV strain. In both cases, neither clinical signs nor histopathological lesions were observed. However, the virus was detected in cloacal bursae and sera, and serological responses were detected at 12 days post infection. These findings suggest firstly that one common genotype of GHPV circulates among ducks and geese, and secondly that ducks may be infected by GHPV but show no pathologic evidence of infection, whereas geese express clinical signs. GHPV infection should therefore be considered as being carried in ducks and of epidemiological relevance in cases of contact with goose flocks. PMID- 21812714 TI - Detection of astrovirus infection in pigeons (Columbia livia) during an outbreak of diarrhoea. AB - Avian astrovirus infections are widespread in many countries, and infections have been linked to enteritis and increased mortality in young poultry. Although pigeons are treated as an important poultry product in some countries, their diseases are often poorly understood and astrovirus infection in pigeons has not been reported. In the present study, faecal samples were collected during an outbreak of gastrointestinal illness in a population of Shanghai pigeons. The samples were examined for astroviruses by reverse transcription-polymerase chain reaction. Eighty-nine per cent (40/45) and 4% (2/45) were found to be positive for avian nephritis virus (ANV) and chicken astrovirus, respectively. One positive sample indicated a co-infection with both ANV and chicken astrovirus. Phylogenetic analysis based on the partial polymerase gene sequence and full length capsid protein from published avian astrovirus sequences in GenBank revealed that the pigeon viruses detected in this study were evolutionarily closely related to chicken ANV. The present study provided evidence for the presence of astrovirus in pigeons and suggests that cross-infection between pigeons and commercial chickens was likely. Whether the astroviruses in pigeons were responsible for the diarrhoea remains to be determined. PMID- 21812715 TI - Mixed infection with Libyostrongylus dentatus and Libyostrongylus douglassii induces a heterophilic inflammatory infiltrate in the proventriculus of ostriches. AB - Libyostrongylus dentatus and Libyostrongylus douglassii are haematophagous nematodes found in the proventriculus and the ventriculus of ostriches. Pathological damage leading to bird death has been attributed to L. douglassii. However, histopathology of the mixed infection has not been reported. The aim of the present work was to characterize the cellular inflammatory infiltrate found in the proventriculus of ostriches with a mixed infection. Analysis of the collected nematodes confirmed a mixed infection in the proventriculus of examined birds. Histopathological examination of the proventriculus showed an inflammatory infiltrate composed of granular cells in close proximity to the nematodes. The granulocyte infiltrate was composed mainly of heterophils identified by the lack of peroxidase and presence of fusiform granules. PMID- 21812716 TI - Bilateral coxofemoral degenerative joint disease in a juvenile male yellow-eyed penguin (Megadyptes antipodes). AB - A juvenile, male, yellow-eyed penguin (Megadyptes antipodes) with abnormal stance and decreased mobility was captured, held in captivity for approximately 6 weeks, and euthanized due to continued clinical signs. Radiographically, there was bilateral degenerative joint disease with coxofemoral periarticular osteophyte formation. Grossly, the bird had bilaterally distended, thickened coxofemoral joints with increased laxity, and small, roughened and angular femoral heads. Histologically, the left femoral articular cartilage and subchondral bone were absent, and the remaining femoral head consisted of trabecular bone overlain by fibrin and granulation tissue. There was no gross or histological evidence of infection. The historic, gross, radiographic, and histopathologic findings were most consistent with bilateral aseptic femoral head degeneration resulting in degenerative joint disease. Although the chronicity of the lesions masked the initiating cause, the probable underlying causes of aseptic bilateral femoral head degeneration in a young animal are osteonecrosis and osteochondrosis of the femoral head. To our knowledge, this is the first reported case of bilateral coxofemoral degenerative joint disease in a penguin. PMID- 21812717 TI - Chicken infectious anaemia vaccinal strain persists in the spleen and thymus of young chicks and induces thymic lymphoid cell disorders. AB - The chicken infectious anaemia virus (CIAV) infection may induce immunosuppression and persistent infection. The use of vaccination in young chicks is still controversial due to its low immune efficiency. In order to verify the viral persistency of a vaccinal strain of CIAV and its associated lymphoid cell disorders, 54 1-day-old specific pathogen free chicks were vaccinated (CIAV-VAC((r)); Intervet, Millsboro, Delaware, USA) and haematologic examination, expression of viral VP3 gene, humoral response and phenotyping of lymphoid cells were studied in lymphoid organs at various times post vaccination (p.v.). No clinical signs were observed but light heteropaenia was detected in CIAV-vaccinated chicks. The VP3 gene of CIAV was detected by polymerase chain reaction in the thymus and spleen from day 7 until 28 days p.v. Thymic larger CD4(+)CD8(+) cells increased only at 7 days p.v. while smaller CD4(+)CD8(+) cells decreased after 14 and 28 days in CIAV-vaccinated birds. The CD4 expression, in contrast to that seen for CD8, decreased in thymocytes from the CIAV-vaccinated group. In the spleen and bursa, the percentage of CD8(+) cells increased at 7 and 28 days p.v. only, while CD4(+) cells decreased simultaneously. The vaccinated chicks also exhibited a higher number of splenic CD3(-)CD8(+) cells (natural killer cells). The anti-CIAV antibody responses, however, remained low in most vaccinated chicks and did not persist up to 18 days p.v. These results suggest that the vaccinal virus strain is clinically attenuated but persists in the thymus and spleen in some birds, inducing a low humoral immune response and altering thymopoiesis. PMID- 21812718 TI - Antimicrobial susceptibility of Brachyspira spp. isolated from commercial laying hens and free-living wild mallards (Anas platyrhynchos). AB - In vitro antimicrobial susceptibility to tylosin, valnemulin, tiamulin, doxycycline, lincomycin and ampicillin was investigated by broth dilution in 48 Brachyspira spp. isolates from commercial laying hens (n=30) and free-living wild mallards (Anas platyrhynchos) (n=18). Presumed pathogens (Brachyspira alvinipulli, Brachyspira intermedia, Brachyspira pilosicoli), commensals (Brachyspira murdochii, Brachyspira innocens, "Brachyspira pulli"), and isolates of undetermined species affiliation were included. The laying hens had not been exposed to therapeutic levels of antimicrobials for at least 50 weeks before sampling, and low levels of environmental antimicrobial exposure were presumed in mallards. No isolates with decreased susceptibility to tylosin, valnemulin, tiamulin or doxycycline were found. Decreased susceptibility to lincomycin (minimum inhibitory concentration 16 ug/ml) was detected in two isolates (Brachyspira sp.) from laying hens. Five isolates showed decreased susceptibility to ampicillin (minimum inhibitory concentration 16 to >32 ug/ml), including two "B. pulli" and one B. alvinipulli from laying hens, and isolates of B. pilosicoli and "B. pulli" from mallards. Decreased susceptibility to ampicillin was associated with beta-lactamase activity in four isolates. A new variant of a class D beta-lactamase gene designated bla (oxa-192) was identified in a B. pilosicoli isolate of mallard origin. This is the first time the genetic basis for antimicrobial resistance is described in Brachyspira spp. from a free-living wild bird. Isolates displaying decreased susceptibility to ampicillin were accompanied by fully susceptible isolates of the same species or other genotypes within three laying hen flocks. This underlines the need for performing antimicrobial susceptibility tests on single clones/genotypes, and to analyse multiple isolates from the same flock. PMID- 21812719 TI - Replication of recombinant herpesvirus of turkey expressing genes of infectious laryngotracheitis virus in specific pathogen free and broiler chickens following in ovo and subcutaneous vaccination. AB - Replication of a recombinant herpesvirus of turkey vaccine expressing infectious laryngotracheitis virus genes (rHVT-LT) was evaluated in specific pathogen free (SPF) and commercial broiler chickens after various vaccination protocols (amniotic route at embryonation day [ED] 18; intra-embryonic route at ED 19; and subcutaneous at 1 day of age [s.c.]). Three experiments were conducted: in the first experiment, replication of rHVT-LT vaccine was chronologically evaluated and compared with the replication of herpesvirus of turkey (HVT) in SPF chickens; in the second experiment, the effect of different in ovo vaccination procedures on rHVT-LT vaccine replication was evaluated in SPF chickens; and in the third experiment, the effect of different in ovo vaccination procedures on rHVT-LT vaccine replication was evaluated in commercial broiler chickens with maternal antibodies against HVT and infectious laryngotracheitis virus (LTV). rHVT-LT vaccine replicated in chickens after in ovo (ED 18 and ED 19) or s.c. administration at a similar level. In vivo replication of rHVT-LT vaccine was slower than HVT vaccine. However, in vivo both rHVT-LT and HVT vaccines replicated at similar levels. Both vaccines were consistently detected in the spleen and feather pulp and at lower frequency in the lung. The frequency of samples with detectable levels of rHVT-LT DNA was lower in broiler chickens than in SPF chickens, probably due to interactions with maternal antibodies. Differences between SPF chickens and broiler chickens were found also in the transcription of the LTV glycoprotein I gene (gI). In SPF chickens, in ovo inoculation resulted in a higher number of spleen samples with detectable gI transcripts than s.c. inoculation. In broiler chickens, however, no differences in the level of gI transcripts in spleen samples were found between chickens vaccinated in ovo and those vaccinated by the s.c. route. Transcription of LTV gI gene in lung samples was very low in both SPF and broiler chickens. Further studies to evaluate the mucosal immune response elicited by rHVT-LT in chicken with and without maternal antibodies are warranted. PMID- 21812720 TI - Pathogenic microorganisms carried by migratory birds passing through the territory of the island of Ustica, Sicily (Italy). AB - Several studies have shown that migratory birds play an important role in the ecology, circulation and dissemination of pathogenic organisms. In October 2006, a health status evaluation was performed on a large population of migratory birds passing through the territory of Ustica (Italy), an island located on the migration route of many species of birds to Africa, and various laboratory tests were conducted. In total, 218 faecal swabs and the internal organs of 21 subjects found dead in nets were collected for bacteriological and virological examination, including avian influenza and Newcastle disease. In addition, 19 pooled fresh faecal samples were collected for mycological examination. The bacteriological analysis produced 183 strains belonging to 28 different species of the Enterobacteriaceae family. In particular, Salmonella bongori, Yersinia enterocolitica and Klebsiella pneumonia strains were isolated. Almost all of the isolates were susceptible to sulphamethoxazole/trimethoprime (99.4%), cefotaxime (98.9%), nalidixic acid (96.7%), chloramphenicol (95.6%), and tetracycline (93.4%). Alternatively, many strains were resistant to ampicillin (42.6%), amoxicillin-clavulanic acid (42.6%), and streptomycin (43.7%). According to reverse transcriptase-polymerase chain reaction analysis, all of the samples were negative for the M gene of avian influenza virus. Moreover, isolation tests conducted on specific pathogen free eggs were negative for avian influenza and Newcastle disease. Several hyphomycetes and yeasts belonging to different genera were present in the specimens, and Cryptococcus neoformans was observed in a pooled faecal sample. Antibiotic resistance in wildlife can be monitored to evaluate the impact of anthropic pressure. Furthermore, migratory birds are potential reservoirs of pathogenic agents; thus, they can be regarded as sentinel species and used as environmental health indicators. PMID- 21812721 TI - Comparative in vivo safety and efficacy of a glycoprotein G-deficient candidate vaccine strain of infectious laryngotracheitis virus delivered via eye drop. AB - Infectious laryngotracheitis (ILT) is an acute respiratory disease in poultry that is commonly controlled by vaccination with conventionally attenuated virus strains. Despite the use of these vaccines, ILT remains a threat to the intensive poultry industry. Our laboratory has developed a novel candidate vaccine strain of infectious laryngotracheitis virus (ILTV) lacking glycoprotein G (DeltagG ILTV). The aim of the present study was to directly compare this candidate vaccine with three currently available commercial vaccines in vivo. Five groups of specific-pathogen-free chickens were eye-drop inoculated with one of the three commercial vaccine strains (SA2-ILTV, A20-ILTV or Serva-ILTV), or DeltagG-ILTV, or sterile medium. Vaccine safety was assessed by examining clinical signs, weight gain and persistence of virus in the trachea. Vaccine efficacy was assessed by scoring clinical signs and conducting post-mortem analyses following challenge with virulent virus. Following vaccination, birds that received DeltagG ILTV had the highest weight gain among the vaccinated groups and had clinical scores that were significantly lower than birds vaccinated with SA2-ILTV or A20 ILTV, but not significantly different from those of birds vaccinated with Serva ILTV. Analysis of clinical scores, weight gain, tracheal pathology and virus replication after challenge revealed a comparable level of efficacy for all vaccines. Findings from this study further demonstrate the suitability of DeltagG ILTV as a vaccine to control ILT. PMID- 21812722 TI - Occurrence of avian bornavirus infection in captive psittacines in various European countries and its association with proventricular dilatation disease. AB - A total of 1442 live birds and 73 dead birds out of 215 bird collections in Spain, Germany, Italy, the UK and Denmark were tested for avian bornavirus (ABV) infection by four different methods. The majority of the birds were psittacines belonging to 54 different genera of the order Psittaciformes. In total, 22.8% of the birds reacted positive for ABV in at least one of the tests. Combined testing of swabs from the crop and cloaca, and serum for the diagnosis of ABV infection in live birds revealed that virus shedding and antibody production coincided in only one-fifth of the positive birds so that the examination of these three samples is recommended for reliable ABV diagnosis. By statistical analysis of this large number of samples, the ABV infection proved to be highly significant (P <0.001) associated with histopathologically confirmed proventricular dilatation disease (PDD) in dead birds as well as with clinically assumed PDD in live birds. However, ABV infection was also detected in psittacines without pathological lesions or clinical signs of PDD. Twelve non-psittacine birds belonging to the genera Aburria, Ciconia, Geopelia, Leucopsar and Pavo were tested negative for ABV infection. Within the order of Psittaciformes, birds belonging to 33 different genera reacted positive for ABV. In 16 of these psittacine genera, the ABV infection was demonstrated for the first time. The present study emphasizes the widespread occurrence of clinically variable ABV infections in Europe by analysing a large number of specimens from a broad range of bird species in several assays. PMID- 21812724 TI - Development and initial validation of the Psychological Characteristics of Developing Excellence Questionnaire. AB - The development of talent is a complex process mediated by a host of psychological, social, physical, and environmental variables. Unfortunately, the multiple processes involved in talent development are frequently ignored by the systems and protocols employed in sport. Modern approaches to talent development are beginning to stress the initial possession, then subsequent development, of generic psychological characteristics (e.g. psychological characteristics of developing excellence; MacNamara, Button, & Collins, 2010a , 2010b ) as the best way to realize latent potential. Accordingly, this paper describes the development and initial validation of the Psychological Characteristics of Developing Excellence Questionnaire (PCDEQ). In the first phase, an initial list of 160 items was developed. A combination of expert panel reviews, cognitive interviews, and a pilot test was used to assess the relevance, representativeness, and validity of each item. Ninety-six items were retained following these steps. Exploratory factor analysis, with a sample of 363 athletes, revealed an interpretable 59-item, 6-factor solution with good internal consistency (0.870, 0.866, 0.847, 0.741, 0.749, and 0.701 respectively). The Psychological Characteristics of Developing Excellence Questionnaire would appear to hold promise as a useful tool to provide coaches and athletes with information about the psychological characteristics of developing excellence that are being properly addressed or neglected during different stages of development or in different contexts. PMID- 21812725 TI - The utility of six over-the-counter (home) pregnancy tests. AB - BACKGROUND: The home pregnancy market is rapidly evolving. It has moved from detection of pregnancy on the day of missed menstrual bleeding, to detection claims 4 days prior. It is moving from all manual tests to digital tests, with a monitor reading the bands and informing women they are pregnant. A thorough study is needed to investigate the validity of claims and evolving usefulness of devices. METHODS: Studies were proposed to examine the sensitivity and specificity of home tests and their abilities to detect pregnancy. Methods examined the abilities of tests to detect human chorionic gonadotropin (hCG), hyperglycosylated hCG, free beta-subunit, a mixture of these antigens in 40 individual early pregnancy urines. RESULTS: Using a mixture of hCG, hyperglycosylated hCG and free beta-subunit typical for early pregnancy, the sensitivity of the First Response manual and digital tests was 5.5 mIU/mL, while the sensitivities of the EPT and ClearBlue brand manual and digital tests was 22 mIU/mL. On further evaluation, the First Response manual and digital tests both detected 97% of 120 pregnancies on the day of missed menstrual bleeding. The EPT manual and digital devices detected 54% and 67% of pregnancies, respectively, and the ClearBlue manual and digital devices detected 64% and 54% of pregnancies, respectively. CONCLUSIONS: First Response manual and digital claim >99% detection on the day of missed menses. The results here suggest similar sensitivity for these two tests. The EPT and ClearBlue manual and digital test make similar >99% claims, the data presented here disputes their elevated claim. PMID- 21812735 TI - Clinical outcomes following switch from venlafaxine ER to desvenlafaxine in nonresponders and responders. AB - OBJECTIVE: This post hoc analysis examined efficacy and tolerability of open label desvenlafaxine in patients with major depressive disorder switched from blinded placebo, venlafaxine extended release (ER), or desvenlafaxine. RESEARCH DESIGN AND METHODS: Patients who completed 8 weeks of double-blind therapy with placebo (n = 176), venlafaxine ER (n = 175), or desvenlafaxine (n = 143) enrolled in a 10-month, open-label extension study and received desvenlafaxine 200 to 400 mg/d. Efficacy (17-item Hamilton Depression Rating Scale [HDRS(17)]) was assessed separately for nonresponders and responders to double-blind treatment. Tolerability during the first month of open-label desvenlafaxine was assessed. RESULTS: Among nonresponders (n = 134) to double-blind placebo, venlafaxine ER, and desvenlafaxine, mean decreases in HDRS(17) scores were -10.9, -7.3, and -7.7, respectively; HDRS(17) response rates were 67%, 53%, and 48%, respectively. Although responders (n = 360) to double-blind placebo, venlafaxine ER, and desvenlafaxine had more modest decreases on the HDRS(17), response rates were higher (84%, 87%, and 83%, respectively). Rates of adverse events were highest during week 1, and decreased afterward for the remainder of the first month of treatment. CONCLUSIONS: Among nonresponders to 8 weeks of double-blind venlafaxine ER, desvenlafaxine, or placebo, 48% to 67% subsequently responded to open-label desvenlafaxine. Over 80% of responders to double-blind therapy maintained response on open-label desvenlafaxine. The switch from venlafaxine ER to desvenlafaxine was well tolerated. PMID- 21812736 TI - Efficacy, safety, and pharmacokinetics of ambrisentan in Japanese adults with pulmonary arterial hypertension. AB - OBJECTIVE: To investigate the efficacy, safety, and pharmacokinetics of ambrisentan in Japanese adults with pulmonary arterial hypertension (PAH). RESEARCH DESIGN AND METHODS: In this open-label, uncontrolled, dose-escalation study, 25 Japanese patients with PAH were scheduled to receive 5 mg of ambrisentan once daily for the first 12 weeks, and 10 mg once daily for an additional 12 weeks. The primary endpoint was improvement in exercise capacity from baseline which was indicated by 6-minute walk distance; the secondary endpoints included World Health Organization functional class, Borg dyspnea index, plasma brain natriuretic peptide level, and cardiopulmonary hemodynamics. CLINICAL TRIAL REGISTRATION: NCT00540436. RESULTS: At week 24, improvements were noted in all endpoints, with no clinically significant elevation of serum aminotransferase level. Pharmacokinetics in these Japanese patients was similar to that of non-Japanese populations, suggesting that once-daily dosing is appropriate in Japanese patients. Ambrisentan was generally well tolerated. No new safety signals were identified. LIMITATION: This study lacked a control group and was insufficiently powered to reach definitive conclusions on the efficacy of ambrisentan. CONCLUSION: Ambrisentan is considered as safe and effective for Japanese adults with PAH. PMID- 21812737 TI - An experimental study on dynamic morphological changes and expression pattern of GFAP and synapsin i in the hippocampus of MTLE models for immature rats. AB - OBJECTIVE: To establish an animal model resembling human mesial temporal lobe epilepsy (MTLE); observe the dynamic changes of mossy fiber sprouting (MFS) and neuron loss in the hippocampus; and investigate the expression changes of Glial fibrillary acidic protein (GFAP) and Synapsin I in the hippocampus in immature rats. METHODS: MTLE models of immature rats were induced by lithium-pilocarpine. The surviving animals were continually monitored for 8 weeks. Nissl staining was used to observe the neuron loss and Timm staining was performed to evaluate MFS. Western blot (WB) and immunohistochemical methods were performed to detect the expression of GFAP and Synapsin I. RESULTS: Status epilepticus (SE) was successfully induced in 94.1% of the rats with a high mortality of 68.8%; 75% of the survived rats were observed for spontaneous recurrent seizures (SRS) which resembles the features of human MTLE. Expression levels of glial fibrillary acidic protein and Synapsin I fluctuated in correspondence with the different stages of MTLE development. CONCLUSION: We established an animal model depicting the human MTLE by using immature rats. GFAP and Synapsin I expressions are involved in MTLE development. Neuron loss and mossy fiber sprouting may have a role in epileptogenesis. PMID- 21812738 TI - Intra-arterial nicardipine for the treatment of cerebral vasospasm in postpartum cerebral angiopathy: a case study and review of literature. AB - INTRODUCTION: Postpartum cerebral angiopathy is one of the many neurological complications seen during pregnancy and the postpartum period. Management of these patients consists of optimal blood pressure control, and general supportive critical care. We present a case of diffuse cerebral vasospasm, which improved with intra-arterial nicardipine. This brief report addresses the utility of interventional management in cases of postpartum cerebral angiopathy. CASE REPORT: A 28-year-old female presented 1 week after cesarean delivery with altered mental status, endotracheal intubation for airway protection, thrombocytopenia, and hypofibrinogenemia. Cerebral angiogram revealed anterior and posterior circulation vasospasm, which responded to repeated selective intra arterial injections of nicardipine. This treatment coupled with optimal blood pressure control resulted in complete recovery. DISCUSSION: Our case report highlights the importance of cerebral angiography for the diagnosis and treatment of patients with postpartum cerebral angiopathy. Although nicardipine is used in patients with aneurysmal subarachnoid hemorrhage for the treatment of cerebral vasospasm, this agent has the potential to be used in patients with cerebral vasospasm due to other etiologies. SUMMARY: Intra-arterial nicardipine is one of the therapeutic measures available to physicians in the management of patients with cerebral vasospasm. In patients with postpartum cerebral angiopathy, early cerebral angiography should be considered to quantify and treat cerebral vasospasm with either angioplasty or selective intra-arterial injections of nicardipine. PMID- 21812739 TI - Genetic variants in the RAB7L1 and SLC41A1 genes of the PARK16 locus in Chinese Parkinson's disease patients. AB - We performed direct DNA sequencing of the RAB7L1 and SLC41A1 genes within the PARK16 locus in 205 Chinese Parkinson's disease (PD) patients. Three novel heterozygous variants were identified in SLC41A1: c.436A > G (causing p.Lys146Glu), c.1440A > G (causing p.Pro480Pro), and c.552 + 50G > A. These three variants were not present in any of the 210 genetically unrelated healthy controls of the same ethnic origin. No changes were identified in the RAB7L1 gene. Additionally, for the eight core PARK16 SNPs, no significant difference in allele or genotype frequencies was observed between PD patients and controls. Further analysis is required to determine the role of genes within the PARK16 locus in development of PD. PMID- 21812743 TI - The use of the Bayley Scales of Infant and Toddler Development III with clinical populations: a preliminary exploration. AB - In response to concerns that the Bayley Scales of Infant and Toddler Development III (BSIDIII) underestimate delay in clinical populations, this study explores developmental quotient scores as an alternative to composite scores for these children. One hundred and twenty-two children aged <=42 months, referred for diagnosis of developmental disability from January 2007 to May 2010, were assessed, and their composite and developmental quotient scores on each scale were compared. Composite scores identified only 22% (cognitive), 27% (motor), and 47.5% (language) of children as having a developmental disability. Developmental quotient scores were significantly lower than composite scores, giving rates of developmental disability of 56.6% (cognitive), 48.4% (motor), and 74.6% (language) and more closely matching both clinical impressions of delay and the proportions of those children who were also delayed on standardized tests of adaptive function. PMID- 21812744 TI - Charles victor dayus. AB - Abstract Extract Charles Victor Dayus, who died on December 7(th) 1982, was born on September 2, 1896 at Craven Arms, Shropshire. He was the last of a long line of veterinary surgeons since 1800: great-grandfather, grandfather, and then father who qualified in London in 1880, with practices over the years at Longnor, Dorrington and Craven Arms. PMID- 21812745 TI - A pulmonary granular cell tumour with associated hypertrophic osteopathy in a horse. AB - Abstract Extract A 15-year-old pony mare developed firm irregular bony swellings on all four legs. These were most severe around the carpal and fetlock joints of the forelegs, restricting both flexion and extension. Over about 6 months the horse had periodic bouts of coughing. She showed moderate weight loss and a depressed demeanour. PMID- 21812746 TI - Thrombogenicity of dietary milkfat, fish oil and hydrogenated coconut oil in a pig model. AB - Abstract Extract Several indicators of thrombosis and thrombolysis were measured in four groups of 16 pigs fed for 10 weeks on either a low fat basal ration or rations containing 10% anhydrous milkfat (AMF), 10% fish oil (MaxEPA), or 10% hydrogenated coconut oil (HCO). At the end of the feeding period, pigs on the three test fat/oil rations were subjected to balloon angioplasty of both femoral arteries. Thrombus size at the site of injury was measured both morphometrically and using autologous blood platelets labelled with (99)Tc-HMPAO (technetium - "Deretec"). PMID- 21812747 TI - Preliminary age-related histological studies of the lymphoid tissues of the respiratory tract and associated structures of the brushtail possum. AB - Abstract Extract Lymphoepithelium was observed in palatine and pharyngeal tonsils in possums from 2 months of age, but was not seen in the lung. Morphological maturity of lymphoid tissue occurred at about 4 months of age, coinciding with first emergence of young from the pouch. Peribronchiolar and/or perivascular lymphoid aggregations were first observed in the lung of a 3.5-month-old possum, and subpleural lymphoid aggregations were first seen at 7 months of age. PMID- 21812748 TI - Pathology of 2-alkyl and 2-hydroxy naphthoquinone toxicity in rats. AB - Abstract Extract The oral administration of 2-methyl-1, 4-naphthoquinone (menadione) to rats caused oxidative destruction of the erythrocyte. Heinz body formation occurred in erythrocytes, lowered PCVs and haemoglobin Occurred in blood, with splenic and hepatic erythroclasis, and iron conservation in the spleen, liver and kidney. These effects diminished when increasingly large alkyl substitutions of the methyl group of thi naphthoquinone were made. No effect was caused by the 2-decyl derivative. PMID- 21812749 TI - The use of immunochistochemistry for the diagnosis of neosporosis in cattle and dogs. AB - Abstract Extract A goat anti-Neosporum caninum serum and an avidinbiotin peroxidase conjugate were used in a retrospective study of paraffin-embedded tissues from aborted calves and CNS tissues from dogs with neurological disease. Labelled cyst-like structures and individual or clusters of zoites were found in the brain of some aborted calves, usually associated with necrotic foci. No protozoa1 organisms could be clearly identified in the placentae of the same animals. Labelled cysts and zoites were found in the brain and spinal cord of three of 15 dogs with CNS lesions. The three dogs had a history of nervous signs and had previously been misdi- agnosed as having toxoplasmosis or granulomatous meningoencephalomyelitis. PMID- 21812750 TI - An outbreak of blindness in kangaroos in western New South Wales. AB - Abstract Extract For several months of the summer-autumn of 1994 there were many reports of blindness, particularly in Western Grey Kangaroos on properties extending from north western Victoria throughout western New South Wales. On some properties, up to 20% of macropods were affected. Many animals probably died, mainly from starvation. PMID- 21812751 TI - Lung-targeted delivery system of curcumin loaded gelatin microspheres. AB - The purpose of the study is to design and evaluate curcumin loaded gelatin microspheres (C-GMS) for effective drug delivery to the lung. C-GMS was prepared by the emulsification-linkage technique and the formulation was optimized by orthogonal design. The mean encapsulation efficiency and drug loading of the optimal C-GMS were 75.5 +/- 3.82 % and 6.15 +/- 0.44%, respectively. The C-GMS presented a spherical shape and smooth surface with a mean particle diameter of 18.9 MUm. The in vitro drug release behavior of C-GMS followed the first-order kinetics. The tissue distribution showed that the drug concentrations at lung tissue for the C-GMS suspension were significantly higher than those for the curcumin solution, and the Ce for lung was 36.19. Histopathological studies proved C-GMS was efficient and safe to be used as a passive targeted drug delivery system to the lung. Hence, C-GMS has a great potential for the targeted delivery of curcumin to the lung. PMID- 21812753 TI - Birth injury in a subsequent vaginal delivery among women with a history of shoulder dystocia. AB - AIM: To examine risk factors for birth injury in a subsequent vaginal delivery among women with a prior delivery complicated by shoulder dystocia. METHODS: Population-based retrospective cohort study, Washington State (1987-2007). Logistic regression was used to assess risk factors associated with subsequent birth injury. RESULTS: Of 9232 women who met inclusion criteria, 223 (2.4%) had a subsequent vaginal delivery with birth injury. Birth injury in an index delivery, adjusted odds ratio (aOR) 2.6 [95% confidence interval (CI) 1.7-4.1] and factors in subsequent delivery: birth weight >=4000 g, aOR 4.4 (95% CI: 3.0-6.3), gestational diabetes, aOR 1.9 (95% CI: 1.2-3.2), Hispanic ethnicity aOR 1.9 (95% CI: 1.2-2.9), and maternal obesity, aOR 1.8 (95% CI: 1.3-2.6) were associated with birth injury. CONCLUSION: Among women with prior delivery complicated by shoulder dystocia, the risk factors identified in this study should be carefully considered prior to deciding upon route of delivery - cesarean vs. vaginal delivery. PMID- 21812752 TI - Brain targeting and toxicity study of odorranalectin-conjugated nanoparticles following intranasal administration. AB - In order to improve brain uptake of nanoparticles following nasal administration, odorranalectin (OL), the smallest lectin with much less immunogenicity than other members of lectin family, was conjugated to the surface of poly (ethylene glycol) poly (lactic-co-glycolic acid) (PEG-PLGA) nanoparticles (NP) in this study. The bioactivity of OL conjugated to the nanoparticles was verified by haemagglutination tests.Tissue distribution of OL-modified and unmodified nanoparticles (OL-NP and NP) was evaluated following intranasal (i.n.) administration by in vivo fluorescence imaging technique using DiR as a tracer, comparing with that of unmodified nanoparticles after intravenous (i.v.) injection. Besides, the nasal toxicity of OL-NP was evaluated on Calu-3 cell lines, toad palate and rat nasal mucosa.The results of TEM examination and dynamic light scattering showed a generally spherical shape of OL-NP with an average volume-based diameter around 90 nm. The haemagglutination test proved that OL retained its haemagglutination activity when conjugated to nanoparticles. The brain targeting indexes of NP and OL-NP following i.n. administration and NP following i.v. injection were 5.8, 11.6 and 0.08, respectively.Thus,i.n. administration demonstrated much better brain targeting efficiency than i.v. injection, and OL modification facilitated the nose-to-brain delivery of nanoparticles.Moreover, the toxicity assessment suggested good safety of OL-NP both in vitro and in vivo. In summary, odorranalectin-conjugated nanoparticle could be potentially used as a nose-to-brain drug delivery carrier for the treatment of CNS diseases. PMID- 21812754 TI - Influence of umbilical cord abnormalities (velamentous/marginal cord insertion and nuchal cord) on the perinatal outcomes of the second twin after vaginal delivery of the first twin. PMID- 21812755 TI - Unexpected intrauterine fetal death in monochorionic-diamniotic twins near term. PMID- 21812756 TI - Improved lentiviral gene transfer into human embryonic stem cells grown in co culture with murine feeder and stroma cells. AB - Genetic modification of human embryonic stem cells (hESCs) using biophysical DNA transfection methods are hampered by the very low single cell survival rate and cloning efficiency of hESCs. Lentiviral gene transfer strategies are widely used to genetically modify hESCs but limited transduction efficiencies in the presence of feeder or stroma cells present problems, particularly if vesicular stomatitis virus glycoprotein (VSV-G) pseudotyped viral particles are applied. Here, we investigated whether the recently described semen derived enhancer of virus infection (SEVI) and alternative viral envelope proteins derived from either Gibbon ape leukaemia virus (GALV) or feline leukaemia virus (RD114) are applicable for transducing hESCs during co-culture with feeder or stroma cells. Our first set of experiments demonstrates that SEVI has no toxic effect on murine or hESCs and that exposure to SEVI does not interfere with the pluripotency associated phenotype. Focusing on hESCs, we were able to further demonstrate that SEVI increases the transduction efficiencies of GALV and RD114 pseudotyped lentiviral vectors. More importantly, aiming at targeted differentiation of hESCs into functional somatic cell types, GALV pseudotyped lentiviral particles could efficiently and exclusively transduce hESCs grown in co-culture with OP9-GFP stroma cells (which were often used to induce differentiation into haematopoietic derivatives). PMID- 21812757 TI - Enhanced targeting efficiency of PLGA microspheres loaded with Lornoxicam for intra-articular administration. AB - Owing to its rationale of targeting the drug to the site of action and minimizing systemic toxic effects of the drug, intra-articular drug delivery system has gained growing interests. In this study, emphasis was placed on intra-articular Lornoxicam-loaded PLGA microspheres (Lnxc-PLGA-MS) preparation and improving the targeting of lornoxicam (Lnxc) in knee joint. The microspheres were prepared by a process involving solid-in-oil-in-water(S/O/W) emulsion, and evaluated for physicochemical properties. Joint cavity's drug leakage into systemic circulation in rabbits was examined to define the drug stagnation. Meanwhile, drug retention in synovial fluid in rats was investigated to further validate the drug targeting. The microspheres were spherical as evidenced by the SEM photographs with mean size of 7.47 MUm, and encapsulation efficiency was observed 82.22% along with drug loading 12.17%. DSC revealed that the drug in the microspheres existed in the phase of uncrystallization. The formulated microspheres could prolong the drug release up to 32 days in vitro. Comparing with animals injected with lornoxicam solution, the plasma drug concentration decreased in rabbits and retention time increased in rats' synovial fluid with intra-articular injections of microspheres, revealing good targeting efficiency. In conclusion, PLGA microspheres could be used to deliver lornoxicam following intra-articular administration for enhancing targeting efficiency. PMID- 21812758 TI - The heterotrimeric G protein subunits Galpha(q) and Gbeta(1) have lysophospholipase D activity. AB - In a previous study we purified a novel lysoPLD (lysophospholipase D) which converts LPC (lysophosphatidylcholine) into a bioactive phospholipid, LPA (lysophosphatidic acid), from the rat brain. In the present study, we identified the purified 42 and 35 kDa proteins as the heterotrimeric G protein subunits Galpha(q) and Gbeta(1) respectively. When FLAG-tagged Galpha(q) or Gbeta(1) was expressed in cells and purified, significant lysoPLD activity was observed in the microsomal fractions. Levels of the hydrolysed product choline increased over time, and the Mg(2+) dependency and substrate specificity of Galpha(q) were similar to those of lysoPLD purified from the rat brain. Mutation of Galpha(q) at amino acids Lys(52), Thr(186) or Asp(205), residues that are predicted to interact with nucleotide phosphates or catalytic Mg(2+), dramatically reduced lysoPLD activity. GTP does not compete with LPC for the lysoPLD activity, indicating that these substrate-binding sites are not identical. Whereas the enzyme activity of highly purified FLAG-tagged Galpha(q) overexpressed in COS-7 cells was ~4 nmol/min per mg, the activity from Neuro2A cells was 137.4 nmol/min per mg. The calculated K(m) and V(max) values for lysoPAF (1-O-hexadecyl-sn glycero-3-phosphocholine) obtained from Neuro2A cells were 21 MUM and 0.16 MUmol/min per mg respectively, similar to the enzyme purified from the rat brain. These results reveal a new function for Galpha(q) and Gbeta(1) as an enzyme with lysoPLD activity. Tag-purified Galpha(11) also exhibited a high lysoPLD activity, but Galpha(i) and Galpha(s) did not. The lysoPLD activity of the Galpha subunit is strictly dependent on its subfamily and might be important for cellular responses. However, treatment of Hepa-1 cells with Galpha(q) and Galpha(11) siRNAs (small interfering RNAs) did not change lysoPLD activity in the microsomal fraction. Clarification of the physiological relevance of lysoPLD activity of these proteins will need further studies. PMID- 21812759 TI - Novel insights into the regulation of antioxidant-response-element-mediated gene expression by electrophiles: induction of the transcriptional repressor BACH1 by Nrf2. AB - A central mechanism in cellular defence against oxidative or electrophilic stress is mediated by transcriptional induction of genes via the ARE (antioxidant response element), a cis-acting sequence present in the regulatory regions of genes involved in the detoxification and elimination of reactive oxidants and electrophiles. The ARE binds different bZIP (basic-region leucine zipper) transcription factors, most notably Nrf2 (nuclear factor-erythroid 2-related factor 2) that functions as a transcriptional activator via heterodimerization with small Maf proteins. Although ARE activation by Nrf2 is relatively well understood, the mechanisms by which ARE-mediated signalling is down-regulated are poorly known. Transcription factor BACH1 [BTB (broad-complex, tramtrack and bric a-brac) and CNC (cap'n'collar protein) homology 1] binds to ARE-like sequences, functioning as a transcriptional repressor in a subset of ARE-regulated genes, thus antagonizing the activator function of Nrf2. In the present study, we have demonstrated that BACH1 itself is regulated by Nrf2 as it is induced by Nrf2 overexpression and by Nrf2-activating agents in an Nrf2-dependent manner. Furthermore, a functional ARE site was identified at +1411 from the transcription start site of transcript variant 2 of BACH1. We conclude that BACH1 is a bona fide Nrf2 target gene and that induction of BACH1 by Nrf2 may serve as a feedback inhibitory mechanism for ARE-mediated gene regulation. PMID- 21812760 TI - Fluorescence detection of GDP in real time with the reagentless biosensor rhodamine-ParM. AB - The development of novel fluorescence methods for the detection of key biomolecules is of great interest, both in basic research and in drug discovery. Particularly relevant and widespread molecules in cells are ADP and GDP, which are the products of a large number of cellular reactions, including reactions catalysed by nucleoside triphosphatases and kinases. Previously, biosensors for ADP were developed in this laboratory, based on fluorophore adducts with the bacterial actin homologue ParM. It is shown in the present study that one of these biosensors, tetramethylrhodamine-ParM, can also monitor GDP. The biosensor can be used to measure micromolar concentrations of GDP on the background of millimolar concentrations of GTP. The fluorescence response of the biosensor is fast, the response time being <0.2 s. Thus the biosensor allows real-time measurements of GTPase and GTP-dependent kinase reactions. Applications of the GDP biosensor are exemplified with two different GTPases, measuring the rates of GTP hydrolysis and nucleotide exchange. PMID- 21812761 TI - Respiratory-induced coenzyme Q biosynthesis is regulated by a phosphorylation cycle of Cat5p/Coq7p. AB - CoQ(6) (coenzyme Q(6)) biosynthesis in yeast is a well-regulated process that requires the final conversion of the late intermediate DMQ(6) (demethoxy-CoQ(6)) into CoQ(6) in order to support respiratory metabolism in yeast. The gene CAT5/COQ7 encodes the Cat5/Coq7 protein that catalyses the hydroxylation step of DMQ(6) conversion into CoQ(6). In the present study, we demonstrated that yeast Coq7 recombinant protein purified in bacteria can be phosphorylated in vitro using commercial PKA (protein kinase A) or PKC (protein kinase C) at the predicted amino acids Ser(20), Ser(28) and Thr(32). The total absence of phosphorylation in a Coq7p version containing alanine instead of these phospho amino acids, the high extent of phosphorylation produced and the saturated conditions maintained in the phosphorylation assay indicate that probably no other putative amino acids are phosphorylated in Coq7p. Results from in vitro assays have been corroborated using phosphorylation assays performed in purified mitochondria without external or commercial kinases. Coq7p remains phosphorylated in fermentative conditions and becomes dephosphorylated when respiratory metabolism is induced. The substitution of phosphorylated residues to alanine dramatically increases CoQ(6) levels (256%). Conversely, substitution with negatively charged residues decreases CoQ(6) content (57%). These modifications produced in Coq7p also alter the ratio between DMQ(6) and CoQ(6) itself, indicating that the Coq7p phosphorylation state is a regulatory mechanism for CoQ(6) synthesis. PMID- 21812762 TI - The future is cold: cryo-preparation methods for transmission electron microscopy of cells. AB - Our knowledge of the organization of the cell is linked, to a great extent, to light and electron microscopy. Choosing either photons or electrons for imaging has many consequences on the image obtained, as well as on the experiment required in order to generate the image. One apparent effect on the experimental side is in the sample preparation, which can be quite elaborate for electron microscopy. In recent years, rapid freezing, cryo-preparation and cryo-electron microscopy have been more widely used because they introduce fewer artefacts during preparation when compared with chemical fixation and room temperature processing. In addition, cryo-electron microscopy allows the visualization of the hydrated specimens. In the present review, we give an introduction to the rapid freezing of biological samples and describe the preparation steps. We focus on bulk samples that are too big to be directly viewed under the electron microscope. Furthermore, we discuss the advantages and limitations of freeze substitution and cryo-electron microscopy of vitreous sections and compare their application to the study of bacteria and mammalian cells and to tomography. PMID- 21812763 TI - Eca20 microsatellite polymorphisms in equine viral arteritis-infected horses from Argentina. AB - We investigated the association of equine arteritis virus (EAV) infection and three short tandem repeat (STR) polymorphisms located within or in close proximity to equine lymphocyte antigen (ELA) region. We used a case-control design as a first approach before proceeding to select candidate genes. One hundred and sixty-five Silla Argentino horses were taken in 2002 from positive serological detections of EAV in Argentina, to determine whether STR genotypes were correlated to genetic susceptibility to EVA. Allele frequency distribution did not show significant differences between both groups (P = 0.0781). However, in particular alleles, Fisher exact test and odds ratio calculations showed significant values >1 for TKY08 and LEX52, and <1 for UM011, TKY08, LEX52 and VHL20. Interestingly, TKY08 STR is located in ELA class I region. PMID- 21812764 TI - A single nucleotide deletion in exon 2 produces a novel null allele, HLA DRB1*01:33N. AB - A single nucleotide deletion in codon 12 of the human leukocyte antigen HLA DRB1*01 results in a novel null allele, DRB1*01:33N. PMID- 21812765 TI - Weak or absent evidence for the association of HLA-DR antigens with risk of thyroid carcinoma: a meta-analysis of observational studies. AB - Inconsistent reports of associations between human leukocyte antigen (HLA)-DR and thyroid cancers exist. We conducted a comprehensive search of the PubMed, Scopus and Web of Science databases. Using random-effects modeling, subgroup analyses, meta-regression and prediction interval (PI) estimation, we combined the existing evidence from 13 studies (977 cases of thyroid cancer and 3735 controls). Only HLA-DR1 and HLA-DR11 were significantly associated; however, the evidence for HLA DR11 came from only three studies while that for HLA-DR1 had large between-study heterogeneity. All the PIs estimated in the study straddled unity. Therefore, current evidence for the studied association is incomplete as well as uncertain. Attempts to include HLA-DR typing as a prognostic or therapeutic marker may be premature at this time. PMID- 21812766 TI - Assessment of the influence of HLA class I and class II loci on the prevalence of keloid disease in Jamaican Afro-Caribbeans. AB - Keloid disease (KD) is a common abnormal cutaneous fibrotic disorder of unknown aetiopathogenesis. KD is reported to have a strong genetic component as it is often familial and has a high incidence in certain ethnicities, in particular those of Afro-Caribbean origin. Genetic risk factors combined with aberrant lesional inflammatory responses point to the human leukocyte antigen (HLA) system as a viable target for investigating disease aetiology. Sequence specific primer polymerase chain reaction with allele sequencing was used to determine HLA-DQA1 and DQB1 allele frequencies (AF) for 165 KD patients and 119 healthy controls of black Jamaican Afro-Caribbean origin. HLA class I alleles A*01, A*03, A*25, B*07 and Cw*08:02, previously identified as KD associated in a different ethnicity, were also analysed. Allele sequencing confirmed typing accuracy but no statistically significant differences in AF were identified between KD patients and controls. Furthermore, KD subgroups including patient gender, family history and multiple- or single-site scarring did not show significant allele-disease associations. PMID- 21812767 TI - Lifestyle factors of people with exceptional longevity. AB - OBJECTIVES: To assess lifestyle factors including physical activity, smoking, alcohol consumption, and dietary habits in men and women with exceptional longevity. DESIGN: Retrospective cohort study. SETTING: A cohort of community dwelling Ashkenazi Jewish individuals with exceptional longevity defined as survival and living independently at age 95 and older. PARTICIPANTS: Four hundred seventy-seven individuals (mean 97.3 +/- 2.8, range 95-109; 74.6% women) and a subset of participants of the National Health and Nutrition Examination Survey (NHANES) I (n = 3,164) representing the same birth cohort as a comparison group. MEASUREMENTS: A trained interviewer administrated study questionnaires to collect information on lifestyle factors and collected data on anthropometry. RESULTS: People with exceptional longevity had similar mean body mass index (men, 25.4 +/- 2.8 kg/m2 vs 25.6 +/- 4.0 kg/m2 , P=.63; women, 25.0 +/- 3.5 kg/m2 vs 24.9 +/- 5.4 kg/m2 ; P = .90) and a similar proportion of daily alcohol consumption (men, 23.9 vs 22.4, P = .77; women, 12.1 vs 11.3, P = .80), of regular physical activity (men: 43.1 vs 57.2; P = .07; women: 47.0 vs 44.1, P = .76), and of a low calorie diet (men: 20.8 vs 21.1, P=.32; women: 27.3 vs 27.1, P=.14) as the NHANES I population. CONCLUSION: People with exceptional longevity are not distinct in terms of lifestyle factors from the general population, suggesting that people with exceptional longevity may interact with environmental factors differently than others. This requires further investigation. PMID- 21812768 TI - Conservative surgical management of subungual (matrix derived) melanoma: report of seven cases and literature review. AB - BACKGROUND: Subungual melanoma (SUM) is a rare entity, comprising approximately 0.7-3.5% of all melanoma subtypes. SUM histopathologically belongs to the acral lentiginous pathological subtype of malignant melanoma. Its diagnosis is helped by dermoscopy but pathological examination of doubtful cases is required. Classical management of SUM is based on radical surgery, namely distal phalanx amputation. Conservative treatment with nonamputative wide excision of the nail unit followed by a skin graft has been insufficiently reported in the medical literature even though it is performed in many centres. OBJECTIVES: To report a series of patients with in situ or minimally invasive SUM treated by conservative surgery, to investigate the postoperative evolution and to evaluate the outcome with a review of the literature. METHODS: We performed a retrospective extraction study from our melanoma register of all patients with in situ and minimally invasive SUM treated with conservative surgery in the University Hospital Department of Dermatology, Lyon, France from 2004 to 2009. The patient demographics, disease presentation, delay to diagnosis, histopathology and postoperative evolution were reviewed. RESULTS: Seven cases of SUM treated as such were identified in our melanoma database. All cases had a clinical presentation of melanonychia striata. The mean delay to diagnosis was 2years. Surgical excision of the entire nail unit with a 5-10mm safety margin without bone resection followed by full-thickness skin graft taken from the arm was performed in all cases. No recurrence was observed with a mean follow-up of 45months. Functional results were found satisfactory by all patients and their referring physicians. Sixty-two other cases have been found in the literature and are also discussed. CONCLUSIONS: Conservative surgical management in patients with in situ or minimally invasive SUM is a procedure with good cosmetic and functional outcome and, in our cases as well as in the literature, the prognosis is not changed. PMID- 21812769 TI - Defining the correct role of minimal residual disease tests in the management of acute lymphoblastic leukaemia. AB - Minimal residual disease (MRD) has acquired a prominent role in the management of childhood and adult Acute Lymphoblastic Leukaemia (ALL) for its high prognostic value. Several studies have demonstrated the strong association between MRD and risk of relapse in childhood and adult ALL, irrespective of the methodology used. MRD is now used in clinical trials for risk assignment and to guide clinical management. Negativity at early time points may be considered to decrease treatment burden in patients who are likely to be cured with reduced intensity regimens. On the other hand, high MRD levels at late time points (end of consolidation) define ALL subgroups which deserve investigation of more effective treatments. The predictivity of MRD as a measurement of drug response in vivo opened new perspectives for its use in clinical decision, to deliver risk-based treatments, and possibly as a surrogate for efficacy in the evaluation of novel therapeutic approaches. PMID- 21812770 TI - Use of NK cell activity in cure by transplant. AB - Analogous to T cells, Natural Killer (NK) cells may facilitate engraftment, combat infection, and control cancer in bone marrow or haematopoietic stem cell transplantation (HSCT); however, NK cells do not cause graft-versus-host disease. Killer immunoglobulin-like receptors (KIRs) regulate NK cell function, and recent data suggest that KIR is as important as its ligand (human leucocyte antigen; HLA) in HSCT for both malignant and non-malignant conditions. Because there is substantial variability in KIR gene content, allelic polymorphism, and cell surface expression among people, careful selection of donors based on HLA and KIR is essential to optimize HSCT outcomes. Furthermore, NK cells may be used for adoptive immunotherapy after HSCT in place of conventional donor lymphocyte infusion, as part of pre-transplant cytoreductive therapy, or as an independent therapeutic agent in high-risk leukaemia in place of sibling donor HSCT. PMID- 21812771 TI - Decreased gene expression of LC3 in peripheral leucocytes of patients with coronary artery disease. AB - BACKGROUND: Coronary artery disease (CAD) is a common and multifactorial arterial disease that is mainly caused by atherosclerosis. Macrophages, lymphocytes and neutrophils have been implicated in atherosclerotic plaque development. Autophagy, a highly conserved cellular process for the removal of long-lived protein and organelles, plays a variety of pathophysiological roles. However, the roles of autophagy in peripheral leucocytes in atherosclerosis and CAD have not been explored. MATERIALS AND METHODS: LC3 is a marker gene for autophagy, and LC3 II, a conjugated form of LC3 protein, is a membrane marker for autophagosome and autophagolysosomes. In this study, LC3 gene expression levels and LC3-II protein levels in peripheral leucocytes were measured in patients with CAD (n = 146) and healthy controls (n = 87). RESULTS: In patients with CAD, LC3 gene expression levels in the peripheral leucocytes were significantly decreased compared with age- and sex-matched healthy controls (P < 0.01). LC3-II protein levels were also significantly decreased in patients with CAD (P < 0.01). Multivariate logistic analyses showed that decreased LC3 gene expression levels were strongly associated with CAD. There were no differences in LC3 transcripts and LC3-II protein levels between subgroups of patients with CAD. CONCLUSIONS: LC3 gene expression in the peripheral leucocytes was significantly decreased in patients with CAD, indicating that autophagosome formation is decreased. These data suggest that autophagy in circulating leucocytes may be involved in the pathogenesis of atherosclerosis and CAD. PMID- 21812772 TI - Neurostimulation for primary headache disorders: Part 2, review of central neurostimulators for primary headache, overall therapeutic efficacy, safety, cost, patient selection, and future research in headache neuromodulation. AB - This article is the second of 2 articles reviewing neurostimulation for primary headaches. In Part 1, we described methods, pathophysiology and anatomy, and history of neuromodulation in the treatment of headache, as well as reviewing the literature on peripheral neuromodulation for primary headaches. Peripheral targets for stimulation include percutaneous nerves, transcranial holocephalic, occipital nerves, auriculotemporal nerves, supraorbital nerves, cervical epidural, and sphenopalatine ganglia. In Part 2, we describe available literature on central neuromodulation in primary headaches. Central stimulation targets include vagus nerve and deep brain structures. Part 2 also analyzes overall therapeutic efficacy, safety, cost, patient selection, and recommendations for further research of neurostimulation modalities based on available data. PMID- 21812773 TI - Migraine with binocular blindness: a clinic-based study. AB - OBJECTIVE: To describe the syndrome of migraine with binocular blindness. BACKGROUND: Rarely do migraine patients complain of losing vision in both eyes during an attack of headache. There are no large clinic-based studies looking at the prevalence of binocular blindness in migraine sufferers and no information about patient demographics, neuroimaging, and laboratory testing. METHODS: Over a 14-month time period, 383 new patients with a diagnosis of migraine were seen at the Geisinger Headache Center. All patients were asked if they ever experienced an episode of complete bilateral blindness along with their headaches. Those with a positive history had coagulopathy testing as well as brain magnetic resonance imaging and magnetic resonance angiography of the intracranial circulation. RESULTS: A total of 6 patients or only 1.6% of the new migraine patients had episodes of binocular blindness with their headaches. All were female and each had a history of migraine for at least 3 years. Five patients had a diagnosis of migraine without aura, while one had a diagnosis of basilar-type migraine. In all patients the blindness episodes occurred in isolation during a migraine headache. In all but one patient the blindness was instantaneous and not a slow evolution. In 2 patients the blindness episode only occurred 1 time; in 3 patients episodes occurred more than once but were rare, while 1 patient had blindness with 50% of her headaches. In regard to duration, in 2 patients blindness lasted only several seconds, 2 patients between 2 and 10 minutes, 1 patient 30 minutes and 1 patient 60-120 minutes. Neuroimaging was normal in all. Three patients had a history of smoking and 3 never smoked. Coagulopathy testing was abnormal in all patients. Two patients were homozygous for methylenetetrahydrofolate reductase (MTHFR) 677TT polymorphism, but both had normal homocysteine levels; 3 patients were heterozygous for MTHFR 677CT polymorphism and 1 had elevated homocysteine levels and 1 patient had a positive lupus anticoagulant (had the most frequent episodes of blindness). CONCLUSION: Binocular blindness with migraine headache is a very rare occurrence at least in a headache specialty clinic population. It is a female-predominant event and occurs mostly in migraine patients who do not have a history of aura. Blindness episodes can be very brief or prolonged and many do not fit the typical duration of a migraine aura. They are typically infrequent events and may occur only 1 time without recurrence. Migraine with binocular blindness may reflect an underlying clotting disorder. A possible etiology outside of a coagulopathy-related event is retinal spreading depression. PMID- 21812774 TI - A curious maneuver for glossopharyngeal neuralgic pain relief. PMID- 21812775 TI - Satisfaction with and confidence in needle-free subcutaneous sumatriptan in patients currently treated with triptans. AB - OBJECTIVE: To evaluate patient satisfaction with and confidence in Sumavel(r) DosePro(r) (needle-free subcutaneous sumatriptan) among current triptan users administering Sumavel DosePro for up to 4 migraine attacks. BACKGROUND: Sumavel DosePro is a needle-free, single-use device that facilitates subcutaneous injection of sumatriptan 6 mg and confers relief as early as 10 minutes after dosing. DESIGN/METHODS: In this open-label, multicenter study, Sumavel DosePro was self-administered for <=4 migraine attacks (over a <=60-day period) involving moderate or severe baseline pain by adult migraineurs who currently were using triptans (any form, any dosage) and reported being less than very satisfied with their current therapy (i.e., baseline satisfaction ranging from satisfied to very dissatisfied). Treatment satisfaction was measured via the Patient Perception of Migraine Questionnaire, revised (PPMQ-R). RESULTS: Among the 212 patients using Sumavel DosePro to treat >=1 migraine attack, PPMQ-R Overall Satisfaction (primary endpoint) increased significantly from baseline to the end of treatment (mean +/- SD 65.7 +/- 19.8 vs. 73.7 +/- 29.1, P = .0007), an improvement that met the criterion for clinical significance. From baseline to the end of treatment, PPMQ-R scores also improved significantly for Efficacy (62.2 +/- 17.6 vs. 76.2 +/ 23.7, P < .0001), Functionality (59.0 +/- 22.3 vs. 73.8 +/- 25.3, P < .0001), and Tolerability (83.9 +/- 13.1 vs. 86.4 +/- 15.0, P = .02), but declined for Ease of Use (82.6 +/- 15.3 vs 67.8 +/- 27.6, P < .0001). For all global satisfaction domains, the percentage of patients satisfied or very satisfied increased from baseline to the end of treatment (Overall Satisfaction 36.3% vs. 64.0%, Satisfaction with Medication Effectiveness 40.1% vs. 68.2%, Satisfaction with Side Effects 48.6% vs. 67.3%). The percentage of patients who were confident or very confident in treating repeated migraine attacks also increased (baseline: 41.0%, 90% confidence interval [CI] 35.4, 46.9 vs. end of treatment: 66.5%, 90% CI 58.9, 70.1). The efficacy results (pain relief, pain-free response, sustained 24-hour pain relief and pain-free response) were consistent with those previously observed with needle-based sumatriptan. CONCLUSIONS: Patients currently treated with triptans and less than very satisfied with their acute migraine therapy experienced a statistically significant and clinically relevant increase in satisfaction with therapy and enhanced confidence in treatment after use of Sumavel DosePro for up to 4 migraine attacks. PMID- 21812776 TI - Development of the human fetal cerebellum in the second trimester: a post mortem magnetic resonance imaging evaluation. AB - The cerebellum is one of the most important structures in the posterior cranial fossa, but the characterization of its development by magnetic resonance imaging (MRI) is incomplete. We scanned 40 fetuses that had no morphological brain disorder at 14-22 weeks of gestation using 7.0 T MRI. Amira 4.1 software was used to determine morphological parameters of the fetal cerebellum, which included the cerebellar volume (CV), transverse cerebellar diameter (TCD), and the length and width of the vermis. The relationship between these measurements and gestational age (GA) was analysed. We found that the primary fissure was visible at week 14 of gestation. From week 16, the prepyramidal fissure, the secondary fissure and the dentate nucleus could be identified. The posterolateral fissure and the fourth ventricle were recognized at week 17, whereas the tentorium of the cerebellum was visible at week 20. The relationships between GA and CV, TCD, and the width and length of the vermis were described adequately by second-order polynomial regression curves. The ratios between TCD and vermis length and between TCD and vermis width decreased with GA. These results show that 7.0 T MRI can show the trajectory of cerebellar development clearly. They increase our understanding of normal cerebellar development in the fetus, and will facilitate the diagnosis of pathological intrauterine changes in the cerebellum. PMID- 21812777 TI - Histomorphometric changes in repaired mouse sciatic nerves are unaffected by the application of a scar-reducing agent. AB - Microsurgical repair of transected peripheral nerves is compromised by the formation of scar tissue and the development of a neuroma, thereby limiting the success of regeneration. The aim of this study was to quantify histomorphometrically the structural changes in neural tissue that result from repair, and determine the effect of mannose-6-phosphate (M6P), a scar-reducing agent previously shown to enhance regeneration. In anaesthetised C57-black-6 mice, the left sciatic nerve was sectioned and repaired using four epineurial sutures. Either 100 MUL of 600 mm M6P (five animals) or 100 MUL of phosphate buffered saline (placebo controls, five animals) was injected into and around the nerve repair site. A further group acted as sham-operated controls. After recovery for 6 weeks, the nerve was harvested for analysis using light and electron microscopy. Analysis revealed that when compared with sham controls, myelinated axons had smaller diameters both proximal and distal to the repair. Myelinated axon counts, axonal density and size all decreased across the repair site. There were normal numbers and densities of non-myelinated axons both proximal and distal to the repair. However, there were more Remak bundles distal to the repair site, and fewer non-myelinated axons per Remak bundle. Application of M6P did not affect any of these parameters. PMID- 21812778 TI - Microscopic characterisation of filamentous microbes: towards fully automated morphological quantification through image analysis. AB - Mycelial morphology is a critically important process property in industrial fermentations of filamentous microorganisms, as particular phenotypes are associated with maximum productivity. The morphological form that develops in a given process results from the combination of various environmental factors, together with the genotype of the organism itself. The design of systems capable of rapidly and accurately characterising morphology within a given process represents a significant challenge to biotechnologists, as the complex phenotypes that are manifested are often not easily quantified. Over the last two decades, the proliferation of high-power personal computers and high-resolution digital cameras has enabled scientists to apply digital image analysis to this challenge. Although several fully automated systems have been designed for this purpose, manual analysis of images is still commonplace, together with qualitative, subjective descriptions of morphologies. This review describes the complex morphologies that can develop in fermentations of filamentous microbes and the application of microscopy and image analysis techniques to the quantification of such structures. PMID- 21812780 TI - Protein tyrosine phosphatase sigma regulates the synapse number of zebrafish olfactory sensory neurons. AB - The formation and refinement of synaptic connections are key steps of neural development to establish elaborate brain networks. To investigate the functional role of protein tyrosine phosphatase (PTP) sigma, we employed an olfactory sensory neuron (OSN)-specific gene manipulation system in combination with in vivo imaging of transparent zebrafish embryos. Knockdown of PTPsigma enhanced the accumulation of synaptic vesicles in the axon terminals of OSNs. The exaggerated accumulation of synaptic vesicles was restored to the normal level by the OSN specific expression of PTPsigma, indicating that presynaptic PTPsigma is responsible for the regulation of synaptic vesicle accumulation. Consistently, transient expression of a dominant-negative form of PTPsigma in OSNs enhanced the accumulation of synaptic vesicles. The exaggerated accumulation of synaptic vesicles was reproduced in transgenic zebrafish lines carrying an OSN-specific expression vector of the dominant-negative PTPsigma. By electron microscopic analysis of the transgenic line, we found the significant increase of the number of OSN-mitral cell synapses in the central zone of the olfactory bulb. The density of docked vesicles at the active zone was also increased significantly. Our results suggest that presynaptic PTPsigma controls the number of OSN-mitral cell synapses by suppressing their excessive increase. PMID- 21812779 TI - Chronic olanzapine treatment decreases arachidonic acid turnover and prostaglandin E2 concentration in rat brain. AB - The atypical antipsychotic, olanzapine (OLZ), is used to treat bipolar disorder, but its therapeutic mechanism of action is not clear. Arachidonic acid (AA, 20:4n 6) plays a critical role in brain signaling and an up-regulated AA metabolic cascade was reported in postmortem brains from bipolar disorder patients. In this study, we tested whether, similar to the action of the mood stabilizers lithium, carbamazepine and valproate, chronic OLZ treatment would reduce AA turnover in rat brain. We administered OLZ (6 mg/kg/day) or vehicle i.p. to male rats once daily for 21 days. A washout group received 21 days of OLZ followed by vehicle on day 22. Two hours after the last injection, [1-14C]AA was infused intravenously for 5 min, and timed arterial blood samples were taken. After the rat was killed at 5 min, its brain was microwaved, removed and analyzed. Chronic OLZ decreased plasma unesterified AA concentration, AA incorporation rates and AA turnover in brain phospholipids. These effects were absent after washout. Consistent with reduced AA turnover, OLZ decreased brain cyclooxygenase activity and the brain concentration of the proinflammatory AA-derived metabolite, prostaglandin E2, In view of up-regulated brain AA metabolic markers in bipolar disorder, the abilities of OLZ and the mood stabilizers to commonly decrease prostaglandin E2, and AA turnover in rat brain phospholipids, albeit by different mechanisms, may be related to their efficacy against the disease. PMID- 21812781 TI - The Swedish APP mutation alters the effect of genetically reduced BACE1 expression on the APP processing. AB - Inhibition of beta-secretase (BACE1) is a key therapeutic approach in Alzheimer's disease (AD), as BACE1 initiates amyloid-beta (Abeta) cleavage from the beta amyloid precursor protein (APP). As Abeta reductions in mice lacking one BACE1 allele diverged considerably between studies we investigated the effect of BACE1 knock-out in more detail. With both BACE1 alleles the Swedish mutation (APP23 mice) increased APP processing and shifted it towards the beta-secretase pathway as compared with non-mutated APP expressed at a similar level (APP51/16 mice). This effect was much smaller then observed in cell culture. An about 50% decrease in BACE1 enzyme activity resulted in a sub-proportional Abeta reduction with the Swedish mutation (-20%) and even less for non-mutated APP (-16%). In wild-type mice, the Abeta reduction may be even further diminished. Other metabolites of the beta-secretase pathway decreased accordingly while the alternative alpha secretase pathway increased. Complete BACE1 deletion strongly enhanced these changes. The remaining Abeta signal also described by others can be explained by assay cross-reactivity with other APP metabolites supporting BACE1 as the major beta-secretase. Our data indicate that BACE1 is in excess over APP at the cleavage site(s). Alterations in APP expression or substrate properties, therefore, quantitatively change its cleavage and Abeta generation. PMID- 21812782 TI - A novel flow cytometry-based technique to measure adult neurogenesis in the brain. AB - The stimulation of neurogenesis is an exciting novel therapeutic option for diseases of the central nervous system, ranging from depression to neurodegeneration. One major bottleneck in screening approaches for neurogenesis inducing compounds is the very demanding in vivo quantification of newborn neurons based on stereological techniques. To effectively develop compounds in this area, novel fast and reliable techniques for quantification of in vivo neurogenesis are needed. In this study, we introduce a flow cytometry-based method for quantifying newly generated neurons in the brain based on the counting of cell nuclei from dissected brain regions. Important steps involve density sedimentation of the cell nuclei, and staining for the proliferation marker bromodeoxy uridine and nuclear cell type markers such as NeuN. We demonstrate the ability of the technique to detect increased neurogenesis in the hippocampus of animals which underwent physical exercise and received fluoxetine treatment. PMID- 21812783 TI - Flow cytometry evaluation of red blood cells mimicking naturally occurring ABO subgroups after modification with variable amounts of function-spacer-lipid A and B constructs. AB - BACKGROUND: Kodecytes bearing synthetic blood group A and B antigens are increasingly being used in transfusion laboratories as serologic mimics of red blood cell (RBC) A(weak) and B(weak) subtypes. The aim of this study was to compare the flow cytometry profile of kodecytes with native ABO subgroups. STUDY DESIGN AND METHODS: A series of A/B kodecytes, each with decreasing A or B antigen expression, were prepared from group O RBCs that were modified with dilutions of function-spacer-lipid KODE technology (FSL) constructs representing a wide serologic range. Using an established flow cytometry method designed for the detection of low levels of A/B antigens, kodecyte profiles were compared with those of native subgroup cells. RESULTS: Kodecytes with positive tube serology from 4+ to 1+ were created with 15 to 2 ug/mL FSL-A or 78 to 10 ug/mL FSL-B transformation solutions. The kodecytes created with higher concentrations of FSL constructs revealed a uniform and/or even distribution of antigens as seen by a single flow cytometry peak more narrow than the broader peaks produced with lower FSL concentrations similar to those found in native A(x) and most B(weak) subgroups. CONCLUSIONS: Although kodecytes are created artificially, they can be designed to mimic the serologic and flow cytometric profiles of native ABO subgroup RBCs. PMID- 21812784 TI - A preliminary report on the feeding of cynomolgus monkeys (Macaca fascicularis) with a high-sugar high-fat diet for 33 weeks. AB - BACKGROUND: The metabolic syndrome is common in populations exposed to a typical Western diet. There is a lack of an animal model that mimics this condition. METHODS: We fed 15 cynomolgus monkeys ad libitum a high-sugar high-fat (HSHF) diet for 33 weeks. Body weight, body composition, serum lipids, and insulin were measured at baseline and at 33 weeks. RESULTS: The animals tolerated the HSHF diet very well. In the intervention group, total serum cholesterol and low density lipoprotein cholesterol were 3- and 5-fold higher, respectively, at 33 weeks as compared with their baseline levels. Serum high-density lipoprotein cholesterol and triglycerides were not significantly affected. Dual-energy X-ray absorptiometry (DXA) analysis of the intervention group indicated that the trunk fat mass increased by 187% during this period. CONCLUSIONS: Cynomolgus monkeys should be a useful model for investigating the interactions of diet and other factors such as genetics in the development of the metabolic syndrome. PMID- 21812785 TI - Caspase-3 detection in human testicular spermatozoa from azoospermic and non azoospermic patients. AB - The apoptotic mechanisms underlying spermatogenesis in testis are poorly understood. In the present study, the rates of testicular spermatozoa with active caspase-3 were quantified in testicular samples with normal and impaired spermatogenesis. Testicular spermatozoa were collected from 18 men after testicular biopsy during assisted reproductive treatments: five presented oligozoospermia, four congenital bilateral absence of the vas deferens (CBAVD), five secondary obstructive azoospermia (sOAZ) and four hypospermatogenesis. Ejaculated samples were derived from six normozoospermic patients. Testicular spermatozoa were analysed using a fluorescence microscope and differences among groups were calculated using regression logistic models. Total rates of spermatozoa with active caspase-3 were significantly higher in sOAZ (78.6+/ 13.9), followed by hypospermatogenesis (70.8+/-5.8), CBAVD (55.9+/-25.5), oligozoospermia (31.7+/-31.0) and normozoospermia (20.4+/-15.5). Distinct patterns of active caspase-3 were observed in testicular spermatozoa compartments: midpiece, equatorial region, acrosomal vesicle region, nucleus and cytoplasm. Hypospermatogenesis showed active caspase-3 mainly in the midpiece. In CBAVD, sOAZ and oligozoospermia, active caspase-3 was mainly in the nucleus, although no differences were found between oligozoospermia and hypospermatogenesis. In sOAZ, active caspase-3 in the spermatozoa nucleus was 1.89-fold higher than in CBAVD. Results suggest that tubular obstruction may induce nuclear lesions and that disrupted spermatozoa production observed in cases of hypospermatogenesis might be associated with mitochondrial lesions. PMID- 21812786 TI - Changing subcellular localization of nuclear transport factors during human spermatogenesis. AB - Spermatogenesis requires progressive changes in gene expression mediated by hormonal and local factors. Regulated macromolecular movement between nuclear and cytoplasmic compartments enables these essential responses to changing extracellular cues, and dynamic production of the nucleocytoplasmic transporters and importin proteins, throughout gametogenesis in rodents implicates them as key mediators of germline differentiation. We examined normal adult human testis expression profiles of six importins plus five additional proteins involved in nucleocytoplasmic transport. Although most were detected in the nucleus during germline differentiation, importin alpha4 was exclusively observed in Sertoli and germ cell cytoplasm. Many proteins were present in round spermatid nuclei (importins alpha1, alpha3, beta1, beta3; exportin-1, Nup62, Ran, RanBP1, RCC1), and remarkable intense nuclear and/or nuclear-associated signals were detected for importin alpha1, importin alpha3 and Nup62 in spermatocytes. This study identifies conserved aspects of nucleocytoplasmic transport during spermatogenesis and extends our knowledge of the dynamic presence of these proteins, which indicates that they contribute to germ cell-specific cargo trafficking and potentially to other functions during human spermatogenesis. We also demonstrate for the first time that importin alpha3 is nuclear in spermatocytes, when exportin-1 is cytoplasmic, suggesting that nuclear transport is altered during meiosis. PMID- 21812787 TI - Influence of 5alpha-dihydrotestosterone and 17beta-estradiol on human Sertoli cells metabolism. AB - Sertoli cells metabolize glucose, converting it to lactate that is used by developing germ cells for their energy metabolism. Androgens and oestrogens have metabolic roles that reach far beyond reproductive processes. So, the main purpose of this study was to examine the effect of sex steroid hormones on metabolite secretion/consumption in human Sertoli cells. Human Sertoli cell enriched primary cultures were maintained in a defined medium for 50 h and glucose, pyruvate, lactate and alanine variations were determined using (1) H-NMR spectra analysis, in the absence or presence of 100 nm 17beta-estradiol (E(2) ) or 100 nm 5alpha-dihydrotestosterone (DHT). The mRNA expression levels of glucose transporters, lactate dehydrogenase and monocarboxylate transporters were also determined using semi-quantitative RT-PCR. Cells cultured in the absence (control) or presence of E(2) consumed the same amounts of glucose at similar rates during the 50 h. During the first 15 h of treatment with DHT, glucose consumption and glucose consumption rate were significantly higher. Nevertheless, DHT-treated cells secreted a significantly lower amount of lactate than control and E(2) -treated cells. Such a decrease was concomitant with a significant decrease in lactate dehydrogenase A mRNA levels after 50 h treatment in DHT treated groups. Finally, alanine production was significantly increased in E(2) treated cells after 25 h treatment, which indicated a lower redox/higher oxidative state for the cells on those conditions. These results support the existence of a relationship between sex steroid hormones action and energy metabolism, providing the first assessment of androgens and oestrogens as metabolic modulators of human Sertoli cells. PMID- 21812788 TI - Are expression and localization of tight and adherens junction proteins in testes of adult boar affected by foetal and neonatal exposure to flutamide? AB - Several recent studies have indicated that androgen disruption induced by the administration of anti-androgen flutamide during critical developmental stages results in various reproductive abnormalities, mainly in rodents. However, scarce data are available regarding the alterations caused by this toxicant on cell-cell adhesion molecules. Of note, there is no report on the expression and regulation of tight and adherens junction proteins in the boar. Therefore, the purpose of this study was to analyse whether foetal and neonatal exposure to flutamide affects the expression and distribution of ZO-1, occludin, beta-catenin, and N cadherin in testes of adult pigs. Moreover, to evaluate whether androgen signal was altered in the boar, testicular levels of testosterone and oestradiol and the expression of androgen receptor were examined. Flutamide (50 mg/kg bw) was injected into pregnant gilts during gestational days 20-28 and 80-88 (GD20, GD80), and into male piglets on postnatal days 2-10 (PD2). In the testes of all flutamide-exposed boars, expressions of ZO-1, N-cadherin and beta-catenin were significantly decreased at mRNA and protein level, whereas expression of occludin was unchanged when compared with the controls. In addition, in severely damaged seminiferous tubules of PD2 pigs, mislocalization of ZO-1, N-cadherin and beta catenin was observed. Changes in junction protein expressions were accompanied by disturbed intratesticular androgen-oestrogen balance, although androgen receptor expression was not altered. Taken together, these results demonstrate that blockade of androgen action by flutamide during both gestational and neonatal periods affects the expression of ZO-1, N-cadherin and beta-catenin in adult pig testes. Of concern, neonatal window seems to be most critical for the organization of BTB and consequently for normal spermatogenesis in the boar. It is likely that altered expression of junction proteins is related to insufficient testosterone production and/or excessive oestradiol synthesis, which may result from impaired Leydig cell function. PMID- 21812789 TI - Comment on the morphology of spermatozoa in air-dried seminal smears. PMID- 21812790 TI - Pharmacokinetic behavior and pharmacokinetic/pharmacodynamic indices of marbofloxacin after intravenous, subcutaneous, and intramuscular administrations in buffalo calves (<10 days old). PMID- 21812791 TI - How pressure is applied in shared decisions about antipsychotic medication: a conversation analytic study of psychiatric outpatient consultations. AB - The professional identity of psychiatry depends on it being regarded as one amongst many medical specialties and sharing ideals of good practice with other specialties, an important marker of which is the achievement of shared decision making and avoiding a reputation for being purely agents of social control. Yet the interactions involved in trying to achieve shared decision-making are relatively unexplored in psychiatry. This study analyses audiotapes of 92 outpatient consultations involving nine consultant psychiatrists focusing on how pressure is applied in shared decisions about antipsychotic medication. Detailed conversation analysis reveals that some shared decisions are considerably more pressured than others. At one end of a spectrum of pressure are pressured shared decisions, characterised by an escalating cycle of pressure and resistance from which it is difficult to exit without someone losing face. In the middle are directed decisions, where the patient cooperates with being diplomatically steered by the psychiatrist. At the other extreme are open decisions where the patient is allowed to decide, with the psychiatrist exerting little or no pressure. Directed and open decisions occurred most frequently; pressured decisions were rarer. Patient risk did not appear to influence the degree of pressure applied in these outpatient consultations. PMID- 21812793 TI - Age-related infertility: a tale of two technologies. AB - The reproductive body has become the site of intensive medical intervention, yet, paradoxically, women have never been more at risk of suffering the distress of infertility. Drawing on in-depth interviews with 22 infertile women, this article explores their reproductive experience from fertility postponement to assisted conception. All had used both modern contraception and in vitro fertilisation, yet none achieved the fertility they desired, when they desired it. All had structured their use of these technologies around the social practice of postponement. Modern contraception, however, while removing the sexual costs of postponement, did not resolve its reproductive dilemmas. Rather it appeared to collapse the experience of this traditionally difficult process, sustaining an illusion of reproductive control in which fertility decisions were 'put on the back burner', undiscussed and sometimes unimagined. For these women this delay then revealed the hidden cost of postponement--infertility--which, in turn, led to their pursuit of assisted conception after the age of 35, at precisely the point when its already limited efficacy begins to fail sharply. In these accounts age-related infertility emerged as a tale of two technologies: two technologies linked to each woman, and each other, through the social practice of postponement. PMID- 21812792 TI - Embryo futures and stem cell research: the management of informed uncertainty. AB - In the social worlds of assisted conception and stem cell science, uncertainties proliferate and particular framings of the future may be highly strategic. In this article we explore meanings and articulations of the future using data from our study of ethical and social issues implicated by the donation of embryos to human embryonic stem cell research in three linked assisted conception units and stem cell laboratories in the UK. Framings of the future in this field inform the professional management of uncertainty and we explore some of the tensions this involves in practice. The bifurcation of choices for donating embryos into accepting informed uncertainty or not donating at all was identified through the research process of interviews and ethics discussion groups. Professional staff accounts in this study contained moral orientations that valued ideas such as engendering patient trust by offering full information, the sense of collective ownership of the National Heath Service and publicly funded science and ideas for how donors might be able to give restricted consent as a third option. PMID- 21812794 TI - Resisting the screening imperative: patienthood, populations and politics in prostate cancer detection technologies for the UK. AB - The introduction of mass screening programmes in the UK has been controversial. It is instructive to examine medical conditions for which screening has been actively considered but not introduced, such as prostate cancer. Incidence of the disease has escalated during the last 20 years, partly due to the upsurge in use of PSA (prostate-specific antigen) detection technology. The controversy is moving into a new phase, associated with the development of new molecular genetic biomarkers and tests derived from genome-association studies. The paper outlines the most recent scientific and technological developments for the three types of detection technology - PSA, genetic, and genomic. Applying concepts of risk, technology governance and technology expectations, it is shown that central public health governance actors continue to resist the tidal wave of new technologies through a variety of increasingly diverse governance modes. In the case of PSA, a governance trend moving beyond 'responsibilisation' to citizen rights is shown, whereas in the case of genetic tests and genomic risk profiling, state public health agencies are shown to be engaging in a form of technology expectation management, as it responds to a new marketplace of private commercial testing and mediatised science-based visions of future healthcare. PMID- 21812795 TI - Comparison of media formulations used to selectively cultivate Dekkera/Brettanomyces. AB - AIMS: The objectives of this research were to (i) optimize the concentration of cycloheximide for use in WL media used in the wine industry and (ii) evaluate Dekkera/Brettanomyces differential medium (DBDM) as a means to detect Dekkera. METHODS AND RESULTS: Dekkera bruxellensis and other yeasts were transferred into WL broths containing 0, 10, 50 or 100 mg l(-1) of cycloheximide. While several grew in 10 mg l(-1) , only Hanseniaspora uvarum, Pichia guillermondii, Schizosaccharomyces pombe and D. bruxellensis tolerated >=50 mg l(-1) of the antibiotic. On solidified WL media after 8-days incubation, colony sizes of two strains of D. bruxellensis (B1b and ATCC 52905) decreased with increased concentrations of cycloheximide, while others (F3 and P2) were unaffected. Although D. bruxellensis B1b did not grow well on another selective medium, DBDM, colony development was improved by the addition of sterilized red wine. CONCLUSIONS: Of the concentrations tested, 50 mg l(-1) cycloheximide inhibited many grape/wine yeasts yet generally yielded countable colonies of Dekkera (1-2.5 mm diameter). Several strains of Dekkera did not grow well on DBDM, probably due to the lack of an unidentified nutrient(s). SIGNIFICANCE AND IMPACT OF THE STUDY: Better media formulations will improve the detection of Dekkera, thereby increasing microbiological control during winemaking. PMID- 21812796 TI - What is the value for money of medicines? A registry study. AB - WHAT IS KNOWN AND OBJECTIVE: Economic evaluation is used to assess the value for money of medicines and inform pharmaceutical pricing/reimbursement decisions in many countries. This paper aims to report on estimates of the value for money of medicines in Europe. METHODS: Estimated cost-utilities were derived from studies included in the Tufts Medical Center Cost-Effectiveness Analysis Registry between 2000 and 2007. For each study, the following variables were examined: publication year, target population, intervention type, country of patient sample, disease classification, prevention stage, funding source, study perspective, discounting, sensitivity analysis, incremental cost-utility ratio (ICUR) and methodological quality. RESULTS AND DISCUSSION: Six hundred and eight ICURs were reported in 231 cost-utility analyses. Around 17.1% of ratios related to medicines that were more effective and less expensive than the comparator; 76.5% related to medicines that improved outcomes, but increased costs; and 6.4% related to medicines that were less effective and more expensive than the comparator. The median ratio was 12,238 ? per quality-adjusted life year (QALY). Using threshold values of 20,000 and 50,000 ? per QALY, the probability that medicines provided value for money was 58% and 81%, respectively. Preventive medicines studied provided more value for money than curative medicines (P=0.002). Studies sponsored by industry generated more favourable results than studies sponsored from other sources (P<0.001). However, no association was observed between the funding source and the methodological quality of economic evaluations. WHAT IS NEW AND CONCLUSION: The evidence base suggests that the majority of medicines provided value for money. Such information informs policy decisions relating to the allocation of scarce health care resources in Europe. PMID- 21812797 TI - Effects of 1-year orlistat treatment compared to placebo on insulin resistance parameters in patients with type 2 diabetes. AB - WHAT IS KNOWN AND OBJECTIVE: The behavioural approach is usually slow and not always sufficient to achieve optimal targets in weight and metabolic control in obese diabetic patients, and a pharmacological treatment is often necessary. The aim of this study was to compare the effects of orlistat and placebo on body weight, glycaemic and lipid profile and insulin resistance in patients with type 2 diabetes. METHODS: Two hundred and fifty-four obese, diabetic patients were enrolled in this study and randomized to take orlistat 360mg or placebo for 1year. We evaluated at baseline and after 3, 6, 9 and 12months body weight, waist circumference (WC), body mass index (BMI), glycated haemoglobin (HbA(1c) ), fasting plasma glucose (FPG), post-prandial plasma glucose (PPG), fasting plasma insulin (FPI), homeostasis model assessment insulin resistance index (HOMA-IR), lipid profile, retinol-binding protein-4 (RBP-4), resistin, visfatin and high sensitivity C-reactive protein (Hs-CRP). RESULTS AND DISCUSSION: We observed a significant reduction in body weight, WC, BMI, lipid profile, RBP-4 and visfatin in the orlistat group but not in control group. Faster improvements in HbA(1c) , PPG, FPI, HOMA-IR, resistin and Hs-CRP were recorded with orlistat than with placebo. A similar decrease in FPG was seen in the two groups. Significant predictors of change in insulin resistance (HOMA-IR) were RBP-4 and resistin concentration in the orlistat group (r=-0.53, P<0.05, and r=-0.59, P<0.01, respectively). WHAT IS NEW AND CONCLUSION: To the best of our knowledge, this is the first study investigating the effect of orlistat on insulin resistance and markers of inflammation. Orlistat improved lipid profile and led to faster glycaemic control and insulin resistance parameters than the control, without any serious adverse event. Orlistat also improved RBP-4 and visfatin, effects not observed with placebo. PMID- 21812798 TI - Responsiveness of the Care Dependency Scale for Rehabilitation (CDS-R). AB - Around 10% of Western Europe's population suffer from a disability which can entail a decrease of independency and quality of life. However, the lives of these people can be improved by rehabilitative treatment and care. Changing the degree of dependency from dependent to independent is essential in rehabilitation, as is the assessment of these changes. To perform such kind of measurements, assessment instruments have to be responsive. In spite of this concern, responsiveness of assessment instruments is studied to a small extent only. This also applies to the Care Dependency Scale for Rehabilitation (CDS-R), a short assessment instrument measuring the care dependency of patients regarding physical and psychosocial aspects. In this longitudinal-study, the responsiveness of the CDS-R, in general and related to different disease-groups, should be determined. Therefore, a convenience sample of 1564 patients was assessed in an Austrian rehabilitation centre with the scale after admission and before discharge. Responsiveness was determined by descriptive analysis, calculation of effect-sizes and significance tests. Differences between admission and discharge occurred on a statistically significant level for patients who changed. Kazis' effect-sizes can be considered as of small/medium effect for patients who changed (0.24/0.49), and as of large effect according to Liang (0.86/1.46). Eta squared was 0.10/0.19 which can be interpreted as of moderate/large effect for patients who changed. Responsiveness-analyses related to different disease-groups showed constantly large effect-sizes for patients with musculoskeletal-disorders. These results indicate that the CDS-R can detect patient-changes over time and discriminate between patients who change under rehabilitation or not. These aspects argue for the responsiveness of the scale, wherefore the CDS-R seems to be appropriate for the assessment of treatment/health-care effectiveness and the evaluation of individual patient-changes. Nevertheless further research is recommended to confirm the level of responsiveness of the scale in general and for different disease-groups. PMID- 21812799 TI - Patients' experiences in hospital following a liver transplantation. AB - Research is scarce regarding patients' experiences, feelings and thoughts the first 4 weeks after liver transplantation. Most research involving patients with a liver transplant are conducted several months, or even years, after the transplantation. The aim of this study is to present results from research interviews that took place post-transplant while patients still were in hospital. The design is explorative and hermeneutic. Fifteen patients were interviewed 3-5 weeks after transplantation. The results are presented in the following themes: (i) general contentment with the hospital stay, (ii) physical discomfort, (iii) dreams, nightmares and hallucinations, (iv) Comedowns experienced during rejection of the transplant and (v) Other psychological/mental reactions. A major result from our study is patients' own descriptions of comedowns experienced during rejection of the transplant, and the seemingly little consolation and support the patients received. Another major result is patients' own descriptions of dreams, nightmares and hallucinations, which are not fully described from the patients' own perspective while still in hospital. PMID- 21812800 TI - Combined IL-12 receptor and IgA deficiency in an adult man intestinally infested by an unknown, non-cultivable mycobacterium. AB - Interleukin-12 receptor deficiency is a well-described cause of human susceptibility to infection with low-virulent mycobacteria and Salmonella species. We identified a male patient presenting in his late forties with severe gastroenteropathy because of outbred infestation by a previously unknown mycobacterium. In addition to selective IgA deficiency, the patient was found to carry a not previously described R283X homozygous mutation in his IL12RBeta1 gene. Two of his sisters, a brother, and his four children were healthy, heterozygous carriers of the mutation. In this patient, the combination of two deficiencies could promote illness. Even though the IgA deficiency in itself does not predispose to mycobacterial disease, the lack of secreted IgA may have disturbed the intestinal homoeostasis and increased the susceptibility to the low virulent mycobacterium that the patient was not able to clear because of his IL12R deficiency. Antimycobacterial chemotherapy and interferon-gamma treatment for 2 years significantly improved his condition. This is the first description of IL12RBeta1 deficiency combined with another immunodeficiency, and we suggest that combinatory defects may circumvent the otherwise low penetrance of IL12RB1 deficiency. PMID- 21812801 TI - Cellular immune responses in mice induced by M. tuberculosis PE35-DNA vaccine construct. AB - The PE35 (Rv3872) gene of Mycobacterium tuberculosis is present in the region of difference (RD) one that is deleted in all vaccine strains of Mycobacterium bovis bacillus Calmette Guerin. The aim of this study was to clone PE35 DNA into a DNA vaccine plasmid with CMV promoter and interleukin-2 secretory signal and evaluate the recombinant plasmid for induction of antigen-specific cellular responses in mice. DNA corresponding to PE35 was PCR amplified from the genomic DNA of M. tuberculosis H(37) Rv, cloned into pGEMT-Easy vector and sub-cloned into the DNA vaccine vector pUMVC6. BALB/c mice were immunized with recombinant pUMVC6/PE35 and spleen cells were tested for T-helper (Th)1-type (antigen-induced proliferation and secretion of IFN-gamma) and Th2-type (IL-5), and anti inflammatory (IL-10) cytokine responses to pure recombinant PE35 protein and its synthetic peptides. Mice immunized with the recombinant plasmid DNA (pUMVC6/PE35) showed positive Th1-type cellular responses to pure PE35, but not to an irrelevant antigen, i.e. PPE68 (Rv3873). However, the vaccine construct did not induce antigen-specific Th2-type (IL-5) or anti-inflammatory (IL-10) reactivity to PE35. Testing with synthetic peptides showed that Th1-type cells recognizing various epitopes of PE35 were induced in mice immunized with pUMVC6/PE35 DNA. These results suggest that pUMVC6/PE35 may be useful as a safer vaccine candidate against TB. PMID- 21812802 TI - Nests with numerous SOX10 and MiTF-positive cells in lichenoid inflammation: pseudomelanocytic nests or authentic melanocytic proliferation? AB - Pseudomelanocytic nests in the setting of lichenoid inflammation can mimic atypical melanocytic proliferations. Both melanocytic and cytokeratin immunohistochemical stains may be utilized to differentiate these entities. Unlike true melanocytic nests, pseudomelanocytic nests contain Melanoma Antigen Recognized by T-cells 1 (MART-1)/ Melan-A-positive cells and cells positive for pan-cytokeratins, CD3 and/or CD68. Recently, rare (1-2 cells/nest) microphthalmia associated transcription factor (MiTF)-positive cells were also reported in pseudomelanocytic nests. We present a 48-year-old man with a 2 * 3 cm violaceous to hyperpigmented, non-blanching, polygonal patch on the neck. Histopathology showed focal epidermal atrophy, irregularly distributed junctional nests and a lichenoid infiltrate with colloid bodies. Immunoperoxidase studies revealed occasional pan-cytokeratin and MART-1/Melan-A-positive staining in nests as well as focal S-100 protein-positive cells. Importantly, the majority of nests showed numerous cells positive for MiTF and SOX10 (>2 cells/nest and some the majority of cells). This combined staining pattern confounds the above-described immunohistochemical distinction between pseudo and true melanocytic nests. Clinically felt to represent unilateral lichen planus pigmentosus/erythema dyschromicum perstans and not malignant melanoma in situ, this lesion highlights the importance of clinicopathologic correlation and suggests either a new melanocytic entity or a novel pattern of benign melanocytic reorganization in a subset of lichenoid dermatitides. PMID- 21812803 TI - On the dosing of lepirudin. PMID- 21812804 TI - Computed tomographical (CT) anatomy of the thoracoabdominal cavity of the male turkey (Meleagris gallopavo). AB - In the present work, our goal was to match high-resolution computed tomography (CT) scans with cross-sectional anatomical pictures of the turkey (Meleagris gallopavo). Two male BUT 6 (a commercial line) turkeys were used. CT scans with 1 mm slice thickness were performed. The images covered the trunk from the level of the 9th cervical vertebra to the end of the coccyx. The anatomical sections and the CT scans were matched, and the important structures were identified and labelled on the corresponding pictures. The aim of this study was to create a reference for evaluating CT scans of avian species. PMID- 21812805 TI - Coxa morphologically adapted to large egg in aepyornithid species compared with various palaeognaths. AB - The coxa of palaeognaths including extinct aepyornithid species was compared by means of osteology, computed tomography (CT) imaging and macroscopic anatomy. The pre-acetabular area of the ilium was proportionally much larger in width and height in aepyornithid species than in other extant palaeognaths. The post acetabular area of the ilium, ischium and pubis was relatively short and bilaterally extended in aepyornithid species. Although the Aepyornis species might have produced egg with a major axis exceeding 300 mm in major axis, the short post-acetabular coxa and widely opened ischium and pubis would not have been able to stably hold the eggs in the posterior space of the pelvic cavity unlike the situation in the ostrich. As aepyornithid species resembled the kiwi in measurement ratios of length and width in the pre-acetabular area, a functional-morphological model of the coxa in the aepyornithid species can be proposed based on that of the kiwi. From our data, we suggest that the extinct species of Aepyornis and Mullerornis species effectively used the anterior space of the pelvic cavity to support their extraordinary large egg. PMID- 21812806 TI - Incomplete longitudinal fractures and fatigue injury of the proximopalmar medial aspect of the third metacarpal bone in 55 horses. AB - REASONS FOR PERFORMING STUDY: Previous descriptions of incomplete longitudinal fractures and fatigue injury of the proximopalmar aspect of the third metacarpal bone (McIII) have focused on diagnostic imaging findings, especially in racehorses. OBJECTIVES: To document the case details, clinical features, response to diagnostic analgesia, diagnostic imaging findings and follow-up data in a large group of horses with an incomplete longitudinal fracture or fatigue injury of the proximopalmar medial aspect of the McIII. MATERIALS AND METHODS: Horses were included in the study if pain was localised to the proximopalmar aspect of the metacarpal region, with radiological evidence of an incomplete longitudinal fracture or generalised increased radiopacity in the proximopalmar medial aspect of the McIII, or focal increased radiopharmaceutical uptake (IRU) in the proximopalmar aspect of the McIII. Age, breed, gender, height, bodyweight, work discipline, work history, duration of lameness, clinical signs and responses to diagnostic analgesia were recorded. Radiographic and scintigraphic images were assessed subjectively and objectively. RESULTS: There were 55 horses representing a broad spectrum of ages and work disciplines, 73% of which had radiological abnormalities. The majority had no localising clinical signs, although 73% of horses with radiological abnormalities showed a characteristic pattern of lameness. Lameness was generally worse in straight lines than in circles. Increased radiopharmaceutical uptake ranged from mild to intense in the lame limb; 14% of nonlame limbs had mild IRU. Of horses for which long-term follow-up was available, 98% returned to full athletic function. CONCLUSIONS AND POTENTIAL RELEVANCE: Incomplete longitudinal fractures and fatigue injury of the proximopalmar medial aspect of the McIII may occur in horses of many types and sports disciplines, and are not confined to immature performance horses. They should be considered an important differential diagnosis for proximal metacarpal region pain. PMID- 21812807 TI - Equine paranasal sinus disease: a long-term study of 200 cases (1997-2009): ancillary diagnostic findings and involvement of the various sinus compartments. AB - REASONS FOR PERFORMING STUDY: There is a lack of objective information on the value of ancillary diagnostic techniques used to investigate equine sinus disease, and also on which sinus compartments are commonly affected in this disorder. OBJECTIVES: To record the ancillary diagnostic findings used to investigate equine sinus disease and to document which compartments are affected. MATERIALS AND METHODS: The clinical case records of 200 consecutive cases of sinus disease, including subacute (<2 months' duration) primary (n = 52); chronic (>2 months' duration) primary (n = 37); dental (n = 40); traumatic (n = 13); sinus cyst (n = 26); sinus neoplasia (n = 10); dental related oromaxillary fistula (n = 8); mycotic sinusitis (n = 7) and intra-sinus progressive ethmoid haematoma (n = 7) were retrospectively examined. RESULTS: Nasal endoscopy showed exudate draining from the sino-nasal ostia in 88% of cases and a sino-nasal fistula was present in 15% of cases. Sinoscopy was performed in 79% of cases and was of great diagnostic value. More recently, 22% of cases had fenestration of the ventral conchal bulla performed to allow sinoscopy of the rostral sinus compartments. Radiography was performed in 97% of cases and showed intra-sinus fluid lines to be common (69% prevalence) in subacute primary sinusitis. Radiographic dental apical changes were not specific to dental sinusitis, e.g. 29% of chronic primary sinusitis cases had radiographic dental changes. Scintigraphy was performed in 20% of cases and was helpful in identifying dental apical changes when radiography was inconclusive. Overall, the caudal maxillary (78% involvement) and rostral maxillary (61%) sinuses were most commonly affected, with the ventral conchal sinus (VCS) (54% involvement) and conchofrontal sinuses (48%) less so. The VCS showed the greatest tendency to contain inspissated pus (present in 46% of all affected VCS). CONCLUSIONS: Nasal endoscopy, sinoscopy and skull radiography are of great value in diagnosing the presence and causes of equine sinus disease. PMID- 21812808 TI - Equine paranasal sinus disease: a long-term study of 200 cases (1997-2009): treatments and long-term results of treatments. AB - REASONS FOR PERFORMING STUDY: There is limited objective information available on the treatment and the long-term response to treatment of the different types of equine sinus disease. OBJECTIVES: To document the treatments and long-term response to these treatments in 200 cases of equine sinus disease (1997-2009). METHODS: The treatments of horses affected with subacute primary sinusitis (n = 52); chronic primary sinusitis (n = 37); dental sinusitis (n = 40); sinus cyst (n = 26); traumatic (n = 13); dental-related oromaxillary fistula (n = 8); sinus neoplasia (n = 10); mycotic sinus disease (n = 7); and intrasinus progressive ethmoid haematoma (n = 7) and the long-term response to these treatments were retrospectively reviewed. RESULTS: Treatments evolved throughout the study and latterly were as conservative as possible, including sinoscopic lavage and standing sinusotomy, with a maxillary sinusotomy approach preferred for the mainly mature horses treated in this study. Removal of intrasinus inspissated pus, including transendoscopically (by sinusotomy and via existing sinonasal fistulae), was the main treatment for chronic primary sinusitis and sinonasal fistulation was seldom performed latterly. Attempted oral extraction of infected cheek teeth, even if unsuccessful, facilitated subsequent dental repulsion, resulting in few post operative problems. Sinus cyst removal carried an excellent prognosis. Except for cases of sinus neoplasia (only 22% cured), an excellent long-term response to treatment (91% fully cured, 7% partially cured) was obtained for all other types of sinus disease following a median of one treatment. CONCLUSIONS: More conservative treatments, including removal of intrasinus inspissated pus by sinoscopy, pre-existing sinonasal fistula or sinusotomy, are effective for chronic primary sinus disease. Standing sinusotomy, mainly using a small maxillary site, was suitable for most cases of sinus disease in mature horses. PMID- 21812809 TI - A novel rapid oral bacteria detection apparatus for effective oral care to prevent pneumonia. AB - OBJECTIVE: To clarify the oral environment, we evaluated the usefulness and clinical applicability of a new apparatus developed for the simple and rapid quantification of oral bacteria. BACKGROUND: Professional oral health care can reduce the number of oral bacteria and days of fever and inhibit the development of pneumonia. A novel detection apparatus was developed by applying the dielectrophoretic impedance measurement method. METHODS: First, to determine the accuracy of this apparatus, employing standard samples of Escherichia coli. Next, to evaluate the oral environment, samples were taken from the tongue in elderly (mean age: 86.6 years) in nursing home. RESULTS: In the first study, a good correlation was observed between the two methods (R = 0.999). In the second study, there were significant correlations between measurement values obtained using this apparatus and those obtained by the culture method (R = 0.852), as well as those obtained by the FM method (R = 0.885). CONCLUSION: Our data showed that this rapid oral bacterial detection apparatus is effective in evaluating the oral hygiene to prevent pneumonia in the elderly. PMID- 21812811 TI - Diabetes-science, serendipity and common sense. AB - This paper is dedicated to young researchers in diabetes. One such person was Frederick Banting who, with his colleagues, isolated insulin in 1921, saving the lives of literally millions of people. What factors allowed Banting and other scientists to produce work that has immensely benefited the human race? I propose that it is the combination of good scientific background (the 'prepared mind'), commonly some serendipity taken with a good dose of common sense and supplemented by enthusiasm, tenacity and good mentoring, which drives the 'power of observation' and the ability to take forward the good idea. I give examples from history to support this and then discuss some of the 'truths, perspectives and controversies' within the diabetes arena when I first started in diabetes research in the late 1970s. I describe how my appetite was initially 'whetted' for research by moving to an excellent clinical research environment with encouragement to test ideas and controversies initially in a clinical research programme, followed by more scientific/basic research. The work that I performed as a young doctor and research fellow led to a lifelong professional interest in three major areas-causes and interventions for diabetes vascular disease, studies of the molecular genetics of Type 1 and Type 2 diabetes and work on diabetes in different ethnic groups. I provide a summation of my own and other people's work to demonstrate how research can be progressed and lead to patient benefit as well as providing an incredibly rewarding career. I believe that we need to encourage and put more resources into development of young doctors and scientists wishing to undertake research in our discipline. Areas ripe for much-needed clinical research programmes, for example, include work on best practice/provision of health care, application of the evidence base from clinical trials to achieve public health gains, attention to adherence issues and better-tolerated therapies. Most importantly, a greater emphasis on prevention through public health measures and 'buy in' from the whole population is urgently required. PMID- 21812812 TI - HbA1c in the diagnosis of diabetes: which cut-off point? PMID- 21812813 TI - Insulin dose requirement in diabetic ketoacidosis. PMID- 21812814 TI - Sir Harold Himsworth. PMID- 21812815 TI - Strategies for the prevention of autoimmune type 1 diabetes. AB - European experts on autoimmune Type 1 diabetes met for 2 days in October 2010 in Cambridge, to review the state-of-the-art and to discuss strategies for prevention of Type 1 diabetes (http://www gene.cimr.cam.ac.uk/todd/sub_pages/T1D_prevention_Cambridge_workshop_20_21Oct2010 pdf). Meeting sessions examined the epidemiology of Type 1 diabetes; possible underlying causes of the continuing and rapid increase in Type 1 diabetes incidence at younger ages; and lessons learned from previous prevention trials. Consensus recommendations from the meeting were: 1. Resources such as national diabetes registries and natural history studies play an essential role in developing and refining assays to be used in screening for risk factors for Type 1 diabetes. 2. It is crucial to dissect out the earliest physiological events after birth, which are controlled by the susceptibility genes now identified in Type 1 diabetes, and the environmental factors that might affect these phenotypes, in order to bring forward a mechanistic approach to designing future prevention trials. 3. Current interventions at later stages of disease, such as in newly diagnosed Type 1 diabetes, have relied mainly on non-antigen-specific mechanisms. For primary prevention-preventing the onset of autoimmunity interventions must be based on knowledge of the actual disease process such that: participants in a trial would be stratified according the disease-associated molecular phenotypes; the autoantigen(s) and immune responses to them; and the manipulation of the environment, as early as possible in life. Combinations of interventions should be considered as they may allow targeting different components of disease, thus lowering side effects while increasing efficacy. PMID- 21812816 TI - Exogenous melatonin modulates apoptosis in the mouse brain induced by high-LET carbon ion irradiation. AB - The aim of this study was to investigate whether melatonin, a free radical scavenger and a general antioxidant, regulates the brain cell apoptosis caused by carbon ions in mice at the level of signal transduction pathway. Young Kun-Ming mice were divided into five groups: control group, irradiation group and three melatonin (1, 5, and 10 mg/kg daily for 5 days i.p.) plus irradiation-treated groups. An acute study was carried out to determine oxidative status, apoptotic cells, and mitochondrial membrane potential (DeltaPsim) as well as pro- and anti apoptotic protein levels in a mouse brain 12 hr after irradiation with a single dose of 4 Gy. In irradiated mice, a significant rise in oxidative stress and apoptosis (TUNEL positive) was accompanied by activated expression of Bax, cytochrome c, caspase-3, and decreased DeltaPsim level. Melatonin supplementation was better able to reduce irradiation-induced oxidative damage marked by carbonyl or malondialdehyde content, and stimulate the antioxidant enzyme activities (superoxide dismutase and catalase) together with total antioxidant capacity. Moreover, administration with melatonin pronouncedly elevated the expression of Nrf2 which regulates redox balance and stress. Furthermore, melatonin treatment mitigated apoptotic rate, maintained DeltaPsim, diminished cytochrome c release from mitochondria, down-regulated Bax/Bcl-2 ratio and caspase-3 levels, and consequently inhibited the important steps of irradiation-induced activation of mitochondrial pathway of apoptosis. Thus, we propose that the anti-apoptotic action with the alterations in apoptosis regulator provided by melatonin may be responsible at least in part for its antioxidant effect by the abolishing of carbon ion-induced oxidative stress along with increasing Nrf2 expression and antioxidant enzyme activity. PMID- 21812817 TI - mtDNA T8993G mutation-induced mitochondrial complex V inhibition augments cardiolipin-dependent alterations in mitochondrial dynamics during oxidative, Ca(2+), and lipid insults in NARP cybrids: a potential therapeutic target for melatonin. AB - Mitochondrial dynamics including morphological fission and mitochondrial movement are essential to normal mitochondrial and cellular physiology. This study investigated how mtDNA T8993G (NARP)-induced inhibition of mitochondrial complex V altered mitochondrial dynamics in association with a protective mitochondrial phospholipid, cardiolipin (CL), as a potential therapeutic target. NARP cybrids harboring 98% of mtDNA T8993G genes and its parental osteosarcoma 143B cells were studied for comparison, and protection provided by melatonin, a potent mitochondrial protector, was explored. We demonstrate for the first time that NARP mutation significantly enhances apoptotic death as a result of three distinct lethal mitochondrial apoptotic insults including oxidative, Ca(2+), and lipid stress. In addition, NARP significantly augmented pathological depletion of CL. NARP-augmented depletion of CL results in enhanced retardation of mitochondrial movement and fission and later swelling of mitochondria during all insults. These results suggest that CL is a common and crucial pathological target for mitochondrial apoptotic insults. Furthermore, CL possibly plays a central role in regulating mitochondrial dynamics that are associated with NARP augmented mitochondrial pathologies. Intriguingly, melatonin, by differentially preserving CL during various stresses (oxidation > Ca(2+) > lipid), rescues differentially CL-altered mitochondrial dynamics and cell death (oxidation > Ca(2+) > lipid). Thus, melatonin, in addition to being a mitochondrial antioxidant to antagonize mitochondrial oxidative stress, a mitochondrial permeability transition modulator to antagonize mitochondrial Ca(2+) stress, may stabilize directly CL to prevent its oxidization and/or depletion and, therefore, exerts great potential in rescuing CL-dependent mitochondrial dynamics-associated mitochondrial pathologies for treatment of NARP-induced pathologies and diseases. PMID- 21812818 TI - Comparative gastroprotective effect of post-treatment with low doses of rutin and cimetidine in rats. AB - The anti-ulcerogenic potentials of low doses of rutin and cimetidine in ethanol-, acetic acid-, and stress-induced ulcers in rats have been evaluated and compared in this study. In each model, male Wistar rats were randomly divided into six groups (I-VI). Groups II-VI were administered 1 mL/100 g ethanol orally, 0.05 mL of 20% acetic acid submucosally or kept in a cold chamber for 6 h to induce ulcer in the ethanol-, acetic acid-, and stress-induced ulceration model, respectively. Thereafter, group III was post-treated with 300 mg/kg cimetidine and groups IV-VI with 20, 40, and 80 mg/kg rutin, respectively, while the control (group I) received distilled water in Tween 20. One hour after post-treatment, all groups were killed and the gastric ulcer index was calculated. Malondialdehyde (MDA) level, vitamin C content, and glutathione peroxidase (GPx) activity were evaluated in the gastric mucosa of animals. Post-treatment with rutin significantly reduced ulcerogen-induced gastric damage in all models. This effect was significant at all dose levels compared with the ulcer-induced groups. Rutin significantly reduced the MDA levels but increased the vitamin C content and GPx activity. Ulcer index and MDA level were highest in the ethanol-induced ulcer model while vitamin C content and GPx activity were lowest in the stress-induced ulcer model. The study showed that all three models of ulceration appeared to be linked to oxidative stress and also ascribed significant anti-ulcerogenic potential to rutin especially at lower doses of 20-80 mg/kg. PMID- 21812819 TI - Fracture load of tooth-implant-retained zirconia ceramic fixed dental prostheses: effect of span length and preparation design. AB - OBJECTIVES: Evaluation of the effect of different span length and preparation designs on the fracture load of tooth-implant-supported fixed dental prostheses (TIFDPs) manufactured from yttrium-stabilized zirconia frameworks. MATERIAL AND METHODS: Forty-eight TIFDPs were manufactured using a CAD/CAM system and veneered with a press ceramic. Rigidly mounted implants (SLA, diameter 4.1 mm, length 10 mm) in the molar region with a titanium abutment were embedded in PMMA bases pairwise with premolars. All premolars were covered with heat-shrink tubing to simulate physiological tooth mobility. Six different test groups were prepared (a) differing in the preparation design of the premolar (inlay [i]; crown [c]), (b) the material of the premolar (metal [m]; natural human [h]) and (c) the length of the TIFDPs (3-unit [3]; 4-unit [4]). All TIFDPs underwent thermomechanical loading (TCML) (10,000 * 6.5 degrees /60 degrees ; 6 * 10(5) * 50 N). The load to fracture (N) was measured and fracture sites were evaluated macroscopically. RESULTS: None of the restorations failed during TCML. The mean fracture loads (standard deviations) were 1,522 N (249) for the 3-unit, inlay retained TIFDPs on a metal abutment tooth (3-im), 1,910 N (165) for the 3-cm group, 1,049 N (183) for group 4-im, 1,274 N (282) for group 4-cm, 1,229 N (174) for group 4-ih and 911 N (205) for group 4-ch. Initial damages within the veneering ceramic occurred before the final failure of the restoration. The corresponding loads were 24-52% lower than the fracture load values. CONCLUSIONS: All restorations tested could withstand the mastication forces expected. Fracture load values for 3- and 4-unit inlay-crown and crown-crown-retained TIFDPs should spur further clinical investigation. PMID- 21812820 TI - Adaptations to aerobic interval training: interactive effects of exercise intensity and total work duration. AB - To compare the effects of three 7-week interval training programs varying in work period duration but matched for effort in trained recreational cyclists. Thirty five cyclists (29 male, 6 female, VO(2peak) 52 +/- 6 mL kg/min) were randomized to four training groups with equivalent training the previous 2 months (~6 h/wk, ~1.5 int. session/wk). Low only (n=8) trained 4-6 sessions/wk at a low-intensity. Three groups (n=9 each) trained 2 sessions/wk * 7 wk: 4 * 4 min, 4 * 8 min, or 4 * 16 min, plus 2-3 weekly low-intensity bouts. Interval sessions were prescribed at the maximal tolerable intensity. Interval training was performed at 88 +/- 2, 90 +/- 2, and 94 +/- 2% of HR(peak) and 4.9, 9.6, and 13.2 mmol/L blood lactate in 4 * 16, 4 * 8, and 4 * 4 min groups, respectively (both P<0.001). 4 * 8 min training induced greater overall gains in VO(2) peak, power@VO(2) peak, and power@4 mM bLa- (Mean +/- 95%CI): 11.4 (8.0-14.9), vs 4.2 (0.4-8.0), 5.6 (2.1 9.1), and 5.5% (2.0-9.0) in Low, 4 * 16, and 4 * 4 min groups, respectively (P<0.02 for 4 * 8 min vs all other groups). Interval training intensity and accumulated duration interact to influence the adaptive response. Accumulating 32 min of work at 90% HR max induces greater adaptive gains than accumulating 16 min of work at ~95% HR max despite lower RPE. PMID- 21812821 TI - Effects of resistance training with whole-body vibration on muscle fitness in untrained adults. AB - The effects of resistance training (RT) combined with whole-body vibration (WBV) on muscle fitness, particularly muscle hypertrophy and neuromuscular performance, are not well understood. We investigated the effects of WBV in healthy, untrained participants after a 13-week RT course by performing magnetic resonance imaging and by measuring maximal isometric (with electromyography) and isokinetic knee extension strengths, isometric lumbar extension torque, countermovement-jump, knee extension endurance, and sit-ups. Thirty-two individuals (22-49 years old) were randomly assigned to RT groups with (RT-WBV, n=16) or without WBV (RT, n=16). Following the RT course, significantly higher increases in the cross sectional areas of m. psoas major (vs baseline values) and erector spinae muscle (vs the RT group) were observed in the RT-WBV group (+10.7%, P<0.05; +8.7%, P<0.05) compared with the RT group (+3.8%, P=0.045; 0.0%). Higher increases from baseline were also observed in maximal isometric force, concentric knee extension torque, countermovement-jump, and maximal isometric lumbar extension torque in RT WBV (+63.5%; +76.7%, +15.0%, and +51.5%, respectively; P<0.05) than in those of RT (+25.6%, P=0.001; +17.8%, P=0.18; +11.3%, P=0.001; and +26.4%, P<0.001, respectively). The WBV-induced increases in muscle hypertrophy and isometric lumbar extension torque suggest a potential benefit of incorporating WBV into slow-velocity RT programs involving exercises of long duration. PMID- 21812822 TI - Effects of different half-time strategies on second half soccer-specific speed, power and dynamic strength. AB - This study compared the effects of whole body vibration (WBV) and a field-based re-warm-up during half-time (HT) on subsequent physical performance measures during a simulated soccer game. Ten semi-professional male soccer players performed 90-min fixed-intensity soccer simulations (SAFT(90)), using a multi directional course. During the HT period players either remained seated (CON), or performed intermittent agility exercise (IAE), or WBV. At regular intervals during SAFT(90), vastus lateralis temperature (T(m)) was recorded, and players also performed maximal counter-movement jumps (CMJ), 10-m sprints, and knee flexion and extension contractions. At the start of the second half, sprint and CMJ performance and eccentric hamstring peak torque were significantly reduced compared with the end of the first half in CON (P<=0.05). There was no significant change in these parameters over the HT period in the WBV and IAE interventions (P>0.05). The decrease in T(m) over the HT period was significantly greater for CON and WBV compared with IAE (P<=0.01). A passive HT interval reduced sprint, jump and dynamic strength performance. Alternatively, IAE and WBV at HT attenuated these performance decrements, with limited performance differences between interventions. PMID- 21812823 TI - Indicators for high physical strain and overload in elite football players. AB - Laboratory, psychological and performance parameters as possible indicators of physical strain and overload during highly demanding competition phases were evaluated in elite male football players. In two studies with the same objective, periods of high (HE: >270 min during 3 weeks before testing) and low (LE: <270 min) match exposure were compared over the course of an entire season. In study 1 (n=88 players of the first and second German leagues; age: 25.6 +/- 4.3 years; body mass index (BMI): 23.2 +/- 1.0 kg/m(2) ), blood count, CK, urea, uric acid, CRP and ferritin were determined. In study 2, 19 players of the third German league and the highest under-19 league (age: 19.7 +/- 2.8 years; BMI: 22.8 +/- 1.7 kg/m(2) ) were screened for individual vertical jump height, maximal velocity and by the Recovery-Stress-Questionnaire for Athletes (REST-Q Sport). The mean differences in exposure times were 180 min (study 1: quartiles: 105, 270 min) and 247 min (study 2: 180, 347 min), respectively. Significant differences were found neither in blood parameters (study 1; P>0.36) nor in physiological testing results or in REST-Q scores (study 2; P>0.20). A 3-week period of high match exposure in elite football players does not affect laboratory, psychometric and performance parameters. PMID- 21812824 TI - Isometric knee extensor fatigue following a Wingate test: peripheral and central mechanisms. AB - Central and peripheral fatigue have been explored during and after running or cycling exercises. However, the fatigue mechanisms associated with a short maximal cycling exercise (30 s Wingate test) have not been investigated. In this study, 10 volunteer subjects performed several isometric voluntary contractions using the leg muscle extensors before and after two bouts of cycling at 25% of maximal power output and two bouts of Wingate tests. Transcranial magnetic stimulation (TMS) and electrical motor nerve stimulation (NM) were applied at rest and during the voluntary contractions. Maximal voluntary contraction (MVC), voluntary activation (VA), twitch amplitude evoked by electrical nerve stimulation, M wave and motor potential evoked by TMS (MEP) were recorded. MVC, VA and twitch amplitude evoked at rest by NM decreased significantly after the first and second Wingate tests, indicating central and peripheral fatigue. MVC and VA, but not the twitch amplitude evoked by NM, recovered before the second Wingate test. These results suggest that the Wingate test results in a decrease in MVC associated with peripheral and central fatigue. While the peripheral fatigue is associated with an intramuscular impairment, the central fatigue seems to be the main reason for the Wingate test-induced impairment of MVC. PMID- 21812825 TI - Objectively measured physical activity and C-reactive protein: National Health and Nutrition Examination Survey 2003-2004. AB - The association between physical activity (PA) and C-reactive protein (CRP) is inconsistent, with nearly all studies using self-report measures of PA. The purpose of this study was to examine the association between objectively measured PA and CRP in US adults and children. Adults (N=2912) and children (N=1643) with valid accelerometer data and CRP data were included in the analyses. Logistic regression analysis was used to assess the odds of meeting PA guidelines across CRP quartiles for children and among adults with low, average, and high CRP levels. For adults, after adjustments for age, gender, race, body mass index, smoking, diabetes, and high-density lipoprotein cholesterol (HDL-C), compared with those with low CRP levels, odds ratios were 0.59 (CI=0.45-0.77) and 0.46 (CI=0.28-0.76) for participants with average and high CRP levels, respectively. For children, after adjustments for age, gender, race, weight status, and HDL-C, compared with those in CRP quartile 1, odds ratios were 0.96 (CI=0.5-1.84), 1.23 (CI=0.71-2.12), and 0.79 (CI=0.33-1.88) for participants in quartiles 2, 3, and 4, respectively. Objectively measured PA is inversely associated with CRP in adults, with PA not related to CRP in children. PMID- 21812826 TI - Effects of training periodization on cardiac autonomic modulation and endogenous stress markers in volleyball players. AB - We investigated the effects of selective loads of periodization model (SLPM) on autonomic modulation of heart rate variability (HRV) and endogenous stress markers before and after a competition period in volleyball players (N=32). The experimental protocol for the evaluation of HRV consisted of using spectral analysis of time series composed of the R-R intervals derived from electrocardiogram obtained in the supine position and during the tilt test. Stress marker levels were determined by quantifying the plasma concentration of endogenous catecholamines, cortisol and free testosterone. The results showed no changes between the levels of HRV before and after a competition period. In contrast, the quantification of the plasma concentration of endogenous stress markers revealed reductions in the levels of total catecholamines, noradrenaline and cortisol. These changes were accompanied by increases in the concentration of free testosterone and in the testosterone/cortisol ratio. In conclusion, our results demonstrate that the SLPM did not change the cardiac autonomic modulation of HRV, but promoted beneficial adaptations in athletes, including positive changes in the plasma concentration of the endogenous stress markers. The absence of changes in HRV indicates that there is no direct relationship between cardiac autonomic modulation and endogenous stress markers in the present study. PMID- 21812827 TI - High injury incidence in TeamGym competition: a prospective cohort study. AB - TeamGym is a relative new form of gymnastics originating from Scandinavia. Little is known regarding injury incidence and injury types. The aim of this study was to examine the injury pattern and incidence in Norwegian TeamGym competition. The study is a prospective cohort, with one 10-month season [17 competitions, n=8418 athlete-exposures (A-Es), a total of 1134 h of exposure]. Injury pattern, incidence and exposure during competition were collected using an injury registration form. During the competitions, 115 injuries were reported including 49 (43%) acute injuries, 58 (50%) exacerbations and eight (7%) re-injuries. The injury incidence was 50.3/1000 h or 6.8/1000 A-Es. Ankle injuries accounted for 25.6/1000 h. A total number of 30 time-loss injuries were found, giving 27 injuries per 1000 h. The high proportion of exacerbations shows that the gymnasts competed even if they had not recovered fully from previous overuse or acute injuries. A higher injury rate was observed in competition than during the pre competition apparatus warm-up. Eighty-four per cent of the injuries occurred in the landing phase of the gymnastic skill. No sex differences were observed. The injury rate in Norwegian TeamGym competition is high, in particular for ankle injuries. PMID- 21812828 TI - Heart rate variability in prediction of individual adaptation to endurance training in recreational endurance runners. AB - The aim of this study was to investigate whether nocturnal heart rate variability (HRV) can be used to predict changes in endurance performance during 28 weeks of endurance training. The training was divided into 14 weeks of basic training (BTP) and 14 weeks of intensive training periods (ITP). Endurance performance characteristics, nocturnal HRV, and serum hormone concentrations were measured before and after both training periods in 28 recreational endurance runners. During the study peak treadmill running speed (Vpeak ) improved by 7.5 +/- 4.5%. No changes were observed in HRV indices after BTP, but after ITP, these indices increased significantly (HFP: 1.9%, P=0.026; TP: 1.7%, P=0.007). Significant correlations were observed between the change of Vpeak and HRV indices (TP: r=0.75, P<0.001; HFP: r=0.71, P<0.001; LFP: r=0.69, P=0.01) at baseline during ITP. In order to lead to significant changes in HRV among recreational endurance runners, it seems that moderate- and high-intensity training are needed. This study showed that recreational endurance runners with a high HRV at baseline improved their endurance running performance after ITP more than runners with low baseline HRV. PMID- 21812829 TI - Human papillomavirus typing of warts and response to cryotherapy. AB - BACKGROUND: Cutaneous warts are common and caused by a number of different types of human papillomaviruses (HPVs). OBJECTIVE: The aim of this study was to investigate the HPV types causing common warts and to determine any association between the HPV type and the duration of warts and response to cryotherapy. METHODS: Eighty wart samples from 76 immunocompetent patients were taken from warts by paring prior to cryotherapy and analysed by in situ hybridization (ISH) with HPV probes specific to HPV 1, 2, 3, 4, 7, 10 and 57 and PCR analysis using degenerate cutaneous HPV primers with subsequent DNA sequencing. Each patient's details, including site, duration and response of the wart to cryotherapy were recorded. Cryotherapy was performed at 2 week intervals for a maximum of 12 weeks. RESULTS: An HPV type was identified in 65 samples. The majority of warts (58 samples) were typed as HPV 2/27/57 by ISH and/or PCR. Three of the 18 samples that were HPV negative with ISH were HPV positive by PCR. Response to treatment did not correlate with HPV type, duration or location. In the 21 wart parings taken from patients aged 16 and under, response to treatment did not correlate with HPV type but warts of shorter duration were more likely to resolve with cryotherapy treatment than longer standing lesions. CONCLUSION: This study demonstrates that HPV type can be determined from wart parings. HPV-2 related viruses are the prevalent HPV types causing common warts on the hands and feet in this population. PMID- 21812830 TI - Prevalence analysis of smoking in rosacea. PMID- 21812831 TI - Management of moderate to severe psoriasis with systemic immunomodulatory therapies: a 5-year experience from two departments of dermatology of Northern France. PMID- 21812832 TI - The effect of a 1550 nm fractional erbium-glass laser in female pattern hair loss. AB - BACKGROUND: Female pattern hair loss (FPHL) is the most common cause of hair loss in women, and its prevalence increases with advancing age. Affected women may experience psychological distress and social withdrawal. A variety of laser and light sources have been tried for treatment of hair loss, and some success has been reported. OBJECTIVE: The purpose of this study was to determine the efficacy and safety of a 1550 nm fractional erbium-glass laser in treatment of female pattern hair loss. PATIENTS AND METHODS: Twenty eight ethnic South Korean patients with varying degrees of FPHL were enrolled in the study. Patients received ten treatments with a 1550 nm fractional Er:Glass Laser (Mosaic, Lutronic Co., Ltd, Seoul, South Korea) at 2-weeks intervals using the same parameters (5-10 mm tip, 6 mJ pulse energy, 800 spot/cm(2) density, static mode). Phototrichogram and global photographs were taken at baseline and at the end of laser treatment, and analysed for changes in hair density and hair shaft diameter. Global photographs underwent blinded review by three independent dermatologists using a 7-point scale. Patients also answered questionnaires assessing hair growth throughout the study. All adverse effects were reported during the study. RESULTS: Twenty seven patients completed a 5-month schedule of laser treatment. One patient was excluded during treatment due to occurrence of alopecia areata. At the initial visit, mean hair density was 100 +/- 14/cm(2) , and mean hair thickness was 58 +/- 12 MUm. After 5 months of laser treatment, hair density showed a marked increase to 157 +/- 28/cm(2) (P < 0.001), and hair thickness also increased to 75 +/- 13 MUm (P < 0.001). Global photographs showed improvement in 24 (87.5%) of the 27 patients. Two patients (7.4%) reported mild pruritus after laser treatment; however, these resolved within 2 h. CONCLUSION: A 1550 nm fractional erbium-glass laser irradiation may be an effective and safe treatment option for women with female pattern hair loss. PMID- 21812833 TI - Current psoriasis treatments in an Italian population and their association with socio-demographical and clinical features. AB - BACKGROUND: Patient adherence is a key element for therapeutic success and represents a major concern for all healthcare professionals. OBJECTIVE: Aim of our study was to assess the frequency of use of treatments currently available for psoriasis and its association with specific socio-demographical and clinical variables. METHODS: The study population consisted of 1689 patients, aged 12-85 years. Information concerning socio-demographical variables, clinical features and the type of current treatment was collected. Items on patients' satisfaction of current treatments and of dermatologist-patient relationship were also included. The chi-squared test was used to estimate the association between the categorical variables, whereas Wilcoxon and Kruskal-Wallis tests were applied to the interval and ordinal variables. The Cochran-Mantel-Haenszel chi-squared trend test was used to evaluate the degree of satisfaction related to dermatologist patient relationship. RESULTS: Of the 1689 psoriatic patients, 54.1% did not use any treatments and 45.9% used at least one treatment. The use of drugs was significantly associated exclusively to severity of disease and affected body surface area. Systemic therapies, both traditional treatments and biological agents, were mainly used in patients with disease duration >10 years and disease severity. Treatment adherence was significantly associated to the degree of patient's satisfaction of his/her relationship with the dermatologist. Alternative treatment such as over the counter medications and acupuncture were used by 33% of patients. CONCLUSION: The majority of psoriatic patients do not use any treatments. However, treatment adherence significantly increases when dermatologists clarify the treatment schedule, inform patients and meet the patients' needs. PMID- 21812834 TI - Efficacy of iontophoresis with glycopyrronium bromide for treatment of primary palmar hyperhidrosis. AB - BACKGROUND: There is limited data on the efficacy of iontophoretic treatment of primary palmar hyperhidrosis using glycopyrronium bromide. The first line treatment for primary palmar hyperhidrosis is usually topical aluminium chloride, but clinical experience indicates that it is not effective for more severe disease. OBJECTIVE: To evaluate the efficacy of using glycopyrronium bromide iontophoresis in the treatment of primary palmar hyperhidrosis, and to evaluate if the benefit of treatment varies with the severity of disease. METHODS: This is an open-label study involving patients undergoing weekly treatment of iontophoresis with glycopyrronium bromide for 4 weeks. Gravimetric measurements of sweat production and subjective scores of palmar sweatiness were recorded prior to starting treatment and 1 week after the last treatment. Side-effects were monitored weekly. RESULTS: Twenty two of the 25 patients recruited completed the 4-week treatment. There was a significant mean improvement of 23.4 mg/min (P = 0.001) between baseline and post-treatment gravimetric measurements. Patients with a higher baseline sweat output demonstrated a trend towards a greater reduction in sweat production (Pearson's correlation correlation coefficient, r = 0.41). The patients experienced dryness of the palms for a mean duration of 5 days after iontophoresis. All patients reported an improvement in satisfaction scores and 81.8% reported an improvement in subjective severity scores. No serious side-effects were encountered during the study. CONCLUSIONS: Iontophoresis using glycopyrronium bromide is an effective and well-tolerated treatment for primary palmar hyperhidrosis. The possibility of its greater benefit in patients with more severe baseline disease requires verification. PMID- 21812835 TI - The effectiveness and safety of adalimumab in the treatment of non-reimbursed patients with mild-to-moderate psoriasis. AB - BACKGROUND: Few reports exist on the use of biologics for treating patients with mild-to-moderate psoriasis, especially for non-reimbursed patients. OBJECTIVES: This study aimed to evaluate the safety and effectiveness of adalimumab in non reimbursed patients with mild-to-moderate psoriasis. METHODS: Fifty one patients with mild-to-moderate psoriasis treated with adalimumab 40 mg every other week (eow) in a tertiary referral hospital in Taiwan between 2007 and 2010 were retrospectively reviewed. The clinical effectiveness of adalimumab was assessed using Subject's Global assessment (SGA) and Physician's Global Assessment (PGA), and the reasons for discontinuation were evaluated. RESULTS: After 12 weeks of adalimumab (40 mg subcutaneously eow without a loading dose) treatment, 66% and 74% of patients had SGA and PGA scores of at least marked improvement (greater than 50% improvement compared with baseline psoriasis), respectively, with 60% and 53% of patients achieving SGA and PGA scores of at least marked improvement after 24 weeks. Ten (71%) of 14 previous non-responders to etanercept achieved a SGA or PGA score of at least marked improvement after adalimumab treatment. Adalimumab was generally well tolerated, but four patients (7.8%) discontinued adalimumab due to adverse events. The mean time required for resumption of systemic anti-psoriatic therapy was 6 months (range, 1-12 months). Apart from financial limitations, the most common reasons for discontinuation were primary (23.5%) and secondary (13.7%) lack of efficacy. CONCLUSION: In non-reimbursed mild-to-moderate psoriasis patients, SGA and PGA remained high for adalimumab. Effectiveness and remission duration were key factors affecting patients' willingness to pay for prolonged adalimumab treatment. PMID- 21812836 TI - Impact of filaggrin mutations on Raman spectra and biophysical properties of the stratum corneum in mild to moderate atopic dermatitis. AB - BACKGROUND: Atopic dermatitis (AD) is associated with null mutations in the filaggrin (FLG) gene. OBJECTIVE: To assess the impact of FLG null mutations on biophysical properties and the molecular composition of the stratum corneum (SC) in healthy individuals and AD patients. METHODS: A total of 196 French adults, including 97 with a history of mild to moderate AD, were genotyped for the three major European FLG mutations. Components of the natural moisturizing factor (NMF), lipids and water content in the SC were determined using Raman spectroscopy. In addition, trans-epidermal water loss, capacitance and pH of the SC were measured. RESULTS: Stratum corneum concentrations of total NMF, water, ornithine and urocanic acid (UCA) were significantly lower in AD patients than in healthy controls. Null mutations of FLG were detected in 4% of controls and 10% of AD patients. FLG mutations were associated with increased SC levels of lactate, reduced concentrations of most other NMF components and higher disease severity in AD patients. In AD patients without FLG mutations, the content of NMF constituents decreased with increasing disease severity. The concomittant presence of low concentrations of histidine, alanine and either glycine or pyrrolidone-5-carboxylic acid (PCA) in the SC was associated with FLG mutations with 92% specificity. CONCLUSIONS: Our findings suggest a low prevalence of FLG mutations in mild AD and support an important role for filaggrin in determining the physicochemical parameters of the SC. The combined measurement of several filaggrin breakdown products in the SC may be useful to specifically predict the presence of FLG mutations. PMID- 21812837 TI - Porokeratosis in patients with polycythemia rubra vera: a new side effect of hydroxyurea? PMID- 21812838 TI - Mild to moderate hidradenitis suppurativa treated with local excision and primary closure. AB - BACKGROUND: Hidradenitis suppurativa (HS) is a chronic skin disease with a great impact on quality of life. Treatment with antibiotics or anti-inflammatory drugs, such as prednisone or TNF-alpha-inhibitors usually achieves only temporary improvement. Surgical intervention is considered as the only curative treatment for recurrent lesions. OBJECTIVE: To determine the efficacy and patient satisfaction of local excision followed by primary closure. METHODS: Between 2005 and 2010, 92 local excisions with primary closure were performed in 57 patients with mild to moderate HS. All patients were treated on an outpatient basis, under local anaesthesia. Local excision was defined as complete excision of the affected tissue, beyond the borders of activity, leaving clear margins. The medical records were reviewed retrospectively in 2010. The final outcome of the procedure, cosmetic appearance and patient satisfaction was measured using a questionnaire. RESULTS: Successful treatment, without recurrence, was accomplished in 66% of the cases. The intervention was generally well tolerated: 84% of the patients stated that they would undergo the same surgical procedure again if necessary, and 89% would recommend the procedure to other patients. CONCLUSION: Local excision followed by primary closure is a valuable treatment for patients with mild to moderate HS (Hurly stage I & II), with low morbidity and a high patient satisfaction rate. PMID- 21812839 TI - Fibre analysis and fibre digestibility in pet foods--a comparison of total dietary fibre, neutral and acid detergent fibre and crude fibre. AB - Six dry dog foods and six dry cat foods with different carbohydrate sources were investigated in digestion trials. Food and faecal samples were analysed for CF, TDF and starch. In dogs, also neutral detergent fibre (aNDFom) and acid detergent fibre (ADFom) were analysed. N-free extract (NfE) was calculated for CF, and similarly for all other fibre analyses. Linear regressions were calculated between fibre intake and faecal fibre excretion. True digestibility was calculated from the regression coefficients [true digestibility in % = (1 - regression coefficient)*100], with the intercept of the equation representing excretion of material of non-food origin. Crude fibre analyses gave the lowest values, and TDF the highest, while ADFom and aNDFom were in between. Variation between diets was lowest in CF and highest in TDF. Total dietary fibre, aNDFom and ADFom in food were positively correlated. Crude fibre in food did not correlate with any other method. The NfE analogue for TDF was closest to the starch content. Methods of fibre analyses in faeces did not agree very well with each other. Crude fibre had the lowest apparent digestibility, followed by ADFom, TDF and aNDFom. For all fibre analyses, there was a significant correlation between fibre intake and faecal fibre excretion. True digestibility was close to zero for CF, with a high uniformity in both species. In dogs, true digestibility of aNDFom was 53%, of ADFom 26% and of TDF 37%; in cats, true digestibility of TDF was 31%. Except for CF, the intercept of the regression equations suggest that faecal excretion of some material of non-food origin is analysed as fibre. A combination of TDF and CF analyses might give good information on the content of total (TDF), unfermentable (CF) and partially fermentable fibre (TDF-CF) in pet foods. PMID- 21812840 TI - Endocannabinoid system and proopiomelanocortin gene expression in peripartal bovine liver in response to prepartal plane of nutrition. AB - Endocannabinoids are fatty acid amides (FAE; oleoylethanolamide and anandamide) which have orexigenic, anorexigenic or anti-inflammatory properties. We examined mRNA expression via qPCR of endocannabinoid receptors (CNR1 and CNR2), enzymes that synthesize FAE (HRASLS5 and N-acyl phosphatidylethanolamine phospholipase D), enzymes that degrade FAE [fatty acid amide hydrolase (FAAH), N acylethanolamine acid amidase (NAAA) and monoglyceride lipase (MGLL)], and the hormone precursor proopiomelanocortin (POMC) in liver at -14, 7, 14 and 30 days around parturition from cows fed with a control (CON; NE(L) = 1.34 Mcal/kg) or moderate-energy (OVER; NE(L) = 1.62 Mcal/kg) diet during the dry period. Expression of CNR2 and POMC was greater at 7 days in cows fed with OVER because of a decrease in expression between -14 and 7 days in cows fed with CON. Cows fed with CON had an increase in expression of FAAH, HRASLS5, NAA, MGLL and POMC between 7 and 14 days; for FAAH and HRASLS5, such response led to greater expression at 14 days vs. cows fed with OVER. Cows fed with OVER vs. CON had a approximately twofold increase in expression of MGLL between -14 and 7 days followed by a gradual decrease through 30 days at which point expression was still greater in OVER vs. CON. FAAH, MGLL and HRASLS5 were the most abundant genes measured. Expression of the hepatic endocannabinoid system and POMC was altered by plane of dietary energy prepartum particularly during the first 2-week postpartum. Such responses may play a role in the physiological adaptations to the onset of lactation, including energy balance and feed intake. PMID- 21812841 TI - Focusing homologous recombination: pilin antigenic variation in the pathogenic Neisseria. AB - Some pathogenic microbes utilize homologous recombination to generate antigenic variability in targets of immune surveillance. These specialized systems rely on the cellular recombination machinery to catalyse dedicated, high-frequency reactions that provide extensive diversity in the genes encoding surface antigens. A description of the specific mechanisms that allow unusually high rates of recombination without deleterious effects on the genome in the well characterized pilin antigenic variation systems of Neisseria gonorrhoeae and Neisseria meningitidis is presented. We will also draw parallels to selected bacterial and eukaryotic antigenic variation systems, and suggest the most pressing unanswered questions related to understanding these important processes. PMID- 21812842 TI - The modular structure of haemagglutinin/adhesin regions in gingipains of Porphyromonas gingivalis. AB - High-molecular-weight arginine- and lysine-specific (Kgp) gingipains are essential virulence factors expressed by the oral pathogen Porphyromonas gingivalis. Haemagglutinin/adhesin (HA) regions of these proteases have been implicated in targeting catalytic domains to biological substrates and in other adhesive functions. We now report the crystal structure of the K3 adhesin domain/module of Kgp, which folds into the distinct beta-jelly roll sandwich topology previously observed for K2. A conserved structural feature of K3, previously observed in the Kgp K2 module, is the half-way point anchoring of the surface exposed loops via an arginine residue found in otherwise highly variable sequences. Small-angle X-ray scattering data for the recombinant construct K1K2K3 confirmed a structure comprising a tandem repeat of three homologous modules, K1, K2 and K3 while also indicating an unusual 'y'-shape arrangement of the modules connected by variable linker sequences. Only the K2 and K3 modules and a K1K2 construct were observed to be potently haemolytic. K2, K3 and the K1K2 construct showed preferential recognition of haem-albumin over albumin whereas only low affinity binding was detected for K1 and the K1K2K3 construct. The data indicate replication of some biological functions over the three adhesin domains of Kgp while other functions are restricted. PMID- 21812843 TI - Prognostic model for total mortality in patients with haemodialysis from the Assessments of Survival and Cardiovascular Events (AURORA) study. AB - OBJECTIVES: Risk factors of mortality in patients with haemodialysis (HD) have been identified in several studies, but few prognostic models have been developed with assessments of calibration and discrimination abilities. We used the database of the Assessment of Survival and Cardiovascular Events study to develop a prognostic model of mortality over 3-4 years. METHODS: Five factors (age, albumin, C-reactive protein, history of cardiovascular disease and diabetes) were selected from experience and forced into the regression equation. In a 67% random try-out sample of patients, no further factors amongst 24 candidates added significance (P < 0.01) to mortality outcome as assessed by Cox regression modelling, and individual probabilities of death were estimated in the try-out and test samples. Calibration was explored by calculating the prognostic index with regression coefficients from the try-out sample to patients in the 33% test sample. Discrimination was assessed by receiver operating characteristic (ROC) areas. RESULTS: The strongest prognostic factor in the try-out sample was age, with small differences between the other four factors. Calibration in the test sample was good when the calculated number of deaths was multiplied by a constant of 1.33. The five-factor model discriminated reasonably well between deceased and surviving patients in both the try-out and test samples with an ROC area of about 0.73. CONCLUSIONS: A model consisting of five factors can be used to estimate and stratify the probability of death for individuals The model is most useful for long-term prognosis in an HD population with survival prospects of more than 1 year. PMID- 21812844 TI - Immunoglobulin E-mediated hypersensitivity to amoxicillin: in vivo and in vitro comparative studies between an injectable therapeutic compound and a new commercial compound. AB - BACKGROUND: Skin testing with amoxicillin (AX) is necessary to diagnose immediate hypersensitivity reactions to this beta-lactam. A commercial AX (DIA-AX) has recently become available for skin testing. OBJECTIVE: The aim of this study was to compare DIA-AX with the injectable form (INJ-AX) in patients who have well demonstrated IgE-mediated hypersensitivity to AX. METHODS: Chemical characterization using high-performance liquid chromatography of both DIA-AX and INJ-AX reagents was performed. Patients diagnosed with an immediate allergic reaction to AX and a positive skin test to INJ-AX (N=55) were re-evaluated within 6 months by performing skin testing with INJ-AX and DIA-AX. Basophil activation test (BAT) and Radioallergosorbent test (RAST) inhibition assay using both reagents were performed in a selected group of patients. RESULTS: The chemical analysis indicated that both DIA-AX and INJ-AX contained an AX compound with a purity above 95%. In the re-evaluation, 53 (96.4%) cases maintained skin test positivity to INJ-AX and were also positive to DIA-AX. Comparison of the papule area between the two reagents showed no significant differences between both reagents. BAT was performed in 30 samples and was positive to both compounds in 15 cases; no patient had a positive result to just one reagent. RAST inhibition studies using three individual cases and a pool of positive sera showed that the percentage inhibition detected with DIA-AX and INJ-AX was parallel and almost exactly the same. CONCLUSIONS: This study shows that DIA-AX is equivalent to INJ AX in terms of skin test response, as well as with in vitro immunochemical and biological tests. DIA-AX can therefore be used in the diagnosis of immediate hypersensitivity reactions. PMID- 21812845 TI - A longitudinal study on emotional adjustment of sarcoma patients: the determinant role of demographic, clinical and coping variables. AB - The present study examined change on emotional distress of sarcoma patients from the diagnostic to treatment phases, the distinct trajectories of adjustment and the influence of demographic, clinical and coping variables on anxiety and depression. Thirty-six sarcoma patients completed questionnaires on emotional distress (Hospital Anxiety and Depression Scale) and coping strategies (Brief Cope) at time of diagnosis, and again during treatment. No significant change in emotional distress levels was found from diagnostic to treatment phase, with mean anxiety and depression scores remaining below the clinical range. Over time, 52.8% and 66.7% of patients maintained non-clinical anxious and depressive symptoms respectively, and 25% and 11.1% remained with clinical anxiety and depression. Living with partner, less use of humour and more denial were associated with high emotional distress at time of diagnosis and during treatments, and high levels of distress at baseline were predictive of poorer emotional adjustment during treatments. Although sarcoma patients, in general, seem to exhibit good psychological adjustment, there is a significant minority that requires mental health services in order to help decrease their emotional distress following the diagnosis, and prevent psychological difficulties during treatments. Our findings are an important contribution to understanding the psychological adjustment of patients with a specific and rare type of cancer. PMID- 21812846 TI - Adolescents' struggle against bone cancer: an explorative study on optimistic expectations of the future, resiliency and coping strategies. AB - The present study aims to assess adolescents' expectations of the future after bone cancer treatment and to investigate in greater depth the relationship between expectations of the future, resilience and coping strategies. Thirty-two adolescents with cancer experience (11-20 years old), who had a complete first remission at least 1 month after the end of successful treatment, were requested to respond to the Expectations for Future Scale, the Ego-Resiliency Scale and Coping Strategy Indicators. Forty-eight gender- and age-matched control adolescents were randomly selected from a normative sample (NORMs). Adolescents with cancer experience had more optimistic expectations of the future and were less open to experience compared to NORMs. They had lower global ego-resiliency, higher impulse control and tended to use more avoidance strategies than NORMs. In adolescents with cancer experience, expectations of the future were negatively related to global ego-resiliency and positively related to impulse control and avoidance. Expectations of the future were positively correlated with global ego resiliency and openness to new experience and negatively correlated with impulse control in NORMs. Patients' positive expectations of the future may relate to positive adjustment to cancer events; however, they could also express unrealistic optimism. PMID- 21812847 TI - The effects of interpersonal counselling on health-related quality of life after myocardial infarction. AB - AIM: To evaluate the effects of interpersonal counselling on health-related quality of life after myocardial infarction. BACKGROUND: Depression is a risk factor for poor health-related quality of life after myocardial infarction. Interpersonal counselling seems to reduce depressive symptoms and distress after myocardial infarction. METHODS: Myocardial infarction patients (n=103) were randomised into an intervention group (n=51) with 1-6 (mean 4.6) interpersonal counselling-sessions focusing on managing depressive symptoms and a control group (n=52). Health-related quality of life after myocardial infarction was measured with EuroQol-5D (EQ-5D) in hospital, at six and 18 months after discharge. RESULTS: No differences in the changes of health-related quality of life were found between the groups during follow-up. However, health-related quality of life improved significantly in the intervention group. In the group of patients under 60 years, the effect of interpersonal counselling was significant in the intervention group compared with the control group. CONCLUSIONS: Interpersonal counselling does not seem to improve health-related quality of life better than standard care after myocardial infarction in general, but it does seem to be beneficial with younger myocardial infarction patients. RELEVANCE TO CLINICAL PRACTICE: There is a need to study the effects of interpersonal counselling further with younger myocardial infarction patients and to develop the intervention further, before using it systematically as part of nursing practice. PMID- 21812848 TI - Predictors of preoperative anxiety in surgical inpatients. AB - AIMS AND OBJECTIVES: The aims of the present study were to identify the levels of preoperative anxiety in patients undergoing elective surgery and the relationship between preoperative anxiety and social support. In addition, predictors of preoperative anxiety were studied in surgical inpatients. BACKGROUND: Major life changes are significant factors that cause anxiety; hospitalisation and surgery are among such changes. Social support may decrease the anxiety associated with surgery. DESIGN: This is a descriptive study that included 500 patients in a surgery clinic. METHODS: The data collected included: A Patient Information Form, Multidimensional Scale of Perceived Social Support and the Surgical Anxiety Scale. The results were analysed using the Chi-square test and logistic regression analysis. RESULTS; Five hundred patients participated in this research: 59.6% were female, 54.6% were 65 years of age or older, 80.6% were married, 70.4% were literate and 62% of the patients had moderate level surgery. There was a significant relationship between the sociodemographic patient features, the level of preoperative anxiety (p < 0.05), the presence of social support and the severity of anxiety (p = 0.001). The age and level of anxiety were not significant factors. The mean anxiety score for all patients was 31.91 (SD 6.30) and the mean social support score was 66.38 (SD 13.69). CONCLUSION: The results of this study showed that the preoperative anxiety of patients awaiting surgery was associated with demographic characteristics as well as social support resources. RELEVANCE TO CLINICAL PRACTICE: Anxiety testing is feasible during the preoperative period. Such testing allows for the detection of patients with high anxiety, and for clinicians to take the appropriate steps to ameliorate this problem. Identification of patient anxiety allows for providing a focus on social support in an attempt to reduce the level of anxiety. PMID- 21812849 TI - The effects of a care map for total knee replacement patients. AB - AIMS: The aim of this study was to establish and evaluate the effectiveness of a care map for total knee replacement patients. BACKGROUND: Bureau of National Health Insurance in Taiwan is about to launch a diagnosis-related group. This major reform has seriously affected the running of medical institutions, which are facing unprecedented management pressure. DESIGN: A quasi-experimental control group design was carried out. METHODS: Eighty-three patients were recruited, with 39 experimental group patients received nursing care based on a care map, while 44 patients who were in control group received routine nursing care. An interdisciplinary team designed the care map, which included items required for patient care from outpatient to postdischarge. RESULTS: (1) The mean age of patients was 72.73 (SD 8.42) years. Mean length of stay was 4.92 (SD 0.77) days for the experimental group and 7.09 (SD = 1.09) for the control group. Difference between groups was significant (t = -10.285, p < 0.001). The medical cost for the experimental group was less than that for the control group (t = 6.03, p < 0.001). (2) The self-care efficacy score before discharge for the experimental group was higher than that for the control group (t = 5.90, p < 0.001). (3) Significant improvements were observed in activities of daily living for both groups with the passage of time after discharge (F = 229.034, p < 0.001), and the experimental group was better than the control group (F = 40.895, p < 0.001). The instrumental activities of daily living abilities of both groups were also significant improvements with the passage of time after discharge (F = 46.568, p < 0.001), and the experimental group was better than the control group (F = 32.163, p < 0.001). CONCLUSIONS: A care map for total knee replacement patient can shorten length of stay, save medical cost and improve patient's functional recovery. RELEVANCE TO CLINICAL PRACTICE: Results of this study can be used as a basis for practical implementation of care map in total knee replacement patients. PMID- 21812850 TI - Exploring the psychological health related profile of nursing students in Singapore: a cluster analysis. AB - AIM: To determine whether definable profiles exist in a cohort of nursing student with regard to factors associated with nurses' perceived emotional intelligence, social support and stress level. BACKGROUND: There is a need to have a basic understanding of a nursing student's psychological health-related life quality profile will have a direct effect on their study and contribution to nursing educators to develop an appropriate learning environment for nursing students. DESIGN: A descriptive survey. METHODS: Data were collected in January 2009 in one nursing school in Singapore. A sample of 112 full-time baccalaureate nursing students from year 1-3 completed the stress in nursing students, social support rating scale and Trait meta-mood scale. RESULTS: Cluster analysis revealed two profiles in four main factors: demographic, perceived emotional intelligence, social support and stress level. CONCLUSIONS: Findings might help by providing important information for health care professionals to develop interventions that improve students' psychological health during their university life. RELEVANCE TO CLINICAL PRACTICE: The findings will assist nursing educators or health care professionals by creating psychological health-related life quality profiles that they can use to develop interventions to improve the health of nursing students. PMID- 21812851 TI - Nurses' perceptions of leadership style in hospitals: a grounded theory study. AB - AIM: This paper explores the leadership style of hospital managers. BACKGROUND: Leadership has been widely studied in nursing from the perspective of nurses' psychological strain caused by nursing leadership. There is, however, little contained in the Western and Eastern literatures on the leadership style of hospital managers and certainly no study has explored managers' leadership style in Taiwanese hospitals from the nurses' stance. DESIGN: Grounded theory. METHODS: A sample of 28 nurses from seven teaching hospitals in Taiwan, Republic of China was selected through theoretical sampling. A multi-step analytic procedure based on the grounded theory approach was used to analyse the qualitative data. RESULTS: The Chinese culture was found to affect the leadership style of Taiwanese hospital managers. They had extreme power and led nurses in a hierarchical manner. Nurse managers followed the autocratic leadership style of their hospital managers. The main category found in this study was thus hierarchical leadership. CONCLUSIONS: The Confucian principles of authoritarianism and obedience were found to be part of the Taiwanese hospitals' organisational cultures and strongly impacted on the managers' leadership style. Hospital managers' treatment of doctors and nurses was dependent on their social rankings. Nurses' lowly ranking fed into these enculturated managerial tendencies of using power and obedience thus increasing psychological strain on nurses. RELEVANCE TO CLINICAL PRACTICE: Managers of the hospitals demonstrate power and misuse obedience through their leadership style, resulting in deterioration of nurses' work environment. Nurses' managers are not given enough power by the hospitals in Taiwan. Subsequently, nurses feel themselves the lowest and most powerless subordinates. This study reveals that the Chinese cultural burdens are embedded in the leadership of Taiwanese hospitals. These findings enhance the knowledge of leadership and add to the understanding of managerial attitudes in Chinese hospitals located worldwide. PMID- 21812852 TI - Critical care nurses' knowledge, attitudes and practices of oral care for patients with oral endotracheal intubation: a questionnaire survey. AB - AIM: This study investigated intensive care unit nurses' knowledge, attitudes and practices of oral care for intubated patients together with the associated factors of the same. BACKGROUND: Effective oral care improves patient comfort and prevents oral infection. Although oral care is a common requirement of nursing practice, providing intubated patients with oral care is a challenging task. DESIGN: A descriptive, cross-sectional design. METHODS: This study applied purposive sampling method at 12 adult intensive care units in one medical centre in northern Taiwan. Two hundred and five nurses were recruited. Data were collected by structured questionnaires which consisted of four sections: knowledge, attitudes and practices of oral care for intubated patients and demographic information for the nurses. RESULTS: The average percentages indicating the intensive care unit nurses' oral care knowledge, attitudes and practices were 58.8, 79.4 and 49.8%, respectively. Higher scores on oral care knowledge were associated with nurses performing oral care more frequently. Nurses learning about oral care from reading related studies and materials of their own accord may increase the frequency with which they provide oral care to intubated patients. The nurses' age and the type of intensive care unit they work in were significant factors related to the frequency of performing practices related to oral care. CONCLUSION: Findings show that nurses who have more resources for learning about oral care have greater knowledge about it and provide oral care to intubated patients more frequently. RELEVANCE TO CLINICAL PRACTICE: Encouraging nurses to learn more about oral care using diverse educational resources will enhance their knowledge and improve their practice. Nursing administrators are encouraged to establish policies and procedures for oral care of intubated patients based on the type of patients cared for, in addition to holding in-service training, with a view to enhancing the quality of oral care for critically ill patients. PMID- 21812853 TI - Association of Mc1r variants with ecologically relevant phenotypes in the European ocellated lizard, Lacerta lepida. AB - A comprehensive knowledge on the genetic basis of coloration is crucial to understand how new colour phenotypes arise and how they contribute to the emergence of new species. Variation in melanocortin-1 receptor (Mc1r), a gene that has been reported as a target for repeated evolution in a wide range of vertebrate taxa, was assessed in European ocellated lizards (Lacerta lepida) to search for associations with melanin-based colour phenotypes. Lacerta lepida subspecies' distribution is associated with the three major bio-climatic regions in the Iberian Peninsula. A nonconserved and derived substitution (T162I) was associated with the L. l. nevadensis phenotype (prevalence of brown scales). Another substitution (S172C) was associated with the presence of black scales in both L. l. lepida and L. l. iberica, but no mutations were found to be associated with the higher proportion of black in L. l. iberica. Extensive genotyping of Mc1r along the contact zone between L. l. nevadensis and L. l. lepida revealed low gene flow (only two hybrids detected). The implications of these findings are discussed in the context of previous knowledge about the evolutionary history of ocellated lizards. PMID- 21812854 TI - Correlated response in plasticity to selection for early flowering in Arabidopsis thaliana. AB - Phenotypic plasticity is an important strategy for coping with changing environments. However, environmental change usually results in strong directional selection, and little is known empirically about how this affects plasticity. If genes affecting a trait value also affect its plasticity, selection on the trait should influence plasticity. Synthetic outbred populations of Arabidopsis thaliana were selected for earlier flowering under simulated spring- and winter annual conditions to investigate the correlated response of flowering time plasticity and its effect on family-by-environment variance (Vg*e) within each selected line. We found that selection affected plasticity in an environmentally dependent manner: under simulated spring-annual conditions, selection increased the magnitude of plastic response but decreased Vg*e; selection under simulated winter-annual conditions reduced the magnitude of plastic response but did not alter Vg*e significantly. As selection may constrain future response to environmental change, the environment for crop breeding and ex situ conservation programmes should be carefully chosen. Models of species persistence under environmental change should also consider the interaction between selection and plasticity. PMID- 21812857 TI - Clinical significance of tumor-infiltrating FOXP3+ T cells in patients with ocular adnexal mucosa-associated lymphoid tissue lymphoma. AB - We evaluated the association between tumor-infiltrating FOXP3+ T cells and clinical outcomes in patients with ocular adnexal lymphoma of mucosa-associated lymphoid tissue type (OAML). Pretreatment formalin-fixed paraffin-embedded tissues from 42 patients with OAML were stained with 236A/E7 anti-FOXP3 murine monoclonal antibody as well as CD3, CD4 and CD8 antibodies. The amount of FOXP3+ T cells was numerically quantified using an image analysis program. Front-line treatments were as follows: combination chemotherapy (n = 25); radiotherapy (n = 9); doxycycline (n = 6); and wait and see (n = 2). Complete response (CR) was observed in 20 (50%) of 40 evaluable patients. Median progression-free survival (PFS) was 50 months. A high number of FOXP3+ T cells (n = 21, >= 180/0.58 mm(2)) showed a higher CR rate (33%vs 71%, P = 0.013) and tendency towards prolonged PFS (48 vs 67 months, P = 0.110). In the combination chemotherapy group, a high number of FOXP3+ T cells was significantly associated with a higher CR rate (29%vs 82%, P = 0.008) and prolonged PFS (17 vs 79 months, P = 0.003). A high number of tumor-infiltrating FOXP3+ T cells correlates with a favorable clinical outcome in OAML patients. PMID- 21812858 TI - Roles of CUB domain-containing protein 1 signaling in cancer invasion and metastasis. AB - Tumor metastasis is a complex multistep process by which cells from the primary tumor invade tissues, move through the vasculature, settle at distant sites and eventually grow to form secondary tumors. Altered tyrosine phosphorylation signals in cancer cells contribute to a number of aberrant characteristics involved in tumor invasion and metastasis. CUB domain-containing protein 1 (CDCP1) is a substrate of Src family kinases and has been shown to regulate anoikis resistance, migration and matrix degradation during tumor invasion and metastasis in a tyrosine phosphorylation-dependent manner. Knockdown of CDCP1 blocks tumor metastasis or peritoneal dissemination in vivo, without significantly affecting cell proliferation. Moreover, expression levels of CDCP1 are of prognostic value in several cancers. Here, we summarize the studies on CDCP1, focusing on structure and signal transduction, to gain insight into its role in cancer progression. Understanding the signaling pathways regulated by CDCP1 could help establish novel therapeutic strategies against the progression of cancer. PMID- 21812859 TI - Semaphorin 4D, a lymphocyte semaphorin, enhances tumor cell motility through binding its receptor, plexinB1, in pancreatic cancer. AB - Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor, for which the development of new biomarkers and therapeutic targets has become critical. The main cause of poor prognosis in PDAC patients is the high invasive and metastatic potential of the cancer. In the present study, we report a new signaling pathway that was found to mediate the enhanced tumor cell motility in pancreatic cancer. Semaphorin 4D (Sema4D) is a ligand known to be expressed on different cell types, and has been reported to be involved in the regulation of immune functions, epithelial morphogenesis, and tumor growth and metastasis. In this study, we revealed for the first time that the cancer tissue cells expressing Sema4D in PDAC are tumor-infiltrating lymphocytes. The overexpression of Sema4D and of its receptor, plexinB1, was found to be significantly correlated with clinical factors, such as lymph node metastasis, distant metastasis, and poor prognosis in patients with PDAC. Through in vitro analysis, we demonstrated that Sema4D can potentiate the invasiveness of pancreatic cancer cells and we identified the downstream molecules. The binding of Sema4D to plexinB1 induced small GTPase Ras homolog gene family, member A activation and resulted in the phosphorylation of MAPK and Akt. In addition, in terms of potential therapeutic application, we clearly demonstrated that the enhanced-cell invasiveness induced by Sema4D could be inhibited by knockdown of plexinB1, suggesting that blockade of plexinB1 might diminish the invasive potential of pancreatic cancer cells. Our findings provide new insight into possible prognostic biomarkers and therapeutic targets in PDAC patients. PMID- 21812860 TI - Biomarkers to predict response to sunitinib therapy and prognosis in metastatic renal cell cancer. AB - Sunitinib is an orally-administered, multitargeted tyrosine kinase inhibitor. The main targets are vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, VEGFR-3, platelet-derived growth factor receptor (PDGFR)-alpha, and PDGFR-beta. Among therapeutic targeting agents, it is the best available in the USA for patients with metastatic renal cell cancer (RCC). Well-constructed clinical trials have led to the worldwide approval of various agents for RCC. However, in clinical practice, it remains difficult to determine the best treatment strategy with these agents. Therefore, the identification of biomarkers to predict response and side-effects and to select optimal dosages is urgently needed. Potential mechanisms of action and resistance need to be understood in order to make accurate predictions. This article briefly reviews candidate biomarkers of sunitinib therapy in terms of clinical variables, genetic factors, and circulating proteins and endothelial cells. Although further validation and implementation is necessary, if validated, biomarkers will help measure the therapeutic response in individual patients and establish treatment strategies for metastatic RCC. PMID- 21812861 TI - Further evidence of heterogeneity of gene defects in Italian families with factor XIII deficiency. PMID- 21812862 TI - The economics of inpatient on-demand treatment for haemophilia with high responding inhibitors: a US retrospective data analysis. AB - Inpatient costs comprise >50% of annual healthcare costs for haemophilia patients with inhibitors but no reports exist on inpatient resource use and costs at a US national level. To quantify inpatient resource use and costs for on-demand treatment of bleeds of US haemophilia patients with inhibitors and compare costs and treatment duration between Factor VIII bypassing agents (BAs). Stays with haemophilia A from 2003-2008 were identified from inpatient billing records. Presence of inhibitors was inferred through use of BA; recombinant activated Factor VII and plasma-derived activated prothrombin complex concentrate. Duration and number of infusions of BA, length of stay, use of opioid-containing analgesics and costs were assessed and compared. Among 1322 stays mean BA treatment duration was 4.6 days with 4.9 infusions, 6.1 nights spent in hospital, and 58% administered opioid-containing analgesics. In unadjusted analyses there were significant differences in the above mentioned outcomes by BA use, reflecting underlying differences between the two patient populations. Average inpatient costs were $82,911. In adjusted analyses, African-American race, greater disease severity, hospital region outside the southern US and older age (cost model only) were significant predictors of longer BA treatment duration and higher costs. The economic burden of inpatient on-demand treatment of haemophilia with inhibitors is substantial and is associated with lengthy stays, high costs and inadequate pain relief. Availability of more effective BAs could reduce the need for re-treatment, reducing treatment costs and other medical costs, while improving health related quality of life. PMID- 21812863 TI - Clinical efficacy, safety and pharmacokinetic properties of the plasma-derived factor IX concentrate Haemonine in previously treated patients with severe haemophilia B. AB - Plasma-derived factor IX (FIX) concentrate remains an important choice for replacement therapy in haemophilia B patients. Haemonine is a high purity double virus inactivated human plasma-derived coagulation FIX concentrate (pdFIX). Aim was to evaluate the clinical efficacy, safety and pharmacokinetic properties of Haemonine in three prospective, open-label uncontrolled studies and a compassionate use program in previously treated patients with severe haemophilia B. Long-term efficacy and safety were investigated in 29 patients treated prophylactically and, in addition, treatment on-demand (TOD) in the case of acute haemorrhage. Pharmacokinetic properties were assessed in 14 patients at baseline and after 3 months of regular treatment. Pharmacokinetic parameters were in accordance with published data and remained nearly unchanged over time, notably recovery and half-life. Mean terminal elimination half-life was 27.6 h and 25.0 h, mean incremental recovery (IU dL(-1) /IU kg(-1)) was 1.55 and 1.60, at baseline and 3 months, respectively. Haemonine was shown to be effective in preventing and controlling bleeds. 55.2% (16/29) of patients were free of bleeds under prophylaxis. 38 haemorrhages occurred, 42% (16/38) required treatment and 87.5% (14/16) resolved after a single infusion, 12.5% after 2 infusions. All responses reported on haemorrhages were rated as 'excellent' or 'good'. Moreover, 'excellent' haemostatic efficacy was demonstrated in 12 surgeries with no complications. Few adverse events (AEs) and no thrombogenic complication, nor induction of FIX inhibitory antibodies were observed. Haemonine is effective, safe and well tolerated in long-term prophylaxis, TOD and when applied after minor and major surgeries. PMID- 21812864 TI - Benefits associated with a broad selection of dosage strengths for recombinant factor VIII products. AB - Factor VIII (FVIII) concentrates for haemophilia A patients are dosed according to body weight. This results in a continuous range of prescribed doses, which challenges pharmacies to find dosage strengths closest to the prescribed dose while utilizing the least number of vials. This study was conducted to determine whether a broader selection of FVIII dosage strengths results in improved dispensing accuracy and an increased number of single-vial users. This research retrospectively analyzed a US pharmacy database of prescriptions filled in 2008. Recombinant FVIII (rFVIII) therapies were classified by the range of dosage strengths offered in 2008: Group 1 had three dosage strengths; Group 2 had four dosage strengths; and Group 3 had six dosage strengths. A total of 76,584 dispensed doses of rFVIII for 1,244 patients were included in this analysis. Dispensing accuracy (calculated as both the absolute and relative difference between dispensed and prescribed dose) was significantly better for Group 3 (23.2 IU, 1.2%) than Groups 1 (33.5 IU, 1.6%) and 2 (50.2 IU, 2.4%) (both P < 0.01). In addition, the average number of unique actual rFVIII potencies dispensed per month was highly correlated (-0.977) with dispensing accuracy for each dosage strength group. Among Groups 1, 2 and 3, 23.0%, 44.9% and 73.4% of patients, respectively, had at least one single vial option dispensed (P < 0.0001). A broader selection of rFVIII dosage strengths and more actual rFVIII potencies were associated with improved dispensing accuracy and more single-vial users. This may translate into less waste, cost savings, increased convenience and improved adherence to physician-prescribed regimens. PMID- 21812865 TI - Diagnosis of type 1 vs. 2A and 2M von Willebrand disease. PMID- 21812867 TI - Genetic variations in the dopaminergic system and alcohol use: a system-level analysis. AB - Alcohol use is highly heritable and has been associated with many gene variants, including those related to dopamine (DA). However, single gene association studies have shown inconsistent and small effects. Using a system-level approach, the current study aimed to estimate the overall effect of genetic variations in the DA system on alcohol use among male drinkers. One hundred seventy-six male college students who reported to have ever drunk alcohol were enrolled. Alcohol use was measured using the Alcohol Use Disorders Identification Test. Ninety eight representative polymorphisms in all major DA neurotransmitter genes were genotyped. Using analysis of variance, we identified six single-nucleotide polymorphisms (SNP)s that made statistically significant contributions to alcohol use. Next, main effects and interactions of these SNPs were assessed using multiple regression. The final model accounted for approximately 20% of the variance for alcohol use. Finally, permutation analyses ascertained the probability of obtaining these findings by chance to be low, p ranging from 0.024 to 0.048. These results confirmed that DA-related gene variants made strong contributions to reported alcohol use and suggest that multiple regression can be a promising way to explore the genetic basis for multi-gene-determined human behaviors. PMID- 21812868 TI - Possible involvement of prolonging spinal u-opioid receptor desensitization in the development of antihyperalgesic tolerance to u-opioids under a neuropathic pain-like state. AB - In the present study, we investigated the possible development of tolerance to the antihyperalgesic effect of u-opioid receptor (MOR) agonists under a neuropathic pain-like state. Repeated treatment with fentanyl, but not morphine or oxycodone, produced a rapid development of tolerance to its antihyperalgesic effect in mice with sciatic nerve ligation. Like the behavioral study, G-protein activation induced by fentanyl was significantly reduced in membranes obtained from the spinal cord of nerve-ligated mice with in vivo repeated injection of fentanyl. In beta-endorphin-knockout mice with nerve ligation, developed tolerance to the antihyperalgesic effect of fentanyl was abolished, and reduced G protein activation by fentanyl after nerve ligation with fentanyl was reversed to the normal level. The present findings indicate that released beta-endorphin within the spinal cord may be implicated in the rapid development of tolerance to fentanyl under a neuropathic pain-like state. PMID- 21812869 TI - Chronic cocaine self-administration modulates ERK1/2 and CREB responses to dopamine receptor agonists in striatal slices. AB - Cocaine abuse leads to adaptations in brain reward circuits, where dopaminergic neurotransmission is a fundamental component. We hypothesized that chronic cocaine self-administration could influence dopamine D1 and D2 receptor activation of extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) and cyclic adenosine monophosphate response element-binding protein (CREB) phosphorylation. Male Sprague Dawley rats were exposed to cocaine self administration for 6-11 weeks. Brains from sham controls and cocaine rats were extracted 1 day after the last session, and slices obtained from the striatum and nucleus accumbens (NAc) were incubated in vitro with or without the D1R agonist SKF38393 or the D2R agonist quinpirole. We found that cocaine self-administration led to a reduction in the capacity of D1R to activate ERK1/2 phosphorylation as compared with control rats. Cocaine self-administration also reduced D1R agonist induced CREB phosphorylation in striatal slices, suggesting a downregulation of D1R signaling. D2R-induced ERK1/2 phosphorylation appeared blunted in striatal slices from cocaine rats. In contrast, surprisingly, cocaine self-administration strongly potentiated D2R agonist-induced CREB phosphorylation selectively in the NAc portion of the slices. Altered agonist-induced signaling was independent of total ERK1/2 and CREB expression. Our finding that selected cellular D2R responses to CREB were strengthened by cocaine self-administration could be relevant to understand how dopaminergic receptors participate in cocaine-induced behaviors. PMID- 21812866 TI - Urban legends: recurrent aphthous stomatitis. AB - Recurrent aphthous stomatitis (RAS) is the most common idiopathic intraoral ulcerative disease in the USA. Aphthae typically occur in apparently healthy individuals, although an association with certain systemic diseases has been reported. Despite the unclear etiopathogenesis, new drug trials are continuously conducted in an attempt to reduce pain and dysfunction. We investigated four controversial topics: (1) Is complex aphthosis a mild form of Behcet's disease (BD)? (2) Is periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome a distinct medical entity? (3) Is RAS associated with other systemic diseases [e.g., celiac disease (CD) and B12 deficiency]? (4) Are there any new RAS treatments? Results from extensive literature searches, including a systematic review of RAS trials, suggested the following: (1) Complex aphthosis is not a mild form of BD in North America or Western Europe; (2) Diagnostic criteria for PFAPA have low specificity and the characteristics of the oral ulcers warrant further studies; (3) Oral ulcers may be associated with CD; however, these ulcers may not be RAS; RAS is rarely associated with B12 deficiency; nevertheless, B12 treatment may be beneficial, via mechanisms that warrant further study; (4) Thirty-three controlled trials published in the past 6 years reported some effectiveness, although potential for bias was high. PMID- 21812871 TI - Striatal and extrastriatal dopamine transporter in cannabis and tobacco addiction: a high-resolution PET study. AB - The dopamine (DA) system is known to be involved in the reward and dependence mechanisms of addiction. However, modifications in dopaminergic neurotransmission associated with long-term tobacco and cannabis use have been poorly documented in vivo. In order to assess striatal and extrastriatal dopamine transporter (DAT) availability in tobacco and cannabis addiction, three groups of male age-matched subjects were compared: 11 healthy non-smoker subjects, 14 tobacco-dependent smokers (17.6 +/- 5.3 cigarettes/day for 12.1 +/- 8.5 years) and 13 cannabis and tobacco smokers (CTS) (4.8 +/- 5.3 cannabis joints/day for 8.7 +/- 3.9 years). DAT availability was examined in positron emission tomography (HRRT) with a high resolution research tomograph after injection of [11C]PE2I, a selective DAT radioligand. Region of interest and voxel-by-voxel approaches using a simplified reference tissue model were performed for the between-group comparison of DAT availability. Measurements in the dorsal striatum from both analyses were concordant and showed a mean 20% lower DAT availability in drug users compared with controls. Whole-brain analysis also revealed lower DAT availability in the ventral striatum, the midbrain, the middle cingulate and the thalamus (ranging from -15 to -30%). The DAT availability was slightly lower in all regions in CTS than in subjects who smoke tobacco only, but the difference does not reach a significant level. These results support the existence of a decrease in DAT availability associated with tobacco and cannabis addictions involving all dopaminergic brain circuits. These findings are consistent with the idea of a global decrease in cerebral DA activity in dependent subjects. PMID- 21812870 TI - Brain region-specific gene expression changes after chronic intermittent ethanol exposure and early withdrawal in C57BL/6J mice. AB - Neuroadaptations that participate in the ontogeny of alcohol dependence are likely a result of altered gene expression in various brain regions. The present study investigated brain region-specific changes in the pattern and magnitude of gene expression immediately following chronic intermittent ethanol (CIE) exposure and 8 hours following final ethanol exposure [i.e. early withdrawal (EWD)]. High density oligonucleotide microarrays (Affymetrix 430A 2.0, Affymetrix, Santa Clara, CA, USA) and bioinformatics analysis were used to characterize gene expression and function in the prefrontal cortex (PFC), hippocampus (HPC) and nucleus accumbens (NAc) of C57BL/6J mice (Jackson Laboratories, Bar Harbor, ME, USA). Gene expression levels were determined using gene chip robust multi-array average followed by statistical analysis of microarrays and validated by quantitative real-time reverse transcription polymerase chain reaction and Western blot analysis. Results indicated that immediately following CIE exposure, changes in gene expression were strikingly greater in the PFC (284 genes) compared with the HPC (16 genes) and NAc (32 genes). Bioinformatics analysis revealed that most of the transcriptionally responsive genes in the PFC were involved in Ras/MAPK signaling, notch signaling or ubiquitination. In contrast, during EWD, changes in gene expression were greatest in the HPC (139 genes) compared with the PFC (four genes) and NAc (eight genes). The most transcriptionally responsive genes in the HPC were involved in mRNA processing or actin dynamics. Of the few genes detected in the NAc, the most representatives were involved in circadian rhythms. Overall, these findings indicate that brain region-specific and time-dependent neuroadaptive alterations in gene expression play an integral role in the development of alcohol dependence and withdrawal. PMID- 21812872 TI - Environmental enrichment counters cocaine abstinence-induced stress and brain reactivity to cocaine cues but fails to prevent the incubation effect. AB - Environmental enrichment (EE) during a period of forced abstinence attenuates incentive motivational effects of cocaine-paired stimuli. Here we examined whether EE during forced abstinence from cocaine self-administration would prevent time-dependent increases in cue-elicited cocaine-seeking behavior (i.e. the incubation effect). Rats were trained to self-administer cocaine, which was paired with light/tone cues, for 15 days while living in isolated conditions (IC). Controls received yoked saline infusions. Subsequently, rats were assigned to live in either continued IC or EE for either 1 or 21 days of forced abstinence prior to a test for cocaine-seeking behavior. During testing, responding resulted only in presentation of the light/tone cues. Contrary to our prediction, cocaine seeking behavior increased over time regardless of living condition during abstinence; however, EE attenuated cocaine-seeking behavior relative to IC regardless of length of abstinence. Brains were harvested and trunk blood was collected immediately after the 60-minute test and later assayed. Results indicated that short-term EE elevated hippocampal brain-derived neurotrophic factor and reduced plasma corticosterone compared with IC. Furthermore, 21 days of EE during forced abstinence prevented increases in the cue-elicited amygdala phosphorylated extracellular signal-regulated kinase expression that was observed in IC rats. These findings suggest that EE attenuates incentive motivational effects of cocaine cues through a mechanism other than preventing the incubation effect, perhaps involving reduction of stress and neural activity in response to cocaine-paired cues during acute withdrawal. PMID- 21812873 TI - Regional homogeneity changes in heavy male smokers: a resting-state functional magnetic resonance imaging study. AB - Recent studies have documented declined global cognitive function and abnormal task-related brain activation in chronic cigarette smokers. However, the effects of long-term heavy smoking on task-independent baseline brain activity are still unknown. Here, we used a regional homogeneity (ReHo) method combined with functional magnetic resonance imaging (fMRI) to investigate spontaneous neural activity in the resting state in heavy smokers. Compared with controls, heavy smokers exhibited decreased ReHo in prefrontal regions, as well as increased ReHo in insula and posterior cingulate cortex. Our study may better our understanding of the neurobiological consequences of smoking. PMID- 21812874 TI - Individual differences in discount rate are associated with demand for self administered cocaine, but not sucrose. AB - Substance abusers, including cocaine abusers, discount delayed rewards to a greater extent than do matched controls. In the current experiment, individual differences in discounting of delayed rewards in rats (choice of one immediate over three delayed sucrose pellets) were assessed for associations with demand for either sucrose pellets or an intravenous dose of 0.1 mg/kg/infusion cocaine. Twenty-four male Sprague Dawley rats were split into three groups based on sensitivity to delay to reinforcement. Then, demand for sucrose pellets and cocaine was determined across a range of fixed-ratio values. Delay discounting was then reassessed to determine the stability of this measure over the course of the experiment. Individual differences in impulsive choice were positively associated with elasticity of demand for cocaine, a measure of reinforcer value, indicating that rats having higher discount rates also valued cocaine more. Impulsive choice was not associated with the level of cocaine consumption as price approached 0 or with any parameter associated with demand for sucrose. Individual sensitivity to delay was correlated with the initial assessment when reassessed at the end of the experiment, although impulsive choice increased for this cohort of rats as a whole. These findings suggest that impulsive choice in rats is positively associated with valuation of cocaine, but not sucrose. PMID- 21812876 TI - Characterization of the staphylococcal bacteriophage lysin CHAP(K). AB - AIMS: To develop an efficient purification strategy for the bacteriophage lysin CHAP(K) . To evaluate its antibacterial spectrum(,) enzymatic properties, optimal reaction conditions and lytic activity against live Staphlyococcus aureus. METHODS AND RESULTS: Recombinant CHAP(K) was purified to homogeneity by cation exchange chromatography, with yields of up to 10 mg from 1 l of Escherichia coli culture. The lytic spectrum of CHAP(K) includes all staphylococcal species and also members of the genera Micrcococcus, Streptococcus, Nesterenkonia, Arthrobacter, Leuconostoc and Carnobacterium. The enzyme was active from pH 6 to 11 with an optimum activity at pH 9, from 5 to 40 degrees C, with an optimum activity at 15 degrees C. When cell lysis by CHAP(K) and lysostaphin was compared over a concentration range of 2.5-10 MUg ml-1 using live Staph. aureus for 5 min at 37 degrees C, CHAP(K) gave rise to greater turbidity reduction indicating that it works more rapidly than lysostaphin. CONCLUSIONS: This study describes in detail the purification and characteristics of the novel phage-derived enzyme CHAP(K) demonstrating that it has excellent biochemical properties as an anti staphylococcal agent. SIGNIFICANCE AND IMPACT OF THE STUDY: Currently, there is a need for new antimicrobial agents due to the increasing worldwide prevalence of antibiotic resistance. Our findings demonstrate the potential for development of CHAP(K) as an alternative therapeutic against pathogenic staphylococci including MRSA. PMID- 21812875 TI - Periadolescent amphetamine treatment causes transient cognitive disruptions and long-term changes in hippocampal LTP depending on the endogenous expression of pleiotrophin. AB - Amphetamine treatment during adolescence causes long-term cognitive deficits in rats. Pleiotrophin (PTN) is a cytokine with important roles in the modulation of synaptic plasticity, whose levels of expression are significantly regulated by amphetamine administration. To test the possibility that the long-term consequences of periadolescent amphetamine treatment cross species and, furthermore, to test the hypothesis that PTN could be one of the factors involved in the adult cognitive deficits observed after periadolescent amphetamine administrations, we comparatively studied the long-term consequences of periadolescent amphetamine treatment (3 mg/kg intraperitoneal, daily during 10 days) in normal wild-type (PTN+/+) and in PTN genetically deficient (PTN-/-) mice. Within the first week after cessation of treatment, significant deficits in the passive avoidance and Y-maze tests were only observed in amphetamine pretreated PTN-/- mice. However, 13 and 26 days after the last administration, we did not find significant differences in Y-maze between amphetamine- and saline pretreated PTN-/- mice. In addition, we did not find any genotype- or treatment related anxiogenic- or depressive-like behaviour in adult mice. Furthermore, we observed a significantly enhanced long-term potentiation (LTP) in CA1 hippocampal slices from saline-pretreated PTN-/- mice compared with saline-pretreated PTN+/+ mice. Interestingly, amphetamine pre-treatment during adolescence significantly enhanced LTP in adult PTN+/+ mice but did not cause any effect in PTN-/- mice, suggesting LTP mechanisms saturation in naive PTN-/- mice. The data demonstrate that periadolescent amphetamine treatment causes transient cognitive deficits and long-term alterations of hippocampal LTP depending on the endogenous expression of PTN. PMID- 21812877 TI - Prediction model for the incidence and prevalence of type 1 diabetes in childhood and adolescence: evidence for a cohort-dependent increase within the next two decades in Germany. AB - OBJECTIVE: To provide data on type 1 diabetes (T1D) epidemiology in childhood over a period of 20 years and to predict prevalence and cohort-age-specific incidence rates (IRs) for the next two decades in Germany. METHODS: The Baden Wuerttemberg Diabetes Incidence Registry (DIARY) includes children and adolescents below 15 years of age with new onset of T1D (period 1987-2006, n = 5108 cases). RESULTS: The mean age- and sex-standardized IR was 15.3/100 000/year (95% CI 14.8-15.7) and the average increase in the IR was 4.4% per year (95% CI 3.9-4.9). Within the next 20 years (2007-2026), the risk for developing diabetes will increase like the square of a linear function with calendar year for all age ranges. There is a strong correlation between the predicted IRs of the cohorts and the observed IRs (n = 300; root mean square error = 0.56; r(2) = 0.71) and a negative correlation between mean age at onset and T1D IR (p = 0.02). On 31 December 2006, the prevalence of T1D was 0.126% (95% CI 0.121-0.132). The predicted prevalence (end of 2026) is estimated to be 0.265% (95% CI 0.25-0.28; predicted cases: n = 2950; 95% CI 2900-3000). CONCLUSIONS: In comparison to observations made in the past, the risk of disease rises even faster than expected: The younger the child, the quicker the increase of the cohort-age specific IR and the higher the risk for T1D during lifetime. PMID- 21812878 TI - Singaporean nurses' provision of guidance to parents on non-pharmacological postoperative pain-relief methods: An educational intervention study. AB - This study examined the impact of an educational intervention (booklet distribution and lectures) on Singaporean nurses' provision of guidance to parents on the use of non-pharmacological methods of pain relief for their child's postoperative pain. Using a quasi-experimental one-group pre- and post test study design, 134 and 112 registered nurses completed the questionnaires pre and post-test, respectively. More than 75% of the nurses "always" guided parents to use breathing techniques, relaxation, positioning, comforting/reassurance, helping with activities of daily living, and creating a comfortable environment in the pretest and touch, presence, and distraction in addition to the aforementioned methods in the post-test. The nurses' provision of guidance to parents on all non-pharmacological methods increased, but statistically significant increases only were found in relation to massage and positive reinforcement. The results suggested that the educational intervention had some impact on nurses' provision of guidance to parents on the use of non pharmacological methods of pain relief for children's postoperative pain. Continuing education in pain management should be provided to nurses in order to equip them with the knowledge to improve their practice. PMID- 21812879 TI - Effectiveness of a self-efficacy program for persons with diabetes: a randomized controlled trial. AB - The aim of this study was to examine the effects of a self-efficacy program for persons with type 2 diabetes in Taiwan. A randomized controlled trial was designed (n = 145), with 72 participants in the intervention group and 73 in the control group. The participants were pretested to establish a baseline and then post-tests were undertaken 3 and 6 months after the baseline data were collected. The participants in the intervention group received the standard diabetes education program and an additional self-efficacy program. The scores for efficacy expectations, outcome expectations, and self-care activities had significantly increased in the intervention group at the 3 and 6 month follow ups, when compared to those of the control group. A smaller proportion of the participants in the intervention group had been hospitalized or had visited an emergency room than in the control group at the 6 month follow-up. This study revealed that a self-efficacy program for diabetes was acceptable and effective in the short term in the self-management of persons with type 2 diabetes. PMID- 21812880 TI - Self-epistemic authority and nurses' reactions to medical information that is retrieved from Internet sites of different credibility. AB - This cross-sectional study investigated nurses' reactions to Internet medical information that was retrieved from sources of different scientific credibility and the association between self-epistemic authority and these reactions. The participants filled in questionnaires on their reactions to Internet medical information and self-epistemic authority. The nurses' reactions to Internet medical information from a highly credible source (Medline) correlated positively with self-epistemic authority. However, no such correlation was found with Internet medical information from a less credible Internet source (Ynet). Compared with the nurses without an academic degree, the nurses with an academic degree had more positive reactions to the information that was retrieved from Medline. The reactions to the medical information that was retrieved from Ynet did not differ by the education of the nurses. This study shows that nurses' reactions to different sources of Internet information vary according to their level of self-epistemic authority and education. As patients' use of Internet medical information is increasing, nurses need to expand their expertise in the various professional and popular medical information sites. Such skills will help to reduce any negative feeling that might arise when they encounter patients who present medical information from the Internet. PMID- 21812881 TI - Development of a community participation program for diabetes mellitus prevention in a primary care unit, Thailand. AB - The purpose of this study was to create and test a prevention model for diabetes mellitus in a primary care unit in Thailand. This study used a three-stage approach: a situational analysis was conducted by a focus group discussion, a model was developed in a brainstorming session with stakeholders, and the model was tested by community participation. Qualitative and quantitative methods were used to collect and analyze the data. The focus group discussion found that co operation between health volunteers and primary care unit personnel in relation to diabetes screening, as well as defining the role of nurse practitioners who provide diabetic treatment, was important. The proactive model that was used for preventing diabetes mellitus was a health promotion program. It was trialed with 160 persons with prediabetes for 3 months. After the intervention, the mean score for exercise activity among the persons with prediabetes was significantly higher, while the mean score of the Body Mass Index, waist circumference, and systolic blood pressure were significantly lower than before the intervention. This meant that community participation provided proactive services to Thai persons with prediabetes. PMID- 21812882 TI - A dispersal-induced paradox: synchrony and stability in stochastic metapopulations. AB - Understanding how dispersal influences the dynamics of spatially distributed populations is a major priority of both basic and applied ecologists. Two well known effects of dispersal are spatial synchrony (positively correlated population dynamics at different points in space) and dispersal-induced stability (the phenomenon whereby populations have simpler or less extinction-prone dynamics when they are linked by dispersal than when they are isolated). Although both these effects of dispersal should occur simultaneously, they have primarily been studied separately. Herein, I summarise evidence from the literature that these effects are expected to interact, and I use a series of models to characterise that interaction. In particular, I explore the observation that although dispersal can promote both synchrony and stability singly, it is widely held that synchrony paradoxically prevents dispersal-induced stability. I show here that in many realistic scenarios, dispersal is expected to promote both synchrony and stability at once despite this apparent destabilising influence of synchrony. This work demonstrates that studying the spatial and temporal impacts of dispersal together will be vital for the conservation and management of the many communities for which human activities are altering natural dispersal rates. PMID- 21812883 TI - Looking back at the doctorate: a qualitative study of Jordanian graduates from PhD programs in the UK. AB - Many countries develop their nursing capacity by sending nurses overseas to gain their doctorates. There is a lack of research on their subsequent experience and career development. Focusing on the Jordanian and UK contexts, this qualitative study explored the doctoral and postdoctoral experience. Interviews were held with 16 PhD nursing graduates in Jordan. The participants had studied in 12 different universities in the UK and now worked as faculty members in seven Jordanian universities. The data were analyzed thematically. The participants reported that the most difficult task (but also the most significant achievement) was the transition to autonomous scholarship. They also described a profound personal transformation as a result of living in another country. However, very few of them could cite examples of how they were using their skills now to influence their current practice within their faculty roles. This suggests a possible under-use of the skills, new perspectives, and enthusiasm that new doctoral graduates bring back home with them. Future research should focus on identifying ways to support and develop doctoral nursing graduates to maximize their potential on their return home. PMID- 21812884 TI - Combining alpha - and beta -diversity models to fill gaps in our knowledge of biodiversity. AB - For many taxonomic groups, sparse information on the spatial distribution of biodiversity limits our capacity to answer a variety of theoretical and applied ecological questions. Modelling community-level attributes (alpha- and beta diversity) over space can help overcome this shortfall in our knowledge, yet individually, predictions of alpha- or beta-diversity have their limitations. In this study, we present a novel approach to combining models of alpha- and beta diversity, with sparse survey data, to predict the community composition for all sites in a region. We applied our new approach to predict land snail community composition across New Zealand. As we demonstrate, these predictions of metacommunity composition have diverse potential applications, including predicting gamma-diversity for any set of sites, identifying target areas for conservation reserves, locating priority areas for future ecological surveys, generating realistic compositional data for metacommunity models and simultaneously predicting the distribution of all species in a taxon consistent with known community diversity patterns. PMID- 21812885 TI - The Staphylococcus aureus CsoR regulates both chromosomal and plasmid-encoded copper resistance mechanisms. AB - Copper is an essential metal which is used as a cofactor in several enzymes and is required for numerous essential biochemical reactions. However, free copper ions can be toxic to cellular systems if the intracellular concentration is not tightly regulated. In this study we show that Staphylococcus aureus copper resistance is not the same in every staphylococcal isolate, but in fact varies considerably between clinical strains. Hyper-copper-resistance was shown to be due to the carriage of an additional plasmid-encoded copper homeostasis mechanism, copBmco. This plasmid can be transferred into the copper-sensitive S. aureus Newman to confer a hyper-copper-resistant phenotype, showing that copper resistance has the potential to spread to other S. aureus strains. This is the first time that plasmid-encoded copper resistance has been reported and shown to be transferable between pathogenic bacteria isolated from humans. A homologue of the Bacillus subtilis and Mycobacterium tuberculosis CsoR regulators was identified in S. aureus. The S. aureus csoR gene is conserved in all sequenced S. aureus genomes and was found to be copper-induced and transcribed along with two downstream genes: a putative copper chaperone (csoZ) and a hypothetical gene. Mutational and complementation studies showed that unlike other homologues, the S. aureus CsoR negatively regulates both chromosomal and plasmid-encoded copper homeostasis mechanisms in response to excess-copper conditions. PMID- 21812886 TI - Relevance of Nitrospira for nitrite oxidation in a marine recirculation aquaculture system and physiological features of a Nitrospira marina-like isolate. AB - In biofilters of recirculation aquaculture systems (RAS), nitrification by lithoautotrophic microorganisms is essential to prevent the cultivated organisms from intoxication with ammonium and nitrite. In moving-bed biofilters nitrifying microorganisms are immobilized together with heterotrophic bacteria in dense biofilms on carrier elements like plastic beads. Analyses of fatty acid profiles of these biofilms from a marine biofilter revealed a high abundance of Nitrospira related lipid markers (8-12% of total fatty acids). Further results of a labeling experiment with (13) C-bicarbonate in mineral salts medium with 3 mM nitrite confirmed that Nitrospira is the major autotrophic nitrite oxidizer in the biofilter system. According to 16S rRNA gene sequence analyses the nitrite oxidizing community in the biofilter consisted of at least two different representatives of Nitrospira, one of which could be successfully isolated. The marine isolate 'Ecomares 2.1' belongs to cluster IVa and showed 98.8% 16S rRNA gene sequence similarity to Nitrospira marina, whereas the enrichment 'M1 marine' is only distantly related (94.0% 16S rRNA gene sequence similarity to N. marina). In laboratory experiments, the isolate exhibited remarkable tolerances against high substrate and product concentrations (30 mM nitrite and 80 mM nitrate) as well as ammonium (50 mM). During the isolation process a strong tendency of this strain to develop biofilms became apparent. Thus, Ecomares 2.1 seems to be well adapted to the attached lifestyle in biofilters and the nitrogenous load prevailing in the effluent waters of RAS. Both members of Nitrospira could be detected by PCR-based methods in environmental samples of marine and brackish RAS biofilters and are therefore considered to be characteristic for these engineered ecosystems. PMID- 21812887 TI - Negative effects on survival and performance of Norway spruce seedlings colonized by dark septate root endophytes are primarily isolate-dependent. AB - Root endophytes are common and genetically highly diverse suggesting important ecological roles. Yet, relative to above-ground endophytes, little is known about them. Dark septate endophytic fungi of the Phialocephala fortinii s.l.-Acephala applanata species complex (PAC) are ubiquitous root colonizers of conifers and Ericaceae, but their ecological function is largely unknown. Responses of Norway spruce seedlings of two seed provenances to inoculations with isolates of four PAC species were studied in vitro. In addition, isolates of Phialocephala subalpina from two populations within and one outside the natural range of Norway spruce were also included to study the effect of the geographic origin of P. subalpina on host response. The interaction of PAC with Norway spruce ranged from neutral to highly virulent and was primarily isolate-dependent. Variation in virulence was much higher within than among species, nonetheless only isolates of P. subalpina were highly virulent. Disease caused by P. subalpina genotypes from the native range of Norway spruce was more severe than that induced by genotypes from outside the natural distribution of Norway spruce. Virulence was not correlated with the phylogenetic relatedness of the isolates but was positively correlated with the extent of fungal colonization as measured by quantitative real-time PCR. PMID- 21812888 TI - The pathogenic Escherichia coli type III secreted protease NleC degrades the host acetyltransferase p300. AB - Enteropathogenic and enterohaemorrhagic Escherichia coli (EPEC and EHEC respectively) are attaching and effacing bacterial pathogens that cause devastating diarrhoeal disease worldwide. These pathogens depend on a type III secretion system, which functions as a molecular syringe to translocate bacterial effector proteins directly into infected host cells. One of these effectors, NleC, was recently described as a zinc metalloprotease that targets NF-kappaB Rel A (p65) and thus contributes to dampening of inflammatory signalling during EPEC and EHEC infection. We have identified the acetyltransferase p300 as an additional target of NleC. Several biochemical techniques were employed to demonstrate specific binding of p300 by NleC. We also show that NleC causes decreased abundance of p300 in cellular nuclei and that the metalloprotease domain of NleC is responsible for this phenotype. Furthermore, we demonstrate that overexpression of p300 can antagonize repression of IL-8 secretion by EPEC and that siRNA knock-down of p300 dampens IL-8 secretion by EPEC DeltanleC infected cells. We have therefore identified a second target of NleC and provided the first example of a bacterial virulence factor targeting the acetyltransferase p300. PMID- 21812889 TI - Comparative long-term efficacy and tolerability of pitavastatin 4 mg and atorvastatin 20-40 mg in patients with type 2 diabetes mellitus and combined (mixed) dyslipidaemia. AB - AIM: To compare the long-term efficacy and safety of pitavastatin with atorvastatin in patients with type 2 diabetes and combined (mixed) dyslipidaemia. METHODS: Randomised, double-blind, active-controlled, multinational non inferiority study. Patients were randomised 2 : 1 to pitavastatin 4 mg (n = 279) or atorvastatin 20 mg (n = 139) daily for 12 weeks. Patients completing the core study could continue on pitavastatin 4 mg (n = 141) or atorvastatin 20 mg (n = 64) [40 mg (n = 7) if lipid targets not reached by week 8] for a further 44 weeks (extension study). The primary efficacy variable was the change in low-density lipoprotein cholesterol (LDL-C). RESULTS: Reductions in LDL-C were not significantly different at week 12 between the pitavastatin (-41%) and atorvastatin (-43%) groups. Attainment of National Cholesterol Education Program and European Atherosclerosis Society targets for LDL-C and non-high-density lipoprotein cholesterol (non-HDL-C) was similarly high for both treatment groups. Changes in secondary lipid variables (e.g. HDL-C, apolipoprotein B and triglycerides) were similar between treatments. Post hoc analysis showed that adjusted mean treatment differences for pitavastatin vs. atorvastatin were within the non-inferiority margin at weeks 16 (+0.11%; 95% confidence interval (CI), 5.23 to 5.44) and 44 (-0.02%; 95% CI, -5.46 to 5.41) of the extension study. Both treatments were well tolerated; atorvastatin increased fasting blood glucose from baseline (+7.2%; p < 0.05), whereas pitavastatin had no significant effect (+2.1%). CONCLUSIONS: Reductions in LDL-C and changes in other lipids were not significantly different in patients treated with pitavastatin 4 mg or atorvastatin 20 or 40 mg. Pitavastatin may, however, have a more favourable effect on the glycaemic status. PMID- 21812890 TI - Influence of preprandial vs. postprandial insulin glulisine on weight and glycaemic control in patients initiating basal-bolus regimen for type 2 diabetes: a multicenter, randomized, parallel, open-label study (NCT00135096). AB - AIM: Insulin therapy is commonly associated with weight gain. The timing of prandial insulin administration may enhance its efficacy/safety and maintain effective weight control. This study examined the effect of postprandial vs. preprandial insulin glulisine on weight gain and glycaemic control in type 2 diabetes patients taking basal insulin. METHODS: This was a multicenter, randomized, open-label trial conducted in 45 centres in the USA. A total of 716 patients with type 2 diabetes and glycated haemoglobin A(1c) (HbA(1c) ) >= 7.5% and <=10.0% were screened; 345 were randomized and 322 comprised the intent-to treat group (premeal, 163; postmeal, 159). Insulin glargine once daily, +/ metformin and subcutaneous injections of premeal or postmeal insulin glulisine were given for 52 weeks. Main outcome measures included changes in HbA(1c) , fasting plasma glucose and weight from study baseline to endpoint (week 52). RESULTS: At study end, insulin glulisine achieved similar glycaemic control whether it was administered before or after meals (HbA(1c) : 7.04% premeal vs. 7.16% postmeal, p = NS). Overall hypoglycaemia incidence and severe hypoglycaemia rates were not significantly different between premeal and postmeal groups; however, symptomatic and nocturnal hypoglycaemia rates were higher in the postprandial group. Mean body weight was lower in the postmeal group, with the difference between postmeal and premeal weight change from baseline to week 52 of -0.87 kg (p = 0.243). CONCLUSION: Postprandial glulisine administration provided similar glycaemic control and was non-inferior to preprandial administration on weight gain, without additional risk of severe hypoglycaemia, showing dosing flexibility and the feasibility of such approach when clinically indicated. PMID- 21812891 TI - Effects of a long-acting GLP-1 mimetic (PF-04603629) on pulse rate and diastolic blood pressure in patients with type 2 diabetes mellitus. AB - PF-04603629, an exendin-transferrin fusion protein, is a long-acting glucagon like peptide-1 (GLP-1) mimetic. This randomized, double-blind study characterized the safety and pharmacodynamics of a single dose of PF-04603629 (n = 57; 1-70 mg) or placebo (n = 14) in subjects with type 2 diabetes mellitus (T2DM). There were dose-dependent decreases from baseline in day 6 glucose area under the curve following a mixed meal test (-27 +/- 12% with 70 mg). Most treatment-related adverse events were gastrointestinal, with nausea and vomiting most frequent at 70 mg. Pulse rate (PR) and diastolic blood pressure (DBP) increased dose dependently within the normal range. At 24 h postdose mean PR increased 23 +/- 9 bpm and mean DBP increased 10 +/- 5 mmHg with 70 mg. In conclusion, PF-04603629 exhibited efficacy and tolerability consistent with its mechanism of action; however, PR and DBP increased. Similar effects have been reported occasionally with other GLP-1 mimetics. These data underscore the importance of careful assessments of haemodynamic effects in GLP-1 analogues. PMID- 21812892 TI - Cancer mortality reduction and metformin: a retrospective cohort study in type 2 diabetic patients. AB - AIMS: Few studies suggest that metformin decreases cancer mortality in type-2 diabetic patients (T2DP). We explored the association between the type and duration of antidiabetic therapies and cancer and other-than-cancer mortality in a T2DP cohort, taking into account the competing risks between different causes of death and multiple potential confounding effects. The mortality rates were compared with the general population from the same area. METHODS: In 1995, all T2DP (n = 3685) at our diabetes clinic in Turin (~12% of all T2DP in the city), without cancer at baseline, were identified. Vital status was assessed after a mean 4.5-year follow-up. RESULTS: Metformin users had greater adiposity, while insulin users had more co-morbidities. All-cause- and cancer-related deaths occurred in: 9.2 and 1.6% of metformin users, 13.1 and 3.0% of sulfonylureas users and 26.8 and 4.8% of insulin users, respectively. In a Cox regression model for competing risks, adjusted for propensity score, metformin users showed a lower cancer mortality risk [hazard ratio (HR) = 0.56; 95% confidence interval (CI) 0.34-0.94], while insulin was positively associated with other-than-cancer mortality (HR = 1.56; 95%CI 1.22-1.99). Each 5-year metformin exposure was associated with a reduction in cancer death by 0.73, whereas every 5-year insulin exposure was associated with 1.25-fold increase in other-than-cancer death. Standardized mortality ratios for cancer and other-than-cancer mortality in metformin users were 43.6 (95%CI 25.8-69.0) and 99.1 (95%CI 79.3-122.5), respectively, in comparison with the general population. CONCLUSIONS: Metformin users showed a lower risk of cancer-related mortality than not users or patients on diet only; this may represent another reason to choose metformin as a first line therapy in T2DP. PMID- 21812893 TI - Discordant effects on central obesity, hepatic insulin resistance, and alanine aminotransferase of low-dose metformin and thiazolidinedione combination therapy in patients with impaired glucose tolerance. AB - Alanine aminotransferase (ALT) predicts incident type 2 diabetes (T2DM), possibly reflecting early fatty liver and hepatic insulin resistance. Thiazolidinediones and metformin can improve fatty liver and hepatic insulin resistance, respectively. In the Canadian Normoglycemia Outcome Evaluation trial, rosiglitazone/metformin (Rosi/Met, 4/1000 mg) reduced incident T2DM by 66% in subjects with impaired glucose tolerance. For insight on the hepatic effects of this therapy in relation to T2DM, we evaluated the temporal changes in waist, hepatic insulin sensitivity (1/Homeostasis Model Assessment of Insulin Resistance) and ALT in the Rosi/Met (n = 103) and placebo (n = 104) arms over median of 3.9 years. Waist did not differ between the arms. Hepatic insulin sensitivity improved in the Rosi/Met arm in year 1, but deteriorated thereafter as in the placebo arm. In contrast, Rosi/Met lowered ALT in year 1 and maintained this effect throughout the trial. Thus, low-dose Rosi/Met had no effect on central obesity, a transient effect on hepatic insulin sensitivity, and a sustained effect on ALT. PMID- 21812894 TI - The therapeutic potential of manipulating gut microbiota in obesity and type 2 diabetes mellitus. AB - Obesity and type 2 diabetes mellitus (T2DM) are attributed to a combination of genetic susceptibility and lifestyle factors. Their increasing prevalence necessitates further studies on modifiable causative factors and novel treatment options. The gut microbiota has emerged as an important contributor to the obesity--and T2DM--epidemic proposed to act by increasing energy harvest from the diet. Although obesity is associated with substantial changes in the composition and metabolic function of the gut microbiota, the pathophysiological processes remain only partly understood. In this review we will describe the development of the adult human microbiome and discuss how the composition of the gut microbiota changes in response to modulating factors. The influence of short-chain fatty acids, bile acids, prebiotics, probiotics, antibiotics and microbial transplantation is discussed from studies using animal and human models. Ultimately, we aim to translate these findings into therapeutic pathways for obesity and T2DM in humans. PMID- 21812895 TI - Using albumin to improve the therapeutic properties of diabetes treatments. AB - Achieving tight glycaemic control remains an unmet need for many patients with type 2 diabetes, despite improved treatments. To meet glycaemic targets, attempts have been made to improve existing drugs and to develop new classes of drugs. Recent advances include insulin analogues that more closely mimic physiologic insulin levels, and incretin-based therapies, which capitalize on the glucoregulatory properties of native glucagon-like peptide-1 (GLP-1). Although promising, these agents are associated with limitations, including hypoglycaemia with insulin, gastrointestinal adverse events with GLP-1 receptor agonists and frequent dosing with both classes. Albumin is an abundant natural drug carrier that has been used to improve the half-life, tolerability and efficacy of a number of bioactive agents. Here, we review the physiologic roles of albumin and how albumin technologies are being used to prolong duration of action of therapies for diabetes, including insulin and incretin-based therapies. PMID- 21812896 TI - Long-term quality of life in pouch patients compared with stoma patients following rectal cancer surgery. AB - AIM: Low and ultralow anterior resection for rectal cancer with colorectal or coloanal anastomosis does not compromise oncological results compared with abdominoperineal excision. Although avoidance of a permanent colostomy is regarded as beneficial for a patient's quality of life (QoL), patients undergoing sphincter-sparing surgery may develop a number of functional problems. A colonic pouch significantly improves functional outcome after rectal resection and low anastomosis and may positively influence QoL. The aim of this study was to compare QoL in long-term survivors who underwent ultralow anterior resection with total mesorectal excision and colonic J-pouch anastomosis (CPA) with patients treated with abdominoperineal excision (APE) and end colostomy for rectal cancer. METHOD: The medical records from our institution's prospectively maintained rectal cancer database of 151 patients who underwent surgery for ultralow rectal cancer from 2001 to 2007 were analysed. QoL in 59 eligible patients was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 core and Colorectal Cancer 29. Results were compared for patients with CPA and APE. RESULTS: The median follow-up in the 59 patients was 74 (37-119) months. QoL was good in all patients, but it was better in CPA than in APE patients. Global health status (P = 0.009), physical functioning (P = 0.0002), role functioning (P = 0.03), cognitive functioning (P = 0.046), social functioning (P = 0.002), body image (P = 0.053), embarrassment (P = 0.002) and urinary frequency (P = 0.003) were significantly improved for patients with CPA. CONCLUSION: QoL after rectal resection and CPA was better than after APE in several respects. However, QoL should not be regarded as an isolated concept but rather as one of several possible clinical outcomes of interest. PMID- 21812897 TI - Transcutaneous implant evacuation system: a new approach to continent stoma construction. AB - AIM: Several attempts have been made to construct a mechanical continent stoma without success. A system based on a titanium implant has been developed in an animal model. Following evaluation of this device in animals, the transcutaneous implant evacuation system (TIES) has now been tested in humans. METHOD: The implant consists of a titanium cylinder including a mesh and a plastic cap. This design allows the intestine and subcutaneous tissue to grow into the device. Four patients with inflammatory bowel disease underwent surgery. The indications for surgery were malfunctioning pouches or skin problems around the stoma. Following abdominal surgery, implantation of the device was made behind the external fascia with diversion of the ileum through the device to create a permanent stoma. RESULTS: Primary surgery was uncomplicated. Skin tissue growth into the implant was delayed in one case and one patient had impaired healing between intestine and the device. In these cases minor surgical correction was necessary. The tested cap design in the current device was inconvenient and needs to be further developed. No local infections occurred. CONCLUSION: This first clinical study of the TIES device has shown few device-related complications and no significant safety concerns. In our experience bridging of connective tissue between the intestine and skin is crucial for healing. Further development of the lid, the implant and the implantation method within clinical trials is necessary before the device can be introduced in general practice. PMID- 21812898 TI - Systematic review of small bowel diaphragm disease requiring surgery. AB - AIM: To perform a systematic review of all cases of small bowel diaphragm disease requiring surgery. Small bowel diaphragm disease is a rare complication of small bowel enteropathy secondary to the use of non-steroidal anti-inflammatory drugs (NSAIDs). The objective was to determine the presenting symptoms, duration of NSAID use, mode of diagnosis and type of surgery associated with cases of small bowel diaphragm disease requiring surgery. METHOD: A comprehensive search of the world literature between January 1980 and December 2010 was undertaken. The search terms 'diaphragm disease' and 'mucosal diaphragm disease' in combination with the terms 'surgery', 'intestine' or 'small bowel' were used. All cases of small bowel diaphragm disease requiring surgery in adult patients within the the last 30 years were included. Data including age, gender, mode of presentation, NSAID use, mode of diagnosis, form of surgery, affected area of small bowel and mortality were recorded and analysed. RESULTS: There were 55 cases of small bowel diaphragm disease requiring surgery (31F:18M) with a median age of 69 years. NSAID use occurred in 44 cases and the mean duration of NSAID use was 7 years. The most common presentation was with anaemia in combination with obstructive symptoms. The diagnosis was established by a laparotomy in 51% of cases followed by capsule endoscopy in 25% of cases. Operations performed included small bowel resection (56), combined resection and strictureplasty (three), strictureplasty (one) and hemicolectomy (two). There was only one death. CONCLUSION: Small bowel diaphragm disease presenting as a surgical emergency is likely to become more common due to the increased use of NSAIDs. A history of NSAID use in patients with iron deficiency anaemia or obstructive symptoms should lead to a high index of suspicion for this condition and should be preoperatively investigated. PMID- 21812899 TI - The consequences of good clinical practice for investigator-initiated research. PMID- 21812900 TI - Letter from the ESCP Executive. PMID- 21812901 TI - The impact of hypertriglyceridemia on prostate cancer development in patients aged >=60 years. AB - OBJECTIVE: * To investigate the relationship between serum triglyceride (TG) levels and the incidence and characteristics of prostate cancer detected on biopsy. PATIENTS AND METHODS: * We evaluated data from consecutive patients who underwent prostatic biopsy. Data analysed included age, total serum prostate specific antigen (PSA) level, prostatic volume, body mass index (BMI), TG levels, and cholesterol-lowering medications. RESULTS: * We analysed data from 905 patients, including 528 (58.3%) with positive biopsy findings. * Using 150 mg/dL as the threshold point of TG levels, multivariate analysis yielded an adjusted odds ratio (OR) reflecting the association of higher TG levels with prostate cancer diagnosis of 1.66 (95% confidence interval (CI) 1.21-2.29, P = 0.002). * Pearson correlation coefficient analysis including age, PSA level, prostatic volume, BMI and TG, showed TG level significantly correlated with BMI (r = 0.185, P < 0.001). * In the analysis by age intervals (<=59, 60-69, and >=70 years), the association between high TG levels and positive biopsy findings was enhanced in the age groups 60-69 and >=70 years (OR 2.10, 95% CI 1.31-3.37, P = 0.002 and OR 1.91, 95% CI 1.03-3.53, P = 0.039, respectively), but not in the group aged <=59 years. * In patients aged >=60 years, high TG levels were statistically significantly associated with a Gleason score of >=8. CONCLUSIONS: * High TG levels correlated well with a higher incidence of prostate cancer, especially in patients aged >=60 years. * High TG levels were also associated with a Gleason score of >=8 in this age group. * Our results suggest that elderly patients with high TG levels may be more vulnerable to the development of prostate cancer with an aggressive biology. PMID- 21812902 TI - Factors influencing post-recurrence survival in bladder cancer following radical cystectomy. AB - OBJECTIVE: To identify prognostic indicators that influence post-recurrence survival following radical cystectomy for bladder cancer. PATIENTS AND METHODS: In all, 2029 patients with bladder cancer underwent radical cystectomy with intent to cure between 1971 and 2005 at our institution. Of these, 447 patients (22%) developed non-urinary tract recurrence and were chosen for further analysis. Clinicopathological characteristics were analysed by univariate and multivariate analysis to identify factors prognostic for post-recurrence survival. RESULTS: Median time to recurrence was 13.21 months and median post recurrence overall survival was 5.59 months. Pathological stage (P < 0.001), intravesical therapy (P= 0.035), tumour upstaging (P < 0.001), lymph node density (P < 0.001) and recurrence site (P= 0.017) were associated with time to recurrence. Age (P= 0.042), type of urinary diversion (P < 0.014), surgical margin status (P= 0.049), pathological stage (P < 0.001), lymph node density (P < 0.001), time to recurrence (P < 0.001), recurrence site (P < 0.001) and post recurrence chemotherapy administration (P < 0.001) were univariately prognostic for post-recurrence overall survival. Multivariate analysis confirmed the associations of pathological stage, type of urinary diversion, lymph node density, time to recurrence after cystectomy, site of recurrence and post recurrence chemotherapy administration with outcome following bladder cancer recurrence. Median post-recurrence survival with either local or distant recurrence was 7.95 months and 5.95 months, respectively, whereas patients with both local and distant recurrences had median post-recurrence survival of 3.98 months. CONCLUSIONS: Bladder cancer recurrence forebodes poor prognosis, with 6 months' median survival following recurrence. Advanced pathological stage, positive surgical margins, high lymph node density and early recurrence portends poorer outcome. Although patients with local recurrence have a slightly better prognosis, those with disease recurrence at local and distant sites perform very poorly; nearly 97% of all patients with recurrence eventually succumb to the disease. Chemotherapy administration following recurrence may improve survival, although further studies are needed to exclude selection bias. PMID- 21812903 TI - A systematic review on changed biomechanics of lower extremities in obese individuals: a possible role in development of osteoarthritis. AB - Obesity has been identified as a risk factor for osteoarthritis. For the weight bearing joints, the combination of increased load and changed joint biomechanics could be regarded as underlying principle for this relation. This systematic review of the literature focused on the differences between obese and normal weight subjects in biomechanics of the hip, knee and ankle joint during every day movements to summarize differences in joint load due to both higher body weight and differences in movement patterns. A systematic search, up to November 2010, was performed in the Pubmed and Embase databases. This review showed that obese individuals adjust their movement strategy of every day movements. At self selected speed, obese individuals walked slower, with shorter and wider steps, had longer stance duration and had a greater toe-out angle compared with normal weight individuals. Obese sit-to-stand movement was characterized by less hip flexion and greater foot displacement. Obese individuals showed altered biomechanics during every day movements. These altered biomechanics could be related to the initiation of osteoarthritis by a change in the load-bearing regions of the articular cartilage in the weight-bearing joints. PMID- 21812904 TI - Comparison of different loading dose of celecoxib on postoperative anti inflammation and analgesia in patients undergoing endoscopic nasal surgery-200 mg is equivalent to 400 mg. AB - OBJECTIVE: To demonstrate the efficacy and noninferiority of loading dose of celecoxib 200 mg compared with 400 mg in pain management after endoscopic nasal surgery. DESIGN: A prospective randomized controlled study. SETTING: A university hospital. PATIENTS: Consecutive 120 patients undergoing endoscopic nasal surgery under general anesthesia were randomly assigned to three groups of 40 patients each, celecoxib 400 mg, celecoxib 200 mg, or a control group with no celecoxib. INTERVENTIONS: Patients received different doses of celecoxib as described 1 hour before anesthesia. Two celecoxib groups received celecoxib 200 mg every 12 hours until the fifth day after surgery. OUTCOME MEASURES: Noninferiority could be claimed if the lower limit of the confidence interval (CI) for pain score difference was greater than -0.6. At 0, 6, and 48 hours after surgery, prostaglandin E2 (PGE2) and thromboxane A2 (TXA2) to prostaglandin I2 (PGI2) ratios were measured from incision drainage and in plasma. RESULTS: Estimated difference between two loading doses for pain scores over 5 days was 0.275 (95%CI -0.255 to 0.805, P > 0.05), indicating the noninferiority of celecoxib 200-400 mg. Local PGE2 at 6 hours and 48 hours positively correlated with pain scores, with correlation coefficients 0.371 (P = 0.005) and 0.288 (P = 0.033). Systemic TXA2 to PGI2 ratios did not differ among groups. CONCLUSIONS: An initial dose of celecoxib 200 mg was equivalent to celecoxib 400 mg with regard to the margin previously specified at -0.6 in reducing moderate postoperative pain in endoscopic nasal surgery both in analgesic efficacy and anti-inflammatory property. One hundred and twenty patients were included in this prospective randomized controlled study. Patients treated with celecoxib had lower pain scores than controls, pain scores correlating with local PGE2 level. An initial dose of celecoxib 200 mg was equivalent to 400 mg in reducing moderate pain after endoscopic nasal surgery. PMID- 21812905 TI - Genetic variations in tumor necrosis factor alpha, interleukin-10 genes, and migraine susceptibility. AB - OBJECTIVES: Migraine is a very common headache disorder and pathogenesis of the disease is still largely unknown. Cytokine genes have been implicated in migraine susceptibility. The present study was designed to explore the associations of polymorphisms in the tumor necrosis factor alpha (TNF-alpha), interleukin-10 (IL 10) gene, and IL-10 haplotypes in Turkish migraine patients. METHODS: TNF-alpha 308G/A, IL-10 -1082G/A, -819C/T, and -592C/A polymorphisms in 203 migraine patients and 202 healthy subjects were analyzed by using amplification refractory mutation system-polymerase chain reaction. RESULTS: The -308G/A genotypic and 308A allelic frequency of TNF-alpha polymorphism was higher in migraine patients than healthy controls, and significant association was found between migraine and TNF-alpha-308G/A polymorphism (Bonferroni correction [Pc]: <0.0001, odds ratio: 2.16, 95% confidence interval: 1.44-3.28). No statistically significant association was found between IL-10 -1082G/A, -819C/T, and -592C/A polymorphisms and haplotypes containing these alleles and migraine. CONCLUSIONS: This study reflect that TNF-alpha-308G/A polymorphism may be one of the many genetic factors for migraine susceptibility in the Turkish population. PMID- 21812906 TI - Peripheral nerve field stimulation for chronic pain: 100 cases and review of the literature. AB - OBJECTIVE: To evaluate the clinical outcomes of 100 consecutive patients receiving peripheral nerve field stimulation (PNFS) for the treatment of chronic intractable pain. DESIGN: Prospective, observational study. SETTING: A private interventional pain specialty referral practice. PATIENTS: One hundred consecutive private practice patients receiving PNFS for the treatment of chronic craniofacial, thorax, lumbosacral, abdominal, pelvic, and groin pain conditions. OUTCOME MEASURES: Pain (11-point numerical rating scale), complications, changes to analgesic use and employment status, disability (Oswestry or Neck Disability Indexes), depression (Zung Depression Index), and patient satisfaction. RESULTS: We demonstrate an average pain reduction of 4.2 +/- 2.5 pain scale points on an 11-point scale following PNFS (preimplant pain score of 7.4 +/- 1.7 to a follow up average of 3.2 +/- 2.3 pain scale points) (P<=0.00). At a follow-up period of 8.1 +/- 4.7 months (range 1-23 months), an overall 72% of patients reduced their analgesic use following PNFS. Patients receiving a lumbosacral PNFS for chronic low back pain reported a significant reduction in disability following treatment, as determined by the Oswestry Disability Index. Of the 100 cases, no long-term complications were reported. CONCLUSIONS: This prospective 100 consecutive PNFS patient outcome study demonstrates that PNFS can be a safe and effective treatment option for, otherwise, intractable chronic pain conditions. PNFS has the potential to fundamentally change the way we think about pain management. PMID- 21812907 TI - Pulsed radiofrequency treatment adjacent to the lumbar dorsal root ganglion for the management of lumbosacral radicular syndrome: a clinical audit. AB - INTRODUCTION: Lumbosacral radicular syndrome (LRS) is probably the most frequent neuropathic pain syndrome. Three months to 1 year after onset, 30% of the patients still experience ongoing pain. The management of those patients is complex, and treatment success rates are rather low. The beneficial effect of pulsed radiofrequency (PRF) therapy has been described for the treatment of LRS in case reports and in retrospective and prospective studies. Up until now, no neurological complications have been reported after PRF treatment. The current clinical audit has been performed to assess the amount of pain relief after a single PRF treatment. METHODS: Sixty consecutive patients who received a PRF treatment adjacent to the lumbar dorsal root ganglion for the management of LRS in the period 2007-2009 were included. The main study objective was to measure the reduction of pain after the pulsed radiofrequency treatment by using the global perceived effect. The primary end point was defined as at least 50% pain relief for a period of 2 months or longer. RESULTS: The primary end point was achieved in 29.5% of all the PRF interventions. After 6 months, 50% pain relief was still present in 22.9% of the cases and after 12 months in 13.1% of the cases. The need for pain medication was significantly lower after pulsed radiofrequency treatment in the success group compared with the nonsuccess group. CONCLUSIONS: PRF treatment can be considered for the management of LRS patients. These results need to be confirmed in a randomized clinical trial. PMID- 21812908 TI - Safety and efficacy of vagus nerve stimulation in fibromyalgia: a phase I/II proof of concept trial. AB - OBJECTIVE: We performed an open-label Phase I/II trial to evaluate the safety and tolerability of vagus nerve stimulation (VNS) in patients with treatment resistant fibromyalgia (FM) as well as to determine preliminary measures of efficacy in these patients. METHODS: Of 14 patients implanted with the VNS stimulator, 12 patients completed the initial 3-month study of VNS; 11 patients returned for follow-up visits 5, 8, and 11 months after start of stimulation. Therapeutic efficacy was assessed with a composite measure requiring improvement in pain, overall wellness, and physical function. Loss of both pain and tenderness criteria for the diagnosis of FM was added as a secondary outcome measure because of results found at the end of 3 months of stimulation. RESULTS: Side effects were similar to those reported in patients treated with VNS for epilepsy or depression and, in addition, dry mouth and fatigue were reported. Two patients did not tolerate stimulation. At 3 months, five patients had attained efficacy criteria; of these, two patients no longer met widespread pain or tenderness criteria for the diagnosis of FM. The therapeutic effect seemed to increase over time in that additional participants attained both criteria at 11 months. CONCLUSIONS: Side effects and tolerability were similar to those found in disorders currently treated with VNS. Preliminary outcome measures suggested that VNS may be a useful adjunct treatment for FM patients resistant to conventional therapeutic management, but further research is required to better understand its actual role in the treatment of FM. PMID- 21812909 TI - Prevalence and anatomical localization of muscle referred pain from active trigger points in head and neck musculature in adults and children with chronic tension-type headache. AB - OBJECTIVE: To compare differences in the prevalence and the anatomical localization of the referred pain areas of active trigger points (TrPs) in head and neck musculature between adults and children with chronic tension-type headache (CTTH). DESIGN: A cross-sectional study. SETTING: Some studies had found that referred pain from active TrPs reproduce the head pain pattern in adults. No study has compared clinical differences between referred pain patterns elicited by active TrPs between adults and children with CTTH. PATIENTS: Twenty adults (10 men, 10 women, mean age: 41 +/- 11 years) and 20 children (10 boys, 10 girls, mean age: 8 +/- 2 years) with CTTH were included. OUTCOME MEASURES: Bilateral temporalis, sternocleidomastoid, upper trapezius, and suboccipital muscles were examined for TrPs. TrPs were identified by palpation and considered active when local and referred pains reproduce the headache pain attacks. The referred pain areas were drawn on anatomical maps, digitalized, and also measured. An analysis technique based on a center of gravity (COG) method was used to provide a quantitative estimate of the localization of the TrP referred pain areas. RESULTS: Adults with CTTH exhibited a greater years with headache, higher intensity, and longer headache duration (P < 0.05) compared with children. The COG coordinates of the spontaneous pain on the dominant side were located more anterior (higher X-value), and spontaneous pain in the frontal and posterior areas was located more inferior (lower Y-value) in adults than in children. The number of active muscle TrPs was significantly higher (P = 0.001) in adults with CTTH (mean +/- standard deviation [SD]: 4 +/- 0.8) as compared with children (mean +/- SD: 3 +/- 0.7). Children with CTTH had larger referred pain areas than adults for upper trapezius, sternocleidomastoid, and temporalis (P < 0.001) muscles. The COG coordinates of the referred pain areas of temporalis and sternocleidomastoid muscle TrPs were more inferior (lower Y-values) in adults than in children with CTTH. CONCLUSIONS: This study showed that the referred pain elicited from active TrPs shared similar pain patterns as spontaneous CTTH in adults and children. Differences in TrP prevalence and location of the referred pain areas can be observed between adults and children with CTTH. PMID- 21812910 TI - Pre-incisional analgesia with intravenous or subcutaneous infiltration of ketamine reduces postoperative pain in patients after open cholecystectomy: a randomized, double-blind, placebo-controlled study. AB - BACKGROUND: In literature, there is controversy on the use of ketamine for management of postoperative pain. The aim of the present study was to evaluate the efficacy of pre-incisional intravenous or subcutaneous infiltration of ketamine on postoperative pain relief after open cholecystectomy. METHODS: One hundred twenty patients, aged 18-60 years, scheduled for open cholecystectomy was enrolled in this randomized, double-blind, placebo-controlled study. Patients were divided into four groups of 30 each and received subcutaneous infiltration of ketamine 1 mg/kg (group KS1), subcutaneous infiltration of ketamine 2 mg/kg (group KS2), intravenous ketamine 1 mg/kg (group KI), or subcutaneous infiltration of normal saline 20 mL (group C) before surgery. Visual analog scale (VAS) values and analgesic consumption were evaluated for 24 hours after operation. RESULTS: VAS scores were significantly lower at arrival to the postanesthesia care unit, 15 and 30 minutes in Group KS1, Group KS2, and Group KI compared with Group C (P<0.05). In Group KS2, VAS scores were significantly lower than Group KS1 (P<0.05). Postoperative VAS scores were significantly lower at 1, 2, 3, 4, 8, 12, and 24 hours after operation in Group KS1, Group KS2, and Group KI compared with Group C (P<0.05). In Group KS2, VAS scores were significantly lower than Group KS1 (P<0.05). CONCLUSION: A 2 mg/kg dose of subcutaneous infiltration ketamine or 1 mg/kg dose of intravenous ketamine given at approximately 15 minutes before surgery provides an adjunctive analgesia during 24 hours after surgery in patients undergoing cholecystectomy surgery. PMID- 21812911 TI - Behcet's disease (syndrome) with myalgia and its response to intravenous amino acids: a case series. AB - OBJECTIVE: To present a case series of patients with refractory Behcet's disease who presented with myalgia and with signs such as mouth and genital ulcerations and skin lesions and were treated with intravenous amino acids. DESIGN AND SETTING: Case series of patients with Behcet's Disease who presented to a clinical practice devoted to Pain Medicine and Neurology between 2000 and 2009 for treatment of myalgia. METHODS: All patients were treated with prednisone 60 mg by mouth daily for exacerbations of their disease. When this failed, eleven patients received intravenous administration of amino acids (Procalamine). RESULTS: Ten of eleven patients had a complete resolution of their Behcet's exacerbation, including myalgia; their painful ulcers became painless and began to heal with the infusion of amino acids for 2-5 days. CONCLUSION: Physicians treating myalgia should observe for signs of Behcet's disease, such as oral and genital ulcerations, and consider intravenous amino acids if steroids are not effective. PMID- 21812912 TI - Antiplatelet effects of aspirin vary with level of P2Y12 receptor blockade supplied by either ticagrelor or prasugrel. PMID- 21812913 TI - Splice variants of tissue factor promote monocyte-endothelial interactions by triggering the expression of cell adhesion molecules via integrin-mediated signaling. AB - BACKGROUND: TF is highly expressed in cancerous and atherosclerotic lesions. Monocyte recruitment is a hallmark of disease progression in these pathological states. OBJECTIVE: To examine the role of integrin signaling in TF-dependent recruitment of monocytes by endothelial cells. METHODS: The expression of flTF and asTF in cervical cancer and atherosclerotic lesions was examined. Biologic effects of the exposure of primary microvascular endothelial cells (MVEC) to truncated flTF ectodomain (LZ-TF) and recombinant asTF were assessed. RESULTS: flTF and asTF exhibited nearly identical expression patterns in cancer lesions and lipid-rich plaques. Tumor lesions, as well as stromal CD68(+) monocytes/macrophages, expressed both TF forms. Primary MVEC rapidly adhered to asTF and LZ-TF, and this was completely blocked by anti-beta1 integrin antibody. asTF- and LZ-TF-treatment of MVEC promoted adhesion of peripheral blood mononuclear cells (PBMCs) under orbital shear conditions and under laminar flow; asTF-elicited adhesion was more pronounced than that elicited by LZ-TF. Expression profiling and western blotting revealed a broad activation of cell adhesion molecules (CAMs) in MVEC following asTF treatment including E-selectin, ICAM-1 and VCAM-1. In transwell assays, asTF potentiated PMBC migration through MVEC monolayers by ~3-fold under MCP-1 gradient. CONCLUSIONS: TF splice variants ligate beta1 integrins on MVEC, which induces the expression of CAMs in MVEC and leads to monocyte adhesion and transendothelial migration. asTF appears more potent than flTF in eliciting these effects. Our findings underscore the pathophysiologic significance of non-proteolytic, integrin-mediated signaling by the two naturally occurring TF variants in cancer and atherosclerosis. PMID- 21812914 TI - Endoplasmic reticulum stress and insulin resistance post-trauma: similarities to type 2 diabetes. AB - Type 2 diabetes, a rapidly growing disease of modern aetiology, has a profound impact on morbidity and mortality. Explosions in the understanding of the underlying cellular mechanisms which lead to type 2 diabetes have recently been elucidated. In particular, the central role of endoplasmic reticulum stress (ER stress) and the unfolding protein response (UPR) in insulin resistance in type 2 diabetes has recently been discovered. We hypothesize that ER stress and UPR are not only central for type 2 diabetes but also for stress-induced diabetes. We review here the evidence that post-burn insulin resistance and hyperglycaemia have pathophysiologic mechanisms in common with type 2 diabetes. These recent discoveries not only highlight the importance of ER stress in the post-burn patient recovery, but furthermore enable new models to study fundamental and interventional aspects of type 2 diabetes. PMID- 21812915 TI - Modification of a novel angiogenic peptide, AG30, for the development of novel therapeutic agents. AB - We previously identified a novel angiogenic peptide, AG30, with antibacterial effects that could serve as a foundation molecule for the design of wound-healing drugs. Toward clinical application, in this study we have developed a modified version of the AG30 peptide characterized by improved antibacterial and angiogenic action, thus establishing a lead compound for a feasibility study. Because AG30 has an alpha-helix structure with a number of hydrophobic and cationic amino acids, we designed a modified AG30 peptide by replacing several of the amino acids. The replacement of cationic amino acids (yielding a new molecule, AG30/5C), but not hydrophobic amino acids, increased both the angiogenic and the antimicrobial properties of the peptide. AG30/5C was also effective against methicillin-resistant Staphylococcus aureus (MRSA) and antibiotic-resistant Pseudomonas aeruginosa. In a diabetic mouse wound-healing model, the topical application of AG30/5C accelerated wound healing with increased angiogenesis and attenuated MRSA infection. To facilitate the eventual clinical investigation/application of these compounds, we developed a large-scale procedure for the synthesis of AG30/5C that employed the conventional solution method and met Good Manufacturing Practice guidelines. In the evaluation of stability of this peptide in saline solution, RP-HPLC analysis revealed that AG30/5C was fairly stable under 5 degrees C for 12 months. Therefore, we propose the use of AG30/5C as a wound-healing drug with antibacterial and angiogenic actions. PMID- 21812916 TI - Complement activation during liver transplantation-special emphasis on patients with atypical hemolytic uremic syndrome. AB - Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy often caused by mutations in complement factor H (CFH), the main regulator of alternative complement pathway. Because CFH is produced mainly by the liver, combined liver-kidney transplantation is a reasonable option in treatment of patients with severe aHUS. We studied complement activation by monitoring activation markers during liver transplantation in two aHUS patients treated extensively with plasma exchange and nine other liver transplantation patients. After the reperfusion, a clear increase in all the activation markers except C4d was observed indicating that the activation occurs mainly through the alternative pathway. Concentration of SC5b-9 was higher in the hepatic than the portal vein indicating complement activation in the graft. Preoperatively and early during the operation, the aHUS patients showed highest C3d concentrations but otherwise their activation markers were similar to the other patients. In the other patients, correlation was found between perioperative SC5b-9 concentration and postoperative alanine aminotransferase and histological changes. This study explains why supply of normal CFH by extensive plasma exchange is beneficial before combined liver-kidney transplantation of aHUS patients. Also the results suggest that perioperative inhibition of the terminal complement cascade might be beneficial if enhanced complement activation is expected. PMID- 21812917 TI - Association of serum uric acid with graft survival after kidney transplantation: a time-varying analysis. AB - The association of serum uric acid (UA) with kidney transplant outcomes is uncertain. We examined the predictive value of UA during the first year posttransplant as a time-varying factor for graft survival after adjustment for time-dependent and independent confounding factors. Four hundred and eighty-eight renal allograft recipients transplanted from January 2004 to June 2006 and followed for 41.1 +/- 17.7 months were included. Data on UA, estimated glomerular filtration rate (eGFR), tacrolimus level, mycophenolate mofetil (MMF) and prednisone doses, use of allopurinol, angiotensin-converting enzyme inhibitor/angiotensin-receptor-blocker (ACEi/ARB) and diuretics at 1, 3, 6, 9 and 12 months were collected. Primary endpoint of the study was graft loss, defined as graft failure and death. Cox proportional hazard models and generalized estimating equations were used for analysis. UA level was associated with eGFR, gender, retransplantation, decease-donor organ, delayed graft function, diuretics, ACEi/ARB and MMF dose. After adjustment for these confounders, UA was independently associated with increased risk of graft loss (HR: 1.15, p = 0.003; 95% CI: 1.05-1.27). Interestingly, UA interacted with eGFR (HR: 0.996, p < 0.05; 95% CI: 0.993-0.999 for interaction term). Here, we report a significant association between serum UA during first year posttransplant and graft loss, after adjustment for corresponding values of time-varying variables including eGFR, immunosuppressive drug regimen and other confounding factors. Its negative impact seems to be worse with lower eGFR. PMID- 21812919 TI - Significant potential utility for donor yield models: but proceed with caution. PMID- 21812918 TI - Revisiting traditional risk factors for rejection and graft loss after kidney transplantation. AB - Single-antigen bead (SAB) testing permits reassessment of immunologic risk for kidney transplantation. Traditionally, high panel reactive antibody (PRA), retransplant and deceased donor (DD) grafts have been associated with increased risk. We hypothesized that this risk was likely mediated by (unrecognized) donor specific antibody (DSA). We grouped 587 kidney transplants using clinical history and single-antigen bead (SAB) testing of day of transplant serum as (1) unsensitized; PRA = 0 (n = 178), (2) third-party sensitized; no DSA (n = 363) or (3) donor sensitized; with DSA (n = 46), and studied rejection rates, death censored graft survival (DCGS) and risk factors for rejection. Antibody-mediated rejection (AMR) rates were increased with DSA (p < 0.0001), but not with panel reactive antibody (PRA) in the absence of DSA. Cell-mediated rejection (CMR) rates were increased with DSA (p < 0.005); with a trend to increased rates when PRA>0 in the absence of DSA (p = 0.08). Multivariate analyses showed risk factors for AMR were DSA, worse HLA matching, and female gender; for CMR: DSA, PRA>0 and worse HLA matching. AMR and CMR were associated with decreased DCGS. The presence of DSA is an important predictor of rejection risk, in contrast to traditional risk factors. Further development of immunosuppressive protocols will be facilitated by stratification of rejection risk by donor sensitization. PMID- 21812920 TI - Guidelines for the diagnosis of antibody-mediated rejection in pancreas allografts-updated Banff grading schema. AB - The first Banff proposal for the diagnosis of pancreas rejection (Am J Transplant 2008; 8: 237) dealt primarily with the diagnosis of acute T-cell-mediated rejection (ACMR), while only tentatively addressing issues pertaining to antibody mediated rejection (AMR). This document presents comprehensive guidelines for the diagnosis of AMR, first proposed at the 10th Banff Conference on Allograft Pathology and refined by a broad-based multidisciplinary panel. Pancreatic AMR is best identified by a combination of serological and immunohistopathological findings consisting of (i) identification of circulating donor-specific antibodies, and histopathological data including (ii) morphological evidence of microvascular tissue injury and (iii) C4d staining in interacinar capillaries. Acute AMR is diagnosed conclusively if these three elements are present, whereas a diagnosis of suspicious for AMR is rendered if only two elements are identified. The identification of only one diagnostic element is not sufficient for the diagnosis of AMR but should prompt heightened clinical vigilance. AMR and ACMR may coexist, and should be recognized and graded independently. This proposal is based on our current knowledge of the pathogenesis of pancreas rejection and currently available tools for diagnosis. A systematized clinicopathological approach to AMR is essential for the development and assessment of much needed therapeutic interventions. PMID- 21812922 TI - Mechanism of action of APOL1 in renal allograft survival (and Native CKD) remains unclear. PMID- 21812923 TI - Cytomegalovirus incidence between everolimus versus mycophenolate in de novo renal transplants: pooled analysis of three clinical trials. AB - Everolimus (EVR) in heart and renal transplant (RTx) recipients may be associated with a decreased incidence of cytomegalovirus (CMV). A detailed analysis of the association between EVR versus mycophenolic acid (MPA) and CMV events has not been reported. CMV data from 2004 de novo RTx recipients from three-randomized, prospective, EVR studies A2309 (N = 833), B201 (N = 588) and B251 (N = 583) were retrospectively analyzed to identify differences between two EVR dosing groups and MPA. EVR groups received 1.5 mg/day, or 3 mg/day with either standard (SD CsA) or reduced dose cyclosporine (RD-CsA). Controls received MPA with SD-CsA. CMV prophylaxis was as per center practice. CMV incidence (infection/syndrome, disease, viremia) was captured per local center evaluations. Kaplan-Meier analyses demonstrated that freedom from CMV viremia and infection/syndrome was significantly greater for EVR versus MPA for recipients without CMV prophylaxis. Among recipients who received prophylaxis, freedom from viremia was greater for EVR 3.0 mg; freedom from infection/syndrome was greater for EVR 3.0 and 1.5 mg. Although freedom from organ involvement was numerically greater for EVR, it was not statistically significant. This analysis documents significant reductions in the incidence of CMV infection/syndrome and viremia in EVR-treated de novo RTx recipients, especially those who did not receive CMV prophylaxis versus MPA. PMID- 21812924 TI - Lifetime probabilities of needing an organ transplant versus donating an organ after death. AB - The lifetime probabilities of becoming a deceased organ donor and requiring or receiving an organ transplant are unknown. An actuarial analysis was performed in a representative Canadian sample. Using Canadian organ donation data 1999-2007, provincial waiting list and population census data, actuarial rates were produced that provide the probabilities, by age band and gender, of (1) becoming a deceased organ donor, (2) needing an organ transplant and (3) receiving all organs needed. Regardless of age, the lifetime probability of needing a transplant for males is approximately twice that of females. Depending on age, Canadians are five to six times more likely to need an organ transplant than to become a deceased organ donor. The lifetime probabilities of not receiving a required organ transplant, expressed as a percentage of individuals on the waiting list, ranges from approximately 30% at birth, 20 years and 40 years to approximately 40% at 60 years. Across provinces and genders, Canadians at all ages are much more likely to need an organ transplant than to become an organ donor. Approximately one-third of those in need of a transplant will never receive one. How this information may influence organ donation decisions is currently under study. PMID- 21812926 TI - Sequence of multiorgan procurement involving face allograft. PMID- 21812925 TI - Transforming growth factor beta expression by human vascular cells inhibits interferon gamma production and arterial media injury by alloreactive memory T cells. AB - Arteriosclerosis is characterized by the local activation of effector T cells leading to production of proinflammatory cytokines, such as IFN (interferon) gamma and IL-17, within the vessel wall. Conversely, the production of antiinflammatory cytokines, for example, TGF-beta, by regulatory lymphocytes is known to inhibit both the differentiation of naive T cells into effector T cells and the development of arteriosclerosis in murine models. We investigated the role of TGF-beta on the alloreactivity of human effector memory T cells (Tem). Quiescent vascular cells, but not Tem, expressed TGF-beta. Blockade of TGF-beta activity in cocultures of CD4(+) Tem with allogeneic endothelial cells significantly increased IFN-gamma, but not IL-17, secretion. Additionally, serologic neutralization of TGF-beta in immunodeficient mouse hosts of human coronary artery grafts into which allogeneic human T cells were adoptively transferred resulted in heavier medial infiltration by Tem, greater loss of medial smooth muscle cells and increased IFN-gamma production within the grafts without significantly reducing either intimal injury or IL-17 production. Protective effects of TGF-beta may be limited by fewer TGF-beta-expressing vascular cells within the intimal compartment, by a reduction in the expression of TGF-beta by vascular cells in rejecting grafts, or possibly to less effective suppression of Tem than naive T cells. PMID- 21812927 TI - Urinary miR-210 as a mediator of acute T-cell mediated rejection in renal allograft recipients. AB - MicroRNAs (miRNAs) are small ribonucleotides regulating gene expression. Circulating miRNAs are remarkably stable in the blood. We tested whether miRNAs are also detectable in urine and may serve as new predictors of outcome in renal transplant patients with acute rejection. We profiled urinary miRNAs of stable transplant patients and transplant patients with acute rejection. The miR-10a, miR-10b and miR-210 were strongly deregulated in urine of the patients with acute rejection. We confirmed these data in urine of a validation cohort of 62 patients with acute rejection, 19 control transplant patients without rejection and 13 stable transplant patients with urinary tract infection by quantitative RT-PCR. The miR-10b and miR-210 were downregulated and miR-10a upregulated in patients with acute rejection compared to controls. Only miR-210 differed between patients with acute rejection when compared to stable transplant patients with urinary tract infection or transplant patients before/after rejection. Low miR-210 levels were associated with higher decline in GFR 1 year after transplantation. Selected miRNAs are strongly altered in urine of the patients with acute renal allograft rejection. The miR-210 levels identify patients with acute rejection and predict long-term kidney function. Urinary miR-210 may thus serve as a novel biomarker of acute kidney rejection. PMID- 21812929 TI - Severe allergic reactions to para-phenylenediamine in children and adolescents: should the patch test concentration of PPD be changed? AB - BACKGROUND: Semipermanent henna tattoos containing para-phenylenediamine (PPD) are a well-known cause of severe contact dermatitis, mainly in children. Another relevant exposure source to PPD are hair dyes, which are increasingly used by children and have also been reported to cause intense facial and scalp dermatitis. German patch test guidelines for children recommend that PPD should only be tested in patients who have had a henna tattoo, and then at a reduced concentration of PPD 0.5 % for 24 hours. PATIENTS AND METHODS: We report on patch test results in four patients, three children and one adolescent, with a history of contact dermatitis to henna tattoos or hair dye. We used the recommended or even lower patch test concentrations of PPD with 24-hours exposure in all patients. RESULTS AND CONCLUSION: All patients showed very strong patch test reactions to PPD and cross-reactions to related compounds even after dilution of PPD to as low as 0.05 %. Therefore, we suggest that in children with a history of allergic reactions to this compound, a titration test should be performed beginning at a concentration of maximal 0.05 %. This procedure has also been proposed previously based on a larger cases series in adults. PMID- 21812928 TI - Urinary chemokines CXCL9 and CXCL10 are noninvasive markers of renal allograft rejection and BK viral infection. AB - Renal transplant recipients require periodic surveillance for immune-based complications such as rejection and infection. Noninvasive monitoring methods are preferred, particularly for children, for whom invasive testing is problematic. We performed a cross-sectional analysis of adult and pediatric transplant recipients to determine whether a urine-based chemokine assay could noninvasively identify patients with rejection among other common clinical diagnoses. Urine was collected from 110 adults and 46 children with defined clinical conditions: healthy volunteers, stable renal transplant recipients, and recipients with clinical or subclinical acute rejection (AR) or BK infection (BKI), calcineurin inhibitor (CNI) toxicity or interstitial fibrosis (IFTA). Urine was analyzed using a solid-phase bead-array assay for the interferon gamma-induced chemokines CXCL9 and CXCL10. We found that urine CXCL9 and CXCL10 were markedly elevated in adults and children experiencing either AR or BKI (p = 0.0002), but not in stable allograft recipients or recipients with CNI toxicity or IFTA. The sensitivity and specificity of these chemokine assays exceeded that of serum creatinine. Neither chemokine distinguished between AR and BKI. These data show that urine chemokine monitoring identifies patients with renal allograft inflammation. This assay may be useful for noninvasively distinguishing those allograft recipients requiring more intensive surveillance from those with benign clinical courses. PMID- 21812930 TI - Biologics in atopic dermatitis. AB - Atopic dermatitis (AD) accounts for a significant share of chronic inflammatory skin disorders. There is a niche for the development of biologics to treat recalcitrant autoinflammatory stage AD seen mostly in adults. The heterogeneity of patient response to various existing biotherapies points to involvement of various immune responses and suggests that therapies must preferably target early development of allergen-specific B- and T-cell clones. In addition to immune targets, tissue factors that help restore the normal epidermal environment constitute interesting therapeutic tools. Several approaches are needed to find the appropriate targets in a field where so many have been investigated without definitive proof of concept for human systemic therapy. The keys to success are probably (1) to influence the inflammatory skin pattern towards less pruritogenic effects, requiring us to better understand pruritogenic inflammation and (2) to limit the amplification loop of disease by attacking abnormal regulatory mechanisms which perpetuate skin autoinflammation. PMID- 21812931 TI - The dynamics of the nucleosome: thermal effects, external forces and ATP. AB - With nucleosomes being tightly associated with the majority of eukaryotic DNA, it is essential that mechanisms are in place that can move nucleosomes 'out of the way'. A focus of current research comprises chromatin remodeling complexes, which are ATP-consuming protein complexes that, for example, pull or push nucleosomes along DNA. The precise mechanisms used by those complexes are not yet understood. Hints for possible mechanisms might be found among the various spontaneous fluctuations that nucleosomes show in the absence of remodelers. Thermal fluctuations induce the partial unwrapping of DNA from the nucleosomes and introduce twist or loop defects in the wrapped DNA, leading to nucleosome sliding along DNA. In this minireview, we discuss nucleosome dynamics from two angles. First, we describe the dynamical modes of nucleosomes in the absence of remodelers that are experimentally fairly well characterized and theoretically understood. Then, we discuss remodelers and describe recent insights about the possible schemes that they might use. PMID- 21812932 TI - Cloning and molecular characterization of a novel acyl-CoA:diacylglycerol acyltransferase 1-like gene (PtDGAT1) from the diatom Phaeodactylum tricornutum. AB - We have identified and isolated a cDNA encoding a novel acyl-CoA:diacylglycerol acyltransferase (DGAT)1-like protein, from the diatom microalga Phaeodactylum tricornutum (PtDGAT1). The full-length cDNA sequences of PtDGAT1 transcripts revealed that two types of mRNA, PtDGAT1short and PtDGAT1long, were transcribed from the single PtDGAT1 gene. PtDGAT1short encodes a 565 amino acid sequence that is homologous to several functionally characterized higher plant DGAT1 proteins, and 55% identical to the putative DGAT1 of the diatom Thalassiosira pseudonana, but shows little homology with other available putative and cloned algal DGAT sequences. PtDGAT1long lacks several catalytic domains, owing to a 63-bp nucleotide insertion in the mRNA containing a stop codon. Alternative splicing consisting of intron retention appears to regulate the amount of active DGAT1 produced, providing a possible molecular mechanism for increased triacylglycerol (TAG) biosynthesis in P. tricornutum under nitrogen starvation. DGAT mediates the last committed step in TAG biosynthesis, so we investigated the changes in expression levels of the two types of mRNA following nitrogen starvation inducing TAG accumulation. The abundance of both transcripts was markedly increased under nitrogen starvation, but much less so for PtDGAT1short. PtDGAT1 activity of PtDGAT1short was confirmed in a heterologous yeast transformation system by restoring DGAT activity in a Saccharomyces cerevisiae neutral lipid-deficient quadruple mutant strain (H1246), resulting in lipid body formation. Lipid body formation was only restored upon the expression of PtDGAT1short, and not of PtDGAT1long. The recombinant yeast appeared to display a preference for incorporating saturated C(16) and C(18) fatty acids into TAG. PMID- 21812933 TI - Selective hydroxylation of alkanes by an extracellular fungal peroxygenase. AB - Fungal peroxygenases are novel extracellular heme-thiolate biocatalysts that are capable of catalyzing the selective monooxygenation of diverse organic compounds, using only H(2)O(2) as a cosubstrate. Little is known about the physiological role or the catalytic mechanism of these enzymes. We have found that the peroxygenase secreted by Agrocybe aegerita catalyzes the H(2)O(2)-dependent hydroxylation of linear alkanes at the 2-position and 3-position with high efficiency, as well as the regioselective monooxygenation of branched and cyclic alkanes. Experiments with n-heptane and n-octane showed that the hydroxylation proceeded with complete stereoselectivity for the (R)-enantiomer of the corresponding 3-alcohol. Investigations with a number of model substrates provided information about the route of alkane hydroxylation: (a) the hydroxylation of cyclohexane mediated by H(2)(18)(2) resulted in complete incorporation of (18)O into the hydroxyl group of the product cyclohexanol; (b) the hydroxylation of n-hexane-1,1,1,2,2,3,3-D(7) showed a large intramolecular deuterium isotope effect [(k(H)/k(D))(obs)] of 16.0 +/- 1.0 for 2-hexanol and 8.9 +/- 0.9 for 3-hexanol; and (c) the hydroxylation of the radical clock norcarane led to an estimated radical lifetime of 9.4 ps and an oxygen rebound rate of 1.06 * 10(11) s(-1). These results point to a hydrogen abstraction and oxygen rebound mechanism for alkane hydroxylation. The peroxygenase appeared to lack activity on long-chain alkanes (> C(16)) and highly branched alkanes (e.g. tetramethylpentane), but otherwise exhibited a broad substrate range. It may accordingly have a role in the bioconversion of natural and anthropogenic alkane containing structures (including alkyl chains of complex biomaterials) in soils, plant litter, and wood. PMID- 21812934 TI - Identification of candidate substrates for poly(ADP-ribose) polymerase-2 (PARP2) in the absence of DNA damage using high-density protein microarrays. AB - Poly(ADP-ribose) polymerase-2 (PARP2) belongs to the ADP-ribosyltransferase family of enzymes that catalyze the addition of ADP-ribose units to acceptor proteins, thus affecting many diverse cellular processes. In particular, PARP2 shares with PARP1 and, as recently highlighted, PARP3 the sole property of being catalytically activated by DNA-strand breaks, implying key downstream functions in the cellular response to DNA damage for both enzymes. However, evidence from several studies suggests unique functions for PARP2 in additional processes, possibly mediated through its basal, DNA-damage unstimulated ADP-ribosylating activity. Here, we describe the development and application of a protein microarray-based approach tailored to identify proteins that are ADP-ribosylated by PARP2 in the absence of DNA damage mimetics and might thus represent useful entry points to the exploration of novel PARP2 functions. Several candidate substrates for PARP2 were identified and global hit enrichment analysis showed a clear enrichment in translation initiation and RNA helicase molecular functions. In addition, the top scoring candidates FK506-binding protein 3 and SH3 and cysteine-rich domain-containing protein 1 were selected and confirmed in a complementary assay format as substrates for unstimulated PARP2. PMID- 21812935 TI - Phosphodiesterase type 5 expression in human and rat lower urinary tract tissues and the effect of tadalafil on prostate gland oxygenation in spontaneously hypertensive rats. AB - INTRODUCTION: In humans, prostate phosphodiesterase type 5 inhibitors (PDE5) expression was prominently localized in the endothelial and smooth muscle cells of the vascular bed, suggesting a possible action of PDE5 inhibitors (PDE5i) on prostate blood flow. AIM: To investigate PDE5 expression in human and rat lower urinary tract (LUT) tissues, including vasculature, and determine the effects of PDE5 inhibition with tadalafil on prostatic blood perfusion. MAIN OUTCOME MEASURES: Human vesicular-deferential arteries (which originate from the inferior vesical artery, the main arterial source of blood supply to the bladder and prostate) were analyzed for PDE5 expression and activity. The effects of tadalafil on prostate oxygenation were studied in spontaneously hypertensive rats (SHR), characterized by ischemia/hypoxia of the genitourinary tract. METHODS: PDE5 expression was evaluated by quantitative reverse transcription-polymerase chain reaction and immunohistochemistry. SHR were treated with tadalafil (2 mg/kg/day) for 1, 7, or 28 days and compared with untreated SHR and the unaffected counterpart Wistar-Kyoto (WKY) rats. Prostate oxygenation was detected by Hypoxyprobe-1 and hypoxia markers (hypoxia-inducible factor-1alpha[HIF-1alpha] and endothelin-1 type B [ETB]) immunostaining. RESULTS: Human vesicular deferential artery expressed high levels of PDE5, similar to corpora cavernosa, immunolocalized in the endothelial and smooth muscle layer. In these arteries, tadalafil inhibited cyclic guanosine monophosphate breakdown (half maximal inhibitory concentration (IC(50) ) in the low nanomolar range, as in corpora cavernosa) and increased the relaxant response to sodium nitroprusside. SHR prostate resulted markedly hypoxic (hypoxyprobe immunopositivity) and positive for HIF-1alpha and ETB, while tadalafil treatment restored oxygenation to WKY level at each time point. The mRNA expression of the HIF-1alpha target gene, BCL2/adenovirus E1B 19 kDa interacting protein 3, was significantly increased in SHR prostate and partially restored to WKY level by tadalafil. CONCLUSION: Human vesicular-deferential artery is characterized by a high expression and activity of PDE5, which was inhibited by tadalafil in vitro. In SHR, tadalafil increases prostate tissue oxygenation, thus suggesting a possible mechanism through which PDE5i exert beneficial effects on LUT symptoms. PMID- 21812936 TI - Expert training with standardized operative technique helps establish a successful penile prosthetics program for urologic resident education. AB - INTRODUCTION: The challenge of resident education in urologic surgery programs is to overcome disparity imparted by diverse patient populations, limited training times, and inequalities in the availability of expert surgical educators. Specifically, in the area of prosthetic urology, only a small proportion of programs have full-time faculty available to train residents in this discipline. AIM: To examine whether a new model using yearly training sessions from a recognized expert can establish a successful penile prosthetics program and result in better outcomes, higher case volumes, and willingness to perform more complex surgeries. METHODS: A recognized expert conducted one to two operative training sessions yearly to teach standardized technique for penile prosthetics to residents. Each session consisted of three to four operative cases performed under the direct supervision of the expert. Retrospective data were collected from all penile prosthetic operations before (February, 2000 to June, 2004: N = 44) and after (July, 2004 to October, 2007: N = 79) implementation of these sessions. MAIN OUTCOME MEASURES: Outcomes reviewed included patient age, race, medical comorbidities, operative time, estimated blood loss, type of prosthesis, operative approach, drain usage, length of stay, and complications including revision/explantation rates. Statistical analysis was performed using Student's t tests, Fisher's tests, and survival curves using the Kaplan-Meier technique (P value <= 0.05 to define statistical significance). RESULTS: Patient characteristics were not significantly different pre- vs. post-training. Operative time and estimated blood loss significantly decreased. Inflatable implants increased from 19/44 (43.2%, pre-training) to 69/79 (87.3%, post training) (P < 0.01). Operations per year increased from 9.96 (pre-training) to 24 (post-training) (P < 0.01). Revision/explantation occurred in 11/44 patients (25%, pre-training) vs. 7/79 (8.9%, post-training) (P < 0.05). CONCLUSIONS: These data demonstrate that yearly sessions with a recognized expert can improve surgical outcomes, type, and volume of implants and can reduce explantation/revision rates. This represents an excellent model for improved training of urologic residents in penile prosthetics surgery. PMID- 21812937 TI - Transtheoretical model-based postpartum sexual health education program improves women's sexual behaviors and sexual health. AB - INTRODUCTION: Postpartum sexual health education was once routinely administered to postpartum women, but few interventions were specifically described or clearly based on theory, and few sexual interventions affected women's sexual behaviors. AIM: To evaluate the effectiveness of a refined theory-based interactive postpartum sexual health education program (IPSHEP) in enhancing postpartum women's sexual behavior and health. METHODS: For this prospective, randomized controlled trial, 250 participants were randomized to three groups. Experimental group A received our refined theory-based IPSHEP. Experimental group B received only an interactive, self-help pamphlet. The control group received routine education (a 10- to 15-minute educational talk and a sexual health pamphlet without an interactive design). Data were collected at baseline, 3 days, 2 months, and 3 months postpartum. MAIN OUTCOME MEASURE: Postpartum women's sexual self-efficacy (SSE), diversity of sexual activity (DSA), return to sexual activity, and sexual satisfaction (SS). RESULTS: Women who received our theory based postpartum sexual health education program had significantly greater SSE (P < 0.05) and greater DSA (P < 0.05), and tended to resume their sexual life earlier than women in the routine teaching and interactive pamphlet-only groups (P < 0.05). However, the SS levels of postpartum women who received our program did not differ significantly from those of women who received routine teaching or the interactive pamphlet only. CONCLUSIONS: Our findings suggest that a theory based postpartum sexual health education program improved women's sexual health and sexual behavior and that the transtheoretical model can be translated into practice, supporting its use to enhance the sexual health of postpartum women. Despite the lack of a significant effect on SS, women who received our theory based postpartum sexual health education program tended to maintain their prepregnancy level of SS in early postpartum. PMID- 21812938 TI - Comparison of overall sexual function, sexual intercourse/activity, sexual satisfaction, and sexual desire during the three trimesters of pregnancy and assessment of their determinants. AB - INTRODUCTION: Pregnancy affects women's sexual function. However, few reports have addressed this phenomenon. AIM: To examine overall sexual function and three dimensions of the Taiwan version of the Female Sexual Function Index and to assess their determinants during the three trimesters of pregnancy. METHODS: Cross-sectional investigation of 663 pregnant women using the International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form, the Body Image Scale for Pregnant Women, and demographics questions. MAIN OUTCOME MEASURES: Urinary incontinence, body image, obstetrical history, demographics, and other factors potentially influencing overall sexual function, intercourse/activity, satisfaction, and desire during pregnancy. RESULTS: Mean scores for overall sexual function, intercourse/activity, and satisfaction differed significantly among the three trimesters (P = or <0.02), whereas mean scores for sexual desire did not. Mean scores for overall sexual function and intercourse were significantly lower during the third trimester than during the first trimester (P < 0.001) or second trimester (P < 0.001). Mean score for satisfaction was significantly higher during the third trimester than during the first trimester (P = 0.01). Significant effects included the following: (i) the discomfort and infertility experiences on overall sexual function and on intercourse, the interaction between body image and artificial abortion on satisfaction, spontaneous abortion on desire during the first trimester; (ii) the full-time work and infertility experiences on overall sexual function and on intercourse, the interactions between body image and medical condition on desire during the second trimester; and (iii) the interaction between gestational age and HoLou ethnicity on overall sexual function, the interaction between body image and discomfort on overall sexual function and on intercourse, the interactions between body image and infertility experiences and gravidity on satisfaction, urinary incontinence on desire during the third trimester. CONCLUSIONS: Results demonstrated that biopsychosocial and cultural factors affected Female Sexual Function Index (FSFIT) scores throughout pregnancy. PMID- 21812939 TI - Acute and sustained actions of hyperglycaemia on endothelial and glomerular barrier permeability. AB - Microalbuminuria is an established marker of systemic endothelial dysfunction, which for patients with diabetes signals an increased risk of both diabetic nephropathy and cardiovascular complications. A better understanding of the pathogenesis of microalbuminuria is important in the quest of finding new approaches to treat patients with diabetes. Direct acute effects of episodes of hyperglycaemia (HG) could have implications for the microalbuminuria seen in early diabetes before renal structural alterations have started, especially in those patients with poor glycaemic control. This review summarizes the literature evidence that acute or sustained HG may lead to an increased vascular or glomerular permeability. Special focus is on glomerular barrier permeability. There is evidence in the literature that HG increases systemic capillary and glomerular barrier permeability within 20-30 min in vivo in rats and mice. Furthermore, exposure of monolayers of cultured endothelial cells to HG has been shown to increase monolayer permeability rapidly and transiently (during 60-100 min). Instant cellular changes following F-actin cytoskeleton rearrangements, which could be abrogated by Rho-kinase (ROCK) inhibition, are implicated. Data in this review also suggest that activation of protein kinase C, the polyol pathway, and an increased release of reactive oxygen species (ROS) and cytokines could contribute to the increase in barrier permeability induced by HG. Recent in vitro data from cultured podocyte monolayers also designates a role of insulin in acute podocyte F-actin remodelling, underpinning the complexity of the mechanisms leading to glomerular and endothelial barrier alterations in diabetes mellitus. PMID- 21812940 TI - Dexamethasone reduces pain, vomiting and overall complications following tonsillectomy in adults: a systematic review and meta-analysis of randomised controlled trials. AB - BACKGROUND: Tonsillectomy is one of the most common surgical procedures, but there is debate whether systemic steroids should be used to reduce pain and post operative complications. OBJECTIVE OF REVIEW: To determine whether peri-operative steroids reduce post-tonsillectomy pain and complications in adults. TYPE OF REVIEW: Systematic review and meta-analysis of randomised controlled trials. SEARCH STRATEGY: We searched MEDLINE (1950-2010), EMBASE (1980-2010), CINAHL (1981-2010), Web of Science, ProQuest, metaRegister, Conference Proceedings Citation Index, the Cochrane Library and reference lists of relevant studies. EVALUATION METHOD: Two reviewers independently selected trials and extracted data on their quality, characteristics and results. Trials included adults (age >16 years) undergoing elective tonsillectomy where peri-operative steroids were used, and the results were compared with control or placebo. RESULTS: There were seven randomised controlled trials (580 patients) reporting post-operative pain. Meta analysis demonstrates that dexamethasone in adults reduces the pain level experienced in the first post-tonsillectomy day [standard mean difference (SMD): 0.63, 95% CI: -1.13 to -0.12] with significant heterogeneity (I(2) = 84%, P < 0.00001). Sub-group analysis to explore heterogeneity demonstrated this reduction in pain was mostly with high total dose steroids (total >10 mg over first 24 h post-operatively; SMD: -1.48, 95% CI: -2.17 to -0.79, P < 0.00001), especially when given both intra-operatively and post-operatively. There was no significant effect with low doses (SMD: -0.12, 95% CI: -0.36 to 0.13, P = 0.35). There were three trials (231 patients) that reported post-operative nausea and vomiting, three other trials (270 patients) reporting on bleeding and three trials (401 patients) reporting other complications (infections and odynophagia). There was a significant reduction in post-operative nausea and vomiting (RR: 0.53, 95% CI: 0.36 to 0.80, P = 0.002, I(2) = 26%) and bleeding (RR: 0.45, 95% CI: 0.25 to 0.80, P = 0.007, I(2) = 0%), but the reduction in the other complications did not reach statistical significance (RR: 0.69, 95% CI: 0.48 to 1.01, P = 0.06, I(2) = 0%). Pooling of these complications (post-operative nausea and vomiting, bleeding, infections and odynophagia) shows that in six trials (501 patients), the use of dexamethasone significantly reduced post-operative complications following tonsillectomy in adults (RR: 0.59, 95% CI: 0.49 to 0.71, P < 0.00001, I(2) = 0%), when compared with placebo or control. CONCLUSIONS: Dexamethasone reduces pain, post-operative nausea and vomiting, bleeding and overall post operative complications in adults undergoing tonsillectomy. However, the effect of the dose of dexamethasone on post-operative pain and whether dexamethasone reduces bleeding require further research. PMID- 21812941 TI - Explained variance for blood gases in a population with COPD. AB - INTRODUCTION: Variation of blood gas levels in chronic obstructive pulmonary disease (COPD) patients has not been extensively reported and there is limited knowledge about predictors of chronic respiratory failure in COPD patients. OBJECTIVES: The aim of this study was to identify predictors of hypoxemia, hypercapnia and increased alveolar-arterial oxygen difference in COPD patients. We hypothesized that prediction of arterial blood gases will be improved in multivariate models including measurements of lung function, anthropometry and systemic inflammation. METHODS: A cross-sectional sample of 382 Norwegian COPD patients, age 40-76, Global Initiative for Chronic Obstructive Lung Disease stage II-IV, with a smoking history of at least 10 pack-years, underwent extensive measurements, including medical examination, arterial blood gases, systemic inflammatory markers, spirometry, plethysmography, respiratory impedance and bioelectrical impedance. Possible predictors of arterial oxygen (PaO(2)), arterial carbon dioxide (PaCO(2)) and alveolar-arterial oxygen difference (AaO(2)) were analyzed with both bivariate and multiple regression methods. RESULTS: We found that various lung function measurements were significantly associated with PaO2, PaCO(2) and AaO(2). In addition, heart rate and Fat Mass Index were predictors of PaO(2) and AaO(2), while heart failure and current smoking status were associated with PaCO(2). The explained variance (R(2)) in the final multivariate regression models was 0.14-0.20. CONCLUSIONS: With a wide assortment of possible clinical predictors, we could explain 14-20% of the variation in blood gas measurements in COPD patients. PMID- 21812942 TI - Changes in causes of low vision between 1988 and 2009 in a Dutch population of children. AB - PURPOSE: Causes of low vision in the Netherlands may have changed over time. The purpose of this study is to assess trends over the last two decades. METHODS: Socio-demographic and medical data, including ophthalmic diagnosis and inheritance patterns for 2843 children with low vision (0-21 years; 50% representation) referred to a Dutch institute for low vision (Bartimeus) over a 21-year period between 1988 and 2009, were included in the analysis. For the 19 most common diagnoses, inheritance and presence of mental impairment, trend analyses were performed with logistic regression models; odds ratios (OR) for a 10-year time span were reported. RESULTS: Cerebral visual impairment (CVI) was found in 27.2% (97% mental impairment), albinism in 8.0%. Over time, nystagmus (6.6%; OR = 1.42), retinitis pigmentosa (2.9%; OR = 1.61), cone-rod dystrophy (2.6%; OR = 1.98) and hyperopia (2.0%; OR = 3.66) increased significantly. Cataract (4.9%; OR = 0.64), aniridia (1.6%; OR = 0.42) and retinopathy of prematurity (ROP; 2.0%; OR = 0.45) decreased significantly. There was a significant increase in genetic disorders (41.0%; OR = 1.49) and in co-occurrence of mental impairment (52.2% OR = 1.16). CONCLUSION: In the last two decades, treatable or preventable disorders (such as cataract and ROP) have become a less common cause of low vision in children. However, the prevalence of complex (genetic) and untreatable disorders (CVI) has taken its place, as a result of increased survival of preterm and low birth weight children and improved diagnostic possibilities. Knowledge of the prevalence of low vision, its causes and trends over time may help policy makers to define effective intervention strategies and to monitor its impact. PMID- 21812943 TI - The evidence base to select a method for assessing glaucomatous visual field progression. AB - A large number of methods have been developed for assessing glaucomatous visual field progression, but their properties have not yet been systematically evaluated. In this systematic literature review, we summarize the evidence base for selecting a method by providing answers to ten relevant questions on the variety, validity and reproducibility of methods. In total, we found 301 different methods in 412 articles. The majority of studies (54%) used the Humphrey Field Analyzer. No data have been published about the reproducibility of methods. Although there is no gold standard to assess glaucomatous visual field progression, we found evidence on validity for 48 different methods. Some methods were less capable of distinguishing between progressive and nonprogressive patients. Choosing among twelve methods is supported by some evidence of their validity. These methods still differ in sensitivity, specificity and predictive values of test results within studies comparing several methods. In conclusion, the current evidence base is not perfect. A selection should be made from a limited number of methods, according to the clinical purpose of progression assessment. Methods that quantify the rate of visual field progression seem to be the most appropriate for guiding subsequent medical actions in individual patients. Future studies should investigate whether using one method to monitor patients is superior to another method in preventing loss of quality of life. PMID- 21812944 TI - Reduction in host-finding behaviour in fungus-infected mosquitoes is correlated with reduction in olfactory receptor neuron responsiveness. AB - BACKGROUND: Chemical insecticides against mosquitoes are a major component of malaria control worldwide. Fungal entomopathogens formulated as biopesticides and applied as insecticide residual sprays could augment current control strategies and mitigate the evolution of resistance to chemical-based insecticides. METHODS: Anopheles stephensi mosquitoes were exposed to Beauveria bassiana or Metarhizium acridum fungal spores and sub-lethal effects of exposure to fungal infection were studied, especially the potential for reductions in feeding and host location behaviours related to olfaction. Electrophysiological techniques, such as electroantennogram, electropalpogram and single sensillum recording techniques were then employed to investigate how fungal exposure affected the olfactory responses in mosquitoes. RESULTS: Exposure to B. bassiana caused significant mortality and reduced the propensity of mosquitoes to respond and fly to a feeding stimulus. Exposure to M. acridum spores induced a similar decline in feeding propensity, albeit more slowly than B. bassiana exposure. Reduced host seeking responses following fungal exposure corresponded to reduced olfactory neuron responsiveness in both antennal electroantennogram and maxillary palp electropalpogram recordings. Single cell recordings from neurons on the palps confirmed that fungal-exposed behavioural non-responders exhibited significantly impaired responsiveness of neurons tuned specifically to 1-octen-3-ol and to a lesser degree, to CO2. CONCLUSIONS: Fungal infection reduces the responsiveness of mosquitoes to host odour cues, both behaviourally and neuronally. These pre lethal effects are likely to synergize with fungal-induced mortality to further reduce the capacity of mosquito populations exposed to fungal biopesticides to transmit malaria. PMID- 21812945 TI - "I'm on it 24/7 at the moment": a qualitative examination of multi-screen viewing behaviours among UK 10-11 year olds. AB - BACKGROUND: Screen-viewing has been associated with increased body mass, increased risk of metabolic syndrome and lower psychological well-being among children and adolescents. There is a shortage of information about the nature of contemporary screen-viewing amongst children especially given the rapid advances in screen-viewing equipment technology and their widespread availability. Anecdotal evidence suggests that large numbers of children embrace the multi functionality of current devices to engage in multiple forms of screen-viewing at the same time. In this paper we used qualitative methods to assess the nature and extent of multiple forms of screen-viewing in UK children. METHODS: Focus groups were conducted with 10-11 year old children (n = 63) who were recruited from five primary schools in Bristol, UK. Topics included the types of screen-viewing in which the participants engaged; whether the participants ever engaged in more than one form of screen-viewing at any time and if so the nature of this multiple viewing; reasons for engaging in multi-screen-viewing; the room within the house where multi-screen-viewing took place and the reasons for selecting that room. All focus groups were transcribed verbatim, anonymised and thematically analysed. RESULTS: Multi-screen viewing was a common behaviour. Although multi-screen viewing often involved watching TV, TV viewing was often the background behaviour with attention focussed towards a laptop, handheld device or smart-phone. There were three main reasons for engaging in multi-screen viewing: 1) tempering impatience that was associated with a programme loading; 2) multi-screen facilitated filtering out unwanted content such as advertisements; and 3) multi screen viewing was perceived to be enjoyable. Multi-screen viewing occurred either in the child's bedroom or in the main living area of the home. There was considerable variability in the level and timing of viewing and this appeared to be a function of whether the participants attended after-school clubs. CONCLUSIONS: UK children regularly engage in two or more forms of screen-viewing at the same time. There are currently no means of assessing multi-screen viewing nor any interventions that specifically focus on reducing multi-screen viewing. To reduce children's overall screen-viewing we need to understand and then develop approaches to reduce multi-screen viewing among children. PMID- 21812946 TI - A simplified and cost-effective enrichment protocol for the isolation of Campylobacter spp. from retail broiler meat without microaerobic incubation. AB - BACKGROUND: To simplify the methodology for the isolation of Campylobacter spp. from retail broiler meat, we evaluated 108 samples (breasts and thighs) using an unpaired sample design. The enrichment broths were incubated under aerobic conditions (subsamples A) and for comparison under microaerobic conditions (subsamples M) as recommended by current reference protocols. Sensors were used to measure the dissolved oxygen (DO) in the broth and the percentage of oxygen (O2) in the head space of the bags used for enrichment. Campylobacter isolates were identified with multiplex PCR assays and typed using pulsed-field gel electrophoresis (PFGE). Ribosomal intergenic spacer analyses (RISA) and denaturing gradient gel electrophoresis (DGGE) were used to study the bacterial communities of subsamples M and A after 48 h enrichment. RESULTS: The number of Campylobacter positive subsamples were similar for A and M when all samples were combined (P = 0.81) and when samples were analyzed by product (breast: P = 0.75; thigh: P = 1.00). Oxygen sensors showed that DO values in the broth were around 6 ppm and O2 values in the head space were 14-16% throughout incubation. PFGE demonstrated high genomic similarity of isolates in the majority of the samples in which isolates were obtained from subsamples A and M. RISA and DGGE results showed a large variability in the bacterial populations that could be attributed to sample-to-sample variations and not enrichment conditions (aerobic or microaerobic). These data also suggested that current sampling protocols are not optimized to determine the true number of Campylobacter positive samples in retail boiler meat. CONCLUSIONS: Decreased DO in enrichment broths is naturally achieved. This simplified, cost-effective enrichment protocol with aerobic incubation could be incorporated into reference methods for the isolation of Campylobacter spp. from retail broiler meat. PMID- 21812947 TI - NT-proBNP levels, atherosclerosis and vascular function in asymptomatic type 2 diabetic patients with microalbuminuria: peripheral reactive hyperaemia index but not NT-proBNP is an independent predictor of coronary atherosclerosis. AB - Intensive multifactorial treatment aimed at cardiovascular (CV) risk factor reduction in type 2 diabetic patients with microalbuminuria can diminish fatal and non-fatal CV. Plasma N-terminal (NT)-proBNP predicts CV mortality in diabetic patients but the utility of P-NT-proBNP in screening for atherosclerosis is unclear. We examined the interrelationship between P-NT-proBNP, presence of atherosclerosis and/or vascular dysfunction in the coronary, carotid and peripheral arteries in asymptomatic type 2 diabetic patients with microalbuminuria that received intensive multifactorial treatment. METHODS AND RESULTS: P-NT-proBNP was measured in 200 asymptomatic type 2 patients without known cardiac disease that received intensive multifactorial treatment for CV risk reduction. Patients were examined for coronary, carotid and peripheral atherosclerosis, as defined by coronary calcium score>=400, carotid intima-media thickness (CIMT)>0.90 mm, ankle-brachial index<0.90, and/or toe-brachial index<0.64, respectively. Carotid artery compliance was also determined and the reactive hyperaemia index (RHI) measured by peripheral artery tonometry was used as a surrogate for endothelial function.P-NT-proBNP was associated with atherosclerosis in the unadjusted analysis, but not after adjustment for conventional risk factors. P-NT-proBNP was not associated with vascular dysfunction. The prevalence of atherosclerosis in the coronary, carotid and peripheral arteries was 35%, 10% and 21% of all patients, respectively. In total 49% had atherosclerosis in one territory and 15.6% and 1.0% in two and three territories. Low RHI was an independent predictor of coronary atherosclerosis (odds ratio [CI], 2.60 [1.15-5.88] and systolic blood pressure was the only independent determinant of CIMT (0.02 mm increase in CIMT per 10 mmHg increase in systolic blood pressure [p=0.003]). CONCLUSIONS: Half of asymptomatic patients with type 2 diabetes mellitus and microalbuminuria had significant atherosclerosis in at least one vascular territory despite receiving intensive multifactorial treatment for CV risk reduction. Coronary atherosclerosis was most prevalent, whereas carotid disease was more rarely observed. RHI but not plasma NT-proBNP was predictive of coronary atherosclerosis. PMID- 21812948 TI - Taking stock: provider prescribing practices in the presence and absence of ACT stock. AB - BACKGROUND: Globally, the monitoring of prompt and effective treatment for malaria with artemisinin combination therapy (ACT) is conducted largely through household surveys. This measure; however, provides no information on case management processes at the health facility level. The aim of this review was to assess evidence from health facility surveys on malaria prescribing practices using ACT, in the presence and absence of ACT stock, at time and place where treatment was sought. METHODS: A systematic search of published literature was conducted. Findings were collated and data extracted on proportion of patients prescribed ACT and alternative anti-malarials in the presence and absence of ACT stock. RESULTS: Of the 14 studies identified in which ACT prescription for uncomplicated malaria in the public sector was evaluated, just six, from three countries (Kenya, Uganda and Zambia), reported this in the context of ACT stock. Comparing facilities with ACT stock to facilities without stock (i) ACT prescribing was significantly higher in all six studies, increasing by a range of 21.3% in children < 5 yrs weighing >= 5 kg (p < 0.001; Kenya 2006) to 51.7% in children >= 10 kg (p < 0.001; Zambia 2006); (ii) SP prescribing decreased significantly in five studies, by a range of 14.4% (p < 0.001; Kenya 2006), to 46.3% (p < 0.001; Zambia 2006); (iii) Where quinine was a reported alternative, prescriptions decreased in five of the six studies by 0.1% (p = 1.0, Kenya 2010) to 10.2% (p < 0.001; Zambia 2006). At facilities with no ACT stock on the survey day, the proportion of febrile patients prescribed ACT was < 10% in five of the nine target groups included in the six studies, with the proportion prescribed ACT ranging from 0 to 28.4% (Uganda 2007). CONCLUSIONS: Prescriber practices vary based on ACT availability. Although ACT prescriptions increased and alternative anti-malarials prescriptions decreased in the presence of ACT stock, ACT was prescribed in the absence, and alternative anti-malarials were prescribed in the presence of, ACT. Presence of stock alone does not ensure that treatment guidelines are followed. More health facility surveys, together with qualitative research, are needed to understand the role of ACT stock-outs on provider prescribing behaviours and preferences. PMID- 21812949 TI - Designing a sustainable strategy for malaria control? AB - Malaria in the 21st century is showing signs of declining over much of its distribution, including several countries in Africa where previously this was not thought to be feasible. Yet for the most part the strategies to attack the infection are similar to those of the 1950s. Three major Journals have recently drawn attention to the situation, stressing the importance of research, describing the successes and defining semantics related to control. But there is a need to stress the importance of local sustainability, and consider somewhat urgently how individual endemic countries can plan and implement the programmes that are currently financed, for the most part, by donor institutions. On an immediate basis research should be more focused on a data driven approach to control. This will entail new thinking on the role of local infrastructure and in training of local scientists in local universities in epidemiology and field malariology so that expanded control programmes can become operational. Donor agencies should encourage and facilitate development of career opportunities for such personnel so that local expertise is available to contribute appropriately. PMID- 21812950 TI - Silver nanoparticles are broad-spectrum bactericidal and virucidal compounds. AB - The advance in nanotechnology has enabled us to utilize particles in the size of the nanoscale. This has created new therapeutic horizons, and in the case of silver, the currently available data only reveals the surface of the potential benefits and the wide range of applications. Interactions between viral biomolecules and silver nanoparticles suggest that the use of nanosystems may contribute importantly for the enhancement of current prevention of infection and antiviral therapies. Recently, it has been suggested that silver nanoparticles (AgNPs) bind with external membrane of lipid enveloped virus to prevent the infection. Nevertheless, the interaction of AgNPs with viruses is a largely unexplored field. AgNPs has been studied particularly on HIV where it was demonstrated the mechanism of antiviral action of the nanoparticles as well as the inhibition the transmission of HIV-1 infection in human cervix organ culture. This review discusses recent advances in the understanding of the biocidal mechanisms of action of silver Nanoparticles. PMID- 21812951 TI - High maternal mortality estimated by the sisterhood method in a rural area of Mali. AB - BACKGROUND: Maternal mortality is high in Mali. Nevertheless, there are few studies on this topic from rural areas, and current estimates are mostly based on studies from urban settings. Our objective was to estimate the maternal mortality ratio in Kita, rural Mali. METHODS: Using the "sisterhood method", we interviewed participants aged 15-50 years from 20 villages in Kita, Mali, and thereby created a retrospective cohort of their sisters in reproductive age. Based on population and fertility estimates, we calculated the lifetime risk of maternal death, and from that the estimated approximate maternal mortality ratio. RESULTS: The 2,039 respondents reported 4,628 sisters who had reached reproductive age. Of these 4,628 sisters, almost a third (1,233; 27%) had died, and 429 (9%) had died during pregnancy or childbirth. This corresponded to a lifetime risk of maternal death of 20% and a maternal mortality ratio of 3,131 per 100,000 live births (95% confidence interval 2,967-3,296), with a time reference around 1999. CONCLUSIONS: We found a very high maternal mortality in rural Mali and this highlights the urgent need for obstetric services in the remote rural areas. PMID- 21812952 TI - NoD: a Nucleolar localization sequence detector for eukaryotic and viral proteins. AB - BACKGROUND: Nucleolar localization sequences (NoLSs) are short targeting sequences responsible for the localization of proteins to the nucleolus. Given the large number of proteins experimentally detected in the nucleolus and the central role of this subnuclear compartment in the cell, NoLSs are likely to be important regulatory elements controlling cellular traffic. Although many proteins have been reported to contain NoLSs, the systematic characterization of this group of targeting motifs has only recently been carried out. RESULTS: Here, we describe NoD, a web server and a command line program that predicts the presence of NoLSs in proteins. Using the web server, users can submit protein sequences through the NoD input form and are provided with a graphical output of the NoLS score as a function of protein position. While the web server is most convenient for making prediction for just a few proteins, the command line version of NoD can return predictions for complete proteomes. NoD is based on our recently described human-trained artificial neural network predictor. Through stringent independent testing of the predictor using available experimentally validated NoLS-containing eukaryotic and viral proteins, the NoD sensitivity and positive predictive value were estimated to be 71% and 79% respectively. CONCLUSIONS: NoD is the first tool to provide predictions of nucleolar localization sequences in diverse eukaryotes and viruses. NoD can be run interactively online at http://www.compbio.dundee.ac.uk/nod or downloaded to use locally. PMID- 21812953 TI - Patterns of perceived barriers to medical care in older adults: a latent class analysis. AB - BACKGROUND: This study examined multiple dimensions of healthcare access in order to develop a typology of perceived barriers to healthcare access in community dwelling elderly. Secondary aims were to define distinct classes of older adults with similar perceived healthcare access barriers and to examine predictors of class membership to identify risk factors for poor healthcare access. METHODS: A sample of 5,465 community-dwelling elderly was drawn from the 2004 wave of the Wisconsin Longitudinal Study. Perceived barriers to healthcare access were measured using items from the Group Health Association of America Consumer Satisfaction Survey. We used latent class analysis to assess the constellation of items measuring perceived barriers in access and multinomial logistic regression to estimate how risk factors affected the probability of membership in the latent barrier classes. RESULTS: Latent class analysis identified four classes of older adults. Class 1 (75% of sample) consisted of individuals with an overall low level of risk for perceived access problems (No Barriers). Class 2 (5%) perceived problems with the availability/accessibility of healthcare providers such as specialists or mental health providers (Availability/Accessibility Barriers). Class 3 (18%) perceived problems with how well their providers' operations arise organized to accommodate their needs and preferences (Accommodation Barriers). Class 4 (2%) perceived problems with all dimension of access (Severe Barriers). Results also revealed that healthcare affordability is a problem shared by members of all three barrier groups, suggesting that older adults with perceived barriers tend to face multiple, co-occurring problems. Compared to those classified into the No Barriers group, those in the Severe Barrier class were more likely to live in a rural county, have no health insurance, have depressive symptomatology, and speech limitations. Those classified into the Availability/Accessibility Barriers group were more likely to live in rural and micropolitan counties, have depressive symptomatology, more chronic conditions, and hearing limitations. Those in the Accommodation group were more likely to have depressive symptomatology and cognitive limitations. CONCLUSIONS: The current study identified a typology of perceived barriers in healthcare access in older adults. The identified risk factors for membership in perceived barrier classes could potentially assist healthcare organizations and providers with targeting polices and interventions designed to improve access in their most vulnerable older adult populations, particularly those in rural areas, with functional disabilities, or in poor mental health. PMID- 21812954 TI - Poly(I:C) promotes TNFalpha/TNFR1-dependent oligodendrocyte death in mixed glial cultures. AB - BACKGROUND: Activation of glial cells via toll-like receptors (TLRs) and other intracellular pathogen recognition receptors promotes the release of potentially toxic acute phase reactants such as TNFalpha and nitric oxide into the extracellular space. As such, prolonged glial activation, as is thought to occur during a persistent viral infection of the CNS, may contribute to both neurodegeneration and demyelination. However, the effects of virus-induced glial activation on oligodendrocytes are not fully understood. METHOD: To determine the effects of glial activation on oligodendrocyte viability we treated primary glial cultures isolated from neonatal rats or mice with the RNA viral mimic poly(I:C) and in some cases other TLR ligands. TLR3 expression was determined by western blot. Cytokine levels were measured by RT-PCR, ELISA, and intracellular cytokine staining. Oligodendrocyte precursor (preOL) viability was determined by Alamar blue assays and immunocytochemistry. RESULT: Stimulation of mixed glial cultures with poly(I:C) resulted in microglia activation, TNFalpha production and preOL toxicity. This toxic effect of poly(I:C) was indirect as it failed to affect preOL viability in pure cultures despite the fact that preOLs express TLR3. Poly(I:C)-induced loss of preOLs was abolished in TNFalpha or TNFR1 deficient mixed glial cultures, suggesting that TNFalpha/TNFR1 signaling is required for poly(I:C) toxicity. Furthermore, although both microglia and astrocytes express functional TLR3, only microglia produced TNFalpha in culture. Consistent with these findings, other TLR agonists similarly triggered TNFalpha production and preOL toxicity in mixed glial cultures. CONCLUSION: Activation of microglia by poly(I:C) promotes TNFalpha/TNFR1-dependent oligodendroglial cell death. These data indicate that during an ongoing viral infection of the CNS, microglial TNFalpha may be detrimental to oligodendrocytes. PMID- 21812955 TI - Serum estradiol levels associated with specific gene expression patterns in normal breast tissue and in breast carcinomas. AB - BACKGROUND: High serum levels of estradiol are associated with increased risk of postmenopausal breast cancer. Little is known about the gene expression in normal breast tissue in relation to levels of circulating serum estradiol. METHODS: We compared whole genome expression data of breast tissue samples with serum hormone levels using data from 79 healthy women and 64 breast cancer patients. Significance analysis of microarrays (SAM) was used to identify differentially expressed genes and multivariate linear regression was used to identify independent associations. RESULTS: Six genes (SCGB3A1, RSPO1, TLN2, SLITRK4, DCLK1, PTGS1) were found differentially expressed according to serum estradiol levels (FDR = 0). Three of these independently predicted estradiol levels in a multivariate model, as SCGB3A1 (HIN1) and TLN2 were up-regulated and PTGS1 (COX1) was down-regulated in breast samples from women with high serum estradiol. Serum estradiol, but none of the differentially expressed genes were significantly associated with mammographic density, another strong breast cancer risk factor. In breast carcinomas, expression of GREB1 and AREG was associated with serum estradiol in all cancers and in the subgroup of estrogen receptor positive cases. CONCLUSIONS: We have identified genes associated with serum estradiol levels in normal breast tissue and in breast carcinomas. SCGB3A1 is a suggested tumor suppressor gene that inhibits cell growth and invasion and is methylated and down regulated in many epithelial cancers. Our findings indicate this gene as an important inhibitor of breast cell proliferation in healthy women with high estradiol levels. In the breast, this gene is expressed in luminal cells only and is methylated in non-BRCA-related breast cancers. The possibility of a carcinogenic contribution of silencing of this gene for luminal, but not basal like cancers should be further explored. PTGS1 induces prostaglandin E2 (PGE2) production which in turn stimulates aromatase expression and hence increases the local production of estradiol. This is the first report studying such associations in normal breast tissue in humans. PMID- 21812956 TI - Mining for genotype-phenotype relations in Saccharomyces using partial least squares. AB - BACKGROUND: Multivariate approaches are important due to their versatility and applications in many fields as it provides decisive advantages over univariate analysis in many ways. Genome wide association studies are rapidly emerging, but approaches in hand pay less attention to multivariate relation between genotype and phenotype. We introduce a methodology based on a BLAST approach for extracting information from genomic sequences and Soft- Thresholding Partial Least Squares (ST-PLS) for mapping genotype-phenotype relations. RESULTS: Applying this methodology to an extensive data set for the model yeast Saccharomyces cerevisiae, we found that the relationship between genotype phenotype involves surprisingly few genes in the sense that an overwhelmingly large fraction of the phenotypic variation can be explained by variation in less than 1% of the full gene reference set containing 5791 genes. These phenotype influencing genes were evolving 20% faster than non-influential genes and were unevenly distributed over cellular functions, with strong enrichments in functions such as cellular respiration and transposition. These genes were also enriched with known paralogs, stop codon variations and copy number variations, suggesting that such molecular adjustments have had a disproportionate influence on Saccharomyces yeasts recent adaptation to environmental changes in its ecological niche. CONCLUSIONS: BLAST and PLS based multivariate approach derived results that adhere to the known yeast phylogeny and gene ontology and thus verify that the methodology extracts a set of fast evolving genes that capture the phylogeny of the yeast strains. The approach is worth pursuing, and future investigations should be made to improve the computations of genotype signals as well as variable selection procedure within the PLS framework. PMID- 21812957 TI - Catheterization and embolization of a replaced left hepatic artery via the right gastric artery through the anastomosis: a case report. AB - INTRODUCTION: Conversion of multiple hepatic arteries into a single vascular supply is a very important technique for repeat hepatic arterial infusion chemotherapy using an implanted port catheter system. Catheterization of a replaced left hepatic artery arising from a left gastric artery using a percutaneous catheter technique is sometimes difficult, despite the recent development of advanced interventional techniques. CASE PRESENTATION: We present a case of a 70-year-old Japanese man with multiple hepatocellular carcinomas in whom the replaced left hepatic artery arising from the left gastric artery needed to be embolized. After several failed procedures, the replaced left hepatic artery was successfully catheterized and embolized with a microcatheter and microcoils via the right gastric artery through the anastomosis. CONCLUSION: A replaced left hepatic artery arising from a left gastric artery can be catheterized via a right gastric artery by using the appropriate microcatheter and microguidewires, and multiple hepatic arteries can be converted into a single supply. PMID- 21812958 TI - Renal cell carcinoma metastasis to the ciliary body responds to proton beam radiotherapy: a case report. AB - INTRODUCTION: We report an unexpected presentation of metastatic renal cell carcinoma (RCC) to the ciliary body and an interesting response to proton beam radiotherapy. CASE PRESENTATION: We encountered a case of angle-closure glaucoma as the initial presentation of ocular metastasis to the ciliary body in a 65-year old Caucasian man who had undergone right radical nephrectomy for RCC 15 years earlier. He underwent YAG (yttrium aluminium garnet) laser peripheral iridotomy while further metastatic workup took place. His condition was eventually diagnosed as stage IV metastatic RCC of the clear cell type and involved multiple sites, including the ciliary body, brain, lungs, liver, and pancreas. The progression of RCC metastasis to the ciliary body was studied for 16 months. The ciliary body mass continued to grow despite systemic treatment with temsirolimus and interleukin-2 and intravitreal injections of bevacizumab. The tumor size peaked at 6.11 * 6.06 mm before the start of proton therapy, which reduced the tumor size to 5.07 * 4.39 mm. CONCLUSIONS: RCC can produce metastases involving unusual sites many years after resection of the primary tumor. Proton therapy was found to be effective in treating RCC metastasis to the ciliary body in settings in which other treatment modalities failed. PMID- 21812959 TI - Synchronous double primary malignant tumor of the gallbladder and liver: a case report. AB - We report a case of synchronous double primary tumor of gallbladder and liver. A 63-year-old male was admitted to the hospital complaining of abdominal discomfort. Enhanced computed tomography of the abdomen showed acute cholecystitis with tiny gallbladder stones and a 2.2 cm size enhanced nodule in the left lobe of the liver. Under the impression of acute cholecystitis with gall bladder stones and hepatocellular carcinoma of the left Liver, the patient underwent a laparotomy. At laparotomy, a mass was palpated on the surface of the neck portion of the gall bladder. Intraoperative frozen diagnosis revealed adenocarcinoma of the gall bladder. The patient was diagnosed as having gall bladder cancer and hepatocellular carcinoma, so extended cholecystectomy with dissection of regional lymph nodes and left hemihepatectomy were performed. Histological examination revealed moderated differentiated adenocarcinoma of gallbladder and hepatocellular carcinoma of liver. To our knowledge, the simultaneous occurrence of primary malignant tumor of the gallbladder and liver has never been published before. The patient is doing well with no evidence of recurrence 17 months after surgery. PMID- 21812960 TI - Identification of nursing assessment models/tools validated in clinical practice for use with diverse ethno-cultural groups: an integrative review of the literature. AB - BACKGROUND: High income nations are currently exhibiting increasing ethno cultural diversity which may present challenges for nursing practice. We performed an integrative review of literature published in North America and Europe between 1990 and 2007, to map the state of knowledge and to identify nursing assessment tools/models which are have an associated research or empirical perspective in relation to ethno-cultural dimensions of nursing care. METHODS: Data was retrieved from a wide variety of sources, including key electronic bibliographic databases covering research in biomedical fields, nursing and allied health, and culture, e.g. CINAHL, MEDline, PUBmed, Cochrane library, PsycINFO, Web of Science, and HAPI. We used the Critical Appraisal Skills Programme tools for quality assessment. We applied Torraco's definition and method of an integrative review that aims to create new knowledge and perspectives on a given phenomena. To add methodological rigor with respect to the search strategy and other key review components we also used the principles established by the Centre for Reviews and Dissemination. RESULTS: Thirteen thousand and thirteen articles were retrieved, from which 53 full papers were assessed for inclusion. Eight papers met the inclusion criteria, describing research on a total of eight ethno-cultural assessment tools/models. The tools/models are described and synthesized. CONCLUSIONS: While many ethno cultural assessment tools exist to guide nursing practice, few are informed by research perspectives. An increased focus on the efficiency and effectiveness of health services, patient safety, and risk management, means that provision of culturally responsive and competent health services will inevitably become paramount. PMID- 21812961 TI - Prenatal testosterone-induced fetal growth restriction is associated with down regulation of rat placental amino acid transport. AB - BACKGROUND: Exposure of pregnant mothers to elevated concentrations of circulating testosterone levels is associated with fetal growth restriction and delivery of small-for-gestational-age babies. We examined whether maternal testosterone crosses the placenta to directly suppress fetal growth or if it modifies placental function to reduce the capacity for transport of nutrients to the fetus. METHODS: Pregnant rats were exposed to testosterone propionate (TP; 0.5 mg/kg) by daily subcutaneous injection from gestational days (GD) 15-19. Maternal and fetal testosterone levels, placental nutrient transport activity and expression of transporters and birth weight of pups and their anogenital distances were determined. RESULTS: This dose of TP doubled maternal testosterone levels but had no effect on fetal testosterone levels. Maternal daily weight gain was significantly lower only on GD 19 in TP treated dams compared to controls. Placental weight and birth weight of pups were significantly reduced, but the anogenital distance of pups were unaffected by TP treatment. Maternal plasma amino acids concentrations were altered following testosterone exposure, with decreases in glutamine, glycine, tyrosine, serine, proline, and hydroxyproline and increases in asparagine, isoleucine, leucine, lysine, histidine and arginine. In the TP dams, placental system A amino acid transport activity was significantly reduced while placental glucose transport capacity was unaffected. Decreased expression of mRNA and protein levels of slc38a2/Snat2, an amino acid transporter, suggests that reduced transporter proteins may be responsible for the decrease in amino acid transport activity. CONCLUSIONS: Taken together, these data suggest that increased maternal testosterone concentrations do not cross the placenta to directly suppress fetal growth but affects amino acid nutrient delivery to the fetus by downregulating specific amino acid transporter activity. PMID- 21812962 TI - Can changes in health related quality of life scores predict survival in stages III and IV colorectal cancer? AB - BACKGROUND: Several studies have demonstrated the predictive significance on survival of baseline quality of life (QoL) in colorectal cancer (CRC) with little information on the impact of changes in QoL scores on prognosis in CRC. We investigated whether changes in QoL during treatment could predict survival in CRC. METHODS: We evaluated 396 stages III-IV CRC patients available for a minimum follow-up of 3 months. QoL was evaluated at baseline and after 3 months of treatment using EORTC QLQ-C30. Cox regression evaluated the prognostic significance of baseline, 3-month and changes in QoL scores after adjusting for age, gender and stage at diagnosis. RESULTS: After adjusting for covariates, every 10-point increase in both baseline appetite loss and global QoL score was associated with a 7% increased risk of death with HR = 1.07 (95% CI, 1.01-1.14; P = 0.02) and (HR = 0.93 (95% CI, 0.87-0.98; P = 0.01) respectively. A lower risk of death was associated with a 10-point improvement in physical function at 3 months (HR, 0.86; 95% CI, 0.78-0.94; P = 0.001). Surprisingly, a higher risk of death was associated with a 10-point improvement in social function at 3 months (HR, 1.08; 95% CI, 1.02-1.13; P = 0.008). CONCLUSIONS: This study provides preliminary evidence to indicate that CRC patients whose physical function improves within 3 months of treatment have a significantly increased probability of survival. These findings should be used in clinical practice to systematically address QoL-related problems of CRC patients throughout their treatment course. PMID- 21812963 TI - Chronic kidney disease in gout in a managed care setting. AB - BACKGROUND: To study the prevalence of chronic kidney disease (CKD) and its impact on allopurinol dosing and uric acid control among patients with gout. METHODS: This was a retrospective study using data from a large US health plan. Claims and laboratory data were analyzed for enrollees from the health plan database from January 2002 through December 2005. Patients with gout were identified from pharmacy and medical claims data based on the presence of codes for gout medication or gout diagnosis. Severity of CKD was determined using the estimated glomerular filtration rate (eGFR). Allopurinol titration was defined as a change in average daily dose from first prescription to last prescription of >= 50 mg. RESULTS: A total of 3,929 patients were identified for inclusion in this study, 39% of whom had CKD (based on having an eGFR < 90 mL/min/1.73 m2). Subjects with CKD were older (p < 0.01) and more likely to be women (p < 0.01), had a greater number of comorbid conditions (p < 0.01), and were more likely to be prescribed allopurinol (p < 0.01) compared to those with no CKD. The average starting dose of allopurinol was lower among those with CKD, and it decreased with worsening kidney function. Among the 3,122 gout patients who used allopurinol, only 25.6% without CKD and 22.2% with CKD achieved a serum uric acid concentration of < 6.0 mg/dL (p = 0.0409). Also, only 15% of allopurinol users had an upward dose titration (by >=50 mg), but the average increase in dose did not differ significantly between those with and without CKD. CONCLUSIONS: About two out of every five patients with gout in this population had CKD. Allopurinol doses were not adjusted in the majority of CKD patients. Serum uric acid control in gout was poor among patients without CKD and even worse among those with CKD. PMID- 21812964 TI - Analysis of the melon (Cucumis melo) small RNAome by high-throughput pyrosequencing. AB - BACKGROUND: Melon (Cucumis melo L.) is a commercially important fruit crop that is cultivated worldwide. The melon research community has recently benefited from the determination of a complete draft genome sequence and the development of associated genomic tools, which have allowed us to focus on small RNAs (sRNAs). These are short, non-coding RNAs 21-24 nucleotides in length with diverse physiological roles. In plants, they regulate gene expression and heterochromatin assembly, and control protection against virus infection. Much remains to be learned about the role of sRNAs in melon. RESULTS: We constructed 10 sRNA libraries from two stages of developing ovaries, fruits and photosynthetic cotyledons infected with viruses, and carried out high-throughput pyrosequencing. We catalogued and analysed the melon sRNAs, resulting in the identification of 26 known miRNA families (many conserved with other species), the prediction of 84 melon-specific miRNA candidates, the identification of trans-acting siRNAs, and the identification of chloroplast, mitochondrion and transposon-derived sRNAs. In silico analysis revealed more than 400 potential targets for the conserved and novel miRNAs. CONCLUSION: We have discovered and analysed a large number of conserved and melon-specific sRNAs, including miRNAs and their potential target genes. This provides insight into the composition and function of the melon small RNAome, and paves the way towards an understanding of sRNA-mediated processes that regulate melon fruit development and melon-virus interactions. PMID- 21812965 TI - Visualization of plant viral suppressor silencing activity in intact leaf lamina by quantitative fluorescent imaging. AB - BACKGROUND: Transient expression of proteins in plants has become a favoured method over the production of stably transformed plants because, in addition to enabling high protein yields, it is both fast and easy to apply. An enhancement of transient protein expression can be achieved by plant virus-encoded RNA silencing suppressor proteins. Since viral suppressor proteins differ in their efficiency to enhance transient protein expression in plants, we developed a whole-leaf green fluorescent protein (GFP)-based imaging assay to quantitatively assess suppressor protein activity. RESULTS: In a transient GFP-expression assay using wild-type and GFP-transgenic N. benthamiana, addition of the plant viral suppressors Beet mild yellowing virus (BMYV-IPP) P0 or Plum pox virus (PPV) HC Pro was shown to increase fluorescent protein expression 3-4-fold, 7 days post inoculation (dpi) when compared to control plants. In contrast, in agroinfiltrated patches without suppressor activity, near complete silencing of the GFP transgene was observed in the transgenic N. benthamiana at 21 dpi. Both co-infiltrated suppressors significantly enhanced GFP expression over time, with HC-Pro co-infiltrations leading to higher short term GFP fluorescence (at 7 dpi) and P0 giving higher long term GFP fluorescence (at 21 dpi). Additionally, in contrast to HC-Pro co-infiltrations, an area of complete GFP silencing was observed at the edge of P0 co-infiltrated areas. CONCLUSIONS: Fluorescence imaging of whole intact leaves proved to be an easy and effective method for spatially and quantitatively observing viral suppressor efficiency in plants. This suppressor assay demonstrates that plant viral suppressors greatly enhanced transient GFP expression, with P0 showing a more prolonged suppressor activity over time than HC-Pro. Both suppressors could prove to be ideal candidates for enhancing target protein expression in plants. PMID- 21812967 TI - Region-specific tauopathy and synucleinopathy in brain of the alpha-synuclein overexpressing mouse model of Parkinson's disease. AB - BACKGROUND: alpha-synuclein [alpha-Syn]-mediated activation of GSK-3beta leading to increases in hyperphosphorylated Tau has been shown by us to occur in striata of Parkinson's diseased [PD] patients and in animal models of PD. In Alzheimer's disease, tauopathy exists in several brain regions; however, the pattern of distribution of tauopathy in other brain regions of PD or in animal models of PD is not known. The current studies were undertaken to analyze the distribution of tauopathy in different brain regions in a widely used mouse model of PD, the alpha-Syn overexpressing mouse. RESULTS: High levels of alpha-Syn levels were seen in the brain stem, with a much smaller increase in the frontal cortex; neither cerebellum nor hippocampus showed any overexpression of alpha-Syn. Elevated levels of p-Tau, hyperphosphorylated at Ser202, Ser262 and Ser396/404, were seen in brain stem, with lower levels seen in hippocampus. In both frontal cortex and cerebellum, increases were seen only in p-Ser396/404 Tau, but not in p Ser202 and p-Ser262. p-GSK-3beta levels were not elevated in any of the brain regions, although total GSK-3beta was elevated in brain stem. p-p38MAPK levels were unchanged in all brain regions examined, while p-ERK levels were elevated in brain stem, hippocampus and cerebellum, but not the frontal cortex. p-JNK levels were increased in brain stem and cerebellum but not in the frontal cortex or hippocampus. Elevated levels of free tubulin, indicating microtubule destabilization, were seen only in the brain stem. CONCLUSION: Our combined data suggest that in this animal model of PD, tauopathy, along with microtubule destabilization, exists primarily in the brain stem and striatum, which are also the two major brain regions known to express high levels of alpha-Syn and undergo the highest levels of degeneration in human PD. Thus, tauopathy in PD may have a very restricted pattern of distribution. PMID- 21812966 TI - Targeting surface nucleolin with multivalent HB-19 and related Nucant pseudopeptides results in distinct inhibitory mechanisms depending on the malignant tumor cell type. AB - BACKGROUND: Nucleolin expressed at the cell surface is a binding protein for a variety of ligands implicated in tumorigenesis and angiogenesis. By using a specific antagonist that binds the C-terminal RGG domain of nucleolin, the HB-19 pseudopeptide, we recently reported that targeting surface nucleolin with HB-19 suppresses progression of established human breast tumor cells in the athymic nude mice, and delays development of spontaneous melanoma in the RET transgenic mice. METHODS: By the capacity of HB-19 to bind stably surface nucleolin, we purified and identified nucleolin partners at the cell surface. HB-19 and related multivalent Nucant pseudopeptides, that present pentavalently or hexavalently the tripeptide Lyspsi(CH2N)-Pro-Arg, were then used to show that targeting surface nucleolin results in distinct inhibitory mechanisms on breast, prostate, colon carcinoma and leukemia cells. RESULTS: Surface nucleolin exists in a 500-kDa protein complex including several other proteins, which we identified by microsequencing as two Wnt related proteins, Ku86 autoantigen, signal recognition particle subunits SRP68/72, the receptor for complement component gC1q-R, and ribosomal proteins S4/S6. Interestingly, some of the surface-nucleolin associated proteins are implicated in cell signaling, tumor cell adhesion, migration, invasion, cell death, autoimmunity, and bacterial infections. Surface nucleolin in the 500-kDa complex is highly stable. Surface nucleolin antagonists, HB-19 and related multivalent Nucant pseudopeptides, exert distinct inhibitory mechanisms depending on the malignant tumor cell type. For example, in epithelial tumor cells they inhibit cell adhesion or spreading and induce reversion of the malignant phenotype (BMC cancer 2010, 10:325) while in leukemia cells they trigger a rapid cell death associated with DNA fragmentation. The fact that these pseudopeptides do not cause cell death in epithelial tumor cells indicates that cell death in leukemia cells is triggered by a specific signaling mechanism, rather than nonspecific cellular injury. CONCLUSIONS: Our results suggest that targeting surface nucleolin could change the organization of the 500-kDa complex to interfere with the proper functioning of surface nucleolin and the associated proteins, and thus lead to distinct inhibitory mechanisms. Consequently, HB-19 and related Nucant pseudopeptides provide novel therapeutic opportunities in treatment of a wide variety of cancers and related malignancies. PMID- 21812968 TI - The prevalence of suicidal ideation identified by the Edinburgh Postnatal Depression Scale in postpartum women in primary care: findings from the RESPOND trial. AB - BACKGROUND: Suicide is a leading cause of perinatal maternal deaths in industrialised countries but there has been little research to investigate prevalence or correlates of postpartum suicidality. The Edinburgh Postnatal Depression Scale is widely used in primary and maternity services to screen for perinatal depressive disorders, and includes a question on suicidal ideation (question 10). We aimed to investigate the prevalence, persistence and correlates of suicidal thoughts in postpartum women in the context of a randomised controlled trial of treatments for postnatal depression. METHODS: Women in primary care were sent postal questionnaires at 6 weeks postpartum to screen for postnatal depression before recruitment into an RCT. The Edinburgh Postnatal Depression Scale (EPDS) was used to screen for postnatal depression and in those with high levels of symptoms, a home visit with a standardised psychiatric interview was carried out using the Clinical Interview Schedule-Revised version (CIS-R). Other socio-demographic and clinical variables were measured, including functioning (SF12) and quality of the marital relationship (GRIMS). Women who entered the trial were followed up for 18 weeks. RESULTS: 9% of 4,150 women who completed the EPDS question relating to suicidal ideation reported some suicidal ideation (including hardly ever); 4% reported that the thought of harming themselves had occurred to them sometimes or quite often. In women who entered the randomised trial and completed the EPDS question relating to suicidal ideation (n = 253), suicidal ideation was associated with younger age, higher parity and higher levels of depressive symptoms in the multivariate analysis. Endorsement of 'yes, quite often' to question 10 on the EPDS was associated with affirming at least two CIS-R items on suicidality. We found no association between suicidal ideation and SF-12 physical or mental health or the EPDS total score at 18 weeks. CONCLUSIONS: Healthcare professionals using the EPDS should be aware of the significant suicidality that is likely to be present in women endorsing 'yes, quite often' to question 10 of the EPDS. However, suicidal ideation does not appear to predict poor outcomes in women being treated for postnatal depression. TRIAL REGISTRATION: Current Controlled Trials ISRCTN16479417. PMID- 21812969 TI - Genome-wide association study identifies candidate genes for Parkinson's disease in an Ashkenazi Jewish population. AB - BACKGROUND: To date, nine Parkinson disease (PD) genome-wide association studies in North American, European and Asian populations have been published. The majority of studies have confirmed the association of the previously identified genetic risk factors, SNCA and MAPT, and two studies have identified three new PD susceptibility loci/genes (PARK16, BST1 and HLA-DRB5). In a recent meta-analysis of datasets from five of the published PD GWAS an additional 6 novel candidate genes (SYT11, ACMSD, STK39, MCCC1/LAMP3, GAK and CCDC62/HIP1R) were identified. Collectively the associations identified in these GWAS account for only a small proportion of the estimated total heritability of PD suggesting that an 'unknown' component of the genetic architecture of PD remains to be identified. METHODS: We applied a GWAS approach to a relatively homogeneous Ashkenazi Jewish (AJ) population from New York to search for both 'rare' and 'common' genetic variants that confer risk of PD by examining any SNPs with allele frequencies exceeding 2%. We have focused on a genetic isolate, the AJ population, as a discovery dataset since this cohort has a higher sharing of genetic background and historically experienced a significant bottleneck. We also conducted a replication study using two publicly available datasets from dbGaP. The joint analysis dataset had a combined sample size of 2,050 cases and 1,836 controls. RESULTS: We identified the top 57 SNPs showing the strongest evidence of association in the AJ dataset (p < 9.9 * 10(-5)). Six SNPs located within gene regions had positive signals in at least one other independent dbGaP dataset: LOC100505836 (Chr3p24), LOC153328/SLC25A48 (Chr5q31.1), UNC13B (9p13.3), SLCO3A1(15q26.1), WNT3(17q21.3) and NSF (17q21.3). We also replicated published associations for the gene regions SNCA (Chr4q21; rs3775442, p = 0.037), PARK16 (Chr1q32.1; rs823114 (NUCKS1), p = 6.12 * 10(-4)), BST1 (Chr4p15; rs12502586, p = 0.027), STK39 (Chr2q24.3; rs3754775, p = 0.005), and LAMP3 (Chr3; rs12493050, p = 0.005) in addition to the two most common PD susceptibility genes in the AJ population LRRK2 (Chr12q12; rs34637584, p = 1.56 * 10(-4)) and GBA (Chr1q21; rs2990245, p = 0.015). CONCLUSIONS: We have demonstrated the utility of the AJ dataset in PD candidate gene and SNP discovery both by replication in dbGaP datasets with a larger sample size and by replicating association of previously identified PD susceptibility genes. Our GWAS study has identified candidate gene regions for PD that are implicated in neuronal signalling and the dopamine pathway. PMID- 21812970 TI - Primary sarcoma of the pancreas, a rare histopathological entity. A case report with review of literature. AB - AIMS: primary pancreatic sarcomas represent an extremely rare histopathological entity accounting for less than 0.1% of all pancreatic malignancies. Pancreatic sarcomas tend to be more aggressive and have a poor prognosis. METHODS: the case of a 52 year old patient presenting with jaundice is presented and the available literature was reviewed. RESULTS: primary pancreatic sarcomas are extremely rare. Pancreatic sarcomas are more aggressive than other pancreatic neoplasms. CONCLUSION: primary sarcomas of the pancreas are extremely rare, are aggressive and are associated with very poor prognosis. PMID- 21812971 TI - Allele-specific transcriptional elongation regulates monoallelic expression of the IGF2BP1 gene. AB - BACKGROUND: Random monoallelic expression contributes to phenotypic variation of cells and organisms. However, the epigenetic mechanisms by which individual alleles are randomly selected for expression are not known. Taking cues from chromatin signatures at imprinted gene loci such as the insulin-like growth factor 2 gene 2 (IGF2), we evaluated the contribution of CTCF, a zinc finger protein required for parent-of-origin-specific expression of the IGF2 gene, as well as a role for allele-specific association with DNA methylation, histone modification and RNA polymerase II. RESULTS: Using array-based chromatin immunoprecipitation, we identified 293 genomic loci that are associated with both CTCF and histone H3 trimethylated at lysine 9 (H3K9me3). A comparison of their genomic positions with those of previously published monoallelically expressed genes revealed no significant overlap between allele-specifically expressed genes and colocalized CTCF/H3K9me3. To analyze the contributions of CTCF and H3K9me3 to gene regulation in more detail, we focused on the monoallelically expressed IGF2BP1 gene. In vitro binding assays using the CTCF target motif at the IGF2BP1 gene, as well as allele-specific analysis of cytosine methylation and CTCF binding, revealed that CTCF does not regulate mono- or biallelic IGF2BP1 expression. Surprisingly, we found that RNA polymerase II is detected on both the maternal and paternal alleles in B lymphoblasts that express IGF2BP1 primarily from one allele. Thus, allele-specific control of RNA polymerase II elongation regulates the allelic bias of IGF2BP1 gene expression. CONCLUSIONS: Colocalization of CTCF and H3K9me3 does not represent a reliable chromatin signature indicative of monoallelic expression. Moreover, association of individual alleles with both active (H3K4me3) and silent (H3K27me3) chromatin modifications (allelic bivalent chromatin) or with RNA polymerase II also fails to identify monoallelically expressed gene loci. The selection of individual alleles for expression occurs in part during transcription elongation. PMID- 21812972 TI - Extensive permethrin and DDT resistance in Anopheles arabiensis from eastern and central Sudan. AB - BACKGROUND: The distribution of insecticide treated nets (ITN) has been dramatically scaled up in eastern and central Sudan. Resistance to insecticides has already been reported in this region and there is an urgent need to develop appropriate resistance management strategies, which requires detailed information on the extent and causes of resistance. This study assessed resistance to permethrin and DDT in seven populations of Anopheles arabiensis from Sudan. RESULTS: Three out of the seven populations were defined as resistant to permethrin and five of six populations resistant to DDT according to WHO criteria. The 1014F kdr allele was present in all six populations tested and the presence of this allele was significantly correlated with resistance to permethrin (P = 0.0460). While homozygous 1014F individuals were statistically not more likely to survive (53.7%) permethrin than to be killed (38.6%) by the diagnostic dose, there was no difference in the likelihood of permethrin survival in heterozygotes (P = 0.7973). The susceptible genotypes were more likely to be killed by permethrin exposure than to survive (P = 0.0460). The 1014F allele failed to confer a survival advantage to the WHO diagnostic dose of DDT in either the homozygous or heterozygous state. The 1014S allele was not detected in any of the populations tested. CONCLUSION: The kdr allele is certainly contributing to the extensive resistance to permethrin and DDT in Sudan but the high number of DDT (43%) and permethrin (16.7%) survivors that did not contain either kdr alleles suggests that other resistance mechanisms are also present in these populations. The high frequency of permethrin resistance throughout central and eastern Sudan is a cause of great concern for malaria control activities. PMID- 21812973 TI - Recurrent locked knee caused by an impaction fracture following inferior patellar dislocation: a case report. AB - INTRODUCTION: Locked knee caused by inferior patellar dislocation is considered rare in elderly patients. It was originally thought that, in the osteoarthritic knee, osteophytes on the pole of the patella become entrapped in the inter condylar notch, which is managed by performing closed reduction and immobilization in a knee splint for three to four weeks. We present an unusual case of a locked knee with an impaction fracture. To the best of our knowledge, there have been no previous reports of such impaction fractures managed with arthroscopy. CASE PRESENTATION: We present an unusual case of an 88-year-old Caucasian woman with moderate arthritis who had a locked knee caused by an impaction fracture of the patella into the lateral femoral condyle. In this case report, we describe the need for arthroscopic surgery to prevent relocking of the knee in these patients. CONCLUSIONS: This case report emphasizes the need for careful assessment of locked knees in elderly patients. Impaction fractures should be considered in all rare cases of patellar dislocation, and we advocate arthroscopic assessment of the articular cartilage in these patients. This is an important consideration, as the population demographics change and such impaction fractures may become more common in patients with degeneration in the knees. PMID- 21812974 TI - Successful pregnancy outcome after laparoscopic-assisted excision of a bizarre leiomyoma: a case report. AB - INTRODUCTION: Bizarre leiomyoma is a rare leiomyoma variant that requires a precise histopathological evaluation. Especially when diagnosed in a younger woman, this tumor leads to challenging treatment issues involving fertility preservation. Owing to the low incidence of bizarre leiomyoma, there is insufficient evidence to support myomectomy alone as an appropriate management option. Also, the impact of bizarre leiomyoma on fertility is not well known. CASE PRESENTATION: A 30-year-old Japanese woman who had never given birth was referred to us because of a uterine tumor with an unusual diagnostic image and was treated by a gasless laparoscopic-assisted excision with a wound retractor. Owing to an unclear margin between her uterine tumor and myometrium, a concomitant excision of adjacent myometrial tissue was required to achieve the maximum resection of her tumor. The histopathological diagnosis was bizarre leiomyoma. Seven months later, she conceived spontaneously and her pregnancy course was uneventful. At 37 weeks of gestation, an elective cesarean section was performed. Although a slight omental adhesion was noted at the postexcisional scar, her uterine wall structure was well preserved and a recurrence of bizarre leiomyoma was not noted. CONCLUSIONS: A laparoscopic-assisted excision of bizarre leiomyoma is a feasible and minimally invasive conservative measure for a woman who wishes to preserve fertility. PMID- 21812975 TI - Pathways leading to coronary revascularisation among patients with diabetes in Finland: a longitudinal register-based study. AB - BACKGROUND: Chronic conditions such as coronary heart disease (CHD) challenge health care to provide systematic and long-lasting disease management. In this study of patients who were revascularized, we examine whether treatment pathways leading to coronary revascularisation differ between patients with and without diabetes. METHODS: This retrospective, nationwide register-based study in Finland in 1998-2007 describes temporal trends in the proportions of 1) revascularisations performed at the first treatment period, and 2) suboptimal treatment pathways to revascularisations, i.e. pathways containing several cardiac emergency hospitalisations. Differences between patient groups were examined using a logistic regression model adjusting for age, comorbidity, and region. RESULTS: Among patients who underwent revascularisation, upward trends were found in the proportions of revascularisations performed during first hospital admission: among men with CHD alone, the percentages were 28% in 1998 and 77% in 2007; among men with insulin-dependent diabetes (IDD) they were 16% vs. 58% for the respective years; and among men with non-insulin dependent diabetes (NIDD) they were 25% vs. 69%, respectively. Among women the percentages were for non-diabetic group 32% vs. 77%; for IDD group 36% vs. 64%; and for NIDD group 33% vs. 73% for the respective years. Patients with diabetes were less likely to undergo revascularisation during the first hospital admission, in 2005 2007, the odds ratio (OR) for IDD among men was 0.52 (95% confidence interval 0.42-0.64) and for NIDD among men it was 0.79 (95% CI 0.73-0.86) compared to patients with CHD alone. The respective ORs among women were 0.59 (95% CI 0.44 0.78), and 0.83 (95% CI 0.74-0.93). CONCLUSIONS: Treatment practices changed substantially during the study period to favour performing revascularisation during the first hospital admission. The large increase in coronary angioplasty operations is likely to be an important factor behind these changes. However, fewer operations are performed during the first CHD hospitalisation of diabetic patients who undergo coronary revascularisation and they experience more often emergency hospital admissions before the operation than patients without diabetes. To avoid adverse cardiac events, more attention is needed in managing diabetic CHD patients' referral pathways to revascularisation. PMID- 21812976 TI - Mode shifting in school travel mode: examining the prevalence and correlates of active school transport in Ontario, Canada. AB - BACKGROUND: Studies examining the correlates of school transport commonly fail to make the distinction between morning and afternoon school trips. The purpose of this study was to examine the prevalence and correlates of mode shift from passive in the morning to active in the afternoon among elementary and secondary school students in Ontario, Canada. METHODS: Data were derived from the 2009 cycle of the Ontario Student Drug Use and Health Survey (OSDUHS). 3,633 students in grades 7 through 12 completed self-administered questionnaires. Socio demographic, behavioural, psychological, and environmental predictors of active school transport (AST) were assessed using logistic regression. RESULTS: Overall, 47% and 38% of elementary school students reported AST to and from school, respectively. The corresponding figures were 23% and 32% for secondary school students. The prevalence of AST varied temporarily and spatially. There was a higher prevalence of walking/biking found for elementary school students than for secondary school students, and there was an approximate 10% increase in AST in the afternoon. Different correlates of active school transport were also found across elementary and secondary school students. For all ages, students living in urban areas, with a shorter travel time between home and school, and having some input to the decision making process, were more likely to walk to and from school. CONCLUSIONS: Future research examining AST should continue to make the analytic distinction between the morning and afternoon trip, and control for the moderating effect of age and geography in predicting mode choice. In terms of practice, these variations highlight the need for school-specific travel plans rather than 'one size fits all' interventions in promoting active school transport. PMID- 21812977 TI - Biochemical study of oxidative stress markers in the liver, kidney and heart of high fat diet induced obesity in rats. AB - BACKGROUND: Obesity has become a leading global health problem owing to its strong association with a high incidence of diseases. AIM: To induce rat obesity using high fat diet (HFD) and to estimate oxidative stress markers in their liver, heart and kidney tissues in order to shed the light on the effect of obesity on these organs. MATERIALS AND METHODS: Sixty white albino rats weighing 150-200 g were randomly divided into two equal groups; group I: received high fat diet for 16 weeks, and group II (control group): received only normal diet (rat chow) for 16 weeks. Blood samples were taken for measurement of lipid profile, tissue samples from liver, heart and kidney were taken for determination of malondialdehyde (MDA), protein carbonyl (PCO), reduced glutathione (GSH) levels, and the activities of glutathione S- transferase (GST) glutathione peroxidase (GPx), catalase (CAT) and paraoxonase1 (PON1) enzymes. RESULTS: Data showed that feeding HFD diet significantly increased final body weight and induced a state of dyslipideamia. Also our results showed a significant increase MDA and PCO levels in the hepatic, heart and renal tissues of obese rats, as well as a significant decrease in the activity of GST, GPx and PON 1 enzymes. On the other hand CAT enzyme activity showed significant decrease only in renal tissues of obese rats with non significant difference in hepatic and heart tissues. GSH levels showed significant decrease in both renal and hepatic tissues of obese animals and significant increase in their heart tissues. Correlation studies in obese animals showed a negative correlation between MDA and PCO tissue levels and the activities of GPx, GST and PON1 in all tissues and also with CAT enzyme activity in renal tissues. Also a negative correlation was detected between MDA & PCO tissues levels and GSH levels in both hepatic and renal tissues. While positive correlation was found between them and GSH levels in heart tissues. CONCLUSION: High fat diet-induced obesity is accompanied by increased hepatic, heart, and renal tissues oxidative stress, which is characterized by reduction in the antioxidant enzymes activities and glutathione levels, that correlate with the increase in MDA and PCO levels in most tissues. This may probably contribute to the additional progression of obesity related problems. PMID- 21812978 TI - Low bone mineral density in men with chronic obstructive pulmonary disease. AB - BACKGROUND: Osteoporosis is common in patients with COPD but the likely multi factorial causes contributing to this condition (e.g. sex, age, smoking, therapy) mask the potential contribution from elements related to COPD. In order to study osteoporosis and bone mineral density (BMD) related to COPD, we studied a well defined group of patients and controls. METHODS: BMD, forced expiratory volume in one second (FEV1), circulating bone biomarkers and biochemistry were determined in 30 clinically stable male ex-smokers with confirmed COPD and 15 age matched "ex-smoker" male controls. None of the patients were on inhaled corticosteroids or received more than one short course of steroids. RESULTS: Mean (SD) FEV1% predicted of patients was 64(6)%, the majority having Global Initiative for Chronic Obstructive Lung Disease (GOLD) II airflow obstruction. There were 5/30 patients and 1/15 controls who were osteoporotic, while a further 17 patients and 5 controls were osteopenic. The BMD at the hip was lower in patients than controls, but not at the lumbar spine. Mean values of procollagen type 1 amino terminal propeptide and osteocalcin, both markers of bone formation, and Type 1 collagen beta C-telopeptide, a marker of bone resorption, were similar between patients and controls. However, all bone biomarkers were inversely related to hip BMD in patients (r = -0.51, r = -0.67, r = -0.57, p < 0.05) but did not relate to lumbar spine BMD. 25-OH Vitamin D was lower in patients. CONCLUSIONS: Men with COPD had a greater prevalence of osteoporosis and osteopenia than age matched male controls, with a marked difference in BMD at the hip. Bone biomarkers suggest increased bone turnover. PMID- 21812979 TI - New non-randomised model to assess the prevalence of discriminating behaviour: a pilot study on mephedrone. AB - BACKGROUND: An advantage of randomised response and non-randomised models investigating sensitive issues arises from the characteristic that individual answers about discriminating behaviour cannot be linked to the individuals. This study proposed a new fuzzy response model coined 'Single Sample Count' (SSC) to estimate prevalence of discriminating or embarrassing behaviour in epidemiologic studies. METHODS: The SSC was tested and compared to the established Forced Response (FR) model estimating Mephedrone use. Estimations from both SSC and FR were then corroborated with qualitative hair screening data. Volunteers (n = 318, mean age = 22.69 +/- 5.87, 59.1% male) in a rural area in north Wales and a metropolitan area in England completed a questionnaire containing the SSC and FR in alternating order, and four questions canvassing opinions and beliefs regarding Mephedrone. Hair samples were screened for Mephedrone using a qualitative Liquid Chromatography-Mass Spectrometry method. RESULTS: The SSC algorithm improves upon the existing item count techniques by utilizing known population distributions and embeds the sensitive question among four unrelated innocuous questions with binomial distribution. Respondents are only asked to indicate how many without revealing which ones are true. The two probability models yielded similar estimates with the FR being between 2.6% - 15.0%; whereas the new SSC ranged between 0% - 10%. The six positive hair samples indicated that the prevalence rate in the sample was at least 4%. The close proximity of these estimates provides evidence to support the validity of the new SSC model. Using simulations, the recommended sample sizes as the function of the statistical power and expected prevalence rate were calculated. CONCLUSION: The main advantages of the SSC over other indirect methods are: simple administration, completion and calculation, maximum use of the data and good face validity for all respondents. Owing to the key feature that respondents are not required to answer the sensitive question directly, coupled with the absence of forced response or obvious self-protective response strategy, the SSC has the potential to cut across self-protective barriers more effectively than other estimation models. This elegantly simple, quick and effective method can be successfully employed in public health research investigating compromising behaviours. PMID- 21812980 TI - Luteal and placental function in the bitch: spatio-temporal changes in prolactin receptor (PRLr) expression at dioestrus, pregnancy and normal and induced parturition. AB - BACKGROUND: Endocrine mechanisms governing canine reproductive function remain still obscure. Progesterone (P4) of luteal origin is required for maintenance of pregnancy. Corpora lutea (CL) are gonadotrop-independent during the first third of dioestrus; afterwards prolactin (PRL) is the primary luteotropic factor. Interestingly, the increasing PRL levels are accompanied by decreasing P4 concentrations, thus luteal regression/luteolysis occurs in spite of an increased availability of gonadotropic support. PRL acts through its receptor (PRLr), the expression of which has not yet been thoroughly investigated at the molecular and cellular level in the dog. METHODS: The expression of PRLr was assessed in CL of non-pregnant dogs during the course of dioestrus (days 5, 15, 25, 35, 45, 65 post ovulation; p.o.) as well as in CL, the utero/placental compartments (Ut/Pl) and interplacental free polar zones (interplacental sites) from pregnant dogs during the pre-implantation, post-implantation and mid-gestation period of pregnancy and during the normal and antigestagen-induced luteolysis. Expression of PRLr was tested by Real Time PCR, immunohistochemistry and in situ hybridization. RESULTS: In non-pregnant CL the PRLr expression was significantly upregulated at day 15 p.o. and decreased significantly afterwards, towards the end of dioestrus. CL of pregnancy showed elevated PRLr expression until mid gestation while prepartal downregulation was observed. Interestingly, placental but not interplacental expression of PRLr was strongly time-related; a significant upregulation was observed towards mid-gestation. Within the CL PRLr was localized to the luteal cells; in the Ut/Pl it was localized to the fetal trophoblast and epithelial cells of glandular chambers. Moreover, in mid-pregnant animals treated with an antigestagen, both the luteal and placental, but not the uterine PRLr were significantly downregulated. CONCLUSIONS: The data presented suggest that the luteal provision of P4 in both pregnant and non-pregnant dogs may be regulated at the PRLr level. Furthermore, a role of PRL not only in maintaining the canine CL function but also in regulating the placental function is strongly suggested. A possible functional interrelationship between luteal P4 and placental and luteal PRLr expression also with respect to the prepartal luteolysis is implied. PMID- 21812981 TI - Biotechnological approaches to determine the impact of viruses in the energy crop plant Jatropha curcas. AB - BACKGROUND: Geminiviruses infect a wide range of plant species including Jatropha and cassava both belonging to family Euphorbiaceae. Cassava is traditionally an important food crop in Sub - Saharan countries, while Jatropha is considered as valuable biofuel plant with great perspectives in the future. RESULTS: A total of 127 Jatropha samples from Ethiopia and Kenya and 124 cassava samples from Kenya were tested by Enzyme-Linked Immunosorbent Assay (ELISA) for RNA viruses and polymerase chain reaction for geminiviruses. Jatropha samples from 4 different districts in Kenya and Ethiopia (analyzed by ELISA) were negative for all three RNA viruses tested: Cassava brown streak virus (CBSV), Cassava common mosaic virus, Cucumber mosaic virus, Three cassava samples from Busia district (Kenya) contained CBSV. Efforts to develop diagnostic approaches allowing reliable pathogen detection in Jatropha, involved the amplification and sequencing of the entire DNA A molecules of 40 Kenyan isolates belonging to African cassava mosaic virus (ACMV) and East African cassava mosaic virus - Uganda. This information enabled the design of novel primers to address different questions: a) primers amplifying longer sequences led to a phylogenetic tree of isolates, allowing some predictions on the evolutionary aspects of Begomoviruses in Jatrophia; b) primers amplifying shorter sequences represent a reliable diagnostic tool. This is the first report of the two Begomoviruses in J. curcas. Two cassava samples were co - infected with cassava mosaic geminivirus and CBSV. A Defective DNA A of ACMV was found for the first time in Jatropha. CONCLUSION: Cassava geminiviruses occurring in Jatropha might be spread wider than anticipated. If not taken care of, this virus infection might negatively impact large scale plantations for biofuel production. Being hosts for similar pathogens, the planting vicinity of the two crop plants needs to be handled carefully. PMID- 21812982 TI - Discrimination learning with variable stimulus 'salience'. AB - BACKGROUND: In nature, sensory stimuli are organized in heterogeneous combinations. Salient items from these combinations 'stand-out' from their surroundings and determine what and how we learn. Yet, the relationship between varying stimulus salience and discrimination learning remains unclear. PRESENTATION OF THE HYPOTHESIS: A rigorous formulation of the problem of discrimination learning should account for varying salience effects. We hypothesize that structural variations in the environment where the conditioned stimulus (CS) is embedded will be a significant determinant of learning rate and retention level. TESTING THE HYPOTHESIS: Using numerical simulations, we show how a modified version of the Rescorla-Wagner model, an influential theory of associative learning, predicts relevant interactions between varying salience and discrimination learning. IMPLICATIONS OF THE HYPOTHESIS: If supported by empirical data, our model will help to interpret critical experiments addressing the relations between attention, discrimination and learning. PMID- 21812983 TI - Terra and Aqua satellites track tiger mosquito invasion: modelling the potential distribution of Aedes albopictus in north-eastern Italy. AB - BACKGROUND: The continuing spread of the Asian tiger mosquito Aedes albopictus in Europe is of increasing public health concern due to the potential risk of new outbreaks of exotic vector-borne diseases that this species can transmit as competent vector. We predicted the most favorable areas for a short term invasion of Ae. albopictus in north-eastern Italy using reconstructed daily satellite data time series (MODIS Land Surface Temperature maps, LST). We reconstructed more than 11,000 daily MODIS LST maps for the period 2001-09 (i.e. performed spatial and temporal gap-filling) in an Open Source GIS framework. We aggregated these LST maps over time and identified the potential distribution areas of Ae. albopictus by adapting published temperature threshold values using three variables as predictors (0 degrees C for mean January temperatures, 11 degrees C for annual mean temperatures and 1350 growing degree days filtered for areas with autumnal mean temperatures > 11 degrees C). The resulting maps were integrated into the final potential distribution map and this was compared with the known current distribution of Ae. albopictus in north-eastern Italy. RESULTS: LST maps show the microclimatic characteristics peculiar to complex terrains, which would not be visible in maps commonly derived from interpolated meteorological station data. The patterns of the three indicator variables partially differ from each other, while winter temperature is the determining limiting factor for the distribution of Ae. albopictus. All three variables show a similar spatial pattern with some local differences, in particular in the northern part of the study area (upper Adige valley). CONCLUSIONS: Reconstructed daily land surface temperature data from satellites can be used to predict areas of short term invasion of the tiger mosquito with sufficient accuracy (200 m pixel resolution size). Furthermore, they may be applied to other species of arthropod of medical interest for which temperature is a relevant limiting factor. The results indicate that, during the next few years, the tiger mosquito will probably spread toward northern latitudes and higher altitudes in north-eastern Italy, which will considerably expand the range of the current distribution of this species. PMID- 21812985 TI - Viral suppression of multiple escape mutants by de novo CD8(+) T cell responses in a human immunodeficiency virus-1 infected elite suppressor. AB - Elite suppressors or controllers (ES) are HIV-1 infected patients who maintain undetectable viral loads without treatment. While HLA-B*57-positive ES are usually infected with virus that is unmutated at CTL epitopes, a single, dominant variant containing CTL escape mutations is typically seen in plasma during chronic infection. We describe an ES who developed seven distinct and rare escape variants at an HLA-B*57-restricted Gag epitope over a five year period. Interestingly, he developed proliferative, de novo CTL responses that suppressed replication of each of these variants. These responses, in combination with low viral fitness of each variant, may contribute to sustained elite control in this ES. PMID- 21812986 TI - Psychometric evaluation of the SF-36 (v.2) questionnaire in a probability sample of Brazilian households: results of the survey Pesquisa Dimensoes Sociais das Desigualdades (PDSD), Brazil, 2008. AB - BACKGROUND: In Brazil, despite the growing use of SF-36 in different research environments, most of the psychometric evaluation of the translated questionnaire was from studies with samples of patients. The purpose of this paper is to examine if the Brazilian version of SF-36 satisfies scaling assumptions, reliability and validity required for valid interpretation of the SF-36 summated ratings scales in the general population. METHODS: 12,423 individuals and their spouses living in 8,048 households were selected from a stratified sample of all permanent households along the country to be interviewed using the Brazilian SF 36 (version 2). Psychometric tests were performed to evaluate the scaling assumptions based on IQOLA methodology. RESULTS: Data quality was satisfactory with questionnaire completion rate of 100%. The ordering of the item means within scales clustered as hypothesized. All item-scale correlations exceeded the suggested criteria for reliability with success rate of 100% and low floor and ceiling effects. All scales reached the criteria for group comparison and factor analysis identified two principal components that jointly accounted for 67.5% of the total variance. Role emotional and vitality were strongly correlated with physical and mental components, respectively, while social functioning was moderately correlated with both components. Role physical and mental health scales were, respectively, the most valid measures of the physical and mental health component. In the comparisons between groups that differed by the presence or absence of depression, subjects who reported having the disease had lower mean scores in all scales and mental health scale discriminated best between the two groups. Among those healthy and with one, two or three and more chronic illness, the average scores were inverted related to the number of diseases. Body pain, general health and vitality were the most discriminating scales between healthy and diseased groups. Higher scores were associated with individuals of male sex, age below 40 years old and high schooling. CONCLUSIONS: The Brazilian version of SF-36 performed well and the findings suggested that it is a reliable and valid measure of health related quality of life among the general population as well as a promising measure for research on health inequalities in Brazil. PMID- 21812984 TI - The testis-specific Calpha2 subunit of PKA is kinetically indistinguishable from the common Calpha1 subunit of PKA. AB - BACKGROUND: The two variants of the alpha-form of the catalytic (C) subunit of protein kinase A (PKA), designated Calpha1 and Calpha2, are encoded by the PRKACA gene. Whereas Calpha1 is ubiquitous, Calpha2 expression is restricted to the sperm cell. Calpha1 and Calpha2 are encoded with different N-terminal domains. In Calpha1 but not Calpha2 the N-terminal end introduces three sites for posttranslational modifications which include myristylation at Gly1, Asp-specific deamidation at Asn2 and autophosphorylation at Ser10. Previous reports have implicated specific biological features correlating with these modifications on Calpha1. Since Calpha2 is not modified in the same way as Calpha1 we tested if they have distinct biochemical activities that may be reflected in different biological properties. RESULTS: We show that Calpha2 interacts with the two major forms of the regulatory subunit (R) of PKA, RI and RII, to form cAMP-sensitive PKAI and PKAII holoenzymes both in vitro and in vivo as is also the case with Calpha1. Moreover, using Surface Plasmon Resonance (SPR), we show that the interaction patterns of the physiological inhibitors RI, RII and PKI were comparable for Calpha2 and Calpha1. This is also the case for their potency to inhibit catalytic activities of Calpha2 and Calpha1. CONCLUSION: We conclude that the regulatory complexes formed with either Calpha1 or Calpha2, respectively, are indistinguishable. PMID- 21812987 TI - Physician practices related to use of BMI-for-age and counseling for childhood obesity prevention: a cross-sectional study. AB - BACKGROUND: Screening for obesity and providing appropriate obesity-related counseling in the clinical setting are important strategies to prevent and control childhood obesity. The purpose of this study is to document pediatricians (PEDs) and general practitioners (GPs) with pediatric patients use of BMI-for-age to screen for obesity, confidence in explaining BMI, access to referral clinics, and characteristics associated with screening and counseling to children and their caregivers. METHODS: The authors used 2008 DocStyles survey data to examine these practices at every well child visit for children aged two years and older. Counseling topics included: physical activity, TV viewing time, energy dense foods, fruits and vegetables, and sugar-sweetened beverages. Chi-square tests were used to examine differences in proportions and logistic regression to identify characteristics associated with screening and counseling. RESULTS: The final analytic sample included 250 PEDs and 621 GPs. Prevalence of using BMI-for age to screen for obesity at every well child visit was higher for PEDs than GPs (50% vs. 22%, chi2 = 67.0, p <= 0.01); more PEDs reported being very/somewhat confident in explaining BMI (94% vs. GPs, 87%, p < 0.01); more PEDs reported access to a pediatric obesity specialty clinic for referral (PEDs = 65% vs. GPs = 42%, chi2 = 37.5, p <= 0.0001).In general, PEDs reported higher counseling prevalence than GPs. There were significant differences in the following topics: TV viewing (PEDs, 79% vs. GPs, 61%, chi2 = 19.1, p <= 0.0001); fruit and vegetable consumption (PEDs, 87% vs. GPs, 78%, chi2 = 6.4, p <= 0.01). The only characteristics associated with use of BMI for GPs were being female (OR = 2.3, 95% CI = 1.5-3.5) and serving mostly non-white patients (OR = 1.8, 95% CI = 1.1 2.9); there were no significant associations for PEDs. CONCLUSIONS: The findings for use of BMI-for-age, counseling habits, and access to a pediatric obesity specialty clinic leave room for improvement. More research is needed to better understand why BMI-for-age is not being used to screen at every well child visit, which may increase the likelihood overweight and obese patients receive counseling and referrals for additional services. The authors also suggest more communication between PEDs and GPs through professional organizations to increase awareness of existing resources, and to enhance access and referral to pediatric obesity specialty clinics. PMID- 21812989 TI - Nanoliposomes for encapsulation and delivery of the potential antitumoral methyl 6-methoxy-3-(4-methoxyphenyl)-1H-indole-2-carboxylate. AB - A potential antitumoral fluorescent indole derivative, methyl 6-methoxy-3-(4 methoxyphenyl)-1H-indole-2-carboxylate, was evaluated for the in vitro cell growth inhibition on three human tumor cell lines, MCF-7 (breast adenocarcinoma), A375-C5 (melanoma), and NCI-H460 (non-small cell lung cancer), after a continuous exposure of 48 h, exhibiting very low GI50 values for all the cell lines tested (0.25 to 0.33 MUM). This compound was encapsulated in different nanosized liposome formulations, containing egg lecithin (Egg-PC), dipalmitoyl phosphatidylcholine (DPPC), dipalmitoyl phosphatidylglycerol (DPPG), DSPC, cholesterol, dihexadecyl phosphate, and DSPE-PEG. Dynamic light scattering measurements showed that nanoliposomes with the encapsulated compound are generally monodisperse and with hydrodynamic diameters lower than 120 nm, good stability and zeta potential values lower than -18 mV. Dialysis experiments allowed to monitor compound diffusion through the lipid membrane, from DPPC/DPPG donor liposomes to NBD-labelled lipid/DPPC/DPPG acceptor liposomes. PMID- 21812988 TI - Evaluation design of a reactivation care program to prevent functional loss in hospitalised elderly: a cohort study including a randomised controlled trial. AB - BACKGROUND: Elderly persons admitted to the hospital are at risk for hospital related functional loss. This evaluation aims to compare the effects of different levels of (integrated) health intervention care programs on preventing hospital related functional loss among elderly patients by comparing a new intervention program to two usual care programs. METHODS/DESIGN: This study will include an effect, process and cost evaluation using a mixed methods design of quantitative and qualitative methods. Three hospitals in The Netherlands with different levels of integrated geriatric health care will be evaluated using a quasi-experimental study design. Data collection on outcomes will take place through a prospective cohort study, which will incorporate a nested randomised controlled trial to evaluate the effects of a stay at the centre for prevention and reactivation for patients with complex problems. The study population will consist of elderly persons (65 years or older) at risk for functional loss who are admitted to one of the three hospitals. Data is prospectively collected at time of hospital admission (T0), three months (T1), and twelve months (T2) after hospital admission. Patient and informal caregiver outcomes (e.g. health related quality of life, activities of daily living, burden of care, (re-) admission in hospital or nursing homes, mortality) as well as process measures (e.g. the cooperation and collaboration of multidisciplinary teams, patient and informal caregiver satisfaction with care) will be measured. A qualitative analysis will determine the fidelity of intervention implementation as well as provide further context and explanation for quantitative outcomes. Finally, costs will be determined from a societal viewpoint to allow for cost effectiveness calculations. DISCUSSION: It is anticipated that higher levels of integrated hospital health care for at risk elderly will result in prevention of loss of functioning and loss of quality of life after hospital discharge as well as in lower burden of care and higher quality of life for informal caregivers. Ultimately, the results of this study may contribute to the implementation of a national integrated health care program to prevent hospital related functional loss among elderly patients. TRIAL REGISTRATION: The Netherlands National Trial Register: NTR2317. PMID- 21812990 TI - First-pass perfusion CMR two days after infarction predicts severity of functional impairment six weeks later in the rat heart. AB - BACKGROUND: In humans, dynamic contrast CMR of the first pass of a bolus infusion of Gadolinium-based contrast agent has become a standard technique to identify under-perfused regions of the heart and can accurately demonstrate the severity of myocardial infarction. Despite the clinical importance of this method, it has rarely been applied in small animal models of cardiac disease. In order to identify perfusion delays in the infarcted rat heart, here we present a method in which a T1 weighted MR image has been acquired during each cardiac cycle. METHODS AND RESULTS: In isolated perfused rat hearts, contrast agent infusion gave uniform signal enhancement throughout the myocardium. Occlusion of the left anterior descending coronary artery significantly reduced the rate of signal enhancement in anterior regions of the heart, demonstrating that the first-pass method was sensitive to perfusion deficits. In vivo measurements of myocardial morphology, function, perfusion and viability were made at 2 and 8 days after infarction. Morphology and function were further assessed using cine-MRI at 42 days. The perfusion delay was larger in rat hearts that went on to develop greater functional impairment, demonstrating that first-pass CMR can be used as an early indicator of infarct severity. First-pass CMR at 2 and 8 days following infarction better predicted outcome than cardiac ejection fraction, end diastolic volume or end systolic volume. CONCLUSION: First-pass CMR provides a predictive measure of the severity of myocardial impairment caused by infarction in a rodent model of heart failure. PMID- 21812991 TI - Internet-based cognitive behavior therapy for obsessive compulsive disorder: a pilot study. AB - BACKGROUND: Cognitive behavior therapy (CBT) is widely regarded as an effective treatment for obsessive compulsive disorder (OCD), but access to CBT therapists is limited. Internet-based CBT (ICBT) with therapist support is a way to increase access to CBT but has not been developed or tested for OCD. The aim of this study was to evaluate ICBT for OCD. METHOD: An open trial where patients (N = 23) received a 15-week ICBT program with therapist support consisting of psychoeducation, cognitive restructuring and exposure with response prevention. The primary outcome was the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), which was assessed by a psychiatrist before and immediately after treatment. Secondary outcomes were self-rated measures of OCD symptoms, depressive symptoms, general functioning, anxiety and quality of life. All assessments were made at baseline and post-treatment. RESULTS: All participants completed the primary outcome measure at all assessment points. There were reductions in OCD symptoms with a large within-group effect size (Cohen's d = 1.56). At post-treatment, 61% of participants had a clinically significant improvement and 43% no longer fulfilled the diagnostic criteria of OCD. The treatment also resulted in statistically significant improvements in self-rated OCD symptoms, general functioning and depression. CONCLUSIONS: ICBT with therapist support reduces OCD symptoms, depressive symptoms and improves general functioning. Randomized trials are needed to confirm the effectiveness of this new treatment format. PMID- 21812993 TI - Multicentre validation of the bedside paediatric early warning system score: a severity of illness score to detect evolving critical illness in hospitalised children. AB - INTRODUCTION: The timely provision of critical care to hospitalised patients at risk for cardiopulmonary arrest is contingent upon identification and referral by frontline providers. Current approaches require improvement. In a single-centre study, we developed the Bedside Paediatric Early Warning System (Bedside PEWS) score to identify patients at risk. The objective of this study was to validate the Bedside PEWS score in a large patient population at multiple hospitals. METHODS: We performed an international, multicentre, case-control study of children admitted to hospital inpatient units with no limitations on care. Case patients had experienced a clinical deterioration event involving either an immediate call to a resuscitation team or urgent admission to a paediatric intensive care unit. Control patients had no events. The scores ranged from 0 to 26 and were assessed in the 24 hours prior to the clinical deterioration event. Score performance was assessed using the area under the receiver operating characteristic (AUCROC) curve by comparison with the retrospective rating of nurses and the temporal progression of scores in case patients. RESULTS: A total of 2,074 patients were evaluated at 4 participating hospitals. The median (interquartile range) maximum Bedside PEWS scores for the 12 hours ending 1 hour before the clinical deterioration event were 8 (5 to 12) in case patients and 2 (1 to 4) in control patients (P < 0.0001). The AUCROC curve (95% confidence interval) was 0.87 (0.85 to 0.89). In case patients, mean scores were 5.3 at 20 to 24 hours and 8.4 at 0 to 4 hours before the event (P < 0.0001). The AUCROC curve (95% CI) of the retrospective nurse ratings was 0.83 (0.81 to 0.86). This was significantly lower than that of the Bedside PEWS score (P < 0.0001). CONCLUSIONS: The Bedside PEWS score identified children at risk for cardiopulmonary arrest. Scores were elevated and continued to increase in the 24 hours before the clinical deterioration event. Prospective clinical evaluation is needed to determine whether this score will improve the quality of care and patient outcomes. PMID- 21812992 TI - Carotid plaque regression following 6-month statin therapy assessed by 3T cardiovascular magnetic resonance: comparison with ultrasound intima media thickness. AB - BACKGROUND: Cardiovascular magnetic resonance (CMR) allows volumetric carotid plaque measurement that has advantage over 2-dimensional ultrasound (US) intima media thickness (IMT) in evaluating treatment response. We tested the hypothesis that 6-month statin treatment in patients with carotid plaque will lead to plaque regression when measured by 3 Tesla CMR but not by IMT. METHODS: Twenty-six subjects (67 +/- 2 years, 7 females) with known carotid plaque (> 1.1 mm) and coronary or cerebrovascular atherosclerotic disease underwent 3T CMR (T1, T2, proton density and time of flight sequences) and US at baseline and following 6 months of statin therapy (6 had initiation, 7 had increase and 13 had maintenance of statin dosing). CMR plaque volume (PV) was measured in the region 12 mm below and up to 12 mm above carotid flow divider using software. Mean posterior IMT in the same region was measured. Baseline and 6-month CMR PV and US IMT were compared. Change in lipid rich/necrotic core (LR/NC) and calcification plaque components from CMR were related to change in PV. RESULTS: Low-density lipoprotein cholesterol decreased (86 +/- 6 to 74 +/- 4 mg/dL, p = 0.046). CMR PV decreased 5.8 +/- 2% (1036 +/- 59 to 976 +/- 65 mm3, p = 0.018). Mean IMT was unchanged (1.12 +/- 0.06 vs. 1.14 +/- 0.06 mm, p = NS). Patients with initiation or increase of statins had -8.8 +/- 2.8% PV change (p = 0.001) while patients with maintenance of statin dosing had -2.7 +/- 3% change in PV (p = NS). There was circumferential heterogeneity in CMR plaque thickness with greatest thickness in the posterior carotid artery, in the region opposite the flow divider. Similarly there was circumferential regional difference in change of plaque thickness with significant plaque regression in the anterior carotid region in region of the flow divider. Change in LR/NC (R = 0.62, p = 0.006) and calcification (R = 0.45, p = 0.03) correlated with PV change. CONCLUSIONS: Six month statin therapy in patients with carotid plaque led to reduced plaque volume by 3T CMR, but ultrasound posterior IMT did not show any change. The heterogeneous spatial distribution of plaque and regional differences in magnitude of plaque regression may explain the difference in findings and support volumetric measurement of plaque. 3T CMR has potential advantage over ultrasound IMT to assess treatment response in individuals and may allow reduced sample size, duration and cost of clinical trials of plaque regression. PMID- 21812994 TI - Self-assembled monolayer of designed and synthesized triazinedithiolsilane molecule as interfacial adhesion enhancer for integrated circuit. AB - Self-assembled monolayer (SAM) with tunable surface chemistry and smooth surface provides an approach to adhesion improvement and suppressing deleterious chemical interactions. Here, we demonstrate the SAM comprising of designed and synthesized 6-(3-triethoxysilylpropyl)amino-1,3,5-triazine-2,4-dithiol molecule, which can enhance interfacial adhesion to inhibit copper diffusion used in device metallization. The formation of the triazinedithiolsilane SAM is confirmed by X ray photoelectron spectroscopy. The adhesion strength between SAM-coated substrate and electroless deposition copper film was up to 13.8 MPa. The design strategy of triazinedithiolsilane molecule is expected to open up the possibilities for replacing traditional organosilane to be applied in microelectronic industry. PMID- 21812995 TI - Long-term exposure to hypoxia inhibits tumor progression of lung cancer in rats and mice. AB - BACKGROUND: Hypoxia has been identified as a major negative factor for tumor progression in clinical observations and in animal studies. However, the precise role of hypoxia in tumor progression has not been fully explained. In this study, we extensively investigated the effect of long-term exposure to hypoxia on tumor progression in vivo. METHODS: Rats bearing transplanted tumors consisting of A549 human lung cancer cells (lung cancer tumor) were exposed to hypoxia for different durations and different levels of oxygen. The tumor growth and metastasis were evaluated. We also treated A549 lung cancer cells (A549 cells) with chronic hypoxia and then implanted the hypoxia-pretreated cancer cells into mice. The effect of exposure to hypoxia on metastasis of Lewis lung carcinoma in mice was also investigated. RESULTS: We found that long-term exposure to hypoxia a) significantly inhibited lung cancer tumor growth in xenograft and orthotopic models in rats, b) significantly reduced lymphatic metastasis of the lung cancer in rats and decreased lung metastasis of Lewis lung carcinoma in mice, c) reduced lung cancer cell proliferation and cell cycle progression in vitro, d) decreased growth of the tumors from hypoxia-pretreated A549 cells, e) decreased Na+-K+ ATPase alpha1 expression in hypoxic lung cancer tumors, and f) increased expression of hypoxia inducible factors (HIF1alpha and HIF2alpha) but decreased microvessel density in the lung cancer tumors. In contrast to lung cancer, the growth of tumor from HCT116 human colon cancer cells (colon cancer tumor) was a) significantly enhanced in the same hypoxia conditions, accompanied by b) no significant change in expression of Na+-K+ ATPase alpha1, c) increased HIF1alpha expression (no HIF2alpha was detected) and d) increased microvessel density in the tumor tissues. CONCLUSIONS: This study demonstrated that long-term exposure to hypoxia repressed tumor progression of the lung cancer from A549 cells and that decreased expression of Na+-K+ ATPase was involved in hypoxic inhibition of tumor progression. The results from this study provide new insights into the role of hypoxia in tumor progression and therapeutic strategies for cancer treatment. PMID- 21812996 TI - Previous hospital admissions and disease severity predict the use of antipsychotic combination treatment in patients with schizophrenia. AB - BACKGROUND: Although not recommended in treatment guidelines, previous studies have shown a frequent use of more than one antipsychotic agent among patients with schizophrenia. The main aims of the present study were to explore the antipsychotic treatment regimen among patients with schizophrenia in a catchment area-based sample and to investigate clinical characteristics associated with antipsychotic combination treatment. METHODS: The study included 329 patients diagnosed with schizophrenia using antipsychotic medication. Patients were recruited from all psychiatric hospitals in Oslo. Diagnoses were obtained by use of the Structured Clinical Interview for DSM-IV Axis I disorders (SCID-I). Additionally, Global Assessment of Functioning (GAF), Positive and Negative Syndrome Scale (PANSS) and number of hospitalisations and pharmacological treatment were assessed. RESULTS: Multiple hospital admissions, low GAF scores and high PANSS scores, were significantly associated with the prescription of combination treatment with two or more antipsychotics. The use of combination treatment increased significantly from the second hospital admission. Combination therapy was not significantly associated with age or gender. Regression models confirmed that an increasing number of hospital admission was the strongest predictor of the use of two or more antipsychotics. CONCLUSIONS: Previous hospital admissions and disease severity measured by high PANSS scores and low GAF scores, predict the use of antipsychotic combination treatment in patients with schizophrenia. Future studies should further explore the use of antipsychotic drug treatment in clinical practice and partly based on such data establish more robust treatment guidelines for patients with persistently high symptom load. PMID- 21812997 TI - 1,3-Propanediol dehydrogenases in Lactobacillus reuteri: impact on central metabolism and 3-hydroxypropionaldehyde production. AB - BACKGROUND: Lactobacillus reuteri metabolizes glycerol to 3 hydroxypropionaldehyde (3-HPA) and further to 1,3-propanediol (1,3-PDO), the latter step catalysed by a propanediol dehydrogenase (PDH). The last step in this pathway regenerates NAD+ and enables therefore the energetically more favourable production of acetate over ethanol during growth on glucose. RESULTS: A search throughout the genome of L. reuteri DSM 20016 revealed two putative PDHs encoded by ORFs lr_0030 and lr_1734. ORF lr_1734 is situated in the pdu operon encoding the glycerol conversion machinery and therefore likely involved in 1,3-PDO formation. ORF lr_0030 has not been associated with PDH-activity so far. To elucidate the role of these two PDHs, gene deletion mutant strains were constructed. Growth behaviour on glucose was comparable between the wild type and both mutant strains. However, on glucose + glycerol, the exponential growth rate of Deltalr_0030 was lower compared to the wild type and the lr_1734 mutant. Furthermore, glycerol addition resulted in decreased ethanol production in the wild type and Deltalr_1734, but not in Deltalr_0030. PDH activity measurements using 3-HPA as a substrate revealed lower activity of Deltalr_0030 extracts from exponential growing cells compared to wild type and Deltalr_1734 extracts.During biotechnological 3-HPA production using non-growing cells, the ratio 3-HPA to 1,3 PDO was approximately 7 in the wild type and Deltalr_0030, whereas this ratio was 12.5 in the mutant Deltalr_1734. CONCLUSION: The enzyme encoded by lr_0030 plays a pivotal role in 3-HPA conversion in exponential growing L. reuteri cells. The enzyme encoded by lr_1734 is active during 3-HPA production by non-growing cells and this enzyme is a useful target to enhance 3-HPA production and minimize formation of the by-product 1,3-PDO. PMID- 21812998 TI - Spatial epidemiology and spatial ecology study of worldwide drug-resistant tuberculosis. AB - BACKGROUND: Drug-resistant tuberculosis (DR-TB) is a major public health problem caused by various factors. It is essential to systematically investigate the epidemiological and, in particular, the ecological factors of DR-TB for its prevention and control. Studies of the ecological factors can provide information on etiology, and assist in the effective prevention and control of disease. So it is of great significance for public health to explore the ecological factors of DR-TB, which can provide guidance for formulating regional prevention and control strategies. METHODS: Anti-TB drug resistance data were obtained from the World Health Organization/International Union Against Tuberculosis and Lung Disease (WHO/UNION) Global Project on Anti-Tuberculosis Drug Resistance Surveillance, and data on ecological factors were collected to explore the ecological factors for DR-TB. Partial least square path modeling (PLS-PM), in combination with ordinary least squares (OLS) regression, as well as geographically weighted regression (GWR), were used to build a global and local spatial regression model between the latent synthetic DR-TB factor ("DR-TB") and latent synthetic risk factors. RESULTS: OLS regression and PLS-PM indicated a significant globally linear spatial association between "DR-TB" and its latent synthetic risk factors. However, the GWR model showed marked spatial variability across the study regions. The "TB Epidemic", "Health Service" and "DOTS (directly-observed treatment strategy) Effect" factors were all positively related to "DR-TB" in most regions of the world, while "Health Expenditure" and "Temperature" factors were negatively related in most areas of the world, and the "Humidity" factor had a negative influence on "DR-TB" in all regions of the world. CONCLUSIONS: In summary, the influences of the latent synthetic risk factors on DR-TB presented spatial variability. We should formulate regional DR-TB monitoring planning and prevention and control strategies, based on the spatial characteristics of the latent synthetic risk factors and spatial variability of the local relationship between DR-TB and latent synthetic risk factors. PMID- 21812999 TI - Increased incidence of kidney diseases in general practice after a nationwide albuminuria self-test program. AB - BACKGROUND: To study the influence of a nationwide albuminuria self-test program on the number of GP contacts for urinary complaints and/or kidney diseases and the number of newly diagnosed patients with kidney diseases by the GP. METHODS: Data were used from the Netherlands Information Network of General Practice (LINH), including a representative sample of general practices with a dynamic population of approximately 300.000 listed patients. Morbidity data were retrieved from electronic medical records, kept in a representative sample of general practices. The incidence of kidney diseases and urinary complaints before and after the albuminuria self-test program was compared with logistic regression analyses. RESULTS: Data were used from 139 general practices, including 444,220 registered patients. The number of GP consultations for kidney diseases and urinary complaints was increased in the year after the albuminuria self-test program and particularly shortly after the start of the program. Compared with the period before the self-test program, more patients have been diagnosed by the GP with symptoms/complaints of kidney disease and urinary diseases (OR=1.7 (CI 1.4-2.0) and OR=2.1 (CI 1.9-2.3), respectively). The odds on an abnormal urine test in the period after the self-test program was three times higher than the year before (OR=3.0 (CI 2.4-3.6)). The effect of the self-test program on newly diagnosed patients with an abnormal urine test was modified by both the presence of the risk factors hypertension and diabetes mellitus. For this diagnosis the highest OR was found in patients without both conditions (OR=4.2 (CI 3.3-5.4)). CONCLUSIONS: A nationwide albuminuria self-test program resulted in an increasing number of newly diagnosed kidney complaints and diseases the year after the program. The highest risks were found in patients without risk factors for kidney diseases. PMID- 21813000 TI - Monophyly of clade III nematodes is not supported by phylogenetic analysis of complete mitochondrial genome sequences. AB - BACKGROUND: The orders Ascaridida, Oxyurida, and Spirurida represent major components of zooparasitic nematode diversity, including many species of veterinary and medical importance. Phylum-wide nematode phylogenetic hypotheses have mainly been based on nuclear rDNA sequences, but more recently complete mitochondrial (mtDNA) gene sequences have provided another source of molecular information to evaluate relationships. Although there is much agreement between nuclear rDNA and mtDNA phylogenies, relationships among certain major clades are different. In this study we report that mtDNA sequences do not support the monophyly of Ascaridida, Oxyurida and Spirurida (clade III) in contrast to results for nuclear rDNA. Results from mtDNA genomes show promise as an additional independently evolving genome for developing phylogenetic hypotheses for nematodes, although substantially increased taxon sampling is needed for enhanced comparative value with nuclear rDNA. Ultimately, topological incongruence (and congruence) between nuclear rDNA and mtDNA phylogenetic hypotheses will need to be tested relative to additional independent loci that provide appropriate levels of resolution. RESULTS: For this comparative phylogenetic study, we determined the complete mitochondrial genome sequences of three nematode species, Cucullanus robustus (13,972 bp) representing Ascaridida, Wellcomia siamensis (14,128 bp) representing Oxyurida, and Heliconema longissimum (13,610 bp) representing Spirurida. These new sequences were used along with 33 published nematode mitochondrial genomes to investigate phylogenetic relationships among chromadorean orders. Phylogenetic analyses of both nucleotide and amino acid sequence datasets support the hypothesis that Ascaridida is nested within Rhabditida. The position of Oxyurida within Chromadorea varies among analyses; in most analyses this order is sister to the Ascaridida plus Rhabditida clade, with representative Spirurida forming a distinct clade, however, in one case Oxyurida is sister to Spirurida. Ascaridida, Oxyurida, and Spirurida (the sampled clade III taxa) do not form a monophyletic group based on complete mitochondrial DNA sequences. Tree topology tests revealed that constraining clade III taxa to be monophyletic, given the mtDNA datasets analyzed, was a significantly worse result. CONCLUSION: The phylogenetic hypotheses from comparative analysis of the complete mitochondrial genome data (analysis of nucleotide and amino acid datasets, and nucleotide data excluding 3rd positions) indicates that nematodes representing Ascaridida, Oxyurida and Spirurida do not share an exclusive most recent common ancestor, in contrast to published results based on nuclear ribosomal DNA. Overall, mtDNA genome data provides reliable support for nematode relationships that often corroborates findings based on nuclear rDNA. It is anticipated that additional taxonomic sampling will provide a wealth of information on mitochondrial genome evolution and sequence data for developing phylogenetic hypotheses for the phylum Nematoda. PMID- 21813001 TI - Selection of Neospora caninum antigens stimulating bovine CD4+ve T cell responses through immuno-potency screening and proteomic approaches. AB - Neospora caninum is recognised worldwide as a major cause of bovine infectious abortion. There is a real need to develop effective strategies to control infection during pregnancy which may lead to either abortion or congenital transmission. Due to the intracellular nature of the parasite, cell-mediated immune (CMI) responses involving CD4(+ve), CD8(+ve), gamma/delta TCR(+ve) T cells and NK cells, as well as production of IFN-gamma, are thought to be important for protective immunity. In this study we applied a combination of proteomic and immunological approaches to identify antigens of N. caninum that are recognized by CD4(+ve) T cell lines derived from infected cattle. Initially, N. caninum tachyzoite Water Soluble Antigens (NcWSA) were fractionated by size-exclusion HPLC and then screened for immune-potency using CD4(+ve) T cell lines. LC-ESI MS/MS (liquid chromatography electrospray ionisation tandem mass spectrometry) was employed to catalogue and identify the proteins comprising three immunologically selected fractions and led to the identification of six N. caninum target proteins as well as sixteen functional orthologues of Toxoplasma gondii. This approach allows the screening of biologically reactive antigenic fractions by the immune cells responsible for protection (such as bovine CD4(+ve) cells) and the subsequent identification of the stimulating components using tandem mass spectrometry. PMID- 21813002 TI - False rumours of disease outbreaks caused by infectious myonecrosis virus (IMNV) in the whiteleg shrimp in Asia. AB - BACKGROUND: Infectious myonecrosis virus (IMNV) disease outbreaks in cultivated whiteleg shrimp Penaeus (Litopenaeus) vannamei are characterized by gross signs of whitened abdominal muscles and by slow mortality reaching up to 70%. In 2006 the first disease outbreaks caused by IMNV in Asia occurred in Indonesia. Since then rumours have periodically circulated about IMNV disease outbreaks in other Asian countries. Our findings indicate that these are false rumours. FINDINGS: Our continual testing by nested RT-PCR of shrimp samples suspected of IMNV infection from various Asian countries since 2006 has yielded negative results, except for samples from Indonesia. Our results are supported by the lack of official reports of IMNV outbreaks since January 2007 in the Quarterly Report on Aquatic Animal Diseases (QAAD) from the Network of Aquaculture Centers in Asia Pacific (NACA). In most cases, our shrimp samples for which tissue sections were possible showed signs of muscle cramp syndrome that also commonly causes muscle whitening in stressed whiteleg shrimp. Thus, we suspect that most of the false rumours in Asia about IMNV outside of Indonesia have resulted because of muscle cramp syndrome. CONCLUSIONS: Results from continual testing of suspected IMNV outbreaks in Asian countries other than Indonesia since 2006 and the lack of official country reports of IMNV outbreaks since January 2007, indicate that rumours of IMNV outbreaks in Asian countries outside of Indonesia are false. We suspect that confusion has arisen because muscle cramp syndrome causes similar signs of whitened tail muscles in whiteleg shrimp. PMID- 21813003 TI - Identification of new IS711 insertion sites in Brucella abortus field isolates. AB - BACKGROUND: Brucellosis is a zoonosis caused by Brucella spp., a group of highly homogeneous bacteria. The insertion sequence IS711 is characteristic of these bacteria, and occurs in variable numbers and positions, but always constant within a given species. This species-associated polymorphism is used in molecular typing and identification. Field isolates of B. abortus, the most common species infecting cattle, typically carry seven IS711 copies (one truncated). Thus far, IS711 transposition has only been shown in vitro and only for B. ovis and B. pinnipedialis, two species carrying a high number of IS711 copies, but never in other Brucella species, neither in vitro nor in field strains. RESULTS: We found several B. abortus strains isolated from milk and aborted fetuses that carried additional IS711 copies in two hitherto undescribed insertion sites: one in an intergenic region near to the 3' end of a putative lactate permease gene and the other interrupting the sequence of a marR transcriptional regulator gene. Interestingly, the second type of insertion was identified in isolates obtained repeatedly from the same herd after successive brucellosis outbreaks, an observation that proves the stability and virulence of the new genotype under natural conditions. Sequence analyses revealed that the new copies probably resulted from the transposition of a single IS711 copy common to all Brucella species sequenced so far. CONCLUSIONS: Our results show that the replicative transposition of IS711 can occur under field conditions. Therefore, it represents an active mechanism for the emergence of genetic diversity in B. abortus thus contributing to intra-species genetic polymorphism. PMID- 21813004 TI - Lay beliefs of TB and TB/HIV co-infection in Addis Ababa, Ethiopia: a qualitative study. AB - BACKGROUND: Knowledge about lay beliefs of etiology, transmission and treatment of TB, and lay perceptions of the relationship between TB and HIV is important for understanding patients' health seeking behavior and adherence to treatment. We conducted a study to explore lay beliefs about TB and TB/HIV co-infection in Addis Ababa, Ethiopia. FINDINGS: We conducted a qualitative study using in-depth interviews with 15 TB/HIV co-infected patients and 9 health professionals and focus group discussions with 14 co-infected patients in Addis-Ababa, Ethiopia. We found that a predominant lay belief was that TB was caused by exposure to cold. Excessive sun exposure, exposure to mud, smoking, alcohol, khat and inadequate food intake were also reported as causes for TB. Such beliefs initially led to self-treatment. The majority of patients were aware of an association between TB and HIV. Some reported that TB could transform into HIV, while others said that the body could be weakened by HIV and become more susceptible to illnesses such as TB. Some patients classified TB as either HIV-related or non-HIV-related, and weight loss was a hallmark for HIV-related TB. The majority of patients believed that people in the community knew that there was an association between TB and HIV, and some feared that this would predispose them to HIV-related stigma. CONCLUSION: There is a need for culturally sensitive information and educational efforts to address misperceptions about TB and HIV. Health professionals should provide information about causes and treatment of TB and HIV to co-infected patients. PMID- 21813005 TI - Oral administration of a probiotic Lactobacillus modulates cytokine production and TLR expression improving the immune response against Salmonella enterica serovar Typhimurium infection in mice. AB - BACKGROUND: Diarrheal infections caused by Salmonella, are one of the major causes of childhood morbidity and mortality in developing countries. Salmonella causes various diseases that range from mild gastroenteritis to enteric fever, depending on the serovar involved, infective dose, species, age and immune status of the host. Probiotics are proposed as an attractive alternative possibility in the prevention against this pathogen infection. Previously we demonstrated that continuous Lactobacillus casei CRL 431 administration to BALB/c mice before and after challenge with Salmonella enterica serovar Typhimurium (S. Typhimurium) decreased the severity of Salmonella infection. The aim of the present work was to deep into the knowledge about how this probiotic bacterium exerts its effect, by assessing its impact on the expression and secretion of pro-inflammatory (TNFalpha, IFNgamma) and anti-inflammatory (IL-10) cytokines in the inductor and effector sites of the gut immune response, and analyzing toll-like receptor (TLR2, TLR4, TLR5 and TLR9) expressions in both healthy and infected mice. RESULTS: Probiotic administration to healthy mice increased the expression of TLR2, TLR4 and TLR9 and improved the production and secretion of TNFalpha, IFNgamma and IL-10 in the inductor sites of the gut immune response (Peyer's patches). Post infection, the continuous probiotic administration, before and after Salmonella challenge, protected the host by modulating the inflammatory response, mainly in the immune effector site of the gut, decreasing TNFalpha and increasing IFNgamma, IL-6 and IL-10 production in the lamina propria of the small intestine. CONCLUSIONS: The oral administration of L. casei CRL 431 induces variations in the cytokine profile and in the TLRs expression previous and also after the challenge with S. Typhimurium. These changes show some of the immune mechanisms implicated in the protective effect of this probiotic strain against S. Typhimurium, providing an alternative way to reduce the severity of the infection. PMID- 21813006 TI - "I do what I have to do to survive": an investigation into the perceptions, experiences and economic considerations of women engaged in sex work in Northern Namibia. AB - BACKGROUND: There is little published research investigating sex work in Namibia, particularly in rural areas. Therefore, the aim of this paper was to determine the views of women engaged in sex work in the Oshakati area of Namibia concerning the main factors influencing their use, or non-use, of male condoms during transactional sexual exchanges. METHODS: Qualitative interviews were used to better understand the perceptions, experiences and economic considerations of female sex workers in Namibia who were involved in a Behavior Change Communication Program encouraging safer sex practices among high-risk populations in 2006 and 2007. RESULTS: While the Behavior Change Communication Program has made significant strides in educating and empowering young women to negotiate more consistent condom use with sexual partners, the gendered economic inequalities and power imbalances within rural and semi-urban Namibian society that favor men hinder further advancement towards positive behavioral change for HIV prevention and also hinder the development of the loving relationships sought by some sex workers. CONCLUSION: This study found that sex workers and transactional sex encounters are heterogeneous entities dependent upon the characteristics of the man (known, stranger, wealthy, attractive to the woman) and the woman (in financial need, desiring love). These features all influence condom use. The 3 E's 'education, empowerment and economic independence' are critical factors needed to encourage and facilitate consistent condom use to prevent HIV transmission. Without financial independence and occupational alternatives building on their health education and empowerment, women who engage in sex work-and transactional sex more generally-will remain largely marginalized from Namibian society, and will continue engaging in risky sexual practices that facilitate HIV acquisition and transmission throughout the community. PMID- 21813007 TI - Adherence to and appropriateness of anti-osteoporotic treatments in patients aged 50 and over in the Valencia Region (Spain). The ESOSVAL-AD study. AB - BACKGROUND: A study to evaluate the adherence to and appropriateness of anti osteoporotic treatments in a cohort of men and women aged 50 and over participating in the ESOSVAL-R study. METHODS/DESIGN: DESIGN: An observational, longitudinal, prospective cohort study; STUDY SUBJECTS: Men and women aged 50 and over living in the Valencia Region (Spain) who initiated treatment between June 15, 2009, and June 15, 2011, in primary healthcare centers with electronic medical records; DATA SOURCES: The main data source will be electronic medical records. Measurement of results: Degree of compliance with and persistence of anti-osteoporotic treatments, and the proportion of patients with appropriate anti-osteoporotic treatment in accordance with the most relevant and high impact recommendations with clearly defined treatment algorithms in Spain (the Spanish National Health System guide (2010), the General Practitioners' Society (2007) and the General Directorate for Pharmacy and Medical Products of Madrid (2007)), and with the National Osteoporosis Foundation (NOF, 2010), and the International Osteoporosis Foundation guidelines (IOF, 2008); ANALYSIS: 1.) Descriptive analysis of patients undergoing treatment and the treatments prescribed; 2.) Descriptive analysis of compliance with and persistence of anti-osteoporotic treatments; 3.) ANALYSIS of factors associated with compliance with and persistence of treatments by Cox proportional hazard regression models, 4.) Descriptive analysis of appropriateness of treatment; 5.) ANALYSIS of factors associated with the appropriateness of treatment by multilevel models (4 levels: patient, doctor, Basic Healthcare Zone/Primary Healthcare Center, and Health Area variables). DISCUSSION: ESOSVAL-AD will provide information regarding adherence to osteoporosis treatments and the factors associated with a higher or lower adherence (including the appropriateness of the treatment) in the Spanish context. A better understanding of this phenomenon and the interventions needed to address it would contribute to the increased effectiveness of therapeutic measures, a reduction in morbidity and mortality, and a corresponding reduction in healthcare costs. PMID- 21813008 TI - Hepatic expression of multidrug resistance protein 2 in biliary atresia. AB - BACKGROUND: Biliary atresia (BA) is an idiopathic inflammatory obliterative cholangiopathy of neonates, leading to progressive biliary cirrhosis. Hepatoportoenterostomy (Kasai procedure) can cure jaundice in 30% to 80% of patients. Postoperative clearance of jaundice is one of the most important factors influencing long-term outcomes of BA patients. Multidrug resistance protein 2 (MRP2) is one of the canalicular export pumps located in hepatocytes; it exports organic anions and their conjugates (e.g., bilirubin) into bile canaliculus. Although MRP2 is an essential transporter for the excretion of bilirubin, its role in the clinical course of BA patients is unclear. The present study investigated the relationship between hepatic MRP2 expression and clinical course in BA patients, with particular emphasis in curing jaundice after hepatoportoenterostomy. RESULTS: No significant differences in hepatic MRP2 expression level were observed between BA and controls groups. There was no correlation between MRP2 expression and age at time of surgery in BA and control groups. In BA patients, MRP2 expression level in the jaundice and jaundice-free group did not differ significantly (2.0 * 10-4 vs 3.1 * 10-4, p = 0.094). Although the serum level of total bilirubin just before surgery did not correlate with MRP2 expression level (rs = 0.031, p = 0.914), the serum level of total bilirubin measured at 2 weeks (rs = -0.569, p = 0.034) and 4 weeks after surgery (rs = -0.620, p = 0.018) were significantly correlated with MRP2 expression level. Furthermore, MRP2 expression level was inversely correlated with ratio of change in serum total bilirubin level over 4 weeks (rs = -0.676, p = 0.008), which represents the serum bilirubin level measured at 4 weeks after surgery divided by value just before surgery. There was no correlation between expression level of MRP2 and nuclear receptors, such as retinoid * receptor alpha, farnesoid * receptor, pregnane * receptor, or constitutive androstane receptor. CONCLUSIONS: Hepatic MRP2 expression level was associated with postoperative clearance of jaundice in BA patients, at least within 1 month after hepatoportoenterostomy. This finding suggests that not only morphological appearance of the liver tissue but also the biological status of hepatocytes is important for BA pathophysiology. PMID- 21813009 TI - Laboratory prediction of the requirement for renal replacement in acute falciparum malaria. AB - BACKGROUND: Acute renal failure is a common complication of severe malaria in adults, and without renal replacement therapy (RRT), it carries a poor prognosis. Even when RRT is available, delaying its initiation may increase mortality. Earlier identification of patients who will need RRT may improve outcomes. METHOD: Prospectively collected data from two intervention studies in adults with severe malaria were analysed focusing on laboratory features on presentation and their association with a later requirement for RRT. In particular, laboratory indices of acute tubular necrosis (ATN) and acute kidney injury (AKI) that are used in other settings were examined. RESULTS: Data from 163 patients were available for analysis. Whether or not the patients should have received RRT (a retrospective assessment determined by three independent reviewers) was used as the reference. Forty-three (26.4%) patients met criteria for dialysis, but only 19 (44.2%) were able to receive this intervention due to the limited availability of RRT. Patients with impaired renal function on admission (creatinine clearance < 60 ml/min) (n = 84) had their laboratory indices of ATN/AKI analysed. The plasma creatinine level had the greatest area under the ROC curve (AUC): 0.83 (95% confidence interval 0.74-0.92), significantly better than the AUCs for, urinary sodium level, the urea to creatinine ratio (UCR), the fractional excretion of urea (FeUN) and the urinary neutrophil gelatinase-associated lipocalcin (NGAL) level. The AUC for plasma creatinine was also greater than the AUC for blood urea nitrogen level, the fractional excretion of sodium (FeNa), the renal failure index (RFI), the urinary osmolality, the urine to plasma creatinine ratio (UPCR) and the creatinine clearance, although the difference for these variables did not reach statistical significance. CONCLUSIONS: In adult patients with severe malaria and impaired renal function on admission, none of the evaluated laboratory indices was superior to the plasma creatinine level when used to predict a later requirement for renal replacement therapy. PMID- 21813010 TI - Feasibility of the adaptive and automatic presentation of tasks (ADAPT) system for rehabilitation of upper extremity function post-stroke. AB - BACKGROUND: Current guidelines for rehabilitation of arm and hand function after stroke recommend that motor training focus on realistic tasks that require reaching and manipulation and engage the patient intensively, actively, and adaptively. Here, we investigated the feasibility of a novel robotic task practice system, ADAPT, designed in accordance with such guidelines. At each trial, ADAPT selects a functional task according to a training schedule and with difficulty based on previous performance. Once the task is selected, the robot picks up and presents the corresponding tool, simulates the dynamics of the tasks, and the patient interacts with the tool to perform the task. METHODS: Five participants with chronic stroke with mild to moderate impairments (> 9 months post-stroke; Fugl-Meyer arm score 49.2 +/- 5.6) practiced four functional tasks (selected out of six in a pre-test) with ADAPT for about one and half hour and 144 trials in a pseudo-random schedule of 3-trial blocks per task. RESULTS: No adverse events occurred and ADAPT successfully presented the six functional tasks without human intervention for a total of 900 trials. Qualitative analysis of trajectories showed that ADAPT simulated the desired task dynamics adequately, and participants reported good, although not excellent, task fidelity. During training, the adaptive difficulty algorithm progressively increased task difficulty leading towards an optimal challenge point based on performance; difficulty was then continuously adjusted to keep performance around the challenge point. Furthermore, the time to complete all trained tasks decreased significantly from pretest to one-hour post-test. Finally, post-training questionnaires demonstrated positive patient acceptance of ADAPT. CONCLUSIONS: ADAPT successfully provided adaptive progressive training for multiple functional tasks based on participant's performance. Our encouraging results establish the feasibility of ADAPT; its efficacy will next be tested in a clinical trial. PMID- 21813011 TI - Mechanical characterization of nanoindented graphene via molecular dynamics simulations. AB - The mechanical behavior of graphene under various indentation depths, velocities, and temperatures is studied using molecular dynamics analysis. The results show that the load, elastic and plastic energies, and relaxation force increased with increasing indentation depth and velocity. Nanoindentation induced pile ups and corrugations of the graphene. Resistance to deformation decreased at higher temperature. Strong adhesion caused topological defects and vacancies during the unloading process. PMID- 21813012 TI - First report of multiple lineages of dengue viruses type 1 in Rio de Janeiro, Brazil. AB - BACKGROUND: In Brazil dengue has been a major public health problem since DENV-1 introduction and spread in 1986. After a low or silent co-circulation, DENV-1 re emerged in 2009 causing a major epidemic in the country in 2010 and 2011. In this study, the phylogeny of DENV-1 strains isolated in RJ after its first introduction in 1986 and after its emergence in 2009 and 2010 was performed in order to document possible evolutionary patterns or introductions in a re emergent virus. FINDINGS: The analysis of the E gene sequences demonstrated that DENV-1 isolated during 2009/2010 still belong to genotype V (Americas/Africa) but grouping in a distinct clade (lineage II) of that represented by earlier DENV-1 (lineage I). However, strains isolated in 2011 grouped together forming another distinct clade (lineage III). CONCLUSIONS: The monitoring of DENV is important to observe the spread of potentially virulent strains as well to evaluate its impact over the population during an outbreak. Whether explosive epidemics reported in Brazil caused mainly by DENV-1 was due to lineage replacement, or due the population susceptibility to this serotype which has not circulated for almost a decade or even due to the occurrence of secondary infections in a hyperendemic country, is not clear. This is the first report of multiple lineages of DENV-1 detected in Brazil. PMID- 21813013 TI - RNAexinv: An extended inverse RNA folding from shape and physical attributes to sequences. AB - BACKGROUND: RNAexinv is an interactive java application that performs RNA sequence design, constrained to yield a specific RNA shape and physical attributes. It is an extended inverse RNA folding program with the rationale behind that the generated sequences should not only fold into a desired structure, but they should also exhibit favorable attributes such as thermodynamic stability and mutational robustness. RNAexinv considers not only the secondary structure in order to design sequences, but also the mutational robustness and the minimum free energy. The sequences that are generated may not fully conform with the given RNA secondary structure, but they will strictly conform with the RNA shape of the given secondary structure and thereby take into consideration the recommended values of thermodynamic stability and mutational robustness that are provided. RESULTS: The output consists of designed sequences that are generated by the proposed method. Selecting a sequence displays the secondary structure drawings of the target and the predicted fold of the sequence, including some basic information about the desired and achieved thermodynamic stability and mutational robustness. RNAexinv can be used successfully without prior experience, simply specifying an initial RNA secondary structure in dot-bracket notation and numerical values for the desired neutrality and minimum free energy. The package runs under LINUX operating system. Secondary structure predictions are performed using the Vienna RNA package. CONCLUSIONS: RNAexinv is a user friendly tool that can be used for RNA sequence design. It is especially useful in cases where a functional stem-loop structure of a natural sequence should be strictly kept in the designed sequences but a distant motif in the rest of the structure may contain one more or less nucleotide at the expense of another, as long as the global shape is preserved. This allows the insertion of physical observables as constraints. RNAexinv is available at http://www.cs.bgu.ac.il/~RNAexinv. PMID- 21813014 TI - Indirect calibration between clinical observers - application to the New York Heart Association functional classification system. AB - BACKGROUND: Previous studies showed an inter-observer agreement for the NYHA classification of approximately 55%. The aim of this study was to calibrate the New York Heart Association (NYHA) classification system between observers, increasing its reliability. RESULTS: Among 1136 community-dwellers in Porto, Portugal, aged >= 45 years, 265 reporting breathlessness answered a 4-item questionnaire to characterize symptom severity. The questionnaire was administered by 7 physicians who also classified the subject's functional capacity according to NYHA. Each subject was assessed by one physician. We calibrated NYHA classifications by the concurrent method, using 1-parameter logistic graded response model. Discrepancies between observers were assessed by differences in ability thresholds between NYHA classes I-II and II-III. The ability estimated by the model was used to predict the NYHA classification for each observer.Estimates of the first and second thresholds for each observer ranged from -1.92 to 0.46 and from 1.42 to 2.30, respectively. The agreement between estimated ability and the observers' NYHA classification was 88% (kappa = 0.61). CONCLUSIONS: The study objectively indicates the main reason why several studies have reported low inter-observer is the existence of discrepant thresholds between observers in the definition of NYHA classes. The concurrent method can be used to minimize the reliability problem of NYHA classification. PMID- 21813015 TI - Novel innate cancer killing activity in humans. AB - BACKGROUND: In this study, we pilot tested an in vitro assay of cancer killing activity (CKA) in circulating leukocytes of 22 cancer cases and 25 healthy controls. METHODS: Using a human cervical cancer cell line, HeLa, as target cells, we compared the CKA in circulating leukocytes, as effector cells, of cancer cases and controls. The CKA was normalized as percentages of total target cells during selected periods of incubation time and at selected effector/target cell ratios in comparison to no-effector-cell controls. RESULTS: Our results showed that CKA similar to that of our previous study of SR/CR mice was present in human circulating leukocytes but at profoundly different levels in individuals. Overall, males have a significantly higher CKA than females. The CKA levels in cancer cases were lower than that in healthy controls (mean +/- SD: 36.97 +/- 21.39 vs. 46.28 +/- 27.22). Below-median CKA was significantly associated with case status (odds ratio = 4.36; 95% Confidence Interval = 1.06, 17.88) after adjustment of gender and race. CONCLUSIONS: In freshly isolated human leukocytes, we were able to detect an apparent CKA in a similar manner to that of cancer-resistant SR/CR mice. The finding of CKA at lower levels in cancer patients suggests the possibility that it may be of a consequence of genetic, physiological, or pathological conditions, pending future studies with larger sample size. PMID- 21813016 TI - The relationship between transcription initiation RNAs and CCCTC-binding factor (CTCF) localization. AB - BACKGROUND: Transcription initiation RNAs (tiRNAs) are nuclear localized 18 nucleotide RNAs derived from sequences immediately downstream of RNA polymerase II (RNAPII) transcription start sites. Previous reports have shown that tiRNAs are intimately correlated with gene expression, RNA polymerase II binding and behaviors, and epigenetic marks associated with transcription initiation, but not elongation. RESULTS: In the present work, we show that tiRNAs are commonly found at genomic CCCTC-binding factor (CTCF) binding sites in human and mouse, and that CTCF sites that colocalize with RNAPII are highly enriched for tiRNAs. To directly investigate the relationship between tiRNAs and CTCF we examined tiRNAs originating near the intronic CTCF binding site in the human tumor suppressor gene, p21 (cyclin-dependent kinase inhibitor 1A gene, also known as CDKN1A). Inhibition of CTCF-proximal tiRNAs resulted in increased CTCF localization and increased p21 expression, while overexpression of CTCF-proximal tiRNA mimics decreased CTCF localization and p21 expression. We also found that tiRNA regulated CTCF binding influences the levels of trimethylated H3K27 at the alternate upstream p21 promoter, and affects the levels of alternate p21 (p21alt) transcripts. Extending these studies to another randomly selected locus with conserved CTCF binding we found that depletion of tiRNA alters nucleosome density proximal to sites of tiRNA biogenesis. CONCLUSIONS: Taken together, these data suggest that tiRNAs modulate local epigenetic structure, which in turn regulates CTCF localization. PMID- 21813017 TI - Situs inversus totalis and secondary biliary cirrhosis: a case report. AB - Situs inversus totalis is is a congenital anomaly associated with various visceral abnormalities, but there is no data about the relationship between secondary biliary cirrhosis and that condition. We here present a case of a 58 year-old female with situs inversus totalis who was admitted to our clinic with extrahepatic cholestasis. After excluding all potential causes of biliary cirrhosis, secondary biliary cirrhosis was diagnosed based on the patient's history, imaging techniques, clinical and laboratory findings, besides histolopathological findings. After treatment with tauroursodeoxycholic acid, all biochemical parameters, including total/direct bilirubin, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and gama glutamyl transferase, returned to normal ranges at the second month of the treatment. We think that this is the first case in literature that may indicate the development of secondary biliary cirrhosis in a patient with situs inversus totalis. In conclusion, situs inversus should be considered as a rare cause of biliary cirrhosis in patients with situs inversus totalis which is presented with extrahepatic cholestasis. PMID- 21813018 TI - On multi-strain model for Hepatitis C. AB - In this paper we present a multi-strain model for hepatitis C virus (HCV) including an immune response term. The model is presented and discussed. Also we argue that the added multi-strain term represents some basic properties of the immune system and that it should be included to study longer term behavior of the disease. PMID- 21813019 TI - Circulating CO3-610, a degradation product of collagen III, closely reflects liver collagen and portal pressure in rats with fibrosis. AB - BACKGROUND: Hepatic fibrosis is characterized by intense tissue remodeling, mainly driven by matrix metalloproteinases. We previously identified CO3-610, a type III collagen neoepitope generated by matrix metalloproteinase (MMP)-9, and tested its performance as a fibrosis marker in rats with bile-duct ligation. In this study, we assessed whether CO3-610 could be used as a surrogate biomarker of liver fibrosis and portal hypertension in carbon tetrachloride-induced experimental fibrosis. RESULTS: For this study, 68 Wistar rats were used. Serum CO3-610 was measured by ELISA. Liver fibrosis was quantified by Sirius red staining. Serum hyaluronic acid (HA) was measured with a binding-protein assay. Gene expression of collagens I and III, Mmp2 and Mmp9, and tissue inhibitors of matrix metalloproteinase 1 (Timp1) and 2(Timp2) was quantified by PCR. Hemodynamic measurements were taken in a subgroup of animals. A close direct relationship was found between serum CO3-610 and hepatic collagen content (r = 0.78; P < 0.001), superior to that found for serum HA (r = 0.49; P < 0.05). CO3 610 levels in rats with severe fibrosis (43.5 +/- 3.3 ng/mL, P < 0.001) and cirrhosis (60.6 +/- 4.3 ng/mL, P < 0.001) were significantly higher than those in control animals (26.6 +/- 1.3 ng/mL). Importantly, a highly significant relationship was found between serum CO3-610 and portal hypertension (r = 0.84; P < 0.001). Liver Mmp9 expression increased significantly in fibrotic animals but decreased to control levels in cirrhotic ones. CONCLUSIONS: Circulating CO3-610 behaves as a reliable indicator of hepatic remodeling and portal hypertension in experimental fibrosis. This peptide could ultimately be a useful marker for the management of liver disease in patients. PMID- 21813020 TI - Mitochondrial genome deletions and minicircles are common in lice (Insecta: Phthiraptera). AB - BACKGROUND: The gene composition, gene order and structure of the mitochondrial genome are remarkably stable across bilaterian animals. Lice (Insecta: Phthiraptera) are a major exception to this genomic stability in that the canonical single chromosome with 37 genes found in almost all other bilaterians has been lost in multiple lineages in favour of multiple, minicircular chromosomes with less than 37 genes on each chromosome. RESULTS: Minicircular mt genomes are found in six of the ten louse species examined to date and three types of minicircles were identified: heteroplasmic minicircles which coexist with full sized mt genomes (type 1); multigene chromosomes with short, simple control regions, we infer that the genome consists of several such chromosomes (type 2); and multiple, single to three gene chromosomes with large, complex control regions (type 3). Mapping minicircle types onto a phylogenetic tree of lice fails to show a pattern of their occurrence consistent with an evolutionary series of minicircle types. Analysis of the nuclear-encoded, mitochondrially targetted genes inferred from the body louse, Pediculus, suggests that the loss of mitochondrial single-stranded binding protein (mtSSB) may be responsible for the presence of minicircles in at least species with the most derived type 3 minicircles (Pediculus, Damalinia). CONCLUSIONS: Minicircular mt genomes are common in lice and appear to have arisen multiple times within the group. Life history adaptive explanations which attribute minicircular mt genomes in lice to the adoption of blood-feeding in the Anoplura are not supported by this expanded data set as minicircles are found in multiple non-blood feeding louse groups but are not found in the blood-feeding genus Heterodoxus. In contrast, a mechanist explanation based on the loss of mtSSB suggests that minicircles may be selectively favoured due to the incapacity of the mt replisome to synthesize long replicative products without mtSSB and thus the loss of this gene lead to the formation of minicircles in lice. PMID- 21813021 TI - Transition of tumor-associated macrophages from MHC class II(hi) to MHC class II(low) mediates tumor progression in mice. AB - BACKGROUND: Tumor-associated macrophages (TAMs) are the most abundant immune cells within the tumor stroma and play a crucial role in tumor development. Although clinical investigations indicate that high levels of macrophage (MPhi) infiltration into tumors are associated with a poor prognosis, the exact role played by TAMs during tumor development remains unclear. The present study aimed to investigate dynamic changes in TAM major histocompatibility complex (MHC) class II expression levels and to assess the effects of these changes on tumor progression. RESULTS: Significant inhibition of tumor growth in the murine hepatocellular carcinoma Hepa1-6 model was closely associated with partial TAM depletion. Strikingly, two distinct TAM subsets were found to coexist within the tumor microenvironment during Hepa1-6 tumor development. An MHC class II(hi) TAM population appeared during the early phase of tumor development and was associated with tumor suppression; however, an MHC class II(low) TAM population became increasingly predominant as the tumor progressed. CONCLUSIONS: Tumor progression was positively correlated with increasing infiltration of the tumor tissues by MHC class II(low) TAMs. Thus, targeting the transition of MPhi may be a novel strategy for drug development and immunotherapy. PMID- 21813022 TI - The activity of the endocannabinoid metabolising enzyme fatty acid amide hydrolase in subcutaneous adipocytes correlates with BMI in metabolically healthy humans. AB - BACKGROUND: The endocannabinoid system (ECS) is a ubiquitously expressed signalling system, with involvement in lipid metabolism and obesity. There are reported changes in obesity of blood concentrations of the endocannabinoids anandamide (AEA) and 2-arachidonoylglcyerol (2-AG), and of adipose tissue expression levels of the two key catabolic enzymes of the ECS, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL). Surprisingly, however, the activities of these enzymes have not been assayed in conditions of increasing adiposity. The aim of the current study was to investigate whether FAAH and MGL activities in human subcutaneous adipocytes are affected by body mass index (BMI), or other markers of adiposity and metabolism. METHODS: Subcutaneous abdominal mature adipocytes, fasting blood samples and anthropometric measurements were obtained from 28 metabolically healthy subjects representing a range of BMIs. FAAH and MGL activities were assayed in mature adipocytes using radiolabelled substrates. Serum glucose, insulin and adipokines were determined using ELISAs. RESULTS: MGL activity showed no relationship with BMI or other adiposity indices, metabolic markers (fasting serum insulin or glucose) or serum adipokine levels (adiponectin, leptin or resistin). In contrast, FAAH activity in subcutaneous adipocytes correlated positively with BMI and waist circumference, but not with skinfold thickness, metabolic markers or serum adipokine levels. CONCLUSIONS: In this study, novel evidence is provided that FAAH activity in subcutaneous mature adipocytes increases with BMI, whereas MGL activity does not. These findings support the hypothesis that some components of the ECS are upregulated with increasing adiposity in humans, and that AEA and 2-AG may be regulated differently. PMID- 21813023 TI - Extracellular secretion of a recombinant therapeutic peptide by Bacillus halodurans utilizing a modified flagellin type III secretion system. AB - BACKGROUND: Through modification of the flagellin type III secretion pathway of Bacillus halodurans heterologous peptides could be secreted into the medium as flagellin fusion monomers. The stability of the secreted monomers was significantly enhanced through gene-targeted inactivation of host cell extracellular proteases. In evaluating the biotechnological potential of this extracellular secretion system an anti-viral therapeutic peptide, Enfuvirtide, was chosen. Currently, Enfuvirtide is synthesised utilizing 106 chemical steps. We used Enfuvirtide as a model system in an effort to develop a more cost effective biological process for therapeutic peptide production. RESULTS: An attempt was made to increase the levels of the fusion peptide by two strategies, namely strain improvement through gene-targeted knock-outs, as well as vector and cassette optimization. Both approaches proved to be successful. Through chromosomal inactivation of the spo0A, lytC and lytE genes, giving rise to strain B. halodurans BhFDL05S, the secretion of recombinant peptide fusions was increased 10-fold. Cassette optimization, incorporating an expression vector pNW33N and the N- and C-terminal regions of the flagellin monomer as an in-frame peptide fusion, resulted in a further 3.5-fold increase in the secretion of recombinant peptide fusions. CONCLUSIONS: The type III flagellar secretion system of B. halodurans has been shown to successfully secrete a therapeutic peptide as a heterologous flagellin fusion. Improvements to both the strain and expression cassette led to increased levels of recombinant peptide, showing promise for a biotechnological application. PMID- 21813024 TI - Family physician decisions following stroke symptom onset and delay times to ambulance call. AB - BACKGROUND: For stroke patients, calling an ambulance has been shown to be associated with faster times to hospital than contacting a family physician. However little is known about the impact of decisions made by family physicians on delay times for stroke patients once they have been called.We aimed to test the hypotheses that among ambulance transported stroke patients:* Factors associated with first calling a family physician, could be identified.* Time to ambulance call will be longer when a family physician is first contacted.* Medical examination prior to the ambulance call will be associated with longer delay times. METHODS: For 6 months in 2004, all ambulance-transported stroke patients who presented from a defined region in Melbourne, Australia to one of three hospitals were assessed. Ambulance and hospital records were analysed. The patient and the person who called the ambulance were interviewed to obtain their description of the stroke event. RESULTS: 198 patients were included in the study. In 32% of cases an ambulance was first called. No demographic or situational factors were associated with first calling a doctor. Patients with a history of stroke or TIA were less likely to call a doctor following symptom onset (p = 0.01). Patients with a severe stroke (Glasgow Coma Scale < 9) never called a doctor first.When a family physician was contacted (22% of cases), the time to ambulance call was significantly longer than when an ambulance was first called (p = 0.0018) (median 143 and 44 minutes, respectively). In 36% of calls to a family physician, the doctor elected to first examine the patient. Time to ambulance call was shorter when the doctor vetted the call and advised the caller to immediately call an ambulance (45%) (median 412 and 92 minutes respectively: p = 0.06). CONCLUSION: Time delays to ambulance call were significantly longer for stroke patients when a family physician was first contacted. Further extensive delays were experienced by patients when the family physician elected to examine the patient.Family physicians and their staff have an important role to play in averting potential delays for stroke patients by screening calls and providing immediate advice to "call an ambulance". PMID- 21813025 TI - The validity and reliability of a home environment preschool-age physical activity questionnaire (Pre-PAQ). AB - BACKGROUND: There is a need for valid population level measures of physical activity in young children. The aim of this paper is to report the development, and the reliability and validity, of the Preschool-age Children's Physical Activity Questionnaire (Pre-PAQ) which was designed to measure activity of preschool-age children in the home environment in population studies. METHODS: Pre-PAQ was completed by 103 families, and validated against accelerometry for 67 children (mean age 3.8 years, SD 0.74; males 53%). Pre-PAQ categorizes activity into five progressive levels (stationary no movement, stationary with limb or trunk movement, slow, medium, or fast-paced activity). Pre-PAQ Levels 1-2 (stationary activities) were combined for analyses. Accelerometer data were categorized for stationary, sedentary (SED), non-sedentary (non-SED), light (LPA), moderate (MPA) and vigorous (VPA) physical activity using manufacturer's advice (stationary) or the cut-points described by Sirard et al and Reilly et al. Bland-Altman methods were used to assess agreement between the questionnaire and the accelerometer measures for corresponding activity levels. Reliability of the Pre-PAQ over one week was determined using intraclass correlations (ICC) or kappa (kappa) values and percentage of agreement of responses between the two questionnaire administrations. RESULTS: Pre-PAQ had good agreement with LPA (mean difference 1.9 mins.day-1) and VPA (mean difference -4.8 mins.day-1), was adequate for stationary activity (mean difference 7.6 mins.day-1) and poor for sedentary activity, whether defined using the cut-points of Sirard et al (mean difference -235.4 mins.day-1) or Reilly et al (mean difference -208.6 mins.day-1) cut-points. Mean difference between the measures for total activity (i.e. Reilly's non-sedentary or Sirard's LMVPA) was 20.9 mins.day-1 and 45.2 mins.day 1. The limits of agreement were wide for all categories. The reliability of Pre PAQ question responses ranged from 0.31-1.00 (ICC (2, 1)) for continuous measures and 0.60-0.97 (kappa) for categorical measures. CONCLUSIONS: Pre-PAQ has acceptable validity and reliability and appears promising as a population measure of activity behavior but it requires further testing on a more broadly representative population to affirm this. Pre-PAQ fills an important niche for researchers to measure activity in preschool-age children and concurrently to measure parental, family and neighborhood factors that influence these behaviors. PMID- 21813026 TI - Determining utility values in patients with anterior cruciate ligament tears using clinical scoring systems. AB - BACKGROUND: Several instruments and clinical scoring systems have been established to evaluate patients with ligamentous knee injuries. A comparison of individual articles in the literature is challenging, not only because of heterogeneity in methodology, but also due to the variety of the scoring systems used to document clinical outcomes. There is limited information about the correlation between used scores and quality of life with no information being available on the impact of each score on the utility values. The aim of this study was to compare the most commonly used scores for evaluating patients with anterior cruciate ligament (ACL) injuries, and to establish corresponding utility values. These values will be used for the interpretation and comparison of outcome results in the currently available literature for different treatment options. METHODS: Four hypothetical vignettes were defined, based on different levels of activities after rupture of the ACL to simulate typical situations seen in daily practice. A questionnaire, including the Health Utility Index (HUI) for utility values, the IKDC subjective score, the Lysholm and the Tegner score, was created and 25 orthopedic surgeons were asked to fill the questionnaire for each hypothetical patient as proxies for all patients they had treated and who would fit in that hypothetical vignette. RESULTS: The utility value as an indicator for quality of life increased with the level of activity. Having discomforts already during normal activities of daily living was rated with a mean utility value of 0.37 +/- 0.19, half of that of a situation where mild sport activity was possible without discomfort (0.78 +/- 0.11). All investigated scores were able to distinguish clearly (p < 0.05) between the hypothetical vignettes. However, the utility values correlated best with the IKDC subjective score (r = 0.86, p < 0.001) followed by the Lysholm score (r = 0.77, p < 0.001) and the Tegner score (r = 0.77, p < 0.001). CONCLUSIONS: Here we report the correlation between the most commonly used scores for the assessment of patients with a ruptured ACL and utility values as an indicator of quality of life. Assumptions were based on expert opinions to provide a possible transformation algorithm. The IKDC subjective knee score showed the highest correlation to the quality of life (i.e. HUI) in patients with a ruptured ACL. Confirmation of our results is needed by systematic inclusion of a measurement instrument for utility values in future clinical studies beside the already used clinical knee scoring systems. PMID- 21813027 TI - Involvement of Cox-2 in the metastatic potential of chemotherapy-resistant breast cancer cells. AB - BACKGROUND: A major problem with the use of current chemotherapy regimens for several cancers, including breast cancer, is development of intrinsic or acquired drug resistance, which results in disease recurrence and metastasis. However, the mechanisms underlying this drug resistance are unknown. To study the molecular mechanisms underlying the invasive and metastatic activities of drug-resistant cancer cells, we generated a doxorubicin-resistant MCF-7 breast cancer cell line (MCF-7/DOX). METHODS: We used MTT (3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide) assays, flow cytometry assays, DNA fragmentation assays, Western blot analysis, cell invasion assays, small interfering RNA (siRNA) transfection, reverse transcription-polymerase chain reaction, experimental lung metastasis models, and gelatin and fibrinogen/plasminogen zymography to study the molecular mechanism of metastatic activities in MCF-7/DOX cells. RESULTS: We found that MCF-7/DOX acquired invasive activities. In addition, Western blot analysis showed increased expression of epidermal growth factor receptor (EGFR) and Cox-2 in MCF-7/DOX cells. Inhibition of Cox-2, phosphoinositide 3-kinase (PI3K)/Akt, or mitogen-activated protein kinase (MAPK) pathways effectively inhibited the invasive activities of MCF-7/DOX cells. Gelatin and fibrinogen/plasminogen zymography analysis showed that the enzymatic activities of matrix metalloproteinase-2 (MMP-2), MMP-9, and urokinase-type plasminogen activator were markedly higher in MCF-7/DOX cells than in the MCF-7 cells. In vitro invasion assays and mouse models of lung metastasis demonstrated that MCF-7/DOX cells acquired invasive abilities. Using siRNAs and agonists specific for prostaglandin E (EP) receptors, we found that EP1 and EP3 played important roles in the invasiveness of MCF-7/DOX cells. CONCLUSIONS: We found that the invasive activity of MCF-7/DOX cells is mediated by Cox-2, which is induced by the EGFR-activated PI3K/Akt and MAPK pathways. In addition, EP1 and EP3 are important in the Cox-2-induced invasion of MCF-7/DOX cells. Therefore, not only Cox-2 but also EP1 and EP3 could be important targets for chemosensitization and inhibition of metastasis in breast cancers that are resistant to chemotherapy. PMID- 21813028 TI - Leishmania donovani: proteasome-mediated down-regulation of methionine adenosyltransferase. AB - Methionine adenosyltransferase (MAT) is an important enzyme for metabolic processes, to the extent that its product, S-adenosylmethionine (AdoMet), plays a key role in trans-methylation, trans-sulphuration and polyamine synthesis. Previous studies have shown that a MAT-overexpressing strain of Leishmania donovani controls AdoMet production, keeping the intracellular AdoMet concentration at levels that are compatible with cell survival. This unexpected result, together with the fact that MAT activity and abundance changed with time in culture, suggests that different regulatory mechanisms acting beyond the post transcriptional level are controlling this protein. In order to gain an insight into these mechanisms, several experiments were carried out to explain the MAT abundance during promastigote cell growth. Determination of MAT turnover in cycloheximide (CHX)-treated cultures resulted in a surprising 5-fold increase in MAT turnover compared to CHX-untreated cultures. This increase agrees with a stabilization of the MAT protein, whose integrity was maintained during culture. The presence of proteasome inhibitors, namely MG-132, MG-115, epoxomycin and lactacystin in the culture medium prevented MAT degradation in both MAT overexpressing and 'mock-transfected' leishmanial strains. The role of the ubiquitin (Ub) pathway in MAT down-regulation was supported using immunoprecipitation experiments. Immunoprecipitated MAT cross-reacted with anti Ub antibodies, which provides evidence of a proteasome-mediated down-regulation of the leishmanial MAT abundance. PMID- 21813029 TI - Differential effectiveness of berry polyphenols as anti-giardial agents. AB - Following previous work on the anti-giardial effect of blueberry polyphenols, a range of polyphenol-rich extracts from berries and other fruits was screened for their ability to kill Giardia duodenalis, an intestinal parasite of humans. Polyphenol-rich extracts were prepared from berries using solid-phase extraction and applied to trophozoites of Giardia duodenalis grown in vitro. All berry extracts caused inhibition at 166 MUg gallic acid equivalents (GAE)/ml phenol content but extracts from strawberry, arctic bramble, blackberry and cloudberry were as effective as the currently used drug, metronidazole, causing complete trophozoite mortality in vitro. Cloudberry extracts were found to be the most effective causing effectively complete trophozoite mortality at 66 MUg GAE/ml. The polyphenol composition of the more effective berry extracts suggested that the presence of ellagitannins could be an important factor. However, the potency of cloudberry could be related to high ellagitannin content but also to the presence of substantial amounts of unconjugated p-coumaric acid and benzoic acid. These in vitro effects occur at concentrations easily achievable in the gut after berry ingestion and we discuss the likelihood that berry extracts could be effective anti-giardial agents in vivo. PMID- 21813030 TI - Relation of Parkinson's disease subtypes to visual activities of daily living. AB - Visual perceptual problems are common in Parkinson's disease (PD) and often affect activities of daily living (ADLs). PD patients with non-tremor symptoms at disease onset (i.e., rigidity, bradykinesia, gait disturbance or postural instability) have more diffuse neurobiological abnormalities and report worse non motor symptoms and functional changes than patients whose initial symptom is tremor, but the relation of motor symptom subtype to perceptual deficits remains unstudied. We assessed visual ADLs with the Visual Activities Questionnaire in 25 non-demented patients with PD, 13 with tremor as the initial symptom and 12 with an initial symptom other than tremor, as well as in 23 healthy control participants (NC). As expected, the non-tremor patients, but not the tremor patients, reported more impairment in visual ADLs than the NC group, including in light/dark adaptation, acuity/spatial vision, depth perception, peripheral vision and visual processing speed. Non-tremor patients were significantly worse than tremor patients overall and on light/dark adaptation and depth perception. Environmental enhancements especially targeted to patients with the non-tremor PD subtype may help to ameliorate their functional disability. PMID- 21813031 TI - The UCLA longitudinal study of neurocognitive outcomes following mild pediatric traumatic brain injury. AB - Comprehensive reviews of neurocognitive outcomes following mild, uncomplicated traumatic brain injury (TBI) in children have shown minimal effects on neurocognition, especially in methodologically rigorous studies. In this study, we report longitudinal (1, 6, and 12 months post injury) results in four domains of neurocognitive functioning in a large sample of children with mild TBI (n = 124, ages 8-17 at injury) relative to two demographically matched control groups (other injury: n = 94 and non-injury: n = 106). After accounting for age and parental education, significant main effects of group were observed on 7 of the 10 neurocognitive tests. However, these differences were not unique to the TBI sample but were found between both the TBI and other injury groups relative to the non-injured group, suggesting a general injury effect. Effects were primarily within the domains measuring memory, psychomotor processing speed, and language. This is the largest longitudinal study to date of neurocognitive outcomes at discrete time points in pediatric mild TBI. When controlling for pre-injury factors, there is no evidence of long-term neurocognitive impairment in this group relative to another injury control group. The importance of longitudinal analyses and use of appropriate control groups are discussed in the context of evaluating the effects of mild TBI on cognition. PMID- 21813032 TI - Characterizing the normal developmental trajectory of expressive language lateralization using magnetoencephalography. AB - To characterize the developmental trajectory for expressive language representation and to test competing explanations for the relative neuroplasticity of language in childhood, we studied 28 healthy children and adolescents (aged 5-19 years) participating in a covert verb generation task in magnetoencephalography. Lateralization of neuromagnetic responses in the frontal lobe was quantified using a bootstrap statistical thresholding procedure for differential beamformer analyses. We observed a significant positive correlation between left hemisphere lateralization and age. Findings suggest that adult typical left hemisphere lateralization emerges from an early bilateral language network, which may explain the pediatric advantage for interhemispheric plasticity of language. PMID- 21813033 TI - Does antiretroviral therapy improve HIV-associated cognitive impairment? A quantitative review of the literature. AB - The development of antiretroviral therapy (ART) has dramatically improved survival for those living with human immunodeficiency virus (HIV), but whether ART improves cognitive functioning remains unclear. The aim of the present review was to examine systematically the extent to which ART improves cognition among individuals with HIV using meta-analytic methods. Twenty-three studies were included in the quantitative review. ART was associated with modest improvements in attention (mean d = .17; p < .001; 95% confidence interval [CI], .09/.25), executive function (mean d = .18; p < .001; 95% CI, .10/.26), and motor function (mean d = .24; p < .001; 95% CI, .16/.32). ART did not improve language, verbal memory, visual memory or visuospatial function. The extent to which cognition improved was correlated with the change in CD4 cell count following ART, suggesting a link between cognitive outcome and immune system integrity. Together, the present findings indicate that the neuropsychological test performance of most HIV patients taking ART is comparable to those not taking ART. Development of pharmaceutical treatments and rehabilitation strategies that target the cognitive effects of HIV infection is needed. PMID- 21813034 TI - A systematic review of the cost-effectiveness of interventions for supporting informal caregivers of people with dementia residing in the community. AB - BACKGROUND: Dementia places a huge demand on healthcare services; however, a large proportion of the cost is borne by informal caregivers. With the number of people affected by dementia set to increase in the future, there is a need for research to consider the effects of interventions on informal caregivers as well as on the individuals with dementia. This paper seeks to systematically review the existing evidence on the cost-effectiveness of interventions to support informal caregivers of people with dementia residing in the community. METHODS: A range of electronic databases was searched. Studies were included if both costs and outcome measures for informal caregivers of people with dementia residing in the community were reported for an intervention. Both pharmacological and non pharmacological interventions were included. Quality of study was assessed using the Drummond ten-item checklist for economic evaluations and results were presented through narrative synthesis. RESULTS: Twelve studies were included in the review; of these only four reported a significant difference in the outcome measure for caregivers. CONCLUSIONS: At present few published studies report costs in enough detail to provide evidence of the effectiveness and cost effectiveness of interventions for supporting caregivers. Future trials need to collect caregiver data alongside patient data in order to increase the evidence base for intervention effectiveness. Further research is required to establish the effectiveness and cost-effectiveness of both pharmacological and non pharmacological approaches. PMID- 21813035 TI - Revised NIA-AA criteria for the diagnosis of Alzheimer's disease: a step forward but not yet ready for widespread clinical use. PMID- 21813036 TI - Psychotropic drug prescription in nursing home patients with dementia: influence of environmental correlates and staff distress on physicians' prescription behavior. AB - BACKGROUND: The aim of the study was to examine whether staff distress and aspects of the nursing home environment were associated with psychotropic drug use (PDU) in patients with dementia. METHODS: This was a cross-sectional study of 1289 nursing home patients with dementia from 56 Dementia Special Care Units (SCUs) in the Netherlands. The primary outcome was PDU. Potential correlates of PDU were staff distress, environmental correlates (the number of patients per unit or per living room, staff/patient ratio, and the presence of a walking circuit), and patient factors (gender, age, dementia severity, and neuropsychiatric symptoms (NPS)). Multilevel logistic regression analysis was used to estimate the relative contributions of predictor variables in explaining PDU. RESULTS: Staff distress, aspects of the physical nursing home environment and patients' neuropsychiatric symptoms were independently associated with PDU. Staff distress at patients' agitation was associated with antipsychotic and anxiolytic drug use (OR 1.66, 95% CI (1.16-2.36) and 1.62 (1.00-2.61), respectively). SCUs with more patients per living room had higher hypnotic drug use (OR 1.08, 95% CI (1.02-1.14)). Low staff/patient ratio was associated with high antidepressant drug use (OR 0.13, 95% CI (0.04-0.47)). The effects of nursing home environment on study outcome were smallest for antidepressant use (intra-SCU correlation 0.005) and highest for hypnotic use (intra-SCU correlation 0.171). CONCLUSION: Staff distress and other environmental aspects are independently associated with PDU. These findings raise questions about the appropriateness of psychoactive drug prescriptions for nursing home patients with dementia. PMID- 21813037 TI - Clock drawing test - screening utility for mild cognitive impairment according to different scoring systems: results of the Leipzig Longitudinal Study of the Aged (LEILA 75+). AB - BACKGROUND: There is a strong demand for screening instruments for mild cognitive impairment (MCI), as a pre-stage of dementia. The clock drawing test (CDT) is widely used to screen for dementia, but the utility in screening for MCI remains uncertain. In particular, it is still questionable which scoring system is the best in order to screen for MCI. We therefore aimed to compare the utility of different CDT scoring systems for screening for MCI. METHODS: In a sample of 428 subjects of the Leipzig Longitudinal Study of the Aged (LEILA 75+) study, CDT scores of different scoring systems were compared between subjects with and without MCI. Comparison of receiver operating characteristic (ROC; area under the curve, sensitivity, specificity) was performed and inter-rater reliability was calculated. RESULTS: The CDT scores differed significantly between MCI and non MCI subjects according to all scoring systems applied. However, ROC of the CDT scores was not adequate. CONCLUSIONS: None of the present CDT scoring systems has sufficient utility to screen reliably for MCI. The clinical value of the CDT could be improved by using semi-quantitative scoring, having a wider score range and focusing on specific details of the clock (e.g. the hands and numbers). PMID- 21813038 TI - Perseverative errors on the Wisconsin Card Sorting Test and brain perfusion imaging in mild Alzheimer's disease. AB - BACKGROUND: The Wisconsin Card Sorting Test (WCST) has long been used to investigate deficits in executive function in humans. The majority of studies investigating deficient WCST performance focused on the number of categories achieved (CA) and the number of perseverative errors of the Nelson type (PEN). However, there is insufficient evidence that these two measures reflect the same neural deficits. METHODS: Twenty AD patients with high PEN scores, and 20 age- and sex-matched AD patients with low PEN scores were selected. All 40 subjects underwent brain SPECT, and the SPECT images were analyzed by Statistical Parametric Mapping. RESULTS: No significant differences were found between high and low PEN score groups with respect to years of education, Addenbrooke's Cognitive Examination scores, and Mini-Mental State Examination scores. However, higher z scores for hypoperfusion in the bilateral rectal and orbital gyri were observed in the high PEN score group compared with the low PEN score group. CONCLUSIONS: Our results suggest that functional activity of the bilateral rectal and orbital gyri is closely related to PEN scores on a modified WCST (mWCST). The PEN score on a mWCST might be a promising index of dysfunction of the orbitofrontal area among patients with mild AD. PMID- 21813039 TI - Identification and recognition of depression in community care assessments: impact of a national policy in England. AB - BACKGROUND: Depression continues to be under-recognized in older people. Most policies addressing this issue focus on the primary health care team. However, recognition may be improved by use of assessment tools and collaboration between secondary health and social care, particularly at the assessment stage. This study aimed to evaluate whether the Single Assessment Process (SAP), introduced in England from April 2004, promoting such processes, improved the identification and correct recognition of depression by enhancing the content of statutory community care assessments by social services care managers. METHODS: An observational study compared depression identification and its accuracy ("correct recognition") in samples of older people before and after SAP introduction. Participants were interviewed using standardized measures including the Geriatric Depression Scale (GDS). Depression elicited from the GDS was compared with that recorded in community care assessments with calculation of inter-rater reliabilities (kappa statistic) pre- and post-SAP. Logistic regression examined the associations between the policy's introduction, potential confounding factors (depression, cognitive impairment, function, behavior and characteristics) and the identification and correct recognition of depression. RESULTS: Whilst the identification of depression was more likely after SAP, its correct recognition did not improve after the policy, with only slight agreement between GDS and community care assessments. The existence of depression and cognitive impairment made identification, but not correct recognition, more likely. CONCLUSIONS: Correct recognition of depression was not improved in these statutory care assessments following the policy. Recognizing and thus responding to depression in a coordinated and appropriate way in the community requires further action. PMID- 21813040 TI - Psychometric properties of the Spanish version of the Geriatric Anxiety Inventory. AB - BACKGROUND: The Geriatric Anxiety Inventory (GAI) was developed for assessing anxiety in older adults. The objectives of this work were: (a) to analyze the psychometric properties of the Spanish version of the GAI, and (b) to explore the associations between anxiety and other variables related to emotional distress (depression) and emotion regulation (rumination, experiential avoidance, and emotion suppression). METHODS: Three-hundred-and-two people (75.5% female) aged 60 years and over living in the community participated in this study. Anxiety, depression, rumination, suppression and experiential avoidance were measured. RESULTS: Three factors explaining 50.11% of the variance were obtained. The obtained internal consistency for the total scale was 0.91, with alphas ranging between 0.71 and 0.89 for the factors. Significant associations between all the GAI factors, the GAI total score, and depression, rumination, and experiential avoidance were found (all p < 0.01). Women reported higher scores than men for both the GAI total score and for all of the subscales. However, no significant gender differences were found between people with scores higher than the cut-off score for the GAI. CONCLUSIONS: The results of this study suggest that the Spanish version of the GAI displays good psychometric properties. Further, our data suggest that the scale can be recommended for measuring anxiety in non clinical older Spanish persons, and may be a useful instrument to be used in research studies aimed at analyzing anxiety and its correlates among older adults. PMID- 21813041 TI - School attainment in childhood is an independent risk factor of dementia in late life: results from a Brazilian sample. AB - BACKGROUND: This study sought to assess whether lower school performance in childhood is a risk factor for dementia in old age. METHODS: Participants aged 60 years or more (n = 111) with documented proof from schools were included. Grades in three subjects - Portuguese, mathematics, and geography - were recorded and the mean final grade in all disciplines were assessed. Dementia was diagnosed using DSM-IV criteria. Sociodemographic data, school performance, and years of education were ascertained by checking documents issued by schools. Health status (hypertension and diabetes) were self reported. Regression models were used to assess the role of school performance and years of education on the risk of dementia. RESULTS: Dementia was diagnosed in 22 subjects. Higher school performance and years of education decreased the chance of dementia by 79% (OR = 0.21; CI 0.08-0.58) and 21% (OR = 0.79; CI 0.69-0.91), respectively. After adjustments for sociodemographic and clinical variables, only school performance remained statistically significant (OR = 0.06; CI 0.01-0.71). CONCLUSIONS: Education in early life should be viewed as a health issue over the life course. School attainment in certain basic disciplines may be important for cognitive reserve and prevention of dementia in the elderly. PMID- 21813043 TI - Spatio-temporal variations and age effect on Toxoplasma gondii seroprevalence in seals from the Canadian Arctic. AB - Toxoplasmosis is a significant public health threat for Inuit in the Canadian Arctic. This study aimed to investigate arctic seals as a possible food-borne source of infection. Blood samples collected from 828 seals in 7 Canadian Arctic communities from 1999 to 2006 were tested for Toxoplasma gondii antibodies using a direct agglutination test. Polymerase chain reaction (PCR) was used to detect T. gondii DNA in tissues of a subsample of seals. Associations between seal age, sex, species, diet, community and year of capture, and serological test results were investigated by logistic regression. Overall seroprevalence was 10.4% (86/828). All tissues tested were negative by PCR. In ringed seals, seroprevalence was significantly higher in juveniles than in adults (odds ratio=2.44). Overall, seroprevalence varied amongst communities (P=0.0119) and by capture year (P=0.0001). Our study supports the hypothesis that consumption of raw seal meat is a significant source of infection for Inuit. This work raises many questions about the mechanism of transfer of this terrestrial parasite to the marine environment, the preponderance of infection in younger animals and the natural course of infection in seals. Further studies to address these questions are essential to fully understand the health risks for Inuit communities. PMID- 21813042 TI - Exposure, infection, systemic cytokine levels and antibody responses in young children concurrently exposed to schistosomiasis and malaria. AB - Despite the overlapping distribution of Schistosoma haematobium and Plasmodium falciparum infections, few studies have investigated early immune responses to both parasites in young children resident in areas co-endemic for the parasites. This study measures infection levels of both parasites and relates them to exposure and immune responses in young children. Levels of IgM, IgE, IgG4 directed against schistosome cercariae, egg and adult worm and IgM, IgG directed against P. falciparum schizonts and the merozoite surface proteins 1 and 2 together with the cytokines IFN-gamma, IL-4, IL-5, IL-10 and TNF-alpha were measured by ELISA in 95 Zimbabwean children aged 1-5 years. Schistosome infection prevalence was 14.7% and that of Plasmodium infection was 0% in the children. 43. 4% of the children showed immunological evidence of exposure to schistosome parasites and 13% showed immunological evidence of exposure to Plasmodium parasites. Schistosome-specific responses, indicative of exposure to parasite antigens, were positively associated with cercariae-specific IgE responses, while Plasmodium-specific responses, indicative of exposure to parasite antigens, were negatively associated with responses associated with protective immunity against Plasmodium. There was no significant association between schistosome-specific and Plasmodium-specific responses. Systemic cytokine levels rose with age as well as with schistosome infection and exposure. Overall the results show that (1) significantly more children are exposed to schistosome and Plasmodium infection than those currently infected and; (2) the development of protective acquired immunity commences in early childhood, although its effects on infection levels and pathology may take many years to become apparent. PMID- 21813044 TI - Association of MMP-2 and MMP-9 with clinical outcome of neurocysticercosis. AB - Matrix metalloproteinases (MMPs) are the major endopeptidases involved in proteolysis of blood brain barrier (BBB) during central nervous system (CNS) infections. The present study detected serum levels and activities of MMP-2 and MMP-9 in patients with neurocysticercosis (NCC) and their association with symptomatic disease. In total, 68 individuals with NCC (36 symptomatic patients with active seizures and 32 asymptomatic individuals) and 37 healthy controls were enrolled for the study. Serum MMP-2 and MMP-9 levels and their activities were measured by ELISA and gel zymography respectively. Mean serum MMP-2 levels (ng/ml) were higher both in asymptomatic and symptomatic NCC cases compared to healthy controls. However, significantly higher levels of serum MMP-9 (ng/ml) were detected only in symptomatic NCC patients compared to asymptomatic NCC cases and healthy controls. Levels of both MMPs positively correlated with symptomatic NCC. Serum MMP-2 activities were significantly higher in symptomatic and asymptomatic NCC compared to healthy controls whereas serum MMP-9 activity was significantly associated with symptomatic NCC compared to healthy controls and asymptomatic NCC. In conclusion, the elevated level of MMP-9 in serum appears to play an important role in the development of symptoms i.e. active seizures in patients with NCC. However, further studies are needed to elucidate its precise role in disease pathogenesis. PMID- 21813045 TI - Surrogate markers of treatment outcome in major depressive disorder. AB - Major depressive disorder (MDD) is a common medical illness affecting millions worldwide. Despite their widespread use since the 1950s and 1960s, the 'downstream' mechanism by which antidepressants ultimately exert their therapeutic effects remains elusive. In addition, except for a few exceptions such as episode severity and the presence of comorbid Axis-I or Axis-III disorders, biological or clinical characteristics which can accurately quantify the risk of poor treatment outcome are lacking, as are factors which could help patients and clinicians select treatment options that would result in superior outcome. The identification of such markers, termed 'surrogate' markers, could help shed further insights into what constitutes illness and recovery, help identify molecular targets for the development of future antidepressants, and lead the way to the design and refinement of a personalized medicine treatment model for MDD. In the following text, several major areas ('leads') where evidence exists regarding the presence of surrogate markers of efficacy outcome in MDD will be briefly reviewed. Leads include evidence from the role of demographic and clinical factors as surrogate markers, to the role of various biological markers including genotype, brain functional imaging, electroencephalography, dichotic listening, and molecular biology and immunology. The purpose of this work is to focus selectively on areas where there have been findings, as opposed to conducting an exhaustive literature review of studies which have failed to yield any significant breakthrough in our knowledge. PMID- 21813054 TI - Assessing fibromyalgia-related fatigue: content validity and psychometric performance of the Fatigue Visual Analog Scale in adult patients with fibromyalgia. AB - OBJECTIVES: To document 1) the content validity and 2) measure improvements in fatigue, using the Fatigue Visual Analogue Scale (VAS) assessment tool in patients with fibromyalgia. METHODS: The relevance and comprehensiveness of the Fatigue VAS were tested through a qualitative analysis of 20 subjects' verbatim transcripts from semi-structured qualitative interviews. Data from two randomised, controller trials in fibromyalgia (n=1121) were used to conduct correlation analyses with the Fatigue and Tiredness items from the Fibromyalgia Impact Questionnaire (FIQ) and the Short Form-36 Vitality scale. Known-groups and cross classification analyses were conducted to demonstrate the ability to measure improvement in fatigue using the Fatigue VAS. RESULTS: All subjects spontaneously reported that fatigue was an important symptom to capture in fibromyalgia. The Fatigue VAS was well understood by most subjects (n=18/20). High correlations (Pearson r>0.75) and good agreement (k>0.66) were found between the Fatigue VAS and the FIQ tiredness items no. 16 and 17 and SF-36TM Vitality scale. In both clinical trials there was a substantial separation of approximately 20 points on the mean change in the Fatigue VAS score between responders (>30% improvement in pain VAS) and non-responders. CONCLUSIONS: Previous studies have confirmed that fatigue is a major component of the fibromyalgia experience. This current study reports that fibromyalgia patients spontaneously rated fatigue as a highly significant feature of their illness, and supports the use of the Fatigue VAS as a valid questionnaire in fibromyalgia clinical trials. PMID- 21813053 TI - Antinuclear antibodies are associated with tumor necrosis factor receptor I gene polymorphism in patients with rheumatoid arthritis. AB - OBJECTIVES: Antinuclear antibodies (ANA) are a common feature of autoimmune diseases such as rheumatoid arthritis (RA). Herein, we investigate the relationship between ANA and polymorphism in the tumour necrosis factor receptor (TNFR) genes. METHODS: Serum titers of ANA at diagnosis were measured in 267 patients with RA and a single nucleotide polymorphism (SNP) in each of the TNFR-I (36A/G) and TNFR-II (676T/G) genes was genotyped by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) analysis. Circulating levels of soluble TNFR (sTNFR) and TNF-alpha were also measured in some patients. RESULTS: Our initial analyses revealed the presence of ANA was associated with the TNFR-I 36A/G SNP, with a trend of increasing ANA frequency with G allele dosage (p=0.004). ANA status was also associated with lower sTNFR-I levels and a raised sTNFR-II/sTNFR-I ratio. The TNFR-II 676T/G SNP and circulating levels of sTNFR-II and TNF-alpha were not associated with ANA status. In an adjusted multivariate regression model the TNFR-I 36 GG genotype (OR 7.8, p=0.008) and levels of sTNFR-I (p=0.018) were independently associated with ANA status. CONCLUSIONS: Our findings suggest a possible link between the production of ANA and the TNF-alpha/TNFR-I signalling system, which may be related to the apoptosis inducing ability of this cytokine. PMID- 21813055 TI - Insular cortex is a trait marker for pain processing in fibromyalgia syndrome- blood oxygenation level-dependent functional magnetic resonance imaging study in Korea. AB - OBJECTIVES: To investigate the variability in cerebral activation according to pain intensity and the association between variability in cerebral activation and clinical features in patients with fibromyalgia syndrome (FMS) using functional magnetic resonance imaging (fMRI). METHODS: Nineteen FMS female patients and 22 age-matched healthy female controls were enrolled in this study. Changes in cerebral activation area were measured using blood oxygenation level-dependent (BOLD) contrast fMRI after application of both medium and high pressure stimuli to the left thumbnail bed. RESULTS: We identified the insular cortex (IC) and superior temporal gyrus (STG) as regions of interest (ROIs) in this analysis. Cerebral activation at the bilateral IC in response to high pressure stimuli was significantly greater in FMS patients than it was in the controls, whereas there were no differences in BOLD signal changes in the STG regions between FMS patients and controls, irrespective of pain level. Prominent signal changes at both ROIs in FMS patients were noted between high and medium pressure (p<0.001 contralateral IC, p=0.001 for ipsilateral IC, p=0.008 for contralateral STG, and p=0.049 for ipsilateral STG). BOLD signal changes on the contralateral STG after medium stimuli were correlated with tender point count (r=0.586, p=0.013). CONCLUSIONS: This study revealed more distinct signal variability in the ICs in FMS patients than in those of controls in response to high pressure stimuli. The IC can therefore be considered to be a region susceptible to pain perception in FMS patients. PMID- 21813056 TI - Assessing the cost-effectiveness of biologic agents for the management of moderate-to-severe rheumatoid arthritis in anti-TNF inadequate responders in Italy: a modelling approach. AB - OBJECTIVES: The objective of this study is to assess cost-effectiveness of different biologic strategies in patients with moderate-to-severe active RA after an insufficient response to anti-TNF agents within the context of the Italian healthcare system. METHODS: Simulation models were developed allowing for potential biologic therapy switch at each 6-month time point in case of an insufficient response to the previous biologic agent. Biologic treatments included etanercept, abatacept, adalimumab, rituximab or infliximab. Effectiveness criteria for these models were defined as achieving a state of low disease activity (LDAS) [DAS28 <=3.2] or remission (RS) [DAS28<2.6]. Monte-Carlo simulations were performed for each sequence to manage data variability. RESULTS: The biologic treatment sequence using abatacept after an insufficient response to a first anti-TNF agent appeared significantly more efficacious over 2 years (102 days in LDAS) compared to rituximab (82 days in LDAS). The sequence using abatacept after 2 anti-TNF agents appeared significantly more efficacious (63 days in LDAS) compared to using a third anti-TNF agent (32 days in LDAS). Mean cost-effectiveness ratios showed significantly lower costs per day in LDAS with abatacept used after one anti-TNF agent (?376) compared to rituximab (?456). The sequence using abatacept after 2 anti-TNF agents was also more cost-effective (?642 per day in LDAS) versus a sequential use of anti-TNF therapies (?1164 per day in LDAS). All comparisons were confirmed when using the remission effectiveness criteria. CONCLUSIONS: The results of this health economics modelling study suggest that the biologic treatment sequence using abatacept after an insufficient response to a first anti-TNF agent appears significantly more effective and cost-effective versus a similar sequence using rituximab for achieving remission or LDAS. The results also indicate that in the case of an insufficient reponse to 2 anti-TNF agents, abatacept appears more effective and cost-effective than using a 3rd anti-TNF agent. PMID- 21813057 TI - Efficacy of the "body movement and perception" method in the treatment of fibromyalgia syndrome: an open pilot study. AB - OBJECTIVES: Group exercises may be useful in fibromyalgia syndrome (FMS). The 'Body movement and perception' (BMP) method is based on low impact exercises, awareness of body perception and relaxation, aimed at treating small groups of patients following the Resseguier method (RM) and integrating RM with exercises derived from soft gymnastics. We assessed the effects of BMP method on FMS. METHODS: 40 women with FMS (age and disease duration: 51.7+/-7.2 and 4.9+/-3.8 years) participated in an open pilot study. BMP sessions were performer twice a week (50 minutes each) for 8 weeks. Patients were assessed at enrolment (T0) and at the end of the study (T1) by a self-administered questionnaire (temporal characteristics of pain, pain interference in working and recreational activities and in night-time rest, awareness of pain, fatigue, irritability, well-being, quality of movement, ability to focus on perception and to perceive whole body, postural selfcontrol, ability to relax) and a clinical evaluation (tender points, assumption of analgesics/NSAIDs, distribution of pain, pain in sitting and standing position, pain during postural passages and gait, postural body alignment, muscular contractures). RESULTS: At T1, FMS patients significantly improved with respect to T0 in pain, fatigue, irritability, well-being, quality of movement, postural self-control, ability to relax mind and body, movement perception, tender point scores, assumption of analgesic/NSAIDs, body alignment and muscle contractures (p<0.05 for all the comparisons T1 versus T0). CONCLUSIONS: In FMS patients, rehabilitation with BMP improves pain and well being, reduces the number of tender points and muscle contractures, thus it is useful in FMS management. PMID- 21813058 TI - Usefulness of tenderness to characterise fibromyalgia severity in women. AB - OBJECTIVES: To investigate the usefulness of tenderness (tender points count (TPC) and algometer score) to characterise fibromyalgia (FM) severity and symptomatology in women. METHODS: The study sample comprised 174 women aged 51+/ 7 years. We ossesse tenderness using pressure algometry; quality of life by means of the Short-Form 36 Health Survey (SF-36) and the Hospital Anxiety and Depression Scale (HADS). We used the FM impact questionnaire (FIQ) to assess FM severity and symptomatology. Patients were categorised according to three FIQ derived categories: FIQ<70 vs. >=70; FIQ<59 vs. >=59; and FM-type I and II. RESULTS: TPC was significantly higher in the group of patients with FIQ>=59 (16.9+/-2 vs. 15.6+/-4, p=0.02), whereas no differences between groups were observed according to FIQ>=70 (17.0+/-2 vs. 16.2+/-3, p=0.12) or FM type (16.8+/ 3 for type II vs. 15.9+/-4 for type I, p=0.13). We observed a significant association between TPC and FIQ-job difficulty, pain, morning tiredness and stiffness dimensions (all p<0.05), yet it was not correlated with total score of FIQ, FIQ-anxiety, fatigue and depression dimensions (all p>0.05). Algometer score was lower in the FIQ>=70 (45.7+/-12 vs. 51.1+/-14, p=0.05) and FIQ>=59 (46.7+/-13 vs. 52.7+/-14, p=0.05) groups, and there were no difference between FM types (48.7+/-13 vs. 49.5+/-14 for type II and I respectively, p=0.81). Algometer score was not associated with total score of FIQ or FIQ dimensions (all p>=0.1). CONCLUSIONS: Widespread pain and pain hypersensitivity, as measured by TPC and algometer score, do not seem to be useful to characterise FM severity and symptomatology (measured by FIQ) in women. PMID- 21813059 TI - Endothelium-dependent and independent dilation capability of peripheral arteries in patients with systemic lupus erythematosus and antiphospholipid syndrome. AB - OBJECTIVES: The study evaluated the systemic inflammatory response and endothelium-dependent and independent function of the brachial artery (BA) in systemic lupus erythematosus (SLE) patients with and without antiphospholipid syndrome (APS). METHODS: The study group consisted of 42 women with SLE (21 without APS; mean age 36.1 +/- 9.1, and 21 with APS; mean age 43.9 +/- 13.1) and 22 healthy controls (mean age 43.5 +/- 10.3). Endothelium-dependent functional response was evacuate using the flow-mediated vasodilatation (FMD) of brachial artery and endothelium-independent vasodilatation by application of glyceryl trinitrate (GTN). Using biochemical methods, circulating inflammatory markers were determined. RESULTS: In comparison to controls, in both groups of patients endothelium-dependent dilation of BA was significantly reduced, and there were no differences in FMD between patients with or without APS: SLE - 7.7% (11.9-12.1), SLE+APS 7.8% (2.4-12.8), controls - 14.6% (11.2-21.1), p<0.001. However, endothelium-independent dilation of the brachial artery was significantly lower in SLE-APS patients than in controls and also lower than in the SLE group: SLE - 24.3% (15.0-28.6), SLE+APS-17.4% (13.1-22.6), controls - 23.0% (17.8-30.1), p=0.015 vs. p=0.027. Patients with SLE had significantly higher values of VCAM-1, hs-CRP, and fibrinogen than controls. In patients with SLE+APS, an additional significant increase of inflammatory markers was registered. CONCLUSIONS: The results of our study indicate that patients with SLE have deteriorated endothelium-dependent and those with APS also independent vascular function which could be, together with increased inflammatory response, involved in vascular complications in these patients. The presence of APS aggravates systemic inflammatory response. PMID- 21813061 TI - A comparison of utility measurement using EQ-5D and SF-6D preference-based generic instruments in patients with rheumatoid arthritis. AB - OBJECTIVES: The purposes of this study were to analyse and compare aspects of validity (concurrent and discriminant) of the two widely used indirect utility instruments, the EuroQol-5D (EQ-5D) and the Short Form-6D (SF-6D) in a representative cohort of patients with rheumatoid arthritis (RA). METHODS: Five hundred and eighty-three consecutive adult patients (435 women, 148 men) with RA and referred to the outpatient Clinic were evaluated. Patients were asked to complete EQ-5D and SF-36. SF-6D utility scores were calculated using the eight mean SF-36 scores, according to published algorithms. Disease-related characteristics included disease duration, co-morbidities, a measure for disease activity [Disease Activity Score-28 joint (DAS28)] and for radiographical damage (Sharp van der Heijde scoring method, SHS). The agreement between the utility instruments was evaluated by Bland-Altman analysis. Construct validity was assessed using the Kruskal-Wallis test, Mann-Whitney U-test, Spearman's correlations, and receiver operating characteristic (ROC) curves. Multivariate analyses were used to assess the relationship among HRQoL and disease-related characteristics and socio-demographic data. RESULTS: A comparison of means showed that SF-6D values exceeded EQ-5D values (p<0.0001). Agreement between both measures was only moderate. Utility scores and domains and summary scores of the SF-36 were highly correlated. The EQ-5D and SF-6D both detected change in different health status (<0.0001). The discriminatory power of both indexes was good, without significant difference, with an AUC of 0.869 and 0.820, respectively for EQ-5D and SF-6D. The EQ-5D and SF-6D both detected change over different health status among RA patients (both al level of p<0.0001) although EQ 5D was more efficient in detecting differences between groups in almost all cases. Comparison of EQ-5D and SF-6D scores within VAS groups showed that, for less healthy individuals (VAS scores 0-50), the median EQ-5D score was significantly lower than the median SF-6D score. The multivariate regression models for EQ-5D and SF-6D included both SHS and DAS28 (p=0.0001). The relative contribution of these domains differed substantially between patients with short and long standing disease duration. The presence of multiple chronic conditions also appeared to contribute to reduce the levels of utility of both instruments. CONCLUSIONS: Although EQ-5D and SF-6D appeared to measure similar constructs, these instruments are quite different from each other in the assessment of RA. For worse health status the median EQ-5D scores were significantly lower than the median SF-6D scores. Moreover, EQ-5D and SF-6D appeared both significantly influenced by disease activity, radiological damage and co-morbidity. For that reason, we advise caution in the employment of these preference-based instruments, especially in RA patients with severe disease. PMID- 21813060 TI - Norms-based assessment of patient-reported outcomes associated with adalimumab monotherapy in patients with ankylosing spondylitis. AB - OBJECTIVES: To compare the impact of ankylosing spondylitis (AS) on health related quality of life (HRQL) and of adalimumab on initial and sustained improvement in HRQL for patients with active AS versus the general US population. METHODS: Data from the 5-year ATLAS trial were analysed. HRQL burden of AS and treatment impact on HRQL were assessed by comparing health status and utility scores from ATLAS (Short Form 36 Health Survey [SF-36] and Health Utilities Index Mark 3 [HUI3]) with population norms. RESULTS: Baseline scores for all measures were comparable between adalimumab and placebo. All scores for both groups were significantly worse than general population norms (all p<0.0001). Within- and between-group improvements in SF-36 Physical Component Summary and SF-6D scores from baseline to Weeks 12 and 24 were clinically relevant for patients receiving adalimumab. For patients initially randomised to adalimumab, HRQL scores improved from Weeks 25 to 52 and remained relatively stable through 3 years but remained lower than for the general US population at all time points. CONCLUSIONS: Findings demonstrate a significant burden of AS on HRQL. Treatment with adalimumab significantly improved physical functioning and other measures of HRQL compared with placebo. Clinically relevant improvements in HRQL outcomes over 3 years represent a significant benefit of adalimumab. Because of the advanced AS disease, patient health status remained below that of the general population. Treatment earlier in the course of AS may be needed to restore HRQL to the level of the general population. PMID- 21813062 TI - PLA1/A2 polymorphism of the platelet glycoprotein receptors IIIA in Behcet's disease. AB - OBJECTIVES: To investigate potential associations between the PlA1/A2 polymorphism of the platelet glycoprotein receptor IIIA (GpIIIa) gene and venous thrombosis and other clinical manifestations in Italian patients with Behcet's disease (BD). METHODS: Two hundred consecutive Italian patients satisfying the International Study Group criteria for BD who were followed up for seven years and 241 healthy Italian age- and gender-matched blood donors were molecularly genotyped for the PlA1/A2 polymorphism of the platelet GpIIIa gene; 118 and 117 of the 200 BD patients were also respectively genotyped for factor V Leiden and prothrombin gene G20210A polymorphisms. A standard microlymphocytotoxicity technique was used to type serological HLA class B51. The patients were grouped on the basis of the presence or absence of clinical manifestations. The diagnoses of deep vein thrombosis (DVT) and superficial thrombophlebitis were initially made clinically, and then confirmed by means of ultrasonography or contrast venography. The distribution of the PlA1/A2 genotype was investigated, and odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. RESULTS: The allele and genotype frequency of the PlA1/A2 polymorphism were not significantly different in the BD patients and controls, but the PlA2 allele was significantly more frequent in the BD patients with DVT than the controls (p=0.023; Pcorr=0.046; OR 2.0, 95% CI 1.1-3.7). There were no associations between thrombotic events and the PlA1/A2 polymorphism in the BD patients carrying factor V Leiden or prothrombin gene G20210A mutations. The PlA2 allele was significantly less frequent in the BD patients with genital genital ulcers than in those without (26.9% vs. 43.2%; p=0.022; P corr 0.044; OR 0.48, CI 0.27-0.88). CONCLUSIONS: The PlA1/A2 polymorphism of the GpIIIa gene was associated with DVT in our Italian BD patients, but does not seem to increase the risk of DVT due to factor V Leiden or prothrombin gene G20210A mutations. There was a negative association between the A2 allele and genital ulcers. PMID- 21813063 TI - A novel ex vivo organotypic culture model of alkaptonuria-ochronosis. AB - OBJECTIVES: Alkaptonuria (AKU) is an orphan disease that has an estimated prevalence of 0.3/100,000. The disease is caused by the lack of activity of homogentisic acid oxidase (HGO), an enzyme involved in tyrosine and phenylalanine metabolism. To date, there is only one drug, the nitisinone, with orphan designation authorised by both Food and Drug Administration (FDA) and European Medical Agency (EMA) for AKU. A clinical trial on AKU patients using nitisinone has recently been completed but it needs further investigation for long-term therapy. In recent years our group has developed a series of AKU in vitro models using cell lines, primary chondrocytes and human plasma in order to test the efficacy of new substances, mainly antioxidant compounds, for AKU therapy. Herein, we report the optimisation of an ex vivo reproducible culture method exploiting cartilage slices in order to investigate the deposition of ochronotic pigment in this kind of connective tissue. METHODS: Human normal cartilage slices, obtained after surgery for prosthesis replacement, were cultured for several days in the presence of a sublethal concentration of homogentisic acid (HGA). RESULTS: After two months of incubation with HGA, the peculiar melanin like ochronotic pigmentation can be observed into the cartilage tissue. CONCLUSIONS: This novel organo-typic ex vivo model could be extremely useful to investigate the efficacy of substances able to ameliorate the conditions of AKU patients. Moreover, it could be used for genetic and proteomic investigations to better define AKU pathophysiology. PMID- 21813064 TI - Anti-IL-6 receptor antibody (tocilizumab): a B cell targeting therapy. AB - BACKGROUND: IL-6 mediated inflammation is induced by binding to IL-6 receptor (IL 6R) or IL-6/IL-6R complex binding gp130. Tocilizumab, a recombinant humanised monoclonal antibody that acts as IL-6R antagonist has been recently introduced for the treatment of rheumatoid arthritis (RA). OBJECTIVES: To evaluate whether tocilizumab therapy may induce B cells to undergo phenotypic changes compatible with regulatory function. METHODS: B cells from treated RA patients were isolated before and after 3 months of treatment with tocilizumab and were stained for the expression of intracellular TGF-beta, IL-10, membrane CD69, and MHCII. These markers were assessed in CD25(high) B cells considered to belong to a regulatory/suppressive subset of B cells. All markers were expressed in mean flow cytometry intensity (MFI), with results given in mean +/- SEM. Data was compared before and after tocilizumab treatment. RESULTS: Clinical improvement was noted three months following the initiation of tocilizumab, namely: DAS improvement from 6.8 +/- 0.3 at baseline to 3.1 +/- 0.4, p<0.002, and ESR decrease from 44.4 +/- 8.6 at baseline to 7.4 +/- 2.3, p<0.006. This clinical benefit was found to occur in association with the expansion of a B cell subset with regulatory properties namely: the expression of intracellular TGF-beta in CD25-high B cells was significantly increased (from 5.2 +/- 2.3 at baseline to 8.1 +/- 2.8; p<0.02); In addition, the expression of MHC-II and of CD69 on B cells were significantly reduced (from 9.1 +/- 2.2 at baseline to 4.2 +/- 0.4; p<0.04), and (from 7.6 +/- 2.4 at baseline to 2.7 +/- 0.7; p<0.03) respectively. CONCLUSIONS: The present finding of a shift in B cell properties following tocilizumab treatment, namely the increase in TGF-beta expression and the alteration in the activation status (CD69 expression) and APC properties (MHC-II expression) in CD25(high) B cells, suggests that the induction/expansion of B regulatory cells may be one of the mechanisms by which tocilizumab may possibly produce its beneficial clinical effects. PMID- 21813066 TI - Association of anti-CCP positivity and carriage of TNFRII susceptibility variant with anti-TNF-alpha response in rheumatoid arthritis. AB - OBJECTIVES: To investigate the possible influence of tumour necrosis factor-alpha (TNF), TNF receptor I (TNFRI) and TNF receptor II (TNFRII) gene polymorphisms on anti-TNF treatment responsiveness, stratified by autoantibody status. METHODS: A Greek multi-centre collaboration was established to recruit a cohort of patients (n=100) with active RA treated with anti-TNF drugs. TNF g.-238G>A (rs361525), g. 308G>A (rs1800629), g.-857C>T (rs1799724), TNFRI c.36A>G (rs4149584) and TNFRII c.676T>G (rs1061622) polymorphisms were genotyped by PCRRFLP assays. Serum RF and anti-CCP antibody status were determined using commercially available kits. Single-SNP, haplotype and stratification by autoantibody status analyses were performed in predicting response to treatment by 6 months, defined as the absolute change in DAS28. RESULTS: 31 patients (31%) were defined as non responders due to failure to fulfill the DAS28 criteria. 79% and 66% were RF and anti-CCP positive, respectively. None of the genotyped SNPs was alone associated with responsiveness to drug treatment. However, after stratification by autoantibody status, carriage of TNFRII c.676G allele was associated with poorer response to drug treatment in anti-CCP positive patients (p=0.03), after 6 months of anti-TNF therapy. CONCLUSIONS: In concordance with previous studies, genetic polymorphisms alone cannot be used to safely predict clinical response to anti TNF therapy however the combination of genetic factors and autoantibody status warrants further investigation in larger independent cohorts. PMID- 21813065 TI - Soluble macrophage-derived CD163 is a marker of disease activity and progression in early rheumatoid arthritis. AB - OBJECTIVES: To investigate the expression of the soluble form of the resident macrophage marker CD163 (sCD163) and its association with core parameters for disease activity, including radiographic progression in early rheumatoid arthritis (RA). METHODS: In a longitudinal sample set from early RA patients (n=34) we measured plasma levels of sCD163 at initiation of treatment and after 9 months of treatment and correlated levels with disease activity in 28 joints (DAS28), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and total Sharp score (TSS). We also measured plasma levels of sCD163 in 55 healthy volunteers (HV) and in a transverse sample set of chronic (>8 years of disease) RA patients (n=24) and OA patients (n=24) with paired plasma and joint fluid. RESULTS: Early RA patients had significantly higher plasma levels of sCD163 (1.69mg/l (1.42-2.10)) (median (IQR)) at baseline than after 9 months of treatment (1.28mg/l (0.963-1.66), p=0.001), but not significantly changed compared with HV (1.66mg/l (1.22-2.02)). In early RA patients, baseline levels of sCD163, correlated with DAS28, CRP and ESR. Interestingly, sCD163 at 9 months was associated with radiographic progression (TSS) between year 0 and 5 (r=0.468, p=0.02). Levels of sCD163 were higher in RA patients, than in OA patients and higher in SF than in plasma. CONCLUSIONS: Plasma levels of macrophage derived sCD163 are associated with disease activity and predict radiographic progression in early RA patients, supporting that sCD163 may have a role as a biomarker of disease activity and that resident macrophages are important for joint destruction. PMID- 21813067 TI - Successful treatment using cyclosporine in a patient with rhupus complicated by aplastic anemia: a case report and review of the literature. AB - Systemic lupus erythematosus (SLE) co-morbid with rheumatoid arthritis (RA) is known as 'Rhupus syndrome' and is estimated to be present in between 0.01 and 2% of SLE and RA patients. The occurrence of aplastic anaemia in a patient with rhupus is very rare and a treatment for this condition has not been reported. A 52-year-old woman presented complaining of nausea and dizziness during the preceding month. She had been treated for rheumatoid arthritis for 16 years. At the time of presentation, she had a malar rash, multiple arthritis, pancytopenia, pleural effusion, proteinuria, and positive anti-nuclear and anti-dsDNA antibodies. A kidney biopsy revealed ISN/RPS class IV-G (A) lupus nephritis. Bone marrow aspiration and biopsy showed aplastic anaemia with no evidence of viral infection. The patient was successfully treated using cyclosporine and prednisolone and she remained symptom-free at the one-and-a-half-year follow-up. To our knowledge, this is the first report of a successful treatment using cyclosporine in a patient with rhupus complicated by aplastic anaemia. PMID- 21813068 TI - Optimising bisphosphonate treatment outcomes in postmenopausal osteoporosis: review and Italian experience. AB - This review aims to investigate ways to optimise treatment outcomes with bisphosphonate therapy of osteoporosis in general, and in Italian clinical practice specifically. Overall, poor adherence to bisphosphonate therapy is a major limiting factor in the treatment of osteoporosis, and is associated to a large extent with gastrointestinal adverse events. An improved patient-doctor relationship and patient motivation are critical factors to improving adherence. However, other medical interventions also play a significant role. Intermittent dosing regimens decrease gastrointestinal adverse events and improve adherence, and demonstrate at least equivalent efficacy to daily regimens. Intravenous formulations also improve gastrointestinal tolerability, and are recommended in Italy for patients at high risk of this adverse event. Other recommendations in Italy to improve treatment outcomes include a case-finding approach to identify patients most suitable for bisphosphonate therapy, thus reducing the numbers needed to treat to avoid fractures. To facilitate this, a comprehensive assessment is advocated which incorporates bone mineral density, previous fractures, parental history of fractures, corticosteroid use and the presence of other diseases associated with secondary osteoporosis. PMID- 21813069 TI - Efficacy of switching to adalimumab in a patient with refractory uveitis of Behcet's disease to infliximab. PMID- 21813071 TI - Familial Mediterranean fever in small children in Turkey. AB - OBJECTIVES: Familial Mediterranean fever (FMF) is an autosomal recessive disease, characterised by recurrent, self limited attacks of fever with serositis. The aim of our study was to describe the demographic, clinical and genetic features of FMF patients who had early disease onset and to compare them with late onset patients. Our second aim was to investigate the factors associated with delay in diagnosis. METHODS: The study group consisted of recently diagnosed FMF patients who came to routine follow-up visits between January and July 2009. Patients were divided into two groups according to age of disease onset (Group I: <= 3 years of age; Group II: >3 years of age). In the second part, patients were analysed according to the duration of delay in diagnosis. RESULTS: There were 83 patients in group I and 73 patients in Group II. Median delay in diagnosis was 4 years in Group I and 2 years in Group II (p<0.001). The presence of M694V mutation was more frequent in Group I (81%) as compared to Group II (65%), (p=0.034). Mean attack Hb was lower (p<0.01) and mean attack leukocyte count was higher (p=0.017) in Group I. Final colchicine dosages were higher in Group I as compared to Group II. There was a statistically significant negative correlation between the age at disease onset and period of delay in diagnosis (p<0.001). CONCLUSIONS: This study suggests that FMF patients with early disease onset have more severe disease. Moreover, the smaller the age of disease onset, the more likely their diagnoses are delayed. PMID- 21813070 TI - Elevated IgG autoantibody production in oligoarticular juvenile idiopathic arthritis may predict a refractory course. AB - OBJECTIVES: Although oligoarticular juvenile idiopathic arthritis (oJIA) is considered to carry the best prognosis among the JIA subtypes, many children evolve to a chronic course. A few studies have identified clinical risk factors for disease extension, and recent studies have evaluated synovial fluid markers. However, the only biological marker from the serum studied to date is the anti nuclear antibody (ANA), regarding which there is mixed data regarding prognosis. No studies have evaluated whether additional autoantibodies may affect the articular prognosis of oJIA. METHODS: Microarrays containing candidate autoantigens were printed on slides, which were used to profile 36 children with oJIA and 18 controls. Unsupervised cluster analysis was used to identify distinct subgroups of JIA patients. Response to therapy after a mean interval of 4.9 months was evaluated. RESULTS: Cluster analysis revealed two subgroups of oJIA patients, with identical clustering observed when children with onset over age six were excluded. Cluster 1 had higher levels of multiple autoantibodies compared to both cluster 2 as well as controls, including antibodies against several extracellular matrix (ECM) and nuclear antigens. Although the two patient clusters were similar with respect to clinical features and treatment decisions, children in cluster 1 were less likely to have attained remission by the follow up visit. CONCLUSIONS: Antibodies against ECM and possibly other antigens may identify a sub-group of children with oJIA who will require more aggressive therapy to attain control of the arthritis. PMID- 21813072 TI - Are Beslan's children learning to cope? A 3-year prospective study of youths exposed to terrorism. AB - OBJECTIVE: This longitudinal study aimed to assess the course of psychological symptoms and coping behaviors in 33 adolescents directly and indirectly exposed to the 2004 terrorist attack in Beslan, Russia. We also investigated the role of coping in the development of posttraumatic stress. METHOD: At 1.5 and 3 years postattack, youths' psychological distress was measured using the Brief Symptom Inventory 18; emotional and behavioral difficulties were assessed via the Strength and Difficulties Questionnaire; and coping behaviors were measured using the Brief COPE. Three years after the attack, posttraumatic stress symptoms were evaluated via the UCLA Posttraumatic Stress Disorder Reaction Index. RESULTS: Directly exposed youths showed a significant increase in psychological distress (P = .05) and a decrease in active coping (P = .042), whereas indirectly exposed youths reported better mental health and more active coping over time. Compared to girls, boys showed a disproportionate increase in psychological distress, emotional and behavioral problems, and avoidant coping. Direct exposure to the attack and the endorsement of avoidant coping behaviors significantly predicted the severity of posttraumatic symptoms at follow-up (P < .05 for both). CONCLUSIONS: Our findings highlight the importance of conducting follow-up studies to monitor long-term psychological functioning and to screen for adolescents who may need additional referral for trauma treatment. The long-term detrimental effects of avoidant coping on youths' psychological well-being underscore the need to implement early psychoeducational interventions to minimize adverse outcomes and prevent the chronicity of posttraumatic reactions. PMID- 21813073 TI - Analysis of gene variants previously associated with iloperidone response in patients with schizophrenia who are treated with risperidone. AB - OBJECTIVE: We examined 6 single nucleotide polymorphisms (SNPs) previously reported to be associated with response to iloperidone therapy for association with response to risperidone therapy. METHOD: Patients with schizophrenia (DSM IV) were assessed during 2006 and 2007 for response/nonresponse (defined as >= 20%/<20% improvement in Positive and Negative Syndrome Scale [PANSS] total score) after 2 weeks of risperidone treatment (2 to 6 mg/d). Responders continued risperidone treatment; nonresponders were randomly assigned to either risperidone or olanzapine treatment (10 to 20 mg/d) for an additional 10 weeks. Associations between change in PANSS total (primary outcome measure), positive, and negative scores and the 6 SNPs were examined in risperidone-treated patients (N = 145). Genotype frequencies and improvement in PANSS total scores were analyzed for those SNPs significantly associated with change in PANSS total score. RESULTS: The SNPs XKR4 rs9643483 and GRIA4 rs2513265 were significantly associated with change in PANSS total response (adjusted P < .05 for both), with the same direction of effect as reported for iloperidone. For patients with nonresponsive genotypes for these SNPs, mean improvement in PANSS total score for African Americans was two-thirds that seen for whites (XKR4: -13.9 versus -21.4; GRIA4: 12.5 versus -20.9). CONCLUSIONS: In this retrospective pharmacogenomic analysis, we found that 2 SNPs previously linked to iloperidone response were also associated with response to risperidone. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00337662. PMID- 21813074 TI - A 12-month randomized, open-label study of the metabolic effects of olanzapine and risperidone in psychotic patients: influence of valproic acid augmentation. AB - OBJECTIVE: Longitudinal data comparing the metabolic effects of olanzapine and risperidone with or without valproic acid supplementation in schizophrenic and bipolar patients are lacking. METHOD: This study compares the metabolic effects of olanzapine and risperidone in a prospective, randomized, open-label trial in 160 patients with DSM-IV-TR schizophrenia, schizoaffective disorder, or bipolar disorder after 1, 3, 6, and 12 months' treatment. The study was conducted between 2000 and 2006. The primary analysis compared all patients randomized to olanzapine or risperidone; the primary outcome measure was changes in triglycerides (TG), and TG/high density lipoprotein cholesterol (HDL-C) ratio, a risk factor for ischemic cardiovascular disease. Secondary analyses included the effect of concomitant valproic acid. RESULTS: Significantly greater increases in weight (F(4,434) = 4.7), body mass index (BMI) (F(4,424) = 5.1), glycosylated hemoglobin (HgbA1c) (F(4,427) = 4.3), total cholesterol (F(4,429) = 4.4), TG (F(4,426) = 5.9), and TG/HDL-C ratio (F(4,426) = 4.3) (P < .005 for all drug * time interaction effects) were observed at all but the initial time points in the olanzapine- compared to the risperidone patients. Olanzapine/+valproic acid produced significantly greater increases in HgbA1c, BMI, weight, TG, and TG/HDL-C than olanzapine/-valproic acid at 3 and 6 months, while risperidone/+valproic acid produced significantly smaller increases in HgbA1c, BMI, and weight at 1, 3, and 6 months than risperidone/-valproic acid. The olanzapine/+valproic acid group had significantly greater BMI, and weight at 1, 3, and 6 months, and greater HgbA1c at 3 and 6 months, compared with the risperidone/+valproic acid group. There were too few patients treated with mood stabilizers other than valproic acid to analyze effects of any other mood stabilizer separately. Metabolic effects did not differ significantly by diagnostic category (schizophrenia/schizoaffective disorder vs bipolar disorder). CONCLUSION: Further study of the metabolic effects of adjunctive valproic acid is indicated, as valproic acid may produce markedly different metabolic effects when combined with various antipsychotic drugs. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00179062. PMID- 21813075 TI - Clinical and cognitive correlates of suicide attempts in bipolar disorder: is suicide predictable? AB - OBJECTIVE: We conducted a retrospective investigation of potential clinical, demographic, and neuropsychological risk factors for suicide attempts in patients diagnosed with bipolar disorder. METHOD: Participants included 67 adult inpatients and outpatients aged 18-60 years meeting DSM-IV criteria for bipolar disorder (bipolar I and II disorders, bipolar disorder not otherwise specified). We assessed demographic factors, mood symptoms, psychosis, trauma history, trait impulsivity, trait aggression, and reasons for living. The primary outcome measures were the Barratt Impulsiveness Scale-version II, Aggression Questionnaire, and 10 cognitive outcome variables. The cognitive outcome variables assessed cognitive performance across several domains, including processing speed, attention, verbal learning, and executive function. Another aspect of cognitive function, decision making, was assessed using the Iowa Gambling Task. The study was conducted from July 2007-July 2009. RESULTS: We found that nonattempters reported significantly higher trait impulsivity scores on the Barratt Impulsiveness Scale compared to attempters (t(57) = 2.2, P = .03) and that, among attempters, lower trait impulsivity score was associated with higher scores of lethality of prior attempts (r(25) = -0.53, P = .01). Analyses revealed no other group differences on demographic, clinical, or neurocognitive variables when comparing attempters versus nonattempters. Regression models failed to identify any significant predictors of past suicide attempt. CONCLUSIONS: The largely negative results of our study are particularly important in highlighting the clinical dilemma faced by many clinicians when trying to predict which patients will make serious suicide attempts and which patients are at a lower risk for acting on suicidal thoughts. A limitation of our work is that we examined stable trait measures of impulsivity among a euthymic sample rather than mood state or the impact of mood state on traits. Overall, we conclude that suicidal behavior is extremely difficult to predict, even when comprehensive clinical and neurocognitive information is available. PMID- 21813077 TI - World Hepatitis Day 2011. PMID- 21813076 TI - Safety and tolerability of aripiprazole for irritability in pediatric patients with autistic disorder: a 52-week, open-label, multicenter study. AB - OBJECTIVE: Evaluate the long-term safety and tolerability of aripiprazole in the treatment of irritability in pediatric subjects (6-17 years) with autistic disorder. METHOD: A 52-week, open-label, flexibly dosed (2-15 mg/d) study of the safety and tolerability of aripiprazole in outpatients with a DSM-IV-TR diagnosis of autistic disorder who either had completed 1 of 2 antecedent, 8-week randomized trials or were enrolled de novo (ie, not treated in the randomized trials). Safety and tolerability measures included incidences of adverse events, extrapyramidal symptoms, weight, metabolic measures, vital signs, and other clinical assessments. RESULTS: Subjects were enrolled between September 2006 and June 2009. Three hundred thirty subjects entered the treatment phase: 86 de novo, 174 prior aripiprazole, and 70 prior placebo. A total of 199 (60.3%) subjects completed 52 weeks of treatment. Adverse events were experienced by 286/330 subjects (86.7%). Common adverse events included weight increase, vomiting, nasopharyngitis, increased appetite, pyrexia, upper respiratory tract infection, and insomnia. Discontinuations due to adverse events occurred in 35/330 randomized subjects (10.6%)-most commonly aggression and weight increase. One patient discontinued from the study due to a laboratory-related adverse event (moderately increased alanine transaminase and aspartate transaminase). Nine subjects experienced serious adverse events-most frequently aggression. Extrapyramidal symptoms-related adverse events occurred in 48/330 subjects (14.5%)-most commonly tremor (3.0%), psychomotor hyperactivity (2.7%), akathisia (2.4%), and dyskinesia (not tardive, 2.4%). At > 9 months' aripiprazole exposure (n = 220), mean change in body weight z score was 0.33 and body mass index z score was 0.31. The percentages of subjects with clinically significant fasting metabolic abnormalities at > 9 months were 2% for glucose, 5% for total cholesterol, 7% for low-density lipoprotein cholesterol, 30% for high-density lipoprotein cholesterol, and 5% for triglycerides. CONCLUSIONS: Aripiprazole was generally safe and well tolerated in the long-term treatment of irritability associated with autistic disorder in pediatric subjects. Weight should be proactively monitored during long-term treatment. TRIAL REGISTRATION: clinical trials.gov Identifier: NCT00365859. PMID- 21813079 TI - Coxsackieviral infections involved in aseptic meningitis: a study in Slovakia from 2005 to 2009. AB - A wide range of diseases is associated with enteroviruses.They are reported to be responsible for viral meningitis, especially in children, but also in adults.This study analysed infection with eight selected coxsackievirus serotypes as the cause of aseptic meningitis in 480 patients in Slovakia from 2005 to 2009,using a quantitative assay for the detection of intrathecal antibodies. Intrathecal production of antibodies against selected coxsackieviruses was proved in 21%of these patients. A significant decrease from 35% in 2005 to 8,5% in 2009 (p=0.004) in the proportion of patients with proven intrathecal production of virus specific antibodies was observed during the study period. We conclude that coxsackievirus B4 was the endemic serotype in Slovakia and was responsible for most cases of coxsackieviral meningitis in the study period. PMID- 21813080 TI - Potential role of asymptomatic kitchen food handlers during a food-borne outbreak of norovirus infection, Dublin, Ireland, March 2009. PMID- 21813081 TI - Outbreak of norovirus infection in a hotel in Oslo, Norway, January 2011. PMID- 21813082 TI - Food-borne outbreak of norovirus infection in a French military parachuting unit, April 2011. AB - On 13 April 2011 the medical service of a French military parachuting unit reported an outbreak of acute gastroenteritis involving 147 persons among the military personnel. Meals suspected to have caused the outbreak (pasta and some raw vegetables) were tested for norovirus by PCR. The same norovirus (genogroup I) was found in some of the food items consumed by the cases and in a cook who prepared the meals. PMID- 21813083 TI - Cognitive control moderates the association between stress and rumination. AB - BACKGROUND AND OBJECTIVES: A prospective design was used to examine whether inter individual differences in cognitive control ability, for non-emotional and emotional material, play a moderating role in the association between the occurrence of a stressful event and the tendency to ruminate. METHODS: At baseline, the Internal Switch Task (IST) was administered in an undergraduate sample to measure the ability to switch attention between items held in working memory. Six weeks after baseline, self-report questionnaires were administered at 4 fixed moments during their first examination period at university, measuring stressors, rumination and depressive symptoms. RESULTS: Results revealed that impaired cognitive control, reflected in larger switch costs, moderated the association between stress and increased rumination. Interestingly, a larger switch cost when processing emotional material was specifically associated with increased depressive brooding in response to stress. No effects with reflective pondering were observed. CONCLUSIONS: Implications for understanding the underlying mechanisms of rumination are discussed. PMID- 21813084 TI - Biological sex and panic-relevant anxious reactivity to abrupt increases in bodily arousal as a function of biological challenge intensity. AB - An emerging pattern of results from panic-relevant biological challenge studies suggests women respond with greater subjective anxiety than men, but only to relatively abrupt and intense challenge procedures. The current investigation examined the relation between biological sex and self-reported anxious reactivity following biological challenges of varying durations and intensity. Participants were 285 (152 females; M(age) = 21.38; SD = 5.92) nonclinical adults who completed one of three protocols: a 3-min voluntary hyperventilation challenge (VH), a 5-min 10% carbon dioxide-enriched air (CO(2)) challenge, or a 25-s 20% CO(2) challenge. As predicted, results indicated that the 20% CO(2) challenge elicited greater self-reported anxiety than the VH and 10% CO(2) challenges. Moreover, women endorsed greater anxious reactivity than men, but only following the 20% CO(2) challenge. Results are discussed in terms of processes likely to account for sex differences in anxious reactivity following relatively abrupt and intense biological challenges. PMID- 21813085 TI - Alumina nanoparticles enhance growth of Lemna minor. AB - The industrial use of nanoparticles is rapidly increasing, and this has given rise to concerns about potential biological impacts of engineered particles released into the environment. So far, relatively little is known about uptake, accumulation and responses to engineered nanoparticles by plants. In this study, the effects of alumina nanoparticles on growth, morphology and photosynthesis of Lemna minor were quantified. It was found that alumina nanoparticles substantially increase biomass accumulation of L. minor. Such a stimulatory effect of alumina nanoparticles on growth has not been reported previously. Enhanced biomass accumulation was paralleled by morphological adjustments such as increased root length and number of fronds per colony, and by increased photosynthetic efficiency. Metal nanoparticles have previously been shown to enhance the energy transfer efficiency of isolated reaction centres; therefore it is proposed that the mechanism underlying the alumina mediated enhancement of biomass accumulation in L. minor is associated with increased efficiencies in the light reactions of photosynthesis. PMID- 21813086 TI - Nutritional support in the pharmacological treatment of metabolic syndrome. AB - The metabolic syndrome is multifactorial in nature and its incidence is rapidly increasing along with its risk factors. This review discusses nutrition, functional foods, and nutraceuticals most frequently adopted in the co-treatment of the metabolic syndrome. In fact, several foods, functional foods, and nutraceuticals with potential "pharmacological" activities are positioned at the border between pharmacology and nutrition. This double food-nutrition approach would help reduce the use of medicines and concomitantly decrease side effects. PMID- 21813087 TI - Application of GM crops in Sub-Saharan Africa: lessons learned from Green Revolution. AB - While the Green Revolution has been successful in some regions like South and East Asia, it could hardly address any achievement in Sub-Saharan Africa (SSA). This paper tries to draw a picture on lessons learned from the failures of this revolution that should be taken into account before implementing the so-called Gene Revolution in the SSA region. After scrutinizing the failures and the pros and cons of GM crops in the region, the paper introduces some potentials for improving the malnutrition situation in SSA through launching a successful GM technology. However, it remains doubtful whether this technology can improve the situation of small-scale farmers as long as they receive no financial support from their national governments. Therefore, before any intervention, the socio economic and environmental impacts of GM technology need to be carefully addressed in the framework of a series of risk assessment studies. Besides, some sort of multi-stakeholder dialog (from small-scale farmers to consumers) involving public-private sector and non-governmental organizations should be heated up at both national and regional levels with regard to the myths and truths of this technology. PMID- 21813088 TI - Differential immune response of adipocytes to virulent and attenuated Mycobacterium tuberculosis. AB - Mycobacterium tuberculosis (M. tb) takes advantage of various cell types, allowing it to remain in the host for long periods. Because adipocytes have been proposed as niches for dormant M. tb in the latent state, understanding the interaction of virulent M. tb with adipocytes is important. We compared changes in cytokine secretion from 3T3-L1 murine adipocytes infected with virulent M. tb H37Rv (V-M. tb) and attenuated M. tb H37Ra (A-M. tb) strains. Both strains maintained non-replicating states within adipocytes until 10 days post-infection. Adipocytes infected with V-M. tb secreted lower levels of pro-inflammatory cytokines, such as tumor necrosis factor-alpha, interleukin (IL)-12p40, IL-6, and IL-17, and lower levels of nitric oxide than those infected with A-M. tb. In contrast, the anti-inflammatory cytokines, IL-10 and IL-4, were markedly induced in V-M. tb-infected adipocytes versus those infected with A-M. tb at an early time point. Heat-killed or formalin-fixed bacteria induced lower levels of cytokines and no difference was observed between strains. Moreover, V-M. tb induced a high level of necrosis versus A-M. tb in conjunction with increased levels of LHD. These results suggest that V-M. tb regulates cytokine expression in its favor, increasing cytokines necessary for immune evasion and decreasing those required for protective immunity. PMID- 21813089 TI - Managing conflict of interest: the academy's preferred practice patterns and ophthalmic technology assessments. PMID- 21813091 TI - Corneal indentation for laser iridotomy. PMID- 21813090 TI - Fluocinolone acetonide intravitreal implant for diabetic macular edema: a 3-year multicenter, randomized, controlled clinical trial. AB - PURPOSE: We studied the 3-year efficacy and safety results of a 4-year study evaluating fluocinolone acetonide (FA) intravitreal implants in eyes with persistent or recurrent diabetic macular edema (DME). DESIGN: Prospective, evaluator-masked, controlled, multicenter clinical trial. PARTICIPANTS: We included 196 eyes with refractory DME. METHODS: Patients were randomized 2:1 to receive 0.59-mg FA implant (n = 127) or standard of care (SOC additional laser or observation; n = 69). The implant was inserted through a pars plana incision. Visits were scheduled on day 2, weeks 1, 3, 6, 12, and 26, and thereafter every 13 weeks through 3 years postimplantation. MAIN OUTCOME MEASURES: The primary efficacy outcome was >=15-letter improvement in visual acuity (VA) at 6 months. Secondary outcomes included resolution of macular retinal thickening and Diabetic Retinopathy Severity Score (DRSS). Safety measures included incidence of adverse events (AEs). RESULTS: Overall, VA improved >=3 lines in 16.8% of implanted eyes at 6 months (P=0.0012; SOC, 1.4%); in 16.4% at 1 year (P=0.1191; SOC, 8.1%); in 31.8% at 2 years (P=0.0016; SOC, 9.3%); and in 31.1% at 3 years (P=0.1566; SOC, 20.0%). The number of implanted eyes with no evidence of retinal thickening at the center of the macula was higher than SOC eyes at 6 months (P<0.0001), 1 year (P<0.0001; 72% vs 22%), 2 years (P=0.016), and 3 years (P=0.861). A higher rate of improvement and lower rate of decline in DRSS occurred in the implanted group versus the SOC group at 6 months (P=0.0006), 1 year (P=0.0016), 2 years (P=0.012), and 3 years (P=0.0207). Intraocular pressure (IOP) >=30 mmHg was recorded in 61.4% of implanted eyes (SOC, 5.8%) at any time and 33.8% required surgery for ocular hypertension by 4 years. Of implanted phakic eyes, 91% (SOC, 20%) had cataract extraction by 4 years. CONCLUSIONS: The FA intravitreal implant met the primary and secondary outcomes, with significantly improved VA and DRSS and reduced DME. The most common AEs included cataract progression and elevated IOP. The 0.59-mg FA intravitreal implant may be an effective treatment for eyes with persistent or recurrent DME. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references. PMID- 21813092 TI - PCR analysis of aqueous in cataract surgery. PMID- 21813093 TI - Intravitreal methotrexate for retinoblastoma. PMID- 21813094 TI - A tale of two systems. PMID- 21813095 TI - IOL power after excimer laser surgery. PMID- 21813096 TI - Pediatric cataract. PMID- 21813098 TI - Conjunctival and orbital lymphoma. PMID- 21813100 TI - Ranibizumab for Age-related Macular Degeneration. PMID- 21813101 TI - Preterm treatment of Norrie disease. PMID- 21813104 TI - Iatrogrenic retinal breaks. PMID- 21813107 TI - Cardiac 64-multislice computed tomography reveals increased epicardial fat volume in patients with acute coronary syndrome. AB - Inflammatory cytokines released from epicardial fat around coronary arteries may modulate the coronary arteries and promote coronary atherosclerosis. We assessed the hypothesis that epicardial fat volume (EFV) is increased in patients with acute coronary syndrome (ACS). EFV was measured in 80 Japanese patients hospitalized for ACS using 64-multislice computed tomography. The ACS group included 51 patients with ST-segment elevated myocardial infarction and 29 patients with non-ST-segment elevated myocardial infarction. All patients underwent emergency coronary angioplasty and 64-multislice computed tomographic scanning during hospitalization. The control group included 90 consecutive outpatients with suspected ACS whose coronary computed tomographic results were normal. EFV was larger in patients with ACS than in the control group (117 +/- 47 vs 95 +/- 33 ml, p <0.001). Multivariate regression analysis showed that EFV was associated with age, body mass index, and visceral fat area in the control group. However, these correlations did not appear in the ACS group. Multivariate logistic regression analysis showed that EFV >100 ml was independently associated with ACS (odds ratio 2.84, 95% confidence interval 1.17 to 6.87, p = 0.021). Receiver operator characteristic analysis determined a cut-off value of 100.3 ml with a sensitivity of 75% and a specificity of 60% for ACS (area under the curve 0.692, 95% confidence interval 0.596 to 0.777, p <0.001). Compared to subcutaneous adipose tissue, epicardial adipose tissue showed inflammatory cell infiltrates on a micrograph. In conclusion, the present study demonstrated significantly increased EFV in patients with ACS. A large amount of epicardial fat may be a risk factor for ACS. PMID- 21813106 TI - Relation of visceral adiposity to circulating natriuretic peptides in ambulatory individuals. AB - Natriuretic peptides have important roles in the regulation of vasomotor tone, salt homeostasis, and ventricular remodeling. Lower natriuretic peptide levels observed in obese individuals may underlie the greater cardiovascular risk associated with obesity. Thus the aim of this study was to determine whether lower natriuretic peptide levels in obesity are attributable to differences in regional fat distribution. We investigated the relation of plasma N-terminal pro B-type natriuretic peptide (NT-pro-BNP) to regional adiposity in 1,873 community based individuals (46% women, mean age 45 years). Subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) volumes were measured by multidetector computed tomography. In gender-specific multivariable analyses adjusting for age and blood pressure, log NT-pro-BNP was inversely associated with VAT in men (beta -0.11 per standard deviation increment, p <0.001) and women (beta -0.19, p <0.001). Log NT-pro-BNP was inversely associated with SAT in women only (beta 0.14, p <0.001). In models containing VAT and SAT, only VAT was significantly associated with log NT-pro-BNP (men, beta -0.137, p <0.001; women, beta -0.184, p <0.001). VAT remained associated with log NT-pro-BNP even after adjustment for body mass index and waist circumference (beta -0.119, p <0.001) and in analyses restricted to nonobese patients (beta -0.165, p <0.001). Adjustment for insulin resistance attenuated the associations of NT-pro-BNP with VAT and SAT. In conclusion, this study demonstrates that circulating NT-pro-BNP is related to variations in regional and particularly visceral adiposity. These findings suggest that excess visceral adiposity and concomitant hyperinsulinemia may contribute to the natriuretic peptide "deficiency" observed in obesity. PMID- 21813108 TI - Meta-analysis of randomized controlled trials comparing isolated left ventricular and biventricular pacing in patients with chronic heart failure. AB - Cardiac resynchronization therapy (CRT) has been mostly achieved by biventricular pacing (BVP) in patients with chronic heart failure (CHF), although it can also be provided by left ventricular pacing (LVP). The superiority of BVP over LVP remains uncertain. The present meta-analysis of randomized controlled trials was performed to compare the effects of LVP to BVP in patients with CHF. Outcomes analyzed included clinical status (6-minute walk distance, peak oxygen consumption, quality of life, New York Heart Association class), LV function (LV ejection fraction), and LV remodeling (LV end-systolic volume). Five trials fulfilled criteria for inclusion in analysis, which included 574 patients with CHF indicated for CRT. After a midterm follow-up, pooled analysis demonstrated that LVP resulted in similar improvements in 6-minute walk distance (weighted mean difference [WMD] 11.25, 95% confidence interval [CI] -12.39 to 34.90, p = 0.35), quality of life (WMD 0.34, 95% CI -3.72 to 4.39, p = 0.87), peak oxygen consumption (WMD 1.00, 95% CI -0.84 to 2.85, p = 0.29), and New York Heart Association class (WMD -0.19, 95% CI -0.79 to 0.42, p = 0.54). There was a trend toward a superiority of BVP over LVP for LV ejection fraction (WMD 1.28, 95% CI 0.11 to 2.68, p = 0.07) and LV end-systolic volume (WMD -5.73, 95% CI -11.86 to 0.39, p = 0.07). In conclusion, LVP achieves similar improvement in clinical status as BVP in patients with CHF, whereas there was a trend toward superiority of BVP over LVP for LV reverse modeling and systolic function. PMID- 21813110 TI - Complexity, signal detection, and the application of ergonomics: reflections on a healthcare case study. AB - Complexity is a defining characteristic of healthcare, and ergonomic interventions in clinical practice need to take into account aspects vital for the success or failure of new technology. The introduction of new monitoring technology, for example, creates many ripple effects through clinical relationships and agents' cross-adaptations. This paper uses the signal detection paradigm to account for a case in which multiple clinical decision makers, across power hierarchies and gender gaps, manipulate each others' sensitivities to evidence and decision criteria. These are possible to analyze and predict with an applied ergonomics that is sensitive to the social complexities of the workplace, including power, gender, hierarchy and fuzzy system boundaries. PMID- 21813109 TI - Effect of colesevelam hydrochloride on glycemia and insulin sensitivity in men with the metabolic syndrome. AB - Colesevelam hydrochloride (colesevelam) lowers low-density lipoprotein (LDL) cholesterol and glycated hemoglobin in patients with type 2 diabetes mellitus. The present study examined the effects of colesevelam treatment in nondiabetic men with metabolic syndrome. Twenty men completed the study, which consisted of two 8-week phases of treatment with colesevelam (3.75 g/day) or placebo and a 6 week washout between study phases. Of the 20 men, 17 took statins throughout. The fasting plasma LDL cholesterol, triglyceride, glucose, and glycated hemoglobin levels were measured in the last 2 weeks of each study phase. Nonesterified fatty acids and 3-hydroxybutyrate, insulin, and glucose were measured hourly for 5 hours during fasting and during an extended glucose tolerance test. The colesevelam treatment reduced LDL cholesterol from 96 +/- 28 mg/dl to 78 +/- 32 mg/dl (p <0.006) and non-high-density lipoprotein cholesterol by 8.2% (p = 0.07). Triglycerides increased by 17% (p <0.02). The fasting plasma glucose was reduced by 5 mg/dl (p <0.03), and glycated hemoglobin remained unchanged by colesevelam. No significant treatment changes were noted for the 2-hour glucose test or insulin sensitivity. The fasting nonesterified fatty acid level was significantly reduced with treatment but the 3-hydroxybutyrate level was unchanged. Insulin mediated suppression of nonesterified fatty acids during extended glucose tolerance test was significantly less effective during treatment than during placebo. In conclusion, colesevelam significantly reduced the LDL cholesterol levels, even though the baseline LDL cholesterol level was low owing to statin treatment. The fasting and postprandial blood glucose level but not the glycated hemoglobin level was lowered by colesevelam therapy. The effect on fasting glucose was unrelated to the changes in insulin resistance or fatty acid oxidation. Finally, an increase in triglycerides with colesevelam therapy might have been related to a lesser suppression of nonesterified fatty acids levels in the postprandial state. PMID- 21813111 TI - Event-related potential (ERP) measures reveal the timing of memory selection processes and proactive interference resolution in working memory. AB - Behavioral studies show that no-longer-relevant information, although presumably removed from working memory (WM), still engenders proactive interference (PI). However, the timing of selecting items within WM and resolving PI is relatively unknown. To assess this, we recorded ERPs during WM from 20 young adults. In all conditions, a 4-digit display was followed by a cue indicating which digits to remember. In the selection condition, 2 digits were cued. The reaction time difference between the intrusion probe, a match of a to-be-rejected digit, and the non-intrusion probe, which did not match any of the 4 digits, was reliable, indicating a robust effect of PI. In the neutral-2 (remember 2 digits) and -4 (remember all 4) conditions, participants maintained the digits following the cue. Relative to neutral-4, selection elicited larger positivity at parietal sites (approximately 260ms) and negativity at frontal sites (approximately 420ms). Relative to the non-intrusion probe ERP, that to the intrusion probe was more negative over frontal scalp (approximately 500ms). We conclude that initial selection occurs over parietal cortex and reflects top-down attention to task relevant items, whereas the subsequent negativity may reflect inhibition of no longer-relevant items over frontal cortex. The probe-locked ERPs suggest that the frontal negativity (approximately 500ms) reflects the final resolution of PI. PMID- 21813112 TI - Origins of endomorphin-2 immunopositive fibers and terminals in the rat medullary dorsal horn. AB - Endomorphin-2-immunoreactive (EM2-IR) fibers and terminals are densely present in the medullary dorsal horn (MDH) and are key factors in regulating central nociceptive processing. However, the origins of these EM2-IR fibers and terminals remain elusive. It was hypothesized that there were at least three possible origins of the EM2-IR fibers and terminals in the MDH: intrinsic dorsal horn neurons, primary afferent fibers, and projection fibers from higher parts of the brain. Different kinds of measures were employed in the current study to elucidate this hypothesis. After intracerebral ventricle administration of colchicine, no EM2-IR neuronal cell bodies were detected in the MDH, suggesting that there was no intrinsic EM2-IR dorsal horn neuron. Disruption of bilateral primary afferents (exposed to the primary afferent neurotoxin, capsaicin) decreased bilateral EM2 expression but did not eliminate it. Transection of the trigeminal nerve sensory root significantly decreased EM2 expression on the ipsilateral but not on the contralateral MDH. After injecting FluoroGold (FG) into the MDH, FG retrogradely labeled some EM2-IR neurons in the bilateral hypothalamus and nucleus tractus solitarii (NTS), and some of the FG retrogradely labeled neurons in the ipsilateral trigeminal ganglion also showed EM2 immunoreactivities. These results indicate that EM2-IR fibers and terminals in the MDH come not only from ipsilateral primary trigeminal afferents but also from bilateral fibers from the hypothalamus and NTS. PMID- 21813113 TI - Activation of spinal and supraspinal cannabinoid-1 receptors leads to antinociception in a rat model of neuropathic spinal cord injury pain. AB - Activation of CNS cannabinoid subtype-1 (CB1) receptors has been shown to mediate the antinociceptive and other effects of systemically administered CB receptor agonists. The endogenous peptide CB receptor ligand hemopressin (HE) has previously demonstrated an antinociceptive effect in rats with a hind paw inflammation, without exhibiting characteristic CB1 receptor-mediated side effects. The current study evaluated the effect of intrathecal (i.t.) and intracerebroventricular (i.c.v.) injection of HE in a rat model of neuropathic spinal cord injury (SCI) pain. The non-subtype selective CB receptor agonist WIN 55,212-2 was also centrally administered in SCI rats as a comparator. Four weeks following an acute compression of the mid-thoracic spinal cord, rats displayed markedly decreased hind paw withdrawal thresholds, indicative of below-level neuropathic pain. Central administration of WIN 55,212-2 significantly increased withdrawal thresholds, whereas HE did not. Hemopressin has been reported to block CB1 receptors in vitro, similar to the CB1 receptor antagonist rimonabant. Pretreatment with rimonabant completely blocked the antinociceptive effect of centrally administered WIN 55,212-2, but pretreatment with HE did not. While the data confirm that activation of either supraspinal or spinal CB1 receptors leads to significant antinociception in SCI rats, the current data do not support an antinociceptive effect from an acute blockade of central CB1 receptors, HE's putative antinociceptive mechanism, in neuropathic SCI rats. Although such a mechanism could be useful in other models of pain with a significant inflammatory component, the current data indicate that activation of CB1 receptors is needed to ameliorate neuropathic SCI pain. PMID- 21813115 TI - Differential expression of 14-3-3 protein isoforms in developing rat hippocampus, cortex, rostral migratory stream, olfactory bulb, and white matter. AB - We investigated the differential immunoexpression of 14-3-3 proteins according to their 7 isoforms during the postnatal development of rat brains, primarily in the hippocampus, cortex, rostral migratory stream (RMS), olfactory bulb, and white matter. Wistar rats at different developmental stages, on postnatal days 2 (P2), P7, P14, P21 and P100 were obtained, and were incubated with each type of anti-14 3-3 isoform antibody. 14-3-3 common (COM)-like immunoreactivity (IR) which represents an epitope shared among the 7 isoforms was initially expressed in the olfactory bulb on P2. This IR was partially expressed in the dentate granule cells and hippocampal pyramidal neurons from P7, and increased during development. These chronological changes were similar to those obtained with beta, gamma, and eta isoforms. Epsilon isoform-like IR was initially identified in the cell body of cortical neurons and glia-like cells on P2. After P7, the IR was more intense in the neuropil of the cortex. This epsilon isoform-like IR was markedly accentuated in the stratum lucidum of the hippocampus after P7, where hippocampal mossy fibers terminate, functioning as a giant synapse. This suggests that epsilon isoforms may be associated with synaptogenesis of the hippocampal mossy fibers. Sigma isoform-like IR was observed in the nuclei of external plexiform layer cells of the olfactory bulb from P2 to P21, in the nuclei of the hippocampal pyramidal and dentate granule cells after P7 and in the nuclei of RMS cells after P7. Zeta and tau isoform-like IRs were mainly identified in the white matter and in oligodendroglial cells from P7 to P21. Different immunolocalizations of the 7 isoforms suggest that 14-3-3 protein isoforms are individually associated with neuronal development and synaptogenesis during postnatal formation of the rat brain. PMID- 21813114 TI - Altered resting-state functional connectivity of thalamus in earthquake-induced posttraumatic stress disorder: a functional magnetic resonance imaging study. AB - BACKGROUND: Thalamic dysfunction has been found in patients with posttraumatic stress disorder (PTSD), suggesting that the thalamus may be implicated in the etiology of PTSD. However, no studies have explored the functional connectivity between the thalamus and other brain regions during resting-state. The objective of the present study was to investigate the resting-state functional connectivity of the thalamus in recent onset medication-naive PTSD sufferers who went through an earthquake in the Sichuan province of China. METHODS: Fifty-four participants with PTSD and seventy-two age and gender matched traumatized controls without PTSD recruited from the 2008 Sichuan earthquake were scanned by 3T functional magnetic resonance imaging (fMRI) in resting state. Region of interest (ROI) based functional connectivity analysis was employed to identify the potential differences in the functional connectivity of the thalamus between the two groups. RESULTS: In the PTSD group, the thalamus-ROIs showed decreased positive functional connectivity to particular brain regions including right medial frontal gyrus and left anterior cingulate cortex. Importantly, we also found increased positive functional connectivity of thalamus-ROIs with bilateral inferior frontal and left middle frontal gyri, left inferior parietal lobule as well as right precuneus in the PTSD participants when compared to traumatized controls without PTSD. CONCLUSION: The results provide evidence that abnormal resting state functional connections linking the thalamus to cortical regions may be involved in the underlying pathology in PTSD. PMID- 21813116 TI - Molecular signatures of phytol-derived immunostimulants in the context of chemokine-cytokine microenvironment and enhanced immune response. AB - In a previous report, we observed that the phytol-derived immunostimulant, PHIS 01 (phytanol), is a nontoxic oil-in-water adjuvant which is superior to most commercial adjuvants. In contrast, the parent diterpene alcohol phytol, though highly effective as an adjuvant, is relatively toxic. To assess the importance of the polar functional group in PHIS-01, we prepared two new compounds PHIS-02 (phytanyl amine) and PHIS-03 (phytanyl mannose). All three phytol derivatives proved to be excellent adjuvants, but differed in solubility and mode of action. To delineate their molecular signatures in the local microenvironment, we performed inflammasome and cytokine microarray analyses with the peritoneal fluid of mice treated with alum or the phytol compounds above, in the presence or absence of soluble protein antigens. We report here that the phytol derivatives had a significant time-dependent impact on the host chemokine-cytokine microenvironment and subsequently on specific humoral responses. Moreover, the inclusion of protein immunogens induced further changes in host microenvironments, including rapid (<2h) expression of cytokines and chemotactic factors (IL-6, MCP-1, KC, MIP-1, and LIX), implying mobilization and activation of neutrophils, and monocytes. PHIS-01 proved to be the most effective in this regard. Inflammatory cytokine cascades were dominant even after 24h possibly to facilitate involvement of the acquired immune system with the release of B lymphocyte chemo-attractant BLC, T-cell activation-3 chemokines TCA, IL-4, IL-12, and TIMP-1. We also noted enhanced expression of NLRP genes including NLRP3 with both alum and phytol derivatives (particularly PHIS-01). PMID- 21813117 TI - Alteration of inhibitory and activating NK cell receptor expression on NK cells in HIV-infected Chinese. AB - Natural killer (NK) cell function, based on the expression of activating and inhibitory natural killer receptors (NKRs), may become abnormal during human immunodeficiency virus (HIV) infection. In this study, we investigated changes in receptor expression with individual and combinational analysis on NK cell subsets in HIV-infected Chinese. The results showed that natural killer group 2 member D (NKG2D) expression on total NK cells decreased significantly in HIV infection, while the expressions of natural killer group 2 member A (NKG2A) and killer cell immunoglobulin-like receptor, three domains, long cytoplasmic tail 1 (KIR3DL1) on total NK cells were not significantly different between any of the groups including HIV-positive treatment-naive group, AIDS treatment-naive group, HAART treatment AIDS group and HIV-negative control group. Individual analysis of NKG2A(+) and KIR3DL1(+) cells revealed no significant differences in expression in any NK cell subsets between any of the groups, but the combinational analysis of NKG2D(-)NKG2A(+), and NKG2D(-)KIR3DL1(+) on the NK CD56(dim) cell subset in the AIDS group were increased compared to the HIV-negative control group. On the contrary, NKG2D(-)NKG2A(+) expression on the CD56(bright) subset decreased in the AIDS group compared to the control group. Highly active antiretroviral therapy (HAART) treatment almost completely restored the levels of these receptor expressions. The results indicate that the distinct alteration of activating and inhibitory NKR expression on NK cells and its subsets occurred during HIV progression. Moreover, the imbalanced change of activating and inhibitory NKRs on NK cells and its subsets may explain the impaired NK cell immunity in HIV infected individuals. PMID- 21813118 TI - Traumatic brain injury and the frontal lobes: what can we gain with diffusion tensor imaging? AB - Traumatic brain injury (TBI) is a leading cause of death in the young population and long-term disability in relation to pervasive cognitive-behavioural disturbances that follow frontal lobe damage. To date, emphasis has been placed primarily on the clinical correlates of frontal cortex damage, whilst identification of the contribution of subjacent white matter lesion is less clear. Our poor understanding of white matter pathology in TBI is primarily due to the low sensitivity of conventional neuroimaging to identify pathological changes in less severe traumatic injury and the lack of methods to localise white matter pathology onto individual frontal lobe connections. In this paper we focus on the potential contribution of diffusion tensor imaging (DTI) to TBI. Our review of the current literature supports the conclusion that DTI is particularly sensitive to changes in the microstructure of frontal white matter, thus providing a valuable biomarker of the severity of traumatic injury and prognostic indicator of recovery of function. Furthermore we propose an atlas approach to TBI to map white matter lesions onto individual tracts. In the cases presented here we showed a direct correspondence between the clinical manifestations of the patients and the damage to specific white matter tracts. We are confident that in the near future the application of DTI to TBI will improve our understanding of the complex and heterogeneous clinical symptomatology which follows a TBI, especially mild and moderate head injury, which still represents 70-80% of all clinical population. PMID- 21813119 TI - [Knowledge and attitude regarding previous instructions for the patients of a public hospital of Madrid]. AB - INTRODUCTION: The level of knowledge and attitudes of patients towards the previous instructions is a little known subject given that their introduction in the Community of Madrid (CM) is recent. AIMS: To assess the level of knowledge and implementation of advance directives in patients admitted to an Internal Medicine Service of a public hospital in the CM, the attitudes of patients regarding these documents and their correlation with demographic variables. PATIENTS AND METHODS: A cross-sectional study through structured survey of opinion, closed and voluntarily given to all patients admitted in the Internal Medicine Unit of the University Hospital Alcorcon Foundation on the dates May 20 and June 3, 2008 was carried out. RESULTS: A total of 155 patients were included, the questions being answered by the patients per se by 57% and by members of theirs families in 42%. Mean age of the patients was 77 years, 50.9% were male and 86.45% were Catholic. Only 7 patients (4.5%) knew what the advance directives were and only one patient had done them. On learning of their existence, 49 patients (31.6%) would like to do the advance instructions. Of the respondents, 80.6% were in favor of having the advance directives document in their medical history and 72.9% do not believe that having these advance directives would change the attitude of their doctor. CONCLUSIONS: Although the regulation of advance directives in the Community of Madrid has already been in force for 5 years, little is known about these documents and they are still in a period of diffusion. PMID- 21813120 TI - [Limitation of the therapeutic effort]. AB - The limitation of the therapeutic effort (LTE) consists in not applying extraordinary or disproportionate measures for therapeutic purposes that are proposed for a patient with poor life prognosis and/or poor quality of life. There are two types. The first is to not initiate certain measures or to withdraw them when they are established. A decision of the LTE should be based on some rigorous criteria, so that we make the following proposal. First, it is necessary to know the most relevant details of the case to make a decision: the preferences of the patient, the preferences of the family when pertinent, the prognosis (severity), the quality of life and distribution of the limited resources. After, the decision should be made. In this phase, participatory deliberation should be established to clarify the end of the intervention. Finally, if it is decided to perform an LTE, it should be decided how to do it. Special procedures, disproportionate measures, that are useless and vain should not be initiated for the therapeutic objective designed (withdraw them if they have been established). When it has been decided to treat a condition (interim measures), the treatment should be maintained. This complex phase may need stratification of he measures. Finally, the necessary palliative measures should be established. PMID- 21813121 TI - Comparison of diabetes mellitus and insulin resistance screening methods for women with polycystic ovary syndrome. AB - OBJECTIVE: To compare screening strategies for type 2 diabetes mellitus (DM), impaired glucose tolerance (pre-DM), and insulin resistance (IR) in women with polycystic ovary syndrome (PCOS). DESIGN: Prospective study. SETTING: Academic reproductive endocrinology practice. PATIENT(S): Adult women with PCOS (n = 111). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Subjects were screened for pre-DM and DM using a 2-hour glucose tolerance test (GTT), hemoglobin A1c (HbA1c), or fasting plasma glucose (FPG) and for IR using homeostasis model assessment (HOMA), insulin levels (fasting and 2 hours after 75 glucose load), or obesity. Screening approaches were compared using positive and negative percent agreement and Cohen's kappa (kappa). RESULT(S): DM and pre-DM were diagnosed by GTT in 4% and 20% of subjects, respectively. Screening with FPG failed to identify 41% of pre-DM and 20% of DM subjects. GTT and HbA1c had only fair agreement (kappa = 0.29). IR was diagnosed in 24% of subjects with pre-DM or DM and in 56% of the remaining subjects using HOMA and insulin levels. HOMA and elevated insulin levels demonstrated substantial agreement for detecting IR (kappa = 0.70-0.73). Obesity demonstrated fair to slight agreement (kappa = 0.33-0.18). CONCLUSION(S): Women with PCOS should be screened for Pre-DM and DM using GTT or HbA1c, and those with Pre-DM or DM are presumed to have IR. In the rest, IR can be detected using either HOMA or insulin levels. PMID- 21813123 TI - Analysis of performance metrics reporting in papers comparing treatments or materials/devices in four important orthopaedic journals for the year 2009. AB - PURPOSE: We propose to look at the quality of performance metrics reporting in papers comparing two or more treatments. Our goal is to provide additional context in the focus on evidence-based medicine. METHODS: We reviewed papers (1082 papers with 98 papers meeting the inclusion criteria) from four important orthopaedic journals published in 2009 to quantify and analyse the quality of papers reporting performance metrics, defined as (1) radiographic evidence; (2) training/experience of surgeon(s); and (3) intra-operative measurements. RESULTS: Our research revealed that only 32 papers (33%) reported performance metrics. There were no significant differences in the rate of performance metrics reporting amongst the journals included or amongst the different orthopaedic subspecialties topics; however, papers from South Korea and China reported both performance metrics in general and radiographic measurements specifically at a higher rate than papers from the western world. CONCLUSIONS: The low rate of performance metric reporting could have an impact on the reader's ability to determine the reproducibility of the results published. We propose a new section on performance metrics reporting for editors to include in their instructions to authors. PMID- 21813122 TI - Bisphenol A exposure reduces the estradiol response to gonadotropin stimulation during in vitro fertilization. AB - OBJECTIVE: To investigate associations between serum bisphenol A (BPA) concentrations and follicular response to exogenous ovary stimulation. DESIGN: Fasting serum was prospectively collected on the day of oocyte retrieval and assessed for unconjugated BPA using high-performance liquid chromatography with Coularray detection. Multivariable linear regression and negative binomial regression were used to assess associations between concentrations of BPA and outcome measures. Models were adjusted for race/ethnicity, antral follicle count at baseline, and cigarette smoking. SETTING: A reproductive health center. PATIENT(S): Forty-four women undergoing IVF. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Peak E(2) level and the number of oocytes retrieved during IVF. RESULT(S): The median unconjugated serum BPA concentration is 2.53 ng/mL (range = 0.3-67.36 ng/mL). Bisphenol A is inversely associated with E(2) (beta = -0.16; 95% confidence interval = -0.32, 0.01), as well as with E(2) normalized to the number of mature-sized follicles at the hCG trigger (beta = -0.14; 95% confidence interval = -0.24, -0.03). No association is observed for BPA and the number of oocytes retrieved (adjusted risk ratio = 0.95; 95% confidence interval = 0.82, 1.10). CONCLUSION(S): Bisphenol A is associated with a reduced E(2) response during IVF. Although limited by the preliminary nature of this study, these results merit confirmation in a future comprehensive investigation. PMID- 21813124 TI - A contoured locking plate for distal fibular fractures in osteoporotic bone: a biomechanical cadaver study. AB - OBJECTIVE: Fixation of ankle fractures in elderly patients is associated with reduced stability conditioned by osteoporotic bone. Therefore, fixation with implants providing improved biomechanical features could allow a more functional treatment, diminish implant failure and avoid consequences of immobilisation. MATERIALS AND METHODS: In the actual study, we evaluated a lateral conventional contoured plate with a locking contoured plate stabilising experimentally induced distal fibular fractures in human cadavers from elderly. Ankle fractures were induced by the supination-external rotation mechanism according to Lauge-Hansen. Stage II fractures (AO 44-B1) were fixed with the 2 contoured plates and a torque to failure test was performed. Bone mineral density (BMD) was measured by quantitative computed tomography to correlate the parameters of the biomechanical experiments with bone quality. RESULTS: The locking plate showed a higher torque to failure, angle at failure, and maximal torque compared to the conventional plate. In contrast to the nonlocking system, fixation with the locking plate was independent of BMD. CONCLUSION: Fixation of distal fibular fractures in osteoporotic bone with the contoured locking plate may be advantageous as compared to the nonlocking contoured plate. The locking plate with improved biomechanical attributes may allow a more functional treatment, reduce complications and consequences of immobilisation. PMID- 21813125 TI - Development and preliminary validation of the Chinese version of the Sleep Associated Monitoring Index. AB - OBJECTIVE: To examine the psychometric properties of the Chinese version of the Sleep-Associated Monitoring Index (SAMI) in Taiwanese haemodialysis patients. DESIGN: An instrument translation and validation study. SETTING: A haemodialysis (HD) unit in a university-affiliated medical centre in northern Taiwan. PARTICIPANTS: 206 patients who were 18 or above, diagnosed with end-stage renal disease and under maintenance HD twice or thrice a week, 3 h or more per session for more than 3 months. METHODS: A principal component analysis was used to examine the construct validity of the SAMI. The participants were classified into poor (n=160) and good sleepers (n=46) using a cut-off value of 5 on the Pittsburgh Sleep Quality Index (PSQI). All participants filled out the Beck Depression Inventory (BDI) and Back Anxiety Inventory (BAI) along with the SAMI. Internal consistency was examined by the Cronbach's alpha. To assess test-retest reliability, the participants were asked to fill out the SAMI on a second occasion at a 2-week interval. RESULTS: Eight subscales emerged from the principal component analysis. Individual with insomnia had significantly higher total SAMI scores (p<0.001). The SAMI total score significantly correlated to the PSQI, BDI, and BAI (r=0.65, 0.67, 0.67; all p<0.001). Cronbach's alpha was 0.95 for the entire scale. The intra-class correlation coefficient between the initial and retest SAMI total score was 0.72 (p<0.001). The SAMI-Chinese demonstrated an area under the receiver operation characteristic curve of 0.771 (SE=0.044; 95% CI: 0.685-0.857; p<0.001) in detecting individuals with poor sleep. A cut-off value of 51 indicated a sensitivity of 0.86 and a specificity of 0.63 in distinguishing between poor and good sleepers. CONCLUSIONS: The SAMI-Chinese demonstrated excellent construct validity, contrast group validity, external validity, internal consistency, and satisfactory test-retest reliability. It also demonstrated satisfactory diagnostic ability for insomnia. PMID- 21813126 TI - Nursing staff numbers and their relationship to conflict and containment rates on psychiatric wards-a cross sectional time series poisson regression study. AB - BACKGROUND: The link between positive outcomes and qualified nurse staffing levels is well established for general hospitals. Evidence on staffing levels and outcomes for mental health nursing is more sparse, contradictory and complicated by the day to day allocation of staff resources to wards with more seriously ill patients. OBJECTIVE: To assess whether rises in staffing numbers precede or follow levels of adverse incidents on the wards of psychiatric hospitals. DESIGN: Time series analysis of the relationship between shift to shift changes over a six month period in total conflict incidents (aggression, self-harm, absconding, drug/alcohol use, medication refusal), total containment incidents (pro re nata medication, special observation, manual restraint, show of force, time out, seclusion, coerced intramuscular medication) and nurse staffing levels. SETTINGS: 32 acute psychiatric wards in England. METHODS: At the end of every shift, nurses on the participating wards completed a checklist reporting the numbers of conflict and containment incidents, and the numbers of nursing staff on duty. RESULTS: Regular qualified nurse staffing levels in the preceding shifts were positively associated with raised conflict and containment levels. Conflict and containment levels in preceding shifts were not associated with nurse staffing levels. CONCLUSIONS: Results support the interpretation that raised qualified nurse staffing levels lead to small increases in risks of adverse incidents, whereas adverse incidents do not lead to consequent increases in staff. These results may be explicable in terms of the power held and exerted by psychiatric nurses in relation to patients. PMID- 21813127 TI - Asymptomatic carotid plaque rupture with unexpected thrombosis over a non canonical vulnerable lesion. AB - OBJECTIVE: Several studies have demonstrated that carotid plaque rupture and thrombosis represent the most important factors correlated with the onset of acute cerebrovascular symptoms. Nevertheless, ruptured thrombotic plaques have been described also in asymptomatic patients. What still needs to be clarified is why a plaque rupture leads either to an acute ischemic syndrome or, in a minor group of patients, remains asymptomatic. The purpose of this study was to systematically compare the histologic features of thrombotic plaques both in asymptomatic and symptomatic patients in order to identify specific findings that could explain the peculiar clinical behavior that characterizes each of the clinical settings. METHODS: A total of 157 thrombotic plaques from 60 asymptomatic patients and 97 with major stroke who consecutively underwent CEA were serially sectioned and studied by histology. RESULTS: A minute cap disruption very frequently characterizes thrombotic plaques of asymptomatic patients and it was always smaller than large ulcers observed in thrombotic symptomatic plaques (651 +/- 687MUm vs. 4150 +/- 3526, p=0.001). In asymptomatics this typical feature was associated with fewer inflammatory cells (20.1 +/- 8.8 vs. 33.9 +/- 26.1 cells * hpf, p=0.001), smaller lipidic-necrotic core (33.9%+/- 2.9% vs. 42.0% +/- 2.4%; p=0.04) and larger calcification (16.2 +/- 12.8% vs. 8.1 +/- 12.2%, p=0.02). Symptomatic patients with thrombotic plaques showed higher incidence of metabolic syndrome (p=0.002) and moderate-high Framingham risk scores (p=0.001) comparing to asymptomatic individuals. CONCLUSION: The transformation from a stable to a vulnerable plaque is a gradual process in the natural history of the disease and plaque rupture is an event not necessarily occurring at a late phase but also at earlier one. In this case, the rupture will be most likely smaller and clinically asymptomatic. PMID- 21813128 TI - The Fcgamma receptor IIA R131H gene polymorphism is associated with endothelial function in patients with hypercholesterolaemia. AB - OBJECTIVE: A gene polymorphism substituting arginine (R) for histidine (H) at position 131 has been described within the Fcgamma receptor IIa (FcgammaRIIa). The R allele is associated with increased binding of CRP and enhanced activation of monocytes. FcgammaRIIa is also expressed on endothelial cells, and we hypothesized this polymorphism would be associated with alterations of endothelial function. METHODS: Genomic DNA was extracted and allele-specific PCR reactions were used to determine the FcgammaRIIa H131R polymorphism in 78 hypercholesterolaemic subjects. Using strain gauge plethysmography, forearm blood flow (FBF) responses were determined to intra-arterial infusion of acetylcholine (ACH), for endothelium-dependent vasodilatation (EDV), to nitroprusside (NP), for endothelium-independent vasodilatation (EIV), to NG-monomethyl-l-arginine (l NMMA), for basal NO activity, and to ACH in the presence of l-NMMA, to assess the contribution of NO release to EDV. RESULTS: Homozygous carriers of the H allele (n=30) had significantly better EDV than homozygous carriers of the R allele (n=15), while heterozygotes showed an intermediate phenotype (n=33) (e.g. % increase of FBF to ACH 48MUg/min: 527+/-359% in H/H versus 452+/-262% in H/R versus 332+/-413% in R/R, p=0.0012 by 2-way ANOVA). EIV and basal NO activity were not affected by genotype, and co-infusion of l-NMMA abolished the differences in EDV. CONCLUSIONS: The R allele of the FcgammaRIIa polymorphism is associated with impaired EDV and reduced NO activity during endothelial cell stimulation. These data suggest that the functional effects of the FcgammaRIIa H131R gene polymorphism previously observed in vitro translate into clinically relevant alterations of endothelial function in vivo. PMID- 21813129 TI - Plasma total and high molecular weight adiponectin levels and risk of coronary heart disease in women. AB - OBJECTIVE: To examine prospectively the association of total and high molecular weight (HMW) adiponectin, and HMW/total adiponectin ratio with risk of incident coronary heart disease (CHD) in women, and to examine to what extent adjustment for potentially intermediary variables would explain this association. METHODS AND RESULTS: Among 30,111 women from the Nurses' Health Study, 468 women developed non-fatal myocardial infarction or fatal CHD during 14 years of follow up. Using risk set sampling, controls were selected 2:1 matched on age, smoking, and date of blood draw. Adjusted for matching factors, parental history of myocardial infarction, hormone replacement therapy, alcohol consumption, physical activity, body mass index, hypertension, and low-density lipoprotein cholesterol levels, the relative risk in the highest versus lowest quintile was 0.50 (95%-CI 0.33-0.75; p trend=0.001) for total adiponectin, 0.53 (95%-CI 0.35-0.80; p trend=0.004) for HMW adiponectin, and 0.63 (95%-CI 0.43-0.93; p trend=0.03) for HMW/total adiponectin ratio. After adjustment for diabetes, HDL-cholesterol, HbA1c, and CRP these associations were attenuated and no longer significant (RRs, 0.84; 95%-CI 0.53-1.33; p trend=0.62; 0.95; 95%-CI 0.60-1.52; p trend=0.98; 0.97; 95%-CI 0.64-1.47; p trend=0.80). CONCLUSIONS: High levels of total and HMW adiponectin, and HMW/total adiponectin ratio are associated with a lower risk of CHD among women. HMW adiponectin and HMW/total adiponectin ratio are not more closely related to risk than total adiponectin. These associations are largely mediated by parameters related to glucose and lipid metabolism and inflammation, especially HDL-cholesterol levels. PMID- 21813130 TI - Advanced liquid chromatography/mass spectrometry profiling of anthocyanins in relation to set of red wine varieties certified in Czech Republic. AB - Hyphenation of micro-liquid and ultra-performance liquid chromatography with a hybrid (QqTOF) tandem mass spectrometry was studied from the viewpoint of their applicability for monitoring of anthocyanin dyes in various cultivars and different vintages of red wine. After appropriate optimization both techniques proved to be suitable for this task. UHPLC system provided lower LOD and LOQ values as well as higher productivity and precision of retention parameters and peak areas with respect to micro-LC method. On the other hand, micro-LC method offers significant savings of mobile phase, less contamination of ion source of mass spectrometer and makes the nebulization process in electrospray much easier. In combination with principal component analysis (PCA), the method allows to elucidate long-term relations in a complete set of certified red wine cultivars grown in South Moravia (certified in Czech Republic until year 2005). Among the studied varieties Rubinet exhibit a specific anthocyanin profile. Especially interesting is a high content of 3-coumaroylglucoside-5-glucosides of malvidin and peonidin. Those dyes can be used as markers of artificial color enhancement. Principal component analysis applied to data processed with regard to enzymatic activity markedly facilitate classification among varieties. This approach allows resolution of teinturiers, variety Blaufrankish and partial classification of other varieties. PMID- 21813131 TI - iMatch: a retention index tool for analysis of gas chromatography-mass spectrometry data. AB - A method was developed to employ National Institute of Standards and Technology (NIST) 2008 retention index database information for molecular retention matching via constructing a set of empirical distribution functions (DFs) of the absolute retention index deviation to its mean value. The effects of different experimental parameters on the molecules' retention indices were first assessed. The column class, the column type, and the data type have significant effects on the retention index values acquired on capillary columns. However, the normal alkane retention index (I(norm)) with the ramp condition is similar to the linear retention index (I(T)), while the I(norm) with the isothermal condition is similar to the Kovats retention index (I). As for the I(norm) with the complex condition, these data should be treated as an additional group, because the mean I(norm) value of the polar column is significantly different from the I(T). Based on this analysis, nine DFs were generated from the grouped retention index data. The DF information was further implemented into a software program called iMatch. The performance of iMatch was evaluated using experimental data of a mixture of standards and metabolite extract of rat plasma with spiked-in standards. About 19% of the molecules identified by ChromaTOF were filtered out by iMatch from the identification list of electron ionization (EI) mass spectral matching, while all of the spiked-in standards were preserved. The analysis results demonstrate that using the retention index values, via constructing a set of DFs, can improve the spectral matching-based identifications by reducing a significant portion of false-positives. PMID- 21813132 TI - Determination of epichlorohydrin and 1,3-dichloro-2-propanol in synthesis of cationic etherifying reagent by headspace gas chromatography. AB - This study demonstrates a headspace gas chromatographic(HS-GC) technique for the determination of residual epichlorohydrin (ECH) and generated 1,3-dichloro-2 propanol (DCP) in synthesis process of 3-chloro-2-hydroxypropyltrimethylammonium chloride (CHTAC). By a weight-based sampling method, coupled with significant dilution in 15.8% sodium sulfate and 0.1% silver nitrate mixed solution rapidly, the sample for HS-GC analysis is prepared. Based on the reaction stoichiometry, the conversion (R) of CHTAC during the synthesis process can be calculated from sampling weight and GC peak area. The results showed that the method has a good measurement precision (RSD<2.5%) and accuracy (recovery=101-104%) for the quantification of both ECH and DCP in the process samples. The present method is simple and accurate, which can be used for the efficient determination of the CHTAC conversion in the synthesis research. PMID- 21813133 TI - Computed tomography for minor head injury: variation and trends in major United States pediatric emergency departments. AB - OBJECTIVES: To investigate the variation and trends in neuroimaging in children examined for minor head injury at major US pediatric emergency departments. STUDY DESIGN: We conducted a retrospective study of children <19 years of age with mild head injury who were examined and discharged home from the emergency department at 40 pediatric hospitals from 2005 to 2009 by using the Pediatric Health Information Systems database. Variation in computed tomography (CT) rates between hospitals was assessed for correlation with hospital-specific rates of intracranial hemorrhage, admission, and return visits. Age-adjusted trends in CT use were calculated for the 5 years. RESULTS: In the 5 years, the median rate of imaging for minor head injured patients was 36% (IQR, 29%-42%; range, 19%-58%). There was no correlation between institution-specific rates of CT imaging and intracranial hemorrhage, admission, or return-visit rates. Age-adjusted rates of CT use decreased in the 5-year period (OR, 0.94; 95% CI, 0.92-0.97; P < .001). CONCLUSIONS: In this study, we found significant practice variation in CT use at pediatric hospitals examining children with minor head injury. These data may help guide national benchmarks for the appropriate use of CT imaging in pediatric patients with minor head injury. PMID- 21813134 TI - Diffusion tensor imaging studies of prenatal drug exposure: challenges of poly drug use in pregnant women. PMID- 21813135 TI - Lower immunoglobulin G antibody responses to pneumococcal conjugate vaccination at the age of 2 years after previous nasopharyngeal carriage of Streptococcus pneumoniae. AB - OBJECTIVE: To determine whether nasopharyngeal pneumococcal carriage with serotypes 6B, 19F, or 23F interferes with immunoglobulin G (IgG) antibody responses to vaccination with 7-valent pneumococcal conjugate vaccine (PCV7) at the age 24 months. STUDY DESIGN: Blood samples were collected before and after a PCV7 challenge vaccination at age 24 months from subsets of children participating in a randomized controlled trial. Children previously had received two doses of PCV7 at 2 and 4 months, two plus one doses of PCV7 at 2, 4, and 11 months, or no dosage until 24 months. Nasopharyngeal swabs were cultured at for Streptococcus pneumoniae at age 6 weeks and at 6, 12, 18, and 24 months. IgG responses were determined with enzyme immunoassay. RESULTS: Lower IgG responses against serotypes 6B, 19F, and 23F were observed on PCV7 challenge vaccination at 24 months in children who had received earlier PCV7 vaccinations and had been found positive for homologous carriage compared with non-carriers of these serotypes. Lower non-homologous IgG responses were observed after the PCV7 challenge at 24 months against serotype 6B after earlier 19F carriage and against serotype 19F after earlier 23F carriage compared with children who had not been positive for carriage of these serotypes. CONCLUSIONS: Pneumococcal colonization with serotypes 6B, 19F, and 23F is associated with diminished immune responses against these serotypes on PCV7 vaccination at 2 years of age. Underlying mechanisms deserve further investigation. PMID- 21813136 TI - PNPLA3 I148M polymorphism and liver damage in obese children. PMID- 21813137 TI - Increased PLA2 activity in the hippocampus of patients with temporal lobe epilepsy and psychosis. AB - OBJECTIVE: The aim of this work was to investigate whether increased activity of the enzyme phospholipase A(2) (PLA(2)) in the brain, as frequently reported in schizophrenia, is also related to psychosis in epilepsy. Our working hypothesis was based on the increased prevalence of schizophrenia-like psychosis in patients with temporal lobe epilepsy (TLE) secondary to mesial temporal sclerosis (MTS), as compared to patients with other forms of epilepsy. METHODS: We determined PLA(2) activity in hippocampal tissue from 7 patients with TLE-MTS and psychosis, as compared to 9 TLE-MTS patients without psychosis. Hippocampal tissue was obtained from patients who underwent an anterior temporal lobectomy due to therapy-resistant epilepsy. RESULTS: We found that patients with TLE-MTS and psychosis had a significantly increased calcium-independent PLA(2) activity as compared to patients without psychosis (p = 0.016). CONCLUSION: Our finding suggest that an increment in brain PLA(2) activity is not specific for schizophrenia, but rather may be associated to the manifestation of schizophrenia like psychotic symptoms in general. PMID- 21813138 TI - Sleep disturbances in multiple sclerosis. AB - OBJECTIVES: The frequency of sleep disturbances in multiple sclerosis (MS), and their impact on the quality of life of MS patients, have traditionally been underestimated. Here we review the most common sleep disorders seen in this disease, their prevalence, pathophysiology, clinical manifestations and current treatments. METHOD: We begin with a brief description of epidemiological data on sleep disturbances in MS, explain how these disturbances increase potential associated morbidities, and discuss the bidirectional relationship established between these two comorbid conditions (i.e. MS worsens sleep disturbances and vice versa). We then analyze the main dyssomnias and parasomnias described in MS: insomnia, circadian rhythm disorders, drug-induced sleep disturbances, restless legs syndrome (RLS) and periodic leg movements (PLM), respiratory disorders during sleep, narcolepsy-cataplexy syndrome and REM sleep behavior disorder (RBD). We also review the relationship between sleep disturbances and chronic fatigue syndrome, which is very frequent in MS patients. CONCLUSION: Sleep disturbances are more common in MS patients than in the general population and limit these patients' quality of life. Therefore, we believe that these disturbances should be a focal point in any multidisciplinary treatment for MS. PMID- 21813139 TI - Contribution of geolocalisation to neuroepidemiological studies: incidence of ALS and environmental factors in Limousin, France. AB - This article aimed to detect clusters of amyotrophic lateral sclerosis (ALS) and their relationships with exposure of the population to various environmental factors in the Limousin region of France. Methods used were extensively described. We adopted a geographical approach that revealed variations in the incidence of ALS and permitted us to identify three regional clusters and their spatial spread. We considered environmental factors and the potent locations or source of substances or activities hypothesized to be associated with ALS. Notably, we determined which industrial activities seem to affect the incidence of ALS in Limousin. The results were interpreted at a regional level. Among the 50 factors this article considered, paper paste and water treatment plants were particularly geostatistically significant and deserve special attention in the ongoing investigations into high resolution spatial clusters (geographical and epidemiological studies). PMID- 21813141 TI - [Metabolic Syndrome as a marker of cardiovascular events in hypertensives in primary prevention]. AB - BACKGROUND AND OBJECTIVES: The aim of this study was to assess the impact of metabolic syndrome (MS) as a predictor of cardiovascular events (CVE) in hypertensives in primary prevention. PATIENTS AND METHODS: This retrospective study involved 2410 non-diabetic, hypertensive patients (52% women, 43% with MS), without previous CVE. The total follow-up was 13096 patient-years with a median of 4,5 years (IIQ; 2,2-7,3). RESULTS: Patients with metabolic syndrome did not have more risk of CVE (HR 1,19; CI 95%:0,89-1,58; p=0,292), 183 patients had a CVE, 88 in patients with MS (15,4; CI 95%:12,4-19,0 patients-years), and 95 in patients without MS (13,0; CI 95%:10,5-15,9 patients/years) (p=0,279). In a multivariate analysis corrected for other factors, only age (HR 1,08; CI 95%: 1,07-1,10; p=0,001), male gender (HR 1,77; CI 95%: 1,27-2,45; p=0,001), smoking (HR 2,95; CI 95%: 2,01-4,34; p=0,001) at the beginning, and values of systolic arterial pressure >=160 mm Hg (HR 1,83; CI 95%: 1,17-2,89; p=0,009) and cholesterol-low density lipoproteins >=160 mg/dl (HR 1,58; CI 95%: 1,05-2,38; p=0,029) during the follow-up, were associated with new CVE. CONCLUSIONS: In hypertensive non-diabetic patients in primary prevention the diagnosis of metabolic syndrome did not add any significant prediction about future CVE over the traditional risk factors. Systolic arterial pressure >=160 mm Hg and cholesterol-low density lipoproteins >=160 mg/dl, respectively, during the follow up were factors related to new CVE. PMID- 21813140 TI - Updates on Somatoform Disorders (SFMD) in Parkinson's Disease and Dementia with Lewy Bodies and discussion of phenomenology. AB - Somatoform Disorders (SFMD) were recently described in Parkinson Disease (PD) and Dementia with Lewy Bodies (DLB). The present paper updates the observations in our cohort of patients and further details clinical phenomenology. Of 3178 patients consecutively referred to our Institutions from 1999, 1572 subjects had neurodegenerative diseases and 1718 psychiatric disorders. After 2-9 years of follow up, 488 patients were labelled as PD, 415 as Alzheimer Disease, 162 as DLB, 48 as Progressive Supranuclear Palsy, 48 as Multiple System Atrophy and 49 as Fronto-Temporal Dementia. The frequency of SFMD (DSM-IV-TR criteria) was determined in each diagnostic category by direct observation of SFMD symptoms, psychiatric interviews, SCL 90Rss, collection of previous general practitioners and hospital charts. The frequency of SFMD was considerably higher in DLB (29 patients, 18%) and PD (37 patients, 7.5%) than in any other group (0-2%). The frequency of SFMD in psychiatric patients was 2%. SFMD in PD and DLB were characterised by motor and non-motor patterns and were often accompanied by catatonic signs consisting of posturing stereotypies and negativism (55%). SFMD symptoms preceded PD motor signs by 6 months-5 years in 92% of the 29 DLB and 37 PD patients and in 70% SFMD were recurrent at follow-up. In 93% of these patients, hypochondria was a preceding or concomitant background. PMID- 21813142 TI - [Hospitalized surgical patients comanaged by Internal Medicine specialists]. PMID- 21813143 TI - [Teleradiology in the emergency department: opportunity and danger]. AB - Teleradiology is an established fact in developed countries. It has been the subject of intense professional and even legal debate in recent years because the quality of care and the role of the radiologist as a medical specialist are at stake. The opportunities and the dangers involved in teleradiology are discussed in this article. The use of teleradiology in certain circumstances in the emergency department can result in significant benefits when done right; however, it is evident that poorly implemented teleradiology services can lead to significant decreases in the quality of care (for example when the aim is to provide a low cost reporting service through outsourcing). Radiologists must use their knowledge and collaboration to ensure that they have the main role in the design, management, and performance of teleradiology services. The stance of our scientific societies together with the legal and regulatory frameworks must be the pillars that support teleradiology as a medical act. PMID- 21813144 TI - Is spleen-preserving distal pancreatectomy with excision of the splenic artery and vein feasible? PMID- 21813145 TI - Loss of mechanical strain impairs abdominal wall fibroblast proliferation, orientation, and collagen contraction function. AB - BACKGROUND: Laparotomy wound load forces are reduced when dehiscence and incisional hernia formation occur. The purpose of this study was to determine the effects of strain loss on abdominal fascial fibroblast proliferation, orientation, and collagen compaction function. METHODS: Cultured rat linea alba fibroblasts were subjected to continuous cyclic strain (CS), CS interrupted at 24 or 48 hours followed by culture at rest (IS-24 and IS-48) or were cultured without mechanical strain (NS). Cell number was measured and images analyzed for cell orientation. Fibroblasts from these groups were seeded onto the surface of (FPCL-S) or mixed into (FPCL-M) a collagen gel matrix and gel area was measured over time. RESULTS: Continuous strain stimulated proliferation when compared with the nonstrained cells. The loss of strain (IS) delayed proliferation compared with CS throughout (P < .05). CS fibroblasts aligned perpendicular to the direction of strain within 12 hours. Within 12 hours of strain loss, IS-48 fibroblasts became significantly less aligned (P < .0001), and seemed similar to the randomly organized NS fibroblasts 48 hours after strain removal. The CS and IS-24 groups demonstrated faster and greater overall FPCL-M compaction than both the IS-48 and NS groups (P < .0002). The CS group contracted the gel faster than the NS group in FPCL-S (P = .029). CONCLUSION: Mechanical strain rapidly induces a proliferative, morphologic, and functional response in abdominal wall fibroblasts that is dependent on the continued presence of the strain signal and quickly lost when the load force is removed. The loss of wound edge tension that occurs during laparotomy wound separation and hernia formation may contribute to impaired wound healing through loss of a key stimulatory mechanical signal with important implications for abdominal wall reconstruction. PMID- 21813147 TI - Endogenous ocular nocardiosis: an interventional case report with a review of the literature. AB - We present an illustrative case of endogenous ocular Nocardia (EON) infection in a man with Hodgkin disease treated by chemotherapy who underwent aggressive vitreoretinal surgery for diagnosis and treatment of a subretinal abscess. Visual acuity recovered from hand movements to 20/25. We review the 38 reported cases of EON published between 1967 and 2007, describe the clinical presentation from a systemic and ocular point of view, examine which ocular procedures were successful in identifying the bacterium, and analyze ocular morbidity and the factors affecting successful treatment. PMID- 21813146 TI - Multifocal versus single vision lenses intervention to slow progression of myopia in school-age children: a meta-analysis. AB - Myopia in school-aged children is a major public health problem in Asians that has been extensively studied. Multifocal lenses (MLs) are advocated as a substitute for single vision lenses (SVLs) to slow myopia progression in children, but results vary greatly across studies. We systematically searched currently available randomized controlled trials that compared the effects of MLs and SVLs in children. A meta-analysis of nine of these trials showed that MLs with powers ranging from +1.50 to +2.00D were associated with a statistically significantly decrease in myopia progression in school-aged children compared with SVLs. The benefit was greater in children with a higher level of myopia at baseline and sustained for a minimum of 24 months. Asian children appeared to have greater benefit from intervention with MLs than white children. PMID- 21813148 TI - Lysine acetylation sites in bovine foamy virus transactivator BTas are important for its DNA binding activity. AB - Cellular acetylation signaling is important for viral gene regulation, particularly during the transactivation of retroviruses. The regulatory protein of bovine foamy virus (BFV), BTas, is a transactivator that augments viral gene transcription from both the long terminal repeat (LTR) promoter and the internal promoter (IP). In this study, we report that the histone acetyltransferase (HAT), p300, specifically acetylates BTas both in vivo and in vitro. Further studies demonstrated that BTas acetylation markedly enhances its transactivation activity. Mutagenesis analysis identified three lysines at positions 66, 109 and 110 in BTas that are acetylated by p300. The K110R mutant lost its binding to BFV promoter as well as its ability to activate BFV promoter. The acetylation of K66 and K109 may contribute to increased BTas binding ability. These results suggest that the p300-acetylated lysines of BTas are important for transactivation of BFV promoters and therefore have an important role in BFV replication. PMID- 21813149 TI - A novel mycovirus closely related to hypoviruses that infects the plant pathogenic fungus Sclerotinia sclerotiorum. AB - Three dsRNA segments, two similarly sized at 9.5kbp and a third one of approximately 3.6kbp, were extracted from a hypovirulent strain SZ-150 of Sclerotinia sclerotiorum. The complete cDNA sequence of one of the two large dsRNA segment (10398bp, excluding the poly (A) tail) reveals a single ORF that encodes a polyprotein with conserved domains of putative papain-like protease, UDP glucose/sterol glycosyltransferase, RNA-dependent RNA polymerase and viral RNA Helicase. This virus is closely related to Cryphonectria hypovirus (CHV) 3/GH2 and CHV4/SR2 in the family Hypoviridae and designated as Sclerotinia sclerotiorum hypovirus 1 (SsHV1/SZ-150). The satellite-like 3.6kbp dsRNA segment (S-dsRNA) shares high sequence identity with the 5'-UTR of SsHV1/SZ-150. SsHV1/SZ 150 alone is not the primary causal agent for hypovirulence of strain SZ-150 since strains without the S-dsRNA show normal phenotype. This is the first report of a naturally occurring hypovirus that infects a fungus other than Cryphonectria parasitica. PMID- 21813150 TI - Induced autophagy reduces virus output in dengue infected monocytic cells. AB - While several studies have shown a role for autophagy in the replication of dengue virus (DENV), these studies have been performed in directly infected cells. However, in severe cases of DENV infection the critical cell in the disease is believed to be monocytes which are poorly infected directly, but are highly susceptible to antibody enhanced infection. This study sought to determine the involvement of autophagy in the DENV infection of monocytic cells, using U937 cells as a model system. While the induction of autophagy was seen in response to DENV-2 infection, biochemical induction of autophagy resulted in a significant decrease in virus output. Down regulation of autophagy resulted in only a very slight increase in intracellular virus levels. In monocytic cells autophagy is not a significant part of the DENV replication mechanism, and there are distinct cell type specific differences in the DENV-autophagy interaction. PMID- 21813152 TI - Phase transformation and its role in stabilizing simulated lead-laden sludge in aluminum-rich ceramics. AB - This study investigated the mechanisms of stabilizing lead-laden sludge by blending it into the production process of aluminum-rich ceramics, and quantitatively evaluated the prolonged leachability of the product phases. Sintering experiments were performed using powder mixtures of lead oxide and gamma-alumina with different Pb/Al molar ratios within the temperature range of 600-1000 degrees C. By mixing lead oxide with gamma-alumina at a Pb/Al molar ratio of 0.5, the formation of PbAl2O4 is initiated at 700 degrees C, but an effective formation was observed when the temperature was above 750 degrees C for a 3-h sintering time. The formation and decomposition of the intermediate phase, Pb9Al8O21, was detected in this system within the temperature range of 800 900 degrees C. When the lead oxide and gamma-alumina mixture was sintered with a Pb/Al molar ratio of 1:12, the PbAl12O19 phase was found at 950 degrees C and effectively formed at 1000 degrees C. In this system, an intermediate phase Pb3(CO3)2(OH)2 was observed at the temperature range of 700-950 degrees C. Over longer leaching periods, both PbAl2O4 and PbAl12O19 were superior to lead oxide in immobilizing lead. Comparing the leaching results of PbAl2O4 and PbAl12O19 demonstrated the higher intrinsic resistance of PbAl12O19 against acid attack. To reduce metal mobility, this study demonstrated a preferred mechanism of stabilizing lead in the aluminate structures by adding metal-bearing waste sludge to the ceramic processing of aluminum-rich products. PMID- 21813151 TI - Identification and functional analysis of a second RBF-2 binding site within the HIV-1 promoter. AB - Transcription from the HIV-1 long terminal repeat (LTR) is mediated by numerous host transcription factors. In this study we characterized an E-box motif (RBE1) within the core promoter that was previously implicated in both transcriptional activation and repression. We show that RBE1 is a binding site for the RBF-2 transcription factor complex (USF1, USF2, and TFII-I), previously shown to bind an upstream viral element, RBE3. The RBE1 and RBE3 elements formed complexes of identical mobility and protein constituents in gel shift assays, both with Jurkat T-cell nuclear extracts and recombinant USF/TFII-I. Furthermore, both elements are regulators of HIV-1 expression; mutations in LTR-luciferase reporters and in HIV-1 molecular clones resulted in decreased transcription, virion production, and proviral expression in infected cells. Collectively, our data indicate that RBE1 is a bona fide RBF-2 binding site and that the RBE1 and RBE3 elements are necessary for mediating proper transcription from the HIV-1 LTR. PMID- 21813153 TI - Denitrification and dissimilatory nitrate reduction to ammonium (DNRA) in a temperate re-connected floodplain. AB - The relative magnitudes of, and factors controlling, denitrification and dissimilatory nitrate reduction to ammonium (DNRA) were measured in the soil of a re-connected temperate floodplain divided into four different land management zones (grazing grassland, hay meadow, fritillary meadow and a buffer zone). Soil samples were collected from each zone to measure their respective potentials for nitrate attenuation using 15N both at the surface and at depth in the soil column and additional samples were collected to measure the lability of the organic carbon. Denitrification capacity ranged between 0.4 and 4.2 (MUmol N g(-1) dry soil d(-1)) across the floodplain topsoil and DNRA capacity was an order of magnitude lower (0.01-0.71 MUmol N g(-1) d(-1)). Land management practice had a significant effect on denitrification but no significant effects were apparent for DNRA. In this nitrogen-rich landscape, spatial heterogeneity in denitrification was explained by differences in lability and the magnitude of organic carbon associated with different management practices (mowing and grazing). The lability of organic carbon was significantly higher in grazing grassland in comparison to other ungrazed areas of the floodplain, and consequently denitrification capacity was also highest in this area. Our results indicate that bacteria capable of DNRA do survive in frequently flooded riparian zones, and to a limited extent, compete with denitrification for nitrate, acting to retain and recycle nitrogen in the floodplain. Exponential declines in both denitrification and DNRA capacity with depth in the floodplain soils of a hay meadow and buffer zone were controlled primarily by the organic carbon content of the soils. Furthermore, grazing could be employed in re-connected, temperate floodplains to enhance the potential for nitrate removal from floodwaters via denitrification. PMID- 21813154 TI - Characterization and risk assessment of polychlorinated biphenyls in soils and vegetations near an electronic waste recycling site, South China. AB - This study aimed at identifying the levels of PCBs generated from e-waste recycling, and their potential impacts on the soils and vegetations as well. The SigmaPCBs concentrations in soil and plant samples ranged from 7.4 to 4000 ng g( 1) and from 6.7 to 1500 ng g(-1), respectively. For the plant samples, Chrysanthemum coronarium L. from vegetable field and the wild plant Bidens pilosa L. from the burning site showed relatively higher PCB concentrations than other species. For the soil samples, the e-waste burning site had relatively higher PCB concentrations than the adjacent areas, and vegetable soils had higher PCB concentrations than paddy soils. The PCB concentrations showed a clear decreasing trend with the increasing distance from the e-waste recycling site. PCB 28, 99, 101, 138, 153, and 180 were the predominant congeners. Principal component analysis results showed a potential fractionation of PCB compositions from the burning site to the surroundings. The PCB congener pattern at the burning site was similar to Arochlor 1260, pointing to an input of non-domestic e-waste. Similar PCB congeners were found in soils and related vegetables, indicating they derived from the same source. The consumption of vegetables grown in soils near e waste recycling sites should be strictly avoided due to the high PCBs in the plant tissues. PMID- 21813155 TI - Removal of emulsified fuel oils from brackish and pond water by dissolved air flotation with and without polyelectrolyte use: pilot-scale investigation for estuarine and near shore applications. AB - In coastal areas, estuaries, and inland waters, dispersant use after oil spills is not allowed due to sensitivity of the ecosystems. The purpose of this study was to investigate the removal of emulsified fuel oils from brackish and pond water by dissolved air flotation (DAF) with and without use of coagulants. Experiments were conducted with a 60L DAF system. Fuel oil-water emulsions were prepared with regular unleaded gasoline, jet fuel, and diesel fuel mixed at 1:1:1 (v/v/v) ratio. Batch and continuous runs were conducted at air pressurization of 354.6kPa. During both batch and continuous modes, significant petroleum hydrocarbon (PHC) removal was achieved within 10 min. Coagulant addition initially increased the PHC removal by about 5-15%. However, effectiveness of the coagulant was not significant after 20 min due to breakage of the aggregates. In general, the pond water had higher PHC removal than the brackish water. With longer run times, PHC removal improved slightly and the effluent contained increasing fractions of higher molecular weight compounds indicating that PHC removal was due to both DAF and stripping processes. Results indicate that DAF process can be effective both with and without the use of coagulants for removing PHCs from brackish and pond waters. PMID- 21813156 TI - The CIC-DUX4 fusion transcript is present in a subgroup of pediatric primitive round cell sarcomas. AB - Pediatric undifferentiated soft tissue sarcomas are a group of diagnostically challenging tumors. Recent studies have identified a subgroup of undifferentiated soft tissue sarcomas with primitive round to plump spindle cell morphology and a t(4;19)(q35;q13.1) translocation resulting in the expression of a CIC-DUX4 fusion transcript, including 2 tumors previously reported by our laboratory (Cancer Genet Cytogenet 2009;195:1). In the present study, reverse transcriptase polymerase chain reaction assays developed for both frozen and paraffin-based tissues were applied to a series of 19 pediatric undifferentiated soft tissue sarcomas using a combination of primer sets covering the CIC-DUX4 fusion transcript. Of the 19 undifferentiated soft tissue sarcomas, 16 had primitive round to plump spindle cell morphology, and 3 had pure spindle cell morphology. Three of the 16 undifferentiated soft tissue sarcomas with primitive round cell morphology were found to harbor the CIC-DUX4 fusion transcript by reverse transcriptase polymerase chain reaction. Automated DNA sequencing of the polymerase chain reaction products identified 2 distinct transcript variants. One CIC-DUX4-positive tumor showed membranous CD99 positivity, 2 showed focal S100 positivity, and 1 showed focal CD57 positivity. With the 2 previously reported cases, the total number of CIC-DUX4-positive primitive round cell sarcomas identified at our institution has been brought to 5 (28%) of 18. Given the consistent involvement of the CIC-DUX4 fusion in a subset of primitive round cell undifferentiated soft tissue sarcomas, these findings suggest a central role for the fusion transcript in such tumors. The current findings further define a novel genetic subset of pediatric primitive round cell sarcomas and provide an additional diagnostic tool for their characterization and diagnosis. PMID- 21813157 TI - Signet ring cell tumor of the minor salivary gland exhibiting benign behavior. AB - Signet ring cell (SRC) carcinomas are usually aggressive malignancies, arising most frequently in the stomach and gastrointestinal tract, but also, although less often, in other organs such as the breast, bladder, and lungs. They are particularly unusual in the salivary glands, and the aim of the present study is to report a case of a tumor of the minor salivary glands of the lower lip composed largely of SRCs but which displayed benign clinical behavior. PMID- 21813158 TI - Myoid gonadal stromal tumor: a distinct testicular tumor with peritubular myoid cell differentiation. AB - We report a distinct, primary testicular tumor with peritubular myoid cell differentiation. A 25-year-old man developed a well-circumscribed testicular tumor composed of cytologically bland spindled cells, which were strongly and diffusely positive for desmin, smooth muscle actin, muscle-specific actin, and smooth muscle myosin. In addition, S-100 was diffusely positive, and cytokeratin (CK5/6 and AE1/3) was focally positive. Calretinin, inhibin, and CD34 were all negative. This pattern of immunoreactivity was very similar to the normal adjacent peritubular myoid cells. Follow-up after radical orchiectomy showed benign behavior. We found reports of 6 similar intratesticular tumors demonstrating peritubular myoid cell-like differentiation and having favorable outcome. We believe that the myoid gonadal stromal tumor is a rare, yet distinct, testicular tumor separate from leiomyoma and deserves recognition. PMID- 21813159 TI - Intraductal tubulopapillary neoplasm of the bile duct: potential origin from peribiliary cysts. AB - We report two patients with unique biliary tumors histologically similar to pancreatic intraductal tubulopapillary neoplasm (ITPN). One patient underwent right hepatectomy for a partly cystic mass in the hepatic hilum. The other patient had liver transplantation for cryptogenic cirrhosis and multiple hilar cysts detected in the explanted liver, some obliterated by papillary nodules. Histologically both tumors consisted of intracystic non-invasive and well differentiated adenocarcinoma with a papillary and tubular architecture. Associated cysts were peribiliary cysts partly lined by carcinoma cells that were continuous with the intracystic papillotubular masses. Both tumors shared the same immunophenotype: K7(+)/K20(-)/MUC1(+)/MUC2(-)/MUC5AC(-)/MUC6(+). Genetic analysis of KRAS and BRAF revealed wild type genotypes. These pathological and genetic features are similar to those of pancreatic ITPNs. This report suggested that ITPNs may rarely develop in the bile duct seemingly in association with peribiliary cysts. PMID- 21813160 TI - Inverted papilloma of the cervix and vagina: report of 2 cases of a rare lesion associated with human papillomavirus 42. AB - We report 2 cases of a lesion that we term inverted papilloma of the lower female genital tract, occurring in the cervix and upper vagina of 60- and 50-year-old women, respectively. Microscopically, the features were similar to those of inverted transitional papilloma of the urinary bladder with interconnecting islands, trabeculae, and solid sheets of bland transitional epithelium with an inverted growth pattern. There were small foci of squamous and glandular differentiation in the cervical case. Linear array human papillomavirus genotyping revealed human papillomavirus type 42 in both cases. Inverted papilloma in the lower female genital tract is extremely rare with, as far as we are aware, only 3 previously reported similar cases in the cervix and none in the vagina. Our results suggest that these neoplasms when occurring in the lower female genital tract may be associated with low-risk human papillomavirus, perhaps specifically human papillomavirus 42. PMID- 21813161 TI - Systematic blade production at late Lower Paleolithic (400-200 kyr) Qesem Cave, Israel. AB - Qesem Cave is assigned to the Acheulo-Yabrudian cultural complex of the late Lower Paleolithic period. The 7.5 m deep stratigraphic sequence is dated to 400 200 ka (thousands of years ago). It is mostly attributed to the Amudian blade dominated industry, one of the earliest blade production technologies in the world. In this paper, we present the results of a detailed study of five Amudian assemblages from Qesem Cave and suggest two trajectories for the production of blades at the site. We argue that the reduction sequences of blades at Qesem Cave represent an innovative and straightforward technology aimed at the systemic and serial production of predetermined blanks. We suggest that this predetermined blank technology shows planning and intensity that is not significantly different from Middle Paleolithic Mousterian technological systems. Furthermore, this well organized serial manufacture of cutting implements mainly for butchering might indicates that a significant change in human behavior had taken place by the late Lower Paleolithic period. PMID- 21813162 TI - Anticoagulation therapy with combined low dose aspirin and warfarin following mechanical heart valve replacement. AB - INTRODUCTION: This study was designed to evaluate safety and efficacy of combined low dose aspirin and warfarin therapy following mechanical heart valve replacement. METHODS: A total of 1496 patients (686 males, mean age 35+/-8.5 years) undergoing mechanical heart valvular replacement were randomly divided into study (warfarin plus 75-100 mg aspirin) or control (warfarin only) group. International normalized ratio (INR) and prothrombin time was maintained at 1.8 2.5 and 1.5-2.0 times of the normal value, respectively. Thromboembolic events and major bleedings were registered during follow up. RESULTS: Patients were followed up for 24+/-9 months. The average dose of warfarin in the study and control group was 2.92+/-0.87 mg and 2.89+/-0.79 mg, respectively (p>0.05). The overall thromboembolic events in study group were lower than in control group (2.1% vs. 3.6%, p=0.044). No statistically significant differences were found in hemorrhage events (3.5% vs. 3.7%, p>0.05) or mortality (0.3% vs 0.4%, p>0.05) between the two groups. CONCLUSIONS: Following mechanical valve replacement, combined low dose aspirin and warfarin therapy was associated with a greater reduction in thromboembolism events than warfarin therapy alone. This combined treatment was not associated with an increase in the rate of major bleeding or mortality. PMID- 21813163 TI - Normal range of mean platelet volume in healthy subjects. PMID- 21813164 TI - Iatrogenic vascular lesions after minimally invasive partial nephrectomy: a multi institutional study of clinical and renal functional outcomes. AB - OBJECTIVES: To report the first large multi-institutional experience, including clinical and renal functional outcomes after treatment of iatrogenic vascular lesions (eg, renal artery pseudoaneurysm, arteriovenous fistula). These lesions are uncommon after minimally invasive partial nephrectomy (MIPN) but can be associated with significant morbidity. METHODS: A retrospective review of MIPN was performed at 4 centers. Patients developing pseudoaneurysm or arteriovenous fistula in the postoperative period were identified. The demographic, disease, and perioperative details and data regarding the presentation and treatment of vascular lesions were collected. RESULTS: Of the 998 patients undergoing MIPN, 20 (2.0%) presented with iatrogenic vascular lesions (17 with pseudoaneurysm and 3 with arteriovenous fistula). The mean age was 55.9 years, the tumor size was 2.6 cm, and the body mass index was 30.8 kg/m(2). Twelve patients (60%) had >50% endophytic tumors, 7 patients (35%) had undergone collecting system repair, and the mean warm ischemia time was 26 minutes. All patients presented with gross hematuria at a mean of 14.5 days postoperatively. The diagnosis was made using urgent computed tomography scan in all cases. Selective embolization was performed in 16 patients; 2 required no intervention and had spontaneous resolution, and 2 had negative angiography findings. Four patients required transfusion during rehospitalization. Although 4 patients had categorical worsening of the glomerular filtration rate after MIPN, all patients had stable function acutely after angioembolization, and 3 patients had categorical glomerular filtration rate improvement through a mean follow-up of 20 months. No patients had recurrent hemorrhagic events. CONCLUSIONS: Iatrogenic vascular lesions occur in ~2% of MIPN cases. Although a subset of patients will have resolution with observation only, most require angioembolization, with excellent clinical and renal function outcomes. PMID- 21813165 TI - Semen parameters and sperm DNA fragmentation as causes of recurrent pregnancy loss. AB - OBJECTIVES: To evaluate and compare standard sperm parameters, and sperm DNA fragmentation in seminal ejaculates from men whose partners had a history of recurrent pregnancy loss (RPL) and in a control group of men who had recently established their fertility. METHODS: Semen samples from 31 patients with a history of recurrent pregnancy loss and 20 men with proven fertility were analyzed according to World Health Organization guidelines. Sperm DNA fragmentation was detected by the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay. RESULTS: When sperm quality of the control group was compared with that of the RPL group, a significant difference was observed in sperm motility, but not in other parameters. The mean number of sperm cells with fragmented DNA was significantly increased in the RPL group (32.22 +/- 6.14%) compared with control donors (10.20 +/- 2.1%). CONCLUSIONS: Our data indicate that sperm from men with a history of RPL have a higher incidence of DNA damage and poor motility than sperm from a control group, and this can explain in part the pregnancy loss in these patients. PMID- 21813166 TI - Increased expression of hypoxia-inducible factor-1alpha and vascular endothelial growth factor associated with glomerulation formation in patients with interstitial cystitis. AB - OBJECTIVE: To examine whether hypoxia occurs in the bladders of patients with interstitial cystitis (IC) by monitoring the expression of hypoxia-inducible factor-1 (HIF-1) and VEGF. Previous studies have reported that bladder perfusion is decreased in patients with IC. Hypoxia induces overexpression of vascular endothelial growth factor (VEGF), which has been reported to be associated with the formation of glomerulations in patients with IC. METHODS: The study group consisted of 32 patients with IC, and the control group consisted of 8 volunteers. We obtained bladder biopsies from both groups and studied the expression of HIF-1alpha and VEGF proteins by immunoblotting and immunohistochemical and double immunofluorescent staining. Data were analyzed using the Mann-Whitney U test. RESULTS: Immunoblotting and immunostaining revealed that the expression of HIF-1alpha and VEGF proteins was increased in the study group compared with the control group. The relative intensities of HIF 1alpha and VEGF proteins were 60.60 +/- 7.81 and 43.60 +/- 5.37 in the study group and 26.20 +/- 4.72 and 20.25 +/- 1.45 in the control group, respectively. The overexpression of VEGF in study group biopsies was particularly evident in umbrella cells examined by confocal microscopy. CONCLUSION: Our findings identified increased expression of HIF-1alpha in bladder tissue and overexpression of VEGF in umbrella cells from patients with IC. These events may be associated with glomerulation formation during hydrodistention in IC bladders. Thus, these molecular findings could offer the therapeutic mechanism for hyperbaric oxygenation application to patients with IC. PMID- 21813167 TI - Detection of circulating tumor cells in metastatic and clinically localized urothelial carcinoma. AB - OBJECTIVE: To examine the incidence and prognostic value of circulating tumor cells (CTCs) in urothelial cancer (UC). The detection of CTCs is prognostic in several cancer types. METHODS: A total of 44 subjects with UC were assessed for CTCs using CellSearch Technology and 7.5 mL of peripheral blood, sorted by magnetic separation (epithelial cell adhesion molecule positive) and immunofluorescent staining (positive for cytokeratin 8, 18, or 19, negative for CD45, positive for 4',6-diamidino-2-phenylindole) to identify the CTCs. RESULTS: Five (17%) of 30 subjects with clinically localized and 7 (50%) of 14 subjects with metastatic UC had >=1 detectable CTC (range 1-177). Six subjects had >=5 CTCs. Fluorescence in situ hybridization analysis was performed in 20 samples from 18 unique subjects using the UroVysion probe set. Copy number gains consistent with neoplasm were observed in those with measurable CTCs but not in any of the CTC-negative samples tested. With a median follow-up of 337 days, all 7 patients with metastasis and detectable CTCs had died compared with 3 (43%) of the 7 with metastasis but without detectable CTCs. CONCLUSION: CTCs are commonly observed in metastatic UC. CTCs were observed in 50% of the patients with metastatic UC tested. Fluorescence in situ hybridization analysis confirmed the aneusomic chromosomal content in the CTCs. These findings suggest that measurable CTCs might be prognostic for shortened survival in patients with metastatic UC, although the optimal threshold for a "positive" finding is unknown. CTCs were also detected in a subset of patients with clinically localized disease, identifying a potential high-risk, preoperative group for future study. PMID- 21813168 TI - Simple cystectomy: outcomes of a new operative technique. AB - OBJECTIVE: To present an efficient technique for simple cystectomy. Urinary diversion for benign indications is a relatively rare procedure. However, diversion alone without accompanying cystectomy results in a significant risk of complications, such as pyocystis, hematuria, pain, and secondary carcinoma. METHODS: We retrospectively reviewed our institutional experience with this simple cystectomy technique, which included 23 patients from 2007-2010 performed by 3 surgeons. There were 14 females and 9 males. All patients had exhausted all other possible conservative therapies. Indication for the procedure included neurogenic bladder and resulting complications in 9 patients, complications from prostate radiation therapy in 5 patients, refractory interstitial cystitis in 5 patients, and refractory incontinence in 4 patients. RESULTS: The average patient was 63.3 years old and had undergone 2.7 prior abdominal or pelvic surgeries and 3.6 prior urinary operations. The average operative time was 27.5 minutes for the simple cystectomy portion of the case (recorded in 19 cases) and average blood loss was 46.7 mL (recorded in 12 cases). For the entire procedure, including diversion with bowel segment, the average blood loss was 231.5 mL. The mean entire operative time was 318.5 minutes. There were no complications noted intraoperatively or postoperatively specifically attributed to the cystectomy portion. All pathology specimens revealed no evidence of malignancy. Mean follow up was 8 months (range 1-33). CONCLUSION: This simple cystectomy technique, in most cases of urinary diversion for benign indications, can be performed quickly with minimal blood loss and complications. PMID- 21813169 TI - Adrenocortical carcinoma masquerading as a benign adenoma on computed tomography washout study. AB - An incidental adrenal mass is a common finding on cross-sectional imaging, with most of these lesions being benign adenomas. Indications for adrenalectomy turn on the likelihood that a mass is malignant or whether it exhibits metabolic activity. Modern imaging is considered highly accurate in differentiating adrenal adenomas from other adrenal pathology. We present a case of a 5-cm adrenal lesion with computed tomography washout characteristics consistent with a benign adenoma, which proved upon resection to be an adrenocortical carcinoma. PMID- 21813171 TI - Let's ask that out front: health and safety screenings in triage. PMID- 21813172 TI - Anaemia in low-income and middle-income countries. AB - Anaemia affects a quarter of the global population, including 293 million (47%) children younger than 5 years and 468 million (30%) non-pregnant women. In addition to anaemia's adverse health consequences, the economic effect of anaemia on human capital results in the loss of billions of dollars annually. In this paper, we review the epidemiology, clinical assessment, pathophysiology, and consequences of anaemia in low-income and middle-income countries. Our analysis shows that anaemia is disproportionately concentrated in low socioeconomic groups, and that maternal anaemia is strongly associated with child anaemia. Anaemia has multifactorial causes involving complex interaction between nutrition, infectious diseases, and other factors, and this complexity presents a challenge to effectively address the population determinants of anaemia. Reduction of knowledge gaps in research and policy and improvement of the implementation of effective population-level strategies will help to alleviate the anaemia burden in low-resource settings. PMID- 21813170 TI - Cadherins, catenins and cell cycle regulators: impact on survival in a Gynecologic Oncology Group phase II endometrial cancer trial. AB - OBJECTIVE: We evaluated the clinical relevance of catenins, cadherins and cell cycle regulators in stage IV or recurrent endometrial carcinoma in a multi-center phase II trial (GOG protocol #119). METHODS: Tissue microarrays of metastatic or recurrent (n=42) tumor were developed and immunohistochemistry was performed. Average expression (percent staining x intensity) was assessed in tumor epithelium ((E)) and stroma ((S)) and categorized into tertiles (T1, T2, T3) for E-cadherin(E), N-cadherin(E), alpha-catenin(E), beta-catenin(E), gamma catenin(E), p120-catenin(E) and Ki-67(E); as negative, below median or above median for p16(E), p27(E) and CD44(S); or as negative or positive for p53(E), Ki 67(S) and APC(S) (adenomatous polyposis coli). End points included response and survival. RESULTS: E-cadherin(E), p16(E), and p53(E) varied by race (p=0.003, p=0.024, p=0.002,) and N-cadherin(E), Ki-67(E), p16(E) and p27(E) by tumor type (p=0.015, p=0.011, p=0.005, p=0.021). Correlations were observed among E cadherin(E) with p120(E) (r=0.66), p53(E) (r=-0.32), alpha-catenin(E) (r=0.52), beta-catenin(E) (r=0.58), and gamma-catenin(E) (r=0.58). High E-cadherin(E) (T2 or T3) versus low (T1) expression was associated with better survival in unadjusted (hazard ratio [HR]=0.14, 95% confidence interval [CI]=0.06-0.37 or HR=0.17, 95% CI=0.07-0.42) and adjusted models (HR=0.18, 95% CI=0.05-0.59 or HR=0.22, 95% CI=0.07-0.70). High p16(E) versus negative expression was associated with worse survival in unadjusted (HR=3.87, 95% CI=1.74-8.61) and adjusted (HR=4.18, 95% CI=1.28-13.6) models. Positive versus negative expression of p53(E) was associated with worse survival in unadjusted (HR=2.31, 95% CI=1.16-4.60) but not adjusted models. CONCLUSIONS: E-cadherin(E) and p16(E) appear to be clinically relevant, independent prognostic factors in stage IV or recurrent endometrial cancers treated with Tamoxifen and Medroxyprogesterone acetate, and merit further study. PMID- 21813173 TI - Minimally invasive, longitudinal monitoring of biomaterial-associated inflammation by fluorescence imaging. AB - Implant-associated inflammation is a major cause for the reduced performance/lifetime and failure of numerous medical devices. Therefore, the ability to non-invasively and quantitatively monitor implant-associated inflammation is critically important. Here we show that implant-associated inflammation can be imaged via fluorescence imaging using near-infrared hydrocyanine dyes delivered either locally or intravenously in living mice. This imaging strategy allowed quantitative longitudinal monitoring of inflammation by detecting reactive oxygen species (ROS) released by inflammatory cells in response to implanted poly(ethylene terephthalate) (PET) disks or injected poly (lactic-co-glycolic acid) (PLGA) microparticles, and exhibited a strong correlation to conventional analysis of inflammation. Furthermore, modulation of inflammatory responses via controlled release of the anti-inflammatory agent dexamethasone was detected using this sensitive imaging approach. Thus, hydrocyanine-based fluorescence imaging of ROS could serve as a surrogate measure for monitoring implant-associated inflammation as well as evaluating the efficacy of therapeutic approaches to modulate host responses to implanted medical devices. PMID- 21813174 TI - Cell adhesion and detachment on gold surfaces modified with a thiol functionalized RGD peptide. AB - The dynamic nature of cell adhesion and detachment is critically important to a variety of physiological and pathophysiological phenomena. Much, however, still remains uncertain and controversial about the mechanochemical players and processes involved in cellular adhesion and detachment. This leads to the need for quantitative characterization of the adhesion and detachment of anchorage dependent cells. Here, cell adhesion and detachment up to subcellular level are examined using gold surfaces modified with a thiol-functionalized arginine glycine-aspartic acid (RGD) peptide. A thiol self-assembled monolayer (SAM) on top of the gold surfaces is reductively desorbed with activation potential to spatiotemporally manipulate both cell adhesion and detachment. This method maintains cells of interest living and intact during experiments, making it possible to quantify cell adhesion and detachment as close as possible to in vivo conditions. Experimental characterizations for NIH 3T3 fibroblasts are carried out with a focus on the following issues: the effect of the size and geometric shape of gold surfaces on cell adhesion; the effect of cell confluency, cell shape, and activation potential magnitude on cell detachment; changes in the material properties of cells during cell detachment. The findings of this study should lead to better understanding of cellular dynamics in anchorage-dependent cells. PMID- 21813175 TI - Concave microwell based size-controllable hepatosphere as a three-dimensional liver tissue model. AB - We have developed a size-controllable spheroidal hepatosphere and heterosphere model by mono-culturing of primary hepatocytes and by co-culturing primary hepatocytes and hepatic stellate cells (HSCs). We demonstrated that uniform-sized heterospheres, which self-aggregated from primary hepatocytes and HSCs, formed within concave microwell arrays in a rapid and homogeneous manner. The effect of HSCs was quantitatively and qualitatively investigated during spheroid formation, and HSC played an important role in controlling the organization of the spheroidal aggregates and formation of tight cell-cell contacts. An analysis of the metabolic function showed that heterospheres secreted 30% more albumin than hepatospheres on day 8. In contrast, the urea secretion from heterospheres was similar to that of hepatospheres. A quantitative cytochrome P450 assay showed that the enzymatic activity of heterospheres cultured for 9 days was higher as compared with primary hepatospheres. These size-controllable heterospheres could be mass-produced using concave plate and be useful for creating artificial three dimensional hepatic tissue constructs and regeneration of failed liver. PMID- 21813176 TI - ROR1 is expressed on hematogones (non-neoplastic human B-lymphocyte precursors) and a minority of precursor-B acute lymphoblastic leukemia. AB - ROR1 is a receptor tyrosine kinase expressed during embryogenesis, on chronic lymphocytic leukemia (CLL) and in other malignancies. Hematogones (non-neoplastic B-lymphocyte precursors) express surface ROR1 at an intermediate stage of maturation that lacks CD34 or TdT. The neoplastic counterpart to hematogones is precursor-B acute lymphoblastic leukemia (B-ALL), but less than 10% of B-ALL express surface ROR1, and these ROR1+ B-ALL cases have an unusually high frequency of lacking CD34 and/or having t(1;19), a chromosomal translocation that defines a specific subtype of B-ALL. PMID- 21813177 TI - Evaluation of PAX5 gene in the early stages of leukemic B cells in the childhood B cell acute lymphoblastic leukemia. AB - B-lineage acute lymphoblastic leukemia (B-ALL) is a common subtype of acute leukemia in children. PAX5 plays a central role in B-cell development and differentiation. In this study, we analyzed PAX5 expression levels, transactivation domain mutations/deletions in B-ALL patients (n=115) and healthy controls (n=10). Relative PAX5 mRNA levels were significantly increased in B-ALL patients (p<0.0001). PAX5 expression was also evaluated in three different B-ALL subgroups (pro B, Common B and Pre B ALL) and showed stage specific expression levels. Pro B (p=0.04) and pre B (p=0.04) patients showed significantly high PAX5 mRNA levels compared to stage specific controls. At least one deletion of exons 7 8 or 9 has been identified in the 41% of the patients. CD34 positivity in patients and presence of large deletions (Delta7/8/9) showed a significant correlation (p=0.05). None of our patients showed PAX5 point mutations, but two previously identified SNPs (rs3780135 and rs35469494) were detected. Our results support that PAX5 is a critical factor in B-ALL development and aberrant PAX5 expression especially at early stages may leads to leukemic transformation. PMID- 21813178 TI - Use of organic amendments as a bioremediation strategy to reduce the bioavailability of chlorpyrifos insecticide in soils. Effects on soil biology. AB - The sorption capacity of both an organic municipal solid waste by-product (MSW) and a cow manure (CM) in a soil polluted with chlorpyrifos, as well as its effect on soil microbial activity, and weight, reproductive parameters and glutathione-S transferase activity of two earthworm species (Eisenia fetida and Lumbricus terrestris) were studied. Chlorpyrifos was added at the recommended application rate (5 L ha(-1); 768 mg chlorpyrifos kg(-1)) and treated with MSW at a rate of 10% and CM at a rate of 5.8% in order to apply the same amount of organic matter to the soil. An unamended polluted soil was used as control. Earthworm cocoon number, average weight of cocoon, and number of juveniles per cocoon were measured after 30 days of incubation, whereas soil enzymatic activities, earthworm weight, and glutathione-S-transferase activity of earthworms were measured after 3, 45 and 90 days. Soil enzymatic activities, reproductive and glutathione-S-transferase activity in both worms decreased in polluted soil. The inhibition percentage of soil enzymatic activities, reproductive and glutathione S-transferase activity in both worms was lower in MSW-amended soil than for CM amended soil. The toxic effect of chlorpyrifos on E. fetida was lowest compared to L. terrestris. This suggested that the addition of organic wastes with higher humic than fulvic acid concentration is more beneficial for remediation of soils polluted with chlorpyrifos. PMID- 21813179 TI - Toxic effect of NaCl on ion metabolism, antioxidative enzymes and gene expression of perennial ryegrass. AB - Two-month old seedlings of perennial ryegrass (Lolium perenne L.) were subjected to four different levels of salinity for 7 days. The NaCl treatments reduced turf quality and normalized transpiration rates. Both chlorophyll (Chl) a and Chl b contents decreased in the grass exposed to 255 mM relative to the control. An increase in the lipid peroxidationin was observed. The activity of leaf superoxide dismutase increased while, peroxidase and catalase activities decreased in response to NaCl treatments. The expression of Chl Cu/ZnSOD, Cyt Cu/ZnSOD, FeSOD, CAT, POD, GPX and GR was up-regulated for NaCl-treated grass. Salt stress increased accumulation of Na(+) and decreased K(+)/Na(+) ratio, Mg(2+) and P content in both shoots and roots of perennial ryegrass. The findings of this study suggest that salt stress may cause toxicity to perennial ryegrass through oxidative injury and damage to Chl and cell membrane integrity. PMID- 21813180 TI - Neutrophils and T cells: bidirectional effects and functional interferences. AB - Polymorphonuclear cells (PMN) are widely recognized as sophisticated killers during microbial infections. In recent years, PMN have been shown to interact and functionally interfere with other cells of the immune system. In this study, we investigated PMN-T cell interactions in an in vitro co-culture system. A relative increase in T cells in the co-culture was associated with the upregulation of CD66b expression on PMN. In addition, PMN were found to dose-dependently impair anti-CD3 induced CD4(+) T cell activation, proliferation and viability. In a transwell co-culture system, proliferation of T cells was, however, enhanced which illustrates that suppression was contact-dependent. The addition of an arginase-inhibitor or blocking antibodies against calprotectin, but not myeloperoxidase (MPO), partially restored T cell proliferation. Furthermore, the presence of PMN in the co-culture dose-dependently increased the fraction of IFN gamma and IL-17 producing T cells and decreased the percentage of IL-10 producing CD4(+) T cells. Altogether, these data show that there is cross-talk between PMN and T cells which, in non-inflammatory conditions, results in the effects described above. Further studies should investigate PMN-T cell functional interference in inflammatory situations and clarify the importance of this PMN-T cell cross-talk in the regulation of the immune response. PMID- 21813181 TI - IFN-alpha primes T- and NK-cells for IL-15-mediated signaling and cytotoxicity. AB - Recently it has become clear that interferon (IFN)-alpha, a type I interferon produced rapidly in response to infection, not only plays a key role in innate immunity, but also promotes adaptive immune responses by influencing the production or function of other cytokines. During infections IFN-alpha fosters the production of IL-15, which plays a pivotal role in the development, survival and function of NK cells and recruitment and activation of T cells. Since these two cytokines exert overlapping functions during infections, this investigation was undertaken to study the priming effect of IFN-alpha on the effect of IL-15 on human T and NK cells. We show that IFN-alpha induces an increased expression of IL-15Ralpha in human activated peripheral T cells, and in CD8(+) and CD4(+) T cell lines. Functionally, the IFN-alpha-enhanced IL-15Ralpha expression resulted in an enhanced IL-15-mediated phosphorylation of STAT5 and STAT3 followed by a further increase in IL-15Ralpha expression. Moreover, IFN-alpha significantly increased the IL-15-induced cytotoxic activity of freshly isolated T and NK cells. Taken together, our data show that IFN-alpha boosts signaling and functional effects of IL-15, at least in part by fostering the increased IL-15R expression, thus add new facet to the emerging role of IFN-alpha as an important primer of adaptive immune responses. PMID- 21813182 TI - The validity of DSM-IV-TR criteria B and C of hair-pulling disorder (trichotillomania): evidence from a clinical study. AB - In both DSM-IV-TR and the ICD-10, hair-pulling disorder (trichotillomania, or TTM) is described as hair-pulling, with a rising urge or tension prior to pulling or when attempting to resist, and pleasure, relief or gratification during or after pulling. However, it has been questioned whether all patients with hair pulling experience these other phenomena, and whether they occur with all pulling episodes. The objective of this study was to examine the DSM-IV-TR requirement of criteria B and C for a diagnosis of TTM in a sample of people with hair-pulling. A multi-site sample of adults with hair-pulling who met both DSM-IV-TR diagnostic criteria B and C (n=82, 89.13%) were compared to those who failed to satisfy both B and C (n=10, 10.87%) on a number of clinical variables. There were no differences in hair-pulling severity, levels of comorbid depressive and anxiety symptoms, number of comorbid body-focused repetitive behaviors, or impairment between those patients who did and did not meet criteria B and C. Our study does not provide convincing support for the inclusion of the current diagnostic criteria B and C for TTM in DSM-5. PMID- 21813183 TI - Insight and negative symptoms as predictors of functioning in a work setting in patients with schizophrenia. AB - The present study was conducted to explore correlates of vocational outcome for individuals with schizophrenia. Seventy-eight individuals with schizophrenia were recruited to take part in a supported employment program in which they were provided with approximately 6 months of part-time work through a VA hospital. Positive symptoms, negative symptoms, and level of insight into mental illness were assessed once every 4 weeks, in addition to a work performance evaluation with participants' supervisors. Hierarchical longitudinal regression analysis revealed that negative symptom severity and impaired insight were significantly associated with poor work performance, and this relationship persisted over time. By contrast, positive symptom severity was not significantly associated with work performance. These results indicate that insight and negative symptoms, which can fluctuate over time, may be driving fluctuations in work performance and may therefore be a valuable target for future interventions. PMID- 21813184 TI - Cognitive-behavioral coping strategies associated with combat-related PTSD in treatment-seeking OEF-OIF Veterans. AB - Posttraumatic stress disorder (PTSD) is associated with intrusive trauma-related thoughts and avoidance behaviors that contribute to its severity and chronicity. This study examined thought control and avoidance coping strategies associated with both a probable diagnosis and symptom severity of combat-related PTSD in a sample of 167 treatment-seeking Operations Enduring Freedom and Iraqi Freedom (OEF-OIF) Veterans. Within one year of returning from deployment, Veterans completed a survey containing measures of combat exposure, coping strategies, psychopathology, and postdeployment social support. Veterans with a positive screen for PTSD scored higher than Veterans without a positive screen for PTSD on measures of worry, self-punishment, social control, behavioral distraction, and avoidance coping strategies. Worry and social avoidance coping were positively related to PTSD symptoms, and greater perceptions of understanding from others were negatively related to these symptoms. A structural equation model revealed that scores on a measure of postdeployment social support were negatively associated with scores on measures of maladaptive cognitive coping (i.e., worry, self-punishment) and avoidance coping (social and non-social avoidance coping) strategies, which were positively associated with combat-related PTSD symptoms. These results suggest that maladaptive thought control and avoidance coping may partially mediate the relation between postdeployment social support and combat related PTSD symptoms in treatment-seeking OEF-OIF Veterans. Consistent with cognitive therapy models, these findings suggest that interventions that target maladaptive coping strategies such as worry, self-punishment, and social avoidance, and that bolster social support, most notably understanding from others, may help reduce combat-related PTSD symptoms in this population. PMID- 21813185 TI - Psychopathology of adolescent detained versus psychiatric inpatient females. AB - Several studies have shown high rates of psychopathology among female adolescents in detention. Although rates of mental health problems have been called alarming, it is unknown whether mental health needs in females in juvenile justice differ substantially from those of females in mental health care. Therefore, this study compared adolescent females in detention with inpatient adolescent females. For this purpose, a sample of 256 detained females (mean age 15.4 +/- 1.3) was compared to 45 psychiatric inpatient females (mean age 15.8 +/-1.4). Socio demographic characteristics, mental health history and psychiatric problems were investigated using file-information and self-report questionnaires. Compared to detained females, inpatients more often showed internalizing problems and dissociation, whereas externalizing problems prevailed in girls in detention centers. Females in detention more often came from an ethnic minority group, while females in mental healthcare more often received mental healthcare previously and had parents with higher employment. This study confirms that mental health needs of girls in mental healthcare and in detention are high. However, non-mental health related factors were different as well - i.e. socio economic factors - and are likely to influence the involvement with either service sector. PMID- 21813186 TI - The pilot study of a Neuropsychological Educational Approach to Cognitive Remediation for patients with schizophrenia in Japan. AB - The main aim of this study is to demonstrate the feasibility and efficacy of a Neuropsychological Educational Approach to Cognitive Remediation (NEAR) in Japan. This multi-site study used a quasi-experimental design. Fifty-one patients with schizophrenia or schizoaffective disorder participated. The NEAR program consisted of two 1-h computer sessions per week and an additional group meeting session lasting 30 to 60 min once a week. The subjects completed 6 months of NEAR sessions before being assessed. Moreover, taking into consideration the possible practice effect, we assessed 21 control patients twice with an interval of 6 months. We assessed cognitive function by using the Japanese version of the Brief Assessment of Cognition in Schizophrenia (BACS-J). Consequently, the NEAR group showed significant improvement in overall cognitive function, and in comparison with the control group, these findings were generally similar except for motor speed. Although the present study has its limitations, it demonstrates that the NEAR is feasible in Japan as well as it is in Western countries. PMID- 21813187 TI - Efficacy of an Internet-based intervention for posttraumatic stress disorder in Iraq: a pilot study. AB - In the past 20 years, war and human rights violations have led to high rates of exposure to traumatic events among the Iraqi population. Due to the ongoing violence, many physicians and mental health professionals have left Iraq in recent years. The Internet offers new possibilities for the psychological treatment of posttraumatic stress disorder (PTSD) in conflict areas. A therapist supported cognitive-behavioral treatment manual that has been evaluated in Western countries was translated into Arabic and culturally adapted. The treatment was conducted via the Internet by Arabic-speaking therapists and was evaluated in an uncontrolled pilot study with 15 participants. Main outcome measures were PTSD (Posttraumatic Diagnostic Scale (PDS)), depression, anxiety (Hopkins Symptom Check List-25 (HSCL-25)), and quality of life (EUROHIS). The intervention resulted in a highly significant decrease in symptoms of PTSD, depression, and anxiety. Quality of life was higher at posttreatment. All treatment effect sizes were in the large range, indicating a significant improvement in mental health symptoms and quality of life. Preliminary clinical evidence indicates that new technologies can be used to provide humanitarian aid in the form of e-mental health services, even in areas that remain highly unstable. PMID- 21813189 TI - Revision surgeries and medical interventions in young cochlear implant recipients. AB - OBJECTIVE: To report devices failures and postoperative or medical complications after cochlear implantation in children and to discuss revision surgeries and medical interventions occurring during follow-up. METHODS: In this retrospective study in a tertiary referral pediatric hospital, we included a consecutive sample of children younger than 15 years old who received implants between January 1994 and June 2010. All complications and treatments were systematically reviewed. RESULTS: One hundred and forty children were included in this study. Four children received bilateral cochlear implantation. Mean age at implantation was 43.6 months (age ranged from 11 months to 15 years). Overall, 74 children were boys (52.1%) and 35 children (25%) received implants before the age of two. Inner ear malformations were found in 19 children (13.5%), while 18 children (12.9%) experienced complications: cochlear reimplantations (n=8), other revision surgeries (n=3) and medical treatment (n=7). Excluding device failures, 13 children (9.2%) experienced complications. Postoperative infection was the principal cause of these complications (10 cases). Four children younger than 2 years at implantation suffered complication postoperatively. In these children, there was no statistically significant increase in complications compared to older children (P>0.05). Complete electrode insertion was achieved in 7 of the 8 reimplanted children. CONCLUSION: Cochlear implantation could be considered a safe and reliable rehabilitation for deafened young children. Reimplantation was feasible and complete electrode insertion was achievable. Long-term follow up was mandatory to minimize and control surgical complication. PMID- 21813188 TI - Restriction of the felid lentiviruses by a synthetic feline TRIM5-CypA fusion. AB - Gene therapy approaches to the treatment of HIV infection have targeted both viral gene expression and the cellular factors that are essential for virus replication. However, significant concerns have been raised regarding the potential toxic effects of such therapies, the emergence of resistant viral variants and unforeseen biological consequences such as enhanced susceptibility to unrelated pathogens. Novel restriction factors formed by the fusion of the tripartite motif protein (TRIM5) and cyclophilin A (CypA), or "TRIMCyps", offer an effective antiviral defence strategy with a very low potential for toxicity. In order to investigate the potential therapeutic utility of TRIMCyps in gene therapy for AIDS, a synthetic fusion protein between feline TRIM5 and feline CypA was generated and transduced into cells susceptible to infection with feline immunodeficiency virus (FIV). The synthetic feline TRIMCyp was highly efficient at preventing infection with both HIV and FIV and the cells resisted productive infection with FIV from either the domestic cat or the puma. Feline TRIMCyp and FIV infection of the cat offers a unique opportunity to evaluate TRIMCyp-based approaches to genetic therapy for HIV infection and the treatment of AIDS. PMID- 21813190 TI - Assessment of hearing organ activity in a group of neonates with central nervous system impairment. AB - OBJECTIVE: Hypoxic-ischemic encephalopathy, primary subarachnoid hemorrhage in term newborns as well as periventricular leukomalacia and intraventricular hemorrhage in premature newborns are the major consequences of perinatal asphyxia. Intrauterine hypoxia and labor prolongation can also affect the hearing organ in newborns causing reversible or irreversible changes in the cochlea, brainstem or cortex. The aim of the study was to carry out the objective assessment of the cochlea and hearing pathway activity using CEOAEs and ABR; to find relationships between hearing status and parameters effecting on nervous system in neonates with central nervous system impairment occurring following perinatal asphyxia. METHODS: To the investigation 36 newborns with hypoxic ischemic encephalopathy, periventricular leukomalacia or intraventricular hemorrhage were included. The control group encompassed 32 health newborns matched as to the age. In all newborns otoscopic examination, CEOAEs after birth and CEOAEs with ABR 3 months later were performed. Perinatal anamnesis, general pediatric status, results of trans-fontanel ultrasonography and biochemical test results were taken into account in statistical analyses. RESULTS: The mean amplitudes of CEOAEs in the first days of life were significantly reduced in investigation group comparing to control babies. 3months later the recorded responses significantly increased but did not reach values of control group. No differences were found between latencies of waves I and II. ABR latencies of waves III, IV, V and interpeak latencies I-III, III-V, I-V were delayed in investigation group when compared to control patients. Also morphology of ABR recordings in investigation group has slightly changed. Perinatal aspyxia leading to hypercapnia, low gestational age, prolonged artificial ventilation and meningitis were the main risk factors related to disturbances in ABR recordings. CONCLUSIONS: The combined use of CEOAEs and ABR in neonates with central nervous system impairment involvement revealed the existence of abnormalities in cochlear micromechanics and retrocochlear auditory pathway. Etiology seems to be multifactoral. PMID- 21813191 TI - The hemostatic efficacy of Ankaferd Blood Stopper in adenoidectomy. AB - OBJECTIVE: To evaluate the efficacy of Ankaferd Blood Stopper (ABS) in the control of intraoperative and postoperative bleeding in adenoidectomy. METHODS: In total, 90 patients underwent traditional cold steel adenoidectomy and were then randomized to receive ABS or 0.9% physiological saline solution to obtain hemostasis. Objective data collected included time of operation and blood loss during operation. Visual analog scales (VAS) were used to record subjective data by the operating surgeon including bleeding following adenoid pack removal and ease of operation. RESULTS: In a comparison between patients in the ABS group (n = 46) and the control group (n = 44), those in the ABS group had significantly shorter operation times (9.11 +/- 1.02 vs. 13.16 +/- 3.96 min; p < 0.001) and less blood loss during the operation (20.19 +/- 8.59 vs. 25.48 +/- 12.96 ml; p <= 0.05) and a shorter hemostasis time (3.83 +/- 0.8 vs. 5.82 +/- 1.67 min; p < 0.001). Regarding hemorrhage after tampon removal, 40 patients (87%) in the ABS group and 17 patients (38.6%) in the control group did not suffer from hemorrhage (p < 0.001). Regarding ease of hemostasis, 40 patients (87%) in the ABS group experienced very easy or easy hemostasis while 26 patients in the control group did so (59.1%; p = 0.004). Patients in the ABS group returned to a regular diet earlier and had less use of analgesics at 7 days postoperatively. Use of electrocautery was less in the ABS group than in the control group (10.9 vs. 40.9%; p = 0.001). CONCLUSIONS: The side on which ABS was used showed significant differences in hemostasis time, blood loss, and ease of hemostasis. ABS appears to be safe and effective; it decreases intraoperative bleeding and reduces operating time when compared to traditional hemostasis methods after curette adenoidectomy. PMID- 21813192 TI - Discovering medical resource utilization in total knee arthroplasty (TKA) using rule-based method. AB - TKA is a highly effective means of treating (advanced knee arthritis) degenerative joint disease. Previous studies have demonstrated that a high surgical volume for total joint arthroplasty reduces morbidity and improved economic outcome, these methods for themselves are fraught with complexity, uncertainty and non-linear problem in terms of medical datasets may be unable to more accurately finding important information. As medical datasets often include a large number of features (attributes), some of which are irrelevant, and therefore it cannot intuitively understand the corresponding to main factors which affecting the resource utilizations of healthcare. In order to solve the problems mentioned above, this study employs specialist advice to filter relevant cases (records) and proposed an integrated five features selection methods to select the important features. Based on rough set theory (RST), the rules are extracted and compared with other methods in terms of accuracy. The contributions contain: (1) data screening based on specialist opinions, (2) two stage feature selection by analysis of variance (ANOVA) and proposed an integrated feature selection approach (IFSA), and (3) data discretization and rule generation by RST. The proposed model is verified by using three datasets for comparison accuracy. The results can provide a valuable reference for National Health Insurance Bureau (NHI) in establishing the TKA standard. PMID- 21813193 TI - Managing the underestimated risk of statin-associated myopathy. AB - In clinical practice 5-10% of patients receiving statins develop myopathy, a side effect that had been systematically underestimated in the randomized controlled trials with statins. The most common manifestation of myopathy is muscle pain (usually symmetrical, involving proximal muscles) without creatinine kinase (CK) elevation or less frequently with mild CK elevation. Clinically significant rhabdomyolysis (muscle symptoms with CK elevation >10 times the upper limit of normal and with creatinine elevation) is extremely rare. Myopathy complicates the use of all statins (class effect) and is dose-dependent. The pathophysiologic mechanism of statin-associated myopathy is unknown and probably multifactorial. The risk of statin-associated myopathy can be minimized by identifying vulnerable patients (i.e. patients with impaired renal or liver function, advanced age, hypothyroidism, etc.) and/or by eliminating-avoiding statin interactions with specific drugs (cytochrome P-450 3A4 inhibitors, gemfibrozil, etc.). In symptomatic patients, the severity of symptoms, the magnitude of CK elevation and the risk/benefit ratio of statin continuation should be considered before statin treatment is discontinued. Potential strategies are the use of the same statin at a lower dose and if symptoms recur the initiation of fluvastatin XL 80 mg daily or rosuvastatin intermittently in low dose (5-10mg), combined usually with ezetimibe 10mg daily. Failure of these approaches necessitates the use of non statin lipid lowering drugs (ezetimibe, colesevelam). In order to provide evidence based recommendations for the appropriate management of statin intolerant patients we need randomized clinical trials directly comparing the myopathic potential of different lipid-lowering medications at comparable doses. PMID- 21813194 TI - Antioxidant supplementation does not attenuate exercise-induced cardiac troponin release. PMID- 21813196 TI - Alcohol consumption and aortic arch calcification in an older Chinese sample: the Guangzhou Biobank Cohort Study. AB - OBJECTIVE: To examine the association between alcohol consumption and aortic arch calcification (AAC) in an older Chinese sample. METHODS: In 27,844 older people aged 50-85, socioeconomic position and lifestyle factors were assessed by a questionnaire. The presence and severity of AAC were diagnosed from chest X-ray by two experienced radiologists. RESULTS: In men, the risk for AAC increased significantly in frequent or excessive drinkers [adjusted odds ratio (OR)=1.36 (95% confidence interval (CI) 1.16-1.59) and 1.49 (1.21-1.83) for those who drank >5 times/week and those who drank excessively, respectively] (P for trend from 0.002 to 0.001). When AAC was analyzed as an outcome variable with 3 categories of severity, significant dose-response relations between the severity of AAC and alcohol consumption were observed, with those who drank frequently (>5/week) or excessively having more serious AAC (P for trend=0.03 and 0.02, respectively). No significant association was found in women as few drank excessively. CONCLUSION: The presence and severity of AAC were associated with quantity or frequency of alcohol consumption in a dose-response pattern, suggesting that alcohol drinking, even when moderate, has no benefit for AAC. Excessive drinking increased the risk of AAC by 50% compared to never drinkers. PMID- 21813197 TI - The impact of preoperative right ventricular dysfunction on early hemodynamic instability after coronary artery bypass graft surgery. PMID- 21813198 TI - Identifying risk factors of highly pathogenic avian influenza (H5N1 subtype) in Indonesia. AB - Highly pathogenic avian influenza (HPAI), subtype H5N1, was first officially reported in Indonesia in 2004. Since then the disease has spread and is now endemic in large parts of the country. This study investigated the statistical relationship between a set of risk factors and the presence or absence of HPAI in Indonesia during 2006 and 2007. HPAI was evaluated through participatory disease surveillance (PDS) in backyard village chickens (the study population), and risk factors included descriptors of people and poultry distribution (separating chickens, ducks and production sectors), poultry movement patterns and agro ecological conditions. The study showed that the risk factors "elevation", "human population density" and "rice cropping" were significant in accounting for the spatial variation of the PDS-defined HPAI cases. These findings were consistent with earlier studies in Thailand and Vietnam. In addition "commercial poultry population", and two indicators of market locations and transport; "human settlements" and "road length", were identified as significant risk factors in the models. In contrast to several previous studies carried out in Southeast Asia, domestic backyard ducks were not found to be a significant risk factor in Indonesia. The study used surrogate estimates of market locations and marketing chains and further work should focus on the actual location of the live bird markets, and on the flow of live poultry and poultry products between them, so that patterns of possible transmission, and regions of particular risk could be better inferred. PMID- 21813199 TI - Knee muscle contributions to joint rotational stiffness. AB - The purpose of this paper was to investigate total joint rotational stiffness (JRS) and relative muscle contributions to JRS with varying extensor moment demands. It was hypothesized that greater co-activation of the flexors at lower levels of moment would result in greater JRS, relative to moment demands. It was also hypothesized that the flexors would have greater relative JRS contributions at lower moment levels. Twelve male participants generated isometric extensor moments about the knee at varying intensities, during plateau and ramping (up and down) conditions. Electromyography was used to estimate individual muscle forces, which were used to calculate JRS about three orthogonal axes. Orthogonal trend analysis revealed a linear relationship (p<.001) between moment and JRS, about all axes. The vastus lateralis provided the greatest JRS about all axes. Of the flexors, the semimembranosis provided the most JRS about the flexion/extension (FE) and axial (AX) axes. However, while most muscle activity increased linearly, the gastrocnemious lateral (GL) had an interaction between condition and moment. Despite an extensor moment, the GL had minor contributions about the FE axis (1.2%), and it was postulated that this increase in activation was to stabilize about the VV axis, where its contribution was as high as 18.9%. PMID- 21813200 TI - Intra-individual stability of neuromotor tasks from 6 to 18 years: a longitudinal study. AB - This study investigates the intra-individual stability of the speed of several motor tasks and the intensity of associated movements in 256 children (131 girls, 125 boys) from the Zurich generational study using the Zurich neuromotor assessment battery (ZNA) over a 12-year period from the age of 6 to 18 years. The stability was assessed by correlograms of standard deviation scores calculated from age- and gender-adjusted normative values and compared with standing height and full scale intelligence quotient (IQ). While motor tasks of hand, finger and foot (HFT) and contralateral associated movements (CAM) exhibited a moderate stability (summary measure as correlation coefficients between two measurements made 4 years apart: .61 and .60), other tasks (dynamic balance, static balance and pegboard) were only weakly stable (.46, .47 and .49). IQ and height were more stable than neuromotor components (.72 and .86). We conclude that the moderately stable HFT and CAM may reflect "motor traits", while the stability of the pegboard and balance tasks is weaker because these skills are more experience related and state-dependent. PMID- 21813201 TI - Long-term prognosis of patients with lung cancer detected on low-dose chest computed tomography screening. AB - The effectiveness of lung cancer screening using low-dose chest computed tomography (CT) remains elusive. The present study examined the prognosis of patients with lung cancer detected on CT screening in Japanese men and women. Subjects were 210 patients with primary lung cancer identified on CT screening at two medical facilities in Hitachi, Japan, where a total of 61,914 CT screenings were performed among 25,385 screenees between 1998 and 2006. Prognostic status of these patients was sought by examining medical records at local hospitals, supplemented by vital status information from local government. The 5-year survival rate was estimated according to the characteristics of patients and lung nodule. A total of 203 (97%) patients underwent surgery. During a 5.7-year mean follow-up period, 19 patients died from lung cancer and 6 died from other causes. The estimated 5-year survival rate for all patients and for those on stage IA was 90% and 97%, respectively. Besides cancer stage, smoking and nodule appearance were independent predictors of a poor survival; multivariable-adjusted hazard ratio (95% confidence interval) was 4.7 (1.3, 16.5) for current and past smokers versus nonsmokers and 4.6 (1.6, 13.9) for solid nodule versus others. Even patients with solid shadow had a 5-year survival of 82% if the lesion was 20mm or less in size. Results suggest that lung cancers detected on CT screening are mostly curative. The impact of CT screening on mortality at community level needs to be clarified by monitoring lung cancer deaths. PMID- 21813202 TI - CD40-mediated cell death requires TRAF6 recruitment. AB - CD40 has an important role in T cell-B cell interaction which rescues B lymphocytes from undergoing apoptosis. However, various studies have demonstrated that CD40 can also play a direct role in the induction of specific cell death and thus in the inhibition of tumour cell proliferation. Our previous studies showed that CD40-mediated cell death was independent of caspases and required no de novo protein synthesis. Knowing that CD40 signaling is mediated by its association with several intracellular effectors, including members of TNFR-associated factors (TRAFs) family, the goal of the present study is to investigate the mechanisms involved in the induction of cell death by CD40. Our data reveals that CD40-mediated cell death required lysosomal membrane permeabilization and the subsequent cathepsin B release. In addition, CD40 homodimer formation, a phenomenon known to be necessary for some CD40-mediated signals, was shown to negatively regulate cell death induced by CD40. Moreover, using HEK293 cells ectopically expressing CD40 deficient in TRAF binding, we showed that CD40 mediated apoptosis occurred in the absence of TRAF2 and TRAF3 association, but was significantly reduced when CD40 was deficient in its TRAF6 binding. Therefore, by outlining the role of lysosomal pathways and intracellular effectors, namely TRAF6 in CD40-mediated cell death, our study identifies new targets for anti-cancer therapy. PMID- 21813203 TI - Roles of Salmonella enterica serovar Typhimurium encoded Peptidase N during systemic infection of Ifngamma-/- mice. AB - Pathogen encoded peptidases are known to be important during infection; however, their roles in modulating host responses in immunocompromised individuals are not well studied. The roles of S. typhimurium (WT) encoded Peptidase N (PepN), a major aminopeptidase and sole M1 family member, was studied in mice lacking Interferon-gamma (IFNgamma), a cytokine important for immunity. S. typhimurium lacking pepN (DeltapepN) displays enhanced colony forming units (CFU) compared to WT in peripheral organs during systemic infection in C57BL/6 mice. However, Ifngamma(-/-) mice show higher CFU compared to C57BL/6 mice, resulting in lower fold differences between WT and DeltapepN. Concomitantly, reintroduction of pepN in DeltapepN (DeltapepN/pepN) reduces CFU, demonstrating pepN-dependence. Interestingly, expression of a catalytically inactive PepN (DeltapepN/E298A) also lowers CFU, demonstrating that the decrease in CFU is independent of the catalytic activity of PepN. In addition, three distinct differences are observed between infection of C57BL/6 and Ifngamma(-/-) mice: First, serum amounts of TNFalpha and IL1beta post infection are significantly lower in Ifngamma(-/-) mice. Second, histological analysis of C57BL/6 mice reveals that damage in spleen and liver upon infection with WT or DeltapepN is greater compared to DeltapepN/pepN or DeltapepN/E298A. On the other hand, Ifngamma(-/-) mice are highly susceptible to organ damage by all strains of S. typhimurium used in this study. Finally, greater survival of C57BL/6, but not Ifngamma(-/-) mice, is observed upon infection with DeltapepN/pepN or DeltapepN/E298A. Overall, the roles of the host encoded IFNgamma during infection with S. typhimurium strains with varying degrees of virulence are highlighted. PMID- 21813204 TI - Serine protease inhibitor, 4-(2-aminoethyl)-benzene sulfonyl fluoride, impairs IL 12-induced activation of pSTAT4beta, NFkappaB, and select pro-inflammatory mediators from estrogen-treated mice. AB - Estrogen, a natural immunomodulator, is believed to be involved in the regulation of not only normal immune responses, but also pathological conditions such as inflammatory and autoimmune diseases. We have previously reported that estrogen exposure induces several pro-inflammatory molecules including nitric oxide, cytokines and chemokines (IFNgamma, IL-12, MCP-1, etc.) and modifies transcription factors (preferential expression of STAT4beta, increased NFkappaB p50/p50 DNA binding, and enhanced T-bet and Bcl-3) from activated splenocytes. Given that estrogen promotes diverse range of pro-inflammatory molecules, and modifies transcription factors, it is plausible that estrogen upregulates a common set of molecular event(s) that favors inflammation. Serine proteases are thought to play an important role in inflammation. Therefore in this study, we investigated the consequence of exposure of splenocytes stimulated with a key Th1/IFNgamma-inducing cytokine IL-12 or ConA from estrogen-treated mice to a serine protease inhibitor, 4-(2-aminoethyl)-benzenesulfonyl fluoride (AEBSF), on inflammatory cytokines (IFNgamma, IL-12) and related transcription factors (STAT4alpha/beta, T-bet, NFkappaB). Exposure of splenocytes to AEBSF for 3h noticeably inhibited the induction of IFNgamma, IL-12, and IL-12-induced STAT4beta, mRNA expression of T-bet and IL-12Rbeta2. The AEBSF-mediated inhibition of cytokines was accompanied by the expression of a normal-sized NFkappaB, downregulation of p50/p50 DNA binding but did not alter Bcl3. These findings provide a new understanding of inflammation and inhibition of serine proteases has important implications for designing novel therapeutic strategies for a broad range of inflammatory diseases. PMID- 21813205 TI - Mycobacterium tuberculosis: immune evasion, latency and reactivation. AB - One-third of the global human population harbours Mycobacterium tuberculosis in dormant form. This dormant or latent infection presents a major challenge for global efforts to eradicate tuberculosis, because it is a vast reservoir of potential reactivation and transmission. This article explains how the pathogen evades the host immune response to establish a latent infection, and how it emerges from a state of latency to cause reactivation disease. This review highlights the key factors responsible for immune evasion and reactivation. It concludes by identifying interesting candidates for drug or vaccine development, as well as identifying unresolved questions for the future research. PMID- 21813206 TI - Connexin32 can restore hearing in connexin26 deficient mice. AB - Functional gap junction channels composed of certain connexin proteins are essential for the function of the cochlea. Homozygous deficiency in the Gjb2 (mice) or GJB2 (human) gene coding for connexin26 (Cx26) in the cochlea leads to hearing impairment in mice and humans, respectively. Here we have studied the functional equivalence of Cx26 and connexin32 (Cx32) isoforms in the cochlea. We analyzed a conditional mouse mutant in which the Gjb2 coding DNA was exchanged by LacZ DNA coding for the reporter protein beta-galactosidase. This allowed us to follow the unrestricted and cell type specific expression of Gjb2 promoter activity. After inner ear specific, Otogelin-Cre recombinase mediated deletion of the loxP-site-flanked LacZ coding DNA, transcription of the Gjb1 gene, coding for Cx32 was activated by the Gjb2 promoter. Interbreeding of these mice with conditional Gjb2 null mice resulted in animals in which Cx32 instead of Cx26 protein is expressed in the non-sensory epithelial network of the cochlea. When we analyzed the auditory function in these mice, we found that the expression of Cx32 protein is sufficient to support hearing in the absence of Cx26. Thus Cx32 can functionally replace Cx26 in the mouse cochlea resulting in almost normal hearing. PMID- 21813207 TI - Staff-to-patient transmission of meticillin-resistant Staphylococcus aureus: do bacterial factors play a role? PMID- 21813208 TI - Overview of adverse events related to invasive procedures in the intensive care unit. AB - BACKGROUND: This study was conducted to determine the frequency, predictors, and clinical impact of adverse events (AEs) related to invasive procedures in the intensive care unit (ICU). METHODS: This was a prospective observational study of ICUs in a university hospital. RESULTS: A total of 893 patients requiring invasive procedures were admitted over a 1-year period. Among these, 310 patients (34.7%) experienced a total of 505 AEs. The mean number of AEs per patient was 1.6 +/- 1.1 (range, 1-7). Infectious AEs were significantly more frequent than mechanical AEs (60.4% vs 39.6%; P = .01). Factors independently associated with AE occurrence were isolation of multidrug-resistant bacteria at ICU admission, >5 invasive procedures, and ICU length of stay >8 days. Thirty-three AEs (6.5%) resulted in severe clinical impact, including 24 deaths. Ventilator-associated pneumonia (VAP) accounted for 62.5% of the deaths related to AEs. CONCLUSIONS: One-third of critically ill patients experienced AEs related to invasive procedures. Severe AEs were associated with 11% of all ICU deaths. VAP was the most frequent AE related to death. An improved assessment of the risk-benefit balance before each invasive procedure and increased efforts to decrease VAP prevalence are needed to reduce AE-related mortality. PMID- 21813209 TI - Accuracy of a urinary catheter surveillance protocol. AB - BACKGROUND: Many hospitals are increasing surveillance for catheter-associated urinary tract infections, which requires documentation of urinary catheter device days. However, device-days are usually obtained by chart review or nursing reports. The aim of this study was to demonstrate that chart review can provide accurate urinary catheter data compared with physical inspection of the urinary catheter at the bedside. METHODS: We compared 2 methods for collecting urinary catheter data over a 6-month period on 10 wards at our VA hospital. For the chart reviews, we created a daily bed-occupancy roster from the electronic medical record. Catheter data were extracted from the daily progress notes for each patient using a standardized review process. Bedside reviews were conducted by visiting the ward and verifying the presence and type of urinary catheters. Agreement between the 2 methods was calculated. RESULTS: We obtained urinary catheter data by both methods in 621 cases. The presence or type of urinary catheter differed between chart and bedside review in only 10 cases (1.6%). Chart review had a sensitivity of 100%, a specificity of 97.7%, raw agreement of 98.4%, and a kappa value of 0.96. CONCLUSIONS: Individual chart review in the electronic medical record provided very accurate data on urinary catheter use. PMID- 21813210 TI - Resting state fMRI in Alzheimer's disease: beyond the default mode network. AB - Using resting state (RS) functional magnetic resonance imaging (fMRI), the connectivity patterns of the default mode (DMN), frontoparietal, executive, and salience networks were explored in 13 Alzheimer's disease (AD) patients, 12 amnestic mild cognitive impairment (aMCI) patients, and 13 healthy controls. Compared with controls and aMCI, AD was associated with opposing connectivity effects in the DMN (decreased) and frontal networks (enhanced). The only RS abnormality found in aMCI patients compared with controls was a precuneus connectivity reduction in the DMN. RS fMRI group differences were only partly related to gray matter atrophy. In AD patients, the mean executive network connectivity was positively associated with frontal-executive and language neuropsychological scores. These results suggest that AD is associated with an alteration of large-scale functional brain networks, which extends well beyond the DMN. In AD, the limited resources of the DMN may be paralleled, in an attempt to maintain cognitive efficiency, by an increased prefrontal connectivity. A medial parietal RS fMRI signal change seems to be present since the early phase of AD. PMID- 21813211 TI - Regulation of beta-amyloid level in the brain of rats with cerebrovascular hypoperfusion. AB - Cerebrovascular hypoperfusion occurs prior to clinical symptoms of Alzheimer's disease (AD) and represents the most accurate indicator predicting whether an individual develops AD in a future time. In order to explore the contribution of cerebrovascular hypoperfusion to AD, cerebrovascular hypoperfusion induced by bilateral carotid occlusion surgery in adult rats was used to investigate its impacts on spatial memory, amyloid-beta protein (Abeta) production and clearance in the brain. The progressive spatial memory deficits were observed through Morris water maze test of the rats with cerebrovascular hypoperfusion induced by occlusion surgery. The memory deficits were accompanied with the increase of brain Abeta associated with Abeta overproduction due to the increased expression of beta-amyloid precursor protein (APP) and enhanced activities of amyloid precursor protein cleavage enzymes such as beta- and gamma-secretases. Western blot and immunohistochemisty studies further revealed that cerebrovascular hypoperfusion could induce abnormal expression of beta-amyloid receptor proteins including the receptor for advanced glycation end products (RAGE) and low-density lipoprotein receptor-related protein-1 (LRP-1), and result in a shift of immunoreactivity between neurons and vasculatures. Taken together, our results suggested that chronic cerebrovascular hypoperfusion could cause memory impairment and Abeta accumulation in brain associated with increased generation and impaired clearance of Abeta. Cerebrovascular hypoperfusion plays an important role in the pathogenesis and development of AD. PMID- 21813212 TI - Hippocampal and ventricular changes in Parkinson's disease mild cognitive impairment. AB - We analyzed T1-weighted brain magnetic resonance imaging data of 100 cognitively normal elderly controls (NC), 127 cognitively normal Parkinson's disease (PD; PDCN) and 31 PD-associated mild cognitive impairment (PDMCI) subjects from the Norwegian ParkWest study. Using automated segmentation methods, followed by the radial distance technique and multiple linear regression we studied the effect of clinical diagnosis on hippocampal and ventricular radial distance while adjusting for age, education, and scanning site. PDCN subjects had significantly smaller bilateral hippocampal radial distance relative to NC. Nonamnestic PDMCI subjects showed smaller right hippocampal radial distance relative to NC. PDMCI subjects showed significant enlargement of all portions of the lateral ventricles relative to NC and significantly larger bilateral temporal and occipital and left frontal lateral ventricular expansion relative to PDCN subjects. Nonamnestic PDMCI subjects showed significant ventricular enlargement spanning all parts of the lateral ventricle while those with amnestic PDMCI showed changes localized to the left occipital horn. Hippocampal atrophy and lateral ventricular enlargement show promise as structural biomarkers for PD. PMID- 21813214 TI - Prion-like acceleration of a synucleinopathy in a transgenic mouse model. AB - Our aim in this study was to investigate experimentally the possible in vivo transmission of a synucleinopathy, using a transgenic mouse model (TgM83) expressing the human A53T mutated alpha-synuclein. Brain homogenates from old TgM83 mice showing motor clinical signs due to the synucleinopathy and containing insoluble and phosphorylated (pSer129) alpha-synuclein were intracerebrally inoculated in young TgM83 mice. This triggered an early onset of characteristic motor clinical signs, compared with uninoculated TgM83 mice or to mice inoculated with a brain homogenate from a young, healthy TgM83 mouse. This early disease was associated with insoluble alpha-synuclein phosphorylated on Ser129, as already identified in old and sick uninoculated TgM83 transgenic mice. Although the molecular mechanisms remain to be determined, acceleration of the pathology following inoculation of mice expressing human mutated alpha-synuclein with tissues from mice affected by the synucleinopathy, could be consistent with "prion-like" propagation of the disease. PMID- 21813215 TI - Development and validation of a nutrition screening tool for hospitalized cancer patients. AB - BACKGROUND & AIMS: Although various nutrition screening tools are used, they are not specific for the screening of malnourished cancer patients. The objective of this study was to develop a nutrition screening tool that could be used to identify cancer patients at risk for malnutrition. METHODS: Of 3010 cancer patients admitted to the National Cancer Center of Korea between April 1 and June 2, 2008, the nutritional status of 1057 patients was assessed by the Scored Patient-Generated Subjective Global Assessment (PG-SGA). Variables used in current nutrition screening tools were analyzed to select indices for a developing malnutrition screening tool for cancer patients (MSTC). The equation for the MSTC was established using receiver operating characteristics curves. Sensitivities and specificities of the MSTC were calculated using the PG-SGA as gold standard. RESULTS: The MSTC was calculated as follows: [MSTC = -0.116 + (1.777 * intake change) + (1.304 * Eastern Cooperative Oncology Group performance status) + (1.568 * weight loss) + (-0.187 * body mass index)]. The MSTC had a sensitivity of 94.0%, a specificity of 84.2%, and high agreement (kappa = 0.70, P < 0.0001) with the PG-SGA. CONCLUSIONS: The MSTC appears to be a valid nutrition screening tool for determining nutritional risk in hospitalized cancer patients. PMID- 21813213 TI - Evidence for motor cortex dedifferentiation in older adults. AB - Older adults (OA) show more diffuse brain activity than young adults (YA) during the performance of cognitive, motor, and perceptual tasks. It is unclear whether this overactivation reflects compensation or dedifferentiation. Typically, these investigations have not evaluated the organization of the resting brain, which can help to determine whether more diffuse representations reflect physiological or task-dependent effects. In the present study we used transcranial magnetic stimulation (TMS) to determine whether there are differences in motor cortex organization of both brain hemispheres in young and older adults. We measured resting motor threshold, motor evoked potential (MEP) latency and amplitude, and extent of first dorsal interosseous representations, in addition to a computerized measure of reaction time. There was no significant age difference in motor threshold, but we did find that OA had larger contralateral MEP amplitudes and a longer contralateral MEP latency. Furthermore, the spatial extent of motor representations in OA was larger. We found that larger dominant hemisphere motor representations in OA were associated with higher reaction times, suggesting dedifferentiation rather than compensation effects. PMID- 21813216 TI - ESPEN disease-specific guideline framework. PMID- 21813217 TI - Innovative mathematical modeling in environmental remediation. AB - There are two different ways to model reactive transport: ad hoc and innovative reaction-based approaches. The former, such as the Kd simplification of adsorption, has been widely employed by practitioners, while the latter has been mainly used in scientific communities for elucidating mechanisms of biogeochemical transport processes. It is believed that innovative mechanistic based models could serve as protocols for environmental remediation as well. This paper reviews the development of a mechanistically coupled fluid flow, thermal transport, hydrologic transport, and reactive biogeochemical model and example applications to environmental remediation problems. Theoretical bases are sufficiently described. Four example problems previously carried out are used to demonstrate how numerical experimentation can be used to evaluate the feasibility of different remediation approaches. The first one involved the application of a 56-species uranium tailing problem to the Melton Branch Subwatershed at Oak Ridge National Laboratory (ORNL) using the parallel version of the model. Simulations were made to demonstrate the potential mobilization of uranium and other chelating agents in the proposed waste disposal site. The second problem simulated laboratory-scale system to investigate the role of natural attenuation in potential off-site migration of uranium from uranium mill tailings after restoration. It showed inadequacy of using a single Kd even for a homogeneous medium. The third example simulated laboratory experiments involving extremely high concentrations of uranium, technetium, aluminum, nitrate, and toxic metals (e.g., Ni, Cr, Co). The fourth example modeled microbially-mediated immobilization of uranium in an unconfined aquifer using acetate amendment in a field-scale experiment. The purposes of these modeling studies were to simulate various mechanisms of mobilization and immobilization of radioactive wastes and to illustrate how to apply reactive transport models for environmental remediation. PMID- 21813218 TI - Sociodemographic and geographic variability in smoking in the U.S.: a multilevel analysis of the 2006-2007 Current Population Survey, Tobacco Use Supplement. AB - Because smoking is a pervasive risk factor for numerous health outcomes, it is essential to understand smoking patterns in different populations and places. Previous studies have described sociodemographic and geographic variation in smoking across the U.S., providing insight to public health scientists aiming to identify high-risk populations and places in the absence of local data. This study extends previous research by considering the influence of a combination of covariates at the U.S. state, core-based statistical area (CBSA), and individual levels, focusing on a time period when smoking prevalence has decreased significantly but disparities remain. We applied multilevel regression to the 2006-2007 Current Population Survey-Tobacco Use Supplement. We conducted a four level logistic regression model and evaluated fixed and random effects to quantify the contribution of sociodemographic characteristics at the individual level, area poverty at the CBSA level, and indoor smoking legislation and cigarette taxes at the state level, to the probability of smoking at the individual level and the variance in smoking at the state and CBSA levels. Sociodemographic covariates were significant predictors of smoking and explained 67% of variance at the CBSA level alone but only 41% at the state level. Contextual covariates alone, such as indoor smoking legislation and cigarette taxes at the state level and area poverty at the CBSA level, explained a larger proportion of state variance (82%) but individually had modest statistical significance. Our findings emphasize the continued disparities in smoking patterns in the U.S. despite the decrease of smoking prevalence in the past decade; as well as the ongoing necessity to consider associations with both compositional and contextual factors. Patterns of residual variance emphasize the continued need to identify and evaluate appropriate contextual covariates, with more refined geographic resolution than that available from national surveys at present. PMID- 21813219 TI - Risk, significance and biomedicalisation of a new population: older women's experience of osteoporosis screening. AB - This article explores the illness experience associated with being diagnosed at risk of a long term chronic condition and discusses the implications of an emergent form of predictive medicine. We report on findings from a study involving 30 older women between the ages of 73-85 years of age recently screened for osteoporosis and informed that they are at a higher than average risk of breaking a bone in the next 10 years, but not formally diagnosed with osteoporosis. Data were gathered by the Adherence to Osteoporosis Medicine (ATOM) study using in-depth interviews with women in their own homes in Norfolk & Suffolk, UK in 2009-2010. We analyse and discuss the significance participants give to their new fracture risk status and consider the practical, physical and existential consequences of this 'diagnosis'. The findings are discussed under three broad themes: Predictive technology, meaning and the risk-of-illness experience; knowledge, understanding and the embodiment of fracture risk status; and, social implications of biomedicine for an ageing population. We argue that screening for osteoporosis and assessment of fracture risk can be understood as a process of biomedicalisation of ageing and bone health. This article offers insight into the meaning of risk status as an illness experience for older women. We conclude by discussing how biomedicalisation of a new population through diagnosis of fracture risk status has significance and consequence at both the individual and the societal level expanding the population of older women labelled at risk and increasing demand for biomedical tests and prescribed medication for the prevention of disease. PMID- 21813220 TI - Bad news and first impressions: patient and family caregiver accounts of learning the cancer diagnosis. AB - Studies in medical journals regarding the delivery of a cancer diagnosis typically focus on a single clinic episode where the definitive news is disclosed to the patient by the physician. Far less research characterizes the diagnosis in the way patients and their family members often describe it: as a longitudinal, multi-sited search process culminating in a news-telling and realization event. This article analyzes lay accounts of learning a cancer diagnosis drawing on ethnographic interviews among a purposive sample of 28 patients recently diagnosed with leukemia, myeloma, or lymphoma and 30 of their family caregivers. The participants, recruited at a large cancer center in the United States, were asked to describe "the day" they learned the diagnosis. Narrative analysis revealed that in almost every case, detailed descriptions of preliminary events - such as the pace and sequence of testing; smooth or disorganized transitions between care providers; and the timeliness or delays in diagnosis - were used to contextualize the actual episode of hearing the diagnosis and reacting to the news. This study finds that patients' and caregivers' experience of the medical system prior to hearing the news played an important role in the way the news was ultimately internalized. The findings also provide empirical support for integrating lay perspectives on the diagnostic experience into future cancer disclosure guidelines. PMID- 21813221 TI - Multiple synchronous cutaneous squamous cell carcinomas of the head and neck: a case report. AB - Cutaneous squamous cell carcinoma (CSCC) is the second most common skin cancer in whites, with a relatively low metastatic potential and a general amenability to local treatment. However, patients with high-risk CSCC is more likely to develop local and distant metastases that could be fatal. We present a case of an 82-year old white man who initially presented with a solitary squamous cell carcinoma (SCC) of the scalp and subsequently developed more than 40 primary CSCC lesions and metastases to the right parotid lymph nodes and thoracic vertebrae within 14 months of the primary diagnosis. Our report highlights the challenges that aggressive SCC can bring in the elderly population and describes some of the treatment modalities of CSCC. PMID- 21813222 TI - Correction of facial asymmetry as a result of unilateral condylar hyperplasia. PMID- 21813223 TI - Propofol dose-dependently increases bite force during sedation. AB - PURPOSE: The purpose of this study was to investigate the dose-dependent effects of propofol on cognitive function and muscle power as well as vital functions. MATERIALS AND METHODS: Twenty volunteers participated in this study. Each subject underwent 2 experiments in a randomized crossover manner (propofol group and control group). After control data were obtained, propofol at predicted effect site concentrations of 0.4, 0.8, 1.2, 1.6, and 2.0 MUg/mL was infused in the propofol group using a target controlled infusion system. Heart rate, noninvasive blood pressure, arterial oxygen saturation, respiratory rate, and bispectral index value were monitored. Observer's assessment of alertness/sedation and the correct answer rate of the Stroop color word test were assessed. Muscle power, grip strength and bite force were measured. RESULTS: In the propofol group, the bispectral index value and observer's assessment of alertness/sedation scale dose dependently reduced. At the predicted effect site propofol concentration of 2.0 MUg/mL, 6 subjects became unconscious. The correct answer rate of Stroop color word test reduced at the predicted effect site propofol concentration of 1.6 and 2.0 MUg/mL. Grip strength slightly increased at the predicted effect site propofol concentration of 1.2 MUg/mL or less, and bite force dose-dependently increased. At the predicted effect site propofol concentration of 2.0 MUg/mL, both muscle powers began to decrease. Bite force dose-dependently increased and reached the maximum at the predicted effect site propofol concentration of 1.6 MUg/mL. CONCLUSION: Although the detailed mechanisms are unknown, propofol dose dependently increases bite force during minimal and moderate sedation. PMID- 21813224 TI - Splint sterilization--a potential registration hazard in computer-assisted surgery. AB - PURPOSE: Registration of preoperative targeting information for the intraoperative situation is a crucial step in computer-assisted surgical interventions. Point-to-point registration using acrylic splints is among the most frequently used procedures. There are, however, no generally accepted recommendations for sterilization of the splint. An appropriate method for the thermolabile splint would be hydrogen peroxide-based plasma sterilization. This study evaluated the potential deformation of the splint undergoing such sterilization. Deformation was quantified using image-processing methods applied to computed tomographic (CT) volumes before and after sterilization. MATERIALS AND METHODS: An acrylic navigation splint was used as the study object. Eight metallic markers placed in the splint were used for registration. Six steel spheres in the mouthpiece were used as targets. Two CT volumes of the splint were acquired before and after 5 sterilization cycles using a hydrogen peroxide sterilizer. Point-to-point registration was applied, and fiducial and target registration errors were computed. Surfaces were extracted from CT scans and Hausdorff distances were derived. Effectiveness of sterilization was determined using Geobacillus stearothermophilus. RESULTS: Fiducial-based registration of CT scans before and after sterilization resulted in a mean fiducial registration error of 0.74 mm; the target registration error in the mouthpiece was 0.15 mm. The Hausdorff distance, describing the maximal deformation of the splint, was 2.51 mm. Ninety percent of point-surface distances were shorter than 0.61 mm, and 95% were shorter than 0.73 mm. No bacterial growth was found after the sterilization process. CONCLUSION: Hydrogen peroxide-based low-temperature plasma sterilization does not deform the splint, which is the base for correct computer navigated surgery. PMID- 21813225 TI - Cervical sympathetic chain schwannoma: an uncommon cause of Horner's syndrome. PMID- 21813226 TI - Excessive intraoperative bleeding with chronic energy drink consumption. PMID- 21813227 TI - Rhinosporidiosis of the parotid duct. PMID- 21813228 TI - Proarrhythmic potential of amiodarone: an underestimated risk? PMID- 21813229 TI - Real time three-dimensional transesophageal echocardiography in the anatomical assessment of complex mitral valve regurgitation secondary to endocarditis. PMID- 21813230 TI - Extreme QT interval prolongation and helicoid ventricular tachycardia (torsade de pointes) in non-ST-elevation acute coronary syndrome. PMID- 21813231 TI - Effect of template in MCM-41 on the adsorption of aniline from aqueous solution. AB - The effect of the surfactant template cetyltrimethylammonium bromide (CTAB) in MCM-41 on the adsorption of aniline was investigated. Various MCM-41 samples were prepared by controlling template removal using an extraction method. The samples were then used as adsorbents for the removal of aniline from aqueous solution. The results showed that the MCM-41 samples with the template partially removed (denoted as C-MCM-41) exhibited better adsorption performance than MCM-41 with the template completely removed (denoted as MCM-41). The reason for this difference may be that the C-MCM-41 samples had stronger hydrophobic properties and selectivity for aniline because of the presence of the template. The porosity and cationic sites generated by the template play an important role in the adsorption process. The optimal adsorbent with moderate template was achieved by changing the ratio of extractant; it has the potential for promising applications in the field of water pollution control. PMID- 21813233 TI - Facile, green encapsulation of cobalt tetrasulfophthalocyanine monomers in mesoporous silicas for the degradative hydrogen peroxide oxidation of azo dyes. AB - A facile and green approach that improves the catalytic lifetime of cobalt tetrasulfophthalocyanine (CoTSPc) for the degradation of dyes is presented. Structurally ordered mesoporous silicas (MCM-41, MCM-48 and SBA-15), microporous aluminosilicates (ZSM-5) and macroporous alumina (gamma-Al(2)O(3)) with different pore sizes were selected for the immobilization of CoTSPc, and a wide range of pH conditions (pH values from 4 to 12) were tested with the CoTSPc immobilization procedure. In the catalytic oxidation study, CoTSPc that was immobilized to MCM 41 silica (CoTSPc@MCM-41) prepared at a pH of 12 showed the longest catalytic lifetime. The TOC removal and discoloration of C. I. Acid Red 73 was approximately 60% and 82%, respectively, in the presence of CoTSPc@MCM-41 with H(2)O(2) after 3h. These results indicate that MCM-41, which has a matching size between its mesopores (30 A) and CoTSPc molecules (25 A), can prevent CoTSPc molecules from aggregating and improve its catalytic lifetime. In addition, the ability of CoTSPc@MCM-41 to degrade other dyes, and the reuse studies, demonstrated that CoTSPc@MCM-41 could be reused for the degradation of most common dyes. PMID- 21813234 TI - Selective extraction of mercury(II) from water samples using mercapto functionalised-MCM-41 and regeneration of the sorbent using microwave digestion. AB - Silica sorbents, based on mesoporous crystalline material-41 (MCM-41), were functionalised using mercaptopropyl (MP) or diethylenetriamine (DETA) to extract mercury (II) ions from water. MP-MCM-41 is an extremely efficient and selective sorbent for the removal of mercury (II) from samples of distilled water doped with heavy metal ions and additionally from more complex matrices including tap and river water. In contrast DETA-MCM-41 preferentially removes hard metal ions (chromium, manganese, lead and zinc) over soft metal ions such as mercury. During extraction, the influence of pH on adsorption capacity was examined; a maximum adsorption capacity of 1245 MUmol g(-1) was achieved for MP-MCM-41 even at pH values as low as 3. Significantly, a method has been developed for the first time to remove Hg (II) from loaded MP-MCM-41 allowing this analyte to be selectively recovered from water contaminated with a wide range of heavy metal ions. The regeneration method does not disrupt the chelating agent which remains on the surface of the silica permitting reuse of the sorbent in further extractions. PMID- 21813235 TI - Salt-assisted thermal desorption of mercury from contaminated dredging sludge. AB - In this study, we tested a new procedure for the decontamination of mercury polluted dredging sludge (Marano-Grado Lagoon, northeastern Italy) based on cationic exchange associated with thermal desorption at a low temperature. Four mercury-polluted sludge slurries were treated using thermal desorption at 393 K for 2h. Three different salts, NaCl (sodium chloride), (CH(3))(4)NCl (tetramethylammonium chloride) and (C(4)H(9))(4)NCl (tetrabutylammonium chloride) were used as exchangers. The selected salts have a monovalent cationic part that progressively increases in molecular weight. The results show that the association of cationic exchange with thermal treatment leads to a significant improvement in the removal of mercury from the contaminated material at a low temperature compared to samples that were not treated with salt. The highest levels of decontamination were attained were obtained when the slurries, which had mercury pollution ranging from 20 to 200 ppm, were treated with a 15% solution of (C(4)H(9))(4)NCl. The efficiency of the removal at 393 K (from 24% up to 60%) depended on the nature of the sample. When the samples were treated at a similar temperature without the salt, no remediation of mercury was detected. Our results show that the thermal decontamination temperature can be significantly lowered by this remediation approach, which is the first example based on cationic exchange of the pollutant with an appropriate salt. PMID- 21813236 TI - Selective removal of 17beta-estradiol with molecularly imprinted particle embedded cryogel systems. AB - The selective removal of 17beta-estradiol (E2) was investigated by using molecularly E2 imprinted (MIP) particle embedded poly(hydroxyethyl methacrylate) (PHEMA) cryogel. PHEMA/MIP composite cryogel was characterized by FTIR, SEM, swelling studies, and surface area measurements. E2 adsorption studies were performed by using aqueous solutions which contain various amounts of E2. The specificity of PHEMA/MIP cryogel to recognition of E2 was performed by using cholesterol and stigmasterol. PHEMA/MIP cryogel exhibited a high binding capacity (5.32 mg/gpolymer) and high selectivity for E2 in the presence of competitive molecules, cholesterol (k(E2/cholesterol) = 7.6) and stigmasterol (k(E2/Stigmasterol) = 85.8). There is no significant decrease in adsorption capacity after several adsorption-desorption cycles. PMID- 21813237 TI - Solid state synthesis of tin-doped ZnO at room temperature: characterization and its enhanced gas sensing and photocatalytic properties. AB - A room temperature solid-state reaction has been used to prepare crystalline tin doped ZnO. Zinc nitrate hexahydrate, cetyltrimethyl ammonium bromide, stannic chloride pentahydrate and sodium hydroxide with proper ratios were ground together. As-synthesized samples were characterized by inductively coupled plasma analysis (ICP), scanning electron microscopy (SEM) and X-ray powder diffraction (XRD); The products were of different morphologies, well dispersed and exhibited good crystallinity, it is also found that the growth direction and morphology of ZnO depend on the amount of Sn doped, which is mainly caused by the difference in sizes between Zn and Sn atoms as well as the change of pH value. Moreover, gas sensing and photocatalytic properties of the obtained products were studied. The materials showed a high gas response to ethanol vapor, and the gas response can reach a maximum of R(a)/R(g) = 124. In addition, tin-doped ZnO materials exhibited improved photocatalytic performance toward methyl orange (MO) solution under a current density of 0.03 mg L(-1) comparison with undoped ZnO. PMID- 21813238 TI - Novel magnetic Fe3O4@C nanoparticles as adsorbents for removal of organic dyes from aqueous solution. AB - The magnetic Fe(3)O(4)/C core-shell nanoparticles have been synthesized by a simple strategy and used as adsorbents for removal of organic dyes from aqueous solution. The resulting products are characterized by scanning electron microscope (SEM), energy dispersive X-ray spectrometry (EDX), X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD), Raman spectra and Fourier transform infrared spectra (FTIR). Adsorption performances of the nanomaterial adsorbents are tested with removal of methylene blue (MB) and cresol red (CR) from aqueous solution. The effects of solution pH value, adsorption time and capacity of the nanocomposites have been fully investigated. The results reveal that the nanospheres can be easily manipulated by an external magnetic field with high separation efficiency. In addition, the process is clean and safe for purifying water pollution. The prepared Fe(3)O(4)/C complex nanomaterials could thus be used as promising adsorbents for the remove organic dyes, especially, cationic dye, from polluted water. PMID- 21813239 TI - Adsorption of tannic acid from aqueous solution onto surfactant-modified zeolite. AB - Surfactant-modified zeolites (SMZs) with various loadings of cetylpyridinium bromide (CPB) were used as adsorbents to remove tannic acid (TA) from aqueous solution. The TA adsorption efficiencies for natural zeolite and various SMZs were compared. SMZ presented higher TA adsorption efficiency than natural zeolite, and SMZ with higher loading amount of CPB exhibited higher TA adsorption efficiency. The adsorption of TA onto SMZ as a function of contact time, initial adsorbate concentration, temperature, ionic strength, coexisting Cu(II) and solution pH was investigated. The adsorbents before and after adsorption were characterized by X-ray diffraction (XRD), field emission scanning electron microscope (FE-SEM), thermogravimetric analysis (TGA), and Fourier transform infrared (FT-IR) spectroscopy. The adsorption kinetics of TA onto SMZ with CPB bilayer coverage (SMZ-CBC) followed a pseudo-second-order model. The equilibrium adsorption data of TA onto SMZ-CBC were well represented by Langmuir, Redlich Peterson and Sips isotherm models. The calculated thermodynamic parameters indicated that TA adsorption onto SMZ-CBC was spontaneous and exothermic. The TA adsorption capacity for SMZ-CBC slightly decreased with increasing ionic strength but significantly increased with increasing Cu(II) concentration. The TA adsorption capacity for SMZ-CBC was relatively high at solution pH 4.0-7.0, and decreased with an increase in solution pH from 7.0 to 8.5. The mechanisms controlling TA adsorption onto SMZ-CBC at solution pH 5.5 include electrostatic attraction, hydrogen bonding and organic partitioning. PMID- 21813240 TI - Use of chemical methods to assess Cd and Pb bioavailability to the snail Cantareus aspersus: a first attempt taking into account soil characteristics. AB - Bioavailability is a key parameter in conditioning contaminant transfer to biota. However, in risk assessment of terrestrial contamination, insufficient attention is being paid to the influence of soil type on trace metal bioavailability. This paper addresses the influence of soil properties on the chemical availability of cadmium (Cd) and lead (Pb) (CaCl(2) extraction and ionic activity) and bioavailability (accumulation kinetics) to the land snail Cantareus aspersus. Snails were exposed to nine contaminated soils differing by a single characteristic (pH or organic matter content or clay content) for 28 days. Toxicokinetic models were applied to determine metal uptake and excretion rates in snails and multivariate regression was used to relate uptake parameters to soil properties. The results showed that alkalinisation of soil and an increase of the organic matter content decreased Pb and Cd bioavailability to snails whereas kaolin clay had no significant influence. The CaCl(2)-extractable concentrations tended to overestimate the effects of pH when used to explain metal uptake rate. We conclude that factors other than those controlling the extractable fraction affect metal bioavailability to snails, confirming the requirement of biota measurements in risk assessment procedures. PMID- 21813241 TI - Improved photocatalytic degradation rates of phenol achieved using novel porous ZrO2-doped TiO2 nanoparticulate powders. AB - This paper studies the photocatalytic degradation of phenol using zirconia-doped TiO(2) nanoparticles. ZrO(2) was chosen due to its promising results during preliminary studies. Particles smaller than 10nm were synthesised and doped with quantities of ZrO(2) ranging from 0.5 to 4% (molar metal content). Particles were calcined at different temperatures to alter the TiO(2) structure, from anatase to rutile, in order to provide an ideal ratio of the two phases. Powder X-ray diffraction (PXRD) analysis was used to examine the transformation between anatase and rutile. Degradation of phenol was carried out using a 40 W UV bulb at 365 nm and results were measured by UV-vis spectrometry. TEM images were obtained and show the particles exhibit a highly ordered structure. TiO(2) doped with 1% ZrO(2) (molar metal content) calcined at 700 degrees C proved to be the most efficient catalyst. This is due to an ideal anatase:rutlie ratio of 80:20, a large surface area and the existence of stable electron-hole pairs. ZrO(2) doping above the optimum loading acted as an electron-hole recombination centre for electron-hole pairs and reduced photocatalytic degradation. Synthesised photocatalysts compared favourably to the commercially available photocatalyst P25. The materials also demonstrated the ability to be recycled with similar results to those achieved on fresh material after 5 uses. PMID- 21813243 TI - Role of pet dogs and cats in the transmission of helminthic zoonoses in Europe, with a focus on echinococcosis and toxocarosis. AB - The close emotional tie between people and companion animals is a beneficial relation known as the human-animal bond. However, pet dogs and cats can play an important role in the transmission of helminthic zoonotic agents such as the tapeworms Echinococcus and the roundworms Toxocara which are directly transmitted from pets to the human environment without the involvement of vectors or intermediate hosts. In humans, echinococcosis has emerged in Europe and toxocarosis is still persisting in large endemic areas despite the availability of highly efficient anthelminthics for dogs and cats. Ecological changes significantly contributed to these trends: the high wild fox populations and the high density of freely roaming dogs and cats maintain a permanent infection pressure of these and other parasites. Further, the establishment of urban recreational environments closer to natural ecological systems boosted vole populations that represent urban reservoirs for zoonotic helminths. A good understanding of the parasites' biology and epidemiology including the transmission to humans is required for planning and implementing effective prevention strategies. The continuous education of veterinarians and the information of the pet owners by providing uniform recommendations are of priority importance. A close collaboration between veterinary and public health professionals in a 'One Health' concept is required. PMID- 21813242 TI - Antiparasitic efficacy of dihydrosanguinarine and dihydrochelerythrine from Macleaya microcarpa against Ichthyophthirius multifiliis in richadsin (Squaliobarbus curriculus). AB - Ichthyophthirius multifiliis is a holotrichous protozoan that invades the gills and skin surfaces of fish and can cause morbidity and high mortality in most species of freshwater fish worldwide. The present study was undertaken to investigate the antiparasitic activity of crude extracts and pure compounds from the leaves of Macleaya microcarpa. The chloroform extract showed a promising antiparasitic activity against I. multifiliis. Based on these finding, the chloroform extract was fractionated on silica gel column chromatography in a bioactivity-guided isolation affording two compounds showing potent activity. The structures of the two compounds were elucidated as dihydrosanguinarine and dihydrochelerythrine by hydrogen and carbon-13 nuclear magnetic resonance spectrum and electron ionization mass spectrometry. The in vivo tests revealed that dihydrosanguinarine and dihydrochelerythrine were effective against I. multifiliis with median effective concentration (EC(50)) values of 5.18 and 9.43 mg/l, respectively. The acute toxicities (LC(50)) of dihydrosanguinarine and dihydrochelerythrine for richadsin were 13.3 and 18.2mg/l, respectively. The overall results provided important information for the potential application of dihydrosanguinarine and dihydrochelerythrine in the therapy of serious infection caused by I. multifiliis. PMID- 21813244 TI - Neuroendocrine response to CRF stimulation in veterans with and without PTSD in consideration of war zone era. AB - BACKGROUND: Alterations in hypothalamic-pituitary-adrenal (HPA) axis activity have been observed in Gulf War veterans with posttraumatic stress disorder (PTSD) which differ from those observed in other veteran groups, raising the possibility that there is a unique neuroendocrine profile in this group of veterans. This study seeks to further characterize the effects of PTSD, military cohort (Vietnam, 1991 Gulf War, Operations Enduring Freedom/Iraqi Freedom (OEF/OIF)), and their interaction on the neuroendocrine response to synthetic corticotrophin releasing factor (CRF) stimulation. METHODS: 51 male veterans were studied consisting of 21 from the Vietnam era, 16 from the Gulf War era, and 14 from the OEF/OIF era. 16 of these veterans were deployed to a war zone and had chronic PTSD (PTSD+), 25 were deployed to a war zone and did not have chronic PTSD (PTSD ), and 10 were not deployed to a war zone and did not have PTSD (non-exposed). The participants underwent the CRF stimulation test in the afternoon (approximately 2:00 p.m.), which measures the integrity and sensitivity of the pituitary-adrenal axis. Plasma cortisol and adrenocorticotropic hormone (ACTH) were measured at baseline and at intervals over a 2h period following intravenous administration of 1 MUg/kg of ovine CRF (o-CRF, max 100 MUg). In a small subset of participants, dehydroepiandrosterone (DHEA) and cortisol binding globulin (CBG) were also assessed. RESULTS: There was a significant group by era interaction in the response of ACTH to CRF, in addition to a main effect of group (PTSD+, PTSD-, non-exposed). The interaction reflected that group differences were only evident in the Gulf War cohort; among Gulf War era veterans, the PTSD+ group had higher elevations in ACTH levels following CRF than the PTSD- group and the non-exposed group. Additionally, the peak change in ACTH was associated with a self-reported environmental exposure (pyridostigmine bromide ingestion) which has been found to be linked to the excess morbidity found in Gulf War veterans. Self-reported childhood trauma was greater in veterans of the Gulf War than Vietnam or OEF/OIF, but did not account for the observed differences. There was a significant effect of group on the cortisol response to CRF, reflecting greater responsivity in both of the deployed groups (PTSD+ and PTSD-) compared to the non exposed group which could be accounted for by baseline differences in cortisol levels; unlike the ACTH response, the cortisol response did not differ by era. There were no effects of group, era, or their interaction on the DHEA and CBG response to CRF. CONCLUSIONS: A uniform pattern of PTSD-related alterations in the response to intravenous CRF was not found. Rather, PTSD-related alterations were found only in veterans of the 1991 Gulf War, and were characterized by an enhanced pituitary response to CRF which may reflect increased sensitivity of pituitary corticotrophs or CRF hyposecretion. Together with previous neuroendocrine findings, the data suggest the HPA axis is dysregulated in Gulf War veterans in unique ways which may reflect the long-term effects of environmental exposures in addition to disease effects. Further work is needed to characterize these effects and their impact on long-term psychological and medical outcomes. PMID- 21813245 TI - AMPK gamma2 subunit gene PRKAG2 polymorphism associated with cognitive impairment as well as diabetes in old age. AB - Metabolic and cognitive disorders are closely related. However, the molecular mechanism underlying this association is still elusive. Given the importance of energy metabolism in neuronal cells, AMP-activated protein kinase (AMPK), a master switch of energy metabolism, could be an independent factor affecting cognitive as well as metabolic functions. Therefore, we examined the relationship between the AMPK gamma2 gene, the PRKAG2 -26C/T polymorphism and cognitive impairment or diabetes in 1609 subjects aged from 60 to 80. We performed multivariate logistic regression analyses with adjustment for age, gender, education, smoking, alcohol, depression, waist circumference, APOE e4, and stroke history. We found a significant association between the -26C/T polymorphism (CC vs. CT/TT) and cognitive impairment (OR, 1.6; 95% CI, 1.1-2.3). Moreover, this polymorphism (CC/CT vs. TT) was also related to the presence of diabetes (OR, 1.8; 95% CI, 1.2-2.8). Importantly, the relationship with cognitive impairment was still significant in non-diabetic individuals (OR, 1.6; 95% CI, 1.1-2.4). Further analyses with a subpopulation (n=611) revealed that CC homozygotes relative to T-allele carriers had significantly better performances in verbal memory and attentional tasks. These findings collectively support a hypothesis that AMPK has a role not only in metabolic functioning but also in cognitive functioning in humans. Extended longitudinal study with a larger number of samples is warranted. PMID- 21813246 TI - Alcohol-involved assault: associations with posttrauma alcohol use, consequences, and expectancies. AB - Victim alcohol consumption is common prior to sexual assault, and a burgeoning literature suggests that victims who were intoxicated during assault may differ in post-assault adjustment compared to those who were not impaired. Less is known about potential relationships between experiencing an alcohol-involved assault (AIA) and later drinking behavior. In this study, we examined the relationships between sexual assault, subsequent drinking behavior and consequences, and alcohol expectancies in a sample of 306 undergraduate women who reported current alcohol use and reported either no trauma history (n=53), non-AIA (n=69), or AIA (n=184). Differences emerged for alcohol use (F(2, 298)=12.78, p<.001), peak blood alcohol content (F(2, 298)=9.66, p<.001), consequences (F(2, 296)=7.38, p<.005), and positive alcohol expectancies (F(14, 796)=1.93, p<.05). In particular, women with an AIA reported greater alcohol use and positive expectancies compared to women with no trauma history and women with a non alcohol influenced assault. In addition, both assault groups reported greater drinking consequences than women with no trauma history. Findings suggest that it is the women who are assaulted while under the influence of alcohol who evidence more alcohol use and alcohol-related problems following assault. PMID- 21813247 TI - Effect of exposure to light on physico-chemical quality attributes of sliced dry cured Iberian ham under different packaging systems. AB - Dry-cured Iberian ham slices were stored under vacuum and under two different atmospheres (N(2)=70% N(2)+30% CO(2); Ar=70% Ar+30% CO(2)) and exposed to lightness or darkness. Physico-chemical, sensory and microbial analysis was carried out throughout 60 days storage. Vacuum samples showed the highest a* value compared to N(2) and Ar after 30 (P<0.05) and 60 days (P<0.05). The influence of illumination during storage was evident after 60 days of storage, L* and a*-values being lower (P<0.01) in hams exposed to light than those kept in darkness, which can be ascribed to the lower nitrosylmioglobin content in samples exposed to light after 60 days (P=0.001). Ham slices stored in darkness showed the lowest TBARS values (P<0.05) and hexanal content (P<0.05) after 60 days. Slices of ham packed in vacuum showed lower TBARS values than N(2) and Ar batches (P=0.001), these samples being perceived as more rancid (P<0.05). The rest of the sensory attributes were not generally affected by gas mixture or illumination (P>0.05). PMID- 21813248 TI - Fertility after age 45: From natural conception to Assisted Reproductive Technology and beyond. AB - The introduction of in vitro fertilization (IVF) in 1978 - an accomplishment awarded with the 2010 Nobel Prize in Physiology or Medicine - has revolutionized the lives of millions of couples previously unable to conceive. Though initially applied primarily to young women with blocked Fallopian tubes, over the past three decades IVF has been increasingly used to combat age-related infertility. It has become clear that the decline in fertility with increasing female age is largely due to a rapid decrease in oocyte (egg) quantity and quality, with a higher proportion of oocytes displaying genetic abnormalities. Despite significant improvements in medical stimulation and laboratory culturing of embryos, IVF success once women reach the age of 45 is exceedingly rare. It has been well established through elegant clinical studies that, unlike the ovary, the reproductive capacity of the uterus does not diminish with age, even into the late 40s and 50s. With the use of oocytes from younger donors, women who are menopausal can attain very high rates of conception. The increased obstetrical risks in this population, which has a higher risk of underlying medical co morbidities, must be considered prior to attempts at assisted conception, often in consultation with a multidisciplinary team of physicians. Finally, attempts to reverse the age-related decline in oocyte quality through micro-manipulation of the nucleus and cytoplasm have yielded disappointing results and are fraught with ethical concerns. PMID- 21813249 TI - International climacteric research: Role of the Collaborative Group for Research of the Climacteric in Latin America (REDLINC). PMID- 21813250 TI - A critical view of the effects of phytoestrogens on hot flashes and breast cancer risk. AB - The increased risk of breast cancer recently observed with some specific estro progestin associations has raised concerns about the harmful effects of menopausal hormone replacement therapy (HRT). It has been proposed that phytoestrogens (PEs), which have a similar chemical structure to estrogens, could be used as HRT. The main selling points of these preparations concern the management of hot flashes and their potential beneficial effects on breast tissue. In this review, we will address the effects of PE on hot flashes and breast cancer risk as well as the questions raised on a chemical point of view. We conclude that the efficacy of a PE rich diet or nutritional supplements is not clearly established. The use of PE as an alternative for HRT cannot be advocated for now, due to insufficient and conflicting data on efficacy and safety. Moreover, due to the hormone dependence of breast cancer, PE use must be contraindicated in breast cancer survivors. PMID- 21813251 TI - Piophila megastigmata (Diptera: Piophilidae): first records on human corpses. AB - Piophila megastigmata McAlpine, 1978, for many years only known from South Africa, was recently recorded in Spain. The present work reports for the first time the occurrence of P. megastigmata in human corpses in Portugal. The species was also collected in succession studies conducted with piglet carcasses, where it coexisted with Stearibia nigriceps (Meigen, 1826), showing similar periods of presence in the carcass. However, P. megastigmata was more abundant than S. nigriceps in autumn, with the opposite in summer. During winter neither species was able to colonize carrion and in spring, only S. nigriceps. This first record of P. megastigmata in human corpses confirms it as a potentially useful forensic species in Europe. The species, well established in the Iberian Peninsula, probably has a wider distribution but has been previously overlooked and possibly confused with Piophila casei (Linnaeus, 1758) in many studies. PMID- 21813252 TI - A robust detection algorithm for copy-move forgery in digital images. AB - With the availability of the powerful editing software and sophisticated digital cameras, region duplication is becoming more and more popular in image manipulation where part of an image is pasted to another location to conceal undesirable objects. Most existing techniques to detect such tampering are mainly at the cost of higher computational complexity. In this paper, we present an efficient and robust approach to detect such specific artifact. Firstly, the original image is divided into fixed-size blocks, and discrete cosine transform (DCT) is applied to each block, thus, the DCT coefficients represent each block. Secondly, each cosine transformed block is represented by a circle block and four features are extracted to reduce the dimension of each block. Finally, the feature vectors are lexicographically sorted, and duplicated image blocks will be matched by a preset threshold value. In order to make the algorithm more robust, some parameters are proposed to remove the wrong similar blocks. Experiment results show that our proposed scheme is not only robust to multiple copy-move forgery, but also to blurring or nosing adding and with low computational complexity. PMID- 21813253 TI - Chemical enhancement of footwear impressions in urine on fabric. AB - A range of chemical techniques were utilised for the enhancement of footwear impressions deposited on a variety of fabric types of different colours with urine as a contaminant. A semi-automated stamping device was used to deliver test impressions at a set force to minimise the variability between impressions; multiple impressions were produced and enhanced by each reagent to determine the repeatability of the enhancement. Urine samples from different donors were analysed using a spectrofluorophotometer revealing differences between individuals. Results indicated that the enhancement of footwear impressions in urine was possible using amino acid staining techniques whereas protein stains failed to achieve successful enhancement. PMID- 21813254 TI - Detection and identification of the new potential synthetic cannabinoids 1-pentyl 3-(2-iodobenzoyl)indole and 1-pentyl-3-(1-adamantoyl)indole in seized bulk powders in Hungary. AB - 3-Naphthoyl- and 3-phenylacetylindoles represent a group of substances of cannabimimetic activity with affinities - strongly influenced by their functional groups - to cannabinoid receptors CB1 and CB2. Some of them have been described as ingredients of herbal blends also known as "smart products" by several research groups. Recently further cannabimimetic substances possessing new chemical structures like benzoylindoles and adamantoylindoles have emerged. In Hungary, two powder samples were seized by the authorities and identified as 1 pentyl-3-(2-iodobenzoyl)indole (AM-679) and 1-pentyl-3-(1-adamantoyl)indole. Structure elucidation was carried out by LC-UV-MS/MS, LC-TOF-MS, GC-MS and NMR. The benzoylindole AM-679 is a known agonist of cannabinoid receptors while the adamantoylindole derivative also carries chemical features typical for cannabimimetics. It is thus assumed that both substances might be detected in "smart products" in the future. PMID- 21813255 TI - Evaluation of the temporary cavity in ordnance gelatine. AB - Gelatine is a recognized tissue simulant in wound ballistic research. The deceleration of a bullet causes a temporary cavity which provokes radial fissures by stretching the gelatine. The evaluation of gelatine destruction was performed with very different methods yet, widely known are the wound profile by Fackler and the total crack length (TCL) method. Aims of the presented experimental study were to cover a wide range of kinetic bullet energy, to gather all destruction associated parameters and to correlate them to energy dissipation. According to recommendations of the Technical Guideline Commission of the German police and to Fackler, a 10% solution of Gelita Ballistic 3 gelatine was moulded in 20 cm * 20 cm * 50 cm dimensioned blocks. In the front of the blocks a 2 mm thin and 8 cm * 8 cm film bag containing about 8 g pasty acryl paint was integrated. The blocks were cooled to 4 degrees C and were shot from a distance of 5m. The bullet's velocity was measured in front of the target. The expanding bullets Silvertip((r)) (Winchester) und First Defense((r)) (Magtech) were used. Varying calibres, loads and barrel lengths bullet velocities from 250 to 686 m/s were achieved while kinetic energy was spread from 71 up to 1450 J. All projectiles were captured in gelatine and had mushroomed, as expected. The blocks were freshly cut into 1cm-slices which were optically scanned. The evaluation was performed with AxioVision (Zeiss) software and in each slice the following parameters were taken: longest fissure radius, wound profile (addition of the two longest fissures), sum of the three longest cracks, TCL, perimeter and area of the polygon created by linking the fissure ends. All analyzed parameters - either crack length based methods (wound profile and the TCL) or destruction area based methods (polygon method) - showed a strong dependence of the gelatine destruction and the energy dissipated. This regularity could be approximated by linear function (correlation coefficient>0.95). The gelatine destruction seems to allow a conclusion on the amount of dissipated energy. PMID- 21813256 TI - Capsule shells adulterated with tadalafil. AB - Following a health complaint a food supplement was brought in for analysis on the suspicion of being adulterated with a synthetic drug substance. When the capsule content did not show evidence of adulteration, the capsule shell was investigated. Using HPLC-DAD and HPLC-MS the capsule shell was found to contain 2.85 mg of the erectile dysfunction drug tadalafil. Using microscopy and RAMAN spectroscopy the presence of tadalafil was shown throughout the gelatine matrix as particles and dissolved into the matrix. The adulteration is probably carried out by adding tadalafil powder to a gelatine jelly in the manufacturing of the capsules shells. Because this technique may also be used for other drug substances, capsules shells should be considered a vehicle for hiding drug substances in general. PMID- 21813257 TI - Deeply infiltrating endometriosis: evaluation of retro-cervical space on MRI after vaginal opacification. AB - OBJECTIVES: To prospectively investigate diagnostic value and tolerability of MRI after intra-vaginal gel opacification for diagnosis and preoperative assessment of deeply infiltrating endometriosis. METHODS: Sixty-three women with clinical suspicion of deeply infiltrating endometriosis were previously examined with trans-vaginal ultrasonography and then with MRI pre and post administration of vaginal gel. We evaluated the tolerability of this procedure with a scoring scale from 0 to 3. We also assessed with a score from 1 to 4 the visibility of four regions: Douglas-pouch, utero-sacral-ligaments, posterior-vaginal-fornix and recto-vaginal-septum. All patients underwent laparoscopic surgery after MRI. RESULTS: Five patients considered procedure intolerable. Visibility of utero sacral-ligaments and posterior-vaginal-fornix showed to be increased with gel (p<0.001). In 57 out of 80 patients the MRI has allowed us to diagnose deeply infiltrating endometriosis. Overall, the percentages of MRI-sensitivity, specificity, positive predictive value and negative predictive value were respectively 67.8%, 95.3%, 89.4 and 83.5% without gel, and 90.8%, 94.6%, 90.8% and 94.6% with gel; trans-vaginal ultrasonography sensitivity, specificity, positive predictive value and negative predictive value were 57.5%, 96.6%, 90.9% and 79.5%. In evaluation of utero-sacral-ligaments trans-vaginal ultrasonography, MRI without gel and with gel sensitivity was respectively 61.9%, 47.6% and 81%; for recto-vaginal-septum these values were 12.5%, 68.7% and 93.7%; for pouch of Douglas 82%, 87% and 97.4%; finally for posterior-vaginal-fornix 27.3%, 36.4% and 81.8%. CONCLUSIONS: MRI with gel opacification of vagina should be recommended for suspicion of deep infiltrating endometriosis, in particular for the added value in evaluation of recto-vaginal septum, utero-sacral ligaments and posterior vaginal fornix. PMID- 21813258 TI - Elemental and structural analysis of silicon forms in herbal drugs using silicon 29 MAS NMR and WD-XRF spectroscopic methods. AB - The objective of this work was to study concentration of silicon and its structural forms present in herbal drugs. Equisetum arvense and Urtica dioica L. from teapot bags, dietary supplements (tablets and capsules) containing those herbs, dry extract obtained from a teapot bag of E. arvense, and samples of the latter herb harvested in wild habitat over four months were studied using wavelength dispersive X-ray spectroscopy (WD-XRF) and high-resolution solid-state (29)Si NMR. The highest concentration of Si, ca. 27mg/g, was found in the herbal material from the teapot bags containing E. arvense. The Si content in natural E. arvense (whole plants) increased from May to August by ca. 7mg/g, reaching value 26mg/g. Three different silicon forms were detected in the studied herbal samples: Si(OSi)4 (Q(4)), Si(OH)(OSi)3 (Q(3)) and Si(OH)2(OSi)2 (Q(2)). Those sites were populated in E. arvense in the following order: Q(4)?Q(3)>Q(2). A dramatic, ca. 50-fold decrease of the Si concentration during the infusion process was observed. The infusion process and the subsequent drying procedure augmented population of the Q(4) sites at the cost of the Q(2) sites. The WD-XRF and (29)Si NMR methods occurred useful and complementary in the study of herbal materials. PMID- 21813259 TI - Comparison of two-dimensional gel electrophoresis patterns and MALDI-TOF MS analysis of therapeutic recombinant monoclonal antibodies trastuzumab and rituximab. AB - The principal objective of this study was the evaluation of two-dimensional gel electrophoresis (2-DE) in combination with MALDI-TOF MS, after tryptic digest with regard to suitability for qualitative characterization and identification of therapeutic recombinant monoclonal antibodies trastuzumab and rituximab. Moreover, the impact of post-translational modifications of these glycoproteins on the electrophoresis behavior has been evaluated. 1-D SDS-PAGE, in reducing and non-reducing conditions, and 2-DE were used for the assessment of M(r) and the monitorization of deglycosylation efficiency. In addition, 2-DE was used for the determination of pIs. 2-DE gels revealed characteristic glycoprotein migration behavior, highly complex spot pattern, typical for recombinant monoclonal antibodies. N-linked oligosaccharides were released with PNGase F; enzymatic desialination was studied with sialidase and carboxypeptidase B was used for the study of lysine truncation. Peptide spots resolved in 2-DE gels were in gel tryptically digested, resulting peptides were subjected to MALDI-TOF MS analysis and peptide mass fingerprinting (PMF) has been used for the identity confirmation of both monoclonal antibodies. PMID- 21813260 TI - Attitudes and anxiety levels of medical students towards the acquisition of competencies in communication skills. AB - OBJECTIVE: Results of third year medical students' attitudes and stress levels towards the acquisition of communication skills before and after a Communication and Clinical Skills Course (CCSC) at the Faculty of Medicine of the University of Porto (FMUP), Portugal, are presented. METHODS: 115 students attending third-year CCSC completed a demographic questionnaire, State-Trait Anxiety Inventory, Communication Skills Attitudes Scale and Interpersonal Behavior Survey. RESULTS: Significant negative correlation was found between anxiety levels and attitudes towards learning communication skills in general as well as the teaching and learning process. At the end of the Course students reported that when compared to the start, their communication skills are less sufficient. CONCLUSION: At the end of this CCSC at FMUP, students recognized its major importance and how they need to invest and improve communication skills. However, it seems important to monitor the attitudes and anxiety levels of students towards patient care and communication during the medical course and to identify ways of overcoming barriers towards learning communication skills. PRACTICE IMPLICATIONS: It is recommended that there should be a complete (transversal and vertical) integration of communication skills, including effective teaching methods, assessments, and examinations in order to be valued by the students. This would necessitate curricular changes. PMID- 21813261 TI - Advance Care Planning in terminally ill and frail older persons. AB - OBJECTIVE: Advance Care Planning (ACP) - the communication process by which patients establish goals and preferences for future care - is encouraged to improve the quality of end-of-life care. Gaining insight into the views of elderly on ACP was the aim of this study, as most studies concern younger patients. METHODS: We conducted and analysed 38 semi-structured interviews in elderly patients with limited prognosis. RESULTS: The majority of participants were willing to talk about dying. In some elderly, however, non-acceptance of their nearing death made ACP conversations impossible. Most of the participants wanted to plan those issues of end-of-life care related to personal experiences and fears. They were less interested in planning other end-of-life situations being outside of their power of imagination. Other factors determining if patients proceed to ACP were trust in family and/or physician and the need for control. CONCLUSIONS: ACP is considered important by most elderly. However, there is a risk of pseudo-participation in case of non-acceptance of the nearing death or planning end-of-life situations outside the patient's power of imagination. This may result in end-of-life decisions not reflecting the patient's true wishes. PRACTICE IMPLICATIONS: Before engaging in ACP conversations, physicians should explore if the patient accepts dying as a likely outcome. Also the experiences and fears concerning death and dying, trust and the need for control should be assessed. PMID- 21813262 TI - Emotion dysregulation and anxiety in late adulthood. AB - Recent research has highlighted the important role of emotion dysregulation in the occurrence and maintenance of anxiety symptoms. The purpose of the present study was to investigate the relationship between anxiety symptoms and older adults' ability to regulate emotional experiences. A total of 167 community dwelling older adults completed self-report measures of affect and were asked to report how often they use specific emotion regulation strategies. Consistent with previous theories older adults experiencing increasing levels of anxiety reported greater difficulties in regulating emotional responses. Present results provide support for previous findings demonstrating that experiencing anxiety symptoms affects the ability to regulate emotional experiences. Current findings are likely to be informative in terms of understanding emotion dysregulation in older adults at risk of experiencing clinical symptoms of anxiety. PMID- 21813263 TI - Childbirths and risk of female predominant and other autoimmune diseases in a population-based Danish cohort. AB - To evaluate the possible biological role of pregnancy on the risk of autoimmune diseases we assessed associations between reproductive history and subsequent risk of autoimmune diseases characterized by female predominance and other autoimmune diseases. Our study cohort comprised 4.6 million Danes born since 1935 for whom a complete record of childbirths was available. Cohort members were followed for hospital contacts for 31 autoimmune diseases from 1982 to 2008. Female predominant autoimmune diseases were those with a female:male sex ratio >2:1. Ratios of first hospitalization rates were calculated using Poisson regression, adjusting for potential confounding by age, birth cohort, calendar period and marital status. During 45.5 million person-years of follow-up 102,260 women were hospitalized with one or more autoimmune diseases. Overall, compared with childless women, women with children were at a relative risk of 1.04 (1.02 1.06) for any autoimmune diseases, 1.11 (1.08-1.14) for female predominant and 0.97 (0.95-1.00) for other autoimmune diseases. Possibly biologically related associations with parity were found for Hashimoto thyroiditis (1.11; 1.00-1.24), Graves' disease (1.19; 1.14-1.24), erythema nodosum (1.15; 1.01-1.32), psoriasis (1.08; 1.01-1.15), sarcoidosis (1.17; 1.06-1.28) and systemic lupus erythematosus (0.83; 0.74-0.93). Especially the one-year postpartum period was associated with an increased risk of Hashimoto thyroiditis, Graves' disease and sarcoidosis. Overall, parity was associated with an 11% increased risk of female predominant autoimmune diseases. Pregnancies resulting in liveborn children therefore seem to contribute only little to the general female predominance in autoimmune diseases. However, for a number of autoimmune diseases; especially autoimmune thyroid diseases, erythema nodosum and sarcoidosis parity might somehow be involved in disease development. PMID- 21813264 TI - The association between delusional-like experiences and suicidal thoughts and behaviour. AB - BACKGROUND: Delusional-like experiences (DLEs) are common in the general population. Whilst it is well known that psychotic disorders increase the risk of suicide, it is unclear if DLEs are also associated with suicidal thoughts and behaviour. This study aims to explore these variables in a large population-based sample. METHOD: Participants were drawn from a national survey of mental health (n=8841) in Australia. The Composite International Diagnostic Interview was used to identify DLEs, psychiatric disorders, and information related to suicidal ideation, suicide plan and suicide attempts. We examined the relationship between DLEs and suicidal ideation, plans and attempts using logistic regression, adjusted for a range of potentially confounding variables. RESULTS: 8.4% of subjects endorsed one or more DLEs. 12.9% subjects reported suicidal ideation, 3.8% suicidal plans, and 3.0% a suicide attempt at some point in their lives. Those with any DLE were about two to four times as likely to report suicidal ideation, plans or attempts. There was a dose response relationship between DLEs and endorsement of suicide-related items. CONCLUSIONS: DLEs are common in the general population and appear to be independently associated with suicidal thoughts and behaviour. DLE may provide a marker of vulnerability to suicide, and thus could be of value in future suicide prevention research. PMID- 21813265 TI - Assessment of 22q11.2 copy number variations in a sample of Brazilian schizophrenia patients. PMID- 21813266 TI - Different hemodynamic response patterns in the prefrontal cortical sub-regions according to the clinical stages of psychosis. AB - BACKGROUND: Symptomatic and functional outcomes in schizophrenia are associated with the duration of untreated psychosis. However, no candidate biomarkers have been adopted in clinical settings. Multichannel near-infrared spectroscopy (NIRS), which can easily and noninvasively measure hemodynamics over the prefrontal cortex, is a candidate instrument for clinical use. AIMS: We intended to explore prefrontal dysfunction among individuals at different clinical stages, including ultra-high-risk (UHR), first-episode psychosis (FEP), and chronic schizophrenia (ChSZ), compared to healthy subjects. METHOD: Twenty-two UHR subjects, 27 patients with FEP, 38 patients with ChSZ, and 30 healthy subjects participated. We measured hemodynamic changes during a block-designed letter fluency task using multichannel NIRS instruments. RESULTS: We found that the activations of the bilateral ventrolateral prefrontal cortex, and the fronto polar and anterior parts of the temporal cortical regions in the UHR group were lower than those of the controls, but similar to those of the FEP and ChSZ groups. However, the activations in the bilateral dorsolateral prefrontal cortex regions decrease with advancing clinical stage. CONCLUSIONS: To the best of our knowledge, this is the first study directly comparing differences in hemodynamic changes with respect to the 3 clinical stages of psychosis. Furthermore, this study also demonstrates different patterns of impairment according to the progression of clinical stages using NIRS instruments. NIRS measurements for UHR and FEP individuals may be candidate biomarkers for the early detection of the clinical stages of psychosis. PMID- 21813267 TI - Validation of the dimensions of psychosis instrument in Mexican patients with schizophrenia spectrum disorders. AB - The objective was to determine the psychometric properties of the Dimensions of Psychosis Instrument (DIPI) in Mexican patients with schizophrenia spectrum disorders. One-hundred patients were recruited. Convergent and divergent validity were determined with the positive and negative scores of the Positive and Negative Syndrome Scale; a forced five-factor exploratory principal-components analysis with varimax rotation was developed. Total DIPI score shows an adequate convergent validity. The rotated principal component matrix accounted for 82.1% of the variance. Our study gives further support of the adequacy of the DIPI for the assessment of the five most common subjective experiences related to psychosis. PMID- 21813268 TI - A 43Ca and 13C NMR study of the chemical interaction between poly(ethylene-vinyl acetate) and white cement during hydration. AB - (43)Ca and (13)C NMR methods were used to study the chemical interaction of poly(ethylene-vinyl acetate) (PEVAc) admixture in commercial-grade white cement. From (43)Ca NMR it is shown both that PEVAc induces modest changes in the hydrated cement structure, and that hydrated commercial cement is significantly more complex than models that have been used for its structure in past work. The (13)C NMR results show that the PEVAc hydrolysis occurs early in the cement hydration acceleration period, with a rate well-fit by an exponential decay using a time constant of 6+/-1 days. PMID- 21813269 TI - Nano-colloidal functionalization of textiles based on polysiloxane as a novel photo-catalyst assistant: processing design. AB - Due to the opposite surface charge of TiO(2) and silver nano-particles, at around neutral pH, it is expected that the interaction between these particles and cross linkable polysiloxane (XPs) resin and thus their final properties would be affected by their processing technique. This paper has focused on the effect of processing design on the interaction, surface orientation and final properties of surface nano-colloidal functionalization. The results disclosed the key role of the applied process on the properties of the treated fabrics which have been well discussed through the modeling of this effect on orientations of nanoparticles on the surface. The developed models are interestingly verified by various characterizations. Applying a premixed TiO(2)/XPs colloid as an after treatment on Ag treated samples caused more enhanced stain photo-degradability and UV protection properties, while the reduction of enhanced hydrophobicity, washing durability, and stain-repellency were observed as compared to applying Ag/XPs premixed colloid on TiO(2). The role of processing on XPs stabilizing efficiency and its co-photo-catalytic function on TiO(2) nanoparticles has been concluded and deeply discussed. The appropriate processing design can be tailored in order to accomplish desirable hydrophilicity/hydrophobicity with a granted bioactivity. The results reveal that ideal bioactivity, stain photo-degradability, self cleaning, UV protection, anti-staining properties, and washing durability can be achieved by applying a mixture of silver and XPs as an after-treatment on TiO(2) treated fabrics. PMID- 21813270 TI - Effects of soy protein on alcoholic liver disease in rats undergoing ethanol withdrawal. AB - OBJECTIVE: This investigation attempted to clarify the effects of soy protein on alcoholic liver disease (ALD) in rats undergoing ethanol withdrawal. METHODS: Alcoholic liver disease was induced in rats by administration of a low carbohydrate ethanol liquid diet for 12 weeks, after which the ethanol was withdrawn and the rats were divided into two experimental groups: a control group (EC group) and a soy protein group (EP group) for 4 weeks. RESULTS: After the 12 week ALD-inducing period, the ethanol group had significantly higher hepatic lipid accumulation, oxidative stress and inflammation. We found that the EP group had significantly lower hepatic lipids, malondialdehyde, tumor necrosis factor alpha, interleukin (IL)-1beta, IL-6, hydroxyproline levels and myeloperoxidase activity compared to the EC group. Moreover, the fecal total cholesterol and total lipids were higher in the EP group. Expression of the hepatic cytochrome P450 2E1 (CYP2E1) protein in the EP group was significantly lower than that in the EC group, and the hepatic peroxisome proliferator-activated receptor (PPAR) alpha and cytochrome P450 4A (CYP4A) protein expressions in the EP group were significantly higher than those in the EC group. In the histopathological analysis, we also found that soy protein ameliorated fat accumulation in the liver. CONCLUSION: These results suggest that soy protein may improve alcohol induced lipid accumulation, oxidative stress and inflammation by decreasing proinflammatory cytokines and CYP2E1 protein expression and by increasing PPARalpha and CYP4A protein expressions and fecal lipid excretion, thereby producing beneficial effects on ALD during ethanol withdrawal. PMID- 21813272 TI - Effects of dry bulk density and particle size fraction on gas transport parameters in variably saturated landfill cover soil. AB - Landfill sites are emerging in climate change scenarios as a significant source of greenhouse gases. The compacted final soil cover at landfill sites plays a vital role for the emission, fate and transport of landfill gases. This study investigated the effects of dry bulk density, rho(b), and particle size fraction on the main soil-gas transport parameters - soil-gas diffusivity (D(p)/D(o), ratio of gas diffusion coefficients in soil and free air) and air permeability (k(a)) - under variably-saturated moisture conditions. Soil samples were prepared by three different compaction methods (Standard and Modified Proctor compaction, and hand compaction) with resulting rho(b) values ranging from 1.40 to 2.10 g cm( 3). Results showed that D(p) and k(a) values for the '+gravel' fraction (<35 mm) became larger than for the '-gravel' fraction (<2mm) under variably-saturated conditions for a given soil-air content (epsilon), likely due to enhanced gas diffusion and advection through less tortuous, large-pore networks. The effect of dry bulk density on D(p) and k(a) was most pronounced for the '+gravel' fraction. Normalized ratios were introduced for all soil-gas parameters: (i) for gas diffusivity D(p)/D(f), the ratio of measured D(p) to D(p) in total porosity (f), (ii) for air permeability k(a)/k(a)(,pF4.1), the ratio of measured k(a) to k(a) at 1235 kPa matric potential (=pF 4.1), and (iii) for soil-air content, the ratio of soil-air content (epsilon) to total porosity (f) (air saturation). Based on the normalized parameters, predictive power-law models for D(p)(epsilon/f) and k(a)(epsilon/f) models were developed based on a single parameter (water blockage factor M for D(p) and P for k(a)). The water blockage factors, M and P, were found to be linearly correlated to rho(b) values, and the effects of dry bulk density on D(p) and k(a) for both '+gravel' and '-gravel' fractions were well accounted for by the new models. PMID- 21813271 TI - Resveratrol up-regulates SIRT1 and inhibits cellular oxidative stress in the diabetic milieu: mechanistic insights. AB - Several lines of evidence support a role for oxidative stress in diabetic complications. Diabetic patients have increased O(2)(-) production in monocytes. Loss of SIRT1 activity may be associated with metabolic diseases such as diabetes. Several studies have shown that SIRT1 can regulate mammalian FOXO transcription factors through direct binding and/or deacetylation. However, interactions between SIRT1 and FOXO under diabetic conditions are unclear. The phytochemical resveratrol has recently gained attention for its protection against metabolic disease. Resveratrol has been shown to increase mitochondrial function by activating SIRT1. In this study, we tested the protective effect of resveratrol on cellular oxidative stress through the SIRT1-FOXO pathway under high-glucose conditions. Human monocytic (THP-1) cells were cultured in the presence of mannitol (osmolar control) or normoglycemic (NG, 5.5 mmol/l glucose) or hyperglycemic (HG, 25 mmol/l glucose) conditions in absence or presence of resveratrol (3 and 6 MUmol/l) for 48 h. We first examined SIRT1 activity and oxidative stress in monocytes of Type 1 diabetes mellitus (T1DM) patients compared with healthy controls. In T1DM patients, monocytic SIRT1 expression was significantly decreased and p47phox expression was increased compared with controls. Under HG in vitro, SIRT1 and FOXO3a were significantly decreased compared with NG, and this was reversed by resveratrol treatment, concomitant with reduction in HG-induced superoxide production and p47phox. Under HG, SIRT1 small interfering RNA (siRNA) inhibited FOXO3a, and there was no beneficial effect of resveratrol in siRNA-treated HG-induced cells. Thus, resveratrol decreases HG-induced superoxide production via up-regulation of SIRT1, induction of FOXO3a and inhibition of p47phox in monocytes. PMID- 21813274 TI - Cryo-electron tomography: gaining insight into cellular processes by structural approaches. AB - Visualization of cellular processes at a resolution of the individual protein should involve integrative and complementary approaches that can eventually draw realistic functional and cellular landscapes. Electron tomography of vitrified but otherwise unaltered cells emerges as a central method for three-dimensional reconstruction of cellular architecture at a resolution of 2-6 nm. While a combination of correlative light-based microscopy with cryo-electron tomography (cryo-ET) provides medium-resolution insight into pivotal cellular processes, fitting high-resolution structural approaches, for example, X-ray crystallography, into reconstructed macromolecular assemblies provides unprecedented information on native protein assemblies. Thus, cryo-ET bridges the resolution gap between cellular and structural biology. In this article, we focus on the study of eukaryotic cells and macromolecular complexes in a close-to-life state. We discuss recent developments and structural findings enabling major strides to be made in understanding complex physiological functions. PMID- 21813273 TI - Understanding the role of TDP-43 and FUS/TLS in ALS and beyond. AB - Dominant mutations in two DNA/RNA binding proteins, TDP-43 and FUS/TLS, are causes of inherited Amyotrophic Lateral Sclerosis (ALS). TDP-43 and FUS/TLS have striking structural and functional similarities, implicating alterations in RNA processing as central in ALS. TDP-43 has binding sites within a third of all mouse and human mRNAs in brain and this binding influences the levels and splicing patterns of at least 20% of those mRNAs. Disease modeling in rodents of the first known cause of inherited ALS-mutation in the ubiquitously expressed superoxide dismutase (SOD1)-has yielded non-cell autonomous fatal motor neuron disease caused by one or more toxic properties acquired by the mutant proteins. In contrast, initial disease modeling for TDP-43 and FUS/TLS has produced highly varied phenotypes. It remains unsettled whether TDP-43 and FUS/TLS mutants provoke disease from a loss of function or gain of toxicity or both. TDP-43 or FUS/TLS misaccumulation seems central not just to ALS (where it is found in almost all instances of disease), but more broadly in neurodegenerative disease, including frontal temporal lobular dementia (FTLD-U) and many examples of Alzheimer's or Huntington's disease. PMID- 21813275 TI - Indolin-2-one p38alpha inhibitors II: Lead optimisation. AB - Optimisation of a series of indolin-2-one p38alpha inhibitors was achieved via both blocking of a potential metabolic 'hot spot' and by increasing overall polarity of the lead series leading to non-cytotoxic compounds which showed improved oral bioavailabilities in the rat. PMID- 21813276 TI - 1,5-Disubstituted indole derivatives as selective human neuronal nitric oxide synthase inhibitors. AB - A series of 1,5-disubstituted indole derivatives was designed, synthesized and evaluated as inhibitors of human nitric oxide synthase. A variety of flexible and restricted basic amine side chain substitutions was explored at the 1-position of the indole ring, while keeping the amidine group fixed at the 5-position. Compounds having N-(1-(2-(1-methylpyrrolidin-2-yl)ethyl)- (12, (R)-12, (S)-12 and 13) and N-(1-(1-methylazepan-4-yl)- side chains (14, 15, (-)-15 and (+)-15) showed increased inhibitory activity for the human nNOS isoform and selectivity over eNOS and iNOS isoforms. The most potent compound of the series for human nNOS (IC(50)=0.02 MUM) (S)-12 showed very good selectivity over the eNOS (eNOS/nNOS=96-fold) and iNOS (iNOS/nNOS=850-fold) isoforms. PMID- 21813277 TI - Discovery and hit-to-lead optimization of novel allosteric glucokinase activators. AB - We report on a hit generation and hit-to-lead program of a novel class of glucokinase activators (GKAs). Hit compounds, activators at low glucose concentration only were identified by vHTS. Scaffold modification reliably afforded activators also at high substrate level. Potency was increased by introduction of a hydrogen bond acceptor as proposed by molecular docking. Replacement of the initial alkylene linkers with a rigid 1,2-phenylene motif followed by further studies eventually furnished a series of potent lead compounds exhibiting steep SAR. PMID- 21813278 TI - Design and synthesis of brain penetrant selective JNK inhibitors with improved pharmacokinetic properties for the prevention of neurodegeneration. AB - The SAR of a series of brain penetrant, trisubstituted thiophene based JNK inhibitors with improved pharmacokinetic properties is described. These compounds were designed based on information derived from metabolite identification studies which led to compounds such as 42 with lower clearance, greater brain exposure and longer half life compared to earlier analogs. PMID- 21813279 TI - Phase 2 trial of temozolomide and pegylated liposomal doxorubicin in the treatment of patients with glioblastoma multiforme following concurrent radiotherapy and chemotherapy. AB - Concurrent and post-radiotherapy temozolomide (T) significantly improves survival in patient with newly diagnosed glioblastoma multiforme. We aimed to assess the activity of the combination of T and pegylated liposomal doxorubicin (PLD) in this population. A combination of T (days 1-5, 200mg/m(2) orally) and PLD (day 1, 40 mg/m(2) intravenous) was given every 4 weeks for six cycles following chemo radiotherapy as a post-operative treatment. The primary endpoint was 6-month progression free survival (6PFS). Of the 40 patients who enrolled (53 years median age, 73% male), the 6PFS was 58% (95% confidence interval [CI], 41-72%). The median time to progression was 6.2 months (95% CI, 5.6-8.0 months) and overall survival (OS) was 13.4 months (95% CI, 12.7-15.8 months). Thirty-four patients had measurable disease: one had a complete response (3%), 28 had stable disease (82%), and five had progressive disease (15%). Treatment was well tolerated: hematological toxicity included grade 3 neutropenia (8%). Grade 3 non hematologic toxicity included nausea and vomiting (8%) and palmar-plantar toxicity (5%). We concluded that combination T and PLD is well tolerated but does not add significant clinical benefit regarding 6PFS and OS. PMID- 21813280 TI - Tylosema esculentum extractives and their bioactivity. AB - The investigation of Tylosema esculentum (Morama) husks, cotyledons, and tuber yielded griffonilide 2, compound 1, griffonin 3, gallic acid 4, protocatechuic acid 5, beta-sitosterol 6, behenic acid 7, oleic acid 8, sucrose 9, 2-O-ethyl alpha-D-glucopyranoside 10, kaempferol 11 and kaempferol-3-O-beta-D glucopyranoside 12. The structures of the isolates were determined by NMR, HR-TOF EIMS, IR and UV-vis spectroscopy, and by comparison with literature data. The husk EtOAc and n-butanol extracts demonstrated >90% DPPH radical scavenging activity at concentrations of 25, 50 and 250 MUg/mL. Furthermore the husk extracts showed higher total phenolic content (233 mg GAE/g). The extractives exhibited minimum inhibitory quantities of 50-100 MUg or no activity against Staphylococcus aureus, Escherichia coli, Bacillus subtilis, Pseudomonas aeruginosa and Candida albicans. The tuber extracts were inactive against Caco-2 and Hela cell lines, while the husk extracts showed low activity against Caco-2 and Vero cell line with IC(50) values >400 MUg/mL. The GC-MS analysis showed the beans and tuber non-polar (n-hexane) extracts major constituents as fatty acids. PMID- 21813281 TI - SEMEDS: an important tool for air pollution bio-monitoring. AB - Plant canopies act as absorbers of air-borne dust particles. Characterization of the dusts present over the leaf surfaces can indicate the nature of contaminant present in the surrounding area and possible sources as well. Dust particulates get adsorbed on both the surfaces of leaves, however more dust particulates get deposited on the upper surface. These dusts contain many inorganic elements, which were analyzed in the present study. For the present investigation, SEMEDS technique used to characterize the dusts adsorbed over the leaf surfaces. Using SEMEDS the samples were analyzed by two types of methods i.e. point analysis and elemental mapping. Both the methods showed the presence of elements like Si, Al, Fe, Mg, and Ca in the dusts adsorbed over the leaf surfaces. Thus, SEMEDS can be used for in situ air pollution monitoring using tree leaves from the area concerned. PMID- 21813282 TI - Experimental and theoretical determination of the low-loss electron energy loss spectroscopy of nanostructured ZnO. AB - The dielectric properties of nanostructured wurtzite-type ZnO are studied by analyzing the low-loss region of the electron energy loss spectroscopy (EELS) in a transmission electron microscope. Characteristic peaks at about 12 and 32 eV in the imaginary part of the dielectric function shift to lower energies as particle size decreases. A comparison of experimental EELS spectra and ab initio density functional theory calculations (WIEN2k code) within the generalized gradient approximation (GGA), GGA+U and modified Becke-Johnson (mBJ) is presented. The origins of interband transitions are identified in the electronic band structure by calculating the partial imaginary part of the dielectric function and the partial density of states of Zn and O. PMID- 21813283 TI - The promoter of a plant defensin gene directs specific expression in nematode induced syncytia in Arabidopsis roots. AB - The beet cyst nematode Heterodera schachtii induces a feeding site, called syncytium, in roots of host plants. In Arabidopsis, one of the genes whose expression is strongly induced in these structures is Pdf2.1 which codes for an antimicrobial plant defensin. Arabidopsis has 13 plant defensin genes. Besides Pdf2.1, the Pdf2.2 and Pdf2.3 genes were strongly expressed in syncytia and therefore the expression of all three Pdf genes was studied in detail. The promoter of the Pdf2.1 gene turned out to be an interesting candidate to drive a syncytium-specific expression of foreign genes as RT-PCR showed that apart from the feeding site it was only expressed in siliques (seeds). The Pdf2.2 and Pdf2.3 genes were in addition expressed in seedlings, roots, leaves, stems, and flowers. These results were supported by the analysis of promoter::GUS lines. After infection with H. schachtii all GUS lines showed a strong staining in syncytia at 5 and 15 dpi. This expression pattern was confirmed by in situ RT-PCR. PMID- 21813284 TI - Washing of irradiated red blood cells in paediatric cardiopulmonary bypass: is it clinically useful? A retrospective audit. AB - OBJECTIVE: Despite the introduction of smaller cardiopulmonary bypass (CPB) circuits for paediatrics, it is frequently necessary to add irradiated red blood cell concentrate (IRBC) to maintain adequate haemoglobin levels and the oxygen carrying capacity. Irradiation of blood weakens the cell membranes and results in an increase of lactate and potassium concentration. In addition, prolonged shelf time of IRBC may enhance its lactate level. To avoid the adverse effects of increased lactate and potassium concentration during paediatric bypass, prewashing of homologous blood in a cell-saving device was implemented at our institution. A retrospective audit of clinical data was performed to assess the relevance of this method. METHODS: Preceding the introduction of the blood pre washing, we investigated 14 units of IRBC for lactate, potassium levels and shelf time. Afterwards, we evaluated the CPB and laboratory data from 69 patients with body weight <10 kg and the lactate levels in the priming of the bypass circuit. RESULTS: The shelf time of blood units was 7.6 +/- 2.7 days (minimum 5, maximum 14 days) with lactate concentration of 12.6 +/- 2 mmol/land potassium concentration of 16.2 +/- 4.7 mmol/l. In the priming after pre-washing, the lactate concentration was significantly lower than the standard priming (2.5 +/- 0.9 vs 4.5 +/- 20 mmol/l, p = 0.002). At the start of bypass, the lactate concentration after pre-washing was still lower (1.5 +/- 0.4 vs 1.9 +/- 0.9 mmol/l; p = 0.04), but at the end of bypass we detected a significant increase of lactate in the pre-washed group (1.5 +/- 0.4 vs 2.2 +/- 1.1 mmol/l, p = 0.01). There was no significant difference between the groups at the end of bypass (1.8 +/- 0.9 vs 2.2. +/- 1.1 mmol/l, p = 0.17). Other clinical and patient data were not significantly different. CONCLUSIONS: Our retrospective audit shows that pre washing of IRBCs is not associated with decreased lactate levels at the end of CPB compared with standard use of IRBCs, suggesting that the added value of pre washing of IRBCs on minimisation of lactate levels during CPB remains doubtful. PMID- 21813285 TI - Vein graft pseudo-aneurysm presenting as a mediastinal mass. PMID- 21813286 TI - Novel glycosylated mycosporine-like amino acids with radical scavenging activity from the cyanobacterium Nostoc commune. AB - Mycosporine-like amino acids (MAAs) are UV absorbing pigments, and structurally distinct MAAs have been identified in taxonomically diverse organisms. Two novel MAAs were purified from the cyanobacterium Nostoc commune, and their chemical structures were characterized. An MAA with an absorption maximum at 335 nm was identified as a pentose-bound porphyra-334 derivative with a molecular mass of 478 Da. Another identified MAA had double absorption maxima at 312 and 340 nm and a molecular mass of 1,050 Da. Its unique structure consisted of two distinct chromophores of 3-aminocyclohexen-1-one and 1,3-diaminocyclohexen and two pentose and hexose sugars. These MAAs had radical scavenging activity in vitro; the 1050 Da MAA contributed approximately 27% of the total radical scavenging activities in a water extract of N. commune. These results suggest that these glycosylated MAAs have multiple roles as a UV protectant and an antioxidant relevant to anhydrobiosis in N. commune. PMID- 21813287 TI - Mouse T helper 17 phenotype: not so different than in man after all. AB - CD4+ T-helper (TH) cells that selectively produce interleukin (IL)-17 (TH17) are thought to be critical for host defense and autoimmunity. Three major dogmas were established, based on initial studies performed in murine models, and initially extrapolated by many researchers to human pathophysiology. First, TH17 cells represent a fixed CD4+ T-cell effector phenotype without any developmental relationship with TH1 cells. Second, TH17 cells are exclusively responsible for pathogenicity in several chronic inflammatory disorders, TH1 cell being instead protective. Finally, TH17 cells originate from naive TH cells in response to the combined activity of transforming growth factor (TGF)-beta and IL-6, whereas in the presence of TGF-beta alone the same cells develop into Foxp3+ T regulatory cells. Studies performed in human demonstrated apparent species-specific differences, such as the expression by TH17 cells of the TH1-related transcription factor T-bet, the IL-12-inducible plasticity of TH17 cells into TH1 cells, and the dispensability of TGF-beta signaling for their development. As discussed in this short review, recent studies in mice have led to reassessment of the three above-mentioned dogmas regarding the TH17 phenotype, suggesting that studies in humans actually better depicted TH17 cells than initial studies in mice did. PMID- 21813288 TI - Sad people are more accurate at face recognition than happy people. AB - Mood has varied effects on cognitive performance including the accuracy of face recognition (Lundh & Ost, 1996). Three experiments are presented here that explored face recognition abilities in mood-induced participants. Experiment 1 demonstrated that happy-induced participants are less accurate and have a more conservative response bias than sad-induced participants in a face recognition task. Using a remember/know/guess procedure, Experiment 2 showed that sad-induced participants had more conscious recollections of faces than happy-induced participants. Additionally, sad-induced participants could recognise all faces accurately, whereas, happy- and neutral-induced participants recognised happy faces more accurately than sad faces. In Experiment 3, these effects were not observed when participants intentionally learnt the faces, rather than incidentally learnt the faces. It is suggested that happy-induced participants do not process faces as elaborately as sad-induced participants. PMID- 21813289 TI - Sympathetic neuropathy in diabetes mellitus patients does not elicit Charcot osteoarthropathy. AB - AIM: The aim of the study was to determine the degree of neuropathy (autonomic and somatic) in patients with diabetes mellitus with or without Charcot osteoarthropathy (CA). METHODS: Forty-nine patients with diabetes mellitus type 1 or 2 were investigated. The patient population of interest was the patients with acute Charcot foot (n=17) or chronic Charcot foot (n=7). The inclusion criterion for an acute Charcot foot was a temperature difference of more than 2 degrees between the two feet, oedema of the affected foot, typical hotspots in a bone scintigram and a typical clinical course. In addition, patients with first toe amputation (n=5), a high-risk group for development of CA, and two control groups consisting of diabetes patients with (n=9) or without somatic neuropathy (n=11) were investigated. Regional blood flow in the feet was measured by venous occlusion plethysmography. Quantitation of somatic neuropathy was done by the Neuropathy Disability Score and modified Neuropathy Symptom Score. Quantitation of autonomic neuropathy was done by measurements of local venoarteriolar sympathetic axon reflex in the feet and of heart rate variability during deep breathing and orthostatic challenge. RESULTS: The patients with acute Charcot foot and first toe amputation had an increased blood flow in the affected foot and weakened but not absent venoarteriolar sympathetic axon reflex. In the other patient groups, a normal venoarteriolar sympathetic axon reflex in the feet was found. CONCLUSIONS: Peripheral sympathetic neuropathy is not likely to be the pathophysiologic mechanism behind the hyperemia in the foot during an acute attack of CA. The hyperemia is more likely secondary to local inflammatory events. PMID- 21813290 TI - Increased IL-6 levels are not related to NF-kappaB or HIF-1alpha transcription factors activity in the vitreous of proliferative diabetic retinopathy. AB - PURPOSE: The purpose was to assess the activity of nuclear factor (NF)-kappaB and hypoxia inducible factor (HIF)-1alpha transcription factors and the expression levels of inflammation markers [interleukin (IL)-6 and IL-8] in the vitreous of patients suffering from proliferative diabetic retinopathy (PDR) scheduled for elective vitreous surgery in a single academic-based retina practice in a prospective clinical study. METHODS: Twenty-seven patients with PDR were enrolled in the study. The severity of retinopathy was classified (0, 1, 2, 3, 4) and the activity of neovascularization was graded (0, 1, 2, 3, 4) by the surgeon intraoperatively. Samples of the vitreous were collected during surgery, and the activity of NF-kappaB and HIF-1alpha transcription factors and the expression levels of IL-6 and IL-8 were measured. RESULTS: The majority of samples fell into the retinopathy class 3 (n = 12) or 4 (n = 13). The level of IL-6 increased from 68.9 +/- 46.8 pg/ml to 102.7 +/- 94.1 pg/ml, and IL-8 increased from 165.1 +/- 136.0 pg/ml to 521.0 +/- 870.9 pg/ml (mean +/- S.D., nonsignificant change: normality test followed with Mann-Whitney Rank Sum Test). According to the neovascularization activity, the samples fell into grade 1 (n = 7), 2 (n = 12) or 3 (n = 7). In IL-6, there was a statistically significant increase (P < .05) from grade 2 to 3: 58.6 +/- 40.3 pg/ml and 158.4 +/- 102.5 pg/ml, respectively (Kruskal-Wallis One-Way Analysis of Variance on Ranks followed with Dunn's Method). The level of IL-8 was as follows: in grade 1: 118.0 +/- 62.4 pg/ml, in grade 2: 192.3 +/- 127.1 pg/ml and in grade 3: 884.3 +/- 1161.0 pg/ml (statistically nonsignificant change). There was a statistically significant linear regression between IL-6 and IL-8 (P < .001): IL-6 = 51.88 pg/ml + (0.092*IL-8), r = 0.772. Increased activity of the NF-kappaB and HIF-1alpha transcription factors was not observed. CONCLUSION: Interleukin-6 is a candidate to indicate activity of neovascularization process in PDR. It might be a new molecular therapeutic target to regulate innate immunity response in vitreous. PMID- 21813291 TI - Obesity and symptoms suggestive of gastroparesis in patients with type 2 diabetes and neuropathy. AB - BACKGROUND: Associated with neuropathy, symptoms suggestive of gastroparesis are common in patients with type 2 diabetes mellitus (T2DM) and include nausea, vomiting, bloating and early satiety. Gastric motor abnormalities have been reported in obese patients, and obesity is associated with T2DM. An association between obesity and gastroparesis symptoms in diabetic patients with neuropathy has not been investigated. METHODS: In this nested case-control study, 161 patients with neuropathy were identified from within a cross-sectional survey of 380 T2DM patients. Of these, 134 (83.2%, "cases") had at least one cardinal symptom suggestive of gastroparesis. The remaining symptom-free subjects served as controls. Logistic and general linear modeling was used to assess associations between obesity and the presence and number of symptoms. RESULTS: Subjects were 66.6+/-10 years of age. Cases were significantly more likely than controls to be obese (89% vs. 77%, P=.04), female (55.6% vs. 33.3%) and hypertensive (90.2% vs. 63%, P=.001) and to report adherence to diet (87.4% vs. 66.7%, P=.007). In a logistic regression model including sex, hypertension, antiaggregant therapy, adherence to diet therapy and an obesity-by-sex interaction term, obesity emerged as a significant independent predictor of any cardinal symptom suggestive of gastroparesis (odds ratio 9.86, 95% confidence interval 1.4-69.2, P=.02). Obesity was also identified as a significant independent predictor of number of cardinal symptoms suggestive of gastroparesis in the general linear model. Obese subjects reported significantly more early satiety (61.5% vs. 35.2%, P=.001), fullness (63.7% vs. 40.8%, P=.004), bloating (70.3% vs. 49.3%, P=.006) and abdominal distention (71.4 vs. 50.7%, P=.007) than nonobese subjects. Further, obese subjects reported more cardinal symptoms suggestive of gastroparesis symptoms (4.2+/-2.4 vs. 3.1+/-2.5, P=.01). CONCLUSIONS: Obesity emerged as a significant independent predictor of cardinal symptoms suggestive of gastroparesis in patients with T2DM and neuropathy. This finding suggests that mechanisms in addition to neuropathy play a role in the generation of symptoms suggestive of gastroparesis in this patient population. PMID- 21813292 TI - PSMD9 is linked to type 2 diabetes neuropathy. AB - OBJECTIVE: Diabetic neuropathy, a long-term complication of type 2 diabetes (T2D), has a genetic inheritance component to its manifestation. We aimed at identifying whether the proteasome modulator 9 (PSMD9) gene responsible for linkage with T2D and maturity-onset diabetes of the young 3 in Italian families may play a role in the inheritance of diabetic neuropathy in T2D as well. METHODS: We characterized the Italian families with T2D for presence and/or absence of diabetic neuropathy. The diabetic neuropathy is reported as unknown in all cases in which either the diagnosis was unclear or the data were not available for the subject studied. Thus, in our 200 Italian families, the data presence was less than 100%. We tested in the 200 Italians families for the presence of the linkage of the PSMD9 single nucleotide polymorphisms (SNPs) with diabetic neuropathy. The nonparametric as well as the parametric linkage analysis was performed by using the Merlin software; the LOD score and correspondent P value were calculated. For the significance and/or trends toward significance linkage score, 1000 replicates were performed to determine the empirical P value. RESULTS: We report the linkage study of the PSMD9 SNPs [intervening sequence IVS3+nt460A/G, IVS3+nt437C/T and E197G] in Italian families with T2D neuropathy. CONCLUSION: In summary, the PSMD9 gene SNPs studied contribute to the genetic risk of diabetic neuropathy in our Italian data set, showing statistical significance for an additive model-based inheritance. PMID- 21813293 TI - The beneficial effect of alpha-glucosidase inhibitor on glucose variability compared with sulfonylurea in Taiwanese type 2 diabetic patients inadequately controlled with metformin: preliminary data. AB - AIMS: Although sulfonylurea added to metformin is the first oral drug combination regimen for patients with type 2 diabetes recommended by the American Diabetes Association/European Association for the Study of Diabetes consensus statement, it does not allow for individualizing and optimizing therapy with respect to sustaining glycemic control and the reduction of glucose variability. We therefore sought to investigate acarbose as an alternative to glibenclamide in combination with metformin and compare the effects on metabolic control and glucose variability. METHODS: Type 2 diabetic patients 30-70 years of age with glycosylated hemoglobin 7.0%-11.0% while treated with one or two oral antidiabetic drugs were successively enrolled. After 8 weeks of run-in with metformin 500 mg thrice daily, either acarbose 50 mg or glibenclamide 2.5 mg three times daily was randomly added on and force titrated to acarbose 100 mg or glibenclamide 5.0 mg three times daily for the subsequent 16 weeks. Demographic data, biochemical data and continuous glucose monitoring system data were recorded upon randomization and at the end of the study. Various parameters that measure glucose variability were derived from the continuous glucose monitoring system data. RESULTS: Of the 51 type 2 diabetes patients enrolled, data from 40 subjects, 20 in each group, were analyzed after excluding those unqualified information. Both drug combinations improved glycemic control. Glucose variability, expressed as mean amplitude of glycemic excursion or continuous overall net glycemic action and mean of daily differences, decreased significantly (all P<.05) after the addition of acarbose but not glibenclamide. The acarbose-metformin combination has the additional benefits of weight reduction and shorter durations of hyperglycemia compared with metformin monotherapy. CONCLUSIONS: This study suggests that both intraday and interday glucose variability are more effectively reduced by the acarbose-metformin combination than by the glibenclamide-metformin combination, while both combinations reduce the overall glucose level equally. PMID- 21813294 TI - Systemic resistin is increased in type 2 diabetic patients treated with loop diuretics. AB - Increased serum resistin was found in rodent models of obesity and insulin resistance, whereas contradictory results have been obtained in human studies. In humans, resistin is primarily released by monocytes/macrophages, suggesting that soluble levels may be associated with macrophage activation. Here, systemic and monocyte-released resistin levels were found to be similar in type 2 diabetic (T2D) patients, overweight controls and normal-weight controls. When adjusted for body mass index and age, serum resistin modestly correlated with gamma glutamyltransferase levels, fasting glucose and interleukin-6. Systemic resistin was marginally increased in T2D patients treated with beta-blockers or urate lowering drugs and was considerably higher in patients treated with loop diuretics. Monocyte-released resistin was even reduced by the loop diuretic furosemide, excluding the possibility that this drug may directly stimulate resistin synthesis. In summary, the current data indicate that changes accompanying renal dysfunction but not obesity or type 2 diabetes are associated with increased serum resistin. PMID- 21813295 TI - Ulnar collateral ligament tear and olecranon stress fracture nonunion in a collegiate pitcher. PMID- 21813297 TI - Two-incision versus one-incision repair for distal biceps tendon rupture: a cadaveric study. AB - HYPOTHESIS: The purpose of this study was to accurately map the insertional footprint of the distal biceps tendon and to test our hypothesis that a superior anatomic repair can be achieved by a 2-incision technique when compared with a 1 incision technique. METHODS: We randomly assigned 20 cadaveric arms to 1 of 2 groups: 1 incision (group I) or 2 incision (group II). The bicipital tuberosity was exposed through either a single anterior incision (group I) or a posterolateral approach (group II). A guide pin was placed into the tuberosity to mark the axis for creating a virtual bone tunnel. Each radius was harvested with the biceps insertion intact. The length, width, and area of the insertion footprint for each tendon were determined with a 3-dimensional computerized digitizer. A 7.5 mm-diameter virtual bone tunnel was centered over the drill hole created by the guidewire. The percentage of the virtual tunnel within the original footprint was determined. RESULTS: The percentage of the virtual tunnel (repair site) within the original tendon footprint was 73.4% for the posterolateral approach and only 9.7% for the anterior approach. There was a statistically significant difference (P <= .001) in the median values of footprint covered when the 2 types of repair were compared. DISCUSSION AND CONCLUSION: The 2-incision technique results in a significantly improved anatomic repair of the biceps tendon to the original insertion site. Prospective clinical studies directly comparing the 2 techniques with regard to the strength of supination after repair may be helpful. PMID- 21813296 TI - Arthrosis of glenohumeral joint after arthroscopic Bankart repair: a long-term follow-up of 13 years. AB - HYPOTHESIS: The purpose of the study was to establish radiologic and clinical occurrence of glenohumeral arthrosis after arthroscopic Bankart repair. MATERIALS AND METHODS: Between January 1994 and December 1998, an arthroscopic Bankart repair was performed in 187 patients at our institution. We were able to assess clinical and radiologic glenohumeral arthrosis in 72 of the 101 patients who met the inclusion criteria (74 shoulders) (71%) after a 13-year follow-up. An additional 9 patients were interviewed by telephone. Radiologic arthrosis was evaluated with the Samilson-Prieto classification and clinical arthrosis with an arthrosis-specific quality-of-life questionnaire (Western Ontario Osteoarthritis of the Shoulder test). In addition, functional impairment was assessed with the Constant score and subjective satisfaction with a questionnaire. RESULTS: Radiologic arthrosis was diagnosed in 50 of 74 shoulders (68%), with 40 (80%) of them classified as mild. The mean score on the Western Ontario Osteoarthritis of the Shoulder questionnaire was 280 points (85% of the best possible score), which is considered relatively good. The mean Constant score was 78 points, and 75% of the patients were extremely satisfied or satisfied with the final results of operative treatment. DISCUSSION: The radiologic evaluation and self-assessment of the patients imply that the incidence of glenohumeral arthrosis after arthroscopic Bankart repair is quite common but the symptoms are generally mild and comparable to nonoperative treatment. CONCLUSION: Arthrosis rarely causes more than minor subjective symptoms or a minor objectively perceived disadvantage during 13 years' follow-up. PMID- 21813298 TI - Anatomic and biomechanical analysis of the short and long head components of the distal biceps tendon. AB - HYPOTHESIS: The short head bundle of the distal biceps tendon is more efficient at elbow flexion, and the long head is more efficient at forearm supination. METHODS: The short and long head bundles of the distal biceps tendon were separated to the bicipital tuberosity in 6 cadavers. The area and centroid of each bundle insertion were computed from surface points measured within each footprint. Each bundle was individually loaded. The supination torque and flexion load generated were recorded at 90 degrees of elbow flexion. The slope of the torque generated versus biceps load was used to define the supination moment arm. The ratio of the flexion load generated to biceps load applied was used to define the relative flexion efficiency. RESULTS: The short head insertion was positioned distal and anterior relative to the long head and typically included the apex of the tuberosity. The areas of the long and short heads were 59 +/- 15 and 94 +/- 44 mm(2) (P = .07), respectively. The long head moment arm was significantly higher in supination. The short head had a significantly higher moment arm in neutral and pronation. The ratio of the flexion load to biceps load was 15% higher for the short head. CONCLUSION: The short and long heads of the biceps have distinct insertions. The short head's insertion allows it to be relatively more efficient at elbow flexion at 90 degrees . In the neutral and pronated forearm, the short head is the relatively more efficient supinator. In the supinated forearm, the long head becomes relatively more efficient at supination. PMID- 21813299 TI - The docking technique for lateral ulnar collateral ligament reconstruction: surgical technique and clinical outcomes. AB - HYPOTHESIS: Lateral ulnar collateral ligament (LUCL) reconstruction is a commonly used surgical approach for the treatment of posterolateral rotatory instability (PLRI). We hypothesized that favorable clinical results could be obtained using the docking technique. MATERIALS AND METHODS: Between 1996 and 2009, the docking technique was used for surgical reconstruction of the LUCL in 8 patients with purely ligamentous posterolateral rotatory instability of the elbow. The clinical results of these patients were retrospectively reviewed. RESULTS: At a mean follow-up of 7.1 years (range, 5.2-9.4 years), 6 patients (75%) demonstrated complete resolution of lateral elbow instability, and 2 (25%) reported occasional instability with activities of daily living. The mean Mayo Elbow Performance Score was 87.5 (range, 75-100). Subjective assessment revealed that all patients were satisfied with their clinical outcome. CONCLUSION: LUCL reconstruction using the docking technique facilitates simple graft tensioning and excellent graft fixation. Clinical results are comparable with previously reported studies with a low complication rate. PMID- 21813300 TI - Scalp EEG does not predict hemispherectomy outcome. AB - BACKGROUND: Functional hemispherectomy is effective in carefully selected patients, resulting in a reduction of seizure burden up to complete resolution, improvement of intellectual development, and developmental benefit despite possible additional neurological deficit. Despite apparent hemispheric pathology on brain magnetic resonance imaging (MRI) or other imaging tests, scalp electroencephalography (EEG) could be suggestive of bilateral ictal onset or even ictal onset contralateral to the dominant imaging abnormality. We aimed to investigate the role of scalp EEG lateralization pre-operatively in predicting outcome. METHODS: We retrospectively reviewed 54 patients who underwent hemispherectomy between 1991 and 2009 at Medical College of Georgia (1991-2006) and Cincinnati Children's Hospital Medical Center (2006-2009) and had at least one year post-operative follow-up. All preoperative EEGs were reviewed, and classified as either lateralizing or nonlateralizing, for both ictal and interictal EEG recordings. RESULTS: Of 54 patients, 42 (78%) became seizure free. Twenty-four (44%) of 54 had a nonlateralizing ictal or interictal EEG. Further analysis was based on etiology of epilepsy, including malformation of cortical development (MCD), Rasmussen syndrome (RS), and stroke (CVA). EEG nonlateralization did not predict poor outcome in any of the etiology groups evaluated. CONCLUSION: Scalp EEG abnormalities in contralateral or bilateral hemispheres do not, in isolation, predict a poor outcome from hemispherectomy. Results of other non-invasive and invasive evaluations should be used to determine candidacy. PMID- 21813301 TI - An unusual cause of intractable heel pain. AB - We report a case of severe heel pain that did not respond to noninvasive measures. Magnetic resonance imaging scans revealed a soft tissue mass that after complete surgical excision was found to be an epidermal cyst. The patient experienced full resolution of the symptoms after excision of the epidermal cyst. To our knowledge, intractable heel pain due to an epidermal cyst is rare. We were unable to identify a previous publication describing the presence of an epidermal cyst localized to the heel without a history of previous trauma. From our experience with the present case, we believe that clinicians should consider the possibility of an epidermal inclusion cyst and should have a low threshold for obtaining magnetic resonance imaging scans, in particular, before the initiation of invasive treatment, in the case of intractable heel pain. PMID- 21813302 TI - Mechanical comparison of two types of fixation for ludloff oblique first metatarsal osteotomy. AB - The Ludloff oblique metatarsal osteotomy is an effective method to correct hallux valgus deformity, although a number of problems have been associated with it, including inherent instability, delayed union, dorsal malunion, and fixation failure. The purpose of the present study was to compare the mechanical characteristics of fixation of the Ludloff osteotomy in 20 identical synthetic bone models, 10 fixated using 2 screws (group I) and 10 fixated using 2 screws augmented with a mini locking plate (group II). Each specimen was loaded to failure, and the mean average load to failure, stiffness, and absorbed energy to failure were compared using unpaired Student's t test. The mean average stiffness of the Ludloff osteotomy fixed with 2 screws (group I) and with the supplementary mini locking plate (group II) was 172.7 +/- 31.7 N/mm and 193.3 +/- 39 N/mm, respectively (p = .21). The mean average load to failure for groups I and II was 278.4 +/- 64.4 N and 356.2 +/- 77.9 N, respectively (p = .025). The mean average energy absorbed before failure for groups I and II was 506.7 +/- 206.4 Nmm and 769.8 +/- 339.4 Nmm, respectively (p = .05). The use of a medially applied supplementary mini locking plate offers a simple and effective method to improve the mechanical stability of the Ludloff oblique osteotomy. PMID- 21813303 TI - Screen-detected lung cancer: a retrospective analysis of CT appearance. AB - RATIONALE AND OBJECTIVES: The aim of this study was to retrospectively evaluate characteristics of lung cancers diagnosed in a low-dose computed tomographic lung cancer screening study. MATERIALS AND METHODS: As part of the International Early Lung Cancer Action Program, a cohort of 4782 at-risk participants were screened. A total of 86 cancers in 84 individuals were detected and evaluated for location, morphology (density, border), size, histology, stage at diagnosis, treatment, and survival. Follow-up imaging for computation of growth rates was available in 41 cases. RESULTS: Eighty-six cancers were detected in 84 individuals (60 women, 24 men). Of these, seven (8%) were incidence cancers. Most cancers were radiologically described as solid (n = 52 [61%]). The median tumor size was 18 * 13 mm (range, 6-56 mm). Histopathologic diagnoses revealed 10 (11.6%) bronchoalveolar carcinomas, 55 (64%) adenocarcinomas, 11 (12.8%) squamous-cell carcinomas, two (2.3%) large-cell carcinomas, three (3.5%) carcinoids, and five (5.8%) small-cell lung cancers. Of the 41 cases with follow-up computed tomographic scans, 36 nodules had increased in size. The mean doubling time for all cancers was 259 days (median, 154 days). In women (n = 25), the mean doubling time was 313 days (median, 156 days), while in men (n = 11), the mean doubling time was 137 days (median, 92 days). Overall, 55 lung cancers (68%) were stage I. Most cancers (n = 62 [73%]) were surgically resected. CONCLUSIONS: In this cohort, screening detected lung cancer in early treatable stages, and women had more slow-growing adenocarcinomas than men. Most screen-detected lung cancers were surgically resectable. PMID- 21813304 TI - Comments regarding 'Stent-assisted remote iliac artery endarterectomy: an alternative approach to treating combined external iliac and common femoral artery disease'. PMID- 21813305 TI - Identification and characterisation of side population cells in the canine pituitary gland. AB - To date, stem/progenitor cells have not been identified in the canine pituitary gland. Cells that efficiently exclude the vital dye Hoechst 33342 can be visualised and identified using fluorescence activated cell sorting (FACS) as a 'side population' (SP), distinct from the main population (MP). Such SPs have been identified in several tissues and display stem/progenitor cell characteristics. In this study, a small SP (1.3%, n=6) was detected in the anterior pituitary glands of healthy dogs. Quantitative PCR indicated significantly higher expression of CD34 and Thy1 in this SP, but no differences in the expression of CD133, Bmi-1, Axin2 or Shh. Pro-opiomelanocortin (POMC) and Lhx3 expression were significantly higher in the MP than in the SP, but no differences in the expression of Tpit, GH or PRL were found. The study demonstrated the existence of an SP of cells in the normal canine pituitary gland, encompassing cells with stem cell characteristics and without POMC expression. PMID- 21813306 TI - Multi-quantum echoes in GdAl2 zero-field high-resolution NMR. AB - In this paper we present a series of high-resolution zero-field NMR spectra of the polycrystalline intermetallic compound GdAl(2). The spectra were obtained with the sample at 4.2K in the ordered magnetic state and in the absence of an external static magnetic field. Using a sequence composed of two RF pulses, we obtained up to five multi-quantum echoes for the (27)Al nuclei, which were used to construct the zero-field NMR spectra. The spectra obtained from the FID observed after the second pulse and the even echoes exhibited higher resolution than the odd ones. In order to explain such behavior, we propose a model in which there are two regions inside the sample with different inhomogeneous spectral line broadenings. Moreover, with the enhanced resolution from the FID signal, we were able to determine quadrupolar couplings with great precision directly from the respective spectra. These results were compared with those obtained from the quadrupolar oscillations of the echo signals, and showed good agreement. Similar data were also obtained from (155)Gd and (157)Gd nuclei. PMID- 21813307 TI - Spinal cord compression in young children with type VI mucopolysaccharidosis. AB - Spinal cord compression (SCC) is a known complication of mucopolysaccharidosis type VI (MPS VI) secondary to atlantoaxial subluxation, craniovertebral stenosis, posterior longitudinal ligament hypertrophy, or dural thickening. SCC is expected to occur in the natural history of the disease, regardless of enzyme replacement therapy (ERT), as intravenous enzyme does not cross the blood-brain barrier. We describe six MPS VI children with SCC, all diagnosed before 7years of age. Within this group, four of the children were diagnosed with SCC after the introduction of ERT. We hypothesize that these patients may illustrate the previously undetected risk of increased joint mobility caused by ERT which may have contributed to increased cervical instability by loosening the neck joint, thus leading to or unmasking SCC. We reinforce the need for close follow-up of SCC, periodic neurological assessment, spine imaging, and neurophysiology in all MPS VI patients before and during ERT. Neurophysiological abnormalities may precede changes in MRI images (as shown in patients 4 and 5 from this sample) and should, therefore, be accessed in MPS VI patient evaluations, allowing for timely intervention and better prognosis. We recognize the limitations of these data due to the small sample size and recommend further investigation into this patient population. PMID- 21813308 TI - ABCC6 does not transport adenosine - relevance to pathomechanism of pseudoxanthoma elasticum. PMID- 21813309 TI - Oxidative stress in phenylketonuric patients. AB - Phenylketonuria is the most frequent disturbance of amino acid metabolism. Untreated patients present mental retardation whose pathophysiology is not completely established. In this work we discuss the oxidative stress in phenylketonuric patients. Several studies have shown reduction in antioxidant defenses, possibly due to dietary restriction of nutrients with antioxidant properties and increase in oxidative damage to biomolecules, probably secondary to increased formation of reactive species. Therefore, antioxidants could be considered an adjuvant therapy in phenylketonuria. PMID- 21813310 TI - A tall man lettering project to enhance medication safety. PMID- 21813311 TI - Biomechanical robustness of a new proximal epiphyseal hip replacement to patient variability and surgical uncertainties: a FE study. AB - The biomechanical behaviour of current hip epiphyseal replacements is notably sensitive to the typical variability of conditions following a standard surgery. The aim of the present study was to assess the biomechanical robustness to the variability of post-operative conditions of an innovative proximal epiphyseal replacement (PER) hip device featuring a short, curved and cemented stem. The risk of femoral neck fractures, prosthesis fractures and aseptic loosening were assessed through a validated finite element procedure following a systematic approach. Risk changes due to anatomical variations were assessed mimicking extreme conditions in terms of femoral size and level of osteoporosis. Failure risks associated with surgical uncertainties were assessed mimicking extreme conditions in terms of uncertainties on the prosthesis position/alignment, cement bone interdigitation depth, and friction between the prosthesis and the hosting cavity. The femoral neck strength increased after implantation from 9% to 49% and was most sensitive to changes of the anatomo-physiological variables. The risk of stem fractures was low in all studied configurations. The risk of stem loosening was low and most sensitive to surgical uncertainties. In conclusion, the new device can be considered an effective alternative to current epiphyseal replacements. Care is recommended in a proper seating of the prosthesis in the femur. PMID- 21813312 TI - Ultrasound transducer shape has no effect on measurements of lumbar multifidus muscle size. AB - OBJECTIVE: Evidence is currently lacking for guidance on ultrasound transducer configuration (shape) when imaging muscle to measure its size. This study compared measurements made of lumbar multifidus on images obtained using curvilinear and linear transducers. METHOD: Fifteen asymptomatic males (aged 21 32 years) had their right lumbar multifidus imaged at L3. Two transverse images were taken with two transducers (5 MHz curvilinear and 6 MHz linear), and linear and cross-sectional area (CSA) measurements were made off-line. Reliability of image interpretation was shown using intra-class correlation coefficients (0.78 0.99). Muscle measurements were compared between transducers using Bland and Altman plots and paired t-tests. Relationships between CSA and linear measurements were examined using Pearson's Correlation Coefficients. RESULTS: There were no significant differences (p > 0.05) in the measurements of the two transducers. Thickness and CSA measurements had small differences between transducers, with mean differences of 0.01 cm (SDdiff = 0.21 cm) and 0.03 cm(2) (SDdiff = 0.58 cm(2)) respectively. Width measures had a mean difference of 0.14 cm, with the linear transducer giving larger measures. Significant correlations (p < 0.001) were found between all linear measures and CSA, with both transducers (r = 0.78-0.89). CONCLUSION: Measurements of multifidus at L3 were not influenced by the configuration of transducers of similar frequency. For the purposes of image interpretation, the curvilinear transducer produced better definition of the lateral muscle border, suggesting it as the preferable transducer for imaging lumbar multifidus. PMID- 21813313 TI - The effects of dynamic stretching on plantar flexor muscle-tendon tissue properties. AB - Dynamic stretching is commonly used in warm-up routines for athletic activities. Even though several positive effects of dynamic stretching on athletic performance have been reported, the effects on the muscle-tendon unit (MTU) itself are still unclear. The objective of this study is to determine the effects of dynamic stretching on the ankle plantar flexor muscle-tendon properties by use of ultrasonography. Twenty healthy male subjects participated in the present study. The subjects were asked to engage in dynamic stretching of plantar flexors for 30 s and to repeat for 5 sets. Ankle dorsiflexion ROM was measured before and after the dynamic stretching. Changes in the displacement of the myotendinous junction (MTJ), pennation angle, and fascicle length were also determined by using ultrasonography. Ankle dorsiflexion ROM increased significantly after the dynamic stretching (p < 0.0001). A significant distal displacement of the MTJ was observed until the second stretching set (p < 0.001) with no significant changes thereafter. Pennation angle, and fascicle length were unaffected by the dynamic stretching. Dynamic stretching was shown to be effective in increasing ankle joint flexibility. Outcomes that could have indicated changes in muscle tissue (such as the pennation angle and fascicle length) were unaltered. However, a significant displacement of the MTJ was found, indicating some change in the tendon tissues. Therefore, dynamic stretching of the plantar flexors was considered an effective means of lengthening the tendon tissues. PMID- 21813314 TI - Forward light scatter and contrast sensitivity in keratoconic patients. AB - PURPOSE: The aim of this study was to obtain intraocular forward light scatter (FLS) data in keratoconus patients and to explore possible relationships with contrast sensitivity. METHOD: Intraocular straylight was assessed in the right eye of 10 visually-normal subjects (31+/-5 years) and 5 keratoconus patients (34+/-9 years) using the van den Berg straylight meter. Contrast sensitivity was also measured in both groups, with and without a glare source provided by the Brightness Acuity Tester (BAT), using a Pelli-Robson chart. Inclusion criteria for the keratoconic patients were chosen to avoid natural causes of increased scatter and to limit the influence of factors that could affect the straylight measurements. RESULTS: Intraocular light scatter was significantly greater in the keratoconic patients than in normal subjects for each of the three eccentricities tested (Mann-Whitney U test (2-tailed): Z<=-2.2, p<=0.027). Baseline Pelli-Robson contrast sensitivity was also found to be lower in the keratoconus group than in the normal subjects (Mann-Whitney U test: Z=-2.2, p=0.023). Under glare conditions contrast loss was significantly greater in the keratoconic patients than in the normal subjects (Mann-Whitney U test: Z=-2.5, p=0.013). High levels of negative correlation were found between the magnitudes of intraocular straylight and baseline contrast sensitivity in the keratoconus group (Spearman's correlation coefficient (RS)<=-0.87, p<=0.027). CONCLUSION: The high values of straylight measured in the keratoconic patients cannot be explained by age or scarring and could be related to the structural degradation of the cornea. Further investigation of intraocular scatter in keratoconus is warranted to improve our current understanding of the visual deficits associated with this pathology. PMID- 21813315 TI - Electrolytic coloration and spectral properties of natural fluorite crystals containing oxygen impurities. AB - Natural fluorite crystals containing oxygen impurities are colored electrolytically by using a pointed cathode and a flat anode at various temperatures and voltages. F and F(2) color centers are produced in colored fluorite crystals. O(2-)-V(a)(+), O(2-)-V(a)(+) aggregate, Yb(2+), Ce(3+) and Sm(2+) absorption bands are observed in absorption spectra of uncolored fluorite crystals. O(2-)-V(a)(+), O(2-)-V(a)(+) aggregate, Yb(2+), Ce(3+), Sm(2+), F, M (F(2)) absorption bands and group of four absorption bands are observed simultaneously in absorption spectra of colored fluorite crystals. Current-time curve for electrolytic coloration of natural fluorite crystal and its relationship with electrolytic coloration process are given. Production and conversion of color centers are explained. PMID- 21813316 TI - Vibrational investigation on FT-IR and FT-Raman spectra, IR intensity, Raman activity, peak resemblance, ideal estimation, standard deviation of computed frequencies analyses and electronic structure on 3-methyl-1,2-butadiene using HF and DFT (LSDA/B3LYP/B3PW91) calculations. AB - FT-IR and FT-Raman (4000-100 cm(-1)) spectral measurements of 3-methyl-1,2 butadiene (3M12B) have been attempted in the present work. Ab-initio HF and DFT (LSDA/B3LYP/B3PW91) calculations have been performed giving energies, optimized structures, harmonic vibrational frequencies, IR intensities and Raman activities. Complete vibrational assignments on the observed spectra are made with vibrational frequencies obtained by HF and DFT (LSDA/B3LYP/B3PW91) at 6 31G(d,p) and 6-311G(d,p) basis sets. The results of the calculations have been used to simulate IR and Raman spectra for the molecule that showed good agreement with the observed spectra. The potential energy distribution (PED) corresponding to each of the observed frequencies are calculated which confirms the reliability and precision of the assignment and analysis of the vibrational fundamentals modes. The oscillation of vibrational frequencies of butadiene due to the couple of methyl group is also discussed. A study on the electronic properties such as HOMO and LUMO energies, were performed by time-dependent DFT (TD-DFT) approach. The calculated HOMO and LUMO energies show that charge transfer occurs within the molecule. The thermodynamic properties of the title compound at different temperatures reveal the correlations between standard heat capacities (C) standard entropies (S), and standard enthalpy changes (H). PMID- 21813317 TI - Determination Co2+ in vitamin B12 based on enhancement of 2-(4-substituted phenyl)-4,5-di(2-furyl) imidazole and H2O2 chemiluminescence reaction. AB - In this paper, three kinds of imidazole derivatives, 2-(4-methylphenyl)-4,5-di(2 furyl) imidazole (MDFI), 2-(4-nitrophenyl)-4,5-di(2-furyl) imidazole (NDFI), and 2-(4-tert-butylphenyl)-4,5-di(2-furyl) imidazole (t-BDFI) were synthesized. In an alkaline medium, the chemiluminescence (CL) reaction of imidazole derivatives with H(2)O(2) has been investigated. It was also found that MDFI/H(2)O(2) and t BDFI/H(2)O(2) systems gave strong CL. When Co(2+) was added into the two CL systems, the CL intensity was remarkably enhanced. In the optimum conditions, the CL intensity is linearly related to the logarithm of concentration of Co(2+). The linear ranges are 5*10(-9)-2.5*10(-7) mol/L for MDFI/H(2)O(2) system and 5*10(-9) 2.5*10(-7) mol/L for t-BDFI/H(2)O(2) system, and the corresponding detection limits are 1.2*10(-9) mol/L and 1.1*10(-9) mol/L, respectively. The method was applied to the determination of Co(2+) in vitamin B(12) injection. Furthermore, the CL mechanism was also discussed. PMID- 21813318 TI - Genotyping of a nosocomial outbreak of pandemic influenza A/H1N1 2009. AB - BACKGROUND: Epidemiological surveys have revealed outbreaks of pandemic influenza A (H1N1) 2009 in several different contexts. Molecular characterization of the influenza virus could help to provide a more accurate description of these outbreaks. OBJECTIVE: To genotype pandemic influenza A (H1N1) 2009 isolates from an epidemiologically defined nosocomial outbreak. STUDY DESIGN: We sequenced the neuraminidase (NA) and hemagglutinin (HA) influenza A (H1N1) 2009 genes from ten HIV-positive patients involved in an epidemiologically defined outbreak in the Clinical Microbiology and Infectious Diseases (CMID) Department. Sequences were aligned to search for specific genetic features of the involved strain. We also analyzed 37 unrelated influenza A (H1N1) 2009 cases from other hospital departments. All the sequences were used to obtain phylogenetic trees. RESULTS: Identical genotypic features were shared by nine of the 10 cases initially considered to be involved in the outbreak, but not by the remaining case. These features involved two silent mutations at N385 and V407 in the NA gene and three amino acid substitutions in the HA gene (D225E, A189T, and P300S). Searching for these substitutions in patients with influenza A (H1N1) 2009 hospitalized in other departments during the same period allowed us to identify an additional unsuspected immunocompetent case. The five outbreak-specific substitutions were absent in the remaining 36 unrelated controls. One of the substitutions (P300S) rendered detection of this variant by the CDC protocol inefficient. The other outbreak-specific substitutions (D225E and A189T) were identified at codons that have been analyzed in the context of virulence. CONCLUSIONS: Genotyping is essential to ensure a more accurate description of pandemic influenza A (H1N1) 2009 outbreaks. PMID- 21813319 TI - Detection of human parechovirus (HPeV)-3 in spinal fluid specimens from pediatric patients in the Chicago area. AB - BACKGROUND: The human parechoviruses (HPeV) have recently been recognized as important viral pathogens causing various illnesses including sepsis and meningitis in children. However, data from the United States is limited. OBJECTIVES: To better understand the epidemiology of HPeV in the United States and its role in pediatric disease through detection and typing of the virus in cerebrospinal fluid specimens. STUDY DESIGN: Four hundred and twenty-one spinal fluid samples collected from 373 patients ranging in age from 1 day to 18 years were tested using a real-time reverse transcription-PCR assay. The specimens were originally collected for routine viral and bacterial testing to assist in the diagnosis of meningitis or sepsis. Amplification products of the VP1 region in the virus genome were sequenced to identify the parechovirus type. RESULTS: Ten positive specimens were identified from 10 different patients. All ten samples were typed as HPeV3 and were negative for bacteria by culture, and for enterovirus and herpes simplex virus by PCR. All of the HPeV3-infected patients were young infants ranging in age from 6 to 59 days. Infants in whom HPeV3 was detected had significantly decreased peripheral white blood cell counts. Positive specimens were all from the summer and early fall. CONCLUSIONS: HPeV3 infection of the central nervous system is found in very young infants in certain years during the summer and early fall, and is associated with leukopenia. Real-time RT PCR is an effective tool for rapid detection of these infections, and could help prevent unnecessary hospitalization and antibiotic use in HPeV infected infants. More widespread use of this tool in diagnosing HPeV infection would aid in further clarifying the prevalence of this disease in the United States. PMID- 21813320 TI - High correlation between the Roche COBAS(r) AmpliPrep/COBAS(r) TaqMan(r) HIV-1, v2.0 and the Abbott m2000 RealTime HIV-1 assays for quantification of viral load in HIV-1 B and non-B subtypes. AB - BACKGROUND: HIV-1 viral load assays are critical tools to monitor antiretroviral therapy efficacy in HIV-infected patients. Two assays based on real-time PCR are available, the Abbott Real-Time HIV-1 assay (Abbott assay) and the new Roche COBAS((r)) AmpliPrep/COBAS((r)) TaqMan((r)) HIV-1 test, v. 2.0 (TaqMan((r)) test v2.0). OBJECTIVES: We have compared the performance of the two assays in 546 clinical plasma specimens of group M strains from Luxembourg and Rwanda. STUDY DESIGN: Our analyses focused on subtype inclusivity and platforms accuracy for 328 low level viremia samples. RESULTS: Strong agreement and linear correlation were observed between the two assays (R(2) = 0.95) over a wide dynamic range. Bland-Altman analysis showed a mean difference of 0.04 log 10 indicating minimal overall viral load quantification differences between both platforms. One subtype C was severely underquantified by TaqMan((r)) test v2.0 for which sequence analysis revealed multiple mismatches between the viral sequence and the primer/probe regions. A non significant lower quantification of the Abbott assay was shown for subtype A1 with a mean log 10 difference of 0.24. For specimens under 200 cp/mL, the overall agreement was 90% at the cut-off of 50 cp/mL and 67% at assay's lower limit of detection of 20 and 40 cp/mL. 309 samples were retested by the COBAS((r)) AMPLICOR((r)) HIV-1 MONITOR Test, v. 1.5 and a lack of agreement between the three assays around their lower limit of quantification was revealed. CONCLUSIONS: Both real-time tests were closely comparable in the quantification of viral load specimens of ten HIV-1 subtypes and recombinant forms. PMID- 21813321 TI - Electrospun conducting polymer nanofibers and electrical stimulation of nerve stem cells. AB - Tissue engineering of nerve grafts requires synergistic combination of scaffolds and techniques to promote and direct neurite outgrowth across the lesion for effective nerve regeneration. In this study, we fabricated a composite polymeric scaffold which is conductive in nature by electrospinning and further performed electrical stimulation of nerve stem cells seeded on the electrospun nanofibers. Poly-L-lactide (PLLA) was blended with polyaniline (PANi) at a ratio of 85:15 and electrospun to obtain PLLA/PANi nanofibers with fiber diameters of 195 +/- 30 nm. The morphology, chemical and mechanical properties of the electrospun PLLA and PLLA/PANi scaffolds were carried out by scanning electron microscopy (SEM), X-ray photo electron spectroscopy (XPS) and tensile instrument. The electrospun PLLA/PANi fibers showed a conductance of 3 * 10-9 S by two-point probe measurement. In vitro electrical stimulation of the nerve stem cells cultured on PLLA/PANi scaffolds applied with an electric field of 100 mV/mm for a period of 60 min resulted in extended neurite outgrowth compared to the cells grown on non stimulated scaffolds. Our studies further strengthen the implication of electrical stimulation of nerve stem cells on conducting polymeric scaffolds towards neurite elongation that could be effective for nerve tissue regeneration. PMID- 21813322 TI - Polypeptide aptamer selection using a stabilized ribosome display. AB - A newly developed ribosome display protocol was applied to the in vitro selection of polypeptide aptamers to small molecular weight chemicals, 6-[hydroxy(4 nitrobenzyl)phosphonyl]hexanoic acid and vitamin B12, chosen from a peptide library of random sequences. New peptide sequences binding to the targets were found after six rounds of this protocol. PMID- 21813323 TI - Use of liposome encapsulated hemoglobin as an oxygen carrier for fetal and adult rat liver cell culture. AB - Engineering liver tissue constructs with sufficient cell mass for transplantation implies culturing large numbers of hepatocytes in a reduced volume; however, providing sufficient oxygen to dense cell cultures is still not feasible using only conventional culture medium. Liposome-encapsulated hemoglobin (LEH), an oxygen-carrying blood substitute originally designed for short-term perfusion, may be a good candidate as an oxygen carrier to cultured liver cells. In this study, we investigated the feasibility of maintaining long term hepatocyte cultures using LEH. Primary fetal and adult rat liver cells were directly exposed to LEH for 6 to 14 days in static culture or in a perfused flat plate bioreactor. The functions and viability of adult rat hepatocytes exposed to LEH were not adversely affected in static monolayer culture and were even improved in the bioreactor. However, some cytotoxicity of LEH was observed with fetal rat liver cells after 4 days of culture. LEH, though a suitable oxygen carrier for long term culture of mature hepatocytes, is not suitable in its present form for perfusing fetal hepatocyte cultures in direct contact with the liposomes; either the LEH will have to be made less toxic or a more sophisticated bioreactor that prevents the direct contact between hepatocytes and perfusates will have to be designed if fetal cells are to be used for liver tissue engineering. PMID- 21813324 TI - Applicability of two mobile analysers for mercury in urine in small-scale gold mining areas. AB - Mercury is still used in developing countries to extract gold from the ore in small-scale gold mining areas. This is a major health hazard for people living in mining areas. The concentration of mercury in urine was analysed in different mining areas in Zimbabwe, Indonesia and Tanzania. First the urine samples were analysed by CV-AAS (cold vapour atomic absorption spectrometry) during the field projects with a mobile mercury analyser (Lumex((r)) or Seefelder((r))) and secondly, in a laboratory with a stationary CV-AAS mercury analyser (PerkinElmer((r))). Caused by the different systems (reduction agent either SnCl(2) (Lumex((r)) or Seefelder((r)))) or NaBH(4) (PerkinElmer((r))), with the mobile analysers only the inorganic mercury was obtained and with the stationary system the total mercury concentration was measured. The aims of the study were whether the results obtained in field with the mobile equipments can be compared with the stationary reference method in the laboratory and allow the application of these mobile analysers in screening studies on concerned populations to select those, who are exposed to critical mercury levels. Overall, the concentrations obtained with the two mobile systems were approximately 25% lower than determined with the stationary system. Nevertheless, both mobile systems seem to be very useful for screening of volunteers in field. Moreover, regional staff may be trained on such analysers to perform screening tests by themselves. PMID- 21813325 TI - Bowel symptom experiences and management following sphincter saving surgery for rectal cancer: A qualitative perspective. AB - PURPOSE OF THE RESEARCH: The aim of this research was to explore participants' qualitative perspectives on bowel symptom experiences and management strategies following sphincter saving surgery for rectal cancer. METHODS AND SAMPLE: The data presented in this paper were gleaned from a semi-structured question that formed part of a larger multi-site quantitative correlational study. From a sample of 143 participants, a total of 77 (62.6%) males and 46 (37.3%) females provided qualitative comments. Participants were aged 30-70 years and over, had undergone sphincter saving surgery for rectal cancer in the past 3-42 months. Data were analysed using pre-determined semi-structured categories. KEY RESULTS: The study demonstrated the subjective nature of the bowel symptoms experienced. It also highlighted the bowel symptoms that were most problematic and the effect of these symptoms on participants' daily lives. In addition, the self-care strategies that worked best for individual participants in the management of bowel symptoms were identified. CONCLUSIONS: There is a need to educate patients on the short-term as well as the long-term bowel symptoms experienced following sphincter saving surgery for rectal cancer. Nurses have an important contribution to make in facilitating patients to choose from a range of self-care strategies to help them manage their bowel symptoms postoperatively. PMID- 21813326 TI - NeurimmiRs: microRNAs in the neuroimmune interface. AB - Recent reports of microRNA (miR) modulators of both neuronal and immune processes (here termed NeurimmiRs) predict therapeutic potential for manipulating NeurimmiR levels in diseases affecting both the immune system and higher brain functions, such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS) and anxiety-related disorders. In our opinion, NeurimmiRs that function within both the nervous and the immune systems, such as miR-132 and miR-124, may act as 'negotiators' between these two interacting compartments. We suggest that NeurimmiRs primarily target transcriptional or other regulatory genes, which enables modulation of both immune and cognitive processes through direct or indirect alterations of neuron-glia and/or brain-to-body signaling. Thus, manipulating NeurimmiR control over the immune contributions to cognitive pathways may offer new therapeutic targets. PMID- 21813327 TI - Clinical symptoms and microbiological outcomes in tuberculosis treatment trials. AB - During a recent Food and Drug Administration workshop on clinical trials to evaluate new TB drugs, questions were raised regarding the use of bacteriologic endpoints such as treatment failure and relapse as measures of improvement in health status and long term outcome after treatment. FDA scientists asked how patients' clinical signs and symptoms changed during therapy, noting that while such information is usually collected during clinical trials, it is not often reported. We analyzed data from an international phase 3 TB treatment trial that included systematic assessments of symptoms. The percentage of subjects with self reported symptoms at baseline ranged from 30% for dyspnea to 81% for cough, with 51% reporting fever. During therapy, fever, sweats, and dyspnea decreased most rapidly, with near resolution by the end of therapy. Chest pain and cough resolved more slowly; 13% of subjects reported cough at six months. Symptom resolution during treatment did not differ between those who relapsed and those who did not. Among those with microbiological relapse, symptoms returned with significant increases in the proportion with fever, cough, and chest pain. At the time of relapse, cough was the most frequent symptom, occurring in 75% of subjects who relapsed but only 12% of those who did not. Our data support the continued use of bacteriologic endpoints based on sputum culture as surrogate measures of the relief of symptoms, improvement in health status and favorable long term treatment outcome in TB drug trials. PMID- 21813328 TI - Effects of a food supplement rich in arginine in patients with smear positive pulmonary tuberculosis--a randomised trial. AB - In tuberculosis (TB), the production of nitric oxide (NO) is confirmed but its importance in host defense is debated. Our aim was to investigate whether a food supplement rich in arginine could enhance clinical improvement in TB patients by increased NO production. Smear positive TB patients from Gondar, Ethiopia (n = 180) were randomized to a food supplementation rich in arginine (peanuts, equivalent to 1 g of arginine/day) or with a low arginine content (wheat crackers, locally called daboqolo) during four weeks. The primary outcome was cure rate according to the WHO classification and secondary outcomes were sputum smear conversion, weight gain, sedimentation rate, reduction of cough and chest X ray improvement as well as levels of NO in urine (uNO) or exhaled air (eNO) at two months. There was no effect of the intervention on the primary outcome (OR 1.44, 95% CI: 0.69-3.0, p = 0.39) or secondary outcomes. In the subgroup analysis according to HIV status, peanut supplemented HIV+/TB patients showed increased cure rate (83.8% (31/37) vs 53.1% (17/32), p < 0.01). A low baseline eNO (<10 ppb) in HIV+/TB patients was associated with a decreased cure rate. We conclude that nutritional supplementation with a food supplement rich in arginine did not have any overall clinical effect. In the subgroup of HIV positive TB patients, it significantly increased the cure rate and as an additional finding in this subgroup, low initial levels of NO in exhaled air were associated with a poor clinical outcome but this needs to be confirmed in further studies. PMID- 21813329 TI - What to do if cystoscopic graspers are not available? Polypropylene loop as an alternative for double J stent extraction, the 'cowboy way'. PMID- 21813330 TI - Paradoxical effect of noradrenaline-mediated neurotransmission in the antinociceptive phenomenon that accompanies tonic-clonic seizures: role of locus coeruleus neurons and alpha(2)- and beta-noradrenergic receptors. AB - The postictal state is generally followed by antinociception. It is known that connections between the dorsal raphe nucleus, the periaqueductal gray matter, and the locus coeruleus, an important noradrenergic brainstem nucleus, are involved in the descending control of ascending nociceptive pathways. The aim of the present study was to determine whether noradrenergic mechanisms in the locus coeruleus are involved in postictal antinociception. Yohimbine (an alpha(2) receptor antagonist) or propranolol (a beta-receptor antagonist) was microinjected unilaterally into the locus coeruleus, followed by intraperitoneal administration of pentylenetetrazole (PTZ), a noncompetitive antagonist that blocks GABA-mediated Cl(-) influx. Although the administration of both yohimbine and propranolol to the locus coeruleus/subcoeruleus area resulted in a significant decrease in tonic or tonic-clonic seizure-induced antinociception, the effect of yohimbine restricted to the locus coeruleus was more distinct compared with that of propranolol, possibly because of the presynaptic localization of alpha(2)-noradrenergic receptors in locus coeruleus neurons. These effects were related to the modulation of noradrenergic activity in the locus coeruleus. Interestingly, microinjections of noradrenaline into the locus coeruleus also decrease the postictal antinociception. The present results suggest that the mechanism underlying postictal antinociception involves both alpha(2)- and beta-noradrenergic receptors in the locus coeruleus, although the action of noradrenaline on these receptors causes a paradoxical effect, depending on the nature of the local neurotransmission. PMID- 21813331 TI - Reflex absence epilepsy induced by gait. AB - Reflex epilepsy is characterized by seizures that are precipitated by a specific identifiable factor. We describe here the case of a 21-year-old man with notable absence epilepsy since the age of 11 who experienced generalized convulsions 2 years after onset (in the absence of antiepileptic therapy) and reflex absence seizures triggered by walking 7-10 steps. To our knowledge, this case report is the first describing reflex absence epilepsy seizures induced by gait. PMID- 21813332 TI - Treatment-seeking behavior of people with epilepsy in Taiwan: a preliminary study. AB - To understand the treatment-seeking behavior of people with epilepsy (PWE), 403 PWE were surveyed using structured face-to-face interviews. Nearly half (49.1%) of them had previously tried complementary and alternative medicine (CAM); traditional Chinese medicine (51.5%) and temple worship (48.0%) were the most frequently used forms of CAM. In the 155 patients with adult-onset epilepsy, seeking CAM was substantially more common among females (OR=2.11, 95% CI=1.05 4.24, P=0.036), patients with frequent seizures (OR=2.68, 95% CI=1.30-5.53, P=0.008), patients with less educated parents (OR=2.16, 95% CI=1.06-4.41, P=0.034), and patients with religious beliefs (OR=2.84, 95% CI=1.23-6.56, P=0.015). In the 248 patients with childhood-onset epilepsy, frequent seizures (OR=2.23, 95% CI=1.32-3.77, P=0.003) and lower level of parental education (OR=2.71, 95% CI=1.45-5.06, P=0.002) were significantly associated with CAM use. The patients who seek CAM before receiving conventional medical treatment decreased after implementation of the National Health Insurance (NHI) (34/188 before NHI vs 22/215 after NHI, P=0.023). This study showed that the prevalence of CAM use by PWE in Taiwan is high and that a convenient NHI program can affect treatment-seeking behavior. PMID- 21813333 TI - Interrater reliability of the international consensus definition of drug resistant epilepsy: a pilot study. AB - We evaluated the interrater reliability of the consensus definition of drug resistant epilepsy proposed by the International League Against Epilepsy. According to the definition framework, outcome of each antiepileptic drug (AED) trial was categorized as "seizure freedom" or "treatment failure." This level 1 assessment was used to determine the level 2 classification, which defined drug resistant epilepsy as the failure of adequate trials of two or more AED schedules to achieve sustained seizure freedom. Two raters classified treatment outcomes of 150 patients independently. The patients had received a total of 428 trials of AEDs. Categorization of level 1 outcome to individual AED trials by the raters was consistent in 413 (96.5%). For the level 2 classification of drug-resistant or drug-responsive epilepsy, there was absolute agreement between the raters in 141 patients (94%), with a kappa index of 0.91 (P<0.001). The definition appeared to have a high degree of interrater reliability in this setting. PMID- 21813334 TI - Recognition of psychogenic nonepileptic seizures diminishes acute care utilization. AB - Patients with psychogenic nonepileptic seizures (PNES) frequently use acute health care resources including emergency departments (EDs), resulting in redundant efforts. We asked whether establishing the diagnosis of PNES via video/EEG telemetry reduces subsequent ED use. Twenty-three patients with PNES were studied over a 48-month period surrounding the diagnosis using a provincewide database. There was a 39% reduction in total ED visits and a 51% reduction in ED visits for neurological causes during the 24 months following the diagnosis, and decreased ED use persisted throughout the follow-up period. There was no significant change in ED utilization for psychiatric causes. The proportion of patients with PNES who used ED services once or not at all per year increased from 26% in the 2 years prior to the diagnosis to 57% following the diagnosis. These findings suggest that a definitive, telemetry-based diagnosis relieves diagnostic uncertainties for the patient and physician, but also has quantifiable economic benefits. PMID- 21813335 TI - Meta-analysis on the association between nonsteroidal anti-inflammatory drug use and lung cancer risk. AB - BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs), especially aspirin, have emerged as the most potential chemopreventive agents. However, epidemiologic studies reported a controversial association between NSAID use and lung cancer risk. We conducted a meta-analysis to summarize the evidence for such relationship. METHODS: Eligible studies were identified by searching the electronic literature PubMed, Medline, Embase, and ScienceDirect databases for relevant reports and bibliographies. Studies were included if they designed as cohort study, case-control study, or clinical trial on the NSAID exposure and lung cancer with sufficient raw data to analyzes. Relative risk (RR) or odds ratio (OR) was used to evaluate the association between NSAIDs and lung cancer. Stratified analysis was also performed. RESULTS: A total of 19 studies including 20,266 lung cancer cases met the inclusion criteria. To the effect of aspirin on lung cancer, the combined RR for cohort studies was 0.96 (95%confidence interval [CI]: 0.78-1.19) and OR for case-control studies was 0.87 (95%CI: 0.69-1.09). When restricted in exposure of aspirin use to 7 tablets per week, the OR was 0.80 (95%CI: 0.67-0.95). The summary risk estimates showed no significant association between non-aspirin NSAID or overall NSAID use and lung cancer risk. CONCLUSIONS: Aspirin use with a dose of 7 tablets per week can significantly reduce lung cancer risk, whereas non-aspirin NSAIDs showed no chemopreventive value. Greater attention should be paid to identifying appropriate individuals for this new indication of aspirin and the optimal dose and duration as a chemopreventive agent. PMID- 21813336 TI - Phase II study of irinotecan and cetuximab given every 2 weeks as second-line therapy for advanced colorectal cancer. AB - BACKGROUND: Irinotecan and weekly cetuximab (I+C) is a standard second-line regimen for metastatic colorectal cancer (mCRC). This study investigated the safety and efficacy of every 2 weeks I+C in patients with mCRC. PATIENTS AND METHODS: Patients with mCRC refractory to first-line fluoropyrimidine/oxaliplatin regimens and not previously treated with I+C were eligible. Response rate (RR) was the primary endpoint. Cetuximab 500 mg/m(2) and irinotecan 180 mg/m(2) were administered intravenously (I.V.) on day 1 every 2 weeks. RESULTS: Patient characteristics (n = 31): male (n = 17), median age 62; Eastern Cooperative Oncology Group (ECOG) performance status (PS) <=1 (n = 30), and PS = 2 (n = 1). Median number of cycles = 3 (range, 1-22). I+C doses were modified in 18 and 12 patients, respectively. Grade 3/4 adverse events: acneiform rash (n = 6); neutropenia (n = 6); and diarrhea (n = 5); there was one grade 5 respiratory failure, possibly related to therapy. Two patients had a partial response, 11 had stable disease, and 18 had progressive disease resulting in an overall RR of 6% and disease control rate of 41.9%. Median overall survival (OS) was 9.3 months (95% CI, 5.1-15), and time to progression (TTP) was 2.4 months (95% CI, 1.3-4.6). K-ras and BRAF mutations were detected in 39% and 9%, respectively, of the patients tested. There was a trend toward longer TTP among patients with wild type K-ras and BRAF (2.6 vs. 1.7 months; P = 0.16), and OS was significantly longer in those patients (14.1 vs. 5.5 months; P = 0.04). CONCLUSIONS: The RR and TTP were lower than expected and may reflect the reduced dose intensity due to toxicities. While the OS was consistent with previous publications, the efficacy of this combination was not demonstrated. PMID- 21813338 TI - Emerging therapies for advanced gastroenteropancreatic neuroendocrine tumors. AB - Neuroendocrine tumors comprise a heterogeneous group of neoplasms derived from peptide- and amine-producing cells of the neuroendocrine system. Gastroenteropancreatic NET are differentiated into tumors and carcinomas based on their malignant potential and subdivided into those arising from the pancreas (islet cell tumors or pancreatic NET) and the more classical gut "carcinoids". Moderate to well differentiated NET have historically been considered rare tumors but recent epidemiological statistics suggest that their frequency has increased substantially over the past three decades. While the incidence of NET is increasing, data from both the US and UK demonstrate no improvement in outcomes over a similar time period. Due to the generally indolent biology of NET, most patients present with advanced disease before symptoms become apparent. In patients with localized NET, the 5-year survival rates after resection range from 60 to 90%, while regional lymph node involvement decreases the 5-year survival rates after surgery to 50-75%. Patients with distant metastases have a 5 year survival rate of approximately 25-40%. Conventional cytotoxic chemotherapy is of unclear benefit in patients with these generally slow growing tumors. Multiple agents have been tested in Phase 2 and Phase 3 trials. In general, the lack of major objective responses with significant toxicities has limited routine use of traditional chemotherapy agents and has emphasized the need to develop new agents in these diseases. This review will focus on emerging molecularly-targeted treatments with an emphasis on their underlying biologic and preclinical rationale. PMID- 21813337 TI - Hepatocelluar carcinoma associated with attenuated familial adenomatous polyposis: a case report and review of the literature. PMID- 21813339 TI - Sympathetic skin response. Glabella stimulation may be more useful than peripheral nerve stimulation in clinical practice. AB - The aim is to verify whether glabella electrical stimulation evokes sympathetic skin responses (SSR) without inter-side differences in latency and area of the responses and is more useful in mononeuropathies than peripheral nerve stimulation. SSRs were recorded in 25 healthy subjects from right palm, third (M3SSR) and fifth fingers and contralateral third finger. The inter-side differences of grand mean area and mean of largest area of M3SSR were significant only by ulnar nerve and not by glabella stimulation. Therefore glabella stimulation may be used in mononeuropathies comparing SSR area recorded from affected side with respect to contralateral healthy side. PMID- 21813341 TI - Development and validation of an EI-GC/MS method for the determination of sertraline and its major metabolite desmethyl-sertraline in blood. AB - A sensitive and specific GC/MS method for the determination of sertraline and its main metabolite desmethyl-sertraline in whole blood has been developed, optimized and validated. Sample preparation included solid-phase extraction of both analytes and their derivatization with heptafluorobutyric anhydride (HFBA). Protriptyline was used as internal standard for the determination of both analytes. Limits of detection and quantification for both sertraline and desmethyl-sertraline were 0.30 and 1.00 MUg/L, respectively. The calibration curves were linear within the dynamic range of each analyte (1.00-500.0 MUg/L) with a correlation coefficient (R(2)) exceeding 0.991. Extraction efficiency ranged from 90.1(+/- 5.8)% to 95.4(+/- 3.0)% for sertraline, and from 84.9(+/- 8.2)% to 107.7(+/- 4.4)% for desmethyl-sertraline. The precision for sertraline and desmethyl-sertraline was between 3.6-5.5% and 4.7-7.2%, respectively, while the accuracy was in the range of -6.67% to 2.20% and -6.33% to 2.88% for sertraline and desmethyl-sertraline, respectively. The method was applied to real blood samples obtained from patients that follow sertraline treatment and also in cases of forensic interest. The developed method can be used in routine every day analysis by clinical and forensic laboratories, for pharmacokinetic studies, for therapeutic sertraline monitoring or for the investigation of forensic cases where sertraline is involved. PMID- 21813340 TI - Guanine repeat-containing sequences confer transcription-dependent instability in an orientation-specific manner in yeast. AB - Non-B DNA structures are a major contributor to the genomic instability associated with repetitive sequences. Immunoglobulin switch Mu (SMU) region sequence is comprised of guanine-rich repeats and has high potential for forming G4 DNA, in which one strand of DNA folds into an array of guanine quartets. Taking advantage of the genetic tractability of Saccharomyces cerevisiae, we developed a recombination assay to investigate mechanisms involved in maintaining stability of G-rich repetitive sequence. By embedding SMU sequence within recombination substrates under the control of a tetracycline-regulatable promoter, we demonstrate that the rate and orientation of transcription both affect the stability of SMU sequence. In particular, the greatest instability was observed under high-transcription conditions when the SMU sequence was oriented with the C-rich strand as the transcription template. The effect of transcription orientation was enhanced in the absence of the Type IB topoisomerase Top1, possibly due to enhanced R-loop formation. Loss of Sgs1 helicase and RNase H activity also increased instability, suggesting they may cooperatively function to reduce the formation of non-B DNA structures in highly transcribed regions. Finally, the SMU sequence was unstable when transcription elongation was perturbed due to a defective THO complex. In a THO-deficient background, there was further exacerbation of orientation-dependent instability associated with the ectopically expressed, single-strand cytosine deaminase AID. The implications of our findings to understanding instability associated with potential G4 DNA forming sequences are discussed. PMID- 21813343 TI - Idiopathic granulomatous mastitis: successful treatment by mastectomy and immediate breast reconstruction. AB - We describe three women with idiopathic granulomatous mastitis (IGM), a rare, benign breast disease. It is a chronic inflammatory lesion of the breast and presents with the clinical symptoms of inflammation, breast mass and tumorous indurations and ulcerations of the skin. Clinical and radiological findings often mimic breast cancer. Histopathologic examination remains the gold standard for the diagnosis. It is a non-malignant entity but it may be both locally aggressive and recurrent. The treatment of choice is unclear, but surgical excision and adjunctive treatment with glucocorticoids or antibiotics is described most frequently. We present three patients with a long history of recurrences that was successfully treated by mastectomy and immediate breast reconstruction. PMID- 21813342 TI - Ibuprofen improves functional outcome after axotomy and immediate repair in the peripheral nervous system. AB - BACKGROUND: Activation of the Small GTP-binding protein Rho following the nerve injury contributes to the lack of regeneration in the peripheral nervous system. By elucidating the mechanisms leading to Rho activation, a nonsteroidal anti inflammatory drug ibuprofen has been identified as a potent inhibitor of Rho activity. In this study we tested the hypothesis, that inhibiting Rho activity by ibuprofen will enhance posttraumatic regeneration after peripheral nerve injury. METHODS: In adult female Wistar rats we introduced an experimental injury by excising a 5 mm piece of the tibial nerve and returning it to the injury site as an interpositional graft. The animals then received ibuprofen or phosphate buffered saline through an osmotic pump for a period of 3 weeks. Following the injury we recorded tibial functional index (TFI) on a weekly basis. After 3 months we measured nerve conduction velocity and peak amplitude of action potential (PAAP). Also, the histomorphometric analysis was carried out in the zone distal to the injury site. RESULTS: We found that the animals receiving ibuprofen recovered the tibial nerve function more rapidly, with the TFI being significantly different 8, 9, 11 and 12 weeks after the injury. We also detected the values of the PAAP, the area of axons and the area of myelin to be significantly greater in the experimental group. CONCLUSIONS: Our results show that ibuprofen significantly enhanced regeneration after tibial nerve axotomy and repair in rats. This study is expected to set a stage for testing the ibuprofen in the human patients. PMID- 21813344 TI - Use of transesophageal atrial pacing to provide temporary chronotropic support in a dog undergoing permanent pacemaker implantation. AB - A 14.5-kg, 13-year-old female spayed Cocker spaniel was evaluated because of episodic hind limb weakness. Results of examination were consistent with sick sinus syndrome with intermittent second-degree atrioventricular block. Transesophageal atrial pacing was successful in providing chronotropic support during permanent pacemaker implantation. Transesophageal atrial pacing appears to be a viable option for temporary atrial pacing in dogs with hemodynamically marked bradycardia without significant atrioventricular blockade. PMID- 21813345 TI - Autosomal STR allele frequencies for the CODIS system from a large random population sample in Chile. AB - The thirteen autosomal STR loci of the CODIS system were typed from DNA of 732 unrelated male individuals sampled from different locations in Chile. This is the first report of allele frequencies for the thirteen STRs loci defined in the CODIS system from the Chilean population. PMID- 21813346 TI - DNA-based eye colour prediction across Europe with the IrisPlex system. AB - The ability to predict Externally Visible Characteristics (EVCs) from DNA, also referred to as Forensic DNA Phenotyping (FDP), is an exciting new chapter in forensic genetics holding great promise for tracing unknown individuals who are unidentifiable via standard forensic short tandem repeat (STR) profiling. For the purpose of DNA-based eye colour prediction, we previously developed the IrisPlex system consisting of a multiplex genotyping assay and a prediction model based on genotype and phenotype data from 3804 Dutch Europeans. Recently, we performed a forensic developmental validation study of the highly sensitive IrisPlex assay, which currently represents the only validated tool available for DNA-based prediction of eye colour in forensic applications. In the present study, we validate the IrisPlex prediction model by extending our initially described model towards genotype and phenotype data from multiple European populations. We performed IrisPlex analysis on 3840 individuals from seven sites across Europe as part of the European Eye (EUREYE) study for which DNA and high-resolution eye images were available. The accuracy rate of correctly predicting an individual's eye colour as being blue or brown, above the empirically established probability threshold of 0.7, was on average 94% across all seven European populations, ranging from 91% to 98%, despite the large variation in eye colour frequencies between the populations. The overall prediction accuracies expressed by the area under the receiver characteristic operating curves (AUC) were 0.96 for blue and 0.96 for brown eyes, which is considerably higher than those established before. The IrisPlex prediction model parameters generated from this multi-population European dataset, and thus its prediction capabilities, were highly comparable to those previously established. Therefore, the increased information regarding eye colour phenotype and genotype distributions across Europe, and the system's ability to provide eye colour predictions across Europe accurately, both highlight additional evidence for the utility of the IrisPlex system in forensic casework. PMID- 21813347 TI - Pentaplex typing of new European Standard Set (ESS) STR loci in Indian population. PMID- 21813348 TI - Population genetic analysis of 12 X-STRs in Swedish population. PMID- 21813349 TI - Updated Brazilian STR allele frequency data using over 100,000 individuals: an analysis of CSF1PO, D3S1358, D5S818, D7S820, D8S1179, D13S317, D16S539, D18S51, D21S11, FGA, Penta D, Penta E, TH01, TPOX and vWA loci. AB - The Brazilian population is one of the most heterogeneous populations of the world, formed mainly by an admixture of European, African and Native American populations. Brazil is the fifth largest country in the world (8,511,960 km(2)), being divided into five geographical regions. This study provides population genetic data of up to 137,161 unrelated individuals representing the entire Brazilian territory. Allelic frequencies and other population data analysis are reported for the 15 autosomal STR loci included in the PowerPlex(r)16 kit (Promega Corporation, Madison, WI, USA). In order to guarantee that individuals were not related, we have considered only F1 data from couples undergoing paternity testing. The number of individuals genotyped for each locus was: CSF1PO (113,526); D3S1358 (135,133); D5S818 (135,181); D7S820 (137,136); D8S1179 (134,211); D13S317 (137,161); D16S539 (136,942); D18S51 (136,739); D21S11 (130,014); FGA (135,839); Penta D (110,333); Penta E (128,055); TH01 (112,695); TPOX (123,102); vWA (127,415). Allele sizes ranged from 1 to 48.2. Statistic parameters (PD, PIC and Ho; considering values >=0.75) suggest that markers D13S317, D16S539, D18S51, D21S11, D7S820, D8S1179, Penta D, Penta E, TH01, FGA and vWA were more informative for genetic identification purposes in the Brazilian population. PMID- 21813350 TI - DNA microarray as a tool in establishing genetic relatedness--Current status and future prospects. AB - In the past decades, microarray technology has definitely put an edge to the field of genetic research. Our aim was to determine whether single nucleotide polymorphism (SNP) microarrays could be used as a tool in establishing genetic relationships where current molecular genetic methods are not sufficient. We used the Genechip, Affymetrix GenomeWide SNP Array 6.0, which detects more than 900,000 SNP markers dispersed throughout the human genome. The intention was to find a good selection of SNP markers that could be used for statistical evaluation of relatedness in a forensic setting. We conducted pairwise comparisons in the R-package FEST as well as pedigree comparisons in Merlin. Our methods were applied on two separate families, where relationships as distant as 3rd cousins were known. In addition, a question about a possible common ancestry between the two families was tested. Relationships as distant as 2nd cousins could be readily distinguished both from unrelated and other, genetically, closer relationships. This was achieved with a selection of 5774 markers, where each pair of markers was separated by a genetic distance of at least 0.5cM (centiMorgan). When considering 3rd cousins, and more distant relationships, the number of markers needs to be extended, consequently decreasing the genetic distance between the markers. However, inclusion of a too large number of markers presents new challenges and our results imply that the use of too dense sets of markers always yields the highest probability for the genetically closest relationship hypothesis. Simulations confirm that this is most probably caused by the fact that the computational model assumes linkage equilibrium between markers, a problem that will be further evaluated. Our results do however suggest that SNP-data derived from microarrays are well suited for kinship determination provided linkage disequilibrium is properly accounted for. PMID- 21813351 TI - Sandwich type ceramic liner fracture rate with the Atlas IIITM socket: A study of 144 primary total hip replacements at a mean 74 months' follow-up. AB - INTRODUCTION: Ceramic friction bearings have been proposed as a means of reducing wear in total hip replacement (THR). A "sandwich" composite concept including a ceramic bearing surface has been proposed as simplifying the modularity while matching metal-back cups with a polyethylene liner. It is not precisely known how frequently abnormal noise would occur during functioning of this type of implant, which moreover entails a risk of ceramic liner fracture. HYPOTHESIS: Results with sandwich type ceramic liners are comparable to those with polyethylene liners, without risk of side effects (noise, fracture). PATIENTS AND METHODS: Clinical and radiological results of 144 cementless Atlas IIITM cups containing a 28mm diameter polyethylene-ceramic sandwich type liner coupled to a ceramic Biolox ForteTM head were retrospectively analyzed at a mean 74 months' follow-up. Mean patient age was 59.4 years. Twelve patients were lost to follow-up. Femoral components comprised 61 ESOPTM anatomic stems and 71 BHSTM Corail stems. The radiologic study used ImagikaTM software. RESULTS: Global function scores were satisfactory: PMA score, 17.2+/-1.2 (range, 9 to 18); global Harris score, 93.6+/ 3.1 (49 to 100). Global survivorship was 91.6% (95% CI: 86.34-96.9). Radioclinical analysis found seven liner fractures (5.3%) at a mean 32 months; all were non-traumatic and asymptomatic. Clinical risk factors for liner fracture were overweight, advanced age, dislocation, prosthetic impingement, increased postoperative offset was a radiologic risk factor. DISCUSSION AND CONCLUSION: Despite these satisfactory radioclinical results, matching those for metal-backed implants containing a polyethylene liner, close surveillance is mandatory with this type of composite implant. The high fracture rate with ceramic-polyethylene sandwich type liners and relative lack of symptoms warrant caution in their use. LEVEL OF EVIDENCE: Level IV, retrospective or historic series. PMID- 21813352 TI - Clinical outcomes of patients with plasma cell leukemia in the era of novel therapies and hematopoietic stem cell transplantation strategies: a single institution experience. AB - BACKGROUND: PCL carries a poor prognosis and the optimal management remains unknown. PATIENTS AND METHODS: To evaluate the outcome of patients with PCL in the era of novel agents and innovative transplantation strategies, we conducted a review of patients with PCL who were treated at our institution from August 2003 to October 2009. Our primary endpoint was to determine overall survival, which was calculated from time of PCL diagnosis to death or last follow-up. Secondary endpoints included response rates and analyses regarding how the novel agents and presence of adverse cytogenetic analyses affected outcomes. RESULTS: We identified 25 patients with PCL (13 with primary PCL [pPCL], 12 with secondary PCL [sPCL]) from our institution. Eighteen patients received bortezomib-based regimens, 19 received high-dose melphalan followed by autologous hematopoietic stem cell transplantation (HCT), and 6 underwent allogeneic HCT. The median overall survival for all patients was 23.6 months. Bortezomib-treated patients had a median survival of 28.4 months vs. 4.0 months for the non-bortezomib treated group (P < .001). CONCLUSIONS: Our analysis suggests that patients with PCL who were treated with bortezomib and/or allogeneic HCT had improved outcomes. PMID- 21813353 TI - The second European evidence-based consensus on the diagnosis and management of Crohn's disease (part 4). PMID- 21813354 TI - Travelling wave expansion: a model fitting approach to the inverse problem of elasticity reconstruction. AB - In this paper, a novel approach to the problem of elasticity reconstruction is introduced. In this approach, the solution of the wave equation is expanded as a sum of waves travelling in different directions sharing a common wave number. In particular, the solutions for the scalar and vector potentials which are related to the dilatational and shear components of the displacement respectively are expanded as sums of travelling waves. This solution is then used as a model and fitted to the measured displacements. The value of the shear wave number which yields the best fit is then used to find the elasticity at each spatial point. The main advantage of this method over direct inversion methods is that, instead of taking the derivatives of noisy measurement data, the derivatives are taken on the analytical model. This improves the results of the inversion. The dilatational and shear components of the displacement can also be computed as a byproduct of the method, without taking any derivatives. Experimental results show the effectiveness of this technique in magnetic resonance elastography. Comparisons are made with other state-of-the-art techniques. PMID- 21813355 TI - New investigator grants expand research opportunities. PMID- 21813356 TI - Rapid detection of small oscillation faults via deterministic learning. AB - Detection of small faults is one of the most important and challenging tasks in the area of fault diagnosis. In this paper, we present an approach for the rapid detection of small oscillation faults based on a recently proposed deterministic learning (DL) theory. The approach consists of two phases: the training phase and the test phase. In the training phase, the system dynamics underlying normal and fault oscillations are locally accurately approximated through DL. The obtained knowledge of system dynamics is stored in constant radial basis function (RBF) networks. In the diagnosis phase, rapid detection is implemented. Specially, a bank of estimators are constructed using the constant RBF neural networks to represent the training normal and fault modes. By comparing the set of estimators with the test monitored system, a set of residuals are generated, and the average L(1) norms of the residuals are taken as the measure of the differences between the dynamics of the monitored system and the dynamics of the training normal mode and oscillation faults. The occurrence of a test oscillation fault can be rapidly detected according to the smallest residual principle. A rigorous analysis of the performance of the detection scheme is also given. The novelty of the paper lies in that the modeling uncertainty and nonlinear fault functions are accurately approximated and then the knowledge is utilized to achieve rapid detection of small oscillation faults. Simulation studies are included to demonstrate the effectiveness of the approach. PMID- 21813357 TI - Convergence of cyclic and almost-cyclic learning with momentum for feedforward neural networks. AB - Two backpropagation algorithms with momentum for feedforward neural networks with a single hidden layer are considered. It is assumed that the training samples are supplied to the network in a cyclic or an almost-cyclic fashion in the learning procedure, i.e., in each training cycle, each sample of the training set is supplied in a fixed or a stochastic order respectively to the network exactly once. A restart strategy for the momentum is adopted such that the momentum coefficient is set to zero at the beginning of each training cycle. Corresponding weak and strong convergence results are then proved, indicating that the gradient of the error function goes to zero and the weight sequence goes to a fixed point, respectively. The convergence conditions on the learning rate, the momentum coefficient, and the activation functions are much relaxed compared with those of the existing results. PMID- 21813358 TI - lp-lq penalty for sparse linear and sparse multiple kernel multitask learning. AB - Recently, there has been much interest around multitask learning (MTL) problem with the constraints that tasks should share a common sparsity profile. Such a problem can be addressed through a regularization framework where the regularizer induces a joint-sparsity pattern between task decision functions. We follow this principled framework and focus on l(p)-l(q) (with 0 <= p <= 1 and 1 <= q <= 2) mixed norms as sparsity-inducing penalties. Our motivation for addressing such a larger class of penalty is to adapt the penalty to a problem at hand leading thus to better performances and better sparsity pattern. For solving the problem in the general multiple kernel case, we first derive a variational formulation of the l(1)-l(q) penalty which helps us in proposing an alternate optimization algorithm. Although very simple, the latter algorithm provably converges to the global minimum of the l(1)-l(q) penalized problem. For the linear case, we extend existing works considering accelerated proximal gradient to this penalty. Our contribution in this context is to provide an efficient scheme for computing the l(1)-l(q) proximal operator. Then, for the more general case, when , we solve the resulting nonconvex problem through a majorization-minimization approach. The resulting algorithm is an iterative scheme which, at each iteration, solves a weighted l(1)-l(q) sparse MTL problem. Empirical evidences from toy dataset and real-word datasets dealing with brain-computer interface single-trial electroencephalogram classification and protein subcellular localization show the benefit of the proposed approaches and algorithms. PMID- 21813359 TI - Adaptive neural output feedback controller design with reduced-order observer for a class of uncertain nonlinear SISO systems. AB - An adaptive output feedback control is studied for uncertain nonlinear single input-single-output systems with partial unmeasured states. In the scheme, a reduced-order observer (ROO) is designed to estimate those unmeasured states. By employing radial basis function neural networks and incorporating the ROO into a new backstepping design, an adaptive output feedback controller is constructively developed. A prominent advantage is its ability to balance the control action between the state feedback and the output feedback. In addition, the scheme can be still implemented when all the states are not available. The stability of the closed-loop system is guaranteed in the sense that all the signals are semiglobal uniformly ultimately bounded and the system output tracks the reference signal to a bounded compact set. A simulation example is given to validate the effectiveness of the proposed scheme. PMID- 21813360 TI - Minimising added classification error using Walsh coefficients. AB - Two-class supervised learning in the context of a classifier ensemble may be formulated as learning an incompletely specified Boolean function, and the associated Walsh coefficients can be estimated without the knowledge of the unspecified patterns. Using an extended version of the Tumer-Ghosh model, the relationship between added classification error and second-order Walsh coefficients is established. In this brief, the ensemble is composed of multilayer perceptron base classifiers, with the number of hidden nodes and epochs systematically varied. Experiments demonstrate that the mean second-order coefficients peak at the same number of training epochs as ensemble test error reaches a minimum. PMID- 21813361 TI - Upper bounds for energy harvesting in the region of the human head. AB - This paper investigates different approaches for supplying power to implantable hearing systems via energy harvesting. Because of the specific nature of the problem, only energy harvesting in the region of the human head is considered. Upper bounds as well as more conservative estimations for harvesting mechanical, thermal, and electromagnetic energy are presented and discussed. PMID- 21813362 TI - Multiscale modeling for image analysis of brain tumor studies. AB - Image-based modeling of tumor growth combines methods from cancer simulation and medical imaging. In this context, we present a novel approach to adapt a healthy brain atlas to MR images of tumor patients. In order to establish correspondence between a healthy atlas and a pathologic patient image, tumor growth modeling in combination with registration algorithms is employed. In a first step, the tumor is grown in the atlas based on a new multiscale, multiphysics model including growth simulation from the cellular level up to the biomechanical level, accounting for cell proliferation and tissue deformations. Large-scale deformations are handled with an Eulerian approach for finite element computations, which can operate directly on the image voxel mesh. Subsequently, dense correspondence between the modified atlas and patient image is established using nonrigid registration. The method offers opportunities in atlas-based segmentation of tumor-bearing brain images as well as for improved patient specific simulation and prognosis of tumor progression. PMID- 21813363 TI - Breakthroughs in computational modeling of cartilage regeneration in perfused bioreactors. AB - We report about two specific breakthroughs, relevant to the mathematical modeling and numerical simulation of tissue growth in the context of cartilage tissue engineering in vitro. The proposed models are intended to form the building blocks of a bottom-up multiscale analysis of tissue growth, the idea being that a full microscale analysis of the construct, a 3-D partial differential equation (PDE) problem with internal moving boundaries, is computationally unaffordable. We propose to couple a PDE microscale model of a single functional tissue subunit with the information computed at the macroscale by 2-D-0-D models of reduced computational cost. Preliminary results demonstrate the effectiveness of the proposed models in describing the interplay among interstitial perfusion flow, nutrient delivery, and consumption and tissue growth in realistic scaffold geometries. PMID- 21813364 TI - Agent-based modeling of the spread of influenza-like illness in an emergency department: a simulation study. AB - The objective of this paper was to develop an agent-based modeling framework in order to simulate the spread of influenza virus infection on a layout based on a representative hospital emergency department in Winnipeg, Canada. In doing so, the study complements mathematical modeling techniques for disease spread, as well as modeling applications focused on the spread of antibiotic-resistant nosocomial infections in hospitals. Twenty different emergency department scenarios were simulated, with further simulation of four infection control strategies. The agent-based modeling approach represents systems modeling, in which the emergency department was modeled as a collection of agents (patients and healthcare workers) and their individual characteristics, behaviors, and interactions. The framework was coded in C++ using Qt4 libraries running under the Linux operating system. A simple ordinary least squares (OLS) regression was used to analyze the data, in which the percentage of patients that became infected in one day within the simulation was the dependent variable. The results suggest that within the given instance context, patient-oriented infection control policies (alternate treatment streams, masking symptomatic patients) tend to have a larger effect than policies that target healthcare workers. The agent based modeling framework is a flexible tool that can be made to reflect any given environment; it is also a decision support tool for practitioners and policymakers to assess the relative impact of infection control strategies. The framework illuminates scenarios worthy of further investigation, as well as counterintuitive findings. PMID- 21813365 TI - A signal-to-noise crossover dose as the point of departure for health risk assessment. AB - BACKGROUND: The U.S. National Toxicology Program (NTP) cancer bioassay database provides an opportunity to compare both existing and new approaches to determining points of departure (PoDs) for establishing reference doses (RfDs). OBJECTIVES: The aims of this study were a) to investigate the risk associated with the traditional PoD used in human health risk assessment [the no observed adverse effect level (NOAEL)]; b) to present a new approach based on the signal to-noise crossover dose (SNCD); and c) to compare the SNCD and SNCD-based RfD with PoDs and RfDs based on the NOAEL and benchmark dose (BMD) approaches. METHODS: The complete NTP database was used as the basis for these analyses, which were performed using the Hill model. We determined NOAELs and estimated corresponding extra risks. Lower 95% confidence bounds on the BMD (BMDLs) corresponding to extra risks of 1%, 5%, and 10% (BMDL01, BMDL05, and BMDL10, respectively) were also estimated. We introduce the SNCD as a new PoD, defined as the dose where the additional risk is equal to the "background noise" (the difference between the upper and lower bounds of the two-sided 90% confidence interval on absolute risk) or a specified fraction thereof. RESULTS: The median risk at the NOAEL was approximately 10%, and the default uncertainty factor (UF = 100) was considered most applicable to the BMDL10. Therefore, we chose a target risk of 1/1,000 (0.1/100) to derive an SNCD-based RfD by linear extrapolation. At the median, this approach provided the same RfD as the BMDL10 divided by the default UF. CONCLUSIONS: Under a standard BMD approach, the BMDL10 is considered to be the most appropriate PoD. The SNCD approach, which is based on the lowest dose at which the signal can be reliably detected, warrants further development as a PoD for human health risk assessment. PMID- 21813366 TI - Low concentrations of bisphenol A induce mouse spermatogonial cell proliferation by G protein-coupled receptor 30 and estrogen receptor-alpha. AB - BACKGROUND: Bisphenol A (BPA) is one of the most prevalent chemicals in daily-use materials; therefore, human exposure to BPA is ubiquitous. The estrogenicity of BPA is generally mediated by nuclear estrogen receptors (ERs). However, low concentrations of BPA stimulate seminoma cell proliferation by an uncertain mechanism that does not involve activation of ERs. OBJECTIVE: We investigated the possible promoting effects of low-concentration BPA and the possible mechanism(s) using the murine ER-beta negative spermatogonial GC-1 cell line. METHODS AND RESULTS: Using the specific signaling inhibitor, BPA at test concentrations ranging from 10-10 to 10-8 M markedly induced proliferation of GC-1 cells by activating both cGMP-dependent protein kinase (PKG) and epidermal growth factor receptor (EGFR) extracellular regulated kinase (ERK) pathways. BPA stimulated a rapid (15-min) phosphorylation of the transcription factor cAMP response element binding protein (CREB) and the cell cycle regulator retinoblastoma protein (Rb). Interestingly, ER-alpha phosphorylation is involved in the proliferation, whereas BPA does not directly transactivate ER-alpha in gene reporter assays. Using specific agonists and gene silencing, we further observed that BPA mediates the proliferation and fos gene expression of GC-1 cells by G protein-coupled receptor 30 (GPR30) and ER-alpha. CONCLUSIONS: Our data suggest that low concentrations of BPA activate the PKG and EGFR/ERK/c-fos pathways through a cross-talk between GPR30 and ER-alpha, which in turn stimulates GC-1 cell proliferation. The present study provides a novel insight regarding the potential role of GPR30 and ER-alpha in mediating the proliferative effects of BPA in male germ cells. PMID- 21813367 TI - Retrospective exposure estimation and predicted versus observed serum perfluorooctanoic acid concentrations for participants in the C8 Health Project. AB - BACKGROUND: People living or working in eastern Ohio and western West Virginia have been exposed to perfluorooctanoic acid (PFOA) released by DuPont Washington Works facilities. OBJECTIVES: Our objective was to estimate historical PFOA exposures and serum concentrations experienced by 45,276 non-occupationally exposed participants in the C8 Health Project who consented to share their residential histories and a 2005-2006 serum PFOA measurement. METHODS: We estimated annual PFOA exposure rates for each individual based on predicted calibrated water concentrations and predicted air concentrations using an environmental fate and transport model, individual residential histories, and maps of public water supply networks. We coupled individual exposure estimates with a one-compartment absorption, distribution, metabolism, and excretion (ADME) model to estimate time-dependent serum concentrations. RESULTS: For all participants (n = 45,276), predicted and observed median serum concentrations in 2005-2006 are 14.2 and 24.3 ppb, respectively [Spearman's rank correlation coefficient (r(s)) = 0.67]. For participants who provided daily public well water consumption rate and who had the same residence and workplace in one of six municipal water districts for 5 years before the serum sample (n = 1,074), predicted and observed median serum concentrations in 2005-2006 are 32.2 and 40.0 ppb, respectively (r(s) = 0.82). CONCLUSIONS: Serum PFOA concentrations predicted by linked exposure and ADME models correlated well with observed 2005-2006 human serum concentrations for C8 Health Project participants. These individualized retrospective exposure and serum estimates are being used in a variety of epidemiologic studies being conducted in this region. PMID- 21813369 TI - Acceptance and tolerability of an adjuvanted nH1N1 vaccine in HIV-infected patients in the Cologne-Bonn cohort. AB - OBJECTIVE: To evaluate the acceptance and tolerability of the nH1N1 2009 vaccine in HIV-positive individuals. METHOD: 758 patients were included in this prospective study. Different study populations were formed: The Tolerability Study Group consists of HIV-infected patients who visited three outpatient clinics (Cologne, Bonn, Freiburg) during a predefined time period. Patients were offered nH1N1 vaccination. Those accepting were administered a standard dose AS03 adjuvant nH1N1 vaccine. Questionnaires to report side effects occurring within 7 days after immunization were handed out. In a substudy conducted during the same time period, acceptance towards immunization was recorded. This Acceptance Study Group consists of all HIV-infected patients visiting the Cologne clinic. They were offered vaccination. In case of refusal, motivation was recorded. RESULTS: In the Tolerability Study Group, a total of 475 patient diaries returned in the three study centres could be evaluated, 119 of those (25%) reported no side effects. Distribution of symptoms was as follows: Pain 285/475 patients (60%), swelling 96 (20%), redness 54 (11%), fever 48/475 (10%), muscle/joint ache 173 (36%), headache 127 (27%), and fatigue 210 (44%). Association of side effects with clinical data was calculated for patients in Cologne and Bonn. Incidence of side effects was significantly associated with CDC stages A, B compared to C, and with a detectable viral load (>50 copies/mL). No correlation was noted for CD4 cell count, age, gender or ethnicity. - In the Acceptance Study Group, 538 HIV infected patients were offered vaccination, 402 (75%) accepted, while 136 (25%) rejected. Main reasons for rejection were: Negative media coverage (35%), indecisiveness with preference to wait until a later date (23%), influenza not seen as personal threat (19%) and scepticism towards immunization in general (10%). CONCLUSION: A total of 622 HIV-infected patients were vaccinated against nH1N1-influenza in the three study centres. No severe adverse events were reported. The tolerability was in most parts comparable to general population. Acceptance rate towards influenza vaccination was high (75%). Those refusing the immunization mentioned negative media coverage as the major influence on their decision. PMID- 21813368 TI - Early-life soy exposure and gender-role play behavior in children. AB - BACKGROUND: Soy-based infant formula contains high levels of isoflavones. These estrogen-like compounds have been shown to induce changes in sexually dimorphic behaviors in animals exposed in early development. OBJECTIVE: We examined gender role play behavior in relation to soy-based and non-soy-based infant feeding methods among children in the Avon Longitudinal Study of Parents and Children. METHODS: We studied 3,664 boys and 3,412 girls. Four exposure categories were created using data from questionnaires administered at 6 and 15 months postpartum: primarily breast, early formula (referent), early soy, and late soy. Gender-role play behavior was assessed using the Pre-School Activities Inventory (PSAI). Associations between infant feeding and PSAI scores at 42 months of age were assessed using linear regression. Post hoc analyses of PSAI scores at 30 and 57 months were also conducted. RESULTS: Early-infancy soy use was reported for approximately 2% of participants. Mean [95% confidence interval (CI)] PSAI scores at 42 months were 62.3 (62.0, 62.6) and 36.9 (36.6, 37.2) for boys and girls, respectively. After adjustment, early soy (vs. early formula) feeding was associated with higher (less feminine) PSAI scores in girls (beta = 2.66; 95% CI: 0.19, 5.12) but was not significantly associated with PSAI scores in boys. The association between soy exposure and PSAI scores in girls was substantially attenuated at 30 and 57 months. CONCLUSIONS: Although not consistent throughout childhood, early-life soy exposure was associated with less female-typical play behavior in girls at 42 months of age. Soy exposure was not significantly associated with play behavior in boys. PMID- 21813370 TI - Development of a novel monoclonal antibody to B7-H4: characterization and biological activity. AB - OBJECTIVE: B7-H4, a member of the B7 family of immunoregulatory receptors, may participate in the negative regulation of cell-mediated immunity. Aberrant B7-H4 expression is detected in some tumors and it plays a role in the occurrence and development of tumors. The aim of this study was to elucidate the functional and structural properties of B7-H4. METHODS: We developed a monoclonal antibody (mAb) against the extracellular domain of B7-H4 through immunization of Balb/c mice with 3T3-mB7-H4 cells which expressed extrinsic B7-H4. A stable hybridoma cell line was established. Then, we analysed the characterization of the mAb through Enzyme linked immunosorbent assay (ELISA), Immunoprecipitation (IP), western blotting, Immunohistochemical (IHC), and tested the biological activity of the mAb. RESULTS: ELISA, IP, and western blotting analyses indicated that the mAb specifically recognized B7-H4. In addition, flow cytometry demonstrated that the mAb exhibits excellent reactivity when applied to leukemic cells. IHC staining revealed that the mAb stained in a predominantly diffuse plasmalemmal or cytoplasmic pattern when applied to certain tumor tissues. The preliminary results of the mAb's biological activity showed that the mAb could effectively inhibit the function of B7-H4 in the inhibition of T cell, while promoting the growth of T cells and the secretion of Interleukin-2 (IL-2), Interleukin-4 (IL 4), Interleukin-10 (IL-10) and Interferon-? (IFN-gamma). CONCLUSION: This mAb will be a valuable tool for the further investigation of B7-H4 function. PMID- 21813371 TI - New hepatitis C therapies in clinical development. AB - With the current standard of care for the treatment of chronic hepatitis C, a combination of pegylated interferon alfa and ribavirin, sustained virologic response rates can be achieved in approximately 50% of patients only. - Improved understanding of the viral life cycle has led to the identification of numerous potential targets for novel, direct-acting antiviral compounds. Inhibitors of the NS3/4A protease are currently the most advanced in clinical development. Recently completed phase 3 studies of the two protease inhibitors telaprevir and boceprevir, each given in combination with standard of care, yielded sustained virologic response rates in the range of 66-75% in treatment-naive patients and 59-66% in treatment-experienced patients with HCV genotype 1 infection. Studies of second-generation protease inhibitors, with the potential advantage of improved potency, drug metabolism and pharmacokinetics profile, are already underway. - Inhibitors of the HCV NS5A protein and NS5B polymerase are potentially active across different HCV genotypes and have shown promising antiviral efficacy in early clinical studies. Other emerging mechanisms include silymarin components and inhibitors of cell proteins required for HCV replication. - While improved formulations of current HCV therapies are also being developed, future hopes lie on the combination of direct-acting antivirals with the eventual possibility of interferon-free treatment regimens. PMID- 21813372 TI - Guideline-adherent initial intravenous antibiotic therapy for hospital acquired/ventilator-associated pneumonia is clinically superior, saves lives and is cheaper than non guideline adherent therapy. AB - INTRODUCTION: Hospital-acquired pneumonia (HAP) often occurring as ventilator associated pneumonia (VAP) is the most frequent hospital infection in intensive care units (ICU). Early adequate antimicrobial therapy is an essential determinant of clinical outcome. Organisations like the German PEG or ATS/ IDSA provide guidelines for the initial calculated treatment in the absence of pathogen identification. We conducted a retrospective chart review for patients with HAP/VAP and assessed whether the initial intravenous antibiotic therapy (IIAT) was adequate according to the PEG guidelines. MATERIALS AND METHODS: We collected data from 5 tertiary care hospitals. Electronic data filtering identified 895 patients with potential HAP/VAP. After chart review we finally identified 221 patients meeting the definition of HAP/VAP. Primary study endpoints were clinical improvement, survival and length of stay. Secondary endpoints included duration of mechanical ventilation, total costs, costs incurred on the intensive care unit (ICU), costs incurred on general wards and drug costs. RESULTS: We found that 107 patients received adequate initial intravenous antibiotic therapy (IIAT) vs. 114 with inadequate IIAT according to the PEG guidelines. Baseline characteristics of both groups revealed no significant differences and good comparability. Clinical improvement was 64% over all patients and 82% (85/104) in the subpopulation with adequate IIAT while only 47% (48/103) inadequately treated patients improved (p< 0.001). The odds ratio of therapeutic success with GA versus NGA treatment was 5.821 (p<0.001, [95% CI: 2.712-12.497]). Survival was 80% for the total population (n = 221), 86% in the adequately treated (92/107) and 74% in the inadequately treated subpopulation (84/114) (p = 0.021). The odds ratio of mortality for GA vs. NGA treatment was 0.565 (p=0.117, [95% CI: 0.276-1.155]). Adequately treated patients had a significantly shorter length of stay (LOS) (23.9 vs. 28.3 days; p = 0.022), require significantly less hours of mechanical ventilation (175 vs. 274; p = 0.001), incurred lower total costs (EUR 28,033 vs. EUR 36,139, p = 0.006) and lower ICU-related costs (EUR 13,308 vs. EUR 18,666, p = 0.003). Drug costs for the hospital stay were also lower (EUR 4,069 vs. EUR 4,833) yet not significant. The most frequent types of inadequate therapy were monotherapy instead of combination therapy, wrong type of penicillin and wrong type of cephalosporin. DISCUSSION: These findings are consistent with those from other studies analyzing the impact of guideline adherence on survival rates, clinical success, LOS and costs. However, inadequately treated patients had a higher complicated pathogen risk score (CPRS) compared to those who received adequate therapy. This shows that therapy based on local experiences may be sufficient for patients with low CPRS but inadequate for those with high CPRS. Linear regression models showed that single items of the CPRS like extrapulmonary organ failure or late onset had no significant influence on the results. CONCLUSION: Guideline-adherent initial intravenous antibiotic therapy is clinically superior, saves lives and is less expensive than non guideline adherent therapy. Using a CPRS score can be a useful tool to determine the right choice of initial intravenous antibiotic therapy. The net effect on the German healthcare system per year is estimated at up to 2,042 lives and EUR 125,819,000 saved if guideline-adherent initial therapy for HAP/VAP were established in all German ICUs. PMID- 21813373 TI - Analysis of clinical features of ocular presentation in cranial venous sinus thrombosis. AB - BACKGROUND: To recognize ocular presentations in cranial venous sinus thrombosis (CVST) which were easy to be misdiagnosis. DESIGN: Retrospective study. METHODS: Review clinical informations including general informations, general performances, and ocular presentations of 118 inpatients with CVST in the general hospital of chinese people's liberation army during 2005-2009. MAIN OUTCOME MEASURES: The ocular symptoms as the initial onset presentations or simultaneous phenomenon among different onset type patients were analyzed. RESULTS: Of all the CVST patients, 21.2% (25/118) presented with ocular symptom as the initial presentation, 30.5% (36/118) presented with ocular symptom as well as the other symptoms, and 48.3% (57/118) presented with non-ocular symptoms as the initial onset. The CVST patients were divided into 3 groups according to the onset type. There was no marked statistical significance among groups. The most common major complaints were blurring and degeneration of acute vision, accounting for 85.9% (61/71) of all abnormal ocular chief complaints. The most common objective sign in eyes was papilloedema, accounting for 48.3% (57/118) in this group of CVST patients. About 22.4% (13/58) showed acute vision deterioration at 1-year follow up, due to optic atrophy. CONCLUSIONS: As ophthalmologists, we should master the onset characteristics and clinical manifestations of CVST. Early diagnosis and treatment is very important for the prevention of vision deterioration, especially for patients with ocular syndrome as the initial onset syndrome. For isolated agnogenic intracranial hypertension, we should consider the possibility of CVST. PMID- 21813374 TI - Histopathological examination of newly-developed adhesive silicone denture relining material. AB - We aimed to evaluate the subcutaneous tissue reaction to a newly developed adhesive silicone denture relining material, SG, (Neo Dental Chemical Products Co., Ltd. Tokyo, Japan). We embedded the experimental material SG and another existing control material, Roeko Seal (RS), in the dorsal area of 22 male ddY mice. One week and 12 weeks after the embedding, the tissues surrounding the embedded materials were removed and a histopathological examination was performed. The results demonstrate that the basic histopathological aspects are the formation of granulation tissue and the change of the tissue to fibrous capsule over time. The results suggests that the newly-developed SG is safe as compared with the control RS, whose composition is similar. PMID- 21813375 TI - Strawberry gingivitis as the first presenting sign of Wegener's granulomatosis: report of a case. AB - Wegener's granulomatosis is a rare multi-system disease characterized by the classic triad of necrotizing granulomas affecting the upper and lower respiratory tracts, disseminated vasculitis and glomerulonephritis. Oral lesions as a presenting feature are only encountered in 2% of these cases. Hyperplastic gingival lesions or strawberry gingivitis, is a characteristic sign of Wegener's granulomatosis. The latter consists of reddish-purple exophytic gingival swellings with petechial haemorrhages thus resembling strawberries. Recognition of this feature is of utmost importance for timely diagnosis and definitive management of this potentially fatal disease. A case of strawberry gingivitis as the first presenting sign of Wegener's granulomatosis affecting a 50-year-old Malay male is reported here. The differential diagnosis of red lesions that may present in the gingiva is discussed. PMID- 21813376 TI - Progression of liver fibrosis in HIV/HCV genotype 1 co-infected patients is related to the T allele of the rs12979860 polymorphism of the IL28B gene. AB - OBJECTIVE: HIV/HCV co-infection is characterised by accelerated progression of liver disease. Recently, the rs12979860 C/T polymorphism in the IL28B gene has been linked to progression towards cirrhosis in HCV mono-infected patients and to treatment response of HCV-infection in HIV/HCV co-infected patients. Our aim was to clarify by non-invasive techniques if this polymorphism affects fibrosis progression in HIV/HCV co-infection. METHODS: In a cross-sectional design, liver stiffness (transient elastography), surrogate markers of liver fibrosis (APRI and FIB-4 scores) and rs12979860 genotypes were analysed in 84 HCV/HIV co-infected patients. IL28B genotypes were determined by real-time PCR using a light cycler. In 56 HIV/HCV co-infected patients we also studied progression of fibrosis in relation to rs12979860 C/T genotypes over two years. RESULTS: 82% of the patients were on HAART (74% without detectable HI viremia) and 67% were haemophiliacs, respectively. HCV genotype 1 was present in 62%. Cross-sectional median liver stiffness was 7.4 kPa and correlated with APRI and FIB-4 scores (r = 0.6 each, p < 0.001). Frequencies of IL28B genotypes were: CC 50%, CT 43% and TT 7%. In the cross-sectional analysis liver stiffness values were not different between the various IL28B-genotypes. Upon follow-up under HAART carriers of a C allele did not show further progression, while liver stiffness significantly increased in HIV/HCV co-infected patients with the T allele (p = 0.047). CONCLUSION: Although progression of liver fibrosis was low under HAART in our cohort, progression was more pronounced in HIV/HCV genotype 1 co-infected patients with the T allele. PMID- 21813377 TI - Long-term outcomes of liver transplant patients with human immunodeficiency virus infection and end-stage-liver-disease: single center experience. AB - OBJECTIVE: Orthotopic-liver-transplantation (OLT) in patients with Human Immunodeficiency-Virus infection (HIV) and end-stage-liver-disease (ESDL) is rarely reported. The purpose of this study is to describe our institutional experience on OLT for HIV positive patients. MATERIAL AND METHODS: This is a retrospective study of all HIV-infected patients who underwent OLT at the University Hospital of Essen, from January 1996 to December 2009. Age, sex, HIV transmission-way, CDC-stage, etiology of ESDL, concomitant liver disease, last CD4cell count and HIV-viral load prior to OLT were collected and analysed. Standard calcineurin-inhibitors-based immunosuppression was applied. All patients received anti-fungal and anti-pneumocystis carinii pneumonia prophylaxis post OLT. RESULTS: Eight transplanted HIV-infected patients with a median age of 46 years (range 35-61years) were included. OLT indications were HCV (n = 5), HBV (n = 2), HCV/HBV/HDV-related cirrhosis (n = 1) and acute liver-failure (n = 1). At OLT, CD4 cell-counts ranged from 113-621 cells/MUl, and HIV viral-loads from <50 175,000 copies/ml. Seven of eight patients were exposed to HAART before OLT. Patients were followed-up between 1-145 months. Five died 1, 3, 10, 31 and 34 months after OLT due to sepsis and graft-failure respectively. Graft-failure causes were recurrent hepatic-artery thrombosis, HCV-associated hepatitis and chemotherapy-induced liver damage due to Hodgkin-disease. One survivor is relisted for OLT due to recurrent chronic HCV-disease but non-progredient HIV infection 145 months post-OLT. Two other survivors show stable liver function and non-progredient HIV-disease under HAART 21 and 58 months post-OLT. CONCLUSIONS: OLT in HIV-infected patients and ESLD is an acceptable therapeutic option in selected patients. Long-term survival can be achieved without HIV disease progression under antiretroviral therapy and management of the viral hepatitis co infection. PMID- 21813378 TI - Idiopathic Recurrent Calcium Urolithiasis (IRCU): pathophysiology evaluated in light of oxidative metabolism, without and with variation of several biomarkers in fasting urine and plasma--a comparison of stone-free and -bearing male patients, emphasizing mineral, acid-base, blood pressure and protein status. AB - BACKGROUND: IRCU is traditionally considered as life?style disease (associations with, among others, overweight, obesity, hypertension, type-2 diabetes), arising from excess, in 24 h urine, of calcium (Ca) salts (calcium oxalate (CaOx), calcium phosphate (CaPi)), supersaturation of, and crystallization in, tubular fluid and urine, causing crystal-induced epithelial cell damage, proteinuria, crystal aggregation and uroliths. METHODS: Another picture emerges from the present uncontrolled study of 154 male adult IRCU patients (75 stone-bearing (SB) and 79 age-matched stone-free (SF)), in whom stone-forming and other parameters in fasting urine and plasma were contrasted with five biomarkers (see footnote) of oxidative metabolism (OM), without and with variation of markers. RESULTS: 1) In SB vs. SF unstratified OM biomarkers were statistically unchanged, but the majority of patients was overweight; despite, in SB vs. SF urine pH, total and non-albumin protein concentration were elevated, fractional urinary uric acid excretion and blood bicarbonate decreased, whereas urine volume, sodium, supersaturation with CaOx and CaPi (as hydroxyapatite) were unchanged; 2) upon variation of OM markers (strata below and above median) numerous stone parameters differed significantly, among others urine volume, total protein, Ca/Pi ratio, pH, sodium, potassium, plasma Ca/Pi ratio and parathyroid hormone, blood pressure, renal excretion of non-albumin protein and other substances; 3) a significant shift from SF to SB patients occurred with increase of urine pH, decrease of blood bicarbonate, and increase of diastolic blood pressure, whereas increase of plasma uric acid impacted only marginally; 4) in both SF and SB patients a strong curvilinear relationship links a rise of urine Ca/Pi to urine Ca/Pi divided by plasma Ca/Pi, but in SB urine Ca/Pi failed to correlate significantly with urine hydroxyapatite supersaturation; 5) also in SB, plasma Ca/Pi and urinary nitrate were negatively correlated, whereas in SF plasma Ca/Pi ratio, PTH and body mass index correlated positively; 6) multivariate regression analysis revealed that PTH, body mass index and nitrate together could explain 22 (p = 0.002) and only 7 (p = 0.06) per cent of variation of plasma Ca/Pi in SF and SB, respectively. CONCLUSIONS: In IRCU a) numerous constituents of fasting urine, plasma, blood and blood pressure change in response to variation of OM biomarkers, suggesting involvement of OM imbalance as factor in functional deterioration of tissue; b) in the majority of patients a positive exponential relationship links urine Ca/Pi to urine Ca/Pi divided by plasma Ca/Pi, presumably to accumulate Ca outside tubular lumen, thereby minimizing intratubular and urinary Ca salt crystallization; c) alteration of interactions of low urine nitrate, PTH and Ca/Pi in plasma may be of importance in formation of new Ca stone and co-regulation of dynamics of blood vasculature; d) overweight, combined with OM-modified renal interstitial environment appears to facilitate these processes, carrying the risk that CaPi mineral develops within or/and close to blood vessel tissue, and spreads towards urothelium. - For future research focussing on IRCU pathogenesis studies are recommended on the role of affluent lifestyle mediated renal ischemia, mild hypertensive nephropathy, rise of uric acid precursor oxypurines and uricemia, clarifying also why loss of significance of interrelationships of OM biomarkers with traditional Ca stone risk factors is characteristic for SB patients. PMID- 21813379 TI - PARP inhibition in atherosclerosis and its effects on dendritic cells, T cells and auto-antibody levels. AB - OBJECTIVE: Atherosclerosis is a chronic inflammatory process. Poly(ADP-ribose) polymerase-1 (PARP), a nuclear enzyme linked to DNA repair, has been shown to be involved in atherogenesis; however, the effects on dendritic cells, T cells and serum auto-antibody levels are not fully understood. METHODS: Male Apoe-/- mice on a western diet were treated with the PARP inhibitor INO-1001 (n = 15), while the control group (n = 15) received 5% glucose solution for 10 weeks. RESULTS: Inhibition of PARP markedly reduced atherosclerotic lesion development (p = 0.001). Immunohistochemistry and mRNA analysis revealed a reduced inflammatory compound inside the lesion. Focusing on dendritic cells, INO-1001 reduced number of cells (p = 0.04), grade of activation, represented by Il12 (p = 0.04) and Cd83 (p = 0.03), and grade of attraction, represented by Mip3alpha (p = 0.02) in the plaque. Furthermore, INO-1001 decreased number of T lymphocyte (p = 0.003) in the lesion and grade of activation after stimulation with oxLDL in vitro. Moreover, serum IgM antibody levels to oxLDL were significantly lower in INO-1001 treated mice (p = 0.03). CONCLUSIONS: Functional blockade of PARP by INO-1001 reduces atherosclerotic lesion development. The anti-atherogenic effect is beside already known mechanisms also moderated due to modulation of DC and T cell invasion and activation, DC attraction as well as IgM antibody levels to oxLDL. PMID- 21813380 TI - Transient hyperthyroidism after surgery for secondary hyperparathyroidism: a common problem. AB - BACKGROUND: Postoperative hyperthyroidism occurs in approximately one third of patients following parathyroidectomy due to primary hyperparathyroidism (PHP), but has only rarely been described in secondary hyperparathyroidism (SHP). The frequency, course, and laboratory markers of postoperative hyperthyroidism in SHP remain unknown. Our purpose was to evaluate the frequency and the clinical course of postoperative hyperthyroidism following surgery of SHP and to determine the diagnostic value of thyroglobulin in this setting. MATERIAL AND METHODS: A total of 40 patients undergoing parathyroidectomy because of SHP were included in this study. Thyroid stimulating hormone (TSH), free triiodothyronine (fT3), free thyroxine (fT4), and thyroglobulin (Tg) were determined one day before and on day 1, 3, 5, 10, and 40 after surgery. At each of these visits patients were clinically evaluated for signs or symptoms of hyperthyroidism. RESULTS: Biochemical evidence of hyperthyroidism was evident in 77% of patients postoperatively despite of preoperatively normal serum levels. TSH dropped from 1.18 +/- 0.06mU/L to 0.15 +/- 0.07mU/L (p = 0.0015). Free triiodothyronine (fT3) and fT4 levels increased from 2.86 +/- 0.02ng/L and 10.32 +/- 0.13ng/L, respectively, to their maximum of 4.83 +/- 0.17ng/L and 19.35 +/- 0.58ng/L, respectively. Thyroglobulin levels rose from 3.8 +/- 0.8ng/mL to 111.8 +/- 45.3ng/mL (p<0.001). At day 40 all thyroid related laboratory values were within normal range. Correlation analysis of postoperative values revealed significant correlations for lowest TSH (r = -0.32; p = 0.038), and highest fT3 (r = 0.55; p<0.001) and fT4 levels (r = 0.67; p<0.001) with Tg. CONCLUSION: Transient hyperthyroidism is frequent after parathyroidectomy for SHP with Tg being a suitable marker. Awareness of this self-limiting disorder is important to avoid inappropriate and potentially harmful treatment. PMID- 21813381 TI - Prognostic role of diabetes mellitus in hepatocellular carcinoma patients after curative treatments: a meta-analysis. AB - BACKGROUND: The prognostic role of diabetes mellitus (DM) coexisting with hepatocellular carcinoma (HCC) remains controversial. To clarify its impact on survival in HCC patients after curative treatments, a meta-analysis was performed. DATA SOURCES: Eligible studies were identified through multiple search strategies in the databases PubMed (MEDLINE), EMBASE, the Cochrane Library and ACP Journal Club between January 1950 and March 2010. Ten studies fulfilled the inclusion criteria, and data were aggregated comparing overall survival and recurrence-free survival in HCC patients according to DM status. RESULTS: The pooled hazard ratios (HRs) estimate for overall survival was 1.34 (95% CI, 1.18 1.51; P<0.0001) and for recurrence-free survival was 1.48 (95% CI, 1.00-2.18; P<0.0001), showing a worse survival for HCC with coexisting DM. However, the patients with DM had a shorter survival time in HCV-related HCC (HR=1.71; 95% CI, 1.10-2.66; P=0.016), while HBV-related cases were not significantly different (HR=1.29; 95% CI, 0.69-2.40; P=0.182). Meanwhile, the coexistence of DM impaired overall survival in HCC patients with a small tumor burden (HR=1.63; 95% CI, 1.25 2.12; P<0.0001). CONCLUSION: HCC patients with coexisting DM have a shorter survival time and a higher risk for tumor recurrence after curative treatments, while the precise value should be defined in more clinical trials with consistent methodology, especially prospective studies. PMID- 21813382 TI - Health-related quality of life in living liver donors after transplantation. AB - BACKGROUND: Living donor liver transplantation (LDLT) has recently emerged as an effective therapeutic alternative for patients with end-stage liver disease. In the meantime, the health-related quality of life (HRQoL) of the donors is becoming better appreciated. Here we aimed to review the current literature and summarize the effects of liver donation on the long-term HRQoL of living donors. DATA SOURCES: A literature search of PubMed using "donors", "living donor liver transplantation", "health-related quality of life", and "donation" was performed, and all the information was collected. RESULTS: The varied postoperative outcomes of liver donors are attributive to the different evaluation instruments used. On the whole, donors experienced good long-term physical and mental well-being with a few complaining of compromised quality of life due to mild symptoms or psychiatric problems. The psychosocial dimension has received increasing attention with the vocational, interpersonal and financial impact of liver donation on donors mostly studied. CONCLUSIONS: Generally, donors have a good HRQoL after LDLT. Nevertheless, to achieve an ideal donor outcome, further work is necessary to minimize the negative effects as well as to incorporate recent progress in regenerative medicine. PMID- 21813383 TI - Noninvasive indocyanine green plasma disappearance rate predicts early complications, graft failure or death after liver transplantation. AB - BACKGROUND: Early detection of graft malfunction or postoperative complications is essential to save patients and organs after orthotopic liver transplantation (OLT). Predictive tests for graft dysfunction are needed to enable earlier implementation of organ-saving interventions following transplantation. This study was undertaken to assess the value of indocyanine green plasma disappearance rates (ICG-PDRs) for predicting postoperative complications, graft dysfunction, and patient survival following OLT. METHODS: Eighty-six patients undergoing OLT were included in this single-centre trial. ICG-PDR was assessed daily for the first 7 days following OLT. Endpoints were graft loss or death within 30 days and postoperative complications, graft loss, or death within 30 days. RESULTS: Postoperative complications of 31 patients included deaths (12 patients) or graft losses. ICG-PDR was significantly different in patients whose endpoints were graft loss or death beginning from day 3 and in those whose endpoints were graft-loss, death, or postoperative complications beginning from day 4 after OLT. For day 7 measurements, receiver operating characteristic curve analysis revealed an ICG-PDR cut-off for predicting death or graft loss of 9.6% per min (a sensitivity of 75.0%, a specificity of 72.6%, positive predictive value 0.35, negative predictive value 0.94). For prediction of graft loss, death, or postoperative complications, the ICG-PDR cut-off was 12.3% per min (a sensitivity of 68.9%, a specificity of 66.7%, positive predictive value 0.57, negative predictive value 0.77). CONCLUSIONS: ICG-PDR measurements on postoperative day 7 are predictive of early patient outcomes following OLT. The added value over that of routinely determined laboratory parameters is low. PMID- 21813384 TI - Efficacy of liver transplantation for acute hepatic failure: a single-center experience. AB - BACKGROUND: Acute hepatic failure (AHF) is a devastating clinical syndrome with a high mortality rate. The outcome of AHF varies with etiology, but liver transplantation (LT) can significantly improve the prognosis and survival rate of such patients. This study aimed to detect the role of LT and artificial liver support systems (ALSS) for AHF patients and to analyze the etiology and outcome of patients with this disease. METHODS: A retrospective analysis was made of 48 consecutive patients with AHF who fulfilled the Kings College Criteria for LT at our center. We analyzed and compared the etiology, outcome, prognosis, and survival rates of patients between the transplantation (LT) group and the non transplantation (N-LT) group. RESULTS: AHF was due to viral hepatitis in 25 patients (52.1%; hepatitis B virus in 22), drug or toxic reactions in 14 (29.2%; acetaminophen in 6), Wilson disease in 4 (8.3%), unknown reasons in 3 (6.3%), and miscellaneous conditions in 2 (4.2%). In the LT group, 36 patients (7 underwent living donor LT, and 29 cadaveric LT) had an average model for end-stage liver disease score (MELD) of 35.7. Twenty-eight patients survived with good graft function after a follow-up of 27.3+/-4.5 months. During the waiting time, 6 patients were treated with ALSS and 2 of them died during hospitalization. The 30 day, 12-month, and 18-month survival rates were 77.8%, 72.2%, and 66.7%, respectively. In the N-LT group, 12 patients had an average MELD score of 34.5. Four patients were treated with ALSS and all died during hospitalization. The 90 day and 1-year survival rates were only 16.7% and 8.3%, respectively. CONCLUSIONS: Hepatitis is the most prominent cause of AHF at our center. Most patients with AHF, who fulfill the Kings College Criteria for LT, did not survive longer without LT. ALSS did not improve the prognosis of AHF patients, but may extend the waiting time for a donor. Currently, LT is still the most effective way to improve the prognosis of AHF patients. PMID- 21813385 TI - Risk factors of severe ischemic biliary complications after liver transplantation. AB - BACKGROUND: Ischemia-related biliary tract complications remain high after orthotopic liver transplantation. Severe ischemic biliary complications often involve the hepatic duct bifurcation and left hepatic duct, resulting finally in obstructive jaundice. Prevention and management of such complications remain a challenge for transplant surgeons. METHODS: All 160 patients were followed up for at least 180 days after transplantation. One-way analysis of variance (ANOVA) and comparative univariate analysis were made using 3 groups (no complications; mild complications; severe complications), to analyze risk factors associated with biliary complications. Multiple logistic regression and linear regression analysis were used to analyze independent risk factors for severe ischemic biliary complications, after excluding other confounding factors. RESULTS: By ANOVA and comparative univariate analysis, the risk factors associated with biliary complications were preoperative bilirubin level (P=0.007) and T-tube stenting of the anastomosis (P=0.016). Multiple logistic regression analysis showed that the use of T-tube and preoperative serum bilirubin were not independent risk factors for severe ischemic biliary complications after orthotopic liver transplantation. Chi-square analysis indicated that in the incidence of severe ischemic biliary lesions, bile duct second warm ischemic time longer than 60 minutes was a significant risk factor. Linear regression demonstrated a negative correlation between cold preservation time and warm ischemia time. CONCLUSIONS: Preoperative serum bilirubin level and the use of T tube stenting of the anastomosis were independent risk factors for biliary complications after liver transplantation, but not for severe ischemic biliary complications. The second warm ischemia time of bile duct longer than 60 minutes and prolonged bile duct second warm ischemia time combined with cold preservation time were significant risk factors for severe ischemic biliary complications after liver transplantation with grafts from non-heart-beating donors. PMID- 21813386 TI - Enteral supplementation with glycyl-glutamine improves intestinal barrier function after liver transplantation in rats. AB - BACKGROUND: Most patients after liver transplantation (LT) suffer from intestinal barrier dysfunction. Glycyl-glutamine (Gly-Gln) by parenteral supplementation is hydrolyzed to release glutamine, which improves intestinal barrier function in intestinal injury. This study aimed to investigate the effect of Gly-Gln by enteral supplementation on intestinal barrier function in rats after allogenetic LT under immunosuppressive therapy. METHODS: Twelve inbred Lewis rats were selected randomly as donors, and 24 inbred Brown Norway (BN) rats as recipients of allogenetic LT. The recipients were divided into a control group (Ala, n=12) and an experimental group (Gly-Gln, n=12). In each group, 6 normal BN rats were sampled for normal parameters on preoperative day 3. The 6 recipients in the control group received alanine (Ala) daily by gastric perfusion for 3 preoperative days and 7 postoperative days, and the 6 recipients in the experimental group were given Gly-Gln in the same manner. The 12 BN recipients underwent orthotopic LT under sterile conditions after a 3-day fast and were given immunosuppressive therapy for 7 days. They were harvested for sampling on postoperative day 8. The following parameters were assessed: intestinal mucosal protein content, mucosal ultrastructure, ileocecal sIgA content, portal plasma levels of endotoxin and TNF-alpha, and bacterial translocation. RESULTS: All recipients were alive after LT. On preoperative day 3, all parameters were similar in the two groups. On postoperative day 8, all parameters in the two groups were remarkably changed from those on preoperative day 3. However, compared to the Ala group, supplementation with Gly-Gln increased the levels of intestinal mucosal protein and ileocecal sIgA, improved mucosal microvilli, and decreased portal plasma levels of endotoxin and TNF-alpha as well as bacterial translocation. CONCLUSION: Enteral supplementation with Gly-Gln improved intestinal barrier function after allogenetic LT in rats. PMID- 21813387 TI - Donor liver natural killer cells alleviate liver allograft acute rejection in rats. AB - BACKGROUND: Liver enriched natural killer (NK) cells are of high immune activity. However, the function of donor liver NK cells in allogeneic liver transplantation (LTx) remains unclear. METHODS: Ten Gy of whole body gamma-irradiation (WBI) from a 60Co source at 0.6 Gy/min was used for depleting donor-derived leukocytes, and transfusion of purified liver NK cells isolated from the same type rat as donor (donor type liver NK cells, dtlNKs) through portal vein was performed immediately after grafting the irradiated liver. Post-transplant survival observation on recipients and histopathological detection of liver grafts were adoptive to evaluate the biological impact of donor liver NK cells on recipients' survival in rat LTx. RESULTS: Transfusion of dtlNKs did not shorten the survival time among the recipients of spontaneous tolerance model (BN to LEW rat) after rat LTx, but prolonged the liver graft survival among the recipients depleted of donor-derived leukocytes in the acute rejection model (LEW to BN rat). Compared to the recipients in the groups which received the graft depleted of donor-derived leukocytes, better survival and less damage in the allografts were also found among the recipients in the two different strain combinations of liver allograft due to transfusion of dtlNKs. CONCLUSIONS: Donor liver NK cells alone do not exacerbate liver allograft acute rejection. Conversely, they can alleviate it, and improve the recipients' survival. PMID- 21813388 TI - Portopulmonary hypertension and serum endothelin levels in hospitalized patients with cirrhosis. AB - BACKGROUND: Cirrhosis is associated with several extrahepatic manifestations including portopulmonary hypertension (PPHT). Recent data suggest that endothelins (ETs) are related to the pathophysiology of PPHT. The study aimed to measure serum ET levels in hospitalized cirrhotic patients and to determine their association with PPHT and patient outcome. METHODS: Fifty-seven cirrhotic patients [43 males; median age 58 (28-87) years] underwent Doppler echocardiography. Patients with systolic pulmonary arterial pressure >=40 mmHg and pulmonary acceleration time <100 ms were deemed to have PPHT. ET-1, 2, and 3 serum levels were measured with an ELISA assay. All-cause mortality was recorded over a median period of 24 months. RESULTS: Nine out of 57 patients (15.8%) had PPHT. Among various clinical variables, only autoimmune hepatitis was associated with PPHT (OR=11.5; 95% CI, 1.58-83.4; P=0.01). ET-1 levels [9.1 (1.6-20.7) vs 2.5 (1.4-9.2) pg/mL, P=0.02] and the ET-1/ET-3 ratio [4.73 (0.9-22.4) vs 1.6 (0.3 10.7), P=0.02] were significantly higher in patients with PPHT than in those without. ET-2 and ET-3 levels did not differ between the two groups. There was no difference in survival between the two groups, although ET-1 levels were associated with an adverse outcome in Cox regression analysis (HR=1.11; 95% CI, 1.02-1.22; P=0.02 per unit increase in ET-1). CONCLUSION: Our data suggest that ET-1 and the ET-1/ET-3 ratio are elevated in patients with PPHT and that ET-1 is associated with a poor outcome irrespective of PPHT. PMID- 21813389 TI - Hepatitis C virus infection and biological false-positive syphilis test: a single center experience. AB - BACKGROUND: Rapid plasma regain positive and/or treponema pallidum hemagglutination negative [RPR(+)/TPHA(-)] results were designated as biologic false-positive (BFP). There are limited data about BFP reactions against syphilis in patients with hepatitis C virus (HCV) infection. This study aimed to determine the prevalence of BFP reactions for syphilis in patients with HCV infection in a large sample and assess the relationship between BFP reactions and HCV infection. METHODS: A total of 2656 patients with positive anti-HCV and 5600 healthy control subjects were enrolled in this study. Hepatitis C serology was determined by a second generation ELISA test for HCV antibody. Syphilis serology was determined by the RPR test. Those subjects with reactive RPR positive underwent the TPHA test. Demographics and laboratory data were collected by trained clinicians. RESULTS: Among 2656 patients, 111 (4.2%) had a reactive RPR test. Of the 111 patients who were subjected to reactive RPR test, 30 (27.0%) showed HCV(+)/RPR(+). Of 5600 healthy controls, 80 (1.4%) had a reactive RPR test. Fourteen (17.5%) controls with HCV(-)/RPR(+) had a non-reactive TPHA test. These represented 1.1% of all HCV-positive and 0.3% of all HCV-negative subjects (P<0.001). A significantly increased prevalence shown by false-positive tests for syphilis was observed in elderly HCV-seropositive patients. BFP-HCV positive group had a higher prevalence of eosinophilia. The eosinophil abnormality was compared between the patients and controls (66.7% vs 21.4%, P=0.0043). No significant results were observed in antinuclear antibodies, antiphospholipid and complement (C3, C4) (P>0.05). CONCLUSIONS: The data of this study demonstrate that HCV infection is associated with a false-positive RPR test. In this study BFPs were significantly more common in HCV positive patients compared to HCV negative ones. Eosinophil abnormality can be considered as a predictor for BFP. Excessive BFPs must be considered in assessing the frequency of syphilis in a HCV positive population and the importance of the treponemal specific serologic test should be emphasized for a diagnosis of syphilis in such population. PMID- 21813390 TI - Success rate and complications of endoscopic extraction of common bile duct stones over 2 cm in diameter. AB - BACKGROUND: Clinically, common bile duct (CBD) stones >2 cm are difficult to remove by endoscopic retrograde cholangiopancreatography (ERCP). To evaluate this observation, the rates of successful clearance of CBD stones and complications were compared between ERCP extraction of CBD stones of >2 cm and <2 cm in diameter. METHODS: All patients who had undergone endoscopic extraction of CBD stones at the Endoscopy Center of Shanghai First People's Hospital from May 2004 to May 2008 were reviewed. Patients with CBD stones of >2 cm in diameter were enrolled in the >2 cm group. Two matched controls with CBD stones of <2 cm in diameter were selected for each enrolled patient (<2 cm group). Patient characteristics, success rates, and complications during and after ERCP were compared. RESULTS: Seventy-two patients constituted the >2 cm group and 144 patients were in the <2 cm group. No significant differences were found in the patient characteristics, except for stone size and CBD diameter. Both the overall success rate and the success rate in the first ERCP session were lower in the >2 cm group (77.8% and 58.3%, respectively) than in the <2 cm group (91.7% and 83.3%, P<0.01). During ERCP, the incidence of hypoxemia (30.6%) and hemorrhaging papillae (18.1%) in the >2 cm group was higher than in the <2 cm group (13.2% and 6.3%, P<0.05). After ERCP, the rates of delayed papillae hemorrhage (13.9%), hyperamylasemia (23.6%), acute pancreatitis (8.3%) and biliary infection (18.1%) were higher in the >2 cm group than in the <2 cm group (3.5%, 11.1%, 2.1%, and 2.8%, respectively, P<0.05). CONCLUSION: The success rate of endoscopic extraction of CBD stones of >2 cm in diameter was lower but the complication rate was higher than that of stones of <2 cm in diameter. PMID- 21813391 TI - Expression profile of cholecystokinin type-A receptor in gallbladder cancer and gallstone disease. AB - BACKGROUND: Regulatory peptide receptors have attracted the interest of oncologists as a new promising approach for cancer pathology, imaging and therapy. Although cholecystokinin (CCK) is a potent modulator of gallbladder contractility and plays a potential role in pancreatic carcinogenesis through CCK type-A receptor (CCKAR), its role in gallbladder cancer (GBC) is still unknown and immunohistochemical detection of CCKAR in the gallbladder has not yet been reported. This novel case-control study aimed to investigate the expression profile of CCKAR in GBC and gallstone disease (GSD). METHODS: This study included 162 samples of gallbladder: 94 from GBC and 68 from GSD. Expression of CCKAR was analyzed by immunohistochemistry and immunoblotting. The results were statistically correlated with disease history including age, sex, presence of gallstone, stage and differentiation. RESULTS: CCKAR was positive in 30/68 (44.1%) of GSD and 72/94 (76.6%) of GBC samples. Fifty-one of the 72 (70.8%) CCKAR-positive GBC samples showed over-expression. Interestingly, consistent results also appeared in the immunoblotting study. CONCLUSIONS: CCKAR expression was significantly increased in GBC compared to GSD. Moreover, CCKAR expression was associated with the degree of tumor differentiation, i.e., less expression in poorly-differentiated tumors. Thus, it has future prognostic and therapeutic implications in the management of GBC. PMID- 21813392 TI - One hundred and seventy-eight consecutive pancreatoduodenectomies without mortality: role of the multidisciplinary approach. AB - BACKGROUND: Pancreatoduodenectomy offers the only chance of cure for patients with periampullary cancers. This, however, is a major undertaking in most patients and is associated with a significant morbidity and mortality. A multidisciplinary approach to the workup and follow-up of patients undergoing pancreatoduodenectomy was initiated at our institution to improve the diagnosis, resection rate, mortality and morbidity. We undertook the study to assess the effect of this approach on diagnosis, resection rates and short-term outcomes such as morbidity and mortality. METHODS: A prospective database of patients presenting with periampullary cancers to a single surgeon between April 2004 and April 2010 was reviewed. All cases were discussed at a multidisciplinary meeting comprising surgeons, gastroenterologists, radiologists, oncologists, radiation oncologists, pathologists and nursing staff. A standardized investigation and management algorithm was followed. Complications were graded according to the Clavien-Dindo classification. RESULTS: A total of 295 patients with a periampullary lesion were discussed and 178 underwent pancreatoduodenectomy (resection rate 60%). Sixty-one patients (34%) required either a vascular or an additional organ resection. Eighty-nine patients experienced complications, of which the commonest was blood transfusion (12%). Thirty-four patients (19%) had major complications, i.e. grade 3 or above. There was no in-hospital, 30-day or 60-day mortality. CONCLUSIONS: Pancreatoduodenectomy can safely be performed in high-volume centers with very low mortality. The surgeon's role should be careful patient selection, intensive preoperative investigations, use of a team approach, and an unbiased discussion at a multidisciplinary meeting to optimize the outcome in these patients. PMID- 21813393 TI - Combined invagination and duct-to-mucosa techniques with modifications: a new method of pancreaticojejunal anastomosis. AB - BACKGROUND: Soft pancreatic texture and a small main pancreatic duct are thought to be the most significant risk factors for the occurrence of pancreatic fistula (PF), a common and serious complication after pancreaticoduodenectomy (PD). This is in part due to the technical difficulties of pancreaticojejunostomy (PJ) posed by a soft gland with a normal-sized duct. To deal with this problem, we developed a new anastomotic technique which combines the two most widely used techniques, namely, the invagination technique and the duct-to-mucosa technique, with a modification of the suture route and insertion of a temporary stent tube. METHODS: Between January 2003 and December 2009, ninety-two consecutive patients underwent PD in which the new PJ technique was used. Charts and follow-up data of these patients were reviewed for operative details, early postoperative events, and outcomes at 6 months after the operation. PF was defined by the International Study Group on Pancreatic Fistula (ISGPF) guidelines and graded (A, B or C) according to the clinical procedures and outcome. RESULTS: In this group of 92 patients, there was only 1 early death from acute renal failure. PF was observed in 11 patients (12.0%), 8 in grade A, 1 in grade B, and 2 in grade C. For the 2 patients in grade C, PF was surgically managed. There were no early or late deaths attributable to PF. Six months after the operation, all of the patients were free of PJ-related symptoms except for 2, who were found to have steatorrhea. CONCLUSIONS: Our modified technique is simple and safe in PD. Present data suggest that this technique produces excellent early and medium-term results. PMID- 21813394 TI - Expression of CD44, CD24 and ESA in pancreatic adenocarcinoma cell lines varies with local microenvironment. AB - BACKGROUND: Emerging evidence suggests that pancreatic adenocarcinoma is hierarchically organized and sustained by pancreatic cancer stem cells. Furthermore, elimination of these cells is possible and therapeutically relevant. This study aimed to investigate the expression patterns of pancreatic cancer stem cell surface markers CD44, CD24 and ESA in pancreatic adenocarcinoma cell lines and explore the influence of their local microenvironment. METHODS: Flow cytometry was used to analyze the expression patterns of CD44, CD24 and ESA in five pancreatic adenocarcinoma cell lines (PANC-1, PC-2, MIA-Paca-2, AsPC-1 and BxPC-3). In addition, the capacity for sphere-formation in serum-free medium of four cell lines (PANC-1, PC-2, MIA-Paca-2 and BxPC-3) was assessed. Then, the same assays were performed when tumor cell spheres were developed. The role of sonic hedgehog (SHH) in cell spheres from PANC-1 and MIA-Paca-2 were also assessed by RT-PCR. RESULTS: CD44 and CD24 were detected in PANC-1. Only CD44 expression was detected in PC-2, MIA-Paca-2 and AsPC-1. CD44, CD24 and ESA were all detected in BxPC-3. Tumor cell spheres developed in PANC-1 and MIA-Paca-2 in serum-free medium. This was accompanied by an increase in CD24 expression and a decrease in CD44 expression in PANC-1. Interestingly, the expression of CD44 and CD24 returned to initial levels once the medium was changed back from serum-free to serum-containing medium. No significant change in the expression of CD44 was detected in MIA-Paca-2. Furthermore, the relative quantification of SHH mRNA in PANC-1 cell spheres was significantly higher than that in cells cultured in the serum-containing medium. CONCLUSION: The expression patterns of the pancreatic cancer stem cell surface markers CD44, CD24 and ESA were diverse in different pancreatic adenocarcinoma cell lines and changed with their local microenvironment. PMID- 21813395 TI - Surgical treatment of Budd-Chiari syndrome: analysis of 221 cases. AB - BACKGROUND: Budd-Chiari syndrome (B-CS) refers to post-hepatic portal hypertension and/or inferior vena cava hypertension caused by obstruction of blood flow at the portal cardinal hepatic vein. The treatments of B-CS include operations on pathological membrane lesions, shunting and combined operations. Studies have shown that China, Japan, India and South Africa have a high incidence of B-CS. In China, the Yellow River Basin in Henan, Shandong, Jiangsu and Anhui Provinces also have a high incidence, around 10 per 100 000. METHODS: The clinical data of 221 B-CS patients were analyzed retrospectively. We focused on pathological types, surgical methods, effectiveness and complications of treatment, and follow-up. RESULTS: Based on imaging findings such as color ultrasonography, angiography or magnetic resonance angiography, the 221 patients were divided into 3 types (five subtypes): type Ia (72 patients), type Ib (20), type II (72), type IIIa (33), and type IIIb (24). Surgical procedures included balloon membranotomy with or without stent (65 patients), improved splenopneumopexy (18), radical resection of membrane and thrombus (17), inferior vena cava bypass [29, with cavocaval transflow (13) and cavoatrial transflow (16)], mesocaval shunt (41), splenocaval shunt (25), splenoatrial shunt (12), splenojugular shunt (6), and combined methods (8). The complication rate was 9.05% (20/221) and the perioperative death rate was 2.26% (5/221). All of the patients were followed up from 6 months to 5 years. The success rate was 84.6% (187/221), and the recurrence rate was 8.9% (9/101) and 13.5% (13/96) after 1- and 5-year follow-up, respectively. CONCLUSION: The rational choice of surgical treatment based on B-CS pathological typing may increase the success rate and decrease the recurrence. PMID- 21813396 TI - Large regenerative nodules in a patient with Budd-Chiari syndrome after TIPS positioning while on the liver transplantation list diagnosed by Gd-EOB-DTPA MRI. AB - BACKGROUND: Large regenerative nodules (LRNs) are hyperplastic benign nodules most commonly associated with Budd-Chiari syndrome (BCS), caused by outflow obstruction of the hepatic veins or vena cava. To our knowledge, no cases of LRNs arising in BCS after transjugular intrahepatic portosystemic shunt (TIPS) positioning and detected by Gd-EOB-DTPA MRI have been reported in the literature. METHODS: A 58-year-old woman with BCS, on the liver transplantation (LT) list, underwent a follow-up enhanced MRI. Two years earlier, a TIPS had been placed. In 2008, recurrent hepaticoencephalopathy resistant to medical treatment fulfilled the LT criteria for BCS treated with TIPS and the patient was therefore added to the LT list. CT performed before TIPS had not detected any hepatic lesions. CT performed six months after TIPS showed its complete patency but documented two indeterminate hypervascular liver lesions. RESULTS: MRI performed with Gd-EOB DTPA revealed additional hypervascular lesions with uptake and retention of the medium in the hepatobiliary phase, thus reflecting a benign behavior of hepatocellular composition. These MRI features were related to LRNs as confirmed by histopathologic analysis. CONCLUSIONS: Gd-EOB-DTPA-enhanced MRI is potentially superior to standard imaging using gadolinium chelates or spiral CT, especially for the differential diagnosis of hypervascular lesions. Gd-EOB-DTPA MRI may become the imaging method of choice for evaluating LT list patients with BCS after TIPS placement. PMID- 21813397 TI - Follicular dendritic cell sarcoma of the liver: unusual presentation of a rare tumor and literature review. AB - BACKGROUND: Hepatic follicular dendritic cell (FDC) sarcoma is an extremely rare neoplasm. Most commonly, FDC sarcoma presents as a solitary mass in lymph nodes, however, several extra-nodal locations have been identified. METHODS: We report a case of a 53-year-old female who presented with symptoms of abdominal pain, fever, anemia, and jaundice. After an extensive review of the literature, we have found only 12 cases of hepatic FDC sarcoma. RESULTS: The tumor was 11.5 cm in diameter and composed of spindle and epithelioid cells with ovoid nuclei and associated with mixed inflammatory infiltrate. Immunohistochemical stains were positive for CD35 and CD21. The patient underwent a left hepatic lobectomy. CONCLUSIONS: Liver follicular dendritic cell sarcoma is a very rare tumor. Most cases present with abdominal pain and weight loss, and most of them can be managed by hepatic resection with excellent short-term outcomes. PMID- 21813398 TI - Rat performance on visual detection task modeled with divisive normalization and adaptive decision thresholds. AB - Performance on any perceptual task depends on both the perceptual capacity and the decision strategy of the subject. We provide a model to fit both aspects and apply it to data from rats performing a detection task. When rats must detect a faint visual target, the presence of other nearby stimuli ("flankers") increases the difficulty of the task. In this study, we consider two specific factors. First, flankers could diminish the sensory response to the target via spatial contrast normalization in early visual processing. Second, rats may treat the sensory signal caused by the flankers as if it belonged to the target. We call this source confusion, which may be sensory, cognitive, or both. We account for contrast normalization and source confusion by fitting model parameters to the likelihood of the observed behavioral data. We test multiple combinations of target and flanker contrasts using a yes/no detection task. Contrast normalization was crucial to explain the rats' flanker-induced detection impairment. By adding a decision variable to the contrast normalization framework, our model provides a new tool to assess differences in visual or cognitive brain function between normal and abnormal rodents. PMID- 21813400 TI - ER stress and its functional link to mitochondria: role in cell survival and death. AB - The endoplasmic reticulum (ER) is the primary site for synthesis and folding of secreted and membrane-bound proteins. Proteins are translocated into ER lumen in an unfolded state and require protein chaperones and catalysts of protein folding to assist in proper folding. Properly folded proteins traffic from the ER to the Golgi apparatus; misfolded proteins are targeted to degradation. Unfolded protein response (UPR) is a highly regulated intracellular signaling pathway that prevents accumulation of misfolded proteins in the ER lumen. UPR provides an adaptive mechanism by which cells can augment protein folding and processing capacities of the ER. If protein misfolding is not resolved, the UPR triggers apoptotic cascades. Although the molecular mechanisms underlying ER stress induced apoptosis are not completely understood, increasing evidence suggests that ER and mitochondria cooperate to signal cell death. Mitochondria and ER form structural and functional networks (mitochondria-associated ER membranes [MAMs]) essential to maintain cellular homeostasis and determine cell fate under various pathophysiological conditions. Regulated Ca(2+) transfer from the ER to the mitochondria is important in maintaining control of prosurvival/prodeath pathways. We discuss the signaling/communication between the ER and mitochondria and focus on the role of the mitochondrial permeability transition pore in these complex processes. PMID- 21813399 TI - Structure of Golgi transport proteins. AB - The function of the Golgi has long been recognized to critically depend on vesicular transport from, to, and within its cisternae, involving constant membrane fission and fusion. These processes are mediated by Arf GTPases and coat proteins, and Rabs, tethers and SNARE proteins, respectively. In this article, we describe structural studies of Golgi coats and tethers and their interactions with SNAREs and GTPases as well as insights regarding membrane traffic processes that these have provided. PMID- 21813402 TI - Characterization of operator learning curve for transradial coronary interventions. AB - BACKGROUND: Transradial percutaneous coronary intervention (TR-PCI) improves clinical outcomes compared to the transfemoral (TF) approach. However, inadequate training and experience has limited widespread adoption by interventional cardiologists. METHODS AND RESULTS: Clinical and procedural characteristics for TR-PCI were prospectively collected from 1999 to 2008. To identify minimum case volume for optimum clinical benefit, single-vessel TR-PCI cases were chronologically ranked and stratified into 1 to 50, 51 to 100, 101 to 150 and 151 to 300 case volume groups for operators starting the TR approach at the study institution. Cases by operators with a >300 TR-PCI case volume comprised the control group. TR-PCI failure rates, contrast use, guide usage, and fluoroscopy time were compared among groups. A total of 1672 patients underwent TR-PCI by 28 operators. TR-PCI failure occurred in 4% and was higher in the 1 to 50 case volume group compared to the 51 to 100 (P=0.007) and control (P=0.01) groups. Contrast use was greater in the 1 to 50 group (180+/-79 mL) compared to the 151 to 300 (157+/-75 mL, P=0.02) and control (168+/-79 mL, P=0.05) groups. Fluoroscopy time was higher in the 1 to 50 group (15+/-10 minutes) compared to the 101 to 150 (13+/-10 minutes, P=0.04) and control (12+/-9 minutes, P=0.02) groups. Reasons for TR-PCI failure included spasm (38%), subclavian tortuousity (16%), poor guide support (16%), failed access (10%), and radial loop (7%). Case volume was significantly correlated with TR-PCI failure (beta=-0.0076, P=0.0028), and odds of failure was reduced by 32% for each 50 increments in case volume. CONCLUSIONS: TR-PCI success depends on operator experience, and a case volume of >=50 cases is required to achieve outcomes comparable to experienced operators. These findings have implications both for PCI operators looking to expand their skills and for defining standards for training. PMID- 21813401 TI - Golgi and related vesicle proteomics: simplify to identify. AB - Despite more than six decades of successful Golgi research, the fundamental question as to how biosynthetic material is transported through the secretory pathway remains unanswered. New technologies such as live cell imaging and correlative microscopy have highlighted the plastic nature of the Golgi, one that is sensitive to perturbation yet highly efficient in regaining both structure and function. Single molecule-microscopy and super resolution-microscopy further adds to this picture. Various models for protein transport have been put forward, each with its own merits and pitfalls but we are far from resolving whether one is more correct than the other. As such, our laboratory considers multiple mechanisms of Golgi transport until proven otherwise. This includes the two classical modes of transport, vesicular transport and cisternal progression/maturation as well as more recent models such as tubular inter- and intra-cisternal connections (long lasting or transient) and inter-Golgi stack transport. In this article, we focus on an emerging inductive technology, mass spectrometry-based proteomics that has already enabled insight into the relative composition of compartments and subcompartments of the secretory pathway including mechanistic aspects of protein transport. We note that proteomics, as with any other technology, is not a stand-alone technology but one that works best alongside complementary approaches. PMID- 21813403 TI - Impact of sirolimus-eluting stent fracture on 4-year clinical outcomes. AB - BACKGROUND: Although stent fracture (SF) after sirolimus-eluting stent (SES) implantation has been recognized as one of the predisposing factors of in-stent restenosis, it remains uncertain whether SF can increase the risk of major adverse cardiac events (MACE), especially beyond 1 year after SES implantation. The aim of this study was to assess the impact of SF relative to non-SF on 4-year clinical outcomes after treatment with SES of comparable unselected lesions. METHODS AND RESULTS: A total of 874 lesions in 793 patients undergoing SES implantation and subsequent angiography 6 to 9 months after index procedure were analyzed. At 6- to 9-month angiographic follow-up, SF was identified in 70 of 874 lesions (8.0%). In-stent late loss was significantly higher in SF lesions versus non-SF lesions (0.42+/-0.59 mm versus 0.13+/-0.49 mm, P<0.001), resulting in a significantly higher in-stent restenosis rate (21.4% versus 4.1%, P<0.001). At 4 years, SF versus non-SF was associated with a significantly higher MACE rate (23.2% versus 12.6%, P=0.014), mainly driven by significantly higher target lesion revascularization (18.8% versus 10.2%, P=0.029) rate. Adverse effects of SF on clinical outcomes occurred mostly within the first year (17.4% versus 6.6%, P=0.001), with similar MACE rate between 1 and 4 years (5.8% versus 5.9%, P=0.611). No significant differences between SF versus non-SF patients were observed in the cumulative frequency of very late stent thrombosis (2.9% versus 1.4%, P=0.281), death (0% versus 2.1%, P=0.252), or myocardial infarction (5.8% versus 2.9%, P=0.165). CONCLUSIONS: SF of SES was associated with higher MACE rate up to 1 year, mainly driven by higher target-lesion revascularization, whereas no significant association was evident between years 1 and 4. PMID- 21813405 TI - Mammary gland density predicts the cancer inhibitory activity of the N-3 to N-6 ratio of dietary fat. AB - This study investigated the effect of a broad range of dietary ratios of n-3:n-6 fatty acids on mammary gland density and mammary cancer risk. Cancer was induced in female rats by N-methyl-N-nitrosourea. Purified diet that provided 30% of dietary kilocalories from fat was formulated to contain ratios of n-3:n-6 fatty acids from 25:1 to 1:25. Mammary gland density was determined by digital analysis, fatty acids by gas chromatography/flame ionization detection, and other plasma analytes via ELISA. Mammary gland density was reduced dose dependently at n-3:n-6 ratios from 1:1 to 25:1 (r = -0.477, P = 0.038), with a 20.3% decrease of mammary gland density between n-3:n-6 of 1:1 versus 25:1, P < 0.001. Mammary carcinogenesis was inhibited in the absence or presence of tamoxifen (1 mg/kg diet) in a manner predicted by mammary gland density. Plasma n-3 fatty acid concentrations failed to increase above an n-3:n-6 ratio of 5:1, and changes in specific plasma n-3 or n-6 fatty acids were not predictive of mammary gland density or cancer inhibitory activity. A strong reciprocal effect of the n-3:n-6 ratio on plasma leptin (decreased, P = 0.005) and adiponectin (increased, P < 0.001) was observed indicating adipose tissue function was modulated. However, neither cytokine was predictive of mammary gland density. Plasma insulin-like growth factor I (IGF-I) decreased with increasing dietary n-3:n-6 ratio (P = 0.004) and was predictive of the changes in mammary gland density (r = 0.362, P < 0.005). These findings indicate that (i) mammary gland density predicted the carcinogenic response, (ii) the n-3:n-6 ratio exerts effects in the presence or absence of hormonal regulation of carcinogenesis, and (iii) signaling pathways regulated by IGF-I are potential targets for further mechanistic investigation. PMID- 21813404 TI - Postmenopausal serum sex steroids and risk of hormone receptor-positive and negative breast cancer: a nested case-control study. AB - Prediagnostic endogenous sex steroid hormone levels have well established associations with overall risk of breast cancer. While evidence toward the existence of distinct subtypes of breast cancer accumulates, few studies have investigated the associations of sex steroid hormone levels with risk of hormone receptor [estrogen receptor (ER) and/or progesterone receptor (PR)] defined breast cancer. In a case-control study nested within the EPIC cohort (European Prospective Investigation into Cancer and Nutrition), estradiol, testosterone, and sex hormone-binding globulin levels were measured in prediagnostic serum samples from postmenopausal women not using hormone replacement therapy at blood donation. A total of 554 women who developed invasive breast cancer with information on receptor status were matched with 821 control subjects. Conditional logistic regression models estimated breast cancer risk with hormone concentrations according to hormone receptor status of the tumor. Sex steroid hormones were associated with risks of not only ER+PR+ breast cancer [estradiol OR for highest vs. lowest tertile = 2.91 (95% CI: 1.62-5.23), P(trend) = 0.002; testosterone OR = 2.27 (95% CI: 1.35-3.81), P(trend) = 0.002] but also of ER-PR- breast cancer [estradiol OR = 2.11 (95% CI: 1.00-4.46), P(trend) = 0.05; testosterone OR = 2.06 (95% CI: 0.95-4.46), P(trend) = 0.03], with associations appearing somewhat stronger in the receptor-positive disease. Serum androgens and estrogens are associated with risks of both hormone receptor-negative as well as receptor-positive breast tumors. Further research is needed to establish through which molecular pathways, and during which evolutionary stages of development, androgens and estrogens can promote the occurrence of both receptor-positive and negative clinical breast tumors. PMID- 21813406 TI - Lung cancer risk prediction to select smokers for screening CT--a model based on the Italian COSMOS trial. AB - Screening with low-dose helical computed tomography (CT) has been shown to significantly reduce lung cancer mortality but the optimal target population and time interval to subsequent screening are yet to be defined. We developed two models to stratify individual smokers according to risk of developing lung cancer. We first used the number of lung cancers detected at baseline screening CT in the 5,203 asymptomatic participants of the COSMOS trial to recalibrate the Bach model, which we propose using to select smokers for screening. Next, we incorporated lung nodule characteristics and presence of emphysema identified at baseline CT into the Bach model and proposed the resulting multivariable model to predict lung cancer risk in screened smokers after baseline CT. Age and smoking exposure were the main determinants of lung cancer risk. The recalibrated Bach model accurately predicted lung cancers detected during the first year of screening. Presence of nonsolid nodules (RR = 10.1, 95% CI = 5.57-18.5), nodule size more than 8 mm (RR = 9.89, 95% CI = 5.84-16.8), and emphysema (RR = 2.36, 95% CI = 1.59-3.49) at baseline CT were all significant predictors of subsequent lung cancers. Incorporation of these variables into the Bach model increased the predictive value of the multivariable model (c-index = 0.759, internal validation). The recalibrated Bach model seems suitable for selecting the higher risk population for recruitment for large-scale CT screening. The Bach model incorporating CT findings at baseline screening could help defining the time interval to subsequent screening in individual participants. Further studies are necessary to validate these models. PMID- 21813407 TI - Targeting the right treatments for neuroblastoma. PMID- 21813408 TI - Semantic Web may be cancer information's next step forward. PMID- 21813409 TI - Assessing survivorship care plans. PMID- 21813410 TI - StatBite. Neuroblastoma: five-year survival. PMID- 21813411 TI - Government programs to support pediatric research. PMID- 21813414 TI - Severe peripheral arterial disease during nilotinib therapy. PMID- 21813412 TI - The role of p27(Kip1) in dasatinib-enhanced paclitaxel cytotoxicity in human ovarian cancer cells. AB - BACKGROUND: Less than 50% of ovarian cancers respond to paclitaxel. Effective strategies are needed to enhance paclitaxel sensitivity. METHODS: A library of silencing RNAs (siRNAs) was used to identify kinases that regulate paclitaxel sensitivity in human ovarian cancer SKOv3 cells. The effect of dasatinib, an inhibitor of Src and Abl kinases, on paclitaxel sensitivity was measured in ovarian cancer cells and HEY xenografts. The roles of p27(Kip1), Bcl-2, and Cdk1 in apoptosis induced by dasatinib and paclitaxel were assessed using a terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, siRNA knockdown of gene expression, transfection with Bcl-2 and Cdk1 expression vectors, and flow cytometry. All statistical tests were two-sided. RESULTS: Src family and Abl kinases were identified as modulators of paclitaxel sensitivity in SKOv3 cells. The siRNA knockdown of Src, Fyn, or Abl1 enhanced paclitaxel mediated growth inhibition in ovarian cancer cells compared with a control siRNA. HEY cells treated with dasatinib plus paclitaxel formed fewer colonies than did cells treated with either agent alone. Treatment of HEY xenograft-bearing mice with dasatinib plus paclitaxel inhibited tumor growth more than treatment with either agent alone (average tumor volume per mouse, dasatinib + paclitaxel vs paclitaxel: 0.28 vs. 0.81 cm3, difference = 0.53 cm3, 95% confidence interval [CI] = 0.44 to 0.62 cm3, P = .014); dasatinib + paclitaxel vs. dasatinib: 0.28 vs. 0.55 cm3, difference = 0.27 cm3, 95% CI = 0.21 to 0.33 cm3, P = .035). Combined treatment induced more TUNEL-positive apoptotic cells than did either agent alone. The siRNA knockdown of p27(Kip1) decreased dasatinib- and paclitaxel induced apoptosis compared with a negative control siRNA (sub-G1 fraction, control siRNA vs. p27(Kip1) siRNA: 42.5% vs. 20.1%, difference = 22.4%, 95% CI = 20.1% to 24.7%, P = .017). Studies with forced expression and siRNA knockdown of Bcl-2 and Cdk1 suggest that dasatinib-mediated induction of p27(Kip1) enhanced paclitaxel-induced apoptosis by negatively regulating Bcl-2 and Cdk1 expression. CONCLUSION: Inhibition of Src family and Abl kinases with either siRNAs or dasatinib enhances paclitaxel sensitivity of ovarian cancer cells through p27(Kip1)-mediated suppression of Bcl-2 and Cdk1 expression. PMID- 21813413 TI - Statin prescriptions and breast cancer recurrence risk: a Danish nationwide prospective cohort study. AB - BACKGROUND: Accumulating evidence suggests that statins affect diseases other than cardiovascular disease, including cancer, and that these effects may depend on the lipid solubility of specific statins. Though many studies have reported an association between statin use and breast cancer incidence, the relationship between statin use and breast cancer recurrence has not been well studied. METHODS: We conducted a nationwide, population-based prospective cohort study of all female residents in Denmark diagnosed with stage I-III invasive breast carcinoma who were reported to the Danish Breast Cancer Cooperative Group registry between 1996 and 2003 (n = 18,769). Women were followed for a median of 6.8 years after diagnosis. Prescriptions for lipophilic and hydrophilic statins were ascertained from the national electronic pharmacy database. Associations between statin prescriptions and breast cancer recurrence were estimated with generalized linear models and Cox proportional hazards regression with adjustment for age and menopausal status at diagnosis; histological grade; estrogen receptor status; receipt of adjuvant therapy; type of primary surgery received; pre diagnosis hormone replacement therapy; and co-prescriptions of aspirin, angiotensin-converting enzyme inhibitors, nonsteroidal anti-inflammatory drugs, or anticoagulants. All statistical tests were two-sided. RESULTS: Most prescriptions for lipophilic statins in the study population were for simvastatin. Exclusive simvastatin users experienced approximately 10 fewer breast cancer recurrences per 100 women after 10 years of follow-up (adjusted 10 year risk difference = -0.10, 95% confidence interval = -0.11 to -0.08), compared with women who were not prescribed a statin. Exclusive hydrophilic statin users had approximately the same risk of breast cancer recurrence as women not prescribed a statin over follow-up (adjusted 10-year risk difference = 0.05, 95% confidence interval = -0.01 to 0.11). CONCLUSIONS: Simvastatin, a highly lipophilic statin, was associated with a reduced risk of breast cancer recurrence among Danish women diagnosed with stage I-III breast carcinoma, whereas no association between hydrophilic statin use and breast cancer recurrence was observed. PMID- 21813415 TI - Irrational beliefs and test anxiety in Turkish school adolescents. AB - The purpose of this descriptive and correlational study was to determine the extent to which irrational beliefs of students in early adolescents predict test anxiety. The study sample consisted of 557 students recruited from primary schools in Turkey. The Irrational Beliefs Scale for Adolescents (IBS-A) and the Test Anxiety scale were used as data-collection instruments. As a result of this study, there was a positive, significant correlation between mean scores on the Text Anxiety scale and total score, and the three subscale (demand for success, demand for comfort, and demand for respect) scores on the IBS-A. It was also found that demand for comfort and success are more statistically significant predictors of test anxiety levels of the students compared to demand for respect. PMID- 21813416 TI - CONSeQuence: prediction of reference peptides for absolute quantitative proteomics using consensus machine learning approaches. AB - Mass spectrometric based methods for absolute quantification of proteins, such as QconCAT, rely on internal standards of stable-isotope labeled reference peptides, or "Q-peptides," to act as surrogates. Key to the success of this and related methods for absolute protein quantification (such as AQUA) is selection of the Q peptide. Here we describe a novel method, CONSeQuence (consensus predictor for Q peptide sequence), based on four different machine learning approaches for Q peptide selection. CONSeQuence demonstrates improved performance over existing methods for optimal Q-peptide selection in the absence of prior experimental information, as validated using two independent test sets derived from yeast. Furthermore, we examine the physicochemical parameters associated with good peptide surrogates, and demonstrate that in addition to charge and hydrophobicity, peptide secondary structure plays a significant role in determining peptide "detectability" in liquid chromatography-electrospray ionization experiments. We relate peptide properties to protein tertiary structure, demonstrating a counterintuitive preference for buried status for frequently detected peptides. Finally, we demonstrate the improved efficacy of the general approach by applying a predictor trained on yeast data to sets of proteotypic peptides from two additional species taken from an existing peptide identification repository. PMID- 21813417 TI - Western blotting via proximity ligation for high performance protein analysis. AB - Western blotting is a powerful and widely used method, but limitations in detection sensitivity and specificity, and dependence upon high quality antibodies to detect targeted proteins, are hurdles to overcome. The in situ proximity ligation assay, based on dual antibody recognition and powerful localized signal amplification, offers increased detection sensitivity and specificity, along with an ability to identify complex targets such as phosphorylated or interacting proteins. Here we have applied the in situ proximity ligation assay mechanism in Western blotting. This combination allowed the use of isothermal rolling circle amplification of DNA molecules formed in target-specific ligation reaction, for 16-fold or greater increase in detection sensitivity. The increased specificity because of dual antibody recognition ensured highly selective assays, detecting the specific band when combinations of two cross-reactive antitubulin antibodies were used (i.e. both producing distinct nonspecific bands in traditional Western blotting). We also demonstrated detection of phosphorylated platelet-derived growth factor receptor beta by proximity ligation with one antibody directed against the receptor and another directed against the phosphorylated tyrosine residue. This avoided the need for stripping and re-probing the membrane or aligning two separate traditional blots. We demonstrate that the high-performance in situ proximity ligation-based Western blotting described herein is compatible with detection via enhanced chemiluminescence and fluorescence detection systems, and can thus be readily employed in any laboratory. PMID- 21813418 TI - The Human Immunopeptidome Project, a suggestion for yet another postgenome next big thing. AB - The time is ripe for staging the Human Immunopeptidome Project, whose goal is to analyze the full repertoires of peptides bound to the HLA molecules, in both health and disease. Mass spectrometry technologies have matured to enable comprehensive analyses of both the membrane-bound and the plasma soluble immunopeptidomes associated with each of the HLA allomorphs and the different diseases. The expected outcomes of such project will include basic understanding of the molecular mechanisms involved with formation of immunopeptidomes, correlating them with their source cellular proteomes, definition of both the consensus motifs and the scope of each allomorphs-specific immunopeptidomes, and most importantly, identification of disease-related HLA peptides, which may eventually serve as biomarkers or immunotherapeutics. Ideally, the Human Immunopeptidome Project will become public and the gathered data will be shared, as soon as possible. Other immunopeptidome projects, of other animals, will follow suit. PMID- 21813419 TI - The cover. Los desastres de la guerra. PMID- 21813420 TI - A piece of my mind. You have no idea. PMID- 21813421 TI - Human rights report details violence against health care workers in Bahrain. PMID- 21813422 TI - Traumatic brain injury a growing problem among troops serving in today's wars. PMID- 21813423 TI - Sensitive troponin I assay in patients with suspected acute coronary syndrome. PMID- 21813424 TI - Sensitive troponin I assay in patients with suspected acute coronary syndrome. PMID- 21813425 TI - Health literacy and patients with heart failure. PMID- 21813426 TI - Stray bullet shootings in the United States. PMID- 21813428 TI - Community-implemented trauma therapy for former child soldiers in Northern Uganda: a randomized controlled trial. AB - CONTEXT: The psychological rehabilitation of former child soldiers and their successful reintegration into postconflict society present challenges. Despite high rates of impairment, there have been no randomized controlled trials examining the feasibility and efficacy of mental health interventions for former child soldiers. OBJECTIVE: To assess the efficacy of a community-based intervention targeting symptoms of posttraumatic stress disorder (PTSD) in formerly abducted individuals. DESIGN, SETTING, AND PARTICIPANTS: Randomized controlled trial recruiting 85 former child soldiers with PTSD from a population based survey of 1113 Northern Ugandans aged 12 to 25 years, conducted between November 2007 and October 2009 in camps for internally displaced persons. Participants were randomized to 1 of 3 groups: narrative exposure therapy (n = 29), an academic catch-up program with elements of supportive counseling (n = 28), or a waiting list (n = 28). Symptoms of PTSD and trauma-related feelings of guilt were measured using the Clinician-Administered PTSD Scale. The respective sections of the Mini International Neuropsychiatric Interview were used to assess depression and suicide risk, and a locally adapted scale was used to measure perceived stigmatization. Symptoms of PTSD, depression, and related impairment were assessed before treatment and at 3 months, 6 months, and 12 months postintervention. INTERVENTION: Treatments were carried out in 8 sessions by trained local lay therapists, directly in the communities. MAIN OUTCOME MEASURES: Change in PTSD severity, assessed over a 1-year period after treatment. Secondary outcome measures were depression symptoms, severity of suicidal ideation, feelings of guilt, and perceived stigmatization. RESULTS: PTSD symptom severity (range, 0-148) was significantly more improved in the narrative exposure therapy group than in the academic catch-up (mean change difference, -14.06 [95% confidence interval, -27.19 to -0.92]) and waiting-list (mean change difference, 13.04 [95% confidence interval, -26.79 to 0.72]) groups. Contrast analyses of the time * treatment interaction of the mixed-effects model on PTSD symptom change over time revealed a superiority of narrative exposure therapy compared with academic catch-up (F(1,234.1) = 5.21, P = .02) and wait-listing (F(1,228.3) = 5.28, P = .02). Narrative exposure therapy produced a larger within-treatment effect size (Cohen d = 1.80) than academic catch-up (d = 0.83) and wait-listing (d = 0.81). CONCLUSION: Among former Ugandan child soldiers, short-term trauma focused treatment compared either with an academic catch-up program including supportive counseling or with wait-listing resulted in greater reduction of PTSD symptoms. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00552006. PMID- 21813429 TI - Lifetime prevalence of gender-based violence in women and the relationship with mental disorders and psychosocial function. AB - CONTEXT: Intimate partner physical violence, rape, sexual assault, and stalking are pervasive and co-occurring forms of gender-based violence (GBV). An association between these forms of abuse and lifetime mental disorder and psychosocial disability among women needs to be examined. OBJECTIVES: To assess the association of GBV and mental disorder, its severity and comorbidity, and psychosocial functioning among women. DESIGN, SETTING, AND PARTICIPANTS: A cross sectional study based on the Australian National Mental Health and Well-being Survey in 2007, of 4451 women (65% response rate) aged 16 to 85 years. MAIN OUTCOME MEASURES: The Composite International Diagnostic Interview version 3.0 of the World Health Organization's World Mental Health Survey Initiative was used to assess lifetime prevalence of any mental disorder, anxiety, mood disorder, substance use disorder, and posttraumatic stress disorder (PTSD). Also included were indices of lifetime trauma exposure, including GBV, sociodemographic characteristics, economic status, family history of mental disorder, social supports, general mental and physical functioning, quality of life, and overall disability. RESULTS: A total of 1218 women (27.4%) reported experiencing at least 1 type of GBV. For women exposed to 3 or 4 types of GBV (n = 139), the rates of mental disorders were 77.3% (odds ratio [OR], 10.06; 95% confidence interval [CI], 5.85-17.30) for anxiety disorders, 52.5% (OR, 3.59; 95% CI, 2.31-5.60) for mood disorder, 47.1% (OR, 5.61; 95% CI, 3.46-9.10) for substance use disorder, 56.2% (OR, 15.90; 95% CI, 8.32-30.20) for PTSD, 89.4% (OR, 11.00; 95% CI, 5.46 22.17) for any mental disorder, and 34.7% (OR, 14.80; 95% CI, 6.89-31.60) for suicide attempts. Gender-based violence was associated with more severe current mental disorder (OR, 4.60; 95% CI, 2.93-7.22), higher rates of 3 or more lifetime disorders (OR, 7.79; 95% CI, 6.10-9.95), physical disability (OR, 4.00; 95% CI, 1.82-8.82), mental disability (OR, 7.14; 95% CI, 2.87-17.75), impaired quality of life (OR, 2.96; 95% CI, 1.60-5.47), an increase in disability days (OR, 3.14; 95% CI, 2.43-4.05), and overall disability (OR, 2.73; 95% CI, 1.99-3.75). CONCLUSION: Among a nationally representative sample of Australian women, GBV was significantly associated with mental health disorder, dysfunction, and disability. PMID- 21813427 TI - Adjunctive risperidone treatment for antidepressant-resistant symptoms of chronic military service-related PTSD: a randomized trial. AB - CONTEXT: Serotonin reuptake-inhibiting (SRI) antidepressants are the only FDA approved pharmacotherapies for the treatment of posttraumatic stress disorder (PTSD). OBJECTIVE: To determine efficacy of the second-generation antipsychotic risperidone as an adjunct to ongoing pharmacologic and psychosocial treatments for veterans with chronic military-related PTSD. DESIGN, SETTING, AND PARTICIPANTS: A 6-month, randomized, double-blind, placebo-controlled multicenter trial conducted between February 2007 and February 2010 at 23 Veterans Administration outpatient medical centers. Of the 367 patients screened, 296 were diagnosed with military-related PTSD and had ongoing symptoms despite at least 2 adequate SRI treatments, and 247 contributed to analysis of the primary outcome measure. INTERVENTION: Risperidone (up to 4 mg once daily) or placebo. MAIN OUTCOME MEASURES: The Clinician-Administered PTSD Scale (CAPS) (range, 0-136). Other measures included the Montgomery-Asberg Depression Rating Scale (MADRS), Hamilton Anxiety Scale (HAMA), Clinical Global Impression scale (CGI), and Veterans RAND 36-Item Health Survey (SF-36V). RESULTS: Change in CAPS scores from baseline to 24 weeks in the risperidone group was -16.3 (95% CI, -19.7 to -12.9) and in the placebo group, -12.5 (95% CI, -15.7 to -9.4); the mean difference was 3.74 (95% CI, -0.86 to 8.35; t = 1.6; P = .11). Mixed model analysis of all time points also showed no significant difference in CAPS score (risperidone: mean, 64.43; 95% CI, 61.98 to 66.89, vs placebo: mean, 67.16; 95% CI, 64.71 to 69.62; mean difference, 2.73; 95% CI, -0.74 to 6.20; P = .12). Risperidone did not reduce symptoms of depression (MADRS mean difference, 1.19; 95% CI, -0.29 to 2.68; P = .11) or anxiety (HAMA mean difference, 1.16; 95% CI, -0.18 to 2.51; P = .09; patient-rated CGI mean difference, 0.20; 95% CI, -0.06 to 0.45; P = .14; observer-rated CGI mean difference, 0.18; 95% CI, 0.01 to 0.34; P = .04), or increase quality of life (SF-36V physical component mean difference, -1.13, 95% CI, -2.58 to 0.32; P = .13; SF-36V mental component mean difference, -0.26; 95% CI, -2.13 to 1.61; P = .79). Adverse events were more common with risperidone vs placebo, including self-reported weight gain (15.3% vs 2.3%), fatigue (13.7% vs 0.0%), somnolence (9.9% vs 1.5%), and hypersalivation (9.9% vs 0.8%), respectively. CONCLUSION: Among patients with military-related PTSD with SRI resistant symptoms, 6-month treatment with risperidone compared with placebo did not reduce PTSD symptoms. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00099983. PMID- 21813430 TI - Prevalence of war-related mental health conditions and association with displacement status in postwar Jaffna District, Sri Lanka. AB - CONTEXT: Nearly 2.7 million individuals worldwide are internally displaced (seeking refuge in secure areas of their own country) annually by armed conflict. Although the psychological impact of war has been well documented, less is known about the mental health symptoms of forced displacement among internally displaced persons. OBJECTIVES: To estimate the prevalence of the most common war related mental health conditions, symptoms of posttraumatic stress disorder (PTSD), anxiety, and depression, and to assess the association between displacement status and these conditions in postwar Jaffna District, Sri Lanka. DESIGN, SETTING, AND PARTICIPANTS: Between July and September 2009, a cross sectional multistage cluster sample survey was conducted among 1517 Jaffna District households including 2 internally displaced persons camps. The response rate was 92% (1448 respondents, 1409 eligible respondents). Two percent of participants (n = 80) were currently displaced, 29.5% (n = 539) were recently resettled, and 68.5% (n = 790) were long-term residents. Bivariable analyses followed by multivariable logistic regression models were performed to determine the association between displacement status and mental health. MAIN OUTCOME MEASURES: Symptom criteria of PTSD, anxiety, and depression as measured by the Harvard Trauma Questionnaire and the Hopkins Symptom Checklist-25. RESULTS: The overall prevalences of symptoms of PTSD, anxiety, and depression were 7.0% (95% confidence interval [CI], 5.1%-9.7%), 32.6% (95% CI, 28.5%-36.9%), and 22.2% (95% CI, 18.2%-26.5%), respectively. Currently displaced participants were more likely to report symptoms of PTSD (odds ratio [OR], 2.71; 95% CI, 1.28-5.73), anxiety (OR, 2.91; 95% CI, 1.89-4.48), and depression (OR, 4.55; 95% CI, 2.47-8.39) compared with long-term residents. Recently resettled residents were more likely to report symptoms of PTSD (OR, 1.96; 95% CI, 1.11-3.47) compared with long-term residents. However, displacement was no longer associated with mental health symptoms after controlling for trauma exposure. CONCLUSION: Among residents of Jaffna District in Sri Lanka, prevalence of symptoms of war-related mental health conditions was substantial and significantly associated with displacement status and underlying trauma exposure. PMID- 21813431 TI - Elder abuse and self-neglect: "I don't care anything about going to the doctor, to be honest...". AB - Elder mistreatment encompasses a range of behaviors including emotional, financial, physical, and sexual abuse, neglect by other individuals, and self neglect. This article discusses the range of elder mistreatment in community living older adults, associated factors, and consequences. Although self-neglect is not considered a type of abuse in many research definitions, it is the most commonly reported form of elder mistreatment and is associated with increased morbidity and mortality. The case on which this article is based describes a 70 year-old woman who neglects herself and dies despite multiple contacts with the medical community. Despite significant gaps in research, enough is known to guide clinical practice. This article presents the practical approaches a health care professional can take when a reasonable suspicion of elder mistreatment arises. Public health and interdisciplinary team approaches are needed to manage what is becoming an increasing problem as the number of older adults around the world increases. PMID- 21813432 TI - Government policies in violation of human rights as a barrier to professionalism. PMID- 21813433 TI - Treating posttraumatic stress disorder via the Internet: does therapeutic alliance matter? PMID- 21813434 TI - Scientific publication and global security. PMID- 21813435 TI - Trade-offs in using indirect sampling to measure conflict violence. PMID- 21813436 TI - Interventions for war-related posttraumatic stress disorder: meeting veterans where they are. PMID- 21813437 TI - JAMA patient page. Elder abuse. PMID- 21813438 TI - Target of tyrosine nitration in diabetic rat retina. PMID- 21813439 TI - Is traumatic brain injury a risk factor for schizophrenia? A meta-analysis of case-controlled population-based studies. AB - Traumatic brain injury (TBI) is known to lead to a range of adverse psychiatric sequelae but the question of whether TBI is a risk factor for psychosis and, in particular, schizophrenia remains unclear. Studies examining this issue have yielded conflicting results. We carried out a systematic review of the literature on TBI and psychosis in order to identify all population-based controlled studies which provide estimates of risk for schizophrenia following TBI. Odds ratios (ORs) were combined using random effects meta-analysis. Our literature search yielded 172 studies which were considered to be potentially relevant. From these, we identified 9 studies that could provide estimates of risk in the form of ORs. The pooled analysis revealed a significant association between TBI and schizophrenia (OR = 1.65; 95% CI = 1.17-2.32), with significant heterogeneity between the studies. Estimates from the family studies (OR = 2.8: 95% CI =1.76 4.47) were higher than those from the cohort/nested case-control studies (OR = 1.42: 95% CI = 1.02-1.97) by a factor of almost 2. There did not appear to be a dose-response relationship between severity of head injury and subsequent risk of schizophrenia. This meta-analysis supports an increased risk of schizophrenia following TBI, with a larger effect in those with a genetic predisposition to psychosis. Further epidemiological and neuroscientific studies to elucidate the mechanisms underlying this association are warranted. PMID- 21813440 TI - Factors affecting rotator cuff healing after arthroscopic repair: osteoporosis as one of the independent risk factors. AB - BACKGROUND: The prognostic factors associated with structural outcome after arthroscopic rotator cuff repair have not yet been fully determined. HYPOTHESIS: The hypothesis of this study was that bone mineral density (BMD) is an important prognostic factor affecting rotator cuff healing after arthroscopic cuff repair. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Among 408 patients who underwent arthroscopic repair for full-thickness rotator cuff tear between January 2004 and July 2008, 272 patients were included whose postoperative cuff integrity was verified by computed tomography arthrography (CTA) or ultrasonography (USG) and simultaneously who were evaluated by various functional outcome instruments. The mean age at the time of operation was 59.5 +/- 7.9 years. Postoperative CTA or USG was performed at a mean 13.0 +/- 5.1 months after surgery, and the mean follow-up period was 37.2 +/- 10.0 months (range, 24-65 months). The clinical, structural, and surgery-related factors affecting cuff integrity including BMD were analyzed using both univariate and multivariate analysis. Evaluation of postoperative cuff integrity was performed by musculoskeletal radiologists who were unaware of the present study. RESULTS: The failure rate of rotator cuff healing was 22.8% (62 of 272). The failure rate was significantly higher in patients with lower BMD (P < .001); older age (P < .001); female gender (P = .03); larger tear size (P < .001); higher grade of fatty infiltration (FI) of the supraspinatus, infraspinatus, and subscapularis (all P < .001); diabetes mellitus (P = .02); shorter acromiohumeral distance (P < .001); and associated biceps procedure (P < .001). However, in the multivariate analysis, only BMD (P = .001), FI of the infraspinatus (P = .01), and the amount of retraction (P = .03) showed a significant relationship with cuff healing failure following arthroscopic rotator cuff repair. CONCLUSION: Bone mineral density, as well as FI of the infraspinatus and amount of retraction, was an independent determining factor affecting postoperative rotator cuff healing. Further studies with prospective, randomized, and controlled design are needed to confirm the relationship between BMD and postoperative rotator cuff healing. PMID- 21813441 TI - Continued significant effect of physical training as treatment for overuse injury: 8- to 12-year outcome of a randomized clinical trial. AB - BACKGROUND: The treatment of exercise-related injuries is often a problem, and recurrent injuries are common. Two recent systematic reviews found only one high quality paper on the treatment of long-standing groin pain. In this randomized clinical trial, a training program including strength training resulted in a return of 79% of the athletes to the previous level of sport without any groin pain. The long-term effect of this exercise program was evaluated. HYPOTHESIS: The effect of the exercise program for adductor-related groin pain is long lasting. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: Forty-seven (80%) of the 59 original participants of the study agreed to participate in this 8- to 12-year follow-up. They were all interviewed and examined using a standardized and reproducible protocol, identical to the one used in the original trial. The investigating physician (P.N.) was not involved in the original study and was unaware of the original treatment allocation. RESULTS: A significant effect of the active training treatment still existed for the whole group (P = .047) and even more for the subgroup of 39 (83%) soccer players (P = .012). No significant differences were found regarding age, present sports activity, reasons for activity reduction, or time to follow-up. CONCLUSION: The beneficial short-term effect of the exercise program used in the primary randomized clinical trial for treating long-standing adductor-related groin pain in athletes was found to be lasting, both for the whole group and even more for the large subgroup of soccer players. This is the first time an exercise treatment for overuse injuries to the musculoskeletal system has been shown to have a long-lasting effect (8-12 years). PMID- 21813442 TI - Patellar tendon ruptures in National Football League players. AB - BACKGROUND: Although knee injuries are common among professional football players, ruptures of the patellar tendon are relatively rare. Predisposing factors, mechanisms of injury, treatment guidelines, and recovery expectations are not well established in high-level athletes. HYPOTHESIS: Professional football players with isolated rupture of the patellar tendon treated with timely surgical repair will return to their sport. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Twenty-four ruptures of the patellar tendon in 22 National Football League (NFL) players were identified from 1994 through 2004. Team physicians retrospectively reviewed training room and clinic records, operative notes, and imaging studies for each of these players. Player game statistics and draft status were analyzed to identify return to play predictors. A successful outcome was defined as participating in 1 regular-season NFL game. RESULTS: Eleven of the 24 injuries had antecedent symptoms. The most common mechanism of injury was an eccentric overload to a contracting extensor mechanism. Physical examination demonstrated a palpable defect in all players. Twenty-two were complete ruptures, and 2 were partial injuries. Three of the 24 cases had a concomitant anterior cruciate ligament (ACL) injury. In 19 of the 24 injuries, the player returned to participate in at least 1 game in the NFL. Players who returned were drafted, on average, in the fourth round, while those who failed to return to play were drafted, on average, in the sixth round. Of those players who returned to play, the average number of games played was 45.4, with a range of 1 to 142 games. CONCLUSION: Patellar tendon ruptures can occur in otherwise healthy professional football players without antecedent symptoms or predisposing factors. The most common mechanism of injury is eccentric overload. Close attention should be paid to stability examination of the knee given the not uncommon occurrence of concomitant ACL injury. Although this is usually a season ending injury when it occurs in isolation, acute surgical repair generally produces good functional results and allows for return to play the following season. Players chosen earlier in the draft are more likely to return to play. PMID- 21813443 TI - Platelet-rich plasma versus autologous whole blood for the treatment of chronic lateral elbow epicondylitis: a randomized controlled clinical trial. AB - BACKGROUND: Chronic lateral elbow epicondylitis is a tendinosis with angiofibrolastic degeneration of the wrist extensors' origin. Healing of this lesion is reported with the use of autologous blood as well as with platelet-rich plasma (PRP). PURPOSE: A comparative study of these 2 treatments was conducted in an effort to investigate the possible advantages of PRP. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: Twenty-eight patients were divided equally into 2 groups, after blocked randomization. Group A was treated with a single injection of 3 mL of autologous blood and group B with 3 mL of PRP under ultrasound guidance. A standardized program of eccentric muscle strengthening was followed by all patients in both groups. Evaluation using a pain visual analog scale (VAS) and Liverpool elbow score was performed at 6 weeks, 3 months, and 6 months. RESULTS: The VAS score improvement was larger in group B at every follow-up interval but the difference was statistically significant only at 6 weeks, when mean improvement was 3.8 points (95% confidence interval [CI], 3.1-4.5) in group B (61.47% improvement) and 2.5 points (95% CI, 1.9-3.1) in group A (41.6% improvement) (P < .05). No statistically significant difference was noted between groups regarding Liverpool elbow score. CONCLUSION: Regarding pain reduction, PRP treatment seems to be an effective treatment for chronic lateral elbow epicondylitis and superior to autologous blood in the short term. Defining details of indications, best PRP concentration, number and time of injections, as well as rehabilitation protocol might increase the method's effectiveness. Additionally, the possibility of cost reduction of the method might justify the use of PRP over autologous whole blood for chronic or refractory tennis elbow. PMID- 21813444 TI - Like like a native. PMID- 21813446 TI - CD8(+) T-cell reconstitution in recipients of umbilical cord blood transplantation and characteristics associated with leukemic relapse. AB - Recipients of umbilical cord blood (UCB) transplantation (UCBT) face a high risk of morbidity and mortality related to opportunistic infections (OI) and leukemic relapse. To understand the molecular basis of these UCBT-related complications, the characteristics of UCB-derived antigen-specific CD8(+) T cells were examined in a group of pediatric UCBT recipients. Compared with the UCB graft inoculum and the late post-UCBT period (12-36 months), declining clonal diversity of UCB derived CD8(+) T cells specific for the Melan-A(26-35) A27L peptide and high frequencies of PD-1-expressing CD8(+) T cells were observed in the first 3 months after UCBT, a period during which OIs are most frequent. The CD8(+) T-cell compartment predominantly comprised CD45RA(+) CCR7(-) terminally differentiated effector-memory T cells until 6 months after UCBT, at which time the polyfunctionality of antigen-specific CD8(+) T cells was reestablished. Finally, the frequency of PD-1(+) CD8(+) T cells was significantly higher in subjects who subsequently experienced leukemic relapse. This study informs the biologic properties of UCB-derived CD8(+) T cells and provides a rationale for the characteristics of UCBT in terms of immune reconstitution and OI. These results also suggest that the elevated frequency of PD-1(+) CD8(+) T cells could be associated with leukemic relapse in pediatric UCBT recipients. PMID- 21813447 TI - NUP98/NSD1 characterizes a novel poor prognostic group in acute myeloid leukemia with a distinct HOX gene expression pattern. AB - Translocations involving nucleoporin 98kD (NUP98) on chromosome 11p15 occur at relatively low frequency in acute myeloid leukemia (AML) but can be missed with routine karyotyping. In this study, high-resolution genome-wide copy number analyses revealed cryptic NUP98/NSD1 translocations in 3 of 92 cytogenetically normal (CN)-AML cases. To determine their exact frequency, we screened > 1000 well-characterized pediatric and adult AML cases using a NUP98/NSD1-specific RT PCR. Twenty-three cases harbored the NUP98/NSD1 fusion, representing 16.1% of pediatric and 2.3% of adult CN-AML patients. NUP98/NSD1-positive AML cases had significantly higher white blood cell counts (median, 147 * 109/L), more frequent FAB-M4/M5 morphology (in 63%), and more CN-AML (in 78%), FLT3/internal tandem duplication (in 91%) and WT1 mutations (in 45%) than NUP98/NSD1-negative cases. NUP98/NSD1 was mutually exclusive with all recurrent type-II aberrations. Importantly, NUP98/NSD1 was an independent predictor for poor prognosis; 4-year event-free survival was < 10% for both pediatric and adult NUP98/NSD1-positive AML patients. NUP98/NSD1-positive AML showed a characteristic HOX-gene expression pattern, distinct from, for example, MLL-rearranged AML, and the fusion protein was aberrantly localized in nuclear aggregates, providing insight into the leukemogenic pathways of these AMLs. Taken together, NUP98/NSD1 identifies a previously unrecognized group of young AML patients, with distinct characteristics and dismal prognosis, for whom new treatment strategies are urgently needed. PMID- 21813448 TI - How I treat thalassemia. AB - The purpose of this article is to set forth our approach to diagnosing and managing the thalassemias, including beta-thalassemia intermedia and beta thalassemia major. The article begins by briefly describing recent advances in our understanding of the pathophysiology of thalassemia. In the discussion on diagnosing the condition, we cover the development of improved diagnostic tools, including the use of very small fetal DNA samples to detect single point mutations with great reliability for prenatal diagnosis of homozygous thalassemia. In our description of treatment strategies, we focus on how we deal with clinical manifestations and long-term complications using the most effective current treatment methods for beta-thalassemia. The discussion of disease management focuses on our use of transfusion therapy and the newly developed oral iron chelators, deferiprone and deferasirox. We also deal with splenectomy and how we manage endocrinopathies and cardiac complications. In addition, we describe our use of hematopoietic stem cell transplantation, which has produced cure rates as high as 97%, and the use of cord blood transplantation. Finally, we briefly touch on therapies that might be effective in the near future, including new fetal hemoglobin inducers and gene therapy. PMID- 21813449 TI - Proteomic analysis of palmitoylated platelet proteins. AB - Protein palmitoylation is a dynamic process that regulates membrane targeting of proteins and protein-protein interactions. We have previously demonstrated a critical role for protein palmitoylation in platelet activation and have identified palmitoylation machinery in platelets. Using a novel proteomic approach, Palmitoyl Protein Identification and Site Characterization, we have begun to characterize the human platelet palmitoylome. Palmitoylated proteins were enriched from membranes isolated from resting platelets using acyl-biotinyl exchange chemistry, followed by identification using liquid chromatography-tandem mass spectrometry. This global analysis identified > 1300 proteins, of which 215 met criteria for significance and represent the platelet palmitoylome. This collection includes 51 known palmitoylated proteins, 61 putative palmitoylated proteins identified in other palmitoylation-specific proteomic studies, and 103 new putative palmitoylated proteins. Of these candidates, we chose to validate the palmitoylation of triggering receptors expressed on myeloid cell (TREM)-like transcript-1 (TLT-1) as its expression is restricted to platelets and megakaryocytes. We determined that TLT-1 is a palmitoylated protein using metabolic labeling with [3H]palmitate and identified the site of TLT-1 palmitoylation as cysteine 196. The discovery of new platelet palmitoyl protein candidates will provide a resource for subsequent investigations to validate the palmitoylation of these proteins and to determine the role palmitoylation plays in their function. PMID- 21813450 TI - T(H)1, T(H)2, and T(H)17 cells instruct monocytes to differentiate into specialized dendritic cell subsets. AB - Monocytes and T helper (T(H)) cells rapidly infiltrate inflamed tissues where monocytes differentiate into inflammatory dendritic cells (DCs) through undefined mechanisms. Our studies indicate that T(H) cells frequently interact with monocytes in inflamed skin and elicit the differentiation of specialized DC subsets characteristic of these lesions. In psoriasis lesions, T(H)1 and T(H)17 cells interact with monocytes and instruct these cells to differentiate into T(H)1- and T(H)17-promoting DCs, respectively. Correspondingly, in acute atopic dermatitis, T(H)2 cells interact with monocytes and elicit the formation of T(H)2 promoting DCs. DC formation requires GM-CSF and cell contact, whereas T(H) subset specific cytokines dictate DC function and the expression of DC subset specific surface molecules. Moreover, the phenotypes of T cell-induced DC subsets are maintained after subsequent stimulation with a panel of TLR agonists, suggesting that T(H)-derived signals outweigh downstream TLR signals in their influence on DC function. These findings indicate that T(H) cells govern the formation and function of specialized DC subsets. PMID- 21813452 TI - Impact of gene dosage, loss of wild-type allele, and FLT3 ligand on Flt3-ITD induced myeloproliferation. AB - Acquisition of homozygous activating growth factor receptor mutations might accelerate cancer progression through a simple gene-dosage effect. Internal tandem duplications (ITDs) of FLT3 occur in approximately 25% cases of acute myeloid leukemia and induce ligand-independent constitutive signaling. Homozygous FLT3-ITDs confer an adverse prognosis and are frequently detected at relapse. Using a mouse knockin model of Flt3-internal tandem duplication (Flt3-ITD) induced myeloproliferation, we herein demonstrate that the enhanced myeloid phenotype and expansion of granulocyte-monocyte and primitive Lin(-)Sca1(+)c Kit(+) progenitors in Flt3-ITD homozygous mice can in part be mediated through the loss of the second wild-type allele. Further, whereas autocrine FLT3 ligand production has been implicated in FLT3-ITD myeloid malignancies and resistance to FLT3 inhibitors, we demonstrate here that the mouse Flt3(ITD/ITD) myeloid phenotype is FLT3 ligand-independent. PMID- 21813451 TI - TLR7 enables cross-presentation by multiple dendritic cell subsets through a type I IFN-dependent pathway. AB - Conjugation of TLR agonists to protein or peptide antigens has been demonstrated in many studies to be an effective vaccine formula in inducing cellular immunity. However, the molecular and cellular mediators involved in TLR-induced immune responses have not been carefully examined. In this study, we identify Type I IFN and IL-12 as critical mediators of cross-priming induced by a TLR7 agonist antigen conjugate. We demonstrate that TLR7-driven cross-priming requires both Type I IFN and IL-12. Signaling through the IFN-alphabetaR was required for the timely recruitment and accumulation of activated dendritic cells in the draining lymph nodes. Although IL-12 was indispensable during cross-priming, it did not regulate DC function. Therefore, the codependency for these 2 cytokines during TLR7-induced cross-priming is the result of their divergent effects on different cell-types. Furthermore, although dermal and CD8alpha(+) DCs were able to cross prime CD8(+) T cells, Langerhans cells were unexpectedly found to potently cross present antigen and support CD8(+) T-cell expansion, both in vitro and in vivo. Collectively, the data show that a TLR7 agonist-antigen conjugate elicits CD8(+) T-cell responses by the coordinated recruitment and activation of both tissue derived and lymphoid organ-resident DC subsets through a Type I IFN and IL-12 codependent mechanism. PMID- 21813453 TI - Comparative characterization of the PvuRts1I family of restriction enzymes and their application in mapping genomic 5-hydroxymethylcytosine. AB - PvuRts1I is a modification-dependent restriction endonuclease that recognizes 5 hydroxymethylcytosine (5hmC) as well as 5-glucosylhydroxymethylcytosine (5ghmC) in double-stranded DNA. Using PvuRts1I as the founding member, we define a family of homologous proteins with similar DNA modification-dependent recognition properties. At the sequence level, these proteins share a few uniquely conserved features. We show that these enzymes introduce a double-stranded cleavage at the 3'-side away from the recognized modified cytosine. The distances between the cleavage sites and the modified cytosine are fixed within a narrow range, with the majority being 11-13 nt away in the top strand and 9-10 nt away in the bottom strand. The recognition sites of these enzymes generally require two cytosines on opposite strand around the cleavage sites, i.e. 5'-CN(11-13)?N(9-10)G-3'/3'-GN(9 10)?N(11-13)C-5', with at least one cytosine being modified for efficient cleavage. As one potential application for these enzymes is to provide useful tools for selectively mapping 5hmC sites, we have compared the relative selectivity of a few PvuRts1I family members towards different forms of modified cytosines. Our results show that the inherently different relative selectivity towards modified cytosines can have practical implications for their application. By using AbaSDFI, a PvuRts1I homolog with the highest relative selectivity towards 5ghmC, to analyze rat brain DNA, we show it is feasible to map genomic 5hmC sites close to base resolution. Our study offers unique tools for determining more accurate hydroxymethylomes in mammalian cells. PMID- 21813454 TI - SNVer: a statistical tool for variant calling in analysis of pooled or individual next-generation sequencing data. AB - We develop a statistical tool SNVer for calling common and rare variants in analysis of pooled or individual next-generation sequencing (NGS) data. We formulate variant calling as a hypothesis testing problem and employ a binomial binomial model to test the significance of observed allele frequency against sequencing error. SNVer reports one single overall P-value for evaluating the significance of a candidate locus being a variant based on which multiplicity control can be obtained. This is particularly desirable because tens of thousands loci are simultaneously examined in typical NGS experiments. Each user can choose the false-positive error rate threshold he or she considers appropriate, instead of just the dichotomous decisions of whether to 'accept or reject the candidates' provided by most existing methods. We use both simulated data and real data to demonstrate the superior performance of our program in comparison with existing methods. SNVer runs very fast and can complete testing 300 K loci within an hour. This excellent scalability makes it feasible for analysis of whole-exome sequencing data, or even whole-genome sequencing data using high performance computing cluster. SNVer is freely available at http://snver.sourceforge.net/. PMID- 21813455 TI - Gln-tRNAGln synthesis in a dynamic transamidosome from Helicobacter pylori, where GluRS2 hydrolyzes excess Glu-tRNAGln. AB - In many bacteria and archaea, an ancestral pathway is used where asparagine and glutamine are formed from their acidic precursors while covalently linked to tRNA(Asn) and tRNA(Gln), respectively. Stable complexes formed by the enzymes of these indirect tRNA aminoacylation pathways are found in several thermophilic organisms, and are called transamidosomes. We describe here a transamidosome forming Gln-tRNA(Gln) in Helicobacter pylori, an epsilon-proteobacterium pathogenic for humans; this transamidosome displays novel properties that may be characteristic of mesophilic organisms. This ternary complex containing the non canonical GluRS2 specific for Glu-tRNA(Gln) formation, the tRNA-dependent amidotransferase GatCAB and tRNA(Gln) was characterized by dynamic light scattering. Moreover, we observed by interferometry a weak interaction between GluRS2 and GatCAB (K(D) = 40 +/- 5 uM). The kinetics of Glu-tRNA(Gln) and Gln tRNA(Gln) formation indicate that conformational shifts inside the transamidosome allow the tRNA(Gln) acceptor stem to interact alternately with GluRS2 and GatCAB despite their common identity elements. The integrity of this dynamic transamidosome depends on a critical concentration of tRNA(Gln), above which it dissociates into separate GatCAB/tRNA(Gln) and GluRS2/tRNA(Gln) complexes. Ester bond protection assays show that both enzymes display a good affinity for tRNA(Gln) regardless of its aminoacylation state, and support a mechanism where GluRS2 can hydrolyze excess Glu-tRNA(Gln), ensuring faithful decoding of Gln codons. PMID- 21813456 TI - The miRNA pathway limits AGO1 availability during siRNA-mediated PTGS defense against exogenous RNA. AB - In plants, most microRNAs (miRNAs) and several endogenous small interfering RNAs (siRNAs) bind to ARGONAUTE1 (AGO1) to regulate the expression of endogenous genes through post-transcriptional gene silencing (PTGS). AGO1 also participates in a siRNA-mediated PTGS defense response that thwarts exogenous RNA deriving from viruses and transgenes. Here, we reveal that plants supporting transgene PTGS exhibit increased levels of AGO1 protein. Moreover, increasing AGO1 levels either by mutating miRNA pathway components or, more specifically, by impairing miR168 directed regulation of AGO1 mRNA leads to increased PTGS efficiency, indicating that the miRNA pathway dampens the efficiency of PTGS, likely by limiting the availability of AGO1. We propose that during the transgene PTGS initiation phase, transgene siRNAs and endogenous siRNAs and miRNA compete to bind to AGO1, leading to a transient reduction in AGO1-miR168 complexes and a decline in AGO1 mRNA cleavage. The concomitant increase in AGO1 protein levels would facilitate the formation of AGO1-transgene siRNA complexes and the entry into the PTGS amplification phase. We suggest that the miRNA pathway imposes an important limitation on PTGS efficiency, which could help protect endogenous mRNAs from being routinely targeted by PTGS. PMID- 21813457 TI - Handpicking epigenetic marks with PHD fingers. AB - Plant homeodomain (PHD) fingers have emerged as one of the largest families of epigenetic effectors capable of recognizing or 'reading' post-translational histone modifications and unmodified histone tails. These interactions are highly specific and can be modulated by the neighboring epigenetic marks and adjacent effectors. A few PHD fingers have recently been found to also associate with non histone proteins. In this review, we detail the molecular mechanisms and biological outcomes of the histone and non-histone targeting by PHD fingers. We discuss the significance of crosstalk between the histone modifications and consequences of combinatorial readout for selective recruitment of the PHD finger containing components of chromatin remodeling and transcriptional complexes. PMID- 21813458 TI - Nucleoside modifications in RNA limit activation of 2'-5'-oligoadenylate synthetase and increase resistance to cleavage by RNase L. AB - The interferon-induced enzymes 2'-5'-oligoadenylate synthetase (OAS) and RNase L are key components of innate immunity involved in sensory and effector functions following viral infections. Upon binding target RNA, OAS is activated to produce 2'-5'-linked oligoadenylates (2-5A) that activate RNase L, which then cleaves single-stranded self and non-self RNA. Modified nucleosides that are present in cellular transcripts have been shown to suppress activation of several RNA sensors. Here, we demonstrate that in vitro transcribed, unmodified RNA activates OAS, induces RNase L-mediated ribosomal RNA (rRNA) cleavage and is rapidly cleaved by RNase L. In contrast, RNA containing modified nucleosides activates OAS less efficiently and induces limited rRNA cleavage. Nucleoside modifications also make RNA resistant to cleavage by RNase L. Examining translation in RNase L( /-) cells and mice confirmed that RNase L activity reduces translation of unmodified mRNA, which is not observed with modified mRNA. Additionally, mRNA containing the nucleoside modification pseudouridine is translated longer and has an extended half-life. The observation that modified nucleosides in RNA reduce 2 5A pathway activation joins OAS and RNase L to the list of RNA sensors and effectors whose functions are limited when RNA is modified, confirming the role of nucleoside modifications in suppressing immune recognition of RNA. PMID- 21813459 TI - A novel TALE nuclease scaffold enables high genome editing activity in combination with low toxicity. AB - Sequence-specific nucleases represent valuable tools for precision genome engineering. Traditionally, zinc-finger nucleases (ZFNs) and meganucleases have been used to specifically edit complex genomes. Recently, the DNA binding domains of transcription activator-like effectors (TALEs) from the bacterial pathogen Xanthomonas have been harnessed to direct nuclease domains to desired genomic loci. In this study, we tested a panel of truncation variants based on the TALE protein AvrBs4 to identify TALE nucleases (TALENs) with high DNA cleavage activity. The most favorable parameters for efficient DNA cleavage were determined in vitro and in cellular reporter assays. TALENs were designed to disrupt an EGFP marker gene and the human loci CCR5 and IL2RG. Gene editing was achieved in up to 45% of transfected cells. A side-by-side comparison with ZFNs showed similar gene disruption activities by TALENs but significantly reduced nuclease-associated cytotoxicities. Moreover, the CCR5-specific TALEN revealed only minimal off-target activity at the CCR2 locus as compared to the corresponding ZFN, suggesting that the TALEN platform enables the design of nucleases with single-nucleotide specificity. The combination of high nuclease activity with reduced cytotoxicity and the simple design process marks TALENs as a key technology platform for targeted modifications of complex genomes. PMID- 21813460 TI - The Streptococcus thermophilus CRISPR/Cas system provides immunity in Escherichia coli. AB - The CRISPR/Cas adaptive immune system provides resistance against phages and plasmids in Archaea and Bacteria. CRISPR loci integrate short DNA sequences from invading genetic elements that provide small RNA-mediated interference in subsequent exposure to matching nucleic acids. In Streptococcus thermophilus, it was previously shown that the CRISPR1/Cas system can provide adaptive immunity against phages and plasmids by integrating novel spacers following exposure to these foreign genetic elements that subsequently direct the specific cleavage of invasive homologous DNA sequences. Here, we show that the S. thermophilus CRISPR3/Cas system can be transferred into Escherichia coli and provide heterologous protection against plasmid transformation and phage infection. We show that interference is sequence-specific, and that mutations in the vicinity or within the proto-spacer adjacent motif (PAM) allow plasmids to escape CRISPR encoded immunity. We also establish that cas9 is the sole cas gene necessary for CRISPR-encoded interference. Furthermore, mutation analysis revealed that interference relies on the Cas9 McrA/HNH- and RuvC/RNaseH-motifs. Altogether, our results show that active CRISPR/Cas systems can be transferred across distant genera and provide heterologous interference against invasive nucleic acids. This can be leveraged to develop strains more robust against phage attack, and safer organisms less likely to uptake and disseminate plasmid-encoded undesirable genetic elements. PMID- 21813461 TI - Regulation of tolerance of Chlamydomonas reinhardtii to heavy metal toxicity by heme oxygenase-1 and carbon monoxide. AB - Investigation of heavy metal tolerance genes in green algae is of great importance because heavy metals have become one of the major contaminants in the aquatic ecosystem. In plants, accumulation of heavy metals modifies many aspects of cellular functions. However, the mechanism by which heavy metals exert detrimental effects is poorly understood. In this study, we identified a role for HO-1 (encoding heme oxygenase-1) in regulating the response of Chlamydomonas reinhardtii, a unicellular green alga, to mercury (Hg). Transgenic algae overexpressing HO-1 showed high tolerance to Hg exposure, with a 48.2% increase in cell number over the wild type, but accumulated less Hg. Physiological analysis revealed that expression of HO-1 suppressed the Hg-induced generation of reactive oxygen species. We further identified the effect of carbon monoxide (CO), a product of HO-1-mediated heme degradation, on growth and physiological parameters. Interestingly, administration of exogenous CO at non-toxic levels also conferred the tolerance of algae to Hg exposure. The CO-mediated alleviation of Hg toxicity was closely related to the lower accumulation of Hg and free radical species. These results indicate that functional identification of HO-1 is useful for molecular breeding designed to improve plant tolerance to heavy metals and reduce heavy metal accumulation in plant cells. PMID- 21813462 TI - Developmental treatment with bisphenol A or ethinyl estradiol causes few alterations on early preweaning measures. AB - Because bisphenol A (BPA) exposure is nearly ubiquitous, increased knowledge of its potential effects on development will enable better risk assessment and regulatory guidance. Here, Sprague-Dawley rats were reared in low exogenous estrogen environments. After breeding at adulthood, dams were gavaged on gestational days (GDs) 6-21 with vehicle (VEH), 2.5 or 25.0 MUg/kg/day BPA, or 5.0 or 10.0 MUg/kg/day ethinyl estradiol (EE2). Offspring were orally treated on postnatal days (PNDs) 1-21 with the same dose the dam received. Relative to the VEH group, dams of both EE2-treated groups weighed less throughout gestation and lactation. PND 1 absolute anogenital distance and anogenital index were unaltered by any treatment. Ages at fur development and eye and ear opening were unaffected by any treatment. Despite a significant treatment effect, no group was significantly different from VEH in PNDs 3-6 righting latencies; although males had shorter latencies and all latencies decreased with age. PNDs 8-11 slant board behavior was unaffected by any treatment; however, males had shorter turning latencies and latencies decreased with age. Preweaning body weights of BPA- and EE2-treated groups as well as naive controls were less than VEH. No treatment affected PND 21 whole or regional brain weights or levels of estradiol, testosterone, corticosterone, T3, T4, luteinizing hormone, ghrelin, or leptin. These results add to the literature indicating that developmental BPA treatment at these doses has no effects on gestational or lactational body weight, offspring anogenital distance, preweaning behaviors or hormone levels, and whole and regional brain weights measured at weaning. PMID- 21813463 TI - Development and evaluation of a genomic signature for the prediction and mechanistic assessment of nongenotoxic hepatocarcinogens in the rat. AB - Evaluating the risk of chemical carcinogenesis has long been a challenge owing to the protracted nature of the pathology and the limited translatability of animal models. Although numerous short-term in vitro and in vivo assays have been developed, they have failed to reliably predict the carcinogenicity of nongenotoxic compounds. Extending upon previous microarray work (Fielden, M. R., Nie, A., McMillian, M., Elangbam, C. S., Trela, B. A., Yang, Y., Dunn, R. T., II, Dragan, Y., Fransson-Stehen, R., Bogdanffy, M., et al. (2008). Interlaboratory evaluation of genomic signatures for predicting carcinogenicity in the rat. Toxicol. Sci. 103, 28-34), we have developed and extensively evaluated a quantitative PCR-based signature to predict the potential for nongenotoxic compounds to induce liver tumors in the rat as a first step in the safety assessment of potential nongenotoxic carcinogens. The training set was derived from liver RNA from rats treated with 72 compounds and used to develop a 22-gene signature on the TaqMan array platform, providing an economical and standardized assay protocol. Independent testing on over 900 diverse samples (66 compounds) confirmed the interlaboratory precision of the assay and its ability to predict known nongenotoxic hepatocarcinogens (NGHCs). When tested under different experimental designs, strains, time points, dose setting criteria, and other preanalytical processes, the signature sensitivity and specificity was estimated to be 67% (95% confidence interval [CI] = 38-88%) and 59% (95% CI = 44-72%), respectively, with an area under the receiver operating characteristic curve of 0.65 (95% CI = 0.46-0.83%). Compounds were best classified using expression data from short-term repeat dose studies; however, the prognostic expression changes appeared to be preserved after longer term treatment. Exploratory evaluations also revealed that different modes of action for nongenotoxic and genotoxic compounds can be discriminated based on the expression of specific genes. These results support a potential early preclinical testing paradigm to catalyze broader understanding of putative NGHCs. PMID- 21813465 TI - How MIKC* MADS-box genes originated and evidence for their conserved function throughout the evolution of vascular plant gametophytes. AB - Land plants have a remarkable life cycle that alternates between a diploid sporophytic and a haploid gametophytic generation, both of which are multicellular and changed drastically during evolution. Classical MIKC MADS domain (MIKCC) transcription factors are famous for their role in sporophytic development and are considered crucial for its evolution. About the regulation of gametophyte development, in contrast, little is known. Recent evidence indicated that the closely related MIKC* MADS-domain proteins are important for the functioning of the Arabidopsis thaliana male gametophyte (pollen). Furthermore, also in bryophytes, several MIKC* genes are expressed in the haploid generation. Therefore, that MIKC* genes have a similar role in the evolution of the gametophytic phase as MIKCC genes have in the sporophyte is a tempting hypothesis. To get a comprehensive view of the involvement of MIKC* genes in gametophyte evolution, we isolated them from a broad variety of vascular plants, including the lycophyte Selaginella moellendorffii, the fern Ceratopteris richardii, and representatives of several flowering plant lineages. Phylogenetic analysis revealed an extraordinary conservation not found in MIKCC genes. Moreover, expression and interaction studies suggest that a conserved and characteristic network operates in the gametophytes of all tested model organisms. Additionally, we found that MIKC* genes probably evolved from an ancestral MIKCC-like gene by a duplication in the Keratin-like region. We propose that this event facilitated the independent evolution of MIKC* and MIKCC protein networks and argue that whereas MIKCC genes diversified and attained new functions, MIKC* genes retained a conserved role in the gametophyte during land plant evolution. PMID- 21813466 TI - Body-methylated genes in Arabidopsis thaliana are functionally important and evolve slowly. AB - DNA methylation of coding regions, known as gene body methylation, is conserved across eukaryotic lineages. The function of body methylation is not known, but it may either prevent aberrant expression from intragenic promoters or enhance the accuracy of splicing. Given these putative functions, we hypothesized that body methylated genes would be both longer and more functionally important than unmethylated genes. To test these hypotheses, we reanalyzed single-base resolution bisulfite sequence data from Arabidopsis thaliana to differentiate body-methylated genes from unmethylated genes using a probabilistic approach. Contrasting genic characteristics between the two groups, we found that body methylated genes tend to be longer and to be more functionally important, as measured by phenotypic effects of insertional mutants and by gene expression, than unmethylated genes. We also found that methylated genes evolve more slowly than unmethylated genes, despite the potential for increased mutation rates in methylated CpG dinucleotides. We propose that slower rates in body-methylated genes are a function of higher selective constraint, lower nucleosome occupancy, and a lower proportion of CpG dinucleotides. PMID- 21813464 TI - ERK crosstalks with 4EBP1 to activate cyclin D1 translation during quinol thioether-induced tuberous sclerosis renal cell carcinoma. AB - The mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase signaling cascades have been implicated in a number of human cancers. The tumor suppressor gene tuberous sclerosis-2 (Tsc-2) functions as a negative regulator of mTOR. Critical proteins in both pathways are activated following treatment of Eker rats (Tsc-2(EK/+)) with the nephrocarcinogen 2,3,5-tris-(glutathion-S yl)hydroquinone (TGHQ), which also results in loss of the wild-type allele of Tsc 2 in renal preneoplastic lesions and tumors. Western blot analysis of kidney tumors formed following treatment of Tsc-2(EK/+) rats with TGHQ for 8 months revealed increases in B-Raf, Raf-1, pERK, cyclin D1, 4EBP1, and p-4EBP1-Ser65, Thr70, and -Thr37/46 expression. Similar changes are observed following TGHQ mediated transformation of primary renal epithelial cells derived from Tsc 2(EK/+) rats (quinol-thioether rat renal epithelial [QTRRE] cells) that are also null for tuberin. These cells exhibit high ERK, B-Raf, and Raf-1 kinase activity and increased expression of all p-4EBP1s and cyclin D1. Treatment of the QTRRE cells with the Raf kinase inhibitor, sorafenib, or the MEK1/2 kinase inhibitor, PD 98059, produced a significant decrease in the protein expression of all p 4EBP1s and cyclin D1. Following siRNA knockdown of Raf-1, Western blot analysis revealed a significant decrease in Raf-1, cyclin D1, and all p-4EBP1 forms noted above. In contrast, siRNA knockdown of B-Raf resulted in a nominal change in these proteins. The data indicate that Raf-1/MEK/ERK participates in crosstalk with 4EBP1, which represents a novel pathway interaction leading to increased protein synthesis, cell growth, and kidney tumor formation. PMID- 21813467 TI - Convergent evolution of endometrial prolactin expression in primates, mice, and elephants through the independent recruitment of transposable elements. AB - Prolactin (PRL) is a multifunctional signaling molecule best known for its role in regulating lactation in mammals. Systemic PRL is produced by the anterior pituitary, but extrapituitary PRL has also been detected in many tissues including the human endometrium. Prolactin is essential for pregnancy in rodents and one of the most dramatically induced genes in the endometrium during human pregnancy. The promoter for human endometrial Prl is located about 5.8 kb upstream of the pituitary promoter and is derived from a transposable element called MER39. Although it has been shown that prolactin is expressed in the pregnant endometrium of a few mammals other than humans, MER39 has been described as primate specific. Thus, in an effort to understand mechanisms of prolactin regulatory evolution, we sought to determine how uterine prolactin is transcribed in species that lack MER39. Using a variety of complementary strategies, including reverse transcriptase-polymerase chain reaction, 5' rapid amplification of cDNA ends, and whole-transcriptome sequencing, we show that endometrial Prl expression is not a shared character of all placental mammals, as it is not expressed in rabbits, pigs, dogs, or armadillos. We show that in primates, mice, and elephants, prolactin mRNA is transcribed in the pregnant endometrium from alternative promoters, different from the pituitary promoter and different from each other. Moreover, we demonstrate that the spider monkey promoter derives from the long terminal repeat (LTR) element MER39 as in humans, the mouse promoter derives from the LTR element MER77, and the elephant promoter derives from the lineage-specific LINE retrotransposon L1-2_LA. We also find surprising variation of transcriptional start sites within these transposable elements and of Prl splice variants, suggesting a high degree of flexibility in the promoter architecture even among closely related species. Finally, the three groups shown here to express endometrial prolactin-the higher primates, the rodents, and the elephant-represent three of the four lineages that showed adaptive evolution of the Prl gene in an earlier study (Wallis M. 2000. Episodic evolution of protein hormones: molecular evolution of pituitary prolactin. J Mol Evol. 50:465-473), which supports our findings and suggests that the selective forces responsible for accelerated Prl evolution were in the endometrium. This is the first reported case of convergent evolution of gene expression through the independent recruitment of different transposable elements, highlighting the importance of transposable elements in gene regulatory, and potentially adaptive, evolution. PMID- 21813468 TI - Methionine adenosyltransferase 2A/2B and methylation: gene sequence variation and functional genomics. AB - Methionine adenosyltransferase (MAT) catalyzes the synthesis of S adenosylmethionine, the major biological methyl donor. MAT1A and MAT2A encode two distinct MAT isoforms in mammals. MAT2A is expressed in nonhepatic tissues, whereas MAT1A is expressed in the liver. A third gene, MAT2B, encodes a MAT2A regulatory protein. We resequenced MAT2A and MAT2B exons, splice junctions, and flanking regions using 288 DNA samples from three ethnic groups and also imputed additional single nucleotide polymorphisms (SNPs) across both genes using data from the 1000 Genomes Project. For MAT2A, resequencing identified 74 polymorphisms, including two nonsynonymous (ns) SNPs. Functional genomic studies of wild type and the two MAT2A variant allozymes (Val11 and Val205) showed that the Val11 allozyme had approximately 40% decreases in levels of enzyme activity and immunoreactive protein after COS-1 cell transfection. For MAT2B, 44 polymorphisms, 2 nonsynonymous, were identified during resequencing. Neither of the two MAT2B nsSNPs displayed alterations in levels of protein. Imputation using 1000 Genomes Project data resulted in 1730 additional MAT2A and 1997 MAT2B polymorphisms within +/- 200 kilobases of each gene, respectively. Coexpression of MAT2A and MAT2B in COS-1 cells resulted in significantly increased MAT enzyme activity that correlated with increased MAT2A and MAT2B immunoreactive protein, apparently as a result of decreased degradation. Finally, studies of mRNA expression in lymphoblastoid cells showed that 7 SNPs in MAT2A and 16 SNPs in MAT2B were significantly associated with mRNA expression with p < 0.01. These observations provide a foundation for future mechanistic and clinical translational pharmacogenomic studies of MAT2A/2B. PMID- 21813469 TI - Intestinal renin-angiotensin system is stimulated after deletion of Lkb1. AB - BACKGROUND AND AIMS: LKB1 is a serine-threonine kinase, mutation of which can lead to the development of multiple benign intestinal hamartomas (Peutz-Jeghers syndrome). In this study, the authors investigate the mechanisms underlying this phenotype by exploring the transcriptional changes associated with Lkb1 deletion in intestinal epithelium. METHODS: The authors used mice with Lkb1 deleted in the intestinal epithelium using a Cyp1a1-specific inducible Cre recombinase and used Affymetrix (Santa Clara, California, USA) microarray analysis to examine the transcriptional changes occurring immediately after Lkb1 loss. The authors also generated crypt-villus organoid culture to analyse Lkb1 role in intestinal responses to exogenous stimuli. RESULTS: Affymetrix analysis identified the most significant change to be in Ren1 expression, a gene encoding a protease involved in angiotensinogen processing. Lkb1 deletion also enhanced ACE expression and subsequently angiotensin II (AngII) production in the mouse intestine. Intestinal apoptosis induced by Lkb1 deficiency was suppressed by ACE inhibitor captopril. Lkb1-deficient intestinal epithelium showed dynamic changes in AngII receptor type 1, suggesting a possible compensatory response to elevated AngII levels. A similar reduction in epithelial AngII receptor type 1 was also observed in human Peutz-Jeghers syndrome tumours contrasting with high expression of the receptor in the tumour stroma. Mechanistically, the authors showed two pieces of data that position Lkb1 in renin expression regulation, and they implied the importance of Lkb1 in linking cell responses with nutrient levels. First, the authors showed that Lkb1 deletion in isolated epithelial organoid culture resulted in renin upregulation only when the organoids were challenged with external cues such as AngII; second, that renin upregulation was dependent upon the MEK/ERK pathway in a circadian fashion and corresponded to active feeding time when nutrient levels were high. CONCLUSIONS: Taken together, these data reveal a novel role for Lkb1 in regulation of the gastrointestinal renin-angiotensin system. PMID- 21813470 TI - Overexpression of EIF5A2 promotes colorectal carcinoma cell aggressiveness by upregulating MTA1 through C-myc to induce epithelial-mesenchymaltransition. AB - BACKGROUND AND AIMS: The authors have previously isolated a putative oncogene, eukaryotic initiation factor 5A2 (EIF5A2) from 3q26. In this study, EIF5A2 was characterised for its role in colorectal carcinoma (CRC) aggressiveness and underlying molecular mechanisms. METHODS: The expression dynamics of EIF5A2 were examined by immunohistochemistry in a cohort of carcinomatous and non-neoplastic colorectal tissues and cells. A series of in-vivo and in-vitro assays was performed to elucidate the function of EIF5A2 in CRC and its underlying mechanisms. RESULTS: The overexpression of EIF5A2 was examined by immunohistochemistry in 102/229 (44.5%) CRC patients, and it was significantly correlated with tumour metastasis and determined to be an independent predictor of shortened survival (p<0.05). Ectopic overexpression of EIF5A2 in CRC cells enhanced cell motility and invasion in vitro and tumour metastasis in vivo, and induced epithelial-mesenchymal transition (EMT). The depletion of EIF5A2 expression prevented CRC cell invasiveness and inhibited EMT. Importantly, the metastasis-associated protein 1 (MTA1) gene was identified as a potential downstream target of EIF5A2 in CRC cells, and knockdown of MTA1 eliminated the augmentation of carcinoma cell migration, invasion and EMT by ectopic EIF5A2. The overexpression of EIF5A2 in CRC cells substantially enhanced the enrichment of c myc on the promoter of MTA1, and MTA1 upregulation by EIF5A2 was partly dependent on c-myc. CONCLUSION: The data suggest that EIF5A2 plays an important oncogenic role in CRC aggressiveness by the upregulation of MTA1 to induce EMT, and EIF5A2 could be employed as a novel prognostic marker and/or effective therapeutic target for CRC. PMID- 21813471 TI - Hepatitis C virus non-structural 3/4A protein interferes with intrahepatic interferon-gamma production. AB - BACKGROUND: The non-structural (NS) 3/4A protease/helicase of the hepatitis C virus is known to modulate signalling pathways in the infected hepatocyte by cleaving CARD adaptor inducing IFNbeta (Cardif), T-cell protein tyrosine phosphatase (TC-PTP) and TIR domain-containing adaptor inducing IFNbeta (TRIF), but the effects of NS3/4A in vivo still remain unclear. AIM: To investigate the influence of NS3/4A on intracellular and intercellular signalling in vivo by analysing the intrahepatic inflammatory response of naive, lipopolysaccharide (LPS)/D-galactosamine (D-galN) or tumour necrosis factor-alpha (TNFalpha)/D-galN treated NS3/4A-transgenic (Tg) mice. METHODS: The intrahepatic immunity of naive and LPS/D-galN- or TNFalpha/D-galN-treated NS3/4A-Tg mice was determined using western blot, ELISA, real-time PCR, flow cytometry and survival monitoring. The injection of cytokines or antibodies against signalling components was performed to analyse the relevance of the respective pathways for the investigated issues. A Tg mouse lineage expressing an inactivated NS3/4A protease (NS3/4A(Ile1073Ala) Tgs) was generated to examine if protective effects were NS3/4A protease dependent. RESULTS: The activation of hepatic signal transducer and activator of transcription 1 and 2 was impaired in NS3/4A-Tg mice after treatment with LPS/D galN or TNFalpha/D-galN. This was paralleled by a reduction in hepatic interferon gamma (IFNgamma). Reconstitution of IFNgamma reverted the resistance to LPS/TNFalpha in NS3/4A-Tg mice. Subsequently, blocking IFNgamma in vivo rendered wild-type mice resistant against treatment with LPS/TNFalpha. A new Tg mouse expressing an inactivated NS3/4A protease had the same phenotype as wild-type mice with respect to hepatic IFNgamma levels and sensitivity to LPS/d-galN. Finally, the chemokine profile was altered in the NS3/4A-Tg mice towards an anti inflammatory state, which helps to explain the altered immune cell subsets and reduction in hepatic IFNgamma production. CONCLUSIONS: Our data demonstrate that the NS3/4A protease reduces the intrahepatic production of IFNgamma and alters TNFalpha-mediated effects, thereby impairing the hepatic inflammatory response. This may contribute to viral persistence. PMID- 21813472 TI - MicroRNA-375 inhibits tumour growth and metastasis in oesophageal squamous cell carcinoma through repressing insulin-like growth factor 1 receptor. AB - BACKGROUND: To understand the involvement of micro-RNA (miRNA) in the development and progression of oesophageal squamous cell carcinoma (ESCC), miRNA profiles were compared between tumour and corresponding non-tumour tissues. METHODS: miRCURY LNA array was used to generate miRNA expressing profile. Real-time quantitative PCR was applied to detectthe expression of miR-375 in ESCC samples and its correlation with insulin-like growth factor 1 receptor (IGF1R). Methylation-specific PCR was used to study the methylation status in the promoter region of miR-375. The tumour-suppressive effect of miR-375 was determined by both in-vitro and in-vivo assays. RESULTS: The downregulation of miR-375 was frequently detected in primary ESCC, which was significantly correlated with advanced stage (p=0.003), distant metastasis (p<0.0001), poor overall survival (p=0.048) and disease-free survival (p=0.0006). Promoter methylation of miR-375 was detected in 26 of 45 (57.8%) ESCC specimens. Functional assays demonstrated that miR-375 could inhibit clonogenicity, cell motility, cell proliferation, tumour formation and metastasis in mice. Further study showed that miR-375 could interact with the 3'-untranslated region of IGF1R and downregulate its expression. In clinical specimens, the expression of IGF1R was also negatively correlated with miR-375 expression (p=0.008). CONCLUSIONS: This study demonstrates that miR-375 has a strong tumour-suppressive effect through inhibiting the expression of IGF1R. The downregulation of miR-375, which is mainly caused by promoter methylation, is one of the molecular mechanisms involved in the development and progression of ESCC. PMID- 21813473 TI - Neuronal guidance molecule netrin-1 attenuates inflammatory cell trafficking during acute experimental colitis. AB - BACKGROUND: Inflammatory bowel diseases, encompassing Crohn's disease and ulcerative colitis, are characterised by persistent leucocyte tissue infiltration leading to perpetuation of an inappropriate inflammatory cascade. The neuronal guidance molecule netrin-1 has recently been implicated in the orchestration of leucocyte trafficking during acute inflammation. We therefore hypothesised that netrin-1 could modulate leucocyte infiltration and disease activity in a model of inflammatory bowel disease. DESIGN: DSS-colitis was performed in mice with partial genetic netrin-1 deficiency (Ntn-1(+/-) mice) or wild-type mice treated with exogenous netrin-1 via osmotic pump to examine the role of endogenous and therapeutically administered netrin-1. These studies were supported by in vitro models of transepithelial migration and intestinal epithelial barrier function. RESULTS: Consistent with our hypothesis, we observed induction of netrin-1 during intestinal inflammation in vitro or in mice exposed to experimental colitis. Moreover, mice with partial netrin-1 deficiency demonstrated an exacerbated course of DSS-colitis compared to littermate controls, with enhanced weight loss and colonic shortening. Conversely, mice treated with exogenous mouse netrin-1 experienced attenuated disease severity. Importantly, permeability studies and quantitative assessment of apoptosis reveal that netrin-1 signalling events do not alter mucosal permeability or intestinal epithelial cell apoptosis. In vivo studies of leucocyte transmigration demonstrate suppression of neutrophil trafficking as a key function mediated by endogenous or exogenously administered netrin-1. Finally, genetic studies implicate the A2B adenosine receptor in netrin 1-mediated protection during DSS-colitis. CONCLUSIONS: The present study identifies a previously unrecognised role for netrin-1 in attenuating experimental colitis through limitation of neutrophil trafficking. PMID- 21813474 TI - Pharmacological inhibition of the chemokine CCL2 (MCP-1) diminishes liver macrophage infiltration and steatohepatitis in chronic hepatic injury. AB - OBJECTIVE: Monocyte chemoattractant protein-1 (MCP-1, CCL2), the primary ligand for chemokine receptor C-C chemokine receptor 2 (CCR2), is increased in livers of patients with non-alcoholic steatohepatitis (NASH) and murine models of steatohepatitis and fibrosis. It was recently shown that monocyte/macrophage infiltration into the liver upon injury is critically regulated by the CCL2/CCR2 axis and is functionally important for perpetuating hepatic inflammation and fibrogenesis. The structured L-enantiomeric RNA oligonucleotide mNOX-E36 (a so called Spiegelmer) potently binds and inhibits murine MCP-1. Pharmacological inhibition of MCP-1 with mNOX-E36 was investigated in two murine models of chronic liver diseases. METHODS: Pharmacological inhibition of MCP-1 by thrice weekly mNOX-E36 subcutaneously was tested in murine models of acute or chronic carbon tetrachloride (CCl(4))- and methionine-choline-deficient (MCD) diet induced chronic hepatic injury in vivo. RESULTS: Antagonising MCP-1 by mNOX-E36 efficiently inhibited murine monocyte chemotaxis in vitro as well as migration of Gr1(+) (Ly6C(+)) blood monocytes into the liver upon acute toxic injury in vivo. In murine models of CCl(4)- and MCD diet-induced hepatic injury, the infiltration of macrophages into the liver was significantly decreased in anti-MCP-1-treated mice as found by fluorescence-activated cell sorting (FACS) analysis and immunohistochemistry. In line with lower levels of intrahepatic macrophages, proinflammatory cytokines (tumour necrosis factor alpha, interferon gamma and interleukin 6) were significantly reduced in liver tissue. Overall fibrosis progression over 6 (CCl(4)) or 8 weeks (MCD diet) was not significantly altered by anti-MCP-1 treatment. However, upon MCD diet challenge a lower level of fatty liver degeneration (histology score, Oil red O staining, hepatic triglyceride content, lipogenesis genes) was detected in mNOX-E36-treated animals. mNOX-E36 also ameliorated hepatic steatosis upon therapeutic administration. CONCLUSIONS: These results demonstrate the successful pharmacological inhibition of hepatic monocyte/macrophage infiltration by blocking MCP-1 during chronic liver damage in two in vivo models. The associated ameliorated steatosis development suggests that inhibition of MCP-1 is an interesting novel approach for pharmacological treatment in liver inflammation and steatohepatitis. PMID- 21813475 TI - Increased risk of end-stage renal disease in individuals with coeliac disease. AB - OBJECTIVE: The prevalence of end-stage renal disease (ESRD) is increasing worldwide. Although increased levels of coeliac disease (CD) autoantibodies are often seen in renal disease, the importance of biopsy-verified CD for the risk of future ESRD is unclear. The aim of this study was therefore to investigate the risk of future ESRD in individuals with CD. METHODS: This was a population-based prospective cohort study. 29,050 individuals with CD (Marsh III) were identified through small-intestinal biopsy reports obtained between July 1969 and February 2008 in Sweden's 28 pathology departments. ESRD was defined as the need for renal dialysis or renal transplant in accordance with the international classification of disease and procedure codes in Swedish patient registers. Using Cox regression, the risk of ESRD in individuals with CD compared with age- and sex matched reference individuals was estimated. RESULTS: During follow-up, 90 individuals with CD developed ESRD (expected count 31). This corresponded to a HR for ESRD of 2.87 (95% CI 2.22 to 3.71, p<0.001). Adjusting for diabetes mellitus had only a marginal effect on the risk estimate (HR 2.52, 95% CI 1.92 to 3.31). Excluding individuals with any urinary/renal disorder before study entry, the HR for ESRD in CD was 2.47 (95% CI 1.80 to 3.40). When restricting the outcome measure to ESRD confirmed by independent data from the Swedish Renal Registry (SRR), the risk estimate increased to 3.20 (95% CI 2.39 to 4.28). CONCLUSION: This study indicates that individuals with biopsy-verified CD suffer increased risk of subsequent ESRD. PMID- 21813476 TI - Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS): a new autosomal dominant syndrome. AB - OBJECTIVE: The purpose of this study was the clinical and pathological characterisation of a new autosomal dominant gastric polyposis syndrome, gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS). METHODS: Case series were examined, documenting GAPPS in three families from Australia, the USA and Canada. The affected families were identified through referral to centralised clinical genetics centres. RESULTS: The report identifies the clinical and pathological features of this syndrome, including the predominant dysplastic fundic gland polyp histology, the exclusive involvement of the gastric body and fundus, the apparent inverse association with current Helicobacter pylori infection and the autosomal dominant mode of inheritance. CONCLUSIONS: GAPPS is a unique gastric polyposis syndrome with a significant risk of gastric adenocarcinoma. It is characterised by the autosomal dominant transmission of fundic gland polyposis, including areas of dysplasia or intestinal-type gastric adenocarcinoma, restricted to the proximal stomach, and with no evidence of colorectal or duodenal polyposis or other heritable gastrointestinal cancer syndromes. PMID- 21813477 TI - The GNAT library for local and remote gene mention normalization. AB - SUMMARY: Identifying mentions of named entities, such as genes or diseases, and normalizing them to database identifiers have become an important step in many text and data mining pipelines. Despite this need, very few entity normalization systems are publicly available as source code or web services for biomedical text mining. Here we present the Gnat Java library for text retrieval, named entity recognition, and normalization of gene and protein mentions in biomedical text. The library can be used as a component to be integrated with other text-mining systems, as a framework to add user-specific extensions, and as an efficient stand-alone application for the identification of gene and protein names for data analysis. On the BioCreative III test data, the current version of Gnat achieves a Tap-20 score of 0.1987. AVAILABILITY: The library and web services are implemented in Java and the sources are available from http://gnat.sourceforge.net. CONTACT: jorg.hakenberg@roche.com. PMID- 21813478 TI - GlobalMIT: learning globally optimal dynamic bayesian network with the mutual information test criterion. AB - MOTIVATION: Dynamic Bayesian networks (DBN) are widely applied in modeling various biological networks including the gene regulatory network (GRN). Due to the NP-hard nature of learning static Bayesian network structure, most methods for learning DBN also employ either local search such as hill climbing, or a meta stochastic global optimization framework such as genetic algorithm or simulated annealing. RESULTS: This article presents GlobalMIT, a toolbox for learning the globally optimal DBN structure from gene expression data. We propose using a recently introduced information theoretic-based scoring metric named mutual information test (MIT). With MIT, the task of learning the globally optimal DBN is efficiently achieved in polynomial time. AVAILABILITY: The toolbox, implemented in Matlab and C++, is available at http://code.google.com/p/globalmit. CONTACT: vinh.nguyen@monash.edu; madhu.chetty@monash.edu SUPPLEMENTARY INFORMATION: Supplementary data is available at Bioinformatics online. PMID- 21813480 TI - Boredom proneness in a psychiatric inpatient population. AB - BACKGROUND: Boredom has been reported as a common experience for service users of acute psychiatric wards. It has been associated with negative mental and physical health. Research has yet to show what factors are associated with boredom proneness within the acute psychiatric population. AIMS: (1) To investigate the distribution of boredom proneness in a population of mentally ill inpatients according to age, gender, diagnosis, Mental Health Act status and length of stay in hospital. (2) To test the hypothesis that boredom proneness is negatively correlated with autonomous activity levels. METHOD: Two self-report questionnaires were used with 55 inpatients of acute psychiatric wards: the Boredom Proneness Scale (Farmer & Sundberg, 1986) and the Hospital Anxiety and Depression Scale (Zigmond & Snaith, 1983). Questions were also asked about individuals' activity engagement during their current admission. Data on age, gender, diagnosis, ethnicity, Mental Health Act status and length of stay were collected from case notes. RESULTS AND CONCLUSIONS: The highest incidence of boredom proneness was in participants with depression. Those detained under the Mental Health Act appeared less boredom prone than those admitted voluntarily. Boredom proneness was not associated with age, gender or length of stay. There was an association between engagement in more autonomous activities and lower boredom proneness. PMID- 21813479 TI - Migrant pathways to community mental health centres in Italy. AB - BACKGROUND: Many studies indicate that migrants in western countries have limited access to and low utilization of community mental health centres (CMHCs) despite the high prevalence of mental disorders. AIMS: We aimed to compare migrant pathways to care across four CMHCs located in different Italian provinces and to identify pathway to care predictors. METHODS: Migrants attending the four CMHCs between 1 July 1999 and 31 December 2007 were included in the study. Data were gathered retrospectively from clinical data sets and chart review. RESULTS: Five hundred and eleven (511) migrants attended the four CMHCs, 61% were referred by GPs or other health services and 39% followed non-medical pathways to care (self referral or through social and voluntary organizations), with important site variations. Younger age and being married were predictors of medical pathways to care; lacking a residence permit and having a diagnosis of substance abuse were related to non-medical pathways. CONCLUSIONS: Pathways to CMHCs are complex and influenced by many factors. Non-medical pathways to care seem to be frequent among migrants in Italy. More attention should be paid to developing psychiatric consultation liaison models that also encompass the social services and voluntary organizations. PMID- 21813481 TI - Employment status, inflation and suicidal behaviour: an analysis of a stratified sample in Italy. AB - BACKGROUND: There is abundant empirical evidence of a surplus risk of suicide among the unemployed, although few studies have investigated the influence of economic downturns on suicidal behaviours in an employment status-stratified sample. AIMS: We investigated how economic inflation affected suicidal behaviours according to employment status in Italy from 2001 to 2008. METHODS: Data concerning economically active people were provided by the Italian Institute for Statistical Analysis and by the International Monetary Fund. The association between inflation and completed versus attempted suicide with respect to employment status was investigated in every year and quarter-year of the study time frame. We considered three occupational categories: employed, unemployed who were previously employed and unemployed who had never worked. RESULTS: The unemployed are at higher suicide risk than the employed. Among the PE, a significant association between inflation and suicide attempt was found, whereas no association was reported concerning completed suicides. No association was found between completed and attempted suicides among the employed, the NE and inflation. Completed suicide in females is significantly associated with unemployment in every quarter-year. CONCLUSION: The reported vulnerability to suicidal behaviours among the PE as inflation rises underlines the need of effective support strategies for both genders in times of economic downturns. PMID- 21813483 TI - Profiles of individually defined recovery of people with major psychiatric problems. AB - BACKGROUND: Research on factors associated with individually defined recovery is limited. Several phases of recovery have been described in the literature. Individuals in these distinct phases have different characteristics and problems. AIMS: To identify classes of people with major psychiatric problems who have comparable profiles of individually defined recovery, to relate these classes to the phases of recovery as described by Spaniol, Wewiorsky, Gagne, and Anthony (2002), and to associate the classes to demographic and psychiatric characteristics, and health-related variables. METHODS: Data of 333 participants with major psychiatric problems were used. A latent class analysis was conducted on the mean scores of four proxy measures of recovery. RESULTS: Three well defined classes were found that differed on the recovery measures. The classes differed significantly on variables corresponding to Spaniol's phases of recovery (Spaniol et al., 2002) and on health care utilization, health care needs and anxiety disorder, but not on demographic variables. CONCLUSIONS: It is possible to identify classes of people with major psychiatric problems who have comparable profiles of individually defined recovery that seem to correspond to phases of recovery. More knowledge of the characteristics of people in different phases of recovery will contribute to more fine-tuned and recovery-oriented health care. PMID- 21813482 TI - Counselling and psychotherapy services in more developed and developing regions in China: a comparative investigation of practitioners and current service delivery. AB - BACKGROUND: Counselling and psychotherapy services have taken off with uneven speed across China since the 1980s after several years of stagnation. Researchers have attributed socioeconomic development (or the lack thereof) and regional differences as main barriers to the development in this field. However, little is known today about the status of counselling and psychotherapy services across China. AIMS: To investigate and compare the current situation of practitioners and service delivery of counselling and psychotherapy in more developed and developing regions across China. METHOD: Convenience sampling methods from counselling and psychological services organizations in 29 Chinese provinces, municipalities or autonomous regions were used to recruit 1,543 participants to take part in the investigation by completing a 93-item self-designed questionnaire. RESULTS: Organizations in developing and more developed regions in China varied in their current practices and employment situation of their practitioners, and in the quality of service delivery. However, counselling and psychotherapy offered at universities in both types of regions are of similar quality. CONCLUSION: In China, the level of socioeconomic development significantly influences the development of professional counselling and psychotherapy services. Important progress is evident in the field; however, the lack of systematic training and the scarcity of professional practitioners remain a challenge. PMID- 21813484 TI - Psychological well-being and risk perceptions of mothers in Kyiv, Ukraine, 19 years after the Chornobyl disaster. AB - BACKGROUND: The Chornobyl nuclear power plant explosion in April 1986 was one of the worst ecological disasters of the 20th century. As with most disasters, its long-term mental health consequences have not been examined. AIMS: This study describes the psychological well-being and risk perceptions of exposed women 19 20 years later and the risk factors associated with mental health. METHODS: We assessed Chornobyl-related post-traumatic stress disorder (PTSD), major depressive episode (MDE) and overall distress among three groups of women in Kyiv, Ukraine (N = 797): mothers of small children evacuated to Kyiv in 1986 from the contaminated area near the plant (evacuees); mothers of their children's classmates (neighbourhood controls); and population-based controls from Kyiv. Risk perceptions and epidemiologic correlates were also obtained. RESULTS: Evacuees reported poorer well-being and more negative risk perceptions than controls. Group differences in psychological well-being remained after adjustment for epidemiologic risk factors but became non-significant when Chornobyl risk perceptions were added to the models. CONCLUSIONS: The relatively poorer psychological well-being among evacuees is largely explained by their continued concerns about the physical health risks stemming from the accident. We suggest that this is due to the long-term, non-resolvable nature of health fears associated with exposure. PMID- 21813485 TI - The Nigerian home video boom: should Nigerian psychiatrists be worried? Lessons from content review and views of community dwellers. AB - BACKGROUND: Media depiction of sufferers of mental illness is a widely viewed source of stigmatization and studies have found stigmatizing depictions of mental illness in Nigerian films. With the recent boom in the Nigerian home video industry, there is a need to know how often Nigerians are exposed to films that contain scenes depicting mental illness and how much premium they place on such portrayals as reflecting reality. AIM: To assess the popularity of Nigerian home videos among Nigerian community dwellers and the frequency of their exposure to scenes depicting mental illness. METHODS: A semi-structured questionnaire was designed to obtain socio-demographic data and to find out how often respondents see scenes depicting 'madness' in home videos, as well as their views about the accuracy of such depictions from the orthodox psychiatry point of view. Current home videos available in video rental shops were selected for viewing and content review. RESULTS: All 676 respondents had seen a Nigerian home video in the preceding 30 days: 528 (78%) reported scenes depicting 'mad persons'; 472 (70%) reported that the scenes they saw agreed with their own initial understanding of the cause and treatment of 'madness'. About 20% of the films depicted mental illness. The most commonly depicted cause was sorcery and enchantment by witches and wizards, while the most commonly depicted treatment was magical and spiritual healing by diviners and religious priests. CONCLUSIONS: Nigerian home video is a popular electronic media in Nigeria and scenes depicting mental illness are not uncommon. The industry could be harnessed for promoting mental health literacy. PMID- 21813486 TI - Trust, choice and power in mental health care: experiences of patients with psychosis. AB - BACKGROUND: Trust, choice and power are critical issues in clinical practice, public policies and a post-modern understanding of mental health care. We aimed to investigate the experiences and attitudes of patients with psychosis in relation to trust, choice and power. METHOD: We conducted 20 in-depth interviews with patients with psychotic disorders in care of NHS services. The interviews were subjected to thematic analysis. DISCUSSION: Patients discussed aspects of their care in terms of dimensions that enhance or undermine trust, choice and power. Two interpretive themes emerged from this data. First, patients perceive the need for a shifting balance of power, according to the severity of their illness and their own experience of care, but feel that threats of coercion and neglect disable them. Second, they appreciate the expertise of clinicians, but particularly value 'the personal touch' that goes beyond this expertise, including personal disclosure about their own lives, common acts of kindness and conversation outside clinical matters. Patients view trust as a two-way process with responsibility shared between patient and clinician. CONCLUSIONS: The active involvement of patients with psychosis in their individual care may be strengthened, particularly when they are not acutely ill and have more experience of their illness. While patients value expertise and respect in interactions with clinicians, they also appreciate a 'personal touch', which may go beyond current notions of professionalism. PMID- 21813487 TI - Trends in home smoking bans in the U.S.A., 1995-2007: prevalence, discrepancies and disparities. AB - BACKGROUND: Home smoking bans significantly reduce the likelihood of secondhand smoke exposure among children and non-smoking adults. The purpose of this study was to examine national trends in (1) the adoption of home smoking bans, (2) discrepancies in parental smoking ban reports and (3) household and parental correlates of home smoking bans among households with underage children from 1995 to 2007. METHODS: The authors used data from the 1995-1996, 1998-1999, 2001-2002, 2003 and 2006-2007 Tobacco Use Supplement of the US Current Population Survey to estimate prevalence rates and logistic regression models of parental smoking ban reports by survey period. RESULTS: Overall, the prevalence of a complete home smoking bans increased from 58.1% to 83.8% (p<0.01), while discrepancies in parental reports decreased from 12.5% to 4.6% (p<0.01) from 1995 to 2007. Households with single parent, low income, one or two current smokers, parents with less than a college education or without infants were consistently less likely to report a home smoking ban over this period (p<0.05). CONCLUSIONS: Despite general improvements in the adoption of home smoking bans and a reduction on parental discrepancies, disparities in the level of protection from secondhand smoke have persisted over time. Children living in households with single parents, low income, current smoker parents, less educated parents or without infants are less likely to be protected by a home smoking ban. These groups are in need of interventions promoting the adoption of home smoking bans to reduce disparities in tobacco-related diseases. PMID- 21813489 TI - Early intervention for schizophrenia: the risk-benefit ratio of antipsychotic treatment in the prodromal phase. PMID- 21813488 TI - A very early-branching Staphylococcus aureus lineage lacking the carotenoid pigment staphyloxanthin. AB - Here we discuss the evolution of the northern Australian Staphylococcus aureus isolate MSHR1132 genome. MSHR1132 belongs to the divergent clonal complex 75 lineage. The average nucleotide divergence between orthologous genes in MSHR1132 and typical S. aureus is approximately sevenfold greater than the maximum divergence observed in this species to date. MSHR1132 has a small accessory genome, which includes the well-characterized genomic islands, nuSAalpha and nuSabeta, suggesting that these elements were acquired well before the expansion of the typical S. aureus population. Other mobile elements show mosaic structure (the prophage phiSa3) or evidence of recent acquisition from a typical S. aureus lineage (SCCmec, ICE6013 and plasmid pMSHR1132). There are two differences in gene repertoire compared with typical S. aureus that may be significant clues as to the genetic basis underlying the successful emergence of S. aureus as a pathogen. First, MSHR1132 lacks the genes for production of staphyloxanthin, the carotenoid pigment that confers upon S. aureus its characteristic golden color and protects against oxidative stress. The lack of pigment was demonstrated in 126 of 126 CC75 isolates. Second, a mobile clustered regularly interspaced short palindromic repeat (CRISPR) element is inserted into orfX of MSHR1132. Although common in other staphylococcal species, these elements are very rare within S. aureus and may impact accessory genome acquisition. The CRISPR spacer sequences reveal a history of attempted invasion by known S. aureus mobile elements. There is a case for the creation of a new taxon to accommodate this and related isolates. PMID- 21813490 TI - Further evidence of infectious insults in the pathogenesis and pathophysiology of schizophrenia. PMID- 21813491 TI - Consequences of antipsychotic medications for the dementia patient. PMID- 21813492 TI - The NIMH-CATIE Schizophrenia Study: what did we learn? PMID- 21813493 TI - Moments of (in)decision. PMID- 21813494 TI - Medical marijuana use and suicide attempt in a patient with major depressive disorder. PMID- 21813495 TI - Aby Warburg, 1866-1929. PMID- 21813496 TI - A new lead from genetic studies in depressed siblings: assessing studies of chromosome 3. AB - Studies by Breen et al. and Pergadia et al. find evidence for genetic linkage between major depressive disorder and the same region on chromosome 3. The linked region contains the gene GRM7, which encodes a protein for the metabotropic glutamate receptor 7 (mGluR7). Both studies used affected sibling pairs, and neither was able to replicate its finding using association studies in individuals from larger population-based studies. Other family-based studies have also failed to find a signal in this region. Furthermore, there are some differences in how the phenotype was classified, with Breen et al. finding evidence only in the most severely affected patients. Nonetheless, the finding is not without other substantive support. A meta-analysis of 3,957 case subjects with major depressive disorder and 3,428 control subjects from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D), Genetics of Recurrent Early-onset Depression (GenRED), and the Genetic Association Information Network MDD (GAIN-MDD) data sets demonstrated a region of association for major depressive disorder within GRM7. Thus, the significance of this finding remains uncertain, although it points to a gene that might hold significant promise for further developments in studying the pathophysiology and treatment of major depressive disorder. PMID- 21813497 TI - Muting the voice: a case of arterial spin labeling-monitored transcranial direct current stimulation treatment of auditory verbal hallucinations. PMID- 21813498 TI - Reduced pain perception in schizophrenia: a case of an undetected intrathoracic pencil. PMID- 21813499 TI - Internet searches for a specific suicide method follow its high-profile media coverage. PMID- 21813500 TI - Involuntary movements associated with cetirizine use. PMID- 21813501 TI - Expression of concern. PMID- 21813502 TI - ZnuABC and ZosA zinc transporters are differently involved in competence development in Bacillus subtilis. AB - Disruptants of genes encoding the ZnuABC high-affinity zinc incorporator and zosA encoding a P-type ATPase for zinc incorporation were identified to show low transformability. The low transformability of the znuB cells was rescued by excess zinc addition and epistatic analysis of the mutation revealed no effect on the expression of comK, which encodes a master regulator for late com operons. We further examined the expression of each late com operon in the znuA mutant and found that the znuA mutation specifically inhibited the expression of comF, but not the other late com operons. The addition of zinc also rescued the low transformability of the zosA cells. In zosA cells, transcription of comK was severely repressed. Using a strain carrying comK driven by a xylose-inducible promoter, we showed that the zosA mutation inhibited the post-transcriptional control of comK. The addition of zinc also rescued the defect of xylose-inducible comK expression in zosA cells, suggesting that post-transcriptional control of comK requires zinc incorporation. Taken together, we propose that the both ZnuABC and ZosA-mediated zinc incorporation is involved in competence development, although the two zinc transporters are differently implicated in this developmental process. PMID- 21813503 TI - Engineering of the glycan-binding specificity of Agrocybe cylindracea galectin towards alpha(2,3)-linked sialic acid by saturation mutagenesis. AB - Sialic acid represents a critical sugar component located at the outermost position of glycoconjugates, playing important roles in extensive biological processes. To date, however, there have been only few probes which show affinity to alpha(2,3)-linked sialic acid-containing glycoconjugates. Agrocybe cylindracea galectin is known to have a relatively high affinity towards Neu5Acalpha(2,3)Galbeta(1,4)Glc (3'-sialyl lactose), but it significantly recognizes various beta-galactosides, such as Galbeta(1,4)GlcNAcbeta (LacNAc) and Galbeta(1,3)GalNAcalpha (T-antigen). To eliminate this background specificity, we focused an acidic amino acid residue (Glu86), which interacts with the glucose unit of 3'-sialyl lactose and substituted it with all other amino acids. Carbohydrate-binding specificity of the derived 14 mutants was analysed by surface plasmon resonance, and it was found that E86D mutant (Glu86 substituted with Asp) substantially lost the binding ability to LacNAc and T-antigen, while it retained the high affinity for 3'-sialyl lactose. Further, frontal affinity chromatography analysis using 132 pyridylaminated oligosaccharides confirmed that the E86D mutant had a strong preference for alpha(2,3)-disialo biantennary N linked glycan. However, it showed the large decrease in the affinity for any of the asialo complex-type N-glycans and the glycolipid-type glycans. Thus, the developed mutant E86D will be of practical use in various fields relevant to cell biology and glycotechnology. PMID- 21813504 TI - Structure of Thermus thermophilus homoisocitrate dehydrogenase in complex with a designed inhibitor. AB - Homoisocitrate dehydrogenase (HICDH) is involved in the alpha-aminoadipate pathway of lysine biosynthesis in some bacteria and higher fungi, and catalyses the oxidative decarboxylation of (2R,3S)-homoisocitrate into 2-ketoadipate using NAD(+) as a coenzyme. In this study, the crystal structure of Thermus thermophilus HICDH in a binary complex with a designed inhibitor, (2S,3S) thiahomoisocitrate, has been determined at 2.6 A resolution. The inhibitor observed as a decarboxylated product interacts through hydrogen bonding to Arg 118, Tyr 125 and Lys 171 in the active site. The induced fitting was also observed around the region consisting of residues 120-141, which shifted up to 2.8 A towards the active site. In addition, it was found that the complex structure adopts a closed conformation in two domains. While the structure of apo HICDH shows that a catalytic residue Tyr 125 and Arg 85 that engages in substrate recognition are flipped out of the active site, these residues turn towards the active site in the complex structure. The results revealed that they directly interact with a substrate and are involved in catalysis or substrate recognition. Furthermore, by comparing the binary complex with the quaternary complex of Escherichia coli isocitrate dehydrogenase, the substrate recognition mechanism of HICDH is also discussed. PMID- 21813505 TI - C/EBPalpha, C/EBPalpha oncoproteins, or C/EBPbeta preferentially bind NF-kappaB p50 compared with p65, focusing therapeutic targeting on the C/EBP:p50 interaction. AB - Canonical nuclear factor kappaB (NF-kappaB) activation signals stimulate nuclear translocation of p50:p65, replacing inhibitory p50:p50 with activating complexes on chromatin. C/EBP interaction with p50 homodimers provides an alternative pathway for NF-kappaB target gene activation, and interaction with p50:p65 may enhance gene activation. We previously found that C/EBPalpha cooperates with p50, but not p65, to induce Bcl-2 transcription and that C/EBPalpha induces Nfkb1/p50, but not RelA/p65, transcription. Using p50 and p65 variants containing the FLAG epitope at their N- or C-termini, we now show that C/EBPalpha, C/EBPalpha myeloid oncoproteins, or the LAP1, LAP2, or LIP isoforms of C/EBPbeta have markedly higher affinity for p50 than for p65. Deletion of the p65 transactivation domain did not increase p65 affinity for C/EBPs, suggesting that unique residues in p50 account for specificity, and clustered mutation of HSDL in the "p50 insert" lacking in p65 weakens interaction. Also, in contrast to Nfkb1 gene deletion, absence of the RelA gene does not reduce Bcl-2 or Cebpa RNA in unstimulated cells or prevent interaction of C/EBPalpha with the Bcl-2 promoter. Saturating mutagenesis of the C/EBPalpha basic region identifies R300 and nearby residues, identical in C/EBPbeta, as critical for interaction with p50. These findings support the conclusion that C/EBPs activate NF-kappaB target genes via contact with p50 even in the absence of canonical NF-kappaB activation and indicate that targeting C/EBP:p50 rather than C/EBP:p65 interaction in the nucleus will prove effective for inflammatory or malignant conditions, alone or synergistically with agents acting in the cytoplasm to reduce canonical NF-kappaB activation. PMID- 21813506 TI - Improving perceptions of teamwork climate with the Veterans Health Administration medical team training program. AB - There are differences between nurse and physician perceptions of teamwork. The purpose of this study was to determine whether these differences would be reduced with medical team training (MTT). The Safety Attitudes Questionnaire was administered to nurses and physicians working in the operating rooms of 101 consecutive hospitals before and at the completion of an MTT program. Responses to the 6 teamwork climate items on the Safety Attitudes Questionnaire were analyzed using nonparametric testing. At baseline, physicians had more favorable perceptions on teamwork climate items than nurses. Physicians demonstrated improvement on all 6 teamwork climate items. Nurses demonstrated improvement in perceptions on all teamwork climate items except "Nurse input is well received." Physicians still had a more favorable perception than nurses on all 6 teamwork climate items at follow-up. Despite an improvement in perceptions by physicians and nurses, baseline nurse-physician differences persisted at completion of the Veterans Health Administration MTT Program. PMID- 21813507 TI - The importance of place of residence in patient satisfaction. AB - OBJECTIVE: To determine the effect of patients' place of residence on their evaluations of care, and to explore related policy implications. STUDY DESIGN: We used a conditional regression analysis of stratum matched case controls to examine whether place of residence of patients living in the Greater Toronto Area (GTA) or in Ontario outside of the GTA affects patient satisfaction with their experiences during hospitalization. SETTING: One hundred and six acute care hospitals located in the province of Ontario, Canada. PARTICIPANTS: A total of 101 683 Ontario residents hospitalized as inpatients between 1 October 2002 and 30 June 2004. MAIN OUTCOME MEASURES: Patient satisfaction indicators publicly reported in Ontario comprising patient perceptions of consideration, responsiveness, communication, and overall impressions, scored on a continuous scale from 1 to 100. RESULTS: Patients who lived outside Toronto were consistently more satisfied than patients who lived inside Toronto when both types of patients were hospitalized in Toronto (P < 0.0001). In contrast, patients who lived inside Toronto were usually and substantially more satisfied than patients who lived outside Toronto when they were hospitalized in facilities outside Toronto (P < 0.02). These findings were consistent after adjustment for several patient-level predictor variables: age, sex, self-assessed health status and number of hospital stays in the last 6 months. CONCLUSION: Findings suggest that where patients live has a small but potentially important impact on how they rate their care. Residence may therefore be considered when designing public reporting systems and pay-for-performance programs. Further attention to patient level factors may be important to accurate and useful public reporting of patient satisfaction. PMID- 21813508 TI - How can managers in the hospital in the home units help to balance technology and physician-patient knowledge? AB - BACKGROUND: With the passing of time, knowledge like other resources can become obsolete. Thus, people in a healthcare system need to update their knowledge in order to keep pace with the ongoing changes in their operational environment. Information technology continually provides a great amount of new knowledge which can lead to healthcare professionals becoming overloaded with knowledge. This overloading can be alleviated by a process of unlearning which enables the professional to retain just the relevant and critical knowledge required to improve the quality of service provided by them. OBJECTIVE: This paper shows some of the tools and methods that Hospital-in-the-Home Units (HHUs) have used to update the physician-patient knowledge and the technology knowledge of the HHUs' personnel. DESIGN: A survey study was carried out in the HHU in Spanish health system in 2010. SETTING: Fifty-five doctors and 62 nurses belonging to 44 HHUs. INTERVENTIONS: None. RESULTS: Three hypotheses are presented and supported, which suggest that technology and physician-patient knowledge is related to the unlearning context and the unlearning context impacts positively on the quality of health services provided. CONCLUSION: The key benefits of the unlearning context for the quality of service provided in HHUs are clear: it enables them to identify and replace poor practices and also avoids the reinvention of the wheel (e.g.: by minimizing unnecessary work caused by the use of poor methods) and it reduces costs through better productivity and efficiency (improving services to patients). PMID- 21813509 TI - A simple approach to fairer hospital benchmarking using patient experience data. AB - OBJECTIVE: To determine the factors contributing most to variability in patient experience in order to present approaches for fairer benchmarking of hospitals and for quality improvement. DESIGN: Secondary analysis of data from a widely used survey on patient experience. SETTING: Inpatients from all 24 acute hospitals in the Canton of Bern in Switzerland. Data collection followed the standardized and validated Picker Institute methodology for a period of 13 weeks in the fall/winter of 2005. PARTICIPANTS: Inpatients age 18 years and older (n = 14 089), discharged within the sampling period. MAIN OUTCOME MEASURES: 'Patient experience', measured by the total Picker Problem Score (PPS) and by six domain scores (care, communication, respect, cooperation, organization, discharge management). RESULTS: In regression analysis, the patient factors self-reported health, age and education explained the highest proportion of variability in the PPS (4.8, 2.2 and 0.7%, respectively). Multiple linear adjustment for factors associated with patients removed between 29 and 33% of variability between hospital categories. The domain score means varied from under 5% for 'respect towards the patient' to 34% for 'discharge management'. Ranking of hospitals by domain scores differed from the ranking based on the total PPS. CONCLUSIONS: Statistical adjustment for patient mix and additional stratification for some hospital factors make benchmarking using patient survey data fairer and more transparent. Use of our approach for presenting quality data may make interpretation easier for the different target groups and may enhance the relevance of such information for decision-making. PMID- 21813510 TI - Gadd45a sensitizes medulloblastoma cells to irradiation and suppresses MMP-9 mediated EMT. AB - Medulloblastomas are the most common malignant tumors of the central nervous system during childhood. Radiation-induced medulloblastoma tumor recurrences are aggressive and metastatic in nature. In the present study, we demonstrate that Gadd45a expression can sensitize medulloblastoma cells to radiotherapy. We have elucidated the role of Gadd45a in ionizing radiation (IR)-induced G2-M arrest and invasion and metastatic potential of the medulloblastoma cancer cell lines DAOY and D283. We demonstrate that Gadd45a is induced by IR and results in p53 phosphorylation. The role of IR-induced Gadd45a in G2-M arrest is demonstrated by fluorescence-activated cell sorting analysis in the cells treated with siRNA Gadd45a and Ov-exp Gadd45a. We show that Ov-exp Gadd45a aggravates G2-M blockage and also increases binding of Gadd45a to Cdc2 by immunocytochemistry analysis. Furthermore, we show the anti-tumorigenic role of Gadd45a to be mediated by the negative regulation of IR-induced cancer cell invasion and migration-associated proteins, such as matrix metallopeptidase (MMP)-9 and beta-catenin. When compared with IR treatment alone, Ov-exp Gadd45a plus IR treatment resulted in decreased nuclear localization and increased membrane localization of beta-catenin, and this was further confirmed by membrane distribution. We also show that Ov-exp Gadd45a resulted in downregulation of MMP-9 and suppression of epithelial mesenchymal transition (EMT). Alternatively, inhibition of MMP-9 (pM) resulted in upregulation of Gadd45a and suppression of EMT. The anti-tumor effect of pM was correlated with increased expression of Gadd45a protein in nude mice intracranial tumors. Taken together, our studies demonstrate that upregulation of Gadd45a or suppression of MMP-9 (pM) with IR retards medulloblastoma tumor metastatic potential. PMID- 21813511 TI - Is surgery at progression a prognostic marker for improved 6-month progression free survival or overall survival for patients with recurrent glioblastoma? AB - Historically, the North American Brain Tumor Consortium used 6-month progression free survival (PFS6) as the primary outcome for recurrent glioma phase II clinical trials. In some trials, a subset of patients received the trial treatment before surgery to assess tumor uptake and biological activity. We compared PFS6 and overall survival (OS) for patients with glioblastoma undergoing surgery at progression to results for those without surgery to evaluate the impact of surgical intervention on these outcomes. Two data sets were analyzed. The first included 511 patients enrolled during the period 1998-2005, 105 of whom had surgery (excluding biopsies) during the study or <= 30 days prior to registration. Analysis was stratified on the basis of whether temozolomide was part of the protocol treatment regimen. The second data set included 247 patients enrolled during 2005-2008, 103 of whom underwent surgery during the clinical trial or immediately prior to study registration. A combined data set consisting of all patients who did not receive temozolomide was also compiled. No statistically significant difference in PFS6 or OS was found between the surgery and nonsurgery groups in either data set alone or in the combined data set (P > .45). We conclude that PFS6 and OS results for patients with and without surgical intervention at the time of progression are similar, allowing data from these patients to be combined in assessing the benefit of new treatments without the need for stratification or other statistical adjustment. PMID- 21813512 TI - International spread of an epidemic population of Salmonella enterica serotype Kentucky ST198 resistant to ciprofloxacin. AB - National Salmonella surveillance systems from France, England and Wales, Denmark, and the United States identified the recent emergence of multidrug-resistant isolates of Salmonella enterica serotype Kentucky displaying high-level resistance to ciprofloxacin. A total of 489 human cases were identified during the period from 2002 (3 cases) to 2008 (174 cases). These isolates belonged to a single clone defined by the multilocus sequence type ST198, the XbaI-pulsed-field gel electrophoresis cluster X1, and the presence of the Salmonella genomic island 1 variant SGI1-K. This clone was probably selected in 3 steps in Egypt during the 1990s and the early 2000s and has now spread to several countries in Africa and, more recently, in the Middle East. Poultry has been identified as a potential major vehicle for infection by this clone. Continued surveillance and appropriate control measures should be implemented by national and international authorities to limit the spread of this strain. PMID- 21813513 TI - Challenges and opportunities to identifying and controlling the international spread of salmonella. PMID- 21813514 TI - Leaf-lamina conductance contributes to an equal distribution of water delivery in current-year shoots of kudzu-vine shoot, Pueraria lobata. AB - Leaf-lamina resistance, R(L), accounts for a large fraction of branch resistance across a wide range of plant species. This work hypothesized that large R(L) is essential for distributing water equally to leaves on the shoot, and tested this hypothesis through theoretical analyses and measurements using over 10-m-long current-year shoots of kudzu vine, Pueraria lobata [Willd.] Ohwi. First, the hydraulic architecture and the distribution of the motive force achieving equal distribution of water delivery were theoretically obtained by simulating water flow through a hypothetical shoot comprising an axial pathway and several lateral pathways as a stem and leaves, respectively, in a kudzu-vine shoot. The model predicts that large resistance of the lateral pathway relative to that of the axial pathway is associated strongly with small variation in the hydraulic conductance of a pathway from the base of the axial pathways to the lateral pathway among the nodes, rendering water delivery to each lateral pathway equal under small variation in motive force for water flow. For the kudzu-vine shoot, the measured ratio of the lateral (a petiole) to the axial (a stem) resistance was 115. When R(L) was added to the lateral pathway, the ratio increased to 1136. According to the model prediction, these values imply that the hydraulic conductance of a pathway comprising a stem and a petiole, K(BP), is favored strongly at the basal nodes, while the hydraulic conductance of a pathway including a stem, a petiole and a lamina, K(SL), is slightly different across the nodes. For the shoots with leaf lamina, the diurnal change in transpiration rate was not different between the leaves on the three nodes dividing the shoot into four parts. K(SL) was not related significantly to node number. Conversely, K(BP) at the distal node was ~0.06-fold that at the basal node. Furthermore, the motive force for water flow should vary by 6.64-fold among nodes to compensate for the favored distribution of K(BP), which is an unrealistic value. These results indicate that R(L) contributes largely to an equal distribution of water delivery in a shoot, supporting our hypothesis. PMID- 21813515 TI - Ultraviolet-B-induced flavonoid accumulation in Betula pendula leaves is dependent upon nitrate reductase-mediated nitric oxide signaling. AB - Nitric oxide (NO) is an important signaling molecule involved in many physiological processes in plants. Nitric oxide generation and flavonoid accumulation are two early reactions of plants to ultraviolet-B (UV-B) irradiation. However, the source of UV-B-triggered NO generation and the role of NO in UV-B-induced flavonoid accumulation are not fully understood. In order to evaluate the origin of UV-B-triggered NO generation, we examined the responses of nitrate reductase (NR) activity and the expression levels of NIA1 and NIA2 genes in leaves of Betula pendula Roth (silver birch) seedlings to UV-B irradiation. The data show that UV-B irradiation stimulates NR activity and induces up regulation of NIA1 but does not affect NIA2 expression during UV-B-triggered NO generation. Pretreatment of the leaves with NR inhibitors tungstate (TUN) and glutamine (Gln) abolishes not only UV-B-triggered NR activities but also UV-B induced NO generation. Furthermore, application of TUN and Gln suppresses UV-B induced flavonoid production in the leaves and the suppression of NR inhibitors on UV-B-induced flavonoid production can be reversed by NO via its donor sodium nitroprusside. Together, the data indicate that NIA1 in the leaves of silver birch seedlings is sensitive to UV-B and the UV-B-induced up-regulation of NIA1 may lead to enhancement of NR activity. Furthermore, our results demonstrate that NR is involved in UV-B-triggered NO generation and NR-mediated NO generation is essential for UV-B-induced flavonoid accumulation in silver birch leaves. PMID- 21813516 TI - Root standing crop and chemistry after six years of soil warming in a temperate forest. AB - Examining the responses of root standing crop (biomass and necromass) and chemistry to soil warming is crucial for understanding root dynamics and functioning in the face of global climate change. We assessed the standing crop, total nitrogen (N) and carbon (C) compounds in tree roots and soil net N mineralization over the growing season after 6 years of experimental soil warming in a temperate deciduous forest in 2008. Roots were sorted into four different categories: live and dead fine roots (<=1mm in diameter) and live and dead coarse roots (1-4 mm in diameter). Total root standing crop (live plus dead) in the top 10 cm of soil in the warmed area was 42.5% (378.4 vs. 658.5 g m(-2)) lower than in the control area, while live root standing crop in the warmed area was 62% lower than in the control area. Soil net N mineralization over the growing season increased by 79.4% in the warmed relative to the control area. Soil warming did not significantly change the concentrations of C and C compounds (sugar, starch, hemicellulose, cellulose and lignin) in the four root categories. However, total N concentration in the live fine roots in the warmed area was 10.5% (13.7 vs. 12.4 mg g(-1)) higher and C:N ratio was 8.6% (38.5 vs. 42.1) lower than in the control area. The increase in N concentration in the live fine roots could be attributed to the increase in soil N availability due to soil warming. Net N mineralization was negatively correlated with both live and dead fine roots in the mineral soil that is home to the majority of roots, suggesting that soil warming increases N mineralization, decreases fine root biomass and thus decreases C allocation belowground. PMID- 21813517 TI - Growth and photosynthetic traits of hybrid larch F1 (Larix gmelinii var. japonica x L. kaempferi) under elevated CO2 concentration with low nutrient availability. AB - The hybrid larch F(1) (Larix gmelinii var. japonica * Larix kaempferi) is considered one of the most important tree species not only for timber production but also as an afforestation material for severe conditions such as infertile soil. To predict the ability of hybrid larch F(1) as an afforestation material under potential climates in the future, it is important to understand the response of hybrid larch F(1) to elevated CO(2) concentration ([CO(2)]) under low nutrient availability. Three-year-old seedlings of hybrid larch F(1) were grown under two different levels of [CO(2)], 360 (ambient) and 720 umol mol(-1) (elevated), in combination with two different levels of nitrogen (N) supply (0 and 30 kg ha(-1)) for one growing season. Elevated [CO(2)] reduced the maximum rates of carboxylation and electron transport in the needles. Net photosynthetic rates at growth [CO(2)] (i.e., 360 and 720 umol mol(-1) for ambient and elevated treatment, respectively) did not differ between the two CO(2) treatments. Reductions in N content and N use efficiency to perform photosynthetic functions owing to the deficiency of nutrients other than N, such as P and K, and/or increase in cell wall mass were considered factors of photosynthetic down regulation under elevated [CO(2)], whereas stomatal closure little affected the photosynthetic down-regulation. Although we observed strong down-regulation of photosynthesis, the dry matter increase of hybrid larch F(1) seedlings was enhanced under elevated [CO(2)]. This is mainly attributable to the increase in the amount of needles on increasing the number of sylleptic branches. These results suggest that elevated CO(2) may increase the growth of hybrid larch F(1) even under low nutrient availability, and that this increase may be regulated by changes in both crown architecture and needle photosynthesis, which is mainly affected not by stomatal limitation but by biochemical limitation. PMID- 21813518 TI - Linking hydraulic conductivity and photosynthesis to water-source partitioning in trees versus seedlings. AB - The relationships between hydraulic and photosynthetic properties in plants have been widely studied, but much less is known about how these properties are linked to water-source partitioning, the spatial and temporal separation of water sources in ecosystems. Plant water-source partitioning is often influenced by the proximity of groundwater from the natural surface. We studied the water acquisition strategy and hydraulic and photosynthetic properties of Tuart (Eucalyptus gomphocephala D.C.), a large coastal tree species that occupies seasonally dry habitats underlain by superficial aquifers. Our goal was to quantify water-source partitioning as the proportion of xylem water derived from the vadose and saturated zones with respect to stage of development and proximity of groundwater. We then sought to associate the proportional contribution of a given water source with xylem hydraulic and photosynthetic properties, thus conferring a linkage. Seedlings were more inclined to use surface soil water when rainfall recharge of the upper profile occurred, suggesting that they maintained or rapidly developed a proportionally high amount of functional roots in the upper, seasonally dry, soil profile. This strategy was associated with a lower xylem-area-specific hydraulic conductivity (K(S)), leaf-area-specific hydraulic conductivity (K(L)) and maximum photon yield of photosystem II (F(V)/F(M)). In contrast, trees acquired water from a variety of sources in different seasons and had a higher K(S), K(L) and F(V)/F(M). Despite the higher K(S) and K(L) in trees, the midday hydrodynamic water potential gradient from soil to leaves, DeltaPsi, was similar. We conclude that there was a linkage between hydraulic and photosynthetic properties with the partitioning of water sources and that this adaptation to long-term hydrological regimes accommodated the different hydraulic characteristics and hydrological environments of trees versus seedlings. PMID- 21813519 TI - Ahead of the curve. PMID- 21813520 TI - Pulmonary arterial hypertension in china: promising news and some surprises. PMID- 21813521 TI - What is in a name?: the dilemma of "prebronchiectasis". PMID- 21813522 TI - Survival and physical activity in COPD: a giant leap forward! PMID- 21813523 TI - Strategies to improve oral anticoagulation management. PMID- 21813524 TI - Managing cough in the aftermath of the decision of the US Food and Drug Administration to remove unapproved prescription cough medications from the market. PMID- 21813525 TI - Point: Is pressure assist-control preferred over volume assist-control mode for lung protective ventilation in patients with ARDS? Yes. PMID- 21813526 TI - Counterpoint: Is pressure assist-control preferred over volume assist-control mode for lung protective ventilation in patients with ARDS? No. PMID- 21813527 TI - Unapproved prescription cough, cold, and allergy drug products: recent US Food and Drug Administration regulatory action on unapproved cough, cold, and allergy medications. AB - The US Food and Drug Administration (FDA) drug approval and over-the-counter drug monograph processes play an essential role in ensuring that all drugs are both safe and effective for their intended uses. Manufacturers of drugs that lack required approval have not provided the FDA with evidence demonstrating that their products are safe and effective. Some of these prescription drugs have been marketed for many years and have remained on the market despite changes to the Federal Food, Drug, and Cosmetic Act, which requires approval for safety and efficacy purposes. Many health-care providers may be unaware that unapproved drugs exist because the product labels of these drugs do not disclose that they lack FDA approval. The FDA recently took action against unapproved prescription oral cough, cold, and allergy drug products because of concerns about the potential risks of these products, particularly some extended-release formulations that have not been reviewed for quality. There is a potential for medication errors because product names and labeling have not been reviewed for potential confusion, with some products inappropriately labeled for use in children aged <= 2 years. FDA-approved prescription drugs or drugs appropriately marketed as over the counter remain available for treatment of cough, cold, and allergy symptoms. Such products are of known efficacy, safety, identity, quality, and purity. Removing unapproved drugs from the marketplace and encouraging manufacturers of unapproved products to seek FDA review and approval is a top priority for the FDA. Since the initiation of the Unapproved Drugs Initiative in 2006, the FDA has removed ~1,500 unapproved products from the market and has worked with firms to bring other unapproved drugs into the approval process. The FDA remains committed to its mission of ensuring that safe and effective drugs are available to American consumers. PMID- 21813528 TI - Advancing respiratory research. AB - Respiratory diseases remain a major public health problem in the United States and worldwide, with increasing morbidity and mortality. Substantial progress has been made to advance understanding of the basic mechanisms of lung disease and to optimize clinical management of patients with a range of respiratory diseases. Despite this progress, our knowledge of how to predict disease prior to symptoms, improve disease definition and subclassification, and target novel and new treatments in a more personalized manner still remains inadequate. This article highlights several future opportunities and challenges related to genomics and molecular characterization of lung disease, lung injury and repair, translational lung research, the microbiome, and sleep and circadian biology as potential frontiers to advance progress in respiratory biology in health and disease. PMID- 21813529 TI - Bronchiolitis obliterans syndrome: the final frontier for lung transplantation. AB - Bronchiolitis obliterans syndrome (BOS) is a form of chronic lung allograft dysfunction that affects a majority of lung transplant recipients and is the principal factor limiting long-term transplant survival. BOS is characterized by progressive airflow obstruction unexplained by acute rejection, infection, or other coexistent condition. Although BOS is a proven useful clinical syndrome that identifies patients at increased risk for death, its clinical course and underlying causative factors are now recognized to be increasingly heterogeneous. Regardless of the clinical history, the primary pathologic correlate of BOS is bronchiolitis obliterans, a condition of intraluminal airway fibrosis. This article highlights the body of developing research illustrating the mechanisms by which BOS is mediated, including alloimmune reactivity, the emerging roles of humoral and autoimmunity, activation of innate immune cells, and response to nonimmune-related allograft insults, such as infection and aspiration. In addition, we underscore emerging clinical implications and promising future translational research directions that have the potential to advance our knowledge and improve patient outcomes. PMID- 21813530 TI - Current approach to the diagnosis of acute nonmassive pulmonary embolism. AB - Pulmonary embolism is a common and potentially lethal disease. Given the variable presentation and associated morbidity of this condition, an accurate and efficient diagnostic algorithm is required. Clinical pretest probability serves as the root of any diagnostic approach. We, thus, review several clinical decision rules that may help standardize this determination. Using a review of the literature, the accuracy, predictive values, and likelihood ratios for several diagnostic tests are described. The combination of these tests, based on the pretest probability of disease, can be used in a Bayesian fashion to make accurate treatment decisions. A completely noninvasive diagnostic algorithm for patients presenting with suspected acute pulmonary embolism is proposed. PMID- 21813531 TI - Accountability for medical error: moving beyond blame to advocacy. AB - Accountability in medicine, once assigned primarily to individual doctors, is today increasingly shared by groups of health-care providers. Because patient safety experts emphasize that most errors are caused not by individual providers, but rather by system breakdowns in complex health-care teams, individual doctors are left to wonder where their accountability lies. Increasingly, teams deliver care. But patients and doctors alike still think of accountability in individual terms, and the law often measures it that way. Drawing on an example of delayed lung cancer diagnosis, we describe the mismatch between how we view errors (systems) and how we apportion blame (individuals). We discuss "collective accountability," suggesting that this construct may offer a way to balance a "just culture" and a doctor's specific responsibilities within the framework of team delivery of care. The concept of collective accountability requires doctors to adopt transparent behaviors, learn new skills for improving team performance, and participate in institutional safety initiatives to evaluate errors and implement plans for preventing recurrences. It also means that institutions need to prioritize team training, develop robust, nonpunitive reporting systems, support clinicians after adverse events and medical error, and develop ways to compensate patients who are harmed by errors. A conceptual leap to collective accountability may help overcome longstanding professional and societal norms that not only reinforce individual blame and impede patient safety but may also leave the patient and family without a true advocate. PMID- 21813532 TI - Complete spontaneous regression of non-small cell lung cancer followed by adrenal relapse. AB - Spontaneous regression (SR) of cancer is a rare phenomenon. SR is recognized as complete or partial disappearance of the disease after inadequate or no treatment. Although reports of this phenomenon have been documented for several malignancies, it is rare in patients with lung cancer. In most documented cases, diagnoses of SR were made based on only the radiologic findings. We herein report a case of complete SR of non-small cell lung cancer (NSCLC) that was pathologically proven using a resected specimen. Moreover, despite the local complete SR, the patient subsequently experienced an adrenal metastasis after surgery. To the best of our knowledge, this is the first report of a patient with NSCLC in whom complete regression of the primary site was observed, but in whom a distant metastasis became apparent. Both phenomena were pathologically proven. Our report suggests that both SR and tumor progression can proceed simultaneously. PMID- 21813533 TI - Acute lung toxicity related to pomalidomide. AB - Pomalidomide is an immunomodulatory derivative (IMiD) active in multiple myeloma. In this report, we review the course of two patients receiving pomalidomide therapy who subsequently developed dyspnea, fever, hypoxia, and ground-glass opacities on CT scan. An extensive workup for infectious causes was negative. Both patients improved with discontinuation of the medication and/or treatment with corticosteroids. Both patients were restarted on pomalidomide therapy at a lower dose, with one patient experiencing an immediate recurrence of pulmonary symptoms. The combination of symptoms, radiographic findings, clinical course, and response to treatment strongly supports the diagnosis of acute pulmonary toxicity secondary to pomalidomide. We then review previously published pulmonary toxicity data on thalidomide and lenalidomide and compare the described clinical courses, radiographic findings, and responses to treatment with those observed in our patients. We conclude that pulmonary toxicity is a potential adverse effect of pomalidomide therapy and encourage physicians to remain cognizant of its clinical presentation. PMID- 21813535 TI - A 38-year-old woman with bilateral cystic lesions in both lower lung lobes. PMID- 21813534 TI - Obstructive sleep apnea: an emerging risk factor for atherosclerosis. AB - Obstructive sleep apnea (OSA) is independently associated with death from cardiovascular diseases, including myocardial infarction and stroke. Myocardial infarction and stroke are complications of atherosclerosis; therefore, over the last decade investigators have tried to unravel relationships between OSA and atherosclerosis. OSA may accelerate atherosclerosis by exacerbating key atherogenic risk factors. For instance, OSA is a recognized secondary cause of hypertension and may contribute to insulin resistance, diabetes, and dyslipidemia. In addition, clinical data and experimental evidence in animal models suggest that OSA can have direct proatherogenic effects inducing systemic inflammation, oxidative stress, vascular smooth cell activation, increased adhesion molecule expression, monocyte/lymphocyte activation, increased lipid loading in macrophages, lipid peroxidation, and endothelial dysfunction. Several cross-sectional studies have shown consistently that OSA is independently associated with surrogate markers of premature atherosclerosis, most of them in the carotid bed. Moreover, OSA treatment with continuous positive airway pressure may attenuate carotid atherosclerosis, as has been shown in a randomized clinical trial. This review provides an update on the role of OSA in atherogenesis and highlights future perspectives in this important research area. PMID- 21813536 TI - A 42-year-old woman with diffuse pulmonary infiltrates and bilateral pneumothoraces. PMID- 21813537 TI - What is the value of midregional proatrial natriuretic peptide in COPD research or clinical practice? PMID- 21813538 TI - Longitudinal and transverse movements of the right ventricle: both are important in pulmonary arterial hypertension. PMID- 21813539 TI - Combined imaging for benign mediastinal lymphadenopathy: endoscopic ultrasonography first or endobronchial ultrasonography first? PMID- 21813540 TI - Benefit or burden? Sending patients with nonresectable lung cancer to the ICU. PMID- 21813541 TI - Rapid on-site evaluation of transbronchial aspirates in mediastinal adenopathy diagnosis. PMID- 21813542 TI - Is the inflammatory response of the lungs in COPD abnormal? PMID- 21813543 TI - IV immunoglobulin might be considered as a first-line treatment of severe interstitial lung disease associated with polymyositis. PMID- 21813544 TI - Transtracheal oxygen therapy success. PMID- 21813545 TI - Concurrent gastric MALT and Hodgkin lymphoma: a case report. AB - This report describes a 60-year-old man with concurrent gastric extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) and classical Hodgkin lymphoma (CHL). Atypical, medium-sized, lymphoid cells proliferated in the mucosa to muscular layer of the stomach showing a lymphoepithelial lesion; admixed with Hodgkin/Reed-Sternberg (HRS) cells and an inflammatory cell background. MALT lymphoma cells expressed CD20, CD79a, PAX5, and BOB.1, and HRS cells expressed CD30, CD15, Epstein-Barr virus-encoded RNA, and EBV-latent membrane protein 1. Only CHL invaded into the regional lymph nodes. Two possibilities of transformation of MALT lymphoma into CHL and de novo CHL within MALT lymphoma are discussed. PMID- 21813546 TI - Cesarean delivery and colon resection in a patient with type III osteogenesis imperfecta. AB - OBJECTIVE. Osteogenesis imperfecta is a connective tissue disorder that results from the inability to produce normal collagen. Eight types are described; type II is considered the lethal variant. Because of abnormal collagen production, these patients possess many anatomic and functional abnormalities. In addition to the obvious brittle bones, osteogenesis imperfecta patients may also possess respiratory, cardiac, spinal, endocrine, and hematologic abnormalities. These numerous derangements can lead to a challenging perioperative course. CASE REPORT. This report describes a case of a 27-year-old woman, G1P0 with history of type III osteogenesis imperfecta presenting at 31+ weeks with preterm premature rupture of membranes, lower extremity edema, and constipation. Because of progressive labor and cephalopelvic disproportion, an urgent cesarean section was performed under general anesthesia. Intraoperative coagulopathy was noted. After hemostasis was achieved, a colonic mass below the splenic flexure that measured 20 * 10 cm was revealed. General surgery was consulted intraoperatively, and a rectosigmoid resection was performed for a presumed colonic pseudo-obstruction. Patient tolerated the procedure well and was extubated at the completion of the case. The patient was discharged home on postoperative day 5. CLINICAL CHALLENGES. (a) Preoperative assessment of an osteogenesis imperfecta patient, (b) determination of anesthetic type, (c) management of hemorrhage/cardiovascular instability, and (d) management of hyperthermia. CONCLUSIONS. This case report illustrates that, with proper knowledge of this disease state, osteogenesis imperfecta patients can undergo a safe anesthetic during a potentially challenging combined cesarean section/colonic resection. PMID- 21813547 TI - EULAR recommendations for vaccination in paediatric patients with rheumatic diseases. AB - Evidence-based recommendations for vaccination of paediatric patients with rheumatic diseases (PaedRD) were developed by following the EULAR standardised procedures for guideline development. The EULAR task force consisted of (paediatric) rheumatologists/immunologists, one expert in vaccine evaluation, one expert in public health and infectious disease control, and one epidemiologist. A systematic literature review was conducted in MEDLINE, EMBASE, and abstracts of the EULAR and American College of Rheumatology meetings of 2008/9. The level of evidence and strength of recommendation were based on customary scoring systems. Delphi voting was applied to assess the level of agreement between task force members. 107 papers and eight abstracts were used. The majority of papers considered seasonal influenza (41) or pneumococcal (23) vaccination. 26 studies were performed specifically in paediatric patients, and the majority in adult rheumatoid arthritis and systemic lupus erythematosus patients. Fifteen recommendations were developed with an overall agreement of 91.7%. More research is needed on the safety and immunogenicity of (live-attenuated) vaccination in PaedRD, particularly in those using biologicals, and the effect of vaccination on prevention of infections. PMID- 21813548 TI - Association with joint damage and physical functioning of nine composite indices and the 2011 ACR/EULAR remission criteria in rheumatoid arthritis. AB - OBJECTIVE: To compare nine disease activity indices and the new American College of Rheumatology (ACR)/European League against Rheumatism (EULAR) remission criteria in rheumatoid arthritis (RA) and to relate these to physical function and joint damage progression. METHODS: Five-year data from the BeSt study were used, a randomised clinical trial comparing four treatment strategies in 508 patients with recent-onset RA. Every three months disease activity was assessed with nine indices (Disease Activity Score (DAS), DAS-C reactive proteine (DAS CRP), Disease Activity Score in 28 joints (DAS-28), DAS28-CRP, Simplified Disease Activity Index (SDAI), Clinical Disease Activity Index (CDAI) and three DAS versions with adjusted tender joint scores) and categorized into remission, low, moderate and high disease activity (LDA, MDA, HDA). In addition, the recent ACR/EULAR clinical trial and practice remission was assessed 3-monthly with 28 and 68/66 joint counts. For each index, Generalized Estimating Equations analyses were performed to relate disease activity levels and the absence/presence of remission to 3-monthly assessments of physical functioning and annual radiological progression. RESULTS: From the composite indices, CDAI and SDAI were the most stringent definitions of remission and classified more patients as LDA. DAS28 and DAS28-CRP had the highest proportions of remission and MDA and a smaller proportion of LDA. ACR/EULAR remission percentages were comparable to CDAI/SDAI: remission percentages. The variant including CRP and 68/66 joint counts was the most stringent. For all indices, higher levels of disease activity were associated with decreased physical functioning and more radiological damage progression. Despite differences in classification between the indices, no major differences in relation to the two outcomes were observed. CONCLUSION: The associations of nine composite indices and ACR/EULAR remission criteria with functional status and joint damage progression showed high accordance, whereas the proportions of patients classified in the disease activity levels differed. PMID- 21813549 TI - Dangerous dining: surface foraging of North Atlantic right whales increases risk of vessel collisions. AB - North Atlantic right whales are critically endangered and, despite international protection from whaling, significant numbers die from collisions with ships. Large groups of right whales migrate to the coastal waters of New England during the late winter and early spring to feed in an area with large numbers of vessels. North Atlantic right whales have the largest per capita record of vessel strikes of any large whale population in the world. Right whale feeding behaviour in Cape Cod Bay (CCB) probably contributes to risk of collisions with ships. In this study, feeding right whales tagged with archival suction cup tags spent the majority of their time just below the water's surface where they cannot be seen but are shallow enough to be vulnerable to ship strike. Habitat surveys show that large patches of right whale prey are common in the upper 5 m of the water column in CCB during spring. These results indicate that the typical spring-time foraging ecology of right whales may contribute to their high level of mortality from vessel collisions. The results of this study suggest that remote acoustic detection of prey aggregations may be a useful supplement to the management and conservation of right whales. PMID- 21813550 TI - Modelling the ecological-functional diversification of marine Metazoa on geological time scales. AB - The ecological traits and functional capabilities of marine animals have changed significantly since their origin in the late Precambrian. These changes can be analysed quantitatively using multi-dimensional parameter spaces in which the ecological lifestyles of species are represented by particular combinations of parameter values. Here, we present models that describe the filling of this multi dimensional 'ecospace' by ecological lifestyles during metazoan diversification. These models reflect varying assumptions about the processes that drove ecological diversification; they contrast diffusive expansion with driven expansion and niche conservatism with niche partitioning. Some models highlight the importance of interactions among organisms (ecosystem engineering and predator-prey escalation) in promoting new lifestyles or eliminating existing ones. These models reflect processes that were not mutually exclusive; rigorous analyses will continue to reveal their applicability to episodes in metazoan history. PMID- 21813551 TI - Variable individual consistency in timing and destination of winter migrating fish. AB - Migration is an important event in the life history of many animals, but there is considerable variation within populations in the timing and final destination. Such differential migration at the population level can be strongly determined by individuals showing different consistencies in migratory traits. By tagging individual cyprinid fish with uniquely coded electronic tags, and recording their winter migrations from lakes to streams for 6 consecutive years, we obtained highly detailed long-term information on the differential migration patterns of individuals. We found that individual migrants showed consistent site fidelities for over-wintering streams over multiple migratory seasons and that they were also consistent in their seasonal timing of migration. Our data also suggest that consistency itself can be considered as an individual trait, with migrants that exhibit consistent site fidelity also showing consistency in migratory timing. The finding of a mixture of both consistent and inconsistent individuals within a population furthers our understanding of intrapopulation variability in migration strategies, and we hypothesize that environmental variation can maintain such different strategies. PMID- 21813552 TI - The Tuberous Sclerosis 2000 Study: presentation, initial assessments and implications for diagnosis and management. AB - AIMS: The Tuberous Sclerosis 2000 Study is the first comprehensive longitudinal study of tuberous sclerosis (TS) and aims to identify factors that determine prognosis. Mode of presentation and findings at initial assessments are reported here. METHODS: Children aged 0-16 years newly diagnosed with TS in the UK were evaluated. RESULTS: 125 children with TS were studied. 114 (91%) met clinical criteria for a definite diagnosis and the remaining 11 (9%) had pathogenic TSC1 or TSC2 mutations. In families with a definite clinical diagnosis, the detection rate for pathogenic mutations was 89%. 21 cases (17%) were identified prenatally, usually with abnormalities found at routine antenatal ultrasound examination. 30 cases (24%) presented before developing seizures and in 10 of these without a definite diagnosis at onset of seizures, genetic testing could have confirmed TS. 77 cases (62%) presented with seizures. Median age at recruitment assessment was 2.7 years (range: 4 weeks-18 years). Dermatological features of TS were present in 81%. The detection rate of TS abnormalities was 20/107 (19%) for renal ultrasound including three cases with polycystic kidney disease, 51/88 (58%) for echocardiography, 29/35 (83%) for cranial CT and 95/104 (91%) for cranial MRI. 91% of cases had epilepsy and 65% had intellectual disability (IQ<70). CONCLUSIONS: Genetic testing can be valuable in confirming the diagnosis. Increasing numbers of cases present prenatally or in early infancy, before onset of seizures, raising important questions about whether these children should have EEG monitoring and concerning the criteria for starting anticonvulsant therapy. PMID- 21813554 TI - A poisonous surprise under the coat of the African crested rat. AB - Plant toxins are sequestered by many animals and the toxicity is frequently advertised by aposematic displays to deter potential predators. Such 'unpalatability by appropriation' is common in many invertebrate groups and also found in a few vertebrate groups. However, potentially lethal toxicity by acquisition has so far never been reported for a placental mammal. Here, we describe complex morphological structures and behaviours whereby the African crested rat, Lophiomys imhausi, acquires, dispenses and advertises deterrent toxin. Roots and bark of Acokanthera schimperi (Apocynaceae) trees are gnawed, masticated and slavered onto highly specialized hairs that wick up the compound, to be delivered whenever the animal is bitten or mouthed by a predator. The poison is a cardenolide, closely resembling ouabain, one of the active components in a traditional African arrow poison long celebrated for its power to kill elephants. PMID- 21813553 TI - Stem cells as a therapeutic tool for the blind: biology and future prospects. AB - Retinal degeneration due to genetic, diabetic and age-related disease is the most common cause of blindness in the developed world. Blindness occurs through the loss of the light-sensing photoreceptors; to restore vision, it would be necessary to introduce alternative photosensitive components into the eye. The recent development of an electronic prosthesis placed beneath the severely diseased retina has shown that subretinal stimulation may restore some visual function in blind patients. This proves that residual retinal circuits can be reawakened after photoreceptor loss and defines a goal for stem-cell-based therapy to replace photoreceptors. Advances in reprogramming adult cells have shown how it may be possible to generate autologous stem cells for transplantation without the need for an embryo donor. The recent success in culturing a whole optic cup in vitro has shown how large numbers of photoreceptors might be generated from embryonic stem cells. Taken together, these threads of discovery provide the basis for optimism for the development of a stem-cell-based strategy for the treatment of retinal blindness. PMID- 21813555 TI - Mini-Mental State Exam performance of older African Americans: effect of age, gender, education, hypertension, diabetes, and the inclusion of serial 7s subtraction versus "world" backward on score. AB - The Mini-Mental State Exam (MMSE) is a clinically ubiquitous yet incompletely standardized instrument. Though the test offers considerable examiner leeway, little data exist on the normative consequences of common administration variations. We sought to: (a) determine the effects of education, age, gender, health status, and a common administration variation (serial 7s subtraction vs. "world" spelled backward) on MMSE score within a minority sample, (b) provide normative data stratified on the most empirically relevant bases, and (c) briefly address item failure rates. African American citizens (N = 298) aged 55-87 living independently in the community were recruited by advertisement, community recruitment, and word of mouth. Total score with "world" spelled backward exceeded total score with serial 7s subtraction across all levels of education, replicating findings in Caucasian samples. Education is the primary source of variance on MMSE score, followed by age. In this cohort, women out-performed men when "world" spelled backward was included, but there was no gender effect when serial 7s subtraction was included in MMSE total score. To ensure an appropriate interpretation of MMSE scores, reports, whether clinical or in publications of research findings, should be explicit regarding the administration method. Stratified normative data are provided. PMID- 21813556 TI - Sustained attention and working memory deficits follow a familial pattern in schizophrenia. AB - Cognitive deficits are core features of schizophrenia and considered putative endophenotypes. This study assessed the familial pattern of deficits in sustained attention, working memory and executive function in remitted-schizophrenia patients and their unaffected siblings. Sixteen patients, 16 unaffected siblings, and 17 healthy control subjects underwent a battery of neuropsychological tasks that have so far yielded mixed findings in performance differences. Both groups had prolonged reaction times compared with controls in sustained attention tasks; the siblings made more false alarms in the working memory task, but only the patients' performance was poorer in the executive function tasks. These findings further support sustained attention and working memory deficits as potential endophenotypes of schizophrenia. Reaction time and false alarm rates are suggested as additional useful endophenotypic measures that could potentially account for differences in performance in tasks that are not purported to examine the specific measures per se. PMID- 21813557 TI - Stem cells in bone diseases: current clinical practice. AB - INTRODUCTION: Bone is an obvious candidate tissue for stem cell therapy. This review provides an update of existing stem cell-based clinical treatments for bone pathologies. SOURCES OF DATA: A systematic computerized literature search was conducted. The following databases were accessed on 10 February 2011: NIH clinical trials database, PubMed, Ovid and Cochrane Reviews. AREAS OF AGREEMENT: Stem cell therapy offers new options for bone conditions, both acquired and inherited. AREAS OF CONTROVERSY: There is still no agreement on the exact definition of 'mesenchymal stem cells'. Consequently, it is difficult to appreciate the effect of culture expansion and the feasibility of allogeneic transplantation. GROWING POINTS: Based on the sound foundations of pre-clinical research, stem cell-based treatments and protocols have recently emerged. AREAS TIMELY FOR DEVELOPING RESEARCH: Well-designed prospective clinical trials are needed in order to establish and develop stem cell therapy for bone diseases. PMID- 21813558 TI - Colorectal liver metastases. AB - BACKGROUND: Despite major advances in therapies for liver metastases, colorectal cancer remains one of the commonest causes of cancer-related deaths in the UK. SOURCES OF DATA: The international literature on the management of colorectal liver metastases (CLM) was reviewed. AREAS OF AGREEMENT: Due to a combination of highly active systemic agents and low perioperative mortality achieved by high volume centres, a growing number of patients are being offered liver resection with curative intent. Patients with bilobar and/or extrahepatic disease who would previously have received palliative treatment only, are undergoing major surgery with good results. This review focuses on preoperative evaluation, surgical planning and the role of adjuvant therapies in the management of patients with CLM. AREAS OF CONTROVERSY: Can ablative therapies match the outcomes of surgical resection? How can even more patients be rendered resectable? GROWING POINTS: The use of other therapies, such as radiofrequency ablation and selective internal radiation therapy. AREAS TIMELY FOR DEVELOPING RESEARCH: New chemotherapy regimens for neo-adjuvant therapy and the development of new modalities of liver tumour ablation. PMID- 21813559 TI - The place of routine HIV testing. AB - In 2009, around 86,500 people in the UK had HIV infection, of whom around a quarter were unaware of their condition. Of adults diagnosed in that year, around half were already at a late stage of disease (with a CD4 count below 350 cells/MUL or presenting with an AIDS-defining event). Such late diagnosis represents a missed opportunity for treatment and prevention, and is associated with significant morbidity and mortality, reduced response to antiretroviral drugs and increased healthcare costs. In genitourinary medicine (GUM) clinics and during antenatal care, there is a high uptake rate of routine testing (i.e. HIV tests are offered as part of standard care and the individual has the option to decline). Increasing such testing across other healthcare settings could reduce late diagnosis. Here we examine issues around routine HIV testing. PMID- 21813560 TI - Which inotrope and when in neonatal and paediatric intensive care? PMID- 21813561 TI - Notch signaling protects retina from nuclear factor-kappaB- and poly-ADP-ribose polymerase-mediated apoptosis under high-glucose stimulation. AB - Proliferative diabetic retinopathy, the primary cause of vision loss in adults, is one of serious microvascular complications caused by diabetes. Both poly-ADP ribose-polymerase (PARP) and nuclear factor (NF)-kappaB signaling are involved in the injury process. Injury activates PARP, which in turn potentiates NF-kappaB activation and causes cell apoptosis. Like the NF-kappaB pathway, Notch1 signaling plays a key role in the regulation of cell proliferation, differentiation, and apoptosis. However, the connections between these signaling pathways are not well understood. In this study, we used both streptozotocin (STZ)-induced diabetic mice and human retinal vascular endothelial cells (HRVECs) cultured in high glucose to detect these relationships. We found that apoptosis was increased in both STZ-induced diabetic mice and high-glucose-treated HRVECs, which was due to increased activation of PARP, cleaved caspase3, and reduced expression of Notch1 and p-Akt. The results of Notch1 overexpression and knockdown indicated that Notch1 signaling participated in the interaction of PARP and p50, and inhibited PARP- and p50-mediated apoptosis directly. These phenomena could be blocked by pretreatment with the PI3K inhibitor wortmannin via reducing p-Akt levels. Thus, our study demonstrated that Notch1 signaling protects cells from PARP- and NF-kappaB-induced apoptosis under high glucose through the activation of Akt. PMID- 21813563 TI - Xylan-degrading enzymes in male and female flower nectar of Cucurbita pepo. AB - BACKGROUND AND AIMS: Nectar is a very complex mixture of substances. Some components (sugars and amino acids) are considered primary alimentary rewards for animals and have been investigated and characterized in numerous species for many years. In contrast, nectar proteins have been the subject of few studies and little is known of their function. Only very recently have detailed studies and characterization of nectar proteins been undertaken, and then for only a very few species. This current work represents a first step in the identification of a protein profile for the floral nectar of Cucurbita pepo. In this regard, the species studied is of particular interest in that it is monoecious with unisexual flowers and, consequently, it is possible that nectar proteins derived from male and female flowers may differ. METHODS: Manually excised spots from two dimensional (2-D) electrophoresis were subjected to in-gel protein digestion. The resulting peptides were sequenced using nanoscale LC-ESI/MS-MS (liquid chromatography-electrospray ionization/tandem mass spectrometry). An MS/MS ions search was carried out in Swiss-Prot and NCBInr databases using MASCOT software. KEY RESULTS: Two-dimensional electrophoresis revealed a total of 24 spots and a different protein profile for male and female flower nectar. Four main proteins recognized by 2-D electrophoresis most closely resemble beta-d-xylosidases from Arabidopsis thaliana and have some homology to a beta-d-xylosidase from Medicago varia. They were present in similar quantities in male and female flowers and had the same molecular weight, but with slightly different isoelectric points. CONCLUSIONS: A putative function for xylosidases in floral nectar of C. pepo is proposed, namely that they may be involved in degrading the oligosaccharides released by the nectary cell walls in response to hydrolytic enzymes produced by invading micro-organisms. Several types of oligosaccharides have been reported to increase the pathogenic potential of micro-organisms. Thus, it is possible that such a mechanism may reduce the virulence of pathogens present in nectar. PMID- 21813564 TI - Cushions of Thylacospermum caespitosum (Caryophyllaceae) do not facilitate other plants under extreme altitude and dry conditions in the north-west Himalayas. AB - BACKGROUND: Cushion plants are commonly considered as keystone nurse species that ameliorate the harsh conditions they inhabit in alpine ecosystems, thus facilitating other species and increasing alpine plant biodiversity. A literature search resulted in 25 key studies showing overwhelming facilitative effects of different cushion plants and hypothesizing greater facilitation with increased environmental severity (i.e. higher altitude and/or lower rainfall). At the same time, emerging ecological theory alongside the cushion-specific literature suggests that facilitation might not always occur under extreme environmental conditions, and especially under high altitude and dryness. METHODS: To assess these hypotheses, possible nursing effects of Thylacospermum caespitosum (Caryophyllaceae) were examined at extremely high altitude (5900 m a.s.l.) and in dry conditions (precipitation <100 mm year(-1)) in Eastern Ladakh, Trans Himalaya. This is, by far, the highest site, and the second driest, at which the effects of cushions have been studied so far. KEY RESULTS: In accordance with the theoretical predictions, no nursing effects of T. caespitosum on other alpine plants were detected. The number and abundance of species were greater outside cushions than within and on the edge of cushions. None of the 13 species detected was positively associated with cushions, while nine of them were negatively associated. Plant diversity increased with the size of the area sampled outside cushions, but no species-area relationship was found within cushions. CONCLUSIONS: The results support the emerging theoretical prediction of restricted facilitative effects under extreme combinations of cold and dryness, integrating these ideas in the context of the ecology of cushion plants. This evidence suggests that cases of missing strong facilitation are likely to be found in other extreme alpine conditions. PMID- 21813566 TI - Novel inborn error of folate metabolism: identification by exome capture and sequencing of mutations in the MTHFD1 gene in a single proband. AB - OBJECTIVE: An infant was investigated because of megaloblastic anaemia, atypical hemolytic uraemic syndrome, severe combined immune deficiency, elevated blood levels of homocysteine and methylmalonic acid, and a selective decreased synthesis of methylcobalamin in cultured fibroblasts. METHODS: Exome sequencing was performed on patient genomic DNA. RESULTS: Two mutations were identified in the MTHFD1 gene, which encodes a protein that catalyses three reactions involved in cellular folate metabolism. This protein is essential for the generation of formyltetrahydrofolate and methylenetetrahydrofolate and important for nucleotide and homocysteine metabolism. One mutation (c.727+1G>A) affects the splice acceptor site of intron 8. The second mutation, c.517C>T (p.R173C), changes a critical arginine residue in the NADP-binding site of the protein. Mutations affecting this arginine have previously been shown to affect enzyme activity. Both parents carry a single mutation and an unaffected sibling carries neither mutation. The combination of two mutations in the MTHFRD1 gene, predicted to have severe consequences, in the patient and their absence in the unaffected sibling, supports causality. CONCLUSION: This patient represents the first case of an inborn error of folate metabolism affecting the trifunctional MTHFD1 protein. This report reinforces the power of exome capture and sequencing for the discovery of novel genes, even when only a single proband is available for study. PMID- 21813565 TI - Breeding crop plants with deep roots: their role in sustainable carbon, nutrient and water sequestration. AB - BACKGROUND: The soil represents a reservoir that contains at least twice as much carbon as does the atmosphere, yet (apart from 'root crops') mainly just the above-ground plant biomass is harvested in agriculture, and plant photosynthesis represents the effective origin of the overwhelming bulk of soil carbon. However, present estimates of the carbon sequestration potential of soils are based more on what is happening now than what might be changed by active agricultural intervention, and tend to concentrate only on the first metre of soil depth. SCOPE: Breeding crop plants with deeper and bushy root ecosystems could simultaneously improve both the soil structure and its steady-state carbon, water and nutrient retention, as well as sustainable plant yields. The carbon that can be sequestered in the steady state by increasing the rooting depths of crop plants and grasses from, say, 1 m to 2 m depends significantly on its lifetime(s) in different molecular forms in the soil, but calculations (http://dbkgroup.org/carbonsequestration/rootsystem.html) suggest that this breeding strategy could have a hugely beneficial effect in stabilizing atmospheric CO(2). This sets an important research agenda, and the breeding of plants with improved and deep rooting habits and architectures is a goal well worth pursuing. PMID- 21813567 TI - Genital warts and cost of care in England. AB - OBJECTIVES: To estimate the total number of cases of, and cost of care for, genital warts (GWs) in England, to inform economic evaluations of human papillomavirus vaccination. METHODS: The number of GW cases seen in general practices (GPs) and in genitourinary medicine (GUM) clinics was estimated using the General Practice Research Database and the GUM Clinic Activity Dataset. The overlap in care of cases in the two settings was estimated. The calculated costs of care in GP and hospitals were added to the costs of care in GUM clinics (estimated elsewhere) to estimate the cost of care for GWs in England. RESULTS: In England, in 2008, GP and GUM saw 80,531 new (157/100,000 population) and 68,259 recurrent (133/100,000 population) episodes, giving a total of 148,790 episodes of care of GWs (289/100,000 population). Seventy-three per cent of cases were seen only in GUM clinics, 22% were seen by a GP before being referred to GUM, and 5% by GPs only. Hospital care was given in 1.3% of cases and contributed 8% of the costs. The average cost of care per episode was L113, and the estimated annual cost of care in England was L16.8 million. CONCLUSIONS: This study provides a fairly comprehensive measure of GW frequency and care in England. GWs exert a considerable impact on health services, a large proportion of which could be prevented through immunisation using the quadrivalent human papillomavirus vaccine. PMID- 21813568 TI - Chlamydia trachomatis serovars in community-based HIV-positive and HIV-negative men who have sex with men in Sydney, Australia. AB - OBJECTIVES: There are few data on the distribution of specific Chlamydia trachomatis serovars among men who have sex with men (MSM) outside clinical settings. To investigate these patterns, serovar determination was performed on chlamydia-positive samples from two community-based cohort studies of HIV positive and HIV-negative MSM in Sydney, Australia. METHODS: From January 2005 to June 2007 all positive C trachomatis pharyngeal, urine and anal samples were evaluated. The serovar of each C trachomatis infection was determined by omp1 gene sequencing with confirmatory quantitative PCR screening. Symptom data were routinely reported by study participants at the time of testing. RESULTS: Serovar determination was possible for 54 samples among 52 participants. Seven samples were not able to be typed. Site-specific symptoms were reported by fewer than 10% of participants diagnosed with pharyngeal and anogenital chlamydia. The most commonly identified serovars were serovar D (n=32, 59.3%, 95% CI 45.0 to 72.4), followed by serovar G (n=11, 20.4%, 95% CI 10.6 to 33.5) and serovar J (n=5, 9.3%, 95% CI 3.1 to 20.3). Only one lymphogranuloma venereum serovar was identified (L2b). CONCLUSIONS: This community-based study found a similar distribution of chlamydia serovars to that observed among Australian community based MSM several years ago, and serovar distribution recently observed among predominantly symptomatic MSM at a Sydney clinic. These findings suggest little change in C trachomatis serovar distribution in Australian MSM over the past decade and a lack of correlation of specific chlamydia serovars with anogenital symptoms among MSM. PMID- 21813569 TI - Transferring preterm infants from incubators to open cots at 1600 g: a multicentre randomised controlled trial. AB - OBJECTIVES: To determine the effects on weight gain and temperature control of transferring preterm infants from incubators to open cots at a weight of 1600 g versus a weight of 1800 g. DESIGN: Randomised controlled trial. SETTING: One tertiary and two regional neonatal units in public hospitals in Queensland, Australia. PARTICIPANTS: 182 preterm infants born with a birth weight less than 1600 g, who were at least 48 h old; had not required ventilation or continuous positive airways pressure within the last 48 h; were medically stable with no oxygen requirement, or significant apnoea or bradycardia; did not require phototherapy; and were enterally fed with an intake (breast milk/formula) of at least 60 ml/kg/day. INTERVENTIONS: Transfer into an open cot at 1600 or 1800 g. MAIN OUTCOME MEASURES: The primary outcomes were temperature stability and average daily weight gain over the first 14 days following transfer to an open cot. RESULTS: 90 infants in the 1600 g group and 92 infants in the 1800 g group were included in the analysis. Over the first 72 h, more infants in the 1800 g group had temperatures <36.4 degrees C than the 1600 g group (p=0.03). From post transfer to discharge, the 1600 g group had more temperatures >37.1 degrees C (p=0.02). Average daily weight gain in the 1600 g group was 17.07 (SD+/-4.5) g/kg/day and in the 1800 g group, 13.97 (SD+/-4.7) g/kg/day (p=<0.001). CONCLUSIONS: Medically stable, preterm infants can be transferred to open cots at a birth weight of 1600 g without any significant adverse effects on temperature stability or weight gain. TRIAL REGISTRATION: ACTRN12606000518561 (http://www.anzctr.org.au). PMID- 21813570 TI - Germ line differentiation factor Bag of Marbles is a regulator of hematopoietic progenitor maintenance during Drosophila hematopoiesis. AB - Bag of Marbles (Bam) is a stem cell differentiation factor in the Drosophila germ line. Here, we demonstrate that Bam has a crucial function in the lymph gland, the tissue that orchestrates the second phase of Drosophila hematopoiesis. In bam mutant larvae, depletion of hematopoietic progenitors is observed, coupled with prodigious production of differentiated hemocytes. Conversely, forced expression of Bam in the lymph gland results in expansion of prohemocytes and substantial reduction of differentiated blood cells. These findings identify Bam as a regulatory protein that promotes blood cell precursor maintenance and prevents hemocyte differentiation during larval hematopoiesis. Cell-specific knockdown of bam function via RNAi expression revealed that Bam activity is required cell autonomously in hematopoietic progenitors for their maintenance. microRNA-7 (mir 7) mutant lymph glands present with phenotypes identical to those seen in bam null animals and mutants double-heterozygous for bam and mir-7 reveal that the two cooperate to maintain the hematopoietic progenitor population. By contrast, analysis of yan mutant lymph glands revealed that this transcriptional regulator promotes blood cell differentiation and the loss of prohemocyte maintenance. Expression of Bam or mir-7 in hematopoietic progenitors leads to a reduction of Yan protein. Together, these results demonstrate that Bam and mir-7 antagonize the differentiation-promoting function of Yan to maintain the stem-like hematopoietic progenitor state during hematopoiesis. PMID- 21813571 TI - Complex interactions between cis-regulatory modules in native conformation are critical for Drosophila snail expression. AB - It has been shown in several organisms that multiple cis-regulatory modules (CRMs) of a gene locus can be active concurrently to support similar spatiotemporal expression. To understand the functional importance of such seemingly redundant CRMs, we examined two CRMs from the Drosophila snail gene locus, which are both active in the ventral region of pre-gastrulation embryos. By performing a deletion series in a ~25 kb DNA rescue construct using BAC recombineering and site-directed transgenesis, we demonstrate that the two CRMs are not redundant. The distal CRM is absolutely required for viability, whereas the proximal CRM is required only under extreme conditions such as high temperature. Consistent with their distinct requirements, the CRMs support distinct expression patterns: the proximal CRM exhibits an expanded expression domain relative to endogenous snail, whereas the distal CRM exhibits almost complete overlap with snail except at the anterior-most pole. We further show that the distal CRM normally limits the increased expression domain of the proximal CRM and that the proximal CRM serves as a 'damper' for the expression levels driven by the distal CRM. Thus, the two CRMs interact in cis in a non additive fashion and these interactions may be important for fine-tuning the domains and levels of gene expression. PMID- 21813572 TI - The roles of maternal Vangl2 and aPKC in Xenopus oocyte and embryo patterning. AB - The Xenopus oocyte contains components of both the planar cell polarity and apical-basal polarity pathways, but their roles are not known. Here, we examine the distribution, interactions and functions of the maternal planar cell polarity core protein Vangl2 and the apical-basal complex component aPKC. We show that Vangl2 is distributed in animally enriched islands in the subcortical cytoplasm in full-grown oocytes, where it interacts with a post-Golgi v-SNARE protein, VAMP1, and acetylated microtubules. We find that Vangl2 is required for the stability of VAMP1 as well as for the maintenance of the stable microtubule architecture of the oocyte. We show that Vangl2 interacts with atypical PKC, and that both the acetylated microtubule cytoskeleton and the Vangl2-VAMP1 distribution are dependent on the presence of aPKC. We also demonstrate that aPKC and Vangl2 are required for the cell membrane asymmetry that is established during oocyte maturation, and for the asymmetrical distribution of maternal transcripts for the germ layer and dorsal/ventral determinants VegT and Wnt11. This study demonstrates the interaction and interdependence of Vangl2, VAMP1, aPKC and the stable microtubule cytoskeleton in the oocyte, shows that maternal Vangl2 and aPKC are required for specific oocyte asymmetries and vertebrate embryonic patterning, and points to the usefulness of the oocyte as a model to study the polarity problem. PMID- 21813573 TI - Blunted local but preserved remote vascular responses after resistance exercise in chronic heart failure. AB - BACKGROUND: A single aerobic exercise session increases blood flow and vascular reactivity in remote vascular areas in chronic heart failure (CHF). We hypothesized that CHF patients would present increased vascular reactivity after a resistance exercise session. METHODS: Ten CHF patients and 10 healthy controls participated in three experiments, on different days: (1) 25-min rest (control); (2) 25-min lower-limb resistance exercises with vascular measurements in the calf (RELL); and (3) 25-min lower-limb resistance exercises with vascular measurements in the forearm (REUL). Heart rate (HR), blood pressure (BP), forearm blood flow (FBF), and calf blood flow (CBF) were measured at baseline, immediately, and 10, 30, and 60 min after the interventions. Calf and forearm reactive hyperaemia (RH) were measured at baseline and at 10, 30, and 60 min post interventions. RESULTS: Mean BP was unchanged throughout the protocols in CHF patients, whereas healthy controls had postexercise reduction up to 60 and 10 min after RELL and REUL sessions, respectively. Forearm RH (30- min post exercise) indicated remote effects and was increased by 36% and 43% (p < 0.05) in CHF patients and controls, respectively. Both groups increased postexercise calf RH (local effect) up to 60 min; however, healthy controls presented larger responses compared with patients (73% vs. 39%, p < 0.05). CONCLUSION: Patients with CHF present blunted vascular responses in the exercised areas, but remote vascular reactivity responses are similar to those observed in healthy individuals, suggesting that resistance exercise may remotely contribute to vascular adaptation in nontrained vasculatures. PMID- 21813574 TI - Clinical performance of the Roche cobas e411 automated assay system for thyrotropin-receptor antibodies for the diagnosis of Graves' disease. AB - BACKGROUND: The clinical performance of the Roche cobas e411 automated assay for the measurement of thyrotropin (TSH)-receptor antibodies (TRAbs) for the diagnosis of Graves' disease was evaluated in the setting of new referrals to a specialized thyroid clinic. METHODS: The final diagnosis of 102 new patients attending their first outpatient appointment at a thyroid clinic was correlated with the TRAbs result. In all cases, the diagnosis was made independently of the TRAbs result by the same consultant (ADT) based on clinical examination, thyroid function tests (TSH, free thyroxine, total triiodothyronine measured on Architect; Abbot Diagnostics), and a technetium-99m uptake and scan. TRAbs were measured using the cobas e411 (Roche Diagnostics). The clinical sensitivity and specificity of the assay were determined and compared with other published performance characteristics of the assay. RESULTS: Optimal sensitivity (95%) and specificity (98%) were obtained using a cut-off of 1.6 IU/L. The positive and negative predictive values at this cut-off were calculated as 98% and 94%, respectively. CONCLUSIONS: Using a cut-off of 1.6 IU/L, considered independently of thyroid function tests, the Roche cobas e411 automated immunoassay for TRAbs is a convenient, sensitive and specific tool for the differential diagnosis of hyperthyroidism. PMID- 21813575 TI - Comparison of serum cortisol measurement by immunoassay and liquid chromatography tandem mass spectrometry in patients receiving the 11beta-hydroxylase inhibitor metyrapone. AB - BACKGROUND: The accurate measurement of cortisol by immunoassay is compromised by the potential for cross-reactivity of reagent antibodies with structurally related steroids present in serum. This susceptibility is potentiated when normal steroid metabolism is altered pharmaceutically by antisteroidogenic drugs utilized in the management of Cushing's syndrome to moderate cortisol production. The clinical implications of falsely elevated cortisol results include over treatment and unrecognized hypoadrenalism. To investigate the effect of the 11beta-hydroxylase inhibitor metyrapone on serum cortisol assay, a comparison of measurement by immunoassay versus liquid chromatography-tandem mass spectrometry (LC-MS/MS) was conducted. METHODS: Cortisol was measured in serum from three patient groups: (1) patients receiving metyrapone (n = 112 samples from 10 patients); (2) control group of patients diagnosed with Cushing's syndrome currently receiving no treatment (n = 31); and (3) control group of patients with no adrenal pathology and not receiving medication known to interfere in cortisol immunoassay (n = 67). RESULTS: Bland-Altman plots showed agreement between methods for the control group (bias = 1.1% [-4.3 nmol/L]) and Cushing's control group (bias = 1.3% [-3.7 nmol/L]). This was in stark contrast to the metyrapone therapy group (bias = 23% [59 nmol/L]). The difference between LC-MS/MS versus immunoassay in the metyrapone therapy group positively correlated with metyrapone dose and serum 11-deoxycortisol concentration (Pearson's correlation coefficient r = 0.47, 95% CI 0.32-0.61; P < 0.0001). CONCLUSIONS: These data show that liability of immunoassay measurement of serum cortisol to interference in patients receiving metyrapone may lead to erroneous clinical decisions concerning dose titration. PMID- 21813576 TI - Review: health care utilization and costs of elderly persons with multiple chronic conditions. AB - This systematic literature review identified and summarized 35 studies that investigated the relationship between multiple chronic conditions (MCCs) and health care utilization outcomes (i.e. physician use, hospital use, medication use) and health care cost outcomes (medication costs, out-of-pocket costs, total health care costs) for elderly general populations. Although synthesis of studies was complicated because of ambiguous definitions and measurements of MCCs, and because of the multitude of outcomes investigated, almost all studies observed a positive association of MCCs and use/costs, many of which found that use/costs significantly increased with each additional condition. Several studies indicate a curvilinear, near exponential relationship between MCCs and costs. The rising prevalence, substantial costs, and the fear that current care arrangements may be inappropriate for many patients with MCCs, bring about a multitude of implications for research and policy, of which the most important are presented and discussed. PMID- 21813577 TI - Effects of erdosteine on cyclosporin-A-induced nephrotoxicity. AB - AIM: In cyclosporin-A (CsA)-induced toxicity, oxidative stress has been implicated as a potential responsible mechanism. Therefore, we aimed to investigate the protective role of erdosteine against CsA-induced nephrotoxicity in terms of tissue oxidant/antioxidant parameters and light microscopy in rats. MATERIALS AND METHODS: Wistar albino rats were randomly separated into four groups. Group 1 rats treated with sodium chloride served as the control, group 2 rats were treated with CsA, group 3 with CsA plus erdosteine, and group 4 with erdosteine alone. Animals were killed and blood samples were analyzed for blood urea nitrogen (BUN), serum creatinine (Cr), uric acid (UA), total protein (TP), and albumin (ALB) levels. Kidney sections were analyzed for malondialdehyde (MDA) and nitric oxide (NO) levels and superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activities, as well as for histopathological changes. RESULTS: In the CsA group, MDA, GSH-Px, BUN, and Cr levels were increased. The TP and ALB levels were decreased. These changes had been improved by erdosteine administration. Other biochemical parameters did not show any significant change. CONCLUSION: These results indicate that erdosteine produces a protective mechanism against CsA-induced nephrotoxicity and suggest a role of oxidative stress in pathogenesis. PMID- 21813578 TI - Comparing the treatment response of great saphenous and small saphenous vein incompetence following surgery and endovenous laser ablation: a retrospective cohort study. AB - OBJECTIVE: Many venous trials mix patients with great saphenous vein (GSV) and small saphenous vein (SSV) diseases. There is no evidence that both respond similarly to treatment and our aim was to test this assumption. METHOD: This cohort study compares patients with isolated GSV and SSV incompetence following treatment with open surgical ligation or endovenous laser ablation (EVLA). Outcomes included: quality of life (QoL; Aberdeen Varicose Vein Questionnaire [AVVQ]; Short Form 36 [SF36]; Euroqol [EQ5D]; and Venous Clinical Severity Score [VCSS]). RESULTS: A total of 370 patients with no differences in baseline QoL, underwent treatment. Despite equivalent morbidity, SSV sufferers had a lower VCSS (P < 0.001). Following surgery, SSV patients scored higher (worse) on AVVQ (P = 0.045) than GSV sufferers, but lower (better) following EVLA (P = 0.042). CONCLUSION: The morbidity associated with SSV incompetence is greater than suggested by its clinical severity and responds differently following treatment to that of the GSV. Trials should consider patients with GSV and SSV reflux separately. EVLA may offer additional benefits to SSV sufferers. PMID- 21813579 TI - Leptospiral antibodies in the breeding goat population of Poland. AB - In 2007, a survey was conducted on the prevalence of antibodies to 19 Leptospira serovars in goats in Poland . Sera were collected from adult females of all 49 breeding goat herds in Poland by applying simple random sampling. In total, 736 sera were tested by the microscopic agglutination test. A herd was considered seropositive if at least one goat with a titre of 100 or more was detected. Herd level seroprevalence of Leptospira was 89.8 per cent and individual-level seroprevalence varied from less than 1.0 to 85.0 per cent among the herds. Antibodies to Leptospira serovars Zanoni, Bratislava, Autumnalis, Australis and Javanica were most frequently detected. Although 40.3 per cent of seropositive goats had high antibody titres (>= 400), suggesting recent infection, no relationship with abortions or other clinical manifestation of leptospirosis in goats was detected. PMID- 21813580 TI - Subcutaneous electronic identification in cattle: a field study. AB - The use of injectable transponders in cattle for identification purposes, for up to 30 months, was investigated. Passive electronic transponders, encapsulated in either polymer or glass, were injected subcutaneously into either the ear base or the earlobe of 652 calves in three populations. The animals were clinically examined weekly, and transponder signalling was checked immediately before and after injection, after two weeks and after about eight months. About 10 per cent of animals in one population were also checked after 20 and 30 months. No severe clinical or visible pathological changes were observed, and the calves' welfare was not apparently affected by the procedure. None of the transponders migrated from their injection sites. Eight months after injection, a signal was detected from 98.2 per cent of transponders injected in the ear base and from 90.5 per cent of those in the earlobe. At 20 and 30 months after injection, 10.4 per cent and 2.6 per cent of transponders, respectively, had ceased to signal. Thus, most transponders in the calves' ear base demonstrated functionality for up to 30 months. PMID- 21813581 TI - Potential of vaccination to confound interpretation of real-time PCR results for equine influenza. PMID- 21813582 TI - Implementing a low-cost web-based clinical trial management system for community studies: a case study. AB - BACKGROUND: Clinical trials with multiple intervention locations and a single research coordinating center can be logistically difficult to implement. Increasingly, web-based systems are used to provide clinical trial support with many commercial, open source, and proprietary systems in use. New web-based tools are available which can be customized without programming expertise to deliver web-based clinical trial management and data collection functions. PURPOSE: To demonstrate the feasibility of utilizing low-cost configurable applications to create a customized web-based data collection and study management system for a five intervention site randomized clinical trial establishing the efficacy of providing evidence-based treatment via teleconferencing to children with attention-deficit hyperactivity disorder. The sites are small communities that would not usually be included in traditional randomized trials. A major goal was to develop database that participants could access from computers in their home communities for direct data entry. METHODS: Discussed is the selection process leading to the identification and utilization of a cost-effective and user friendly set of tools capable of customization for data collection and study management tasks. RESULTS: An online assessment collection application, template based web portal creation application, and web-accessible Access 2007 database were selected and customized to provide the following features: schedule appointments, administer and monitor online secure assessments, issue subject incentives, and securely transmit electronic documents between sites. Each tool was configured by users with limited programming expertise. As of June 2011, the system has successfully been used with 125 participants in 5 communities, who have completed 536 sets of assessment questionnaires, 8 community therapists, and 11 research staff at the research coordinating center. LIMITATIONS: Total automation of processes is not possible with the current set of tools as each is loosely affiliated, creating some inefficiency. This system is best suited to investigations with a single data source e.g., psychosocial questionnaires. CONCLUSIONS: New web-based applications can be used by investigators with limited programming experience to implement user-friendly, efficient, and cost-effective tools for multi-site clinical trials with small distant communities. Such systems allow the inclusion in research of populations that are not usually involved in clinical trials. PMID- 21813584 TI - Altruism among participants in cancer clinical trials. AB - BACKGROUND: Patients' motivations for participation in cancer clinical trials are incompletely understood. Even less is known about the factors that influence participants' motivations for enrolling in trials. PURPOSE: We studied the reasons why adult patients and parents of pediatric patients agree to participate in cancer trials. We focused on the role of altruism across all phases of trial. METHODS: We surveyed adult patients and parents of pediatric patients participating in phase I, II, or III cancer clinical trials. We asked respondents why they agreed to enroll, and examined correlates of altruistic motivation using univariate and multivariate analyses. RESULTS: Among 205 adults and 48 parents of children participating in cancer trials, 47% reported that altruistic motivations were 'very important' to their decisions to enroll. In multivariate analysis with phase III trial participants as the reference group, phase I trial participants least often identified altruism as a 'very important' motivation for enrolling (phase I OR 0.4, 95% CI (confidence interval) 0.2-0.8; phase II OR 0.9, 95% CI 0.5-1.5, overall P = 0.017). Thirty-three respondents (13%) reported being motivated primarily by altruism. In multivariate analysis, participants with poor prognoses-defined as an expected 5-year disease-free survival of <= 10%-reported altruism as their primary motivation less often than those with better prognoses (OR 0.2, 95% CI 0.1-0.5, P = 0.001). Altruistic motivations did not differ between adult patients and parents of pediatric participants. LIMITATIONS: The data are derived from related academic medical centers in one city, and the study sample reflects limited sociodemographic diversity, thereby limiting generalizability to other settings. CONCLUSIONS: Although cancer trial participants commonly report that altruism contributed to their decision to enroll, it is rarely their primary motivation for study participation. Participants in early phase trials and those with poor prognoses are least often motivated by altruism. PMID- 21813585 TI - Fibromyalgia in primary antiphospholipid (Hughes) syndrome. AB - Fibromyalgia (FM) is a syndrome that can be associated with several rheumatic diseases. However, no study has evaluated its frequency in patients with primary antiphospholipid syndrome (PAPS). The objective of this study was to analyze the frequency of FM in PAPS patients compared with healthy controls, to determine the possible associations between FM and PAPS features, and also to evaluate quality of life and depression in these patients. This case-control study included 30 PAPS patients (by the Sapporo criteria) and 40 healthy subjects. Demographic and clinical data, drug use, and antiphospholipid antibodies were analyzed. FM was diagnosed based on international criteria (ACR). Questionnaires on quality of life, including the Short Form 36 Health Survey (SF-36), Beck Depression Inventory (BDI), Fibromyalgia Impact Questionnaire (FIQ), and Visual Analog Scale (VAS), were also applied. PAPS patients and controls were similar in mean age as well as in distributions of gender and Caucasian race. Mean disease duration was 5.4 +/- 4.2 years. A diagnosis of fibromyalgia was made in five (16.7%) PAPS patients and no controls (p = 0.012). PAPS patients had more diffuse pain (53% vs. 0%, respectively, p < 0.0001), >=11 tender points (23% vs. 5%, respectively, p = 0.032), and a greater total number (175 vs. 57, respectively, p < 0.0001) as well as median number of tender points per patient than controls (5 [0-18] vs. 0 [0-11], respectively, p < 0.0001). PAPS patients had lower values in all dimensions of the SF-36, as well as higher FIQ scores, higher BDI scores, more depression diagnoses according to BDI results, and increased VAS in comparison with controls. Analysis of PAPS patients with FM compared with those subjects without FM revealed no significant differences regarding demographic features or thrombotic or clinical events; however, PAPS patients who also had FM had lower values in SF-36 dimensions as well as higher FIQ (82.6 +/- 9.6 vs. 33.6 +/- 29.8, respectively, p < 0.0001) and VAS scores (6.6 +/- 2.97 vs. 3.25 +/- 3.11, respectively, p = 0.03). BDI scores, in contrast, were similar in both groups. In conclusion, one-fifth of PAPS patients had fibromyalgia and a low quality of life when compared with healthy subjects. PMID- 21813586 TI - Pregnancy in patients with undifferentiated connective tissue disease: a prospective case-control study. AB - OBJECTIVES: To assess the outcome of pregnancy and disease flare or differentiation into well-defined connective tissue disease (CTD), in a cohort of pregnant patients with undifferentiated connective tissue disease (UCTD) and to compare these findings with those obtained from a population of non-pregnant women with UCTD. METHODS: In total, 55 pregnancies (in 50 UCTD patients) were monitored from the positive pregnancy test until the sixth month after delivery. Likewise, during a 15-month timeframe, the incidence of flares or evolution into a major CTD was also recorded in a population of 53 non-pregnant women with UCTD. The Student t-test was applied for unpaired, continuous variables and chi-square was applied when percentages were compared. RESULTS: The mean duration of the successful pregnancies was 38.6 weeks (range 28-42) while the mean birth weight was 3190 g (range 1200-4600 g). Three pregnancies (5.4%) ended in miscarriage. The following obstetric complications were found: five premature membrane ruptures, two preeclampsia and two intra-uterine growth restrictions. In a total of 16 patients (32%) the disease flared during pregnancy or during the 6-month post-delivery period. Of these, five developed well-defined CTD after delivery. In the control population, six patients flared (11%) and, of these, only one developed a well-defined CTD. CONCLUSIONS: If pregnancy is properly treated, the outcome in UCTD patients is generally good while, considering disease activity, pregnancy appears to be a clear risk factor for flare up or evolution into well defined CTD. PMID- 21813587 TI - Anti-C1q antibodies have higher correlation with flares of lupus nephritis than other serum markers. AB - OBJECTIVE: Autoantibodies are important in the diagnosis and classification of systemic lupus erythematosus (SLE), but whether they correlate with changes in disease activity within individual patients is controversial. We assessed the association between changes in SLE global and renal activity and changes in several autoantibodies and cell adhesion molecules in patients with SLE. METHODS: Stored sera collected at two or three clinic visits from each of 49 SLE patients (91% female, 59% African-American, 31% Caucasian, 10% other ethnicity, 38% under 30 years, 41% between 30-44 years, and 21% 45-63 years) were analyzed. The visits were chosen to include one visit with proteinuria, and one or two without, for each patient. Global disease activity was measured by the Physician's Global Assessment (PGA), SELENA-SLEDAI (SLE Disease Activity Index modified to exclude anti-dsDNA and complement) and renal activity assessed by urine protein (by urine dipstick) and Renal Activity Score. Sera were assayed for anti-C1q, anti chromatin, anti-dsDNA, anti-ribosomal P, monocyte chemotactic protein-1 (MCP-1), vascular cell adhesion molecule (VCAM) intercellular adhesion molecule (ICAM) and complement. The associations between changes in disease activity and changes in biomarker levels were assessed. RESULTS: In terms of global disease activity, anti-C1q had the highest association with the PGA (p = 0.09) and was strongly associated with modified SELENA-SLEDAI (p = 0.009). In terms of renal activity, anti-C1q had the highest association with proteinuria (p = 0.079), and was strongly associated with Renal Activity Score (p = 0.006). CONCLUSION: Anti-C1q performed the best of the potential biomarkers, being significantly associated with the modified SELENA-SLEDAI and with the Renal Activity Score. This study indicates the potential superior utility of anti-C1q over anti-dsDNA and other measures to track renal activity. PMID- 21813583 TI - Medication adherence assessment in a clinical trial with centralized follow-up and direct-to-patient drug shipments. AB - BACKGROUND: Assessment of adherence to study medications is a common challenge in clinical research. Counting unused study medication is the predominant method by which adherence is assessed in outpatient clinical trials but it has limitations that include questionable validity and burdens on research personnel. PURPOSE: To compare capsule counts, patient questionnaire responses, and plasma drug levels as methods of determining adherence in a clinical trial that had 2056 participants and used centralized drug distribution and patient follow-up. METHODS: Capsule counts from study medication bottles returned by participants and responses to questions regarding adherence during quarterly telephone interviews were averaged and compared. Both measures were compared to plasma drug levels obtained at the 3-month study visit of patients in the treatment group. Counts and questionnaire responses were converted to adherence rates (doses taken divided by days elapsed) and were categorized by stringent (>=85.7%) and liberal (>=71.4%) definitions. We calculated the prevalence-adjusted bias-adjusted kappa to assess agreement between the two measures. RESULTS: Using a pre-paid mailer, participants returned 76.0% of study medication bottles to the central pharmacy. Both capsule counts and questionnaire responses were available for 65.8% of participants and were used to assess adherence. Capsule counts identified more patients who were under-adherent (18.8% by the stringent definition and 7.5% by the liberal definition) than self-reports did (10.4% by the stringent definition and 2.1% by the liberal definition). The prevalence-adjusted bias-adjusted kappa was 0.58 (stringent) and 0.83 (liberal), indicating fair and very good agreement, respectively. Both measures were also in agreement with plasma drug levels determined at the 3-month visit (capsule counts: p = 0.005 for the stringent and p = 0.003 for the liberal definition; questionnaire: p = 0.002 for both adherence definitions). LIMITATIONS: Inconsistent bottle returns and incomplete notations of medication start and stop dates resulted in missing data but exploratory missing data analyses showed no reason to believe that the missing data resulted in systematic bias. CONCLUSIONS: Depending upon the definition of adherence, there was fair to very good agreement between questionnaire results and capsule counts among returned study bottles, confirmed by plasma drug levels. We conclude that a self-report of medication adherence is potentially comparable to capsule counts as a method of assessing adherence in a clinical trial, if a relatively low adherence threshold is acceptable, but adherence should be confirmed by other measures if a high adherence threshold is required. PMID- 21813588 TI - Predictors of mortality and end stage renal disease in Saudi patients with lupus nephritis. AB - The purpose of this study was to investigate the presentation and factors affecting outcome over a 9-year period in 99 consecutive Saudi patients with biopsy proven lupus nephritis (LN), 35.5% of whom had nephrotic range proteinuria, 46.8% had estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m(2) and 65.5% had histological class IV. The female:male ratio was 3.7:1. During the observation period, there were significant rises in eGFR (p = 0.005), C4 (p = 0.000) and significant decrease in 24-h urine protein (p = 0.028). No correlation was found between final eGFR and baseline 24-h protein, anti-DNA, C3 or C4. Female patients had a significantly higher rise in eGFR (p = 0.05).During follow-up (FU), 28.2% required dialysis. The survival rates at 5, 10 and 15 years were 92%, 77% and 77% respectively. Baseline C3 and C4 levels were significantly lower in the patients who died (p = 0.0001 and 0.02 respectively). Those who required dialysis were more likely to die (p < 0.000) (risk ratio = 4.46; 95% confidence interval 2.8-7.2). Hypertension at presentation was associated with lower baseline eGFR (p = 0.01) and final eGFR (p = 0.002) but did not affect the baseline proteinuria. Baseline eGFR of <60 ml/min/1.73 m(2) at presentation was associated with lower eGFR at end of FU (p = 0.000), higher activity score (p = 0.0001) and chronicity scores (p = 0.017). PMID- 21813589 TI - The Patient Reported Outcomes in Lupus (PATROL) study: role of depression in health-related quality of life in a Southern California lupus cohort. AB - This study examines the relationship between psychosocial factors, ethnicity, disease activity and quality of life in systemic lupus erythematosus. METHODS: One hundred and twenty-five adult Caucasian and Hispanic lupus patients were recruited from four Southern California medical centers. Linear regression analysis was performed to assess the correlation of ethnicity, socioeconomic factors (age, income), and disease activity (patient and physician reported), as well as psychological (depression, internality, helplessness) variables with quality of life (QOL) as measured by the Short Form (SF)-36. Hierarchical multiple regression analysis was then used to determine the stepwise contribution of the above determinants on the eight domains of the SF-36 questionnaire. RESULTS: Depression negatively correlated with QOL in both Caucasians (r -0.488 to -0.660) and Hispanics (r -0.456 to -0.723). Patient-reported disease activity was moderately related (r -0.456 to -0.698) to seven of the eight SF-36 domains in Hispanics, and none in Caucasians. Physician-reported disease activity, measured by SLEDAI, did not correlate with QOL among Hispanics or Caucasians. When linear and hierarchical regression was used, depression significantly correlated (p < 0.0001) with the majority of the SF-36 domains, except general health, while age had a significant effect in only one domain of the SF-36, physical functioning (p < 0.0001). CONCLUSION: Depression, and not disease activity, appears to have a major influence on quality of life in both Hispanic and Caucasian patients in this lupus cohort. PMID- 21813590 TI - Complement and antibody primary immunodeficiency in juvenile systemic lupus erythematosus patients. AB - OBJECTIVE: To evaluate the frequency of primary immunodeficiencies (PID) in juvenile systemic lupus erythematosus (JSLE) patients. METHODS: Some 72 JSLE patients were analyzed for levels of immunoglobulin classes and IgG subclasses and early components of the classical complement pathway. Determination of C4 gene copy number (GCN) and detection of type I C2 deficiency (D) were also performed. RESULTS: PID was identified in 16 patients (22%): C2D in three, C4D in three, C1qD in two, IgG2D (<20 mg/dl) in four, IgAD (<7 mg/dl) in three, and IgMD (<35 mg/dl) in three; one of these patients presented IgA, C2 and C4D. Two patients had low C4 GCN and two had type I C2D. Demographic data, family history of autoimmune disease and PID, JSLE clinical findings, occurrence of infections, disease activity and therapies were similar in patients with and without PID (p > 0.05). Remarkably, the median of Systemic Lupus International Collaborating Clinics/ACR-damage index (SLICC/ACR-DI) was significantly higher in JSLE patients with PID compared with patients without these abnormalities (p = 0.0033), likewise the high frequency of SLICC/ACR-DI > 1 (p = 0.023). CONCLUSIONS: A high frequency of PID was observed in JSLE patients, suggesting that these defects may contribute to lupus development. Our findings indicate that these two groups of PID should be investigated in severe pediatric lupus. PMID- 21813591 TI - Simultaneous presentation of systemic lupus erythematosus and lupus nephritis in mother and son. AB - The pathogenesis of systemic lupus erythematosus (SLE) has been attributed to complex interactions between genetic, hormonal and environmental factors. The influence of a genetic predisposition to SLE is supported by family aggregation and a high concordance rate in monozygotic twins. Here we present a rare case of simultaneous presentation of SLE and lupus nephritis in a mother and son. Both patients had nephrotic-range proteinuria, and the renal pathological classifications of the son and his mother were Class IV-G (A) and Class III (A/C), respectively, according to the International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 classification of lupus nephritis. Apart from the renal involvement, both patients had leucopenia and anemia, and the mother also had typical cutaneous lesions and secondary Sjogren's syndrome. This case supports the genetic role in the etiology of SLE, and displayed different clinical presentations and disease severity in familial SLE patients of different gender and age. PMID- 21813592 TI - Oxidative stress is associated with liver damage, inflammatory status, and corticosteroid therapy in patients with systemic lupus erythematosus. AB - Oxidative stress exerts an important role on the pathophysiological mechanisms of systemic lupus erythematosus (SLE). This study investigated oxidative stress in patients with SLE and its correlation with disease activity, corticosteroid therapy, and liver function biomarkers. The study included 58 patients with SLE and 105 healthy volunteers. Patients showed oxidative stress increase evaluated by tert-butyl hydroperoxide-initiated chemiluminescence (CL-LOOH), advanced oxidation protein products (AOPP), and nitric oxide metabolites. C-reactive protein (CRP) was associated with CL-LOOH and with AOPP. Aspartate aminotransferase correlated significantly with CL-LOOH and with AOPP. Patients with disease activity showed an inverse significant correlation of daily prednisone doses and CL-LOOH and a direct correlation with total antioxidant capacity. In conclusion, patients with SLE have persistent lipoperoxidation and protein oxidation even with inactive disease or mild disease activity. The significant correlation between oxidative stress and CRP suggests that, despite clinical remission, the persistence of an inflammatory condition favors oxidative stress. Oxidative stress was associated with liver enzymes, and this relationship seems to support the hypothesis of drug-induced oxidative stress with consequent liver injury. In relation to non-active disease, patients with active SLE did not present oxidative stress and antioxidant capacity changes, due to the antioxidant drugs used in SLE treatment, especially prednisone. PMID- 21813593 TI - Monocarboxylate transporter 8 deficiency: altered thyroid morphology and persistent high triiodothyronine/thyroxine ratio after thyroidectomy. AB - CONTEXT: Thyroid hormone transport across the plasma membrane depends on transmembrane transport proteins, including monocarboxylate transporter 8 (MCT8). Mutations in MCT8 (or SLC16A2) lead to a severe form of X-linked psychomotor retardation, which is characterised by elevated plasma triiodothyronine (T(3)) and low/normal thyroxine (T(4)). MCT8 contributes to hormone release from the thyroid gland. OBJECTIVE: To characterise the potential impact of MCT8-deficiency on thyroid morphology in a patient and in Mct8-deficient mice. DESIGN: Thyroid morphology in a patient carrying the A224V mutation was followed by ultrasound imaging for over 10 years. After thyroidectomy, a histopathological analysis was carried out. The findings were compared with histological analyses of mouse thyroids from the Mct8(-/y) model. RESULTS: We show that an inactivating mutation in MCT8 leads to a unique, progressive thyroid follicular pathology in a patient. After thyroidectomy, histological analysis revealed gross morphological changes, including several hyperplastic nodules, microfollicular areas with stromal fibrosis and a small focus of microfollicular structures with nuclear features reminiscent of papillary thyroid carcinoma (PTC). These findings are supported by an Mct8-null mouse model in which we found massive papillary hyperplasia in 6- to 12-month-old mice and nuclear features consistent with PTC in almost 2-year-old animals. After complete thyroidectomy and substitution with levothyroxine (l T(4)), the preoperative, inadequately low T(4) and free T(4) remained, while increasing the l-T(4) dosage led to T(3) serum concentrations above the normal range. CONCLUSIONS: Our results implicate peripheral deiodination in the peculiar hormonal constellation of MCT8-deficient patients. Other MCT8-deficient patients should be closely monitored for potential thyroid abnormalities. PMID- 21813594 TI - Impact of cooking and drying on the phenolic, carotenoid contents and in vitro antioxidant capacity of Andean arracacha (Arracacia xanthorrhiza Bancr.) root. AB - The influence of different cooking regimes such as boiling, oven, microwave and hot-air drying on the retention of total phenolics (TP), total carotenoids (TC) and in vitro antioxidant capacity (AC) for three colored arracacha roots was studied. Continuous losses of TP, TC and AC during the course of the different cooking processes were observed. Boiling at 99.5 degrees C for 20 min turned to be the best method to cook this root due to a high retention of TP, TC and AC in comparison to oven cooking at 200 degrees C for 45 min and microwave cooking at 800 W for 5 min. During boiling, chlorogenic and caffeic acids and derivatives remained relatively stable. The drying temperature was negatively correlated to the residual content of TP and AC for the yellow and cream arracacha roots, but for the cream/purple arracacha variety, blanching preserved the TP and AC. Significant losses in chlorogenic and caffeic acids and derivatives were mainly observed during hot-air drying. These results suggested that TP are responsible to a large extent of the AC displayed by arracacha root during the different evaluated cooking regimes. PMID- 21813595 TI - Extraction of bromelain from pineapple peels. AB - Large amount of pineapple peels (by-products) is left over after processing and they are a potential source for bromelain extraction. Distilled water (DI), DI containing cysteine and ethylenediaminetetraacetic acid (EDTA) (DI-CE), sodium phosphate buffer pH 7.0 (PB) and PB containing cysteine and EDTA (PB-CE) were used as extractants for bromelain from the pineapple peels. The highest bromelain activity was obtained when it was extracted with PB-CE (867 and 1032 units for Nang Lae and Phu Lae cultv, respectively). The PB could maintain the pH of the extract (pH 5.1-5.7) when compared with others. Under sodium dodecyl sulfate polyacrylamide gel electrophoresis, the extract showed protein bands in the range 24-28 kDa. The protein band with a molecular weight of ~28 kDa exposed the clear zone on blue background under the casein-substrate gel electrophoresis. The effects of the bromelain extract on the protein patterns of beef, chicken and squid muscles were also determined. Trichloroacetic acid soluble peptide content of all the treated muscles increased when the amount of bromelain extract increased. Decrease in myosin heavy chains and actin was observed in all the muscle types when bromelain extract was used. The best extractant for bromelain from pineapple peels was PB-CE. Moreover, bromelain extract could be used as a muscle food tenderizing agent in food industries. PMID- 21813596 TI - Comparison of waste pumpkin material and its potential use in extruded snack foods. AB - Material was produced from Crown pumpkin (Cucurbita maxima) processed from fractions of the fruit which are regarded as waste stream products (peel, flesh and seed). The flour from the three different fractions (peel, flesh and seed) of Crown pumpkin flour was incorporated into an extruded snack product formulation at levels 10%, 30% and 50% (w/w with corn grit) and processed in a twin-screw extruder to make 10 expanded snack products. Proximate analysis was carried out to determine the nutritional value of the raw pumpkin and pumpkin flour. A physical analysis of the product was used to determine its color, the expansion ratio, bulk density and texture. Inclusion of waste stream material (peel and seed) at 10%, yielded extruded products with similar expansion and density characteristics to the control sample; however, an inclusion of greater than 10% yielded significant challenges to product quality (hardness of the product). PMID- 21813597 TI - Immunization with a vaccine combining herpes simplex virus 2 (HSV-2) glycoprotein C (gC) and gD subunits improves the protection of dorsal root ganglia in mice and reduces the frequency of recurrent vaginal shedding of HSV-2 DNA in guinea pigs compared to immunization with gD alone. AB - Attempts to develop a vaccine to prevent genital herpes simplex virus 2 (HSV-2) disease have been only marginally successful, suggesting that novel strategies are needed. Immunization with HSV-2 glycoprotein C (gC-2) and gD-2 was evaluated in mice and guinea pigs to determine whether adding gC-2 to a gD-2 subunit vaccine would improve protection by producing antibodies that block gC-2 immune evasion from complement. Antibodies produced by gC-2 immunization blocked the interaction between gC-2 and complement C3b, and passive transfer of gC-2 antibody protected complement-intact mice but not C3 knockout mice against HSV-2 challenge, indicating that gC-2 antibody is effective, at least in part, because it prevents HSV-2 evasion from complement. Immunization with gC-2 also produced neutralizing antibodies that were active in the absence of complement; however, the neutralizing titers were higher when complement was present, with the highest titers in animals immunized with both antigens. Animals immunized with the gC-2 plus-gD-2 combination had robust CD4+ T-cell responses to each immunogen. Multiple disease parameters were evaluated in mice and guinea pigs immunized with gC-2 alone, gD-2 alone, or both antigens. In general, gD-2 outperformed gC-2; however, the gC-2-plus-gD-2 combination outperformed gD-2 alone, particularly in protecting dorsal root ganglia in mice and reducing recurrent vaginal shedding of HSV-2 DNA in guinea pigs. Therefore, the gC-2 subunit antigen enhances a gD-2 subunit vaccine by stimulating a CD4+ T-cell response, by producing neutralizing antibodies that are effective in the absence and presence of complement, and by blocking immune evasion domains that inhibit complement activation. PMID- 21813598 TI - Major histocompatibility complex class II transactivator CIITA is a viral restriction factor that targets human T-cell lymphotropic virus type 1 Tax-1 function and inhibits viral replication. AB - Human T-cell lymphotropic virus type 1 (HTLV-1) is the causative agent of an aggressive malignancy of CD4+ T lymphocytes. Since the viral transactivator Tax-1 is a major player in T-cell transformation, targeting Tax-1 protein is regarded as a possible strategy to arrest viral replication and to counteract neoplastic transformation. We demonstrate that CIITA, the master regulator of major histocompatibility complex class II gene transcription, inhibits HTLV-1 replication by blocking the transactivating function of Tax-1 both when exogenously transfected in 293T cells and when endogenously expressed by a subset of U937 promonocytic cells. Tax-1 and CIITA physically interact in vivo via the first 108 amino acids of Tax-1 and two CIITA adjacent regions (amino acids 1 to 252 and 253 to 410). Interestingly, only CIITA 1-252 mediated Tax-1 inhibition, in agreement with the fact that CIITA residues from positions 64 to 124 were required to block Tax-1 transactivation. CIITA inhibitory action on Tax-1 correlated with the nuclear localization of CIITA and was independent of the transcription factor NF-YB, previously involved in CIITA-mediated inhibition of Tax-2 of HTLV-2. Instead, CIITA severely impaired the physical and functional interaction of Tax-1 with the cellular coactivators p300/CBP-associated factor (PCAF), cyclic AMP-responsive element binding protein (CREB), and activating transcription factor 1 (ATF1), which are required for the optimal activation of HTLV-1 promoter. Accordingly, the overexpression of PCAF, CREB, and ATF1 restored Tax-1-dependent transactivation of the viral long-terminal-repeat promoter inhibited by CIITA. These findings strongly support our original observation that CIITA, beside increasing the antigen-presenting function for pathogen antigens, acts as an endogenous restriction factor against human retroviruses by blocking virus replication and spreading. PMID- 21813599 TI - Recombination-mediated changes in coreceptor usage confer an augmented pathogenic phenotype in a nonhuman primate model of HIV-1-induced AIDS. AB - Evolution of the env gene in transmitted R5-tropic human immunodeficiency virus type 1 (HIV-1) strains is the most widely accepted mechanism driving coreceptor switching. In some infected individuals, however, a shift in coreceptor utilization can occur as a result of the reemergence of a cotransmitted, but rapidly controlled, X4 virus. The latter possibility was studied by dually infecting rhesus macaques with X4 and R5 chimeric simian simian/human immunodeficiency viruses (SHIVs) and monitoring the replication status of each virus using specific primer pairs. In one of the infected monkeys, both SHIVs were potently suppressed by week 12 postinoculation, but a burst of viremia at week 51 was accompanied by an unrelenting loss of total CD4+ T cells and the development of clinical disease. PCR analyses of plasma viral RNA indicated an env gene segment containing the V3 region from the inoculated X4 SHIV had been transferred into the genetic background of the input R5 SHIV by intergenomic recombination, creating an X4 virus with novel replicative, serological, and pathogenic properties. These results indicate that the effects of retrovirus recombination in vivo can be functionally profound and may even occur when one of the recombination participants is undetectable in the circulation as cell-free virus. PMID- 21813600 TI - Engineering T cells specific for a dominant severe acute respiratory syndrome coronavirus CD8 T cell epitope. AB - Severe acute respiratory syndrome (SARS) is a highly contagious and life threatening disease, with a fatality rate of almost 10%. The etiologic agent is a novel coronavirus, severe acute respiratory syndrome coronavirus (SARS-CoV), with animal reservoirs found in bats and other wild animals and thus the possibility of reemergence. In this study, we first investigated at 6 years postinfection whether SARS-specific memory T cells persist in SARS-recovered individuals, demonstrating that these subjects still possess polyfunctional SARS-specific memory CD4+ and CD8+ T cells. A dominant memory CD8+ T cell response against SARS CoV nucleocaspid protein (NP; amino acids 216 to 225) was then defined in SARS recovered individuals carrying HLA-B*40:01, a HLA-B molecule present in approximately one-quarter of subjects of Asian ethnicities. To reconstitute such a CD8+ T cell response, we isolated the alpha and beta T cell receptors of the HLA-B*40:01-restricted SARS-specific CD8+ T cells. Using T cell receptor gene transfer, we generated SARS-specific redirected T cells from the lymphocytes of normal individuals. These engineered CD8+ T cells displayed avidity and functionality similar to that of natural SARS-specific memory CD8+ T cells. They were able to degranulate and produce gamma interferon, tumor necrosis factor alpha, and macrophage inflammatory proteins 1alpha and 1beta after antigenic stimulation. Since there is no effective treatment against SARS, these transduced T cells specific for an immunodominant SARS epitope may provide a new avenue for treatment during a SARS outbreak. PMID- 21813601 TI - Identification of chemoattractive factors involved in the migration of bone marrow-derived mesenchymal stem cells to brain lesions caused by prions. AB - Bone marrow-derived mesenchymal stem cells (MSCs) have been reported to migrate to brain lesions of neurodegenerative diseases; however, the precise mechanisms by which MSCs migrate remain to be elucidated. In this study, we carried out an in vitro migration assay to investigate the chemoattractive factors for MSCs in the brains of prion-infected mice. The migration of immortalized human MSCs (hMSCs) was reduced by their pretreatment with antibodies against the chemokine receptors, CCR3, CCR5, CXCR3, and CXCR4 and by pretreatment of brain extracts of prion-infected mice with antibodies against the corresponding ligands, suggesting the involvement of these receptors, and their ligands in the migration of hMSCs. In agreement with the results of an in vitro migration assay, hMSCs in the corpus callosum, which are considered to be migrating from the transplanted area toward brain lesions of prion-infected mice, expressed CCR3, CCR5, CXCR3, and CXCR4. The combined in vitro and in vivo analyses suggest that CCR3, CCR5, CXCR3, and CXCR4, and their corresponding ligands are involved in the migration of hMSCs to the brain lesions caused by prion propagation. In addition, hMSCs that had migrated to the right hippocampus of prion-infected mice expressed CCR1, CX3CR1, and CXCR4, implying the involvement of these chemokine receptors in hMSC functions after chemotactic migration. Further elucidation of the mechanisms that underlie the migration of MSCs may provide useful information regarding application of MSCs to the treatment of prion diseases. PMID- 21813602 TI - Mapping a region of hepatitis C virus E2 that is responsible for escape from neutralizing antibodies and a core CD81-binding region that does not tolerate neutralization escape mutations. AB - Understanding the interaction between broadly neutralizing antibodies and their epitopes provides a basis for the rational design of a preventive hepatitis C virus (HCV) vaccine. CBH-2, HC-11, and HC-1 are representatives of antibodies to overlapping epitopes on E2 that mediate neutralization by blocking virus binding to CD81. To obtain insights into escape mechanisms, infectious cell culture virus, 2a HCVcc, was propagated under increasing concentrations of a neutralizing antibody to isolate escape mutants. Three escape patterns were observed with these antibodies. First, CBH-2 escape mutants that contained mutations at D431G or A439E, which did not compromise viral fitness, were isolated. Second, under the selective pressure of HC-11, escape mutations progressed from a single L438F substitution at a low antibody concentration to double substitutions, L438F and N434D or L438F and T435A, at higher antibody concentrations. Escape from HC-11 was associated with a loss of viral fitness. An HCV pseudoparticle (HCVpp) containing the L438F mutation bound to CD81 half as efficiently as did wild-type (wt) HCVpp. Third, for HC-1, the antibody at a critical concentration completely suppressed viral replication and generated no escape mutants. Epitope mapping revealed contact residues for CBH-2 and HC-11 in two regions of the E2 glycoprotein, amino acids (aa) 425 to 443 and aa 529 to 535. Interestingly, contact residues for HC-1 were identified only in the region encompassing aa 529 to 535 and not in aa 425 to 443. Taken together, these findings point to a region of variability, aa 425 to 443, that is responsible primarily for viral escape from neutralization, with or without compromising viral fitness. Moreover, the region aa 529 to 535 is a core CD81 binding region that does not tolerate neutralization escape mutations. PMID- 21813603 TI - Rous sarcoma virus gag has no specific requirement for phosphatidylinositol-(4,5) bisphosphate for plasma membrane association in vivo or for liposome interaction in vitro. AB - The MA domain of the retroviral Gag protein mediates interactions with the plasma membrane, which is the site of productive virus release. HIV-1 MA has a phosphatidylinositol-(4,5)-bisphosphate [PI(4,5)P2] binding pocket; depletion of this phospholipid from the plasma membrane compromises Gag membrane association and virus budding. We used multiple methods to examine the possible role of PI(4,5)P2 in Gag-membrane interaction of the alpharetrovirus Rous sarcoma virus (RSV). In contrast to HIV-1, which was tested in parallel, neither membrane localization of RSV Gag-GFP nor release of virus-like particles was affected by phosphatase-mediated depletion of PI(4,5)P2 in transfected avian cells. In liposome flotation experiments, RSV Gag required acidic lipids for binding but showed no specificity for PI(4,5)P2. Mono-, di-, and triphosphorylated phosphatidylinositol phosphate (PIP) species as well as high concentrations of phosphatidylserine (PS) supported similar levels of flotation. A mutation that increases the overall charge of RSV MA also enhanced Gag membrane binding. Contrary to previous reports, we found that high concentrations of PS, in the absence of PIPs, also strongly promoted HIV-1 Gag flotation. Taken together, we interpret these results to mean that RSV Gag membrane association is driven by electrostatic interactions and not by any specific association with PI(4,5)P2. PMID- 21813605 TI - Membrane perturbation elicits an IRF3-dependent, interferon-independent antiviral response. AB - We previously found that enveloped virus binding and penetration are necessary to initiate an interferon-independent, IRF3-mediated antiviral response. To investigate whether membrane perturbations that accompany membrane fusion dependent enveloped-virus entry are necessary and sufficient for antiviral-state induction, we utilized a reovirus fusion-associated small transmembrane (FAST) protein. Membrane disturbances during FAST protein-mediated fusion, in the absence of additional innate immune response triggers, are sufficient to elicit interferon-stimulated gene induction and establishment of an antiviral state. Using sensors of membrane disruption to activate an IRF3-dependent, interferon independent antiviral state may provide cells with a rapid, broad-spectrum innate immune response to enveloped-virus infections. PMID- 21813604 TI - Gag induces the coalescence of clustered lipid rafts and tetraspanin-enriched microdomains at HIV-1 assembly sites on the plasma membrane. AB - The HIV-1 structural protein Gag associates with two types of plasma membrane microdomains, lipid rafts and tetraspanin-enriched microdomains (TEMs), both of which have been proposed to be platforms for HIV-1 assembly. However, a variety of studies have demonstrated that lipid rafts and TEMs are distinct microdomains in the absence of HIV-1 infection. To measure the impact of Gag on microdomain behaviors, we took advantage of two assays: an antibody-mediated copatching assay and a Forster resonance energy transfer (FRET) assay that measures the clustering of microdomain markers in live cells without antibody-mediated patching. We found that lipid rafts and TEMs copatched and clustered to a greater extent in the presence of membrane-bound Gag in both assays, suggesting that Gag induces the coalescence of lipid rafts and TEMs. Substitutions in membrane binding motifs of Gag revealed that, while Gag membrane binding is necessary to induce coalescence of lipid rafts and TEMs, either acylation of Gag or binding of phosphatidylinositol-(4,5)-bisphosphate is sufficient. Finally, a Gag derivative that is defective in inducing membrane curvature appeared less able to induce lipid raft and TEM coalescence. A higher-resolution analysis of assembly sites by correlative fluorescence and scanning electron microscopy showed that coalescence of clustered lipid rafts and TEMs occurs predominantly at completed cell surface virus-like particles, whereas a transmembrane raft marker protein appeared to associate with punctate Gag fluorescence even in the absence of cell surface particles. Together, these results suggest that different membrane microdomain components are recruited in a stepwise manner during assembly. PMID- 21813606 TI - A Kaposi's sarcoma-associated herpesvirus-encoded ortholog of microRNA miR-155 induces human splenic B-cell expansion in NOD/LtSz-scid IL2Rgammanull mice. AB - MicroRNAs (miRNAs) are small noncoding RNA molecules that function as posttranscriptional regulators of gene expression. Kaposi's sarcoma (KS) associated herpesvirus (KSHV), a B-cell-tropic virus associated with KS and B cell lymphomas, encodes 12 miRNA genes that are highly expressed in these tumor cells. One viral miRNA, miR-K12-11, shares 100% seed sequence homology with hsa miR-155, an oncogenic human miRNA that functions as a key regulator of hematopoiesis and B-cell differentiation. So far, in vitro studies have shown that both miRNAs can regulate a common set of cellular target genes, suggesting that miR-K12-11 may mimic miR-155 function. To comparatively study miR-K12-11 and miR-155 function in vivo, we used a foamy virus vector to express the miRNAs in human hematopoietic progenitors and performed immune reconstitutions in NOD/LtSz scid IL2Rgamma(null) mice. We found that ectopic expression of miR-K12-11 or miR 155 leads to a significant expansion of the CD19(+) B-cell population in the spleen. Subsequent quantitative PCR analyses of these splenic B cells revealed that C/EBPbeta, a transcriptional regulator of interleukin-6 that is linked to B cell lymphoproliferative disorders, is downregulated when either miR-K12-11 or miR-155 is ectopically expressed. In addition, inhibition of miR-K12-11 function using antagomirs in KSHV-infected human primary effusion lymphoma B cells resulted in derepression of C/EBPbeta transcript levels. This in vivo study validates miR-K12-11 as a functional ortholog of miR-155 in the context of hematopoiesis and suggests a novel mechanism by which KSHV miR-K12-11 induces splenic B-cell expansion and potentially KSHV-associated lymphomagenesis by targeting C/EBPbeta. PMID- 21813607 TI - Functional interactions between polydnavirus and host cellular innexins. AB - Polydnaviruses are double-stranded DNA viruses associated with some subfamilies of ichneumonoid parasitoid wasps. Polydnavirus virions are delivered during wasp parasitization of a host, and virus gene expression in the host induces alterations of host physiology. Infection of susceptible host caterpillars by the polydnavirus Campoletis sonorensis ichnovirus (CsIV) leads to expression of virus genes, resulting in immune and developmental disruptions. CsIV carries four homologues of insect gap junction genes (innexins) termed vinnexins, which are expressed in multiple tissues of infected caterpillars. Previously, we demonstrated that two of these, VinnexinD and VinnexinG, form functional gap junctions in paired Xenopus oocytes. Here we show that VinnexinQ1 and VinnexinQ2, likewise, form junctions in this heterologous system. Moreover, we demonstrate that the vinnexins interact differentially with the Innexin2 orthologue of an ichnovirus host, Spodoptera frugiperda. Cell pairs coexpressing a vinnexin and Innexin2 or pairs in which one cell expresses a vinnexin and the neighboring cell Innexin2 assemble functional junctions with properties that differ from those of junctions composed of Innexin2 alone. These data suggest that altered gap junctional intercellular communication may underlie certain cellular pathologies associated with ichnovirus infection of caterpillar hosts. PMID- 21813608 TI - The genome of Yoka poxvirus. AB - Yoka poxvirus was isolated almost four decades ago from a mosquito pool in the Central African Republic. Its classification as a poxvirus is based solely upon the morphology of virions visualized by electron microscopy. Here we describe sequencing of the Yoka poxvirus genome using a combination of Roche/454 and Illumina next-generation sequencing technologies. A single consensus contig of ~175 kb in length that encodes 186 predicted genes was generated. Multiple methods were used to show that Yoka poxvirus is most closely related to viruses in the Orthopoxvirus genus, but it is clearly distinct from previously described poxviruses. Collectively, the phylogenetic and genomic sequence analyses suggest that Yoka poxvirus is the prototype member of a new genus in the family Poxviridae. PMID- 21813609 TI - Mechanisms governing the selection of translation initiation sites on foot-and mouth disease virus RNA. AB - Translation initiation dependent on the foot-and-mouth disease virus (FMDV) internal ribosome entry site (IRES) occurs at two sites (Lab and Lb), 84 nucleotides (nt) apart. In vitro translation of an mRNA comprising the IRES and Lab-Lb intervening segment fused to a chloramphenicol acetyltransferase (CAT) reporter has been used to study the parameters influencing the ratio of the two products and the combined product yield as measures of relative initiation site usage and productive ribosome recruitment, respectively. With wild-type mRNA, ~40% of initiation occurred at the Lab site, which was increased to 90% by optimization of its context, but decreased to 20% by mutations that reduced downstream secondary structure, with no change in recruitment in either case. Inserting 5 nt into the pyrimidine-rich tract located just upstream of the Lab site increased initiation at this site by 75% and ribosome recruitment by 50%. Mutating the Lab site to RCG or RUN codons decreased recruitment by 20 to 30% but stimulated Lb initiation by 20 to 40%. An antisense oligodeoxynucleotide annealing across the Lab site inhibited initiation at both sites. These and related results lead to the following conclusions. Recruitment by the wild-type IRES is limited by its short oligopyrimidine tract. At least 90% of internal ribosome entry occurs at the Lab AUG, but initiation at this site is restricted by its poor context, despite a counteracting effect of downstream secondary structure. Initiation at the Lb site is by ribosomes that access it by linear scanning from the original entry site, and not by an independent entry process. PMID- 21813610 TI - Low-pH-dependent changes in the conformation and oligomeric state of the prefusion form of herpes simplex virus glycoprotein B are separable from fusion activity. AB - The cellular requirements for activation of herpesvirus fusion and entry remain poorly understood. Low pH triggers change in the antigenic reactivity of the prefusion form of the herpes simplex virus (HSV) fusion protein gB in virions, both in vitro and during viral entry via endocytosis (S. Dollery et al., J. Virol. 84:3759-3766, 2010). However, the mechanism and magnitude of gB conformational change are not clear. Here we show that the conformation and oligomeric state of gB with mutations in the bipartite fusion loops were similarly altered despite the fusion-inactivating mutations. Together with previous studies, this suggests that fusion loop mutants undergo conformational changes but are defective for fusion because they fail to make productive contact with the outer leaflet of the host target membrane. A direct, reversible effect of low pH on the structure of gB was detected by fluorescence spectroscopy. A soluble form of gB containing cytoplasmic tail sequences (s-gB) was triggered by mildly acidic pH to undergo changes in tryptophan fluorescence emission, hydrophobicity, antigenic conformation, and oligomeric structure and thus resembled the prefusion form of gB in the virion. In contrast, soluble gB730, for which the postfusion crystal structure is known, was only marginally affected by pH using these measures. The results underscore the importance of using a prefusion form of gB to assess the activation and extent of conformation change. Further, acidic pH had little to no effect on the conformation or hydrophobicity of gD or on gD's ability to bind nectin-1 or HVEM receptors. Our results support a model in which endosomal low pH serves as a cellular trigger of fusion by activating conformational changes in the fusion protein gB. PMID- 21813611 TI - Vesicular stomatitis virus expressing tumor suppressor p53 is a highly attenuated, potent oncolytic agent. AB - Vesicular stomatitis virus (VSV), a negative-strand RNA rhabdovirus, preferentially replicates in and eradicates transformed versus nontransformed cells and is thus being considered for use as a potential anticancer treatment. The genetic malleability of VSV also affords an opportunity to develop more potent agents that exhibit increased therapeutic activity. The tumor suppressor p53 has been shown to exert potent antitumor properties, which may in part involve stimulating host innate immune responses to malignancies. To evaluate whether VSV expressing p53 exhibited enhanced oncolytic action, the murine p53 (mp53) gene was incorporated into recombinant VSVs with or without a functional viral M gene-encoded protein that could either block (VSV-mp53) or enable [VSV M(mut)-mp53] host mRNA export following infection of susceptible cells. Our results indicated that VSV-mp53 and VSV-M(mut)-mp53 expressed high levels of functional p53 and retained the ability to lyse transformed versus normal cells. In addition, we observed that VSV-DeltaM-mp53 was extremely attenuated in vivo due to p53 activating innate immune genes, such as type I interferon (IFN). Significantly, immunocompetent animals with metastatic mammary adenocarcinoma exhibited increased survival following treatment with a single inoculation of VSV DeltaM-mp53, the mechanisms of which involved enhanced CD49b+ NK and tumor specific CD8+ T cell responses. Our data indicate that VSV incorporating p53 could provide a safe, effective strategy for the design of VSV oncolytic therapeutics and VSV-based vaccines. PMID- 21813612 TI - Crystal structures of enterovirus 71 3C protease complexed with rupintrivir reveal the roles of catalytically important residues. AB - EV71 is the primary pathogenic cause of hand-foot-mouth disease (HFMD), but an effective antiviral drug currently is unavailable. Rupintrivir, an inhibitor against human rhinovirus (HRV), has potent antiviral activities against EV71. We determined the high-resolution crystal structures of the EV71 3C(pro)/rupintrivir complex, showing that although rupintrivir interacts with EV71 3C(pro) similarly to HRV 3C(pro), the C terminus of the inhibitor cannot accommodate the leaving group pockets of EV71 3C(pro). Our structures reveal that EV71 3C(pro) possesses a surface-recessive S2' pocket that is not present in HRV 3C(pro) that contributes to the additional substrate binding affinity. Combined with mutagenic studies, we demonstrated that catalytic Glu71 is irreplaceable for maintaining the overall architecture of the active site and, most importantly, the productive conformation of catalytic His40. We discovered the role of a previously uncharacterized residue, Arg39 of EV71 3C(pro), that can neutralize the negative charge of Glu71, which may subsequently assist deprotonation of His40 during proteolysis. PMID- 21813613 TI - Loss of protease dimerization inhibition activity of darunavir is associated with the acquisition of resistance to darunavir by HIV-1. AB - Dimerization of HIV protease is essential for the acquisition of protease's proteolytic activity. We previously identified a group of HIV protease dimerization inhibitors, including darunavir (DRV). In the present work, we examine whether loss of DRV's protease dimerization inhibition activity is associated with HIV development of DRV resistance. Single amino acid substitutions, including I3A, L5A, R8A/Q, L24A, T26A, D29N, R87K, T96A, L97A, and F99A, disrupted protease dimerization, as examined using an intermolecular fluorescence resonance energy transfer (FRET)-based HIV expression assay. All recombinant HIV(NL4-3)-based clones with such a protease dimerization-disrupting substitution failed to replicate. A highly DRV-resistant in vitro-selected HIV variant and clinical HIV strains isolated from AIDS patients failing to respond to DRV-containing antiviral regimens typically had the V32I, L33F, I54M, and I84V substitutions in common in protease. None of up to 3 of the 4 substitutions affected DRV's protease dimerization inhibition, which was significantly compromised by the four combined substitutions. Recombinant infectious clones containing up to 3 of the 4 substitutions remained sensitive to DRV, while a clonal HIV variant with all 4 substitutions proved highly resistant to DRV with a 205-fold 50% effective concentration (EC(50)) difference compared to HIV(NL4-3). The present data suggest that the loss of DRV activity to inhibit protease dimerization represents a novel mechanism contributing to HIV resistance to DRV. The finding that 4 substitutions in PR are required for significant loss of DRV's protease dimerization inhibition should at least partially explain the reason DRV has a high genetic barrier against HIV's acquisition of DRV resistance. PMID- 21813614 TI - Virus progeny of murine cytomegalovirus bacterial artificial chromosome pSM3fr show reduced growth in salivary Glands due to a fixed mutation of MCK-2. AB - Murine cytomegalovirus (MCMV) Smith strain has been cloned as a bacterial artificial chromosome (BAC) named pSM3fr and used for analysis of virus gene functions in vitro and in vivo. When sequencing the complete BAC genome, we identified a frameshift mutation within the open reading frame (ORF) encoding MCMV chemokine homologue MCK-2. This mutation would result in a truncated MCK-2 protein. When mice were infected with pSM3fr-derived virus, we observed reduced virus production in salivary glands, which could be reverted by repair of the frameshift mutation. When looking for the source of the mutation, we consistently found that virus stocks of cell culture-passaged MCMV Smith strain are mixtures of viruses with or without the MCK-2 mutation. We conclude that the MCK-2 mutation in the pSM3fr BAC is the result of clonal selection during the BAC cloning procedure. PMID- 21813615 TI - Role of the endocytic pathway in the counteraction of BST-2 by human lentiviral pathogens. AB - The interferon-inducible transmembrane protein BST-2 (CD317, tetherin) restricts the release of several enveloped viruses from infected cells. BST-2 is broadly active against retroviruses, including HIV-1 and HIV-2. To counteract this host defense, HIV-1 uses the accessory protein Vpu, whereas HIV-2 uses its envelope glycoprotein (Env). In both cases, viral antagonism is associated with decreased expression of BST-2 at the cell surface. Here, we provide evidence supporting a role for the clathrin-mediated endocytic pathway in the downregulation of BST-2 from the cell surface and the counteraction of restricted virion release. A catalytically inactive, dominant negative version of the vesicle "pinch-ase" dynamin 2 (dyn2K44A) inhibited the downregulation of BST-2 by Vpu, and it inhibited the release of wild-type (Vpu-expressing) HIV-1 virions. Similarly, dyn2K44A inhibited the downregulation of BST-2 by HIV-2 Env, and it inhibited the release of vpu-negative HIV-1 virions when HIV-2 Env was provided in trans. dyn2K44A inhibited Env more robustly than Vpu, suggesting that dynamin 2, while a cofactor for both Env and Vpu, might support just one of several pathways though which Vpu counteracts BST-2. In support of a role for clathrin in these effects, the C-terminal domain of the clathrin assembly protein AP180 also inhibited the downregulation of BST-2 by either Vpu or HIV-2 Env. Consistent with modulation of the postendocytic itinerary of BST-2, Vpu enhanced the accumulation of cell surface-derived BST-2 in transferrin-containing endosomes. Vpu also inhibited the transport of BST-2 from a brefeldin A-insensitive compartment to the cell surface, consistent with a block to endosomal recycling. We propose that HIV-1 Vpu, and probably HIV-2 Env, traps BST-2 in an endosomal compartment following endocytosis, reducing its level at the cell surface to counteract restricted viral release. PMID- 21813616 TI - HLA-DR+ CD38+ CD4+ T lymphocytes have elevated CCR5 expression and produce the majority of R5-tropic HIV-1 RNA in vivo. AB - Percentages of activated T cells correlate with HIV-1 disease progression, but the underlying mechanisms are not fully understood. We hypothesized that HLA DR(+) CD38(+) (DR(+) 38(+)) CD4(+) T cells produce the majority of HIV-1 due to elevated expression of CCR5 and CXCR4. In phytohemagglutinin (PHA)-stimulated CD8 depleted peripheral blood mononuclear cells (PBMC) infected with HIV-1 green fluorescent protein (GFP) reporter viruses, DR(-) 38(+) T cells constituted the majority of CCR5 (R5)-tropic (median, 62%) and CXCR4 (X4)-tropic HIV-1-producing cells (median, 61%), although cell surface CCR5 and CXCR4 were not elevated in this subset of cells. In lymph nodes from untreated individuals infected with R5 tropic HIV-1, percentages of CCR5(+) cells were elevated in DR(+) 38(+) CD4(+) T cells (median, 36.4%) compared to other CD4(+) T-cell subsets (median values of 5.7% for DR(-) 38(-) cells, 19.4% for DR(+) 38(-) cells, and 7.6% for DR(-) 38(+) cells; n = 18; P < 0.001). In sorted CD8(-) lymph node T cells, median HIV-1 RNA copies/10(5) cells was higher for DR(+) 38(+) cells (1.8 * 10(6)) than for DR(-) 38(-) (0.007 * 10(6)), DR(-) 38(+) (0.064 * 10(6)), and DR(+) 38(-) (0.18 * 10(6)) subsets (n = 8; P < 0.001 for all). After adjusting for percentages of subsets, a median of 87% of viral RNA was harbored by DR(+) 38(+) cells. Percentages of CCR5(+) CD4(+) T cells and concentrations of CCR5 molecules among subsets predicted HIV-1 RNA levels among CD8(-) DR/38 subsets (P < 0.001 for both). Median HIV-1 DNA copies/10(5) cells was higher in DR(+) 38(+) cells (5,360) than in the DR(-) 38(-) (906), DR(-) 38(+) (814), and DR(+) 38(-) (1,984) subsets (n = 7; P <= 0.031). Thus, DR(+) 38(+) CD4(+) T cells in lymph nodes have elevated CCR5 expression, are highly susceptible to infection with R5-tropic virus, and produce the majority of R5-tropic HIV-1. PBMC assays failed to recapitulate in vivo findings, suggesting limited utility. Strategies to reduce numbers of DR(+) 38(+) CD4(+) T cells may substantially inhibit HIV-1 replication. PMID- 21813617 TI - Targeted bacterial immunity buffers phage diversity. AB - Bacteria have evolved diverse defense mechanisms that allow them to fight viral attacks. One such mechanism, the clustered, regularly interspaced, short palindromic repeat (CRISPR) system, is an adaptive immune system consisting of genetic loci that can take up genetic material from invasive elements (viruses and plasmids) and later use them to reject the returning invaders. It remains an open question how, despite the ongoing evolution of attack and defense mechanisms, bacteria and viral phages manage to coexist. Using a simple mathematical model and a two-dimensional numerical simulation, we found that CRISPR adaptive immunity allows for robust phage-bacterium coexistence even when the number of virus species far exceeds the capacity of CRISPR-encoded genetic memory. Coexistence is predicted to be a consequence of the presence of many interdependent species that stress but do not overrun the bacterial defense system. PMID- 21813618 TI - A story of success: continuous quality improvement in cystic fibrosis care in the USA. AB - BACKGROUND: Continuous quality improvement (CQI) in healthcare can be described as a reiterative approach to improving processes to reduce unexpected variation in health outcomes. CQI represents one model to achieve quality improvement (QI) and has long been recognized as a key to success in the manufacturing industry with companies like Toyota leading the way. OBJECTIVE: Healthcare, and specifically pulmonary, critical care and sleep medicine represent ideal settings for the application of CQI. METHODS: This opinion piece will describe QI and CQI initiatives in the US Cystic fibrosis (CF) population. RESULTS: QI in CF care in the United States has been ongoing since inception of the US CF Foundation (CFF) in 1955. This effort has included work to improve the quality of clinical care provided at CF centers and work to improve clinical outcomes in CF. More recently, QI methods have been applied to the conduct of clinical research. CONCLUSIONS: The CF community has become a leader in the area of QI and has pointed out the opportunities for others to follow in the area of lung diseases. PMID- 21813619 TI - Who will benefit from tracheostomy ventilation in motor neuron disease? PMID- 21813620 TI - Muscle mass and strength in obstructive lung disease: a smoking gun? PMID- 21813621 TI - Action plans for COPD self-management. Integrated care is more than the sum of its parts. PMID- 21813622 TI - Utility of endobronchial ultrasound-guided transbronchial needle aspiration in patients with tuberculous intrathoracic lymphadenopathy: a multicentre study. AB - BACKGROUND: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has emerged as an important tool for the diagnosis and staging of lung cancer but its role in the diagnosis of tuberculous intrathoracic lymphadenopathy has not been established. The aim of this study was to describe the diagnostic utility of EBUS-TBNA in patients with intrathoracic lymphadenopathy due to tuberculosis (TB). METHODS: 156 consecutive patients with isolated intrathoracic TB lymphadenitis were studied across four centres over a 2 year period. Only patients with a confirmed diagnosis or unequivocal clinical and radiological response to antituberculous treatment during follow-up for a minimum of 6 months were included. All patients underwent routine clinical assessment and a CT scan prior to EBUS-TBNA. Demographic data, HIV status, pathological findings and microbiological results were recorded. RESULTS: EBUS-TBNA was diagnostic of TB in 146 patients (94%; 95% CI 88% to 97%). Pathological findings were consistent with TB in 134 patients (86%). Microbiological investigations yielded a positive culture of TB in 74 patients (47%) with a median time to positive culture of 16 days (range 3-84) and identified eight drug-resistant cases (5%). Ten patients (6%) did not have a specific diagnosis following EBUS; four underwent mediastinoscopy which confirmed the diagnosis of TB while six responded to empirical antituberculous therapy. There was one complication requiring an inpatient admission. CONCLUSIONS: EBUS-TBNA is a safe and effective first-line investigation in patients with tuberculous intrathoracic lymphadenopathy. PMID- 21813623 TI - Genome-wide depletion of replication initiation events in highly transcribed regions. AB - This report investigates the mechanisms by which mammalian cells coordinate DNA replication with transcription and chromatin assembly. In yeast, DNA replication initiates within nucleosome-free regions, but studies in mammalian cells have not revealed a similar relationship. Here, we have used genome-wide massively parallel sequencing to map replication initiation events, thereby creating a database of all replication initiation sites within nonrepetitive DNA in two human cell lines. Mining this database revealed that genomic regions transcribed at moderate levels were generally associated with high replication initiation frequency. In genomic regions with high rates of transcription, very few replication initiation events were detected. High-resolution mapping of replication initiation sites showed that replication initiation events were absent from transcription start sites but were highly enriched in adjacent, downstream sequences. Methylation of CpG sequences strongly affected the location of replication initiation events, whereas histone modifications had minimal effects. These observations suggest that high levels of transcription interfere with formation of pre-replication protein complexes. Data presented here identify replication initiation sites throughout the genome, providing a foundation for further analyses of DNA-replication dynamics and cell-cycle progression. PMID- 21813624 TI - A comprehensively molecular haplotype-resolved genome of a European individual. AB - Independent determination of both haplotype sequences of an individual genome is essential to relate genetic variation to genome function, phenotype, and disease. To address the importance of phase, we have generated the most complete haplotype resolved genome to date, "Max Planck One" (MP1), by fosmid pool-based next generation sequencing. Virtually all SNPs (>99%) and 80,000 indels were phased into haploid sequences of up to 6.3 Mb (N50 ~1 Mb). The completeness of phasing allowed determination of the concrete molecular haplotype pairs for the vast majority of genes (81%) including potential regulatory sequences, of which >90% were found to be constituted by two different molecular forms. A subset of 159 genes with potentially severe mutations in either cis or trans configurations exemplified in particular the role of phase for gene function, disease, and clinical interpretation of personal genomes (e.g., BRCA1). Extended genomic regions harboring manifold combinations of physically and/or functionally related genes and regulatory elements were resolved into their underlying "haploid landscapes," which may define the functional genome. Moreover, the majority of genes and functional sequences were found to contain individual or rare SNPs, which cannot be phased from population data alone, emphasizing the importance of molecular phasing for characterizing a genome in its molecular individuality. Our work provides the foundation to understand that the distinction of molecular haplotypes is essential to resolve the (inherently individual) biology of genes, genomes, and disease, establishing a reference point for "phase-sensitive" personal genomics. MP1's annotated haploid genomes are available as a public resource. PMID- 21813627 TI - Perioperative assessment of diastolic dysfunction. AB - Assessment of diastolic function should be a component of a comprehensive perioperative transesophageal echocardiographic examination. Abnormal diastolic function exists in >50% of patients presenting for cardiac and high-risk noncardiac surgery, and has been shown to be an independent predictor of adverse postoperative outcome. Normalcy of systolic function in 50% of patients with congestive heart failure implicates diastolic dysfunction as the probable etiology. Comprehensive evaluation of diastolic function requires the use of various, load-dependent Doppler techniques This is further complicated by the additional effects of dehydration and anesthetic drugs on myocardial relaxation and compliance as assessed by these Doppler measures. The availability of more sophisticated Doppler techniques, e.g., Doppler tissue imaging and flow propagation velocity, makes it possible to interrogate left ventricular diastolic function with greater precision, analyze specific stages of diastole, and to differentiate abnormalities of relaxation from compliance. Additionally, various Doppler-derived ratios can be used to estimate left ventricular filling pressures. The varying hemodynamic environment of the operating room mandates modification of the diagnostic algorithms used for ambulatory cardiac patients when left ventricular diastolic function is evaluated with transesophageal echocardiography in anesthetized surgical patients. PMID- 21813626 TI - Transcriptome dynamics through alternative polyadenylation in developmental and environmental responses in plants revealed by deep sequencing. AB - Polyadenylation sites mark the ends of mRNA transcripts. Alternative polyadenylation (APA) may alter sequence elements and/or the coding capacity of transcripts, a mechanism that has been demonstrated to regulate gene expression and transcriptome diversity. To study the role of APA in transcriptome dynamics, we analyzed a large-scale data set of RNA "tags" that signify poly(A) sites and expression levels of mRNA. These tags were derived from a wide range of tissues and developmental stages that were mutated or exposed to environmental treatments, and generated using digital gene expression (DGE)-based protocols of the massively parallel signature sequencing (MPSS-DGE) and the Illumina sequencing-by-synthesis (SBS-DGE) sequencing platforms. The data offer a global view of APA and how it contributes to transcriptome dynamics. Upon analysis of these data, we found that ~60% of Arabidopsis genes have multiple poly(A) sites. Likewise, ~47% and 82% of rice genes use APA, supported by MPSS-DGE and SBS-DGE tags, respectively. In both species, ~49%-66% of APA events were mapped upstream of annotated stop codons. Interestingly, 10% of the transcriptomes are made up of APA transcripts that are differentially distributed among developmental stages and in tissues responding to environmental stresses, providing an additional level of transcriptome dynamics. Examples of pollen-specific APA switching and salicylic acid treatment-specific APA clearly demonstrated such dynamics. The significance of these APAs is more evident in the 3034 genes that have conserved APA events between rice and Arabidopsis. PMID- 21813625 TI - Post-transcriptional generation of miRNA variants by multiple nucleotidyl transferases contributes to miRNA transcriptome complexity. AB - Modification of microRNA sequences by the 3' addition of nucleotides to generate so-called "isomiRs" adds to the complexity of miRNA function, with recent reports showing that 3' modifications can influence miRNA stability and efficiency of target repression. Here, we show that the 3' modification of miRNAs is a physiological and common post-transcriptional event that shows selectivity for specific miRNAs and is observed across species ranging from C. elegans to human. The modifications result predominantly from adenylation and uridylation and are seen across tissue types, disease states, and developmental stages. To quantitatively profile 3' nucleotide additions, we developed and validated a novel assay based on NanoString Technologies' nCounter platform. For certain miRNAs, the frequency of modification was altered by processes such as cell differentiation, indicating that 3' modification is a biologically regulated process. To investigate the mechanism of 3' nucleotide additions, we used RNA interference to screen a panel of eight candidate miRNA nucleotidyl transferases for 3' miRNA modification activity in human cells. Multiple enzymes, including MTPAP, PAPD4, PAPD5, ZCCHC6, ZCCHC11, and TUT1, were found to govern 3' nucleotide addition to miRNAs in a miRNA-specific manner. Three of these enzymes MTPAP, ZCCHC6, and TUT1-have not previously been known to modify miRNAs. Collectively, our results indicate that 3' modification observed in next generation small RNA sequencing data is a biologically relevant process, and identify enzymatic mechanisms that may lead to new approaches for modulating miRNA activity in vivo. PMID- 21813628 TI - Immune cell populations decrease during craniotomy under general anesthesia. AB - BACKGROUND: Postoperative infections are common and potentially fatal complications in neurosurgical intensive care medicine. An impairment of immune function after central nervous system surgery is associated with higher risk of infection and postoperative complications. The aim of our study was to investigate how the immune cell population changes during the anesthesia process in patients undergoing craniotomy surgery. METHODS: Patients undergoing craniotomy who had an inhaled general anesthetic were studied. Blood samples were collected before anesthesia and 30, 45, 60, 120, and 240 minutes after anesthesia began. Blood counts for neutrophils, monocytes, and lymphocytes were determined along with lymphocyte subpopulations (T cells, inducer and helper T cells, suppressor and cytotoxic T cells, natural killer cells, and B cells). Plasma concentrations of interleukin (IL)-2, IL-4, IL-6, and IL-10 were also measured along with tumor necrosis factor-alpha and interferon-gamma. Data were analyzed by SPSS 13.0 software using repeated-measures analysis of variance followed by a Bonferroni correction. RESULTS: Eighteen patients were enrolled in this study. In the comparison of the immune cell counts during neuroanesthesia, we found that at 30 minutes after anesthesia induction, neutrophils, monocytes, and lymphocytes decreased 18% (95% confidence interval [CI]: 11.0%-24.6%), 34% (95% CI: 16.2% 51.1%), and 39% (95% CI: 29.0%-48.9%) compared with their levels before anesthesia. At extubation the neutrophils returned to the base level. It also showed that natural killer cells decreased significantly during anesthesia. The concentration of cytokines in peripheral blood did not change significantly. CONCLUSION: Our results showed that anesthesia and surgery upset the balance of the immune system during craniotomy, and a significant decrease in immune cell populations emerged after induction under general anesthesia. PMID- 21813629 TI - An intraoperative small dose of ketamine prevents remifentanil-induced postanesthetic shivering. AB - Patients undergoing gynecological laparotomy were randomized to receive either 0.5 mg/kg ketamine at induction of anesthesia followed by an infusion of 0.3 mg/kg/h until the end of surgery (ketamine group, n = 32), or an equivalent volume of normal saline (control group, n = 32). Anesthesia was maintained with IV propofol, a fixed infusion rate of remifentanil (0.25 MUg/kg/min), and epidural ropivacaine. Postanesthetic shivering (PAS) was evaluated for 30 minutes after emergence. Intraoperative temperatures were similar between the 2 groups. The incidence of PAS was less frequent in the ketamine group (n = 2, 6%) compared with the control group (n = 12, 38%, P = 0.005). We conclude that, during the early recovery phase, intraoperative ketamine reduces remifentanil-induced PAS. PMID- 21813630 TI - Gamma-aminobutyric acid type A receptor beta3 subunit forebrain-specific knockout mice are resistant to the amnestic effect of isoflurane. AB - BACKGROUND: beta3 containing gamma-aminobutyric acid type A receptors (GABA(A) Rs) mediate behavioral end points of IV anesthetics such as immobility and hypnosis. A knockout mouse with targeted forebrain deletion of the beta3 subunit of the GABA(A)-R shows reduced sensitivity to the hypnotic effect of etomidate, as measured by the loss of righting reflex. The end points of amnesia and immobility produced by an inhaled anesthetic have yet to be evaluated in this conditional knockout. METHODS: We assessed forebrain selective beta3 conditional knockout mice and their littermate controls for conditional fear to evaluate amnesia and MAC, the minimum alveolar concentration of inhaled anesthetic necessary to produce immobility in response to noxious stimulation, to assess immobility. Suppression of conditional fear was assessed for etomidate and isoflurane, and MAC was assessed for isoflurane. RESULTS: Etomidate equally suppressed conditional fear for both genotypes. The knockout showed resistance to the suppression of conditional fear produced by isoflurane in comparison with control littermates. Controls and knockouts did not differ in isoflurane MAC values. CONCLUSIONS: These results suggest that beta3 containing GABA(A)-Rs in the forebrain contribute to hippocampal-dependent memory suppressed by isoflurane, but not etomidate. PMID- 21813631 TI - Characterization of a cleavage stimulation factor, 3' pre-RNA, subunit 2, 64 kDa (CSTF2) as a therapeutic target for lung cancer. AB - PURPOSE: This study aims to discover novel biomarkers and therapeutic targets for lung cancers. EXPERIMENTAL DESIGN: We screened for genes showing elevated expression in the majority of lung cancers by genome-wide gene expression profile analysis of 120 lung cancers obtained by cDNA microarray representing 27,648 genes or expressed sequence tags. In this process, we detected a gene encoding cleavage stimulation factor, 3' pre-RNA, subunit 2, 64 kDa (CSTF2) as a candidate. Immunohistochemical staining using tissue microarray consisting of 327 lung cancers was applied to examine the expression of CSTF2 protein and its prognostic value. A role of CSTF2 in cancer cell growth was examined by siRNA experiments. RESULTS: Northern blot and immunohistochemical analyses detected the expression of CSTF2 only in testis among 16 normal tissues. Immunohistochemical analysis using tissue microarray showed an association of strong CSTF2 expression with poor prognosis of patients with non-small cell lung cancer (P = 0.0079), and multivariate analysis showed that CSTF2 positivity is an independent prognostic factor. In addition, suppression of CSTF2 expression by siRNAs suppressed lung cancer cell growth, whereas exogenous expression of CSTF2 promoted growth and invasion of mammalian cells. CONCLUSIONS: CSTF2 is likely to play an important role in lung carcinogenesis and be a prognostic biomarker in the clinic. PMID- 21813632 TI - Killing of resistant cancer cells with low Bak by a combination of an antimesothelin immunotoxin and a TRAIL Receptor 2 agonist antibody. AB - PURPOSE: Many solid tumors express cell surface mesothelin making them attractive targets for antibody-based therapies of cancer. SS1P [antimesothelin(Fv)PE38] is a recombinant immunotoxin (RIT) that has potent cytotoxic activity on several cancer cell lines and clinical activity in mesothelioma patients. Pancreatic cancers express mesothelin and are known to be resistant to most chemotherapeutic agents. The goal of this study is to treat pancreatic cancer with RIT by targeting mesothelin. EXPERIMENTAL DESIGN: We measured the cytotoxic activity of an antimesothelin immunotoxin on pancreatic cancer cells. We also measured the levels of several pro- and antiapoptotic proteins, as well as the ability of TNF related apoptosis-inducing ligand (TRAIL) or the anti-TRAIL receptor 2 agonist antibody (HGS-ETR2) to kill pancreatic cells, and the cytotoxic activity of the two agents together in cell culture and against tumors in mice. RESULTS: In two pancreatic cancer cell lines, immunotoxin treatment inhibited protein synthesis but did not produce significant cell death. The resistant lines had low levels of the proapoptotic protein Bak. Increasing Bak expression enhanced the sensitivity to immunotoxins, whereas Bak knockdown diminished it. We also found that combining immunotoxin with TRAIL or HGS-ETR2 caused synergistic cell death, and together triggered caspase-8 recruitment and activation, Bid cleavage and Bax activation. Combining SS1P with HGS-ETR2 also acted synergistically to decrease tumor burden in a mouse model. CONCLUSION: Our data show that low Bak can cause cancer cells to be resistant to immunotoxin treatment and that combining immunotoxin with TRAIL or a TRAIL agonist antibody can overcome resistance. PMID- 21813633 TI - Targeting human B-cell malignancies through Ig light chain-specific cytotoxic T lymphocytes. AB - PURPOSE: The variable regions of Ig (idiotype, Id) expressed by malignant B cells can be used as tumor-specific antigens that induce humoral and cellular immunity. However, epitopes derived from Id that stimulate human CD8(+) T-cell immunity are incompletely characterized. EXPERIMENTAL DESIGN: The clonal Ig V(L) of human myeloma cell line U266 and five primary B-cell tumors were sequenced, and peptides corresponding to the Ig V(L) region were tested for their ability to stimulate CTLs from 10 HLA-A*0201-positive normal donors. The CTLs thus generated were tested against peptide-pulsed T2 cells and autologous tumor cells. RESULTS: Fourteen peptides derived from Ig light chain (V(L)) of U266 and primary B-cell tumors were used to generate 68 CTLs lines that specifically produced IFN-gamma when cocultured with peptide-pulsed T2 cells. These CTLs lysed peptide-pulsed T2 cell as well as U266 or autologous tumor targets in an HLA class I-dependent manner. Sequence analysis revealed shared V(L) T-cell epitopes in U266 and primary B-cell tumors, not previously reported within Ig heavy chain (V(H)) sequences. CONCLUSION: This study thus identifies novel immunogenic CTLs epitopes from Id V(L), suggests that they are naturally presented on the surface of B-cell malignancies, and supports their inclusion in next-generation Id vaccines. The ability to prime T cells derived from normal HLA-matched donors, rather than patients, may also have direct application to current strategies, designed to generate allogeneic tumor-specific T cells for adoptive transfer. PMID- 21813634 TI - Thrombotic microangiopathy with targeted cancer agents. AB - Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are clinically similar disorders characterized by microvascular thrombosis, hemolysis, thrombocytopenia, and end-organ damage. Although they may present with overlapping symptoms, multiple etiologies have been proposed for these thrombotic microangiopathies (TMA). Chemotherapy-induced TMA, which has been described with the use of mitomycin, gemcitabine, and other drugs, has a poor prognosis. Recently, reports of TMA associated with targeted cancer agents have surfaced in the literature. We discuss the clinical presentation, outcome, and etiology of TMA reported with the use of immunotoxins, monoclonal antibodies, and tyrosine kinase inhibitors. A search of PubMed and meeting abstracts was conducted for cases of TMA with the use of targeted cancer agents. The defining symptoms, laboratory values, time to onset, and patient outcomes were compiled. Consistent definitions of TMA and grading of severity in these cases are lacking. However, presentation of TMA in these cases revealed the importance of monitoring for renal toxicity, hemolysis, and thrombocytopenia. Patient outcomes seem to differ from those seen in cases of chemotherapy-induced TMA and may reflect a different underlying etiology. Little is known about the pathogenesis of TMA with targeted cancer agents. In contrast to chemotherapy-induced TMA, partial to full reversibility may be a common outcome. However, further research is warranted into optimal management of patients diagnosed with TMA following treatment with targeted agents. PMID- 21813635 TI - Human leukocyte antigen-G in the male reproductive system and in seminal plasma. AB - One of the non-classical human leukocyte antigen (HLA) class Ib proteins, HLA-G, is believed to exert important immunoregulatory functions, especially during pregnancy. The presence of HLA protein in paternal seminal fluid has been suggested to have an influence on the risk of developing pre-eclampsia. We have investigated whether HLA-G protein is present in human seminal plasma and in different tissue samples of the male reproductive system. Western blot technique and a soluble HLA-G (sHLA-G) assay were used to detect sHLA-G in human seminal plasma samples. Immunohistochemical staining was performed on paraffin-embedded tissue samples. We detected sHLA-G protein in seminal plasma, and HLA-G expression in normal testis and in epididymal tissue of the male reproductive system but not in the seminal vesicle. Furthermore, the results indicated a weak expression of HLA-G in hyperplastic prostatic tissue. In summary, several of the findings reported in this study suggest an immunoregulatory role of HLA-G in the male reproductive system and in seminal plasma. PMID- 21813636 TI - The antiangiogenic effects of integrin alpha5beta1 inhibitor (ATN-161) in vitro and in vivo. AB - PURPOSE: Integrin alpha5beta1 is involved in the development of choroidal neovascularization (CNV). Thus, the inhibition of integrin alpha5beta1 may provide an alternative to the current standard of CNV therapy, which involves inhibition of vascular endothelial growth factor (VEGF) and is not effective in all patients. This study evaluated the antiangiogenic effects of ATN-161, a small peptide inhibitor of integrin alpha5beta1, in human choroidal endothelial cells (hCECs) and in laser-induced CNV in rats. Furthermore, the utility of spectral domain optical coherence tomography (SD-OCT) for dynamic observation of the development of CNV in animal models was assessed. METHODS: The antiangiogenic potential of ATN-161 was evaluated in VEFG-stimulated hCECs by MTS proliferation assays, migration assays, and synthetic matrix capillary tube formation assays. To evaluate the antiangiogenic effects of ATN-161 in vivo, CNV was induced in rats by laser photocoagulation. ATN-161, scrambled peptide, or AF564 anti-VEGF antibody, were injected intravitreally immediately after photocoagulation. Eyes were examined by SD-OCT and fluorescein angiography on days 1, 7, and 14 after injection, and the areas of CNV were measured by analysis of choroidal flatmounts at day 14. RESULTS: ATN-161 inhibited VEGF-induced migration and capillary tube formation in hCECs, but did not inhibit proliferation. In vivo, injection of ATN 161 after laser photocoagulation inhibited CNV leakage and neovascularization to an extent similar to AF564. Furthermore, SD-OCT and histologic examinations indicated that ATN-161 significantly decreased the size of laser-induced lesions. CONCLUSIONS: Integrin alpha5beta1 inhibition by ATN-161 may be a promising alternative therapy for CNV-related angiogenesis. In addition, SD-OCT technology allows excellent visualization of experimentally induced CNV in vivo. PMID- 21813637 TI - Autophagy in protein and organelle turnover. AB - Macroautophagy is an evolutionarily conserved degradation system in the cell. In autophagy, intracellular components are sequestered by autophagosomes and subsequently degraded upon fusion with lysosomes. Genetic analysis of autophagy in mammals has revealed that autophagy is important for various physiological processes, such as adaptive responses to starvation, embryogenesis, quality control of intracellular proteins and organelles, tumor suppression, degradation of intracellular pathogens, and anti-aging. In this review I describe the various roles of autophagy, with a particular focus on the turnover of cytoplasmic proteins and organelles. PMID- 21813638 TI - Roles of FGF19 in liver metabolism. AB - Fibroblast growth factor 19 (FGF19) is an ileum-derived postprandial enterokine that governs bile acid and nutrient metabolism. Synthesis of FGF19 is up regulated by bile acids and, conversely, bile acid synthesis is down-regulated by FGF19. FGF19 also controls gallbladder volume. FGF19 has been shown to have profound effects on glucose and lipid metabolism. Recent studies have described FGF19 as a postprandial regulator of hepatic glucose and protein metabolism. Like insulin, FGF19 induces protein and glycogen synthesis and suppresses gluconeogenesis in liver. However, unlike insulin, FGF19 does not stimulate lipogenesis. A key difference between FGF19 and insulin lies in their use of different cellular signaling pathways. The beneficial effects of FGF19 on liver metabolism raise the question of whether FGF19 and its variants can be used as therapeutic agents in the treatment of diabetes. PMID- 21813639 TI - Schizosaccharomyces pombe minichromosome maintenance-binding protein (MCM-BP) antagonizes MCM helicase. AB - The minichromosome maintenance (MCM) complex, a replicative helicase, is a heterohexamer essential for DNA duplication and genome stability. We identified Schizosaccharomyces pombe mcb1(+) (Mcm-binding protein 1), an apparent orthologue of the human MCM-binding protein that associates with a subset of MCM complex proteins. mcb1(+) is an essential gene. Deletion of mcb1(+) caused cell cycle arrest after several generations with a cdc phenotype and disrupted nuclear structure. Mcb1 is an abundant protein, constitutively present across the cell cycle. It is widely distributed in cytoplasm and nucleoplasm and bound to chromatin. Co-immunoprecipitation suggested that Mcb1 interacts robustly with Mcm3-7 but not Mcm2. Overproduction of Mcb1 disrupted the association of Mcm2 with other MCM proteins, resulting in inhibition of DNA replication, DNA damage, and activation of the checkpoint kinase Chk1. Thus, Mcb1 appears to antagonize the function of MCM helicase. PMID- 21813640 TI - Structural basis for matrix metalloproteinase-2 (MMP-2)-selective inhibitory action of beta-amyloid precursor protein-derived inhibitor. AB - Unlike other synthetic or physiological inhibitors for matrix metalloproteinases (MMPs), the beta-amyloid precursor protein-derived inhibitory peptide (APP-IP) having an ISYGNDALMP sequence has a high selectivity toward MMP-2. Our previous study identified amino acid residues of MMP-2 essential for its selective inhibition by APP-IP and demonstrated that the N to C direction of the decapeptide inhibitor relative to the substrate-binding cleft of MMP-2 is opposite that of substrate. However, detailed interactions between the two molecules remained to be clarified. Here, we determined the crystal structure of the catalytic domain of MMP-2 in complex with APP-IP. We found that APP-IP in the complex is indeed embedded into the substrate-binding cleft of the catalytic domain in the N to C direction opposite that of substrate. With the crystal structure, it was first clarified that the aromatic side chain of Tyr(3) of the inhibitor is accommodated into the S1' pocket of the protease, and the carboxylate group of Asp(6) of APP-IP coordinates bidentately to the catalytic zinc of the enzyme. The Ala(7) to Pro(10) and Tyr(3) to Ile(1) strands of the inhibitor extend into the nonprime and the prime sides of the cleft, respectively. Therefore, the decapeptide inhibitor has long range contact with the substrate-binding cleft of the protease. This mode of interaction is probably essential for the high MMP-2 selectivity of the inhibitor because MMPs share a common architecture in the vicinity of the catalytic center, but whole structures of their substrate-binding clefts have sufficient variety for the inhibitor to distinguish MMP-2 from other MMPs. PMID- 21813641 TI - Mono-ubiquitination drives nuclear export of the human DCN1-like protein hDCNL1. AB - Conjugation of Nedd8 to a cullin protein, termed neddylation, is an evolutionarily conserved process that functions to activate the cullin-RING family E3 ubiquitin ligases, leading to increased proteasomal degradation of a wide range of substrate proteins. Recent emerging evidence demonstrates that cellular neddylation requires the action of Dcn1, which, in humans, consists of five homologues designated as hDCNL1-5. Here we revealed a previously unknown mechanism that regulates hDCNL1. In cultured mammalian cells ectopically expressed hDCNL1 was mono-ubiquitinated predominantly at K143, K149, and K171. Using a classical chromatographic purification strategy, we identified Nedd4-1 as an E3 ligase that can catalyze mono-ubiquitination of hDCNL1 in a reconstituted ubiquitination system. In addition, the hDCNL1 N-terminal ubiquitin-binding domain is necessary and sufficient to mediate mono-ubiquitination. Finally, fluorescence microscopic and subcellular fractionation analyses revealed a role for mono-ubiquitination in driving nuclear export of hDCNL1. Taken together, these results suggest a mono-ubiquitination-mediated mechanism that governs nuclear-cytoplasmic trafficking of hDCNL1, thereby regulating hDCNL1-dependent activation of the cullin-RING E3 ubiquitin ligases in selected cellular compartments. PMID- 21813642 TI - Phosphorylation of Ran-binding protein-1 by Polo-like kinase-1 is required for interaction with Ran and early mitotic progression. AB - Polo-like kinase-1 (Plk1) is essential for progression of mitosis and localizes to centrosomes, central spindles, midbody, and kinetochore. Ran, a small GTPase of the Ras superfamily, plays a role in microtubule dynamics and chromosome segregation during mitosis. Although Ran-binding protein-1 (RanBP1) has been reported as a regulator of RanGTPase for its mitotic functions, the action mechanism between Ran and RanBP1 during mitosis is still unknown. Here, we demonstrated in vitro and in vivo phosphorylation of RanBP1 by Plk1 as well as the importance of phosphorylation of RanBP1 in the interaction between Plk1 and Ran during early mitosis. Both phosphorylation-defective and N-terminal deletion mutant constructs of RanBP1 disrupted the interaction with Ran, and depletion of Plk1 also disrupted the formation of a complex between Ran and RanBP1. In addition, the results from both ectopic expression of phosphorylation-defective mutant construct and a functional complementation on RanBP1 deficiency with this mutant indicated that phosphorylation of RanBP1 by Plk1 might be crucial to microtubule nucleation and spindle assembly during mitosis. PMID- 21813643 TI - Conversion of 7-dehydrocholesterol to 7-ketocholesterol is catalyzed by human cytochrome P450 7A1 and occurs by direct oxidation without an epoxide intermediate. AB - 7-Ketocholesterol is a bioactive sterol, a potent competitive inhibitor of cytochrome P450 7A1, and toxic in liver cells. Multiple origins of this compound have been identified, with cholesterol being the presumed precursor. Although routes for formation of the 7-keto compound from cholesterol have been established, we found that 7-dehydrocholesterol (the immediate precursor of cholesterol) is oxidized by P450 7A1 to 7-ketocholesterol (k(cat)/K(m) = 3 * 10(4) m(-1) s(-1)). P450 7A1 converted lathosterol (Delta(5)-dihydro-7 dehydrocholesterol) to a mixture of the 7-keto and 7alpha,8alpha-epoxide products (~1:2 ratio), with the epoxide not rearranging to the ketone. The oxidation of 7 dehydrocholesterol occured with predominant formation of 7-ketocholesterol and with the 7alpha,8alpha-epoxide as only a minor product; the synthesized epoxide was stable in the presence of P450 7A1. The mechanism of 7-dehydrocholesterol oxidation to 7-ketocholesterol is proposed to involve a Fe(III)-O-C-C(+) intermediate and a 7,8-hydride shift or an alternative closing to yield the epoxide (Liebler, D. C., and Guengerich, F. P. (1983) Biochemistry 22, 5482 5489). Accordingly, reaction of P450 7A1 with 7-[(2)H(1)]dehydrocholesterol yielded complete migration of deuterium in the product 7-ketocholesterol. The finding that 7-dehydrocholesterol is a precursor of 7-ketocholesterol has relevance to an inborn error of metabolism known as Smith-Lemli-Opitz syndrome (SLOS) caused by defective cholesterol biosynthesis. Mutations within the gene encoding 7-dehydrocholesterol reductase, the last enzyme in the pathway, lead to the accumulation of 7-dehydrocholesterol in tissues and fluids of SLOS patients. Our findings suggest that 7-ketocholesterol levels may also be elevated in SLOS tissue and fluids as a result of P450 7A1 oxidation of 7-dehydrocholesterol. PMID- 21813645 TI - Potentiation of Helicobacter pylori CagA protein virulence through homodimerization. AB - Chronic infection with Helicobacter pylori cagA-positive strains is associated with atrophic gastritis, peptic ulceration, and gastric carcinoma. The cagA gene product, CagA, is delivered into gastric epithelial cells via type IV secretion, where it undergoes tyrosine phosphorylation at the EPIYA motifs. Tyrosine phosphorylated CagA binds and aberrantly activates the oncogenic tyrosine phosphatase SHP2, which mediates induction of elongated cell morphology (hummingbird phenotype) that reflects CagA virulence. CagA also binds and inhibits the polarity-regulating kinase partitioning-defective 1 (PAR1)/microtubule affinity-regulating kinase (MARK) via the CagA multimerization (CM) sequence independently of tyrosine phosphorylation. Because PAR1 exists as a homodimer, two CagA proteins appear to be passively dimerized through complex formation with a PAR1 dimer in cells. Interestingly, a CagA mutant that lacks the CM sequence displays a reduced SHP2 binding activity and exhibits an attenuated ability to induce the hummingbird phenotype, indicating that the CagA-PAR1 interaction also influences the morphological transformation. Here we investigated the role of CagA dimerization in induction of the hummingbird phenotype with the use of a chemical dimerizer, coumermycin. We found that CagA dimerization markedly stabilizes the CagA-SHP2 complex and thereby potentiates SHP2 deregulation, causing an increase in the number of hummingbird cells. Protrusions of hummingbird cells induced by chemical dimerization of CagA are further elongated by simultaneous inhibition of PAR1. This study revealed a role of the CM sequence in amplifying the magnitude of SHP2 deregulation by CagA, which, in conjunction with the CM sequence-mediated inhibition of PAR1, evokes morphological transformation that reflects in vivo CagA virulence. PMID- 21813644 TI - Structures of Phytophthora RXLR effector proteins: a conserved but adaptable fold underpins functional diversity. AB - Phytopathogens deliver effector proteins inside host plant cells to promote infection. These proteins can also be sensed by the plant immune system, leading to restriction of pathogen growth. Effector genes can display signatures of positive selection and rapid evolution, presumably a consequence of their co evolutionary arms race with plants. The molecular mechanisms underlying how effectors evolve to gain new virulence functions and/or evade the plant immune system are poorly understood. Here, we report the crystal structures of the effector domains from two oomycete RXLR proteins, Phytophthora capsici AVR3a11 and Phytophthora infestans PexRD2. Despite sharing <20% sequence identity in their effector domains, they display a conserved core alpha-helical fold. Bioinformatic analyses suggest that the core fold occurs in ~44% of annotated Phytophthora RXLR effectors, both as a single domain and in tandem repeats of up to 11 units. Functionally important and polymorphic residues map to the surface of the structures, and PexRD2, but not AVR3a11, oligomerizes in planta. We conclude that the core alpha-helical fold enables functional adaptation of these fast evolving effectors through (i) insertion/deletions in loop regions between alpha-helices, (ii) extensions to the N and C termini, (iii) amino acid replacements in surface residues, (iv) tandem domain duplications, and (v) oligomerization. We hypothesize that the molecular stability provided by this core fold, combined with considerable potential for plasticity, underlies the evolution of effectors that maintain their virulence activities while evading recognition by the plant immune system. PMID- 21813648 TI - Protein phosphatase 2A (B55alpha) prevents premature activation of forkhead transcription factor FoxM1 by antagonizing cyclin A/cyclin-dependent kinase mediated phosphorylation. AB - The forkhead transcription factor FoxM1 controls expression of a large number of genes that are specifically expressed during the G(2) phase of the cell cycle. Throughout most of the cell cycle, FoxM1 activity is restrained by an autoinhibitory mechanism, involving a repressor domain present in the N-terminal part of the protein. Activation of FoxM1 in G(2) is achieved by Cyclin A/Cyclin dependent kinase (Cdk)-mediated phosphorylation, which alleviates autoinhibition by the N-terminal repressor domain. Here, we show that FoxM1 interacts with B55alpha, a regulatory subunit of protein phosphatase 2A (PP2A). B55alpha binds the catalytic subunit of PP2A, and this promotes dephosphorylation and inactivation of FoxM1. Indeed, we find that overexpression of B55alpha results in decreased FoxM1 activity. Inversely, depletion of B55alpha results in premature activation of FoxM1. The activation of FoxM1 that is observed upon depletion of B55alpha is fully dependent on Cyclin A/Cdk-mediated phosphorylation of FoxM1. Taken together, these data demonstrate that B55alpha acts to antagonize Cyclin A/Cdk-dependent activation of FoxM1, to ensure that FoxM1 activity is restricted to the G(2) phase of the cell cycle. PMID- 21813646 TI - Nitric oxide inhibits nociceptive transmission by differentially regulating glutamate and glycine release to spinal dorsal horn neurons. AB - Nitric oxide (NO) is involved in many physiological functions, but its role in pain signaling remains uncertain. Surprisingly, little is known about how endogenous NO affects excitatory and inhibitory synaptic transmission at the spinal level. Here we determined how NO affects excitatory and inhibitory synaptic inputs to dorsal horn neurons using whole-cell recordings in rat spinal cord slices. The NO precursor L-arginine or the NO donor SNAP significantly increased the frequency of glycinergic spontaneous and miniature inhibitory postsynaptic currents (IPSCs) of lamina II neurons. However, neither L-arginine nor SNAP had any effect on GABAergic IPSCs. L-arginine and SNAP significantly reduced the amplitude of monosynaptic excitatory postsynaptic currents (EPSCs) evoked from the dorsal root with an increase in paired-pulse ratio. Inhibition of the soluble guanylyl cyclase abolished the effect of L-arginine on glycinergic IPSCs but not on evoked monosynaptic EPSCs. Also, inhibition of protein kinase G blocked the increase in glycinergic sIPSCs by the cGMP analog 8-bromo-cGMP. The inhibitory effects of L-arginine on evoked EPSCs and high voltage-activated Ca(2+) channels expressed in HEK293 cells and dorsal root ganglion neurons were abolished by blocking the S-nitrosylation reaction with N-ethylmaleimide. Intrathecal injection of L-arginine and SNAP significantly increased mechanical nociceptive thresholds. Our findings suggest that spinal endogenous NO enhances inhibitory glycinergic input to dorsal horn neurons through sGC-cGMP-protein kinase G. Furthermore, NO reduces glutamate release from primary afferent terminals through S-nitrosylation of voltage-activated Ca(2+) channels. Both of these actions probably contribute to inhibition of nociceptive transmission by NO at the spinal level. PMID- 21813647 TI - Crystal structure of Mycobacterium tuberculosis zinc-dependent metalloprotease-1 (Zmp1), a metalloprotease involved in pathogenicity. AB - Mycobacterium tuberculosis, the causative agent of tuberculosis, parasitizes host macrophages. The resistance of the tubercle bacilli to the macrophage hostile environment relates to their ability to impair phagosome maturation and its fusion with the lysosome, thus preventing the formation of the phago-lysosome and eventually arresting the process of phagocytosis. The M. tuberculosis zinc dependent metalloprotease Zmp1 has been proposed to play a key role in the process of phagosome maturation inhibition and emerged as an important player in pathogenesis. Here, we report the crystal structure of wild-type Zmp1 at 2.6 A resolution in complex with the generic zinc metalloprotease inhibitor phosphoramidon, which we demonstrated to inhibit the enzyme potently. Our data represent the first structural characterization of a bacterial member of the zinc dependent M13 endopeptidase family and revealed a significant degree of conservation with eukaryotic enzymes. However, structural comparison of the Zmp1 phosphoramidon complex with homologous human proteins neprilysin and endothelin converting enzyme-1 revealed unique features of the Zmp1 active site to be exploited for the rational design of specific inhibitors that may prove useful as a pharmacological tool for better understanding Zmp1 biological function. PMID- 21813649 TI - Cyclin-dependent kinase-5 is a key molecule in tumor necrosis factor-alpha induced insulin resistance. AB - The mechanism of TNF-alpha-induced insulin resistance has remained unresolved with evidence for down-regulation of insulin effector targets effects or blockade of proximal as well as distal insulin signaling events depending upon the dose, time, and cell type examined. To address this issue we examined the acute actions of TNF-alpha in differentiated 3T3L1 adipocytes. Acute (5-15 min) treatment with 20 ng/ml (~0.8 nm) TNF-alpha had no significant effect on IRS1-associated phosphatidylinositol 3-kinase. In contrast, TNF-alpha increased insulin stimulated cyclin-dependent kinase-5 (CDK5) phosphorylation on tyrosine residue 15 through an Erk-dependent pathway and up-regulated the expression of the CDK5 regulator protein p35. In parallel, TNF-alpha stimulation also resulted in the phosphorylation and GTP loading of the Rho family GTP-binding protein, TC10alpha. TNF-alpha enhanced the depolymerization of cortical F-actin and inhibited insulin stimulated glucose transporter-4 (GLUT4) translocation. Treatment with the MEK inhibitor, PD98059, blocked the TNF-alpha-induced increase in CDK5 phosphorylation and the depolymerization of cortical F-actin. Conversely, siRNA mediated knockdown of CDK5 or treatment with the MEK inhibitor restored the impaired insulin-stimulated GLUT4 translocation induced by TNF-alpha. Furthermore, siRNA-mediated knockdown of p44/42 Erk also rescued the TNF-alpha inhibition of insulin-stimulated GLUT4 translocation. Together, these data demonstrate that TNF-alpha-mediated insulin resistance of glucose uptake can occur through a MEK/Erk-dependent activation of CDK5. PMID- 21813650 TI - Green tea polyphenols control dysregulated glutamate dehydrogenase in transgenic mice by hijacking the ADP activation site. AB - Glutamate dehydrogenase (GDH) catalyzes the oxidative deamination of L-glutamate and, in animals, is extensively regulated by a number of metabolites. Gain of function mutations in GDH that abrogate GTP inhibition cause the hyperinsulinism/hyperammonemia syndrome (HHS), resulting in increased pancreatic beta-cell responsiveness to leucine and susceptibility to hypoglycemia following high protein meals. We have previously shown that two of the polyphenols from green tea (epigallocatechin gallate (EGCG) and epicatechin gallate (ECG)) inhibit GDH in vitro and that EGCG blocks GDH-mediated insulin secretion in wild type rat islets. Using structural and site-directed mutagenesis studies, we demonstrate that ECG binds to the same site as the allosteric regulator, ADP. Perifusion assays using pancreatic islets from transgenic mice expressing a human HHS form of GDH demonstrate that the hyperresponse to glutamine caused by dysregulated GDH is blocked by the addition of EGCG. As observed in HHS patients, these transgenic mice are hypersensitive to amino acid feeding, and this is abrogated by oral administration of EGCG prior to challenge. Finally, the low basal blood glucose level in the HHS mouse model is improved upon chronic administration of EGCG. These results suggest that this common natural product or some derivative thereof may prove useful in controlling this genetic disorder. Of broader clinical implication is that other groups have shown that restriction of glutamine catabolism via these GDH inhibitors can be useful in treating various tumors. This HHS transgenic mouse model offers a highly useful means to test these agents in vivo. PMID- 21813651 TI - Glycerol 3-phosphate alters Trypanosoma brucei hexokinase activity in response to environmental change. AB - The African trypanosome, Trypanosoma brucei, compartmentalizes some metabolic enzymes within peroxisome-like organelles called glycosomes. The amounts, activities, and types of glycosomal enzymes are modulated coincident with developmental and environmental changes. Pexophagy (fusion of glycosomes with acidic lysosomes) has been proposed to facilitate this glycosome remodeling. Here, we report that, although glycosome-resident enzyme T. brucei hexokinase 1 (TbHK1) protein levels are maintained during pexophagy, acidification inactivates the activity. Glycerol 3-phosphate, which is produced in vivo by a glycosome resident glycerol kinase, mitigated acid inactivation of lysate-derived TbHK activity. Using recombinant TbHK1, we found that glycerol 3-P influenced enzyme activity at pH 6.5 by preventing substrate and product inhibition by ATP and ADP, respectively. Additionally, TbHK1 inhibition by the flavonol quercetin (QCN) was partially reversed by glycerol 3-P at pH 7.4, whereas at pH 6.5, enzyme activity in the presence of QCN was completely maintained by glycerol 3-P. However, glycerol 3-P did not alter the interaction of QCN with TbHK1, as the lone Trp residue (Trp-177) was quenched under all conditions tested. These findings suggest potential novel mechanisms for the regulation of TbHK1, particularly given the acidification of glycosomes that can be induced under a variety of parasite growth conditions. PMID- 21813652 TI - SO2907, a putative TonB-dependent receptor, is involved in dissimilatory iron reduction by Shewanella oneidensis strain MR-1. AB - Shewanella oneidensis strain MR-1 utilizes soluble and insoluble ferric ions as terminal electron acceptors during anaerobic respiration. The components of respiratory metabolism are localized in the membrane fractions which include the outer membrane and cytoplasmic membrane. Many of the biological components that interact with the various iron forms are proposed to be localized in these membrane fractions. To identify the iron-binding proteins acting either as an iron transporter or as a terminal iron reductase, we used metal-catalyzed oxidation reactions. This system catalyzed the oxidation of amino acids in close proximity to the iron binding site. The carbonyl groups formed from this oxidation can then be labeled with fluoresceinamine (FLNH(2)). The peptide harboring the FLNH(2) can then be proteolytically digested, purified by HPLC and then identified by MALDI-TOF tandem MS. A predominant peptide was identified to be part of SO2907 that encodes a putative TonB-dependent receptor. Compared with wild type (wt), the so2907 gene deletion (DeltaSO2907) mutant has impaired ability to reduce soluble Fe(III), but retains the same ability to respire oxygen or fumarate as the wt. The DeltaSO2907 mutant was also impacted in reduction of insoluble iron. Iron binding assays using isothermal titration calorimetry and fluorescence tryptophan quenching demonstrated that a truncated form of heterologous-expressed SO2907 that contains the Fe(III) binding site, is capable of binding soluble Fe(III) forms with K(d) of approximate 50 MUm. To the best of our knowledge, this is the first report of the physiological role of SO2907 in Fe(III) reduction by MR-1. PMID- 21813653 TI - Male Sterile2 encodes a plastid-localized fatty acyl carrier protein reductase required for pollen exine development in Arabidopsis. AB - Male Sterile2 (MS2) is predicted to encode a fatty acid reductase required for pollen wall development in Arabidopsis (Arabidopsis thaliana). Transient expression of MS2 in tobacco (Nicotiana benthamiana) leaves resulted in the accumulation of significant levels of C16 and C18 fatty alcohols. Expression of MS2 fused with green fluorescent protein revealed that an amino-terminal transit peptide targets the MS2 to plastids. The plastidial localization of MS2 is biologically important because genetic complementation of MS2 in ms2 homozygous plants was dependent on the presence of its amino-terminal transit peptide or that of the Rubisco small subunit protein amino-terminal transit peptide. In addition, two domains, NAD(P)H-binding domain and sterile domain, conserved in MS2 and its homologs were also shown to be essential for MS2 function in pollen exine development by genetic complementation testing. Direct biochemical analysis revealed that purified recombinant MS2 enzyme is able to convert palmitoyl-Acyl Carrier Protein to the corresponding C16:0 alcohol with NAD(P)H as the preferred electron donor. Using optimized reaction conditions (i.e. at pH 6.0 and 30 degrees C), MS2 exhibits a K(m) for 16:0-Acyl Carrier Protein of 23.3 +/- 4.0 MUm, a V(max) of 38.3 +/- 4.5 nmol mg-1 min-1, and a catalytic efficiency/K(m) of 1,873 M-1 s-1. Based on the high homology of MS2 to other characterized fatty acid reductases, it was surprising that MS2 showed no activity against palmitoyl- or other acyl-coenzyme A; however, this is consistent with its plastidial localization. In summary, genetic and biochemical evidence demonstrate an MS2 mediated conserved plastidial pathway for the production of fatty alcohols that are essential for pollen wall biosynthesis in Arabidopsis. PMID- 21813654 TI - Cytokinins mediate resistance against Pseudomonas syringae in tobacco through increased antimicrobial phytoalexin synthesis independent of salicylic acid signaling. AB - Cytokinins are phytohormones that are involved in various regulatory processes throughout plant development, but they are also produced by pathogens and known to modulate plant immunity. A novel transgenic approach enabling autoregulated cytokinin synthesis in response to pathogen infection showed that cytokinins mediate enhanced resistance against the virulent hemibiotrophic pathogen Pseudomonas syringae pv tabaci. This was confirmed by two additional independent transgenic approaches to increase endogenous cytokinin production and by exogenous supply of adenine- and phenylurea-derived cytokinins. The cytokinin mediated resistance strongly correlated with an increased level of bactericidal activities and up-regulated synthesis of the two major antimicrobial phytoalexins in tobacco (Nicotiana tabacum), scopoletin and capsidiol. The key role of these phytoalexins in the underlying mechanism was functionally proven by the finding that scopoletin and capsidiol substitute in planta for the cytokinin signal: phytoalexin pretreatment increased resistance against P. syringae. In contrast to a cytokinin defense mechanism in Arabidopsis (Arabidopsis thaliana) based on salicylic acid-dependent transcriptional control, the cytokinin-mediated resistance in tobacco is essentially independent from salicylic acid and differs in pathogen specificity. It is also independent of jasmonate levels, reactive oxygen species, and high sugar resistance. The novel function of cytokinins in the primary defense response of solanaceous plant species is rather mediated through a high phytoalexin-pathogen ratio in the early phase of infection, which efficiently restricts pathogen growth. The implications of this mechanism for the coevolution of host plants and cytokinin-producing pathogens and the practical application in agriculture are discussed. PMID- 21813655 TI - The tomato terpene synthase gene family. AB - Compounds of the terpenoid class play numerous roles in the interactions of plants with their environment, such as attracting pollinators and defending the plant against pests. We show here that the genome of cultivated tomato (Solanum lycopersicum) contains 44 terpene synthase (TPS) genes, including 29 that are functional or potentially functional. Of these 29 TPS genes, 26 were expressed in at least some organs or tissues of the plant. The enzymatic functions of eight of the TPS proteins were previously reported, and here we report the specific in vitro catalytic activity of 10 additional tomato terpene synthases. Many of the tomato TPS genes are found in clusters, notably on chromosomes 1, 2, 6, 8, and 10. All TPS family clades previously identified in angiosperms are also present in tomato. The largest clade of functional TPS genes found in tomato, with 12 members, is the TPS-a clade, and it appears to encode only sesquiterpene synthases, one of which is localized to the mitochondria, while the rest are likely cytosolic. A few additional sesquiterpene synthases are encoded by TPS-b clade genes. Some of the tomato sesquiterpene synthases use z,z-farnesyl diphosphate in vitro as well, or more efficiently than, the e,e-farnesyl diphosphate substrate. Genes encoding monoterpene synthases are also prevalent, and they fall into three clades: TPS-b, TPS-g, and TPS-e/f. With the exception of two enzymes involved in the synthesis of ent-kaurene, the precursor of gibberellins, no other tomato TPS genes could be demonstrated to encode diterpene synthases so far. PMID- 21813656 TI - Excess cones in the retinal degeneration rd7 mouse, caused by the loss of function of orphan nuclear receptor Nr2e3, originate from early-born photoreceptor precursors. AB - The orphan nuclear receptor NR2E3 is a direct transcriptional target of NRL, the key basic motif leucine zipper transcription factor that dictates rod versus cone photoreceptor cell fate in the mammalian retina. The lack of NR2E3 function in humans and in retinal degeneration rd7 mutant mouse leads to increased S-cones accompanied by rod degeneration, whereas ectopic expression of Nr2e3 in the cone only Nrl(-/-) retina generates rod-like cells that do not exhibit any visual function. Using GFP to tag the newborn rods and by 5-bromo-2'-deoxyuridine birthdating, we demonstrate that early-born post-mitotic photoreceptor precursors in the rd7 retina express cone-specific genes. Transgenic mouse studies in the rd7 background show that Nr2e3 when expressed under the control of Crx promoter can restore rod photoreceptor function and suppress cone gene expression. Furthermore, Nr2e3 expression in photoreceptor precursors committed to be rods (driven by the Nrl promoter) could completely rescue the retinal phenotype of the rd7 mice. We conclude that excess of S-cones in the rd7 retina originate from photoreceptor precursors with a 'default' fate and not from proliferation of cones and that Nr2e3 is required to suppress the expression of S-cone genes during normal rod differentiation. These studies further support the 'transcriptional dominance' model of photoreceptor cell fate determination and provide insights into the pathogenesis of retinal disease phenotypes caused by NR2E3 mutations. PMID- 21813657 TI - Memory T-cell immune response in healthy young adults vaccinated with live attenuated influenza A (H5N2) vaccine. AB - Cellular immune responses of both CD4 and CD8 memory/effector T cells were evaluated in healthy young adults who received two doses of live attenuated influenza A (H5N2) vaccine. The vaccine was developed by reassortment of nonpathogenic avian A/Duck/Potsdam/1402-6/68 (H5N2) and cold-adapted A/Leningrad/134/17/57 (H2N2) viruses. T-cell responses were measured by standard methods of intracellular cytokine staining of gamma interferon (IFN-gamma) producing cells and a novel T-cell recognition of antigen-presenting cells by protein capture (TRAP) assay based on the trogocytosis phenomenon, namely, plasma membrane exchange between interacting immune cells. TRAP enables the detection of activated trogocytosis-positive T cells after virus stimulation. We showed that two doses of live attenuated influenza A (H5N2) vaccine promoted both CD4 and CD8 T-memory-cell responses in peripheral blood of healthy young subjects in the clinical study. Significant differences in geometric mean titers (GMTs) of influenza A (H5N2)-specific IFN-gamma(+) cells were observed at day 42 following the second vaccination, while peak levels of trogocytosis(+) T cells were detected earlier, on the 21st day after the second vaccination. The inverse correlation of baseline levels compared to postvaccine fold changes in GMTs of influenza-specific CD4 and CD8 T cells demonstrated that baseline levels of these specific cells could be considered a predictive factor of vaccine immunogenicity. PMID- 21813658 TI - Cross-reactivity in the Histoplasma antigen enzyme immunoassay caused by sporotrichosis. AB - Several endemic mycoses cause cross-reactions in the Histoplasma antigen enzyme immunoassay. Herein, a positive Histoplasma antigen result has been recognized in a patient with sporotrichosis. PMID- 21813660 TI - Comparison of a new multiplex binding assay versus the enzyme-linked immunosorbent assay for measurement of serotype-specific pneumococcal capsular polysaccharide IgG. AB - The measurement of serotype-specific anti-capsular polysaccharide antibodies remains the mainstay of pneumococcal (Pn) vaccine evaluation. New methods that allow the simultaneous measurement of antibodies to several antigens in small volumes of serum, and that agree well with existing techniques, are urgently required to support the increasing number of concomitant vaccines delivered in the infant immunization schedules and the use of extended-valency Pn vaccines. We therefore compared a relatively new multiplexed platform for measuring anti-Pn antibodies with the existing WHO consensus enzyme-linked immunosorbent assay (ELISA). A panel of 50 pediatric samples (34 collected after receipt of a heptavalent pneumococcal conjugate vaccine [PCV7] and 16 without PCV7) was analyzed across two different laboratories using a new multiplex electrochemiluminescence (ECL)-based detection assay developed for the quantitation of IgG serotype-specific antipneumococcal antibodies, and the results were compared to those obtained using the WHO consensus ELISA. For the seven serotypes measured, there was good agreement between the techniques and laboratories. The most notable difference was found between the ECL assay and the ELISA: concentrations tended to be higher in the ECL assay. For serotypes 6B, 9V, 18C, and 23F, the average increases in concentration ranged from 48 to 102%. However, the agreement rates on the proportions of samples with concentrations surrounding 0.35 MUg/ml were >82% for all serotypes tested. Agreement between the two laboratories running the ECL assay was generally good: agreement on proportions of samples with concentrations surrounding 0.35 MUg/ml was in excess of 92%, and agreement on average antibody concentrations was within 31%. We conclude that the Meso Scale Discovery (MSD) platform provides a promising new technique for the simultaneous measurement of antipneumococcal antibodies. PMID- 21813659 TI - Detection of antibodies against Paracoccidioides brasiliensis melanin in in vitro and in vivo studies during infection. AB - Several cell wall constituents, including melanins or melanin-like compounds, have been implicated in the pathogenesis of a wide variety of microbial diseases caused by diverse species of pathogenic bacteria, fungi, and helminthes. Among these microorganisms, the dimorphic fungal pathogen Paracoccidioides brasiliensis produces melanin in its conidial and yeast forms. In the present study, melanin particles from P. brasiliensis were injected into BALB/c mice in order to produce monoclonal antibodies (MAbs). We identified five immunoglobulin G1 (IgG1) kappa chain and four IgM melanin-binding MAbs. The five IgG1 kappa-chain isotypes are the first melanin-binding IgG MAbs ever reported. The nine MAbs labeled P. brasiliensis conidia and yeast cells both in vitro and in pulmonary tissues. The MAbs cross-reacted with melanin-like purified particles from other fungi and also with commercial melanins, such as synthetic and Sepia officinalis melanin. Melanization during paracoccidioidomycosis (PCM) was also further supported by the detection of IgG antibodies reactive to melanin from P. brasiliensis conidia and yeast in sera and bronchoalveolar lavage fluids from P. brasiliensis-infected mice, as well as in sera from human patients with PCM. Serum specimens from patients with other mycoses were also tested for melanin-binding antibodies by enzyme-linked immunosorbent assay, and cross-reactivities were detected for melanin particles from different fungal sources. These results suggest that melanin from P. brasiliensis is an immunologically active fungal structure that activates a strong IgG humoral response in humans and mice. PMID- 21813661 TI - Expression and solubilization of insect cell-based rabies virus glycoprotein and assessment of its immunogenicity and protective efficacy in mice. AB - Rabies is a fatal zoonotic disease of serious public health and economic significance worldwide. The rabies virus glycoprotein (RVG) has been the major target for subunit vaccine development, since it harbors domains responsible for induction of virus-neutralizing antibodies, infectivity, and neurovirulence. The glycoprotein (G) was cloned using the baculovirus expression vector system (BEVS) and expressed in Spodoptera frugiperda (Sf-9) cells. In order to obtain a soluble form of G suitable for experimentation in mice, 18 different combinations of buffers and detergents were evaluated for their ability to solubilize the insect cell membrane-associated G. The combination that involved 3-[(3-cholamidopropyl) dimethylammonio]-1-propanesulfonate (CHAPS) detergent in lysis buffer 1, formulated with Tris, NaCl, 10% dimethyl sulfoxide (DMSO), and EDTA, gave the highest yield of soluble G, as evidenced by the experimental data. Subsequently, several other parameters, such as the concentration of CHAPS and the duration and temperature of the treatment for the effective solubilization of G, were optimized. The CHAPS detergent, buffered at a concentration of 0.4% to 0.7% (wt/vol) at room temperature (23 to 25 degrees C) for 30 min to 1 h using buffer 1, containing 10% DMSO, resulted in consistently high yields. The G solubilized using CHAPS detergent was found to be immunogenic when tested in mice, as evidenced by high virus-neutralizing antibody titers in sera and 100% protection upon virulent intracerebral challenge with the challenge virus standard (CVS) strain of rabies virus. The results of the mice study indicated that G solubilized with CHAPS detergent retained the immunologically relevant domains in the native conformation, thereby paving the way for producing a cell-free and efficacious subunit vaccine. PMID- 21813662 TI - Correlation of HIV-specific immunity, viral control, and diversification following planned multiple exposures to autologous HIV in a pediatric population. AB - Repeated controlled exposure to autologous virus was previously shown to result in increased CD8 T lymphocyte response to HIV antigens and accompanying reduction in viremia. We attempted to see if this immunity contributed to virologic control by correlating the immune response with quasispecies envelope diversification, an indicator of immune selection. The greatest diversification was seen in those with the greatest reduction in viremia but was unrelated to the frequency of Env specific gamma interferon-producing cells. There was a trend toward correlation between the response to multiple HIV antigens and diversification. PMID- 21813663 TI - Imbalance of Th17 cells and regulatory T cells in tuberculous pleural effusion. AB - Both T helper interleukin 17 (IL-17)-producing cells (Th17 cells) and regulatory T cells (Tregs) have been found to be increased in human tuberculous pleural effusion (TPE); however, the possible interaction between Th17 cells and Tregs in TPE remains to be elucidated. The objective of the present study was to investigate the distribution of Th17 cells in relation to Tregs, as well as the mechanism of Tregs in regulating generation and differentiation of Th17 cells in TPE. In the present study, the numbers of Th17 cells and Tregs in TPE and blood were determined by flow cytometry. The regulation and mechanism of CD39(+) Tregs on generation and differentiation of Th17 cells were explored. Our data demonstrated that the numbers of Th17 cells and CD39(+) Tregs were both increased in TPE compared with blood. Th17 cell numbers were correlated negatively with Tregs in TPE but not in blood. When naive CD4(+) T cells were cultured with CD39(+) Tregs, Th17 cell numbers decreased as CD39(+) Treg numbers increased, and the addition of the anti-latency-associated peptide monoclonal antibody to the coculture reversed the inhibitory effect exerted by CD39(+) Tregs. This study shows that Th17/Treg imbalance exists in TPE and that pleural CD39(+) Tregs inhibit generation and differentiation of Th17 cells via a latency-associated peptide-dependent mechanism. PMID- 21813664 TI - A conformational change of C fragment of tetanus neurotoxin reduces its ganglioside-binding activity but does not destroy its immunogenicity. AB - The C fragment of tetanus neurotoxin (TeNT-Hc) with different conformations was observed due to the four cysteine residues within it which could form different intramolecular disulfide bonds. In this study, we prepared and compared three types of monomeric TeNT-Hc with different conformational components: free sulfhydryls (50 kDa), bound sulfhydryls (44 kDa), and a mixture of the two conformational proteins (half 50 kDa and half 44 kDa). TeNT-Hc with bound sulfhydryls reduced its binding activity to ganglioside G(T1b) and neuronal PC-12 cells compared to what was seen for TeNT-Hc with free sulfhydryls. However, there was no significant difference among their immunogenicities in mice, including induction of antitetanus toxoid IgG titers, antibody types, and protective capacities against tetanus neurotoxin challenge. Our results showed that the conformational changes of TeNT-Hc resulting from disulfide bond formation reduced its ganglioside-binding activity but did not destroy its immunogenicity, and the protein still retained continuous B cell and T cell epitopes; that is, the presence of the ganglioside-binding site within TeNT-Hc may be not essential for the induction of a fully protective antitetanus response. TeNT-Hc with bound sulfhydryls may be developed into an ideal human vaccine with a lower potential for side effects. PMID- 21813665 TI - A tripartite fusion, FaeG-FedF-LT(192)A2:B, of enterotoxigenic Escherichia coli (ETEC) elicits antibodies that neutralize cholera toxin, inhibit adherence of K88 (F4) and F18 fimbriae, and protect pigs against K88ac/heat-labile toxin infection. AB - Enterotoxigenic Escherichia coli (ETEC) strains expressing K88 (F4) or F18 fimbriae and heat-labile (LT) and/or heat-stable (ST) toxins are the major cause of diarrhea in young pigs. Effective vaccines inducing antiadhesin (anti-K88 and anti-F18) and antitoxin (anti-LT and anti-ST) immunity would provide broad protection to young pigs against ETEC. In this study, we genetically fused nucleotides coding for peptides from K88ac major subunit FaeG, F18 minor subunit FedF, and LT toxoid (LT(192)) A2 and B subunits for a tripartite adhesin-adhesin toxoid fusion (FaeG-FedF-LT(192)A2:B). This fusion was used for immunizations in mice and pigs to assess the induction of antiadhesin and antitoxin antibodies. In addition, protection by the elicited antiadhesin and antitoxin antibodies against a porcine ETEC strain was evaluated in a gnotobiotic piglet challenge model. The data showed that this FaeG-FedF-LT(192)A2:B fusion elicited anti-K88, anti-F18, and anti-LT antibodies in immunized mice and pigs. In addition, the anti-porcine antibodies elicited neutralized cholera toxin and inhibited adherence against both K88 and F18 fimbriae. Moreover, immunized piglets were protected when challenged with ETEC strain 30302 (K88ac/LT/STb) and did not develop clinical disease. In contrast, all control nonvaccinated piglets developed severe diarrhea and dehydration after being challenged with the same ETEC strain. This study clearly demonstrated that this FaeG-FedF-LT(192)A2:B fusion antigen elicited antibodies that neutralized LT toxin and inhibited the adherence of K88 and F18 fimbrial E. coli strains and that this fusion could serve as an antigen for vaccines against porcine ETEC diarrhea. In addition, the adhesin-toxoid fusion approach used in this study may provide important information for developing effective vaccines against human ETEC diarrhea. PMID- 21813666 TI - Detection of Mycoplasma genitalium-reactive cervicovaginal antibodies among infected women. AB - Mycoplasma genitalium-reactive cervicovaginal IgA and IgG antibodies were detected in 51.9% and 70.4% of 27 infected women and 22.2% and 18.5% of 27 uninfected controls, respectively. The predominance of MgpB- and MgpC-reactive antibodies at the site of infection is consistent with their hypothesized role in selecting antigenic variants during persistent infection. PMID- 21813667 TI - Reduced antibody responses to the pandemic (H1N1) 2009 vaccine after recent seasonal influenza vaccination. AB - The vaccination program against the 2009 pandemic H1N1 influenza virus (2009 H1N1) provided a unique opportunity to determine if immune responses to the 2009 H1N1 vaccine were affected by a recent, prior vaccination against seasonal influenza virus. In the present study, we studied the immune responses to the 2009 H1N1 vaccine in subjects who either received the seasonal influenza virus vaccination within the prior 3 months or did not. Following 2009 H1N1 vaccination, subjects previously given a seasonal influenza virus vaccination exhibited significantly lower antibody responses, as determined by hemagglutination inhibition assay, than subjects who had not received the seasonal influenza virus vaccination. This result is compatible with the phenomenon of "original antigenic sin," by which previous influenza virus vaccination hampers induction of immunity against a new variant. Our finding should be taken into account for future vaccination programs against pandemic influenza virus outbreaks. PMID- 21813668 TI - Impaired lung 123I-MIBG uptake on SPECT in pulmonary emphysema. AB - The aim of this study was to evaluate impaired lung uptake of (123)I metaiodobenzylguanidine ((123)I-MIBG) on SPECT, compared with perfusion SPECT and morphologic CT, in patients with pulmonary emphysema (PE). METHODS: (123)I-MIBG SPECT was performed at 15 min and 4 h after intravenous injection of (123)I-MIBG in 36 PE patients with a history of smoking and variable-extent low-attenuation areas on CT, indicative of emphysematous changes, and in 16 controls with no history of smoking and no noticeable low-attenuation areas. The distribution of (123)I-MIBG was compared with that of low-attenuation areas on CT and perfusion on SPECT at the base of the 180 lung lobes of the PE patients. Total-lung (123)I MIBG kinetics were calculated, including early and delayed lung-to-mediastinum uptake ratios and washout rate. RESULTS: The controls showed a fairly uniform lung (123)I-MIBG distribution nearly consistent with perfusion. PE patients had heterogeneous (123)I-MIBG defects showing frequent discordance with low attenuation areas or perfusion distribution; (123)I-MIBG defects were more extensive than low-attenuation areas in 76 lobes (42.2%) of 31 patients (86%) and more extensive than perfusion defects in 44 lobes (24.4%) of 22 patients (61%). (123)I-MIBG defects were seen regardless of the absence of noticeable low attenuation areas and perfusion defects in 19 lobes (10.5%) of 16 patients (44%). All total-lung (123)I-MIBG kinetic parameters in PE patients were significantly lower than the control values (P < 0.0001), with significant correlation with alveolar-arterial oxygen tension gradient but without correlation with the extent of perfusion defects or low-attenuation areas. CONCLUSION: (123)I-MIBG SPECT allows evaluation of lung pathophysiology in PE independently of perfusion SPECT or morphologic CT, and impairment of lung (123)I-MIBG uptake may be more extensive than perfusion or morphologic abnormalities in PE. PMID- 21813669 TI - Influence of BMI on risk of miscarriage after single blastocyst transfer. AB - BACKGROUND: Debate exists regarding the effect of raised BMI on the outcome of pregnancies after assisted reproduction technology. We assessed the effect of BMI on the risk of miscarriage in women conceiving following single blastocyst transfer (SBT) after controlling for confounding factors. METHODS: Fresh and cryo thawed cycles of SBT that resulted in a pregnancy between January 2006 and March 2010 were included. Patients with BMI < 18.5 kg/m(2) or older than 40 years were excluded. Patients were grouped according to their BMI at the start of treatment cycle. The main outcome measure was the miscarriage rate before 23 weeks gestation. Confounding variables examined included female age, duration and cause of infertility, previous miscarriage, smoking status and quality of blastocyst replaced. RESULTS: A total of 413 women conceived following SBT in fresh (n = 325) or cryo-thawed (n = 88) IVF cycles, of whom 244 had a normal BMI (18.5-24.9) and 169 had a raised BMI of >= 25. Overall, 27% (113/413) of women miscarried before 23 weeks gestation. Women with a BMI of >= 25 had more than double the risk of miscarriage compared with women who had normal BMI [38 versus 20%, odds ratio (OR): 2.4, 95% confidence interval (CI) 1.6-3.8, P < 0.001, respectively]. After adjusting for confounding variables, having a BMI of >= 25 significantly increased the risk of clinical miscarriage before 23 weeks gestation in both fresh (adjusted OR = 2.7, 95% CI 1.5-4.9, P = 0.001) and cryo-thawed IVF cycles (OR = 6.8, 95% CI 1.5-31.1, P = 0.012). CONCLUSIONS: Raised BMI is independently associated with higher miscarriage rate after IVF treatment. PMID- 21813670 TI - Homeostatic plasticity of neurotransmitter release probability is determined by presynaptic calcium influx. PMID- 21813671 TI - Suppression of a neocortical potassium channel activity by intracellular amyloid beta and its rescue with Homer1a. AB - It is proposed that intracellular amyloid-beta (Abeta), before extracellular plaque formation, triggers cognitive deficits in Alzheimer disease (AD). Here we report how intracellular Abeta affects neuronal properties. This was done by injecting Abeta protein into rat and mouse neocortical pyramidal cells through whole-cell patch pipettes and by using 3xTg AD model mice, in which intracellular Abeta is accumulated innately. In rats, intracellular application of a mixed Abeta(1-42) preparation containing both oligomers and monomers, but not a monomeric preparation of Abeta(1-40), broadened spike width and augmented Ca(2+) influx via voltage-dependent Ca(2+) channels in neocortical neurons. Both effects were mimicked and occluded by charybdotoxin, a blocker of large-conductance Ca(2+)-activated K(+) (BK) channels, and blocked by isopimaric acid, a BK channel opener. Surprisingly, augmented Ca(2+) influx was caused by elongated spike duration, but not attributable to direct Ca(2+) channel modulation by Abeta(1 42). The Abeta(1-42)-induced spike broadening was blocked by electroconvulsive shock (ECS), which we previously showed to facilitate BK channel opening via expression of the scaffold protein Homer1a. In young 3xTg and wild mice, we confirmed spike broadening by Abeta(1-42), which was again mimicked and occluded by charybdotoxin and blocked by ECS. In Homer1a knock-out mice, ECS failed to block the Abeta(1-42) effect. Single-channel recording on BK channels supported these results. These findings suggest that the suppression of BK channels by intracellular Abeta(1-42) is a possible key mechanism for early dysfunction in the AD brain, which may be counteracted by activity-dependent expression of Homer1a. PMID- 21813672 TI - Coordination of high gamma activity in anterior cingulate and lateral prefrontal cortical areas during adaptation. AB - The anterior cingulate cortex (ACC) and the lateral prefrontal cortex (LPFC) process complementary information for planning and evaluating behavior. This suggests at least that processes in these two areas are coordinated during behavioral adaptation. We analyzed local field potentials recorded in both regions in two monkeys performing a problem-solving task that alternated exploration and repetitive behaviors with the specific prediction that neural activity should reveal interareal coordination mainly during exploration. Both areas showed increased high gamma power after errors in exploration and after rewards in exploitation. We found that high gamma (60-140 Hz) power increases in ACC were followed by a later increase in LPFC only after negative feedback (errors) or first positive feedback (correct) during the exploration period. The difference in latencies between the two structures disappeared in repetition period. Simultaneous recordings revealed correlations between high gamma power in the two areas around feedback; however, correlations were observed in both exploration and repetition. In contrast, postfeedback beta (10-20 Hz) power in ACC and LPFC correlated more frequently during repetition. Together, our data suggest that the coordination between ACC and LPFC activity is expressed during adaptive as well as stable behavioral periods but with different modes depending on the behavioral period. PMID- 21813673 TI - Two transcription factors can direct three photoreceptor outcomes from rod precursor cells in mouse retinal development. AB - The typical mammalian visual system is based upon three photoreceptor types: rods for dim light vision and two types of cones (M and S) for color vision in daylight. However, the process that generates photoreceptor diversity and the cell type in which diversity arises remain unclear. Mice deleted for thyroid hormone receptor beta2 (TRbeta2) and neural retina leucine zipper factor (NRL) lack M cones and rods, respectively, but gain S cones. We therefore tested the hypothesis that NRL and TRbeta2 direct a common precursor to a rod, M cone, or S cone outcome using Nrl(b2/b2) "knock-in" mice that express TRbeta2 instead of NRL from the endogenous Nrl gene. Nrl(b2/b2) mice lacked rods and produced excess M cones in contrast to the excess S cones in Nrl(-/-) mice. Notably, the presence of both factors yielded rods in Nrl(+/b2) mice. The results demonstrate innate plasticity in postmitotic rod precursors that allows these cells to form three functional photoreceptor types in response to NRL or TRbeta2. We also detected precursor cells in normal embryonic retina that transiently coexpressed Nrl and TRbeta2, suggesting that some precursors may originate in a plastic state. The plasticity of the precursors revealed in Nrl(b2/b2) mice suggests that a two-step transcriptional switch can direct three photoreceptor fates: first, rod versus cone identity dictated by NRL, and second, if NRL fails to act, M versus S cone identity dictated by TRbeta2. PMID- 21813674 TI - Progranulin deficiency decreases gross neural connectivity but enhances transmission at individual synapses. AB - Frontotemporal dementia (FTD) has been linked to mutations in the progranulin gene (GRN) that lead to progranulin (PGRN) haploinsufficiency. Thus far, our understanding of the effects of PGRN depletion in the brain has been derived from investigation of gross pathology, and more detailed analyses of cellular function have been lacking. We report that knocking down PGRN levels in rat primary hippocampal cultures reduces neural connectivity by decreasing neuronal arborization and length as well as synapse density. Despite this, the number of synaptic vesicles per synapse and the frequency of mEPSCs are increased in PGRN knockdown cells, suggesting an increase in the probability of release at remaining synapses. Interestingly, we demonstrate that the number of vesicles per synapse is also increased in postmortem brain sections from FTD patients with PGRN haploinsufficiency, relative to controls. Our observations show that PGRN knockdown severely alters neuronal connectivity in vitro and that the synaptic vesicle phenotype observed in culture is consistent with that observed in the hippocampus of FTD patients. PMID- 21813675 TI - Visual-induced excitation leads to firing pauses in striatal cholinergic interneurons. AB - Tonically active neurons in the primate striatum, believed to be cholinergic interneurons (CINs), respond to sensory stimuli with a pronounced pause in firing. Although inhibitory and neuromodulatory mechanisms have been implicated, it is not known how sensory stimuli induce firing pauses in CINs in vivo. Here, we used intracellular recordings in anesthetized rats to investigate the effectiveness of a visual stimulus at modulating spike activity in CINs. Initially, no neuron was visually responsive. However, following pharmacological activation of tecto-thalamic pathways, the firing pattern of most CINs was significantly modulated by a light flashed into the contralateral eye. Typically, this induced an excitation followed by a pause in spike firing, via an underlying depolarization-hyperpolarization membrane sequence. Stimulation of thalamic afferents in vitro evoked similar responses that were independent of synaptic inhibition. Thus, visual stimulation likely induces an initial depolarization via a subcortical tecto-thalamo-striatal pathway, pausing CIN firing through an intrinsic afterhyperpolarization. PMID- 21813676 TI - Pool-specific regulation of motor neuron survival by neurotrophic support. AB - The precise control of motor neuron (MN) death and survival following initial innervation of skeletal muscle targets is a key step in sculpting a functional motor system, but how this is regulated at the level of individual motor pools remains unclear. Hepatocyte growth factor (HGF) and its receptor Met play key developmental roles in both muscle and MNs. We generated mice (termed "Nes-Met") in which met is inactivated from midembryonic stages onward in the CNS only. Adult animals showed motor behavioral defects suggestive of impaired innervation of pectoral muscles. Correspondingly, in neonatal spinal cords of Nes-Met mutants, we observed death of a discrete population of pea3-expressing MNs at brachial levels. Axonal tracing using pea3 reporter mice revealed a novel target muscle of pea3-expressing MNs: the pectoralis minor muscle. In Nes-Met mice, the pectoralis minor pool initially innervated its target muscle, but required HGF/Met for survival, hence for proper maintenance of muscle innervation. In contrast, HGF/Met was dispensable for the survival of neighboring Met-expressing MN pools, despite its earlier functions for their specification and axon growth. Our results demonstrate the exquisite degree to which outcomes of signaling by receptor tyrosine kinases are regulated on a cell-by-cell basis. They also provide a model for one way in which the multiplicity of neurotrophic factors may allow for regulation of MN numbers in a pool-specific manner. PMID- 21813677 TI - Distinct and non-redundant roles of microglia and myeloid subsets in mouse models of Alzheimer's disease. AB - Mononuclear phagocytes are important modulators of Alzheimer's disease (AD), but the specific functions of resident microglia, bone marrow-derived mononuclear cells, and perivascular macrophages have not been resolved. To elucidate the spatiotemporal roles of mononuclear phagocytes during disease, we targeted myeloid cell subsets from different compartments and examined disease pathogenesis in three different mouse models of AD (APP(swe/PS1), APP(swe), and APP23 mice). We identified chemokine receptor 2 (CCR2)-expressing myeloid cells as the population that was preferentially recruited to beta-amyloid (Abeta) deposits. Unexpectedly, AD brains with dysfunctional microglia and devoid of parenchymal bone marrow-derived phagocytes did not show overt changes in plaque pathology and Abeta load. In contrast, restriction of CCR2 deficiency to perivascular myeloid cells drastically impaired beta-amyloid clearance and amplified vascular Abeta deposition, while parenchymal plaque deposition remained unaffected. Together, our data advocate selective functions of CCR2-expressing myeloid subsets, which could be targeted specifically to modify disease burden in AD. PMID- 21813678 TI - Identification of a dopamine receptor-mediated opiate reward memory switch in the basolateral amygdala-nucleus accumbens circuit. AB - The basolateral amygdala (BLA), ventral tegmental area (VTA), and nucleus accumbens (NAc) play central roles in the processing of opiate-related associative reward learning and memory. The BLA receives innervation from dopaminergic fibers originating in the VTA, and both dopamine (DA) D1 and D2 receptors are expressed in this region. Using a combination of in vivo single unit extracellular recording in the NAc combined with behavioral pharmacology studies, we have identified a double dissociation in the functional roles of DA D1 versus D2 receptor transmission in the BLA, which depends on opiate exposure state; thus, in previously opiate-naive rats, blockade of intra-BLA D1, but not D2, receptor transmission blocked the acquisition of associative opiate reward memory, measured in an unbiased conditioned place preference procedure. In direct contrast, in rats made opiate dependent and conditioned in a state of withdrawal, intra-BLA D2, but not D1, receptor blockade blocked opiate reward encoding. This functional switch was dependent on cAMP signaling as comodulation of intra-BLA cAMP levels reversed or replicated the functional effects of intra-BLA D1 or D2 transmission during opiate reward processing. Single-unit in vivo extracellular recordings performed in neurons of the NAc confirmed an opiate-state-dependent role for BLA D1/D2 transmission in NAc neuronal response patterns to morphine. Our results characterize and identify a novel opiate addiction switching mechanism directly in the BLA that can control the processing of opiate reward information as a direct function of opiate exposure state via D1 or D2 receptor signaling substrates. PMID- 21813679 TI - CNGA3: a target of spinal nitric oxide/cGMP signaling and modulator of inflammatory pain hypersensitivity. AB - A large body of evidence indicates that nitric oxide (NO) and cGMP contribute to central sensitization of pain pathways during inflammatory pain. Here, we investigated the distribution of cyclic nucleotide-gated (CNG) channels in the spinal cord, and identified the CNG channel subunit CNGA3 as a putative cGMP target in nociceptive processing. In situ hybridization revealed that CNGA3 is localized to inhibitory neurons of the dorsal horn of the spinal cord, whereas its distribution in dorsal root ganglia is restricted to non-neuronal cells. CNGA3 expression is upregulated in the superficial dorsal horn of the mouse spinal cord and in dorsal root ganglia following hindpaw inflammation evoked by zymosan. Mice lacking CNGA3 (CNGA3(-/-) mice) exhibited an increased nociceptive behavior in models of inflammatory pain, whereas their behavior in models of acute or neuropathic pain was normal. Moreover, CNGA3(-/-) mice developed an exaggerated pain hypersensitivity induced by intrathecal administration of cGMP analogs or NO donors. Our results provide evidence that CNGA3 contributes in an inhibitory manner to the central sensitization of pain pathways during inflammatory pain as a target of NO/cGMP signaling. PMID- 21813680 TI - Effects of brain amyloid deposition and reduced glucose metabolism on the default mode of brain function in normal aging. AB - Brain beta-amyloid (Abeta) deposition during normal aging is highlighted as an initial pathogenetic event in the development of Alzheimer's disease. Many recent brain imaging studies have focused on areas deactivated during cognitive tasks [the default mode network (DMN), i.e., medial frontal gyrus/anterior cingulate cortex and precuneus/posterior cingulate cortex], where the strength of functional coordination was more or less affected by cerebral Abeta deposits. In the present positron emission tomography study, to investigate whether regional glucose metabolic alterations and Abeta deposits seen in nondemented elderly human subjects (n = 22) are of pathophysiological importance in changes of brain hemodynamic coordination in DMN during normal aging, we measured cerebral glucose metabolism with [(18)F]FDG, Abeta deposits with [(11)C]PIB, and regional cerebral blood flow during control and working memory tasks by H(2)(15)O on the same day. Data were analyzed using both region of interest and statistical parametric mapping. Our results indicated that the amount of Abeta deposits was negatively correlated with hemodynamic similarity between medial frontal and medial posterior regions, and the lower similarity was associated with poorer working memory performance. In contrast, brain glucose metabolism was not related to this medial hemodynamic similarity. These findings suggest that traceable Abeta deposition, but not glucose hypometabolism, in the brain plays an important role in occurrence of neuronal discoordination in DMN along with poor working memory in healthy elderly people. PMID- 21813681 TI - The importance of having Arc: expression of the immediate-early gene Arc is required for hippocampus-dependent fear conditioning and blocked by NMDA receptor antagonism. AB - Long-lasting, experience-dependent changes in synaptic strength are widely thought to underlie the formation of memories. Many forms of learning-related plasticity are likely mediated by NMDA receptor activation and plasticity-related gene expression in brain areas thought to be important for learning and memory, including the hippocampus. Here, we examined the putative role of activity regulated cytoskeletal-associated protein (Arc), an immediate-early gene (IEG) whose expression is tightly linked to the induction and maintenance of some forms of neuronal plasticity, in hippocampus-dependent and hippocampus-independent forms of learning. The extent to which learning-induced Arc expression may depend on NMDA receptor activation was also assessed. First, we observed an increase in Arc gene and protein products in both dorsal hippocampus (DH) and ventral hippocampus (VH) of male Sprague Dawley rats after hippocampus-dependent trace and contextual fear conditioning, but not after hippocampus-independent delay fear conditioning. Specific knockdown of Arc using antisense oligodeoxynucleotides (ODNs) in DH or VH attenuated the learning-related expression of Arc protein, and resulted in a dramatic impairment in trace and contextual, but not delay, fear conditioning. Finally, pretraining infusions of the NMDA receptor antagonist APV into the DH or VH blocked the learning-induced enhancement of Arc in a regionally selective manner, suggesting that NMDA receptor activation and Arc translation are functionally coupled to support hippocampus-dependent memory for fear conditioning. Collectively these results provide the first evidence suggesting that NMDA receptor-dependent expression of the IEG Arc in both DH and VH likely underlies the consolidation of a variety of forms of hippocampus-dependent learning. PMID- 21813682 TI - Lack of evidence for direct corticospinal contributions to control of the ipsilateral forelimb in monkey. AB - Strong experimental evidence implicates the corticospinal tract in voluntary control of the contralateral forelimb. Its potential role in controlling the ipsilateral forelimb is less well understood, although anatomical projections to ipsilateral spinal circuits are identified. We investigated inputs to motoneurons innervating hand and forearm muscles from the ipsilateral corticospinal tract using multiple methods. Intracellular recordings from 62 motoneurons in three anesthetized monkeys revealed no monosynaptic and only one weak oligosynaptic EPSP after stimulation of the ipsilateral corticospinal tract. Single stimulus intracortical microstimulation of the primary motor cortex (M1) in awake animals failed to produce any responses in ipsilateral muscles. Strong stimulation (>500 MUA, single stimulus) of the majority of corticospinal axons at the medullary pyramids revealed only weak suppressions in ipsilateral muscles at longer latencies than the robust facilitations seen contralaterally. Spike-triggered averaging of ipsilateral muscle activity from M1 neural discharge (184 cells) did not reveal any postspike effects consistent with monosynaptic corticomotoneuronal connections. We also examined the activity of 191 M1 neurons during ipsilateral or contralateral "reach to precision grip" movements. Many cells (67%) modulated their activity during ipsilateral limb movement trials (compared with 90% with contralateral trials), but the timing of this activity was best correlated with weak muscle activity in the contralateral nonmoving arm. We conclude that, in normal adults, any inputs to forelimb motoneurons from the ipsilateral corticospinal tract are weak and indirect and that modulation of M1 cell firing seems to be related primarily to control of the contralateral limb. PMID- 21813683 TI - Experience-dependent plasticity acts via GluR1 and a novel neuronal nitric oxide synthase-dependent synaptic mechanism in adult cortex. AB - Synaptic plasticity directs development of the nervous system and is thought to underlie memory storage in adult animals. A great deal of our current understanding of the role of AMPA receptors in synaptic plasticity comes from studies on developing cortex and cell cultures. In the present study, we instead focus on plasticity in mature neurons in the neocortex of adult animals. We find that the glutamate receptor 1 (GluR1) subunit of the AMPA receptor is involved in experience-dependent plasticity in adult cortex in vivo and that it acts in addition to neuronal nitric oxide synthase (alphaNOS1), an enzyme that produces the rapid synaptic signaling molecule nitric oxide (NO). Potentiation of the spared whisker response, following single whisker experience, is ~33% less in GluR1-null mutants than in wild types. We found that the remaining plasticity depended on alphaNOS1. Potentiation was reduced by >42% in the single alphaNOS1 null mutants and completely abolished in GluR1/alphaNOS1 double-knock-out mice. However, potentiation in GluR1/NOS3 double knock-outs occurred at similar levels to that seen in GluR1 single knock-outs. Synaptic plasticity in the layer IV to II/III pathway in vitro mirrored the results in vivo, in that LTP was present in GluR1/NOS3 double-knock-out mice but not in the GluR1/alphaNOS1 animals. While basal levels of NO in cortical slices depended on both alphaNOS1 and NOS3, NMDA receptor-dependent NO release only depended on alphaNOS1 and not on NOS3. These findings demonstrate that alphaNOS1 acts in concert with GluR1 to produce experience-dependent plasticity in the neocortex. PMID- 21813684 TI - In situ visualization of protein interactions in sensory neurons: glutamic acid rich proteins (GARPs) play differential roles for photoreceptor outer segment scaffolding. AB - Vertebrate photoreceptors initiate vision via a G-protein-mediated signaling cascade organized within a specialized cilium, the outer segment (OS). The membranous "stacked pancake" architecture of this organelle must be partially renewed daily to maintain cell function and viability; however, neither its static structure nor renewal process is well described in molecular terms. Glutamic acid-rich proteins (GARPs), including the cyclic nucleotide-gated cation channel (CNGB1) and GARP2 (a CNGB1 splice-variant), are proposed to contribute to OS organization in concert with peripherin/rds (P/rds), a retinal tetraspanin. We developed and applied an in situ fluorescence complementation approach that offers an unprecedented glimpse at the formation, trafficking, and localization of GARP-P/rds interactions in transgenic Xenopus laevis rod photoreceptors. Interactions for these (and other) proteins could be readily visualized using confocal microscopy. Nearly all associations, including CNGB1-P/rds interaction, were initiated within inner segments (ISs) before trafficking to OSs. In contrast, GARP2-P/rds interactions were only observed downstream, at or near sites of disk morphogenesis. These results suggest that GARP2-P/rds interaction participates directly in structuring disk stacks but CNGB1-P/rds interaction does not and instead serves mainly to localize plasma membrane ion channels. Altogether, the results lead us to propose that differential interaction of GARPs with P/rds may contribute to the broad phenotypic heterogeneity produced by inherited defects in P/rds. Analogous experiments applied to the synaptic protein RIBEYE suggest that monomers can oligomerize at the level of the IS before ribbon assembly and demonstrate the general applicability of this strategy for in situ analysis of protein interactions in sensory neurons. PMID- 21813685 TI - Extracellular signal-regulated kinase signaling in the ventral tegmental area mediates cocaine-induced synaptic plasticity and rewarding effects. AB - Drugs of abuse such as cocaine induce long-term synaptic plasticity in the reward circuitry, which underlies the formation of drug-associated memories and addictive behavior. We reported previously that repeated cocaine exposure in vivo facilitates long-term potentiation (LTP) in dopamine neurons of the ventral tegmental area (VTA) by reducing the strength of GABAergic inhibition and that endocannabinoid-dependent long-term depression at inhibitory synapses (I-LTD) constitutes a mechanism for cocaine-induced reduction of GABAergic inhibition. The present study investigated the downstream signaling mechanisms and functional consequences of I-LTD in the VTA in the rat. Extracellular signal-regulated kinase (ERK) signaling has been implicated in long-term synaptic plasticity, associative learning, and drug addiction. We tested the hypothesis that VTA ERK activity is required for I-LTD and cocaine-induced long-term synaptic plasticity and behavioral effects. We show that the activation of receptors required for I LTD increased ERK1/2 phosphorylation and inhibitors of ERK activation blocked I LTD. We further demonstrate that ERK mediates cocaine-induced reduction of GABAergic inhibition and facilitation of LTP induction. Finally, we show that cocaine conditioned place preference (CPP) training (15 mg/kg; four pairings) increased ERK1/2 phosphorylation in the VTA, while bilateral intra-VTA injections of a CB(1) antagonist or an inhibitor of ERK activation attenuated ERK1/2 phosphorylation and the acquisition, but not the expression, of CPP to cocaine. Our study has identified the CB(1) and ERK signaling cascade as a key mediator of several forms of cocaine-induced synaptic plasticity and provided evidence linking long-term synaptic plasticity in the VTA to rewarding effects of cocaine. PMID- 21813686 TI - Characterizing the spontaneous blink generator: an animal model. AB - Although spontaneous blinking is one of the most frequent human movements, little is known about its neural basis. We developed a rat model of spontaneous blinking to identify and better characterize the spontaneous blink generator. We monitored spontaneous blinking for 55 min periods in normal conditions and after the induction of mild dry eye or dopaminergic drug challenges. The normal spontaneous blink rate was 5.3 +/- 0.3 blinks/min. Dry eye or 1 mg/kg apomorphine significantly increased and 0.1 mg/kg haloperidol significantly decreased the blink rate. Additional analyses revealed a consistent temporal organization to spontaneous blinking with a median 750 s period that was independent of the spontaneous blink rate. Dry eye and dopaminergic challenges significantly modified the regularity of the normal pattern of episodes of frequent blinking interspersed with intervals having few blinks. Dry eye and apomorphine enhanced the regularity of this pattern, whereas haloperidol reduced its regularity. The simplest explanation for our data is that the spinal trigeminal complex is a critical element in the generation of spontaneous blinks, incorporating reflex blinks from dry eye and indirect basal ganglia inputs into the blink generator. Although human subjects exhibited a higher average blink rate (17.6 +/- 2.4) than rats, the temporal pattern of spontaneous blinking was qualitatively similar for both species. These data demonstrate that rats are an appropriate model for investigating the neural basis of human spontaneous blinking and suggest that the spinal trigeminal complex is a major element in the spontaneous blink generator. PMID- 21813687 TI - Single-pixel optical fluctuation analysis of calcium channel function in active zones of motor nerve terminals. AB - We used high-resolution fluorescence imaging and single-pixel optical fluctuation analysis to estimate the opening probability of individual voltage-gated calcium (Ca(2+)) channels during an action potential and the number of such Ca(2+) channels within active zones of frog neuromuscular junctions. Analysis revealed ~36 Ca(2+) channels within each active zone, similar to the number of docked synaptic vesicles but far less than the total number of transmembrane particles reported based on freeze-fracture analysis (~200-250). The probability that each channel opened during an action potential was only ~0.2. These results suggest why each active zone averages only one quantal release event during every other action potential, despite a substantial number of docked vesicles. With sparse Ca(2+) channels and low opening probability, triggering of fusion for each vesicle is primarily controlled by Ca(2+) influx through individual Ca(2+) channels. In contrast, the entire synapse is highly reliable because it contains hundreds of active zones. PMID- 21813688 TI - Repeated amphetamine exposure disrupts dopaminergic modulation of amygdala prefrontal circuitry and cognitive/emotional functioning. AB - Repeated exposure to psychostimulants such as amphetamine (AMPH) disrupts cognitive and behavioral processes mediated by the medial prefrontal cortical (mPFC) and basolateral amygdala (BLA). The present study investigated the effects of repeated AMPH exposure on the neuromodulatory actions of dopamine (DA) on BLA mPFC circuitry and cognitive/emotional processing mediated by these circuits. Rats received five AMPH (2 mg/kg) or saline injections (controls) over 10 d, followed by 2-4 week drug washout. In vivo neurophysiological extracellular recordings in urethane-anesthetized rats were used to obtain data from mPFC neurons that were either inhibited or excited by BLA stimulation. In controls, acute AMPH attenuated BLA-evoked inhibitory or excitatory responses; these effects were mimicked by selective D(2) or D(1) agonists, respectively. However, in AMPH-treated rats, the ability of these dopaminergic manipulations to modulate BLA-driven decreases/increases in mPFC activity was abolished. Repeated AMPH also blunted the excitatory effects of ventral tegmental area stimulation on mPFC neural firing. Behavioral studies assessed the effect of repeated AMPH on decision making with conditioned punishment, a process mediated by BLA-mPFC circuitry and mesocortical DA. These treatments impaired the ability of rats to use conditioned aversive stimuli (footshock-associated cue) to guide the direction of instrumental responding. Collectively, these data suggest that repeated AMPH exposure can lead to persistent disruption of dopaminergic modulation of BLA-mPFC circuitry, which may underlie impairments in cognitive/emotional processing observed in stimulant abusers. Furthermore, they suggest that impairments in decision making guided by aversive stimuli observed in stimulant abusers may be the result of repeated drug exposure. PMID- 21813689 TI - Arrangement of subunits in functional NMDA receptors. AB - Ionotropic glutamate receptors (iGluRs), including the NMDA receptor subtype, are ligand-gated ion channels critical to fast signaling in the CNS. NMDA receptors are obligate heterotetramers composed of two GluN1 and typically two GluN2 subunits. However, the arrangement of GluN subunits in functional receptors whether like subunits are adjacent to (N1/N1/N2/N2) or diagonal to (N1/N2/N1/N2) one another-remains unclear. Recently, a crystal structure of a homomeric AMPA receptor revealed that the four identical subunits adopt two distinct and subunit specific conformations termed A/C and B/D with subunits of like conformations (e.g., A/C) diagonal to one another. In the structure, the two conformers were notable at the level of the linkers (S1-M1, M3-S2, and S2-M4) that join the ligand-binding domain to the transmembrane ion channel with the M3-S2 linker positioned more proximal to the central axis of the channel pore in the A/C conformation and S2-M4 more proximal in the B/D conformation. Using immunoblots and functional assays, we show that introduced cysteines in the M3/M3-S2 linker of GluN1, but not GluN2, show dimer formation and oxidation-induced changes in current amplitudes predictive of the A/C conformation. Conversely, introduced cysteines in the S2-M4 linker of GluN2, but not GluN1, showed similar functional effects, suggesting that the GluN2 subunit adopts the B/D conformation. Thus, we show that NMDA receptors, like AMPA receptors, possess distinct subunit-specific conformations with GluN1 approximating the A/C and GluN2 the B/D conformation. GluN subunits are therefore positioned in a N1/N2/N1/N2 arrangement in functional NMDA receptors. PMID- 21813690 TI - Mirror-image sensitivity and invariance in object and scene processing pathways. AB - Electrophysiological and behavioral studies in many species have demonstrated mirror-image confusion for objects, perhaps because many objects are vertically symmetric (e.g., a cup is the same cup when seen in left or right profile). In contrast, the navigability of a scene changes when it is mirror reversed, and behavioral studies reveal high sensitivity to this change. Thus, we predicted that representations in object-selective cortex will be unaffected by mirror reversals, whereas representations in scene-selective cortex will be sensitive to such reversals. To test this hypothesis, we ran an event-related functional magnetic resonance imaging adaptation experiment in human adults. Consistent with our prediction, we found tolerance to mirror reversals in one object-selective region, the posterior fusiform sulcus, and a strong sensitivity to these reversals in two scene-selective regions, the transverse occipital sulcus and the retrosplenial complex. However, a more posterior object-selective region, the lateral occipital sulcus, showed sensitivity to mirror reversals, suggesting that the sense information that distinguishes mirror images is represented at earlier stages in the object-processing hierarchy. Moreover, one scene-selective region (the parahippocampal place area or PPA) was tolerant to mirror reversals. This last finding challenges the hypothesis that the PPA is involved in navigation and reorientation and suggests instead that scenes, like objects, are processed by distinct pathways guiding recognition and action. PMID- 21813691 TI - Temporal precision in the visual pathway through the interplay of excitation and stimulus-driven suppression. AB - Visual neurons can respond with extremely precise temporal patterning to visual stimuli that change on much slower time scales. Here, we investigate how the precise timing of cat thalamic spike trains-which can have timing as precise as 1 ms-is related to the stimulus, in the context of both artificial noise and natural visual stimuli. Using a nonlinear modeling framework applied to extracellular data, we demonstrate that the precise timing of thalamic spike trains can be explained by the interplay between an excitatory input and a delayed suppressive input that resembles inhibition, such that neuronal responses only occur in brief windows where excitation exceeds suppression. The resulting description of thalamic computation resembles earlier models of contrast adaptation, suggesting a more general role for mechanisms of contrast adaptation in visual processing. Thus, we describe a more complex computation underlying thalamic responses to artificial and natural stimuli that has implications for understanding how visual information is represented in the early stages of visual processing. PMID- 21813692 TI - Opposing synaptic regulation of amyloid-beta metabolism by NMDA receptors in vivo. AB - The concentration of amyloid-beta (Abeta) within the brain extracellular space is one determinant of whether the peptide will aggregate into toxic species that are important in Alzheimer's disease (AD) pathogenesis. Some types of synaptic activity can regulate Abeta levels. Here we demonstrate two distinct mechanisms that are simultaneously activated by NMDA receptors and regulate brain interstitial fluid (ISF) Abeta levels in opposite directions in the living mouse. Depending on the dose of NMDA administered locally to the brain, ISF Abeta levels either increase or decrease. Low doses of NMDA increase action potentials and synaptic transmission which leads to an elevation in synaptic Abeta generation. In contrast, high doses of NMDA activate signaling pathways that lead to ERK (extracellular-regulated kinase) activation, which reduces processing of APP into Abeta. This depression in Abeta via APP processing occurs despite dramatically elevated synaptic activity. Both of these synaptic mechanisms are simultaneously active, with the balance between them determining whether ISF Abeta levels will increase or decrease. NMDA receptor antagonists increase ISF Abeta levels, suggesting that basal activity at these receptors normally suppresses Abeta levels in vivo. This has implications for understanding normal Abeta metabolism as well as AD pathogenesis. PMID- 21813693 TI - Physical and perceptual factors shape the neural mechanisms that integrate audiovisual signals in speech comprehension. AB - Face-to-face communication challenges the human brain to integrate information from auditory and visual senses with linguistic representations. Yet the role of bottom-up physical (spectrotemporal structure) input and top-down linguistic constraints in shaping the neural mechanisms specialized for integrating audiovisual speech signals are currently unknown. Participants were presented with speech and sinewave speech analogs in visual, auditory, and audiovisual modalities. Before the fMRI study, they were trained to perceive physically identical sinewave speech analogs as speech (SWS-S) or nonspeech (SWS-N). Comparing audiovisual integration (interactions) of speech, SWS-S, and SWS-N revealed a posterior-anterior processing gradient within the left superior temporal sulcus/gyrus (STS/STG): Bilateral posterior STS/STG integrated audiovisual inputs regardless of spectrotemporal structure or speech percept; in left mid-STS, the integration profile was primarily determined by the spectrotemporal structure of the signals; more anterior STS regions discarded spectrotemporal structure and integrated audiovisual signals constrained by stimulus intelligibility and the availability of linguistic representations. In addition to this "ventral" processing stream, a "dorsal" circuitry encompassing posterior STS/STG and left inferior frontal gyrus differentially integrated audiovisual speech and SWS signals. Indeed, dynamic causal modeling and Bayesian model comparison provided strong evidence for a parallel processing structure encompassing a ventral and a dorsal stream with speech intelligibility training enhancing the connectivity between posterior and anterior STS/STG. In conclusion, audiovisual speech comprehension emerges in an interactive process with the integration of auditory and visual signals being progressively constrained by stimulus intelligibility along the STS and spectrotemporal structure in a dorsal fronto-temporal circuitry. PMID- 21813694 TI - The detection of visual contrast in the behaving mouse. AB - The mouse is becoming a key species for research on the neural circuits of the early visual system. To relate such circuits to perception, one must measure visually guided behavior and ask how it depends on fundamental stimulus attributes such as visual contrast. Using operant conditioning, we trained mice to detect visual contrast in a two-alternative forced-choice task. After 3-4 weeks of training, mice performed hundreds of trials in each session. Numerous sessions yielded high-quality psychometric curves from which we inferred measures of contrast sensitivity. In multiple sessions, however, choices were influenced not only by contrast, but also by estimates of reward value and by irrelevant factors such as recent failures and rewards. This behavior was captured by a generalized linear model involving not only the visual responses to the current stimulus but also a bias term and history terms depending on the outcome of the previous trial. We compared the behavioral performance of the mice to predictions of a simple decoder applied to neural responses measured in primary visual cortex of awake mice during passive viewing. The decoder performed better than the animal, suggesting that mice might not use optimally the information contained in the activity of visual cortex. PMID- 21813696 TI - Operant conditioning of rat soleus H-reflex oppositely affects another H-reflex and changes locomotor kinematics. AB - H-reflex conditioning is a model for studying the plasticity associated with a new motor skill. We are exploring its effects on other reflexes and on locomotion. Rats were implanted with EMG electrodes in both solei (SOL(R) and SOL(L)) and right quadriceps (QD(R)), and stimulating cuffs on both posterior tibial (PT) nerves and right posterior femoral nerve. When SOL(R) EMG remained in a defined range, PT(R) stimulation just above M-response threshold elicited the SOL(R) H-reflex. Analogous procedures elicited the QD(R) and SOL(L) H-reflexes. After a control period, each rat was exposed for 50 d to a protocol that rewarded SOL(R) H-reflexes that were above (HRup rats) or below (HRdown rats) a criterion. HRup conditioning increased the SOL(R) H-reflex to 214 +/- 37% (mean +/- SEM) of control (p = 0.02) and decreased the QD(R) H-reflex to 71 +/- 26% (p = 0.06). HRdown conditioning decreased the SOL(R) H-reflex to 69 +/- 2% (p < 0.001) and increased the QD(R) H-reflex to 121 +/- 7% (p = 0.02). These changes remained during locomotion. The SOL(L) H-reflex did not change. During the stance phase of locomotion, ankle plantarflexion increased in HRup rats and decreased in HRdown rats, hip extension did the opposite, and hip height did not change. The plasticity that changes the QD(R) H-reflex and locomotor kinematics may be inevitable (i.e., reactive) due to the ubiquity of activity-dependent CNS plasticity, and/or necessary (i.e., compensatory) to preserve other behaviors (e.g., locomotion) that would otherwise be disturbed by the change in the SOL(R) H-reflex pathway. The changes in joint angles, coupled with the preservation of hip height, suggest that compensatory plasticity did occur. PMID- 21813695 TI - The contribution of NMDA receptor signaling in the corticobasal ganglia reward network to appetitive Pavlovian learning. AB - NMDA receptors (NMDARs) contribute to phasic transmission and synaptic plasticity and are thought to be important for learning. To better understand where NMDAR signaling is necessary for learning, we combined viral genetic strategies with genetic mouse models to investigate the contribution of NMDARs in the dopamine system to appetitive Pavlovian conditioning. NMDAR signaling in dopamine neurons was not required for Pavlovian conditioning; however, NMDARs in D(1) dopamine receptor (D(1)R)-expressing medium spiny neurons (MSNs), which receive input from dopamine neurons, were critical for this type of learning. NMDAR signaling was also required in brain regions that project to dopamine neurons, because removing NMDARs from afferent neurons to the ventral tegmental area (VTA) also prevented learning. This effect was likely attributable to loss of NMDAR signaling in the neurons of the prefrontal cortex (PFC), because learning could be restored in these animals by rescuing NMDAR expression in the PFC. Moreover, removing NMDARs exclusively from the PFC also prevented learning. Our findings suggest that NMDARs in neurons that project to and receive projections from the VTA are necessary for Pavlovian conditioning and specifically implicate the PFC and D(1)R expressing MSNs in associative learning. PMID- 21813697 TI - Inflammation-induced lethargy is mediated by suppression of orexin neuron activity. AB - In response to illness, animals subvert normal homeostasis and divert their energy utilization to fight infection. An important and unexplored feature of this response is the suppression of physical activity and foraging behavior in the setting of negative energy balance. Inflammatory signaling in the hypothalamus mediates the febrile and anorectic responses to disease, but the mechanism by which locomotor activity (LMA) is suppressed has not been described. Lateral hypothalamic orexin (Ox) neurons link energy status with LMA, and deficiencies in Ox signaling lead to hypoactivity and hypophagia. In the present work, we examine the effect of endotoxin-induced inflammation on Ox neuron biology and LMA in rats. Our results demonstrate a vital role for diminished Ox signaling in mediating inflammation-induced lethargy. This work defines a specific population of inflammation-sensitive, arousal-associated Ox neurons and identifies a proximal neural target for inflammatory signaling to Ox neurons, while eliminating several others. PMID- 21813698 TI - Drosophila QVR/SSS modulates the activation and C-type inactivation kinetics of Shaker K(+) channels. AB - The quiver/sleepless (qvr/sss) gene encodes a small, glycosylphosphatidylinositol anchored protein that plays a critical role in the regulation of sleep in Drosophila. Loss-of-function mutations in qvr/sss severely suppress sleep and effect multiple changes in in situ Shaker K(+) currents, including decreased magnitude, slower time-to-peak, and cumulative inactivation. Recently, we demonstrated that SLEEPLESS (SSS) protein modulates Shaker channel activity, possibly through a direct interaction at the plasma membrane. We show here that SSS accelerates the activation of heterologously expressed Shaker channels with no effect on deactivation or fast N-type inactivation. Furthermore, this SSS induced acceleration is sensitive to the pharmacological disruption of lipid rafts and sufficiently accounts for the slower time-to-peak of in situ Shaker currents seen in qvr/sss mutants. We also find that SSS decreases the rate of C type inactivation of heterologously expressed Shaker channels, providing a potential mechanism for the cumulative inactivation phenotype induced by qvr/sss loss-of-function mutations. Kinetic modeling based on the in vitro results suggests that the SSS-dependent regulation of channel kinetics accounts for nearly 40% of the decrease in Shaker current magnitude in flies lacking SSS. Sleep duration in qvr/sss-null mutants is restored to normal by a qvr/sss transgene that fully rescues the Shaker kinetic phenotypes but only partially rescues the decrease in current magnitude. Together, these results suggest that the role of SSS in the regulation of sleep in Drosophila correlates more strongly with the effects of SSS on Shaker kinetics than current magnitude. PMID- 21813699 TI - Augmented cocaine seeking in response to stress or CRF delivered into the ventral tegmental area following long-access self-administration is mediated by CRF receptor type 1 but not CRF receptor type 2. AB - Stressful events are determinants of relapse in recovering cocaine addicts. Excessive cocaine use may increase susceptibility to stressor-induced relapse through alterations in brain corticotropin-releasing factor (CRF) regulation of neurocircuitry involved in drug seeking. We previously reported that the reinstatement of cocaine seeking by a stressor (footshock) is CRF dependent and is augmented in rats that self-administered cocaine under long-access (LgA; 6 h daily) conditions for 14 d when compared with rats provided shorter daily cocaine access [short access (ShA) rats; 2 h daily]. Further, we have demonstrated that reinstatement in response to intracerebroventricular CRF administration is heightened in LgA rats. This study examined the role of altered ventral tegmental area (VTA) responsiveness to CRF in intake-dependent increases in CRF- and stress induced cocaine seeking. Bilateral intra-VTA administration of CRF (250 or 500 ng/side) produced reinstatement in LgA but not ShA rats. In LgA rats, intra-VTA CRF-induced reinstatement was blocked by administration of the CRF-receptor type 1 (CRF-R1) antagonist antalarmin (500 ng/side) or CP-376395 (500 ng/side), but not the CRF-R2 antagonist astressin-2B (500 ng or 1 MUg/side) or antisauvagine-30 (ASV-30; 500 ng/side) into the VTA. Likewise, intra-VTA antalarmin, but not astressin-2B, blocked footshock-induced reinstatement in LgA rats. By contrast, neither intra-VTA antalarmin nor CP-376395 altered food-reinforced lever pressing. Intra-VTA injection of the CRF-R1-selective agonist cortagine (100 ng/side) but not the CRF-R2-selective agonist rat urocortin II (rUCN II; 250 ng/side) produced reinstatement. These findings reveal that excessive cocaine use increases susceptibility to stressor-induced relapse in part by augmenting CRF-R1 dependent regulation of addiction-related neurocircuitry in the VTA. PMID- 21813701 TI - Neuroaxonal dystrophy in calcium-independent phospholipase A2beta deficiency results from insufficient remodeling and degeneration of mitochondrial and presynaptic membranes. AB - Infantile neuroaxonal dystrophy (INAD) is a fatal neurodegenerative disease characterized by the widespread presence of axonal swellings (spheroids) in the CNS and PNS and is caused by gene abnormality in PLA2G6 [calcium-independent phospholipase A(2)beta (iPLA(2)beta)], which is essential for remodeling of membrane phospholipids. To clarify the pathomechanism of INAD, we pathologically analyzed the spinal cords and sciatic nerves of iPLA(2)beta knock-out (KO) mice, a model of INAD. At 15 weeks (preclinical stage), periodic acid-Schiff (PAS) positive granules were frequently observed in proximal axons and the perinuclear space of large neurons, and these were strongly positive for a marker of the mitochondrial outer membrane and negative for a marker of the inner membrane. By 100 weeks (late clinical stage), PAS-positive granules and spheroids had increased significantly in the distal parts of axons, and ultrastructural examination revealed that these granules were, in fact, mitochondria with degenerative inner membranes. Collapse of mitochondria in axons was accompanied by focal disappearance of the cytoskeleton. Partial membrane loss at axon terminals was also evident, accompanied by degenerative membranes in the same areas. Imaging mass spectrometry showed a prominent increase of docosahexaenoic acid-containing phosphatidylcholine in the gray matter, suggesting insufficient membrane remodeling in the presence of iPLA(2)beta deficiency. Prominent axonal degeneration in neuroaxonal dystrophy might be explained by the collapse of abnormal mitochondria after axonal transportation. Insufficient remodeling and degeneration of mitochondrial inner membranes and presynaptic membranes appear to be the cause of the neuroaxonal dystrophy in iPLA(2)beta-KO mice. PMID- 21813700 TI - Role of Drp1, a key mitochondrial fission protein, in neuropathic pain. AB - While oxidative stress has been implicated in small-fiber painful peripheral neuropathies, antioxidants are only partially effective to treat patients. We have tested the hypothesis that Drp1 (dynamin-related protein 1), a GTPase that catalyzes the process of mitochondrial fission, which is a mechanism central for the effect and production of reactive oxygen species (ROS), plays a central role in these neuropathic pain syndromes. Intrathecal administration of oligodeoxynucleotide antisense against Drp1 produced a decrease in its expression in peripheral nerve and markedly attenuated neuropathic mechanical hyperalgesia caused by HIV/AIDS antiretroviral [ddC (2',3'-dideoxycytidine)] and anticancer (oxaliplatin) chemotherapy in male Sprague Dawley rats. To confirm the role of Drp1 in these models of neuropathic pain, as well as to demonstrate its contribution at the site of sensory transduction, we injected a highly selective Drp1 inhibitor, mdivi-1, at the site of nociceptive testing on the dorsum of the rat's hindpaw. mdivi-1 attenuated both forms of neuropathic pain. To evaluate the role of Drp1 in hyperalgesia induced by ROS, we demonstrated that intradermal hydrogen peroxide produced dose-dependent hyperalgesia that was inhibited by mdivi-1. Finally, mechanical hyperalgesia induced by diverse pronociceptive mediators involved in inflammatory and neuropathic pain-tumor necrosis factor alpha, glial-derived neurotrophic factor, and nitric oxide-was also inhibited by mdivi-1. These studies provide support for a substantial role of mitochondrial fission in preclinical models of inflammatory and neuropathic pain. PMID- 21813702 TI - Junin virus infection impairs stress-granule formation in Vero cells treated with arsenite via inhibition of eIF2alpha phosphorylation. AB - Stress granules (SGs) are ephemeral cytoplasmic aggregates containing stalled translation preinitiation complexes involved in mRNA storage and triage during the cellular stress response. SG formation is triggered by the phosphorylation of the alpha subunit of eIF2 (eIF2alpha), which provokes a dramatic blockage of protein translation. Our results demonstrate that acute infection of Vero cells with the arenavirus Junin (JUNV), aetiological agent of Argentine haemorrhagic fever, does not induce the formation of SGs. Moreover, JUNV negatively modulates SG formation in infected cells stressed with arsenite, and this inhibition correlates with low levels of eIF2alpha phosphorylation. Transient expression of JUNV nucleoprotein (N) or the glycoprotein precursor (GPC), but not of the matrix protein (Z), inhibits SG formation in a similar manner, comparable to infectious virus. Expression of N and GPC also impaired eIF2alpha phosphorylation triggered by arsenite. A moderate inhibition of SG formation was also observed when DTT and thapsigargin were employed as stress inducers. In contrast, no inhibition was observed when infected cells were treated with hippuristanol, a translational inhibitor and inducer of SGs that bypasses the requirement for eIF2alpha phosphorylation. Finally, we analysed SG formation in persistently JUNV-infected cells, where N and GPC are virtually absent and truncated N products are expressed abundantly. We found that persistently infected cells show a quite normal response to arsenite, with SG formation comparable to that of uninfected cells. This suggests that the presence of GPC and/or N is crucial to control the stress response upon JUNV infection of Vero cells. PMID- 21813703 TI - Identification of heat-shock protein 90 beta in Japanese encephalitis virus induced secretion proteins. AB - Five host cellular proteins were identified in the secretion medium from Japanese encephalitis virus (JEV)-infected baby hamster kidney-21 (BHK-21) cells, including three molecular chaperones: Hsp70, GRP78 and Hsp90. Hsp90 isoforms were characterized further. Hsp90alpha was observed to be retained inside the nuclei, whereas Hsp90beta associated with virus particles during assembly and was released into the secretion medium upon JEV infection. The association of Hsp90beta and viral E protein was demonstrated by using sucrose-density fractionation and Western blot analysis. Moreover, JEV viral RNA replication was not affected by treatment with geldanamycin, an Hsp90 inhibitor, but impaired virus infectivity that was determined by a plaque-forming assay. Our results show that Hsp90beta, not Hsp90alpha, is present in the JEV-induced secretion medium and is required for JEV infectivity in BHK-21 cells. PMID- 21813705 TI - Disruption of repressive p130-DREAM complexes by human papillomavirus 16 E6/E7 oncoproteins is required for cell-cycle progression in cervical cancer cells. AB - Human papillomaviruses (HPVs) with tropism for mucosal epithelia are the major aetiological factors in cervical cancer. Most cancers are associated with so called high-risk HPV types, in particular HPV16, and constitutive expression of the HPV16 E6 and E7 oncoproteins is critical for malignant transformation in infected keratinocytes. E6 and E7 bind to and inactivate the cellular tumour suppressors p53 and Rb, respectively, thus delaying differentiation and inducing proliferation in suprabasal keratinocytes to enable HPV replication. One member of the Rb family, p130, appears to be a particularly important target for E7 in promoting S-phase entry. Recent evidence indicates that p130 regulates cell-cycle progression as part of a large protein complex termed DREAM. The composition of DREAM is cell cycle-regulated, associating with E2F4 and p130 in G0/G1 and with the B-myb transcription factor in S/G2. In this study, we addressed whether p130 DREAM is disrupted in HPV16-transformed cervical cancer cells and whether this is a critical function for E6/E7. We found that p130-DREAM was greatly diminished in HPV16-transformed cervical carcinoma cells (CaSki and SiHa) compared with control cell lines; however, when E6/E7 expression was targeted by specific small hairpin RNAs, p130-DREAM was reformed and the cell cycle was arrested. We further demonstrated that the profound G1 arrest in E7-depleted CaSki cells was dependent on p130-DREAM reformation by also targeting the expression of the DREAM component Lin-54 and p130. The results show that continued HPV16 E6/E7 expression is necessary in cervical cancer cells to prevent cell-cycle arrest by a repressive p130-DREAM complex. PMID- 21813704 TI - Evolutionary analysis of serotype A foot-and-mouth disease viruses circulating in Pakistan and Afghanistan during 2002-2009. AB - Foot-and-mouth disease (FMD) is endemic in Pakistan and Afghanistan. Three different serotypes of the virus, namely O, A and Asia-1, are responsible for the outbreaks of this disease in these countries. In the present study, the nucleotide-coding sequences for the VP1 capsid protein (69 samples) or for all four capsid proteins (P1, seven representative samples) of the serotype A FMD viruses circulating in Pakistan and Afghanistan were determined. Phylogenetic analysis of the foot-and-mouth disease virus (FMDV) VP1-coding sequences from these countries collected between 2002 and 2009 revealed the presence of at least four lineages within two distinct genotypes, all belonging to the Asia topotype, within serotype A. The predominant lineage observed was A-Iran05 but three other lineages (a new one is named here A-Pak09) were also identified. The A-Iran05 lineage is still evolving as revealed by the presence of seven distinct variants, the dominant being the A-Iran05AFG-07 and A-Iran05BAR-08 sublineages. The rate of evolution of the A-Iran05 lineage was found to be about 1.2*10(-2) substitutions per nucleotide per year. This high rate of change is consistent with the rapid appearance of new variants of FMDV serotype A in the region. The A22/Iraq FMDV vaccine is antigenically distinct from the A-Iran05BAR-08 viruses. Mapping of the amino acid changes between the capsid proteins of the A22/Iraq vaccine strain and the A-Iran05BAR-08 viruses onto the A22/Iraq capsid structure identified candidate amino acid substitutions, exposed on the virus surface, which may explain this antigenic difference. PMID- 21813706 TI - Modification of the trypsin cleavage site of rotavirus VP4 to a furin-sensitive form does not enhance replication efficiency. AB - The infectivity of rotavirus (RV) is dependent on an activation process triggered by the proteolytic cleavage of its spike protein VP4. This activation cleavage is performed by exogenous trypsin in the lumen of the intestines in vivo. Here, we report the generation and characterization of a recombinant RV expressing cDNA derived VP4 with a modified cleavage site (arginine at position 247) recognized by endogenous furin as well as exogenous trypsin. Unexpectedly, the mutant virus (KU//rVP4-R247Furin) was incapable of plaque formation without an exogenous protease, although the mutant VP4s on virions were efficiently cleaved by endogenous furin. Furthermore, KU//rVP4-R247Furin showed impaired infectivity in MA104 and CV-1 cells even in the presence of trypsin compared with the parental virus carrying authentic VP4 (KU//rVP4). Although the total titre of KU//rVP4 R247Furin was comparable to that of KU//rVP4, the extracellular titre of KU//rVP4 R247Furin was markedly lower than its cell-associated titre in comparison with that of KU//rVP4. In contrast, the two viruses showed similar growth in a furin defective LoVo cell line. These results suggest that intracellular cleavage of VP4 by furin may be disadvantageous for RV infectivity, possibly due to an inefficient virus release process. PMID- 21813707 TI - Identification of Epstein-Barr virus-infected CD27+ memory B-cells in liver or stem cell transplant patients. AB - To analyse the phenotype of Epstein-Barr virus (EBV)-infected lymphocytes in EBV associated infections, cells from eight haematopoietic stem cell/liver transplantation recipients with elevated EBV viral loads were examined by a novel quantitative assay designed to identify EBV-infected cells by using a flow cytometric detection of fluorescent in situ hybridization (FISH) assay. By this assay, 0.05-0.78% of peripheral blood lymphocytes tested positive for EBV, and the EBV-infected cells were CD20+ B-cells in all eight patients. Of the CD20+ EBV infected lymphocytes, 48-83% of cells tested IgD positive and 49-100% of cells tested CD27 positive. Additionally, the number of EBV-infected cells assayed by using FISH was significantly correlated with the EBV-DNA load, as determined by real-time PCR (r2 = 0.88, P < 0.0001). The FISH assay enabled us to characterize EBV-infected cells and perform a quantitative analysis in patients with EBV infection after stem cell/liver transplantation. PMID- 21813708 TI - Infection with cytomegalovirus but not herpes simplex virus induces the accumulation of late-differentiated CD4+ and CD8+ T-cells in humans. AB - Human cytomegalovirus (CMV) establishes persistent, usually asymptomatic, infection in healthy people. Because CMV infection is associated with the presence of lower proportions of peripheral naive CD8+ T-cells and a higher fraction of late-differentiated CD8+ cells, commonly taken as biomarkers of age associated compromised adaptive immunity ('immunosenescence'), we asked whether chronic exposure to any persistent virus mediates these effects. Herpes simplex virus (HSV) is also a widespread herpesvirus that establishes lifelong persistence, but, unlike CMV, its impact on the distribution of T-cell subsets has not been established. Here, we analysed T-cell subsets in 93 healthy people aged 42-81 years infected or not infected with CMV and/or HSV. Individuals harbouring CMV were confirmed to possess lower frequencies of naive CD8+ T-cells (defined as CD45RA+CCR7+CD27+CD28+) and greater proportions of late differentiated effector memory (CD45RA-CCR7-CD27-CD28-) and so-called TEMRA (CD45RA+CCR7-CD27-CD28-) CD4 and CD8 subsets, independent of HSV seropositivity. In CMV-seronegative donors, HSV did not affect T-cell subset distribution significantly. We conclude that these hallmarks of age-associated alterations to immune signatures are indeed observed in the general population in people infected with CMV and not those infected with a different persistent herpesvirus. PMID- 21813709 TI - With-No-Lysine Kinase 3 (WNK3) stimulates glioma invasion by regulating cell volume. AB - Among the most prevalent and deadly primary brain tumors, high-grade gliomas evade complete surgical resection by diffuse invasion into surrounding brain parenchyma. Navigating through tight extracellular spaces requires invading glioma cells to alter their shape and volume. Cell volume changes are achieved through transmembrane transport of osmolytes along with obligated water. The sodium-potassium-chloride cotransporter isoform-1 (NKCC1) plays a pivotal role in this process, and previous work has demonstrated that NKCC1 inhibition compromises glioma invasion in vitro and in vivo by interfering with the required cell volume changes. In this study, we show that NKCC1 activity in gliomas requires the With-No-Lysine Kinase-3 (WNK3) kinase. Western blots of patient biopsies and patient-derived cell lines shows prominent expression of Ste-20 related, proline-alanine-rich kinase (SPAK), oxidative stress response kinase (OSR1), and WNK family members 1, 3, and 4. Of these, only WNK3 colocalized and coimmunoprecipitated with NKCC1 upon changes in cell volume. Stable knockdown of WNK3 using specific short hairpin RNA constructs completely abolished NKCC1 activity, as measured by the loss of bumetanide-sensitive cell volume regulation. Consequently, WNK3 knockdown cells showed a reduced ability to invade across Transwell barriers and lacked bumetanide-sensitive migration. This data indicates that WNK3 is an essential regulator of NKCC1 and that WNK3 activates NKCC1 mediated ion transport necessary for cell volume changes associated with cell invasion. PMID- 21813710 TI - Contribution of Kv2.1 channels to the delayed rectifier current in freshly dispersed smooth muscle cells from rabbit urethra. AB - We have characterized the native voltage-dependent K(+) (K(v)) current in rabbit urethral smooth muscle cells (RUSMC) and compared its pharmacological and biophysical properties with K(v)2.1 and K(v)2.2 channels cloned from the rabbit urethra and stably expressed in human embryonic kidney (HEK)-293 cells (HEK(Kv2.1) and HEK(Kv2.2)). RUSMC were perfused with Hanks' solution at 37 degrees C and studied using the patch-clamp technique with K(+)-rich pipette solutions. Cells were bathed in 100 nM Penitrem A (Pen A) to block large conductance Ca(2+)-activated K(+) (BK) currents and depolarized to +40 mV for 500 ms to evoke K(v) currents. These were unaffected by margatoxin, kappa dendrotoxin, or alpha-dendrotoxin (100 nM, n = 3-5) but were blocked by stromatoxin-1 (ScTx, IC(50) ~130 nM), consistent with the idea that the currents were carried through K(v)2 channels. RNA was detected for K(v)2.1, K(v)2.2, and the silent subunit K(v)9.3 in urethral smooth muscle. Immunocytochemistry showed membrane staining for both K(v)2 subtypes and K(v)9.3 in isolated RUSMC. HEK(Kv2.1) and HEK(Kv2.2) currents were blocked in a concentration-dependent manner by ScTx, with estimated IC(50) values of ~150 nM (K(v)2.1, n = 5) and 70 nM (K(v)2.2, n = 6). The mean half-maximal voltage (V(1/2)) of inactivation of the USMC K(v) current was -56 +/- 3 mV (n = 9). This was similar to the HEK(Kv2.1) current (-55 +/- 3 mV, n = 13) but significantly different from the HEK(Kv2.2) currents (-30 +/- 3 mV, n = 11). Action potentials (AP) evoked from RUSMC studied under current-clamp mode were unaffected by ScTx. However, when ScTx was applied in the presence of Pen A, the AP duration was significantly prolonged. Similarly, ScTx increased the amplitude of spontaneous contractions threefold, but only after Pen A application. These data suggest that K(v)2.1 channels contribute significantly to the K(v) current in RUSMC. PMID- 21813711 TI - Expression of a naturally occurring angiotensin AT(1) receptor cleavage fragment elicits caspase-activation and apoptosis. AB - Several transmembrane receptors are documented to accumulate in nuclei, some as holoreceptors and others as cleaved receptor products. Our prior studies indicate that a population of the 7-transmembrane angiotensin type-1 receptor (AT(1)R) is cleaved in a ligand-augmented manner after which the cytoplasmic, carboxy terminal cleavage fragment (CF) traffics to the nucleus. In the present report, we determine the precise cleavage site within the AT(1)R by mass spectrometry and Edman sequencing. Cleavage occurs between Leu(305) and Gly(306) at the junction of the seventh transmembrane domain and the intracellular cytoplasmic carboxy terminal domain. To evaluate the function of the CF distinct from the holoreceptor, we generated a construct encoding the CF as an in-frame yellow fluorescent protein fusion. The CF accumulates in nuclei and induces apoptosis in CHO-K1 cells, rat aortic smooth muscle cells (RASMCs), MCF-7 human breast adenocarcinoma cells, and H9c2 rat cardiomyoblasts. All cell types show nuclear fragmentation and disintegration, as well as evidence for phosphotidylserine displacement in the plasma membrane and activated caspases. RASMCs specifically showed a 5.2-fold increase (P < 0.001) in CF-induced active caspases compared with control and a 7.2-fold increase (P < 0.001) in cleaved caspase-3 (Asp174). Poly(ADP-ribose)polymerase was upregulated 4.8-fold (P < 0.001) in CF expressing cardiomyoblasts and colocalized with terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL). CF expression also induces DNA laddering, the gold-standard for apoptosis in all cell types studied. CF-induced apoptosis, therefore, appears to be a general phenomenon as it is observed in multiple cell types including smooth muscle cells and cardiomyoblasts. PMID- 21813712 TI - Real-time measurement of the length of a single sarcomere in rat ventricular myocytes: a novel analysis with quantum dots. AB - As the dynamic properties of cardiac sarcomeres are markedly changed in response to a length change of even ~0.1 MUm, it is imperative to quantitatively measure sarcomere length (SL). Here we show a novel system using quantum dots (QDs) that enables a real-time measurement of the length of a single sarcomere in cardiomyocytes. First, QDs were conjugated with anti-alpha-actinin antibody and applied to the sarcomeric Z disks in isolated skinned cardiomyocytes of the rat. At partial activation, spontaneous sarcomeric oscillations (SPOC) occurred, and QDs provided a quantitative measurement of the length of a single sarcomere over the broad range (i.e., from ~1.7 to ~2.3 MUm). It was found that the SPOC amplitude was inversely related to SL, but the period showed no correlation with SL. We then treated intact cardiomyocytes with the mixture of the antibody-QDs and FuGENE HD, and visualized the movement of the Z lines/T tubules. At a low frequency of 1 Hz, the cycle of the motion of a single sarcomere consisted of fast shortening followed by slow relengthening. However, an increase in stimulation frequency to 3-5 Hz caused a phase shift of shortening and relengthening due to acceleration of relengthening, and the waveform became similar to that observed during SPOC. Finally, the anti-alpha-actinin antibody QDs were transfected from the surface of the beating heart in vivo. The striated patterns with ~1.96-MUm intervals were observed after perfusion under fluorescence microscopy, and an electron microscopic observation confirmed the presence of QDs in and around the T tubules and Z disks, but primarily in the T tubules, within the first layer of cardiomyocytes of the left ventricular wall. Therefore, QDs are a useful tool to quantitatively analyze the movement of single sarcomeres in cardiomyocytes, under various experimental settings. PMID- 21813713 TI - Novel loss-of-function PCSK9 variant is associated with low plasma LDL cholesterol in a French-Canadian family and with impaired processing and secretion in cell culture. AB - BACKGROUND: PCSK9 (proprotein convertase subtilisin/kexin type 9) is a polymorphic gene whose protein product regulates plasma LDL cholesterol (LDLC) concentrations by shuttling liver LDL receptors (LDLRs) for degradation. PCSK9 variants that cause a gain or loss of PCSK9 function are associated with hyper- or hypocholesterolemia, which increases or reduces the risk of cardiovascular disease, respectively. We studied the clinical and molecular characteristics of a novel PCSK9 loss-of-function sequence variant in a white French-Canadian family. METHODS: In vivo plasma and ex vivo secreted PCSK9 concentrations were measured with a commercial ELISA. We sequenced the PCSK9 exons for 15 members of a family, the proband of which exhibited very low plasma PCSK9 and LDLC concentrations. We then conducted a structure/function analysis of the novel PCSK9 variant in cell culture to identify its phenotypic basis. RESULTS: We identified a PCSK9 sequence variant in the French-Canadian family that produced the PCSK9 Q152H substitution. Family members carrying this variant had mean decreases in circulating PCSK9 and LDLC concentrations of 79% and 48%, respectively, compared with unrelated noncarriers (n=210). In cell culture, the proPCSK9-Q152H variant did not undergo efficient autocatalytic cleavage and was not secreted. Cells transiently transfected with PCSK9-Q152H cDNA had LDLR concentrations that were significantly higher than those of cells overproducing wild-type PCSK9 (PCSK9-WT). Cotransfection of PCSK9-Q152H and PCSK9-WT cDNAs produced a 78% decrease in the secreted PCSK9-WT protein compared with control cells. CONCLUSIONS: Collectively, our results demonstrate that the PCSK9-Q152H variant markedly lowers plasma PCSK9 and LDLC concentrations in heterozygous carriers via decreased autocatalytic processing and secretion, and hence, inactivity on the LDLR. PMID- 21813714 TI - Unbiased parallel detection of viral pathogens in clinical samples by use of a metagenomic approach. AB - Viral infectious diseases represent a major threat to public health and are among the greatest disease burdens worldwide. Rapid and accurate identification of viral agents is crucial for both outbreak control and estimating regional disease burdens. Recently developed metagenomic methods have proven to be powerful tools for simultaneous pathogen detection. Here, we performed a systematic study of the capability of the short-read-based metagenomic approach in the molecular detection of viral pathogens in nasopharyngeal aspirate samples from patients with acute lower respiratory tract infections (n = 16). Using the high-throughput capacity of ultradeep sequencing and a dedicated data interpretation method, we successfully identified seven species of known respiratory viral agents from 15 samples, a result that was consistent with results of conventional PCR assays. We also detected a coinfected case that was missed by regular PCR testing. Using the metagenomic data, 11 draft genomes of the abundantly detected viruses in the samples were reconstructed with 21.84% to 98.53% coverage. Our results show the power of the short-read-based metagenomic approach for accurate and parallel screening of viral pathogens. Although there are some inherent difficulties in applying this approach to clinical samples, including a lack of controls, limited specimen quantity, and high contamination rate, our work will facilitate further application of this unprecedented high-throughput method to clinical samples. PMID- 21813715 TI - Pyrosequencing for rapid molecular detection of rifampin and isoniazid resistance in Mycobacterium tuberculosis strains and clinical specimens. AB - The aim of this study was to evaluate a pyrosequencing method for the detection of Mycobacterium tuberculosis isolates resistant to rifampin and isoniazid using both clinical strains and clinical samples, comparing the results with those of the Bactec 460TB and GenoType MTBDRplus assays. In comparison to Bactec 460TB as the gold standard, the sensitivity of pyrosequencing for detecting isoniazid and rifampin resistance was 76.9% and 97.2%, respectively, for clinical strains, and the specificity was 97.2 and 97.9%, respectively. For clinical specimens, the sensitivity and specificity for both drugs were 85.7% and 100%, respectively. The overall concordance between pyrosequencing and the GenoType MTBDRplus assay for clinical strains was 99.1%, and for clinical samples, it was 98.2%. Pyrosequencing is a valuable tool for rifampin and isoniazid resistance detection. PMID- 21813716 TI - MassARRAY spectrometry is more sensitive than PreTect HPV-Proofer and consensus PCR for type-specific detection of high-risk oncogenic human papillomavirus genotypes in cervical cancer. AB - Type-specific detection of human papillomavirus (HPV) is indicated for better risk stratification and clinical management of women testing positive for HPV and for epidemiologic surveillance. MassARRAY spectrometry (MassARRAY; Sequenom) is a novel method for type-specific detection of 15 high-risk oncogenic HPV types: HPV 16, -18, -31, -33, -35, -39, -45, -51, -52, -56, -58, -59, -66, -68, and -73. PreTect HPV-Proofer (Proofer; Norchip) is a type-specific assay that detects E6/E7 mRNA from five high-risk oncogenic HPV types: HPV-16, -18, -31, -33, and 45. The performance of these tests for type-specific identification of HPV was assessed with cervical specimens from 192 cases of cervical cancer in comparison with consensus MY09/MY11 PCR followed by nucleotide sequencing (consensus PCR). The overall HPV detection rates were 94.8% (95% confidence interval [CI], 91.7, 97.9), 83.3% (95% CI, 78.1, 88.5), and 86.5% (95% CI, 81.7, 91.3) for MassARRAY, Proofer, and consensus PCR, respectively. All tests were negative in six (3.1%) of the 192 cases. Considering only the specimens that contained at least one of the five types targeted by Proofer, the detection rates were 96.6%, 91.4%, and 86.9% for MassARRAY, Proofer, and consensus PCR, respectively. MassARRAY detected multiple infections in 14.1%, Proofer detected multiple infections in 3.6%, and consensus PCR failed to detect any multiple infections. The agreement was highest at 86.0% (kappa = 0.76) between MassARRAY and Proofer and lowest at 81.8% (kappa = 0.69) between Proofer and consensus PCR. In conclusion, MassARRAY is a highly sensitive and accurate method for type-specific detection of oncogenic HPV in cervical cancer, with Proofer showing impressive performance. PMID- 21813717 TI - Controlled performance evaluation of the DiversiLab repetitive-sequence-based genotyping system for typing multidrug-resistant health care-associated bacterial pathogens. AB - Fast, reliable, and versatile typing tools are essential to differentiate among related bacterial strains for epidemiological investigation and surveillance of health care-associated infection with multidrug-resistant (MDR) pathogens. The DiversiLab (DL) system is a semiautomated repetitive-sequence-based PCR system designed for rapid genotyping. The DL system performance was assessed by comparing its reproducibility, typeability, discriminatory power, and concordance with those of pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST) and by assessing its epidemiological concordance on well characterized MDR bacterial strains (n = 165). These included vanA Enterococcus faecium, extended-spectrum beta-lactamase (ESBL)-producing strains of Klebsiella pneumoniae, Escherichia coli, and Acinetobacter baumannii, and ESBL- or metallo beta-lactamase (MBL)-producing Pseudomonas aeruginosa strains. The DL system showed very good performance for E. faecium and K. pneumoniae and good performance for other species, except for a discrimination index of <95% for A. baumannii and E. coli (93.9% and 93.5%, respectively) and incomplete concordance with MLST for P. aeruginosa (78.6%) and E. coli (97.0%). Occasional violations of MLST assignment by DL types were noted for E. coli. Complete epidemiological concordance was observed for all pathogens, as all outbreak-associated strains clustered in identical DL types that were distinct from those of unrelated strains. In conclusion, the DL system showed good to excellent performance, making it a reliable typing tool for investigation of outbreaks caused by study pathogens, even though it was generally less discriminating than PFGE analysis. For E. coli and P. aeruginosa, MLST cannot be reliably inferred from DL type due to phylogenetic group violation or discordance. PMID- 21813718 TI - An international collaboration to standardize HIV-2 viral load assays: results from the 2009 ACHI(E)V(2E) quality control study. AB - Accurate HIV-2 plasma viral load quantification is crucial for adequate HIV-2 patient management and for the proper conduct of clinical trials and international cohort collaborations. This study compared the homogeneity of HIV-2 RNA quantification when using HIV-2 assays from ACHI(E)V(2E) study sites and either in-house PCR calibration standards or common viral load standards supplied to all collaborators. Each of the 12 participating laboratories quantified blinded HIV-2 samples, using its own HIV-2 viral load assay and standard as well as centrally validated and distributed common HIV-2 group A and B standards (http://www.hiv.lanl.gov/content/sequence/HelpDocs/subtypes-more.html). Aliquots of HIV-2 group A and B strains, each at 2 theoretical concentrations (2.7 and 3.7 log(10) copies/ml), were tested. Intralaboratory, interlaboratory, and overall variances of quantification results obtained with both standards were compared using F tests. For HIV-2 group A quantifications, overall and interlaboratory and/or intralaboratory variances were significantly lower when using the common standard than when using in-house standards at the concentration levels of 2.7 log(10) copies/ml and 3.7 log(10) copies/ml, respectively. For HIV-2 group B, a high heterogeneity was observed and the variances did not differ according to the type of standard used. In this international collaboration, the use of a common standard improved the homogeneity of HIV-2 group A RNA quantification only. The diversity of HIV-2 group B, particularly in PCR primer-binding regions, may explain the heterogeneity in quantification of this strain. Development of a validated HIV-2 viral load assay that accurately quantifies distinct circulating strains is needed. PMID- 21813719 TI - Clostridium sordellii as a cause of constrictive pericarditis with pyopericardium and tamponade. AB - Systemic infections caused by Clostridium sordellii are rare. They are usually reported in cases of skin and soft tissue infections and sometimes in cases of toxic shock syndrome involving exotoxins. We report here the first case of Clostridium sordellii infection associated with acute constrictive pericarditis and with pyopericardium and tamponade. PMID- 21813720 TI - Improved polyacrylamide-based artificial sputum with formalin-fixed tubercle bacilli for training of tuberculosis microscopists. AB - Sputum smear microscopy is an easy, inexpensive, and rapid method for detecting tubercle bacilli when there are more than 10,000 bacilli/ml in the original sputum. Furthermore, because the microscopic method provides not only quantitative, but also qualitative information, such as the shape of bacilli, it has remained significant. We have previously developed and reported panel test slides made from polyacrylamide-based artificial sputum (PBAS) mixed with both cultured THP-1 cells and nonpathogenic mycobacteria. In this paper, we report an improved preparation method for PBAS for panel test slides that provides a simplified method and enhanced availability with high consistency in each grade and in which only negative PBAS is prepared from polyacrylamide and cultured THP 1 cells and mixed with graded formalin-fixed Mycobacterium tuberculosis solution (FFTBS) containing oral flora and Pseudomonas aeruginosa on the slides. In the smears prepared using this improved method, the numbers (average +/- standard deviation [SD]) of acid-fast bacilli (AFB) in 300 fields (2- by 3-cm smear) in eight smears of each grade ranged from 5 to 9 (6.4 +/- 1.4), from 59 to 88 (74.6 +/- 10.0), from 503 to 912 (705.0 +/- 145.7), and from 1,819 to 3,256 (2133.3 +/- 478.0) in +/-, +, ++, and +++ smears, respectively. In addition, this preparation method provided high similarity to the microscopic appearance of bacilli and background seen in the actual patient sputum, with high feasibility. These results revealed that our new PBAS had high authenticity in the appearance and consistency in each grade, which could make it valuable as a reliable artificial sputum for the training of microscopists. PMID- 21813721 TI - Evaluation of six commercial nucleic acid amplification tests for detection of Neisseria gonorrhoeae and other Neisseria species. AB - Molecular detection of Neisseria gonorrhoeae in extragenital samples may result in false-positive results due to cross-reaction with commensal Neisseria species or Neisseria meningitidis. This study examined 450 characterized clinical culture isolates, comprising 216 N. gonorrhoeae isolates and 234 isolates of nongonococcal Neisseria species (n = 218) and 16 isolates of other closely related bacteria, with six commercial nucleic acid amplification tests (NAATs). The six NAATs tested were Gen-Probe APTIMA COMBO 2 and APTIMA GC, Roche COBAS Amplicor CT/NG and COBAS 4800 CT/NG tests, BD ProbeTec GC Qx amplified DNA assay, and Abbott RealTime CT/NG test. All assays except COBAS Amplicor CT/NG test where four (1.9%) isolates were not detected showed a positive result with all N. gonorrhoeae isolates (n = 216). Among the 234 nongonococcal isolates examined, initial results from all assays displayed some false-positive results due to cross-reactions. Specifically, the COBAS Amplicor and ProbeTec tests showed the highest number of false-positive results, detecting 33 (14.1%) and 26 (11%) nongonococcal Neisseria isolates, respectively. On the first testing, APTIMA COMBO 2, APTIMA GC, Abbott RealTime, and Roche COBAS 4800 showed lower level of cross-reactions with five (2.1%), four (1.7%), two (1%), and two (1%) of the isolates showing low-level positivity, respectively. Upon retesting of these nine nongonococcal isolates using freshly cultured colonies, none were positive by the APTIMA COMBO 2, Abbott RealTime, or COBAS 4800 test. In conclusion, the COBAS Amplicor and ProbeTec tests displayed high number of false-positive results, while the remaining NAATs showed only sporadic low-level false-positive results. Supplementary testing for confirmation of N. gonorrhoeae NAATs remains recommended with all samples tested, in particular those from extragenital sites. PMID- 21813722 TI - Cervicovaginal self-sampling is a reliable method for determination of prevalence of human papillomavirus genotypes in women aged 20 to 30 years. AB - Self-sampling by cervicovaginal lavage could be an attractive method to detect high-risk human papillomavirus (hr-HPV) infections to identify women with a risk of cervical precancer. The objective of our study was to use self-sampling for the first time in a cross-sectional approach to determine HPV prevalence and genotype distribution. We evaluated participants' acceptance and laboratory results from self-obtained samples versus endocervical brush samples obtained by gynecologists. To determine the sensitivity of both sampling methods in presumed high- and low-prevalence settings, two groups of women 20 to 30 years of age with (n = 55) and without (n = 101) a recent suspicious cytological smear were compared. Overall, 76% (95% confidence interval [95% CI], 65 to 88) of women with and 40% (95% CI, 30 to 49) of women without a recent suspicious cytological smear tested HPV positive. The prevalences of high-risk HPV strains were 71% (95% CI, 59 to 83) and 32% (95% CI, 22 to 41), respectively, for these two groups. The agreement for hr-HPV between the two sampling methods for women with and without suspicious cytology was 84% (kappa = 0.65; 95% CI, 0.44 to 0.86) and 91% (kappa = 0.78; 95% CI, 0.64 to 0.92), respectively. Participants rated the user friendliness of the self-sampling method on a visual analog scale from 0 (easy) to 100 (difficult) with a median of 12. In conclusion, self-sampling by cervicovaginal lavage is a reliable method to determine hr-HPV prevalence and is well accepted by young adult females. PMID- 21813723 TI - Novel sensitive real-time PCR for quantification of bacterial 16S rRNA genes in plasma of HIV-infected patients as a marker for microbial translocation. AB - We developed a real-time PCR to quantify 16S rRNA gene levels in plasma from HIV infected patients as a marker of microbial translocation. The assay uses shrimp nuclease (SNuc) to eliminate DNA contamination, giving high sensitivity and low variability. The 16S rRNA gene levels measured in plasma from HIV patients correlated significantly with lipopolysaccharide levels. PMID- 21813724 TI - Pythium aphanidermatum infection following combat trauma. AB - Pythium aphanidermatum is a fungus-like plant pathogen which has never been reported as a cause of human infection. We report a case of P. aphanidermatum invasive wound infection in a 21-year-old male injured during combat operations in Afghanistan. PMID- 21813725 TI - Evaluation of a novel multiplex human papillomavirus (HPV) genotyping assay for HPV types in skin warts. AB - Human papillomaviruses (HPV) of the genera alpha, mu, and nu induce benign tumors of the cutaneous epithelia that constitute a significant burden for immunocompromised adults. Currently, no gold standard for genotyping of these HPV types exists. In this study, we describe the prevalence of genus alpha, mu, and nu HPV types in cutaneous warts. We developed a novel multiplex HPV genotyping assay, BSwart-PCR/MPG (BSwart), to type sensitively and specifically 19 cutaneous HPV types frequently found in warts. BSwart-PCR/MPG is based on a multiplex PCR using broad-spectrum primers and subsequent multiplex hybridization to type specific probes coupled to Luminex beads. In a first application comprising 100 cutaneous warts, the assay was compared to another, recently described genotyping assay, the HSL-PCR/MPG. When a 10-fold dilution series was used, the detection limit was between 10 and 100 HPV genomes per PCR. When comparing the two assays, there was an excellent agreement in detecting dominant HPV types; however, we also obtained evidence for a higher sensitivity of the BSwart assay for multiple infections in these cutaneous warts. Using BSwart, HPV was found in 95% of wart preparations, with HPV1 being most prevalent, followed by types 27, 57, and 2. Both novel BSwart and HSL-PCR/MPG HPV genotyping assays are powerful high throughput tools that could be used to learn more about the natural history of cutaneous HPV. They would be advantageous to monitor the efficacy of future skin HPV vaccines and to identify novel HPV vaccine candidates. PMID- 21813726 TI - Alaska sentinel surveillance study of Helicobacter pylori isolates from Alaska Native persons from 2000 to 2008. AB - Helicobacter pylori infection is more common in Alaska Native persons than in the general U.S. population, with seroprevalence to H. pylori approaching 75%. Previous studies in Alaska have demonstrated elevated proportions of antimicrobial resistance among H. pylori isolates. We analyzed H. pylori data from the Centers for Disease Control and Prevention's sentinel surveillance in Alaska from January 2000 to December 2008 to determine the proportion of culture positive biopsy specimens with antimicrobial resistance from Alaska Native persons undergoing endoscopy. The aim of the present study was to monitor antimicrobial resistance of H. pylori isolates over time and by region in Alaska Native persons. Susceptibility testing of H. pylori isolates to metronidazole, clarithromycin, amoxicillin, and tetracycline was performed using agar dilution. Susceptibility testing for levofloxacin was performed by Etest. Overall, 45% (532/1,181) of persons undergoing upper endoscopy were culture positive for H. pylori. Metronidazole resistance was demonstrated in isolates from 222/531 (42%) persons, clarithromycin resistance in 159/531 (30%) persons, amoxicillin resistance in 10/531 (2%) persons, and levofloxacin resistance in 30/155 (19%) persons; no tetracycline resistance was documented. The prevalence of metronidazole, clarithromycin, and levofloxacin resistance varied by region. Female patients were more likely than male patients to demonstrate metronidazole (P < 0.05) and clarithromycin (P < 0.05) resistance. No substantial change in the proportion of persons with resistant isolates was observed over time. Resistance to metronidazole, clarithromycin, and levofloxacin is more common among H. pylori isolates from Alaska Native persons than those from elsewhere in the United States. PMID- 21813727 TI - Patient-rated importance and receipt of information for colorectal cancer screening. AB - BACKGROUND: Physician recommendation is one of the most important determinants of obtaining colorectal cancer (CRC) screening; however, little is known about the degree to which CRC screening discussions include information that patients report as important to guide screening decisions. This study examines and compares both patient rated importance and physician communication of key information elements about CRC screening during annual physical examinations. METHODS: DESIGN: Cross-sectional cohort. SETTING: 26 ambulatory clinics of an integrated delivery system in the Midwest. PARTICIPANTS: 64 primary care physicians and 415 patients aged 50 to 80 due for CRC screening. Patients completed a previsit survey to assess importance of specific information when making a preventive screening decision. Visits were audio recorded to assess the content of screening discussions. RESULTS: Most patients rated test accuracy (85%), testing alternatives (83%), the pros and cons of testing (86%), and the testing process (78%) very important when making preventive screening decisions. Ninety-one percent of visits included a CRC screening discussion; however, CRC screening talk rarely included information that patients rated as important. Physicians infrequently asked whether patients had questions pertaining to CRC screening (5%); however, 49% of patients asked a CRC screening question, with the vast majority pertaining to screening logistics. CONCLUSIONS: Audio recordings confirm that discussions of CRC screening are often lacking information that patients indicate is very important when making preventive health decisions and patient questions during the visit are not eliciting information to fill the gap. IMPACT: These findings provide actionable information to improve CRC screening discussions. PMID- 21813728 TI - Predictors of breast density change after hormone therapy cessation: results from a randomized trial. AB - BACKGROUND: Postmenopausal hormone therapy cessation is associated with a decrease in mammographic density (MD), but it is unknown whether this effect is modified by woman-level characteristics. We investigated whether we could identify characteristics of women who were most likely to experience a decrease in MD due to hormone therapy cessation. METHODS: Postmenopausal hormone therapy users with a prior screening mammogram (n = 1,168) were randomized to continue hormone therapy or to suspend hormone therapy for 1 month or 2 months before their next screening mammogram. We estimated relative risks (RR) and attributable risks with 95% CIs of a >=7.5% decrease in percentage MD (%MD) versus no change associated with hormone therapy cessation, stratified by age, body mass index (BMI), parity, and other factors. RESULTS: Hormone therapy cessation increased a woman's likelihood of experiencing a >=7.5% decrease in %MD by 30% (95% CI = 1.03 1.7), but we found little evidence of effect modification by age, race, BMI, change in BMI, baseline %MD, parity, family history of breast cancer, hormone therapy type, or duration of hormone therapy use. CONCLUSIONS: Woman-level factors do not appear to explain why some women experience a decrease in %MD following hormone therapy cessation and others do not. IMPACT: We were unable to identify subgroups of women who are more likely to experience a decrease in MD due to hormone therapy cessation; other factors, such as genetic factors, may be important determinants of hormone therapy-related changes in MD. PMID- 21813729 TI - The impact of ovulation on fallopian tube epithelial cells: evaluating three hypotheses connecting ovulation and serous ovarian cancer. AB - Ovarian cancer is the most lethal gynecological malignancy affecting American women. Current hypotheses concerning the etiology of ovarian cancer propose that a reduction in the lifetime number of ovulations decreases ovarian cancer risk. Advanced serous carcinoma shares several biomarkers with fallopian tube epithelial cells, suggesting that some forms of ovarian carcinoma may originate in the fallopian tube. Currently, the impact of ovulation on the tubal epithelium is unknown. In CD1 mice, ovulation did not increase tubal epithelial cell (TEC) proliferation as measured by bromodeoxyuridine incorporation and proliferating cell nuclear antigen staining as compared to unstimulated animals. In superovulated mice, an increase in the number of pro-inflammatory macrophages was detected in the oviduct. Ovulation also increased levels of phospho-gammaH2A.X in TEC, indicating that these cells were susceptible to double-strand DNA breakage following ovulation. To determine which components of ovulation contributed to DNA damage in the fallopian tube, an immortalized baboon TEC cell line and a three-dimensional organ culture system for mouse oviduct and baboon fallopian tubes were developed. TEC did not proliferate or display increased DNA damage in response to the gonadotropins or estradiol alone in vitro. Oxidative stress generated by treatment with hydrogen peroxide or macrophage-conditioned medium increased DNA damage in TEC in culture. Ovulation may impact the fallopian tube epithelium by generating DNA damage and stimulating macrophage infiltration but does not increase proliferation through gonadotropin signaling. PMID- 21813730 TI - Inhibition of gap junction transfer sensitizes thyroid cancer cells to anoikis. AB - Resistance to anoikis (matrix deprivation-induced apoptosis) is a critical component of the metastatic cascade. Molecular mechanisms underlying resistance to anoikis have not been reported in thyroid cancer cells. For an in vitro model of anoikis, we cultured follicular, papillary, and anaplastic thyroid cancer cell lines on poly-HEMA-treated low-adherent plates. We also performed immunohistochemical analysis of human cancer cells that had infiltrated blood and/or lymphatic vessels. Matrix deprivation was associated with establishment of contacts between floating thyroid cancer cells and formation of multi-cellular spheroids. This process was associated with activation of gap junctional transfer. Increased expression of the gap junction molecule Connexin43 was found in papillary and anaplastic cancer cells forming spheroids. All non-adherent cancer cells showed a lower proliferation rate compared with adherent cells but were more resistant to serum deprivation. AKT was constitutively activated in cancer cells forming spheroids. Inhibition of gap junctional transfer through Connexin43 silencing, or by treatment with the gap junction disruptor carbenoxolone, resulted in loss of pAKT and induction of apoptosis in a cell-type specific manner. In human thyroid tissue, cancer cells that had infiltrated blood vessels showed morphological similarity to cancer cells forming spheroids in vitro. Intra-vascular cancer cells demonstrated prominent AKT activation in papillary and follicular cancers. Increased Connexin43 immunoreactivity was observed only in intra-vascular papillary cancer cells. Our data demonstrate that establishment of inter-cellular communication contributes to thyroid cancer cell resistance to anoikis. These findings suggest that disruption of gap junctional transfer could represent a potential therapeutic strategy for prevention of metastases. PMID- 21813731 TI - Insulin therapy for management of type 2 diabetes mellitus: strategies for initiation and long-term patient adherence. AB - Effective glycemic control is essential to minimize the long-term complications of type 2 diabetes mellitus (T2DM). However, it is well documented that many patients spend prolonged periods outside of the optimal glycemic range. The use of insulin is important to effectively control the disease process in patients with T2DM. Even so, resistance to insulin use among patients and healthcare providers often limits initiation and intensification of insulin therapy. With the increasing prevalence of T2DM across all socioeconomic strata, an expanded viewpoint of early and sustained insulin use is crucial to enhance glycemic control in patients. To manage the effects of T2DM on cardiovascular disease in the aging population, physicians can promote insulin therapy as an affordable and effective treatment option. The author reviews beliefs and myths about the use of insulin in the management of T2DM and discusses strategies to overcome barriers to initiation of insulin therapy in the primary care setting. PMID- 21813732 TI - Assessing cardiovascular risk factors and selecting agents to successfully treat patients with type 2 diabetes mellitus. AB - Type 2 diabetes mellitus (T2DM), obesity, and cardiovascular disease (CVD) share a common pathogenic mechanism. The prevalence of each of these conditions is increasing at an alarming rate. Despite the availability of several treatment options for patients with T2DM and the use of intensive regimens combining several antidiabetic drugs, less than half of all patients reach a target glycosylated hemoglobin level of less than 7%. Given the rapid increase in the number of patients with T2DM and obesity, as well as the CVD morbidity and mortality associated with this burden, efforts must be made to change the course of disease. The author reviews clinical trial data on the effect of glucose control on CVD risk, the selection and timing of antihyperglycemic agents, the management of associated CVD risk factors, and strategies to improve patient adherence and acceptance-with the goal of assisting physicians in selecting appropriate management strategies for their patients with T2DM. PMID- 21813733 TI - Novel incretin-based agents and practical regimens to meet needs and treatment goals of patients with type 2 diabetes mellitus. AB - As knowledge of pathophysiologic mechanisms of diabetes mellitus has increased, clinical attention has shifted to the incretin system. Incretin hormones, including glucagon-like peptide-1, or GLP-1, and glucose-dependent insulinotropic polypeptide, are vital to the control of glucose homeostasis and pancreatic beta cell preservation. Novel strategies for the treatment of patients with type 2 diabetes mellitus (T2DM) engage the incretin system. Glucagon-like peptide-1 receptor agonists provide robust glycemic control as well as beneficial reductions in body weight. Dipeptidyl peptidase-4, or DPP-4, inhibitors exhibit beneficial glycemic effects and are weight-neutral. Incretin-based medications are becoming increasingly recognized in guidelines as early treatment options because of their efficacy and well-tolerated profiles. The author reviews the safety and efficacy of currently approved incretin-based agents, as well as the role of these medications in treatment paradigms for patients with T2DM. He also discusses investigational incretin-based agents. PMID- 21813734 TI - Syndecan-2 is a novel ligand for the protein tyrosine phosphatase receptor CD148. AB - Syndecan-2 is a heparan sulfate proteoglycan that has a cell adhesion regulatory domain contained within its extracellular core protein. Cell adhesion to the syndecan-2 extracellular domain (S2ED) is beta1 integrin dependent; however, syndecan-2 is not an integrin ligand. Here the protein tyrosine phosphatase receptor CD148 is shown to be a key intermediary in cell adhesion to S2ED, with downstream beta1 integrin-mediated adhesion and cytoskeletal organization. We show that S2ED is a novel ligand for CD148 and identify the region proximal to the transmembrane domain of syndecan-2 as the site of interaction with CD148. A mechanism for the transduction of the signal from CD148 to beta1 integrins is elucidated requiring Src kinase and potential implication of the C2beta isoform of phosphatidylinositol 3 kinase. Our data uncover a novel pathway for beta1 integrin-mediated adhesion of importance in cellular processes such as angiogenesis and inflammation. PMID- 21813735 TI - Trs65p, a subunit of the Ypt1p GEF TRAPPII, interacts with the Arf1p exchange factor Gea2p to facilitate COPI-mediated vesicle traffic. AB - The TRAPP complexes are multimeric guanine exchange factors (GEFs) for the Rab GTPase Ypt1p. The three complexes (TRAPPI, TRAPPII, and TRAPPIII) share a core of common subunits required for GEF activity, as well as unique subunits (Trs130p, Trs120p, Trs85p, and Trs65p) that redirect the GEF from the endoplasmic reticulum Golgi pathway to different cellular locations where TRAPP mediates distinct membrane trafficking events. Roles for three of the four unique TRAPP subunits have been described before; however, the role of the TRAPPII-specific subunit Trs65p has remained elusive. Here we demonstrate that Trs65p directly binds to the C-terminus of the Arf1p exchange factor Gea2p and provide in vivo evidence that this interaction is physiologically relevant. Gea2p and TRAPPII also bind to the yeast orthologue of the gamma subunit of the COPI coat complex (Sec21p), a known Arf1p effector. These and previous findings reveal that TRAPPII is part of an Arf1p GEF-effector loop that appears to play a role in recruiting or stabilizing TRAPPII to membranes. In support of this proposal, we show that TRAPPII is more soluble in an arf1Delta mutant. PMID- 21813736 TI - Role of malectin in Glc(2)Man(9)GlcNAc(2)-dependent quality control of alpha1 antitrypsin. AB - Malectin was first discovered as a novel endoplasmic reticulum (ER)-resident lectin from Xenopus laevis that exhibits structural similarity to bacterial glycosylhydrolases. Like other intracellular lectins involved in glycoprotein quality control, malectin is highly conserved in animals. Here results from in vitro membrane-based binding assays and frontal affinity chromatography confirm that human malectin binds specifically to Glc(2)Man(9)GlcNAc(2) (G2M9) N-glycan, with a K(a) of 1.97 * 10(5) M(-1), whereas binding to Glc(1)Man(9)GlcNAc(2) (G1M9), Glc(3)Man(9)GlcNAc(2) (G3M9), and other N-glycans is barely detectable. Metabolic labeling and immunoprecipitation experiments demonstrate that before entering the calnexin cycle, the folding-defective human alpha1-antitrypsin variant null Hong Kong (AT(NHK)) stably associates with malectin, whereas wild type alpha1-antitrypsin (AT) or N-glycan-truncated variant of AT(NHK) (AT(NHK) Q3) dose not. Moreover, malectin overexpression dramatically inhibits the secretion of AT(NHK) through a mechanism that involves enhanced ER-associated protein degradation; by comparison, the secretion of AT and AT(NHK)-Q3 is only slightly affected by malectin overexpression. ER-stress induced by tunicamycin results in significantly elevated mRNA transcription of malectin. These observations suggest a possible role of malectin in regulating newly synthesized glycoproteins via G2M9 recognition. PMID- 21813738 TI - Metallofullerene-based nanoplatform for brain tumor brachytherapy and longitudinal imaging in a murine orthotopic xenograft model. AB - PURPOSE: To demonstrate in an orthotopic xenograft brain tumor model that a functionalized metallofullerene (f-Gd3N@C80) can enable longitudinal tumor imaging and, when radiolabeled with lutetium 177 (177Lu) and tetraazacyclododecane tetraacetic acid (DOTA) (177Lu-DOTA-f-Gd3N@C80), provide an anchor to deliver effective brachytherapy. MATERIALS AND METHODS: All experiments involving the use of mice were carried out in accordance with protocols approved by the institutional animal care and use committee. Human glioblastoma U87MG cells were implanted by using stereotactic procedures into the brains of 37 female athymic nude-Foxn1nu mice and allowed to develop into a tumor for 8 days. T1- and T2-weighted magnetic resonance (MR) imaging was performed in five mice. Biodistribution studies were performed in 12 mice at four time points over 7 days to evaluate gadolinium content. Survival studies involved 20 mice that received infusion of a nanoplatform by means of convection-enhanced delivery (CED) 8 days after tumor implantation. Mice in survival studies were divided into two groups: one comprised untreated mice that received f-Gd3N@CC80 alone and the other comprised mice treated with brachytherapy that received 1.11 MBq of 177Lu-DOTA-f Gd3N@CC80. Survival data were evaluated by using Kaplan-Meier statistical methods. RESULTS: MR imaging showed extended tumor retention (25.6% +/- 1.2 of the infused dose at 52 days, confirmed with biodistribution studies) of the f Gd3N@CC80 nanoplatform, which enabled longitudinal imaging. Successful coupling of 177Lu to the f-Gd3N@CC80 surface was achieved by using a bifunctional macrocyclic chelator. The extended tumor retention allowed for effective brachytherapy, as indicated by extended survival time (> 2.5 times that of the untreated group) and histologic signs of radiation-induced tumor damage. CONCLUSION: The authors have developed a multimodal nanoplatform and have demonstrated longitudinal tumor imaging, prolonged intratumoral probe retention, biodistribution, and extended survival in an orthotopic xenograft brain tumor model. PMID- 21813737 TI - Heat shock factor 2 is required for maintaining proteostasis against febrile range thermal stress and polyglutamine aggregation. AB - Heat shock response is characterized by the induction of heat shock proteins (HSPs), which facilitate protein folding, and non-HSP proteins with diverse functions, including protein degradation, and is regulated by heat shock factors (HSFs). HSF1 is a master regulator of HSP expression during heat shock in mammals, as is HSF3 in avians. HSF2 plays roles in development of the brain and reproductive organs. However, the fundamental roles of HSF2 in vertebrate cells have not been identified. Here we find that vertebrate HSF2 is activated during heat shock in the physiological range. HSF2 deficiency reduces threshold for chicken HSF3 or mouse HSF1 activation, resulting in increased HSP expression during mild heat shock. HSF2-null cells are more sensitive to sustained mild heat shock than wild-type cells, associated with the accumulation of ubiquitylated misfolded proteins. Furthermore, loss of HSF2 function increases the accumulation of aggregated polyglutamine protein and shortens the lifespan of R6/2 Huntington's disease mice, partly through alphaB-crystallin expression. These results identify HSF2 as a major regulator of proteostasis capacity against febrile-range thermal stress and suggest that HSF2 could be a promising therapeutic target for protein-misfolding diseases. PMID- 21813739 TI - Noninvasive assessment of transstenotic pressure gradients in porcine renal artery stenoses by using vastly undersampled phase-contrast MR angiography. AB - PURPOSE: To compare noninvasive transstenotic pressure gradient (TSPG) measurements derived from high-spatial- and temporal-resolution four-dimensional magnetic resonance (MR) flow measurements with invasive measurements obtained from endovascular pressure wires with digital subtraction angiographic guidance. MATERIALS AND METHODS: After Animal Care and Use Committee approval, bilateral renal artery stenosis (RAS) was created surgically in 12 swine. Respiratory-gated phase-contrast vastly undersampled isotropic projection (VIPR) MR angiography of the renal arteries was performed with a 1.5-T clinical MR system (repetition time, 11.4 msec; echo time [first echo], 3.7 msec; 18,000 projection angles; imaging volume, 260 * 260 * 200 mm; acquired isotropic spatial resolution, 1.0 * 1.0 * 1.0 mm; velocity encoding, 150 cm/sec). Velocities measured with phase contrast VIPR were used to calculate TSPGs by using Navier-Stokes equations. These were compared with endovascular pressure measurements (mean and peak) performed by using fluoroscopic guidance with regression analysis. RESULTS: In 19 renal arteries with an average stenosis of 62% (range, 0%-87%), there was excellent correlation between the noninvasive TSPG measurement with phase contrast VIPR and invasive TSPG measurement for mean TSPG (R2 = 95.4%) and strong correlation between noninvasive TSPG and invasive TSPG for the peak TSPG measures (R2 = 82.6%). The phase-contrast VIPR-derived TSPG measures were slightly lower than the endovascular measurements. In four arteries with severe stenoses and one occlusion (mean, 86%; range, 75%-100%), the residual lumen within the stenosis was too small to determine TSPG with phase-contrast VIPR. CONCLUSION: The unenhanced MR angiographic technique with phase-contrast VIPR allows for accurate noninvasive assessment of hemodynamic significance in a porcine model of RAS with highly accurate TSPG measurements. PMID- 21813741 TI - Chronic obstructive pulmonary disease: quantification of bronchodilator effects by using hyperpolarized 3He MR imaging. AB - PURPOSE: To evaluate short-acting bronchodilator effects in chronic obstructive pulmonary disease (COPD) by using hyperpolarized helium 3 (3He) magnetic resonance (MR) imaging, spirometry, and plethysmography. MATERIALS AND METHODS: Fourteen ex-smokers with COPD provided written informed consent to a local ethics board-approved and Health Insurance and Portability Accountability Act-compliant protocol and underwent hyperpolarized 3He and hydrogen 1 MR imaging, spirometry, and plethysmography before and a mean of 25 minutes +/- 2 (standard deviation) after administration of 400 MUg salbutamol. Distribution of 3He gas was evaluated by using semiautomated segmentation of 3He voxel intensities, where cluster 1 represented regions of signal void or ventilation defect volume (VDV), and clusters 2-5 (C2-C5) represented gradations of signal intensity from hypointensity (C2) to hyperintensity (C5). 3He ventilation defect percentage (VDP) was calculated as VDV normalized to the thoracic cavity volume. Comparisons of pre- and post-salbutamol means were performed by using a two-way mixed-design repeated measures analysis of variance, and comparisons of the magnitude of the treatment effect between pulmonary function and 3He MR imaging measurements were performed by using effect size (ES) calculations. The relationships between pulmonary function and 3He MR imaging findings were determined by using Spearman correlation coefficients. RESULTS: After salbutamol administration, there were significant changes in forced expiratory volume in 1 second (FEV1) (P = .001), total lung capacity (P = .04), and functional residual capacity (P = .03), as well as VDP (P < .0001) and 3He gas distribution (C2, P = .01; C3, P = .03; C4, P < .0001; and C5, P = .02). Treatment ES was greater for 3He VDP than for FEV(1) (0.50 vs 0.22). There was a significant correlation between baseline VDP and post salbutamol FEV1 change (r = -0.77, P = .001). Although five patients were classified as bronchodilator responders and nine patients were classified as bronchodilator nonresponders according to American Thoracic Society and European Respiratory Society criteria, there was no significant difference in the magnitude of the 3He MR imaging changes after salbutamol administration between responder groups. CONCLUSION: 3He MR imaging depicted significant improvements in the distribution of 3He gas after bronchodilator therapy in ex-smokers with COPD with and those without clinically important changes in FEV1. PMID- 21813742 TI - Non-small cell lung cancer: prognostic importance of positive FDG PET findings in the mediastinum for patients with N0-N1 disease at pathologic analysis. AB - PURPOSE: To assess the prognostic implications of mediastinal positron emission tomographic (PET) findings in patients undergoing curative resection of non-small cell lung cancer (NSCLC) who have histologically negative mediastinal lymph nodes (LNs), with the hypothesis that positive findings at PET are prognostic even in patients with negative histologic findings in the LNs. MATERIALS AND METHODS: Records of patients with a preoperative PET undergoing curative surgery, without adjuvant radiation, for pathologic T1-3N0-1 NSCLC at the University of North Carolina between 2000 and 2006 were reviewed as an institutional review board approved HIPAA-compliant retrospective study. Ninety patients were evaluable (all histologically negative in mediastinum; 44 with both mediastinoscopy and surgery); 13 patients had positive mediastinal PET findings, and 77 had negative mediastinal PET findings. Local-regional and distant failure rates in patients with and those without mediastinal abnormalities at preoperative PET were compared by using logistic regression and log-rank tests. RESULTS: Median follow up was 54.3 months (range, 1-99 months). There were higher rates of local regional (P = .001) and distant (P < .001) failure as well as death (P = .001) in patients with postive PET findings than in patients with negative findings. In multivariable analysis (adjusting for other prognostic factors), positive PET findings in the mediastinum remained prognostic for distant failure (P < .001, hazard ratio = 6.9) and were marginally prognostic for local-regional failure (P = .093, hazard ratio = 1.9). CONCLUSION: Positive findings at preoperative PET in the mediastinum appear to have prognostic implications despite the mediastinal LNs being histologically negative. The high rate of local-regional and distant failure suggests that postoperative radiation therapy and/or chemotherapy may be particularly helpful in patients with positive mediastinal findings at preoperative PET. PMID- 21813740 TI - Comparative economic evaluation of data from the ACRIN National CT Colonography Trial with three cancer intervention and surveillance modeling network microsimulations. AB - PURPOSE: To estimate the cost-effectiveness of computed tomographic (CT) colonography for colorectal cancer (CRC) screening in average-risk asymptomatic subjects in the United States aged 50 years. MATERIALS AND METHODS: Enrollees in the American College of Radiology Imaging Network National CT Colonography Trial provided informed consent, and approval was obtained from the institutional review board at each site. CT colonography performance estimates from the trial were incorporated into three Cancer Intervention and Surveillance Modeling Network CRC microsimulations. Simulated survival and lifetime costs for screening 50-year-old subjects in the United States with CT colonography every 5 or 10 years were compared with those for guideline-concordant screening with colonoscopy, flexible sigmoidoscopy plus either sensitive unrehydrated fecal occult blood testing (FOBT) or fecal immunochemical testing (FIT), and no screening. Perfect and reduced screening adherence scenarios were considered. Incremental cost-effectiveness and net health benefits were estimated from the U.S. health care sector perspective, assuming a 3% discount rate. RESULTS: CT colonography at 5- and 10-year screening intervals was more costly and less effective than FOBT plus flexible sigmoidoscopy in all three models in both 100% and 50% adherence scenarios. Colonoscopy also was more costly and less effective than FOBT plus flexible sigmoidoscopy, except in the CRC-SPIN model assuming 100% adherence (incremental cost-effectiveness ratio: $26,300 per life-year gained). CT colonography at 5- and 10-year screening intervals and colonoscopy were net beneficial compared with no screening in all model scenarios. The 5-year screening interval was net beneficial over the 10-year interval except in the MISCAN model when assuming 100% adherence and willingness to pay $50,000 per life year gained. CONCLUSION: All three models predict CT colonography to be more costly and less effective than non-CT colonographic screening but net beneficial compared with no screening given model assumptions. PMID- 21813743 TI - Assessment of response to tyrosine kinase inhibitors in metastatic renal cell cancer: CT texture as a predictive biomarker. AB - PURPOSE: To assess changes in tumor computed tomographic (CT) texture after two cycles of treatment with tyrosine kinase inhibitors (TKIs) and to determine if tumor texture correlates with measured time to progression in patients with metastatic renal cell cancer who received TKIs. MATERIALS AND METHODS: A waiver of institutional review board approval was obtained for this retrospective analysis. Contrast material-enhanced CT texture parameters were assessed in 39 patients with metastatic renal cell cancer who received a TKI. A total of 87 metastases were analyzed at baseline and after two treatment cycles. Changes in tumor entropy and uniformity were derived with a software algorithm that selectively filters and extracts texture at different scales (fine to coarse detail: 1.0-2.5) and were recorded. Response assessment was also obtained by using response evaluation criteria in solid tumors (RECIST), as well as Choi and modified Choi criteria. The correlation of texture parameters and standard criteria with measured time to progression was assessed by using Kaplan-Meier analysis and a Cox regression model. Statistical significance was set at 5%. RESULTS: Tumor entropy decreased by 3%-45% and uniformity increased by 5%-21% for the different scale values after administration of a TKI. With a threshold change of -2% or less for uniformity at a coarse scale value of 2.5, Kaplan-Meier curves of the proportion of patients without disease progression were significantly different and better than those for standard response assessment (P = .008 vs P = .267, P = .053, and P = .042 for RECIST, Choi, and modified Choi criteria, respectively). Cox regression analysis showed that texture uniformity was an independent predictor of time to progression (odds ratio, 4.02; 95% confidence interval: 1.52, 10.65; P = .005). CONCLUSION: CT texture analysis reflecting tumor heterogeneity is an independent factor associated with time to progression and has potential as a predictive imaging biomarker of response of metastatic renal cancer to targeted therapy. PMID- 21813744 TI - Neuronal integration and the depolarizing effects of axonal GABA(A) receptors. AB - Despite their presence throughout the central nervous system, the impact of axonally expressed gamma-amino-butyric acid type-A receptors (GABA(A)Rs) on neuronal signaling is just beginning to be understood. A recently published article (Pugh JR and Jahr CE, J Neurosci 31: 565-574, 2011) tackled this important issue by investigating GABA(A)R-mediated function in axons of cerebellar granule cells. The results of Pugh and Jahr indicate parallel fiber GABA(A)Rs enhance neurotransmitter release probability and boost axonal and somatic excitability. PMID- 21813745 TI - Developmental switch in the polarity of experience-dependent synaptic changes in layer 6 of mouse visual cortex. AB - Layer 6 (L6) of primary sensory cortices is distinct from other layers in that it provides a major cortical input to primary sensory thalamic nuclei. L6 pyramidal neurons in the primary visual cortex (V1) send projections to the lateral geniculate nucleus (LGN), as well as to the thalamic reticular nucleus and higher order thalamic nuclei. Although L6 neurons are proposed to modulate the activity of thalamic relay neurons, how sensory experience regulates L6 neurons is largely unknown. Several days of visual deprivation homeostatically adjusts excitatory synapses in L4 and L2/3 of V1 depending on the developmental age. For instance, L4 exhibits an early critical period during which visual deprivation homeostatically scales up excitatory synaptic transmission. On the other hand, homeostatic changes in L2/3 excitatory synapses are delayed and persist into adulthood. In the present study we examined how visual deprivation affects excitatory synapses on L6 pyramidal neurons. We found that L6 pyramidal neurons homeostatically increase the strength of excitatory synapses following 2 days of dark exposure (DE), which was readily reversed by 1 day of light exposure. This effect was restricted to an early critical period, similar to that reported for L4 neurons. However, at a later developmental age, a longer duration of DE (1 wk) decreased the strength of excitatory synapses, which reversed to normal levels with light exposure. These changes are opposite to what is predicted from the homeostatic plasticity theory. Our results suggest that L6 neurons differentially adjust their excitatory synaptic strength to visual deprivation depending on the age of the animals. PMID- 21813746 TI - Rhythmic movements are larger and faster but with the same frequency on removal of visual feedback. AB - The brain controls rhythmic movement through neural circuits combining visual information with proprioceptive information from the limbs. Although rhythmic movements are fundamental to everyday activities the specific details of the responsible control mechanisms remain elusive. We tested 39 young adults who performed flexion/extension movements of the forearm. We provided them with explicit knowledge of the amplitude and the speed of their movements, whereas frequency information was only implicitly available. In a series of 3 experiments, we demonstrate a tighter control of frequency compared with amplitude or speed. We found that in the absence of visual feedback, movements had larger amplitude and higher peak speed while maintaining the same frequency as when visual feedback was available; this was the case even when participants were aware of performing overly large and fast movements. Finally, when participants were asked to modulate continuously movement frequency, but not amplitude, we found the local coefficient of variability of movement frequency to be lower than that of amplitude. We suggest that a misperception of the generated amplitude in the absence of visual feedback, coupled with a highly accurate perception of generated frequency, leads to the performance of larger and faster movements with the same frequency when visual feedback is not available. Relatively low local coefficient of variability of frequency in a task that calls for continuous change in movement frequency suggests that we tend to operate at a constant frequency at the expense of variation in amplitude and peak speed. PMID- 21813748 TI - Effects of dopamine depletion on information flow between the subthalamic nucleus and external globus pallidus. AB - Abnormal oscillatory synchrony is increasingly acknowledged as a pathophysiological hallmark of Parkinson's disease, but what promotes such activity remains unclear. We used novel, nonlinear time series analyses and information theory to capture the effects of dopamine depletion on directed information flow within and between the subthalamic nucleus (STN) and external globus pallidus (GPe). We compared neuronal activity recorded simultaneously from these nuclei in 6-hydroxydopamine-lesioned Parkinsonian rats with that in dopamine-intact control rats. After lesioning, both nuclei displayed pronounced augmentations of beta-frequency (~20 Hz) oscillations and, critically, information transfer between STN and GPe neurons was increased. Furthermore, temporal profiles of the directed information transfer agreed with the neurochemistry of these nuclei, being "excitatory" from STN to GPe and "inhibitory" from GPe to STN. Separation of the GPe population in lesioned animals into "type-inactive" (GP-TI) and "type-active" (GP-TA) neurons, according to definitive firing preferences, revealed distinct temporal profiles of interaction with STN and each other. The profile of GP-TI neurons suggested their output is of greater causal significance than that of GP-TA neurons for the reduced activity that periodically punctuates the spiking of STN neurons during beta oscillations. Moreover, STN was identified as a key candidate driver for recruiting ensembles of GP-TI neurons but not GP-TA neurons. Short-latency interactions between GP-TI and GP-TA neurons suggested mutual inhibition, which could rhythmically dampen activity and promote anti-phase firing across the two subpopulations. Results thus indicate that information flow around the STN-GPe circuit is exaggerated in Parkinsonism and further define the temporal interactions underpinning this. PMID- 21813747 TI - Serotonin regulates voltage-dependent currents in type I(e(A)) and I(i) interneurons of Hermissenda. AB - Serotonin (5-HT) has both direct and modulatory actions on central neurons contributing to behavioral arousal and cellular-synaptic plasticity in diverse species. In Hermissenda, 5-HT produces changes in intrinsic excitability of different types of identified interneurons in the circumesophageal nervous system. Using whole cell patch-clamp techniques we have examined membrane conductance changes produced by 5-HT that contribute to intrinsic excitability in two identified classes of interneurons, types I(i) and I(eA). Whole cell currents were examined before and after 5-HT application to the isolated nervous system. A 4-aminopyridine-sensitive transient outward K(+) current [I(K(A))], a tetraethylammonium-sensitive delayed rectifier K(+) current [I(K(V))], an inward rectifier K(+) current [I(K(IR))], and a hyperpolarization-activated current (I(h)) were characterized. 5-HT decreased the amplitude of I(K(A)) and I(K(V)) in both type I(i) and I(eA) interneurons. However, differences in 5-HT's effects on the activation-inactivation kinetics were observed in different types of interneurons. 5-HT produced a depolarizing shift in the activation curve of I(K(V)) and a hyperpolarizing shift in the inactivation curve of I(K(A)) in type I(i) interneurons. In contrast, 5-HT produced a depolarizing shift in the activation curve and a hyperpolarizing shift in the inactivation curve of both I(K(V)) and I(K(A)) in type I(eA) interneurons. In addition, 5-HT decreased the amplitude of I(K(IR)) in type I(i) interneurons and increased the amplitude of I(h) in type I(eA) interneurons. These results indicate that 5-HT-dependent changes in I(K(A)), I(K(V)), I(K(IR)), and I(h) contribute to multiple mechanisms that synergistically support modulation of increased intrinsic excitability associated with different functional classes of identified type I interneurons. PMID- 21813749 TI - FM velocity selectivity in the inferior colliculus is inherited from velocity selective inputs and enhanced by spike threshold. AB - Frequency modulation (FM) is computed from the temporal sequence of activated auditory nerve fibers representing different frequencies. Most studies in the inferior colliculus (IC) have inferred from extracellular recordings that the precise timing of nonselective inputs creates selectivity for FM direction and velocity (Andoni S, Li N, Pollak GD. J Neurosci 27: 4882-4893, 2007; Fuzessery ZM, Richardson MD, Coburn MS. J Neurophysiol 96: 1320-1336, 2006; Gordon M, O'Neill WE. Hear Res 122: 97-108, 1998). We recently reported that two additional mechanisms were more important than input timing for directional selectivity in some IC cells: spike threshold and inputs that were already selective (Gittelman JX, Li N, Pollak GD. J Neurosci 29: 13030-13041, 2009). Here, we show that these same mechanisms, selective inputs and spike threshold, underlie selectivity for FM velocity and intensity. From whole cell recordings in awake bats, we recorded spikes and postsynaptic potentials (PSPs) evoked by downward and upward FMs that swept identical frequencies at different velocities and intensities. To determine the synaptic mechanisms underlying PSP selectivity (relative PSP height), we derived sweep-evoked synaptic conductances. Changing FM velocity or intensity changed conductance timing and size. Modeling indicated that excitatory conductance size contributed more to PSP selectivity than conductance timing, indicating that the number of afferent spikes carried more FM information to the IC than precise spike timing. However, excitation alone produced mostly suprathreshold PSPs. Inhibition reduced absolute PSP heights, without necessarily altering PSP selectivity, thereby rendering some PSPs subthreshold. Spike threshold then sharpened selectivity in the spikes by rectifying the smaller PSPs. This indicates the importance of spike threshold, and that inhibition enhances selectivity via a different mechanism than previously proposed. PMID- 21813751 TI - Defining success for translational research organizations. AB - Translational research organizations (TROs) seek to enhance the clinical impact of scientific discoveries and play a multifaceted role characterized by multidisciplinary collaboration, outreach initiatives, and the provision of shared resources and facilities. Given this complexity, TROs require a flexible framework for performance assessment that tracks their progress, incentivizes fruitful activities, and aligns individuals throughout the organization. We suggest a framework that assesses TRO performance along seven main dimensions funding, talent, creation, validation, dissemination, external uptake, and collaboration-and we encourage individual organizations to develop additional metrics as needed. PMID- 21813750 TI - The roles of conserved and nonconserved cysteinyl residues in the oligomerization and function of mammalian prestin. AB - The creation of several prestin knockout and knockin mouse lines has demonstrated the importance of the intrinsic outer hair cell membrane protein prestin to mammalian hearing. However, the structure of prestin remains largely unknown, with even its major features in dispute. Several studies have suggested that prestin forms homo-oligomers that may be stabilized by disulfide bonds. Our phylogenetic analysis of prestin sequences across chordate classes suggested that the cysteinyl residues could be divided into three groups, depending on the extent of their conservation between prestin orthologs and paralogs or homologs. An alanine scan functional analysis was performed of all nine cysteinyl positions in mammalian prestin. Prestin function was assayed by measurement of prestin associated nonlinear capacitance. Of the nine cysteine-alanine substitution mutations, all were properly membrane targeted and all demonstrated nonlinear capacitance. Four mutations (C124A, C192A, C260A, and C415A), all in nonconserved cysteinyl residues, significantly differed in their nonlinear capacitance properties compared with wild-type prestin. In the two most severely disrupted mutations, substitution of the polar residue seryl for cysteinyl restored normal function in one (C415S) but not the other (C124S). We assessed the relationship of prestin oligomerization to cysteine position using fluorescence resonance energy transfer. With one exception, cysteine-alanine substitutions did not significantly alter prestin-prestin interactions. The exception was C415A, one of the two nonconserved cysteinyl residues whose mutation to alanine caused the most disruption in function. We suggest that no disulfide bond is essential for prestin function. However, C415 likely participates by hydrogen bonding in both nonlinear capacitance and oligomerization. PMID- 21813753 TI - Progress toward development of a hepatitis C vaccine with broad shoulders. AB - Hepatitis C virus (HCV) infection in humans can cause progressive and end-stage liver disease. As such, preventive measures against HCV, including vaccine development, are a priority among researchers in the field. The report from Garrone et al. describes the development of a vaccine platform to generate HCV neutralizing antibodies that are based on retrovirus-derived virus-like particles (VLPs) pseudotyped with heterologous viral envelope proteins. Immunization with these VLPs induced neutralizing antibodies in mouse and macaque models. These results, when considered in the context of an earlier clinical trial that used recombinant HCV E1/E2 purified protein as a subunit vaccine and additional findings from the VLP strategy, may lead to a new HCV vaccine that induces a neutralizing antibody response. PMID- 21813754 TI - Targeting GLUT1 and the Warburg effect in renal cell carcinoma by chemical synthetic lethality. AB - Identifying new targeted therapies that kill tumor cells while sparing normal tissue is a major challenge of cancer research. Using a high-throughput chemical synthetic lethal screen, we sought to identify compounds that exploit the loss of the von Hippel-Lindau (VHL) tumor suppressor gene, which occurs in about 80% of renal cell carcinomas (RCCs). RCCs, like many other cancers, are dependent on aerobic glycolysis for ATP production, a phenomenon known as the Warburg effect. The dependence of RCCs on glycolysis is in part a result of induction of glucose transporter 1 (GLUT1). Here, we report the identification of a class of compounds, the 3-series, exemplified by STF-31, which selectively kills RCCs by specifically targeting glucose uptake through GLUT1 and exploiting the unique dependence of these cells on GLUT1 for survival. Treatment with these agents inhibits the growth of RCCs by binding GLUT1 directly and impeding glucose uptake in vivo without toxicity to normal tissue. Activity of STF-31 in these experimental renal tumors can be monitored by [(18)F]fluorodeoxyglucose uptake by micro-positron emission tomography imaging, and therefore, these agents may be readily tested clinically in human tumors. Our results show that the Warburg effect confers distinct characteristics on tumor cells that can be selectively targeted for therapy. PMID- 21813755 TI - A prime-boost strategy using virus-like particles pseudotyped for HCV proteins triggers broadly neutralizing antibodies in macaques. AB - Chronic hepatitis C virus (HCV) infection, with its cohort of life-threatening complications, affects more than 200 million persons worldwide and has a prevalence of more than 10% in certain countries. Preventive and therapeutic vaccines against HCV are thus much needed. Neutralizing antibodies (NAbs) are the foundation for successful disease prevention for most established vaccines. However, for viruses that cause chronic infection such as HIV or HCV, induction of broad NAbs from recombinant vaccines has remained elusive. We developed a vaccine platform specifically aimed at inducing NAbs based on pseudotyped virus like particles (VLPs) made with retroviral Gag. We report that VLPs pseudotyped with E2 and/or E1 HCV envelope glycoproteins induced high-titer anti-E2 and/or anti-E1 antibodies, as well as NAbs, in both mouse and macaque. The NAbs, which were raised against HCV 1a, cross-neutralized the five other genotypes tested (1b, 2a, 2b, 4, and 5). Thus, the described VLP platform, which can be pseudotyped with a vast array of virus envelope glycoproteins, represents a new approach to viral vaccine development. PMID- 21813756 TI - Urine TMPRSS2:ERG fusion transcript stratifies prostate cancer risk in men with elevated serum PSA. AB - More than 1,000,000 men undergo prostate biopsy each year in the United States, most for "elevated" serum prostate-specific antigen (PSA). Given the lack of specificity and unclear mortality benefit of PSA testing, methods to individualize management of elevated PSA are needed. Greater than 50% of PSA screened prostate cancers harbor fusions between the transmembrane protease, serine 2 (TMPRSS2) and v-ets erythroblastosis virus E26 oncogene homolog (avian) (ERG) genes. Here, we report a clinical-grade, transcription-mediated amplification assay to risk stratify and detect prostate cancer noninvasively in urine. The TMPRSS2:ERG fusion transcript was quantitatively measured in prospectively collected whole urine from 1312 men at multiple centers. Urine TMPRSS2:ERG was associated with indicators of clinically significant cancer at biopsy and prostatectomy, including tumor size, high Gleason score at prostatectomy, and upgrading of Gleason grade at prostatectomy. TMPRSS2:ERG, in combination with urine prostate cancer antigen 3 (PCA3), improved the performance of the multivariate Prostate Cancer Prevention Trial risk calculator in predicting cancer on biopsy. In the biopsy cohorts, men in the highest and lowest of three TMPRSS2:ERG+PCA3 score groups had markedly different rates of cancer, clinically significant cancer by Epstein criteria, and high-grade cancer on biopsy. Our results demonstrate that urine TMPRSS2:ERG, in combination with urine PCA3, enhances the utility of serum PSA for predicting prostate cancer risk and clinically relevant cancer on biopsy. PMID- 21813757 TI - Growth cones as soft and weak force generators. AB - Many biochemical processes in the growth cone finally target its biomechanical properties, such as stiffness and force generation, and thus permit and control growth cone movement. Despite the immense progress in our understanding of biochemical processes regulating neuronal growth, growth cone biomechanics remains poorly understood. Here, we combine different experimental approaches to measure the structural and mechanical properties of a growth cone and to simultaneously determine its actin dynamics and traction force generation. Using fundamental physical relations, we exploited these measurements to determine the internal forces generated by the actin cytoskeleton in the lamellipodium. We found that, at timescales longer than the viscoelastic relaxation time of tau = 8.5 +/- 0.5 sec, growth cones show liquid-like characteristics, whereas at shorter time scales they behaved elastically with a surprisingly low elastic modulus of E = 106 +/- 21 Pa. Considering the growth cone's mechanical properties and retrograde actin flow, we determined the internal stress to be on the order of 30 pN per MUm(2). Traction force measurements confirmed these values. Hence, our results indicate that growth cones are particularly soft and weak structures that may be very sensitive to the mechanical properties of their environment. PMID- 21813758 TI - Experimental evidence for the role of domain swapping in the evolution of the histone fold. AB - The histone fold forms the fundamental endoskeleton of the protein core of the nucleosome and is also found in several transcription factors. We have investigated the evolutionary origins of this ubiquitous protein motif, which is found soluble exclusively as an antiparallel (handshake motif) dimer. We introduced a three amino acid insertion into the middle of a homodimeric archaeal histone fold motif. The engineered molecule was found to be a soluble and stable monomer with properties consistent with a four-helix-bundle protein. The experimental evidence presented here support the hypothesis that the handshake association motif characteristic of present-day histone dimers is the evolutionary product of domain swapping between two four-helix bundle domains, each of which derived from the tandem duplication of a primitive helix-strand helix unit. PMID- 21813759 TI - Structure of the rotor ring modified with N,N'-dicyclohexylcarbodiimide of the Na+-transporting vacuolar ATPase. AB - The prokaryotic V-ATPase of Enterococcus hirae, closely related to the eukaryotic enzymes, provides a unique opportunity to study the ion-translocation mechanism because it transports Na(+), which can be detected by radioisotope (22Na(+)) experiments and X-ray crystallography. In this study, we demonstrated that the binding affinity of the rotor ring (K ring) for 22Na(+) decreased approximately 30-fold by reaction with N,N(')-dicyclohexylcarbodiimide (DCCD), and determined the crystal structures of Na(+)-bound and Na(+)-unbound K rings modified with DCCD at 2.4- and 3.1-A resolutions, respectively. Overall these structures were similar, indicating that there is no global conformational change associated with release of Na(+) from the DCCD-K ring. A conserved glutamate residue (E139) within all 10 ion-binding pockets of the K ring was neutralized by modification with DCCD, and formed an "open" conformation by losing hydrogen bonds with the Y68 and T64 side chains, resulting in low affinity for Na(+). This open conformation is likely to be comparable to that of neutralized E139 forming a salt bridge with the conserved arginine of the stator during the ion translocation process. Based on these findings, we proposed the ion-translocation model that the binding affinity for Na(+) decreases due to the neutralization of E139, thus releasing bound Na(+), and that the structures of Na(+)-bound and Na(+)-unbound DCCD-K rings are corresponding to intermediate states before and after release of Na(+) during rotational catalysis of V-ATPase, respectively. PMID- 21813761 TI - Nonrandom attrition of the naive CD8+ T-cell pool with aging governed by T-cell receptor:pMHC interactions. AB - Immunity against new infections declines in the last quartile of life, as do numbers of naive T cells. Peripheral maintenance of naive T cells over the lifespan is necessary because their production drastically declines by puberty, a result of thymic involution. We report that this maintenance is not random in advanced aging. As numbers and diversity of naive CD8(+) T cells declined with aging, surviving cells underwent faster rates of homeostatic proliferation, were selected for high T-cell receptor:pMHC avidity, and preferentially acquired "memory-like" phenotype. These high-avidity precursors preferentially responded to infection and exhibited strong antimicrobial function. Thus, T-cell receptor avidity for self-pMHC provides a proofreading mechanism to maintain some of the fittest T cells in the otherwise crumbling naive repertoire, providing a degree of compensation for numerical and diversity defects in old T cells. PMID- 21813762 TI - The early history of tumor virology: Rous, RIF, and RAV. AB - One hundred years ago Peyton Rous recovered a virus, now known as the Rous sarcoma virus (RSV), from a chicken sarcoma, which reproduced all aspects of the tumor on injection into closely related chickens. There followed recovery of causal viruses of tumors of different morphology from 4 more of 60 chicken tumors. Subsequent studies in chickens of the biology of the first RSV isolated moved slowly for 45 y until an assay of ectodermal pocks of the chorioallantoic membrane of chicken embryos was introduced. The inadequacies of that assay were resolved with the production of transformed foci in cultures of chicken fibroblasts. There followed a productive period on the dynamics of RSV infection. An avian leukosis virus (ALV) was found in some chicken embryos and named resistance-inducing factor (RIF) because it interferes with RSV. Its epidemiology in chickens is described. Another ALV was found in stocks of RSV and called Rous associated virus (RAV). Cells preinfected with RAV interfere with RSV infection, but RSV does not produce infectious virus unless RAV is added during or after RSV infection. Intracellular RAV provides the infectious coat for the otherwise defective RSV. The coat determines the antigenicity, host range, and maturation rate of RSV. RSV particles carry reverse transcriptase, an enzyme that converts their RNA into DNA and allows integration into the cell's DNA, where it functions as a cellular gene. This was the bridge that joined the biological era to the molecular era. Its relation to oncogenes and human cancer is discussed. PMID- 21813763 TI - In a battle between parental chromosomes, a failure to reload. PMID- 21813764 TI - Speciation in a small space. PMID- 21813767 TI - Where are the spatial relationships in the spatial ontologies? PMID- 21813766 TI - Stress exposure in intrauterine life is associated with shorter telomere length in young adulthood. AB - Leukocyte telomere length (LTL) is a predictor of age-related disease onset and mortality. The association in adults of psychosocial stress or stress biomarkers with LTL suggests telomere biology may represent a possible underlying mechanism linking stress and health outcomes. It is, however, unknown whether stress exposure in intrauterine life can produce variations in LTL, thereby potentially setting up a long-term trajectory for disease susceptibility. We, therefore, as a first step, tested the hypothesis that stress exposure during intrauterine life is associated with shorter telomeres in adult life after accounting for the effects of other factors on LTL. LTL was assessed in 94 healthy young adults. Forty-five subjects were offspring of mothers who had experienced a severe stressor in the index pregnancy (prenatal stress group; PSG), and 49 subjects were offspring of mothers who had a healthy, uneventful index pregnancy (comparison group; CG). Prenatal stress exposure was a significant predictor of subsequent adult telomere length in the offspring (178-bp difference between prenatal stress and CG; d = 0.41 SD units; P < 0.05). The effect was substantially unchanged after adjusting for potential confounders (subject characteristics, birth weight percentile, and early-life and concurrent stress level), and was more pronounced in women (295-bp difference; d = 0.68 SD units; P < 0.01). To the best of our knowledge, this study provides the first evidence in humans of an association between prenatal stress exposure and subsequent shorter telomere length. This observation may help shed light on an important biological pathway underlying the developmental origins of adult health and disease risk. PMID- 21813768 TI - Emergence of fibroblasts with a proinflammatory epigenetically altered phenotype in severe hypoxic pulmonary hypertension. AB - Persistent accumulation of monocytes/macrophages in the pulmonary artery adventitial/perivascular areas of animals and humans with pulmonary hypertension has been documented. The cellular mechanisms contributing to chronic inflammatory responses remain unclear. We hypothesized that perivascular inflammation is perpetuated by activated adventitial fibroblasts, which, through sustained production of proinflammatory cytokines/chemokines and adhesion molecules, induce accumulation, retention, and activation of monocytes/macrophages. We further hypothesized that this proinflammatory phenotype is the result of the abnormal activity of histone-modifying enzymes, specifically, class I histone deacetylases (HDACs). Pulmonary adventitial fibroblasts from chronically hypoxic hypertensive calves (termed PH-Fibs) expressed a constitutive and persistent proinflammatory phenotype defined by high expression of IL-1beta, IL-6, CCL2(MCP-1), CXCL12(SDF 1), CCL5(RANTES), CCR7, CXCR4, GM-CSF, CD40, CD40L, and VCAM-1. The proinflammatory phenotype of PH-Fibs was associated with epigenetic alterations as demonstrated by increased activity of HDACs and the findings that class I HDAC inhibitors markedly decreased cytokine/chemokine mRNA expression levels in these cells. PH-Fibs induced increased adhesion of THP-1 monocytes and produced soluble factors that induced increased migration of THP-1 and murine bone marrow-derived macrophages as well as activated monocytes/macrophages to express proinflammatory cytokines and profibrogenic mediators (TIMP1 and type I collagen) at the transcriptional level. Class I HDAC inhibitors markedly reduced the ability of PH Fibs to induce monocyte migration and proinflammatory activation. The emergence of a distinct adventitial fibroblast population with an epigenetically altered proinflammatory phenotype capable of recruiting, retaining, and activating monocytes/macrophages characterizes pulmonary hypertension-associated vascular remodeling and thus could contribute significantly to chronic inflammatory processes in the pulmonary artery wall. PMID- 21813769 TI - IgG autoantibodies against deposited C3 inhibit macrophage-mediated apoptotic cell engulfment in systemic autoimmunity. AB - Defective clearance of apoptotic cells has been shown in systemic lupus erythematosus (SLE) and is postulated to enhance autoimmune responses by increasing access to intracellular autoantigens. Until now, research has emphasized inherited rather than acquired impairment of apoptotic cell engulfment in the pathogenesis of SLE. In this study, we confirm previous results that efficient removal of apoptotic cells (efferocytosis) is bolstered in the presence of wild-type mouse serum, through the C3 deposition on the apoptotic cell surface. In contrast, sera from three mouse models of SLE, Mer(KD), MRL(lpr), and New Zealand Black/WF1 did not support and in fact actively inhibited apoptotic cell uptake. IgG autoantibodies were responsible for the inhibition, through the blockade of C3 recognition by macrophages. Consistent with this, IgG removal reversed the inhibitory activity within autoimmune serum, and purified autoimmune IgG blocked both the detection of C3 on apoptotic cells and C3-dependent efferocytosis. Sera from SLE patients demonstrated elevated anti-C3b IgG that blocked detection of C3 on apoptotic cells, activity that was not found in healthy controls or patients with rheumatoid arthritis, nor in mice prior to the onset of autoimmunity. We propose that the suppression of apoptotic cell disposal by Abs against deposited C3 may contribute to increasing severity and/or exacerbations in SLE. PMID- 21813771 TI - Misfolded truncated protein tau induces innate immune response via MAPK pathway. AB - Neuroinflammation plays a key role in the pathogenesis of Alzheimer's disease and related tauopathies. We have previously shown that expression of nonmutated human truncated tau (151-391, 4R), derived from sporadic Alzheimer's disease, induced neurofibrillary degeneration accompanied by microglial and astroglial activation in the brain of transgenic rats. The aim of the current study was to determine the molecular mechanism underlying innate immune response induced by misfolded truncated tau. We found that purified recombinant truncated tau induced morphological transformation of microglia from resting into the reactive phenotype. Simultaneously, truncated tau caused the release of NO, proinflammatory cytokines (IL-1beta, IL-6, TNF-alpha), and tissue inhibitor of metalloproteinase-1 from the mixed glial cultures. Notably, when the pure microglial culture was activated with truncated tau, it displayed significantly higher levels of the proinflammatory cytokines, suggesting a key role of microglia in the tau-mediated inflammatory response. Molecular analysis showed that truncated tau increased the mRNA levels of three MAPKs (JNK, ERK1, p38beta) and transcription factors AP-1 and NF-kappaB that ultimately resulted in enhanced mRNA expression of IL-1beta, IL-6, TNF-alpha, and NO. Our results showed for the first time, to our knowledge, that misfolded truncated protein tau is able to induce innate immune response via a MAPK pathway. Consequently, we suggest that misfolded truncated protein tau represents a viable target for immunotherapy of Alzheimer's disease. PMID- 21813770 TI - Notch ligand delta-like 4 blockade alleviates experimental autoimmune encephalomyelitis by promoting regulatory T cell development. AB - Notch signaling pathway plays an important role in T cell differentiation. Delta like ligand (Dll)4, one of five known Notch ligands, has been implicated in regulating Th2 cell differentiation in animal models of human diseases. However, the role of Dll4 in Th1/Th17-mediated autoimmune diseases remains largely unknown. Using an anti-Dll4 blocking mAb, we show that neutralizing Dll4 during the induction phase of experimental autoimmune encephalomyelitis in C57BL/6 mice significantly increased the pool of CD4(+)Foxp3(+) regulatory T cells (Treg) in the periphery and in the CNS, and decreased the severity of clinical disease and CNS inflammation. Dll4 blockade promoted induction of myelin-specific Th2/Treg immune responses and impaired Th1/Th17 responses compared with IgG-treated mice. In vitro, we show that signaling with recombinant Dll4 inhibits the TGF-beta induced Treg development, and inhibits Janus kinase 3-induced STAT5 phosphorylation, a transcription factor known to play a key role in Foxp3 expression and maintenance. Depletion of natural Treg using anti-CD25 Ab reversed the protective effects of anti-Dll4 Ab. These findings outline a novel role for Dll4-Notch signaling in regulating Treg development in EAE, making it an encouraging target for Treg-mediated immunotherapy in autoimmune diseases, such as multiple sclerosis. PMID- 21813773 TI - IFN-induced TPR protein IFIT3 potentiates antiviral signaling by bridging MAVS and TBK1. AB - Intracellular RNA viruses are sensed by receptors retinoic acid-inducible gene I/MDA5, which trigger formation of the mitochondrial antiviral signaling (MAVS) complex on mitochondria. Consequently, this leads to the activation of TNFR associated factor family member-associated NF-kappaB activator-binding kinase 1 (TBK1) and phosphorylation of IFN regulatory factor 3 (IRF3). It remains to be elucidated how MAVS activates TBK1/IRF3. In this study, we report that IFN induced protein with tetratricopeptide repeats 3 (IFIT3) is significantly induced upon RNA virus infection. Ectopic expression or knockdown of IFIT3 could, respectively, enhance or impair IRF3-mediated gene expression. Mechanistically, the tetratrico-peptide repeat motif (E164/E165) of IFIT3 interacts with the N terminus (K38) of TBK1, thus bridging TBK1 to MAVS on the mitochondrion. Disruption of this interaction markedly attenuates the activation of TBK1 and IRF3. Furthermore, host antiviral responses are significantly boosted or crippled in the presence or absence of IFIT3. Collectively, our study characterizes IFIT3 as an important modulator in innate immunity, revealing a new function of the IFIT family proteins (IFN-induced protein with tetratricopeptide repeats). PMID- 21813772 TI - Identification of a novel proinflammatory human skin-homing Vgamma9Vdelta2 T cell subset with a potential role in psoriasis. AB - gammadelta T cells mediate rapid tissue responses in murine skin and participate in cutaneous immune regulation including protection against cancer. The role of human gammadelta cells in cutaneous homeostasis and pathology is characterized poorly. In this study, we show in vivo evidence that human blood contains a distinct subset of proinflammatory cutaneous lymphocyte Ag and CCR6-positive Vgamma9Vdelta2 T cells, which is rapidly recruited into perturbed human skin. Vgamma9Vdelta2 T cells produced an array of proinflammatory mediators including IL-17A and activated keratinocytes in a TNF-alpha- and IFN-gamma-dependent manner. Examination of the common inflammatory skin disease psoriasis revealed a striking reduction of circulating Vgamma9Vdelta2 T cells in psoriasis patients compared with healthy controls and atopic dermatitis patients. Decreased numbers of circulating Vgamma9Vdelta2 T cells normalized after successful treatment with psoriasis-targeted therapy. Taken together with the increased presence of Vgamma9Vdelta2 T cells in psoriatic skin, these data indicate redistribution of Vgamma9Vdelta2 T cells from the blood to the skin compartment in psoriasis. In summary, we report a novel human proinflammatory gammadelta T cell involved in skin immune surveillance with immediate response characteristics and with potential clinical relevance in inflammatory skin disease. PMID- 21813774 TI - TLR6-driven lipid droplets in Mycobacterium leprae-infected Schwann cells: immunoinflammatory platforms associated with bacterial persistence. AB - The mechanisms responsible for nerve injury in leprosy need further elucidation. We recently demonstrated that the foamy phenotype of Mycobacterium leprae infected Schwann cells (SCs) observed in nerves of multibacillary patients results from the capacity of M. leprae to induce and recruit lipid droplets (LDs; also known as lipid bodies) to bacterial-containing phagosomes. In this study, we analyzed the parameters that govern LD biogenesis by M. leprae in SCs and how this contributes to the innate immune response elicited by M. leprae. Our observations indicated that LD formation requires the uptake of live bacteria and depends on host cell cytoskeleton rearrangement and vesicular trafficking. TLR6 deletion, but not TLR2, completely abolished the induction of LDs by M. leprae, as well as inhibited the bacterial uptake in SCs. M. leprae-induced LD biogenesis correlated with increased PGE(2) and IL-10 secretion, as well as reduced IL-12 and NO production in M. leprae-infected SCs. Analysis of nerves from lepromatous leprosy patients showed colocalization of M. leprae, LDs, and cyclooxygenase-2 in SCs, indicating that LDs are sites for PGE(2) synthesis in vivo. LD biogenesis Inhibition by the fatty acid synthase inhibitor C-75 abolished the effect of M. leprae on SC production of immunoinflammatory mediators and enhanced the mycobacterial-killing ability of SCs. Altogether, our data indicated a critical role for TLR6-dependent signaling in M. leprae-SC interactions, favoring phagocytosis and subsequent signaling for induction of LD biogenesis in infected cells. Moreover, our observations reinforced the role of LDs favoring mycobacterial survival and persistence in the nerve. These findings give further support to a critical role for LDs in M. leprae pathogenesis in the nerve. PMID- 21813775 TI - The requirement for potent adjuvants to enhance the immunogenicity and protective efficacy of protein vaccines can be overcome by prior immunization with a recombinant adenovirus. AB - A central goal in vaccinology is the induction of high and sustained Ab responses. Protein-in-adjuvant formulations are commonly used to achieve such responses. However, their clinical development can be limited by the reactogenicity of some of the most potent preclinical adjuvants and the cost and complexity of licensing new adjuvants for human use. Also, few adjuvants induce strong cellular immunity, which is important for protection against many diseases, such as malaria. We compared classical adjuvants such as aluminum hydroxide to new preclinical adjuvants and adjuvants in clinical development, such as Abisco 100, CoVaccine HT, Montanide ISA720, and stable emulsion glucopyranosyl lipid A, for their ability to induce high and sustained Ab responses and T cell responses. These adjuvants induced a broad range of Ab responses when used in a three-shot protein-in-adjuvant regimen using the model Ag OVA and leading blood-stage malaria vaccine candidate Ags. Surprisingly, this range of Ab immunogenicity was greatly reduced when a protein-in-adjuvant vaccine was used to boost Ab responses primed by a human adenovirus serotype 5 vaccine recombinant for the same Ag. This human adenovirus serotype 5-protein regimen also induced a more cytophilic Ab response and demonstrated improved efficacy of merozoite surface protein-1 protein vaccines against a Plasmodium yoelii blood stage challenge. This indicates that the differential immunogenicity of protein vaccine adjuvants may be largely overcome by prior immunization with recombinant adenovirus, especially for adjuvants that are traditionally considered poorly immunogenic in the context of subunit vaccination and may circumvent the need for more potent chemical adjuvants. PMID- 21813776 TI - MPYS is required for IFN response factor 3 activation and type I IFN production in the response of cultured phagocytes to bacterial second messengers cyclic-di AMP and cyclic-di-GMP. AB - Cyclic-di-GMP and cyclic-di-AMP are second messengers produced by bacteria and influence bacterial cell survival, differentiation, colonization, biofilm formation, virulence, and bacteria-host interactions. In this study, we show that in both RAW264.7 macrophage cells and primary bone marrow-derived macrophages, the production of IFN-beta and IL-6, but not TNF, in response to cyclic-di-AMP and cyclic-di-GMP requires MPYS (also known as STING, MITA, and TMEM173). Furthermore, expression of MPYS was required for IFN response factor 3 but not NF kappaB activation in response to these bacterial metabolites. We also confirm that MPYS is required for type I IFN production by cultured macrophages infected with the intracellular pathogens Listeria monocytogenes and Francisella tularensis. However, during systemic infection with either pathogen, MPYS deficiency did not impact bacterial burdens in infected spleens. Serum IFN-beta and IL-6 concentrations in the infected control and MPYS(-/-) mice were also similar at 24 h postinfection, suggesting that these pathogens stimulate MPYS independent cytokine production during in vivo infection. Our findings indicate that bifurcating MPYS-dependent and -independent pathways mediate sensing of cytosolic bacterial infections. PMID- 21813777 TI - Physiologic control of IDO competence in splenic dendritic cells. AB - Dendritic cells (DCs) competent to express the regulatory enzyme IDO in mice are a small but distinctive subset of DCs. Previously, we reported that a high-dose systemic CpG treatment to ligate TLR9 in vivo induced functional IDO exclusively in splenic CD19(+) DCs, which stimulated resting Foxp3-lineage regulatory T cells (Tregs) to rapidly acquire potent suppressor activity. In this paper, we show that IDO was induced in spleen and peripheral lymph nodes after CpG treatment in a dose-dependent manner. Induced IDO suppressed local T cell responses to exogenous Ags and inhibited proinflammatory cytokine expression in response to TLR9 ligation. IDO induction did not occur in T cell-deficient mice or in mice with defective B7 or programmed death (PD)-1 costimulatory pathways. Consistent with these findings, CTLA4 or PD-1/PD-ligand costimulatory blockade abrogated IDO induction and prevented Treg activation via IDO following high-dose CpG treatment. Consequently, CD4(+)CD25(+) T cells uniformly expressed IL-17 shortly after TLR9 ligation. These data support the hypothesis that constitutive interactions from activated T cells or Tregs and IDO-competent DCs via concomitant CTLA4->B7 and PD-1->PD-ligand signals maintain the default potential to regulate T cell responsiveness via IDO. Acute disruption of these nonredundant interactions abrogated regulation via IDO, providing novel perspectives on the proinflammatory effects of costimulatory blockade therapies. Moreover, interactions between IDO-competent DCs and activated T cells in lymphoid tissues may attenuate proinflammatory responses to adjuvants such as TLR ligands. PMID- 21813778 TI - IL-1 blockade attenuates islet amyloid polypeptide-induced proinflammatory cytokine release and pancreatic islet graft dysfunction. AB - Islets from patients with type 2 diabetes exhibit beta cell dysfunction, amyloid deposition, macrophage infiltration, and increased expression of proinflammatory cytokines and chemokines. We sought to determine whether human islet amyloid polypeptide (hIAPP), the main component of islet amyloid, might contribute to islet inflammation by recruiting and activating macrophages. Early aggregates of hIAPP, but not nonamyloidogenic rodent islet amyloid polypeptide, caused release of CCL2 and CXCL1 by islets and induced secretion of TNF-alpha, IL-1alpha, IL 1beta, CCL2, CCL3, CXCL1, CXCL2, and CXCL10 by C57BL/6 bone marrow-derived macrophages. hIAPP-induced TNF-alpha secretion was markedly diminished in MyD88-, but not TLR2- or TLR4-deficient macrophages, and in cells treated with the IL-1R antagonist (IL-1Ra) anakinra. To determine the significance of IL-1 signaling in hIAPP-induced pancreatic islet dysfunction, islets from wild-type or hIAPP expressing transgenic mice were transplanted into diabetic NOD/SCID recipients implanted with mini-osmotic pumps containing IL-1Ra (50 mg/kg/d) or saline. IL 1Ra significantly improved the impairment in glucose tolerance observed in recipients of transgenic grafts 8 wk following transplantation. Islet grafts expressing hIAPP contained amyloid deposits in close association with F4/80 expressing macrophages. Transgenic grafts contained 50% more macrophages than wild-type grafts, an effect that was inhibited by IL-1Ra. Our results suggest that hIAPP-induced islet chemokine secretion promotes macrophage recruitment and that IL-1R/MyD88, but not TLR2 or TLR4 signaling is required for maximal macrophage responsiveness to prefibrillar hIAPP. These data raise the possibility that islet amyloid-induced inflammation contributes to beta cell dysfunction in type 2 diabetes and islet transplantation. PMID- 21813779 TI - The protein kinase IKKepsilon is a potential target for the treatment of inflammatory hyperalgesia. AB - Inhibitor-kappaB kinase epsilon (IKKepsilon) was only recently identified as an enzyme with high homology to the classical I-kappaB kinase subunits, IKKalpha and IKKbeta. Despite this similarity, it is mainly discussed as a repressor of viral infections by modulating type I IFNs. However, in vitro studies also showed that IKKepsilon plays a role in the regulation of NF-kappaB activity, but the distinct mechanisms of IKKepsilon-mediated NF-kappaB activation are not clear. Given the paramount role of NF-kappaB in inflammation, we investigated the regulation and function of IKKepsilon in models of inflammatory hyperalgesia in mice. We found that IKKepsilon was abundantly expressed in nociceptive neurons in the spinal cord and in dorsal root ganglia. IKKepsilon mRNA and protein levels rapidly increased in spinal cord and dorsal root ganglia during hind paw inflammation evoked by injection of zymosan or formalin. IKKepsilon knockout mice showed normal nociceptive responses to acute heat or mechanical stimulation. However, in inflammatory pain models, IKKepsilon-deficient mice exhibited a significantly reduced nociceptive behavior in comparison with wild type mice, indicating that IKKepsilon contributed to the development of inflammatory hyperalgesia. Antinociceptive effects were associated with reduced activation of NF-kappaB and attenuated NF-kappaB-dependent induction of cyclooxygenase-2, inducible NO synthase, and metalloproteinase-9. In contrast, IRF-3, which is an important IKKepsilon target in viral infections, was not regulated after inflammatory nociceptive stimulation. Therefore, we concluded that IKKepsilon modulates inflammatory nociceptive sensitivity by activation of NF-kappaB-dependent gene transcription and may be useful as a therapeutic target in the treatment of inflammatory pain. PMID- 21813780 TI - The impact of adopting ethnic or civic conceptions of national belonging for others' treatment. AB - National belonging is often defined in terms of "ethnic" ancestry and "civic" commitment (with the latter typically implying a more inclusive conception of belonging). The authors report three Scottish studies manipulating the prominence of these criteria. In Study 1 (N = 80), a Chinese-heritage target was judged more Scottish (and his criticisms of Scotland better received) when Scotland was defined in civic terms. In Study 2 (N = 40), a similar manipulation in a naturalistic setting showed a civic conception of belonging resulted in more help being given to a Chinese-heritage confederate. Study 3 (N = 71) replicated Study 2 and showed the effect was mediated by judgments of the confederate's Scottishness. These studies emphasize the importance of exploring how ingroup identity is defined. PMID- 21813781 TI - Pain in neuromyelitis optica and its effect on quality of life: a cross-sectional study. AB - OBJECTIVE: To assess the features of pain and its impact on the health-related quality of life (HRQOL) in neuromyelitis optica (NMO). METHODS: We analyzed 37 patients with NMO or NMO spectrum disorders seen at the Department of Neurology, Tohoku University Hospital, Sendai, Japan, during the period from November 2008 to February 2009. A total of 35 of them were aquaporin-4 antibody-positive. We used Short Form Brief Pain Inventory (BPI) to assess pain and Short Form 36-item (SF-36) health survey to evaluate the HRQOL. Fifty-one patients with multiple sclerosis (MS) were also studied for comparison. RESULTS: Pain in NMO (83.8%) was far more common than in MS (47.1%). The Pain Severity Index score in BPI was significantly higher in NMO than in MS, and patients' daily life assessed by BPI was highly interfered by pain in NMO as compared with MS. Pain involving the trunk and both legs was much more frequent in NMO than in MS. SF-36 scores in NMO were lower than MS, especially in bodily pain. CONCLUSION: Our study showed that pain in NMO is more frequent and severe than in MS and that pain has a grave impact on NMO patients' daily life and HRQOL. Therapy to relieve pain is expected to improve their HRQOL. PMID- 21813782 TI - Historical controls in ALS trials: a high seas rescue? PMID- 21813783 TI - Does detection of anti-AQP4 antibodies trump clinical criteria for neuromyelitis optica? PMID- 21813784 TI - Paraneoplastic upbeat nystagmus. PMID- 21813785 TI - AQP4 antibody-positive Thai cases: clinical features and diagnostic problems. AB - OBJECTIVE: To evaluate the prevalence of aquaporin-4 (AQP4) antibody in Thai patients with idiopathic inflammatory demyelinating CNS diseases (IIDCDs) and to analyze the significance of the autoantibody to distinguish neuromyelitis optica (NMO) and other NMO spectrum disorders (ONMOSDs) from other IIDCDs, especially multiple sclerosis (MS). METHODS: We retrospectively evaluated 135 consecutive patients with IIDCDs seen at the MS clinic at Siriraj Hospital, Bangkok, Thailand, and classified them into NMO, ONMOSDs, optic-spinal MS (OSMS), classic MS (CMS), and clinically isolated syndrome (CIS) groups in this order with accepted diagnostic criteria. The patients' coded sera were tested separately for AQP4 antibody. Then the relations between the clinical diagnosis and the AQP4 antibody serologic status were analyzed. RESULTS: Among the 135 patients, 53 (39.3%) were AQP4 antibody-positive. Although the AQP4 antibody-positive group had features of NMO, such as female predominance, long cord lesions (>3 vertebral bodies), and CSF pleocytosis, only 18 patients (33% of 54) fully met Wingerchuk 2006 criteria except for AQP4 antibody-seropositive status. We also detected some AQP4 antibody-positive patients in the OSMS (4 of 7), CMS (11 of 46), and CIS (1 of 16) groups. These patients had been misdiagnosed with MS because they often had brain lesions and never underwent spinal cord MRI examination or lacked long cord lesions. CONCLUSIONS: AQP4 antibody was highly prevalent (almost 40%) in Thai patients with IIDCDs. Moreover, only one-third of AQP4 antibody-positive patients fully met Wingerchuk 2006 criteria, and many were misdiagnosed with MS. A sensitive AQP4 antibody assay is required in this region because the therapy for NMO is different from that for MS. PMID- 21813786 TI - Retinal atrophy correlates with fMRI response in patients with recovered optic neuritis. AB - OBJECTIVE: We wanted to investigate if retinal nerve fiber layer thickness (RNFLT) measured by optical coherence tomography (OCT) might be a good marker of acute and chronic changes in the afferent visual pathway following acute optic neuritis (ON). METHODS: We studied the relationship of optic nerve lesion length, optic nerve mean area, and RNFLT, quantified by OCT, with fMRI response to a visual paradigm in 40 patients with acute ON and 19 healthy controls in a prospective cohort study over a 6-month period. RESULTS: The main finding was a significant correlation of optic nerve lesion length and mean area with fMRI response in affected eyes in the acute phase and between RNFLT and fMRI response in affected eyes after recovery. CONCLUSION: RNFLT is a very good measure of damage to the afferent visual pathway in recovered patients with ON and should be included in future fMRI studies when looking for visual reorganization in recovered patients with ON. PMID- 21813787 TI - Longitudinal changes of structural connectivity in traumatic axonal injury. AB - OBJECTIVES: To identify structural connectivity change occurring during the first 6 months after traumatic brain injury and to evaluate the utility of diffusion tensor tractography for predicting long-term outcome. METHODS: The participants were 28 patients with mild to severe traumatic axonal injury and 20 age- and sex matched healthy control subjects. Neuroimaging was obtained 0-9 days postinjury for acute scans and 6-14 months postinjury for chronic scans. Long-term outcome was evaluated on the day of the chronic scan. Twenty-eight fiber regions of 9 major white matter structures were reconstructed, and reliable tractography measurements were determined and used. RESULTS: Although most (23 of 28) patients had severe brain injury, their long-term outcome ranged from good recovery (16 patients) to moderately (5 patients) and severely disabled (7 patients). In concordance with the diverse outcome, the white matter change in patients was heterogeneous, ranging from improved structural connectivity, through no change, to deteriorated connectivity. At the group level, all 9 fiber tracts deteriorated significantly with 7 (corpus callosum, cingulum, angular bundle, cerebral peduncular fibers, uncinate fasciculus, and inferior longitudinal and fronto occipital fasciculi) showing structural damage acutely and 2 (fornix body and left arcuate fasciculus) chronically. Importantly, the amount of change in tractography measurements correlated with patients' long-term outcome. Acute tractography measurements were able to predict patients' learning and memory performance; chronic measurements also determined performance on processing speed and executive function. CONCLUSIONS: Diffusion tensor tractography is a valuable tool for identifying structural connectivity changes occurring between the acute and chronic stages of traumatic brain injury and for predicting patients' long term outcome. PMID- 21813788 TI - Azathioprine: tolerability, efficacy, and predictors of benefit in neuromyelitis optica. AB - OBJECTIVE: To evaluate the efficacy, tolerability, optimal dosing, and monitoring of azathioprine in patients with neuromyelitis optica (NMO). METHODS: This was a chart review and telephone follow-up study of 99 patients with NMO spectrum of disorders (NMOSD) treated with azathioprine (1994-2009). NMOSD were NMO (2006 diagnostic criteria) or partial NMO forms (NMO-immunoglobulin G seropositive). Wilcoxon signed rank test was used to compare pretreatment and postinitiation of azathioprine (posttreatment) annualized relapse rates (ARR), Expanded Disability Status Scale (EDSS) score, and visual acuity outcome. Linear regression was used to assess the effects of various factors on ARR change and disability. RESULTS: The median duration of NMOSD symptoms prior to initiation of azathioprine was 2 years (range 1-27); 79 patients were women. Eighty-six patients had NMO and 13 limited NMO versions, including transverse myelitis in 8 and optic neuritis in 5. Median posttreatment follow-up was 22 months. Thirty-eight patients discontinued drug (side effects, 22; no efficacy, 13; lymphoma, 3). Among 70 patients with >12 months follow-up, 48 received >=2.0 mg/kg/day (ARR: pretreatment, 2.20; posttreatment, 0.52); 22 received <2.0 mg/kg/day (ARR: pretreatment, 2.09; posttreatment, 0.82); 52 received concomitant prednisone (ARR: pretreatment, 2.20; posttreatment, 0.89) and 18 did not (ARR: pretreatment, 1.54; posttreatment, 0.23); p < 0.0001 for each comparison. EDSS was stable or improved despite ongoing attacks in 22 patients (31%). Twenty-six patients tolerated azathioprine and were relapse-free (37%, median follow-up 24 months; range 12 151). Mean corpuscular volume increase influenced ARR change (p = 0.049). CONCLUSIONS: Azathioprine is generally effective and well-tolerated. Early initiation, adequate dosing, and hematologic parameter monitoring may optimize efficacy. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that azathioprine is effective for reducing relapse rates and improving EDSS and visual acuity scores in patients with NMO spectrum of disorders. PMID- 21813789 TI - White matter in traumatic brain injury: Dis- or dysconnection? PMID- 21813790 TI - Phase II screening trial of lithium carbonate in amyotrophic lateral sclerosis: examining a more efficient trial design. AB - OBJECTIVE: To use a historical placebo control design to determine whether lithium carbonate slows progression of amyotrophic lateral sclerosis (ALS). METHODS: A phase II trial was conducted at 10 sites in the Western ALS Study Group using similar dosages (300-450 mg/day), target blood levels (0.3-0.8 mEq/L), outcome measures, and trial duration (13 months) as the positive trial. However, taking riluzole was not a requirement for study entry. Placebo outcomes in patients matched for baseline features from a large database of recent clinical trials, showing stable rates of decline over the past 9 years, were used as historical controls. RESULTS: The mean rate of decline of the ALS Functional Rating Scale-Revised was greater in 107 patients taking lithium carbonate ( 1.20/month, 95% confidence interval [CI] -1.41 to -0.98) than that in 249 control patients (-1.01/month, 95% CI -1.11 to -0.92, p = 0.04). There were no differences in secondary outcome measures (forced vital capacity, time to failure, and quality of life), but there were more adverse events in the treated group. CONCLUSIONS: The lack of therapeutic benefit and safety concerns, taken together with similar results from 2 other recent trials, weighs against the use of lithium carbonate in patients with ALS. The absence of drift over time and the availability of a large database of patients for selecting a matched historical control group suggest that use of historical controls may result in more efficient phase II trials for screening putative ALS therapeutic agents. CLASSIFICATION OF EVIDENCE: This study provided Class IV evidence that lithium carbonate does not slow the rate of decline of function in patients with ALS over 13 months. PMID- 21813791 TI - Static ocular counterroll reflex in skew deviation. AB - OBJECTIVE: The static ocular counterroll (OCR) reflex generates partially compensatory torsional eye movements during head roll. It is mediated by the utricle in the inner ear. Skew deviation is a vertical strabismus thought to be caused by imbalance in the utriculo-ocular pathway. We hypothesized that if skew deviation is indeed caused by damage to this reflex pathway, patients with skew deviation would show abnormal OCR. METHODS: Eighteen patients with skew deviation caused by brainstem or cerebellar lesions and 18 normal participants viewed a target at 1 m. Ocular responses to static passive head roll-tilts of approximately 20 degrees were recorded using search coils. Static OCR gain was calculated as the change in torsional eye position divided by the change in head position during sustained head roll. Perception of the subjective visual vertical (SVV) was also measured. RESULTS: Group mean OCR gain was reduced by 45% in patients. At an individual level, OCR gains were asymmetric between eyes and between torsional directions in 90% of patients. In addition, the hypotropic eye incyclotorting gain was lower than the hypertropic eye excyclotorting gain during head roll toward the hypotropic eye in 94% of patients. No consistent pattern of gain asymmetry was found during head roll toward the hypertropic eye. The SVV was tilted toward the hypotropic eye. CONCLUSION: Static OCR gain is significantly reduced in skew deviation. Interocular and directional gain asymmetries are also prevalent. The asymmetries provide further evidence that disruption of the utriculo-ocular pathway is a mechanism for skew deviation. PMID- 21813793 TI - Socioeconomic differences in cardiometabolic factors: social causation or health related selection? Evidence from the Whitehall II Cohort Study, 1991-2004. AB - In this study, the health-related selection hypothesis (that health predicts social mobility) and the social causation hypothesis (that socioeconomic status influences health) were tested in relation to cardiometabolic factors. The authors screened 8,312 United Kingdom men and women 3 times over 10 years between 1991 and 2004 for waist circumference, body mass index, systolic and diastolic blood pressure, fasting glucose, fasting insulin, serum lipids, C-reactive protein, and interleukin-6; identified participants with the metabolic syndrome; and measured childhood health retrospectively. Health-related selection was examined in 2 ways: 1) childhood health problems as predictors of adult occupational position and 2) adult cardiometabolic factors as predictors of subsequent promotion at work. Social causation was assessed using adult occupational position as a predictor of subsequent change in cardiometabolic factors. Hospitalization during childhood and lower birth weight were associated with lower occupational position (both P's <= 0.002). Cardiometabolic factors in adulthood did not consistently predict promotion. In contrast, lower adult occupational position predicted adverse changes in several cardiometabolic factors (waist circumference, body mass index, fasting glucose, and fasting insulin) and an increased risk of new-onset metabolic syndrome (all P's <= 0.008). These findings suggest that health-related selection operates at younger ages and that social causation contributes to socioeconomic differences in cardiometabolic health in midlife. PMID- 21813792 TI - Missing data on the estimation of the prevalence of accumulated human immunodeficiency virus drug resistance in patients treated with antiretroviral drugs in north america. AB - Determination of the prevalence of accumulated antiretroviral drug resistance among persons infected with human immunodeficiency virus (HIV) is complicated by the lack of routine measurement in clinical care. By using data from 8 clinic based cohorts from the North American AIDS Cohort Collaboration on Research and Design, drug-resistance mutations from those with genotype tests were determined and scored using the Genotypic Resistance Interpretation Algorithm developed at Stanford University. For each year from 2000 through 2005, the prevalence was calculated using data from the tested subset, assumptions that incorporated clinical knowledge, and multiple imputation methods to yield a complete data set. A total of 9,289 patients contributed data to the analysis; 3,959 had at least 1 viral load above 1,000 copies/mL, of whom 2,962 (75%) had undergone at least 1 genotype test. Using these methods, the authors estimated that the prevalence of accumulated resistance to 2 or more antiretroviral drug classes had increased from 14% in 2000 to 17% in 2005 (P < 0.001). In contrast, the prevalence of resistance in the tested subset declined from 57% to 36% for 2 or more classes. The authors' use of clinical knowledge and multiple imputation methods revealed trends in HIV drug resistance among patients in care that were markedly different from those observed using only data from patients who had undergone genotype tests. PMID- 21813794 TI - The glycolytic enzyme, phosphoglycerate mutase, has critical roles in stomatal movement, vegetative growth, and pollen production in Arabidopsis thaliana. AB - Stomatal movements require massive changes in guard cell osmotic content, and both stomatal opening and stomatal closure have been shown to be energy-requiring processes. A possible role for glycolysis in contributing to the energetic, reducing requirements, or signalling processes regulating stomatal movements has not been investigated previously. Glycolysis, oxidization of glucose to pyruvate, is a central metabolic pathway and yields a net gain of 2 ATP and 2 NADH. 2,3 biphosphoglycerate-independent phosphoglycerate mutase (iPGAM) is a key enzymatic activity in glycolysis and catalyses the reversible interconversion of 3 phosphoglycerate to 2-phosphoglycerate. To investigate functions of iPGAMs and glycolysis in stomatal function and plant growth, Arabidopsis insertional mutants in At1g09780 and At3g08590, both of which have been annotated as iPGAMs on the basis of sequence homology, were identified and characterized. While single mutants were indistinguishable from the wild type in all plant phenotypes assayed, double mutants had no detectable iPGAM activity and showed defects in blue light-, abscisic acid-, and low CO(2)-regulated stomatal movements. Vegetative plant growth was severely impaired in the double mutants and pollen was not produced. The data demonstrate that iPGAMs and glycolytic activity are critical for guard cell function and fertility in Arabidopsis. PMID- 21813795 TI - The Mediterranean evergreen Quercus ilex and the semi-deciduous Cistus albidus differ in their leaf gas exchange regulation and acclimation to repeated drought and re-watering cycles. AB - Plants may exhibit some degree of acclimation after experiencing drought, but physiological adjustments to consecutive cycles of drought and re-watering (recovery) have scarcely been studied. The Mediterranean evergreen holm oak (Q. ilex) and the semi-deciduous rockrose (C. albidus) showed some degree of acclimation after the first of three drought cycles (S1, S2, and S3). For instance, during S2 and S3 both species retained higher relative leaf water contents than during S1, despite reaching similar leaf water potentials. However, both species showed remarkable differences in their photosynthetic acclimation to repeated drought cycles. Both species decreased photosynthesis to a similar extent during the three cycles (20-40% of control values). However, after S1 and S2, photosynthesis recovered only to 80% of control values in holm oak, due to persistently low stomatal (g(s)) and mesophyll (g(m)) conductances to CO(2). Moreover, leaf intrinsic water use efficiency (WUE) was kept almost constant in this species during the entire experiment. By contrast, photosynthesis of rockrose recovered almost completely after each drought cycle (90-100% of control values), while the WUE was largely and permanently increased (by 50-150%, depending on the day) after S1. This was due to a regulation which consisted in keeping g(s) low (recovering to 50-60% of control values after re-watering) while maintaining a high g(m) (even exceeding control values during re-watering). While the mechanisms to achieve such particular regulation of water and CO(2) diffusion in leaves are unknown, it clearly represents a unique acclimation feature of this species after a drought cycle, which allows it a much better performance during successive drought events. Thus, differences in the photosynthetic acclimation to repeated drought cycles can have important consequences on the relative fitness of different Mediterranean species or growth forms within the frame of climate change scenarios. PMID- 21813796 TI - Identification and expression pattern of a new carotenoid cleavage dioxygenase gene member from Bixa orellana. AB - Carotenoid cleavage dioxygenases (CCDs) are a class of enzymes involved in the biosynthesis of a broad diversity of secondary metabolites known as apocarotenoids. In plants, CCDs are part of a genetic family with members which cleave specific double bonds of carotenoid molecules. CCDs are involved in the production of diverse and important metabolites such as vitamin A and abscisic acid (ABA). Bixa orellana L. is the main source of the natural pigment annatto or bixin, an apocarotenoid accumulated in large quantities in its seeds. Bixin biosynthesis has been studied and the involvement of a CCD has been confirmed in vitro. However, the CCD genes involved in the biosynthesis of the wide variety of apocarotenoids found in this plant have not been well documented. In this study, a new CCD1 gene member (BoCCD1) was identified and its expression was charaterized in different plant tissues of B. orellana plantlets and adult plants. The BoCCD1 sequence showed high homology with plant CCD1s involved mainly in the cleavage of carotenoids in several sites to generate multiple apocarotenoid products. Here, the expression profiles of the BoCCD1 gene were analysed and discussed in relation to total carotenoids and other important apocarotenoids such as bixin. PMID- 21813798 TI - Diagnosing criterion-level effects on memory: what aspects of memory are enhanced by repeated retrieval? AB - Previous research has shown that increasing the criterion level (i.e., the number of times an item must be correctly retrieved during practice) improves subsequent memory, but which specific components of memory does increased criterion level enhance? In two experiments, we examined the extent to which the criterion level affects associative memory, target memory, and cue memory. Participants studied Lithuanian-English word pairs via cued recall with restudy until items were correctly recalled one to five times. In Experiment 1, participants took one of four recall tests and one of three recognition tests after a 2-day delay. In Experiment 2, participants took only recognition tests after a 1-week delay. In both experiments, increasing the criterion level enhanced associative memory, as indicated by enhanced performance on forward and backward cued-recall tests and on tests of associative recognition. An increased criterion level also improved target memory, as indicated by enhanced free recall and recognition of targets, and improved cue memory, as indicated by enhanced free recall and recognition of cues. PMID- 21813799 TI - Rewriting the self-fulfilling prophecy of social rejection: self-affirmation improves relational security and social behavior up to 2 months later. AB - Chronically insecure individuals often behave in ways that result in the very social rejection that they most fear. We predicted that this typical self fulfilling prophecy is not immutable. Self-affirmation may improve insecure individuals' relational security, and this improvement may allow them to express more welcoming social behavior. In a longitudinal experiment, a 15-min self affirmation improved both the relational security and experimenter-rated social behavior of insecure participants up to 4 weeks after the initial intervention. Moreover, the extent to which self-affirmation improved insecure participants' relational security at 4 weeks predicted additional improvements in social behavior another 4 weeks after that. Our finding that insecure participants continued to reap the social benefits of self-affirmation up to 8 weeks after the initial intervention demonstrates that it is indeed possible to rewrite the self fulfilling prophecy of social rejection. PMID- 21813797 TI - The barley amo1 locus is tightly linked to the starch synthase IIIa gene and negatively regulates expression of granule-bound starch synthetic genes. AB - In this study of barley starch synthesis, the interaction between mutations at the sex6 locus and the amo1 locus has been characterized. Four barley genotypes, the wild type, sex6, amo1, and the amo1sex6 double mutant, were generated by backcrossing the sex6 mutation present in Himalaya292 into the amo1 'high amylose Glacier'. The wild type, amo1, and sex6 genotypes gave starch phenotypes consistent with previous studies. However, the amo1sex6 double mutant yielded an unexpected phenotype, a significant increase in starch content relative to the sex6 phenotype. Amylose content (as a percentage of starch) was not increased above the level observed for the sex6 mutation alone; however, on a per seed basis, grain from lines containing the amo1 mutation (amo1 mutants and amo1sex6 double mutants) synthesize significantly more amylose than the wild-type lines and sex6 mutants. The level of granule-bound starch synthase I (GBSSI) protein in starch granules is increased in lines containing the amo1 mutation (amo1 and amo1sex6). In the amo1 genotype, starch synthase I (SSI), SSIIa, starch branching enzyme IIa (SBEIIa), and SBEIIb also markedly increased in the starch granules. Genetic mapping studies indicate that the ssIIIa gene is tightly linked to the amo1 locus, and the SSIIIa protein from the amo1 mutant has a leucine to arginine residue substitution in a conserved domain. Zymogram analysis indicates that the amo1 phenotype is not a consequence of total loss of enzymatic activity although it remains possible that the amo1 phenotype is underpinned by a more subtle change. It is therefore proposed that amo1 may be a negative regulator of other genes of starch synthesis. PMID- 21813800 TI - Spontaneous gestures influence strategy choices in problem solving. AB - Do gestures merely reflect problem-solving processes, or do they play a functional role in problem solving? We hypothesized that gestures highlight and structure perceptual-motor information, and thereby make such information more likely to be used in problem solving. Participants in two experiments solved problems requiring the prediction of gear movement, either with gesture allowed or with gesture prohibited. Such problems can be correctly solved using either a perceptual-motor strategy (simulation of gear movements) or an abstract strategy (the parity strategy). Participants in the gesture-allowed condition were more likely to use perceptual-motor strategies than were participants in the gesture prohibited condition. Gesture promoted use of perceptual-motor strategies both for participants who talked aloud while solving the problems (Experiment 1) and for participants who solved the problems silently (Experiment 2). Thus, spontaneous gestures influence strategy choices in problem solving. PMID- 21813801 TI - Knowledge, misconceptions, and future intentions towards breastfeeding among female university students in Kuwait. AB - A cross-sectional study using a self-administered questionnaire was conducted on female university students (N = 1106) to explore their knowledge and misconceptions on breastfeeding. Most participants recognized the benefits of breastfeeding, but only a few were aware of the recommendation for exclusive breastfeeding in the first 6 months of life. Misconceptions were common; 66%, 60%, and 55% of participants thought mothers should temporarily stop breastfeeding if they had a fever, skin rash, or sore throat, respectively. Approximately 20% thought mothers should stop breastfeeding if the child had diarrhea, vomiting, or skin rash. Support of breastfeeding in public places was low, but 38% supported breastfeeding in female prayer rooms in public places. Efforts should be made to correct common misconceptions on breastfeeding and increase the support of breastfeeding in public places among university students. Female prayer rooms that exist in all public places in Kuwait can be used to promote breastfeeding in public places in Kuwait. PMID- 21813802 TI - Brain-lung-thyroid disease: clinical features of a kindred with a novel thyroid transcription factor 1 mutation. AB - Brain-lung-thyroid disease is a rare familial disorder caused by mutations in thyroid transcription factor 1, a gene that regulates neuronal migration. We report the clinical features of ten patients from a single family with a novel gene mutation, including observations regarding treatment. Neurologic features of the kindred included developmental delay, learning difficulties, psychosis, chorea, and dystonia. Three patients had a history of seizure, which has not been previously reported in genetically confirmed cases. Low-dose dopamine-receptor blocking drugs were poorly tolerated in 2 patients who received this therapy, levodopa improved chorea in 3 of 4 children, and diazepam was markedly effective in a single adult patient. Chorea related to brain-lung-thyroid disease appears to respond paradoxically to antidopaminergic drugs. The unusual therapeutic response seen in our patients and others may help elucidate how disease-related migratory deficits affect neural pathways associated with motor control. PMID- 21813804 TI - Lipid concentrations in children and adolescents: it is not all about obesity. PMID- 21813803 TI - Acute sulfonylurea therapy at disease onset can cause permanent remission of KATP induced diabetes. AB - OBJECTIVE: Neonatal diabetes mellitus (NDM) can be caused by gain-of-function ATP sensitive K(+) (K(ATP)) channel mutations. This realization has led to sulfonylurea therapy replacing insulin injections in many patients. In a murine model of K(ATP)-dependent NDM, hyperglycemia and consequent loss of beta-cells are both avoided by chronic sulfonylurea treatment. Interestingly, K(ATP) mutations may underlie remitting-relapsing, transient, or permanent forms of the disease in different patients, but the reason for the different outcomes is unknown. RESEARCH DESIGN AND METHODS: To gain further insight into disease progression and outcome, we examined the effects of very early intervention by injecting NDM mice with high-dose glibenclamide for only 6 days, at the beginning of disease onset, then after the subsequent progression with measurements of blood glucose, islet function, and insulin sensitivity. RESULTS: Although ~70% of mice developed severe diabetes after treatment cessation, ~30% were essentially cured, maintaining near-normal blood glucose until killed. Another group of NDM mice was initiated on oral glibenclamide (in the drinking water), and the dose was titrated daily, to maintain blood glucose <200 mg/dL. In this case, ~30% were also essentially cured; they were weaned from the drug after ~4 weeks and again subsequently maintained near-normal blood glucose. These cured mice maintain normal insulin content and were more sensitive to insulin than control mice, a compensatory mechanism that together with basal insulin secretion may be sufficient to maintain near-normal glucose levels. CONCLUSIONS: At least in a subset of animals, early sulfonylurea treatment leads to permanent remission of NDM. These cured animals exhibit insulin-hypersensitivity. Although untreated NDM mice rapidly lose insulin content and progress to permanently extremely elevated blood glucose levels, early tight control of blood glucose may permit this insulin-hypersensitivity, in combination with maintained basal insulin secretion, to provide long-term remission. PMID- 21813805 TI - Women with bulimia nervosa exhibit attenuated secretion of glucagon-like peptide 1, pancreatic polypeptide, and insulin in response to a meal. AB - BACKGROUND: The eating disorder bulimia nervosa (BN) is characterized by frequent episodes of binge eating, followed regularly by inappropriate compensatory behavior, such as self-induced vomiting. OBJECTIVE: The current investigation was designed to examine possible alterations in the secretion of the gastrointestinal satiety peptides glucagon-like peptide 1 (GLP-1) and pancreatic polypeptide (PP) in women with BN. DESIGN: Twenty-one women with BN and 17 healthy control subjects of comparable age and BMI were recruited. After fasting overnight, the subjects provided blood samples during ingestion of a standardized meal and self rated their appetite on a visual analog scale. Fasting and meal-related secretion of the incretin GLP-1 and the meal-related feedback signal PP and insulin and glucose as indicators of the metabolic homeostasis were analyzed. RESULTS: Women with BN had significantly lower fasting and postprandial serum concentrations of GLP-1 (P < 0.01) and PP (P < 0.05) than did the control subjects. Furthermore, both the basal (P < 0.001) and peak (P < 0.05) concentrations of insulin were significantly attenuated in the bulimic subjects, whereas glucose concentrations were normal. As a consequence, the bulimic homeostasis model assessment of insulin index values were also lower (P < 0.001). CONCLUSIONS: Women with BN secrete abnormally low amounts of GLP-1 and PP, possibly because of the adaption to large meals in the form of enlarged gastric capacity and reduced muscle tone in the gastric wall. Attenuated secretion of these gastrointestinal satiety peptides may play a role in the maintenance of bulimic behavior. PMID- 21813808 TI - A higher ratio of beans to white rice is associated with lower cardiometabolic risk factors in Costa Rican adults. AB - BACKGROUND: A high intake of white rice is associated with the metabolic syndrome and type 2 diabetes. Costa Ricans follow a staple dietary pattern that includes white rice and beans, yet the combined role of these foods on cardiometabolic risk factors has not been studied. OBJECTIVE: We aimed to determine the association between intake of white rice and beans and the metabolic syndrome and its components in Costa Rican adults (n = 1879) without diabetes. DESIGN: Multivariate-adjusted means were calculated for components of the metabolic syndrome by daily servings of white rice and beans (<1, 1, or >1) and by the ratio of beans to white rice. The OR for the metabolic syndrome was calculated by substituting one serving of beans for one serving of white rice. RESULTS: An increase in daily servings of white rice was positively associated with systolic blood pressure (BP), triglycerides, and fasting glucose and inversely associated with HDL cholesterol (P-trend <0.01 for all). An increase in servings of beans was inversely associated with diastolic BP (P = 0.049). Significant trends for higher HDL cholesterol and lower BP and triglycerides were observed for 1:3, 1:2, 1:1, and 2:1 ratios of beans to white rice. Substituting one serving of beans for one serving of white rice was associated with a 35% (95% CI: 15%, 50%) lower risk of the metabolic syndrome. CONCLUSION: Increasing the ratio of beans to white rice, or limiting the intake of white rice by substituting beans, may lower cardiometabolic risk factors. PMID- 21813806 TI - Pre- and postfortification intake of folate and risk of colorectal cancer in a large prospective cohort study in the United States. AB - BACKGROUND: A higher folate intake is associated with a decreased colorectal cancer risk in observational studies, but recent evidence suggests that excessive folate supplementation may increase colorectal cancer risk in some individuals. Therefore, mandatory folic acid fortification of grain products in the United States may have unintended negative consequences. OBJECTIVE: We examined the association between folate intake and colorectal cancer risk, including 8.5 y of postfortification follow-up. DESIGN: We examined the association between folate intake and colorectal cancer in the NIH-AARP Diet and Health Study-a US cohort study of 525,488 individuals aged 50-71 y initiated in 1995-1996. Dietary, supplemental, and total folate intakes were calculated for the pre- and postfortification periods (before and after 1 July 1997) based on a baseline food frequency questionnaire. HRs and 95% CIs were calculated by using multivariable Cox proportional hazards regression models. RESULTS: During follow-up through 31 December 2006 (mean follow-up: 9.1 y), 7212 incident colorectal cancer cases were identified. In the postfortification analysis (6484 cases), a higher total folate intake was associated with a decreased colorectal cancer risk (HR for >=900 compared with <200 MUg/d: 0.70; 95% CI: 0.58, 0.84). The highest intakes specifically from supplements (HR: 0.82; 95% CI: 0.72, 0.92) or from diet (HR: 0.81; 95% CI: 0.67, 0.97) were also protective. The pattern of associations was similar for the prefortification period, and no significant differences between time periods were observed. CONCLUSIONS: In this large prospective cohort study that included 8.5 y of postfortification follow-up, folate intake was associated with a decreased colorectal cancer risk. Given that the adenoma-carcinoma sequence may take >=10 y, additional follow-up time is needed to fully examine the effect of folic acid fortification. PMID- 21813811 TI - Distinguished contribution to Family Nursing Award 2011: Lawrence H. Ganong, PhD. PMID- 21813810 TI - Supplementation of bitter melon to rats fed a high-fructose diet during gestation and lactation ameliorates fructose-induced dyslipidemia and hepatic oxidative stress in male offspring. AB - This study examined the impact of maternal high-fructose intake and if metabolic control in the offspring could benefit from supplementing bioactive food components such as bitter melon (BM) to the maternal diet. In Expt. 1, virgin female rats received control (C), high-fructose (F; 60%), or BM-supplemented fructose (FBM; 1%) diet before conception until d 21 of lactation. Weaned male offspring were fed the C diet for 11 wk, forming C/C, F/C, and FBM/C groups. The F/C group had elevated serum insulin, TG, and FFA concentrations and hepatic lipid alterations compared with the C/C and FBM/C groups (P < 0.05). The 2 latter groups did not differ. Expt. 2 had similar dam treatment groups, but offspring were weaned to the C or F diet, forming C/C, C/F, F/F, and FBM/F groups, and the dietary treatment was extended to 20 wk. The hepatic levels of stearyl-CoA desaturase and microsomal TG transfer protein mRNA were lower, but that of PPARgamma coactivator 1-alpha and fibroblast growth factor 21 mRNA and fatty acid binding protein 1 protein were higher in the FBM/F group compared with the C/F and F/F groups (P < 0.05), indicating that maternal BM supplementation may reduce lipogenesis and promote lipid oxidation in offspring. The FBM/F group had significantly higher activities of liver glutathione peroxidase, superoxide dismutase, and catalase than the F/F group. The results indicate that supplementing BM to dams could offset the adverse effects of maternal high fructose intake on lipid metabolism and antioxidant status in adult offspring. PMID- 21813807 TI - Serum vitamin C and other biomarkers differ by genotype of phase 2 enzyme genes GSTM1 and GSTT1. AB - BACKGROUND: Glutathione S-transferases (GSTs) detoxify environmental chemicals and are involved in oxidative stress pathways. Deletion polymorphisms affect enzyme activities and have been associated with risk of disease. OBJECTIVE: The objective was to clarify whether biomarkers of oxidation, antioxidation, inflammation, and nutritional factors differ by GST genotype in healthy adults. DESIGN: Subjects (n = 383) consisted of nonsmokers and nonusers of antiinflammatory drugs and antioxidant vitamin supplements. Deletion polymorphisms of GSTM1 and GSTT1 were genotyped. F(2)-isoprostanes, malondialdehyde, C-reactive protein, serum vitamin C, carotenoids, tocopherols, and other nutritional factors were assessed. RESULTS: The concentration of serum vitamin C was higher in persons with the inactive GSTM1-0 genotype (P = 0.006). This relation was unchanged after adjustment for age, sex, BMI, or dietary vitamin C. F(2)-isoprostanes and malondialdehyde were lower in the GSTM1-0 and GSTT1-0 groups, respectively, but significance was lost after control for serum vitamin C. The dual deletion, GSTM1-0/GSTT1-0 (n = 37), was associated with higher serum iron and total and LDL-cholesterol concentrations (all P < 0.01) and lower malondialdehyde concentrations, which persisted after adjustment for age, sex, BMI, and serum vitamin C. Carotenoids and alpha- and gamma-tocopherols were not associated with either genotype. CONCLUSIONS: Oxidative stress and inflammation biomarkers differ by GST genotype, but serum vitamin C appears to be the most consistent factor. Examination of other relevant genes may be needed to understand the concentration and function of ascorbic acid in the GST enzyme system. This trial is registered at clinicaltrials.gov as NCT00079963. PMID- 21813809 TI - High platelet count as a link between renal cachexia and cardiovascular mortality in end-stage renal disease patients. AB - BACKGROUND: It is not clear why cardiac or renal cachexia in chronic diseases is associated with poor cardiovascular outcomes. Platelet reactivity predisposes to thromboembolic events in the setting of atherosclerotic cardiovascular disease, which is often present in patients with end-stage renal disease (ESRD). OBJECTIVES: We hypothesized that ESRD patients with relative thrombocytosis (platelet count >300 * 10(3)/MUL) have a higher mortality rate and that this association may be related to malnutrition-inflammation cachexia syndrome (MICS). DESIGN: We examined the associations of 3-mo-averaged platelet counts with markers of MICS and 6-y all-cause and cardiovascular mortality (2001-2007) in a cohort of 40,797 patients who were receiving maintenance hemodialysis. RESULTS: The patients comprised 46% women and 34% African Americans, and 46% of the patients had diabetes. The 3-mo-averaged platelet count was 229 +/- 78 * 10(3)/MUL. In unadjusted and case-mix adjusted models, lower values of albumin, creatinine, protein intake, hemoglobin, and dialysis dose and a higher erythropoietin dose were associated with a higher platelet count. Compared with patients with a platelet count of between 150 and 200 * 10(3)/MUL (reference), the all-cause (and cardiovascular) mortality rate with platelet counts between 300 and <350, between 350 and <400, and >=400 *10(3)/MUL were 6% (and 7%), 17% (and 15%), and 24% (and 25%) higher (P < 0.05), respectively. The associations persisted after control for case-mix adjustment, but adjustment for MICS abolished them. CONCLUSIONS: Relative thrombocytosis is associated with a worse MICS profile, a lower dialysis dose, and higher all-cause and cardiovascular disease death risk in hemodialysis patients; and its all-cause and cardiovascular mortality predictability is accounted for by MICS. The role of platelet activation in cachexia-associated mortality warrants additional studies. PMID- 21813812 TI - Transitioning care of an adolescent with cystic fibrosis: development of systemic hypothesis between parents, adolescents, and health care professionals. AB - This qualitative study explored the experience of parents and adolescents living with cystic fibrosis prior to the transfer of the adolescent's care from a pediatric to an adult health care facility. Semistructured interviews were conducted with seven families receiving care from a specialized cystic fibrosis clinic; parents and adolescents were interviewed separately, followed by a group interview with members of a health care team comprising eight professionals from the clinic. Interviews were analyzed through a systemic lens which accounts for interaction and reciprocity in relationships. The parents' experience was marked by suffering and uncertainty that remained unexpressed to the health care team, even though team members had known the family since the child was first diagnosed. Findings led to identifying a systemic hypothesis that accounted for the interactions and relational processes between parents and the health care team. This hypothesis may guide the development of systemic family nursing interventions that target this complex, relational, transition process. PMID- 21813813 TI - Refinement and psychometric reevaluation of the instrument: Families' Importance In Nursing Care--Nurses' Attitudes. AB - The instrument Families' Importance in Nursing Care--Nurses' Attitudes (FINC-NA) was developed to measure nurses' attitudes toward the importance of families in nursing care. The low variations in item responses, which affect the discrimination ability and unstable internal consistency, have been considered as limitations. The aim of this study was to refine and revalidate FINC-NA regarding score distribution, homogeneity, dimensionality, differential item functioning for gender, stability, and internal consistency. There were 246 registered nurses studying at advanced levels who answered the revised FINC-NA. The FINC-NA had five response alternatives. The findings showed that although some subscales still deviated from a normal distribution, the variability of the scores and the homogeneity was improved. In addition, the dimensionality was reproduced and minor problems with differential item functioning for gender were detected. All FINC-NA scales showed good reliability. The results allow the use of the revised FINC-NA in studies where an assessment of nurses' attitudes toward families' importance in nursing care is desired. PMID- 21813814 TI - Bereaved parents' perception of the grandparents' reactions to perinatal loss and the pregnancy that follows. AB - This article presents bereaved parents' perceptions of their parents' (the grandparents) reactions at the time of loss and in the pregnancy that follows. Data originated from two phenomenological studies conducted to understand bereaved parents' experiences during their loss and subsequent pregnancy. However, this article reports a secondary thematic analysis focused on bereaved parents perceptions of the grandparents' support (or lack of) at the time of loss and during the pregnancy following loss. Our findings illustrate some families found the means to share their grief at the time of loss in a constructive manner, while in others the intergenerational relationship was strained. Most important to parents was intergenerational acknowledgment of the ongoing relationship to the deceased child as an important, though absent family member, especially during the pregnancy that followed. Those supporting bereaved families can play an important role in helping intergenerational communication around perinatal loss and the subsequent pregnancy. PMID- 21813815 TI - Online solutions to support needs and preferences of parents of children with asthma and allergies. AB - Many families of children with asthma and allergies experience support deficits and isolation. However, support interventions have not been designed to meet their needs. Consequently, parents' intervention preferences were elicited, and an online peer support group intervention was designed based on these preferences and piloted in the study described. In-depth interviews with 44 parents elicited preferences for support interventions for both children and parents. Many said they felt alone and wanted support from others in similar situations. Based on the parents' preferences for accessible online peer support groups, a pilot online intervention was designed and implemented. Parents received information and reassurance from other parents in peer support sessions. Parents appreciated the accessibility and anonymity of the online support group. This innovative online peer support intervention, informed by parents' preferences, could be adapted and tested in intervention trials and guide programs and practice for families affected by asthma, allergies, and other chronic conditions. PMID- 21813816 TI - "Like a Mexican wedding": psychosocial intervention needs of predominately Hispanic low-income female co-survivors of cancer. AB - Although recent work has recognized that the influence and consequences of cancer extend beyond the individual receiving the diagnosis, no studies have focused on the specific psychosocial intervention needs of female co-survivors in low-income populations. In this qualitative study, the co-survivors, 16 women, representing 10 low-income families and predominately Hispanic, were interviewed about their experience of having someone in their family diagnosed with cancer. Several themes emerged from the data, including family stress, lack of skill in coping with the effects of cancer (e.g., depression of their loved one), a need for financial help, a willingness to share with others, and reliance on faith to see them through the cancer experience. Whereas no agreement existed as to where and how to provide an intervention, participants reported that tailoring an intervention to family needs and delivering it in a way that was accessible to them was important. PMID- 21813818 TI - The therapeutic use of vaptans for the treatment of dilutional hyponatremia. AB - Hyponatremia is a very common electrolyte abnormality. Dilutional hyponatremia is very difficult to treat effectively due to the complications of conventional treatment. Arginine-vasopressin (AVP) plays an integral role in circulatory and water homeostasis. AVP is a hormone released in response to increases in plasma tonicity or decreases in plasma volume in an attempt to maintain the plasma osmolality between 284 and 295 mOsm/L. AVP receptor antagonists or "vaptans" are a new class of drugs that allow for the safe and efficacious treatment of dilutional hyponatremia. Conivaptan, a mixed V1a/V2 receptor antagonist, and tolvaptan, a selective V2 receptor antagonist, are the only 2 vaptans approved by the US Food and Drug Administration. PMID- 21813819 TI - Clinical efficacy of colesevelam in type 2 diabetes mellitus. AB - PURPOSE: The clinical experience and role in therapy of colesevelam in type 2 diabetes mellitus (T2DM) is discussed. SUMMARY: Colesevelam HCl is a bile acid sequestrant (BAS) with proven efficacy in reducing elevated low-density lipoprotein cholesterol (LDL-C) in patients with primary hyperlipidemia. Colesevelam HCl gained food and drug administration (FDA) approval in 2008 as an adjunct to diet and exercise to improve glycemic control in adults with T2DM. In randomized controlled studies, colesevelam (add-on therapy with metformin, sulfonylureas, and insulin) has shown significant percentage reductions in glycosylated hemoglobin A1c (HbA1c) ranging from 0.5% to 0.54%. Reductions in LDL C and non-high-density lipoprotein cholesterol (non-HDL-C) ranging from -12.8% to -16.7% and -4.0% to -10.3%, respectively, were also observed. Although no direct comparisons have been made, the safety and tolerability profile of this agent appears to be better than other BAS, with the most common side effects being gastrointestinal related. CONCLUSION: Colesevelam is effective as an adjunct to diet and exercise to improve glycemic control in adults with T2DM. Due to its effects upon LDL-C and glycemic parameters and favorable safety profile, colesevelam can play a role in an array of T2DM patients. PMID- 21813821 TI - Facilitating children's ability to distinguish symbols for emotions: the effects of background color cues and spatial arrangement of symbols on accuracy and speed of search. AB - PURPOSE: Communication about feelings is a core element of human interaction. Aided augmentative and alternative communication systems must therefore include symbols representing these concepts. The symbols must be readily distinguishable in order for users to communicate effectively. However, emotions are represented within most systems by schematic faces in which subtle distinctions are difficult to represent. We examined whether background color cuing and spatial arrangement might help children identify symbols for different emotions. METHOD: Thirty nondisabled children searched for symbols representing emotions within an 8 choice array. On some trials, a color cue signaled the valence of the emotion (positive vs. negative). Additionally, the symbols were either (a) organized with the negatively valenced symbols at the top and the positive symbols on the bottom of the display or (b) distributed randomly throughout. Dependent variables were accuracy and speed of responses. RESULTS: The speed with which children could locate a target was significantly faster for displays in which symbols were clustered by valence, but only when the symbols had white backgrounds. Addition of a background color cue did not facilitate responses. CONCLUSIONS: Rapid search was facilitated by a spatial organization cue, but not by the addition of background color. Further examination of the situations in which color cues may be useful is warranted. PMID- 21813820 TI - A qualitative study of interference with communicative participation across communication disorders in adults. AB - PURPOSE: To explore the similarities and differences in self-reported restrictions in communicative participation across different communication disorders in community-dwelling adults. METHOD: Interviews were conducted with 44 adults representing 7 different medical conditions: spasmodic dysphonia, multiple sclerosis, stroke, stuttering, Parkinson's disease, amyotrophic lateral sclerosis, and laryngectomy. This article represents a secondary analysis of qualitative data collected in cognitive interviews during development of the Communicative Participation Item Bank. The data were analyzed to identify themes in participants' experiences related to communicative participation. RESULTS: Participants described many situations in which they experienced interference in communicative participation. Two themes emerged from the data. The first theme was Interference is both "functional" and "emotional," in which participants defined interference as limitations in accomplishing tasks and emotional consequences. The second theme was "It depends"-sources of interference, in which participants described many variables that contribute to interference in participation. Participants had limited control of some variables such as symptoms and environmental contexts, but personal decisions and priorities also influenced participation. CONCLUSIONS: Despite different impairments and activity limitations, participants described similar communicative participation restrictions. These similarities may have theoretical and clinical implications in terms of how we assess, treat, and study the participation restrictions associated with communication disorders. PMID- 21813822 TI - Clinical experience using the Mann assessment of swallowing ability for identification of patients at risk for aspiration in a mixed-disease population. AB - PURPOSE: To determine the clinical performance characteristics of the Mann Assessment of Swallowing Ability (MASA) for predicting aspiration (determined by videofluoroscopic swallowing study [VFSS]) in a mixed population. METHOD: We selected 133 cases clinically evaluated using MASA and VFSS from January through June 2007. Ordinal risk rating (ORR) and total numeric score (TNS) were evaluated as predictors of aspiration on VFSS. To account for missing items, the maximum possible score was determined and a weighted percentage score calculated for each patient. We used receiver operating characteristic (ROC) analysis to compare the sensitivity and specificity of ORR and TNS for predicting aspiration. RESULTS: VFSS identified 51 (38.4%) aspirators, while ORR identified 54 (40.6%) as probable or definite aspiration and TNS 19 (14.3%) as moderate to severe aspiration risk. ROC analysis demonstrated an area under the curve of 0.74, 95% CI [0.66, 0.82], for ORR and 0.51, 95% CI [0.41, 0.61], for TNS. These ROC scores suggest that the MASA ORR is better at predicting aspiration on VFSS than the numeric score. CONCLUSION: In this sample, the subjective ORR had good predictive ability, while the percentage TNS failed to predict aspiration on VFSS. The MASA ORR assessment was a better predictor for a patient's aspiration risk in this population. PMID- 21813823 TI - The utility of pitch elevation in the evaluation of oropharyngeal Dysphagia: preliminary findings. AB - PURPOSE: To evaluate the utility of a pitch elevation task in the assessment of oropharyngeal dysphagia. METHOD: This study was a pilot prospective cohort study including 40 consecutive patients (16 male and 24 female) who were referred by their physician for a swallowing evaluation. Patients were evaluated with a noninstrumental clinical examination and a videofluoroscopic swallow study, and participated in a pitch elevation task during videofluoroscopic image acquisition. Relationships between pitch elevation measurements (acoustic and perceptual) and swallow parameters (penetration/aspiration and residue) were investigated. RESULTS: Results of this pilot study revealed that both maximum fundamental frequency (F(0)) and perceptual evaluation of pitch elevation independently significantly predicted Penetration-Aspiration Scale scores for thin liquid swallows (p = .01 and .03, respectively). Vocal range (average pitch to falsetto) was not sensitive in predicting likelihood of oropharyngeal dysphagia. CONCLUSIONS: Findings indicate that reduced pitch elevation can be indicative of reduced airway protection and swallowing impairment in some dysphagia patients and may be a useful supplement to dysphagia screening and diagnosis. Further investigation is warranted to determine the optimal utility of this procedure for different diagnostic categories of patients. PMID- 21813824 TI - The renal histopathological spectrum of patients with nephrotic syndrome: an analysis of 1523 patients in a single Chinese centre. PMID- 21813825 TI - Echocardiographic parameters are independently associated with increased cardiovascular events in patients with chronic kidney disease. AB - BACKGROUND: Patients with chronic kidney disease (CKD) are associated with increased cardiovascular (CV) morbidity and mortality. Echocardiographic measures of heart structure and function have been reported to predict adverse CV outcomes in various pathologic conditions. The aim of this study is to assess whether echocardiographic parameters are independently associated with increased CV events in patients with CKD Stages 3-5. METHODS: We consecutively enrolled 505 CKD patients from our outpatient department of internal medicine. CV events were defined as CV death, hospitalization for unstable angina, non-fatal myocardial infarction, sustained ventricular arrhythmia, hospitalization for congestive heart failure, transient ischemia attack and stroke. The relative CV events' risk was analyzed by Cox regression methods. RESULTS: In the multivariate analysis, old age, the presence of diabetes, coronary artery disease and atrial fibrillation; decreased serum albumin and hematocrit levels; left atrial diameter (LAD) >4.7 cm [hazard ratio (HR), 2.141; 95% confidence interval (CI), 1.155 3.971, P = 0.016]; increased left ventricular mass index (LVMI) (HR, 1.006; 95% CI, 1.002 to 1.010, P = 0.003) and left ventricular ejection fraction (LVEF) <55% (HR, 2.007; 95% CI, 1.007-3.743, P = 0.028) were independently associated with increased CV events. CONCLUSIONS: Our findings show that LAD >4.7 cm, increased LVMI and LVEF <55% are independently associated with adverse CV outcomes in CKD patients. Screening CKD patients by means of echocardiography may help identify a high-risk group of poor CV prognosis. PMID- 21813827 TI - Impact of early kidney resistance index on kidney graft and patient survival during a 5-year follow-up. AB - BACKGROUND: Resistance index (RI) measured by Doppler sonography during the early post-transplant period reflects interstitial oedema within the transplanted kidney. We have prospectively analysed the relationship between RI measured shortly after kidney transplantation (KTx), patient and graft survival, as well as kidney graft function during a 5-year follow-up. METHODS: RI was measured at the second to fourth day after KTx in 364 consecutive patients, who were divided into tertiles, according to baseline RI value (Group 1: RI < 0.73, Group 2: RI between 0.73 and 0.85 and Group 3: RI > 0.85). The kidney graft function [estimated glomerular filtration rate (eGFR)] during the follow-up period was calculated according to the Modification of Diet in Renal Disease formula. RESULTS: During the 5-year follow-up period, 23 patients died (2.6 versus 6.5 versus 9.6% in RI tertiles, respectively) and 59 lost their kidney graft (12.1 versus 17.7 versus 18.4%, respectively). Survival analyses showed that the effect of RI was significant for a combined outcome [graft loss or death; hazard ratio (HR) = 10.88] and in relation to death, it was of borderline significance (HR = 45.3, P = 0.09). The effect of delayed graft function (DGF) was only significant on graft loss (HR = 1.73). eGFR in the highest tertile was lower than in the lowest tertile during the entire follow-up period. CONCLUSIONS: High RI values measured in segmental arteries in the very early post-transplant period predict worse kidney graft function and increased risk of all-cause graft loss, including patient death in the 5-year follow-up period. (ii) The predictive value of RI is not completely independent from the adverse influence of DGF on the premature graft loss. PMID- 21813828 TI - FGF23 and paediatric transplantation: a single-centre French experience. PMID- 21813829 TI - Three kidneys, two diseases, one antibody? AB - Anti-factor H antibody has been recently described as responsible for thrombotic microangiopathies (TMA) as well as membranoproliferative glomerulonephritis (MPGN). We report here, for the first time, the case of a woman with an anti factor H antibody, who developed MPGN on native kidney, rapid recurrence on first graft, and TMA on second graft despite immunosuppressive therapy and plasma exchanges. This case supports the hypothesis that MPGN and TMA are closely linked by common pathogenic mechanisms and the need for complete exploration of complement pathway including factor H activity and autoantibody in front of any MPGN. PMID- 21813831 TI - Pneumocystis jiroveci pneumonia in renal transplantation: time to review our practice? PMID- 21813830 TI - Papillary stones with Randall's plaques in children: clinicobiological features and outcome. PMID- 21813832 TI - Post-Kala-Azar dermal leishmaniasis in Mymensingh, Bangladesh. PMID- 21813833 TI - Nasal fish tank granuloma: an uncommon cause for epistaxis. PMID- 21813835 TI - Placental malaria and mother-to-child transmission of human immunodeficiency virus-1 in rural Rwanda. AB - We conducted a nested case-control study of placental malaria (PM) and mother-to child transmission (MTCT) of human immunodeficiency virus-1 (HIV-1) within a prospective cohort of 627 mother-infant pairs followed from October 1989 until April 1994 in rural Rwanda. Sixty stored placentas were examined for PM and other placental pathology, comparing 20 HIV-infected mother-infant (perinatal transmitter) pairs, 20 HIV-uninfected pairs, and 20 HIV-infected mothers who did not transmit to their infant perinatally. Of 60 placentas examined, 45% showed evidence of PM. Placental malaria was associated with increased risk of MTCT of HIV-1 (adjusted odds ratio [aOR] = 6.3; 95% confidence interval [CI] = 1.4-29.1), especially among primigravidae (aOR = 12.0; 95% CI = 1.0-150; P < 0.05). Before antiretroviral therapy or prophylaxis, PM was associated with early infant HIV infection among rural Rwandan women living in a hyper-endemic malaria region. Primigravidae, among whom malaria tends to be most severe, may be at higher risk. PMID- 21813834 TI - In vitro anti-malarial drug susceptibility of temperate Plasmodium vivax from central China. AB - In the face of recent increase of Plasmodium vivax malaria in central China, we conducted a study to evaluate in vitro susceptibility of temperate-zone P. vivax parasites to antimalarial drugs. During 2005-2006, in vitro drug susceptibility was measured for 42 clinical P. vivax isolates by using a schizont maturation inhibition technique. Geometric means of 50% inhibitory concentrations (IC(50)s) and 95% confidence intervals (CIs) were 10.87 (4.50-26.26) ng/mL for chloroquine, 4.21 (1.88-9.42-8) ng/mL for mefloquine, 11.82 (6.20-22.56) ng/mL for quinine, 0.13 (0.09-0.20) ng/mL for artesunate, 18.32 (8.08-41.50) ng/mL for pyrimethamine, and 17.73 (10.29-30.57) ng/mL for piperaquine. The IC(50) for chloroquine was lower than those obtained from isolates from Thailand and South Korea, suggesting that chloroquine remained effective against P. vivax malaria in central China. The results further indicated that temperate-zone P. vivax isolates from China were more susceptible to chloroquine, quinine, and mefloquine than isolates from Thailand. PMID- 21813836 TI - Lack of molecular correlates of Plasmodium vivax ookinete development. AB - Previous studies of Plasmodium vivax transmission to Anopheles spp. mosquitoes have not been able to predict mosquito infectivity on the basis of microscopic or molecular quantification of parasites (total parasites in the sample or total number of gametocytes) in infected blood. Two methods for production of P. vivax ookinete cultures in vitro, with yields of 10(6) macrogametocytes, 10(4) zygotes, and 10(3) ookinetes, respectively, per 10 mL of P. vivax-infected patient blood with approximately 0.01% parasitemia, were used to study P. vivax sexual stage development. The quantity of gametocytes, determined by counting Giemsa-stained blood smears, and quantity and type of gametocyte as determined by quantitative reverse transcriptase-polymerase chain reaction for Pvalpha tubulin II and macrogametocyte-specific pvg377 did not predict ookinete yield. Factors that affect the efficiency of in vitro P. vivax ookinete transformation remain poorly understood. PMID- 21813837 TI - Influence of the timing of malaria infection during pregnancy on birth weight and on maternal anemia in Benin. AB - Abstract. Although consequences of malaria in pregnancy are well known, the period of pregnancy in which infection has the highest impact is still unclear. In Benin, we followed up a cohort of 1,037 women through pregnancy until delivery. The objective was to evaluate the relationship between the timing of infection and birth weight, and maternal anemia at delivery. At the beginning of pregnancy, peripheral infections were associated with a decrease in mean birth weight (-98.5 g; P = 0.03) and an increase in the risk of anemia at delivery (adjusted odds ratio [aOR] = 1.6; P = 0.03). Infections in late pregnancy were related to a higher risk of maternal anemia at delivery (aOR = 1.7; P = 0.001). To fully protect the women during the whole pregnancy, already implemented measures (insecticide-treated nets and intermittent preventive treatment) should be reinforced. In the future, a vaccine against pregnancy-associated malaria parasites could protect the women in early pregnancy, which seems to be a high risk period. PMID- 21813838 TI - Trypanosoma lewisi or T. lewisi-like infection in a 37-day-old Indian infant. AB - Trypanosomes were observed in the peripheral blood smear of a 37-day-old Indian infant admitted off feeds, with fever and convulsions. Trypanosoma (Herpetosoma) lewisi was identified in the blood. The species identification was confirmed by morphometry, polymerase chain reaction, and sequencing. Human infection with this organism is rare. Only seven cases of this infection have been reported previously in humans. The cases reported are reviewed to develop a composite picture of this disease. PMID- 21813839 TI - Association between onchocerciasis and epilepsy in the Itwara hyperendemic focus, West Uganda: controlling for time and intensity of exposure. AB - In 38 pairs of epilepsy patients and controls matched for time and intensity of exposure to transmission of onchocerciasis, the presence of microfilariae in the skin of epilepsy patients was found insignificantly elevated compared with controls (odds ratio = 1.68; 95% confidence interval [CI] = 0.60-4.57; P = 0.31). This difference was more pronounced when detection of subcutaneous nodules was used as indication of infection with Onchocerca volvulus (odds ratio = 2.77; 95% CI = 0.92-8.33; P = 0.065). These findings from a patient group of limited size suggest that intensity of infection may play a substantial role in the development of onchocerciasis-associated epilepsy. Our results are in contrast to the results of two other independent studies from the identical endemic area; one case concluded a significant positive correlation between onchocerciasis and epilepsy, and the other case concluded a clearly negative correlation. Studies with a greater sample size are needed to confirm this possible relationship. PMID- 21813840 TI - Multiplex bead assay for serum samples from children in Haiti enrolled in a drug study for the treatment of lymphatic filariasis. AB - A multiplex bead assay (MBA) was used to analyze serum samples collected longitudinally from children enrolled in a drug trial for treatment of filariasis in Leogane, Haiti. Recombinant antigens Bm14 and Bm33 from Brugia malayi, third polar tube protein (PTP3) from Encephalitozoon cuniculi, and merozoite surface protein-1(19) (MSP-1(19)) from Plasmodium falciparum were coupled to carboxylated polystyrene microspheres. IgG responses to PTP3 and MSP-1(19) were not affected by albendazole (ALB), diethylcarbamazine (DEC), or combination of diethylcarbamazine and albendazole (DEC/ALB). However, IgG and IgG4 responses to Bm14 and Bm33 were significantly decreased (P < 0.001) by DEC and DEC/ALB treatment. Antibody responses to Bm14 and Bm33 decreased after DEC treatment (but not placebo) among children who were negative for microfilaremia and antigenemia at baseline, suggesting that these children harbored early stages of infection. The MBA is an excellent serologic technique for multiple antigens that offers substantial advantages over single-antigen based enzyme-linked immunosorbent assay in mass drug administration studies for monitoring changes in antibody levels. PMID- 21813841 TI - Cryptosporidium meleagridis: infectivity in healthy adult volunteers. AB - Most Cryptosporidium infections in humans are caused by C. parvum or C. hominis. However, genotyping techniques have identified infections caused by unusual Cryptosporidium species. Cryptosporidium meleagridis has been identified in <= 1% of persons with diarrhea, although prevalence is higher in developing nations. We examined the infectivity of C. meleagridis in healthy adults. Five volunteers were challenged with 10(5) C. meleagridis oocysts and monitored six weeks for fecal oocysts and clinical manifestations. Four volunteers had diarrhea; three had detectable fecal oocysts; and one infected volunteer remained asymptomatic. Fecal DNA from two volunteers was amplified by using a polymerase chain reaction specific for the Cryptosporidium small subunit ribosomal RNA gene. Nucleotide sequence of these amplicons was diagnostic for C. meleagridis. All infections were self-limited; oocysts were cleared within <= 12 days of challenge. These studies establish that healthy adults can be infected and become ill from ingestion of C. meleagridis oocysts. PMID- 21813842 TI - Toxoplasmosis-serological evidence and associated risk factors among pregnant women in southern Thailand. AB - Toxoplasma gondii is an important parasite in pregnant women. This case controlled study assessed the seroprevalence of toxoplasmosis in 640 pregnant women in southern Thailand and identified their associated risk factors. The overall seroprevalence of toxoplasmosis was 181 (28.3%). Of this, 138 (21.6%) were positive for only anti-Toxoplasma immunoglobulin G (IgG) antibody, 43 (6.7%) were positive for both IgG and IgM antibodies, and none were positive for IgM antibody. Multivariate analysis revealed that increasing age (adjusted odds ratio [OR] = 1.64, 95% confidence interval [CI] = 1.01-2.67), living outside Songkhla province (adjusted OR = 1.56, 95% CI = 1.08-2.24), parity (adjusted OR = 1.65, 95% CI = 1.01-2.68), contact with cats (adjusted OR = 1.70, 95% CI = 1.20-2.43), and drinking of unclean water (adjusted OR = 1.70, 95% CI = 1.08-2.68) were factors associated with Toxoplasma seroprevalence. On the basis of the results obtained, a health surveillance program should be initiated as a primary preventive measure for congenital toxoplasmosis and focus on educating women of the child-bearing age group to avoid contact with cats and to strictly practice personal hygiene. PMID- 21813843 TI - Development of a semi-field system for contained field trials with Aedes aegypti in southern Mexico. AB - Abstract. Development of new genetic approaches to either interfere with the ability of mosquitoes to transmit dengue virus or to reduce vector population density requires progressive evaluation from the laboratory to contained field trials, before open field release. Trials in contained outdoor facilities are an important part of this process because they can be used to evaluate the effectiveness and reliability of modified strains in settings that include natural environmental variations without releasing mosquitoes into the open field. We describe a simple and cost-effective semi-field system designed to study Aedes aegypti carrying a dominant lethal gene (fsRIDL) in semi-field conditions. We provide a protocol for establishing, maintaining, and monitoring stable Ae. aegypti population densities inside field cages. PMID- 21813844 TI - Parameterization and sensitivity analysis of a complex simulation model for mosquito population dynamics, dengue transmission, and their control. AB - Models can be useful tools for understanding the dynamics and control of mosquito borne disease. More detailed models may be more realistic and better suited for understanding local disease dynamics; however, evaluating model suitability, accuracy, and performance becomes increasingly difficult with greater model complexity. Sensitivity analysis is a technique that permits exploration of complex models by evaluating the sensitivity of the model to changes in parameters. Here, we present results of sensitivity analyses of two interrelated complex simulation models of mosquito population dynamics and dengue transmission. We found that dengue transmission may be influenced most by survival in each life stage of the mosquito, mosquito biting behavior, and duration of the infectious period in humans. The importance of these biological processes for vector-borne disease models and the overwhelming lack of knowledge about them make acquisition of relevant field data on these biological processes a top research priority. PMID- 21813845 TI - Competitive reduction by satyrization? Evidence for interspecific mating in nature and asymmetric reproductive competition between invasive mosquito vectors. AB - Abstract. Upon mating, male mosquitoes transfer accessory gland proteins (Acps) that induce refractoriness to further mating in females. This can also occur because of cross-insemination by males of related species, a process known as mating interference (satyrization). This mechanism could explain the competitive displacement of resident Aedes aegypti by the invasive Aedes albopictus where they co-occur. We tested this hypothesis in mosquito populations in Florida. A new polymerase chain reaction species diagnostic applied to sperm dissected from 304 field-collected females revealed bidirectional cross-mating in five (1.6%) individuals. Cross-injections of females with Acps showed that Ae. albopictus males induced monogamy in heterospecific females but not Ae. aegypti males. Despite its low frequency in the areas under study, the first evidence of cross mating in nature and the asymmetric effect of Acps on mating suggest that satyrization may have initially contributed to the observed competitive reduction of Ae. aegypti by invasive Ae. albopictus in many areas. PMID- 21813846 TI - Highly virulent Leptospira borgpetersenii strain characterized in the hamster model. AB - Abstract. A recent study by our group reported the isolation and partial serological and molecular characterization of four Leptospira borgpetersenii serogroup Ballum strains. Here, we reproduced experimental leptospirosis in golden Syrian hamsters (Mesocricetus auratus) and carried out standardization of lethal dose 50% (LD50) of one of these strains (4E). Clinical disease features and histopathologic analyses of tissue lesions were also observed. As results, strain 4E induced lethality in the hamster model with inocula lower than 10 leptospires, and histopathological examination of animals showed typical lesions found in severe leptospirosis. Gross pathological findings were peculiar; animals that died early had more chance of presenting severe jaundice and less chance of presenting pulmonary hemorrhages (P < 0.01). L. borgpetersenii serogroup Ballum has had a considerable growth in human leptospirosis cases in recent years. This strain has now been thoroughly characterized and can be used in more studies, especially evaluations of vaccine candidates. PMID- 21813847 TI - Leptospirosis among hospitalized febrile patients in northern Tanzania. AB - We enrolled consecutive febrile admissions to two hospitals in Moshi, Tanzania. Confirmed leptospirosis was defined as a >= 4-fold increase in microscopic agglutination test (MAT) titer; probable leptospirosis as reciprocal MAT titer >= 800; and exposure to pathogenic leptospires as titer >= 100. Among 870 patients enrolled in the study, 453 (52.1%) had paired sera available, and 40 (8.8%) of these met the definition for confirmed leptospirosis. Of 832 patients with >= 1 serum sample available, 30 (3.6%) had probable leptospirosis and an additional 277 (33.3%) had evidence of exposure to pathogenic leptospires. Among those with leptospirosis the most common clinical diagnoses were malaria in 31 (44.3%) and pneumonia in 18 (25.7%). Leptospirosis was associated with living in a rural area (odds ratio [OR] 3.4, P < 0.001). Among those with confirmed leptospirosis, the predominant reactive serogroups were Mini and Australis. Leptospirosis is a major yet underdiagnosed cause of febrile illness in northern Tanzania, where it appears to be endemic. PMID- 21813848 TI - Case report: melioidosis imported from West Africa to Europe. AB - We report the first case of imported melioidosis in Spain from a diabetic immigrant who visited West Africa during the rainy season. Because of the unusual presentation of this disease in Africa, clinical and microbiological diagnosis of imported melioidosis from this continent can be very elusive. PMID- 21813849 TI - Effect of sex, age, and race on the clinical presentation of tuberculosis: a 15 year population-based study. AB - Extrapulmonary tuberculosis (EPTB) is an important health problem that may cause serious morbidity and diagnostic challenges. We conducted a case-control study involving 5,684, approximately 99% of bacteriologically confirmed TB patients (including 1,925 EPTB cases) diagnosed in Denmark and Greenland during 1992-2007 to gain insight to the role of host factors in EPTB pathogenesis. Among patients from Somalia and Asia, persons 25-44 and 45-64 years of age were more likely to have EPTB than persons 15-24 years of age. In contrast, among persons from Greenland, the two oldest age groups were significantly less likely to have EPTB than the youngest age group. For all the age groups, the odds for having EPTB was significantly higher among patients from Somalia and Asia and significantly lower among the patients from Greenland than among patients from Denmark. Furthermore, the occurrence of specific types of EPTB significantly varied among different age groups or origins. PMID- 21813850 TI - Adverse events after mass azithromycin treatments for trachoma in Ethiopia. AB - During a cluster-randomized clinical trial for trachoma in Ethiopia, two rounds of adverse event surveillance were performed in a random sample of communities after community-wide mass azithromycin treatment. The prevalence of any reported adverse event ranged from 4.9% to 7.0% in children 1-9 years of age and from 17.0% to 18.7% in persons >= 10 years of age. Adverse events appeared to cluster by household and perhaps by village. Mass azithromycin distributions were well tolerated in this setting. PMID- 21813851 TI - Urine antibiotic activity in patients presenting to hospitals in Laos: implications for worsening antibiotic resistance. AB - Widespread use of antibiotics may be important in the spread of antimicrobial resistance. We estimated the proportion of Lao in- and outpatients who had taken antibiotics before medical consultation by detecting antibiotic activity in their urine added to lawns of Bacillus stearothermophilus, Escherichia coli, and Streptococcus pyogenes. In the retrospective (N = 2,058) and prospective studies (N = 1,153), 49.7% (95% confidence interval [CI] = 47.4-52.0) and 36.2% (95% CI = 33.4-38.9), respectively, of Vientiane patients had urinary antibiotic activity detected. The highest frequency of estimated antibiotic pre-treatment was found in patients recruited with suspected central nervous system infections and community-acquired septicemia (both 56.8%). In Vientiane, children had a higher frequency of estimated antibiotic pre-treatment than adults (60.0% versus 46.5%; P < 0.001). Antibiotic use based on patients histories was significantly less frequent than when estimated from urinary antibiotic activity (P < 0.0001). PMID- 21813852 TI - Warming oceans, phytoplankton, and river discharge: implications for cholera outbreaks. AB - Phytoplankton abundance is inversely related to sea surface temperature (SST). However, a positive relationship is observed between SST and phytoplankton abundance in coastal waters of Bay of Bengal. This has led to an assertion that in a warming climate, rise in SST may increase phytoplankton blooms and, therefore, cholera outbreaks. Here, we explain why a positive SST-phytoplankton relationship exists in the Bay of Bengal and the implications of such a relationship on cholera dynamics. We found clear evidence of two independent physical drivers for phytoplankton abundance. The first one is the widely accepted phytoplankton blooming produced by the upwelling of cold, nutrient-rich deep ocean waters. The second, which explains the Bay of Bengal findings, is coastal phytoplankton blooming during high river discharges with terrestrial nutrients. Causal mechanisms should be understood when associating SST with phytoplankton and subsequent cholera outbreaks in regions where freshwater discharge are a predominant mechanism for phytoplankton production. PMID- 21813853 TI - An assessment of continued use and health impact of the concrete biosand filter in Bonao, Dominican Republic. AB - The biosand filter (BSF) is a promising point of use (POU) technology for water treatment; however there has been little follow-up of initial implementation to assess sustainability. The purpose of this study was to examine continued use, performance, and sustainability of previously implemented concrete BSFs in Bonao, Dominican Republic. Of 328 households visited and interviewed, 90% of BSFs were still in use after approximately 1 year since installation. Water-quality improvement, measured by fecal indicator bacteria reduction, was found to be 84 88%, which is lower than reductions in controlled laboratory studies but similar to other field assessments. In a short prospective cohort study comparing BSF to non-BSF households, odds of reported diarrheal disease in BSF households were 0.39 times the odds of reported diarrheal disease in non-BSF households. These results document high levels of sustained and effective concrete BSF use and associated improvements in water quality and health. PMID- 21813855 TI - A hand-powered, portable, low-cost centrifuge for diagnosing anemia in low resource settings. AB - This report describes the development of a hand-powered centrifuge to determine hematocrit values in low-resource settings. A hand-powered centrifuge was constructed by using a salad spinner. Hematocrit values were measured by using the hand-powered device, and results were compared with those of a benchtop centrifuge. The packed cell volume (PCV) measured with the hand-powered device correlated linearly with results obtained with a benchtop centrifuge (r = 0.986, P < 0.001). The PCVs measured with the hand-powered centrifuge were consistently 1.14 times higher than those measured with the benchtop system. The 14% increase in PCV measured with the hand-powered centrifuge is caused by increased plasma trapped in the cell column. The reader card was adjusted to compensate for trapped plasma. A hand-powered centrifuge and calibrated reader card can be constructed for U.S. $35 and can accurately determine hematocrit values. It is suitable for use in low-resource settings because it is mechanically-powered, inexpensive, and accurate. PMID- 21813854 TI - Drinking water quality, feeding practices, and diarrhea among children under 2 years of HIV-positive mothers in peri-urban Zambia. AB - In low-income settings, human immunodeficiency virus (HIV)-positive mothers must choose between breastfeeding their infants and risking transmission of HIV or replacement feeding their infants and risking diarrheal disease from contaminated water. We conducted a cross-sectional study of children < 2 years of age of 254 HIV-positive mothers in peri-urban Zambia to assess their exposure to waterborne fecal contamination. Fecal indicators were found in 70% of household drinking water samples. In a multivariable analysis, factors associated with diarrhea prevalence in children < 2 years were mother having diarrhea (adjusted odds ratio [aOR] = 5.18, 95% confidence interval [CI] = 1.65-16.28), child given water in the past 2 days (aOR = 4.08, 95% CI = 1.07-15.52), child never being breastfed (aOR = 2.67, 95% CI = 1.06-6.72), and rainy (versus dry) season (aOR = 4.60, 95% CI = 1.29-16.42). Children born to HIV-positive mothers were exposed to contaminated water through direct intake of drinking water, indicating the need for interventions to ensure microbiological water quality. PMID- 21813856 TI - Decreased parasite load and improved cognitive outcomes caused by deworming and consumption of multi-micronutrient fortified biscuits in rural Vietnamese schoolchildren. AB - Micronutrient deficiencies are associated with impaired growth and cognitive function. A school-based fortification program might benefit schoolchildren but a high prevalence of parasite infestation might affect effectiveness. A randomized, double-blind, placebo-controlled 2 * 2 factorial trial was conducted to assess the efficacy of multi-micronutrient fortified biscuits with or without de-worming on growth, cognitive function, and parasite load in Vietnamese schoolchildren. Schoolchildren (n = 510), 6-8 years of age were randomly allocated to receive albendazole or placebo at baseline and four months of multi-micronutrient fortified biscuits (FB) or non-fortified biscuits. Children receiving FB for four months scored higher on two cognitive tests: Raven's Colored Progressive Matrices and the Digit Span Forward test. Children receiving albendazole plus FB had the lowest parasite load after four months. In children receiving FB, mid-upper arm circumference was slightly improved (+0.082 cm) but there were no differences in other indexes of anthropometry. Combining multi-micronutrient fortified biscuits with de-worming is an effective strategy. PMID- 21813857 TI - Safety and immunogenicity of a tetravalent live-attenuated dengue vaccine in flavivirus-naive infants. AB - A Phase I/II observer-blind, randomized, controlled trial evaluated the safety and immunogenicity of a dengue virus (DENV) vaccine candidate in healthy Thai infants (aged 12-15 months) without measurable pre-vaccination neutralizing antibodies to DENV and Japanese encephalitis virus. Fifty-one subjects received two doses of either DENV (N = 34; four received 1/10th dose) or control vaccine (N = 17; dose 1, live varicella; dose 2, Haemophilus influenzae type b). After each vaccine dose, adverse events (AEs) were solicited for 21 days, and non serious AEs were solicited for 30 days; serious AEs (SAEs) were recorded throughout the study. Laboratory safety assessments were performed at 10 and 30 days; neutralizing antibodies were measured at 30 days. The DENV vaccine was well tolerated without any related SAEs. After the second dose, 85.7% of full-dose DENV vaccinees developed at least trivalent and 53.6% developed tetravalent neutralizing antibodies >= 1:10 to DENV (control group = 0%). This vaccine candidate, therefore, warrants continued development in this age group (NCT00322049; clinicaltrials.gov). PMID- 21813858 TI - Toll-like receptor 4 polymorphisms in dengue virus-infected children. AB - Differential viral recognition by cells bearing Toll-like receptor 4 (TLR4) polymorphisms Asp299Gly and Thr399Ile may influence susceptibility and severity of dengue virus infection. In central Java, Indonesia, we investigated 201 children with dengue hemorrhagic fever (DHF) and 179 healthy controls. Patients and controls were mostly ethnic Javanese. A nearly complete cosegregation of the two mutations was observed. The TLR4 299/399 genotype was found in five patients and four controls. Prevalence of the TLR4 299/399 genotype did not differ significantly between controls and DHF patients or between patients with different severities of DHF. Also, vascular leakage in patients with different TLR4 genotypes did not differ. Thus, the 299/399 TLR4 haplotype has only minor influence on susceptibility and severity of complicated dengue virus infection. PMID- 21813859 TI - Decay and persistence of maternal dengue antibodies among infants in Bangkok. AB - Abstract. Maternal dengue antibodies are important in determining the optimal age of dengue vaccination, but no study has quantified the heterogeneity of antibody decay and persistence in infants. We used longitudinal regression methods and survival analysis to measure decay and persistence times of serotype-specific neutralizing antibodies in 139 infants in Bangkok. A biphasic decay pattern was found with half-life times of 24-29 days between birth and 3 months and 44-150 days after 3 months. Atypical decay rates were found in 17% of infants for dengue virus-1 and -4. Median persistence times of plaque reduction neutralization tests > 10 ranged from 6 to 9 months. Persistence times for individuals could not be predicted based on antibody values at birth. Vaccination against dengue before 12 months of age would be ineffective if maternal antibodies at plaque reduction neutralization test levels below 80 interfere with vaccine uptake. Projections of average antibody persistence based on values at birth should be avoided in studies on dengue pathogenesis in infants. PMID- 21813860 TI - An experimental model of meningoencephalomyelitis by Rocio flavivirus in BALB/c mice: inflammatory response, cytokine production, and histopathology. AB - Rocio virus (ROCV) is a flavivirus, probably transmitted by Culex mosquitoes and maintained in nature as a zoonosis of wild birds. Rocio virus caused a human epidemic of severe encephalitis that lasted from 1973 to 1980 in the Ribeira valley, in the southeastern coast of Brazil. After this outbreak, serologic evidence of ROCV circulation has been reported and public health authorities are concerned about a return of ROCV outbreaks in Brazil. We show here a study on the pathogenesis and the physiopathology of ROCV disease in the central nervous system of a Balb/C young adult mice experimental model. The animals were intraperitoneally infected by ROCV and followed from 0 to 9 days after infection, when all of them died. Nervous tissue samples were collected from infected animals for immunohistochemistry and molecular biology analysis. We observed the virus in the central nervous system, the inflammatory changes induced by Th1 and Th2 cytokines, and the final irreversible damage of nervous tissues by neuronal degeneration and apoptosis. These findings can help to better understand the pathogenesis and physiopathology of the human meningoencephalomyelitis by ROCV and other flaviviruses. PMID- 21813861 TI - Requirement of glycosylation of West Nile virus envelope protein for infection of, but not spread within, Culex quinquefasciatus mosquito vectors. AB - Most of sequenced West Nile virus (WNV) genomes encode a single N-linked glycosylation site on their envelope (E) proteins. We previously found that WNV lacking the E protein glycan was severely inhibited in its ability to replicate and spread within two important mosquito vector species, Culex pipiens and Cx. tarsalis. However, recent work with a closely related species, Cx. pipiens pallens, found no association between E protein glycosylation and either replication or dissemination. To examine this finding further, we expanded upon our previous studies to include an additional Culex species, Cx. quinquefasciatus. The non-glycosylated WNV-N154I virus replicated less efficiently in mosquito tissues after intrathoracic inoculation, but there was little difference in replication efficiency in the midgut after peroral infection. Interestingly, although infectivity was inhibited when WNV lacked the E protein glycan, there was little difference in viral spread throughout the mosquito. These data indicate that E protein glycosylation affects WNV-vector interactions in a species-specific manner. PMID- 21813862 TI - A novel low-cost approach to estimate the incidence of Japanese encephalitis in the catchment area of three hospitals in Bangladesh. AB - Acute meningoencephalitis syndrome surveillance was initiated in three medical college hospitals in Bangladesh in October 2007 to identify Japanese encephalitis (JE) cases. We estimated the population-based incidence of JE in the three hospitals' catchment areas by adjusting the hospital-based crude incidence of JE by the proportion of catchment area meningoencephalitis cases who were admitted to surveillance hospitals. Instead of a traditional house-to-house survey, which is expensive for a disease with low frequency, we attempted a novel approach to identify meningoencephalitis cases in the hospital catchment area through social networks among the community residents. The estimated JE incidence was 2.7/100,000 population in Rajshahi (95% confidence interval [CI] = 1.8-4.9), 1.4 in Khulna (95% CI = 0.9-4.1), and 0.6 in Chittagong (95% CI = 0.4-0.9). Bangladesh should consider a pilot project to introduce JE vaccine in high incidence areas. PMID- 21813863 TI - Case reports of neuro-Chikungunya in southern Thailand. AB - There has been a recent increase in reports of neurologic complications as major causes of morbidity and mortality in chikungunya virus infection. As a part of 2004-2009 global outbreaks, an unprecedented large chikungunya epidemic occurred in Southern Thailand during 2008-2009 in which 49,069 cases were reported. During this period, we encountered two patients with meningoencephalitis and another patient with myeloneuropathy among 1,018 cases diagnosed as chikungunya in our hospital. The clinical pictures are presented and the key points are used to recognize and differentiate chikungunya from Japanese encephalitis virus, dengue virus, and herpesvirus infections, which are more common causes of meningoencephalitis and myelitis in this region. PMID- 21813864 TI - Prevalence of hepatitis B and hepatitis C coinfections in an adult HIV centre population in Gaborone, Botswana. AB - The objective of this study was to assess the prevalence of hepatitis B and hepatitis C coinfections in human immunodeficiency virus (HIV) -infected adults at an HIV center in Gaborone, Botswana. A retrospective review was performed of charts of currently active HIV-infected adult patients in the Family Model Clinic (FMC) of the Botswana-Baylor Children's Clinical Center of Excellence (BCOE) in Gaborone, Botswana, for the results of serum hepatitis B surface antigen (HBsAg) and antihepatitis C IgG tests performed between January 1, 2005 and December 15, 2009. Of 308 active FMC patients, 266 underwent HBsAg serology testing within the period of study. The HBsAg coinfection prevalence was 5.3% (14/266); 2 of 252 patients had at least one positive antihepatitis C IgG serology, a 0.8% prevalence. Hepatitis B coinfection is relatively common in HIV-infected adults at our center in Botswana, whereas hepatitis C coinfection is rare. In this setting, where the diagnosis of hepatitis B coinfection with HIV has implications for choice of first-line antiretroviral therapy and prevention of perinatal hepatitis B transmission, broader sampling to establish the true population prevalence of hepatitis B coinfection and the desirability of adding screening to HIV management should be considered. These findings provide little justification for adding hepatitis C coinfection screening to the management of HIV infection in Botswana. PMID- 21813865 TI - Following federal guidelines to increase nutrient consumption may lead to higher food costs for consumers. AB - The federal Dietary Guidelines for Americans, 2010, emphasized the need for Americans to consume more potassium, dietary fiber, vitamin D, and calcium, and to get fewer calories from saturated fat and added sugar. We examined the economic impact of meeting these guidelines for adults in King County, Washington. We found that increasing consumption of potassium--the most expensive of the four recommended nutrients--would add $380 per year to the average consumer's food costs. Meanwhile, each time consumers obtained 1 percent more of their daily calories from saturated fat and added sugar, their food costs significantly declined. These findings suggest that improving the American diet will require additional guidance for consumers, especially those with little budget flexibility, and new policies to increase the availability and reduce the cost of healthful foods. PMID- 21813866 TI - US physician practices versus Canadians: spending nearly four times as much money interacting with payers. AB - Physician practices, especially the small practices with just one or two physicians that are common in the United States, incur substantial costs in time and labor interacting with multiple insurance plans about claims, coverage, and billing for patient care and prescription drugs. We surveyed physicians and administrators in the province of Ontario, Canada, about time spent interacting with payers and compared the results with a national companion survey in the United States. We estimated physician practices in Ontario spent $22,205 per physician per year interacting with Canada's single-payer agency--just 27 percent of the $82,975 per physician per year spent in the United States. US nursing staff, including medical assistants, spent 20.6 hours per physician per week interacting with health plans--nearly ten times that of their Ontario counterparts. If US physicians had administrative costs similar to those of Ontario physicians, the total savings would be approximately $27.6 billion per year. The results support the opinion shared by many US health care leaders interviewed for this study that interactions between physician practices and health plans could be performed much more efficiently. PMID- 21813867 TI - SR59230A, a beta-3 adrenoceptor antagonist, inhibits ultradian brown adipose tissue thermogenesis and interrupts associated episodic brain and body heating. AB - Brown adipose tissue (BAT) thermogenesis occurs episodically in an ultradian manner approximately every 80-100 min during the waking phase of the circadian cycle, together with highly correlated increases in brain and body temperatures, suggesting that BAT thermogenesis contributes to brain and body temperature increases. We investigated this in conscious Sprague-Dawley rats by determining whether inhibition of BAT thermogenesis via blockade of beta-3 adrenoceptors with SR59230A interrupts ultradian episodic increases in brain and body temperatures and whether SR59230A acts on BAT itself or via sympathetic neural control of BAT. Interscapular BAT (iBAT), brain, and body temperatures, tail artery blood flow, and heart rate were measured in unrestrained rats. SR59230A (1, 5, or 10 mg/kg ip), but not vehicle, decreased iBAT, body, and brain temperatures in a dose dependent fashion (log-linear regression P < 0.01, R(2) = 0.3, 0.4, and 0.4, respectively, n = 10). Ultradian increases in BAT, brain, and body temperature were interrupted by administration of SR59230A (10 mg/kg ip) compared with vehicle, resuming after 162 +/- 24 min (means +/- SE, n = 10). SR59230A (10 mg/kg ip) caused a transient bradycardia without any increase in tail artery blood flow. In anesthetized rats, SR59230A reduced cooling-induced increases in iBAT temperature without affecting cooling-induced increases in iBAT sympathetic nerve discharge. Inhibition of BAT thermogenesis by SR59230A, thus, reflects direct blockade of beta-3 adrenoceptors in BAT. Interruption of episodic ultradian increases in body and brain temperature by SR59230A suggests that BAT thermogenesis makes a substantial contribution to these increases. PMID- 21813869 TI - Vasoactivity of the gasotransmitters hydrogen sulfide and carbon monoxide in the chicken ductus arteriosus. AB - Besides nitric oxide (NO) and carbon monoxide (CO), hydrogen sulfide (H(2)S) is a third gaseous messenger that may play a role in controlling vascular tone and has been proposed to serve as an O(2) sensor. However, whether H(2)S is vasoactive in the ductus arteriosus (DA) has not yet been studied. We investigated, using wire myography, the mechanical responses induced by Na(2)S (1 MUM-1 mM), which forms H(2)S and HS(-) in solution, and by authentic CO (0.1 MUM-0.1 mM) in DA rings from 19-day chicken embryos. Na(2)S elicited a 100% relaxation (pD(2) 4.02) of 21% O(2)-contracted and a 50.3% relaxation of 62.5 mM KCl-contracted DA rings. Na(2)S-induced relaxation was not affected by presence of the NO synthase inhibitor l-NAME, the soluble guanylate cyclase (sGC) inhibitor ODQ, or the K(+) channel inhibitors tetraethylammonium (TEA; nonselective), 4-aminopyridine (4-AP, K(V)), glibenclamide (K(ATP)), iberiotoxin (BK(Ca)), TRAM-34 (IK(Ca)), and apamin (SK(Ca)). CO also relaxed O(2)-contracted (60.8% relaxation) and KCl-contracted (18.6% relaxation) DA rings. CO-induced relaxation was impaired by ODQ, TEA, and 4-AP (but not by L-NAME, glibenclamide, iberiotoxin, TRAM-34 or apamin), suggesting the involvement of sGC and K(V) channel stimulation. The presence of inhibitors of H(2)S or CO synthesis as well as the H(2)S precursor L-cysteine or the CO precursor hemin did not significantly affect the response of the DA to changes in O(2) tension. Endothelium-dependent and -independent relaxations were also unaffected. In conclusion, our results indicate that the gasotransmitters H(2)S and CO are vasoactive in the chicken DA but they do not suggest an important role for endogenous H(2)S or CO in the control of chicken ductal reactivity. PMID- 21813868 TI - Serotonin nerve terminals in the dorsomedial medulla facilitate sympathetic and ventilatory responses to hemorrhage and peripheral chemoreflex activation. AB - Serotonin neurons of the caudal raphe facilitate ventilatory and sympathetic responses that develop following blood loss in conscious rats. Here, we tested whether serotonin projections to the caudal portion of the dorsomedial brain stem (including regions of the nucleus tractus solitarius that receive cardiovascular and chemosensory afferents) contribute to cardiorespiratory compensation following hemorrhage. Injections of the serotonin neurotoxin 5,7 dihydroxytryptamine produced >90% depletion of serotonin nerve terminals in the region of injection. Withdrawal of ~21% of blood volume over 10 min produced a characteristic three-phase response that included 1) a normotensive compensatory phase, 2) rapid sympathetic withdrawal and hypotension, and 3) rapid blood pressure recovery accompanied by slower recovery of heart rate and sympathetic activity. A gradual tachypnea developed throughout hemorrhage, which quickly reversed with the advent of sympathetic withdrawal. Subsequently, breathing frequency and neural minute volume (determined by diaphragmatic electromyography) declined below baseline following termination of hemorrhage but gradually recovered over time. Lesioned rats showed attenuated sympathetic and ventilatory responses during early compensation and later recovery from hemorrhage. Both ventilatory and sympathetic responses to chemoreceptor activation with potassium cyanide injection were attenuated by the lesion. In contrast, the gain of sympathetic and heart rate baroreflex responses was greater, and low-frequency oscillations in blood pressure were reduced after lesion. Together, the data are consistent with the view that serotonin innervation of the caudal dorsomedial brain stem contributes to sympathetic compensation during hypovolemia, possibly through facilitation of peripheral chemoreflex responses. PMID- 21813870 TI - High-sweat Na+ in cystic fibrosis and healthy individuals does not diminish thirst during exercise in the heat. AB - Sweat Na(+) concentration ([Na(+)]) varies greatly among individuals and is particularly high in cystic fibrosis (CF). The purpose of this study was to determine whether excess sweat [Na(+)] differentially impacts thirst drive and other physiological responses during progressive dehydration via exercise in the heat. Healthy subjects with high-sweat [Na(+)] (SS) (91.0 +/- 17.3 mmol/l), Controls with average sweat [Na(+)] (43.7 +/- 9.9 mmol/l), and physically active CF patients with very high sweat [Na(+)] (132.6 +/- 6.4 mmol/l) cycled in the heat without drinking until 3% dehydration. Serum osmolality increased less (P < 0.05) in CF (6.1 +/- 4.3 mosmol/kgH(2)O) and SS (8.4 +/- 3.0 mosmol/kgH(2)O) compared with Control (14.8 +/- 3.5 mosmol/kgH(2)O). Relative change in plasma volume was greater (P < 0.05) in CF (-19.3 +/- 4.5%) and SS (-18.8 +/- 3.1%) compared with Control (-14.3 +/- 2.3%). Thirst during exercise and changes in plasma levels of vasopressin, angiotensin II, and aldosterone relative to percent dehydration were not different among groups. However, ad libitum fluid replacement was 40% less, and serum NaCl concentration was lower for CF compared with SS and Control during recovery. Despite large variability in sweat electrolyte loss, thirst appears to be appropriately maintained during exercise in the heat as a linear function of dehydration, with relative contributions from hyperosmotic and hypovolemic stimuli dependent upon the magnitude of salt lost in sweat. CF exhibit lower ad libitum fluid restoration following dehydration, which may reflect physiological cues directed at preservation of salt balance over volume restoration. PMID- 21813872 TI - Angiotensin II utilizes Janus kinase 2 in hypertension, but not in the physiological control of blood pressure, during low-salt intake. AB - Janus kinase (JAK) 2 is activated by ANG II in vitro and in vivo, and chronic blockade of JAK2 by the JAK2 inhibitor AG-490 has been shown recently to attenuate ANG II hypertension in mice. In this study, AG-490 was infused intravenously in chronically instrumented rats to determine if the blunted hypertension was linked to attenuation of the renal actions of ANG II. In male Sprague-Dawley rats, after a control period, ANG II at 10 ng.kg(-1).min(-1) was infused intravenously with or without AG-490 at 10 ng.kg(-1).min(-1) iv for 11 days. ANG II infusion (18 h/day) increased mean arterial pressure from 91 +/- 3 to 168 +/- 7 mmHg by day 11. That response was attenuated significantly in the ANG II + AG-490 group, with mean arterial pressure increasing only from 92 +/- 5 to 127 +/- 3 mmHg. ANG II infusion markedly decreased urinary sodium excretion, caused a rapid and sustained decrease in glomerular filtration rate to ~60% of control, and increased renal JAK2 phosphorylation; all these responses were blocked by AG-490. However, chronic AG-490 treatment had no effect on the ability of a separate group of normal rats to maintain normal blood pressure when they were switched rapidly to a low-sodium diet, whereas blood pressure fell dramatically in losartan-treated rats on a low-sodium diet. These data suggest that activation of the JAK/STAT pathway is critical for the development of ANG II induced hypertension by mediating its effects on renal sodium excretory capability, but the physiological control of blood pressure by ANG II with a low salt diet does not require JAK2 activation. PMID- 21813871 TI - Role of an apical K,Cl cotransporter in urine formation by renal tubules of the yellow fever mosquito (Aedes aegypti). AB - The K,Cl cotransporters (KCCs) of the SLC12 superfamily play critical roles in the regulation of cell volume, concentrations of intracellular Cl(-), and epithelial transport in vertebrate tissues. To date, the role(s) of KCCs in the renal functions of mosquitoes and other insects is less clear. In the present study, we sought molecular and functional evidence for the presence of a KCC in renal (Malpighian) tubules of the mosquito Aedes aegypti. Using RT-PCR on Aedes Malpighian tubules, we identified five alternatively spliced partial cDNAs that encode putative SLC12-like KCCs. The majority transcript is AeKCC1-A(1); its full length cDNA was cloned. After expression of the AeKCC1-A protein in Xenopus oocytes, the Cl(-)-dependent uptake of (86)Rb(+) is 1) activated by 1 mM N ethylmaleimide and cell swelling, 2) blocked by 100 MUM dihydroindenyloxyalkanoic acid (DIOA), and 3) dependent upon N-glycosylation of AeKCC1-A. In Aedes Malpighian tubules, AeKCC1 immunoreactivity localizes to the apical brush border of principal cells, which are the predominant cell type in the epithelium. In vitro physiological assays of Malpighian tubules show that peritubular DIOA (10 MUM): 1) significantly reduces both the control and diuretic rates of transepithelial fluid secretion and 2) has negligible effects on the membrane voltage and input resistance of principal cells. Taken together, the above observations indicate the presence of a KCC in the apical membrane of principal cells where it participates in a major electroneutral transport pathway for the transepithelial secretion of fluid in this highly electrogenic epithelium. PMID- 21813873 TI - Exertional dyspnea in mitochondrial myopathy: clinical features and physiological mechanisms. AB - Exertional dyspnea limits exercise in some mitochondrial myopathy (MM) patients, but the clinical features of this syndrome are poorly defined, and its underlying mechanism is unknown. We evaluated ventilation and arterial blood gases during cycle exercise and recovery in five MM patients with exertional dyspnea and genetically defined mitochondrial defects, and in four control subjects (C). Patient ventilation was normal at rest. During exercise, MM patients had low Vo(2peak) (28 +/- 9% of predicted) and exaggerated systemic O(2) delivery relative to O(2) utilization (i.e., a hyperkinetic circulation). High perceived breathing effort in patients was associated with exaggerated ventilation relative to metabolic rate with high VE/VO(2peak), (MM = 104 +/- 18; C = 42 +/- 8, P <= 0.001), and Ve/VCO(2peak)(,) (MM = 54 +/- 9; C = 34 +/- 7, P <= 0.01); a steeper slope of increase in DeltaVE/DeltaVCO(2) (MM = 50.0 +/- 6.9; C = 32.2 +/- 6.6, P <= 0.01); and elevated peak respiratory exchange ratio (RER), (MM = 1.95 +/- 0.31, C = 1.25 +/- 0.03, P <= 0.01). Arterial lactate was higher in MM patients, and evidence for ventilatory compensation to metabolic acidosis included lower Pa(CO(2)) and standard bicarbonate. However, during 5 min of recovery, despite a further fall in arterial pH and lactate elevation, ventilation in MM rapidly normalized. These data indicate that exertional dyspnea in MM is attributable to mitochondrial defects that severely impair muscle oxidative phosphorylation and result in a hyperkinetic circulation in exercise. Exaggerated exercise ventilation is indicated by markedly elevated VE/VO(2), VE/VCO(2), and RER. While lactic acidosis likely contributes to exercise hyperventilation, the fact that ventilation normalizes during recovery from exercise despite increasing metabolic acidosis strongly indicates that additional, exercise-specific mechanisms are responsible for this distinctive pattern of exercise ventilation. PMID- 21813875 TI - Island technique for prominent ears: an update of the Ivo Pitanguy clinic experience. AB - BACKGROUND: Prominent ears are a relatively common and instantly-recognizable condition. Numerous studies have reported psychological distress, emotional trauma, and behavioral problems associated with this deformity in childhood. The multitude of approaches clearly indicates the lack of a definitive technique to correct this issue in all patients. OBJECTIVES: The authors describe the "island technique," originated by the senior author (IP), which involves dissecting a cartilaginous island to reconstruct the antihelix and the triangular fossa and correct the conchascaphal angle. METHODS: The authors retrospectively reviewed the charts of all patients (n = 111) who underwent otoplasty with the island technique at the senior author's private clinic between July 1990 and July 2008. Patients who underwent treatment with a modified island technique or any other approach were excluded. Charts were examined for patient history and demographics, etiology, concurrent procedures, and complications. RESULTS: Eighty patients were female (72%); 31 were male (28%). The average age was 28.2 years (range, five to 65). The most common etiology was a combination of overdeveloped concha and an underdeveloped antihelical fold (n = 76, 69%). Other facial aesthetic procedures were simultaneously performed in 54 patients (49%). Early complications occurred in two patients (1.8%), including hematoma and wound dehiscence. Late complications were observed in 12 patients (10.8%). All complications were addressed without consequence to the surgical outcome. No recurrence was observed. CONCLUSIONS: The island technique is an effective, simple, and reliable surgical option to correct prominent ears. Its greatest advantages are the absence of recurrence and the minimal incidence of complications. PMID- 21813876 TI - Management and avoidance of complications in chin augmentation. AB - Chin augmentation is an extremely rewarding cosmetic operation, particularly when performed as an adjunct to rhinoplasty and rhytidectomy. There has been much debate regarding the ideal surgical approach and whether implant placement or osseous genioplasty is the superior operation. Regardless of the technique, all surgery carries an inherent risk for complications, and it is the surgeon's responsibility to learn which techniques will work best in his or her hands for each patient. Certain complications can be almost unavoidable, but a solid foundation in anatomy and a review of the existing literature can help minimize the risk of certain problems while providing an improved understanding of how to recognize and manage them when they occur. The authors present a comprehensive review of genioplasty and chin implant complications, how they might be avoided, and management methods if they occur. PMID- 21813874 TI - Adaptive mechanisms to compensate for overnutrition-induced cardiovascular abnormalities. AB - In conditions of overnutrition, cardiac cells must cope with a multitude of extracellular signals generated by changes in nutrient load (glucose, amino acids, and lipids) and the hormonal milieu [increased insulin (INS), ANG II, and adverse cytokine/adipokine profile]. Herein, we review the diverse compensatory/adaptive mechanisms that counter the deleterious effects of excess nutrients and growth factors. We largely focus the discussion on evidence obtained from Zucker obese (ZO) and Zucker diabetic fatty (ZDF) rats, which are useful models to evaluate adaptive and maladaptive metabolic, structural, and functional cardiac remodeling. One adaptive mechanism present in the INS resistant ZO, but absent in the diabetic ZDF heart, involves an interaction between the nutrient sensor kinase mammalian target of rapamycin complex 1 (mTORC1) and ANG II-type 2 receptor (AT2R). Recent evidence supports a cardioprotective role for the AT2R; for example, suppression of AT2R activation interferes with antihypertrophic/antifibrotic effects of AT1R blockade, and AT2R agonism improves cardiac structure and function. We propose a scenario, whereby mTORC1-signaling-mediated increase in AT2R expression in the INS-resistant ZO heart is a cardioprotective adaptation to overnutrition. In contrast to the ZO rat, heart tissues of ZDF rats do not show activation of mTORC1. We posit that such a lack of activation of the mTOR<->AT2R integrative pathway in cardiac tissue under conditions of obesity-induced diabetes may be a metabolic switch associated with INS deficiency and clinical diabetes. PMID- 21813877 TI - Rhytidectomy approach for recurrent Madelung disease. AB - Benign symmetrical lipomatosis (Madelung disease) is a rare metabolic disorder characterized by the presence of multiple, symmetric, nonencapsulated fat masses in the face, neck, and shoulders. The clinical course is slow, typically one of slow progressive enlargement with cosmetic and functional sequelae. The authors describe a case in which an open surgical approach was performed to treat this disorder, with good results. There are many aspects of treatment currently lacking a consensus, and the authors discuss these, principally in relation to the location of the fat, the role of liposuction versus surgery, the staging of surgical procedures, and the placement of the incisions. PMID- 21813878 TI - Perioperative steroids for minimizing edema and ecchymosis after rhinoplasty: a meta-analysis. AB - BACKGROUND: Minimizing complications after rhinoplasty is a priority for every surgeon performing the procedure. Perioperative steroid administration has been shown to decrease postoperative edema and ecchymosis in a number of prospective randomized trials. OBJECTIVES: In an effort to further elucidate the significance of the data and develop an evidence-based algorithm for steroid administration, the authors offer a meta-analysis of the existing literature. METHODS: A systematic review of the literature was performed. All articles were reviewed for relevant data, which were extracted, pooled, and compared. Seven prospective randomized trials investigating perioperative steroid use in rhinoplasty have been conducted and reported. Four of these studies had the same method of patient edema and ecchymosis assessment, and their data were compared. RESULTS: Based on results from the four relevant studies, perioperative steroid use significantly reduces postoperative edema and ecchymosis of the upper and lower eyelids at one day and seven days postoperatively (P < .0001). Preoperative steroid administration decreases postoperative upper and lower eyelid edema at one day preoperatively, when compared to postoperative administration (P < .05). Extended dosing is superior to one-time dosing (P < .05). CONCLUSIONS: Perioperative steroid use decreases postoperative edema and ecchymosis associated with rhinoplasty. Preoperative administration is superior to postoperative, and extended dosing is superior to singular. Based on these results, evidence-based guidelines for perioperative steroid administration can be given. PMID- 21813879 TI - Lateral breast flap with superomedial pedicle breast lift. AB - BACKGROUND: Single-stage, durable aesthetic contouring of the volume-depleted and ptotic breast remains a challenge for plastic and reconstructive surgeons. These challenges are often even more difficult in the patient who has undergone massive weight loss (MWL). OBJECTIVES: The authors describe their technique of reshaping the breasts of MWL patients with laterally-based breast flaps during a superomedial pedicle breast lift. METHODS: A total of 20 patients were treated in a private clinic by one of the authors between April 2006 and January 2010 were included in this study. Each patient underwent breast reshaping with mastopexy, lateral breast autoaugmentation, and implant insertion. A laterally-based breast flap was developed to augment the involuted and ptotic breast and was dissected in conjunction with the superomedial pedicle breast lift to maintain the implant position, prevent bottoming out, and provide tissue coverage between the skin and breast implant in the advent of wound breakdown. RESULTS: Mean follow-up for this patient series was 19.5 months (range, two to 47). The average patient age was 41 years (range, 21 to 56), and the majority of patients had Grade 2 ptosis (14 out of 20). The average volume of the implants in this study was 350 cc (range, 275 to 600). There were no instances of seroma or wound infection. Five patients had minor instances of wound breakdown, but none required surgical revision. One patient developed early capsular contracture and required revision. That same patient developed a small hematoma. Patient self-evaluation revealed a high level of satisfaction; all 20 patients reported being happy with their results. CONCLUSIONS: The laterally-based breast flap, in combination with the superomedial pedicle mastopexy, is a powerful tool for use in the postbariatric or postpartum patient in whom the majority of the breast parenchyma is needed to fill the skin envelope. This flap serves to improve overall breast shape by providing added tissue along the deficient inferior pole, relieving some of the unaesthetic lateral chest wall excess and providing an additional layer of support inferiorly along the fold. PMID- 21813880 TI - Repair of the midline fascial defect in abdominoplasty with long-acting barbed and smooth absorbable sutures. AB - BACKGROUND: Traditionally, repair of the midline fascial defect has been performed with interrupted or running permanent sutures during abdominoplasty. Barbed suture devices, however, eliminate the need for knot tying and potentially are equally effective at maintaining the repair while allowing for faster deployment and elimination of a potential nidus for infection. OBJECTIVE: The authors report their experience with long-acting absorbable barbed and smooth sutures. METHODS: A retrospective chart review was conducted on 34 consecutive patients who underwent abdominoplasty, alone or in conjunction with other procedures, between August 2006 and December 2009. Seventeen patients had repair of the midline abdominal wall rectus diastasis performed with a smooth running absorbable polydioxanone suture, and 17 underwent repair with a barbed suture. RESULTS: All 34 patients were women; their mean age was 43.6 years, and their mean body mass index was 23.0 kg/m(2). Sixty-eight percent of the patients elected to undergo concurrent procedures. Patients were followed for a mean of 34 months (27 months barbed; 42 months smooth). No cases of recurrent diastasis were observed. Complications included minor seroma (two cases in the barbed suture group, one in the smooth group) and infected hematoma (one in the barbed suture group). CONCLUSIONS: Based on the data from this series of patients, long-acting absorbable barbed or smooth sutures appear to be equally effective in maintaining rectus diastasis repair. Barbed sutures therefore hold promise as a useful alternative to permanent sutures for the plication of the rectus fascia during abdominoplasty. PMID- 21813881 TI - A comparative, long-term assessment of four soft tissue substitutes. AB - BACKGROUND: The ideal product for soft tissue replacement is durable, nonimmunogenic, and noninfectious. AlloDerm (LifeCell Corp., Branchburg, New Jersey), Enduragen (Stryker Corp., Kalamazoo, Michigan), and DermaMatrix (Synthes, Inc., West Chester, Pennsylvania) are frequently used for soft tissue replacement, but comparative analysis of these materials over an extended time period has not been reported. DuraMatrix (bovine tendon matrix; Stryker Corp.) is also promising, demonstrating desirable properties not only as a dural substitute but also for soft tissue replacement. OBJECTIVES: The authors analyze in vivo gross and microscopic changes over time with four commercially available dermal matrices, utilizing the murine model for a controlled environment. METHODS: AlloDerm, Enduragen, DermaMatrix, and DuraMatrix implants measuring 1 * 1 cm were each implanted in 40 adult mice, in individual dorsal submuscular pockets. The mice were then sacrificed in groups of 10 at three, six, nine, and 12 months. The implants and surrounding tissues were excised and evaluated for gross and microscopic appearance. RESULTS: Histological analysis of the specimens demonstrated similar encapsulation, implant infiltration, and surrounding inflammation over time. Enduragen implants demonstrated the least amount of host cell infiltration, whereas AlloDerm demonstrated the most. Grossly, Enduragen maintained its original shape and became firmer over time, whereas AlloDerm became spherical and softer. DermaMatrix and DuraMatrix both maintained their original shape and consistency. Implant migration, explantation, infection, or allergic reactions were not noted. CONCLUSIONS: All of the materials studied demonstrated high levels of host tolerance and tissue integration. AlloDerm demonstrated signs of resorption, whereas Enduragen maintained its size and became firmer in consistency. Together with the histological results, this suggests a proportional relationship between the amount of host cell integration and implant resorption. PMID- 21813882 TI - Autologous fat transplantation versus adipose-derived stem cell-enriched lipografts: a study. AB - BACKGROUND: Several techniques for lipoinjection have been described in the literature. Recently, the role of adult stem cells in adipose tissue has gained interest. OBJECTIVES: The authors compare autologous fat transplantation to adipose-derived stem cell-enriched lipografts. METHODS: A group of 20 patients with congenital or acquired facial tissue defects were included in this study and randomly divided into two groups. Ten patients were treated with autologous fat transplantation (Group A; 12-165 mL per session), and the remaining ten were treated with adipose-derived stem cell-enriched lipografts (Group B; 8-155 mL per session). Overall patient satisfaction after both treatments was evaluated at six, 12, and 18 months after the initial surgical procedure. RESULTS: In Group A, three patients achieved aesthetically-acceptable results after the first treatment; the remaining seven patients required additional sessions. In Group B, all patients required only one treatment. Analysis of patient satisfaction in the first six months clearly demonstrated better results in Group B. However, by the 18-month evaluation, there was no statistical difference between the two groups in terms of patient satisfaction. CONCLUSIONS: Adipose-derived stem cell-enriched lipografts produced aesthetically-acceptable results without the need for repeat treatment sessions, which are necessary with autologous fat transplantation. Further long-term studies are necessary to confirm the favorable results seen in this study. PMID- 21813883 TI - Complications from international surgery tourism. AB - Medical tourism is an increasing trend, particularly in cosmetic surgery. Complications resulting from these procedures can be quite disruptive to the healthcare industry in the United States since patients often seek treatment and have no compensation recourse from insurance. Despite the increasing number of plastic surgery patients seeking procedures abroad, there have been little reported data concerning outcomes, follow-up, or complication rates. Through a survey of American Society of Plastic Surgeons (ASPS) members, the authors provide data on trends to help define the scope of the problem. PMID- 21813884 TI - Commentary on: Complications From International Surgery Tourism. PMID- 21813885 TI - Revisionary breast surgery with acellular dermal matrices. AB - Revisionary breast surgeries are challenging, and advanced techniques must often be utilized in the correction of the underlying anatomical deformities. In this Featured Operative Technique, the authors describe their method, which includes a combination of revisionary surgery techniques with site change and acellular dermal matrices. This use of acellular dermal matrices has four indications based on the underlying clinical presentation: (1) as a lower pole implant interface (usually for revision mastopexy), (2) as a capsular contracture treatment (technically similar to lower pole interface), (3) as a tissue thickener (superomedial or inferolateral implant interface), or (4) as an implant stabilizer (malposition correction). PMID- 21813886 TI - Patient safety at 10 years. PMID- 21813887 TI - An integrated model of patient safety and quality of care. PMID- 21813888 TI - ASAPS/ASPS position statement on stem cells and fat grafting. PMID- 21813889 TI - Got evidence? Stem cells, bias, and the level of evidence ladder: commentary on: "ASAPS/ASPS position statement on stem cells and fat grafting". PMID- 21813890 TI - The nomenclature of "vaginal rejuvenation" and elective vulvovaginal plastic surgery. PMID- 21813891 TI - Persistence of urinary symptoms after cessation of ketamine abuse. PMID- 21813892 TI - A synopsis of current care of thalassaemia major patients in Hong Kong. AB - OBJECTIVE: To provide a synopsis of current thalassaemia major patient care in Hong Kong. DESIGN: Retrospective study. SETTING: All haematology units of the Hospital Authority in Hong Kong. PATIENTS: All patients with thalassaemia major with regular transfusion. RESULTS: To date, there were 363 thalassaemia major patients under the care of the Hospital Authority. Prenatal diagnosis has helped to reduce the number of indigenous new cases, but in recent years immigrant cases are appearing. The patients have a mean age of 23 (range, 1-52) years, and 78% of them are adults. In 2009, they received 18 782 units of blood. This accounted for 9.5% of all blood consumption from the Hong Kong Red Cross. In the past, cardiac iron overload was the major cause of death (65%) and few patients survived beyond the age of 45 years. The availability of cardiac iron assessment by magnetic resonance imaging (T2 MRI) to direct the use of oral deferiprone chelation has reduced the prevalence of heart failure and cardiac haemosiderosis, which should reduce mortality and improve life expectancy. CONCLUSION: The future for thalassaemia care in Hong Kong is bright. With better transfusion and chelation, it should be possible to avoid growth and endocrine deficiencies in younger patients. PMID- 21813893 TI - Urinary symptoms and impaired quality of life in female ketamine users: persistence after cessation of use. AB - OBJECTIVE: To compare the urinary symptoms and quality of life in ex-ketamine abusers and controls. DESIGN: Prospective observational study. SETTING: A hospital in Hong Kong. PATIENTS: Female ex-ketamine abusers admitted to a local drug rehabilitation centre and age-matched controls attending a general gynaecology clinic between December 2009 and April 2010. MAIN OUTCOME MEASURES: Evaluation of urinary symptoms based on a 3-day bladder diary, and responses to the Urogenital Distress Inventory Short Form (UDI-6) and the Incontinence Impact Questionnaire Short Form (IIQ-7). The study group had repeat measurements 3 months later. RESULTS: Overall, 90% of ex-ketamine abusers had active urinary symptoms. On average, they had increased 24-hour urinary frequency (10.0 vs 5.8; P=0.001) and lower maximum voided volume (253.3 mL vs 401.9 mL; P<0.001) compared to controls. Correspondingly, the median functional bladder capacity was smaller (195.3 mL vs 261.2 mL; P=0.011) and the mean UDI-6 and IIQ-7 scores were higher (P<0.001). Among those who abused ketamine for 2 years or more, the mean UDI-6 and IIQ-7 scores were higher (P=0.03, P=0.02 respectively). When they stopped abusing ketamine for 3 months or more, their mean 24-hour urinary frequency had decreased (P=0.03), the maximum voided volume had increased (P=0.03) and the mean UDI-6 and IIQ-7 scores had decreased (P=0.04, P=0.02 respectively), although they were still higher than in controls. After 3 more months, in the ex-ketamine abusers there had been a further decrease in 24-hour urinary frequency (P=0.01) and a further improvement in quality of life based on mean UDI-6 scores (P=0.04) but nevertheless poorer than the control group (P<0.01). CONCLUSION: Female ex ketamine abusers had significant urinary symptoms affecting their quality of life when studied at a mean of 8 (range, 0.5-48) months after cessation of use. The symptom severity was inversely correlated with the duration of cessation; though they improved with time, some still persisted. PMID- 21813894 TI - Using bevacizumab in the fight against malignant glioma: first results in Asian patients. AB - OBJECTIVES: To investigate the efficacy and safety profile of bevacizumab in combination with irinotecan in Hong Kong Chinese patients with recurrent malignant glioma and to determine whether their response differed from that reported in other populations. DESIGN: Retrospective study. SETTING: Two private clinics and a public hospital in Hong Kong. PATIENTS: Fourteen individuals who presented with recurrent glioma presenting to the hospital between November 2005 and November 2009. INTERVENTION: Salvage therapy with bevacizumab (10 mg/kg) and irinotecan (125 mg/m(2) [340 mg/m(2) for those taking enzyme-inducing antiepileptic drugs]) on a 14-day schedule. RESULTS: A radiological response was observed in 12 (86%) of the patients, four (33%) of whom had a complete response. The median progression-free survival was 6 (range, 1-15) months; 71% remained progression-free at 6 months. The median overall survival was 18 (range, 9-61) months. The most common adverse events during the bevacizumab and irinotecan treatment period were haematological; five patients had grade 2/3 adverse events. Pulmonary embolism occurred in two patients, one of whom died. Intracranial haemorrhage was not detected in any of the 14 treated patients. CONCLUSIONS: Bevacizumab plus irinotecan was at least as effective at treating Chinese patients with recurrent glioma as previously reported in clinical trials in different patient populations. PMID- 21813895 TI - Immunoglobulin G4-related sclerosing disease: experience with this novel entity in a local hospital. AB - OBJECTIVE: To review the site of involvement, clinical presentation, and treatment outcome of patients having immunoglobulin G4-related sclerosing disease in a local regional hospital. DESIGN: Retrospective case series. SETTING: Pamela Youde Nethersole Eastern Hospital, Hong Kong. PATIENTS: All patients with a diagnosis of immunoglobulin G4-related sclerosing disease in the hospital diagnosed in the period from April 2008 to March 2010. RESULTS: A total of 12 patients with involvement of various organs were identified. There was a male predominance (male-to-female ratio=5:1). The mean age at diagnosis was 65 years. The salivary glands, biliary tract, pancreas, and cervical lymph nodes were the commonest involved sites. The immunoglobulin G4 level was elevated in 83% of the patients. Patients usually appeared to respond well to steroid treatment. CONCLUSION: Immunoglobulin G4-related sclerosing disease is a systemic disease and can involve various systems. PMID- 21813896 TI - Small bowel enema use in an Asian population: our eleven years of local experience. AB - OBJECTIVE: To retrospectively analyse the outcome of patients who underwent investigation by small bowel enema in a local centre. DESIGN: Case series. SETTING: Regional hospital, Hong Kong. PATIENTS: All patients referred for small bowel enema in a local hospital from 1 January 1999 to 31 December 2009 were identified; respective findings from imaging and clinical records were reviewed. RESULTS: A total of 341 patients were referred for small bowel enema, of whom 289 successfully completed the examination. There were 211 patients whose small bowel enema findings were considered normal and 78 were regarded as abnormal. The sensitivity of this investigation was 73% and its specificity was 91%. The respective positive and negative predictive values were 66% and 93%. CONCLUSIONS: The selection of patients by clinicians with specific indications for small bowel enema is essential for making effective use of small bowel enema as an investigative tool. PMID- 21813897 TI - Mercury exposure: the experience of the Hong Kong Poison Information Centre. AB - OBJECTIVES: To review the characteristics of the consultation about the management of mercury exposure and identify the controversial issues on the clinical management of individuals with a history of mercury exposure. DESIGN: Descriptive case series. SETTING: Hong Kong Poison Information Centre, Hong Kong. PARTICIPANTS: Persons consulting the Hong Kong Poison Information Centre about individuals with possible or definitive mercury exposure. MAIN OUTCOME MEASURES: Characteristics of the consultations, including: the demographics of affected individuals, source and reason for the consultation, tissue mercury levels, the source of mercury exposure, specific intervention if any, and clinical outcomes. RESULTS: Forty-one consultations were analysed. Most consultations were from the public sector. Reasons of the consultation were very variable. Individuals with abnormal tissue mercury levels were uncommon. There was only one case of acute mercury poisoning. The majority of identified individuals were not subjected to specific interventions. Chelation therapy was given to three patients, but in one of them it was considered to be contra-indicated. CONCLUSION: The management of mercury exposure is highly variable. Recommendations were made on the approach to an individual with potential mercury exposure or poisoning. PMID- 21813898 TI - Validation study of the Chinese Identification Pain Questionnaire for neuropathic pain. AB - OBJECTIVES: For diagnosing neuropathic pain, a simple 6-item patient-completed identification pain questionnaire has been validated among Caucasians. We aimed to study the validity and reliability of this questionnaire among Hong Kong Chinese patients. DESIGN: Questionnaire survey. SETTING: Two pain clinics and two neurology clinics in Hong Kong. PATIENTS: Patients with either neuropathic pain or nociceptive pain were recruited randomly from the four clinics. The patients completed the questionnaire themselves and the diagnosis of neuropathic pain and nociceptive pain was made by the pain specialists. We determined the optimal cutoff, positive and negative predictive values, sensitivity, specificity, the area under the receiver operating characteristic curve, and test-retest reliability of the translated version. RESULTS: Among the 92 participants, 60 (65%) had neuropathic pain and 32 (35%) had nociceptive pain. At an optimal cutoff score of 3 or higher, the positive predictive value was 87% while the negative predictive value was 55%, and it correctly classified 71% of cases. The specificity and sensitivity were 81% and 65%, respectively. The area under the curve was 0.78 (P<0.001). Test-retest reliability in the 10 randomly selected patients showed a good intraclass correlation of 0.72. CONCLUSION: The Chinese Identification Pain Questionnaire is a valid and reliable scale that may be used as an initial diagnostic tool for neuropathic pain among Hong Kong Chinese patients. PMID- 21813899 TI - Laparoscopic sacrocolpopexy for uterine and post-hysterectomy prolapse: anatomical and functional outcomes. AB - OBJECTIVE: To evaluate the anatomical and functional outcomes following laparoscopic sacrocolpopexy in a local unit. DESIGN: Retrospective case series. SETTING: A regional hospital in Hong Kong. PATIENTS: All women who underwent laparoscopic sacrocolpopexy for symptomatic uterine or post-hysterectomy prolapse from January 2003 to December 2008. MAIN OUTCOME MEASURES: Anatomical outcomes, functional outcomes including complications. RESULTS: A total of 31 patients were recruited. The success rate in treating apical vaginal wall prolapse was 100%. There were no recurrences of vault prolapse (defined as stage II or higher). Approximately 19% of women had anterior vaginal wall prolapse and 23% had urinary stress incontinence postoperatively; 6% had a second operation because of anterior vaginal wall prolapse. The rates of dyspareunia and constipation were low. The mean hospital stay was 4 (range, 2-11) days. Two patients sustained bladder injuries and one rectal injury resulting in a rectovaginal fistula. For three patients the procedure was converted to a laparotomy. CONCLUSIONS: Laparoscopic sacrocolpopexy is feasible in our population and has a high success rate for treating apical vaginal wall prolapse. The incidence of complications was acceptable. PMID- 21813901 TI - Clinical Epidemiology Workshop - introduction: workshop 1 -dissection of a medical journal paper. PMID- 21813900 TI - Treatment of patients with chronic obstructive pulmonary disease as practised in a defined Hong Kong community: a cross-sectional pilot survey. AB - OBJECTIVES: To examine the characteristics of chronic obstructive pulmonary disease patients of the Kwai-Tsing area, Hong Kong, and the chronic treatments they received. DESIGN. Cross-sectional survey. SETTING: Four clinic settings in Hong Kong: Respiratory Specialist Clinic, Princess Margaret Hospital (group 1); Medical Specialist Clinics, Princess Margaret Hospital (group 2); General Outpatient Clinics, Princess Margaret Hospital (group 3); South Kwai Chung Chest Clinic, Department of Health (group 4). PATIENTS: Thirty physician-diagnosed chronic obstructive pulmonary disease patients in each of the above groups with post-bronchodilator 1-second forced expiratory volume/forced vital capacity ratios of less than 70% predicted values, who had been followed up at any of the participating clinics for at least 6 months. RESULTS: There were 111 male and nine female patients. The median age was 72.5 years and 79% had at least one medical co-morbidity. The mean duration of their chronic obstructive pulmonary disease was 9.8 years, and their mean post-bronchodilator 1-second forced expiratory volumes were 45% (for males) and 58% (for females) of predicted values. There were significantly fewer stage I and more stage IV patients in group 1. Influenza vaccination coverage within the previous 1 year was 54% and did not differ significantly between groups. Chronic obstructive pulmonary disease education was given significantly more often to group 1 patients. Short acting beta agonists were used to treat all patients but long-acting bronchodilators and pulmonary rehabilitation were used almost exclusively in group 1. Overall, long-acting bronchodilators and pulmonary rehabilitation were offered to 16% and 5%, respectively, of those for whom these were indicated (according to international guidelines). CONCLUSION: In general there was insufficient education and under-treatment for chronic obstructive pulmonary disease patients. Management of such patients warrants improvements by way of increased accessibility to structured education programmes, pulmonary rehabilitation programmes, long-acting bronchodilator drugs, and respiratory specialist care. PMID- 21813902 TI - Enzyme replacement therapy for mucopolysaccharidosis VI (Maroteaux-Lamy syndrome): experience in Hong Kong. AB - Mucopolysaccharidosis VI (Maroteaux-Lamy syndrome) is a very rare inherited lysosomal storage disease. We evaluated the efficacy and safety of weekly infusions of recombinant human arylsulfatase B as enzyme replacement therapy for two patients in whom this condition was advanced. The primary outcome variables were the distance walked in a 6-minute walk test, forced vital capacity, and ejection fraction. The secondary outcome variables were the number of stairs climbed in a 3-minute stair climbing test, joint mobility, urinary glycosaminoglycan excretion, auto-continuous positive airway pressure study and liver size. After 24 weeks of treatment, patient A walked 40 m (36%) and patient B walked 66 m (58%) more in the walk test than at baseline. After 48 weeks, in patient A the corresponding improvements were 142 m (129%) in the walk test and 33 stairs (60%) in the 3-minute stair climbing test, and in patient B the respective improvements were 198 m (174%) and 77 stairs (140%). There was a significant decline in urinary glycosaminoglycan excretion and improvement in range of motion of joints in both patients. The auto-continuous positive airway pressure study revealed improvements in patient A, while other efficacy variables remained static. There were no drug-related adverse events or allergic reactions reported during and after the infusions of recombinant human arylsulfatase B. Recombinant human arylsulfatase B significantly improves endurance and reduces urinary glycosaminoglycan excretion. The drug is generally safe and well tolerated. PMID- 21813903 TI - Post-oesophagectomy anastomotic-bronchial fistula. AB - Anastomotic leakage after oesophagectomy is a dreaded complication. It has a wide range of presentations ranging from the patient being totally asymptomatic to septic with multi-organ failure. From the literature, in general, cervical anastomoses have a higher leakage rate than those that are intra-thoracic, but leaks from the latter confer greater morbidity. Cervical anastomotic leaks that are truly confined to the neck can be managed conservatively, but can extend into the mediastinum and result in more serious complications. Herein, we report on a patient with an oesophago-gastric anastomosis constructed in the neck but with extension into the mediastinum. Subsequently, the patient developed a fistulous erosion into the tracheobronchial tree, which was successfully managed endoscopically. PMID- 21813904 TI - An uncommon cause of recurrent falls in an elderly man. AB - Falls are common among the elderly population. Examinations for the cause of falls are usually mundane, but may be challenging, leading to surprising diagnoses. We report on a previously healthy elderly man who presented with repeated falls and rapidly progressive limitations in mobility, in addition to a stutter. Neuroimaging was particularly helpful for making the diagnosis in this patient. PMID- 21813905 TI - An unusual cause of obstructive jaundice. AB - Small-cell carcinomas of lung origin have been well characterised for their clinico-histopathological features. However, extrapulmonary small-cell carcinomas are rare, and in particular, they are extremely rare at the ampullary region. We report herein a case of small-cell carcinoma of ampulla of Vater and review its clinical, histological, and immunohistochemical features. PMID- 21813906 TI - Necrotising fasciitis caused by Vibrio vulnificus in the lower limb following exposure to seafood on the hand. AB - Vibrio vulnificus infection mainly manifests as primary bacteraemia or gastroenteritis following injection of the microorganism, and wound infection through direct inoculation. Injury from exposure to the microorganism and development of necrotising fasciitis at a remote site and sepsis are rare. This report is of a high-risk patient with haemoglobin H disease who developed necrotising fasciitis in the lower limb after exposure to seafood on the hand. PMID- 21813907 TI - Congenital abnormalities of bilateral kidneys. PMID- 21813908 TI - Medulloblastoma with leptomeningeal metastases. PMID- 21813909 TI - A new Chinese terminology for dementia and cognitive impairment. PMID- 21813910 TI - Dietary supplementation habits and perceptions of supplement use among elite Finnish athletes. AB - The aim of this study was to evaluate the frequency of dietary supplement (DS) use among elite Finnish athletes in 2002 and 2009. In 2009, the authors also wanted to examine the reasons for athletes' DS use, whether athletes feel they have experienced benefits from their supplement use, and whether athletes had had an opportunity to consult dietary specialists. Cross-sectional studies were conducted in 2002 and 2009 among Finnish Olympic athletes. Data were collected using semistructured questionnaires, mainly in national team camps. The study population in 2002 was 446 athletes, and in 2009 it was 372. The number of DS users was high in both study years (81% in 2002 and 73% in 2009). Vitamin D consumption was low in both 2002 and 2009 (0.7% and 2.0%, respectively). An increase was found in consumption of omega-3 fatty acids between study years (11% in 2002 and 19% in 2009; p = .002), and their regular use nearly doubled (8% and 15%, p = .002). For vitamin and mineral users, the main reason for DS use was to prevent nutritional deficiencies, and for nutritional supplement users the main reason was recovery from exercise. Only 27% of all athletes and 30% of DS users had an opportunity to consult dietary specialists in 2009. This survey shows that supplementation rates among elite Finnish athletes are high and there may be over and underuse of some micronutrient supplements. There is a need for professional nutritional counseling among national elite athletes. PMID- 21813911 TI - The association of a high drive for thinness with energy deficiency and severe menstrual disturbances: confirmation in a large population of exercising women. AB - A high drive-for-thinness (DT) score obtained from the Eating Disorder Inventory 2 is associated with surrogate markers of energy deficiency in exercising women. The purposes of this study were to confirm the association between DT and energy deficiency in a larger population of exercising women that was previously published and to compare the distribution of menstrual status in exercising women when categorized as high vs. normal DT. A high DT was defined as a score >=7, corresponding to the 75th percentile for college-age women. Exercising women age 22.9 +/- 4.3 yr with a BMI of 21.2 +/- 2.2 kg/m2 were retrospectively grouped as high DT (n = 27) or normal DT (n = 90) to compare psychometric, energetic, and reproductive characteristics. Chi-square analyses were performed to compare the distribution of menstrual disturbances between groups. Measures of resting energy expenditure (REE) (4,949 +/- 494 kJ/day vs. 5,406 +/- 560 kJ/day, p < .001) and adjusted REE (123 +/- 16 kJ/LBM vs. 130 +/- 9 kJ/LBM, p = .027) were suppressed in exercising women with high DT vs. normal DT, respectively. Ratio of measured REE to predicted REE (pREE) in the high-DT group was 0.85 +/- 0.10, meeting the authors' operational definition for an energy deficiency (REE:pREE <0.90). A greater prevalence of severe menstrual disturbances such as amenorrhea and oligomenorrhea was observed in the high-DT group (chi2 = 9.3, p = .003) than in the normal-DT group. The current study confirms the association between a high DT score and energy deficiency in exercising women and demonstrates a greater prevalence of severe menstrual disturbances in exercising women with high DT. PMID- 21813912 TI - Effects of 7 days of arginine-alpha-ketoglutarate supplementation on blood flow, plasma L-arginine, nitric oxide metabolites, and asymmetric dimethyl arginine after resistance exercise. AB - BACKGROUND: Arginine-alpha-ketoglutarate (AAKG) supplements are alleged to increase nitric oxide production, thereby resulting in vasodilation during resistance exercise. This study sought to determine the effects of AAKG supplementation on hemodynamics and brachial-artery blood flow and the circulating levels of L-arginine, nitric oxide metabolites (NOx; nitrate/nitrite), asymmetric dimethyl arginine (ADMA), and L-arginine:ADMA ratio after resistance exercise. METHODS: Twenty-four physically active men underwent 7 days of AAKG supplementation with 12 g/day of either NO(2) Platinum or placebo (PLC). Before and after supplementation, a resistance-exercise session involving the elbow flexors was performed involving 3 sets of 15 repetitions with 70-75% of 1-repetition maximum. Data were collected immediately before, immediately after (PST), and 30 min after (30PST) each exercise session. Data were analyzed with factorial ANOVA (p < .05). RESULTS: Heart rate, blood pressure, and blood flow were increased in both groups at PST (p = .001) but not different between groups. Plasma L-arginine was increased in the NO(2) group (p = .001). NOx was shown to increase in both groups at PST (p = .001) and at 30PST (p = .001) but was not different between groups. ADMA was not affected between tests (p = .26) or time points (p = .31); however, the L-arginine:ADMA ratio was increased in the NO(2) group (p = .03). CONCLUSION: NO(2) Platinum increased plasma L-arginine levels; however, the effects observed in hemodynamics, brachial-artery blood flow, and NOx can only be attributed to the resistance exercise. PMID- 21813913 TI - Effect of a carbohydrate-electrolyte beverage, lemon tea, or water on rehydration during short-term recovery from exercise. AB - PURPOSE: This study examined the rehydration achieved by drinking different beverages during a short-term recovery period (REC) after exercise-induced dehydration. METHODS: Thirteen well-trained men (age 22.1 +/- 3.3 yr, body mass 61.2 +/- 9.1 kg, VO(2max) 64.9 +/- 4.0 ml . kg-1 . min-1, maximum heart rate 198 +/- 7 beats/min) ran for 60 min on 3 occasions on a level treadmill at 70% VO(2max). All trials were performed in thermoneutral conditions (21 degrees C, 71% relative humidity) and were separated by at least 7 d. During 4 hr REC, the subjects consumed either a volume of a carbohydrate-electrolyte beverage (CE), lemon tea (LT), or distilled water (DW) equal to 150% of the body weight (BW) lost during the previous run. The fluid was consumed in 6 equal volumes at 30, 60, 90, 120, 150, and 180 min of REC. RESULTS: After the completion of the 60-min run, the subjects lost ~2.0% of their preexercise BW in all trials, and no differences were observed in these BW changes between trials. At the end of REC, the greatest fraction of the retained drink occurred when the CE drink was consumed (CE vs. LT vs. DW: 52% +/- 18% vs. 36% +/- 15% vs. 30% +/- 14%, p < .05). The CE drink also caused the least diuretic effect (CE vs. LT vs. DW: 638 +/- 259 vs. 921 +/- 323 vs. 915 +/- 210 ml, p < .05) and produced the optimal restoration of plasma volume (CE vs. LT vs. DW: 11.2% +/- 2.0% vs. -3.1% +/- 1.8% vs. 0.2% +/- 2.1%, p < .05). CONCLUSION: The results of this study suggest that CE drinks are more effective than DW or LT in restoring fluid balance during short-term REC after exercise-induced dehydration. PMID- 21813914 TI - Effects of lactate consumption on blood bicarbonate levels and performance during high-intensity exercise. AB - The authors sought to determine the effects of oral lactate consumption on blood bicarbonate (HCO(3)-) levels, pH levels, and performance during high-intensity exercise on a cycle ergometer. Subjects (N = 11) were trained male and female cyclists. Time to exhaustion (TTE) and total work were measured during high intensity exercise bouts 80 min after the consumption of 120 mg/kg body mass of lactate (L), an equal volume of placebo (PL), or no treatment (NT). Blood HCO(3)- increased significantly after ingestion of lactate (p < .05) but was not affected in PL or NT (p > .05). No changes in pH were observed as a result of treatment. TTE and total work during the performance test increased significantly by 17% in L compared with PL and NT (p = .02). No significant differences in TTE and total work were seen between the PL and NT protocols (p = .85). The authors conclude that consuming 120 mg/kg body mass of lactate increases HCO(3)- levels and increases exercise performance during high-intensity cycling ergometry to exhaustion. PMID- 21813915 TI - The relationship between physical fitness, urine iodine status, and body-mass index in 6- to 7-year-old Polish children. AB - The aim of this study was to assess physical fitness in 6- to 7-yr-old children and determine if there is any relationship between children's physical fitness, their urine iodine status, and their body-mass index (BMI). The studied population included 121 children from southern Poland. Physical fitness was measured using a physical fitness test for children age 3-7 yr. Urinary iodine concentrations were measured in the children's first urine output on waking using the modified PAMM (Program Against Micronutrient Malnutrition) method. Body height and weight were measured and BMI was calculated. The subjects were characterized by low physical fitness. Boys obtained better results in agility, power, and strength exercises (p <= .05). In girls, 11 correlation coefficients between the scores obtained in the physical fitness test, urinary iodine, and anthropometric measures were statistically significant, and in boys, only 2. BMI correlated positively with agility in girls and with strength in girls and boys. Our study revealed low physical fitness in Polish 6- to 7-yr-old children, which shows the need to implement programs aimed at increasing their physical activity. The relationship found between physical fitness and urine iodine status in girls indicates that future research in this area is needed. PMID- 21813916 TI - Effect of mixed flavonoids, n-3 fatty acids, and vitamin C on oxidative stress and antioxidant capacity before and after intense cycling. AB - Consumption of plant flavonoids, antioxidants, and n-3 fatty acids is proposed to have many potential health benefits derived primarily through antioxidant and anti-inflammatory activities. This study examined the effects of 1,000 mg quercetin + 1,000 mg vitamin C (QC); 1,000 mg quercetin, 1,000 mg vitamin C, 400 mg isoquercetin, 30 mg epigallocatechin gallate, and 400 mg n-3 fatty acids (QFO); or placebo (P), taken each day for 2 wk before and during 3 d of cycling at 57% W(max) for 3 hr, on plasma antioxidant capacity (ferricreducing ability of plasma [FRAP], oxygen-radical absorbance capacity [ORAC]), plasma oxidative stress (F(2)-isoprostanes), and plasma quercetin and vitamin C levels. Thirty nine athletes were recruited and randomized to QC, QFO, or P. Blood was collected at baseline, after 2 wk supplementation, immediately postexercise, and 14 hr postexercise. Statistical design used a 3 (groups) * 4 (times) repeated-measures ANOVA with post hoc analyses. Plasma quercetin was significantly elevated in QC and QFO compared with P. Plasma F(2)-isoprostanes, FRAP, and vitamin C were significantly elevated and ORAC significantly decreased immediately postexercise, but no difference was noted in the overall pattern of change. Post hoc analyses revealed that the QC and QFO groups did not exhibit a significant increase in F(2)-isoprostanes from baseline to immediately postexercise compared with P. This study indicates that combining flavonoids and antioxidants with n-3 fatty acids is effective in reducing the immediate postexercise increase in F(2) isoprostanes. Moreover, this effect occurs independently of changes in plasma antioxidant capacity. PMID- 21813917 TI - The acute effect of ingesting a quercetin-based supplement on exercise-induced inflammation and immune changes in runners. AB - This study tested the acute anti-inflammatory and immune-modulating influence of a quercetin-based supplement consumed by endurance athletes 15 min before an intense 2-hr run. In this randomized, crossover study, 20 runners (11 men, 9 women, age 38.4 +/- 2.1 yr) completed two 2-hr treadmill runs at 70% VO(2max) (3 wk apart). Subjects ingested either 4 quercetin-based chews (Q-chew) or placebo chews (PL) 15 min before the runs. The 4 Q-chews provided 1,000 mg quercetin, 120 mg epigallocatechin 3-gallate, 400 mg isoquercetin, 400 mg each eicosapentaenoic acid and docosahexaenoic acid, 1,000 mg vitamin C, and 40 mg niacinamide. Subjects provided blood samples 30 min before, immediately after, and 1 hr postexercise and were analyzed for plasma quercetin, total blood leukocytes (WBC), C-reactive protein (CRP), 9 cytokines (IL-6, TNFalpha, GM-CSF, IFNgamma, IL-1beta, IL-2, IL-8, IL-10, and IL-12p70), granulocyte (GR) and monocyte (MO) phagocytosis (PHAG), and oxidative-burst activity (OBA). Plasma quercetin increased from 80.0 +/- 26.0 MUg/L to 6,337 +/- 414 MUg/L immediately postexercise and 4,324 +/- 310 MUg/L 1 hr postexercise after ingestion of Q chews, compared with no change in PL (p < .001). Exercise caused significant increases in, CRP, GM-CSF, IL-10, IL-1beta, IL-2, IL-6, IL-8, TNFalpha, GR-PHAG, and MO-PHAG and decreases in GR-OBA and MO-OBA, but no differences in the pattern of change were measured between Q-chew and PL trials. Acute ingestion of Q-chews 15 min before heavy exertion caused a strong increase in plasma quercetin levels but did not counter postexercise inflammation or immune changes relative to placebo. PMID- 21813918 TI - Feeding strategies of a female athlete during an ultraendurance running event. AB - The aim of this case study was to describe the race nutrition practices of a female runner who completed her first 100-km off-road ultraendurance running event in 12 hr 48 min 55 s. Food and fluid intake during the race provided 10,890 kJ (736 kJ/hr) and 6,150 ml (415 ml/hr) of fluid. Hourly reported carbohydrate intake was 44 g, with 34% provided by sports drink. Hourly carbohydrate intake increased in the second half (53 g/hr) compared with the first half (34 g/h) of the race, as the athlete did not have access to individualized food and fluid choices at the early checkpoints and felt satiated in the early stages of the race after consuming a prerace breakfast. Mean sodium intake was 500 mg/hr (52 mmol/L), with a homemade savory broth and sports drink (Gatorade Endurance) being the major contributors. The athlete consumed a variety of foods of varying textures and tastes with no complaints of gastrointestinal discomfort. Despite thinking she would consume sweet foods exclusively, as she had done in training, the athlete preferred savory foods and fluids at checkpoints during the latter stages of the race. This case study highlights the importance of the sports nutrition team in educating athletes about race-day nutrition strategies and devising a simple yet effective system to allow them to manipulate their race-day food and fluid intake to meet their nutritional goals. PMID- 21813920 TI - Allergic Rhinitis and Co-morbidities Training Module (ARCTM). PMID- 21813919 TI - Effects of exercise intensity and altered substrate availability on cardiovascular and metabolic responses to exercise after oral carnitine supplementation in athletes. AB - The effects of 15 d of supplementation with L-carnitine L-tartrate (LC) on metabolic responses to graded-intensity exercise under conditions of altered substrate availability were examined. Fifteen endurance-trained male athletes undertook exercise trials after a 2-d high-carbohydrate diet (60% CHO, 25% fat) at baseline (D0), on Day 14 (D14), and after a single day of high fat intake (15% CHO, 70% fat) on Day 15 (D15) in a double-blind, placebo-controlled, pair-matched design. Treatment consisted of 3 g LC (2 g L-carnitine/d; n = 8) or placebo (P, n = 7) for 15 d. Exercise trials consisted of 80 min of continuous cycling comprising 20-min periods at each of 20%, 40%, 60%, and 80% VO2peak. There was no significant difference between whole-body rates of CHO and fat oxidation at any workload between D0 and D14 trials for either the P or LC group. Both groups displayed increased fat and reduced carbohydrate oxidation between the D14 and D15 trials (p < .05). During the D15 trial, heart rate (p < .05 for 20%, 40%, and 60% workloads) and blood glucose concentration (p < .05 for 40% and 60% workloads) were lower during exercise in the LC group than in P. These responses suggest that LC may induce subtle changes in substrate handling in metabolically active tissues when fatty-acid availability is increased, but it does not affect whole-body substrate utilization during short-duration exercise at the intensities studied. PMID- 21813921 TI - Managing specific learning disability in schools in India. AB - Specific learning disability (dyslexia, dysgraphia, and dyscalculia) afflicts 5 15% of school-going children. Over the last decade; awareness about this invisible handicap has grown in India. However, much needs to be done to ensure that each afflicted child gets an opportunity to achieve his or her full academic potential in regular mainstream schools. In order to achieve this ideal scenario, all regular classroom teachers should be sensitized to suspect, and trained to screen for this disability when the child is in primary school. School managements should become proactive to set up resource rooms and employ special educators to ensure that these children receive regular and affordable remedial education; and be diligent in ensuring that these children get the mandatory provisions both during school and board examinations. Once specific learning disability is recognized as a disability by the Government of India, these children with the backing of the Right to Education Act, would be able to benefit significantly. PMID- 21813922 TI - Treating hyperglycemia in the critically ill child: is there enough evidence? AB - NEED AND PURPOSE OF REVIEW: Hyperglycemia is prevalent among critically ill pediatric patients. Previously thought to be an adaptive response to stress, hyperglycemia is now recognized to be associated with an adverse outcome. Correction of such hyperglycemia with insulin infusion has been shown to improve outcome but carries risk of hypoglycemia. This review addresses these issues related to treatment of hyperglycemia. METHODS: A Pubmed search was performed using the search strategy: (hyperglycemia OR blood glucose OR insulin therapy) AND (critical illness OR critical care OR intensive care unit). Randomized controlled trials, clinical trials, meta-analysis and observational studies (adult and pediatric) published in the last 10 years were included. CONCLUSION: Blood sugar monitoring and correction of hyperglycemia while caring for critically ill children is crucial. A modest blood glucose target of <150 mg/dL is appropriate. Providing adequate nutrition along with training of the nursing personnel would prevent any adverse effect such as hypoglycemia. PMID- 21813923 TI - Community based newborn care: a systematic review and metaanalysis of evidence: UNICEF-PHFI series on newborn and child health, India. AB - BACKGROUND: The neonatal mortality rate (NMR) in India has remained virtually unchanged in the last 5 years. To achieve the Millennium Development Goal (MDG) 4 on child mortality (two thirds reduction from 1990 to 2015), it is essential to reduce NMR. A systematic review of the evidence on community-based intervention packages to reduce NMR is essential for advocacy and action to reach MDG-4. OBJECTIVE: To assess the effect of community based neonatal care by community health workers (CHWs) on NMR in resource-limited settings. DESIGN: Systematic review and meta-analysis of controlled trials. DATA SOURCES: Electronic databases and hand search of reviews, and abstracts and proceedings of conferences. RESULTS: A total of 13 controlled trials involving about 192000 births were included in this systematic review. Community based neonatal care by CHWs was associated with reduced neonatal mortality in resource-limited settings [RR=0.73 (0.65 to 0.83); P<0.0001]. The identified studies were a heterogeneous mix with respect to the extent and quality of community based neonatal care provided and the characteristics of the CHWs delivering the intervention. There was no consistent effect of training duration of the health workers, type of intervention (home visitation versus community participatory action and learning), number of home visits done by CHWs, and provision of only preventive versus both preventive and therapeutic care. Limited data suggests that the ideal time for the first postnatal visit is the first two days of life. The interventions are highly effective when baseline NMR is above 50/1000 live births [RR=0.64(0.54 to 0.77)]. The interventions show a significant decrease in efficacy as the NMR drops below 50/1000 live births [RR=0.85 (0.73 to 0.99)], however is still substantial. NMR gains from home visitation approach are going to materialize only in the presence of high program coverage of 50% or more. CONCLUSION: A significant decrease in NMR is possible by providing community based neonatal care in areas with high NMR by community health workers with a modest training duration and ensuring high program coverage with home visitation on the first two days of life. PMID- 21813924 TI - Cartilage-hair hypoplasia caused by novel compound heterozygous RMRP mutations. AB - Cartilage-hair hypoplasia is a rare, autosomal recessive skeletal dysplasia, caused by mutations in the RMRP gene. The skeletal abnormalities include irregular metaphyses and cone shaped epiphyses of the hands. Molecular diagnosis confirmed two novel RMRP mutations in a compound heterozygous state in two siblings with this condition. PMID- 21813925 TI - Atypical Cogan syndrome mimicking acute rheumatic fever. AB - Cogan syndrome is a syndrome of non-syphilitic interstitial keratitis associated with vestibuloauditory deficits. We report a 10 year-old male child who presented with fever, acute polyarthritis, and unilateral red eye and was diagnosed as acute rheumatic fever. Subsequently unilateral hearing loss was detected and the child was diagnosed to have atypical Cogan syndrome. PMID- 21813926 TI - Scarlet fever caused by community-associated methicillin-resistant Staphylococcus aureus. AB - We describe a previously healthy 2.5-year-old boy with staphylococcal scarlet fever associated with acute suppurative otitis media due to community-associated methicillin-resistant Staphylococcus aureus. The patient was successfully treated by spontaneous drainage in combination with trimethoprim-sulfamethoxazole therapy. PMID- 21813927 TI - Congenital myotonic dystrophy with asymptomatic mother. AB - Myotonic dystrophy is an autosomal dominant neuromuscular disorder characterised by extreme pleiotropism and variability in disease expression. A congenital form is rare and is observed in infants born to symptomatic mothers with multisystem involvement. We report a case of a neonate with congenital myotonic dystrophy born to an asymptomatic mother. PMID- 21813929 TI - Improving child health in India. PMID- 21813928 TI - Growth of VLBW infants. PMID- 21813932 TI - Sildenafil, neonates and regulation. PMID- 21813934 TI - Infant and young child feeding guidelines 2010. PMID- 21813935 TI - Rasburicase for hyperuricemia in an extremely low birth weight infant. PMID- 21813936 TI - Survival of a rabies patient. PMID- 21813937 TI - Multiple discharging sinuses with disseminated dactylitis. PMID- 21813938 TI - Calcinosis cutis. PMID- 21813939 TI - Erythema nodosum as the presenting feature of rheumatic heart disease. PMID- 21813940 TI - Electrical biopsy of irradiated intestinal tissue with a simple electrical impedance spectroscopy system for radiation enteropathy in rats--a pilot study. AB - Electrical impedance is one of the most often used parameters for characterizing material properties, especially in biomedical applications. Electrical impedance spectroscopy (EIS), used for revealing both resistive and capacitive characteristics, is good for use in tissue characterization. In this study, a portable and simple EIS system based on a commercially available chip was used to assess rat intestinal tissues following irradiation. The EIS results were fitted to a resistor and capacitor electrical circuit model to solve the electrical properties of the tissue. The variation in the tissue's electrical characteristics was compared to the morphological and histological findings. From the experimental results, it was clear that the electrical properties, based on receiver operation curve analysis, demonstrated good detection performance relative to the histological changes. The electrical parameters of the tissues could be used to distinguish the tissue's status for investigation, which introduced a concept of 'electrical biopsy', and this 'electrical biopsy' approach may be used to complement histological examinations. PMID- 21813941 TI - Calibrating a novel multi-sensor physical activity measurement system. AB - Advancing the field of physical activity (PA) monitoring requires the development of innovative multi-sensor measurement systems that are feasible in the free living environment. The use of novel analytical techniques to combine and process these multiple sensor signals is equally important. This paper describes a novel multi-sensor 'integrated PA measurement system' (IMS), the lab-based methodology used to calibrate the IMS, techniques used to predict multiple variables from the sensor signals, and proposes design changes to improve the feasibility of deploying the IMS in the free-living environment. The IMS consists of hip and wrist acceleration sensors, two piezoelectric respiration sensors on the torso, and an ultraviolet radiation sensor to obtain contextual information (indoors versus outdoors) of PA. During lab-based calibration of the IMS, data were collected on participants performing a PA routine consisting of seven different ambulatory and free-living activities while wearing a portable metabolic unit (criterion measure) and the IMS. Data analyses on the first 50 adult participants are presented. These analyses were used to determine if the IMS can be used to predict the variables of interest. Finally, physical modifications for the IMS that could enhance the feasibility of free-living use are proposed and refinement of the prediction techniques is discussed. PMID- 21813942 TI - Multi-component transparent conducting oxides: progress in materials modelling. AB - Transparent conducting oxides (TCOs) play an essential role in modern optoelectronic devices through their combination of electrical conductivity and optical transparency. We review recent progress in our understanding of multi component TCOs formed from solid solutions of ZnO, In(2)O(3), Ga(2)O(3) and Al(2)O(3), with a particular emphasis on the contributions of materials modelling, primarily based on density functional theory. In particular, we highlight three major results from our work: (i) the fundamental principles governing the crystal structures of multi-component oxide structures including (In(2)O(3))(ZnO)(n) and (In(2)O(3))(m)(Ga(2)O(3))(l)(ZnO)(n); (ii) the relationship between elemental composition and optical and electrical behaviour, including valence band alignments; (iii) the high performance of amorphous oxide semiconductors. On the basis of these advances, the challenge of the rational design of novel electroceramic materials is discussed. PMID- 21813943 TI - Orientation dependent ionization potential of In2O3: a natural source for inhomogeneous barrier formation at electrode interfaces in organic electronics. AB - The ionization potentials of In(2)O(3) films grown epitaxially by magnetron sputtering on Y-stabilized ZrO(2) substrates with (100) and (111) surface orientation are determined using photoelectron spectroscopy. Epitaxial growth is verified using x-ray diffraction. The observed ionization potentials, which directly affect the work functions, are in good agreement with ab initio calculations using density functional theory. While the (111) surface exhibits a stable surface termination with an ionization potential of ~ 7.0 eV, the surface termination and the ionization potential of the (100) surface depend strongly on the oxygen chemical potential. With the given deposition conditions an ionization potential of ~ 7.7 eV is obtained, which is attributed to a surface termination stabilized by oxygen dimers. This orientation dependence also explains the lower ionization potentials observed for In(2)O(3) compared to Sn-doped In(2)O(3) (ITO) (Klein et al 2009 Thin Solid Films 518 1197-203). Due to the orientation dependent ionization potential, a polycrystalline ITO film will exhibit a laterally varying work function, which results in an inhomogeneous charge injection into organic semiconductors when used as electrode material. The variation of work function will become even more pronounced when oxygen plasma or UV-ozone treatments are performed, as an oxidation of the surface is only possible for the (100) surface. The influence of the deposition technique on the formation of stable surface terminations is also discussed. PMID- 21813944 TI - The interplay between dopants and oxygen vacancies in the magnetism of V-doped TiO2. AB - Density functional theory calculations indicate that the incorporation of V into Ti lattice positions of rutile TiO(2) leads to magnetic V(4+) species, but the extension and sign of the coupling between dopant moments confirm that ferromagnetic order cannot be reached via low-concentration doping in the non defective oxide. Oxygen vacancies can introduce additional magnetic centres, and we show here that one of the effects of vanadium doping is to reduce the formation energies of these defects. In the presence of both V dopants and O vacancies all the spins tend to align with the same orientation. We conclude that V doping favours the ferromagnetic behaviour of TiO(2) not only by introducing spins associated with the dopant centres but also by increasing the concentration of oxygen vacancies with respect to the pure oxide. PMID- 21813945 TI - Thickness dependence of the strain, band gap and transport properties of epitaxial In2O3 thin films grown on Y-stabilised ZrO2(111). AB - Epitaxial films of In(2)O(3) have been grown on Y-stabilised ZrO(2)(111) substrates by molecular beam epitaxy over a range of thicknesses between 35 and 420 nm. The thinnest films are strained, but display a 'cross-hatch' morphology associated with a network of misfit dislocations which allow partial accommodation of the lattice mismatch. With increasing thickness a 'dewetting' process occurs and the films break up into micron sized mesas, which coalesce into continuous films at the highest coverages. The changes in morphology are accompanied by a progressive release of strain and an increase in carrier mobility to a maximum value of 73 cm(2) V(-1) s(-1). The optical band gap in strained ultrathin films is found to be smaller than for thicker films. Modelling of the system, using a combination of classical pair-wise potentials and ab initio density functional theory, provides a microscopic description of the elastic contributions to the strained epitaxial growth, as well as the electronic effects that give rise to the observed band gap changes. The band gap increase induced by the uniaxial compression is offset by the band gap reduction associated with the epitaxial tensile strain. PMID- 21813946 TI - Reactive force field simulation of proton diffusion in BaZrO3 using an empirical valence bond approach. AB - A new reactive force field to describe proton diffusion within the solid oxide fuel cell material BaZrO(3) has been derived. Using a quantum mechanical potential energy surface, the parameters of an interatomic potential model to describe hydroxyl groups within both pure and yttrium-doped BaZrO(3) have been determined. Reactivity is then incorporated through the use of the empirical valence bond model. Molecular dynamics simulations (EVB-MD) have been performed to explore the diffusion of hydrogen using a stochastic thermostat and barostat whose equations are extended to the isostress-isothermal ensemble. In the low concentration limit, the presence of yttrium is found not to significantly influence the diffusivity of hydrogen, despite the proton having a longer residence time at oxygen adjacent to the dopant. This lack of influence is due to the fact that trapping occurs infrequently, even when the proton diffuses through octahedra adjacent to the dopant. The activation energy for diffusion is found to be 0.42 eV, in good agreement with experimental values, though the prefactor is slightly underestimated. PMID- 21813947 TI - Resonant Raman scattering in ZnO:Mn and ZnO:Mn:Al thin films grown by RF sputtering. AB - Raman spectroscopy results obtained under visible (non-resonant) and UV (resonant) excitation for nanocrystalline ZnO, ZnO:Mn and ZnO:Mn:Al thin films grown by radio frequency magnetron sputtering are presented and compared. The origin of the multiple longitudinal optical (LO) phonon Raman peaks, strongly enhanced under resonance conditions, and the effects of the dopants on them are discussed in the framework of the 'cascade' model. It is suggested that the observed suppression of the higher-order LO phonon lines for ZnO:Mn:Al is caused by the dissociation of excitons in the heavily n-type doped material. On the basis of the cascade model interpretation of the higher-order Raman peaks in the resonant spectra, the LO phonon frequencies for wavevectors away from the Gamma point are evaluated and compared to previously published phonon dispersion curves. PMID- 21813948 TI - Holes bound as small polarons to acceptor defects in oxide materials: why are their thermal ionization energies so high? AB - Holes bound to acceptor defects in oxide materials usually need comparatively high energies, of the order of 0.5-1.0 eV, to be ionized thermally to the valence band maximum. It is discussed that this has to be attributed to the stabilization of such holes by mainly short range interactions with the surrounding lattice, leading to the formation of small O(-) polarons. This is tantamount to the localization of the hole at only one of several equivalent oxygen ions next to the defect. The hole stabilizing energies can be determined experimentally from the related intense optical absorption bands. This paper exploits previous phenomenological studies of bound-hole small polarons in order to account for the large hole stabilization energies on this basis. A compilation demonstrates that bound-hole small polarons occur rather often in oxides and also in some related materials. The identification of such systems is based on EPR and optical studies and also on recent advanced electronic structure calculations. PMID- 21813949 TI - A theoretical study of a ZnO graphene analogue: adsorption on Ag(111) and hydrogen transport. AB - A single sheet of zinc oxide (ZnO) based on the same flat two-dimensional (2D) hexagonal topology as graphene, but with alternating neighbouring Zn and O atoms in place of carbon atoms, is studied theoretically. Following experimental studies, the adsorption of 2D-ZnO with the Ag(111) surface is investigated using density functional theory, with and without a semi-empirical correction for dispersive interactions, and with classical interatomic potentials. The interaction of H atoms with the hexagonal Zn(3)O(3) rings of 2D-ZnO is given special attention where multi-centre bond formation is observed to significantly assist the transport of H atoms through the 2D-ZnO sheet. PMID- 21813950 TI - Chemical bonding in copper-based transparent conducting oxides: CuMO2 (M = In, Ga, Sc). AB - The geometry and electronic structure of copper-based p-type delafossite transparent conducting oxides, CuMO(2) (M = In, Ga, Sc), are studied using the generalized gradient approximation (GGA) corrected for on-site Coulomb interactions (GGA + U). The bonding and valence band compositions of these materials are investigated, and the origins of changes in the valence band features between group 3 and group 13 cations are discussed. Analysis of the effective masses at the valence and conduction band edge explains the experimentally reported conductivity trends. PMID- 21813951 TI - Deep level transient spectroscopy studies of n-type ZnO single crystals grown by different techniques. AB - In the present study single-crystalline ZnO samples grown from the vapor phase, the melt, and a high-temperature aqueous solution (hydrothermal growth) are investigated before and after hydrogen plasma treatments, by means of deep level transient spectroscopy (DLTS) and high-resolution Laplace DLTS. Dominant DLTS peaks are found to appear in the range of 120-350 K for all materials. The DLTS spectra depend on the procedure of growth of the ZnO. The thermal stabilities of the defects in an oxygen atmosphere and in an oxygen-lean atmosphere are analyzed. The origin of the DLTS peaks is discussed. PMID- 21813952 TI - Semiconducting oxides. PMID- 21813953 TI - Charge compensation in trivalent cation doped bulk rutile TiO2. AB - Doping of TiO(2) is a very active field, with a particularly large effort expended using density functional theory (DFT) to model doped TiO(2); this interest has arisen from the potential for doping to be used in tuning the band gap of TiO(2) for photocatalytic applications. Doping is also of importance for modifying the reactivity of an oxide. Finally, dopants can also be unintentionally incorporated into an oxide during processing, giving unexpected electronic properties. To unravel properly how doping impacts on the properties of a metal oxide requires a modelling approach that can describe such systems consistently. Unfortunately, DFT, as used in the majority of studies, is not suitable for application here and in many cases cannot even yield a qualitatively consistent description. In this paper we investigate the doping of bulk rutile TiO(2) with trivalent cations, Al, Ga and In, using DFT, DFT corrected for on site Coulomb interactions (DFT + U, with U on oxygen 2p states) and hybrid DFT (the screened exchange HSE06 exchange correlation functional) in an effort to better understand the performance of DFT in describing such fundamental doping scenarios and to analyse the process of charge compensation with these dopants. With all dopants, DFT delocalizes the oxygen hole polaron that results from substitution of Ti with the lower valence cation. DFT also finds an undistorted geometry and does not produce the characteristic polaron state in the band gap. DFT + U and hybrid DFT both localize the polaron, and this is accompanied by a distortion to the structure around the oxygen hole site. DFT + U and HSE06 both give a polaron state in the band gap. The band gap underestimation present in DFT + U means that the offset of the gap state from both the valence and the conduction band cannot be properly described, while the hybrid DFT offsets should be correct. We have investigated dopant charge compensation by formation of oxygen vacancies. Due to the large number of calculations required, we use DFT + U for these studies. We find that the most stable oxygen vacancy site has either a very small positive formation energy or is negative, so under typical experimental conditions, anion vacancy formation will compensate for the dopant. PMID- 21813954 TI - Conductivity in transparent oxide semiconductors. AB - Despite an extensive research effort for over 60 years, an understanding of the origins of conductivity in wide band gap transparent conducting oxide (TCO) semiconductors remains elusive. While TCOs have already found widespread use in device applications requiring a transparent contact, there are currently enormous efforts to (i) increase the conductivity of existing materials, (ii) identify suitable alternatives, and (iii) attempt to gain semiconductor-engineering levels of control over their carrier density, essential for the incorporation of TCOs into a new generation of multifunctional transparent electronic devices. These efforts, however, are dependent on a microscopic identification of the defects and impurities leading to the high unintentional carrier densities present in these materials. Here, we review recent developments towards such an understanding. While oxygen vacancies are commonly assumed to be the source of the conductivity, there is increasing evidence that this is not a sufficient mechanism to explain the total measured carrier concentrations. In fact, many studies suggest that oxygen vacancies are deep, rather than shallow, donors, and their abundance in as-grown material is also debated. We discuss other potential contributions to the conductivity in TCOs, including other native defects, their complexes, and in particular hydrogen impurities. Convincing theoretical and experimental evidence is presented for the donor nature of hydrogen across a range of TCO materials, and while its stability and the role of interstitial versus substitutional species are still somewhat open questions, it is one of the leading contenders for yielding unintentional conductivity in TCOs. We also review recent work indicating that the surfaces of TCOs can support very high carrier densities, opposite to the case for conventional semiconductors. In thin film materials/devices and, in particular, nanostructures, the surface can have a large impact on the total conductivity in TCOs. We discuss models that attempt to explain both the bulk and surface conductivity on the basis of bulk band structure features common across the TCOs, and compare these materials to other semiconductors. Finally, we briefly consider transparency in these materials, and its interplay with conductivity. Understanding this interplay, as well as the microscopic contenders for providing the conductivity of these materials, will prove essential to the future design and control of TCO semiconductors, and their implementation into novel multifunctional devices. PMID- 21813955 TI - Electron and hole stability in GaN and ZnO. AB - We assess the thermodynamic doping limits of GaN and ZnO on the basis of point defect calculations performed using the embedded cluster approach and employing a hybrid non-local density functional for the quantum mechanical region. Within this approach we have calculated a staggered (type-II) valence band alignment between the two materials, with the N 2p states contributing to the lower ionization potential of GaN. With respect to the stability of free electron and hole carriers, redox reactions resulting in charge compensation by ionic defects are found to be largely endothermic (unfavourable) for electrons and exothermic (favourable) for holes, which is consistent with the efficacy of electron conduction in these materials. Approaches for overcoming these fundamental thermodynamic limits are discussed. PMID- 21813956 TI - Cathodoluminescence studies of electron irradiation effects in n-type ZnO. AB - The lifetime of non-equilibrium carriers in n-type unintentionally doped ZnO increases when the sample is exposed to the electron beam of a scanning electron microscope. This is observed by studying the ZnO cathodoluminescence (CL) spectra at different irradiation time durations and temperatures. We found that the decrease in the CL spectra's peak intensity is related to a thermo-activated energy barrier, determined by the calculated activation energy value of 259 +/- 30 meV. This energy value comes close to the defect energy level of the zinc interstitial, which is possibly the nature of the energy barrier responsible for this decrease. PMID- 21813957 TI - Electrospun biocomposite nanofibrous patch for cardiac tissue engineering. AB - A bioengineered construct that matches the chemical, mechanical, biological properties and extracellular matrix morphology of native tissue could be suitable as a cardiac patch for supporting the heart after myocardial infarction. The potential of utilizing a composite nanofibrous scaffold of poly(dl-lactide-co glycolide)/gelatin (PLGA/Gel) as a biomimetic cardiac patch is studied by culturing a population of cardiomyocyte containing cells on the electrospun scaffolds. The chemical characterization and mechanical properties of the electrospun PLGA and PLGA/Gel nanofibers were studied by Fourier transform infrared spectroscopy, scanning electron microscopy and tensile measurements. The biocompatibility of the scaffolds was also studied and the cardiomyocytes seeded on PLGA/Gel nanofibers were found to express the typical functional cardiac proteins such as alpha-actinin and troponin I, showing the easy integration of cardiomyocytes on PLGA/Gel scaffolds. Our studies strengthen the application of electrospun PLGA/Gel nanofibers as a bio-mechanical support for injured myocardium and as a potential substrate for induction of endogenous cardiomyocyte proliferation, ultimately reducing the cardiac dysfunction and improving cardiac remodeling. PMID- 21813958 TI - Effects of the penalty on the penalized weighted least-squares image reconstruction for low-dose CBCT. AB - Statistical iterative reconstruction (SIR) algorithms have shown potential to substantially improve low-dose cone-beam CT (CBCT) image quality. The penalty term plays an important role in determining the performance of SIR algorithms. In this work, we quantitatively evaluate the impact of the penalties on the performance of a statistics-based penalized weighted least-squares (PWLS) iterative reconstruction algorithm for improving the image quality of low-dose CBCT. Three different edge-preserving penalty terms, exponential form anisotropic quadratic (AQ) penalty (PWLS-Exp), inverse square form AQ penalty (PWLS InverseSqr) and total variation penalty (PWLS-TV), were compared against the conventional isotropic quadratic form penalty (PWLS-Iso) using both computer simulation and experimental studies. Noise in low-dose CBCT can be substantially suppressed by the PWLS reconstruction algorithm and edges are well preserved by both AQ- and TV-based penalty terms. The noise-resolution tradeoff measurement shows that the PWLS-Exp exhibits the best spatial resolution of all the three anisotropic penalty terms at matched noise level for reconstructing high-contrast objects. For the reconstruction of low-contrast objects, the TV-based penalty outperforms the AQ-based one with better resolution preservation at matched noise levels. Different penalty terms may be used for better edge preservation at different targeted contrast levels. PMID- 21813959 TI - Mitigation of motion artifacts in CBCT of lung tumors based on tracked tumor motion during CBCT acquisition. AB - An algorithm capable of mitigating respiratory motion blurring artifacts in cone beam computed tomography (CBCT) lung tumor images based on the motion of the tumor during the CBCT scan is developed. The tumor motion trajectory and probability density function (PDF) are reconstructed from the acquired CBCT projection images using a recently developed algorithm Lewis et al (2010 Phys. Med. Biol. 55 2505-22). Assuming that the effects of motion blurring can be represented by convolution of the static lung (or tumor) anatomy with the motion PDF, a cost function is defined, consisting of a data fidelity term and a total variation regularization term. Deconvolution is performed through iterative minimization of this cost function. The algorithm was tested on digital respiratory phantom, physical respiratory phantom and patient data. A clear qualitative improvement is evident in the deblurred images as compared to the motion-blurred images for all cases. Line profiles show that the tumor boundaries are more accurately and clearly represented in the deblurred images. The normalized root-mean-squared error between the images used as ground truth and the motion-blurred images are 0.29, 0.12 and 0.30 in the digital phantom, physical phantom and patient data, respectively. Deblurring reduces the corresponding values to 0.13, 0.07 and 0.19. Application of a -700 HU threshold to the digital phantom results in tumor dimension measurements along the superior inferior axis of 2.8, 1.8 and 1.9 cm in the motion-blurred, ground truth and deblurred images, respectively. Corresponding values for the physical phantom are 3.4, 2.7 and 2.7 cm. A threshold of -500 HU applied to the patient case gives measurements of 3.1, 1.6 and 1.7 cm along the SI axis in the CBCT, 4DCT and deblurred images, respectively. This technique could provide more accurate information about a lung tumor's size and shape on the day of treatment. PMID- 21813960 TI - Theoretical modeling of yields for proton-induced reactions on natural and enriched molybdenum targets. AB - Recent acute shortage of medical radioisotopes prompted investigations into alternative methods of production and the use of a cyclotron and 100Mo(p,2n)(99m)Tc reaction has been considered. In this context, the production yields of (99m)Tc and various other radioactive and stable isotopes which will be created in the process have to be investigated, as these may affect the diagnostic outcome and radiation dosimetry in human studies. Reaction conditions (beam and target characteristics, and irradiation and cooling times) need to be optimized in order to maximize the amount of (99m)Tc and minimize impurities. Although ultimately careful experimental verification of these conditions must be performed, theoretical calculations can provide the initial guidance allowing for extensive investigations at little cost. We report the results of theoretically determined reaction yields for (99m)Tc and other radioactive isotopes created when natural and enriched molybdenum targets are irradiated by protons. The cross section calculations were performed using a computer program EMPIRE for the proton energy range 6-30 MeV. A computer graphical user interface for automatic calculation of production yields taking into account various reaction channels leading to the same final product has been created. The proposed approach allows us to theoretically estimate the amount of (99m)Tc and its ratio relative to (99g)Tc and other radioisotopes which must be considered reaction contaminants, potentially contributing to additional patient dose in diagnostic studies. PMID- 21813961 TI - EQPlanar: a maximum-likelihood method for accurate organ activity estimation from whole body planar projections. AB - Optimizing targeted radionuclide therapy requires patient-specific estimation of organ doses. The organ doses are estimated from quantitative nuclear medicine imaging studies, many of which involve planar whole body scans. We have previously developed the quantitative planar (QPlanar) processing method and demonstrated its ability to provide more accurate activity estimates than conventional geometric-mean-based planar (CPlanar) processing methods using physical phantom and simulation studies. The QPlanar method uses the maximum likelihood-expectation maximization algorithm, 3D organ volume of interests (VOIs), and rigorous models of physical image degrading factors to estimate organ activities. However, the QPlanar method requires alignment between the 3D organ VOIs and the 2D planar projections and assumes uniform activity distribution in each VOI. This makes application to patients challenging. As a result, in this paper we propose an extended QPlanar (EQPlanar) method that provides independent organ rigid registration and includes multiple background regions. We have validated this method using both Monte Carlo simulation and patient data. In the simulation study, we evaluated the precision and accuracy of the method in comparison to the original QPlanar method. For the patient studies, we compared organ activity estimates at 24 h after injection with those from conventional geometric mean-based planar quantification using a 24 h post-injection quantitative SPECT reconstruction as the gold standard. We also compared the goodness of fit of the measured and estimated projections obtained from the EQPlanar method to those from the original method at four other time points where gold standard data were not available. In the simulation study, more accurate activity estimates were provided by the EQPlanar method for all the organs at all the time points compared with the QPlanar method. Based on the patient data, we concluded that the EQPlanar method provided a substantial increase in accuracy of organ activity estimates from 24 h planar images compared to the CPlanar using 24 h SPECT as the golden standard. For other time points, where no golden standard is available, better agreement between estimated and measured projections was observed by using the EQPlanar method compared to the QPlanar method. This phenomenon is consistent with the improvement in goodness of fit seen in both simulation data and 24 h patient data. Therefore, this indicates the improved reliability of organ activity estimates obtained though the EQPlanar method. PMID- 21813962 TI - Scattered radiation from dental metallic crowns in head and neck radiotherapy. AB - We aimed to estimate the scattered radiation from dental metallic crowns during head and neck radiotherapy by irradiating a jaw phantom with external photon beams. The phantom was composed of a dental metallic plate and hydroxyapatite embedded in polymethyl methacrylate. We used radiochromic film measurement and Monte Carlo simulation to calculate the radiation dose and dose distribution inside the phantom. To estimate dose variations in scattered radiation under different clinical situations, we altered the incident energy, field size, plate thickness, plate depth and plate material. The simulation results indicated that the dose at the incident side of the metallic dental plate was approximately 140% of that without the plate. The differences between dose distributions calculated with the radiation treatment-planning system (TPS) algorithms and the data simulation, except around the dental metallic plate, were 3% for a 4 MV photon beam. Therefore, we should carefully consider the dose distribution around dental metallic crowns determined by a TPS. PMID- 21813963 TI - Treatment precision of image-guided liver SBRT using implanted fiducial markers depends on marker-tumour distance. AB - The purpose of this study is to assess the accuracy of day-to-day predictions of liver tumour position using implanted gold markers as surrogates and to compare the method with alternative set-up strategies, i.e. no correction, vertebrae and 3D diaphragm-based set-up. Twenty patients undergoing stereotactic body radiation therapy (SBRT) with abdominal compression for primary or metastatic liver cancer were analysed. We determined the day-to-day correlation between gold marker and tumour positions in contrast-enhanced CT scans acquired at treatment preparation and before each treatment session. The influence of marker-tumour distance on the accuracy of prediction was estimated by introducing a method extension of the set up error paradigm. The distance between gold markers and the centre of the tumour varied between 5 and 96 mm. Marker-guidance was superior to guiding treatment using other surrogates, although both the random and systematic components of the prediction error SD depended on the tumour-marker distance. For a marker-tumour distance of 4 cm, we observed sigma = 1.3 mm and Sigma = 1.6 mm. The 3D position of the diaphragm dome was the second best predictor. In conclusion, the tumour position can be predicted accurately using implanted markers, but marker-guided set-up accuracy decreases with increasing distance between implanted markers and the tumour. PMID- 21813964 TI - Structure and electrical properties of nanoparticulate tungsten oxide prepared by microwave plasma synthesis. AB - Nanoparticulate WO(3) films were prepared using microwave plasma synthesis and studied with respect to the electrical conductivity in dependence of ambient conditions. The WO(3) films with a monoclinic structure were made from cluster assembled nanoparticles (diameter 3 nm) by means of dispersion and spin-coating. Above 100 degrees C a thermally activated decrease of the electrical resistance due to oxygen vacancy donors is found. A reversible increase of the electrical resistance R due to oxygen uptake is observed. The decrease of R in response to reducing H(2)S in the ppm range is studied in dependence of temperature and pre annealing conditions. PMID- 21813965 TI - Hydrogenated cation vacancies in semiconducting oxides. AB - Using first-principles calculations we have studied the electronic and structural properties of cation vacancies and their complexes with hydrogen impurities in SnO(2), In(2)O(3) and beta-Ga(2)O(3). We find that cation vacancies have high formation energies in SnO(2) and In(2)O(3) even in the most favorable conditions. Their formation energies are significantly lower in beta-Ga(2)O(3). Cation vacancies, which are compensating acceptors, strongly interact with H impurities resulting in complexes with low formation energies and large binding energies, stable up to temperatures over 730 degrees C. Our results indicate that hydrogen has beneficial effects on the conductivity of transparent conducting oxides: it increases the carrier concentration by acting as a donor in the form of isolated interstitials, and by passivating compensating acceptors such as cation vacancies; in addition, it potentially enhances carrier mobility by reducing the charge of negatively charged scattering centers. We have also computed vibrational frequencies associated with the isolated and complexed hydrogen, to aid in the microscopic identification of centers observed by vibrational spectroscopy. PMID- 21813966 TI - Electrical properties of (Ba, Sr)TiO3 thin films with Pt and ITO electrodes: dielectric and rectifying behaviour. AB - The electrical properties of (Ba, Sr)TiO(3) (BST) thin films are studied using different combinations of Pt and tin-doped indium oxide (In(2)O(3):Sn, ITO) as electrode material. With Pt as bottom and top electrode the films show insulating behaviour with a low leakage current. A rectifying current-voltage characteristic is obtained by replacing the top electrode with ITO. As shown by photoemission as well as by electrical measurements, the property of the BST/ITO interface depends strongly on the deposition sequence, and can be related to the level of oxidation of the ITO film. Highly doped ITO as top electrode forms an Ohmic contact with BST. This enables the preparation of highly rectifying diodes that exhibit a space-charge-limited current behaviour. Larger barriers are obtained when ITO is used as bottom electrode. This is related to the oxidation of the ITO layer during BST deposition and results in a low interface-limited current. Due to the large energy gaps of both BST and ITO, the combination of these materials provides an additional route to transparent electronics. PMID- 21813967 TI - Microstructural and conductivity changes induced by annealing of ZnO:B thin films deposited by chemical vapour deposition. AB - Zinc oxide (ZnO) thin films have attracted much attention in recent years due to progress in crystal growth for a large variety of technological applications including optoelectronics and transparent electrodes in solar cells. Boron (B) doped ZnO thin films are deposited by low pressure chemical vapour deposition (LPCVD) on Si(100). These films exhibit a strong (002) texture with a pyramidal grain structure. The ZnO films were annealed after growth; the annealing temperature and the atmosphere appear to strongly impact the layer conductivity. This work will first present the modification of the physical properties (carrier concentration, mobility) extracted from the simulation of layer reflection in the infrared range. At low annealing temperatures the mobility increases slightly before decreasing drastically above a temperature close to 250 degrees C. The chemical and structural evolution (XPS, x-ray diffraction) of the films was also studied to identify the relationship between microstructural modifications and the variations observed in the film conductivity. An in situ XRD study during annealing has been performed under air and low pressure conditions. As observed for electrical properties, the microstructural modifications shift to higher temperatures for vacuum annealing. PMID- 21813968 TI - Recent ARPES experiments on quasi-1D bulk materials and artificial structures. AB - The spectroscopy of quasi-one-dimensional (1D) systems has been a subject of strong interest since the first experimental observations of unusual line shapes in the early 1990s. Angle-resolved photoemission (ARPES) measurements performed with increasing accuracy have greatly broadened our knowledge of the properties of bulk 1D materials and, more recently, of artificial 1D structures. They have yielded a direct view of 1D bands, of open Fermi surfaces, and of characteristic instabilities. They have also provided unique microscopic evidence for the non conventional, non-Fermi-liquid, behavior predicted by theory, and for strong and singular interactions. Here we briefly review some of the remarkable experimental results obtained in the last decade. PMID- 21813969 TI - Electronic excitations in nanostructures: an empirical pseudopotential based approach. AB - Physics at the nanoscale has emerged as a field where discoveries of fundamental physical effects lead to a greater understanding of the solid state. Additionally, the field is believed to have a large potential for technological applications, which has driven a high pace of experimental achievements in fabrication and characterization. From the side of theoretical modeling-so successful in solid state physics in general, since the emergence of density functional theory-we must acknowledge a weak connection to state of the art experimental achievements in the realm of nanostructures. The cause for this partial disconnect resides in the difficulty of the matter, nanostructures being small in size but large in the number of atoms constituting them, and the relevant observables being accessible only through proper treatment of excitations. The large number of atoms and the need for excited state properties makes this a challenging task for theory and modeling. In this contribution we will outline the framework, based on empirical pseudopotentials and configuration interaction, to obtain quantitative predictions of the excited state properties of semiconductor nanostructures using their experimental sizes, compositions and shapes. The methodology can be used to describe colloidal nanostructures of a few hundred atoms all the way to epitaxial structures requiring millions of atoms. The aim is to fill the gap existing between ab initio approaches and continuum descriptions. Based on the pseudopotential idea and the developments of empirical pseudopotentials for bulk materials in the early 1960s, the method has evolved into a powerful tool where the pseudopotential construction has lost some of its empirical character and is now based on modern density functional theory. We will present the construction of these potentials and the way the ensuing wavefunctions are used in a subsequent configuration interaction treatment of the excitation. We will illustrate the available capabilities by recent applications of the methodology to unveil new effects in the optics of nanostructures, quantum entanglement and wavefunction imaging. PMID- 21813970 TI - Wigner crystal physics in quantum wires. AB - The physics of interacting quantum wires has attracted a lot of attention recently. When the density of electrons in the wire is very low, the strong repulsion between electrons leads to the formation of a Wigner crystal. We review the rich spin and orbital properties of the Wigner crystal, in both the one dimensional and the quasi-one-dimensional regimes. In the one-dimensional Wigner crystal the electron spins form an antiferromagnetic Heisenberg chain with exponentially small exchange coupling. In the presence of leads, the resulting inhomogeneity of the electron density causes a violation of spin-charge separation. As a consequence the spin degrees of freedom affect the conductance of the wire. Upon increasing the electron density, the Wigner crystal starts deviating from the strictly one-dimensional geometry, forming a zigzag structure instead. Spin interactions in this regime are dominated by ring exchanges, and the phase diagram of the resulting zigzag spin chain has a number of unpolarized phases as well as regions of complete and partial spin polarization. Finally we address the orbital properties in the vicinity of the transition from a one dimensional to a quasi-one-dimensional state. Due to the locking between chains in the zigzag Wigner crystal, only one gapless mode exists. Manifestations of Wigner crystal physics at weak interactions are explored by studying the fate of the additional gapped low-energy mode as a function of interaction strength. PMID- 21813971 TI - Large quantum rings in the nu > 1 quantum Hall regime. AB - We study computationally the ground-state properties of large quantum rings in the filling-factor nu>1 quantum Hall regime. We show that the arrangement of electrons into different Landau levels leads to clear signatures in the total energies as a function of the magnetic field. In this context, we discuss possible approximations for the filling factor nu in the system. We are able to characterize integer-nu states in quantum rings in an analogy with conventional quantum Hall droplets. We also find a partially spin-polarized state between nu = 2 and 3. Despite the specific topology of a quantum ring, this state is strikingly reminiscent of the recently found nu = 5/2 state in a quantum dot. PMID- 21813972 TI - Carrier transport investigation in short-wavelength InAs/AlGaAs quantum dots. AB - Spatially resolved photoluminescence has been used to investigate the details of the carrier capture and recombination dynamics in InAs/AlGaAs self-assembled quantum dots. The spatial PL distribution displays a Gaussian-like profile, whose width depends upon the temperature and detection energy being analyzed. The results give evidence of carrier thermalization between dots with different sizes. The effects of carrier transport in the quantum dot (QD) structure and carrier capture cannot be separated. The results can be modeled by assuming a carrier hopping process. PMID- 21813973 TI - Quantum interference of magnetic edge channels activated by intersubband optical transitions in magnetically confined quantum wires. AB - We investigate the photoresistance of a magnetically confined quantum wire in which microwave-coupled edge channels interfere at two pinning sites in the fashion of a Mach-Zehnder interferometer. The conductance is strongly enhanced by microwave power at B = 0 and develops a complex series of oscillations when the magnetic confinement increases. Both results are quantitatively explained by the activation of forward scattering in a multimode magnetically confined quantum wire. By varying the strength of the magnetic confinement we are able to tune the phase of electrons in the arms of the interferometer. Quantum interferences which develop between pinning sites explain the oscillations of the conductance as a function of the magnetic field. A fit of the data gives the distance between pinning sites as 11 um. This result suggests that quantum coherence is conserved over a distance three times longer than the electron mean free path. PMID- 21813974 TI - Deformation mechanisms leading to auxetic behaviour in the alpha-cristobalite and alpha-quartz structures of both silica and germania. AB - Analytical expressions have been developed in which the elastic behaviour of the alpha-quartz and alpha-cristobalite molecular tetrahedral frameworks of both silica and germania are modelled by rotation, or dilation or concurrent rotation and dilation of the tetrahedra. Rotation and dilation of the tetrahedra both produce negative Poisson's ratios (auxetic behaviour), whereas both positive and negative values are possible when these mechanisms act concurrently. Concurrent rotation and dilation of the tetrahedra reproduces with remarkable accuracy both the positive and negative nu(31) Poisson's ratios observed for silica alpha quartz and alpha-cristobalite, respectively, when loaded in the x(3) direction. A parametric fit of the concurrent model to the germania alpha-quartz experimental nu(31) Poisson's ratio is used to predict nu(31) for germania alpha-cristobalite, for which no experimental value exists. This is predicted to be +0.007. Strain dependent nu(31) trends, due to concurrent rotation and dilation in the silica structures, are in broad agreement with those predicted from pair-potential calculations, although significant differences do occur in the absolute values. With the model of concurrent dilation and rotation of the tetrahedra we predict that an alternative uniaxial stress (sigma(3))-induced phase exists for both silica, alpha-quartz and alpha-cristobalite, and germania, alpha-cristobalite, having geometries in reasonable agreement with beta-quartz and idealized beta cristobalite, respectively. PMID- 21813976 TI - A high pressure x-ray diffraction study of titanium disulfide. AB - A high pressure angle dispersive synchrotron x-ray diffraction study of titanium disulfide (TiS(2)) was carried out to pressures of 45.5 GPa in a diamond-anvil cell. We observed a phase transformation of TiS(2) beginning at about 20.7 GPa. The structure of the high pressure phase needs further identification. By fitting the pressure-volume data to the third-order Birch-Murnaghan equation of state, the bulk modulus, K(0T), was determined to be 45.9 +/- 0.7 GPa with its pressure derivative, K'(0T), being 9.5 +/- 0.3 at pressures lower than 17.8 GPa. It was found that the compression behavior of TiS(2) is anisotropic along the different axes. The compression ratio of the c-axis is about nine times larger than the a axis when pressures are lower than 1 GPa. It suddenly decreases to three times larger at pressures of about 3 GPa. This ratio shows a linear decrease with a slope of negative 0.048 at pressures below phase transformation. PMID- 21813975 TI - Bonding characteristics in NiAl intermetallics with O impurity: a first principles computational tensile test. AB - We have performed a first-principles computational tensile test on NiAl intermetallics with O impurity along the [001] crystalline direction on the (110) plane to investigate the tensile strength and the bonding characteristics of the NiAl-O system. We show that the ideal tensile strength is largely reduced due to the presence of O impurity in comparison with pure NiAl. The investigations of the atomic configuration and bond-length evolution show that O prefers to bond with Al, forming an O-Al cluster finally with the break of O-Ni bonds. The O-Ni bonds are demonstrated to be weaker than the O-Al bonds, and the reduced tensile strength originates from such weaker O-Ni bonds. A void-like structure forms after the break of the O-Ni and some Ni-Al bonds. Such a void-like structure can act as the initial nucleation or the propagation path of the crack, and thus produce large effects on the mechanical properties of NiAl. PMID- 21813977 TI - Spectroscopic and crystal field studies of YAlO(3) single crystals doped with Mn ions. AB - Detailed analysis of the spectroscopic properties of the YAlO(3) crystals doped with manganese ions has been performed. The exchange charge model of the crystal field was used to calculate the crystal field parameters and energy levels of the Mn(4+) and Mn(5+) ions in YAlO(3). It was shown that both ions contribute to the formation of the absorption spectra. The calculated energy levels are in good agreement with the main observed absorption peaks. Comparison of the Racah parameters B for both ions in YAlO(3) with those for free ions shows a significant role played by the covalent effects, especially for Mn(5+). PMID- 21813978 TI - Electronic and structural properties of group III nitrides and phosphides using density functional theory. AB - In recent years group III nitrides have gained recognition as being the most important materials for optoelectronics and electronics applications. The zinc blende modification of GaN and AlN is receiving much attention over their wurtzite structure. Our present work deals with the detailed ab initio calculations of group III nitrides and phosphides in the zinc-blende phase. The plane wave pseudopotential approach is used to study the different properties of the material based on the concept of density functional theory (DFT). The converged plane wave cut-off energy (E(cut)) is used to set the number of plane waves, which varies from material to material. The calculated energy bandgaps are based on our theoretical equilibrium lattice constants. Our reported energy bandgap for InN (0.86 eV) is in good agreement with the recently reported experimental result (>0.7 eV and<1.0 eV). PMID- 21813979 TI - Electronic band structures of AV(2) (A = Ta, Ti, Hf and Nb) Laves phase compounds. AB - First-principles density functional calculations, using the all-electron full potential linearized augmented plane wave method, have been performed in order to investigate the structural and electronic properties for Laves phase AV(2) (A = Ta, Ti, Hf and Nb) compounds. The generalized gradient approximation and the Engel-Vosko-generalized gradient approximation were used. Our calculations show that these compounds are metallic with more bands cutting the Fermi energy (E(F)) as we move from Nb to Ta, Hf and Ti, consistent with the increase in the values of the density of states at the Fermi level N(E(F)). N(E(F)) is controlled by the overlapping of V-p/d, A-d and A-p states around the Fermi energy. The ground state properties of these compounds, such as equilibrium lattice constant, are calculated and compared with the available literature. There is a strong/weak hybridization between the states, V-s states are strongly hybridized with A-s states below and above E(F). Around the Fermi energy we notice that V-p shows strong hybridization with A-p states. PMID- 21813980 TI - Coupled electron-phonon transport from molecular dynamics with quantum baths. AB - Based on generalized quantum Langevin equations for the tight-binding wavefunction amplitudes and lattice displacements, electron and phonon quantum transport are obtained exactly using molecular dynamics (MD) in the ballistic regime. The electron-phonon interactions can be handled with a quasi-classical approximation. Both charge and energy transport and their interplay can be studied. We compare the MD results with those of a fully quantum mechanical nonequilibrium Green's function (NEGF) approach for the electron currents. We find a ballistic to diffusive transition of the electron conduction in one dimensional chains as the chain length increases. PMID- 21813981 TI - Electron-phonon relaxation in disordered two-dimensional electron gas with dynamically screened deformation potential. AB - We study the effect of a dynamically screened deformation potential on the electron longitudinal phonon relaxation in a disordered two-dimensional electron gas. On consideration of the dynamic dielectric function and polarization operator, and the frequency omega dependence, we find a significant change in the temperature exponent as well as the pre-factor alpha from the earlier reported approximate temperature power law dependence alphaT(4) obtained under static strong screening and impurity limit. More strikingly, a reversal in the character of the dependence of scattering rate on the mean free path takes place on the incorporation of dynamic screening, where the behaviour changes from the static 1/l to the dynamic l(2) at T = 1.0 K and l = 10 nm. PMID- 21813982 TI - First-principles calculations of elastic and electronic properties of NbB(2) under pressure. AB - The structural parameters, elastic constants and electronic structure of NbB(2) under pressure are investigated by using first-principles plane-wave pseudopotential density functional theory within the generalized gradient approximation (GGA). The obtained results are in agreement with the available theoretical data. It is found that the elastic constants and the Debye temperature of NbB(2) increase monotonically and the anisotropies weaken with pressure. The band structure and density of states (DOS) of NbB(2) under pressure are also presented. It is the sigma hole that determines the superconductivity in NbB(2), and the features of the sigma bands are unchanged after applying pressure except for a shift of position. The density of states (DOS) at the Fermi level decreases with increasing pressure, in conjunction with Bardeen-Cooper-Schrieffer (BCS) theory, which can predict T(c) decreasing with pressure, in agreement with the trend of the theoretical T(c) versus pressure. PMID- 21813983 TI - Dynamical polarization, screening, and plasmons in gapped graphene. AB - The one-loop polarization function of graphene has been calculated at zero temperature for arbitrary wavevector, frequency, chemical potential (doping), and band gap. The result is expressed in terms of elementary functions and is used to find the dispersion of the plasmon mode and the static screening within the random phase approximation. At long wavelengths the usual square root behaviour of plasmon spectra for two-dimensional (2D) systems is obtained. The presence of a small (compared to a chemical potential) gap leads to the appearance of a new undamped plasmon mode. At greater values of the gap this mode merges with the long-wavelength one, and vanishes when the Fermi level enters the gap. The screening of charged impurities at large distances differs from that in gapless graphene by slower decay of Friedel oscillations (1/r(2) instead of 1/r(3)), similarly to conventional 2D systems. PMID- 21813984 TI - Quantum well effect in bulk PbI(2) crystals revealed by the anisotropy of photoluminescence and Raman spectra. AB - On subjecting a bulk 2H-PbI(2) crystal to vacuum annealing at 500 K followed by a sudden cooling at liquid nitrogen temperature stacking faults are generated that separate distinct layers of nanometric thickness in which different numbers of I Pb-I atomic layers are bundled together. Such structures, containing two, three, four, five etc I-Pb-I atomic layers, behave as quantum wells of different widths. The signature of such a transformation is given by a shift towards higher energies of the fundamental absorption edge, which is experimentally revealed by specific anisotropies in the photoluminescence and Raman spectra. The quantum confining effect is made visible by specific variations of a wide extra-excitonic band (G) at 2.06 eV that originates in the radiative recombination of carriers (electrons and holes), trapped on the surface defects. The excitation spectrum of the G band, with p polarized exciting light, reveals a fine structure comprised of narrow bands at 2.75, 2.64, 2.59 and 2.56 eV, which are associated with the PbI(2) quantum wells formed from two, three, four and five I-Pb-I atomic layers of 0.7 nm thickness. Regardless of the polarization state of the laser exciting light of 514.5 nm (2.41 eV), which is close to the band gap energy of PbI(2) (2.52 eV), the Raman scattering on bulk as-grown PbI(2) crystals has the character of a resonant process. For p polarized exciting light, the Raman scattering process on vacuum annealed PbI(2) becomes non-resonant. This originates from the quantum well structures generated inside the crystal, whose band gap energies are higher than the energy of the exciting light. PMID- 21813985 TI - Peierls transition in sodium under high pressure: a first-principles study. AB - We have used first-principles calculations to investigate the electronic structure of the new oP8 phase of sodium which was experimentally reported recently (Gregoryanz et al 2008 Science 320 1054). Our results show the transition from I-43d to oP8 structure, which happens at room temperature, can also happen at 0 K. The I-43d structure will change to the oP8 structure at about 155 GPa and 0 K, rather than the CsIV structure at 190 GPa and 0 K, as the previous studies (Neaton et al 2001 Phys. Rev. Lett. 86 2830) predicted. It is also found that the oP8 structure forms a new nonequilateral triangle Na(3) structure and mainly distributes charge accumulation in the voids of the structure, rather than within the Na(3) triangles. Electronic density of states analysis shows that the oP8 structure opens a deeper pseudogap close to the Fermi level through symmetry breaking of the structure compared with that of the I-43d structure. Together with its unusual charge density distribution, it is found that the Peierls mechanism works for the transition to the oP8 structure. Differing from previous results about the Peierls mechanism of light alkali metals, the unit which produces a one-dimensional charge density wave is the Na(3) cluster instead of the pairing mechanism. PMID- 21813986 TI - Entanglement of systems of dipolar coupled nuclear spins at the adiabatic demagnetization. AB - We consider the adiabatic demagnetization in the rotating reference frame (ADRF) of a system of dipolar coupled nuclear spins s = 1/2 in an external magnetic field. The demagnetization starts with the offset of the external magnetic field (in frequency units) from the Larmor frequency being several times greater than the local dipolar field. For different subsystem sizes, we have found from numerical simulations the temperatures at which subsystems of a one-dimensional nine-spin chain and a plane nine-spin cluster become entangled. These temperatures are of the order of microkelvins and are almost independent of the subsystem size. There is a weak dependence of the temperature on the space dimension of the system. PMID- 21813987 TI - Electron-phonon coupling and spin fluctuations in 3d and 4d transition metals: implications for superconductivity and its pressure dependence. AB - We have calculated the electron-phonon coupling for the complete 4d series and the nonmagnetic 3d transition metals using the linear response method and the linear muffin-tin orbitals' basis. A comparison of the linear response results and those obtained via the rigid muffin-tin approximation is provided. Based on the calculated values of the electron-phonon coupling constants, band density of states and the measured values of the electronic specific heat constants, we estimate the spin-fluctuation effects, i.e. the electron-spin-fluctuation (electron-paramagnon) coupling constants in these systems. For the sake of comparison, several other metals, Cu, Zn, Ag, Cd, Al and Pb, are also studied. Alternative estimates of the electron-paramagnon coupling constants are obtained from the values of the Stoner parameters and the band densities of states at the Fermi level. Implications of these results on the superconductivity and its pressure dependence as well as the alloying effects of superconductivity in these systems are discussed. It is pointed out that spin fluctuations play an important role in the validity of the Matthias rule that in metallic systems the optimum conditions for (electron-phonon) superconductivity occur for 5 and 7 valence electrons/atom. PMID- 21813988 TI - Electronic structure of Na(2)CuP(2)O(7): a nearly 2D Heisenberg antiferromagnetic system. AB - We have employed first principles calculations to study the electronic structure and the implications for the magnetic properties of Na(2)CuP(2)O(7). Using the self-consistent tight-binding linearized muffin-tin orbital method and the Nth order muffin-tin orbital downfolding method, we have calculated the various intrachain and interchain hopping parameters between the magnetic Cu(2+) ions. Our calculations for Na(2)CuP(2)O(7) reveal dominant intrachain hopping, but in contrast to the typical quantum spin chains the interchain hoppings are not negligible. The Wannier function plot of the Cu d(x(2)-y(2)) orbitals shows that the exchange interactions are primarily mediated by the oxygens and the distance between the oxygens in Na(2)CuP(2)O(7) is favorable for both intrachain and interchain interactions, suggesting the inapplicability of the one-dimensional Heisenberg model for this system, in agreement with recent experimental results. PMID- 21813989 TI - An alternative theory on relaxation rates in cuprate superconductors. AB - Transport properties of high transition temperature (high-T(c)) superconductors apparently demonstrate two distinct relaxation rates in the normal state. We propose that this superficial inconsistence can be resolved with an effective carrier (quasiparticle) density n almost linear in temperature T. Experimental evidence both for and against this explanation is analyzed and we conclude that this offers a clear yet promising scenario. Band structure calculation was utilized to determine the Fermi surface topology of the cuprate superconductor versus doping. The results demonstrate that an electron-like portion of the Fermi surface exists in a wide range of doping levels even for a p-type superconductor, exemplified by La(2-x)Sr(x)CuO(4-delta) (LSCO). Such electron-like segments have also been confirmed in recent photoemission electron spectroscopy. The Coulomb interaction between electron-like and hole-like quasiparticles then forms a bound state, similar to that of an exciton. As a result the number of charge carriers upon cooling temperature is decreased. A quantum mechanical calculation of scattering cross section demonstrates that a T(2) relaxation rate is born out of an electron-hole collision process. Above the pseudogap temperature T(*) the normal state of high-T(c) cuprates is close to a two-component Fermi liquid. It, however, assumes non-Fermi-liquid behavior below T(*). PMID- 21813990 TI - NaNbO(3):Pr(3+): a new red phosphor showing persistent luminescence. AB - The Pr(3+)-doped NaNbO(3) perovskite is introduced as a new red phosphor excitable in the near UV region at around 350 nm. A bright single red emission is observed at room temperature and ascribed to transitions between the (1)D(2) excited state and the ground state (3)H(4) of Pr(3+) ions. This peculiar behavior is related to the presence of a low-lying intervalence charge transfer state that contributes to quench the emission from the otherwise emitting (3)P(0) level. Red afterglow is also evidenced in NaNbO(3):Pr(3+). A preliminary model is discussed to clarify the afterglow mechanism. PMID- 21813991 TI - Memory effect in triglycine sulfate induced by a transverse electric field: specific heat measurement. AB - The influence of a transverse electric field on the specific heat of triglycine sulfate (TGS) has been studied. The specific heat of TGS has been measured on heating the sample from the ferroelectric to the paraelectric phase after prolonged application of transverse electric field (i.e. perpendicular to the ferroelectric axis). It is shown that the specific heat of TGS can 'remember' the temperature T(s) at which the transverse field was previously applied. PMID- 21813992 TI - A gradational system for ferroelectric nanosized (Pb(0.7)Sr(0.3))TiO(3) particles. AB - Synchrotron radiation x-ray diffraction measurement was performed to investigate the size effect in ferroelectric nanosized (Pb(0.7)Sr(0.3))TiO(3) particles with various sizes ranging from 10 to 200 nm. The 200 and 002 Bragg reflections were separated using low energy synchrotron radiation x-rays. The peak profiles of the 002 reflections show a large broadening and asymmetry for all particle sizes compared with those of the 200 reflections. These anomalously wide and asymmetric peak profiles become marked for peaks with a large l. The aspect ratio of the lattice constants c/a and the atomic distance between the anions and cations decrease gradually in the vicinity of the surface of the particles, indicating that the asymmetrical profiles can be attributed to the formation of a gradational system. PMID- 21813993 TI - Dispersive dielectric and conductive effects in 2D resistor-capacitor networks. AB - How to predict and better understand the effective properties of disordered material mixtures has been a long-standing problem in different research fields, especially in condensed matter physics. In order to address this subject and achieve a better understanding of the frequency-dependent properties of these systems, a large 2D L * L square structure of resistors and capacitors was used to calculate the immittance response of a network formed by random filling of binary conductor/insulator phases with 1000 Omega resistors and 10 nF capacitors. The effects of percolating clusters on the immittance response were studied statistically through the generation of 10 000 different random network samples at the percolation threshold. The scattering of the imaginary part of the immittance near the dc limit shows a clear separation between the responses of percolating and non-percolating samples, with the gap between their distributions dependent on both network size and applied frequency. These results could be used to monitor connectivity in composite materials. The effects of the content and structure of the percolating path on the nature of the observed dispersion were investigated, with special attention paid to the geometrical fractal concept of the backbone and its influence on the behavior of relaxation-time distributions. For three different resistor-capacitor proportions, the appropriateness of many fitting models was investigated for modeling and analyzing individual resistor capacitor network dispersed frequency responses using complex-nonlinear-least squares fitting. Several remarkable new features were identified, including a useful duality relationship and the need for composite fitting models rather than either a simple power law or a single Davidson-Cole one. Good fits of data for fully percolating random networks required two dispersive fitting models in parallel or series, with a cutoff at short times of the distribution of relaxation times of one of them. In addition, such fits surprisingly led to cutoff parameters, including a primitive relaxation or crossover time, with estimated values comparable to those found for real dispersive materials. PMID- 21813994 TI - Spin density induced by equilibrium spin current in a magnetic field. AB - We propose theoretically to use an external magnetic field to detect the equilibrium spin current which flows in a narrow strip. The spin current is generated by two noncollinear ferromagnets attached to the strip and the applied magnetic field is perpendicular to the plane of the strip. It is demonstrated by using the Keldysh Green's function that the interaction between the spin current and the magnetic field causes an antisymmetrical spin density at the two lateral edges of the strip. The spin density can be directly measured experimentally. Its magnitude and direction can be readily controlled by the magnetizations of the ferromagnets. The proposed scheme offers a new approach to the detection of the pure spin current. PMID- 21813995 TI - Conversion of a glassy antiferromagnetic-insulating phase to an equilibrium ferromagnetic-metallic phase by devitrification and recrystallization in Al substituted Pr(0.5)Ca(0.5)MnO(3). AB - We show that Pr(0.5)Ca(0.5)MnO(3) with 2.5% Al substitution and La(0.5)Ca(0.5)MnO(3) (LCMO) exhibit qualitatively similar and visibly anomalous M H curves at low temperature. Magnetic field causes a broad first order but irreversible antiferromagnetic (AF)-insulating (I) to ferromagnetic (FM)-metallic (M) transition in both and gives rise to a soft FM state. However, the low temperature equilibrium state of Pr(0.5)Ca(0.5)Mn(0.975)Al(0.025)O(3) (PCMAO) is FM-M whereas that of LCMO is AF-I. In both systems the respective equilibrium phase coexists with the other phase with contrasting order, which is not in equilibrium, and the cooling field can tune the fractions of the coexisting phases. It is shown earlier that the coexisting FM-M phase behaves like 'magnetic glass' in LCMO. Here we show from specially designed measurement protocols that the AF-I phase of PCMAO has all the characteristics of magnetic glassy states. It devitrifies on heating and also recrystallizes to an equilibrium FM-M phase after annealing. This glass-like AF-I phase also shows a similar intriguing feature observed in FM-M magnetic glassy state of LCMO, that when the starting coexisting fraction of glass is larger, successive annealing results in a larger fraction of the equilibrium phase. This similarity between two manganite systems with contrasting magnetic orders of respective glassy and equilibrium phases points to a possible universality. PMID- 21813996 TI - Study of the relationship between electrical and magnetic properties and Jahn Teller distortion in R(0.7)Ca(0.3)Mn(0.95)Fe(0.05)O(3) perovskites. AB - In this work structural, magnetic and electrical properties of R(0.7)Ca(0.3)Mn(0.95)Fe(0.05)O(3) (R = Pr and Nd) perovskite manganites are presented. Structural characterization of these compounds shows that both have orthorhombic (Pbnm) phase. The Mossbauer spectra show clear evidence of the local structural distortion of the Mn(Fe)O(6) octahedron on the basis of non-zero nuclear quadrupole interactions for high-spin Fe(3+) ions. It was found that the local structural distortion decreases significantly on replacing Pr(3+) by Nd(3+). This replacement dependence of the Jahn-Teller coupling strength estimated from the Mossbauer results was found to be consistent with the electrical and magnetic properties. PMID- 21813997 TI - The pressure effect on magnetism in CeTe(1.82). AB - We report the pressure effect of the normal-state transport and magnetic properties of CeTe(1.82) up to 9 kbar. We found that the applied pressure increases the Kondo temperature (T(K)(*)~170 K), which is associated with the two dimensional motion of carriers confined within the Te plane. Both the short-range ferromagnetic ordering temperature (T(SRF)~6 K) and the long-range antiferromagnetic transition temperature (T(N)~4.3 K) are slightly increased with pressure. We suggest that the application of pressure enhances coupling between the 4f and conduction electrons. While applying the magnetic field, a large magnetoresistance is observed in the vicinity of T(SRF), which is analogous to that at ambient pressure. PMID- 21813998 TI - The effect of Coulomb interaction at ferromagnetic-paramagnetic metallic perovskite junctions. AB - We study the effect of Coulomb interactions in transition metal oxide junctions. In this paper we analyze charge transfer at the interface of a three layer ferromagnetic-paramagnetic-ferromagnetic metallic oxide system. We choose a charge model considering a few atomic planes within each layer and obtain results for the magnetic coupling between the ferromagnetic layers. For large numbers of planes in the paramagnetic spacer we find that the coupling oscillates with the same period as in Ruderman-Kittel-Kasuya-Yoshida (RKKY) theory but the amplitude is sensitive to the Coulomb energy. At small spacer thickness however, large differences may appear as a function of the number of electrons per atom in the ferromagnetic and paramagnetic materials, the dielectric constant at each component, and the charge defects at the interface plane, emphasizing the effects of charge transfer. PMID- 21813999 TI - Ferromagnetic ordering and weak spin-glass-like effect in Pr(2)CuSi(3) and Nd(2)CuSi(3). AB - We present the results of the temperature dependences of ac and dc susceptibilities, high-field magnetization, magnetic relaxation, specific heat, and electrical resistivity of Pr(2)CuSi(3) and Nd(2)CuSi(3), compounds previously shown in the literature to exhibit interesting properties. It is observed that the investigated compounds undergo a ferromagnetic phase transition at a characteristic temperature T(C) (= 9.8 K for Pr(2)CuSi(3) and 5.6 K for Nd(2)CuSi(3)), where zero-field-cooled dc susceptibility shows a rapid increase followed by a sharp peak just below T(C). Below T(C), the magnetization curve displays an open hysteresis loop and a steep rise at low fields, while irreversible magnetism and long-time magnetic relaxation effects can be observed. Furthermore, near T(C) both the real and imaginary components of the ac susceptibility show a large peak with a small frequency shift of the peak position, and a sharp anomaly appears in the specific heat and electrical resistivity curves. These unusual features observed for Pr(2)CuSi(3) and Nd(2)CuSi(3) strongly suggest the formation of huge ferromagnetic clusters accompanied by a very weak spin-glass-like effect in both samples. The obtained results are discussed by comparing them with the data reported for other 2:1:3 intermetallic compounds and some alloyed compounds with different stoichiometry. PMID- 21814000 TI - Magnetic studies of multiferroic Bi(1-x)Sm(x)FeO(3) ceramics synthesized by mechanical activation assisted processes. AB - Bi(1-x)Sm(x)FeO(3) (x = 0.0-0.2) ceramic samples were prepared by mechanical activation assisted solid-state-reaction synthesis. A stoichiometric mixture of Bi(2)O(3), Sm(2)O(3), and Fe(2)O(3) powders was mechanically milled and this was followed by heat treatment at 700 degrees C for 1 h. Room temperature x-ray diffraction patterns confirmed the formation of perovskite structured Bi(1 x)Sm(x)FeO(3) phase. Vibrating sample magnetometry measurements showed that to a certain extent, Sm doping of BiFeO(3) leads to increased magnetization and a sharp magnetic transition at ~380 degrees C. Mossbauer spectroscopy confirmed the presence of single-phase material for the doped compositions whereas electron paramagnetic resonance analysis showed the effect of doping on the variation in the degree of canting in the samples. At doping levels of 10 at.% Sm, the improvement in the magnetic behaviour appears to arise from a combination of the propensity of the samples to form pure phase material, partial destruction of spin cycloids, increased canting of spins and interaction between magnetic ions. PMID- 21814001 TI - Multiple quantum NMR dynamics in pseudopure states. AB - We investigate numerically the multiple quantum (MQ) NMR dynamics in systems of nuclear spins 1/2 coupled by dipole-dipole interactions in the case of the pseudopure initial state. Simulations of the MQ NMR with real molecular structures such as six dipolar-coupled proton spins of benzene, hydroxyl proton chains in calcium hydroxyapatite, and fluorine chains in calcium fluorapatite open the way to experimental NMR testing of the obtained results. It was found that multiple-spin correlations are created faster in such experiments than in the usual MQ NMR experiments and can be used for the investigation of many-spin dynamics of nuclear spins in solids. PMID- 21814002 TI - The relationship of the magnetic properties of M (M = Mn, Fe, Co)-doped ZnO single crystals and their electronic structures. AB - The electronic density of states and magnetic properties were investigated by tunneling spectroscopy and SQUID, respectively, for a series of 3d transition metal (Mn, Fe, Co)-doped ZnO. By tunneling spectroscopy an additional density of states was observed in Mn- and Co-doped ZnO adjacent to the top of the valence band of the host ZnO. Instead, in the Fe-doped sample, a band of density of states was observed across the Fermi level in the mid-gap. The magnetization curve (M versus H) obtained by SQUID showed a ferromagnetic hysteresis at room temperature for the Fe-doped sample, whereas for the Mn- and Co-doped samples, the M versus H curve showed only a linear characteristic without hysteresis. From the comparison of the density of states and the magnetization characteristics, it is strongly suggested that the ferromagnetism in Fe-doped ZnO at room temperature originates from the half-filled Fe 3d band in the mid-gap of the host ZnO. PMID- 21814003 TI - Contribution of energy-gap in the ferromagnetic spin-wave spectrum on magnetocaloric parameters of CeRu(2)Ge(2). AB - A study of the magnetocaloric effect has been performed on a polycrystalline CeRu(2)Ge(2) compound, which exhibits an antiferromagnetic ordering below T(N) = 8.3 K and enters into a ferromagnetic ground state at T(C) = 7.4 K. The origins of the magnetocaloric parameters (the isothermal entropy change: -DeltaS and the adiabatic temperature change: DeltaT(ad)) of the CeRu(2)Ge(2) compound below T(C) have been analyzed. A sharp decrease in -DeltaS has been observed below T(C). However, the DeltaT(ad) does not fall as sharply as -DeltaS with decreasing temperature in the corresponding temperature region. This behavior results in an additional value of DeltaT(ad) at low temperature, which originates from the exponential decrease of the magnetic contribution of specific heat associated with an increase of energy-gap in the ferromagnetic spin-wave spectrum with the application of magnetic field. PMID- 21814004 TI - Pressure-induced hysteresis in the high spin [Formula: see text] low spin transition in bis(2,4-bis(pyridin-2-yl)thiazole) iron(II) tetrafluoroborate. AB - Studies of the spin transition behavior of the mononuclear compound [Fe(pythiaz)(2)](BF(4))(2) have been carried out under hydrostatic pressures up to 9.13 kbar in the 5-300 K temperature range. Under ambient pressure this compound exhibits an approximately half-step (incomplete) HS [Formula: see text] LS transition with T(1/2) = 146 K without any thermal hysteresis. At pressures up to 4.5 kbar the behavior remains similar but with an upward displacement of T(1/2) and a slight decrease in the residual high spin fraction at low T. Application of higher pressures resulted in an almost complete two-step spin transition with several unusual pressure effects. Along with the expected pressure dependence of T(1/2) the surprising appearance of hysteresis in the spin transition curves was observed. It is suggested that the likely origin of this unprecedented behavior is a pressure-induced structural change. PMID- 21814005 TI - Thermodynamics of the Mn(12)-ac molecule in a skew magnetic field at [Formula: see text] K. AB - We derive the high-temperature expansion of the Helmholtz free energy of the quantum and classical models for the Mn(12)-ac molecule in the presence of a skew magnetic field, including the transverse term in the Hamiltonians, for [Formula: see text] K. In this region of temperature, we show that the transverse term can give a measurable contribution to the x component of the magnetization. We obtain the specific heat per site of a powder sample of Mn(12)-ac under a constant magnetic field. For strong skew magnetic fields (h/D>1), the specific heat differs up to 20% from its value of a crystal sample under purely longitudinal magnetic fields. Finally, we obtain that in the limit [Formula: see text], the values of the classical and quantum specific heat differ; in particular, for [Formula: see text] this difference is 0.96%. PMID- 21814006 TI - Strain-induced effects on antiferromagnetic ordering and magnetocapacitance in orthorhombic HoMnO(3) thin films. AB - We investigated the magnetic and ferroelectric properties of c-axis oriented orthorhombic phase HoMnO(3) (o-HMO in Pbnm symmetry setting) thin films grown on Nb-doped SrTiO(3)(001) substrates. The o-HMO films exhibit an antiferromagnetic ordering near 42 K, irrespective of the orientation of the applied field. However, an additional magnetic ordering occurring around 35 K was observed when the field was applied along the c-axis of o-HMO, which was absent when the field was applied in the ab-plane. The magnetocapacitance measured along the c-axis showed that although there is evidence of dielectric constant enhancement when the temperature is below 35 K the expected abrupt change in dielectric constant appears at a much lower temperature and reaches maximum around 13.5 K, indicating that the low-temperature c-axis polarization might be related to the ordering of the Ho(3+) moment. The lattice constant analyses using x-ray diffraction and the observation of a slight magnetization hysteresis suggest that the weak second magnetic transition along the c-axis at 35 K might be more relevant to the strain induced effect on antiferromagnetism. PMID- 21814007 TI - Anharmonic effect on lattice distortion, orbital ordering and magnetic properties in Cs(2)AgF(4). AB - We develop the cluster self-consistent field method incorporating both electronic and lattice degrees of freedom to study the origin of ferromagnetism in Cs(2)AgF(4). After self-consistently determining the harmonic and anharmonic Jahn Teller distortions, we show that the anharmonic distortion stabilizes the staggered x(2)-z(2)/y(2)-z(2) orbital and ferromagnetic ground state, rather than the antiferromagnetic one. The amplitudes of lattice distortions, Q(2) and Q(3), the magnetic coupling strengths, J(x,y), and the magnetic moment are in good agreement with the experimental observations. PMID- 21814008 TI - Evolution of the inter-layer coupling in bilayered manganites revealed by ferromagnetic resonance spectra. AB - Ferromagnetic resonance has been used to investigate the inter-layer coupling in a bilayered manganite La(2-2x)Sr(1+2x)Mn(2)O(7) (x = 0.38) single crystal. The coexistence of a ferromagnetic resonance line and a paramagnetic resonance line was observed over a broad temperature range. Antiferromagnetic coupling between the adjacent MnO(2) bilayers can be identified from the observation of an optical mode in the resonance spectra. Analysis of the temperature dependence of the resonance field and intensity reveals the evolution of the inter-layer coupling as a function of temperature. Our study suggests that ferromagnetic resonance provides a useful method for investigating the inter-layer coupling in bilayered manganites. PMID- 21814009 TI - A controllable spin prism. AB - Based on Khodas et al (2004 Phys. Rev. Lett. 92 086602), we propose a device acting like a controllable prism for an incident spin. The device is a large quantum well where Rashba and Dresselhaus spin-orbit interactions are present and controlled by the plunger gate potential, the electric field and the barrier height. A totally destructive interference can be manipulated externally between the Rashba and Dresselhaus couplings. The spin-dependent transmission/reflection amplitudes are calculated as the control parameters are changed. The device operates as a spin prism/converter/filter in different regimes and may stimulate research in promising directions in spintronics in analogy with linear optics. PMID- 21814010 TI - Colossal enhancement of magnetoresistance in La(0.67)Sr(0.33)MnO(3) thin films: possible evidence of electronic phase separation. AB - A gigantic three orders of magnitude change of resistivity in La(0.67)Sr(0.33)MnO(3) (LSMO) thin film, on application of magnetic field, has been observed. The transport and magnetic properties are characteristic of electronic phase separation between ferromagnetic metallic and antiferromagnetic charge-ordered insulating regions, unusual for a canonical double exchange system such as LSMO. PMID- 21814011 TI - Field-dependent ac susceptibility of Ce(2)Fe(17). AB - Over part of the H-T plane, the field- and temperature-dependent ac susceptibility, chi(H,T), of Ce(2)Fe(17) is found to exhibit maxima, the amplitude of which increase with increasing field. While the appearance of such a maximum seems intuitively correct along a so-called 'S-shaped' magnetization (M) versus field (H) curve characterizing a metamagnetic/first-order phase transition, it has not been previously observed in the ac susceptibility of other systems exhibiting such transitions. In an attempt to identify the origin of this effect, detailed magnetization data, M(H,T), are used to reconstruct a phase diagram for this system-specifically by using the derivatives [Formula: see text] and [Formula: see text]-as detailed recently by Janssen and co-workers. This behaviour is then shown to occur on crossing the boundary from a ferromagnetic into a spin flop (SFI) phase in Ce(2)Fe(17). As a corollary, this previously atypical behaviour of chi(H,T) may be a defining characteristic of such transitions; specifically, it may reflect the possibly unique combination of ferromagnetic and antiferromagnetic interactions that are present in this system. PMID- 21814012 TI - Spin dynamics in the manganese tetramer compound alpha-MnMoO(4). AB - alpha-MnMoO(4) is a tetrameric magnetic cluster system which undergoes a transition to three-dimensional antiferromagnetic order at T(N) = 10.7 K. In the ordered state the Mn(2+) spins (s(nu) = 5/2) are ferromagnetically aligned within the tetramer, resulting in a total cluster spin S = 10. The magnetic excitation spectrum consists of eight excitation modes of tetramer origin propagating in the whole reciprocal space. From single-crystal inelastic neutron scattering investigations the three-dimensional coupling scheme is rationalized in the framework of a tetramer-based dispersion model. The tetramer states and the energy dispersion of all the magnetic excitations are described by Heisenberg like intra- and intercluster exchange interactions, respectively, thus alpha MnMoO(4) is a suitable tetrameric model system to study the interplay of these interactions. PMID- 21814013 TI - Temperature and time dependent magnetic phenomena in a nearly stoichiometric Ni(2)MnGa alloy. AB - In this work, the temperature and time dependence of the magnetic properties of a polycrystalline Ni(49.7)Mn(24.1)Ga(26.2) alloy is analysed. The law of approach to magnetic saturation has been employed to estimate the magnetic anisotropy in the three structural phases of the alloy (martensitic, pre-martensitic and austenitic). The temperature dependences of magnetic parameters, such as the magnetic susceptibility and coercive field, are interpreted in terms of the changes in the magnetic anisotropy taking place with the structural transformations. The strong magnetocrystalline anisotropy is confirmed to mainly control the magnetic response of the low temperature martensitic phase. Furthermore, magnetic relaxation studies (magnetic after-effect) have been employed to analyse the main differences between the magnetization processes in the three characteristic structural phases. The time decay of the magnetization displays a distinctive response in the pre-martensitic state. The results (logarithmic time decay of the remanent magnetization and field dependence of the magnetic viscosity) indicate the thermally activated nature of the relaxation process. PMID- 21814014 TI - The great effect of magnetic Fe(2+) ions on electromagnetic behavior in the Cu(1 x)Fe(x)Ir(2)S(4) system. AB - The substitution of magnetic Fe(2+) for nonmagnetic Cu(+) in the Cu(1 x)Fe(x)Ir(2)S(4) system causes drastic changes in electromagnetic behavior. For x = 0.01 and 0.025, the Peierls-like phase transition step DeltaM in magnetization increases with x increasing, and an unexpected spin transition occurs at T(*)~120 K. This may be attributed to the spin-polarization of the Ir(4+) ions by the Fe(2+) ions. When x exceed 0.1, the Peierls-like phase transition is suppressed completely. The magnetic state for Fe doped samples transforms from ferromagnetic (FM) to paramagnetic (PM), and back to the FM state again with the increase of x. For the highly doped samples, the FM domains formed by Fe(2+) ions result in another transition at T(**)~110 K and the cluster-spin glass transition. PMID- 21814015 TI - On van der Waals friction between half-spaces at low temperature. AB - We determine, in the van der Waals regime (neglecting retardation and relativistic effects), the frictional power loss P and the drag force F = P/u per unit area between two Drude-modelled half-spaces, with surface plasmon frequency omega(S) and realistically weak dissipation, separated by a gap of width zeta, and constrained to uniform parallel motion with relative speed u. The calculation uses only textbook-level adiabatic and perturbative methods of nonrelativistic quantum mechanics. The initial temperature is taken to be low, with tau = k(B)T/homega(S) << 1. At strictly zero temperature, P is proportional to u(4)/zeta(6) when nu = u/omega(S)zeta << 1, and to 1/uzeta when nu >> 1. But at fixed nonzero tau, as v rises from zero, P is at first dominated by a temperature dependent component proportional to u(2)T(2)/zeta(4). The assumptions of the model as regards the half-spaces are satisfied by most quantum-electrodynamics based approaches, whose results in the nonretarded limit should therefore be the same as ours. We also find that the frequency distribution of the friction induced energy increments is not thermal, suggesting that in this respect the Huttner-Barnett theory (which we use to describe dissipative materials) needs further refinement. PMID- 21814016 TI - [Control of bone resorption by RANKL-RANK system]. AB - Differentiation and function of osteoclasts is regulated by RANKL and OPG, both of which are produced by osteoblasts. Osteoclast precursors express RANK, the receptor of RANKL. The activation of the RANKL-RANK system stimulates osteoclast differentiation and function. OPG is a decoy receptor of RANKL, which inhibits the RANKL-RANK interaction. Several genetic disorders in RANKL, RANK and OPG genes cause osteoclast abnormalities. Therefore, the development of anti osteoporosis drugs that suppress the RANKL-RANK system is advanced now. Recently, anti-RANKL antibody, denosumab, is developed and being used as a new treatment for osteoporosis. PMID- 21814017 TI - [RANKL signal and osteoimmunology]. AB - The bony skeleton enables the locomotive activity, the storage of calcium, and the harboring of the hematopoietic stem cells from which blood and immune cells are derived. The immune and skeletal systems share various molecules including cytokines, signaling molecules, transcription factors and membrane receptors. Investigation into rheumatoid arthritis (RA) as well as cloning of RANKL and various bone phenotypes found in immune-compromised gene deficient mice has highlighted the importance of the dynamic interplay between the both systems. These findings have recently led to both the emergence and subsequent rapid evolution of the field of osteoimmunology. The scope of osteoimmunology has been extended to encompass a wide range of molecular and cellular interactions, the elucidation of which will provide a scientific basis for future therapeutic approaches to diseases related to the immune and skeletal systems. PMID- 21814018 TI - [Suppressive effects for osteoclastogenesis regulated by RANKL signal]. AB - RANKL signal promotes osteoclast differentiation through a transcriptional activation of responsible genes for osteoclast formation and functions. Recent works revealed that RANKL signal plays a role to repress transcription of suppressive factors for osteoclastogenesis. Some transcriptional repressors actively inhibit expressions of osteoclast-specific genes in the precursors through canceling the functions of transcription activators to prevent uncontrollable osteoclast formation and pathological bone resorption. The mouse models lacking those transcriptional repressors exhibited accelerated osteoclast differentiation and bone loss. Although the suppressive factors are important for maintaining bone homeostasis, they have to be removed for osteoclast formation in the presence of RANKL. The transcriptional repressor Blimp1 was identified as a new target of RANKL signal and strongly attenuated expressions of various suppressive factors including Bcl6. The osteoclast-specific Blimp1 knockout mice exhibited defect of osteclast formation and loss of bone resorption. Thus, RANKL signal regulates osteoclast differentiation by inducing transcriptional activators such as NFATc1 as well as transcriptional repressors such as Blimp1.The former is essential for expressions of osteclast-specific genes, while the latter is required for terminating suppressions of osteoclast differentiation. PMID- 21814019 TI - [Osteoporosis and RANKL signal]. AB - Osteoporosis is caused by imbalance between osteoclastic bone resorption and osteoblastic bone formation. From the recent results of several kinds of knockout mice, osteoclast differentiation factor (RANKL) and its soluble decoy receptor for RANKL (OPG) are essentially involved in pathogenesis of osteoporosis. Deficiency of RANKL in human has been shown to result in osteopetrosis. Furthermore, it has been reported that anti-RANKL neutralizing antibody (denosumab) will be effective new drug for osteoporosis. PMID- 21814020 TI - [Involvement of RANKL/RANK pathway in bone metastasis in breast cancer]. AB - Breast cancer has a predilection for spreading to bone. Accumulating data suggest that the interactions between breast cancer cells and bone-resorbing osteoclasts mediated initially by bone-derived growth factors and consequently by RANKL in osteoblasts and RANK in pre-osteoclasts are critical to the development and progression of bone metastases. In addition, recent studies have revealed that breast cancer cells strongly express RANK and thereby can be directly influenced by osteoblast-derived RANKL. These results warrant the use of the humanized anti RANKL neutralizing antibody (denosumab) as a specific and more effective therapeutic agent for the treatment of bone metastasis in breast cancer patients. PMID- 21814021 TI - [Myeloma bone disease and RANKL signaling]. AB - Multiple myeloma develops and expands almost exclusively in the bone marrow, and generates devastating bone destruction. Myeloma cells produce a variety of cytokines including MIP-1 to stimulate bone resorption by enhancing RANKL expression, and suppress bone formation by inhibiting osteoblast differentiation, leading to bone destruction and rapid loss of bone. The emerging role of the RANKL/RANK signaling axis provide a molecular rationale for consideration of targeting RANKL/RANK in a bone disease in myeloma. Given formation of vicious cycle between bone destruction and tumor progression, inhibiting RANKL signaling may also contribute to the suppression of myeloma expansion. PMID- 21814022 TI - [RANKL/RANK signaling in rheumatoid arthritis]. AB - Rheumatoid arthritis (RA) is a chronic inflammatory disease, which is induced by abundant inflammatory cytokines releasing from synovial fibroblasts and T lymphocytes. These cytokines differentiate monocyte-macrophage lineage cells to mature osteoclasts, which cause bone resorption and then joint destruction. RANKL is involved in the development of osteoclasts, cooperating with another key molecule, M-CSF. Indeed, RANKL is over-expressed in the synovium of RA. We summarize RANKL/RANK signaling in RA, including recent therapeutic topics. PMID- 21814023 TI - [In vivo imaging of mature osteoclasts and RANKL signaling]. AB - Osteoclasts are 'bone-resorbing' giant polykaryons that differentiate from mononuclear macrophage/monocyte-lineage hematopoietic precursors. However how the activity of mature osteoclasts is regulated in vivo remains unclear. To answer the question, we utilized an advanced imaging system for visualizing live bone tissues with intravital multiphoton microscopy that we have recently established. By means of the system we have recently succeeded in visualization of mature osteoclasts in live bones and revealed that RANKL regulates bone-resorptive functions of mature osteoclasts in vivo . Here we show the latest data and the detailed methodology of intravital imaging of bone tissues, and also discuss its further application. PMID- 21814024 TI - [RANKL signaling and bone diseases. Quiescent osteoclast precursors and RANKL signaling]. AB - It is well known that bone marrow macrophages differentiate into osteoclasts in response to M-CSF and RANKL in culture. However, the characteristics and dynamics of osteoclast precursors in vivo are not clear. Cell cycle arrest in osteoclast precursors is a prerequisite step for their differentiation into osteoclasts. We named such precursors "QOPs (cell cycle-arrested quiescent osteoclast precursors) " . Injection of 2MD [a potent analogue of 1alpha, 25 (OH) (2)D(3)] , RANKL, or M CSF to mice induced osteoclast differentiation from QOPs. Moreover, osteoclasts appearing in BMP (bone morphogenetic protein) -induced ectopic bone were also differentiated from QOPs without cell proliferation. These results indicate that (1)osteoclasts are formed from QOPs in response to bone resorbing stimuli in vivo, (2) QOPs circulate in the bloodstream and settle in the right place for osteoclastogenesis. Here I review recent advances in our understanding of osteoclast precursors in vivo. PMID- 21814025 TI - [Regulation of central tolerance by RANKL signaling]. AB - RANKL (receptor activator of NF-kappaB ligand) is a member of TNF (tumor-necrosis factor) family cytokine. Several genetic studies indicated critical roles of RANKL and its receptor RANK in bone homeostasis. RANKL-RANK signal regulates differentiation, survival and activation of osteoclasts. Therefore, suppression of the RANKL signal would be a promising strategy for interventions in osteoporosis or rheumatoid arthritis. Indeed, humanized anti-RANKL neutralizing antibody is coming onto the market as an antiresorptive agent for osteoporosis treatment. In addition to the role on bone homeostasis, several studies suggested that the RANKL-RANK interaction regulates immune response and development. For instance, RANKL was previously identified as a survival factor for dendritic cells. Moreover, we and other groups reported that the RANKL signal contributes to development of medullary thymic epithelial cells (mTECs) . mTECs ectopically express and present a number of tissue restricted antigens (e.g. insulin) of which expressions are in part regulated by autoimmune regulator (Aire) , a factor responsible for a genetic human autoimmune disorder, thereby eliminating T cells reactive to these tissue restricted self-antigens. As result, RANKL is involved in establishment of self-tolerance in thymus by regulating the development of mTECs expressing Aire and tissue restricted antigens. PMID- 21814026 TI - [Central regulation of body temperature by RANKL/RANK pathway]. AB - Receptor-activator of NF-kappaB ligand (RANKL) and its specific receptor RANK are key regulators of bone remodeling, lymph node formation, establishment of the thymic microenviroment, mammary gland development during pregnancy, bone metastasis in cancer and sex-hormone, progestin, -driven breast cancer. RANKL and RANK are also expressed in the central nervous systems (CNS) especially existed in the main region of thermoregulation. Central RANKL injection to the rodents induces fever via PGE(2)/EP3R pathway. This pathway is related with inflammation related fever. On the other hand, female mice with RANK gene deletion in neuron and astrocytes show increased their basal body temperature at the dark phase, which suggests RANKL/RANK system also regulates physiological thremoregulation in female. Not only in rodents but also in human, two children with a homozygous RANK mutation exhibit an abrogated fever response in pneumonia compare with the age-matched children with pneumonia. Thus, the central RANKL/RANK pathway has an important role for thermoregulation. PMID- 21814027 TI - [Osteoporosis treatment by anti-RANKL antibody]. AB - Anti-RANKL antibody, that is called Denosumab, is a fully human monoclonal antibody to the receptor activator of nuclear factor-kappaB ligand (RANKL) which blocks its binding to RANK, inhibiting the differentiation, activation and survival of osteoclact. Denosumab given subcutaneously twice yearly for 3 years was associated with a reduction in the risk of vertebral, non-vertebral and hip fractures but not with serious adverse events in postmenopausal women with osteoporosis. Evidence is available about its effect in patients with varying degrees of fracture risk. New horizon would be brought about by Denosumab in Japan, new molecular targeting pharmaceutics in the treatment of osteoporosis. PMID- 21814028 TI - [Treatment of bone metastasis with anti-RANKL antibody]. AB - Bone metastases are a frequent complication of solid cancers including breast, prostate, and lung cancers. Control of this complication is clinically important, because they cause skeletal-related events including pathological fractures that impair quality of life (QOL) or shorten survival of patient with bone metastasis. Recently, denosumab, a fully human monoclonal antibody against receptor activator of nuclear factor-kappaB ligand was developed as a therapeutic agent for bone metastases. In three phase III trials, denosumab is superior to zoledronic acid, a potent bisphosphonate used as the standard therapy for bone metastases, for patients with prostate or breast cancers and is noninferior for patients with other solid tumors in terms of the median time to first on-study skeletal-related event. It will be an effective new treatment option for patients with bone metastases. PMID- 21814029 TI - [Anti-RANKL antibody for the treatment of rheumatoid arthritis]. AB - Rheumatoid arthritis (RA) is a systemic, chronic and destructive inflammatory disease that causes severe disability and mortality. Since joint destruction occurs from the early disease, its diagnosis and treatment have to be done timely. The combinational use of methotrexate and biologics targeting TNF and IL 6 has revolutionized the treatment of RA, producing significant improvements in clinical and structural outcomes. On the other hand, an anti-RANKL antibody denosumab possesses a potential to inhibit joint destruction as well as systemic and glucocorticoid-mediated osteoporosis. Thus, differential efficacy of different therapies in bone destruction and osteoporosis would warrant further study to clarify the mechanisms of bone and joints diseases. PMID- 21814030 TI - [Denosumab as the potent therapeutic agent against Paget's disease of bone]. AB - Denosumab directly targets osteoclastgenesis by its specific action on the RANKL pathway, while bisphosphonate acts as antiresorptive agents mainly by their suppression on function of osteoclasts. The previous clinical trials showed that denosumab resulted in a quicker decrease in markers of bone resorption than bisphosphonate, that denosumab has beneficial effect against the prevention of fracture in postmenopausal women and bone erosion in patients with rheumatoid arthritis and that recombinant osteoprotegerin provided the therapeutic efficacy in two adult siblings with juvenile Paget's disease. Taken together, it is strongly expected that denosumab would be developed to be one of potent therapeutic agents for Paget's disease of bone which is characterized with the accerelated bone resorpton by osteoclasts as the primitive pathological condition. PMID- 21814031 TI - [ RANKL antibody for treatment of cancer treatment-induced bone loss (CTIBL)]. AB - Treatment for cancer may cause gonadal dysfunction and bone loss (cancer treatment-induced bone loss ; CTIBL) . Especially, endocrine therapies for breast cancer or prostate cancer carry a significant risk of CTIBL. Therapy-induced premature menopause in premenopausal breast cancer patients, aromatase inhibitor in postmenopausal breast cancer patients, and LHRH agonist with or without anti androgen in prostate cancer patients may cause bone loss of 5% or more. RANKL (receptor activator of nuclear factor-kappaB ligand) antibody (denosumab) is effective for prevention of CTIBL and it may prevent CTIBL-induced fracture. During cancer treatment with gonadal dysfunction, bone mineral density should be carefully followed to avoid QOL impairment due to osoteoporosis. PMID- 21814032 TI - Prion protein in ESC regulation. AB - A large number of studies have analysed the putative functions of the prion protein (PrP(C)) in mammals. Although its sequence conservation over a wide range of different animals may indicate that this protein could have a key role in prion diseases, an absolutely accepted involvement has not been found so far. We have recently reported that PrP(C) regulates Nanog mRNA expression, the first non redundant function of PrP(C) in embryonic stem cells (ESC), which translates into control of pluripotency and early differentiation. Contrary to what it is believed, the other two members of the prion protein family, Doppel and Shadoo, cannot replace the absence of PrP(C), causing the appearance of a new embryoid body (EB) population in our in vitro culture. The similarities between EB and an early post-implantation embryo suggest that this might also occur in vivo, enhancing the importance of this finding. On the other hand, our data may support the hypothesis of a relationship between the loss of PrP(C) function and neuronal degeneration in prion diseases. A reduction in brain stem cells pluripotency after PrP(C) is misfolded into the pathological conformation (PrP(Sc)) could lead to a delay or a disappearance of the normal brain damage recovery. PMID- 21814033 TI - Regulation of adult stem cell behavior by nutrient signaling. AB - Adult stem cells play an essential role throughout life, maintaining tissue and organ function by providing a reservoir of cells for homeostasis and repair. Maintenance and activity of adult stem cells have been the focus of numerous studies that have revealed stem cell-intrinsic factors and signals from the local microenvironment that regulate stem cell behavior. A growing body of work has provided evidence that circulating, systemic factors also contribute to the regulation of stem cell behavior in numerous tissues. We have demonstrated that Drosophila male germline stem cells (GSCs) and intestinal stem cells (ISCs) respond to changes in nutrient availability, specifically amino acids. Furthermore, we have shown that insulin signaling plays an important role in mediating the effects of changes in nutritional conditions. Notably, insulin signaling is cell-autonomously required within male GSCs for maintenance. Here we discuss our data regarding the effects and mechanisms by which changes in systemic nutritional conditions may influence the maintenance and activity of adult stem cells via insulin signaling. PMID- 21814035 TI - Evidence for age-related and individual-specific changes in DNA methylation profile of mononuclear cells during early immune development in humans. AB - Environment induced epigenetic effects on gene expression in early life are likely to play important roles in mediating the risk of several immune-related diseases. In order to investigate this fully, it is essential to first document temporal changes in epigenetic profile in disease-free individuals as a prelude to defining environmentally mediated changes. Mononuclear cells (MC) were collected longitudinally from a small number of females at birth, 1 year, 2.5 years and 5 years of age and examined for changes in genome-scale DNA methylation profiles using the Illumina Infinium HumanMethylation27 BeadChip array platform. MC from two males were included for comparative purposes. Flow cytometry was used to define MC cell populations in each sample in order to exclude this as the major driver of epigenetic change. The data underwent quality control and normalization within the R programming environment. Unsupervised hierarchical clustering of samples clearly delineated neonatal MC from all other ages. A further clear distinction was observed between 1 year and 5 year samples, with 2.5 year samples showing a mixed distribution between the 1 and 5 year groups. Gene ontology of probes significantly variable over the neonatal period revealed methylation changes in genes associated with cell surface receptor and signal transduction events. In the postnatal period, methylation changes were mostly associated with the development of effector immune responses and homeostasis. Unlike all other chromosomes tested, a predominantly genetic effect was identified as controlling maintenance of X-chromosome methylation profile in females, largely refractory to change over time. This data suggests that the primary driver of neonatal epigenome is determined in utero, whilst postnatally, multiple genetic and environmental factors are implicated in the development of MC epigenetic profile, particularly between the ages of 1-5 years, when the highest level of inter individual variation is apparent. This supports a model for differential sensitivity of specific individuals to disruption in the developing epigenome during the first years of life. Further studies are now needed to examine evolving epigenetic variations in specific cell populations in relation to environmental exposures, immune phenotype and subsequent disease susceptibility. PMID- 21814034 TI - DNA mismatch repair proficiency executing 5-fluorouracil cytotoxicity in colorectal cancer cells. AB - BACKGROUND: 5-fluorouracil (5FU)-based chemotherapy is the standard treatment for advanced stage colorectal cancer (CRC) patients. Several groups including ours have reported that stage II-III colorectal cancer patients whose tumors retain DNA Mismatch repair (MMR) function derive a benefit from 5FU, but patients with tumors that lost MMR function do not. Although MMR recognition of 5FU incorporated in DNA has been demonstrated biochemically, it has not been demonstrated within cells to execute 5FU cytotoxicity. AIM: To establish an efficient construction model for 5FU within DNA and demonstrate that 5FU incorporated into DNA can trigger cellular cytotoxicity executed by the DNA MMR system. METHODS: We constructed a 5FdU-containing heteroduplex plasmid (5FdU plasmid) and 5FdU-containing linear dsDNA (5FdU linear DNA), and transfected these into MMR-proficient, hMLH1-/- and hMSH6-/- cells. We observed cell growth characteristics of both transfectants for 5FU-induced cytotoxicity. RESULTS: MMR- proficient cells transfected with the 5FdU plasmid but not the 5FdU linear DNA showed reduced cell proliferation by MTS and clonogenic assays, and demonstrated cell morphological change consistent with apoptosis. In MMR-deficient cells, neither the 5FdU plasmid nor 5FdU linear DNA induced cell growth or morphological changes different from controls. CONCLUSION: 5FdU as heteroduplex DNA in plasmid but not linear form triggered cytotoxicity in a MMR-dependent manner. Thus 5FU incorporated into DNA, separated from its effects on RNA, can be recognized by DNA MMR to trigger cell death. PMID- 21814036 TI - Dam methylase accessibility as an instrument for analysis of mammalian chromatin structure. AB - For a 140-kb human genome locus, an analysis of the distribution of Dam methylase accessible sites, DNase I sensitive and resistant regions, unmethylated CpG sites and acetylated histone H3 molecules was performed and compared with transcriptional activity of the genes within the locus. A direct correlation was found between the extent of Dam methylation and C5 cytosine (CpG) methylation. It was also demonstrated that promoter regions of all highly and moderately transcribed genes are highly accessible to methylation by Dam methylase. In contrast, promoters of non-transcribed genes showed a very low extent of Dam methylation. Promoter regions of non-transcribed genes were also highly CpG methylated, and the promoter and more distant 5'-regions of the housekeeping gene COX6B1 were substantially CpG-demethylated. Some highly Dam methylase accessible regions are present in the intergenic regions of the locus suggesting that the latter contain either unidentified non-coding transcripts or extended regulatory elements like locus control regions. PMID- 21814038 TI - Transcriptional and epigenetic regulation of the p53 tumor suppressor gene. AB - The p53 tumor suppressor is one of the most studied molecules in cancer research. Despite the fact that there is a detailed understanding involving multiple aspects of the p53-associated biology, many aspects of its transcriptional regulation are still not well clarified. Limited information is available on how the p53 gene is transcriptional and epigenetically regulated. The p53 gene expression is tightly controlled through a variety of transcription factors, miRNAs, its anti-sense RNA Wrap53, the insulator protein CTCF and very likely by other genetic and epigenetic mechanisms. It's the intent of this article to review in depth important aspects concerning the transcriptional regulation of the p53 gene and perhaps serve as a stepping-stone to begin a conceptual change on how future p53 research can be approached. PMID- 21814037 TI - Histone H3K9 modifications are a local chromatin event involved in ethanol induced neuroadaptation of the NR2B gene. AB - Expression of the NMDA receptor 2B (NR2B) gene is upregulated following chronic intermittent ethanol (CIE) treatment and withdrawal, which underlies behavioral alterations in addiction. The goal of this study was to characterize the changes of histone modifications induced by CIE treatment and its subsequent removal associated to the upregulation of NR2B gene transcription. To investigate the involvement of histone acetylation in the effect of ethanol on the NR2B gene, we examined the influence of CIE on histone acetylation in the 5' regulatory region of NR2B using a qChIP assay. CIE treatment and its subsequent removal produced a remarkable and selected increase in histone H3K9 acetylation. Interestingly, the majority of the increased H3K9 acetylation occurred after ethanol removal, which was coincident with a decrease in H3K9 methylation in the same time duration. Further examination of the mechanisms of ethanol-induced alterations on the histone modifications revealed that CIE-induced acetylation of H3K9 was not due to the changes in global enzyme activities or the expression of histone acetyltransferases (HATs) and deacetylase (HDACs). Instead, we found a significant downregulation in some histone methyltransferases (HMTs) at both the global level and the local chromatin of the NR2B gene following CIE treatment. Moreover, our experiments also indicated a decrease of G9a, Suv39 h1 and HDAC1-3 in the chromatin of the NR2B gene promoter, which may be responsible for the altered H3K9 modifications. Taken together, the findings suggest a mechanism where the changes in H3K9 modifications in the local chromatin of the NR2B gene underlie alcohol-induced neuroadaptation. PMID- 21814039 TI - Ligand association rates to the inner-variable-domain of a dual-variable-domain immunoglobulin are significantly impacted by linker design. AB - The DVD-Ig (TM) protein is a dual-specific immunoglobulin. Each of the two arms of the molecule contains two variable domains, an inner variable domain and an outer variable domain linked in tandem, each with binding specificity for different targets or epitopes. One area of on-going research involves determining how the proximity of the outer variable domain affects the binding of ligands to the inner variable domain. To explore this area, we prepared a series of DVD-Ig proteins with binding specificities toward TNFalpha and an alternate therapeutic target. Kinetic measurements of TNFalpha binding to this series of DVD-Ig proteins were used to probe the effects of variable domain position and linker design on ligand on- and off-rates. We found that affinities for TNFalpha are generally lower when binding to the inner domain than to the outer domain and that this loss of affinity is primarily due to reduced association rate. This effect could be mitigated, to some degree, by linker design. We show several linker sequences that mitigate inner domain affinity losses in this series of DVD Ig proteins. Moreover, we show that single chain proteolytic cleavage between the inner and outer domains, or complete outer domain removal, can largely restore inner domain TNFalpha affinity to that approaching the reference antibody. Taken together, these results suggest that a loss of affinity for inner variable domains in this set of DVD-Ig proteins may be largely driven by simple steric hindrance effects and can be reduced by careful linker design. PMID- 21814041 TI - Transmission of prions within the gut and towards the central nervous system. AB - The prion protein is a glycoprotein characterized by a folded alpha-helical structure that, under pathological conditions, misfolds and aggregates into its infectious isoform as beta-sheet rich amyloidic deposits. The accumulation of the abnormal protein is responsible for a group of progressive and fatal disorders characterized by vacuolation, gliosis, and spongiform degeneration. Prion disorders are characterized by a triple aetiology: familial, sporadic or acquired, although most cases are sporadic. The mechanisms underlying prion neurotoxicity remain controversial, while novel findings lead to hypothesize intriguing pathways responsible for prion spreading. The present review aims to examine the involvement of the gastrointestinal tract and hypothesizes the potential mechanisms underlying cell-to-cell transmission of the prion protein. In particular, a special emphasis is posed on the mechanisms of prion transmission within the gut and towards the central nervous system. The glycation of prion protein to form advanced glycation end-products (AGE) interacting with specific receptors placed on neighboring cells (RAGE) represents the key hypothesis to be discussed. PMID- 21814040 TI - Utilization of monoclonal antibody-targeted nanomaterials in the treatment of cancer. AB - Due to their excellent specificity for a single epitope, monoclonal antibodies (mAbs) present a means of influencing the function of cells at the molecular level. In particular they show great promise in the treatment of cancer because they can inhibit cancer cell proliferation, tumor angiogenesis, invasiveness and malignant spread of cancerous cells. Many mAbs are in various stages of testing and 11 are currently marketed in the US or Europe for the treatment of cancers that express particular antigens such as human epidermal growth factor receptor 2, CD20, epidermal growth factor receptor and vascular endothelial growth factor. Strategies to conjugate mAbs to toxins, radioactive isotopes and chemotherapeutic drugs to improve efficacy are under intense investigation and numerous immunoconjugates have been studied in the clinical setting. However, the molecules have limitations, and so nanomaterials (NMs), which potentially offer more flexibility of design and functionality in providing platforms for binding of multiple therapeutic agents in a single structure, are being examined as an alternative. Studies utilizing mAb-targeted NMs have shown that they exhibit focused targeting, improved pharmacokinetics and improved "passive" drug delivery via leaky vasculature. Nevertheless, before they can be utilized to treat cancer, potential NM toxicity must be thoroughly investigated. Thus, rigorous testing of NM-mAb conjugates in both in vitro and in vivo systems is underway to determine how NM-mAb conjugates will interact with cells and tissues of the body. In this review, we discuss the broad range of nanomaterials that are under investigation as potential platforms for the presentation of mAbs either as single therapeutics or in combination with other drugs and their advantages and limitations in specifically targeting cancer. PMID- 21814042 TI - Mechanisms of glucose sensing in the pancreatic beta-cell: A computational systems-based analysis. AB - Pancreatic beta-cells respond to rising blood glucose by increasing oxidative metabolism, leading to an increased ATP/ADP ratio in the cytoplasm with a subsequent influx of calcium and the eventual secretion of insulin. The mechanisms of glucose sensing in the pancreatic beta-cell involve the coupling of cytoplasmic and mitochondrial processes. Our analysis, based on mathematical models of data from multiple sources has implications for beta-cell function and the treatment of type 2 diabetes (Fridlyand and Philipson, 2010). This beta-cell glucose response model correctly predicts changes in the ATP/ADP ratio, cytoplasmic and mitochondrial calcium levels, and other metabolic parameters in response to alterations in substrate delivery at steady-state and during cytoplasmic calcium oscillations. Here we consider how peculiarities of beta-cell pathways that result in dysfunction can be a consequence of specific mechanisms of glucose sensitivity, using our computational systems-based analysis. We found that the mitochondrial membrane potential must be relatively low in beta-cells compared with other cell types to permit precise mitochondrial regulation of the cytoplasmic ATP/ADP ratio. This key difference may follow from a relative reduction in cellular respiratory activity. Our analysis additionally demonstrates how activity of lactate dehydrogenase, uncoupling proteins, and the redox shuttles all working in concert can regulate beta-cell function. We further show that a decreased mitochondrial membrane potential may lead to a low rate of production of reactive oxygen species in beta-cells under physiological conditions. This computational systems analysis aids in providing a more complete understanding of the complex process of beta-cell glucose sensing. PMID- 21814043 TI - The p75NTR extracellular domain: a potential molecule regulating the solubility and removal of amyloid-beta. AB - Senile plaques composed of amyloid-beta (Abeta) in the brain are one of the hallmarks of Alzheimer disease (AD). Removal of Abeta from the brain is the most important therapeutic strategy for AD. The solubility of Abeta is critical for its endocytosis, transcytosis and removal from the brain. Our recent study has found that the extracellular domain of p75NTR, the neurotrophin receptor, plays an important role in the solubility of Abeta and might be one of the endogenous mechanisms in the regulation of Abeta plaque formation. The physiologically shedded extracellular domain of p75NTR is able to inhibit Abeta aggregation and diasggregate preformed Abeta fibrils, while the full p75NTR expressed on neurites, endothelial cells and smooth muscle cells in blood-brain barrier (BBB) might initiate Abeta endocytosis and degradation, and/or remove Abeta from the brain via BBB. Understanding the roles of p75NTR in the solubility and clearance of Abeta may allow targetting p75NTR as a unique opportunity to develop therapeutic drugs for the prevention and treatment of AD. PMID- 21814044 TI - Autophagy anomalies in the diabetic myocardium. AB - The prominent occurrence of autophagy in fetal/neonatal myocardial tissue has been recognized for more than three decades as a key process in managing the period of perinatal nutrient deprivation. Fasting-induced autophagy has similarly been characterized as an expedient short-term cardiomyocyte response to nutrient restriction. Discerning how autophagy operates in the heart in disease contexts of substrate dysregulation is proving to be a much more complex challenge. Recent studies relating to insulin signaling and cardiac autophagy activation have provided new insights-and generated new contradictions. We highlight several anomalies and pose a number of questions, which emerge from these studies. How can myocardial autophagy induction be associated with both PtdIns3K-Akt activation (in ischemia) and suppression (in insulin resistance)? What is the explanation for the contrasting findings that myocardial autophagy is elevated in a murine model of type 2 diabetes, yet suppressed in the type 1 diabetic state? And finally, in the type 1 diabetic setting, what could be the basis for downregulated cardiac AMP-activated protein kinase (AMPK)-driven autophagic activity, when activation of this 'energy stress' kinase is usually integral to the cellular response to glucose deficit? We summarize and discuss these interesting ambiguities of myocardial autophagy regulation. PMID- 21814046 TI - Sorafenib enhances pemetrexed cytotoxicity through an autophagy-dependent mechanism in cancer cells. AB - Pemetrexed (ALIMTA) is a folate anti-metabolite that has been approved for the treatment of non-small cell lung cancer, and has been shown to stimulate autophagy. In the present study, we sought to further understand the role of autophagy in the response to pemetrexed and to test if combination therapy could enhance the level of toxicity through altered autophagy in tumor cells. The multikinase inhibitor sorafenib (NEXAVAR), used in the treatment of renal and hepatocellular carcinoma, suppresses tumor angiogenesis and promotes autophagy in tumor cells. We found that sorafenib interacted in a greater than additive fashion with pemetrexed to increase autophagy and to kill a diverse array of tumor cell types. Tumor cell types that displayed high levels of cell killing after combination treatment showed elevated levels of AKT, p70 S6K and/or phosphorylated mTOR, in addition to class III RTKs such as PDGFRb and VEGFR1, known in vivo targets of sorafenib. In xenograft and in syngeneic animal models of mammary carcinoma and glioblastoma, the combination of sorafenib and pemetrexed suppressed tumor growth without deleterious effects on normal tissues or animal body mass. Taken together, the data suggest that premexetred and sorafenib act synergistically to enhance tumor killing via the promotion of a toxic form of autophagy that leads to activation of the intrinsic apoptosis pathway, and predict that combination treatment represents a future therapeutic option in the treatment of solid tumors. PMID- 21814045 TI - Cilia and cell cycle re-entry: more than a coincidence. AB - With the exception of the final stages of spermatogenesis in butterfly and some unicellular ciliates and flagellates, ciliated cells undergo cell division without cilia. This reciprocal relationship between cilia formation and cell division has prompted investigators to propose that ciliogenesis and cell cycle progression are mutually exclusive processes. Early work in fibroblasts showed that deciliation occurs in two waves, as cells depart from quiescence. The first wave of deciliation occurs before entry into S, while the second wave occurs between S and mitosis. Since then, it has remained a mystery whether and how (de)ciliation is coupled to the cell cycle and further, whether ciliation can affect cell cycle progression. Several recent publications provide evidence for a causative role of ciliary resorption in influencing the duration of the G1 phase of the cell cycle impacting on several developmental processes, including left right patterning, kidney, skeletal and brain development. This body of work argues for the existence of a molecular crosstalk between ciliary factors and regulators of the cell cycle. Here, we review the evidence connecting primary cilia and the cell cycle and evaluate the idea that the primary cilium may function as a physical checkpoint in cell cycle re-entry. PMID- 21814049 TI - Bibliography current world literature. PMID- 21814048 TI - Collectrin and ACE2 in renal and intestinal amino acid transport. AB - Neutral amino acid transporters of the SLC6 family are expressed at the apical membrane of kidney and/or small intestine, where they (re-)absorb amino acids into the body. In this review we present the results concerning the dependence of their apical expression with their association to partner proteins. We will in particular focus on the situation of B0AT1 and B0AT3, that associate with members of the renin-angiotensin system (RAS), namely Tmem27 and angiotensin-converting enzyme 2 (ACE2), in a tissue specific manner. The role of this association in relation to the formation of a functional unit related to Na+ or amino acid transport will be assessed. We will conclude with some remarks concerning the relevance of this association to Hartnup disorder, where some mutations have been shown to differentially interact with the partner proteins. PMID- 21814047 TI - Mice lacking functional TRPV1 are protected from pressure overload cardiac hypertrophy. AB - TRPV1 (transient receptor potential cation channel, subfamily V, member 1) is best studied in peripheral sensory neurons as a pain receptor; however TRPV1 is expressed in numerous tissues and cell types including those of the cardiovascular system. TRPV1 expression is upregulated in the hypertrophic heart, and the channel is positioned to receive stimulatory signals in the hypertrophic heart. We hypothesized that TRPV1 has a role in regulating cardiac hypertrophy. Using transverse aortic constriction to model pressure overload cardiac hypertrophy we show that mice lacking functional TRPV1, compared to wild type, have improved heart function, and reduced hypertrophic, fibrotic and apoptotic markers. This suggests that TRPV1 plays a role in the progression of cardiac hypertrophy, and presents a possible therapeutic target for the treatment of cardiac hypertrophy and heart failure. PMID- 21814051 TI - Treatment of uncommon malignant tumours of the bladder. AB - PURPOSE OF REVIEW: Urothelial carcinoma is the most common histological type of bladder tumours. Nevertheless, its variants and less common types represent 20% of all bladder cancers. The objective was to update the recent publications on these rare diseases and to draw conclusions for clinical management. RECENT FINDINGS: Recent retrospective studies have been published. They refine the description of histological patterns and of immunochemistry diagnosis. Taking into account the heterogeneity of these pathologies, several groups have benefited of increased knowledge such as sarcomas and lymphomas. The need of international collaboration to study prospectively some subgroups of tumours is crucial. SUMMARY: Rare bladder cancers have generally poor outcome and in a majority of the cases surgery, namely cystectomy remains the most important curative treatment. Specific subgroups, as lymphoma, sarcoma and dedifferentiated epithelial tumours may benefit of molecular characterization and trials with targeted drugs. PMID- 21814052 TI - Bladder cancer imaging: an update. AB - PURPOSE OF REVIEW: To present the recent advances in imaging for diagnosis, staging, and follow-up of bladder cancer. RECENT FINDINGS: The use of multidetector 64-slice computed tomography (CT) and diffusion-weighted imaging has enabled higher-resolution imaging of bladder cancer on CT and MRI, respectively, increasing both specificity and sensitivity in the detection of bladder tumors and extravesical disease relative standard imaging. Although urinary excretion of F-FDG produces difficulties in the interpretation of F-FDG PET/CT, new techniques have been described to overcome this limitation. The use of the agent C-acetate with PET/CT may be another option when performing imaging for staging and treatment decision-making. SUMMARY: Accurate and reproducible imaging is critical in the management of bladder cancer. The resolution of a number of imaging modalities has increased, likely allowing for improved treatment decisions. Further research is needed to improve the diagnosis of small and/or flat lesions. PMID- 21814053 TI - Perioperative management of nonmuscle-invasive bladder cancer. AB - PURPOSE OF REVIEW: The management of nonmuscle-invasive bladder cancer is a challenge. Despite current guidelines, the treatment is suboptimal as illustrated by the high risk of recurrence and progression. Transurethral resection plays a pivotal role in the management of bladder cancer, but the quality varies dramatically. In this review, we discuss the latest developments that aim to improve the outcome of a transurethral resection such as photodynamic diagnosis, a second resection and adjuvant therapy. RECENT FINDINGS: The treatment of a bladder cancer patient can be improved, for example, with a standard second resection in a subset of the patients or the use of visual enhancement techniques. There is conflicting data on the clinical value of techniques like photodynamic diagnosis, as it does not always seem to translate into a better long-term outcome. Comparison of studies is difficult because of differences in patient selection and endpoints. Better classification in (personalized) risk categories may facilitate the treatment choice and prediction of the long-term outcome. SUMMARY: The outcome of bladder cancer patients can be improved. A good quality transurethral resection of the bladder tumor is crucial and novel technological developments may improve the outcome, but they remain the subject of discussion. PMID- 21814054 TI - Cost-effectiveness of open versus laparoscopic versus robotic-assisted laparoscopic cystectomy and urinary diversion. AB - PURPOSE OF REVIEW: To provide insight into the recently published cost comparisons in the context of open, laparoscopic, and robotic-assisted laparoscopic radical cystectomy and to demonstrate the complexity of such economic analyses. RECENT FINDINGS: Most economic evaluations are from a hospital perspective and summarize short-term perioperative therapeutic costs. However, the contributing factors (e.g. study design, included variables, robotic amortization plan, supply contract, surgical volume, surgeons' experience, etc.) vary substantially between the institutions. In addition, a real cost-effective analysis considering cost per quality-adjusted life-year gained is not feasible because of the lack of long-term oncologic and functional outcome data with the robotic procedure. On the basis of a modeled cost analysis using results from published series, robotic-assisted cystectomy was - with few exceptions - found to be more expensive when compared with the open approach. Immediate costs are affected most by operative time, followed by length of hospital stay, robotic supply, case volume, robotic cost, and transfusion rate. Any complication substantially impacts overall costs. SUMMARY: Economic cost evaluations are complex analyses influenced by numerous factors that hardly allow an interinstitutional comparison. Robotic-assisted cystectomy is constantly refined with many institutions being somewhere on their learning curve. Transparent reports of oncologic and functional outcome data from centers of expertise applying standardized methods will help to properly analyze the real long-term benefits of robotic surgery and successor technologies and prevent us from becoming slaves of successful marketing strategies. PMID- 21814056 TI - Current world literature. PMID- 21814055 TI - Biomarkers for prognosis and treatment selection in advanced bladder cancer patients. AB - PURPOSE OF REVIEW: Patients with locally 'advanced' or muscle invasive bladder cancer have higher mortality rates than patients with nonmuscle invasive ('superficial') bladder cancer. Biomarkers can stratify clinical outcomes and thus promise to more accurately prognosticate and thus help assign patients to the appropriate treatments. The aim of this review is to summarize biomarker developments in the past year and to discuss their implications in prognosis and treatment selection in locally advanced bladder cancer. RECENT FINDINGS: Prognostic biomarkers for bladder cancer are identified at the DNA, RNA and/or protein levels. Some are new markers, whereas others are established markers with new roles in bladder cancer. Markers can report on the risk of disease recurrence or metastasis, or treatment responsiveness and thus are useful in determining 'who to treat' and 'what to treat with'. SUMMARY: The list of biomarkers for prognosis and treatment selection for advanced bladder cancer is growing. For most, their clinical relevance is unclear due to their lack of validation in external datasets. MicroRNAs and new techniques including next-generation sequencing offer additional opportunities for biomarker discovery, validation, and clinical applications. PMID- 21814057 TI - A farewell to diagnostic ERCP in acute pancreatitis. PMID- 21814059 TI - Healing and restoration: we need to practice what we preach. PMID- 21814060 TI - Postoperative care for the robotic surgery bowel resection patient. AB - A new surgical method is available for colon and rectal surgery. Robotic surgery, using the daVinci Si HD Surgical System, offers surgical advances compared with the traditional open or laparoscopic surgical methods. The potential advantages of robotic technology continue to be explored and its most appropriate functions are yet to be determined. In clinical experience, the use of this surgical method has resulted in changes to postoperative nursing care management. This article describes changes in the management of postoperative patient care including fluid and electrolyte balance, and patient and staff education. Modifications were instituted in the clinical pathway to facilitate an accelerated standard of care. New discharge strategies were implemented to ensure ongoing fluid and electrolyte balance by the patient. A true team effort from a multitude of disciplines was required for the changes in patient care routine to be effective. Outcomes including length of stay and patient satisfaction are presented. PMID- 21814061 TI - The association between the exacerbation of irritable bowel syndrome and menstrual symptoms in young Taiwanese women. AB - Studies of irritable bowel syndrome (IBS) have focused on the relationship between IBS and the menstrual cycle in Western societies. Specifically, an exacerbation of bowel symptoms, gas, distention, diarrhea, and constipation in the premenstrual and menstrual phases has been recognized among female IBS clients. Menstrual experience is culturally specific. Thus, the purpose of this study is to determine the prevalence rate of IBS in young Taiwanese women and to identify the most prevalent symptoms of IBS among this population. Moreover, this study explores the exacerbation of IBS during menses among young Taiwanese women. A cross-sectional survey was applied. A composite of validated questionnaires including the Modified Woods Daily Health Diary and Talley's Bowel Disease Questionnaire were administered to a stratified random sample of 971 female high school students in Taipei City, Taiwan. The results indicated that exacerbation of gastrointestinal symptoms during menstruation is present among young Taiwanese women with IBS. The IBS prevalence rate was 16.2% based on the Rome II criteria. Abdominal pain had the highest severity level, and bloating was ranked second among young Taiwanese women with IBS. These symptoms significantly increased in magnitude across time from postmenstrual to premenstrual to menses. PMID- 21814062 TI - Leisure-time physical activity in Canadians living with Crohn disease and ulcerative colitis: population-based estimates. AB - The purpose of this study was to provide population-based estimates of leisure time physical activity (LTPA) in Canadians diagnosed with Crohn disease (CD) or ulcerative colitis (UC). Data were derived from the Canadian Community Health Survey Cycle 3.1 (2005). Those diagnosed with CD (n = 474; 61.60% female) or UC (n = 637; 65.10% female) were compared with those not reporting CD/UC (n = 113,685; 53.60% female). The most prevalent forms of LTPA reported were walking and gardening/yard work. Individuals with CD were more likely to be classified as "inactive" (OR = 1.34; 95% CI [1.12, 1.61]) and less likely to be "active" (OR = 0.69; 95% CI [0.55, 0.87]) than those not reporting CD/UC. These trends were mirrored for those living with UC, although statistical significance was not attained. Despite claims advocating the benefits of LTPA for ameliorating complications associated with CD/UC, prevalence estimates from a population-based sample of Canadians living with CD/UC suggest that the majority do not meet current public health guidelines. Results offer benchmarks for prevalence of LTPA in those diagnosed with CD/UC. Findings suggest that many living with this condition will not benefit from the protective role of LTPA on complications associated with CD/UC. PMID- 21814063 TI - Intraprocedural evaluation of comfort for sedated outpatient upper endoscopy and colonoscopy: the La Crosse (WI) intra-endoscopy sedation comfort score. AB - Patient comfort is often assessed during gastrointestinal procedures to guide sedation. There are, however, no validated scales appropriate for routine comfort assessment. This study validated a single-item La Crosse (WI) intra-endoscopy sedation comfort score (L-WISC) by determining interobserver agreement and correlation with patient outcomes. The study was conducted in prospective outpatient cohorts of patients undergoing outpatient esophagogastroduodenoscopy and/or colonoscopy at a regional healthcare medical center endoscopy unit. In Phase 1, independent assessments of 100 patients' intraprocedural comfort by the endoscopist and nurse determined interobserver agreement. In Phase 2, nurses assessed 200 patients, who were provided surveys to self-report their comfort 2 weeks postprocedure. In Phase 1, there was fair interobserver agreement (weighted kappa = 0.36, with 95% confidence intervals [CI] [0.19, 0.53]). After L-WISC revisions, Phase 1 was repeated with moderate agreement (weighted kappa = 0.45; 95% CI [0.31, 0.60]). In Phase 2, using the revised score, there was poor agreement (weighted kappa = 0.098; 95% CI [-0.0020, 0.20]) between nurses' and patients' scores. The L-WISC is the first intraprocedural gastrointestinal comfort score appropriate for routine use to be validated with interobserver agreement and correlation with patient outcomes. It has reproducibility between endoscopists and nurses. It does not predict patient recollection of sedation comfort, but it remains unclear whether such prediction is possible with the use of amnestic sedatives. The L-WISC provides standardized levels of patient comfort to guide sedation titration routinely during outpatient endoscopy. PMID- 21814064 TI - Influence of operator experience and reporting time on the accuracy of esophageal capsule endoscopy screening for varices. AB - Conflicting data exist concerning the accuracy of esophageal capsule endoscopy (ECE) for the screening of varices. No study has examined the influence of operator factors on the accuracy of ECE reporting. The primary aims of this study were, therefore, to examine how operator experience with esophagogastroduodenoscopy (EGD) and operator reporting times of capsule videos influenced test accuracy. Twelve cirrhotic patients presenting for EGD had same day ECE performed. The gold standard for variceal grade was determined using a panel of experienced endoscopists. Six novice capsule endoscopists, blinded to results of EGD, subsequently reported capsule videos for each of the 12 patients.Novice capsule endoscopists accurately identified high-risk varices. The mean area under the receiver operating characteristic curve for identifying high risk varices for the six operators was 0.88 +/-/-0.14. The mean sensitivity, specificity, positive, and negative predictive values for identifying high-risk varices for the six operators were 83%, 93%, 82%, and 97%, respectively. Years of prior EGD experience were not associated with accuracy of capsule reporting (OR = 0.9, 95% CI [0.74, 1.08]; p = .26). Time spent reporting capsule videos was associated with accuracy of capsule reporting for high-risk varices using British Society of Gastroenterology criteria (OR = 1.33, 95% CI [1.05, 1.08]; p = .018). Novice capsule endoscopists are able to accurately identify high-risk esophageal varices. Time taken to report capsule videos, but not amount of prior EGD experience, influenced capsule report accuracy. These findings may have implications for the design of further trials and the cost-effectiveness of ECE screening of varices. PMID- 21814065 TI - Quality of life in adult celiac disease in a mountain area of northeast Italy. AB - The aim of this study was to evaluate the health-related quality of life in patients diagnosed as having celiac disease and to study the factors involved in its impairment of quality of life. We conducted a cross-sectional study in a randomized sample of patients with celiac disease by administering the Celiac Disease Questionnaire distributed by mail. The association between the quality of life and sociodemographic and clinical variables was verified by means of a stepwise multiple regression model. One hundred ninety-one questionnaires were returned (participation rate = 63.66%), and 187 were analyzed. Women comprised 78.61% of the participants, and the median age was 36 years, 10 months. The mean summary total score in the Celiac Disease Questionnaire was 154.53 (possible range 1-196; higher scores equate with higher quality of life), and the score was lower in the subscale of emotion. Women scored significantly lower than men. Participants with the symptomatic disease scored significantly lower than the nearly asymptomatic patients in the total score and in all the subscales. Symptomatic patients need interventions for improving their quality of life, in particular psychological support. PMID- 21814066 TI - Pharmacologic matters of herbal supplements. PMID- 21814067 TI - Getting the team through the death of a colleague. PMID- 21814068 TI - Multisite research: a spirit of cooperation. PMID- 21814069 TI - Addressing gaps in physician education using personal genomic testing. PMID- 21814071 TI - Introduction to the Festchrift for Eugene B. Brody, MD. PMID- 21814072 TI - Evidence-based psychotherapy for schizophrenia: 2011 update. AB - Many patients with schizophrenia have psychological distress and receive some form of psychotherapy. Several different psychotherapeutic approaches for schizophrenia have been developed and studied. Of these approaches, cognitive behavior therapy (CBT) has the strongest evidence base and has shown benefit for symptom reduction in outpatients with residual symptoms. In addition to CBT, other approaches include compliance therapy, personal therapy, acceptance and commitment therapy, and supportive therapy. Although usually studied as distinct approaches, these therapies overlap with each other in their therapeutic elements. Psychotherapy for schizophrenia continues to evolve with the recent advent of such approaches as metacognitive therapy, narrative therapies, and mindfulness therapy. Future research may also consider three different goals of psychotherapy in this patient population: to provide emotional support, to enhance functional recovery, and to alter the underlying illness process. PMID- 21814073 TI - Psychodynamic psychotherapy: adults and children. AB - Psychodynamic psychotherapy is a major therapeutic modality for adults and children. It covers a number of related therapies based on psychoanalytic concepts and models. In this paper, we address new developments in thinking and practice, recent changes relating to teaching, and new findings from research and developmental science. A child case is presented to illustrate the complexity of arriving at a diagnosis and treatment. PMID- 21814074 TI - Refugee resettlement to the United States: recommendations for a new approach. AB - Hmong acculturation to the United States has involved high prevalence of several psychosocial challenges: acculturation failure, welfare dependency, psychiatric disorder, mistrust, malignant youth gangs, and violence. Conversely, resettlement of the Thai Dam-a tribal group, also from Laos-has gone remarkably well in comparison. Strategies used for resettlement of these two groups differed greatly. Based on these differences, the author recommends a refugee resettlement strategy aimed at improved mental health and optimal acculturation for future refugee groups. PMID- 21814075 TI - Psychiatry and terrorism. AB - Terrorism has dominated the domestic and international landscape since 9/11. Like other fields, psychiatry was not well prepared. With the 10th anniversary of the 9/11 attack approaching, it is timely to consider what can be done to prepare before the next event. Much has been learned to provide knowledge and resources. The roles of psychiatrists are challenged by what is known of the causes of, consequences of, and responses to terrorism. Reflecting on knowledge from before and since 9/11 introduces concepts, how individuals become terrorists, how to evaluate the psychiatric and behavioral effects of terrorism, and how to expand treatments, behavioral health interventions, public policy initiatives, and other responses for its victims. New research, clinical approaches, and policy perspectives inform strategies to reduce fear and cope with the aftermath. This article identifies the psychiatric training, skills and services, and ethical considerations necessary to prevent or reduce terrorism and its tragic consequences and to enhance resilience. PMID- 21814076 TI - Posttraumatic stress disorder from Vietnam to today: the evolution of understanding during Eugene Brody's tenure at the journal of nervous and mental disease. AB - The psychological and behavioral consequences of exposure to traumatic events have been described throughout our history. However, the term posttraumatic stress disorder (PTSD) was not formally introduced into the Diagnostic and Statistical Manual of Mental Disorders, Third Edition, until after Dr Eugene Brody--whose broad interests included refugee populations and victims of trauma- had already served as editor-in-chief of the Journal of Nervous and Mental Disease (JNMD) for 15 years. Advances in molecular biology, genetics, and imaging that occurred during Brody's tenure at the JNMD contributed significantly to our current understanding of the human fear response and the neurobiology of PTSD. Comprehensive treatment guidelines summarizing evidence-based treatment were published during his tenure, and the most recent American Psychiatric Association update to practice standards was published in the year before his passing. Thus, this review of the history and present state of the science of PTSD summarizes the lessons learned while Dr Brody dedicated his life to teaching us. PMID- 21814077 TI - A look at cultural psychiatry in the 21st century. AB - Cultural psychiatry, as a subspecialty of psychiatry and thus medicine, has grown steadily and extensively in the 20th century, especially during the second part of this century. In this article, we look at the origins of cultural psychiatry; at its history through the centuries; at its role in the clinical, educational, and research domains; at its significance in today's conceptualization of the fields of psychiatry and mental health; and at its future perspectives within the realms of both medicine and psychiatry. PMID- 21814078 TI - International mental health advocacy organizations: an interview with Norman Sartorius by John A. Talbott. AB - International professional and nonprofessional associations and organizations could be immensely useful in the promotion of mental health and in the control of mental disorders. Unfortunately, their potential is not always used. Organizations go through periods of crisis and often vegetate for sometime until somebody resuscitates them. The impact of a good leader or leadership group lasts for a few years. A great achievement would be to structure associations in a manner that will ensure their stability and continuous contributions even when their leaders are weak. PMID- 21814079 TI - Psychiatric ethics: foundational and evolutionary. AB - As with the basic and clinical sciences, the field of medical ethics, in particular, that of psychiatric ethics, has grown and developed during the last four decades, the time when Dr. Eugene Brody edited the Journal of Nervous and Mental Disease. In this paper, the authors will consider a series of ethical problems that psychiatrists have identified in their clinical practice and suggest paths to resolution that may artfully balance conflicts in core moral beliefs. PMID- 21814080 TI - Reproductive psychiatry: contemporary controversies. PMID- 21814081 TI - Psychiatric aspects of induced abortion. AB - Approximately one third of the women in the United States have an abortion during their lives. In the year 2008, 1.21 million abortions were performed in the United States (Jones and Koolstra, Perspect Sex Reprod Health 43:41-50, 2011). The psychiatric outcomes of abortion are scientifically well established (Adler et al., Science 248:41-43, 1990). Despite assertions to the contrary, there is no evidence that abortion causes psychiatric problems (Dagg, Am J Psychiatry 148:578 585, 1991). Those studies that report psychiatric sequelae suffer from severe methodological defects (Lagakos, N Engl J Med 354:1667-1669, 2006). Methodologically sound studies have demonstrated that there is a very low incidence of frank psychiatric illness after an abortion; women experience a wide variety of feelings over time, including, for some, transient sadness and grieving. However, the circumstances that lead a woman to terminate a pregnancy, including previous and/or ongoing psychiatric illness, are independently stressful and increase the likelihood of psychiatric illness over the already high baseline incidence and prevalence of mood and anxiety disorders among women of childbearing age. For optimal psychological outcomes, women, including adolescents, need to make autonomous and supported decisions about problem pregnancies. Clinicians can help patients facing these decisions and those who are working through feelings about having had abortions in the past. PMID- 21814082 TI - Dilemmas related to pregnancy loss. AB - Women who lose desired pregnancies by miscarriage, stillbirth, genetic termination, or unsuccessful in vitro fertilization are at risk of suffering from grief, anxiety, guilt, and self-blame that may even present in subsequent pregnancies. A review of the literature reveals the dilemmas about effective means of helping women deal with these losses. The approach to stillbirth has shifted from immediately removing the child from the mother to encouraging viewing and holding the baby. This approach has been questioned as possibly causing persistent anxiety. Women who miscarry are currently encouraged to find ways to memorialize the lost fetus. Immediate crisis intervention and follow-up care should be available, recognizing that individual women may experience different reactions and their specific postloss needs must be assessed. PMID- 21814083 TI - Perinatal mental health. AB - Pregnancy is the time during which physiological and psychological preparation for motherhood takes place. It has long been considered a blessed time, free of psychiatric disorders. However, there is now strong evidence that major depressive disorder may occur not only after birth but even during the prepartum. Most often, mental illness during this period is underestimated, not assessed, therefore not diagnosed, and consequently goes untreated. Reviewing the literature on the negative impact of both maternal and infant health in case of perinatal depression, we underline that recognizing and treating prenatal depression will lead to preventive and curative treatments for mothers, enhance infant health, and therefore positively influence mother-infant relationships. PMID- 21814084 TI - The rights of americans with mental illness. AB - This contribution to the literature starts by summarizing the history of psychiatric services in America from the time of our colonization to the present. It then discusses the Bill of Rights and the subsequent "rights" gained by the mentally ill, largely through state legislative or legal actions. Finally, it concludes with a discussion of how the entire area of rights has been swept up in a larger attempt to achieve a federal Bill of Patients' Rights and then a Health Reform Act in 2010. PMID- 21814085 TI - The state of the art in medical sociology. AB - This is a review of the state of the art in Medical Sociology. Three approaches are used. One is looking at the work of the pioneers. Another approach involves examining textbooks, books of reading, and handbooks. The third approach is reporting on the 50th anniversary of the Medical Sociology Section of the American Sociological Association. Special attention is given to the way medical sociologists examine issues in psychiatric diagnosis and treatment. PMID- 21814086 TI - Medical anthropology enters the 21st century. AB - Medical anthropology is the smallest and perhaps least understood of the social and behavioral sciences of medicine. In this article, we indicate what makes the field distinctive and describe significant developments during the past two decades. PMID- 21814087 TI - Preface: Guidelines for the prevention of infections associated with combat related injuries: 2011 update. AB - Infection is an all-too-common complication of combat-related injuries. The Prevention of Combat-Related Infections Guidelines Panel was established to review pertinent data that have become available since 2007 on prevention of these infections and to update guidelines by this group previously published in 2008. These updated guidelines, Guidelines for the Prevention of Infections Associated With Combat-related Injuries: 2011 Update, are published in this Journal of Trauma supplement along with evidence-based medicine reviews of the supporting data. PMID- 21814088 TI - Executive summary: Guidelines for the prevention of infections associated with combat-related injuries: 2011 update: endorsed by the Infectious Diseases Society of America and the Surgical Infection Society. AB - Despite advances in resuscitation and surgical management of combat wounds, infection remains a concerning and potentially preventable complication of combat related injuries. Interventions currently used to prevent these infections have not been either clearly defined or subjected to rigorous clinical trials. Current infection prevention measures and wound management practices are derived from retrospective review of wartime experiences, from civilian trauma data, and from in vitro and animal data. This update to the guidelines published in 2008 incorporates evidence that has become available since 2007. These guidelines focus on care provided within hours to days of injury, chiefly within the combat zone, to those combat-injured patients with open wounds or burns. New in this update are a consolidation of antimicrobial agent recommendations to a backbone of high-dose cefazolin with or without metronidazole for most postinjury indications and recommendations for redosing of antimicrobial agents, for use of negative pressure wound therapy, and for oxygen supplementation in flight. PMID- 21814089 TI - Guidelines for the prevention of infections associated with combat-related injuries: 2011 update: endorsed by the Infectious Diseases Society of America and the Surgical Infection Society. AB - Despite advances in resuscitation and surgical management of combat wounds, infection remains a concerning and potentially preventable complication of combat related injuries. Interventions currently used to prevent these infections have not been either clearly defined or subjected to rigorous clinical trials. Current infection prevention measures and wound management practices are derived from retrospective review of wartime experiences, from civilian trauma data, and from in vitro and animal data. This update to the guidelines published in 2008 incorporates evidence that has become available since 2007. These guidelines focus on care provided within hours to days of injury, chiefly within the combat zone, to those combat-injured patients with open wounds or burns. New in this update are a consolidation of antimicrobial agent recommendations to a backbone of high-dose cefazolin with or without metronidazole for most postinjury indications, and recommendations for redosing of antimicrobial agents, for use of negative pressure wound therapy, and for oxygen supplementation in flight. PMID- 21814090 TI - Prevention of infections associated with combat-related extremity injuries. AB - During combat operations, extremities continue to be the most common sites of injury with associated high rates of infectious complications. Overall, ~ 15% of patients with extremity injuries develop osteomyelitis, and ~ 17% of those infections relapse or recur. The bacteria infecting these wounds have included multidrug-resistant bacteria such as Acinetobacter baumannii, Pseudomonas aeruginosa, extended-spectrum beta-lactamase-producing Klebsiella species and Escherichia coli, and methicillin-resistant Staphylococcus aureus. The goals of extremity injury care are to prevent infection, promote fracture healing, and restore function. In this review, we use a systematic assessment of military and civilian extremity trauma data to provide evidence-based recommendations for the varying management strategies to care for combat-related extremity injuries to decrease infection rates. We emphasize postinjury antimicrobial therapy, debridement and irrigation, and surgical wound management including addressing ongoing areas of controversy and needed research. In addition, we address adjuvants that are increasingly being examined, including local antimicrobial therapy, flap closure, oxygen therapy, negative pressure wound therapy, and wound effluent characterization. This evidence-based medicine review was produced to support the Guidelines for the Prevention of Infections Associated With Combat Related Injuries: 2011 Update contained in this supplement of Journal of Trauma. PMID- 21814091 TI - Prevention of infections associated with combat-related central nervous system injuries. AB - Combat-related injuries to the central nervous system (CNS) are of critical importance because of potential catastrophic outcomes. Although the overall infection rate of combat-related CNS injuries is between 5% and 10%, the development of an infectious complication is associated with a very high morbidity and mortality. This review focuses on the prevention of infections related to injuries to the brain or the spinal cord and provides evidence-based medicine recommendations from military and civilian data for the prevention of infection from combat-related CNS injuries. Prevention strategies emphasize the importance of expert evaluation and management by a neurosurgeon as expeditiously as possible. Areas of focus include elimination of cerebrospinal fluid leaks, wound coverage, postinjury antimicrobial therapy, irrigation, and debridement. Given that these recommendations are not supported by randomized control trials or adequate cohort studies in a military population, further efforts are needed to determine the best treatment strategies. This evidence-based medicine review was produced to support the Guidelines for the Prevention of Infections Associated With Combat-Related Injuries: 2011 Update contained in this supplement of Journal of Trauma. PMID- 21814092 TI - Prevention of infections associated with combat-related eye, maxillofacial, and neck injuries. AB - The percentage of combat wounds involving the eyes, maxillofacial, and neck regions reported in the literature is increasing, representing 36% of all combat related injuries at the start of the Iraq War. Recent meta-analysis of 21st century eye, maxillofacial, and neck injuries described combat injury incidences of 8% to 20% for the face, 2% to 11% for the neck, and 0.5% to 13% for the eye and periocular structures. This article reviews recent data from military and civilian studies to support evidence-based recommendations for the prevention of infections associated with combat-related eye, maxillofacial, and neck injuries. The major emphasis of this review is on recent developments in surgical practice as new antimicrobial studies were not performed. Further studies of bacterial infection epidemiology and postinjury antimicrobial use in combat-related injuries to the eyes, maxillofacial, and neck region are needed to improve evidence-based medicine recommendations. This evidence-based medicine review was produced to support the Guidelines for the Prevention of Infections associated with Combat-related Injuries: 2011 Update contained in this supplement of Journal of Trauma. PMID- 21814094 TI - Prevention of infections associated with combat-related burn injuries. AB - Burns are a very real component of combat-related injuries, and infections are the leading cause of mortality in burn casualties. The prevention of infection in the burn casualty transitioning from the battlefield to definitive care provided at the burn center is critical in reducing overall morbidity and mortality. This review highlights evidence-based medicine recommendations using military and civilian data to provide the most comprehensive, up-to-date management strategies for initial care of burned combat casualties. Areas of emphasis include antimicrobial prophylaxis, debridement of devitalized tissue, topical antimicrobial therapy, and optimal time to wound coverage. This evidence-based medicine review was produced to support the Guidelines for the Prevention of Infections Associated With Combat-Related Injuries: 2011 Update contained in this supplement of Journal of Trauma. PMID- 21814093 TI - Prevention of infections associated with combat-related thoracic and abdominal cavity injuries. AB - Trauma-associated injuries of the thorax and abdomen account for the majority of combat trauma-associated deaths, and infectious complications are common in those who survive the initial injury. This review focuses on the initial surgical and medical management of torso injuries intended to diminish the occurrence of infection. The evidence for recommendations is drawn from published military and civilian data in case reports, clinical trials, meta-analyses, and previously published guidelines, in the interval since publication of the 2008 guidelines. The emphasis of these recommendations is on actions that can be taken in the forward-deployed setting within hours to days of injury. This evidence-based medicine review was produced to support the Guidelines for the Prevention of Infections Associated With Combat-Related Injuries: 2011 Update contained in this supplement of Journal of Trauma. PMID- 21814095 TI - Infection prevention and control in deployed military medical treatment facilities. AB - Infections have complicated the care of combat casualties throughout history and were at one time considered part of the natural history of combat trauma. Personnel who survived to reach medical care were expected to develop and possibly succumb to infections during their care in military hospitals. Initial care of war wounds continues to focus on rapid surgical care with debridement and irrigation, aimed at preventing local infection and sepsis with bacteria from the environment (e.g., clostridial gangrene) or the casualty's own flora. Over the past 150 years, with the revelation that pathogens can be spread from patient to patient and from healthcare providers to patients (including via unwashed hands of healthcare workers, the hospital environment and fomites), a focus on infection prevention and control aimed at decreasing transmission of pathogens and prevention of these infections has developed. Infections associated with combat-related injuries in the recent operations in Iraq and Afghanistan have predominantly been secondary to multidrug-resistant pathogens, likely acquired within the military healthcare system. These healthcare-associated infections seem to originate throughout the system, from deployed medical treatment facilities through the chain of care outside of the combat zone. Emphasis on infection prevention and control, including hand hygiene, isolation, cohorting, and antibiotic control measures, in deployed medical treatment facilities is essential to reducing these healthcare-associated infections. This review was produced to support the Guidelines for the Prevention of Infections Associated With Combat-Related Injuries: 2011 Update contained in this supplement of Journal of Trauma. PMID- 21814096 TI - Antimicrobial prescribing practices following publication of guidelines for the prevention of infections associated with combat-related injuries. AB - BACKGROUND: Timely and limited antibiotic prophylaxis (postinjury antimicrobial therapy) targeting specific traumatic injuries is a well-recognized measure to lessen posttraumatic infection. Modern military combat injuries raise significant challenges because of complex multiple injuries and limited data derived directly from well-controlled trials to base recommendations. Expert consensus review of available evidence led to published guidance for selection and duration of antimicrobial therapy for combat-related trauma infection prevention. This analysis evaluates antibiotic-prescribing practices by military physicians in the operational theater relative to the published guidance. METHODS: Trauma history and infectious disease-specific inpatient care information is captured through the Joint Theater Trauma Registry along with a supplemental infectious disease module. Injury patterns are classified based on documented International Classification of Diseases-9th Revision codes with a composite assessment of each patient's injury pattern. Antimicrobial use categorized as prophylaxis is prescribed within the first 48 hours postinjury. Adherence to published guidance is reported along with patient characteristics and injury severity to assess for potential explanations of nonadherence. RESULTS: During June to November 2009, 75% of the 610 eligible trauma patients received antimicrobial prophylaxis. Adherence to the recommended antibiotic agent on the day of injury was in the range of 46% to 50% for the most common extremity injury patterns and <10% in penetrating abdominal injuries. Antibiotics were given in 39% of patients sustaining injuries that are recommendations to not receive antimicrobial prophylaxis. CONCLUSIONS: This first evaluation of combat trauma-related antibiotic prophylaxis shows adherence levels comparable or superior to reported rates in civilian settings despite the austere, frequently mass casualty environment. Areas for interval surveillance and education-based strategies for improved adherence to practice guidance are identified. PMID- 21814097 TI - Efficacy of point-of-injury combat antimicrobials. AB - BACKGROUND: Infection is a major complication associated with combat-related injuries. One strategy to decrease infections is immediate delivery of antimicrobials at or near the point-of-injury by the casualty or the first medical responder. The 75th Ranger Regiment systematically collects data on prehospital battlefield care, including antimicrobial administration. We review infectious complications and colonization rates associated with delivery of point of-injury antimicrobial therapy. METHODS: We retrospectively reviewed casualty treatment data from the 75th Ranger Regiment prehospital trauma registry on patients injured between March 2003 and March 2010 and linked this to electronic medical record data to look for the presence of bacterial infection or colonization within 30 days of injury. Patient demographics, antimicrobial therapy, and outcomes were evaluated. Assessment of colonization included surveillance screening cultures performed for multidrug-resistant bacteria, including Acinetobacter baumannii and methicillin-resistant Staphylococcus aureus, at US military hospitals in the combat zone, Germany, and stateside. RESULTS: Of 405 total casualties, 28 (6.9%) were infected with gram-negative bacteria, primarily A. baumannii. Of those who were not returned to duty or died near the time of injury, 28 of 211 (13.3%) were infected. The only identified risk factor for infection was higher military Injury Severity Score. Prehospital administration of antimicrobials to 113 of 405 casualties (27.9%), including 8 of the 28 infected casualties, did not affect infection or colonization rates. CONCLUSIONS: Although limited by population size, a significant difference in infection rates and multidrug-resistant pathogen colonization was not seen in those casualties who received single-dose broad-spectrum antimicrobials at the point-of-injury, confirming neither benefit nor harm. Overall adherence with initiating point-of-injury antimicrobials was low. PMID- 21814098 TI - Defining present blood component transfusion practices in trauma patients: papers from the Trauma Outcomes Group. PMID- 21814099 TI - Increased platelet:RBC ratios are associated with improved survival after massive transfusion. AB - BACKGROUND: Several recent military and civilian trauma studies demonstrate that improved outcomes are associated with early and increased use of plasma-based resuscitation strategies. However, outcomes associated with platelet transfusions are poorly characterized. We hypothesized that increased platelet:red blood cells (RBC) ratios would decrease hemorrhagic death and improve survival after massive transfusion (MT). METHODS: A transfusion database of patients transported from the scene to 22 Level I Trauma Centers over 12 months in 2005 to 2006 was reviewed. MT was defined as receiving >= 10 RBC units within 24 hours of admission. To mitigate survival bias, 25 patients who died within 60 minutes of arrival were excluded from analysis. Six random donor platelet units were considered equal to a single apheresis platelet unit. Admission and outcome data associated with the low (>1:20), medium (1:2), and high (1:1) platelet:RBC ratios were examined. These groups were based on the median value of the tertiles for the ratio of platelets:RBC units. RESULTS: Two thousand three hundred twelve patients received at least one unit of blood and 643 received an MT. Admission vital signs, INR, temperature, pH, Glasgow Coma Scale, Injury Severity Score, and age were similar between platelet ratio groups. The average admission platelet counts were lower in the patients who received the high platelet:RBC ratio versus the low ratio (192 vs. 216, p = 0.03). Patients who received MT were severely injured, with a mean (+/- standard deviation) Injury Severity Score of 33 +/- 16 and received 22 +/- 15 RBCs and 11 +/- 14 platelets within 24 hours of injury. Increased platelet ratios were associated with improved survival at 24 hours and 30 days (p < 0.001 for both). Truncal hemorrhage as a cause of death was decreased (low: 67%, medium: 60%, high: 47%, p = 0.04). Multiple organ failure mortality was increased (low: 7%, medium: 16%, high: 27%, p = 0.003), but overall 30-day survival was improved (low: 52%, medium: 57%, high: 70%) in the high ratio group (medium vs. high: p = 0.008; low vs. high: p = 0.007). CONCLUSION: Similar to recently published military data, transfusion of platelet:RBC ratios of 1:1 was associated with improved early and late survival, decreased hemorrhagic death and a concomitant increase in multiple organ failure-related mortality. Based on this large retrospective study, increased and early use of platelets may be justified, pending the results of prospective randomized transfusion data. PMID- 21814100 TI - High ratios of plasma and platelets to packed red blood cells do not affect mortality in nonmassively transfused patients. AB - BACKGROUND: Administration of high transfusion ratios in patients not requiring massive transfusion might be harmful. We aimed to determine the effect of high ratios of fresh frozen plasma (FFP) and platelets (PLT) to packed red blood cells (PRBC) in nonmassively transfused patients. METHODS: Records of 1,788 transfused trauma patients who received <10 units of PRBC in 24 hours at 23 United States Level I trauma centers were reviewed. The relationship between ratio category (low and high) and in-hospital mortality was assessed with propensity-adjusted multivariate proportional hazards models. RESULTS: At baseline, patients transfused with a high FFP:PRBC ratio were younger, had a lower Glasgow Coma Scale score, and a higher Injury Severity Score. Those receiving a high PLT:PRBC ratio were older. The risk of in-hospital mortality did not vary significantly with FFP:PRBC ratio category. Intensive care unit (ICU)-free days, hospital-free days, and ventilator-free days did not vary significantly with FFP:PRBC ratio category. ICU-free days and ventilator-free days were significantly decreased among patients in the high (>=1:1) PLT:PRBC category, and hospital-free days did not vary significantly with PLT:PRBC ratio category. The analysis was repeated using 1:2 as the cutoff for high and low ratios. Using this cutoff, there was still no difference in mortality with either FFP:PRBC ratios or platelet:PRBC ratios. However, patients receiving a >1:2 ratio of FFP:PRBCs or a >1:2 ratio PLT:PRBCs had significantly decreased ICU-free days and ventilator-free days. CONCLUSIONS: FFP:PRBC and PLT:PRBC ratios were not associated with in-hospital mortality. Depending on the threshold analyzed, a high ratio of FFP:PRBC and PLT:PRBC transfusion was associated with fewer ICU-free days and fewer ventilator free days, suggesting that the damage control infusion of FFP and PLT may cause increased morbidity in nonmassively transfused patients and should be rapidly terminated when it becomes clear that a massive transfusion will not be required. PMID- 21814101 TI - A normal platelet count may not be enough: the impact of admission platelet count on mortality and transfusion in severely injured trauma patients. AB - BACKGROUND: Platelets play a central role in hemostasis after trauma. However, the platelet count of most trauma patients does not fall below the normal range (100-450 * 10(9)/L), and as a result, admission platelet count has not been adequately investigated as a predictor of outcome. The purpose of this study was to examine the relationship between admission platelet count and outcomes after trauma. METHODS: A retrospective cohort study of 389 massively transfused trauma patients. Regression methods and the Kruskal-Wallis test were used to test the association between admission platelet count and 24-hour mortality and units of packed red blood cells (PRBCs) transfused. RESULTS: For every 50 * 10(9)/L increase in admission platelet count, the odds of death decreased 17% at 6 hours (p = 0.03; 95% confidence interval [CI], 0.70-0.99) and 14% at 24 hours (p = 0.02; 95% CI, 0.75-0.98). The probability of death at 24 hours decreased with increasing platelet count. For every 50 * 10(9)/L increase in platelet count, patients received 0.7 fewer units of blood within the first 6 hours (p = 0.01; 95% CI, -1.3 to -0.14) and one less unit of blood within the first 24 hours (p = 0.002; 95% CI, -1.6 to -0.36). The mean number of units of PRBCs transfused within the first 6 hours and 24 hours decreased with increasing platelet count. CONCLUSIONS: Admission platelet count was inversely correlated with 24-hour mortality and transfusion of PRBCs. A normal platelet count may be insufficient after severe trauma, and as a result, these patients may benefit from a lower platelet transfusion threshold. Future studies of platelet number and function after injury are needed. PMID- 21814102 TI - The association of blood component use ratios with the survival of massively transfused trauma patients with and without severe brain injury. AB - BACKGROUND: The effect of blood component ratios on the survival of patients with traumatic brain injury (TBI) has not been studied. METHODS: A database of patients transfused in the first 24 hours after admission for injury from 22 Level I trauma centers over an 18-month period was queried to find patients who (1) met different definitions of massive transfusion (5 units red blood cell [RBC] in 6 hours vs. 10 units RBC in 24 hours), (2) received high or low ratios of platelets or plasma to RBC units (<1:2 vs. >= 1:2), and (3) had severe TBI (head abbreviated injury score >= 3) (TBI+). RESULTS: Of 2,312 total patients, 850 patients were transfused with >= 5 RBC units in 6 hours and 807 could be classified into TBI+ (n = 281) or TBI- (n = 526). Six hundred forty-three patients were transfused with >= 10 RBC units in 24 hours with 622 classified into TBI+ (n = 220) and TBI- (n = 402). For both high-risk populations, a high ratio of platelets:RBCs (not plasma) was independently associated with improved 30-day survival for patients with TBI+ and a high ratio of plasma:RBCs (not platelets) was independently associated with improved 30-day survival in TBI- patients. CONCLUSIONS: High platelet ratio was associated with improved survival in TBI+ patients while a high plasma ratio was associated with improved survival in TBI- patients. Prospective studies of blood product ratios should include TBI in the analysis for determination of optimal use of ratios on outcome in injured patients. PMID- 21814103 TI - Effect of high product ratio massive transfusion on mortality in blunt and penetrating trauma patients. AB - BACKGROUND: Recent data suggest that massively transfused patients have lower mortality rates when high ratios (>1:2) of plasma or platelets to red blood cells (RBCs) are used. Blunt and penetrating trauma patients have different injury patterns and may respond differently to resuscitation. This study was performed to determine whether mortality after high product ratio massive transfusion is different in blunt and penetrating trauma patients. METHODS: Patients receiving 10 or more units of RBCs in the first 24 hours after admission to one of 23 Level I trauma centers were analyzed. Baseline physiologic and biochemical data were obtained. Univariate and logistic regression analyses were performed. Adjusted mortality in patients receiving high (>= 1:2) and low (<1:2) ratios of plasma or platelets to RBCs was calculated for blunt and penetrating trauma patients. RESULTS: The cohort contained 703 patients. Blunt injury patients receiving a high ratio of plasma or platelets to RBCs had lower 24-hour mortality (22% vs. 31% for plasma, p = 0.007; 20% vs. 30% for platelets, p = 0.032), but there was no difference in 30-day mortality (40% vs. 44% for plasma, p = 0.085; 37% vs. 44% for platelets, p = 0.063). Patients with penetrating injuries receiving a high plasma:RBC ratio had lower 24-hour mortality (21% vs. 37%, p = 0.005) and 30-day mortality (29% vs. 45%, p = 0.005). High platelet:RBC ratios did not affect mortality in penetrating patients. CONCLUSION: Use of high plasma:RBC ratios during massive transfusion may benefit penetrating trauma patients to a greater degree than blunt trauma patients. High platelet:RBC ratios did not benefit either group. PMID- 21814104 TI - A high fresh frozen plasma: packed red blood cell transfusion ratio decreases mortality in all massively transfused trauma patients regardless of admission international normalized ratio. AB - BACKGROUND: Coagulopathy is present in 25% to 38% of trauma patients on arrival to the hospital, and these patients are four times more likely to die than trauma patients without coagulopathy. Recently, a high ratio of fresh frozen plasma (FFP) to packed red blood cells (PRBCs) has been shown to decrease mortality in massively transfused trauma patients. Therefore, we hypothesized that patients with elevated International Normalized Ratio (INR) on arrival to the hospital may benefit more from transfusion with a high ratio of FFP:PRBC than those with a lower INR. METHODS: Retrospective multicenter cohort study of 437 massively transfused trauma patients was conducted to determine whether the effect of the ratio of FFP:PRBC on death at 24 hours is modified by a patient's admission INR on arrival to the hospital. Contingency tables and logistic regression were used. RESULTS: Trauma patients who arrived to the hospital with an elevated INR had a greater risk of death than those with a lower INR. However, as the ratio of FFP:PRBC transfused increased, mortality decreased similarly between the INR quartiles. CONCLUSIONS: The mortality benefit from a high FFP:PRBC ratio is similar for all massively transfused trauma patients. This is contrary to the current belief that only coagulopathic trauma patients benefit from a high FFP:PRBC ratio. Furthermore, it is unnecessary to determine whether INR is elevated before transfusing a high FFP:PRBC ratio. Future studies are needed to determine the mechanism by which a high FFP:PRBC ratio decreases mortality in all massively transfused trauma patients. PMID- 21814105 TI - Profoundly abnormal initial physiologic and biochemical data cannot be used to determine futility in massively transfused trauma patients. AB - BACKGROUND: Improvements in prehospital care and resuscitation have led to increases in the number of severely injured patients who are salvageable. Massive transfusion has been increasingly used. Patients often present with markedly abnormal physiologic and biochemical data. The purpose of this study was to identify objective data that can be used to identify clinical futility in massively transfused trauma patients to allow for early termination of resuscitative efforts. METHODS: A multicenter database was used. Initial physiologic and biochemical data were obtained, and mortality was determined for patients in the 5th and 10th percentiles for each variable. Raw data from the extreme outliers for each variable were also examined to determine whether a point of excessive mortality could be identified. Injury scoring data were also analyzed. A classification tree model was used to look for variable combinations that predict clinical futility. RESULTS: The cohort included 704 patients. Overall mortality was 40.2%. The highest mortality rates were seen in patients in the 10th percentile for lactate (77%) and pH (72%). Survivors at the extreme ends of the distribution curves for each variable were not uncommon. The classification tree analysis failed to identify any biochemical and physiologic variable combination predictive of >90% mortality. Patients older than 65 years with severe head injuries had 100% mortality. CONCLUSION: Consideration should be given to withholding massive transfusion for patients older than 65 years with severe head injuries. Otherwise we did not identify any objective variables that reliably predict clinical futility in individual cases. Significant survival rates can be expected even in patients with profoundly abnormal physiologic and biochemical data. PMID- 21814106 TI - A predictive model for mortality in massively transfused trauma patients. AB - BACKGROUND: Improvements in trauma systems and resuscitation have increased survival in severely injured patients. Massive transfusion has been increasingly used in the civilian setting. Objective predictors of mortality have not been well described. This study examined data available in the early postinjury period to identify variables that are predictive of 24-hour- and 30-day mortality in massively transfused trauma patients. METHODS: Massively transfused trauma patients from 23 Level I centers were studied. Variables available on patient arrival that were predictive of mortality at 24 hours were entered into a logistic regression model. A second model was created adding data available 6 hours after injury. A third model evaluated mortality at 30 days. Receiver operating characteristic curves and the Hosmer-Lemeshow test were used to assess model quality. RESULTS: Seven hundred four massively transfused patients were analyzed. The model best able to predict 24-hour mortality included pH, Glasgow Coma Scale score, and heart rate, with an area under the receiver operating characteristic curve (AUROC) of 0.747. Addition of the 6-hour red blood cell requirement increased the AUROC to 0.769. The model best able to predict 30-day mortality included the above variables plus age and Injury Severity Score with an AUROC of 0.828. CONCLUSION: Glasgow Coma Scale score, pH, heart rate, age, Injury Severity Score, and 6-hour red blood cell transfusion requirement independently predict mortality in massively transfused trauma patients. Models incorporating these data have only a modest ability to predict mortality and should not be used to justify withholding massive transfusion in individual cases. PMID- 21814107 TI - Gender-based differences in mortality in response to high product ratio massive transfusion. AB - BACKGROUND: Recent data suggest that patients undergoing massive transfusion have lower mortality rates when ratios of plasma and platelets to red blood cells (RBCs) of >= 1:2 are used. This has not been examined independently in women and men. A gender dichotomy in outcome after severe injury is known to exist. This study examined gender-related differences in mortality after high product ratio massive transfusion. METHODS: A retrospective study was conducted using a database containing massively transfused trauma patients from 23 Level I trauma centers. Baseline demographic, physiologic, and biochemical data were obtained. Univariate and logistic regression analyses were performed. Adjusted mortality in patients receiving high (>= 1:2) or low (<1:2) ratios of plasma or platelets to RBCs was compared in women and men independently. RESULTS: Seven hundred four patients were analyzed. In males, mortality was lower for patients receiving a high plasma:RBC ratio at 24 hours (20.6% vs. 33.0% for low ratio, p = 0.005) and at 30 days (34.9% vs. 42.8%, p = 0.032). Males receiving a high platelet:RBC ratio also had lower 24-hour mortality (17.6% vs. 31.5%, p = 0.004) and 30-day mortality (32.1% vs. 42.2%, p = 0.045). Females receiving high ratios of plasma or platelets to RBCs had no improvement in 24-hour mortality (p = 0.119 and 0.329, respectively) or 30-day mortality (p = 0.199 and 0.911, respectively). Use of high product ratio transfusions did not affect 24-hour RBC requirements in males or females. CONCLUSION: Use of high plasma:RBC or platelet:RBC ratios in massive transfusion may benefit men more than women. This may be due to gender related differences in coagulability. Further study is needed to determine whether separate protocols for women and men should be established. PMID- 21814108 TI - Crystalloid resuscitation improves survival in trauma patients receiving low ratios of fresh frozen plasma to packed red blood cells. AB - BACKGROUND: Current trauma resuscitation guidelines recommend giving an initial crystalloid bolus as first line for resuscitation. Recent studies have shown a survival benefit for trauma patients resuscitated with high ratios of fresh frozen plasma (FFP) to packed red blood cells (PRBC). Our aim was to determine whether the volume of crystalloid given during resuscitation correlated with differences in morbidity or mortality based on the ratio of FFP:PRBC given. METHODS: This was a retrospective review of 2,473 transfused trauma patients at 23 Level I trauma centers from July 2005 to October 2007. Patients were separated based on the ratios of FFP:PRBC they received (<1:4, 1:4-1:1, and >1:1) and then analyzed for morbidity and mortality based on whether or not they received at least 1 L crystalloid for each unit of PRBC. Outcomes analyzed were 6-hour, 24 hour, and 30-day survival as well as intensive care unit (ICU)-free days, ventilator-free days, and hospital-free days. RESULTS: Massive transfusion patients who received <1:4 ratios of FFP:PRBC had significantly improved 6-hour, 24-hour, and 30-day mortality and significantly more ventilator-free days if they received at least 1 L of crystalloid for each unit of PRBC. Nonmassive transfusion patients who received <1:4 ratios of FFP:PRBC had significantly improved 6-hour, 24-hour, and 30-day mortality and significantly more ICU-free days, ventilator-free days, and hospital-free days if they received at least 1 L crystalloid for each unit of PRBC. In both massive and nonmassive transfusion groups, the survival benefit and morbidity benefit was progressively less for the 1:4 to 1:1 FFP:PRBC groups and >1:1 FFP:PRBC groups. CONCLUSIONS: If high ratios of FFP:PRBC are unable to be given to trauma patients, resuscitation with at least 1 L of crystalloid per unit of PRBC is associated with improved overall mortality. PMID- 21814111 TI - Clinical activity and mode of action of poly-N-acetyl glucosamine fiber materials: hemostasis and wound healing. Foreword. PMID- 21814109 TI - Specific abbreviated injury scale values are responsible for the underestimation of mortality in penetrating trauma patients by the injury severity score. AB - BACKGROUND: The Injury Severity Score (ISS) is widely used as a method for rating severity of injury. The ISS is the sum of the squares of the three worst Abbreviated Injury Scale (AIS) values from three body regions. Patients with penetrating injuries tend to have higher mortality rates for a given ISS than patients with blunt injuries. This is thought to be secondary to the increased prevalence of multiple severe injuries in the same body region in patients with penetrating injuries, which the ISS does not account for. We hypothesized that the mechanism-based difference in mortality could be attributed to certain ISS ranges and specific AIS values by body region. METHODS: Outcome and injury scoring data were obtained from transfused patients admitted to 23 Level I trauma centers. ISS values were grouped into categories, and a logistic regression model was created. Mortality for each ISS category was determined and compared with the ISS 1 to 15 group. An interaction term was added to evaluate the effect of mechanism. Additional logistic regression models were created to examine each AIS category individually. RESULTS: There were 2,292 patients in the cohort. An overall interaction between ISS and mechanism was observed (p = 0.049). Mortality rates between blunt and penetrating patients with an ISS between 25 and 40 were significantly different (23.6 vs. 36.1%; p = 0.022). Within this range, the magnitude of the difference in mortality was far higher for penetrating patients with head injuries (75% vs. 37% for blunt) than truncal injuries (26% vs. 17% for blunt). Penetrating trauma patients with an AIS head of 4 or 5, AIS abdomen of 3, or AIS extremity of 3 all had adjusted mortality rates higher than blunt trauma patients with those values. CONCLUSION: Significant differences in mortality between blunt and penetrating trauma patients exist at certain ISS and AIS category values. The mortality difference is greatest for head injured patients. PMID- 21814112 TI - mRDH bandage for surgery and trauma: data summary and comparative review. AB - BACKGROUND: Bleeding often poses significant life-threatening situations to surgeons. After trauma, a one-third of civilian casualties and one-half of combat casualties die as a result of exsanguination. Recent advances have provided promising new hemostatic dressings that are applied directly to severely bleeding wounds in the pre-hospital period. METHODS: The modified Rapid Deployment Hemostat (mRDH) trauma/surgery bandage, containing fully acetylated, diatom derived, poly-N-acetyl-glucosamine fibers, has a unique multifactorial hemostatic action that incorporates vasoconstriction, erythrocyte agglutination, and platelet and RBC activation. RESULTS: Animal studies have shown that the mRDH bandage quickly and completely stops both venous and arterial bleeding, even in the presence of a coagulopathy. A prospective study in humans is in accord with these findings. CONCLUSION: The mRDH trauma/surgery bandage was able to increase survival of patients after high-grade liver trauma with an associated coagulopathy. Additional clinical studies support this result. PMID- 21814110 TI - Variations between level I trauma centers in 24-hour mortality in severely injured patients requiring a massive transfusion. AB - BACKGROUND: Significant differences in outcomes have been demonstrated between Level I trauma centers. Usually these differences are ascribed to regional or administrative differences, although the influence of variation in clinical practice is rarely considered. This study was undertaken to determine whether differences in early mortality of patients receiving a massive transfusion (MT, >= 10 units pf RBCs within 24 hours of admission) persist after adjustment for patient and transfusion practice differences. We hypothesized differences among centers in 24-hour mortality could predominantly be accounted for by differences in transfusion practices as well as patient characteristics. METHODS: Data were retrospectively collected over a 1-year period from 15 Level I centers on patients receiving an MT. A purposeful variable selection strategy was used to build the final multivariable logistic model to assess differences between centers in 24-hour mortality. Adjusted odds ratios for each center were calculated. RESULTS: : There were 550 patients evaluated, but only 443 patients had complete data for the set of variables included in the final model. Unadjusted mortality varied considerably across centers, ranging from 10% to 75%. Multivariable logistic regression identified injury severity score (ISS), abbreviated injury scale (AIS) of the chest, admission base deficit, admission heart rate, and total units of RBC transfused, as well as ratios of plasma:RBC and platelet:RBC to be associated with 24-hour mortality. After adjusting for severity of injury and transfusion, treatment variables between center differences were no longer significant. CONCLUSIONS: In the defined population of patients receiving an MT, between-center differences in 24-hour mortality may be accounted for by severity of injury as well as transfusion practices. PMID- 21814113 TI - The mRDH bandage provides effective hemostasis in trauma and surgical hemorrhage. AB - BACKGROUND: Traumatic injury is a major global health problem, accounting for approximately 1 in 10 deaths worldwide. Hemorrhagic shock accounts for 30% to 40% of injury-associated deaths (2/3 of those patients surviving to reach the hospital) and is the leading cause of preventable and early in-hospital mortality. Excessive blood loss is an infrequent but important complication of both elective and emergency surgery, increasing the risk of morbidity and mortality and prolonging the duration of hospital stay. RESULTS: The modified rapid deployment hemostat (mRDH) trauma bandage has been developed and tested during the past several years. The mRDH has a unique mechanism of action involving vasoconstriction, platelet activation, and red blood cell activation and is effective in the absence of clotting factors or platelets. The mRDH bandage has shown hemostatic efficacy in patients with severe visceral injuries and hepatic rupture. CONCLUSIONS: The following case studies illustrate the effective use of the mRDH bandage in a variety of settings, as follows: (1) application of the mRDH to control severe hemorrhage from an improvised explosive device-induced lower extremity injury in Iraq and (2) the mRDH terminates bleeding from a penetrating groin wound allowing safe neurosurgical intervention while avoiding a groin exploration. PMID- 21814115 TI - Poly-N-acetyl glucosamine fibers accelerate hemostasis in patients treated with antiplatelet drugs. AB - BACKGROUND: Nanofibers consisting of poly-N-acetyl glucosamine (pGlcNAc), as the functional component of products for surface hemostasis, have been shown to activate platelets and thereby the clotting mechanism. The nanofiber-activated platelets provide a catalytic surface for acceleration of the intrinsic coagulation cascade, thrombin generation, and fibrin polymerization. METHODS: Thromboelastographic analysis was undertaken to study the role of the pGlcNAc nanofibers in platelet activation and acceleration of fibrin polymerization. Thromboelastographic studies were performed without added activators of coagulation. RESULTS: The pGlcNAc nanofibers were found to accelerate fibrin polymerization in whole blood and platelet-rich plasma. Treatment with eptifibatide (an inhibitor of the platelet GPIIbIIIa receptor) and corn trypsin inhibitor inhibited clotting of whole blood and platelet-rich plasma. The inhibition was reversed by treatment with pGlcNAc nanofibers. Inhibition was not observed after treatment with aspirin alone, MRS2359 (platelet ADP receptor inhibitor), or by a combination of aspirin and MRS2359. The pGlcNAc nanofibers accelerate clotting in normal blood treated with aspirin and MRS2359. Clopidogrel (Plavix) and aspirin did not affect the kinetics of pGlcNAc-mediated fibrin polymerization in blood from patients treated with antiplatelet drugs compared with nontreated blood. CONCLUSIONS: These results provide evidence that pGlcNAc nanofibers activate platelets and accelerate the clotting of blood, and on how best to achieve surface hemostasis when patients are coagulopathic because of shock and/or to treatment with antiplatelet drugs. PMID- 21814114 TI - Poly-N-acetylglucosamine fibers amplify the effectiveness of recombinant factor VIIA on clot formation in hemophilia B canine blood. AB - BACKGROUND: Achieving hemostasis in anticoagulated patients is an increasingly important clinical issue. Poly-N-acetylglucosamine (pGlcNAc) nanofibers activate platelets by beta3 subunit (CD61) and the von Willebrand receptor GP1b (CD42b) integrin signaling for generation of a prothrombotic surface membrane. Recombinant coagulation factor VIIa (rFVIIa) functions in hemophilia A and B by catalyzing formation of the Xa/Va complex on the surface of activated platelets. These observations suggest that pGlcNAc nanofibers may amplify the activity of rFVIIa in hemophilic blood. METHODS: The activity of rFVIIa on platelets was tested by performing thromboelastographic analysis with blood from hemophilia B dogs in the presence of pGlcNAc nanofibers and increasing concentrations of rFVIIa. Mechanisms for hemostatic system activation were investigated with inhibitors of tissue factor, factor XIIa, and platelet function. RESULTS: Recombinant FVIIa was observed to partially restore the ability of the hemophiliac blood to form fibrin clots in a dose-dependent manner with thromboelastographic analysis. The addition of pGlcNAc nanofibers amplified the rFVIIa effect. The activity of rFVIIa and the amplification effect of pGlcNAc were dependent on platelet integrin function but independent of FXIIa and tissue factor activities. CONCLUSIONS: The pGlcNAc nanofibers amplify rFVIIa activity in hemophilia B canine blood by activating platelets through integrin-dependent mechanisms. PMID- 21814116 TI - Poly-N-acetyl glucosamine fibers induce angiogenesis in ADP inhibitor-treated diabetic mice. AB - BACKGROUND: It has been previously demonstrated that short-fiber poly-N-acetyl glucosamine (sNAG) nanofibers specifically interact with platelets, are hemostatic, and stimulate diabetic wound healing by activating angiogenesis, cell proliferation, and reepithelialization. Platelets play a significant physiologic role in wound healing. The influence of altered platelet function by treatment with the ADP inhibitor Clopidogrel (CL) on wound healing and the ability of sNAG to repair wounds in diabetic mice treated with CL were studied. METHODS: Dorsal 1 cm2 skin wounds were excised on genetically diabetic 8-week to 12-week-old, Lep/r db/db male mice, and wound healing kinetics were determined. Microscopic analysis was performed for angiogenesis (PECAM-1) and cell proliferation (Ki67). Mice were either treated with CL (P2Y12 ADP receptor antagonist, CL) or saline solution (NT). CL wounds were also treated with either a single application of topical sNAG (CL-sNAG) or were left untreated (CL-NT). RESULTS: CL treatment did not alter wound healing kinetics, while sNAG induced faster wound closure in CL treated mice compared with controls. CL treatment of diabetic mice caused an augmentation of cell proliferation and reduced angiogenesis compared with nontreated wounds. However, sNAG reversed the effects of CL on angiogenesis and partially reversed the effect on cell proliferation in the wound beds. The sNAG treated wounds in CL-treated mice showed higher levels of cell proliferation and not did inhibit angiogenesis. CONCLUSIONS: CL treatment of diabetic mice decreased angiogenesis and increased cell proliferation in wounds but did not influence macroscopic wound healing kinetics. sNAG treatment did not inhibit angiogenesis in CL-treated mice and induced faster wound closure; sNAG technology is a promising strategy to facilitate the healing of complex bleeding wounds in CL-treated diabetic patients. PMID- 21814118 TI - Poly-N-acetyl glucosamine fibers activate bone regeneration in a rabbit femur injury model. AB - BACKGROUND: The purpose of this study was to evaluate the ability of a membrane material, consisting only of short poly-N-acetyl glucosamine (sNAG) nanofibers, to regenerate bone tissue after implantation into circular holes in the rabbit femur. METHODS: Three circular holes were created in the femurs of five male New Zealand white rabbits. The holes were ~ 2.0 mm in diameter. Three holes in the left femur were implanted with the comparative control substance (Bone Wax; Ethicon, Inc.); three holes in the right femur were implanted with the sNAG membrane test article. Animals were killed 4 weeks after surgery, and macroscopic evaluation of the implant sites was made. Hematoxylin and eosin histology was performed on both control and test sites. RESULTS: All control (bone wax) sites had visible holes (defects) at the 28-day end point of the study and showed no evidence of new bone formation. All the 15 sNAG test sites were found to have new bone tissue present in the bone hole defects. Hematoxylin and eosin histology of the sNAG-treated test sites showed the presence of osteoblasts, osteocytes, and trabecula of new bone formation at the 28-day end point of the study. CONCLUSIONS: The sNAG membrane test material activated the regeneration of new bone tissue in a rabbit femur bone model after 28 days of implantation, whereas the control bone wax material did not. PMID- 21814117 TI - Poly-N-acetyl glucosamine fibers are synergistic with vacuum-assisted closure in augmenting the healing response of diabetic mice. AB - BACKGROUND: Vacuum-assisted closure (VAC) has become the preferred modality to treat many complex wounds but could be further improved by methods that minimize bleeding and facilitate wound epithelialization. Short fiber poly-N-acetyl glucosamine nanofibers (sNAG) are effective hemostatic agents that activate platelets and facilitate wound epithelialization. We hypothesized that sNAG used in combination with the VAC device could be synergistic in promoting wound healing while minimizing the risk of bleeding. METHODS: Membranes consisting entirely of sNAG nanofibers were applied immediately to dorsal excisional wounds of db/db mice followed by application of the VAC device. Wound healing kinetics, angiogenesis, and wound-related growth factor expression were measured. RESULTS: The application of sNAG membranes to wounds 24 hours before application of the VAC device was associated with a significant activation of wounds (expression of PDGF, TGFbeta, EGF), superior granulation tissue formation rich in Collagen I as well as superior wound epithelialization (8.6% +/- 0.3% vs. 1.8% +/- 1.1% of initial wound size) and wound contraction. CONCLUSIONS: The application of sNAG fiber-containing membranes before the application of the polyurethane foam interface of VAC devices leads to superior healing in db/db mice and represents a promising wound healing adjunct that can also reduce the risk of bleeding complications. PMID- 21814123 TI - Pretransplant screening for donor-specific antibodies and graft loss. PMID- 21814124 TI - Immunological monitoring for guidance of preemptive antiviral therapy for active cytomegalovirus infection in allogeneic stem-cell transplant recipients: a pilot experience. PMID- 21814125 TI - Renal transplantation with arterial inflow from an axillofemoral graft. PMID- 21814126 TI - A prospective analysis of the natural course of donor chimerism including the natural killer cell fraction after liver transplantation. PMID- 21814127 TI - Graft versus host disease with glomerular infiltration of CD8+/perforin+ cytotoxic T lymphocytes causes nephrotic syndrome. PMID- 21814129 TI - Allopurinol-induced DRESS syndrome with a histologic pattern consistent with interstitial granulomatous drug reaction. PMID- 21814130 TI - Capillary malformation of port-wine stain: differentiation from early arteriovenous malformation by histopathological clues. AB - BACKGROUND: Cutaneous arteriovenous malformations (AVMs) of stage I may mimic port-wine stains (PWSs) clinicopathologically; therefore, it may be misdiagnosed and mistreated as being PWS. OBJECTIVE: To suggest the clinicopathological differential clues between early AVMs and PWSs. METHODS: A set of 10 radiologically proven AVMs of stage I was selected in conjunction with a set of 10 age-/sex-matched PWSs as a control. Their clinical features, hematoxylin and eosin, CD31, and smooth muscle actin immunohistochemistry were then compared. RESULTS: Four pathological clues for differential diagnosis with statistical significance (P < 0.05) were found: the vessel density (CD31), presence of vascular luminal red blood cells, elongation and haphazard branching of vessels, and thickened vessel walls highlighted by smooth muscle actin. CONCLUSION: Therefore, 4 differential clues with respect to stage I AVM and PWS in their earlier developmental stages have been proposed. PMID- 21814131 TI - Diffuse unilateral swelling of the forearm after weight-training exercise: an enigma? PMID- 21814132 TI - Diurnal variation in clinical and electrophysiologic parameters associated with carpal tunnel syndrome. AB - OBJECTIVE: Patients with carpal tunnel syndrome (CTS) often report aggravated symptoms in the early morning. In this study, we aimed to identify diurnal variations in clinical and electrophysiologic parameters of patients with CTS. DESIGN: A cross-sectional clinical and electrophysiologic study was designed. First, electrophysiologic examinations were performed at 2 p.m. to confirm the diagnosis of patients who had been clinically labeled with CTS. Patients who were electrophysiologically and clinically diagnosed with CTS were included in the study, and electrophysiologic examinations were repeated at 7 p.m. and 7 a.m. A total of 64 hands with CTS (27 bilateral, 10 unilateral) and 40 control hands were studied. Grip and pinch strength of all the patients included in the study were measured using a hand dynamometer. Finally, a CTS clinical symptom severity scale and functional status scale were used to measure the symptoms and functional impairment, respectively. RESULTS: The median motor nerve distal latency and median F-minimum latency were found to be prolonged in the CTS group in the morning, and the grip strength was also markedly reduced at this time. Similar results were obtained for the median palm mixed nerve conduction velocity and amplitude. CONCLUSIONS: This study demonstrated that the clinical and electrophysiologic parameters of CTS patients were clearly different in the morning hours, with the symptoms of CTS manifesting at that time. PMID- 21814133 TI - Catastrophizing, pain, and pain interference in individuals with disabilities. AB - OBJECTIVE: The aim of this study was to examine the influence of sex and disability on catastrophizing, pain intensity, and pain interference in individuals with a spinal cord injury or multiple sclerosis. DESIGN: A cross sectional survey design was used. Two hundred forty-eight community-dwelling adults with a physical disability (spinal cord injury, n = 124; multiple sclerosis, n = 124) and chronic pain completed measures of demographic and clinical characteristics, pain intensity and interference, psychologic functioning, and pain catastrophizing. RESULTS: Men reported marginally greater catastrophizing (P < 0.10) than did the women across both disability groups; however, there was no significant difference in catastrophizing between the disability groups. Catastrophizing was the only significant predictor of pain intensity in the multivariate regression analysis, with greater catastrophizing associated with greater pain. Pain intensity and catastrophizing were the only significant variables in the regression analyses predicting pain interference and psychologic functioning; as hypothesized, greater pain intensity and catastrophizing were associated with more pain interference and poorer psychologic functioning. There was also a trend (P < 0.10) for women, relative to men, to have a stronger association between catastrophizing and pain interference. CONCLUSIONS: These findings are consistent with a biopsychosocial conceptualization of pain and functioning in individuals with chronic pain secondary to a physical disability. In addition, these data suggest that assessment and treatment (when indicated) of catastrophizing should be a regular part of the clinical management of these patients. PMID- 21814135 TI - Salvinorin B derivatives, EOM-Sal B and MOM-Sal B, produce stimulus generalization in male Sprague-Dawley rats trained to discriminate salvinorin A. AB - Salvinorin A, the main active component of Salvia divinorum, is a potent and selective kappa opioid receptor agonist. Synthetic derivatives of this substance may be useful in the development of medicinal treatments for pain, mood disorders, and drug dependence. Such developments require extensive preclinical screening of these compounds. The drug discrimination assay is a valuable method for exploring potential similarities between novel compounds and known drugs of abuse with respect to their interoceptive stimulus properties, and can be used to investigate the potency of salvinorin A and its derivatives in vivo. This study used drug discrimination methods to compare two synthetic derivatives of salvinorin B, the ethoxymethyl ether (EOM-Sal B) and methoxymethyl ether (MOM-Sal B) with salvinorin A. Male Sprague-Dawley rats were trained to discriminate 2.0 mg/kg of salvinorin A from its vehicle (75% dimethylsulfoxide/25% water) in a fixed ratio 20 food-reinforced drug discrimination procedure, and were tested for stimulus generalization with EOM-Sal B and MOM-Sal B. For comparison, substitution tests were also conducted with a MU agonist, morphine, a dissociative hallucinogen, ketamine, and two serotonergic hallucinogens, D lysergic diethylamide (LSD) and 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane. Time-course tests were also conducted with salvinorin A and EOM-Sal B. Both EOM Sal B and MOM-Sal B substituted fully for salvinorin A and displayed greater potency than salvinorin A. EOM-Sal B was discriminated at longer postinjection intervals than salvinorin A. Morphine and 1-(2,5-dimethoxy-4-methylphenyl)-2 aminopropane failed to substitute for salvinorin A, although ketamine and LSD produced significant drug-appropriate responding. The current findings are consistent with previous reports that salvinorin A produces detectable stimulus effects that are distinct from those of other drug classes and, for the first time, establish that synthetic derivatives of this substance produce similar discriminative stimulus effects. The unexpected partial substitution with LSD and ketamine indicate that further preclinical studies of these novel kappa opioid receptor agonists may be warranted. PMID- 21814134 TI - Potential serotonin 5-HT(1A) and dopamine D(4) receptor modulation of the discriminative stimulus effects of amphetamine in rats. AB - Activation of the dopaminergic system underlies the behavioral effects of (+) amphetamine, and plays a major role in its discriminative stimulus properties. Although serotonin receptors modulate dopamine levels in the brain, and 5-HT(1A) and 5-HT(2) receptor agonists do not mimic (+)-amphetamine, pretreatment with 5 HT(2A/2C) agonists significantly potentiates the (+)-amphetamine cue. Further, 5 HT(2) antagonists do not modify the discriminative stimulus effect of (+) amphetamine, but 5-HT(1A) antagonists have never been tested in (+)-amphetamine trained rats. This study sought to characterize the effects of the 5-HT(1A) antagonist WAY 100635 on (+)-amphetamine-induced discriminative stimulus effects. Male Sprague-Dawley rats were trained in a two-lever, fixed ratio 50, food reinforced task with (+)-amphetamine sulfate (1.0 mg/kg, i.p., 30 min pretreatment time) as the discriminative stimulus. Substitution and combination tests with WAY 100635 were then performed. WAY 100635 did not produce substitution in amphetamine-trained rats, but significantly increased behavioral disruption. In combination tests 0.4 and 5.4 mg/kg doses of WAY 100635 potentiated the amphetamine cue. We suggest that low doses of WAY 100635 potentiated the (+)-amphetamine cue by blockade of 5-HT(1A) receptors, but stimulation of the dopamine D(4) receptor by higher doses of WAY 100635 may be responsible for potentiation of amphetamine-induced behavioral sensitization. The high percentage of behavioral disruption in substitution tests might suggest that rats trained to discriminate (+)-amphetamine from saline show behavioral sensitization that is not detectable by the drug discrimination assay but may be expressed as hyperactivity and stereotypic behavior that disrupts operant behavior. PMID- 21814136 TI - Tel Hashomer camptodactyly syndrome in identical twin infants. PMID- 21814137 TI - Facial dysmorphism associated with distinctive spine abnormalities in a girl and her mother: novel syndromic association. AB - Facial dysmorphism associated with distinctive spine abnormalities has been encountered in a girl and her mother. A three-dimensional reformatted spinal computed tomography scan showed a combination of distinctive abnormalities such as failure of anterior formation of the vertebral bodies, malsegmentation, and Forestier disease. Mutations were not found in the GDF6 gene. We describe a hitherto undescribed autosomal dominant entity. PMID- 21814138 TI - Growth hormone abuse and biological passport: is mannan-binding lectin a complementary candidate? AB - OBJECTIVE: In the detection of human growth hormone (GH) abuse, the approach based on altered GH-related biomarkers is also being considered with respect to its application within the context of a biological passport. As a potential biomarker, mannan-binding lectin (MBL), which is reported to respond to recombinant GH (rGH) administration, is evaluated here. DESIGN: Randomized and single blind and approved by the Ethical Committee (Comite Etico de Investigacion Clinica-Instituto Municipal de Asistencia Sanitaria). PARTICIPANTS: One group of 12 male subjects (24.2 +/- 2.2 years; 76.1 +/- 6.1 kg) was studied. INTERVENTIONS: Mannan-binding lectin concentration was measured in 12 healthy individuals after subcutaneous daily doses of 6 IU of rGH administration. Mannan binding lectin serum concentration increased after rGH administration. Mannan binding lectin concentration increases were observed 48 hours after the first administration and remained elevated for several days after the final dose. MAIN OUTCOME MEASURES: Mannan-binding lectin concentration increase and elapsed time to recover initial MBL values after the last rGH administration. RESULTS: Absolute values displayed high interindividual variability, and 1 individual did not show any MBL increase (potential MBL deficiency). Mannan-binding lectin protein showed a clear concentration increase after continued rGH administration, despite the high heterogeneity found between individuals. CONCLUSIONS: The use of MBL as a complementary GH-related biomarker could be of interest, taking advantage of the high increases (up to 700%) and the relatively slow recovery time. PMID- 21814139 TI - Scapular muscle activity in overhead and nonoverhead athletes during closed chain exercises. AB - OBJECTIVE: To compare scapular muscle activity in healthy overhead and nonoverhead athletes. DESIGN: One between (group) and 1 within (exercise) repeated measures. SETTING: Controlled laboratory environment. PARTICIPANTS: Fifteen overhead sport athletes (10 women and 5 men) and 15 nonoverhead sport athletes (10 women and 5 men). INTERVENTIONS: Subjects completed 5 individual trials of a Cuff Link, standard push-up, and supine pull-up while surface electromyography (EMG) recorded muscle activity of 4 scapular muscles on the throwing dominant side. Mean EMG data were normalized to a maximum voluntary isometric contraction. MAIN OUTCOME MEASURES: Normalized mean EMG. RESULTS: The upper trapezius was significantly more active (F2,56 = 70.118; P < 0.001) during supine pull-up (61.57 +/- 29.67%) than during push-up (27.89 +/- 16.21%) and Cuff Link (5.50 +/- 2.94%). The middle trapezius was significantly more active (F2,56 = 134.192; P < 0.001) during supine pull-up (62.89 +/- 24.17%) than during push up (21.12 +/- 13.10%) and Cuff Link (6.59 +/- 4.81%). The lower trapezius was significantly more active (F2,56 = 41.326; P < 0.001) during supine pull-up (60.47 +/- 34.80%) than during push-up (34.80 +/- 30.81%) and Cuff Link (9.67 +/- 4.34%). For upper trapezius, middle trapezius, and lower trapezius, the levels of activation during push-up were significantly greater compared with those during Cuff Link. The serratus anterior was significantly more active (F2,56 = 25.652; P < 0.001) during push-up (49.97 +/- 18.86%) and Cuff Link (43.81 +/- 19.70%) than during supine pull-up (25.52 +/- 19.80%). There were no significant influences of group on muscle activation. CONCLUSIONS: Overhead and nonoverhead athletes elicited similar levels of muscle activation. Differences in muscle activation existed within the 3 exercises. Clinicians should consider the muscle of interest when prescribing one of these exercises. PMID- 21814140 TI - Efficacy of treatment of trochanteric bursitis: a systematic review. AB - OBJECTIVE: Trochanteric bursitis (TB) is a self-limiting disorder in the majority of patients and typically responds to conservative measures. However, multiple courses of nonoperative treatment or surgical intervention may be necessary in refractory cases. The purpose of this systematic review was to evaluate the efficacy of the treatment of TB. DATA SOURCES: A literature search in the PubMed, MEDLINE, CINAHL, and ISI Web of Knowledge databases was performed for all English language studies up to April 2010. Terms combined in a Boolean search were greater trochanteric pain syndrome, trochanteric bursitis, trochanteric, bursitis, surgery, therapy, drug therapy, physical therapy, rehabilitation, injection, Z-plasty, Z-lengthening, aspiration, bursectomy, bursoscopy, osteotomy, and tendon repair. STUDY SELECTION: All studies directly involving the treatment of TB were reviewed by 2 authors and selected for further analysis. Expert opinion and review articles were excluded, as well as case series with fewer than 5 patients. Twenty-four articles were identified. According to the system described by Wright et al, 2 studies, each with multiple arms, qualified as level I evidence, 1 as level II, 1 as level III, and the rest as level IV. More than 950 cases were included. DATA EXTRACTION: The authors extracted data regarding the type of intervention, level of evidence, mean age of patients, patient gender, number of hips in the study, symptom duration before the study, mean number of injections before the study, prior hip surgeries, patient satisfaction, length of follow-up, baseline scores, and follow-up scores for the visual analog scale (VAS) and Harris Hip Scores (HHS). DATA SYNTHESIS: Symptom resolution and the ability to return to activity ranged from 49% to 100% with corticosteroid injection as the primary treatment modality with and without multimodal conservative therapy. Two comparative studies (levels II and III) found low-energy shock-wave therapy (SWT) to be superior to other nonoperative modalities. Multiple surgical options for persistent TB have been reported, including bursectomy (n = 2), longitudinal release of the iliotibial band (n = 2), proximal or distal Z-plasty (n = 4), osteotomy (n = 1), and repair of gluteus medius tears (n = 4). CONCLUSIONS: Efficacy among surgical techniques varied depending on the clinical outcome measure, but all were superior to corticosteroid therapy and physical therapy according to the VAS and HHS in both comparison studies and between studies. This systematic review found that traditional nonoperative treatment helped most patients, SWT was a good alternative, and surgery was effective in refractory cases. PMID- 21814141 TI - Systematic review and meta-analysis of the role of somatostatin and its analogues in the treatment of enterocutaneous fistula. AB - OBJECTIVE: Somatostatin analogues may help pancreatic fistula although it remains unclear whether they help nonpancreatic fistula. This study involved meta analysis of somatostatin analogues for treatment of enterocutaneous fistula. METHODS: Meta-analysis of studies was undertaken, to estimate the effect of somatostatin analogues on spontaneous closure, time to closure and mortality. RESULTS: Results showed significant associations between somatostatin and both spontaneous closure rate [odds ratio (OR) 6.61, 95% (CI) confidence interval 1.35 32.43] and time to closure (standardized mean difference -0.80, 95% CI: -1.34 to 0.26). Octreotide reduced closure time (standardized mean difference -0.57, 95% CI: -0.95 to -0.20) but not spontaneous closure (OR: 1.74, 95% CI: 0.64-4.76). Lanreotide also improved time to closure (mean of 17 days vs. 26 days, standard deviation not stated) but not spontaneous closure (OR: 0.94, 95% CI: 0.42-2.12). Somatostatin, octreotide and lanreotide did not significantly affect mortality (OR: 0.30, 0.82, and 0.48; 95% CI: 0.03-3.47, 0.38-1.78, and 0.04-5.07 respectively). CONCLUSION: Somatostatin and octreotide improved fistula closure time but only somatostatin improved spontaneous closure rate. PMID- 21814142 TI - Prospective noninvasive analysis of hepatic fibrosis in patients with Crohn's disease: correlation of transient elastography and laboratory-based markers. AB - BACKGROUND AND AIMS: Hepatobiliary disorders, associated either with extraintestinal manifestations or with consequences of treatment, are prevalent among patients with inflammatory bowel disease (IBD). This study aimed to prospectively assess the potential of noninvasive markers for the evaluation of liver fibrosis in patients with Crohn's disease. METHODS: A total of 114 patients were recruited. Established markers of fibrosis, namely, aspartate transaminase to-platelet ratio index (APRI), fibrotest, Forns, sonography, and transient elastography were performed and correlated with disease parameters. In addition to descriptive statistical analysis, Pearson's correlation coefficients were determined. The t-test and the Mann-Whitney U-test were applied and univariate and multivariate data analyses were performed. RESULTS: Ultrasound indicated hepatic steatosis in 33 patients, hepatomegaly in 10, and cirrhosis in two. Liver stiffness as quantified by transient elastography was determined to be 5.06+/ 2.33 kPa (2.6-21.5). Results of noninvasive liver fibrosis markers were as follows: fibrotest,-1.65+/-0.94; APRI, 0.33+/-0.22; and Forns, 3.11+/-2.00. Correlation coefficients were found to be fibrotest/transient elastography: r=0.35291; APRI/transient elastography: r=0.38442; Forns/transient elastography: r=0.33949; fibrotest/APRI: r=0.52937; fibrotest/Forns: r=0.42413; and APRI/Forns: r=0.56491. Correlation of inflammatory markers and noninvasive liver fibrosis tests, respectively, was generally negative, whereas correlation of parameters indicating liver damage and liver fibrosis tests, respectively, was generally positive. CONCLUSION: In a center-based, unselected cohort of patients with Crohn's disease, the positive correlations between laboratory-based markers of fibrosis and transient elastography were highly significant. A study correlating noninvasive and invasive tools for the assessment of liver fibrosis in IBD is reasonable. PMID- 21814143 TI - The impact of race/ethnicity on the clinical epidemiology of autoimmune hepatitis. AB - GOALS: To evaluate race/ethnicity-specific variations in autoimmune hepatitis (AIH) with a focus on Asians and Hispanics, the fastest growing populations in the United States. BACKGROUND: AIH is a chronic inflammatory disease in which race/ethnicity-specific variations in clinical epidemiology have been reported. However, earlier studies were small or did not include a comprehensive analysis of Asians and Hispanics, the 2 fastest growing population cohorts in the United States. STUDY: A retrospective study analyzing patient data from 1999 to 2010 in a large tertiary-care community hospital to assess AIH epidemiology among a racially diverse population. RESULTS: One hundred eighty-three patients with AIH were included in the study with 81 patients having "definite" AIH by International Autoimmune Hepatitis Group criteria and 63 were diagnosed with overlap syndromes. Women and whites were the largest cohorts. The average age of diagnosis was similar among all groups. Biopsy-confirmed cirrhosis was present in 34% of AIH patients with Hispanics demonstrating the highest prevalence of cirrhosis (55%). When compared with whites, Asians had higher international normalized ratio (INR) (1.4 U vs. 1.1 U, P<0.01), and Hispanics had lower serum albumin (3.3 g/dL vs. 3.7 g/dL, P<0.001) and platelets (123.8 thousand/mcL vs. 187.5 thousand/mcL, P<0.001) and higher international normalized ratio (1.5 U vs. 1.1 U, P=0.05). Kaplan-Meier survival analysis demonstrated a trend toward worse outcomes among Asians. CONCLUSIONS: Among AIH patients, Hispanics had the highest prevalence of cirrhosis, and Asians had poorer survival outcomes. Race/ethnicity specific disparities in AIH epidemiology may reflect underlying genetic differences, contributing to variations in disease severity, response to therapy, and overall mortality. PMID- 21814144 TI - A longitudinal cohort study of mucocutaneous drug eruptions during interferon and ribavirin treatment of hepatitis C. AB - GOALS: To describe dermatologic side effects encountered during treatment of patients with chronic hepatitis C, and analyze factors predisposing to such reactions. BACKGROUND: Treatment of hepatitis C virus (HCV) infection with interferon (IFN) and ribavirin is associated with a number of mucocutaneous adverse reactions that have not been adequately studied. STUDY: A retrospective cohort study design was used to longitudinally describe mucocutaneous drug eruptions during IFN and ribavirin therapy in HCV-infected patients. Factors predictive of mucocutaneous eruptions were analyzed by the use of Kaplan-Meier curves and Cox proportional hazard model. RESULTS: A total of 286 HCV-infected consecutive patients were treated with one of the IFNalpha formulations plus ribavirin. The mean age was 51.1 years (SD 5.6). There were 6 female patients. There were 5 patients who were also infected with human immunodeficiency virus (HIV). Fifty-six percent of the patients were white, 37% were African American, and 14% were Hispanic. Twenty-one percent of all study patients developed mucocutaneous drug eruptions. The most common drug eruptions were eczematous drug eruptions (48%), seborrheic dermatitis (11%), and xerosis (8%). Dermatologic eruptions were a contributing factor in the decision to discontinue antiviral treatment in 10% of cases. Use of Pegylated IFN formulations (hazard ratio=1.86; 95% confidence interval, 1.04-3.34) and presence of HIV coinfection (hazard ratio=4.46; 95% confidence interval, 1.61-12.92) were associated with increased rate of skin reactions. CONCLUSIONS: Mucocutaneous reactions during IFN and ribavirin treatment of hepatitis C are common and are associated with HIV infection and use of Pegylated IFN. PMID- 21814145 TI - Long-term clinical course of decompensated alcoholic cirrhosis: a prospective study of 165 patients. AB - BACKGROUND: Prognosis of decompensated alcoholic cirrhosis is based mainly on studies that included patients with different severities of liver disease and did not recognize either hepatitis C virus epidemic or changes in clinical management of cirrhosis. AIM: To define the long-term course after the first hepatic decompensation in alcoholic cirrhosis. METHODS: Prospective inclusion at the start point of decompensated cirrhosis of 165 consecutive patients with alcoholic cirrhosis without known hepatocellular carcinoma hospitalized from January 1998 to December 2001 was made. Follow-up was maintained until death or the end of the observation period (April 1, 2010). RESULTS: The patients were followed for 835.75 patient years. Median age was 56 years (95% confidence interval: 54-58). Baseline Child-Pugh score was 9 (95% CI: 8-9), and model for end-stage liver disease (MELD) was 13.8 (95% CI: 12.5-14.7). Ascites was the most frequent first decompensation (51%). During follow-up, 99 (60%) patients were abstinent, hepatocellular carcinoma developed in 18 (11%) patients, and 116 patients died (70%). Median overall survival was 61 months (95% CI: 48-74). Median survival probability after onset of hepatic encephalopathy (HE) was only 14 months (95% CI: 5-23). Age, baseline MELD, albumin, development of HE, and persistence of alcohol use were independently correlated with mortality. CONCLUSIONS: Patients with alcoholic cirrhosis show a high frequency of complications. The low mortality rate in our cohort of patients probably reflects the improvement in the management of patients with cirrhosis; it is mainly influenced by baseline MELD, age, HE development, and continued abstinence. Patients who develop HE should be considered for hepatic transplantation. PMID- 21814146 TI - An evaluation of the ability of the probiotic strain Lactobacillus rhamnosus GG to eliminate the gastrointestinal carrier state of vancomycin-resistant enterococci in colonized children. AB - GOALS: To evaluate the efficacy of Lactobacillus rhamnosus GG (LGG) supplementation in eliminating the gastrointestinal carrier state of vancomycin resistant enterococci (VRE) in colonized children, and to evaluate the affect of the probiotic on Lactobacillus spp. counts in the gastrointestinal tract. STUDY: A randomized, single-blind, placebo-controlled study. Children (0 to 18 y old) hospitalized at the wards of the children's hospital who were diagnosed with gastrointestinal carrier state of VRE were randomized to group receiving 3 billion colony forming unit of LGG/day or placebo for 21 consecutive days. A total of 61 children completed the study (32 in the treatment group and 29 in the control group). Rectal swabs for VRE and Lactobacillus spp. were collected at baseline, during supplementation at weekly intervals and 1 month after supplementation. Antibiotic supply was controlled throughout the duration of the analysis. RESULTS: A significant difference in the number of children colonized with VRE between the groups was observed at 3 weeks (P = 0.002). The VRE carrier state was lost by 20 of 32 participants in the treatment group and 7 of 29 in the control group. We also observed increased gastrointestinal counts of Lactobacillus spp. in children receiving LGG. A statistically significant difference in the occurrence of bacteria was observed from week 1 onwards, whereas in the aspect of growth intensity from week 2 onwards. CONCLUSIONS: LGG supplementation temporarily eliminates the VRE carrier state and increases gastrointestinal counts of Lactobacillus spp. in children versus placebo. PMID- 21814147 TI - Can percutaneous cholecystostomy be a definitive management for acute acalculous cholecystitis? AB - GOALS: To evaluate the safety, efficacy, and long-term outcome of percutaneous cholecystostomy without additional cholecystectomy as a definitive treatment for acute acalculous cholecystitis (AAC). BACKGROUND: AAC mainly occurs in seriously ill patients, and for those considered to be at high-risk for cholecystectomy, immediate percutaneous cholecystostomy can be a simple alternative interim treatment. However, no consensus has been reached on the issue of additional cholecystectomy. STUDY: The medical records of 57 patients that underwent percutaneous cholecystostomy for AAC at a single institution between 1995 and 2010 were retrospectively analyzed. RESULTS: Percutaneous cholecystostomy was technically successful in all patients, and no major complications relating to the procedure were encountered. Symptoms resolved within 4 days in 53 of the 57 (93%) patients. The in-hospital mortality rate was 21% (11/57) and elective cholecystectomy was performed in 18/57 (31%). Twenty-eight patients were managed non-operatively and cholecystostomy tubes were subsequently removed. These 28 patients were follow-up over a median 32 months and recurrent cholecystitis occurred in 2 (7%). CONCLUSION: Percutaneous cholecystostomy is an effective procedure and a good alternative for patients unfit to undergo immediate surgery because of severe sepsis or an underlying comorbidity. After patients with AAC have recovered from percutaneous cholecystostomy, further treatment such as cholecystectomy might not be needed. PMID- 21814148 TI - Effects of varying type of exertion on children's attention capacity. AB - PURPOSE: The aim of this investigation was to examine the potential influence of varying types of exertion on immediate attentional performance on 138 primary school boys and girls. METHODS: Subjects performed three different types of exertion [cognitive exertion (school curricular lesson), physical exertion (traditional physical education lesson), and mixed cognitive and physical exertion (coordinative physical education lesson)] at the same time of the school day for 3 wk. Before and immediately after each exertion session, subjects were administered the d2 Test of Attention. RESULTS: Results showed that participants' attentional performances were significantly affected by exertion type (cognitive exertion vs physical exertion vs mixed cognitive and physical exertion; P < 0.05), by intervention (before vs after; P < 0.05), and by exertion type * intervention interactions (P < 0.01). CONCLUSIONS: Our findings suggest that varying types of exertion have different beneficial influences on schoolchildren's immediate cognitive performance. PMID- 21814149 TI - Effects of supervised exercise on motivational outcomes and longer-term behavior. AB - INTRODUCTION: Supervised exercise may have positive effects on motivation and continued exercise in cancer survivors, but few randomized controlled trials have examined this issue. Here, we report the motivational outcomes and longer-term exercise behavior from the Healthy Exercise for Lymphoma Patients trial. METHODS: Lymphoma patients were randomly assigned to 12 wk of supervised aerobic exercise (SUP, n = 60) or usual care (UC, n = 62). Motivational outcomes from the theory of planned behavior were assessed at baseline, after intervention, and at 6-month follow-up using standardized measures. Exercise behavior was self-reported at baseline and 6-month follow-up using the Godin Leisure Time Exercise Questionnaire. RESULTS: Data were available from 95% of participants after intervention and 90% at 6-month follow-up. SUP attended a median of 92% of the supervised exercise sessions. After intervention, SUP was superior to UC for intention (+0.41 (+0.09 to +0.72), P = 0.012) and perceived behavioral control (+0.36 (+0.01 to +0.72), P = 0.047) and borderline superior for self-efficacy (+0.35 (-0.02 to +0.72), P = 0.060). At 6-month follow-up, SUP reported significantly more exercise minutes compared with UC (+133 (+38 to +227), P = 0.006), and a higher percentage of SUP participants were meeting public health exercise guidelines (+25.6% (+8.2% to +43.0%), P = 0.004). Path analysis showed that perceived behavioral control partially mediated the effects of supervised exercise (group assignment) on exercise behavior at 6-month follow-up (meeting exercise guidelines). CONCLUSIONS: Supervised exercise has motivational effects in lymphoma patients and improves longer-term exercise behavior. Strategies to further enhance the motivational value of supervised exercise are warranted. PMID- 21814150 TI - Changes in cardiorespiratory fitness in 9- to 10.9-year-old children: SportsLinx 1998-2010. AB - PURPOSE: The study's purposes were to 1) assess changes in cardiorespiratory fitness (CRF) from 1998 to 2010, controlling for decimal age and body mass index (BMI), and 2) repeat the analysis in cohorts from 2005 to 2010, controlling for maturation, deprivation, and BMI. METHODS: A total of 27,942 (n = 14,247 boys) 9- to 10.9-yr-old participants from one UK city were included in this serial cross sectional study from 1998-1999 to 2009-2010. An indices of multiple deprivation (IMD) score was assigned to each participant on the basis of home postcode. Stature, sitting stature, and body mass were estimated. BMI and somatic maturity were calculated. Performance on the 20-m multistage shuttle run test (20mSRT) was used to estimate CRF (total shuttles). One-way ANCOVAs were completed to assess temporal trends in CRF, separately by sex. Model 1 assessed changes from 1998 to 2010 and included decimal age and BMI as covariates. Model 2 assessed changes from 2005 to 2010 and included maturity, IMD, and BMI as covariates. RESULTS: Results indicate that 20mSRT performance has declined in UK schoolchildren. An annual decline of 1.34% and 2.29% was observed in boys and girls, respectively. In model 1, for boys, the baseline cohort performed better than all other groups with the exception of the 1999-2000 group. For girls, declines in 20mSRT performance were observed from 2003 onward. In model 2, for boys, the 2007-2008 and 2008-2009 cohorts completed fewer 20mSRT shuttles than all other groups. For girls, the 2007-2008 and 2008-2009 cohorts also performed worse than all other years. CONCLUSIONS: The decline in CRF suggests children in the more recent SportsLinx cohorts may be at an increased risk of cardiometabolic illness in comparison with earlier cohorts. The promotion of vigorous physical activity is urged to promote CRF in children. PMID- 21814151 TI - Effect of an after-school intervention on increases in children's physical activity. AB - PURPOSE: Evaluate the effect of an after-school intervention on physical activity program changes and individual behaviors among children. METHODS: A quasi experimental evaluation of a YMCA-driven environmental change intervention with 16 intervention and 16 control sites in four metropolitan areas in the United States. Intervention sites participated in learning collaboratives designed to promote physical activity and nutrition through environmental change, educational activities, and parent engagement. Behavioral foci included increasing overall physical activity levels as well as combined moderate and vigorous physical activity and vigorous physical activity. Outcomes were assessed longitudinally using preintervention and follow-up surveys of program implementation and accelerometer measures of physical activity. ActiGraph accelerometer data were collected from a sample of 212 children, ages 5-11 yr, attending the programs. On average, 3 d of data were gathered per child. Reliability of the accelerometer counts averaged 0.78. Multivariate regression models were used to control for potential confounding variables and to account for clustering of observations. RESULTS: Data indicate greater physical activity increases in children in intervention versus control sites after modest intervention implementation. Controlling for baseline covariates, children in intervention sites showed greater increases in average physical activity level than in control sites (76 counts per minute, P = 0.037, 95% confidence interval (CI) = 8.1-144) and more minutes of moderate and vigorous physical activity (10.5 min.d(-1), P = 0.017, 95% CI = 1.5-18.6), minutes of moderate physical activity (5.6 min.d(-1), P = 0.020, 95% CI = 0.99-10.2), and minutes of vigorous physical activity (5.1 min.d( 1), P = 0.051, 95% CI = 0.21-9.93). CONCLUSIONS: Results indicate significant increases in daily physical activity among children in intervention versus control sites. This study documents the effectiveness of an environmental change approach in an applied setting. PMID- 21814152 TI - Medical errors snare more than one victim. PMID- 21814153 TI - Congenital cytomegalovirus infection as a cause of sensorineural hearing loss in a highly immune population. AB - BACKGROUND: The burden of congenital cytomegalovirus (CMV)-associated sensorineural hearing loss (SNHL) in populations with CMV seroprevalence approaching 100% is unknown. The purpose of this study was to assess the rate, associated factors, and predictors of SNHL in CMV-infected infants identified by newborn screening in a highly seropositive maternal population. METHODS: Newborns with positive saliva CMV-DNA that was confirmed by virus isolation in the first 2 weeks of life were enrolled in a prospective follow-up study to monitor hearing outcome. RESULTS: Of 12,195 infants screened, 121 (1%) were infected with CMV and 12 (10%) had symptomatic infection at birth. Hearing function could be assessed in 102/121 children who underwent at least one auditory brainstem evoked response testing at a median age of 12 months. SNHL was observed in 10/102 (9.8%; 95% confidence interval: 5.1-16.7) children. Median age at the latest hearing evaluation was 47 months (12-84 months). Profound loss (>90 dB) was found in 4/5 children with bilateral SNHL while all 5 children with unilateral loss had moderate to severe deficit. The presence of symptomatic infection at birth (odds ratio, 38.1; 95% confidence interval: 1.6-916.7) was independently associated with SNHL after adjusting for intrauterine growth restriction, gestational age, gravidity, and maternal age. Among 10 infants with SNHL, 6 (60%) were born to mothers with nonprimary CMV infection. CONCLUSIONS: Even in populations with near universal immunity to CMV, congenital CMV infection is a significant cause of SNHL demonstrating the importance of CMV as a major cause of SNHL in children worldwide. As in other populations, SNHL is more frequently observed in symptomatic CMV infection. PMID- 21814154 TI - Cryptococcus gattii genotype VGI infection in New England. AB - Cryptococcus gattii is a known, emerging infectious disease pathogen predominantly in the Pacific Northwest, the United States, and British Columbia, Canada. We report a case of an immunocompetent adolescent from New England who had severe pulmonary and central nervous system infection caused by the VGI genotype of C. gattii. PMID- 21814156 TI - Corticosteroids increase protein breakdown and loss in newly diagnosed pediatric Crohn disease. AB - Children with Crohn disease have altered growth and body composition. Previous studies have demonstrated decreased protein breakdown after either corticosteroid or anti-TNF-alpha therapy. The aim of this study was to evaluate whole body protein metabolism during corticosteroid therapy in children with newly diagnosed Crohn disease. Children with suspected Crohn disease and children with abdominal symptoms not consistent with Crohn disease underwent outpatient metabolic assessment. Patients diagnosed with Crohn disease and prescribed corticosteroid therapy returned in 2 wk for repeat metabolic assessment. Using the stable isotopes [d5] phenylalanine, [1-(13)C] leucine, and [(15)N(2)] urea, protein kinetics were determined in the fasting state. Thirty-one children (18 controls and 13 newly diagnosed with Crohn disease) completed the study. There were no significant differences in protein breakdown or loss between patients with Crohn disease at diagnosis and controls. After corticosteroid therapy in patients with Crohn disease, the rates of appearance of phenylalanine (32%) and leucine (26%) increased significantly, reflecting increased protein breakdown, and the rate of appearance of urea also increased significantly (273%), reflecting increased protein loss. Whole body protein breakdown and loss increased significantly after 2 wk of corticosteroid therapy in children with newly diagnosed Crohn disease, which may have profound effects on body composition. PMID- 21814155 TI - Mechanism of reduced lung injury by high-frequency nasal ventilation in a preterm lamb model of neonatal chronic lung disease. AB - The mechanism underlying the potentially beneficial effects of the "gentler" modes of ventilation on chronic lung disease (CLD) of the premature infant is not known. We have previously demonstrated that alveolar parathyroid hormone-related protein-peroxisome proliferator-activated receptorgamma (PTHrP-PPARgamma) signaling is critically important in alveolar formation, and this signaling pathway is disrupted in hyperoxia- and/or volutrauma-induced neonatal rat lung injury. Whether the same paradigm is also applicable to CLD, resulting from prolonged intermittent mandatory ventilation (IMV), and whether differential effects of the mode of ventilation on the PTHrP-PPARgamma signaling pathway explain the potential benefits of the "gentler" modes of ventilation are not known. Using a well-established preterm lamb model of neonatal CLD, we tested the hypothesis that ventilatory support using high-frequency nasal ventilation (HFNV) promotes alveolar PTHrP-PPARgamma signaling, whereas IMV inhibits it. Preterm lambs managed by HFNV or IMV for 21 d following preterm delivery at 132-d gestation were studied by Western hybridization and immunofluorescence labeling for key markers of alveolar homeostasis and injury/repair. In lambs managed by IMV, the abundance of key homeostatic alveolar epithelial-mesenchymal markers was reduced, whereas it was significantly increased in the HFNV group, providing a potential molecular mechanism by which "gentler" modes of ventilation reduce neonatal CLD. PMID- 21814157 TI - IL10 family member genes IL19 and IL20 are associated with recurrent wheeze after respiratory syncytial virus bronchiolitis. AB - Mechanisms underlying the increased risk of recurrent wheeze after respiratory syncytial virus lower respiratory tract infection (RSV LRTI) are unclear. Specifically, information about genetic determinants of recurrent wheeze after RSV LRTI is limited. We performed a candidate gene association study to identify genetic determinants of recurrent wheeze after RSV LRTI. We investigated 346 single nucleotide polymorphisms (SNPs) in 220 candidate genes in 166 Dutch infants hospitalized for RSV LRTI. Logistic regression analysis was used to study associations between genotypes and haplotypes and recurrent wheeze after RSV LRTI. We found associations with recurrent wheeze for SNPs in IL19, IL20, MUC5AC, TNFRSF1B, C3, CTLA4, CXCL9, IL4R, and IL7 genes. Haplotype analysis of the combined IL19/IL20 genotyped polymorphisms demonstrated an inverse association between the TGG haplotype and recurrent wheeze after RSV LRTI. IL19 and IL20 genes were notably associated with recurrent wheeze in infants without asthmatic parents. The association of IL20 SNP rs2981573 with recurrent wheeze was confirmed in a healthy birth cohort. We concluded that genetic variation in adaptive immunity genes and particularly in IL19/IL20 genes associates with the development of recurrent wheeze after RSV LRTI, suggesting a role for these IL10 family members in the etiology of airway disease during infancy. PMID- 21814159 TI - Premature ovarian failure and body composition changes with adjuvant chemotherapy for breast cancer. AB - OBJECTIVE: Premature ovarian failure and weight gain are both common in women receiving adjuvant chemotherapy for breast cancer. The objective of this preliminary analysis was to characterize changes in weight and body composition in premenopausal women receiving adjuvant chemotherapy for early stage breast cancer and investigate whether these changes were associated with chemotherapy induced ovarian failure (CIOF). METHODS: The body composition of 43 premenopausal women with stage I or II breast cancer was measured using dual-energy x-ray absorptiometry within 4 weeks before beginning chemotherapy and after 12 months from baseline. At 12 months, the CIOF was determined using the history of amennorhea for 3 months or more and serum follicle-stimulating hormone. RESULTS: Of the 43 women, 30 (70%) developed CIOF by the 12-month follow-up. Significant weight gain occurred in women with and without CIOF and consisted of fat but not lean mass in the trunk and legs. In women who developed CIOF, truncal fat increased by a median of 1.8 kg (P = 0.0004), whereas truncal lean mass decreased by 0.6 kg (P = 0.02). Women who retained ovarian function gained a median of 0.9 kg (P = 0.06) in truncal fat with no significant change in truncal lean mass. Women with CIOF tended to lose lean mass. Loss of total body lean mass was directly correlated with the decrease in bone density as measured by bone mineral density at the femoral neck (Spearman correlation coefficient, 0.4; P = 0.03). Energy intake decreased similarly in women with and without CIOF (-184 vs -290 kcal, respectively; P = 0.77). CONCLUSIONS: The results of this small preliminary analysis suggest that body composition changes in women receiving adjuvant chemotherapy for breast cancer include an increase in fat mass in the trunk and leg regions without an increase in fat-free mass. Future research with a larger study cohort and longer follow-up is needed to further investigate the role of CIOF in body composition changes in women with breast cancer. Further research is also needed to evaluate the potential effects of body composition changes on breast cancer outcomes. PMID- 21814158 TI - Hypertension is associated with cognitive decline in elderly people at high risk for dementia. AB - Cardiovascular risk factors including hypertension (HTN) have been shown to increase the risk of Alzheimer disease. The current study investigated whether individuals with HTN are more susceptible to increased cognitive decline and whether the influence of HTN on cognitive decline varied as a function of dementia severity. A total of 224 nursing home and assisted living residents, with a mean age of 84.9 (+/-7.6) years, were assessed longitudinally with Mini Mental State Exams (MMSEs) and Clinical Dementia Ratings (CDR). Baseline dementia status was defined by the CDR score. As described in , MMSE scores in persons with HTN and questionable dementia (CDR = 0.5) declined significantly faster than nonhypertensive questionably demented persons. Hypertensive participants did not decline significantly faster than nonhypertensive participants in persons with intact cognition (CDR = 0) or frank dementia (CDR >= 1). These results suggest an increased risk of subsequent cognitive decline in hypertensive individuals who are especially vulnerable to developing dementia and raises the possibility that avoiding or controlling HTN might reduce the rate of cognitive decline in cognitively vulnerable individuals, potentially delaying their conversion to full fledged dementia. PMID- 21814160 TI - Phenylacetonitrile from the giant knotweed, Fallopia sachalinensis, infested by the Japanese beetle, Popillia japonica, is induced by exogenous methyl jasmonate. AB - Phenylacetonitrile, (E)-beta-ocimene, linalool, (E)-4,8-dimethyl-1,3,7-nonatriene and (E,E)-alpha-farnesene were identified as Japanese beetle, Popillia japonica, feeding-induced volatiles from the leaves of the giant knotweed, Fallopia sachalinensis, but not by mechanical damage. Volatile emission was also induced by treatment with a cellular signaling molecule, methyl jasmonate. These results suggest that volatiles will be synthesized de novo by a biotic elicitor from P. japonica oral secretion. PMID- 21814161 TI - Inhibitory effect and possible mechanism of action of patchouli alcohol against influenza A (H2N2) virus. AB - In the present study, the anti-influenza A (H2N2) virus activity of patchouli alcohol was studied in vitro, in vivo and in silico. The CC50 of patchouli alcohol was above 20 uM. Patchouli alcohol could inhibit influenza virus with an IC50 of 4.03 +/- 0.23 uM. MTT assay showed that the inhibition by patchouli alcohol appears strongly after penetration of the virus into the cell. In the influenza mouse model, patchouli alcohol showed obvious protection against the viral infection at a dose of 5 mg/kg/day. Flexible docking and molecular dynamic simulations indicated that patchouli alcohol was bound to the neuraminidase protein of influenza virus, with an interaction energy of -40.38 kcal mol-1. The invariant key active-site residues Asp151, Arg152, Glu119, Glu276 and Tyr406 played important roles during the binding process. Based on spatial and energetic criteria, patchouli alcohol interfered with the NA functions. Results presented here suggest that patchouli alcohol possesses anti-influenza A (H2N2) virus properties, and therefore is a potential source of anti-influenza agents for the pharmaceutical industry. PMID- 21814162 TI - 1,1'-(3-methyl-4-phenylthieno[2,3-b]thiophene-2,5-diyl)diethanone as a building block in heterocyclic synthesis. Novel synthesis of some pyrazole and pyrimidine derivatives. AB - A series of new bis(heterocycles) featuring thieno[2,3-b]thiophene rings was synthesized in a combinatorial manner. Intramolecular cyclization of enaminone derivatives with appropriate N-nucleophiles afforded the target compounds. All compounds were characterized by 1H-, 13C-NMR, GCMS, IR, and UV-Vis spectrometry. These compounds represent a new class of sulfur- and nitrogen-containing heterocycles that should also be of interest as new materials. PMID- 21814163 TI - West Nile virus disease and other arboviral diseases--United States, 2010. AB - Arthropod-borne viruses (arboviruses) are transmitted to humans primarily through the bites of infected mosquitoes and ticks. Since West Nile virus (WNV) was first detected in the Western Hemisphere in 1999, it has become the leading cause of neuroinvasive arboviral disease in the United States. However, several other arboviruses continue to cause sporadic cases and seasonal outbreaks of neuroinvasive disease (i.e., meningitis, encephalitis, or acute flaccid paralysis). This report summarizes surveillance data reported to CDC in 2010 for WNV and other nationally notifiable arboviruses (excluding dengue, which is reported separately). In 2010, 40 states and the District of Columbia (DC) reported 1,021 cases of WNV disease. Of these, 629 (62%) were classified as WNV neuroinvasive disease, for a national incidence of 0.20 per 100,000 population. States with the highest incidence were Arizona (1.60), New Mexico (1.03), Nebraska (0.55), and Colorado (0.51). After WNV, the next most commonly reported cause of neuroinvasive arboviral disease was California serogroup viruses (CALV), with 68 cases, followed by eastern equine encephalitis virus (EEEV), 10 cases, St. Louis encephalitis virus (SLEV), eight cases, and Powassan virus (POWV), eight cases. WNV and other arboviruses continue to cause focal outbreaks and severe illness in substantial numbers of persons in the United States. Maintaining surveillance remains important to guide arboviral disease prevention activities. PMID- 21814164 TI - Carbon monoxide exposures--United States, 2000-2009. AB - Carbon monoxide (CO) poisoning is a leading cause of unintentional poisoning deaths in the United States. CO is an odorless, colorless gas that usually remains undetectable until exposure results in injury or death. CO poisoning is preventable; nonetheless, unintentional, non--fire-related CO poisoning is responsible for approximately 15,000 emergency department visits and nearly 500 deaths annually in the United States. National estimates of CO exposures have been based on secondary data sources, such as hospital administrative records, and are limited to exposures treated within the health-care system. To describe more completely the national burden of CO exposure and risk factors associated with vulnerable populations, CDC used data from the National Poison Data System (NPDS) to characterize reported unintentional, non--fire-related CO exposures, including those that were managed at the site of exposure and were not treated at a health-care facility. Among 68,316 CO exposures reported to poison centers during 2000--2009, a total of 30,798 (45.1%) were managed at the site of exposure with instructions from the poison center by telephone, 36,691 (53.7%) were treated at a health-care facility, and the management site for the remainder was unknown. Although symptoms varied slightly between persons managed on-site and those treated at a health-care facility, most CO exposures occurred at home and most often involved females, children aged <=17 years, and adults aged 18--44 years. Surveillance and analysis of data from NPDS and secondary sources might provide a more comprehensive description of the burden of CO exposure in the United States and assist in the development of interventions better targeted to high-risk populations. PMID- 21814165 TI - Licensure of a meningococcal conjugate vaccine for children aged 2 through 10 years and updated booster dose guidance for adolescents and other persons at increased risk for meningococcal disease--Advisory Committee on Immunization Practices (ACIP), 2011. AB - In January 2011, the Food and Drug Administration lowered the approval age range for use of MenACWY-CRM (Menveo, Novartis Vaccines and Diagnostics), a quadrivalent meningococcal conjugate vaccine, to include persons aged 2 through 55 years. One other quadrivalent meningococcal conjugate vaccine, MenACWY D(Menactra, Sanofi Pasteur), is licensed in the United States for prevention of meningococcal disease caused by serogroups A, C, Y, and W-135 among persons aged 2 through 55 years; MenACWY-D also is licensed as a 2-dose series for children aged 9 through 23 months. The Advisory Committee on Immunization Practices (ACIP) recommends that persons aged 2 through 55 years at increased risk for meningococcal disease and all adolescents aged 11 through 18 years be immunized with meningococcal conjugate vaccine. ACIP further recommended, in January 2011, that all adolescents receive a booster dose of quadrivalent meningococcal conjugate vaccine at age 16 years. This report summarizes data supporting the extended age indication for MenACWY-CRM and the interchangeability of the two licensed meningococcal conjugate vaccines. PMID- 21814166 TI - Vital signs: hospital practices to support breastfeeding--United States, 2007 and 2009. AB - BACKGROUND: Childhood obesity is a national epidemic in the United States. Increasing the proportion of mothers who breastfeed is one important public health strategy for preventing childhood obesity. The World Health Organization and United Nations Children's Fund (UNICEF) Baby-Friendly Hospital Initiative specifies Ten Steps to Successful Breastfeeding that delineate evidence-based hospital practices to improve breastfeeding initiation, duration, and exclusivity. METHODS: In 2007 and 2009, CDC conducted a national survey of U.S. obstetric hospitals and birth centers. CDC analyzed these data to describe the prevalence of facilities using maternity care practices consistent with the Ten Steps to Successful Breastfeeding. RESULTS: In 2009, staff members at most hospitals provide prenatal breastfeeding education (93%) and teach mothers breastfeeding techniques (89%) and feeding cues (82%). However, few hospitals have model breastfeeding policies (14%), limit breastfeeding supplement use (22%), or support mothers postdischarge (27%). From 2007 to 2009, the percentage of hospitals with recommended practices covering at least nine of 10 indicators increased only slightly, from 2.4% to 3.5%. Recommended maternity care practices vary by region and facility size. CONCLUSION: Most U.S. hospitals have policies and practices that do not conform to international recommendations for best practices in maternity care and interfere with mothers' abilities to breastfeed. IMPLICATIONS FOR PUBLIC HEALTH PRACTICE: Hospitals providing maternity care should adopt evidence-based practices to support breastfeeding. Public health agencies can set quality standards for maternity care and help hospitals achieve Baby-Friendly designation. Because nearly all births in the United States occur in hospitals, improvements in hospital policies and practices could increase rates of exclusive and continued breastfeeding nationwide, contributing to improved child health, including lower rates of obesity. PMID- 21814167 TI - Notes from the field: malnutrition and mortality--southern Somalia, July 2011. AB - In July 2011, the internationally supported Food Security and Nutrition Analysis Unit-Somalia conducted nutrition and mortality surveys across 17 livelihood zones in southern Somalia to assess the impact of 18 months of insecurity and drought, which have resulted in crop failure, livestock mortality, increased cereal prices, and widespread malnutrition. On July 14, CDC was asked to assist with analyzing the survey data. This report describes the results of that analysis. PMID- 21814168 TI - Macrophages are essential contributors to kidney injury in murine cryoglobulinemic membranoproliferative glomerulonephritis. AB - Mice transgenic for thymic stromal lymphopoietin (TSLP), under regulation of the lymphocyte-specific promoter Lck, develop cryoglobulinemia and membranoproliferative glomerulonephritis (MPGN) similar to the disease in patients. To determine whether infiltrating macrophages, a hallmark of this disease, are deleterious or beneficial in the injury process, we developed Lck TSLP transgenic mice expressing the human diphtheria toxin receptor (DTR) under control of the monocyte/macrophage-restricted CD11b promoter (Lck-TSLP;CD11b DTR). Treatment with DT resulted in a marked reduction of monocytes/macrophages in the peritoneal cavity of both CD11b-DTR and Lck-TSLP;CD11b-DTR mice and marked reduction of macrophage infiltration in glomeruli of Lck-TSLP;CD11b-DTR mice. Lck TSLP;CD11b-DTR mice, with or without toxin treatment, had similar levels of cryoglobulinemia and glomerular immunoglobulin deposition as Lck-TSLP mice. Lck TSLP;CD11b-DTR mice, treated with toxin, had reduced mesangial matrix expansion, glomerular collagen IV accumulation, expression of the activation marker alpha smooth muscle actin and transforming growth factor-beta1 in mesangial cells, and proteinuria compared with control mice. Thus, macrophage ablation confers protection in this model and indicates a predominately deleterious role for macrophages in the progression of kidney injury in cryoglobulinemic MPGN. PMID- 21814169 TI - Renal tubular dysfunction in patients with American cutaneous leishmaniasis. AB - Renal dysfunction seen in patients with American cutaneous leishmaniasis (ACL) has been attributed to the use of antimonials for treatment. To determine whether ACL itself causes tubular dysfunction, we measured renal function in 37 patients with ACL prior to their treatment and compared results to that in 10 healthy volunteers of similar mean age. None of the patients presented with glomerular dysfunction; however, 27 had a urinary concentrating defect. There was no statistical difference between groups in the pre- and post-desmopressin test of urine osmolality, but the post-test urine osmolality of the controls was significantly higher. Urinary AQP2 levels, determined by western blot of isolated exosomes, were found to be significantly lower in patients than in controls, whereas that of the cotransporter (NKCC2) was significantly higher. A urinary acidification defect (post-test pH greater than 5.50 following calcium chloride) was found in 15 patients. Pretest plasma bicarbonate was below normal in 12 patients as was the pretest plasma pH in 14. Expression of the Na/H exchanger (NHE3), H(+)-ATPase, and pendrin were all significantly higher in patients with ACL than in controls. A combined urinary concentration and acidification defect was found in 12 patients. Thus, the urinary concentrating defect of ACL may be caused by decreased AQP2, with increased NKCC2 compensatory. Pendrin upregulation may be related to the urinary acidification defect with increased NHE3 and H(+) ATPase also compensatory. Hence, ACL can cause asymptomatic renal tubular dysfunction. PMID- 21814170 TI - The peroxisome proliferator-activated receptor-alpha agonist, BAY PP1, attenuates renal fibrosis in rats. AB - Recent studies have shown renoprotective effects of the peroxisome proliferator activated receptor-alpha (PPAR-alpha), but its role in kidney fibrosis is unknown. In order to gain insight into this, we examined the effect of a novel PPAR-alpha agonist, BAY PP1, in two rat models of renal fibrosis: unilateral ureteral obstruction and the 5/6 nephrectomy. In healthy animals, PPAR-alpha was expressed in tubular but not in interstitial cells. Upon induction of fibrosis, PPAR-alpha was significantly downregulated, and treatment with BAY PP1 significantly restored its expression. During ureteral obstruction, treatment with BAY PP1 significantly reduced tubulointerstitial fibrosis, proliferation of interstitial fibroblasts, and TGF-beta(1) expression. Treatment with a less potent PPAR-alpha agonist, fenofibrate, had no effects. Treatment with BAY PP1, initiated in established disease in the 5/6 nephrectomy, halted the decline of renal function and significantly ameliorated renal fibrosis. In vitro, BAY PP1 had no direct effect on renal fibroblasts but reduced collagen, fibronectin, and TGF-beta(1) expression in tubular cells. Conditioned media of BAY PP1-treated tubular cells reduced fibroblast proliferation. Thus, renal fibrosis is characterized by a reduction of PPAR-alpha expression, and treatment with BAY PP1 restores PPAR-alpha expression and ameliorates renal fibrosis by modulating the cross-talk between tubular cells and fibroblasts. Hence, potent PPAR-alpha agonists might be useful in the treatment of renal fibrosis. PMID- 21814171 TI - Renal microenvironments and macrophage phenotypes determine progression or resolution of renal inflammation and fibrosis. AB - Chronic kidney disease involves renal inflammation, interstitial fibrosis, and tubular and vascular atrophy. Macrophages seem to foster all of these histomorphological abnormalities, but their specific contributions remain controversial. Recruited monocytes differentiate into different tissue macrophage phenotypes, but current classifications are largely based on in vitro studies that do not adequately mirror tissue environments in vivo. To overcome this limitation, we propose to classify tissue macrophages according to their predominant roles in the phases of wound healing tissue environments, that is, inflammation, epithelial healing, mesenchymal healing, and fibrolysis. In this review, we discuss the evidence on respective macrophage phenotypes in renal pathology. This view sheds light on several aspects of renal remodeling in kidney disease: (1) renal infection or cell necrosis induces proinflammatory 'M1' macrophages that exacerbate renal cell damage, (2) uptake of apoptotic cells induces anti-inflammatory 'M2c/suppressor' macrophages that promote epithelial and vascular repair, (3) insufficient vascular and epithelial healing despite abundant growth factor secretion promotes profibrotic 'M2a/wound healing' macrophages that accelerate fibrogenesis, and (4) theoretically, fibrolytic macrophages should exist and await investigation. PMID- 21814172 TI - Acute pyelonephritis and renal scarring are caused by dysfunctional innate immunity in mCxcr2 heterozygous mice. AB - The CXCR1 receptor and chemokine CXCL8 (IL-8) support neutrophil-dependent clearance of uropathogenic Escherichia coli from the urinary tract. CXCR1 is reduced in children prone to pyelonephritis, and heterozygous hCXCR1 polymorphisms are more common in this patient group than in healthy individuals, strongly suggesting a disease association. Since murine CXCR2 (mCXCR2) is functionally similar to human CXCR1, we determined effects of gene heterozygosity on the susceptibility to urinary tract infection by infecting heterozygous (mCxcr2(+/-)) mice with uropathogenic Escherichia coli. Clearance of infection and tissue damage were assessed as a function of innate immunity in comparison to that in knockout (mCxcr2(-/-)) and wild-type (mCxcr2(+/+)) mice. Acute sepsis associated mortality was increased and bacterial clearance drastically impaired in heterozygous compared to wild-type mice. Chemokine and neutrophil responses were delayed along with evidence of neutrophil retention and unresolved kidney inflammation 1 month after infection. This was accompanied by epithelial proliferation and subepithelial fibrosis. The heterozygous phenotype was intermediate, between knockout and wild-type mice, but specific immune cell infiltrates that accompany chronic infection in knockout mice were not found. Hence, the known heterozygous CXCR1 polymorphisms may predispose patients to acute pyelonephritis and urosepsis. PMID- 21814173 TI - Critical care nephrology: management of acid-base disorders with CRRT. AB - Normal acid-base homeostasis is severely challenged in the intensive care setting. In this review, we address acid-base disturbances, with a special focus on the use of continuous (rather than intermittent) extracorporeal technologies in critical ill patients with acute kidney injury. We consider hypercapnic acidosis and lactic acidosis as examples in which continuous modalities may have different roles and indications than the traditional intermittent approaches to renal replacement therapy. Hypercapnic acidosis develops as a consequence of alveolar hypoventilation. In this condition, correction of pH above 7.2 is not currently recommended, and may even abrogate the beneficial effects of hypercapnic acidosis on overall outcomes. Extracorporeal technologies support lung protection while maintaining overall patient homeostasis. Similarly, in lactic acidosis, current evidence does not support bicarbonate infusions to correct acidosis. The management of lactic acidosis should correct the underlying causative disturbances. Most often, lactic acidosis is a biomarker denoting unfavorable outcomes, rather than an intrinsic pathogenetic mechanism. Extracorporeal procedures may assist in the removal of pathogenic drugs or toxins, as well as partially correcting acidemia. Whether or not these approaches will permit normalization of systemic pH, and the impact of these approaches on patient outcomes, needs to be addressed with prospective controlled trials. PMID- 21814174 TI - Long-term follow-up of patients randomized to biocompatible or conventional peritoneal dialysis solutions show no difference in peritonitis or technique survival. AB - Peritonitis remains a common clinical problem for patients on peritoneal dialysis (PD). There are, however, retrospective studies with historical controls that suggest that biocompatible PD solutions may reduce the rates of peritonitis. We conducted a randomized controlled study comparing the use of biocompatible and conventional solutions, accumulating over 7000 patient-months experience. We included peritonitis episodes from patients who discontinued PD during the follow up period. The study was powered to detect a reduction in the peritonitis rate of over half in the 267 randomized patients in demographically similar groups. There were no intergroup differences in PD technique survival irrespective of whether the outcome was censored for death. Peritonitis-free survival was 26.7 months using conventional compared to 23.1 months using biocompatible PD solutions. The peritonitis rates were also not statistically different when measured in patient months. Thus, despite the finding of non-randomized studies suggesting benefits of the biocompatible PD solutions, we could not detect any clinically significant advantages in terms of technique survival or peritonitis. Although our study is the largest randomized study comparing different PD solutions to date, we do not exclude the possibility that our results are a consequence of the lack of statistical power. Meta-analysis of randomized control trials in this field is essential. PMID- 21814175 TI - Pdlim2 is a novel actin-regulating protein of podocyte foot processes. AB - The slit diaphragm and the apical and basal membrane domains of podocytes are connected to each other by an actin-based cytoskeleton critical to the maintenance of the glomerular filtration barrier. In an effort to discover novel regulatory proteins of the podocyte foot process, we identified and characterized pdlim2, a member of the actin-associated LIM protein subfamily of cytosolic proteins typified by an N-terminal PDZ domain and a C-terminal LIM domain. In the kidney, the pdlim2 protein is highly specific for the glomerulus and podocyte foot processes as shown by RT-PCR, western blotting, immunofluorescence, and immunoelectron microscopy. In cultured podocytes, pdlim2 was associated with stress fibers and cortical actin. Pdlim2 seems to regulate actin dynamics in podocytes since stress fibers were stabilized in its presence. Mechanistically, pdlim2 interacts with two actin-associated podocyte proteins, alpha-actinin-4 and angiomotin-like-1, as shown by immunoprecipitation and yeast two-hybrid analyses. By semi-quantitative immunoelectron microscopy, there was a reduced expression of pdlim2 in podocytes of patients with minimal change nephrotic syndrome and membranous nephropathy, whereas its expression was unchanged in patients with focal segmental glomerulosclerosis. Hence, pdlim2 is a novel actin-regulating protein of podocyte foot processes that may have a role in the pathogenesis of glomerular diseases. PMID- 21814177 TI - The distant organ effects of acute kidney injury. AB - Despite the availability of renal replacement therapy, acute kidney injury (AKI) is associated with high mortality and morbidity. In humans, it is difficult to determine whether AKI is a cause or consequence of excess morbidity. In animal models, however, it is increasingly clear that AKI induces distant organ dysfunction. Identified pathways include inflammatory cascades, apoptosis, the induction of remote oxidative stress, and differential molecular expression. Specifically, growing evidence implicates renal injury as an instigator and multiplier of pulmonary, cardiac, hepatic, and neurologic dysfunction. Accurate identification of these pathways will be critical in developing targeted therapies to improve outcomes in AKI. The purpose of this review is to summarize both clinical and preclinical studies of AKI and its role in distant organ injury. PMID- 21814176 TI - Downregulation of the antioxidant protein peroxiredoxin 2 contributes to angiotensin II-mediated podocyte apoptosis. AB - Podocytes have a significant role in establishing selective permeability of the glomerular filtration barrier. Sustained renin-angiotensin-aldosterone system activation is crucial to the pathogenesis of podocyte injury, but the mechanisms by which angiotensin II modulates podocyte survival due to physiological or injurious stimuli remain unclear. Here, we used proteomic analysis to find new mediators of angiotensin II-induced podocyte injury. Antioxidant protein peroxiredoxin 2 expression was decreased in cultured podocytes stimulated with angiotensin II. Peroxiredoxin 2 was found to be expressed in podocytes in vivo, and its expression was decreased in the glomeruli of rats transgenic for angiotensin II type 1 receptors in a podocyte-specific manner, or in rats infused with angiotensin II. Downregulation of peroxiredoxin 2 in podocytes resulted in increased reactive oxygen species release, protein overoxidation, and inhibition of the Akt pathway. Both treatment with angiotensin II and downregulation of peroxiredoxin 2 expression led to apoptosis of podocytes. Thus, peroxiredoxin 2 is an important modulator of angiotensin II-induced podocyte injury. PMID- 21814179 TI - Does reducing salt intake increase cardiovascular mortality? AB - Overwhelming evidence shows that reducing salt intake from 9-12 to 5-6 g/d lowers blood pressure, thereby preventing cardiovascular disease. A recent paper claims that lower salt intake is associated with higher cardiovascular mortality despite lower blood pressure. The study is flawed and cannot refute the evidence for the benefits of salt reduction. The WHO recommends salt reduction as crucial in tackling the global non-communicable-disease crisis. A reduction in population salt intake remains a public-health priority. PMID- 21814180 TI - Demographics of blood pressure and hypertension in children on renal replacement therapy in Europe. AB - Hypertension is a well-known complication in children on renal replacement therapy and an important risk factor for cardiovascular disease in later life. In order to define the prevalence of and risk factors for hypertension among children, we enrolled 3337 pediatric patients from 15 countries in the ESPN/ERA EDTA Registry of whom 464 were on hemodialysis, 851 on peritoneal dialysis, and 2023 had received a renal allograft. Hypertension was defined as either systolic or diastolic blood pressures in the 95th percentile or greater for age, height, and gender or use of antihypertensive medication. Analyses were adjusted for age, gender, duration, and modality of renal replacement therapy. In 10 countries in which information on the use of antihypertensive medication was available, hypertension was present in over two-thirds of hemodialysis, peritoneal dialysis, or transplant patients. Blood pressure values above the 95th percentile were significantly more prevalent in very young patients (under 3 years) compared to 13- to 17-year olds (odds ratio 2.47), during the first year compared to over 5 years of renal replacement therapy (odds ratio 1.80), and in patients on hemodialysis compared to transplant recipients or those on peritoneal dialysis (odds ratios of 2.48 and 1.59, respectively). Over time, mean blood pressures decreased in both hemodialysis and transplant patients, but not in peritoneal dialysis patients. Hence, our findings highlight the extent of the problem of hypertension in children with end-stage renal disease in Europe. PMID- 21814178 TI - The reduction of Na/H exchanger-3 protein and transcript expression in acute ischemia-reperfusion injury is mediated by extractable tissue factor(s). AB - Ischemic renal injury is a formidable clinical problem, the pathophysiology of which is incompletely understood. As the Na/H exchanger-3 (NHE3) mediates the bulk of apical sodium transport and a significant fraction of oxygen consumption in the proximal tubule, we examined mechanisms by which ischemia-reperfusion affects the expression of NHE3. Ischemia-reperfusion dramatically decreased NHE3 protein and mRNA (immunohistochemistry, immunoblot, and RNA blot) in rat kidney cortex and medulla. The decrease in NHE3 protein was uniform throughout all tubules, including those appearing morphologically intact. In the kidney cortex, a decrease in NHE3 surface protein preceded that of NHE3 total protein and mRNA. Kidney homogenates from rats exposed to mild renal ischemia-reduced cell surface NHE3 protein expression in opossum kidney cells in vitro, whereas homogenates from animals with moderate-to-severe ischemia reduced both total NHE3 protein and mRNA. The decrease in total NHE3 protein was dependent on the proteasomal degradation associated with NHE3 ubiquitylation measured by coimmunoprecipitation. The transferable factor(s) from the ischemic homogenate that reduce NHE3 expression were found to be heat sensitive and to be associated with a lipid-enriched fraction, and did not include regulatory RNAs. Thus, transferable factor(s) mediate the ischemia-reperfusion injury-induced decrease in NHE3 of the kidney. PMID- 21814181 TI - Severe serotonin depletion after conditional deletion of the vesicular monoamine transporter 2 gene in serotonin neurons: neural and behavioral consequences. AB - The vesicular monoamine transporter type 2 gene (VMAT2) has a crucial role in the storage and synaptic release of all monoamines, including serotonin (5-HT). To evaluate the specific role of VMAT2 in 5-HT neurons, we produced a conditional ablation of VMAT2 under control of the serotonin transporter (slc6a4) promoter. VMAT2(sert-cre) mice showed a major (-95%) depletion of 5-HT levels in the brain with no major alterations in other monoamines. Raphe neurons contained no 5-HT immunoreactivity in VMAT2(sert-cre) mice but developed normal innervations, as assessed by both tryptophan hydroxylase 2 and 5-HT transporter labeling. Increased 5-HT(1A) autoreceptor coupling to G protein, as assessed with agonist stimulated [(35)S]GTP-gamma-S binding, was observed in the raphe area, indicating an adaptive change to reduced 5-HT transmission. Behavioral evaluation in adult VMAT2(sert-cre) mice showed an increase in escape-like reactions in response to tail suspension and anxiolytic-like response in the novelty-suppressed feeding test. In an aversive ultrasound-induced defense paradigm, VMAT2(sert-cre) mice displayed a major increase in escape-like behaviors. Wild-type-like defense phenotype could be rescued by replenishing intracellular 5-HT stores with chronic pargyline (a monoamine oxidase inhibitor) treatment. Pargyline also allowed some form of 5-HT release, although in reduced amounts, in synaptosomes from VMAT2(sert-cre) mouse brain. These findings are coherent with the notion that 5 HT has an important role in anxiety, and provide new insights into the role of endogenous 5-HT in defense behaviors. PMID- 21814183 TI - Overexpression of Reelin prevents the manifestation of behavioral phenotypes related to schizophrenia and bipolar disorder. AB - Despite the impact of schizophrenia and mood disorders, which in extreme cases can lead to death, recent decades have brought little progress in the development of new treatments. Recent studies have shown that Reelin, an extracellular protein that is critical for neuronal development, is reduced in schizophrenia and bipolar disorder patients. However, data on a causal or protective role of Reelin in psychiatric diseases is scarce. In order to study the direct influence of Reelin's levels on behavior, we subjected two mouse lines, in which Reelin levels are either reduced (Reelin heterozygous mice) or increased (Reelin overexpressing mice), to a battery of behavioral tests: open-field, black-white box, novelty-suppressed-feeding, forced-swim-test, chronic corticosterone treatment followed by forced-swim-test, cocaine sensitization and pre-pulse inhibition (PPI) deficits induced by N-methyl-D-aspartate (NMDA) antagonists. These tests were designed to model some aspects of psychiatric disorders such as schizophrenia, mood, and anxiety disorders. We found no differences between Reeler heterozygous mice and their wild-type littermates. However, Reelin overexpression in the mouse forebrain reduced the time spent floating in the forced-swim-test in mice subjected to chronic corticosterone treatment, reduced behavioral sensitization to cocaine, and reduced PPI deficits induced by a NMDA antagonist. In addition, we demonstrate that while stress increased NMDA NR2B mediated synaptic transmission, known to be implicated in depression, Reelin overexpression significantly reduced it. Together, these results point to the Reelin signaling pathway as a relevant drug target for the treatment of a range of psychiatric disorders. PMID- 21814184 TI - Transient inactivation of the neonatal ventral hippocampus permanently disrupts the mesolimbic regulation of prefrontal cholinergic transmission: implications for schizophrenia. AB - These experiments determined the mesolimbic modulation of cortical cholinergic transmission in a neurodevelopmental model of schizophrenia. Mesolimbic cholinergic abnormalities are hypothesized to contribute to the cognitive deficits seen in schizophrenia. Stimulation of NMDA receptors in nucleus accumbens (NAC) increases acetylcholine (ACh) release in the prefrontal cortex (PFC), a mechanism recently demonstrated to contribute to the control of attentional performance. We determined the ability of intra-NAC administration of NMDA to increase prefrontal ACh levels in adult rats that had received bilateral infusions of tetrodotoxin (TTX) to transiently interrupt impulse flow in the ventral hippocampus (VH) during development. Rats received infusions of TTX or saline on postnatal day 7 (PD7) or day 32 (PD32), and the effects of NAC NMDA receptor stimulation on prefrontal cholinergic neurotransmission were assessed in adulthood. In animals treated as controls on PD7, NMDA increased prefrontal ACh levels by 121% above baseline. In contrast, PD7 infusions of TTX into the VH abolished the ability of NAC NMDA to activate prefrontal cholinergic neurotransmission (7% increase). In animals that received TTX infusions on PD32, NMDA-evoked cholinergic activity did not differ from controls, indicating a restricted, neonatal critical period during which VH TTX impacts the organization of mesolimbic-basal forebrain-cortical circuitry. Importantly, the failure of NAC NMDA to evoke cholinergic activity in rats treated with TTX on PD7 did not reflect a reduced excitability of corticopetal cholinergic neurons because administration of amphetamine produced similar elevations of prefrontal ACh levels in PD7 TTX and PD7 control animals. A third series of experiments demonstrated that the effects of PD7 TTX are a specific consequence of transient disruption of impulse flow in the VH. Intra-NAC NMDA evoked prefrontal ACh release in rats receiving TTX, on PD7, into the dorsal hippocampus (DH), basolateral amygdala, or NAC. Thus, impulse flow specifically within the VH, during a sensitive period of development, is necessary for the functional organization of a mesolimbic-cortical circuit known to mediate attentional control processes. Therefore, neonatal inactivation of VH represents an effective animal model for studying the basis of certain cognitive symptoms of schizophrenia. PMID- 21814182 TI - Functional biomarkers of depression: diagnosis, treatment, and pathophysiology. AB - Major depressive disorder (MDD) is a heterogeneous illness for which there are currently no effective methods to objectively assess severity, endophenotypes, or response to treatment. Increasing evidence suggests that circulating levels of peripheral/serum growth factors and cytokines are altered in patients with MDD, and that antidepressant treatments reverse or normalize these effects. Furthermore, there is a large body of literature demonstrating that MDD is associated with changes in endocrine and metabolic factors. Here we provide a brief overview of the evidence that peripheral growth factors, pro-inflammatory cytokines, endocrine factors, and metabolic markers contribute to the pathophysiology of MDD and antidepressant response. Recent preclinical studies demonstrating that peripheral growth factors and cytokines influence brain function and behavior are also discussed along with their implications for diagnosing and treating patients with MDD. Together, these studies highlight the need to develop a biomarker panel for depression that aims to profile diverse peripheral factors that together provide a biological signature of MDD subtypes as well as treatment response. PMID- 21814186 TI - Treating mouse models of Huntington disease. PMID- 21814185 TI - Astrocytic hypertrophy in anterior cingulate white matter of depressed suicides. AB - Increasing evidence suggests that cortical astrocytic function is disrupted in mood disorders and suicide. The fine neuroanatomy of astrocytes, however, remains to be investigated in these psychiatric conditions. In this study, we performed a detailed morphometric analysis of 3D-reconstructed gray and white matter astrocytes in Golgi-impregnated anterior cingulate cortex (ACC) samples from depressed suicides and matched controls. Postmortem ACC samples (BA24) from 10 well-characterized depressed suicides and 10 matched sudden-death controls were obtained from the Quebec Suicide Brain Bank. Golgi-impregnated protoplasmic astrocytes (gray matter, layer VI) and fibrous astrocytes (adjacent white matter) were reconstructed, and their morphometric features were analyzed using the Neurolucida software. For each cell, the soma size as well as the number, length, and branching of processes were determined. The densities of thorny protrusions found along the processes of both astrocytic subtypes were also determined. Protoplasmic astrocytes showed no significant difference between groups for any of the quantified parameters. However, fibrous astrocytes had significantly larger cell bodies, as well as longer, more ramified processes in depressed suicides, with values for these parameters being about twice as high as those measured in controls. These results provide the first evidence of altered cortical astrocytic morphology in mood disorders. The presence of hypertrophic astrocytes in BA24 white matter is consistent with reports suggesting white matter alterations in depression, and provides further support to the neuroinflammatory theory of depression. PMID- 21814187 TI - Haloperidol regulates the state of phosphorylation of ribosomal protein S6 via activation of PKA and phosphorylation of DARPP-32. AB - Administration of typical antipsychotic drugs, such as haloperidol, promotes cAMP dependent signaling in the medium spiny neurons (MSNs) of the striatum. In this study, we have examined the effect of haloperidol on the state of phosphorylation of the ribosomal protein S6 (rpS6), a component of the small 40S ribosomal subunit. We found that haloperidol increases the phosphorylation of rpS6 at the dual site Ser235/236, which is involved in the regulation of mRNA translation. This effect was exerted in the MSNs of the indirect pathway, which express specifically dopamine D2 receptors (D2Rs) and adenosine A2 receptors (A2ARs). The effect of haloperidol was decreased by blockade of A2ARs or by genetic attenuation of the Galpha(olf) protein, which couples A2ARs to activation of adenylyl cyclase. Moreover, stimulation of cAMP-dependent protein kinase A (PKA) increased Ser235/236 phosphorylation in cultured striatal neurons. The ability of haloperidol to promote rpS6 phosphorylation was abolished in knock-in mice deficient for PKA activation of the protein phosphatase-1 inhibitor, dopamine- and cAMP-regulated phosphoprotein of 32 kDa. In contrast, pharmacological or genetic inactivation of p70 rpS6 kinase 1, or extracellular signal-regulated kinases did not affect haloperidol-induced rpS6 phosphorylation. These results identify PKA as a major rpS6 kinase in neuronal cells and suggest that regulation of protein synthesis through rpS6 may be a potential target of antipsychotic drugs. PMID- 21814188 TI - The mu-opioid receptor and the NMDA receptor associate in PAG neurons: implications in pain control. AB - The capacity of opioids to alleviate inflammatory pain is negatively regulated by the glutamate-binding N-methyl-D-aspartate receptor (NMDAR). Increased activity of this receptor complicates the clinical use of opioids to treat persistent neuropathic pain. Immunohistochemical and ultrastructural studies have demonstrated the coexistence of both receptors within single neurons of the CNS, including those in the mesencephalic periaqueductal gray (PAG), a region that is implicated in the opioid control of nociception. We now report that mu-opioid receptors (MOR) and NMDAR NR1 subunits associate in the postsynaptic structures of PAG neurons. Morphine disrupts this complex by protein kinase-C (PKC)-mediated phosphorylation of the NR1 C1 segment and potentiates the NMDAR-CaMKII, pathway that is implicated in morphine tolerance. Inhibition of PKC, but not PKA or GRK2, restored the MOR-NR1 association and rescued the analgesic effect of morphine as well. The administration of N-methyl-D-aspartic acid separated the MOR-NR1 complex, increased MOR Ser phosphorylation, reduced the association of the MOR with G-proteins, and diminished the antinociceptive capacity of morphine. Inhibition of PKA, but not PKC, CaMKII, or GRK2, blocked these effects and preserved morphine antinociception. Thus, the opposing activities of the MOR and NMDAR in pain control affect their relation within neurons of structures such as the PAG. This finding could be exploited in developing bifunctional drugs that would act exclusively on those NMDARs associated with MORs. PMID- 21814189 TI - Membrane mineralocorticoid but not glucocorticoid receptors of the dorsal hippocampus mediate the rapid effects of corticosterone on memory retrieval. AB - This study was aimed at determining the type of the glucocorticoid membrane receptors (mineralocorticoid receptors (MRs) or glucocorticoid receptors (GRs)) in the dorsal hippocampus (dHPC) involved in the rapid effects of corticosterone or stress on memory retrieval. For that purpose, we synthesized corticosterone-3 O-carboxymethyloxime-bovine serum albumin conjugate (Cort-3CMO-BSA) conjugate (a high MW complex that cannot cross the cell membrane) totally devoid of free corticosterone, stable in physiological conditions. In a first experiment, we evidenced that an acute stress (electric footshocks) induced both a dHPC corticosterone rise measured by microdialysis and memory retrieval impairment on delayed alternation task. Both the endocrinal and cognitive effects of stress were blocked by metyrapone (a corticosterone synthesis inhibitor). In a second experiment, we showed that bilateral injections of either corticosterone or Cort 3CMO-BSA in dHPC 15 min before memory testing produced impairments similar to those resulting from acute stress. Furthermore, we showed that anisomycin (a protein synthesis inhibitor) failed to block the deleterious effect of Cort-3CMO BSA on memory. In a third experiment, we evidenced that intra-hippocampal injection of RU-28318 (MR antagonist) but not of RU-38486 (GR antagonist) totally blocked the Cort-3CMO-BSA-induced memory retrieval deficit. In a fourth experiment, we demonstrated that RU-28318 administered 15 min before stress blocked the stress-induced memory impairments when behavioral testing occurred 15 min but not 60 min after stress. Overall, this study provides strong in vivo evidence that the dHPC membrane GRs, mediating the rapid and non-genomic effects of acute stress on memory retrieval, are of MR but not GR type. PMID- 21814190 TI - Effect of rifampicin and CYP2B6 genotype on long-term efavirenz autoinduction and plasma exposure in HIV patients with or without tuberculosis. AB - We performed a prospective comparative study to examine, from a pharmacogenetics perspective, the effect of rifampicin (RIF) on long-term efavirenz (EFV) autoinduction and kinetics. In a study population of patients with HIV receiving EFV with RIF (arm 2, n = 54) or without RIF (arm 1, n = 128 controls), intraindividual and interindividual plasma EFV and 8-hydroxyefavirenz levels were compared at weeks 4 and 16 of EFV therapy. In arm 2, RIF was initiated 4 weeks before starting EFV. In controls (arm 1), the plasma EFV was significantly lower whereas 8-hydroxyefavirenz was higher at week 16 as compared to week 4. By contrast, there were no significant differences in plasma EFV and 8 hydroxyefavirenz concentrations over time in arm 2. At week 4, the plasma EFV concentration was significantly lower in arm 2 as compared to arm 1, but no significant differences were observed by week 16. When stratified by CYP2B6 genotype, significant differences were observed only with respect to CYP2B6*1/*1 genotypes. Ours is the first report of the CYP2B6 genotype-dependent effect of RIF on long-term EFV autoinduction. PMID- 21814191 TI - Chemotherapy and cognitive impairment: treatment options. AB - Chemotherapy has improved survival rates in patients with many of the common cancers. However, there is reliable evidence that, as a result of treatment, a subset of cancer survivors experience cognitive problems that can last for many years after the completion of chemotherapy. The etiology of this phenomenon is largely unknown, and currently there are no proven treatments. This article explores the clinical and preclinical literature on potential therapies for chemotherapy-induced cognitive impairments. Emerging results suggest that both pharmacological and behavioral approaches may offer patients some benefits. However, research in this area has been limited and is sometimes fraught with methodological flaws. As a result, it is difficult to draw definite conclusions regarding treatment efficacy. These issues, along with predictors of cognitive decline, are discussed in the light of possible interventions. PMID- 21814192 TI - STAT6 links IL-4/IL-13 stimulation with pendrin expression in asthma and chronic obstructive pulmonary disease. AB - Signaling through the interleukin-4/interleukin-13 (IL-4/IL-13) receptor complex is a crucial mechanism in the development of bronchial asthma and chronic obstructive pulmonary disease (COPD). In bronchial epithelial cells, this signaling pathway leads to changes in the expression levels of several genes that are possibly involved in protection against and/or pathogenesis of these diseases. The expression of pendrin (SLC26A4), a candidate for the latter category, is upregulated by IL-4/IL-13 and leads to overproduction of mucus and increased viscosity of the airway surface liquid (ASL). Therefore, elucidating the transcriptional regulation of pendrin could aid in the development of new pharmacological leads for asthma and/or COPD therapy. Here we show that IL-4/IL 13 significantly increased human pendrin promoter activity in HEK-Blue cells but not in STAT6-deficient HEK293 Phoenix cells; that mutation of the STAT6 binding site (N(4) GAS motif) rendered the promoter insensitive to IL-4/IL-13; and that addition of the N(4) GAS motif to an IL-4/IL-13-unresponsive sequence of the human pendrin promoter conferred sensitivity to both ILs. PMID- 21814194 TI - In vitro testing for hypersensitivity-mediated adverse drug reactions: challenges and future directions. PMID- 21814193 TI - The use of beat-to-beat electrocardiogram analysis to distinguish QT/QTc interval changes caused by moxifloxacin from those caused by vardenafil. AB - QT correction factors (QTc) can cause errors in the interpretation of drug effects on cardiac repolarization because they do not adequately differentiate changes when heart rate or autonomic state deviates from the baseline QT/RR interval relationship. The purpose of our study was to determine whether the new method of QT interval dynamic beat-to-beat (QTbtb) analysis could better discriminate between impaired repolarization caused by moxifloxacin and normal autonomic changes induced by subtle reflex tachycardia after vardenafil. Moxifloxacin produced maximum mean increases of 13-14 ms in QTbtb, QTcF, and QTcI after 4 h. After vardenafil administration, a 10-ms effect could be excluded at all time points with QTbtb but not with QTcF or QTcI. Subset analysis of the vardenafil upper pharmacokinetic quartile showed that the upper bound of QTcF and QTcI was >10 ms, whereas that of QTbtb was <8 ms. This study demonstrated that newer methods of electrocardiogram (ECG) analysis can differentiate changes in the QT interval to improve identification of proarrhythmia risk. PMID- 21814195 TI - Effects of HIV protease inhibitors on cardiac conduction velocity in unselected HIV-infected patients. AB - We examined the prevalence and the extent of prolongation of the PR and QRS intervals and their relation to anti-HIV treatments and other clinical characteristics in 970 HIV-infected patients, 749 treated with antiretroviral therapy and 221 untreated. Age, body mass index, heart rate, and treatment with beta-blockers and HIV protease inhibitors (PIs) were independent predictors of increase in the duration of the PR interval. Male gender, Caucasian ethnicity, heart rate, duration of antiretroviral therapy, and use of PIs were independent predictors of an increase in the duration of the QRS interval. Users of HIV PIs had an adjusted QRS-interval duration that was 2.6 ms (95% confidence interval (CI) 1.4-3.9) longer than the interval in nonusers (P = 0.0004). The adjusted odds ratios of first-degree atrioventricular block (n = 54) and complete bundle branch block (n = 23) were 1.62 (95% CI 0.90-2.89; P = 0.10) and 2.71 (95% CI 1.10-7.13; P = 0.03), respectively, in patients taking PIs. These findings may have important clinical implications, particularly with respect to QRS prolongation in patients with myocardial ischemia or heart failure. PMID- 21814196 TI - The population pharmacokinetics of fentanyl in patients undergoing living-donor liver transplantation. AB - Fentanyl, an opioid analgesic with a high hepatic extraction ratio, is frequently used to supplement general anesthesia during liver transplantation and is also continuously infused to provide postoperative analgesia. However, because fentanyl is metabolized mainly in the liver, the pharmacokinetics of fentanyl may vary widely during the different phases of the surgery, potentially leading to adverse events. Using nonlinear mixed-effects modeling, we characterized the pharmacokinetics of fentanyl in 15 patients (American Society of Anesthesiologists Physical Status Classification 2 or 3) undergoing living-donor liver transplantation (LDLT). Fentanyl was continuously infused at the rate of 200-400 ug/h throughout the operation. The time course of the fentanyl plasma concentration levels was best described in terms of a two-compartment model. Estimates were made of the pharmacokinetic parameters during the preanhepatic, anhepatic, and neohepatic phases: central volume of distribution (V(1)) (l): 59.0 + hourly volume infused by rapid infusion system (RIS) * 42.5, 113.0, and 189.0, respectively, * (body weight/69)(1.3); peripheral volume of distribution (V(2)) (l): 94.3, 412.0, and 427.0, respectively; intercompartmental clearance (Q) (l/h): 96.4 * (cardiac output (CO)/6.7)(2.5), 22.6, and 28.2, respectively; metabolic clearance (Cl) (l/h): 21.7 during the preanhepatic and neohepatic phases, and 0 during the anhepatic phase. The preanhepatic central volume of distribution was found to be markedly influenced by the massive infusion of fluids and blood products. The more hyperdynamic the circulation was during the preanhepatic phase, the higher the distributional clearance. PMID- 21814197 TI - Chemotherapy-induced peripheral neuropathy: prevention and treatment. AB - Chemotherapy-induced peripheral neuropathy (CIPN) is a common, dose-limiting side effect of many chemotherapeutic agents. Although many therapies have been investigated for the prevention and/or treatment of CIPN, there is no well accepted proven therapy. In addition, there is no universally accepted, well validated measure for the assessment of CIPN. The agents for which there are the strongest preliminary data regarding their potential efficacy in preventing CIPN are intravenous calcium and magnesium (Ca/Mg) infusions and glutathione. Agents with the strongest supporting evidence for efficacy in the treatment of CIPN include topical pain relievers, such as baclofen/amitriptyline/ketamine gel, and serotonin and norepinephrine reuptake inhibitors, such as venlafaxine and duloxetine. Other promising therapies are also reviewed in this paper. Cutaneous electrostimulation is a nonpharmacological therapy that appears, from an early pilot trial, to be potentially effective in the treatment of CIPN. Finally, there is a lack of evidence of effective treatments for the paclitaxel acute pain syndrome (P-APS), which appears to be caused by neurologic injury. PMID- 21814198 TI - Analysis of labeling decisions regarding therapeutic indications during new drug application reviews in Japan. AB - We analyzed regulatory reviews in Japan to study the modifications made in drug labeling with respect to proposed therapeutic indications, and investigated factors associated with these changes so as to gain insight into the reasons behind the decisions. Of 220 new molecular entities (NMEs) approved in Japan from 2000 to 2009, 70 received more restricted indications and 14 received more expanded indications than those proposed by the applicants. Multinomial regression analysis suggested that the presence of competitive drugs in the market, higher estimated peak sales, and higher complexity of the proposed indication were factors that significantly increased the likelihood of the indications being restricted on review, in addition to factors related to adequacy of efficacy data. Our results give us a clue to how the approved therapeutic indications reflect the characteristics of the applicants, drugs, review areas (RAs), and clinical evidence in the submitted data package, as well as to the principle behind the decisions. PMID- 21814201 TI - Adult hippocampal neurogenesis buffers stress responses and depressive behaviour. AB - Glucocorticoids are released in response to stressful experiences and serve many beneficial homeostatic functions. However, dysregulation of glucocorticoids is associated with cognitive impairments and depressive illness. In the hippocampus, a brain region densely populated with receptors for stress hormones, stress and glucocorticoids strongly inhibit adult neurogenesis. Decreased neurogenesis has been implicated in the pathogenesis of anxiety and depression, but direct evidence for this role is lacking. Here we show that adult-born hippocampal neurons are required for normal expression of the endocrine and behavioural components of the stress response. Using either transgenic or radiation methods to inhibit adult neurogenesis specifically, we find that glucocorticoid levels are slower to recover after moderate stress and are less suppressed by dexamethasone in neurogenesis-deficient mice than intact mice, consistent with a role for the hippocampus in regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Relative to controls, neurogenesis-deficient mice also showed increased food avoidance in a novel environment after acute stress, increased behavioural despair in the forced swim test, and decreased sucrose preference, a measure of anhedonia. These findings identify a small subset of neurons within the dentate gyrus that are critical for hippocampal negative control of the HPA axis and support a direct role for adult neurogenesis in depressive illness. PMID- 21814200 TI - RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. AB - Epigenetic pathways can regulate gene expression by controlling and interpreting chromatin modifications. Cancer cells are characterized by altered epigenetic landscapes, and commonly exploit the chromatin regulatory machinery to enforce oncogenic gene expression programs. Although chromatin alterations are, in principle, reversible and often amenable to drug intervention, the promise of targeting such pathways therapeutically has been limited by an incomplete understanding of cancer-specific dependencies on epigenetic regulators. Here we describe a non-biased approach to probe epigenetic vulnerabilities in acute myeloid leukaemia (AML), an aggressive haematopoietic malignancy that is often associated with aberrant chromatin states. By screening a custom library of small hairpin RNAs (shRNAs) targeting known chromatin regulators in a genetically defined AML mouse model, we identify the protein bromodomain-containing 4 (Brd4) as being critically required for disease maintenance. Suppression of Brd4 using shRNAs or the small-molecule inhibitor JQ1 led to robust antileukaemic effects in vitro and in vivo, accompanied by terminal myeloid differentiation and elimination of leukaemia stem cells. Similar sensitivities were observed in a variety of human AML cell lines and primary patient samples, revealing that JQ1 has broad activity in diverse AML subtypes. The effects of Brd4 suppression are, at least in part, due to its role in sustaining Myc expression to promote aberrant self-renewal, which implicates JQ1 as a pharmacological means to suppress MYC in cancer. Our results establish small-molecule inhibition of Brd4 as a promising therapeutic strategy in AML and, potentially, other cancers, and highlight the utility of RNA interference (RNAi) screening for revealing epigenetic vulnerabilities that can be exploited for direct pharmacological intervention. PMID- 21814202 TI - C4 grasses prosper as carbon dioxide eliminates desiccation in warmed semi-arid grassland. AB - Global warming is predicted to induce desiccation in many world regions through increases in evaporative demand. Rising CO(2) may counter that trend by improving plant water-use efficiency. However, it is not clear how important this CO(2) enhanced water use efficiency might be in offsetting warming-induced desiccation because higher CO(2) also leads to higher plant biomass, and therefore greater transpirational surface. Furthermore, although warming is predicted to favour warm-season, C(4) grasses, rising CO(2) should favour C(3), or cool-season plants. Here we show in a semi-arid grassland that elevated CO(2) can completely reverse the desiccating effects of moderate warming. Although enrichment of air to 600 p.p.m.v. CO(2) increased soil water content (SWC), 1.5/3.0 degrees C day/night warming resulted in desiccation, such that combined CO(2) enrichment and warming had no effect on SWC relative to control plots. As predicted, elevated CO(2) favoured C(3) grasses and enhanced stand productivity, whereas warming favoured C(4) grasses. Combined warming and CO(2) enrichment stimulated above-ground growth of C(4) grasses in 2 of 3 years when soil moisture most limited plant productivity. The results indicate that in a warmer, CO(2)-enriched world, both SWC and productivity in semi-arid grasslands may be higher than previously expected. PMID- 21814203 TI - Southern Ocean dust-climate coupling over the past four million years. AB - Dust has the potential to modify global climate by influencing the radiative balance of the atmosphere and by supplying iron and other essential limiting micronutrients to the ocean. Indeed, dust supply to the Southern Ocean increases during ice ages, and 'iron fertilization' of the subantarctic zone may have contributed up to 40 parts per million by volume (p.p.m.v.) of the decrease (80 100 p.p.m.v.) in atmospheric carbon dioxide observed during late Pleistocene glacial cycles. So far, however, the magnitude of Southern Ocean dust deposition in earlier times and its role in the development and evolution of Pleistocene glacial cycles have remained unclear. Here we report a high-resolution record of dust and iron supply to the Southern Ocean over the past four million years, derived from the analysis of marine sediments from ODP Site 1090, located in the Atlantic sector of the subantarctic zone. The close correspondence of our dust and iron deposition records with Antarctic ice core reconstructions of dust flux covering the past 800,000 years (refs 8, 9) indicates that both of these archives record large-scale deposition changes that should apply to most of the Southern Ocean, validating previous interpretations of the ice core data. The extension of the record beyond the interval covered by the Antarctic ice cores reveals that, in contrast to the relatively gradual intensification of glacial cycles over the past three million years, Southern Ocean dust and iron flux rose sharply at the Mid-Pleistocene climatic transition around 1.25 million years ago. This finding complements previous observations over late Pleistocene glacial cycles, providing new evidence of a tight connection between high dust input to the Southern Ocean and the emergence of the deep glaciations that characterize the past one million years of Earth history. PMID- 21814205 TI - Does subclinical thyroid dysfunction affect blood pressure? PMID- 21814206 TI - Reduction of circulating superoxide dismutase activity in type 2 diabetic patients with microalbuminuria and its modulation by telmisartan therapy. AB - Growing evidence indicates that oxidative stress induced by excessive superoxide has a central role in the pathogenesis of diabetic nephropathy (DN). Telmisartan, one of the currently available angiotensin II type 1 receptor blockers (ARBs), has been shown to exert a more powerful proteinuria (albuminuria) reduction in patients with DN, but whether the prominent renoprotective effect of telmisartan is mediated through enhancing antioxidant defense capacity and reducing oxidative stress has not been fully elucidated. The present study first revealed that the serum activity of superoxide dismutase (SOD) responsible for superoxide removal is reduced in the DN stage of microalbuminuria, but not in normoalbuminuria in type 2 diabetic patients. We next examined the alteration of SOD and oxidative stress following an 8-week treatment with telmisartan (40 mg per day) in 12 type 2 diabetic patients with microalbuminuria. Interestingly, the telmisartan treatment not only reduced the circulating levels of two oxidative stress markers, 8-hydroxy-2'-deoxyguanosine (8-OHdG) and nitrotyrosine (NT), but also enhanced serum SOD activity. Notably, a significant correlation was observed between the increase in serum SOD activity and the reduction in albuminuria. We further compared the anti-oxidative effect of telmisartan with that of losartan, another member of the ARB class, by implementing an 8-week interval crossover treatment with these ARBs in another 12 microalbuminuric type 2 diabetic patients. The patients showed higher serum SOD activity, and lower circulating levels of 8-OHdG and NT, during treatment with telmisartan than with losartan. These results suggest that telmisartan has a more potent antioxidative effect through its ability to enhance SOD activity in type 2 diabetic patients with microalbuminuria. PMID- 21814207 TI - Aldosterone-induced osteopontin gene transcription in vascular smooth muscle cells involves glucocorticoid response element. AB - Osteopontin (OPN) is known to be one of the cytokines that is involved in the vascular inflammation caused by aldosterone (Aldo). Previous reports have shown that Aldo increases OPN transcripts, and the mechanisms for this remain to be clarified. In this study, we investigated how Aldo increases OPN transcripts in the vascular smooth muscle cells of rats. Aldosterone increased OPN transcripts time-dependently as well as dose-dependently. This increase was diminished by eplerenone, a mineralocorticoid receptor (MR) antagonist. Luciferase promoter assays showed that the OPN promoter deleted to the -1599 site retained the same promoting ability as the full-length OPN promoter when stimulated by 10(-7) M Aldo, but the promoter deleted to the -1300 site lost the promoting ability. A glucocorticoid response element (GRE) is located in that deleted region. Luciferase assays of a mutated promoter without the GRE lost the luciferase upregulation, although mutated promoters with the deletion of other consensus sites maintained the promoter activity. The binding of the Aldo-MR complex to the GRE fragment was confirmed by an electrophoretic-mobility shift assay. This is the first report showing that Aldo regulates the transcriptional levels of OPN and inflammatory responses in the vasculature through a specific GRE site in the OPN promoter region. PMID- 21814208 TI - Association of a fat-derived plasma protein omentin with carotid artery intima media thickness in apparently healthy men. AB - Obesity is causally linked with the development of atherosclerosis. Omentin is an adipocytokine whose concentrations are reduced in obese individuals. Here we examined the relationship between plasma omentin levels and carotid intima-media thickness (IMT), a marker of early atherosclerosis, in apparently healthy Japanese men. Participants were 100 Japanese men who underwent a medical checkup. Maximal IMT (max-IMT) and mean-IMT in common carotid artery were measured by high resolution carotid ultrasound system. Plasma omentin concentrations were determined by enzyme-linked immunosorbent assay. Circulating omentin levels correlated negatively with body mass index, waist circumference, fasting glucose, creatinine, max-IMT and mean-IMT, and positively with estimated glomerular filtration rates (eGFR). Single regression analysis demonstrated that max-IMT associated with age, eGFR and omentin levels, and that mean-IMT associated with age, fasting glucose, eGFR and omentin levels. Multiple regression analysis revealed that omentin levels, together with age, correlated with max-IMT and mean IMT. Our data document that circulating omentin levels independently and negatively associate with carotid IMT in this population, suggesting that measurement of omentin may be useful for assessment of carotid IMT. PMID- 21814210 TI - The combination of chronic kidney disease and increased arterial stiffness is a predictor for stroke and cardiovascular disease in hypertensive patients. AB - To clarify the clinical utility of pulse wave velocity (PWV) and chronic kidney disease (CKD) in hypertension, we analyzed the prognostic impact of PWV and CKD on cerebrocardiovascular disease in hypertensive patients. This study consisted of 531 patients with essential hypertension (male/female=292/239, mean age=61.7+/ 12.3, mean follow-up=7.0+/-3.0 years) and was performed between January 1998 and June 2004. We used questionnaires to assess stroke (n=57), cardiovascular diseases (CVDs; myocardial infarction, angina and congestive heart failure; n=44) and death (n=53) as primary end points. At baseline, we evaluated the carotid femoral PWV (9.1+/-1.8 m s(-1)), the glomerular filtration rate and urinary protein excretions. We divided these subjects into those in the highest quartile of PWV and other subjects and into CKD (n=149) and non-CKD (n=458). We evaluated the prognostic influences of PWV and CKD with Kaplan-Meier analysis and Cox's proportional hazard model. PWV in CKD (9.6+/-1.9 m s(-1)) was higher than in non CKD (8.8+/-1.6 m s(-1); P<0.0001), and creatinine was slightly decreased in the highest PWV group (1.09+/-0.35 mg dl(-1), P<0.0001). On the basis of Kaplan-Meier analysis, the highest PWV group (PWV>10.1 m s(-1); P=0.0003) and the CKD group (P=0.0005) showed significantly higher proportions of stroke and CVD events. In addition, the highest PWV group showed the highest percentage of stroke (P=0.0007), and the CKD group showed the highest proportion of CVD (P<00001). High PWV and CKD were independent predictors for stroke and CVD (P=0.0332) by Cox's proportional hazard model. These data suggest that increased aortic stiffness and CKD may be predictors for stroke and cardiovascular events in hypertensive patients. PMID- 21814211 TI - Role of angiotensin II in plasma PAI-1 changes induced by imidapril or candesartan in hypertensive patients with metabolic syndrome. AB - To evaluate the relationship between plasma plasminogen activator inhibitor-1 (PAI-1) and angiotensin II (Ang II) changes during treatment with imidapril and candesartan in hypertensive patients with metabolic syndrome. A total of 84 hypertensive patients with metabolic syndrome were randomized to imidapril 10 mg or candesartan 16 mg for 16 weeks. At weeks 4 and 8, there was a dose titration to imidapril 20 mg and candesartan 32 mg in nonresponders (systolic blood pressure (SBP) >140 and/or diastolic blood pressure (DBP) >90 mm Hg). We evaluated, at baseline and after 2, 4, 8, 12 and 16 weeks, clinic blood pressure, Ang II and PAI-1 antigen. Both imidapril and candesartan induced a similar SBP/DBP reduction (-19.4/16.8 and -19.5/16.3 mm Hg, respectively, P<0.001 vs. baseline). Both drugs decreased PAI-1 antigen after 4 weeks of treatment, but only the PAI-1 lowering effect of imidapril was sustained throughout the 16 weeks (-9.3 ng ml(-1), P<0.01 vs. baseline), whereas candesartan increased PAI-1 (+6.5 ng ml(-1), P<0.05 vs. baseline and P<0.01 vs. imidapril). Imidapril significantly decreased Ang II levels (-14.6 pg ml(-1) at week 16, P<0.05 vs. baseline), whereas candesartan increased them (+24.2 pg ml(-1), P<0.01 vs. baseline and vs. imidapril). In both groups there was a positive correlation between Ang II and PAI-1 changes (r=0.61, P<0.001 at week 16 for imidapril, and r=0.37, P<0.005 at week 16 for candesartan). Imidapril reduced plasma PAI-1 and Ang II levels, whereas candesartan increased them. This suggests that the different effect of angiotensin-converting enzyme inhibitors and Ang II blockers on Ang II production has a role in their different influence on fibrinolysis. PMID- 21814212 TI - The coefficient variation of home blood pressure is a novel factor associated with macroalbuminuria in type 2 diabetes mellitus. AB - The purpose of this study was to investigate the association between day-by-day variability in home blood pressure (HBP) on 14 consecutive days and macroalbuminuria in patients with type 2 diabetes. We compared the coefficient of variation (CV) of HBP in 858 Japanese patients with and without macroalbuminuria. Next, we analyzed the relationship between the logarithm of urinary albumin excretion (UAE) and the CV of HBP using linear regression analysis. Then, we evaluated the association between the CV of HBP and macroalbuminuria, defined as UAE >=300 mg g(-1) creatinine, using logistic regression analysis. The CVs of morning and evening systolic blood pressure (SBP) were significantly greater in patients with macroalbuminuria than in those without (8.08+/-3.35 vs. 7.19+/ 2.25%, P<0.05 and 9.01+/-3.58 vs. 7.98+/-2.57%, P<0.05, respectively). Multivariate linear regression analyses indicated that the CVs of morning SBP (P<0.05) and diastolic blood pressure (DBP; P<0.05), and those of evening SBP (P<0.05) were the independent explanatory variables for the logarithm of UAE. Multivariate logistic regression analyses also demonstrated that the odds ratio for the CVs of morning SBP, morning DBP and evening SBP for macroalbuminuria were 1.35 (P<0.05), 1.29 (P<0.05) and 1.44 (P<0.05), respectively. We conclude that the CV of HBP is correlated with macroalbuminuria, independent of the known risk factors, in Japanese patients with type 2 diabetes. PMID- 21814213 TI - Antihypertensive treatment using an angiotensin receptor blocker and a thiazide diuretic improves patients' quality of life: the Saga Challenge Antihypertensive Study (S-CATS). AB - The aim of the Saga Challenge Antihypertensive Study (S-CATS), a single-arm, prospective and multi-center trial, was to evaluate the effectiveness of combined antihypertensive treatment with losartan and hydrochlorothiazide (HCTZ). Enrolled in the study were a total of 161 patients with hypertension, who in spite of treatment with an angiotensin receptor blocker (ARB) alone or an ARB and calcium channel blocker (CCB), had not been able to reach blood pressure control goals set by the Japanese Society of Hypertension Guidelines (JSH 2004). The ARBs were replaced with a combination pill containing losartan (50 mg) and HCTZ (12.5 mg), and this treatment was continued for 3 months. This change in therapy resulted in significant decreases in systolic (158+/-14 to 137+/-15 mm Hg, P<0.001) and diastolic (85+/-11 to 76+/-10 mm Hg, P<0.001) blood pressure and heart rate (73+/ 3 to 72+/-3) during the study. The patients' quality of life (QOL) score, the EuroQol 5 dimensions (EQ-5D) and the visual analog scale (VAS) (n=96; 70.0 (68.8 80.0) to 80.0 (70.0-90.0), P<0.01) all improved significantly. Another QOL score, the hypertension symptom score (HSS), which we originally developed for the S CATS trial, decreased significantly (n=93; 4.0 (1.0-9.0) to 2.0 (1.0-8.0), P<0.05). The Pittsburgh sleep quality index (PSQI), which is a psychometric assessment of subjective sleep quality, also decreased significantly (n=45; 4.0 (2.0-7.0) to 3.0 (2.0-5.0), P<0.05). There was a significant correlation between a change in HSS (baseline value -3-months value) and a decrease in systolic blood pressure (n=93; R=0.241, P<0.05). These results suggest that an anti-hypertensive treatment combined with an ARB and a thiazide diuretic may improve patients' QOL, including sleep quality. PMID- 21814214 TI - Nifedipine increases energy expenditure by increasing PGC-1alpha expression in skeletal muscle. AB - Nifedipine, an L-type calcium (Ca) channel blocker, is one of the most widely used Ca channel-blocking medications for hypertension. Previous studies have reported an association of nifedipine hypertensive treatment with decreased body weight in obese hypertensive humans and rat models. However, the precise mechanism underlying how nifedipine functions metabolically has not been elucidated. Here, we investigated the long-term effect of a non-hypotensive nifedipine dose using a mildly obese, endothelial NO synthase-deficient mouse model. Treating these mice with nifedipine decreased their body weight gain ratio, and white adipose tissue weight compared with the untreated controls. Metabolic analyses indicated that nifedipine treatment upregulated whole-body energy expenditure through increasing oxygen consumption and reducing the respiratory exchange ratio, suggesting that nifedipine promotes lipid oxidation rather than carbohydrate utilization. Furthermore, nifedipine treatment upregulated the expression of the peroxisome proliferator-activated receptor gamma coactivator -1alpha (PGC-1alpha) in skeletal muscle. Overall, these results suggest that a non-hypotensive dose of nifedipine has pleiotropic effects on energy expenditure that could ameliorate obesity. PMID- 21814209 TI - The central mechanism underlying hypertension: a review of the roles of sodium ions, epithelial sodium channels, the renin-angiotensin-aldosterone system, oxidative stress and endogenous digitalis in the brain. AB - The central nervous system has a key role in regulating the circulatory system by modulating the sympathetic and parasympathetic nervous systems, pituitary hormone release, and the baroreceptor reflex. Digoxin- and ouabain-like immunoreactive materials were found >20 years ago in the hypothalamic nuclei. These factors appeared to localize to the paraventricular and supraoptic nuclei and the nerve fibers at the circumventricular organs and supposed to affect electrolyte balance and blood pressure. The turnover rate of these materials increases with increasing sodium intake. As intracerebroventricular injection of ouabain increases blood pressure via sympathetic activation, an endogenous digitalis-like factor (EDLF) was thought to regulate cardiovascular system-related functions in the brain, particularly after sodium loading. Experiments conducted mainly in rats revealed that the mechanism of action of ouabain in the brain involves sodium ions, epithelial sodium channels (ENaCs) and the renin-angiotensin aldosterone system (RAAS), all of which are affected by sodium loading. Rats fed a high-sodium diet develop elevated sodium levels in their cerebrospinal fluid, which activates ENaCs. Activated ENaCs and/or increased intracellular sodium in neurons activate the RAAS; this releases EDLF in the brain, activating the sympathetic nervous system. The RAAS promotes oxidative stress in the brain, further activating the RAAS and augmenting sympathetic outflow. Angiotensin II and aldosterone of peripheral origin act in the brain to activate this cascade, increasing sympathetic outflow and leading to hypertension. Thus, the brain Na(+) ENaC-RAAS-EDLF axis activates sympathetic outflow and has a crucial role in essential and secondary hypertension. This report provides an overview of the central mechanism underlying hypertension and discusses the use of antihypertensive agents. PMID- 21814215 TI - Relationship of visit-to-visit and ambulatory blood pressure variability to vascular function in African Americans. AB - Visit-to-visit clinic blood pressure variability (BPV) and 24-h BPV have both been identified as independent risk factors for cardiovascular (CV) morbidity and mortality; however, the mechanisms contributing to the increased CV risk as yet are unclear. The purpose of this study was to assess the relationship between BPV and endothelial function in a cohort of putatively healthy African Americans. A total of 36 African Americans who were sedentary, non-diabetic, non-smoking, free of CV and renal disease and not on antihypertensive medication followed an American Heart Association low fat, low salt diet for 6 weeks. Upon completion of the 6-week dietary stabilization period, participants underwent 24-h ambulatory BP monitoring and had their office blood pressure (BP) measured on 3 separate days. Right brachial artery diameter was assessed at rest, during reactive hyperemia (flow-mediated vasodilation: FMD), and after nitroglycerin administration (nitroglycerin-mediated vasodilation: NMD). Participants classified as having decreased endothelial function according to either %FMD or the FMD/NMD ratio had significantly higher 24-h BPV and a trend for higher visit to-visit BPV when compared with participants with normal endothelial function. Continuous variable analyses revealed a significant positive association between NMD and 24-h diastolic BPV (DBPV). Visit-to-visit systolic BPV (SBPV), 24-h SBPV and 24-h DBPV were all negatively associated with the FMD/NMD ratio. All relationships remained significant after adjustment for age, body mass index and mean BP levels. These results may suggest that BPV is increased in African Americans with decreased endothelial function and is associated with the vascular smooth muscle response to nitric oxide. PMID- 21814216 TI - Angiotensin II inhibits chemokine CCL5 expression in vascular smooth muscle cells from spontaneously hypertensive rats. AB - Angiotensin II (Ang II) exerts some of its effects on the vasculature by stimulating chemokines and 12-lipoxygenase (12-LO). In addition, a high expression of chemokines by Ang II has been observed in vascular smooth muscle cells (VSMCs) in spontaneously hypertensive rats (SHR). In this study, the action mechanism of Ang II on CCL5 expression in SHR VSMCs was examined. Expression of CCL5 in SHR thoracic aorta tissues and VSMCs was lower than that in normotensive Wistar-Kyoto rats (WKY) thoracic aorta tissues and VSMCs. Moreover, Ang II inhibited CCL5 expression in SHR VSMCs, but not in WKY VSMCs. Inhibition of CCL5 by Ang II was mediated by both Ang II subtype 1 receptor (AT(1)R) and subtype 2 receptor (AT(2)R) activation in SHR VSMCs. However, Ang II did not inhibit CCL5 expression in SHR VSMCs that were transfected with 12-LO small interfering RNA. In addition, 12-LO metabolite, 12(S)-hydroxyeicosatetraenoic acid (HETE) inhibited CCL5 mRNA expression in SHR VSMCs. The expression of Ang II-induced 12 LO was also blocked by both AT(1)R and AT(2)R inhibitors. Mitogen-activated protein (MAP) kinase, extracellular signal-regulated kinase (ERK)1/2, p38 and Jun N-terminal kinase pathways all mediated the inhibitory action of Ang II on CCL5 expression in SHR VSMCs. Taken together, the inhibitory action of Ang II on CCL5 expression was shown to be mediated by the 12-LO pathway through the activation of both of AT(1)R and AT(2)R and this process was associated with MAP kinase pathways in SHR VSMCs. This result suggests that upregulation of 12-LO by Ang II leads to the downregulation of CCL5 expression in SHR VSMCs. PMID- 21814217 TI - Dietary methyl-consuming compounds and metabolic syndrome. AB - The metabolic syndrome, a major risk factor for type 2 diabetes and cardiovascular disease, is a cluster of metabolic abnormalities including obesity, insulin resistance, hypertension and dyslipidemia. Although systemic oxidative stress and aberrant methylation status are known to have important roles in the development of metabolic syndrome, how they occur remains unclear. The metabolism of methyl-consuming compounds generates reactive oxygen species and consumes labile methyl groups; therefore, a chronic increase in the levels of methyl-consuming compounds in the body can induce not only oxidative stress and subsequent tissue injury, but also methyl-group pool depletion and subsequent aberrant methylation status. In the past few decades, the intake amount of methyl consuming compounds has substantially increased primarily due to pollution, food additives, niacin fortification and high meat consumption. Thus, increased methyl consumers might have a causal role in the development and prevalence of metabolic syndrome and its related diseases. Moreover, factors that decrease the elimination/metabolism of methyl-consuming compounds and other xenobiotics (for example, sweat gland inactivity and decreased liver function) or increase the generation of endogenous methyl-consuming compounds (for example, mental stress induced increase in catecholamine release) may accelerate the progression of metabolic syndrome. Based on current nutrition knowledge and the available evidence from epidemiological, ecological, clinical and laboratory studies on metabolic syndrome and its related diseases, this review outlines the relationship between methyl supply-consumption imbalance and metabolic syndrome, and proposes a novel mechanism for the pathogenesis and prevalence of metabolic syndrome and its related diseases. PMID- 21814218 TI - Different mechanisms in weight loss-induced blood pressure reduction between a calorie-restricted diet and exercise. AB - The present study compared the effectiveness of a mild calorie-restricted diet (D) alone, exercise (EX) alone and a combination of D+EX on weight loss-induced blood pressure (BP) reduction over 24 weeks. We focussed especially on the relationship between sympathetic nervous activity, as indicated from measures of plasma norepinephrine (NE), and insulin resistance (homeostasis model of insulin resistance, HOMA-IR). The three groups each comprised 30 obese, hypertensive men. Body mass index (BMI), fat mass, waist-to-hip ratio, BP, plasma NE and HOMA-IR were measured every 2 weeks during the first 4 weeks and subsequently every 4 weeks for the next 20 weeks. All basal parameters were similar among the three groups. At 24 weeks, the combination group with D+EX comprised a significantly higher prevalence of normotensive subjects than the D alone or EX alone group (P<0.05). In the D alone group, plasma NE was decreased significantly at 2 weeks, reductions in BMI, fat mass and BP were observed at 8 weeks, and waist-to-hip ratios and HOMA-IR were decreased at 12 weeks. In comparison, in the EX alone group, significant reductions of fat mass and HOMA-IR were observed at 4 weeks. Plasma NE and HOMA-IR were reduced at 8 weeks while decreases in BP were detected at 12 weeks. In the D+EX group, significant reductions in plasma NE were observed at 2 weeks followed by significant decreases in BMI, fat mass, waist-to-hip ratio, BP levels and HOMA-IR at 4 weeks. The magnitudes of reductions of all parameters were greatest in the D+EX group. These results demonstrate that D+EX exerts a stronger ameliorative effect on weight loss, weight loss-induced BP reduction, normalization of BP, sympathetic activation and insulin resistance compared with D or EX alone. D and EX might, perhaps, exert different mechanisms on weight loss and weight loss-induced BP reduction; however, a combination of caloric restriction and exercise is preferred to control BP levels in obese hypertensive patients. PMID- 21814219 TI - Refined mapping of blood pressure quantitative trait loci using congenic strains developed from two genetically hypertensive rat models. AB - Previously linkage and substitution mapping were conducted between the Dahl Salt sensitive (S) rat and the Spontaneously Hypertensive Rat (SHR) to address the hypothesis that genetic contributions to blood pressure (BP) in two genetically hypertensive rat strains are different. Among the BP quantitative trait loci (QTLs) detected, two are located on chromosome 9 within large genomic segments. The goal of the current study was to develop new iterations of congenic substrains, to further resolve both of these BP QTLs on chromosome 9 as independent congenic segments. A total of 10 new congenic substrains were developed and characterized. The newly developed congenic substrains S.SHR(9)x8Ax11A and S.SHR(9)x10Ax1, with introgressed segments of 2.05 and 6.14 Mb, represented the shortest genomic segments. Both of these congenic substrains, S.SHR(9)x8Ax11A and S.SHR(9)x10Ax1 lowered BP of the S rat by 56 mm Hg (P<0.001) and 15 mm Hg (P<0.039), respectively. The BP measurements were corroborated by radiotelemetry. Urinary protein excretion was significantly lowered by SHR alleles within S.SHR(9)x10Ax1 but not by S.SHR(9)x8Ax11A. The shorter of the two congenic segments, 2.05 Mb was further characterized and found to contain a single differentially expressed protein-coding gene, Tomoregulin-2 (Tmeff2). The protein expression of Tmeff2 was higher in the S rat compared with S.SHR(9)x8Ax11A, which also had lower cardiac hypertrophy as measured by echocardiography. Tmeff2 is known to be upregulated in patients from multiple cohorts with cardiac hypertrophy. Taken together, Tmeff2 can be prioritized as a candidate gene for hypertension and associated cardiac hypertrophy in both rats and in humans. PMID- 21814220 TI - Association of the CYP3A5 polymorphism (6986G>A) with blood pressure and hypertension. AB - The cytochrome P450 family 3 subfamily A polypeptide 5 (CYP3A5) gene has been implicated in the regulation of blood pressure (BP) and thus, may serve as a potential risk factor for the development of hypertension. However, current results regarding the association between CYP3A5 single nucleotide polymorphisms and BP/hypertension have been inconsistent. In this study, we performed a meta analysis to evaluate the association between the CYP3A5 rs776746 (6986G>A) polymorphism and BP/hypertension. Ten studies (representing 2799 cases and 6794 controls) were included to determine the association of this single nucleotide polymorphism with hypertension, and 12 studies (9076 subjects) were included to determine the association of this single nucleotide polymorphism with BP. Overall, no associations were observed between the rs776746 polymorphism and BP/hypertension. In subgroup analysis, CYP3A5*1 carriers had lower systolic BP, compared with non-carriers in white populations (mean difference=-1.322, 95% confidence interval -2.401 to -0.242 mm Hg, P=0.016). This meta-analysis suggested a modestly significant association between the CYP3A5 rs776746 polymorphism and systolic BP in white populations. Given the limited sample size, additional studies are necessary to investigate the role of CYP3A5 in the regulation of BP and the pathogenesis of hypertension. PMID- 21814221 TI - Association of variants in genes involved in pancreatic beta-cell development and function with type 2 diabetes in North Indians. AB - Variants in genes involved in pancreatic beta-cell development and function are known to cause monogenic forms of type 2 diabetes and are also associated with complex form. In this study, we studied the genetic association of polymorphisms in such important genes with type 2 diabetes in the high-risk Indians. We genotyped 91 polymorphisms in 19 genes (ABCC8, HNF1A, HNF1B, HNF4A, INS, INSM1, ISL1, KCNJ11, MAFA, MNX1, NEUROD1, NEUROG3, NKX2.2, NKX6.1, PAX4, PAX6, PDX1, USF1 and WFS1) in 2025 unrelated North Indians of Indo-European ethnicity comprising of 1019 diabetic and 1006 non-diabetic subjects. HNF4A promoter P2 polymorphisms rs1884613 and rs2144908, which are in high linkage disequilibrium, showed significant association with type 2 diabetes (odds ratio (OR)=1.37 (95% confidence interval (CI) 1.19-1.57), P=9.4 * 10(-6) for rs1884613 and OR=1.37 (95%CI 1.20-1.57), P=6.0 * 10(-6) for rs2144908), as previously shown in other populations. We observed body mass index-dependent association of these variants with type 2 diabetes in normal-weight/lean subjects. Variants in USF1, ABCC8, ISL1 and KCNJ11 showed nominal association, while haplotypes in these genes were significantly associated. rs3812704 upstream of NEUROG3 significantly increased risk for type 2 diabetes in normal-weight/lean subjects (OR=1.68 (95%CI 1.25 2.24), P=4.9 * 10(-4)). Thus, pancreatic beta-cell development and function genes contribute to susceptibility to type 2 diabetes in North Indians. PMID- 21814222 TI - A nonsense mutation in the HOXD13 gene underlies synpolydactyly with incomplete penetrance. AB - Synpolydactyly 1 (SPD1; OMIM 186000), also known as type II syndactyly, is a dominantly inherited limb malformation that is characterized by an increased number of digits. SPD1 is most commonly caused by polyalanine repeat expansions in the coding region of the HOXD13 gene, which are believed to show a dominant negative effect. In addition, missense and out-of-frame deletion mutations in the HOXD13 gene are also known to cause SPD, and the mechanism responsible for the phenotype appears to be haploinsufficiency. Here, we analyzed a large consanguineous family from Pakistan with SPD showing a wide variation in phenotype among affected individuals. We performed genetic linkage analysis, which identified a region on chromosome 2 containing the HOXD13 gene. Haplotype analysis with microsatellite markers suggested segregation of the phenotype with HOXD13 gene with incomplete penetrance. Direct sequencing analysis of HOXD13 gene revealed a nonsense mutation, designated as Q248X. All affected individuals with the severe SPD phenotype are homozygous for the mutation, whereas those with the mild SPD phenotype are heterozygous for the mutation. Furthermore, some unaffected individuals also carry the mutation in the heterozygous state, showing incomplete penetrance. Our results show the first nonsense mutation in the HOXD13 gene underlying a severe form of SPD in the homozygous state, and a milder form of SPD with ~50% penetrance in the heterozygous state, most likely because of the production of 50% of protein compared with normal individuals. PMID- 21814223 TI - Common variants of FTO and the risk of obesity and type 2 diabetes in Indians. AB - Common variants of fat mass and obesity-associated gene (FTO, fat mass- and obesity-associated gene) have been shown to be associated with obesity and type 2 diabetes in population of European and non-European ethnicity. However, studies in Indian population have provided inconsistent results. Here, we examined association of eight FTO variants (rs1421085, rs8050136, rs9939609, rs9930506, rs1861867, rs9926180, rs2540769 and rs708277) with obesity and type 2 diabetes in 5364 North Indians (2474 type 2 diabetes patients and 2890 non-diabetic controls) in two stages. None of the variants including previously reported intron 1 variants (rs1421085, rs8050136, rs9939609 and rs9930506) showed body mass index (BMI)-dependent/independent association with type 2 diabetes. However, rs1421085, rs8050136 and rs9939609 were associated with obesity status and measures of obesity (BMI, waist circumference and waist-to-hip ratio) in stage 2 and combined study population. Meta-analysis of the two study population results also revealed that rs1421085, rs8050136 and rs9939609 were significantly associated with BMI both under the random- and fixed-effect models (P (random/fixed)=0.02/0.0001, 0.004/0.0006 and 0.01/0.01, respectively). In conclusion, common variants of FTO were associated with obesity, but not with type 2 diabetes in North Indian population. PMID- 21814224 TI - p53 Arg72Pro and MDM2 309 SNPs in hereditary retinoblastoma. AB - The tumor suppressor p53 and its negative regulator MDM2 have crucial roles in a variety of cellular functions such as the control of the cell cycle, senescence, genome stability and apoptosis, and are frequently deregulated in carcinogenesis. Previous studies have highlighted the contribution of the common functional polymorphisms p53 p.Arg72Pro and MDM2 309SNP to the risk of both common cancers and Li-Fraumeni syndrome. Their possible role in retinoblastoma has recently been addressed by Castera et al, who however only studied the MDM2 309SNP. Here, for the first time, we analyzed both single nucleotide polymorphisms (SNPs) in a case control study of 111 Italian hereditary retinoblastoma patients. We found a significant association of the p53 Pro/Pro genotype with the disease (odds ratio=3.58, P=0.002). The MDM2 309SNP showed a weak negative association of allele G that deserves further investigation. These findings further support the hypothesis that genetic variability of the p53 pathway contributes to the individual susceptibility to retinoblastoma, as shown for Li-Fraumeni syndrome and a variety of non-hereditary cancers. PMID- 21814225 TI - An association analysis of Per2 with panic disorder in the Japanese population. AB - Panic disorder (PD) is a severe and chronic psychiatric disorder, with genetic components underlying in its etiology. The PERIOD2 (Per2) gene has been reported to be associated with familial advanced sleep phase syndrome. Considering the high frequency of sleep disturbance in PD, Per2 may be a candidate gene for PD. Therefore, we conducted a two-stage case-control association study in the Japanese population. In the first screening sample of 203 patients and 409 controls, we investigated three single-nucleotide polymorphisms in Per2. We found a potential association in the screening sample (rs2304672, genotype P=0.046, uncorrected), whereas we could not replicate the association in the second sample of 460 patients and 460 controls. Our results suggest that Per2 may not have a major role in the pathogenesis of PD in the Japanese population. PMID- 21814226 TI - Sexual function in male patients with ankylosing spondylitis. AB - Sexuality is an important part of healthy life. Patients with ankylosing spondylitis (AS) may be vulnerable to sexual problems because of disease activity and comorbid emotional problems. However, sexuality is a scarcely studied subject in AS. The aim of this study is to compare patients with AS with healthy control. A total of 43 male patients, who referred to the Department of Physical Medicine and Rehabilitation Clinics of the Karadeniz Technical University Farabi Hospital between May 2010 and July 2010, and were diagnosed as AS according to modified New York criteria, were included in the study. Control group consisted of healthy 43 age- and sex-matched male individuals with normal inflammatory levels. The AS patients were compared in means of sociodemographic variables and sexual function with Glombok-Rust Sexual Satisfaction Scale (GRSSS) and clinical interview. Beck Anxiety Inventory (BAI) and Beck Depression Inventory (BDI) were used to determine anxiety and depression levels, respectively. The disease activity and functional conditions were evaluated with the Bath Ankylosing Spondylitis Functional Index (BASFI), the Bath Ankylosing Spondylitis Metrology Index (BASMI) and the Bath Ankylosing Spondylitis Disease Activity Index (BASDI). A total of 43 patients with AS and 43 healthy heterosexual male were included in the study. The total GRSSS score was significantly higher in patients with AS, whereas they also had significantly higher sexual complaint than healthy control. The diagnosis of sexual dysfunction according to DSM-IV was significantly higher in the patients with AS as well as depression and anxiety. In study group, GRSSS total score was modestly correlated with disease activity. The psychological status had close relation with sexual functions in AS. Overall assessment is required for complete evaluation in patients with AS. PMID- 21814227 TI - Efficacy and safety of combination therapy with mirodenafil and alpha1-blocker for benign prostatic hyperplasia-induced lower urinary tract symptoms accompanied by erectile dysfunction: a multicenter, open-label, prospective study. AB - This study was conducted to determine whether mirodenafil 100 mg, when administered on demand to patients with benign prostatic hyperplasia (BPH) who are receiving alpha1-blocker therapy, is safe with regard to the cardiovascular system and whether it improves lower urinary tract symptoms (LUTS) and sexual function. The study involved 121 LUTS/BPH patients who had been treated for at least 3 months with alpha1-blockers before being administered with mirodenafil 100 mg on demand. Before the start of mirodenafil administration, the blood pressure, heart rate, international prostate symptom score (IPSS)/quality of life (QoL), peak urine flow rate (Qmax), post-voiding residual urine volume (PVR), and international index of erectile function-5 (IIEF-5) of each patient were measured. At 4 and 8 weeks after commencing mirodenafil administration, the blood pressure and heart rate were measured again, any adverse effects of mirodenafil were assessed, and sexual function and voiding symptoms were re-evaluated. Of the 121 patients, 73 (60.3%) completed the 8-week clinical trial. Significant changes in blood pressure and heart rate were not observed during the study. Significant improvements in the IIEF-5 and the IPSS/QoL, but not the Qmax or PVR, were observed. The results of this study suggest that the administration of mirodenafil 100 mg on demand may induce few hypotensive interactions and may be acceptably effective with regard to improving LUTS and sexual function. PMID- 21814229 TI - Nanomaterials: DNA brings quantum dots to order. PMID- 21814230 TI - Graphene electronics: thinking outside the silicon box. PMID- 21814232 TI - Silicon nanoparticles: isolation leads to change. PMID- 21814231 TI - Biocomputing: DNA computes a square root. PMID- 21814233 TI - Repeated suberythemal UVB preexposure protects against high-dose UVB-induced expression of vitamin D receptor protein in human Skin. PMID- 21814235 TI - Safe, not secure. PMID- 21814234 TI - Overexpression of hedgehog signaling is associated with epidermal tumor formation in vitamin D receptor-null mice. AB - The vitamin D receptor (VDR) ligand, 1,25 dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), reduces proliferation and enhances differentiation, and thus has been investigated for a role in preventing or treating cancer. Mice deficient for the VDR display a hyperproliferative response in the hair follicle and epidermis and decreased epidermal differentiation. Unlike their wild-type littermates, when treated with 7,12 dimethylbenzanthracene (DMBA) or UVB, they develop skin tumors, including some characteristic of overexpression of the hedgehog (Hh) pathway. Both the epidermis and utricles of the VDR-null animals overexpress elements of the Hh pathway (sonic hedgehog (Shh) 2.02-fold, patched1 1.58-fold, smoothened 3.54-fold, glioma-associated oncogene homolog (Gli)1 1.17 fold, and Gli2 1.66-fold). This overexpression occurs at an age (11 weeks) at which epidermal hyperproliferation is most visible and is spatially controlled in the epidermis. DMBA- or UVB-induced tumors in the VDR-null mice also overexpress elements of this pathway. Moreover, 1,25(OH)(2)D(3) downregulates the expression of some members of the Hh pathway in an epidermal explants culture system, suggesting a direct regulation by 1,25(OH)(2)D(3). Our results suggest that increased expression of Shh in the keratinocytes of the VDR-null animal activates the Hh pathway, predisposing the skin to the development of both malignant and benign epidermal neoplasms. PMID- 21814236 TI - Staying at home. PMID- 21814237 TI - We thought trouble was coming. PMID- 21814249 TI - Closing in on Jupiter's past. PMID- 21814250 TI - Court quashes stem-cell lawsuit. PMID- 21814251 TI - Bear researcher frozen out. PMID- 21814252 TI - Conflict disclosure plan dropped. PMID- 21814253 TI - Computing giants launch free science metrics. PMID- 21814254 TI - Gene pool offers way to save Mexican oasis. PMID- 21814255 TI - The challenge of microbial diversity: Out on a limb. PMID- 21814256 TI - Neuroscience in China: Growth factor. PMID- 21814257 TI - Search needs a shake-up. PMID- 21814258 TI - Growth of genome screening needs debate. PMID- 21814264 TI - Admin burden is part of the job. PMID- 21814265 TI - Insurers could help address climate risks. PMID- 21814266 TI - China's grain relies on foreign fertilizer. PMID- 21814267 TI - No tech gaps in E. coli outbreak. PMID- 21814268 TI - Planetary science: Making mountains out of a moon. PMID- 21814269 TI - High-temperature superconductivity: The great quantum conundrum. PMID- 21814270 TI - Anthropology: Shades of the savannah. PMID- 21814271 TI - Neuroscience: Heat-thirsty bats. PMID- 21814273 TI - Oceanography: Forecasting the rain ratio. PMID- 21814274 TI - Non-CO2 greenhouse gases and climate change. AB - Earth's climate is warming as a result of anthropogenic emissions of greenhouse gases, particularly carbon dioxide (CO(2)) from fossil fuel combustion. Anthropogenic emissions of non-CO(2) greenhouse gases, such as methane, nitrous oxide and ozone-depleting substances (largely from sources other than fossil fuels), also contribute significantly to warming. Some non-CO(2) greenhouse gases have much shorter lifetimes than CO(2), so reducing their emissions offers an additional opportunity to lessen future climate change. Although it is clear that sustainably reducing the warming influence of greenhouse gases will be possible only with substantial cuts in emissions of CO(2), reducing non-CO(2) greenhouse gas emissions would be a relatively quick way of contributing to this goal. PMID- 21814275 TI - Woody cover and hominin environments in the past 6 million years. AB - The role of African savannahs in the evolution of early hominins has been debated for nearly a century. Resolution of this issue has been hindered by difficulty in quantifying the fraction of woody cover in the fossil record. Here we show that the fraction of woody cover in tropical ecosystems can be quantified using stable carbon isotopes in soils. Furthermore, we use fossil soils from hominin sites in the Awash and Omo-Turkana basins in eastern Africa to reconstruct the fraction of woody cover since the Late Miocene epoch (about 7 million years ago). (13)C/(12)C ratio data from 1,300 palaeosols at or adjacent to hominin sites dating to at least 6 million years ago show that woody cover was predominantly less than ~40% at most sites. These data point to the prevalence of open environments at the majority of hominin fossil sites in eastern Africa over the past 6 million years. PMID- 21814276 TI - On the growth and form of the gut. AB - The developing vertebrate gut tube forms a reproducible looped pattern as it grows into the body cavity. Here we use developmental experiments to eliminate alternative models and show that gut looping morphogenesis is driven by the homogeneous and isotropic forces that arise from the relative growth between the gut tube and the anchoring dorsal mesenteric sheet, tissues that grow at different rates. A simple physical mimic, using a differentially strained composite of a pliable rubber tube and a soft latex sheet is consistent with this mechanism and produces similar patterns. We devise a mathematical theory and a computational model for the number, size and shape of intestinal loops based solely on the measurable geometry, elasticity and relative growth of the tissues. The predictions of our theory are quantitatively consistent with observations of intestinal loops at different stages of development in the chick embryo. Our model also accounts for the qualitative and quantitative variation in the distinct gut looping patterns seen in a variety of species including quail, finch and mouse, illuminating how the simple macroscopic mechanics of differential growth drives the morphology of the developing gut. PMID- 21814277 TI - A critical role for TCF-1 in T-lineage specification and differentiation. AB - The vertebrate thymus provides an inductive environment for T-cell development. Within the mouse thymus, Notch signals are indispensable for imposing the T-cell fate on multipotential haematopoietic progenitors, but the downstream effectors that impart T-lineage specification and commitment are not well understood. Here we show that a transcription factor, T-cell factor 1 (TCF-1; also known as transcription factor 7, T-cell specific, TCF7), is a critical regulator in T-cell specification. TCF-1 is highly expressed in the earliest thymic progenitors, and its expression is upregulated by Notch signals. Most importantly, when TCF-1 is forcibly expressed in bone marrow (BM) progenitors, it drives the development of T-lineage cells in the absence of T-inductive Notch1 signals. Further characterization of these TCF-1-induced cells revealed expression of many T lineage genes, including T-cell-specific transcription factors Gata3 and Bcl11b, and components of the T-cell receptor. Our data suggest a model where Notch signals induce TCF-1, and TCF-1 in turn imprints the T-cell fate by upregulating expression of T-cell essential genes. PMID- 21814278 TI - Forming the lunar farside highlands by accretion of a companion moon. AB - The most striking geological feature of the Moon is the terrain and elevation dichotomy between the hemispheres: the nearside is low and flat, dominated by volcanic maria, whereas the farside is mountainous and deeply cratered. Associated with this geological dichotomy is a compositional and thermal variation, with the nearside Procellarum KREEP (potassium/rare-earth element/phosphorus) Terrane and environs interpreted as having thin, compositionally evolved crust in comparison with the massive feldspathic highlands. The lunar dichotomy may have been caused by internal effects (for example spatial variations in tidal heating, asymmetric convective processes or asymmetric crystallization of the magma ocean) or external effects (such as the event that formed the South Pole/Aitken basin or asymmetric cratering). Here we consider its origin as a late carapace added by the accretion of a companion moon. Companion moons are a common outcome of simulations of Moon formation from a protolunar disk resulting from a giant impact, and although most coplanar configurations are unstable, a ~1,200-km-diameter moon located at one of the Trojan points could be dynamically stable for tens of millions of years after the giant impact. Most of the Moon's magma ocean would solidify on this timescale, whereas the companion moon would evolve more quickly into a crust and a solid mantle derived from similar disk material, and would presumably have little or no core. Its likely fate would be to collide with the Moon at ~2-3 km s(-1), well below the speed of sound in silicates. According to our simulations, a large moon/Moon size ratio (~0.3) and a subsonic impact velocity lead to an accretionary pile rather than a crater, contributing a hemispheric layer of extent and thickness consistent with the dimensions of the farside highlands and in agreement with the degree-two crustal thickness profile. The collision furthermore displaces the KREEP-rich layer to the opposite hemisphere, explaining the observed concentration. PMID- 21814279 TI - Link between spin fluctuations and electron pairing in copper oxide superconductors. AB - Although it is generally accepted that superconductivity is unconventional in the high-transition-temperature copper oxides, the relative importance of phenomena such as spin and charge (stripe) order, superconductivity fluctuations, proximity to a Mott insulator, a pseudogap phase and quantum criticality are still a matter of debate. In electron-doped copper oxides, the absence of an anomalous pseudogap phase in the underdoped region of the phase diagram and weaker electron correlations suggest that Mott physics and other unidentified competing orders are less relevant and that antiferromagnetic spin fluctuations are the dominant feature. Here we report a study of magnetotransport in thin films of the electron doped copper oxide La(2 - x)Ce(x)CuO(4). We show that a scattering rate that is linearly dependent on temperature--a key feature of the anomalous normal state properties of the copper oxides--is correlated with the electron pairing. We also show that an envelope of such scattering surrounds the superconducting phase, surviving to zero temperature when superconductivity is suppressed by magnetic fields. Comparison with similar behaviour found in organic superconductors strongly suggests that the linear dependence on temperature of the resistivity in the electron-doped copper oxides is caused by spin-fluctuation scattering. PMID- 21814280 TI - Sensitivity of coccolithophores to carbonate chemistry and ocean acidification. AB - About one-third of the carbon dioxide (CO(2)) released into the atmosphere as a result of human activity has been absorbed by the oceans, where it partitions into the constituent ions of carbonic acid. This leads to ocean acidification, one of the major threats to marine ecosystems and particularly to calcifying organisms such as corals, foraminifera and coccolithophores. Coccolithophores are abundant phytoplankton that are responsible for a large part of modern oceanic carbonate production. Culture experiments investigating the physiological response of coccolithophore calcification to increased CO(2) have yielded contradictory results between and even within species. Here we quantified the calcite mass of dominant coccolithophores in the present ocean and over the past forty thousand years, and found a marked pattern of decreasing calcification with increasing partial pressure of CO(2) and concomitant decreasing concentrations of CO(3)(2-). Our analyses revealed that differentially calcified species and morphotypes are distributed in the ocean according to carbonate chemistry. A substantial impact on the marine carbon cycle might be expected upon extrapolation of this correlation to predicted ocean acidification in the future. However, our discovery of a heavily calcified Emiliania huxleyi morphotype in modern waters with low pH highlights the complexity of assemblage-level responses to environmental forcing factors. PMID- 21814281 TI - Ganglion-specific splicing of TRPV1 underlies infrared sensation in vampire bats. AB - Vampire bats (Desmodus rotundus) are obligate blood feeders that have evolved specialized systems to suit their sanguinary lifestyle. Chief among such adaptations is the ability to detect infrared radiation as a means of locating hotspots on warm-blooded prey. Among vertebrates, only vampire bats, boas, pythons and pit vipers are capable of detecting infrared radiation. In each case, infrared signals are detected by trigeminal nerve fibres that innervate specialized pit organs on the animal's face. Thus, vampire bats and snakes have taken thermosensation to the extreme by developing specialized systems for detecting infrared radiation. As such, these creatures provide a window into the molecular and genetic mechanisms underlying evolutionary tuning of thermoreceptors in a species-specific or cell-type-specific manner. Previously, we have shown that snakes co-opt a non-heat-sensitive channel, vertebrate TRPA1 (transient receptor potential cation channel A1), to produce an infrared detector. Here we show that vampire bats tune a channel that is already heat sensitive, TRPV1, by lowering its thermal activation threshold to about 30 degrees C. This is achieved through alternative splicing of TRPV1 transcripts to produce a channel with a truncated carboxy-terminal cytoplasmic domain. These splicing events occur exclusively in trigeminal ganglia, and not in dorsal root ganglia, thereby maintaining a role for TRPV1 as a detector of noxious heat in somatic afferents. This reflects a unique organization of the bat Trpv1 gene that we show to be characteristic of Laurasiatheria mammals (cows, dogs and moles), supporting a close phylogenetic relationship with bats. These findings reveal a novel molecular mechanism for physiological tuning of thermosensory nerve fibres. PMID- 21814282 TI - HIV-1 adaptation to NK-cell-mediated immune pressure. AB - Natural killer (NK) cells have an important role in the control of viral infections, recognizing virally infected cells through a variety of activating and inhibitory receptors. Epidemiological and functional studies have recently suggested that NK cells can also contribute to the control of HIV-1 infection through recognition of virally infected cells by both activating and inhibitory killer immunoglobulin-like receptors (KIRs). However, it remains unknown whether NK cells can directly mediate antiviral immune pressure in vivo in humans. Here we describe KIR-associated amino-acid polymorphisms in the HIV-1 sequence of chronically infected individuals, on a population level. We show that these KIR associated HIV-1 sequence polymorphisms can enhance the binding of inhibitory KIRs to HIV-1-infected CD4(+) T cells, and reduce the antiviral activity of KIR positive NK cells. These data demonstrate that KIR-positive NK cells can place immunological pressure on HIV-1, and that the virus can evade such NK-cell mediated immune pressure by selecting for sequence polymorphisms, as was previously described for virus-specific T cells and neutralizing antibodies. NK cells might therefore have a previously underappreciated role in contributing to viral evolution. PMID- 21814284 TI - Blood pressure re-screening for healthy adults: what is the best measure and interval? AB - Blood pressure (BP) screening is important to identify those at risk of cardiovascular disease, but there has been little data on the appropriate interval of screening. We aimed to evaluate the optimal interval and the best measure for BP re-screening by estimating the long-term, true change variance ('signal') and short-term, within-person variance ('noise'). Study design was a cohort study from 2005 to 2008. Target population was Japanese healthy adults not taking antihypertensive medication at baseline, in a teaching hospital. We measured annually the systolic BP (SBP) and the diastolic BP (DBP), and calculated the pulse pressure (PP) and the mean arterial pressure (MAP). A total of 15,055 individuals (51% male) with a mean age of 49 years had annual check ups. Short-term coefficient of variation was lowest for MAP at 5.2%, followed by SBP (5.7%) and DBP (5.8%), and highest for PP (12%). After 3 years, the 'signal' of true BP changes of only SBP and MAP equaled the 'noise' of BP measurement; however, it was larger for those with higher initial BPs. SBP or MAP appears to be a better screening measure. The optimal interval should be 3 years or more, with SBP<130 mm Hg and 2 years for those with SBP >= 130 mm Hg. PMID- 21814285 TI - Mechanism of cell death resulting from DNA interstrand cross-linking in mammalian cells. AB - DNA interstrand cross-links (ICLs) are critical cytotoxic lesions produced by cancer chemotherapeutic agents such as the nitrogen mustards and platinum drugs; however, the exact mechanism of ICL-induced cell death is unclear. Here, we show a novel mechanism of p53-independent apoptotic cell death involving prolonged cell-cycle (G(2)) arrest, ICL repair involving HR, transient mitosis, incomplete cytokinesis, and gross chromosomal abnormalities resulting from ICLs in mammalian cells. This characteristic 'giant' cell death, observed by using time-lapse video microscopy, was reduced in ICL repair ERCC1- and XRCC3-deficient cells. Collectively, the results illustrate the coordination of ICL-induced cellular responses, including cell-cycle arrest, DNA damage repair, and cell death. PMID- 21814286 TI - Gene-dependent cell death in yeast. AB - Caspase-dependent apoptotic cell death has been extensively studied in cultured cells and during embryonic development, but the existence of analogous molecular pathways in single-cell species is uncertain. This has reduced enthusiasm for applying the advanced genetic tools available for yeast to study cell death regulation. However, partial characterization in mammals of additional genetically encoded cell death mechanisms, which lead to a range of dying cell morphologies and necrosis, suggests potential applications for yeast genetics. In this light, we revisited the topic of gene-dependent cell death in yeast to determine the prevalence of yeast genes with the capacity to contribute to cell autonomous death. We developed a rigorous strategy by allowing sufficient time for gene-dependent events to occur, but insufficient time to evolve new populations, and applied this strategy to the Saccharomyces cerevisiae gene knockout collection. Unlike sudden heat shock, a ramped heat stimulus delivered over several minutes with a thermocycler, coupled with assessment of viability by automated counting of microscopic colonies revealed highly reproducible gene specific survival phenotypes, which typically persist under alternative conditions. Unexpectedly, we identified over 800 yeast knockout strains that exhibit significantly increased survival following insult, implying that these genes can contribute to cell death. Although these death mechanisms are yet uncharacterized, this study facilitates further exploration. PMID- 21814287 TI - Reactive oxygen species initiate luminal but not basal cell death in cultured human mammary alveolar structures: a potential regulator of involution. AB - Post-lactational involution of the mammary gland is initiated within days of weaning. Clearing of cells occurs by apoptosis of the milk-secreting luminal cells in the alveoli and through stromal tissue remodeling to return the gland almost completely to its pre-pregnant state. The pathways that specifically target involution of the luminal cells in the alveoli but not the basal and ductal cells are poorly understood. In this study we show in cultured human mammary alveolar structures that the involution process is initiated by fresh media withdrawal, and is characterized by cellular oxidative stress, expression of activated macrophage marker CD68 and finally complete clearing of the luminal but not basal epithelial layer. This process can be simulated by ectopic addition of reactive oxygen species (ROS) in cultures without media withdrawal. Cells isolated from post-involution alveoli were enriched for the CD49f(+) mammary stem cell (MaSC) phenotype and were able to reproduce a complete alveolar structure in subcultures without any significant loss in viability. We propose that the ROS produced by accumulated milk breakdown post-weaning may be the mechanism underlying the selective involution of secretory alveolar luminal cells, and that our culture model represents an useful means to investigate this and other mechanisms further. PMID- 21814288 TI - Microbial gene functions enriched in the Deepwater Horizon deep-sea oil plume. AB - The Deepwater Horizon oil spill in the Gulf of Mexico is the deepest and largest offshore spill in the United State history and its impacts on marine ecosystems are largely unknown. Here, we showed that the microbial community functional composition and structure were dramatically altered in a deep-sea oil plume resulting from the spill. A variety of metabolic genes involved in both aerobic and anaerobic hydrocarbon degradation were highly enriched in the plume compared with outside the plume, indicating a great potential for intrinsic bioremediation or natural attenuation in the deep sea. Various other microbial functional genes that are relevant to carbon, nitrogen, phosphorus, sulfur and iron cycling, metal resistance and bacteriophage replication were also enriched in the plume. Together, these results suggest that the indigenous marine microbial communities could have a significant role in biodegradation of oil spills in deep-sea environments. PMID- 21814289 TI - Evolution of symbiotic organs and endosymbionts in lygaeid stinkbugs. AB - We investigated seed bugs of the genus Nysius (Insecta: Hemiptera: Lygaeidae) for their symbiotic bacteria. From all the samples representing 4 species, 18 populations and 281 individuals, specific bacterial 16S rRNA gene sequences were consistently identified, which formed a distinct clade in the Gammaproteobacteria. In situ hybridization showed that the bacterium was endocellularly localized in a pair of large bacteriomes that were amorphous in shape, deep red in color, and in association with gonads. In the ovary of adult females, the endosymbiont was also localized in the 'infection zone' in the middle of each germarium and in the 'symbiont ball' at the anterior pole of each oocyte, indicating vertical transmission of the endosymbiont through the ovarial passage. Phylogenetic analyses based on bacterial 16S rRNA, groEL and gyrB genes consistently supported a coherent monophyly of the Nysius endosymbionts. The possibility of a sister relationship to 'Candidatus Kleidoceria schneideri', the bacteriome-associated endosymbiont of a lygaeid bug Kleidocerys resedae, was statistically rejected, indicating independent evolutionary origins of the endosymbionts in the Lygaeidae. The endosymbiont genes consistently exhibited AT biased nucleotide compositions and accelerated rates of molecular evolution, and the endosymbiont genome was only 0.6 Mb in size. The endosymbiont phylogeny was congruent with the host insect phylogeny, suggesting strict vertical transmission and host-symbiont co-speciation over evolutionary time. Based on these results, we discuss the evolution of bacteriomes and endosymbionts in the Heteroptera, most members of which are associated with gut symbiotic bacteria. The designation 'Candidatus Schneideria nysicola' is proposed for the endosymbiont clade. PMID- 21814290 TI - Expression of Na+-K+ -2Cl- cotransporter 1 is epigenetically regulated during postnatal development of hypertension. AB - BACKGROUND: The expression of Na(+)-K(+)-2Cl(-) cotransporter 1 (NKCC1) is upregulated in spontaneously hypertensive rat (SHR). We investigated whether expression of NKCC1 is epigenetically regulated during postnatal development of hypertension. METHODS: The mesenteric arteries from 5-, 10-, and 18-week-old Wistar-Kyoto rats (WKY) and SHRs were subjected to vascular contraction. We determined expression levels of Nkcc1 mRNA and protein, methylation status, and histone modification of Nkcc1 promoter, and DNA methyltransferase (DNMT) activity. RESULTS: The inhibition of dose-response curves by bumetanide, an inhibitor of NKCC1, as well as the expression of Nkcc1 mRNA and protein was comparable between 5-week-old SHR and age-matched WKY, but greater in 18-week-old SHR than in age-matched WKY. Nkcc1 promoter in WKY was getting methylated with age whereas that in SHR mostly remained hypomethylated after development of hypertension. DNMT3B was highly associated with the promoter of WKY, whereas the CXXC finger protein 1 (Cfp1) was highly bound to the promoter of SHR. At the age of 18 weeks, the DNMT activity in aorta of WKY was about threefold higher than that of SHR. The transcription-activating histone code acetyl H3 was higher in SHR than in WKY, whereas suppressive histone code dimethyl H3K9 was greater in WKY than in SHR. CONCLUSION: It is concluded that expression of NKCC1 is epigenetically upregulated during postnatal development of hypertension. Our data indicate that maintenance of hypomethylation in Nkcc1 promoter of SHR resulting from low DNMT activity plays an important role in the upregulation of NKCC1 during development of spontaneous hypertension. PMID- 21814291 TI - Dietary intake of vitamin B12 and folic acid is associated with lower blood pressure in Japanese preschool children. AB - BACKGROUND: An elevated plasma homocysteine level is an independent risk factor for high blood pressure and cardiovascular disease, and its level is regulated by three vitamins; vitamin B6, B12, and folic acid. Until now, the association between the intake of these vitamins and blood pressure has been examined only in adult populations. We purposed to examine the association between dietary intake of these three vitamins and blood pressure of young children. METHODS: We conducted a cross-sectional study at Japanese preschools in 2006. Blood pressure was measured among 418 children aged 3-6 years. Diets including vitamins were assessed by a 3-day dietary record. We compared the blood pressure levels among the four groups defined according to quartile of energy-adjusted vitamin intake by using analysis of covariance after controlling for age, sex, and body mass index. RESULTS: The mean systolic blood pressure was 6.6 mm Hg lower and the mean diastolic blood pressure was 5.7 mm Hg lower in the highest quartile than in the lowest quartile of vitamin B12 intake (P for trend was <0.001 and 0.006, respectively). The mean systolic blood pressure was 4.1 mm Hg lower in the highest quartile than in the lowest quartile of folic acid intake (P for trend = 0.004). Vitamin B6 intake was not significantly associated with blood pressure. CONCLUSIONS: The data suggest that high intakes of folic acid and vitamin B12 are associated with lower levels of blood pressure among preschool children. PMID- 21814292 TI - Epicardial adipose tissue and metabolic syndrome in hypertensive patients with normal body weight and waist circumference. AB - BACKGROUND: Metabolic syndrome (MetS) is a cluster of risk factors, related to visceral adiposity, which is frequently observed in overweight patients. However, it has also been reported in normal weight subjects. Epicardial adipose tissue (EAT) is a visceral fat. The aim of the study was to evaluate whether EAT is associated with MetS in hypertensive patients with normal weight and waist. METHODS: We studied 174 Caucasian hypertensive patients, aged >=40 years, with body mass index (BMI) <25 kg/m(2) and waist circumference <102 cm in men and 88 cm in women. MetS was defined according to NCEP ATP III criteria, not including waist circumference. EAT was measured by echocardiography above the free wall of the right ventricle, at end diastole. RESULTS: MetS was present in 21 (12%) patients. EAT was significantly higher in patients with MetS than in those without MetS, 4.0 +/- 0.8 vs 2.5 +/- 0.9 mm, P < 0.01, respectively, but BMI and waist circumference were not. Multivariate analysis showed that EAT was independently associated with MetS. Receiver operating characteristic (ROC) curve analysis showed that EAT significantly improved prediction of MetS when added to BMI and waist circumference. Indeed, the area under the curve improved from 0.63 (0.50-0.76) to 0.91 (0.87-0.96), and resulted significantly higher (P < 0.01). ROC curve for EAT alone indicated that the cutoff value of 3.1 mm had the best performance in predicting MetS, that is, 100% sensitivity and 79% specificity. CONCLUSION: EAT thickness is associated with MetS in hypertensive patients with normal weight and waist. PMID- 21814293 TI - Association of blood pressure control and metabolic syndrome with cardiovascular risk in elderly Japanese: JATOS study. AB - BACKGROUND: The impact of the metabolic syndrome (MS) on cardiovascular events in elderly subjects has not been clarified. We hypothesized that the impact differs between patients with and without strictly controlled blood pressure (BP) and also between early elderly (<75 years) and late (>=75 years) elderly patients. METHODS: Elderly hypertensive patients (65-85 years old) were randomly assigned to strict (target systolic BP <140 mm Hg) or mild (140-159 mm Hg) BP target, and were treated for 2 years with efonidipine-based regimen. MS was defined according to the National Cholesterol Education Program Adult Treatment Panel III criteria, except for the use of body mass index (BMI) >=25 kg/m(2) instead of waist circumference. Primary endpoint was combined incidence of cardiovascular and renal events. Data were obtained from 2,865 patients. RESULTS: The prevalence of MS was 31.4%. The incidence of primary endpoint in patients with and without MS was 4.0% and 3.1%, respectively. MS was a significant risk factor for cardiovascular events in patients <75 years old (adjusted hazard ratio (HR) 2.17, P = 0.01), but not in patients >=75 years old (adjusted HR 0.98, P = 0.94). In patients with MS, the event rate was significantly lower with strict treatment than with mild treatment among patients aged <75 years (P = 0.0006) but not in those aged >=75 years (P = 0.82). CONCLUSIONS: MS was associated with cardiovascular risk in elderly hypertensive patients <75 years old, and strict BP control was beneficial for those with MS. However, MS and intensive control of BP may have little effect on cardiovascular events in elderly patients >=75 years old. PMID- 21814294 TI - Representations of efficient score for coarse data problems based on Neumann series expansion. AB - We derive new representations of the efficient score for coarse data problems based on Neumann series expansion. The representations can be applied to both ignorable and nonignorable coarse data. An approximation to the new representation may be used for computing locally efficient scores in such problems. We show that many of the successive approximation approaches to the computation of the locally efficient score proposed in the literature for coarse data problems can be derived as special cases of the representations. In addition, the representations lead to new algorithms for computing the locally efficient scores for the coarse data problems. PMID- 21814295 TI - Nickel-Catalyzed Coupling Reactions of Alkenes. AB - Several reactions of simple, unactivated alkenes with electrophiles under nickel(0) catalysis are discussed. The coupling of olefins with aldehydes and silyl triflates provides allylic or homoallylic alcohol derivatives, depending on the supporting ligands and, to a lesser extent, the substrates employed. Reaction of alkenes with isocyanates yields N-alkyl acrylamides. In these methods, alkenes act as the functional equivalents of alkenyl- and allylmetal reagents. PMID- 21814296 TI - Prepping Students for Authentic Science. PMID- 21814297 TI - Prospective Predictors of Suicidal Ideation during Depressive Episodes among Older Adolescents and Young Adults. AB - Suicide is a leading cause of death among older adolescents and young adults; however, few studies have prospectively examined risk for suicidal ideation. The present study in older adolescents and young adults investigated whether two personality traits previously implicated in risk for suicidal ideation, neuroticism and extraversion, as well as certain aspects of interpersonal functioning, prospectively predicted endorsement of suicidal ideation during depressive episodes. Participants (n=117) are a subset of the Northwestern-UCLA Youth Emotion Project sample, which started with a group of high school juniors oversampled for high neuroticism. Baseline interpersonal functioning was measured using the Life Stress Interview. Baseline personality trait composite scores were created from multiple inventories. Depressive disorders and suicidal ideation were assessed at the baseline and three annual follow-up interviews using the SCID. Cox regression was employed to predict suicidal ideation during depressive episodes diagnosed at any follow-up interview. Results showed that baseline extraversion inversely predicts suicidal ideation in males only, and that baseline interpersonal problems in one's social circle, regardless of gender, predict suicidal ideation during depressive episodes. PMID- 21814298 TI - Commitment Without Marriage: Union Formation Among Long-Term Same-Sex Couples. AB - The majority of Americans will marry in their lifetimes, and for many, marriage symbolizes the transition into long-term commitment. However, many Americans cannot legally marry. This article analyzes in-depth interviews with gays and lesbians in long-term partnerships to examine union formation and commitment making histories. Using a life course perspective that emphasizes historical and biographical contexts, the authors examine how couples conceptualize and form committed relationships despite being denied the right to marry. Although previous studies suggest that commitment ceremonies are a way to form same-sex unions, this study finds that because of their unique social, historical, and biographical relationship to marriage and ceremonies, long-term same-sex couples do not follow normative commitment-making trajectories. Instead, relationships can transition more ambiguously to committed formations without marriage, public ceremony, clear-cut act, or decision. Such an understanding of commitment making outside of marriage has implications for theorizing alternative forms of union making. PMID- 21814299 TI - Off-lattice Eden-C cluster growth model. AB - A non-trivial cluster growth model, equivalent to the lattice-free Eden-C model, is proposed. The model is constructed by randomly adding contiguous circles without overlapping. Large-scale computer simulations show the interior density is constant at 0.650, while the boundary is fractal, with a thickness proportional to the 0.396 power of the mean radius. PMID- 21814300 TI - Antiestrogen therapy in recurrent ovarian cancer resulting in 28 months of stable disease: a case report and review of the literature. AB - Hormonal therapy for adjuvant treatment of ovarian cancer may provide a low toxicity option in some patients with refractory disease. A 53 year-old patient with stage IIIC papillary serous ovarian cancer previously treated with multiple chemotherapy regimens with platinum-resistant disease was treated with antiestrogen therapy for 28 months before requiring reinstitution of cytotoxic chemotherapy. Hormonal therapy may be effective in a subset of epithelial ovarian cancer patients with endocrine sensitivity and should be considered in the treatment of platinum-resistant patients. PMID- 21814301 TI - Photo-induced regeneration of hormones by electron transfer processes: Potential biological and medical consequences. AB - Based on the previous results concerning electron transfer processes in biological substances, it was of interest to investigate if hormone transients resulting by e.g. electron emission can be regenerated.The presented results prove for the first time that the hormone transients originating by the electron emission process can be successfully regenerated by the transfer of electrons from a potent electron donor, such as vitamin C (VitC). Investigations were performed using progesterone (PRG), testosterone (TES) and estrone (E1) as representatives of hormones. By irradiation with monochromatic UV light (lambda=254 nm) in a media of 40% water and 60% ethanol, the degradation as well as the regeneration of the hormones was studied with each hormone individually and in the mixture with VitC as a function of the absorbed UV dose, using HPLC. Calculated from the obtained initial yields, the determined regeneration of PRG amounted to 52.7%, for TES to 58.6% and for E1 to 90.9%. The consumption of VitC was determined in the same way.The reported results concerning the regeneration of hormones by the transfer of electrons from an electron donor offer a new, promising method for the therapy with hormones. As a consequence of the regeneration of hormones, a decreased formation of carcinogenic metabolites is expected. PMID- 21814302 TI - Bladder cancer - When will the paradigm change? PMID- 21814303 TI - Hemodialysis vascular access options after failed Brescia-Cimino arteriovenous fistula. AB - The survival of patients on long-term hemodialysis has improved. End-stage renal disease patients now need maintenance of their vascular access for much longer periods. Arteriovenous fistulae formed at the wrist are the first choice for this purpose, but, in many patients, these fistulae fail over time or are not feasible because of thrombosed veins. We searched the Pubmed database to evaluate the various options of vascular access in this group of patients based on the published literature. It is quite evident that, whenever possible, autogenous fistulae should be preferred over prosthetic grafts. Use of upper arm cephalic and basilic veins with transpositions wherever required can enhance autogenous fistula options to a large extent. Upper arm grafts should be used when no autogenous fistula is possible. Lower limb and body wall fistula sites are to be considered at the end, when all options in both upper limbs are exhausted. PMID- 21814304 TI - Measurement of renal dimensions in vivo: A critical appraisal. AB - Kidney volume is regarded as the most precise indicator of kidney size. However, volume assessment is not widely used clinically because its measurement is difficult due to the complex kidney shape. Apart from the conventional methods of measurement of renal dimensions from X-rays, ultrasound scan, computed tomography scan and magnetic resonance imaging have evolved as the three best modalities for this purpose currently. Assessment of kidney size should also be made individually since many factors like body mass index, height, gender, age, position of kidneys, sex, stenoses and number of renal arteries influence the measurements. In this paper, we have critically analysed the advantages and disadvantages of the various methods of renal morphometry, by reviewing the literature spanning over the period of 1976 - 2009. PMID- 21814305 TI - Second transurethral resection in T1G3 bladder tumors - Selectively avoidable? AB - AIM: To assess the need of a second transurethral resection (TUR) in select T1G3 bladder tumor patients. MATERIALS AND METHODS: All the pT1G3 bladder tumors diagnosed during the period between January 2005 and December 2008 were included. Second TUR was routinely performed in all the pT1G3 bladder tumors within 4-6 weeks. Fifty out of the 68 patients with T1G3 underwent a second TUR and were retrospectively reviewed. The primary bladder lesions were grouped as solitary papillary, multiple papillary and sessile lesions. Statistical analysis was performed using STATA version 11 (STATA Corp., Texas, USA). RESULTS: Forty percent (n = 20) of the lesions were solitary papillary, 48% (n = 24) were multiple papillary and 12% (n = 6) were sessile lesions. All our resections had muscularis propria sampled at the end of the resection and separately sent for histopathological examination (HPE), which showed them to be tumor free. Thirty six percent of patients had residual disease at the second resection and 4% were upstaged. Ninety-five percent of the patients (n = 19) with solitary papillary lesions did not have any residual disease and 50% (n = 12) of the multiple papillary and 83.3% (n = 5) of the sessile group had residual disease at the second TUR. CONCLUSIONS: Patients with T1G3 tumors do not represent a homogenous group. Second TUR is recommended in patients with high-grade T1 urothelial bladder carcinoma as it identifies residual disease and invasive disease. Solitary papillary lesions may be the only group where the need for the second TUR is questionable. PMID- 21814306 TI - Transumbilical laparoendoscopic single-site donor nephrectomy: Without the use of a single port access device. AB - INTRODUCTION: Laparoendoscopic single-site donor nephrectomy (LESS-DN) is a procedure in evolution. Currently described techniques utilize single port access devices and articulating, flexible, and bent working instruments. We describe a modified technique of transumbilical LESS-DN with conventional laparoscopic instruments in five kidney donors. MATERIALS AND METHODS: Three standard laparoscopic ports (10 mm * 1, 5 mm * 2) were placed through a 4.5 cm vertical transumbilical incision. A 10 mm 45 degrees , long bariatric lens (Karl Storz) was used. Renal mobilization was performed using conventional rigid laparoscopy instruments. A port closure needle loaded with a blunt plastic needle cap was used for traction. After hilar clamping, an incision was made connecting the three ports, and the kidney was extracted using a preplaced suture over the lower pole fat. All data were prospectively recorded. RESULTS: LESS-DN was performed successfully in all five patients. The mean operative time was 157.2 minutes (range, 134-184) and the mean warm ischemia time was 3.2 minutes (range, 3-4). All donors were discharged on postoperative day 3 and were able to resume normal physical activity by 2 weeks after the procedure. All donors had an excellent cosmetic outcome. The mean serum creatinine (recipient) at discharge was 1.14 mg% (range, 0.9-1.4). CONCLUSIONS: Transumbilical LESS-DN can be cost-effectively performed using conventional laparoscopy instruments and without the need for a single port access device. Warm ischemia times with this technique are comparable with that during conventional multiport laparoscopic donor nephrectomy. PMID- 21814307 TI - Results of laparoscopic cryoablation in the treatment of small renal masses. AB - CONTEXT: Study of clinical outcome in renal cryoablation. AIMS: Laparoscopic cryoablation (LCA) is emerging as a reliable treatment option for small renal masses (SRMs) particularly in elderly patients. Our aim was to study the results of cryoablation for small renal masses in our cohort of patients. SETTINGS AND DESIGN: We retrospectively studied all patients who underwent LCA for SRMs between September 2005 and July 2008. MATERIALS AND METHODS: All patients were discussed in our multidisciplinary meeting prior to cryoablation. Our LCA protocol included two freeze-thaw cycles, achieving a core temperature of -70 degrees C and a peripheral temperature of at least -40 degrees C. Follow-up included serum creatinine measurements and pre- and postcontrast CT scans at 3, 6, 12, 18, and 24 months and yearly thereafter. STATISTICAL ANALYSIS USED: Paired samples t-test was used to study statistical difference. RESULTS: Twenty-two patients underwent LCA with a mean (range) age of 68 (39-81 years) years. The mean (range) tumor size was 29 (19-45 mm) mm. Two patients required blood transfusions, one patient developed pneumonia, and another patient developed a small area of skin necrosis at the cryoneedle entry site. The average (range) hospital stay was 4 (2-14 days) days. Twenty-one patients have had CT follow-up at a mean (range) of 24 (4-42 months) months. Three of the 21 tumors showed central enhancement on follow-up CT scans, consistent with treatment failure. CONCLUSIONS: Laparoscopic cryoablation is a safe treatment option for SRM in a selected group of patients. PMID- 21814308 TI - Suprapubic transvesical single-port technique for control of lower end of ureter during laparoscopic nephroureterectomy for upper tract transitional cell carcinoma. AB - CONTEXT: Various minimally invasive techniques - laparoscopic, endoscopic or combinations of both - have been described to handle the lower ureter during laparoscopic nephroureterectomy but none has received wide acceptance. AIMS: We describe an endoscopic technique for the management of lower end of ureter during laparoscopic nephroureterectomy using a single suprapubic laparoscopic port. MATERIALS AND METHODS: Transurethral resectoscope is used to make a full thickness incision in the bladder cuff around the ureteric orifice from 1 o'clock to 11 o'clock. A grasper inserted through the transvesical suprapubic port is used to retract the ureter to complete the incision in the bladder cuff overlying the anterior aspect of the ureteric orifice. The lower end of ureter is subsequently sealed with a clip applied through the port. This is followed by a laparoscopic nephrectomy and the specimen is removed by extending the suprapubic port incision. Our technique enables dissection and control of lower end of ureter under direct vision. Moreover, surgical occlusion of the lower end of the ureter prior to dissection of the kidney may decrease cell spillage. The clip also serves as a marker for complete removal of the specimen. RESULTS: Three patients have undergone this procedure with an average follow up of 19 months. Operative time for the management of lower ureter has been 35, 55 and 40 minutes respectively. A single recurrence was detected on the opposite bladder wall after 9 months via a surveillance cystoscopy. There has been no residual disease or any other locoregional recurrence. CONCLUSIONS: The described technique for management of lower end of ureter during laparoscopic nephroureterectomy adheres to strict oncologic principles while providing the benefit of a minimally invasive approach. PMID- 21814309 TI - Staged buccal mucosa urethroplasty in reoperative hypospadias. AB - INTRODUCTION: Repeated attempts at surgical repair of serious complications involving either the partial or complete breakdown of the hypospadias repair are less likely to succeed because the penis is densely scarred, or significantly shortened, and the skin over the penis is immobile and hypovascular. Buccal mucosa (BM) has become the preferred material for reconstruction, whenever a child with skin-deficient hypospadias needs reoperation. We report the results of our surgical experience with staged reoperation using BM, in the repair of hypospadias in children with complications after multiple failed repairs. MATERIALS AND METHODS: Children needing reoperation for hypospadias underwent a staged repair using buccal mucosa. The complications were noted. RESULTS: Twenty one children aged 3 - 16 years underwent this staged repair during the period May 2000 - April 2010. Two of these 21 children had a failed first stage. One child developed a urethro-cutaneous fistula following the second stage, which was corrected in an additional stage. CONCLUSIONS: The use of the buccal mucosa graft for urethral reconstruction in a child with hypospadias, needing a reoperation, is a successful method, with a low incidence of complications. PMID- 21814310 TI - Positive HER-2 protein expression in circulating prostate cells and micro metastasis, resistant to androgen blockage but not diethylstilbestrol. AB - INTRODUCTION: HER-2 expression in prostate cancer is associated with a worse prognosis and is suggested to play a role in androgen resistance. We present a study of HER-2 expression in circulating tumor cells and micrometastasis in bone marrow and the effect of androgen blockage or DES in the presence of HER-2 expressing cells. PATIENTS AND METHODS: A multicenter study of men with prostate cancer, treated with surgery, radiotherapy, or observation, and with or without hormone therapy. Mononuclear cells were separated from blood and bone marrow aspirate by differential centrifugation, touch preps were made from bone marrow biopsy samples. Prostate cells were detected using anti-PSA monoclonal antibody and standard immunocytochemistry. Positive samples were processed using Herceptest(r) to determine HER-2 expression. After 1 year, patients were re evaluated and the findings of HER-2 expression and PSA change compared with treatment. RESULTS: Total 199 men participated, and 97 had a second evaluation 1 year later, frequency of HER-2 expression in circulating tumor cells and micrometastasis was 18% and 21%, respectively. There was no significant difference in HER-2 expression in the pretreatment group, after radical surgery or radiotherapy or with biochemical failure. Men with androgen blockade had a significantly higher expression of HER-2 (58%) (P =0.001). Of the 97 men with a second evaluation, 56 were in the observation arm, 27 androgen blockade, and 14 DES. Use of androgen blockade or DES significantly reduced serum PSA levels in comparison with observation (P =0.001). However, there was a significant increase in HER-2 expression in patients with androgen blockade (P =0.05) en comparison with observation or DES treatment. No patient with observation or DES became HER 2 positive, en comparison 4/22 patients initially HER-2 negative became HER-2 positive with androgen blockade. CONCLUSIONS: The results suggest that HER-2 positive cells are resistant to androgen blockade. In an environment lacking androgens, HER-2 positive cells are selected and survive, while HER-2 negative cells are eliminated thus decreasing the serum PSA. The population of HER-2 positive cells proliferate producing androgen-independent disease. DES does not increase HER-2 expression possibly by stimulating beta-estrogen receptors and blocking HER-2 androgen receptor activation. PMID- 21814312 TI - The management of urothelial cancer in 2010 and beyond. PMID- 21814311 TI - Epidermal growth factor receptor expression in urinary bladder cancer. AB - OBJECTIVE: To evaluate the expression pattern of epidermal growth factor receptor (EGFR) in urinary bladder cancer and its association with human epidermal growth factor receptor 2 (HER2), epidermal growth factor (EGF), interleukin-6 (IL-6), and high risk human papilloma virus (HPV) types 16 and 18. MATERIALS AND METHODS: Thirty cases of urothelial carcinoma were analyzed. EGFR, HER2, EGF, and IL-6 expressions in the tissue were evaluated by immunohistochemical staining. For HPV, DNA from tissue samples was extracted and detection of HPV was done by PCR technique. Furthermore, evaluation of different intracellular molecules associated with EGFR signaling pathways was performed by the western blot method using lysates from various cells and tissues. RESULTS: In this study, the frequencies of immunopositivity for EGFR, HER2, EGF, and IL-6 were 23%, 60%, 47%, and 80%, respectively. No cases were positive for HPV-18, whereas HPV-16 was detected in 10% cases. Overall, expression of EGFR did not show any statistically significant association with the studied parameters. However, among male patients, a significant association was found only between EGFR and HER2. CONCLUSIONS: Overexpression of EGFR and/or HER2, two important members of the same family of growth factor receptors, was observed in a considerable proportion of cases. Precise knowledge in this subject would be helpful to formulate a rational treatment strategy in patients with urinary bladder cancer. PMID- 21814313 TI - Rationale for an early detection program for bladder cancer. AB - INTRODUCTION: A total of 356,557 new cases were diagnosed annually worldwide in 2009, it was estimated that 52,810 new patients were to be diagnosed with bladder cancer and there were 10,180 projected deaths from the disease in the USA. Despite being the fourth commonest cancer in men, we do not have an early detection/screening program for bladder cancer. The review was aimed at looking at the evidence for the rationale for an early detection program for bladder cancer. MATERIALS AND METHODS: A detailed search on bladder cancer epidemiology, diagnosis, pathology, tumor markers, treatment outcomes, screening, morbidity and mortality of bladder cancer was carried out on Pubmed central/Medline. Original articles, review articles, monograms, book chapters on bladder cancer, text books on urological oncology, oncology and urology were reviewed. The latest information for new articles before publication was last accessed in June 2010. DISCUSSION AND CONCLUSIONS: Bladder cancer is the fourth commonest cancer in men, the annual death rate from this disease is significant and every year there is an increase in its incidence globally. The prognosis of bladder cancer is stage and grade dependent; the lower the stage (T2 or less) the better is the survival. Delay in the diagnosis and treatment does alter the overall outcome. Therefore, there is a clear need for early detection of bladder cancer and screening program. Although we do not have an ideal marker for bladder cancer, it is time we maximize the potential of markers such as UroVysion, NMP22 along with cytology to start such a program. May be as a first step the early detection and screening program could be started in high-risk population. It is not worth waiting till we find the best marker as it would be unfair to our patients. The fear of unnecessary tests and treatment in bladder cancer after its detection in screening program is without any substance. The cost-effectiveness of such a program is certainly comparable to that is used for colon or breast and for prostate as well. PMID- 21814315 TI - Proactive approach to treat high-grade lamina-invasive bladder cancer. AB - Urothelial cancer, despite advances in the field of medicine, remains an enigmatic problem with no tangible solution to treat it once it goes beyond the detrusor muscle. Nonmuscle-invasive bladder cancer form the majority of bladder cancer at presentation and high-grade lamina-invasive bladder cancer (HGLIbc) previously known as T1G3 is the most controversial subtype as far as treatment is concerned. Should the patient be given BCG or is an initial cystectomy a better outcome? If BCG is started should the patient be kept on maintenance? Urothelial cancer has no effective adjuvant treatment, therefore being proactive in identifying aggressive tumors to begin with would help in improving survival. This short review, based on the contemporary literature has tried to evolve an approach which may help in making clinical decision to treat HGLIbc. PMID- 21814314 TI - Perioperative morbidity of radical cystectomy: A review. AB - A systematic review of the literature on perioperative morbidity (POM) was done using Medline software with a combination of keywords like mortality, morbidity, and complications. In addition, we review the analysis of our hospital data of 261 Radical cystectomies (RCs) performed in an 11-year period and our latest clinical pathway for RC. Age range in our series was 50 to 81 years with 240 males and 21 females. RCs were performed by intraperitoneal method in 172 patients and by our extraperitoneal (EP) method in 89 patients. Urinary diversion was ileal conduit in 159 patients and neobladder in 102 patients. Blood loss ranged between 500 and 1500 ccs. Postoperative mortality occurred in eight patients (3%). Among the other early post-op complications, major urinary leak was seen in nine and minor in 11, requiring PCN in five patients and reoperation in four patients. Bowel leak or obstruction was seen in six and four patients, respectively, requiring reoperation in six patients. EP RC in our series showed some benefit in reduction of POM. The mortality of RC has declined but the POM still ranges from 11 to 68%, as reported in 23 series (1999-2008) comprising of 14 076 patients. Various risk factors leading to POM and some corrective measures are discussed in detail. However, most of these series are retrospective and lack standard complication reporting, which limits the comparison of outcomes. Various modifications in open surgical technique and laparoscopic and Robotic approaches are aimed at reduction in mortality and POM of RC. PMID- 21814316 TI - Monitoring of the upper urinary tract in patients with bladder cancer. AB - Upper urinary tract (UUT) transitional cell carcinoma (TCC) is relatively rare tumor. Approximately 0.7-4% of patients with primary bladder cancer develops UUT TCC. The symptoms related to an UUT-TCC often occur with an advanced stage which leads one to emphasize a surveillance strategy to monitor the UUT to allow for an earlier diagnosis. Although the risk of UUT-TCC after bladder cancer is well established, there is a paucity of recommendations suggesting the optimal method and frequency of monitoring the UUT and there is no consensus among them. This article reviews the recommendations on monitoring the UUT in patients with bladder cancer. PMID- 21814317 TI - Emerging optical techniques in advanced cystoscopy for bladder cancer diagnosis: A review of the current literature. AB - BACKGROUND AND OBJECTIVE: The current standard for the diagnosis and followup of bladder cancer remains white light cystoscopy, despite its well-known limitations. The aim of this paper is to review the current literature on three optical diagnostics that have been developed to improve the performance of white light cystoscopy: photodynamic diagnosis, narrow-band imaging and optical coherence tomography. MATERIALS AND METHODS: A PubMed search was performed for all articles on bladder cancer and photodynamic diagnosis, narrow-band imaging, and optical coherence tomography. Relevant papers on the working mechanism or clinical performance of the techniques were selected. RESULTS: Photodynamic diagnosis and narrow-band imaging both aim to improve the visualization of bladder cancer. Both techniques have demonstrated an improved detection rate of bladder cancer. For photodynamic diagnosis, decreased residual tumor rates and increased recurrence free survival after photodynamic diagnosis-assisted transurethral resection have been shown. Both techniques have a relatively high false positive rate. Optical coherence tomography is a technique aiming at real time noninvasive pathological diagnosis. Studies have shown that optical coherence tomography can accurately discriminate bladder cancer from normal bladder mucosa, and even suggest that a reliable estimation of the stage of a bladder tumor can be made. CONCLUSIONS: Photodynamic diagnosis is the technique with most evidence of clinical effectiveness to date, but low specificity is limiting a widespread use. For the novelties, narrow-band imaging, and optical coherence tomography, more evidence is needed before these techniques can be implemented in daily urological practice. PMID- 21814320 TI - Testicular masses in a man with a plausible sarcoidosis. AB - Genitourinary involvement with sarcoidosis is very rare. The objective of this report was to present a case of a patient with testicular swelling. The patient was an infertile 42-year-old man with bilateral testicular swelling. Semen analysis in the past 10 years revealed no abnormality; however, gradually he became azoospermic in 3 years. A diagnosis of sarcoidosis made on the basis of hilar and mediastinal lymphadenopathy in chest CT scan was confirmed through testicular and epididymal biopsy. Testicular masses vanished after administering steroids, and azoospermia recovered. To conclude, although genitourinary sarcoidosis is rare, it must be kept in mind in patients with confirmed sarcoidosis. PMID- 21814318 TI - Intravesical therapy for urothelial carcinoma of the bladder. AB - Transurethral resection is an effective therapy for non-muscle-invasive bladder cancer. However, the high rates of recurrence and significant risk of progression in higher grade tumors mandates additional therapy with intravesical agents. In this review we discuss the role of various intravesical agents currently in use including the immunomodualtory agent BCG and chemotherapeutic agents. We discuss the current guidelines and the role of these therapeutic agents in the context of higher grade Ta and T1 tumors. PMID- 21814321 TI - Hyperbaric oxygen-A new horizon in treating cyclophosphamide-induced hemorrhagic cystitis. AB - Hemorrhagic cystitis consists of acute or insidious diffuse bleeding from the bladder mucosa. It can be caused by radiation, drugs, autoimmune diseases, viral and bacterial infections, etc. Hemorrhagic cystitis is a well-recognized complication of cyclophosphamide therapy and it can be potentially fatal. We discuss two cases of cyclophosphamide-induced hemorrhagic cystitis where outcome of conventional management was not satisfactory and a novel therapy using hyperbaric oxygen was used. Hyperbaric oxygen therapy (HBOT) reduces inflammation, stimulates neoangiogenesis, maintains tissue oxygenation and heals tissue hypoxia and radio necrosis. Patients received 100% oxygen in a hyperbaric chamber at 2.5 atmosphere absolute (ATA) for 90 minutes, 5 days a week. One patient was given 36 sessions and the other was given 19 sessions of HBOT. HBOT resulted in complete cessation of bleeding; no side effect was noted during the course of therapy. There was no relapse after 12 months of cessation of treatment. In future, this form of therapy can offer a safe alternative in the treatment of cyclophosphamide-induced hemorrhagic cystitis. PMID- 21814319 TI - Role of systemic peri-operative chemotherapy in management of transitional cell carcinoma of bladder. AB - Bladder cancer has variable biological behavior pattern in different individuals and the debate regarding peri-operative use of systemic chemotherapy with the surgical management remains. The optimal treatment strategy, regimen and the timing of peri-operative chemotherapy are not yet known. Here we review the existing literature for the use of systemic peri-operative chemotherapy in management of advanced bladder cancer. PMID- 21814322 TI - Tuberculosis in postchemotherapy residual masses in germ cell tumor of the testis. AB - Residual masses following chemotherapy in testicular tumors have been characterized as necrosis, mature or immature teratoma, and malignant tumors. Twenty four patients had retroperitoneal lymph node dissection for postchemotherapy residual masses between January 2000 and December 2008. We report two patients; one with late relapse and other with postchemotherapy residual mass, who had tuberculosis. Tumor markers were normal, and PET scan showed increased uptake in residual mass. There are no previous reports of tuberculosis in postchemotherapy residual masses. PMID- 21814323 TI - Medial thigh pain: An unusual presentation of giant calculi in sigmoid neobladder. AB - Calculi in a neobladder usually present with irritative lower urinary tract symptoms, flank pain, and haematuria. We report a case of giant stones in a sigmoid neobladder, who presented with medial thigh pain. PMID- 21814324 TI - Testicular leiomyosarcoma with metastasis. AB - Primary leiomyosarcoma of testis is a rare entity with few cases reported in literature. Primary leiomyosarcoma of testis usually occurs following radiotherapy or long-term anabolic steroid use. Without these predisposing factors, its occurrence is rare. In the present study, we present a rare case of primary leiomyosarcoma of testis occurring in an elderly patient, with an unusual presentation mimicking epididymo-orchitis and metastasis eight months following high inguinal orchidectomy. PMID- 21814325 TI - Testicular germ cell tumor fungating through anterior abdominal wall. AB - Retroperitoneal lymph node metastases from testicular germ cell tumor are common, but fungation of such mass through the anterior abdominal wall is extremely rare. We report such a case which had a favorable response to chemotherapy. PMID- 21814326 TI - Migration of forgotten stent into renal pelvis. AB - Stent migration is a well recognized complication of forgotten stents, but migration into the renal pelvis is rarely documented. We present a case of migration and coiling of a forgotten stent in the renal pelvis, and discuss briefly, the etiological factors for the phenomenon and associated problems in management. PMID- 21814327 TI - Mixed epithelial stromal tumor of the kidney. AB - In recent years, a rare distinctive kidney tumor composed of a mixture of stroma and epithelium with solid and cystic architecture has been recognized, which has to be distinguished from other renal neoplasms. The term mixed epithelial and stromal tumor was first introduced by Michal and Syrucek in 1998.[1] The vast majority of cases show a benign course without tumor recurrence. Here, we present a case of this entity, found incidentally. PMID- 21814328 TI - Responsible authorship. PMID- 21814329 TI - Comments on: Comparison of three different endoscopic techniques in management of bladder calculi. PMID- 21814330 TI - Graft dysfunction and transplant renal artery stenosis. PMID- 21814331 TI - Authors' reply. PMID- 21814332 TI - Fast-track urology training without a Masters in General Surgery. PMID- 21814333 TI - Technical steps of open radical cystectomy and orthotopic neobladder to achieve the goals of "minimally invasive surgery"? PMID- 21814334 TI - Quantitation of HBV DNA; another modification of the test: Will it withstand the test of time? PMID- 21814335 TI - Proteomics in obstetrics and gynecology. AB - Proteomics helps to understand the basic biological processes critical to normal cellular functions as well as the development of diseases. It identifies the essential components of these processes and exploits these components as targets in the development of new methods to prevent or treat diseases. Proteomics, although in an infancy stage in India, has the potential to complement and further enlarge the wealth of information in medicine, especially in the field of cancer. This article reviews the recent progress in proteomic techniques and their applications in the field of obstetrics and gynecology. PMID- 21814336 TI - Evaluation of smoking genotoxicity in Turkish young adults. AB - BACKGROUND: For the past few decades, it has been widely known in developed countries that tobacco is dangerous, but it is still insufficiently realized how big these dangers really are. AIMS: To determine and evaluate micronuclei (MN) frequencies of young smokers and nonsmokers in three different tissues (peripheric blood lymphoctes, buccal mucosa, and exfoliative urothelial cells) at the same time. MATERIALS AND METHODS: MN assay was performed on buccal mucosa, urothelial cells, and peripheric blood lymphocyte samples obtained from 15 healthy male smokers (>5 pack-years) and 15 healthy male nonsmoker controls who had not been exposed to any known genotoxic agent. STATISTICAL ANALYSIS USED: The statistical differences between smoker and nonsmoker groups were calculated by using student t test. The differences between smoker-group tissues were compared by ANOVA. RESULTS: It was found that MN frequency (mean value +/- standard deviation) in oral mucosa cells from smokers and controls were 1.20 +/- 0.22% and 0.26 +/- 0.10%; in urothelial exfoliative cells, 1.29 +/- 0.28% and 0.12 +/- 0.08%; in peripheric blood lymphocytes, 1.53 +/- 0.23% and 0.38 +/- 0.12%, respectively. The mean MN frequencies in buccal mucosa, urothelial exfoliative cells, and peripheric blood lymphocytes were significantly higher in smokers than in those of controls (P<0.05). All tissues were affected from smoking, but the most destructive effect was seen in urothelial cells of smokers (P<0.05). CONCLUSIONS: Our data showed that cigarette smoke is a DNA damage causitive agent on exfoliative buccal mucosa and urothelial cells and peripheric blood lymphocytes of young smokers, but it has most destructive effect on urothelial cells. PMID- 21814337 TI - Genetic markers for idiopathic scoliosis on chromosome 19p 13.3 among Saudi Arabian girls: A pilot study. AB - BACKGROUND AND OBJECTIVE: Genetic locus linked to chromosome 19p for Adolescent idiopathic scoliosis (AIS) has been described. This study was carried out with the aim to find any significant linkage or association between three microsatellite markers (D19S216, D19S894, and DS1034) of chromosome 19p13.3 in Saudi Arabian girls with AIS. MATERIALS AND METHODS: In eleven unrelated Saudi Arabian girls who were treated for AIS with Cobb angle of >=30 degrees and in 10 unrelated healthy individuals, linkage analysis was performed using parametric and nonparametric methods by use of GENEHUNTER version 2.1. Multipoint linkage analysis was used in specifying an autosomal dominant trait with a gene frequency of 0.01 and an estimated penetrance of 80% at the genotype and the allele level. Fisher's exact test was used in the analysis of contingency tables for the D19S216, D19S894, and DS1034 markers. RESULTS: The analysis between the patient group and healthy girls showed that at genotypic level there was no significant association of the markers and scoliosis D19S216 (P = 0.21), D19S894 (P = 0.37), and DS1034 (P = 0.25). Whereas, at the allele level, there was statistically significant association between the marker DS1034 (P = 0.008) and no significant association with the other two markers D19S216 (P = 0.25) and D19S894 (P = 0.17). CONCLUSIONS: Our study shows that at genotypic level none of the markers reported earlier were associated with scoliosis but at allele level, marker DS1034 was significantly associated with patients with AIS. This allele marker on chromosome 19p appears important in the etiology of AIS. PMID- 21814338 TI - A latest and promising approach for prediction of viral load in hepatitis B virus infected patients. AB - INTRODUCTION: Designing a rapid, reliable and sensitive assay for detection of hepatitis B virus (HBV) variants by real-time PCR is challenging at best. A recent approach for quantifying the viral load using a sensitive fluorescent principle was brushed in this study. MATERIALS AND METHODS: : A total of 250 samples were collected from the outpatient unit, CLRD. Complete Human HBVDNA sequences (n = 944) were selected from the National Centre for Biotechnology Information (NCBI), primers and probes were designed and synthesized from the core, surface, and x region. Real-time based quantification was carried out using a standard kit and in-house generated standards and RT-PCR protocols. RESULTS AND DISCUSSION: The standard calibration curve was generated by using serial dilution 10(2) to 10(8). The calibration curve was linear in a range from 10(2) to 10(8) copies/ml, with an R(2) value of 0.999. Reproducibility as measured by dual testing of triplicates of serum samples was acceptable, with coefficients of variation at 6.5%, 7.5%, and 10.5%. Our results showed that amplification performance was good in the case of the x-region-based design (98%). Out of 100 negative samples screened by enzyme linked immunosorbent assay and the standard RT-PCR kit, one sample was detected as positive with the in-house developed RT PCR assay, the positivity of the sample was confirmed by sequencing the amplified product, NCBI accession EU684022. CONCLUSION: This assay is reproducible showing limited inter- and intra-assay variability. We demonstrate that the results of our assay correlated well with the standard kit for the HBV viral load monitor. PMID- 21814339 TI - Escobar syndrome in three male patients of same family. AB - We describe three male individuals from a consanguineous south Indian family affected with the multiple pterygium syndrome (Escobar syndrome). Common clinical features included short stature, multiple pterygium, skeletal anomalies, and normal intelligence. The first report of this condition was made in 1902 from this same place (Pondicherry) and the disease received its present popular name Escobar syndrome in 1982. The genetic defect for this condition was identified in 2006 as mutation in the fetal acetylcholine receptor. PMID- 21814340 TI - Familial clustering of a rare syndrome. AB - Ectrodactyly, ectodermal dysplasia and cleft palate syndrome is a rare autosomal dominant multiple congenital anomaly syndrome with variable expressivity and reduced penetration. The cardinal features are cleft palate/lip, lobster hand deformity, sparse hypopigmented hair, dry scaly skin, and lacrimal and urogenital anomalies. A neonate presented to us with typical features, his mother and other two siblings were also affected. PMID- 21814342 TI - A case of short stature with anterior vertebral beaking. PMID- 21814341 TI - MCT oil-based diet reverses hypertrophic cardiomyopathy in a patient with very long chain acyl-coA dehydrogenase deficiency. AB - Very long chain acyl-CoA dehydrogenase (VLCAD) deficiency is one of the genetic defects of mitochondrial fatty acid beta-oxidation presenting in early infancy or childhood. If undiagnosed and untreated, VLCAD deficiency may be fatal, secondary to cardiac involvement. We assessed the effect of replacing part of the fat in the diet of a 2 1/2-month-old male infant, who was diagnosed with VLCAD deficiency,with medium-chain triglyceride (MCT) oil and essential fats. The patient presented with vomiting, dehydration, and was found to have persistent elevation of liver function tests, hepatomegaly, pericardial and pleural effusion, right bundle branch block, and biventricular hypertrophy. Because of the cardiomyopathy, hepatomegaly, and an abnormal acylcarnitine profile and urine organic acids, he was suspected of having VLCAD deficiency. This was confirmed on acyl-coA dehydrogenase, very long chain (ACADVL) gene analysis. He was begun on an MCT oil-based formula with added essential fatty acids, uncooked cornstarch (around 1 year of age), and frequent feeds. By 7 months of age, cardiomyopathy had reversed and by 18 months of age, all cardiac medications were discontinued and hypotonia had improved such that physical therapy was no longer required. At 5 years of age, he is at the 50(th) percentile for height and weight along with normal development. Pediatricians need to be aware about the basic pathophysiology of the disease and the rationale behind its treatment as more patients are being diagnosed because of expansion of newborn screen. The use of MCT oil as a medical intervention for treatment of VLCAD deficiency remains controversial mostly because of lack of clear phenotype-genotype correlations, secondary to the genetic heterogeneity of the mutations. Our case demonstrated the medical necessity of MCT oil-based nutritional intervention and the need for the further research for the development of specific guidelines to improve the care of these patients. PMID- 21814343 TI - Third national science symposium on HIV/AIDS: HIV Science 2010. PMID- 21814344 TI - J conserv dent - citius, altius, fortius.... PMID- 21814345 TI - Role of titanium tetrafluoride (TiF(4)) in conservative dentistry: A systematic review. AB - The role of fluoride to reduce demineralization and enhance remineralization of dental hard tissue has been well documented. Different forms of fluoride solutions have been topically used in dentistry as prophylactic agents against tooth decay. In the recent past, metal fluorides, especially titanium tetrafluoride, have become popular in the fraternity of dental research due to their unique interaction with dental hard tissue. Many studies on titanium tetrafluoride, with positive and negative conclusions, have been published in many research journals. This gives the reader a plethora of inconclusive results with one study neutralizing the outcome of other, which confuses us regarding the present status of titanium tetrafluoride in the field of dentistry. This is an endeavor to organize and present the various studies of this unique compound, to provide us with a lucid overall review of its versatile potential application in dentistry, along with its fallacy/drawbacks. We have discussed its role as a cariostatic agent, pit and fissure sealant, tooth desensitizer, against dental erosion, as a root canal irrigant and others. PMID- 21814346 TI - An in vitro evaluation of microleakage in class V preparations restored with Hybrid versus Silorane composites. AB - AIM: To compare the difference in microleakage values using conventional and new low-shrink Silorane composites using the dye penetration method. BACKGROUND: With improvement in adhesive technology, problems associated with composites have been largely overcome. However, microleakage due to polymerization shrinkage still remains a challenge. New Silorane-based composites are alleged to have less than 1% polymerization shrinkage, which would potentially decrease the microleakage, and hence, resolve this longstanding issue. MATERIALS AND METHODS: The teeth were randomly divided into three groups (A,B, and C). Group A was restored with conventional composite (Valux(TM) Plus), with a total-etch protocol, Group B was restored with conventional composite, with a self-etch protocol, and group C were restored with a silorane-based composite (Filtek TMP90). Thermocycling at 200 cycles between 5 and 55 degrees C +/- 2 degrees C with a dwell time of 60 seconds was conducted. The teeth were stained with methylene blue dye and then sectioned and viewed under a dissection microscope, afer which the microleakage was evaluated. RESULTS: The interexaminer reliability was evaluated using the kappa score, which was acceptable (61 - 78%). The total-etch group performed statistically and significantly better (P < 0.001) at the occlusal margin and was marginally and statistically significant (P = 0.05) at the gingival margin compared to the self-etch conventional and Silorane groups. CONCLUSIONS: The Silorane composite did not perform better than the conventional composites, however, it may have its uses and requires further research. PMID- 21814347 TI - Biocompatibility assessment of pastes containing Copaiba oilresin, propolis, and calcium hydroxide in the subcutaneous tissue of rats. AB - AIM: To assess the biocompatibility of two endodontic pastes based on calcium hydroxide and propolis, using two vehicles - non-fractionated Copaiba-oilresin (A) and volatile fraction of Copaiba-oilresin (B), in the connective tissue of rats. MATERIALS AND METHODS: Fifteen rats had four polyethylene tubes implanted in their backs; each pair of tubes contained one of the pastes. The tube side was considered the control. After 7, 21, and 42 days, the animals were euthanized. RESULTS: The inflammatory reaction was moderate at seven days for A and severe for B. At 21 days, it was slight for A and moderate for B; and at 42 days, it was slight for A and B. Tissue reaction ranged from slight (7 / 21 days) to no inflammation (42 days) for the control group. Statistical analysis (Kruskal Wallis test, P < 0.01) demonstrated no significant difference between the pastes and control group (P > 0.01). CONCLUSION: Both pastes presented satisfactory tissue reaction in the connective tissue of rats. PMID- 21814348 TI - An ex vivo study to evaluate the remineralizing and antimicrobial efficacy of silver diamine fluoride and glass ionomer cement type VII for their proposed use as indirect pulp capping materials - Part I. AB - AIM: Indirect pulp capping (IPC) preserves the pulp vitality by disinfecting and remineralizing remaining carious dentin. In the present study, glass ionomer (GC, FUJI VII) and silver diamine fluoride (SDF) were tested and compared to calcium hydroxide for their antimicrobial efficacy and remineralizing potential. MATERIALS AND METHODS: Dentin disks prepared from 45 freshly extracted first premolars were divided into three groups (n = 15). Each disk was cut into two equal parts, in which one half formed the control. Thirty dentin samples were used for ion estimation and the other 15 for microhardness testing. Atomic absorption spectrophotometry, colorimetric and potentiometric titration analyses were performed for calcium, phosphate and fluoride ion detection, respectively. The antimicrobial efficacy was analyzed using pure culture of Streptococcus mutans and mixed flora. RESULTS: Increase in the levels of calcium and phosphate ions was the highest in calcium hydroxide group. Both SDF and GC VII groups showed significant increase in fluoride ion levels. Samples treated with GC VII showed maximum increase in micro hardness. The highest zone of bacterial inhibition was found with SDF group. CONCLUSIONS: This in vitro study documented the remineralizing, re-hardening and antimicrobial efficacy of both SDF and GC VII and hence can act as effective IPC materials. PMID- 21814349 TI - Cutting efficiency of four different rotary nickel: Titanium instruments. AB - AIM: The aim of this study was to evaluate the cutting efficiency of rotary nickel-titanium (NiTi) instruments K3, NiTi Tee, Profile, and Quantec with taper size 04/25. MATERIALS AND METHODS: The number of samples was 10 for each group (n = 10). The cutting efficiency was measured by the mass loss from each acrylic resin block after instrumentation of a simulated canal using the Crown-down technique. RESULTS: The analysis of variance (ANOVA) showed that there was a statistically significant difference among the studied groups. The Tukey's test showed that the acrylic resin blocks prepared with instruments K3 (0.00369 +/- 0.00022), NiTi Tee (0.00368 +/- 0.00023), and Profile (0.00351 +/- 0.00026) presented the greatest mass loss, showing no statistically significant difference among them (P < 0.05). The lowest mass loss was found in the blocks prepared with Quantec instruments (0.00311 +/- 0.0003) (P < 0.05). CONCLUSIONS: It could be concluded that the K3, NiTi Tee, and Profile instruments presented a greater cutting efficiency than the Quantec instruments. PMID- 21814350 TI - "Electromyographic pattern of masticatory muscles in altered dentition" Part II. AB - AIM: The aim of this study is to show that a change in occlusal contacting pattern of tooth has definite influence over the behavior of orofacial musculature, resulting deleterious effect on it. Keeping this in view, the electromyographic (EMG) activity of temporalis and masseter muscles in rest position of mandible, maximum clenching and chewing, was studied in total 24 subjects--14 subjects with normal occlusion and rest 10 with normal occlusion and one tooth carious which was prepared to receive an inlay with high point. This high point or occlusal interference was introduced intentionally to have a change in occlusion or "altered dentition". The subjects were all male medical volunteers with average age group of 20 years. A particular variety of chewing substance - chewing gum was used in this study. No EMG activity was detected in the rest position of mandible. In maximum clenching, balanced type of activity was seen bilaterally in normal occlusion. Whereas in changed occlusion, an unbalanced type of muscle activity was seen in temporalis muscle during maximum clenching. There was an overall decrease in activity in both the muscles during maximum clenching and during chewing. This decrease in activity was statistically significant in most of the times. A non-specific pattern of muscle activity resembling spasm in skeletal muscle -- a state of "hyperactivity" was also found during chewing in presence of occlusal interference. This spasm-like activity may cause pain in the muscles of masticatory apparatus. All these abnormal types of behavior of muscle were abolished after removal of high point and establishing the previous normal occlusion. It is therefore, for the clinicians to understand the importance of establishing occlusal equilibrium in day to day practice. PMID- 21814351 TI - A comparative in vitro study of microleakage by a radioactive isotope and compressive strength of three nanofilled composite resin restorations. AB - AIM: This study compares the compressive strength and microleakage of three nanofilled composites using radioactive isotope Ca(45). MATERIALS AND METHODS: Thirty-six freshly extracted human premolars were used in this study. Standardized Class I preparation was carried out and then randomly divided into three different groups: A, B, and C with 12 teeth in each group which were restored with nanofilled composite restoration and then subjected to thermocycling. Microleakage was tested using radioactive isotope Ca(45). Kruskal Wallis and Mann-Whitney tests were used to compare the microleakage scores of the three groups. For measuring the compressive strength of three nanofilled composite resin restorations, 12 specimens of each material were prepared in customized stainless steel cylindrical moulds of 6 mm *4 mm. The compressive test was performed using the Universal Testing Machine. The values were analyzed with ANOVA and Bonferroni's test. RESULTS: The findings of this study indicate that the synergy has the least microleakage and highest compressive strength followed by the Grandio and Filtek Z-350. CONCLUSIONS: Introduction of nanocomposites (packable) appears to have improved the performance of both anterior and posterior restorations with regard to mechanical properties, marginal integrity, and esthetics. PMID- 21814352 TI - The influence of grain size coating and shaft angulation of different diamond tips on dental cutting. AB - OBJECTIVES: To evaluate the influence of the grain size coating and shaft angulation of ultrasonic and high-speed diamond burs on the dental cutting effectiveness. MATERIALS AND METHODS: For the grain size evaluation, cavities were prepared on 40 incisors using high-speed (1092 and 1093F KG Sorensen((r))) and ultrasonic tips (8.2142 and 6.2142-CVDentus((r))). For the shaft angulation evaluation, cavities were prepared on 40 incisors using uniangulated (T1 CVDentus((r))) and biangulated (T1-A CVDentus((r))) ultrasonic tips. The cavities were bisected and examined at *50 magnification. The width and depth of cavities were measured by Leica QWin software. Kruskal-Wallis non-parametric test was used for analysis. RESULTS: The grain size did not affect the cutting effectiveness, but the high-speed burs promoted deeper and wider cavities than the ultrasonic tips. The shaft angulation did not affect the cutting effectiveness; both the angulated and biangulated tips had greater cutting efficiency in dentin than in enamel. CONCLUSIONS: Ultrasonic tips promoted more conservative preparations and seemed promising for cavity preparation. PMID- 21814353 TI - The effects of halogen and light-emitting diode light curing on the depth of cure and surface microhardness of composite resins. AB - AIM: Light-emitting diode light curing units (LED LCUs) have become more popular than halogen LCUs in routine dental restorative treatment. The aim of the study was to compare the effects of two conventional halogen (Hilux Plus and VIP) and two LED (Elipar FreeLight 2 and Smart Lite) light curing units on the depth of cure and the microhardness of various esthetic restorative materials. MATERIALS AND METHODS: The curing depth and microhardness of a compomer (Dyract Extra), a resin-modified glass ionomer (Vitremer), a packable composite (Sculpt It), an ormocer (Admira), a hybrid composite (Tetric Ceram), two microhybrid composites (Miris and Clearfil Photo Posterior) and, a nanofil composite (Filtek Supreme) were determined using a scraping method and a hardness tester. A total of 320 samples were prepared using the eight different materials (n = 10 samples for each subgroup). The scraping test was based on ISO 4049:2000. Vicker's microhardness testing was carried out using hardness tester (Zwick 3212). Data were analyzed using one-way analysis of variance (ANOVA), Bonferroni and the Kolmogorov-Smirnov tests. RESULTS: Best microhardness results were obtained with the LED light curing units and Tetric EvoCeram and Filtek Supreme achieved the highest hardness values. The nanofil composite, Filtek Supreme, showed the best curing depth results in all the tested light curing systems. CONCLUSIONS: The LEDs were found to be more successful than the halogen units with respect to both curing depth and microhardness properties. PMID- 21814354 TI - Treatment of endodontically induced periapical lesions using hydroxyapatite, platelet-rich plasma, and a combination of both: An in vivo study. AB - AIM AND OBJECTIVES: To evaluate bone regeneration in endodontically induced periapical lesions using Hydroxyapatite, Platelet-Rich Plasma (PRP), and a combination of Hydroxyapatite and Platelet-Rich Plasma for a period of one year. MATERIALS AND METHODS: Twenty systemically healthy patients of both genders between the ages 20 and 40 years were included. To qualify, the patient had to have a tooth where non-surgical root canal therapy had failed, periapical radiolucency was present, and periapical root end surgery was required. The bony defect had to be confined to the apical area, with the bone covering the entire root surface coronally, with an intact lingual cortical plate. Patients were randomly divided into four groups, with five patients each, as follows: Group I - Replacement with Hydroxyapatite, Group II - Replacement with PRP, Group III - Replacement with PRP and Hydroxyapatite, and Group IV - Control group with no substitutes. The patients were evaluated both clinically and radiographically. RESULTS: The radiographic evaluation revealed that Group I patients showed complete bone regeneration with evidence of a trabecular pattern, at the end of one year, Group II patients showed complete bone regeneration at the end of nine months, Group III patients showed complete bone regeneration at the end of six months, and Group IV patients showed bone regeneration, which was not satisfactory even after one year. CONCLUSIONS: The PRP and Hydroxyapatite combination facilitated better and faster bone regeneration when compared to PRP alone. PMID- 21814356 TI - Effect of frequency and amplitude of vibration and role of a surfactant on void formation in models poured from polyvinyl siloxane impressions. AB - AIMS: To determine whether the frequency and amplitude of vibration and the use of surfactant has any effect on the formation of voids on the cast surface, poured from a polyvinyl siloxane impression material, using a mechanical model vibrator. MATERIALS AND METHODS: A total of 100 impressions of a master die were made using Reprosil, Type 1, Medium Viscosity, Regular body, and Dentsply Caulk. The test group was subdivided into a surfactant and non-surfactant group, 50 impressions each. The impressions were poured in a dental stone with a mechanical model vibrator that was set at a vibration frequency of 3000 cycles / minute (low) and 6000 cycles / minute (high) with the help of a knob. The resultant casts were examined with a Stereomicroscope (LABOMED CZM4) under *10 magnifications. RESULTS: For the low and high frequencies, when surfactant and non-surfactant groups were compared, for all the amplitudes and for both the material groups, the surfactant groups resulted in fewer void formations and showed very high statistical significance (P-value = 0.001). CONCLUSIONS: The lowest mean voids were obtained for high frequency surfactant groups. Reprosil: High frequency amplitude 2 being the most prominent, produced the least mean voids (mean = 23.2000, P = 0.001, very highly significant). In comparison, the surfactant groups produced the least voids for both frequencies. PMID- 21814355 TI - Comparative evaluation of the enamel bond strength of 'etch-and-rinse' and 'all in-one' bonding agents on cut and uncut enamel surfaces. AB - AIMS AND OBJECTIVES: To compare tensile bond strength of an 'etch-and-rinse' bonding agent (Single bond,3M ESPE, MN, USA) with an 'all-in-one' bonding agent (iBond, Heraeus Kulzer, NY, USA) on cut and uncut enamel surfaces. The null hypothesis tested is that the 'all-in-one' bonding agent matches the 'etch-and rinse' bonding agent in terms of tensile bond strength to enamel. MATERIALS AND METHODS: Forty extracted human mandibular teeth were used for the study. Twenty teeth with intact enamel surfaces were divided into two groups of 10 teeth each. The enamel surfaces of the 20 teeth were prepared and assigned to two more groups of 10 teeth each. One group each of intact and prepared enamel surfaces were used to bond with the 'etch-and-rinse' bonding agent [Single bond (SB), 3M ESPE, MN, USA] and the other two groups one each of intact and prepared enamel surfaces were used to bond with the 'all-in-one' bonding agent [ iBond (IB), Heraeus Kulzer, NY, USA]. The tensile bond strength was measured on the universal testing machine (Unitek, 9450 PC, FIE, INDIA) at a cross head speed of 1 mm / minute. RESULTS: The results were statistically analyzed using a one-way ANOVA and student 't' test. The values for the 'etch-and-rinse' bonding agent SB were significantly higher for both the cut and uncut surfaces, compared to the 'all-in one' bonding agent IB (P < 0.05). The all-in-one bonding agent resulted in a higher bond strength on the cut enamel surfaces. CONCLUSIONS: Based on the results, it is advisable to use the 'etch-and-rinse system' in a clinical situation requiring bonding on enamel alone. PMID- 21814357 TI - Influence of different organic solvents on degree of swelling of poly (dimethyl siloxane)-based sealer. AB - The study evaluated the compatibility of chloroform, ether, and xylene with poly(dimethyl siloxane) (PDMS) based sealer. Freshly mixed sealer was placed in 90 glass molds with 5 mm diameter and 2 mm thickness. All samples were stored in 75% relative humidity at 37 degrees C for 2 weeks. All the samples were divided into three groups: group A - chloroform; group B - ether, and group C - xylene and immersed in fresh solvent at room temperature. The specimens were weighed before and after immersion for each group at the end of 2, 5, and 10 min. The swelling ratio was calculated for all the groups. Intergroup comparison revealed no difference in the mean swelling ratio for 2, 5, and 10 min (P > 0.001; Tukey HSD Post Hoc). Intragroup comparison revealed significant difference in swelling ratio between 2 and 5 min for group B and group C (P < 0.001; Paired t test). Ether has the highest compatibility with PDMS-based sealer after 2 min followed by xylene after 5 min. PMID- 21814358 TI - The Effect of 4% Lignocaine gel, 5% Amiloride HCl and 10% Chlorpromazine on E.faecalis. AB - INTRODUCTION: Thorough disinfection of the root canal system is essential for the success of root canal therapy. Enterococcus faecalis is the most frequently found species in persistent/secondary intracanal infection associated endodontic treatment failure. The aim of this study was to evaluate the disinfection of dentinal tubules using 10% Chlorpromazine, 4% Lignocaine gel, 5% Amiloride hydrochloride in comparison with 2% chlorhexidine gel. MATERIALS AND METHODS: The antibacterial efficacy of the four medicaments against Enterococcus faecalis was assessed in vitro using extracted human first and second mandibular premolar teeth at the depths of 200 MUm and 400 MUm. RESULTS: The overall percentage inhibition of bacterial growth was 100% with 2% chlorhexidine gel followed by 10% chlorpromazine (88.8%), 4% lignocaine gel (76.4%) and 5% amiloride hydrochloride (71.4%). CONCLUSION: 2% chlorhexidine gel was most effective against E. faecalis followed by the newer non- antibiotic medicament 10% chlorpromazine when compared to the other medicaments tested. PMID- 21814359 TI - Comparing microleakage and layering methods of silorane-based resin composite in class V cavities using confocal microscopy: An in vitro study. AB - AIMS: This in vitro study compared the effects of different layering techniques on the microleakage of silorane-based resin composite using confocal laser scanning microscope. MATERIALS AND METHODS: Forty caries free premolars extracted for orthodontic reasons were used. A class V cavity was prepared on the buccal surface in each of the premolars, with the gingival margin of the cavity being 1 mm above cementoenamel junction. The cavities were restored with a silorane-based resin composite (Filtek(TM) P90 Silorane Low Shrink Restorative, 3M ESPE) using two different layering techniques - split incremental and oblique layering technique. All samples were subjected to 1000 thermal cycles of 5 degrees C/55 degrees C in water with a 30 second dwell time, and after the procedure, the teeth were immersed in 0.6% aqueous rhodamine dye for 48 hours. Sectioned samples were examined under a Confocal Fluorescence Imaging Microscope (Leica TCS-SP5, DM6000-CFS) at 10* magnification, and microleakage scores were analyzed statistically using paired "t" test and Mann-Whitney test. Width of interface between the tooth surface and resin composite was measured using a digital scale (Snagit digital scale). RESULTS: Microleakage was seen along the entire perimeter of restoration irrespective of the layering technique used. The microleakage score was same in both the groups. Statistical analysis of width of interface showed significant difference between the two layering techniques. The width was significantly less in split incremental technique, indicating less polymerization shrinkage. CONCLUSIONS: This in vitro study showed that the silorane-based resin composite shows microleakage irrespective of the layering technique used for class V cavities. However, this problem can be minimized significantly by using split incremental technique for restoration of class V lesions. PMID- 21814360 TI - An in vitro evaluation of the effect of deep dry cryotreatment on the cutting efficiency of three rotary nickel titanium instruments. AB - CONTEXT: Cryogenic methods have been used to increase the strength of metals. AIM: The aim of this study was to evaluate the effect of deep dry cryotherapy on the cyclic fatigue resistance of rotary nickel titanium instruments. MATERIALS AND METHODS: Twenty K3, RaCe and Hero Shaper nickel titanium instruments, size 25, 0.06 taper, were taken for this study. Ten files were untreated (control group) and 10 files were deep dry cryogenically treated. Both the untreated and cryotreated files were subjected to cyclic fatigue evaluation. Cyclic fatigue was evaluated as the number of cycles it took for fracture of the instrument within a stainless steel shaping block of specific radius and angle of curvature. STATISTICAL ANALYSIS: Mean values were compared between different study groups by using one-way analysis of variance (ANOVA) with P < 0.05 considered as the level of significance. RESULTS: The results showed a significant increase in the resistance to cyclic fatigue of deep dry cryotreated NiTi files over untreated files. CONCLUSIONS: It may thus be concluded that deep cryotherapy has improved the cyclic fatigue of NiTi rotary endodontic files. PMID- 21814361 TI - An in vitro assessment of apical microleakage in root canals obturated with gutta flow, resilon, thermafil and lateral condensation: A stereomicroscopic study. AB - AIM: The purpose of this study was to evaluate and compare the apical microleakage of Resilon to Thermafil, Gutta-flow and Cold lateral condensation using a dye penetration method. MATERIALS AND METHODS: Sixty extracted human maxillary single rooted teeth with intact roots were selected. Decoronation was followed by canal preparation upto ISO size 50. Teeth were then randomly divided into four groups for obturation. Group I - Cold lateral condensation with AH Plus, Group II - Gutta-flow with master cone, Group III- Thermafil with AH Plus, Group IV- Resilon with Self-etch epiphany. Apical microleakage was assessed by dye penetration test under stereomicroscope. RESULT: The result was analyzed statistically and showed that Resilon provides a best seal. Gutta-flow exhibited maximum microleakage. All the four groups at some level or the other exhibited some percentage of microleakage. CONCLUSIONS: None of the methods showed a fluid tight seal. PMID- 21814362 TI - Evaluation of microleakage in posterior nanocomposite restorations with adhesive liners. AB - AIMS AND OBJECTIVES: To compare the microleakage in class II nanocomposite restorations without liner, with resin-modified glass ionomer liner and flowable composite liner. MATERIALS AND METHODS: Thirty-six sound premolars extracted for orthodontic reasons were selected and randomly assigned into three groups of 12 teeth each (Group I, II and III). Class II cavities of specified dimensions were prepared with margins located in the enamel. Cavities in group I were lined with resin modified glass ionomer (GC Fuji II LC-Improved), group II were lined with flowable composite (Filtex Z350 Flowable Restorative) and no liner was placed for cavities in group III. All the teeth were restored with nanocomposite (Z 350 Universal Restorative). The teeth were immersed in 0.5% methylene blue dye, sectioned mesiodistally and observed under stereomicroscope. RESULTS: Group III showed maximum leakage compared to group I and II which was statistically significant. Microleakage was lesser in group lined with resin-modified glass ionomer as compared to flowable composite group but not statistically significant. CONCLUSIONS: Placement of liner beneath nanocomposite restoration results in significant reduction in microleakage. Both resin-modified and flowable composite liners under nanocomposite restorations result in comparable reduction of microleakage. PMID- 21814363 TI - Disinfection of dentinal tubules with two different formulations of calcium hydroxide as compared to 2% chlorhexidine: As intracanal medicaments against Enterococcus faecalis and Candida albicans: An in vitro study. AB - AIM: To evaluate the disinfection of dentinal tubules using calcium hydroxide with propylene glycol and calcium hydroxide with iodoform in silicone oil, as compared to 2% chlorhexidine gel. MATERIALS AND METHODS: The antimicrobial efficacy of the medicaments against E.faecalis and C.albicans were assessed in vitro, using a dentinal tubule model at depths of 200 MUm and 400 MUm in extracted single rooted teeth. Saline was taken as the negative control (Group I) RESULTS: All three medicaments used in this study exerted antibacterial and antifungal activity. Group II (calcium hydroxide with propylene glycol) and Group IV (2% chlorhexidine gel) had the highest antimicrobial activity and the differences between their antibacterial activities were not statistically significant. Group III (calcium hydroxide with iodoform in silicone oil) and Group IV had the highest antifungal activity and the differences between their antifungal activities were not statistically significant. The inhibition of growth at 200 MUm and 400 MUm was uniform, with no statistical difference. CONCLUSIONS: Two percent chlorhexidine gel was effective against both E.faecalis and C.albicans. Calcium hydroxide with propylene glycol was the most effective intracanal medicament along with 2% chlorhexidine against E.faecalis, whereas, calcium hydroxide with iodoform in silicone oil was the most effective intracanal medicament along with 2% chlorhexidine against C.albicans. PMID- 21814364 TI - Apical extrusion of debris and irrigant using hand and rotary systems: A comparative study. AB - AIM: To evaluate and compare the amount of debris and irrigant extruded quantitatively by using two hand and rotary nickel-titanium (Ni-Ti) instrumentation techniques. MATERIALS AND METHODS: Eighty freshly extracted mandibular premolars having similar canal length and curvature were selected and mounted in a debris collection apparatus. After each instrument change, 1 ml of distilled water was used as an irrigant and the amount of irrigant extruded was measured using the Meyers and Montgomery method. After drying, the debris was weighed using an electronic microbalance to determine its weight. STATISTICAL ANALYSIS USED: The data was analyzed statistically to determine the mean difference between the groups. The mean weight of the dry debris and irrigant within the group and between the groups was calculated by the one-way ANOVA and multiple comparison (Dunnet D) test. RESULTS: The step-back technique extruded a greater quantity of debris and irrigant in comparison to other hand and rotary Ni Ti systems. CONCLUSIONS: All instrumentation techniques extrude debris and irrigant, it is prudent on the part of the clinician to select the instrumentation technique that extrudes the least amount of debris and irrigant, to prevent a flare-up phenomena. PMID- 21814365 TI - Effect of pre-heating composite resin on gap formation at three different temperatures. AB - AIM: The study aims to evaluate and compare total gap surface area formed after restoration of class II cavities with Filtek Z350 and P60 at room temperature, 37 degrees C and 54 degrees C. MATERIALS AND METHODS: Thirty extracted maxillary and mandibular molars were taken and divided into six groups of five teeth each. Standardized class II cavities were made and were restored with Filtek Z350 and P60, both at room temperature, 37 degrees C and 54 degrees C. Group 1(a) was restored with Filtek Z350 at room temperature, Group 1(b) with Filtek Z350 at 37 degrees C and Group 1(c) with Filtek Z350 at 54 degrees C. Group 2(a) was restored with P60 at room temperature, Group 2(b) with P60 at 37 degrees C and Group 2(c) with P60 at 54 degrees C. After storing the samples in distilled water at room temperature for 48 hours, longitudinal sectioning was done to obtain tooth restoration interface. The interfaces were then examined under compound light microscope with digital output and analyzed using Image J analysis software. RESULTS: The results demonstrated better adaptation and less total gap area formation at 54 degrees C as compared to room temperature and 37 degrees C. CONCLUSIONS: Based on the results of this study, it is suggested that use of P60 is better suited for posterior restorations at 54 degrees C as compared to Filtek Z350 universal nanohybrid at room temperature. PMID- 21814366 TI - Spiral computed tomographic evaluation and endodontic management of a mandibular first molar with three distal canals. AB - The use of spiral computed tomography serves as a boon in endodontic diagnosis of complex anatomic variations. The present case demonstrates the spiral tomographic evaluation and endodontic management of a mandibular first molar with 5 canals (2 mesial and 3 distal canals), which is a very rare anatomic variant. Such anatomic variations should be taken into account in day to day endodontic practice to ensure a high degree of clinical success. PMID- 21814367 TI - Tailor-made endodontic obturator for the management of Blunderbuss canal. AB - The complex anatomy of the blunderbuss root canal often poses a major challenge to accomplish adequate obturation for a biological seal. Moreover, the roll-cone, Gutta-percha obturation technique, which is routinely practiced, also results in a mismatch and failure to configure to the canal volume in the absence of an apical barrier. Hence, an attempt has been made to tailor-make a heat polymerized polymethyl methacrylate resin as an endodontic obturator, to match the canal volume, which has been ascertained by Spiral computed tomography and mathematical integration. A one-year follow-up examination has revealed that the tooth is asymptomatic, with the repair of the lesion evident radiographically. PMID- 21814368 TI - Survival rates of porcelain laminate restoration based on different incisal preparation designs: An analysis. PMID- 21814369 TI - Vasopressin: Its current role in anesthetic practice. AB - Vasopressin or antidiuretic hormone is a potent endogenous hormone, which is responsible for regulating plasma osmolality and volume. In high concentrations, it also raises blood pressure by inducing moderate vasoconstriction. It acts as a neurotransmitter in the brain to control circadian rhythm, thermoregulation and adrenocorticotropic hormone release. The therapeutic use of vasopressin has become increasingly important in the critical care environment in the management of cranial diabetes insipidus, bleeding abnormalities, esophageal variceal hemorrhage, asystolic cardiac arrest and septic shock. After 10 years of ongoing research, vasopressin has grown to a potential component as a vasopressor agent of the anesthesiologist's armamentarium in the treatment of cardiac arrest and severe shock states. PMID- 21814370 TI - Critical illness myopathy and polyneuropathy - A challenge for physiotherapists in the intensive care units. AB - The development of critical patient related generalized neuromuscular weakness, referred to as critical illness polyneuropathy (CIP) and critical illness myopathy (CIM), is a major complication in patients admitted to intensive care units (ICU). Both CIP and CIM cause muscle weakness and paresis in critically ill patients during their ICU stay. Early mobilization or kinesiotherapy have shown muscle weakness reversion in critically ill patients providing faster return to function, reducing weaning time, and length of hospitalization. Exercises in the form of passive, active, and resisted forms have proved to improve strength and psychological well being. Clinical trials using neuromuscular electrical stimulation to increase muscle mass, muscle strength and improve blood circulation to the surrounding tissue have proved beneficial. The role of electrical stimulation is unproven as yet. Recent evidence indicates no difference between treated and untreated muscles. Future research is recommended to conduct clinical trials using neuromuscular electrical stimulation, exercises, and early mobilization as a treatment protocol in larger populations of patients in ICU. PMID- 21814371 TI - Prediction of outcome and prognosis of patients on mechanical ventilation using body mass index, SOFA score, C-Reactive protein, and serum albumin. AB - CONTEXT: Body mass index (BMI), serum albumin, and C-reactive protein (CRP) appear to be major determinants of hospitalization. AIM: To determine the predictive ability of BMI, Sequential Organ Failure Assessment (SOFA score), serum albumin, and CRP to assess the duration and outcome of mechanical ventilation (MV). MATERIALS AND METHODS: Thirty patients aged >18 years who required mechanical ventilation (MV) were enrolled for the study. They were divided into two groups; patients who improved (Group 1), patients who expired (Group 2). Group 1 was further divided into two groups: patients on MV for <5 days (Group A), and patients on MV for >5days (Group B). BMI and SOFA score were calculated, and serum albumin and CRP were estimated. RESULTS AND DISCUSSION: Out of the 30 patients, 18 patients successfully improved after MV (Group 1) and 12 patients expired (Group 2). Among the 18 patients in group 1, ten patients improved within 5 days (Group A) and 8 patients after 5 days (Group B). SOFA score and CRP were significantly increased (P value 0.0003 and 0.0001, respectively) in group 2 when compared to group 1. CRP >24.2 mg/L or SOFA score >7 at the start of MV increases the probability of mortality by factor 13.08 or 3.92, respectively The above parameters did not show any statistical difference when group A was compared to group B. CONCLUSION: Simple, economic and easily accessible markers like CRP and assessment tools of critically ill patients with SOFA score are important determinants of possible outcomes of a patient from MV. PMID- 21814372 TI - Hot climate and perioperative outcome in elderly patients. AB - BACKGROUND: It is well known that heat wave is a major cause of weather related mortality in extreme of ages. While auditing our hospital mortality record, we found higher surgical mortality in the months of summer season which inspired us to look into the impact of hot climate in elderly surgical patients. MATERIALS AND METHODS: An observational prospective cohort study was undertaken to study the impact of hot climate on elderly (age > 60 yrs) surgical patients over one year when outside temperature was more than 20 degrees C. 98 elderly patients requiring general anaesthesia for surgery were enrolled. Patients were grouped on the basis of peak outdoor temperature with a cut off value of 30 degrees C. Group I- when peak outdoor temperature ranged between 20-30 degrees C (comfortable zone) and Group II - when peak outdoor temperature ranged above 30 degrees C. To reduce the bias, inclusion and exclusion criterion were defined. Meteorological factors, patient characteristics, surgical risk factors and other related data were noted. Data was analyzed using student's't' and z-test for statistical significance. RESULTS: There were statistically significant complications and prolonged hospital stay in group II as compared to I (13.21+/-6.44 Vs 9.81+/-3.54 days, P value =0.01) on univariate analysis. High risk patients had more complications in hot weather. Stepwise multivariate regression analysis showed higher adverse impact of poor physical and cardiac status than hot climate. CONCLUSION: Hot and humid weather adversely affect the perioperative outcome in elderly surgical patients. Patients with poor reserves are at greater perioperative risk during hot and humid climate. PMID- 21814373 TI - Incidence, risk stratification, antibiogram of pathogens isolated and clinical outcome of ventilator associated pneumonia. AB - BACKGROUND: The initial empirical therapy of Ventilator Associated Pneumonia (VAP) modified based on the knowledge of local microbiological data is associated with decreased morbidity and mortality. The objective was to find the incidence and risk factors associated with VAP, the implicated pathogens and their susceptibility pattern as well as to assess the final clinical outcome in VAP. MATERIALS AND METHODS: This was a prospective cohort study of 107 patients taken on ventilatory support for two or more days and those not suffering from pneumonia prior were to be taken on ventilator. The study was done over a period of one year. VAP was diagnosed using clinical pulmonary infection score of >6. The mortality, incidence of VAP, frequency of different pathogens isolated, their antibiotic sensitivity pattern, duration of mechanical ventilation and duration of hospital stay were assessed. STATISTICAL ANALYSIS: Univariate analysis, chi(2) test and paired t-test. RESULTS: The incidence of VAP was 28.04%. Mortality in VAP group was 46.67%, while in the non-VAP group was 27.28%. High APACHE II score was associated with a high mortality rate as well as increased incidence of VAP. The most common organisms isolated from endotracheal aspirate of patients who developed VAP were Pseudomonas aeruginosa, Methicillin-resistant Staphylococcus aureus (MRSA), Klebsiella pneumoniae and Acinetobacter baumannii. Most strains of Pseudomonas (55.56%) were resistant to commonly used beta-lactam antibiotics known to be effective against Pseudomonas. All strains of Staphylococcus aureus were MRSA and most isolates of K. pneumoniae (85.71%) were extended-spectrum beta lactamase producing. About 50% isolates of Acinetobacter were resistant to carbapenems. Mortality was highest for infections caused by A. baumannii (83.33%) and K. pneumoniae (71.42%). CONCLUSIONS: APACHE II score can be used to stratify the risk of development of VAP and overall risk of mortality. Drug-resistant strains of various organisms are an important cause of VAP in our setting. PMID- 21814375 TI - Efficacy and safety of parenteral omega 3 fatty acids in ventilated patients with acute lung injury. AB - OBJECTIVE: To determine the effects of parenteral omega 3 fatty acids (10% fatty acids) on respiratory parameters and outcome in ventilated patients with acute lung injury. MEASUREMENTS AND MAIN RESULTS: Patients were randomized into two groups - one receiving standard isonitrogenous isocaloric enteral diet and the second receiving standard diet supplemented with parenteral omega 3 fatty acids (Omegaven, Fresenius Kabi) for 14 days. Patients demographics, APACHE IV, Nutritional assessment and admission category was noted at the time of admission. No significant difference was found in nutritional variables (BMI, Albumin). Compared with baseline PaO(2)/FiO(2) ratio (control vs. drug group: 199 +/- 124 vs. 145 +/- 100; P = 0.06), by days 4, 7, and 14, patients receiving the drug did not show a significant improvement in oxygenation (PaO(2)/FiO(2): 151.83 +/- 80.19 vs. 177.19 +/- 94.05; P = 0.26, 145.20 +/- 109.5 vs. 159.48 +/- 109.89; P = 0.61 and 95.97 +/- 141.72 vs. 128.97 +/- 140.35; P = 0.36). However, the change in oxygenation from baseline to day 14 was significantly better in the intervention as compared to control group (145/129 vs. 199/95; P < 0.0004). There was no significant difference in the length of ventilation (LOV) and length of ICU stay (LOS). There was no difference in survival at 28 days. Also, there was no significant difference in the length of ventilation and ICU stay in the survivors group as compared to the non survivors group. CONCLUSIONS: In ventilated patients with acute respiratory distress syndrome, intravenous Omega 3 fatty acids alone do not improve ventilation, length of ICU stay, or survival. PMID- 21814376 TI - Anasarca sparing one limb. AB - Upper extremity deep vein thrombosis commonly refers to thrombosis of the axillary and/or subclavian veins. This condition may lead to some serious complications like pulmonary embolism if the diagnosis and treatment are delayed. We introduce here one such case where the diagnosis of this rare condition was difficult because of the atypical clinical manifestation but the chylous ascites provided a valuable clue which led to early diagnosis and treatment of this patient. PMID- 21814374 TI - Serum lactate levels as the predictor of outcome in pediatric septic shock. AB - BACKGROUND AND AIMS: An association of high lactate levels with mortality has been found in adult patients with septic shock. However, there is controversial literature regarding the same in children. The aim of this study was to find the correlation of serum lactate levels in pediatric septic shock with survival. SETTINGS AND DESIGN: This was a prospective observational study at PICU of a tertiary care center of North India. MATERIALS AND METHODS: A total of 30 children admitted to PICU with diagnosis of septic shock were included in the study. PRISM III score and demographic characteristics of all children were recorded. Serum lactate levels were measured in arterial blood at 0-3, 12, and 24 h of PICU admission. The outcome (survival or death) was correlated with serum lactate levels. RESULTS: Septic shock was the most common (79.3%) type of shock and had 50% mortality. Initial as well as subsequent lactate levels were significantly higher in nonsurvivors. A lactate value of more than 45 mg/dl (5 mmol/l) at 0-3, 12, and 24 h of PICU admission had an odds ratio for death of 6.7, 12.5, and 8.6 (95% CI: 1.044-42.431, 1.850-84.442, 1.241-61.683) with a positive predictive value (PPV) of 38%, 71%, 64% and a negative predictive value (NPV) of 80%, 83%, and 83%, respectively. CONCLUSIONS: Nonsurvivors had higher blood lactate levels at admission as well as at 12 and 24 h. A lactate value of more than 45 mg/dl (5 mmol/l) was a good predictor of death. PMID- 21814377 TI - Unusual complication of aluminum phosphide poisoning: Development of hemolysis and methemoglobinemia and its successful treatment. AB - Methemoglobinemia and hemolysis are rare findings following phosphine poisoning. In this paper, a case of aluminum phosphide (AlP) poisoning complicated by methemoglobinemia and hemolysis with a successful treatment is reported. A 28 year-old male patient presented following intentional ingestion of an AlP tablet. In this case, hematuria, hemolysis and methemoglobinemia were significant events. A methemoglobin level of 46% was detected by CO-oximetry. The patient was treated with ascorbic acid and methylene blue and he also received supportive care. Two weeks after admission, the patient was discharged from the hospital. Hemolysis and methemoglobinemia may complicate the course of phosphine poisoning. PMID- 21814378 TI - Effectiveness of hemodialysis in a case of severe valproate overdose. AB - A case of severe sodium valproate overdose is presented in which medicinal management failed to reverse coma of the patient. High-flux hemodialysis was then used to eliminate sodium valproate. This case demonstrated the effectiveness of hemodialysis in not only decreasing valproate levels very rapidly but also as an effective anti-coma management. PMID- 21814379 TI - Carbamzepine-induced toxic epidermal necrolysis. AB - Toxic epidermal necrolysis (TEN), also known as Lyell's syndrome, is a widespread life-threatening mucocutaneous disease where there is extensive detachment of the skin and mucous membrane. Many factors involved in the etiology of TEN including adverse drug reactions. Here we are reporting a case of toxic epidermal necrolysis in an adult male patient after receiving carbamazepine in a 38 year old male. On the 18(th) day of carbamazepine, patient developed blisters which first appeared on the trunk, chest and arms. The erythematous rash was covering almost all over the body with epidermal detachment of 70% body surface area. There was loss of eye lashes, congestion of conjunctiva with mucopurulent discharge and exposure keratitis. The clinical impression was TEN induced by carbamazepine. Carbamazepine was stopped immediately. He was treated with high dose intravenous betamethasone and systemic and topical antibiotics. After one month, the progression of the skin lesions halted and he was discharged. PMID- 21814380 TI - Life-threatening postpartum hemolysis, elevated liver functions tests, low platelets syndrome versus thrombocytopenic purpura - Therapeutic plasma exchange is the answer. AB - The differential diagnosis of life-threatening microangiopathic disorders in a postpartum female includes severe preeclampsia-eclampsia, hemolysis, elevated liver functions tests, low platelets syndrome and thrombotic thrombocytopenic purpura. There is considerable overlapping in the clinical and laboratory findings between these conditions, and hence an exact diagnosis may not be always possible. However, there is considerable maternal mortality and morbidity associated with these disorders. This case underlines the complexity of pregnancy related microangiopathies regarding their differential diagnosis, multiple organ dysfunction and role of therapeutic plasma exchange in their management. PMID- 21814381 TI - An unusual case of Weil's syndrome with paraparesis. AB - Leptospirosis is an important emerging zoonosis with a worldwide distribution that is characterized by a broad spectrum of clinical manifestations ranging from inapparent infection to fulminant disease. Leptospirosis has protean clinical manifestations. The classical presentation of the disease is an acute biphasic febrile illness with or without jaundice. Unusual clinical manifestations may result from involvement of pulmonary, cardiovascular, neural, gastrointestinal, ocular and other systems. Immunological phenomena secondary to antigenic mimicry may also be an important component of many clinical features and may be responsible for reactive arthritis. The presentation of paraparesis in combination with Weil's syndrome is rare. Few cases were reported with leptospirosis and paraparesis in India and abroad. It is important to bear in mind that leptospiral illness may be a significant component in cases of dual infections or in simultaneous infections with more than two pathogens. Here we are reporting a case of Weil's syndrome with paraparesis in 28-year-old male patient who was critically ill due to severe hepatorenal dysfunction and hyperkalemia. PMID- 21814382 TI - Intramural hematoma of duodenum: An unusual complication after endoscopic therapy for a bleeding peptic ulcer. AB - Intramural hematoma of duodenum (IDH) is a relatively unusual complication associated with endoscopic treatment of bleeding peptic ulcer. This unusual condition is usually seen in children following blunt trauma to the abdomen. We describe here a case of IDH occurring following endoscopic therapy for bleeding duodenal ulcer in an adult patient with end-stage renal disease. The hematomas appeared on the second day of endoscopic intervention, caused transient duodenal obstruction and resolved spontaneously with conservative treatment in a week. PMID- 21814383 TI - Difficulties with neurological prognostication in a young woman with delayed onset generalised status myoclonus after cardiac arrest due to acute severe asthma. AB - Neurological prognostication in cardiac arrest survivors is difficult, especially when the primary etiology is respiratory arrest. Prognostic factors designed to have zero false-positive rates to robustly confirm poor outcome are usually inadequate to rule out poor outcomes (i.e., high specificity and low sensitivity). One of the least understood prognosticators is generalised status myoclonus (GSM), with case reports confusing GSM, isolated myoclonic jerks and post-hypoxic intention myoclonus (Lance Adams syndrome [LAS]). With several prognostic indicators (including status myoclonus) having been validated in the pre-hypothermia era, their current relevance is debatable. New modalities such as brain magnetic resonance imaging (MRI) and continuous electroencephalography are being evaluated. We describe here a pregnant woman resuscitated from a cardiac arrest due to acute severe asthma, and an inability to reach a consensus based on published guidelines, with a brief overview of myoclonus, LAS and the role of MRI brain in assisting prognostication. PMID- 21814384 TI - A dangerous clinical practice3. PMID- 21814385 TI - Alveolar recruitment maneuvers in ventilated children: Caution required. PMID- 21814386 TI - Authors' reply. PMID- 21814387 TI - Contralateral hyperinflation: Computed tomography demonstration of an unusual complication of unrecognized endobronchial intubation. PMID- 21814388 TI - 3-base periodicity in coding DNA is affected by intercodon dinucleotides. AB - All coding DNAs exhibit 3-base periodicity (TBP), which may be defined as the tendency of nucleotides and higher order n-tuples, e.g. trinucleotides (triplets), to be preferentially spaced by 3, 6, 9 etc, bases, and we have proposed an association between TBP and clustering of same-phase triplets. We here investigated if TBP was affected by intercodon dinucleotide tendencies and whether clustering of same-phase triplets was involved. Under constant protein sequence intercodon dinucleotide frequencies depend on the distribution of synonymous codons. So, possible effects were revealed by randomly exchanging synonymous codons without altering protein sequences to subsequently document changes in TBP via frequency distribution of distances (FDD) of DNA triplets. A tripartite positive correlation was found between intercodon dinucleotide frequencies, clustering of same-phase triplets and TBP. So, intercodon C|A (where "|" indicates the boundary between codons) was more frequent in native human DNA than in the codon-shuffled sequences; higher C|A frequency occurred along with more frequent clustering of C|AN triplets (where N jointly represents A, C, G and T) and with intense CAN TBP. The opposite was found for C|G, which was less frequent in native than in shuffled sequences; lower C|G frequency occurred together with reduced clustering of C|GN triplets and with less intense CGN TBP. We hence propose that intercodon dinucleotides affect TBP via same-phase triplet clustering. A possible biological relevance of our findings is briefly discussed. PMID- 21814389 TI - Molecular docking studies of 1-(substituted phenyl)-3-(naphtha [1, 2-d] thiazol-2 yl) urea/thiourea derivatives with human adenosine A(2A) receptor. AB - Computational assessment of the binding interactions of drugs is an important component of computer-aided drug design paradigms. In this perspective, a set of 30 1-(substituted phenyl)-3-(naphtha[1, 2-d] thiazol-2-yl) urea/thiourea derivatives showing antiparkinsonian activity were docked into inhibitor binding cavity of human adenosine A(2A) receptor (AA2AR) to understand their mode of binding interactions in silico. Lamarckian genetic algorithm methodology was employed for docking simulations using AutoDock 4.2 program. The results signify that the molecular docking approach is reliable and produces a good correlation coefficient (r(2) = 0.483) between docking score and antiparkinsonian activity (in terms of % reduction in catalepsy score). Potent antiparkinsonian agents carried methoxy group in the phenyl ring, exhibited both hydrophilic and lipophilic interactions with lower energy of binding at the AA(2A)R. These molecular docking analyses should, in our view, contribute for further development of selective AA(2A)R antagonists for the treatment of Parkinson's disease. PMID- 21814390 TI - Structure-Activity relationship in mutated pyrazinamidases from Mycobacterium tuberculosis. AB - The pncA gene codes the pyrazinamidase of Mycobacterium tuberculosis, which converts pyrazinamide to ammonia and pyrazinoic-acid, the active antituberculous compound. Pyrazinamidase mutations are associated to pyrazinamide-resistant phenotype, however how mutations affect the structure of the pyrazinamidase, and how structural changes affect the enzymatic function and the level of pyrazinamide-resistance is unknown. The structures of mutated pyrazinamidases from twelve Mycobacterium tuberculosis strains and the pyrazinamide-susceptible H37Rv reference strain were modelled using homology modelling and single amino acid replacement. Physical-chemical and structural parameters of each pyrazinamidase were calculated. These parameters were: The change of electrical charge of the mutated amino acid, the change of volume of the mutated amino acid, the change of a special amino acid, the distance of the mutated amino acid to the active site, the distance of the mutated amino acid to the metal-coordination site, and the orientation of the side-chain of the mutated amino acid. The variability of the enzymatic activity of the recombinant pyrazinamidases, and the microbiological susceptibility to pyrazinamide determined by BACTEC 460TB, were modelled in multiple linear regressions. Physical-chemical and structural parameters of the mutated pyrazinamidases were tested as predictors. Structural and physical-chemical variations of the pyrazinamidase explained 75% of the variability of the enzymatic activity, 87% of the variability of the kinetic constant and 40% of the variability of the pyrazinamide-resistance level. Based on computer models of mutated pyrazinamidases, the structural parameters explained a high variability of the enzymatic function, and to a lesser extent the resistance level. PMID- 21814391 TI - Selection of predicted siRNA as potential antiviral therapeutic agent against influenza virus. AB - Influenza virus A (IVA) infection is responsible for recent death worldwide. Hence, there is a need to develop therapeutic agents against the virus. We describe the prediction of short interfering RNA (siRNA) as potential therapeutic molecules for the HA (Haemagglutinin) and NA (Neuraminidase) genes. We screened 90,522 siRNA candidates for HA and 13,576 for NA and selected 1006 and 1307 candidates for HA and NA, respectively based on the proportion of viral sequences that are targeted by the corresponding siRNA, with complete matches. Further short listing to select siRNA with no off-target hits, fulfilling all the guidelines mentioned in approach, provided us 13 siRNAs for haemagglutinin and 13 siRNAs for neuraminidase. The approach of finding siRNA using multiple sequence alignments of amino acid sequences has led to the identification of five conserved amino acid sequences, three in hemagglutinin i.e. RGLFGAIAGFIE, YNAELLV and AIAGFIE and two in neuraminidase i.e. RTQSEC and EECSYP which on reveres translation provided siRNA sequences as potential therapeutic candidates. The approaches used during this study have enabled us to identify potentially therapeutic siRNAs against divergent IVA strains. PMID- 21814392 TI - A rapid protein structure alignment algorithm based on a text modeling technique. AB - Structural alignment of proteins is widely used in various fields of structural biology. In order to further improve the quality of alignment, we describe an algorithm for structural alignment based on text modelling techniques. The technique firstly superimposes secondary structure elements of two proteins and then, models the 3D-structure of the protein in a sequence of alphabets. These sequences are utilized by a step-by-step sequence alignment procedure to align two protein structures. A benchmark test was organized on a set of 200 non homologous proteins to evaluate the program and compare it to state of the art programs, e.g. CE, SAL, TM-align and 3D-BLAST. On average, the results of all against-all structure comparison by the program have a competitive accuracy with CE and TM-align where the algorithm has a high running speed like 3D-BLAST. PMID- 21814393 TI - Analysis of distribution and significance of simple sequence repeats in enteric bacteria Shigella dysenteriae SD197. AB - We have explored the possible role of SSR density in genome to generate biological information. In our study, we have checked the SSR (simple sequence repeats) status in virulent and non virulent genes of enteric bacteria to see whether the SSRs distribution contributes to virulence. The genome, plasmid and virulent genes sequences in fasta format were downloaded from NCBI GenBank and VFDB. The sequences were subjected to SSR analysis using software tool ssr.exe. The resulting data was pasted in excel sheet and further analyzed for percentage of each type of SSR. Higher nucleotide repeats have been observed in our study. Overall high density of SSRs can enhance antigenic variance of the pathogen population in a strategy that counteracts the host immune response. Frequency of A and T repeats is higher in the chromosome, plasmid and the virulence genes. However, in dinucleotide repeats the frequencies of GC/CG repeats are higher in genome, whereas plasmid has more of AT/TA repeats. Genome has trinucleotide repeats having predominantly G and C whereas plasmid has trinucleotide repeats having predominantly A and T. The repeat number obtained and percentage of repeats is higher in virulence genes as compared to other gene families. Due to the presence of this large number of SSRs, the organism has an enormous potential for generating this genomic and phenotypic diversity. PMID- 21814394 TI - Computational analysis reveals abundance of potential glycoproteins in Archaea, Bacteria and Eukarya. AB - Glycosylation is the most common type of post-translational modification (PTM) and is known to affect protein stability, folding and activity. Inactivity of enzymes mediating glycosylation can result in serious disorders including colon cancer and brain disorders. Out of five main types of glycosylation, N-linked glycosylation is most abundant and characterized by the addition of a sugar group to an Asparagine residue at the N-X-S/T motif. Enzyme mediating such transfer is known as oligosaccharyl transferase (OST). It has been hypothesized before that a significant number of proteins serve as glycoproteins. In this study, we used programming implementations of Python to statistically quantify the representation of glycoproteins by scanning all the available proteome sequence data at ExPASy server for the presence of glycoproteins and also the enzyme which plays critical role in glycosylation i.e. OST. Our results suggest that more than 50% of the proteins carry N-X-S/T motif i.e. they could be potential glycoproteins. Furthermore, approximately 28-36% (1/3) of proteins possesses signature motifs which are characteristic features of enzyme OST. Quantifying this bias individually reveals that both the number of proteins tagged with N-X S/T motif and the average number of motifs per protein is significantly higher in case of eukaryotes when compared to prokaryotes. In the light of these results we conclude that there is a significant bias in the representation of glycoproteins in the proteomes of all species and is manifested substantially in eukaryotes and claim for glycosylation to be the most common and ubiquitous PTM in cells, especially in eukaryotes. PMID- 21814395 TI - Identification of membrane associated drug targets in Borrelia burgdorferi ZS7- subtractive genomics approach. AB - Lyme disease is an infectious disease caused by a spirochete Borrelia burgdorferi ZS7. This spirochete is most often spread by ticks. Single antibiotic therapy is sufficient for containment of the early stage progression of the disease but combinational therapy is more preferred in later stages. Research is in progress for the development of drugs against the pathogen, but till date no vaccines have been developed to effect the late stage infections. There is a rapid rise in the cases of antibiotic-resistant population which is more than 10% of the total infected individuals. In such condition vaccine becomes the sole alternative for prevention. Therefore effective treatment includes antibiotic combination and combination of antigenic surfaces (for vaccine preparation). Thus, a comprehensive list of drug targets unique to the microorganisms is often necessary. Availability of Borrelia burgdorferi ZS7 proteome has enabled insilico analysis of protein sequences for the identification of drug targets and vaccine targets. In this study, 272 essential proteins were identified out of which 42 proteins were unique to the microorganism. The study identified 15 membrane localized drug targets. Amongst these 15, molecular modeling and structure validation of the five membrane localized drug target proteins could only be achieved because of the low sequence identity of the remaining proteins with RCSB structures. These 3D structures can be further characterized by invitro and invivo studies for the development of novel vaccine epitopes and novel antibiotic therapy against Borrelia burgdorferi. PMID- 21814396 TI - Survey and characterization of NBS-LRR (R) genes in Curcuma longa transcriptome. AB - Resistance genes are among the most important gene classes for plant breeding purposes being responsible for activation of plant defense mechanisms. Among them, the nucleotide binding site-leucine rich repeat (NBS-LRR) class R-genes are the most abundant and actively found in all types of plants. Insilico characterization of EST database resulted in the detection of 28 NBS types R-gene sequences in Curcuma longa. All the 28 sequences represented the NB-ARC domain, 21 of which were found to have highly conserved motif characteristics and categorized as regular NBS genes. The Open Reading Frames varied from 361 (CL.CON.3566) to 112 (CL.CON.1267) with an average of 279 amino acids. Most alignment occurred with monocots (67.8%) with emphasis on Oryza sativa and Zingiber sequences. All best alignments with dicots occurred with Arabidopsis thaliana, Populus trichocarpa and Medicago sativa. These detected NBS type Rgenes from Curcuma longa can be used as a valuable resource for molecular marker development, molecular mapping of R-genes, and identification of resistance gene analogs and functional and evolutionary characterization of NBS-LRR-encoding resistance genes in asexually reproducing plants. PMID- 21814397 TI - Sequence trademarks in oncogene associated microRNAs. AB - The last decade was taken by storm when the existence of a class of small (~22nt long) non - coding RNA species, known as microRNAs (miRNAs) came into light. MicroRNAs are one of the most abundant groups of regulatory genes in multicellular organisms and play fundamental roles in many cellular processes. Among these, miRNAs have been shown to prevent cell division and drive terminal differentiation, thus playing a causal role in the generation or maintenance of cancerous tumours. The unique expression profiles of different miRNAs in various types and stages of cancer suggest their performance as novel biomarkers. This discussion focuses on miRNAs implicated in cancer-associated events and strives to re-establish their sequential features which may classify them to be oncogenic. PMID- 21814399 TI - Delayed serum calcium biochemical response to successful parathyroidectomy in primary hyperparathyroidism. AB - BACKGROUND: Parathyroidectomy is considered the standard treatment for primary hyperparathyroidism, however, though the onset of biochemical response is variable and is different from one patient to the other. AIM: To evaluate the onset of systemic response and the biochemical normalization of serum calcium levels to a successful surgery. PATIENTS AND METHODS: In a retrospective fashion, we collected clinical data from 303 patients admitted to our hospital between 2005 and 2008, with a diagnosis of primary hyperparathyroidism after sestamibi localization. The pathology reports, parathyroidectomy results, the preoperative and postoperative parathormone (PTH) and serum calcium levels were reviewed. Response of each patient to the surgery was studied and all the data were analyzed to determine how fast the serum calcium levels drop. RESULTS: The majority of patients (72.9%, 221/303) showed a decrease in their serum calcium levels to normal values within 48 h. While in 40 patients it took 72 hours and 42 patients (13.8%) had a delayed normalization for more than 72 h. The pathology in the PH group was predominantly of a single adenoma 80.9% vs.19.1 with hyperplasia with a P of 0.03. Preoperative parathyroid hormone PTH elevation was not significantly deferent between the two groups (PH and EN) with a mean of 7.9+/ 5.36 vs. 7.41+/-14.5 pmol/L respectively with a P of 0.43. CONCLUSION: The majority of patients with primary hyperparathyroidism (PHP) respond to parathyroidectomy in the form of normalization of their serum calcium levels and PTH within 48 h; however, a certain group of patients will need more than 3 days. PMID- 21814398 TI - Endometriosis - morphology, clinical presentations and molecular pathology. AB - Endometriosis is found predominantly in women of childbearing age. The prevalence of endometriosis is difficult to determine accurately. Laparoscopy or surgery is required for the definitive diagnosis. The most common symptoms are dysmenorrhea, dyspareunia, and low back pain that worsen during menses. Endometriosis occurring shortly after menarche has been frequently reported. Endometriosis has been described in a few cases at the umbilicus, even without prior history of abdominal surgery. It has been described in various atypical sites such as the fallopian tubes, bowel, liver, thorax, and even in the extremities. The most commonly affected areas in decreasing order of frequency in the gastrointestinal tract are the recto-sigmoid colon, appendix, cecum, and distal ileum. The prevalence of appendiceal endometriosis is 2.8%. Malignant transformation is a well-described, although rare (<1% of cases), complication of endometriosis. Approximately 75% of these tumors arise from endometriosis of the ovary. Other less common sites include the rectovaginal septum, rectum, and sigmoid colon. Unopposed estrogens therapy may play a role in the development of such tumors. A more recent survey of 27 malignancies associated with endometriosis found that 17 (62%) were in the ovary, 3 (11%) in the vagina, 2 (7%) each in the fallopian tube or mesosalpinx, pelvic sidewall, and colon, and 1 (4%) in the parametrium. Two cases of cerebral endometriosis and a case of endometriosis presenting as a cystic mass in the cerebellar vermis has been described. Treatment for endometriosis can be expectant, medical, or surgical depending on the severity of symptoms and the patient's desire to maintain or restore fertility. PMID- 21814400 TI - Metallo-beta-lactamase Producing Pseudomonas aeruginosa in Neonatal Septicemia. AB - Gram-negative bacilli are important agents causing neonatal sepsis. The organisms isolated are often resistant to multiple antimicrobials specially which are metallo-beta-lactamases (MbetaL) producers. Therefore, the present study was conducted with the objective to examine the incidence of MbetaL producing strains in multidrug resistant (MDR) Pseudomonas aeruginosa from cases of neonatal sepsis. Between January-December 2006, 1994 cases of neonatal sepsis were investigated. The isolates obtained were identified and tested for susceptibility to various antimicrobial agents. The multidrug resistant P. aeruginosa isolates were screened for the presence of MbetaL by imipenem-EDTA disc method. Five hundred and ninety three (29.73%) isolates were obtained from culture of neonates. Most frequent offender was P. aeruginosa (48.2%). There was an overall predominance of gram-negative organisms. MbetaL production was seen in 69.5% of imipenem-resistant P. aeruginosa isolates. MbetaL producing P. aeruginosa is an emerging threat in neonatal septicemia and a cause of concern for physicians treating such infections. PMID- 21814401 TI - Clinical patterns and hematological spectrum in autoimmune hemolytic anemia. AB - BACKGROUND: Autoimmune hemolytic anemia (AIHA) results from red cell destruction due to circulating autoantibodies against red cell membrane antigens. They are classified etiologically into primary and secondary AIHAs. A positive direct antiglobulin test (DAT) is the hallmark of diagnosis for AIHA. METHODS AND RESULTS: One hundred and seventy-five AIHA cases diagnosed based on positive DAT were included in the study. The cases showed a female predilection (M: F = 1:2.2) and a peak incidence in the third decade. Forty cases were found to be due to primary AIHA, while a majority (n = 135) had AIHA secondary to other causes. The primary AIHA cases had severe anemia at presentation (65%) and more often showed a blood picture indicative of hemolysis (48%). Forty-five percent of primary AIHAs showed positivity for both DAT and indirect antiglobulin test (IAT). Connective tissue disorders were the most common associated etiology in secondary AIH A0 (n = 63). CONCLUSION: AIHAs have a female predilection and commonly present with symptoms of anemia. AIHA secondary to other diseases (especially connective tissue disorders) is more common. Primary AIHAs presented with severe anemia and laboratory evidence of marked hemolysis. PMID- 21814402 TI - Laboratory diagnosis of tuberculous meningitis - is there a scope for further improvement? AB - AIMS: Tuberculous meningitis (TBM) still remains a diagnostic challenge because of inconsistent clinical presentation and lack of rapid, sensitive and specific tests. This study was carried out to diagnose TBM by a combination of direct microscopy on Ziehl-Neelsen (ZN) staining, culture by conventional Lowenstein Jensen (LJ) media and Bactec MGIT 960 system in clinically suspected cases, supported by laboratory parameters. MATERIALS AND METHODS: A total of 164 cerebrospinal fluid (CSF) samples from suspected cases of TBM were processed for direct acid fast bacilli (AFB) smear examination, and culture on Bactec MGIT 960 and LJ media. RESULTS: AFB were detected on direct smears in 13 of 164 (7.9%) specimens and Mycobacterium tuberculosis was isolated by at least one of the culture methods from 49 (29.8%) CSF samples of which 45 (27.4%) were detected positive for M. tuberculosis by MGIT 960 culture and 18 (10.9%) by culture on LJ medium. The mean time of detection in MGIT and LJ media for M. tuberculosis were 18 and 38 days, respectively. CONCLUSIONS: A combination of laboratory parameters like smear microscopy, conventional culture and automated method like Bactec MGIT increases the sensitivity of diagnosing TBM as compared to any single method. PMID- 21814403 TI - Lipid profile of type 2 diabetic and hypertensive patients in the jamaican population. AB - AIMS: Previous studies have shown that diabetes mellitus (DM) increases the risk of cardiovascular diseases in females to a greater extent than in males. In this cross-sectional study, we evaluated the lipid profiles of type 2 diabetic males and females. MATERIALS AND METHODS: The study included 107 type 2 diabetic patients (41 males and 66 females), and 122 hypertensive type 2 diabetic patients (39 males and 83 females), aged 15 years and older. Total cholesterol (TC), triglycerides (TG), low density lipoprotein-cholesterol (LDL-C), very low density lipoprotein-cholesterol (VLDL-C) and high density lipoprotein-cholesterol (HDL-C) concentrations were assayed for each group using standard biochemical methods. RESULTS: The mean TC, TG, VLDL-C, HDL-C and LDL-C concentrations, TG/HDL and LDL/HDL ratios were higher in type 2 diabetic and hypertensive type 2 diabetic patients compared with non-diabetic, and hypertensive non-diabetic control subjects, although these were not significant (P > 0.05). Hypertensive type 2 diabetic females had significantly higher serum TC (7.42 +/- 1.63 mmol/L) than hypertensive non-diabetic males (5.76+/-1.57 mmol/L; P < 0.05). All the other lipid and lipoprotein parameters except HDL-C were non-significantly higher in females with type 2 DM and those with hypertension and type 2 DM, compared with type 2 diabetic and hypertensive type 2 diabetic males, respectively (P > 0.05). CONCLUSION: This study demonstrated that dyslipidemia exists in our type 2 diabetic population with greater TC in hypertensive type 2 diabetic females compared with hypertensive type 2 diabetic males. This suggests that hypertensive type 2 diabetic females are exposed more profoundly to risk factors including atherogenic dyslipidemia compared with males. PMID- 21814404 TI - Detection of Human Papillomavirus in Cervical Gradings by Immunohistochemistry and Typing of HPV 16 and 18 in High-Grades by Polymerase Chain Reaction. AB - BACKGROUND: Cervical cancer has a major impact on developing countries, where screening programs are not well established or effective. AIM: This study aims to investigate Human papillomavirus (HPV) 6, 11 and 18 expression in cervical biopsies by immunohistochemistry, (IHC) followed by typing of high-risk HPV 16 and 18 in high-grades by polymerase chain reaction (PCR). SETTINGS AND DESIGN: During the study period of six months, 30 biopsy samples were obtained from patients attending various gynecology clinics in and around Trichy District, Tamil Nadu, between January and June 2009. MATERIALS AND METHODS: The ecto- and endoscopic biopsy specimens of the cervix were fixed in 10% buffered formalin; routine paraffin sections were taken for processing and stained with hematoxylin and eosin. The samples were graded as Normal cervicitis, Cervical intraepithelial neoplasia (CIN) I, II, III, and squamous cell carcinoma (SCC), for original diagnosis by pathologists. The extra sections were studied for the expression of HPV 6, 11 and 18 by immunohistochemistry and HPV DNA 16 and18 by PCR. RESULTS: Out of thirty samples, 15 expressed positive and 15 negative for HPV marker. Twenty-seven cases of cervical gradings have been categorized into high grade CIN II/III, SCC (23) and low grade CIN I (4). The high grades were subjected to PCR for high-risk typing. The results revealed that 15 cases were positive for HPV genotype 16 and eight cases for HPV genotype 18. The prevalence of HPV infection was found to be higher in women aged between 50 and 59. CONCLUSION: This study reveals a significant detection of HPV in the South Indian suspected individuals, by the use of advanced techniques such as IHC and PCR. PMID- 21814405 TI - Fusarium solani: An Emerging Fungus in Chronic Diabetic Ulcer. AB - Fusarium species, a mold which causes disease mainly in plants has emerged as pathogen in immunocompromised patients. Fusarium is known to cause keratitis, onychomycosis, and endophthalmitis. Fusarium solani, is the most common isolate from clinical specimen. Here is a case, a 65-year-old male with type II diabetes mellitus since 10 years presented with a large ulcer on the left leg since 8 months following trauma. The fungal culture of the escar of the ulcer isolated a mold, Fusarium solani. The patient's leg was amputated and was treated with amphotericin B. The patient was discharged on healing of the stump. This case gives emphasis on fungal culture in chronic diabetic ulcer. PMID- 21814406 TI - Chryseomonas luteola from Bile Culture in an Adult Male with Severe Jaundice. AB - A 60-year-old male was admitted in this hospital with severe jaundice, who had open cholecystectomy done 2 months ago. ERCP was performed and bile was sent for culture. It grew Chryseomonas luteola in pure culture. He underwent hepaticojejunostomy after 1 month. Total bilirubin improved gradually. His condition was stable on discharge. Prompt diagnosis of non-fermenters is required, as some of them are resistant to multiple antibiotics. Clinicians have to be made aware of the pathogenic role of C. luteola and its resistance to ampicillin and cephalosporins. PMID- 21814407 TI - Myeloperoxidase-antineutrophil Cytoplasmic Antibodies with Cytoplasmic Fluorescence Pattern. AB - We report here two rare cases of myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA)-positive Wegener's granulomatosis (limited variant) which deceptively produced a cytoplasmic (C-ANCA) pattern on indirect immunofluorescence. PMID- 21814408 TI - Disseminated cutaneous rhinosporidiosis. AB - Rhinosporidiosis is a granulomatous disorder caused by Rhinosporidium seeberi. It frequently involves the nasopharynx and occasionally affects the skin. We hereby report a case of 46-year-old male who presented with multiple cutaneous plaque like lesions with nasal obstruction. On examination, multiple cutaneous lesions were found to be present on malar aspect, infraorbital and supraorbital region, right shoulder and over the back near the tip of scapula. Oral cavity revealed a polypoidal lesion, in the base of the tongue. Excision biopsy confirmed the lesions as disseminated cutaneous rhinosporidiosis. The patient was treated with excision and dapsone therapy. After 1 year of therapy, the patient has disease free survival. We report this rare case of rhinosporidiosis with disseminated cutaneous involvement. PMID- 21814409 TI - Chromoblastomycosis due to Cladosporium carrionii. AB - An 81-year-old male presented with irregular verrucous growth of 6 years duration over the right leg. KOH preparation of the scrapings and histopathology of the lesion showed "sclerotic" bodies diagnostic of chromoblastomycosis. Culture on Sabouraud's dextrose agar yielded Cladosporium carrionii. PMID- 21814410 TI - Steroids: a promising drug for abdominal tuberculosis? PMID- 21814411 TI - Editorial preface to the second issue of 2011. PMID- 21814412 TI - The role of endogenous aryl hydrocarbon receptor signaling in cardiovascular physiology. AB - The aryl hydrocarbon receptor (AHR) is an orphan nuclear receptor with a primary function of mediating xenobiotic metabolism through transcriptional activation of Phase I and Phase II drug-metabolizing enzymes. Although no high-affinity physiological activators of AHR have been discovered, the endogenous signaling of the AHR pathway is believed to play an important role in the development and function of the cardiovascular system, based on the observations on ahr gene deficient mice. The AHR knockout mice develop cardiac hypertrophy, abnormal vascular structure in multiple organs and altered blood pressure depending on their host environment. In this review, the endogenous role of AHR in cardiovascular physiology, including heart function, vascular development and blood pressure regulation has been summarized and discussed. PMID- 21814414 TI - Effects of right ventricular septal versus apical pacing on plasma natriuretic peptide levels. AB - BACKGROUND: To investigate the contribution of right ventricular (RV) pacing sites to the cardiac function, this study compares plasma B-type natriuretic peptide (BNP) levels during RV septal and apical pacing in patients implanted with a pacemaker. MATERIALS AND METHODS AND RESULTS: Seventy-four consecutive patients with indication for permanent pacing were included. To provide for the possibility of appropriate subgroup analyses, patients were stratified according to their pacing mode into two groups: Those with dual chamber DDD(R)/VDD pacemakers (41 patients, mean age 54.1+/-18.4 years), and those with single chamber VVI pacemakers (33 patients, mean age 60.6+/-18.4 years). A prospective single-blinded randomized design was used. Randomization (1:1 way) was between lead placement on the RV septum or RV apex and occurred during the implant in both groups. Compared to baseline, a significant decrease in BNP (429.8+/-103 pg/ml and 291.7+/-138 pg/ml, respectively) levels was observed during DDD(R) /VDD pacing after two months. In contrast, during VVI (R) pacing, a significant increase in BNP levels was observed (657.5+/-104 pg/ml and 889.5+/-139 pg/ml, respectively). To determine the impact of pacing sites on cardiac function, we assessed the changes in BNP levels in each group separately. Despite the significant difference in the pattern of changes between the two groups (P < 0.02), no significant changes were observed within groups regarding the acute effect of the pacing site (RV apex vs. RV septal) on BNP levels (P=NS). CONCLUSIONS: Our main result showed no significant differences between pacing sites and concluded that hemodynamic improvement could be substantially influenced by pacing mode, more than by pacing site. PMID- 21814415 TI - Habitual short sleep duration and circulating endothelial progenitor cells. AB - Chronic short sleep duration has been linked to endothelial dysfunction and increased risk of cardiovascular disease. Circulating endothelial progenitor cells (EPCs) are vital to endogenous vascular repair processes and cardiovascular health. We tested the hypothesis that habitual short sleep duration is associated with impairment in EPC number and function. Cells with phenotypic EPC characteristics were isolated from 37 healthy, sedentary adults: 20 with normal sleep duration (13M/7F; age: 59+/-1 years; sleep duration: 7.7+/-0.1 h/night) and 17 with short sleep duration (9M/8F; 56+/-2 years; 6.0+/-0.2 h/night). EPC number was assessed by flow cytometric analysis of the percentage of peripheral blood mononuclear cells negative for CD45 and positive for CD34, VEGFR-2, and CD133 antigens. EPC colony-forming capacity was determined by colony-forming unit (CFU) assay; migration by Boyden chamber; and intracellular caspase-3 concentrations by immunoassay. There were no significant differences between groups in EPC number (0.001+/-0.0004 vs. 0.001+/-0.0003 %), colony-forming capacity (6.1+/-1.5 vs. 5.4+/-1.7 CFUs), or migration to VEGF (1410.1+/-151.2 vs. 1334.3+/-111.1 AU). Furthermore, there were no group differences in basal and staurosporine stimulated intracellular concentrations of active caspase-3 (0.3+/-0.03 vs. 0.5+/ 0.1 ng/mL; and 2.9+/-0.4 vs. 2.7+/-0.3 ng/mL), a marker of apoptotic susceptibility. Taken together, these data indicate that short sleep duration is not associated with EPC dysfunction in healthy adults. Numerical and functional impairment in circulating EPCs may not contribute to the increased cardiovascular risk with habitual short sleep duration. PMID- 21814413 TI - Inflammation and diabetic retinal microvascular complications. AB - Diabetic retinopathy (DR) is one of the most common complications of diabetes and is a leading cause of blindness in people of the working age in Western countries. A major pathology of DR is microvascular complications such as non perfused vessels, microaneurysms, dot/blot hemorrhages, cotton-wool spots, venous beading, vascular loops, vascular leakage and neovascularization. Multiple mechanisms are involved in these alternations. This review will focus on the role of inflammation in diabetic retinal microvascular complications and discuss the potential therapies by targeting inflammation. PMID- 21814416 TI - Heart rate variability study of childhood anxiety disorders. AB - BACKGROUND: The current study aims at assessment of heart rate variability among children and adolescents with childhood anxiety disorder, using the case-control design. MATERIALS AND METHODS: The study was carried out at a tertiary care multispecialty hospital. It included 34 children and adolescents with diagnosis of childhood anxiety disorder, in the age range of eight to eighteen years, and 30 age- and sex-matched healthy controls. Heart-rate variability was studied using the standard protocol. RESULTS: Significantly reduced variability of the heart rate was observed in both the time as well as frequency domains in the disorder group as compared to the control group. These findings indicate decreases in the sympathetic and parasympathetic activity in the disorder group, thus representing diminished physiological variability at rest. CONCLUSIONS: The notion of autonomic inflexibility, as seen in the current study, has important implications for stability in biological systems. The loss of variability in the physiological systems in general, and in the cardiovascular system in particular, has an association with a number of diseases and dysfunctions. PMID- 21814417 TI - A single-center prospective study analyzing the cardiac referrals made to a tertiary care center in India. AB - BACKGROUND: Healthcare system in most parts of the world functions on a three tier system, involving primary, secondary, and tertiary care centers. The appropriate and efficient referral system plays crucial role in maximally efficient healthcare delivery. MATERIALS AND METHODS: In all, 46 referrals made to the medicine department of the hospital over a period of 1 month with chief complaint of chest pain and presumptive diagnosis of myocardial ischemia/infarct by outside physicians were selected randomly. Analysis was done both for extent and clarity of useful information provided. RESULTS: Out of 46 referrals, exact indication for referral was mentioned in 4 (8.7%), time of referral in 2 (4.3%), blood pressure in 38 (17.4%), pulse rate in 29 (63.04%), respiratory rate in 1 (2.17%), electrocardiograph diagnosis was not mentioned in 12 (26.08%), and the contact number/details of referring physician were mentioned in 2 (4.34%). Correct dose of aspirin was given to 27 (58.69%), clopidogrel to 19 (41.30%), statins to 9 (19.45%), angiotensin-converting enzyme inhibitors to 6 (13.04%), beta-blockers to 8 (17.39%), low-molecular weight heparin in 6 (13.04%), and 22 (47.82%) patients warranted thrombolysis, but was given in 12 (54.54%). CONCLUSIONS: There is a serious lack of quality and clarity of important information provided while making referrals. PMID- 21814418 TI - Infectious endocarditis complicated by an ischemic stroke and revealing Marfan syndrome. AB - Marfan syndrome is a systematic genetic disease of the connective tissue. The cardiac affection would predict the prognosis and ischemic stroke might complicate it. The purpose of this work is to discuss the mechanisms of the ischemic stroke in Marfan syndrome which have to be considered in all young patients of ischemic strokes. We report the case of a 17-year-old male patient who presented with right hemiparesis with brachio-facial dominance, hemihypoesthesia and Broca's aphasia; these symptoms were followed by partial right somato-motor epileptic seizure. The cerebral computed tomographic (CT) scan demonstrated early signs of ischemic stroke in the left Sylvian artery. Cardiovascular examination revealed a systolic murmur in the mitral site. Marfan syndrome with infectious endocarditis complicated by ischemic stroke was diagnosed. However, the family pathological history was negative. The Marfan syndrome diagnosis was approved considering the following criteria: Ligamentous hyperlaxity, crystalline ectopia and mitral valve prolapsus with mitral insufficiency. The patient benefited of antibiotherapy for 4 weeks. The patient underwent sessions of motor physical therapy and orthophonic rehabilitation. Then, cardiac surgery was carried out and valvuloplasty was performed. The surgical treatment confirmed the presence of mitral insufficiency and prolapsus of the big mitral valve and multiple friable anterior-posterior vegetations with broken cordage of the small mitral valve. Replacement of the mitral valve was achieved, and the post-surgery follow-ups were simple. The diagnosis of Marfan syndrome was based on well-defined criteria. The evolution of the patient was marked by a complete improvement of the cardiac and motor deficits, and disappearance of the Broca's aphasia. A fibroelastic disease such Marfan syndrome has to be considered in unexplained ischemic stroke in all young patients. Hence, the diagnosis of Marfan syndrome involves an anticipation of the neurovascular complications by early cardiovascular care. PMID- 21814419 TI - Single dominant left coronary artery: An autopsy case report with review of literature. AB - Coronary artery anomalous course is rare, reported incidence is approximately 0.3 1.3% of patients undergoing coronary angiography and approximately 1% of routine autopsy examinations. A single coronary artery is an unusual congenital anomaly where only one coronary artery arises from the aortic trunk from a single coronary ostium, supplying the entire heart. We describe here a rare case with an unusual dominant left circumflex artery and absent right coronary artery. PMID- 21814420 TI - Evaluation of the autologous bone marrow mononuclear therapy and functional restoration in the scarred myocardium by imaging analysis. AB - A 62-year-old male patient with previous history of myocardial infarction, akinetic myocardial segments, and an ejection fraction of 31% with the NYHA class III category was selected for the autologous bone marrow (ABM)-derived mononuclear cell fraction injection during CABG surgery. Nitrate augmented myocardial tracer uptake was imaged by ECG gated SPECT pre- and 1 year post-ABM therapy, using radiotracer Tc99m Sestamibi. The baseline gated SPECT demonstrated full thickness infarct in 40% area of LAD territory. Bone marrow aspirate of 20.0 ml from sternum yielding a mono nuclear cell fraction of 4.5 * 10(7) cells/ml was suspended in 2.0 ml of sterile normal saline to be injected at eight sites of the injured myocardium. There were no apparent side effects due to the procedure, i.e., life threatening events, major bleeds, reaction, or shock. The case was followed at the end of 1, 3, 6 months by ECG and Holter monitor and ECG gated SPECT at the end of 12 months. The gated SPECT images demonstrated mild but definitely improved tracer uptake within part of the infarcted segments along with improvement in ejection fraction to 45%, and a clinical change in the NYHA Class to II. Cell-based therapy may offer benefits of induction of normal tissue microenvironment. PMID- 21814421 TI - Journal of pharmacy and bioallied science. PMID- 21814422 TI - Patent protection strategies. AB - It is widely recognized that the pharmaceutical industry faces serious financial challenges. Large numbers of blockbuster drugs are losing patent protection and going generic. The pipeline of new drugs is too sparse to fill the gap and generate a platform for future growth. Moreover, many of the new products are biologics with much narrower target patient populations and comparatively higher prices relative to traditional pharmaceuticals. So now the time has come for pharmaceutical scientists to have a better understanding of patent fundamentals. This need is illustrated by analyses of key scientific and legal issues that arose during recent patent infringement cases involving Prozac, Prilosec, and Buspar. Facing this scenario, the pharmaceutical industry has moved to accelerate drug development process and to adopt at the same time different strategies to extend the life time of the patent monopoly to provide the economic incentives and utilizing it for drug discovery and development. This review covers the need of patent protection and various strategies to extend the patent. PMID- 21814423 TI - Drug utilization pattern of antibacterials used in ear, nose and throat outpatient and inpatient departments of a university hospital at New Delhi, India. AB - OBJECTIVE: We explored the antibacterial prescribing patterns of physicians in ear, nose and throat (ENT) outpatient and inpatient departments (OPD, IPD) of a University Hospital, New Delhi, India. MATERIALS AND METHODS: A prospective study was conducted, with a sample size of 276 patients, who visited the ENT OPD and IPD over a period of 4 months. RESULTS: It was found that 62.68% were males, 26% patients were in the age group 26-35 years, followed by 22.8% belonging to the age group 26-35 years. Maximum number of patients were diagnosed with ear (37.3%) and throat (36.2%) infections. The most frequently prescribed antibacterials were beta-lactams (45.52%) followed by quinolones (26.31%). The most commonly used agent in penicillins was amoxicillin and clavulanic acid (21.74%), in cepahalosporins was cefpodoxime proxetil (5.49%) and in quinolones was gemifloxacin (14.41%). Further, 66.67% of the patients received single antibacterial drug and the average number of antibacterial agents prescribed per patient per course was found to be 1.58. It was also observed that 70.71% of the antibacterials were prescribed by oral route. The most concomitant conditions were found to be diabetes (10.5%), hypertension (6.16%) and coronary heart disease (5.07%). All the drugs were prescribed by their brand names and 48.91% patients showed good adherence with the prescribed therapy. CONCLUSIONS: The present work is the maiden drug utilization study conducted in ENT department at our university hospital. It highlighted some rational prescription patterns including less utilization of antibiotics in ENT infections, good adherence by patients and prescription by brand names. The data presented here will be useful in future, long-term and more extensive drug utilization studies in the hospital and in promotion of rational prescribing and drug use in hospitals. PMID- 21814424 TI - Formulation and evaluation of antisebum secretion effects of sea buckthorn w/o emulsion. AB - PURPOSE: This study was designed to formulate and evaluate the anti-sebum secretion effects of a topical skin-care cream (w/o emulsion) of sea buckthorn versus its vehicle (Base) as control. MATERIALS AND METHODS: Concentrated sea buckthorn (H.rhamnoides) fruit extract was entrapped in the inner aqueous phase of w/o emulsion. Base containing no extract and a Formulation containing 1% concentrated extract of H.rhamnoides was formulated. Lemon oil was incorporated to the odor. Both the Base and the Formulation were stored at different storage conditions for a period of 4 weeks to predict their stability. Different stability parameters i.e.; physical stability, centrifugation, and pH were monitored at different time intervals. Both the Base and the Formulation were applied to the cheeks of 10 healthy human volunteers (n=10) for a period of 8 weeks. RESULT: The expected organoleptic stability of creams was achieved from 4 weeks in-vitro study period. Odor disappeared with the passage of time due to volatilization of lemon oil. The pH of the Formulation showed significant (P = 0.0002) decline due to high concentration of organic acids present in sea buckthorn. Similarly the Formulation showed statistically significant (P < 0.05) effects on skin sebum secretion. CONCLUSION: The in vitro results showed a good stability over 4 weeks of observation period of both the Base and Formulation and the Formulation has anti sebum secretion effects over 8 weeks of observation period. PMID- 21814425 TI - Antidiabetic activity of Crateva nurvala stem bark extracts in alloxan-induced diabetic rats. AB - OBJECTIVES: The aim of this study was to investigate the antidiabetic activity of Crateva nurvala stem bark (family: Capparidaceae) extracts in alloxan-induced diabetic albino rats. A comparison was made between the action of different extracts of C. nurvala and a known antidiabetic drug glibenclamide (600 MUg/kg b. wt.). An oral glucose tolerance test (OGTT) was also performed in diabetic rats. MATERIALS AND METHODS: The petroleum ether, chloroform, alcohol, and aqueous extracts of C. nurvala stem bark were obtained by simple maceration method and were subjected to standardization by following pharmacognostical and phytochemical screening methods. Dose selection was made on the basis of acute oral toxicity study (50-5000 mg/kg b. wt.) as per Organization for Economic Co operation and Development (OECD) guidelines. RESULTS AND CONCLUSIONS: C. nurvala petroleum ether extract (CNPEE) and ethanolic extract (CNEE) showed significant (P< 0.001) antidiabetic activities. In alloxan-induced model, blood glucose level of these extracts on seventh day of study were CNPEE (126.33+/-13.703 mg/dl) and CNEE (126.66+/-13.012 mg/dl) when compared with diabetic control (413.50+/-4.752 mg/dl) and chloroform extract (320.83+/-13.516 mg/dl). In OGGT model (glucose loaded rats), CNPEE showed a glucose level of 178.83+/-3.070 mg/dl after 30 min and 131.66+/-2.486 mg/dl after 90 min, whereas CNEE showed 173.66+/-4.224 mg/dl after 30 min and 115.50+/-3.394 mg/dl after 90 min. These extracts also prevented body weight loss in diabetic rats. The drug has the potential to act as an antidiabetic drug. PMID- 21814427 TI - QSAR studies of benzofuran/benzothiophene biphenyl derivatives as inhibitors of PTPase-1B. AB - OBJECTIVES: Insulin resistance is associated with a defect in protein tyrosine phosphorylation in the insulin signal transduction cascade. The PTPase enzyme dephosphorylates the active form of the insulin receptor and thus attenuates its tyrosine kinase activity, therefore, the need for a potent PTPase inhibitor exists, with the intention of which the QSAR was performed. MATERIALS AND METHODS: Quantitative structure-activity relationship (QSAR) has been established on a series of 106 compounds considering 27 variables, for novel biphenyl analogs, using the SYSTAT (Version 7.0) software, for their protein tyrosine phosphatase (PTPase-1B) inhibitor activity, in order to understand the essential structural requirement for binding with the receptor. RESULTS: Among several regression models, one per series was selected on the basis of a high correlation coefficient (r, 0.86), least standard deviation (s, 0.234), and a high value of significance for the maximum number of subjects (n, 101). CONCLUSIONS: The influence of the different physicochemical parameters of the substituents in various positions has been discussed by generating the best QSAR model using multiple regression analysis, and the information thus obtained from the present study can be used to design and predict more potent molecules as PTPase-1B inhibitors, prior to their synthesis. PMID- 21814426 TI - Development and validation of stability indicating method for the quantitative determination of venlafaxine hydrochloride in extended release formulation using high performance liquid chromatography. AB - OBJECTIVE: Venlafaxine,hydrochloride is a structurally novel phenethyl bicyclic antidepressant, and is usually categorized as a serotonin-norepinephrine reuptake inhibitor (SNRI) but it has been referred to as a serotonin-norepinephrine dopamine reuptake inhibitor. It inhibits the reuptake of dopamine. Venlafaxine HCL is widely prescribed in the form of sustained release formulations. In the current article we are reporting the development and validation of a fast and simple stability indicating, isocratic high performance liquid chromatographic (HPLC) method for the determination of venlafaxine hydrochloride in sustained release formulations. MATERIALS AND METHODS: The quantitative determination of venlafaxine hydrochloride was performed on a Kromasil C18 analytical column (250 * 4.6 mm i.d., 5 MUm particle size) with 0.01 M phosphate buffer (pH 4.5): methanol (40: 60) as a mobile phase, at a flow rate of 1.0 ml/min. For HPLC methods, UV detection was made at 225 nm. RESULTS: During method validation, parameters such as precision, linearity, accuracy, stability, limit of quantification and detection and specificity were evaluated, which remained within acceptable limits. CONCLUSIONS: The method has been successfully applied for the quantification and dissolution profiling of Venlafaxine HCL in sustained release formulation. The method presents a simple and reliable solution for the routine quantitative analysis of Venlafaxine HCL. PMID- 21814428 TI - Development and validation of a headspace gas chromatographic method for the determination of residual solvents in arterolane (RBx11160) maleate bulk drug. AB - OBJECTIVE: Arterolane maleate is an antimalarial drug currently under Phase III clinical evaluation, and presents a simple, economical and scalable synthesis, and does not suffer from safety problems. Arterolane maleate is more active than artemisinin; and is cheap to produce. It has a longer lifetime in the plasma, so it stays active longer in the body. To provide quality control over the manufacture of any API, it is essential to develop highly selective analytical methods. In the current article we are reporting the development and validation of a rapid and specific Head space gas chromatographic (HSGC) method for the determination of organic volatile impurities (residual solvents) in Arterolane Maleate bulk drug. MATERIALS AND METHODS: The method development and its validation were performed on Perkin Elmer's gas chromatographic system equipped with Flame Ionization detector and head space analyzer. The method involved a thermal gradient elution of ten residual solvents present in arterolane maleate salt in RTx-624, 30 m * 0.32 mm, 1.8 MU column using nitrogen gas as a carrier. The flow rate was 0.5 ml/min and flame ionization detector (FID) was used. RESULTS: During method validation, parameters such as precision, linearity, accuracy, limit of quantification and detection and specificity were evaluated, which remained within acceptable limits. CONCLUSIONS: The method has been successfully applied for the quantification of the amount of residual solvents present in arterolane maleate bulk drug.The method presents a simple and reliable solution for the routine quantitative analysis of residual solvents in Arterolane maleate bulk drug. PMID- 21814429 TI - Isolation and purification of fungal pathogen (Macrophomina phaseolina) induced chitinase from moth beans (Phaseolus aconitifolius). AB - OBJECTIVE: Chitinase (EC 3.2.1.14) is one of the major pathogenesis-related proteins, which is a polypeptide that accumulates extracellularly in infected plant tissue. An attempt was made to isolate and purify the chitanase enzyme using moth beans as an enzyme source. MATERIALS AND METHOD: The enzyme was isolated and purified from moth beans against the fungal pathogen Macrophomina phaseolina strain 2165. The isolation and purification was done in both in vitro and in vivo conditions. Purification of chitinase was carried out to obtain three fractions, viz. 50 degrees C heated, ammonium sulfate precipitated and sephadex G 25 column-eluted fractions. The molecular mass of Chitinase was directly estimated by sodium dodecyl sulfate-polyacryamide gel electroresis (SDS-PAGE). RESULT: The yield is sufficient for initial characterization studies of the enzyme. The molecular study of the enzyme shows the possibility of generating the defense mechanism in plants in which it cannot occur. Chitinase was purified by gel filtration chromatography with 20.75-fold and 32.78-fold purification in the in vitro and in vivo conditions, respectively. The enzyme shows a maximum activity after 90 min with 0.1 ml of colloidal chitin as a substrate and 0.4 ml of crude chitinase extract. The optimum pH of 5.0 and an optimum temperature of 40 degrees C was found for maximal activity. The molecular weight of purified chitinase was estimated to be 30 kDa by SDS-PAGE. CONCLUSION: The chitinase isolated in both in vitro and in vivo conditions is stable andactive. PMID- 21814430 TI - Screening of nutrient parameters for mevastatin production by Penicillium citrinum MTCC 1256 under submerged fermentation using the Plackett-Burman design. AB - OBJECTIVE: Mevastain, an HMG-CoA reductase inhibitor produced by Penicillium citrinum. The Placket-Burman experimental design was used to identify the important nutrients influencing the production of mevastatin by Penicillium citrinum MTCC 1256 under submerged fermentation. MATERIALS AND METHODS: Nine nutritional parameters, such as, glucose, glycerol, arrowroot, oats, urea, peptone, yeast extract, MgSO(4).7H(2)O, and CaCl(2).2H(2)O were screened by Placket-Burman experimental design in 12 experimental run. RESULTS: Nine nutritional parameters, glucose, glycerol, arrowroot, oats, urea, peptone, yeast extract, MgSO(4).7H(2)O, and CaCl(2).2H(2)O contributed with 0.8114%, 24.0390%, 2.2786%, 0.1491%, 0.5608%, 47.5029%, 6.8092 %, 4.0980%, 10.5823% respectively towards mevastatin production by Penicillium citrinum under submerged fermentation. CONCLUSION: Among the nine nutrient components glycerol, peptone, yeast extract, MgSO(4).7H(2)0, and CaCl(2).2H(2)O contributed to a large extent, urea had little impact, while glucose, oats, and arrowroot contributed moderately on production of mevastatin. PMID- 21814431 TI - Evaluation of a sunscreen during a typical beach period. AB - PURPOSE: Amongst the radiations reaching the Earth's surface, the ultraviolet rays are the ones receiving most attention from the scientists, given their damaging potential for humans exposed to them. To minimize the harm caused by such exposure, human beings are strongly recommended to use sunscreens, which are pharmaceutical preparations containing filters that confer protection against radiation. As this protection is strongly dependent on the properties of these filters, it is very important to ensure their stability even when under aggressive conditions, such as the typical high temperatures of summer in South Europe. In this study, a commercial sunscreen emulsion was tested in vitro for a period of time intended to simulate a beach period of 15 days, with regard to the maintenance of its sun protection factor (SPF). Moreover, the organoleptic characteristics were also monitored by macroscopic analysis. MATERIALS AND METHODS: To perform this study, temperature conditions similar to those observed from June to August in Faro (Portugal) were simulated in vitro. The SPF was determined by spectrophotometry, with subsequent application of the Mansur equation. RESULTS AND CONCLUSION: No significant alterations were observed during the considered period under the specific conditions of this study. PMID- 21814432 TI - Pacemakers charging using body energy. AB - Life-saving medical implants like pacemakers and defibrillators face a big drawback that their batteries eventually run out and patients require frequent surgery to have these batteries replaced. With the advent of technology, alternatives can be provided for such surgeries. To power these devices, body energy harvesting techniques may be employed. Some of the power sources are patient's heartbeat, blood flow inside the vessels, movement of the body parts, and the body temperature (heat). Different types of sensors are employed, such as for sensing the energy from the heartbeat the piezoelectric and semiconducting coupled nanowires are used that convert the mechanical energy into electricity. Similarly, for sensing the blood flow energy, nanogenerators driven by ultrasonic waves are used that have the ability to directly convert the hydraulic energy in human body to electrical energy. Another consideration is to use body heat employing biothermal battery to generate electricity using multiple arrays of thermoelectric generators built into an implantable chip. These generators exploit the well-known thermocouple effect. For the biothermal device to work, it needs a 2 degrees C temperature difference across it. But there are many parts of the body where a temperature difference of 5 degrees C exists - typically in the few millimeters just below the skin, where it is planned to place this device. This study focuses on using body heat as an alternative energy source to recharge pacemaker batteries and other medical devices and prevent the possibility of life risk during repeated surgery. PMID- 21814433 TI - Graduate pharmacy aptitude test. PMID- 21814434 TI - Journal of pharmacy and bioallied sciences. PMID- 21814435 TI - Structural modifications of quinoline-based antimalarial agents: Recent developments. AB - Antimalarial drugs constitute a major part of antiprotozoal drugs and have been in practice for a long time. Antimalarial agents generally belong to the class of quinoline which acts by interfering with heme metabolism. The recent increase in development of chloroquine-resistant strains of Plasmodium falciparum and failure of vaccination program against malaria have fuelled the drug discovery program against this old and widespread disease. Quinoline and its related derivative comprise a class of heterocycles, which has been exploited immensely than any other nucleus for the development of potent antimalarial agents. Various chemical modifications of quinoline have been attempted to achieve analogs with potent antimalarial properties against sensitive as well as resistant strains of Plasmodium sp., together with minimal potential undesirable side effects. This review outlines essentially some of the recent chemical modifications undertaken for the development of potent antimalarial agents based on quinoline. PMID- 21814436 TI - Cyclodextrins in delivery systems: Applications. AB - Cyclodextrins (CDs) are a family of cyclic oligosaccharides with a hydrophilic outer surface and a lipophilic central cavity. CD molecules are relatively large with a number of hydrogen donors and acceptors and, thus in general, they do not permeate lipophilic membranes. In the pharmaceutical industry, CDs have mainly been used as complexing agents to increase aqueous solubility of poorly soluble drugs and to increase their bioavailability and stability. CDs are used in pharmaceutical applications for numerous purposes, including improving the bioavailability of drugs. Current CD-based therapeutics is described and possible future applications are discussed. CD-containing polymers are reviewed and their use in drug delivery is presented. Of specific interest is the use of CD containing polymers to provide unique capabilities for the delivery of nucleic acids. Studies in both humans and animals have shown that CDs can be used to improve drug delivery from almost any type of drug formulation. Currently, there are approximately 30 different pharmaceutical products worldwide containing drug/CD complexes in the market. PMID- 21814438 TI - The role of assay methods in characterizing the quality of bulk pharmaceuticals. AB - This study presents the role of assay methods in characterizing the quality of bulk substances in pharmaceutical analysis. High-performance liquid chromatography (HPLC) is the most remarkable development and the technique has become very significant in the quality control of bulk drugs and pharmaceutical formulations, even at the pharmacopoeial level. Development of HPLC and other chtromatographic techniques, coupled with mass spectrometry, is also useful in the determination of drugs and their metabolites in biological samples. The role of electrophoretic, spectroscopic, and other methods in pharmaceutical analysis are discussed here. There are separate sections devoted to microscopy techniques that are useful in the pharmaceutical field, as also the regulatory aspects of drug analysis, with emphasis on questions related to validation. PMID- 21814437 TI - Electron paramagnetic resonance spectroscopy in radiation research: Current status and perspectives. AB - Exposure to radiation leads to a number of health-related malfunctions. Ionizing radiation is more harmful than non-ionizing radiation, as it causes both direct and indirect effects. Irradiation with ionizing radiation results in free radical induced oxidative stress. Free radical-mediated oxidative stress has been implicated in a plethora of diseased states, including cancer, arthritis, aging, Parkinson's disease, and so on. Electron Paramagnetic Resonance (EPR) spectroscopy has various applications to measure free radicals, in radiation research. Free radicals disintegrate immediately in aqueous environment. Free radicals can be detected indirectly by the EPR spin trapping technique in which these forms stabilize the radical adduct and produce characteristic EPR spectra for specific radicals. Ionizing radiation-induced free radicals in calcified tissues, for example, teeth, bone, and fingernail, can be detected directly by EPR spectroscopy, due to their extended stability. Various applications of EPR in radiation research studies are discussed in this review. PMID- 21814439 TI - Khamiras, a natural cardiac tonic: An overview. AB - The Unani system of Medicine (Unanipathy), which originated in Greece, is based on the principles proposed by Galen, a Greek practitioner. Since then, many Arab and Persian scholars have contributed to the system. Among them Ibn-e-Sina, an Arab philosopher and Physicist who wrote 'Kitab-al-shifa' are worth mentioning. This system has an extensive and inspiring record in India. It was introduced in India around the tenth century A.D with the spread of Islamic civilization. At present, Unanipathy has become an important part of the Indian system of Medicine. Unani medicines have been used since ancient times, as medicines for the treatment of various ailments. In spite of the great advances observed in modern medicine in recent decades, Unani drugs still make an important contribution to healthcare. The Unani system of medicine is matchless in treating chronic diseases like arthritis, asthma, mental, cardiac, and digestive disorders, urinary infections, and sexual diseases. The medicines administered go well with the temperament of the patient, thus speeding up the process of recovery and also reducing the risk of drug reaction. The Unani system of medicine recognizes the influence of the surroundings and ecological conditions on the state of health of human beings. The system aims at restoring the equilibrium of various elements and faculties of the human body. It has laid down six essential prerequisites for the prevention of diseases and places great emphasis, on the one hand, on the maintenance of proper ecological balance, and on the other, on keeping water, food, and air free from pollution. These essentials, known as 'Asbab-e-Sitta Zarooriya', are air, food, and drink, bodily movement and repose, psychic movement and repose, sleep and wakefulness, and excretion and retention. The Unani system is a secular system in temperament and is popular among the masses. In Unani medicine, although the general preference is for single drugs, compound formulations are also used in the treatment of various complex and chronic disorders. In the light of the present knowledge, this review is a small effort to discuss the efficacious nature of 'Khamira', a semi-solid preparation, which is traditionally used for cardiac ailments, such as, palpitations, weakness of the heart, and so on. On the basis of their constituents these are named as, Khamira Aabresham, Khamira Gaozaban, Khamira Marwareed, and so on. Khameeras are also used as general tonics for other vital organs like the liver and brain. In view of the increasing number of cardiac diseases, a thorough evaluation of this ancient work on Khamira is of special significance. PMID- 21814440 TI - Synergistic activity of Fagonia arabica and Heteropneustes fossilis extracts against myocardial, cerebral infarction, and embolism disorder in mice. AB - OBJECTIVE: Extract of Fagonia arabica, (family Zygophyllaceae) has thrombolytic activity against the clotted blood in blood vessels and the extract of Heteropneustes fossilis shows the cardiotonic activity. Therefore, combinatory pharmacology shows the synergistic activity in tied mice for a long duration. MATERIALS AND METHODS: The cardiotonic activity of Heteropneustes fossilis fish extract was examined on a frog intact heart and then pharmacologically performed on 20 mice without plant extract as well as with a combination of plant extract, which gave a remarkable synergistic activity in an in-vivo experiment on mice kept tied for the duration of 12, 18, and 24 hours and injected within one minute after untying. RESULT AND DISCUSION: The plant extract was compared with streptokinase as well as a non-thrombolytic agent (control). A study showed a percentage of clot lysis, which was 65.5% for plant extract, but streptokinase had 71%. The study was done in 11 healthy volunteers representing a mean value and SD of 65% +/- 2.01% and 71.67% +/- 0.71% of the plant extract and streptokinase, respectively, in contrast to the non-thrombolytic (control), that is, 0.86% +/- 0.08%. CONCLUSION: Injection of plant and fish extract acts both synergistically in the blood clotted mice and in mice suffering from myocardial or cerebral infarction and embolized mice. PMID- 21814441 TI - Determination of gallic acid in Phyllanthus emblica Linn. dried fruit powder by HPTLC. AB - OBJECTIVE: Emblica (Phyllanthus emblica L.), an euphorbiaceous plant, is widely distributed in subtropical and tropical areas of India, China and Indonesia. The fruits possess antimicrobial, antioxidant, anti-inflammatory, analgesic and antipyretic properties. In the current article a new, simple, sensitive, selective, precise, and robust high-performance thin-layer chromatographic (HPTLC) method was developed and validated for the determination of gallic acid in dried fruit powder of Phyllanthus emblica. MATERIALS AND METHODS: The quantitative determination of gallic acid was performed on TLC aluminium plates pre-coated with silica gel 60F-254 as the stationary phase. The linear ascending development was carried out in a twin trough glass chamber saturated with a mobile phase consisting of toluene: ethyl acetate: formic acid: methanol (3:3:0.8:0.2) at room temperature (25 +/- 2 degrees C). Camag TLC scanner III was used for spectrodensitometric scanning and analysis, in the absorbance mode, at 278 nm. RESULTS: The linear regression analysis data for the calibration plots showed good linear relationship with r(2) = 0.99977 in the concentration range of 40 - 240 ng spot-1, with respect to the peak area. According to the guidelines of the International Conference on Harmonization (ICH), the method was validated for precision, accuracy, and recovery. CONCLUSION: Statistical analysis of the data showed that the method was reproducible and selective for the estimation of gallic acid. PMID- 21814442 TI - Synthesis, spectral characterization, and pharmacological screening of some 4-[{1 (aryl)methylidene}-amino]-3-(4-pyridyl)-5-mercapto-4H-1,2,4-triazole derivatives. AB - BACKGROUND: Pain is an unpleasant and subjective sensation that results from a harmful sensorial stimulation, which alerts the body about current or potential damage to its tissues and organs. Fever is a complex physiological response triggered by infections or aseptic stimuli. Elevation in body temperature occurs when the concentration of prostaglandin E(2) (PGE(2)) increases within parts of the brain. Triazole derivatives have been found to possess various pharmacological and biological activities, such as, anti-inflammatory, analgesics, antipyretic, and antifungal. MATERIALS AND METHODS: Various 4-[{1 (aryl)methylidene}-amino]-3-(4-pyridyl)-5-mercapto-4H-1,2,4-triazole derivatives were synthesized by a sequence of reactions starting from isonicotinic acid hydrazide. The synthesized compounds were screened for in-vivo analgesic by the tail-flick method and anti-pyretic activities at a dose of 25 and 100 mg/kg body weight respectively. The antipyretic activity was evaluated using Brewer's yeast induced pyrexia in rats. Fever was induced by subcutaneously injecting 20 ml/kg of 20% aqueous suspension of Brewer's yeast in normal saline. RESULTS AND DISCUSSION: The analgesic screening results revealed that the compounds 3b, 3c, and 3d exhibited excellent analgesic activity at 60 and 90 minutes compared to the standard drug (Analgin). Results revealed that the compounds 3a, 3e, and 3f significantly decreased the temperature of pyretic (P<0.001) rats at one, three and six hours after compound administration as compared to Aspirin (standard drug). CONCLUSION: Compounds 3b, 3c, and 3d exhibited significant analgesic activity comparable with the standard drug analgin, using the tail flick model. Compounds 3a, 3e, and 3f showed significant anti-pyretic activities comparable with the standard drug aspirin using the yeast-induced pyrexia model. PMID- 21814443 TI - Assessment of lithium ingestion on cognition and some subset of motor skill. AB - BACKGROUND: Patients taking lithium often report of difficulties in concentration, memory, learning, and attention. Laboratory tests of cognitive functions in healthy volunteers on chronic lithium demonstrate that disruptions in memory-learning processes are apparent at the time of memory retrieval. AIM: This study has attempted to evaluate the impact of lithium ingestion on cognition and some subset of sensory skill, by examining comparatively how lithium or a lithium / saline supplement either harms or helps the brain. MATERIALS AND METHODS: Wistar Rats (male and female) were housed in individual improvised cages. The rats were acclimatized for two weeks after which they were randomly grouped into three, namely, control, lithium-treated, and lithium with saline treated groups, and treated for four weeks. The lithium-treated group received 40 mM lithium bicarbonate per kg of feed for the first one week, and the dosage was increased to 60mM per kg of feed for the rest of the three weeks. The lithium saline group received saline solution in addition to lithium. The control group was given normal feed and water liberally for the period of the experiment. The rats were subjected to a cognitive test using the Barnes maze, assessments of negative geotaxis, cliff avoidance, and some neurotransmitters (acetylcholine and glutamate). The data were analyzed by Microsoft excel 2007. RESULTS: This study shows that lithium ingestion is characterized by a significant (P <= 0.05) decline in learning and memory as compared to the control. While the lithium saline-treated animals exhibit enhanced cognitive ability. The subset of sensory activity was assessed; negative geotaxis and cliff avoidance were grossly compromised, thus lithium carbonate appeared to have definite negative effects on the psychsensory speed. CONCLUSION: In conclusion lithium should be co administered with saline to counter the detrimental effects of lithium noticed in this study, which include impairment of tasks on psychomotor speed and cognition. PMID- 21814444 TI - Comparative bioavailability studies of citric acid and malonic acid based aspirin effervescent tablets. AB - PURPOSE: The present investigation is aimed at comparing the pharmacokinetic profile (Bioavailability) of aspirin in tablet formulations, which were prepared by using different effervescent excipients such as citric acid and malonic acid. MATERIALS AND METHODS: The relative bioavailability and pharmacokinetics of citric acid based aspirin effervescent tablet (Product A) and malonic acid based aspirin effervescent tablet (Product B) formulations were evaluated for an in vitro dissolution study and in-vivo bioavailability study, in 10 normal healthy rabbits. The study utilized a randomized, crossover design with a one-week washout period between doses. Blood samples were collected at 0, 1, 2, 4, 6, 8, 12 and 24 hours following a 100 mg/kg dose. Plasma samples were assayed by High Performance Liquid Chromatography. T(max), C(max), AUC(0-24), AUC(0- infinity,) MRT, K(a,) and relative bioavailability were estimated using the traditional pharmacokinetic methods and were compared by using the paired t-test. RESULT: In the present study, Products A and B showed their T(max), C(max), AUC(0-24), AUC(0 infinity,) MRT, and K(a) values as 2.5 h, 2589 +/- 54.79 ng/ml, 9623 +/- 112.87 ng.h/ml, 9586 +/- 126.22 ng.h/ml, 3.6 +/- 0.10 h, and 0.3698 +/- 0.003 h (-1) for Product A and 3.0 h, 2054 +/- 55.79 ng/ml, 9637 +/- 132.87 ng.h/ml, 9870 +/- 129.22 ng.h/ml, 4.76 +/- 0.10 h, and 0.3812 +/- 0.002 h (-1) for Product B, respectively. CONCLUSION: The results of the paired t-test of pharmacokinetics data showed that there was no significant difference between Products A and B. From both the in vitro dissolution studies and in vivo bioavailability studies it was concluded that products A and B had similar bioavailability. PMID- 21814445 TI - Spectrophotometric estimation of betahistine hydrochloride in tablet formulations. AB - AIM: The study aims to develop simple, sensitive, rapid, accurate and precise spectrophotometric method for estimation of Betahistine hydrochloride in tablet dosage forms. MATERIALS AND METHODS: For method I and II, in a series of 10 ml volumetric flask, aliquots of standard drug solution (100 MUg/ml) in double distilled water were transferred and diluted with same so as to give several dilutions in concentration range of 15-90 MUg/ml and 10-80 MUg/ml respectively of betahistine hydrochloride. To 5 ml of each dilution taken in a separating funnel, (5 ml of methyl orange for method I and 5 ml of bromo phenol blue for method II) reagent and 5 ml of chloroform was added. Reaction mixture was shaken gently for 5 min and allowed to stand so as to separate aqueous and chloroform layer. Absorbance maxima measured at 421.6 nm and 412 nm for method I and II respectively. RESULTS: The recovery studies were found close to 100 % that indicates accuracy and precision of the proposed methods. The statistical analysis was carried out and results of which were found satisfactory. Standard deviation values were found low that indicated reproducibility of the proposed methods. CONCLUSION: Based on results the developed methods could be used for routine estimation of betahistine hydrochloride from tablet formulations. PMID- 21814446 TI - Chitosan superporous hydrogel composite-based floating drug delivery system: A newer formulation approach. AB - OBJECTIVE: In this study efforts have been made to design a drug delivery system based on a superporous hydrogel composite, for floating and sustained delivery of Ranitidine hydrochloride. MATERIALS AND METHODS: The characterization studies were performed by the measurement of apparent density, porosity, swelling studies, mechanical strength studies, and scanning electron microscopy studies. The prepared formulation was evaluated for buoyant behavior, in vitro drug release, kinetics of drug release, and stability. The release profile of Ranitidine hydrochloride was investigated by changing the release retardant polymer in the formulation. To ascertain the kinetics of drug release, the drug release profiles were fitted to mathematical models that included zero-order, first-order, Higuchi, Hixson-Crowell, Korsmeyer-Peppas, Weibull, and Hopfenberg models. RESULTS: Scanning electron microscopy images clearly indicated the formation of interconnected pores and capillary channels, and cross-linked Chitosan molecules were observed around the peripheries of the pores. The prepared drug delivery system floated and delivered the Ranitidine hydrochloride for about 17 hours. The in vitro drug release from the proposed system was best explained by the Korsmeyer-Peppas model. The values of the diffusion exponent in the Korsmeyer-Peppas model ranged between 0.47 +/- 0.02 and 0.66 +/- 0.02, which appeared to indicate a coupling of the diffusion and erosion mechanisms, anomalous non-Fickian transport. CONCLUSION: It was concluded that the proposed floating drug delivery system, based on the superporous hydrogel composite containing Chitosan as a composite material, is promising for stomach-specific delivery of Ranitidine hydrochloride. PMID- 21814447 TI - Current scenario of attitude and knowledge of physicians about rational prescription: A novel cross-sectional study. AB - BACKGROUND: In the last 30 years concepts in pharmacology have moved from Essential Medicines (EM) to P-drugs via the Rational Use of Medicines (RUM), but no structured study has evaluated the level of understanding among the working clinicians about these concepts. AIM: The present study was designed to assess the attitude and knowledge of clinical practitioners about the concepts of RUM, EM, P-drugs, and sources of drug-information, across North India. MATERIALS AND METHODS: A cross-sectional study was carried out in and around the teaching hospitals attached to Medical Colleges, enrolling 504 clinicians from six centers across North India to fill-up a questionnaire containing 25 questions. STATISTICAL ANALYSIS: The results were compiled using percentages and averages. Univariate analysis, which explores each variable in a data set separately, was carried out by using the Fisher's exact test. RESULTS: Only one-fourth of the participants claimed that they always prescribed Essential Medicine; no one could correctly count the number of drugs / drug combinations in the Indian Essential Drug list; only 15.1% of the clinicians wrote the generic names of drugs on the prescription slip; about one-third of clinicians were not fully aware about the adverse effects, drug interactions, and contraindications of the drugs they prescribed; about 83% of physicians admitted to relying on information from Medical Representatives and an interest in research activities seemed to be lost. CONCLUSION: Results show a sorry state of affairs among clinicians, as far as the level of understanding about EM, P-drugs, and RUM is concerned, and it points toward arranging more continuing medical education (CME) for clinicians with regard to these concepts. PMID- 21814449 TI - Microsatellites in varied arenas of research. AB - Microsatellites known as simple-sequence repeats (SSRs) or short-tandem repeats (STRs), represent specific sequences of DNA consisting of tandemly repeated units of one to six nucleotides. The repetitive nature of microsatellites makes them particularly prone to grow or shrink in length and these changes can have both good and bad consequences for the organisms that possess them. They are responsible for various neurological diseases and hence the same cause is now utilized for the early detection of various diseases, such as, Schizophrenia and Bipolar Disorder, Congenital generalized Hypertrichosis, Asthma, and Bronchial Hyperresponsiveness. These agents are widely used for forensic identification and relatedness testing, and are predominant genetic markers in this area of application. The application of microsatellites is an extending web and covers the varied scenarios of science, such as, conservation biology, plant genetics, and population studies. At present, researches are progressing round the globe to extend the use of these genetic repeaters to unmask the hidden genetic secrets behind the creation of the world. PMID- 21814448 TI - Substance use among adolescent high school students in India: A survey of knowledge, attitude, and opinion. AB - BACKGROUND: Is knowledge regarding the consequences of substance use among adolescents enough to prevent them from initiating and continuing its use, is a question that needs to be clarified further? OBJECTIVE: To assess the knowledge regarding harm of use and to obtain information about attitudes among high school students. Also, to discover the opinion of substance use held by users. MATERIALS AND METHODS: This was a population based cross-sectional study conducted in two high schools of West Bengal, India, among 416 students, in classes VIII, IX, and X, with no interventions. Primary outcome measurements were substance use: knowledge regarding harm, attitude, and opinion. Following this proportions and the chi-square test were used for statistical analysis. RESULTS: Out of 416 students, 52 (12.5%) used or abused any one of the substances irrespective of time and frequency in lifetime; 26 (15.1 %) were among the urban students and 26 (10.7 %) were among their rural counterparts. More than two-thirds (73.07%) of the respondents expressed a desire to quit substance use and 57.69% had tried to stop. 'Easy availability' and 'relief from tension' were the most frequent reasons for continuation of substance use. Level of knowledge on harmfulness of substance use among students was very high (urban - -84.6% and rural - 61.5%) and they stated media as the most frequent source of information. Users were successful in influencing their peers into taking up this habit (urban - 15.4% and rural - 26.9%). CONCLUSIONS: Inspite of being aware of the harmful effects of substance use, adolescents take up this habit. This requires comprehensive prevention and control programs in schools and the community, targeted toward adolescents and their parents and other family members. Effective measures are required to encourage shaping the attitude of school children toward self confidence and adequacy, as also to prevent risk behavior among adolescents. PMID- 21814450 TI - Effect of soybean supplementation on the memory of alprazolam-induced amnesic mice. AB - Soybean, Glycine max (L.) Merr. (Leguminoseae), is known as golden bean. It contains vegetable protein, oligosaccharide, dietary fiber, vitamins, isoflavones and minerals. Earlier studies have demonstrated a cholesterol lowering, skin protective, antitumour, antidiabetic and antioxidative potential of soybean. Soy isoflavones are also utilized as estrogen replacement therapy in postmenopausal women. The present study was undertaken to investigate the effect of soybean on memory of mice when consumed along with diet. Soybean was administered chronically for 60 consecutive days as three soybean diets viz. Soy2, Soy5, Soy10. These diet contains soybean in normal diet at concentration of 2%, 5%, 10% w/w respectively. Passive avoidance paradigm and elevated plus maze served as exteroceptive behavioral models for testing memory. Alprazolam (0.5 mg/kg; i.p.) induced amnesia served as interoceptive behavioral model. The administration of soybean significantly reversed alprazolam-induced amnesia in a dose-dependent manner as indicated by the increased step down latency of mice using passive avoidance paradigm and increased transfer latency using elevated plus maze. Theses results suggest that consumption of soybean in diet may not only improve memory but also reverse the memory deficits, owing to its multifarious activities. It would be worthwhile to explore the potential of this nutrient in the management of Alzheimer's disease. PMID- 21814451 TI - Bromocriptine mesylate: Food and Drug Administration approved new approach in therapy of non-insulin dependant diabetes mellitus with poor glycemic control. AB - Food and Drug Administration (FDA) approved bromocriptine mesylate, a quick release formulation, 0.8 mg tablets, as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Bromocriptine products were previously approved by the FDA for the treatment of pituitary tumors and Parkinson's disease. Bromocriptine is thought to act on circadian neuronal activities within the hypothalamus to reset abnormally elevated hypothalamic drive for increased plasma glucose, triglyceride, and free fatty acid levels in fasting and postprandial states in insulin-resistant patients. Adverse events most commonly reported in clinical trials of bromocriptine included nausea, fatigue, vomiting, headache, and dizziness. These events lasted a median of 14 days and were more likely to occur during initial titration of the drug. Due to novel mechanism of action, single daily dose, and lower incidence of stroke, myocardial infarction and vascular events, bromocriptine may act as landmark in treatment of type 2 diabetes. PMID- 21814452 TI - Attitude of doctors towards physical characteristics of solid oral dosage forms. PMID- 21814453 TI - To study the effect of 'Isabgol' on absorption of 'Aspirin'. PMID- 21814454 TI - Release behavior of different physicochemical properties drug models from the ethylcellulose microcapsules. PMID- 21814455 TI - Exact Efficient Handling of Interrupted Illumination in Helical Cone-Beam Computed Tomography with Arbitrary Pitch. AB - We present a theoretically-exact and stable computed tomography (CT) reconstruction algorithm that is capable of handling interrupted illumination and therefore of using all measured data at arbitrary pitch. This algorithm is based on a differentiated backprojection (DBP) on M-lines. First, we discuss the problem of interrupted illumination and how it affects the DBP. Then we show that it is possible to take advantage of some properties of the DBP to compensate for the effects of interrupted illumination in a mathematically exact way. From there, we have developed an efficient algorithm which we have successfully implemented. We show encouraging preliminary results using both computer simulated data and real data. Our results show that our method is capable of achieving a substantial reduction of image noise when decreasing the helix pitch compared with the maximum pitch case. We conclude that the proposed algorithm defines for the first time a theoretically-exact and stable reconstruction method that is capable of beneficially using all measured data at arbitrary pitch. PMID- 21814456 TI - Sex Similarities/Differences in Trajectories of Delinquency among urban Chicago Youth: The Role of Delinquent Peers. AB - A growing body of literature has recently emerged examining sex-specific pathways of offending. Yet, despite significant gains, this area of research is still rather underexplored. With a particular focus on the role of delinquent peers, this current study investigates the sex similarities/differences in offending trajectories among a large sample of urban Chicago male and female youth (n=3,038) from 6th through 8th grade (e.g., ages 12-14). The results suggest that the pathways of offending appear to be more similar than different across sex, and that associating with delinquent peers is significantly related to baseline delinquency. Furthermore, delinquent peers significantly distinguished the moderate and high-rate trajectory groups from the non-delinquents for both males and females, yet once estimated in a more fully specified model, the role of delinquent peers appeared to be indirect (operating through its effect on baseline delinquency). Study limitations and implications for theory and policy are also discussed. PMID- 21814457 TI - Research With Cognitively Impaired Participants. AB - Illnesses that cause cognitive impairment are a considerable health problem in the United States. These include Alzheimer's disease, Huntington's chorea, cerebrovascular disease, psychiatric disorders, chronic alcoholism, and AIDS dementia complex. Illness associated with cognitive impairment may cause great suffering to the affected patients and their families. Research involving individuals who may be at risk for or have cognitive impairment is necessary to improve our understanding of these illnesses. For example, this may occur during efforts to develop effective therapies to treat them. However, research with participants who have cognitive impairment presents additional ethical concerns because they may be vulnerable to coercion. Therefore, nurse researchers must not only understand the principles of informed consent (i.e., autonomy, beneficence, nonmaleficence, and justice), but also the additional safeguards provided in the common rule to protect cognitively impaired participants in research. These safeguards include advanced informed consent, legal representative, and assent. Gaps exist in federal regulations related to adhering to these safeguards such as how to assess for decision-making capacity and variations on who can be a legal representative. The nurse researchers have potential roles as educators and advocates in research involving participants with cognitive impairment. PMID- 21814458 TI - Functional Evolution of BRCT Domains from Binding DNA to Protein. AB - The BRCT domain (BRCA1 C-terminal domain) is an important signaling and protein targeting motif in the DNA damage response system. The BRCT domain, which mainly occurs as a singleton (single BRCT) or tandem pair (double BRCT), contains a phosphate-binding pocket that can bind the phosphate from either the DNA end or a phosphopeptide. In this work, we performed a database search, phylogeny reconstruction, and phosphate-binding pocket comparison to analyze the functional evolution of the BRCT domain. We identified new BRCT-containing proteins in bacteria and eukaryotes, and found that the number of BRCT-containing proteins per genome is correlated with genome complexity. Phylogeny analyses revealed that there are two groups of single BRCT domains (sGroup I and sGroup II) and double BRCT domains (dGroup I and dGroup II). These four BRCT groups differ in their phosphate-binding pockets. In eukaryotes, the evolution of the BRCT domain can be divided into three phases. In the first phase, the sGroup I BRCT domain with the phosphate-binding pocket that can bind the phosphate of nicked DNA invaded eukaryotic genome. In the second phase, the phosphate-binding pocket changed from a DNA-binding type to a protein-binding type in sGroup II. The tandem duplication of sGroup II BRCT domain gave birth to double BRCT domain, from which two structurally and functionally distinct groups were evolved. The third phase is after the divergence between animals and plants. Both sGroup I and sGroup II BRCT domains originating in this phase lost the phosphate-binding pocket and many evolved protein-binding sites. Many dGroup I members were evolved in this stage but few dGroup II members were observed. The results further suggested that the BRCT domain expansion and functional change in eukaryote may be driven by the evolution of the DNA damage response system. PMID- 21814459 TI - Long-acting beta-adrenoceptor agonists in the management of COPD: focus on indacaterol. AB - Bronchodilators are the cornerstone of severe chronic obstructive pulmonary disease (COPD) treatment to improve airflow, symptoms, exercise tolerance, and exacerbations. There is convincing evidence that regular treatment with long acting bronchodilators is more effective and convenient than treatment with short acting bronchodilators. Long-acting beta-2-agonists include the twice-daily drugs formoterol and salmeterol and, more recently, once-daily indacaterol. Studies with head-to-head comparisons of long-acting bronchodilators are scant, but novel data from controlled trials with the once-daily beta(2)-agonist indacaterol indicate superior bronchodilation and clinical efficacy of indacaterol at recommended doses over twice-daily long-acting beta(2)-agonists, and at least equipotent bronchodilation compared with once-daily tiotropium. The recent therapeutic developments in COPD underscore a shift from short-acting bronchodilators with multiple dosings per day to reduced dosing frequency and prolonged duration of action, including once-daily treatment, with more consistent effects on various clinical outcomes. This review summarizes relevant clinical data for twice-daily beta-2-agonists in COPD, and further focuses on novel data for once-daily indacaterol, including head-to-head comparison trials. PMID- 21814460 TI - Lack of paradoxical bronchoconstriction after administration of tiotropium via Respimat(r) Soft MistTM Inhaler in COPD. AB - Bronchoconstriction has been reported in asthma and chronic obstructive pulmonary disease (COPD) patients after administration of some aqueous inhalation solutions. We investigated the incidence of this event during long-term clinical trials of tiotropium delivered via Respimat((r)) Soft MistTM Inhaler (SMI). We retrospectively analyzed pooled data from two identical Phase III clinical trials, in which 1990 patients with COPD received 48 weeks' treatment with once daily tiotropium (5 or 10 MUg) or placebo inhaled via Respimat((r)) SMI. We recorded the incidence of bronchospasm and of a range of respiratory events that could suggest bronchoconstriction during the first 30 minutes after inhalation of study treatment on each of the eight test days. No patients reported bronchospasm. Six patients (0.3%) reported a combination of at least two events suggestive of bronchoconstriction, and 21 (1.1%) reported either rescue medication use or a respiratory adverse event. Asymptomatic falls in forced expiratory volume in one second (FEV(1)) of >=15% were recorded on all test days, with no change in incidence over time, and affected 8.2% of those in the tiotropium groups and 14.5% of those on placebo. In COPD patients receiving long term treatment with tiotropium 5 or 10 MUg via Respimat((r)) SMI, no bronchospasm was recorded, and the number of events possibly indicative of paradoxical bronchoconstriction was very low. PMID- 21814461 TI - Long-term survival in elderly patients with a do-not-intubate order treated with noninvasive mechanical ventilation. AB - BACKGROUND: Noninvasive mechanical ventilation (NIMV) is an effective tool in treating patients with acute respiratory failure (ARF), since it reduces both the need for endotracheal intubation and the mortality in comparison with nonventilated patients. A particular issue is represented by the outcome of NIMV in patients referred to the emergency department for ARF and with a do-not intubate (DNI) status because of advanced age or excessively critical conditions. This study evaluated long-term survival in a group of elderly patients with acute hypercapnic ARF who had a DNI order and who were successfully treated by NIMV. METHODS: The population consisted of 54 patients with a favorable outcome after NIMV for ARF. They were followed up for 3 years by regular control visits, with at least one visit every 4 months, or as needed according to the patient's condition. Of these, 31 continued NIMV at home and 23 were on long-term oxygen therapy (LTOT) alone. RESULTS: A total of 16 of the 52 patients had not survived at the 1-year follow-up, and another eight patients died during the 3-year observation, with an overall mortality rate of 30.8% after 1 year and 46.2% after 3 years. Comparing patients who continued NIMV at home with those who were on LTOT alone, 9 of the 29 patients on home NIMV died (6 after 1 year and 3 after 3 years) and 15 of the 23 patients on LTOT alone died (10 after 1 year and 5 after 3 years). CONCLUSION: These results show that elderly patients with ARF successfully treated by NIMV following a DNI order have a satisfactory long-term survival. PMID- 21814462 TI - Improved patient outcome with smoking cessation: when is it too late? AB - Smoking is the leading modifiable risk factor for chronic obstructive pulmonary disease (COPD), cardiovascular disease (CVD), and lung cancer. Smoking cessation is the only proven way of modifying the natural course of COPD. It is also the most effective way of reducing the risk for myocardial infarction and lung cancer. However, the full benefits of tobacco treatment may not be realized until many years of abstinence. All patients with COPD, regardless of severity, appear to benefit from tobacco treatment. Similarly, patients with recent CVD events also benefit from tobacco treatment. The risk of total mortality and rate of recurrence of lung cancer is substantially lower in smokers who manage to quit smoking following the diagnosis of early stage lung cancer or small cell lung cancer. Together, these data suggest that tobacco treatment is effective both as a primary and a secondary intervention in reducing total morbidity and mortality related to COPD, CVD, and lung cancer. In this paper, we summarize the evidence for tobacco treatment and the methods by which smoking cessation can be promoted in smokers with lung disease. PMID- 21814464 TI - Survival of patients with primary liver cancer in central and northern Denmark, 1998-2009. AB - OBJECTIVE: Primary liver cancer (PLC) is a serious disease with high mortality. During the last decade, improvements in the diagnostic procedures and treatment of PLC may have improved survival. However, few updated longitudinal studies examined this issue. In a population-based setting, we studied changes in the prognoses over time. METHODS: Between 1998 and 2009, we identified all patients with PLC in the central and northern Denmark regions, with a combined population of 1.8 million. We determined age- and period-stratified survival, and computed mortality rate ratios (MRRs) with 95% confidence intervals (CIs), using Cox proportional hazard regression to assess changes over time, while controlling for age and gender. We conducted the analyses for PLC overall and separately for hepatocellular carcinoma (HCC) and cholangiocarcinoma, respectively. RESULTS: We included 1064 patients with PLC. Their median age was 69 years (range 17-94 years). The number of patients diagnosed with PLC in the period 2007-2009 was approximately 40% higher than the number in 1998-2000. One-year survival increased from 16% in 1998-2000 to 28% in 2007-2009, corresponding to an adjusted 1-year MRR of 0.65 (95% CI: 0.54-0.79). In patients aged <60 years, we found the most pronounced increase in 1-year survival, from 14% to 49% in women and from 19% to 41% in men. The 3- and 5-year survival in the entire cohort increased from 5% to a predicted 11% and from 2% to a predicted 7% during our study period, respectively. Accordingly, the expected 3- and 5-year adjusted MRRs were 0.68 (95% CI: 0.57-0.82) and 0.68 (95% CI: 0.57-0.81), respectively. One-, 3-, and 5 year survival improved during the study period for both HCC and cholangiocarcinoma. CONCLUSION: PLC survival remains poor in the Danish population, although we observed an increase over the period 1998-2009, particularly in young people. PMID- 21814463 TI - Effect of gene environment interactions on lung function and cardiovascular disease in COPD. AB - BACKGROUND: The objective of this study was to determine if gene-environment interactions between cigarette smoking and interleukin-6 (IL6), interferon-gamma (IFNG), interleukin-1beta (IL1B), or interleukin-1 receptor antagonist (IL1RN) single nucleotide polymorphisms are associated with lung function decline and cardiovascular disease in chronic obstructive pulmonary disease (COPD). METHODS: Single nucleotide polymorphisms (SNPs) in IL6, IFNG, IL1B, and IL1RN were genotyped in the Lung Health Study and correlated with rate of decline of forced expiratory volume in 1 second (FEV(1)) over 5 years, baseline FEV(1), serum protein levels, cardiovascular disease, and interactions with smoking. RESULTS: The IL6 rs2069825 single nucleotide polymorphism was associated with the rate of decline of prebronchodilator FEV(1) (P = 0.049), and was found to have a significant interaction (P = 0.004) with mean number of cigarettes smoked per day. There was also a significant interaction of IFNG rs2069727 with smoking on prebronchodilator (P = 0.008) and postbronchodilator (P =0.01) FEV(1.) The IL6 polymorphism was also associated with cardiovascular disease in heterozygous individuals (P = 0.044), and was found to have a significant interaction with smoking (P = 0.024). None of the genetic variants were associated with their respective serum protein levels. CONCLUSION: The results suggest interactions of IL6 rs2069825 and IFNG rs2069727 single nucleotide polymorphisms with cigarette smoking on measures of lung function. The IL6 rs2069825 single nucleotide polymorphism also interacted with smoking to affect the risk of cardiovascular disease in COPD patients. PMID- 21814466 TI - Pancreatic cancer survival in central and northern Denmark from 1998 through 2009: a population-based cohort study. AB - OBJECTIVES: Pancreatic cancer has a relatively low incidence but ranks fourth among cancer- related deaths in western countries. In Denmark, cancer survival generally is lower than in other countries with comparable health care systems. As a result, in 2000, a national strategy to improve cancer survival was introduced. Here we examine time trends in survival and relative mortality among pancreatic cancer patients, using Danish population and medical databases. METHODS: Using the Danish National Patient Registry (DNPR), we identified all incident pancreatic cancer patients (n = 2968) diagnosed between 1998 and 2009 in the Central and North Denmark Regions. We computed the 1-, 3-, and 5-year survival and relative mortality (MRR) and associated 95% confidence intervals (CI) adjusting for age and gender. Among surgical patients, we also computed 30 day mortality and 30-day MRR. RESULTS: Median age at diagnosis was approximately 71 years. The annual number of patients increased from 189 in 1998-2000 to 302 in 2007-2009. There was a slight improvement in 1-, 3-, and 5-year survival over time from 14.8% to 17.7%; 3.5% to a predicted 5.6%; and from 2.0% to a predicted 3.8%, from 1998-2000 to 2007-2009, respectively. Correspondingly, the adjusted relative mortality decreased from 1998-2000 to 2007-2009. Thirty-day post operative mortality decreased from 12.2% in 1998-2000 to 5.8% in 2007-2009, corresponding to a 30-day MRR of 0.38, 95% CI = 0.09, 1.6 in 2007-2009. CONCLUSION: There was a slight, albeit modest, improvement in survival and relative mortality in pancreatic cancer patients between 1998 and 2009. As we lacked staging information, it is not clear if this improvement is attributable to earlier stage at diagnosis. However, these improvements likely reflect the national cancer strategy which aimed to centralize cancer services and involved the introduction of palliative and adjuvant chemotherapy for pancreatic cancer in Denmark. The dismal prognosis of pancreatic cancer means that efforts to improve survival need to be intensified. PMID- 21814465 TI - Survival in patients with synchronous liver metastases in central and northern Denmark, 1998 to 2009. AB - OBJECTIVE: In Denmark, the strategy for treatment of cancer with metastases to the liver has changed dramatically during the period 1998 to 2009, when multidisciplinary care and a number of new treatments were introduced. We therefore examined the changes in survival in Danish patients with colorectal carcinoma (CRC) or other solid tumors (non-CRC) who had liver metastases at time of diagnosis. STUDY DESIGN AND METHODS: We included patients diagnosed with liver metastases synchronous with a primary cancer (ie, a solid cancer diagnosed at the same date or within 60 days after liver metastasis diagnosis) during the period 1998 to 2009 identified through the Danish National Registry of Patients. We followed those who survived for more than 60 days in a survival analysis (n = 1021). Survival and mortality rate ratio (MRR) at 1, 3, and 5 years stratified by year of diagnosis were estimated using Cox proportional hazards regression analysis. RESULTS: In the total study population of 1021 patients, 541 patients had a primary CRC and 480 patients non-CRC. Overall, the 5-year survival improved from 3% (95% confidence interval [CI]: 1%-6%) in 1998-2000 to 10% (95% CI: 6% 14%) in 2007 to 2009 (predicted value). The 5-year survival for CRC-patients improved from 1% (95% CI: 0%-5%) to 11% (95% CI: 6%-18%) whereas survival for non CRC patients only increased from 5% (95% CI: 1%-10%) to 8% (95% CI: 4%-14%). CONCLUSION: We observed improved survival in patients with liver metastases in a time period characterized by introduction of a structured multidisciplinary care and improved treatment options. The survival gain was most prominent for CRC patients. PMID- 21814467 TI - Survival of patients with colon and rectal cancer in central and northern Denmark, 1998-2009. AB - OBJECTIVE: The prognosis for colon and rectal cancer has improved in Denmark over the past decades but is still poor compared with that in our neighboring countries. We conducted this population-based study to monitor recent trends in colon and rectal cancer survival in the central and northern regions of Denmark. MATERIAL AND METHODS: Using the Danish National Registry of Patients, we identified 9412 patients with an incident diagnosis of colon cancer and 5685 patients diagnosed with rectal cancer between 1998 and 2009. We determined survival, and used Cox proportional hazard regression analysis to compare mortality over time, adjusting for age and gender. Among surgically treated patients, we computed 30-day mortality and corresponding mortality rate ratios (MRRs). RESULTS: The annual numbers of colon and rectal cancer increased from 1998 through 2009. For colon cancer, 1-year survival improved from 65% to 70%, and 5-year survival improved from 37% to 43%. For rectal cancer, 1-year survival improved from 73% to 78%, and 5-year survival improved from 39% to 47%. Men aged 80+ showed most pronounced improvements. The 1- and 5-year adjusted MRRs decreased: for colon cancer 0.83 (95% confidence interval CI: 0.76-0.92) and 0.84 (95% CI: 0.78-0.90) respectively; for rectal cancer 0.79 (95% CI: 0.68-0.91) and 0.81 (95% CI: 0.73-0.89) respectively. The 30-day postoperative mortality after resection also declined over the study period. Compared with 1998-2000 the 30-day MRRs in 2007-2009 were 0.68 (95% CI: 0.53-0.87) for colon cancer and 0.59 (95% CI: 0.37-0.96) for rectal cancer. CONCLUSION: The survival after colon and rectal cancer has improved in central and northern Denmark during the 1998-2009 period, as well as the 30-day postoperative mortality. PMID- 21814468 TI - Survival of women with breast cancer in central and northern Denmark, 1998-2009. AB - OBJECTIVE: Breast cancer is the most common cancer among women worldwide. The Nordic countries have relatively high survival, but Denmark has a lower survival than neighboring countries. A breast cancer screening program was introduced in 2007 and 2008 in the northern and central regions of Denmark respectively. We aimed to examine possible changes in survival of Danish breast cancer patients in central and northern Denmark in the period 1998-2009. MATERIALS AND METHODS: From the northern and central Denmark regions, we included all women (n = 13,756) with an incident diagnosis of breast cancer, as recorded in the Danish National Registry of Patients during the period January 1, 1998 through December 31, 2009. We calculated age-stratified survival and used Cox proportional hazard regression to estimate mortality rate ratios (MRRs) for all breast cancer patients. RESULTS: Median age was 62 years (21-102 years). The overall 1-year survival improved steadily over the period from 90.9% in 1998-2000 to 94.4% in 2007-2009, corresponding to a 1-year age adjusted MRR of 0.68 in 2007-2009 compared with the reference period 1998-2000. We estimated the 5-year survival to improve from 70.0% in 1998-2000 to 74.7% in 2007-2009, corresponding to a 5-year age adjusted MRR of 0.82 in 2007-2009 compared with the reference period 1998-2000. For middle aged women (50-74 years) 1-year survival increased from 92.8% in 1998-2000 to 96.6% in 2008-2009, and 5-year survival was expected to increase from 73.9% in 1998-2000 to 80.2% in 2007-2009. Among younger women (15-49 years) and elderly women (>75 years), 1-year survival and 5-year predicted survival did not change over the two time periods. CONCLUSION: Survival of breast cancer patients has improved in Denmark over the period 1998-2009, and this change was most distinct in women aged 50-74 years. Survival improved even before the implementation of a formal breast cancer screening program. PMID- 21814469 TI - Survival of prostate cancer patients in central and northern Denmark, 1998-2009. AB - OBJECTIVE: Prostate cancer is the most common noncutaneous cancer among Danish men. During the last decade, use of prostate specific antigen (PSA) testing has increased, and in clinically localized prostate cancer, curative intended treatment has gained a footing. Our aim was to examine possible changes in the short- and long-term survival of patients with prostate cancer during 1998-2009. STUDY DESIGN AND SETTING: From two Danish regions (population, 1.8 million) we included all patients (N = 10,547) with an incident diagnosis of prostate cancer retrieved from the Danish National Registry of Patients. We determined survival after 1, 3, and 5 years, stratified by age, and estimated mortality rate ratios (MRRs) using Cox proportional hazard regression to assess changes over time, controlling for age. RESULTS: During the study period, the annual number of incident prostate cancer patients more than doubled, and the median age at diagnosis decreased from 74 to 70 years. The survival improved over the study period, particularly in the last half of the period (2004-2009). Thus, 1-year survival increased from 80% (1998-2000) to 90% (2007-2009), corresponding to an age-adjusted MRR of 0.54 (95% confidence interval CI: 0.46-0.63). The expected increase in 3- and 5-year survival was even more pronounced: 47%-73% and 34%-60%, respectively. This corresponded to a 3-year age-adjusted MRR of 0.46 (95% CI: 0.42-0.51) and a 5-year MRR of 0.50 (95% CI: 0.46-0.54). The 1-, 3-, and 5-year overall survival increased in all age groups (<70 years, 70-79 years, >=80 years). CONCLUSION: Survival after prostate cancer has improved in Denmark within the last decade. Although diagnosis and treatment improvements could explain this, length and lead time bias are likely to have influenced our results. PMID- 21814470 TI - Survival of invasive bladder cancer patients, 1998-2009; a central and northern Denmark population-based cohort study. AB - OBJECTIVE: Invasive bladder cancer (IBC) is a common urological malignancy accounting for 4%-5% of all cancers in Denmark. Our aim was to examine possible changes in short- and long-term survival of patients with IBC during 1998-2009. STUDY DESIGN AND SETTING: Data on all patients (N = 4032) with an incident diagnosis of IBC within a population of 1.8 million were retrieved from the Danish National Registry of Patients from 1998 to 2009. We computed survival after 1, 3, and 5 years, stratified by age and gender, and estimated mortality rate ratios (MRR) using Cox proportional hazard regression to compare mortality over time, controlling for age and gender. Data on tumor stage or histology were not included. RESULTS: During the study period, the annual numbers of incident IBC patients remained stable. The median age was 74 years in each of the four 3 year periods in the study. The survival was relatively stable during the first three periods, whilst data from the last period showed modest improvement. The overall 1-year survival increased from 68% in 1998-2000 to 70% in 2007-2009, corresponding to an age and gender adjusted MRR of 0.89 (95% confidence interval [CI] 0.76-1.03). The 3- and 5-year survival was predicted to increase from 44% to 49% and from 35% to 40% respectively. This corresponded to a 3-year age and gender adjusted MRR of 0.87 (95% CI 0.77-0.98) and a 5-year MRR of 0.88 (95% CI 0.79-0.99). The 1-, 3-, and 5-year survival increased for men in all age groups (<70 years, 70-79 years, >=80 years) and in women only in the 70-79-year age group. CONCLUSION: The survival of IBC patients increased slightly in northern and central Denmark in the 1998-2009 period. PMID- 21814471 TI - Survival of patients with kidney cancer in central and northern Denmark, 1998 2009. AB - OBJECTIVE: For decades, kidney cancer patients in Denmark have had lower survival than patients in the other Scandinavian countries. Our aim was to study possible changes in survival of patients with kidney cancer after implementation of two national Danish cancer plans. STUDY DESIGN AND SETTING: From 1998 through 2009 we included all patients (N = 2659) with an incident diagnosis of kidney cancer in two Danish regions (population 1.8 million). Data were retrieved from the Danish National Registry of Patients. We computed survival after 1, 3, and 5 years, stratified by age, and estimated mortality rate ratios (MRRs) using Cox regression to assess changes over time, controlling for age and gender. We lacked data on stage distribution. Among patients who had a nephrectomy we also computed 30-day mortality and 30-day MRRs. RESULTS: During the study period, we identified 2659 patients with kidney cancer. The annual number of patients increased from 583 in the period 1998-2000 to 853 in the period 2007-2009. The median age at diagnosis was 69 years throughout the study period. The overall 1-year survival improved from 56% (1998-2000) to 63% (2007-2009), corresponding to an adjusted MRR of 0.78 (95% confidence interval [CI] 0.66-0.93). We predicted the 3-year survival to increase from 40% to 51% and the 5-year survival to increase from 33% to 42%, corresponding to predicted MRRs of 0.76 (95% CI 0.66-0.87) and 0.77 (95% CI 0.68-0.89), respectively. Survival increased in all age groups (15-59 years, 60-74 years, 75+ years) and in both genders, except for men below 60 years, for whom the 1-year survival declined from 76% to 69%. The 30-day mortality after nephrectomy declined from 4% to 2% during the study period. CONCLUSION: We observed an improvement in the survival and relative mortality in kidney cancer patients, although not in men younger than 60 years. PMID- 21814472 TI - Survival of patients with ovarian cancer in central and northern Denmark, 1998 2009. AB - OBJECTIVE: To examine time trends of survival and mortality of ovarian cancer in the central and northern Denmark regions during the period 1998-2009. STUDY DESIGN AND SETTING: We conducted a cohort study including women recorded with a first-time diagnosis of ovarian cancer in the Danish National Registry of Patients (DNRP) between 1998 and 2009. Patients were followed for survival through the Danish Civil Registration System. We determined survival stratified by age, and used Cox proportional hazard regression analyses to obtain mortality rate ratios (MRRs) to assess changes over time. RESULTS: We found no improvement in overall ovarian cancer survival between 1998 and 2009. One-year survival was 71% in 1998-2000 and 68% in 2007-2009. Three-year survival declined from 48% in 1998-2000 to 46% in 2007-2009 (predicted), and 5-year survival declined from 40% in 1998-2000 to 37% in 2007-2009 (predicted). Compared with the period 1998-2000, the age-adjusted 1-year MRR was 1.05 (95% confidence interval CI: 0.86-1.28) for the period 2007-2009, and the predicted age-adjusted 3- and 5-year MRRs were 0.96 (95% CI: 0.83-1.12) and 0.99 (95% CI: 0.86-1.14), respectively. Results are not adjusted for tumor stage as this information was not available. We also observed a decline in the annual number of incident ovarian cancer patients during the study period, most pronounced in the youngest age group. CONCLUSION: The survival of ovarian cancer patients did not improve during the study period. This lack of improvement contrasts with the national cancer strategies implemented during this last decade, focusing on improving the survival of ovarian cancer patients. PMID- 21814475 TI - Placenta percreta-induced uterine rupture diagnosed by laparoscopy in the first trimester. AB - Spontaneous uterine rupture is lethal in pregnant women. Placenta percreta induced spontaneous uterine rupture in the first trimester is extremely rare and difficult to diagnose. A 35-year-old pregnant woman, with a history of 2 vaginal deliveries and 2 spontaneous abortions treated by dilatation and curettage, was admitted to the emergency department because of sudden severe abdominal pain; the gestational age as calculated by sonography was 14 weeks. Diagnostic laparoscopy was considered for surgical abdomen and fluid collection that was noted in sonography. During laparoscopy, uterine rupture with massive bleeding was detected; therefore, total abdominal hysterectomy was performed. The patient was discharged without any complications. Pathological analysis of the uterine specimen revealed placenta percreta to be the cause of the rupture. Uterine rupture should be considered in the differential diagnosis in all pregnant women who present with acute abdomen, show fluid collection in the peritoneal cavity. In addition, we recommend laparoscopy for the investigation of acute abdomen with unclear diagnosis in the first trimester of pregnancy. PMID- 21814474 TI - Spinal intramedullary cysticercosis: a case report and literature review. AB - Neurocysticercosis, involvement of the central nervous system by taenia solium, is one of the most common parasitic diseases of the CNS. However, spinal involvement by neurocysticercosis is uncommon. Here, we reported a 40-year-old woman with intramedullary cysticercosis in the thoracic spinal cord. MRI revealed two well-defined round intramedullary lesions at T4 and T5 vertebral levels, which were homogeneously hypointense on T1WI and hyperintense on T2WI with peripheral edema. Since the patient had progressive neurological deficits, surgery was performed to decompress the spinal cord. Histopathology examination of the removed lesion proved it was intramedullary cysticercosis. In this report, we also discussed the principles of diagnosis and treatment of intramedullary cysticercosis in combination of literature review. PMID- 21814476 TI - A comparison of immuncapture agglutination and ELISA methods in serological diagnosis of brucellosis. AB - BACKGROUND: Different serological tests are used in serologic diagnosis of brucellosis. The most widely used of these are Standard Tube Agglutination and Coombs anti-brucella tests. Whereas ELISA Ig M and Ig G tests have been in use for a long time, immuncapture agglutination test has been recently introduced and used in serological diagnosis. The aim of this study was to compare diagnostic values of ELISA Ig M and Ig G and immuncapture agglutination tests with Coombs anti-brucella test. METHODS: Sera from 200 patients with presumptive diagnosis of brucellosis were included into the study. Coombs anti-brucella test, ELISA Ig M and Ig G tests and Immuncapture test were investigated in these sera. Then, sensitivity, specificity, negative predictive and positive predictive values were calculated. RESULTS: Sensitivity, specificity, negative predictive and positive predictive values were found to be 90.6%, 76.3%, 94.2%, and 65.9% respectively for the Immuncapture test, whereas they were found to be 73.7%, 58.9%, 84.2%, and 42.8% for Ig G and 72.2%, 67.8%, 85.2%, and 48.7% for Ig M. The Immuncapture test was found to be compatible with ELISA Ig M and Ig G tests but it was statistically incompatible with Coombs anti-brucella test. CONCLUSIONS: Immuncapture agglutination test yields similar results to those of Coombs anti brucella test. This test is a useful test by virtue of the fact that it determines blocking antibodies in the diagnosis and follow-up of brucellosis. PMID- 21814473 TI - Mitochondrial Medicine and the Neurodegenerative Mitochondriopathies. AB - Neurodegenerative diseases are a common late-life scourge for which disease modifying treatments are sorely needed. Mitochondrial perturbation is commonly observed in these diseases, so pursuing treatment development strategies that target mitochondria or processes affected by mitochondria seems reasonable. This review discusses the rationale underlying past and current efforts to treat neurodegenerative diseases using mitochondrial medicine, and tries to predict how future efforts might proceed. PMID- 21814477 TI - Lack of preemptive analgesia by intravenous flurbiprofen in thyroid gland surgery: a randomized, double-blind and placebo-controlled clinical trial. AB - BACKGROUND: Nowadays, increasingly more preemptive analgesia studies focus on postoperative pain; however, the impact of preemptive analgesia on perioperative opioid requirement is not well defined. This study was carried out in order to evaluate whether preoperative intravenous flurbiprofen axetil can reduce perioperative opioid consumption and provide postoperative analgesia in patients undergoing thyroid gland surgery. METHODS: Ninety patients undergoing elective thyroid gland surgery were randomly assigned to three groups. Group A (Control) was administered Intralipid((r)) 2 ml as a placebo 15 min before the cervical plexus block and at the end of the surgery; Group B (Routine analgesia) was administered a placebo 15 min before the cervical plexus block and flurbiprofen 50 mg at the end of the surgery; Group C (Preemptive analgesia) was administered intravenous flurbiprofen 50 mg 15 min before the cervical plexus block and a placebo at the end of the surgery. Sufentanil administration during the surgery and the 24 h satisfaction score on analgesic therapy were both recorded. The analgesic efficacy was assessed at 1, 2, 4, 6, 8, 12, and 24 hours after the surgery, based on visual analog scales. RESULTS: Ninety patients were involved in the study. One patient from Group B did not have their scheduled surgery; eighty nine patients completed the study. There were no significant differences in the patient demographics between the three groups. Visual analog scales: 1, 2, 4 h for Group A was significantly higher than Groups B and C (P<0.05); Sufentanil administration during surgery: Group C was obviously lower compared to Groups A and B (P<0.05); 24 h satisfaction score: Groups B and C were higher than Group A (P<0.05). CONCLUSION: Preoperative administration of intravenous Flurbiprofen axetil reduced analgesic consumption during surgery, but not postoperative pain scores. PMID- 21814478 TI - Maternal outcomes according to placental position in placental previa. AB - PURPOSE: The purpose of this retrospective cohort study was to elucidate whether the location of placenta below uterine incision in cesarean section is important in the development of maternal complications in placenta previa patients. METHODS: The study was conducted on 409 patients 414 parturition at 3 hospitals in affiliation with the Catholic Medical Center, Seoul, Korea from May 1999 to December 2009. The subjects were divided to two groups: the group whose placenta was located in the anterior portion of the uterus (anterior group) and the group whose placenta was located in the posterior portion of the uterus (posterior group). And then they are compared to each other. Logistic regression was used to control for confounding factors. RESULTS: In the anterior group, regardless of confounding factors, the incidence of excessive blood loss (OR 2.97; 95% CI: 1.64 5.37), massive transfusion (OR 3.31; 95% CI: 1.33-8.26), placental accreta (OR 2.60, 95% CI: 1.40-4.83), and hysterectomy (OR 3.47, 95% CI: 1.39-8.68) was higher. CONCLUSION: Sonographic determination of the placental position where its location beneath the uterine incision is very important to predict maternal outcomes in placenta previa patients, and such cases, close attention should be paid for massive hemorrhage. PMID- 21814479 TI - Cloning and characterization of a 2-cys peroxiredoxin in the pine wood nematode, Bursaphelenchus xylophilus, a putative genetic factor facilitating the infestation. AB - The pine wood nematode, Bursaphelenchus xylophilus, is an invasive plant parasitic nematode and a worldwide quarantine pest. An indigenous species in North America and the causal agent of pine wilt disease, B. xylophilus has devastated pine production in Southeastern Asia including Japan, China, and Korea since its initial introduction in the early 1900s. The reactive oxygen species (ROS) is the first line of defense utilized by host plants against parasites, while nematodes, counteractively, employ antioxidants to facilitate their infection. Peroxiredoxins (Prxs) are a large class of antioxidants recently found in a wide variety of organisms. In this report, a gene encoding a novel 2 cysteine peroxiredoxin protein in B. xylophilus was cloned and characterized. The 2-cysteine peroxiredoxin in B. xylophilus (herein refers to as "BxPrx") is highly conserved in comparison to 2-cysteine peroxiredoxins (Prx2s) in other nematodes, which have two conserved cysteine amino acids (Cp and Cr), a threonine-cysteine arginine catalytic triad, and two signature motifs (GGLG and YF) sensitive to hydrogen peroxide. In silico assembly of BxPrx tertiary structure reveals the spatial configuration of these conserved domains and the simulated BxPrx 3 dimensional structure is congruent with its presumed redox functions. Although no signal peptide was identified, BxPrx was abundantly expressed and secreted under the B. xylophilus cuticle. Upon further analysis of this leader-less peptide, a single transmembrane alpha-helix composed of 23 consecutive hydrophobic amino acids was found in the primary structure of BxPrx. This transmembrane region and/or readily available ATP binding cassette transporters may facilitate the transport of non-classical BxPrx across the cell membrane. Recombinant BxPrx showed peroxidase activity in vitro reducing hydrogen peroxide using glutathione as the electron donor. The combined results from gene discovery, protein expression and distribution profiling (especially the "surprising" presence under the nematode cuticle), and recombinant antioxidant activity suggest that BxPrx plays a key role in combating the oxidative burst engineered by the ROS defense system in host plants during the infection process. In summary, BxPrx is a genetic factor potentially facilitating B. xylophilus infestation. PMID- 21814480 TI - Effects of diosgenin on myometrial matrix metalloproteinase-2 and -9 activity and expression in ovariectomized rats. AB - Diosgenin, a traditional Yam extraction, has been used in hormone replacement for menopausal women. We aimed to investigate the influences of diosgenin administration upon the MMP-2 and -9 activity and expression and reproductive hormones of ovariectomized (OVX) rats, a model of menopausal status. Seven-week old female Wistar rats with bilateral OVX or sham operation (controls) were divided and administered different dosages of diosgenin (0, 10, 50, or 100 mg/kg/day) for 8 weeks. Serum was then sampled for progesterone (P4) and estradiol (E2) assay and uterine horns harvested. Myometrial MMP-2 and -9 activity and expression were surveyed and myometrial collagen expression was also assayed. The results show higher body weight in OVX rats across the 8 weeks post surgery and no significant differences were noted among OVX or Sham rats with diosgenin supplements. There were lower P4 and E2 concentrations in OVX rats compared to Sham rats, and higher P4 concentration of Sham rats post diosgenin supplement. MMP-2 and -9 mRNA expression and activity was lower in OVX rats, although higher MMP-2 and lower MMP-9 activity/mRNA expression was observed in OVX rats post diosgenin supplementation. Collagen mRNA expression was higher in OVX rats compared to Sham controls, and diosgenin administration decreased collagen mRNA expression in OVX rats. In conclusion, diosgenin is associated with gelatinase expression and collagen metabolism in OVX rats. Diosgenin administration can partially reverse the effects of OVX upon MMP functions and hormone status. Adequate diosgenin supplement might modulate myometrial gelatinase expression and collagen metabolism in menopausal subjects. PMID- 21814481 TI - Ultrastructural characterization of olfactory sensilla and immunolocalization of odorant binding and chemosensory proteins from an ectoparasitoid Scleroderma guani (Hymenoptera: Bethylidae). AB - The three-dimensional structures of two odorant binding proteins (OBPs) and one chemosensory protein (CSP) from a polyphagous ectoparasitoid Scleroderma guani (Hymenoptera: Bethylidae) were resolved bioinformatically. The results show that both SguaOBP1 and OBP2 are classic OBPs, whereas SguaCSP1 belongs to non-classic CSPs which are considered as the "Plus-C" CSP in this report. The structural differences between the two OBPs and between OBP and CSP are thoroughly described, and the structural and functional significance of the divergent C terminal regions (e.g., the prolonged C-terminal region in SguaOBP2 and the additional pair of cysteines in SguaCSP1) are discussed. The immunoblot analyses with antisera raised against recombinant SguaOBP1, OBP2, and CSP1, respectively, indicate that two SguaOBPs are specific to antennae, whereas SguaCSP1, which are more abundant than OBPs and detected in both male and female wasps, expresses ubiquitously across different tissues.We also describe the ultrastructure of the antennal sensilla types in S. guani and compare them to 19 species of parasitic Hymenoptera. There are 11 types of sensilla in the flagellum and pedicel segments of antennae in both male and female wasps. Seven of them, including sensilla placodea (SP), long sensilla basiconica (LSB), sensilla coeloconica (SC), two types of double-walled wall pore sensilla (DWPS-I and DWPS-II), and two types of sensilla trichodea (ST-I and ST-II), are multiporous chemosensilla. The ultralsturctures of these sensilla are morphologically characterized. In comparison to monophagous specialists, the highly polyphagous generalist ectoparasitoids such as S. guani possess more diverse sensilla types which are likely related to their broad host ranges and complex life styles. Our immunocytochemistry study demonstrated that each of the seven sensilla immunoreacts with at least one antiserum against SguaOBP1, OBP2, and CSP1, respectively. Anti-OBP2 is specifically labeled in DWPS-II, whereas the anti-OBP1 shows a broad spectrum of immunoactivity toward four different sensilla (LSB, SP, ST-I and ST-II). On the other hand, anti-CSP1 is immunoactive toward SP, DWPS-I and SC. Interestingly, a cross co-localization pattern between SguaOBP1 and CSP1 is documented for the first time. Given that the numbers of OBPs and CSPs in many insect species greatly outnumber their antennal sensilla types, it is germane to suggest such phenomenon could be the rule rather than the exception. PMID- 21814482 TI - Dimerumic acid inhibits SW620 cell invasion by attenuating H2O2-mediated MMP-7 expression via JNK/C-Jun and ERK/C-Fos activation in an AP-1-dependent manner. AB - Reactive oxygen species (ROS) such as hydrogen peroxide (H2O2) in the tumor microenvironment play important roles in tumor invasion and metastasis. Recently, ROS have been reported to cause a significant increase in the production and expression of matrix metalloproteinase (MMP)-7, which is closely correlated with metastatic colorectal cancer. The present study was undertaken to evaluate the scavenging activity of dimerumic acid (DMA) for H2O2 isolated from Monascus fermented rice to investigate the inhibitory effects of DMA on the invasive potential of SW620 human colon cancer cells, and to explore the mechanisms underlying both these phenomena. Our results showed that increased MMP-7 expression due to H2O2 exposure was mediated by activation of mitogen-activated protein kinases (MAPKs) such as Jun N-terminal kinase (JNK), extracellular regulated kinase (ERK), and p38 kinase. DMA pretreatment suppressed activation of H2O2-mediated MAPK pathways and cell invasion. Moreover, H2O2-triggered MMP-7 production was demonstrated via JNK/c-Jun and ERK/c-Fos activation in an activating protein 1 (AP-1)-dependent manner. Taken together, these results suggest that DMA suppresses H2O2-induced cell invasion by inhibiting AP-1 mediated MMP-7 gene transcription via the JNK/c-Jun and ERK/c-Fos signaling pathways in SW620 human colon cancer cells. Our data suggest that DMA may be useful in minimizing the development of colorectal metastasis. In the future, DMA supplementation may be a beneficial antioxidant to enhance surgical outcomes. PMID- 21814483 TI - NADPH oxidase: a target for the modulation of the excessive oxidase damage induced by overtraining in rat neutrophils. AB - OBJECTIVE: The purpose of this study is to demonstrate that NADPH oxidase mediating the ROS production is the major pathway for ROS generation in neutrophils during exercise. NADPH oxidase, as a target can modulate oxidative damage induced by overtraining, which can be value to the prevention of exercise induced immunosuppression. METHODS: Thirty male Wistar rats were randomly divided into three groups: a negative control group (C, n = 10), an overtraining group (E, n = 10) and an overtraining + DPI intervention group (D, n =10). Groups E and D were trained on a standard treadmill with progressive load for 11 weeks. After 36-40 h from the last training, eight rats were randomly selected from each group, and blood was sampled from the orbital vein. ELISAs were used to measure serum cytokine levels and lipid peroxidation in blood plasma. Flow cytometry with Annexin V/PI double staining was used to measure neutrophil apoptosis and necrosis. DNA damage in lymphocytes was tested using single cell gel electrophoresis (SCGE). The co-localization between gp91(phox) and p47(phox) of the NADPH-oxidase was detected using immunocytochemistry and confocal microscopy. RESULTS: 1) Compared with group C, the concentrations of IL-1beta, IL-8, and TNF alpha were significantly increased and MCP-1, and CINC were significantly decreased in blood plasma from group E (P < 0.01 and P < 0.05, respectively). Concentrations of IL-1beta and MCP-1 were decreased (P < 0.05), and IL-8 and TNF alpha were significantly increased (P <0.05) in blood plasma from group D. MDA and MPO were elevated in plasma from groups E and D (P < 0.01 and P < 0.05, respectively). 2) Compared with group C, the percentage of neutrophils apoptosis were significantly elevated (P < 0.01) in both groups E and D, and the percentage of cell death was raised in group E (P < 0.05). No significant change was observed in group D. 3) Compared with group C, the number of comet cells, an indicator of DNA damage, was significantly increased (P < 0.01), and the width and tail length of comet cells were notably increased in group E, while no significant increase was observed in group D. 4) The p47(phox )protein translocated to the cell membrane and co-localized with the gp91(phox) subunit of NADPH oxidase in neutrophils activated by overtraining. CONCLUSION: 1) Excessive exercise led to an increased secretion of inflammatory cytokines and chemokines in peripheral blood, and it may have induced tissue inflammation 2) Overtraining can activate the NADPH oxidase-mediated overproduction of ROS, leading to increased lipid peroxidation. 3) NADPHoxidase in neutrophils as a target, was responsible for ROS, oxidative damage to phagocytes and lymphocytes and changes to inflammatory cytokines and immune regulatory factors all affect cellular immune functions and may be causative factors for exercise-induced immunosuppression. PMID- 21814484 TI - Long-term cultured human neural stem cells undergo spontaneous transformation to tumor-initiating cells. AB - In this report, we describe the spontaneous malignant transformation of long-term cultured human fetal striatum neural stem cells (hsNSCs, passage 17). After subcutaneous transplantation of long-term cultured hsNSCs into immunodeficient nude mice, 2 out of 15 mice formed xenografts which expressed neuroendocrine tumor markers CgA and NSE. T1 cells, a cell line that we derived from one of the two subcutaneous xenografts, have undergone continuous expansion in vitro. These T1 cells showed stem cell-like features and expressed neural stem cell markers nestin and CD133. The T1 cells were involved in abnormal karyotype, genomic instability and fast proliferation. Importantly, after long-term in vitro culture, the T1 cells did not result in subcutaneous xenografts, but induced intracranial tumor formation, indicating that they adjusted themselves to the intracranial microenvironment. We further found that the T1 cells exhibited an overexpressed level of EGFR, and the CD133 positive T1 cells showed a truncation mutation in the exons 2-7 of the EGFR (EGFRvIII) gene. These results suggest that continuous expansion of neural stem cells in culture may lead to malignant spontaneous transformation. This phenomenon may be functionally related to EGFR by EGFRvIII gene mutation. PMID- 21814485 TI - Autosomal interactions and mechanisms of pyrethroid resistance in house flies, Musca domestica. AB - Five BC1 lines and 16 house fly mass-cross homozygous lines were generated from crosses of the pyrethroid resistant ALHF (wild-type) and susceptible aabys (bearing recessive morphological markers on each of five autosomes) strains. Each of the resulting homozygous lines had different combinations of autosomes from the resistant ALHF strain. Levels of resistance to permethrin were measured for each line to determine the autosomal linkage, interaction and, possibly, regulation in pyrethroid resistance of house flies. Results indicated that factors on autosome 4 are not involved in the development of resistance in house flies, while factors on autosomes 1, 2, 3 and 5 play important roles in pyrethroid resistance. The sodium channel gene has been mapped on autosome 3 and multiple cytochrome P450 genes overexpressed in resistant ALHF house flies have been genetically mapped on autosome 5, suggesting that P450 mediated detoxification and sodium channel-mediated target site insensitivity located on autosomes 3 and 5, respectively, are major factors related to resistance development in house flies. However, neither the factors on autosome 3 or 5 alone, nor the factors from both autosomes 3 and 5 combined could confer high levels of resistance to pyrethroid. In addition, strong synergistic effects on resistance was obtained when autosomes 1 and 2 interact with autosome 3 and/or 5, suggesting that the trans factors on autosomes 1 and 2 may interact with factors on autosomes 3 and 5, therefore, playing regulatory roles in the development of sodium channel insensitivity- and P450 detoxification-mediated resistance. PMID- 21814486 TI - Treatments for Depression in Older Persons with Dementia. PMID- 21814487 TI - Race differences in psychopathology and disparities in treatment seeking: Community and jail-based treatment seeking patterns. AB - Whites in community samples utilize mental health services at a much higher rate than African Americans (Kessler, et al., 2005). Is this also the case among those in jails? In this study of jail inmates (229 African American, 185 White) there were no race difference in the overall need for mental health treatment (63% of participants had significant symptoms on the Personality Assessment Inventory) but race differences in the level and types of symptoms were evident. Additionally, while Whites were more likely to report pre-incarceration treatment there were no differences in treatment seeking or access to mental health programs while in jail, implying that if barriers to treatment in the community were removed (cost/insurance, location/transportation, time) racial disparities in treatment utilization may be reduced. PMID- 21814488 TI - Antagonism of LIN-17/Frizzled and LIN-18/Ryk in nematode vulva induction reveals evolutionary alterations in core developmental pathways. AB - Most diversity in animals and plants results from the modification of already existing structures. Many organ systems, for example, are permanently modified during evolution to create developmental and morphological diversity, but little is known about the evolution of the underlying developmental mechanisms. The theory of developmental systems drift proposes that the development of conserved morphological structures can involve large-scale modifications in their regulatory mechanisms. We test this hypothesis by comparing vulva induction in two genetically tractable nematodes, Caenorhabditis elegans and Pristionchus pacificus. Previous work indicated that the vulva is induced by epidermal growth factor (EGF)/RAS and WNT signaling in Caenorhabditis and Pristionchus, respectively. Here, we show that the evolution of vulva induction involves major molecular alterations and that this shift of signaling pathways involves a novel wiring of WNT signaling and the acquisition of novel domains in otherwise conserved receptors in Pristionchus vulva induction. First, Ppa-LIN-17/Frizzled acts as an antagonist of WNT signaling and suppresses the ligand Ppa-EGL-20 by ligand sequestration. Second, Ppa-LIN-18/Ryk transmits WNT signaling and requires inhibitory SH3 domain binding motifs, unknown from Cel-LIN-18/Ryk. Third, Ppa-LIN 18/Ryk signaling involves Axin and beta-catenin and Ppa-axl-1/Axin is epistatic to Ppa-lin-18/Ryk. These results confirm developmental system drift as an important theory for the evolution of organ systems and they highlight the significance of protein modularity in signal transduction and the dynamics of signaling networks. PMID- 21814489 TI - Formation of the long range Dpp morphogen gradient. AB - The TGF-beta homolog Decapentaplegic (Dpp) acts as a secreted morphogen in the Drosophila wing disc, and spreads through the target tissue in order to form a long range concentration gradient. Despite extensive studies, the mechanism by which the Dpp gradient is formed remains controversial. Two opposing mechanisms have been proposed: receptor-mediated transcytosis (RMT) and restricted extracellular diffusion (RED). In these scenarios the receptor for Dpp plays different roles. In the RMT model it is essential for endocytosis, re-secretion, and thus transport of Dpp, whereas in the RED model it merely modulates Dpp distribution by binding it at the cell surface for internalization and subsequent degradation. Here we analyzed the effect of receptor mutant clones on the Dpp profile in quantitative mathematical models representing transport by either RMT or RED. We then, using novel genetic tools, experimentally monitored the actual Dpp gradient in wing discs containing receptor gain-of-function and loss-of function clones. Gain-of-function clones reveal that Dpp binds in vivo strongly to the type I receptor Thick veins, but not to the type II receptor Punt. Importantly, results with the loss-of-function clones then refute the RMT model for Dpp gradient formation, while supporting the RED model in which the majority of Dpp is not bound to Thick veins. Together our results show that receptor mediated transcytosis cannot account for Dpp gradient formation, and support restricted extracellular diffusion as the main mechanism for Dpp dispersal. The properties of this mechanism, in which only a minority of Dpp is receptor-bound, may facilitate long-range distribution. PMID- 21814490 TI - Hypoxia-inducible factor directs POMC gene to mediate hypothalamic glucose sensing and energy balance regulation. AB - Hypoxia-inducible factor (HIF) is a nuclear transcription factor that responds to environmental and pathological hypoxia to induce metabolic adaptation, vascular growth, and cell survival. Here we found that HIF subunits and HIF2alpha in particular were normally expressed in the mediobasal hypothalamus of mice. Hypothalamic HIF was up-regulated by glucose to mediate the feeding control of hypothalamic glucose sensing. Two underlying molecular pathways were identified, including suppression of PHDs by glucose metabolites to prevent HIF2alpha degradation and the recruitment of AMPK and mTOR/S6K to regulate HIF2alpha protein synthesis. HIF activation was found to directly control the transcription of POMC gene. Genetic approach was then employed to develop conditional knockout mice with HIF inhibition in POMC neurons, revealing that HIF loss-of-function in POMC neurons impaired hypothalamic glucose sensing and caused energy imbalance to promote obesity development. The metabolic effects of HIF in hypothalamic POMC neurons were independent of leptin signaling or pituitary ACTH pathway. Hypothalamic gene delivery of HIF counteracted overeating and obesity under conditions of nutritional excess. In conclusion, HIF controls hypothalamic POMC gene to direct the central nutrient sensing in regulation of energy and body weight balance. PMID- 21814491 TI - Different paths, same structure: "developmental systems drift" at work. PMID- 21814492 TI - Invertebrate post-segregation distorters: a new embryo-killing gene. AB - Cytoplasmic incompatibility induced by inherited intracellular bacteria of arthropods, and Medea elements found in flour beetles, are both forms of postsegregation distortion involving the killing of embryos in order to increase the ratio of progeny that inherit them. The recently described peel-zeel element of Caenorhabditis elegans also uses this mechanism; like Medea the genes responsible are in the nuclear genome but it shares a paternal mode of action with the bacteria. The peel-1 gene has now been shown to encode a potent toxin that is delivered by sperm, and rescued by zygotic transcription of the linked zeel-1. The predominance of self-fertilization in C. elegans has produced an unusual distribution pattern for a selfish genetic element; further population and functional studies will shed light on its evolution. The element might also have potential for use in disease control. PMID- 21814494 TI - Nothing Iffy about HIF in the Hypothalamus. AB - Two crucial biological processes are (1) the sensing and coordination of responses to low oxygen levels and (2) the control of food intake and energy expenditure. The hypoxia-inducible factor (HIF) family of proteins is known to regulate responses to low oxygen, whereas neuropeptides derived from proopiomelanocortin (POMC) are implicated in the control of food intake and energy expenditure. It is now becoming apparent that these two apparently disparate processes may be linked, with the exciting discovery that HIF proteins can act in the brain to regulate food intake and energy expenditure as reported in the current issue of PLoS Biology. This primer discusses the traditional role of HIF proteins in terms of responding to oxygen levels in the periphery and also their new role in coordinating responses to nutrients in the brain through regulation of POMC. PMID- 21814493 TI - A novel sperm-delivered toxin causes late-stage embryo lethality and transmission ratio distortion in C. elegans. AB - The evolutionary fate of an allele ordinarily depends on its contribution to host fitness. Occasionally, however, genetic elements arise that are able to gain a transmission advantage while simultaneously imposing a fitness cost on their hosts. We previously discovered one such element in C. elegans that gains a transmission advantage through a combination of paternal-effect killing and zygotic self-rescue. Here we demonstrate that this element is composed of a sperm delivered toxin, peel-1, and an embryo-expressed antidote, zeel-1. peel-1 and zeel-1 are located adjacent to one another in the genome and co-occur in an insertion/deletion polymorphism. peel-1 encodes a novel four-pass transmembrane protein that is expressed in sperm and delivered to the embryo via specialized, sperm-specific vesicles. In the absence of zeel-1, sperm-delivered PEEL-1 causes lethal defects in muscle and epidermal tissue at the 2-fold stage of embryogenesis. zeel-1 is expressed transiently in the embryo and encodes a novel six-pass transmembrane domain fused to a domain with sequence similarity to zyg 11, a substrate-recognition subunit of an E3 ubiquitin ligase. zeel-1 appears to have arisen recently, during an expansion of the zyg-11 family, and the transmembrane domain of zeel-1 is required and partially sufficient for antidote activity. Although PEEL-1 and ZEEL-1 normally function in embryos, these proteins can act at other stages as well. When expressed ectopically in adults, PEEL-1 kills a variety of cell types, and ectopic expression of ZEEL-1 rescues these effects. Our results demonstrate that the tight physical linkage between two novel transmembrane proteins has facilitated their co-evolution into an element capable of promoting its own transmission to the detriment of organisms carrying it. PMID- 21814495 TI - Comparison of Xpert MTB/RIF with other nucleic acid technologies for diagnosing pulmonary tuberculosis in a high HIV prevalence setting: a prospective study. AB - BACKGROUND: The Xpert MTB/RIF (Cepheid) non-laboratory-based molecular assay has potential to improve the diagnosis of tuberculosis (TB), especially in HIV infected populations, through increased sensitivity, reduced turnaround time (2 h), and immediate identification of rifampicin (RIF) resistance. In a prospective clinical validation study we compared the performance of Xpert MTB/RIF, MTBDRplus (Hain Lifescience), LightCycler Mycobacterium Detection (LCTB) (Roche), with acid fast bacilli (AFB) smear microscopy and liquid culture on a single sputum specimen. METHODS AND FINDINGS: Consecutive adults with suspected TB attending a primary health care clinic in Johannesburg, South Africa, were prospectively enrolled and evaluated for TB according to the guidelines of the National TB Control Programme, including assessment for smear-negative TB by chest X-ray, clinical evaluation, and HIV testing. A single sputum sample underwent routine decontamination, AFB smear microscopy, liquid culture, and phenotypic drug susceptibility testing. Residual sample was batched for molecular testing. For the 311 participants, the HIV prevalence was 70% (n = 215), with 120 (38.5%) culture-positive TB cases. Compared to liquid culture, the sensitivities of all the test methodologies, determined with a limited and potentially underpowered sample size (n = 177), were 59% (47%-71%) for smear microscopy, 76% (64%-85%) for MTBDRplus, 76% (64%-85%) for LCTB, and 86% (76%-93%) for Xpert MTB/RIF, with specificities all >97%. Among HIV+ individuals, the sensitivity of the Xpert MTB/RIF test was 84% (69%-93%), while the other molecular tests had sensitivities reduced by 6%. TB detection among smear-negative, culture-positive samples was 28% (5/18) for MTBDRplus, 22% (4/18) for LCTB, and 61% (11/18) for Xpert MTB/RIF. A few (n = 5) RIF-resistant cases were detected using the phenotypic drug susceptibility testing methodology. Xpert MTB/RIF detected four of these five cases (fifth case not tested) and two additional phenotypically sensitive cases. CONCLUSIONS: The Xpert MTB/RIF test has superior performance for rapid diagnosis of Mycobacterium tuberculosis over existing AFB smear microscopy and other molecular methodologies in an HIV- and TB-endemic region. Its place in the clinical diagnostic algorithm in national health programs needs exploration. Please see later in the article for the Editors' Summary. PMID- 21814496 TI - Is scale-up worth it? Challenges in economic analysis of diagnostic tests for tuberculosis. AB - David Dowdy and colleagues discuss the complexities of costing new TB diagnostic tests, including GeneXpert, and argue that flexible analytic tools are needed for decision-makers to adapt large-sample cost-effectiveness data to local conditions. PMID- 21814497 TI - GeneXpert--a game-changer for tuberculosis control? PMID- 21814498 TI - Health care systems and conflict: a fragile state of affairs. PMID- 21814499 TI - Configuring balanced scorecards for measuring health system performance: evidence from 5 years' evaluation in Afghanistan. AB - BACKGROUND: In 2004, Afghanistan pioneered a balanced scorecard (BSC) performance system to manage the delivery of primary health care services. This study examines the trends of 29 key performance indicators over a 5-year period between 2004 and 2008. METHODS AND FINDINGS: Independent evaluations of performance in six domains were conducted annually through 5,500 patient observations and exit interviews and 1,500 provider interviews in >600 facilities selected by stratified random sampling in each province. Generalized estimating equation (GEE) models were used to assess trends in BSC parameters. There was a progressive improvement in the national median scores scaled from 0-100 between 2004 and 2008 in all six domains: patient and community satisfaction of services (65.3-84.5, p<0.0001); provider satisfaction (65.4-79.2, p<0.01); capacity for service provision (47.4-76.4, p<0.0001); quality of services (40.5-67.4, p<0.0001); and overall vision for pro-poor and pro-female health services (52.0 52.6). The financial domain also showed improvement until 2007 (84.4-95.7, p<0.01), after which user fees were eliminated. By 2008, all provinces achieved the upper benchmark of national median set in 2004. CONCLUSIONS: The BSC has been successfully employed to assess and improve health service capacity and service delivery using performance benchmarking during the 5-year period. However, scorecard reconfigurations are needed to integrate effectiveness and efficiency measures and accommodate changes in health systems policy and strategy architecture to ensure its continued relevance and effectiveness as a comprehensive health system performance measure. The process of BSC design and implementation can serve as a valuable prototype for health policy planners managing performance in similar health care contexts. Please see later in the article for the Editors' Summary. PMID- 21814500 TI - The dynamical mechanism of auto-inhibition of AMP-activated protein kinase. AB - We use a novel normal mode analysis of an elastic network model drawn from configurations generated during microsecond all-atom molecular dynamics simulations to analyze the mechanism of auto-inhibition of AMP-activated protein kinase (AMPK). A recent X-ray and mutagenesis experiment (Chen, et al Nature 2009, 459, 1146) of the AMPK homolog S. Pombe sucrose non-fermenting 1 (SNF1) has proposed a new conformational switch model involving the movement of the kinase domain (KD) between an inactive unphosphorylated open state and an active or semi active phosphorylated closed state, mediated by the autoinhibitory domain (AID), and a similar mutagenesis study showed that rat AMPK has the same auto-inhibition mechanism. However, there is no direct dynamical evidence to support this model and it is not clear whether other functionally important local structural components are equally inhibited. By using the same SNF1 KD-AID fragment as that used in experiment, we show that AID inhibits the catalytic function by restraining the KD into an unproductive open conformation, thereby limiting local structural rearrangements, while mutations that disrupt the interactions between the KD and AID allow for both the local structural rearrangement and global interlobe conformational transition. Our calculations further show that the AID also greatly impacts the structuring and mobility of the activation loop. PMID- 21814501 TI - The Eps8/IRSp53/VASP network differentially controls actin capping and bundling in filopodia formation. AB - There is a body of literature that describes the geometry and the physics of filopodia using either stochastic models or partial differential equations and elasticity and coarse-grained theory. Comparatively, there is a paucity of models focusing on the regulation of the network of proteins that control the formation of different actin structures. Using a combination of in-vivo and in-vitro experiments together with a system of ordinary differential equations, we focused on a small number of well-characterized, interacting molecules involved in actin dependent filopodia formation: the actin remodeler Eps8, whose capping and bundling activities are a function of its ligands, Abi-1 and IRSp53, respectively; VASP and Capping Protein (CP), which exert antagonistic functions in controlling filament elongation. The model emphasizes the essential role of complexes that contain the membrane deforming protein IRSp53, in the process of filopodia initiation. This model accurately accounted for all observations, including a seemingly paradoxical result whereby genetic removal of Eps8 reduced filopodia in HeLa, but increased them in hippocampal neurons, and generated quantitative predictions, which were experimentally verified. The model further permitted us to explain how filopodia are generated in different cellular contexts, depending on the dynamic interaction established by Eps8, IRSp53 and VASP with actin filaments, thus revealing an unexpected plasticity of the signaling network that governs the multifunctional activities of its components in the formation of filopodia. PMID- 21814502 TI - Automatic annotation of spatial expression patterns via sparse Bayesian factor models. AB - Advances in reporters for gene expression have made it possible to document and quantify expression patterns in 2D-4D. In contrast to microarrays, which provide data for many genes but averaged and/or at low resolution, images reveal the high spatial dynamics of gene expression. Developing computational methods to compare, annotate, and model gene expression based on images is imperative, considering that available data are rapidly increasing. We have developed a sparse Bayesian factor analysis model in which the observed expression diversity of among a large set of high-dimensional images is modeled by a small number of hidden common factors. We apply this approach on embryonic expression patterns from a Drosophila RNA in situ image database, and show that the automatically inferred factors provide for a meaningful decomposition and represent common co-regulation or biological functions. The low-dimensional set of factor mixing weights is further used as features by a classifier to annotate expression patterns with functional categories. On human-curated annotations, our sparse approach reaches similar or better classification of expression patterns at different developmental stages, when compared to other automatic image annotation methods using thousands of hard-to-interpret features. Our study therefore outlines a general framework for large microscopy data sets, in which both the generative model itself, as well as its application for analysis tasks such as automated annotation, can provide insight into biological questions. PMID- 21814503 TI - Understanding the origins of bacterial resistance to aminoglycosides through molecular dynamics mutational study of the ribosomal A-site. AB - Paromomycin is an aminoglycosidic antibiotic that targets the RNA of the bacterial small ribosomal subunit. It binds in the A-site, which is one of the three tRNA binding sites, and affects translational fidelity by stabilizing two adenines (A1492 and A1493) in the flipped-out state. Experiments have shown that various mutations in the A-site result in bacterial resistance to aminoglycosides. In this study, we performed multiple molecular dynamics simulations of the mutated A-site RNA fragment in explicit solvent to analyze changes in the physicochemical features of the A-site that were introduced by substitutions of specific bases. The simulations were conducted for free RNA and in complex with paromomycin. We found that the specific mutations affect the shape and dynamics of the binding cleft as well as significantly alter its electrostatic properties. The most pronounced changes were observed in the U1406C?U1495A mutant, where important hydrogen bonds between the RNA and paromomycin were disrupted. The present study aims to clarify the underlying physicochemical mechanisms of bacterial resistance to aminoglycosides due to target mutations. PMID- 21814504 TI - Modelling the effects of population structure on childhood disease: the case of varicella. AB - Realistic, individual-based models based on detailed census data are increasingly used to study disease transmission. Whether the rich structure of such models improves predictions is debated. This is studied here for the spread of varicella, a childhood disease, in a realistic population of children where infection occurs in the household, at school, or in the community at large. A methodology is first presented for simulating households with births and aging. Transmission probabilities were fitted for schools and community, which reproduced the overall cumulative incidence of varicella over the age range of 0 11 years old.Moreover, the individual-based model structure allowed us to reproduce several observed features of VZV epidemiology which were not included as hypotheses in the model: the age at varicella in first-born children was older than in other children, in accordance with observation; the same was true for children residing in rural areas. Model predicted incidence was comparable to observed incidence over time. These results show that models based on detailed census data on a small scale provide valid small scale prediction. By simulating several scenarios, we evaluate how varicella epidemiology is shaped by policies, such as age at first school enrolment, and school eviction. This supports the use of such models for investigating outcomes of public health measures. PMID- 21814505 TI - Cadherin-dependent cell morphology in an epithelium: constructing a quantitative dynamical model. AB - Cells in the Drosophila retina have well-defined morphologies that are attained during tissue morphogenesis. We present a computer simulation of the epithelial tissue in which the global interfacial energy between cells is minimized. Experimental data for both normal cells and mutant cells either lacking or misexpressing the adhesion protein N-cadherin can be explained by a simple model incorporating salient features of morphogenesis that include the timing of N cadherin expression in cells and its temporal relationship to the remodeling of cell-cell contacts. The simulations reproduce the geometries of wild-type and mutant cells, distinguish features of cadherin dynamics, and emphasize the importance of adhesion protein biogenesis and its timing with respect to cell remodeling. The simulations also indicate that N-cadherin protein is recycled from inactive interfaces to active interfaces, thereby modulating adhesion strengths between cells. PMID- 21814506 TI - In silico evidence for gluconeogenesis from fatty acids in humans. AB - The question whether fatty acids can be converted into glucose in humans has a long standing tradition in biochemistry, and the expected answer is "No". Using recent advances in Systems Biology in the form of large-scale metabolic reconstructions, we reassessed this question by performing a global investigation of a genome-scale human metabolic network, which had been reconstructed on the basis of experimental results. By elementary flux pattern analysis, we found numerous pathways on which gluconeogenesis from fatty acids is feasible in humans. On these pathways, four moles of acetyl-CoA are converted into one mole of glucose and two moles of CO2. Analyzing the detected pathways in detail we found that their energetic requirements potentially limit their capacity. This study has many other biochemical implications: effect of starvation, sports physiology, practically carbohydrate-free diets of inuit, as well as survival of hibernating animals and embryos of egg-laying animals. Moreover, the energetic loss associated to the usage of gluconeogenesis from fatty acids can help explain the efficiency of carbohydrate reduced and ketogenic diets such as the Atkins diet. PMID- 21814507 TI - Proteins with complex architecture as potential targets for drug design: a case study of Mycobacterium tuberculosis. AB - Lengthy co-evolution of Homo sapiens and Mycobacterium tuberculosis, the main causative agent of tuberculosis, resulted in a dramatically successful pathogen species that presents considerable challenge for modern medicine. The continuous and ever increasing appearance of multi-drug resistant mycobacteria necessitates the identification of novel drug targets and drugs with new mechanisms of action. However, further insights are needed to establish automated protocols for target selection based on the available complete genome sequences. In the present study, we perform complete proteome level comparisons between M. tuberculosis, mycobacteria, other prokaryotes and available eukaryotes based on protein domains, local sequence similarities and protein disorder. We show that the enrichment of certain domains in the genome can indicate an important function specific to M. tuberculosis. We identified two families, termed pkn and PE/PPE that stand out in this respect. The common property of these two protein families is a complex domain organization that combines species-specific regions, commonly occurring domains and disordered segments. Besides highlighting promising novel drug target candidates in M. tuberculosis, the presented analysis can also be viewed as a general protocol to identify proteins involved in species-specific functions in a given organism. We conclude that target selection protocols should be extended to include proteins with complex domain architectures instead of focusing on sequentially unique and essential proteins only. PMID- 21814508 TI - In vivo conditions induce faithful encoding of stimuli by reducing nonlinear synchronization in vestibular sensory neurons. AB - Previous studies have shown that neurons within the vestibular nuclei (VN) can faithfully encode the time course of sensory input through changes in firing rate in vivo. However, studies performed in vitro have shown that these same VN neurons often display nonlinear synchronization (i.e. phase locking) in their spiking activity to the local maxima of sensory input, thereby severely limiting their capacity for faithful encoding of said input through changes in firing rate. We investigated this apparent discrepancy by studying the effects of in vivo conditions on VN neuron activity in vitro using a simple, physiologically based, model of cellular dynamics. We found that membrane potential oscillations were evoked both in response to step and zap current injection for a wide range of channel conductance values. These oscillations gave rise to a resonance in the spiking activity that causes synchronization to sinusoidal current injection at frequencies below 25 Hz. We hypothesized that the apparent discrepancy between VN response dynamics measured in in vitro conditions (i.e., consistent with our modeling results) and the dynamics measured in vivo conditions could be explained by an increase in trial-to-trial variability under in vivo vs. in vitro conditions. Accordingly, we mimicked more physiologically realistic conditions in our model by introducing a noise current to match the levels of resting discharge variability seen in vivo as quantified by the coefficient of variation (CV). While low noise intensities corresponding to CV values in the range 0.04-0.24 only eliminated synchronization for low (<8 Hz) frequency stimulation but not high (>12 Hz) frequency stimulation, higher noise intensities corresponding to CV values in the range 0.5-0.7 almost completely eliminated synchronization for all frequencies. Our results thus predict that, under natural (i.e. in vivo) conditions, the vestibular system uses increased variability to promote fidelity of encoding by single neurons. This prediction can be tested experimentally in vitro. PMID- 21814509 TI - 13C metabolic flux analysis identifies an unusual route for pyruvate dissimilation in mycobacteria which requires isocitrate lyase and carbon dioxide fixation. AB - Mycobacterium tuberculosis requires the enzyme isocitrate lyase (ICL) for growth and virulence in vivo. The demonstration that M. tuberculosis also requires ICL for survival during nutrient starvation and has a role during steady state growth in a glycerol limited chemostat indicates a function for this enzyme which extends beyond fat metabolism. As isocitrate lyase is a potential drug target elucidating the role of this enzyme is of importance; however, the role of isocitrate lyase has never been investigated at the level of in vivo fluxes. Here we show that deletion of one of the two icl genes impairs the replication of Mycobacterium bovis BCG at slow growth rate in a carbon limited chemostat. In order to further understand the role of isocitrate lyase in the central metabolism of mycobacteria the effect of growth rate on the in vivo fluxes was studied for the first time using 13C-metabolic flux analysis (MFA). Tracer experiments were performed with steady state chemostat cultures of BCG or M. tuberculosis supplied with 13C labeled glycerol or sodium bicarbonate. Through measurements of the 13C isotopomer labeling patterns in protein-derived amino acids and enzymatic activity assays we have identified the activity of a novel pathway for pyruvate dissimilation. We named this the GAS pathway because it utilizes the Glyoxylate shunt and Anapleurotic reactions for oxidation of pyruvate, and Succinyl CoA synthetase for the generation of succinyl CoA combined with a very low flux through the succinate--oxaloacetate segment of the tricarboxylic acid cycle. We confirm that M. tuberculosis can fix carbon from CO2 into biomass. As the human host is abundant in CO2 this finding requires further investigation in vivo as CO2 fixation may provide a point of vulnerability that could be targeted with novel drugs. This study also provides a platform for further studies into the metabolism of M. tuberculosis using 13C-MFA. PMID- 21814510 TI - A role for the chemokine RANTES in regulating CD8 T cell responses during chronic viral infection. AB - RANTES (CCL5) is a chemokine expressed by many hematopoietic and non hematopoietic cell types that plays an important role in homing and migration of effector and memory T cells during acute infections. The RANTES receptor, CCR5, is a major target of anti-HIV drugs based on blocking viral entry. However, defects in RANTES or RANTES receptors including CCR5 can compromise immunity to acute infections in animal models and lead to more severe disease in humans infected with west Nile virus (WNV). In contrast, the role of the RANTES pathway in regulating T cell responses and immunity during chronic infection remains unclear. In this study, we demonstrate a crucial role for RANTES in the control of systemic chronic LCMV infection. In RANTES-/- mice, virus-specific CD8 T cells had poor cytokine production. These RANTES-/- CD8 T cells also expressed higher amounts of inhibitory receptors consistent with more severe exhaustion. Moreover, the cytotoxic ability of CD8 T cells from RANTES-/- mice was reduced. Consequently, viral load was higher in the absence of RANTES. The dysfunction of T cells in the absence of RANTES was as severe as CD8 T cell responses generated in the absence of CD4 T cell help. Our results demonstrate an important role for RANTES in sustaining CD8 T cell responses during a systemic chronic viral infection. PMID- 21814511 TI - Microbial virulence as an emergent property: consequences and opportunities. PMID- 21814512 TI - An interaction between KSHV ORF57 and UIF provides mRNA-adaptor redundancy in herpesvirus intronless mRNA export. AB - The hTREX complex mediates cellular bulk mRNA nuclear export by recruiting the nuclear export factor, TAP, via a direct interaction with the export adaptor, Aly. Intriguingly however, depletion of Aly only leads to a modest reduction in cellular mRNA nuclear export, suggesting the existence of additional mRNA nuclear export adaptor proteins. In order to efficiently export Kaposi's sarcoma associated herpesvirus (KSHV) intronless mRNAs from the nucleus, the KSHV ORF57 protein recruits hTREX onto viral intronless mRNAs allowing access to the TAP mediated export pathway. Similarly however, depletion of Aly only leads to a modest reduction in the nuclear export of KSHV intronless mRNAs. Herein, we identify a novel interaction between ORF57 and the cellular protein, UIF. We provide the first evidence that the ORF57-UIF interaction enables the recruitment of hTREX and TAP to KSHV intronless mRNAs in Aly-depleted cells. Strikingly, depletion of both Aly and UIF inhibits the formation of an ORF57-mediated nuclear export competent ribonucleoprotein particle and consequently prevents ORF57 mediated mRNA nuclear export and KSHV protein production. Importantly, these findings highlight that redundancy exists in the eukaryotic system for certain hTREX components involved in the mRNA nuclear export of intronless KSHV mRNAs. PMID- 21814513 TI - A concerted action of hepatitis C virus p7 and nonstructural protein 2 regulates core localization at the endoplasmic reticulum and virus assembly. AB - Hepatitis C virus (HCV) assembly remains a poorly understood process. Lipid droplets (LDs) are thought to act as platforms for the assembly of viral components. The JFH1 HCV strain replicates and assembles in association with LD associated membranes, around which viral core protein is predominantly detected. In contrast, despite its intrinsic capacity to localize to LDs when expressed individually, we found that the core protein of the high-titer Jc1 recombinant virus was hardly detected on LDs of cell culture-grown HCV (HCVcc)-infected cells, but was mainly localized at endoplasmic reticulum (ER) membranes where it colocalized with the HCV envelope glycoproteins. Furthermore, high-titer cell culture-adapted JFH1 virus, obtained after long-term culture in Huh7.5 cells, exhibited an ER-localized core in contrast to non-adapted JFH1 virus, strengthening the hypothesis that ER localization of core is required for efficient HCV assembly. Our results further indicate that p7 and NS2 are HCV strain-specific factors that govern the recruitment of core protein from LDs to ER assembly sites. Indeed, using expression constructs and HCVcc recombinant genomes, we found that p7 is sufficient to induce core localization at the ER, independently of its ion-channel activity. Importantly, the combined expression of JFH1 or Jc1 p7 and NS2 induced the same differential core subcellular localization detected in JFH1- vs. Jc1-infected cells. Finally, results obtained by expressing p7-NS2 chimeras between either virus type indicated that compatibilities between the p7 and the first NS2 trans-membrane domains is required to induce core-ER localization and assembly of extra- and intra-cellular infectious viral particles. In conclusion, we identified p7 and NS2 as key determinants governing the subcellular localization of HCV core to LDs vs. ER and required for initiation of the early steps of virus assembly. PMID- 21814515 TI - Nonlinear fitness landscape of a molecular pathway. AB - Genes are regulated because their expression involves a fitness cost to the organism. The production of proteins by transcription and translation is a well known cost factor, but the enzymatic activity of the proteins produced can also reduce fitness, depending on the internal state and the environment of the cell. Here, we map the fitness costs of a key metabolic network, the lactose utilization pathway in Escherichia coli. We measure the growth of several regulatory lac operon mutants in different environments inducing expression of the lac genes. We find a strikingly nonlinear fitness landscape, which depends on the production rate and on the activity rate of the lac proteins. A simple fitness model of the lac pathway, based on elementary biophysical processes, predicts the growth rate of all observed strains. The nonlinearity of fitness is explained by a feedback loop: production and activity of the lac proteins reduce growth, but growth also affects the density of these molecules. This nonlinearity has important consequences for molecular function and evolution. It generates a cliff in the fitness landscape, beyond which populations cannot maintain growth. In viable populations, there is an expression barrier of the lac genes, which cannot be exceeded in any stationary growth process. Furthermore, the nonlinearity determines how the fitness of operon mutants depends on the inducer environment. We argue that fitness nonlinearities, expression barriers, and gene environment interactions are generic features of fitness landscapes for metabolic pathways, and we discuss their implications for the evolution of regulation. PMID- 21814514 TI - Somatic genetics empowers the mouse for modeling and interrogating developmental and disease processes. AB - With recent advances in genomic technologies, candidate human disease genes are being mapped at an accelerated pace. There is a clear need to move forward with genetic tools that can efficiently validate these mutations in vivo. Murine somatic mutagenesis is evolving to fulfill these needs with tools such as somatic transgenesis, humanized rodents, and forward genetics. By combining these resources one is not only able to model disease for in vivo verification, but also to screen for mutations and pathways integral to disease progression and therapeutic intervention. In this review, we briefly outline the current advances in somatic mutagenesis and discuss how these new tools, especially the piggyBac transposon system, can be applied to decipher human biology and disease. PMID- 21814516 TI - A functional variant at a prostate cancer predisposition locus at 8q24 is associated with PVT1 expression. AB - Genetic mapping studies have identified multiple cancer susceptibility regions at chromosome 8q24, upstream of the MYC oncogene. MYC has been widely presumed as the regulated target gene, but definitive evidence functionally linking these cancer regions with MYC has been difficult to obtain. Here we examined candidate functional variants of a haplotype block at 8q24 encompassing the two independent risk alleles for prostate and breast cancer, rs620861 and rs13281615. We used the mapping of DNase I hypersensitive sites as a tool to prioritise regions for further functional analysis. This approach identified rs378854, which is in complete linkage disequilibrium (LD) with rs620861, as a novel functional prostate cancer-specific genetic variant. We demonstrate that the risk allele (G) of rs378854 reduces binding of the transcription factor YY1 in vitro. This factor is known to repress global transcription in prostate cancer and is a candidate tumour suppressor. Additional experiments showed that the YY1 binding site is occupied in vivo in prostate cancer, but not breast cancer cells, consistent with the observed cancer-specific effects of this single nucleotide polymorphism (SNP). Using chromatin conformation capture (3C) experiments, we found that the region surrounding rs378854 interacts with the MYC and PVT1 promoters. Moreover, expression of the PVT1 oncogene in normal prostate tissue increased with the presence of the risk allele of rs378854, while expression of MYC was not affected. In conclusion, we identified a new functional prostate cancer risk variant at the 8q24 locus, rs378854 allele G, that reduces binding of the YY1 protein and is associated with increased expression of PVT1 located 0.5 Mb downstream. PMID- 21814517 TI - Genome-wide association study identifies HLA-DP as a susceptibility gene for pediatric asthma in Asian populations. AB - Asthma is a complex phenotype influenced by genetic and environmental factors. We conducted a genome-wide association study (GWAS) with 938 Japanese pediatric asthma patients and 2,376 controls. Single-nucleotide polymorphisms (SNPs) showing strong associations (P<1*10(-8)) in GWAS were further genotyped in an independent Japanese samples (818 cases and 1,032 controls) and in Korean samples (835 cases and 421 controls). SNP rs987870, located between HLA-DPA1 and HLA DPB1, was consistently associated with pediatric asthma in 3 independent populations (P(combined) = 2.3*10(-10), odds ratio [OR] = 1.40). HLA-DP allele analysis showed that DPA1*0201 and DPB1*0901, which were in strong linkage disequilibrium, were strongly associated with pediatric asthma (DPA1*0201: P = 5.5*10(-10), OR = 1.52, and DPB1*0901: P = 2.0*10(-7), OR = 1.49). Our findings show that genetic variants in the HLA-DP locus are associated with the risk of pediatric asthma in Asian populations. PMID- 21814518 TI - DAF-12 regulates a connected network of genes to ensure robust developmental decisions. AB - The nuclear receptor DAF-12 has roles in normal development, the decision to pursue dauer development in unfavorable conditions, and the modulation of adult aging. Despite the biologic importance of DAF-12, target genes for this receptor are largely unknown. To identify DAF-12 targets, we performed chromatin immunoprecipitation followed by hybridization to whole-genome tiling arrays. We identified 1,175 genomic regions to be bound in vivo by DAF-12, and these regions are enriched in known DAF-12 binding motifs and act as DAF-12 response elements in transfected cells and in transgenic worms. The DAF-12 target genes near these binding sites include an extensive network of interconnected heterochronic and microRNA genes. We also identify the genes encoding components of the miRISC, which is required for the control of target genes by microRNA, as a target of DAF 12 regulation. During reproductive development, many of these target genes are misregulated in daf-12(0) mutants, but this only infrequently results in developmental phenotypes. In contrast, we and others have found that null daf-12 mutations enhance the phenotypes of many miRISC and heterochronic target genes. We also find that environmental fluctuations significantly strengthen the weak heterochronic phenotypes of null daf-12 alleles. During diapause, DAF-12 represses the expression of many heterochronic and miRISC target genes, and prior work has demonstrated that dauer formation can suppress the heterochronic phenotypes of many of these target genes in post-dauer development. Together these data are consistent with daf-12 acting to ensure developmental robustness by committing the animal to adult or dauer developmental programs despite variable internal or external conditions. PMID- 21814519 TI - Replication and explorations of high-order epistasis using a large advanced intercross line pedigree. AB - Dissection of the genetic architecture of complex traits persists as a major challenge in biology; despite considerable efforts, much remains unclear including the role and importance of genetic interactions. This study provides empirical evidence for a strong and persistent contribution of both second- and third-order epistatic interactions to long-term selection response for body weight in two divergently selected chicken lines. We earlier reported a network of interacting loci with large effects on body weight in an F(2) intercross between these high- and low-body weight lines. Here, most pair-wise interactions in the network are replicated in an independent eight-generation advanced intercross line (AIL). The original report showed an important contribution of capacitating epistasis to growth, meaning that the genotype at a hub in the network releases the effects of one or several peripheral loci. After fine mapping of the loci in the AIL, we show that these interactions were persistent over time. The replication of five of six originally reported epistatic loci, as well as the capacitating epistasis, provides strong empirical evidence that the originally observed epistasis is of biological importance and is a contributor in the genetic architecture of this population. The stability of genetic interaction mechanisms over time indicates a non-transient role of epistasis on phenotypic change. Third-order epistasis was for the first time examined in this study and was shown to make an important contribution to growth, which suggests that the genetic architecture of growth is more complex than can be explained by two-locus interactions only. Our results illustrate the importance of designing studies that facilitate exploration of epistasis in populations for obtaining a comprehensive understanding of the genetics underlying a complex trait. PMID- 21814520 TI - Cut-off scores for the Minimal Eating Observation and Nutrition Form - Version II (MEONF-II) among hospital inpatients. AB - BACKGROUND AND OBJECTIVE: The newly developed Minimal Eating Observation and Nutrition Form - Version II (MEONF-II) has shown promising sensitivity and specificity in relation to the Mini Nutritional Assessment (MNA). However, the suggested MEONF-II cut-off scores for deciding low/moderate and high risk for undernutrition (UN) (>2 and >4, respectively) have not been decided based on statistical criteria but on clinical reasoning. The objective of this study was to identify the optimal cut-off scores for the MEONF-II in relation to the well established MNA based on statistical criteria. DESIGN: Cross-sectional study. METHODS: The study included 187 patients (mean age, 77.5 years) assessed for nutritional status with the MNA (full version), and screened with the MEONF-II. The MEONF-II includes assessments of involuntary weight loss, Body Mass Index (BMI) (or calf circumference), eating difficulties, and presence of clinical signs ofUN. MEONF-II data were analysed by Receiver Operating Characteristics (ROC) curves and the area under the curve (AUC); optimal cut-offs were identified by the Youden index (J=sensitivity+specificity-1). RESULTS: According to the MEONF-II, 41% were at moderate or high UN risk and according to the MNA, 50% were at risk or already undernourished. The suggested cut-off scores were supported by the Youden indices. The lower cut-off for MEONF-II, used to identify any level of risk for UN (>2; J=0.52) gave an overall accuracy of 76% and the AUC was 80%. The higher cut-off for identifying those with high risk for UN (>4; J=0.33) had an accuracy of 63% and the AUC was 70%. CONCLUSIONS: The suggested MEONF-II cut-off scores were statistically supported. This improves the confidence of its clinical use. PMID- 21814521 TI - Bilateral endoprosthetic total hip or knee arthroplasty. AB - BACKGROUND: More than 300 000 joint replacement operations are performed in Germany every year, and the number is rising. In this article, we consider the question of simultaneous bilateral joint replacement at the hips or knees. Such procedures are indicated in patients suffering from bilateral, symptomatic arthrosis. METHODS: The article is based on a selective review of the relevant literature, and on the authors' own prospective comparative study of simultaneous bilateral hip replacement. RESULTS: The morbidity and mortality of simultaneous bilateral hip arthroplasty are no different than those of a unilateral procedure. Rehabilitation is easier when both joints are replaced at the same time. Simultaneous bilateral knee arthroplasty has comparable morbidity to a unilateral procedure, but a slightly higher mortality (0.30% vs. 0.14%). Allogenic blood transfusion is more likely to be needed in a bilateral procedure, particularly of the knees. Simultaneous bilateral arthroplasty of either the hips or the knees in one surgical procedure is better than two-staged arthroplasty during a single hospital stay. CONCLUSION: Simultaneous bilateral hip arthroplasty is safer for the patient and facilitates rehabilitation, regardless of the patient's age and ASA status (ASA, American Society of Anesthesiologists). With regard to the knees, there are two additional issues, namely the more frequent need for transfusion and somewhat higher mortality of a simultaneous bilateral procedure. Therefore, we recommend simultaneous bilateral knee arthroplasty only for patients in ASA classes 1 and 2. Simultaneous bilateral arthroplasty of either the hip or knee incurs lower costs than two separate operations. PMID- 21814522 TI - Is anesthesia dangerous? AB - BACKGROUND: Recent years have seen a rise in overall anesthesia-related mortality. METHOD: Selective review of the literature. RESULTS: Anesthesia related mortality has fallen from 6.4/10 000 in the 1940s to 0.4/100 000 at present, largely because of the introduction of safety standards and improved training. The current figure of 0.4/100 000 applies to patients without major systemic disease; mortality is higher among patients with severe accompanying illnesses, yet in this group, too, perioperative mortality can be reduced by appropriate anesthetic management. Moreover, the use of regional anesthesia can also improve the outcome of major surgery. CONCLUSION: A recent increase in the percentage of older and multimorbid patients among persons undergoing surgery, along with the advent of newer types of operation that would have been unthinkable in the past, has led to an apparent rise in anesthesia-associated mortality, even though the quality of anesthesiological care is no worse now than in the past. On the contrary, in recent years, better anesthetic management has evidently played an important role in improving surgical outcomes. PMID- 21814524 TI - Be prepared!: hospital planning for major public events. PMID- 21814523 TI - Epidemic keratoconjunctivitis: the current situation and recommendations for prevention and treatment. AB - BACKGROUND: Epidemic keratoconjunctivitis (EKC) is a highly contagious infection of the ocular surface. 316 cases were diagnosed in Germany in the first 8 months of 2010, corresponding to a 300% increase above the typical figures for recent years. This outbreak motivates us to present the current recommendations concerning EKC. METHODS: Selective literature review. RESULTS: EKC is an adenoviral infection that typically starts with a unilateral foreign body sensation and then develops, within a few hours or days, into bilateral keratoconjunctivitis with marked chemosis, epiphora, and photophobia. Visual impairment can persist for months because of subepithelial corneal infiltrates (nummuli) and irregular astigmatism. Randomized clinical trials have not shown any clear benefit in the acute phase from any of a variety of treatments, including steroids, calcineurin inhibitors, virostatic drugs and disinfecting agents. In the chronic phase, cyclosporin A eye drops can accelerate the regression of subepithelial infiltrates. Hygienic measures, including conscientious hand and surface disinfection, can lessen the spread of the disease. CONCLUSION: The first priority in the treatment of patients with definite or suspected EKC is the rigorous application of hygienic measures in medical facilities, particularly because there is still no effective drug treatment for this disease. No virostatic agent has yet been demonstrated to influence its course, either subjectively or objectively. PMID- 21814525 TI - Patient care at the 2010 Love Parade in Duisburg, Germany: clinical experiences. AB - BACKGROUND: The mass panic at the Love Parade 2010 attracted a great deal of public attention in Germany and abroad. The goals of this paper are to summarize the available data on the injured persons and their treatment, and to assess the preparations that should be made for such an eventuality and the acute measures that should be taken if it occurs. METHODS: Patient data from the Duisburg hospitals were subjected to a structured statistical analysis, and all of the measures taken were assessed by qualified evaluators on the basis of questionnaires, a consensus conference, and individual interviews of the clinical coordinators. RESULTS: A total of 250,000 persons took part in the Love Parade; 5600 patient contacts occurred at first-aid posts and 473 patients (mean age, 25.5 years; male:female ratio, 1.4:1) were treated in 12 hospital emergency rooms, 41.7% were admitted to the hospital. Among the admitted patients, 73% stayed in the hospital for less than 24 hours, and 41% signed out against medical advice; 62.2% had a surgical diagnosis, 40.6% a medical one, and 8.0% a psychiatric one (some patients had more than one diagnosis). 47.6% of the surviving patients were classified as mildly injured, 47.8% as moderately injured, and 4.0% as severely injured. Most medical activity was concentrated in three areas: the treatment of drug abuse, the care of many mild and moderate injuries, and Shock Room diagnostic assessment of patients potentially harboring serious injuries. Hospitals were subject to the highest strain 2 to 3 hours after the mass panic, at which time they received up to 20 new patients per hour. CONCLUSION: These data permit a detailed view of the medical care that was provided. In situations of this kind, the main problems can be dealt with through targeted and structured preparation and optimized emergency plans which consider both foreseeable and unforeseeable events. Priority must be given to rapid diagnostic assessment and clinical decision-making; the prerequisites for these are transparent institutional structures and clear assignments of responsibility. PMID- 21814526 TI - Consultations not informed by mutual trust. PMID- 21814527 TI - Quality of treatment is almost identical. PMID- 21814528 TI - Crucial characteristics. PMID- 21814529 TI - Barriers to guideline implementation. PMID- 21814530 TI - Multimorbidity as a dilemma. PMID- 21814531 TI - Incomprehensible jargon. PMID- 21814534 TI - Don't forget celiac disease. PMID- 21814536 TI - Timing Nutriceuticals? AB - Evidence on time-dependent effects of drugs and nutrition is succinctly reviewed in order to illustrate and advocate investigations of the timing of nutriceuticals. Emphasis is placed on the merits of coordinated, individually, inferentially, statistically examined sets of N-of-1 studies. PMID- 21814537 TI - Maternal obesity, diabetes mellitus and cord blood biomarkers in large-for gestational age infants. AB - Infants born large-for-gestational age (LGA) are at risk for early childhood obesity. The aims of this study were to investigate factors associated with LGA status and their relationship to inflammatory biomarkers that have been implicated in the LGA infant at birth. Included were 364 mother-infant pairs enrolled as part of an ongoing longitudinal cohort study of infant birth weight being conducted at Boston Medical Center (BMC). LGA was defined as birth weight (BW) >=90(th) percentile of the reference population at BMC (N=45). Appropriate for-gestational age (AGA) was defined as BW<90(th) and >10(th) percentile (N=319). Cord blood IL-6, IL-8, TNF-alpha and RANTES levels were analyzed from a larger panel of immune biomarkers measured using multiplex immunoassay. Multivariate regression models were used to determine the associations between LGA status, maternal BMI and diabetes (DM), which included either gestational or type 2 diabetes (T2DM), and cord blood biomarkers, with adjustment for important demographic and clinical variables. Maternal pre-pregnancy BMI within the obesity range (>=30 kg/m(2)), as well as DM, were each associated with increased risk of LGA (OR=2.64, 95%CI 1.31-6.20; OR=5.58, 95%CI 2.06-15.13, respectively). Among the 4 biomarkers, only RANTES (regulated on activation, normal T cell express and secreted upon uptake), which is a chemokine secreted by white adipose tissue, was significantly increased in LGA infants (beta-coefficient=0.37; 95% CI: 0.09, 0.65; P<0.01). This association remained essentially unchanged after adjustment for maternal DM and BMI (beta-coefficient=0.37; 95% CI: 0.08, 0.65; P=0.01). Ponderal index (PI=BW*100/length(3)) was also positively correlated with RANTES. Cord blood RANTES is selectively elevated with fetal macrosomia, independent of maternal factors. Further investigation of RANTES as a marker of LGA and future childhood health is warranted. PMID- 21814535 TI - Hormonal contraception--what kind, when, and for whom? AB - BACKGROUND: In Germany today, one-third of the 20 million women of child-bearing age use combined oral contraceptives (COCs). In this article, we summarize the current knowledge of the mode of action, wanted and unwanted side effects, and long-term risks of COCs. The levonorgestrel intrauterine device (IUD) and long acting injectable or implantable monophasic progestogen preparations offer comparable contraceptive efficacy to COCs. Nonetheless, they are less frequently used in Germany than COCs, because of their propensity to cause breakthrough bleeding. METHOD: Selective review of the literature. RESULTS: COCs suppress gonadotropin secretion and thereby inhibit follicular maturation and ovulation. Their correct use is associated with 0.3 pregnancies per 100 women per year, their typical use, with 1 pregnancy per 100 women per year (Pearl index). COCs have effects on the cardiovascular and hemostatic systems as well as on lipid and carbohydrate metabolism. When given in the presence of specific risk factors, they significantly increase the likelihood of cardiovascular disease and thromboembolism. Women with persistent human papilloma virus (HPV) infection who take COCs are at increased risk of developing invasive cervical cancer. On the other hand, COCs lower the cumulative incidence of endometrial and ovarian cancer by 30% to 50%, and that of colorectal cancer by 20% to 30%. Other malignancies seem to be unaffected by COC use. CONCLUSION: As long as personal and familial risk factors are carefully considered, COCs constitute a safe, reversible, and well-tolerated method of contraception. PMID- 21814540 TI - Entrepreneurs, chance, and the deterministic concentration of wealth. AB - In many economies, wealth is strikingly concentrated. Entrepreneurs--individuals with ownership in for-profit enterprises--comprise a large portion of the wealthiest individuals, and their behavior may help explain patterns in the national distribution of wealth. Entrepreneurs are less diversified and more heavily invested in their own companies than is commonly assumed in economic models. We present an intentionally simplified individual-based model of wealth generation among entrepreneurs to assess the role of chance and determinism in the distribution of wealth. We demonstrate that chance alone, combined with the deterministic effects of compounding returns, can lead to unlimited concentration of wealth, such that the percentage of all wealth owned by a few entrepreneurs eventually approaches 100%. Specifically, concentration of wealth results when the rate of return on investment varies by entrepreneur and by time. This result is robust to inclusion of realities such as differing skill among entrepreneurs. The most likely overall growth rate of the economy decreases as businesses become less diverse, suggesting that high concentrations of wealth may adversely affect a country's economic growth. We show that a tax on large inherited fortunes, applied to a small portion of the most fortunate in the population, can efficiently arrest the concentration of wealth at intermediate levels. PMID- 21814538 TI - Unconscious knowledge: A survey. AB - The concept of unconscious knowledge is fundamental for an understanding of human thought processes and mentation in general; however, the psychological community at large is not familiar with it. This paper offers a survey of the main psychological research currently being carried out into cognitive processes, and examines pathways that can be integrated into a discipline of unconscious knowledge. It shows that the field has already a defined history and discusses some of the features that all kinds of unconscious knowledge seem to share at a deeper level. With the aim of promoting further research, we discuss the main challenges which the postulation of unconscious cognition faces within the psychological community. PMID- 21814541 TI - An ensemble analysis of electromyographic activity during whole body pointing with the use of support vector machines. AB - We explored the use of support vector machines (SVM) in order to analyze the ensemble activities of 24 postural and focal muscles recorded during a whole body pointing task. Because of the large number of variables involved in motor control studies, such multivariate methods have much to offer over the standard univariate techniques that are currently employed in the field to detect modifications. The SVM was used to uncover the principle differences underlying several variations of the task. Five variants of the task were used. An unconstrained reaching, two constrained at the focal level and two at the postural level. Using the electromyographic (EMG) data, the SVM proved capable of distinguishing all the unconstrained from the constrained conditions with a success of approximately 80% or above. In all cases, including those with focal constraints, the collective postural muscle EMGs were as good as or better than those from focal muscles for discriminating between conditions. This was unexpected especially in the case with focal constraints. In trying to rank the importance of particular features of the postural EMGs we found the maximum amplitude rather than the moment at which it occurred to be more discriminative. A classification using the muscles one at a time permitted us to identify some of the postural muscles that are significantly altered between conditions. In this case, the use of a multivariate method also permitted the use of the entire muscle EMG waveform rather than the difficult process of defining and extracting any particular variable. The best accuracy was obtained from muscles of the leg rather than from the trunk. By identifying the features that are important in discrimination, the use of the SVM permitted us to identify some of the features that are adapted when constraints are placed on a complex motor task. PMID- 21814542 TI - Treatment outcome and mortality at one and half year follow-up of HIV infected TB patients under TB control programme in a district of South India. AB - BACKGROUND: There is paucity of data from India on the impact of HIV related immunosuppression in response to TB treatment and mortality among HIV infected TB patients. We assessed the TB treatment outcome and mortality in a cohort of HIV infected TB patients treated with intermittent short course chemotherapy under TB control programme in a high HIV prevalent district of south India. METHODOLOGY/ FINDINGS: Among 3798 TB patients registered for treatment in Mysore district from July 2007 to June 2008, 281 HIV infected patients formed the study group. The socio-demographic and treatment related data of these patients was obtained from TB and HIV programme records and patient interviews 19 months after TB treatment initiation by field investigators. Treatment success rate of 281 patients was 75% while in smear positive pulmonary tuberculosis cases it was 62%, attributable to defaults (16%) and deaths (19%). Only 2 patients had treatment failure. Overall, 83 (30%) patients were reported dead; 26 while on treatment and 57 after TB treatment. Association of treatment related factors with treatment outcome and survival status was studied through logistic regression analysis. Factors significantly associated with 'unfavourable outcome' were disease classification as Pulmonary [aOR-1.96, CI (1.02-3.77)], type of patient as retreatment [aOR 4.78, CI (2.12-10.76)], and non initiation of ART [aOR-4.90, CI (1.85-12.96)]. Factors associated with 'Death' were non initiation of ART [aOR-2.80, CI (1.15 6.81)] and CPT [aOR-3.46, CI (1.47-8.14)]. CONCLUSION: Despite the treatment success of 75% the high mortality (30%) in the study group is a matter of concern and needs immediate intervention. Non initiation of ART has emerged as a high risk factor for unfavourable treatment outcome and mortality. These findings underscore the importance of expanding and improving delivery of ART services as a priority and reconsideration of the programme guidelines for ART initiation in HIV infected TB patients. PMID- 21814543 TI - Combining feature selection and integration--a neural model for MT motion selectivity. AB - BACKGROUND: The computation of pattern motion in visual area MT based on motion input from area V1 has been investigated in many experiments and models attempting to replicate the main mechanisms. Two different core conceptual approaches were developed to explain the findings. In integrationist models the key mechanism to achieve pattern selectivity is the nonlinear integration of V1 motion activity. In contrast, selectionist models focus on the motion computation at positions with 2D features. METHODOLOGY/PRINCIPAL FINDINGS: Recent experiments revealed that neither of the two concepts alone is sufficient to explain all experimental data and that most of the existing models cannot account for the complex behaviour found. MT pattern selectivity changes over time for stimuli like type II plaids from vector average to the direction computed with an intersection of constraint rule or by feature tracking. Also, the spatial arrangement of the stimulus within the receptive field of a MT cell plays a crucial role. We propose a recurrent neural model showing how feature integration and selection can be combined into one common architecture to explain these findings. The key features of the model are the computation of 1D and 2D motion in model area V1 subpopulations that are integrated in model MT cells using feedforward and feedback processing. Our results are also in line with findings concerning the solution of the aperture problem. CONCLUSIONS/SIGNIFICANCE: We propose a new neural model for MT pattern computation and motion disambiguation that is based on a combination of feature selection and integration. The model can explain a range of recent neurophysiological findings including temporally dynamic behaviour. PMID- 21814544 TI - Use of microRNA Let-7 to control the replication specificity of oncolytic adenovirus in hepatocellular carcinoma cells. AB - Highly selective therapy for hepatocellular carcinoma (HCC) remains an unmet medical need. In present study, we found that the tumor suppressor microRNA, let 7 was significantly downregulated in a proportion of primary HCC tissues (12 of 33, 36.4%) and HCC cell lines. In line with this finding, we have engineered a chimeric Ad5/11 fiber oncolytic adenovirus, SG7011(let7T), by introducing eight copies of let-7 target sites (let7T) into the 3' untranslated region of E1A, a key gene associated with adenoviral replication. The results showed that the E1A expression (both RNA and protein levels) of the SG7011(let7T) was tightly regulated according to the endogenous expression level of the let-7. As contrasted with the wild-type adenovirus and the control virus, the replication of SG7011(let7T) was distinctly inhibited in normal liver cells lines (i.e. L-02 and WRL-68) expressing high level of let-7 (>300 folds), whereas was almost not impaired in HCC cells (i.e. Hep3B and PLC/PRF/5) with low level of let-7. Consequently, the cytotoxicity of SG7011(let7T) to normal liver cells was successfully decreased while was almost not attenuated in HCC cells in vitro. The antitumor ability of SG7011(let7T)in vivo was maintained in mice with Hep3B xenograft tumor, whereas was greatly decreased against the SMMC-7721 xenograft tumor expressing a high level of let-7 similar with L-02 when compared to the wild-type adenovirus. These results suggested that SG7011(let7T) may be a promising anticancer agent or vector to mediate the expression of therapeutic gene, broadly applicable in the treatment for HCC and other cancers where the let 7 gene is downregulated. PMID- 21814545 TI - Cryptic species? Patterns of maternal and paternal gene flow in eight neotropical bats. AB - Levels of sequence divergence at mitochondrial loci are frequently used in phylogeographic analysis and species delimitation though single marker systems cannot assess bi-parental gene flow. In this investigation I compare the phylogeographic patterns revealed through the maternally inherited mitochondrial COI region and the paternally inherited 7(th) intron region of the Dby gene on the Y-chromosome in eight common Neotropical bat species. These species are diverse and include members of two families from the feeding guilds of sanguivores, nectarivores, frugivores, carnivores and insectivores. In each case, the currently recognized taxon is comprised of distinct, substantially divergent intraspecific mitochondrial lineages suggesting cryptic species complexes. In Chrotopterus auritus, and Saccopteryx bilineata I observed congruent patterns of divergence in both genetic regions suggesting a cessation of gene flow between intraspecific groups. This evidence supports the existence of cryptic species complexes which meet the criteria of the genetic species concept. In Glossophaga soricina two intraspecific groups with largely sympatric South American ranges show evidence for incomplete lineage sorting or frequent hybridization while a third group with a Central American distribution appears to diverge congruently at both loci suggesting speciation. Within Desmodus rotundus and Trachops cirrhosus the paternally inherited region was monomorphic and thus does not support or refute the potential for cryptic speciation. In Uroderma bilobatum, Micronycteris megalotis and Platyrrhinus helleri the gene regions show conflicting patterns of divergence and I cannot exclude ongoing gene flow between intraspecific groups. This analysis provides a comprehensive comparison across taxa and employs both maternally and paternally inherited gene regions to validate patterns of gene flow. I present evidence for previously unrecognized species meeting the criteria of the genetic species concept but demonstrate that estimates of mitochondrial diversity alone do not accurately represent gene flow in these species and that contact/hybrid zones must be explored to evaluate reproductive isolation. PMID- 21814546 TI - Education as a predictor of chronic periodontitis: a systematic review with meta analysis population-based studies. AB - BACKGROUND: The impact of socioeconomic inequalities on health is well documented. Despite the links of periodontal disease with cardiovascular diseases, adverse pregnancy outcomes and diabetes, no meta-analysis of socioeconomic variations in periodontal disease exists. This meta-analytic review was conducted to determine the extent to which education attainment influences risk of periodontitis in adults aged 35+ years in the general population. METHODS: The authors searched studies published until November 2010 using EMBASE and MEDLINE databases. References listed were then scrutinised, our own files were checked, and, finally, we contacted experts in the field. The authors included only general population-based studies conducted in adults aged 35 years and more. All articles were blind reviewed by two investigators. In the case of disagreement, a third investigator arbitrated. Using PRISMA statement, two reviewers independently extracted papers of interest. RESULTS: Relative to the higher education group, people with low education attainment experience a greater risk of periodontitis (OR: 1.86 [1.66-2.10]; p<0.00001). The association was partially attenuated after adjustment for covariates (OR: 1.55 [1.30-1.86]; p<0.00001). Sensitivity analyses showed that methods used to assess periodontitis, definition of cases, study country and categorization of education are largely responsible for the heterogeneity between studies. No significant bias of publication was shown using both the Egger (p = 0.16) and rank correlation tests (p = 0.35). CONCLUSIONS: In the studies reviewed, low educational attainment was associated with an increased risk of periodontitis. Although this evidence should be cautiously interpreted due to methodological problems in selected studies, efforts to eliminate educational inequalities in periodontitis should focus on early life interventions. PMID- 21814548 TI - Statistical modeling of single target cell encapsulation. AB - High throughput drop-on-demand systems for separation and encapsulation of individual target cells from heterogeneous mixtures of multiple cell types is an emerging method in biotechnology that has broad applications in tissue engineering and regenerative medicine, genomics, and cryobiology. However, cell encapsulation in droplets is a random process that is hard to control. Statistical models can provide an understanding of the underlying processes and estimation of the relevant parameters, and enable reliable and repeatable control over the encapsulation of cells in droplets during the isolation process with high confidence level. We have modeled and experimentally verified a microdroplet based cell encapsulation process for various combinations of cell loading and target cell concentrations. Here, we explain theoretically and validate experimentally a model to isolate and pattern single target cells from heterogeneous mixtures without using complex peripheral systems. PMID- 21814550 TI - A stochastic simulator of a blood product donation environment with demand spikes and supply shocks. AB - The availability of an adequate blood supply is a critical public health need. An influenza epidemic or another crisis affecting population mobility could create a critical donor shortage, which could profoundly impact blood availability. We developed a simulation model for the blood supply environment in the United States to assess the likely impact on blood availability of factors such as an epidemic. We developed a simulator of a multi-state model with transitions among states. Weekly numbers of blood units donated and needed were generated by negative binomial stochastic processes. The simulator allows exploration of the blood system under certain conditions of supply and demand rates, and can be used for planning purposes to prepare for sudden changes in the public's health. The simulator incorporates three donor groups (first-time, sporadic, and regular), immigration and emigration, deferral period, and adjustment factors for recruitment. We illustrate possible uses of the simulator by specifying input values for an 8-week flu epidemic, resulting in a moderate supply shock and demand spike (for example, from postponed elective surgeries), and different recruitment strategies. The input values are based in part on data from a regional blood center of the American Red Cross during 1996-2005. Our results from these scenarios suggest that the key to alleviating deficit effects of a system shock may be appropriate timing and duration of recruitment efforts, in turn depending critically on anticipating shocks and rapidly implementing recruitment efforts. PMID- 21814549 TI - Different requirement for Wnt/beta-catenin signaling in limb regeneration of larval and adult Xenopus. AB - BACKGROUND: In limb regeneration of amphibians, the early steps leading to blastema formation are critical for the success of regeneration, and the initiation of regeneration in an adult limb requires the presence of nerves. Xenopus laevis tadpoles can completely regenerate an amputated limb at the early limb bud stage, and the metamorphosed young adult also regenerates a limb by a nerve-dependent process that results in a spike-like structure. Blockage of Wnt/beta-catenin signaling inhibits the initiation of tadpole limb regeneration, but it remains unclear whether limb regeneration in young adults also requires Wnt/beta-catenin signaling. METHODOLOGY/PRINCIPAL FINDINGS: We expressed heat shock-inducible (hs) Dkk1, a Wnt antagonist, in transgenic Xenopus to block Wnt/beta-catenin signaling during forelimb regeneration in young adults. hsDkk1 did not inhibit limb regeneration in any of the young adult frogs, though it suppressed Wnt-dependent expression of genes (fgf-8 and cyclin D1). When nerve supply to the limbs was partially removed, however, hsDkk1 expression blocked limb regeneration in young adult frogs. Conversely, activation of Wnt/beta catenin signaling by a GSK-3 inhibitor rescued failure of limb-spike regeneration in young adult frogs after total removal of nerve supply. CONCLUSIONS/SIGNIFICANCE: In contrast to its essential role in tadpole limb regeneration, our results suggest that Wnt/beta-catenin signaling is not absolutely essential for limb regeneration in young adults. The different requirement for Wnt/beta-catenin signaling in tadpoles and young adults appears to be due to the projection of nerve axons into the limb field. Our observations suggest that nerve-derived signals and Wnt/beta-catenin signaling have redundant roles in the initiation of limb regeneration. Our results demonstrate for the first time the different mechanisms of limb regeneration initiation in limb buds (tadpoles) and developed limbs (young adults) with reference to nerve-derived signals and Wnt/beta-catenin signaling. PMID- 21814551 TI - TRAIL/TRAIL receptor system and susceptibility to multiple sclerosis. AB - The TNF-related apoptosis inducing ligand (TRAIL)/TRAIL receptor system participates in crucial steps in immune cell activation or differentiation. It is able to inhibit proliferation and activation of T cells and to induce apoptosis of neurons and oligodendrocytes, and seems to be implicated in autoimmune diseases. Thus, TRAIL and TRAIL receptor genes are potential candidates for involvement in susceptibility to multiple sclerosis (MS). To test whether single nucleotide polymorphisms (SNPs) in the human genes encoding TRAIL, TRAILR-1, TRAILR-2, TRAILR-3 and TRAILR-4 are associated with MS susceptibility, we performed a candidate gene case-control study in the Spanish population. 59 SNPs in the TRAIL and TRAIL receptor genes were analysed in 628 MS patients and 660 controls, and validated in an additional cohort of 295 MS patients and 233 controls. Despite none of the SNPs withstood the highly conservative Bonferroni correction, three SNPs showing uncorrected p values<0.05 were successfully replicated: rs4894559 in TRAIL gene, p = 9.8*10(-4), OR = 1.34; rs4872077, in TRAILR-1 gene, p = 0.005, OR = 1.72; and rs1001793 in TRAILR-2 gene, p = 0.012, OR = 0.84. The combination of the alleles G/T/A in these SNPs appears to be associated with a reduced risk of developing MS (p = 2.12*10(-5), OR = 0.59). These results suggest that genes of the TRAIL/TRAIL receptor system exerts a genetic influence on MS. PMID- 21814552 TI - Expansion of the Multi-Link FrontierTM coronary bifurcation stent: micro-computed tomographic assessment in human autopsy and porcine heart samples. AB - BACKGROUND: Treatment of coronary bifurcation lesions remains challenging, beyond the introduction of drug eluting stents. Dedicated stent systems are available to improve the technical approach to the treatment of these lesions. However dedicated stent systems have so far not reduced the incidence of stent restenosis. The aim of this study was to assess the expansion of the Multi-Link (ML) FrontierTM stent in human and porcine coronary arteries to provide the cardiologist with useful in-vitro information for stent implantation and selection. METHODOLOGY/PRINCIPAL FINDINGS: Nine ML FrontierTM stents were implanted in seven human autopsy heart samples with known coronary artery disease and five ML FrontierTM stents were implanted in five porcine hearts. Proximal, distal and side branch diameters (PD, DD, SBD, respectively), corresponding opening areas (PA, DA, SBA) and the mean stent length (L) were assessed by micro computed tomography (micro-CT). PD and PA were significantly smaller in human autopsy heart samples than in porcine heart samples (3.54+/-0.47 mm vs. 4.04+/ 0.22 mm, p = 0.048; 10.00+/-2.42 mm(2) vs. 12.84+/-1.38 mm(2), p = 0.034, respectively) and than those given by the manufacturer (3.54+/-0.47 mm vs. 4.03 mm, p = 0.014). L was smaller in human autopsy heart samples than in porcine heart samples, although data did not reach significance (16.66+/-1.30 mm vs. 17.30+/-0.51 mm, p = 0.32), and significantly smaller than that given by the manufacturer (16.66+/-1.30 mm vs. 18 mm, p = 0.015). CONCLUSIONS/SIGNIFICANCE: Micro-CT is a feasible tool for exact surveying of dedicated stent systems and could make a contribution to the development of these devices. The proximal diameter and proximal area of the stent system were considerably smaller in human autopsy heart samples than in porcine heart samples and than those given by the manufacturer. Special consideration should be given to the stent deployment procedure (and to the follow-up) of dedicated stent systems, considering final intravascular ultrasound or optical coherence tomography to visualize (and if necessary optimize) stent expansion. PMID- 21814553 TI - Altering pyrroloquinoline quinone nutritional status modulates mitochondrial, lipid, and energy metabolism in rats. AB - We have reported that pyrroloquinoline quinone (PQQ) improves reproduction, neonatal development, and mitochondrial function in animals by mechanisms that involve mitochondrial related cell signaling pathways. To extend these observations, the influence of PQQ on energy and lipid relationships and apparent protection against ischemia reperfusion injury are described herein. Sprague Dawley rats were fed a nutritionally complete diet with PQQ added at either 0 (PQQ-) or 2 mg PQQ/Kg diet (PQQ+). Measurements included: 1) serum glucose and insulin, 2) total energy expenditure per metabolic body size (Wt(3/4)), 3) respiratory quotients (in the fed and fasted states), 4) changes in plasma lipids, 5) the relative mitochondrial amount in liver and heart, and 6) indices related to cardiac ischemia. For the latter, rats (PQQ- or PQQ+) were subjected to left anterior descending occlusions followed by 2 h of reperfusion to determine PQQ's influence on infarct size and myocardial tissue levels of malondialdehyde, an indicator of lipid peroxidation. Although no striking differences in serum glucose, insulin, and free fatty acid levels were observed, energy expenditure was lower in PQQ- vs. PQQ+ rats and energy expenditure (fed state) was correlated with the hepatic mitochondrial content. Elevations in plasma di- and triacylglyceride and beta-hydroxybutryic acid concentrations were also observed in PQQ- rats vs. PQQ+ rats. Moreover, PQQ administration (i.p. at 4.5 mg/kg BW for 3 days) resulted in a greater than 2-fold decrease in plasma triglycerides during a 6-hour fast than saline administration in a rat model of type 2 diabetes. Cardiac injury resulting from ischemia/reperfusion was more pronounced in PQQ- rats than in PQQ+ rats. Collectively, these data demonstrate that PQQ deficiency impacts a number of parameters related to normal mitochondrial function. PMID- 21814554 TI - Six types of multistability in a neuronal model based on slow calcium current. AB - BACKGROUND: Multistability of oscillatory and silent regimes is a ubiquitous phenomenon exhibited by excitable systems such as neurons and cardiac cells. Multistability can play functional roles in short-term memory and maintaining posture. It seems to pose an evolutionary advantage for neurons which are part of multifunctional Central Pattern Generators to possess multistability. The mechanisms supporting multistability of bursting regimes are not well understood or classified. METHODOLOGY/PRINCIPAL FINDINGS: Our study is focused on determining the bio-physical mechanisms underlying different types of co existence of the oscillatory and silent regimes observed in a neuronal model. We develop a low-dimensional model typifying the dynamics of a single leech heart interneuron. We carry out a bifurcation analysis of the model and show that it possesses six different types of multistability of dynamical regimes. These types are the co-existence of 1) bursting and silence, 2) tonic spiking and silence, 3) tonic spiking and subthreshold oscillations, 4) bursting and subthreshold oscillations, 5) bursting, subthreshold oscillations and silence, and 6) bursting and tonic spiking. These first five types of multistability occur due to the presence of a separating regime that is either a saddle periodic orbit or a saddle equilibrium. We found that the parameter range wherein multistability is observed is limited by the parameter values at which the separating regimes emerge and terminate. CONCLUSIONS: We developed a neuronal model which exhibits a rich variety of different types of multistability. We described a novel mechanism supporting the bistability of bursting and silence. This neuronal model provides a unique opportunity to study the dynamics of networks with neurons possessing different types of multistability. PMID- 21814556 TI - A combination of compositional index and genetic algorithm for predicting transmembrane helical segments. AB - Transmembrane helix (TMH) topology prediction is becoming a focal problem in bioinformatics because the structure of TM proteins is difficult to determine using experimental methods. Therefore, methods that can computationally predict the topology of helical membrane proteins are highly desirable. In this paper we introduce TMHindex, a method for detecting TMH segments using only the amino acid sequence information. Each amino acid in a protein sequence is represented by a Compositional Index, which is deduced from a combination of the difference in amino acid occurrences in TMH and non-TMH segments in training protein sequences and the amino acid composition information. Furthermore, a genetic algorithm was employed to find the optimal threshold value for the separation of TMH segments from non-TMH segments. The method successfully predicted 376 out of the 378 TMH segments in a dataset consisting of 70 test protein sequences. The sensitivity and specificity for classifying each amino acid in every protein sequence in the dataset was 0.901 and 0.865, respectively. To assess the generality of TMHindex, we also tested the approach on another standard 73-protein 3D helix dataset. TMHindex correctly predicted 91.8% of proteins based on TM segments. The level of the accuracy achieved using TMHindex in comparison to other recent approaches for predicting the topology of TM proteins is a strong argument in favor of our proposed method. AVAILABILITY: The datasets, software together with supplementary materials are available at: http://faculty.uaeu.ac.ae/nzaki/TMHindex.htm. PMID- 21814555 TI - Ligation of macrophage Fcgamma receptors recapitulates the gene expression pattern of vulnerable human carotid plaques. AB - Stroke is a leading cause of death in the United States. As ~60% of strokes result from carotid plaque rupture, elucidating the mechanisms that underlie vulnerability is critical for therapeutic intervention. We tested the hypothesis that stable and vulnerable human plaques differentially express genes associated with matrix degradation. Examination established that femoral, and the distal region of carotid, plaques were histologically stable while the proximal carotid plaque regions were vulnerable. Quantitative RT-PCR was used to compare expression of 22 genes among these tissues. Distal carotid and femoral gene expression was not significantly different, permitting the distal carotid segments to be used as a paired control for their corresponding proximal regions. Analysis of the paired plaques revealed differences in 16 genes that impact plaque stability: matrix metalloproteinases (MMP, higher in vulnerable), MMP modulators (inhibitors: lower, activators: higher in vulnerable), activating Fc receptors (FcgammaR, higher in vulnerable) and FcgammaR signaling molecules (higher in vulnerable). Surprisingly, the relative expression of smooth muscle cell and macrophage markers in the three plaque types was not significantly different, suggesting that macrophage distribution and/or activation state correlates with (in)stability. Immunohistochemistry revealed that macrophages and smooth muscle cells localize to distinct and non-overlapping regions in all plaques. MMP protein localized to macrophage-rich regions. In vitro, treatment of macrophages with immune complexes, but not oxidized low density lipoprotein, C reactive protein, or TNF-alpha, induced a gene expression profile similar to that of the vulnerable plaques. That ligation of FcgammaR recapitulates the pattern of gene expression in vulnerable plaques suggests that the FcgammaR -> macrophage activation pathway may play a greater role in human plaque vulnerability than previously appreciated. PMID- 21814547 TI - TCF7L2 polymorphism, weight loss and proinsulin:insulin ratio in the diabetes prevention program. AB - AIMS: TCF7L2 variants have been associated with type 2 diabetes, body mass index (BMI), and deficits in proinsulin processing and insulin secretion. Here we sought to test whether these effects were apparent in high-risk individuals and modify treatment responses. METHODS: We examined the potential role of the TCF7L2 rs7903146 variant in predicting resistance to weight loss or a lack of improvement of proinsulin processing during 2.5-years of follow-up participants (N = 2,994) from the Diabetes Prevention Program (DPP), a randomized controlled trial designed to prevent or delay diabetes in high-risk adults. RESULTS: We observed no difference in the degree of weight loss by rs7903146 genotypes. However, the T allele (conferring higher risk of diabetes) at rs7903146 was associated with higher fasting proinsulin at baseline (P<0.001), higher baseline proinsulin:insulin ratio (p<0.0001) and increased proinsulin:insulin ratio over a median of 2.5 years of follow-up (P = 0.003). Effects were comparable across treatment arms. CONCLUSIONS: The combination of a lack of impact of the TCF7L2 genotypes on the ability to lose weight, but the presence of a consistent effect on the proinsulin:insulin ratio over the course of DPP, suggests that high-risk genotype carriers at this locus can successfully lose weight to counter diabetes risk despite persistent deficits in insulin production. PMID- 21814557 TI - Artificial skin--culturing of different skin cell lines for generating an artificial skin substitute on cross-weaved spider silk fibres. AB - BACKGROUND: In the field of Plastic Reconstructive Surgery the development of new innovative matrices for skin repair is in urgent need. The ideal biomaterial should promote attachment, proliferation and growth of cells. Additionally, it should degrade in an appropriate time period without releasing harmful substances, but not exert a pathological immune response. Spider dragline silk from Nephila spp meets these demands to a large extent. METHODOLOGY/PRINCIPAL FINDINGS: Native spider dragline silk, harvested directly out of Nephila spp spiders, was woven on steel frames. Constructs were sterilized and seeded with fibroblasts. After two weeks of cultivating single fibroblasts, keratinocytes were added to generate a bilayered skin model, consisting of dermis and epidermis equivalents. For the next three weeks, constructs in co-culture were lifted on an originally designed setup for air/liquid interface cultivation. After the culturing period, constructs were embedded in paraffin with an especially developed program for spidersilk to avoid supercontraction. Paraffin cross sections were stained in Haematoxylin & Eosin (H&E) for microscopic analyses. CONCLUSION/SIGNIFICANCE: Native spider dragline silk woven on steel frames provides a suitable matrix for 3 dimensional skin cell culturing. Both fibroblasts and keratinocytes cell lines adhere to the spider silk fibres and proliferate. Guided by the spider silk fibres, they sprout into the meshes and reach confluence in at most one week. A well-balanced, bilayered cocultivation in two continuously separated strata can be achieved by serum reduction, changing the medium conditions and the cultivation period at the air/liquid interphase. Therefore spider silk appears to be a promising biomaterial for the enhancement of skin regeneration. PMID- 21814558 TI - The G1613A mutation in the HBV genome affects HBeAg expression and viral replication through altered core promoter activity. AB - Infection of hepatitis B virus (HBV) causes acute and chronic hepatitis and is closely associated with the development of cirrhosis and hepatocellular carcinoma (HCC). Previously, we demonstrated that the G1613A mutation in the HBV negative regulatory element (NRE) is a hotspot mutation in HCC patients. In this study, we further investigated the functional consequences of this mutation in the context of the full length HBV genome and its replication. We showed that the G1613A mutation significantly suppresses the secretion of e antigen (HBeAg) and enhances the synthesis of viral DNA, which is in consistence to our clinical result that the G1613A mutation associates with high viral load in chronic HBV carriers. To further investigate the molecular mechanism of the mutation, we performed the electrophoretic mobility shift assay with the recombinant RFX1 protein, a trans activator that was shown to interact with the NRE of HBV. Intriguingly, RFX1 binds to the G1613A mutant with higher affinity than the wild-type sequence, indicating that the mutation possesses the trans-activating effect to the core promoter via NRE. The trans-activating effect was further validated by the enhancement of the core promoter activity after overexpression of RFX1 in liver cell line. In summary, our results suggest the functional consequences of the hotspot G1613A mutation found in HBV. We also provide a possible molecular mechanism of this hotspot mutation to the increased viral load of HBV carriers, which increases the risk to HCC. PMID- 21814559 TI - Different factors affecting human ANP amyloid aggregation and their implications in congestive heart failure. AB - AIMS: Atrial Natriuretic Peptide (ANP)-containing amyloid is frequently found in the elderly heart. No data exist regarding ANP aggregation process and its link to pathologies. Our aims were: i) to experimentally prove the presumptive association of Congestive Heart Failure (CHF) and Isolated Atrial Amyloidosis (IAA); ii) to characterize ANP aggregation, thereby elucidating IAA implication in the CHF pathogenesis. METHODS AND RESULTS: A significant prevalence (85%) of IAA was immunohistochemically proven ex vivo in biopsies from CHF patients. We investigated in vitro (using Congo Red, Thioflavin T, SDS-PAGE, transmission electron microscopy, infrared spectroscopy) ANP fibrillogenesis, starting from alpha-ANP as well as the ability of dimeric beta-ANP to promote amyloid formation. Different conditions were adopted, including those reproducing beta ANP prevalence in CHF. Our results defined the uncommon rapidity of alpha-ANP self-assembly at acidic pH supporting the hypothesis that such aggregates constitute the onset of a fibrillization process subsequently proceeding at physiological pH. Interestingly, CHF-like conditions induced the production of the most stable and time-resistant ANP fibrils suggesting that CHF affected people may be prone to develop IAA. CONCLUSIONS: We established a link between IAA and CHF by ex vivo examination and assessed that beta-ANP is, in vitro, the seed of ANP fibrils. Our results indicate that beta-ANP plays a crucial role in ANP amyloid deposition under physiopathological CHF conditions. Overall, our findings indicate that early IAA-related ANP deposition may occur in CHF and suggest that these latter patients should be monitored for the development of cardiac amyloidosis. PMID- 21814560 TI - Development, problem behavior, and quality of life in a population based sample of eight-year-old children with Down syndrome. AB - OBJECTIVE: Children with Down syndrome (DS) have delayed psychomotor development. We investigated levels of development, problem behavior, and Health-Related Quality of Life (HRQoL) in a population sample of Dutch eight-year-old children with DS. Developmental outcomes were compared with normative data of eight-year old children from the general population. METHOD: Over a three-year-period all parents with an eight-year-old child with DS were approached by the national parent organization. Developmental skills were assessed by means of the McCarthy Scales of Children's Ability. To measure emotional and behavioral problems we used the Child Behavior Checklist. HRQoL was assessed with the TNO-AZL Children's Quality of Life questionnaire. Analyses of variance were applied to compare groups. RESULTS: A total of 337 children participated. Mean developmental age was substantially lower than mean calendar age (3.9 years, SD 0.87 and 8.1 years, SD 0.15 respectively). Mean developmental age was significantly lower among boys than girls (3.6 (SD 0.85) and 4.2 years (SD 0.82) respectively; p<0.001). Compared with the general population, children with DS had more emotional and behavioral problems (p<0.001). However on the anxious/depressed scale, they scored significantly more favorably (p<0.001). Significantly lower HRQoL scores for the scales gross motor skills, autonomy, social functioning and cognitive functioning were found (p-values<0.001). Hardly any differences were observed for the scales physical complaints, positive and negative emotions. CONCLUSION: Eight year-old children with DS have an average developmental delay of four years, more often have emotional and behavioral problems, and have a less favorable HRQoL compared with children from the general population. PMID- 21814561 TI - Identification of conversion from mild cognitive impairment to Alzheimer's disease using multivariate predictors. AB - Prediction of conversion from mild cognitive impairment (MCI) to Alzheimer's disease (AD) is of major interest in AD research. A large number of potential predictors have been proposed, with most investigations tending to examine one or a set of related predictors. In this study, we simultaneously examined multiple features from different modalities of data, including structural magnetic resonance imaging (MRI) morphometry, cerebrospinal fluid (CSF) biomarkers and neuropsychological and functional measures (NMs), to explore an optimal set of predictors of conversion from MCI to AD in an Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. After FreeSurfer-derived MRI feature extraction, CSF and NM feature collection, feature selection was employed to choose optimal subsets of features from each modality. Support vector machine (SVM) classifiers were then trained on normal control (NC) and AD participants. Testing was conducted on MCIc (MCI individuals who have converted to AD within 24 months) and MCInc (MCI individuals who have not converted to AD within 24 months) groups. Classification results demonstrated that NMs outperformed CSF and MRI features. The combination of selected NM, MRI and CSF features attained an accuracy of 67.13%, a sensitivity of 96.43%, a specificity of 48.28%, and an AUC (area under curve) of 0.796. Analysis of the predictive values of MCIc who converted at different follow-up evaluations showed that the predictive values were significantly different between individuals who converted within 12 months and after 12 months. This study establishes meaningful multivariate predictors composed of selected NM, MRI and CSF measures which may be useful and practical for clinical diagnosis. PMID- 21814562 TI - Dissecting the serotonergic food signal stimulating sensory-mediated aversive behavior in C. elegans. AB - Nutritional state often modulates olfaction and in Caenorhabditis elegans food stimulates aversive responses mediated by the nociceptive ASH sensory neurons. In the present study, we have characterized the role of key serotonergic neurons that differentially modulate aversive behavior in response to changing nutritional status. The serotonergic NSM and ADF neurons play antagonistic roles in food stimulation. NSM 5-HT activates SER-5 on the ASHs and SER-1 on the RIA interneurons and stimulates aversive responses, suggesting that food-dependent serotonergic stimulation involves local changes in 5-HT levels mediated by extrasynaptic 5-HT receptors. In contrast, ADF 5-HT activates SER-1 on the octopaminergic RIC interneurons to inhibit food-stimulation, suggesting neuron specific stimulatory and inhibitory roles for SER-1 signaling. Both the NSMs and ADFs express INS-1, an insulin-like peptide, that appears to cell autonomously inhibit serotonergic signaling. Food also modulates directional decisions after reversal is complete, through the same serotonergic neurons and receptors involved in the initiation of reversal, and the decision to continue forward or change direction after reversal is dictated entirely by nutritional state. These results highlight the complexity of the "food signal" and serotonergic signaling in the modulation of sensory-mediated aversive behaviors. PMID- 21814563 TI - Lethal mutants and truncated selection together solve a paradox of the origin of life. AB - BACKGROUND: Many attempts have been made to describe the origin of life, one of which is Eigen's cycle of autocatalytic reactions [Eigen M (1971) Naturwissenschaften 58, 465-523], in which primordial life molecules are replicated with limited accuracy through autocatalytic reactions. For successful evolution, the information carrier (either RNA or DNA or their precursor) must be transmitted to the next generation with a minimal number of misprints. In Eigen's theory, the maximum chain length that could be maintained is restricted to 100 1000 nucleotides, while for the most primitive genome the length is around 7000 20,000. This is the famous error catastrophe paradox. How to solve this puzzle is an interesting and important problem in the theory of the origin of life. METHODOLOGY/PRINCIPAL FINDINGS: We use methods of statistical physics to solve this paradox by carefully analyzing the implications of neutral and lethal mutants, and truncated selection (i.e., when fitness is zero after a certain Hamming distance from the master sequence) for the critical chain length. While neutral mutants play an important role in evolution, they do not provide a solution to the paradox. We have found that lethal mutants and truncated selection together can solve the error catastrophe paradox. There is a principal difference between prebiotic molecule self-replication and proto-cell self replication stages in the origin of life. CONCLUSIONS/SIGNIFICANCE: We have applied methods of statistical physics to make an important breakthrough in the molecular theory of the origin of life. Our results will inspire further studies on the molecular theory of the origin of life and biological evolution. PMID- 21814564 TI - These squatters are not innocent: the evidence of parasitism in sponge-inhabiting shrimps. AB - Marine sponges are frequently inhabited by a wide range of associated invertebrates, including caridean shrimps. Symbiotic shrimps are often considered to be commensals; however, in most cases, the relationship with sponge hosts remains unclear. Here we demonstrate that sponge-inhabiting shrimps are often parasites adapted to consumption of sponge tissues. First, we provide detailed examination of morphology and stomach contents of Typton carneus (Decapoda: Palaemonidae: Pontoniinae), a West Atlantic tropical shrimp living in fire sponges of the genus Tedania. Remarkable shear-like claws of T. carneus show evidence of intensive shearing, likely the result of crushing siliceous sponge spicules. Examination of stomach contents revealed that the host sponge tissue is a major source of food for T. carneus. A parasitic mode of life is also reflected in adaptations of mouth appendages, in the reproduction strategy, and in apparent sequestration of host pigments by shrimp. Consistent results were obtained also for congeneric species T. distinctus (Western Atlantic) and T. spongicola (Mediterranean). The distribution of shrimps among sponge hosts (mostly solitary individuals or heterosexual pairs) suggests that Typton shrimps actively prevent colonisation of their sponge by additional conspecifics, thus protecting their resource and reducing the damage to the hosts. We also demonstrate feeding on host tissues by sponge-associated shrimps of the genera Onycocaris, Periclimenaeus, and Thaumastocaris (Pontoniinae) and Synalpheus (Alpheidae). The parasitic mode of life appears to be widely distributed among sponge-inhabiting shrimps. However, it is possible that under some circumstances, the shrimps provide a service to the host sponge by preventing a penetration by potentially more damaging associated animals. The overall nature of interspecific shrimp sponge relationships thus warrants further investigation. PMID- 21814565 TI - Evidence for a prepore stage in the action of Clostridium perfringens epsilon toxin. AB - Clostridium perfringens epsilon toxin (ETX) rapidly kills MDCK II cells at 37 degrees C, but not 4 degrees C. The current study shows that, in MDCK II cells, ETX binds and forms an oligomeric complex equally well at 37 degrees C and 4 degrees C but only forms a pore at 37 degrees C. However, the complex formed in MDCK cells treated with ETX at 4 degrees C has the potential to form an active pore, since shifting those cells to 37 degrees C results in rapid cytotoxicity. Those results suggested that the block in pore formation at 4 degrees C involves temperature-related trapping of ETX in a prepore intermediate on the MDCK II cell plasma membrane surface. Evidence supporting this hypothesis was obtained when the ETX complex in MDCK II cells was shown to be more susceptible to pronase degradation when formed at 4 degrees C vs. 37 degrees C; this result is consistent with ETX complex formed at 4 degrees C remaining present in an exposed prepore on the membrane surface, while the ETX prepore complex formed at 37 degrees C is unaccessible to pronase because it has inserted into the plasma membrane to form an active pore. In addition, the ETX complex rapidly dissociated from MDCK II cells at 4 degrees C, but not 37 degrees C; this result is consistent with the ETX complex being resistant to dissociation at 37 degrees C because it has inserted into membranes, while the ETX prepore readily dissociates from cells at 4 degrees C because it remains on the membrane surface. These results support the identification of a prepore stage in ETX action and suggest a revised model for ETX cytotoxicity, i) ETX binds to an unidentified receptor, ii) ETX oligomerizes into a prepore on the membrane surface, and iii) the prepore inserts into membranes, in a temperature-sensitive manner, to form an active pore. PMID- 21814566 TI - Source of previous treatment for re-treatment TB cases registered under the National TB control Programme, India, 2010. AB - BACKGROUND: In 2009, nearly half (289,756) of global re-treatment TB notifications are from India; no nationally-representative data on the source of previous treatment was available to inform strategies for improvement of initial TB treatment outcome. OBJECTIVES: To assess the source of previous treatment for re-treatment TB patients registered under India's Revised National TB control Programme (RNTCP). METHODOLOGY: A nationally-representative cross sectional study was conducted in a sample of 36 randomly-selected districts. All consecutively registered retreatment TB patients during a defined 15-day period in these 36 districts were contacted and the information on the source of previous treatment sought. RESULTS: Data was collected from all 1712 retreatment TB patients registered in the identified districts during the study period. The data includes information on 595 'relapse' cases, 105 'failure' cases, 437 'treatment after default (TAD)' cases and 575 're-treatment others' cases. The source of most recent previous anti-tuberculosis therapy for 754 [44% (95% CI, 38.2%-49.9%)] of the re-treatment TB patients was from providers outside the TB control programme. A higher proportion of patients registered as TAD (64%) and 'retreatment others' (59%) were likely to be treated outside the National Programme, when compared to the proportion among 'relapse' (22%) or 'failure' (6%). Extrapolated to national registration, of the 292,972 re-treatment registrations in 2010, 128,907 patients would have been most recently treated outside the national programme. CONCLUSIONS: Nearly half of the re-treatment cases registered with the national programme were most recently treated outside the programme setting. Enhanced efforts towards extending treatment support and supervision to patients treated by private sector treatment providers are urgently required to improve the quality of treatment and reduce the numbers of patients with recurrent disease. In addition, reasons for the large number of recurrent TB cases from those already treated by the national programme require urgent detailed investigation. PMID- 21814567 TI - Mitigation of quantum dot cytotoxicity by microencapsulation. AB - When CdSe/ZnS-polyethyleneimine (PEI) quantum dots (QDs) are microencapsulated in polymeric microcapsules, human fibroblasts are protected from acute cytotoxic effects. Differences in cellular morphology, uptake, and viability were assessed after treatment with either microencapsulated or unencapsulated dots. Specifically, QDs contained in microcapsules terminated with polyethylene glycol (PEG) mitigate contact with and uptake by cells, thus providing a tool to retain particle luminescence for applications such as extracellular sensing and imaging. The microcapsule serves as the "first line of defense" for containing the QDs. This enables the individual QD coating to be designed primarily to enhance the function of the biosensor. PMID- 21814568 TI - Combined treatment of heterocyclic analogues and benznidazole upon Trypanosoma cruzi in vivo. AB - Chagas disease caused by Trypanosoma cruzi is an important cause of mortality and morbidity in Latin America but no vaccines or safe chemotherapeutic agents are available. Combined therapy is envisioned as an ideal approach since it may enhance efficacy by acting upon different cellular targets, may reduce toxicity and minimize the risk of drug resistance. Therefore, we investigated the activity of benznidazole (Bz) in combination with the diamidine prodrug DB289 and in combination with the arylimidamide DB766 upon T. cruzi infection in vivo. The oral treatment of T.cruzi-infected mice with DB289 and Benznidazole (Bz) alone reduced the number of circulating parasites compared with untreated mice by about 70% and 90%, respectively. However, the combination of these two compounds decreased the parasitemia by 99% and protected against animal mortality by 100%, but without providing a parasitological cure. When Bz (p.o) was combined with DB766 (via i.p. route), at least a 99.5% decrease in parasitemia levels was observed. DB766+Bz also provided 100% protection against mice mortality while Bz alone provided about 87% protection. This combined therapy also reduced the tissular lesions induced by T. cruzi infection: Bz alone reduced GPT and CK plasma levels by about 12% and 78% compared to untreated mice group, the combination of Bz with DB766 resulted in a reduction of GPT and CK plasma levels of 56% and 91%. Cure assessment through hemocultive and PCR approaches showed that Bz did not provide a parasitological cure, however, DB766 alone or associated with Bz cured >=13% of surviving animals. PMID- 21814569 TI - HrpA, a DEAH-box RNA helicase, is involved in global gene regulation in the Lyme disease spirochete. AB - Spirochetes causing Lyme borreliosis are obligate parasites that can only be found in a tick vector or a vertebrate host. The ability to survive in these two disparate environments requires up and downregulation of specific genes by regulatory circuits that remain largely obscure. In this work on the Lyme spirochete, B. burgdorferi, we show that a disruption of the hrpA gene, which encodes a putative RNA helicase, results in a complete loss in the ability of the spirochetes to infect mice by needle inoculation. Studies of protein expression in culture by 2D gels revealed a change in the expression of 33 proteins in hrpA clones relative to the wild-type parent. Quantitative characterization of protein expression by iTRAQ analysis revealed a total of 187 differentially regulated proteins in an hrpA background: 90 downregulated and 97 upregulated. Forty-two of the 90 downregulated and 65 of the 97 upregulated proteins are not regulated under any conditions by the previously reported regulators in B. burgdorferi (bosR, rrp2, rpoN, rpoS or rrp1). Downregulated and upregulated proteins also fell into distinct functional categories. We conclude that HrpA is part of a new and distinct global regulatory pathway in B. burgdorferi gene expression. Because an HrpA orthologue is present in many bacteria, its participation in global regulation in B. burgdorferi may have relevance in other bacterial species where its function remains obscure. We believe this to be the first report of a role for an RNA helicase in a global regulatory pathway in bacteria. This finding is particularly timely with the recent growth of the field of RNA regulation of gene expression and the ability of RNA helicases to modulate RNA structure and function. PMID- 21814571 TI - Dynamic distribution of nuclear coactivator 4 during mitosis: association with mitotic apparatus and midbodies. AB - The cytoplasmic localization of Nuclear Receptor Coactivator 4 (NcoA4), also referred to as androgen receptor associated protein 70 (ARA70), indicates it may possess activities in addition to its role within the nucleus as a transcriptional enhancer. Towards identifying novel functions of NcoA4, we performed an in silico analysis of its amino acid sequence to identify potential functional domains and related proteins, and examined its subcellular distribution throughout the cell cycle. NcoA4 has no known or predicted functional or structural domains with the exception of an LxxLL and FxxLF nuclear receptor interaction motif and an N-terminal putative coiled-coil domain. Phylogenetic analysis indicated that NcoA4 has no paralogs and that a region referred to as ARA70-I family domain, located within the N-terminus and overlapping with the coiled-coil domain, is evolutionarily conserved in metazoans ranging from cnidarians to mammals. An adjacent conserved region, designated ARA70-II family domain, with no significant sequence similarity to the ARA70-I domain, is restricted to vertebrates. We demonstrate NcoA4 co-localizes with microtubules and microtubule organizing centers during prophase. Strong NcoA4 accumulation at the centrosomes was detected during interphase and telophase, with decreased levels at metaphase and anaphase. NcoA4 co-localized with tubulin and acetylated tubulin to the mitotic spindles during metaphase and anaphase, and to midbodies during telophase. Consistent with these observations, we demonstrated an interaction between NcoA4 and alpha-tubulin. Co-localization was not observed with microfilaments. These findings indicate a dynamic distribution of NcoA4 with components of the mitotic apparatus that is consistent with a potential non-transcriptional regulatory function(s) during cell division, which may be evolutionarily conserved. PMID- 21814570 TI - A newly described bovine type 2 scurs syndrome segregates with a frame-shift mutation in TWIST1. AB - The developmental pathways involved in horn development are complex and still poorly understood. Here we report the description of a new dominant inherited syndrome in the bovine Charolais breed that we have named type 2 scurs. Clinical examination revealed that, despite a strong phenotypic variability, all affected individuals show both horn abnormalities similar to classical scurs phenotype and skull interfrontal suture synostosis. Based on a genome-wide linkage analysis using Illumina BovineSNP50 BeadChip genotyping data from 57 half-sib and full-sib progeny, this locus was mapped to a 1.7 Mb interval on bovine chromosome 4. Within this region, the TWIST1 gene encoding a transcription factor was considered as a strong candidate gene since its haploinsufficiency is responsible for the human Saethre-Chotzen syndrome, characterized by skull coronal suture synostosis. Sequencing of the TWIST1 gene identified a c.148_157dup (p.A56RfsX87) frame-shift mutation predicted to completely inactivate this gene. Genotyping 17 scurred and 20 horned founders of our pedigree as well as 48 unrelated horned controls revealed a perfect association between this mutation and the type 2 scurs phenotype. Subsequent genotyping of 32 individuals born from heterozygous parents showed that homozygous mutated progeny are completely absent, which is consistent with the embryonic lethality reported in Drosophila and mouse suffering from TWIST1 complete insufficiency. Finally, data from previous studies on model species and a fine description of type 2 scurs symptoms allowed us to propose different mechanisms to explain the features of this syndrome. In conclusion, this first report on the identification of a potential causal mutation affecting horn development in cattle offers a unique opportunity to better understand horn ontogenesis. PMID- 21814572 TI - HSF1 is essential for the resistance of zebrafish eye and brain tissues to hypoxia/reperfusion injury. AB - Ischemia and subsequent reperfusion (IR) produces injury to brain, eye and other tissues, contributing to the progression of important clinical pathologies. The response of cells to IR involves activation of several signaling pathways including those activating hypoxia and heat shock responsive transcription factors. However, specific roles of these responses in limiting cell damage and preventing cell death after IR have not been fully elucidated. Here, we have examined the role of heat shock factor 1 (HSF1) in the response of zebrafish embryos to hypoxia and subsequent return to normoxic conditions (HR) as a model for IR. Heat shock preconditioning elevated heat shock protein expression and protected zebrafish embryo eye and brain tissues against HR-induced apoptosis. These effects were inhibited by translational suppression of HSF1 expression. Reduced expression of HSF1 also increased cell death in brain and eye tissues of embryos subjected to hypoxia and reperfusion without prior heat shock. Surprisingly, reduced expression of HSF1 had only a modest effect on hypoxia induced expression of Hsp70 and no effect on hypoxia-induced expression of Hsp27. These results establish the zebrafish embryo as a model for the study of ischemic injury in the brain and eye and reveal a critical role for HSF1 in the response of these tissues to HR. Our results also uncouple the role of HSF1 expression from that of Hsp27, a well characterized heat shock protein considered essential for cell survival after hypoxia. Alternative roles for HSF1 are considered. PMID- 21814573 TI - Wnt/beta-catenin signaling pathway is a direct enhancer of thyroid transcription factor-1 in human papillary thyroid carcinoma cells. AB - The Wnt/beta-catenin signaling pathway is involved in the normal development of thyroid gland, but its disregulation provokes the appearance of several types of cancers, including papillary thyroid carcinomas (PTC) which are the most common thyroid tumours. The follow-up of PTC patients is based on the monitoring of serum thyroglobulin levels which is regulated by the thyroid transcription factor 1 (TTF-1): a tissue-specific transcription factor essential for the differentiation of the thyroid. We investigated whether the Wnt/beta-catenin pathway might regulate TTF-1 expression in a human PTC model and examined the molecular mechanisms underlying this regulation. Immunofluorescence analysis, real time RT-PCR and Western blot studies revealed that TTF-1 as well as the major Wnt pathway components are co-expressed in TPC-1 cells and human PTC tumours. Knocking-down the Wnt/beta-catenin components by siRNAs inhibited both TTF-1 transcript and protein expression, while mimicking the activation of Wnt signaling by lithium chloride induced TTF-1 gene and protein expression. Functional promoter studies and ChIP analysis showed that the Wnt/beta-catenin pathway exerts its effect by means of the binding of beta-catenin to TCF/LEF transcription factors on the level of an active TCF/LEF response element at [ 798, -792 bp] in TTF-1 promoter. In conclusion, we demonstrated that the Wnt/beta catenin pathway is a direct and forward driver of the TTF-1 expression. The localization of TCF-4 and TTF-1 in the same area of PTC tissues might be of clinical relevance, and justifies further examination of these factors in the papillary thyroid cancers follow-up. PMID- 21814574 TI - Cysteine-rich secretory protein-3 (CRISP3) is strongly up-regulated in prostate carcinomas with the TMPRSS2-ERG fusion gene. AB - A large percentage of prostate cancers harbor TMPRSS2-ERG gene fusions, leading to aberrant overexpression of the transcription factor ERG. The target genes deregulated by this rearrangement, however, remain mostly unknown. To address this subject we performed genome-wide mRNA expression analysis on 6 non-malignant prostate samples and 24 prostate carcinomas with (n = 16) and without (n = 8) TMPRSS2-ERG fusion as determined by FISH. The top-most differentially expressed genes and their associations with ERG over-expression were technically validated by quantitative real-time PCR and biologically validated in an independent series of 200 prostate carcinomas. Several genes encoding metabolic enzymes or extracellular/transmembrane proteins involved in cell adhesion, matrix remodeling and signal transduction pathways were found to be co-expressed with ERG. Within those significantly over-expressed in fusion-positive carcinomas, CRISP3 showed more than a 50-fold increase when compared to fusion-negative carcinomas, whose expression levels were in turn similar to that of non-malignant samples. In the independent validation series, ERG and CRISP3 mRNA levels were strongly correlated (r(s) = 0.65, p<0.001) and both were associated with pT3 disease staging. Furthermore, immunohistochemistry results showed CRISP3 protein overexpression in 63% of the carcinomas and chromatin immunoprecipitation with an anti-ERG antibody showed that CRISP3 is a direct target of the transcription factor ERG. We conclude that ERG rearrangement is associated with significant expression alterations in genes involved in critical cellular pathways that define a subset of locally advanced PCa. In particular, we show that CRISP3 is a direct target of ERG that is strongly overexpressed in PCa with the TMPRSS2-ERG fusion gene. PMID- 21814575 TI - Multiphoton fluorescence microscopy with GRIN objective aberration correction by low order adaptive optics. AB - Graded Index (GRIN) rod microlenses are increasingly employed in the assembly of optical probes for microendoscopy applications. Confocal, two-photon and optical coherence tomography (OCT) based on GRIN optical probes permit in-vivo imaging with penetration depths into tissue up to the centimeter range. However, insertion of the probe can be complicated by the need of several alignment and focusing mechanisms along the optical path. Furthermore, resolution values are generally not limited by diffraction, but rather by optical aberrations within the endoscope probe and feeding optics. Here we describe a multiphoton confocal fluorescence imaging system equipped with a compact objective that incorporates a GRIN probe and requires no adjustment mechanisms. We minimized the effects of aberrations with optical compensation provided by a low-order electrostatic membrane mirror (EMM) inserted in the optical path of the confocal architecture, resulting in greatly enhanced image quality. PMID- 21814576 TI - Myeloid IkappaBalpha deficiency promotes atherogenesis by enhancing leukocyte recruitment to the plaques. AB - Activation of the transcription factor NF-kappaB appears to be involved in different stages of atherogenesis. In this paper we investigate the role of NF kappaB inhibitor IkappaBalpha in atherosclerosis. Myeloid-specific deletion of IkappaBalpha results in larger and more advanced lesions in LDL-R-deficient mice without affecting the compositional phenotype of the plaques or systemic inflammatory markers in the plasma. We show that IkappaBalpha-deleted macrophages display enhanced adhesion to an in vitro endothelial cell layer, coinciding with an increased expression of the chemokine CCL5. Also, in vivo we found that IkappaBalpha(del) mice had more leukocytes adhering to the luminal side of the endothelial cell layers that cover the atherosclerotic plaques. Moreover, we introduce ER-MP58 in this paper as a new immunohistochemical tool for quantifying newly recruited myeloid cells in the atherosclerotic lesion. This staining confirms that in IkappaBalpha(del) mice more leukocytes are attracted to the plaques. In conclusion, we show that IkappaBalpha deletion in myeloid cells promotes atherogenesis, probably through an induced leukocyte recruitment to plaques. PMID- 21814577 TI - High resolution structure of the ba3 cytochrome c oxidase from Thermus thermophilus in a lipidic environment. AB - The fundamental chemistry underpinning aerobic life on Earth involves reduction of dioxygen to water with concomitant proton translocation. This process is catalyzed by members of the heme-copper oxidase (HCO) superfamily. Despite the availability of crystal structures for all types of HCO, the mode of action for this enzyme is not understood at the atomic level, namely how vectorial H(+) and e(-) transport are coupled. Toward addressing this problem, we report wild type and A120F mutant structures of the ba(3)-type cytochrome c oxidase from Thermus thermophilus at 1.8 A resolution. The enzyme has been crystallized from the lipidic cubic phase, which mimics the biological membrane environment. The structures reveal 20 ordered lipid molecules that occupy binding sites on the protein surface or mediate crystal packing interfaces. The interior of the protein encloses 53 water molecules, including 3 trapped in the designated K-path of proton transfer and 8 in a cluster seen also in A-type enzymes that likely functions in egress of product water and proton translocation. The hydrophobic O(2)-uptake channel, connecting the active site to the lipid bilayer, contains a single water molecule nearest the Cu(B) atom but otherwise exhibits no residual electron density. The active site contains strong electron density for a pair of bonded atoms bridging the heme Fe(a3) and Cu(B) atoms that is best modeled as peroxide. The structure of ba(3)-oxidase reveals new information about the positioning of the enzyme within the membrane and the nature of its interactions with lipid molecules. The atomic resolution details provide insight into the mechanisms of electron transfer, oxygen diffusion into the active site, reduction of oxygen to water, and pumping of protons across the membrane. The development of a robust system for production of ba(3)-oxidase crystals diffracting to high resolution, together with an established expression system for generating mutants, opens the door for systematic structure-function studies. PMID- 21814578 TI - A nuclear localization of the infectious haematopoietic necrosis virus NV protein is necessary for optimal viral growth. AB - The nonvirion (NV) protein of infectious hematopoietic necrosis virus (IHNV) has been previously reported to be essential for efficient growth and pathogenicity of IHNV. However, little is known about the mechanism by which the NV supports the viral growth. In this study, cellular localization of NV and its role in IHNV growth in host cells was investigated. Through transient transfection in RTG-2 cells of NV fused to green fluorescent protein (GFP), a nuclear localization of NV was demonstrated. Deletion analyses showed that the (32)EGDL(35) residues were essential for nuclear localization of NV protein, and fusion of these 4 amino acids to GFP directed its transport to the nucleus. We generated a recombinant IHNV, rIHNV-NV-DeltaEGDL in which the (32)EGDL(35) was deleted from the NV. rIHNVs with wild-type NV (rIHNV-NV) or with the NV gene replaced with GFP (rIHNV DeltaNV-GFP) were used as controls. RTG-2 cells infected with rIHNV-DeltaNV-GFP and rIHNV-NV-DeltaEGDL yielded 12- and 5-fold less infectious virion, respectively, than wild type rIHNV-infected cells at 48 h post-infection (p.i.). While treatment with poly I?C at 24 h p.i. did not inhibit replication of wild type rIHNVs, replication rates of rIHNV-DeltaNV-GFP and rIHNV-NV-DeltaEGDL were inhibited by poly I?C. In addition, both rIHNV-DeltaNV and rIHNV-NV-DeltaEGDL induced higher levels of expressions of both IFN1 and Mx1 than wild-type rIHNV. These data suggest that the IHNV NV may support the growth of IHNV through inhibition of the INF system and the amino acid residues of (32)EGDL(35) responsible for nuclear localization are important for the inhibitory activity of NV. PMID- 21814579 TI - The spleen CD4+ T cell response to blood-stage Plasmodium chabaudi malaria develops in two phases characterized by different properties. AB - The pivotal role of spleen CD4(+) T cells in the development of both malaria pathogenesis and protective immunity makes necessary a profound comprehension of the mechanisms involved in their activation and regulation during Plasmodium infection. Herein, we examined in detail the behaviour of non-conventional and conventional splenic CD4(+) T cells during P. chabaudi malaria. We took advantage of the fact that a great proportion of CD4(+) T cells generated in CD1d(-/-) mice are I-A(b)-restricted (conventional cells), while their counterparts in I-A(b-/-) mice are restricted by CD1d and other class IB major histocompatibility complex (MHC) molecules (non-conventional cells). We found that conventional CD4(+) T cells are the main protagonists of the immune response to infection, which develops in two consecutive phases concomitant with acute and chronic parasitaemias. The early phase of the conventional CD4(+) T cell response is intense and short lasting, rapidly providing large amounts of proinflammatory cytokines and helping follicular and marginal zone B cells to secrete polyclonal immunoglobulin. Both TNF-alpha and IFN-gamma production depend mostly on conventional CD4(+) T cells. IFN-gamma is produced simultaneously by non conventional and conventional CD4(+) T cells. The early phase of the response finishes after a week of infection, with the elimination of a large proportion of CD4(+) T cells, which then gives opportunity to the development of acquired immunity. Unexpectedly, the major contribution of CD1d-restricted CD4(+) T cells occurs at the beginning of the second phase of the response, but not earlier, helping both IFN-gamma and parasite-specific antibody production. We concluded that conventional CD4(+) T cells have a central role from the onset of P. chabaudi malaria, acting in parallel with non-conventional CD4(+) T cells as a link between innate and acquired immunity. This study contributes to the understanding of malaria immunology and opens a perspective for future studies designed to decipher the molecular mechanisms behind immune responses to Plasmodium infection. PMID- 21814580 TI - Low-level laser therapy activates NF-kB via generation of reactive oxygen species in mouse embryonic fibroblasts. AB - BACKGROUND: Despite over forty years of investigation on low-level light therapy (LLLT), the fundamental mechanisms underlying photobiomodulation at a cellular level remain unclear. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we isolated murine embryonic fibroblasts (MEF) from transgenic NF-kB luciferase reporter mice and studied their response to 810 nm laser radiation. Significant activation of NF-kB was observed at fluences higher than 0.003 J/cm(2) and was confirmed by Western blot analysis. NF-kB was activated earlier (1 hour) by LLLT compared to conventional lipopolysaccharide treatment. We also observed that LLLT induced intracellular reactive oxygen species (ROS) production similar to mitochondrial inhibitors, such as antimycin A, rotenone and paraquat. Furthermore, we observed similar NF-kB activation with these mitochondrial inhibitors. These results, together with inhibition of laser induced NF-kB activation by antioxidants, suggests that ROS play an important role in the laser induced NF-kB signaling pathways. However, LLLT, unlike mitochondrial inhibitors, induced increased cellular ATP levels, which indicates that LLLT also upregulates mitochondrial respiration. CONCLUSION: We conclude that LLLT not only enhances mitochondrial respiration, but also activates the redox-sensitive NFkB signaling via generation of ROS. Expression of anti-apoptosis and pro-survival genes responsive to NFkB could explain many clinical effects of LLLT. PMID- 21814581 TI - Stage-specific histone modification profiles reveal global transitions in the Xenopus embryonic epigenome. AB - Vertebrate embryos are derived from a transitory pool of pluripotent cells. By the process of embryonic induction, these precursor cells are assigned to specific fates and differentiation programs. Histone post-translational modifications are thought to play a key role in the establishment and maintenance of stable gene expression patterns underlying these processes. While on gene level histone modifications are known to change during differentiation, very little is known about the quantitative fluctuations in bulk histone modifications during development. To investigate this issue we analysed histones isolated from four different developmental stages of Xenopus laevis by mass spectrometry. In toto, we quantified 59 modification states on core histones H3 and H4 from blastula to tadpole stages. During this developmental period, we observed in general an increase in the unmodified states, and a shift from histone modifications associated with transcriptional activity to transcriptionally repressive histone marks. We also compared these naturally occurring patterns with the histone modifications of murine ES cells, detecting large differences in the methylation patterns of histone H3 lysines 27 and 36 between pluripotent ES cells and pluripotent cells from Xenopus blastulae. By combining all detected modification transitions we could cluster their patterns according to their embryonic origin, defining specific histone modification profiles (HMPs) for each developmental stage. To our knowledge, this data set represents the first compendium of covalent histone modifications and their quantitative flux during normogenesis in a vertebrate model organism. The HMPs indicate a stepwise maturation of the embryonic epigenome, which may be causal to the progressing restriction of cellular potency during development. PMID- 21814583 TI - The struggle of neglected scientific groups: ten years of NeTropica efforts to promote research in tropical diseases in Central America. PMID- 21814582 TI - Linking global HIV/AIDS treatments with national programs for the control and elimination of the neglected tropical diseases. PMID- 21814584 TI - Cystic echinococcosis: chronic, complex, and still neglected. PMID- 21814585 TI - Leishmaniasis: Middle East and North Africa research and development priorities. PMID- 21814586 TI - Improved PCR-RFLP for the detection of diminazene resistance in Trypanosoma congolense under field conditions using filter papers for sample storage. PMID- 21814587 TI - Effects of irritant chemicals on Aedes aegypti resting behavior: is there a simple shift to untreated "safe sites"? AB - BACKGROUND: Previous studies have identified the behavioral responses of Aedes aegypti to irritant and repellent chemicals that can be exploited to reduce man vector contact. Maximum efficacy of interventions based on irritant chemical actions will, however, require full knowledge of variables that influence vector resting behavior and how untreated "safe sites" contribute to overall impact. METHODS: Using a laboratory box assay, resting patterns of two population strains of female Ae. aegypti (THAI and PERU) were evaluated against two material types (cotton and polyester) at various dark:light surface area coverage (SAC) ratio and contrast configuration (horizontal and vertical) under chemical-free and treated conditions. Chemicals evaluated were alphacypermethrin and DDT at varying concentrations. RESULTS: Under chemical-free conditions, dark material had significantly higher resting counts compared to light material at all SAC, and significantly increased when material was in horizontal configuration. Cotton elicited stronger response than polyester. Within the treatment assays, significantly higher resting counts were observed on chemical-treated dark material compared to untreated light fabric. However, compared to matched controls, significantly less resting observations were made on chemical-treated dark material overall. Most importantly, resting observations on untreated light material (or "safe sites") in the treatment assay did not significantly increase for many of the tests, even at 25% SAC. Knockdown rates were <=5% for all assays. Significantly more observations of flying mosquitoes were made in test assays under chemical-treatment conditions as compared to controls. CONCLUSIONS/SIGNIFICANCE: When preferred Ae. aegypti resting sites are treated with chemicals, even at reduced treatment coverage area, mosquitoes do not simply move to safe sites (untreated areas) following contact with the treated material. Instead, they become agitated, using increased flight as a proxy indicator. It is this contact irritant response that may elicit escape behavior from a treated space and is a focus of exploitation for reducing man-vector contact inside homes. PMID- 21814588 TI - Randomized clinical trial on ivermectin versus thiabendazole for the treatment of strongyloidiasis. AB - BACKGROUND: Strongyloidiasis may cause a life-threatening disease in immunosuppressed patients. This can only be prevented by effective cure of chronic infections. Direct parasitologic exams are not sensitive enough to prove cure if negative. We used an indirect immune fluorescent antibody test (IFAT) along with direct methods for patient inclusion and efficacy assessment. METHODOLOGY/PRINCIPAL FINDINGS: Prospective, randomized, open label, phase III trial conducted at the Centre for Tropical Diseases (Verona, Italy) to compare efficacy and safety of ivermectin (single dose, 200 ug/kg) and thiabendazole (two daily doses of 25 mg/Kg for two days) to cure strongyloidiasis. The first patient was recruited on 6(th) December, 2004. Follow-up visit of the last patient was on 11(th) January, 2007. Consenting patients responding to inclusion criteria were randomly assigned to one of the treatment arms. Primary outcome was: negative direct and indirect (IFAT) tests at follow-up (4 to 6 months after treatment) or subjects with negative direct test and drop of two or more IFAT titers. Considering 198 patients who concluded follow-up, efficacy was 56.6% for ivermectin and 52.2% for thiabendazole (p = 0.53). If the analysis is restricted to 92 patients with IFAT titer 80 or more before treatment (virtually 100% specific), efficacy would be 68.1% for ivermectin and 68.9% for thiabendazole (p = 0.93). Considering direct parasitological diagnosis only, efficacy would be 85.7% for ivermectin and 94.6% for thiabendazole (p = 0.21). In ivermectin arm, mild to moderate side effects were observed in 24/115 patients (20.9%), versus 79/108 (73.1%) in thiabendazole arm (p = 0.00). CONCLUSION: No significant difference in efficacy was observed, while side effects were far more frequent in thiabendazole arm. Ivermectin is the drug of choice, but efficacy of single dose is suboptimal. Different dose schedules should be assessed by future, larger studies. TRIAL REGISTRATION: Portal of Clinical Research with Medicines in Italy 2004-004693-87 PMID- 21814589 TI - Real-Time Infrared Overtone Laser Control of Temperature in Picoliter H(2)O Samples: "Nanobathtubs" for Single Molecule Microscopy. AB - An approach for high spatiotemporal control of aqueous sample temperatures in confocal microscopy is reported. This technique exploits near-IR diode-laser illumination to locally heat picoliter volumes of water via first-overtone excitation in the OH-stretch manifold. A thin water cell after the objective resonantly removes any residual IR light from the detection system, allowing for continuous observation of single-molecule fluorescence throughout the heating event. This technique is tested quantitatively by reproducing single-molecule RNA folding results obtained from "bulk" stage heating measurements. Calibration of sample temperatures is obtained from time-correlated single-photon counting studies of Rhodamine B fluorescence decay. We obtain an upper limit to the heating response time (tau(heat) < 20 ms) consistent with even faster estimates (tau(heat) ~ 0.25 ms) based on laser spot size, H(2)O heat capacit,y and absorption cross section. This combination of fast, noncontact heating of picoliter volumes provides new opportunities for real-time thermodynamic/kinetic studies at the single-molecule level. PMID- 21814592 TI - Pathology of epstein-barr virus-associated gastric carcinoma and its relationship to prognosis. AB - Among Epstein-Barr virus (EBV)-associated neoplasms, EBV-associated gastric carcinoma (EBVaGC) is the most common tumor worldwide. In contrast to the predominant site of occurrence of EBV-negative gastric carcinoma in the antrum, EBVaGC occurs most frequently in the proximal stomach, including the cardia, fundus and body. Microscopically, EBVaGC can be subclassified into three histological subtypes according to the host cellular immune responses: lymphoepithelioma-like carcinoma, carcinoma with Crohn's disease-like lymphoid reaction, and conventional-type adenocarcinoma. Recent studies have shown that patients with the lymphoepithelioma-like carcinoma subtype of EBVaGC have the best overall and disease-free survival, followed by Crohn's disease-like reactions, which in turn have better survival than patients with conventional type adenocarcinoma. Histologic subclassifications of EBVaGCs are based on the differing degree and pattern of infl ammatory response and the extent of desmoplasia. Because these subclassifications appear to be a powerful prognostic parameter, further research into the underlying mechanisms of the cellular immune reaction in these pathologic subtypes of EBVaGCs may play a key role in understanding the innate immune response of patients with this highly aggressive carcinoma. PMID- 21814591 TI - Biliary strictures after liver transplantation. AB - Biliary strictures are one of the most common complications following liver transplantation, representing an important cause of morbidity and mortality in transplant recipients. The reported incidence of biliary stricture is 5% to 15% following deceased donor liver transplantations and 28% to 32% following living donor liver transplantations. Bile duct strictures following liver transplantation are easily and conveniently classified as anastomotic strictures (AS) or non-anastomotic strictures (NAS). NAS are characterized by a far less favorable response to endoscopic management, higher recurrence rates, graft loss and the need for retransplantation. Current endoscopic strategies to correct biliary strictures following liver transplantation include repeated balloon dilatations and the placement of multiple side-by-side plastic stents. Endoscopic balloon dilatation with stent placement is successful in the majority of AS patients. In patients for whom gaining biliary access is technically difficult, a combined endoscopic and percutaneous/surgical approach proves quite useful. Future directions, including novel endoscopic retrograde cholangiopancreatography techniques, advanced endoscopy, and improved stents could allow for a decreased number of interventions, increased intervals before retreatment, and decreased reliance on percutaneous and surgical modalities. The aim of this review is to detail the present status of endoscopy in the diagnosis, treatment, outcome, and future directions of biliary strictures related to orthotopic liver transplantation from the viewpoint of a clinical gastroenterologists. PMID- 21814590 TI - Chronic hepatitis C. AB - The goal of antiviral therapy for patients with chronic hepatitis C virus (HCV) infection is to attain a sustained virologic response (SVR), which is defined as undetectable serum HCV-RNA levels at 6 months after the cessation of treatment. Major improvements in antiviral therapy for chronic hepatitis C have occurred in the past decade. The addition of ribavirin to interferon-alfa therapy and the introduction of pegylated interferon (PEG-IFN) have substantially improved SVR rates in patients with chronic hepatitis C. The optimization of HCV therapy with PEG-IFN and ribavirin continues to evolve. Studies are ongoing that use viral kinetics to tailor therapy to an individual's antiviral response and determine the ideal length of treatment to maximize the chance of SVR. Improved SVR can be achieved with new specific inhibitors that target the HCV NS3/4A protease and the NS5B polymerase. Several long-term follow-up studies have shown that SVR, when achieved, is associated with a very low risk of virologic relapse. Furthermore, antiviral therapy can reduce the morbidity and mortality rates associated with chronic hepatitis C by reducing fibrosis progression, the incidence of cirrhosis, and hepatocellular carcinoma. PMID- 21814593 TI - Differential LINE-1 Hypomethylation of Gastric Low-Grade Dysplasia from High Grade Dysplasia and Intramucosal Cancer. AB - BACKGROUND/AIMS: Gastric epithelial dysplasia is considered a precancerous lesion with a variable clinical course. There is disagreement, however, regarding histology-based diagnoses, which has led to confusion in choosing a therapeutic plan. New objective markers are needed to determine which lesions progress to true malignancy. We measured LINE-1 methylation levels, which have been reported to strongly correlate with the global methylation level in gastric epithelial dysplasia and intramucosal cancer. METHODS: A total of 145 tissue samples were analyzed by two histopathologists. All tissues were excised by therapeutic endoscopic mucosal resection and paired with adjacent normal tissue samples. A modified long interspersed nucleotide elements-combined bisulfite restriction analysis (COBRA-LINE-1) method was used. RESULTS: Gastric epithelial dysplasia and intramucosal cancer tissues had significantly lower levels of LINE-1 methylation than adjacent normal gastric tissues. High-grade dysplasia and intramucosal cancer were distinguishable from low-grade dysplasia based on LINE-1 methylation levels. Furthermore, the distinction could be determined with high sensitivity and specificity, as shown by the receiver operating characteristic (ROC) curve (AUC, 0.82; 95% confidence interval, 0.74 to 0.88). CONCLUSIONS: LINE 1 methylation levels may provide a diagnostic tool for identifying high-grade dysplasia and intramucosal cancer. PMID- 21814594 TI - KLF4 Expression Correlates with the Degree of Differentiation in Colorectal Cancer. AB - BACKGROUND/AIMS: Kruppel-like factor 4 (KLF4) is an epithelial-specific transcription factor primarily expressed in the gastrointestinal tract that mediates growth arrest in the colonic epithelium. We tried to find whether KLF4 expression is associated with the progression and differentiation of colorectal cancer. METHODS: We detected KLF4 expression in 109 colorectal specimens (40 normal appearing mucosa, 7 adenomas, and 62 carcinomas) by immunohistochemistry using a tissue microarray. Western blot and RT-PCR analyses were also performed. RESULTS: The upregulation of KLF4 expression in carcinoma tissue was statistically significant (p<0.05) when compared to normal appearing mucosa. The negative and weak positive staining rates in normal appearing mucosa, adenoma, and carcinoma were 42.5%, 71.4%, and 82.3%, respectively, indicating a decreased degree of KLF4 expression over the course of progressive transformation of normal cells into malignant derivatives. KLF4 protein levels showed no correlation with sex, age, or metastatic state (p>0.05), while KLF4 protein expression correlated with the diagnostic stage (p<0.05). Furthermore, strong KLF4 staining was detected in 22.9% (11/48) and 0% (0/14) of well/moderately and poorly differentiated colorectal cancers, respectively. Our results clearly indicate that KLF4 protein expression significantly correlates with the degree of differentiation in colorectal cancers (p<0.05). KLF4 expression in RKO cells is also upregulated by butyrate, an inducer of differentiation. CONCLUSIONS: Downregulation of KLF4 expression may lead to more poorly differentiated tumors. PMID- 21814595 TI - Efficacy of Bispectral Index Monitoring for Midazolam and Meperidine Induced Sedation during Endoscopic Submucosal Dissection: A Prospective, Randomized Controlled Study. AB - BACKGROUND/AIMS: Propofol induced sedation with bispectral index (BIS) monitoring has been reported to lead to higher satisfaction in patients and endoscopists during endoscopic submucosal dissection (ESD) procedures. There are no data, however, regarding the efficacy of midazolam and meperidine (M/M) induced sedation with BIS monitoring during ESD. The purpose of this study was to evaluate whether M/M induced sedation with BIS monitoring could improve satisfaction and reduce the dose of M/M required during ESD. METHODS: Between September 2009 and January 2010, 56 patients were prospectively enrolled and randomly assigned to a BIS group (n=28) and a non-BIS group (n=28). Patient and endoscopist satisfaction scores were assessed using the visual analog scale (0 to 100) following the ESD. RESULTS: The mean satisfaction scores did not significantly differ between the BIS and non-BIS groups (92.3+/-16.3 vs 93.3+/ 15.5, p=0.53) or endoscopists (83.1+/-15.4 vs 80.0+/-16.7, p=0.52). Although the mean meperidine dose did not differ (62.5+/-27.6 vs 51.0+/-17.3, p=0.18) between the two groups, the mean dose of midazolam in the non-BIS group was lower than in the BIS group (6.8+/-2.0 vs 5.4+/-2.1, p=0.01). CONCLUSIONS: BIS monitoring during ESD did not increase the satisfaction of endoscopists or patients and did not lead to an M/M dose reduction. These results demonstrate that BIS monitoring provides no additional benefit to M/M induced sedation during ESD. PMID- 21814596 TI - Clinical outcome of self-expandable metal stent placement in the management of malignant proximal colon obstruction. AB - BACKGROUND/AIMS: There are limited data regarding the clinical outcomes of self expandable metal stents in the treatment of proximal colon obstruction. We compared the clinical outcomes of stent placement in patients with malignant proximal to distal colon obstructions. METHODS: We reviewed medical records from 37 consecutive patients from three institutions (19 men; mean age, 72 years) who underwent endoscopic stent placement at a malignant obstruction of the proximal colon. We also examined the records from 99 patients (50 men; mean age, 65 years) who underwent endoscopic stent placement for a distal colon obstruction. Technical success, clinical improvements, complications and stent patency were compared between treatments. RESULTS: The technical success rate tended to be lower in stents inserted to treat proximal colon obstructions than in those used to treat distal colon obstructions (86% vs 97%, p=0.06). Clinical improvement was achieved in 78% of patients (29/37) with proximal colonic stenting and in 91% of patients (90/99) with distal colonic stenting (p=0.08). Complications (24% vs 27%), stent migration (8% vs 8%) and stent reocclusion rates (11% vs 17%) did not differ significantly between groups. Two cases of bowel perforation related to stenting (5%) occurred in patients with proximal colonic stenting. CONCLUSIONS: The technical success and clinical improvement associated with self-expandable metal stents used to treat proximal colon obstruction tend to be lower than cases of distal colon obstruction. Technical failure is an important cause of poor clinical improvement in patients with proximal colon stenting. Complication rates and stent patency appear to be similar in both groups. PMID- 21814597 TI - Expression of DOG1, PDGFRA, and p16 in Gastrointestinal Stromal Tumors. AB - BACKGROUND/AIMS: The diagnosis of gastrointestinal stromal tumors (GIST) relies on the demonstration of KIT expression, but KIT expression is absent or reduced in approximately 15% of GIST. METHODS: Eighty-one GISTs were diagnosed between January 1998 and December 2007 at the Department of Pathology at both Chungnam National University Hospital and Eulji University Hospital, Daejeon. Medical history, patient follow-up, and radiographic data were collected if available in the medical records. To determine diagnostic and prognostic markers for GISTs focused on PDGFRA mutation and clinicopathologic features, we analyzed 81 GIST cases for KIT, PDGFRA, DOG1, and p16 expression and for mutation of PDGFRA genes. RESULTS: Among 81 GIST cases, 20 high risk cases (24.7%) were recurred or metastasized. Immunohistochemically, KIT was positive in 76 (93.8%), PDGFRA in 75 (92.7%), and DOG1 in 77 (95.1%). With a cutoff value of 50%, p16 expression was positive in 26 cases were positive (32.1%). A correlation between p16 expression or negative DOG1 expression and recurrence or metastasis was demonstrated (p<0.05). Four cases showed a missense mutation in exon 12 of PDGFRA gene, three of these were of epithelioid GISTs. Two cases showed a silent mutation in exon 18 of PDGFRA. CONCLUSIONS: These results indicate that the expression of DOG1 and PDGFRA is observed in a majority of GIST cases. Expression of p16 and negative DOG1 expression is predictive for development of recurrence and/or metastasis. Even though mutation of the PDGFRA gene is frequently seen in epithelioid GISTs, a clinicopathologic correlation was not demonstrated. PMID- 21814598 TI - Clinical Characteristics of Microscopic Colitis in Korea: Prospective Multicenter Study by KASID. AB - BACKGROUND/AIMS: Microscopic colitis (MC) encompasses collagenous and lymphocytic colitis and is characterized by chronic diarrhea. In cases of MC, colonic mucosae are macroscopically normal, and diagnostic histopathological features are observed only upon microscopic examination. We designed a prospective multicenter study to determine the clinical features, pathological distribution in the colon and prevalence of MC in Korea. METHODS: We prospectively enrolled patients having watery diarrhea no more than 3 times a day between March 2008 and February 2009. We obtained patient histories and performed colonoscopies with random biopsies at each colon segment. RESULTS: A total of 100 patients with chronic diarrhea were enrolled for a normal colonoscopy and stool exam. MC was observed in 22 patients (22%) (M:F 1.2:1; mean age, 47.5 years). Of those 22 patients, 18 had lymphocytic colitis and 4 had collagenous colitis. The entire colon was affected in only 3 cases (13.6%), the ascending colon in 6 cases (27.2%), the transverse colon in 3 cases (13.6%), and the left colon in 3 cases (13.6%). More than 2 segments were affected in 7 cases (31.8%). Nonsteroidal anti-inflammatory drug-associated MCs were observed in 4 cases (18.2%), 3 of which showed improved diarrhea symptoms following discontinuation of the medication. Frequently associated symptoms were abdominal pain and weight loss. Autoimmune diseases were observed in 4 cases (18.2%). Half of the 22 patients with MC improved with conservative care by loperamide or probiotics. CONCLUSIONS: In a prospective multicenter study of Korean patients with chronic diarrhea, the frequency of MC was found to be approximately 20%, similar to the percentage observed in Western countries. Therefore, the identification of MC is important for the adequate management of Korean patients with chronic diarrhea. PMID- 21814599 TI - Upgrade of Lesions Initially Diagnosed as Low-Grade Gastric Dysplasia upon Forceps Biopsy Following Endoscopic Resection. AB - BACKGROUND/AIMS: Gastric dysplasia is generally accepted to be the precursor lesion of gastric carcinoma. Approximately 25% to 35% of histological diagnoses based on endoscopic forcep biopsies for gastric dysplastic lesions change following endoscopic resection (ER). The aim of this study was to determine the predictive endoscopic features of high-grade gastric dysplasia (HGD) or early gastric cancer (EGC) following ER for lesions initially diagnosed as low-grade dysplasia (LGD) by a forceps biopsy. METHODS: To determine predictive variables for upgraded histology (LGD to HGD or EGC). The lesion size, gross endoscopic appearance, location, and surface nodularity or redness as well as the presence of a depressed portion, Helicobacter pylori infection, and intestinal metaplasia were retrospectively investigated. RESULTS: Among 251 LGDs diagnosed by an initial forceps biopsy, the diagnoses of 100 lesions (39.8%) changed following the ER; 56 of 251 LGDs (22.3%) were diagnosed as HGD, 39 (15.5%) as adenocarcinoma, and 5 (2.0%) as chronic gastritis. In a univariate analysis, large lesions (>15 mm), those with a depressed portion, and those with surface nodularity were significantly correlated with a upgraded histology classification following ER. In a multivariate analysis, a large size (>15 mm; odds ratio [OR], 2.8; 95% confidence interval [CI], 1.46 to 5.43) and a depressed portion in the lesion (OR, 2.7; 95% CI, 1.44 to 5.03) were predictive factors for upgraded histology following ER. CONCLUSIONS: Our study shows that a substantial proportion of diagnoses of low-grade gastric dysplasias based on forceps biopsies were not representative of the entire lesion. We recommend ER for lesions with a depressed portion and for those larger than 15 mm. PMID- 21814600 TI - Is health screening beneficial for early detection and prognostic improvement in pancreatic cancer? AB - BACKGROUND/AIMS: The aim of this study was to evaluate the usefulness of health screening for early detection and improved prognosis in pancreatic cancer. METHODS: Between 1995 and 2008, 176,361 examinees visited the Health Promotion Center (HPC). Twenty patients diagnosed with pancreatic cancer were enrolled. During the same period, 40 patients were randomly selected from 2,202 patients diagnosed with pancreatic cancer at the Out Patient Clinic (OPC) for comparison. RESULTS: Within the HPC group, 10 patients were initially suspected of having pancreatic cancer following abnormal ultrasonographic findings, and 9 patients had suspected cases following the detection of elevated serum CA 19-9. The curative resection rate was higher in the HPC group than in the OPC group (p=0.011). The median survival was longer in the HPC group than in the OPC group (p=0.000). However, there was no significant difference in the 3-year survival rate between the two groups. Asymptomatic patients (n=6/20) in the HPC group showed better curative resection and survival rates than symptomatic patients. However, the difference was not statistically significant. CONCLUSIONS: Health screening is somewhat helpful for improving the curative resection rate and median survival of patients with pancreatic cancer detected by screening tests. However, the benefit of this method in improving long-term survival is limited by how early the cancer is detected. PMID- 21814601 TI - Endoscopic Papillary Large Balloon Dilation Combined with Guidewire-Assisted Precut Papillotomy for the Treatment of Choledocholithiasis in Patients with Billroth II Gastrectomy. AB - BACKGROUND/AIMS: Endoscopic extraction of bile duct stones is difficult and often complicated in patients with a Billroth II gastrectomy. We evaluated a simpler technique to achieve an adequate ampullary opening for the removal of choledocholithiasis using endoscopic papillary large balloon dilation (EPLBD) combined with a guidewire-assisted needle-knife papillotomy. METHODS: Sixteen patients who had a Billroth II gastrectomy were included in this study. Following placement of the guidewire in the bile duct, a precut incision was made over the guidewire with a needle knife sphincterotome inserted alongside the guidewire. Balloon dilation of the ampullary orifice was gradually performed. RESULTS: Needle knife papillotomy over the guidewire with subsequent EPLBD was successful in all patients. Complete stone removal was achieved in 15 (93.7%) patients in 1 session. However, 1 (6.3%) patient required mechanical lithotripsy with an additional procedure for complete ductal clearance, and there was 1 case of minor bleeding following the EPLBD. There were no cases of pancreatitis or perforation. CONCLUSIONS: EPLBD followed by guidewire-assisted needle-knife papillotomy appears to be a useful method with few technical difficulties and a low risk of complications for the removal of bile duct stones in patients with prior Billroth II gastrectomy. PMID- 21814602 TI - Expression of the Transmembrane Glycoprotein CD44s Is Potentially an Independent Predictor of Recurrence in Hepatocellular Carcinoma. AB - BACKGROUND/AIMS: Cluster differentiation 44 standard isoform (CD44s) is a transmembrane glycoprotein. CD44s is a known prognostic factor in various cancers, due to its involvement in tumor cell growth, invasion and metastasis. Its prognostic role, however, is debated because it can be a positive or negative prognostic factor depending on tumor type and is still an ambiguous prognostic indicator in other cancers, especially hepatocellular carcinoma (HCC). We investigated the relationship between CD44s expression and survival in HCC patients. METHODS: A total of 260 HCC samples were collected to generate a tissue microarray. Staining of the arrays with a primary mouse CD44s monoclonal antibody was followed by evaluation of the relationship between CD44s expression and tumor differentiation. The effect of CD44s expression on patient survival was analyzed. RESULTS: CD44s protein expression correlated with histological grade (most and worst Edmondson grade) of the HCC (p=0.029 and p=0.039, respectively) and adversely affected the disease free survival period based on univariate and multivariate analyses (p=0.038 and p=0.077, respectively). CONCLUSIONS: High CD44s protein expression correlates with shorter disease free survival and poorly differentiated HCC. CD44s-targeted therapy may be efficacious for HCC treatment in the future. PMID- 21814603 TI - Distribution Characteristics of Hepatitis B Serological Markers in Hospitalized Children and Adolescents in Zhejiang, China between 2006 and 2010. AB - BACKGROUND/AIMS: To investigate serological patterns of hepatitis B based on electrochemiluminescent immunoassays and the distribution characteristics of these patterns in hospitalized children and adolescents in Zhejiang, China between 2006 and 2010. METHODS: Five serological markers, including hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg), antibody to hepatitis B surface antigen (anti-HBs), antibody to hepatitis B e antigen (anti-HBe), and antibody to hepatitis B c antigen (anti-HBc), were chosen as a routine panel to monitor hepatitis B virus (HBV) infection and vaccination efficacy. A total of 33,187 children (21,187 boys and 12,000 girls) were selected using the following exclusion criteria: a previous diagnosis of hepatitis, age >16 years or an address outside of Zhejiang. RESULTS: The average HBV vaccination coverage rates among 20,766 boys and 11,782 girls were 98.62% and 98.68%, respectively. Seventeen serological patterns of hepatitis B were found, and the dominant pattern was 'anti-HBs (+) alone' (62.03%) followed by 'negative pattern' (23.46%). The rates of the other 15 patterns ranged from 8.14% to 0.003%. Of 236 HBsAg-positive patients, the overall rate of seropositivity was 0.71%. The anti HBs levels were grouped into 3 ranges (10-100 mIU/mL, 100-1,000 mIU/mL, and >1,000 mIU/mL) for all anti-HBs-positive children (36.08%, 43.43%, and 20.49%, respectively). CONCLUSIONS: A low HBsAg carrier rate and a relatively high anti HBs positive rate are present in hospitalized children and adolescents in Zhejiang. The distribution of serological patterns is associated with age but is mostly independent of gender. PMID- 21814604 TI - The Seroconversion Rate of Hepatitis A Virus Vaccination among Patients with Hepatitis B Virus-Related Chronic Liver Disease in Korea. AB - BACKGROUND/AIMS: The aim of this study was to evaluate the seroconversion rate of a hepatitis A virus (HAV) vaccination in patients with hepatitis B virus (HBV) related chronic liver disease (CLD). METHODS: Analyses were conducted using clinical records from 94 patients with chronic HBV infection who were seronegative for IgG anti-HAV antibodies between September 2008 and June 2009. Two doses of an HAV vaccine were administered 24 weeks apart. A third vaccine dose was administered only for patients seronegative for anti-HAV antibodies at week 48. RESULTS: The seroconversion rate of anti-HAV following the two-dose vaccination was 86.17%. The seroconversion rate of anti-HAV was not significantly different according to age or status of liver disease. The rate was higher in female than in male patients. A third HAV vaccine dose was administered to 13 patients seronegative for anti-HAV after the two-dose regimen, and 84.62% of these patients showed seroconversion at week 72. CONCLUSIONS: HAV vaccination is effective in most Korean patients with HBV-related CLD, and it might be necessary to evaluate three-dose vaccination approach for non-responders to the conventional regimen to maximize the success of an HAV vaccination program. PMID- 21814605 TI - A 10-year retrospective analysis of clinical profiles, laboratory characteristics and management of pyogenic liver abscesses in a chinese hospital. AB - BACKGROUND/AIMS: Pyogenic liver abscess (PLA) is a serious, life threatening condition with a high mortality rate that represents a diagnostic and therapeutic challenge. The aim of this study was to collect demographic data and clinical, laboratory and microbiological characteristics of PLA patients treated between 2000 and 2010. We also aimed to collect information regarding our management experience of these cases. METHODS: As a retrospective review, 47 patients with PLA in a tertiary referral center were examined to determine their demographic characteristics, clinical features, and laboratory, imaging, and microbiologic findings as well as the treatment outcome. RESULTS: Cryptogenic PLA was the most frequently identified type of PLA, while benign biliary tract disease was the most frequently identifiable cause of PLA (18/47 patients; 38.3%). Leukocytosis and elevated alanine transaminase were common laboratory findings and were observed in 35 (74.5%) and 22 (46.8%) patients, respectively. Increased fibrinogen was also detected in 11 of 15 investigated cases (73.3%). Notably, infection-induced thrombocytopenia occurred in 8 patients (17%). Diabetes mellitus was associated with the occurrence of infection induced shock when compared to the non-diabetic group (p<0.05). Patients with two or more comorbid diseases had longer hospitalizations when compared to patients with one comorbid disease or those without comorbidities (p<0.001). The number of days needed to establish diagnosis was correlated with the length of hospitalization (p<0.001). The overall hospital mortality rate was 2.1% (1/47). CONCLUSIONS: Characteristics of PLA patients from the past 10 years are presented. The number of days needed to establish a PLA diagnosis was correlated with the length of the hospital stay. The hospital stay of PLA patients can be further improved by early diagnosis and effective treatments during the early stages of PLA progression. PMID- 21814606 TI - Surgical Management for Giant liver Hemangiomas Greater Than 20 cm in Size. AB - BACKGROUND/AIMS: The aim of this study was to investigate the primary management experience for giant liver hemangiomas greater than 20 cm in size. METHODS: Records of patients referred for evaluation of radiologically and/or histopathologically proven giant liver hemangiomas between January 2007 and March 2010 were retrospectively analyzed. The reasons for referral, results of imaging studies, preoperative and surgical treatments, and outcome were reviewed. RESULTS: A retrospective analysis was performed for 14 patients diagnosed with a giant hemangioma on the basis of an imaging study and/or a histopathological examination. All cases were diagnosed as giant liver hemangioma with at least one lesion greater than 20 cm in size. Abdominal discomfort was the main presenting complaint for the referral in 9 patients (64.2%). Abdominal ultrasound established the diagnosis in 12 patients (85.7%). Twelve patients underwent liver resection, 2 of whom underwent staged resection. Enucleation was performed in 2 patients. Selective transcatheter arterial embolization was implemented in 9 patients. Postoperative morbidity occurred in 3 patients (21.4%). No complications related to the hemangiomas occurred during follow up. CONCLUSIONS: Liver resection is indicated for giant liver hemangiomas with abdominal discomfort, especially for lesions greater than 20 cm in size. Staged operations are performed for patients with multiple lesions. Preoperative selective transcatheter arterial embolization alleviates progressive abdominal pain. PMID- 21814608 TI - A case of stenotic change from gastric candidiasis managed with temporary stent insertion. AB - Invasive gastric Candida infection in patient with co-morbidity can cause stenotic change if it is developed at anatomically narrowing portion, such as distal antrum, pylorus, or duodenal bulb. However, proper management of benign stenosis by diffuse gastric Candidasis is still under controversy and palliative bypass surgery has several shortcomings because high risk operative group may be included in this case. Palliative placement of self-expandable metallic stent has been settled as a standard management of malignant gastric pyloric obstruction and it is expected to be applied in benign stenotic lesions due to its gradual dilation effect. We described a case of stenosis by diffuse gastric Candidasis at anastomosis of subtotal gastrectomy, which was managed by temporary placement of self-expandable metallic stent. PMID- 21814607 TI - Massive lower gastrointestinal bleeding from the appendix. AB - Massive rectal bleeding from the appendix, considered a rare case of lower gastrointestinal bleeding, is not easily recognized by various diagnostic modalities. A multidisciplinary approach for both a diagnosis and a differential diagnosis is important because the identification of the bleeding site is crucial to proceed to a proper intervention and there are various causes of appendiceal bleeding. Because early colonoscopy plays an important role in the diagnosis and management of lower gastrointestinal hemorrhage, we report a case of a life threatening massive rectal bleeding from the appendix diagnosed by colonoscopy. We also present a review of the literature. PMID- 21814609 TI - Two Cases of Adrenal Abscesses Following Histoacryl(r) (N-butyl-2-cyanocrylate) Injection. AB - We report two cases of adrenal abscesses that occurred following a Histoacryl(r) (N-butyl-2-cyanocrylate) injection for variceal bleeding. Patients had been diagnosed with alcoholic liver cirrhosis and gastric varices bleeding and received a Histoacryl(r) injection for the variceal bleeding. Patients had fever and abdominal tenderness and were diagnosed with an adrenal abscess at 2 months following the Histoacryl(r) injection. One patient received open drainage and the other underwent percutaneous drainage. When a patient has previously been injected with Histoacryl(r) for the treatment of variceal bleeding and presents with fever, an evaluation for an unusual complication such as adrenal abscess is recommended. PMID- 21814610 TI - Diagnostic dilemma in an unusual case of common bile duct obstruction. AB - Biliary obstructions are rarely caused by a foreign body and have received sparse attention. We present an unusual case with pruritis and abdominal pain caused by impacted full length surgical gauze within the common bile duct. The patient had previously undergone an open cholecystectomy. Radiological investigations were inconclusive and suggestive of either a calculus or a cholangiocarcinoma. Surgical exploration revealed full length surgical gauze within the common bile duct. Because imaging modalities are often non-determinant, the possibility of biliary tract obstruction from a foreign body should be borne in mind for patients with unusual presentations, especially those who have previously undergone surgery. PMID- 21814611 TI - De Novo Superinfection of Hepatitis B Virus in an Anti-HBs Positive Patient with Recurrent Hepatitis C Following Liver Transplantation. AB - A 60-year-old woman with end stage liver cirrhosis caused by genotype 2 hepatitis C virus (HCV) infection received an orthotopic liver transplantation (OLT). The patient was negative for the hepatitis B surface antigen (HBsAg) and positive for the anti-hepatitis B surface antibody (anti-HBs) prior to and one and a half months following the OLT. Due to reactivation of hepatitis C, treatment with interferon-alpha and Ribavirin started two months following the OLT and resulted in a sustained virological response. We performed a liver biopsy because a biochemical response was not achieved. Surprisingly, liver pathology showed HBsAg positive hepatocytes with a lobular hepatitis feature, which had been negative in the liver biopsy specimen obtained one and a half months post-OLT. High titers of both HBsAg and HBeAg were detected, while anti-HBs antibodies were not found. Tests for IgM anti-hepatitis B core antibody and anti-delta virus antibodies were negative. The serum HBV DNA titer was over 1*10(7) copies/mL. A sequencing analysis showed no mutation in the "a" determinant region, but revealed a mixture of wild and mutant strains at an overlapping region of the S and P genes (S codon 213 (Leu/Ile); P codons 221 (Phe/Tyr) and 222 (Ala/Thr)). These findings suggest that de novo hepatitis B can develop in patients with HCV infection during the post-OLT period despite the presence of protective anti-HBs. PMID- 21814612 TI - The effect of ceramic thickness and number of firings on the color of a zirconium oxide based all ceramic system fabricated using CAD/CAM technology. AB - PURPOSE: Ceramics have a long history in fixed prosthodontics for achieving optimal esthetics and various materials have been used to improve ceramic core strength. However, there is a lack of information on how color is affected by fabrication procedure. The purpose of this study was to evaluate the effects of various dentin ceramic thicknesses and repeated firings on the color of zirconium oxide all-ceramic system (LavaTM) fabricated using CAD/CAM technology. MATERIALS AND METHODS: Thirty disc-shaped cores, 12 mm in diameter with a 1 mm thickness were fabricated from zirconium oxide based all ceramic systems (LavaTM, 3M ESPE, St Paul, MN, USA) and divided into three groups (n = 10) according to veneering with dentin ceramic thicknesses: as 0.5, 1, or 1.5 mm. Repeated firings (3, 5, 7, or 9) were performed, and the color of the specimens was compared with the color after the initial firing. Color differences among ceramic specimens were measured using a spectrophotometer (VITA Easyshade, VITA Zahnfabrik, Bad Sackingen, Germany) and data were expressed in CIELAB system coordinates. A repeated measures ANOVA and Bonferroni post hoc test were used to analyze the data (n = 10, alpha=.05). RESULTS: L*a*b* values of the ceramic systems were affected by the number of firings (3, 5, 7, or 9 firings) (P<.001) and ceramic thickness (0.5, 1, or 1.5 mm) (P<.001). Significant interactions were present in L*a*b* values between the number of firings and ceramic thickness (P<.001). An increase in number of firings resulted in significant increase in L* values for both 0.5 mm and 1.5 mm thicknesses (P<.01, P=.013); however it decreased for 1 mm thickness (P<.01). The a* values increased for 1 mm and 1.5 mm thicknesses (P<.01), while it decreased for 0.5 mm specimens. The b* values increased significantly for all thicknesses (P<.01, P=.022). As the dentin ceramic thickness increased, significant reductions in L* values (P<.01) were recorded. There were significant increases in both a* and b* values (P<.01) as the dentin ceramic thickness increased. CONCLUSION: The number of firings and dentin ceramic thickness have a definite effect on the final color of all ceramic system tested. The mean DeltaE value increased as the dentin ceramic thicknesses increased for zirconium-oxide based all ceramic specimens tested. However, the mean DeltaE values were less than 3.7DeltaE units which is rated as a match in the oral environment. PMID- 21814613 TI - Wettability and cellular response of UV light irradiated anodized titanium surface. AB - PURPOSE: The object of this study was to investigate the effect of UV irradiation (by a general commercial UV sterilizer) on anodized titanium surface. Surface characteristics and cellular responses were compared between anodized titanium discs and UV irradiated anodized titanium discs. MATERIALS AND METHODS: TITANIUM DISCS WERE ANODIZED AND DIVIDED INTO THE FOLLOWING GROUPS: Group 1, anodized (control), and Group 2, anodized and UV irradiated for 24 hours. The surface characteristics including contact angle, roughness, phase of oxide layer, and chemical elemental composition were inspected. The osteoblast-like human osteogenic sarcoma (HOS) cells were cultured on control and test group discs. Initial cellular attachment, MTS-based cell proliferation assay, and ALP synthesis level were compared between the two groups for the evaluation of cellular response. RESULTS: After UV irradiation, the contact angle decreased significantly (P<.001). The surface roughness and phase of oxide layer did not show definite changes, but carbon showed a considerable decrease after UV irradiation. Initial cell attachment was increased in test group (P=.004). Cells cultured on test group samples proliferated more actively (P=.009 at day 2, 5, and 7) and the ALP synthesis also increased in cells cultured on the test group (P=.016 at day 3, P=.009 at day 7 and 14). CONCLUSION: UV irradiation induced enhanced wettability, and increased initial cellular responses of HOS cells on anodized titanium surface. PMID- 21814614 TI - Comparative analysis of the clinical techniques used in evaluation of marginal accuracy of cast restoration using stereomicroscopy as gold standard. AB - PURPOSE: This study assessed the effect of preparation design on marginal adaptation and also compared the sensitivity and specificity of clinical evaluation techniques for marginal accuracy of cast restorations to stereomicroscopy. MATERIALS AND METHODS: Three Ivorine molar teeth of different designs were prepared. (A)-A complete crown preparation with buccal shoulder and beveled finish line. (B)-A complete crown preparation with chamfer finish line. (C)-A three-quarter crown preparation with proximal boxes and beveled finish line. Twenty four castings were prepared with eight castings for each design respectively. Each casting underwent examination with an explorer, disclosing media, and a stereomicroscope. Stereomicroscopy at a value less than or equal to 30 microns was used as a gold standard to evaluate the significance of different designs on marginal adaptation. Chi-square tests of independence and Kruskal Wallis were used to evaluate the effect of preparation design and compare the agreement between examination methods for detection of marginal gap size of greater than or equal to 30 microns (alpha=.05). Sensitivity and specificity for explorer and disclosing media as compared to stereomicroscope was calculated using statistical formula given by Park. RESULTS: The preparation design did not significantly affect overall marginal adaptation. Examination by explorer and disclosing media at 30 um revealed 39% and 10.06% sensitivity and 91% and 82% specificity respectively. CONCLUSION: Preparation designs examined in this study did not significantly affect the marginal adaptation of the castings. Commonly used clinical evaluation techniques using explorer and disclosing media appeared to be inadequate for assessment of marginal accuracy. PMID- 21814615 TI - The relationship between initial implant stability quotient values and bone-to implant contact ratio in the rabbit tibia. AB - PURPOSE: Implant stability quotient (ISQ) values have been supposed to predict implant stability. However, the relationship between ISQ values and bone-to implant contact ratio (BIC%) which is one of the predictors of implant stability is still unclear. The aim of the present study was to evaluate initial ISQ values in relation to BIC% using rabbit model. MATERIALS AND METHODS: Four New Zealand white rabbits received a total of 16 implants in their tibia. Immediately after implant placement ISQ values were assessed. The measurements were repeated at the time of sacrifice of the rabbits after 4 weeks. Peri-implant bone regeneration was assessed histomorphometrically by measuring BIC% and bone volume to total volume values (bone volume %). The relationships between ISQ values and the histomorphometric output were assessed, and then, the osseointegration prediction model via the initial ISQ values was processed. RESULTS: Initial ISQ values showed significant correlation with the BIC%. The bone volume % did not show any significant association with the ISQ values. CONCLUSION: In the limitation of this study, resonance frequency analysis is a useful clinical method to predict the BIC% values and examine the implant stability. PMID- 21814616 TI - Initial bacterial adhesion on resin, titanium and zirconia in vitro. AB - PURPOSE: The aim of this in vitro study was to investigate the adhesion of initial colonizer, Streptococcus sanguis, on resin, titanium and zirconia under the same surface polishing condition. MATERIALS AND METHODS: Specimens were prepared from Z-250, cp-Ti and 3Y-TZP and polished with 1 um diamond paste. After coating with saliva, each specimen was incubated with Streptococcus sanguis. Scanning electron microscope, crystal violet staining and measurement of fluorescence intensity resulting from resazurin reduction were performed for quantifying the bacterial adhesion. RESULTS: Surface of resin composite was significantly rougher than that of titanium and zirconia, although all tested specimens are classified as smooth. The resin specimens showed lower value of contact angle compared with titanium and zirconia specimens, and had hydrophilic surfaces. The result of scanning electron microscopy demonstrated that bound bacteria were more abundant on resin in comparison with titanium and zirconia. When total biofilm mass determined by crystal violet, absorbance value of resin was significantly higher than that of titanium or zirconia. The result of relative fluorescence intensities also demonstrated that the highest fluorescence intensity was found on the surface of resin. Absorbance value and fluorescence intensity on titanium was not significantly different from those on zirconia. CONCLUSION: Resin specimens showed the roughest surface and have a significantly higher susceptibility to adhere Streptococcus sanguis than titanium and zirconia when surfaces of each specimen were polished under same condition. There was no significant difference in bacteria adhesion between titanium and zirconia in vitro. PMID- 21814617 TI - Resorption of labial bone in maxillary anterior implant. AB - PURPOSE: The purpose of this study was to evaluate the amount of resorption and thickness of labial bone in anterior maxillary implant using cone beam computed tomography with Hitachi CB Mercuray (Hitachi, Medico, Tokyo, Japan). MATERIALS AND METHODS: Twenty-one patients with 26 implants were followed-up and checked with CBCT. 21 OSSEOTITE NT(r) (3i/implant Innovations, Florida, USA) and 5 OSSEOTITE(r) implants (3i/implant Innovations, Florida, USA) were placed at anterior region and they were positioned vertically at the same level of bony scallop of adjacent teeth. Whenever there was no lesion or labial bone was intact, immediate placement was tried as possible as it could be. Generated bone regeneration was done in the patients with the deficiency of hard tissue using Bio-Oss(r) (Geistlich, Wolhusen, Switzerland) and Bio-Gide(r) (Geistlich, Wolhusen, Switzerland). Second surgery was done in 6 months after implant placement and provisionalization was done for 3 months. Definite abutment was made of titanium abutment with porcelain, gold and zirconia, and was attached after provisionalization. Two-dimensional slices were created to produce sagittal, coronal, axial and 3D by using OnDemand3D (Cybermed, Seoul, Korea). RESULTS: The mean value of bone resorption (distance from top of implant to labial bone) was 1.32 +/- 0.86 mm and the mean thickness of labial bone was 1.91 +/- 0.45 mm. CONCLUSION: It is suggested that the thickness more than 1.91 mm could reduce the amount and incidence of resorption of labial bone in maxillary anterior implant. PMID- 21814618 TI - A comparative evaluation of fracture resistance of endodontically treated teeth restored with different post core systems - an in-vitro study. AB - PURPOSE: To compare the fracture resistance and the mode of failure of endodontically treated teeth restored with different post-core systems. MATERIALS AND METHODS: Root canal treatment was performed on 40 maxillary incisors and the samples were divided into four groups of 10 each. For three experimental groups post space preparation was done and teeth were restored with cast post-core (Group B), stainless steel post with composite core (Group C) and glass fiber post with composite core using adhesive resin cement (Group D). Control group (A) samples were selected with intact coronal structure. All the samples were prepared for ideal abutment preparation. All the samples were subjected to a load of 0.5 mm/min at 130 degrees until fracture occurred using the universal testing machine. The fracture resistance was measured and the data were analyzed statistically. The fracture above the embedded resin was considered to be favorable and the fracture below the level was considered as unfavorable. The statistical analysis of fracture resistance between different groups was carried out with t-test. For the mode of failure the statistical analysis was carried out by Kruskal-Wallis test and Chi-Square test. RESULTS: For experimental group Vs control group the fracture resistance values showed significant differences (P<.05). For the mode of failure the chi-square value is 16.1610, which means highly significant (P=.0009) statistically. CONCLUSION: Endodontically treated teeth without post core system showed the least fracture resistance demonstrating the need to reinforce the tooth. Stainless steel post with composite core showed the highest fracture resistance among all the experimental groups. Teeth restored with the Glass fiber post showed the most favorable fractures making them more amenable to the re-treatment. PMID- 21814620 TI - Prosthodontic rehabilitation of a patient with bilateral auricular deformity. AB - Maxillofacial prosthodontics is an art and science which provides life like appearance to the person with facial deformity. Maxillofacial prosthetic rehabilitation for acquired defects has become more complex and sophisticated with advancement in techniques and materials. This case report describes the clinical and laboratory procedure for fabricating an auricular prosthesis for a patient with trauma related bilateral auricular deformity. Ear prosthesis was fabricated in two parts taking retention from external auditory canal. PMID- 21814619 TI - Full mouth implant rehabilitation of a patient with ectodermal dysplasia after orthognathic surgery, sinus and ridge augmentation: a clinical report. AB - An 18-year-old male presented severe hypodontia due to hypohidrotic ectodermal dysplasia was treated with Le Fort I maxillary osteotomy with simultaneous sinus floor augmentation using the mixture of cortical autogenous bone graft harvested from iliac crest and organic Bio-Oss to position the maxilla in a right occlusal plane with respect to the mandible, and to construct adequate bone volume at posterior maxilla allowing proper implant placement. Due to the poor bone quality at other sites, ridge augmentation with onlay graft was done to construct adequate bone volume allowing proper implant placement, using tissue harvested from the iliac bone. Seven implants were placed in the maxilla and 7 implants were inserted in the mandible and screw-retained metal ceramic FPDs were fabricated. The two year follow up data showed that dental implants should be considered as a good treatment modality for patients with ectodermal dysplasia. PMID- 21814621 TI - A simple technique to fabricate a surgical obturator restoring the defect in original anatomical form. AB - Oral cancer treatment involves the surgical removal of all or part of the maxilla, leaving the patient with a defect that compromises the integrity and function of the oral cavity. The postoperative restoration of esthetics, deglutition, and speech shortens recovery time in the hospital and expedites the patient's return to the community as a functioning member. The surgical obturator is the proven treatment option in such situations. This article describes a simple technique to fabricate a surgical obturator that restores patient's original dentition and facial and palatal tissue form. The obturator fabricated with this technique utilizes the vacuum formed index of patient's original tissue form and duplicated partly in heat and partly in auto polymerizing acrylic resin. Duplication of the original tissue form helps patient to minimize the immense physiological trauma immediately after the surgical resection. The obturator fabricated with this technique supports soft tissues after surgery and minimizes scar contracture and disfigurement, and thus may have a positive effect on the patients' psychology. PMID- 21814622 TI - Epigenetics of estrogen receptor signaling: role in hormonal cancer progression and therapy. AB - Estrogen receptor (ERalpha) signaling plays a key role in hormonal cancer progression. ERalpha is a ligand-dependent transcription factor that modulates gene transcription via recruitment to the target gene chromatin. Emerging evidence suggests that ERalpha signaling has the potential to contribute to epigenetic changes. Estrogen stimulation is shown to induce several histone modifications at the ERalpha target gene promoters including acetylation, phosphorylation and methylation via dynamic interactions with histone modifying enzymes. Deregulation of enzymes involved in the ERalpha-mediated epigenetic pathway could play a vital role in ERalpha driven neoplastic processes. Unlike genetic alterations, epigenetic changes are reversible, and hence offer novel therapeutic opportunities to reverse ERalpha driven epigenetic changes. In this review, we summarize current knowledge on mechanisms by which ERalpha signaling potentiates epigenetic changes in cancer cells via histone modifications. PMID- 21814624 TI - Superimposition of 3D cone-beam CT models in orthognathic surgery. AB - INTRODUCTION: Limitations of 2D quantitative and qualitative evaluation of surgical displacements can be overcome by CBCT and three-dimensional imaging tools. OBJECTIVES: The method described in this study allows the assessment of changes in the condyles, rami, chin, maxilla and dentition by the comparison of CBCT scans before and after orthognathic surgery. METHODS: 3D models are built and superimposed through a fully automated voxel-wise method using the pre surgery cranial base as reference. It identifies and compares the grayscale of both three-dimensional structures, avoiding observer landmark identification. The distances between the anatomical surfaces pre and post-surgery are then computed for each pair of models in the same subject. The evaluation of displacement directions is visually done through color maps and semi-transparencies of the superimposed models. CONCLUSIONS: It can be concluded that this method, which uses free softwares and is mostly automated, shows advantages in the long-term evaluation of orthognathic patients when compared to conventional 2D methods. Accurate measurements can be acquired by images in real size and without anatomical superimpositions, and great 3D information is provided to clinicians and researchers. PMID- 21814625 TI - 'Consort 2010: a standard for reporting clinical trials revised anew? PMID- 21814626 TI - Registration of medical devices. AB - Globally the medical device (MD) market has been growing quite rapidly over the past decade. The regulatory framework for pharmaceuticals and devices differ substantially. The regulatory authorities in different regions of the world recognize different classes of medical devices (MDs), based on their design complexity, their use characteristics, and their potential for harm, if misused. With the vast majority of MDs in developing countries being imported, the respective governments need to put in place policies & regulations to address all elements related to MDs, ranging from its development, manufacturing, registration to post-marketing obligations & disposal so that public can have access to high quality, safe & affordable products for appropriate use. This article highlights current regulations pertaining to registration of MDs in India, in light of those existing in Global Harmonization Task Force (GHTF) member countries & Association of Southeast Asian Nations (ASEAN) countries. PMID- 21814623 TI - Targeting Rb inactivation in cancers by synthetic lethality. AB - The retinoblastoma protein, pRb, is a key regulator of cell proliferation, differentiation, apoptosis, as well as checkpoint and stress responses. The function of Rb is often inactivated in many types of cancers, a feature that can potentially be used to target this specific subset of cancers. However little is known about how the loss of Rb function can be exploited in cancer therapies. In this review, we overview the functions of Rb, and discuss a genetic screen that led to the finding that inactivation of TSC2 and Rb induces synergistic cell death in both Drosophila developing tissues and human cancer cells. The mechanisms for synergistic cell death involve the accumulation of cellular stress, suggesting that inactivation of TSC2 and chemotherapeutic agents that result in induction of cellular stress can potentially be combined to treat cancers harboring inactivated Rb. PMID- 21814627 TI - Survey on perceptions of Indian investigators on research ethics. AB - INTRODUCTION: The last decade has witnessed globalization of drug development with early phase studies being increasingly placed in the developing world. Whether research related ethical principles around informed consent, adverse event (AE) reporting, post trial drug commitments and others are being observed, merits evaluation METHODS: A specially designed survey questionnaire was served to 29 investigators in India, having prior experience of participating in drug development studies with pharmaceutical companies. The survey included questions on investigator profile, study design, informed consent process, safety reporting, patient and physician compensation, post trial drug commitments among others RESULTS: Most respondents had nearly two decades of clinical experience. Majority believed that the research they conducted was relevant to the needs of society, but wanted common research goals established between the sponsors and the community. All investigators cited their expertise, reliability, patient pool, and low costs as the principal reasons for greater placement of studies. However, very few investigators felt that all their patients in studies were "truly autonomous". Most investigators indicated confidence in the adverse event reporting ability and expressed satisfaction with their Ethics Committees. A third of investigators accepted some form of conflict of interest between their role as a physician and researcher. Opinion was divided regarding satisfaction with the post trial drug commitments of the sponsor companies CONCLUSION: The survey revealed a good understanding of the ethical issues around conduct of clinical research in a developing country. The sooner ethical institutions and practices are fortified, the better it is for communities, patients, investigators and pharmaceutical sponsors. PMID- 21814628 TI - Readability and comprehensibility of informed consent forms for clinical trials. AB - The signed informed consent form provides documentary evidence that the patient has given informed consent to participate in a clinical trial and that the patient has been given the requisite information. However, this document must not only provide the necessary information, it must also be provided in a way that can be understood by the patient. Non conclusive information suggests that research participants frequently may not understand the information presented during the informed consent procedure. Comprehension requires that the patient be able to understand the information presented and have the time and opportunity to read, evaluate and consider the information presented.A shortened Informed Consent Form, with information that a reasonable person would want to understand along with specific information that the person wants in particular would be a good option to improve understanding or comprehensibility. Additional informational meetings with a qualified person like a counselor could help in comprehension. Questionnaires designed to test comprehension of patient, peer review, patient writing the salient features could help evaluate the comprehensibility of the Informed Consent Form. PMID- 21814629 TI - Patient protection in clinical trials in India: some concerns. AB - Clinical trial participants should not be influenced by undue inducement. Clinical trial investigators should be guided by ethical principles, and patient protection should be a top priority. This does not seem to be the case in India. PMID- 21814630 TI - Outcomes research and drug development. AB - With increasing health care cost, focus needs to be given towards value-for money, especially in the context of innovative drugs. A multi-disciplinary approach towards drug development is important in order to demonstrate the value of innovation to physicians and patients. Input into the drug development process at various stages of clinical trials must incorporate patient-focused endpoints and analyses. Demonstrating value of drugs will help ensure that innovative therapies should be seen as health care investment and not expense. PMID- 21814631 TI - Conducting feasibilities in clinical trials: an investment to ensure a good study. AB - Conducting clinical trial feasibility is one of the first steps in clinical trial conduct. This process includes assessing internal and environmental capacity, alignment of the clinical trial in terms of study design, dose of investigational product, comparator, patient type, with the local environment and assessing potential of conducting clinical trial in a specific country. A robust feasibility also ensures a realistic assessment and capability to conduct the clinical trial. For local affiliates of pharmaceutical organizations, and contract research organizations, this is a precursor to study placement and influences the decision of study placement. This article provides details on different types of feasibilities, information which is to be included and relevance of each. The article also aims to provide practical hands-on suggestions to make feasibilities more realistic and informative. PMID- 21814632 TI - Data management Redefined. AB - Core perspectives on the traditional approach to CDM are rapidly changing and EDC and new eclincal initiatives are redefining the face of data management. Associated with EDC are not only the higher efficiencies, resulting in lower study costs, but its applications in key areas such as adaptive trials and clinical event adjudication; however the cost and effort involved in deployment and integration remain a deterrent. The role of the data manager may change to that of a data broker who manages the exchange of data from multiple sources, and semantic interoperability, data standards and data privacy will prove to be the defining factors. Simulation modeling, pharmacogenomics, personalized medicine and EHRs will no longer exist as silos and seamless data flows will be the drivers of healthcare solutions. PMID- 21814633 TI - A threaded Java concurrent implementation of the Monte-Carlo Metropolis Ising model. AB - This paper describes a concurrent Java implementation of the Metropolis Monte Carlo algorithm that is used in 2D Ising model simulations. The presented method uses threads, monitors, shared variables and high level concurrent constructs that hide the low level details. In our algorithm we assign one thread to handle one spin flip attempt at a time. We use special lattice site selection algorithm to avoid two or more threads working concurently in the region of the lattice that "belongs" to two or more different spins undergoing spin-flip transformation. Our approach does not depend on the current platform and maximizes concurrent use of the available resources. PMID- 21814634 TI - A Human Capital Approach to Reduce Health Disparities. AB - OBJECTIVE: To introduce a human capital approach to reduce health disparities in South Carolina by increasing the number and quality of trained minority professionals in public health practice and research. METHODS: The conceptual basis and elements of Project EXPORT in South Carolina are described. Project EXPORT is a community based participatory research (CBPR) translational project designed to build human capital in public health practice and research. This project involves Claflin University (CU), a Historically Black College University (HBCU) and the African American community of Orangeburg, South Carolina to reduce health disparities, utilizing resources from the University of South Carolina (USC), a level 1 research institution to build expertise at a minority serving institution. The elements of Project EXPORT were created to advance the science base of disparities reduction, increase trained minority researchers, and engage the African American community at all stages of research. CONCLUSION: Building upon past collaborations between HBCU's in South Carolina and USC, this project holds promise for a public health human capital approach to reduce health disparities. PMID- 21814635 TI - Evaluating Populations of Tactile Sensors for Curvature Discrimination. AB - The high density of receptors in fingertip skin is a limiting factor for replicating tactile feedback for neural prosthetics. At present, the large size of engineered sensors and the dense network of neural connections from finger to brain inhibit duplicating the approximately 100 receptors/cm(2). The objective of this work is to build a model of the skin and neural response with which populations of sensors can be positioned and evaluated when discriminating spheres. The effort combines a 3D finite element model of the fingertip, a bi phasic transduction model, and a leaky-integrate-and-fire neuronal model. Populations of sensors are configured with three average densities (10,000/cm(2), 1,000/cm(2), and 100/cm(2)). For these populations, the firing rates for the dynamic (40-70 ms) and static (650 ms-900 ms) phases and first spike latencies are predicted. The model can differentiate indenters at a level similar to human performance at each sampling density, including of the human finger (100/cm(2)). PMID- 21814636 TI - A multi-timescale adaptive threshold model for the SAI tactile afferent to predict response to mechanical vibration. AB - The Leaky Integrate and Fire (LIF) model of a neuron is one of the best known models for a spiking neuron. A current limitation of the LIF model is that it may not accurately reproduce the dynamics of an action potential. There have recently been some studies suggesting that a LIF coupled with a multi-timescale adaptive threshold (MAT) may increase LIF's accuracy in predicting spikes in cortical neurons. We propose a mechanotransduction process coupled with a LIF model with multi-timescale adaptive threshold to model slowly adapting type I (SAI) mechanoreceptor in monkey's glabrous skin. In order to test the performance of the model, the spike timings predicted by this MAT model are compared with neural data. We also test a fixed threshold variant of the model by comparing its outcome with the neural data. Initial results indicate that the MAT model predicts spike timings better than a fixed threshold LIF model only. PMID- 21814637 TI - One practice's experiment in refusing detail rep visits. AB - PURPOSE: The physician-pharmaceutical industry relationship has come under increasing scrutiny. Little guidance exists concerning how smaller practices should manage this relationship.In 2006, Madras Medical Group, a small family practice in rural Oregon, implemented a policy prohibiting visits from representatives of the pharmaceutical industry and the acceptance of drug samples. This qualitative study documents the attitudes of clinic personnel in response to this policy. METHODS: Semistructured interviews were conducted using standardized questions related to 4 areas of policy perception: verification of policy decision, impact on clinic operations,influence of pharmaceutical industry, and lessons to share. Common themes were identified. RESULTS: Three physicians and 3 nurses participated in the study. There was consensus on the existence and effectiveness of the clinic policy. Key themes identified from both groups of interviewees included the perception of enhanced clinic operation after eliminating interruptions from pharmaceutical representatives, positive response from the public, and reduced diversion of samples for personal use. Clinicians interviewed agreed that samples were of questionable benefit,that information obtained from industry representatives was incomplete or of questionable veracity or objectivity, and that it was helpful to substitute other drug information sources and clinic-sponsored lunches for past industry offerings. CONCLUSION: In this case study, a policy prohibiting pharmaceutical representatives from a small family practice was well accepted and a source of pride among physicians and nurses. Other clinics wishing to enact a similar policy may wish to supplement their efforts by proactively using other sources of drug information. PMID- 21814638 TI - Memo to FDA: too much information. PMID- 21814639 TI - The dangers of colon cleansing. PMID- 21814640 TI - Hoarseness and chronic cough: would you suspect reflux? PMID- 21814641 TI - Managing seizures: achieving control while minimizing risk. PMID- 21814642 TI - Beta-blockers for heart failure: why you should use them more. PMID- 21814643 TI - More help for patients with less severe heart failure. PMID- 21814644 TI - Dermatomal rash on a 6 year-old boy. PMID- 21814645 TI - Clinical inquiries. Does pneumococcal conjugate vaccine prevent otitis media? PMID- 21814647 TI - Risks and comedy. AB - The old adage that an alcoholic is someone who drinks more than their doctor always brings a smile. It also reveals a deeper truth. What is 'normal drinking' depends on the environment you were raised in and your current social, emotional and employment context. PMID- 21814646 TI - Clinical inquiries. When is discectomy indicated for lumbar disc disease? PMID- 21814648 TI - Improving clinical decision support tools - challenges and a way forward. AB - Would you prescribe a drug without regulatory approval, for which the safety and efficacy are unknown? Unlikely. Would you use a clinical practice guideline that is not endorsed by a peak body, with no accessible evidence for its recommendations and with its authorship unknown? Unlikely. Do you currently use decision support tools in your prescribing software that have not been evaluated or accredited, with unknown or variable quality and reliability? Very likely. PMID- 21814649 TI - Binge drinking. AB - Binge' drinking is defined as episodic excessive drinking, but there is no worldwide consensus on how many drinks constitute a 'binge'. BEACH (Bettering the Evaluation and Care of Health) used three questions from the World Health Organization's Alcohol Use Disorders Identification Test (AUDIT) to gather information on alcohol consumption of patients aged 18 years or over from a subsample (40%) of participants. We defined regular binge drinkers as those who have six or more standard drinks on one occasion, either weekly or monthly. PMID- 21814650 TI - Problem drinking - detection and assessment in general practice. AB - BACKGROUND: Alcohol has long been an integral part of the social life of many Australians. However, alcohol is associated with significant harm to drinkers, and also to nondrinkers. OBJECTIVE: This article explores the role of the general practitioner in the detection and assessment of problem drinking. DISCUSSION: Excessive alcohol use is a major public health problem and the majority of people who drink excessively go undetected. General practitioners are in a good position to detect excessive alcohol consumption; earlier intervention can help improve outcomes. AUDIT-C is an effective screening tool for the detection of problem drinking. National Health and Medical Research Council guidelines suggest that no more than two standard drinks on each occasion will keep lifetime risk of death from alcohol related disease or injury at a low level. Once an alcohol problem is detected it is important to assess for alcohol dependence, other substance use, motivation to change, psychiatric comorbidities and examination and investigation findings that may be associated with excessive alcohol use. A comprehensive assessment of the impact and risk of harm of the patient's drinking to themselves and others is vital, and may require several consultations. PMID- 21814651 TI - Problem drinking--management in general practice. AB - BACKGROUND: Management of problem drinking presents the general practitioner with similar challenges and rewards to those associated with the management of other chronic conditions. OBJECTIVE: This article presents a framework for managing alcohol problems in general practice based on national guidelines for the treatment of alcohol problems. DISCUSSION: General practitioners are well placed to undertake the management of drinking problems following an assessment of the amount of alcohol taken and the risks this poses for the individual and the people around them. This assessment starts the process of engagement and reflection on drinking habits and will inform the appropriate management approach. Brief interventions can result in reduction in drinking in nondependent drinkers. For dependent drinkers, treatment steps include assessing need for withdrawal management and developing a comprehensive management plan, which includes consideration of relapse prevention pharmacotherapy and psychosocial interventions. The patient's right to choose what they drink must be respected, and those who continue to drink in a problematic way can still be assisted, with compassion, within a harm reduction framework. PMID- 21814652 TI - Risky drinking among young Australians - causes, effects and implications for GPs. AB - BACKGROUND: Rates of risky drinking among young Australians have increased substantially over the past 2 decades, resulting in significant community concern. OBJECTIVE: To explore the social, cultural and economic contexts that underlie risky drinking among young people and the implications of these for general practitioners. DISCUSSION: Effective strategies for reducing alcohol related harm among young people must be developed in the context of the social and cultural forces to which risky drinking is inextricably linked. It is important that GPs not only play the role of health provider (by identifying risky drinking where possible and providing harm reduction advice), but also act as public health advocates, using their position as respected health experts to encourage a shift in alcohol policy, legislation, marketing and promotion. PMID- 21814653 TI - Alcoholic liver disease - assessment and management. AB - BACKGROUND: Alcohol is a major cause of liver disease in Australia and the incidence of end stage liver disease among young adult Australians is rising. OBJECTIVE: This article explores the types of alcoholic liver disease, their pathogenesis and detection, and the investigation and management of these conditions. DISCUSSION: Alcoholic liver disease is often silent until complications develop; therefore clinicians need a high index of suspicion to detect individuals with heavy alcohol consumption and evolving liver disease. At a population level, strategies to reduce per capita alcohol consumption can be expected to reduce mortality from alcohol related disease. At an individual level, early diagnosis, abstinence and effective treatment of complications are pivotal to reducing mortality. The cornerstone of management of chronic alcoholic liver disease is abstinence from alcohol and good nutrition. Other important aspects of management include care when prescribing medications, immunisations and early referral for complications. PMID- 21814654 TI - Ambulatory electrocardiographic monitoring. AB - This article forms part of our 'Tests and results' series for 2011 which aims to provide information about common tests that general practitioners order regularly. It considers areas such as indications, what to tell the patient, what the test can and cannot tell you, and interpretation of results. PMID- 21814655 TI - Patient information - Holter monitors/event recorders. AB - A Holter monitor is a portable way of taking an electrical trace of your heartbeat over a period of time (usually 24 hours) while you go about your normal day-to-day activities. The machine records this trace so that a technician and cardiologist (heart doctor) can review your heart rhythm and report back information about your heart to your general practitioner. The test can help pick up if your heartbeat is too fast, too slow or irregular. PMID- 21814656 TI - Asymptomatic hilar nodules. AB - CASE STUDY: Mr Lin, a Chinese man aged 38 years, presented for review of a recent chest X-ray. The X-ray was ordered as part of a pre-employment assessment. He was asymptomatic, a nonsmoker and had no significant past medical history. Full blood examination, lipids, glucose and liver and renal function were normal (also ordered as part of the pre-employment assessment). On examination, he looked well, with blood pressure 134/78 mmHg, heart rate 72/min, and chest and cardiovascular examinations normal. PMID- 21814657 TI - Not just another sore throat. AB - Case study A man, 26 years of age, presented to a hospital emergency department complaining of a sudden onset of a sore throat 6 hours previously while consuming a carbonated drink at work. The pain commenced about lunchtime, after he had been mixing concrete powder, and since then had been intermittent and was becoming more severe. PMID- 21814658 TI - Green concretions on the left axillae. AB - Case study A man, 47 years of age, with an unremarkable past medical history, attended our dermatology outpatient clinic having developed changes in the colour and texture of the hair of his left axillae 2 weeks earlier, causing him moderate itching. He did not remember any changes in his lifestyle or recall any changes in sweating patterns. PMID- 21814659 TI - Odorous vaginal discharge - a case study for thorough investigation. AB - Odorous vaginal discharge is a common presentation to general practitioners, and a frequent presentation for bacterial infections and sexually transmissible diseases. Busy GPs may be tempted to make a diagnosis from the clinical history and symptoms, and prescribe antibiotics as a first line treatment. This case highlights an unusual cause of persistent odorous vaginal discharge. If a thorough examination had not been conducted, the cause would have been overlooked, first line antibiotics would most likely have been ineffective, and potentially life threatening consequences may have occurred. PMID- 21814660 TI - The inverse care law - is Australian primary care research funding headed this way? AB - Tudor Hart's Inverse Care Law classically described the inequity in medical service access in South Wales. From his primary care perspective, the availability of good medical care varied inversely with the need and the population served. In Australia, future funding for primary care research capacity building appears headed in a similar direction - at least for newly established medical schools. PMID- 21814661 TI - Insulin in general practice - barriers and enablers for timely initiation. AB - BACKGROUND: Insulin is effective at lowering blood glucose, and most people with type 2 diabetes need insulin within 10 years of diagnosis. However, initiating insulin is often delayed in general practice. This study explores barriers and enablers to insulin initiation in general practice. METHOD: A qualitative study using semistructured, in-depth interviews. Ten general practitioners, four diabetes nurse educators and 12 patients were interviewed. Participants were purposively selected and recruited through snowballing. Data analysis drew on the Normalisation Process Model framework. RESULTS: The understanding of the primary aim of diabetes care and its context (improving pathophysiology, complex multimorbidity, the patient-doctor relationship, impact of living with the condition) was important. There was disagreement and uncertainty about whose role it is to initiate insulin. It was also important whether insulin initiation was conceptualised as a simple, protocol driven intervention, or as a complex and demanding addition to an overwhelming clinical picture. DISCUSSION: Insulin initiation seems more likely if the multiple perspectives on the primary aim of clinical care are acknowledged, and if roles are explicitly discussed and clarified. PMID- 21814662 TI - Data extraction and feedback - does this lead to change in patient care? AB - BACKGROUND Computers enable general practitioners to collate clinical data within their practices. The improvements that this can make to clinical care remain the subject of enquiry. OBJECTIVE Does the analysis of clinical data for the purpose of instigating quality improvement strategies in general practice, with support from a local division of general practice, lead to positive changes in measures of care after 12 months? DISCUSSION This study demonstrated that, in this setting, the collection and analysis of clinical data, with support from a division of general practice, led to modest increases in the recording of information rather than improvements in clinical outcomes. PMID- 21814663 TI - Understanding insurance - the GP's professional and ethical responsibilities. AB - BACKGROUND: General practitioners will often consult with patients in situations where professional skill is required to support a decision regarding insurance. OBJECTIVE: The aim of this article is to assist doctors' understanding of the basis of insurance and risk, in order to support their own practice in this important area. DISCUSSION: This article provides information about insurance and the professional skills required to assist in decisions made by insurance companies (for which, commercial factors predominate), and/or by patients (in whom, social and emotional factors may be more important). A quality improvement activity is provided for those interested in making changes to their practice. PMID- 21814664 TI - Designing practices - using evidence to do better. AB - The physical layout of general practices has generally been overlooked in research on safety in the health system. This article provides an overview of the evidence that is available on physical design, and the implications of this research for general practice. PMID- 21814665 TI - Heatwaves and the elderly - The role of the GP in reducing morbidity. AB - BACKGROUND Heatwaves are increasing in frequency, intensity and duration, and are associated with an increase in mortality and morbidity, particularly in the very young and the very old. Concurrently, the Australian population is aging, with the prediction that by 2036 approximately 27% of Australians will be aged over 65 years. OBJECTIVE This article reviews the evidence on heat related health risk and discusses the role of the general practitioner in reducing morbidity in older people as a result of heatwaves. DISCUSSION Heatwaves are associated with increased mortality and morbidity in people aged over 65 years, and more so in those aged over 75 years. Older people are more vulnerable to the effects of extreme heat through a range of physiological and physical factors. As key providers of healthcare to older people, GPs play a crucial role in identifying those at risk and implementing strategies to minimise the risks of mortality and morbidity during periods of extreme heat. PMID- 21814666 TI - Influence of halide ions on the chirality and luminescent property of ionothermally synthesized lanthanide-based metal-organic frameworks. AB - Four lanthanide-based metal-organic frameworks, [Emim][Ln(1.5)(2,5-tdc)(2)]Cl(1.5 x)Br(x) (Ln = Nd 1, Eu 2) and [Emim][Ln(2,5-tdc)(2)] (Ln = Nd 3, Eu 4) (2,5-tdc = thiophene-2,5-dicarboxylate, Emim = 1-methyl-3-ethylimidazolium), were synthesized under ionothermal conditions. Compounds 1 and 2 crystallize in the polar space group P2(1)2(1)2, while 3 and 4 crystallize in the central symmetry space group P2(1)/c. Luminescence studies revealed a significantly higher quantum yield of 4 than that of 2, with similar lifetimes. It is clear that the coordination of the halide ions has profound effects on the structures and properties of these lanthanide-based metal-organic frameworks. PMID- 21814667 TI - Microscopic solvation of NaBO2 in water: anion photoelectron spectroscopy and ab initio calculations. AB - We investigated the microscopic solvation of NaBO(2) in water by conducting photoelectron spectroscopy and ab initio studies on NaBO(2)(-)(H(2)O)(n) (n = 0 4) clusters. The vertical detachment energy (VDE) of NaBO(2)(-) is estimated to be 1.00 +/- 0.08 eV. The photoelectron spectra of NaBO(2)(-)(H(2)O)(1) and NaBO(2)(-)(H(2)O)(2) are similar to that of bare NaBO(2)(-), except that their VDEs shift to higher electron binding energies (EBE). For the spectra of NaBO(2)( )(H(2)O)(3) and NaBO(2)(-)(H(2)O)(4), a low EBE feature appears dramatically in addition to the features observed in the spectra of NaBO(2)(-)(H(2)O)(0-2). Our study shows that the water molecules mainly interact with the BO(2)(-) unit in NaBO(2)(-)(H(2)O)(1) and NaBO(2)(-)(H(2)O)(2) clusters to form Na-BO(2)( )(H(2)O)(n) type structures, while in NaBO(2)(-)(H(2)O)(3) and NaBO(2)( )(H(2)O)(4) clusters, the water molecules can interact strongly with the Na atom, therefore, the Na-BO(2)(-)(H(2)O)(n) and Na(H(2)O)(n)...BO(2)(-) types of structures coexist. That can be seen as an initial step of the transition from a contact ion pair (CIP) structure to a solvent-separated ion pair (SSIP) structure for the dissolution of NaBO(2). PMID- 21814668 TI - Possible mechanism underlying high-pressure unfolding of proteins: formation of a short-period high-density hydration shell. AB - Hydration effects on high-pressure unfolding of a hydrophobic polymer chain are investigated through a multiscale simulation based on density-functional theory. The results strongly suggest the following: a thermodynamic origin for high pressure denaturation, i.e., the decrease in volume due to the unfolding can be explained by the formation of a short-period high-density hydration shell. PMID- 21814669 TI - Deeply bound cold caesium molecules formed after 0(-)(g) resonant coupling. AB - Translationally cold caesium molecules are created by photoassociation below the 6s + 6p(1/2) excited state and selectively detected by resonance enhanced two photon ionization (RE2PI). A series of excited vibrational levels belonging to the 0(-)(g) symmetry is identified. The regular progression of the vibrational spacings and of the rotational constants of the 0(-)(g) (6s + 6p(1/2)) levels is strongly altered in two energy domains. These deviations are interpreted in terms of resonant coupling with deeply bound energy levels of two upper 0(-)(g) states dissociating into the 6s + 6p(3/2) and 6s + 5d(3/2) asymptotes. A theoretical model is proposed to explain the coupling and a quantum defect analysis of the perturbed level position is performed. Moreover, the resonant coupling changes dramatically the spontaneous decay products of the photoexcited molecules, strongly enhancing the decay into deeply bound levels of the a(3)Sigma(+)(u) triplet state and of the X(1)Sigma(+)(g) ground state. These results may be relevant when conceiving population transferring schemes in cold molecule systems. PMID- 21814670 TI - A DFT study of IRMOF-3 catalysed Knoevenagel condensation. AB - It has been recently reported that IRMOF-3 [Gascon et al., J. Catal, 2009, 261, 75] may behave as a basic catalyst, active in the Knoevenagel condensation. In particular, it has been shown that the basicity of aniline-like amino moieties is enhanced, along with the catalytic activity, when incorporated into MOF structures. The computational study here was aimed at finding possible atomistic explanations of the increased basicity and catalytic activity of the IRMOF-3 embedded aniline groups, experimentally claimed. It was, moreover, aimed at guessing a reaction mechanism for the IRMOF-3 catalysed Knoevenagel condensation of benzaldehyde and ethyl-cyanoacetate. Within the DFT framework we have studied structure and basicity properties of IRMOF-3 and we have analysed the energetics of the catalytic cycle as well as of possible deactivation paths, including it. The increased basicity of IRMOF-3 over other amminic catalysts has been explained via the formation of protonated conjugate derivatives, involving hydrogen-bonds and originating quasi-planar 6-term rings. Several plausible reaction steps have been moreover taken into account and a mechanism for the Knoevenagel condensation, including catalyst deactivation, has been proposed for aniline molecules and embedded aniline moieties. This allowed us to suggest that the increased IRMOF-3 activity, as a basic catalyst, should be mostly related to its water adsorption ability, preserving the properties of the catalytically active amino moieties. PMID- 21814671 TI - Core-shell H-ZSM-5/silicalite-1 composites: Bronsted acidity and catalyst deactivation at the individual particle level. AB - A combination of in situ UV-Vis and confocal fluorescence micro-spectroscopy is applied to investigate the influence of an external silicalite-1 shell on the Bronsted acidity and coke formation process of individual H-ZSM-5 zeolite crystals. Three probe reactions were used: oligomerization of styrene, methanol to-olefin (MTO) conversion and aromatization of light naphtha (LNA) derivatives. Oligomerization of styrene leads to the formation of optically active carbocationic oligomers. Different styrene substitutions indicate the conversion ability of the catalyst acid core, a preferred alignment of the oligomers within the straight zeolite channels and a Bronsted acidity gradient throughout the zeolite crystal. Both the MTO conversion and the LNA process lead to limited carbonaceous deposition within the external silicalite-1 layer. This outer shell furthermore prevents the growth of extended coke species at the zeolite external surface. During MTO, the formation of carbonaceous compounds initiates at the center of the H-ZSM-5 zeolite core and expands towards the zeolite exterior. This coke build-up starts with a 420 nm UV-Vis absorption band, assigned to methyl substituted aromatic carbocations, and a second band around 550 nm, which is indicative of their growth towards larger conjugated systems. Aromatization of linear and branched C5 paraffins causes negligible darkening of the zeolite crystals though it forms fluorescent coke deposits and their precursors within the H-ZSM-5 catalyst. Olefin homologues on the contrary cause pronounced darkening of the zeolite composite. Methyl-branching of these reactants slows down the coke formation rate and produces carbonaceous species that are more restricted in their molecular size. PMID- 21814672 TI - Structural models for yttrium aluminium borate laser glasses: NMR and EPR studies of the system (Y2O3)(0.2)-(Al2O3)x-(B2O3)(0.8-x). AB - The structure of laser glasses in the system (Y(2)O(3))(0.2){(Al(2)O(3))(x))(B(2)O(3))(0.8-x)} (0.15 <= x <= 0.40) has been investigated by means of (11)B, (27)Al, and (89)Y solid state NMR as well as electron spin echo envelope modulation (ESEEM) of Yb-doped samples. The latter technique has been applied for the first time to an aluminoborate glass system. (11)B magic-angle spinning (MAS)-NMR spectra reveal that, while the majority of the boron atoms are three-coordinated over the entire composition region, the fraction of three-coordinated boron atoms increases significantly with increasing x. Charge balance considerations as well as (11)B NMR lineshape analyses suggest that the dominant borate species are predominantly singly charged metaborate (BO(2/2)O(-)), doubly charged pyroborate (BO(1/2)(O(-))(2)), and (at x = 0.40) triply charged orthoborate groups. As x increases along this series, the average anionic charge per trigonal borate group increases from 1.38 to 2.91. (27)Al MAS NMR spectra show that the alumina species are present in the coordination states four, five and six, and the fraction of four-coordinated Al increases markedly with increasing x. All of the Al coordination states are in intimate contact with both the three- and the four-coordinate boron species and vice versa, as indicated by (11)B/(27)Al rotational echo double resonance (REDOR) data. These results are consistent with the formation of a homogeneous, non-segregated glass structure. (89)Y solid state NMR spectra show a significant chemical shift trend, reflecting that the second coordination sphere becomes increasingly "aluminate like" with increasing x. This conclusion is supported by electron spin echo envelope modulation (ESEEM) data of Yb-doped glasses, which indicate that both borate and aluminate species participate in the medium range structure of the rare-earth ions, consistent with a random spatial distribution of the glass components. PMID- 21814673 TI - Double ionization of cycloheptatriene and the reactions of the resulting C7H(n)2+ dications (n = 6, 8) with xenon. AB - The formation and fragmentation of the molecular dication C(7)H(8)(2+) from cycloheptatriene (CHT) and the bimolecular reactivities of C(7)H(8)(2+) and C(7)H(6)(2+) are studied using multipole-based tandem mass spectrometers with either electron ionization or photoionization using synchrotron radiation. From the photoionization studies, an apparent double-ionization energy of CHT of (22.67 +/- 0.05) eV is derived, and the appearance energy of the most abundant fragment ion C(7)H(6)(2+), formed via H(2) elimination, is determined as (23.62 +/- 0.07) eV. Analysis of both the experimental data as well as results of theoretical calculations strongly indicate, however, that an adiabatic transition to the dication state is not possible upon photoionization of neutral CHT and the experimental value is just considered as an upper bound. Instead, an analysis via two different Born-Haber cycles suggests (2)IE(CHT) = (21.6 +/- 0.2) eV. Further, the bimolecular reactivities of the C(7)H(n)(2+) dications (n = 6, 8), generated via double ionization of CHT as a precursor, with xenon as well as nitrogen lead, inter alia, to the formation of the organo-xenon dication C(7)H(6)Xe(2+) and the corresponding nitrogen adduct C(7)H(6)N(2)(2+). PMID- 21814675 TI - Brownian dynamics of a compressed polymer brush model. Off-equilibrium response as a function of surface coverage and compression rate. AB - We study the compressive behaviour of a polymer-covered surface (i.e., a "polymer brush") using Brownian dynamics simulations. The model consists of grafted chains with variable flexibility, variable intra- and inter-chain interactions, as well as different surface coverage. We discuss the polymer brush response to confinement by considering variable rates of compression under a hard plane. Our results show a small degree of inter-chain entanglement, regardless of whether the interaction is attractive or merely excluded volume. We observe that the molecular shape depends strongly on the surface coverage. Dense brushes exhibit a limited degree of lateral deformation under compression; instead, chains undergo a transition that produces a local patch with near-solid packing. This effect due to surface density can be undone partially by increasing the attractive nature of the chain interaction, by modulating the rate of compression, or by allowing "soft anchoring", i.e., the possible Brownian drift of the grafting bead on the surface. We have also studied the polymer brush relaxation while maintaining the compressing plane, as well as after its sudden removal. We find evidence that also the relaxation depends on surface density; dense brushes appear to be configurationally frustrated at high compression and are unable to undergo swelling, regardless of the pressure applied. PMID- 21814674 TI - Synthesis and X-ray crystal structure of a difunctionalized pillar[5]arene at A1/B2 positions by in situ cyclization and deprotection. AB - The reaction of 1,4-dimethoxybenzene and paraformaldehyde using AlBr(3) yields multiple-deprotected pillar[5]arenes. A1/B2 di-deprotected pillar[5]arene can be isolated by silica gel chromatography and washing procedures. The X-ray structure and polymerization of the A1/B2 di-deprotected pillar[5]arene are reported. PMID- 21814686 TI - Nickel complexes of a bis(benzimidazolin-2-ylidene)pyridine pincer ligand with four- and five-coordinate geometries. AB - The four- and five-coordinate complexes [(CNC)NiX(2)] (X = Cl, Br, I), [(CNC)NiX]PF(6) (X = Cl, Br) and [(CNC)NiCl]Cl.H(2)O have been isolated, where CNC is the bis(N-butylbenzimidazolin-2-ylidene)-2,6-pyridine pincer ligand. A five-coordinate geometry is rare for this class of complex. Where amenable, the complexes have been structurally characterised by single crystal X-ray diffraction studies and in solution by NMR, UV-vis and MS studies. The five coordinate dibromo complex [(CNC)NiBr(2)] is readily prepared on the gram-scale from the benzimidazolium salt precursor and Ni(OAc)(2).4H(2)O in DMSO without the exclusion of air. Halide exchange and salt metathesis reactions using [(CNC)NiBr(2)] afford the other four- and five-coordinate complexes. [(CNC)NiBr(2)] displays very low solubility, and upon dissolution affords solutions of the four-coordinate [(CNC)NiBr](+). Factors that influence the formation of four- or five-coordinate complexes with this ligand class are discussed. PMID- 21814677 TI - An efficient approach to pyrazolo[5,1-a]isoquinolin-2-amines via a silver(I) catalyzed three-component reaction of 2-alkynylbenzaldehyde, sulfonohydrazide, and nitrile. AB - A three-component reaction of 2-alkynylbenzaldehyde, sulfonohydrazide, and nitrile catalyzed by silver triflate under mild conditions is reported, which generates pyrazolo[5,1-a]isoquinolin-2-amines in good to excellent yields. PMID- 21814688 TI - Chemical reaction mediated self-assembly of PTCDA into nanofibers. AB - Uniform and crystalline nanofibers of perylene-3,4,9,10-tetracarboxylic dianhydride (PTCDA), an insoluble organic semiconducting molecule, have been achieved by self-assembling the molecules using chemical reaction mediated conversion of an appropriately designed soluble precursor, perylene tetracarboxylic acid (PTCA) using carbodiimide chemistry. PMID- 21814687 TI - Reduction of CO2 and SO2 with low valent nickel compounds under mild conditions. AB - The reaction of [(dippe)Ni(MU-H)](2) (A) (dippe = 1,2-bis(diisopropyl phosphinoethane) with CO(2) in toluene afforded the carbonyl nickel(0) compounds of the type {(dippe)Ni(CO)](2)(MU-dippe)}(1) and (dippe)Ni(CO)(dippe==O)] (2), which were characterized by standard spectroscopic methods; complex (1) was also characterized by single crystal X-ray diffraction. Reaction of (A) with SO(2) yields the thiosulfate nickel(II) compound [Ni(dippe)(S(2)O(3))] (5), which was fully characterized by standard spectroscopic methods and X-ray crystallography. In both cases, a reduction reaction of CO(2) to CO and SO(2) to S(2)O(3)(2-) with (A) took place under mild conditions. PMID- 21814689 TI - Acid-base modulation of a versatile heteroditopic calix[6]arene based receptor. AB - A new calix[6]crypturea (3) has been efficiently synthesized through a domino Staudinger/aza-Wittig reaction followed by a [1 + 1] macrocyclization step. In comparison to the previously reported tren-based calix[6]crypturea, this heteroditopic receptor 3 displays a more flexible and larger tris-ureido cap. Due to this structural alteration, 3 exhibits unique host-guest properties: (i) the protonation of its basic cap leads to a rigidification of the whole structure and, thus, allosteric control of the binding properties and selective guest switching processes are possible, (ii) its versatility is unprecedented in the literature since it can bind either neutral molecules, anions, primary/secondary ammonium ions, quaternary ammonium ions or contact ion pairs according to different modes of recognition and with a remarkable selectivity within each family of guest, (iii) cascade complexes even stable in a protic environment can be obtained. These remarkable features are nicely illustrated by the fact that, according to the nature of its counterion, an ammonium ion R(1)R(2)NH(2)(+) can be accommodated into the cavity either as an independent guest, as a contact ion pair or as a cascade complex. All these results are reminiscent of biological receptors and validate the strategy that consists of designing receptors presenting a high flexibility that can be controlled by an external stimulus. PMID- 21814690 TI - A dual organic/organometallic approach for catalytic ring-opening polymerization. AB - A dual catalytic system combining an original cationic zinc complex and a tertiary amine is shown to promote efficiently the polymerization of lactide under mild conditions. PMID- 21814692 TI - Diastereoselective and enantioselective capture of chiral zinc enolate using nitroolefins: a rapid access to chiral gamma-nitro carbonyl compounds. AB - Highly diastereoselective and enantioselective catalytic capture of chiral zinc enolates using nitroolefins as electrophiles is described. The tandem products gamma-nitro ketones were obtained in good yields with high diastereoselectivities and enantioselectivities. The gamma-nitro ketones were readily hydrogenated to the optically enriched and diastereomerically pure chiral pyrrolidines with four contiguous stereocentres under mild conditions. PMID- 21814691 TI - Highly diastereoselective vinylogous Mukaiyama aldol reaction of alpha-keto phosphonates with 2-(trimethylsilyloxy)furan catalyzed by Cu(OTf)2. AB - The diastereospecific formation of delta-hydroxyalkylbutenolide phosphonate has been achieved via a vinylogous Mukaiyama aldol reaction. The reaction was performed using alpha-ketophosphonate 1 and 2-(trimethylsilyloxy)furan 2 mediated by Cu(OTf)(2) and 2,2,2-trifluoroethanol as additive in CH(2)Cl(2). The reaction proceeds rapidly and affords the corresponding 5-(hydroxy(aryl)methyl) furan 2(5H)-one phosphonates 3 in high yields with good to excellent diastereoselectivities (d.r. up to >99 : 1). 5-(Hydroxy(alkyl)methyl)furan-2(5H) one phosphonates could also be obtained with good diastereoselectivities. PMID- 21814693 TI - Rapid synthesis of nucleotide pyrophosphate linkages in a ball mill. AB - Using a ball mill, rapid, atom-economic coupling between adenosine-5' phosphoromorpholidate and phosphorylated ribose derivatives as their sodium or barium salts was achieved. Facile purification by reversed-phase HPLC enabled product isolation within hours. PMID- 21814694 TI - Harnessing molecule-solid duality of nanoclusters/nanoparticles for nanoscale control of size, shape and alloying. AB - This report demonstrates a molecule-solid duality concept for nanoscale control of size, shape and alloying by showing novel evolution of binary copper and gold nanoclusters or nanoparticles towards alloy nanocubes, as evidenced by in situ real time synchrotron X-ray diffraction characterization. PMID- 21814695 TI - 2-Lithiated-2-phenyloxetane: a new attractive synthon for the preparation of oxetane derivatives. AB - A valuable and direct method to access 2-substituted-2-phenyloxetanes by electrophilic quenching of the corresponding 2-lithiated derivative has, for the first time, been described. 2-Lithiated-2-phenyloxetane was found to be configurationally unstable. Evidence is presented to show that electron-transfer processes are also operative in the coupling reactions with electrophiles. PMID- 21814696 TI - A universal method to synthesize nanoscale carbides as electrocatalyst supports towards oxygen reduction reaction. AB - We have developed a general ion-exchange method of preparing a composite of low nanometre size carbide particles with controllable size less than 10 nm on carbon foams. The nanoarchitectures of the carbide nanoparticles on carbon foam are used to load Pt nanoparticles as electrocatalysts which show enhanced activity for the oxygen reduction reaction. PMID- 21814697 TI - A new photocatalyst: Bi2TiO4F2 nanoflakes synthesized by a hydrothermal method. AB - A pure phase of Bi(2)TiO(4)F(2) nanoflakes with layered Aurivillius structure are synthesized by a simple hydrothermal method. The as-prepared sample is characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), high-resolution transmission electron microscopy (HRTEM) and UV-vis diffuse reflectance spectroscopy. The OH radicals produced during the photocatalytic reaction is detected by a photoluminescence (PL) technique. The electronic structure is investigated by DFT calculations. The photocatalytic properties of Bi(2)TiO(4)F(2) are explored by degradation of Rhodamine B (RhB) and phenol. The results show that Bi(2)TiO(4)F(2) exhibits much higher photocatalytic performances than Bi(4)Ti(3)O(12) due to the unique layered structure and the existence of F. F acts as an electron trapper, which enhances the separation of photogenerated electron-hole pairs, and lead to higher photocatalytic activity. Reaction with terephthalic acid demonstrates that OH radicals are formed as a result of UV irradiation of Bi(4)TiO(4)F(2) in solution, in agreement with the proposed mechanism. Thus, Bi(2)TiO(4)F(2) can be used as a new efficient photocatalyst. PMID- 21814698 TI - The Th=C double bond: an experimental and computational study of thorium poly carbene complexes. AB - The first thorium poly-carbene complexes [(Ph(2)P=S)(2)C](2)Th(DME) (2) and [{[(Ph(2)P=S)(2)C](3)Th}Li(2)(DME)](n) (3) have been prepared and structurally characterized. DFT calculations reveal that the Th=C bond is polarized toward the nucleophilic carbene carbon atom, which is further verified by the experimental observation that the Th=C bond shows a nucleophilic behavior with Ph(2)CO. PMID- 21814699 TI - Diagnosis of early stage nasopharyngeal carcinoma using ultraviolet autofluorescence excitation-emission matrix spectroscopy and parallel factor analysis. AB - We report the diagnostic ability of ultraviolet (UV)-excited autofluorescence (AF) excitation-emission matrix (EEM) spectroscopy associated with parallel factor (PARAFAC) analysis for differentiating cancer from normal nasopharyngeal tissue. A bifurcated fiber-optic probe coupled with an EEM system was used to acquire tissue AF EEMs using excitation wavelengths between 260 and 400 nm, and emission collection between 280 and 500 nm. A total of 152 AF EEM landscapes were acquired from 13 normal and 16 nasopharyngeal carcinoma (NPC) thawed ex vivo tissue samples from 23 patients. PARAFAC was introduced for curve resolution of individual AF EEM landscapes associated with the endogenous tissue constituents. The significant factors were further fed to a support vector machine (SVM) and cross-validated to construct diagnostic algorithms. Both the EEM intensity landscapes and the PARAFAC model revealed tryptophan, collagen, and elastin to be the three major endogenous fluorophores responsible for the AF signal from normal and NPC tissues. The EEM intensity distribution and PARAFAC factors suggest an increase of tryptophan and a decrease of collagen and elastin in NPC tissues compared to the normal. The classification results obtained from the PARAFAC-SVM modeling yielded a diagnostic accuracy of 94.7% (sensitivity of 95.0% (76/80); specificity of 94.4% (68/72)) for normal and NPC tissue differentiation. This study suggests that UV-excited AF EEM spectroscopy integrated with PARAFAC algorithms has the potential to provide clinical diagnostics of early onset and progression of NPC. PMID- 21814700 TI - Interpretation of substituent effects on 13C and 15N NMR chemical shifts in 6 substituted purines. AB - A range of purine derivatives modified at position 6 of the basic purine skeleton exhibit a variety of biological activities. Several derivatives are used or tested nowadays for pharmacological treatments. The present work aims to analyze the effects of substituents on the electron distribution in the purine core as reflected by NMR chemical shifts. We collected a comprehensive set of experimental NMR data for a variety of 6-substituted purines (-NH(2), -NHMe, NMe(2), -OMe, -Me, -CCH, and -CN) and determined the molecular and crystal structures of three derivatives (-NHMe, -CCH, and -CN) by X-ray diffraction. The density-functional methods calibrated in our recent study (Phys. Chem. Chem. Phys., 2010, 12, 5126) have been employed to enable understanding of the substituent-induced changes in the NMR chemical shifts of the atoms in the purine skeleton. Analyses of the nuclear shielding using localized molecular orbitals (LMOs), specifically the natural LMOs (NLMOs) and Pipek-Mezey LMOs, were used to break down the values of the isotropic (13)C and (15)N NMR chemical shifts and the chemical shift tensors into the contributions of the individual LMOs. The experimental and calculated trends in the chemical shift of the N-3 atom correlate nicely with the Hammett constants (sigma(para)) and the calculated natural charges on N-3, whereas the contributions of the LMOs to the N-1 and C-6 chemical shifts are found to be more complex. PMID- 21814701 TI - Solution patterning of ultrafine ITO and ZnRh2O4 nanowire array below 20 nm without etching process. AB - Transparent conductive patterns have significant applications in various optoelectronic devices. A low cost solution process to directly fabricate transparent conductive oxide nanopatterns was developed without a conventional lithographic or etching process. A uniform and high density array of ITO and ZnRh(2)O(4) nanopatterns was fabricated with block copolymer self-assembly and spin coating technology. A low resistivity of about 3-9 * 10(-4)Omega cm and high transmission of 90% in the visible spectrum region was demonstrated with uniform ITO nanopatterns with feature size of 24 nm. The first p-type ZnRh(2)O(4) nanopattern was also fabricated with low resistivity and small feature size of 15 nm. This cost-efficient and large area scalable process can fabricate patterns with feature size down to sub-20 nm, providing a faster patterning capability compared to conventional photolithography and etching processes. PMID- 21814702 TI - Enhanced Cr(vi) removal using iron nanoparticle decorated graphene. AB - Nanoscale iron particles decorated graphene sheets synthesized via sodium borohydride reduction of graphene oxide, showed enhanced magnetic property, surface area and Cr(vi) adsorption capacity compared to bare iron nanoparticles. PMID- 21814703 TI - An unusual reaction of alpha-alkoxyphosphonium salts with Grignard reagents under an O2 atmosphere. AB - An unusual and novel reaction of alpha-alkoxyphosphonium salts, generated from O,O-acetals and Ph(3)P, with Grignard reagents under an O(2) atmosphere afforded alcohols in moderate to high yields. It was clarified by isotopic labelling experiments that the reaction proceeded via a novel radical pathway. PMID- 21814704 TI - A PDMS-based biochip with integrated sub-micrometre position control for TIRF microscopy of the apical cell membrane. AB - A poly(dimethylsiloxane) (PDMS)-based biochip with an integrated pressure controlled positioning system with sub-micrometre precision was realized. The biochip was easy and cheap to manufacture and enabled positioning in a wet environment. It allowed the application of total internal reflection fluorescence (TIRF) microscopy at the dorsal cell membrane, which is not adhering to a support. Specifically, the chip enabled TIRF microscopy at the apical membrane of polarized epithelial cells. Thereby, the device allowed us for the first time to monitor individual fusion events of GPI-GFP bearing vesicles at the apical membrane in live Madin-Darby canine kidney II (MDCK II) cells. Moreover, a mapping of fusion sites became feasible and revealed that the whole apical membrane is fusion competent. In total, the biochip offers an all-in-one solution for apical TIRF microscopy and contributes a novel tool to study trafficking processes close to the apical plasma membrane in polarized epithelial cells. PMID- 21814705 TI - Sickness absence, office types, and advances in absenteeism research. PMID- 21814706 TI - The role of coalitions in drug policy. Some theoretical and observational considerations. AB - Democratically organised societies have to find ways how to proceed when in need of a reformulation of strategies in face of new societal and technological developments, especially in dealing with controversial preferences and interests. The area of drug policy change presents an excellent example for discussing the problem and the process of coalition building for finding acceptable answers to new challenges. Modern sociological theory has developed concepts and tools for a description and analysis of such processes. Some concrete case studies from Swiss cities are available as a basis for advanced discussion of theoretical concepts. The observational description of the coalition building in the city of Zurich helps to illustrate the inherent elements, problems and outcomes; a more detailed process analysis focuses on the initial phases and further development of the various formal and informal coalitions, introducing the importance of shared objectives for action and the need for concerted activities. A clear policy concept and a consistent action plan were not available at first, but they proved to be an important step in the consolidation of what was a non-systematic beginning. What started at local level and led to a new national policy was not so much a continued clash between two ideologies - harm reduction versus strict prohibition -, but was the beginning of a new thinking about how the various policy elements could successfully work together in the pursuit of a shared concrete objective. These observations may be considered in further theory development and policy considerations. PMID- 21814707 TI - [Pathological gambling, personality patterns and clinical syndromes]. AB - The aim of this study is to evaluate the prevalence and percentages of personality patterns, and explore their relationship with clinical syndromes in a sample of 212 pathological gamblers from a rehabilitation center. The study also explores the possibility of profiles, common in gamblers, in which personality disorders and clinical syndromes coexist. The Millon Clinical Multiaxial Inventory (MCMIII) was employed. Four clinical personality patterns were the most frequently identified: dependent, obsessive-compulsive, narcissistic and antisocial. The relationship between personality patterns and clinical syndromes was also analyzed. Subsequent cluster analysis revealed two personality profiles, with features belonging to different scales, called "antisocial profile" and "obsessive-compulsive profile". These two profiles differ considerably in their relation to clinical syndromes. The "antisocial" group scores significantly higher on all clinical syndromes, and close to the clinical score in the cases of alcohol abuse, drug abuse, psychotic thinking and delusional disorder. PMID- 21814708 TI - Alcohol poisonings and fatal accidents in Belarus. AB - BACKGROUND: High accidental deaths rate in the former Soviet republics (FSR) and its profound fluctuation over the past decades have attracted considerable interest. The mounting body of evidence point to binge drinking pattern as a potentially important contributor to accident mortality crisis in FSR. AIM: The aim of this study was to estimate the aggregate-level effect of binge drinking on the accident mortality rate in the former Soviet Slavic republic Belarus. METHOD: Trends in fatal alcohol poisoning (as a proxy for binge drinking) and accidental deaths rates from 1979 to 2007 were analyzed employing a distributed lag analysis in order to asses bivariate relationship between the two time series. RESULTS: According to Bureau of Forensic Medicine autopsy reports the number of deaths due to accidents and injuries increased by 94.5% (from 38.7 to 75.6 per 100.000 of residents), and fatal alcohol poisoning rate increased by 108.6% (from 12.8 to 26.7 per 100.000 of residents) in Belarus between 1979 and 2007. Alcohol in blood was found in 51.4% victims of deaths from accidents and injuries for the whole period, with the minimum figure 43.1% in 1986 and maximum 59.1% in 2005. The outcome of distributed lags analysis indicated statistically significant association between the number of alcohol poisoning deaths and the number BAC (blood alcohol concentration)- positive deaths from accidents and injuries at zero lag. CONCLUSION: The outcome of this study supports the hypothesis that alcohol and deaths from accidents and injuries are closely connected in culture with prevailing intoxication-oriented drinking pattern. This research evidence points to binge drinking pattern as a potentially important contributor to accident mortality crisis in Belarus. PMID- 21814709 TI - [Drunkenness, driving and sexual relations in young cocaine and ecstasy users]. AB - Traffic accidents, sexually-transmitted diseases, unwanted pregnancies, drunkenness, and drug use (especially psychostimulants) are negative aspects associated with recreational nightlife. The aim of the present study is to analyze in a sample of 1214 young people (aged 15-25; 49.7% males, 50.3% females) whether psychostimulant users (cocaine and ecstasy) have a higher frequency of drunkenness and risk behaviours related to sex and to driving. We also analyze the importance of these behaviours in the prediction of psychostimulant use in the last year. The results indicate that psychostimulant users get drunk more frequently, are more likely to have seen a relative drunk, and present more risk behaviours in the contexts of driving and full sexual relations. Therefore, cocaine and ecstasy users are a risk population who need specific preventive programs. PMID- 21814710 TI - [Addictive, criminal and psychopathological profile of a sample of women in prison]. AB - This study examines the addictive, criminal and psychopathological profile of a sample of 59 women incarcerated in the Villabona prison in Asturias (a region in northern Spain). The instruments administered were the EuropASI, the SCL-90-R and a semi-structured interview. Results showed that the profile is a young, single women with family dependents serving an average of 5 years' imprisonment. Of the total sample, 64.4% met criteria for a substance abuse disorder. We found a statistically significant relationship between the variables use-nonuse and type of crime: women who used substances had committed the most crimes against property and against the socioeconomic order. As regards psychopathology, 44.06% of the sample fulfilled the requirements for clinical case according to Derogatis' (1994) criteria. The results of the SCL-90-R showed that the predominant psychological disorders were, in the following order, depression, somatization, obsessive-compulsive disorder and paranoid ideation. Moreover, in the group of female users, 47.4% had dual pathology. Our results revealed a statistically significant relationship between clinical case and substance use. Finally, statistically significant differences were found between the user and nonuser groups in the EuropASI severity profile. Highest scores were found for the medical, psychiatric and family areas in the user group. PMID- 21814711 TI - [Longitudinal study on quality of life, craving and psychological adjustment in alcohol-dependent patients: variations depending on the personality disorders]. AB - The goal of this study was to determine the evolution of variables such as quality of life, craving, or psychological adjustment during treatment in a sample of 65 patients with alcohol-dependence disorder, 56.3% of whom also presented a personality disorder (PD). Five measurements were taken over the course of the treatment, at 3-month intervals. The analysis of tendencies of the variables craving, quality of life, and psychological adjustment assessed at the five assessment points revealed that the cognitive-behavioral treatment influences each one of these variables differently: a quadratic and cubic relation was identified for craving, whereas for quality of life there were linear, quadratic and cubic relationships in its diverse scales depending on the time point in question, and for psychological adjustment there were linear and quadratic relationships. At the end of treatment, the patients assessed presented significantly higher levels of quality of life than at the beginning, but the results showed that, although the patients with PD had better perceived quality of life at three months, it was lower over the entire course of the treatment compared to patients without PD. It was also found that quality of life and craving at the start of the treatment predicted alcohol use during the first three months. The implications of these results are discussed with a view to psychological intervention with alcohol-dependent patients. PMID- 21814712 TI - [Self-concept and drug use in adolescence]. AB - This study analyzes the relationship between a multidimensional measure of self concept, the Self-concept Form-5 Questionnaire (AF5), and drug use among adolescents. From the responses of 632 participants (47.5% females) aged 12 to 17 years (M = 14.88 years, SD = 1.71 years), results showed negative relationships between family, academic and physical self-concept, and drug use. Although a positive relationship between social self-concept and drug use was found, this significant relationship disappeared once the age and sex of adolescents was controlled statistically. Moreover, the study includes other adjustment indicators in adolescence (psychological adjustment, personal competence, antisocial behavior and parenting). Results support the idea of self-concept as an important correlate of psychological well-being and a basic theoretical construct for explaining adjusted and adaptive behaviors in adolescence. Likewise, our results underline the need for statistical control of the effect of a third variable (sex), which could explain some contradictory results reported in the literature (a positive relationship between social self-concept and drug use), so as to avoid reaching conclusions based on spurious relationships. self concept, multigroup confirmatory factor analysis, adolescence, psychosocial adjustment, drug use. PMID- 21814713 TI - [Pilot study on the prevalence of dual pathology in community mental health and substance misuse services in Madrid]. AB - AIM: To evaluate retrospectively the comorbidity of mental and addictive disorders in community mental health and substance misuse services in Madrid. METHODS: The medical records of 400 patients from mental health and substance misuse services in Madrid were evaluated. Records were examined for the last 20 patients from each service unit. RESULTS: Dual pathology was constituted when a current diagnosis of mental and addictive disorders, excluding nicotine addiction, appeared on the patient's records. Prevalence of dual pathology was 34%. There were differences in the prevalence figures for the two kinds of service: 36.78% in substance misuse services, and 28.78% in mental health services. There was an association of dual diagnosis with alcohol or cocaine dependence, but not with opioid dependence. The mental disorders more prevalent in dually diagnosed than in non-dually diagnosed patients were mood disorders, personality disorders, and schizophrenia. CONCLUSION: There is a high prevalence of dual pathology in those seeking treatment, being higher in substance misuse services than in mental health services, and higher in patients with alcohol or cocaine dependence. These findings could be of help in the planning of care resource policies for these patients. PMID- 21814714 TI - [Evaluation of a program for changing attitudes in pre-drivers to prevent road accidents related to drink-driving in Catalonia]. AB - This study appraises the results of an intervention to prevent drink-driving in a cohort of pre-drivers in the region of Catalonia (Spain). The program applied, based on attitude change, sets out to reduce significantly the risk of being involved in drink-driving. A classic quasi-experimental pretest-posttest design with control group was used, and two questionnaires were applied: a general one measuring several risk factors, and another one specifically addressing the question of alcohol. The study was carried out with three groups: a) experimental 1, which received the entire program, b) experimental 2, which received a part of the program, and c) control, which did not receive the benefits of the program. Results from the factor analysis (PCA) and the repeated-measures ANOVA suggest that young pre-drivers who received the program obtained better results in road safety and showed less risk of drink-driving than those who did not receive the program or received only part of it. Significant differences were also found between men and women. The results confirm the effectiveness of the attitude change program and the possibility of reducing alcohol use among young pre drivers. PMID- 21814715 TI - Human lung fibroblasts prematurely senescent after exposure to ionizing radiation enhance the growth of malignant lung epithelial cells in vitro and in vivo. AB - Cellular senescence, being the result of serial subculturing or of exogenous stresses, is considered to be a potent anticancer mechanism. However, it has been proposed that senescent cells may enhance the growth of adjacent malignant epithelial cells. On the other hand, exposure of tumors to repeated low doses of gamma-irradiation is a common treatment regime. Nevertheless, gamma-irradiation also affects the neighboring stromal cells and the interaction of the latter with cancer cells. Accordingly, in this study, we have exposed confluent cultures of human lung fibroblasts to repeated subcytotoxic doses of 4 Gy of gamma irradiation. We found that a single dose immediately activates a DNA damage response, leading to an intense, but reversible, cell cycle arrest. After a series of doses (total dose approximately 50 Gy) cellular senescence was accelerated, as shown by permanent growth arrest and the upregulation of specific biochemical and morphological senescence-associated markers. This process was found to be p53-dependent. Next, we studied the effect of these prematurely senescent cells on the growth of human malignant lung cell lines (A549 and H1299) and found that the presence of irradiation-mediated senescent cells strongly enhances the growth of these cancer cells in vitro and in immunocompromised (SCID) mice in vivo. This effect seems not to be related to an induction of epithelial-to-mesenchymal transdifferentiation but, to a significant extent, to the increased expression of matrix metalloproteases (MMPs), as a specific MMP inhibitor significantly restrains the growth of cancer in the presence of senescent fibroblasts. These findings indicate that lung fibroblasts that become senescent after ionizing radiation may contribute to lung cancer progression. PMID- 21814716 TI - Waste management in small hospitals: trouble for environment. AB - Small hospitals are the grassroots for the big hospital structures, so proper waste management practices require to be initiated from there. Small hospitals contribute a lot in the health care facilities, but due to their poor waste management practices, they pose serious biomedical waste pollution. A survey was conducted with 13 focus questions collected from the 100 hospital present in Dehradun. Greater value of per day per bed waste was found among the small hospitals (178 g compared with 114 g in big hospitals), indicating unskilled waste management practices. Small hospitals do not follow the proper way for taking care of segregation of waste generated in the hospital, and most biomedical wastes were collected without segregation into infectious and noninfectious categories. PMID- 21814717 TI - Assessment of liquid disposal originated by uranium enrichment at Aramar Experimental Center Sao Paulo--Brazil. AB - This work presents a liquid disposal monitoring originated from uranium enrichment process at Aramar Experimental Center from 1990 to 1998. Assessment of uranium, fluorides, ammoniacal nitrogen, chemical oxygen demand, and pH measurements were made in water samples and compared with results achieved in other countries, as North America and India. The liquid disposal evaluation, generated by uranium enrichment process, showed low levels, considering most parameters established by Federal and State Legislation, aiming environmental pollution control. However, uranium levels were above the limits established by Conselho Nacional do Meio Ambiente, Environment Protection Agency and mainly by the World Health Organization. PMID- 21814718 TI - Estimation of suspended sediment concentration from turbidity measurements using artificial neural networks. AB - Suspended sediment concentration (SSC) is generally determined from the direct measurement of sediment concentration of river or from sediment transport equations. Direct measurement is very costly and cannot be conducted for all river gauge stations. Therefore, correct estimation of suspended sediment amount carried by a river is very important in terms of water pollution, channel navigability, reservoir filling, fish habitat, river aesthetics and scientific interests. This study investigates the feasibility of using turbidity as a surrogate for SSC as in situ turbidity meters are being increasingly used to generate continuous records of SSC in rivers. For this reason, regression analysis (RA) and artificial neural networks (ANNs) were employed to estimate SSC based on in situ turbidity measurements. The SSC was firstly experimentally determined for the surface water samples collected from the six monitoring stations along the main branch of the stream Harsit, Eastern Black Sea Basin, Turkey. There were 144 data for each variable obtained on a fortnightly basis during March 2009 and February 2010. In the ANN method, the used data for training, testing and validation sets are 108, 24 and 12 of total 144 data, respectively. As the results of analyses, the smallest mean absolute error (MAE) and root mean square error (RMSE) values for validation set were obtained from the ANN method with 11.40 and 17.87, respectively. However these were 19.12 and 25.09 for RA. It was concluded that turbidity could be a surrogate for SSC in the streams, and the ANNs method used for the estimation of SSC provided acceptable results. PMID- 21814720 TI - Dissipation and residue of 2,4-D isooctyl ester in wheat and soil. AB - A simple analytical method was developed to determine the 2,4-D isooctyl ester residue in wheat and soil by gas chromatography coupled with electron capture detector. Using the method, the dissipation and residue of 2,4-D isooctyl ester in wheat field was investigated. The average recoveries of 2,4-D isooctyl ester ranged from 80.1% to 110.0% with relative standard deviations of 2.4% to 16.1%. The pesticide showed a rapid dissipation rate either in wheat seedling or soil, with the half-lives of 1.0 to 3.0 days. The terminal residue results in wheat grain were much lower than the codex MRL (2.0 mg/kg). It could be considered safe to food and environment when using this herbicide for controlling weeds in wheat field. PMID- 21814719 TI - Reproductive endocrine disruption in smallmouth bass (Micropterus dolomieu) in the Potomac River basin: spatial and temporal comparisons of biological effects. AB - A high prevalence of intersex or testicular oocytes (TO) in male smallmouth bass within the Potomac River drainage has raised concerns as to the health of the river. Studies were conducted to document biomarker responses both temporally and spatially to better understand the influence of normal physiological cycles, as well as water quality and land-use influences. Smallmouth bass were collected over a 2-year period from three tributaries of the Potomac River: the Shenandoah River, the South Branch Potomac and Conococheague Creek, and an out-of-basin reference site on the Gauley River. The prevalence of TO varied seasonally with the lowest prevalence observed in July, post-spawn. Reproductive maturity and/or lack of spawning the previous spring, as well as land-use practices such as application of manure and pesticides, may influence the seasonal observations. Annual, seasonal, and site differences were also observed in the percentage of males with measurable concentrations of plasma vitellogenin, mean concentration of plasma vitellogenin in females, and plasma concentrations of 17beta-estradiol and testosterone in both sexes. Bass collected in the South Branch Potomac (moderate to high prevalence of TO) had less sperm per testes mass with a lower percentage of those sperm being motile when compared to those from the Gauley River (low prevalence of TO). An inverse relationship was noted between TO severity and sperm motility. An association between TO severity and wastewater treatment plant flow, percent of agriculture, total number of animal feeding operations, the number of poultry houses, and animal density within the catchment was observed. PMID- 21814721 TI - Sewage pollution effects on mesozooplankton structure in a shallow temperate estuary. AB - The effects of a sewage effluent with no treatment on the mesozooplankton structure and the environmental quality were evaluated in the Bahia Blanca Estuary, during June to November 1995. The highest values of particulate organic matter, nutrients and specially phosphate, were observed in the effluent discharge zone. In addition, taxa richness, mesozooplankton abundance and Shannon diversity values were lower in the sewage discharge area compared with the less polluted area. Eurytemora americana and Acartia tonsa as well as larvae of Balanus glandula, Neohelice granulata and Spionidae were found in the discharge area with lower densities. These results highlight the importance of sewage effluent effects on mesozooplankton community providing background data to use in other monitoring programmes. PMID- 21814722 TI - Even sampling designs generation by charges repulsion simulation. AB - Evenly distributed sampling design is generally considered as an efficient sampling design. It is widely used in sampling for the environmental survey. In this paper, we present a novel method for generating N evenly distributed samples within a given irregular polygon via simulating the movements of some ideal homogeneous point charges. Initially, charges are randomly put into the sampling region; then, they are freed and held orderly; and after enough runs, the charges will finally reach a stable state with all of them having a zero resultant force and velocity; and so they distribute evenly within the region. Their layout can thus be considered as an evenly distributed sampling design. The main advantages of this method are: (1) it is easy to understand and implement; (2) it is efficient in both running and generating better designs. Analysis and experimental results indicate that this method is an efficient and robust method for generating even sampling designs for 2D polygonal sampling region. PMID- 21814723 TI - Expression of matrix metalloproteinase-9, type IV collagen and vascular endothelial growth factor in adamantinous craniopharyngioma. AB - To explore the expression of matrix metalloproteinase 9 (MMP-9), type IV collagen (Col IV) and vascular endothelial growth factor (VEGF) in adamantinomatous craniopharyngioma (ACP) and analyze the correlation between the level of these markers and adamantimous craniopharyngiomas recurrence. Expressions of MMP-9, Col IV and VEGF were tested by immunohistochemistry (IHC) in 40 cases of ACP, including 24 cases of primary group and 16 cases of recurred group. The expression level of MMP-9 and VEGF in recurred group were significantly higher than primary group (93.7% vs. 41.7%, P < 0.05, 87.5% vs. 45.8%, P < 0.05, respectively). The expression of Col IV in the recurred group was significant different from the primary group (Z = -2.619, P < 0.05). MMP-9, Col IV and VEGF may be the potential specific bio-marker related to the recurrence of ACP. PMID- 21814724 TI - Efficient production and characterization of recombinant human NELL1 protein in human embryonic kidney 293-F cells. AB - NELL1 is a secretory protein that induces osteogenic differentiation and bone formation by osteoblastic cells. Because of its potent osteoinductive activity, NELL1 may be useful for bone regeneration therapy. However, at present, we have little knowledge regarding NELL1 receptors and NELL1-mediated signaling pathways. We have previously produced NELL1 using an insect's cell expression system; however, the protein was relatively unstable and was degraded by proteases released from dead cells. In the present study, NELL1 protein was expressed in human embryonic kidney 293-F cells. Stable cell lines expressing NELL1 fused to a C-terminal hexahistidine-tag were obtained by G418 selection of transfected cells. Cells grown in serum-free medium showed high levels of NELL1 protein production (approximately 4 mg/l cell culture) for up to 6 months. NELL1 protein was purified from culture medium using a one-step nickel-chelate affinity chromatography protocol. Purified NELL1 protein immobilized onto culture dishes induced the expression of both early and late osteogenic markers on mouse mesenchymal C3H10T1/2 cells. When NELL1-expressing 293-F cells were grown on gelatin-coated glass cover slips, recombinant NELL1 was deposited in the extracellular matrix after detachment of cells. These results suggest that NELL1 acts as an extracellular matrix component. Recombinant NELL1 formed multimers and was glycosylated. An abundant source of functionally active NELL1 protein will be useful for more advanced studies, such as the development of novel techniques for bone regeneration. PMID- 21814728 TI - Infant with gross hematuria and nephrotic syndrome: questions. PMID- 21814730 TI - Should the ossicle be denuded prior to the application of glass ionomer cement? An experimental study on rabbit. AB - The objective of this study was to assess whether denudation of the auditory ossicle prior to the application of glass ionomer cement (GIC) durably strengthens the adhesion between bone and GIC. The tympanic bullas of 34 rabbits were opened bilaterally. The mucosa was removed from the lateral surface of the right-side incudi with a diamond burr, while the left-side incudi were left intact. GIC was then applied bilaterally to the lateral surface of the incudi of 30 of these rabbits which were subsequently killed 1, 3, 7, 14, 21, 30, 60, 90, 180 or 365 days postoperatively. The 4 sham-operated animals were killed on day 1, 7, 30 or 365. The incudi were removed and processed for histological evaluation. On exploration, the cement was visible on the incus within the tympanic bulla in all 30 GIC-treated animals. During surgical removal, the GIC was separated from the incus in 3 ears. Histological examination further revealed separation in 5 ears after processing. All 8 separations occurred in the right (not denuded) ears, and at least 60 days postoperatively. The difference between the two sides in the number of separations was significant (p < 0.05). The initial inflammatory reaction elicited by the surgical trauma to the right-side ossicles had substantially decreased by day 7. No foreign body reaction was observed and the GIC became overgrown with mucosa by day 60. In conclusion, the GIC proved biocompatible, and preliminary denudation of the ossicle resulted in stronger and more durable bone-GIC adhesion. PMID- 21814729 TI - Urinary calcium and uric acid excretion in children with vesicoureteral reflux. AB - Urolithiasis is relatively common in children, and identifiable predisposing factors for stone formation, including metabolic and structural derangements, can be established in most cases. Vesicoureteral reflux (VUR) is a common cause of kidney stone formation. The pathophysiological mechanism of urolithiasis in reflux is related to urinary tract infection and urinary stasis, both of which promote urinary crystal formation, but metabolic causes, such as crystallurias (mostly hypercalciuria), may also be involved in this process. However, few studies on urinary calcium and uric acid excretion in children with VUR have been conducted. We have studied the frequency of hypercalciuria and hyperuricosuria in children with VUR and compared the results with those from a control group. The VUR group comprised 108 children with VUR (19 boys, 89 girls; age range 3 months to 12 years), and the control group comprised 110 healthy children without any history of reflux or urinary tract infection (30 boys, 80 girls; age range 2 months to 12 years). Fasting urine was analyzed for the calcium/creatinine (Ca/Cr) and uric acid/creatinine (UA/Cr) ratios. Hypercalciuria was more frequently diagnosed in the VUR patients than in the control group (21.3 vs. 3.6%; P = 0.0001). Significant differences between the two groups were also found for the mean Ca/Cr and UA/Cr ratios (P = 0.0001 and P = 0.0001, respectively). No differences were found in the urinary Ca/Cr or UA/Cr ratios related to VUR grading or unilateral/bilateral VUR in the patient group, with the exception of those for hypercalciuria and mild VUR (P = 0.03). The association of urinary stones and microlithiasis in the VUR group was 29.6%. Our results demonstrate that the frequency of hypercalciuria and hyperuricosuria was higher in pediatric patients with VUR than in healthy children. Knowing this relationship, preventive and therapeutic interventions for stone formation in VUR could be greatly expanded. PMID- 21814731 TI - The use of internal carotid artery stenting in management of bilateral carotid body tumors. PMID- 21814732 TI - Relationship between pure tone audiometry and tone burst auditory brainstem response at low frequencies gated with Blackman window. AB - To assess the reliability of Blackman windowed tone burst auditory brainstem response (ABR) as a predictor of hearing threshold at low frequencies. Fifty-six subjects were divided in to three groups (normal hearing, conductive hearing loss, sensorineural hearing loss) after pure tone audiometry (PTA) testing. Then they underwent tone burst ABR using Blackman windowed stimuli at 0.5 kHz and 1 kHz. Results were compared with PTA threshold. Mean threshold differences between PTA and ABR ranged between 11 dB at 0.5 kHz and 14 dB at 1 kHz. ABR threshold was worse than PTA in each but 2 cases. Mean discrepancy between the two thresholds was about 20 dB in normal hearing, reducing in presence of hearing loss, without any differences in conductive and sensorineural cases. Tone burst ABR is a good predictor of hearing threshold at low frequencies, in case of suspected hearing loss. Further studies are recommended to evaluate an ipsilateral masking such as notched noise to ensure greater frequency specificity. PMID- 21814733 TI - Tularemia: a rare cause of neck mass, evaluation of 33 patients. AB - The objective of the study is to report 33 cases presenting with neck masses later diagnosed with tularemia and to raise attention to this rare zoonotic infection. A retrospective analysis of 33 patients, who were diagnosed with tularemia and treated at Erciyes University Department of Otorhinolaryngology between January 2010 and December 2010 was conducted. In conclusion, because tularemia is a rare infection, its diagnosis is frequently delayed and the symptoms of the patients may last for months without any appropriate treatment. The diagnosis of tularemia rests on clinical suspicion. For the patients, who carry risk factors for tularemia and having cervical lymphadenopathies with or without oropharyngeal symptoms and who do not response to treatment with beta lactam antibiotics, tularemia must be kept in mind. PMID- 21814734 TI - Evaluation of bacterial adherence and biofilm arrangements as new targets in treatment of chronic rhinosinusitis. AB - Several promising candidate drugs that target bacterial adherence and biofilm formation are being developed. Such hopeful drugs cannot be studied in chronic rhinosinusitis (CRS) without the evaluation of such virulence criteria in different forms of the disease with and without nasal polyposis (CRSwNP and CRSsNP). The aim of this study was to evaluate bacterial adherence, response to antibiotics and degree of accumulation of bacterial biofilms as new targets of treatment in CRSwNP and CRSsNP. Twenty CRS patients and 10 normal subjects with airway obstructing concha bullosa were prospectively enrolled in the present study. Scanning electron microscopy and cultures were performed on paranasal sinus tissue samples. Bacterial adherence tests using the tissue culture plate method were measured quantitatively. Strongly adherent bacteria were identified significantly in 6/9 (77%) cases of CRSsNP in comparison to 1/7 (14%) cases of CRSwNP. Strongly adherent bacteria that were sensitive to ciprofloxacin, vancomycin, and impenim were identified in 75% of the cultured coagulase positive staphylococci. A significant difference (P = 0.007) in the degree of accumulation of bacterial biofilms existed between the two groups. In CRSsNP, a more advanced stage of bacterial biofilms with strong bacterial adherence was observed which make them attractive targets for new drugs. In CRSwNP, lower stage bacterial biofilms with low bacterial adhesion were identified, which may help explain the low bacterial virulence in an environment of suboptimal, organizational arrangements. PMID- 21814735 TI - Inflammatory cytokines are suppressed by light-emitting diode irradiation of P. gingivalis LPS-treated human gingival fibroblasts: inflammatory cytokine changes by LED irradiation. AB - Human gingival fibroblasts (hGFs) play an important role in the inflammatory reaction to lipopolysaccharide (LPS) from P. gingivalis, which infects periodontal connective tissue. In addition, although light-emitting diode (LED) irradiation has been reported to have biostimulatory effects, including anti inflammatory activity, the pathological mechanisms of these effects are unclear. This study examined the effects of 635-nm irradiation of P. gingivalis LPS treated human gingival fibroblasts on inflammatory cytokine profiles and the mitogen-activated protein kinase (MAPK) pathway, which is involved in cytokine production. Gingival fibroblasts treated or not treated with P. gingivalis LPS were irradiated with 635-nm LED light, and cytokine profiles in the supernatant were assessed using a human inflammation antibody array. Expression of cyclooxyginase-2 (COX-2) protein and phosphorylation of extracellular signal regulated kinase (ERK 1/2), p38, and c-Jun-N-terminal kinase (JNK) were assessed by Western-blot analysis to determine the effects on the MAPK pathway, and prostaglandin E(2) (PGE(2)) in the supernatant was measured using an enzyme linked immunoassay. COX-2 protein expression and PGE(2) production were significantly increased in the LPS-treated group and decreased by LED irradiation. LPS treatment of gingival fibroblasts led to the increased release of the pro-inflammatory-related cytokines interleukin-6 (IL-6) and IL-8, whereas LED irradiation inhibited their release. Analysis of MAPK signal transduction revealed a considerable decrease in p38 phosphorylation in response to 635-nm radiation either in the presence or absence of LPS. In addition, 635-nm LED irradiation significantly promoted JNK phosphorylation in the presence of LPS. LED irradiation can inhibit activation of pro-inflammatory cytokines, mediate the MAPK signaling pathway, and may be clinically useful as an anti-inflammatory tool. PMID- 21814737 TI - The utility of recovery biopsies in determining donor suitability. AB - Tissue recovery personnel often find themselves in a situation in which, upon donor physical assessment, they discover an unusual or suspicious skin or tissue lesion. Because of the concern about the possibility of recovering tissues from a donor who may have an occult malignancy or infection, the Recovery Team may elect not to recover. Otherwise they may continue with the recovery, documenting their concern on the physical assessment form. At the time of evaluation of donor suitability the Medical Director must determine what the lesion is. This is inherently difficult and sometimes has led to the discard of recovered tissues. In order to optimize the gift of donation and avoid unnecessary deferral or discard of tissues we instituted a recovery biopsy procedure several years ago. Between January, 2005 and March, 2010, 561 biopsies were performed. In 552 donors (98.4%) there was no negative effect on medical suitability. Nine donors (1.6%) were found unsuitable based on the biopsy results. The recovery biopsy has allowed Recovery Teams to better manage their time by quickly identifying and biopsying suspicious lesions without trying to make a determination of donor eligibility and possibly ruling ineligible a qualified donor. The recovery biopsy has allowed the Medical Directors to make suitability decisions to accept or reject based on diagnostic certainty. PMID- 21814736 TI - Red (660 nm) and infrared (830 nm) low-level laser therapy in skeletal muscle fatigue in humans: what is better? AB - In animal and clinical trials low-level laser therapy (LLLT) using red, infrared and mixed wavelengths has been shown to delay the development of skeletal muscle fatigue. However, the parameters employed in these studies do not allow a conclusion as to which wavelength range is better in delaying the development of skeletal muscle fatigue. With this perspective in mind, we compared the effects of red and infrared LLLT on skeletal muscle fatigue. A randomized double-blind placebo-controlled crossover trial was performed in ten healthy male volunteers. They were treated with active red LLLT, active infrared LLLT (660 or 830 nm, 50 mW, 17.85 W/cm(2), 100 s irradiation per point, 5 J, 1,785 J/cm(2) at each point irradiated, total 20 J irradiated per muscle) or an identical placebo LLLT at four points of the biceps brachii muscle for 3 min before exercise (voluntary isometric elbow flexion for 60 s). The mean peak force was significantly greater (p < 0.05) following red (12.14%) and infrared LLLT (14.49%) than following placebo LLLT, and the mean average force was also significantly greater (p < 0.05) following red (13.09%) and infrared LLLT (13.24%) than following placebo LLLT. There were no significant differences in mean average force or mean peak force between red and infrared LLLT. We conclude that both red than infrared LLLT are effective in delaying the development skeletal muscle fatigue and in enhancement of skeletal muscle performance. Further studies are needed to identify the specific mechanisms through which each wavelength acts. PMID- 21814739 TI - Bone fragility and decline in stem cells in prematurely aging DNA repair deficient trichothiodystrophy mice. AB - Trichothiodystrophy (TTD) is a rare, autosomal recessive nucleotide excision repair (NER) disorder caused by mutations in components of the dual functional NER/basal transcription factor TFIIH. TTD mice, carrying a patient-based point mutation in the Xpd gene, strikingly resemble many features of the human syndrome and exhibit signs of premature aging. To examine to which extent TTD mice resemble the normal process of aging, we thoroughly investigated the bone phenotype. Here, we show that female TTD mice exhibit accelerated bone aging from 39 weeks onwards as well as lack of periosteal apposition leading to reduced bone strength. Before 39 weeks have passed, bones of wild-type and TTD mice are identical excluding a developmental defect. Albeit that bone formation is decreased, osteoblasts in TTD mice retain bone-forming capacity as in vivo PTH treatment leads to increased cortical thickness. In vitro bone marrow cell cultures showed that TTD osteoprogenitors retain the capacity to differentiate into osteoblasts. However, after 13 weeks of age TTD females show decreased bone nodule formation. No increase in bone resorption or the number of osteoclasts was detected. In conclusion, TTD mice show premature bone aging, which is preceded by a decrease in mesenchymal stem cells/osteoprogenitors and a change in systemic factors, identifying DNA damage and repair as key determinants for bone fragility by influencing osteogenesis and bone metabolism. PMID- 21814741 TI - Effects of social exclusion on depressive symptoms: elderly Chinese living alone in Shanghai, China. AB - Research has identified social exclusion as one of the social determinants of health. There are risks of social exclusion in later life in recent years. However, despite the fact that China has the largest aging population in the world and reports a rapid growth in the proportion of older people living alone, research on the role of social exclusion on depression is limited. This study examined the effects of social exclusion on depressive symptoms in older Chinese who are living alone in China, based on the data from one Shanghai neighbourhood. The data used were obtained between August and October 2008 through face-to-face interviews, using a structured survey questionnaire, from a simple random sample of 228 Chinese 60 and older living alone in a Shanghai community. Depressive symptoms were measured by a 15-item Chinese version Geriatric Depression Scale. Social exclusion was represented by income adequacy, social relations, civic participation, and housing condition. Over 30% of participants reported symptoms of a mild or above mild level of depression. When controlled for the demographics and health variables in hierarchical multiple regression, social exclusion variables, represented by a lower level income adequacy, a less favourable housing condition, and feeling more lonely correlated significantly with more depressive symptoms. Contrary to previous studies on depression in the older adults in China, this study has obtained findings indicating that social exclusion variables are more important than other socio-demographic factors in the context of contemporary China. While two significant social exclusion variables (i.e. income and housing) are related to structural changes in the economic context in China, the intra-personal role of feeling lonely that ties strongly living alone and role of older adults in an increasingly competitive market economy should not be underestimated. To address depression and mental health of older Chinese who live alone, social policies and programs to reduce various forms of social exclusion should be developed. In additional to providing assistance in financial support and housing improvement, services to strengthen the social networks and social relations of these older people are essential. PMID- 21814743 TI - [Impedance pH monitoring: key to understanding effects and side-effects of fundoplication?]. PMID- 21814740 TI - Advanced penile cancer. AB - Penile cancer is an uncommon disease in the industrialized world that most frequently presents at low stage and is cured with treatment of local and regional surgery. In cases of advanced cancer, the use of more aggressive surgical techniques and the addition of adjuvant therapy may be warranted. So far, few agents have been found that improve survival with metastatic disease and thus aggressive primary treatment is required. This review discusses diagnosis, staging, and therapy for high risk penile cancer. PMID- 21814744 TI - [Report on notifications according to Section 8d of the German Transplantation Act (TPG) for the year 2008]. AB - In Germany, the tissue law came into effect on 1 August 2007. The law implemented the requirements of EC directives on quality and safety of human tissues and cells in the German Transplantation Act ("Transplantationsgesetz," TPG) and in the German Medicinal Products Act. Accordingly, tissue establishments are obligated to keep a record of their activities and to submit an annual report to the Paul-Ehrlich-Institut (PEI). The report shall include the types and quantities of tissues procured, conditioned, processed, stored, and distributed, or otherwise disposed of, imported and exported. For this purpose, the PEI published TPG-based notification forms in the Bundesanzeiger and in the Internet. The data provided by tissue establishments have been anonymized and compiled in a general report. The analysis revealed inconclusive data, which can be due to a number of different causes. To achieve better consistency of data provided in the future, the explanations for completing the notification forms will be amended. Thus far, compiled data are not appropriate to draw conclusions on the availability of tissues and tissue preparations in Germany, but the data can serve as reference points. PMID- 21814745 TI - Neck Pain and Disability Scale and Neck Disability Index: validity of Dutch language versions. AB - PURPOSE: To investigate the validity of the Neck Pain and Disability Scale Dutch Language Version (NPAD-DLV) and the Neck Disability Index (NDI)-DLV. METHODS: NPAD-DLV, NDI-DLV, Short-Form-36 Health Survey (SF-36)-DLV, visual analog scale (VAS)(pain) and VAS(disability) were administered to 112 patients with non specific chronic neck pain in an outpatient tertiary rehabilitation setting. Twenty seven hypotheses were formulated regarding validity. NPAD-DLV and NDI-DLV were evaluated for content validity (normal distribution total scores, missing items, floor and ceiling effects), internal consistency (Cronbach's alpha and Spearman Item-total correlations), construct validity (Pearson correlations with SF-36 domains, VAS(pain) and VAS(disability) and Pearson correlation between total scores of NPAD-DLV and NDI-DLV). RESULTS: NPAD-DLV and NDI-DLV scores were distributed normally. Missing items were negligible. Floor and ceiling effects were absent in NPAD-DLV and in NDI-DLV two items had floor effects and one item had a ceiling effect. Cronbach's alpha of NPAD-DLV was 0.93 and of NDI-DLV 0.83. Item-total correlations ranged for NPAD-DLV from 0.45 to 0.73 and for NDI-DLV from 0.40 to 0.64. The correlation between, respectively, NPAD-DLV and NDI-DLV and: SF-36 domains ranged from -0.36 to -0.70 and from -0.34 to -0.63; VAS(pain) was 0.54 and 0.43; VAS(disability) was 0.57 and 0.52. The correlation between the total scores of NPAD-DLV and NDI-DLV was 0.77. Twenty six hypotheses were not rejected and one hypothesis was rejected. CONCLUSION: The NPAD-DLV and NDI-DLV are valid measures of self-reported neck-pain related disability. PMID- 21814746 TI - A painful tic convulsif due to double neurovascular impingement. AB - Here we present the case of a 50-year-old man suffering from "painful tic convulsif", on the left side of the face, i.e., left trigeminal neuralgia associated with ipsilateral hemifacial spasm. An angio-MRI scan showed a neurovascular confliction of left superior cerebellar artery with the ipsilateral V cranial nerve and of the left inferior cerebellar artery with the ipsilateral VII cranial nerve. Neurophysiological evaluation through esteroceptive blink reflex showed the involvement of left facial nerve. An initial carbamazepine treatment (800 mg/daily) was completely ineffective, so the patient was shifted to lamotrigine 50 b.i.d. that was able to reduce attacks from 4 to 6 times per day to 1 to 2 per week. Considering the good response to the drug, the neurosurgeon decided to delay surgical treatment. PMID- 21814747 TI - The tamoxifen metabolite norendoxifen is a potent and selective inhibitor of aromatase (CYP19) and a potential lead compound for novel therapeutic agents. AB - To improve the treatment of breast cancer, there has been a need for alternative aromatase inhibitors (AIs) that bring about adequate aromatase inhibition, while limiting side effects. Since two tamoxifen metabolites have been documented as AIs, we tested a wide range of tamoxifen metabolites on aromatase in order to better understand structural interactions with aromatase and constructed structure-function relationships as a first step toward the development of novel inhibitors. The ability of ten tamoxifen metabolites to inhibit recombinant aromatase (CYP19) was tested using microsomal incubations. The selectivity of the most potent aromatase inhibitor identified, norendoxifen, was characterized by studying its ability to inhibit CYP450 enzymes important in clinical drug-drug interactions, including CYP2B6, 2C9, 2C19, 2D6, and 3A. Computerized molecular docking with the X-ray crystallographic structure of aromatase was used to describe the detailed biochemical interactions involved. The inhibitory potency order of the tested compounds was as follows: norendoxifen ? 4,4'-dihydroxy tamoxifen > endoxifen > N-desmethyl-tamoxifen, N-desmethyl-4'-hydroxy-tamoxifen, tamoxifen-N-oxide, 4'-hydroxy-tamoxifen, N-desmethyl-droloxifene > 4-hydroxy tamoxifen, tamoxifen. Norendoxifen inhibited recombinant aromatase via a competitive mechanism with a K ( i ) of 35 nM. Norendoxifen inhibited placental aromatase with an IC(50) of 90 nM, while it inhibited human liver CYP2C9 and CYP3A with IC(50) values of 990 and 908 nM, respectively. Inhibition of human liver CYP2C19 by norendoxifen appeared even weaker. No substantial inhibition of CYP2B6 and CYP2D6 by norendoxifen was observed. These data suggest that multiple metabolites of tamoxifen may contribute to its action in the treatment of breast cancer via aromatase inhibition. Most of all, norendoxifen may be able to serve as a potent and selective lead compound in the development of improved therapeutic agents. The range of structures tested in this study and their pharmacologic potencies provide a reasonable pharmacophore upon which to build novel AIs. PMID- 21814749 TI - A diagnostic gene profile for molecular subtyping of breast cancer associated with treatment response. AB - Classification of breast cancer into molecular subtypes maybe important for the proper selection of therapy, as tumors with seemingly similar histopathological features can have strikingly different clinical outcomes. Herein, we report the development of a molecular subtyping profile (BluePrint), that enables rationalization in patient selection for either chemotherapy or endocrine therapy prescription. An 80-Gene Molecular Subtyping Profile (BluePrint) was developed using 200 breast cancer patient specimens and confirmed on four independent validation cohorts (n = 784). Additionally, the profile was tested as a predictor of chemotherapy response in 133 breast cancer patients, treated with T/FAC neoadjuvant chemotherapy. BluePrint classification of a patient cohort that was treated with neoadjuvant chemotherapy (n = 133) shows improved distribution of pathological Complete Response (pCR), among molecular subgroups compared with local pathology: 56% of the patients had a pCR in the Basal-type subgroup, 3% in the MammaPrint Low-risk, Luminal-type subgroup, 11% in the MammaPrint High-risk, Luminal-type subgroup, and 50% in the HER2-type subgroup. The group of genes identifying Luminal-type breast cancer is highly enriched for genes having an Estrogen Receptor binding site proximal to the promoter-region, suggesting that these genes are direct targets of the Estrogen Receptor. Implementation of this profile may improve the clinical management of breast cancer patients, by enabling the selection of patients who are most likely to benefit from either chemotherapy or from endocrine therapy. PMID- 21814748 TI - Identification of the receptor tyrosine kinase AXL in breast cancer as a target for the human miR-34a microRNA. AB - The identification of molecular features that contribute to the progression of breast cancer can provide valuable insight into the pathogenesis of this disease. Deregulated microRNA expression represents one type of molecular event that has been associated with many different human cancers. In order to identify a miRNA/mRNA regulatory interaction that is biologically relevant to the triple negative breast cancer genotype/phenotype, we initially conducted a miRNA profiling experiment to detect differentially expressed miRNAs in cell line models representing triple-negative (MDA-MB-231), ER(+) (MCF7), and HER-2 overexpressed (SK-BR-3) histotypes. We identified human miR-34a expression as being >3-fold down (from its median expression value across all cell lines) in MDA-MB-231 cells, and identified AXL as a putative mRNA target using multiple miRNA/target prediction algorithms. The miR-34a/AXL interaction was functionally characterized through ectopic overexpression experiments with a miR-34a mimic in two independent triple-negative breast cancer cell lines. In reporter assays, miR 34a binds to its putative target site within the AXL 3'UTR to inhibit luciferase expression. We also observed degradation of AXL mRNA and decreased AXL protein levels, as well as cell signaling effects on AKT phosphorylation and phenotypic effects on cell migration. Finally, we present an inverse correlative trend in miR-34a and AXL expression for both cell line and patient tumor samples. PMID- 21814750 TI - Prevalence and antimicrobial resistance profiles of Salmonella enterica serovars isolated from slaughtered cattle in Bahir Dar, Ethiopia. AB - A study was undertaken from October 2006 to March 2007 to determine the prevalence and antimicrobial resistance patterns of Salmonella serovars. Liver, mesenteric lymph nodes, intestinal content, and carcass swab samples (each n = 186) were collected from 186 apparently healthy slaughtered cattle at Bahir Dar abattoir. Bacteriological analysis was done according to the International Organization for Standardization (ISO 6579 2002). Isolates were serotyped at Agence Francaise de Securite Sanitaire des Aliments, Cedex, France. Twenty-eight isolates consisting of Salmonella Typhimurium, Salmonella Newport, Salmonella Haifa, Salmonella Heidelberg, Salmonella Infantis, and Salmonella Mishmarhaemek were identified. Salmonella Typhimurium and Salmonella Newport were most frequently isolated while Salmonella Heidelberg and Salmonella Mishmarhaemek were isolated least. Eleven of the 28 (39.3%) were resistant to one or more of the antimicrobials tested. Resistance was shown to ampicillin, chloramphenicol, gentamycin, norfloxacin, polymyxin-B, streptomycin, tetracycline, and trimethoprim. Four of 11 (36.4%) were multiple antimicrobial resistant. All the isolates tested were susceptible to the antimicrobial effects of gentamycin, norfloxacin, and trimethoprim. Eleven, four, and two isolates of the 28 were resistant to streptomycin, tetracycline, and ampicillin, respectively. All isolates of Salmonella Infantis, Salmonella Typhimurium (except one), and Salmonella Mishmarhaemek were susceptible to the tested antimicrobials. One Typhimurium isolate was resistant to chloramphenicol, streptomycin, and tetracycline. Salmonella Haifa was multiply antimicrobial resistant to ampicillin, tetracycline, and streptomycin. All isolates of Salmonella Heidelberg were resistant to streptomycin. Results of this study indicated high level of carcass contamination with antimicrobial-resistant Salmonella serovars which could pose public health risk; suggests need for hygienic slaughtering operations and proper cooking of meat before consumption. Further detailed studies involving different abattoirs, animal products, food items, and animals on different settings were recommended in the study area. PMID- 21814751 TI - Prevalence of subclinical coccidiosis in broiler farms in Turkey. AB - The presence of Eimeria spp. oocysts in fecal samples collected from 1,108 broiler houses in six regions, representing about 12% of all broiler farms in Turkey, was studied using the modified McMaster method. The age of the chickens in the 1,108 pens varied from 1 to 50 days. Oocysts were found in 602 (54.3%) of these broiler houses, and the mean OPG (oocysts per gram of feces) in those samples was 36,498.7 (50-952,000). No indication of clinical coccidiosis or other clinically evident infection or wide mortality was encountered in any of the pens studied. Further study showed that the age of the chickens, the occurrence of diarrhea on the houses and the density of broiler breeding in the area correlated with subclinical coccidiosis prevalence. PMID- 21814752 TI - Economic impact of Przhevalskiana silenus infestation in native goats of Northern India. AB - Economic losses incurred by Przhevalskiana silenus in goats of Jammu province of Jammu and Kashmir (North India) were assessed from July 2005 to June 2006. Abattoir studies revealed holes in hides for 112 days (mid-December 2005 to first week of April 2006) and trimming of carcass for 243 days (July 2005 to February 2006) during a lifecycle, leading to annual losses of Rs. 7,391,432 and Rs. 10,510,837, respectively. An effect on production traits (weight gain and milk) was assessed on naturally P. silenus-infested Beetal goats. The mean body weight loss of warbled goats was 2.40 kg (equal to 1.096 kg of meat, assuming 45.7% dressing percentage of goat) leading to an annual loss of Rs. 35,473,265. The mean milk yield loss per warbled goat per day was 101.7 g resulting in losses to the tune of Rs. 19,879,012. It can be concluded that P. silenus infestation resulted in an overall loss of Rs. 73,254,547, i.e. 73.26 million annually (equivalent to US $1.62 million; US $1 = Rs. 45.24), where reduced growth alone contributed 49% of the total losses. A study recommends that a control scheme against P. silenus infestation in goats using an effective insecticide should be followed to prevent huge economic losses in hide, milk and meat production. Economic losses associated with P. silenus infestation in goats were estimated for the first time from India. PMID- 21814753 TI - Ultrasound imaging of carotid intima-media thickness: an office-based tool to assist physicians in cardiovascular risk assessment. AB - Traditional coronary heart disease risk prediction schemes such as the Framingham Risk Score, although useful, do not adequately identify all individuals who experience an adverse coronary heart disease event. Therefore, additional tools, including biomarkers, genetic markers, and imaging markers, are being evaluated for their value in improving cardiovascular risk assessment. Of the two accepted imaging markers of atherosclerosis, namely coronary artery calcium score (CACS) measured by CT scan and carotid intima-media thickness (CIMT) measured by ultrasound, CIMT has the potential to be widely adopted as a clinical tool for physician offices. Ultrasound-based CIMT measurement is safe but has several challenges, including reproducibility and operator-dependency. We review and present data with respect to the added value of CIMT and information about plaque presence or absence in improving coronary heart disease risk prediction and further provide information related to adequate scanning protocols. New developments in the area of automated CIMT measurement, three-dimensional, ultrasound-based plaque volume estimation are promising and have the potential to create a quantum leap in our ability to measure, characterize, and monitor carotid atherosclerosis and in turn prediction of cardiovascular disease risk. PMID- 21814754 TI - Rheumatoid factor and antibodies against citrullinated peptides in Moroccan patients with rheumatoid arthritis: association with disease parameters and quality of life. AB - We aimed to evaluate the immunological status and its relationships with disease related parameters of activity, severity and quality of life in Moroccan patients with rheumatoid arthritis (RA). Two hundred forty-five consecutive patients with RA were recruited. The following data were collected: demographic characteristics, disease duration (years), disease activity (evaluated by the disease activity score, DAS28), structural damage (evaluated by Sharp's method as modified by van der Heijde), functional disability (assessed by using the Moroccan version of the Health Assessment Questionnaire, HAQ) and quality of life (by using the Arabic version of the Medical Outcomes Study Short Form 36 Health Survey: the SF-36). Immunological status (rheumatoid factor rate, RF) and antibodies against citrullinated peptides rate (ACPAs) by the Elisa method were examined. ACPAs were detected in 75.1% of patients with a mean rate of 79.2 +/- 43.8 UI. RF was detected in 80.8% of patients with a mean rate of 80.1 +/- 50.6 UI. Patients with positive RF and ACPAs had higher disease activity, impaired functional ability, severe structural damage, more ocular symptoms and altered aspects of quality of life. In univariate analysis, higher levels of ACPAs were significantly correlated with the age at onset (r = 0.307), disease duration (r = 0.520), disease activity (DAS28) (r = 0.531), Sharp score (r = 0.431), and with the deterioration of all domains of SF-36 (for all p <= 0.01). RF levels were correlated with disease duration (r = 0.517), disease activity (r = 0.470), functional disability (r = 0.521), and the alteration of physical domains of SF 36 (for all p <= 0.01). In multivariate analysis, the main factors associated to ACPAs and RF levels were functional disability, structural damage and impaired QoL. Furthermore, using the SF-36 scores as dependent variables, the impairment of physical domains and the domain of vitality were significantly associated with ACPA levels while the decrease of the domain of physical function was associated with the level of RF. Our study suggests that the presence and the levels of ACPAs and RF in our RA patients are associated with more active disease, more severe joint damage, worst functional disability and altered aspects of quality of life. PMID- 21814755 TI - Re-evaluation of 129 patients with systemic necrotizing vasculitides by using classification algorithm according to consensus methodology. AB - Recently, a new classification algorithm (CA) for systemic necrotizing vasculitides was proposed by Watts et al. (Annals Rheum Dis 66:222-227, 2007) by using the American College of Rheumatology (ACR), Chapel Hill Consensus Criteria (CHCC) and Sorensen surrogate markers (So). We aimed to validate CA in our patients. One hundred twenty-nine patients followed up in our vasculitis clinic were reclassified according to CA in different categories (ACR or Lanham criteria in "1" for Churg-Strauss Syndrome (CSS); ACR in "2a"; CHCC-Wegener's granulomatosis (WG) in "2b"; CHCC-microscopic polyangiitis (MPA), So-WG in "2c"; So-WG, proteinase 3 (PR3) or myeloperoxidase antineutrophil cytoplasmic antibody (MPO ANCA) serology in "2d" for WG; clinical features and histology compatible with small vessel vasculitis without So-WG in "3a"; So-MPA, PR3 or MPO ANCA serology in "3b" for MPA; CHCC-classic-polyarteritis nodosa (c-PAN) or typical angiographic features in "4" for c-PAN; unclassifiable in "5"). Kappa statistic was used to analyse the agreement of the criteria that formed the algorithm. All of 12 CSS, 91% of 69 WG, 78% of 18 MPA and 93% of 26 c-PAN patients remained in their previous diagnosis. WG patients were placed in 2a (83%), 2c (3%), 2d (14%) categories. Four WG (6%) and four MPA (22%) patients were categorized as MPA (in 3a (75%), 3b (25%)) and WG (in 2c (75%), 2d (25%)), respectively. Three of four unclassified patients could be classified as c-PAN (two) and MPA (one). Significant agreement was demonstrated only for ACR and So criteria in WG (kappa = 0.62, p < 0.001). The majority of our patients stayed on their previous diagnosis in "CA". Our findings suggest that this algorithm is helpful and practical for epidemiological studies. Poor correlation of defined criteria was thought to be related to the fact that each criteria mainly consist of different characteristics of vasculitides such as clinical, histopathological and serological features. PMID- 21814756 TI - Highly accelerated PSF-mapping for EPI distortion correction with improved fidelity. AB - OBJECTIVE: This study presents an improved point-spread-function (PSF) mapping based distortion correction method and accelerated PSF acquisition for distortion correction in EPI without loss of quality or reliability compared to full encoding. MATERIALS AND METHODS: To correct geometric distortions accurately, the PSF in the EPI phase-encoding coordinates (EPI-PSF) was measured and used as a kernel for distortion correction. FOV reduction was applied in the PSF mapping dimension for highly accelerated PSF acquisition. A novel approach for fold-over artifact correction in this reduced dimension is introduced. Conventional gradient-echo EPI and corresponding full PSF reference data were acquired in phantoms and in human brain at 7 T. The distortion corrected EPI data with the proposed acceleration were compared to result with full encoding. Previously published interpolation methods based on shift maps, non-uniform Fourier transformation and a b-spline interpolation were compared with the proposed method. RESULTS: The results demonstrate that the proposed method corrects geometric distortions in EPI with high accuracy and quality despite the high acceleration. In contrast to partial parallel imaging acceleration, no noise enhancement is introduced. CONCLUSION: The proposed EPI-PSF-based distortion correction improves correction of EPI and accelerates PSF reference data acquisition and computation. PMID- 21814757 TI - Stripline resonator and preamplifier for preclinical magnetic resonance imaging at 4.7 T. AB - OBJECT: To design and evaluate a fully shielded, lambda/4 stripline resonator as a receive-only surface coil for preclinical MRI at 4.7 T. MATERIALS AND METHODS: A 20 mm diameter stripline surface coil was fabricated from double-sided Duroid 5880 PCB material and was directly coupled to the input of a MOSFET preamplifier, without requiring a matching network. The new coil was compared with a conventional 20 mm, wire loop, receive-only surface coil in imaging experiments with a separate transmit-only saddle coil. RESULTS: The stripline surface coil exhibits a loaded Q-factor of 132 at 200 MHz, compared to 138 for a conventional wire loop coil and its resonant frequency drops by 0.2 MHz under loading, rather than 0.5 MHz for the wire loop. The stripline coil displays a more symmetrical B1 map compared to the wire loop, but the SNR falls off more rapidly with depth so it is 30% poorer 8 mm from the coil plane. It should be possible, however, to reduce this difference by using a thicker dielectric in future versions of the stripline coil. CONCLUSION: Compared to a conventional surface coil, the stripline coil is easy to manufacture, requires shorter set-up times and shows reduced dielectric interaction with conductive samples. PMID- 21814758 TI - Validation of the MicroScan-96 for the species identification and methicillin susceptibility testing of clinical significant coagulase-negative staphylococci. AB - An automated system, MicroScan WalkAway-96, in conjugation with Combo Pos(r) 28 panels, was validated for the identification and methicillin susceptibility of coagulase-negative staphylococci (CNS). The performance of this system was evaluated on 428 CNS. Identification results were compared using a validated in house method. Methicillin susceptibility was compared with oxacillin MIC testing and the presence of the mecA gene by PCR (in-house real-time method). The MicroScan system correctly identified 94.6% of the staphylococci (405 out of 428). 3.5% of the strains (15 out of 428) were not correctly identified. 1.9% of the isolates (8 out of 428) were correctly identified with a low probability. Identification of Staphylococcus warneri and Staphylococcus lugdunensis was determined with the least accuracy. Microscan combines both oxacillin and cefoxitin for determination of the methicillin susceptibility result. Correlation between this result and the mecA method was 97.6%. Correlation with the oxacillin MIC method was also 97.6%. Fourteen isolates showed a discrepant result, 8 were reported to be resistant in mecA-negative strains, 2 were reported false susceptible in mecA positive strains and 4 strains showed a discrepant result with oxacillin MIC, but not with mecA determination. The automated system can be considered a simple and reliable method for identification and methicillin susceptibility of CNS. PMID- 21814759 TI - When the resistance gets clingy: Pseudomonas aeruginosa harboring metallo-beta lactamase gene shows high ability to produce biofilm. AB - The ability to produce biofilm and the presence of metallo-beta-lactamase (MBL) among Pseudomonas aeruginosa isolates were evaluated. A total of 91 isolates were recovered from sputa of patients with (CF, n = 44) and without (non-CF, n = 47) cystic fibrosis diagnosis. Seventy-nine (86.8%; 95% CI 78.3-92.3%) were biofilm producers. Interestingly, all isolates harboring MBL showed ability (most strong or moderate) to produce biofilm in vitro. We alert to an "overlapping of mechanisms" that together represent an even greater challenge for the treatment of pulmonary infections by P. aeruginosa. PMID- 21814760 TI - Gastrointestinal colonization with ESBL-producing Klebsiella in preterm babies- is vancomycin to blame? AB - In this study, we examine the possible association between treatment with vancomycin and colonization with extended-spectrum beta-lactamase (ESBL) producing Klebsiella in our neonatal intensive care unit (NICU). Variables compared between newborns which developed rectal colonization and those who did not include: gestational age, birth weight, gender, and total length of hospital stay until positive stool culture or discharge, treatment with vancomycin, and positive blood culture for coagulase-negative Staphylococcus. We found that lower birth weight, younger gestational age, and treatment with vancomycin were statistically significant risk factors for gastrointestinal colonization with ESBL-producing Klebsiella. When applying a multivariate model, treatment with vancomycin, both for a full 10-day course and for a short 3-day empirical treatment, remained statistically significant. Treatment with vancomycin is a risk factor for gastrointestinal colonization with ESBL-producing Klebsiella in premature babies. PMID- 21814761 TI - Intraductal Hepatocellular Carcinoma without Parenchymal Tumor: A Case Report. AB - INTRODUCTION: Obstructive jaundice due to hepatocellular carcinoma is rare. We present a case of hepatocellular carcinoma presenting as an intraductal tumor, which was clinically and radiologically diagnosed as cholangiocarcinoma. CLINICAL PRESENTATION: A 59-year-old male was admitted with recurrent episodes of jaundice. He was found to have a tumor in the right hepatic duct extending into intrahepatic ducts, which was clinically and radiologically diagnosed as cholangiocarcinoma. RESULTS: The patient underwent right hepatectomy with excision of the bile duct and left hepaticojejunostomy. Histological examination revealed an intraductal moderately differentiated hepatocellular carcinoma. The rest of the liver parenchyma showed features secondary to biliary obstruction but no tumor. CONCLUSION: A case of hepatocellular carcinoma presenting as an intraductal tumor with obstructive jaundice and no evidence of parenchymal tumor is presented. PMID- 21814762 TI - Evaluation of fluorescent phosphatidylserine substrates for the aminophospholipid flippase in mammalian cells. AB - A series of fluorescent phosphatidylserine and phosphatidylcholine derivatives were prepared and evaluated by cell microscopy for ability to translocate across mammalian plasma membranes via the putative aminophospholipid flippase. Phosphatidylserine derivatives, with either a neutral 7-nitrobenz-2-oxa-1,3 diazol-4-yl (NBD) or a coumarin fluorophore appended to the 2-acyl chain, entered the cytosol of all three cell lines tested and control experiments showed that the translocation was due to flippase activity. In contrast, a phosphatidylserine conjugate containing a charged and polar carboxyfluorescein was not translocated and remained in the cell plasma membrane. The phosphatidylserine-coumarin derivative exhibits bright fluorescence and higher photostability than the NBD analogues, and thus is a promising new fluorescent probe for extended-imaging studies of flippase action in living cells using laser confocal microscopes. PMID- 21814763 TI - Simultaneous suppression of TGF-beta and ERK signaling contributes to the highly efficient and reproducible generation of mouse embryonic stem cells from previously considered refractory and non-permissive strains. AB - Mouse embryonic stem cells (ESCs) are pluripotent stem cell lines derived from pre-implantation embryos. The efficiency of mESC generation is affected by genetic variation in mice; that is, some mouse strains are refractory or non permissive to ESC establishment. Developing an efficient method to derive mESCs from strains of various genetic backgrounds should be valuable for establishment of ESCs in various mammalian species. In the present study, we identified dual inhibition of TGF-beta and ERK1/2, by SB431542 and PD0325901, respectively led to the highly efficient and reproducible generation of mESC lines from NMRI, C57BL/6, BALB/c, DBA/2, and FVB/N strains, which previously considered refractory or non-permissive for ESC establishment. These mESCs expressed pluripotency markers and retained the capacity to differentiate into derivatives of all three germ layers. The evaluated lines exhibited high rates of chimerism when reintroduced into blastocysts. To our knowledge, this is the first report of efficient (100%) mESC lines generation from different genetic backgrounds. The application of these two inhibitors will not only solve the problems of mESC derivation but also clarifies new signaling pathways in pluripotent mESCs. PMID- 21814764 TI - Pseudoaneurysm of the peroneal artery: an unusual complication of open docking site procedure in bone transport with Taylor Spatial Frame. AB - A docking site is the terminus of travel of two segments of bone that are gradually brought into approximation, normally associated with the bone transport technique in limb reconstruction. Traumatic pseudoaneurysm of the peroneal artery have been reported following different types of trauma and orthopedic procedures performed in the distal leg. One uncommon case of delayed peroneal artery pseudoaneurysm following surgical docking site is described. The diagnosis was supported by angiography. Embolization with coil was a successful method of treatment. We recommend a safe method of osteotomy with good bone exposure and adequate soft tissue protection. PMID- 21814765 TI - Intracortical chondromyxoid fibroma of the tibia. AB - Intracortical chondromyxoid fibroma is an extremely rare benign neoplasm of cartilaginous origin that usually occurs as an eccentric lesion at the medullar metaphyseal region of long bones. We report the clinicoradiologic aspect of a new case located in the metaphyseal region of the upper tibia and discuss about the differential diagnosis. PMID- 21814767 TI - Assignments of backbone 1H, 13C and 15N resonances in H-Ras (1-166) complexed with GppNHp at physiological pH. AB - The small GTPase Ras is an important signaling molecule acting as a molecular switch in eukaryotic cells. Recent findings of global conformational exchange and a putative allosteric binding site in the G domain of Ras opened an avenue to understanding novel aspects of Ras function. To facilitate detailed NMR studies of Ras in physiological solution conditions, we performed backbone resonance assignments of Ras bound to slowly hydrolysable GTP mimic, guanosine 5'-[beta, gamma-imido]triphosphate at pH 7.2. Out of 163 non-proline residues of the G domain, signals from backbone amide proton, nitrogen and carbon spins of 127 residues were confidently assigned with the remaining unassigned residues mostly located at the exchange-broadened effectors interface. PMID- 21814766 TI - Resonance assignments and secondary structure of a phytocystatin from Ananas comosus. AB - A cDNA encoding a cysteine protease inhibitor, cystatin was cloned from pineapple (Ananas comosus L.) stem. This clone was constructed into an expression vector and expressed in E. coli and purified to homogeneous. The recombinant pineapple cystatins (AcCYS) showed effectively inhibitory activity toward cysteine proteases including papain, bromelain, and cathepsin B. In order to unravel its inhibitory action from structural point of view, multidimensional heteronuclear NMR techniques were used to characterize the structure of AcCYS. The full (1)H, (15)N, and (13)C resonance assignments of AcCYS were determined. The secondary structure of AcCYS was identified by using the assigned chemical shift of (1)Halpha, (13)Calpha, (13)Cbeta, and (13)CO through the consensus chemical shift index (CSI). The results of CSI analysis suggest 5 beta-strands (residues 45-47, 84-91, 94-104, 106-117, and 123-130) and one alpha-helix (residues 55-73). PMID- 21814768 TI - Recent insights into the pathobiology of innate immune deficiencies. AB - Primary immunodeficiencies are a heterogeneous group of genetically inherited diseases affecting the innate and adaptive immune systems that confer susceptibility to infection, autoimmunity, and cancer. Innate immunity includes neutrophils, macrophages, dendritic cells, natural killer cells, and natural killer T cells in conjunction with natural barriers (mostly skin and gastrointestinal and respiratory mucosa), as well as antimicrobial agents, opsonins (e.g., complement), and cytokines. Although somewhat primitive, innate immune cells can orchestrate discrete immune responses through the recognition of diverse pathogens by different pattern-recognition receptors. In this review, we discuss the most recent discoveries as well as the already established pathophysiologic mechanisms underlying innate immunity defects associated with primary immunodeficiencies. PMID- 21814769 TI - Efficiency of percutaneous nephrolithotomy in pediatric patients using adult-type instruments. AB - To evaluate the efficiency of percutaneous nephrolithotomy using adult-type instruments in children with kidney stones. Between September 2004 and October 2009, 18 children (19 renal units) underwent percutaneous nephrolithotomy using adult-type instruments. Following percutaneous access under fluoroscopy, 20-30F tract dilatation was performed (1,92,427F), and lithotripters were used. Postoperatively, kidney-ureter-bladder X-ray and antegrade pyelography were performed to evaluate residual stones and contrast passage to the bladder. 8 boys and 10 girls with a mean age of 9.8 +/- 4.56 years were evaluated. Mean stone burden was 338 +/- 196.21 mm2. Stones were located in the left and right kidneys in 16 (84.2%) and 3 (16.8%) patients, respectively. Horse-shoe kidney was present in one patient. Mean operation (including cystoscopy) and fluoroscopy times were 106 +/- 49.60 and 5.2 +/- 2.14 min, respectively. Postoperatively, 10(52.6%) patients were stone free and 4 (21.1%) patients had clinically insignificant stones. Saline extravasation developed in three patients and surgery was aborted in one patient. Stone fragments migrated into the ureter in two patients and managed by additional endourological interventions. Nephrostomy catheters were kept for a mean of 2.6 +/- 1.12 days. Four patients required blood transfusion due to bleeding. Postoperative fever of <39 degrees C developed in five patients and >39 degrees C in one patient. Mean hospitalization time was 5.3 +/- 3.12 days. Overall, 73.7% of our patients were stone free, including patients with clinically insignificant stones. Particularly in children with a high-stone burden, the use of adult-type instruments might have a positive impact on stone free rate, operation time and fluoroscopy time without increasing the complication rate. PMID- 21814771 TI - Coding region analysis of vitamin D receptor gene and its association with active calcium stone disease. AB - The purpose of this study was to evaluate the impact of vitamin D receptor (VDR) gene polymorphisms on the status of active renal calcium stone formation. Male active renal calcium stone formers (ASF, final N = 106) with two episodes of stone relapse in the past 5 years were enrolled from December 2008 to April 2009. Controls (N = 109) were selected from age range- and gender-matched individuals who had no evidence or history of stone disease. Sequencing and single-strand conformational polymorphism were used to determine VDR polymorphisms in the patients and controls. Three polymorphisms were identified in the VDR gene: (1) start codon polymorphism (rs2228570T>C; p.M1T); (2) C/T polymorphism in the second intron (NT-029419.12: g.10416049C>T); (3) a silent polymorphism in exon 9 (rs731236T>C; p.I352I). Start codon polymorphism was the only one that was associated with the status of calcium stone formation (p < 0.05). We performed a complete coding genome analysis of VDR gene and observed that only start codon polymorphism was related to the status of active calcium stone formation. PMID- 21814772 TI - Rate of avascular necrosis following proximal humerus fractures treated with a lateral locking plate and endosteal implant. AB - INTRODUCTION: Treatment of displaced proximal humerus fractures remains challenging. The introduction of locking plates has renewed interest in treating these fractures with joint-preserving techniques rather than hemiarthroplasty, but high complication rates are still reported. Avascular necrosis is not solely dependent on the initial fracture pattern, but can also result from intraoperative and postoperative vascular insults. METHOD: We describe a technique to minimize disruption of humeral head blood supply and maximize fracture fixation. A total of 34 patients with complex proximal humerus fractures were treated with a locking plate and endosteal implant through an anterolateral approach and followed for an average of 66 weeks to determine the rates of avascular necrosis. RESULTS: No patient suffered complete osteonecrosis (0%) and only one patient suffered partial necrosis (2.8%) of the humeral head. The length of the posteromedial hinge was not predictive of this complication. CONCLUSION: Use of the anterolateral approach and endosteal augment of a lateral locking plate can minimize avascular necrosis following proximal humerus fracture. PMID- 21814770 TI - Selective Rac1 inhibition protects renal tubular epithelial cells from oxalate induced NADPH oxidase-mediated oxidative cell injury. AB - Oxalate-induced oxidative cell injury is one of the major mechanisms implicated in calcium oxalate nucleation, aggregation and growth of kidney stones. We previously demonstrated that oxalate-induced NADPH oxidase-derived free radicals play a significant role in renal injury. Since NADPH oxidase activation requires several regulatory proteins, the primary goal of this study was to characterize the role of Rac GTPase in oxalate-induced NADPH oxidase-mediated oxidative injury in renal epithelial cells. Our results show that oxalate significantly increased membrane translocation of Rac1 and NADPH oxidase activity of renal epithelial cells in a time-dependent manner. We found that NSC23766, a selective inhibitor of Rac1, blocked oxalate-induced membrane translocation of Rac1 and NADPH oxidase activity. In the absence of Rac1 inhibitor, oxalate exposure significantly increased hydrogen peroxide formation and LDH release in renal epithelial cells. In contrast, Rac1 inhibitor pretreatment, significantly decreased oxalate-induced hydrogen peroxide production and LDH release. Furthermore, PKC alpha and delta inhibitor, oxalate exposure did not increase Rac1 protein translocation, suggesting that PKC resides upstream from Rac1 in the pathway that regulates NADPH oxidase. In conclusion, our data demonstrate for the first time that Rac1 dependent activation of NADPH oxidase might be a crucial mechanism responsible for oxalate-induced oxidative renal cell injury. These findings suggest that Rac1 signaling plays a key role in oxalate-induced renal injury, and may serve as a potential therapeutic target to prevent calcium oxalate crystal deposition in stone formers and reduce recurrence. PMID- 21814773 TI - Short reconstruction nail for intertrochanteric fracture: does it really fit Asian feature? AB - BACKGROUND: The Trigen short reconstruction trochanteric antegrade nail (TAN) is considered most suitable for the small skeletons of Asian patients. We have evaluated the results of TAN for intertrochanteric fractures in Asian patients. METHODS: Between January 2006 and March 2009, 174 fractures in 164 patients were treated by TAN in our department. Epidemiological data, radiological changes, fracture types, cortical bone indices, clinical outcomes, and complications over a mean of 26 months were analyzed retrospectively. RESULTS: We observed a 17.0% fracture rate at the tip of the nail, a poor reduction rate of 15.9%, and a 41.4% cracking rate of the lateral trochanter for type 31-A3 fracture. Review of these cracking cases showed that they were all type 31-A3 unstable fractures combined with comminuted lateral trochanter fractures. Two shaft fractures required revision, with other fractures showing no delayed union, nonunion or infection. No screw breakage but one cut-out occurred, which received total hip arthroplasty revision. All other fractures healed at last. Risk of distal shaft fractures was not associated with patient age, gender, fracture type or cortical bone index. CONCLUSION: Despite the theoretically better design of TAN and the healing of most fractures and good activity at last follow-up, poor reduction and coxa vara caused by insertion of the nail could not be completely avoided, and the design of the distal part of the nail had the potential to cause femoral shaft fracture. Future improvements are necessary to enable the use of this system in Asians. PMID- 21814774 TI - Technique for intraoperative determination of femoral rotation with a lateral femur nail (LFN, Synthes, Oberdorf, Switzerland). AB - Endomedullary femur nails with a head-neck implant offer an up to now unused point of reference for the determination of rotation during osteosynthesis. The lateral femur nail (LFN) or the long Proximal Femur Nail (long PFNA), for example, have recon screws or a blade placed at a 10 degrees angle to the distal locking screw in the transversal plane. If the head-neck implant is inserted properly, the rotation of the femur can be measured with the C-arm taking the hole of the distal locking screw and the posterior condylar tangential line as reference lines. If the posterior condylar tangential line is parallel to the axes of the hole of the distal locking screw, then the rotation or anteversion of the femur is equal to the angle between the head-neck implant and the distal locking screw which is 10 degrees with LFN or long PFNA. Differing rotation angles can be made visible by rotating the C-arm from the axial projection of the distal locking screw up to the posterior condylar tangential line. Three exemplary cases are presented. The recommended method was effective. The rotation of the femur can be measured intraoperatively with this technique and many revisions can be avoided. PMID- 21814775 TI - Eight-year wear analysis in Longevity highly cross-linked polyethylene liners comparing 26- and 32-mm heads. AB - INTRODUCTION: Although wear reduction of highly cross-linked polyethylene has been demonstrated to be independent of femoral head diameter in some simulation studies, the clinical effects of femoral head diameter on wear of highly cross linked polyethylene sockets remain unclear. We compared the in vivo wear of Longevity highly cross-linked polyethylene liners at 8-year follow-up using 26- or 32-mm cobalt-chromium heads. MATERIALS AND METHODS: A retrospective cohort study was performed on 90 cementless total hip arthroplasties (THAs) using Longevity highly cross-linked polyethylene liners combined with 26- (45 THAs) or 32-mm (45 THAs) cobalt-chromium heads. Annual radiographs were analyzed using PolyWare computer-assisted methods and linear and volumetric total head penetration rates and linear and volumetric steady-state wear rates were compared. RESULTS: The two groups showed similar background data, and no significant differences were identified between groups in total head penetration rate or steady-state wear rate. Steady-state wear rates were negligible. Osteolysis was not observed in any hips in either group. CONCLUSIONS: At the 8 year follow-up, wear of the Longevity was the same irrespective of the use 26- or 32-mm heads. PMID- 21814776 TI - Intra-articular injection of hyaluronic acid (MW 1,500-2,000 kDa; HyalOne) in symptomatic osteoarthritis of the hip: a prospective cohort study. AB - INTRODUCTION: Clinical trials have demonstrated the safety and efficacy of hyaluronic acid-based products for the treatment of hip osteoarthritis, but data from observational studies of normal medical practice are scarce. This study investigated the long-term efficacy and tolerability of ultrasound-guided intra articular sodium hyaluronate (MW 1,500-2,000 kDa; Hyalone) injections in daily clinical practice. METHODS: In this observational, cohort study of patients with hip osteoarthritis, Hyalone was administered under the ultrasound guidance, every 6 months, with the possibility of an additional injection at the intervening 3 month intervals on clinical request. Efficacy measurements included the Lequesne algofunctional index, self-reported pain via the visual analogue scale (VAS), the concomitant use of non-steroidal anti-inflammatory drugs (NSAIDs) and safety. The patients were followed up for 18 months after the first intra-articular injection. RESULTS: Data from 120 patients were collected. During the study, a statistically significant reduction in algofunctional indexes was demonstrated at 3 months after study product injection, while at 12 months 80% of the patients achieved a decrease of at least 30% in symptoms. These results were maintained over time through cyclical and personalized repetition of ultrasound guided injections, at least one injection every 6 months. CONCLUSIONS: The study treatment reduced pain and improved mobility in osteoarthritis of the hip. These results in daily clinical practice demonstrate a beneficial effect and the safety of the study product and suggest adding intra-articular injections of HyalOne to the armamentarium of conservative management of symptomatic hip osteoarthritis. PMID- 21814777 TI - Fear of deportation may limit legal immigrants' access to HIV/AIDS-related care: a survey of Swedish language school students in Northern Sweden. AB - The increasing rates of HIV infection that are currently being reported in high income countries can be partly explained by migration from countries with generalized epidemics. Yet, early diagnosis of HIV/AIDS in immigrants remains a challenge. This study investigated factors that might be limiting immigrants' access to HIV/AIDS care. Data from 268 legal immigrant students of two Swedish language schools in Northern Sweden were analyzed using logistic regression. Thirty-seven percent reported reluctance to seek medical attention if they had HIV/AIDS. Fear of deportation emerged as the most important determinant of reluctance to seek care after adjusting for socio-demographic factors, knowledge level, stigmatizing attitudes and fear of disclosure. Targeted interventions should consider the heterogeneity of migrant communities and the complex interplay of various factors which may impede access to HIV-related services. The myth about deportation because of HIV/AIDS should be countered. PMID- 21814778 TI - Expression of JL1 in Burkitt lymphoma is associated with improved overall survival. AB - JL1 is a novel molecule expressed in the surface of hematopoietic precursor cells, but not on any other mature human tissue. Accordingly, JL1 is expressed in acute lymphoblastic leukemia (ALL) cells and can be used both for specific diagnosis and as a target for treatment. However, expression of JL1 by lymphomas has not been thoroughly assessed. Burkitt lymphoma is a potentially curable aggressive lymphoma, but prognostic markers that stratify risk have not been established. We therefore assayed JL1 expression in Burkitt lymphoma patients to assess its value as a prognostic marker for this disease. Tissue microarray blocks of formalin-fixed paraffin-embedded tissue samples from patients with Burkitt lymphoma and other B-cell lymphomas, at the Asan Medical Center and Seoul National University Hospital from January 1998 to December 2008 were immunohistochemically assayed using a mouse monoclonal antibody against JL1. We found that 30.2% of Burkitt lymphoma samples, but no other lymphoma samples, were positive for JL1. JL-1 expression was significantly correlated with patient survival (P = 0.022), but not with other clinical manifestations of the disease, with 91.6% of JL1-positive patients achieving complete remission in response to chemotherapy and 6.25% experiencing disease recurrence. JL1 positivity was significantly correlated with prolonged overall survival by both Kaplan-Meier survival (P = 0.035) and Cox proportional hazard model (P = 0.043) analysis. JL1 expression in Burkitt lymphoma was positively correlated with overall survival and better response to chemotherapy, suggesting that JL1 may be a prognostic marker for risk stratification in these patients. PMID- 21814780 TI - Treatment of epidermal growth factor receptor inhibitor-induced skin toxicities: do the data support the current practice? PMID- 21814779 TI - Duloxetine improves oxaliplatin-induced neuropathy in patients with colorectal cancer: an open-label pilot study. AB - BACKGROUND: This open-label pilot study is aimed to evaluate the efficacy and tolerability of the antidepressant duloxetine, which is effective for diabetic neuropathic pain, in the treatment of chronic oxaliplatin-induced peripheral neuropathy (OIPN). METHODS: We enrolled a total of 39 patients with stage III or IV colorectal cancer with chronic OIPN. They were treated with duloxetine by increasing the dose from 30 mg/day to 60 mg/day. Patients' pain intensity was rated at baseline and 12 weeks after duloxetine administration. The severity of neuropathic pain was evaluated using the visual analog scale (VAS) score and the National Cancer Institute Common Toxicity Criteria for Adverse Events, version 3 (NCI-CTCAE v3.0). RESULTS: Nine patients (23.1%) discontinued duloxetine before the end of treatment because of adverse events. Of the remaining 30 patients, 19 patients (63.3%) had a VAS score improvement. Among them, nine (47.4%) showed a simultaneous grade improvement, and the other 10 patients (52.6%) had a stable grade according to NCI-CTCAE v3.0. Treatment with duloxetine did not impair renal or liver function and did not interfere with chemotherapy. CONCLUSIONS: Duloxetine is feasible in treating chronic OIPN with tolerable toxicity at a daily dose of 60 mg/day. PMID- 21814781 TI - Caregivers' morbidity in palliative care unit: predicting by gender, age, burden and self-esteem. AB - PURPOSE: This study assesses psychological distress suffered by caregivers of patients with a disease at an advanced and terminal state admitted at a palliative care unit. Specifically, these areas were examined in how distress was perceived: the contribution of caregiving burden, caregivers' self-esteem, caregivers' age and gender. METHODS: The sample constituted of 159 caregivers. Measurements included the Hospital Anxiety and Depression Scale (HADS) to assess distress, the shortened version of the Zarit Burden Inventory and Rosenberg self esteem scale. RESULTS: Approximately 77% of the caregivers reported probable significant distress (HADS >= 12), with a similar proportion with anxiety (76.1%) and depression (77.4%) within the caregivers' symptomatology. Multiple regression analysis revealed that the caregivers' self-esteem (p < 0.01) and caregivers' burden (p < 0.01) were stronger predictors of caregivers' distress than the socio demographic characteristics, age or gender (p < 0.05). CONCLUSIONS: A high prevalence of morbidity was noticed in caregivers of patients admitted at the palliative care unit. The early provision of psychological support to caregivers by healthcare staff may indeed help to decrease comorbidity symptoms. PMID- 21814782 TI - An old drug for use in the prevention of sudden infant unexpected death due to vagal hypertonia. AB - Reflex vagal hypertonia (RVH) has been identified as a possible cause of sudden unexpected death in infants during the first year of life. Homatropine methylbromide (HM) is an anticholinergic drug known to inhibit muscarinic acetylcholine receptors, thus affecting the parasympathetic nervous system. The aim of the present study was to investigate the effects of HM on 24-h Holter electrocardiographic signs of RVH (pre-HM treatment vs post-HM treatment; post-HM treatment vs a control group of healthy infants). A total of 50 patients (mean age, 6.1 +/- 2.7 months; 28 males, 22 females; 12 born pre-term) affected by RVH were enrolled in the study. Pre-HM treatment vs post-HM treatment: statistically significant differences were detected for higher heart rate, lower heart rate, mean heart rate, longer sinusal pause, presence of advanced atrio-ventricular blocks, and systolic blood pressure (p < 0.001, p < 0.00001, p < 0.02, p < 0.00001, p < 0.05, and p < 0.04, respectively). A statistically significant correlation was revealed between HM-administered dose and both average heart rate and systolic blood pressure (r = 0.93, p < 0.0001; r = 0.94, p < 0.0001, respectively). No significant differences were detected between post-HM treatment electrocardiographic data and those of the control group. By antagonizing action of the vagus nerve of the parasympathetic system on the heart, thus increasing cardiac frequency, HM treatment appears to feature a good safety profile and be highly effective in preventing transient infantile hypervagotonia, the potential cause of several cases of sudden unexpected death during the first year of life. PMID- 21814784 TI - The members of Arabidopsis thaliana PAO gene family exhibit distinct tissue- and organ-specific expression pattern during seedling growth and flower development. AB - Polyamine oxidases (PAOs) are FAD-dependent enzymes involved in polyamine catabolism. In Arabidopsis thaliana, five PAOs (AtPAO1-5) are present with cytosolic or peroxisomal localization. Here, we present a detailed study of the expression pattern of AtPAO1, AtPAO2, AtPAO3 and AtPAO5 during seedling and flower growth and development through analysis of promoter activity in AtPAO::beta-glucuronidase (GUS) transgenic Arabidopsis plants. The results reveal distinct expression patterns for each studied member of the AtPAO gene family. AtPAO1 is mostly expressed in the transition region between the meristematic and the elongation zone of roots and anther tapetum, AtPAO2 in the quiescent center, columella initials and pollen, AtPAO3 in columella, guard cells and pollen, and AtPAO5 in the vascular system of roots and hypocotyls. Furthermore, treatment with the plant hormone abscisic acid induced expression of AtPAO1 in root tip and AtPAO2 in guard cells. These data suggest distinct physiological role(s) for each member of the AtPAO gene family. PMID- 21814783 TI - Pulmonary hypertension in a stable community-based COPD population. AB - STUDY OBJECTIVES: The etiology and prevalence of pulmonary hypertension (PH) in patients with stable chronic obstructive pulmonary disease (COPD) is uncertain. This study was done to determine the prevalence of PH in stable COPD outpatients and to evaluate the relationship between PH and indices of pulmonary function. DESIGN: The study was a retrospective review of outpatients with COPD and PH defined as a history of cigarette smoking, pulmonary function tests (PFTs) that met GOLD criteria for airway obstruction, an echocardiogram within 6 months of PFTs, and a left ventricular ejection fraction (LVEF) >55%. Of the 159 individuals who met all inclusion criteria, 105 had a sufficient tricuspid regurgitant jet to measure systolic pulmonary artery pressure (sPAP). PH was defined as sPAP >=36 mmHg. MEASUREMENTS AND RESULTS: The prevalence of PH was 60% (63/105) in the study group. The mean sPAP in patients with PH was 45 +/- 6 mmHg. COPD patients with PH were older (71.1 +/- 11.8 vs. 63.7 +/- 10.2 years, P = 0.001), had lower FEV(1)% predicted (51.8 +/- 18.8 vs. 62.7 +/- 20.5%, P = 0.006), a higher RV/TLC (0.55 +/- 0.10 vs. 0.48 +/- 0.11, P = 0.001), and a lower % predicted DL(CO) (59.6 +/- 19.5% vs. 71.9 +/- 24.9%, P = 0.006). Only age (P < 0.002) and prebronchodilator FEV(1)% predicted (P < 0.006) predicted PH by logistic regression analysis. No differences were observed in gender, BMI, smoking status, pack years, total lung capacity (TLC), or residual volume (RV). CONCLUSION: PH is common in COPD. Older individuals and those with more airway obstruction are at greater risk for developing PH. PMID- 21814786 TI - Role of polyamines in hypertrophy and terminal differentiation of osteoarthritic chondrocytes. AB - Polyamines are naturally occurring, positively charged polycations which are able to control several cellular processes in different cell types, by interacting with negatively charged compounds and structures within the living cell. Functional genomics in rodents targeting key biosynthetic or catabolic enzymes have revealed a series of phenotypic changes, many of them related to human diseases. Several pieces of evidence from the literature point at a role of polyamines in promoting chondrocyte differentiation, a process which is physiological in growth plate maturation or fracture healing, but has pathological consequences in articular chondrocytes, programmed to keep a maturational arrested state. Inappropriate differentiation of articular chondrocytes results in osteoarthritis. Thus, we have studied the effects of exogenously added spermine or spermidine in chondrocyte maturation recapitulated in 3D cultures, to tease out the effects on gene and protein expression of key chondrogenesis regulatory transcription factors, markers and effectors, as well as their posttranscriptional regulation. The results indicate that both polyamines are able to increase the rate and the extent of chondrogenesis, with enhanced collagen 2 deposition and remodeling with downstream generation of collagen 2 bioactive peptides. These were able to promote nuclear localization of RUNX-2, the pivotal transcription factor in chondrocyte hypertrophy and osteoblast generation. Indeed, samples stimulated with polyamines showed an enhanced mineralization, along with increased caspase activity, indicating increased chondrocyte terminal differentiation. In conclusion these results indicate that the polyamine pathway can represent a potential target to control and correct chondrocyte inappropriate maturation in osteoarthritis. PMID- 21814787 TI - Distamycin A and derivatives as synergic drugs in cisplatin-sensitive and resistant ovarian cancer cells. AB - Acquired resistance to cisplatin (cDDP) is a multifactorial process that represents one of the main problems in ovarian cancer therapy. Distamycin A is a minor groove DNA binder whose toxicity has limited its use and prompted the synthesis of derivatives such as NAX001 and NAX002, which have a carbamoyl moiety and different numbers of pyrrolamidine groups. Their interaction with a B-DNA model and with an extended-TATA box model, [Polyd(AT)], was investigated using isothermal titration calorimetry (ITC) to better understand their mechanism of interaction with DNA and therefore better explain their cellular effects. Distamycin A interactions with Dickerson and Poly[d(AT)(6)] oligonucleotides show a different thermodynamic with respect to NAX002. The bulkier distamycin A analogue shows a non optimal binding to DNA due to its additional pyrrolamidine group. Cellular assays performed on cDDP-sensitive and -resistant cells showed that these compounds, distamycin A in particular, affect the expression of folate cycle enzymes even at cellular level. The optimal interaction of distamycin A with DNA may account for the down-regulation of both dihydrofolate reductase (DHFR) and thymidylate synthase (TS) and the up-regulation of spermidine/spermine N1-acetyltransferase (SSAT) caused by this compound. These effects seem differently modulated by the cDDP-resistance phenotype. NAX002 which presents a lower affinity to DNA and slightly affected these enzymes, showed a synergic inhibition profile in combination with cDDP. In addition, their combination with cDDP or polyamine analogues increased cell sensitivity to the drugs suggesting that these interactions may have potential for development in the treatment of ovarian carcinoma. PMID- 21814785 TI - Recent advances in the molecular biology of metazoan polyamine transport. AB - Very limited molecular knowledge exists about the identity and protein components of the ubiquitous polyamine transporters found in animal cells. However, a number of reports have been published over the last 5 years on potential candidates for metazoan polyamine permeases. We review the available evidence on these putative polyamine permeases, as well as establish a useful "identikit picture" of the general polyamine transport system, based on its properties as found in a wide spectrum of mammalian cells. Any molecular candidate encoding a putative "general" polyamine permease should fit that provided portrait. The current models proposed for the mechanism of polyamine internalization in mammalian cells are also briefly reviewed. PMID- 21814788 TI - A combined model of hepatic polyamine and sulfur amino acid metabolism to analyze S-adenosyl methionine availability. AB - Many molecular details remain to be uncovered concerning the regulation of polyamine metabolism. A previous model of mammalian polyamine metabolism showed that S-adenosyl methionine availability could play a key role in polyamine homeostasis. To get a deeper insight in this prediction, we have built a combined model by integration of the previously published polyamine model and one-carbon and glutathione metabolism model, published by different research groups. The combined model is robust and it is able to achieve physiological steady-state values, as well as to reproduce the predictions of the individual models. Furthermore, a transition between two versions of our model with new regulatory factors added properly simulates the switch in methionine adenosyl transferase isozymes occurring when the liver enters in proliferative conditions. The combined model is useful to support the previous prediction on the role of S adenosyl methionine availability in polyamine homeostasis. Furthermore, it could be easily adapted to get deeper insights on the connections of polyamines with energy metabolism. PMID- 21814789 TI - Differential expression of ornithine decarboxylase antizyme inhibitors and antizymes in rodent tissues and human cell lines. AB - Ornithine decarboxylase antizyme inhibitors, AZIN1 and AZIN2, are regulators and homologous proteins of ornithine decarboxylase (ODC), the rate limiting enzyme in the biosynthesis of polyamines. In this study, we have examined by means of real time RT-PCR the relative abundance of mRNA of the three ODC paralogs in different rodent tissues, as well as in several cell lines derived from human tumors. With the exception of mouse and rat testes, ODC mRNA was the most expressed gene in all tissues examined (values higher than 60%). AZIN2 was more expressed than AZIN1 in testis, epididymis, brain, adrenal gland and lung, whereas the opposite was found in liver, kidney, heart, intestine and pancreas, as well as in all the cell lines examined. mRNA abundance of the three antizymes (AZ1, AZ2 and AZ3) that interact with ODC and antizyme inhibitors was also analyzed. AZ1 and AZ2 mRNA were ubiquitously expressed, AZ1 mRNA being more abundant than that of AZ2, although the ratio was dependent on the mouse tissue. In carcinoma-derived cells AZ1 was more expressed than AZ2, whereas in neuroblastoma-derived cells AZ2 mRNA was much more abundant than that of AZ1. AZ3 was expressed exclusively in rodent testes, where it was the most abundant of the three antizymes (~80%). This study is the first comparative-quantitative analysis on the expression of antizymes and antizyme inhibitors in different types of mammalian cells. PMID- 21814791 TI - Plant ornithine decarboxylase is not post-transcriptionally feedback regulated by polyamines but can interact with a cytosolic ribosomal protein S15 polypeptide. AB - The formation of putrescine by ornithine decarboxylase (ODC) is a key regulatory step in polyamine biosynthesis in metazoa and fungi. Excess polyamines post transcriptionally induce the synthesis of a unique non-competitive protein inhibitor of ODC, termed antizyme. Binding of antizyme to an ODC monomer subunit results in enzymatic inhibition, rapid ubiquitin-independent degradation of ODC by the 26S proteasome and recycling of antizyme. Plants possess an additional route for synthesizing putrescine via arginine decarboxylase (ADC). No homologue of ODC antizyme has been detected in plant genomes but several biochemical studies have reported plant ODC antizyme proteins of 9 and 16 kDa. Here we show that plant cells grown in liquid culture do not exhibit any substantial post transcriptional, polyamine-responsive feedback regulation of ODC or ADC. However, using the yeast two hybrid system, a plant ODC-binding polypeptide was detected: the C-terminal 84-87 amino acids of cytosolic ribosomal protein (rp) S15. The Arabidopsis rpS15 polypeptide interacted specifically with plant ODC but not with human or Saccharomyces cerevisiae ODCs. Co-expression of either the full length or C-terminal rpS15 polypeptides with a plant ODC in yeast did not reduce ODC enzymatic activity. Only the full length mRNA encoding rpS15 was detected in Arabidopsis cells, suggesting that the C-terminal rpS15 polypeptide is encoded by a low abundance mRNA or the polypeptide is not physiologically relevant in plants. These results confirm the primacy of S-adenosylmethionine decarboxylase as the key regulatory enzyme in plant polyamine biosynthesis. PMID- 21814790 TI - Knockdown of ornithine decarboxylase antizyme 1 causes loss of uptake regulation leading to increased N1, N11-bis(ethyl)norspermine (BENSpm) accumulation and toxicity in NCI H157 lung cancer cells. AB - Ornithine decarboxylase antizyme 1 (AZ1) is a major regulatory protein responsible for the regulation and degradation of ornithine decarboxylase (ODC). To better understand the role of AZ1 in polyamine metabolism and in modulating the response to anticancer polyamine analogues, a small interfering RNA strategy was used to create a series of stable clones in human H157 non-small cell lung cancer cells that expressed less than 5-10% of basal AZ1 levels. Antizyme 1 knockdown clones accumulated greater amounts of the polyamine analogue N (1),N (11)-bis(ethyl)norspermine (BENSpm) and were more sensitive to analogue treatment. The possibility of a loss of polyamine uptake regulation in the knockdown clones was confirmed by polyamine uptake analysis. These results are consistent with the hypothesis that AZ1 knockdown leads to dysregulation of polyamine uptake, resulting in increased analogue accumulation and toxicity. Importantly, there appears to be little difference between AZ1 knockdown cells and cells with normal levels of AZ1 with respect to ODC regulation, suggesting that another regulatory protein, potentially AZ2, compensates for the loss of AZ1. The results of these studies are important for the understanding of both the regulation of polyamine homeostasis and in understanding the factors that regulate tumor cell sensitivity to the anti-tumor polyamine analogues. PMID- 21814792 TI - Lipopolysaccharide-induced anti-inflammatory acute phase response is enhanced in spermidine/spermine N1-acetyltransferase (SSAT) overexpressing mice. AB - Bacterial lipopolysaccharide (LPS) is an effective activator of the components of innate immunity. It has been shown that polyamines and their metabolic enzymes affect the LPS-induced immune response by modulating both pro- and anti inflammatory actions. On the other hand, LPS causes changes in cellular polyamine metabolism. In this study, the LPS-induced inflammatory response in spermidine/spermine N(1)-acetyltransferase overexpressing transgenic mice (SSAT mice) was analyzed. In liver and kidneys, LPS enhanced the activity of the polyamine biosynthetic enzyme ornithine decarboxylase and increased the intracellular putrescine content in both SSAT overexpressing and wild-type mice. In survival studies, the enhanced polyamine catabolism and concomitantly altered cellular polyamine pools in SSAT mice did not affect the LPS-induced mortality of these animals. However, in the acute phase of LPS-induced inflammatory response, the serum levels of proinflammatory cytokines interleukin-1beta and interferon gamma were significantly reduced and, on the contrary, anti-inflammatory cytokine interleukin-10 was significantly increased in the sera of SSAT mice compared with the wild-type animals. In addition, hepatic acute-phase proteins C-reactive protein, haptoglobin and alpha(1)-acid glycoprotein were expressed in higher amounts in SSAT mice than in the wild-type animals. In summary, the study suggests that SSAT overexpression obtained in SSAT mice enhances the anti inflammatory actions in the acute phase of LPS-induced immune response. PMID- 21814793 TI - Overexpression of spermidine/spermine N1-acetyltransferase or treatment with N1 N11-diethylnorspermine attenuates the severity of zinc-induced pancreatitis in mouse. AB - Depletion of pancreatic intracellular polyamine pools has been observed in acute pancreatitis both in the animal models and in humans. In this study, the wild type mice, polyamine catabolic enzyme spermidine/spermine N(1)-acetyltransferase overexpressing (SSAT mice) and SSAT-deficient mice were used to characterize the new zinc-induced acute pancreatitis mouse model and study the role of polyamines and polyamine catabolism in this model. Intraperitoneal zinc injection induced acute necrotizing pancreatitis in wild-type mice as well as in SSAT overexpressing and SSAT-deficient mice. Serum alpha-amylase activity was significantly increased in all zinc-treated mice compared with the untreated controls. However, the alpha-amylase activities in SSAT mice were constantly lower than those in the other groups. Histopathological examination of pancreatic tissue revealed edema, acinar cell necrosis and necrotizing inflammation, typical for acute pancreatitis. Compared with the other zinc-treated mice less damage according to the histopathological analysis was observed in the pancreatic tissue of SSAT mice. Levels of intracellular spermidine, and occasionally spermine, were significantly decreased in pancreases of all zinc-treated animals and SSAT enzyme activity was enhanced both in wild-type and SSAT mice. Interestingly, a spermine analog, N(1), N(11)-diethylnorspermine (DENSpm), enhanced the proliferation of pancreatic cells and reduced the severity of zinc-induced pancreatitis in wild type mice. The results show that in mice a single intraperitoneal zinc injection causes acute necrotizing pancreatitis accompanied by decrease of intracellular polyamine pools. The study supports the important role of polyamines for the integrity and function of the pancreas. In addition, the study suggests that whole body overexpression of SSAT obtained in SSAT mice reduces inflammatory pancreatic cell injury. PMID- 21814794 TI - Overexpression of ornithine decarboxylase decreases ventricular systolic function during induction of cardiac hypertrophy. AB - Ornithine decarboxylase (ODC), the first enzyme of polyamine metabolism, is rapidly upregulated in response to agents that induce a pathological cardiac hypertrophy. Transgenic mice overexpressing ODC in the heart (MHC-ODC mice) experience a much more dramatic left ventricular hypertrophy in response to beta adrenergic stimulation with isoproterenol (ISO) compared to wild-type (WT) controls. ISO also induced arginase activity in transgenic hearts but not in controls. The current work studies the cooperation between the cardiac polyamines and L-arginine (L-Arg) availability in MHC-ODC mice. Although ISO-induced hypertrophy is well-compensated, MHC-ODC mice administered L-Arg along with ISO showed a rapid onset of systolic dysfunction and died within 48 h. Myocytes isolated from MHC-ODC mice administered L-Arg/ISO exhibited reduced contractility and altered calcium transients, suggesting an alteration in [Ca(2+)] homeostasis, and abbreviated action potential duration, which may contribute to arrhythmogenesis. The already elevated levels of spermidine and spermine were not further altered in MHC-ODC hearts by L-Arg/ISO treatment, suggesting alternative L-Arg utilization pathways lead to dysregulation of intracellular calcium. MHC ODC mice administered an arginase inhibitor (Nor-NOHA) along with ISO died almost as rapidly as L-Arg/ISO-treated mice, while the iNOS inhibitor S-methyl isothiourea (SMT) was strongly protective against L-Arg/ISO. These results point to the induction of arginase as a protective response to beta-adrenergic stimulation in the setting of high polyamines. Further, NO generated by exogenously supplied L-Arg may contribute to the lethal consequences of L-Arg/ISO treatment. Since considerable variations in human cardiac polyamine and L-Arg content are likely, it is possible that alterations in these factors may influence myocyte contractility. PMID- 21814795 TI - The activation of hepatic and muscle polyamine catabolism improves glucose homeostasis. AB - The mitochondrial biogenesis and energy expenditure regulator, PGC-1alpha, has been previously reported to be induced in the white adipose tissue (WAT) and liver of mice overexpressing spermidine/spermine N (1)-acetyltransferase (SSAT). The activation of PGC-1alpha in these mouse lines leads to increased number of mitochondria, improved glucose homeostasis, reduced WAT mass and elevated basal metabolic rate. The constant activation of polyamine catabolism produces a futile cycle that greatly reduces the ATP pools and induces 5'-AMP-activated protein kinase (AMPK), which in turn activates PGC-1alpha in WAT. In this study, we have investigated the effects of activated polyamine catabolism on the glucose and energy metabolisms when targeted to specific tissues. For that we used a mouse line overexpressing SSAT under the endogenous SSAT promoter, an inducible SSAT overexpressing mouse model using the metallothionein I promoter (MT-SSAT), and a mouse model with WAT-specific SSAT overexpression (aP2-SSAT). The results demonstrated that WAT-specific SSAT overexpression was sufficient to increase the number of mitochondria, reduce WAT mass and protect the mice from high-fat diet induced obesity. However, the improvement in the glucose homeostasis is achieved only when polyamine catabolism is enhanced at the same time in the liver and skeletal muscle. Our results suggest that the tissue-specific targeting of activated polyamine catabolism may reveal new possibilities for the development of drugs boosting mitochondrial metabolism and eventually for treatment of obesity and type 2 diabetes. PMID- 21814796 TI - Polyamines modulate nitrate reductase activity in wheat leaves: involvement of nitric oxide. AB - In the present work, the effect of polyamines (PAs) on nitrate reductase (NR) activity was studied in wheat leaves exposed to exogenously added PAs while assessing the nitric oxide (NO) involvement in the regulation of the enzyme activity. A biphasic response was observed along the time of treatment using 0.1 mM of putrescine (Put), spermidine (Spd) or spermine (Spm). At 3 h, Spd and Spm significantly reduced NR activity by 29 or 35%, respectively, whereas at 6 h, the activity of the enzyme decreased by an average of 25%. At 21 h, Put increased NR activity by 63%, while Spd and Spm elevated the enzyme activity by 114%. NR activity, that was reduced by 0.1 mM Spm at 3 and 6 h, returned almost to control values when c-PTIO (an NO scavenger) was used, confirming that NO was involved in the inhibition of NR activity. Nitric oxide was also mediating the PA-increase of the enzyme activity at longer incubation times, evidenced when the raise in NR activity produced by 0.1 mM Spm at the longest incubation time returned to the value of the control in the presence of cPTIO. Neither the protein expression nor the nitrate content were modified by PAs treatments. The involvement of PAs and NO in the regulation of NR activity is discussed. PMID- 21814797 TI - Methyl jasmonate deficiency alters cellular metabolome, including the aminome of tomato (Solanum lycopersicum L.) fruit. AB - Exogenous treatment with jasmonates (JA) has been shown to reduce the levels of polyamines in many plants. But the role of endogenous JA on polyamine biosynthesis or other cellular metabolites has thus far remained uninvestigated. We developed transgenic tomato (Solanum lycopersicum L.) having severely reduced methyl JA levels by silencing a fruit ripening-associated lipoxygenase (LOX), SlLoxB, using a truncated LOX gene under the control of the constitutive CaMV35S promoter. The LOX suppressed and MeJA-deficient fruits had lowered polyamine levels. Thus, these transgenic fruits were used as a plant model to evaluate the effects of reduced endogenous MeJA on cellular metabolites in ripening tomato fruits using NMR spectroscopy. During on-shelf ripening, transgenic fruits were significantly reduced in the content of 19 out of 30 metabolites examined, including Ile, Val, Ala, Thr, Asn Tyr, Glu, Gln, His, Phe, Trp, GABA, citrate, succinate, myo-inositol, unidentified compound B, nucleic acid compound Nucl1, choline, and trigonelline as compared to the wild-type azygous counterparts. A significant increase in beta-glucose levels in transgenic fruits was observed at the pink stage. The transgenic fruits were equivalent to the wild type in lycopene level and chlorophyll degradation rates. Taken together, these results show that intracellular MeJA significantly regulates overall primary metabolism, especially aminome (amino acids and polyamines) of ripening fruits. PMID- 21814798 TI - Biobanking residual tissues. AB - Health-care research relies largely on human materials stored in highly specialised biorepositories. Medical translational research on tissues can be performed using a variety of resources in distinct situations. The best known is the secondary use of pathology archives where paraffin-embedded tissues are stored for diagnostic reasons. Another is collecting and storing frozen material obtained from leftover surgical diagnosis. Such residual tissues can either be used directly in research projects or used in the context of a clinical trial with new interventional medicinal products. The latter can make the regulations governing the use of these materials for medical research much more complicated. The use of residual materials is very distinct from biobanking projects for which tissue is specifically collected. This article describes the consequences of using residual human material from different sources in distinct situations and why signed informed consent is not always the preferred choice of individual countries regarding the use of residual material. In addition, signed informed consent is overdone when using residual tissues in medical research. We maintain that the opt-out system is a balanced choice if certain requirements are met, relating to sufficient transparency about using residual tissue for research, the purpose of such research and to the confidentiality of the data used in that research. Finally, the international exchange of samples can be based on the laws and regulations of the countries of origin. Respecting these form the basis of what can and cannot be done in the country where the research on the samples is being performed. PMID- 21814799 TI - Involvement of hydrogen peroxide, calcium, and ethylene in the induction of the alternative pathway in chilling-stressed Arabidopsis callus. AB - The roles of ethylene, hydrogen peroxide (H(2)O(2)), and calcium in inducing the capacity of the alternative respiratory pathway (AP) under chilling temperature in Arabidopsis thaliana calli were investigated. Exposure of wild-type (WT) calli, but not the calli of ethylene-insensitive mutants, etr1-3 and ein2-1, to chilling led to a marked increase of the AP capacity and triggered a rapid ethylene emission and H(2)O(2) generation. Increasing ethylene emission by applying 1-aminocyclopropane-1-carboxylic (an ethylene precursor) markedly enhanced the AP capacity in WT calli, but not in etr1-3 and ein2-1 calli, whereas suppressing ethylene emission by applying aminooxyacetic acid (an ethylene biosynthesis inhibitor) abolished the chilling-induced AP capacity in WT calli. Furthermore, exogenous H(2)O(2) treatment increased the AP capacity in WT calli, but not in etr1-3 and ein2-1 calli, while both catalase (H(2)O(2) scavenger) and diphenylene iodonium (DPI, an inhibitor of NADPH oxidase) completely inhibited the chilling-induced H(2)O(2) generation and largely inhibited the chilling induced AP capacity. Interestingly, the chilling-induced AP capacity was completely inhibited by DPI and EGTA (calcium chelator). Further investigation demonstrated that H(2)O(2) and calcium induced ethylene emission under chilling stress. Ethylene modulated the chilling-induced increase of pyruvate content and the expression of alternative oxidase genes (AOX1a and AOX1c). Taken together, these results indicate that H(2)O(2)-, calcium- and ethylene-dependent pathways are required for chilling-induced increase in AP capacity. However, only ethylene is indispensable for the activation of the AP capacity. PMID- 21814800 TI - Investigation of the clinical breakpoints of piperacillin-tazobactam against infections caused by Pseudomonas aeruginosa. AB - The pharmacokinetics-pharmacodynamics (PK-PD) breakpoint of piperacillin/tazobactam (PIPC/TAZ) for hospital-acquired pneumonia (HAP) and Pseudomonas aeruginosa-induced bacteremia is controversial, since the susceptibility of P. aeruginosa to PIPC/TAZ is known to be lower than that set by the Clinical Laboratory Standards Institute (CLSI), <=64 mg/L. The association between MIC levels and bacterial eradication after various PIPC/TAZ treatments was investigated. In all, 61 and 17 Japanese patients from the microbiology laboratory database with HAP and P. aeruginosa-induced bacteremia, respectively, who were treated with PIPC/TAZ (4.5 g, b.i.d., t.i.d., or q.i.d.) between 2008 and 2009 were retrospectively analyzed. Pertinent clinical data were retrieved from medical records. The MIC level was determined using the microdilution method. Appropriate empirical therapy with PIPC/TAZ was selected for all patients within 24 h of positive culture results. The microbiological effect after treatment was used to determine the efficacy of each PIPC/TAZ administration method. In PIPC/TAZ-treated HAP patients (4.5 g, t.i.d.), the microbiological efficacy was 93.3% (28/30) when the MIC was <=16 mg/L, while it was 50.0 (5/9) and 0% (0/3) with MICs of 32 (p < 0.05) and 64 mg/L, respectively. In PIPC/TAZ treated bacteremia patients (4.5 g, t.i.d. or q.i.d.), the microbiological efficacy was 100% (11/11) when the MIC was <16 mg/L, while it was 33.3 (1/3) and 0% (0/3) with MICs of 32 (p < 0.05) and >=64 mg/L, respectively. The present CLSI susceptibility breakpoints do not necessarily predict clinical outcomes. The appropriateness evaluation of the current CLSI resistance breakpoint of PIPC/TAZ and the PK-PD breakpoint determination warrant further studies. PMID- 21814801 TI - Preventive effect of selenium on chronic bacterial prostatitis. AB - The antibiotic treatment rate of chronic bacterial prostatitis (CBP) is low, and long-term administration can result in adverse events and bacterial resistance. For these reasons, a new preventive modality, which can replace traditional antibiotic therapy, is required. To evaluate the preventive effect of selenium on CBP, the pre-treatments were divided into four groups, administered for 4 weeks, as follows: (1) control, (2) ciprofloxacin, (3) selenium, and (4) ciprofloxacin and selenium. Then, drip infusion of a bacterial suspension (Escherichia coli Z17, O2:K1; H-) into the prostatic urethra of Wistar rats was conducted to induce CBP. In 4 weeks, the results of microbiological culture of prostate and urine samples as well as histological findings of the prostate in each group were analyzed. Selenium decreased bacterial infection significantly; the decrease in infiltration rate of inflammatory cells into prostate tissues in the selenium group was similar to that in the control group. The effect of hindering bacterial infection on prostate tissue was greater in the group administered both selenium and an antibiotic than in other groups given only one of the agents. Although the findings of this study suggest that selenium can have a preventive effect against the occurrence of CBP, methods to prevent CBP are still controversial. PMID- 21814802 TI - Increase of colonic mast cells in obstructed defecation and their relationship with enteric glia. AB - BACKGROUND: Mast cells are involved in visceral hypersensitivity and motor activity of the gastrointestinal tract. However, there is almost no information concerning mast cells in constipated patients. AIMS: The purpose of this study was to investigate mast cells distribution in all colonic layers in controls and severely constipated patients with obstructed defecation. METHODS: Full-thickness specimens from colons of patients undergoing surgery for obstructed defecation due to refractoriness to other therapeutic interventions (n = 11), compared to controls, were obtained and the number of mast cells (evaluated by specific monoclonal antibodies) were counted in the whole viscus and in the various colonic segments (cecum, ascending, transverse, descending, and sigmoid). RESULTS: Compared to controls, constipated patients had significantly higher numbers of mast cells, both as an overall number and in single colonic segments. This increase was especially evident in the mucosa and submucosa. Mast cells were homogeneously represented in the various segment of the large bowel, in both controls and patients. Degranulated mast cells were found to be close to enteric glial cells and glial filaments. CONCLUSIONS: Colonic mast cells are increased in obstructed defecation patients. This might represent a vicariating mechanism to the impaired colonic propulsive activity of these patients. PMID- 21814803 TI - Clinical characteristics of small bowel tumors diagnosed by double-balloon endoscopy: KASID multi-center study. AB - BACKGROUND: Small bowel tumors are relatively rare, and their confirmative diagnosis before surgery is not easy. AIMS: This study was performed to investigate the clinical characteristics of patients with small bowel tumors who received double-balloon enteroscopy (DBE). Secondary end points were to evaluate the usefulness and safety of DBE for the diagnosis of patients with suspected SB tumors derived from other previous procedures. METHODS: We retrospectively analyzed consecutive DBE examinations to explore the small intestine in eight university hospitals over a 5-year period. RESULTS: A total of 877 DBE examinations (per oral 487, per anal 390) were performed in 645 patients (405 males, mean age 48.2 years). Small bowel tumors were diagnosed in 112 patients (17.4%), of which 38 patients had benign polyps, 29 had gastrointestinal stromal tumors/leiomyomata, 18 had lymphomas, 14 had adenocarcinomas, five had metastatic or invasive cancers, five had lipomas, and three patients had cystic tumors. The main reasons for DBE among patients with small bowel tumors were obscure gastrointestinal bleeding (OGIB, 40.2%) followed by abnormal imaging study (25.2%). The concordance rate of diagnoses based on DBE with diagnoses based on small bowel follow-through, CT, and capsule endoscopy among patients with small bowel tumors was 68.9% (42/61), 75.3% (70/93), and 78.3% (18/23), respectively. Therapeutic plans were changed due to the DBE results in 64.2% of patients with small bowel tumors. CONCLUSIONS: Approximately one-sixth of patients who received DBE had small bowel tumors, and the most common reason for DBE among patients with small bowel tumors was OGIB. DBE is a useful method for the confirmative diagnosis of small bowel tumors and has a good clinical impact on therapeutic plans and short-term clinical results. PMID- 21814804 TI - Effects of macrophage metalloelastase on the basic fibroblast growth factor expression and tumor angiogenesis in murine colon cancer. AB - BACKGROUND AND AIM: Previous studies have shown that overexpression of macrophage metalloelastase (MME) suppresses tumor growth in mice. The purpose of this study was to investigate the effects of MME on basic fibroblast growth factor (bFGF) expression and tumor angiogenesis in murine colon cancer. METHODS: Murine CT-26 colon cancer cells stably transfected with MME were inoculated subcutaneously. Reverse-transcriptase polymerase chain reaction (RT-PCR), immunoblotting, and immunohistochemistry were used to explore the bFGF mRNA and protein expression. Immunohistochemical staining of CD34 was used to measure the microvessel density (MVD). RESULTS: bFGF mRNA levels in tumor tissues of CT-26-EGFP and nontransfected cells were respectively 2.7-fold (0.56 +/- 0.063 vs. 0.21 +/- 0.042) and 2.5-fold (0.53 +/- 0.066 vs. 0.21 +/- 0.042) higher than that in tumors of CT-26-EGFP-MME cells (p < 0.01). bFGF protein levels exhibited a similar trend. Tumors of CT-26-EGFP-MME cells demonstrated a lower microvessel density (9.35 +/- 2.79) than control tumors of CT-26-EGFP cells (22.85 +/- 3.80) and nontransfected cells (23.45 +/- 4.49) (p < 0.001). CONCLUSIONS: We found that expression of MME inversely correlates with the expression of bFGF and tumor angiogenesis in a model of murine colon cancer. These data indicate that manipulation of MME expression could be a novel modality approach to colon cancer therapy. PMID- 21814805 TI - Bioproduction of vanillin using an organic solvent-tolerant Brevibacillus agri 13. AB - Nowadays, majority of vanillin supplied to the world market is chemically synthesized from a petroleum-based raw material, raising a concern among the consumers regarding the product safety. In this study, an organic solvent tolerant Brevibacillus agri 13 previously reported for a strong predilectic property was utilized as a whole-cell biocatalyst for bioproduction of vanillin from isoeugenol (IG). B. agri 13 is the first biocatalyst reported for bioproduction of vanillin at a temperature as high as 45 degrees C. Both pH and temperature were found to affect vanillin production significantly. An extreme level of organic solvent tolerance of B. agri 13 allowed us to utilize it in a biphasic system using organic solvents generally considered as highly toxic to most bacteria. With an addition of butyl acetate at 30% (v/v) as an organic second phase, toxicity of IG exerted onto the biocatalyst was reduced dramatically while faster and more efficient vanillin production was obtained (1.7 g/L after 48 h with 27.8% molar conversion). PMID- 21814806 TI - Flocculation in ale brewing strains of Saccharomyces cerevisiae: re-evaluation of the role of cell surface charge and hydrophobicity. AB - Flocculation is an eco-friendly process of cell separation, which has been traditionally exploited by the brewing industry. Cell surface charge (CSC), cell surface hydrophobicity (CSH) and the presence of active flocculins, during the growth of two (NCYC 1195 and NCYC 1214) ale brewing flocculent strains, belonging to the NewFlo phenotype, were examined. Ale strains, in exponential phase of growth, were not flocculent and did not present active flocculent lectins on the cell surface; in contrast, the same strains, in stationary phase of growth, were highly flocculent (>98%) and presented a hydrophobicity of approximately three to seven times higher than in exponential phase. No relationship between growth phase, flocculation and CSC was observed. For comparative purposes, a constitutively flocculent strain (S646-1B) and its isogenic non-flocculent strain (S646-8D) were also used. The treatment of ale brewing and S646-1B strains with pronase E originated a loss of flocculation and a strong reduction of CSH; S646 1B pronase E-treated cells displayed a similar CSH as the non-treated S646-8D cells. The treatment of the S646-8D strain with protease did not reduce CSH. In conclusion, the increase of CSH observed at the onset of flocculation of ale strains is a consequence of the presence of flocculins on the yeast cell surface and not the cause of yeast flocculation. CSH and CSC play a minor role in the auto-aggregation of the ale strains since the degree of flocculation is defined, primarily, by the presence of active flocculins on the yeast cell wall. PMID- 21814807 TI - Quantitative expression analysis of mleP gene and two genes involved in the ABC transport system in Oenococcus oeni during rehydration. AB - Oenococcus oeni is recognized as the principal microorganism responsible for malolactic fermentation, and the control of its activity is of primary importance in winemaking. The aim of this study was to quantify the levels of expression of the malate transporter gene (mleP) and of two genes putatively involved in the ATP-binding cassette transport system (oeoe_1651, oeoe_0550) to better understand the physiological response of bacteria during rehydration. These genes coding for transporters were studied in different rehydration media. Initially, three different statistical algorithms were used to identify suitable reference genes to be used for the normalization of expression data in O. oeni during rehydration, and to this purpose, the best genes found were ddl and gyrB. The results showed that the genes for transporters of malate and sugar (mleP, oeoe_1651) were activated immediately after a few minutes of rehydration, when specific medium compositions were used. PMID- 21814808 TI - Bioactive metabolites from Phoma species, an endophytic fungus from the Chinese medicinal plant Arisaema erubescens. AB - Through bioassay-guided fractionation, the EtOAc extract of a culture broth of the endophytic fungus Phoma species ZJWCF006 in Arisaema erubescens afforded a new alpha-tetralone derivative, (3S)-3,6,7-trihydroxy-alpha-tetralone (1), together with cercosporamide (2), beta-sitosterol (3), and trichodermin (4). The structures of compounds were established on the basis of spectroscopic analyses. Compounds 1, 2, and 3 were obtained from Phoma species for the first time. Additionally, the compounds were subjected to bioactivity assays, including antimicrobial activity, against four plant pathogenic fungi (Fusarium oxysporium, Rhizoctonia solani, Colletotrichum gloeosporioides, and Magnaporthe oryzae) and two plant pathogenic bacteria (Xanthomonas campestris and Xanthomonas oryzae), as well as in vitro antitumor activities against HT-29, SMMC-772, MCF-7, HL-60, MGC80-3, and P388 cell lines. Compound 1 showed growth inhibition against F. oxysporium and R. solani with EC50 values of 413.22 and 48.5 MUg/mL, respectively. Additionally, compound 1 showed no cytotoxicity, whereas compound 2 exhibited cytotoxic activity against the six tumor cell lines tested, with IC50 values of 9.3 +/- 2.8, 27.87 +/- 1.78, 48.79 +/- 2.56, 37.57 +/- 1.65, 27.83 +/- 0.48, and 30.37 +/- 0.28 MUM, respectively. We conclude that endophytic Phoma are promising sources of natural bioactive and novel metabolites. PMID- 21814809 TI - Intuitive visualization and quantification of intraventricular convection in acute ischemic left ventricular failure during early diastole using color Doppler based echocardiographic vector flow mapping. AB - The aim of this study was to make an intuitive visualization of intraventricular convection (IC) and quantification of intraventricular convection velocity (ICV) in acute ischemic left ventricular (LV) failure of open-chest canines during early diastole contrast to the baseline conditions using color Doppler-based echocardiographic vector flow mapping (VFM). The animal care committee approved this prospective study. In 6 anesthetized open-chest beagle models, the emergence time and the emergence sites of IC in the LV cavity during early diastole were visualized at the standard apical 3-chamber (AP3c) views with the VFM at baseline conditions and after coronary artery ligation. The global ICV and the ICV at the basal, middle and apical levels of LV at the AP3c views at T1, T2, T3, T4, and T5 between both states were compared respectively (T1: the beginning of LV rapid filling period; T2: the middle of LV rapid filling period; T3: the peak of LV rapid filling period; T4: the middle of period of reduced filling; T5: the end of early diastole.). Acute ischemic LV failure with a marked increase in LV end diastolic volume and LV minimal diastolic pressure was induced by coronary artery ligation. The IC appeared only during the period of reduced filling at baseline conditions, and limited to the basal level of LV cavity. But the IC appeared throughout all the early diastole, and was seen almost occupying whole LV cavity during ischemia. The peak of the global ICV for both states appeared at T4. The global ICV at the AP3c views in acute ischemic failure LV cavity increased than those of baseline conditions at the T1 (6.593 +/- 0.834 cm(2)/s vs. 0.000 +/- 0.000 cm(2)/s, P < 0.001), T2 (9.457 +/- 0.852 cm(2)/s vs. 0.000 +/- 0.000 cm(2)/s, P < 0.001), T3 (14.765 +/- 1.791 cm(2)/s vs. 2.030 +/- 0.502 cm(2)/s, P < 0.001), T4 (25.392 +/- 4.640 cm(2)/s vs. 6.688 +/- 1.343 cm(2)/s, P < 0.001), and T5 (15.890 +/- 3.159 cm(2)/s vs. 2.518 +/- 0.869 cm(2)/s, P < 0.001). And the ICV at the basal, middle and apical levels at AP3c views in acute ischemic failure LV cavity also increased than those of baseline conditions at the same phase of early diastole (P < 0.01), except for the ICV at the LV basal level at T1. VFM is a powerful tool for visualization IC and quantification of ICV on profiles of LV flow fields, which can give intriguing insights into the subtle, flow-associated LV fluid dynamics of normal and abnormal cardiac function. It will be of great practical importance to elucidate the accurate physiological and the pathophysiological significance of the IC in further studies, so as to determine whether the cardiac function can be precisely evaluated with IC related index, and to incorporate VFM into clinical routine practice in the future. PMID- 21814810 TI - Paratenic hosts as regular transmission route in the acanthocephalan Pomphorhynchus laevis: potential implications for food webs. AB - Although trophically transmitted parasites are recognized to strongly influence food-web dynamics through their ability to manipulate host phenotype, our knowledge of their host spectrum is often imperfect. This is particularly true for the facultative paratenic hosts, which receive little interest. We investigated the occurrence and significance both in terms of ecology and evolution of paratenic hosts in the life cycle of the fish acanthocephalan Pomphorhynchus laevis. This freshwater parasite uses amphipods as intermediate hosts and cyprinids and salmonids as definitive hosts. Within a cohort of parasite larvae, usually reported in amphipod intermediate hosts, more than 90% were actually hosted by small-sized fish. We demonstrated experimentally, using one of these fish, that they get infected through the consumption of parasitized amphipods and contribute to the parasite's transmission to a definitive host, hence confirming their paratenic host status. A better knowledge of paratenic host spectrums could help us to understand the fine tuning of transmission strategies, to better estimate parasite biomass, and could improve our perception of parasite subwebs in terms of host-parasite and predator-parasite links. PMID- 21814811 TI - Anatomical localization and stereoisomeric composition of Tribolium castaneum aggregation pheromones. AB - We report that the abdominal epidermis and associated tissues are the predominant sources of male-produced pheromones in the red flour beetle, Tribolium castaneum and, for the first time, describe the stereoisomeric composition of the natural blend of isomers of the aggregation pheromone 4,8-dimethyldecanal (DMD) in this important pest species. Quantitative analyses via gas chromatography-mass spectrometry showed that the average amount of DMD released daily by single feeding males of T. castaneum was 878 +/- 72 ng (SE). Analysis of different body parts identified the abdominal epidermis as the major source of aggregation pheromone; the thorax was a minor source, while no DMD was detectable in the head. No internal organs or obvious male-specific glands were associated with pheromone deposition. Complete separation of all four stereoisomers of DMD was achieved following oxidation to the corresponding acid, derivatization with (1R, 2R)- and (1S, 2S)-2-(anthracene-2,3-dicarboximido)cyclohexanol to diastereomeric esters, and their separation on reversed-phase high-performance liquid chromatography at -54 degrees C. Analysis of the hexane eluate from Porapak-Q collected volatiles from feeding males revealed the presence of all four isomers (4R,8R)/(4R,8S)/(4S,8R)/(4S,8S) at a ratio of approximately 4:4:1:1. A walking orientation bioassay in a wind tunnel with various blends of the four synthetic isomers further indicated that the attractive potency of the reconstituted natural blend of 4:4:1:1 was equivalent to that of the natural pheromone and greater than that of the 1:1 blend of (4R,8R)/(4R,8S) used in commercial lures. PMID- 21814812 TI - Molecular characterization of eight Indian Snakehead species (Pisces: Perciformes Channidae) using RAPD markers. AB - Murrels (Perciformes; Channidei; Channidae) are unique group of freshwater air breathing fishes having a confined distribution to African and Asian continents. The phylogenetic relationship among eight Channid species viz. Channa aurantimaculata, Channa bleheri, Channa diplogramma, Channa gachua, Channa marulius, Channa punctatus, Channa stewartii and Channa striatus were investigated using RAPD markers. Eight random oligodecamers viz. OPAC03, OPAC05, OPAC07, OPAC09, OPAC19, OPA10, OPA11 and OPA16 were used to generate the RAPD profile. Estimates of Nei's (Genetics, 89:583-590, 1978) unbiased genetic distance (D) demonstrated sufficient genetic divergence to discriminate the samples of different species and the values ranged from 0.3292 to 0.800 The present RAPD analyses strongly substantiate the view of earlier morphological and osteological studies of Channid species, the closer association among species in "gachua" and "marulius" groups. PMID- 21814813 TI - Human herpesvirus 6-associated uveitis with optic neuritis diagnosed by multiplex PCR. AB - PURPOSE: Human herpesvirus 6 (HHV-6), which is usually responsible for exanthem subitum in children, can be reactivated from its latent state. We report a case of unilateral optic disc edema and retinal vasculitis associated with HHV-6 infection. CASE: A healthy 63-year-old man noted a decrease in the vision of his left eye. On examination, his left eye had moderate mutton-fat keratic precipitates, vitreous opacities, significant optic disc edema surrounded by yellowish-white swelling in the inner retina, retinal arteritis, and cotton-wool like exudates. He was started on corticosteroid therapy and aspirin. After 1 month, the disc edema was reduced, the cotton wool-like exudates had decreased, and his visual acuity had improved to 10/20 OS. Multiplex polymerase chain reaction (PCR) of an aqueous humor sample revealed the presence of genomic DNA of HHV-6 but not of the other HHVs. CONCLUSIONS: The HHVs are known to infect the ocular tissues, but the differential diagnostic signs of HHV-6 are still not well known. We recommend that multiplex PCR of the aqueous humor be performed to search for the genomic DNA of HHV-6 in suspected cases of herpesviral infection. PMID- 21814814 TI - Characterization of high rate composting of vegetable market waste using Fourier transform-infrared (FT-IR) and thermal studies in three different seasons. AB - Fourier transform-infrared (FT-IR), Thermogravimetry (TG), Differential thermal analyses (DTA) and Differential Thermogravimetric (DTG) studies of a mixture of vegetable waste, saw dust, tree leaves and cow dung for microbial activity (feedstock) and their compost were reported in three different seasons i.e. winter, spring and summer. The correlation between spectral studies and compost composition provide information regarding their stability and maturity during composting. FT-IR spectra were conferred the functional groups and their intensity and TG, DTG and DTA for wt. loss, rate of wt. loss and enthalpy change in compost. Weight loss in feedstock and compost at two different temperatures 250-350 and 350-500 degrees C was found 38.06, 28.15% for inlet and 14.08, 25.67% for outlet zones in summer and 50.59, 29.76% for inlet and 18.08, 25.67% in outlet zones in spring season, higher (5-10%) than winter. The corresponding temperatures in DTA in the samples from inlet to outlet zone were; endotherm (100 200 degrees C), due to dehydration, exotherm (300-320 degrees C), due to peptidic structure loss and exotherm (449-474 degrees C) due to the loss of polynuclear aromatic structures, which were higher by 4 degrees C and 10-20 degrees C and rate of wt. loss was higher by 5-10% in spring and summer season, respectively than winter season composting, reported regardless of the maturation age of the compost. Relative intensity of exotherms (300-320/449-474 degrees C) gave the thermally more stable fractions of organic compound. Our results indicated that the rotary drum composting of organic matters in spring and summer season gave higher molecular complexity and stability than the winter season. PMID- 21814815 TI - Mercury contamination in agricultural soils from abandoned metal mines classified by geology and mineralization. AB - This survey aimed to compare mercury concentrations in soils related to geology and mineralization types of mines. A total of 16,386 surface soils (0~15 cm in depth) were taken from agricultural lands near 343 abandoned mines (within 2 km from each mine) and analyzed for Hg by AAS with a hydride-generation device. To meaningfully compare mercury levels in soils with geology and mineralization types, three subclassification criteria were adapted: (1) five mineralization types, (2) four valuable ore mineral types, and (3) four parent rock types. The average concentration of Hg in all soils was 0.204 mg kg(-1) with a range of 0.002-24.07 mg kg(-1). Based on the mineralization types, average Hg concentrations (mg kg(-1)) in the soils decreased in the order of pegmatite (0.250) > hydrothermal vein (0.208) > hydrothermal replacement (0.166) > skarn (0.121) > sedimentary deposits (0.045). In terms of the valuable ore mineral types, the concentrations decreased in the order of Au-Ag-base metal mines ~ base metal mines > Au-Ag mines > Sn-W-Mo-Fe-Mn mines. For parent rock types, similar concentrations were found in the soils derived from sedimentary rocks and metamorphic rocks followed by heterogeneous rocks with igneous and metamorphic processes. Furthermore, farmland soils contained relatively higher Hg levels than paddy soils. Therefore, it can be concluded that soils in Au, Ag, and base metal mines derived from a hydrothermal vein type of metamorphic rocks and pegmatite deposits contained relatively higher concentrations of mercury in the surface environment. PMID- 21814817 TI - Genomics of iron acquisition in the plant pathogen Erwinia amylovora: insights in the biosynthetic pathway of the siderophore desferrioxamine E. AB - Genomics has clarified the biosynthetic pathway for desferrioxamine E critical for iron acquisition in the enterobacterial fire blight pathogen Erwinia amylovora. Evidence for each of the individual steps and the role of desferrioxamine E biosynthesis in pathogen virulence and cell protection from host defenses is presented. Using comparative genomics, it can be concluded that desferrioxamine biosynthesis is ancestral within the genera Erwinia and Pantoea. PMID- 21814816 TI - Longevity of organic layers of vertical flow ponds for sulfate reduction in treating mine drainages in South Korea. AB - This study was carried out to evaluate longevity of available organic materials used for sulfate-reducing bacteria (SRB) activity in vertical flow ponds (VFPs) to treat mine drainage in South Korea. Spent mushroom compost samples (SMC) were tested as substrates in VFPs and analyzed for total organic carbon in VFPs, and were collected to analyze total organic carbon (TOC), T-N, T-P, K, metals and residual cellulose to check the longevity assessment. Chemical analysis revealed that the average contents of Fe, Al and Mn in SMC of VFPs were 19,907, 32,137 and 434 mg/kg, respectively. The contents of Fe and Al in SMC of VFPs were much higher than those of the unused SMC (control), but to the contrary, those of Mn showed a reversed tendency. Average TOC content of the controls was 64.19% but in one of the VFP substrates was as low as 15.92%. This might be resulted from SRB consumed the available organic carbon in SMC as VFPs system aged. Contents of T-N in VFPs tended to decrease as VFPs aged. The residual cellulose ranged from 3.88 to 6.72% (g/g). There existed a negative relationship between residual cellulose contents and ages of VFPs. Assuming that SMC in all VFPs had similar compositions when the VFPs were initially established, trend analysis predicted that the amount of carbon source for SRB might be available for 12-15 years further, depending on VFPs. PMID- 21814818 TI - Gut microbiota as a candidate for lifespan extension: an ecological/evolutionary perspective targeted on living organisms as metaorganisms. AB - An emerging central concept in evolutionary biology suggests that symbiosis is a universal characteristic of living organisms that can help in understanding complex traits and phenotypes. During evolution, an integrative circuitry fundamental for survival has been established between commensal gut microbiota and host. On the basis of recent knowledge in worms, flies, and humans, an important role of the gut microbiota in aging and longevity is emerging. The complex bacterial community that populates the gut and that represents an evolutionary adapted ecosystem correlated with nutrition appears to limit the accumulation of pathobionts and infections in all taxa, being able of affecting the efficiency of the host immune system and exerting systemic metabolic effects. There is an urgent need to disentangle the underpinning molecular mechanisms, which could shed light on the basic mechanisms of aging in an ecological perspective. Thus, it appears possible to extend healthy aging and lifespan by targeting the host as a metaorganism by manipulating the complex symbiotic ecosystem of gut microbiota, as well as other possible ecosystems of the body. PMID- 21814820 TI - Blue light's benefits vs blue-blocking intraocular lens chromophores. PMID- 21814819 TI - Appraisal of the current staging system for residual medulloblastoma by volumetric analysis. AB - AIM: This study aims to investigate the accuracy of the current staging system of childhood medulloblastoma by using volumetric image analysis on immediate post operative MRI scans. MATERIAL AND METHODS: Tumour volume and maximum cross area of residual medulloblastoma were measured on immediate post-operative MR scans of 37 children operated between 1999 and 2005. RESULTS: Mean preoperative volume was 32 cm(3) (range 4.5-71.9 cm(3)). Mean post-operative volume was 3.3 cm(3) (range 0-23.3 cm(3)). At mean follow-up of 50.08 months (range 6-129), 15 (40%) patients had died. Cut-off limit for residual post-operative tumour volume employed was maximum cross section of 1.5 cm(2), which corresponds to volume of 1.376 cm(3); 14 patients (38%) had no residual tumour, 7 patients (19%) had less than 1.5 cm(2) and 16 patients (43%) had more than 1.5 cm(2) residual tumour in its maximum cross section area. In three patients (8.2%) there was mismatch between the measured maximum cross section area and volume. In particular, in two patients, the cross section areas were more than 1.5 cm(2) but the residual tumour volumes were less than 1.376 cm(3) (the cross section area overestimated the residual volume) and in one case, the cross section area was less than 1.5 cm(2) but the residual tumour volume was more than 1.376 cm(3) (the cross section area underestimated the residual volume; difference statistically significant, Fisher's exact test, p < 0.01). CONCLUSIONS: It appears that volumetric measurement of residual medulloblastoma on immediate post-operative MRI scans may further improve the accuracy of staging process. PMID- 21814821 TI - Cerebrospinal fluid pressure correlated with body mass index. PMID- 21814822 TI - The role of advanced magnetic resonance imaging techniques in primary progressive MS. AB - Primary progressive multiple sclerosis (PPMS) is characterized by a steady progression of irreversible disability from the onset of the disease. Although magnetic resonance imaging (MRI) is a valuable tool to quantify the disease burden in the brain and spinal cord of patients with MS, measures derived from conventional MRI, including T2-visible lesions, gadolinium-enhancing lesions and atrophy, are correlated only weakly with the clinical manifestations of PPMS. On the contrary, advanced MRI techniques are contributing significantly to the understanding of the mechanisms underlying the irreversible accumulation of disability in PPMS patients. Data from quantitative MRI studies suggest that the extent and topography of "diffuse" damage in different central nervous system (CNS) compartments (i.e. normal-appearing brain white matter and grey matter and the spinal cord) is associated with the severity of disability in PPMS and can predict subsequent medium-term disease evolution. Functional MRI studies have shown that the impairment of the adaptive capacity of the cortex to limit the clinical consequences of structural CNS damage is yet another factor contributing to the manifestations of this condition. PMID- 21814824 TI - Neural network algorithm for image reconstruction using the "grid-friendly" projections. AB - The presented paper describes a development of original approach to the reconstruction problem using a recurrent neural network. Particularly, the "grid friendly" angles of performed projections are selected according to the discrete Radon transform (DRT) concept to decrease the number of projections required. The methodology of our approach is consistent with analytical reconstruction algorithms. Reconstruction problem is reformulated in our approach to optimization problem. This problem is solved in present concept using method based on the maximum likelihood methodology. The reconstruction algorithm proposed in this work is consequently adapted for more practical discrete fan beam projections. Computer simulation results show that the neural network reconstruction algorithm designed to work in this way improves obtained results and outperforms conventional methods in reconstructed image quality. PMID- 21814823 TI - Anti-LRP4 autoantibodies in AChR- and MuSK-antibody-negative myasthenia gravis. AB - Myasthenia gravis (MG) is an autoimmune disorder characterized by a defect in synaptic transmission at the neuromuscular junction causing fluctuating muscle weakness with a decremental response to repetitive nerve stimulation or altered jitter in single-fiber electromyography (EMG). Approximately 80% of all myasthenia gravis patients have autoantibodies against the nicotinic acetylcholine receptor in their serum. Autoantibodies against the tyrosine kinase muscle-specific kinase (MuSK) are responsible for 5-10% of all myasthenia gravis cases. The autoimmune target in the remaining cases is unknown. Recently, low density lipoprotein receptor-related protein (LRP4) has been identified as the agrin receptor. LRP4 interacts with agrin, and the binding of agrin activates MuSK, which leads to the formation of most if not all postsynaptic specializations, including aggregates containing acetylcholine receptors (AChRs) in the junctional plasma membrane. In the present study we tested if autoantibodies against LRP4 are detectable in patients with myasthenia gravis. To this end we analyzed 13 sera from patients with generalized myasthenia gravis but without antibodies against AChR or MuSK. The results showed that 12 out of 13 antisera from double-seronegative MG patients bound to proteins concentrated at the neuromuscular junction of adult mouse skeletal muscle and that approximately 50% of the tested sera specifically bound to HEK293 cells transfected with human LRP4. Moreover, 4 out of these 13 sera inhibited agrin-induced aggregation of AChRs in cultured myotubes by more than 50%, suggesting a pathogenic role regarding the dysfunction of the neuromuscular endplate. These results indicate that LRP4 is a novel target for autoantibodies and is a diagnostic marker in seronegative MG patients. PMID- 21814825 TI - Surveillance of AF recurrence post-surgical AF ablation using implantable cardiac monitor. AB - BACKGROUND: Although pulmonary vein isolation is an effective treatment for recurrent atrial fibrillation (AF), there is no consensus on the definition of success or follow-up strategies. Existing data are limited to intermittent Holter or transtelephonic monitoring with reliance on patient symptoms. OBJECTIVE: We sought to determine the outcomes of surgical ablation and post-ablation AF surveillance with a leadless implantable cardiac monitor (ICM). METHODS: Forty five patients with drug-refractory paroxysmal or persistent AF underwent video assisted epicardial ablation using a bipolar radiofrequency clamp. An ICM was implanted subcutaneously post-ablation to assess AF recurrence. AF recurrence was defined as >=1 AF episode with a duration of >=30 s. The device-stored data was downloaded weekly over the internet, and all transmitted events were reviewed. RESULTS: A total of 1,220 AF automatic and patient-activated AF episodes were analyzed over a follow-up of 12 +/- 3 months. Of these episodes, 46% were asymptomatic. Furthermore, only 66% of the patient-activated episodes were AF. AF recurrence was highest in first 4 weeks and substantially decreased 6 months post ablation. The overall freedom from AF recurrence at the end of follow-up was 60%. When 48-h Holter recordings were compared with the device-stored episodes, the sensitivity of the device to detect AF was 98%, and the specificity was 71%. CONCLUSIONS: The ICM provides an objective measure of AF ablation success and may be useful in making clinical decisions. This device may be used in future ablation studies to develop a more rigorous definition of procedural success. PMID- 21814826 TI - Increased hepatic apoptosis in high-fat diet-induced NASH in rats may be associated with downregulation of hepatic stimulator substance. AB - The mechanisms of progression from fatty liver to steatohepatitis and cirrhosis are not well elucidated. Hepatocellular apoptosis could be one of the key factors in the pathogenesis of non-alcoholic steatohepatitis (NASH). Hepatic stimulator substance (HSS) protects liver cells from various toxins. We previously reported that HSS is critically important for the survival of hepatocytes due to its mitochondrial association. This study aims to investigate the relationship between HSS and hepatocellular apoptosis in vivo models of high-fat diet-induced NASH and in vitro models of palmitic acid-induced hepatocyte injury. Sprague Dawley rats were fed a high-fat diet for 8, 12 and 16 weeks. Hepatic histological lesions, liver function and apoptosis were examined. HSS expression, in association with caspase-3 and cytochrome c leakage, which are both indicators of cell apoptosis, was measured. Results showed that a high-fat diet altered liver function and histology in a manner resembling NASH. Hepatic protein and mRNA HSS expression was decreased as NASH progressed. Meanwhile, cell apoptosis increased as result of caspase-3 activation and cytochrome c release, indicating that HSS might be involved in NASH pathogenesis. Furthermore, in palmitic acid-induced hepatic cell damage, over-expression of HSS decreased cells apoptosis. In contrast, repression of HSS expression by siRNA increased cell apoptosis. In conclusion, these data imply that cell apoptosis contributes to the pathogenesis of NASH, during which HSS expression is downregulated. Increasing HSS expression in hepatocytes may forestall cell apoptosis as result of fatty acid insult. PMID- 21814827 TI - Electroretinogram measures in a septuagenarian population. AB - This study reports electroretinogram (ERG) data in a septuagenarian population. Fifty healthy adults without diabetes or dementia aged 70-79 years underwent standardised electrophysiological testing incorporating current ISCEV Standards as baseline assessment for the OPAL (Older People And n-3 Long-chain polyunsaturated fatty acids) study. These data were compared with those from 53 healthy adults aged 20-50 years. Amplitudes and peak times of the major components were assessed. There were no significant differences in amplitude or peak time between sexes or between eyes. ERG amplitudes were 25-40% smaller and peak-times were longer in the older compared with the younger age group. In all participants, the bright flash ERG b-wave amplitude had the highest variability; the bright flash ERG a-wave peak time had the lowest. ERGs in a septuagenarian age group show 25-40% lower amplitude than those of a 20 to 50-year-old group and are of longer peak time. With an increasingly ageing population involved in clinical trials, and the potential use of ERG in the assessment both of efficacy and safety in forthcoming therapeutic interventions, it is important that the effects of age are given adequate consideration. PMID- 21814828 TI - Discrepancies in histologic diagnoses of early gastric cancer between biopsy and endoscopic mucosal resection specimens. AB - BACKGROUND: A preoperative histologic diagnosis of neoplasia is a requirement for endoscopic resection (ER). However, discrepancies may occur between histologic diagnoses based on biopsy specimens versus ER specimens. The aim of this study was to assess the rate of discrepancy between histologic diagnoses from biopsy specimens and ER specimens. METHODS: A total of 1705 gastric lesions, from 1419 patients with a biopsy diagnosis of neoplasia, were treated by ER from September 2002 to December 2008. We compared the histologic diagnosis from the biopsy sample and the final diagnosis from the ER specimen to assess the discrepancy rate. Clinicopathological characteristics of the lesions that were related to the histologic discrepancies were also studied. RESULTS: An ER diagnosis of gastric cancer was made in 49% (118/241) of lesions diagnosed as borderline lesions from biopsy specimens; this included adenomas and lesions difficult to diagnose as regenerative or neoplastic. The size, existence of a depressed area, and ulceration findings were significant factors observed in these lesions. An ER diagnosis of differentiated type cancer was obtained for 17% (12/63) of lesions diagnosed as undifferentiated type cancer from the biopsy specimens; for these lesions, the color and a mixed histology were significant factors related to the histologic discrepancies. CONCLUSION: A biopsy diagnosis of borderline lesions or undifferentiated type cancer is more likely to disagree with the diagnosis from ER specimens. Endoscopic characteristics should be considered together with the biopsy diagnosis to determine the treatment strategy for these lesions. PMID- 21814829 TI - How do strategic decisions and operative practices affect operating room productivity? AB - Surgical operating rooms are cost-intensive parts of health service production. Managing operating units efficiently is essential when hospitals and healthcare systems aim to maximize health outcomes with limited resources. Previous research about operating room management has focused on studying the effect of management practices and decisions on efficiency by utilizing mainly modeling approach or before-after analysis in single hospital case. The purpose of this research is to analyze the synergic effect of strategic decisions and operative management practices on operating room productivity and to use a multiple case study method enabling statistical hypothesis testing with empirical data. 11 hypotheses that propose connections between the use of strategic and operative practices and productivity were tested in a multi-hospital study that included 26 units. The results indicate that operative practices, such as personnel management, case scheduling and performance measurement, affect productivity more remarkably than do strategic decisions that relate to, e.g., units' size, scope or academic status. Units with different strategic positions should apply different operative practices: Focused hospital units benefit most from sophisticated case scheduling and parallel processing whereas central and ambulatory units should apply flexible working hours, incentives and multi-skilled personnel. Operating units should be more active in applying management practices which are adequate for their strategic orientation. PMID- 21814830 TI - Microarchitecture and nanomechanical properties of trabecular bone after strontium administration in osteoporotic goats. AB - Strontium (Sr) ralenate is a new agent used for the prevention and treatment of osteoporosis. As a bone-seeking element, 98% of Sr is deposited in the bone and teeth after oral ingestion. However, the effect of Sr treatment on bone microarchitecture and bone nanomechanical properties remains unclear. In this study, 18 osteoporotic goats were divided into four groups according to the treatment regimen: control, calcium alone (Ca), calcium and Sr at 24 mg/kg (Ca + 24Sr), and calcium and Sr at 40 mg/kg (Ca + 40Sr). The effects of Sr administration on bone microarchitecture and nanomechanical properties of trabecular bones were analyzed with micro-CT and nanoindentation test, respectively. Serum Sr levels increased six- and tenfold in the Ca + 24Sr and Ca + 40Sr groups, respectively. Similarly, Sr in the bone increased four- and sixfold in these two groups. Sr administration significantly increased trabecular bone volume fraction, trabecular thickness, and double-labeled new bone area. Sr administration, however, did not significantly change the nanomechanical properties of trabecular bone (elastic modulus and hardness). The data suggested that Sr administration increased trabecular bone volume and improved the microarchitecture while maintaining the intrinsic tissue properties in the osteoporotic goat model. PMID- 21814831 TI - Flavonoid glycosides and naphthodianthrones in the sawfly Tenthredo zonula and its host-plants, Hypericum perforatum and H. hirsutum. AB - Larvae of the sawfly Tenthredo zonula are specialized on Hypericum. Whether the sawfly is able to sequester plant metabolites was unknown. Aerial materials of Hypericum perforatum and H. hirsutum, as well as dissected larvae and prepupae of T. zonula, were analyzed by HPLC to determine the presence and content of flavonoid glycosides (rutin, hyperoside, isoquercitrin, and quercitrin) and naphthodianthrones (pseudohypericin and hypericin). All flavonoid glycosides were detected in both Hypericum species, with hyperoside as major compound in H. perforatum (ca. 1.7 MUmol/g fresh weight, FW) and isoquercitrin in H. hirsutum (0.7 MUmol/g FW). Naphthodianthrones were present at low concentrations (0.02 MUmol/g FW) in the former, and almost undetected in the latter species. In the body parts (i.e., hemolymph, digestive tract, salivary glands, or miscellaneous organs) of T. zonula, the surveyed compounds were detected more frequently in prepupae than in larvae. The compounds were not present in every sample, and flavonoid glycosides especially occurred in highly variable amounts, with maximal concentrations of 41 MUg rutin/prepupa in salivary glands, 8 MUg hyperoside/prepupa in hemolymph (= 0.36 MUmol/g FW), 32 MUg isoquercitrin/prepupa in salivary glands, and 63 MUg quercitrin/larva in miscellaneous organs (mainly composed of the integument). We conclude that flavonoid glycosides are sequestered since they were detected in organs other than the digestive tract of larvae, and because prepupae are a non-feeding stage. The naphthodianthrone pseudohypericin, but not hypericin, occurred generally in the digestive tract (up to 0.25 MUg/larva). Both naphthodianthrones and related unidentified compounds, but not flavonoid glycosides, were found in the larval excrement. The highly variable distributions of flavonoid glycosides and naphthodianthrones in T. zonula larvae and prepupae make it difficult to determine the ecological significance of these metabolites. PMID- 21814832 TI - Applicability of molecular markers to determine parasitic infection origins in the animal trade: a case study from Sarcoptes mites in wildebeest. AB - The development of non-manipulative molecular tools to determine the origin of parasite infections in the animal trade (if infected before their export or import) is of great interest worldwide for both the animal trade industry and for animal welfare. Molecular tools have a wide range of applications, including forensic identification, wildlife preservation and conservation, veterinary public health protection, and food safety. Nonetheless, genetic markers were not reported to detect the source of infection in the animal trade. In this study we tested the applicability of molecular tools to detect the origin of Sarcoptes mite infection of wildebeest imported by the United Arab Emirate (UAE) from Tanzania. Using one multiplex of seven microsatellite markers and control samples from UAE, Kenya and Italy, we demonstrated the usefulness of the multiplex STR typing as a molecular tool of pivotal interest to help commercialist, authorities, and conservationists, to identify the geographical origin of parasitic infections. PMID- 21814833 TI - Extensive electrical injuries with opening of the chest wall due to arcing of high-voltage current. PMID- 21814834 TI - Detecting temporal reversals in human locomotion. AB - An experiment investigated the ability by human observers to detect temporal reversals in dynamic displays of human locomotion. We video-taped the lower portion of the body of actors walking at their preferred speed either in the normal, forward direction (FW) or in the backward direction (BW). The videos were presented in a random order either as recorded (N) or in reverse (R). In one session, we presented both normal and time-reversed stimuli in the original upright orientation. In a second session, the stimuli were rotated by 180 degrees around the horizontal axis. Observers were informed that the real recorded movement was either forward or backward and were asked to decide whether or not the movement had been time-reversed prior to the presentation. Although the kinematics of forward and backward human locomotion is quite similar, the detection of temporal reversals followed a consistent pattern showing a good accuracy in condition FW-N and a reduced but still above-chance performance in condition BW-R (by design, in both conditions actors appeared to walk forward). Performance was instead at chance level in the other two conditions where the apparent direction of the movement was backward. Inverting the spatial orientation of the stimuli reduced but did not suppress the ability to detect temporal reversals in the two conditions with apparent forward direction of movement. It is argued that implicit motor competence is at least in part instrumental for extracting the subtle discriminal information from the stimuli. PMID- 21814835 TI - Contingent capture and inhibition of return: a comparison of mechanisms. AB - We investigated the cause(s) of two effects associated with involuntary attention in the spatial cueing task: contingent capture and inhibition of return (IOR). Previously, we found that there were two mechanisms of involuntary attention in this task: (1) a (serial) search mechanism that predicts a larger cueing effect in reaction time with more display locations and (2) a decision (threshold) mechanism that predicts a smaller cueing effect with more display locations (Prinzmetal et al. 2010). In the present study, contingent capture and IOR had completely different patterns of results when we manipulated the number of display locations and the presence of distractors. Contingent capture was best described by a search model, whereas the inhibition of return was best described by a decision model. Furthermore, we fit a linear ballistic accumulator model to the results and IOR was accounted for by a change of threshold, whereas the results from contingent capture experiments could not be fit with a change of threshold and were better fit by a search model. PMID- 21814836 TI - Collaboration of prevention science and the family court. AB - This paper describes 27 years of collaborative activities between a team of researchers at the Arizona State University Prevention Research Center (ASU PRC) and the Maricopa County Family Court Division of the Superior Court. The complementary goals and expertise of the family court and prevention science are described as providing the foundation in which the missions of each can be advanced through collaborative activities. Four kinds of collaborative activities are described, which are differentiated according to the initiator of the activity and the primary immediate beneficiary. Nineteen separate collaborative activities that were conducted over the 27 years are described. Finally, lessons learned from this long-term collaboration are described including; mutual benefits of each activity, the benefit of complementary perspectives, the cumulative value of collaborations over time, the key role of the local key champion, and the societal benefit from the synergistic roles of university-based research and the family courts. PMID- 21814838 TI - The sustainability of European health care systems: beyond income and aging. AB - During the last 30 years, health care expenditure (HCE) has been growing much more rapidly than GDP in OECD countries. In this paper, we review the determinants of HCE dynamics in Europe, taking into account the role of income, aging population, technological progress, female labor participation and public budgetary variables. We show that HCE is a multifaceted phenomenon where demographic, social, economic, technological and institutional factors all play an important role. The comparison of total, public and private HCE reveals an imbalance of European welfare toward the care of the elderly. European Governments should increasingly rely on pluralistic systems to balance sustainability and access and equilibrate the distribution of resources across the functions of the public welfare system. PMID- 21814837 TI - Connective tissue growth factor modulates podocyte actin cytoskeleton and extracellular matrix synthesis and is induced in podocytes upon injury. AB - Structural changes of podocytes and retraction of their foot processes are a critical factor in the pathogenesis of minimal change nephritis and glomerulosclerosis. Here we tested, if connective tissue growth factor (CTGF) is involved in podocyte injury during acute and chronic puromycin aminonucleoside nephrosis (PAN) as animal models of minimal change nephritis, and focal segmental glomerulosclerosis, respectively. Rats were treated once (acute PAN) or for 13 weeks (chronic PAN). In both experimental conditions, CTGF and its mRNA were found to be highly upregulated in podocytes. The upregulation correlated with onset and duration of proteinuria in acute PAN, and glomerulosclerosis and high expression of glomerular fibronectin, and collagens I, III, and IV in chronic PAN. In vitro, treatment of podocytes with recombinant CTGF increased amount and density of actin stress fibers, the expression of actin-associated molecules such as podocalyxin, synaptopodin, ezrin, and actinin-4, and activation of focal adhesion kinase (FAK) and extracellular signal-regulated kinase (ERK). Moreover, we observed increased podocyte expression of mRNA for transforming growth factor (TGF)-beta2, TGF-beta receptor II, fibronectin, and collagens I, III, and IV. Treatment of cultured podocytes with puromycin aminonucleoside resulted in loss of actin stress fibers and cell death, effects that were partially prevented when CTGF was added to the culture medium. Depletion of CTGF mRNA in cultured podocytes by RNA interference reduced both the number of actin stress fibers and the expression of actin-associated molecules. We propose that the expression of CTGF is acutely upregulated in podocytes as part of a cellular attempt to repair structural changes of the actin cytoskeleton. When the damaging effects on podocyte structure and function persist chronically, continuous CTGF expression in podocytes is a critical factor that promotes progressive accumulation of glomerular extracellular matrix and glomerulosclerosis. PMID- 21814839 TI - Combined promoter haplotypes of the IL10R genes are associated with protection against severe malaria in Gabonese children. AB - The critical barrier in control of infections remains the failure of the immune system to clear parasites despite antigen recognition. We examined and validated possible association of regulatory immune gene polymorphisms in a cohort of children with mild and severe malaria. We focussed on two precursors of the Interleukin 10 Receptor (IL10R) gene namely the IL10R alpha and IL10R beta that play a fundamental role in initiation of signal transduction. Initial screening across 40 Gabonese adult individuals revealed two promoter variants for the IL10R alpha and three for the IL10R beta precursor, respectively. Validation of these variants for their allelic gene expression by transient transfection assays exhibited an altered expression in rs56356146 and rs7925112 of the IL10R alpha (P < 0.5); rs8178435 and rs999788 in the IL10R beta constructs (P < 0.0001), respectively. We further investigated the functional role of those SNP variants exhibiting altered expression in a cohort of children with mild and severe malaria. We genotyped 145 children with mild and 185 children with severe malaria for IL10R alpha; for IL10R beta, 102 children with mild and 101 children with severe malaria. We found that none of the SNP variants had any significant association neither in children with mild or severe malaria. The haplotype -185/ 116 of IL10R alpha (TT) in combination with the haplotype -754/-750 of IL10R beta (AC) contributed towards mild malaria in comparison to severe malaria [TT + AC odds ratio of 0.73 (95% CI 0.56-0.94) P = 0.01]. This study may provide a better understanding on the role of IL10R promoter allelic variants contribution to a protective effect on the development of severe malaria. PMID- 21814840 TI - Antimalarial drug interactions of compounds isolated from Kigelia africana (Bignoniaceae) and their synergism with artemether, against the multidrug resistant W2mef Plasmodium falciparum strain. AB - For decades, drug resistance has been the major obstacle in the fight against malaria, and the search for new drugs together with the combination therapy constitutes the major approach in responding to this situation. The present study aims at assessing the in vitro antimalarial activity of four compounds isolated from Kigelia africana stem bark (atranorin - KAE1, specicoside - KAE7, 2beta,3beta,19alpha-trihydroxy-urs-12-20-en-28-oic acid - KAE3, and p-hydroxy cinnamic acid - KAE10) and their drug interactions among themselves and their combination effects with quinine and artemether. The antiplasmodial activity and drug interactions were evaluated against the multidrug-resistant W2mef strain of Plasmodium falciparum using the parasite lactate dehydrogenase assay. Three of the four compounds tested were significantly active against W2mef: specicoside (IC(50) = 1.02 +/- 0.17 MUM), 2beta,3beta,19alpha-trihydroxy-urs-12-en-28-oic acid (IC(50) = 1.86 +/- 0.15 MUM) and atranorin (IC(50) = 1.78 +/- 0.18 MUM), whereas p-hydroxy-cinnamic acid showed a weak activity (IC(50) = 12.89 +/- 0.87 MUM). A slight synergistic effect was observed between atranorin and 2beta,3beta,19alpha-trihydroxy-urs-12-en-28-oic acid (Combination index, CI = 0.82) whereas the interaction between specicoside and p-hydroxy-cinnamic acid were instead antagonistic (CI = 2.67). All the three compounds showed synergistic effects with artemether, unlike the slight antagonistic interactions of atranorin and 2beta,3beta,19alpha-trihydroxy-urs-12-en-28-oic acid in combination with quinine. K. africana compounds are therefore likely to serve as leads in the development of new partner drugs in artemether-based combination therapy. PMID- 21814841 TI - Discordance in variation of the ITS region and the mitochondrial COI gene in the subterranean amphipod Crangonyx islandicus. AB - The amphipod Crangonyx islandicus is a recently discovered species endemic to Iceland. Populations of C. islandicus are highly structured geographically and genetically. The COI and 16S mitochondrial genes confine six monophyletic groups which have diverged for up to 5 million years within Iceland, and may present two cryptic species. To investigate the potential cryptic species status we analyse here the internal transcribed spacers (ITS1 and ITS2) and compare its variation with the patterns obtained with the mtDNA. The ITS regions present much less divergence among the geographic regions in comparison with the mtDNA, distances based on ITS1 are correlated with the COI distances as well as with geographic distances, but most of the variation is observed within individuals. The variation in the ITS region appears to have been shaped both by homogenization effect of concerted evolution and divergent evolution. A duplication of 269 base pairs is found in the ITS1 of all individuals from the southern populations, its divergence from its paralog appears to predate the split of the different groups within Iceland but some evidence point to rapid diversification after the split. This duplication does not affect the secondary structures found in the 3' and 5' ends of the sequence, suggested to have a role in the excision of the ITS1. Compensatory base changes within the ITS2 sequences which have been suggested to be a species indicator were not detected. PMID- 21814842 TI - Study on the state of implementation of HER2 testing and positive ratios in patients with breast cancer in the Kyushu-Okinawa region of Japan. AB - BACKGROUND: The development of molecular-targeted agents has improved the recovery rate for cancer. In Japan, trastuzumab has been approved as an adjuvant treatment for human epidermal growth factor receptor-2 (HER2)-positive breast cancer; therefore, accurate management of HER2 testing has become more important. In addition, proper patient selection is required from the viewpoint of health care economics. METHODS: The current situation of HER2 testing in patients with infiltrating breast cancer from April 2008 to March 2009 was evaluated in 49 institutions (50 departments) treating breast cancer in the Kyushu-Okinawa region. RESULTS: In a total of 5286 samples, HER2-positive ratio was 14.2%, which may reasonably reflect the current state of HER2 testing for breast cancer in the Kyushu-Okinawa region. There was a moderate discrepancy in HER2-positive ratio between institutions. Immunohistochemistry (IHC) analysis was outsourced in 15 institutions, and fluorescence in situ hybridization (FISH) analysis was outsourced in 23 institutions. The ratio of retesting by FISH analysis for samples judged as 2+ on IHC was 86.1%. There was no correlation between HER2 positive ratio and the number of HER2 tests at the institution. However, a high percentage of HER2 IHC 0-1+ results and a low percentage of HER2 2+ and 3+ results at the institution were significantly correlated with a high percentage of HER2 FISH-positive results for HER2 IHC 2+ cases. CONCLUSIONS: There is a moderate discrepancy in HER2-positive ratio between institutions. Institutions with a high percentage of HER2 IHC 0-1+ and a low percentage of HER2 2+ and 3+ may have more false negative cases. These institutions should perform internal accuracy evaluations in order to maintain proper diagnostic judgment. PMID- 21814843 TI - Strategy of radiation therapy for bone metastases and MSCC in breast cancer patients. AB - Bone metastasis is a common event in advanced cancers such as prostate, breast, lung, and renal cancers. Radiation therapy has been widely used for bone metastasis. However, it remains a challenging therapy because no radiation therapeutic guidelines, including radiation dose, radiation field, and fractionation, for patients with bone metastasis have been established. Many randomized controlled trials for bone metastasis have been carried out. They showed no significant difference in pain relief with a short course of radiation therapy such as 8 Gy/1 Fr and 20 Gy/5 Fr or with a long course of radiation therapy such as 30 Gy/10 Fr, 37.5 Gy/15 Fr, and 40 Gy/20 Fr. Toxicity rates with short and long courses were also the same. Recurrence rate at 2 years, however, was significantly higher in patients irradiated with a short course than in patients irradiated with a long course. Those trials also showed that response rate is affected by patient's age, performance state, tumor type, pathological state, number of metastatic tumors, and span from diagnosis of cancer to development of metastatic tumor. Breast cancer has a better prognosis than most other cancers. Recently, there have been significant advances in cancer therapy techniques and improvement in clinical results. Bone metastasis can cause extreme pain and motor deficits. Quality of life for patients with bone metastasis is drastically worsened. Patients with bad prognosis should be treated with radiation therapy when analgesia is the main aim of treatment. Survival of patients with oligometastasis or predominantly bone metastasis is expected to be better than that of patients with visceral metastasis. For patients with vertebral or weight-bearing long bone metastasis, long-course therapy is recommended. Many patients who are expected to have a good prognosis should be treated with a long course of radiation. PMID- 21814844 TI - Assessment of pollution with aquatic bryophytes in Maritsa River (Bulgaria). AB - Bryophyte species composition and 26 common physico-chemical and inorganic chemical parameters were assessed at 23 selected sites in the Maritsa River (BG) over a 4-year period. Principal components analyses (PCA) of both bryophytes and water variables distinguished different locations in the ecosystem. The data imply that the content of elements measured in bryophytes represents river contamination, while species compositional patterns reflect hydromorphology and general degradation. This study for the first time combined aquatic bryophyte occurrence, the bioaccumulation of 17 macro-and microelements in 17 species, and 26 water factors by principal components analysis (PCA) in an assessment of river pollution. PMID- 21814845 TI - Advanced computational framework for the automatic analysis of the acetabular morphology from the pelvic bone surface for hip arthroplasty applications. AB - 2D- and 3D-based innovative methods for surgical planning and simulation systems in orthopedic surgery have emerged enabling the interactive or semi-automatic identification of the clinical landmarks (CL) on the patient individual virtual bone anatomy. They enable the determination of the optimal implant sizes and positioning according to the computed CL, the visualization of the virtual bone resections and the simulation of the overall intervention prior to surgery. The virtual palpation of CL, highly dependent upon the examiner's expertise, was proved to be time consuming and to suffer from considerable inter-observer variability. In this article, we propose a fully automatic algorithmic framework that processes the pelvic bone surface, integrating surface curvature analysis, quadric fitting, recursive clustering and clinical knowledge, aiming at computing the main parameters of the acetabulum. The performance of the method was evaluated using pelvic bone surfaces reconstructed from CT scans of cadavers and subjects with pathological conditions at the hip joint. The repeatability error of the automated computation of acetabular center, size and axis parameters was less than 1 mm, 0.5 mm, and 1.5 degrees , respectively. The computed parameters were in agreement (<1.5 mm; <0.5 mm; <3.0 degrees ) with the corresponding reference parameters manually identified in the original datasets by medical experts. According to our results, the proposed method is put forward to improve the degree of automation of image/model-based planning systems for hip surgery. PMID- 21814846 TI - Cadmium toxicokinetics and bioaccumulation in turtles: trophic exposure of Trachemys scripta elegans. AB - Ecotoxicological data in reptiles are mainly represented by field studies reporting the tissue burden of wild-captured individuals but much less is known regarding the processes of uptake, depuration, accumulation and the effects of inorganic contaminants in these species. In the present study, the accumulation, the path and the effects of exposure to cadmium (Cd) through diet intake were investigated in female red eared slider turtles, Trachemys scripta elegans. In the first phase of the experiment, turtles underwent an acclimatization period during which they were fed a control diet. In the second phase, the turtles were exposed to cadmium through a CdCl(2) supplemented-diet with increased environmentally relevant concentrations for a period of 13 weeks. Following this, the turtles went through a third phase, a recovery phase of 3 weeks, during which they were fed uncontaminated food. Blood and feces were collected during the three phases of the experiment. The turtles were euthanized at the end of the experiment and organ samples collected. The Cd-concentrations in blood remained stable over the course of the experiment while Cd-concentrations in feces increased with time and with the amount of Cd ingested. The proportional accumulation in liver and kidney together was comprised between 0.7 and 6.1% and they represented the main organs of accumulation. Cd accumulated in the organs in the following order of concentration: kidney > liver > pancreas > muscle. In terms of burden in organs, the Cd-burden was the highest in liver followed by kidney and pancreas. The proportional accumulation decreased as Cd ingestion increased, suggesting that at a higher dose of Cd, assimilation decreased. Mineral content of the liver and pancreas became modified according to Cd level; increasing dietary Cd exposure increased concentrations of zinc and iron in liver and copper in pancreas in a dose-dependent manner. Accumulation of Cd had no effect on survival, food consumption, growth, weight or length suggesting no effect of the treatment on female turtle body condition. PMID- 21814847 TI - Longitudinal associations between family characteristics and measures of childhood obesity. AB - OBJECTIVES: The objective of this study was to investigate cross-sectional and longitudinal associations between different family characteristics and body mass index (BMI) and waist-to-height ratio (WHtR) in children. METHODS: This was a prospective follow-up study conducted in Helsinki region with data collected in 2006 and 2008. The sample consisted of 550 children aged 9-11 at baseline. Children were measured and weighed by research staff, and they completed a questionnaire about their family characteristics. RESULTS: More meals together with the family, more parenting practices at meals, less time home without adult company after school, and child's perception of receiving care from mother in 2006 predicted a lower BMI in 2008 and partly a smaller increase in BMI from 2006 to 2008. Fewer associations were found to WHtR. Physical activity with either parent was not associated with BMI or WHtR. CONCLUSIONS: Several family characteristics predicted child BMI and WHtR 2 years later. These results contribute new knowledge about parental influence on child weight and weight gain and should be taken into account when planning interventions on the matter. PMID- 21814848 TI - Modifiable cardiovascular risk factors among adults in Aleppo, Syria. AB - OBJECTIVES: This report provides the first comprehensive and standardized assessment of the distribution of cardiovascular disease (CVD) risk factors in Syria, where such data are still scarce. METHODS: A population-based household survey was conducted in Aleppo (population >2.5 million), involving 1,168 subjects >=25 years old (47.7% men; mean age 44.7 +/- 12.7 years). Information about socio-demographics, personal behavior, and other CVD risk factors was collected. Anthropometric measurements and fasting blood samples were obtained. RESULTS: The prevalence of clinical risk factors of CVD (ClinRFs) was 45.6% for hypertension, 43.2% for obesity, 21.9% for hypercholesterolemia and 15.6% for diabetes. The prevalence of behavioral risk factors (BehRFs) was 82.3% for physical inactivity, 39.0% for smoking, and 33.4% for unhealthy diet. All ClinRFs increased with age, while gender was associated only with obesity and smoking. Education was associated with obesity and diabetes (P < 0.05 for all). CONCLUSIONS: Adults in Syria have some of the world's highest prevalence of CVD risk factors. Unhealthy behaviors and social norms unfavorable to women may explain some of such risk profiles. PMID- 21814849 TI - Socioeconomic position, gender, and inequalities in self-rated health between Roma and non-Roma in Serbia. AB - OBJECTIVE: Roma experience high levels of discrimination and social exclusion. Our objective was to examine differences in self-rated health (SRH) between Roma and non-Roma in Serbia. METHODS: Using data from the 2007 Living Standards Measurement Survey in Serbia (n = 14,313), we used binomial regression to estimate the relative risk (RR) of poor (SRH) among Roma (n = 267) relative to non-Roma. We additionally conducted group comparisons of combinations of Romani ethnicity, poverty, and gender, relative to the baseline group of non-Roma males not in poverty. RESULTS: Adjusting for age, Roma were more than twice as likely as non-Roma to report poor SRH (RR = 2.3, 95% Confidence Interval (CI) = 1.8, 2.8). After adjustment for household consumption, employment, and education, the RR was reduced to 1.6 (95% CI = 1.3, 2.0). Romani women, regardless of whether they were living in poverty or not, experienced the greatest risk of poor SRH, with risks relative to non-Roma males not in poverty of 3.2 (95% CI = 2.3, 4.2) and 3.1 (95% CI = 2.4, 4.0), respectively. CONCLUSION: Roma in Serbia are at increased risk of poor SRH; Romani women experience the greatest burden of poor SRH. PMID- 21814851 TI - First ex vivo study demonstrating that 99mTc-NTP 15-5 radiotracer binds to human articular cartilage. AB - PURPOSE: Preclinical data pointed to (99m)Tc-NTP 15-5 as a good candidate for single photon emission computed tomography (SPECT) imaging of cartilaginous disease. We set out to investigate and quantify (99m)Tc-NTP 15-5 ex vivo uptake by human articular cartilage relative to bone (99m)Tc-hydroxymethylene diphosphonate (HMDP) radiotracer. METHODS: Three osteoarthritic human tibial plateaux and four tibiofemoral joints were incubated with (99m)Tc-NTP 15-5 and (99m)Tc-HMDP for 2 h. Affinity of tracers for cartilage was determined by visual analysis of SPECT/CT acquisitions and measurement of cartilage to cortical bone uptake ratios. RESULTS: Cartilage to cortical bone uptake ratios were 3.90 +/- 2.35 and 0.76 +/- 0.24, respectively, for (99m)Tc-NTP 15-5 and (99m)Tc-HMDP radiotracers. Visual analysis of fused SPECT/CT slices showed selective, intense (99m)Tc-NTP 15-5 accumulation in articular cartilage, whereas (99m)Tc-HMDP binding was low. Interestingly, a cartilage defect visualized on CT was clearly associated with focal decreased uptake of (99m)Tc-NTP 15-5. CONCLUSION: The tracer (99m)Tc-NTP 15-5 is of major interest for human cartilage molecular imaging and could find clinical applications in osteoarthritis staging and monitoring. PMID- 21814850 TI - Myocardial perfusion scintigraphy and echocardiography for detecting coronary artery disease in hypertensive patients: a meta-analysis. AB - PURPOSE: This meta-analysis summarized the accuracy of stress myocardial perfusion scintigraphy (MPS) and stress echocardiography for the diagnosis of coronary artery disease (CAD) in patients with arterial hypertension. METHODS: We searched for studies in which stress MPS or stress echocardiography were performed to detect CAD in hypertensive patients, with coronary angiography used as the reference test, published from January 1980 to December 2010. Studies performed in patients with known CAD, acute coronary syndrome and previous revascularization procedures were excluded. RESULTS: Of 1,263 studies, 13 met the inclusion criteria. Pooled summary estimates showed that stress MPS had a sensitivity of 0.90 [95% confidence interval (CI) 0.82-0.95] and a specificity of 0.63 (95% CI 0.53-0.72). For stress MPS, the area under the curve (AUC) at the summary receiver-operating characteristic (SROC) graph was 0.83 (95% CI 0.80 0.86). At meta-regression analysis, the presence of positive stress electrocardiography as inclusion criterion was the only significant effect modifier (p < 0.01). Pooled summary estimates showed that stress echocardiography had a sensitivity of 0.77 (95% CI 0.69-0.83) and a specificity of 0.89 (95% CI 0.83-0.93). For stress echocardiography, the AUC at SROC was 0.91 (95% CI 0.88 0.93). At the meta-regression analysis no significant effect modifier was detected. CONCLUSION: MPS has high sensitivity for detecting CAD in hypertensive patients, with specificity comparable to that reported in the general population, whereas stress echocardiography shows higher specificity but substantially reduced sensitivity compared to MPS. PMID- 21814852 TI - In vivo near-infrared fluorescence imaging of CD105 expression during tumor angiogenesis. AB - PURPOSE: Angiogenesis is an indispensable process during tumor development. The currently accepted standard method for quantifying tumor angiogenesis is to assess microvessel density (MVD) based on CD105 staining, which is an independent prognostic factor for survival in patients with most solid tumor types. The goal of this study is to evaluate tumor angiogenesis in a mouse model by near-infrared fluorescence (NIRF) imaging of CD105 expression. METHODS: TRC105, a human/murine chimeric anti-CD105 monoclonal antibody, was conjugated to an NIRF dye (IRDye 800CW; Ex: 778 nm; Em: 806 nm). FACS analysis and microscopy studies were performed to compare the CD105 binding affinity of TRC105 and 800CW-TRC105. In vivo/ex vivo NIRF imaging, blocking studies, and ex vivo histology were performed on 4T1 murine breast tumor-bearing mice to evaluate the ability of 800CW-TRC105 to target tumor angiogenesis. Another chimeric antibody, cetuximab, was used as an isotype-matched control. RESULTS: FACS analysis of human umbilical vein endothelial cells (HUVECs) revealed no difference in CD105 binding affinity between TRC105 and 800CW-TRC105, which was further validated by fluorescence microscopy. 800CW conjugation of TRC105 was achieved in excellent yield (> 85%), with an average of 0.4 800CW molecules per TRC105. Serial NIRF imaging after intravenous injection of 800CW-TRC105 revealed that the 4T1 tumor could be clearly visualized as early as 30 min post-injection. Quantitative region of interest (ROI) analysis showed that the tumor uptake peaked at about 16 h post injection. Based on ex vivo NIRF imaging at 48 h post-injection, tumor uptake of 800CW-TRC105 was higher than most organs, thus providing excellent tumor contrast. Blocking experiments, control studies with 800CW-cetuximab and 800CW, as well as ex vivo histology all confirmed the in vivo target specificity of 800CW-TRC105. CONCLUSION: This is the first successful NIRF imaging study of CD105 expression in vivo. Fast, prominent, persistent, and CD105-specific uptake of the probe during tumor angiogenesis was observed in a mouse model. 800CW TRC105 may be used in the clinic for imaging tumor angiogenesis within the lesions close to the skin surface, tissues accessible by endoscopy, or during image-guided surgery. PMID- 21814853 TI - Imaging tumor endothelial marker 8 using an 18F-labeled peptide. AB - PURPOSE: Tumor endothelial marker 8 (TEM8) has been reported to be upregulated in both tumor cells and tumor-associated endothelial cells in several cancer types. TEM8 antagonists and TEM8-targeted delivery of toxins have been developed as effective cancer therapeutics. The ability to image TEM8 expression would be of use in evaluating TEM8-targeted cancer therapy. METHODS: A 13-meric peptide, KYNDRLPLYISNP (QQM), identified from the small loop in domain IV of protective antigen of anthrax toxin was evaluated for TEM8 binding and labeled with 18F for small-animal PET imaging in both UM-SCC1 head-and-neck cancer and MDA-MB-435 melanoma models. RESULTS: A modified ELISA showed that QQM peptide bound specifically to the extracellular vWA domain of TEM8 with an IC50 value of 304 nM. Coupling 4-nitrophenyl 2-(18)F-fluoropropionate with QQM gave almost quantitative yield and a high specific activity (79.2+/-7.4 TBq/mmol, n=5) of 18F FP-QQM at the end of synthesis. 18F-FP-QQM showed predominantly renal clearance and had significantly higher accumulation in TEM8 high-expressing UM-SCC1 tumors (2.96+/-0.84 %ID/g at 1 h after injection) than TEM8 low-expressing MDA-MB-435 tumors (1.38+/-0.56 %ID/g at 1 h after injection). CONCLUSION: QQM peptide bound specifically to the extracellular domain of TEM8. 18F-FP-QQM peptide tracer would be a promising lead compound for measuring TEM8 expression. Further efforts to improve the affinity and specificity of the tracer and to increase its metabolic stability are warranted. PMID- 21814854 TI - Impact of overweight and obesity on postmenopausal breast cancer: analysis of 20 year data from Switzerland. AB - PURPOSE: Greater body fatness has been identified as a risk factor for postmenopausal breast cancer. For countries with low overweight/obesity rates, data on prevalence and time course of overweight/obesity in women with breast cancer in comparison to women in the general population is limited. The Swiss female population is distinctive for two reasons: (a) low rates of overweight/obesity compared with other western countries, and (b) no obesity epidemic, i.e. stable rates of overweight/obesity for more than 10 years. METHODS: Overweight and obesity were analyzed in 51 to 80-year-old breast cancer patients initially diagnosed between 1990 and 2009. Patient data was derived from the Basel Breast Cancer Database (BBCD). This data was compared with the data of women of the same age from the four Swiss Health Surveys (SHS) conducted between 1992 and 2007. Differences between measured (BBCD) and self-reported (SHS) data were corrected using equations approved for the Swiss population. RESULTS: Of 958 postmenopausal BBCD patients, 32% were overweight and 20% were obese. Of the 14,476 women of the SHS, 38% were overweight and 17% were obese. In the BBCD, there was no change in the prevalence of overweight/obesity over the last 20 years. The four SHS show a convex curvature for obesity, i.e. a transient increase. No significant differences were observed between BBCD and corrected SHS data for overweight and obesity during this period. CONCLUSIONS: In this Swiss study group with a comparably low prevalence of overweight and obesity, no association between body fatness and postmenopausal breast cancer was observed. PMID- 21814855 TI - Agonist-like autoantibodies against calcium channel in patients with dilated cardiomyopathy. AB - The calcium channel may be an important target in the autoimmune pathogenesis of dilated cardiomyopathy (DCM). The presence and function of serum autoantibodies against calcium channels (CC-AAbs) in patients with DCM were studied. Calcium channel AAbs were detected in 80 patients with DCM and 80 controls by enzyme linked immunosorbent assay (ELISA). Calcium-channel AAbs were further purified by affinity chromatography for characterization by immunoblotting and immunofluorescence. Voltage-clamp experiments were performed to identify the function of CC-AAbs. The presence of CC-AAbs was shown effectively by ELISA, and CC-AAbs were able specifically to bind to the calcium channel on the myocyte, confirmed by immunoblotting and immunofluorescence. Calcium currents were enhanced by CC-AAbs on Xenopus oocytes expressing human Ca(V)1.2 channels, which suggested CC-AAbs in patients with DCM were agonist-like. Our results suggest there are novel agonist-like CC-AAbs in patients with DCM. Calcium-channel AAbs might play an important role in the pathogenesis of DCM. PMID- 21814856 TI - Comparison of CT, PET, and PET/CT for staging of patients with indolent non hodgkin's lymphoma: statistical errors in Fueger et al. (2009). PMID- 21814857 TI - Identification of the BrRHP1 locus that confers resistance to downy mildew in Chinese cabbage (Brassica rapa ssp. pekinensis) and development of linked molecular markers. AB - Inheritance of resistance to downy mildew (Hyaloperonospora parasitica) in Chinese cabbage (Brassica rapa ssp. pekinensis) was studied using inbred parental lines RS1 and SS1 that display strong resistance and severe susceptibility, respectively. F(1), F(2), and BC(1)F(1) populations were evaluated for their responses to downy mildew infection. Resistance to downy mildew was conditioned by a single dominant locus designated BrRHP1. A random amplified polymorphic DNA (RAPD) marker linked to BrRHP1 was identified using bulked segregant analysis and two molecular markers designated BrPERK15A and BrPERK15B were developed. BrPERK15B was polymorphic between the parental lines used to construct the reference linkage map of B. rapa, allowing the mapping of the BrRHP1 locus to the A1 linkage group. Using bacterial artificial chromosome clone sequences anchored to the A1 linkage group, six simple polymerase chain reaction (PCR) markers were developed for use in marker-assisted breeding of downy mildew resistance in Chinese cabbage. Four simple PCR markers flanking the BrRHP1 locus were shown to be collinear with the long-arm region of Arabidopsis chromosome 3. The two closely linked flanking markers delimit the BrRHP1 locus within a 2.2-Mb interval of this Arabidopsis syntenic region. PMID- 21814858 TI - CRT or CRT-D devices? The case for 'high energy' devices. AB - The decision to implant a CRT or CRT-D device is an important one that requires a careful look at the patient and discussion with the patient as to the benefits and risks associated with each approach. The good news is that CRT provided in any device is a robust therapy that improves many measures of heart failure outcome in very high-risk patients. We argue that in most circumstances, it is much easier to turn a tachycardia device off than not to have the benefit of prompt defibrillation should a tachycardia event occur. While cost is always a consideration, the responsibility of the physician is to individualize patient care and advocate for each patient, based upon the best available therapies. PMID- 21814859 TI - No transfer of calibration between action and perception in learning a golf putting task. AB - We assessed calibration of perception and action in the context of a golf putting task. Previous research has shown that right-handed novice golfers make rightward errors both in the perception of the perfect aiming line from the ball to the hole and in the putting action. Right-handed experts, however, produce accurate putting actions but tend to make leftward errors in perception. In two experiments, we examined whether these skill-related differences in directional error reflect transfer of calibration from action to perception. In the main experiment, three groups of right-handed novice participants followed a pretest, practice, posttest, retention test design. During the tests, directional error for the putting action and the perception of the perfect aiming line were determined. During practice, participants were provided only with verbal outcome feedback about directional error; one group trained perception and the second trained action, whereas the third group did not practice. Practice led to a relatively permanent annihilation of directional error, but these improvements in accuracy were specific to the trained task. Hence, no transfer of calibration occurred between perception and action. The findings are discussed within the two visual-system model for perception and action, and implications for perceptual learning in action are raised. PMID- 21814860 TI - The genetic profiling of preferentially expressed genes in murine splenic CD8alpha+ dendritic cells. AB - In the murine splenocytes, CD8alpha+ dendritic cells (abbreviated as 8+DC) and CD8alpha- dendritic cells (abbreviated as 8-DC) are identified with some vague features for each of them. 8+DCs but not 8-DCs cross-prime cytotoxic T cells in vivo. We aim to distinguish the two subtypes of DC based on gene expression profiling. Suppressive subtractive hybridization was undertaken to get differentially expressed genes from such subtracted cDNA library specific to 8+DC. A total of 114 sequences from the subtracted cDNA library specific to 8+DC library were analyzed. Most of them are known proteins, but some of them were novel, either totally novel genes or homologs to known genes, but with novel exon. About 55 probably novel exons were discovered, and 11 exons had longer length than those in gene bank. The clones 12, 44, 79, and 110 have no match with known sequences in gene bank. Then, semi-quantitative PCR was done to compare the expression of the enriched sequences between 8+DC and 8-DC. About 14 genes are differentially expressed in 8+DC. Therefore, SSH is an effective method to clone differentially expressed genes for 8+DC compared to 8-DC. PMID- 21814861 TI - Influence of cholesterol and beta-sitosterol on the structure of EYPC bilayers. AB - The influence of cholesterol and beta-sitosterol on egg yolk phosphatidylcholine (EYPC) bilayers is compared. Different interactions of these sterols with EYPC bilayers were observed using X-ray diffraction. Cholesterol was miscible with EYPC in the studied concentration range (0-50 mol%), but crystallization of beta sitosterol in EYPC bilayers was observed at X >= 41 mol% as detected by X-ray diffraction. Moreover, the repeat distance (d) of the lamellar phase was similar upon addition of the two sterols up to mole fraction 17%, while for X >= 17 mol% it became higher in the presence of beta-sitosterol compared to cholesterol. SANS data on suspensions of unilamellar vesicles showed that both cholesterol and beta sitosterol similarly increase the EYPC bilayer thickness. Cholesterol in amounts above 33 mol% decreased the interlamellar water layer thickness, probably due to "stiffening" of the bilayer. This effect was not manifested by beta-sitosterol, in particular due to the lower solubility of beta-sitosterol in EYPC bilayers. Applying the formalism of partial molecular areas, it is shown that the condensing effect of both sterols on the EYPC area at the lipid-water interface is small, if any. The parameters of ESR spectra of spin labels localized in different regions of the EYPC bilayer did not reveal any differences between the effects of cholesterol and beta-sitosterol in the range of full miscibility. PMID- 21814862 TI - [Diagnosis of tumours of the liver and the biliary tract: new tissue and serum markers]. AB - Hepatocellular carcinomas (HCC) and bile duct carcinomas (BDC) have a poor prognosis since they are often detected at advanced stages and respond poorly to adjuvant therapy. Serum markers (e.g. AFP, CA19-9, etc.) can be used for early detection of these tumours but have only moderate sensitivity and specificity. The Golgi-associated protein GOLPH2 was found in the tissue and serum of patients with HCC and CCC and might be used to detect these tumours in time. The biopsy still remains the gold standard in the diagnosis of HCC and CCC. When biopsies are taken from these tumours they are often fragmented and contain reactive changes. Therefore immunohistochemical markers can aid in excluding or ascertaining malignancy. Studies have shown that the oncofetal protein "IGF-II mRNA-binding protein 3" (IMP3), the cell adhesion molecules P-cadherin and CD24, the cancer testis antigen MAGE-C2/CT-10 as well as the protein periostin can be used as tissue markers in the diagnosis of HCC and CCC. PMID- 21814863 TI - HIV-2 A-subtype gp125c2-v3-c3 mutations and their association with CCR5 and CXCR4 tropism. AB - The early events of the HIV replication cycle involve the interaction between viral envelope glycoproteins and their cellular CD4-chemokine (CCR5/CXCR4) receptor complex. In this study, for the first time, the HIV-2 A-subtype gp125(C2 V3-C3) mutations and their tropism association were characterized by analyzing 149 HIV-2 sequences from the Los Alamos database. The analysis has strengthened the importance of C2-V3-C3 region as a determinant factor for co-receptor selection. Moreover, statistically significant correlations were observed between C2-V3-C3 mutations, and several correlated mutations were associated with CXCR4 and CCR5 co-receptor usage. A dendrogram showed two distinct clusters, with numerous associated mutations grouped, thus dividing CCR5- and CXCR4-tropic viruses. Fourteen X4-tropic virus mutations, all in V3 and C3 domains and forming highly significant subclusters, were found. Finally, R5 associations, two strong subclusters were observed, grouping several C2-V3-C3 mutated positions. These data indicate the possible contribution of C2-V3-C3 mutational patterns in regulating HIV-2 tropism. PMID- 21814864 TI - Infection of cynomolgus macaques with a recombinant monkeypox virus encoding green fluorescent protein. AB - Monkeypox virus (MPXV) causes a vesiculopustular rash illness resembling smallpox in humans and produces a similar disease in nonhuman primates. To enhance the ability of researchers to study experimental MPXV infections, we inserted a gene encoding green fluorescent protein (GFP) into Monkeypox virus Zaire-79. Wild-type and MPXV-GFP replicated with similar kinetics in cell culture and caused a similar disease when injected intravenously into cynomolgus macaques. In MPXV-GFP infected animals, examination under fluorescent light facilitated the identification of skin lesions during disease development and internal sites of replication at necropsy. MPXV-GFP could improve the quantitative assessment of antiviral therapy and vaccine efficacy. PMID- 21814865 TI - Comparison of two objective monitors for assessing physical activity and sedentary behaviors in bariatric surgery patients. AB - BACKGROUND: Objective quantification of physical activity (PA) is needed to understand PA and sedentary behaviors in bariatric surgery patients, yet it is unclear whether PA estimates produced by different monitors are comparable and can be interpreted similarly across studies. METHODS: We compared PA estimates from the Stayhealthy RT3 triaxial accelerometer (RT3) and the Sensewear Pro(2) Armband (SWA) at both the group and individual participant level. Bariatric surgery candidates were instructed to wear the RT3 and SWA during waking hours for 7 days. Participants meeting valid wear time requirements (>=4 days of >=8 h/day) for both monitors were included in the analyses. Time spent in sedentary (<1.5 METs), light (1.5-2.9 METs), moderate-to-vigorous (MVPA; >=3.0 METs), and total PA (TPA; >=1.5 METs) according to each monitor was compared. RESULTS: Fifty five participants (BMI 48.4 +/- 8.2 kg/m(2)) met wear time requirements. Daily time spent in sedentary (RT3 582.9 +/- 94.3; SWA 602.3 +/- 128.6 min), light (RT3 131.9 +/- 60.0; SWA 120.6 +/- 65.7 min), MVPA (RT3 25.9 +/- 20.9; SWA 29.9 +/- 19.5 min), and TPA (RT3 157.8 +/- 74.5; SWA 150.6 +/- 80.7 min) was similar between monitors (p > 0.05). While the average difference in TPA between the two monitors at the group level was 7.2 +/- 64.2 min; the average difference between the two monitors for each participant was 45.6 +/- 45.4 min. At the group level, the RT3 and SWA provide similar estimates of PA and sedentary behaviors; however, concordance between monitors may be compromised at the individual level. CONCLUSIONS: Findings related to PA and sedentary behaviors at the group level can be interpreted similarly across studies when either monitor is used. PMID- 21814866 TI - Frequency of multiple renal arteries in human fetuses. AB - PURPOSE: The aim of the present study was to determine the frequency of occurrence of multiple renal arteries in human fetuses. METHODS: Sixty kidneys from human fetuses (32 males and 28 females) were used, fixed and kept in 10% formol solution. The fetal age was estimated from the hallux-calcaneus length and ranged from 20 to 37 weeks of gestation, with a mean of 25.63 weeks. The renal arteries were dissected without the aid of optical instruments, and their number, length, topographical layout in relation to their origins in the aorta walls and distribution according to gender and kidney (left or right) were determined. RESULTS: Out of the 60 kidneys investigated, 78.33% had a single renal artery and 21.67% had multiple renal arteries. Most of the renal arteries emerged from the lateral wall of the aorta between the levels of the lower third of the twelfth thoracic vertebra and the upper third of the first lumbar vertebra. The length ranged from 0.15 to 1.5 cm and was slightly greater in females. CONCLUSIONS: The frequency of findings of multiple renal arteries was 21.67%. PMID- 21814867 TI - Loads of housework? Biomechanical assessments of the upper limbs in women performing common household tasks. AB - PURPOSE: Housework is a form of regular manual work that is often performed by women. Little is known about the entity of biomechanical exposure to the upper limbs during typical housework tasks. This study aims to make an initial quantitative estimate of some such exposures. METHODS: We conducted objective assessments of biomechanical exposure to the upper limbs during nine frequent housework tasks performed by 12 women without domestic help. For the main evaluations, we implemented five instruments: the OCRA (Occupational Repetitive Actions) checklist; OREGE (Outil de Reperage et d'Evaluation des Gestes); the American Conference of Governmental Industrial Hygienists (ACGIH) assessment of hand activity levels (HAL); RULA (Rapid Upper Limb Assessment); and the full checklist of the Washington State Department of Labor and Industries. RESULTS: The ACGIH evaluation suggested light/moderate biomechanical exposure levels, as did the RULA. For the OCRA checklist and OREGE, time-weighted average scores (not adjusted by a duration multiplier because women may also routinely undergo biomechanical loads in other domestic or professional settings) were: OCRA checklist, 12.0 ("mild risk", light red) and OREGE, 10.2 ("not recommended"). The full checklist of Washington State Department of Labor and Industries showed that repetitive/similar movements (for >2 h/day) accompanied by other risk factors such as >=30 degrees bending of the wrists, >=45 degrees stretched wrists, >=30 degrees ulnar stretches, and manual force. CONCLUSIONS: Housework commonly entails light-moderate biomechanical loads that nevertheless could conceivably contribute to the genesis/worsening of musculoskeletal disorders. Biomechanical loads experienced by women during housework deserve greater consideration in epidemiologic studies of musculoskeletal disorders. PMID- 21814868 TI - Echocardiographic detection of early myocardial calcification in acute neonatal myocarditis due to Coxsackie virus type B. PMID- 21814869 TI - Does practice make perfect? A randomized control trial of behavioral rehearsal on suicide prevention gatekeeper skills. AB - Suicide is the third leading cause of death among 10-24-year-olds and the target of school-based prevention efforts. Gatekeeper training, a broadly disseminated prevention strategy, has been found to enhance participant knowledge and attitudes about intervening with distressed youth. Although the goal of training is the development of gatekeeper skills to intervene with at-risk youth, the impact on skills and use of training is less known. Brief gatekeeper training programs are largely educational and do not employ active learning strategies such as behavioral rehearsal through role play practice to assist skill development. In this study, we compare gatekeeper training as usual with training plus brief behavioral rehearsal (i.e., role play practice) on a variety of learning outcomes after training and at follow-up for 91 school staff and 56 parents in a school community. We found few differences between school staff and parent participants. Both training conditions resulted in enhanced knowledge and attitudes, and almost all participants spread gatekeeper training information to others in their network. Rigorous standardized patient and observational methods showed behavioral rehearsal with role play practice resulted in higher total gatekeeper skill scores immediately after training and at follow-up. Both conditions, however, showed decrements at follow-up. Strategies to strengthen and maintain gatekeeper skills over time are discussed. PMID- 21814870 TI - Parasagittal compartmentation of cerebellar mossy fibers as revealed by the patterned expression of vesicular glutamate transporters VGLUT1 and VGLUT2. AB - The cerebellum receives sensory signals from spinocerebellar (lower limbs) and dorsal column nuclei (upper limbs) mossy fibers. In the cerebellum, mossy fibers terminate in bands that are topographically aligned with stripes of Purkinje cells. While much is known about the molecular heterogeneity of Purkinje cell stripes, little is known about whether mossy fiber compartments have distinct molecular profiles. Here, we show that the vesicular glutamate transporters VGLUT1 and VGLUT2, which mediate glutamate uptake into synaptic vesicles of excitatory neurons, are expressed in complementary bands of mossy fibers in the adult mouse cerebellum. Using a combination of immunohistochemistry and anterograde tracing, we found heavy VGLUT2 and weak VGLUT1 expression in bands of spinocerebellar mossy fibers. The adjacent bands, which are in part comprised of dorsal column nuclei mossy fibers, strongly express VGLUT1 and weakly express VGLUT2. Simultaneous injections of fluorescent tracers into the dorsal column nuclei and lower thoracic-upper lumbar spinal cord revealed that upper and lower limb sensory pathways innervate adjacent VGLUT1/VGLUT2 parasagittal bands. In summary, we demonstrate that VGLUT1 and VGLUT2 are differentially expressed by dorsal column nuclei and spinocerebellar mossy fibers, which project to complementary cerebellar bands and respect common compartmental boundaries in the adult mouse cerebellum. PMID- 21814871 TI - Extracurricular participation and academic outcomes: testing the over-scheduling hypothesis. AB - There is a growing concern that some youth are overscheduled in extracurricular activities, and that this increasing involvement has negative consequences for youth functioning. This article used data from the Educational Longitudinal Study (ELS: 2002), a nationally representative and ethnically diverse longitudinal sample of American high school students, to evaluate this hypothesis (N = 13,130; 50.4% female). On average, 10th graders participated in between 2 and 3 extracurricular activities, for an average of 5 h per week. Only a small percentage of 10th graders reported participating in extracurricular activities at high levels. Moreover, a large percentage of the sample reported no involvement in school-based extracurricular contexts in the after-school hours. Controlling for some demographic factors, prior achievement, and school size, the breadth (i.e., number of extracurricular activities) and the intensity (i.e., time in extracurricular activities) of participation at 10th grade were positively associated with math achievement test scores, grades, and educational expectations at 12th grade. Breadth and intensity of participation at 10th grade also predicted educational status at 2 years post high school. In addition, the non-linear function was significant. At higher breadth and intensity, the academic adjustment of youth declined. Implications of the findings for the over scheduling hypothesis are discussed. PMID- 21814872 TI - Changes of fecal Bifidobacterium species in adult patients with hepatitis B virus induced chronic liver disease. AB - The beneficial effects of Bifidobacteria on health have been widely accepted. Patients with chronic liver disease have varying degrees of intestinal microflora imbalance with a decrease of total Bifidobacterial counts. Since different properties have been attributed to different Bifidobacterium species and there is no information available for the detailed changes in the genus Bifidobacterium in patients with chronic liver disease heretofore, it is meaningful to investigate the structure of this bacterium at the species level in these patients. The aim of this study was to characterize the composition of intestinal Bifidobacterium in patients with hepatitis B virus-induced chronic liver disease. Nested-PCR based denaturing gradient gel electrophoresis (PCR-DGGE), clone library, and real time quantitative PCR were performed on the fecal samples of 16 patients with chronic hepatitis B (CHB patients), 16 patients with hepatitis B virus-related cirrhosis (HBV cirrhotics), and 15 healthy subjects (Controls). Though there was no significant difference in the diversity among the three groups (P = 0.196), Bifidobacterium dentium seems to be specifically enhanced in patients as the PCR DGGE profiles showed, which was further validated by clone library and real-time quantitative PCR. In contrast to the B. dentium, Bifidobacterium catenulatum/Bifidobacterium pseudocatenulatum were detected less frequently in the predominant profile and by quantitative PCR in HBV cirrhotics than in the controls, and the level of this species was also significantly different between these two groups (P = 0.023). Although having no quantitative difference among the three groups, Bifidobacterium longum was less commonly detected in HBV cirrhotics than in CHB patients and Controls by quantitative PCR (P = 0.011). Thus, the composition of intestinal Bifidobacterium was deeply altered in CHB and HBV cirrhotic patients with a shift from beneficial species to opportunistic pathogens. The results provide further insights into the dysbiosis of the intestinal microbiota in patients with hepatitis B virus-induced chronic liver disease and might potentially serve as guidance for the probiotics interventions of these diseases. PMID- 21814873 TI - A large multi-centre European study validates high-sensitivity C-reactive protein (hsCRP) as a clinical biomarker for the diagnosis of diabetes subtypes. AB - AIMS/HYPOTHESIS: An accurate molecular diagnosis of diabetes subtype confers clinical benefits; however, many individuals with monogenic diabetes remain undiagnosed. Biomarkers could help to prioritise patients for genetic investigation. We recently demonstrated that high-sensitivity C-reactive protein (hsCRP) levels are lower in UK patients with hepatocyte nuclear factor 1 alpha (HNF1A)-MODY than in other diabetes subtypes. In this large multi-centre study we aimed to assess the clinical validity of hsCRP as a diagnostic biomarker, examine the genotype-phenotype relationship and compare different hsCRP assays. METHODS: High-sensitivity CRP levels were analysed in individuals with HNF1A-MODY (n = 457), glucokinase (GCK)-MODY (n = 404), hepatocyte nuclear factor 4 alpha (HNF4A) MODY (n = 54) and type 2 diabetes (n = 582) from seven European centres. Three common assays for hsCRP analysis were evaluated. We excluded 121 participants (8.1%) with hsCRP values >10 mg/l. The discriminative power of hsCRP with respect to diabetes aetiology was assessed by receiver operating characteristic curve derived C-statistic. RESULTS: In all centres and irrespective of the assay method, meta-analysis confirmed significantly lower hsCRP levels in those with HNF1A-MODY than in those with other aetiologies (z score -21.8, p < 5 * 10( 105)). HNF1A-MODY cases with missense mutations had lower hsCRP levels than those with truncating mutations (0.03 vs 0.08 mg/l, p < 5 * 10(-5)). High-sensitivity CRP values between assays were strongly correlated (r (2) >= 0.91, p <= 1 * 10( 5)). Across the seven centres, the C-statistic for distinguishing HNF1A-MODY from young adult-onset type 2 diabetes ranged from 0.79 to 0.97, indicating high discriminative accuracy. CONCLUSIONS/INTERPRETATION: In the largest study to date, we have established that hsCRP is a clinically valid biomarker for HNF1A MODY in European populations. Given the modest costs and wide availability, hsCRP could translate rapidly into clinical practice, considerably improving diagnosis rates in monogenic diabetes. PMID- 21814874 TI - Comparative study of hypocholesterolemic and hypolipidemic effects of conjugated linolenic acid isomers against induced biochemical perturbations and aberration in erythrocyte membrane fluidity. AB - AIM OF STUDY: The purpose of the study was to evaluate hypolipidemic and hypocholesterolemic activities of conjugated linolenic acid (CLnA) isomers, present in bitter gourd and snake gourd seed, in terms of amelioration of plasma lipid profile, lipoprotein oxidation and erythrocyte membrane fluidity after oral administration. METHODS: Male albino rats were divided into six groups. Group 1 was control, and others were induced with oxidative stress by oral gavage of sodium arsenite (Sa). Group 2 was kept as treated control, and groups 3-6 were further treated with different oral doses of seed oils to maintaining definite concentration of CLnA isomers (0.5 and 1.0% of total lipid for each CLnA isomer). RESULTS: CLnA isomers normalized cholesterol, LDL-cholesterol, HDL-cholesterol and triglyceride contents in plasma and body weight of experimental rats and decreased cholesterol synthesis by reducing hepatic HMG-CoA reductase activity. Administration of Sa caused alteration in erythrocyte membrane fluidity due to increase in cholesterol and decrease in phospholipid content. Tissue cholesterol and lipid contents were also increased by Sa administration. These altered parameters were reversed by experimental oil administration. Protective effect of CLnA isomers on erythrocyte morphology was observed by atomic force microscopy (AFM). Fatty acid composition of erythrocyte membrane showed decrease in polyunsaturated fatty acid (PUFA) and increase in arachidonic acid content after Sa administration, which was normalized with the treatment of these oils. Supplementation of CLnA isomers restored erythrocyte membrane (EM) lipid peroxidation and lipoprotein oxidation. CONCLUSION: CLnA isomers, present in vegetable oils, showed potent hypolipidemic and hypocholesterolemic activities against biochemical perturbations. PMID- 21814875 TI - Psychometric properties of instruments to measure the quality of end-of-life care and dying for long-term care residents with dementia. AB - PURPOSE: Quality of care for long-term care (LTC) residents with dementia at the end-of-life is often evaluated using standardized instruments that were not developed for or thoroughly tested in this population. Given the importance of using appropriate instruments to evaluate the quality of care (QOC) and quality of dying (QOD) in LTC, we compared the validity and reliability of ten available instruments commonly used for these purposes. METHODS: We performed prospective observations and retrospective interviews and surveys of family (n = 70) and professionals (n = 103) of LTC decedents with dementia in the Netherlands. RESULTS: Instruments within the constructs QOC and QOD were highly correlated, and showed moderate to high correlation with overall assessments of QOC and QOD. Prospective and retrospective ratings using the same instruments differed little. Concordance between family and professional scores was low. Cronbach's alpha was mostly adequate. The EOLD-CAD showed good fit with pre-assumed factor structures. The EOLD-SWC and FPCS appear most valid and reliable for measuring QOC, and the EOLD-CAD and MSSE for measuring QOD. The POS performed worst in this population. CONCLUSIONS: Our comparative study of psychometric properties of instruments allows for informed selection of QOC and QOD measures for LTC residents with dementia. PMID- 21814876 TI - Latent variable mixture models: a promising approach for the validation of patient reported outcomes. AB - PURPOSE: A fundamental assumption of patient-reported outcomes (PRO) measurement is that all individuals interpret questions about their health status in a consistent manner, such that a measurement model can be constructed that is equivalently applicable to all people in the target population. The related assumption of sample homogeneity has been assessed in various ways, including the many approaches to differential item functioning analysis. METHODS: This expository paper describes the use of latent variable mixture modeling (LVMM), in conjunction with item response theory (IRT), to examine: (a) whether a sample is homogeneous with respect to a unidimensional measurement model, (b) implications of sample heterogeneity with respect to model-predicted scores (theta), and (c) sources of sample heterogeneity. An example is provided using the 10 items of the Short-Form Health Status (SF-36((r))) physical functioning subscale with data from the Canadian Community Health Survey (2003) (N = 7,030 adults in Manitoba). RESULTS: The sample was not homogeneous with respect to a unidimensional measurement structure. Specification of three latent classes, to account for sample heterogeneity, resulted in significantly improved model fit. The latent classes were partially explained by demographic and health-related variables. CONCLUSION: The illustrative analyses demonstrate the value of LVMM in revealing the potential implications of sample heterogeneity in the measurement of PROs. PMID- 21814877 TI - Rasch analysis in the development of a simplified version of the National Eye Institute Visual-Function Questionnaire-25 for utility estimation. AB - PURPOSE: Preference-based health measures value how people feel about the desirability of a health state. Generic measures may not effectively capture the impact of vision loss from ocular diseases. Disease-targeted measures could address this limitation. This study developed a vision-targeted health state classification system based on the National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25). METHODS: Secondary analysis of NEI VFQ-25 data from studies of patients with central (n = 932)- and peripheral-vision loss (n = 2,451) were used to develop a health state classification system. Classical test theory and Rasch analyses were used to identify a smaller set of NEI VFQ-25 items suitable for the central- and peripheral-vision-loss groups. RESULTS: Rasch analysis of the NEI VFQ-25 items using the peripheral vision-loss data indicated that 11 items fit a unidimensional model, while 14 NEI VFQ-25 items fit using the central-vision-loss data. Combining peripheral-vision-loss data and central vision-loss data resulted in 9 items fitting a unidimensional model. Six items covering near vision, distance vision, social vision, role difficulties, vision dependency, and vision-related mental health were selected for the health-state classification. CONCLUSIONS: The derived health-state classification system covers relevant domains of vision-related functioning and well-being. PMID- 21814878 TI - Computational modeling on the recognition of the HRE motif by HIF-1: molecular docking and molecular dynamics studies. AB - Hypoxia inducible factor-1 (HIF-1) is a bHLH-family transcription factor that controls genes involved in glycolysis, angiogenesis, migration, as well as invasion factors that are important for tumor progression and metastasis. HIF-1, a heterodimer of HIF-1alpha and HIF-1beta, binds to the hypoxia responsive element (HRE) present in the promoter regions of hypoxia responsive genes, such as vascular endothelial growth factor (VEGF). Neither the structure of free HIF-1 nor that of its complex with HRE is available. Computational modeling of the transcription factor-DNA complex has always been challenging due to their inherent flexibility and large conformational space. The present study aims to model the interaction between the DNA-binding domain of HIF-1 and HRE. Experiments showed that rigid macromolecular docking programs (HEX and GRAMM-X) failed to predict the optimal dimerization of individually modeled HIF-1 subunits. Hence, the HIF-1 heterodimer was modeled based on the phosphate system positive regulatory protein (PHO4) homodimer. The duplex VEGF-DNA segment containing HRE with flanking nucleotides was modeled in the B form and equilibrated via molecular dynamics (MD) simulation. A rigid docking approach was used to predict the crude binding mode of HIF-1 dimer with HRE, in which the putative contacts were found to be present. An MD simulation (5 ns) of the HIF-1 HRE complex in explicit water was performed to account for its flexibility and to optimize its interactions. All of the conserved amino acid residues were found to play roles in the recognition of HRE. The present work, which sheds light on the recognition of HRE by HIF-1, could be beneficial in the design of peptide or small molecule therapeutics that can mimic HIF-1 and bind with the HRE sequence. PMID- 21814879 TI - In vivo bladder selectivity of imidafenacin, a novel antimuscarinic agent, assessed by using an effectiveness index for bladder capacity in rats. AB - Imidafenacin (KRP-197) is a novel antimuscarinic agent for overactive bladder treatment. The inhibitory effect of imidafenacin on detrusor contraction has been adopted for assessing their bladder selectivity, but this is becoming less convincing as an effectiveness index. We, therefore, reevaluated the bladder selectivity of imidafenacin and other antimuscarinics using their effects on the bladder capacity as an effectiveness index. Bladder capacity was measured by intermittent cystometry in urethane-anesthetized rats. In the tissues related to antimuscarinic side effects, the inhibitory actions were measured each on salivary secretion by electrical stimulation of chorda tympani, on rhythmical contractions in colon, and on carbamylcholine-induced bradycardia. Imidafenacin, solifenacin succinate, tolterodine tartrate, and propiverine hydrochloride significantly increased the bladder capacity, with minimum effective doses of 0.003, 1, 0.03, and 3 mg/kg (i.v.), respectively. The antimuscarinics tested, except for propiverine hydrochloride, shared a common property of increasing bladder capacity at a dose which did not affect micturition pressure. The relative bladder selectivity of imidafenacin, solifenacin succinate, and tolterodine tartrate was 15-, 1.7-, and 2.5-fold higher over salivary gland; 150 , 1.9-, and 9.2-fold higher over colon; and 50-, 12-, and 4.6-fold higher over heart, respectively, than that of propiverine hydrochloride. Thus, imidafenacin shows the most highly selective for bladder over the tissues related to major antimuscarinic side effects, compared to the other three well-known antimuscarinics tested in the rat. PMID- 21814880 TI - A mathematical model for the effects of HER2 over-expression on cell cycle progression in breast cancer. AB - In this paper, we present a mathematical model predicting the fraction of proliferating cells in G1, S, and G2/M phases of the cell cycle as a function of EGFR and HER2. We show that it is possible to find parameters for the mathematical model so that its predictions agree with the experimental observations that HER2 over-expression results in: (1) a shorter G1-phase and early S-phase entry; (2) and that with a 1-to-1 ration between EGFR and HER2, the growth advantage in HER2 over-expressing cells is indeed associated with the increase of the HER2 expression level. PMID- 21814882 TI - Dominant lymph drainage in the facial region: evaluation of lymph nodes of facial melanoma patients. AB - BACKGROUND: The purpose of this study was to evaluate the superficial lymph drainage patterns from primary lesions, with the primary focus on cheek/eyelid and lip melanomas. METHOD: We conducted a retrospective study of 22 patients with facial melanomas who had undergone neck dissection or sentinel lymph node biopsy at the hospital from 1981 to April 2011. We then analyzed the dominant lymph drainage patterns from the cheek/eyelid and lip regions. RESULTS: The cheek/eyelid regions have two lymph drainage patterns: one is to the parotid nodes and the other is to level IB. The lymph drainage patterns in the lip region are to level IA or IB. The lymph drainage patterns to superficial lymph nodes from the primary sites were determined in both regions. CONCLUSIONS: Cheek/eyelid and lip melanomas have lymph drainage patterns different from those of malignant tumors of the oropharyngeal and larynx regions. Superficial lymph node groups also play an important role in facial melanomas. PMID- 21814881 TI - Critical roles of NOTCH1 in acute T-cell lymphoblastic leukemia. AB - NOTCH1 plays a central role in T-cell development and, when aberrantly activated, in acute T-cell lymphoblastic leukemia (T-ALL). As a transmembrane receptor that is ultimately converted into a transcription factor, NOTCH1 directly activates a spectrum of target genes, which function to mediate NOTCH1 signaling in normal or transformed T cells. During physiologic T-cell development, NOTCH1 has important functions in cell fate determination, proliferation, survival and metabolism. Activating NOTCH1 mutations occur in more than half of human patients with T-ALL, suggesting an important role for aberrant NOTCH1 signaling in the pathogenesis of this disease. Inhibiting NOTCH1 signaling in patient-derived cell lines and murine T-ALLs leads to growth arrest and/or apoptosis suggesting that NOTCH1 inhibitors can improve T-ALL treatment. However, there are challenges to translate NOTCH1 inhibitors to the clinic because of toxicity and resistance. This review focuses on molecular mechanisms of oncogenic NOTCH1 signaling, molecular and functional analysis of NOTCH1 transcriptional targets in T-ALL, and recent advances in therapeutic targeting of NOTCH1. PMID- 21814884 TI - [Calcific tendinitis of the shoulder]. AB - Calcific tendinitis of the shoulder is a process involving crystal calcium deposition in the rotator cuff tendons, which mainly affects patients between 30 and 50 years of age. The etiology is still a matter of dispute. The diagnosis is made by history and physical examination with specific attention to radiologic and sonographic evidence of calcific deposits. Patients usually describe specific radiation of the pain to the lateral proximal forearm, with tenderness even at rest and during the night. Nonoperative management including rest, nonsteroidal anti-inflammatory drugs, subacromial corticosteroid injections, and shock wave therapy is still the treatment of choice. Nonoperative treatment is successful in up to 90% of patients. When nonsurgical measures fail, surgical removal of the calcific deposit may be indicated. Arthroscopic treatment provides excellent results in more than 90% of patients. The recovery process is very time consuming and may take up to several months in some cases. PMID- 21814885 TI - How do mosquito eggs self-assemble on the water surface? AB - This work reports a detailed numerical study of the behavior of ellipsoid-shaped particles adsorbed at fluid interfaces. Former experiments have shown that micrometer-sized prolate ellipsoids aggregate under the action of strong and long ranged capillary interactions. The latter are due to nonplanar contact lines and to the resulting deformations of the interface in the vicinity of the trapped objects. We first consider the case of a single ellipsoid and examine in detail the influence of contact angle and ellipsoid aspect ratio on interfacial distortions. We then focus on two contacting ellipsoids and study the optimum packing configuration depending on their size and/or aspect ratio mismatch. We thoroughly explore the variety of contact configurations between both ellipsoids and provide corresponding energy maps. Whereas the side-by-side configuration is the most stable state for identical ellipsoids, we find that the mismatched pair adopts an "arrow" configuration in which a finite angle exists between the particles long axes. Such arrows are actually seen in experiments with micron sized ellipsoids and similarly with millimeter-sized mosquito eggs. These results complement our previous work (J.C. Loudet, B. Pouligny, EPL 85, 28003 (2009)) and highlight the importance of geometrical factors to explain the morphology of aggregated structures at fluid interfaces. PMID- 21814886 TI - [Thyroid illness during pregnancy]. AB - Pregnancy causes a number of physiological alterations in thyroid hormone metabolism that need to be distinguished from the pathophysiological states of thyroid dysfunction. Both hypothyroidism and thyrotoxicosis may impair the course of pregnancy and may negatively affect the fetus. In particular, maternal hypothyroidism may lead to irreparable and detrimental deficits in the neurocognitive development of the fetus. Autoimmune thyroid disease is the most common cause of thyroid dysfunction in pregnancy. Hashimoto's thyroiditis is associated with impaired fertility and miscarriage, and may first manifest in pregnancy due to the increased thyroid hormone requirement. Graves' disease often shows a characteristic course in pregnancy with amelioration of thyrotoxicosis in the second half of pregnancy and exacerbation after delivery. In addition transplacental passage of maternal TSH receptor antibodies may lead to thyrotoxicosis in the fetus and/or newborn. PMID- 21814887 TI - An unusual association of neuroendocrine tumors in MEN 1A. AB - Multiple Endocrine Neoplasia type 1 is an autonomic dominant disease with a high degree of penetrance. It is characterized by combinations of over 20 different endocrine and nonendocrine tumors. A 25-year-old woman was referred for 1 year evolution amenorrhea and bilateral galactorrhea. She also had fasting hypoglycaemia and hypercalcemia, and she was diagnosed of Multiple Endocrine Neoplasia type 1A. Resection of three parathyroid glands was performed showing hyperplasia of principal cells. Post-parathyroidectomy serum levels of calcium and intact PTH were normal but 3 years later serum calcium levels rose again. A 99mTc-sestamibi scan showed increased uptake in the low right area compatible with adenoma. After biochemical test showing probable insulinoma, somatostatin receptor scintigraphy showed a focal captation in head and body of pancreas. MRI found two nodules in the same localization. An antral gastrectomy, total pancreatoduodenectomy, colecistectomy and truncal vagotomy was performed and histopathologic examination revealed a combination of neuroendocrine tumors: gastrinomas, somastotinomas, glucagonomas and insulinomas. After surgery she started with tingling in fingers, toes and lips, and calcium levels was 5.9 mg/dl and PTH intact 3 pg/ml. A new 99m Tc-sestamibi scan showed no captation and cervical ultrasonography was normal. Now, 2 years later, she continues with normal calcium and i-PTH levels. This report represents an unusual case of MEN 1A with association of insulinomas, gastrinomas glucagonomas and somatostatinomas in the same patient. PMID- 21815055 TI - In vitro neurotoxicology: an introduction. AB - This introductory Chapter provides a brief overview of the field of neurotoxicology and of the role played by in vitro approaches in investigations on mechanisms of neurotoxicity and of developmental neurotoxicity, and in providing suitable models for neurotoxicity screening. PMID- 21815056 TI - Primary neurons in culture and neuronal cell lines for in vitro neurotoxicological studies. AB - Primary neuronal cultures and neuronal cell lines derived from rodents are widely used to study basic physiological properties of neurons, and represent a useful tool to study the potential neurotoxicity of chemicals. While short-term culturing of neurons can be a very straightforward process, long-term cultures of relatively pure neuronal populations require more effort. This chapter describes methods and protocols to isolate and culture primary neurons obtained from the rodent cerebellum (cerebellar granule cells), the hippocampus, and the striatum. Furthermore, culturing of rat pheochromocytoma (PC-12) cells is also described, as these cells represent a useful and widely used cell line for in vitro neurotoxicological studies. PMID- 21815057 TI - Determination of metal interactions with the chaperone Hspa5 in human astrocytoma cells and rat astrocyte primary cultures. AB - Molecular chaperones assist the folding of nascent proteins during translation into their correct conformations. Neurotoxic metals such as copper (Cu) and lead (Pb) may produce a deficiency in chaperone function that compromises protein secretion and exacerbates protein aggregation, potentially promoting neurodegenerative diseases that exhibit protein aggregation. Because astrocytes function as depots in the brain for certain metals, including Cu and Pb, the interaction of metals with chaperones in these cells is of interest. Furthermore, Pb and Cu bind strongly to the molecular chaperone heat shock 70 kDa protein Hspa5, also known as glucose-regulated protein 78 (Grp78) or immunoglobulin binding protein (BiP). This chapter describes methods for expressing fluorescent chimeric proteins in astrocytes and astrocytoma cells in order to examine the metal-induced cytosolic redistribution of Hspa5, as well as associated effects on the secretion of interleukin-6 (IL-6). PMID- 21815058 TI - Microglia cell culture: a primer for the novice. AB - Microglial cells are the resident immune cells of the central nervous system. Progress in the recent decade has clearly established that microglial cells participate or even actively drive neurological disease. Much of our current knowledge has been generated by investigating microglial cells in cell culture. The aim of this chapter is to give the uninitiated a basic and adaptable protocol for the culturing of microglial cells. We discuss the challenges of microglial cell culture and provide a collection of tips which reflect our 25+ years of collective experience. PMID- 21815059 TI - Neural stem cells for developmental neurotoxicity studies. AB - The developing nervous system is particularly susceptible to toxicants, and exposure during development may result in long-lasting neurological impairments. The damage can range from subtle to severe, and it may impose substantial burdens on affected individuals, their families, and society. Given the little information available on developmental neurotoxicity (DNT) and the growing number of chemicals that need to be tested, new testing strategies and approaches are necessary to identify developmental neurotoxic agents with speed, reliability, and respect for animal welfare. So far, there are no validated alternative methods for DNT testing. Recently, neural stem/progenitor cells have been proposed as relevant models for alternative DNT testing. In this chapter, we provide detailed protocols for culturing neural stem cells (NSCs), in vitro experimental models, including primary cultures of rat and human embryonic NSCs, rat and mouse adult NSCs, as well as the mouse NSC line C17.2 that we have implemented and successfully used for neurotoxicity studies. PMID- 21815060 TI - Preparation, maintenance, and use of serum-free aggregating brain cell cultures. AB - Serum-free aggregating brain cell cultures are free-floating three-dimensional primary cell cultures able to reconstitute spontaneously a histotypic brain architecture to reproduce critical steps of brain development and to reach a high level of structural and functional maturity. This culture system offers, therefore, a unique model for neurotoxicity testing both during the development and at advanced cellular differentiation, and the high number of aggregates available combined with the excellent reproducibility of the cultures facilitates routine test procedures. This chapter presents a detailed description of the preparation, maintenance, and use of these cultures for neurotoxicity studies and a comparison of the developmental characteristics between cultures derived from the telencephalon and cultures derived from the whole brain. For culture preparation, mechanically dissociated embryonic brain tissue is used. The initial cell suspension, composed of neural stem cells, neural progenitor cells, immature postmitotic neurons, glioblasts, and microglial cells, is kept in a serum-free, chemically defined medium under continuous gyratory agitation. Spherical aggregates form spontaneously and are maintained in suspension culture for several weeks. Within the aggregates, the cells rearrange and mature, reproducing critical morphogenic events, such as migration, proliferation, differentiation, synaptogenesis, and myelination. For experimentation, replicate cultures are prepared by the randomization of aggregates from several original flasks. The high yield and reproducibility of the cultures enable multiparametric endpoint analyses, including "omics" approaches. PMID- 21815061 TI - Neurospheres as a model for developmental neurotoxicity testing. AB - Developmental neurotoxicity (DNT) of environmental chemicals is a serious threat to human health. So far, DNT testing is performed in animals. Such in vivo testing is time-consuming, expensive, and uses large numbers of animals. Moreover, species differences (rat-human) bear the problem of extrapolation. Thus, alternative tests are needed to provide faster and cheaper methods for DNT testing. Neurospheres are free-floating three-dimensional structures consisting of neural progenitor cells. Within the "neurosphere assay," basal processes of brain development, such as proliferation, migration, differentiation, and apoptosis, are mimicked. These processes can be disturbed by chemicals, and thus predict DNT. Therefore, we consider this cell system as a promising tool for DNT in vitro testing. The methods to determine the effects of chemicals on DNT specific endpoints are described in this chapter. PMID- 21815062 TI - Acute hippocampal slice preparation and hippocampal slice cultures. AB - A major advantage of hippocampal slice preparations is that the cytoarchitecture and synaptic circuits of the hippocampus are largely retained. In neurotoxicology research, organotypic hippocampal slices have mostly been used as acute ex vivo preparations for investigating the effects of neurotoxic chemicals on synaptic function. More recently, hippocampal slice cultures, which can be maintained for several weeks to several months in vitro, have been employed to study how neurotoxic chemicals influence the structural and functional plasticity in hippocampal neurons. This chapter provides protocols for preparing hippocampal slices to be used acutely for electrophysiological measurements using glass microelectrodes or microelectrode arrays or to be cultured for morphometric assessments of individual neurons labeled using biolistics. PMID- 21815063 TI - Glia-neuron sandwich cocultures: an in vitro approach to evaluate cell-to-cell communication in neuroinflammation and neurotoxicity. AB - Glia-neuron sandwich cocultures are "in vitro" cell systems suitable to evaluate cell-to-cell interactions relaying on the release of soluble factors, such as proinflammatory cytokines. This chapter presents a protocol to obtain a sandwich coculture from primary rat glial cells and hippocampal neurons. Furthermore, it provides details to evaluate the release of tumor necrosis factor-alpha by a biological assay and neuronal cell survival, as well as examples of practical application in the investigation of neuroinflammation and its impact on neuronal function. PMID- 21815064 TI - In vitro models to study the blood brain barrier. AB - The blood brain barrier regulates the transport of chemicals from entering and leaving the brain. Brain capillaries establish the barrier and restrict transport into the brain by providing a physical and chemical barrier. The physical barrier is due to tight membrane junctions separating the capillary endothelial cells resulting in limited paracellular transport. The chemical barrier is due to the expression of multidrug transporters that mediate the efflux of a broad range of hydrophobic chemicals. Because of the unusual nutrient demands of the brain, this limited permeability is compensated by the expression of a large number of transporters that are responsive to the metabolic demands of the brain. Consequently, the blood brain barrier indirectly regulates brain function by directly controlling the uptake of nutrients. Two widely used methods for studying the blood brain are a cell culture model using rat, pig, or cow brain endothelial cells and isolated microvessels. The cell culture model is more popular likely because it is easier to use and less costly compared to isolated microvessels. In some laboratories, brain endothelial cells are cocultured with astrocyte- or astroglial-conditioned media. The endothelial cells express many of the transporters displayed in vivo but not all. Although cell culture models vary, none express the tight barrier observed in vivo. Because microvessels are isolated directly from the brain, they express all of the transporters displayed in vivo. Their disadvantage is that the preparation is laborious, requires animals, and has a shorter lifespan in vitro. We present an approach in which transport is first verified in isolated microvessels, and then the mechanism is studied in cell culture. PMID- 21815065 TI - Measurements of cell death in neuronal and glial cells. AB - During brain development, cell death is a physiological process which allows the elimination of cells produced in excess. During adulthood, when there is no or little physiologic cell death, an increase in cell loss is usually caused by neurologic disorders or by exposure to neurotoxic chemicals. Measurements of cell death are often used a first line of investigation on chemicals. Cell death in neuronal or glial cultures in vitro can be quantified with a variety of assays based on different properties of live and dead cells. Thus, healthy cells exclude dye (e.g., trypan blue, propidium iodide) or possess metabolic activity to cause a compound's conversion to a colored or fluorescent one (e.g., MTT, calcein AM) while dead cells do not. Conversely, dying cells release enzymes in the medium (e.g., LDH) whose quantification is proportional to the number of dead cells. This chapter describes several relatively rapid, inexpensive and reliable methods for measuring cell death and in neurons and astrocytes in primary cultures or in neuronal and glial cell lines. PMID- 21815066 TI - Measurements of neuronal apoptosis. AB - Apoptosis is a natural process occurring during the development of central nervous system resulting in the elimination of neurons that may have formed faulty synapses. Apoptosis can also be triggered by deprivation of growth factors or by exposure to a variety of endogenous or exogenous compounds. Several methods exist to assess apoptosis in neuronal cells. The choice of a particular method for apoptosis detection is dependent on the cell system, the nature of the toxin or toxicant, the type of information being sought, and, finally, on technical limitations. In this chapter, we describe techniques to evaluate apoptosis in primary neuronal cell cultures based on the evaluation of three criteria: cell morphology, biochemical changes, and DNA degradation. To draw correct conclusions regarding the mode of cell death, a combination of some of the methods mentioned above should be used. PMID- 21815067 TI - Measurement of isoprostanes as markers of oxidative stress. AB - Oxidative stress results from an imbalance between production of reactive oxygen and nitrogen species (ROS and RNS, respectively) and endogenous antioxidant defense mechanisms. Increased generation of ROS/RNS is implicated in the pathogenesis of a variety of human diseases, including neurodegenerative disease, atherosclerosis, cancer, and aging. However, measuring oxidative stress in biological systems is complex and requires accurate quantification of either free radicals or damaged biomolecules. One method to quantify oxidative injury is to measure lipid peroxidation. Lipids are readily attacked by free radicals, resulting in the formation of a number of peroxidation products. F2-isoprostanes (F2-IsoPs) are one group of these compounds and they are derived by the free radical peroxidation of arachidonic acid (AA). The F2-IsoPs, prostaglandine F2 like compounds, provide an accurate measure of oxidative stress both in vitro and in vivo. This protocol details current methodology used to quantify these molecules using gas chromatography-mass spectrometry (GC/MS). PMID- 21815068 TI - Assessment of glutathione homeostasis. AB - The tripeptide glutathione (gamma-glutamylcysteinylglycine; GSH) is the most abundant antioxidant thiol in the brain. GSH plays a critical role in protecting brain cells from oxidative stress and xenobiotics, as well as maintaining the thiol redox state. High levels of GSH are present in the central nervous system, particularly in astrocytes. GSH is synthesized into two enzymatic steps, the first, and the rate-limiting one, is catalyzed by glutamate-cysteine ligase (GCL) to form a dipeptide which is then converted to GSH by GSH synthetase. In this chapter, we describe assays for the measurements of GSH levels and GCL activity. The first spectrophotometric assay is based on the affinity of 2,3 naphthalenedicarboxaldehyde (NDA) for GSH. In the second assay, GSH levels are measured after being derivatized using the fluorescent thiol reactive compound monobromobimane (MBB) and are detected by high-performance liquid chromatography (HPLC). The third assay allows the assessment of GCL activity, also by HPLC. PMID- 21815070 TI - Fluorescent assessment of intracellular calcium in individual cells. AB - Calcium is an important intracellular ion involved in numerous cell processes. There are multiple factors that contribute to the release of Ca2+. Some factors induce release as part of intracellular signaling cascades, while others result in unwanted changes to both basal and inducible Ca2+ levels. The accurate measurement of intracellular Ca2+ is, therefore, an important tool in neurotoxicology for assessing compounds/substances that disrupt Ca2+ homeostasis. Fluorescent, Ca2+-sensitive probes Indo-1 and Fluo-3 allow for the quantification of intracellular Ca2+ in individual cells to determine what effects neurotoxins have on both basal and stimulus-dependent Ca2+ concentrations. PMID- 21815069 TI - Assessing neuronal bioenergetic status. AB - Drug discovery and therapeutic development for disorders of the central nervous system (CNS) represents one of the largest unmet markets in modern medicine. We have increasingly recognized that the lack of stringent assessment of mitochondrial function during the discovery process has resulted in drug recalls, black box warnings, and an urgent need to understand the metabolic liability of small molecules in neural systems. Given that the brain is the most energetically demanding organ, even modest perturbations in neuronal energetic pathways have been shown to impact growth, signaling, connectivity, and the restorative capacity of the CNS. In this work, we describe several tools to assess metabolic activity of primary neuronal cultures and neural cell lines using an acute model of injury induced by oxygen glucose deprivation. Methods include the measurement of total ATP and NADH, enzymatic assessment of lactate production by anaerobic respiration, as well as viability assays. We also present a modified screening method for assessing aerobic respiration of immortalized cell lines using galactose challenge. PMID- 21815071 TI - Homeostatic regulation of glutamate neurotransmission in primary neuronal cultures. AB - Glutamate is the mayor excitatory neurotransmitter in vertebrate nervous system. It has a crucial role in most brain functions under physiological conditions through the activation of both ionotropic and metabotropic glutamate receptors. In addition, extracellular glutamate concentration is tightly regulated through different excitatory amino acid transporters (EAAT). Glutamate neurotransmission is also involved in the neurotoxic effects of many environmental chemicals and drugs. Furthermore, homeostatic changes in glutamate neurotransmission appear in response to prolonged block/enhancement of electrical activity. Here, we describe different approaches to evaluate alterations in glutamate neurotransmission regarding glutamate receptors and glutamate transporters by using primary cultures of neurons and astrocytes. The methods are based on the increased fluorescence of calcium-sensitive probes in response to glutamate agonists, on radioligand binding to glutamate receptors and transport sites, and on inmunocytochemistry visualization of glutamate receptors. PMID- 21815072 TI - Detection of nitric oxide formation in primary neural cells and tissues. AB - Nitric oxide (NO) is a free radical molecule with a short half-life (<5 s). Because its synthesis from L-arginine by constitutive NO synthase (NOS) is low in many cell types, including neurons and endothelial cells, direct detection of NO in biological systems is a difficult task. During pathological conditions in the CNS, the inducible form of NOS (iNOS or NOS2) is expressed in activated astrocytes and microglial cells and can result in higher levels of NO. However, it may still be difficult to detect NO in these cell types using typical spectrophotometric methods. Of particular note, NO is readily oxidized to nitrite and nitrate (relatively stable products) in cells and medium, which can be measured as a valid indicator of NO synthesis. The conversion of NO to peroxynitrite leads to the formation of stable protein adducts that can be detected by immunohistochemical or immunofluorescence methods. Additionally, intracellular levels of NO can be detected in real time using fluorescence imaging and NO-specific, cell permeable indicator dyes. PMID- 21815073 TI - JNK3-mediated apoptotic cell death in primary dopaminergic neurons. AB - Investigation of mechanisms responsible for dopaminergic neuron death is critical for understanding the pathogenesis of Parkinson's disease, yet this is often quite challenging technically. Here, we describe detailed methods for culturing primary mesencephalic dopaminergic neurons and examining the activation of c-Jun N-terminal protein Kinase (JNK) in these cultures. We utilized immunocytochemistry and computerized analysis to quantify the number of surviving dopaminergic neurons and JNK activation in dopaminergic neurons. TUNEL staining was used to quantify apoptotic cell death. siRNA was used to specifically inhibit JNK3, the neural specific isoform of JNK. Our data implicate the activation of JNK3 in rotenone-induced dopaminergic neuron apoptosis. PMID- 21815074 TI - Measurement of proteasomal dysfunction in cell models of dopaminergic degeneration. AB - Parkinson's disease (PD) is the second most common neurodegenerative diseases, which occurs in both inheritable and sporadic forms. The interplay of the genetic mutations and environmental exposure to disease risk factors contributes to the pathogenic events leading to the demise of dopaminergic neurons in PD. Proteasome is one of the major proteolytic machinery responsible for degrading unwanted and damaged intracellular proteins. Emerging evidence implicates the incomplete proteolysis by ubiquitin-proteasome system (UPS) in PD pathogenesis. Proteasome inhibition recapitulates some of the key features of PD in vivo and in vitro. Varieties of dopaminergic neurotoxins emerge to inhibit proteasomal function. Given that some PD-related gene mutations impair proteolytic function of UPS, it has been well-accepted that both genetic and environmental factors may conspire to compromise the UPS in the initiation and progression of the disease. The enzymatic assays for the proteasomal activities with fluorogenic substrates and western blot analysis of ubiquitinated proteins provide an entry point to determine UPS function in the process of dopaminergic degeneration. PMID- 21815075 TI - Cell signaling and neurotoxicity: protein kinase C in vitro and in vivo. AB - There is a growing concern about the effects of chemicals on the developing nervous system. Chemical exposure at critical periods of development can be associated with effects ranging from subtle to profound on the structure and/or function of the nervous system. Understanding critical biological molecular targets, which underlie chemical-induced neurotoxicity, will provide a scientific basis for risk assessment. Cell signaling molecules such as protein kinase C (PKC) have been shown to play critical roles in motor activity, development of the nervous system, and in learning and memory. PKC also has been shown to be associated with several neurological disorders including Alzheimer's disease, status epilepticus, and cerebellar ataxia. In the literature, there is abundant information linking PKC to cognitive function, long-term potentiation, or brain structural changes. Here, we show the relationship between changes in PKC (as assayed using radioactive material or by western blots) and the neurotoxic effects caused by environmental chemicals in vitro and in vivo. PMID- 21815076 TI - Cell signaling and neurotoxicity: 3H-arachidonic acid release (phospholipase A2) in cerebellar granule neurons. AB - Cell signaling is a complex process which controls basic cellular activities and coordinates actions to -maintain normal cellular homeostasis. Alterations in signaling processes have been associated with -neurological diseases, such as Alzheimer's and cerebellar ataxia, as well as cancer, autoimmunitiy, and diabetes. Recent evidence also indicates a role for signaling molecules in the adverse effects associated with the exposure to environmental chemicals. One of these signaling molecules is arachidonic acid (AA). AA is abundant in the membrane phospholipids of the brain, where its release has been shown to be involved in synaptic plasticity processes, such as long-term potentiation. AA release is primarily produced by the activation of phospholipases, most commonly by phospholipase A2 (PLA2). The release of 3H-AA is often used as a measure of PLA2 activity in cell culture studies. In our laboratory, we have demonstrated the relationship between the stimulation of 3H-AA release by persistent chemicals, such as polychlorinated biphenyls and polybrominated diphenyl ethers, and the associated cytotoxicity following in vitro exposure. Understanding the role of the AA signaling pathway in chemically-induced effects on the nervous system will provide specific mode of action information that can be used in assessing the compound risk. PMID- 21815077 TI - Quantitative assessment of neurite outgrowth in PC12 cells. AB - In vitro test methods can provide a rapid approach for the screening of large numbers of chemicals for their potential to produce toxicity. In order to identify potential developmental neurotoxicants, assessment of critical neurodevelopmental processes, such as neuronal differentiation and growth has been proposed. PC12 cells have been widely used to study the neurotrophic factor induced signaling pathways that control differentiation, and as in vitro models to detect the effect of chemicals on neurite outgrowth. Upon exposure to nerve growth factor (NGF), PC12 cells cease to proliferate, extend multiple neurites, and acquire the properties of sympathetic neurons. Measurement of the number and length of neurites during exposure to NGF provides a quantitative assessment of neuronal differentiation and growth. Differentiation and neurite outgrowth can be measured using simple contrast microscopy in live cells, or using automated imaging systems in cells prepared with immunocytochemistry. PMID- 21815078 TI - Measurements of astrocyte proliferation. AB - Astrocytes, the most abundant cell type in the brain, proliferate during brain development. While it is generally accepted that mature astrocytes do not proliferate, neural stem cells, which have characteristics of astrocytes, retain the ability of self-renewal. Furthermore, astrocytes can regain their proliferative properties under pathological situations, such as reactive astrogliosis, a consequence of brain injury and brain tumors. Measurements of astrocyte proliferation can thus be used in investigations of physiological and pathological processes occurring in the developing and the adult brain. This chapter describes two methods for the determination of astrocyte proliferation: the incorporation of a radioactive nucleotide [(3)H]thymidine into DNA, which occurs during the process of DNA synthesis preceding cell division, and the flow cytometric analysis of cell cycle progression through the different phases of the cell cycle by BrDu/Hoechst and ethidium bromide labeling. PMID- 21815079 TI - Quantification of synaptic structure formation in cocultures of astrocytes and hippocampal neurons. AB - The ability to quantify changes of synaptic structure, whether associated with the formation of synapse in early development or the degeneration of synapses in adult life in an in vitro culture system, is important for understanding the underlying mechanisms. Astrocytes play a vital role in neuronal development and functioning, including synapse formation and stabilization. The method described in this chapter allows for the determination of the modulation by astrocytes of synaptic structure formation in hippocampal neurons. Using a sandwich coculture system, highly pure, hippocampal neurons are grown in culture for 14 days on glass coverslips, after which they are inverted, without contact, over separately cultured astrocytes or pretreated astrocytes for 24 h. Neuronal immunocytochemical staining of the presynaptic marker, synaptophysin, and the postsynaptic marker, PSD-95, is used to assess the localization of synaptic proteins into pre and postsynaptic structures. Deconvolved, confocal images are used to determine a mean puncta intensity threshold for use in rendering the surface of the synaptic structures using three-dimensional object analysis software. Once rendered in three-dimensional space, automatic quantification of the number of pre- and postsynaptic specializations and the number of those structures that overlap is obtained, allowing the ability to compare how different treatments may modulate the formation of synapses. Because synapses not only consist of distinct pre- and postsynaptic specializations, but are also defined by their apposition, the determination and study of synapse formation can only benefit by methods that use all of the available data to assess the actual structure. PMID- 21815080 TI - Volume measurements in cultured primary astrocytes. AB - Damage to the central nervous system (CNS) is selective, likely reflecting the intrinsic properties of -individual cell types. Targets of chemical injury are diverse hence assessing neurotoxicity is extremely difficult. Overcoming this obstacle requires a general screen or "marker" for injury that reflects cellular damage. The "marker" must be reliable and represent a biochemical event which broadly reflects cellular stress and damage. One such "marker" is cell swelling; it occurs in response to a diversity of insults, such as physical damage, disease (ischemia, trauma, and hypoxia), and chemicals (methylmercury, lead, 1,3 dinitrobenzene, and triethyltin). In astrocytes, a type of glia, astrocytic swelling can be measured with several methods. Commonly, freshly isolated astrocytes are grown to confluence on coverslips, a period requiring 3 weeks in culture. At this time, astrocytic volume can be measured using either an impedance technique or 3-O-methyl-D-glucose to assess cell volume. This review will briefly detail these methods and provide insight into molecular mechanisms associated with cell swelling and the ensuing regulatory decrease (RVD). PMID- 21815081 TI - Assessment of cholesterol homeostasis in astrocytes and neurons. AB - Cholesterol homeostasis is highly regulated in the nervous system; dysregulation in cholesterol trafficking and content have been involved in the pathogenesis of neurodegenerative diseases (such as Parkinson's and Alzheimer's diseases). Furthermore, low cholesterol levels during brain development are associated with neurodevelopmental deficits and mental retardation. The methods described in this chapter can be used to investigate the effect of neurotoxicants on cholesterol homeostasis. Astrocytes and neurons are two major cell types in the brain in which cholesterol synthesis and efflux are highly regulated to keep a proper cellular cholesterol level. Disruption in cholesterol synthesis and/or cholesterol efflux may result in cholesterol deficiency or accumulation in these cells leading to brain dysfunctions. PMID- 21815082 TI - Dose-response or dose-effect curves in in vitro experiments and their use to study combined effects of neurotoxicants. AB - Interactions among neurotoxicants in in vitro models, where the molecular mechanisms of toxicity are generally studied, represent today an emerging field in the experimental neurotoxicology. In this chapter, we define some general concepts about the optimization of in vitro experiments to assess the dose/concentration-effect/response relationships and to extrapolate the functions describing them. After describing the available models to study interactions (the Bliss independence criterion and the Loewe additivity model), we present a method to practically apply these models to experimental data. Finally, we provide some examples of the theory of interactions among neurotoxicants in in vitro models. PMID- 21815083 TI - Bacterial genome reengineering. AB - The web application PrimerPair at ecogene.org generates large sets of paired DNA sequences surrounding- all protein and RNA genes of Escherichia coli K-12. Many DNA fragments, which these primers amplify, can be used to implement a genome reengineering strategy using complementary in vitro cloning and in vivo recombineering. The integration of a primer design tool with a model organism database increases the level of quality control. Computer-assisted design of gene primer pairs relies upon having highly accurate genomic DNA sequence information that exactly matches the DNA of the cells being used in the laboratory to ensure predictable DNA hybridizations. It is equally crucial to have confidence that the predicted start codons define the locations of genes accurately. Annotations in the EcoGene database are queried by PrimerPair to eliminate pseudogenes, IS elements, and other problematic genes before the design process starts. These projects progressively familiarize users with the EcoGene content, scope, and application interfaces that are useful for genome reengineering projects. The first protocol leads to the design of a pair of primer sequences that were used to clone and express a single gene. The N-terminal protein sequence was experimentally verified and the protein was detected in the periplasm. This is followed by instructions to design PCR primer pairs for cloning gene fragments encoding 50 periplasmic proteins without their signal peptides. The design process begins with the user simply designating one pair of forward and reverse primer endpoint positions relative to all start and stop codon positions. The gene name, genomic coordinates, and primer DNA sequences are reported to the user. When making chromosomal deletions, the integrity of the provisional primer design is checked to see whether it will generate any unwanted double deletions with adjacent genes. The bad designs are recalculated and replacement primers are provided alongside the requested primers. A list of all genes with overlaps includes those expressed from the translational coupling motifs 5'-UGAUG-3' and 5'-AUGA-3'. Rigid alignments of the 893 ribosome binding sites (RBSs) linked to the AUG codons of this coupled subset are assessed for information content using WebLogo 3.0. These specialized logos are missing the G at the prominent information peak position normally seen in the rigid alignment of all genes. This novel GHOLE motif was apparently masked by the normal RBSs in two previously published rigid alignments. We propose a model constraining the distance between the ATG and the RBS, obviating- the need for a flexible linker model to reveal a Shine-Dalgarno-like sequence. PMID- 21815084 TI - Targeted chromosomal gene knockout using PCR fragments. AB - The development of recombineering technology has converged to a point that virtually any type of genetic modification can be made in the Escherichia coli chromosome. The most straightforward -modification is a chromosomal gene knockout, which is done by electroporation of a PCR fragment that contains a selectable drug marker flanked by 50 bp of target DNA. The phage lambda Red recombination system expressed in vivo from a plasmid promotes deletion of the gene of interest at high efficiency. The combination of this technology with site specific recombination systems of Cre and Flp has enabled genetic engineers to construct a variety of marked and precise gene knockouts in a variety of microbial chromosomes. The basic protocols for designing PCR substrates for recombineering, generating -recombineering-proficient electrocompetent strains of E. coli, and for selection and verification of recombinant clones are described. PMID- 21815085 TI - Scarless chromosomal gene knockout methods. AB - An improved and rapid genomic engineering method has been developed for the construction of -custom-designed microorganisms by scarless chromosomal gene knockouts. This method, which can be performed in 2 days, permits restructuring of the Escherichia coli genome via scarless deletion of selected genomic regions. The deletion process is mediated by a special plasmid, pREDI, which carries two independent inducible promoters: (1) an arabinose-inducible promoter that drives expression of lambda-RED recombination proteins, which carry out the replacement of a target genomic region with a marker-containing linear DNA cassette, and (2) a rhamnose-inducible promoter that drives expression of I-SceI endonuclease, which accomplishes deletion of the introduced marker by double-strand breakage - mediated intramolecular recombination. This genomic deletion is performed simply by changing the carbon source in the bacterial growth medium from arabinose to rhamnose. The efficiencies of targeted region replacement and deletion of the inserted linear DNA cassette are nearly 70 and 100%, respectively. This rapid and efficient procedure can be adapted for use in generating a variety of genome modifications. PMID- 21815086 TI - Random chromosomal gene disruption in vivo using transposomes. AB - Strain engineering of bacteria has been accomplished by many methods where mobile DNA elements (transposons) are inserted into the genomic DNA of a host organism. This chapter addresses engineering with transposable elements complexed with transposase enzyme. In traditional techniques, transposon and transposase are introduced as distinct entities. The method of mobilization into cells is often unique for each class of DNA element, and for each organism. The discovery of pre formed transposon/transposase complexes (transposomes) that can be electroporated into living cells opens a new gateway to strain mutagenesis. Described are the preparation of electrocompetent bacterial cells and their transformation with transposomes. Once within the cell, the transposome is equipped to randomly insert its DNA into chromosomes without needing additional components. Ocr, a T7 phage protein that inhibits the host restriction of electroporated DNAs, will also be discussed as an adjunct reagent that can widen the applicability of transposomes. The transposomes used in most of the applications are commercially available, but also described is the process of making custom transposon DNAs and transposomes. The techniques are not limited to bacterial strain engineering per se and may be adapted for single-cell eukaryotes as well. PMID- 21815088 TI - Microarray-based genetic footprinting strategy to identify strain improvement genes after competitive selection of transposon libraries. AB - Successful strain engineering involves perturbing key nodes within the cellular network. How the -network's connectivity affects the phenotype of interest and the ideal nodes to modulate, however, are frequently not readily apparent. To guide the generation of a list of candidate nodes for detailed investigation, designers often examine the behavior of a representative set of strains, such as a library of transposon insertion mutants, in the environment of interest. Here, we first present design principles for creating a maximally informative competitive selection. Then, we describe how to globally quantify the change in distribution of strains within a transposon library in response to a competitive selection by amplifying the DNA adjacent to the transposons and hybridizing it to a microarray. Finally, we detail strategies for analyzing the resulting hybridization data to identify genes and pathways that contribute both negatively and positively to fitness in the desired environment. PMID- 21815087 TI - Genome engineering using targeted oligonucleotide libraries and functional selection. AB - The lambda phage Red proteins greatly enhance homologous recombination in Escherichia coli. Red-mediated recombination or "recombineering" can be used to construct targeted gene deletions as well as to introduce point mutations into the genome. Here, we describe our method for scanning mutagenesis using recombineered oligonucleotide libraries. This approach entails randomization of specific codons within a target gene, followed by functional selection to isolate mutants. Oligonucleotide library mutagenesis has generated hundreds of novel antibiotic resistance mutations in genes encoding ribosomal proteins, and should be applicable to other systems for which functional selections exist. PMID- 21815089 TI - Optimization of synthetic operons using libraries of post-transcriptional regulatory elements. AB - Constructing polycistronic operons is an advantageous strategy for coordinating the expression of -multiple genes in a prokaryotic host. Unfortunately, a basic construct consisting of an inducible promoter and genes cloned in series does not generally lead to optimal results. Here, a combinatorial approach for tuning relative gene expression in operons is presented. The method constructs libraries of post--transcriptional regulatory elements that can be cloned into the noncoding sequence between genes. Libraries can be screened to identify sequences that optimize expression of metabolic pathways, multisubunit proteins, or other situations where precise stoichiometric ratios of proteins are desired. PMID- 21815090 TI - Marker-free chromosomal expression of foreign and native genes in Escherichia coli. AB - Genetic manipulation of Escherichia coli strains for desired traits is the most applied strain engineering approach in industrial applications. For chromosomal insertion of genes and controlled expression of genomic genes in E. coli, the replicon-free and markerless method is described based on a series of conditional replication plasmids called phage-integration vectors. They mainly carry the multiple cloning site and the prophage attachment site, which are sandwiched by two FRT sites. With the aid of the phage integrase from conditional-replication helper plasmids, the passenger genes of either foreign or native type incorporated into the integration vectors can be specifically integrated into bacterial genome at the prophage attachment site. Finally, the inserted DNA containing replicon and/or selective markers in integrants can be eliminated by the act of the FLP recombinase provided from a conditional-replication helper plasmid. PMID- 21815091 TI - Array-based synthetic genetic screens to map bacterial pathways and functional networks in Escherichia coli. AB - Cellular processes are carried out through a series of molecular interactions. Various experimental approaches can be used to investigate these functional relationships on a large-scale. Recently, the power of investigating biological systems from the perspective of genetic (gene-gene or epistatic) interactions has been evidenced by the ability to elucidate novel functional relationships. Examples of functionally related genes include genes that buffer each other's function or impinge on the same biological process. Genetic interactions have traditionally been investigated in bacteria by combining pairs of mutations (e.g., gene deletions) and assessing deviation of the phenotype of each double mutant from an expected neutral (or no interaction) phenotype. Fitness is a particularly convenient phenotype to measure: when the double mutant grows faster or slower than expected, the two mutated genes are said to show alleviating or aggravating interactions, respectively. The most commonly used neutral model assumes that the fitness of the double mutant is equal to the product of individual single mutant fitness. A striking genetic interaction is exemplified by the loss of two nonessential genes that buffer each other in performing an essential biological function: deleting only one of these genes produces no detectable fitness defect; however, loss of both genes simultaneously results in systems failure, leading to synthetic sickness or lethality. Systematic large scale genetic interaction screens have been used to generate functional maps for model eukaryotic organisms, such as yeast, to describe the functional organization of gene products into pathways and protein complexes within a cell. They also reveal the modular arrangement and cross talk of pathways and complexes within broader functional neighborhoods (Dixon et al., Annu Rev Genet 43:601-625, 2009). Here, we present a high-throughput quantitative Escherichia coli Synthetic Genetic Array (eSGA) screening procedure, which we developed to systematically infer genetic interactions by scoring growth defects among large numbers of double mutants in a classic Gram-negative bacterium. The eSGA method exploits the rapid colony growth, ease of genetic manipulation, and natural efficient genetic exchange via conjugation of laboratory E. coli strains. Replica pinning is used to grow and mate arrayed sets of single gene mutant strains and to select double mutants en masse. Strain fitness, which is used as the eSGA readout, is quantified by the digital imaging of the plates and subsequent measuring and comparing single and double mutant colony sizes. While eSGA can be used to screen select mutants to probe the functions of individual genes, using eSGA more broadly to collect genetic interaction data for many combinations of genes can help reconstruct a functional interaction network to reveal novel links and components of biological pathways as well as unexpected connections between pathways. A variety of bacterial systems can be investigated, wherein the genes impinge on a essential biological process (e.g., cell wall assembly, ribosome biogenesis, chromosome replication) that are of interest from the perspective of drug development (Babu et al., Mol Biosyst 12:1439-1455, 2009). We also show how genetic interactions generated by high-throughput eSGA screens can be validated by manual small-scale genetic crosses and by genetic complementation and gene rescue experiments. PMID- 21815092 TI - Assembling new Escherichia coli strains by transduction using phage P1. AB - A protocol is described that allows the transfer of genetic material from one Escherichia coli strain to another using bacteriophage P1. P1 transduction can be used to construct new bacterial strains containing multiple alleles, to restore a locus to wild type, to move specific genetic markers from one strain to another, to relocate different mutant genes to a common genetic background, and to evaluate second-site suppression of a mutant allele. Because of these abilities, P1 transduction remains a staple in the arsenal of genetic tools that have kept E. coli at the forefront of model bacterial systems. The protocol incorporates some updated steps and discusses general principles of bacteriophage handling and the infection process. PMID- 21815093 TI - Yeast bioinformatics and strain engineering resources. AB - Saccharomyces cerevisiae, commonly known as baker's or budding yeast, is an attractive organism for design-based engineering because it is an industrially important organism with a well-annotated genome sequence and an extensive collection of resources for molecular analyses. This chapter describes the utility of Saccharomyces Genome Database for analysis of S. cerevisiae genes and identification of homologs, strategies for integration and analysis of gene expression data, and the genetic resources available for doing experiments using S. cerevisiae. PMID- 21815094 TI - Delete and repeat: a comprehensive toolkit for sequential gene knockout in the budding yeast Saccharomyces cerevisiae. AB - Gene inactivation is an essential step in the molecular dissection of gene function. In the yeast Saccharomyces cerevisiae, many tools for gene disruption are available. Gene disruption cassettes comprising completely heterologous marker genes flanked by short DNA segments homologous to the regions to the left and right of the gene to be deleted mediate highly efficient one-step gene disruption events. Routinely, in more than 50% of analyzed clones, the marker cassette is integrated in the targeted location. The inclusion of loxP sites flanking the disruption marker gene allows sequence-specific Cre recombinase mediated marker rescue so that the marker can be reused to disrupt another gene. Here, we describe a comprehensive toolbox for multiple gene disruptions comprising a set of seven heterologous marker genes including four dominant resistance markers for gene disruption, plus a set of Cre expression plasmids carrying eight different selection markers, four of them dominant. PMID- 21815096 TI - Signature-tagged mutagenesis to characterize genes through competitive selection of bar-coded genome libraries. AB - The availability of collections of genome-wide deletion mutants greatly accelerates systematic analyses of gene function. However, each of the thousands of genes that comprise a genome must be phenotyped individually unless they can be assayed in parallel and subsequently deconvolved. To this end, unique molecular identifiers have been developed for a variety of microbes. Specifically, the addition of DNA "tags," or "bar codes," to each mutant allows all mutants in a collection to be pooled and phenotyped in parallel, greatly increasing experimental throughput. In this chapter, we provide an overview of current methodologies used to create such tagged mutant collections and outline how they can be applied to understand gene function, gene-gene interactions, and drug-gene interactions. Finally, we present a methodology that uses universal TagModules, capable of bar coding a wide range of microorganisms, and demonstrate its reduction to practice by creating tagged mutant collections in the pathogenic yeast Candida albicans. PMID- 21815095 TI - Genome-wide transposon mutagenesis in Saccharomyces cerevisiae and Candida albicans. AB - Transposon mutagenesis is an effective method for generating large sets of random mutations in target DNA, with applicability toward numerous types of genetic screens in prokaryotes, single-celled eukaryotes, and metazoans alike. Relative to methods of random mutagenesis by chemical/UV treatment, transposon insertions can be easily identified in mutants with phenotypes of interest. The construction of transposon insertion mutants is also less labor-intensive on a genome-wide scale than methods for targeted gene replacement, although transposon insertions are not precisely targeted to a specific residue, and thus coverage of the target DNA can be problematic. The collective advantages of transposon mutagenesis have been well demonstrated in studies of the budding yeast Saccharomyces cerevisiae and the related pathogenic yeast Candida albicans, as transposon mutagenesis has been used extensively for phenotypic screens in both yeasts. Consequently, we present here protocols for the generation and utilization of transposon-insertion DNA libraries in S. cerevisiae and C. albicans. Specifically, we present methods for the large-scale introduction of transposon insertion alleles in a desired strain of S. cerevisiae. Methods are also presented for transposon mutagenesis of C. albicans, encompassing both the construction of the plasmid-based transposon mutagenized DNA library and its introduction into a desired strain of Candida. In total, these methods provide the necessary information to implement transposon mutagenesis in yeast, enabling the construction of large sets of identifiable gene disruption mutations, with particular utility for phenotypic screening in nonstandard genetic backgrounds. PMID- 21815097 TI - Global strain engineering by mutant transcription factors. AB - Cellular hosts are widely used for the production of chemical compounds including pharmaceutics, fuels, and specialty chemicals. Strain engineering focuses on manipulating and improving these hosts for new and enhanced functionalities including increased titers and better bioreactor performance. These tasks have traditionally been accomplished using a combination of random mutation, screening and selection, and metabolic engineering. However, common metabolic engineering techniques are limited in their capacity to elicit multigenic, complex phenotypes. These phenotypes can also include nonpathway-based traits such as tolerance and productivity. Global transcription machinery engineering (gTME) is a generic methodology for engineering strains with these complex cellular phenotypes. In gTME, dominant mutant alleles of a transcription-related protein are screened for their ability to reprogram cellular metabolism and regulation, resulting in a unique and desired phenotype. gTME has been successfully applied to both prokaryotic and eukaryotic systems, resulting in improved environmental tolerances, metabolite production, and substrate utilization. The underlying principle involves creating mutant libraries of transcription factors, screening for a desired phenotype, and iterating the process in a directed evolution fashion. The successes of this approach and details for its implementation and application are described here. PMID- 21815098 TI - Genomic promoter replacement cassettes to alter gene expression in the yeast Saccharomyces cerevisiae. AB - Promoter substitutions are frequently used to regulate the expression of genes in a specific manner such as for their conditional expression or for their overexpression. Chromosomal integration of a regulatable promoter upstream of an open reading frame (ORF) by homologous recombination using PCR-based gene targeting is straightforward and enables stable alterations of the genome. Furthermore, together with the promoter exchange, the target proteins can be tagged N-terminally with an epitope or a fluorescent protein. Expression levels can be constitutively lowered or increased by using promoters of different strengths. Reversible regulation of gene expression at the level of transcription can be achieved by using either regulatable yeast-endogenous promoters (e.g., GAL1-10) or heterogeneous promoters with synthetic transcription factors (e.g., TetO). To regulate gene expression at the translational level, insertion of tetracycline-binding aptamers into the 5' untranslated region (5' UTR) of target genes can be used. PMID- 21815099 TI - Microbial genome analysis and comparisons: Web-based protocols and resources. AB - Fully annotated genome sequences of many microorganisms are publicly available as a resource. However, in-depth analysis of these genomes using specialized tools is required to derive meaningful information. We describe here the utility of three powerful publicly available genome databases and analysis tools. Protocols outlined here are particularly useful for performing pairwise genome comparisons between closely related microorganisms to identify similarities and unique features, for example to identify genes specific to a pathogenic strain of Escherichia coli compared to a nonpathogenic strain. PMID- 21815100 TI - Plasmid artificial modification: a novel method for efficient DNA transfer into bacteria. AB - Bacterial transformation is an essential component of many molecular biological techniques, but bacterial restriction-modification (R-M) systems can preclude the efficient introduction of shuttle vector plasmids into target bacterial cells. Whole-genome DNA sequences have recently been published for a variety of bacteria. Using homology and motif analyses, putative R-M genes can be identified from genome sequences. Introducing DNA methyltransferase genes into Escherichia coli cells causes subsequently transformed plasmids to be modified by these enzymes. We propose a new method, designated Plasmid Artificial Modification (PAM). A PAM plasmid encoding the modification enzymes expressed by the target bacterial host is transformed into E. coli (PAM host). Propagation of a shuttle vector from the PAM host to the target bacterium ensures that the plasmid will be modified such that it is protected from restriction endonuclease digestion in the target bacterium. The result will be a higher transformation efficiency. Here, we describe the use of PAM and electroporation to transform Bifidobacterium adolescentis ATCC15703. By introducing two genes encoding modification enzymes, we improved transformation efficiency 10(5)-fold. PMID- 21815101 TI - Broad-host-range plasmid vectors for gene expression in bacteria. AB - This chapter provides methods and insights into the use of broad-host-range plasmid vectors useful for expression of genes in a variety of bacteria. The main focus is on IncQ, IncW, IncP, and pBBR1-based plasmids which have all been used for such applications. The specific design of each vector is adapted to its use, and here we describe, as an example, a protocol for construction (in Escherichia coli) of large insert DNA libraries in an IncP type vector and transfer of the library to the desired host. The genes of interest will in this case have to be expressed from their own promoters and the libraries will be screened by a method that best fits the functions of the gene or gene clusters searched for. PMID- 21815103 TI - Transposon-mediated random mutagenesis of Bacillus subtilis. AB - The depth of knowledge concerning its physiology and genetics make Bacillus subtilis an attractive system for strain engineering and analysis. Transposon based mutagenesis strategies generate large libraries of mutant strains that can be used to investigate molecular mechanisms relevant in fundamental research or to generate desirable phenotypes in applied research. This section presents a mini-Tn10-based transposon mutagenesis system that is capable of genome-wide insertional mutagenesis in B. subtilis and related organisms. Using appropriately designed selections or screens, the desired strain phenotypes can be isolated from transposon mutant libraries. This transposon system then allows rapid identification of the genetic locus responsible for the desired phenotype, and, due to the natural competence of B. subtilis, the identified genotypic change can easily be confirmed as responsible for the phenotypic change. PMID- 21815102 TI - A simple method for introducing marker-free deletions in the Bacillus subtilis genome. AB - A genetic tool for introducing marker-free deletions is essential for multiple manipulations of genomes. We have developed a simple and efficient method for creating marker-free deletion mutants of Bacillus subtilis through transformation with recombinant PCR products, using the Escherichia coli mazF gene encoding an endoribonuclease that cleaves free mRNAs as a counterselection tool. PMID- 21815104 TI - Integrative food grade expression system for lactic acid bacteria. AB - Lactobacillus acidophilus NCFM is a probiotic microbe with the ability to survive passage to the -gastrointestinal tract, interact intimately with the host and induce immune responses. The genome of NCFM has been determined and the bacterium is genetically accessible. Therefore, L. acidophilus has excellent potential for use as a vaccine delivery vehicle to express antigens at mucosal surfaces. Plasmids, commonly used to carry antigen encoding genes, are inherently unstable and require constant selection by antibiotics, which can be problematic for in vivo studies and clinical trials. Chromosomal expression of gene cassettes encoding antigens offers enhanced genetic stability by eliminating requirements for marker selection. This work illustrates the integration and inducible expression of the reporter gene gusA3, -encoding a beta-glucuronidase (GusA3), in the L. acidophilus chromosome. A previously described upp-counterselectable gene replacement system was used to direct insertion of the gusA3 gene into an intergenic chromosomal location downstream of lacZ (LBA1462), encoding a beta galactosidase. The transcriptional activity of integrated gusA3 was evaluated by GUS activity assays using 4-methyl-umbelliferyl-beta-D: -glucuronide (MUG) and was determined to be one to two orders of magnitude higher than the GusA3 negative parent, NCK1909. The successful chromosomal integration and expression of GusA3 demonstrate the potential of this method for higher levels of inducible gene expression in L. acidophilus. PMID- 21815105 TI - ClosTron-mediated engineering of Clostridium. AB - The genus Clostridium is a diverse assemblage of Gram positive, anaerobic, endospore-forming bacteria. Whilst certain species have achieved notoriety as important animal and human pathogens (e.g. Clostridium difficile, Clostridium botulinum, Clostridium tetani, and Clostridium perfringens), the vast majority of the genus are entirely benign, and are able to undertake all manner of useful biotransformations. Prominent amongst them are those species able to produce the biofuels, butanol and ethanol from biomass-derived residues, such as Clostridium acetobutylicum, Clostridium beijerinkii, Clostridium thermocellum, and Clostridium phytofermentans. The prominence of the genus in disease and biotechnology has led to the need for more effective means of genetic modification. The historical absence of methods based on conventional strategies for "knock-in" and "knock-out" in Clostridium has led to the adoption of recombination-independent procedures, typified by ClosTron technology. The ClosTron uses a retargeted group II intron and a retro-transposition-activated marker to selectively insert DNA into defined sites within the genome, to bring about gene inactivation and/or cargo DNA delivery. The procedure is extremely efficient, rapid, and requires minimal effort by the operator. PMID- 21815106 TI - High-throughput transposon mutagenesis of Corynebacterium glutamicum. AB - Construction of gene disruption mutants and analysis of the resultant phenotypes are an important strategy to study gene function. A simple and high-throughput method developed for microorganisms combines two different types of transposons, direct genomic DNA amplification and thermal asymmetric interlaced-PCR. The considerable utility of this approach is demonstrable in Corynebacterium glutamicum, where 18,000 transposon disruptants enabled the generation of an insertion library covering nearly 80% of the organism's 2,990 ORFs. PMID- 21815107 TI - Mini-Mu transposon mutagenesis of ethanologenic Zymomonas mobilis. AB - Zymomonas mobilis is a facultatively anaerobic alpha-proteobacterium with a considerable potential for industrial ethanol production. An important tool in the generation of stable mutants for this organism is described in this chapter; it entails insertional mutagenesis with the help of the transposable element mini Mu. The latter is delivered into Z. mobilis with the use of plasmid pULB113 (RP4::mini-Mu) that self-transfers in the organism at notable frequencies and remains highly stable even under nonselective conditions. Transposition of mini Mu and subsequent mutagenesis occur readily in Z. mobilis pULB113 transconjugants and result in the generation of large numbers of random mutants. This can be demonstrated by the isolation of various auxotrophs with single or multiple nutritional requirements, the vast majority of which bears insertions at different chromosomal locations, even when exhibiting the same requirement. Therefore, transposon mutagenesis with the use of mini-Mu serves as a simple and effective tool for indiscriminate mutant production in Z. mobilis. PMID- 21815108 TI - Engineering thermoacidophilic archaea using linear DNA recombination. AB - Thermoacidophilic archaea comprise one of the major classes of extremophiles. Most belong to the family Sulfolobales within the phylum Crenarchaeota. They are of applied interest as sources of hyperstable enzymes, for biomining of base and precious metals, and for evolutionary studies because of their use of eukaryotic like subcellular mechanisms. Genetic methods are available for several species particularly Sulfolobus solfataricus. This organism has a considerable number of methods available for the construction of novel cell lines with unique functions. This chapter presents recent developments in the use of homologous recombination and linear DNA for the engineering of site-specific changes in the genome of S. solfataricus. PMID- 21815109 TI - Targeted gene disruption in Koji mold Aspergillus oryzae. AB - Filamentous fungi have received attentions as hosts for heterologous protein production because of their high secretion capability and eukaryotic post translational modifications. One of the safest hosts for heterologous protein production is Koji mold Aspergillus oryzae since it has been used in the production of Japanese fermented foods for over 1,000 years. The production levels of proteins from higher eukaryotes are much lower than those of homologous (fungal) proteins. Bottlenecks in the heterologous protein production are suggested to be proteolytic degradation of the produced protein in the medium and the secretory pathway. For construction of excellent host strains, many genes causing the bottlenecks should be disrupted rapidly and efficiently. We developed a marker recycling system with the highly efficient gene-targeting background in A. oryzae. By employing this technique, we performed multiple gene disruption of the ten protease genes. The decuple protease gene disruptant showed fourfold production level of a heterologous protein compared with the wild-type strain. PMID- 21815110 TI - Selectable and inheritable gene silencing through RNA interference in the unicellular alga Chlamydomonas reinhardtii. AB - Reverse genetic approaches have become invaluable tools to tap into the wealth of information provided by sequenced genomes. In 2007, sequencing of the Chlamydomonas reinhardtii genome was completed, and with this an increased demand for the development of reverse genetic strategies for gene analysis. In a variety of organisms, including Chlamydomonas, inverted repeat transgenes have been used to produce strains silenced for a specific gene due to the production of double stranded RNA (dsRNA). Here, we describe a tandem inverted repeat system designed to overcome some of the typical challenges that arise when transgenes are used to trigger gene silencing including the lack of a screenable phenotype, unpredictable levels of silencing, silencing of the transgene itself and thus loss of target gene silencing, and finally silencing of unintended genes (off target genes). The described strategy allows selection of target gene silencing by inducing co-silencing of the target gene and a gene, MAA7, silencing of which produces a selectable RNAi-induced phenotype. This selection, therefore, precludes extensive molecular screening for transgenic strains exhibiting target gene silencing, and also ensures heritable silencing through many generations. PMID- 21815112 TI - The International Journal of Sports Medicine "centurions". PMID- 21815111 TI - Diagnosis and treatment of follicular lymphoma. AB - Follicular lymphoma is a slow-growing disease exhibiting a heterogeneous clinical course, with a subset of patients experiencing a rapid disease course in the first two years and some developing disease transformation to a more aggressive phenotype. The advent of highly effective therapies has resulted in an increasing number of patients who achieve long-term progression-free survival alongside a good quality of life. Monoclonal antibodies, such as rituximab, either alone or in combination with chemotherapy regimens or radioimmunotherapy have been used with significant improvements in outcome. New treatment strategies such as new antibodies, biologic agents or vaccination therapy are also under investigation for the treatment of relapsed or refractory disease, further expanding the available options for patients and physicians alike. This article presents an overview of the current therapeutic strategies for the management of follicular lymphoma, focusing on the issues encountered in clinical practice. PMID- 21815113 TI - Cycling: to race or to live - reflections on skewed priorities? PMID- 21815114 TI - [Patient blood management (part 2). Practice: the 3 pillars]. AB - Patient blood management (PBM) is a patient-specific multidisciplinary, multimodal, evidence-based concept to appropriately conserve and manage a patient's own blood as a vital resource. PBM is based on 3 pillars: the first is the optimization of the patient's endogenous red cell mass, the second is the minimization of bleeding and blood loss and the third involves harnessing and optimizing the patient-specific physiological tolerance of anemia, including adopting more restrictive transfusion thresholds. PBM primarily identifies patients at risk of transfusion and provides a management plan aimed at reducing or eliminating the need for allogeneic transfusion, thus reducing the inherent risks, inventory pressures and the escalating costs associated with transfusion. PBM is applicable to surgical and medical patients. The application of PBM systematically reduces the impact of 3 major contributors to negative outcome: anemia, blood loss and transfusion. PMID- 21815115 TI - [In-hospital resuscitation--definitely better than in the field?]. AB - Despite favorable conditions, in-hospital resuscitations do not lead to higher survival rates than those in the field. Recent studies show an average survival rate of 18%. One of the most important predictors for an unfavorable survival is a delay of defibrillation of greater than 2 minutes, which leads to a reduction of ROSC, 24-hour survival and survival to discharge. With respect to the guidelines of the European Resuscitation Council for cardiopulmonary resuscitation from 2010, track and trigger systems to detect the deteriorating patient should be used. Of note, the survival rate for in-hospital resuscitation is significantly lower over the weekend and at night than on workdays and during the day--most likely because fewer staff is available. More than 80% of patients with an unexpected cardiac arrest exhibit cardiopulmonary and neurological abnormalities prior to this event. A Medical Emergency Teams (MET) could intervene in such cases and thus decrease the likelihood of cardiac arrest. METs are more time-consuming and more labor-intensive than simple resuscitation teams, but these resources are well spent, as unexpected admissions to the intensive care unit can be avoided and patients receive treatment before their conditions deteriorate. Hospitals should therefore analyze and evaluate their internal emergency response plans. PMID- 21815116 TI - [Chest trouble and hemiparesis. A paradoxical emergency?]. AB - The case of a young female patient with progressive chest trouble and dyspnea is reported. After development of a massive cerebral infarction, thrombolysis and afterwards decompressive craniectomy had to be performed. A patent foramen ovale (PFO) could be detected by transesophageal contrast-echocardiography accountable for a paradox embolism in existence with a deep vein thrombosis. The patient survived this situation but sustained persistent hemiparesis. PMID- 21815117 TI - [Triem JG, Rohm KD, Boldt J, Piper SN. [Comparison of a propofol-based anesthesia regimen using optimated target-controlled-infusion (OTCI) and manually-controlled infusion (MCI) technique]. Anasthesiol Intensivmed Notfallmed Schmerzther 2006; 41: 150-155. Retraction]. AB - The editorial board of AINS requests the retraction of the named article, as the studie has no IRB-approval. PMID- 21815118 TI - [Obstetrical anesthesia--to which group of anesthesiologists do you belong?]. PMID- 21815119 TI - [Resuscitation of newborn infants]. AB - Successful resuscitation of newborn infants depends on adequate preparation, exact evaluation and prompt initiation of support according to the recently updated recommendations by trained personnel. The key step in postnatal adaptation is the initiation of breathing with a subsequent increase in pulmonary blood flow and pulmonary gas exchange. Therefore, in compromised newborn infants, adequate ventilation is the most important step in cardiopulmonary resuscitation. Ventilation should be initiated with room air in term infants and with low concentrations of supplemental oxygen in preterm infants. Subsequently, oxygen supplementation should always be guided by pulse oximetry. Chest compressions are only effective if adequate ventilation has been ensured. The compression ventilation ratio remains 3:1. The prevention of heat loss and maintaining a normal body temperature by adequate measures is an essential part of the care for healthy as well as asphyxiated infants. Therapeutic hypothermia should only be initiated after successful resuscitation and consultation with the regional neonatal intensive care unit. PMID- 21815120 TI - [Postpartum hemorrhage--an update]. AB - Postpartum hemorrhage remains a major cause of maternal morbidity and mortality. The incidence of postpartum hemorrhage appears to be increasing in developed countries due to an increased number of placenta accreta or percreta after previous Cesarean deliveries. The initial therapy of postpartum hemorrhage consists of uterotonic drugs and inspection of the uterine cavum. At the same time, optimization of the clotting potential should be initiated early. Tranexamic acid may be considered as a first line choice, followed by fibrinogen if necessary. If bleeding continues, fresh frozen plasma and packed red cells should be ordered in a ratio of 1:1, as this ratio has been shown to improve survival in trauma victims. All labor and delivery suites should have standard operating procedures for the management of postpartum hemorrhage in place with regular drills. PMID- 21815121 TI - [Obstetric anaesthesia and analgesia--new aspects from the literature]. AB - This review summarises the current (and controversial) topics in the field of anaesthesia and analgesia in obstetrics. In the British report "Saving mothers' lives 2006-2008" it is shown that the direct causes of maternal deaths are as before mainly sepsis, preeclampsia and eclampsia, thrombosis, thromboembolisms, and amniotic fluid embolism as well as haemorrhagic complications. Deaths associated with anaesthesia still involve airway complications. In the "closed claims" in U.S. American statistics, in the meantime ones finds maternal and perinatal deaths and brain damage to be less frequent whereas liability claims due to nerve damage and back pain have increased, presumably as a result of the change away from the use of general anaesthesia to the use of regional anaesthesia in obstetrics. PMID- 21815122 TI - [Theme Teaching Award 2011 - resuscitation training for seventh graders and Play mobile Hospital for primary school students]. PMID- 21815123 TI - [Theme Teaching Award 2011 - simulator-based CRM training at the Clinic for Anesthesiology and Intensive Care Medicine, University Hospital Dresden]. PMID- 21815124 TI - [Echocardiography in anesthesia and intensive care--is it time for "Do it yourself"?]. PMID- 21815125 TI - Prediction of neonatal metabolic acidosis in women with a singleton term pregnancy in cephalic presentation. AB - We sought to predict neonatal metabolic acidosis at birth using antepartum obstetric characteristics (model 1) and additional characteristics available during labor (model 2). In 5667 laboring women from a multicenter randomized trial that had a high-risk singleton pregnancy in cephalic presentation beyond 36 weeks of gestation, we predicted neonatal metabolic acidosis. Based on literature and clinical reasoning, we selected both antepartum characteristics and characteristics that became available during labor. After univariable analyses, the predictors of the multivariable models were identified by backward stepwise selection in a logistic regression analysis. Model performance was assessed by discrimination and calibration. To correct for potential overfitting, we (internally) validated the models with bootstrapping techniques. Of 5667 neonates born alive, 107 (1.9%) had metabolic acidosis. Antepartum predictors of metabolic acidosis were gestational age, nulliparity, previous cesarean delivery, and maternal diabetes. Additional intrapartum predictors were spontaneous onset of labor and meconium-stained amniotic fluid. Calibration and discrimination were acceptable for both models (c-statistic 0.64 and 0.66, respectively). In women with a high-risk singleton term pregnancy in cephalic presentation, we identified antepartum and intrapartum factors that predict neonatal metabolic acidosis at birth. PMID- 21815126 TI - Effect of exercise on vascular superoxide dismutase expression in high-risk pregnancy. AB - Endothelial dysfunction of the maternal vasculature induced by pro-oxidants may contribute to the development of preeclampsia. Obesity results in vascular inflammation and oxidative stress and is therefore a risk factor for preeclampsia. Regular exercise is known to induce antioxidants. We recently demonstrated that stretchers (subjects who performed low-intensity exercises) had a lower incidence of preeclampsia as opposed to walkers (moderate-intensity exercise; 2.6% versus 14.6%). We now seek to determine the possible protective mechanisms. We hypothesized that stretchers will have higher vascular levels of the antioxidant superoxide dismutase (SOD) and plasma transferrin levels, an antioxidant marker. We conducted immunohistochemical analyses of blood vessels embedded in fat biopsy samples obtained during cesarean sections from women who were randomized to either stretching ( N = 6) or walking ( N = 5) exercises. In addition, levels of plasma transferrin were measured. SOD expression was increased ( P < 0.05) in stretchers [106.3 (interquartile range 84.2 to 127.8 arbitrary units (AU)] when compared with that of walkers [56.92 (interquartile range 46.35 to 82.32 AU)]. Transferrin levels continued to increase throughout gestation only among the stretchers. There appears to be a higher antioxidant protective effect in subjects who performed low-intensity exercise during pregnancy. PMID- 21815127 TI - The stillbirth collaborative research network postmortem examination protocol. AB - After reviewing the state of knowledge about the scope and causes of stillbirth (SB) in a special workshop sponsored by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the participants determined that there is little guidance regarding the best use of postmortem examination (PM) to address the pathogenesis of stillbirth. In this report, we describe the PM procedure designed and used in the NICHD-supported Stillbirth Cooperative Research Network (SCRN). Perinatal pathologists, clinicians, epidemiologists, and biostatisticians at four tertiary care centers, a data coordinating center, and NICHD developed a standardized approach to perinatal PM, which was applied to a population-based study of stillbirth as part of the SCRN. The SCRN PM protocol was successfully instituted and used at the four medical centers. A total of 663 women with stillbirth were included: 620 delivered a single stillborn infant, 42 delivered twins, and one delivered triplets for a total of 676 stillborn infants. Of these women, 560 (84.5%) consented to PM (572 stillborn infants) that was conducted according to the SCRN protocol. A standardized PM protocol was developed to evaluate stillbirth consistently across centers in the United States. Novel testing and approaches that increase the yield of the PM can be developed using this model. PMID- 21815128 TI - The 2010 Guidelines on Neonatal Resuscitation (AHA, ERC, ILCOR): similarities and differences--what progress has been made since 2005? AB - In 2010, the American Heart Association (AHA), the European Resuscitation Council (ERC) and the International Liaison Committee on Resuscitation (ILCOR) issued new guidelines on newborn resuscitation. The new recommendations include: (1) pulse oximetry for patient assessment during newborn resuscitation; (2) to start resuscitation of term infants with an FiO (2) of 0.21; (3) cardio-respiratory resuscitation with a 3:1 chest compression/inflation ratio for a heart rate <60 beats/min; (4) regarding infants born from meconium stained amniotic fluid: no recommendation is given to suction the upper airways at the perineum (when the head is born), but it is recommended to inspect the oropharynx and trachea for obstruction and suction the lower airway before inflations are given when the infant is depressed; (5) for birth asphyxia in term or near term infants, to induce hypothermia (33.5-34.5 degrees C) within 6 h after birth. AHA, ERC and ILCOR used nearly identical literature for their evidence evaluation process. While the AHA and ILCOR guidelines are almost identical, the ERC guidelines differ slightly from the latter with regards to (i) promoting sustained inflations at birth, (ii) promoting a wider range in applied inflations during resuscitation, and (iii) to suction the airways in infants born from meconium stained amniotic fluid, before inflations are given. PMID- 21815129 TI - Acupuncture for treatment of acute vomiting in children with gastroenteritis and pneumonia. AB - OBJECTIVE: Acupuncture is successfully used to alleviate vomiting in children after general anesthesia. However there is no data on treatment of vomiting in children with gastroenteritis (GE) and pneumonia (PM). METHODS: Descriptive analysis of 18 cases, where acupuncture was used as an individual therapy attempt to treat vomiting in children with GE or PM before starting the conventional antiemetic therapy. Feasibility and acceptance by patients and parents as well as the incidence of vomiting and use of antiemetic drugs after acupuncture were recorded. RESULTS: Acupuncture was feasible in all children and application of the indwelling needles was tolerated without fear. Side effects were not observed. 13 patients stopped vomiting immediately after the insertion of acupuncture needles, none of the patients required conventional antiemetic medication. CONCLUSION: Acupuncture for the treatment of vomiting is feasible and acceptable. Suggested antiemetic effect should be examined in a randomized multicenter controlled trial. PMID- 21815130 TI - [Approaches to reduce shortage of general practitioners in rural areas--results of an online survey of trainee doctors]. AB - BACKGROUND: In times of shortage of general practitioners (GPs), especially in rural areas, it is of particular interest to explore expectations and interests of GP trainees relating to their future work. The aim of this study was, to survey the willingness of trainee doctors to work in or open a general practice, as well as their expectations and plans concerning future work as a GP in a rural area. METHODS: The survey was conducted online between April to October 2010 with trainee doctors. The questionaire contained 25 questions about the trainees' sociodemographic status, expectations and conception of their future work, factors influencing setting up a GP practice and their ideas about working in a rural area. RESULTS: 528 trainee doctors from across Germany responded. More than half of them were female, more than 40% older than 35 years. 89% could image themselves settling in a GP practice, 77% in a rural area. The three most important factors influencing working in a rural practice were family friendly surrounding, the rural village itself and cooperation with colleagues. Most trainees would accepted having to travel 30 minutes to work. CONCLUSION: As the basic willingness to set up practice in rural areas is quite high, relevant influencing factors such as family friendly surroundings, out-of-hour services arrangements und working models offering the opportunity to work in group handed practices should be emphasized in recruitment. PMID- 21815131 TI - ASCO highlights new findings on cancer screening. Discoveries connected to ovarian, cervical, and prostate cancers. PMID- 21815132 TI - Studies at ASCO report results on new drug therapies and survivorship issues. PMID- 21815133 TI - Combined weekly topotecan and biweekly bevacizumab in women with platinum resistant ovarian, peritoneal, or fallopian tube cancer: results of a phase 2 study. AB - BACKGROUND: A phase 2 trial was conducted to determine the toxicity and efficacy of combined weekly topotecan and biweekly bevacizumab in patients with primary or secondary platinum-resistant ovarian, peritoneal, or fallopian tube cancer (OC). METHODS: Patients were treated with bevacizumab 10 mg/kg on days 1 and 15 and topotecan 4 mg/m(2) on days 1, 8, and 15 of a 28-day cycle until progressive disease (PD) or excessive toxicity. The primary endpoint was progression-free survival (PFS); secondary objectives included overall survival (OS), objective response, and toxicity. RESULTS: Patients (N = 40) received a median of 8 treatment cycles. Toxicity was generally mild or moderate, with neutropenia (18%), hypertension (20%), gastrointestinal toxicity (18%), pain (13%), metabolic toxicity (15%), bowel obstruction (10%), and cardiotoxicity (8%) being the most common grade 3 and 4 adverse events. No bowel perforations, febrile neutropenia, or treatment-related deaths occurred. Median PFS and OS were 7.8 (95% confidence interval [CI], 3.0-9.4) and 16.6 months (95% CI, 12.8-22.9), with 22 (55%) patients progression-free for >=6 months. Ten (25%) patients had partial response (PR), 14 (35%) had stable disease (SD), and 16 (40%) had PD. Patients treated with 2 prior regimens received greater benefit than patients treated with 1: PR/SD, 78.9% versus 42.9% (P = .03); median PFS, 10.9 versus 2.8 months (P = .08); median OS, 22.9 versus 12.8 months (P = .02). CONCLUSIONS: A weekly topotecan and biweekly bevacizumab combination demonstrates acceptable toxicity and encouraging efficacy in patients with platinum-resistant OC; further study is warranted. PMID- 21815134 TI - Having health insurance does not eliminate race/ethnicity-associated delays in breast cancer diagnosis in the District of Columbia. AB - BACKGROUND: Delays in follow-up after breast cancer screening contribute to disparities in breast cancer outcomes. The objective of this research was to determine the impact of race/ethnicity and health insurance on diagnostic time, defined as number of days from suspicious finding to diagnostic resolution. METHODS: This retrospective cohort study of 1538 women examined for breast abnormalities between 1998-2010 at 6 hospitals/clinics in the District of Columbia measured mean diagnostic times between non-Hispanic whites (NHWs), non Hispanic blacks (NHBs), and Hispanics with private, government, or no health insurance by using a full-factorial ANOVA model. RESULTS: Respective average- geometric mean (95% CI)--diagnostic times (in days) for NHWs, NHBs, and Hispanics were 16 (12, 21), 27 (23, 33), and 51 (35, 76) among privately insured; 12 (7, 19), 39 (32, 48), and 71 (48, 105) among government insured; 45 (17, 120), 60 (39, 92), and 67 (56, 79) among uninsured. Government insured NHWs had significantly shorter diagnostic times than government insured NHBs (P = .0003) and Hispanics (P < .0001). Privately insured NHWs had significantly shorter diagnostic times than privately insured NHBs (P = .03) and Hispanics (P < .0001). Privately insured NHBs had significantly shorter diagnostic times than uninsured NHBs (P = .03). CONCLUSIONS: Insured minorities waited >2 times longer to reach their diagnostic resolution than insured NHWs. Having private health insurance increased the speed of diagnostic resolution in NHBs; however, their diagnostic time remained significantly longer than for privately insured NHWs. These results suggest diagnostic delays in minorities are more likely caused by other barriers associated with race/ethnicity than by insurance status. PMID- 21815135 TI - Body mass index and risk of colorectal cancer in Chinese Singaporeans: the Singapore Chinese Health Study. AB - BACKGROUND: The authors chose to examine the association between body mass index (BMI) and incident colorectal cancer across the spectrum of BMI, including underweight persons, because detailed prospective cohort data on this topic in Asians is scarce, as is data on underweight persons (BMI, <18.5 kg/m(2)) in any population. METHODS: Analysis of the Singapore Chinese Health Study included 51,251 men and women aged 45-74 years enrolled in 1993-1998 and followed through 2007. Incident cancer cases and deaths among cohort members were identified through record linkage, and 980 cases were identified. Cox regression models were used to investigate the association of baseline BMI with risk of incident colorectal cancer during a mean of 11.5 years of follow-up. RESULTS: A significant, U-shaped, quadratic association was observed between BMI and colon cancer risk, with increased risk in BMIs >=27.5 and <18.5 kg/m(2). The association was more pronounced in never smokers and most prominent when further limiting the sample to those free of diabetes and cases with longer than 5 years of follow-up. Localized cases had a more pronounced association in BMIs >=27.5, whereas advanced cases had a more pronounced association in BMIs <18.5 kg/m(2) . No association was found in relation to rectal cancer risk. The association was also stronger among patients aged 65 years and older. CONCLUSIONS: BMI displays a U-shaped, quadratic association with colon cancer risk in this Chinese population in Southeast Asia. PMID- 21815136 TI - Electrocortical and behavioral measures of response monitoring in young children during a Go/No-Go task. AB - The current study examined behavioral measures and response-locked event-related brain potentials (ERPs) derived from a Go/No-Go task in a large (N = 328) sample of 5- to 7-year-olds in order to better understand the early development of response monitoring and the impact of child age and sex. In particular, the error related negativity (ERN, defined on both error trials alone and the difference between error and correct trials, or DeltaERN), correct response negativity (CRN), and error positivity (P(e)) were examined. Overall, the ERN, CRN, and the P(e) were spatially and temporally similar to those measured in adults and older children. Even within our narrow age range, older children were faster and more accurate; a more negative DeltaERN and a more positive P(e) were associated with: increasing age, increased accuracy, and faster reaction times on errors, suggesting these enhanced components reflected more efficient response monitoring of errors over development. Girls were slower and more accurate than boys, although both genders exhibited comparable ERPs. Younger children and girls were characterized by increased posterror slowing, although they did not demonstrate improved posterror accuracy. Posterror slowing was also related to a larger P(e) and reduced posterror accuracy. Collectively, these data suggest that posterror slowing may be unrelated to cognitive control and may, like the P(e), reflect an orienting response to errors. PMID- 21815137 TI - Transgenerational effects of infantile adversity and enrichment in male and female rats. AB - To discover whether the accumulation of life's experiences, adverse and enriching, inform, and serve the following generation by inheritance we examine whether stress to a weanling female will influence her future offspring, whether prereproductive enrichment to the dam, or postweaning enrichment to the offspring, can reverse the transgenerational effects of stress, and whether, like adversity, enrichment might have transgenerational effects. Female rats were exposed to stressors when they were 27-29 days old. Half of these females and their controls were then raised in an enriched environment from weaning until mating at 60 days to examine whether preproduction enrichment reverses the effects of preproduction stress on offspring. Half of the offspring of each group were raised in an enriched environment after weaning, to see whether it reverses the effects of preproduction stress and buttresses prereproductive enrichment. Behavior was examined in 625 adult offspring in 16 groups covering all permutations of the experimental variables (preproduction weanling stress (PS), preproduction enrichment (PE), offspring enrichment (OE), sex). Exploration, avoidance learning, startle, and social interaction were tested. Results reveal that very early prereproductive experience in females, adverse or enriching, will transgenerationally influence their future offspring, depending on the behavior tested and sex. Our finding that enrichment, whether to the parent or offspring generation, can ameliorate the transgenerational impact of adversity, has novel implications for the malleability of transgenerational inheritance, and its individual, social, and therapeutic impact. PMID- 21815138 TI - Pulling to stand: common trajectories and individual differences in development. AB - This longitudinal study of 27 infants examined the development of pulling-to stand (PTS). In general, infants began PTS using a two-leg strategy and transitioned to a half-kneel strategy. As a group, infants showed no preference for either strategy at the onset of PTS, switching between strategies until half kneeling became the dominant pattern about 1 month after the onset of PTS. Examination of individual developmental trajectories revealed variability in age at PTS onset, time between PTS onset and half-kneel strategy onset, duration of the two-leg strategy as the dominant pattern, time until the half-kneel strategy became the dominant pattern, shape of the transition between strategies (gradual vs. abrupt), and timing of PTS relative to onset of other motor milestones. We discuss variation in developmental trajectory in terms of adaptive behavior during the acquisition of new skills and as a process shaped by infants' unique experiences prior to and during the acquisition period. PMID- 21815139 TI - High prevalence and breast cancer predisposing role of the BLM c.1642 C>T (Q548X) mutation in Russia. AB - The BLM gene belongs to the RecQ helicase family and has been implicated in the maintenance of genomic stability. Its homozygous germline inactivation causes Bloom syndrome, a severe genetic disorder characterized by growth retardation, impaired fertility and highly elevated cancer risk. We hypothesized that BLM is a candidate gene for breast cancer (BC) predisposition. Sequencing of its entire coding region in 95 genetically enriched Russian BC patients identified two heterozygous carriers of the c.1642 C>T (Q548X) mutation. The extended study revealed this allele in 17/1,498 (1.1%) BC cases vs. 2/1,093 (0.2%) healthy women (p = 0.004). There was a suggestion that BLM mutations were more common in patients reporting first-degree family history of BC (6/251 (2.4%) vs. 11/1,247 (0.9%), p = 0.05), early-onset cases (12/762 (1.6%) vs. 5/736 (0.7%), p = 0.14) and women with bilateral appearance of the disease (2/122 (1.6%) vs. 15/1376 (1.1%), p = 0.64). None of the BLM-associated BC exhibited somatic loss of heterozygosity at the BLM gene locus. This study demonstrates that BLM Q548X allele is recurrent in Slavic subjects and may be associated with BC risk. PMID- 21815140 TI - Serum endostatin levels correlate with enhanced extracellular matrix degradation and poor patients' prognosis in bladder cancer. AB - Endostatin, the proteolytic fragment of collagen XVIII, is an inhibitor of angiogenesis and tumor growth. Interestingly, elevated circulating endostatin levels have been found to correlate with poor patients' prognosis in several cancers. The aim of this study was to assess the prognostic value of endostatin in bladder cancer (BC) and to gain insight into the mechanisms involved in its production. This retrospective study included a total of 337 patients with BC and 103 controls. Collagen XVIII gene expression was analyzed using real-time PCR (n = 82). Endostatin tissue localization was assessed by immunohistochemistry (n = 27). Endostatin serum (n = 87) and urine (n = 153) levels were determined by ELISA. In 12 cases, both serum and paraffinized tissue samples from the same patients were available. We found decreased collagen XVIII tissue expression and increased endostatin urine and serum concentration in samples of patients with BC compared to controls. High serum endostatin levels correlated with the presence of lymph node metastases and MMP-7 concentrations and were independently associated with poor metastasis-free and disease-specific survival. Immunohistochemical analysis revealed a strong endostatin staining in the wall of tumor associated blood vessels in superficial but not in muscle-invasive BCs. Based on these, we concluded that elevated endostatin levels in patients with BC are the consequence of enhanced extracellular matrix degradation and are independent from collagen XVIII expression. Furthermore, serum endostatin levels may provide prognostic information independent from histopathological parameters and may therefore help to optimize therapy decisions. Loss of endostatin expression in tumor associated blood vessels might represent an important step supporting tumor-induced angiogenesis. PMID- 21815141 TI - Mutagenesis and carcinogenesis induced by dibenzo[a,l]pyrene in the mouse oral cavity: a potential new model for oral cancer. AB - Cancer of the oral cavity is a serious disease, affecting about 30,000 individuals in US annually. There are several animal models of oral cancer, but each has certain disadvantages. As a new model, we investigated whether topical application of the tobacco smoke carcinogen, dibenzo[a,l]pyrene (DB[a,l]P) is mutagenic and carcinogenic in the oral cavity of the B6C3F1 lacI and B6C3F1 mouse, respectively. B6C3F1 lacI mice received DB[a,l]P (0, 3, 6, 12 nmol) 3* per week. B6C3F1 mice received the same doses and also 24 nmol. At 38 weeks mutagenesis was measured in oral tissues in lacI mice. For the high dose group, the mutant fraction (MF) in upper mucosa and tongue increased about twofold relative to that in vehicle-alone. The increases were statistically significant. The mutational profile in the DB[a,l]P-induced mutants was compared with that induced by benzo[a]pyrene (BaP) in oral tissue. BaP is mutagenic in many tissues when administered by gavage. The mutational profile for DB[a,l]P was more similar to that reported for p53 mutations in head and neck cancers than was that of BaP. At 47 weeks, oral squamous cell carcinomas (OSCC) were found in 31% of the high dose B6C3F1 group. Elevations of p53 and COX-2 protein were observed in tumor and dysplastic tissue. As DB[a,l]P induces mutations and tumors in the oral cavity, and has a mutational profile in oral tissue similar to that found in p53 in human OSCC, the treatment protocol described here may represent a new and relevant model for cancer of the oral cavity. PMID- 21815142 TI - Different DNA damage and cell cycle checkpoint control in low- and high-risk human papillomavirus infections of the vulva. AB - Human papillomavirus (HPV) infections may result in benign hyperplasia, caused by low-risk HPV types, or (pre)malignant lesions caused by high-risk HPV types. The molecular basis of this difference in malignant potential is not completely understood. Here, we performed gene profiling of different HPV infected vulvar tissues (condylomata acuminata (n = 5), usual type vulvar intraepithelial neoplasia (uVIN) (n = 9)) and control samples (n = 14) using Affymetrix Human U133A plus 2 GeneChips. Data were analyzed using OmniViz(r), Partek(r) and Ingenuity(r) Software. Results were validated by real-time RT-PCR and immunostaining. Although similarities were observed between gene expression profiles of low- and high-risk HPV infected tissues (e.g., absence of estrogen receptor in condylomata and uVIN), high-risk HPV infected tissues showed more proliferation and displayed more DNA damage than tissues infected with low-risk HPV. These observations were confirmed by differential regulation of cell cycle checkpoints and by increased expression of DNA damage-biomarkers p53 and gammaH2AX. Furthermore, FANCA, FANCD2, BRCA1 and RAD51, key players in the DNA damage response, were significantly upregulated (p < 0.05). In addition, we compared our results with publicly available gene expression profiles of various other HPV-induced cancers (vulva, cervix and head-and-neck). This showed p16(INK4a) was the most significant marker to detect a high-risk HPV infection, but no other markers could be found. In conclusion, this study provides insight into the molecular basis of low- and high-risk HPV infections and indicates two main pathways (cell cycle and DNA damage response) that are much stronger affected by high-risk HPV as compared to low-risk HPV. PMID- 21815143 TI - BARD1: an independent predictor of survival in non-small cell lung cancer. AB - BRCA1 mRNA overexpression is correlated with poor survival in NSCLC. However, BRCA1 functions depend on the interaction with BARD1 for its stability, nuclear localization and ubiquitin ligase activity. Expression of alternatively spliced BARD1 isoforms that lack the BRCA1-interaction domain was found upregulated and correlated with poor prognosis in breast and ovarian cancer. These BARD1 isoforms are essential for proliferation of cancer cells in vitro. We investigated whether BARD1 isoforms are expressed in NSCLC. While in lung tissues from healthy controls BARD1 expression was undetectable on the mRNA level and protein level, we found two novel isoforms in addition to previously identified mRNAs expressed in all NSCLC samples tested. Furthermore, the pattern of BARD1 isoform expression was similar in tumor and morphologically normal peri-tumor tissues, and only one novel isoform pi was specifically upregulated in tumors. Immunohistochemistry revealed that all 100 NSCLC cases tested expressed isoform-specific BARD1 epitopes, while BARD1 expression was undetectable in biopsies from healthy controls. Statistical analysis showed that the expression of epitopes PVC and WFS, present on isoform pi, or epitope WFS alone, expressed on isoforms pi, kappa and beta, were significantly correlated with decreased patient survival. These findings were corroborated in a mouse model of chemically induced lung cancer. Immunostaining of mouse tumors showed that BARD1 epitopes PVC and WFS were specifically upregulated in invasive, but not in confined lung tumors. Thus, BARD1 isoforms might be involved in tumor initiation and invasive progression and might represent a novel prognostic marker for NSCLC. PMID- 21815145 TI - Impact of lymph-node metastasis site in patients with thoracic esophageal cancer: does the lymph node metastasis site matter? PMID- 21815146 TI - Dermatofibrosarcoma protuberans: clinical diagnoses and treatment results of 260 cases in China. AB - BACKGROUND AND OBJECTIVES: Dermatofibrosarcoma protuberans (DFSP) is a low-grade malignant tumor but has high local recurrence rate. The objectives of this study were to analyze their clinicopathologic factors and review the experience of multidisciplinary treatments. METHODS: A total of 260 patients who were treated between 1985 and 2006 in Fudan University Shanghai Cancer Center were evaluated. Outcomes were compared focusing on recurrence and survival. Classical DFSP and transformed DFSP were the two subtypes. RESULTS: After local excision, 50.2% of the patients were found to have residual tumors. The recurrence rate after local excision was significantly higher than that after wide excision (45.0% vs. 8.5%, P < 0.0001). Patients undergoing wide excision with margins >=3 cm were found to have lower recurrence rate compared with those margins 1.5-2.5 cm (5.7% vs. 13.6%, P = 0.043). Compared with classical DFSPs, transformed DFSPs had significantly higher recurrence rate (34.5% vs. 6.3%, P < 0.0001), higher metastatic rate (23.5% vs. 0.4%, P < 0.0001), and worse prognosis (10-year survival rate 66.0% vs. 98.6%, P < 0.0001). CONCLUSIONS: Performing adequate initial resection is important for patients with DFSP. Once DFSP was diagnosed, wide excision with a best margin of >=3 cm is necessary. Transformed DFSPs are more aggressive tumors which need more energetic treatments. PMID- 21815147 TI - Clinical significance of decreased nidogen-2 expression in the tumor tissue and serum of patients with hepatocellular carcinoma. AB - BACKGROUND AND OBJECTIVES: Nidogen-2 is a ubiquitous component of basement membrane (BM), which is modified by tumor cells to facilitate tumor invasion. However, the expression and function of nidogen-2 in hepatocellular carcinoma (HCC) remains unknown at present. In this study, we sought to investigate the potential role of nidogen-2 in HCC. METHODS: Nidogen-2 expression in HCC tissues, cell lines, and serum was evaluated by immunohistochemistry, immunoassay, and real-time PCR assays. The regulation of nidogen-2 expression was investigated using doxycycline induction and small interfering RNA analyses. RESULTS: Nidogen 2 was significantly decreased in both HCC tissues and serum (P < 0.001). The decreased expression of nidogen-2 in HCC tissues was significantly correlated with tumor progression factors (P < 0.05). Inhibition of matrix metalloproteinase (MMP)-9 led to significantly upregulate nidogen-2 expression in vitro assays. Moreover, patients with HCC had lowest serum nidogen-2 levels compared with patients with benign liver diseases and normal volunteers. Furthermore, the receiver operating characteristic curve analysis revealed a good diagnostic performance of nidogen-2 for HCC. CONCLUSIONS: These findings suggest that decreased expression of nidogen-2 may have a potential pathogenetic role in the development of HCC and may also have potential diagnostic value for HCC. PMID- 21815148 TI - Underweight patients show an increased rate of postoperative death after surgery for hepatocellular carcinoma. AB - OBJECTIVE: To evaluate the influence of body mass index (BMI) on postoperative death in patients undergoing surgery for HCC. METHODS: Three hundred forty-two patients were enrolled, and divided into three groups: Group A, BMI <22.5; Group B, BMI >=22.5 to <25; Group C, BMI >=25. Univariate and multivariate analyses of postoperative death were performed to compare BMI with clinical factors. Kaplan Meier analysis and log rank test were used to compare such outcome in Groups A, B, and C. RESULTS: Kaplan-Meier analysis and log rank test revealed that Group A had a higher rate of postoperative death than Group B or C (P = 0.010). Univariate and multivariate analyses selected being underweight (Group B, C/Group A) (odds ratio, 1.829; 95% C.I., 1.091-3.068; P = 0.022) as one of the factors predictive of postoperative death, together with aspartate aminotransferase level (P = 0.042) and HCC growth pattern (P = 0.032). CONCLUSIONS: BMI is a simple but important predictor of postoperative death in patients undergoing surgery for HCC, and is able to classify such patients into three independent groups. PMID- 21815149 TI - Lymph node ratio is an important and independent prognostic factor for patients with stage III melanoma. AB - INTRODUCTION: The incidence of melanoma is dramatically increasing worldwide. We hypothesized that the ratio of metastatic to examined lymph node ratio (LNR) would be the most important prognostic factor for stage III patients. METHODS: We retrospectively reviewed our institutional database of melanoma patients and identified 168 patients who underwent lymph node dissection (LND) for stage III disease between 1993 and 2007. Patients were divided into three groups based on LNR (<=10%, n = 93; 10-<=25%, n = 45; and >25%, n = 30). Univariate and multivariate analysis was performed using Cox proportional hazards model. RESULTS: The median survival time of the entire group of patients was 34 months. The median number of positive nodes was 2 (range = 1, 55), and the median number of examined nodes was 22 (range = 5-123). Tumor characteristics of the primary melanoma (such as thickness, ulceration, and primary site) were not significant predictors of survival in this analysis. By univariate analysis, LNR was an important prognostic factor. Patients with LNR 10-25% and >25% had decreased survival compared to those patients with LNR <=10% (HR = hazard ratio = 2.0 and 3.1, respectively; P <= 0.005). The number of positive lymph nodes also impacted on survival (P = 0.001). In multivariate analysis, LNR of 10-25% and >25% predicted survival (HR = 2.5 and 4.0, respectively). CONCLUSION: LNR is an important prognostic factor in patients undergoing LND for stage III melanoma. It can be used to stratify patients being considered for adjuvant therapy trials and should be evaluated using a larger prospective database. PMID- 21815150 TI - The toxicity and long-term efficacy of nedaplatin and paclitaxel treatment as neoadjuvant chemotherapy for locally advanced cervical cancer. AB - BACKGROUND: The use of neoadjuvant chemotherapy (NACT) for the treatment of locally advanced cervical cancer (LACC) remains controversial. In current clinical practice, platinum-based chemotherapy is the major option for patients with LACC. However, serious adverse events have been reported after platinum based chemotherapy treatment for LACC patients. In this study, the authors evaluated whether nedaplatin and paclitaxel (NP), as a new NACT regimen, offers less toxicity and better long-term efficacy for LACC (stages IB2-IIB) treatment. Comparisons between NP and paclitaxel and cisplatin (PC) in terms of toxicity and long-term efficacy are also presented. METHODS: The authors retrospectively reviewed 252 consecutive patients with LACC, of whom 104 received NP; the others received PC. Toxicity was assessed according to the International WHO (1979) criteria for chemotherapy side effects, and the chi-squared test was used to identify whether there was a statistically significant difference in toxicity between the NP regimen and the PC regimen. A univariate and a Cox regression model were used to assess whether the patients who were administered NP were statistically significantly different from those who were administered PC with respect to the disease-free survival rate (DFS) and the overall survival rate (OS). RESULTS: The overall response rate for NP and PC were 80.77% and 68.24%, respectively (P = 0.0267). The incidences of toxic reactions for NP and PC were 32.69% and 85.14%, respectively (P < 0.0001). The DFS for patients who were given the NP and the PC regimens were 81.41% and 67.28%, respectively (P = 0.014). The OS was 81.54% for patients who received the PC program and 93.89% for those who received the NP program (P = 0.0084). The NP program participants experienced a significant increase in the survival rate when compared to the group that received the PC program (DFS hazard ratio = 0.539, P = 0.0144 and OS hazard ratio = 0.354, P = 0.0077). CONCLUSIONS: NP NACT followed by radical hysterectomy offers a higher response rate, lower incidence of toxic reactions and better long term DFS and OS for patients with LACC compared with the chemotherapy regimen of PC followed by radical hysterectomy. PMID- 21815151 TI - The predictors of response to neoadjuvant chemotherapy in advanced epithelial ovarian cancer. AB - OBJECTIVES: To investigate the predictors of response to neoadjuvant chemotherapy (NACT) in advanced stage epithelial ovarian cancer (EOC). METHODS: Thirty-five patients with nonoptimally cytoreductable at stage III-IV EOC who were treated with NACT and interval cytoreductive surgery in our center between January 2002 and February 2009 were enrolled into this retrospective pilot study. Response to NACT was evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST). RESULTS: All patients received three courses platinum-based chemotherapy [24 (69%) received pactitaxel plus carboplatin and 11 (31%) received paclitaxel plus cisplatin]. There were 12 (34%) partial response to and 23 (66%) stable disease after NACT. Optimal cytoreduction was subsequently achieved in 32 of 35 patients (91%). Among age, hystology, ovarian size, CA-125 level, severity of pleural effusion, extensive omental disease, diaphragmatic implants, liver parenchyma metastasis, used chemotherapy regimen; only extensive omental disease was found to be predictive (P = 0.004). CONCLUSIONS: Ovarian cancer patients with extensive omental disease were possibly better treated with primary cytoreductive surgery, since they were more likely to have less responsive to NACT. This finding can be used to identify patients who will get poor response to NACT and to design future tailored randomized clinical trials. PMID- 21815152 TI - Overall survival peri-hilar cholangiocarcinoma: R1 resection with curative intent compared to primary endoscopic therapy. AB - BACKGROUND AND OBJECTIVES: Patients with peri-hilar cholangiocarcinoma who undergo R1 resection with curative intent will have an improved survival compared to patients who were not resected. METHODS: Review of a prospective hepatobiliary database identified 130 patients. Survival was compared using the log-rank test. RESULTS: Seventy-nine patients (61%) were resected while 51 (49%) patients were not. Forty-two patients (54%) had an R0 resection. There was no difference in mean age (69 vs. 67; P = 0.8), BMI (27.8 vs. 27.9; P = 1.0), gender (73% vs. 43% male; P = 0.1), presence of jaundice (77% vs. 64%; P = 0.5), vascular involvement on pre operative imaging (77% vs. 64%; P = 0.5), stent (73.1% vs. 64.3%; P = 0.72), and lobar atrophy (27% vs. 7%, P = 0.2) in the resected versus non resected patients. All patients underwent chemotherapy and/or radiation therapy. After a median follow up of 35.6 months the median OSl for all peri-hilar patients was 16.2 months (95% CI = 11.2-23.4). The median OS for resected patients was 18.9 months (95% CI = 12.5-24.7) versus 5.0 months (95% CI = 0-6.9) for patients not resected (P < 0.001). The only pre-operative predictor of OS was resection (P = 0.041). Vascular invasion, lobar atrophy, and stent placement were not statistically significant predictors. CONCLUSION: Overall survival is improved in patients undergoing R1 resection and multi-modality therapy compared to patients not resected. PMID- 21815153 TI - Expressive levels of MUC1 and MUC5AC and their clinicopathologic significances in the benign and malignant lesions of gallbladder. AB - OBJECTIVE: This article is intended to make a study on the expressive levels of mucin core proteins (MUC1 and MUC5AC) and detect their clinicopathologic significances in the benign and malignant lesions of gallbladder. METHODS: EnVision immunohistochemical method for determining the expressions of MUC1 and MUC5AC was used in routinely paraffin-embedded sections of surgically resected specimens from gallbladder adenocarcinoma (n = 108), peritumoral tissues (n = 46), adenoma (n = 15), and chronic cholecystitis (n = 35). RESULTS: The positive rate of MUC1 expression was significantly higher in gallbladder adenocarcinoma than that in peritumoral tissues (chi(2) = 16.49, P < 0.01), adenoma (chi(2) = 7.40, P < 0.01), and chronic cholecystitis (chi(2) = 28.57, P < 0.01), while the positive rate of MUC5AC expression was significantly lower in gallbladder adenocarcinoma than that in peritumoral tissues (chi(2) = 12.83, P < 0.01), adenoma (chi(2) = 4.22, P < 0.05), and chronic cholecystitis (chi(2) = 20.25, P < 0.01). The positive cases of MUC1 and the negative ones of MUC5AC in the benign lesions showed moderate- or severe-dysplasia of gallbladder epithelium. The positive rates of MUC1 were significantly lower in gallbladder adenocarcinomas with maximal diameter of mass <2 cm, no metastasis of lymph node, and no invasiveness of regional tissues (P < 0.05 or P < 0.01) than those in gallbladder adenocarcinomas with maximal diameter of mass >2 cm, metastasis of lymph node, and invasiveness of regional tissues (P < 0.05 or P < 0.01). However, the positive rates of MUC5AC were significantly higher in the highly differentiated adenocarcinoma with maximal diameter of mass <2 cm than those in the low differentiated adenocarcinoma with maximal diameter of mass >=2 cm. Univariate Kaplan-Meier analysis showed that increased expression of MUC1 (P = 0.064) or decreased expression of MUC5AC (P = 0.017) was associated with decreased overall survival. Multivariate Cox regression analysis showed that decreased expression of MUC5AC (P = 0.008) was an independent prognostic predictor to gallbladder adenocarcinoma. CONCLUSIONS: The expression of MUC1 and MUC5AC might be closely related to the carcinogenesis, clinical biological behaviors, and prognosis of gallbladder adenocarcinoma. PMID- 21815154 TI - Survival analysis of patients with femoral metastases. AB - BACKGROUND: Previous studies reported on surgical indications for patients with femoral metastases. However, few studies analyzed the spectrum of femoral metastatic presentation. We performed this study to evaluate the survival of patients with femoral metastases, and clarify the treatment of femoral impending and actual pathological fractures. MATERIALS AND METHODS: We retrospectively studied 110 patients with femoral metastases from various cancers treated with nailing or resection and megaprosthetic reconstruction from 1995 to 2010. The mean follow-up was 18 months. Survival was analyzed with respect to different metastatic presentations regarding gender, type of cancer, number, and location of femoral metastases, type of surgery, and pathological fracture. RESULTS: Univariate predictors of survival were the pathological fracture and type of surgery; multivariate predictor was only the pathological fracture. Survival was significantly higher in patients with resection compared to nailing, impending compared to actual fracture, solitary metastasis and impending fracture, actual fracture treated with resection, proximal femoral actual fracture and distal femoral impending fracture treated with resection. CONCLUSIONS: Patients with femoral metastases have better survival when present with impending compared to actual pathological fracture. Although with a higher rate of complications, patients with pathological fractures of the proximal and distal femur may benefit from resection. PMID- 21815155 TI - Influence of growth rate on occurrences of pale muscle in broilers. AB - BACKGROUND: Pale broiler breast meat is a defect in commercial production operations. The incidence of pale broiler breast meat was examined in two commercial processing plants which had average growth rates of 59 g day(-1) and 46 g day(-1) and final average weights of 3.36 kg and 1.93 kg. Color measurements of dorsal and ventral surfaces and pH were completed to evaluate the impact of selection for growth on meat water-holding capacity. RESULTS: L* greater than 60 were observed in 57% of broilers selected for greater yield and 26% of slower growing broilers. Average L* between 10 growers was significantly different (P = 0.001). Pearson's correlation coefficients for pH and L* were - 0.51 and - 0.27 for the faster growing broilers and slower growing broilers, respectively. The Pearson correlation coefficients between water-holding capacity and L* and pH was - 0.35 and 0.42, respectively. There was a higher correlation between production factors (age, weight and grower) and a* and b* than L* for ventral surface measurements. CONCLUSION: Breasts from broilers selected for faster growth tend to have lighter color. Weak correlation with water-holding capacity suggests that quality remains the same and light color is probably related to other factors. PMID- 21815156 TI - Comparative proteome analysis of glutenin synthesis and accumulation in developing grains between superior and poor quality bread wheat cultivars. AB - BACKGROUND: Wheat glutenins are the major determinants of wheat quality. In this study, grains at the development stage from three wheat cultivars (Jimai 20, Jin 411 and Zhoumai 16) with different bread-making quality were harvested based on thermal times from 150 degrees C(d) to 750 degrees C(d) , and were used to investigate glutenin accumulation patterns and their relationships with wheat quality. RESULTS: High and low molecular weight glutenin subunits (HMW-GSs and LMW-GSs) were synthesised concurrently. No obvious correlations between HMW/LMW glutenin ratios and dough property were observed. Accumulation levels of HMW-GSs and LMW-GSs as well as 1Bx13 + 1By16 and 1Dx4 + 1Dy12 subunits were higher in superior gluten quality cultivar Jimain 20 than in poor quality cultivar Jing 411 and Zhoumai 16. According to the results of two-dimensional gel electrophoresis, six types of accumulation patterns in LMW-GSs were identified and classified. The possible relationships between individual LMW-GSs and gluten quality were established. CONCLUSION: The high accumulation level of HMW-GSs and LMW-GSs as well as 1Bx13 + 1By16 and 1Dx4 + 1Dy12 subunits contributed to the superior gluten quality of Jimai 20. Two highly expressed and 16 specifically expressed LMW glutenin subunits in Jimain 20 had positive effects on dough quality, while 17 specifically expressed subunits in Zhoumai 16 and Jing 411 appeared to have negative effects on gluten quality. PMID- 21815157 TI - Chemical composition, angiotensin-converting enzyme-inhibitory activity and antioxidant activities of few-flower wild rice (Zizania latifolia Turcz.). AB - BACKGROUND: The chemical compositions of the stem and leaf sheath of few-flower wild rice were analysed. In addition, their extracts were evaluated for diphenylpicrylhydrazyl (DPPH) free radical-scavenging activity, ferric-reducing antioxidant power and angiotensin-converting enzyme (ACE)-inhibitory activity, since these are important properties of sources of nutraceuticals or functional foods. RESULTS: The stems contained more ascorbic acid (0.06 g kg(-1) fresh weight), protein (28.18 g kg(-1) dry weight (DW)), reducing sugars (308.54 g kg( 1) DW), water-soluble pectin (20.63 g kg(-1) DW), Na(2) CO(3) -soluble pectin (44.14 g kg(-1) DW), K (8 g kg(-1) dry matter (DM), S (6 g kg(-1) DM) and P (5 g kg(-1) DM) but less starch, total dietary fibre, Si, Na and Ca than the leaf sheaths. The DPPH free radical-scavenging IC(50) values of the stem and leaf sheath extracts were 19.28 and 21.22 mg mL(-1) respectively. In addition, the ACE inhibitory IC(50) value of the stem extracts was 38.54 mg mL(-1). CONCLUSION: Both the stem and leaf sheath extracts exhibited good antioxidant properties, while good ACE-inhibitory activity was detected only in the phosphate buffer solution extracts of the stem. Few-flower wild rice could be processed into formula feeds for fish, poultry, etc. or functional foods for persons with high blood pressure. PMID- 21815158 TI - Effects of ripening, 1-methylcyclopropene and ultra-high-pressure pasteurisation on the change of volatiles in Chinese pear cultivars. AB - BACKGROUND: Aroma is one important fruit sensory attribute influenced by the volatile constituents related to species, variety and technological treatments. We analysed the variations of volatile compounds in five pear cultivars and investigated their changes related to different pear organs, different ripening stages, 1-MCP treatment and ultra-high-pressure pasteurisation. RESULTS: Considerable variations exist in the quantity of 10 volatile compounds among five pear cultivars. Their levels generally showed an increasing trend when collected at later harvest time in Ya pear. In Whangkeumbae pear, most volatile compounds reached their maximum levels in skin and pulp. After treating pears with 42 umol L(-1) 1-methylcyclopropene (1-MCP), the levels of volatiles remained basically unchanged or only slightly increased in Ya pear during a shelf life of 21 days. When Huangguan pear juice was pasteurised by using ultra-high pressure, the levels of volatiles significantly changed during the shelf life. CONCLUSION: The volatile compositions of five different Chinese pear cultivars differ considerably. The levels of these volatiles vary along with ripening stages and pear tissues. A moderate concentration of 1-MCP could keep the levels of volatile compounds basically unchanged during storage and ultra-high-pressure pasteurisation could change the levels of volatiles significantly during the following shelf life. PMID- 21815159 TI - Optimisation of chocolate formulation using dehydrated peanut-cowpea milk to replace dairy milk. AB - BACKGROUND: The rheological properties of chocolate, based upon its acceptability by consumers, are determined largely by the ingredients and their proportions used in the formulations. Milk chocolates are very popular because milk provides flavour and smooth texture to the product. This study aimed to determine the optimal ingredient formulation for vegetable milk chocolate using peanut-cowpea milk as a substitute for dairy milk. The study followed a four-component constrained mixture design, with cocoa liquor, vegetable milk, cocoa butter and sugar as the components. Lecithin and vanillin were added at a constant amount to all formulations. Critical attributes of the chocolates were evaluated using descriptive sensory tests and instrumental techniques. RESULTS: Regression models were fitted to the data, and the optimum ingredient formulation for acceptable vegetable milk chocolate was determined. The vegetable milk had significant (P = 0.05) influence on flavour, mouth feel, hardness and after taste of chocolates. CONCLUSIONS: The optimum ingredient formulation for acceptable vegetable milk chocolates was determined to be cocoa liquor (18.00%), sugar (30.75%), peanut cowpea milk (28.93%), and cocoa butter (22.32%). The results demonstrate that it is feasible to use vegetable source milk for chocolate. The findings also provide clues for scale-up criteria for large-scale production of vegetable milk chocolate. PMID- 21815160 TI - Quality changes in sea urchin (Strongylocentrotus nudus) during storage in artificial seawater saturated with oxygen, nitrogen and air. AB - BACKGROUND: Sea urchin gonads are highly valued seafood that degenerates rapidly during the storage period. To study the influence of dissolved oxygen concentration on quality changes of sea urchin (Strongylocentrotus nudus) gonads, they were stored in artificial seawater saturated with oxygen, nitrogen or air at 5 +/- 1 degrees C for 12 days. RESULTS: The sensory acceptability limit was 11 12, 6-7 and 7-8 days for gonads with oxygen, nitrogen or air packaging, respectively. Total volatile basic nitrogen (TVB-N) values reached 22.60 +/- 1.32, 32.37 +/- 1.37 and 24.91 +/- 1.54 mg 100 g(-1) for gonads with oxygen, nitrogen or air packaging at the points of near to, exceeding and reaching the limit of sensory acceptability, indicating that TVB-N values of about 25 mg 100 g(-1) should be regarded as the limit of acceptability for sea urchin gonads. Relative ATP content values were 56.55%, 17.36% and 18.75% for gonads with oxygen, nitrogen or air packaging, respectively, on day 2. K-values were 19.37%, 25.05% and 29.02% for gonads with oxygen, nitrogen or air packaging, respectively, on day 2. Both pH and aerobic plate count values showed no significant difference (P > 0.05) for gonads with the three treatments. CONCLUSION: Gonads with oxygen packaging had lower sensory demerit point (P < 0.05) and TVB-N values (P < 0.05), and higher relative ATP content (P < 0.01) and K-values (P < 0.05), than that with nitrogen or air packaging, with an extended shelf life of 4-5 days during storage in artificial seawater at 5 +/- 1 degrees C. PMID- 21815161 TI - Aluminium-phosphorus interactions in plants growing on acid soils: does phosphorus always alleviate aluminium toxicity? AB - Aluminium (Al) toxicity and phosphorus (P) deficiency are considered to be the main constraints for crop production in acid soils, which are widely distributed in tropical and subtropical regions. Conventionally, P addition is regarded as capable of alleviating Al toxicity in plants. However, this field is still rife with unsubstantiated theories, especially for different plant species growing on acid soils. In this review, the responses of plants to different methods of Al-P treatments are briefly summarized, and possible reasons are proposed by considering recent results from our laboratory. It is shown that: (1) long-term Al-P alternate treatment is advantageous for studying Al-P interactions in plants; (2) under the long-term Al-P alternate treatment, the roles of P in Al phytotoxicity might be associated with the Al resistance capability and P use efficiency of the plant, and a P/Al molar ratio exceeding 5 in roots may be the threshold of P alleviating Al toxicity based on the calculation of the tested plants; (3) in acid soils, P application may be effective only after Al stress is overcome for Al-sensitive species. Thus it is concluded that P application does not always alleviate Al toxicity under long-term Al-P alternate treatment. PMID- 21815162 TI - Radioactivity and heavy metal concentrations in food samples from Rize, Turkey. AB - BACKGROUND: Rize in Turkey was contaminated by the Chernobyl accident in 1986. A comprehensive study was planned and carried out to determine the radioactivity levels and heavy metal concentrations in four food categories collected in Rize in 2008, 2009 and 2010. RESULTS: Tomato showed the highest concentration of (238) U, at 9.43 +/- 0.128 Bq kg(-1) , whereas the lowest concentration of 0.20 +/- 0.02 Bq kg(-1) was measured in aubergine samples. The highest concentration of (232) Th was measured at 3.22 +/- 0.29 Bq kg(-1) in grape samples. (40) K was found to contribute the highest activity in all the food samples. The highest activity concentration of (137) Cs was 10.20 +/- 4.19 Bq kg(-1) , for parsley. The average contribution range of each of the heavy metals to the dietary intake was 0.13-9.14, 0.27-34.63, 0.05-3.62, 0.11-14.97, 0.78-8.51 and 0.01-1.57 mg, respectively, for Mn, Fe, Cu, Zn, Ni and As. CONCLUSION: The range of radioactivity levels in food samples of the present study is of no risk to public health. Heavy metal concentrations of Mn, Fe, Cu, Zn, Ni and As obtained were far below the established values by FAO/WHO limits. PMID- 21815163 TI - Effect of bioactive compounds in lactobacilli-fermented soy skim milk on femoral bone microstructure of aging mice. AB - BACKGROUND: Soy skim milks fermented with lactobacilli contain various phytochemicals such as isoflavones and peptides. We used lactobacilli-fermented soy skim milk as a nutritional supplement for 6 weeks to investigate its anti osteoporosis effect in 13-month-old female BALB/c aging mice. Freeze-dried powder of soy skim milk fermented by Lactobacillus paracasei subsp. paracasei NTU 101 (NTU 101F) and L. plantarum NTU 102 (NTU 102F) were used in this study. RESULTS: The trabecular bone volumes in mice fed NTU 101F and NTU 102F increased by a factor of 3.48 and 2.16 compared with control values, respectively. The network density and thickness of distal metaphyseal trabecular bone in mice fed with NTU 101F and NTU 102F milks were significantly denser than that of control mice; moreover, the NTU 101F group had the largest resting area ratio and smallest resorbing area compared with other groups. The beneficial effect may due to isoflavones as well as higher amounts of polysaccharide and peptide in NTU 101F milk. CONCLUSION: The results suggest that dietary supplement with fermented soy skim milk can attenuate aging-induced bone loss in BALB/c mice and possibly lower the risk of osteopenia or osteoporosis in aging. PMID- 21815164 TI - Phytoavailability, human risk assessment and transfer characteristics of cadmium and zinc contamination from urban gardens in Kano, Nigeria. AB - BACKGROUND: Quantitative data about phytoavailability and transfer into consumed plant parts for heavy metals in intensively managed urban vegetable production areas of sub-Saharan Africa are scarce. We therefore studied the transfer of zinc (Zn) and cadmium (Cd) from soil to the root and subsequent translocation to edible portions of four vegetables in six urban gardens. RESULTS: While respective diethylenetriaminepentaacetic acid (DTPA)-available Zn and Cd concentrations ranged from 18 to 66 mg kg(-1) and from 0.19 to 0.35 mg kg(-1) , respectively, in soils, total Zn and Cd were 8.4-256 mg kg(-1) and 0.04-1.7 mg kg(-1) in shoot parts. Metal transfer factor (MTF) ratios were higher in Zn (0.2 0.9) than in Cd (0.1-0.6). Our data suggest that total Zn concentration in soil is a reliable indicator to assess its transfer from soil to crop in lettuce, carrot and parsley, while for Cd DTPA-extractable concentration may be used to estimate soil-crop transfer of Cd in amaranthus and carrot. Overall, Cd was more easily translocated to the aerial plant parts than Zn. CONCLUSION: Zinc and Cd accumulation by vegetables in our soils is mainly a metabolically controlled process. Such accumulation can contaminate the ecosystem but under our conditions intake and ingestion of these metals will likely have to occur over a prolonged period to experience health hazard. PMID- 21815165 TI - Artificial aging of Uva di Troia and Primitivo wines using oak chips inoculated with Penicillium purpurogenum. AB - BACKGROUND: Two red wines (Primitivo and Uva di Troia) treated with oak chips inoculated with Penicillium purpurogenum were analysed in order to assess their contents of furfural, cis-beta-methyl-gamma-octalactone, syringol, eugenol, vanillin and 4-vinylguaiacol. Two different sizes of oak chips (small and big, of length 2 and 8 mm respectively) and two different degrees of toasting (low and high) were used in the study. Aroma compounds were analysed by gas chromatography/mass spectrometry to determine differences among samples after 15 days of chip contact time. RESULTS: Big oak chips inoculated with P. purpurogenum increased the level of 4-vinylguaiacol, while small oak chips inoculated with P. purpurogenum, in some conditions, increased the level of eugenol. Chip size and degree of toasting also played an important role in the content of eugenol. CONCLUSION: The use of oak chips inoculated with mould might be a promising alternative to barrel aging. Moreover, different fungal inocula could contribute to the enrichment of wine with specific compounds (e.g. 4-vinylguaiacol and eugenol). PMID- 21815166 TI - Expression of modified tocopherol content and profile in sunflower tissues. AB - BACKGROUND: Alpha-tocopherol is the predominant tocopherol form in sunflower seeds. Sunflower lines that accumulate increased levels of beta-, gamma- and delta-tocopherol in seeds as well as lines with reduced and increased total seed tocopherol content have been developed. The objective of this research was to evaluate whether the modified tocopherol levels are expressed in plant tissues other than seeds. RESULTS: Lines with increased levels of beta-, gamma- and delta tocopherol in seeds also possessed increased levels of these tocopherols in leaves, roots and pollen. Correlation coefficients for the proportion of individual tocopherols in different plant tissues were significantly positive in all cases, ranging from 0.68 to 0.97. A line with reduced tocopherol content in seeds also showed reduced content in roots and pollen. CONCLUSION: Genetic modifications producing altered seed tocopherol profiles in sunflower are also expressed in leaves, roots and pollen. Reduced total seed tocopherol content is mainly expressed at the root and pollen level. The expression of tocopherol mutations in other plant tissues will enable further studies on the physiological role of tocopherols and could be of interest for early selection for these traits in breeding programmes. PMID- 21815167 TI - Facilitative effects of Eucommia ulmoides on fatty acid oxidation in hypertriglyceridaemic rats. AB - BACKGROUND: Tea made from Eucommia ulmoides leaves is widely consumed as a health food, since recent studies have revealed various pharmacological effects of the tea, e.g. a hypotriglyceridaemic effect. This study was conducted to elucidate the mechanisms underlying the plasma triglyceride-lowering effect of E. ulmoides leaves. RESULTS: Rats were divided into four groups: a normal group, a group fed a high-fat/high-fructose diet (untreated group) and two groups fed a high fat/high-fructose diet and E. ulmoides tea (4 or 20 g L(-1) extract, treated groups). Plasma triglyceride concentrations were reduced in treated groups in a dose-dependent manner compared with the untreated group. DNA microarray analysis revealed that genes involved in hepatic alpha-, beta- and omega-oxidation, mainly related to the peroxisome proliferator-activated receptor alpha and delta signalling pathway, were up-regulated in the treated group. High-performance liquid chromatography analysis showed that E. ulmoides leaves contain three phytochemicals that make up 60 mg g(-1) of the material and are likely to be the active components. CONCLUSION: This study indicates that the promotion of fatty acid oxidation, probably by the action of phytochemicals, participates in the ameliorative effect of E. ulmoides leaves on hypertriglyceridaemia. These findings provide the scientific evidence for the functionality of E. ulmoides. PMID- 21815168 TI - Egg yolk fatty acid profile in relation to dietary fatty acid concentrations. AB - BACKGROUND: The health benefits of n-3 fatty acids have led to much research on manipulating the fatty acid composition of animal-derived foods. In this study, two experiments were conducted to investigate the interaction of dietary fatty acids on egg yolk fatty acid concentrations. In experiment I, 32 dietary treatments with three replicates of three birds each were fed for 35 days. Diets were prepared by mixing one type of fish oil with four vegetable oils in different proportions. In experiment II, three different types and two levels of fish oil in combination with two vegetable oils were tested under the same conditions as in experiment I. RESULTS: In experiment I the results showed that the egg yolk saturated (SFA) and monounsaturated (MUFA) fatty acid concentration was determined by the dietary SFA, MUFA and 18:2n-6 content. The egg 18:2n-6 concentration was mainly explained by the dietary inclusion of 18:2n-6 and negatively by the dietary MUFA content. The egg C18:3n-3, C20:5n-3 and C22:6n-3 concentration is almost exclusively determined by their direct supply from the diet. The egg 20:4n-6 concentration was inversely proportional to the long-chain n-3 polyunsaturated fatty acid content of the diet. The results of experiment II showed that the egg yolk C20:5n-3 and C22:6n-3 concentration was determined by both the level of dietary fish oil (1 or 2%) and the C20:5n-3/C22:6n-3 ratio in the fish oil. CONCLUSION: The results of this study demonstrated that the direct dietary supply of fatty acids is the most important factor determining the egg yolk fatty acid composition, in particular for the n-3 fatty acids. The interaction effect from other dietary fatty acids was in general small. PMID- 21815169 TI - Quantitative descriptive analysis of Italian polenta produced with different corn cultivars. AB - BACKGROUND: Polenta is a porridge-like dish, generally made by mixing cornmeal with salt water and stirring constantly while cooking over a low heat. It can be eaten plain, straight from the pan, or topped with various foods (cheeses, meat, sausages, fish, etc.). It is most popular in northern Italy but can also be found in Switzerland, Austria, Croatia, Argentina and other countries in Eastern Europe and South America. Despite this diffusion, there are no data concerning the sensory characteristics of this product. A research study was therefore carried out to define the lexicon for a sensory profile of polenta and relationships with corn cultivars. RESULTS: A lexicon with 13 sensory parameters was defined and validated before references were determined. After panel training, the sensory profiles of 12 autochthonous maize cultivars were defined. CONCLUSION: The results of this research highlighted that quantitative descriptive analysis can also be used for the sensory description of polenta, and that the defined lexicon can be used to describe the sensory qualities of polenta for both basic research, such as maize selection, and product development. PMID- 21815170 TI - Pharmacokinetic study of a novel sonosensitizer chlorin-e6 and its sonodynamic anti-cancer activity in hepatoma-22 tumor-bearing mice. AB - PURPOSE: The sonodynamically induced anti-tumor effect of chlorin-e6 (Ce6) was studied in mice bearing hepatoma-22 solid tumors. METHODS: In order to determine the optimum timing of ultrasound exposure after administration of Ce6, the Ce6 concentrations in plasma, skin, muscle and tumor were estimated by measuring the fluorescence intensity of tissue extractions with a fluorescence photometer based on the standard curve. A three-dimensional optical imaging system (IVIS spectrum) was used further to characterize the distribution of Ce6 in H-22 tumor. The anti tumor effects were estimated by measuring tumor size after sonodynamic therapy. RESULTS: Similar pharmacokinetic trends of Ce6 in mice were observed either by fluorescence spectrophotometry or by bio-optical imaging. The results also demonstrated that Ce6 has a preferential localization in tumors, but low accumulation and rapid clearance in normal tissues. The results of anti-tumor effects revealed that at an ultrasound intensity of 4 W/cm(2) and a Ce6 dose of >=10 mg/kg, a significant synergistic effect of ultrasound combined with Ce6 was observed, reducing the tumor volume significantly. CONCLUSION: Chlorin-e6 is a potential sonosensitizer for fluorescence imaging as well as for sonodynamic therapy for cancer. The anti-tumor effect of ultrasound could be enhanced in the presence of Ce6, which might be involved in a sonochemical mechanism. PMID- 21815171 TI - Development and characterization of skin permeation retardants and enhancers: a comparative study of levothyroxine-loaded PNIPAM, PLA, PLGA and EC microparticles. AB - Polymeric microparticles suitable for topical and transdermal delivery systems were studied using poly D,L lactide (PLA), poly D,L lactide co glycoside (PLGA), poly (N-isopropylacrylamide) (PNIPAM) and ethyl cellulose (EC). Drug encapsulation efficacy, microparticle stability and skin permeation studies of levothyroxine loaded microparticles were carried out using excised human skin, and the skin permeation pattern was observed using confocal laser scanning microscopy. It was found that ethyl cellulose microparticles had the highest drug encapsulation and minimal drug leakage during the 14 week storage period. The PNIPAM microparticles had the lowest drug encapsulation efficiency and a fast degradation rate. The PLGA microparticles exhibited a temperature dependent drug leakage. Permeation studies using a flow-through diffusion cell indicated that the polymer transition temperature (T(g)) may influence the skin permeation rate of levothyroxine. Polyesters (PLA and PLGA) and PNIPAM acted as a skin penetration retardant and caused skin accumulation of the drug. These microparticles have potential use in skin formulations containing sunscreens and other active ingredients that are meant to be concentrated on the skin surface. However, skin permeation was observed from EC microparticles, therefore such polymers may be used as carriers in transdermal formulations to help achieve therapeutic concentrations of the drug in the plasma. PMID- 21815172 TI - Peripheral nerve and muscle ultrasound in amyotrophic lateral sclerosis. AB - INTRODUCTION: High-resolution ultrasound has been used to evaluate several neuromuscular conditions, but it has only been used on a limited basis in amyotrophic lateral sclerosis (ALS) patients. It has not been used to assess their peripheral nerves. This study was designed to use neuromuscular ultrasound to investigate nerve cross-sectional area and muscle thickness in ALS. METHODS: Twenty individuals with ALS and 20 matched controls underwent neuromuscular ultrasound to measure the cross-sectional area of their median and sural nerves and the thickness of their biceps/brachialis muscle complex. RESULTS: The cross sectional area of the median nerve in the mid-arm was smaller in the ALS group than in controls (10.5 mm(2) vs. 12.7 mm(2) , P = 0.0023), but no difference was seen in the sural nerve (4.5 mm(2) vs. 5.0 mm(2) , P = 0.1927). The ALS group also had thinner biceps/brachialis than controls (2.1 cm vs. 2.9 cm, P = 0.0007). CONCLUSIONS: Neuromuscular ultrasound demonstrates nerve and muscle atrophy in ALS and should be further explored as a disease biomarker. PMID- 21815174 TI - Specific interactions and binding free energies between thermolysin and dipeptides: molecular simulations combined with ab initio molecular orbital and classical vibrational analysis. AB - Thermolysin (TLN) is a metalloprotease widely used as a nonspecific protease for sequencing peptide and synthesizing many useful chemical compounds by the chemical industry. It was experimentally shown that the activity and functions of TLN are inhibited by the binding of many types of amino acid dipeptides. However, the binding mechanisms between TLN and dipeptides have not been clarified at the atomic and electronic levels. In this study, we investigated the binding mechanisms between TLN and four dipeptides. Specific interactions and binding free energies (BFEs) between TLN and the dipeptides were calculated using molecular simulations based on classical molecular dynamics and ab initio fragment molecular orbital (FMO) methods. The molecular systems were embedded in solvating water molecules during calculations. The calculated BFEs were qualitatively consistent with the trend of the experimentally observed inhibition of TLN activity by binding of the dipeptides. In addition, the specific interactions between the dipeptides and each amino acid residue of TLN or solvating water molecules were elucidated by the FMO calculations. PMID- 21815173 TI - Glycan Reader: automated sugar identification and simulation preparation for carbohydrates and glycoproteins. AB - Understanding how glycosylation affects protein structure, dynamics, and function is an emerging and challenging problem in biology. As a first step toward glycan modeling in the context of structural glycobiology, we have developed Glycan Reader and integrated it into the CHARMM-GUI, http://www.charmm gui.org/input/glycan. Glycan Reader greatly simplifies the reading of PDB structure files containing glycans through (i) detection of carbohydrate molecules, (ii) automatic annotation of carbohydrates based on their three dimensional structures, (iii) recognition of glycosidic linkages between carbohydrates as well as N-/O-glycosidic linkages to proteins, and (iv) generation of inputs for the biomolecular simulation program CHARMM with the proper glycosidic linkage setup. In addition, Glycan Reader is linked to other functional modules in CHARMM-GUI, allowing users to easily generate carbohydrate or glycoprotein molecular simulation systems in solution or membrane environments and visualize the electrostatic potential on glycoprotein surfaces. These tools are useful for studying the impact of glycosylation on protein structure and dynamics. PMID- 21815175 TI - Elucidation of the methyl transfer mechanism catalyzed by chalcone O methyltransferase: a density functional study. AB - The mechanism of the methyl transfer catalyzed by chalcone O-methyltransferase has been computationally investigated by employing the hybrid functional B3LYP. Two models are constructed based on the two conformations of the substrate isoliquiritigenin in the X-ray structure. Our calculations show that the overall reaction is divided into two elementary steps: the water-assisted deprotonation of the substrate by His278 as a catalytic base, followed by the methyl transfer from S-adenosyl-L-methionine (SAM) to the substrate. The calculated rate-limiting barriers for the methyl-transfer step indicate that the catalytic reactions are energetically feasible for both conformations adopted by the substrate. PMID- 21815176 TI - Proton-coupled electron transfer of the phenoxyl/phenol couple: effect of Hartree Fock exchange on transition structures. AB - Proton-coupled electron transfer (PCET) and hydrogen atom transfer (HAT) reactions of the phenoxyl/phenol couple are studied theoretically by using wave function theory (WFT) as well as DFT methods. At the complete active space self consistent field (CASSCF) level, geometry optimization is found to give two transition states (TSs); one is the PCET type with two benzene rings being nearly coplanar, and the other is the HAT type with two benzene rings taking a stacking structure. Geometry optimization at the (semilocal) DFT level, on the other hand, is found to give only one transition state (i.e., the PCET-type one) and fail to obtain the stacking TS structure. By comparing various levels of theories (including long-range corrected DFT functionals), we demonstrate that the Hartree Fock exchange at long range plays a critical role in obtaining the sufficient stacking stabilization of the present open-shell system, and that the sole addition of empirical dispersion correction to semilocal DFT functionals may not be adequate for describing such a stacking interaction. Next, we investigate the solvent effect on the PCET and HAT TS thus obtained using the reference interaction site model self-consistent field (RISM-SCF) method. The results suggest that the free energy barrier increases with increasing polarity of the solvent, and that the solvent effects are stronger for the PCET TS than the stacking HAT TS pathway. The reason for this is discussed based on the dipole moment of different TS structures in solution. PMID- 21815177 TI - Toward a new approach for determination of solute's charge distribution to analyze interatomic electrostatic interactions in quantum mechanical/molecular mechanical simulations. AB - We present an alternative approach to determine "density-dependent property" derived charges for molecules in the condensed phase. In the case of a solution, it is essential to take into consideration the electron polarization of molecules in the active site of this system. The solute and solvent molecules in this site have to be described by a quantum mechanical technique and the others are allowed to be treated by a molecular mechanical method (QM/MM scheme). For calculations based on this scheme, using the forces and interaction energy as density dependent property our charges from interaction energy and forces (CHIEF) approach can provide the atom-centered charges on the solute atoms. These charges reproduce well the electrostatic potentials around the solvent molecules and present properly the picture of the electron density of the QM subsystem in the solution system. Thus, the CHIEF charges can be considered as the atomic charges under the conditions of the QM/MM simulation, and then enable one to analyze electrostatic interactions between atoms in the QM and MM regions. This approach would give a view of the QM nuclei and electrons different from the conventional methods. PMID- 21815178 TI - Application of the thin-shell formulation to the numerical modeling of Stern layer in biomolecular electrostatics. AB - In this article, the thin-shell formulation is applied to efficiently modeling the Stern layer within computational algorithms oriented toward the boundary element solution of the linearized Poisson-Boltzmann equation. The attention is focused on the calculation of the electrostatic potential in proximity to a biomolecule immersed in an electrolyte medium. Following the proposed approach, the Stern layer is made to collapse to a zero-thickness region (two-dimensional surface) with interface conditions linking the electrostatic potential over the molecular and the bulk ion accessible surfaces. Advantages lie in the limitation of divergent integral problems and in the halving of the unknown number, with a significant impact on computational time and memory requirements when modeling large biomolecules. PMID- 21815179 TI - First-principles prediction on electronic and magnetic properties of hydrogenated AlN nanosheets. AB - Based on first-principles calculations, the geometric, electronic, and magnetic properties as well as the relative stability of the fully hydrogenated and semihydrogenated AlN nanosheets (NSs) have been investigated. The results show that different with the bare graphite-like AlN NSs terminating with polar (0001) surfaces, the hydrogenated configurations preserve the initial wurtzite structure. Depending on surface hydrogenation and the thickness of AlN NSs, three magnetic configurations, that is, semiconductor, half metal, and metal states, are all observed. Analysis of formation energies indicates that, for the configuration n = 1, the hydrogen atoms adsorb on the top of Al sites is the most stable structure, while for the other configurations (n > 2), AlN-nH structure is more favorable energetically. The results indicated that hydrogenation on different Al and N sites might be an efficient route to tune their electronic and magnetic properties to realize potential applications in the fields of electronics and spintronics. PMID- 21815180 TI - Subgroup identification from randomized clinical trial data. AB - We consider the problem of identifying a subgroup of patients who may have an enhanced treatment effect in a randomized clinical trial, and it is desirable that the subgroup be defined by a limited number of covariates. For this problem, the development of a standard, pre-determined strategy may help to avoid the well known dangers of subgroup analysis. We present a method developed to find subgroups of enhanced treatment effect. This method, referred to as 'Virtual Twins', involves predicting response probabilities for treatment and control 'twins' for each subject. The difference in these probabilities is then used as the outcome in a classification or regression tree, which can potentially include any set of the covariates. We define a measure Q(A) to be the difference between the treatment effect in estimated subgroup A and the marginal treatment effect. We present several methods developed to obtain an estimate of Q(A), including estimation of Q(A) using estimated probabilities in the original data, using estimated probabilities in newly simulated data, two cross-validation-based approaches, and a bootstrap-based bias-corrected approach. Results of a simulation study indicate that the Virtual Twins method noticeably outperforms logistic regression with forward selection when a true subgroup of enhanced treatment effect exists. Generally, large sample sizes or strong enhanced treatment effects are needed for subgroup estimation. As an illustration, we apply the proposed methods to data from a randomized clinical trial. PMID- 21815181 TI - Leukocytosis: the mysteries within. PMID- 21815182 TI - Combination decitabine, arsenic trioxide, and ascorbic acid for the treatment of myelodysplastic syndrome and acute myeloid leukemia: a phase I study. PMID- 21815183 TI - Monitoring toxicity, impact, and adherence of hydroxyurea in children with sickle cell disease. PMID- 21815184 TI - When children with sickle-cell disease become adults: lack of outpatient care leads to increased use of the emergency department. PMID- 21815185 TI - Cyclophosphamide and prednisone induction followed by cyclophosphamide mobilization effectively decreases the incidence of engraftment syndrome in patients with POEMS syndrome who undergo stem cell transplantation. AB - High-dose chemotherapy with autologous stem cell transplantation (ASCT) can achieve excellent clinical responses in patients with POEMS syndrome (Jimenez Zepeda et al., Blood 2010;116:2403; Gertz et al., Am J Hematol 2005;79:319-328; Gherardi et al., Ann Neurol 1994;35:501-505; Gattinoni et al., Nat Rev Immunol 2006;6:383-393; Salem et al., J Immunol 2009;182:2030-2040; Salem et al., Cancer Immunol Immunother 2010;59:341-353; Salem et al., Cell Immunol 2010;261:134-143). However, High-dose melphalan with ASCT should be considered carefully due to its treatment-related morbidity (Vuckovic et al., Blood 2003;101:2314-2317), especially in patients with poor performance status owing to polyneuropathy and multiorgan involvement, such as cardiac, respiratory, and renal failure. Significant increases in the concentration of circulating macrophage colony stimulating factor, erythropoietin, IL-6, and TNF-alpha, reach near maximal values at approximately day +12, predating neutrophil engraftment, and clinically manifest with fever, rash and edema (Dispenzieri et al., Eur J Haematol 2008;80:397-406). Depending on the definition used, approximately 50% of patients satisfied criteria for engraftment syndrome (ES) (Vuckovic et al., Blood 2003;101:2314-2317). ES occurs in 27-47% of patients who undergo ASCT; mortality rate is reported from 8% to 18% (Gattinoni et al., Nat Rev Immunol 2006;6:383 393; Vuckovic et al., Blood 2003;101:2314-2317). We have therefore reviewed our experience with ASCT in patients with POEMS syndrome who were treated with cyclophosphamide and prednisone as induction therapy followed by cyclophosphamide mobilization with an emphasis on treatment-related morbidity and frequency of ES. Our study confirms that ASCT is a feasible and efficacious treatment for patients with POEMS syndrome. In addition, the use of CP followed by cyclophosphamide mobilization decreases the incidence of PES leading to less morbidity and mortality rates. PMID- 21815186 TI - Primary pulmonary diffuse large B-cell lymphoma. PMID- 21815187 TI - Reciprocal osteoblastic and osteoclastic modulation in co-cultured MG63 osteosarcoma cells and human osteoclast precursors. AB - Osteosarcoma is usually associated with a disturbed bone metabolism. The aim of this work was to characterize the reciprocal interactions between MG63 osteosarcoma cells and osteoclasts, in a co-culture system. Co-cultures were characterized throughout 21 days for the osteoclastogenic response and the expression of osteoblastic markers. Monocultures of MG63 cells and peripheral blood mononuclear cell (PBMC) and co-cultures of PBMC + human bone marrow cells (hBMC) were also performed. Compared to PBMC cultures, co-cultures yielded significantly increased gene expression of osteoclast-related markers, tartarate acid resistant phosphatase (TRAP) activity, TRAP-positive multinucleated cells, cells with actin rings and vitronectin receptors (VNR) and calcitonin receptors (CTR) and calcium phosphate resorbing ability. Results showed that the development of functional osteoclasts required a very low number of MG63 cells, suggesting a high osteoclastogenic-triggering capacity of this cell line. Subjacent mechanisms involved the pathways MEK and NF-kB, although with a lower relevance than that observed on PBMC monocultures or co-cultures of hBMC + PBMC; PGE2 production also had a contribution. Compared to MG63 cell monocultures, the co-culture expressed lower levels of COL1 and ALP, and higher levels of BMP-2, suggesting that PBMC also modulated the osteoblastic behavior. While M-CSF appeared to be involved in the osteoclastogenic response on the MG63 + PBMC co cultures, RANKL does not seem to be a key player in the process. On the other hand, sphingosine-1-phosphate production might contribute to the modulation of the osteoblastic behavior. Results suggest that the reciprocal modulation between osteosarcoma and osteoclastic cells might contribute to the disturbed bone metabolism associated with bone tumors. PMID- 21815189 TI - p21Cip1/Waf1 protein and its function based on a subcellular localization [corrected]. AB - Protein p21(Cip1/Waf1) is a cyclin-dependent kinase inhibitor, which is important in the response of cells to genotoxic stress and a major transcriptional target of p53 protein. Based on the localization, p21(Cip1/Waf1) protein executes various functions in the cell. In the nucleus p21(Cip1/Waf1) binds to and inhibits the activity of cyclin dependent kinases Cdk1 and Cdk2 and blocks the transition from G1 phase into S phase or from G2 phase into mitosis after DNA damage. This enables the repair of damaged DNA. p21(Cip1/Waf1) was also found as an important protein for the induction of replication senescence as well as stress-induced premature senescence. In the cytoplasm, p21(Cip1/Waf1) protein has an anti-apoptotic effect. It is able to bind to and inhibit caspase 3, as well as the apoptotic kinases ASK1 and JNK. The function of p21(Cip1/Waf1) in response to a DNA damage probably depends on the extent of the damage. In the case of low level DNA damage, the expression of p21(Cip1/Waf1) is increased, it induces cell cycle arrest, and performs also anti-apoptotic activities. However, after extensive DNA damage the amount of p21(Cip1/Waf1) protein is decreased and the cell undergoes apoptosis. Dual function of p21(Cip1/Waf1) was also observed in cancerogenesis. On the one hand, p21(Cip1/Waf1) acts as a tumor suppressor; on the other hand it prevents apoptosis and acts as an oncogene. Better understanding of the role of p21(Cip1/Waf1) in various conditions would help to develop better cancer-treatment strategies. PMID- 21815188 TI - Erythrocyte pyruvate kinase deficiency in an old-order Amish cohort: longitudinal risk and disease management. AB - Pyruvate kinase deficiency is a chronic illness with age specific consequences. Newborns suffer life-threatening hemolytic crisis and hyperbilirubinemia. Adults are at risk for infections because of asplenia, pregnancy-related morbidity, and may suffer organ damage because of systemic iron overload. We describe 27 Old Order Amish patients (ages 8 months-52 years) homozygous for c.1436G>A mutations in PKLR. Each subject had a predictable neonatal course requiring packed red blood cell transfusions (30 +/- 5 mL/kg) to control hemolytic disease and intensive phototherapy to prevent kernicterus. Hemochromatosis affected 29% (n = 4) of adult patients, who had inappropriately normal serum hepcidin (34.5 +/- 12.7 ng/mL) and GDF-15 (595 +/- 335pg/mL) relative to hyperferritinemia (769 +/- 595 mg/dL). A high prevalence of HFE gene mutations exists in this population and may contribute to iron-related morbidity. Based on our observations, we present a strategy for long-term management of pyruvate kinase deficiency. PMID- 21815190 TI - Sex-specific effects of estrogen and androgen on gene expression in human monocyte-derived osteoclasts. AB - Estrogen and androgen are both critical for the maintenance of bone, but the target cells, mechanisms, and responses could be sex-specific. To compare sex specific actions of estrogen and androgen on osteoclasts, human peripheral blood mononuclear precursor cells from adult Caucasian males (n = 3) and females (n = 3) were differentiated into osteoclasts and then treated for 24 h with 17beta estradiol (10 nM) or testosterone (10 nM). Gene expression was studied with a custom designed qPCR-based array containing 94 target genes related to bone and hormone action. In untreated osteoclasts, 4 genes showed significant gender differences. 17beta-estradiol significantly affected 12 genes in osteoclasts from females and 6 genes in osteoclasts from males. Fifteen of the 18 17beta-estradiol responsive genes were different in the cells from the two sexes; 2 genes affected by 17beta-estradiol in both sexes were regulated oppositely in the two sexes. Testosterone significantly affected 6 genes in osteoclasts from females and 2 genes in osteoclasts from males; all except one were different in the two sexes. 17beta-estradiol and testosterone largely affected different genes, suggesting that conversion of testosterone to 17beta-estradiol had a limited role in the responses. The findings indicate that although osteoclasts from both sexes respond to 17beta-estradiol and testosterone, the effects of both 17beta estradiol and testosterone differ in the two sexes, highlighting the importance of considering gender in the design of therapy. PMID- 21815191 TI - ADAMTS-4 and ADAMTS-5: key enzymes in osteoarthritis. AB - Osteoarthritis (OA) is a progressive disease of the joints characterized by degradation of articular cartilage. Although disease initiation may be multi factorial, the cartilage destruction appears to be a result of uncontrolled proteolytic extracellular matrix destruction. A major component of the cartilage extracellular matrix is aggrecan, a proteoglycan that imparts compressive resistance to the tissue. Aggrecanase-mediated aggrecan degradation is a significant event in early stage OA. The relative contribution of individual ADAMTS-4 and ADAMTS-5 proteinases to cartilage destruction during OA has not been resolved completely. This review reveals that both ADAMTS-4/ADAMTS-5 are responsible for aggrecan degradation in a human model of OA, and is expected to list down the rational strategies which are being focussed for therapeutic intervention in OA. PMID- 21815192 TI - H2 O2 stimulates Cl- /HCO 3- exchanger activity through oxidation of thiol groups in immortalized SHR renal proximal tubular epithelial cells. AB - Cl(-) /HCO (3)(-) exchanger and Na(+) /H(+) exchanger 3 are the main transporters responsible for NaCl reabsorption in kidney proximal tubules (PT). It is well accepted that membrane exchangers can be regulated by reactive oxygen species (ROS). In the kidney, ROS are known to contribute to decreases in Na(+) excretion and consequently increase blood pressure. The present study investigated mechanisms by which H(2) O(2) -induced stimulation of Cl(-) /HCO (3)(-) exchanger activity is enhanced in proximal tubular epithelial (PTE) cells immortalized from spontaneously hypertensive rats (SHR) as compared to normotensive Wistar Kyoto (WKY). H(2) O(2) decreased K(m) values for Cl(-) /HCO (3)(-) exchanger activity in SHR PTE cells, but had no effect on the kinetic parameters in WKY cells. DTDP stimulated in a concentration-dependent manner Cl(-) /HCO (3)(-) exchanger activity in both cell lines, but SHR PTE cells were 2.4-fold more responsive to this oxidant. In contrast, thimerosal had no effect on exchanger activity in both cell lines. The effects of H(2) O(2) and DTDP upon the exchanger activity were blocked by DTT in WKY and SHR PTE cells. Similar to H(2) O(2), DTDP decreased K(m) values for Cl(-) /HCO (3)(-) exchanger activity in SHR PTE cells. Basal content of free thiol groups was higher in WKY PTE cells than in SHR. Upon H(2) O(2) treatment the free thiol groups decreased in both cell lines; however, this decrease was more pronounced in WKY cells. In conclusion, in SHR PTE cells H(2) O(2) stimulates Cl(-) /HCO (3)(-) exchanger activity via modification of thiol groups of intracellular and/or transmembrane protein. Furthermore, the thiol oxidation-dependent pathway also increases the HCO (3)(-) affinity in SHR PTE cells. PMID- 21815193 TI - Discoidin domain receptor 1 expression in activated T cells is regulated by the ERK MAP kinase signaling pathway. AB - The expression and function of discoidin domain receptor 1 (DDR1) in T cells are still poorly explored. We have recently shown that activation of primary human T cells via their T cell receptor leads to increased expression of DDR1, which promoted their migration in three-dimensional collagen. In the present study, we provide evidence that activated T cells bind collagen through DDR1. We found that the DDR1:Fc blocking molecule significantly reduced the ability of activated T cells to bind soluble biotinylated collagen. However, DDR1:Fc had no impact on the adhesion of activated T cells to collagen and overexpression of DDR1 in Jurkat T cells did not enhance their adhesion. Together, our results indicate that DDR1 can promote T cell migration without enhancing adhesion to collagen, suggesting that it can contribute to the previously described amoeboid movement of activated T cells in collagen matrices. Our results also show that CD28, in contrast to IL-2 expression, did not costimulate the expression of DDR1 in primary human T cells. Using specific inhibitors, we demonstrated that TCR induced expression of DDR1 in T cells is regulated by the Ras/Raf/ERK MAP Kinase and PKC pathways but not by calcium/calcineurin signaling pathway or the JNK and P38 MAP Kinases. Thus, our study provides additional insights into the physiology of DDR1 in T cells and may therefore further our understanding of the regulatory mechanisms of T cell migration. PMID- 21815194 TI - The activation state of the inositol 1,4,5-trisphosphate receptor regulates the velocity of intracellular Ca2+ waves in bovine aortic endothelial cells. AB - Ca(2+) is a highly versatile second messenger that plays a key role in the regulation of many cell processes. This versatility resides in the fact that different signals can be encoded spatio-temporally by varying the frequency and amplitude of the Ca(2+) response. A typical example of an organized Ca(2+) signal is a Ca(2+) wave initiated in a given area of a cell that propagates throughout the entire cell or within a specific subcellular region. In non-excitable cells, the inositol 1,4,5-trisphosphate receptor (IP(3) R) is responsible for the release of Ca(2+) from the endoplasmic reticulum. IP(3) R activity can be directly modulated in many ways, including by interacting molecules, proteins, and kinases such as PKA, PKC, and mTOR. In the present study, we used a videomicroscopic approach to measure the velocity of Ca(2+) waves in bovine aortic endothelial cells under various conditions that affect IP(3) R function. The velocity of the Ca(2+) waves increased with the intensity of the stimulus while extracellular Ca(2+) had no significant impact on wave velocity. Forskolin increased the velocity of IP(3) R-dependent Ca(2+) waves whereas PMA and rapamycin decreased the velocity. We used scatter plots and Pearson's correlation test to visualize and quantify the relationship between the Ca(2+) peak amplitude and the velocity of Ca(2+) waves. The velocity of IP(3) R-dependent Ca(2+) waves poorly correlated with the amplitude of the Ca(2+) response elicited by agonists in all the conditions evaluated, indicating that the velocity depended on the activation state of IP(3) R, which can be modulated in many ways. PMID- 21815196 TI - Reactive oxygen species-mediated endoplasmic reticulum stress and mitochondrial dysfunction contribute to polydatin-induced apoptosis in human nasopharyngeal carcinoma CNE cells. AB - Previous studies revealed that polydatin, a natural small compound, possessed protective effect against ischemia/reperfusion injury and inflammation. However, the action and molecular mechanism of its potent anti-cancer activity remain poorly understood. In the present study, polydatin significantly killed several human tumor cell lines in a dose- and time-dependent manner. The compound also dose-dependently caused mitochondrial apoptosis in human nasopharyngeal carcinoma CNE cells. In addition, polydatin triggered endoplasmic reticulum (ER) stress and down-regulated the phosphorylation of Akt in CNE cells, while knock-down of CCAAT/enhancer-binding protein homologous protein (CHOP) dramatically abrogated the inactivation of Akt and reversed the pro-apoptotic effect of polydatin. Furthermore, polydatin provoked the generation of reactive oxygen species in CNE cells, while the antioxidant N-acetyl cysteine almost completely blocked the activation of ER stress and apoptosis, suggesting polydatin-induced reactive oxygen species is an early event that triggers ER stress mitochondrial apoptotic pathways in CNE cells. Taken together, these findings strongly suggest that polydatin might be a promising anti-tumor drug and our data provide the molecular theoretical basis for clinical application of polydatin. PMID- 21815195 TI - Lipolytic signaling in response to acute exercise is altered in female mice following ovariectomy. AB - Impaired ovarian function alters lipid metabolism, ultimately resulting in increased visceral fat mass. Currently, we have a poor understanding of alterations in signaling events regulating lipolysis after ovarian function declines. The purpose of this study was to determine if cellular mechanisms regulating lipolysis are altered in mice after ovariectomy (OVX) and if OVX mice exhibit impaired lipolytic signaling when stimulated by acute exercise. SHAM and OVX mice were divided into two groups: control (SHAM cont; OVX cont) or acute treadmill exercise (SHAM ex; OVX ex). The omental/mesenteric (O/M) fat mass of all OVX mice was significantly greater than the SHAM mice. Serum glycerol and blood glucose levels were significantly elevated in OVX cont compared to SHAM cont. Treadmill exercise increased serum glycerol levels only in SHAM mice, with no exercise-induced change detected in OVX mice. NEFA levels were significantly elevated by acute exercise in the SHAM and OVX groups. In O/M fat from both OVX groups there were significant increases in cytosolic ATGL and PLIN2 in the fat cake fraction with concurrent reductions in PLIN1 in the fat cake compared to SHAM. Further, exercise induced significant increases in HSL Ser660 phosphorylation in SHAM mice, but not OVX mice. This suggests that reduced ovarian function has significant effects on critical lipolytic cell signaling mechanisms in O/M adipose tissue. PMID- 21815197 TI - The neuropeptide VIP regulates the expression of osteoclastogenic factors in osteoblasts. AB - Osteoclast formation is controlled by stromal cells/osteoblasts expressing macrophage colony-stimulating factor (M-CSF) and receptor activator of NF-kappaB ligand (RANKL), crucial for osteoclast progenitor cell proliferation, survival and differentiation, and osteoprotegerin (OPG) that inhibits the interaction between RANKL and its receptor RANK. Recent data have strongly indicated that the nervous system plays an important role in bone biology. In the present study, the effects of the neuropeptide vasoactive intestinal peptide (VIP), present in peptidergic skeletal nerve fibers, on the expression of RANKL, OPG, and M-CSF in osteoblasts and stromal cells have been investigated. VIP and pituitary adenylate cyclase-activating polypeptide 38 (PACAP-38), but not secretin, stimulated rankl mRNA expression in mouse calvarial osteoblasts. In contrast, VIP inhibited the mRNA expressions of opg and m-csf, effects shared by PACAP-38, but not by secretin. VIP did not affect rankl, opg, or m-csf mRNA expression in mouse bone marrow stromal cells (BMSCs). The effects by VIP on the mRNA expression of rankl, opg, and m-csf were all potentiated by the cyclic AMP phosphodiesterase inhibitor rolipram. In addition, VIP robustly enhanced the phosphorylation of ERK and the stimulatory effect by VIP on rankl mRNA was inhibited by the MEK1/2 inhibitor PD98059. These observations demonstrate that activation of VPAC(2) receptors in osteoblasts enhances the RANKL/OPG ratio by mechanisms mediated by cyclic AMP and ERK pathways suggesting an important role for VIP in bone remodeling. PMID- 21815198 TI - Signal transducer and activator of transcription 1 (Stat1) maintains basal mRNA expression of pro-survival stat3-target genes in glioma C6 cells. AB - The STAT proteins (signal transducers and activators of transcription) are transcription factors mediating cytokine/growth factor signaling, which play important role in controlling cell cycle progression and apoptosis. In many cancer cell lines and tumors (including gliomas) the STAT proteins (in particular Stats 1, 3, and 5) are persistently activated. In this study, we employed DNA decoys, siRNAs, and protein overexpression, to elucidate the role of Stat1 and Stat3 in regulation of expression of endogenous Stat3-target genes (Bcl2l1, Myc, Ccnd1) and a Stat-driven reporter plasmid, in rat C6 glioma cells. The results obtained with the decoys and siRNA suggest that in proliferating C6 cells, Stat1 supports the basal expression of Bcl2l1, while the decoy and chromatin immunoprecipitation results suggest it also plays a similar role for Myc. In the Stat-driven reporter system, overexpression of Stat1 stimulated, while overexpression of Stat3 inhibited the reporter gene expression. The level of Stat1 phosphorylation observed under basal conditions in proliferating glioma C6 cells is very low. Therefore, we speculate that it is the activity of the unphosphorylated Stat1 that is inhibited by Stat1 decoy or Stat1 siRNA. Taken together, our results demonstrate that it is Stat1 not Stat3 that maintains the expression of Bcl2l1 and possibly Myc in proliferating glioma C6 cells. An established paradigm is that Stat3 exerts a pro-survival and potentially oncogenic effects, while Stat1 is mainly associated with the immune response. Our results add to a number of reports that challenge this paradigm. PMID- 21815199 TI - Molecular mediators involved in Ferulago campestris essential oil effects on osteoblast metabolism. AB - This study was performed to investigate the effects of the essential oil obtained from fruits of Ferulago campestris (FC) on primary calvarial mouse osteoblasts (COBs). The composition of the oil was dominated by monoterpene hydrocarbons (78.8-80.3%), with myrcene (33.4-39.7%), alpha-pinene (22.7-23.0%), and gamma terpinene (8.1-10.9%) as the major components. Owing to their lipophilic properties, these compounds easily cross cell membranes and affect bone cell function by stimulating or inhibiting specific molecular pathways. We demonstrated, for the first time, that FC oil increased osteoblast proliferation by MAP kinase activation; in addition, oils enhanced the protein kinase AKT, which is known to be critical for control of cell survival, also in presence of the MEK-1 inhibitor PD98059, and this effect was accompanied with a down regulation of pro-apototic molecules such as Bax and caspases. Interestingly, FC oil significantly increased Runx2 (Runx2/Pebp2alphaA/AML3) and phospho-Smad1/5/8 protein level, the master regulators of osteoblast differentiation, and their nuclear localization. PD98059 pre-treatment further improved Runx2/phospho-Smads up-regulation. Thus, FC oils influence osteoblast metabolism probably using alternative signaling pathways depending also on the maturation stage of the cells. Taken together our data delineate a positive function of FC oil on osteoblast metabolism, suggesting its possible use as a dietetic integrator in the prevention or in the therapy of pathologies due to impaired bone remodeling. PMID- 21815200 TI - Relational Aggression in Women during Emerging Adulthood: A Social Process Model. AB - Two studies investigated potential mediators of the association between relational victimization and relational aggression. Self-report measures of aggressive behavior among peers, exclusivity, hostile attribution biases, and borderline personality disorder (BPD) symptoms were collected. In study 1, participants were 180 female emerging adults (M = 18.82, SD = 1.18). Both exclusivity and hostile attribution biases for relational provocations were found to partially mediate the association between relational victimization and relational aggression. In study 2, participants were 54 female emerging adults (M = 19.16, SD = 1.11). Symptoms of BPD were not found to mediate the association between relational victimization and relational aggression, yet unique associations with relational aggression were observed. The results add to recent research guided by a social process model in which links between victimization and aggression are more clearly understood. PMID- 21815201 TI - Clinical syndromes, personality disorders, and neurocognitive differences in male and female inmates. AB - This study examined clinical syndromes, personality disorders, and neurocognitive problems in adult male (n = 523) and female inmates (n = 523) and a sample of unincarcerated adult women (n = 523). Inmates were administered the Coolidge Correctional Inventory (CCI), and the unincarcerated sample was given an identical test, the Coolidge Axis II Inventory. Although there were significant differences between the two inmate groups on a majority of the 32 CCI scales, only two scales achieved a medium effect size. The two inmate groups were found to be highly similar in a comparison of ranked personality disorder prevalence rates. Consistent with previous literature, male inmates had a significantly higher prevalence of antisocial personality disorder than female inmates (24% vs. 18%). Female inmates had double the prevalence of male inmates on the borderline and histrionic personality disorder scales. Female inmates also reported significantly more general neuropsychological dysfunction, specifically memory problems and neurosomatic symptoms, than male inmates. Female inmates also reported significantly higher levels of anxiety, depression, symptoms of schizophrenia, post-traumatic stress disorder, attention deficit hyperactivity disorder, and depersonalization than male inmates. Overall, the findings support previous research of high levels of psychological and neuropsychological problems in inmates, regardless of gender, and reinforces the need for comprehensive mental health screening of offender populations. PMID- 21815202 TI - High psychopathic trait females exhibit reduced startle potentiation and increased p3 amplitude. AB - While there has been steady progress in identifying psychophysiological traits associated with psychopathy, most of the existing research has been carried out using incarcerated male participants, and data that include females are particularly rare. This study examined both affective startle blink modulation and P3 amplitude in a sample of female undergraduates grouped by scores on the Psychopathic Personality Inventory-Revised (PPI-R). Those scoring high for psychopathic traits lacked startle blink potentiation and demonstrated larger P3 amplitudes during auditory and visual oddball tasks. These data support the generalizability of deficient startle potentiation to non-incarcerated females with psychopathic traits, and add to a growing body of literature suggesting that psychopathic traits are associated with distinctive information-processing characteristics as indexed by P3 amplitude. PMID- 21815203 TI - Effects of treadmill running on rat gastrocnemius function following botulinum toxin A injection. AB - Exercise can improve and maintain neural or muscular function, but the effects of exercise in physiological adaptation to paralysis caused by botulinum toxin A has not been well studied. Twenty-four rats were randomly assigned into control and treadmill groups. The rats assigned to the treadmill group were trained on a treadmill three times per week with the running speed set at 15 m/min. The duration of training was 20 min/session. Muscle strength, nerve conduction study and sciatic functional index (SFI) were used for functional analysis. Treadmill training improved the SFI at 2, 3, and 4 weeks (p = 0.01, 0.004, and 0.01, respectively). The maximal contraction force of the gastrocnemius muscle in the treadmill group was greater than in the control group (p < 0.05). The percentage of activated fibers was higher in the treadmill botox group than the percentage for the control botox group, which was demonstrated by differences in amplitude and area of compound muscle action potential (CMAP) under the curve between the groups (p < 0.05). After BoNT-A injection, treadmill improved the physiological properties of muscle contraction strength, CMAP amplitude, and the recovery of SFI. PMID- 21815204 TI - Implant stability in the treatment of MRSA bone implant infections with linezolid versus vancomycin in a rabbit model. AB - The increasing prevalence of methicillin-resistant Staphylococcus aureus (MRSA) infections represents a significant healthcare burden. Vancomycin and linezolid exhibit potent clinical and microbiological activity in MRSA infections. Our purpose was to investigate the efficacy of linezolid versus vancomycin in experimental implant infections and the influence on implant stability in a rabbit model. Thirty-six female New Zealand White rabbits received surgical insertion of titanium implants into their distal femurs and were randomly assigned to six groups (A: infected, no treatment; B: infected, vancomycin; C: infected, linezolid; D: no infection, no treatment; E/F: no infection, vancomycin or linezolid, respectively). Antibiotics were administered, and plasma levels determined. Bone-implant specimens were tested for mechanical stability of fixation. Quantitative histomorphometry of bone and soft tissue was performed using computerized image analysis. Plasma levels of linezolid and vancomycin were within the respective therapeutic ranges. Microbiological analysis of specimens from infected rabbits showed MRSA tissue colonization in all untreated animals, in two of six vancomycin-treated animals, and in none of the linezolid-treated animals. Antibiotic treatment improved mechanical stability significantly (p = 0.004) with both vancomycin and linezolid. Mechanical testing correlated with histomorphometry results. A significant negative correlation was found between displacement of the implant and the percentage of calcified tissue around the implant, and a significant positive correlation was found between displacement of the implant and the amount of noncalcified tissue. Our data indicate that both treatment regimens improved implant stability. PMID- 21815206 TI - Hyperbaric oxygen therapy in a mouse model of implant-associated osteomyelitis. AB - Implant associated osteomyelitis (OM) is difficult to treat with antibiotics, and outcomes remain poor. Some reports suggest that hyperbaric oxygen treatment is a safe and effective means of treating OM. We tested this hypothesis in a murine model. Clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa, and Klebsiella pneumoniae were used. The mice were infected with each of the three pathogens, treated with 100% oxygen at high pressure, hyperbaric oxygen (HBO), and monitored for the ability of HBO to prevent and/or clear the OM infection. Assessments included bacterial burden of the tibias and lesion scores, as well as receptor activator of NF-kappaB ligand (RANKL) and myeloperoxidase (MPO) concentrations. HBO resulted in more severe lesion scores and higher RANKL and MPO concentrations for MRSA. A significant positive correlation was found between RANKL concentration and lesion score. No significant difference was found with HBO in P. aeruginosa infections and K. pneumoniae seems to either not infect bone well or get cleared before establishing an infection. The model is useful for studying OM infections caused by MRSA and P. aeruginosa, but HBO does not appear to be an efficacious treatment of an implant-associated OM infection. PMID- 21815205 TI - Additive effects of exogenous IL-12 supplementation and antibiotic treatment in infection prophylaxis. AB - The increasing clinical incidence and host risk of open fracture-associated infections, as well as the reduced effectiveness of conventional antibiotics to treat such infections, have driven the development of new therapies for the prophylaxis of open fracture-associated infections. We investigated percutaneous supplementation of a natural cytokine (i.e., interleukin 12p70 or IL-12) at an open fracture site to reduce open fracture-associated infections. We also determined the efficacy of the combination therapy of IL-12 and conventional antibiotic therapy in the prophylaxis of open fracture-associated infections. An open femur fracture infection model was produced by direct inoculation of a clinical isolate of Staphylococcus aureus after creating a femur fracture using rats. The animals were assigned to one of four groups: no drug administration, percutaneous supplementation of IL-12, intraperitoneal administration of the antibiotic ampicillin, or percutaneous IL-12 in combination with intraperitoneal ampicillin. Animals were euthanized at postoperative days 6, 10, 14, and 21. Percutaneous IL-12 led to a reduction in infection at postoperative days 6 and 10. For the first time, exogenous IL-12 was found to have additive effects in the prevention of infection when combined with conventional treatment (i.e., antibiotic therapy). Combination therapy of ampicillin and IL-12 substantially reduced the infection rate at postoperative day 6 and also decreased the time needed for complete inhibition of infection. Therefore, exogenous IL-12, providing a mechanism of protection independent of antibiotic resistance, complements the routine use of antibiotics. PMID- 21815208 TI - NMR spectra and structures of oridonin derivatives complexes with beta cyclodextrin. AB - Complexations between three oridonin derivatives and beta-cyclodextrin (betaCD) were studied by nuclear magnetic resonance (NMR) method. Job's plots for complexes were depicted by (1)H NMR spectra chemical shifts, which proved the 1:1 stoichiometry inclusion complex formation between each derivative and betaCD. Two dimensional rotating frame overhauser effect spectroscopy (2D ROESY) support the above conclusion and also proved that ring A of each oridonin derivative deeply enters into hydrophobic cavity from the wider rim and the other parts are outside the cavity. Apparent formation constants (Ka) of complexes between three oridonin derivatives and two CDs are calculated according to Scott's equation. PMID- 21815209 TI - Assignment of phycocyanobilin in HMPT using triple resonance experiments. AB - A complete assignment of all resonances of a small organic molecule is a prerequisite for a structure determination using NMR spectroscopy. This is conventionally obtained using a well-established strategy based on COSY, HMQC and HMBC spectra. In case of phycocyanobilin (PCB) in HMPT this strategy was unsuccessful due to the symmetry of the molecule and extreme signal overlap. Since (13)C and (15)N labeled material was available, an alternative strategy for resonance assignment was used. Triple resonance experiments derived from experiments conventionally performed for proteins are sensitive and easy to analyze. Their application led to a complete and unambiguous assignment using three types of experiments. PMID- 21815210 TI - DFT calculation of structures and NMR chemical shifts of simple models of small diameter zigzag single wall carbon nanotubes (SWCNTs). AB - Linearly conjugated benzene rings (acenes), belt-shape molecules (cyclic acenes) and model single wall carbon nanotubes (SWCNTs) were fully optimized at the unrestricted level of density functional theory (UB3LYP/6-31G*). The models of SWCNTs were selected to get some insight into the potential changes of NMR chemical shift upon systematic increase of the molecular size. The theoretical NMR chemical shifts were calculated at the B3LYP/pcS-2 level of theory using benzene as reference. In addition, the change of radial breathing mode (RBM), empirically correlated with SWCNT diameter, was directly related with the radius of cyclic acenes. Both geometrical and NMR parameters were extrapolated to infinity upon increase in the studied systems size using a simple two-parameter mathematical formula. Very good agreement between calculated and available experimental CC bond lengths of acenes was observed (RMS of 0.0173 A). The saturation of changes in CC bond lengths and (1)H and (13)C NMR parameters for linear and cyclic acenes, starting from 7-8 conjugated benzene rings, was observed. The (13)C NMR parameters of individual carbon atoms from the middle of ultra-thin (4,0) SWCNT formed from 10 conjugated cyclic acenes differ by about 130 ppm from the corresponding open end carbon nuclei. PMID- 21815211 TI - Selective observation of Asp and Glu resonances in (13)CO detected experiments. AB - We present a filter element to observe exclusively the resonances of Asp and Glu residues in several (13)C detected experiments, CACO, CBCACO, and CCCO. As in these experiments the carboxylate resonances appear in the directly detected dimension, it is possible to measure their chemical shifts with a high precision. Therefore, the experiments can be of great utility in the accurate determination of the pKa 's of these residues. Furthermore, the experiments can be applied in the study of deuterated proteins, where the usual experiments for pKa determination cannot be used. Finally, the good resolution with which the carboxylate spectrum is obtained allows observing the coupling between the carboxyl carbon and the backbone CO in Asp residues, what provides information on their side chain conformation. PMID- 21815212 TI - Electron beam radiation effects on UHMWPE: an EPR study. AB - Electron paramagnetic resonance (EPR) technique has been employed to detect and characterise a series of different radical species generated in ultra-high molecular weight polyethylene (UHMWPE) via electron beam irradiation. Three different radical species have been found and assigned on the basis of their EPR spectra and of the related computer simulations. A secondary alkyl species, the prevalent one, is present immediately after irradiation, an allyl species appears only 24 h after irradiation when the alkyl species disappears.The third species, clearly visible at high microwave power only, has been observed for the first time and assigned to a tertiary alkyl carbon radical, whose formation is strictly connected with a Y-shape crosslink and a migration of the unpaired electron on a carbon atom localised in an adjacent position. PMID- 21815213 TI - Application of diffusion-edited NMR spectroscopy for selective suppression of water signal in the determination of monomer composition in alginates. AB - Alginate is a linear copolymer of 1-4 linked beta-D-mannuronic acid (M) and 1-4 linked alpha-L-guluronic acid (G). The physical properties of these polysaccharides such as gel properties and viscosity are largely correlated to the monomer composition (M/G ratio), the sequence of the polymer and the molecular weight. Determination of the M/G ratio is therefore important and NMR spectroscopy is among the most common methods used to accurately obtain this ratio. Instead of using time consuming, possibly sample altering, acid hydrolysis to reduce the viscosity of the alginate sample prior to analysis, samples of low concentrations can be used. However, this results in a water peak in the NMR spectrum that is several orders of magnitude larger than the alginate signals and water suppression is required. In this article, a diffusion-edited NMR experiment that suppresses the water peak while retaining the signals of interest has been used to enable correct M/G ratio determination. This approach exploits the difference in translational diffusion between the larger alginate molecules and the smaller water molecules. Using this method, the monomer composition of 20 different alginate powders was determined. The diffusion parameters were optimized to allow measurement for samples covering a large range of M/G ratios and viscosities. Thus, such method should be useful for analyzing large numbers of unknown alginate samples using, for example, automation procedures. PMID- 21815214 TI - (13)C shielding scale for MAS NMR spectroscopy. AB - We have performed the direct measurements of (13)C magnetic shielding for pure liquid TMS, solution of 1% TMS in CDCl3 and solid fullerene. The measurements were carried out in spherical ampoules exploring the relation between the resonance frequencies, shielding constants and magnetic moments of (13)C and (3)He nuclei. Next the (13)C shielding constants of glycine, hexamethylbenzene and adamantane were established on the basis of appropriate chemical shifts measured in the solid state. All the new results are free from susceptibility effects and can be recommended as the reference standards of (13)C shielding scale in the magic angle spinning NMR experiments. PMID- 21815215 TI - Combinatorial patterns of histone modifications in Saccharomyces cerevisiae. AB - Histone modification is an important subject of epigenetics that plays an intrinsic role in transcriptional regulation. It has been suggested that multiple histone modifications act in a combinatorial fashion to form a 'histone code'. In this study, the combinatorial patterns of histone modifications were studied by using a Bayesian network at the level of individual nucleosomes in S. cerevisiae. Our results indicated that there were 23 combinatorial patterns for 12 histone modifications investigated when a general Bayesian network was constructed. Meanwhile, different networks were also constructed for the genes with high transcript levels (H-network) and low transcript levels (L-network), respectively. Comparison among the general network, H-network and L-network illustrated four conserved combinations: H2BK16Ac -> H3K4me3; H3K14Ac -> H3K4me3; H2AK7Ac -> H3K14Ac; and H4K12Ac -> H3K18Ac. The detailed analysis for some combinations demonstrated that the combinations were ascribed to some histone modifying enzymes. PMID- 21815216 TI - The course of mental health disorders after a disaster: predictors and comorbidity. AB - Current longitudinal disaster studies usually focus only on posttraumatic stress disorder (PTSD), although some studies have shown that increased risks for other disorders and comorbidity is common. To obtain an insight into the course of postdisaster psychopathology, a community sample of survivors of the Enschede fireworks disaster was followed from 2-3 weeks to 4-years postdisaster. Diagnostic interviews (Composite International Diagnostic Interview [CIDI]; World Health Organization, 1997) and childhood stressor interviews were administered at 2-years postdisaster (n = 260); the CIDI was repeated at 4-years postdisaster (n = 201, response rate 77.3%). At 2-years postdisaster many survivors (40.6%) suffered from PTSD (21.8%), specific phobia (21.5%), and/or depression (16.1%). These disorders were highly comorbid. At 4-years postdisaster, prevalence significantly diminished. Instead of full recovery, diagnostic classifications shifted in several survivors over time. This resulted in low rates of PTSD but still elevated rates of depression and specific phobia. The course of the 3 entangled disorders of PTSD, depression, and specific phobia was further studied by constructing 4 groups of survivors based on the diagnostic status at 2- and 4 years postdisaster: healthy, recovered, chronic, and delayed-onset. Initial depressive symptoms, maternal dysfunction, childhood physical abuse, and disaster exposure were found to discriminate between the groups and predict long-term psychopathology. PMID- 21815217 TI - Dark age of sourcing cadavers in developing countries: a Nigerian survey. AB - Throughout the history of medical science, the sourcing, storage, and management of cadavers for the study of gross anatomy have been problematic issues. As presented in this report, a study of these issues was conducted in the departments of anatomy of medical schools in Nigeria. To establish the extent and depth of the prevailing difficulties in the sourcing of cadavers, 18 (62.1%) of the Departments of Anatomy that qualified for this study were used. In sum, 94.4% of these schools reported an inadequate number of cadavers for study. The estimated ages of the cadavers were between 20 and 40 years and 85% of the schools reported more than 75% of the cadavers to be from the lower socioeconomic class. Altogether, 94.4% of the schools reported a male dominance of more than 95%. More than 72% of the schools reported that more than 90% of the cadavers were criminals that had been killed by shooting, less than 10% were unclaimed and unidentified corpses, and 0% originated from body bequest. No form of screening exercises for diseases and infective microorganisms was noted for all the schools, and there were no set standards for the acceptance or rejection of cadavers. Causative factors for the profile of available cadavers such as culture and religion were noted. This study was designed to look at various issues associated with the sourcing of cadavers for Anatomy education in typical developing African countries like Nigeria. As outlined in this report, the creation of legislation and the promotion and funding of programs highlighting the importance of body donation are crucial for improving the field of medical education. PMID- 21815218 TI - Significance of interfacet distance, facet joint orientation, and lumbar lordosis in spondylolysis. AB - The aim of this study is to reveal the association between lumbar spondylolysis and several radiologic parameters, which had been suggested to be significant. The authors examine interfacet distance (IFD), facet joint orientation (FJO), and lumbar segmental lordosis (LSL) all together on the basis of lumbar computed tomography (CT) scan of 35 patients with L5 spondylolysis and 36 unaffected control groups. Thirty-five Korean military recruits, aged 19-23 (mean 20.9 years), were diagnosed as L5 spondylolysis by lumber CT scans. As a control group, 36 male Korean military recruits, aged 18-25 (mean 21.3 years), were reconfirmed as not affected by lumbar spondylolysis by CT scan when they visited our hospital complaining of back pain. This study compares IFD, FJO, and LSL for each lumbar segment between the spondylolytic and unaffected groups. We also propose the use of normal mean data of IFD, FJO, and LSL of lumbar vertebrae from 36 Korean young military recruits because each measurement has power as an absolute value, like data from an osteologic collection in other studies. Comparison of IFD between spondylolytic and unaffected individuals reveals significant differences at the L3, L4, and L5 level (P = 0.0384, P = 0.0219, and P < 0.0001, respectively). In the group of spondylolysis, the increase of IFD from L4 to S1 was less pronounced (P < 0.0001) and the LSL at L5-S1 was more lordotic (P = 0.0203). Interfacet distance and lumbar lordosis were significantly different between patients with L5 spondylolysis and individuals without pars defect on L5. In the spondylolysis group, and the increase of IFD from L4 to S1 was less pronounced and the LSL at L5-S1 was more lordotic. PMID- 21815219 TI - The development of quantitative methods using virtual models for the measurement of tooth wear. AB - Tooth wear is an unavoidable process associated with aging. Currently, virtual three-dimensional dental models are widely used and provide an advantage for studying tooth wear. However, there are no wear assessment parameters using virtual tooth models for the quantitative analysis of wear. Therefore, the aim of this study is to develop and evaluate quantitative wear measurement parameters. Ninety maxillary and mandibular dental casts were prepared and rendered as virtual three-dimensional models. For qualitative wear scoring, Hooper's new tooth wear index (NTWI) was used. For quantitative wear measurement, virtual vectors and occlusal planes were generated with reference points. Angles, height, and distance parameters were measured from reference points, vectors or planes. Intra- and interobserver reproducibility was determined for NTWI scoring and quantitative measurements. Quantitatively measurements for all parameters were subgrouped according to age groups and NTWI score groups. The mean and standard deviation were calculated for each group. One-way analysis of variance (ANOVA) test and the coefficients test were performed on the groups. Overall, intra- and interobserver reproducibility was good for both qualitative and quantitative measurement. In the ANOVA test, angle and height parameters showed significant differences between groups, whereas distance parameters did not. Similar results were observed in the coefficients test. However, plane heights and lingual side measurement parameters of the mandible are not recommended. In conclusion, this study indicates that all angle or height parameters of the maxilla and angle or vector height parameters of the buccal side of the mandible can be used as meaningful parameters in a quantitative wear study. PMID- 21815220 TI - Orientation to dissection: Assisting students through the transition. AB - Human dissection continues to be strongly argued for teaching human anatomy to medical students and is technically and emotionally demanding. An orientation to dissection and the laboratory are provided for students before beginning their work because students' and families' reactions to dissection are often complex. This study explored medical students' experiences of attending an orientation to human dissection and the anatomy laboratory. Students' reactions, feelings, and thoughts were enquired about 1 year after beginning dissection at the University of Auckland, New Zealand. Qualitative research methods, specifically one-on-one semistructured interview were utilized. Third-year medical students self-selected into the study and were interviewed 1 year after entering the laboratory. Transcribed audiotapes of the interviews were analyzed for themes across the interviews. One year after dissection students have vivid memories with differing ways of viewing the body that may help or hinder with dissection. The themes presented include orientation, student anticipation, psychological approach to the body, normalizing-continuing disquiet, and social reference. The orientation eases student entry into the laboratory. There can be ongoing feelings of ambivalence regards the body for some students. Novel findings include that students not only have their own feelings to deal with but also those of friends and family who question them and may feel uncomfortable with the idea of them dissecting. Even one year after beginning dissection, students may emotionally struggle with their work and may require further support, including how they talk about sensitive topics with other people. PMID- 21815221 TI - Sub-micrometer-thick all-solid-state supercapacitors with high power and energy densities. PMID- 21815222 TI - Piezoelectric properties of non-polar block copolymers. PMID- 21815223 TI - Temperature-memory polymer networks with crystallizable controlling units. PMID- 21815224 TI - Nick sealing by T4 DNA ligase on a modified DNA template: tethering a functional molecule on D-threoninol. AB - Efficient DNA nick sealing catalyzed by T4 DNA ligase was carried out on a modified DNA template in which an intercalator such as azobenzene had been introduced. The intercalator was attached to a D-threoninol linker inserted into the DNA backbone. Although the structure of the template at the point of ligation was completely different from that of native DNA, two ODNs could be connected with yields higher than 90% in most cases. A systematic study of sequence dependence demonstrated that the ligation efficiency varied greatly with the base pairs adjacent to the azobenzene moiety. Interestingly, when the introduced azobenzene was photoisomerized to the cis form on subjection to UV light (320-380 nm), the rates of ligation were greatly accelerated for all sequences investigated. These unexpected ligations might provide a new approach for the introduction of functional molecules into long DNA strands in cases in which direct PCR cannot be used because of blockage of DNA synthesis by the introduced functional molecule. The biological significance of this unexpected enzymatic action is also discussed on the basis of kinetic analysis. PMID- 21815225 TI - Deprotonative metalation of aromatic compounds by using an amino-based lithium cuprate. AB - Deprotonative cupration of aromatic compounds by using amino-based lithium cuprates was optimized with 2,4-dimethoxypyrimidine and 2-methoxypyridine as the substrates and benzoyl chloride as the electrophile. [(tmp)(2)CuLi] (+2 LiCl) (tmp=2,2,6,6-tetramethylpiperidino) was identified as the best reagent and its use was extended to anisole, 1,4-dimethoxybenzene, other substituted pyridines, furan, thiophene and derivatives, and N-Boc-indole (Boc=tert-butyloxycarbonyl). Of the electrophiles employed to attempt the interception of the generated aryl cuprates, aroyl chlorides, iodomethane, and diphenyl disulfide efficiently reacted. In addition, different oxidative agents were identified to afford symmetrical biaryls. Finally, palladium-catalyzed coupling with aryl halides was optimized and allowed the synthesis of different aryl derivatives in medium to good yields. PMID- 21815226 TI - Homothiacalix[4]arenes: synthetic exploration and solid-state structures. AB - Homothiacalix[n]arenes have been largely underexposed compared with related (homo)heteracalixarenes, although their inherent structural features are particularly attractive for supramolecular host-guest chemistry. In this contribution, the synthetic macrocyclization protocols that afford homothiacalix[n]arenes have been reinvestigated and optimized, providing straightforward access to the parent homothiacalix[4]arene skeleton. Moreover, inner-rim (bis and tetrakis) ester functionalization and dimethylenethia bridge oxidation were successfully performed as well. Solution-phase (variable temperature) NMR spectroscopy studies and solid-state X-ray structures provided complementary information on the conformational features of the novel macrocycles. PMID- 21815227 TI - Efficient preparation and biological evaluation of a novel multivalency bifunctional chelator for 64Cu radiopharmaceuticals. PMID- 21815228 TI - Antimicrobial activity against bacteria with dermatological relevance and skin tolerance of the essential oil from Coriandrum sativum L. fruits. AB - The aim of this work was to determine the antibacterial activity of essential coriander oil (ECO) on bacteria with dermatological relevance and to assess the skin tolerance of antimicrobial effective ECO concentrations. Essential coriander oil was tested on clinical isolates of different bacteria species, all of which may cause superficial skin infections. Antimicrobial susceptibility testing was performed using a standardized macrodilution test. Essential coriander oil showed good antibacterial activity towards the majority of the bacterial strains tested, including Streptococcus pyogenes (Lancefield group A) and methicillin resistant Staphylococcus aureus (MRSA), with mean minimal inhibitory concentrations of 0.04% v/v and 0.25% v/v, respectively. The skin tolerance of a cream and a lotion containing 0.5% and 1.0% ECO was assessed in 40 healthy volunteers using the occlusive patch test. No skin irritation could be observed by sensitive photometric assessment in any of the volunteers. Because of its activity against Streptococcus pyogenes, Staphylococcus aureus and MRSA combined with excellent skin tolerance, ECO might be useful as an antiseptic for the prevention and treatment of skin infections with Gram-positive bacteria. PMID- 21815229 TI - Effects of different garlic-derived allyl sulfides on peroxidative processes and anaerobic sulfur metabolism in mouse liver. AB - Biological activity of garlic has been attributed to organosulfur compounds, most of all to oil-soluble allyl sulfides, such as diallyl sulfide (DAS), diallyl disulfide (DADS) and diallyl trisulfide (DATS). This study evaluated the effectiveness of garlic-derived allyl sulfides in influencing peroxidative processes, levels of thiols and sulfane sulfur and its metabolic enzymes in normal mouse liver cells. Various allyl sulfides (DAS, DADS and DATS) dissolved in corn oil were given intraperitoneally to mice for 10 days. After sacrificing the mice, biochemical assays were performed in liver homogenates and in plasma in order to establish liver function. All allyl sulfides under study had a beneficial effect in the mouse liver since they decreased reactive oxygen species and malondialdehyde levels and increased glutathione S-transferase activity and non-protein sulfhydryl group level. Moreover, DADS and DATS elevated total sulfane sulfur pool and activity of sulfane sulfur biosynthetic enzymes. The increase in sulfane sulfur level entailed augmentation of its antioxidant and regulatory capacities. Garlic-derived allyl sulfides exhibited antioxidant action in the liver and elevated anaerobic cysteine metabolism leading to the formation of sulfane sulfur-containing compounds. Thus, DADS and DATS showed beneficial action in the liver, which can be used for protection of normal liver cells during chemotherapy or for alleviation of liver damage. PMID- 21815230 TI - Validation of the detergent micelle classification for membrane protein crystals and explanation of the Matthews Graph for soluble proteins. AB - Protein crystals are of wide-spread interest because many of them allow structure analyses at atomic resolution. For soluble proteins, the packing density of such crystals is distributed according to the Matthews Graph. For integral membrane proteins, the respective graph is similar but at lower density and much broader. By visualizing the relative positions and orientations of membrane proteins in crystals, it has been suggested that the detergent micelles surrounding these proteins form sheets, filaments, or remain isolated in the crystal giving rise to three distinct packing density distributions that superimpose to form the observed broad distribution. This classification was indirect because detergent is not visible in X-ray crystallography. Given the extensive work involved in analyzing detergent structure directly by neutron diffraction, it seems unlikely that a statistically relevant number of them will be established in the near future. Therefore, the proposed classification is here scrutinized by a simulation in which an average detergent-carrying membrane protein was randomly packed to form crystals. The analysis reproduced the three types of detergent structures together with their packing density distributions and relative frequencies, which validates the previous classification. The simulation program was also run for crystals from soluble proteins using ellipsoids as reference shapes and defining a shape factor that quantifies the deviation from the nearest ellipsoid. This series reproduced and thus explained the Matthews Graph. PMID- 21815232 TI - A combination of in vivo selection and cell sorting for the identification of enantioselective biocatalysts. PMID- 21815231 TI - The Dutch Cannabis Dependence (CanDep) study on the course of frequent cannabis use and dependence: objectives, methods and sample characteristics. AB - This paper presents an overview of the prospective cohort design of the Dutch Cannabis Dependence (CanDep) study, which investigates (i) the three-year natural course of frequent cannabis use (>= three days per week in the past 12 months) and cannabis dependence; and (ii) the factors involved in the transition from frequent non-dependent cannabis use to cannabis dependence, and remission from dependence. Besides its scientific relevance, this knowledge may contribute to improve selective and indicated prevention, early detection, treatment and cannabis policies. The secondary objectives are the identification of factors related to treatment seeking and the validation of self report measures of cannabis use. Between September 2008 and April 2009, baseline data were collected from 600 frequent cannabis users with an average age of 22.1 years, predominantly male (79.3%) and an average cannabis use history of 7.1 years; 42.0% fulfilled a (12-month DSM-IV) diagnosis of cannabis dependence. The response rate was 83.7% after the first follow up at 18 months. The second and last follow-up is planned at 36 months. Computer assisted personal interviews (CAPI) were conducted which covered: cannabis use (including detailed assessments of exposure, motives for use and potency preference); use of other substances; DSM-IV internalizing and externalizing mental disorders; treatment seeking; personality; life events; social support and social functioning. PMID- 21815233 TI - Polymerization catalyst laser-interference patterning. PMID- 21815236 TI - Fatty acyl-AMP ligase involvement in the production of alkylresorcylic acid by a Myxococcus xanthus type III polyketide synthase. AB - Fatty acyl-AMP ligases (FAALs) activate fatty acids as acyladenylates, and subsequently catalyze their transfer onto the acyl carrier proteins (ACPs) of polyketide synthases (PKSs) or nonribosomal peptide synthetases to produce lipidic metabolites. Myxococcus xanthus contains a polyketide biosynthesis gene cluster in which putative FAAL (FtpD) and ACP (FtpC) genes are located close to a type III PKS (FtpA) gene. Here we describe the characterization of these three proteins in vitro. FtpD adenylated stearic acid and produced stearoyl-FtpC. The stearoyl moiety was then transferred to FtpA. When extender substrates (malonyl CoA and methylmalonyl-CoA) were added to the reaction, the alkylresorcinol 5 heptadecyl-4-methyl-benzene-1,3-diol was synthesized. Further in vitro analysis indicated that FtpA produces an alkylresorcylic acid as the direct product, and that this decarboxylates to alkylresorcinol nonenzymatically. This is the first report of a FAAL supplying a long-chain fatty acyl-ACP starter substrate to a type III PKS. PMID- 21815238 TI - Evolution of autonomous and semi-autonomous robotic surgical systems: a review of the literature. AB - BACKGROUND: Autonomous control of surgical robotic platforms may offer enhancements such as higher precision, intelligent manoeuvres, tissue-damage avoidance, etc. Autonomous robotic systems in surgery are largely at the experimental level. However, they have also reached clinical application. METHODS: A literature review pertaining to commercial medical systems which incorporate autonomous and semi-autonomous features, as well as experimental work involving automation of various surgical procedures, is presented. Results are drawn from major databases, excluding papers not experimentally implemented on real robots. RESULTS: Our search yielded several experimental and clinical applications, describing progress in autonomous surgical manoeuvres, ultrasound guidance, optical coherence tomography guidance, cochlear implantation, motion compensation, orthopaedic, neurological and radiosurgery robots. CONCLUSION: Autonomous and semi-autonomous systems are beginning to emerge in various interventions, automating important steps of the operation. These systems are expected to become standard modality and revolutionize the face of surgery. PMID- 21815237 TI - Novel low-cost prostate resection trainer-description and preliminary evaluation. AB - BACKGROUND: Transurethral resection of the prostate (TURP) is a challenging operation for residents with limited endoscopic experience. A number of virtual TURP simulators have been validated in the past. This study is the first description and preliminary evaluation of a non-virtual, low-cost TURP trainer as a teaching tool for residents in urology. METHODS: Dr K. Forke's prostatic resection trainer (PRT; LS 10-2/S, Samed GmbH, Dresden, Germany) was tested during the surgical training of a resident. Under the supervision of an experienced senior surgeon, three aspects were examined: the resection trainer's approximation to reality, the ease of instruction, and the potential capability to improve surgeons' psychomotor abilities with regard to the three-dimensional (3D) guidance of the instrument. The improvement in resection speed (RS) of residents with no PRT training (control group) was also compared to the results of the PRT-trained resident. RESULTS: During the PRT training, the resident displayed clear improvement in resection quality (RQ) and a 27% increase in RS (p = 0.03). In the post-training stage, the PRT-trained resident showed a more constant progress rate, to a maximum RS of 0.37 g/min (35% increase; p = 0.01), whereas the control group displayed varied RS learning curves. Composed of a synthetic material, which can be resected by standard instruments, the trainer offers a haptical experience that is particularly realistic and may provide an increased learning rate. CONCLUSION: From the findings, we conclude that this novel PRT is suitable for daily use and offers an effective and more affordable alternative to virtual simulators. Further validation studies will follow and new fields of application will be tested. PMID- 21815239 TI - Haemodynamics and cardiac function during robotic-assisted laparoscopic prostatectomy in steep Trendelenburg position. AB - BACKGROUND: Robotic-assisted laparoscopic prostatectomy (RALP) is usually performed in steep Trendelenburg position, which can be associated with cardiac impairment due to positioning and capnoperitoneum. This study investigated haemodynamic consequences and cardiac function in this type of surgery and evaluated the hypothesis that steep Trendelenburg position and capnoperitoneum results in haemodynamic and ventricular impairment. METHODS: 10 patients (ASA I III) scheduled for RALP in steep Trendelenburg position with capnoperitoneum were prospectively studied. Heart rate (HR), mean arterial pressure (MAP) and central venous pressure (CVP) were recorded. Stroke volume variation (SVV) and cardiac output (CO) were measured using pulse-contour analysis. Further, cardiac function was assessed using trans-oesophageal echocardiography before positioning (T1) and 10 min (T2) and 60 min (T3) after implementation of steep Trendelenburg position and capnoperitoneum. RESULTS: HR did not change statistically. MAP (T1, 69.7 +/- 1.55; T2, 82.9 +/- 3.05; T3, 79.4 +/- 2.18 mmHg), CVP (T1, 7.7 +/- 1.3; T2, 17.3 +/- 2.01; T3, 16.9 +/- 1.66 mmHg) and CO (T1, 4.0 +/- 0.15; T2, 4.9 +/- 0.26; T3, 4.9 +/- 0.36 l/min) increased significantly at T2 and T3. Echocardiography showed no deterioration of left or right ventricular function. In one patient with pre existing mitral valve insufficiency (I degrees ) an aggravation of the insufficiency (III degrees ) was observed. No other valve dysfunctions were observed. CONCLUSIONS: The steep Trendelenburg position may improve haemodynamic function and does not deteriorate left or right ventricular function during RALP. However, mitral valve insufficiency may be aggravated by positioning and capnoperitoneum. PMID- 21815240 TI - A miniature patient-mount navigation system for assisting needle placement in CT guided intervention. AB - BACKGROUND: CT-guided intervention is routinely performed in an iterative fashion that often leads to lengthy operation and high X-ray exposure to patients. To streamline the workflow, we develop a patient-mount navigation system for assisting needle placement in CT-guided interventions. METHODS: The system comprises three components, a miniature patient-mount tracking unit, an auto registered reference-frame unit and an intuitive image-processing unit. The system is operated like a virtual biplane fluoroscopy with augmented CT reconstructed images to streamline the conventional CT-guided intervention workflow. Surgery efficiency and safety can be increased, while radiation for patients and surgeons can be reduced. Two preclinical validations were conducted to evaluate the technical applicability and accuracy of the system. RESULTS: The results of the rigid physical phantom test showed a machine position error of 1.6 mm and a tilting error of 1.5 degrees . The results of the deformable porcine phantom test showed the operation position error to be 3.6 mm and tilting error to be 2.9 degrees . CONCLUSIONS: We concluded that the accuracy of our system is within the comparable range of the existing navigation systems. PMID- 21815241 TI - Cholesteryl-ester transfer protein enhances the ability of high-density lipoprotein to inhibit low-density lipoprotein oxidation. AB - Therapeutic strategies to increase high-density lipoprotein (HDL) to treat or prevent vascular disease include the use of cholesteryl-ester transfer protein (CETP) inhibitors. Here, we show, to the best of our knowledge for the first time, that addition of CETP to HDL enhances the ability of HDL to inhibit low density lipoprotein oxidation by ~ 30% for total HDL and HDL(2) (both P < 0.05) and 75% for HDL(3) (P < 0.01). Therefore, CETP inhibition may be detrimental to the antiatherosclerotic properties of HDL, and these findings may partly explain the failure of the CETP inhibitor, torcetrapib, treatment to retard vascular disease despite large increases in HDL, in addition to its "off target" toxicity, a property which appears not to be shared by other members of this class of CETP inhibitor currently under clinical trial. Further, detailed studies are urgently required. PMID- 21815242 TI - Mechanisms involved in alpha1B-adrenoceptor desensitization. AB - alpha(1B)-Adrenergic receptors mediate many of the actions of the natural catecholamines, adrenaline and noradrenaline. They belong to the seven transmembrane domains G protein-coupled receptor superfamily and exert their actions mainly through activation of Gq proteins and phosphoinositide turnover/calcium signaling. Many hormones and neurotransmitters are capable of inducing alpha(1B)-adrenergic receptor phosphorylation and desensitization; among them: adrenaline and noradrenaline, phorbol esters, endothelin-I, bradykinin, lysophosphatidic acid, insulin, EGF, PDGF, IGF-I, TGF-beta, and estrogens. Key protein kinases for these effects are G protein coupled receptor kinases and protein kinase C. The lipid/protein kinase, phosphoinositide-3 kinase also appears to play a key role, acting upstream of protein kinase C. In addition to the agents employed for cells stimulation, we observed that paracrine/autocrine mediators also participate; these processes include EGF transactivation and sphingosine-1-phosphate production and action. The complex regulation of these receptors unlocks opportunities for therapeutic intervention. PMID- 21815243 TI - Can a chitin-synthesis-inhibiting turfgrass fungicide enhance black cutworm susceptibility to a baculovirus? AB - BACKGROUND: Developmental resistance, i.e. reduced virulence and speed of kill of late instars, is a limiting factor in the use of baculoviruses for caterpillar control. Agrotis ipsilon multicapsid nucleopolyhedrovirus (AgipMNPV) is highly infective to young black cutworms, Agrotis ipsilon, but too slow-acting against late instars for effective curative control on golf courses or sports fields. Chitin-synthesis-inhibiting fungicides containing the active ingredient polyoxin d are used to control fungal diseases in turfgrass, and similar compounds have been shown in the laboratory to synergize baculoviruses by disrupting peritrophic membrane function. This study tested whether applying the virus together with such a fungicide can synergize AgipMNPV activity against A. ipsilon in turfgrass. RESULTS: The addition of a chitin synthesis inhibitor failed to increase AgipMNPV infectivity to A. ipsilon in the field. Rather, delayed and slightly reduced mortality from viral infection was seen when larvae fed on fungicide/virus treated grasses as opposed to virus-only treatments. Choice tests revealed the fungicide residues to be a mild feeding deterrent. CONCLUSION: Because polyoxin-d does not deactivate AgipMNPV, the two substances are compatible. However, combination applications of polyoxin-d and Agip MNPV on turfgrass might interfere with larval ingestion of a lethal virus dose, resulting in prolonged larval feeding in the field. PMID- 21815244 TI - Spotted wing drosophila infestation of California strawberries and raspberries: economic analysis of potential revenue losses and control costs. AB - BACKGROUND: Economic costs of spotted wing drosophila (SWD) include yield and associated revenue losses, labor and material costs for monitoring and management and revenue losses due to the closure of export markets should fruit from SWD infested regions be banned by trading partners. This analysis focuses on two types of loss in the California raspberry and strawberry industries: yield losses in the absence of management, and insecticide material costs on a per treatment basis. It computes the cost of a specific management program for raspberries in California's Central Coast region. RESULTS: Insecticide material and application costs per treatment and the cost of the management program are small relative to the yield losses in the absence of management that are observed by growers, researchers and others in initial infestations. CONCLUSION: It is difficult to evaluate precisely the share of pest management program costs due to SWD because insecticides are sometimes used to manage multiple pests, and because labor intensive field sanitation efforts to control SWD are recommended practices already. Given these considerations, this analysis finds that the benefits to SWD management well outweigh the costs examined here. Evaluating the efficacy of managing SWD is essential in assessing the risks that SWD poses and the benefits of pest management programs. PMID- 21815245 TI - Possible case of sirenomelia in the Tumaco-Tolita pottery pre-Columbian culture, 2000 years before the epidemic focus of sirenomelia in Cali-Colombia. PMID- 21815246 TI - Branchial arch defects and 19p13.12 microdeletion: defining the critical region into a 0.8 M base interval. AB - We present a patient with preauricular tags, preauricular and branchial pits, stenosis of the external auditory canals, mild hearing loss, and mild developmental delay who had a de novo 19p13.12 submicroscopic deletion. The size of the deletion was 760-kb, extending from 15,300,338 to 16,064,271 (hg18; NCBI Build 36.1). Our finding supports the notion that 19p13.12 represents a unique microdeletion syndrome characterized by branchial arch defects and the concept of exclusion mapping indicates that the putative locus for the branchial arch development is included in the 0.8-Mb interval defined by the deletion in the presently reported patient. PMID- 21815247 TI - Reproductive success in patients with Hallermann-Streiff syndrome. PMID- 21815248 TI - Autosomal dominant inheritance of a predisposition to thoracic aortic aneurysms and dissections and intracranial saccular aneurysms. AB - A genetic predisposition for thoracic aortic aneurysms and dissections (TAAD) can be inherited in an autosomal dominant manner with decreased penetrance and variable expression. Four genes identified to date for familial TAAD account for approximately 20% of the heritable predisposition. In a cohort of 514 families with two or more members with presumed autosomal dominant TAAD, 48 (9.3%) families have one or more members who were at 50% risk to inherit the presumptive gene causing TAAD had an intracranial vascular event. In these families, gender is significantly associated with disease presentation (P < 0.001), with intracranial events being more common in women (65.4%) while TAAD events occurred more in men (64.2%,). Twenty-nine of these families had intracranial aneurysms (ICA) that could not be designated as saccular or fusiform due to incomplete data. TGFBR1, TGFBR2, and ACTA2 mutations were found in 4 families with TAAD and predominantly fusiform ICAs. In 15 families, of which 14 tested negative for 3 known TAAD genes, 17 family members who were at risk for inheriting TAAD had saccular ICAs. In 2 families, women who harbored the genetic mutation causing TAAD had ICAs. In 2 additional families, intracranial, thoracic and abdominal aortic aneurysms were observed. This study documents the autosomal dominant inheritance of TAADs with saccular ICAs, a previously recognized association that has not been adequately characterized as heritable. In these families, routine cerebral and aortic imaging for at risk members could prevent cerebral hemorrhages and aortic dissections. PMID- 21815249 TI - Wilms tumor incidence in children with 2q terminal deletions: a cohort study. AB - Three individuals with chromosome 2q terminal deletions have been reported in the medical literature to have developed Wilms tumor. By looking at a UK national cohort, we aimed to ascertain the chance of an individual with a 2q terminal deletion developing a Wilms tumor. The objective was to clarify screening recommendations. All individuals over a 40-year period with chromosome 2q terminal deletions were ascertained from the Chromosome Abnormality Database. The names and dates of birth of these individuals were obtained from the Regional Cytogenetic Departments where the original chromosome analyses were performed. These data were collated and compared with the National Registry of Childhood Tumors. One hundred twenty-nine subjects were identified over a 40-year study period. Only a single individual in our national cohort was affected by Wilms tumor. This individual had an add(2)(q35) karyotype. We conclude that the incidence of Wilms tumor in the majority of individuals with a 2q terminal deletion is low, and is below the recommended threshold for surveillance for tumor development. PMID- 21815250 TI - The microcephaly-capillary malformation syndrome. AB - We report on three children from two families with a new pattern recognition malformation syndrome consisting of severe congenital microcephaly (MIC), intractable epilepsy including infantile spasms, and generalized capillary malformations that was first reported recently in this journal [Carter et al. (2011); Am J Med Genet A 155: 301-306]. Two of our reported patients are an affected brother and sister, suggesting this is an autosomal recessive severe congenital MIC syndrome. PMID- 21815251 TI - A novel 4p16.3 microduplication distal to WHSC1 and WHSC2 characterized by oligonucleotide array with new phenotypic features. AB - Larger imbalances on chromosome 4p in the form of deletions associated with Wolf Hirschhorn syndrome (WHS) and duplications of chromosome 4p have a defined clinical phenotype. The critical region for both these clinical disorders has been narrowed based on the genotype-phenotype correlations. However, cryptic rearrangements in this region have been reported infrequently. We report on a male patient with a microduplication of chromosome 4p, who presents with findings of macrocephaly, irregular iris pigmentation-heterochromia, and preserved linear growth in addition to overlapping features of trisomy 4p such as seizures, delayed psychomotor development, and dysmorphic features including prominent glabella, low-set ears, and short neck. Using a high-density oligonucleotide microarray, we have identified a novel submicroscopic duplication involving dosage sensitive genes TACC3, FGFR3, and LETM1. The microduplication did not involve WHSC1 and WHSC2 which are considered in the critical region for WHS and trisomy 4p. This patient's presentation and genomic findings help further delineate clinical significance of re-arrangements in the 4p16 region without the involvement of WHS critical region. PMID- 21815252 TI - Two novel heterozygous mutations of EVC2 cause a mild phenotype of Ellis-van Creveld syndrome in a Chinese family. AB - Ellis-van Creveld syndrome (EvC, chondroectodermal dysplasia; OMIM 225500) is an autosomal recessive skeletal dysplasia with associated multisystem involvement. The syndrome is characterized by short limbs, short ribs, postaxial polydactyly, dysplastic nails, and abnormal teeth. Congenital heart defects occur in 50-60% of cases. In this study, we report EvC in a 6-year-old Chinese girl with hypodontia and polydactyly, mild short stature, and abnormalities of the knee joints. No signs of short ribs, narrow thorax, or congenital heart defects were found in this patient. The EvC phenotype shares some similarity with Weyers acrofacial dysostosis (Weyer; OMIM 193530), an autosomal dominant disorder clinically characterized by mild short stature, postaxial polydactyly, nail dystrophy, and dysplastic teeth. Mutations in EVC or EVC2 are associated with both EvC syndrome and Weyers acrodental dysostosis, but the two conditions differ in the severity of the phenotype and their pattern of inheritance. In this study, two novel heterozygous EVC2 mutations, IVS5-2A > G and c.2653C > T (Arg885X), were identified in the patient. The IVS5-2A > G mutation was inherited from the patient's mother and the c.2653C > T from her father. Her parents have no phenotypic symptoms similar to those of the patient. These findings extend the mutation spectrum of this malformation syndrome and provide the possibility of prenatal diagnosis for future offspring in this family. PMID- 21815253 TI - Maternal age and prevalence of isolated congenital heart defects in an urban area of the United States. AB - Although maternal age has been associated with a number of birth defects in several reports, the literature on the association of maternal age with isolated congenital heart defect (CHD) phenotypes has been limited. We evaluated CHD prevalence based on a cohort of 5,289 infants and fetuses with isolated CHDs born during the period 1968-2005 and ascertained by the Metropolitan Atlanta Congenital Defects Program (MACDP) among residents of five central counties in Atlanta. For our denominator, we obtained information on births to residents of the same counties from vital records (n = 1,301,143). We calculated prevalence ratios for 23 CHD phenotypes by several maternal age categories, using the group 25-29 years of age as a reference group. We used Poisson regression models to estimate adjusted prevalence ratios (aPRs) and 95% confidence intervals (CIs), controlling for maternal race, infant sex, and birth cohort. A maternal age of 35 years or older was associated with an increased prevalence for several CHD phenotypes: laterality defects (aPR = 2.06; CI 1.22-3.48), all conotruncal defects (aPR = 1.30; CI 1.03-1.65), and specifically for dextro-transposition of the great arteries (aPR = 1.65; CI 1.10-2.48), coarctation of the aorta (aPR = 1.54; CI 1.10-2.16), ventricular septal defects (aPR = 1.20; CI 1.06-1.36), and atrial septal defects (aPR = 1.36; CI 1.05-1.77). Our findings suggest that the birth prevalence of specific isolated CHDs varies with maternal age. Further studies are warranted to corroborate these observations, taking into account potential confounding by known modifiable risk factors. PMID- 21815254 TI - Ebstein anomaly: Genetic heterogeneity and association with microdeletions 1p36 and 8p23.1. AB - Ebstein anomaly is an uncommon congenital heart defect (CHD), characterized by downward displacement of the tricuspid valve into the right ventricle. To uncover the genetic associations with Ebstein anomaly, we have searched chromosomal imbalances using standard cytogenetic and array-CGH analysis, and single gene conditions associated with syndromic Ebstein anomaly (with extracardiac anomalies), and screened GATA4 and NKX2.5 mutations in nonsyndromic patients (without extracardiac anomalies). Between January 1997 and September 2009, 44 consecutive patients with Ebstein anomaly were evaluated in two centers of Pediatric Cardiology. Ebstein anomaly was syndromic in 12 (27%) patients, and nonsyndromic in 32 (73%). A recognizable syndrome or complex was diagnosed by clinical criteria in seven patients. In one syndromic patient an 18q deletion was diagnosed by standard cytogenetic analysis. Array-CGH analysis performed in 10 of the 12 syndromic patients detected an interstitial deletion of about 4 Mb at 8p23.1 in one patient, and a deletion 1pter > 1p36.32/dup Xpter- > Xp22.32 in another patient. In the 28 of 32 nonsyndromic patients who underwent molecular testing, no mutation in GATA4 and NKX2.5 genes were detected. We conclude that Ebstein anomaly is a genetically heterogeneous defect, and that deletion 1p36 and deletion 8p23.1 are the most frequent chromosomal imbalances associated with Ebstein anomaly. Candidate genes include the GATA4 gene (in patients with del 8p23.1), NKX2.5 (based on published patients with isolated Ebstein anomaly) and a hypothetical gene in patients with del 1p36). PMID- 21815255 TI - Familial cardiac valvulopathy due to filamin A mutation. AB - We report on the clinical findings in siblings affected by the recently characterized X-linked form of hereditary cardiac valvular dystrophy or cardiac valve disease (OMIM 314400) due to mutations in the FLNA gene and review the literature on this condition. Although FLNA related cardiac valve disease is presumed to be a rare disorder, it is likely underdiagnosed. Several features of this condition may aid in its identification. FLNA related valvular disease can be recognized on the basis of its distinctive inheritance, early age of onset, and frequent multi-valve involvement. PMID- 21815256 TI - Screening for celiac disease in the joint hypermobility syndrome/Ehlers-Danlos syndrome hypermobility type. PMID- 21815257 TI - The Niemann-Pick C1 gene interacts with a high-fat diet and modifying genes to promote weight gain. PMID- 21815258 TI - Homozygous microdeletion of the POU1F1, CHMP2B, and VGLL3 genes in chromosome 3- a novel syndrome. AB - Microdeletion syndromes include numerous syndromic phenotypes associated with intellectual disability and dysmorphic features. We report on a patient with a novel microdeletion of chromosomal region 3p11.2-p12.1 containing POU1F1, chromatin-modifying protein 2B (CHMP2B), and vestigial-like 3 (VGLL3) genes. Our patient was diagnosed as having a neonatal multiple pituitary hormone [growth hormone (GH), thyroid-stimulating hormone (TSH), and prolactin] deficiency. In addition to the typical findings associated with these hormonal deficiencies, she exhibited clinical features resembling those of Laron syndrome (frontal bossing, saddle nose, small chin, blue sclera, and acromicria), with moderate intellectual disability. She also displayed an unusual growth pattern characterized by unresponsiveness to high doses of GH replacement therapy during infancy and early childhood and an accelerated growth rate beginning at the age of 4.5 years. Insulin-like growth factor (IGF)-1 levels were consistently extremely low or undetectable. Extensive medical and genetic analysis ruled out primary and secondary GH insensitivity. The distinct phenotype and the peculiar growth pattern observed in this affected patient, not reported to have been observed in other cases with POU1F1 gene inactivity, suggest that the other two deleted genes play a possible role in the development of this syndrome. This hypothesis may be supported by the fact that both the CHMP2B and VGLL3 genes are expressed in the liver and the growth plate, the two main target organs of the GH/IGF-1 axis. The homozygous deletion of the CHMP2B gene, previously associated with frontotemporal dementia, may contribute to the intellectual disability observed in this patient. PMID- 21815259 TI - Potential teratogenic effects of allopurinol: a case report. AB - We report on a case of a multiple congenital anomalies in a newborn infant whose mother was on allopurinol treatment through the pregnancy. The pattern of congenital anomalies that was noted in our patient was similar to the pattern described in a number of published reports following mycophenolate mofetil [CellCept(r)] treatment during pregnancy. The anomalies present in our patient include: diaphragmatic hernia, unilateral microtia and absence of external auditory canal, micrognathia, microphthalmia, optic nerve hypoplasia, hypoplasia of the corpus callosum, unilateral renal agenesis, pulmonary agenesis, and cleft lip and palate. Since both allopurinol and mycophenolate mofetil act by disrupting purine biosynthesis and given the similarities in anomalies seen after prenatal exposure, we suggest that allopurinol should also be considered a teratogen. PMID- 21815260 TI - Monozygotic twin discordance for phacomatosis cesioflammea further supports the post-zygotic mutation hypothesis. AB - Phacomatosis pigmentovascularis (PPV) is a group of sporadic skin disorders combining widespread cutaneous capillary malformations and pigmented nevi. Etiopathogenesis of the various forms of PPV is unknown, although a non-allelic twin spotting has been proposed as the most likely underlying mechanism. We report on the second instance of monozygotic twin discordance for PPV. Identical twins were observed shortly after birth, one affected by PPV and the other healthy, except for a standard Mongolian spot. Membrane examination was compatible with a monochorionic diamniotic pregnancy, and microsatellite analysis demonstrated monozygosity. This report confirms that PPV likely originates from a post-zygotic mutation rising shortly after conception and affecting different cell lineages. Speculations about mechanisms linked to phenotypic discrepancies among identical twins were also put forward. PMID- 21815261 TI - Automated syndrome detection in a set of clinical facial photographs. AB - Computer systems play an important role in clinical genetics and are a routine part of finding clinical diagnoses but make it difficult to fully exploit information derived from facial appearance. So far, automated syndrome diagnosis based on digital, facial photographs has been demonstrated under study conditions but has not been applied in clinical practice. We have therefore investigated how well statistical classifiers trained on study data comprising 202 individuals affected by one of 14 syndromes could classify a set of 91 patients for whom pictures were taken under regular, less controlled conditions in clinical practice. We found a classification accuracy of 21% percent in the clinical sample representing a ratio of 3.0 over a random choice. This contrasts with a 60% accuracy or 8.5 ratio in the training data. Producing average images in both groups from sets of pictures for each syndrome demonstrates that the groups exhibit large phenotypic differences explaining discrepancies in accuracy. A broadening of the data set is suggested in order to improve accuracy in clinical practice. In order to further this goal, a software package is made available that allows application of the procedures and contributions toward an improved data set. PMID- 21815262 TI - Limb-body wall defect. Is there a defensible hypothesis and can it explain all the associated anomalies? AB - Aside from gastroschisis and omphalocele, major defects of the ventral body (thoracoabdominal) wall are relatively uncommon and almost universally lethal. They are most often associated with other anomalies including those of the limbs that may range from amelia to mild positional deformations, unusual craniofacial malformations, and a variety of visceral abnormalities that include the heart, lungs, genitourinary system, and gut. This complex of ventral wall anomalies has been discussed under a broad and changing nomenclature that has included amniotic band disruption complex, amnion rupture sequence, limb-body wall defect (or complex), and simply body wall complex. Three major theories have been suggested to explain this complex: early amnion rupture (operating through uterine pressure and/or disruption by amniotic bands), vascular compromise (primarily hypoperfusion), and an early intrinsic defect of the developing embryo. We present four patients that illustrate the spectrum of ventral body wall defects, and from there critique the current hypotheses of pathogenesis. We conclude that this association of malformations originates as early as the embryonic disc stage, and that some of the observed associated anomalies are secondary complications of the primary disturbance in embryogenesis. We propose a new explanation for the atypical facial clefts and cranial malformations that are often observed. PMID- 21815263 TI - The clinical delineation of malformation syndromes: historical prospective and future direction. PMID- 21815264 TI - Mosaic partial trisomy 19p12-q13.11 due to a small supernumerary marker chromosome: a locus associated with Asperger syndrome? AB - In the neurodevelopmentally impaired population the frequency of small supernumerary marker chromosomes (sSMC) is about 0.3%. To find the origin of a sSMC in a 4-year-old boy with Asperger syndrome (AS) a microarray-based comparative genomic hybridization (aCGH), using a 135K-feature whole-genome microarray, and Metaphase FISH analysis, was performed. The sSMC was characterized as being composed of 18.4 Mb from 19p12q13.11. Based on the size and genic content, it is expected that the partial trisomy detected is responsible for the characteristics observed in the patient. In that case it could be an indication of a novel locus associated with AS. PMID- 21815265 TI - Revisiting the origin of the vertebrate Hox14 by including its relict sarcopterygian members. AB - Bilaterian Hox genes play pivotal roles in the specification of positional identities along the anteroposterior axis. Particularly in vertebrates, their regulation is tightly coordinated by tandem arrays of genes [paralogy groups (PGs)] in four gene clusters (HoxA-D). Traditionally, the uninterrupted Hox cluster (Hox1-14) of the invertebrate chordate amphioxus was regarded as an archetype of the vertebrate Hox clusters. In contrast to Hox1-13 that are globally regulated by the "Hox code" and are often phylogenetically conserved, vertebrate Hox14 members were only recently revealed to be present in an African lungfish, a coelacanth, chondrichthyans and a lamprey, and decoupled from the Hox code. In this study we performed a PCR-based search of Hox14 members from diverse vertebrates, and identified one in the Australian lungfish, Neoceratodus forsteri. Based on a molecular phylogenetic analysis, this gene was designated NfHoxA14. Our real-time RT-PCR suggested its hindgut-associated expression, previously observed also in cloudy catshark HoxD14 and lamprey Hox14alpha. It is likely that this altered expression scheme was established before the Hox cluster quadruplication, probably at the base of extant vertebrates. To investigate the origin of vertebrate Hox14, by including this sarcopterygian Hox14 member, we performed focused phylogenetic analyses on its relationship with other vertebrate posterior Hox PGs (Hox9-13) as well as amphioxus posterior Hox genes. Our results confirmed the hypotheses previously proposed by other studies that vertebrate Hox14 does not have any amphioxus ortholog, and that none of 1-to-1 pairs of vertebrate and amphioxus posterior Hox genes, based on their relative location in the clusters, is orthologous. PMID- 21815266 TI - Centimeter-scale high-resolution metrology of entire CVD-grown graphene sheets. AB - A high-throughput metrology method for measuring the thickness and uniformity of entire large-area chemical vapor deposition-grown graphene sheets on arbitrary substrates is demonstrated. This method utilizes the quenching of fluorescence by graphene via resonant energy transfer to increase the visibility of graphene on a glass substrate. Fluorescence quenching is visualized by spin-coating a solution of polymer mixed with fluorescent dye onto the graphene then viewing the sample under a fluorescence microscope. A large-area fluorescence montage image of the dyed graphene sample is collected and processed to identify the graphene and indicate the graphene layer thickness throughout the entire graphene sample. Using this metrology method, the effect of different transfer techniques on the quality of the graphene sheet is studied. It is shown that small-area characterization is insufficient to truly evaluate the effect of the transfer technique on the graphene sample. The results indicate that introducing a drop of acetone or liquid poly(methyl methacrylate) (PMMA) on top of the transfer PMMA layer before soaking the graphene sample in acetone improves the quality of the graphene dramatically over immediately soaking the graphene in acetone. This work introduces a new method for graphene quantification that can quickly and easily identify graphene layers in a large area on arbitrary substrates. This metrology technique is well suited for many industrial applications due to its repeatability and flexibility. PMID- 21815267 TI - Nanoparticle-loaded aerogels and layered aerogels cast from sol-gel mixtures. PMID- 21815268 TI - A heterodimeric glucuronide prodrug for cancer tritherapy: the double role of the chemical amplifier. PMID- 21815269 TI - Cassia obtusifolia MetE as a cytosolic target for potassium isolespedezate, a leaf-opening factor of Cassia plants: target exploration by a compact molecular probe strategy. AB - Affinity chromatography by using ligand-immobilized bead technology is generally the first choice for target exploration of a bioactive ligand. However, when a ligand has comparatively low affinity against its target, serious difficulties will be raised in affinity-based target detection. We report here that the use of compact molecular probes (CMP) will be advantageous in such cases; it enables the retention of moderate affinity between the ligand and its target in contrast to immobilizing the ligand on affinity beads that will cause a serious drop in affinity to preclude target detection. In the CMP strategy, a CMP containing an azide handle is used for an initial affinity-based labeling of target, and subsequent tagging by CuAAC with a large FLAG tag will give a tagged target protein. By using the CMP strategy, we succeeded in the identification of Cassia obtusifolia MetE as a cytosolic target protein of potassium isolespedezate (1), a moderately bioactive ligand. PMID- 21815271 TI - Preparation and acid-responsive photophysical properties of T-shaped pi conjugated molecules containing a benzimidazole junction. AB - T-shaped pi-conjugated molecules with an N-methyl-benzimidazole junction have been synthesized and their acid-responsive photophysical properties owing to the change in the pi-conjugation system are discussed. T-shaped pi-conjugated molecules consist of two orthogonal pi-conjugated systems including a phenyl thiophene extended from the 2-position and alkyl phenylenes connected through various pi-spacers from the 4,7-positions of the N-methyl-benzimidazole junction. The pi-spacers, such as thiophene, ethyne, and ethane, have an effect on the acid response of photophysical properties in terms of changes in conformation, excited state energy and charge-transfer (CT) characteristics. In particular, the pi conjugated molecule with ethynyl spacers exhibited a marked redshift in the fluorescence spectrum with a large Stokes shift upon the addition of acid, whereas the other molecules showed substantial quenching. The redshift in emission was studied in detail by temperature-dependent fluorescence measurements, which indicated the transition to a CT state over the finite activation energy at the excited state. The change in the frontier molecular orbitals upon acid addition was further discussed by means of DFT calculations. PMID- 21815270 TI - Synthesis of optically active N-aryl amino acid derivatives through the asymmetric petasis reaction catalyzed by a novel hydroxy-thiourea catalyst. PMID- 21815272 TI - Comparison of adrenocortical responses to acute stress in lowland and highland Eurasian tree sparrows (Passer montanus): similar patterns during the breeding, but different during the prebasic molt. AB - Previous studies indicate most free-living avian species in both extreme and temperate environments seasonally modulate the adrenocortical responses to acute stress, and those breeding in harsh environments always express reduced adrenocortical responses, which may allow them to obtain maximal reproductive success. However, recent investigations showing a human commensal species, house sparrows (Passer domesticus), expressed similar corticosterone (CORT) responses in both benign and harsh environments. In this study, focusing on another human commensal species, Eurasian tree sparrows (P. montanus), we examined the adrenocortical response to acute stress in lowland populations, among the early and late breeding, the prebasic molt, and the wintering stages, and compared them with previously published data from populations on the Tibetan Plateau. Our results show: (1) similar to highland Eurasian tree sparrows, lowland populations show no differences in baseline CORT levels among life history stages, and the stress-induced CORT (maximal CORT, total and corrected integrated CORT) levels are lower during the early breeding and the prebasic molt stages than those in the late breeding and the wintering stages; (2) highland Eurasian tree sparrows show stronger adrenocortical responses during the prebasic molt stage than lowland populations, whereas there are no differences between the early and the breeding stages (except for maximal CORT). Our results suggest that Eurasian tree sparrows from both harsh and benign environments have similar patterns of adrenocortical responses in the breeding stage, whereas they are different in the prebasic molt stage. In highland birds, the increased maximal CORT levels during the late breeding and the small increases in adrenocortical responses during the prebasic molt are interesting but remain unexplained. PMID- 21815273 TI - In vitro adipogenesis of adipose-derived stem cells in 3D fibrin matrix of low component concentration. AB - This study evaluated the suitability of adipose-derived stem cells (ASCs) combined with fibrin matrix of variable composition for adipose tissue-equivalent formation in vitro. Therefore, undifferentiated ASCs were embedded in fibrin clots composed of 2 IU/ml thrombin and fibrinogen of varying concentrations (6.25, 12.5 and 25 mg/ml) and kept under control or adipogenic conditions. Fibrin cell composites were evaluated by scanning electron microscopy, live/dead staining, lactate-dehydrogenase (LDH) assay, quantitative PCR for the adipogenic markers fatty acid binding protein 4 (FABP4), peroxisome proliferative activated receptor-gamma (PPARgamma) and leptin, leptin ELISA and oil red O staining. Cells were found homogeneously distributed throughout the clot. Their number increased to day 7 (up to 3.62-fold median) and decreased thereafter until day 28. The proliferation was unaffected by fibrinogen concentration in the control. Adipogenic conditions generally yielded higher cell numbers, which were in addition increasing with increasing fibrinogen concentrations. FABP4, PPARgamma and leptin mRNA expression was strongly upregulated by adipogenic medium, which was confirmed by the levels of leptin secretion and lipid vesicles formation demonstrated by oil red O staining. When embedded in 25 mg/ml fibrinogen clots, ASCs showed the highest expression levels of FABP4 (up to 629.0-fold), PPARgamma (up to 1.6-fold) and leptin (up to 57.9-fold), corroborated by significantly elevated leptin secretion (median 33.29 ng/ml) on day 14. Constructs composed of fibrin matrix of low component concentrations-allowing homogeneous cell distribution-with ASCs should represent a suitable strategy for adipose tissue formation in vivo. PMID- 21815274 TI - Use of flexible bronchoscopy in pediatric patients receiving extracorporeal membrane oxygenation (ECMO) support. AB - INTRODUCTION: Critically ill children treated with extracorporeal membrane oxygenation (ECMO) support frequently have respiratory complications amenable to evaluation by flexible bronchoscopy (FB). The safety and efficacy of FB in this setting has not been well described in children. METHODS: Retrospective analysis of 153 FBs in 79 children treated with ECMO at a single institution from 2000 to 2008. Demographic data, clinical findings, and complications were obtained. Chest radiographs reports were evaluated prior to and following FB. Physiologic variables were compared prior to and following FB. RESULTS: Seventy-nine patients underwent FB on ECMO [58 veno-venous (VV) and 21 veno-arterial (VA) ECMO], with 153 total FBs performed. Indications for FB included clearance of tenacious airway secretions (n = 118, 77%), or evaluation of suspected secondary infections with bronchoalveolar lavage (n = 26, 17%). Two patients also had surfactant instillation following secretion removal. FB was performed a median 5 days following cannulation for ECMO (range 2-14 days). Most common findings included thick secretions (n = 77, 50.3%), mucoid secretions (n = 15, 9.8%), and mucopurulent secretions (n = 28, 18.3%). No deterioration in radiographic lung findings was described post-FB. FB was not associated with any significant change in heart rate, systemic blood pressure, or temperature. No significant changes in ECMO pump flow rate or sweep gas flow was seen during or after FB. Cannula dislodgement, inadvertent extubation, fever, pneumothorax, or intraprocedural hypoxemia was not reported. Fifty-three FBs (35%) resulted in blood-tinged secretions from the endotracheal tube post-FB, which resolved spontaneously. Three patients received high frequency oscillatory ventilation (HFOV) following FB in association with mild hemorrhage. CONCLUSIONS: FB is a well-tolerated and safe procedure in critically ill pediatric patients on ECMO. FB may have a diagnostic as well as therapeutic benefit in such patients. PMID- 21815275 TI - Erythrocyte zinc levels in children with bronchial asthma. AB - Zinc deficiency may be suspected to play a role in the pathogenesis, control, and severity of asthma because of its antioxidant, antiapoptotic, and anti inflammatory effects. We aimed to investigate whether there was any relationship between erythrocyte zinc levels and childhood asthma. The erythrocyte zinc levels of 67 asthmatic and 45 healthy children were analyzed in this case-control study. The mean concentrations of erythrocyte zinc were 1215.8 +/- 145.1 ug/dl in asthma patients and 1206.9 +/- 119.5 ug/dl in controls with no significant difference (P = 0.472). The erythrocyte zinc level was below 1,000 ug/dl in 6 asthmatic patients (8.9%) and 2 control group patients (4.4%). There was no relationship between erythrocyte zinc levels and duration of follow-up, severity, and control of the asthma (P > 0.05). On the other hand, patients hospitalized for an asthma attack had significantly lower erythrocyte zinc levels compared with nonhospitalized patients and the control group (P = 0.000 and P = 0.004 respectively). This study's findings indicate that asthmatic children are not a risk group for zinc deficiency. We emphasize that checking zinc levels in children who are hospitalized for an asthma attack may be useful. PMID- 21815276 TI - Tuberculous damaged lung in a child. AB - Tuberculosis (TB) remains the "great pretender." We report the case of a 10-year old female, who presented with a mass in the left chest that was suspected initially to be a tumor. This was later confirmed to be tuberculous in nature, with dissemination to the liver. A large granuloma eventually replaced the left lung, leaving her with "tuberculous destroyed lung" (TDL), an extremely rare, life-threatening sequela of the disease. We review the pathophysiology, radiologic findings, and management options, which includes pneumonectomy, for this seldom seen but preventable condition. PMID- 21815277 TI - Kinetics of oxygenation improvement and the timing of HFOV institution. PMID- 21815278 TI - Therapeutic role of probiotics in asthma and allergic rhinitis. PMID- 21815279 TI - Subcutaneous emphysema and pneumomediastinum due to foreign body aspiration in children with asthma. AB - Pneumomediastinum (PM) and subcutaneous emphysema (SCE) are well recognized as complications of acute asthma exacerbation in children with asthma. We present herein a report of three cases of asthmatic children who presented with PM and SCE found to be secondary to foreign body aspiration. The cases highlight that clinicians must remain vigilant for co-morbidities in an asthma exacerbation, and less common etiologies of PM and SCE, such as foreign body aspiration, should also be carefully considered in asthmatic children. PMID- 21815281 TI - Critique of GINA global strategy. PMID- 21815280 TI - A comprehensive approach to the prevention of bronchopulmonary dysplasia. AB - The current bronchopulmonary dysplasia (BPD) is seen in infants born extremely premature, with less severe respiratory distress syndrome (RDS) and who received prenatal steroids-"new BPD". The pathophysiology of BPD is based on an impairment of lung maturation with prenatal and postnatal multi-hit insults and genetic susceptibility. This multifactorial pathophysiology of BPD suggests that no single "magic bullet" will prevent it. Thus, to avoid BPD we need to implement a complex and comprehensive strategy. This strategy is based on ventilatory and non ventilatory measures. The ventilatory route allows an individualized endotracheal intubation approach. Early lung recruitment with nasal respiratory support (nasal continuous positive airway pressure [NCPAP] or nasal intermittent positive pressure ventilation [NIPPV] / synchronized NIPPV [SNIPPV]) and the INSURE (intubation, surfactant and early extubation) approach are discussed. Initial treatment with NCPAP did not reduce the rate of BPD compared to endotracheal ventilation and surfactant administration. While NIPPV/SNIPPV may have short-term advantages over NCPAP, the effect on BPD needs to be further studied. During hospitalization the respiratory goals should aim for adequate oxygenation, permissive hypercapnia, and gentle ventilation. However, these goals were found to have short-term benefits but did not reduce significantly the rate of BPD. Selective use of a short course of low dose corticosteroids can be considered after the first or second week of life in infants who are unable to be weaned from the ventilator and are at high risk for BPD. Non-ventilatory measures include early nutritional support with fluid restriction, caffeine and consideration of vitamin A. Hemodynamic significant patent ductus arteriosus (PDA) may be associated with BPD, but medical or surgical treatment of PDA were not shown to decrease BPD. Each component and the strategy as a whole needs to be further studied in large randomized prospective studies or by meta-analyses, especially in the target population of extremely premature infants who are the most prone to BPD. PMID- 21815282 TI - Reduced mortality in cystic fibrosis patients treated with tobramycin inhalation solution. AB - BACKGROUND: Though tobramycin inhalation solution has been used for over a decade to improve lung function and reduce exacerbations in patients with cystic fibrosis (CF), its effects on mortality have not been well-described. This study aimed to assess the association between use of tobramycin inhaled solution and mortality in patients with CF and chronic Pseudomonas aeruginosa (PA) infection. METHODS: Longitudinal logistic regression was used to assess the association between current-year reported use of tobramycin inhalation solution and subsequent-year mortality of patients meeting recommended criteria for tobramycin inhalation solution use in the United States Cystic Fibrosis Foundation's Patient Registry (1996-2008). RESULTS: Among 12,740 patients meeting inclusion criteria, 2,538 deaths were observed during a median follow-up of 6 years. After regression adjustment, use of tobramycin inhaled solution was associated with a 21% reduction in the odds of subsequent year mortality (odds ratio (95% CI): 0.79 (0.72-0.88), P < 0.001). In our model, use of dornase alfa was also associated with a 15% reduction in the odds of subsequent year mortality (odds ratio (95% CI): 0.85 (0.76-0.95), P = 0.005). Underweight for age, CF-related diabetes, female gender, worse lung function and cultures positive for Pseudomonas aeruginosa or Burkholderia cepacia complex, among multiple other patient characteristics, were associated with significantly increased mortality. Adjusted mortality rates for patients reporting tobramycin inhalation solution use in all versus none of the follow-up years were 1.3% versus 2.1% at 2 years, 5.2% versus 8.0% at 5 years, and 9.9% versus 15.0% at 10 years. CONCLUSION: After adjustment for multiple patient characteristics and known risk factors, use of tobramycin inhalation solution was associated with significantly reduced mortality among patients with CF. PMID- 21815284 TI - Efficacy of intratracheal instillation of a meropenem/perfluorochemical suspension in acute lung injury. AB - Perfluorochemical (PFC) is theoretically a good vehicle for delivering biological agents to the lungs. This study was designed to investigate the efficacy of intratracheal (IT) instillation of meropenem using PFC liquid as a vehicle in a piglet model of acute lung injury (ALI). Eighteen piglets were injured with lung lavages to induce ALI, and randomly assigned to intravenous (IV) infusion or IT instillation groups, the latter using either PFC or normal saline (NS) as a delivery vehicle for meropenem. Blood samples were obtained at 0, 15, 30, and 60 min, and then hourly for 6 hr. Sera and extracts of lung tissues were assayed for meropenem content using high-performance liquid chromatography. We found that the IV group had significantly higher serum concentrations of meropenem during the first hour after dosing (P < 0.05). There was no significant difference between IT-PFC and IT-NS groups regarding changes in serum meropenem concentrations during the experimental period. Meropenem content in lung tissue was highest in the IT-PFC group, lower in the IT-NS group, and undetectable in the IV group (P < 0.05). The IT-NS group had the highest peak inspiratory pressure (P < 0.05), but there were no significant differences in other cardiopulmonary parameters among the three groups studied. In conclusion, meropenem can be safely administered to injured lungs by IT instillation in a meropenem/PFC suspension. Using PFC liquid as an IT vehicle to carry meropenem provides better pulmonary drug depositions than IV injection or IT instillation with NS in ALI. PMID- 21815283 TI - Polysomnography in preterm infants and children with chronic lung disease. AB - OBJECTIVE: To determine the utility of overnight polysomnography (PSG) in assessing pulmonary reserve in stable preterm children with chronic lung disease (CLD). STUDY DESIGN: A retrospective review and descriptive study of overnight PSGs and clinic visits of preterm infants/children less than 3 years of age who were diagnosed with bronchopulmonary dysplasia at discharge from the hospital and enrolled in the Johns Hopkins CLD patient registry between 2008 and 2010. RESULTS: Sixty-two clinically stable patients underwent at least one overnight polysomnogram for clinical indications. The majority of patients were referred for oxygen titration (71%). PSGs from first studies revealed a mean respiratory disturbance index (RDI) of 8.2 +/- 10.1 events/hr and a mean O(2) saturation (SaO(2) ) nadir of 86.2 +/- 5.7%. In patients who underwent more than one PSG (n = 23), a significant decrease in RDI (P < 0.001) was found between the first study (mean age: 8.0 +/- 3.3 months) and second study (mean age: 13.4 +/- 5.2 months). Outpatient clinical measures of mean room air SaO(2) and respiratory rate were not predictive of PSG measures of RDI and SaO(2) nadir. CONCLUSION: Mean RDI was higher in stable preterm infants/children with CLD compared to previously published controls. RDI decreased with age in stable preterm infants/children with CLD suggesting improved pulmonary reserve with age. Outpatient clinical measures (respiratory rate and room air SaO(2) ) did not correlate with RDI and SaO(2) nadir indicating that overnight PSG is more sensitive in assessing pulmonary reserve than outpatient clinical measures. PMID- 21815285 TI - [Smartphones--how useful are medical Apps?]. PMID- 21815286 TI - Morphological study of the effects of the GnRH superagonist deslorelin on the canine testis and prostate gland. AB - The present study is part of a programme of research designed to evaluate the efficacy of the GnRH superagonist,deslorelin (D-Trp6-Pro9-des-Gly10-LHRH ethylamide), as a contraceptive for male dogs. Adult dogs were assigned to a completely randomized design comprising six groups of four animals. Each dog in the control group received a blank implant (placebo) and each dog in the other five groups received a 6 mg deslorelin implant. One group of deslorelin treated dogs was sacrificed on each of days 16, 26, 41, 101 and 620, and testicular and prostate tissues were collected for study by light and electron microscopy. On days 16 and 26 after implantation, we observed partial disruption of the seminiferous tubules, with early spermatids shed into the lumen. On days 41 and 101 after implantation, 90-100% of the seminiferous tubules were atrophic and aspermatogenic.On day 101 after implantation, 99% of all sections showed atrophy of the epithelium and shrinkage of epithelial height in the ductus epididymides. On days 41 and 101 after implantation, prostate tissue showed complete atrophy of the glandular epithelium (100% of sections) and an apparent increase in the relative proportion of connective tissue. At the electron microscopic level, in dogs treated with deslorelin for 41 and 101 days, the Sertoli cells were smaller and their nucleoli appeared smaller than in the control dogs. The nucleoli of the Leydig cells were atrophied and prostate glandular epithelium showed reduced epithelial height, a trophy of the nucleolus and an absence of secretory granules.Tissues collected during the recovery phase revealed a complete recovery of spermatogenesis. In conclusion, slow release implants containing deslorelin induce a striking a trophy of the testes and prostate gland by 26 days after implantation, explaining the previously reported loss of ejaculate and arrest of sperm output. At histological level,the entire process appears to be completely reversible, in accordance with data on endocrine variables and semen production. PMID- 21815287 TI - Offspring from heterotopic transplantation of newborn mice ovaries. AB - This study is aimed at investigating the developmental potential of the primordial follicles from ovaries of newborn mice after cryopreservation in liquid nitrogen for long-term storage, thawing, and heterografting into the kidney capsules of ovariectomized adult female mice. After stimulation of recipient mice with pregnant mare serum gonadotropin on day-19 after heterografting, the primordial follicles of the transplanted ovaries could develop into antral follicles. When the oocyte-cumulus cell complexes were retrieved from these antral follicles, they could mature after in vitro culture for 16-17 h. After in vitro fertilization, the rates of embryos derived from these oocytes that developed into the two-cell stage and the blastocyst stage after 16-17 h and after day-4, respectively,in the culture medium were 55.40% (55/107) and 9.09% (5/55),respectively. In the ovarian transplantation groups, no pups were derived from the 410 embryos that were transferred into 10 pseudopregnant mothers at the pronuclear stage. However,of the 10 surrogate mothers in whom 570 embryos were transferred at the two-cell stage, four achieved pregnancy and gave birth to 20 live offspring. These results demonstrated that primordial follicles in newborn mice ovaries were capable of sustaining their developmental potential after freezing and thawing. Once transplanted into the kidney capsules of ovariectomized adult female mice, these primordial follicles could develop and respond to gonadotropin stimulation and reach the antral stage; further, live offspring could be derived from these follicles. PMID- 21815288 TI - FDA Advisory Committee reviews safety of boceprevir. PMID- 21815289 TI - The heterogeneity in clinical presentation among individuals on the autism spectrum is a remarkably puzzling facet of this set of disorders. PMID- 21815290 TI - Peritonitis and catheter guidelines--a 2010 update. PMID- 21815291 TI - Nurses must define nursing. PMID- 21815292 TI - Thanks for the memories. PMID- 21815293 TI - White-spot lesions. PMID- 21815294 TI - Experimental studies on the intrinsic fibers of the cerebellum II. The cortico nuclear projection. 1940. PMID- 21815295 TI - Normal CSF ferritin levels in MS suggest against etiologic role of chronic venous insufficiency. PMID- 21815296 TI - Abstracts from the American Heart Association scientific sessions 2010. PMID- 21815297 TI - Correction: milnacipran for treatment of fibromyalgia. PMID- 21815298 TI - Cardiovascular medicine and the Israel Heart Society. AB - A review of cardiology in Israel by Prof. Gad Keren. PMID- 21815299 TI - Rediscovering the third coronary artery. AB - A second right coronary artery is not at all unusual, as described here from Oxford, England. PMID- 21815300 TI - Cardiac centres of excellence. 'Royal Brompton': the specialist centre in London that specialist centres consult. AB - It may be diagnosing Thalassaemia with magnetic resonance, navigating catheters round tight corners with magnets, or treating Marfan's syndrome with the Brompton Sheath--but if it is state of the art and it works, the Royal Brompton & Harefield NHS Foundation Trust, London, will almost certainly have pioneered it, reports Barry Shurlock MA, PhD. PMID- 21815301 TI - Vaccines: a model for prevention. PMID- 21815304 TI - [Plan of action for promoting vaccination. Nurses sought]. PMID- 21815302 TI - Highlights of historical events leading to national surveillance of vaccination coverage in the United States. PMID- 21815303 TI - Vaccination coverage among U.S. adolescents aged 13-17 years eligible for the Vaccines for Children program, 2009. AB - OBJECTIVES: We compared (1) characteristics of adolescents who are and are not entitled to receive free vaccines from the Vaccines for Children (VFC) program and (2) vaccination coverage with meningococcal conjugate (MCV4), quadrivalent human papillomavirus (HPV4), and tetanus-diphtheria-acellular pertussis (Tdap) vaccines among VFC-eligible and non-VFC-eligible adolescents. METHODS: We analyzed data from the 2009 National Immunization Survey-Teen, a nationally representative, random-digit-dialed survey of households with adolescents aged 13 17 years (n = 20,066). Differences in sociodemographic characteristics and provider-reported vaccination coverage were evaluated using t-tests. RESULTS: Overall, 32.1% (+/- 1.2%) of adolescents were VFC-eligible. VFC-eligible adolescents were significantly less likely than non-VFC-eligible adolescents to be white and to live in suburban areas, and more likely to live in poverty and to have younger and less educated mothers. Nationally, coverage among non-VFC eligible adolescents was 57.1% (+/-1.5%) for > or = 1 dose of Tdap, 55.4% (+/ 1.5%) for > or = 1 dose of MCV4, and 43.2% (+/- 2.2%) for > or = 1 dose of HPV4. Coverage among VFC-eligible adolescents was 52.5% (+/- 2.4%) for > or = 1 dose of Tdap, 50.1% (+/- 2.4%) for > or = 1 dose of MCV4, and 46.6% (+/- 3.5%) for > or =1 dose of HPV4. Only 27.5% (+/- 1.8%) of non-VFC-eligible adolescents and 25.0% (+/- 2.9%) of VFC-eligible adolescents received > or = 3 doses of HPV4. Vaccination coverage was significantly higher among non-VFC-eligible adolescents for Tdap and MCV4, but not for one-dose or three-dose HPV4. Conclusions. Coverage with some recommended vaccines is lower among VFC-eligible adolescents compared with non-VFC-eligible adolescents. Continued monitoring of adolescent vaccination rates, particularly among VFC-eligible populations, is needed to ensure that all adolescents receive all routinely recommended vaccines. PMID- 21815305 TI - Normal CSF ferritin levels in MS suggest against etiologic role of chronic venous insufficiency. PMID- 21815306 TI - [Studies of T cells for better understanding of immunity and allergy]. PMID- 21815308 TI - Celebrating all food. PMID- 21815310 TI - Medicare program; hospice wage index for fiscal year 2012. Final rule. AB - This final rule will set forth the hospice wage index for fiscal year (FY) 2012 and continue the phase-out of the wage index budget neutrality adjustment factor (BNAF), with an additional 15 percent BNAF reduction, for a total BNAF reduction in FY 2012 of 40 percent. The BNAF phase-out will continue with successive 15 percent reductions from FY 2013 through FY 2016. This final rule will change the hospice aggregate cap calculation methodology. This final rule will also revise the hospice requirement for a face-to-face encounter for recertification of a patient's terminal illness. Finally, this final rule will begin implementation of a hospice quality reporting program. PMID- 21815311 TI - Low vision assistive technology device usage and importance in daily occupations. AB - When selected, accepted and used appropriately, low vision assistive technology devices (ATDs) have the potential to facilitate the performance of occupations that lead to positive outcomes. OBJECTIVE: This paper identifies some low vision ATDs currently used and explores their relative importance for the performance of daily occupation from participants' perspectives. PARTICIPANTS: 17 adults (M=56 years old, SD=15.8) with low vision we0re recruited through a purposeful sampling strategy. METHODS: Through one-on-one semi-structured telephone interviews, ATD usage data, ranking of perceived importance of ATDs and verbal data were collected from the participants. RESULTS: A total of 124 devices were identified by the participants of which 104 (83.9%) were used and 20 (16.1%), mostly adaptive computer technologies, were not. 22 (21%) mainstream aids to daily living were identified (large monitor, large screen TV, DVD player) and they ranked high in terms of perceived importance by the participants for daily activities. Verbal feedback from participants supplemented this finding. CONCLUSION: Concepts related to usage and ranking of importance of ATDs for daily occupations are multi-faceted and complex(e.g. combination of devices used, multiple equal rankings, etc.). The authors suggested future research opportunities to examine these concepts through qualitative means. PMID- 21815309 TI - Promoting optimal monitoring of child growth in Canada: using the new WHO growth charts. PMID- 21815312 TI - Shoulder injury reduction with post-offer testing. AB - OBJECTIVE: This study is an interventional evaluation of a post-offer employment testing. The study is designed to determine if shoulder injury rates are lowered when employees are placed at jobs they demonstrate the physical ability to perform. METHODS: A physical capacity evaluation based testing protocol was utilized to determine if each new employee had the physical work capacity to perform the job for which they were hired. Injuries to the shoulder were specifically scrutinized. The interventional group was compared to a historical control. RESULTS: The incidence of shoulder injuries was 0% in the tested group and 3.8% in the untested historical control. Over a 6 year study timeframe the utilization of physical capacity testing for work placement appeared to be the major factor in decreasing work related shoulder injuries. The annual cost of administering the tests for three years was $9,543, while the net annual cost savings was $124,451. This represented a 37% decrease in medical costs for shoulder and other work-related injuries. For every dollar spent on testing there was a $14 savings in medical costs secondary to injury prevention. CONCLUSION: The use of post-offer physical capacity testing resulted in a substantial and noticeable decrease in shoulder related non-accidental injuries. Furthermore, it is evident that a properly conceived and implemented post-offer testing program may help in the reduction of work-related injuries. PMID- 21815313 TI - Peduncular hallucinosis. PMID- 21815314 TI - Single-session psychoeducation in schizophrenia: a feasibility and effectiveness study in an Indian patient population. PMID- 21815315 TI - Dental implants for the geriatric patient. PMID- 21815316 TI - Food pyramid replaced by plate. PMID- 21815317 TI - Antimicrobial stewardship. PMID- 21815318 TI - The downside: weathering a difficult economy. PMID- 21815319 TI - Putting the scope issue into perspective. PMID- 21815320 TI - 'Non sibised omnibus'. PMID- 21815321 TI - Question: does isosorbide dinitrate/hydralazine therapy benefit systolic heart failure patients with renal insufficiency? PMID- 21815322 TI - How to read financial statements--Part 2: application. PMID- 21815323 TI - Benzodiazepine withdrawal seizures and management. AB - Since the first report of benzodiazepine withdrawal seizure in 1961, many case reports have followed. Withdrawal seizures have occurred with short, medium, and long halflife benzodiazepine, if discontinued abruptly. Withdrawal seizures usually occur in patients who have been taking these medications for long periods of time and at high doses. Seizures have also been reported with less than 15 days of use and at therapeutic dosage. Almost all the withdrawal seizures reported were grand mal seizures. The severity of seizures range from a single episode to coma and death. Benzodiazepine dose tapering can be done faster in a hospital setting in high-dose abusers, but must be done more slowly in the outpatient setting in therapeutic dosage users. PMID- 21815324 TI - A look back may help Oklahoman's look forward. PMID- 21815325 TI - Senate Bill 5: bad for nurses, bad for patients. PMID- 21815326 TI - Social media: implications for nursing nursing practice statement NP 85. PMID- 21815327 TI - What women need to know about retirement. PMID- 21815328 TI - Whistleblower protection. PMID- 21815329 TI - The nursing list. Registered nurses and collective bargaining. PMID- 21815330 TI - [Less antibiotics should be given in otitis. Active expectancy for 1-12 years old -antibiotics for teenagers and adults]. PMID- 21815331 TI - [Otitis media--from self-healing to life-threatening. New therapeutic guidelines]. PMID- 21815332 TI - [Good results in robot-assisted radical prostatectomy. Prostatic cancer can be treated more effectively and carefully]. PMID- 21815333 TI - [Clinical experience and science: balancing uncertainty]. PMID- 21815334 TI - [Swedish clinical research can be better]. PMID- 21815335 TI - [Smoke screens on adverse effect of Pandemrix]. PMID- 21815336 TI - [Long-term treatment with antipsychotics: new research strengthens the information about the risk of brain atrophy]. PMID- 21815337 TI - [The Medical Products Agency on vitamin D deficiency: food habits surveys can give basis for new recommendations]. PMID- 21815338 TI - [Not only the language requires translation]. PMID- 21815339 TI - [Paradigmatic shift in oncology: individualized melanoma treatment]. PMID- 21815340 TI - [The Drug Registry--good resource for quality assurance in health care]. PMID- 21815341 TI - [A simple way to register postoperative infections. The Drug Registry should be open for professional quality assurance work]. PMID- 21815342 TI - [Percutaneous coronary interventions. Modern techniques improve quality of life]. PMID- 21815343 TI - [Coronary disease is investigated and treated with advantage via catheter]. PMID- 21815344 TI - [Transcatheter aortic valve implantation a new alternative to surgery]. PMID- 21815345 TI - [Mitral valve disease:"Now we can both open and close"]. PMID- 21815346 TI - [Patent foramen ovale: a harmless fetal remnant that can be a threat in adulthood]. PMID- 21815347 TI - [Catheter ablation of atrial fibrillation good when medication doesn't help]. PMID- 21815348 TI - [How should primary health care meet the governmental proposal on the care of substance abuse?]. PMID- 21815349 TI - [The most seriously ill children have the right to emergency hospital services with child psychiatric competence]. PMID- 21815350 TI - The ties that bind: Consistent assignment gives residents a sense of security, family. PMID- 21815351 TI - Focus on: urinary incontinence: Reducing risk and improving quality of care can be done simultaneously as providers face renewed scrutiny. PMID- 21815352 TI - Remembering when: Facilitators can use resident memories to spur social interaction and aid in the treatment of dementia-related disease. PMID- 21815353 TI - Worth a thousand words. PMID- 21815354 TI - Top 50: Largest nursing facility companies. PMID- 21815355 TI - Top 40: Largest assisted living companies. PMID- 21815356 TI - Patient safety and the medical physicist. PMID- 21815357 TI - Point/counterpoint. The adoption of new technology in radiation oncology should rely on evidence-based medicine. PMID- 21815358 TI - Estimation of CT cone-beam geometry using a novel method insensitive to phantom fabrication inaccuracy: implications for isocenter localization accuracy. AB - PURPOSE: Mechanical instabilities that occur during gantry rotation of on-board cone-beam computed tomography (CBCT) imaging systems limit the efficacy of image guided radiotherapy. Various methods for calibrating the CBCT geometry and correcting errors have been proposed, including some that utilize dedicated fiducial phantoms. The purpose of this work was to investigate the role of phantom fabrication imprecision on the accuracy of a particular CT cone-beam geometry estimate and to test a new method to mitigate errors in beam geometry arising from imperfectly fabricated phantoms. METHODS: The authors implemented a fiducial phantom-based beam geometry estimation following the one described by Cho et al. [Med Phys 32(4), 968-983 (2005)]. The algorithm utilizes as input projection images of the phantom at various gantry angles and provides a full nine parameter beam geometry characterization of the source and detector position and detector orientation versus gantry angle. A method was developed for recalculating the beam geometry in a coordinate system with origin at the source trajectory center and aligned with the axis of gantry rotation, thus making the beam geometry estimation independent of the placement of the phantom. A second CBCT scan with the phantom rotated 180 degrees about its long axis was averaged with the first scan to mitigate errors from phantom imprecision. Computer simulations were performed to assess the effect of 2D fiducial marker positional error on the projections due to image discretization, as well as 3D fiducial marker position error due to phantom fabrication imprecision. Experimental CBCT images of a fiducial phantom were obtained and the algorithm used to measure beam geometry for a Varian Trilogy with an on-board CBCT. RESULTS: Both simulations and experimental results reveal large sinusoidal oscillations in the calculated beam geometry parameters with gantry angle due to displacement of the phantom from CBCT isocenter and misalignment with the gantry axis, which are eliminated by recalculating the beam geometry in the source coordinate system. Simulations and experiments also reveal an additional source of oscillations arising from fiducial marker position error due to phantom fabrication imprecision that are mitigated by averaging the results with those of a second CBCT scan with phantom rotated. With a typical fiducial marker position error of 0.020 mm (0.001 in.), source and detector position are found in simulations to be within 250 microm of the true values, and detector and gantry angles less than 0.2 degrees. Detector offsets are within 100 microm of the known value. Experimental results verify the efficacy of the second scan in mitigating beam geometry errors, as well as large apparent source/detector isocenter offsets arising from phantom fabrication imprecision. CONCLUSIONS: The authors have developed and validated a novel fiducial phantom-based CBCT beam geometry estimation algorithm that does not require precise positioning of the phantom at machine isocenter and is insensitive to positional imprecision of fiducial markers within the phantom due to fabrication errors. The method can accurately locate source and detector isocenters even when using an imprecise phantom, which is very important for measurement of isocenter coincidence of the therapy and on-board imaging systems. PMID- 21815359 TI - A slit method to determine the focal spot size and shape of TomoTherapy system. AB - PURPOSE: To obtain accurate x-ray source profile measurements using a slit collimator, the slit-collimator should have a narrow width, large height, and be positioned near the source. However, these conditions may not always be met. In this paper, the authors provide a detailed analysis of the slit measurement geometry and the relationship between the slit parameters and the measured x-ray source profile. The slit model allows the use of a shorter and more easily available slit-collimator, while accurate source profile measurements can still be obtained. METHODS: Measurements were performed with a variety of slit widths and/or slit to source distances. The relationship derived between the slit parameters and the measured profile was used to determine the true focal spot profile through a least square fit of the profile data. The model was verified by comparing the predicted profiles at a variety of slit-collimator parameters with the measured results on the TomoTherapy Hi-Art system. RESULTS: Both the treatment beam and the imaging beam were measured. For treatment mode, it was found that a source consisting of one Gaussian with a 0.75 mm full-width-half maximum (FWHM) and 72% peak amplitude and a second Gaussian with a 2.27 mm FWHM and 18% peak amplitude matched measurement profiles. The overall source profile has a FWHM of 0.93 mm, but with a higher amplitude in the tail region than a single Gaussian. For imaging mode, the source consists of one Gaussian with a 0.68 mm FWHM and 82% peak amplitude and a second Gaussian with a 1.83 mm FWHM and 18% peak amplitude. The overall source profile has a FWHM of 0.77 mm. CONCLUSIONS: Our study of the focal spot measurement using slit-collimators showed that accurate source profile measurements can be achieved through fitting of measurement results at different slit widths and source-to-slit distances (SSD). Quantitative measurements of the TomoTherapy linac focal spot showed that the source distribution could be better described with a model consisting of two Gaussian components rather than a single Gaussian model as assumed in previous studies. PMID- 21815360 TI - Optimized low-kV spectrum of dual-energy CT equipped with high-kV tin filtration for electron density measurements. AB - PURPOSE: This paper describes the low-kV spectral optimization of dual-energy CT (DECT) equipped with high-kV tin filtration for the quantitative acquisition of electron density information, which is essential for treatment planning in radiotherapy. In addition, an analytical DECT image simulation was preliminarily performed to demonstrate the effectiveness of the optimized DECT with respect to the beam-hardening reduction. METHODS: To optimize the low-kV spectrum of DECT, the author calculated the beam-hardening error, CT dose index, and tube loadings for a 50-cm diameter cylindrical water phantom with various combinations of filter materials, a range of thicknesses, and low-kV tube potentials. In addition, a single tube potential of 140 kV filtered by 0.4 mm tin (Sn) was employed for high-kV scanning, as is similar to the commercial implementation of the second-generation dual-source CT scanner. The optimized spectral parameters were then applied to the analytical DECT image simulation using two-dimensional fan-beam geometry for a virtual solid water phantom with 16 bodylike tissue inserts. RESULTS: The author predicts that an optimal low-kV filtration would be 0.144-mm tungsten (W) at 90 kV, as it yields a minimal beam-hardening error with lower tube loadings and dose. The high-kV tube loading and dose obtained using the W filtration were 99 mAs and 2.2 mGy, respectively. These values are nearly equal to those obtained in the case of 2.5 mm Al at 100 kV (100 mAs and 2.3 mGy), which was regarded in this study as a reference filtration; however, the W filtration significantly reduced the beam-hardening error, from 9.5 to 1.4%. The corresponding low-kV tube loading (112 mAs) was five times greater than that of the reference case (21 mAs), but it was maintained at a certain practical level since the low-kV tube loading was comparable to the high-kV tube loading of the reference (100 mAs). The superiority of the beam-hardening reduction is reflected in the simulated images; for example, by the use of the W filter, the beam hardening-induced deviation between the simulated and theoretical electron density values of cortical bone was reduced from 7.4 to 1.2% as compared with the reference filtration, even though no correction for beam hardening was performed. CONCLUSIONS: In terms of beam hardening reduction, the DECT with the low-kV W filtration is more effective for the quantitative measurement of electron density within a practical limit of tube loadings and without additional dose. PMID- 21815361 TI - Use of machine learning methods for prediction of acute toxicity in organs at risk following prostate radiotherapy. AB - PURPOSE: The goal of this study is to investigate the advantages of large scale optimization methods vs conventional classification techniques in predicting acute toxicity for urinary bladder and rectum due to prostate irradiation. METHODS: Clinical and dosimetric data of 321 patients undergoing prostate conformal radiotherapy were recorded. Gastro-intestinal and genito-urinary acute toxicities were scored according to the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer (RTOG/EORTC) scale. Patients were classified in two categories to separate mild (Grade < 2) from severe toxicity levels (Grade > 2). Machine learning methods at different complexity were implemented to predict toxicity as a function of multiple variables. The first approach consisted of a large scale optimization method, based on genetic algorithms (GAs) and artificial neural networks (ANN). The second approach was a binary classifier based on support vector machines (SVM). RESULTS: The ANN and SVM-based solutions showed comparable prediction accuracy, exhibiting an area under the receiver operating characteristic (ROC) curve of 0.7. Different sensitivity and specificity features were measured for the two approaches. The ANN algorithm showed enhanced sensitivity if combined with appropriate classification criteria. CONCLUSIONS: The results demonstrate that high sensitivity in toxicity prediction can be achieved with optimized ANNs, that are put forward to represent a valuable support in medical decisions. Future studies will be focused on enlarging the available patient database to increase the reliability of toxicity prediction algorithms and to define optimal classification criteria. PMID- 21815362 TI - New approaches to region of interest computed tomography. AB - PURPOSE: In classical x-ray CT, the diameter of the field of measurement (FOM) must not fall below the transversal diameter of the patient or specimen. Thereby, the ratio of the diameter of FOM and the number of transversal detector elements typically defines the spatial resolution. The authors aim at improving the spatial resolution within a region of interest (ROI) by a factor of 10-100 while maintaining artifact-free CT image reconstruction inside and outside the ROI. Two novel methods are proposed for artifact-free reconstruction of the truncated ROI scan (data weighting method and data filtering method) and compared with the gold standard (data completion method) for this problem. METHODS: First, an overview scan with low spatial resolution and a large FOM that exceeds the object transversally is performed. Second, a high-resolution scan is performed, where the scanner's magnification is changed such that the FOM matches the ROI at the cost of laterally truncated projection data. The gold standard is forward projecting the low-resolution scan on the rays missing in the high-resolution scan. The authors propose the data filtering method, which uses the low resolution reconstruction and calculates a high frequency correction term from the high-resolution scan, and the data weighting method, which reconstructs the truncated high-resolution data and calculates a detruncation image from the low resolution data. RESULTS: The methods are compared using a simulation of the Forbild head phantom and a measurement of a spinal disk implant. The results of the data weighting method and the data completion method show the same image quality. The data filtering method yields slightly inferior image quality that may still be sufficient for many applications. Both new methods considerably outperform the data completion method regarding the computational load. CONCLUSIONS: The new ROI reconstruction methods are superior to the gold standard regarding the computational load. Comparing the image quality with the gold standard, the data filtering method is slightly inferior and the data weighting method yields equal quality. PMID- 21815363 TI - A multiscale and multiblock fuzzy C-means classification method for brain MR images. AB - PURPOSE: Classification of magnetic resonance (MR) images has many clinical and research applications. Because of multiple factors such as noise, intensity inhomogeneity, and partial volume effects, MR image classification can be challenging. Noise in MRI can cause the classified regions to become disconnected. Partial volume effects make the assignment of a single class to one region difficult. Because of intensity inhomogeneity, the intensity of the same tissue can vary with respect to the location of the tissue within the same image. The conventional "hard" classification method restricts each pixel exclusively to one class and often results in crisp results. Fuzzy C-mean (FCM) classification or "soft" segmentation has been extensively applied to MR images, in which pixels are partially classified into multiple classes using varying memberships to the classes. Standard FCM, however, is sensitive to noise and cannot effectively compensate for intensity inhomogeneities. This paper presents a method to obtain accurate MR brain classification using a modified multiscale and multiblock FCM. METHODS: An automatic, multiscale and multiblock fuzzy C-means (MsbFCM) classification method with MR intensity correction is presented in this paper. We use a bilateral filter to process MR images and to build a multiscale image series by increasing the standard deviation of spatial function and by reducing the standard deviation of range function. At each scale, we separate the image into multiple blocks and for every block a multiscale fuzzy C-means classification method is applied along the scales from the coarse to fine levels in order to overcome the effect of intensity inhomogeneity. The result from a coarse scale supervises the classification in the next fine scale. The classification method is tested with noisy MR images with intensity inhomogeneity. RESULTS: Our method was compared with the conventional FCM, a modified FCM (MFCM) and multiscale FCM (MsFCM) method. Validation studies were performed on synthesized images with various contrasts, on the simulated brain MR database, and on real MR images. Our MsbFCM method consistently performed better than the conventional FCM, MFCM, and MsFCM methods. The MsbFCM method achieved an overlap ratio of 91% or higher. Experimental results using real MR images demonstrate the effectiveness of the proposed method. Our MsbFCM classification method is accurate and robust for various MR images. CONCLUSIONS: As our classification method did not assume a Gaussian distribution of tissue intensity, it could be used on other image data for tissue classification and quantification. The automatic classification method can provide a useful quantification tool in neuroimaging and other applications. PMID- 21815365 TI - Lateral dose profile characterization in scanning particle therapy. AB - PURPOSE: In light-ion beam dose delivery with the scanning technique the spacing between adjacent spots is an important parameter during treatment planning. In order to study the effect of spot spacing on dose conformity and robustness for single field uniform dose configurations, fundamental geometrical properties of placement of Gaussian beamlets are explored. In particular, the dependence of penumbra width and flatness on spot width and spot spacing is investigated. METHODS: Infinitesimal calculus and analytical methods are used to derive simple expressions for the lateral penumbra and the flatness of one-dimensional dose profiles in continuous scanning and uniform discrete spot scanning. In the same way expressions for the fundamental modes of perturbation of the spot sequence are developed. A numerical, matrix-based approach is followed to optimize weights spot-by-spot. RESULTS: Generally the lateral penumbra widths lie between 1.13 sigma(b) and 1.68 sigma(b) with sigma(b) being the standard deviation of the beam spot profile. For regularly placed spots of equal weight with spot spacing lambda the lateral penumbra is given by 1.68 sigma' where sigma' results from quadratic subtraction of lambda/square root of 12 from sigma(b). The quantization error is identified as additional parameter describing the lateral dose conformity. It's variance is given by lambda2/12 for a bunch of spots with uniform weights. The matrix-based optimization of weights for a one-dimensional dose box results in a lateral penumbra of typically 1.4 sigma(b). This value reduces to about 1.3 sigma(b) if also the positions of the beam spots are optimized for the considered field size. The analytical formulas for uniform discrete scanning can be used as rough approximations of the best-case scenarios for weight-optimized dose profiles if the spot spacing is defined as effective spot spacing. CONCLUSIONS: The trade-off between flatness, quantization error, and robustness on the one side and penumbra width on the other side can be described analytically for equally weighted spots. Treatment planning systems often perform a least-squares optimization of the individual spot weights which results in smaller lateral penumbras and smaller quantization errors than for uniform discrete scanning. However, the benefit of this weight optimization decreases with increasing lambda (in the regime lambda > sigma(b)). The spot spacing, which is obtained from the scenario that the optimization objective is met by uniform discrete scanning, poses a sharp upper limit for the spot spacing lambda in weight optimization methods. PMID- 21815364 TI - A model of cellular dosimetry for macroscopic tumors in radiopharmaceutical therapy. AB - PURPOSE: In the radiopharmaceutical therapy approach to the fight against cancer, in particular when it comes to translating laboratory results to the clinical setting, modeling has served as an invaluable tool for guidance and for understanding the processes operating at the cellular level and how these relate to macroscopic observables. Tumor control probability (TCP) is the dosimetric end point quantity of choice which relates to experimental and clinical data: it requires knowledge of individual cellular absorbed doses since it depends on the assessment of the treatment's ability to kill each and every cell. Macroscopic tumors, seen in both clinical and experimental studies, contain too many cells to be modeled individually in Monte Carlo simulation; yet, in particular for low ratios of decays to cells, a cell-based model that does not smooth away statistical considerations associated with low activity is a necessity. The authors present here an adaptation of the simple sphere-based model from which cellular level dosimetry for macroscopic tumors and their end point quantities, such as TCP, may be extrapolated more reliably. METHODS: Ten homogenous spheres representing tumors of different sizes were constructed in GEANT4. The radionuclide 131I was randomly allowed to decay for each model size and for seven different ratios of number of decays to number of cells, N(r): 1000, 500, 200, 100, 50, 20, and 10 decays per cell. The deposited energy was collected in radial bins and divided by the bin mass to obtain the average bin absorbed dose. To simulate a cellular model, the number of cells present in each bin was calculated and an absorbed dose attributed to each cell equal to the bin average absorbed dose with a randomly determined adjustment based on a Gaussian probability distribution with a width equal to the statistical uncertainty consistent with the ratio of decays to cells, i.e., equal to Nr-1/2. From dose volume histograms the surviving fraction of cells, equivalent uniform dose (EUD), and TCP for the different scenarios were calculated. Comparably sized spherical models containing individual spherical cells (15 microm diameter) in hexagonal lattices were constructed, and Monte Carlo simulations were executed for all the same previous scenarios. The dosimetric quantities were calculated and compared to the adjusted simple sphere model results. The model was then applied to the Bortezomib-induced enzyme-targeted radiotherapy (BETR) strategy of targeting Epstein-Barr virus (EBV)-expressing cancers. RESULTS: The TCP values were comparable to within 2% between the adjusted simple sphere and full cellular models. Additionally, models were generated for a nonuniform distribution of activity, and results were compared between the adjusted spherical and cellular models with similar comparability. The TCP values from the experimental macroscopic tumor results were consistent with the experimental observations for BETR-treated 1 g EBV expressing lymphoma tumors in mice. CONCLUSIONS: The adjusted spherical model presented here provides more accurate TCP values than simple spheres, on par with full cellular Monte Carlo simulations while maintaining the simplicity of the simple sphere model. This model provides a basis for complementing and understanding laboratory and clinical results pertaining to radiopharmaceutical therapy. PMID- 21815366 TI - Report of AAPM TG 135: quality assurance for robotic radiosurgery. AB - The task group (TG) for quality assurance for robotic radiosurgery was formed by the American Association of Physicists in Medicine's Science Council under the direction of the Radiation Therapy Committee and the Quality Assurance (QA) Subcommittee. The task group (TG-135) had three main charges: (1) To make recommendations on a code of practice for Robotic Radiosurgery QA; (2) To make recommendations on quality assurance and dosimetric verification techniques, especially in regard to real-time respiratory motion tracking software; (3) To make recommendations on issues which require further research and development. This report provides a general functional overview of the only clinically implemented robotic radiosurgery device, the CyberKnife. This report includes sections on device components and their individual component QA recommendations, followed by a section on the QA requirements for integrated systems. Examples of checklists for daily, monthly, annual, and upgrade QA are given as guidance for medical physicists. Areas in which QA procedures are still under development are discussed. PMID- 21815367 TI - Coupling surface cameras with on-board fluoroscopy: a feasibility study. AB - PURPOSE: To investigate the feasibility of using three-dimensional surface imaging cameras as an external surrogate of tumor motion through a temporal synchronization with kV imaging. METHODS: To obtain an "x-ray on" signal from the on-board kV fluoroscopy system (XVI, Elekta), a hardware controller (Gate Controller) was interfaced between the kV fluoroscopy and Gate CT (VisionRT Ltd., London) computers. First, phantom experiments were performed using a programmable respiratory motion platform (sinusoidal motion, period = 3-5 s). The platform included a chest-wall component (A-P amplitude = 1 cm) tracked with the surface camera, while tumorlike objects translated in the superior-inferior direction were tracked using kV fluoroscopy (300 frames, frequency 5.5 fps). Accuracy of tracking the chest-wall platform was assessed, and the latency of the system was characterized by performing linear regression between the peak times obtained from Gate CT and fluoroscopy. Increasing the complexity of experiments, tumor displacement curves from three patients were simulated using synchronous tumor abdomen data (RTRT). Our approach was further validated by imaging four free breathing lung cancer patients with simultaneous Gate CT and kV fluoroscopy for approximately 55 s. Consideration was also given to varied sizes and locations of the tracked region of interest on the patient surface. RESULTS: For simple sinusoidal curves, measured amplitude (peak-to-peak) was 1.005 +/- 0.003 cm, 1.013 +/- 0.003 cm, and 1.003 +/- 0.005 cm for periods of 5, 4, and 3.3 s, respectively, demonstrating an excellent agreement with the actual chest platform amplitude of 1.0 cm. Period measurements were within 0.2% of actual using the surface cameras and within 0.9% of actual value using fluoroscopy. For the sinusoidal motion, the system latency was 0.64 +/- 0.02 s. This was further validated for the simulated tumor motion from three patients (latency = 0.65 +/- 0.03 s). Five of the nine patient fractions studied showed the associations between the abdomen and tumor were equivalent or better (Pearson r = 0.93-0.98) than those observed between the diaphragm and tumor (Pearson r = 0.89-0.95). A repeat analysis of five different tracked surfaces on the same patient further demonstrated strong agreement with the diaphragm and tumor, although no improvement in association strength was observed with increased size of region of interest. CONCLUSIONS: The feasibility of using surface imaging cameras to track the patient's abdomen as an external surrogate, while using kV imaging to track internal anatomy in synchrony, has been demonstrated. With further validation through additional patient studies to confirm these findings, gated radiation therapy treatments using surface imaging cameras as the external surrogate can be facilitated. PMID- 21815368 TI - Effects of MR surface coils on PET quantification. AB - PURPOSE: The goal of this work was to investigate the effects of MRI surface coils on attenuation-corrected PET emission data. The authors studied the cases where either an MRI or a CT scan would be used to provide PET attenuation correction (AC). Combined MR/PET scanners that use the MRI for PET AC (MR-AC) face the challenge of absent surface coils in MR images and thus cannot directly account for attenuation in the coils. Combining MR and PET images could be achieved by transporting the subject on a stereotactically registered table between independent MRI and PET scanners. In this case, conventional PET CT-AC methods could be used. A challenge here is that high atomic number materials within MR coils cause artifacts in CT images and CT based AC is typically not validated for coil materials. METHODS: The authors evaluated PET artifacts when MR coils were absent from AC data (MR-AC), or when coil attenuation was measured by CT scanning (CT-AC). They scanned PET phantoms with MR surface coils on a clinical PET/CT system and used CT-AC to reconstruct PET data. The authors then omitted the coil from the CT-AC image to mimic the MR-AC scenario. Images were acquired using cylinder and anthropomorphic phantoms. They evaluated and compared the following five scenarios: (1) A uniform cylinder phantom and head coil scanned and reconstructed using CT-AC; (2) similar emission data (with head coil present) were reconstructed without the head coil in the AC data; (3) the same cylinder scanned without the head coil present (reference scan); (4) a PET torso phantom with a full MR torso coil present in both PET and CT; (5) only half of the separable torso coil present in the PET/CT acquisition. The authors also performed analytic simulations of the first three scenarios. RESULTS: Streak artifacts were present in CT images containing MR surface coils due to metal components. These artifacts persisted after the CT images were converted for PET AC. The artifacts were significantly reduced when half of the separable coil was removed during the scan. CT scans tended to over-estimate the linear attenuation coefficient (micro) of the metal components when using conventional methods for converting from CT number to micro(511 keV). Artifacts were visible outside the phantom in some of the PET emission images, corresponding to the MRI coil geometry. However, only subtle artifacts were apparent in the emission images inside the phantoms. On the other hand, the PET emission image quantitative accuracy was significantly affected: the activity was underestimated by 19% when AC did not include the head coil, and overestimated by 28% when the CT-AC included the head coil. CONCLUSIONS: The presence of MR coils during PET or PET/CT scanning can cause subtle artifacts and potentially important quantification errors. Alternative CT techniques that mitigate artifacts should be used to improve AC accuracy. When possible, removing segments of an MR coil prior to the PET/CT exam is recommended. Further, MR coils could be redesigned to reduce artifacts by rearranging placement of the most attenuating materials. PMID- 21815369 TI - Accuracy assessment of the superposition principle for evaluating dose distributions of elongated and curved 103Pd and 192Ir brachytherapy sources. AB - PURPOSE: The current brachytherapy dose calculation formalism determines clinical dose distributions using the superposition principle. However, this approach cannot account for intersource attenuation for extended brachytherapy sources such as elongated and curved sources. The purpose of this study is to determine the line segment length required for optimal accuracy of dose calculations in the vicinity of elongated and curved 103Pd and 192Ir sources using the superposition technique intrinsic to the AAPM TG-43 formalism. METHODS: Monte Carlo (MC) simulations were performed in water for 103Pd and 192Ir sources with linear, toroidal, and hairpin geometries. Dose distributions for 0.1-8.0 cm line segments from MC simulations were entered into treatment planning system (TPS) using the TG-43 approach with 0.05 cm spatial resolution. Line source dose distributions were benchmarked using MC-to-MC comparisons with the superposition principle, TPS to-TPS fluence map comparisons, and MC-to-TPS gamma-index comparisons. Toroidal and hairpin geometries were constructed using line segments in the TPS, then TPS calculated dose distributions were compared to the MC-simulation results. Gamma index comparisons were performed in the iba(Dosimetry) Omni-Pro I'mRT software using 2 mm distance-to-agreement Ad and 2% dose error deltaD criteria, with a passing rate of > or = 98% of pixels meeting the gamma < or = 1.00 tolerance deemed acceptable. RESULTS: For the MC-to-MC superposition check for line source, the average ratio of the superposition to the solid source length was 1.051 for 103Pd and 1.009 for 192Ir through the whole volume with maximum ratios of 1.34 and 1.32, respectively. TPS-to-TPS comparisons between a solid line source and multiple line segments also provided good agreement. The MC-to-TPS benchmarking indicated where the gamma-index comparison failed were inside the source and within 0.25 cm of the source long-axis. Excluding these regions, 99.6% and 99.9% of the 57 600 in-plane pixels satisfied the gamma-index criteria for 103Pd and 192Ir, respectively. The optimal line segment length for both 103Pd and 192Ir toroidal sources was about 0.5 cm or one-fifth of the torus diameter, whichever was smaller. For all toroidal geometries and all line segment lengths examined, at least 98.9% and 100.0% pixels met the gamma-index criteria for 103Pd and 192Ir, respectively. For both 103Pd and 192Ir hairpin source, all geometric variations had passing rates exceeding 99.2%. However, the best results were obtained from 0.4 cm line segments on the curved part for 103Pd while it was independent of line segment length for 192Ir. CONCLUSIONS: A method for using a conventional TPS for brachytherapy treatment planning of elongated and curvilinear brachytherapy sources was developed and benchmarked. This method was evaluated using a gamma-index comparison technique, where appropriate pass-rate criteria were identified. Using a variety of subsegment lengths, the total length for a straight-line source was generally reproduced with accuracy improving as subsegment length increased, approaching the total straight-line length. Toroidal sources were similarly modeled with line segments, and an accuracy tradeoff was found between geometric errors and simulating dose anisotropy along the long axes. The gamma-index comparison method to analyze the results was shown to be more powerful than point-wise comparison methods, and more versatile than dose ratios on the same plane. PMID- 21815370 TI - Investigation of effective decision criteria for multiobjective optimization in IMRT. AB - PURPOSE: To investigate how using different sets of decision criteria impacts the quality of intensity modulated radiation therapy (IMRT) plans obtained by multiobjective optimization. METHODS: A multiobjective optimization evolutionary algorithm (MOEA) was used to produce sets of IMRT plans. The MOEA consisted of two interacting algorithms: (i) a deterministic inverse planning optimization of beamlet intensities that minimizes a weighted sum of quadratic penalty objectives to generate IMRT plans and (ii) an evolutionary algorithm that selects the superior IMRT plans using decision criteria and uses those plans to determine the new weights and penalty objectives of each new plan. Plans resulting from the deterministic algorithm were evaluated by the evolutionary algorithm using a set of decision criteria for both targets and organs at risk (OARs). Decision criteria used included variation in the target dose distribution, mean dose, maximum dose, generalized equivalent uniform dose (gEUD), an equivalent uniform dose (EUD(alpha,beta) formula derived from the linear-quadratic survival model, and points on dose volume histograms (DVHs). In order to quantatively compare results from trials using different decision criteria, a neutral set of comparison metrics was used. For each set of decision criteria investigated, IMRT plans were calculated for four different cases: two simple prostate cases, one complex prostate Case, and one complex head and neck Case. RESULTS: When smaller numbers of decision criteria, more descriptive decision criteria, or less anti correlated decision criteria were used to characterize plan quality during multiobjective optimization, dose to OARs and target dose variation were reduced in the final population of plans. Mean OAR dose and gEUD (a = 4) decision criteria were comparable. Using maximum dose decision criteria for OARs near targets resulted in inferior populations that focused solely on low target variance at the expense of high OAR dose. Target dose range, (D(max) - D(min)), decision criteria were found to be most effective for keeping targets uniform. Using target gEUD decision criteria resulted in much lower OAR doses but much higher target dose variation. EUD(alpha,beta) based decision criteria focused on a region of plan space that was a compromise between target and OAR objectives. None of these target decision criteria dominated plans using other criteria, but only focused on approaching a different area of the Pareto front. CONCLUSIONS: The choice of decision criteria implemented in the MOEA had a significant impact on the region explored and the rate of convergence toward the Pareto front. When more decision criteria, anticorrelated decision criteria, or decision criteria with insufficient information were implemented, inferior populations are resulted. When more informative decision criteria were used, such as gEUD, EUD(alpha,beta), target dose range, and mean dose, MOEA optimizations focused on approaching different regions of the Pareto front, but did not dominate each other. Using simple OAR decision criteria and target EUD(alpha,beta) decision criteria demonstrated the potential to generate IMRT plans that significantly reduce dose to OARs while achieving the same or better tumor control when clinical requirements on target dose variance can be met or relaxed. PMID- 21815371 TI - Sub-Nyquist acquisition and constrained reconstruction in time resolved angiography. AB - In 1980 DSA provided a real time series of digitally processed angiographic images that facilitated and reduced the risk of angiographic procedures. This technique has become an enabling technology for interventional radiology. Initially it was hoped that intravenous DSA could eliminate the need for arterial injections. However the 2D nature of the images resulted in overlap of vessels and repeat injections were often required. Ultimately the use of smaller arterial catheters and reduced iodine injections resulted in significant reduction in complications. During the next two decades time resolved MR DSA angiographic methods were developed that produced time series of 3D images. These 4D displays were initially limited by tradeoffs in temporal and spatial resolution when acquisitions obeying the Nyquist criteria were employed. Then substantial progress was made in the implementation of undersampled non-Cartesian acquisitions such as VIPR and constrained reconstruction methods such as HYPR, which removed this tradeoff and restored SNR usually lost by accelerated techniques. Recently, undersampled acquisition and constrained reconstruction have been applied to generate time series of 3D x-ray DSA volumes reconstructed using rotational C-arm acquisition completing a 30 year evolution from DSA to 4D DSA. These 4D DSA volumes provide a flexible series of roadmaps for interventional procedures and solve the problem of vessel overlap for intravenous angiography. Full time-dependent behavior can be visualized in three dimensions. When a biplane system is used, 4D fluoroscopy is also possible, enabling the interventionalist to track devices in vascular structures from any angle without moving the C-arm gantrys. Constrained reconstruction methods have proved useful in a broad range of medical imaging applications, where substantial acquisition accelerations and dose reductions have been reported. PMID- 21815372 TI - Automated prostate cancer localization without the need for peripheral zone extraction using multiparametric MRI. AB - PURPOSE: Multiparametric magnetic resonance imaging (MRI) has been shown to have higher localization accuracy than transrectal ultrasound (TRUS) for prostate cancer. Therefore, automated cancer segmentation using multiparametric MRI is receiving a growing interest, since MRI can provide both morphological and functional images for tissue of interest. However, all automated methods to this date are applicable to a single zone of the prostate, and the peripheral zone (PZ) of the prostate needs to be extracted manually, which is a tedious and time consuming job. In this paper, our goal is to remove the need of PZ extraction by incorporating the spatial and geometric information of prostate tumors with multiparametric MRI derived from T2-weighted MRI, diffusion-weighted imaging (DWI) and dynamic contrast enhanced MRI (DCE-MRI). METHODS: In order to remove the need of PZ extraction, the authors propose a new method to incorporate the spatial information of the cancer. This is done by introducing a new feature called location map. This new feature is constructed by applying a nonlinear transformation to the spatial position coordinates of each pixel, so that the location map implicitly represents the geometric position of each pixel with respect to the prostate region. Then, this new feature is combined with multiparametric MR images to perform tumor localization. The proposed algorithm is applied to multiparametric prostate MRI data obtained from 20 patients with biopsy-confirmed prostate cancer. RESULTS: The proposed method which does not need the masks of PZ was found to have prostate cancer detection specificity of 0.84, sensitivity of 0.80 and dice coefficient value of 0.42. CONCLUSIONS: The authors have found that fusing the spatial information allows us to obtain tumor outline without the need of PZ extraction with a considerable success (better or similar performance to methods that require manual PZ extraction). Our experimental results quantitatively demonstrate the effectiveness of the proposed method, depicting that the proposed method has a slightly better or similar localization performance compared to methods which require the masks of PZ. PMID- 21815373 TI - Effect of detector lag on CT noise power spectra. AB - PURPOSE: The authors examined the effect of detector lag on the noise power spectrum (NPS) of CT images reconstructed with filtered backprojection (FBP). METHODS: The authors derived an analytical expression of the NPS with detector lag, and then verified it using computer simulations with parallel beam and fan beam geometries. The dependence of the NPS on the amount of lag, location within the scanned field of view (FOV), and the number of views used in the reconstruction (samples per rotation) was investigated using constant and view dependent noise in the raw data. RESULTS: Detector lag introduces noise correlation in the azimuthal direction. The effect on the NPS is a frequency dependent reduction in amplitude. In small regions of the image, the effect is primarily in the frequencies corresponding to the azimuthal direction. The noise blurring and NPS filtering increases with increasing radial distance, and therefore regions at larger radial distances have lower noise power. With the same detector lag response function, the amount of noise correlation and NPS filtering decreases with increasing number of views. CONCLUSIONS: The shape of the NPS depends on the detector lag coefficients, location of the region, and the number of views used in the reconstruction. In general, the noise correlation caused by detector lag decreased the amplitude of the NPS. PMID- 21815374 TI - Development of an optical-based image guidance system: technique detecting external markers behind a full facemask. AB - PURPOSE: Optical image-guided systems (e.g., AlignRT, frameless SonArray, ExacTrac) have been used with advantages of avoiding excessive radiation exposure and real-time patient monitoring. Although these systems showed proven accuracy, they need to modify a full facemask for patients with H&N cancer and brain tumor. We developed an optical-based guidance system to manage interfractional and intrafractional setup errors by tracking external markers behind a full facemask. METHODS: Infra-red (IR) reflecting markers were attached on the face of a head phantom and then the phantom was immobilized by a full face thermoplastic mask. A stereo camera system consisting of two CCD cameras was mounted on the inferior wall of treatment room. The stereo camera system was calibrated to reconstruct 3D coordinates of multiple markers with respect to the isocenter using the direct linear transform (DLT) algorithm. The real-time position of the phantom was acquired, through the stereo camera system, by detecting the IR markers behind the full facemask. The detection errors with respect to the reference positions of planning CT images were calculated in six degrees of freedom (6-DOF) by a rigid-body registration technique. RESULTS: The calibration accuracy of the system was in submillimeter (0.33 mm +/- 0.27 mm), which was comparable to others. The mean distance between each of marker positions of optical images and planning CT images was 0.50 mm +/- 0.67 mm. The maximum deviations of 6-DOF registration were less than 1 mm and 1 degrees for the couch translation and rotation, respectively. CONCLUSIONS: The developed system showed the accuracy and consistency comparable to the commercial optical guided systems, while allowing us to simultaneously immobilize patients with a full face thermoplastic mask. PMID- 21815375 TI - Dynamic tomotherapy delivery. AB - PURPOSE: Several dynamic techniques are introduced to speed up TomoTherapy delivery and improve longitudinal conformity. These techniques include dynamic jaws, dynamic couch, and their combinations. METHODS: In general, dynamic jaws techniques allow jaws to move during a treatment. On the one hand, the jaws open wide to increase efficiency and thus reduce beam-on time. On the other hand, the jaws can close and follow the target border when sharp penumbra is required near the superior and inferior borders of tumor sites, which results in improved longitudinal dose conformity. The main purpose of the dynamic couch technique is to move the couch as fast as possible at variable speed to reduce beam-on time. Delivering most conformal dose as fast as possible requires a combination of dynamic jaws and dynamic couch techniques (DJDC). Motions of the jaws and couch are determined from the longitudinal fluence profile, which is calculated from an optimized leaf sinogram of small jaw width regular delivery or running start and stop delivery (RSS). We focused on RSS and DJDC in this study and also discussed other delivery techniques. RESULTS: Several conceptual cases are simulated to compare different delivery techniques. The results show that beam-on time can be reduced by about 60% compared to regular delivery with a 2.5 cm jaw width (REG 2.5 cm) for these cases and arbitrary longitudinal fluence profiles can be delivered. Two clinical cases, a prostate and a head-and-neck case, with different delivery techniques are calculated. The results show that plan quality yielded by DJDC with a maximum 5.0 cm jaw width is overall comparable to or better than that of the existing REG 2.5 cm. CONCLUSIONS: The DVH comparisons show better critical structure avoidance with the dynamic techniques. At the same time, beam-on time is reduced by about one half compared to REG 2.5 cm. Dynamic delivery techniques provide users more tools to speed up delivery and/or improve plan quality. PMID- 21815376 TI - Nonrigid PET motion compensation in the lower abdomen using simultaneous tagged MRI and PET imaging. AB - PURPOSE: We propose a novel approach for PET respiratory motion correction using tagged-MRI and simultaneous PET-MRI acquisitions. METHODS: We use a tagged-MRI acquisition followed by motion tracking in the phase domain to estimate the nonrigid deformation of biological tissues during breathing. In order to accurately estimate motion even in the presence of noise and susceptibility artifacts, we regularize the traditional HARP tracking strategy using a quadratic roughness penalty on neighboring displacement vectors (R-HARP). We then incorporate the motion fields estimated with R-HARP in the system matrix of an MLEM PET reconstruction algorithm formulated both for sinogram and list-mode data representations. This approach allows reconstruction of all detected coincidences in a single image while modeling the effect of motion both in the emission and the attenuation maps. At present, tagged-MRI does not allow estimation of motion in the lungs and our approach is therefore limited to motion correction in soft tissues. Since it is difficult to assess the accuracy of motion correction approaches in vivo, we evaluated the proposed approach in numerical simulations of simultaneous PET-MRI acquisitions using the NCAT phantom. We also assessed its practical feasibility in PET-MRI acquisitions of a small deformable phantom that mimics the complex deformation pattern of a lung that we imaged on a combined PET MRI brain scanner. RESULTS: Simulations showed that the R-HARP tracking strategy accurately estimated realistic respiratory motion fields for different levels of noise in the tagged-MRI simulation. In simulations of tumors exhibiting increased uptake, contrast estimation was 20% more accurate with motion correction than without. Signal-to-noise ratio (SNR) was more than 100% greater when performing motion-corrected reconstruction which included all counts, compared to when reconstructing only coincidences detected in the first of eight gated frames. These results were confirmed in our proof-of-principle PET-MRI acquisitions, indicating that our motion correction strategy is accurate, practically feasible, and is therefore ready to be tested in vivo. CONCLUSIONS: This work shows that PET motion correction using motion fields measured with tagged-MRI in simultaneous PET-MRI acquisitions can be made practical for clinical application and that doing so has the potential to remove motion blur in whole-body PET studies of the torso. PMID- 21815377 TI - The importance of tissue segmentation for dose calculations for kilovoltage radiation therapy. AB - PURPOSE: The aim of this work was to evaluate the effect of tissue segmentation on the accuracy of Monte Carlo (MC) dose calculations for kilovoltage radiation therapy, which are commonly used in preclinical radiotherapy studies and are also being revisited as a clinical treatment modality. The feasibility of tissue segmentation routinely done on the basis of differences in tissue mass densities was studied and a new segmentation scheme based on differences in effective atomic numbers was developed. METHODS: MC dose calculations in a cylindrical mouse phantom with small cylindrical inhomogeneities consisting of 34 ICRU-44 tissues were performed using the EGSnrc/BEAMnrc and DOSXYZnrc codes. The dose to tissue was calculated for five different kilovoltage beams currently used in small animal radiotherapy: a microCT 120 kV beam, two 225 kV beams filtered with either 4 mm of Al or 0.5 mm of Cu, a heavily filtered 320 kV beam, and a 192Ir beam. The mean doses to the 34 ICRU-44 tissues as a function of tissue mass density and effective atomic number and beam energy were studied. A treatment plan for an orthotopic lung tumor model was created, and the dose distribution was calculated for three tissue segmentation schemes using 4, 8, and 39 tissue bins to assess the significance of the simulation results for kilovoltage radiotherapy. RESULTS: In our model, incorrect assignment of adipose tissue to muscle caused dose calculation differences of 27%, 13%, and 7% for the 120 kV beam and the 225 kV beams filtered with 4 mm Al and 0.5 mm Cu, respectively. For the heavily filtered 320 kV beam and a 192Ir source, potential dose calculation differences due to tissue mis-assignment were below 4%. There was no clear relationship between the dose to tissue and its mass density for x-ray beams generated by tube potentials equal or less than 225 kV. A second order polynomial fit approximated well the absorbed dose to tissue as a function of effective atomic number for these beams. In the mouse study, the 120 kV beam dose to bone was overestimated by 100% and underestimated by 10% for the 4 and 8-tissue segmentation schemes compared to the 39-tissue segmentation scheme, respectively. Dose to adipose tissue was overestimated by 30% and underestimated by 10%, respectively. In general, organ at risk (OAR) doses were overestimated in the 4 tissue and the 8-tissue segmentation schemes compared to the 39-tissue segmentation. CONCLUSIONS: Tissue segmentation was shown to be a key parameter for dose calculations with kilovoltage beams used in small animal radiotherapy when an x-ray tube with a potential < or = 225 kV is used as a source. A new tissue segmentation scheme with 39 tissues based on effective number differences derived from mass density differences has been implemented. PMID- 21815378 TI - An innovative iterative thresholding algorithm for tumour segmentation and volumetric quantification on SPECT images: Monte Carlo-based methodology and validation. AB - PURPOSE: Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) imaging play an important role in the segmentation of functioning parts of organs or tumours, but an accurate and reproducible delineation is still a challenging task. In this work, an innovative iterative thresholding method for tumour segmentation has been proposed and implemented for a SPECT system. This method, which is based on experimental threshold-volume calibrations, implements also the recovery coefficients (RC) of the imaging system, so it has been called recovering iterative thresholding method (RIThM). The possibility to employ Monte Carlo (MC) simulations for system calibration was also investigated. METHODS: The RIThM is an iterative algorithm coded using MATLAB: after an initial rough estimate of the volume of interest, the following calculations are repeated: (i) the corresponding source-to-background ratio (SBR) is measured and corrected by means of the RC curve; (ii) the threshold corresponding to the amended SBR value and the volume estimate is then found using threshold-volume data; (iii) new volume estimate is obtained by image thresholding. The process goes on until convergence. The RIThM was implemented for an Infinia Hawkeye 4 (GE Healthcare) SPECT/CT system, using a Jaszczak phantom and several test objects. Two MC codes were tested to simulate the calibration images: SIMIND and SimSet. For validation, test images consisting of hot spheres and some anatomical structures of the Zubal head phantom were simulated with SIMIND code. Additional test objects (flasks and vials) were also imaged experimentally. Finally, the RIThM was applied to evaluate three cases of brain metastases and two cases of high grade gliomas. RESULTS: Comparing experimental thresholds and those obtained by MC simulations, a maximum difference of about 4% was found, within the errors (+/- 2% and +/- 5%, for volumes > or = 5 ml or < 5 ml, respectively). Also for the RC data, the comparison showed differences (up to 8%) within the assigned error (+/- 6%). ANOVA test demonstrated that the calibration results (in terms of thresholds or RCs at various volumes) obtained by MC simulations were indistinguishable from those obtained experimentally. The accuracy in volume determination for the simulated hot spheres was between -9% and 15% in the range 4-270 ml, whereas for volumes less than 4 ml (in the range 1-3 ml) the difference increased abruptly reaching values greater than 100%. For the Zubal head phantom, errors ranged between 9% and 18%. For the experimental test images, the accuracy level was within +/- 10%, for volumes in the range 20-110 ml. The preliminary test of application on patients evidenced the suitability of the method in a clinical setting. CONCLUSIONS: The MC-guided delineation of tumor volume may reduce the acquisition time required for the experimental calibration. Analysis of images of several simulated and experimental test objects, Zubal head phantom and clinical cases demonstrated the robustness, suitability, accuracy, and speed of the proposed method. Nevertheless, studies concerning tumors of irregular shape and/or nonuniform distribution of the background activity are still in progress. PMID- 21815379 TI - Frequency bandwidth extension by use of multiple Zeeman field offsets for electron spin-echo EPR oxygen imaging of large objects. AB - PURPOSE: Electron spin-echo (ESE) oxygen imaging is a new and evolving electron paramagnetic resonance (EPR) imaging (EPRI) modality that is useful for physiological in vivo applications, such as EPR oxygen imaging (EPROI), with potential application to imaging of multicentimeter objects as large as human tumors. A present limitation on the size of the object to be imaged at a given resolution is the frequency bandwidth of the system, since the location is encoded as a frequency offset in ESE imaging. The authors' aim in this study was to demonstrate the object size advantage of the multioffset bandwidth extension technique. METHODS: The multiple-stepped Zeeman field offset (or simply multi-B) technique was used for imaging of an 8.5-cm-long phantom containing a narrow single line triaryl methyl compound (trityl) solution at the 250 MHz imaging frequency. The image is compared to a standard single-field ESE image of the same phantom. RESULTS: For the phantom used in this study, transverse relaxation (T(2e)) electron spin-echo (ESE) images from multi-B acquisition are more uniform, contain less prominent artifacts, and have a better signal to noise ratio (SNR) compared to single-field T(2e) images. CONCLUSIONS: The multi-B method is suitable for imaging of samples whose physical size restricts the applicability of the conventional single-field ESE imaging technique. PMID- 21815380 TI - A dosimetry study of the Oncoseed 6711 using glass rod dosimeters and EGS5 Monte Carlo code in a geometry lacking radiation equilibrium scatter conditions. AB - PURPOSE: The aim of this study was to develop a dose calculation method which is applicable to the interseed attenuation and the geometry lacking the equilibrium radiation scatter conditions in brachytherapy. METHODS: The dose obtained from measurement with a radiophotoluminescent glass rod dosimeter (GRD) was compared to the dose calculated with the Monte Carlo (MC) code "EGS5," using the 125I source structure detailed in by Kennedy et al. The GRDs were irradiated with 125I Oncoseed 6711 in a human head phantom. The phantom was a cylinder made of 2 mm thick PMMA with a diameter of 18 cm and length of 16 cm. Some of the GRD positions were so close to the phantom surface that the backscatter margin was less than 5 cm, insufficient for photons. RESULTS: The EGS5 simulations were found to reproduce the relative dose distributions as measured with the GRDs to within 25% uncertainty in the geometry lacking the equilibrium radiation scatter conditions. The absolute value of the GRD measurement agreed with the American Association of Physicist in Medicine Task Group No 43 Updated Protocol (AAPM TG43U1) formalism to within 3% of the reference point (r = 1 cm, theta = 90 degrees), where the TG43U1 is especially reliable because of the abundant data accumulation in composing the formalism. The factor to normalize the measured or calculated dose to the TG43U1 estimate at the reference point was evaluated to be 0.97 for the GRD measurement and 1.8 for the MC calculation, which uses the integration of the apparent activity with the time as the amount of disintegration during the irradiation. Also, F(r,theta) and g(r) estimated by this calculation method were consistent with those proposed in the TG43U1. CONCLUSIONS: The results of this investigation support the validity of both the MC calculation method and GRD measurement in this study as well as the TG-43U1 formalism. Also, this calculation is applicable to interseed attenuation and the geometry lacking the equilibrium radiation scatter. PMID- 21815381 TI - Registration of the endoluminal surfaces of the colon derived from prone and supine CT colonography. AB - PURPOSE: Computed tomographic (CT) colonography is a relatively new technique for detecting bowel cancer or potentially precancerous polyps. CT scanning is combined with three-dimensional (3D) image reconstruction to produce a virtual endoluminal representation similar to optical colonoscopy. Because retained fluid and stool can mimic pathology, CT data are acquired with the bowel cleansed and insufflated with gas and patient in both prone and supine positions. Radiologists then match visually endoluminal locations between the two acquisitions in order to determine whether apparent pathology is real or not. This process is hindered by the fact that the colon, essentially a long tube, can undergo considerable deformation between acquisitions. The authors present a novel approach to automatically establish spatial correspondence between prone and supine endoluminal colonic surfaces after surface parameterization, even in the case of local colon collapse. METHODS: The complexity of the registration task was reduced from a 3D to a 2D problem by mapping the surfaces extracted from prone and supine CT colonography onto a cylindrical parameterization. A nonrigid cylindrical registration was then performed to align the full colonic surfaces. The curvature information from the original 3D surfaces was used to determine correspondence. The method can also be applied to cases with regions of local colonic collapse by ignoring the collapsed regions during the registration. RESULTS: Using a development set, suitable parameters were found to constrain the cylindrical registration method. Then, the same registration parameters were applied to a different set of 13 validation cases, consisting of 8 fully distended cases and 5 cases exhibiting multiple colonic collapses. All polyps present were well aligned, with a mean (+/- std. dev.) registration error of 5.7 (+/- 3.4) mm. An additional set of 1175 reference points on haustral folds spread over the full endoluminal colon surfaces resulted in an error of 7.7 (+/- 7.4) mm. Here, 82% of folds were aligned correctly after registration with a further 15% misregistered by just onefold. CONCLUSIONS: The proposed method reduces the 3D registration task to a cylindrical registration representing the endoluminal surface of the colon. Our algorithm uses surface curvature information as a similarity measure to drive registration to compensate for the large colorectal deformations that occur between prone and supine data acquisitions. The method has the potential to both enhance polyp detection and decrease the radiologist's interpretation time. PMID- 21815382 TI - Dependence of image quality on geometric factors in breast tomosynthesis. AB - PURPOSE: Accurate and precise knowledge of the geometric relationships between the physical components (x-ray source, pivot point, and elements of the x-ray detector) critically influences the quality of reconstructed images in digital breast tomosynthesis (DBT). The sensitivity of image reconstruction to geometric inaccuracies is investigated by simulation of image formation and reconstruction for a DBT system. METHODS: A mathematical simulation of a partial isocentric system is described. A block "phantom" containing small calcific particles is used to evaluate the effect of three linear and three angular parameters on localization of structures within the reconstructed image and on lesion contrast. Two types of geometric errors are studied: fixed offset inaccuracies and random interprojection inaccuracies in the context of a filtered back projection reconstruction algorithm. RESULTS: It is shown that, in general, fixed offset errors lead to little degradation of image quality. However, a lack of precision in interprojection geometric parameters can cause a loss in lesion contrast and introduce artifacts. For example, projection mismatches of the gantry angle of 0.14 degrees (standard deviation) can reduce reconstructed lesion intensity by 20%. Reconstruction is particularly sensitive to detector yaw angle mismatches; even small fixed offset errors (0.31 degrees) in detector yaw can reduce lesion intensity by 20%. Interprojection variations in geometric parameters can also cause localization errors. For example, if detector yaw variations between projections occur and these are not accounted for, a standard deviation of 0.34 degrees can be expected to induce 1 mm root-mean-square error shift in lesion location. CONCLUSIONS: In a simulation of image acquisition in DBT, the sensitivities in image quality to six geometric parameters were evaluated. Image reconstructions are relatively tolerant of fixed offset errors except for detector yaw. However, uncorrected variations in interprojection geometric parameters induce losses in lesion contrast and localization. Lesion contrast is affected more strongly by these errors compared to lesion localization in tomosynthesis. PMID- 21815383 TI - Surface dose measurement for helical tomotherapy. AB - PURPOSE: To compare the surface dose measurements made by different dosimeters for the helical tomotherapy (HT) plan in the case of the target close to the surface. METHODS: Surface dose measurements in different points for the HT plan to deliver 2 Gy to the planning target volume (PTV) at 5 mm below the surface of the cylindrical phantom were performed by radiochromic films, single use metal oxide semiconductor field-effect transistor (MOSFET) dosimeters, silicon IVD QED diode, and optically stimulated luminescence (OSL) dosimeters. RESULTS: The measured doses by all dosimeters were within 12 +/- 8% difference of each other. CONCLUSIONS: Radiochromic films, EBT, and EBT2, provide high spatial resolution, although it is difficult to get accurate measurements of dose. Both the OSL and QED measured similar dose to that of the MOSFET detectors. The QED dosimeter is promising as a reusable on-line wireless dosimeter, while the OSL dosimeters are easier to use, require minimum setup time and are very precise. PMID- 21815384 TI - Technical note: estimating absorbed doses to the thyroid in CT. AB - PURPOSE: To describe a method for estimating absorbed doses to the thyroid in patients undergoing neck CT examinations. METHODS: Thyroid doses in anthropomorphic phantoms were obtained for all 23 scanner dosimetry data sets in the ImPACT CT patient dosimetry calculator. Values of relative thyroid dose [R(thy)(L)], defined as the thyroid dose for a given scan length (L) divided by the corresponding thyroid dose for a whole body scan, were determined for neck CT scans. Ratios of the maximum thyroid dose to the corresponding CTDI(vol) and [D'(thy)], were obtained for two phantom diameters. The mass-equivalent water cylinder of any patient can be derived from the neck cross-sectional area and the corresponding average Hounsfield Unit, and compared to the 16.5-cm diameter water cylinder that models the ImPACT anthropomorphic phantom neck. Published values of relative doses in water cylinders of varying diameter were used to adjust thyroid doses in the anthropomorphic phantom to those of any sized patient. RESULTS: Relative thyroid doses R(thy)(L) increase to unity with increasing scan length and with very small difference between scanners. A 10-cm scan centered on the thyroid would result in a dose that is, nearly 90% of the thyroid dose from a whole body scan when performed using the constant radiographic techniques. At 120 kV, the average value of D'(thy) for the 16-cm diameter was 1.17 +/- 0.05 and was independent of CT vendor and year of CT scanner, and choice of x-ray tube voltage. The corresponding average value of D'(thy) in the 32-cm diameter phantom was 2.28 +/- 0.22 and showed marked variations depending on vendor, year of introduction into clinical practice as well as x-ray tube voltage. At 120 kV, a neck equivalent to a 10-cm diameter cylinder of water would have thyroid doses 36% higher than those in the ImPACT phantom, whereas a neck equivalent to a 25-cm cylinder diameter would have thyroid doses 35% lower. CONCLUSIONS: Patient thyroid doses can be estimated by taking into account the amount of radiation used to perform the CT examination (CTDI(vol)) and accounting for scan length and patient anatomy (i.e., neck diameter) at the thyroid location. PMID- 21815385 TI - Quasi-breath-hold technique using personalized audio-visual biofeedback for respiratory motion management in radiotherapy. AB - PURPOSE: To introduce a respiratory motion management technique, so called quasi breath-hold (QBH) technique and evaluate its feasibility. As a hybrid technique combining free-breathing-based gating (denoted as gating for convenience) and breath-hold (BH), the QBH is designed to overcome typical limitations existing in either one such as phase-shift, residual motion, complexity, and discomfort. METHODS: The QBH is realized using an audio-visual biofeedback system (AVBFS) and a respiratory motion management program (RMMP). The AVBFS, consisting of two infra-red stereo cameras and a head mounted display, monitors respiratory motion and provides dynamic feedback to patients. The RMMP establishes a personalized respiration model based on deep free breathing. The model is further processed to generate a QBH model by inserting a short breath-hold period into the end point of the-end-of-expiration phase. Then the patient is guided to follow the QBH model through the AVBFS. A simulation study with ten volunteers was performed to evaluate the feasibility of the proposed technique. In the simulation, an in house developed macro program automatically controlled the QBH procedure to virtually deliver an intensity modulated radiation therapy (IMRT) plan. For each volunteer subject, three QBH maneuvers with different breath-hold times of 3, 5, and 7s (denoted as QBH3s, QBH5s, and QBH7s, respectively) and a conventional gating maneuver with 30% duty cycle (for comparison purpose) were applied. External respiration motion signals obtained during the gating window were analyzed to obtain mean absolute error (MAE) between the measured and guiding curve, mean absolute deviation (MAD) of the measured curve, and an inverse uncertainty time histogram (IUTH). RESULTS: Every volunteer successfully performed all of the four maneuvers (1 gating and 3 QBH patterns). The average treatment times were 466.8, 452.3, and 430.8 s for the QBH3s, QBH5s, and QBH7s, respectively, compared to 530.4 s for the gating technique. The mean absolute errors between measured and guiding curve during the gating window were 0.9 +/- 0.7, 0.8 +/- 0.6, 0.7 +/- 0.6, and 0.6 +/- 0.7 mm for the gating, QBH3s, QBH5s, and QBH7s, respectively. The mean absolute deviations of the measured curve during the gating window were 0.7 +/- 0.7, 0.5 +/- 0.5, 0.5 +/- 0.4, and 0.5 +/- 0.6 mm for the gating, QBH3s, QBH5s, and QBH7s, respectively. In the analysis of the IUTH during the gating window, the QBH simulations showed similar (QBH3s) or less (QBH5s and QBH7s) motion uncertainties compared to the gating simulation. CONCLUSIONS: The proposed QBH technique with personalized audio-visual biofeedback was feasible for respiratory motion management. It showed equivalent or less motion uncertainty and shorter treatment time than the conventional free breathing-based gating technique did. The technique is expected to optimally compromise between patient comfort and treatment efficiency. PMID- 21815386 TI - Effect of respiratory trace shape on optimal treatment margin. AB - PURPOSE: To evaluate the effect of target trajectory shape on the optimal treatment margin. METHODS: Intensity-modulated radiation therapy and volumetric modulated arc therapy plans were created for three spherical targets (3, 5, and 7 cm diameter) simulated in exhalation phases, each with margins of 2, 4, 6, 8, and 10 mm to account for motion. The plans were delivered to a stationary 2D ion chamber array, and dose movies were obtained of the delivered doses. The dose movie frames were then displaced to simulate different respiratory traces. Five traces were used: sin2, sin4 sin6, and two patient traces. The optimal margin was defined as the margin for which the dose delivered to 95% of the target was closest to that obtained with no margin or motion. The equivalent uniform dose was also investigated as an alternative cost function. RESULTS: The optimal margin was always smaller than the peak-to-peak motion. When the respiratory trace spent less time in the inhale phases, the optimal margin was consistently smaller than when more time was spent in the inhale phases. The target size and treatment modality also affected the optimal margin. CONCLUSIONS: The necessary margin for targets that spend less time in the exhale phase (sin6) is 2-4 mm smaller than for targets that spend equal time in the inhale and exhale phases (sin). PMID- 21815387 TI - Conversion of helical tomotherapy plans to step-and-shoot IMRT plans--Pareto front evaluation of plans from a new treatment planning system. AB - PURPOSE: The resulting plans from a new type of treatment planning system called SharePlan have been studied. This software allows for the conversion of treatment plans generated in a TomoTherapy system for helical delivery, into plans deliverable on C-arm linear accelerators (linacs), which is of particular interest for clinics with a single TomoTherapy unit. The purpose of this work was to evaluate and compare the plans generated in the SharePlan system with the original TomoTherapy plans and with plans produced in our clinical treatment planning system for intensity-modulated radiation therapy (IMRT) on C-arm linacs. In addition, we have analyzed how the agreement between SharePlan and TomoTherapy plans depends on the number of beams and the total number of segments used in the optimization. METHODS: Optimized plans were generated for three prostate and three head-and-neck (H&N) cases in the TomoTherapy system, and in our clinical treatment planning systems (TPS) used for IMRT planning with step-and-shoot delivery. The TomoTherapy plans were converted into step-and-shoot IMRT plans in SharePlan. For each case, a large number of Pareto optimal plans were created to compare plans generated in SharePlan with plans generated in the Tomotherapy system and in the clinical TPS. In addition, plans were generated in SharePlan for the three head-and-neck cases to evaluate how the plan quality varied with the number of beams used. Plans were also generated with different number of beams and segments for other patient cases. This allowed for an evaluation of how to minimize the number of required segments in the converted IMRT plans without compromising the agreement between them and the original TomoTherapy plans. RESULTS: The plans made in SharePlan were as good as or better than plans from our clinical system, but they were not as good as the original TomoTherapy plans. This was true for both the head-and-neck and the prostate cases, although the differences between the plans for the latter were small. The evaluation of the head-and-neck cases also showed that the plans generated in SharePlan were improved when more beams were used. The SharePlan Pareto front came close to the front for the TomoTherapy system when a sufficient number of beams were added. The results for plans generated with varied number of beams and segments demonstrated that the number of segments could be minimized with maintained agreement between SharePlan and TomoTherapy plans when 10-19 beams were used. CONCLUSIONS: This study showed (using Pareto front evaluation) that the plans generated in Share-Plan are comparable to plans generated in other TPSs. The evaluation also showed that the plans generated in SharePlan could be improved with the use of more beams. To minimize the number of segments needed in a plan with maintained agreement between the converted IMRT plans and the original TomoTherapy plans, 10-19 beams should be used, depending on target complexity. SharePlan has proved to be useful and should thereby be a time-saving complement as a backup system for clinics with a single TomoTherapy system installed alongside conventional C-arm linacs. PMID- 21815388 TI - Population dose from medical exposure in Taiwan for 2008. AB - PURPOSE: The largest contribution to the population dose from man-made ionizing radiation sources is the medical exposure. Exposure to patients from medical examinations is of interest because it is a global indicator for the quality of radiology practice. Due to the different healthcare systems and the considerable variations in the equipment and manpower in radiology, the population dose from medical exposure varies by a large extent in different countries. This dose from different diagnostic procedures provides information that can be used to establish national reference levels. It is also useful to determine the priority in terms of dose reduction so as to optimize the protection of patients in a cost effective manner. In the present work, the collective effective doses due to different medical modalities were estimated for the Taiwan population in 2008. METHODS: The collective effective dose from medical exposure was calculated using information on the number of procedures and the average effective dose per procedure. The frequency of procedures was extracted from the National Health Insurance (NHI) research database. The enrollment of Taiwan population in the NHI program was 99.48% in 2008. The average effective dose per procedure was derived from hospital surveys, measured data, and published results. RESULTS: Estimates of the collective effective dose were made for different medical modalities, i.e., the conventional radiography and fluoroscopy, computed tomography, interventional fluoroscopy, nuclear medicine, and dental radiography. Each modality was further divided into relevant classes by the body part or organ system. Among 23 037 031 Taiwan population in 2008, the annual examination frequencies per 1000 population were 550, 55.1, 15.6, 13.6, and 112 for the conventional radiography and fluoroscopy, computed tomography, interventional fluoroscopy, nuclear medicine, and dental radiography, respectively. The corresponding collective effective doses were 3277, 8608, 2743, 2303, and 28 man Sv, respectively. Thus, the average effective dose per caput was 0.74 mSv, which was in the range of 0.3-1.5 mSv for the 12 European countries estimated for 2008. CONCLUSIONS: In the period from 1997 to 2008, the procedure frequency per 1000 population increased by a factor of 2.3 for computed tomography, 2.2 for interventional fluoroscopy, 1.8 for conventional radiography and fluoroscopy, and 1.5 for nuclear medicine. It demonstrated that the medical utilization of imaging facilities raised rapidly. PMID- 21815389 TI - Comparative simulations of neutron dose in soft tissue and phantom materials for proton and carbon ion therapy with actively scanned beams. AB - PURPOSE: In the clinical environment phantom materials are usually used to simulate the patient for neutron dosimetric measurements. It is not clear that the results of such phantom measurements represent the actual neutron dose in the patient. The aim of this study was to compare the difference in secondary neutron equivalent dose for different phantom materials to that in human tissue, for both proton and carbon ion radiation therapy. METHODS: In order to compare the neutron equivalent dose induced by primary particles in different materials, Monte Carlo simulations were performed using the FLUKA Monte Carlo package. The scored dosimetric quantities were absorbed dose and neutron ambient dose equivalent for monoenergetic proton and carbon ion beams of clinically relevant energies. It was shown that neutron equivalent dose, for which no scoring routine exists in the current FLUKA release, can be approximated by neutron ambient dose equivalent within 4% for the investigated energies of proton and carbon ion beams. RESULTS: The Monte Carlo simulations performed in this work showed differences in neutron ambient dose equivalent in radiation therapy phantom materials compared to ICRP soft tissue for primary proton and carbon ion beams. For Alderson soft tissue the maximum deviation was 11% for protons and 8% for carbon ions. For water the maximum deviation was 10% for protons and 9% for carbon ions. In the case of RW3 solid water, the maximum deviation compared to ICRP soft tissue was as large as 28% and 21% for protons and carbon ions, respectively. CONCLUSIONS: Alderson soft tissue and water are suitable phantom materials for neutron dosimetry for the accuracy which is achievable. When using solid water phantoms, the chemical and therefore nuclear composition of the phantom material has to be accounted for. PMID- 21815390 TI - Technical note: Correlation of respiratory motion between external patient surface and internal anatomical landmarks. AB - PURPOSE: Current respiratory motion monitoring devices used for motion synchronization in medical imaging and radiotherapy provide either 1D respiratory signal over a specific region or 3D information based on few external or internal markers. On the other hand, newer technology may offer the potential to monitor the entire patient external surface in real time. The main objective of this study was to assess the motion correlation between such an external patient surface and internal anatomical landmarks motion. METHODS: Four dimensional computed tomography (4D CT) volumes for ten patients were used in this study. Anatomical landmarks were manually selected in the thoracic region across the 4D CT datasets by two experts. The landmarks included normal structures as well as the tumor location. In addition, a distance map representing the entire external patient surface, which corresponds to surfaces acquired by a time of flight (ToF) camera or similar devices, was created by segmenting the skin of all 4D CT volumes using a thresholding algorithm. Finally, the correlation between the internal landmarks and external surface motion was evaluated for different regions (placement and size) throughout a patient's surface. RESULTS: Significant variability was observed in the motion of the different parts of the external patient surface. The larger motion magnitude was consistently measured in the central regions of the abdominal and the thoracic areas for the different patient datasets considered. The highest correlation coefficients were observed between the motion of these external surface areas and internal landmarks such as the diaphragm and mediastinum structures as well as the tumor location landmarks (0.8 +/- 0.18 and 0.72 +/- 0.12 for the abdominal and the thoracic regions, respectively). Worse correlation was observed when one considered landmarks not significantly influenced by respiratory motion such as the apex and the sternum. CONCLUSIONS: There were large differences in the motion correlation observed considering different regions of interest placed over a patients' external surface and internal anatomical landmarks. The positioning of current devices used for respiratory motion synchronization may reduce such correlation by averaging the motion over correlated and poorly correlated external regions. The potential of capturing in real-time the motion of the complete external patient surface as well as choosing the area of the surface that correlates best with the internal motion should allow reducing such variability and associated errors in both respiratory motion synchronization and subsequent motion modeling processes. PMID- 21815391 TI - Development and characterization of an anthropomorphic breast software phantom based upon region-growing algorithm. AB - PURPOSE: We present a novel algorithm for computer simulation of breast anatomy for generation of anthropomorphic software breast phantoms. A realistic breast simulation is necessary for preclinical validation of volumetric imaging modalities. METHODS: The anthropomorphic software breast phantom simulates the skin, regions of adipose and fibroglandular tissue, and the matrix of Cooper's ligaments and adipose compartments. The adipose compartments are simulated using a seeded region-growing algorithm; compartments are grown from a set of seed points with specific orientation and growing speed. The resulting adipose compartments vary in shape and size similar to real breasts; the adipose region has a compact coverage by adipose compartments of various sizes, while the fibroglandular region has fewer, more widely separated adipose compartments. Simulation parameters can be selected to cover the breadth of variations in breast anatomy observed clinically. RESULTS: When simulating breasts of the same glandularity with different numbers of adipose compartments, the average compartment volume was proportional to the phantom size and inversely proportional to the number of simulated compartments. The use of the software phantom in clinical image simulation is illustrated by synthetic digital breast tomosynthesis images of the phantom. The proposed phantom design was capable of simulating breasts of different size, glandularity, and adipose compartment distribution. The region-growing approach allowed us to simulate adipose compartments with various size and shape. Qualitatively, simulated x-ray projections of the phantoms, generated using the proposed algorithm, have a more realistic appearance compared to previous versions of the phantom. CONCLUSIONS: A new algorithm for computer simulation of breast anatomy has been proposed that improved the realism of the anthropomorphic software breast phantom. PMID- 21815392 TI - Organ dose and inherent uncertainty in helical CT dosimetry due to quasiperiodic dose distributions. AB - PURPOSE: The purpose of this study was to characterize relative magnitudes of peripheral dose modulations present in helical MDCT resulting from variation in x ray tube starting position and phantom position relative to isocenter using a novel methodology that employs direct dosimetric measurements and knowledge of scan geometry. The magnitudes of potential dose savings to specific radiosensitive tissues related to the phase of the quasiperiodic dose distribution are also quantified and compared to similar Monte Carlo based studies. METHODS: For this study, a Siemens SOMATOM Sensation 16 helical MDCT scanner and a tomographic adult anthropomorphic phantom from the University of Florida phantom series were used for all scans. In addition, a plastic scintillator-based fiber-optic-coupled dosimetry system was used to record real time axial dosimetric measurements. These direct measurements were used to derive cumulative point doses and tissue doses for helical MDCT using different pitch values and surface to isocenter distances. RESULTS: Cumulative point doses and doses for the lens of the eye and thyroid showed strong variation with both the phase of the dose distribution and phantom positioning relative to isocenter. Depending on the phantom positioning relative to isocenter, individual in-phantom cumulative point dose values were shown to vary anywhere from 0 to 25% lower than the maximum value for scans of pitch 1, and greater than 60% for scans of pitch 1.5. Reduction in total tissue dose to the lens of the eye (thyroid) varied from 0 to 20% (4%) lower than the maximum value for pitch 1, and from 59 (14%) to 71% (19%) lower than the maximum value for scans using pitch 1.5. These values are similar to those found in previous Monte Carlo based studies. The reduction in average total tissue dose between the extremes (+/- 3 cm from nominal) of phantom positioning relative to isocenter for the eye (thyroid) was 16% (13%) for pitch 1, and 14% (12%) for pitch 1.5. CONCLUSIONS: As recent Monte Carlo simulations have shown, there exists an inherent uncertainty when performing dose measurements within a phantom during helical MDCT scans. The periodic dose distributions in helical MDCT means that low resolution sampling of local phantom doses could result in dose measurement aliasing. For reliable results, these considerations should be accounted for in helical MDCT phantom dosimetry studies. The variability in surface dose has a strong dependence on phantom positioning relative to isocenter. Dose to tissues such as the lens of the eye and thyroid can be minimized by positioning patients, so these tissues are closer to isocenter because the decrease in x-ray intensity due to beam divergence dominates the increases resulting from increased primary beam exposure overlap. Of course, this dose decrease would have to be balanced against any diminished image quality resulting from misalignment of the patient with the bowtie filter. Additionally, significantly reduced dose to small radiosensitive tissues such as the lens of the eye could occur if it were possible to shift the phase of the periodic dose distribution present in helical MDCT. These dose reductions would come at no cost to image quality. PMID- 21815393 TI - A scatter and randoms weighted (SRW) iterative PET reconstruction. AB - PURPOSE: In positron emission tomography (PET) imaging, the main function of scatter and randoms corrections is to improve contrast and quantitative accuracy. Both corrections are essential and critically important. Several iterative reconstruction schemes incorporating scatter and randoms corrections have been developed over the years. In this work, the authors propose a new method to incorporate the scatter and randoms corrections into the iterative image reconstruction, which has shown promising results in regards to improving reconstruction performance and image quality as compared to the standard methods. METHODS: The authors describe a scatter and randoms weighted (SRW) iterative PET reconstruction algorithm. The SRW method is based on the estimation of the trues fraction (TF) within the prompts. Once the TF is estimated, it is then incorporated into the weighting component of the system matrix, and the net result is a scatter and randoms weighting in the sensitivity image similar to the attenuation correction weighting. Although using the measured prompts in the TF estimation was demonstrated to achieve the fastest convergence at high statistics, it is not reliable in low counts situations due to the sparse and noisy nature of the measured prompts. Therefore, a mean estimation of the prompts derived from the forward projection of the reconstructed prompts image was introduced into the TF estimation. A contrast phantom was scanned, and the data were reconstructed using the standard and the SRW methods. RESULTS: The contrast vs noise, precision vs accuracy in contrast, absolute error vs number of iterations comparisons, and standard deviation image over different realizations of the same object were evaluated at low counts situations, and it was observed that the SRW method outperforms the standard approaches such as the scatter and randoms data precorrection and the ordinary Poisson methods. The image intensity (activity) outside the object can also be minimized using the SRW method. In addition, further improvement in accuracy, precision, convergence, and noise properties can be achieved by further improving the TF and the prompts estimate. CONCLUSIONS: The authors have developed a practical scatter and randoms weighting scheme in the sensitivity image for iterative PET reconstructions. Our proposed SRW method has a number of advantages over the conventional methods, and it has shown promising results with additional optimization for various applications to be further investigated. PMID- 21815394 TI - Development and evaluation of a model-based downscatter compensation method for quantitative I-131 SPECT. AB - PURPOSE: The radionuclide 131I has found widespread use in targeted radionuclide therapy (TRT), partly due to the fact that it emits photons that can be imaged to perform treatment planning or posttherapy dose verification as well as beta rays that are suitable for therapy. In both the treatment planning and dose verification applications, it is necessary to estimate the activity distribution in organs or tumors at several time points. In vivo estimates of the 131I activity distribution at each time point can be obtained from quantitative single photon emission computed tomography (QSPECT) images and organ activity estimates can be obtained either from QSPECT images or quantification of planar projection data. However, in addition to the photon used for imaging, 131I decay results in emission of a number of other higher-energy photons with significant abundances. These higher-energy photons can scatter in the body, collimator, or detector and be counted in the 364 keV photopeak energy window, resulting in reduced image contrast and degraded quantitative accuracy; these photons are referred to as downscatter. The goal of this study was to develop and evaluate a model-based downscatter compensation method specifically designed for the compensation of high-energy photons emitted by 131I and detected in the imaging energy window. METHODS: In the evaluation study, we used a Monte Carlo simulation (MCS) code that had previously been validated for other radionuclides. Thus, in preparation for the evaluation study, we first validated the code for 131I imaging simulation by comparison with experimental data. Next, we assessed the accuracy of the downscatter model by comparing downscatter estimates with MCS results. Finally, we combined the downscatter model with iterative reconstruction-based compensation for attenuation (A) and scatter (S) and the full (D) collimator detector response of the 364 keV photons to form a comprehensive compensation method. We evaluated this combined method in terms of quantitative accuracy using the realistic 3D NCAT phantom and an activity distribution obtained from patient studies. We compared the accuracy of organ activity estimates in images reconstructed with and without addition of downscatter compensation from projections with and without downscatter contamination. RESULTS: We observed that the proposed method provided substantial improvements in accuracy compared to no downscatter compensation and had accuracies comparable to reconstructions from projections without downscatter contamination. CONCLUSIONS: The results demonstrate that the proposed model-based downscatter compensation method is effective and may have a role in quantitative 131I imaging. PMID- 21815395 TI - Technical note: DTI measurements of fractional anisotropy and mean diffusivity at 1.5 T: comparison of two radiofrequency head coils with different functional designs and sensitivities. AB - PURPOSE: Diffusion tensor imaging (DTI) is highly sensitive to noise and improvement of radiofrequency coil technology represents a straightforward way for augmenting signal-to-noise ratio (SNR) performance in magnetic resonance imaging (MRI) scanners. The aim of this study was to characterize the dependence of DTI measurements of fractional anisotropy (FA) and mean diffusivity (MD) on the choice of head coil, comparing two head coils with different functional designs and sensitivities. METHODS: Fourteen healthy subjects underwent DTI acquisitions at 1.5 T. Every subject was scanned twice, using a standard quadrature birdcage head coil (coil-A) and an eight-channel array head coil (coil B). FA and MD maps, estimated using both the linear least squares (LLS) and nonlinear least squares (NLLS) methods, were nonlinearly normalized into a standard space. Then, volumetric regions of interest encompassing typical white and gray matter structures [splenium of the corpus callosum (SCC), internal capsule (IC), cerebral peduncles (CP), middle cerebellar peduncles (MCP), globus pallidus (GP), thalamus (TH), caudate (CA), and putamen (PU)] were analyzed. Significant differences and trends of variation in DTI measurements were assessed by the Wilcoxon test for paired samples with and without Bonferroni correction for multiple comparisons, respectively. RESULTS: The overall SNR of coil-B was 30% higher than that of coil-A. When comparing DTI measurements (coil-B versus coil-A), mean FA values (SCC, IC, and TH), mean MD values (IC, CP, GP, and TH), FA standard deviation (CP, MCP, GP, and CA), and MD standard deviation (IC, CP, TH, and PU) resulted decreased (significant difference, p(cor) < 0.05, or trend of variation, P(uncor) < 0.05) in several gray and white matter regions of the human brain. With the exception of CP, the results in terms of revealed significant difference or trend of variation were independent of the method (LLS and NLLS) used for estimating the diffusion tensor. CONCLUSIONS: In various gray and white matter structures, the eight-channel array head coil yielded more precise and accurate measurements of DTI derived indices compared to the standard quadrature birdcage head coil. PMID- 21815396 TI - Validation of CT brain perfusion methods using a realistic dynamic head phantom. AB - PURPOSE: Development and evaluation of a realistic hybrid head phantom for the validation of quantitative CT brain perfusion methods. METHODS: A combination, or hybrid, of CT images of an anthropomorphic head phantom together with clinically acquired MRI brain images was used to construct a dynamic hybrid head phantom. Essential CT imaging parameters such as spatially dependent noise, effects of resolution, tube settings, and reconstruction parameters were intrinsically included by scanning a skull phantom using CT perfusion (CTP) protocols with varying mAs. These data were combined with processed high resolution 7T clinical MRI images to include healthy and diseased brain parenchyma, as well as the cerebral vascular system. Time attenuation curves emulating contrast bolus passage based on perfusion as observed in clinical studies were added. Using the phantom, CTP images were generated using three brain perfusion calculation methods: bcSVD, sSVD, and fit-based deconvolution, and the linearity and accuracy of the three calculation methods was assessed. Dependency of perfusion outcome on calculation method was compared to clinical data. Furthermore, the potential of the phantom to optimize brain perfusion packages was investigated. RESULTS: All perfusion calculation methods showed overestimation of low perfusion values and underestimation of high perfusion values. Good correlation in behavior between phantom and clinical data was found (R2 = 0.84). CONCLUSIONS: A dynamic hybrid head phantom constructed from CT and MRI data was demonstrated to realistically represent clinical CTP studies, which is useful for assessing CT brain perfusion acquisition, reconstruction, and analysis. PMID- 21815397 TI - 3-D fiducial motion tracking using limited MV projections in arc therapy. AB - PURPOSE: In-treatment fiducial tracking has recently received attention as a method for improving treatment accuracy, dose conformity, and sparing of healthy tissue. 3-D fiducial localization in arc-radiotherapy remains challenging due to the motion of targets and the complexity of arc deliveries. We propose a novel statistical method for estimating 3-D fiducial motion using limited 2-D megavoltage (MV) projections. METHODS: 3-D fiducial motion was estimated by a maximum a posteriori (MAP) approach to integrating information of fiducial projections with prior knowledge of target motion. To obtain the imaging geometries, short sequences of MV projections were selected in which fiducials were continuously visible. The MAP algorithm estimated the 3-D motion by maximizing the probability of displacement of fiducials in the sequences. Prior knowledge of target motion from a large statistical sample was built into the model to enhance the accuracy of estimation. In the case that a motion prior was unavailable, the algorithm can be simplified to the maximum likelihood (ML) approach. To compare tracking performance, a multiprojection geometric method was also presented by extending the typical two-project ion geometric estimation approach. The algorithms were evaluated using clinical prostate motion traces, and the performance was measured in quality indices and statistical evaluation. RESULTS: The results showed that the MAP method significantly outperforms the geometric method in all measures. In our simulations, the MAP method achieved an accuracy of less than 1 mm RMS error using only five continuous projections, whereas the geometric method required 15 projections to achieve a similar result. CONCLUSIONS: The approach presented can accurately estimate tumor motion using a limited number of continuous projections. The MAP motion estimation is superior to both the ML and geometric estimation methods. PMID- 21815399 TI - Computer-assisted trajectory planning for percutaneous needle insertions. AB - PURPOSE: Computed tomography (CT) guided minimally invasive interventions such as biopsies or ablation therapies often involve insertion of a needle-shaped instrument into the target organ (e.g., the liver). Today, these interventions still require manual planning of a suitable trajectory to the target (e.g., the tumor) based on the slice data provided by the imaging modality. However, taking into account the critical structures and other parameters crucial to the success of the intervention--such as instrument shape and penetration angle--is challenging and requires a lot of experience. METHODS: To overcome these problems, we present a system for the automatic or semiautomatic planning of optimal trajectories to a target, based on 3D reconstructions of all relevant structures. The system determines possible insertion zones based on so-called hard constraints and rates the quality of these zones by so-called soft constraints. The concept of pareto optimality is utilized to allow for a weight independent proposal of insertion trajectories. In order to demonstrate the benefits of our method, automatic trajectory planning was applied retrospectively to n = 10 data sets from interventions in which complications occurred. RESULTS: The efficient (graphics processing unit-based) implementation of the constraints results in a mean overall planning time of about 9 s. The examined trajectories, originally chosen by the physician, have been rated as follows: in six cases, the insertion point was labeled invalid by the planning system. For two cases, the system would have proposed points with a better rating according to the soft constraints. For the remaining two cases the system would have indicated poor rating with respect to one of the soft constraints. The paths proposed by our system were rated feasible and qualitatively good by experienced interventional radiologists. CONCLUSIONS: The proposed computer-assisted trajectory planning system is able to detect unsafe and propose safe insertion trajectories and may especially be helpful for interventional radiologist at the beginning or during their interventional training. PMID- 21815398 TI - Evaluation of the absorbed dose to the breast using radiochromic film in a dedicated CT mammotomography system employing a quasi-monochromatic x-ray beam. AB - PURPOSE: A dual modality SPECT-CT prototype system dedicated to uncompressed breast imaging (mammotomography) has been developed. The computed tomography subsystem incorporates an ultrathick K-edge filtration technique producing a quasi-monochromatic x-ray cone beam that optimizes the dose efficiency of the system for lesion imaging in an uncompressed breast. Here, the absorbed dose in various geometric phantoms and in an uncompressed and pendant cadaveric breast using a normal tomographic cone beam imaging protocol is characterized using both thermoluminescent dosimeter (TLD) measurements and ionization chamber-calibrated radiochromic film. METHODS: Initially, two geometric phantoms and an anthropomorphic breast phantom are filled in turn with oil and water to simulate the dose to objects that mimic various breast shapes having effective density bounds of 100% fatty and glandular breast compositions, respectively. Ultimately, an excised human cadaver breast is tomographically scanned using the normal tomographic imaging protocol, and the dose to the breast tissue is evaluated and compared to the earlier phantom-based measurements. RESULTS: Measured trends in dose distribution across all breast geometric and anthropomorphic phantom volumes indicate lower doses in the medial breast and more proximal to the chest wall, with consequently higher doses near the lateral peripheries and nipple regions. Measured doses to the oil-filled phantoms are consistently lower across all volume shapes due to the reduced mass energy-absorption coefficient of oil relative to water. The mean measured dose to the breast cadaver, composed of adipose and glandular tissues, was measured to be 4.2 mGy compared to a mean whole-breast dose of 3.8 and 4.5 mGy for the oil- and water-filled anthropomorphic breast phantoms, respectively. CONCLUSIONS: Assuming rotational symmetry due to the tomographic acquisition exposures, these results characterize the 3D dose distributions in an uncompressed human breast tissue volume for this dedicated breast imaging device and illustrate advantages of using the novel ultrathick K-edge filtered beam to minimize the dose to the breast during fully 3D imaging. PMID- 21815400 TI - Accounting for the fringe magnetic field from the bending magnet in a Monte Carlo accelerator treatment head simulation. AB - PURPOSE: Monte Carlo (MC) simulation can be used for accurate electron beam treatment planning and modeling. Measurement of large electron fields, with the applicator removed and secondary collimator wide open, has been shown to provide accurate simulation parameters, including asymmetry in the measured dose, for the full range of clinical field sizes and patient positions. Recently, disassembly of the treatment head of a linear accelerator has been used to refine the simulation of the electron beam, setting tightly measured constraints on source and geometry parameters used in simulation. The simulation did not explicitly include the known deflection of the electron beam by a fringe magnetic field from the bending magnet, which extended into the treatment head. Instead, the secondary scattering foil and monitor chamber were unrealistically laterally offset to account for the beam deflection. This work is focused on accounting for this fringe magnetic field in treatment head simulation. METHODS: The magnetic field below the exit window of a Siemens Oncor linear accelerator was measured with a Tesla-meter from 0 to 12 cm from the exit window and 1-3 cm off-axis. Treatment head simulation was performed with the EGSnrc/BEAMnrc code, modified to incorporate the effect of the magnetic field on charged particle transport. Simulations were used to analyze the sensitivity of dose profiles to various sources of asymmetry in the treatment head. This included the lateral spot offset and beam angle at the exit window, the fringe magnetic field and independent lateral offsets of the secondary scattering foil and electron monitor chamber. Simulation parameters were selected within the limits imposed by measurement uncertainties. Calculated dose distributions were then compared with those measured in water. RESULTS: The magnetic field was a maximum at the exit window, increasing from 0.006 T at 6 MeV to 0.020 T at 21 MeV and dropping to approximately 5% of the maximum at the secondary scattering foil. It was up to three times higher in the bending plane, away from the electron gun, and symmetric within measurement uncertainty in the transverse plane. Simulations showed the magnetic field resulted in an offset of the electron beam of 0.80 cm (mean) at the machine isocenter for the exit window only configuration. The fringe field resulted in a 3.5%-7.6% symmetry and 0.25-0.35 cm offset of the clinical beam R(max) profiles. With the magnetic field included in simulations, a single (realistic) position of the secondary scattering foil and monitor chamber was selected. Measured and simulated dose profiles showed agreement to an average of 2.5%/0.16 cm (maximum: 3%/0.2 cm), which is a better match than previously achieved without incorporating the magnetic field in the simulation. The undulations from the 3 stepped layers of the secondary scattering foil, evident in the measured profiles of the higher energy beams, are now aligned with those in the simulated beam. The simulated fringe magnetic field had negligible effect on the central axis depth dose curves and cross-plane dose profiles. CONCLUSIONS: The fringe magnetic field is a significant contributor to the electron beam in plane asymmetry. With the magnetic field included explicitly in the simulation, realistic monitor chamber and secondary scattering foil positions have been achieved, and the calculated fluence and dose distributions are more accurate. PMID- 21815401 TI - Studies on separating the impedance change components of blood vessels and ventricles in thorax from mixed impedance signals on chest surface. AB - PURPOSE: The aim of the present study is to separate the impedance change components of the blood vessels and ventricles in thorax from the mixed impedance signals detected on the chest surface. METHODS: The mixed impedance signals on the chest surface are measured with a 15 electrode lead system. The thoracic impedance equations are established and solved iteratively with the algebraic reconstructed technique. Experiments were performed on 80 healthy, otherwise normal, adults. RESULTS: Five impedance change components for the aorta (AO), blood vessel in left lung (PL), blood vessel in right lung (PR), left ventricle (LV), and right ventricle (RV) are separated from the mixed impedance signals. The experiments show that the main waveform of the ventricular components LV and RV is contrary to that of the vascular components AO, PL, and PR, and the negative peak point of the waveform graphs of LV and RV are in phase with the second cardiac sound (S2). The waveform graphs of various components correspond with the physiological activities of the heart and blood vessels in a cardiac cycle. The statistical results for 80 normal adults show that the amplitude of AO is the largest and that of PL and PR is the next, while that of LV and RV is the smallest. There are significant differences between them (P < 0.01). CONCLUSIONS: The mathematical model and the measurement method for the separation in the present paper are feasible. PMID- 21815402 TI - Iridoid glucosides from Wendlandia tinctoria roots. AB - A new iridoid glucoside, 8-O-(E)-caffeoylmussaenosidic acid (1), together with ixoside (2), was isolated from the roots of Wendlandia tinctoria. The structure of the new compound was established on the basis of detailed spectroscopic (2D NMR) and chemical analysis. PMID- 21815403 TI - Janceolaroside A and janceoside A, two new compounds from the stems and roots of Jasminum lanceolarium. AB - From the stems and roots of Jasminum lanceolarium Roxb., two new compounds, janceolaroside A and janceoside A, have been isolated along with three known compounds, (-)olivil 4'-O-beta-D-glucopyranoside, (+)-cycloolivil-6-O-beta-D glucopyranoside and syringin. The structures of the new compounds were determined by spectroscopic methods. PMID- 21815404 TI - Chionanthus virginicus L.: phytochemical analysis and quality control of herbal drug and herbal preparations. AB - Root barks of Chionanthus virginicus L. are used in homeopathic medicines in the treatment of icterus and hepatitis. The objective of this study is to identify novel secoiridoids and lignans and to develop a simple and reliable HPLC method for the determination of oleuropein, phillyrin, total secoiridoids and total lignans for quality control and stability studies of C. virginicus herbal drug and preparations. Secoiridoids and lignans were purified by preparative HPLC. Compounds previously described were identified by HPLC according to their retention times and UV spectra. Structures of new compounds were determined by NMR. Two compounds namely excelside B and acetoxypinoresinol-4"-O-beta-D glucoside are described for the first time in the drug. HPLC separation was performed on Symmetry C18 (Waters) by gradient elution using acetonitrile and 0.2% aqueous phosphoric acid. The method was validated for specificity, linearity, precision, accuracy, limits of detection and quantification for simultaneous determination of secoiridoids and lignans in herbal drug and herbal preparations as mother tinctures. The proposed HPLC method is linear in the range studied (r2 > or = 0.9989) for all the analytes. The method is precise with intra and inter-day variations of less than 4%. The mean recoveries of the analytes range from 99.65 to 102.81%. The method is successfully applied to the quantification of nine compounds belonging to secoiridoids and lignans and for the stability studies of these compounds. The study allowed completing the phytochemical knowledge of C. virginicus. This simple developed assay could be used as tools for routine quality control of C. virginicus herbal drug and herbal medicinal products. PMID- 21815405 TI - Solid state structure and absolute configuration of filifolinol acetate. AB - Careful reevaluation of the 1H and 13C NMR spectroscopic data of filifolinol acetate (4) led to the reassignment of the C-10 and C-11 signals, as well as the gem-dimethyl signals. Single crystal X-ray analysis provided an independent structural confirmation of 4, and comparison of the experimental vibrational circular dichroism spectrum with calculations performed using density functional theory provided the absolute configuration of this 3H-spiro-1-benzofuran-2,1' cyclohexane and related molecules. PMID- 21815406 TI - A novel sesquiterpene alcohol from Fimetariella rabenhorstii, an endophytic fungus of Aquilaria sinensis. AB - A novel sesquiterpene alcohol, named frabenol (1), was isolated from liquid cultures of Fimetariella rabenhorstii A20, an endophytic fungus of the agarwood forming plant Aquilaria sinensis (Lour.) Gilg. The structure of the new compound was elucidated on the basis of spectroscopic methods. The finding of a sesquiterpenoid compound in F. rabenhorstii A20 implied that endophytic fungi of agarwood-producing plants could also contribute to the generation of fragrant chemicals during the agarwood formation processes. PMID- 21815407 TI - Lipophilic components from the Ecuadorian plant Schistocarpha eupatorioides. AB - Phytochemical investigation of secondary metabolites of the Ecuadorian plant Schistocarpha eupatorioides (Fenzl) Kuntze (Asteraceae) afforded three phytyl fatty acid esters along with a mixture of unidentified polyprenols, the very well known sterols beta-sitosterol and stigmasterol, and their corresponding fatty acid esters and glucosyl derivatives. The structures of the compounds were elucidated on the basis of various spectroscopic means. In addition, a volatile fraction was separated the composition of which, comprising sesquiterpene hydrocarbons as the main fraction, was determined by GC-MS. PMID- 21815408 TI - Terpenoid metabolites from Spongia spp. and their effects on nucleic acid biosynthesis in sea urchin eggs. AB - 19-Norspongia-13(16),14-diene-3-one (1) was isolated for the first time from a natural source, along with a series of known spongiane diterpenoids (2-11) and sesquiterpene (12) from two unidentified species belonging to the genus Spongia. The effects of 1, 4, 5, 8-12 on biosynthesis of nucleic acids and embryonic development of the sea urchin Strongylocentrotus intermedius have been studied. All the compounds inhibit sea urchin embryo development at concentration of 20 microg/mL and above and DNA biosynthesis at the dose of 10 microg/mL. The inhibitory effect of diterpenoids at least partly may be explained by the inhibition of thymidine kinase activity. PMID- 21815409 TI - Evaluation of ent-kaurenoic acid derivatives for their anticariogenic activity. AB - Ent-kaur-16(17)-en-19-oic acid (kaurenoic acid, KA) is a tetracyclic diterpene prototype for natural anticaries agents. Six KA derivatives were prepared and their antimicrobial activity against the main microorganisms involved in the caries process evaluated. The sodium salt of KA (KA-Na) was the most active, displaying very promising MIC values for most pathogens. Time-kill assays against the primary causative agent of caries (Streptococcus mutans) indicated that KA and KA-Na only inhibited growth in the first 12 h, suggesting a bacteriostatic effect. After this period (12-24 h), their bactericidal effect was clearly noted. KA and KA-Na showed no synergy when combined with the gold standard anticariogenic (chlorhexidine dihydrochloride, CHD) in the checkerboard assays against S. mutans. PMID- 21815410 TI - Microbial transformation of deoxyandrographolide by Alternaria alternata AS 3.4578. AB - Biotransformation of deoxyandrographolide (1) by Alternaria alternata AS 3.4578 gave five derivatives identified by spectral methods including 2D NMR as the known dehydroandrographolide (2) and 9beta-hydroxy-dehydroandrographolide (3) and the new compounds 9beta-hydroxy-deoxyandrographolide (4), 3alpha,17,19-trihydroxy 8,13-ent-labdadien-15,16-olide (5) and 3-oxo-9beta-hydroxy-deoxyandrographolide (6). PMID- 21815411 TI - Limonoids from Meliaceae with lipid peroxidation inhibitory activity. AB - In this study the antioxidant activity of natural limonoids from Meliaceae swietenolide (1), 3,6-O,O-diacetylswietenolide (2), swietenine (3), swietemahonin G (4) and 2-hydroxyswietenine (5) were investigated along with the semi-synthetic analogues (6-25) of compounds 1, 3-4. Lipid peroxidation (LPO) inhibitory assays revealed 85.6, 13.3, 77.3, 61.2 and 24.6% inhibition for the natural compounds 1 5. Excellent antioxidant activity was seen for the semi-synthetic analogues 10 (98.3%), 16-17, 21-22 and 25 (100%), which were more active than the positive controls BHA (91.3%) and TBHQ (95.7%). PMID- 21815412 TI - Chemical diversity of iridal-type triterpenes in Iris delavayi collected in Yunnan Province of China. AB - From Iris delavayi collected in the northwestern Yunnan Province of China, eight iridal-type triterpenoids were isolated, three of which were new. Both 2(7)Z- and 2(7)E-iridals were isolated in about equal amounts from the sample collected at Laojunshan, while only 2(7)Z-iridals were isolated from samples collected in Shangrila area, indicating the presence of chemical diversity in the species. PMID- 21815413 TI - Triterpene derivatives from Abies spectabilis leaves of Nepalese origin. AB - Our ongoing studies of Nepalese medicinal plants has led to the isolation and characterization of five new triterpenes, two known triterpenes and two phenolic derivatives from Abies spectabilis (D.Don) Mirb leaves grown in the high mountain. The structures of the isolated compounds were characterized by means of 1D and 2D NMR spectroscopic and MS techniques. PMID- 21815414 TI - Quinone reductase inducing activity of the dichloromethane /ethanol extract of the roots of Pulsatilla chinensis. AB - Agents with phase II enzyme inducing activities play important roles in intervening in the carcinogenic process. In the present study, the quinone reductase (QR) inducing activities of nine known triterpene saponins from the dichloromethane/ethanol extract of the roots of Pulsatilla chinensis were tested. The oleanane saponins exhibited more potent QR inducing activities than the lupane saponins, and the CD value of the compound with the most potent QR inducing activity was 1.1 microM. The chemopreventive activity of the dichloromethane/ethanol extract was also evaluated using the DMBA-induced mice model. PMID- 21815415 TI - Cytotoxic cardenolide and sterols from Calotropis gigantea. AB - The dichloromethane extract from the leaves of Calotropis gigantea Linn. was strongly cytotoxic against non-small cell lung carcinoma (A549), colon carcinoma (HCT 116) and hepatocellular carcinoma (Hep G2), and non toxic to Chinese hamster ovary (AA8). The extract afforded uscharin (1), 3,5,8-trihydroxy-24-methylcholest 6,22-diene (2), a mixture of (24R)-3beta-hydroxy-24-ethylcholest-5-en-7-one (3a) and 6beta-hydroxy-24-ethylcholest-4,22-dien-3-one (3b), and another mixture of (24R)-24-ethylcholest-4-en-3-one (4a) and (24S)-24-ethylcholest-4,22-dien-3-one (4b). Cardenolide 1 exhibited extreme toxicity to A549, HCT 116 and Hep G2 with IC50 values of 0.003 microg/mL, 0.013 microg/mL, and 0.018 microg/mL, respectively, while sample 3 exhibited an IC50 of 1.35 microg/mL, 4.46 microg/mL, and 3.83 microg/mL, respectively. PMID- 21815416 TI - Sartoryglabrins, analogs of ardeemins, from Neosartorya glabra. AB - Chemical investigation of a collection of the fungus Neosartorya glabra from Thailand furnished sartoryglabins A-C (1a, 1b and 2) which are analogs of the reverse prenylated indole alkaloids known as (-) ardeemins. Structures of these compounds were established by NMR spectrometry and an X-ray analysis. Sartoryglabins A-C were evaluated for their in vitro growth inhibitory activity on three human tumor cell lines: MCF-7 (breast adenocarcinoma), NCI-H460 (non small cell lung cancer) and A375-C5 (melanoma). All the compounds exhibited strong to moderate activity against the MCF-7 cell line but weak or no activity against the NCI-H460 and A375-C5 cell lines. Sartoryglabin B was found to exhibit selectivity towards the MCF-7 cell line. PMID- 21815417 TI - Identification by LC-ESI-MS of flavonoids responsible for the antioxidant properties of Mallotus species from Vietnam. AB - Several Mallotus species (Euphorbiaceae) are used in Vietnam as edible plants or as traditional medicines for different indications, some related to the treatment of inflammatory diseases. This study investigated the antioxidant activities of 33 samples from 17 Vietnamese Mallotus species. We also evaluated potential cytotoxic activity against human cervix carcinoma HeLa and human lung fibroblast WI-38 cells. Our aim is to develop safe dietary supplements with a protective effect against various diseases caused by tissue damage and the acceleration of the aging process linked to reactive oxygen species. These tests allowed the identification of non-cytotoxic plant species exhibiting significant antiradical properties. These antioxidant properties may be explained by their polyphenol composition. The antioxidant activity of the most active Mallotus species was further analyzed with and without tannins removal. We also identified by LC-ESI MS some flavonoids responsible for a part of this activity. PMID- 21815418 TI - Antiradical and cytotoxic activity of different Helichrysum plicatum flower extracts. AB - Flowers of Helichrysum plicatum were extracted under different experimental conditions, and their antioxidant activity was determined by DPPH radical scavenging assay. Extracts obtained with higher concentration of ethyl acetate (90% or 100%) were found to contain the greatest amount of total phenolics (> 250 mg gallic acid equivalents/g of dried extract), and high correlation between total phenolic content and antiradical activity was observed (r = -0.79). Based on the total phenolic content and antiradical activity, some extracts were selected for investigation of cytotoxic activity toward PC3, HeLa and K562 human cancer cell lines in vitro. All tested extracts exhibited moderate activity against HeLa cells (41.9-42.1 microg/mL), whereas the extract obtained with 100% ethyl acetate was the most active against K562 and PC3 cell lines (25.9 and 39.2 microg/mL, respectively). Statistical analysis revealed significant correlation between total phenolic content and cytotoxic activity against PC3 and K562 cells. HPLC identification of phenolic compounds from the extracts indicated the presence of apigenin, naringenin and kaempferol as free aglycones, and glycosides of apigenin, naringenin, quercetin and kaempferol. Among aglycones, kaempferol displayed moderate cytostatic activity against all cell lines (24.8-64.7 microM). PMID- 21815419 TI - Chemical composition of Argentinean propolis collected in extreme regions and its relation with antimicrobial and antioxidant activities. AB - This paper reveals, for the first time, the functional properties of propolis from an extreme region of Argentine (El Rincon, Province of Catamarca, Argentina), as well as the isolation and identification of bioactive compounds. The antioxidant activity was determined by the ABTS method and beta-carotene bleaching. The antibacterial activity was determined on methicillin resistant Staphylococcus aureus (MRSA) by the microdilution method and bioautographic assays. Twelve compounds were isolated and identified by NMR spectroscopy. The main bioactive compounds were 2',4'-dihydroxy-3'-methoxychalcone (3), 2',4' dihydroxychalcone (9), 2',4',4-trihydroxy-6'- methoxychalcone (8), 5-hydroxy-4',7 dimethoxyflavone (4), 4',5-dihydroxy-3,7,8-trimethoxyflavone (10) and 7-hydroxy- 5,8-dimethoxyflavone (11). All compounds were active against clinical isolates (MIC50 10 microg/mL) and displayed antioxidant activity (SC50 values of 20 microg/mL). The MIC and SC50 values of the isolated compounds were lower than those obtained with crude propolis extracts, chloroform sub-extracts and isolated fractions. PMID- 21815420 TI - Tannins of tamarind seed husk: preparation, structural characterization, and antioxidant activities. AB - The high content (about 39%) of polymeric tannins in tamarind (Tamarindus indica L.) seed husk (TSH) was demonstrated, and an extract (crude TSE) with a high content (about 94%) of polymeric tannins was prepared from TSH with a one pot extraction using ethanol/water (3:2, v/v). The crude TSE was further purified with Sephadex LH20 to give one fraction (metTSE) eluted with methanol/water (3:2, v/v) and another (acTSE) eluted with acetone/water (3:2, v/v). The tannins of acTSE were established as polymeric proanthocyanidins (PA) by 13C NMR spectroscopy; this was further confirmed by IR and UV spectroscopy, n-BuOH/HCl and vanillin assays, and from HPLC pattern. The ratio of procyanidins to prodelphinidins was 2:3, and the average degree of polymerization of acTSE was 7. Galloylated flavan-3-ols were not detected in acTSE. The main ingredients of metTSE were confirmed to be polymeric PA by 13C NMR spectroscopy. The antioxidant activities using DPPH and ABTS assays were investigated. The IC50 values of acTSE were 4.2 +/- 0.2 (DPPH assay) and 6.2 +/- 0.3 microg/mL (ABTS assay). PMID- 21815421 TI - Chemical constituents of the new endophytic fungus Mycosphaerella sp. nov. and their anti-parasitic activity. AB - Chemical investigation of a new endophytic fungus, Mycosphaerella sp. nov. strain F2140, associated with the foliage of the plant Psychotria horizontalis (Rubiaceae) in Panama, resulted in the isolation of cercosporin (1) and a new cercosporin analog (3) as the major components. The structures of minor compounds in the extract were elucidated by detailed spectroscopic analysis as 2-(2-butyl) 6-ethyl-3-hydroxy-6-methylcyclohex-2-ene-1,5-dione (4), 3-(2-butyl)-6-ethyl-5 hydroxy-2-methoxy-6-methyl-cyclohex-2-enone (5), and an isomer of 5 (6). To study the influence of the hydroxy groups on the anti-parasitic activity of cercosporin, compound 1 was acetylated to obtain derivative 2. The isolated compounds 1- 6 were tested in vitro to determine their anti-parasitic activity against the causal agents of malaria (Plasmodium falciparum), leishmaniasis (Leishmania donovani), and Chagas disease (Trypanosoma cruzi). Cytotoxicity and potential anticancer activity of these compounds were evaluated using mammalian Vero cells and MCF7 cancer cell lines, respectively. Compounds 1 and 2 displayed high potency against L. donovani (IC50 0.46 and 0.64 microM), T. cruzi (IC50 1.08 and 0.78 microM), P. falciparum (IC50 1.03 and 2.99 microM), and MCF7 cancer cell lines (IC50 4.68 and 3.56 microM). Compounds 3-6 were not active in these assays at a concentration of 10 microg/mL. PMID- 21815422 TI - Synthesis of a 4H-anthra[1,2-b]pyran derivative and its antimicrobial activity. AB - The five-step synthesis of the new 4H-anthra[1,2-b]pyran derivative 1 is reported. The key steps in this approach included a Marschalk alkylation of 1,4 dihydroxyanthraquinone followed by a Baker-Venkataraman reaction and then an acid catalyzed cyclization of ring A to form the 4H-anthra[1,2-b]pyran system. Two compounds, the 4H-anthra[1,2-b]pyran 1 and the anthraquinone derivative 6 were evaluated for antimicrobial activity and showed moderate antialgal, antifungal, and antibacterial activities. PMID- 21815423 TI - Antioxidant activity and total phenolic content in shiitake mycelial exudates. AB - Exudates (DE) secreted from two shiitake mushroom mycelia (strains 1358 and L5458) were evaluated for their antioxidative properties and phenolic content. 1358DE and L5458DE showed distinct antioxidant activity in different in vitro assays, including scavenging activity on 1,1-diphenyl-2-picrylhydrazyl (DPPH) radicals, hydroxyl radical, superoxide anions and hydrogen peroxide; the ability to chelate ferrous ions; reducing power; hemolysis inhibition activity in rat erythrocyte; and lipid peroxidation inhibition (IC50 values of 1358DE and L5458DE were 3.3 and 132.6; 44.5 and > 1000; 26.9 and 53.7; 153.6 and > 175.0; 176.0 and 521.0; 26.7 and 746.4; 47.8 and 736.9; and 3.1 and > 1000 microg/mL, respectively). Their total phenolic content was 237.33 and 24.08 mg gallic acid equivalent (GAE)/g of dry DE, respectively. Overall, these results show that 1358DE generally possesses better antioxidant properties than L5458DE, possibly due to its larger total phenolic content. Shiitake mushroom mycelial exudates, particularly of 1358DE, could be a good source of natural antioxidants. PMID- 21815424 TI - Phenylethyl cinnamides as potential alpha-glucosidase inhibitors from the roots of Solanum melongena. AB - Bioassay-guided fractionation against alpha-glucosidase resulted in isolation and identification of six phenolic compounds (1-6) from the 70% EtOH extract of the roots of Solanum melongena L. (Solanaceae). Of these, three phenylethyl cinnamides, N-trans-feruloyl tyramine (1), N-trans-p-coumaroyl tyramine (2) and N cis-p-coumaroyl tyramine (3) possessed inhibitory activity against alpha glucosidase with IC50 values of 500.6, 5.3 and 46.3 microM, respectively. Mechanism analysis revealed these phenylethyl cinnamides were non-competitive inhibitors. This is the first study of the alpha-glucosidase inhibitory activities of the roots of S. melongena, and this preliminary observation suggested potential medicinal use of this herb. PMID- 21815425 TI - New phenylalkanoids from Zingiber officinale. AB - Two new phenylalkanoids, 3-hydroxy-1-(4'-hydroxy-3'-methoxy-phenyl)-hexan-5-one (1) and 3-hydroxy-1-(3',5'-dimethoxy-4'-hydroxyphenyl)-hexan-5-one (2) were isolated from the rhizomes of Chinese ginger (Zingiber officinale Roscoe (Zingiberaceae)). The structures of two new phenylalkanoids were elucidated by chemical and physical evidence. PMID- 21815426 TI - Valine and phenylalanine as precursors in the biosynthesis of alkamides in Acmella radicans. AB - Acmella radicans (Asteraceae) produces at least seven alkamides, most with either an isobutyl- or phenylethyl group as the amine moiety. These moieties suggest that the amino acids valine and phenylalanine are the biosynthetic precursors of these alkamides. On the basis of labeled feeding experiments using either L [2H8]valine or L-[2H8]phenylalanine we present evidence for the involvement of these two amino acids in the biosynthesis of (2E,6Z,8E)-N-isobutyl-2,6,8 decatrienamide (affinin) (1), (2Z,4E)-N-(2-phenylethyl)-2,4-octadienamide (2), (2E)-N-(2-phenylethyl)-nona-2-en-6,8-diynamide (3), and 3-phenyl-N-(2 phenylethyl)-2-propenamide (4). Alkamides were isolated from young A. radicans plants and analyzed by gas chromatography-mass spectrometry (GC-MS). Additionally, in cell free in vitro experiments based on isobutyl and phenylethylamide biosynthesis, using a colorimetric assay and GC-MS, valine and phenylalanine decarboxylase activities were assayed in the soluble extract of A. radicans leaves. PMID- 21815427 TI - A novel antinociceptive sulphated polysaccharide of the brown marine alga Spatoglossum schroederi. AB - Sulfated polysaccharides (SP) of brown algae (Phaeophyta) are composed mainly of alpha- L-fucose, being classified as fucans, with recognized role in inflammation but not in nociception, which was already described for SP obtained from red algae. Here the SP of the brown marine alga S. schroederi (named Ss-SP) was isolated and assayed for the antinociceptive effect. Ss-SP was isolated by DEAE cellulose, analyzed by agarose gel electrophoresis and evaluated in nociception models (Formalin, Hot plate, Von Frey) using Swiss mice (20-25g). Anion exchange chromatography provided four major fractions being F1 (Ss-SP) that of highest metachromatic activity and sugar content. Ss-SP inhibited both phases of the formalin test. In the first phase the paw licking (55.2 +/- 8.07s) was reduced by 45% (30.5 +/- 6.51s) and 40% (32.85 +/- 8.66s) at 0.1 and 1 mg/kg, respectively. In the second phase, Ss-SP was also inhibitory about 39%, but only at 1 mg/kg (83.0 +/- 15.70s) compared to formalin (136.8 +/- 10.27s). This inhibitory effect suggests a mixed mechanism similar to morphine, which was not confirmed in the hot plate test, a model of pain associated with central neurotransmission. However, Ss-SP reduced the animal reaction in response to stimulation withVon Frey filament at the 2nd and 3rd h (20.8 +/- 6.86% versus carrageenan: 47.9 +/- 5.83%; 33.3 +/- 7.71% versus carrageenan: 62.5 +/- 9.83%). Accordingly, the paw edema induced by carrageenan (0.08 +/- 0.01g) was potently reduced in 45.35% by Ss-SP pre-treatment (0.02 +/- 0.003g), corroborating the anti-inflammatory activity demonstrated for brown seaweed polysaccharides. In conclusion our data revealed for the first time the antinociceptive effect of Ss-SP which could be used as a new source of analgesic substances. PMID- 21815428 TI - Orally administered Dendrobium officinale and its polysaccharides enhance immune functions in BALB/c mice. AB - The immunoactivity was evaluated of Dendrobium officinale Kimura & Migo, a Chinese herbal plant, and its crude polysaccharides. Different dosages of D. officinale and its polysaccharides were orally administered to healthy BALB/c mice. The control group was given distilled water. After 4 weeks, immune parameters, including cellular immunity (delayed-type hypersensitivity and natural killer cell activity), humoral immunity (serum hemolytic complement activity), nonspecific immunity (peritoneal macrophage phagocytosis) and interferon-gamma production by splenocytes were measured. The results showed that D. officinale and its polysaccharides can significantly enhance cellular immunity and nonspecific immunity in mice. Humoral immunity was also enhanced after oral administration of D. officinale, but the polysaccharides had no influence. Both D. officinale and its polysaccharides markedly increased IFN-gamma production by murine splenocytes. Six fractions were isolated from the polysaccharides; the molecular weight of the major fraction was 533,700 Da, and composed of mannose, glucose and rhamnose in a molar ratio of 7.3:1.3:1.0. PMID- 21815429 TI - Hypotensive effects of the Crotalus durissus cascavella venom: involvement of NO. AB - Crotalus durissus cascavella is a snake native of northeastern Brazil. The aim of the study was to investigate the effects of C. d. cascavella venom on rat mean arterial pressure and vascular reactivity in the mesenteric vascular bed. The venom evoked a dose-dependent decrease in mean arterial pressure, cardiac and respiratory frequency with increased plasma nitrite levels. L-NAME (10 mg/kg) blunted both the hypotension and increased nitrite production observed after the venom administration. To investigate the effects of C. d. cascavella in resistance vessels, the vascular mesenteric bed was studied, and the results suggested that the hypotensive effect of the venom is not dependent on a direct vasodilatory activity. In conclusion, C. d. cascavella venom presented indirect hypotensive effects with the involvement of nitric oxide. PMID- 21815430 TI - Citrus essential oil of Nigeria. Part V: Volatile constituents of sweet orange leaf oil (Citrus sinensis). AB - The volatile oils extracted from leaves of eight cultivars of Citrus sinensis (L) Osbeck were comprehensively analysed by a combination of GC and GC-MS. Fifty four constituents accounting for 82.3-98.2% were identified. Sabinene (20.9-49.1%), delta-3-carene (0.3-14.3%), (E)-beta-ocimene (4.4-12.6%), linalool (3.7-11.1%) and terpinen-4-ol (1.7-12.5%) were the major constituents that are common to all the volatile oils. In addition, a cluster analysis was carried out and indicated at least four different chemotypes for the C. sinensis cultivars. PMID- 21815431 TI - Comparison of the essential oils of leaves and stem bark from two different populations of Drimys winteri a Chilean herbal medicine. AB - The chemical composition of the essential oils obtained by hydrodistillation of stem bark and leaves of Drimys winteri J.R. et G. Foster var. chilensis /DC A. Gray (Winteraceae) from Chiloe Island (ID) and Continental Chile (Santiago) (CD) were studied by GC and GC/MS. Sesquiterpene hydrocarbons constituted the main chemical groups in the stem bark oils, with alpha-santalene, trans-beta bergamotene and curcumenes as the major components. Monoterpenes constituted the main chemical groups in the leaves of Island plants with alpha-pinene (23.1%) beta-pinene (43.6%) and linalool (10.5%) as the main components whereas sesquiterpenes (germacrene D 17.6%) and phenylpropanoids (safrole 20.8%) are the most abundant in the leaves of Continental plants. PMID- 21815432 TI - A myristicin-rich essential oil from Daucus sahariensis growing in Algeria. AB - The essential oils obtained by hydrodistillation from leaves and fruits of Daucus sahariensis Murb. were analyzed by GC/MS. The main constituents of the essential oil from the leaves were myristicin (34.3%), alpha-pinene (5.4%), cis chrysanthenyl acetate (5.3%) and epi-alpha-bisabolol (4.8%), and those from the fruits myristicin (43.9%), alpha-pinene (13.1%), limonene (9.4%), and cis chrysanthenyl acetate (7.4%). Myristicin, the main constituent of both essential oils, is generally absent in the oils from other Daucus species, permitting the hypothesis that this compound is a chemical marker of this Saharan species. PMID- 21815433 TI - Activity of Schinus areira (Anacardiaceae) essential oils against the grain storage pest Tribolium castaneum. AB - Essential oils extracted from leaves and fruits of Schinus areira (Anacardiaceae) were tested for their repellent, toxic and feeding deterrent properties against Tribolium castaneum (Coleoptera: Tenebrionidae) larvae and adults. A topical application assay was employed for the contact toxicity study and filter paper impregnation for the fumigant assay. A treated diet was also used to evaluate the repellent activity and a flour disk bioassay for the feeding deterrent action and nutritional index alteration. The essential oil of the leaves contained mainly monoterpenoids, with alpha-phellandrene, 3-carene and camphene predominant, whereas that from the fruits contained mainly alpha-phellandrene, 3-carene and beta-myrcene. The leaf essential oil showed repellent effects, whereas that from the fruit was an attractant. Both oils produced mortality against larvae in topical and fumigant bioassays, but fumigant toxicity was not found against adults. Moreover, both essential oils produced some alterations in nutritional index. These results show that the essential oils from S. areira could be applicable to the management of populations of Tribolium castaneum. PMID- 21815434 TI - Acaricidal activity against Tetranychus urticae and essential oil composition of four Croton species from Caatinga biome in northeastern Brazil. AB - Volatile components of essential oils from the leaves and stems of Croton jacobinensis, C. rhamnifolius, C. muscicapa and C. micans, which are medicinal plants found in the Caatinga biome of northeastern Brazil, were analyzed using GC and GC/MS. The acaricidal activity of these oils against Tetranychus urticae was evaluated using the fumigation method. Oil yields from the Croton species ranged from 1.1 +/- 0.0 to 0.6 +/- 0.0%, w/w, for leaves and 0.7 +/- 0.0 to 0.1 +/- 0.0% for stems. Sesquiterpenoids were dominant in all oils, except the stem oil from C. rhamnifolius, which exhibited a high monoterpene content, and the leaf and stem oils from C. muscicapa, which were rich in phenylpropanoids. The major volatile components of the leaf and stem oils from C. jacobinensis were (Z)-alpha atlantone (24.3 +/- 0.4%) and trans-isolongifolanone (22.8 +/- 0.5%), respectively. The most abundant constituents detected in C. rhamnifolius were alpha-cedrene epoxide (23.3 +/- 0.1%) and caryophyllene oxide (21.9 +/- 0.0%) in the leaf oil, and camphor (16.6 +/- 0.5%) and tricyclene (12.8 +/- 0.1%) in the stem oil. Foenicolin was the main compound identified in the leaf (50.6 +/- 0.2%) and stem (72.7 +/- 0.6%) oils of C. muscicapa, while alpha-bulnesene (32.9 +/- 0.2%) and guaiol (17.9 +/- 0.7%) were the principal components of C. micans oils. These oils exhibited a high degree of toxicity in the fumigation assay. The stem oils from C. jacobinensis and C. rhamnifolius exhibited high lethality rates, with LC50 values of 0.3 and 0.2 microL/L of air after 24 h, respectively. The results suggest the potential use of stem essential oil, especially from C. rhamnifolius and C. jacobinensis, for the integrated control of Tetranychus urticae. PMID- 21815435 TI - Composition, antioxidant and antimicrobial activities of leaf and twig essential oils of Litsea akoensis from Taiwan. AB - This study analyzed the hydrodistilled essential oils in the leaves and twigs of Litsea akoensis to determine composition and yield. Seventy-one and 40 compounds were identified in the leaf and twig oils, respectively. The main components of leaf oil were limonene (18.5%), thymol (10.1%), p-cymene (9.6%), beta caryophyllene (8.9%), and carvacrol (8.2%). The main components of twig oil were beta-phellandrene (43.7%) and trans-beta-ocimene (10.4%). The results demonstrated that leaf oil had excellent antioxidant and antimicrobial activities, superior to those of twig oil. PMID- 21815436 TI - Composition and antimicrobial activity of Achillea distans essential oil. AB - The essential oil of Achillea distans W. et K. flower heads was analyzed by GC and GC-MS. Altogether 43 components in concentrations more than 0.1% were identified representing 93.5% of the oil composition. The main constituents were 1,8-cineole (16.8%), trans-thujone (9.8%), sabinene (8.2%), borneol (7.5%), beta pinene (6.5%), and camphor (5.8%). The oil showed moderate activity against Staphylococcus aureus and Candida albicans, and weak activity against Salmonella typhimurium, Proteus vulgaris, and Escherichia coli. PMID- 21815437 TI - Chemical composition and antioxidant, antimicrobial, and larvicidal activities of the essential oils of Annona salzmannii and A. pickelii (Annonaceae). AB - The essential oils from the leaves of Annona salzmannii and A. pickelii (Annonaceae) growing in Sergipe, northeastern region of Brazil, were obtained by hydrodistillation using a Clevenger-type apparatus, and analyzed by GC/MS and GC/FID. Thirty-four compounds were identified in the essential oil of A. salzmannii and twenty-seven in that of A. pickelii; sesquiterpenes predominated in both essential oils. Bicyclogermacrene (20.3%), (E)-caryophyllene (19.9%), delta-cadinene (15.3%), alpha-copaene (10.0%), and allo-aromadendrene (5.7%) were the main components of A. salzmannii, and bicyclogermacrene (45.4%), (E) caryophyllene (14.6%), and alpha-copaene (10.6%) of A. pickelii. The essential oils showed significant antioxidant capacity in the ORAC(FL) and DPPH assays. The antimicrobial activity of these essential oils was also evaluated against bacteria and fungi, as well as the larvicidal activity against Aedes aegypti larvae. PMID- 21815438 TI - Chemical and pharmacological aspects of the genus Cecropia. AB - The Cecropia genus consists of about 60 species distributed throughout Latin America, mostly in Brazil. These species are widely used in traditional medicine to treat cough, asthma, bronchitis, high blood pressure, inflammation, heart disease, and as a diuretic. In recent years, there has been an increase in research on Cecropia species, with several phytochemical and pharmacological reports. Concerning its chemical composition, C-glycosylflavonoids and proanthocyanidins have been described as the main constituents of C. glaziovii, C. hololeuca and C. pachystachya, while terpenoids and steroids have been reported in several species, including C. adenopus and C. pachystachya. Among the pharmacological properties described for the genus, the most frequently reported are hypoglycemic activity for C. obtusifolia and C. peltata, and hypotensive and central nervous system activity for C. glaziovii. The present review compiles the information available on this genus because of its ethnopharmacological relevance and the potential therapeutic uses of these species. PMID- 21815439 TI - Does Pseudomonas fluorescens produce N-mercapto-4-formylcarbostyril? AB - The claim that N-mercapto-4-formylcarbostyril was isolated from Pseudomonas fluorescens strain G308 is questioned since N-thiols appear to be unstable compounds at ambient temperature. PMID- 21815440 TI - Adolescent dermatology. Preface. PMID- 21815441 TI - Dermatoses in adolescents of color. AB - In this article, we delineate some of the unique features of dermatoses in adolescents of color. The information provided should help assist practitioners in making accurate and timely diagnoses so that appropriate therapies can be prescribed. PMID- 21815442 TI - Alopecia in adolescents. AB - It is important for practitioners to accurately diagnose hair loss in adolescents so that prompt and appropriate therapy can be initiated. PMID- 21815443 TI - Cutaneous manifestations of connective tissue disease. AB - There is evidence that early treatment of connective tissue in adolescence improves clinical outcomes; thus, recognition of the cutaneous manifestation of CTD is critical. This review summarizes the clinical features that are unique to children and adolescents in cutaneous (CLE) and systemic lupus erythematosus (SLE), juvenile dermatomyositis (JDM), juvenile systemic scleroderma (JSS), juvenile localized scleroderma (JLS), and juvenile inflammatory arthritis (JIA). PMID- 21815444 TI - Cutaneous malignancy in adolescents. AB - There is compelling epidemiologic evidence that cutaneous malignancies, most notably malignant melanoma and cutaneous T-cell lymphoma, are increasing in incidence. The adolescent population is also affected by this rise in incidence, but can represent both a unique diagnostic and therapeutic challenge. Herein we present up-to-date epidemiology, clinical presentation, risk factors for development, and management options for malignant melanoma, basal cell carcinoma, squamous cell carcinoma, and cutaneous T-cell lymphoma as each pertains to the adolescent population. Prevention in this age group is particularly addressed. One unifying theme that emerges is that a high degree of clinical suspicion and vigilance must be maintained to recognize these entities early on in their presentations. PMID- 21815445 TI - Acne therapy in primary care: comprehensive review of current evidence-based interventions and treatments. AB - In this article, we have presented evidenced-based recommendations for primary care providers in their approach to the treatment of acne in adolescents. Table 2 summarizes the treatment recommendations proposed in this article. PMID- 21815446 TI - Body art in adolescents: paint, piercings, and perils. AB - Tattoos and body piercings are becoming increasingly popular, particularly in adolescents and young adults. As the frequency of body art increases, so does the potential for adverse outcomes. Reasons for obtaining body art include need for individual expression and peer support. Techniques for tattooing are advancing, along with development of newer inks that may be less reactive. When patients become tired of their body art, or develop complications from the art itself, removal needs to be considered. Newer laser modalities may provide tattoo removal options with less scarring potential. PMID- 21815447 TI - Dermatologic findings in the evaluation of adolescents with suspected eating disorders. AB - Eating disorders are important causes of morbidity, with peak incidence and prevalence during adolescence and young adulthood. The assessment of adolescent patients with suspected eating disorders is not always straightforward. Youth may underreport eating disorder behaviors or deny that the behaviors are occurring. Moreover, symptoms of other medical or psychiatric conditions may be mistaken for an eating disorder and cooccurring conditions may complicate the clinical presentation. A thorough and careful evaluation is needed to establish the diagnosis and exclude other conditions. Dermatologic findings may provide important clues in this evaluation. PMID- 21815448 TI - Cutaneous infestations and infections. AB - Cutaneous infections and infestations are common problems in childhood and adolescence. This article provides an update focusing on the diagnosis and management of several frequently encountered infections and infestations: scabies, bedbugs, head lice, tinea capitis, and tinea versicolor. PMID- 21815449 TI - Skin findings associated with obesity. AB - We are facing an obesity epidemic in adolescents in the United States. Thus, practitioners will need to become familiar with cutaneous findings associated with obesity in order to diagnose and treat them properly. This article addresses some of the cutaneous findings associated with obesity. PMID- 21815450 TI - Papulosquamous disorders: atopic dermatitis, psoriasis, seborrheic dermatitis, and nickel contact dermatitis. AB - This article has addressed some of the recent discoveries in pathogenesis and treatment options of 4 papulosquamous disorders: atopic dermatitis, psoriasis, seborrheic dermatitis, and nickel contact dermatitis. PMID- 21815451 TI - [Improvement of quality of life of patients with internal stents by changing the shape of the stents]. AB - Transurethral stenting of the ureter was made in 130 patients (51 males and 79 females, aged 19-81, mean age 51.3 years) after contact ureterolithotripsy (n=86), endoureterotomy (n=13) and endopyelotomy (n=31). All the patients received internal polyuretanic stents (size N 6 F) made by one company. The patients were randomized into two groups by the shape of the stent. Group 1 (n=65) received a modified mono-pigtail stent made of the standard polyuretanic double-pigtail stent by cutting off 2-4 cm of the distal end and distal (vesical) curl. In group 2 (n=65) stenting was made with standard double-pigtail stent. Questionnaire survey was made 2 weeks after stenting, 1 month before stent removal and 1.5 months after stent removal. In the postoperative period 12 patients of group 2 (18.5%) developed acute pyelonephritis resultant from vesicorenal reflux. In other cases pyelonephritis was managed by draining bladder with urethral catheter. In group 1 vesicoureteral reflux was absent, but in 3 cases (4.6%) there was an attack of acute pyelonephritis because of obstruction of the intramural (not intubated by the stent) part of the ureter with fragments of the crushed concrement. This attack required urgent ureterolithoextraction and removal of the stent in 2 cases, transcutaneous nephrostomy in 1 case. Mean postoperative stay in the hospital was 3.1 +/- 0.6 in group 1 and 6.7 +/- 1.2 (p = 0.001) days in group 2. The comparison of the stent-related symptoms 2 weeks after stenting and before stent removal showed that severity of the symptoms was significantly greater in group 2 vs group 1 (21.3 and 9.6, respectively). Thus, the proposed mono-pigtail stent reduces severity of stent-related symptoms 2.5 times and improves quality of life. Further prospective studies are planned for final assessment of efficacy of the modified stents and their influence on quality of life. PMID- 21815452 TI - [Classification of hydroureteronephrosis by ultrasonography findings]. AB - A complex examination including blood and urine biochemistry, pyelomanometry, x ray-radionuclide and endoscopic investigations of the urinary tract as well as ultrasonography with estimation of morphometric and functional parameters of different parts of the urinary tract was conducted in 525 patients with various diseases of the pelvic ureter and urinary bladder complicated by hydroureteronephrosis (HUN) and 50 healthy controls. The findings made it possible to distinguish four stages of HUN: hyperkinetic, dyskinetic, hypokinetic and akinetic. This gradation rests on the results of sonographic assessment of morphofunctional condition of the urinary tract which were compared with findings of the other methods of urological examination. The proposed 4-stage HUN classification based finally only on ultrasonography data describes not only severity of anatomic changes but, indirectly, functional reserves of the upper urinary tract. Sonography is an available, non-invasive, cost-effective method without contraindications. This allows recommendation of this HUN classification for wide application. According to the stage of urodynamic disorder, therapeutic policy is proposed. PMID- 21815453 TI - [Prediction of changes in chemical form of urolithiasis]. AB - The course of recurrent urolithiasis was studied in 131 patients (64 females, 67 males, age 27-69 years). Before the start of 1-15-year followup the patients' condition was: after spontaneous elimination of the concrements, after extracorporeal shock-wave lithotripsy and/or percutaneous nephrolitholapaxy, after open surgical interventions, after surgery and spontaneous elimination of the concriments, after litholysis (patients with hyperuricemic urolithiasis). At the start of the follow-up 127 patients had no uroliths, 4 patients had bilateral concrements. The group of patients free of uroliths consisted of 33 patients with hyperuricemic urolithiasis, 52--with calcium-oxalate, 42--with magnesium-ammonium phosphate form of the disease. As shown by follow-up ultrasound and x-ray examinations, each of these patients had 1 to 7 recurrent concrements. Infrared spectrophotometry and x-ray diffraction determined chemical composition of both primary and 352 recurrent concrements. The patients were also examined with biochemical, microbiological methods, urine clinical examination was made. Possibility, metabolic and microbiological evidence for changes in urolithogenesis type in patients with different forms of the disease were found. In hyperuricemic urolithiasis recurrent concrements can be calcium-oxalate and phosphate, in calcium-oxalate urolithiasis--phosphate. Transformation of magnesium-ammonium-phosphate urolithiasis into hyperuricemic or calcium-oxalate urolithiasis was observed. Changes in the form of the disease more frequently occur in hyperuricemic and calcium-oxalate urolithiasis than in phosphate one. Phosphate concrements form less frequently in patients with hyperuricemic urolithiasis. One kidney can simultaneously contain hyperuricemic or calcium oxalate concrement while the contralateral kidney--phosphate concrement associated with uric urease producing infection. PMID- 21815454 TI - [Effects of magnesium salts on the course of experimental calcium-oxalate urolithiasis]. AB - Experimental urolithiasis was induced in 80 white non-inbred male rats by adding 0.75% ethylene glycol and 2% ammonium chloride to drinking water by Fan et al. After significant differences in crystalluria, oxaluria and urine pH were achieved in hyperoxaluric rats vs controls one, hyperoxaluric rats were given magnesium (Mg) salts Mg chloride, Mg L-aspartate either alone or in combination with pyridoxine hydrochloride (B6) in comparison with Mg sulfate and magne B6 (mg lactate in combination with B6) in a dose of 50 mg of elementary Mg per 1 kg of body weight. All the rats were fed with Mg-adequate diet containing 0.84 g of Mg oxide (0.5 g of elementary Mg per kg of diet). Calcium-oxalate urolithiasis has developed in rats taking ethylene glycol and ammonium chloride for 28 days. An urinary oxalates levels increased threefold, oxalate/creatinine--fourfold. Calcium oxalate crystals were detected in the urine of rats drinking solution of ethylene glycol and ammonium chloride, pH decreased by 20%, fractional excretion (FE) of Mg increased by 60%, FE of phosphate--by 58.2%, FE of calcium--by 95.8%, creatinine clearance lowered by 39.2% in comparison with intact group. Magnesium salts administration resulted in reduction of urine oxalates, crystalluria, phosphate excretion, Ca/Mg and oxalate/creatinine ratios, increased urine pH and creatinine clearance. Mg L-aspartate in combination with vitamin B6 appeared the most effective salt and significantly more effective than magnesium sulfate. PMID- 21815455 TI - [Russian results of the international epidemiological study of clinical aspects and resistance to antimicrobial medicines of cystitis uropathogens in females (ARESC): significance of empiric therapy]. AB - A total of 656 female patients from Russia aged between 18 to 65 years with uncomplicated cystitis entered the international ARESC trial, of them 647 were eligible for final analysis. Positive cultural urine tests ( > 10(4) CFU/ml) were in 419 (64.7%) patients, 393 (93.8%) patients had monoinfection. The central laboratory of Genoa (to which the isolated samples were sent) has tested 416 uropathogens from 399 patients. The following pathogens were isolated: E. coli (72.6%), enterococcus (7.0%), Klebsiella pneumoniae (4.6%), Staphylococcus saprophyticus (3.6%), Proteus mirabilis (2.4%) and Staphylococcus aureus (1.7%). E. coli was most sensitive to phosphomycin (99.3%), mecillinam (97.3%), nitrofurantoin (94.7%), ciprofloxacin (87.4%). The lowest sensitivity was to ampicillin (42.1%) and cotrimoxasol (69.4%). As to the whole bacterial spectrum, the highest sensitivity was found to phosphomycin (96.5%), nitrofurantoin (85.6%) and citrofloxacin (82.8%), the less sensitivity--to ampicyllin (44.3%) and co trimoxasol (70.1%). Phosphomycin, mecillinam (not registered in Russia) and nitrofurantoin showed activity in vitro and can be considered as drugs of choice for empiric therapy of cystitis. Because of high resistance of pathogens, co trimoxasol (trimetoprim) and fluoroquinalones are not recommended as first-line treatment for uncomplicated cystitis in females. PMID- 21815456 TI - [Application of fibrinolysis inhibitor tranexam in transurethral resection of the prostate]. AB - Prostatic surgery is often accompanied with increased intra- and postoperative bleeding which is caused, among other reasons, by enhancement of general and local fibrinolysis due to mechanical impact on prostatic tissue in operation. We proposed to inhibit enhanced fibrinolysis with preparation of tranexamic acid tranexam and tried it in 53 patients with prostatic adenoma undergoing transurethral prostatic resection (TUR). The comparison of bleeding severity in surgery with and without tranexam administration before, in and early after prostatic TUR showed that tranexam significantly lowers blood loss. PMID- 21815457 TI - [Microbial contamination of penile tissues as a risk factor for complications in the treatment of hypospadia]. AB - Biopsy of the skin, fascia and urethra was performed in 29 cases of urethroplasty for hypospadia in children and adults. The patients were divided into two groups: group 1 (n=14) with primary plastic urethra and group 2 (n=15) with secondary urethroplasty of hypospadia with complication. Tissue samples were examined microbiologically and morphologically. Focal infection of penile skin was found after iodopiron sterilization as well as contamination of the skin, fascia and urethra in all the patients of group 2. Nonclostridial anaerobes dominated among the bacteria. Microbiological investigations in groups 1 and 2 proved a great role of Bacteriodes fragilic in the development of penile tissue inflammation. PMID- 21815458 TI - [Efficacy of combined physiotherapeutic methods in complex treatment of patients with chronic infectious urethroprostatitis]. AB - The study is aimed at investigation of efficacy and safety of a combined effect of laser therapy and vibromagnetotherapy in complex treatment of patients with chronic urethroprostatitis in the presence of sexually transmitted infection (STI). A total of 35 males aged 20 to 51 years entered the study. They were divided into 3 groups. Group 1 received standard basic therapy, group 2 received basic and laser therapy, group 3 - basic treatment and laser plus vibromagnetotherapy. Effectiveness of the treatment was assessed by the evidence obtained from clinical, bacteriological, device and functional examinations. The results of the treatments were evaluated after 2 weeks of the follow-up. It is shown that patients of groups 2 and 3 achieved more pronounced improvement of clinical and laboratory indices, parameters of basal blood flow. Thus, physiotherapy, added to antibacterial treatment, is safe and effective in the treatment of chronic urethroprostatitis and STI. PMID- 21815459 TI - [New methods of pubic approximation in extrophy of the bladder in children]. AB - A new less traumatic method of pubic bone approximation in extrophy of the urinary bladder in children is proposed. To ascertain efficacy of the method, results of 3-stage reconstructive plastic operations with pubic bone approximation without osteotomy (group 1, n=27), one-stage reconstructive plastic operations with transversal suturing of the anterior abdominal wall (group 2, n=19), and one-stage reconstructive plastic operations according to the new techniques of pubic bone approximation (group 3, n=9) were compared. To receive satisfactory results, 27 patients of group 1 had to undergo 97 operative interventions for complications, 19 patients of group 2 had undergone 33 operative interventions. As to group 3, early postoperative period complications such as urethrocutaneous and vesicocervical fistulas were observed only in 22.2% cases. Pubic bone diastasis was observed in none the cases showing 100 efficacy. PMID- 21815460 TI - [Chlamydial infection: quality of medical care]. AB - The analysis of case histories of patients with chlamydial infection has detected some typical errors in management of patients: the absence of topical diagnosis, choice of antibacterial drugs and treatment duration do not satisfy standard recommendations both in uncomplicated and complicated disease. A standard approach to management of patients with Chlamydia infection will help to avoid situations when experts conclude on inadequate quality of medical care delivered by medical professionals. PMID- 21815461 TI - [Empiric treatment of pyelonephritis]. AB - The article analyses the most typical clinical situations in empirical treatment of pyelonephritis including situations with comorbid severe diseases: decompensated diabetes mellitus, chronic renal failure, HIV-infection. Choice of antibacterial medicines for empiric treatment of pyelonephritis is based on the results of the latest studies of antibioticoresistance of pyelonephritis pathogens as well as on specific features of pharmacokinetics and pharmacodynamics of antibacterial drugs. PMID- 21815462 TI - [A rare cause of recurrent orchoepididymitis in a child]. PMID- 21815463 TI - [Pelvic dystopia of the left kidney with extrarenal position of the calycopelvic system with stricture of the pelvicoureteral segment complicated with hydronephrosis]. PMID- 21815464 TI - [Transcutaneous nephrolithotripsy on the spine]. PMID- 21815465 TI - [Experience in administration of cholinolytics in the treatment of patients with prostatic adenoma and symptoms of the lower urinary tract]. PMID- 21815467 TI - [Clinical issues of younger patients with dementia--Japan Psychogeriatric Society]. AB - Younger patients with Alzheimer's disease (YPAD) present many clinical aspects different from people with late-onset Alzheimer's disease. The author reviewed terminological, diagnostic, and therapeutic issues, as well as support systems for YPAD and concerns related to disclosure. The Japanese Psychogeriatric Society is a leader in this field, focusing not only on treatment of AD, but also comprehensive support systems for people with dementia. PMID- 21815466 TI - [Clinical characteristics of patients with workplace-associated mood disorder - comparison with non-workplace-associated group]. AB - AIM: The purpose of this study was to describe the clinical characteristics of patients with workplace-associated mood disorder. METHOD: We conducted a clinical survey involving 84 clinical cases (regular employees suffering from mood disorder) who were hospitalized in the Psychiatry Department of Jichi Medical University Hospital, for a period over 8 years and 4 months between April 1st, 2000 and July 31st, 2008. RESULTS: The size of the workplace-associated group as a percentage of those patients in whom the onset of the symptom was occasioned by an evident issue at their workplace was 65%. This rate accounted for 74% of the total patients if clinical cases in which an evident issue at the workplace served as a significant trigger for the symptom were added to these patients in the case of an initial episode in the "non-workplace associated group". In the workplace-associated group, cases in which the premorbid character was a "depression-related personality" comprised only 42%, and was noticeably characterized by a perfection-oriented habit, enthusiastic character, conformity with other people, etc. Furthermore, the percentage of patients who were diagnosed with a "depression-related personality" comprised only 59% of the "overworked group", in which a heavy workload was evident in the workplace associated group. In the workplace-associated group, the percentage of cases involving managerial workers was significantly high; their rate as initial cases was significantly high, as well the proportion of favorable outcomes. In the workplace-associated group, the percentage of patients who showed unambiguous depression at the initial stage was significantly low. Likewise, a similar result was obtained in the overworked group. CONCLUSIONS: Workplace-associated mood disorder today tends to have a stress-related aspect, or aspect of adjustment disorder. There was a period in many cases during which the main symptoms were insomnia, headache, panic attack, etc., prior to the onset of unambiguous depression in the workplace-associated mood disorder group. In depression associated with workplace-associated mood disorder, there are two pathological stages. The stage of adjustment disorder is the period in which such conditions are the main symptoms, and a serious or moderate stage of major depressive disorder is the period after full-scale depression develops in the wake of the former stage. What contributes to protection against depression are a proper diagnosis of depression whose pathological condition is at an early adjustment disorder stage and appropriate therapeutic measures. PMID- 21815468 TI - [Molecular pathology and disease-modifying therapy of Alzheimer disease]. AB - Disease-modifying therapies for Alzheimer's disease are under development based on the outcomes of molecular pathological studies that have progressed over the last 25 years. The current status of basic research on Alzheimer's disease, its translation into clinical applications, and associated problems, will be discussed. PMID- 21815469 TI - [A new dementia group caused by TDP-43 abnormality]. AB - The TAR DNA-binding protein Mr 43 kDa (TDP-43) is a major component of the tau negative and ubiquitin-positive inclusions that characterize amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration, which is now referred to as FTLD-TDP. Concurrent TDP-43 pathology has been reported in a variety of other neurodegenerative disorders such as Alzheimer's disease, forming a group of TDP 43 proteinopathies. Accumulated TDP-43 is characterized by phosphorylation and fragmentation. There is a close relationship between the pathological subtypes of FTLD-TDP and the immunoblot pattern of the C-terminal fragments of phosphorylated TDP-43. These results suggest that proteolytic processing of accumulated TDP-43 may play an important role in the pathological process. Understanding the mechanism of phosphorylation and truncation of TDP-43, and aggregate formation, may be crucial to clarifying the pathogenesis of TDP-43 proteinopathy and for developing useful therapies. PMID- 21815470 TI - [Current topics about mild cognitive impairment (MCI)]. AB - One hundred years has passed since the appearance of the first article on Alzheimer's disease (AD), by Alois Alzheimer. AD is the most common form of dementia, accounting for over 50% of all dementia and affecting more than 26 million people worldwide. Since the 1980s, the pace of research into the nature of AD has greatly accelerated, and investigators currently believe that it will become possible to treat or prevent AD, which is a major socioeconomic concern in all developed countries of the world. Mild cognitive impairment (MCI) is a relatively recent term used to describe people who have some memory problems, but do not actually have dementia. In recent years, some drug treatments that can improve the symptoms of AD have become available. Other treatments that may slow down the progression of AD in the brain are also being developed. It is important that people with AD be identified as early as possible, so that they can benefit from these treatments in the future. Identifying people with MCI is one way to try to achieve this. In Japan, the Japanese Alzheimer's Disease Neuroimaging Initiative (J-ADNI) was launched in 2008. It follows the protocols established by US-ADNI, and aims to conduct a longitudinal workup of standardized neuroimaging, biomarker, and clinico-psychological surveys. The Japanese research protocol was designed to maximize compatibility with that of US-ADNI, including structural magnetic resonance imaging (MRI) analysis for the evaluation of brain atrophy, fluorodeoxyglucose (FDG) and amyloid positron emission tomography (PIB-PET), cerebrospinal fluid (CSF) sampling, and APOE genotyping, as well as a set of clinical and psychometric tests that were prepared so as to achieve the greatest compatibility possible with those used in US-ADNI. J-ADNI has recruited approximately 357 participants (142 with amnestic mild cognitive impairment, some 134 elders without impairment, and 72 persons with mild Alzheimer's disease) as of April 15, 2010. Worldwide ADNI activities will allow the establishment of rigorous quantitative descriptions of the natural course of AD in its very early stages. In addition, this project will aid in the clarification and differentiation of MCI and AD. The major goal of this research is the establishment of surrogate markers for AD based on MRI, PET, and CSF data. This data, as well as the methodologies and infrastructure used, will facilitate clinical trials of disease-modifying therapies for AD using surrogate biomarkers, enabling the application of effective therapies with AD/MCI patients, and eventually the prevention of AD. In this symposium, I will speak about MCI and early-stage AD, with a particular focus on the latest clinical neuroimaging data from J-ADNI. PMID- 21815471 TI - [The current research on support skills on ACT team]. AB - The author describes the support skills of Assertive Community Treatment (ACT) based on the activities of community mental health teams such as the Assertive Outreach Team (AOT) from Birmingham, Britain; ACT/PACT teams from the states of Indiana and Washington in the U.S.; and three ACT (primarily ACT-K) teams from Japan. The author contrasts skills used in Britain and the United States with those used in Japan. Japanese ACT teams have demonstrated effectiveness using skills considered to be taboo in conventional psychiatric hospitals, and the author illustrates examples of such skills. Finally, the author qualitatively analyzes and explains the skills utilized by psychiatrists on ACT teams. PMID- 21815472 TI - [Antipsychotic medication change and reduction of rehospitalization in clients of ACT-J]. AB - Polypharmacy and high-dose treatment of antipsychotics have been major problems in Japanese mental health. Although importance of simplifying prescription has been recognized, polypharmacy and high-dose medication especially for Schizophrenia remains prevalent. It's considered that psycho-social approach; for example, improvement of coping skills and social support such as care management can make reform of treatment efficiently and also improve patient's QOL. In ACT service, Medication, rehabilitation and social support work closely together and it could make prescription change even for SMI patients. Low-dose medication leads improvement of cognitive function and furthermore social activity. Considering the higher dose of antipsychotics prescribed concurrency in Japan, it's important to evaluate the change in medication for patients of ACT in Japan. We did one year follow up study about prescription change for 52 patients who have used ACT program at ACT-J team for more than one year at the end of December 2009. It was found that the dosage antipsychotics significantly decreased from 1131.3 mg converted to the relative potency equivalent of 100 mg of Chlorpromazine (CPZ eq), to 731.3 mg (CPZ eq) over the course of the 12 months. But there was no significant change about polyphamacy. Also it could be possible to reduce rehospitalization under the ACT program. Because recovery model could make improve not only drop out from psychiatric service, but user's dependency for hospitalization. PMID- 21815473 TI - [Assertive community treatment in Japan: results of fidelity measurements]. AB - Mental health system reform oriented toward realizing the transition from "institution-based medical treatment" to "community-based care" is now taking place in Japan. Although the number of psychiatric beds is slow to decrease, community resources are increasing, and differentiation of those services is the next challenge. Assertive Community Treatment (ACT) is a service which provides 24/7 community outreach by a multidisciplinary team to persons with severe mental illness. Currently, some 10 to 15 ACT teams are providing services in Japan; this number is far from adequate. This is due to the lack of direct funding for ACT in the current mental health system. However, ACT is increasing as a result of combining available funding sources, such as psychiatric home visit nursing and welfare funding. The ACT Network, a voluntary association, was established to disseminate ACT and ensure its quality. Fidelity scales measure faithfulness to the original model. DACTS, a fidelity scale developed in the U.S., is widely used to measure ACT fidelity. In Japan, ACT Network implements a Japanese version of fidelity measurement for ACT around Japan. Results of fidelity measurements of 12 ACT teams in 2009 showed that the ACT teams were providing services which adhered more closely to the original model than in the previous year, but problems remained. Some issues, such as increasing care management in services, can be addressed through maturation of ACT teams, but other issues, such as relatively low service density and allocation of employment specialists, cannot be resolved without a funding mechanism. To disseminate ACT and support more people with severe mental illness in the community, it is necessary to build ACT into the community mental health system with sufficient funding, and to monitor its quality using measures such as fidelity scales. PMID- 21815474 TI - [Consideration to implementation of ACT in Japan]. AB - Recently in Japan, to build a new community mental health support system, Assertive Community Treatment (ACT) has been trying to implement. In this paper, four problems were discussed. 1) Problems of applying DACTS to Japan. 2) The historical problems of mental health and welfare of Japan. 3) Problems of modern mental health care and welfare systems in Japan. 4) How does the forensic psychiatry in Japan influences the philosophy of ACT. As a result, considerable contemplation and preparation is needed to implement the ACT. Following point was proposed to achieve ideal mental health system. We must carry out deinstitutionalization policy (ex. reduction of mental hospital beds, review the budget allocations for mental health system, etc.) before ACT would be implemented. PMID- 21815475 TI - [Comparison of portable apnea monitors in the detection of apnea episode during daytime rest]. AB - Although polysomnography (PSG) is the golden standard for the diagnosis of sleep apnea syndrome (SAS), access to this procedure is limited because it requires special institution and trained technicians. Therefore, many portable recording devices have been developed for detection of SAS including home monitoring. The present study evaluated the usefulness of four portable devices in detecting apneic events. The four devices are, (1) FM-500 thermister sensor type III device, (2) LS-300 pressure sensor type III device, (3) Morpheus pressure sensor type III device, and (4) SD-101, a sheet-type type IV device that detects chest wall movement. This study included 1,114 patients who underwent a daytime rest session during a routine clinic visit. The subjects were asked to remain quiet and in a supine position in a dark room. We compared the respiratory disturbance index (RDI) and number of oxygen desaturation events (OD) measured by the four portable devices in each patient. The RDI and number of OD measured by the device using the thermister sensor were significantly lower than those measured by the three other devices. These findings suggest that when using a portable recording device to screen for SAS, the characteristics of the device should be taken into account. PMID- 21815477 TI - [Hepatitis B tests as screenings for the reactivation of HBV infection at Fukuoka University Hospital]. AB - The Hepatitis B virus (HBV) reactivation is defined as proliferation of HBV and hepatitis flare after medication of anti-cancer drugs and/or immunosuppressant drugs in inactive HBV carriers or patients with past illness by HBV infection. In January 2009, the guideline for prevention of immunosuppressive or chemotherapy induced reactivation of HBV infection was established by Japanese study groups of the Ministry of Health, Labour and Welfare. We then surveyed and analyzed order numbers of the tests of HBV DNA and anti-HBc, the rate of positive results and the department of the doctors who ordered those tests, the patient ages and clinical profiles and the purpose of the tests, from 2008 to 2009 before and after announcement of the guideline. The total numbers of tests of HBV DNA were 942 in 2008 and 1350 in 2009, and those of anti-HBc were 430 in 2008 and 904 in 2009. The percentage of the orders for anti-HBc from doctors in department of gastroenterology and medicine was 71.4% in 2008 and decreased to 53.4% in 2009, instead those of hematology and oncology, pulmonary surgery and gynecology increased remarkably. The positive rates of anti-HBc increased among the patients over age 40, especially it was more than 40% over age 50. The number of the tests for the follow-up after immunosuppressive or chemotherapy increased over 4 folds. This report made clear the actual situation of screenings for the HBV reactivation by analyses of the bases in the orders and the results of the virus tests in our hospital. PMID- 21815476 TI - Rapid detection of spontaneous bacterial peritonitis by granulocyte elastase latex immunoassay and reagent strip. AB - Spontaneous bacterial peritonitis (SBP) is a serious complication in patients with liver cirrhosis that requires rapid recognition for effective antibiotic therapy. Elevated levels of granulocyte elastase (GE), an enzyme that is released from degranulated polymorphonuclear neutrophils(PMN), have been reported in ascitic fluid of SBP patients. The aim of this study was to assess the utility of GE measurement by a latex immunoassay (LIA) and by reagent strips for rapid diagnosis of SBP. In 26 ascitic samples which had differing GE concentrations, the results of this LIA method closely correlated with those of a GE/alpha1-PI complex ELISA and an EIA using monoclonal antibodies against GE. The evaluation parameters of linearity (r > 0.99), analytical recovery (96-107%) and within assay variation[coefficient of variation(CV): 0.97-2.35%] were found to be satisfactory. In 58 ascitic samples from patients with liver cirrhosis, GE levels confirmed by LIA in SBP ascites (n=14) at the time of diagnosis were higher (1436.9 +/- 715.1 ng/ml) than those in non SBP ascites (n=44)(13.1 +/- 3.9 ng/ml). The receiver operating characteristic (ROC) curve showed that ascitic GE by LIA enabled discrimination between SBP and non-SBP, and a cut-off value of 49.5 ng/ml had a sensitivity of 85.7% and specificity of 97.7%. In addition, the usefulness of reagent strips designed for testing cervical mucus for rapid bedside detection of SBP was assessed for GE. The sensitivity, specificity, and positive and negative predictive values of the reagent strips for diagnosis of SBP were 92.9%, 90.9%, 76.5%, and 97.6%, respectively. These results indicate that GE-LIA and GE reagent strips are rapid and sensitive and can aid diagnosis of SBP. PMID- 21815478 TI - [Usefulness of reticulocyte hemoglobin equivalent for the safety of pre-operative autologous blood donation]. AB - Pre-operative autologous blood donation (PABD) provides safe blood for patients at the expense of the risk of iron deficiency anemia that may compromise the patients. The reticulocyte hemoglobin equivalent (RET-He) is an indirect measure of the functional iron available for the erythropoiesis over the previous 2-3 days. The aim of this study was to evaluate the clinical usefulness of RET-He quickly measured by the automated hematology analyzer Sysmex XE-2100 in patients undergoing PABD at our hospital. Receiver-operating characteristic curve analysis revealed that RET-He was reliable in the diagnosis of iron deficiency anemia. Two of 14 patients in the absence of post-PABD iron replacement developed marked anemia with low RET-He levels after PABD, suggesting that this anemia was due to iron deficiency. Of 26 patients receiving post-PABD iron replacement, 8 who had already showed low RET-He levels at PABD developed statistically significant reduction in hemoglobin levels after PABD despite adequate iron replacement, indicating that the 8 patients had iron deficiency prior to PABD. These findings suggest that automated measurement of RET-He may contribute to improve the safety of PABD. PMID- 21815479 TI - [Case of tuberous sclerosis complex with pulmonary lymphangioleiomyomatosis and angiomyolipomas of the liver and kidney]. AB - A 17-year-old woman, who complained of left abdominal pain, was diagnosed as left renal bleeding by ultrasonography at emergency room in Shimane University Hospital. Further ultrasonography revealed numberless round-shaped hyperechoic liver nodules (maximum 16 mm in a diameter) and dissemination of the same type of nodules in both kidneys, which was characterized as angiomyolipomas. The lesions were also detected by abdominal CT and MRI. In addition, the findings of tuberous calcification of the cerebral ventricles and parenchyma, facial angiofibromas and shagreen patches led to the diagnosis of tuberous sclerosis complex. Since two years later, she had recurrent attacks of spontaneous pneumothorax. The histopathological examination found out lymphangioleiomyomatosis from the biopsied lung tissues. Although she became pregnant, she selected a therapeutic abortion due to the high risk for renal failure which would be induced by pressure of the grown uterine. Abdominal ultrasonography was very useful for diagnosis in this case. PMID- 21815480 TI - [Questionnaire survey of the POCT device antsense ROSE for blood glucose analysis on healthcare professionals--evaluation focused on preventive measures against cross-infections]. AB - Considering the possibility of being used for any patients, such a risk-managed medical device is necessary in the perspective of the prevention of hospital infections. Antsense ROSE, a newly developed POCT (Point of Care Testing) diagnostic device for blood glucose analysis, is designed for safety in hospital use. Use of a disposable chip filter for blood sampling prevents cross-infection through device. As to infection control, we carried out a questionnaire survey of healthcare professionals specialists in diabetes to evaluate the feasibility of this device in clinical practice. Despite the infection control system of this device, the survey participants pointed out only a little improvement in infection risk compared with conventional methods. Some were concerned about the cross-infection because blood sampling itself increases the risk of infection, and because it is difficult for examiners to prevent infections completely due to handling blood samples. Systems ensuring safety, such as a fail-safe, are essential for in-hospital use to prevent hospital infections due to the possibility of using a device for several patients, and to ensure the security even for wrong operations. Further investigations, developments and educational campaign will be required for the use of risk managed devices against in-hospital infections. PMID- 21815482 TI - [Possible application of pharmacogenomics to warfarin therapy]. AB - Vitamin K-dependent gamma-carboxylation system is crucial to generate active coagulation factors. It consists of gamma-Glutamylcarboxylase (GGCX) and vitamin K-epoxide reductase (VKOR). Warfarin is an anticoagulant that blocks VKOR. Recent studies have shown that genetic variations in a subunit of VKOR complex, VKORC1, and in cytochrome P 450 (CYP) 2C9 genes are strong determinants of individuals' warfarin sensitivity. Algorithms have been proposed to predict warfarin doses, and about 55% of the variance in warfarin dose could be attributed to variations in the VKORC1 and CYP2C9 genes together with age, sex, body-surface area, and presence or absence of heart valve replacement. Contributions of polymorphisms in VKORC1 and CYP2C9 to inter-individual differences of warfarin dose, however, are different among races. Studies have shown that potential clinical and economic benefits of CYP2C9/VKORC1 genotype-guided dosing are only marginal. Thus, evidence is still limited and application of warfarin pharmacogenomics to clinical practice at present needs careful consideration. PMID- 21815483 TI - [KRAS mutation test]. AB - KRAS mutation is detected in around 40% of colorectal cancer (CRC). Recent clinical trials revealed the ineffectiveness of anti-EGFR antibodies in CRC patients with mutated KRAS. Consequently, KRAS test is now thought to be essential to the determination of indication for anti-EGFR antibody therapy in CRC. However, there are still the following problems to be solved. (1) Prospective studies are needed to validate these clinical trial results. We recently performed KRAS genotype-driven phase II clinical trial evaluating FOLFIR/FOLFILI plus cetuximab as second-line therapy in refractory advanced CRC. KRAS codon 12 and 13 mutations were detected in 45 out of 112 patients (40.2%) for whom cetuximab was not indicated. The relation of clinical response with KRAS mutation status is now under investigation. (2) The clinical significance of the KRAS mutations except for those of codons 12 and 13 remains unclear. Clinical evaluation is necessary for KRAS codon 15, 18, 61, 117 and 146 mutations. (3) The detection methods, which are divided into sequencing and non-sequencing ones, are not standardized. Non-sequencing methods are rapid and sensitive, but costly. Furthermore, to validate their ambiguous data, sequencing methods are needed. At the present time dideoxy sequencing method seems to be preferentially chosen when considering that it is widespread and general-purposive. (4) Heterogeneous distribution of KRAS mutation in CRC tissues. (5) Effects of other genes abnormalities such as BRAF and PIK3CA mutations, PTEN down-regulation and EGFR gene amplification on the efficacy of anti-EGFR antibodies in CRC patients with or without KRAS mutation. PMID- 21815484 TI - [Companion diagnostics: significances and issues in its clinical application]. AB - Studies on the biological significance of human genome sequence variations revealed their association with diversity in patient's individual response to a particular drug. Based on it, pharmacogenomic tests have been developed and could be used as an indication of pharmacological responses to a therapeutic intervention to select appropriate patients to be treated with a particular drug, and adjust dosage to have maximum efficacy while minimizing adverse events. Companion diagnostic tests are used in a specific context that provides information that enables better decision-making about the development and use of a potential drug therapy. It is a key tool in personalized medicine and a solution to develop individualized drugs. However, in development and clinical application of such tests, there are problems in biological, technical and clinical aspects. Of primary importance is coordination among government, industry and academic professionals, to make standards and evidences for system development and application and to guide society including public and care providers, hence providing health care service with good quality. PMID- 21815485 TI - [Education of medical technology and graduate school in Japan]. AB - Now the education of medical technologists has reached the fourth turning point. The first turning point was the start of the two year education in 1958 and the second was the start of the three year education of medical Technologists in 1971 and the third was the start of the full-fledged university education in 2004 and, this time, the fourth turning point is the start of graduate school education of medical technology. From this situation, for education of graduate school, mind education that polishes personality practically is may be demanded, Therefore, human resource development with not only knowledge and technique as medical technologists but also with humanly nurtured sentiment is expected in the future. PMID- 21815486 TI - [Glaucoma drainage device surgery: present and future in Japan]. PMID- 21815487 TI - [Long term clinical outcomes of Baerveldt glaucoma implantation via the pars plana]. AB - PURPOSE: To present the long-term follow-up results of Baerveldt glaucoma implant (BGI) with a drainage tube from the pars plana in secondary glaucoma patients. METHODS: The subjects were patients with light perception and secondary glaucoma (> 21 mmHg) who had received more than 2 glaucoma operations: 11 were neovascular glaucoma patients and 5 angle-closure glaucoma patients with peripheral anterior synechia. After vitreous surgery, a BGI plate was fixed at the sclera in the superior temporal equator, and a drainage tube inserted from the pars plana into the vitreous cavity. The successful criteria needed to satisfy the 3 following conditions: 1) vision of more than light perception, 2) IOP > or = 5 mmHg and not higher than 22 mmHg, 3) no need for further glaucoma operations. RESULTS: The follow-up period was 82.5 months (from 5 to 172 months). Eight patients were judged a success, 4 patients a failure and 4 patients quit for personal reasons. The 10-year success rate was estimated at 72.8%. CONCLUSIONS: BGI via the pars plana is a useful method for long term IOP lowering effect in secondary glaucoma. PMID- 21815488 TI - [Survey of ocular injury by solar eclipse 2009]. AB - PURPOSE: Incidence of ocular injury caused by the solar eclipse of 2009 has been investigated using the questionnaire of the Japan Committee of the International Year of Astronomy 2009. METHODS: The questionnaire was available to the public on the website. RESULTS: Answers were obtained from 14 people (12 men, 2 women), aged from sixteen to fifty-four. All had looked at the sun either with the naked eye or through some shading device (plastic sheet, plastic bag, compact disc, etc.) the safty of which is unknown. Reported symptoms included a sense of incongruity, heat, pain, central scotoma or visual disturbance, classified into four periods of duration. Three people with transient symptoms watched the eclipse with the naked eye for one minute in cloudy weather. Three people with symptoms lasting for one day and three people with symptoms lasting for one week had watched it with the naked eye and some shading device for 10 minutes in cloudy weather. Five people with symptoms lasting for more than one week watched the eclipse with the naked eye and through some sort of device in fine or slightly cloudy weather. Three people consulted their ophthalmologist. CONCLUSIONS: Those who reported adverse symptoms did not comply with the instructions for safe watching of the eclipse and the duration of the symptoms depended on the weather and the type of device used. PMID- 21815489 TI - [Three cases of uveitis induced by mycobacteriosis therapy using rifabutin]. AB - BACKGROUND: Rifabutin has been used clinically to combat tuberculosis as well as nontuberculosis Mycobacterium since 2008 in Japan. Uveitis associated with rifabutin is described in many reports, but none of these are of Japanese. We report three Japanese cases of nontuberculosis Mycobacterium with rifabutin associated uveitis. CASE 1: A 91-year-old woman developed bilateral uveitis with hypopyon and vitreous opacity at 2 months after the initiation of rifabutin administration. The uveitis persisted regardless of topical administration of corticosteroids and the discontinuance of rifabutin. Her right eye required goniosynechiolysis in order to cure a secondary glaucoma, and the left eye required vitrectomy in order to cure vitreous inflammation. CASE 2: A 72-year-old woman developed uveitis in her right eye at 7 months after the initiation of rifabutin administration. Rifabutin was stopped two days after she presented, and the uveitis resolved quickly with topical administration of corticosteroids. CASE 3: An 83-year-old woman developed bilateral uveitis at 6 months after the initiation of rifabutin administration. The rifabutin was stopped two months after the initiation and the uveitis resolved with topical corticosteroids. CONCLUSION: Rifabutin rarely causes uveitis as an ocular side effect. Early diagnosis and is important and reduction or discontinuance of the rifabutin as well as anti-inflammatory therapy need to be implemented when a patient develops this condition. PMID- 21815490 TI - [Three cases of optic neuropathy associated with hypertrophic pachymeningitis]. AB - PURPOSE: We report 3 cases of patients with hypertrophic pachymeningitis associated with perinuclear anti-neutrophil cytoplasmic antibody and IgG 4 positive plasma cell infiltration. CASES: The patients' ages ranged from 61 to 76. Two were women and 2 cases involved one eye only. Initial visual acuity of the 4 eyes were counting fingers to 0.3. Decreasing of critical flicker frequency and moderate headache were observed in all cases. Definite diagnosis of hypertrophic pachymeningitis was made by enhanced MRI (magnetic resonance imaging) using Gadolinium. After systemic administration of methylprednisolone, all patients showed improvement in their visual acuity from 0.8 to 2.0 and had no recurrence. CONCLUSIONS: Hypertrophic pachymeningitis is common in elderly patients. It is highly associated with headaches accompanied by symptoms and signs of ischemic optic neuropathy and retrobulbar optic neuritis. Enhanced MRI is helpful in making a definite diagnosis. PMID- 21815491 TI - [A case of intraocular lymphoma having retinal adverse events associated with intravitreal methotrexate]. AB - BACKGROUND: We report a case of intraocular lymphoma that developed macular edema and cotton wool spots after treatment with intravitreal methotrexate. CASE: A 56 year-old woman presented with blurred vision OU. Twelve months prior, she had been diagnosed with primary central nervous system lymphoma. She was in remission after high-dose methotrexate therapy and whole brain radiation therapy. Fundus examination demonstrated bilateral vitreous opacities and subretinal lesions and she was diagnosed with intraocular lymphoma by vitreous biopsy. After treatment with intavitreal methotrexate the subretinal lesions disappeared, but corneal epitheliopathy, macular edema, and cotton wool spots appeared in both eyes. After stopping the intravitreal methotrexate, the corneal epitheliopathy resolved rapidly, but the macular edema and cotton-wool spots remained. These findings disappeared gradually after a posterior sub-Tenon injection of triamcinolone acetonide. Although there was no recurrence of the intraocular lymphoma for 16 months, the patient died from a relapse of the central nervous system lymphoma. CONCLUSIONS: The use of intravitreal methotrexate after radiation therapy may be associated with adverse events in the retina, including possible radiation retinopathy. PMID- 21815492 TI - [Guideline of clinical practice for blepharospasm]. PMID- 21815493 TI - [Opioid placebo: allies to be protected]. PMID- 21815494 TI - [Analgesic placebo effect: contribution of the neurosciences]. AB - Over the past twenty years, neuroscience has changed our understanding of placebo analgesia. Often perceived by researchers as a response bias adding noise to the assessment of efficacy, in the patients' view, it is associated with charlatanism. The origin of the word, qualifying a patient's response to "please" the doctor, did not help its rightful appreciation. However, today the placebo analgesia is considered as a psychobiological phenomenon. Thanks to pharmacological manipulations and the development of functional brain imaging, the neural circuitry involved in this effect as well as the role of endorphins and dopamine have been identified. This article describes our current knowledge about this fascinating phenomenon: a psychological modulation can lead to a biological effect. PMID- 21815495 TI - [Placebo, an underestimated ally]. AB - Patients' views and patient-oriented outcomes are increasingly acknowledged, including beliefs about pain and illness, and expectations of treatment. Indeed, how far patient expectations influence outcomes has developed into an important area of research, and all the more so as the impact of expectations on subjective outcome is related to the placebo effects; indeed, expectations can both mediate and modulate these effects. Surgery has been suggested as conveying a placebo effect related to the ceremony of surgical preparation, the use of sophisticated techniques and the need for hospitalization possibly leading to increased pain management, more active sympathy and disease recognition. PMID- 21815496 TI - [Opioid rotation: from theory to practice. Interdisciplinary recommendations from the Geneva University Hospitals pain network]. AB - Opioids are widely used to treat moderate to severe pain of cancer or non cancer origin. Although opioids provide an adequate analgesia in many patients, their use can be limited by inefficacy and/or intolerable side effects. Opioid rotation is one of the strategies that have been proposed to overcome these therapeutic difficulties. This article revisits the concept of opioid rotation, from pharmacological rational to clinical application. PMID- 21815497 TI - [Chronic pain in elderly people: psychosocial dimension]. AB - Chronic pain in elderly people requires to take into account somatic co morbidities as well as its psychosocial dimensions. Chronic pain often represents a distress signal addressed to the environment and the care providers. Psychological suffering or mood disorders can be presented in the form of somatic complaints often associated with functional impairments, sometimes severe. Therapeutic care has to address functionality through an image-enhancing approach aiming to summon the patients' resources. The treatment of a concomitant depressive state necessitates a true commitment from the therapist. Its benefits are documented in elderly patients. Analgesic treatment as a whole will seek in particular to restore feelings of self-esteem and help the patient recover a good quality of life. PMID- 21815498 TI - [A year of chronic pain with Targin--experience from daily practice. Interview with Dr. Patricia Fehlmann]. PMID- 21815499 TI - [Sleep disorder and pain: the good hypnotic]. AB - Chronic pain and sleep disorder can put the patient in a vicious circle (bidirectional relation between those two morbid entities). Clinical management must be global. The physiopathology includes chronic sleep deficit, mainly in deep sleep (the "restoring" sleep) generated principally by the prefrontal regions. These areas are also implicated in the modulation of pain. To break this "loops", we advocate an approach based on three main components: hygiene principles, cognitive and behavioral therapy, medications with analgesic and hypnotic proprieties. PMID- 21815500 TI - [What's about overactive lifestyle in fibromyalgia and chronic fatigue syndrome]. AB - Fibromyalgia and chronic fatigue syndrome are clinical conditions different but they share common components, particularly multifactorial aetiology. High level of action proneness and "overactive" lifestyle can be considered as predisposing risk factors and perpetuating factors for these somatic functional syndromes. For the clinicians managing complex situations, only a holistic, circular and biopsychosocial approach could restore a new equilibrium (allostasis) with strategies of coping with chronic pain and planification of activities. PMID- 21815501 TI - [Sex workers: limited access to healthcare]. AB - Sex workers constitute a heterogeneous group possessing a combination of vulnerability factors such as geographical instability, forced migration, substance addiction and lack of legal residence permit. Access to healthcare for sex workers depends on the laws governing the sex market and on migration policies in force in the host country. In this article, we review different European health strategies established for sex workers, and present preliminary results of a pilot study conducted among 50 sex workers working on the streets in Lausanne. The results are worrying: 56% have no health insurance, 96% are migrants and 66% hold no legal residence permit. These data should motivate public health departments towards improving access to healthcare for this vulnerable population. PMID- 21815502 TI - [Conflicts of interest for Swiss physicians]. PMID- 21815503 TI - [Advocacy for genetically modified human]. PMID- 21815504 TI - [Animal meal and cannibalism]. PMID- 21815505 TI - [Nights and days]. PMID- 21815506 TI - Panorama whistleblower blames managers for care home brutality. PMID- 21815507 TI - Healthcare staff told to report patients at risk of radicalisation. PMID- 21815508 TI - Nurses failing to recognise the value of assistant practitioners. PMID- 21815510 TI - 'I knew things had to change with the organ donor process'. PMID- 21815509 TI - Unannounced visits reveal the best and worst of today's NHS. PMID- 21815511 TI - Loaded issue. AB - The rising number of obese people in the population is providing various challenges to nurses inthe acute sector. PMID- 21815512 TI - Ready to fight TB. AB - With tuberculosis on the increase in ScotlIand, nurses are at the heart of an action plan t reverse the trend. PMID- 21815513 TI - Cup of tea and a chat. AB - One hospital has made changes to improve care and nutrition of older people on acute wards. PMID- 21815514 TI - A case for action on clots. AB - The NHS is paying large amounts of compensation to patients as a result of a failure to assess patients' risk of venous thromboembolism. PMID- 21815515 TI - Promoting interprofessional care in the peri-operative environment. AB - One of the key aspects of successful collaborative working is the relevant and effective exchange of information between professionals. Boundaries exist not only between health and social care in a community setting, but also in acute care between and within departments and professions. Patients continuously cross these boundaries during transfers and transitions, when nurses interact with other professionals and are in a prime position to demonstrate exemplary interprofessional relationships and seamless patient care to other staff and to students. Mentors act as role models for students of all professions and are expected to promote opportunities that will maximise student learning and enhance patient care. This article provides mentors with some suggestions for maximising these opportunities. Mentors are encouraged to reflect on practice-based learning opportunities for students, particularly situations that are challenging and involve critical judgement. The article focuses on learning opportunities in the peri-operative department, however the same challenges are experienced in other clinical areas and the principles of good interprofessional care can be applied to any team that aspires to work collaboratively. PMID- 21815516 TI - Education for healthcare assistants working in acute NHS hospitals. AB - Healthcare assistants (HCAs) are an integral part of the workforce in acute NHS hospitals. They carry out a variety of roles depending on the needs of the clinical area in which they work. However, there are no nationally agreed training standards for HCAs and consequently they work to varying levels of ability and skill. This article explores the education and training opportunities that are available to HCAs in acute NHS hospitals and the problems associated with accessing them. It also discusses how training HCAs to a uniform standard is an important requisite for the regulation of this workforce. PMID- 21815517 TI - Reducing inequalities in healthcare provision for older adults. AB - The UK has a rapidly ageing population with increasing healthcare needs. Yet social isolation and exclusion, resulting from stigma and age discrimination, means that many older people are faced with unequal access to health care, referral and treatment. Inequalities in health care are particularly prevalent among older people with mental health issues and those from black and minority ethnic backgrounds. Healthcare professionals need to encourage greater involvement of older people in health promotion and community-based healthcare services. Nurses are exemplars for health service delivery and are ideally placed to promote health care that is free from age-related discrimination. PMID- 21815518 TI - Type 2 diabetes. PMID- 21815519 TI - Successful entry. PMID- 21815521 TI - Reach for the stars. PMID- 21815520 TI - Reversing a brutal act. PMID- 21815523 TI - Prevalence and distribution of the main cardiovascular risk factors in Portugal- the AMALIA study. AB - OBJECTIVES: To assess the self-reported prevalence of the main risk factors for cardiovascular disease in Portugal and their distribution by gender, age-group and region. METHODS: We surveyed 38,893 individuals aged 40 or over, with a distribution by region and age-group proportional to the national population, through a questionnaire applied in the community in a household approach using the random route method, between October 2006 and February 2007. RESULTS: The self-reported prevalence of hypertension was 23.5%, increasing with age in both genders, but slightly higher in women (24.9% vs. 21.8%). The prevalence of hypercholesterolemia, based on respondents' statements, was 19.7%, and higher in women (20.7% vs. 18.6%), with the highest values in the 6th and 7th decades of life (23.9% and 23.6%). The prevalence of diabetes was 8.9%, increasing with age, and slightly higher in women (9.3% vs. 8.5%). The prevalence of smoking was 16.3%, decreasing with age, but always higher in men (25.3% vs. 8.8%). The prevalence of overweight/obesity (BMI equal to or higher than 25/30 kg/m2) was 51.6%, higher in those aged 60-69 (57.1%) and 70-79 years (56%). Most participants (65.3%) declared they never took part in structured physical activity, while 24% claimed to take exercise, on average for 11 years, and 10.6% stated that they no longer exercised. In the Azores, there was a higher prevalence of hypertension, hypercholesterolemia, diabetes and overweight/obesity, while the North and Algarve regions presented the lowest values of these risk factors, although they had higher levels of smoking. CONCLUSIONS: Based on respondents' statements, the AMALIA study found the following prevalences of the six risk factors under investigation, in descending order: sedentarism--76%; overweight/obesity--52%; hypertension--24%; hypercholesterolemia--20%; smoking--16%; and diabetes--9%. Notwithstanding possible under-reporting, the differences in prevalence of these major risk factors by gender and region could influence cardiovascular prevention strategies in Portugal. PMID- 21815522 TI - Non-cardiac comorbidities in the very elderly with acute myocardial infarction: prevalence and influence on management and in-hospital mortality. AB - INTRODUCTION: Acute myocardial infarction (AMI) in the very elderly is common and is associated with increased mortality. Despite this, the majority of such patients do not receive the most effective cardiovascular therapies. The presence of non-cardiac comorbidities constitutes an additional challenge to the management of AMI in very elderly patients. OBJECTIVE: To determine the prevalence of non-cardiac comorbidities in the very elderly (age > or = 80 years) with AMI and how it influences their management and in-hospital mortality. METHODS: A total of 132 patients consecutively admitted with a diagnosis of AMI from January 2005 to December 2007 were analyzed retrospectively. Two groups were considered: patients with non-cardiac comorbidities (group 1) and those without non-cardiac comorbidities (group 2). Cardiovascular risk factors and non-cardiac comorbidities (anemia, chronic obstructive pulmonary disease, chronic renal failure, cancer, neurologic or psychiatric disorders, and prostatic hyperplasia in men) were recorded. Use of an invasive strategy and the therapy prescribed at discharge were compared between the groups. RESULTS: Non-cardiac comorbidities were found in 56.8% of patients, with the following prevalences: anemia 18.2%; chronic obstructive pulmonary disease 11.4%; chronic renal failure 25.8%; cancer 3.0%; neurologic or psychiatric disorders 11.4%; and prostatic hyperplasia 20.5%. Patients with comorbidities had longer hospital stay than those without (12.1 +/- 5.5 and 10.1 +/- 3.5 days, respectively; p = 0.014). An invasive strategy, with coronary angiography, was used in 12.1% of patients, with no differences between groups (12.3% in patients without comorbidities and 12.0% in those with, p = 0.82). At discharge, more than 70% of the patients were prescribed aspirin, statins and nitrates. With the exception of non-dihydropyridine calcium antagonists, which were more frequently prescribed in patients with comorbidities (15.9% vs. 2.2%; p = 0.04), no other differences in therapy were observed between the two groups. CONCLUSION: In our population of very elderly patients, the prevalence of non-cardiac comorbidities was high (56.8%), but this did not significantly influence the management of these patients. PMID- 21815524 TI - Effusive-constrictive pericarditis: the role of noninvasive imaging. AB - Effusive-constrictive pericarditis is a rare entity in which clinical suspicion is of paramount importance, and although cardiac catheterization remains the gold standard for diagnosis, noninvasive imaging techniques are very useful in consolidating the diagnosis prior to confirmation by invasive means. The authors describe the case of a 52-year-old man, who had undergone heart surgery in the past, with a long history of heart failure refractory to medical therapy and chronic recurrent pericardial effusion, in whom noninvasive imaging techniques were decisive in arriving at the correct diagnosis of effusive-constrictive pericarditis, which was later confirmed by cardiac catheterization, thus enabling the correct therapeutic approach to be adopted and leading to improvement in clinical status. PMID- 21815525 TI - Ascending aortic aneurysm and patent foramen ovale: a rare cause of platypnea orthodeoxia. AB - Platypnea-orthodeoxia is a rare syndrome characterized by dyspnea and hypoxia induced by the upright position and relieved by the supine position. Several factors related to atrial anatomy can facilitate shunting through an atrial septal defect; in many cases, the syndrome is associated with patent foramen ovale and right-to-left shunt, and has also been linked to aortic aneurysm. We present a case of platypnea-orthodeoxia syndrome in a 61-year-old woman with patent foramen ovale and ascending aortic aneurysm. PMID- 21815526 TI - An unusual aortic valve mass [36]. PMID- 21815527 TI - Exercise stress echocardiography. A new perspective in cardiac syndrome. PMID- 21815528 TI - Making I.T. fit the mission. PMID- 21815529 TI - 6 ways to stretch I.T. investments. PMID- 21815530 TI - What's the C-level looking at in I.T? PMID- 21815531 TI - Consensus builder. PMID- 21815532 TI - [Surgery and quality control]. PMID- 21815533 TI - [Acute small bowel obstruction: conservative or surgical treatment?]. AB - Small bowel obstruction (SBO) is a common clinical syndrome caused mainly by postoperative adhesions. In complement to clinical and biological evaluations, CT scan has emerged as a valuable imaging modality and may provide reliable information. The early recognition of signs suggesting bowel ischemia is essential for urgent operation. However appropriate management of SBO remains a common clinical challenge. Although a conservative approach can be successful in a substantial percentage of selected patients, regular and close re-assessement is mandatory. Any persistance or progression of the critical symptoms and signs should indeed lead to surgical exploration. Here we review the principles of adhesive SBO management and suggest a decision procedure for conservative versus surgical treatment. PMID- 21815534 TI - [The advantage of a specialized HPV clinic within the department of proctology]. AB - The "Human Papilloma Virus" (HPV) is the cause of carcinoma of the cervix. With 275000 deaths per year worldwide, this virus is the direct cause of the most common carcinoma in women. If these figures demonstrate that it is a true scourge, then the fact is that routine screening for the precancerous lesion linked to HPV infection has managed to significantly lower the mortality rate in countries where this has been introduced. The frequency of the anal carcinoma has grown in recent years, particularly in HIV+ patients participating in anal sex. Systematic screening and early vaccination should be able to stem this worrying development in the same way that screening for carcinoma of the cervix has in women. PMID- 21815535 TI - [Outpatient hernia surgery]. AB - Inguinal hernias are frequent and have an enormous socio-economic impact. Surgical treatment is indicated in most of the patients to relieve symptoms and to prevent complications. Modem treatment should focus on low complication and recurrence rates, short recovery times, and--last but not least acceptable costs. Inguinal hernia repair can be carried out by an open or minimal invasive approach. Surgery is traditionally performed under general anesthesia, but local or locoregional anesthesia are other feasible options. Nowadays, inguinal hernia surgery can easily performed as an outpatient procedure. However, stringent selection criteria, an optimized infrastructure and a close and standardized follow-up are mandatory prerequisites in order to obtain excellent results under secure conditions. PMID- 21815536 TI - [Preoperative nutrition in abdominal surgery: recommendations and reality]. AB - Malnutrition concerns up to 50% at in-hospital admission. Its diagnosis and treatment are fundamental parts of the surgical approach because nutritional status directly influences the clinical outcome. The Nutritional Risk Score (NRS 2002) represents the recommended screening tool by the European Society of Parenteral and Enteral Nutrition (ESPEN). Patients with a score > or = 3 and aged > 70 years old, should receive a nutritional support during 7-14 day before surgery. Depending on patient's clinical conditions, the enteral route of administration should be preferred. Despite strong evidence in favor of nutritional supplementation, much effort must be done to implement these supportive strategies in the everyday clinical practice. PMID- 21815537 TI - [Epithelial neoplasia of the appendix: what has recently changed?]. AB - Appendicular tumors are mostly found incidentally in up to 1.5% of all appendectomies. Neuroendocrine tumors are the commonest malignancies, and are associated with an excellent long-term prognosis. While small lesions located at the appendicular tip can be treated with simple appendectomy, advanced tumors require right hemicolectomy. Goblet cell carcinoids are rare tumors showing a mixed phenotype. Long-term outcome is impaired, and for most cases a right hemicolectomy is mandatory. Colonic-type adenocarcinomas have a similar behavior like conventional colonic cancer and should be treated similarly. Mucinous neoplasias possess the characteristic of extensive mucin production with intraperitoneal spread. Treatment options are ranging from right hemicolectomy to multivisceral resection with intraperitoneal chemotherapy. PMID- 21815538 TI - [Latin organ donation programme (LODP): an effective initiative to increase organ donation in Switzerland]. AB - The 1st federal transplant law was enforced in July 2007 with the obligation to promote quality and efficiency in the procedures for organ and tissue donation for transplantation. The Latin organ donation programme (LODP) created in 2008 aims to develop organ donation in 17 public hospitals in 7 Latin cantons, covering 2.2 million people; 29% of the Swiss population. The implementation of various effective measures by the LODP enabled the increase in the number of donors by 70% between 2008 and 2010, with four organs procured per donor; greatly exceeding the European average of three. The results show that LODP has successfully professionalised the system and we can only hope that similar organisations will be put into place throughout Switzerland. PMID- 21815539 TI - [A partnership between doctors and the state: the "new deal Vadois". Interview by Michael Balavoine and Bertrand Kiefer]. PMID- 21815540 TI - [Africa: towards the eradication of meningitis A?]. PMID- 21815541 TI - [The life and deaths of Jack Kevorkian (1928-2011)]. PMID- 21815542 TI - [Down syndrome--is it a disease or not?]. PMID- 21815543 TI - [A new alliance of the physicians and of the state]. PMID- 21815544 TI - "Dear states, healthcare reform is now up to you". PMID- 21815545 TI - Introduction of the Balanced Scorecard into an academic department of medicine: creating a road map to success. AB - In this paper, we describe: 1) the environmental forces driving performance measurement and management in the University of California San Diego Department of Medicine; 2) the systematic process used by the department to implement a Balanced Scorecard; 3) the initial direct and indirect outcomes of this effort; 4) the opportunities and challenges to the Balanced Scorecard as a management directive; and 5) future directions. PMID- 21815546 TI - How to increase upfront collections, reduce patient accounts receivable, and improve your cash flow. PMID- 21815547 TI - Some evidentiary considerations for physician billing. AB - In a criminal prosecution for medical billing fraud alleging up-coding and overbilling, the government's evidence may encompass the practice's entire billings and draw inferences from them. In addition, fraud may be demonstrated through statistical analysis comparing a physician's billings relative to other providers of the same specialty. The Federal Rules of Evidence govern the admissibility of evidence during a trial, to provide fairness for both the prosecution and the defense. Physicians and practice managers should be well versed in the billing requirements and particularly careful when CPT codes are expressed in terms of "required times" as opposed to "typical times." PMID- 21815548 TI - Introduction of an electronic medical record system into physician practice offices: why is it so #%!&-ing hard for everybody?-Part II. AB - Medical practice offices are experiencing a revolutionary change in the microprocesses that have been the norm for documenting and communicating patient care for decades. While this revolution is welcome for dozens of good reasons, migration of data storage from the paper-based record to electronic form often causes considerable stress for all involved. This three-part series looks at electronic medical record implementations from organizational and sociological perspectives, and draws attention to the often unappreciated aspects of medical work that give rise to the stress. In addition, IT professionals' perspectives are also addressed to highlight how medical /IT professional differences affect the experience of implementation. PMID- 21815549 TI - Coding and billing won't "take care of itself". PMID- 21815550 TI - The clinician's guide to composing effective business plans. AB - In today's challenging healthcare environment, clinicians need to understand the fundamentals of financial analysis, which are the underpinnings of their clinical programs, especially when seeking administrative support for new initiatives. The business plan for new clinical program initiatives is composed of diverse elements such as the mission statement, market and competitive analyses, operations plan, and financial analysis. Armed with a basic knowledge of financial analysis of clinical programs, as well as forward-looking analysis of an initiative's added value, the healthcare provider can work much more effectively with administration in developing or creating new healthcare program initiatives. PMID- 21815551 TI - Reading and using body language in your medical practice: 25 research findings. AB - Your patients and your coworkers will make judgments the moment they see you based upon your body language cues. As well, you can tell what they are thinking and feeling if you know how to read their body language behaviors. This article provides 25 research-based findings about workplace body language that medical practice personnel can use immediately to improve their communication and effectiveness. It suggests numerous telltale nonverbal signs of hidden deception, superiority, fear, discomfort, anxiety, subordination, weakness, strength, openness, and disgust. As well, this article explores proxemics, the area of nonverbal communication that explores how we use space to communicate. This article is loaded with practical tips to help every member of the medical practice staff read others better and harness nonverbal savvy to convey effective and appropriate nonverbal messages to patients and to one another. PMID- 21815552 TI - Five rules for connecting with patients to enhance compliance: building a bridge of credibility and trust. AB - Communication is the cornerstone for being an effective doctor. With improved communication, patient satisfaction is increased as well as patient compliance. This article will review five rules for becoming a better communicator. This applies to physicians speaking to patients, staff speaking to patients, or physicians communicating with their staffs. PMID- 21815553 TI - Everyone looks good on paper: how to hire your ideal employee. AB - It is important to streamline the interviewing and recruiting process. From the start, it is critical to establish a process that facilitates identification of the right person for the job at this time in the life of your practice. Following the above suggestions will ensure that you comply with state and federal regulations to operate at your peak efficiency, which will save you time and money. The above suggestions must be tailored to each practice and culture. What is important is that each practice has a process in place that is understood by the group and the candidates under consideration. PMID- 21815554 TI - How to add a new midlevel provider to your practice. AB - The ever-changing environment of healthcare leads many practices to consider how they will control the cost of overhead, give access to their patients, and maintain or increase practice income. The solution may be to add a midlevel provider (MLP)--a Physician Assistant (PA) or Nurse Practitioner (NP)--to the staff. Both of these specialties train to see patients independently. The difference between a PA and an NP is the type of training and level of supervision required. The addition of an MLP can address many of the impending changes in healthcare, while increasing the quality and profitability of the practice. This article outlines the initial steps to take when adding an MLP to your practice. PMID- 21815555 TI - What if your boss really is a jerk? AB - If you think your boss is really a jerk, first make certain that you have done everything within your power to engage in regular one-on-one conversations; help your boss spell out expectations for your performance; and then monitor, measure, and document your own performance in relation to those expectations. If that doesn't work, then figure out which type of "jerk-boss" your boss really is. This article presents strategies for dealing with each the seven most common jerk-boss scenarios. PMID- 21815556 TI - Safety works: getting past the very thought of change. PMID- 21815557 TI - Surgical hospitalist: can this be a program for your group? AB - A shortage of general surgeons is creating issues for the coverage of many emergency departments. This article outlines a new way of thinking about how to diagnosis and treat this problem. Learn the basics behind the possible creation of a surgical hospitalist program from assessing the need; reviewing physician issues; computing the financial analysis; understanding the political and bureaucratic issues; and, finally, recruiting to fill the positions. PMID- 21815558 TI - Security breaches: tips for assessing and limiting your risks. AB - As part of their compliance planning, medical practices should undergo a risk assessment to determine any vulnerability within the practice relative to security breaches. Practices should also implement safeguards to limit their risks. Such safeguards include facility access controls, information and electronic media management, use of business associate agreements, and education and enforcement. Implementation of specific policies and procedures to address security incidents is another critical step that medical practices should take as part of their security incident prevention plan. Medical practices should not only develop policies and procedures to prevent, detect, contain, and correct security violations, but should make sure that such policies and procedures are actually implemented in their everyday operations. PMID- 21815559 TI - Medicare and "incident-to" rule. PMID- 21815560 TI - Developing physician referrals for the new physician: techniques to market your physician's practice. AB - New physicians will need to be proactive to market and promote their practices. Generating referrals from colleagues is one of the best ways to attract new patients to a start-up practice. This article will provide techniques that will help new physicians enhance their relationships with their colleagues in the community. PMID- 21815561 TI - Ways to improve your cash at the bottom line. PMID- 21815562 TI - Risk or reward? Laying the IT foundation for ACOs presents daunting challenges for healthcare leaders nationwide. AB - Industry experts and healthcare IT leaders agree that the recently released proposed rule on the creation of accountable care organizations (ACOs) is offering a heady mix of opportunity and risk, and that laying the IT foundation for success under ACO initiatives will be massively challenging for the vast majority of patient care organizations nationwide. Those a bit further along on the journey say that interoperability, connectivity, and the leveraging of clinical lT for intensive care management and data analysis will be essential to ACO success. PMID- 21815563 TI - Growing pains: medical device interoperability. Regulators and new standards are helping to bring about the convergence of medical devices and information management systems on IT networks. AB - Both provider organizations and medical device vendors have made significant, if slow-going, progress over the last several years to network their digitally enabled medical devices. Recent strides in both the regulatory and standards arenas have provided renewed impetus on the part of both stakeholder groups to bring more interoperability to disparate medical devices, resulting in better security and quality of patient data. PMID- 21815564 TI - Persuasion principles. CMIOs move forward to help guide their colleagues forward on meaningful use. AB - Nationwide, CMIOs in every type of hospital organization are developing strategies for leading their clinical, IT, and administrative colleagues forward through the complex area of quality data reporting under meaningful use. Those CMIOs in organizations at various stages along the journey agree that it will require a subtle combination of persuasion, sharing evidence and data, and a lot of granular hard work in order to get their clinician colleagues fully on board. PMID- 21815565 TI - Smaller margins, clear fundamentals. Revenue cycle management in the medical group environment. PMID- 21815566 TI - Innovation in the elCU. Interview by Mark Hagland. PMID- 21815567 TI - Beacon communities reach milestone. Program grantees mark one-year anniversary by sharing success stories. PMID- 21815568 TI - First-day attestation. Ferdinand Velasco, M.D., CMIO of Texas health resources, shares his experiences regarding his organization's attestation under stage 1 of meaningful use. PMID- 21815569 TI - Coping with the real estate blues. Short-term solutions to help potential hires deal with relocation issues in a down market. PMID- 21815570 TI - [Practice guideline for the preoperative management of platelet aggregation antagonists in non-cardiac surgery. Sociedad Espanola de Anestesiologia y Reanimacion]. PMID- 21815571 TI - Total hip arthroplasty with shortening osteotomy in congenital major hip dislocation sequelae. AB - We retrospectively evaluated the postoperative results of total hip arthroplasty (THA) in patients presenting with Crowe group IV dislocated hips. Overall, results were compared with regard to the type of osteotomy performed (Z or oblique) to define the correct indications for surgical technique and choice of prosthetic implant. Thirty-three subtrochanteric shortening and derotational osteotomies in primary THA were performed in 26 patients secondary to congenital hip dislocation. A Z osteotomy was performed in 14 cases and an oblique osteotomy in 19. The surgical approach was direct lateral, and surgery was aimed at restoring the anatomic hip center. Femoral and acetabular fixation was uncemented. The most used stem was the S-ROM (DePuy, Leeds, United Kingdom), and the couplings used were ceramic-ceramic (7 cases), ceramic-polyethylene (3 cases), metal-polyethylene (15 cases), and metal-metal (3 cases). Mean follow-up was 88+/-45 months. According to the Merle D'Aubigne score, the overall clinical results were good in 23 cases, satisfactory in 6, and fair in 4. Union of the osteotomy occurred in 97% of cases, and the mean time required for osteotomy union was 6+/-2 months without significant differences between Z and oblique osteotomies. At last follow-up, there was loosening of 1 cup and 1 stem, and revision was necessary. Twelve percent of patients experienced postoperative dislocation and 9% developed neuropraxia of the femoral nerve. The clinical and radiological results were similar in both groups, with a high rate of pain relief, an improvement in limb-length discrepancy, and reduced limping, leading to a smaller or no insole. Currently, the more complex Z osteotomy has been abandoned, because a modular stem prosthesis with metaphyseal sleeve allows the oblique osteotomy to be used with an easier and shorter surgical procedure. PMID- 21815572 TI - Long-term results of an unloader brace in patients with unicompartmental knee osteoarthritis. AB - Previously, we reported a prospective study of 30 patients with unicompartmental osteoarthritis of the knee treated nonoperatively with an unloader brace and average follow-up of 2.7 years. Although the initial study suggested short-term benefit according to pain and function measures, the objective of the current study was to evaluate these same patients via telephone questionnaire to determine the status of their brace use and any surgical procedures on the affected limb. Because we noted that even at 2.7 years, some patients opted for surgical management despite good response to bracing, our hypothesis was that these patients would not opt for long-term brace wear. Twenty-four of 30 patients were available for reporting based on telephone interview; in addition, we talked with family members of 5 patients who had died. When evaluated at 2.7 years, 41% of the 30 patients were still using the brace, 35% had discontinued brace use, and 24% had undergone arthroplasty. When contacted for the follow-up survey at an average of 11.2 years, 17 (58.6%) of the 29 patients had undergone arthroplasty. The mean interval between initial evaluation and arthroplasty was 3.9 years. In addition, 7 patients had undergone arthroscopic surgery. Importantly, none of the patients were still wearing the brace. The use of an unloader brace is effective in providing short-term pain relief and improved function; however, most patients subsequently opt for total knee replacement on the symptomatic knee. PMID- 21815573 TI - Arthrodiatasis for management of knee osteoarthritis. AB - Osteoarthritic disease is the result of mechanical and biological events that destabilize the normal processes of degradation and synthesis of articular cartilage chondrocytes, extracellular matrix, and subchondral bone. Osteoarthritis of the knee can cause symptoms ranging from mild to disabling. Initial management of most patients should be nonoperative, but because of the progressive nature of the disease, many patients with osteoarthritis of the knee eventually benefit from operative treatment. Various procedures have been described for treatment of the osteoarthritic knee, ranging from arthroscopic lavage and debridement to total knee arthroplasty. The aim of this study was to evaluate the clinical results of distraction arthroplasty combined with arthroscopic lavage and drilling of cartilage defects for treatment of osteoarthritis of the knee. Nineteen patients (15 women and 4 men; age range, 39 65 years) were operated on. Pre- and postoperative findings were compared. A control group comprising 42 patients treated with only arthroscopic procedures was evaluated for comparison. Follow-up ranged from 3 to 5 years. Results were evaluated both clinically and radiologically postoperatively and throughout the follow-up period. Clinically, pain and walking capacity improved in most patients. Radiologically, joint space widening and improvement of the tibiofemoral angle was noted in nearly all patients. PMID- 21815574 TI - A biomechanical comparison of patellar tendon repair materials in a bovine model. AB - We evaluated the biomechanical properties of FiberWire (Arthrex, Inc, Naples, Florida), a new suture material, for both repair and augmentation as compared to standard Ethibond suture (Ethicon, Inc, Somerville, New Jersey), hypothesizing that primary repair and cerclage augmentation with the new suture material would have similar biomechanical properties as a standard repair with wire augmentation. Forty-five fresh bovine knees were placed in 3 groups of equal size: (1) #5 Ethibond tendon repair plus 18-gauge wire augmentation; (2) #5 FiberWire repair plus #5 FiberWire augmentation; and (3) #5 Ethibond repair plus #5 FiberWire augmentation. A straight static pullout test was performed, randomly alternating between the different groups. Gap formation was measured at the center of the repair by a metric ruler, with the examiner blinded to the developing force-tension readout. For each millimeter of gap formation (1-10 mm), the force on the repair was recorded, as well as the force at the ultimate failure of the repair, designated by breakage of any repair material. Analysis showed no significant difference between the standard Ethibond/wire repair and the FiberWire/FiberWire repair. The Ethibond/FiberWire repair was shown to be significantly weaker than the other 2 groups. Ultimate failure data indicated that the Ethibond/wire repair was significantly stronger than both other groups. No significant differences were found between the FiberWire/FiberWire repair and the Ethibond/FiberWire repair. Newer, stronger suture material for both primary repair and augmentation may provide equivalent biomechanical strength at clinically significant levels. PMID- 21815575 TI - Medial malleolar fractures: a biomechanical study of fixation techniques. AB - Fracture fixation of the medial malleolus in rotationally unstable ankle fractures typically results in healing with current fixation methods. However, when failure occurs, pullout of the screws from tension, compression, and rotational forces is predictable. We sought to biomechanically test a relatively new technique of bicortical screw fixation for medial malleoli fractures. Also, the AO group recommends tension-band fixation of small avulsion type fractures of the medial malleolus that are unacceptable for screw fixation. A well-documented complication of this technique is prominent symptomatic implants and secondary surgery for implant removal. Replacing stainless steel 18-gauge wire with FiberWire suture could theoretically decrease symptomatic implants. Therefore, a second goal was to biomechanically compare these 2 tension-band constructs. Using a tibial Sawbones model, 2 bicortical screws were compared with 2 unicortical cancellous screws on a servohydraulic test frame in offset axial, transverse, and tension loading. Second, tension-band fixation using stainless steel wire was compared with FiberWire under tensile loads. Bicortical screw fixation was statistically the stiffest construct under tension loading conditions compared to unicortical screw fixation and tension-band techniques with FiberWire or stainless steel wire. In fact, unicortical screw fixation had only 10% of the stiffness as demonstrated in the bicortical technique. In a direct comparison, tension-band fixation using stainless steel wire was statistically stiffer than the FiberWire construct. PMID- 21815576 TI - Comparison of MRI and arthroscopy in modified MOCART scoring system after autologous chondrocyte implantation for osteochondral lesion of the talus. AB - Magnetic resonance imaging (MRI) and arthroscopy have frequently been used to evaluate articular cartilage. Many studies have compared the accuracy of MRI to that of arthroscopy. However, there have been no previous comparison studies between MRI and arthroscopy in the evaluation of repaired cartilage after autologous chondrocyte implantation using the Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) scoring system. The purpose of this study was to compare the results between MRI and arthroscopy after autologous chondrocyte implantation of an osteochondral lesion of the talus using a modified MOCART scoring system. Our study investigated 27 consecutive cases in 26 patients who underwent follow-up MRI and second-look arthroscopy 1 year following autologous chondrocyte implantation based on their osteochondral lesion of the talus diagnosis. According to the comparison results of those 5 categories, the agreement between MRI and arthroscopy evaluation results was statistically significant with good reliability in the categories of the degree of defect repair and defect filling, the quality of repaired tissue surface, and synovitis. However, the integration with the border zone and the adhesion category showed poor to moderate reliability. There has been no well-established correlation method between arthroscopy and MRI after autologous chondrocyte implantation of an osteochondral lesion of the talus. PMID- 21815577 TI - Management of combined bone defect and limb-length discrepancy after tibial chronic osteomyelitis. AB - Bone defects and leg shortening due to chronic osteomyelitis are rare yet challenging problems to treat. The aim of this study was to summarize our experience with a distraction osteogenesis technique performed with an external fixator for these conditions. Twenty-three consecutive patients with tibial bone defects and limb-length discrepancy caused by osteomyelitis were treated from January 1994 to January 2009. Thirteen boys and 10 girls had a mean age of 12.2 years (range, 8-16 years). Twenty of the 23 patients (87.0%) had undergone an unsuccessful bone grafting procedure. Mean amount of bone defect was 3.6 cm (range, 1.5-6.2 cm) as measured on plain radiographs. Mean leg-length discrepancy was 4.0 cm (range, 0-8.0 cm). All patients were followed for a mean of 116 months (range, 31-182 months). Mean external fixation index was 48.0 days/cm (range, 40.7-66.5 days/cm). Mean lengthening was 9.3 cm (range, 5.8-12.1 cm). Based on the criteria recommended by Paley et al, 16 bone results were excellent, 6 good, and 1 fair. Fifteen functional results were excellent, 7 good, 1 fair, and 0 poor. This study shows that distraction osteogenesis with an external fixator is an effective treatment for massive postosteomyelitis bone defects and leg shortening. PMID- 21815578 TI - A qualitative and quantitative needs assessment of pain management for hospitalized orthopedic patients. AB - Despite advances in pain management, little formal teaching is given to practitioners and nurses in its use for postoperative orthopedic patients. The goal of our study was to determine the educational needs for orthopedic pain management of our residents, nurses, and physical therapists using a quantitative and qualitative assessment. The needs analysis was conducted in a 10-bed orthopedic unit at a teaching hospital and included a survey given to 20 orthopedic residents, 9 nurses, and 6 physical therapists, followed by focus groups addressing barriers to pain control and knowledge of pain management. Key challenges for nurses included not always having breakthrough pain medication orders and the gap in pain management between cessation of patient-controlled analgesia and ordering and administering oral medications. Key challenges for orthopedic residents included treating pain in patients with a history of substance abuse, assessing pain, and determining when to use long-acting vs short acting opioids. Focus group assessments revealed a lack of training in pain management and the need for better coordination of care between nurses and practitioners and improved education about special needs groups (the elderly and those with substance abuse issues). This needs assessment showed that orthopedic residents and nurses receive little formal education on pain management, despite having to address pain on a daily basis. This information will be used to develop an educational program to improve pain management for postoperative orthopedic patients. An integrated educational program with orthopedic residents, nurses, and physical therapists would promote understanding of issues for each discipline. PMID- 21815579 TI - Are terminally threaded guide pins from cannulated screw systems dangerous? AB - Threaded and smooth pins are often used in orthopedic surgery. Although uncommon, injury to the soft tissues can and do occur, including nerve or vessel injury from aberrant pin placement. The purpose of this study was to compare the risk of nerve injury from threaded pins versus smooth guide pins due to: (1) past-point drilling of the pin, or (2) entanglement of the pin with soft tissue. Past-point drilling was tested by a blindfolded participant drilling a 1.6-mm guide pin (terminally threaded or smooth) through a porcine femur until they felt they had drilled through the second cortex. The distance over-drilled was measured in millimeters. Twenty trials were randomly completed, 10 with each pin type. Entanglement of soft tissue was tested by placing the terminal portion of the guide pin on the nerve. Two drilling positions were tested: (1) drilling at 90 degrees and (2) parallel to the nerve. The drill was run for 1 second and assessed for entanglement and magnitude of entanglement (measured in millimeters of nerve wrapped by the pin). Sixty trials were completed, 15 with each pin type, and in each of the 2 positions. The average past-point drilling depths were 4.6 and 16.9 mm for the smooth and threaded pins, respectively (P<.05). The mean nerve overwrapping was 0.45 and 4.7 mm, for the smooth and threaded pins, respectively (P<.05), drilled at 90 degrees and 0.15 and 0.92 mm, respectively (P<.05) in the parallel position. In 13 of 60 trials with the smooth pin and 50 of 60 trials with the threaded pin, wrapping was observed (P<.05). This study demonstrates that it is difficult to determine by feel when the threaded pin has drilled through the second cortex of the bone, in contrast to the smooth pin. Furthermore, soft tissue entanglement is more likely and to a greater magnitude with threaded pins than with smooth. PMID- 21815580 TI - The in vitro elution characteristics of antifungal-loaded PMMA bone cement and calcium sulfate bone substitute. AB - The use of antimicrobial-loaded delivery vehicles, most often as antibiotic beads, is common practice for the treatment of deep musculoskeletal infections. The elution of antibacterial drugs from various bone cements has been extensively studied. However, much less is known about the elution of other antimicrobials from these materials. In particular, the use of this approach for fungal infections has not been well studied despite growing concern about these difficult-to-treat organisms. Voriconazole is a broad-spectrum and highly effective antifungal that has been used in the treatment of resistant fungal pathogens. We examined the in vitro elution characteristics of voriconazole from nonabsorbable polymethylmethacrylate (PMMA) beads and from absorbable calcium sulfate beads. Voricanazole-containing beads were immersed in a 5-mL bath of phosphate-buffered saline at room temperature and placed on an orbital shaker. Eluent samples were collected over the course of 2 weeks. Concentrations of the antifungal drug in solution were measured using high-performance liquid chromatography. To verify biologic activity of the eluted antifungal, collected samples were also tested against control yeasts. We found that samples collected out to 2 weeks contained relatively high voriconazole concentrations and enough active antifungal activity to inhibit growth of the control yeasts. These data demonstrate that voriconazole retains its antifungal activity when mixed into either PMMA or calcium sulfate beads, and elutes out of beads at biologically effective concentrations over a time period of at least 2 weeks. Therefore, incorporation of voriconazole into either absorbable or nonabsorbable beads appears to be a reasonable strategy for the local delivery of a potent, broad spectrum antifungal agent to an infected wound bed. PMID- 21815582 TI - Posterior short-segmental fixation combined with intermediate screws vs conventional intersegmental fixation for monosegmental thoracolumbar fractures. AB - Posterior short-segmental fixation is reliable for the management of thoracolumbar fractures; however, it is associated with recurrence of kyphosis and failure of fixation. This study compared the short-term results of short segmental fixation combined with intermediate screws with those of conventional intersegmental fixation in the treatment of monosegmental thoracolumbar fractures. The records of 62 consecutive patients with thoracolumbar monosegmental fractures who underwent conventional 4-screw intersegmental fixation (35 patients) or short-segmental fixation combined with intermediate screws (27 patients) were reviewed. The study population included 43 men and 19 women (mean age, 44.1+/-13.6 years). The majority of fractures were L1 (28 [45.1%]) and T12 (21 [33.9%]) fractures. There were no significant differences between the 2 groups with respect to the preoperative relative height of the fractured vertebra or the segmental kyphotic angle. There was a significant difference in the restoration rate between the conventional and short-segmental fixation groups (62.6+/-38.7% vs 100.4+/-25.4%, respectively; P<.001). However, a statistically significant decrease in postoperative segmental kyphotic angle was noted in both groups (P<.001). The mean change of segmental kyphotic angle in the short-segmental fixation group was greater than in the conventional fixation group (14.4+/-6.8 degrees vs 8.3+/-7.9 degrees , respectively; P<.002). Patients in the short-segmental fixation group ambulated an average of 10 days earlier than those in the conventional fixation group. These findings indicate that compared to conventional intersegmental fixation, short-segmental fixation combined with intermediate screws more effectively restores fractured vertebral height, is associated with a decrease in the segmental kyphotic angle, and allows earlier ambulation. PMID- 21815581 TI - Age-related biological characterization of mesenchymal progenitor cells in human articular cartilage. AB - Adult articular cartilage has a low regeneration capacity due to lack of viable progenitor cells caused by limited blood supply to cartilage. However, recent studies have demonstrated the existence of chondroprogenitor cells in articular cartilage. A critical question is whether these mesenchymal progenitor cells are functionally viable for tissue renewal and cartilage repair to postpone cartilage degeneration. This study was designed to compare the number and function of mesenchymal progenitor cells in articular cartilage collected from human fetuses, healthy adults (aged 28-45 years), and elderly adults (aged 60-75 years) and cultured in vitro. We detected multipotent mesenchymal progenitor cells, defined as CD105+/CD166+ cells, in human articular cartilage of all ages. However, mesenchymal progenitor cells accounted for 94.69%+/-2.31%, 4.85%+/-2.62%, and 6.33%+/-3.05% of cells in articular cartilage obtained from fetuses, adults, and elderly patients, respectively (P<.001). Furthermore, fetal mesenchymal progenitor cells had the highest rates of proliferation measured by cell doubling times and chondrogenic differentiation as compared to those from adult and elderly patients. In contrast, alkaline phosphatase levels, which are indicative of osteogenic differentiation, did not show significant reduction with aging. However, spontaneous osteogenic differentiation was detected only in mesenchymal progenitor cells from elderly patients (with lower Markin scales). The lower chondrogenic and spontaneous osteogenic differentiation of mesenchymal progenitor cells derived from elderly patients may be associated with the development of primary osteoarthritis. These results suggest that measuring cartilage mesenchymal progenitor cells may not only identify underlying mechanisms but also offer new diagnostic and therapeutic potential for patients with osteoarthritis. PMID- 21815583 TI - Systematic review of cohort studies comparing surgical treatment for multilevel ossification of posterior longitudinal ligament: anterior vs posterior approach. AB - There have been no standards or guidelines for the treatment of ossification of posterior longitudinal ligament, especially multilevel ossification of posterior longitudinal ligament. The purpose of this study was to compare results of major surgical treatment for multilevel ossification of posterior longitudinal ligament. Databases including MEDLINE, EMBASE, the Cochrane library, and bibliographies of identified and review articles were searched to find randomized, controlled trials or retrospective cohort studies comparing anterior and posterior approach from 1980 to December 2010. Approximately 1375 articles were found initially, 92 abstracts were screened, 23 articles were retrieved in full; 3 studies were included in the review. No randomized, controlled studies were identified. Because all the studies included in this study are cohort studies with disparity of surgical interventions, heterogeneity of outcome measures and different qualities, we were unable to perform a meta-analysis. All comparison studies are retrospective cohort studies, comparing surgical outcomes of anterior approach (corpectomy and fusion) with that of posterior approach (laminoplasty or laminectomy) for the treatment of multilevel ossification of posterior longitudinal ligament in the cervical spine. A systematic review of retrospective cohort studies was performed to determine which surgical treatment is the most effective in patients with multilevel ossification of posterior longitudinal ligament. Definitive conclusions regarding the surgical treatment of multilevel ossification of posterior longitudinal ligament could not be made in this article. Multilevel corpectomy and fusion are more technical and have a significantly higher rate of cerebrospinal fluid leakage and graft, instrumentation related complications. A well-designed, prospective, randomized controlled, multicenter trial is needed. PMID- 21815584 TI - Long-term outcomes following en bloc resection for sacral tumor: a retrospective analysis of 93 cases. AB - Sacral tumors are rare. Appropriate surgical resection is crucial to treat the disease while minimizing disease recurrence. We present the results of 93 patients with sacral tumors to analyze the long-term functional and oncological results of patients undergoing en bloc resection. The medical data between January 2003 and July 2010 was retrospectively reviewed. None of the 93 patients died intra- or postoperatively. Patients undergoing intralesional curettage (range, 6500-25,000 mL; mean, 13,500 mL) lost more blood than those patients with wide excision (range, 1000-8100 mL; mean, 3590 mL). Mean follow-up duration from the time of surgery until most recent clinic visit or death was 44.5 months (range, 6-105 months). This study is an educational tool regarding primary sacral tumors and provides evidence on the treatment. It presents results from a large group of patients with sacral tumor. After follow-up, we did not find that sacrificed nerve roots and surgical margins have an impact on the recurrence of the tumor. Patients undergoing intralesional curettage lost more blood than those patients with wide excision. Postoperative bladder/bowel dysfunction was more severe for patients with removal of S1 and S2. PMID- 21815585 TI - Three cases of slipped capital femoral epiphysis in one family. AB - Slipped capital femoral epiphysis is a relatively common disorder of the hip that affects children in late childhood and early adolescence, with an incidence in the United States of approximately 10 per 100,000. Although the diagnosis and treatment of slipped capital femoral epiphysis have been well described, the search for its cause and a method of early identification continues. Recent publications have suggested that there is a familial association among individuals with slipped capital femoral epiphysis, but there is no current genetic marker established for the disorder. This article reports a series of 3 biologically related Caucasian sisters who were athletic; had body mass indices <26 kg/m(2); had no record of any hormonal imbalances or endocrine abnormalities; had good nutrition; and presented with atypical characteristics of slipped capital femoral epiphysis. This is the first report of a series of 3 sisters with slipped capital femoral epiphysis in the United States. Our goals were to document our experience in the identification and treatment of these patients to highlight the complexities of slipped capital femoral epiphysis presentation patterning, to increase the awareness and reporting of familial cases of slipped capital femoral epiphysis by other physicians, and to encourage additional research in this area. As clinicians progress in the ability to diagnose and treat patients with slipped capital femoral epiphysis, they also must be mindful of the varying presentation characteristics. PMID- 21815586 TI - Total knee arthroplasty in a patient with pseudopseudohypoparathyroidism. AB - Pseudopseudohypoparathyroidism (PPH) is a rare genetic disorder characterized by multiple musculoskeletal anomalies and normal serum calcium, phosphate, and parathyroid hormone levels. Although the musculoskeletal manifestations of PPH are well known, little has been reported on the management of orthopedic problems. We report a case of total knee arthroplasty (TKA) performed in a patient with PPH. To our knowledge, this case is not only unique to the arthroplasty literature but is the first report of its kind. This report illustrates the unique pathoanatomy of PPH, the medical and surgical management required, and a previously unreported musculoskeletal abnormality associated with PPH: synovial osteochondromatosis of the knee. Common musculoskeletal anomalies associated with PPH include shortening/bowing of long bones; shortening of metacarpals, metatarsals, and/or phalanges; exostoses; calcification/ossification of subcutaneous and/or periarticular soft tissues; a thickened calvarium; microcephaly; bony coalitions of the hand; vertebral column abnormalities; cubitus valgus; radius/ulna curvus; coxa vara; coxa valga; and genu valgum. This case is the first to report an association of synovial osteochondromatosis with PPH. Because synovial osteochondromatosis and PPH share a common disorder of soft tissue calcification/ossification, as well as abnormal bone formation, this clinical finding does not seem merely coincidental. PMID- 21815587 TI - Pigmented villonodular synovitis after TKA associated with tibial component loosening. AB - There is no known causal link between total knee arthroplasty (TKA) and pigmented villonodular synovitis (PVNS). There also is no known relationship between PVNS and implant loosening after TKA in the literature. This article presents a case of PVNS in a patient undergoing revision TKA for tibial component loosening. A 74 year-old woman who had undergone cemented bilateral TKA 5 years earlier presented with painful swelling in her right knee. At the time of the primary TKA, no abnormal signs were found in the synovial membrane. Routine follow-up radiographs did not indicate implant loosening. At the patient's final follow-up examination before revision surgery, a radiolucent lesion was found below the tibial component. During revision surgery, there was focal proliferation of the synovial tissue with heavy pigmentation around the anteromedial part of the tibial component. The abnormal tissue was removed, and the tibial component was exchanged. The articular surface of the polyethylene was not damaged, and backside wear was not found. For the revision surgery, 5-mm thick medial metal block and extension stem were used. Histological analysis of the resected tissue revealed the typical appearance of PVNS. We present a typical case of PVNS found during revision TKA 5 years after primary TKA. It is hoped this report will encourage surgeons to consider PVNS in the differential diagnosis of patients who present with painful swelling of the knee and to consider PVNS as one of the causes of implant loosening after TKA. Further research about causal factors between PVNS and implant loosening are needed. PMID- 21815588 TI - Amputation of finger by horse bite with complete avulsion of both flexor tendons. AB - Amputation of fingers with tendon avulsion occurs through a traction injury, and most occur through a ring avulsion mechanism. Usually the flexor digitorum profundus is torn out with the amputated finger. Replantation usually is recommended only when the amputation is distal to the flexor digitorum superficialis insertion. Animal bites are relatively common, with a decreasing order of frequency of dogs, cats, and humans. Horse bites are relatively infrequent but are associated with crush injuries and tissue loss when they occur. This article describes a 23-year-old man with amputation of his middle finger at the level of the proximal phalanx after being bitten by a horse. The amputated stump was avulsed with the middle finger flexor digitorum profundus and flexor digitorum superficialis torn from the muscle-tendon junction from approximately the middle of the forearm. The patient had no other injuries, and he was able to move his other 4 fingers with only mild pain. As the amputated digit was not suitable for replantation, the wound was irrigated and debrided. The edges of the phalanx were trimmed, and the edges of the wound were sutured. Tetanus toxoid and rabies vaccine were administered, along with intravenous amoxicillin and clavulanic acid. The patient was discharged from the hospital 2 days later, with no sign of infection of the wound or compartment syndrome of the forearm. This case demonstrates the weakest point in the myotendinous junction and emphasizes the importance of a careful physical examination in patients with a traumatic amputation. PMID- 21815589 TI - Percutaneous distraction lengthening in brachymetacarpia. AB - Brachymetacarpia is a condition manifesting a shortened metacarpal that is caused by early closure of the epiphyseal plate and believed to arise idiopathically. The correction for brachymetacarpia is usually for cosmetic reasons as brachymetacarpia does not impair function. The literature indicates several different approaches to lengthening digits, including single-stage lengthening and rapid distraction lengthening with a bone graft. However, gradual distraction is the preferred method due to excellent cosmetic outcomes and few postoperative complications. This article reports a case of brachymetacarpia treated with distraction lengthening using a minimally invasive, percutaneous approach. A 16 year-old girl presented with a shortened left ring finger and underwent surgery to correct the deformity. The left ring finger measured 12 mm shorter than her right ring finger; however, there was normal mobility at the joints. In the operating room, an external fixator was attached using 4 self-drilling, self tapping pins through several 3-mm skin incisions. The total fixation time was 14 weeks; however, the achieved length of 12 mm was achieved 6 weeks postoperatively. The healing index of the fixation period was 81 days/cm. The postoperative course and fixation period were uneventful, with no complications except for 2 pin infections that were treated with oral antibiotics. The method of gradual distraction lengthening in this case successfully achieved the desired length and yielded an excellent cosmetic result. PMID- 21815590 TI - Malignant granular cell tumor of the thigh. AB - Malignant granular cell tumor is a rare neural tumor characterized by abundant granular-appearing tumor cells. These tumors account for <2% of all granular cell tumors. Unlike its benign counterpart, a malignant granular cell tumor presents primarily in the lower limb and is notably larger. Both the uncommon occurrence of malignant granular cell tumors and its similarities in feature with their benign counterparts make diagnosis of this particular malignancy difficult. By 1998, Fanburg-Smith et al developed a diagnostic criteria in which granular cell tumors were divided into 3 categories-benign, atypical, and malignant-based on 6 histological characteristics of the tumor: necrosis, spindling, vesicular nuclei with large nucleoli, increased mitotic activity, high nuclear-to-cytoplasmic ratio, and pleomorphism. This article presents a case of a large malignant granular cell tumor in the right thigh of a 69-year-old woman. Gross examination of the mass showed the well-demarcated, tan, white tumor measuring 18.2 cm long and 7.6 cm wide at its largest width. Histological examination of the mass, performed by an oncological pathologist, demonstrated foci of tumor necrosis, scattered apoptotic cells, prominent nucleoli, increased nuclear-to-cytoplasmic ratio, increased mitotic activity, and areas of spindling with significant atypia. To our knowledge, this is the largest reported case of malignant granular cell tumor in the lower limb diagnosed using the histological criteria established by Fanburg-Smith et al. This case stresses the importance of thorough evaluation in instances of atypical granular cell tumor presentations. PMID- 21815591 TI - Osteoid osteoma of the great toe. AB - Osteoid osteoma is a relatively common osteoblastic lesion of benign skeletal neoplasms and occurs most commonly in the cortex of long bones, especially the femur and the tibia. Radiological characteristics are a nidus that appears as a small, relatively radiolucent zone within an area of extensive reactive sclerosis. Clinically, the lesion presents with increasing pain, is worse at night, and is relived by nonsteroidal anti-inflammatory drugs (NSAIDs). Osteoid osteomas involving the phalanges of the toes are uncommon, and its accurate preoperative diagnosis is difficult due to the unique clinical and radiological features. The features in the phalanx of the toe are soft tissue swelling and a nidus frequently located in the cancellous without osteosclerosis. This article presents a case of a 22-year-old man with osteoid osteoma in his distal phalanx of the hallux. A needle biopsy of his great toe revealed a small number of bacteria, so he was initially treated for osteomyelitis but with unsatisfactory results. The particular characteristics of clinical and imaging findings supported a diagnosis of osteoid osteoma in the distal phalanx of the hallux. After surgical removal of the tumor, his symptoms resolved. The pathological examination confirmed the suspected diagnosis. In a patient with chronic foot pain that changes to become nocturnal and disappears with NSAID administration, it is important to include osteoid osteoma as a differential diagnosis. A detailed assessment of both clinical and radiological features can lead to the correct diagnosis, which must be confirmed with histopathological examination to ensure adequate excision. PMID- 21815592 TI - Imaging presentation highly manifested as tuberculosis in a case of spinal metastatic carcinoma. AB - Usually the clinical manifestations between spinal tuberculosis (Pott's disease) and metastasis are not characteristic. Nevertheless, their respective imaging presentations are typical and specific, which makes it relatively easier to attain a correct diagnosis. Imaging features of Pott's disease, in general, include narrowing of intervertebral disk space, collapse of vertebral bodies with eventual progression to kyphotic deformity, destruction of the anterior parts of adjacent vertebrae, formation of a large paravertebral abscess, and calcifications or sequestra within the paravertebral abscess. Spinal tuberculosis is usually endemic, especially in Eastern countries. However, the trend of cancer incidence is also increasing in modern society, which makes it difficult to diagnose spinal osseous lesions. This article presents a case of a 45-year-old man with a 9-month history of low back pain. Both computed tomography and magnetic resonance imaging of the lumbar spine supported the initial diagnosis of spinal tuberculosis. However, pathological examination on the excised specimen resulted in the diagnosis of spinal metastatic adenocarcinoma. We suggest that a definitive diagnosis of spinal metastasis or tuberculosis should not be based on imaging alone. Instead, more attention should be paid to atypical imaging presentations. In addition, biopsy is usually necessary for final diagnosis. PMID- 21815593 TI - The future of laser-assisted refractive cataract surgery. PMID- 21815594 TI - Intracorneal ring segments and phakic intraocular lens. PMID- 21815595 TI - Subjective refraction before LASIK enhancement in bioptics procedures with refractive multifocal intraocular lenses. PMID- 21815596 TI - Nutritional challenges in children. PMID- 21815597 TI - A 10-year-old boy with muscle cramps. PMID- 21815598 TI - A 16-year-old boy with anemia, pica. PMID- 21815599 TI - An 18-month-old boy with severe dermatitis, edema, muscle wasting. PMID- 21815600 TI - A 15-year-old girl with dysphagia, failure to thrive. PMID- 21815601 TI - A 9-year-old girl with stabbing stomach pain, low-grade fever. PMID- 21815602 TI - Pre-term neonate with intestinal failure, feeding issues. PMID- 21815603 TI - An obese 16-year-old male with acanthosis nigricans, cardiac risk factors. PMID- 21815604 TI - Prominent decrease of superior midperipheral endothelial cell density after iris fixated phakic intraocular lens implantation. AB - PURPOSE: To evaluate changes in endothelial cell density (ECD) in the corneal region after implantation of an iris-fixated phakic intraocular lens (PIOL). METHODS: Forty-five eyes of 25 myopic patients implanted with Artisan iris fixated PIOLs (Ophtec BV) and 30 eyes of 15 myopic controls were enrolled. Corneal ECD and the distance between endothelium and the PIOL optic were evaluated in five different regions (central, nasal, superior, temporal, and inferior) using noncontact specular microscopy and rotating Scheimpflug imaging. RESULTS: In PIOL-implanted patients, significant differences between the ECD in the superior region, compared with the lowest ECD in any region, and the ECD of the central region, compared with that of the region with highest ECD, were evident. When PIOL-implanted eyes were divided based on time since operation, a significant difference was observed only in patients for whom at least 48 postoperative months had elapsed. In untreated myopic controls, the greatest ECD was observed at the superior cornea. The distance between the central corneal endothelium and PIOL was significantly longer than that of the peripheral locations. CONCLUSIONS: The extent of ECD decrease was not consistent throughout the cornea after implantation of an iris-fixated PIOL. Therefore, ECD measurement not only at the corneal center but also at midperipheral corneal locations, especially in the superior cornea, may be important in patients with irisfixated PIOLs. PMID- 21815605 TI - Central and peripheral corneal iron deposits after implantation of a small aperture corneal inlay for correction of presbyopia. AB - PURPOSE: To describe central and peripheral corneal iron deposition after implantation of the AcuFocus corneal inlay (ACI 7000, AcuFocus Inc) for the surgical correction of presbyopia. METHODS: Patients who underwent inlay implantation between September 2006 and May 2007 and displaying corneal iron deposits were enrolled in the study. RESULTS: Eighteen (56%) eyes of 32 patients developed corneal iron deposition within 36 months after corneal inlay implantation. One (5.5%) eye had a central spot-like iron deposition only, 10 (55.5%) eyes had formation of deposits in a half-moon shape in the inferior cornea parallel to the outer margin of the inlay or a complete circular ring formation, and 7 (39%) eyes demonstrated deposits in both areas. The median interval between implantation and diagnosis of corneal iron deposition was 18 +/- 9 months. CONCLUSIONS: Corneal iron deposition can develop in different shapes after implantation of the small-aperture ACI 7000. Alterations in tear film thickness, its composition, and corneal epithelial basal cell storage, resulting from changes in corneal topography, may be contributing factors for these specific iron depositions. PMID- 21815606 TI - Effects of preoperative punctal plug treatment on visual function and wound healing in laser epithelial keratomileusis. AB - PURPOSE: To evaluate the effect of preoperative punctal plug treatment on early postoperative visual function and wound healing after laser epithelial keratomileusis (LASEK). METHODS: Punctal plugs were implanted in 188 eyes from 95 patients (plug group; 41 men, 54 women; mean age 30.8 +/- 6.6 years) before undergoing LASEK. Punctal plugs were inserted into both the superior and inferior puncta. Wound healing, visual acuity, and haze score after surgery were compared in 175 eyes of 88 age- and sex-matched control patients without punctal plug treatment (non-plug group; 43 men, 45 women; mean age 30.3 +/- 8.0 years). RESULTS: One week after LASEK, the mean fluorescein score in the plug group was significantly lower than the non-plug group (P<.0001). One week after surgery, uncorrected distance visual acuity (UDVA) of 20/20 or better was achieved in 82% and 53% of plug and non-plug patients, respectively. Compared with the non-plug group, better mean UDVA was seen in the plug group 7 days after surgery (non-plug group, 0.02 +/- 0.17; plug group, -0.06 +/- 0.13; P<.0001). Incidence of haze after LASEK was higher in the non-plug group (7.4%) compared with the plug group (1.6%) (P=.014). CONCLUSIONS: Preoperative punctal plug treatment prior to LASEK promoted corneal epithelial wound healing and was associated with better visual acuity in the early postoperative period. PMID- 21815607 TI - Comparative study of the effect of incorporated individual wheat storage proteins on mixing properties of rice and wheat doughs. AB - The aim of this work was to compare the effects of incorporated wheat storage proteins on the functional properties of rice and wheat flours. The advantage of rice as a base flour compared to wheat is that it does not contain any wheat flour components and, therefore, has no interactive effect between wheat glutenin proteins. The incorporation of individual HMW glutenin subunit proteins (Bx6, Bx7, and By8) in different ratios had significant positive effects on the mixing requirements of both rice and wheat doughs. Reconstitution experiments using two x+y type HMW-GS pairs together with a bacterially expressed LMW-GS have been also carried out in this study. The largest effects of polymer formation and mixing properties of rice flour dough were observed when Bx and By subunits were used in a 1:1 ratio and HMW and LMW glutenin subunits in a 1:3 ratio. However, using the same subunit ratios in wheat as the base flour, these synergistic effects were not observed. PMID- 21815608 TI - Evolved phase separation toward balanced charge transport and high efficiency in polymer solar cells. AB - Understanding effect of morphology on charge carrier transport within polymer/fullerene bulk heterojunction is necessary to develop high-performance polymer solar cells. In this work, we synthesized a new benzodithiophene-based polymer with good self-organization behavior as well as favorable morphology evolution of its blend films with PC(71)BM under improved processing conditions. Charge carrier transport behavior of blend films was characterized by space charge limited current method. Evolved blend film morphology by controlling blend composition and additive content gradually reaches an optimized state, featured with nanoscale fibrilla polymer phase in moderate size and balanced mobility ratio close to 1:1 for hole and electron. This optimized morphology toward more balanced charge carrier transport accounts for the best power conversion efficiency of 3.2%, measured under simulated AM 1.5 solar irradiation 100 mW/cm(2), through enhancing short circuit current and reducing geminate recombination loss. PMID- 21815609 TI - Dietary alkylresorcinols and lignans in the Spanish diet: development of the alignia database. AB - The intake of alkylresorcinols and lignans in Spain is unknown due to the lack of information on the content of these compounds in particular foods. This paper describes the development of the first alkylresorcinol and lignan database adapted to the Spanish diet, including foods items especially relevant for this population. The values of alkylresorcinols and lignans in common foods and beverages were collected from scientific publications in refereed journals, and other foods particularly consumed in Spain, for which values were not available, were analyzed by standardized protocols and included into the database. The Alignia database presents the content of alkylresorcinols in 88 food items and the lignan content of 593 foods and beverages. Using the database, the intake of lignans in Spain, calculated using data from the Food Composition Panel based on household consumption, was estimated to be 0.76 mg/day. PMID- 21815610 TI - Triggered dye release via photodissociation of nitric oxide from designed ruthenium nitrosyls: turn-ON fluorescence signaling of nitric oxide delivery. AB - Two new fluorescein-tethered nitrosyls derived from designed tetradentate ligands with carboxamido-N donors have been synthesized and characterized by spectroscopic techniques. These two diamagnetic {Ru-NO}(6) nitrosyls, namely, [(Me(2)bpb)Ru(NO)(FlEt)] (1-FlEt, Me(2)bpb = 1,2-bis(pyridine-2-carboxamido)5 dimethylbenzene, FlEt = fluorescein ethyl ester) and [((OMe)(2)IQ1)Ru(NO)(FlEt)] (2-FlEt, (OMe)(2)IQ1 = 1,2-bis(isoquinoline-1-carboxamido)-4,5-dimethoxybenzene), display NO stretching frequencies (nu(NO)) at 1846 and 1832 cm(-1) in addition to their FlEt carbonyl stretching frequencies (nu(CO)) at 1715 and 1712 cm(-1), respectively. Coordination of the dye ligand enhances the absorptivity and NO photolability of these two nitrosyls in the visible region (450-600 nm) of light. Exposure to visible light promotes rapid loss of NO from both {Ru-NO}(6) nitrosyls to generate Ru(III) photoproducts in dry aprotic solvents, such as MeCN and DMF. The FlEt(-) moiety remains bound to the paramagnetic Ru(III) center in such cases, and hence, the photoproducts exhibit very weak fluorescence from the dye unit. In the presence of water, the Ru(III) photoproducts undergo further aquation and loss of the FlEt(-) moiety via protonation. These steps lead to turn ON fluorescence (from the free FlEt unit) and provide a visual signal of the NO photorelease from 1-FlEt and 2-FlEt in aqueous media. PMID- 21815611 TI - A highly distorted open-shell endohedral Zintl cluster: [Mn@Pb12]3-. AB - Reaction of an ethylenediamine (en) solution of K(4)Pb(9) and 2,2,2-crypt (4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo[8.8.8]hexacosane) with a tetrahydrofuran (THF) solution of Mn(3)(Mes)(6) (Mes = 2,4,6-trimethylphenyl) yielded the anionic cluster [Mn@Pb(12)](3-). This species was observed in the positive and negative ion-mode electrospray mass-spectra of the crude reaction mixture. The crystalline samples obtained from such solutions allowed us to confirm the composition of the sample as [K(2,2,2-crypt)](3)[Mn@Pb(12)].1.5en (1). Because of numerous issues related to crystal sample quality and crystallographic disorder a high-quality crystal structure solution could not be obtained. Despite this, however, the data collected permit us to draw reasonable conclusions about the charge and connectivity of the [Mn@Pb(12)](3-) cluster anion. Crystals of 1 were further characterized by elemental analysis and electron paramagnetic resonance (EPR). Density Functional Theory (DFT) calculations on such a system reveal a highly distorted endohedral cluster anion, consistent with the structural distortions observed by single crystal X-ray diffraction. The cluster anions are considerably expanded compared to the 36 electron closed-shell analogue [Ni@Pb(12)](2-) and, moreover, exhibit significant low-symmetry distortions from the idealized icosahedral (I(h)) geometry that is characteristic of related endohedral clusters. Our computations indicate that there is substantial transfer of electron density from the formally Mn(-I) center to the low-lying vacant orbitals of the [Pb(12)](2-) cage. PMID- 21815612 TI - On-road emissions of light-duty vehicles in europe. AB - For obtaining type approval in the European Union, light-duty vehicles have to comply with emission limits during standardized laboratory emissions testing. Although emission limits have become more stringent in past decades, light-duty vehicles remain an important source of nitrogen oxides and carbon monoxide emissions in Europe. Furthermore, persisting air quality problems in many urban areas suggest that laboratory emissions testing may not accurately capture the on road emissions of light-duty vehicles. To address this issue, we conduct the first comprehensive on-road emissions test of light-duty vehicles with state-of the-art Portable Emission Measurement Systems. We find that nitrogen oxides emissions of gasoline vehicles as well as carbon monoxide and total hydrocarbon emissions of both diesel and gasoline vehicles generally remain below the respective emission limits. By contrast, nitrogen oxides emissions of diesel vehicles (0.93 +/- 0.39 grams per kilometer [g/km]), including modern Euro 5 diesel vehicles (0.62 +/- 0.19 g/km), exceed emission limits by 320 +/- 90%. On road carbon dioxide emissions surpass laboratory emission levels by 21 +/- 9%, suggesting that the current laboratory emissions testing fails to accurately capture the on-road emissions of light-duty vehicles. Our findings provide the empirical foundation for the European Commission to establish a complementary emissions test procedure for light-duty vehicles. This procedure could be implemented together with more stringent Euro 6 emission limits in 2014. The envisaged measures should improve urban air quality and provide incentive for innovation in the automotive industry. PMID- 21815613 TI - Alkynylisocyanide gold mesogens as precursors of gold nanoparticles. AB - Gold nanoparticles (Au NPs) have been synthesized using simple thermolysis, whether from the mesophase or from toluene solutions, of mesogenic alkynyl isocyanide gold complexes [Au(C=C-C(6)H(4)-C(m)H(2m+1))(C=N-C(6)H(4)-O C(n)H(2n+1))]. The thermal decomposition from the mesophase is much slower than from solution and produces a more heterogeneous size distribution of the nanoparticles. Working in toluene solution, the size of nanoparticles can be modulated from ~2 to ~20 nm by tuning the chain lengths of the ligands present in the precursor. Different experimental conditions have been analyzed to reveal the processes governing the formation of the gold nanoparticles. Experiments on the effect of adding ligands or bubbling oxygen support that the thermal decomposition is a bimolecular process that starts by decoordination of the isocyanide ligand, producing an oxidative coupling of the akynyl group to [R-C=C C=C-R] and reduction of gold(I) to gold(0) as nanoparticles. The nanoparticles obtained behave as a catalyst in the oxidation of isocyanide (CNR) to isocyanate (OCNR), which in turn cooperates to catalyze the decomposition. PMID- 21815615 TI - Tertiary amine-catalyzed chemoselective and asymmetric [3 + 2] annulation of Morita-Baylis-Hillman carbonates of isatins with propargyl sulfones. AB - A chemo- and enantioselective [3 + 2] annulation of Morita-Baylis-Hillman carbonates of isatins with propargyl sulfones was catalyzed by a beta-ICD O-MOM ether 1c, affording spirocyclic 2-oxindoles bearing an unusual cyclopentadiene motif in outstanding ee values (up to >99%). More electrophiles, such as N phenylmaleimide, have been also utilized to deliver complex spirocyclic 2 oxindoles with good results. PMID- 21815614 TI - Coamorphous drug systems: enhanced physical stability and dissolution rate of indomethacin and naproxen. AB - One of the challenges in drug development today is that many new drug candidates are poorly water-soluble, and one of the approaches to overcome this problem is to transfer a crystalline drug into its amorphous form, thus increasing dissolution rate and apparent solubility of the compound. In this study, a coamorphous drug/drug combination between the two nonsteroidal anti-inflammatory drugs, naproxen and gamma-indomethacin, was prepared and investigated. At molar ratios of 2:1, 1:1 and 1:2, the drugs were quench cooled in order to obtain a coamorphous binary phase. Physical stability was examined at 277.15 and 298.15 K under dry conditions (phosphorus pentoxide) and analyzed with X-ray powder diffraction (XRPD). Intrinsic dissolution testing was carried out to identify dissolution advantages of the coamorphous form over its crystalline counterparts or amorphous indomethacin. Fourier transform infrared spectroscopy (FTIR) was used for analyses at the molecular level to detect potential molecular interactions. Differential scanning calorimetry (DSC) thermograms were employed to assess the glass transition temperatures (T(g)), and the results were compared with predicted T(g)s from the Gordon-Taylor equation. Results showed that naproxen could be made amorphous in combination with indomethacin while this was not possible with naproxen alone. Peak shifts in the FTIR spectra indicated molecular interactions between both drugs, and it is suggested that the two drugs formed a heterodimer. Therefore, samples at the 1:2 and 2:1 ratios showed recrystallization of the excess drug upon storage whereas the 1:1 ratio samples remained amorphous. Intrinsic dissolution testing showed increased dissolution rate of both drugs in the coamorphous form as well as a synchronized release for the 1:1 coamorphous blend. All T(g)s displayed negative deviations from the Gordon-Taylor equation with the 1:1 ratio showing the largest deviation. In a novel approach of predicting the glass transition temperature, the 1:1 drug ratio was inserted as an individual component in the Gordon-Taylor equation with the excess drug representing the second compound. This approach resulted in a good fit to the experimentally determined T(g)s. PMID- 21815616 TI - Minimizing nonspecific protein adsorption in liquid crystal immunoassays by using surfactants. AB - In this paper, we report the role of surfactants in minimizing nonspecific protein adsorption in liquid crystal (LC)-based immunoassays in which LC is used as a readout system. Among all surfactants tested, only nonionic surfactant such as Tween 20 can effectively reduce the nonspecific protein adsorption, while maintaining the selectivity of the LC-based immunoassay. We also show that to minimize nonspecific protein adsorption, Tween 20 can be added directly into the antibody solution to a final concentration of 0.8 mM. After the addition of Tween 20, better correlations between the antibody concentrations and the interference colors of LCs can therefore be obtained. For example, when Cy3 antibiotin was used, black, yellow, red, and green interference colors correspond to a concentration of 5, 25, 50, and 100 MUg/mL, respectively. This feature gives LC immunoassay a unique advantage over the fluorescence-based immunoassay. PMID- 21815617 TI - Iminium ion cascade reaction in the total synthesis of (+)-vincadifformine. AB - An iminium ion triggered cascade reaction is described in the total synthesis of (+)-vincadifformine by the coupling of 3,3-substituted tetrahydropyridine and indole derivative. The strategy allows simultaneous construction of two new rings, three new sigma bonds, and two new stereogenic centers in one pot with complete stereochemical control. PMID- 21815618 TI - Fluorination effects on rotational correlation times of tris(beta diketonato)aluminum(III) in CO2 by 27Al NMR relaxation measurements. AB - (27)Al NMR longitudinal relaxation times, T(1,obs)((27)Al), of [Al(acac)(3)] and [Al(hfa)(3)] (Hacac = acetylacetone, Hhfa = hexafluoroacetylacetone) in CH(3)CN and CO(2) were measured over a wide range of temperature and pressure. The rotational correlation times, tau(r), of the tris(beta-diketonato)aluminum(III) complexes were determined from T(1,obs)((27)Al) using (27)Al quadrupole coupling constants, eQq/h((27)Al), which were also obtained to be 3.11 and 3.22 MHz for [Al(acac)(3)] and [Al(hfa)(3)], respectively, in CD(3)CN by the dual spin probe technique in the present study. At each temperature, tau(r) increased almost linearly with increasing viscosity, eta, in both CH(3)CN and CO(2); however, tau(r) in CO(2) at near critical densities deviated appreciably upward, as shown in a similar analogue of bis(acetylacetonato)beryllium(II), [Be(acac)(2)] (Umecky; et al. J. Phys. Chem. B 2002, 106, 11114). The eta/T dependence of tau(r) was examined to discuss intermolecular interactions between the complexes and solvent molecules in terms of the fluorination and geometrical effects. The degree of solute-solvent interactions increases in the order [Be(acac)(2)] < [Al(hfa)(3)] < [Al(acac)(3)] in CH(3)CN and [Al(acac)(3)] < [Be(acac)(2)] < [Al(hfa)(3)] in CO(2). The results suggest that dipolar CH(3)CN molecules interact with negatively charged oxygen atoms in the complexes, whereas nonpolar CO(2) prefers fluorinated substituents as well as quasi-aromatic rings in the ligands. Moreover, the relationship between the rotational and translational motions of tris(acetylacetonato)metal(III), [M(III)(acac)(3)], in CO(2) was investigated. PMID- 21815619 TI - Functionalized and postfunctionalizable porous polymeric films through evaporation-induced phase separation using mixed solvents. AB - Condensation of water droplets during rapid evaporation of a polymer solution, under humid conditions, has been known to generate uniformly porous polymer films. Similar porous films are also formed when a solution of the polymer in THF containing small amounts of water, is allowed to evaporate rapidly under air flow; this suggests that water droplets may be formed during the final stages of film formation. In the presence of added surfactants, the interface of water droplets could become lined with the surfactants and consequently the internal walls of the pores generated, upon removal of the water, could become decorated with the hydrophilic head groups of the surfactant molecules. In a series of carefully designed experiments, we have examined the effect of added surfactants, both anionic and cationic, on the formation of porous PMMA films; the films were prepared by evaporating a solution of the polymer in THF containing controlled amounts of aqueous surfactant solutions. We observed that the average size of the pores decreases with increasing surfactant concentration, while it increases with increasing amounts of added water. The size of the pores and their distribution were examined using AFM and IR imaging methods. Although IR imaging possessed inadequate resolution to confirm the presence of surfactants at the pore surface, exchange of the inorganic counterion, such as the sodium-ion of SDS, with suitable ionic organic dyes permitted the unequivocal demonstration of the presence of the surfactants at the interface by the use of confocal fluorescence microscopy. PMID- 21815620 TI - Thermal transformation of a layered multifunctional network into a metal-organic framework based on a polymeric organic linker. AB - The preparation of layered [La(H(3)nmp)] as microcrystalline powders from optimized microwave-assisted synthesis or dynamic hydrothermal synthesis (i.e., with constant rotation of the autoclaves) from the reaction of nitrilotris(methylenephosphonic acid) (H(6)nmp) with LaCl(3).7H(2)O is reported. Thermogravimetry in conjunction with thermodiffractometry showed that the material undergoes a microcrystal-to-microcrystal phase transformation above 300 degrees C, being transformed into either a three-dimensional or a two-dimensional network (two models are proposed based on dislocation of molecular units) formulated as [La(L)] (where L(3-) = [-(PO(3)CH(2))(2)(NH)(CH(2)PO(2))O(1/2) ](n)(3n-)). The two crystal structures were solved from ab initio methods based on powder X-ray diffraction data in conjunction with structural information derived from (13)C and (31)P solid-state NMR, electron microscopy (SEM and EDS mapping), FT-IR spectroscopy, thermodiffractometry, and photoluminescence studies. It is shown that upon heating the coordinated H(3)nmp(3-) anionic organic ligand undergoes a polymerization (condensation) reaction to form in situ a novel and unprecedented one-dimensional polymeric organic ligand. The lanthanum oxide layers act, thus, simultaneously as insulating and templating two dimensional scaffolds. A rationalization of the various steps involved in these transformations is provided for the two models. Photoluminescent materials, isotypical with both the as-prepared ([(La(0.95)Eu(0.05))(H(3)nmp)] and [(La(0.95)Tb(0.05))(H(3)nmp)]) and the calcined ([(La(0.95)Eu(0.05))(L)]) compounds and containing stoichiometric amounts of optically active lanthanide centers, have been prepared and their photoluminescent properties studied in detail. The lifetimes of Eu(3+) vary between 2.04 +/- 0.01 and 2.31 +/- 0.01 ms (considering both ambient and low-temperature studies). [La(H(3)nmp)] is shown to be an effective heterogeneous catalyst in the ring opening of styrene oxide with methanol or ethanol, producing 2-methoxy-2-phenylethanol or 2-ethoxy-2 phenylethanol, respectively, in quantitative yields in the temperature range 40 70 degrees C. The material exhibits excellent regioselectivity to the beta alkoxy alcohol products even in the presence of water. Catalyst recycling and leaching tests performed for [La(H(3)nmp)] confirm the heterogeneous nature of the catalytic reaction. Catalytic activity may be attributed to structural defect sites. This assumption is somewhat supported by the much higher catalytic activity of [La(L)] in comparison to [La(H(3)nmp)]. PMID- 21815621 TI - In situ biosensing with a surface plasmon resonance fiber grating aptasensor. AB - Surface plasmon resonance (SPR) biosensors prepared using optical fibers can be used as a cost-effective and relatively simple-to-implement alternative to well established biosensor platforms for monitoring biomolecular interactions in situ or possibly in vivo. The fiber biosensor presented in this study utilizes an in fiber tilted Bragg grating to excite the SPR on the surface of the sensor over a large range of external medium refractive indices, with minimal cross-sensitivity to temperature and without compromising the structural integrity of the fiber. The label-free biorecognition scheme used demonstrates that the sensor relies on the functionalization of the gold-coated fiber with aptamers, synthetic DNA sequences that bind with high specificity to a given target. In addition to monitoring the functionalization of the fiber by the aptamers in real-time, the results also show how the fiber biosensor can detect the presence of the aptamer's target, in various concentrations of thrombin in buffer and serum solutions. The findings also show how the SPR biosensor can be used to evaluate the dissociation constant (K(d)), as the binding constant agrees with values already reported in the literature. PMID- 21815622 TI - Lipopolyplex ternary delivery systems incorporating C14 glycerol-based lipids. AB - The structure, biophysical properties and biological behavior of lipopolyplex ternary gene delivery vectors incorporating novel C14 glycerol based lipids of varying alkyl chain geometry (containing cis, trans or alkyne double bonds) have been studied in the presence and absence of a bifunctional targeting peptide designed to both condense DNA and confer integrin-specific targeting. In vitro transfection studies in breast cancer MDA-MB-231 cells revealed that ternary formulations of lipid:peptide:DNA (LPD) complexes prepared using the aforementioned lipids possessed highly synergistic transfection activity up to 2500-fold higher than their respective lipid:DNA (LD) or peptide:DNA (PD) counterparts. Furthermore, the small structural differences in the lipid alkyl chain geometries also resulted in pronounced differences in transfection within each type of formulation, whereby the trans lipids showed best activity when formulated as LD complexes, whereas the cis lipids were superior in LPD formulations. Confocal fluorescence internalization studies using labeled components of the formulations showed both the lipid and the DNA of LD complexes to be trapped in endocytic compartments, whereas in the case of LPD complexes, the DNA was clearly released from the endosomal compartments and, together with the peptide, internalized within the cell nucleus. Physicochemical characterization of the formulations carried out by light and neutron scattering, zeta potential measurement, and negative staining electron microscopy detected major structural differences between LD and LPD complexes. Gel electrophoresis assays additionally showed differences between the individual lipids tested in each type of formulation. In conclusion, the superior transfection of the trans lipids in the LD complexes was thought to be attributed to superior DNA binding caused by a more closely matched charge distribution of the more rigid, trans lipids with the DNA. In the case of the LPD complexes, the DNA was thought to be predominantly condensed by the cationic portion of the peptide forming a central core surrounded by a lipid bilayer from which the targeting sequence partially protrudes. The more fluid, cis lipids were thought to confer better activity in this formulation due to allowing more of the targeting peptide sequence to protrude. PMID- 21815623 TI - Generation of counter ion radical (Br2(*-)) and its reactions in water-in-oil (CTAB or CPB)/n-butanol/cyclohexane/water) microemulsion. AB - Herein we report the generation of counterion radicals and their reactions in quaternary water-in-oil microemulsion. Hydrated electrons in the microemulsion CTAB/H(2)O/n-butanol/cyclohexane have a remarkably short half-life (~1 MUs) and lower yield as compared to that in the pure water system. Electrons are solvated in two regions: one is the water core and other the interface; however, the electrons in the water core have a shorter half-life than those in the interface. The decay of the solvated electrons in the interface is found to be water content dependent and it has been interpreted in terms of increased interfacial fluidity with the increase in water content of the microemulsion. Interestingly another species, dibromide radical anion (Br(2)(*-)) in CTAB and CPB microemulsions have been observed after the electron beam irradiation. Assuming that the extinction coefficient of the radicals is the same as that in the aqueous solution, the yields of the radicals per 100 eV are 0.29 and 0.48 for the Br(2)(*-) radical in CTAB and CPB containing microemulsions (W(0) = 40), respectively, under N(2)O saturated conditions. Further, we intended to study electron transfer reactions, which occur at and through the interface. The reaction of the Br(2)(*-) radical anion with ABTS [2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)] has been studied to generate the ABTS radical in the water core, and further, its reaction has been investigated with the water-insoluble molecule vitamin E (tocopherol) and water-soluble vitamin C (ascorbic acid). In the present study, we were able to show that, even for molecules which are completely insoluble in water, ABTS scavenging assay is possible by pulse radiolysis technique. Furthermore, these results show that it is possible to follow the reaction of the hydrated inorganic radical with solutes dissolved in the organic phase in a microemulsion without use of a phase transfer catalyst. PMID- 21815624 TI - SAFT-gamma force field for the simulation of molecular fluids. 1. A single-site coarse grained model of carbon dioxide. AB - An application of the "top-down" concept for the development of accurate coarse grained intermolecular potentials of complex fluids is presented. With the more common "bottom-up" procedure, coarse-grained models are constructed from a suitable simplification of a detailed atomistic representation, and small adjustments to the intermolecular parameters are made by comparison with limited experimental data where necessary. In contrast, in the top-down approach, a molecular-based equation of state is used to obtain an effective coarse-grained intermolecular potential that reproduces the macroscopic experimental thermophysical properties over a wide range of conditions. These coarse-grained intermolecular potentials can then be used in conventional molecular simulation to obtain properties (such as structure or dynamics) that are not directly accessible from the equation of state or at extreme conditions where the theory is expected to fail. To demonstrate our procedure, a coarse-grained model for carbon dioxide (CO(2)) is obtained from a recent implementation of the statistical associating fluid theory of variable range (SAFT-VR) employing a Mie (generalized Lennard-Jones) potential; the parameters of this single-site Mie model of CO(2) are estimated by optimizing the equation of state's description of the experimental vapor-pressure and saturated liquid density data. This approach is only viable because of the excellent agreement of the SAFT-VR Mie EoS with simulation data. Our single-site SAFT-gamma coarse-grained model for CO(2) is used in Monte Carlo molecular simulation to assess the adequacy of the description of the fluid-phase behavior and properties that were not used to develop the potential model such as the enthalpy of vaporization, interfacial tension, density profiles, supercritical densities, and second-derivative thermodynamic properties (thermal expansivity, isothermal compressibility, heat capacity, Joule-Thompson coefficient, and speed of sound). The accuracy of the description with the single-site SAFT-gamma model of CO(2) is found to be of similar quality to that of more sophisticated intermolecular potentials such as a six-site (three LJ centers and three charged sites) all-atom model. The SAFT gamma top-down approach to coarse-graining resolves a key challenge with coarse graining techniques: the provision of a direct robust link between the microscopic and macroscopic scales. PMID- 21815626 TI - Core-shell structured carbonyl iron microspheres prepared via dual-step functionality coatings and their magnetorheological response. AB - The dispersion stability of soft magnetic carbonyl iron (CI)-based magnetorheological (MR) fluids was improved by applying a unique functional coating composed of a conducting polyaniline layer and a multiwalled carbon nanotube nest to the surfaces of the CI particles via conventional dispersion polymerization, followed by facile solvent casting. The coating morphology and thickness were analyzed by SEM and TEM imaging. Chemical composition of the polyaniline layer was detected by Raman spectroscope, which also confirmed the coating performance successfully. The influence of the functional coating on the magnetic properties was investigated by measuring the MR performance and sedimentation properties using a vibrating sample magnetometer, rotational rheometer, and Turbiscan apparatus. Improved dispersion characteristics of the MR fluid were observed. PMID- 21815627 TI - Thermal modulation for multidimensional liquid chromatography separations using low-thermal-mass liquid chromatography (LC). AB - We report on a proof-of-principle experiment with a novel thermal modulation device with potential use in two-dimensional liquid chromatography (LC * LC) systems. It is based on the thermal desorption concept used in two-dimensional gas chromatography (GC * GC) systems. Preconcentration of neutral analytes eluting from the first dimension column is performed in a capillary "trap" column packed with highly retentive porous graphitic carbon particles, placed in an aluminum low-thermal-mass LC heating sleeve. Remobilization of the trapped analytes is achieved by rapidly heating the trap column, by applying temperature ramps up to +1200 degrees C/min. Compared to the nonmodulated signal, the presented thermal modulator yielded narrow peaks, and a concentration enhancement factor up to 18 was achieved. With a thermally modulated LC separation of an epoxy resin, it is shown that when the thermal modulation is applied periodically, the trapped and concentrated molecules can be released periodically and that the modulating interface can both serve as a preconcentration device and as an injector for the second dimension column of an LC * LC setup. Because of the thermal modulation, a high-molecular-weight epoxy resin could be adequately separated and the different fractions were identified with a GPC analysis, as well as an offline second dimension LC analysis. PMID- 21815625 TI - Permeation of styryl dyes through nanometer-scale pores in membranes. AB - Styryl dyes are widely used to study synaptic vesicle (SV) recycling in neurons; vesicles are loaded with dye during endocytosis, and dye is subsequently released via exocytosis. During putative kiss-and-run exocytosis, efflux of dye from individual SVs has been proposed to occur via two sequential steps: dissociation from the membrane followed by permeation through a small fusion pore. To improve our understanding of the kinetics of efflux of dye from vesicles during kiss-and run events, we examined the rates of efflux of different dyes through nanometer scale pores formed in membranes by the toxins melittin and alpha-hemolysin; these pores approximate the size of fusion pores measured in neuroendocrine cells. We found that the axial diameter of each dye was a crucial determinant for permeation. Moreover, the two dyes with the largest cross-sectional areas were completely unable to pass through pores formed by a mutant alpha-hemolysin that has a slightly smaller pore than the wild-type toxin. The overall time constant for efflux (seconds) of each dye was orders of magnitude slower than the time constant for dissociation from membranes (milliseconds). Thus, the permeation step is rate-limiting, and this observation was further supported by atomistic molecular dynamics simulations. Together, the data reported here help provide a framework for interpreting dye destaining rates from secretory vesicles. PMID- 21815628 TI - Proteomic analysis of 3T3-L1 adipocyte mitochondria during differentiation and enlargement. AB - The increase in adipose tissue mass arises in part from progressive lipid loading and triglyceride accumulation in adipocytes. Enlarged adipocytes produce the highest levels of pro-inflammatory molecules and reactive oxygen species (ROS). Since mitochondria are the site for major metabolic processes (e.g., TCA cycle) that govern the extent of triglyceride accumulation as well as the primary site of ROS generation, we quantitatively investigated changes in the adipocyte mitochondrial proteome during different stages of differentiation and enlargement. Mitochondrial proteins from 3T3-L1 adipocytes at different stages of lipid accumulation (days 0-18) were digested and labeled using the iTRAQ 8-plex kit. The labeled peptides were fractionated using a liquid phase isoelectric fractionation system (MSWIFT) to increase the depth of proteome coverage and analyzed using LC-MS/MS. A total of 631 proteins in the mitochondrial fraction, including endoplasmic reticulum-associated and golgi-related mitochondrial proteins, were identified and classified into 12 functional categories. A total of 123 proteins demonstrated a statistically significant change in expression in at least one of the time points over the course of the experiment. The identified proteins included enzymes and transporters involved in the TCA cycle, fatty acid oxidation, and ATP synthesis. Our results indicate that cultured adipocytes enter a state of metabolic-overdrive where increased flux through the TCA cycle and increased fatty acid oxidation occur simultaneously. The proteomic data also suggest that accumulation of reduced electron carriers and the resultant oxidative stress may be attractive targets for modulating adipocyte function in metabolic disorders. PMID- 21815629 TI - Schizosaccharomyces pombe protection of telomeres 1 utilizes alternate binding modes to accommodate different telomeric sequences. AB - The ends of eukaryotic chromosomes consist of long tracts of repetitive GT-rich DNA with variable sequence homogeneity between and within organisms. Telomeres terminate in a conserved 3'-ssDNA overhang that, regardless of sequence variability, is specifically and tightly bound by proteins of the telomere-end protection family. The high affinity ssDNA-binding activity of S. pombe Pot1 protein (SpPot1) is conferred by a DNA-binding domain consisting of two subdomains, Pot1pN and Pot1pC. Previous work has shown that Pot1pN binds a single repeat of the core telomere sequence (GGTTAC) with exquisite specificity, while Pot1pC binds an extended sequence of nine nucleotides (GGTTACGGT) with modest specificity requirements. We find that full-length SpPot1 binds the composite 15mer, (GGTTAC)(2)GGT, and a shorter two-repeat 12mer, (GGTTAC)(2), with equally high affinity (<3 pM), but with substantially different kinetic and thermodynamic properties. The binding mode of the SpPot1/15mer complex is more stable than that of the 12mer complex, with a 2-fold longer half-life and increased tolerance to nucleotide and amino acid substitutions. Our data suggest that SpPot1 protection of heterogeneous telomeres is mediated through 5'-sequence recognition and the use of alternate binding modes to maintain high affinity interaction with the G strand, while simultaneously discriminating against the complementary strand. PMID- 21815630 TI - Improving depth in phosphoproteomics by using a strong cation exchange-weak anion exchange-reversed phase multidimensional separation approach. AB - Several enrichment and separation strategies are available that allow nearly pure phosphopeptide pools to be created. These phosphopeptide pools are too complex to be completely unraveled by RP-LC-MS analysis alone. Here, we implement weak anion exchange (WAX) chromatography as an additional, complementary dimension to strong cation exchange (SCX) and reversed phase (RP). Initially, we used SCX to fractionate a human lysate digest to generate a fraction highly enriched for phosphopeptides. Analysis of this single fraction by RP-LC-MS with a 140 min gradient method allowed the identification of 4045 unique phosphopeptides (false discovery rate (FDR) < 1%; Mascot score > 20) using an Orbitrap Velos. Triplicate analysis (420 min total gradient time) of the same sample increased the total to just over 5000 unique phosphopeptides. When we separated the same sample by WAX and analyzed 14 WAX fractions by 30 min gradient RP-LC-MS (420 min total gradient time) we were able to identify 7251 unique phosphopeptides, an approximate increase of 40%, while maintaining the same total gradient time. We performed a more comprehensive, albeit also more time-consuming, analysis of the same 14 WAX fractions by the use of 140 min gradient LC-MS analyses, which resulted in the detection of over 11 000 unique phosphopeptides. Our results clearly demonstrate that additional separation dimensions are still necessary for in-depth phosphoproteomics and that WAX is a suitable dimension to be combined and sandwiched between SCX and RP chromatography. PMID- 21815631 TI - Comparative toxicity of arsenic metabolites in human bladder cancer EJ-1 cells. AB - The human bladder is one of the primary target organs for arsenic-induced carcinogenicity, and arsenic metabolites in urine have been suspected to be directly involved in carcinogenesis. Thioarsenicals are commonly found in human and animal urine and are also considered to be highly toxic arsenic metabolites. The present study was performed to gain insight into the toxicity and accumulation of arsenic species found in urine, including arsenate (iAs(V)), arsenite (iAs(III)), monomethylarsonic acid (MMA(V)), monomethylmonothioarsonic acid (MMMTA(V)), dimethylarsinic acid (DMA(V)), dimethylarsinous acid (DMA(III)), dimethylmonothioarsinic acid, (DMMTA(V)), and dimethyldithioarsinic acid (DMDTA(V)) in human bladder cancer EJ-1 cells. The order of cytotoxicity of these arsenic compounds in EJ-1 human bladder cancer cells was DMA(III), DMMTA(V) > iAs(III) ? iAs(V) > MMMTA(V) > MMA(V), DMA(V), and DMDTA(V), indicating that the sulfur-containing DMMTA(V) was among the most toxic arsenic compounds similar to trivalent DMA(III). We further characterized the DNA damage, generation of highly reactive oxygen species (hROS), and expression of proteins p21 and p53 in cells after exposure to iAs(III), DMA(III), and DMMTA(V). Cellular exposure to DMMTA(V) resulted in reduced protein expression of p53 and p21, increased DNA damage, and increased intracellular hROS (hydroxyl radical). In contrast, iAs(III) significantly increased the protein expression of p21 and p53 and did not increase the hROS at the IC(50). Intracellular glutathione (GSH) was reduced by 60% after exposure to DMA(III) or DMMTA(V), suggesting that DMMTA(V) causes cell death through oxidative stress. In contrast, GSH levels increased in cells exposed to iAs(III), and hROS only increased after a long exposure to iAs(III). Our findings demonstrate that DMMTA(V) may be one of the most toxicologically potent arsenic species, relevant to arsenic-induced carcinogenicity in the urinary bladder. PMID- 21815632 TI - C-linked antifreeze glycoprotein (C-AFGP) analogues as novel cryoprotectants. AB - Significant cell damage occurs during cryopreservation resulting in a decreased number of viable and functional cells post-thawing. Recent studies have correlated the unsuccessful outcome of regenerative therapies with poor cell viability after cryopreservation. Cell damage from ice recrystallization during freeze-thawing is one cause of decreased viability after cryopreservation. We have assessed the ability of two C-AFGPs that are potent inhibitors of ice recrystallization to increase cell viability after cryopreservation. Our results indicate that a 1-1.5 mg/mL (0.5-0.8 mM) solution of C-AFGP 1 is an excellent alternative to a 2.5% DMSO solution for the cryopreservation of human embryonic liver cells. PMID- 21815633 TI - Molecular packing of high-mobility diketo pyrrolo-pyrrole polymer semiconductors with branched alkyl side chains. AB - We describe a series of highly soluble diketo pyrrolo-pyrrole (DPP)-bithiophene copolymers exhibiting field effect hole mobilities up to 0.74 cm(2) V(-1) s(-1), with a common synthetic motif of bulky 2-octyldodecyl side groups on the conjugated backbone. Spectroscopy, diffraction, and microscopy measurements reveal a transition in molecular packing behavior from a preferentially edge-on orientation of the conjugated plane to a preferentially face-on orientation as the attachment density of the side chains increases. Thermal annealing generally reduces both the face-on population and the misoriented edge-on domains. The highest hole mobilities of this series were obtained from edge-on molecular packing and in-plane liquid-crystalline texture, but films with a bimodal orientation distribution and no discernible in-plane texture exhibited surprisingly comparable mobilities. The high hole mobility may therefore arise from the molecular packing feature common to the entire polymer series: backbones that are strictly oriented parallel to the substrate plane and coplanar with other backbones in the same layer. PMID- 21815636 TI - Lyotropic liquid crystals formed from ACHC-rich beta-peptides. AB - We have examined the effect of beta-peptide modifications on the propensity of these helical molecules to form lyotropic liquid crystalline (LC) phases in water. All of the beta-peptides we have examined contain 10 residues. In each case, at least three residues are derived from trans-2-aminocyclohexanecarboxylic acid (ACHC), which strongly promotes folding to a 14-helical conformation. The structural features varied include the number of ACHC residues, the nature and spatial arrangement of charged side chains (cationic vs anionic), and the identity of groups at the beta-peptide termini. We found that relatively small changes (e.g., swapping the positions of a cationic and an anionic side chain) could have large effects, such as abrogation of LC phase formation. The trends revealed by sequence-property studies led to the design of LC-forming beta peptides that bear biomolecular recognition groups (biotin or the tripeptide Arg Gly-Asp). Structural analysis via circular dichroism and cryo-transmission electron microscopy revealed the existence of two different types of self associated species, globular aggregates and nanofibers. Nanofibers are the predominant assembly formed at concentrations that lead to LC phase formation, and we conclude that these nanofibers are the functional mesogens. Overall, these studies show how the modularity of beta-peptide oligomers enables elucidation of the relationship between molecular structure and large-scale self-assembly behavior. PMID- 21815634 TI - Design and characterization of a potent and selective dual ATP- and substrate competitive subnanomolar bidentate c-Jun N-terminal kinase (JNK) inhibitor. AB - c-Jun N-terminal kinases (JNKs) represent valuable targets in the development of new therapies. Present on the surface of JNK is a binding pocket for substrates and the scaffolding protein JIP1 in close proximity to the ATP binding pocket. We propose that bidentate compounds linking the binding energies of weakly interacting ATP and substrate mimetics could result in potent and selective JNK inhibitors. We describe here a bidentate molecule, 19, designed against JNK. 19 inhibits JNK kinase activity (IC(50) = 18 nM; K(i) = 1.5 nM) and JNK/substrate association in a displacement assay (IC(50) = 46 nM; K(i) = 2 nM). Our data demonstrate that 19 targets for the ATP and substrate-binding sites on JNK concurrently. Finally, compound 19 successfully inhibits JNK in a variety of cell based experiments, as well as in vivo where it is shown to protect against Jo-2 induced liver damage and improve glucose tolerance in diabetic mice. PMID- 21815637 TI - Effect of nanowire number, diameter, and doping density on nano-FET biosensor sensitivity. AB - Semiconductive nanowire-based biosensors are capable of label-free detection of biological molecules. Nano-FET (field-effect transistor) biosensors exhibiting high sensitivities toward proteins, nucleic acids, and viruses have been demonstrated. Rational device design methodologies, particularly those based on theoretical predictions, were reported. However, few experimental studies have investigated the effect of nanowire diameter, doping density, and number on nano FET sensitivity. In this study, we devised a fabrication process based on parallel approaches and nanomanipulation-based post-processing for constructing nano-FET biosensor devices with carefully controlled nanowire parameters (diameter, doping density, and number). We experimentally reveal the effect of these nanowire parameters on nano-FET biosensor sensitivity. The experimental findings quantitatively demonstrate that device sensitivity decreases with increasing number of nanowires (4 and 7 nanowire devices exhibited a ~38 and ~82% decrease in sensitivity as compared to a single-nanowire device), larger nanowire diameters (sensors with 81-100 and 101-120 nm nanowire diameters exhibited a ~16 and ~37% decrease in sensitivity compared to devices with nanowire diameters of 60-80 nm), and higher nanowire doping densities (~69% decrease in sensitivity due to an increase in nanowire doping density from 10(17) to 10(19) atoms.cm(-3)). These results provide insight into the importance of controlling nanowire properties for maximizing sensitivity and minimizing performance variation across devices when designing and manufacturing nano-FET biosensors. PMID- 21815635 TI - Structure-function analysis from the outside in: long-range tertiary contacts in RNA exhibit distinct catalytic roles. AB - The conserved catalytic core of the Tetrahymena group I ribozyme is encircled by peripheral elements. We have conducted a detailed structure-function study of the five long-range tertiary contacts that fasten these distal elements together. Mutational ablation of each of the tertiary contacts destabilizes the folded ribozyme, indicating a role of the peripheral elements in overall stability. Once folded, three of the five tertiary contact mutants exhibit defects in overall catalysis that range from 20- to 100-fold. These and the subsequent results indicate that the structural ring of peripheral elements does not act as a unitary element; rather, individual connections have distinct roles as further revealed by kinetic and thermodynamic dissection of the individual reaction steps. Ablation of P14 or the metal ion core/metal ion core receptor (MC/MCR) destabilizes docking of the substrate-containing P1 helix into tertiary interactions with the ribozyme's conserved core. In contrast, ablation of the L9/P5 contact weakens binding of the guanosine nucleophile by slowing its association, without affecting P1 docking. The P13 and tetraloop/tetraloop receptor (TL/TLR) mutations had little functional effect and small, local structural changes, as revealed by hydroxyl radical footprinting, whereas the P14, MC/MCR, and L9/P5 mutants show structural changes distal from the mutation site. These changes extended into regions of the catalytic core involved in docking or guanosine binding. Thus, distinct allosteric pathways couple the long range tertiary contacts to functional sites within the conserved core. This modular functional specialization may represent a fundamental strategy in RNA structure-function interrelationships. PMID- 21815638 TI - Regio- and stereoselective synthesis of 2-deoxy-C-aryl glycosides via palladium catalyzed decarboxylative reactions. AB - An efficient and versatile approach for the synthesis of 2-deoxy-C-aryl glycosides is reported. This strategy is based on a palladium-catalyzed decarboxylative Heck coupling reaction of benzoic acids and glycals. A wide variety of glycals and benzoic acids have been screened, and all these reactions could afford the desired C-aryl glycoside products in moderate to good yields with exclusive regio- and stereoselectivities. PMID- 21815639 TI - Label-free electrochemical monitoring of concentration enrichment during bipolar electrode focusing. AB - We show that a label-free electrochemical method can be used to monitor the position of an enriched analyte band during bipolar electrode focusing in a microfluidic device. The method relies on formation of a depleted buffer cation region, which is responsible for concentration enrichment of the charged analyte. However, this depletion region also leads to an increase in the local electric field in the solution near a bipolar electrode (BPE), and this in turn results in enhanced faradaic reactions (oxidation and reduction of water) at the BPE. Therefore, it is possible to detect the presence of the concentrated analyte band by measuring the current passing through the BPE used for concentration enrichment, or the concentrated band can be detected at a secondary BPE dedicated to that purpose. Both experiments and simulations are presented that fully elucidate the underlying phenomenon responsible for these observations. PMID- 21815640 TI - A LIN28-dependent structural change in pre-let-7g directly inhibits dicer processing. AB - Several recent studies have provided evidence that LIN28, a cytoplasmic RNA binding protein, inhibits the biogenesis of members of the let-7 microRNA family at the Dicer step in both mammals and Caenorhabditis elegans. However, the precise mechanism of inhibition is still poorly understood. Here we report on an in vitro study, which combined RNase footprinting, gel shift binding assays, and processing assays, to investigate the molecular basis and function of the interaction between the native let-7g precursor (pre-let-7g) and LIN28. We have mapped the structure of pre-let-7g and identified some regions of the terminal loop of pre-let-7g that physically interact with LIN28. We have also identified a conformational change upon LIN28 binding that results in the unwinding of an otherwise double-stranded region at the Dicer processing site of pre-let-7g. Furthermore, we showed that a mutant pre-let-7g that displays an open upper stem inhibited pre-let-7g Dicer processing to the same extent as LIN28. The data support a mechanism by which LIN28 can directly inhibit let-7g biogenesis at the Dicer processing step. PMID- 21815641 TI - Photoinduced trans-to-cis isomerization of cyclocurcumin. AB - The photophysical properties of cyclocurcumin in various solvents are studied for the first time to shed light on the nonradiative processes of the parent compound, curcumin, which has a range of medicinal properties. Steady-state fluorescence and fluorescence-excitation spectra of cyclocurcumin in polar aprotic solvents are strongly dependent on excitation (lambda(ex)) and emission (lambda(em)) wavelength, respectively. The fluorescence quantum yield also depends on lambda(ex) and increases with the viscosity of the medium. Time resolved studies show nonexponential fluorescence decay in all solvents studied. The two fluorescence decay components of cyclocurcumin in alcohols exhibit a strong dependence on viscosity and temperature. NMR spectroscopy indicates that cyclocurcumin is entirely in the trans form with respect to the C6-C7 double bond in methanol, chloroform, and acetone. It is suggested that at least two conformational isomers about another single bond (C5-C6 or C7-C1" or both) and that trans-to-cis isomerization about the C6-C7 double bond of these isomers provide the most likely means of rationalizing the steady-state spectra and the nonradiative decay mechanisms in both protic and aprotic polar solvents. PMID- 21815642 TI - Effect of various sludge digestion conditions on sulfonamide, macrolide, and tetracycline resistance genes and class I integrons. AB - Wastewater treatment processes are of growing interest as a potential means to limit the dissemination of antibiotic resistance. This study examines the response of nine representative antibiotic resistance genes (ARGs) encoding resistance to sulfonamide (sulI, sulII), erythromycin (erm(B), erm(F)), and tetracycline (tet(O), tet(W), tet(C), tet(G), tet(X)) to various laboratory-scale sludge digestion processes. The class I integron gene (intI1) was also monitored as an indicator of horizontal gene transfer potential and multiple antibiotic resistance. Mesophilic anaerobic digestion at both 10 and 20 day solids retention times (SRTs) significantly reduced sulI, suII, tet(C), tet(G), and tet(X) with longer SRT exhibiting a greater extent of removal; however, tet(W), erm(B) and erm(F) genes increased relative to the feed. Thermophilic anaerobic digesters operating at 47 degrees C, 52 degrees C, and 59 degrees C performed similarly to each other and provided more effective reduction of erm(B), erm(F), tet(O), and tet(W) compared to mesophilic digestion. However, thermophilic digestion resulted in similar or poorer removal of all other ARGs and intI1. Thermal hydrolysis pretreatment drastically reduced all ARGs, but they generally rebounded during subsequent anaerobic and aerobic digestion treatments. To gain insight into potential mechanisms driving ARG behavior in the digesters, the dominant bacterial communities were compared by denaturing gradient gel electrophoresis. The overall results suggest that bacterial community composition of the sludge digestion process, as controlled by the physical operating characteristics, drives the distribution of ARGs present in the produced biosolids, more so than the influent ARG composition. PMID- 21815643 TI - In vitro and in vivo antitumor activities and DNA binding mode of five coordinated cyclometalated organoplatinum(II) complexes containing biphosphine ligands. AB - New complexes [Pt(C(?)N)Cl(dppa)] (1), and [Pt(C(?)N)Cl(dppm)] (2), (C(?)N. deprotonated 2-phenylpyridine; dppa. bis(diphenylphosphino)amine; dppm. bis(diphenylphosphino)methane) were suggested to have pentacoordinated geometry as investigated by NMR and conductometry. Pharmacological effects of 1 and 2 were evaluated for their proteasome-inhibitory and apoptosis-inducing activities under in vitro and in vivo conditions, showing significant proteasome-inhibitory activity against purified 20S proteasome, while 2 demonstrated superior inhibitory activity against cellular 26S proteasome. Consistently, this effect was associated with higher levels of proteasome target proteins and apoptosis induction in breast cancer cells. Importantly, preliminary studies show 1 and 2 were able to exert a similar effect in vivo by inhibiting the growth of breast cancer xenografts in mice, which was associated with proteasome inhibition and apoptosis induction. Interaction of 1 and 2 with herring sperm DNA was investigated by fluorimeteric emission, suggesting that Pt(II)-containing biphosphine complexes with DNA binding capabilities can also target and inhibit the tumor proteasome. PMID- 21815644 TI - Evidence for the mechanism of hydroxylation by 4-hydroxyphenylpyruvate dioxygenase and hydroxymandelate synthase from intermediate partitioning in active site variants. AB - 4-Hydroxyphenylpyruvate dioxygenase (HPPD) and hydroxymandelate synthase (HMS) each catalyze similar complex dioxygenation reactions using the substrates 4 hydroxyphenylpyruvate (HPP) and dioxygen. The reactions differ in that HPPD hydroxylates at the ring C1 and HMS at the benzylic position. The HPPD reaction is more complex in that hydroxylation at C1 instigates a 1,2-shift of an aceto substituent. Despite that multiple intermediates have been observed to accumulate in single turnover reactions of both enzymes, neither enzyme exhibits significant accumulation of the hydroxylating intermediate. In this study we employ a product analysis method based on the extents of intermediate partitioning with HPP deuterium substitutions to measure the kinetic isotope effects for hydroxylation. These data suggest that, when forming the native product homogentisate, the wild type form of HPPD produces a ring epoxide as the immediate product of hydroxylation but that the variant HPPDs tended to also show the intermediacy of a benzylic cation for this step. Similarly, the kinetic isotope effects for the other major product observed, quinolacetic acid, showed that either pathway is possible. HMS variants show small normal kinetic isotope effects that indicate displacement of the deuteron in the hydroxylation step. The relatively small magnitude of this value argues best for a hydrogen atom abstraction/rebound mechanism. These data are the first definitive evidence for the nature of the hydroxylation reactions of HPPD and HMS. PMID- 21815645 TI - Similarities and differences between two modes of antagonism of the thyroid hormone receptor. AB - Thyroid hormone (T3) mediates diverse physiological functions including growth, differentiation, and energy homeostasis through the thyroid hormone receptors (TR). The TR binds DNA at specific recognition sequences in the promoter regions of their target genes known as the thyroid hormone response elements (TREs). Gene expression at TREs regulated by TRs is mediated by coregulator recruitment to the DNA bound receptor. This TR-coregulator interaction controls transcription of target genes by multiple mechanisms including covalent histone modifications and chromatin remodeling. Our previous studies identified a beta-aminoketone as a potent inhibitor of the TR-coactivator interaction. We describe here the activity of one of these inhibitors in modulating effects of T3 signaling in comparison to an established ligand-competitive inhibitor of TR, NH-3. The beta-aminoketone was found to reverse thyroid hormone induced gene expression by inhibiting coactivator recruitment at target gene promoters, thereby regulating downstream effects of thyroid hormone. While mimicking the downstream effects of NH-3 at the molecular level, the beta-aminoketone affects only a subset of the thyroid responsive signaling network. Thus antagonists directed to the coregulator binding site have distinct pharmacological properties relative to ligand-based antagonists and may provide complementary activity in vivo. PMID- 21815646 TI - Bolaform supramolecular amphiphiles as a novel concept for the buildup of surface imprinted films. AB - Stable multilayer films were fabricated on the basis of the alternating layer-by layer assembly of a two-component bolaform supramolecular amphiphile and diazoresins, followed by photochemical cross-linking of the structure. UV-visible spectroscopy and atomic force microscopy revealed a uniform deposition process. Moreover, one component of the supramolecular amphiphile can be removed from the multilayer films after cross-linking between the second component and the diazoresin. The release and uptake of the imprinted supramolecular amphiphile component are shown to be reversible. Furthermore, uptake experiments of different molecules show the selectivity of the imprinted sites for the template molecule. Thus, surface-imprinted films can be formed by employing dissociable two-component supramolecular amphiphiles. This research reveals that supramolecular amphiphiles can be used as a novel concept for the construction of multilayer films, and it also provides a new method of generating surface imprinted multilayers. PMID- 21815647 TI - Transcription factor beacons for the quantitative detection of DNA binding activity. AB - The development of convenient, real-time probes for monitoring protein function in biological samples represents an important challenge of the postgenomic era. In response, we introduce here "transcription factor beacons," binding-activated fluorescent DNA probes that signal the presence of specific DNA-binding activities. As a proof of principle, we present beacons for the rapid, sensitive detection of three transcription factors (TATA Binding Protein, Myc-Max, and NF kappaB), and measure binding activity directly in crude nuclear extracts. PMID- 21815649 TI - Three-dimensional hybrid framework containing U2O13 dimers connected via cation cation interactions. AB - A three-dimensional metal-organic framework with cation-cation interactions, UO(2)(NO(2)TA)(2)(H(2)O) (1), was synthesized hydrothermally and characterized via single-crystal X-ray diffraction, powder X-ray diffraction, UV-vis spectroscopy, and fluorescence spectroscopy (NO(2)TA = 2-nitroterephthalic acid). 1 crystallizes in the monoclinic space group P2(1)/n [a = 11.6970(7) A, b = 15.1449(9) A, c = 12.2564(8) A, and beta = 109.193(1) degrees ] and contains U(2)O(13) dimers. The UV-vis spectrum of 1 contains peaks attributable to both the ligand and the uranium cation. Furthermore, the ligand and the uranium cation of 1 can be independently excited, giving rise to two different luminescent spectra. PMID- 21815650 TI - Self-aligned coupled nanowire transistor. AB - The integration of multiple functionalities into individual nanoelectronic components is increasingly explored as a means to step up computational power, or for advanced signal processing. Here, we report the fabrication of a coupled nanowire transistor, a device where two superimposed high-performance nanowire field-effect transistors capable of mutual interaction form a thyristor-like circuit. The structure embeds an internal level of signal processing, showing promise for applications in analogue computation. The device is naturally derived from a single NW via a self-aligned fabrication process. PMID- 21815648 TI - Levodopa activates apoptosis signaling kinase 1 (ASK1) and promotes apoptosis in a neuronal model: implications for the treatment of Parkinson's disease. AB - Oxidative stress is implicated in the etiology of Parkinson's disease (PD), the second most common neurodegenerative disease. PD is treated with chronic administration of l-3,4-dihydroxyphenylalanine (levodopa, L-DOPA), and typically, increasing doses are used during progression of the disease. Paradoxically, L DOPA is a pro-oxidant and induces cell death in cellular models of PD through disruption of sulfhydryl homeostasis involving loss of the thiol-disulfide oxidoreductase functions of the glutaredoxin (Grx1) and thioredoxin (Trx1) enzyme systems [Sabens, E. A., Distler, A. M., and Mieyal, J. J. (2010) Biochemistry 49 (12), 2715-2724]. Considering this loss of both Grx1 and Trx1 activities upon L DOPA treatment, we sought to elucidate the mechanism(s) of L-DOPA-induced apoptosis. In other contexts, both the NFkappaB (nuclear factor kappaB) pathway and the ASK1 (apoptosis signaling kinase 1) pathway have been shown to be regulated by both Grx1 and Trx1, and both pathways have been implicated in cell death signaling in model systems of PD. Moreover, mixed lineage kinase (MLK) has been considered as a potential therapeutic target for PD. Using SHSY5Y cells as model dopaminergic neurons, we found that NFkappaB activity was not altered by L DOPA treatment, and the selective MLK inhibitor (CEP-1347) did not protect the cells from L-DOPA. In contrast, ASK1 was activated with L-DOPA treatment as indicated by phosphorylation of its downstream mitogen-activated protein kinases (MAPK), p38 and JNK. Chemical inhibition of either p38 or JNK provided protection from L-DOPA-induced apoptosis. Moreover, direct knockdown of ASK1 protected from L-DOPA-induced neuronal cell death. These results identify ASK1 as the main pro apoptotic pathway activated in response to L-DOPA treatment, implicating it as a potential target for adjunct therapy in PD. PMID- 21815651 TI - Synthesis and characterization of sulfuryl diazide, O2S(N3)2. AB - Sulfuryl diazide, O(2)S(N(3))(2), previously described as an "exceedingly explosive" compound, has been isolated and characterized by IR (Ar matrix, gas) and Raman (solid) spectroscopy, and its structure has been determined by X-ray crystallography. It has a melting point of -15 degrees C and can be handled in small quantities in gas, liquid, and solid states. Vibrational spectroscopic studies suggest the presence of only one conformer in both gas and solid states, and the X-ray crystallography revealed an anti conformation of the two azido groups with respect to the NSN plane. Calculations predict the anti (C(2)) conformer to be 6.6 kJ mol(-1) lower in energy than the syn (C(s)) one at the CBS QB3 level of theory. The related chlorosulfuryl azide, ClSO(2)N(3), has also been prepared and characterized by IR and Raman spectroscopy. PMID- 21815652 TI - Static friction between silicon nanowires and elastomeric substrates. AB - This paper reports the first direct measurements of static friction force and interfacial shear strength between silicon (Si) nanowires (NWs) and poly(dimethylsiloxane) (PDMS). A micromanipulator is used to manipulate and deform the NWs under a high-magnification optical microscope in real time. The static friction force is measured based on "the most-bent state" of the NWs. The static friction and interface shear strength are found to depend on the ultraviolet/ozone (UVO) treatment of PDMS. The shear strength starts at 0.30 MPa without UVO treatment, increases rapidly up to 10.57 MPa at 60 min of treatment and decreases for longer treatment. Water contact angle measurements suggest that the UVO-induced hydrophobic-to-hydrophilic conversion of PDMS surface is responsible for the increase in the static friction, while the hydrophobic recovery effect contributes to the decrease. The static friction between NWs and PDMS is of critical relevance to many device applications of NWs including NW based flexible/stretchable electronics, NW assembly and nanocomposites (e.g., supercapacitors). Our results will enable quantitative interface design and control for such applications. PMID- 21815653 TI - Water oxidation by a mononuclear ruthenium catalyst: characterization of the intermediates. AB - A detailed characterization of intermediates in water oxidation catalyzed by a mononuclear Ru polypyridyl complex [Ru(II)-OH(2)](2+) (Ru = Ru complex with one 4 t-butyl-2,6-di-(1',8'-naphthyrid-2'-yl)-pyridine ligand and two 4-picoline ligands) has been carried out using electrochemistry, UV-vis and resonance Raman spectroscopy, pulse radiolysis, stopped flow, and electrospray ionization mass spectrometry (ESI-MS) with H(2)(18)O labeling experiments and theoretical calculations. The results reveal a number of intriguing properties of intermediates such as [Ru(IV)?O](2+) and [Ru(IV)-OO](2+). At pH > 2.9, two consecutive proton-coupled one-electron steps take place at the potential of the [Ru(III)-OH](2+)/[Ru(II)-OH(2)](2+) couple, which is equal to or higher than the potential of the [Ru(IV)?O](2+)/[Ru(III)-OH](2+) couple (i.e., the observation of a two-electron oxidation in cyclic voltammetry). At pH 1, the rate constant of the first one-electron oxidation by Ce(IV) is k(1) = 2 * 10(4) M(-1) s(-1). While pH-independent oxidation of [Ru(IV)?O](2+) takes place at 1420 mV vs NHE, bulk electrolysis of [Ru(II)-OH(2)](2+) at 1260 mV vs NHE at pH 1 (0.1 M triflic acid) and 1150 mV at pH 6 (10 mM sodium phosphate) yielded a red colored solution with a Coulomb count corresponding to a net four-electron oxidation. ESI-MS with labeling experiments clearly indicates that this species has an O-O bond. This species required an additional oxidation to liberate an oxygen molecule, and without any additional oxidant it completely decomposed slowly to form [Ru(II) OOH](+) over 2 weeks. While there remains some conflicting evidence, we have assigned this species as (1)[Ru(IV)-eta(2)-OO](2+) based on our electrochemical, spectroscopic, and theoretical observations alongside a previously reported analysis by T. J. Meyer's group (J. Am. Chem. Soc. 2010, 132, 1545-1557). PMID- 21815654 TI - Charge-gated transport of proteins in nanostructured optical films of mesoporous silica. AB - The admission into and diffusion through nanoscale pores by molecules is a fundamental process of great importance to biology and separations science. Systems (e.g., chromatography, electrophoresis) designed to harness such processes tend to remove the separation process from the detection event, both spatially and temporally. Here, we describe the preparation and characterization of thin optical Fabry-Perot films of mesoporous silica (pSiO(2)) that can detect protein infiltration by optical interferometry, which probes the separation process in real time and in the same ultrasmall physical volume (5 nL). Admission of a protein into the pores is controlled by the diameter (~50 nm) and the surface charge of the pores, and both the rate and the degree of protein infiltration are a function of solution pH. Test proteins bovine serum albumin (BSA, 66 kDa), bovine hemoglobin (BHb, 65 kDa), and equine myoglobin (EMb, 18 kDa) are admitted to or excluded from the nanophase pores of this material based on their size and charge. The rate of protein transport within the pores of the pSiO(2) film is slowed by 3 orders of magnitude relative to the free-solution diffusion values, and it is maximized when pH = pI. PMID- 21815655 TI - Photothermally enhanced photodynamic therapy delivered by nano-graphene oxide. AB - Graphene with unique physical and chemical properties has shown various potential applications in biomedicine. In this work, a photosensitizer molecule, Chlorin e6 (Ce6), is loaded on polyethylene glycol (PEG)-functionalized graphene oxide (GO) via supramolecular pi-pi stacking. The obtained GO-PEG-Ce6 complex shows excellent water solubility and is able to generate cytotoxic singlet oxygen under light excitation for photodynamic therapy (PDT). Owing to the significantly enhanced intracellular trafficking of photosensitizers, our GO-PEG-Ce6 complex offers a remarkably improved cancer cell photodynamic destruction effect compared to free Ce6. More importantly, we show that the photothermal effect of graphene can be utilized to promote the delivery of Ce6 molecules by mild local heating when exposed to a near-infrared laser at a low power density, further enhancing the PDT efficacy against cancer cells. Our work highlights the promise of using graphene for potential multifunctional cancer therapies. PMID- 21815656 TI - Dynamic changes of acoustic load and complex impedance as reporters for the cytotoxicity of small molecule inhibitors. AB - Cellular motility is the major driving force of numerous biological phenomena including wound healing, immune response, embryogenesis, cancer formation, and metastasis. We studied the response of epithelial FaDu monolayers cultured on gold electrodes of an acoustic resonator (quartz crystal microbalance, QCM) and impedance sensor (electric cell-substrate impedance sensing, ECIS) to externally applied chemical stimuli interfering with cytoskeleton organization. Epithelial cell motility of confluent monolayers is characterized by subtle cell shape changes and variations in the cell-substrate as well as cell-cell distance without net directionality of individual cells. The impact of small molecules such as cytochalasin D, phalloidin, and blebbistatin as well as paclitaxel, nocodazol, and colchicin on actin and microtubules organization was quantified by conventional sensors' readouts and by comparing the noise pattern of the signals which is attributed to cellular dynamics. The responsiveness of noninvasive and label-free techniques relying on cellular dynamics is compared to classical viability assays and changes of the overall impedance of ultrasmall electrodes or acoustic loads of a thickness shear mode resonator. Depending on the agent used, a distinct sensor response was found, which can be used as a fingerprint of the cellular response. Cytoskeletal rearrangements and nuclear integrity were corroborated by fluorescence microscopy and correlated to the readouts of QCM and ECIS. PMID- 21815657 TI - Evolutionary dynamics in cancer therapy. AB - Disseminated cancer remains a largely fatal disease. While systemic therapy can have some initial success, it is rarely durable. Typically, populations of cancer cells resistant to therapy emerge quickly requiring progressively less effective second, third, and fourth line therapies until the patient succumbs. Cancer cells possess a large repertoire of heritable phenotypic strategies that can be used to confer resistance to one or more therapeutic drugs. In addition, environmental factors such as ischemia and hypoxia can reduce therapeutic effects by limiting drug delivery or toxicity. Here, we use a fitness generating function (G function) approach to model tumor response with respect to evolutionary adaptation and microenvironmental conditions in response to various therapeutic strategies. We examine tumor cell death and the evolution of resistance in single and two drug therapies as well as alternative "evolutionary" approaches. We demonstrate that even monotherapy would be highly successful in the absence of tumor evolution or environmentally mediated resistance. However, environmental and evolutionary factors dramatically reduce the effectiveness of therapy. Two drug therapy in which adaptation requires two different phenotypic changes will maximally reduce tumor size and delay onset of resistance, but actual eradication of the tumor population is rare. We demonstrate that multiagent therapies in which the first drug both achieves tumor cell toxicity and drives phenotypic adaptation that renders the cell more vulnerable to a second therapy can be highly successful in maintaining durable tumor control. Examples of clinical trials that exploit these results are presented. We conclude that the development of more lethal (cytotoxic) drugs is not likely to fundamentally change the outcome of therapy. Instead, new approaches that incorporate evolutionary strategies into target and drug selection are needed. PMID- 21815658 TI - Joule-assisted silicidation for short-channel silicon nanowire devices. AB - We report on a technique enabling electrical control of the contact silicidation process in silicon nanowire devices. Undoped silicon nanowires were contacted by pairs of nickel electrodes, and each contact was selectively silicided by means of the Joule effect. By a real-time monitoring of the nanowire electrical resistance during the contact silicidation process we were able to fabricate nickel-silicide/silicon/nickel-silicide devices with controlled silicon channel length down to 8 nm. PMID- 21815660 TI - A ratiometric fluorescent probe for thiols based on a tetrakis(4 hydroxyphenyl)porphyrin-coumarin scaffold. AB - In this work, we have designed and synthesized the compound Ratio-HPSSC, based on a tetrakis(4-hydroxyphenyl)porphyrin-coumarin scaffold, as a new ratiometric fluorescent probe for thiols. The ratiometric probe Ratio-HPSSC is highly selective and sensitive to thiols. Importantly, the novel ratiometric probe exhibited a remarkable change in emission color from red to blue. This key feature allows Ratio-HPSSC to be employed for thiol detection by simple visual inspection. Furthermore, we have demonstrated that Ratio-HPSSC is suitable for ratiometric fluorescence imaging of thiols in living cells. We believe that the new ratiometric probe will find interesting applications in chemistry, biology, and medicine. PMID- 21815659 TI - Noncanonical amino acids in the interrogation of cellular protein synthesis. AB - Proteins in living cells can be made receptive to bioorthogonal chemistries through metabolic labeling with appropriately designed noncanonical amino acids (ncAAs). In the simplest approach to metabolic labeling, an amino acid analog replaces one of the natural amino acids specified by the protein's gene (or genes) of interest. Through manipulation of experimental conditions, the extent of the replacement can be adjusted. This approach, often termed residue-specific incorporation, allows the ncAA to be incorporated in controlled proportions into positions normally occupied by the natural amino acid residue. For a protein to be labeled in this way with an ncAA, it must fulfill just two requirements: (i) the corresponding natural amino acid must be encoded within the sequence of the protein at the genetic level, and (ii) the protein must be expressed while the ncAA is in the cell. Because this approach permits labeling of proteins throughout the cell, it has enabled us to develop strategies to track cellular protein synthesis by tagging proteins with reactive ncAAs. In procedures similar to isotopic labeling, translationally active ncAAs are incorporated into proteins during a "pulse" in which newly synthesized proteins are tagged. The set of tagged proteins can be distinguished from those made before the pulse by bioorthogonally ligating the ncAA side chain to probes that permit detection, isolation, and visualization of the labeled proteins. Noncanonical amino acids with side chains containing azide, alkyne, or alkene groups have been especially useful in experiments of this kind. They have been incorporated into proteins in the form of methionine analogs that are substrates for the natural translational machinery. The selectivity of the method can be enhanced through the use of mutant aminoacyl tRNA synthetases (aaRSs) that permit incorporation of ncAAs not used by the endogenous biomachinery. Through expression of mutant aaRSs, proteins can be tagged with other useful ncAAs, including analogs that contain ketones or aryl halides. High-throughput screening strategies can identify aaRS variants that activate a wide range of ncAAs. Controlled expression of mutant synthetases has been combined with ncAA tagging to permit cell-selective metabolic labeling of proteins. Expression of a mutant synthetase in a portion of cells within a complex cellular mixture restricts labeling to that subset of cells. Proteins synthesized in cells not expressing the synthetase are neither labeled nor detected. In multicellular environments, this approach permits the identification of the cellular origins of labeled proteins. In this Account, we summarize the tools and strategies that have been developed for interrogating cellular protein synthesis through residue-specific tagging with ncAAs. We describe the chemical and genetic components of ncAA-tagging strategies and discuss how these methods are being used in chemical biology. PMID- 21815661 TI - Versatile solid-phase synthesis of chromenes resembling classical cannabinoids. AB - A novel solid-phase approach toward classical cannabinoids is described. The desired tricyclic natural product analogues are assembled in only four atom economic steps: domino oxa-Michael-aldol condensation, Wittig reaction/enol-ether formation, Diels-Alder cycloaddition and cleavage. The synthesis is designed to allow combinatorial chemistry at several stages of the sequence. The variation of commercially available reagents at three of the reactions (enals/enones, Wittig salts, and dienophiles) allows the introduction of various diversity points. As proof of concept, a small library of 20 members has been synthesized with overall yields ranging from 10% to 60%. PMID- 21815662 TI - Ti-amide catalyzed synthesis of cyclic guanidines from di-/triamines and carbodiimides. AB - A titanacarborane monoamide catalyzed, one-step synthesis of mono/bicyclic guanidines from commercially available di/triamines and carbodiimides is reported. The reaction mechanism is also proposed. PMID- 21815664 TI - A useful synthetic equivalent of a hydroxyacetone enolate. AB - Indium promoted allylation of carbonyl compounds with 4-(bromomethyl)-1,3-dioxol 2-one diastereoselectively affords anti-alpha,beta-dihydroxyketones, protected as enol carbonates. These initial products can be deprotected to free dihydroxyketones or transformed under mild conditions into the corresponding cyclic carbonates, which constitutes a useful approach to hydroxyacetone aldols. PMID- 21815665 TI - Synthesis and structural investigations of functionalizable hybrid beta-hairpin. AB - The solution and solid state conformations of a designed beta-hairpin containing functionalizable alpha,beta-unsaturated gamma-amino acids at the antiparallel beta-strands and a single step transformation to its saturated gamma-peptide analogue are studied. PMID- 21815666 TI - Chiral Bronsted acid from a cationic gold(I) complex: catalytic enantioselective protonation of silyl enol ethers of ketones. AB - A chiral Bronsted acid has been developed from a cationic gold(I) disphosphine complex in the presence of alcoholic solvent and applied to the enantioselective protonation reaction of silyl enol ethers of ketones. Various optically active cyclic ketones were obtained in excellent yields and high enantioselectivities, including cyclic ketones bearing aliphatic substrates at the alpha-position. Furthermore, the application of this Bronsted acid was extended to the first Bronsted acid-catalyzed enantioselective protonation reaction of silyl enol ethers of acyclic substrates, regardless of their E/Z ratio. PMID- 21815667 TI - Graphene-polypyrrole nanocomposite as a highly efficient and low cost electrically switched ion exchanger for removing ClO4- from wastewater. AB - Perchlorate (ClO(4)(-)) contamination is a widespread concern affecting water utilities. In the present study, functionalized graphene sheets were employed as the scaffold to synthesize a novel graphene-polypyrrole (Ppy) nanocomposite, which served as an excellent electrically switched ion exchanger for perchlorate removal. Scanning electron microscopy and electrochemical measurements showed that the 3D nanostructured graphene-Ppy nanocomposite exhibited a significantly improved uptake capacity for ClO(4)(-) compared with Ppy film alone. X-ray photoelectron spectroscopy confirmed the uptake and release process of ClO(4)(-) in graphene-Ppy nanocomposite. In addition, the presence of graphene substrate resulted in high stability of graphene-Ppy nanocomposite during potential cycling. The present work provides a promising method for large scale water treatment. PMID- 21815668 TI - High-yield synthesis of ultrathin and uniform Bi2WO6 square nanoplates benefitting from photocatalytic reduction of CO2 into renewable hydrocarbon fuel under visible light. AB - Ultrathin and uniform Bi(2)WO(6) square nanoplates of ~9.5 nm thickness corresponding to six repeating cell units were prepared in the presence of oleylamine using a hydrothermal route. The Bi(2)WO(6) nanoplates show great potential in the utilization of visible light energy to the highly efficient reduction of CO(2) into a renewable hydrocarbon fuel. On the one hand, the ultrathin geometry of the nanoplates promotes charge carriers to move rapidly from the interior to the surface to participate in the photoreduction reaction. This should also favor the improved separation of photogenerated electron and hole and a lower electron-hole recombination rate; on the other hand, the Bi(2)WO(6) square nanoplate is proven to provide the well-defined {001} facet for two dominantly exposed surfaces, which is a prerequisite for the high level of photocatalytic activity of CO(2) fixation. PMID- 21815669 TI - Discovery and assembly-line biosynthesis of the lymphostin pyrroloquinoline alkaloid family of mTOR inhibitors in Salinispora bacteria. AB - The pyrroloquinoline alkaloid family of natural products, which includes the immunosuppressant lymphostin, has long been postulated to arise from tryptophan. We now report the molecular basis of lymphostin biosynthesis in three marine Salinispora species that maintain conserved biosynthetic gene clusters harboring a hybrid nonribosomal peptide synthetase-polyketide synthase that is central to lymphostin assembly. Through a series of experiments involving gene mutations, stable isotope profiling, and natural product discovery, we report the assembly line biosynthesis of lymphostin and nine new analogues that exhibit potent mTOR inhibitory activity. PMID- 21815671 TI - Multi-site reactivity: reduction of six equivalents of nitrite to give an Fe6(NO)6 cluster with a dramatically expanded octahedral core. AB - Reaction of NO(2)(-) with the octahedral cluster ((H)L)(2)Fe(6) in the presence of a proton source affords the hexanitrosyl cluster ((H)L)(2)Fe(6)(NO)(6). This species forms via a proton-induced reduction of six nitrite molecules per cluster, utilizing each site available on the polynuclear core. Formation of the hexanitrosyl cluster is accompanied by a near 2-fold expansion of the ((H)L)(2)Fe(6) core volume, where intracore Fe-Fe interactions are overcome by strong pi-bonding between Fe centers and NO ligands. A core volume of this magnitude is rare in octahedral metal clusters not supported by interstitial atoms. Moreover, the structural flexibility afforded by the ((H)L)(2)Fe(6) platform highlights the potential for other reaction chemistry involving species with metal-ligand multiple bonds. Carrying out the reaction of the cluster [((H)L)(2)Fe(6)(NCMe)(6)](4+) with nitrite in the absence of a proton source serves to forestall the nitrite reduction and enables clean isolation of the intermediate hexanitro cluster [((H)L)(2)Fe(6)(NO(2))(6)](2-). PMID- 21815672 TI - Hierarchical nanostructured ZnO with nanorods engendered to nanopencils and pin cushion cactus with its field emission study. AB - In the present investigation, we report the synthesis of highly crystalline ZnO nanorods engendered to pin-cushion cactus and 1D nanopencil like nanoforms on zinc (Zn) foil via a simple sonochemical assisted hydrothermal route. The work reported herewith is attractive for two reasons: (i) the facile one step solution approach assisted by prior ultrasonication converts nanorods/nanobelts into nanopencils, and (ii) the sharp and quasi-aligned ZnO nanopencils are potential field electron emitters. In addition, the controlled growth of pinhole like ZnO nanopencils and aligned hexagonal ZnO nanodisc was obtained. The changes in the growth rate, diameter, density, and surface area of highly oriented ZnO nanorods are examined. Considering the significances of such novel morphologies, technically detailed formation mechanism has been proposed. The field emission study of pin-cushion cactus like ZnO nanopencils was performed. Field emission measurements demonstrate remarkably low turn-on field which is explained on the basis of a sequential enhancement mechanism involving the consecutive stem and tip contribution. The Folwer-Nordheim (F-N) plot showed nonlinear behavior indicating the semiconducting nature of the emitter. Significantly, emission current is stable at the preset value of 3 MUA over the period of 3 h. The simplicity of the synthesis route coupled with the promising emission properties is envisaged to be an important candidate for potential nanoelectronic devices. These unique imperative ZnO nanostructures may have potential for sensors, solar cell, photocatalysis, varisters, etc. PMID- 21815670 TI - The total synthesis of immunostimulant alpha-galactosylceramides from naturally configured alpha-galactoside raffinose. AB - The total synthesis of absolute anomeric confirmation alpha-galactosylceramide analogues from raffinose is described. Using the naturally occurring alpha galactoside raffinose as the starting material, the easily maneuverable protocol without glycosylation reactions ensured the critical alpha-linkage in the product and simplified the synthetic procedures. The immunostimulatory activities of the new alpha-galactosylceramides were validated by both in vitro and in vivo NKT cell stimulation assays. PMID- 21815673 TI - Determination of molecular configuration by debye length modulation. AB - Silicon nanowire field effect transistors (FETs) have emerged as ultrasensitive, label-free biodetectors that operate by sensing bound surface charge. However, the ionic strength of the environment (i.e., the Debye length of the solution) dictates the effective magnitude of the surface charge. Here, we show that control of the Debye length determines the spatial extent of sensed bound surface charge on the sensor. We apply this technique to different methods of antibody immobilization, demonstrating different effective distances of induced charge from the sensor surface. PMID- 21815674 TI - Highly efficient plasmon-enhanced dye-sensitized solar cells through metal@oxide core-shell nanostructure. AB - We have investigated the effects of localized surface plasmons (LSPs) on the performance of dye-sensitized solar cells (DSSCs). The LSPs from Ag nanoparticles (NPs) increase the absorption of the dye molecules, allowing us to decrease the thickness of photoanodes, which improves electron collection and device performance. The plasmon-enhanced DSSCs became feasible through incorporating core-shell Ag@TiO(2) NPs into conventional TiO(2) photoanodes. The thin shell keeps the photoelectrons from recombining on the surface of metal NPs with dye and electrolyte and improves the stability of metal NPs. With 0.6 wt % Ag@TiO(2) NPs, the power conversion efficiency of DSSCs with thin photoanodes (1.5 MUm) increases from 3.1% to 4.4%. Moreover, a small amount of Ag@TiO(2) NPs (0.1 wt %) improves efficiency from 7.8% to 9.0% while decreasing photoanode thickness by 25% for improved electron collection. In addition, plasmon-enhanced DSSCs require 62% less material to maintain the same efficiency as conventional DSSCs. PMID- 21815675 TI - Intermolecular migratory insertion of unactivated olefins into palladium-nitrogen bonds. Steric and electronic effects on the rate of migratory insertion. AB - We report a detailed examination of the effect of the steric and electronic properties of the ancillary ligand and the alkene reactant on the rate of migratory insertion of unactivated alkenes into the palladium-nitrogen bond of isolated palladium amido complexes. A series of THF-bound and THF-free amidopalladium complexes ligated by cyclometalated benzylphosphine ligands possessing varied steric and electronic properties were synthesized. The THF-free complexes react with ethylene at -50 degrees C to form olefin-amido complexes that were observed directly and that undergo migratory insertion, followed by beta-hydride elimination to generate enamine products. The effect of the steric properties of the ancillary ligand on the binding of the alkene and the rate of migratory insertion were evaluated individually. The relative binding affinity of ethylene vs THF is larger for the less sterically hindered complex than for the more hindered complex, but the less hindered complex undergoes the insertion of ethylene more slowly than does the more hindered complex. These two changes in relative equilibrium and rate constants cause the rates of reaction of ethylene with the two THF-ligated species having different steric properties to be similar to each other. Reactions of the complexes containing electronically varied ancillary ligands showed that the more electron-poor complexes underwent the migratory insertion step faster than the more electron-rich complexes. Reactions of a THF-ligated palladium-amide with substituted vinylarenes showed that electron-poor vinylarenes reacted with the amido complex slightly faster than electron-rich vinylarenes. Separation of the energetics of binding and insertion indicate that the complex of an electron-rich vinylarene is more stable in this system than the complex of a more electron-poor vinylarene but that the insertion step of the bound, electron-rich vinylarene is slower than the insertion step with the bound, electron-poor vinylarene. PMID- 21815676 TI - Probing eudesmane cation-pi interactions in catalysis by aristolochene synthase with non-canonical amino acids. AB - Stabilization of the reaction intermediate eudesmane cation (3) through interaction with Trp 334 during catalysis by aristolochene synthase from Penicillium roqueforti was investigated by site-directed incorporation of proteinogenic and non-canonical aromatic amino acids. The amount of germacrene A (2) generated by the mutant enzymes served as a measure of the stabilization of 3. 2 is a neutral intermediate, from which 3 is formed during PR-AS catalysis by protonation of the C6,C7 double bond. The replacement of Trp 334 with para substituted phenylalanines of increasing electron-withdrawing properties led to a progressive accumulation of 2 that showed a good correlation with the interaction energies of simple cations such as Na(+) with substituted benzenes. These results provide compelling evidence for the stabilizing role played by Trp 334 in aristolochene synthase catalysis for the energetically demanding transformation of 2 to 3. PMID- 21815677 TI - Nanosecond Stokes shift dynamics, dynamical transition, and gigantic reorganization energy of hydrated heme proteins. AB - We report numerical simulations of three hydrated heme proteins, myoglobin, cytochrome c, and cytochrome B562. The properties of interest are the dynamics and statistics of the electric field and electrostatic potential at heme's iron, as well as their separation into the protein and water components. We find that the electric field produced by both the protein and the hydration water relaxes on the time scale of 3-6 ns, and the relaxation time of the electrostatic potential is close to 1 ns. The slow dynamics of the electrostatic observables is accompanied by their large variances. For the electrostatic potential, a large amplitude of its fluctuations leads to a gigantic reorganization energy of a half redox reaction changing the redox state of the protein. Both a large magnitude and a slow relaxation time of the electric field fluctuations are required to explain the onset of large mean-square displacements of iron at the point of protein's dynamical transition. These requirements are met by the simulations which are used to explain the temperature dependence of heme iron displacements measured by Mossbauer spectroscopy. All three phenomena, (i) nanosecond dynamics, (ii) protein dynamical transition and a large high-temperature excess of atomic mean-square displacements, and (iii) the gigantic reorganization energy, are explained here by one physical mechanism. This mechanism involves two components: nanosecond motions of the protein surface residues and polarization of the interfacial water by the protein charges. Global nanosecond conformations of the protein move the surface water. Since water is polarized, these movements create large-amplitude electrostatic fluctuations, sufficient to modify displacements of groups inside the protein and yield reorganization energies of protein electron transfer far exceeding those found for small molecules. Water follows adiabatically the protein motions. Therefore, the relaxation times of the protein and its hydration layer are close, leading to matching temperatures of the dynamical transition for the two components. PMID- 21815678 TI - Charge density analysis of a pentaborate ion in an ammonium borate: toward the understanding of topological features in borate minerals. AB - Structural and charge density distribution studies have been carried out on a single crystal data of an ammonium borate, [C(10)H(26)N(4)][B(5)O(6)(OH)(4)](2), synthesized by solvothermal method. Further, the experimentally observed geometry is used for the theoretical charge density calculations using the B3LYP/6-31G** level of theory, and the results are compared with the experimental values. Topological analysis of charge density based on the Atoms in Molecules approach for B-O bonds exhibit mixed covalent/ionic character. Detailed analysis of the hydrogen bonds in the crystal structure in the ammonium borate provides insights into the understanding of the reaction pathways that could result in the formation of borate minerals. The net atomic charges and electrostatic potential isosurfaces also give additional input to evaluate chemical and physical properties in such systems. PMID- 21815679 TI - Design and development of novel linker for PbS quantum dots/TiO2 mesoscopic solar cell. AB - A novel bifunctional linker molecule, bis(4-mercaptophenyl)phosphinic acid, is designed to be used in a QDs solar cells. The linker anchors to TiO(2) mesoporous film through the phosphinic acid functional group and to the PbS QDs through the two thiol groups. The way of attachment of this new linker molecule in a photovoltaic PbS QDs/TiO(2) mesoporous device was studied by FTIR measurements. The photovoltaic performance of this new linker in a heterojunction PbS QDs solar cell show high V(oc) relative to QDs based solar cells, which will allow to receive high power conversion efficiency using this novel designed linker. This novel bifunctional linker molecule should pave the way for enhancing binding strength, and efficiency of QDs solar cells compared to the state-of-the-art linkers. PMID- 21815681 TI - Engineering of an "unnatural" natural product by swapping polyketide synthase domains in Aspergillus nidulans. AB - An StcA-AfoE hybrid polyketide synthase (PKS), generated by swapping the AfoE (asperfuranone biosynthesis) SAT domain with the StcA (sterigmatocystin biosynthesis) SAT domian, produced a major new metabolite with the same chain length as the native AfoE product. Structure elucidation allowed us to propose a likely pathway, and feeding studies supported the hypothesis that the chain length of PKS metabolites may be under precise control of KS and PT domains. PMID- 21815680 TI - Factors influencing the DNA nuclease activity of iron, cobalt, nickel, and copper chelates. AB - A library of complexes that included iron, cobalt, nickel, and copper chelates of cyclam, cyclen, DOTA, DTPA, EDTA, tripeptide GGH, tetrapeptide KGHK, NTA, and TACN was evaluated for DNA nuclease activity, ascorbate consumption, superoxide and hydroxyl radical generation, and reduction potential under physiologically relevant conditions. Plasmid DNA cleavage rates demonstrated by combinations of each complex and biological co-reactants were quantified by gel electrophoresis, yielding second-order rate constants for DNA(supercoiled) to DNA(nicked) conversion up to 2.5 * 10(6) M(-1) min(-1), and for DNA(nicked) to DNA(linear) up to 7 * 10(5) M(-1) min(-1). Relative rates of radical generation and characterization of radical species were determined by reaction with the fluorescent radical probes TEMPO-9-AC and rhodamine B. Ascorbate turnover rate constants ranging from 3 * 10(-4) to 0.13 min(-1) were determined, although many complexes demonstrated no measurable activity. Inhibition and Freifelder-Trumbo analysis of DNA cleavage supported concerted cleavage of dsDNA by a metal associated reactive oxygen species (ROS) in the case of Cu(2+)(aq), Cu-KGHK, Co KGHK, and Cu-NTA and stepwise cleavage for Fe(2+)(aq), Cu-cyclam, Cu-cyclen, Co cyclen, Cu-EDTA, Ni-EDTA, Co-EDTA, Cu-GGH, and Co-NTA. Reduction potentials varied over the range from -362 to +1111 mV versus NHE, and complexes demonstrated optimal catalytic activity in the range of the physiological redox co-reactants ascorbate and peroxide (-66 to +380 mV). PMID- 21815682 TI - Rapid, one-pot synthesis of beta-siloxy-alpha-haloaldehydes. AB - The Mukaiyama cross-aldol reaction of alpha-fluoro-, alpha-chloro-, and alpha bromoacetaldehyde-derived (Z)-tris(trimethylsilyl)silyl enol ethers is described, furnishing anti-beta-siloxy-alpha-haloaldehydes. A highly diastereoselective, one pot, sequential double-aldol process is developed, affording novel beta,delta bissiloxy-alpha,gamma-bishaloaldehydes. Reactions are catalyzed by C(6)F(5)CHTf(2) and C(6)F(5)CTf(2)AlMe(2) (0.5-1.5 mol %) and provide access to halogenated polyketide fragments. PMID- 21815683 TI - Chemical fractionation of radionuclides and stable elements in aquatic plants of the Yenisei River. AB - The Yenisei River is contaminated with artificial radionuclides released by one of the Russian nuclear plants. The aquatic plants growing in the radioactively contaminated parts of the river contain artificial radionuclides. The aim of the study was to investigate accumulation of artificial radionuclides and stable elements by submerged plants of the Yenisei River and estimate the strength of their binding to plant biomass by using a new sequential extraction scheme. The aquatic plants sampled were: Potamogeton lucens, Fontinalis antipyretica, and Batrachium kauffmanii. Gamma-spectrometric analysis of the samples of aquatic plants has revealed more than 20 radionuclides. We also investigated the chemical fractionation of radionuclides and stable elements in the biomass and rated radionuclides and stable elements based on their distribution in biomass. The greatest number of radionuclides strongly bound to biomass cell structures was found for Potamogeton lucens and the smallest for Batrachium kauffmanii. For Fontinalis antipyretica, the number of distribution patterns that were similar for both radioactive isotopes and their stable counterparts was greater than for the other studied species. The transuranic elements (239)Np and (241)Am were found in the intracellular fraction of the biomass, and this suggested their active accumulation by the plants. PMID- 21815684 TI - High-accuracy vapor pressure data of the extended [C(n)C1im][Ntf2] ionic liquid series: trend changes and structural shifts. AB - For the first time, two distinct trends are clearly evidenced for the enthalpies and entropies of vaporization along the [Cnmim][Ntf2] ILs series. The trend shifts observed for Delta(l)(g)H(m)(o) and Delta(l)(g)S(m)(o), which occur at [C6mim][Ntf2], are related to structural modifications. The thermodynamic results reported in the present article constitute the first quantitative experimental evidence of the structural percolation phenomenon and make a significant contribution to better understanding of the relationship among cohesive energies, volatilities, and liquid structures of ionic liquids. A new Knudsen effusion apparatus, combined with a quartz crystal microbalance, was used for the high accuracy volatility study of the 1-alkyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide series ([Cnmim][Ntf2], where n = 2, 3, 4, 5, 6, 7, 8, 10, 12). Vapor pressures in the (450-500) K temperature range were measured, and the molar standard enthalpies, entropies, and Gibbs energies of vaporization were derived. The thermodynamic parameters of vaporization were reported, along with molecular dynamic simulations of the liquid phase structure, allowing the establishment of a link between the thermodynamic properties and the percolation phenomenon in ILs. PMID- 21815685 TI - Total synthesis of (-)-4,8,10-tridesmethyl telithromycin. AB - Novel sources of antibiotics are required to address the serious problem of antibiotic resistance. Telithromycin (2) is a third-generation macrolide antibiotic prepared from erythromycin (1) and used clinically since 2004. Herein we report the details of our efforts that ultimately led to the total synthesis of (-)-4,8,10-tridesmethyl telithromycin (3) wherein methyl groups have been replaced with hydrogens. The synthesis of desmethyl macrolides has emerged as a novel strategy for preparing bioactive antibiotics. PMID- 21815686 TI - Origin of the surprising enhancement of electrostatic energies by electron donating substituents in substituted sandwich benzene dimers. AB - A recent study of substituted face-to-face benzene dimers by Lewis and co-workers [J. Am. Chem. Soc. 2011, 133, 3854-3862] indicated a surprising enhancement of electrostatic interactions for both electron-withdrawing and electron-donating substituents. Here we demonstrate that charge penetration (an attractive electrostatic interaction arising from the overlap of the electron densities on the two monomers) is the cause of this counterintuitive effect. These charge penetration effects are significant at typical pi-pi interaction distances, and they are not easily described by multipole models. A simple measure of a substituent's electron-donating or electron-withdrawing character, such as the Hammett parameter sigma(m), is unlikely to capture subtle charge penetration effects. Indeed, correlation of the relative total energies or relative electrostatic energies with ?sigma(m) breaks down for multiply substituted face to-face benzene dimers. PMID- 21815687 TI - Proteomic profiling of human melanoma metastatic cell line secretomes. AB - During the last few years, the incidence and mortality of human melanoma have rapidly increased. Metastatic spread of malignant melanoma is often associated with cancer progression with poor prognosis and survival. These processes are controlled by dynamic interactions between tumor melanocytes and neighboring stromal cells, whose deregulation leads to the acquisition of cell proliferation capabilities and invasiveness. It is increasingly clear that a key role in carcinogenesis is played by secreted molecules either by tumor and surrounding stromal cells. To address the issue of the proteins secreted during cancer progression, the proteomic profiling of secretomes of cancer cell lines from different melanoma metastases of the same patient (PE-MEL-41, PE-MEL-47, and PE MEL-43) was performed by applying a shotgun LC-MS/MS-based approach. The results provide a list of candidate proteins associated with the metastatic potential of PE-MEL melanoma cell lines. Among them, several matricellular proteins previously reported as involved in melanoma aggressiveness were identified (i.e., SPARC, osteopontin). In addition, the extracellular matrix protein 1 that stimulates proliferation and angiogenesis of endothelial cells as well as the fibronectin, involved in cell adhesion and motility, were identified. The present work provides the basis to clarify the complex extracellular protein networks implicated in human melanoma cell invasion, migration, and motility. PMID- 21815688 TI - Microwave-assisted solvent-dependent reaction: chemoselective synthesis of quinoxalin-2(1H)-ones, benzo[d]imidazoles and dipeptides. AB - A microwave-assisted solvent-dependent chemoselective reaction dealing with 4 arylidene-2-phenyloxazol-5-ones and diverse ortho-diamines to achieve three types of molecular scaffolds, 3-benzylquinoxalin-2(1H)-ones, benzimidazole and beta amino dipeptides is reported. The procedures feature short reaction time, good to excellent yields, operational simplicity, as well as easily available starting materials. These compounds are of importance for organic chemistry and medicinal chemistry research. PMID- 21815689 TI - The International Proteomics Tutorial Programme--reaching out to the next generation proteome scientists. AB - One of the most critical functions of the various Proteomics organizations is the training of young scientists and the dissemination of information to the general scientific community. The education committees of the Human Proteome Organisation (HUPO) and the European Proteomics Association (EuPA) together with the other local proteomics associations are therefore launching a joint Tutorial Program to meet these needs. The level is aimed at Masters/PhD level students with good basic training in biology, biochemistry, mathematics and statistics. The Tutorials will consist of a review/teaching article with an accompanying talk slide presentation for classroom teaching. The Tutorial Program will cover core techniques and basics as an introduction to scientists new to the field. The entire series of articles and slides will be made freely available for teaching use at the Journals and Organizations homepages. PMID- 21815690 TI - Metabolic flux analysis and visualization. AB - One of the ultimate goals of systems biology research is to obtain a comprehensive understanding of the control mechanisms of complex cellular metabolisms. Metabolic Flux Analysis (MFA) is a important method for the quantitative estimation of intracellular metabolic flows through metabolic pathways and the elucidation of cellular physiology. The primary challenge in the use of MFA is that many biological networks are underdetermined systems; it is therefore difficult to narrow down the solution space from the stoichiometric constraints alone. In this tutorial, we present an overview of Flux Balance Analysis (FBA) and (13)C-Metabolic Flux Analysis ((13)C-MFA), both of which are frequently used to solve such underdetermined systems, and we demonstrate FBA and (13)C-MFA using the genome-scale model and the central carbon metabolism model, respectively. Furthermore, because such comprehensive study of intracellular fluxes is inherently complex, we subsequently introduce various pathway mapping and visualization tools to facilitate understanding of these data in the context of the pathways. Specific visualization of MFA results using the BioCyc Omics Viewer and Pathway Projector are shown as illustrative examples. PMID- 21815691 TI - An introduction to membrane proteins. AB - alpha-Helical membrane proteins are important for many biological functions. Due to physicochemical constraints, the structures of membrane proteins differ from the structure of soluble proteins. Historically, membrane protein structures were assumed to be more or less two-dimensional, consisting of long, straight, membrane-spanning parallel helices packed against each other. However, during the past decade, a number of the new membrane protein structures cast doubt on this notion. Today, it is evident that the structures of many membrane proteins are equally complex as for many soluble proteins. Here, we review this development and discuss the consequences for our understanding of membrane protein biogenesis, folding, evolution, and bioinformatics. PMID- 21815692 TI - Assessment of the aroma impact of major odor-active thiols in pan-roasted white sesame seeds by calculation of odor activity values. AB - Eleven odor-active thiols, namely, 2-methyl-1-propene-1-thiol, (Z)-3-methyl-1 butene-1-thiol, (E)-3-methyl-1-butene-1-thiol, (Z)-2-methyl-1-butene-1-thiol, (E) 2-methyl-1-butene-1-thiol, 2-methyl-3-furanthiol, 3-mercapto-2-pentanone, 2 mercapto-3-pentanone, 4-mercapto-3-hexanone, 3-mercapto-3-methylbutyl formate, and 2-methyl-3-thiophenethiol, recently identified in an extract prepared from white sesame seeds, were quantitated in sesame using stable isotope dilution analyses. For that purpose, the following deuterium-labeled compounds were synthesized and used as internal standards in the quantitation assays: [2H6]-2 methyl-1-propene-1-thiol, [2H3]-(E)- and [2H3]-(Z)-2-methyl-1-butene-1-thiol, [2H3]-2-methyl-3-furanthiol, [2H2]-3-mercapto-2-pentanone, [2H3]-4-mercapto-3 hexanone, [2H6]-3-mercapto-3-methylbutyl formate, and [2H3]-2-methyl-3 thiophenethiol. On the basis of the results obtained, odor activity values (OAVs) were calculated as ratio of the concentration and odor threshold of the individual compounds in cooking oil. According to their high OAVs, particularly the 3-methyl-1-butene-1-thiols (OAV: 2400) and the 2-methyl-1-butene-1-thiols (OAV: 960) were identified as the most odor-active compounds in pan-roasted white sesame seeds. These compounds were therefore suggested to be mainly responsible for the characteristic but rather unstable sulfury aroma of freshly pan-roasted white sesame seeds. PMID- 21815693 TI - Complementary pi-pi interactions induce multicomponent coassembly into functional fibrils. AB - Noncovalent self-assembled materials inspired by amyloid architectures are useful for biomedical applications ranging from regenerative medicine to drug delivery. The selective coassembly of complementary monomeric units to provide ordered multicomponent fibrils is a possible strategy for enhancing the sophistication of these noncovalent materials. Herein we report that complementary pi-pi interactions can be exploited to promote the coassembly of phenylalanine (Phe) derivatives that possess complementary aromatic side-chain functionality. Specifically, equimolar mixtures of Fmoc-Phe and Fmoc-F(5)-Phe, which possess side-chain groups with complementary quadrupole electronics, readily coassemble to form two-component fibrils and hydrogels under conditions where Fmoc-Phe alone fails to self-assemble. In addition, it was found that equimolar mixtures of Fmoc Phe with monohalogenated (F, Cl, and Br) Fmoc-Phe derivatives also coassembled into two-component fibrils. These results collectively indicate that face-to-face quadrupole stacking between benzyl side-chain groups does not account for the molecular recognition between Phe and halogenated Phe derivatives that promote cofibrillization but that coassembly is mediated by more subtle pi-pi effects arising from the halogenation of the benzyl side chain. The use of complementary pi-pi interactions to promote the coassembly of two distinct monomeric units into ordered two-component fibrils dramatically expands the repertoire of noncovalent interactions that can be used in the development of sophisticated noncovalent materials. PMID- 21815694 TI - Proteasomal degradation from internal sites favors partial proteolysis via remote domain stabilization. AB - The ubiquitin-proteasome system controls the concentrations of hundreds of regulatory proteins and removes misfolded and damaged proteins in eukaryotic cells. The proteasome recognizes ubiquitinated proteins and then engages its substrates at unstructured initiation regions. After initiation, it proceeds along the polypeptide chain, unraveling folded domains sequentially and degrading the protein completely. In vivo the proteasome can, and likely often does, initiate degradation at internal sites within its substrates, but it is not known how this affects the outcome of the degradation reaction. Here we find that domains flanking the initiation region can protect each other against degradation without interacting directly. The magnitude of this effect is related to the stability of both domains and can be tuned from complete degradation to complete protection of one domain. Partial proteasomal degradation has been observed in the cell in three signaling pathways and is associated with internal initiation. Thus, the basic biochemical mechanism of remote stabilization of protein domains is important in proteasome biology. PMID- 21815695 TI - Nanocomposite films based on xylan-rich hemicelluloses and cellulose nanofibers with enhanced mechanical properties. AB - Interest in xylan-rich hemicelluloses (XH) film is growing, and efforts have been made to prepare XH films with improved mechanical properties. This work described an effective approach to produce nanocomposite films with enhanced mechanical properties by incorporation of cellulose nanofibers (CNFs) into XH. Aqueous dispersions of XH (64-75 wt %), sorbitol (16-25 wt %), and CNF (0-20 wt %) were cast at a temperature of 23 degrees C and 50% relative humidity. The surface morphology of the films was revealed by scanning electron microscopy (SEM) and atomic force microscopy (AFM). The thermal properties and crystal structure of the films were evaluated by thermal analysis (TG) and X-ray diffraction (XRD). The surface of XH films with and without CNF was composed primarily of nanonodules, and CNFs were embedded in the XH matrix. Freeze-dried XH powder was amorphous, whereas the films with and without CNF showed a distinct peak at around 2theta = 18 degrees , which suggested that XH molecules aggregated or reordered in the casting solution or during water evaporation. Furthermore, the nanocomposite films had improved thermal stability. XH film with 25 wt % plasticizer (sorbitol, based on dry XH weight) showed poor mechanical properties, whereas incorporation of CNF (5-20 wt %, based on the total dry mixture) into the film resulted in enhanced mechanical properties due to the high aspect ratio and mechanical strength of CNF and strong interactions between CNF and XH matrix. This effective method makes it possible to produce hemicellulose-based biomaterials of high quality. PMID- 21815696 TI - New approaches to the treatment of pancreatic cancer: from tumor-directed therapy to immunotherapy. AB - The development of novel therapeutic strategies for pancreatic adenocarcinoma (PAC) has traditionally been considered particularly challenging for clinical and laboratory investigators due to its aggressive underlying biology and inherent resistance to currently available therapies. More recently, however, advances have been made in the identification of promising therapeutic targets for intervention, along with several key insights into the complex sequence of genetic alterations involved in the evolution of PAC from premalignant precursor lesion to malignant cells with metastatic potential. FOLFIRINOX (5 fluorouracil/leucovorin/irinotecan/oxaliplatin) has recently been identified as a combination cytotoxic therapy associated with a significant survival benefit over single-agent gemcitabine in good performance status patients with advanced disease; it is hoped that a similar benefit will be seen in planned trials of FOLFIRINOX as perioperative therapy. The success of immune therapy with the anti cytotoxic T-lymphocyte antigen-4 antibody ipilimumab in advanced melanoma has spurred interest in the development of vaccines and immune therapies for other solid tumors. Certainly, the concept of harnessing the power of the immune system for cancer treatment is an attractive concept to patients and clinicians alike. Herein we discuss recent advances in the development of novel therapeutic approaches to PAC, focusing in particular on recent developments in immune and vaccine therapy. PMID- 21815697 TI - Development of an AS04-adjuvanted HPV vaccine with the adjuvant system approach. AB - A novel human papillomavirus (HPV) vaccine has been formulated with virus-like particles of the L1 protein of HPV-16 and HPV-18, and the Adjuvant System 04 (AS04). AS04 is a combination of the toll-like receptor 4 agonist monophosphoryl lipid A (MPL) and aluminum hydroxide. The AS04-adjuvanted HPV vaccine induces a high and sustained immune response against HPV, including high levels of neutralizing antibodies at the cervical mucosa in women aged 15-55 years. Recently, the mechanism of action of AS04 has been evaluated in vitro in human cells and in vivo in mice and the data provide evidence for the molecular and cellular basis of the observed immunogenicity, efficacy, and safety profile of this formulation. In this review, we discuss how the results of GlaxoSmithKline's clinical studies on immunogenicity, protection, and reactogenicity with the AS04 adjuvanted HPV vaccine are supported by the observed mechanism of action for the adjuvant. The adjuvant activity of AS04, as measured by enhanced antibody response to HPV antigens, was found to be strictly dependent on AS04 and the HPV antigens being injected at the same intramuscular site within 24 hours of each other. The addition of MPL to aluminum salt enhances humoral and cell-mediated response by rapidly triggering a local and transient cytokine response that leads to an increased activation of antigen-presenting cells and results in an improved presentation of antigen to CD4+ T cells. The added value of MPL in AS04 for an HPV vaccine was demonstrated in clinical studies by high vaccine-elicited antibody responses and the induction of high levels of memory B cells. The vaccine elicits cross protection against some other oncogenic HPV types (specifically HPV-31, -33, and -45) not contained in the vaccine. The localized and transient nature of the innate immune response supports the acceptable safety profile observed in clinical studies. PMID- 21815698 TI - The application of delivery systems for DNA methyltransferase inhibitors. AB - DNA methylation, which often occurs at the cytosine residue of cytosine-guanine dinucleotides, is critical for the control of gene expression and mitotic inheritance in eukaryotes. DNA methylation silences gene expression either by directly hindering the access of transcription factors to the target DNA, or through recruitment of histone deacetylases to remodel the chromatin structure to an inactive state. Aberrant hypermethylation of tumor suppressor genes is commonly associated with the development of cancer. A number of anti-cancer agents have been developed that function through demethylation, reversing regional hypermethylation to restore the expression of tumor suppressor genes. Azacitidine and decitabine are used in the clinic, but their applications are limited to myelodysplastic syndrome and other blood-related diseases. Despite the potency of these drugs, their broader clinical application is restricted by cytotoxicity, nonspecific targeting, structural instability, catabolism, and poor bioavailability. Further improvements in the delivery systems for these drugs could overcome the issues associated with inefficient bioavailability, whilst facilitating the administration of combinations of demethylating agents and histone deacetylase inhibitors to enhance efficacy. This review focuses on the current limitations of existing demethylating agents and highlights possible approaches using recent developments in drug delivery systems to improve the clinical potential of these drugs. PMID- 21815699 TI - Corifollitropin alfa: a review of its use in controlled ovarian stimulation for assisted reproduction. AB - Corifollitropin alfa (Elonva(r)) is a fusion product of human follicle stimulating hormone (FSH) and the C-terminal peptide of the beta-subunit of human chorionic gonadotropin (hCG) produced by recombinant DNA technology. It has the same pharmacologic activity as FSH and recombinant FSH (rFSH; follitropin alfa; follitropin beta), but with a slower absorption and a longer half-life. Corifollitropin alfa is indicated as a multifollicular stimulant for women undergoing controlled ovarian stimulation using gonadotropin-releasing hormone (GnRH) antagonist-assisted reproduction protocols. In two large, randomized, double-blind, phase III trials, a single subcutaneous injection of corifollitropin alfa was no less effective as a multifollicular stimulant than seven once-daily injections of rFSH when used as part of a GnRH antagonist assisted controlled ovarian stimulation cycle. With regard to primary endpoints, the mean number of retrieved oocytes per started cycle demonstrated that the two treatments were equivalent, and the ongoing pregnancy rate in recipients of corifollitropin alfa was noninferior to that in recipients of rFSH. The median duration of stimulation with FSH was 9 days in both treatment arms of both trials, which means that, on average, recipients of corifollitropin alfa required only 2 further days of stimulation with rFSH prior to triggering oocyte maturation with the administration of hCG. Fertilization rates were high, ranging from 66% to 68%, in recipients of corifollitropin alfa or rFSH in both trials. When used as part of a GnRH antagonist-assisted reproduction protocol, corifollitropin alfa was generally well tolerated, with a tolerability profile similar to that of rFSH. In large, pooled analyses of clinical trials, the incidence of ovarian hyperstimulation syndrome in both the corifollitropin alfa and rFSH treatment arms was consistent with that expected in the relatively young patient population. Furthermore, there were no clinically relevant differences in pregnancy complications and the incidence of infant adverse events between treatment arms. In conclusion, a single subcutaneous injection of corifollitropin alfa provides sustained multifollicular stimulation for up to a week in women undergoing controlled ovarian stimulation. Compared with seven once-daily injections of rFSH, a single injection of corifollitropin alfa achieves equivalent efficacy, and provides a well tolerated and more convenient treatment option to induce multiple follicular growth prior to assisted reproduction. PMID- 21815700 TI - Sipuleucel-T in metastatic castration-resistant prostate cancer: profile report. PMID- 21815701 TI - Trastuzumab in HER2-positive metastatic gastric cancer: profile report. PMID- 21815702 TI - Spotlight on denosumab in postmenopausal osteoporosis. AB - Denosumab (Prolia(r)) is a human recombinant monoclonal antibody that is approved for the treatment of postmenopausal osteoporosis in women at high or increased risk of fracture in the US, the EU, and several other countries. Denosumab has a novel mechanism of action; it binds to receptor activator of nuclear factor kappaB ligand and inhibits bone resorption by inhibiting osteoclast formation, function, and survival. In postmenopausal women with osteoporosis, denosumab reduced the risk of vertebral, nonvertebral, and hip fractures compared with placebo over 3 years in the large, phase III FREEDOM study. In postmenopausal women with low bone mineral density (BMD) or osteoporosis, treatment with denosumab increased BMD and decreased markers of bone turnover more than alendronate in those who were essentially treatment-naive in the 1-year DECIDE study and also in the 1-year STAND study, in which women were switched from alendronate to denosumab or continued alendronate treatment. Denosumab was generally well tolerated in clinical trials, although long-term effects of very low bone turnover remain to be established. Denosumab is administered once every 6 months via subcutaneous injection, which may be a preferred method of administration and may improve adherence to treatment compared with other osteoporosis treatments. Denosumab is a valuable new option for the treatment of postmenopausal osteoporosis in women at increased or high risk of fractures, and may be useful as a first-line treatment in women at increased risk of fractures who are unable to take other osteoporosis treatments. PMID- 21815703 TI - Spotlight on AS04-adjuvanted human papillomavirus (HPV) types 16 and 18 vaccine (Cervarix(r)). AB - The AS04-adjuvanted human papillomavirus (HPV) 16/18 vaccine (Cervarix(r)) is a noninfectious recombinant vaccine produced using purified virus-like particles (VLPs) that induce a strong immunogenic response eliciting high levels of anti-L1 VLP antibodies that persist at levels markedly greater than those observed with natural infection. The vaccine adjuvant (AS04) is composed of monophosphoryl lipid A, which enhances cellular and humoral immune response, adsorbed to aluminum hydroxide. The vaccine is indicated for the prevention of premalignant cervical lesions and cervical cancer causally related to certain oncogenic HPV types in females aged >=10 years. The AS04-adjuvanted HPV 16/18 vaccine, administered via an intramuscular injection in a three-dose schedule over 6 months, elicits a high immunogenic response and is highly protective against cervical intraepithelial neoplasia and infection causally related to high-risk oncogenic HPV types. In well designed clinical trials in young women aged 15-25 years who were HPV 16/18 seronegative and DNA negative to 14 HPV high-risk types, high levels of immunogenicity and protection were sustained for follow-up periods of up to 8.4 years. High and persistent immunogenicity against infection with HPV 16/18 has also been demonstrated in older and younger females (aged 10-55 years) who were seronegative for vaccine HPV types. The AS04-adjuvanted HPV 16/18 vaccine elicited a greater immunogenic response than the quadrivalent HPV vaccine in women aged 18-45 years who were seronegative and DNA negative for HPV 16/18. The AS04-adjuvanted HPV 16/18 vaccine confers cross protection against certain non-vaccine, high-risk HPV types. A rapid and strong anamnestic humoral immune response was elicited following a fourth dose of the vaccine. The AS04-adjuvanted HPV 16/18 vaccine is generally well tolerated, and pharmacoeconomic analyses have demonstrated the potential for public health benefits and cost effectiveness when vaccination programs are run in conjunction with screening programs. Thus, the AS04-adjuvanted HPV 16/18 vaccine prevents cervical disease associated with certain oncogenic HPV types, thereby reducing the burden of premalignant cervical lesions and, very likely, cervical cancer. PMID- 21815704 TI - Receptor kinase inhibitors target NSCLC: two antibodies and a small-molecule MET inhibitor. AB - Joining cetuximab, sorafenib, afatinib, intedanib, and crizotinib in phase III development for non-small cell lung cancer (NSCLC) are ramucirumab (developed by ImClone, a subsidiary of Lilly), necitumumab (developed by ImClone and Bristol Myers Squibb), and tivantinib (ARQ 197, developed by ArQule and Daiichi Sankyo). Necitumumab is a second-generation anti-EGFR monoclonal antibody (mAb) similar to cetuximab. Enrollment has been stopped in one of two necitumumab phase III trials because of safety concerns. Ramucirumab is an anti-VEGFR2 mAb targeting the same pathway as bevacizumab. Although the phase II safety data for ramucirumab appear better than the data for necitumumab, fewer phase III data are available. Tivantinib is a highly selective, orally available MET tyrosine kinase inhibitor. MET is overexpressed in 61% of NSCLC cases. Although tivantinib is the last of the three agents discussed here to enter phase III, its phase II results are the most robust. PMID- 21815705 TI - Atorvastatin metabolite measurements as a diagnostic tool for statin-induced myopathy. AB - BACKGROUND: Myopathic complaints are common in the general population and are more frequent with increasing age. When myopathic symptoms arise in a patient treated with a HMG-CoA reductase inhibitor (statin), it is always a question of whether the symptoms are due to statin-induced myopathy (SIM) or not (non-SIM). Diagnosis of SIM is not as straightforward as previously thought, because the most commonly used biomarker, serum creatine kinase, shows low specificity and selectivity, except in serious cases of rhabdomyolysis. There is a definite need for a novel biomarker for SIM. OBJECTIVE: Based on a previous study reporting an altered metabolic profile with increased systemic exposure to the suspected muscle-toxic metabolite atorvastatin lactone in patients with SIM compared with healthy controls, this study aimed to explore the use of atorvastatin metabolite measurements to diagnose muscular complaints during statin treatment as being either SIM or non-SIM. PATIENTS, SETTING, AND STUDY DESIGN: Fifty-three patients with self-reported myopathic symptoms during atorvastatin treatment were recruited from our outpatient clinic. The symptoms were clinically evaluated as being SIM or non-SIM, on the basis of atorvastatin re-challenge testing. Atorvastatin and its metabolites were measured at steady state in all patients and compared with the clinical evaluation to see if this could predict the outcome and hence be suitable as a diagnostic tool for SIM. MAIN OUTCOME MEASURE: This was an exploratory study to investigate the proportion of patients correctly diagnosed by different metabolite cut-off ratios. RESULTS: With a cut-off ratio set at 1.1 for the atorvastatin lactone to atorvastatin acid ratio, 15 of 28 SIM patients (sensitivity of 54%) and 20 of 24 non-SIM patients (specificity of 83%) were correctly diagnosed. This corresponds to a positive predictive value of 79% and a negative predictive value of 61% (p = 0.006). CONCLUSION: The present study confirms an altered metabolic pattern of atorvastatin in patients with SIM and substantiates a central role of the lactone forms of statins in future investigations of statin myotoxicity. The atorvastatin lactone to acid ratio seems to be a valuable supportive diagnostic tool with high specificity and moderate sensitivity, adding to ordinary clinical evaluations when diagnosing SIM. PMID- 21815706 TI - Societal values in the allocation of healthcare resources: is it all about the health gain? AB - Over the past decade, public distrust in unavoidable value-laden decisions on the allocation of resources to new health technologies has grown. In response, healthcare organizations have made considerable efforts to improve their acceptability by increasing transparency in decision-making processes. However, the social value judgments (distributive preferences of the public) embedded in them have yet to be defined. While the need to explicate such judgments has become widely recognized, the most appropriate approach to accomplishing this remains unclear. The aims of this review were to identify factors around which distributive preferences of the public have been sought, create a list of social values proposed or used in current resource allocation decision-making processes for new health technologies, and review approaches to eliciting such values from the general public. Social values proposed or used in making resource allocation decisions for new health technologies were identified through three approaches: (i) a comprehensive review of published, peer-reviewed, empirical studies of public preferences for the distribution of healthcare; (ii) an analysis of non technical factors or social value statements considered by technology funding decision-making processes in Canada and abroad; and (iii) a review of appeals to funding decisions on grounds in part related to social value judgments. A total of 34 empirical studies, 10 technology funding decision-making processes, and 12 appeals to decisions were identified and reviewed. The key factors/patient characteristics addressed through policy statements and around which distributive preferences of the public have been sought included severity of illness, immediate need, age (and its relationship to lifetime health), health gain (amount and final outcome/health state), personal responsibility for illness, caregiving responsibilities, and number of patients who could benefit (rarity). Empirical studies typically examined the importance of these factors in isolation. Therefore, the extent to which preferences around one factor may be modified in the presence of others is still unclear. Research that seeks to clarify interactions among factors by asking the public to weigh several of them at once is needed to ensure the relevance of elicited preferences to real-world technology funding decisions. PMID- 21815707 TI - Treatment of myasthenia gravis: focus on pyridostigmine. AB - Acquired myasthenia gravis (MG) is a chronic autoimmune disorder of the neuromuscular junction, characterized clinically by muscle weakness and abnormal fatigability on exertion. Current guidelines and recommendations for MG treatment are based largely on clinical experience, retrospective analyses and expert consensus. Available therapies include oral acetylcholinesterase (AChE) inhibitors for symptomatic treatment, and short- and long-term disease-modifying treatments. This review focuses on treatment of MG, mainly on the use of the AChE inhibitor pyridostigmine. Despite a lack of data from well controlled clinical trials to support their use, AChE inhibitors, of which pyridostigmine is the most commonly used, are recommended as first-line therapy for MG. Pyridostigmine has been used as a treatment for MG for over 50 years and is generally considered safe. It is suitable as a long-term treatment in patients with generalized non progressive milder disease, and as an adjunctive therapy in patients with severe disease who are also receiving immunotherapy. Novel AChE inhibitors with oral antisense oligonucleotides have been developed and preliminary results appear to be promising. In general, however, AChE inhibitors provide only partial benefit and most patients eventually switch to long-term immunosuppressive therapies, most frequently corticosteroids and/or azathioprine. Although AChE inhibitors are known to be well tolerated and effective in relieving the symptoms of MG, further efforts are required to improve treatment options for the management of this disorder. PMID- 21815709 TI - Associations between repeated deployments to OEF/OIF/OND, October 2001-December 2010, and post-deployment illnesses and injuries, active component, U.S. Armed Forces. PMID- 21815710 TI - Carpal tunnel syndrome, active component, U.S. Armed Forces, 2000-2010. PMID- 21815711 TI - Herpes zoster, active component, U.S. Armed Forces, 2000-2010. PMID- 21815708 TI - Low-dose pravastatin and age-related differences in risk factors for cardiovascular disease in hypercholesterolaemic Japanese: analysis of the management of elevated cholesterol in the primary prevention group of adult Japanese (MEGA study). AB - BACKGROUND: Limited data are available regarding the relationship between age and the effect of HMG-CoA reductase inhibitor (statin) treatment. OBJECTIVE: The aim of the present analysis was to evaluate the relationships between age, baseline patient characteristics, and pravastatin treatment with respect to the development of cardiovascular disease (CVD) in the Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) study, a large-scale clinical study conducted in Japanese patients with mild or moderate hyperlipidaemia to evaluate the primary preventive effect of pravastatin against coronary heart disease. METHODS: To compare the prevalence of CVD risk factors, the incidence of CVD in relation to each risk factor, and final values and changes in lipid parameters, the 7832 patients were classified into six age groups: <45, 45-49, 50-54, 55-59, 60-64 and >=65 years. The relationship between pravastatin (10-20 mg/day) treatment efficacy and aging and the incidence of events in relation to the age groups were compared using the multivariable Cox proportional hazards model. RESULTS: The prevalences of diabetes mellitus and hypertension were higher in older men than in younger men, while the prevalences of smoking and obesity were higher in younger men. However, a similar difference in risk factors was not seen in women. High-density lipoprotein cholesterol was higher in women than in men across all age groups. Triglycerides were higher in younger men than in older men and all groups of women. The mean follow-up levels of total cholesterol and low-density lipoprotein cholesterol were lower in older patients than in younger patients. Pravastatin (10-20 mg/day) reduced the risk of CVD by about 30-40% across all age groups, and there was no difference between men and women. Of particular note in this analysis, CVD risk was markedly reduced in older women compared with younger women (53% vs 30% in women aged >=65 vs >=45 years). CONCLUSION: A similar satisfactory risk reduction for CVD was achieved with low-dose pravastatin in all men and in older women in particular, despite differences in the prevalence of risk factors. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00211705. PMID- 21815712 TI - Plant dermatitis, active component, 2001-2010. PMID- 21815713 TI - The role of managed care in improving outcomes in epilepsy. AB - The burden of epilepsy for patients and payers is large and onerous. The heterogeneous nature of the condition and the lack of diagnostic or treatment biomarkers present considerable clinical challenge. Despite expansion of the treatment armamentarium, selection of maximally appropriate therapy for individual patients remains a challenge, especially in those with treatment refractory epilepsy. While numerous factors play a role in resolving these uncertainties, 3 key factors stand out. An overwhelming quantity of clinical data support the notion that the most effective therapies-measured by the ability to control seizures while minimizing adverse effects-are typically the most cost effective. A second consideration is maximizing adherence to prescribed therapies, which has been an ongoing dilemma in the treatment of epilepsy because the condition occurs episodically. Poor adherence has a profound effect on treatment and costs, and several strategies for improving adherence have been identified. If properly observed, these can improve outcomes and lower expenditures. The third consideration is the monitoring of therapeutic response. This is essentially through ongoing care by the prescriber with careful assessment of seizures, patient satisfaction with treatment, dose-related adverse effects, and the subjective aspects of idiosyncratic toxicity; however, laboratory testing can also have a role. The resources needed to provide this monitoring vary across treatments. From a systemic point of view, engagement of all stakeholders-patients, payers, and physicians-in overseeing the effective and efficient use of healthcare resources will benefit all parties involved. PMID- 21815715 TI - The management of subarachnoid haemorrhage in London. PMID- 21815716 TI - Management of acute hydrocephalus following aneurysmal subarachnoid haemorrhage: the role of serial lumbar puncture and continuous lumbar drainage. PMID- 21815717 TI - Periodontal status of adults with systemic sclerosis: case-control study. AB - BACKGROUND: Systemic sclerosis (SSc) is a systemic autoimmune disease that affects connective tissue in the skin, blood vessels, and major organs of the body. This project aims to compare the periodontal status of dentate Hong Kong Chinese with and without SSc. METHODS: Thirty-six non-smoking adults with SSc (one male and 35 females: aged 50.6 +/- 11.7 years; free from Sjogren syndrome) attending a teaching hospital were age- and sex-matched to systemically healthy controls attending a dental hospital. Both groups had similar demographic characteristics but a lower proportion of patients with SSc were working or studying (P <0.05). Twenty-three (32%) of all participants were regular dental attendees. Orthopantomogram radiographs were taken. Participants were surveyed and periodontally examined. RESULTS: Both groups had a similar number of erupted teeth, proportion of sites with detectable plaque, and mean full-mouth clinical attachment level, whereas controls had less bleeding on probing (49.3% +/- 22.6% versus 78.4% +/- 19.6%; P <0.001) and a shallower mean full-mouth probing depth (1.92 +/- 0.44 mm versus 2.52 +/- 0.58 mm; P <0.001). Radiographically, patients with SSc had wider periodontal ligament spaces (0.36 +/- 0.06 mm versus 0.33 +/- 0.03 mm; P <0.01). CONCLUSIONS: Hong Kong Chinese adults with SSc seem to exhibit higher levels of periodontal inflammation and wider radiographic periodontal ligament spaces than age- and sex-matched controls. Future studies are warranted to further investigate any associations between these periodontal features and SSc. PMID- 21815720 TI - Molecular analysis of Italian patients with congenital glaucoma. AB - Purpose: Congenital glaucoma (CG) results from poorly understood developmental abnormalities of the aqueous drainage structures and is clinically characterized by high intraocular pressure (IOP), epiphora, corneal oedema, photophobia, blepharospasm and ocular enlargement. To date, more than 50 pathogenic mutations in the CYP1B1 gene, a member of the cytochrome P450 gene family, have been reported in CG patients. The aim of this paper was to determine the genetic defects underlying CG in Italian patients. Methods: Molecular analysis of CYP1B1 was performed on the DNA of 120 patients and the transcript region of the MYOC/TIGR gene was also studied in all the patients bearing only one mutation in CYP1B1 gene. Previously described CYP1B1 polymorphisms (R48G, A119S, L432V, D449D and N453S) were also analyzed in our patients. Results: Seventeen different variations of CYP1B1 were found in 30 of the 120 (25.0%) CG patients. Twelve of these changes had been identified in previous reports as disease-causing mutations, while L26R, P52L, A106D, A237E and F440L are described here for the first time. F440L has always been found in cis with P52L, both in patients and healthy carriers, suggesting its role as a rare polymorphism linked to the P52L, while the other new variations we found could possibly play a pathogenetic role. G61E and 1775-1801dup27 are the most frequent mutations in our patients. Two amino acid variations (A447V and R76K) were identified in MYOC/TIGR analysis. Conclusions: Our results confirm the major role of the CYP1B1 gene in congenital glaucoma and also suggest an autosomal recessive role of MYOC/TIGR in a digenic inheritance model. PMID- 21815719 TI - Ocular manifestations of Noonan syndrome. AB - PURPOSE: To describe the ophthalmological characteristics in a group of Noonan syndrome patients with proven mutations in the PTPN11 gene. METHODS: Thirty-five Noonan syndrome patients with PTPN11 gene mutations underwent ophthalmological exams, which consisted of external inspection, slit-lamp biomicroscopy examination and an ophthalmoscopic examination after instillation of 1.0% tropicamide or 1.0% cyclopentolate. RESULTS: All 35 patients had at least one abnormality upon ophthalmological examination. The eyelid and external eye abnormalities were the prevailing features, followed by prominent corneal nerves on slit-lamp exam. Fundus changes were detected in 8% of the subjects, mainly associated with high myopia. No statistically significant differences were observed among the patients presenting specific mutations in the PTPN11 gene. CONCLUSIONS: The current study further supports the finding that ocular symptoms account for a large fraction of the clinical manifestations of NS. Additional characteristics are described here. The roles for the various mutations of PTPN11 in ocular development are yet to be established. PMID- 21815721 TI - Insecticidal activity of the root bark essential oil of Periploca sepium Bunge and its main component. AB - During our screening programme for agrochemicals from Chinese medicinal herbs, the root bark essential oil of Periploca sepium was found to possess strong contact toxicity against the fruit flies, Drosophila melanogaster with a LD(50) value of 1.22 ug/adult. The main component of the essential oil was identified to be 2-hydroxy-4-methoxy-benzaldehyde (78.8%), followed by linalool (2.8%) and (-) alpha-terpineol (2.7%). The 2-hydroxy-4-methoxy-benzaldehyde was further isolated and identified by bioassay-directed fractionation. The compound showed strong contact toxicity against D. melanogaster and the maize weevil (Sitophilus zeamais) with LD(50) values of 1.47 and 6.99 ug/adult, respectively. PMID- 21815722 TI - Isolation of the new anacardic acid 6-[16'Z-nonadecenyl]-salicylic acid and evaluation of its antimicrobial activity against Streptococcus mutans and Porphyromonas gingivalis. AB - A new anacardic acid, 6-[16'Z-nonadecenyl]-salicylic acid (1), along with seven known compounds, 6-[8'Z-pentadecenyl] salicylic acid (15:1 anacardic acid) (2), 6 nonadecenyl salicylic acid (anacardic acid 19:0) (3), 6-pentadecyl salicylic acid (anacardic acid 15:0) (4), masticadienonic acid (5), 3alpha hydroxymasticadienonic acid (6), 3-epi-oleanolic acid (7) and beta-sitosterol, were isolated from the bark of Amphipterygium adstringens using a bioassay-guided fractionation method. The structure of the new compound (1) was elucidated by spectroscopic data interpretation. The known compounds (2-7) were identified by comparison of their spectroscopic data with reported values in the literature. Compounds 1-4 exhibited antibacterial activity against Streptococcus mutans and Porphyromonas gingivalis with minimum inhibitory concentrations ranging from 7 to 104 ug mL and from 12 to 126 ug mL, respectively. PMID- 21815723 TI - A new flavonoid and other constituents from Centaurea nicaeensis All. var. walliana M. AB - A new flavone glucoside, apigenin 4'-(6"-methylglucuronide) (1), together with six known compounds, cirsilineol, jaceosidin, melitensin, apigenin, apigenin 7 (6"-methylglucuronide) and prunasin, were isolated from the ethanolic extract of the aerial parts of Centaurea nicaeensis All. var. walliana M. (Asteraceae) collected from Souk-Ahras, eastern Algeria. The structures were established by spectral analysis, mainly HRESI-MS, UV and 2D-NMR experiments (COSY, HSQC and HMBC). PMID- 21815724 TI - Chemical markers in Origanum vulgare L. from Kumaon Himalayas: a chemosystematic study. AB - The essential oils of four wild growing Origanum vulgare L. (family Lamiaceae) collected from different locations in Kumaon region (Uttarakhand, India) were analysed by capillary GC and GC/MS. The comparative results of O. vulgare L. collected from four different regions showed differences in the chemical constituents of the essential oils. The oil of O. vulgare L. collected from Dhoulchina and Champawat (chemotype I) shows p-cymene (6.7-9.8%), gamma-terpinene (12.4-14.0%), thymol (29.7-35.1%) and carvacrol (12.4-20.9%) as major constituents while the oil from Kilbury and Rushi village (chemotype II) shows linalool (6.7-9.7%), bornyl acetate (12.6-16.8%), beta-caryophyllene (10.5-13.8%) and germacrene D (6.3-11.3%) as the major constituents. These features highlight the chemosystematics of this genus. PMID- 21815725 TI - New secoiridoid from olive mill wastewater. AB - A new secoiridoid, olenoside A (1a) and its known epimer olenoside B (1b), were isolated from olive mill wastewater as a mixture of two isomers. Their structures, 1-methyl-7-oxo-6,6a,8,8a-tetrahydro-1H,3H-pyrano[3,4-c]pyran-4 carboxylic acid methyl ester, were determined by spectroscopic methods including 2-D NMR. The structure of major compound 1a was confirmed by X-ray diffraction. PMID- 21815726 TI - Beyond sexual desire and curiosity: sexuality among senior high school students in Papua and West Papua Provinces (Indonesia) and implications for HIV prevention. AB - When it comes to sexuality and norms, young Indonesians are becoming more open. Concern about this is related to the rapid increase in HIV prevalence in Indonesia, especially in Papua and West Papua Provinces. While much research has been conducted among youth who have left school, little is known about senior high school students' sexuality and sexual practices in these provinces. Using qualitative and quantitative data, we explore perspectives on and experiences of sexuality, contraceptive use, unintended pregnancy and unsafe abortion among 1082 Year 11 students from 16 senior high schools in both provinces. Findings suggest that around 38.3% of students reported having had sexual intercourse and 36.5% of these having had their first sexual encounter before they were 15 years old. Furthermore, contraceptive use among sexually active students was very low. Around 32% of female students who reported having had sexual intercourse also reported having an unintended pregnancy and the majority of them had had unsafe abortions. The paper points to the implications of students' high-risk sexual behaviours for HIV prevention. PMID- 21815727 TI - Volatile constituents and antioxidant activity of flowers, stems and leaves of Nasturtium officinale R. Br. AB - GC-MS analyses of the essential oils of leaves, stems and flower of Nasturtium officinale resulted in the identification of 9, 8 and 15 compounds, representing 97%, 100% and 94.7% of the oils, respectively. The main compounds of the oil of leaves were myristicin (57.6%), alpha-terpinolene (8.9%) and limonene (6.7%). Caryophyllene oxide (37.2%), p-cymene-8-ol (17.6%), alpha-terpinolene (15.2%) and limonene (11.8%) were the main components in stems, whereas limonene (43.6%), alpha-terpinolene (19.7%), p-cymene-8-ol (7.6%) and caryophyllene oxide (6.7%) were the major constituents in the oil of flowers. All the samples were subjected to a screening for their possible antioxidant activities using 2,2-diphenyl-1 picrylhydrazyl (DPPH) and beta-carotene-linoleic acid assays. In the above tests, methanol extracts of leaves showed higher antioxidant activity than the oils and methanol extracts of stems and flowers. PMID- 21815728 TI - Male adolescent concubinage in Peshawar, Northwestern Pakistan. AB - This paper reports on findings from four interviews held with young men who have experienced male adolescent concubinage relationships with adult men in Peshawar, Northwestern Pakistan. These relationships are referred to by the Pashtun people involved as bacha baazi. Similar relationships (called bacabozlik) were described by Ingeborg Baldauf among the Uzbeks and Pashtun of Afghanistan, based on observations made in the late-1970s. This paper compares Baldauf's observations with our own, indicating significant differences and similarities. Implications for future research and for social protection programmes are discussed. PMID- 21815729 TI - Lysophosphatidic acid and lovastatin might protect kidney in renal I/R injury by downregulating MCP-1 in rat. AB - Abstract Renal ischemia/reperfusion (I/R) injury is a major cause of renal failure. The aim of our study is to explore the role of lysophosphatidic acid (LPA) and lovastatin on renal I/R injury and its mechanism in the rat. Male Wistar rats were randomly divided into sham-operated group; renal I/R for 0 h, 4 h, 12 h, and 24 h groups; LPA treatment group; and lovastatin treatment group (n = 10). Rats were killed to determine the level of monocyte chemotactic protein-1 (MCP-1) in renal tissue, renal function [serum creatinine (Cr) and blood urea nitrogen (BUN)], and renal histomorphology to evaluate the effectiveness of LPA and lovastatin. Normal renal tissue had a low level of MCP-1. The level of MCP-1 began to rise at 0 h after reperfusion, reached peak value at 4 h, and then gradually fell off. Compared with sham-operated group, MCP-1 was increased in all renal I/R injury groups (p < 0.01). With the extension of reperfusion, Cr and BUN were significantly increased (p < 0.01). There were damages in kidney tubules, renal interstitium, and kidney glomerulus in renal I/R injury groups. Paller's score was significantly increased in all renal I/R injury groups compared with sham-operated group (p < 0.01). LPA and lovastatin reduced the level of MCP-1, Cr, BUN, and damages of renal histomorphology (p < 0.01). The level of MCP-1 in renal tissue dynamically increases in renal I/R injury, indicating that MCP-1 is involved in renal I/R injury. LPA and lovastatin might protect renal function by downregulating MCP-1 in renal I/R injury. PMID- 21815730 TI - Prehospital administration of tenecteplase for ST-segment elevation myocardial infarction in a rural EMS system. AB - INTRODUCTION: In the setting of ST-segment elevation myocardial infarction (STEMI), early reperfusion yields better patient outcomes. Emergency medical services (EMS) is the first medical contact for half of the afflicted population, and prehospital thrombolysis may result in considerably faster reperfusion compared with percutaneous coronary intervention (PCI) in rural settings. However, there are few reports of prehospital thrombolysis in rural EMS systems. OBJECTIVE: To describe a rural EMS system's experience with tenecteplase in STEMI. METHODS: Data were retrospectively abstracted from the medical records of patients receiving tenecteplase using standard chart review guidelines. Primary outcomes included time saved by EMS-initiated thrombolysis, aborted infarctions, serious bleeding events, and in-hospital mortality. Secondary outcomes included reinfarction, rescue angioplasty, and appropriateness of treatment. Time savings was defined as transport time after tenecteplase administration plus 90 minutes, which is the typical door-to-balloon time for PCI laboratories. Aborted infarction was defined as resolution of the cumulative ST-segment elevation to <= 50% of that on the initial electrocardiogram (ECG) within two hours after treatment, and peak creatine kinase (CK)/CK-MB levels less than or equal to twice the upper limit of normal. RESULTS: Seventy-three patients received prehospital tenecteplase; this treatment was determined to be appropriate in 86.4% of cases. The mean patient age was 59 years, and 71.6% of the patients were male. Mean (+/- standard deviation) scene-arrival-to-drug time was 26.2 (+/- 11.4) minutes, the mean scene-arrival-to-hospital-arrival time was 73.0 (+/- 20.6) minutes, and the mean transport time was 46.0 (+/- 11.1) minutes. Tenecteplase was administered 35.9 (+/- 25.0) minutes prior to hospital arrival, and the estimated reperfusion time savings over PCI was 125.9 (+/- 25.0) minutes. Aborted infarctions were observed in 24.1% of patients, whereas 9.6% suffered reinfarction, 47.9% underwent rescue angioplasty, and 16.7% required coronary artery bypass grafting (CABG). Serious bleeding events occurred in 15 patients (20.5%), and four (5.5%) died. CONCLUSION: In this retrospective review of rural STEMI patients, tenecteplase was administered 36 minutes prior to hospital arrival, saving approximately two hours over typical PCI strategies and resulting in aborted infarctions in one-fourth of patients. In a rural setting with lengthy transport times to PCI facilities, tenecteplase appears to be a feasible prehospital intervention. Randomized controlled trials are needed to fully evaluate the safety and effectiveness of this intervention prior to widespread adoption. PMID- 21815731 TI - Semiautomatic intraosseous devices in pediatric prehospital care. AB - BACKGROUND: Intraosseous (IO) access is attempted when intravenous access cannot be established during an emergency. The U.S. Food and Drug Administration-cleared semiautomatic IO access device (EZ-IO; Vidacare Corp., Shavano Park, TX) has been shown to be safe and effective. OBJECTIVE: To examine the characteristics of pediatric patients receiving IO infusions, primary clinical impressions of emergency medical services providers, success rates, and subsequent treatment after use of a manual IO device or the semiautomatic IO device. METHODS: A midwestern, 12-site, statewide ambulance service began using the semiautomatic device instead of a manual IO device in 2007. Retrospective review included analysis of device placement rates and subsequent treatment of children (younger than 18 years) who underwent an IO access procedure with either the manual device (January 2003 through February 2007) or the semiautomatic device (March 2007 through May 2009). RESULTS: First-attempt success was achieved in 80.6% of patients (25 of 31) in the manual device group and in 83.9% of patients (52 of 62) in the semiautomatic device group (p = 0.98). In the manual device group, there were 37 attempts for 25 successful device placements (67.6% success), and in the semiautomatic group, there were 72 attempts for 58 successful placements (80.6% success) (p = 0.52). Intravenous attempts were made before IO attempts in 35.5% of patients (11 of 31) in the manual group and in 1.7% of patients (1 of 60) in the semiautomatic group (p < 0.001). Treatment (medication use, excluding lidocaine for local anesthetic purposes and intravenous crystalloid) was administered IO in 84.0% of the patients (21 of 25) in the manual device group and in 73.2% of the patients (41 of 56) in the semiautomatic device group. CONCLUSIONS: For the pediatric cohort, use of a semiautomatic IO access device in place of a manual device offered no statistically significant difference in first attempt success (3.3%) or in success per attempt (13.0%). However, the rate at which IO access was used by emergency medical services providers more than tripled with use of the semiautomatic device. PMID- 21815732 TI - EMS Provider assessment of vehicle damage compared with assessment by a professional crash reconstructionist. AB - OBJECTIVE: To determine the accuracy of emergency medical services (EMS) provider assessments of motor vehicle damage when compared with measurements made by a professional crash reconstructionist. METHODS: EMS providers caring for adult patients injured during a motor vehicle crash and transported to the regional trauma center in a midsized community were interviewed upon emergency department arrival. The interview collected provider estimates of crash mechanism of injury. For crashes that met a preset severity threshold, the vehicle's owner was asked to consent to having a crash reconstructionist assess the vehicle. The assessment included measuring intrusion and external automobile deformity. Vehicle damage was used to calculate change in velocity. Paired t-test, correlation, and kappa were used to compare EMS estimates and investigator-derived values. RESULTS: Ninety-one vehicles were enrolled; of these, 58 were inspected and 33 were excluded because the vehicle was not accessible. Six vehicles had multiple patients. Therefore, a total of 68 EMS estimates were compared with the inspection findings. Patients were 46% male, 28% were admitted to hospital, and 1% died. The mean EMS-estimated deformity was 18 inches and the mean measured deformity was 14 inches. The mean EMS-estimated intrusion was 5 inches and the mean measured intrusion was 4 inches. The EMS providers and the reconstructionist had 68% agreement for determination of external automobile deformity (kappa 0.26) and 88% agreement for determination of intrusion (kappa 0.27) when the 1999 American College of Surgeons Field Triage Decision Scheme criteria were applied. The mean (+/- standard deviation) EMS-estimated speed prior to the crash was 48 +/- 13 mph and the mean reconstructionist-estimated change in velocity was 18 +/- 12 mph (correlation -0.45). The EMS providers determined that 19 vehicles had rolled over, whereas the investigator identified 18 (kappa 0.96). In 55 cases, EMS and the investigator agreed on seat belt use; for the remaining 13 cases, there was disagreement (five) or the investigator was unable to make a determination (eight) (kappa 0.40). CONCLUSIONS: This study found that EMS providers are good at estimating rollover. Vehicle intrusion, deformity, and seat belt use appear to be more difficult for EMS to estimate, with only fair agreement with the crash reconstructionist. As expected, the EMS provider estimated speed prior to the crash does not appear to be a reasonable proxy for change in velocity. PMID- 21815734 TI - Cervical arthroplasty: the beginning, the middle, the end? AB - Cervical arthroplasty has developed as an alternative to spinal fusion for the treatment of cervical radiculopathy and myelopathy. The popularity of artificial discs has grown as the evidence of complications following arthrodesis has increased, making the theoretical advantages (motion preservation, altering the natural history of disease, prevention of adjacent segment disease) of disc replacement more attractive. However, as more discs are implanted and the length of follow-up increases, reported complications such as heterotopic ossification, device migration and spontaneous fusion of arthroplasty devices are growing. As a result, surgeons and patients face a challenge when deciding between motion preserving or fusion surgery. Currently, there is inadequate evidence to promote extensive use of artificial discs for cervical spondylosis, despite promising short-term and intermediate clinical outcomes. However, there is also insufficient evidence to cease using them completely. The use of arthroplasty over fusion in the long term can only be justified if the incidence of adjacent segment disease decreases as a result. Despite the level of investment and research into arthroplasty outcomes, long-term follow-up has yet to be completed and has not convincingly demonstrated the effect of artificial discs on adjacent segment disease. Further long-term randomised trials are necessary to determine whether cervical arthroplasty is able to reduce the incidence of adjacent segment disease and, in doing so, replace arthrodesis as the gold standard treatment for cervical spondylosis. PMID- 21815735 TI - Recognition of mental incapacity when consenting patients with intracranial tumours for surgery: how well are we doing? AB - INTRODUCTION: Many patients with intracranial tumours have cognitive deficits that might affect their mental capacity to give valid consent to neurosurgical treatment. The aim of this study was to determine the incidence of mental incapacity, as assessed by neurosurgeons, in patients with intracranial tumours undergoing neurosurgery. METHODS: The case notes of successive patients undergoing brain tumour surgery between 16 October 2008 and 16 October 2010 were reviewed. The frequency of use of standard consent forms and Certificates of Incapacity was recorded. In addition, the frequency and scores of pre-operative cognitive assessments were recorded. RESULTS: Case notes of 247 of 262 patients undergoing surgery for intracranial tumours were reviewed since there was no record of either a standard consent form or a Certificate of Incapacity in the case notes for 15 patients. Nine of 247 brain tumour patients were issued with a Certificate of Incapacity (3.6%, 95% CI 1.6-6.8%), while 238 (96.4%) signed a standard consent form. Seven of these nine had high-grade gliomas, for an incidence of incapacity of 5.9% (95% CI 2.8-11.8%), while the remaining two Certificates of Incapacity were issued for patients with meningiomas (incidence 3%; 95% CI 0.04-10.4%). Fifty of the 262 patients (19%) had some form of pre operative cognitive assessment documented, but only three of these were issued with a Certificate of Incapacity. All three patients issued with a Certificate of Incapacity had Mini-Mental State Examination scores suggestive of cognitive impairment. CONCLUSIONS: Incapacity to consent to brain tumour surgery, as assessed by neurosurgeons, is uncommon. The incidence of incapacity is less than might be expected given the level of cognitive impairment known in this population. Decisions about capacity by neurosurgeons are often made in the absence of any documented assessment of cognition or other objective evidence that could support their decision in the event of dispute. PMID- 21815736 TI - Stereotactic radiosurgery for trigeminal neuralgia: outcomes and complications. AB - Stereotactic radiosurgery is one of a number of recognised treatments for the management of trigeminal neuralgia refractory to drug therapy. The reported success of stereotactic radiosurgery in managing patients with trigeminal neuralgia varies in different units from 22 to 75%. This paper reports the outcomes of patients with trigeminal neuralgia who were treated at the National Centre for Stereotactic Radiosurgery in Sheffield, UK. The study reports the outcome of 72 patients treated consecutively between October 2004 and May 2008. Data were collected prospectively by a postal questionnaire sent to patients at 6, 12 and 24 months after treatment. The median age was 65.6 years (39 males: 33 females). Fourteen patients had secondary trigeminal neuralgia (eight multiple sclerosis). Fifteen of the patients included in the study were receiving a second treatment (an initial treatment having improved their pain significantly for at least 6 months). All radiosurgical procedures were performed using a single 4 mm collimator isocenter covering the region of the dorsal root entry zone with a maximal radiation dose of 80 Gy. The percentage of patients defined as having an excellent outcome (pain free without medication) was 39% after 6 months, 36% after 12 months and 64% after 24 months. The percentage of patients who reported being very satisfied with treatment was 71% after 6 months, 57% after 12 months and 53% after 24 months. Half the patients with secondary trigeminal neuralgia were pain free without medication after treatment, and 60% of patients who underwent a second treatment were pain free. A new trigeminal sensory deficit was reported by 31% of patients after radiosurgical treatment. PMID- 21815737 TI - Partial recovery from amnesia following bilateral surgical fornix transection is correlated with cortical plasticity. AB - We report a case of an interventricular ependymoma which was surgically removed but also required bilateral transection of the fornices resulting in memory impairment which gradually improved. Functional MR images using a memory paradigm showed that recovery correlated with cortical plasticity involving activation of the orbitofrontal cortex and the middle temporal gyrus. PMID- 21815738 TI - Bilateral trochlear nerve palsy subsequent to ventriculoperitoneal shunting of normal pressure hydrocephalus. AB - Misplacement of the ventricular catheters of shunt systems may result in shunt dysfunction or a variety of neurological symptoms. Bilateral fourth nerve palsy has not been reported thus far after shunting. Here, we describe the occurrence of this unusual neurological deficit in a patient who underwent shunting for normal pressure hydrocephalus, and demonstrate its pathoanatomical correlate. PMID- 21815739 TI - Educational content and health literacy issues in direct-to-consumer advertising of pharmaceuticals. AB - Direct-to-consumer (DTC) pharmaceutical advertisements have been analyzed in many ways, but richer conceptualizations of health literacy have been largely absent from this research. With approximately half of U.S. adults struggling to understand health information, it is important to consider consumers' health literacy when analyzing DTC advertisements. This project, framed by the health belief model, analyzed 82 advertisements. Advertisements provided some kinds of educational content (e.g., drugs' medical benefits) but typically failed to offer other useful information (e.g., other strategies for dealing with conditions). Issues likely to be barriers to low health literate consumers, such as nonstandard text formatting, are common. PMID- 21815740 TI - The effects of message framing, involvement, and nicotine dependence on anti smoking public service announcements. AB - Anti-smoking Public Service Announcements (PSAs) typically emphasize the negative consequences of failing to quit smoking (negative frame), as opposed to emphasizing the benefits of quitting (positive frame). However, stressing the benefits of quitting sometimes produces better communication outcomes. Previous research on message framing has tried to identify factors affecting the impact of positive framing and negative framing. Data were collected on 188 undergraduates attending a southeastern university in the United States who were assigned randomly to view either positive or negative messages. Our study found that involvement and nicotine dependence moderated the impact of framed smoking cessation messages on attitude toward the ad. PMID- 21815741 TI - Best practices of total quality management implementation in health care settings. AB - Due to the growing prominence of total quality management (TQM) in health care, the present study was conducted to identify the set of TQM practices for its successful implementation in healthcare institutions through a systematic review of literature. A research strategy was performed on the selected papers published between 1995 and 2009. An appropriate database was chosen and 15 peer-reviewed research papers were identified through a screening process and were finally reviewed for this study. Eight supporting TQM practices, such as top-management commitment, teamwork and participation, process management, customer focus and satisfaction, resource management, organization behavior and culture, continuous improvement, and training and education were identified as best practices for TQM implementation in any health care setting. The article concludes with a set of recommendations for the future researchers to discuss, develop, and work upon in order to achieve better precision and generalizations. PMID- 21815742 TI - Traveling abroad for medical care: U.S. medical tourists' expectations and perceptions of service quality. AB - The SERVQUAL scale has been widely used to measure service quality in the health care industry. This research is the first study that used SERVQUAL to assess U.S. medical tourists' expectations and perceptions of the service quality of health care facilities located outside the United States. Based on a sample of U.S. consumers, who had traveled abroad for medical care, the results indicated that there were significant differences between U.S. medical tourists' perceived level of service provided and their expectations of the service that should be provided for four of the five dimensions of service quality. Reliability had the largest service quality gap followed by assurance, tangibles, and empathy. Responsiveness was the only dimension without a significantly different gap score. The study establishes a foundation for future research on service quality in the rapidly growing medical tourism industry. PMID- 21815743 TI - Marketing retail health clinics: challenges and controversies arising from a health care innovation. AB - Since their founding in 2000, retail-based health care clinics, also called convenient care clinics, have flourished but continue to generate controversy. This article examines the literature with respect to the industry's background, establishment of industry standards, types of services offered, marketing of retail health clinics, industry growth with new target markets, and patient demographics. It also examines the growing relationship with insurers and third party payers, quality-of-care concerns by medical associations, and legal regulations and their potential impact on industry growth nationwide. PMID- 21815744 TI - Pathogenesis of experimental amyloid protein A amyloidosis in sore hocks-affected rabbits. AB - Although the experimental transmission of amyloid protein A (AA) amyloidosis with amyloid-enhancing factor has been studied intensively, its pathogenesis remains obscure. We previously found that rabbits affected with 'sore hocks' (SH) uniquely developed AA amyloidosis in response to primary inflammatory stimulation followed by the administration of bovine AA fibrils. However, it is unknown why only the rabbits with preexisting SH developed experimental AA amyloidosis. There may be hidden factors in the SH status that stimulate the mechanism of cross species transmission of AA amyloidosis. To examine the essential factors in the development of experimental AA amyloidosis in SH-affected rabbits, we studied the etiology of SH in rabbits pathologically and bacteriologically. In addition, we developed artificial SH symptoms in normal rabbits by use of an adjuvant prepared from Staphylococcus aureus (StA) isolated from a spontaneous SH-affected rabbit, and we evaluated the incidence of AA amyloidosis in rabbits with or without experimental SH symptoms. We found that StA administration was extremely efficient at stimulating the induction of experimental AA amyloidosis, and the influence of SH was required. We found that the persistent S. aureus infection in SH facilitates the development of experimental AA amyloidosis in rabbits and that the inflammatory stimulation provided by SH acts as an additional accelerator in experimental AA amyloidosis. PMID- 21815747 TI - 7th International Workshop On Neonatology. PMID- 21815746 TI - Prenatal lung-head ratio: threshold to predict outcome for congenital diaphragmatic hernia. AB - OBJECTIVE: The literature suggests that lung-head ratio (LHR) and liver position may inconsistently predict outcome for congenital diaphragmatic hernia (CDH). We reviewed our inborn neonates with isolated left-sided CDH to determine whether these variables predicted survival and to estimate the optimal LHR threshold. METHODS: Prenatal LHR and liver position were obtained from 2002 to 2009. The primary endpoint was survival. RESULTS: LHR was greater in survivors after adjusting for gestational age (median 1.40 versus 0.81; p < 0.001). LHR demonstrated excellent diagnostic discrimination, with area under receiver operating characteristic (ROC) curve 0.93 (95% CI 0.86-0.99). LHR threshold of 1.0 was 83% sensitive and 91% specific in predicting survival. An optimal LHR threshold of 0.85 predicted survival with 95% sensitivity and 64% specificity, reducing false negatives (survivors with low LHR). LHR > 0.85 predicted survival after adjustment for gestational age (OR = 33.6, 95% CI = 5.4-209.5). Liver position did not predict survival. CONCLUSIONS: Prenatal LHR >0.85 predicts survival for infants with isolated left-sided CDH without compromising discrimination of survivors from non-survivors. The diagnostic utility of LHR may be confounded by gestational age at measurement. Stringent LHR threshold may minimize false-negative attribution and improve utility of this measurement as predictor of survival. PMID- 21815745 TI - Guanylyl cyclase / atrial natriuretic peptide receptor-A: role in the pathophysiology of cardiovascular regulation. AB - Atrial natriuretic factor (ANF), also known as atrial natriuretic peptide (ANP), is an endogenous and potent hypotensive hormone that elicits natriuretic, diuretic, vasorelaxant, and anti-proliferative effects, which are important in the control of blood pressure and cardiovascular events. One principal locus involved in the regulatory action of ANP and brain natriuretic peptide (BNP) is guanylyl cyclase / natriuretic peptide receptor-A (GC-A/NPRA). Studies on ANP, BNP, and their receptor, GC-A/NPRA, have greatly increased our knowledge of the control of hypertension and cardiovascular disorders. Cellular, biochemical, and molecular studies have helped to delineate the receptor function and signaling mechanisms of NPRA. Gene-targeted and transgenic mouse models have advanced our understanding of the importance of ANP, BNP, and GC-A/NPRA in disease states at the molecular level. Importantly, ANP and BNP are used as critical markers of cardiac events; however, their therapeutic potentials for the diagnosis and treatment of hypertension, heart failure, and stroke have just begun to be realized. We are now just at the initial stage of molecular therapeutics and pharmacogenomic advancement of the natriuretic peptides. More investigations should be undertaken and ongoing ones be extended in this important field. PMID- 21815748 TI - gamma-radiation induces cellular sensitivity and aberrant methylation in human tumor cell lines. AB - PURPOSE: Ionizing radiation induces cellular damage through both direct and indirect mechanisms, which may include effects from epigenetic changes. The purpose of this study was to determine the effect of ionizing radiation on DNA methylation patterns that may be associated with altered gene expression. MATERIALS AND METHODS: Sixteen human tumor cell lines originating from various cancers were initially tested for radiation sensitivity by irradiating them with gamma-radiation in vitro and subsequently, radiation sensitive and resistant cell lines were treated with different doses of a demethylating agent, 5-Aza-2' Deoxycytidine (5-aza-dC) and a chromatin modifier, Trichostatin-A (TSA). Survival of these cell lines was measured using 3-(4, 5-Dimethylthiazol- 2-yl)-2, 5 diphenyltetrazolium (MTT) and clonogenic assays. The effect of radiation on global DNA methylation was measured using reverse phase high performance liquid chromatography (RP-HPLC). The transcription response of methylated gene promoters, from cyclin-dependent kinase inhibitor 2A (p16(INK4a)) and ataxia telangiectasia mutated (ATM) genes, to radiation was measured using a luciferase reporter assay. RESULTS: gamma-radiation resistant (SiHa and MDAMB453) and sensitive (SaOS2 and WM115) tumor cell lines were examined for the relationship between radiation sensitivity and DNA methylation. Treatment of cells with 5-aza dC and TSA prior to irradiation enhanced DNA strand breaks, G2/M phase arrest, apoptosis and cell death. Exposure to gamma-radiation led to global demethylation in a time-dependent manner in tumor cells in relation to resistance and sensitivity to radiation with concomitant activation of p16(INK4a) and ATM gene promoters. CONCLUSION: These results provide important information on alterations in DNA methylation as one of the determinants of radiation effects, which may be associated with altered gene expression. Our results may help in delineating the mechanisms of radiation resistance in tumor cells, which can influence diagnosis, prognosis and eventually therapy for human cancers. PMID- 21815750 TI - Guanylin peptide family: history, interactions with ANP, and new pharmacological perspectives. AB - The guanylin family of peptides has 3 subclasses of peptides containing either 3 intramolecular disulfide bonds found in bacterial heat-stable enterotoxins (ST), or 2 disulfides observed in guanylin and uroguanylin, or a single disulfide exemplified by lymphoguanylin. These peptides bind to and activate cell-surface receptors that have intrinsic guanylate cyclase (GC) activity. These hormones are synthesized in the intestine and released both luminally and into the circulation, and are also produced within the kidney. Stimulation of renal target cells by guanylin peptides in vivo or ex vivo elicits a long-lived diuresis, natriuresis, and kaliuresis by both cGMP-dependent and independent mechanisms. Uroguanylin may act as a hormone in a novel endocrine axis linking the digestive system and kidney as well as a paracrine system intrarenally to increase sodium excretion in the postprandial period. This highly integrated and redundant mechanism allows the organism to maintain sodium balance by eliminating excess sodium in the urine. In addition, small concentrations of the atrial natriuretic peptide (ANP) can synergize with low concentrations of both guanylin or uroguanylin, which do not induce natriuresis per se, to promote significant natriuresis. Interestingly, the activation of the particulate guanylate cyclase receptors by natriuretic peptides can promote relaxation of animal and human penile erectile tissue and increase intracavernosal pressure to induce penile erection. These peptides can be prototypes for new drugs to treat erectile dysfunction, especially in patients with endothelial and nitrergic dysfunction, such as in diabetes. PMID- 21815749 TI - Vascular effects of plinabulin (NPI-2358) and the influence on tumour response when given alone or combined with radiation. AB - PURPOSE: This study investigated the anti-tumour effects of the novel vascular disrupting agent plinabulin (NPI-2358) when given alone or combined with radiation. MATERIALS AND METHODS: Foot implanted C3H mammary carcinomas or leg implanted KHT sarcomas were used, with plinabulin injected intraperitoneally. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) measurements were made with gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) on a 7-tesla magnet. Treatment response was assessed using regrowth delay (C3H tumours), clonogenic survival (KHT sarcomas) or histological estimates of necrosis for both models. RESULTS: Plinabulin (7.5 mg/kg) significantly reduced the initial area under curve (IAUC) and the transfer constant (K(trans)) within 1 hour after injection, reaching a nadir at 3 h, but returning to normal within 24 h. A dose dependent decrease in IAUC and K(trans), was seen at 3 h. No significant anti tumour effects were observed in the C3H tumours until doses of 12.5 mg/kg were achieved, but started at 1.5 mg/kg in the KHT sarcoma. Irradiating tumours 1 h after injecting plinabulin enhanced response in both models. CONCLUSIONS: Plinabulin induced a time- and dose-dependent decrease in tumour perfusion. The KHT sarcoma was more sensitive than the C3H tumour to the anti-tumour effects of plinabulin, while radiation response was enhanced in both models. PMID- 21815751 TI - Glycemic variability: measurement and utility in clinical medicine and research- one viewpoint. PMID- 21815752 TI - Autopsy and grief: a case of transformative postmortem examination. AB - BACKGROUND: A physician's obligations to deliver compassionate care do not end with a patient's death. When a patient dies there remains a responsibility to assist grieving family members. Unfortunately, many physicians feel ill prepared to assist in the bereavement process, not knowing what to say or how to say it. Although underutilized, the medical autopsy can play an important role in families' grief processes, particularly in those cases wherein uncertainties exist regarding the ultimate cause of death. DISCUSSION: Here we postulate a role for the medical autopsy in assisting families through the grief process, which we demonstrate via an illustrative case. Effective communication of these results to family members is the key to its therapeutic effect. PMID- 21815769 TI - Motif difficulty (MD): a predictive measure of problem difficulty for evolutionary algorithms using network motifs. AB - One of the major challenges in the field of evolutionary algorithms (EAs) is to characterise which kinds of problems are easy and which are not. Researchers have been attracted to predict the behaviour of EAs in different domains. We introduce fitness landscape networks (FLNs) that are formed using operators satisfying specific conditions and define a new predictive measure that we call motif difficulty (MD) for comparison-based EAs. Because it is impractical to exhaustively search the whole network, we propose a sampling technique for calculating an approximate MD measure. Extensive experiments on binary search spaces are conducted to show both the advantages and limitations of MD. Multidimensional knapsack problems (MKPs) are also used to validate the performance of approximate MD on FLNs with different topologies. The effect of two representations, namely binary and permutation, on the difficulty of MKPs is analysed. PMID- 21815770 TI - Formal analysis, hardness, and algorithms for extracting internal structure of test-based problems. AB - Problems in which some elementary entities interact with each other are common in computational intelligence. This scenario, typical for coevolving artificial life agents, learning strategies for games, and machine learning from examples, can be formalized as a test-based problem and conveniently embedded in the common conceptual framework of coevolution. In test-based problems, candidate solutions are evaluated on a number of test cases (agents, opponents, examples). It has been recently shown that every test of such problem can be regarded as a separate objective, and the whole problem as multi-objective optimization. Research on reducing the number of such objectives while preserving the relations between candidate solutions and tests led to the notions of underlying objectives and internal problem structure, which can be formalized as a coordinate system that spatially arranges candidate solutions and tests. The coordinate system that spans the minimal number of axes determines the so-called dimension of a problem and, being an inherent property of every problem, is of particular interest. In this study, we investigate in-depth the formalism of a coordinate system and its properties, relate them to properties of partially ordered sets, and design an exact algorithm for finding a minimal coordinate system. We also prove that this problem is NP-hard and come up with a heuristic which is superior to the best algorithm proposed so far. Finally, we apply the algorithms to three abstract problems and demonstrate that the dimension of the problem is typically much lower than the number of tests, and for some problems converges to the intrinsic parameter of the problem--its a priori dimension. PMID- 21815771 TI - Dietary supplementation with an extract of North American ginseng in adult and juvenile mice increases natural killer cells. AB - Cells belonging to the innate immune system are referred to as natural killer (NK) cells. We recently demonstrated that normal, pre-weaned infant mice, injected with a proprietary extract of ginseng (CVT-E002) had augmented NK cell numbers vs. sham-injected mice. In the present study, we extended these observations into juvenile and adult mice. Thus, young adult (age: 8-9 wk) C3H mice were given daily dietary CVT-E002 for 4 wk followed by untreated chow for the following 2 months, then euthanized (age: 20-21 wk). Other C3H mice (juvenile: 4-wk-old) were given CVT-E002 under the same protocol and sampled at 18 wk of age. In spite of withdrawing the extract 2 months earlier, the absolute numbers of NK cells in the young adults, remained significantly (p < 0.01), and slightly, elevated in the spleen and bone marrow (BM), respectively. The relative numbers (%) of NK cells in the blood also remained elevated (p < 0.05). In juvenile mice fed CVT-E002, the absolute numbers (spleen, BM) and % (blood) of NK cells were all elevated (p<0.01 - p<0.05). The mechanisms responsible for these super-normal numbers of NK cells long after withdrawal of CVT-E002, is as yet unknown. PMID- 21815772 TI - Inhibition of human carbonic anhydrase isozymes I, II and VI with a series of bisphenol, methoxy and bromophenol compounds. AB - Carbonic anhydrase inhibitors (CAI) are valuable molecules as they have several therapeutic applications, including anti-glaucoma activity. In this study, inhibition of three human carbonic anhydrase (hCA, EC 4.2.1.1) isozymes I, II and VI with a series of bisphenol and bromophenol derivatives was investigated. Molecular docking studies of a set of such inhibitors within CA I and II were also performed. K(I) values of the molecules 2-9 were in the range of 10.025 892.109 MUM for hCA I, 1.437-59.107 MUM for hCA II and 11.143-919.182 MUM for hCA VI, respectively. Reported inhibitory activities of molecules 2-9 will assist in better understanding of structure-activity relationship studies of CAI. PMID- 21815773 TI - A new approach to antiglaucoma drugs: carbonic anhydrase inhibitors with or without NO donating moieties. Mechanism of action and preliminary pharmacology. AB - The clinically used sulfonamide carbonic anhydrase (CA, EC 4.2.1.1) inhibitor dorzolamide (DRZ), a new sulfonamide CA inhibitor also incorporating NO-donating moieties, NCX250, and isosorbide mononitrate (ISMN) (an NO-donating compound with no CA inhibitory properties) were investigated for their intraocular pressure (IOP) lowering effects in rabbits with carbomer-induced glaucoma. NCX250 was more effective than DRZ or ISMN on lowering IOP, increasing ocular hemodynamics, decreasing the inflammatory processes and ocular apoptosis in this animal model of glaucoma. NO participate to the regulation of IOP in glaucoma, having also antiapoptotic and anti-inflammatory effects. The ophthalmic artery, both systolic and diastolic velocities, were significantly reduced in NCX250-treated eyes in comparison to DRZ treated ones, suggesting thus a beneficial effect of NCX250 on the blood supply to the optic nerve. Combining CA inhibition with NO-donating moieties in the same compound offers an excellent approach for the management of glaucoma. PMID- 21815774 TI - Metal-based new sulfonamides: Design, synthesis, antibacterial, antifungal, and cytotoxic properties. AB - Cobalt(II), copper(II), nickel(II) and zinc(II) metal complexes with 5 chlorosalicyladehyde derived Schiff base sulfonamides have been synthesized and characterized. Structure and bonding nature of all the synthesized compounds have been deduced from physical, analytical, and spectral (IR, (1)H NMR, (13)C NMR, Mass, electronic) data. An octahedral geometry has been proposed for all the metal complexes. The ligands and their metal complexes have been screened for their in vitro antibacterial, antifungal, and cytotoxic properties and results are reported. PMID- 21815775 TI - Studies on the cytotoxic, apoptotic and antitumoral effects of Au(III) and Pt(II) complexes of 1, 10-phenanthroline on V79 379A and A549 cell lines. AB - In the present study, Au(III) and Pt(II) complexes of 1, 10-phenanthroline (phen) were synthesized and used as the test compounds. The structure elucidation of the synthesized compounds was performed by IR, (1)H-NMR and MASS spectroscopic data and the results of elemental analyses. The cytotoxic and apoptotic effects of test compounds were elucidated on V79 379A (Chinese hamster lung fibroblast like) and A549 (human lung carcinoma epithelial like) cell lines. Cytotoxicity was measured with MTT assay and antitumoral effect was determined by colony forming ability methods. In addition, nuclear fragmentation and activation of apoptotic enzyme (caspase-3) and DAPI staining were used to detect the apoptotic effect of the compounds. All the test compounds induced time and concentration-dependent cytotoxic and antitumoral effects. Significant increases in the levels of apoptosis were observed with increasing exposure concentration. PMID- 21815776 TI - T cell immunity and vaccines against invasive fungal diseases. AB - Over the past two decades much has been learned about the immunology of invasive fungal infection, especially invasive candidiasis and invasive aspergillosis. Although quite different in their pathogenesis, the major common protective host response is Th1 mediated. It is through Th1 cytokine production that the effector cells, phagocytes, are activated to kill the fungus. A more thorough understanding of the pathogenesis of disease, the elicited protective Th1 immune response, the T cell antigen(s) which elicit this response, and the mechanism(s) whereby one can enhance, reconstitute, or circumvent the immunosuppressed state will, hopefully, lead to the development of a vaccine(s) capable of protecting even the most immunocompromised of hosts. PMID- 21815777 TI - Prognostic significance of neuron-specific enolase in patients with diffuse large B-cell lymphoma treated with rituximab-based immunochemotherapy. AB - The present study examined the clinical significance of serum neuron-specific enolase (NSE) in patients with diffuse large B-cell lymphoma (DLBCL). Serum NSE values were measured using a electrochemiluminescence assay in 106 patients and tissue NSE expression was examined using immunohistochemistry in 65 patients. Fifty-four percent of patients had a positive expression of serum NSE (>15.20 ng/mL), and cytoplasmic NSE was pathologically demonstrated in 26/65 cases, which showed a positive correlation with that of serum NSE expression. The serum NSE value was closely correlated with performance status, serum lactate dehydrogenase (LDH) level, International Prognostic Index (IPI) score, and Ann Arbor stage, and declined significantly in patients who responded to treatment. In the rituximab immunochemotherapy group, there was a significant difference in the 5-year overall survival (OS) rate between the NSE-positive and -negative groups (93% vs. 44%, p = 0.001), and the serum NSE level was found to be an independent prognostic factor. Serum NSE may be a novel marker of disease aggressiveness as well as a prognostic factor for DLBCL in the era of rituximab. PMID- 21815778 TI - Designer natriuretic peptides: a vision for the future of heart failure therapeutics. AB - Despite recent pharmacological advances in heart failure therapy, mortality from acute decompensated heart failure remains high. Conventional therapies are often insufficient to address the complex interplay between structural, functional, neurohumoral, and renal mechanisms involved in the heart failure syndrome. The natriuretic peptide system, however, offers a unique pleiotropic strategy which could bridge this gap in heart failure therapy. Exogenous administration of native A-type and B-type natriuretic peptides has been met with both success and limitations, and despite the limitations, remains a worthwhile endeavor. Alternatively, synthetic modification to create "designer" chimeric peptides holds the possibility to extend both the application and therapeutic benefits possible with a natriuretic peptide based approach. Herein we describe the development of natriuretic peptide based heart failure therapies, including the design, rationale, and preliminary studies of the novel chimeric peptides CD-NP and CU-NP. PMID- 21815779 TI - Body image as a mediator of the relationship between body mass index and weight related quality of life in black women. AB - BACKGROUND: Body image (BI) may be important in understanding weight-related attitudes and behaviors in black women. Specifically, body dissatisfaction may mediate the relationship between body mass index (BMI) and weight-related quality of life (QOL) in black women. We examined the relationship between BMI and weight related QOL in black women and tested for mediation by body dissatisfaction. METHODS: The sample included 149 black women recruited from Birmingham, Alabama, for a one-time clinic visit. BIs were self-reported using the Pulvers figure rating scale. Body discrepancy (BD), a surrogate measure of body dissatisfaction, was calculated as perceived current image minus ideal image. QOL was self reported using the Impact of Weight on Quality of Life-Lite (IWQOL-Lite). Baron and Kenny's test for mediation was conducted where BMI was the predictor, IWQOL Lite score was the outcome, and BD was the mediator under investigation. RESULTS: Mean age was 40.5 years, and mean BMI was 36.1 kg/m(2). The mean IWQOL-Lite score was 81.1+/-15.8 out of 100. Participants had a BD score of 2.3, indicating a desire to be two figure sizes smaller than their current perceived body size. Tests for mediation revealed that BD partially mediated the relationship between BMI and IWQOL-Lite scores in this sample. CONCLUSIONS: BD was in the pathway of the association between BMI and IWQOL-Lite scores. BI dissatisfaction may contribute to explaining more about black women's weight-related QOL beyond actual BMI alone. Additional research is needed to better understand black women's perception of weight and subsequent weight-related behaviors. PMID- 21815781 TI - Recent success in the discovery of coronary artery disease genes. AB - For more than 50 years, epidemiological studies have indicated that genetic predisposition accounts for approximately 50% of the susceptibility to coronary artery disease (CAD) and its sequelae, including myocardial infarction. Since common diseases such as CAD are caused by multiple genes, the age-old method of linkage analysis used to map monogenic Mendelian disorders in families unfortunately lacks the required sensitivity. The technology to identify genes predisposing individuals to CAD and other common diseases did not become available until 2005. This technology provided computerized arrays containing hundreds of thousands of DNA markers in the form of single-nucleotide polymorphisms (SNPs). This made it possible to pursue an unbiased approach referred to as genome-wide association studies. The first gene for CAD was simultaneously identified by 2 independent groups in 2007. In a very short interval, a total of 23 loci were mapped that were linked to increased risk for CAD. The results of these studies confirm that CAD is caused by multiple genes, each contributing minimal risk. The most exciting and novel findings are that these loci do not act through known risk factors for CAD and that the loci are more likely to be in DNA regions that regulate transcription rather than being in coding regions for protein. PMID- 21815780 TI - Effects of isotretinoin on obsessive compulsive symptoms, depression, and anxiety in patients with acne vulgaris. AB - BACKGROUND: Depression, anxiety, and obsessive compulsive symptoms are known to be common among patients with acne vulgaris. In contrast to earlier reports, a number of recent studies suggested isotretinoin to be beneficial for depression and anxiety symptoms in acne patients. Moreover, its effects on obsessive compulsive symptomatology are still widely unknown. OBJECTIVES: To examine the effects of isotretinoin treatment on obsessive compulsive symptoms, depression, and anxiety in acne vulgaris patients. METHODS: The Hospital Anxiety and Depression Scale, Maudsley Obsessive Compulsive Questionnaire, and Sheehan Disability Scale were administered to 43 patients with acne vulgaris who accepted isotretinoin treatment and agreed to participate in the study. Severity of acne was evaluated with Global Acne Grading System. Thirty-three patients completed 6 months treatment with oral isotretinoin at 0.5-1.0 mg/kg daily doses. Measurements were repeated at the end of 6 months. RESULTS: Depression, anxiety, and obsessive rumination symptoms were significantly improved after isotretinoin treatment. On the other hand, obsessive doubting of acne patients was worse at the end of the treatment. There was no significant change in disease related disability of patients. CONCLUSION: Besides worsening of obsessive doubting, successful treatment with oral isotretinoin seems to be related with improvement in depression, anxiety, and obsessive rumination symptoms in acne vulgaris patients. These changes were not reflected in the disability level that acne patients have reported. PMID- 21815782 TI - Ginseng aqueous extract attenuates the production of virulence factors, stimulates twitching and adhesion, and eradicates biofilms of Pseudomonas aeruginosa. AB - This study was carried out to examine the antimicrobial activity of the aqueous extract of Panax quinquefolius from North American ginseng (NAGE) root against Pseudomonas aeruginosa . The minimum inhibitory concentrations of reference and clinical isolates of Pseudomonas aeruginosa were measured by a standard agar dilution method. At subinhibitory NAGE concentrations, the secretion of virulence factors, motility on agar, and adhesion to 96-well microplates were studied on the nonmucoid Pseudomonas aeruginosa O1 strain. At suprainhibitory concentrations, the activity of NAGE against mature biofilm complexes formed in the Calgary Biofilm Device and the Stovall flow cell were assessed. NAGE possessed an antibacterial activity against all the Pseudomonas aeruginosa strains at 1.25%-2.5% w/v. NAGE also significantly attenuated pyocyanin, pyoverdine, and lipase concentrations, stimulated twitching, and attenuated swarming and swimming motility. At 1.25% w/v, NAGE augmented adhesion, and at 5% w/v detached 1-day-old biofilms in microplates. The extract also eradicated 6-day old mature biofilms (5% w/v), and fluorescence microscopy displayed a reduction of live cells and biofilm complexes compared with nontreated biofilms. These data suggest that the aqueous extract from North American ginseng possesses antimicrobial activities in vitro. PMID- 21815783 TI - No evidence for a cumulative impact effect on concussion injury threshold. AB - Recent studies using a helmet-based accelerometer system (Head Impact Telemetry System [HITS]) have demonstrated that concussions result from a wide range of head impact magnitudes. Variability in concussion thresholds has been proposed to result from the cumulative effect of non-concussive head impacts prior to injury. We used the HITS to collect biomechanical data representing >100,000 head impacts in 95 high school football players over 4 years. The cumulative impact histories prior to 20 concussive impacts in 19 athletes were compared to the cumulative impact histories prior to the three largest magnitude non-concussive head impacts in the same athletes. No differences were present in any impact history variable between the concussive and non-concussive high magnitude impacts. These analyses included the number of head impacts, cumulative HIT severity profile value, cumulative linear acceleration, and cumulative rotational acceleration during the same practice or game session, as well as over the 30 min and 1 week preceding these impacts. Our data do not support the proposal that impact volume or intensity influence concussion threshold in high school football athletes. PMID- 21815784 TI - Delayed anti-nogo-a antibody application after spinal cord injury shows progressive loss of responsiveness. AB - Blocking the function of the myelin protein Nogo-A or its signaling pathway is a promising method to overcome an important neurite growth inhibitory factor of the adult central nervous system (CNS), and to enhance axonal regeneration and plasticity after brain or spinal cord injuries. Several studies have shown increased axonal regeneration and enhanced compensatory sprouting, along with substantially improved functional recovery after treatment with anti-Nogo-A antibodies, Nogo-receptor antagonists, or inhibition of the downstream mediator RhoA/ROCK in adult rodents. Proof-of-concept studies in spinal cord-injured macaque monkeys with anti-Nogo-A antibodies have replicated these findings; recently, clinical trials in spinal cord-injured patients have begun. However, the optimal time window for successful Nogo-A function blocking treatments has not yet been determined. We studied the effect of acute as well as 1- or 2-weeks delayed intrathecal anti-Nogo-A antibody infusions on the regeneration of corticospinal tract (CST) axons and the recovery of motor function after large but anatomically incomplete thoracic spinal cord injuries in adult rats. We found that lesioned CST fibers regenerated over several millimeters after acute or 1 week-delayed treatments, but not when the antibody treatment was started with a delay of 2 weeks. Swimming and narrow beam crossing recovered well in rats treated acutely or with a 1-week delay with anti-Nogo-A antibodies, but not in the 2-week-delayed group. These results show that the time frame for treatment of spinal cord lesions with anti-Nogo-A antibodies is restricted to less than 2 weeks in adult rodents. PMID- 21815785 TI - Impact of GOS misclassification on ordinal outcome analysis of traumatic brain injury clinical trials. AB - This study extends our previous investigation regarding the effect of nondifferential dichotomous Glasgow Outcome Scale (GOS) misclassification in traumatic brain injury (TBI) clinical trials to the effect of GOS misclassification on ordinal analysis in TBI clinical trials. The impact of GOS misclassification and ordinal outcome analysis was explored via probabilistic sensitivity analyses using TBI patient datasets from the IMPACT database (n = 9205). Three patterns of misclassification were explored given the pre-specified misclassification distributions. For the random pattern, we specified a trapezoidal distribution (minimum: 80%, mode: 85%, and 95%, maximum: 100%) for both sensitivity and specificity; for the upward pattern, the same trapezoidal distribution for sensitivity but with a perfect specificity; and for the downward pattern, the same trapezoidal distribution for specificity but with a perfect sensitivity. The conventional 95% confidence intervals and simulation intervals, which accounts for the misclassification and random errors together, were reported. The results showed that given the specified misclassification distributions, the misclassification with a random or upward pattern would have caused a slightly underestimated outcome in the observed data. However, the misclassification with a downward pattern would have resulted in an inflated estimation. Thus the sensitivity analysis suggests that the nondifferential misclassification can cause uncertainties on the primary outcome estimation in TBI trials. However, such an effect is likely to be small when ordinal analysis is applied, compared with the impact of dichotomous GOS misclassifications. The result underlines that the ordinal GOS analysis may gain from both statistical efficiency, as suggested by several recent studies, and a relatively smaller impact from misclassification as compared with conventional binary GOS analysis. PMID- 21815788 TI - Self-retaining barbed suture for parenchymal repair during minimally invasive partial nephrectomy. AB - A secure and hemostatic renorrhaphy is the primary challenge of minimally invasive nephron-sparing surgery (MINSS). The laparoscopic surgeon's ability to maintain constant tension on the suture while oversewing the transected parenchyma and collecting system is difficult, even when using robotic technology. A self-retaining barbed suture (SRBS) is a recent innovation that maintains tissue apposition and tension using a novel "self-cinching" mechanism. We describe our technique for SRBS use during MINSS. In our experience, the use of SRBS in this setting is safe and improves suturing efficiency during the time constraint of warm ischemia. We believe that intracorporeal suturing with SRBS during MINSS may help shorten the learning curve associated with this technically challenging step and have adopted it in our standard practice. PMID- 21815786 TI - Effects of nicotine administration on striatal dopamine signaling after traumatic brain injury in rats. AB - Previous studies on the therapeutic potential of agents affecting the dopamine system in traumatic brain injury (TBI) suggest that dopamine dysregulation may have a major role in behavioral deficit after TBI. We have previously identified that TBI reduces striatal dopamine synthesis and release at 7 days post-injury. In order to reverse deficits in the activity of tyrosine hydroxylase and dopamine release following TBI, we administered nicotine by intraperitoneal injection into rats for 7 days. Tyrosine hydroxylase activity assay demonstrated recovery of activity with nicotine treatment in injured animals. Microdialysis experiments using potassium stimulation to induce dopamine release showed recovery of dopamine release in injured animals receiving nicotine treatment. There was no effect of nicotine injection on extracellular dopamine metabolite levels, indicating the specificity of nicotine's effect on dopamine synthesis and release. Also, the activation of downstream postsynaptic molecule dopamine and cAMP regulated phosphoprotein 32 (DARPP-32) was assessed by Western blots for DARPP-32 phosphorylated at threonine 34 (pDARPP-32-T34). Injury reduced pDARPP-32 T34 levels, but nicotine treatment of injured animals did not alter pDARPP-32-T34 levels, indicating that postsynaptic dopamine signaling is complex, and the recovery of dopamine release may not be sufficient for the recovery of DARPP-32 activity. PMID- 21815791 TI - Variables that influence operative time during percutaneous nephrolithotomy: an analysis of 1897 cases. AB - BACKGROUND AND PURPOSE: Operative time is an important perioperative factor and is related to postoperative complications and procedural cost-effectiveness. There are few studies, however, investigating factors that affect operative time during percutaneous nephrolithotomy (PCNL). In this study, patient and kidney stone-related factors that influence operative time were analyzed. MATERIALS AND METHODS: Clinical records from 1897 patients with renal calculi who underwent PCNL were retrospectively reviewed, and these patients were divided into two groups based on their median operative time (group 1: <=60 min; group 2: >60 min). Multivariate analyses as well as univariate analyses including chi-square, Fisher exact and Mann Whitney U tests were used to investigate the effects of independent variables on operative time, including patient and kidney stone related factors such as age, sex, body mass index, history of ipsilateral open surgery, shockwave lithotripsy, presence of hydronephrosis, stone burden, stone type and opacity, and surgical experience. RESULTS: The mean operative time was 64.9+/-27.6 minutes (range 10-220 min). Univariate analyses determined that a history of open surgery, presence of hydronephrosis, stone type and size, and surgical experience correlated with operative time (P<0.05 for all). Multivariate analyses revealed that presence of hydronephrosis (odds ratio [OR]: 1.44, 95% confidence interval [CI]: 1.17-1.78, P=0.002), stone type (OR: 2.12, 95% CI: 1.69 2.70, P<0.0001), stone burden (OR: 2.44, 95% CI: 1.85-3.12, P<0.0001), and surgical experience (OR: 0.56, 95% CI: 0.46-0.70, P<0.0001) were significant independent factors in influencing operative time. CONCLUSIONS: Presence of hydronephrosis, renal stone size and type significantly affect the operative time during PCNL. The duration of the operation was also observed to decrease with increased surgical experience. PMID- 21815793 TI - Long-term comparative outcomes of open versus laparoscopic nephroureterectomy for upper urinary tract urothelial-cell carcinoma after a median follow-up of 13 years*. AB - BACKGROUND AND PURPOSE: Open nephroureterectomy (ONU) rather than laparoscopic nephroureterectomy (LNU) is still regarded as the standard of care for extirpative surgical management of upper urinary tract urothelial-cell carcinoma (UUT-UCC). The longest published follow-up of LNU is 7 years. We report outcomes for patients having surgery >=10 years ago. PATIENTS AND METHODS: Consecutive patients with UUT-UCC who were treated with ONU (n=39) or LNU (n=23) between April 1992 to September 2000 were included. Preoperative, tumor, operative and postoperative characteristics, recurrence, and outcomes were collated. Survival was estimated using the Kaplan-Meier method. RESULTS: Median follow-up of censored patients was 163 months (13.6 y). Estimated mean overall survival (OS) was 111 months for ONU and 103 months for LNU. Mean progression free survival (PFS) was 175 months for ONU and 143 months for LNU. Probability of PFS at 10 years was 79% for ONU and 76% for LNU and was unchanged at 15 years. There was no significant difference between ONU and LNU in terms of OS (P=0.51, log-rank test), PFS (P=0.70) or cancer-specific survival (CSS; P=0.43). There were no prognostic differences between ONU and LNU after correcting for confounding variables. There was no increase in the probability of a bladder cancer recurrence from 10 to 15 years postoperation. CONCLUSION: Long-term follow-up of patients who were operated on more than 10 years ago suggests that LNU has oncologic equivalence to ONU because there were no significant differences in OS, PFS, or CSS between ONU and LNU patients followed for a median of 13 years. PMID- 21815792 TI - Preoperative and intraoperative observations may differ during laparoscopic nephron-sparing surgery. AB - PURPOSE: We retrospectively reviewed the preoperative radiologic findings and operational videos of a group of patients who were undergoing laparoscopic nephron-sparing surgery (NSS), to determine whether we should decide the operational approach (laparoscopic vs open or radical nephrectomy) on the basis of only the preoperative aspects and dimensions used for an anatomic (PADUA) classification. PATIENTS AND METHODS: In total, 41 laparoscopic NSS operations were performed during a 34-month period for suspicious solid renal lesions. Clinicopathologic variables, PADUA scores, operative parameters, and renal functional outcomes were prospectively recorded and analyzed. Meanwhile, a similar classification (intraoperative aspects and dimensions used for an anatomic [IADUA] classification) was used to compare the preoperative imaging modality findings with intraoperative findings. RESULTS: There was a 73.2% difference between PADUA and IADUA scores. Sixteen (39%) patients had PADUA scores >IADUA scores, 14 (34%) had PADUA scores 4 times compared with those with <=4 times but with no statistical significance. Regarding other risk factors, it was noted that the frequency of mutations among cases with no or just one risk factor did not differ significantly from those having two or more risk factors (p=0.98). CONCLUSIONS: Mutations related to the MTHFR gene are increased but not statistically significant in Egyptian women with unexplained pregnancy loss. Interaction with other genetic variants might be speculated and need to be investigated. PMID- 21815802 TI - Increasing the pore size of electrospun scaffolds. AB - Electrospinning has gained much attention in the past decade as an effective means of generating nano- to micro-scale polymer fibers that resemble native extracellular matrix. High porosity, pore interconnectivity, and large surface area to volume ratio of electrospun scaffolds make them highly conducive to cellular adhesion and growth. However, inherently small pores of electrospun scaffolds do not promote adequate cellular infiltration and tissue ingrowth. Cellular infiltration into the scaffold is essential for a range of tissue engineering applications and is particularly important in skin and musculoskeletal engineering. Pore size, porosity, and pore interconnectivity dictate the extent of cellular infiltration and tissue ingrowth into the scaffold; influence a range of cellular processes; and are crucial for diffusion of nutrients, metabolites, and waste products. A number of electrospinning techniques and postelectrospinning modifications have, therefore, been developed in order to increase the pore size of electrospun scaffolds. Diverse techniques ranging from simple variations in the electrospinning parameters to complex methodologies requiring highly specialized equipment have been explored and are described in this article. PMID- 21815803 TI - Fibroblast growth factor-2-overexpressing myoblasts encapsulated in alginate spheres increase proliferation, reduce apoptosis, induce adipogenesis, and enhance regeneration following skeletal muscle injury in rats. AB - The fibroblast growth factor 2 (FGF-2) is known as pleiotropic cytokine with myoblast proliferative properties. In the present study, we tested the hypothesis that gene transfer of human FGF-2 via transplantation of genetically modified L8 myoblast encapsulated in alginate modulates the skeletal muscle recovery after crush injury in Wistar rats. Therefore, we performed a crush injury to the soleus muscle and transplanted alginate spheres containing myoblasts genetically modified to overexpress human FGF-2 (FGF-2) or a luciferase (LUC) cDNA at the site of injury. Animals that underwent muscle injury without transplantation of alginate spheres served as control (control). At day 4 after trauma the FGF-2 group showed significant higher mean values of cell proliferation (bromodeoxyuridine immunohistochemistry) and significant lower values of cell apoptosis (terminal deoxynucleotidyl transferase nick end labeling histology) compared to animals receiving luciferase-overexpressing myoblasts. At the same time point adiponectin expression (ACRP30 immunohistochemistry) was increased in the FGF-2 group exclusively. The p75(NTR) expression (p75(NTR) immunohistochemistry) significantly improved in both the FGF-2 and LUC group compared to the control group. Functional analysis of the injured muscle did not reveal a significant increase of the muscle force in the FGF-2 group compared to the control and LUC group 14 days after injury. In vitro analysis for 14 days of the FGF-2-modified spheres demonstrated at day 7 and day 14 a significant increase of the relative cell count as well as of the relative viable cell count in the FGF-2 myoblast spheres compared to luciferase myoblast spheres. Additionally, the expression of FGF-2 (enzyme-linked immunosorbent assay analysis) and luciferase (chemiluminescence analysis) persisted in vitro for 4 and 14 days, respectively. These results demonstrate that FGF-2-overexpressing myoblasts cannot considerably improve muscle strength but are able to modulate the proliferation as well as the apoptosis of injured muscle tissue mainly by conducting adipogenesis. PMID- 21815804 TI - Effect of body mass index on perioperative outcomes for laparoscopic partial nephrectomy. AB - BACKGROUND AND PURPOSE: Obesity is becoming an increasing problem and is associated with increased incidence of renal-cell carcinoma. We sought to assess the impact of obesity on outcomes of laparoscopic partial nephrectomy for renal masses. PATIENTS AND METHODS: We retrospectively reviewed the pathologic and clinical outcomes from January 2004 through August 2010 of consecutive partial nephrectomies that were performed at a single institution. Patients were segregated according to preoperative body mass index (BMI), and outcomes were compared. RESULTS: Seventy-eight nonobese (BMI<30), 24 obese (BMI 30-35), and 24 morbidly obese (BMI>35) patients were identified. Obese patients were significantly more likely to be female (66% >35 vs 32% <30). Other baseline characteristics were similar. There was a significant relationship between estimated blood loss (P=0.03) and increasing BMI when compared as a trend. No significant differences were observed in regard to operative time, transfusion rate, complications, or surgical margin status between groups. CONCLUSION: Laparoscopic partial nephrectomy can be safely performed in obese patients without significant expected difference in outcomes. PMID- 21815805 TI - Evaluation of bioimpedance as novel predictor of extracorporeal shockwave lithotripsy success. AB - BACKGROUND AND PURPOSE: Obesity has been identified as a limitation of extracorporeal shockwave lithotripsy (SWL). The obesity metrics of body mass index (BMI) and skin-to-stone distance (SSD) have been evaluated as predictors of SWL success. While SSD has demonstrated a strong correlation with success, BMI has not. Bioimpedance analysis (BIA) is an accurate way of determining body adiposity. We evaluated fat mass percentage (FMP) as measured by BIA as a predictor of SWL success. PATIENTS AND METHODS: We prospectively collected body composition data using the Imp-DF50 Body Impedance Analyzer on consecutive patients undergoing SWL. All generated variables, including FMP, along with demographics, BMI, stone size, and stone composition, were analyzed. Patients were evaluated for success, defined as no evidence of stones on radiography of the kidneys, ureters, and bladder at follow-up. RESULTS: Fifty-two consecutive patients were enrolled in the study, of which 37 had the necessary metrics to be included in the analysis. Twenty-three (62.2%) patients were stone free while 14 (37.8%) were found to have residual stone at follow-up. There was no difference in sex, stone laterality, mean age, and stone size between the groups. For the success and failure groups, the mean BMI was 25.8 kg/m(2) and 29.8 kg/m(2) (P=0.0091), and mean FMP 24.6% and 32.2% (P=0.0034). On mirrored multivariable analysis, both BMI (OR=0.735, P=0.026) and FMP (OR=0.806, P=0.010) were associated with success. Patients with a FMP >=35% had a reduced success rate compared with those with a FMP <35% (14% vs 73%, respectively, P=0.0028). CONCLUSIONS: Both BMI and FMP both appear to be independent predictors of success. Based on these findings, a large study examining the relationship between BMI, FMP, SSD, and SWL success is warranted. A preoperative FMP >=35% is associated with a 14% success rate, and alternative treatment strategies for urolithiasis should be considered. PMID- 21815806 TI - Safe and effective obtainment of access for percutaneous nephrolithotomy by urologists: the Louisiana State University experience. AB - BACKGROUND AND PURPOSE: Access for percutaneous nephrolithotomy (PCNL) is critical to successful removal of stone burden and is often performed by a specialist other than a urologist. In many regions, however, there is limited availability of such personnel. We reviewed the complication rates that were related to PCNL access when performed at a teaching hospital to establish that access for PCNL may be safely taught to and performed by urology residents. Chief urology residents across the nation were also anonymously surveyed to better understand the current trends and dynamics regarding PCNL access in teaching institutions. PATIENTS AND METHODS: A retrospective chart review was performed of all PCNLs performed at our institution from 1995 to 2009 for any complications that were related to surgery. Patients with access gained at outside institutions or not attempted at the time of surgery by residents were excluded. The complication rate was compared with those of the American College of Radiology. An eight-question survey was also sent by e-mail to all current urology chief residents regarding their experience with PCNL access during residency. RESULTS: A total of 290 patients underwent PCNL with 338 separate access sites gained at the time of surgery under the supervision of nine teaching staff. Access was gained in all cases at the time of surgery. Major complications included: Transfusion in 20 (5.9%) patients, sepsis in 2 (0.6%) patients, pseudoaneurysm necessitating intervention in 2 (0.6%) patients, hydrothorax in 2 (0.6%) patients, pneuomothorax in 1 (0.3%) patient, ureteropelvic junction disruption in 1 (0.3%) patient, and one death (0.3%) after surgery. Minor complications included: Urinary tract infection in five (1.5%) patients, and collecting system injuries in 6 (1.8%) patients necessitating placement of a ureteral stent. Our survey of residents demonstrated that 53% did not routinely gain access for PCNL at their institution. The 94% who did not get instruction on PCNL access, however, thought it would be a valuable addition to their training. CONCLUSION: Our results show that access for PCNL surgery can be safely and successfully obtained by genitourinary residents under the supervision of trained staff at the time of surgery. We think that access for PCNL is a valuable tool that should be in the armamentarium of all urologic surgeons on leaving an accredited urology training program. PMID- 21815807 TI - Histotripsy homogenization of the prostate: thresholds for cavitation damage of periprostatic structures. AB - BACKGROUND AND PURPOSE: Histotripsy is a noninvasive, pulsed ultrasound technology that produces mechanically homogenized tissue within targeted volumes. Previous work has demonstrated prostatic tissue debulking in a canine model. The aim was to establish safety thresholds by evaluating histologic changes of urinary sphincter, neurovascular bundle (NVB), and rectum after targeted histotripsy treatment of these critical structures. MATERIALS AND METHODS: Rectum, urinary sphincter, and NVB in five anesthetized canines were targeted for histotripsy treatment (50 total points). Locations received 1k, 10k, or 100k acoustic pulses (4 microsecond, 1 MHz) at a repetition frequency of 500 Hz. Canine subjects were euthanized immediately (2), survived 3 days (1), or 2 weeks (3) after treatment. Prostates, periprostatic tissue, and rectum were harvested and processed for histology. RESULTS: The sphincter was structurally intact with minimal muscle fiber disruption even after 100k pulses (n=10). Undamaged nerves, arteries, and veins of the NVB were seen despite mechanical homogenization of surrounding loose connective tissue (n=19). The rectum, however, exhibited dose dependent damage (n=20). 1k pulses yielded mild submucosal hemorrhage. 10k pulses resulted in moderate collagen disruption and focal mucosal homogenization. 100k pulses produced damage to the mucosa and muscularis propria with extensive hemorrhage and collagen disruption. One canine treated with 100k pulses needed early euthanasia (day 3) because of complications from a urine leak. CONCLUSIONS: Histotripsy histologic tissue effect varied based on targeted structure with substantial structural preservation of NVB and sphincter. Rectal subclinical damage was apparent after 1k pulses and increased in extent and severity with escalating doses. Future work will include assessment of functional outcomes and refinement of these initial safety thresholds. PMID- 21815808 TI - Impact of repeated hilar clamping on renal function during laparoscopic and robot assisted partial nephrectomy. AB - BACKGROUND AND PURPOSE: Conventional wisdom and small animal studies suggest repeated hilar clamping during partial nephrectomy is deleterious to renal function. We describe the impact of repeated renal hilar clamping during laparoscopic partial nephrectomy (LPN) and robot-assisted partial nephrectomy (RPN) on the overall function of the operated kidney. PATIENTS AND METHODS: A retrospective analysis of all patients undergoing RPN or LPN with repeated hilar clamping was performed. Patient and tumor characteristics were recorded. All patients had preoperative and postoperative mercaptoacetyltriglycine (MAG)3 renal scans, and the change in function was calculated. Change in glomerular filtration rate (GFR) was calculated with the modified Modification of Diet in Renal Disease equation as well. RESULTS: Seven patients were studied with an average age of 60 and a body mass index of 32. Tumors averaged 3.6 cm, and there were four and three right- and left-sided tumors, respectively. The reasons for repeated clamping were bleeding in three patients and either gross or microscopic positive margins in four patients, all of whom had repeated resection. The average initial clamp time was 20 minutes, and the average reclamp time was 12 minutes. The average operative time was 185 minutes. and average blood loss was 171 mL. All renal units were functioning postoperatively. The average change in absolute renal function on the operated kidney was -4.9%, and the relative loss of function was -10%, both measured on MAG3 scan. The average GFR before surgery was 61.4 (mL/min/1.73m(2)); after surgery, the average GFR was 57.1 (mL/min/1.73m(2)), for an average loss of -7%. The range of change in GFR was from 0% to -23%. CONCLUSIONS: Although not optimal, repeated clamping of the renal hilum during partial nephrectomy to control bleeding or to obtain a clear surgical margin is associated with minimal loss of renal function. PMID- 21815809 TI - Simple method to predict return of continence after robot-assisted radical prostatectomy. AB - BACKGROUND AND PURPOSE: After removal of the Foley catheter after robot-assisted radical prostatectomy (RARP), recovery of continence can take days to months. We sought to identify a simple means to predict time to recovery of postoperative continence. PATIENTS AND METHODS: Preoperative characteristics on 172 men who were undergoing RARP were entered into an electronic database. All men were queried via telephone and/or returned a 7-day log of pad use. Men without need for pads were excluded (n=41). At 4 to 7 days, responses were grouped as: one pad (n=55), two pads (n=35), or three or more pads (n=41). Patients returned self addressed postcards noting the date of 0-pad urinary status. Univariate and multivariate analysis of variables were assessed for ability to predict time to continence. RESULTS: No preoperative factors, such as age, International Index of Erectile Function-5, prostate-specific antigen level, American Urological Association symptom score, body mass index, uroflowmetry, nerve-sparing status, estimated blood loss, or prostate weight, were found to predict time to continence. Pad use at 4 to 7 days, however, was highly correlated with median time to continence. The median time to continence for men using one pad was 35 days, two pads was 42 days, and for three or more pads was 73 days (P=0.0001). CONCLUSIONS: As has been previously reported, we found no reliable baseline factors that predicted postoperative time to 0-pad continence. We did find that determining pad usage at 4 to 7 days after catheter removal strongly predicted time to pad-free continence. This method is simpler then pad weights, predicts high- and low-risk men for delayed continence, and can be used for counseling/intervention. PMID- 21815810 TI - Ethnic disparities in metabolic syndrome in malaysia: an analysis by risk factors. AB - BACKGROUND: This study investigates ethnic disparities in metabolic syndrome in Malaysia. METHODS: Data were obtained from the Malaysia Non-Communicable Disease Surveillance-1 (2005/2006). Logistic regressions of metabolic syndrome health risks on sociodemographic and health-lifestyle factors were conducted using a multiracial (Malay, Chinese, and Indian and other ethnic groups) sample of 2,366 individuals. RESULTS: Among both males and females, the prevalence of metabolic syndrome amongst Indians was larger compared to both Malays and Chinese because Indians are more likely to exhibit central obesity, elevated fasting blood glucose, and low high-density lipoprotein cholesterol. We also found that Indians tend to engage in less physical activity and consume fewer fruits and vegetables than Malays and Chinese. Although education and family history of chronic disease are associated with metabolic syndrome status, differences in socioeconomic attributes do not explain ethnic disparities in metabolic syndrome incidence. The difference in metabolic syndrome prevalence between Chinese and Malays was not statistically significant. Whereas both groups exhibited similar obesity rates, ethnic Chinese were less likely to suffer from high fasting blood glucose. CONCLUSIONS: Metabolic syndrome disproportionately affects Indians in Malaysia. Additionally, fasting blood glucose rates differ dramatically amongst ethnic groups. Attempts to decrease health disparities among ethnic groups in Malaysia will require greater attention to improving the metabolic health of Malays, especially Indians, by encouraging healthful lifestyle changes. PMID- 21815811 TI - The top five "game changers" in vaccinology: toward rational and directed vaccine development. AB - Despite the tremendous success of the classical "isolate, inactivate, and inject" approach to vaccine development, new breakthroughs in vaccine research are increasingly reliant on novel approaches that incorporate cutting edge technology and advances in innate and adaptive immunology, microbiology, virology, pathogen biology, genetics, bioinformatics, and many other disciplines in order to: (1) deepen our understanding of the key biological processes that lead to protective immunity, (2) observe vaccine responses on a global, systems level, and (3) directly apply the new knowledge gained to the development of next-generation vaccines with improved safety profiles, enhanced efficacy, and even targeted utility in select populations. Here we highlight five key components foundational to vaccinomics efforts: applied immunogenomics, next generation sequencing and other cutting-edge "omics" technologies, advanced bioinformatics and analysis techniques, and finally, systems biology applied to immune profiling and vaccine responses. We believe these "game changers" will play a critical role in moving us toward the rational and directed development of new vaccines in the 21st century. PMID- 21815812 TI - Patterns of third-molar agenesis in an orthodontic patient population with different skeletal malocclusions. AB - OBJECTIVE: To examine the relationship between third-molar agenesis and different skeletal malocclusion patterns. MATERIALS AND METHODS: Pretreatment records of 1046 orthodontic patients (aged 13-17 years; mean age, 14.07 +/- 1.27) were used. Third-molar agenesis was calculated with respect to genders, number of missing teeth, jaws, and skeletal malocclusion patterns. The Pearson chi-square test was performed to determine potential differences. RESULTS: Among the 1046 subjects, 237 subjects were diagnosed with third-molar agenesis (22.7%) with no statistical gender difference (P > .05). It was more common in the maxilla than in the mandible or in both jaws (P < .01). The prevalence of patients with a third-molar agenesis was the most commonly found type (P < .001). The prevalence of third molar agenesis in those with a Class III malocclusion was significantly higher than in those with Class I or Class II (P < .05). However, there was similar prevalence among the hyper-divergent (24.5%), normal (23.8%), and hypo-divergent (19.2%) groups (P > .05). CONCLUSION: These results suggest that agenesis of the third molar does not depend on vertical patterns of the skeletal malocclusions, but does depend on sagittal skeletal malocclusions in this orthodontic patient population. PMID- 21815813 TI - Liver X receptor protects against liver injury in sepsis caused by rodent cecal ligation and puncture. AB - BACKGROUND: Liver X receptor (LXR) is a transcription factor of the nuclear receptor family, regulating genes involved in metabolism, inflammation, and apoptosis. In the present investigation, we examined the role of LXR in organ injury and systemic inflammation in rodent models of polymicrobial peritonitis caused by cecal ligation and puncture (CLP). METHODS: Rats were subjected to CLP sepsis or a sham operation. Some were treated with the synthetic LXR agonist GW3965 0.3 mg/kg 30 min prior to the CLP procedure, and organs and plasma were harvested at 3, 10, 18, or 24 h. Organs were analyzed for RNA expression by quantitative polymerase chain reaction or for morphologic differences by histologic review. Organ injury and inflammatory markers were measured in plasma. RESULTS: Expression of the LXRalpha gene was decreased in the livers of CLP rats compared with sham-operated rats. Administration of a synthetic agonist of LXR (GW3965) reduced biochemical indices of liver injury in the blood of CLP rats. We also demonstrated that liver injury associated with CLP is aggravated in LXRalpha and LXRalphabeta-deficient mice compared with wild-type and LXRbeta-deficient mice, indicating a role for LXRalpha in protecting the liver. The enhanced liver injury in LXR-deficient mice was associated with elevated plasma concentrations of high mobility group box 1, a late mediator of inflammation and a known factor in the pathology of this model. CONCLUSIONS: Collectively, these results argue in favor of a role for LXRalpha in protection against liver injury in experimental sepsis induced by CLP. PMID- 21815814 TI - Infectious complications after vehicular trauma in the United States. AB - BACKGROUND: The purpose of this analysis was to evaluate and define the rates of infectious complications (IC) after vehicular trauma. Secondary goals were to identify the injuries associated with the greatest risk of nosocomial infection and to measure the utilization of hospital resources associated with IC and vehicular trauma. METHODS: A secondary analysis of the Nationwide Inpatient Sample (2003-2007) was performed to classify major vehicular trauma injuries utilizing International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) Emergency (E) codes. The post-traumatic IC evaluated were pneumonia, urinary tract infection (UTI), sepsis, and surgical site infection (SSI). All data were analyzed by chi(2) analysis, multivariable logistic regression, and the Cochran-Armitage test for trends. RESULTS: A total of 784,037 vehicular trauma patients were identified (462,543 [59.0%] motor vehicle drivers, 142,283 [18.2%] motor vehicle passengers, 98,767 [12.6%] motorcyclists; 6,568 [<1%] motorcycle passengers, and 73,876 [9.4%] pedestrians). Of those sustaining injuries, 44,331 [5.7%] had post-traumatic IC. Pneumonia and UTI were most common after spinal cord injury (SCI), whereas sepsis and SSI were most common after colon injuries. After adjustment by age, sex, and co-morbidities, patients with SCI were 4.4 times as likely (95% confidence interval [CI] 4.20-4.63) and those with cranial injuries were 2.1 times as likely (95% CI 2.06-2.19) to develop IC as patients without these injuries. Secondary infection increased significantly the length of stay and hospital charges in all groups. CONCLUSIONS: Patients sustaining vehicular trauma in combination with SCI had the highest rate of IC. Infectious complications increased hospital resource utilization significantly after vehicular trauma. Future root-cause analysis of high-risk groups may decrease complications and hospital utilization. PMID- 21815815 TI - Case report: are clinicians obligated to medically treat a suicide attempt in a patient with a prognosis of weeks? AB - BACKGROUND: There is broad ethical and professional consensus that preventing a patient from initiating or successfully completing a suicide attempt is a core physician obligation and justifies the use of aggressive interventions such as emergency detention and mechanical ventilation. This case examines the acute medical care of an individual with a progressive brain tumor after an apparent suicide attempt. RESULTS: In guiding the care of this patient, we found that the patient's prognosis of days to weeks made the ethical rationale of implementing aggressive medical interventions to treat the sequelae of his suicide attempt less compelling. PMID- 21815816 TI - Is individual educational level related to end-of-life care use? Results from a nationwide retrospective cohort study in Belgium. AB - BACKGROUND: Educational level has repeatedly been identified as an important determinant of access to health care, but little is known about its influence on end-of-life care use. OBJECTIVES: To examine the relationship between individual educational attainment and end-of-life care use and to assess the importance of individual educational attainment in explaining differential end-of-life care use. RESEARCH DESIGN: A retrospective cohort study via a nationwide sentinel network of general practitioners (GPs; SENTI-MELC Study) provided data on end-of life care utilization. Multilevel analysis was used to model the association between educational level and health care use, adjusting for individual and contextual confounders based upon Andersen's behavioral model of health services use. SUBJECTS: A Belgian nationwide representative sample of people who died not suddenly in 2005-2007. RESULTS: In comparison to their less educated counterparts, higher educated people equally often had a palliative treatment goal but more often used multidisciplinary palliative care services (odds ratios [OR] for lower secondary education 1.28 [1.04-1.59] and for higher [secondary] education: 1.31 [1.02-1.68]), moved between care settings more frequently (OR: 1.68 [1.13-2.48] for lower secondary education and 1.51 [0.93-2.48] for higher [secondary] education) and had more contacts with the GP in the final 3 months of life. CONCLUSIONS: Less well-educated people appear to be disadvantaged in terms of access to specialist palliative care services, and GP contacts at the end of life, suggesting a need for empowerment of less well-educated terminally ill people regarding specialist palliative and general end-of-life care use. PMID- 21815817 TI - Uterine neuroectodermal tumor with ependymoblastic features in an infant with clonal +del (2)(q11.2),-13: a possible role of increased gene dosage on 2pter 2q11.2 in the tumorigenesis. AB - Clonal +(2)(q11.2),-13 was detected in a uterine neuroectodermal tumor with ependymoblastic features arising in an infant. The tumor expressed vimentin, nestin, CD56, CD99, microtubule-associated protein 1B (MAP 1B), focally microtubule-associated protein 2 (MAP 2), synaptophysin, neuron-specific enolase, and, very focally, epithelial membrane antigen. Because trisomy 2 was previously detected in a medulloepithelioma of pelvic soft tissue and in several neuroectodermal tumors of the central nervous system, this finding is indicative of a possible role of increased dosage of gene(s) on chromosome 2 in the tumorigenesis of these neoplasms and of their histogenetic relatedness. PMID- 21815818 TI - A functional polymorphism in miRNA-196a2 is associated with colorectal cancer risk in a Chinese population. AB - Single-nucleotide polymorphisms in microRNAs (miRNAs) may alter miRNA expression levels or processing and, thus, may contribute to cancer development. We hypothesized that miRNA-196a2 polymorphism is associated with risk of colorectal cancer (CRC). In a case-control study of 573 patients with CRC and 588 cancer free controls frequency matched by age and sex, we genotyped the functional polymorphism rs11614913 (T>C) and assessed its association with the risk of CRC in a Chinese population. We found that the CT/CC genotypes were associated with a significantly increased risk of CRC (odds ratio [OR]=1.44, 95% confidence interval [CI]=1.10-1.88), compared with the TT genotype. Further, the polymorphism was significantly associated with the risk of patients with advanced stage tumor (Dukes C and D) (OR=1.65, 95% CI=1.11-2.46). Our results suggest that the functional polymorphism rs11614913 in miRNA-196a2 is involved in the etiology of CRC and, thus, may be a marker for genetic susceptibility to CRC. PMID- 21815819 TI - Comparison of commercial DNA extraction kits for isolation and purification of bacterial and eukaryotic DNA from PAH-contaminated soils. AB - Molecular characterization of the microbial populations of soils and sediments contaminated with polycyclic aromatic hydrocarbons (PAHs) is often a first step in assessing intrinsic biodegradation potential. However, soils are problematic for molecular analysis owing to the presence of organic matter, such as humic acids. Furthermore, the presence of contaminants, such as PAHs, can cause further challenges to DNA extraction, quantification, and amplification. The goal of our study was to compare the effectiveness of four commercial soil DNA extraction kits (UltraClean Soil DNA Isolation kit, PowerSoil DNA Isolation kit, PowerMax Soil DNA Isolation kit, and FastDNA SPIN kit) to extract pure, high-quality bacterial and eukaryotic DNA from PAH-contaminated soils. Six different contaminated soils were used to determine if there were any biases among the kits due to soil properties or level of contamination. Extracted DNA was used as a template for bacterial 16S rDNA and eukaryotic 18S rDNA amplifications, and PCR products were subsequently analyzed using denaturing gel gradient electrophoresis (DGGE). We found that the FastDNA SPIN kit provided significantly higher DNA yields for all soils; however, it also resulted in the highest levels of humic acid contamination. Soil texture and organic carbon content of the soil did not affect the DNA yield of any kit. Moreover, a liquid-liquid extraction of the DNA extracts found no residual PAHs, indicating that all kits were effective at removing contaminants in the extraction process. Although the PowerSoil DNA Isolation kit gave relatively low DNA yields, it provided the highest quality DNA based on successful amplification of both bacterial and eukaryotic DNA for all six soils. DGGE fingerprints among the kits were dramatically different for both bacterial and eukaryotic DNA. The PowerSoil DNA Isolation kit revealed multiple bands for each soil and provided the most consistent DGGE profiles among replicates for both bacterial and eukaryotic DNA. PMID- 21815820 TI - Postpartum depression after mild and severe preeclampsia. AB - OBJECTIVE: To describe the prevalence of postpartum depressive symptoms after preeclampsia, to assess the extent to which the prevalence of postpartum depressive symptoms differs after mild and severe preeclampsia, and to investigate which factors contribute to such differences. METHODS: Women diagnosed with preeclampsia (n=161) completed the Edinburgh Postnatal Depression Scale (EPDS) at 6, 12, or 26 weeks postpartum. Multiple logistic regression analysis was used to investigate the association between severity of preeclampsia, contributing factors and postpartum depression (PPD) (1) at any time during the first 26 weeks postpartum and (2) accounting for longitudinal observations at three time points. RESULTS: After mild preeclampsia, 23% reported postpartum depressive symptoms at any time up to 26 weeks postpartum compared to 44% after severe preeclampsia (unadjusted odds ratio [OR] 2.65, 95% confidence interval [CI] 1.16-6.05) for depression at any time up to 26 weeks postpartum (unadjusted OR 2.57, 95% CI, 1.14-5.76) while accounting for longitudinal observations. Admission to the neonatal intensive care unit (NICU) (adjusted OR 3.19, 95% CI 1.15-8.89) and perinatal death (adjusted OR 2.96, 95% CI 1.09-8.03) contributed to this difference. CONCLUSIONS: It appears that not the severity of preeclampsia itself but rather the consequences of the severity of the disease (especially admission to the NICU and perinatal death) cause postpartum depressive symptoms. Obstetricians should be aware of the high risk of postpartum depressive symptoms after severe preeclampsia, particularly among women whose infant has been admitted to the NICU or has died. PMID- 21815822 TI - Continuous gradients of material composition and growth factors for effective regeneration of the osteochondral interface. AB - Most contemporary biomaterial designs for osteochondral regeneration utilize monolithic, biphasic, or even multiphasic constructs. We have introduced a microsphere-based approach to create a continuous gradient in both material composition and encapsulated growth factors. The gradients were fabricated by filling a cylindrical mold with opposing gradients of two different types of poly(D,L-lactic-co-glycolic acid) microspheres. The chondrogenic microspheres were loaded with transforming growth factor-beta1, whereas the osteogenic microspheres contained bone morphogenetic protein-2 with or without nanophase hydroxyapatite. The gradient scaffolds (material gradient only, signal gradient only, or material/signal gradient combination) or blank control scaffolds were implanted in 3.5 mm-diameter defects in rabbit knees for 6 or 12 weeks. This is the first in vivo evaluation of these novel gradient scaffolds in the knee. The gross morphology, MRI, and histology indicated that the greatest extent of regeneration was achieved when both signal and material gradients were included together. This combination resulted in complete bone ingrowth, with an overlying cartilage layer with high glycosaminoglycan content, appropriate thickness, and integration with the surrounding cartilage and underlying bone. The results suggest that osteochondral regeneration may benefit from biomaterials that integrate a continuous gradient in both material composition and encapsulated growth factors. PMID- 21815821 TI - Community engagement about genetic variation research. AB - The aim of this article is to describe the methods and effectiveness of the Public Engagement in Genetic Variation and Haplotype Mapping Issues (PEGV) Project, which engaged a community in policy discussion about genetic variation research. The project implemented a 6-stage community engagement model in New Rochelle, New York. First, researchers recruited community partners. Second, the project team created community oversight. Third, focus groups discussed concerns generated by genetic variation research. Fourth, community dialogue sessions addressed focus group findings and developed policy recommendations. Fifth, a conference was held to present these policy recommendations and to provide a forum for HapMap (haplotype mapping) researchers to dialogue directly with residents. Finally, findings were disseminated via presentations and papers to the participants and to the wider community beyond. The project generated a list of proposed guidelines for genetic variation research that addressed the concerns of New Rochelle residents. Project team members expressed satisfaction with the engagement model overall but expressed concerns about how well community groups were utilized and what segment of the community actually engaged in the project. The PEGV Project represents a model for researchers to engage the general public in policy development about genetic research. There are benefits of such a process beyond the desired genetic research. PMID- 21815823 TI - The learning curve of robot-assisted radical prostatectomy. AB - PURPOSE: To evaluate the learning curve of a surgeon with no previous laparoscopy experience in performing robot-assisted radical prostatectomy (RARP). PATIENTS AND METHODS: A total of 120 patients with a 1-year follow-up after RARP were included to the study prospectively. Patients were grouped as the first, second, and third 40 patients. Surgical, oncologic, and functional outcomes were compared among groups. Analysis of variance, chi-square, and Kruskal-Wallis test were used for statistical analysis. RESULTS: All groups were similar with respect to age, prostate-specific antigen level, body mass index, Gleason score, and distribution of the clinical stage. The operative time was 182 minutes for group 1, 168 minutes for group 2, and 139 minutes for group 3 (P=0.01). Individual times of various stages of the procedure (dissection of the seminal vesicles, entering the extraperitoneal space and dissection of the endopelvic fascia, incision of the bladder neck, division of the prostatic pedicles and preservation of the neurovascular bundle, and urethrovesical anastomosis) decreased significantly over time. Estimated blood loss was 287 mL for group 1 238 mL for group 2, and 170 mL for group 3 (P=0.04). The length of stay was 5.1 days for group 1, 4.0 days for group 2, and 3.1 days for group 3 (P=0.005). Positive surgical margin rates were 22% (9) for group 1, 17% (7) for group 2, and 6% (2) for group 3 (P=0.03). While seven patients in group 1 and two patients in group 2 had biochemical recurrence, no patient in group 3 had biochemical recurrence (P=0.04). Continence rates at 12 months were 72.5%, 85%, and 92.5% in groups 1, 2, and 3, respectively (P=0.01). Potency rates at 12 months for groups 1, 2, and 3 were 60.5%, 66.7%, and 76.6%, respectively (P=0.03). CONCLUSION: Surgical, oncologic, and functional outcomes of RARP improve with increasing experience. Outcomes similar to the published series by high-volume centers could be achieved after 80 to 120 RARP cases. PMID- 21815824 TI - Water-jet-aided transurethral dissection of urothelial carcinoma: a prospective clinical study. AB - BACKGROUND AND PURPOSE: The application of a water-jet dissector for mucosal elevation was shown to improve resection of lesions of the gastrointestinal tract. We present the first prospective clinical trial on the application of a combined water-jet dissector and needle-knife (HybridKnife) in transurethral dissection (TUD) of urothelial carcinoma of the bladder (UCB). PATIENTS AND METHODS: Thirty separate urothelial tumors of the bladder in 17 unselected patients were elevated and dissected with the HybridKnife. The goal was to determine the safety, effectiveness of resection, and overall applicability of the HybridKnife. RESULTS: No perforation or other complication was seen. All tumors could be dissected from the bladder wall en bloc. TUD of UCB by using the HybridKnife is technically feasible and safe in the resection of papillary and solid tumors. CONCLUSION: The application of the HybridKnife in TUD of UCB appears to be a feasibly safe and applicable for en-bloc dissection technique potentially following principles of oncologic surgery in transurethral removal of UCB. It seems to facilitate histopathologic assessment. A possibly improved oncologic outcome has to be addressed in further studies. PMID- 21815825 TI - Robotics training program: evaluation of the satisfaction and the factors that influence success of skills training in a resident robotics curriculum. AB - PURPOSE: We present our experience of training residents in a weekend robotic training program to assess its effectiveness and perceived usefulness. METHODS: Bimonthly training sessions were arranged such that residents could sign up for hour-long, weekend training sessions. They are required to complete four training sessions. Five tasks were scored for time and accuracy: Peg-Board, checkerboard, string running, pattern cutting, and suturing. Participants completed surveys (5 point Likert scale) regarding program utility, ease of attendance, and interest in future weekend training sessions. RESULTS: Mean number of trials completed by 19 residents was >4, and 16 completed the trials within an average of 13.7+/-8.1 mos. Significant improvements (P<0.05) were seen in final trials for Peg-Board accuracy (95.8% vs 79.0%), checkerboard deviation (4.8% vs 18.2%), and time (293 s vs 404 s), pattern-cutting time (257 s vs 399 s), and suture time (203 s vs 305 s). Time to previous session correlated with relative improvement in Peg-Board and pattern-cutting time (r=0.300 and 0.277, P=0.021 and 0.041), but no specific training interval was predictive of improvement. Residents found the course easy to attend (3.6), noted skills improvement (4.1), and found it useful (4.0). CONCLUSION: Training in the weekend sessions improved performance of basic tasks on the robot. Training interval had a modest effect on some exercises and may be more important for difficult tasks. This training program is a useful supplement to resident training and would be easy to implement in most programs. PMID- 21815826 TI - Coccidioides, cryptococcus, or blastomyces? A diagnostic dilemma encountered during frozen section evaluation. AB - Intraoperative consultation via frozen section is an important part of modern day surgical pathology. Recognizing fungi in tissues on frozen and permanent sections is not always a simple task, and correctly identifying the agent can be a significant challenge, even for experienced microscopists. We present a case of a 17-year-old boy with chronic osteomyelitis involving the right proximal ulna. During an irrigation and debridement operation, a frozen section was sent to surgical pathology for evaluation. A limited patient history coupled with sparse organisms present in the frozen section led to the diagnosis of fungal osteomyelitis, favor Coccidioides . Follow-up permanent sections with special staining and successful fungal culture clarified the causal agent to be Blastomyces dermatitidis . The role of frozen sections is not to perfectly speciate the fungal pathogen but to describe the morphology and infectious process and provide a differential diagnosis of the candidate fungi. The importance of intraoperative culture in infectious cases cannot be understated, and it is the responsibility of pathologists to inform surgeons that tissue is needed for culture. A brief overview of Blastomyces , including histopathologic features and key microscopic differences from Coccidioides and Cryptococcus , is discussed. PMID- 21815827 TI - Splenda(r) improves tolerance of oral potassium citrate supplementation for prevention of stone formation: results of a randomized double-blind trial. AB - BACKGROUND AND PURPOSE: Oral citrate supplements have been shown to decrease kidney stone recurrence rates in both laboratory and clinical studies. The taste of the citrate supplements, however, is poor, and long-term compliance is low. Our objective was to determine if Splenda((r)) added to potassium citrate (KCit) improves palatability without changing 24-hour urine parameters. PATIENTS AND METHODS: 12 subjects were randomly assigned to receive either KCit alone for 3 days or KCit + Splenda in a double-blind trial. The 24-hour urine collections were performed before and after 3 days of therapy. After 1 week, the two groups switched treatments. After each treatment, a visual analog taste scale was completed to gauge the taste and palatability. The 24-hour urine parameters of kidney stone risk factors were compared between groups. The primary end points were to determine whether Splenda improved palatability of citrate supplementation and whether it altered 24-hour urine parameters. RESULTS: Taste was judged to be 2.5 +/- 0.9 points better in the Splenda + KCit compared with KCit alone (P=0.02). The 24-hour Cit, K, and pH were significantly higher in the KCit and KCit + Splenda groups compared with baseline, but not significantly different from each other. CONCLUSION: Splenda significantly improves the palatability of KCit therapy and does not alter the beneficial effects of KCit on 24-hour urine Cit, K, or pH. The addition of Splenda altered the average taste score from one that might prohibit compliance to one that would not. PMID- 21815828 TI - Stray electrical currents in laparoscopic instruments used in da Vinci(r) robot assisted surgery: an in vitro study. AB - BACKGROUND AND PURPOSE: The da Vinci((r)) surgical system requires the use of electrosurgical instruments. The re-use of such instruments creates the potential for stray electrical currents from capacitive coupling and/or insulation failure. We used objective measures to report the prevalence and magnitude of such stray currents. MATERIALS AND METHODS: Thirty-seven robotic instruments were tested using an electrosurgical unit (ESU) at pure coagulation and cut waveforms at four different settings. Conductive gel-coated instruments were tested at 40W, 80W, and maximum ESU output (coagulation 120W, cut 300W). The magnitude of stray currents was measured by an electrosurgical analyzer. RESULTS: At coagulation waveform in open air, 86% of instruments leaked a mean of 0.4W. In the presence of gel-coated instruments, stray currents were detected in all instruments with means (and standard deviation) of 3.4W (+/- 2), 4.1W (+/- 2.3), and 4.1W (+/- 2.3) at 40W, 80W, and 120W, respectively. At cut waveform in open air, none of the instruments leaked current, while gel-coated instruments leaked a mean of 2.2W (+/- 1.3), 2.2W (+/- 1.9) and 3.2W (+/- 1.9) at 40W, 80W, and 300W, respectively. CONCLUSIONS: All tested instruments in our study demonstrated energy leakage. Stray currents were higher during coagulation (high voltage) waveforms, and the magnitude was not always proportionate to the ESU settings. Stray currents have the potential to cause electrical burns. We support the programmed end of life of da Vinci instruments on the basis of safety. Consideration should be given to alternate energy sources or the adoption of active electrode monitoring technology to all monopolar instruments. PMID- 21815829 TI - The long-term results of using low-concentration atropine eye drops for controlling myopia progression in schoolchildren. AB - PURPOSE: The purpose of this article was to evaluate the long-term efficacy of a low-concentration (LC) atropine eye drop regimen (0.05%-0.1%) for controlling myopia progression in schoolchildren. METHODS: This retrospective, case-control study enrolled myopic schoolchildren who had been followed-up for at least 3 years from 1999 to 2007. Children who received LC doses of atropine eye drops [initial prescription 0.05%, if progression over -0.5 diopter (D) during a 6 month follow-up then changed to 0.1% atropine] every night at bedtime were included in the LC atropine group, and untreated children served as controls. RESULTS: A total of 117 children were included in this study. The mean age was 8.4 years. There were 97 children in the LC atropine group and 20 children in the control group. The mean follow-up duration was 4.5 years. In a mixed model analysis, the adjusted myopia progression in the LC atropine group was -0.23 D/year, significantly lower than that of the control group, which was -0.86 D/year (P<0.001). About 80% of the treatment group had slow myopia progression (less than -0.5 D progression per year). In a multivariate analysis, factors such as initial spherical refraction with less myopia and treatment with LC atropine were significantly associated with less myopia progression, but age, sex, and initial astigmatism were not significantly associated (P<0.001, P<0.001, P=0.442, 0.494, and 0.547, respectively). CONCLUSION: The results of this study demonstrate that long-term and regular instillation of LC atropine eye drops is effective for controlling myopia progression and provides a possible strategy for an initial myopia regimen. PMID- 21815830 TI - A dual-targeted soybean protein is involved in Bradyrhizobium japonicum infection of soybean root hair and cortical cells. AB - The symbiotic interaction between legumes and soil bacteria (e.g., soybean [Glycine max L.] and Bradyrhizobium japonicum]) leads to the development of a new root organ, the nodule, where bacteria differentiate into bacteroids that fix atmospheric nitrogen for assimilation by the plant host. In exchange, the host plant provides a steady carbon supply to the bacteroids. This carbon can be stored within the bacteroids in the form of poly-3-hydroxybutyrate granules. The formation of this symbiosis requires communication between both partners to regulate the balance between nitrogen fixation and carbon utilization. In the present study, we describe the soybean gene GmNMNa that is specifically expressed during the infection of soybean cells by B. japonicum. GmNMNa encodes a protein of unknown function. The GmNMNa protein was localized to the nucleolus and also to the mitochondria. Silencing of GmNMNa expression resulted in reduced nodulation, a reduction in the number of bacteroids per infected cell in the nodule, and a clear reduction in the accumulation of poly-3-hydroxybutyrate in the bacteroids. Our results highlight the role of the soybean GmNMNa gene in regulating symbiotic bacterial infection, potentially through the regulation of the accumulation of carbon reserves. PMID- 21815831 TI - beta-glucosidases from a new Aspergillus species can substitute commercial beta glucosidases for saccharification of lignocellulosic biomass. AB - beta-Glucosidase activity plays an essential role for efficient and complete hydrolysis of lignocellulosic biomass. Direct use of fungal fermentation broths can be cost saving relative to using commercial enzymes for production of biofuels and bioproducts. Through a fungal screening program for beta-glucosidase activity, strain AP (CBS 127449, Aspergillus saccharolyticus ) showed 10 times greater beta-glucosidase activity than the average of all other fungi screened, with Aspergillus niger showing second greatest activity. The potential of a fermentation broth of strain AP was compared with the commercial beta-glucosidase containing enzyme preparations Novozym 188 and Cellic CTec. The fermentation broth was found to be a valid substitute for Novozym 188 in cellobiose hydrolysis. The Michaelis-Menten kinetics affinity constant as well as performance in cellobiose hydrolysis with regard to product inhibition were found to be the same for Novozym 188 and the broth of strain AP. Compared with Novozym 188, the fermentation broth had higher specific activity (11.3 U/mg total protein compared with 7.5 U/mg total protein) and also increased thermostability, identified by the thermal activity number of 66.8 vs. 63.4 degrees C for Novozym 188. The significant thermostability of strain AP beta-glucosidases was further confirmed when compared with Cellic CTec. The beta-glucosidases of strain AP were able to degrade cellodextrins with an exo-acting approach and could hydrolyse pretreated bagasse to monomeric sugars when combined with Celluclast 1.5L. The fungus therefore showed great potential as an onsite producer for beta glucosidase activity. PMID- 21815832 TI - Surface microbial consortia from Livarot, a French smear-ripened cheese. AB - The surface microflora (902 isolates) of Livarot cheeses from three dairies was investigated during ripening. Yeasts were mainly identified by Fourier transform infrared spectroscopy. Geotrichum candidum was the dominating yeast among 10 species. Bacteria were identified using Biotype 100 strips, dereplicated by repetitive extragenic palindromic PCR (rep-PCR); 156 representative strains were identified by either BOX-PCR or (GTG)(5)-PCR, and when appropriate by 16S rDNA sequencing and SDS-PAGE analysis. Gram-positive bacteria accounted for 65% of the isolates and were mainly assigned to the genera Arthrobacter , Brevibacterium , Corynebacterium , and Staphylococcus . New taxa related to the genera Agrococcus and Leucobacter were found. Yeast and Gram-positive bacteria strains deliberately added as smearing agents were sometimes undetected during ripening. Thirty-two percent of the isolates were Gram-negative bacteria, which showed a high level of diversity and mainly included members of the genera Alcaligenes , Hafnia , Proteus , Pseudomonas , and Psychrobacter . Whatever the milk used (pasteurized or unpasteurized), similar levels of biodiversity were observed in the three dairies, all of which had efficient cleaning procedures and good manufacturing practices. It appears that some of the Gram-negative bacteria identified should now be regarded as potentially useful in some cheese technologies. The assessment of their positive versus negative role should be objectively examined. PMID- 21815833 TI - Analysis of genetic diversity of Lactarius hatsudake in south China. AB - Lactarius hatsudake is a type of ectomycorrhizal fungus that significantly influences the growth of pine trees. It is widely prevalent in Asian countries and has a high economic value. Artificial cultivation of this fungus has not been achieved as yet; therefore, excessive manual harvesting may cause serious damages to the site of its production. In this study, we analyzed 41 samples of L. hatsudake from south China using internal transcribed spacer (ITS) sequences. By comparing the differences among ITS sequences to identify the haplotype diversity within each population, the relationships among local populations, the relationship between the level of genetic differentiation and geographical separation, and the contributions of local and regional geographical separations to the overall ITS haplotype variation were analyzed. Genetic analysis indicates that ITS sequences obtained from these 41 L. hatsudake samples could be identified as 18 haplotypes, of which 13 haplotypes were contained in only a single sample, whereas the remaining sequence types all were contained in two or more samples. The most common sequence type, haplotype 6, was found in 16 samples and was distributed across nearly every region. The Mantel test demonstrated that there is no significant linear relationship between geographical distance and the F(ST) value of genetic difference. Results of this research illustrates that there exists a certain degree of genetic intermixing among natural populations of L. hatsudake. From the group genetic analysis, it appears that there exists genetic differentiation of lower frequencies in natural populations of L. hatsudake; however, the linear relationship between the degree of genetic differentiation and geographical distance is not distinctly apparent. PMID- 21815834 TI - Expression patterns of Sema3F, PlexinA4, -A3, Neuropilin1 and -2 in the postnatal mouse molar suggest roles in tooth innervation and organogenesis. AB - OBJECTIVE: Semaphorins form a family of axon wiring molecules but still little is known about their role in tooth formation. A class 3 semaphorin, Semaphorin3F (Sema3F), besides acting as a chemorepellant for different types of axons, controls a variety of non-neuronal developmental processes. MATERIALS AND METHODS: Cellular mRNA expression patterns of Sema3F as well as neuropilin 1 (Npn1), neuropilin 2 (Npn2), plexinA3 and plexinA4 receptors were analyzed by sectional in situ hybridization in the mouse molar tooth during postnatal days 0 7. The expression of the receptors was studied in PN5 trigeminal ganglia. RESULTS: Sema3F, Npn1, -2 and plexinA4 exhibited distinct, spatiotemporally changing expression patterns, whereas plexinA3 was not observed in the tooth germs. Besides being expressed in the base of the dental mesenchyme Sema3F, like plexinA4, Npn1 and -2, was present in the ameloblast cell lineage. Npn1 and Npn2 were additionally seen in the pulp horns and endothelial cells and like PlexinA4 in the developing alveolar bone. Npn1, plexinA3 and -A4 were observed in trigeminal ganglion neurons. CONCLUSIONS: Sema3F may act as a tooth target derived axonal chemorepellant controlling establishment of the tooth nerve supply. Furthermore, Sema3F, like Npn1, -2 and plexinA4 may serve non-neuronal functions by controlling the development of the ameloblast cell lineage. Moreover, Npn1 and Npn2 may regulate dental vasculogenesis and, together with PlexinA4, alveolar bone formation. Further analyses such as investigation of transgenic mouse models will be required to elucidate in vivo signaling functions of Sema3F and the receptors in odontogenesis. PMID- 21815835 TI - Effect of storage temperature on sealing ability and solubility of white mineral trioxide aggregate. AB - OBJECTIVE: Knowledge about the effect of storage conditions on the clinical performance of Mineral Trioxide Aggregate (MTA) is of great importance for clinicians. The aim of this study was to evaluate the effect of storage temperature on sealing ability and solubility of white MTA. MATERIALS AND METHODS: This study was divided into two parts: sealing ability and solubility tests. Forty single-rooted human pre-molars were divided into three experimental (n = 10) and two control groups (n = 5). The root canals were instrumented and root apices were resected. Root-end cavities were prepared and filled with white MTA stored at 4 degrees C, 25 degrees C or 40 degrees C. Microleakage was evaluated using a protein leakage test with bovine serum albumin at 24-h intervals for 120 days. The solubility test was also performed based on ISO specifications (ISO 2001-6876). Data were analyzed by one-way analysis of variance and post-hoc Tukey test, with a significance level set at p = 0.05. RESULTS: The highest bovine serum albumin microleakage and the highest solubility rates were observed in 4 degrees C followed by 25 degrees C and 40 degrees C groups. At higher temperatures, leakage needed significantly longer times to occur (p < 0.05). CONCLUSIONS: Based on these findings, storage temperature appears to play an important role in the properties and hence clinical outcomes of MTA. PMID- 21815836 TI - The oxidant/antioxidant status and cell death mode in oral squamous cell carcinoma. AB - OBJECTIVE: Oxidative stress and imbalance in the oxidant/antioxidant system have a critical role in carcinogenesis by affecting necrosis and apoptosis. The aim of this study is to evaluate the oxidant/antioxidant status and cell death modes in patients with oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: Twenty nine patients with OSCC and 29 control subjects were included in the study. The levels of malondialdehyde (MDA), advanced oxidation protein products (AOPP) and ferric reducing antioxidant power (FRAP) were determined in plasma samples of all subjects. The necrotic and apoptotic cell death modes were evaluated with M65 ELISA and M30 ELISA, respectively. RESULTS: MDA and AOPP values as oxidative stress markers were higher in patients with OSCC than in the control group. FRAP values evaluating plasma antioxidant status increased in OSCC patients. M65 and M30 levels indicating necrosis and apoptosis were significantly higher in OSCC patients compared to controls. There were significant correlations between MDA, AOPP and FRAP; M65 and M30 values. CONCLUSIONS: The elevated levels of oxidative stress markers together with the increase of antioxidant capacity and the presence of a strong correlation between MDA, AOPP and FRAP suggest an activation of antioxidant defense against accentuated oxidative stress determined in OSCC. Enhanced oxidation of lipids and proteins may cause decomposition of cell membranes with subsequent leakage of cytoskeletal cytokeratins as CK18 and caspase-cleaved CK18 (evaluated as M65 and M30, respectively) in the circulation, suggesting that both cell death modes are affected in OSCC. PMID- 21815837 TI - Finite element stress analysis of Ti-6Al-4V and partially stabilized zirconia dental implant during clenching. AB - OBJECTIVE: The purpose of this paper is to compare the differences in stress between Ti-6Al-4V and PS-ZrO(2) dental implant during clenching and whether these changes are clinically significant to limit the use of zirconia in oral implantology. MATERIALS AND METHODS: The model geometry was derived from position measurements taken from 28 diamond blade cut cross-sections of an average size human adult edentulous mandible and generated using a special sequencing method. Data on anatomical, structural, functional aspects and material properties were obtained from measurements and published data. Ti-6Al-4V and PS-ZrO(2) dental implants were modelled as cylindrical structure with a diameter of 3.26 mm and length of 12.00 mm was placed in the first molar region on the right hemimandible. RESULTS: The analysis revealed an increase of 2-3% in the averaged tensile and compressive stress and an increase of 8% in the averaged Von Mises stress were recorded in the bone-implant interface when PS-ZrO(2) dental implant was used instead of Ti-6Al-4V dental implant. The results also revealed only relatively low levels of stresses were transferred from the implant to the surrounding cortical and cancellous bone, with the majority of the stresses transferred to the cortical bone. CONCLUSION: Even though high magnitudes of tensile, compressive and Von Mises stresses were recorded on the Ti-6Al-4V and PS ZrO(2) dental implants and in the surrounding osseous structures, the stresses may not be clinically critical since the mechanical properties of the implant material and the cortical and cancellous bone could withstand stress magnitudes far greater than those recorded in this analysis. PMID- 21815838 TI - Fiber post placement with core build-up materials or resin cements-an evaluation of different adhesive approaches. AB - OBJECTIVE: To compare push-out bond strength of fiber-posts luted with different adhesive approaches to root canal dentin. MATERIALS AND METHODS: Forty maxillary first incisors were decoronated and endodontically treated. Specimens were randomly distributed into five groups (n = 8) and fiber-posts (DentinPost coated, Komet) were inserted using five different luting materials: etch-and-rinse adhesive systems and corresponding core-and-post material in groups 1 (DentinBond/DentinBuild, Komet) and 2 (XP Bond + SCA/Core-X flow, Densply), self adhesive resin cements in groups 3 (RelyX Unicem, 3M Espe) and 4 (SmartCem 2, Dentsply) and a self-etch adhesive/resin cement in group 5 (ED-Primer II/Panavia F 2.0, Kuraray). The roots were sectioned into eight 1 mm thick serial slices and within 48 h push-out bond strength was investigated. Statistical analyses were performed using non-parametrical Kruskal-Wallis H-test and Mann-Whitney U-test for differences between experimental groups at p < 0.05. The failure modes were analyzed using Chi square test. RESULTS: The bond strength [MPa] (mean/min-max) for groups 3 (12.35/3.60-32.44), 4 (13.52/4.48-30.69) and 2 (11.15/5.23-35.58) were significantly higher (p < 0.001) compared to groups 1 (6.66/2.34-24.89) and 5 (7.41/0.28-34.18). Adhesive failure between dentin and luting agent was the most frequent failure mode. CONCLUSIONS: Bond strength of fiber-posts adhesively luted to root canal dentin was significantly higher when self-adhesive resin cements were used. One (group 2) of the tested core-and-post materials/etch-and rinse adhesive achieved comparable bond strength values. PMID- 21815840 TI - Strains of toxic and harmful microalgae, from waste water, marine, brackish and fresh water. AB - Some microalgae are economically important in Mexico and the world because they can be potentially toxic. Algal explosive population growths are named harmful algal blooms and are frequently recorded in Mexico. The authors set up potentially toxic microalgae cultures from the Gulf of Mexico (Garrapatas tideland, Barberena river, Carpintero lagoon in Tamaulipas State; Chalchoapan and Catemaco lakes in Veracruz State), from the Mexican Pacific Ocean, Guerrero, Colima and Michoacan States, and from interior water bodies such as Vicente Aguirre dam, Chapultepec lake and several waste water treatment plants. This research is about the diversity and abundance of phytoplankton in relation a specific site because of harmful algal bloom events. Microalgae cultures are useful in order to solve taxonomic problems, to know life cycles, molecular studies, for the study of toxic species, and the isolation of useful metabolites. The cultures for this research are clonal, non-axenic, semi-continuous, 12:12 light/dark photoperiod, 20 +/- 1 degrees C temperature and 90.5 umol m(-2)s(-1) illumination. Four different culture media were used. This collection is open to the worldwide scientific community as a source of organisms in controlled conditions that can be used as a useful tool for microalgae research work. PMID- 21815839 TI - Sexual health and life experiences: voices from behaviourally bisexual Latino men in the Midwestern USA. AB - Research on behaviourally bisexual Latino men in the USA has not yet examined sexual health issues among men living in diverse areas of the nation, including the Midwest. A community-based participatory research approach was used to engage a diverse sample of 75 behaviourally bisexual men (25 White, 25 Black and 25 Latino). Semi-structured interviews were conducted and standard qualitative analysis procedures were used to explore data from the 25 Latino participants. Men described their unique migration experiences as behaviourally bisexual men in this area of the USA, as well as related sexual risk behaviours and health concerns. Lack of culturally congruent public health and community resources for behaviourally bisexual men in the Midwestern USA were identified as significant barriers. As in other studies, familial and community relationships were significant for the participants, especially in terms of the decision to disclose or not disclose their bisexuality. Additionally, alcohol and other drugs were often used while engaging in sexual behaviours particularly with male and transgender, as well as female, partners. Behaviourally bisexual Latino men may benefit from receiving positive and affirmative individual- and structural-level support in regards to their unique experiences in this and other settings. PMID- 21815842 TI - The Internet profiles of men who have sex with men within bareback websites. AB - The Internet has become a venue for men who have sex with men to search for sexual partners. Some of these men intentionally seek unprotected anal intercourse with other men ('bareback' sex). This paper focuses on the creation, use, and content of Internet personal profiles of men who have sex with men in the greater New York City metropolitan area who use bareback sites for sexual networking. We used a mixed-methods approach to examine data from a cybercartography of Internet sites conducted during the first phase of the research (199 personal profiles) and from in-depth interviews conducted during its second phase (120 men who have sex with men who sought partners online for bareback sex). Results indicate that men generally followed offline stereotypical patterns in their online profiles. However, men who disclosed being HIV-positive were more likely to include face and head pictures. Overall, the images they used were heavily sexualised in accordance with group norms perceived and reinforced by the websites' design and imagery. Bottom-identified men tended to be more explicit in the exposition of their sexual and drug use interests online. This paper highlights how certain virtual and social performances play upon and reinforce other, in the flesh, performances. PMID- 21815843 TI - Antimicrobial activities of phenethyl isothiocyanate isolated from horseradish. AB - Phenethyl isothiocyanate (PEITC) was obtained from horseradish. The preparation procedure was as follows: the horseradish powder was hydrolysed in the water first, and then, after filtration, the residue was extracted by petroleum ether; finally, PEITC was isolated by silica gel column. The structure of PEITC was identified by IR, MS, 1H-NMR and 13C-NMR chromatography methods. The inhibitory activities of PEITC against Gibberella zeae, Xanthomonas axonopodis pv . citri, Cytospora sp . and Phytophthora capsisi showed that PEITC had good inhibition effects. The EC50 values of G. zeae, X. axonopodis pv . citri, Cytospora sp . and P. capsisi were 13.92, 1.20, 0.73 and 3.69 ug mL-1, respectively. PMID- 21815844 TI - Normal and frictional interactions of purified human statherin adsorbed on molecularly-smooth solid substrata. AB - Human salivary statherin was purified from parotid saliva and adsorbed to bare hydrophilic (HP) mica and STAI-coated hydrophobic (HB) mica in a series of Surface Force Balance experiments that measured the normal (F(n)) and friction forces (F(s)*) between statherin-coated mica substrata. Readings were taken both in the presence of statherin solution (HP and HB mica) and after rinsing (HP mica). F(n) measurements showed, for both substrata, monotonic steric repulsion that set on at a surface separation D ~20 nm, indicating an adsorbed layer whose unperturbed thickness was ca 10 nm. An additional longer-ranged repulsion, probably of electrostatic double-layer origin, was observed for rinsed surfaces under pure water. Under applied pressures of ~1 MPa, each surface layer was compressed to a thickness of ca 2 nm on both types of substratum, comparable with earlier estimates of the size of the statherin molecule. Friction measurements, in contrast with F(n) observations, were markedly different on the two different substrata: friction coefficients, MU = ?F(s)*/?F(n), on the HB substratum (MU ~ 0.88) were almost an order of magnitude higher than on the HP substratum (MU ~ 0.09 and 0.12 for unrinsed and rinsed, respectively), and on the HB mica there was a lower dependence of friction on sliding speed than on the HP mica. The observations were attributed to statherin adsorbing to the mica in multimer aggregates, with internal re-arrangement of the protein molecules within the aggregate dependent on the substratum to which the aggregate adsorbed. This internal re-arrangement permitted aggregates to be of similar size on HP and HB mica but to have different internal molecular orientations, thus exposing different moieties to the solution in each case and accounting for the very different friction behaviour. PMID- 21815845 TI - Is reciprocity always beneficial? Age differences in the association between support balance and life satisfaction. AB - OBJECTIVES: Reciprocity in support exchanges is believed to be beneficial to psychological well-being. This study examined perceived emotional and instrumental support balance from either family or friends, and the relationship between each support balance and life satisfaction among young and older adults. METHOD: The sample included 107 older adults and 96 young adults. They rated their life satisfaction, as well as the emotional and instrumental support they provided to and received from family members and friends. RESULTS: Consistent with the socioemotional selectivity theory, age differences were found in perceived emotional support balance with friends. Older adults reported more emotionally reciprocal friendships than did young adults. Moreover, contrary to the equity rule, emotionally over-benefited friendships were associated with higher life satisfaction for older adults than were reciprocal friendships. CONCLUSION: Age, type of support, and source of support should be considered when studying the relationships between support balance and psychological well-being. PMID- 21815846 TI - Care home design for people with dementia: What do people with dementia and their family carers value? AB - OBJECTIVES: To report on the views of people with dementia who live in care homes and their family carers on aspects of design that are important to them, and discuss these in relation to developing physical care environments that respond to the wishes of people with dementia and their family carers. METHOD: Six focus groups were held: two in Northern Ireland and four in Scotland. A total of 40 people participated in the focus groups. Twenty nine people were with dementia (24 female and five male), and 11 were family carers (10 female and one male). RESULTS: Carers discussed the features of a building they took into account when selecting a care home, and discussed this in relation to 'bricks and mortar versus people'. Key themes reported by people with dementia and their family carers included how the space in the environment is used, for example, what happens in the building and the presence or absence of certain design features. Outside space and wayfinding aids were identified as positive features of the home, along with a general lack of concern about ensuite provision. CONCLUSION: The results demonstrate the complexity of building design as it must provide living space acceptable to people with dementia living there and family members who visit, as well as provide a workable environment for staff. The findings highlight areas that should be considered by care home teams involved in the build of a new home or the redevelopment of an existing care home. PMID- 21815847 TI - The long-term effect of group living homes versus regular nursing homes for people with dementia on psychological distress of informal caregivers. AB - OBJECTIVE: In this follow-up study, the long-term influence of group living homes (GLHs) on informal caregiver distress was compared with modern yet regular nursing homes (NHs). METHOD: Informal caregivers of GLH (N = 37) and NH residents (N = 49) were studied at the time of admission, 6 months thereafter, and approximately 24 months after admission. Repeated measures of ANOVA were performed to study group-by-time effects on psychopathology, role overload, and feelings of competence. RESULT: All outcomes of psychological distress in GLH caregivers showed significantly greater decline compared with NH caregivers during the first six months after admission. The course of psychological distress stabilized in both caregiver groups after six months. CONCLUSION: GLHs may have played a role in reducing caregiver burden during the first six months after the nursing home admission of the care recipient. The stabilization of caregivers' psychological distress between T1 and T2 may indicate that there is no further room for improvement in the GLH and NH groups after six months. The implication would be that both GLHs and NHs succeeded in keeping caregivers' distress relatively low over the long term. More knowledge is needed on whether and how caregivers' psychological distress after institutionalization of the care recipient can be reduced to a greater extent. PMID- 21815848 TI - 'I hate having nobody here. I'd like to know where they all are': Can qualitative research detect differences in quality of life among nursing home residents with different levels of cognitive impairment? AB - OBJECTIVE: To ascertain if similarities or differences exist in perceptions of quality of life (QoL) amongst nursing home (NH) residents with different levels of cognitive impairment (CI). METHOD: Face-to-face interviews using a simple 15 item semi-structured interview schedule with 61 older people with a CI (13 mild, 20 moderate and 28 severe) living in three Dublin area based NHs. RESULTS: Four key themes of QoL with accompanying sub-themes were identified: (1) social contact, (2) attachment, (3) pleasurable activities and (4) affect. Whilst some similarities existed between the three groups, results showed emerging differences, particularly between those with a mild and severe CI. In particular, the narratives of those with a severe CI reflected an absence of social contact, a quest for human contact and a lack of awareness of structured pleasurable activities. A large majority also reported feelings of loneliness, isolation and a search for home. CONCLUSIONS: Findings support the increasing evidence that people with a CI and even those with a probable advanced dementia can often still communicate their views and preferences about what is important to them. Whilst apathy, depression and anxiety are common features of advanced dementia, the social inclusion of these people in the day-to-day ethos of NH life needs a lot more careful consideration. More research is also needed to better understand the chronic and unique needs of this very vulnerable group of people. PMID- 21815849 TI - Physically violent behaviour in dementia care: Characteristics of residents and management of violent situations. AB - OBJECTIVE: Physically violent behaviour (PVB) is common among residents with dementia and often complicates nursing care. This study aims to explore types of caring situations, resident characteristics related to PVB and professional caregivers' management of PVB. METHODS: The study included 40 group homes for 309 residents with dementia. Data was gathered by means of structured interviews, the Multi-Dimensional Dementia Assessment Scale and the Geriatric Rating Scale. RESULTS: Ninety-eight of the residents (31.7%) were assessed as showing PVB during the preceding week. Three factors were independently associated with PVB: male gender, antipsychotic treatment and decline in orientation. Violent residents were more likely to have impaired speech, difficulties understanding verbal communication and prescribed analgesics and antipsychotics than were non violent residents. PVB occurred mainly in intimate helping situations and was managed by symptom-oriented approaches, such as distraction, medication and isolation. The working team also held frequent discussions about the residents with PVB. CONCLUSION: This study shows that PVB is frequently displayed among residents in group homes for persons with dementia and the caregivers mainly manage PVB in a symptom-oriented way. To enhance the quality of care for patients with dementia, there is a need for interventions that aim to understand and manage the residents' physical violent behaviour. PMID- 21815850 TI - Effects of gerotranscendence support group on gerotranscendence perspective, depression, and life satisfaction of institutionalized elders. AB - OBJECTIVE: The purpose of this research was to test the clinical use of the gerotranscendence (GT) theory and its influence on GT perspective, depression, and life satisfaction among a group of institutionalized elders. METHODS: An experimental study utilizing pre-post group design and random assignment of elders into intervention and control group was conducted. The intervention support group was implemented in the experimental group once a week for eight weeks for 60 min. Over the eight-week period, 35 subjects in the experimental group and 41 in the control group completed the study. Data were collected one week before and one week after the intervention for both groups. Instruments include the GT Scale, Geriatric Depression Scale short form, and Life Satisfaction scale. Data were analyzed by paired t-test, Wilcoxon, McNemar, and analysis of co-variance. RESULTS: Pre- and post-test scores on the GT perspective and life satisfaction were significantly increased (p = 0.0000) in the experimental group. The mean depression score of the experimental group showed a slight but not significant decrease (p = 0.06). However, significant post-test differences were noted between groups in GT perspective, depression, and life satisfaction (p = 0.000, 0.01, and 0.000). CONCLUSION: The findings of this study suggest that after participating in a GT support group, institutionalized elders' GT perspective and life satisfaction were enhanced, and depression reduced. The positive effects demonstrated by this study can be extended and applied to the clinical health promotion of institutionalized elders. Ongoing GT intervention is encouraged to promote mental and spiritual health among institutionalized elders. PMID- 21815851 TI - The relationships between major lifetime discrimination, everyday discrimination, and mental health in three racial and ethnic groups of older adults. AB - OBJECTIVES: To evaluate the relationships between perceived exposure to major lifetime discrimination, everyday discrimination, and mental health in three racial/ethnic groups of older adults. DESIGN: The Health and Retirement Study is a nationally representative sample of individuals 50 years and older living in the United States. A total of 6455 Whites, 716 Latinos, and 1214 Blacks were eligible to complete a self-report psychosocial questionnaire in the year 2006. RESULTS: Whereas 30% of the general population reported at least one type of major lifetime discrimination, almost 45% of Black older adults reported such discrimination. Relative to the other two racial/ethnic groups (82% Whites, 82.6% Blacks), Latinos were significantly less likely to report any everyday discrimination (64.2%), whereas Blacks reported the greatest frequency of everyday discrimination. Whites reported the highest levels of life satisfaction and the lowest levels of depressive symptoms. Relative to major lifetime discrimination, everyday discrimination had a somewhat stronger correlation with mental health indicators. The relationships between discrimination and mental health outcomes were stronger for White compared to Black older adults, although everyday discrimination was still significantly associated with outcomes for Black older adults. CONCLUSIONS: Black older adults experience the greatest number of discriminative events, but weaker associated mental health outcomes. This could be because they have become accustomed to these experiences, benefit from social or cultural resources that serve as buffers, or selective survival, with the present sample capturing only the most resilient older adults who have learned to cope with the deleterious effects of discrimination. PMID- 21815852 TI - Suitability of the WHOQOL-BREF and WHOQOL-OLD for Spanish older adults. AB - BACKGROUND: People are living longer and healthier than at any other time point in history. Therefore, in the last decade, international interest has focussed on the study of quality of life (QoL) in older people. Our aim was to study the psychometric properties of the generic QoL measure WHOQOL-BREF (WHOQOL, World Health Organization Quality of Life) and specific older adult module WHOQOL-OLD in a sample of 286 Spanish elderly. METHODS: Participants were 60 years and older from community centres, primary care centres, family associations and nursing homes. The following information was collected: demographics, self-perception of health, depressive symptoms (Geriatric Depression Scale, GDS-30), functional status (SF-12) and QoL (WHOQOL-BREF and WHOQOL-OLD). Analysis was performed using classic psychometric techniques with SPSS v15.0. RESULTS: We found no ceiling and floor effects, and missing data was low. The internal consistency measured by Cronbach's alpha was 0.90 for the WHOQOL-BREF total scale and 0.80 for the WHOQOL OLD. A priori expected associations were found between WHOQOL-BREF and WHOQOL-OLD with the SF-12 and the GDS-30, indicating good construct validity. WHOQOL-BREF and WHOQOL-OLD domain scores differentiated between participants with lower and higher level of education, and between groups of older people (healthy vs. unhealthy; non-depressed vs. depressed; non-carers vs. carers and non-residents vs. residents). CONCLUSIONS: The WHOQOL-BREF and WHOQOL-OLD questionnaires demonstrate acceptable psychometric performance in a convenience sample of Spanish older people. They are valuable measures of QoL for use with older people. PMID- 21815853 TI - Developing capacities in aging studies in the Middle East: Implementation of an Arabic version of the CANE IV among community-dwelling older adults in Lebanon. AB - OBJECTIVE: To assess the feasibility, reliability, and construct validity of the Camberwell Assessment of Need for the Elderly (CANE) in identifying needs among community-dwelling older adults in South Lebanon with a view towards expanding ageing research in the country. METHODS: A cross-sectional study was undertaken with 322 individuals, using the CANE, the EQ5d and a socio-demographic questionnaire. Reliability was determined through measuring internal consistency of the CANE. Construct validity was performed through examining CANE inter-item correlations, and comparing correlations with the EQ5d and socio-demographic indicators. A factor analysis was conducted using varimax orthogonal rotation. RESULTS: Cronbach alpha was 0.71. For construct validity, correlations were highest in items measuring needs in looking after the house and food (r = 0.557); company and intimate relationships (r = 0.572); and medication and written/verbal information (r = 0.586). Moderate correlations were found with EQ5d items assessing the same measure, including: EQ5d 'problems taking care of self' and CANE self-care (r = 0.578) and daytime activities (r = 0.523); EQ5d 'problems performing usual activities' and CANE daytime activities (r = 0.553), self-care (r = 0.511) and mobility (r = 0.500); and EQ5d 'problems while walking' and CANE mobility/falls (r = 0.509). Corresponding items of the CANE and EQ-5d were significantly correlated with similar socio-demographic variables. The factor analysis supported results obtained in the CANE inter-item correlations. CONCLUSIONS: The Arabic version of the CANE appears acceptable in assessing needs of older adults in South Lebanon. Given that the CANE is an interesting tool that promotes the integration of older persons' perspectives for appropriate interventions, further research is recommended to establish its validity and applicability in other communities in Lebanon and the region. PMID- 21815854 TI - Psychotropic medication discussions in older adults' primary care office visits: So much to do, so little time. AB - OBJECTIVES: To examine discussions of psychotropic medications during the older patient's visit to primary care physicians, identify how physician's competing demands influence these discussions, describe different scenarios physicians utilize to address mental health complaints of older adults, and recommend best practices for diagnosing and treating such patients. METHOD: Convenience sample of 59 videotapes of primary care office visits involving mental health discussions in the United States complemented by patient and physician surveys. Videotaped visits were examined using logistic regression for grouped-level data to explore contributions of physician's competing demands to the likelihood of having psychotropic medication discussions. Tape transcripts were selected to provide examples of prescribing and referral behaviors. RESULTS: One-third of these visits contained no psychotropic medication discussions despite its important role in treating mental illnesses. When prescribing psychotropic medicines, physicians presented information about the medication's purpose and brand name more often than adverse effects or usage. More competing demands (i.e., more topics discussed or more leading causes of disability addressed during the visit) were associated with less psychotropic medication discussions. Selected case scenarios illustrate the importance of acknowledging mental illness, prescribing psychotropic medications, explaining the medications, and/or referring patients to mental health providers to address their mental health complaints. CONCLUSION: Competing demands may constrain discussions of psychotropic medications. Given the seriousness of mental illness in late life, system-level changes may be needed to correctly diagnose mental illness, take more proactive actions to improve mental health, and enhance information exchange concerning psychotropic medication in a manner that meets patients' needs. PMID- 21815855 TI - Quality of life and menopause: Developing a theoretical model based on meaning in life, self-efficacy beliefs, and body image. AB - GOAL: There are various views on variables that influence quality of life, such as meaning in life, self-efficacy, and body image (including body area satisfaction, health evaluation, and appearance evaluation), in menopausal women. This study looked at the relationships among these variables both in terms of their codetermination and intensity of relationship to quality of life. METHODS: The research study included menopausal women (45-55 years old) who lived in the city of Tehran and had at least a high school education. The sample consisted of 349 women selected at random from the attendees of cultural centers in the city of Tehran during June 2009-December 2009. Each participant completed four questionnaires, including a questionnaire on meaning in life [Salehi, M. (1994). Evaluating the issue of adolescents and the youth from the view of humanistic psychologists (Psychology PhD dissertation). Islamic Azad University, Research and Sciences Campus, Tehran.], general self-efficacy, multidimensional relation of self and body, and quality of life (sf-36). Structural equation modeling was used to analyze the relationships among variables. Path analysis was used to study the direct and indirect effects of variables as cause. A primary hypothetical model was developed that included the expected relationships among the variables. Confirmation or rejection of the expected relationships in the model was determined after executing the questionnaires and scoring the data. RESULTS: The model fitness was analyzed using various methods. Results showed that there is a significant direct relationship between quality of life and meaning in life, self-efficacy, body area satisfaction, and health evaluation. In addition, the model predicted 33% of quality of life variance in menopausal women. The best predictors were body area satisfaction, health evaluation, and self-efficacy. Step-by-step regression analysis confirmed the results. CONCLUSION: Based on our results, there is a direct and meaningful relationship between the independent variables of this study and the quality of life. Therefore, in order to improve the quality of life in menopausal women, one or all of these variables needs to be improved. PMID- 21815856 TI - Reminiscence and adaptation to critical life events in older adults with mild to moderate depressive symptoms. AB - OBJECTIVES: The role of reminiscence as a way of adapting to critical life events and chronic medical conditions was investigated in older adults with mild to moderate depressive symptoms. Reminiscence is the (non)volitional act or process of recollecting memories of one's self in the past. METHOD: 171 Dutch older adults with a mean age of 64 years (SD = 7.4) participated in this study. All of them had mild to moderate depressive symptoms. Participants completed measures on critical life events, chronic medical conditions, depressive symptoms, symptoms of anxiety and satisfaction with life. The reminiscence functions included were: identity, problem solving, bitterness revival and boredom reduction. RESULTS: Critical life events were positively correlated with identity and problem solving. Bitterness revival and boredom reduction were both positively correlated with depressive and anxiety symptoms, and negatively to satisfaction with life. Problem solving had a negative relation with anxiety symptoms. When all the reminiscence functions were included, problem solving was uniquely associated with symptoms of anxiety, and bitterness revival was uniquely associated with depressive symptoms and satisfaction with life. Interestingly, problem solving mediated the relation of critical life events with anxiety. DISCUSSION: This study corroborates the theory that reminiscence plays a role in coping with critical life events, and thereby maintaining mental health. Furthermore, it is recommended that therapists focus on techniques which reduce bitterness revival in people with depressive symptoms, and focus on problem-solving reminiscences among people with anxiety symptoms. PMID- 21815857 TI - Rhythmic stepping exercise under cognitive conditions improves fall risk factors in community-dwelling older adults: Preliminary results of a cluster-randomized controlled trial. AB - OBJECTIVE: The purpose of this pilot trial was to evaluate whether a 24-week program of rhythmic stepping exercise (RSE) would be effective in improving physical function and reducing fear of falling in older adults. PARTICIPANTS: Four units (n = 52) randomized into an RSE group (two units, n = 25) and a non rhythmic stepping exercise (NRSE) group (two units, n = 27) participated in a pilot cluster randomized controlled trial. METHODS: Each exercise group received 60 min group training sessions once a week for 24 weeks. Measurement was based on the difference in physical functions between the RSE and NRSE groups. RESULTS: Significant differences were observed between the two groups for locomotive function with significant group * time interaction. Relative risk was calculated as 2.778 (95% CI: 1.030-7.492) for fear of falling for participants in the NRSE group compared with patients in the RSE group (p = 0.037). CONCLUSIONS: The results of this pilot trial suggest that the RSE program is more effective in improving locomotive function and fear of falling. PMID- 21815858 TI - How depression and other mental health problems can affect future living standards of those out of the labour force. AB - OBJECTIVES: To estimate the extent to which those who exit the workforce early due to mental health problems have less savings by the time they reach retirement age. METHODS: Using Health & WealthMOD--a microsimulation model of Australians aged 45-64 years that predicts accumulated savings at age 65, regression models were used to analyse the differences between the projected savings and the retirement incomes of people at age 65 for those currently working with no chronic condition, and people not in the labour force due to mental health problems. RESULTS: Females who retire early due to depression have a median value of total savings by the time they are 65 of $300. For those with other mental health problems the median figure was $0. This is far lower than the median value of $227,900 for females with no chronic condition who remained employed full time. Males showed similar differences. Both males and females who were out of the labour force due to depression or other mental health problems had at least 97% (95% CI: -99.9% to -68.7%) less savings and retirement income by age 65 that those who remained employed full-time. CONCLUSIONS: People who retire from the labour force early due to mental health problems will face long term financial disadvantage compared to people who are able to remain in employment. PMID- 21815859 TI - Changes in locomotive rates during senior elite rugby league matches. AB - The aim of this study was to quantify the changes in locomotive rates across the duration of senior elite rugby league matches. A semi-automated image recognition system (ProZone 3, ProZone(r), Leeds, England) was used to track the movements of 59 players from six teams during three competitive matches. The players were classified into one of four positional groups: props (n = 9), back row (n = 9), pivots (n = 14) or outside backs (n = 27). Players' movements were classified as low, high or very high intensity running and reported as locomotive rates (distance covered per minute played) for successive quarters of each match. Analysis of variance revealed that only the outside backs showed a significantly lower overall locomotive rate during the final quarter compared to the first (P < 0.05). However, locomotive rates for high and very high intensity running during the final quarter were significantly lower (P < 0.05) than the first quarter among outside backs, pivots and props despite no change in the rate of involvements in contact. On the basis of these findings, it is suggested that high and very high intensity running locomotive rates may be more affective methods of detecting fatigue during competitive matches than overall locomotive rate. PMID- 21815861 TI - A prospective registration of catheter life and catheter interventions in patients with long-term indwelling urinary catheters. AB - OBJECTIVE: The aims of this study were to register the incidence of scheduled and acute urinary catheter changes and rinses (acute interventions) among nursing home patients, to relate the incidence of acute interventions to catheter material and time of catheterization, and to register the use of antibiotics for catheter-associated urinary tract infections. MATERIAL AND METHODS: Catheter life and catheter-related interventions were followed prospectively for 1 year in all patients with long-term indwelling catheters in all 78 nursing homes in a county in western Sweden. RESULTS: Altogether, 366 patients were followed: 117 (32%) women and 249 (68%) men. Acute changes (n = 718) were more common than scheduled ones (n = 519). The rate of acute interventions was not related to catheter material and was significantly lower in patients with a catheter for over 2 years. In 25% of the patients, acute interventions were virtually never necessary, in contrast to 10% where acute interventions were registered nearly every month. Antibiotic treatment for reasons assumed to be related to the urinary tract was instituted on 170 occasions among 85 men (34%) and 20 women (17%), a significant difference between the genders (p < 0.01). CONCLUSIONS; No catheter material appeared to be superior. The surprising finding that acute interventions were less common after 2 years' catheterization needs further study to be verified and explained. Only 10-25% had a more frequent need for acute interventions and are candidates for future interventional studies. PMID- 21815862 TI - Gastrointestinal transit in patients with systemic sclerosis. AB - BACKGROUND: Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis and collagen deposits. Gastrointestinal symptoms of SSc, including abdominal pain, bloating and discomfort, are common but diffuse and their pathophysiology remains obscure. AIM: To investigate the pathophysiology of abdominal pain and discomfort in individuals with SSc. METHODS: A total of 15 individuals with SSc (13 women, median age 58 years), all suffering from diffuse abdominal symptoms, and 17 healthy volunteers (12 women, median age 52 years) were evaluated with the Motility Tracking System, MTS-1, measuring gastric emptying (GE) and velocity through the small intestine. SSc patients were also examined for bacterial overgrowth using the hydrogen breath test and with radiopaque markers to determine the total gastrointestinal transit time (GITT). RESULTS: Assessed with the MTS-1, the velocity through the proximal small intestine was significantly reduced in SSc patients (median 0.525 m/h, range 0.11 1.15) when compared to healthy subjects (median 0.91 m/h, range 0.51-1.74) (p = 0.02). Prolonged GE was found in 4 SSc patients (27%) but in none of the healthy volunteers (p = 0.04). Only 3 SSc patients (21%) had positive breath tests for small intestinal bacterial overgrowth. GITT was >3 days in 8 patients (53%). Slow small intestinal transit was associated with a prolonged GITT (p < 0.05). CONCLUSION: Velocity through the small intestine is significantly reduced in SSc patients with diffuse abdominal symptoms. PMID- 21815863 TI - Strong predictors for alcohol recidivism after liver transplantation: non acceptance of the alcohol problem and abstinence of <3 months. AB - OBJECTIVE: Alcohol-toxic liver cirrhosis (ALC) is one of the main indications for liver transplantation (LT). The aim of the study is to define predictors for alcohol recidivism and to identify the outcome and quality of life of such patients. MATERIAL AND METHODS: From March 2003 to July 2009, 226 patients underwent LT in our centre. In 53% liver cirrhosis was caused by alcohol abuse (sole/cofactor). Outcome and alcohol recidivism were assessed using patients' records, laboratory tests and interviews (patient, family members and family doctor). Furthermore, patients received an SF-36 quality of life and a self designed questionnaire anonymously. RESULTS: Mean follow-up after LT was 31 + 23 months. The 5-year survival rate after LT in patients with ALC was significantly better compared to patients with other indications (78 vs. 64%; p = 0.016). Quality of life of both patient groups was comparable. After LT, alcohol recidivism rate was 16%. Patients with an alcohol abstinence of <3 months before LT had a significantly higher (p = 0.012) rate of alcohol recidivism in comparison to those with an abstinence of >3 months. Another predictor for alcohol recidivism was the patients' non-acceptance of having an alcohol problem before LT (p = 0.001). CONCLUSIONS: ALC is a good indication for LT. An alcohol abstinence of <3 months before LT and a non-acceptance of having an alcohol problem are strong predictors for alcohol recidivism after LT. PMID- 21815864 TI - HVR-1 heterogeneity during treatment with telaprevir with or without pegylated interferon alfa-2a. AB - BACKGROUND: The extensive heterogeneity of the hypervariable region-1 (HVR-1) of hepatitis C virus (HCV) evidences the high genetic flexibility of HCV and was shown to be associated with virologic response to interferon-alpha-based therapies. However, the evolution of HVR-1 heterogeneity during treatment with directly acting antivirals has not been studied. METHODS: Clonal sequence analysis of HVR-1 quasispecies in the serum of patients who were treated with telaprevir (3 * 750 mg/day) alone, telaprevir plus pegylated interferon-alpha-2a (pegIFN-alpha-2a), or pegIFN-alpha-2a plus placebo for 14 days was performed. HVR 1 heterogeneity, expressed as Shannon complexity and Hamming distance, was analyzed with virologic response and with the emergence of variants associated with resistance to telaprevir. RESULTS: HVR-1 heterogeneity at baseline was not associated with response to telaprevir-based therapy (Shannon complexity 0.34 vs. 0.55, p = 0.38; Hamming distance 0.15 vs. 0.23, p = 0.51; for patients with or without viral breakthrough, respectively). No significant changes in HVR-1 complexity were observed from baseline to day 4 of therapy in patients in whom a continued decline in HCV RNA was observed (Shannon complexity = 0.55 vs. 0.51, p = 0.67; Hamming distance = 0.23 vs. 0.25, p = 0.81, respectively). This was similar in patients with viral breakthrough associated with telaprevir-resistant variants (Shannon complexity = 0.34 vs. 0.42, p = 0.68; Hamming distance = 0.15 vs. 0.2, p = 0.50, at baseline and day 4, respectively). CONCLUSIONS: Baseline and on-treatment HVR-1 heterogeneity are not associated with early viral response to telaprevir-based therapy. PMID- 21815865 TI - Impedance measurements and high-resolution manometry help to better define rumination episodes. AB - BACKGROUND: Rumination syndrome is a disorder of unknown etiology characterized by regurgitation of recently ingested food. We aimed to improve the diagnosis of rumination syndrome by classification of separate rumination symptoms using (1) an ambulatory manometry/impedance (AMIM) measurement and (2) a single-catheter high-resolution manometry/impedance (HRIM) measurement. METHODS: A total of 96 symptoms during AMIM and 37 symptoms during HRIM were analyzed in five patients with clinically diagnosed rumination syndrome. KEY RESULTS: AMIM identified rumination events in 85 out of 96 reported symptoms (symptom index (SI): 89%). Of these events, 63% were non-acidic and would have been missed by pH-metry. HRIM identified 32 out of 37 reported symptoms (SI: 86%). Upper esophageal sphincter (UES) relaxation was observed during all rumination events identified by HRIM and could be an additional criterion in the definition of rumination events. CONCLUSIONS: Impedance measurement and high-resolution manometry contribute to a more detailed description of rumination events. Rumination events defined as gastric strain, common cavity phenomenon, retrograde esophageal fluid flow, and UES relaxation show a high SI when measured with AMIM or single-catheter HRIM. PMID- 21815866 TI - Risk factors for peptic ulcer bleeding in terms of Helicobacter pylori, NSAIDs, and antiplatelet agents. AB - OBJECTIVES: The role of the Helicobacter pylori, nonsteroidal anti-inflammatory drugs (NSAIDs), and antiplatelet agents in the risk of peptic ulcer bleeding has not yet been established. This study was performed to identify the risk factors for peptic ulcer bleeding compared with non-bleeding peptic ulcer disease (PUD). MATERIAL AND METHODS: A total of 475 patients, 265 with bleeding PUD and 210 with non-bleeding PUD were consecutively recruited. H. pylori status was determined by histology, rapid urease test, and culture. Exposure to NSAIDs, aspirin, and antiplatelet agents (clopidogrel and ticlopidine) within 4 weeks was obtained. RESULTS: Compared with non-bleeding PUD, bleeding PUD had a higher proportion of male gender and current smoking, alcohol drinking, history of aspirin/antiplatelet use, and history of PUD. Whereas the proportion of H. pylori infection and history of H. pylori eradication in bleeding PUD were significantly lower than that in non-bleeding PUD. In multivariate analysis, male gender (OR 1.78, 95% CI 1.10-2.89), drinking alcohol (OR 2.08, 95% CI 1.29-3.14), aspirin/antiplatelet use (OR 2.35, 95% CI 1.45-3.82), and history of PUD (OR 2.46, 95% CI 1.36-4.46) remained independent risk factors for bleeding PUD. When H. pylori status and aspirin/antiplatelet agent use were combined, highest risk of bleeding peptic ulcers was found among H. pylori-negative patients with a history of aspirin/antiplatelet agent use (OR 3.03 95% CI 1.48-6.18) compared with H. pylori-positive patients with no history of aspirin/antiplatelet agent use. CONCLUSIONS: Patients with H. pylori-negative peptic ulcers who continuously took aspirin or antiplatelet agents had the highest peptic ulcer bleeding risk. PMID- 21815867 TI - Emergency surgery for ruptured sinus of Valsalva aneurysms. AB - OBJECTIVES: A ruptured sinus of Valsalva aneurysm is a very rare cardiac anomaly. Successful repair of these aneurysms was first described in the late 1950s. Several approaches for repair, through the aortic root or the chamber into which the aneurysm ruptures or a combination of both, have been described. We present our experience with emergency surgical repair of ruptured sinus of Valsalva aneurysms and our current surgical policy. DESIGN: A review of the St. Antonius Hospital database from January 1972 to December 2010 identified a total of 16 patients. A retrospective review of their medical records and telephonic follow up was performed. RESULTS: Fifteen patients (13 male, three female) aged 46 ? 13 years were operated. The ruptured aneurysm arose from the right coronary (63%) and non-coronary sinus (37%) and ruptured into the right ventricle (67%) and into right atrium (33%). Primary suture closure was done in six patients and patch closure was performed in the remaining 10 patients. No intra-operative death occurred. Long-term follow-up identified one recurrent fistula from right coronary sinus to right atrium 28 years after primary suture closure. CONCLUSIONS: We performed prompt surgical repair of the ruptured sinus of Valsalva aneurysm preferably with a patch. PMID- 21815870 TI - Permissible performance limits of regression analyses in method comparisons. AB - Method comparisons are indispensable tools for the extensive validation of analytic procedures. Laboratories often only want to know whether an established procedure (x-method) can be replaced by another one (y-method) without interfering with diagnostic purposes. Then split patients' samples are analyzed more or less simultaneously with both procedures designed to measure the same quantity. The measured values are usually presented graphically as a scatter or difference plots. The two methods are considered to be equivalent (comparable) if the data pairs scatter around the line of equality (x=y line) within permissible equivalence lines. It is proposed to derive these limits of permissible imprecision limits which are based on false-positive error rates. If all data pairs are within the limits, both methods lead to comparable false error rates. If one or more data pairs are outside the permissible equivalence limits, the x method cannot simply be replaced by the y-method and further studies are required. The discordance may be caused either by aberrant values (outliers), non linearity, bias or a higher variation of e.g., the y-values. The spread around the line of best fit can detect possible interferences if more than 1% of the data pairs are outside permissible spread lines in a scatter plot. Because bias between methods and imprecision can be inter-related, both require specific examinations for their identification. PMID- 21815871 TI - Evaluation of the gene encoding calcium and diacylglycerol regulated guanine nucleotide exchange factor I (CalDAG-GEFI) in human patients with congenital qualitative platelet disorders. PMID- 21815872 TI - Hypothermia-induced thrombocytopenia in an elderly woman. PMID- 21815868 TI - Cardiac function in relation to rhythm outcome after intraoperative epicardial left atrial cryoablation. AB - OBJECTIVES: To assess the effects of intraoperative left atrial epicardial cryoablation on rhythm and atrial and ventricular function. DESIGN: Thirty five patients with coronary artery disease and documented atrial fibrillation underwent coronary artery bypass surgery and concomitant cryoablation. An age and gender matched control group of 35 patients with atrial fibrillation underwent bypass surgery alone. Echocardiography was performed 9 ? 32 days before and 22 ? 6 months after surgery. RESULTS: The proportion of patients in sinus rhythm at follow-up was 63% and 34% (p = 0.04) in the cryoablation and control groups, respectively. In patients with sinus rhythm both before surgery and at follow-up, the left atrial area increased (p = 0.002) and the mitral annular excursion during atrial contraction decreased (p = 0.01) after cryoablation. The mitral flow velocity during atrial systole decreased after cryoablation (p = 0.002). The LV diameter increased (p = 0.03) and the left ventricular ejection fraction (LVEF) decreased (p = 0.03) in cryoablated but not in control patients. Continued deterioration was seen in patients with atrial fibrillation both pre- and postoperatively. CONCLUSIONS: At long-term follow-up, a significantly higher proportion of patients was in sinus rhythm in the cryoablation than in the control group. The atrial and ventricular function had decreased at follow-up two years after surgery. This decrease was small and occurred within or close to the reference values in patients with sinus rhythm at follow-up, while patients remaining in atrial fibrillation showed a significant continued deterioration. Some subgroups were small, and the findings, although statistically significant, should be interpreted with caution. PMID- 21815873 TI - Investigation of CD24 and its expression in Iranian relapsing-remitting multiple sclerosis. AB - CD24 is a glycosylphosphatidylinositol (GPI)-linked cell surface glycoprotein expressed in central nervous system cells. Recent investigations have suggested that CD24 participates in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). However, a limited number of studies have been published regarding the contribution of CD24 to the risk and severity of MS in humans. We investigated the contribution of a CD24 single nucleotide polymorphism (SNP) to MS disease risk and severity. We also studied mRNA expression of the CD24 gene in Iranian MS patients using quantitative real-time polymerase chain reaction (PCR). Our findings showed that the CD24(v/v) genotype was significantly more frequent in MS patients compared with controls (p(c) = .004). Moreover, a statistically significant difference in the Multiple Sclerosis Severity Score (MSSS) was found between MS patients carrying CD24(a/a) and CD24(v/v) genotypes (p = .008). The results also indicated that the expression of CD24 mRNA was 1.7 times more in MS patients compared with controls. In conclusion, our results suggest that the CD24(v/v) genotype influences both MS disease risk and severity in Iranian MS patients, and the high disease severity in CD24(v/v) patients may indicate that they require more aggressive treatment than do patients carrying CD24(a/a). PMID- 21815874 TI - Congestive heart failure after physical exercise in a young patient with myotonic dystrophy type 1. AB - Cardiac involvement, such as conduction defects, is common in myotonic dystrophy type 1 (DM1), but congestive heart failure (CHF) is rare in young patients. A 21 year-old recruit was admitted in the department of cardiology with acute CHF after daily physical exercise for about one week in the boot camp. After recovery, neurologic consultation was requested for his general weakness and lean body mass. He was diagnosed as DM1. He denied any prior cardiac symptoms. We cautiously postulated that excessive physical activity might contribute to develop CHF in DM1 patients. Other possible mechanisms will be discussed. Comprehensive cardiac evaluation might be helpful to identifying high-risk patients early to prevent cardiac complications, even without cardiac symptoms. PMID- 21815876 TI - Effect of ibuprofen on bilirubin-albumin binding during the treatment of patent ductus arteriosus in preterm infant. AB - Ibuprofen carries the theoretical risk of increasing bilirubin encephalopathy by displacing bilirubin from albumin binding sites. Indeed, ibuprofen displaces bilirubin from albumin binding site at high concentrations in vitro. The first results in vivo seem to demonstrate no displacement of bilirubin in preterm infants treated by the current recommended doses of 10-5-5 mg/kg/day and when total bilirubin levels are below 10 mg/dL. However, this study does not provide information about possible risks of ibuprofen (IBU) use, when the bilirubin levels are higher than 10 mg/dL or if higher IBU doses are used. PMID- 21815877 TI - New therapeutic strategies for the treatment of patent ductus arteriosus in preterm infants. AB - A high percentage of preterm infants fails to respond to a single course of indomethacin or ibuprofen. Thus, it has been suggested that the actual dose regimens of these drugs could be inadequate because of large interindividual pharmacokinetics variations in premature infants. We tested the hypothesis that a high-dose regimen of ibuprofen was more effective than the current regimen in closing PDA. We demonstrated that a single course of ibuprofen at 20-10-10 mg/kg/day is more effective than a 10-5-5 mg/kg/day course in closing PDA without significant adverse effects. Many other questions regarding the pharmacological treatment of PDA are still debated. PMID- 21815878 TI - Topical Imiquimod 5% cream therapy for external anogenital warts in pregnant women: report of four cases and review of the literature. AB - OBJECTIVES: Imiquimod 5% cream (Aldara, Meda Farm, Milan, Italy) is largely used for the treatment of anogenital warts. However, its use during pregnancy is not consolidated with only a small number of patients worldwide that have been treated. The aim of this study is to assess the first line therapeutic efficacy and safety of Imiquimod 5% cream in pregnant women with external anogenital warts, including extensive condylomata. STUDY DESIGN: Four pregnant women's with external anogenital warts were treated with Imiquimod 5% cream, three times a week for four weeks. RESULTS: Mean number of warts treated per patient was 4.5 (5 SD) and mean area treated was 3.2 cm(2) (1.7 SD). A complete response was observed in two women, while two women had a partial response with a rate of clearing of 70% and 84% respectively. No cases of severe adverse local effects were observed in the sites of Imiquimod application. No adverse fetal outcomes or fetal and neonatal abnormalities were observed. No complications were observed in the postpartum and follow-up period. CONCLUSIONS: Anogenital warts treatment with Imiquimod in pregnancy seems to be promising and not compromise a good pregnancy outcome, in extensive condylomata too. These preliminary data need to be confirmed by larger studies. Similarly, no definitive conclusion may be obtained form a systematic review of the English literature. PMID- 21815880 TI - Determination of the carrier frequencies of selected GJB2 mutations in the Korean population. AB - OBJECTIVE: Mutations in the GJB2 gene are a major cause of hereditary hearing loss. However, only a few studies have investigated carrier frequencies of GJB2 mutations in the general population. The aim of this study was to estimate the carrier frequencies of three GJB2 mutations, including 235delC, V37I, and G45E, in the general Korean population. DESIGN: A standard questionnaire of self reported hearing loss was used to identify and recruit subjects. Screening for three mutations was performed using an allele-specific polymerase chain reaction (PCR), PCR-restriction fragment length polymorphism, and direct DNA sequencing. STUDY SAMPLE: A total of 1256 unrelated healthy individuals were analysed in the present study. RESULTS: Of the 1256 individuals, 24 had GJB2 mutations; 11 were found to be heterozygous for 235delC, 11 were heterozygous and one was homozygous for V37I, and one was heterozygous for G45E. One individual had a compound heterozygous mutation of 235delC/V37I. The allele frequencies of 235delC, V37I, and G45E mutations were 0.44%, 0.52%, and 0.04%, respectively. The carrier frequency of either the 235delC or V37I mutation was estimated to be 0.88% with 95% binomial CI, 0.44-1.56. CONCLUSIONS: These results will facilitate diagnosis of, and genetic counseling for, hearing loss in Koreans. PMID- 21815879 TI - Overcoming limitations of current antiplatelet drugs: a concerted effort for more profitable strategies of intervention. AB - Platelets play a central role in the pathophysiology of atherothrombosis, an inappropriate platelet activation leading to acute ischemic complications (acute myocardial infarction, ischemic stroke). In view of this, platelets are a major target for pharmacotherapy. Presently, the main classes of antiplatelet agents approved for the use in such complications are aspirin and thienopyridines. Although antiplatelet treatment with these two types of drugs, alone or in combination, leads to a significant reduction of non-fatal myocardial infarction (-32%), non-fatal stroke (-25%), and of cardiovascular death (-17%), a residual risk persists. Newer antiplatelet agents have addressed some, but not all, these limitations. Vis-a-vis their net clinical benefit, the higher potency of some of them is associated with a rise in bleeding complications. Moreover, newer thienopyridines do not show advantages over and above the older ones as to reduction of stroke. A concerted effort that takes into consideration clinical, genetic, and laboratory information is increasingly recognized as a major direction to be pursued in the area. The well-established road signs of clinical epidemiology will provide major information to define newer potentially useful targets for platelet pharmacology. PMID- 21815881 TI - Lapabot: a compact telesurgical robot system for minimally invasive surgery: part II. Telesurgery evaluation. AB - As described in Part I, the Lapabot was developed considering telesurgery from the initial design stage. The robot configuration is based on the master-slave structure in which the operator can be separated spatially from the patient. The distributed control architecture communicating through high-speed network enables remote control of surgical robot manipulators. In this work, we added network communication modules using user datagram protocol/internet protocol for implementation of the telesurgical system. For a stable network environment, a dedicated research network was adopted. To characterize the network environment, a data packet sender and a repeater whose packet length and packet structure are similar to those of the real data packet were developed. The developed system was evaluated through in-vitro and in-vivo experiments. With the developed system, we have successfully performed remote control of the Lapabot. The roundtrip time delay for the control signal ranged from 1.4 to 4.1 ms. The total time delay for the operator including image signal acquisition and transmission delays was under 333 ms. It did not impede surgical procedures. Initial evaluation results demonstrate the feasibility of the developed telesurgical system. PMID- 21815882 TI - Calcium and magnesium in exhaled breath condensate of children with endogenous and exogenous airway acidification. AB - BACKGROUND AND AIMS: Regulation of pH in the airways is of physiological importance. As acidification of the airways causes bronchoconstriction, the aim of the present study was to find out whether there is any difference in calcium and magnesium in exhaled breath condensate (EBC) of children with uncontrolled asthma (i.e., with endogenous acidification) and children with gastroesophageal reflux disease, GERD (i.e., with exogenous acidification). MATERIAL AND METHODS: A total of 142 children were included in the study: children with uncontrolled asthma (N = 51), children with GERD (N = 61), and healthy controls (N = 30). In addition, according to the pH cut-off value children with asthma and GERD were divided into two subgroups, that is, patients with pH <= 6.93 (subgroup A) and patients with pH > 6.93 (subgroup B). RESULTS: The mean EBC pH was significantly lower in children with asthma than in children with GERD (6.791 +/- 0.374 vs. 7.002 +/- 0.361, p = .006). Concentration [median and interquartile range-M (IQR)] of total magnesium, but not calcium, was lower in both asthmatic [(10 (10 40) MUmol/L, p = .016)] and GERD children [(20 (10-40) MUmol/L, p = .012)] in comparison with controls (47 +/- 27 MUmol/L). There was no statistically significant difference in EBC calcium and magnesium concentrations between asthmatic and GERD children. In asthmatic children a positive correlation was confirmed between forced expiratory volume in the first second (FEV1) and magnesium in EBC (r = 0.307; p = .030), and negative correlation was found between FEV1 and calcium/magnesium ratio (r = -0.290; p = .047). In addition, positive correlation was confirmed between fractional concentration of exhaled NO and calcium/magnesium ratio (r = 0.360; p = .018). In GERD patients a negative correlation (r = -0.404; p = .003) was found between magnesium and pH values. Concentration of calcium was higher in the GERD subgroup A children [(50 (30-90) MUmol/L)] than in the subgroup B children [(30 (20-45) MUmol/L, p = .031)]. In addition, concentration of magnesium was higher in the GERD subgroup A children [(30 (20-70) MUmol/L)] than in the subgroup B children [(10 (10-20) MUmol/L, p < .001)]. CONCLUSION: The present study indicates that decreased total magnesium concentration may be found in EBCs, irrespective of whether the acidification is the result of endogenous pathomechanisms or reflux-induced mechanisms. In children with GERD, EBC pH-metry should be performed after acute coughing episode. Future research is needed to investigate the mechanisms of onset and dynamics of these changes. SCIENTIFIC SIGNIFICANCE: Lower concentration of magnesium may indicate its role in bronchoconstiction. PMID- 21815883 TI - Evidence for Serpentine as a novel antioxidant by a redox sensitive HABP1 overexpressing cell line by inhibiting its nuclear translocation of NF-kappaB. AB - Herbal antioxidants are gradually gaining importance as dietary supplements considering the growing implications of oxidative stress in most degenerative diseases and aging. Thus, continuous attempts are made to search for novel herbal molecules with antioxidative properties, using chemical methods predominantly with the need arising for cell based assays. We have generated a stable cell line F-HABP07, by constitutively overexpressing human Hyaluronan Binding Protein1 (HABP1) in murine fibroblasts which accumulates in the mitochondria leading to excess ROS generation without any external stimuli. In the present study, we demonstrated the nuclear translocation of p65 subunit of NF-kappaB in F-HABP07 cells, an important signature of ROS induced signalling cascade providing us an opportunity to use it as a screening system for ROS scavengers. Using known antioxidants on our designer cell line, we have demonstrated a dose dependant reduction in ROS generation and observed inhibition of p65 subunit of NF-kappaB nuclear translocation, increase in glutathione content and down-regulation of apoptotic marker Bax establishing its antioxidant biosensing capacity. With the help of this cell line, we for the first time demonstrated serpentine, one of the active components from the roots of Rauwolfia serpentina (a traditional medicinal plant), to be a novel non-cytotoxic antioxidant. The authenticity of this cell line screening system based discovery was validated using standard chemical assays thus, opening up new therapeutic avenues for this herbal compound and the use of this designer cell line. PMID- 21815884 TI - A novel homozygous mutation of DARS2 may cause a severe LBSL variant. PMID- 21815885 TI - Screening for nuclear genetic defects in the ATP synthase-associated genes TMEM70, ATP12 and ATP5E in patients with 3-methylglutaconic aciduria. PMID- 21815886 TI - First large rearrangement in the MUTYH gene and attenuated familial adenomatous polyposis syndrome. PMID- 21815887 TI - Visit-to-visit variability in blood pressure strongly predicts all-cause mortality in patients with type 2 diabetes: a 5.5-year prospective analysis. AB - BACKGROUND: Elevations in blood pressure and visit-to-visit variability have been found to significantly increase the risk of cardiovascular morbidity and mortality in nondiabetic individuals. This study has assessed the association between all-cause mortality and blood pressure parameters [systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP), mean arterial pressure (MAP) and visit-to-visit variability] in patients with type 2 diabetes. MATERIALS AND METHODS: A longitudinal cohort study of 2161 patients with type 2 diabetes and a mean follow-up period of 66.7 +/- 7.5 months. Using Cox regression models, blood pressure parameters were related to the risk of all cause mortality. RESULTS: Visit-to-visit variability in SBP [HR: 1.048 (95% CI: 1.005-1.092; P = 0.03)], DBP [HR: 1.090 (95% CI: 1.021-1.163; P = 0.01)] and MAP [HR: 1.099 (95% CI: 1.033-1.170; P = 0.003)] significantly predicted all-cause mortality in patients with type 2 diabetes after adjusting for baseline data, mean follow-up blood pressure profiles and HbA1c. Visit-to-visit variability in PP [HR: 1.139 (95% CI: 1.030-1.258; P = 0.01)] significantly predicted cardiovascular mortality. Neither baseline nor follow-up SBP, DBP, PP nor MAP was significantly associated with all-cause and cardiovascular mortality after adjusting for blood pressure variability. The risk of all-cause mortality with a mean follow-up SBP has a U-shaped distribution. Patients with a mean follow-up DBP > 90 mmHg were at higher risk of mortality than those with DBP < 90 mmHg. CONCLUSIONS: Visit-to-visit variability in blood pressure was significantly associated with all-cause mortality independent of mean BP in patients with type 2 diabetes. The data for blood pressure variability might be regarded as a potentially important therapeutic target in the management of type 2 diabetes. PMID- 21815889 TI - Neurostimulation for primary headache disorders, part 1: pathophysiology and anatomy, history of neuromodulation in headache treatment, and review of peripheral neuromodulation in primary headaches. AB - Neurostimulation for primary headaches is being increasingly utilized as a treatment modality. Use of neuromoduation has generated multiple case reports as well as some controlled studies. This article is the first of 2 systematic reviews of available data regarding neurostimulation for primary headache conditions. The pathophysiology, relative anatomy, theoretical mechanisms, and history of neurostimulation for primary headache are covered in this section, Part 1 of 2. The literature regarding peripheral neurostimulatory targets is also reviewed in Part 1. These peripheral targets include: percutaneous nerves, transcranial holocephalic, occipital nerves, auriculotemporal nerves, supraorbital nerves, cervical epidural, and sphenopalatine ganglia. Part 2 will focus on central stimulation, covering vagus nerve, and deep brain stimulation. Part 2 also contains an overall analysis of efficacy, safety, cost, patient selection, and suggestions for further study based on available evidence. PMID- 21815890 TI - Evaluating sampling completeness in a desert plant-pollinator network. AB - 1. The study of plant-pollinator interactions in a network context is receiving increasing attention. This approach has helped to identify several emerging network patterns such as nestedness and modularity. However, most studies are based only on qualitative information, and some ecosystems, such as deserts and tropical forests, are underrepresented in these data sets. 2. We present an exhaustive analysis of the structure of a 4-year plant-pollinator network from the Monte desert in Argentina using qualitative and quantitative tools. We describe the structure of this network and evaluate sampling completeness using asymptotic species richness estimators. Our goal is to assess the extent to which the realized sampling effort allows for an accurate description of species interactions and to estimate the minimum number of additional censuses required to detect 90% of the interactions. We evaluated completeness of detection of the community-wide pollinator fauna, of the pollinator fauna associated with each plant species and of the plant-pollinator interactions. We also evaluated whether sampling completeness was influenced by plant characteristics, such as flower abundance, flower life span, number of interspecific links (degree) and selectiveness in the identity of their flower visitors, as well as sampling effort. 3. We found that this desert plant-pollinator network has a nested structure and that it exhibits modularity and high network-level generalization. 4. In spite of our high sampling effort, and although we sampled 80% of the pollinator fauna, we recorded only 55% of the interactions. Furthermore, although a 64% increase in sampling effort would suffice to detect 90% of the pollinator species, a fivefold increase in sampling effort would be necessary to detect 90% of the interactions. 5. Detection of interactions was incomplete for most plant species, particularly specialists with a long flowering season and high flower abundance, or generalists with short flowering span and scant flowers. Our results suggest that sampling of a network with the same effort for all plant species is inadequate to sample interactions. 6. Sampling the diversity of interactions is labour intensive, and most plant-pollinator networks published to date are likely to be undersampled. Our analysis allowed estimating the completeness of our sampling, the additional effort needed to detect most interactions and the plant traits that influence the detection of their interactions. PMID- 21815888 TI - Microcephalic osteodysplastic primordial dwarfism type I with biallelic mutations in the RNU4ATAC gene. AB - Microcephalic osteodysplastic primordial dwarfism type I (MOPD I) is a rare autosomal recessive developmental disorder characterized by extreme intrauterine growth retardation, severe microcephaly, central nervous system abnormalities, dysmorphic facial features, skin abnormalities, skeletal changes, limb deformations, and early death. Recently, mutations in the RNU4ATAC gene, which encodes U4atac, a small nuclear RNA that is a crucial component of the minor spliceosome, were found to cause MOPD I. MOPD I is the first disease known to be associated with a defect in small nuclear RNAs. We describe here the clinical and molecular data for 17 cases of MOPD I, including 15 previously unreported cases, all carrying biallelic mutations in the RNU4ATAC gene. PMID- 21815891 TI - Dying like rabbits: general determinants of spatio-temporal variability in survival. AB - 1. Identifying general patterns of how and why survival rates vary across space and time is necessary to truly understand population dynamics of a species. However, this is not an easy task given the complexity and interactions of processes involved, and the interpopulation differences in main survival determinants. 2. Here, using European rabbits (Oryctolagus cuniculus) as a model and information from local studies, we investigated whether we could make inferences about trends and drivers of survival of a species that are generalizable to large spatio-temporal scales. To do this, we first focused on overall survival and then examined cause-specific mortalities, mainly predation and diseases, which may lead to those patterns. 3. Our results show that within the large-scale variability in rabbit survival, there exist general patterns that are explained by the integration of factors previously known to be important at the local level (i.e. age, climate, diseases, predation or density dependence). We found that both inter- and intrastudy survival rates increased in magnitude and decreased in variability as rabbits grow old, although this tendency was less pronounced in populations with epidemic diseases. Some causes leading to these higher mortalities in young rabbits could be the stronger effect of rainfall at those ages, as well as, other death sources like malnutrition or infanticide. 4. Predation is also greater for newborns and juveniles, especially in population without diseases. Apart from the effect of diseases, predation patterns also depended on factors, such as, density, season, and type and density of predators. Finally, we observed that infectious diseases also showed general relationships with climate, breeding (i.e. new susceptible rabbits) and age, although the association type varied between myxomatosis and rabbit haemorrhagic disease. 5. In conclusion, large-scale patterns of spatio-temporal variability in rabbit survival emerge from the combination of different factors that interrelate both directly and through density dependence. This highlights the importance of performing more comprehensive studies to reveal combined effects and complex relationships that help us to better understand the mechanisms underlying population dynamics. PMID- 21815893 TI - An emerging income differential for adolescent emotional problems. AB - BACKGROUND: While there is considerable evidence of income gradients in child and adolescent behaviour problems, evidence relating to children and young people's emotional difficulties is more mixed. Older studies reported no income differentials, while recent reports suggest that adolescents from low-income families are more likely to experience emotional difficulties than their more affluent peers. METHODS: We compared the association between low- versus medium /high-family income and parent-reported emotional difficulties in 15- and 16-year olds in three large nationally representative cohorts studied in 1974, 1986 and 1999/2004. We then examined whether increases in the income differential could be accounted for by changes in the association of a range of sociodemographic factors (family type or size, maternal education or housing tenure) with either family income or emotional difficulties. Finally, in the most recent cohorts, we considered whether the effects of these sociodemographic variables were mediated by more proximal family factors (maternal distress, stressful life events or family dysfunction). RESULTS: An increasing income differential in adolescent emotional problems emerged over the period, with standardized coefficients for associations with low income increasing from .07 in 1974 and 1986 to .30 in 1999/2004. This was due partially (~10%) to sociodemographic risk factors for emotional difficulties becoming more strongly associated with low-income families over time, and partially (~40%) to the increasing impact of these risk factors. In the most recent cohorts, about 40% of the effects of sociodemographic risks appear to have been mediated by more proximal family factors. CONCLUSIONS: These findings have implications for our understanding of the health burden of emotional problems, recognition of the health burden associated with inequality and public concern about the consequences of social change. PMID- 21815892 TI - Trends in psychopathology across the adolescent years: what changes when children become adolescents, and when adolescents become adults? AB - BACKGROUND: Little is known about changes in the prevalence of psychiatric disorders between childhood and adolescence, and adolescence and adulthood. METHODS: We reviewed papers reporting prevalence rates of psychiatric disorders separately for childhood, adolescence, and early adulthood. Both longitudinal and cross-sectional papers published in the past 15 years were included. RESULTS: About one adolescent in five has a psychiatric disorder. From childhood to adolescence there is an increase in rates of depression, panic disorder, agoraphobia, and substance use disorders (SUD), and a decrease in separation anxiety disorder (SAD) and attention-deficit hyperactivity disorder (ADHD). From adolescence to early adulthood there is a further increase in panic disorder, agoraphobia, and SUD, and a further decrease in SAD and ADHD. Other phobias and disruptive behavior disorders also fall. CONCLUSIONS: Further study of changes in rates of disorder across developmental stages could inform etiological research and guide interventions. PMID- 21815894 TI - Impact of oppositional defiant disorder dimensions on the temporal ordering of conduct problems and depression across childhood and adolescence in girls. AB - BACKGROUND: Little is known about the role of oppositional defiant disorder (ODD) dimensions on the temporal unfolding of conduct disorder (CD) and depression in girls between childhood and adolescence. METHOD: The year-to-year associations between CD and depressive symptomatology were examined using nine waves of annually collected data (ages 8 through 16 years) from 1215 participants of the Pittsburgh Girls Study. A series of autoregressive path models were tested that included ODD-Emotion Dysregulation (ODD-ED) and ODD-Defiance, as time-varying covariates on CD predicting depression severity in the following year, and vice versa. RESULTS: Conduct problems, depression, and ODD dimensions were relatively stable throughout childhood and adolescence, and a moderate degree of covariance was observed between these variables. Path analyses showed that CD often preceded depression across this developmental period, although the effect sizes were small. There was less consistent prediction from depression to CD. The overlap between ODD-ED and CD partially explained the prospective relations from CD to depression, whereas these paths were fully explained by the overlap between ODD ED and depression. The overlap between ODD-Defiance and CD did not account for the prospective relations from CD to depression. In contrast, the overlap between ODD-Defiance and depression accounted for virtually all paths from CD to depression. Accounting for the overlap between ODD dimensions and both CD and depression eliminated all significant predictive paths. CONCLUSIONS: Symptoms of CD tend to precede depression in girls during childhood and adolescence. However, covariance between depression and both ODD-ED and ODD-Defiance accounts for these prospective relations. ODD dimensions should be assessed when evaluating risk for comorbid depression in girls with conduct problems, and emotion dysregulation and defiance aspects of ODD should be identified as targets for treatment in order to prevent depression in the future. PMID- 21815897 TI - The European College of Veterinary Surgeons 1991-2011: a 20-year success story. AB - The first meeting leading to the formation of the European College of Veterinary Surgeons (ECVS) was held August 30/31, 1990 in Lenzburg, Switzerland. Specialists in small animal and large animal surgery from practice and academicians from many European countries were invited. The constitution was developed based on that of the American College of Veterinary Surgeons (ACVS). ECVS was founded during the ACVS European Surgical Forum in Nice in 1991. The provisional Board elected at this meeting stayed active during the initial 4 years to provide stability. For the 146 Charter Members to become a Diplomate, they had to pass an examination. Therefore, the ECVS is the only Specialty College that does not have a "Grand Father Clause." In 2000 ECVS, was the first College to acquire full recognition status by the European Board of Specialization (EBVS), which underlines the leading role the surgeons play in the development of the European veterinary specialty colleges. Like its American Sister College, ECVS maintains high standards for surgical training programs for Residents and administers rigorous certifying examinations. It is appropriate to recall the facts that lead to foundation of ECVS on its 20-year anniversary. PMID- 21815896 TI - Auditory brainstem response (ABR) abnormalities across the life span of rats prenatally exposed to alcohol. AB - BACKGROUND: Fetal alcohol syndrome (FAS) is a leading cause of neurodevelopmental impairments (NDIs) in developed countries. Sensory deficits can play a major role in NDI, yet few studies have investigated the effects of prenatal alcohol exposure on sensory function. In addition, there is a paucity of information on the lifelong effects of prenatal alcohol exposure. Thus, we sought to investigate the effects of prenatal alcohol exposure on auditory function across the life span in an animal model. Based on prior findings with prenatal alcohol exposure and other forms of adverse prenatal environments, we hypothesized that animals prenatally exposed to alcohol would show an age-dependent pattern of (i) hearing and neurological abnormalities as postweanling pups, (ii) a substantial dissipation of such abnormalities in young adulthood, and (iii) a resurgence of such abnormalities in middle-aged adulthood. METHODS: Pregnant rats were randomly assigned to an untreated control (CON), a pair-fed control (PFC), or an alcohol treated (ALC) group. The ALC dams were gavaged with 6 mg/kg alcohol daily from gestation day (GD) 6 to 21. The PFC dams were gavaged daily from GD6 to GD21 with an isocaloric and isovolumetric water-based solution of maltose-dextrins and pair fed to the ALC dams. The CON dams were the untreated group to which the ALC and CON groups were compared. Hearing and neurological functions in the offspring were assessed with the auditory brainstem response (ABR) at the postnatal ages of 22, 220, and 520 days. RESULTS: In accord with our hypothesis, ABR abnormalities were first observed in the postweanling pups, largely dissipated in young adulthood, and then resurged in middle-aged adulthood. This age-related pattern suggests that the ALC pups had a developmental delay that dissipated in young adulthood and an enhanced age-related deterioration that occurred in middle-aged adulthood. Such a pattern is consistent with the fetal programming hypothesis of adult-onset diseases (the Barker hypothesis). CONCLUSIONS: Our findings have important clinical implications for the assessment and management of (i) childhood hearing disorders and their comorbidities (i.e., speech-and-language, learning, and attention deficit disorders) and (ii) enhanced age-related hearing and neurological degeneration in middle-aged adulthood that can result from prenatal alcohol exposure. We recommend hearing evaluation be a part of any long term follow-up for FAS patients and patients exposed to any adverse prenatal environment. PMID- 21815898 TI - Peritoneal and plasma D-lactate concentrations in horses with colic. AB - OBJECTIVE: To evaluate the association between peritoneal fluid and plasma d lactate concentration with variables used in the diagnosis and prognosis of horses with colic. ANIMALS: Clinically healthy horses (n=6) and 90 horses with colic. STUDY DESIGN: Prospective cross-sectional study. METHODS: D-lactate concentration was determined in peritoneal fluid and plasma of all horses. Information on other blood and peritoneal fluid variables, signalment, results from the physical examination, outcome, need for surgery, lesion location, and type was retrieved from medical records. RESULTS: Peritoneal D-lactate concentration was strongly correlated with plasma D-lactate concentration (r=0.71; P<.001). Peritoneal and plasma D-lactate concentrations were positively correlated with peritoneal (r=0.8; P<.001) and plasma L-lactate (r=0.33; P=.001) concentrations, respectively. Peritoneal D-lactate concentration was negatively correlated with survival to discharge (U=430.5; P<.001). Median peritoneal D lactate concentration of horses with septic peritonitis (455.2 MUmol/L) and horses with gastrointestinal rupture (599.5 MUmol/L) were higher compared with horses with nonstrangulating obstructions (77.7 MUmol/L). A cut-off concentration of peritoneal D-lactate of 116.6 MUmol/L had a sensitivity of 0.813 and a specificity of 0.651 to differentiate between nonstrangulating and strangulating obstructions. CONCLUSIONS: Peritoneal D-lactate concentration may be more useful for identifying horses with strangulating obstructions (high sensitivity, low probability of a false negative) than to ruling out strangulating obstruction (moderate specificity, high probability of a false positive). PMID- 21815899 TI - Review article: cinnamon- and benzoate-free diet as a primary treatment for orofacial granulomatosis. AB - BACKGROUND: Orofacial granulomatosis is a rare chronic granulomatous inflammatory disease of the lips, face and mouth. The aetiology remains unclear but may involve an allergic component. Improvements have been reported with cinnamon- and benzoate-free diets. AIMS: To explore the prevalence of compound and food sensitivity and examine the dietary treatments used in orofacial granulomatosis. METHODS: A comprehensive literature search was carried out and relevant studies from January 1933 to January 2010 were identified using the electronic database search engines; AGRIS 1991-2008, AMED 1985-2008, British Nursing and Index archive 1985-2008, EMBASE 1980-2008, evidence based medicine review databases (e.g. Cochrane DSR), International Pharmaceutical and Medline 1950-2008. RESULTS: Common sensitivities identified, predominantly through patch testing, were to benzoic acid (36%) food additives (33%), perfumes and flavourings (28%), cinnamaldehyde (27%), cinnamon (17%), benzoates (17%) and chocolate (11%). The cinnamon- and benzoate-free diet has been shown to provide benefit in 54-78% of patients with 23% requiring no adjunctive therapies. A negative or positive patch test result to cinnamaldehyde, and benzoates did not predict dietary outcome. The most concentrated source of benzoate exposure is from food preservatives. Use of liquid enteral formulas can offer a further dietary therapy, particularly in children with orofacial granulomatosis. CONCLUSION: Management of orofacial granulomatosis is challenging but cinnamon- and benzoate-free diets appear to have a definite role to play. PMID- 21815900 TI - Pregnancy outcome in inflammatory bowel disease: prospective European case control ECCO-EpiCom study, 2003-2006. AB - BACKGROUND: Inflammatory bowel disease (IBD) frequently affects women during their reproductive years. Pregnancy outcome in women with IBD is well described, particularly in retrospective studies. AIM: To evaluate the pregnancy outcome in patients with IBD in a prospective European multicentre case-control study. METHODS: Inflammatory bowel disease pregnant women from 12 European countries were enrolled between January 2003 and December 2006 and matched (1:1) to non-IBD pregnant controls by age at conception and number of previous pregnancies. Data on pregnancy and newborn outcome, disease activity and therapy were prospectively collected every third month using a standard questionnaire. Logistic regression analysis with odds ratio was used for statistical analyses. P value<0.05 was considered significant. RESULTS: A total of 332 pregnant women with IBD were included: 145 with Crohn's disease (CD) and 187 with ulcerative colitis (UC). Median age (range) at conception was 31 years (15-40) in CD and 31 (19-42) in UC patients. No statistically significant differences in frequency of abortions, preterm deliveries, caesarean sections, congenital abnormalities and birth weight were observed comparing CD and UC women with their non-IBD controls. In CD, older age was associated with congenital abnormalities and preterm delivery; smoking increased the risk of preterm delivery. For UC, older age and active disease were associated with low birth weight; while older age and combination therapy were risk factors for preterm delivery. CONCLUSION: In this prospective case-control study, women with either Crohn's disease or ulcerative colitis have a similar pregnancy outcome when compared with a population of non-inflammatory bowel disease pregnant women. PMID- 21815901 TI - Association of lactose sensitivity with inflammatory bowel disease--demonstrated by analysis of genetic polymorphism, breath gases and symptoms. AB - BACKGROUND: Sensitivity to lactose has been reported in Crohn's disease, but its true role in inflammatory bowel disease (IBD) is unclear. The genetic marker CC13910, on chromosome2, with measurement of breath hydrogen and methane, and gut and systemic symptoms, are now the most comprehensive tests for evaluating sensitivity to lactose. AIM: To investigate, for the first time, the prevalence of lactose sensitivity in IBD, using the most comprehensive tests for diagnosing this condition. METHODS: Prevalence of CC13910 genotype was investigated using RT PCR in 165 patients (Crohn's disease = 70, ulcerative colitis = 95), and 30 healthy volunteers. Genotype was correlated with breath hydrogen and methane up to 6 h after 50 g of oral lactose, all symptoms being recorded for up to 48 h. Critically, Crohn's disease and ulcerative colitis patients were selected with no record of lactose sensitivity, in remission at the time of the test. RESULTS: Lactose sensitivity occurred in a much higher proportion of patients, (approximately 70%), with IBD than previously thought. Seventeen per cent had raised methane, without raised breath hydrogen; those with ulcerative colitis exhibiting most symptoms. All CC patients were lactose sensitive. There was no correlation between genetic phenotype and IBD. As substantial numbers of IBD patients were CT or TT, and were lactose sensitive, this polymorphism cannot explain full down-regulation of the lactase gene. CONCLUSIONS: Our results have implications for the clinical management of IBD. The high breath methane raised the possibility of a pathogenic role for methanogenic archaebacteria (Archaea) in IBD. This needs to be investigated. PMID- 21815902 TI - Plasma C-type natriuretic peptide forms and thyroid status in prepubertal children with acquired thyroid disease. AB - OBJECTIVE: C-type natriuretic peptide (CNP) and thyroid hormone (TH) are essential for normal skeletal growth. Plasma CNP peptides correlate with growth velocity, but the relationship between thyroid status and CNP production is unknown. This study examined the impact of restoring normal TH levels on CNP and height velocity (HV) in children with acquired hypo- and hyperthyroidism. DESIGN: We performed a prospective, observational study in prepubertal children with acquired hypothyroidism (n = 15) and hyperthyroidism (n = 12). MEASUREMENTS: Blood levels of CNP, amino-terminal proCNP (NTproCNP), bone-specific alkaline phosphatase (BSAP), IGF-I and TH levels were measured before and during the first 6 months of standard treatment for hypo- and hyperthyroidism, and correlations were determined. RESULTS: At baseline, HV, CNP, NTproCNP and BSAP were significantly higher in hyper- than in hypothyroid subjects. Changes in TH after treatment were closely coupled to change in CNP and NTproCNP in hyperthyroid, but not in hypothyroid, children. In addition, a positive association of HV with CNP peptides was found during treatment of hyperthyroidism. Normalizing TH did not correlate with changes in BSAP or IGF-I in either group. CONCLUSIONS: Plasma CNP peptides are higher in children with hyperthyroidism than in those with hypothyroidism at diagnosis and, in hyperthyroid children, change concordantly with TH and HV during treatment. Differential responses of CNP in the two groups suggest CNP production is dependent on growth plate activity and not a direct effect of TH on CNP gene expression. Our findings suggest novel mechanisms underlying changes in skeletal response during treatment in children with acquired thyroid disease. PMID- 21815903 TI - Non steroidal anti-inflammatory drug use and levels of oestrogens and androgens in men. AB - OBJECTIVE: Studies suggest that regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) may lower oestrogen levels in women. However, no large, population based studies have assessed NSAID/hormone associations in men. Our objective was to examine the association between use of prescription and over-the-counter NSAIDs, and levels of oestrogens and androgens in men. DESIGN: The Boston Area Community Health Survey, an observational survey with initial data collection in 2002-2005. PATIENTS: A total of 1766 men who provided a blood sample and data on recent analgesic use. MEASUREMENTS: Adjusted geometric mean levels of androgens, oestrogens, SHBG, LH and FSH for each category of NSAID use and the per cent difference in hormone levels for users vs nonusers. RESULTS: There was no significant association between prescription/over-the-counter NSAID use and any hormone examined after adjustment for potential confounders. For example, geometric mean testosterone levels were 13.8, 13.6 and 14.2 nM in nonusers, prescription users and over-the-counter NSAID users, respectively; the corresponding levels for estradiol were 80.3, 70.4 and 79.9 pM. In stratified analyses, however, prescription NSAID use was associated with lower testosterone, estradiol and estrone levels in obese men and lower testosterone and dehydroepiandrosterone sulphate levels in inactive men. CONCLUSIONS: While overall these data do not provide strong support for an association between NSAID use and hormone levels in men, prescription NSAIDs may decrease levels of certain oestrogens and androgens in obese and inactive men. PMID- 21815904 TI - Endocrine and metabolic characteristics of polycystic ovary syndrome in Chinese women with different phenotypes. AB - OBJECTIVE: The aim of this study was to describe the endocrine and metabolic characteristics of Chinese women with polycystic ovarian syndrome (PCOS) according to different phenotypes, including menstrual cycle pattern and body mass index (BMI). DESIGN: Retrospective study. PATIENT(S): A total of 3539 patients with PCOS and 590 controls were recruited from the Centre for Reproductive Medicine. Patients with PCOS were divided into three groups according to the characteristics of the menstrual cycle (amenorrhoea, oligomenorrhea and eumenorrhea) and the BMI (<25 kg/m(2) ; 25 <= and <= 30 kg/m(2) ; and BMI > 30 kg/m(2) ). MEASUREMENTS: Waist circumference, hip circumference, weight, height, Ferriman-Gallwey score, and endocrine and metabolic variables were measured. RESULTS: The serum testosterone, luteinizing hormone (LH) and oral glucose tolerance test 2 h-glucose levels were increased in the amenorrhoea group (P < 0.05). The triglycerides (TG) and low-density lipoprotein-cholesterol (LDL) levels were the highest in the amenorrhoea group (P < 0.05). The same trend existed in total cholesterol and non- high-density lipoprotein-cholesterol (HDL) levels, although there was no statistical significance (P > 0.05). Subjects with a BMI<25 kg/m(2) had higher values of follicle stimulating hormone (FSH), LH, LH/FSH and prolactin (P < 0.001) than the other two groups. The levels of TG, LDL and non-HDL and the indices of glucose and insulin metabolism increased with the change in BMI (P < 0.001). CONCLUSIONS: The amenorrhoea group had severe endocrine and metabolic abnormalities, which appeared to be related to latent long-term complications and higher morbidity. The degree of dysbolism was positively associated with the change in BMI. PMID- 21815905 TI - Possible involvement of IL-21 and IL-10 on salivary IgA levels in chronic periodontitis subjects. AB - Specific cytokines and the costimulatory protein CD40 play role in inducing immunoglobulin (Ig)A production by B cells in the humoral immune response. However, to date, the role of these mediators was not investigated in chronic periodontitis. Therefore, the aim of this study was to assess the local levels of interleukin (IL)-21, IL-21 receptor (IL-21R), IL-4, IL-10 and CD40 ligand (CD40L) on chronic periodontitis subjects and their relationship with the salivary levels of IgA. Gingival biopsies and un-stimulated saliva were collected from chronic periodontitis (n = 15) and periodontally healthy (n = 15) subjects. The mRNA levels of IL-4, IL-10, IL-21, IL-21R, CD40L in the gingival biopsies were evaluated by quantitative real-time polymerase chain reaction. The salivary levels of IgA and the levels of IL-4 and IL-10 in the gingival biopsies were analyzed by ELISA. The mean levels of IgA were significantly higher in the chronic periodontitis compared to periodontally healthy group (P < 0.05). The mRNA levels for IL-21 was higher (P < 0.05) in the chronic periodontitis when compared to the healthy group. However, the expression of IL-21R and CD40L did not differ between groups. The IL-10 was significantly elevated at mRNA and protein levels in chronic periodontitis when compared to periodontally healthy group (P < 0.05). Conversely, the mRNA levels as well as the protein amount of IL 4 were significantly lower (P < 0.05) in chronic periodontitis than healthy ones. In conclusion, the upregulation of IL-21 and IL-10 and downregulation of IL-4 in periodontitis tissues may be collectively involved in the increased levels of salivary IgA in chronic periodontitis subjects. PMID- 21815906 TI - Identification of a novel CD8+ T cell epitope derived from cancer-testis antigen MAGE-4 in oesophageal carcinoma. AB - MAGE-4 is considered as an attractive cancer-testis (CT) antigen for tumour immunotherapy, and it is overexpressed in oesophageal carcinoma (EC). To identify MAGE-4-derived HLA-A2 restricted epitopes, native peptides and their analogues were predicted with prediction programs. The native peptide, p286 (KVLEHVVRV), and its analogues, p286-1Y2L and p286-1Y2L9L, showed potent binding affinity and stability towards HLA-A*0201 molecule. Cytotoxic T lymphocytes (CTLs) induced by p286-1Y2L9L could release IFN-gamma in ELISPOT assay. In cytotoxicity assay, p286 1Y2L9L showed the capability to induce specific CTLs which could lyse the target cancer cells from both PBMCs of healthy donors and HLA-A2.1/K(b) transgenic mice. Our results indicated that the peptide p286-1Y2L9L could serve as a novel candidate epitope to develop peptide vaccines against oesophageal carcinoma. PMID- 21815907 TI - Role of natural killer T cells in the mouse colitis-associated colon cancer model. AB - Invariant natural killer T (iNKT) cells are considered innate-like lymphocytes, and regulate the immunity against inflammation and tumorigenesis. However, the impact of iNKT cells in inflammation-associated tumorigenesis remains unclear. In this study, we examined the physiological role of iNKT cells in a mouse colitis associated colorectal cancer model. C57BL/6 (B6) and Jalpha18 NKT cell-deficient KO (KO) mice were used. Colitis-associated colorectal cancer was induced by azoxymethane (AOM) and dextran sodium sulfate (DSS). The resulting inflammation and tumours were examined. The surface markers of mononuclear cells from the liver and the colon were assessed by FACS. The levels of IL-13 from the colon were measured by ELISA. alpha-galactosylceramide (GC), or its close analog OCH, was administered intraperitoneally on the first day of each cycle of DSS administration. In the AOM/DSS model, hepatic iNKT cells were significantly decreased. In KO mice there were significantly greater numbers of colon tumours and more severe inflammation than in B6 mice. FACS analysis revealed that the population of NK1.1 (+) T cells (non-invariant NKT cells) in the colon was increased when compared to B6 mice. The secretion of IL-13 was increased in the colon of KO mice after AOM/DSS. The number of colon tumours was significantly decreased in the GC-treated group compared to the control group. GC-treatment significantly inhibited IL-13 secretion from the colonic mononuclear cells and the number of colonic NK1.1 (+) T cells was significantly decreased. These results suggest that iNKT cells may play a critical role in the prevention of tumour progression and inflammation in the AOM/DSS model. PMID- 21815908 TI - A variant of the Il2ra / Cd25 gene predisposing to graves' disease is associated with increased levels of soluble interleukin-2 receptor. AB - Alpha-subunit of the IL-2 receptor (IL-2Ralpha) encoded by the IL2RA/CD25 gene binds IL-2 that plays a pivotal role in the regulation of T cell function. Levels of a soluble form of IL-2Ralpha (sIL-2Ralpha) lacking the transmembrane and cytoplasmic domains were shown to be increased in several autoimmune diseases including Graves' disease (GD). Recent studies showed association between the IL2RA/CD25 gene variants and several autoimmune diseases including GD. In this study, we analyzed whether polymorphic markers rs2104286, rs41295061, and rs11594656 located at the IL2RA/CD25 locus confer susceptibility to GD and are related to increased concentrations of sIL-2Ralpha. A total of 1474 Russian GD patients and 1609 control subjects were genotyped for rs2104286, rs41295061, and rs11594656 using a Taqman assay. Concentrations of sIL-2Ralpha in sera of affected and non-affected individuals were measured using an ELISA test. A minor allele A of rs41295061 showed significant association with increased risk of GD [odds ratio (OR) = 1.43, P(c) = 0.00102]. The allele A of rs41295061 and allele A of rs11594656 constitute a higher risk haplotype AA (OR = 1.47, P(c) = 0.0477). Compared to carriers of the protective haplogenotype GT/GT, the carriage of two copies of the haplogenotype AA/AA was associated with elevated levels of sIL-2Ralpha in both GD patients (AA/AA versus GT/GT: 1.35 +/- 0.47 ng/ml versus 1.12 +/- 0.45 ng/ml, P = 0.0065) and healthy controls (AA/AA versus GT/GT: 0.67 +/- 0.28 ng/ml versus 0.51 +/- 0.33 ng/ml, P = 0.0098). This is the first report presenting correlation between the carriage of disease-associated variants of IL2RA/CD25 with increased levels of sIL-2Ralpha in GD. PMID- 21815909 TI - Age-matched reference values for B-lymphocyte subpopulations and CVID classifications in children. AB - Age-matched reference values are generally presented with 5th and 95th percentiles as 'normal' reference range. However, they are mostly determined in relatively small groups, which renders this presentation inaccurate. We determined reference values for B-lymphocyte subpopulations in healthy children with the statistical method of tolerance intervals that deals far better with the relatively small numbers tested, and compared these to the cut-off values used in the currently used EUROclass classification for common variable immunodeficiency disorders (CVID) in children. CVID is a heterogeneous group of primary immunodeficiency diseases characterized by low serum immunoglobulin levels and inadequate response to vaccination. Disease-modifying heterozygous amino acid substitutions in TACI are found in around +/-10% of CVID patients. Interestingly, we found that age is the primary determinant of TACI-expression on B-lymphocytes, independent of switched memory B-lymphocyte numbers. Immunophenotyping of B lymphocyte subpopulations is increasingly used to classify patients with CVID into subgroups with different clinical prognosis according to the composition of their B-lymphocyte compartment. These classifications were mainly developed with data obtained in adults. Because of the maturing paediatric immune system, they may not be equally applicable in children: our and other age-matched reference values show great changes in the composition of the B-lymphocyte compartment during development. Although the greatest changes in B-lymphocyte subpopulations occur below the age of 2 years, when the diagnosis of CVID cannot yet be made, it is likely that a classification developed in adults cannot be used to classify the prognosis of children. PMID- 21815910 TI - A population-based investigation of the autoantibody profile in mothers of children with atrioventricular block. AB - The objective of the study was to investigate the antigen specificity and occurrence of individual autoantibodies in mothers of children diagnosed with atrioventricular (AV) block in a nation-wide setting. Patients with AV block detected before 15 years of age were identified using national quality registries as well as a network of pediatric and adult cardiologists and rheumatologists at the six university hospitals in Sweden. Patients with gross heart malformations, surgically or infectiously induced blocks were excluded. Blood samples were obtained from the mothers and maternal autoantibody profile, including the occurrence of antibodies against Ro52, Ro60, La, SmB, SmD, RNP-70k, RNP-A, RNP-C, CENP-C, Scl-70, Jo-1, ribosomal RNP and histones was investigated in 193 mothers of children with AV block by immunoblotting and ELISA. Autoantibody reactivity was detected in 48% (93/193) of the mothers of children with AV block. In autoantibody-positive mothers, the vast majority, 95% (88/93), had antibodies against Ro52, while 63% (59/93) had autoantibodies to Ro60 and 58% (54/93) had autoantibodies to La. In addition, 13% (12/93) of the autoantibody-positive mothers had antibodies to other investigated antigens besides Ro52, Ro60 and La, and of these anti-histone antibodies were most commonly represented, detected in 8% (7/93) of the mothers. In conclusion, this Swedish population-based study confirms that maternal autoantibodies may associate with heart block in the child. Further, our data demonstrate a dominant role of Ro52 antibodies in association with AV block. PMID- 21815912 TI - Metabolic capabilities of cytochrome P450 enzymes in Chinese liver microsomes compared with those in Caucasian liver microsomes. AB - AIM: The most common causes of variability in drug response include differences in drug metabolism, especially when the hepatic cytochrome P450 (CYP) enzymes are involved. The current study was conducted to assess the differences in CYP activities in human liver microsomes (HLM) of Chinese or Caucasian origin. METHODS: The metabolic capabilities of CYP enzymes in 30 Chinese liver microsomal samples were compared with those of 30 Caucasian samples utilizing enzyme kinetics. Phenacetin O-deethylation, coumarin 7-hydroxylation, bupropion hydroxylation, amodiaquine N-desethylation, diclofenac 4'-hydroxylation (S) mephenytoin 4'-hydroxylation, dextromethorphan O-demethylation, chlorzoxazone 6 hydroxylation and midazolam 1'-hydroxylation/testosterone 6beta-hydroxylation were used as probes for activities of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A, respectively. Mann-Whitney U test was used to assess the differences. RESULTS: The samples of the two ethnic groups were not significantly different in cytochrome-b(5) concentrations but were significantly different in total CYP concentrations and NADPH-P450 reductase activity (P < 0.05). Significant ethnic differences in intrinsic clearance were observed for CYP1A2, CYP2C9, CYP2C19 and CYP2E1; the median values of the Chinese group were 54, 58, 26, and 35% of the corresponding values of the Caucasian group, respectively. These differences were associated with differences in Michaelis constant or maximum velocity. Despite negligible difference in intrinsic clearance, the Michaelis constant of CYP2B6 appeared to have a significant ethnic difference. No ethnic difference was observed for CYP2A6, CYP2C8, CYP2D6 and CYP3A. CONCLUSIONS: These data extend our knowledge on the ethnic differences in CYP enzymes and will have implications for drug discovery and drug therapy for patients from different ethnic origins. PMID- 21815913 TI - Understanding people's experience of vitreo-retinal day surgery: a Gadamerian guided study. AB - AIM: This paper is a report of a study that aimed to understand the individual's experience of day surgery for repair of vitreo-retinal pathology. BACKGROUND: Day surgery evolved as a global phenomenon in response to tensions existing between community demand for health-care services and fiscal limitations. Since then vitreo-retinal surgery has been routinely performed as day surgery. Whilst studies have reported on patients' experience's following inpatient surgery, there has been limited investigation of vitreo-retinal day surgery from the patient's perspective. METHODS: In-depth unstructured interviews with 18 people were conducted between July 2006 and December 2007. Data analysis using philosophical hermeneutic techniques enabled a co-constructed understanding, where, the 'conditions of understanding' as described by Gadamer were established. FINDINGS: Guided by a Gadamerian approach to analysis, four constitutive themes were identified: 'the physical Self', 'the psychological Self', 'the historically located Self' and 'the Self located in the community'. Within each theme the participant's positive and negative experiences were understood in the context of human need, and gaps in nursing care became illuminated. These experiences included: pain, nausea, problematic self-care and psychological angst. CONCLUSION: Insights into the experience of vitreo-retinal day surgery, gained from this study can be used to inform nurses planning care for people with vitreo-retinal pathology. Nursing care must address broader patient needs that span multiple human domains, particularly when vision has been threatened by complex pathology. PMID- 21815911 TI - Disturbed development of the enteric nervous system after in utero exposure of selective serotonin re-uptake inhibitors and tricyclic antidepressants. Part 1: Literature review. AB - The increase in selective serotonin re-uptake inhibitor (SSRI) use during pregnancy, questions concerning abnormal development of the enteric nervous system (ENS), increase in laxative use in children and the association of fluoxetine with infantile hypertrophic pyloric stenosis (IHPS) gave rise to this pharmacological literature review. The role of 5-HT and the NE uptake in ontogeny of the ENS and the effects SSRIs and TCAs might have on the development of the ENS were investigated. The literature study showed that SSRIs may influence the development of the ENS in two ways. Blockage of the serotonin re-uptake transporter (SERT) during foetal development could influence migration, differentiation and survival of cells. This could lead to abnormal development in the first trimester of pregnancy. The other way is that 5-HT seems to be a growth factor in the primitive ENS. This growth factor like action is mediated through the 5-HT(2B) receptor and stimulation of this receptor by SSRIs influences the fate of late-developing enteric neurons. This could lead to abnormal development in the second and third trimester. TCAs could influence the development of the ENS, besides through inhibition of the SERT, through inhibition of the norepinephrine transporter (NET). Expression of the NET seems to be essential for a full development of enteric neurons and especially for serotonergic neurons. In addition the NET was detected early in ontogeny and precedes neuronal differentiation, which suggests that TCAs might influence development of the ENS when exposed early in pregnancy. The insights of this study gave rise to hypotheses which will be tested in an epidemiological cohort study. PMID- 21815914 TI - Familial risk of early suicide: variations by age and sex of children and parents. AB - To determine familial risk of early suicide, data on cause of death of all Dutch residents aged 20-55 years who died between 1995 and 2001 were linked to data of their parents. Men whose father died by suicide had a higher odds of suicide themselves, relative to men whose father died of other causes (Odds Ratio (OR): 2.5; 95% confidence interval: 1.8-3.6). This effect was slightly stronger in the case of mother's suicide (OR: 3.4; 2.3-5.0). The same effect was observed for women, for suicide by father (OR: 2.2; 1.3-3.7) and mother (OR: 4.6; 2.6-8.0). The odds of suicide increased with decreasing age at death of parent. Parental suicide is predictive for offspring suicide. Our data suggest that the predictive value is higher in case the mother died by suicide, particularly if the mother died by suicide at a young age. PMID- 21815915 TI - Predictors of suicide-related hospitalization among U.S. veterans receiving treatment for comorbid depression and substance dependence: who is the riskiest of the risky? AB - This study examined whether widely accepted suicide risk factors are useful in predicting suicide-related hospitalization, beyond history of a suicide attempt, in high-risk treatment-seeking veterans with depression and substance dependence. Negative mood regulation expectancies were the only significant predictor of hospitalization during 6-months of outpatient treatment. History of a suicide attempt was the only significant predictor of hospitalization during the one-year follow-up period. Results suggest that within high-risk populations, standard suicide risk factors may not identify individuals who will engage in suicidal behaviors resulting in hospitalization. Assessing negative mood regulation expectations may assist in identifying those most at risk. PMID- 21815916 TI - Clinical comparison between a continuous Lembert pattern wrapped in a carboxymethylcellulose and hyaluronate membrane with an interrupted Lembert pattern for one-layer jejunojejunostomy in horses. AB - REASONS FOR PERFORMING STUDY: Although experimental studies have demonstrated differences in performance between methods for handsewn jejunojejunostomy in horses, information on clinical results after different methods of anastomosis are rare. HYPOTHESIS: A continuous Lembert pattern wrapped in a carboxymethylcellulose and hyaluronate membrane would perform better than an interrupted Lembert pattern for jejunojejunostomy in horses. METHODS: Data was reviewed on 32 horses that underwent jejunojejunostomy from 1993-2002. Kaplan Meier analyses and rates for post operative colic and death were used to compare outcomes after an interrupted Lembert pattern (15 horses with strangulating lesions and 5 horses with nonstrangulating lesions) and a continuous Lembert pattern with membrane (12 horses with strangulating diseases). RESULTS: None of the 32 horses had post operative ileus or post operative endotoxaemia. One horse with a continuous pattern required a repeat celiotomy for anastomotic impaction. Short-term survivals for the interrupted Lembert were 100% (nonstrangulating lesions) and 93% (strangulating lesions) and for the continuous pattern 92% (all strangulating). Long-term rates for mortality and colic episodes were less for the continuous Lembert pattern with membrane compared with the interrupted Lembert for strangulating lesions (P<0.05) and were less for strangulating lesions than for nonstrangulating lesions (P<0.05). For strangulating lesions, Kaplan-Meier analyses yielded a survival probability of 70% for up to 9 years after the interrupted Lembert pattern and 80% for up to 5 years for the continuous Lembert pattern. CONCLUSIONS AND RELEVANCE: Both Lembert patterns performed well in clinical use, although the continuous pattern with the carboxymethylcellulose and hyaluronate membrane had superior long-term outcomes with less colic and mortality from colic. PMID- 21815917 TI - Equine amnionitis and fetal loss: mare abortion following experimental exposure to Processionary caterpillars (Ochrogaster lunifer). AB - REASONS FOR PERFORMING STUDY: In Australia, there have been recent reports of unusual abortions in mid- to late-gestation mares. These were clinically distinct from other recognised causes of pregnancy loss and the term 'equine amnionitis and fetal loss' (EAFL) was adopted to describe this syndrome. Initial investigations concluded that possible causal factors included the presence on affected stud farms of Processionary caterpillars (Ochrogaster lunifer). OBJECTIVES: To determine if exposure of pregnant mares to Processionary caterpillars or their shed exoskeletons can induce EAFL. METHODS: Processionary caterpillars and their shed exoskeletons were collected and stored frozen. Mid gestation mares were dosed with a slurry of caterpillars or shed exoskeleton by nasogastric intubation. Their clinical responses and times to abortion were recorded. All aborted fetuses were autopsied and samples taken for bacteriological and virological culture and histopathology. RESULTS: Intubating mares in mid-pregnancy with preparations of either whole Processionary caterpillars or shed caterpillar exoskeletons induced abortion with few impending clinical signs. The gross pathological and bacteriological findings of the aborted fetuses were similar to those observed in field cases of EAFL. POTENTIAL RELEVANCE: Possible exposure to Processionary caterpillars should be considered when examining cases of fetal loss in the mare. The present results provide a starting point to further explore the aetiology and pathogenesis of EAFL. PMID- 21815918 TI - Alcohol and non-communicable diseases (NCDs): time for a serious international public health effort. PMID- 21815919 TI - Beware of allowing the ideal to be the enemy of the good. PMID- 21815920 TI - Individualized versus population-based approaches to tobacco control - a false dichotomy. PMID- 21815921 TI - Setting minimum standards of evidence for population health interventions. PMID- 21815922 TI - Commentary on Bryant et al. (2011): behavioral and population-level interventions for reducing disparities in tobacco use. PMID- 21815923 TI - Commentary on Laslett et al. (2011): alcohol-related collateral damage and the broader issue of alcohol's social costs. PMID- 21815924 TI - Commentary on Pidd et al. (2011): Booze and drugs on the job - zeroing in on the industries at risk. PMID- 21815925 TI - Commentaries on Pedersen (2011): does cannabis cause poverty too? Moving beyond the malevolence paradigm. PMID- 21815927 TI - Commentary on Reimer et al. (2011): more work needed. PMID- 21815928 TI - Charles Robert (Bob) Schuster: 1930-2011. PMID- 21815931 TI - The inter-university consortium for political and social research. PMID- 21815930 TI - Weight gain according to gum use in participants in the intervention groups: comment on Ferguson et al. 2011. PMID- 21815932 TI - Prevalence of radiographic changes in yearling and 2-year-old Quarter Horses intended for cutting. AB - REASONS FOR PERFORMING STUDY: There have been many studies that document radiographic findings in young Thoroughbred and Standardbred horses. No such studies have been performed in Quarter Horses. OBJECTIVE: To describe the prevalence of radiographic changes in the stifles, tarsi, carpi and fetlocks of young Quarter Horses intended for cutting. METHODS: Radiographs of yearling and 2 year-old Quarter Horses were obtained from a radiograph repository and a private farm. The carpi, tarsi, fetlocks and stifles were evaluated and radiographic changes categorised by type and location. The frequency of changes was calculated and comparisons were made between the 2 age groups. RESULTS: Of 458 included horses, 408 (89.1%) had radiographic changes, most of which were in the tarsi (304, 69.4%) followed by the stifles (202, 44.5%), hind fetlocks (155 of 355, 43.7%), fore fetlocks (131 of 361, 36.3%) and carpi (27 of 342, 7.9%). Of the horses with stifle changes, 188 (93.1%) were in the medial femoral condyle (MFC). There was a significant difference between the age groups for changes on the distal intermediate ridge of the tibia (DIRT), hindlimb middle phalanx (P2) osteophytes and proximal tibial osteophytes. CONCLUSIONS: There is a high prevalence of radiographic changes in presale survey radiographs, especially in the stifles and tarsi, of young Quarter Horses intended for cutting. POTENTIAL RELEVANCE: Veterinarians examining presale radiographs at cutting horse sales should expect a high prevalence of radiographic changes in this population of horses. Work to determine the clinical relevance of these radiographic changes is currently ongoing. PMID- 21815933 TI - Recent developments in drug resistance mechanism in chronic myeloid leukemia: a review. AB - A revolution in medical science was marked with the advent of imatinib, a site specific drug for the management of patients with chronic myeloid leukemia (CML). Imatinib mesylate (also known as Glivec, Gleevec, STI-571, CGP57148), an orally administered 2-phenylaminopyrimidine derivative approved by FDA in 2001 for the treatment for CML, is highly effective in treating the early stages of CML, but remission induced in advanced phase was observed to be relatively short-lived. The primary cause of resistance in patients with CML is the mutations in the BCR ABL kinase domain. This review discusses the different mechanisms leading to imatinib resistance and various treatment options to over-ride imatinib resistance. PMID- 21815934 TI - Aspergillus tracheobronchitis in allogeneic stem cell transplanted recipient. PMID- 21815935 TI - Distribution of exhaled contaminants and personal exposure in a room using three different air distribution strategies. AB - The level of exposure to human exhaled contaminants in a room depends not only on the air distribution system but also on people's different positions, the distance between them, people's activity level and height, direction of exhalation, and the surrounding temperature and temperature gradient. Human exhalation is studied in detail for different distribution systems: displacement and mixing ventilation as well as a system without mechanical ventilation. Two thermal manikins breathing through the mouth are used to simulate the exposure to human exhaled contaminants. The position and distance between the manikins are changed to study the influence on the level of exposure. The results show that the air exhaled by a manikin flows a longer distance with a higher concentration in case of displacement ventilation than in the other two cases, indicating a significant exposure to the contaminants for one person positioned in front of another. However, in all three cases, the exhalation flow of the source penetrates the thermal plume, causing an increase in the concentration of contaminants in front of the target person. The results are significantly dependent on the distance and position between the two manikins in all three cases. PRACTICAL IMPLICATIONS: Indoor environments are susceptible to contaminant exposure, as contaminants can easily spread in the air. Human breathing is one of the most important biological contaminant sources, as the exhaled air can contain different pathogens such as viruses and bacteria. This paper addresses the human exhalation flow and its behavior in connection with different ventilation strategies, as well as the interaction between two people in a room. This is a key factor for studying the airborne infection risk when the room is occupied by several persons. The paper only takes into account the airborne part of the infection risk. PMID- 21815936 TI - Decompressive surgery in combination with preoperative transcatheter arterial embolization: successful improvement of ambulatory function in renal cell carcinoma patients with metastatic extradural spinal cord compression. AB - We analyzed the results of direct decompressive surgery plus stabilization of the vertebrae involved (DDSS) in six non-ambulatory patients with metastatic extradural spinal cord compression (MESCC) due to renal cell carcinoma (RCC). Transcatheter arterial embolization (TAE) was performed prior to surgery to reduce intraoperative blood loss. Radiotherapy and systemic therapy, including cytokine or targeted therapy and zoledronic acid, were added to the surgery. The DDSS procedure was performed successfully in all patients, with an estimated mean blood loss of 1726 mL. After surgery, all patients regained ambulatory function within 2 months. Patients were ambulatory with the use of assisting apparatus for 4-29 months (median 10.5 months). Median overall survival time after surgery was 15 months (range 4-38 months). In conclusion, DDSS with preoperative TAE can be performed safely and significantly improves the ambulatory function of non ambulatory RCC patients with MESCC. PMID- 21815937 TI - Diffusion-weighted magnetic resonance imaging in the differentiation of angiomyolipoma with minimal fat from clear cell renal cell carcinoma. AB - The aim of the present study was to evaluate diffusion-weighted (DW) magnetic resonance imaging (MRI) in differentiating between minimal fat angiomyolipoma (MFAML) and clear cell renal cell carcinoma (CCRCC). Forty-one solid renal tumors without visible macroscopic fat on unenhanced computed tomography images were evaluated by MRI, including DW-MRI, and were diagnosed pathologically as CCRCC (n = 36) or MFAML (n = 5). To evaluate the heterogeneity of diffusion in each tumor, the signals of the tumors on DW-MRI were analyzed subjectively and the apparent diffusion coefficient (ADC) values and histograms assessed objectively. Thirty three of 36 CCRCC (92%) exhibited a heterogeneous signal on DW-MRI and several peaks in the ADC value histogram, whereas four of five MFAML exhibited a homogeneous signal on DW-MRI and a single prominent peak in the histogram. The standard deviations of the ADC values were significantly smaller for MFAML than for CCRCC (P = 0.0015). In conclusion, DW-MRI can be considered a useful and noninvasive addition to the preoperative differentiation of CCRCC and MFAML. PMID- 21815938 TI - Lymphoepithelioma-like bladder cancer: clinicopathologic study of six cases. AB - Herein, we report on our experience with six patients (0.3%) diagnosed with lymphoepithelioma-like bladder carcinoma (LELBC) over the past 15 years at our department. The mean age of the patients with LELBC was 73 years (range 69-80 years). All patients had at least pT2 disease. The primary treatment was transurethral resection of the bladder tumor, radical cystectomy (RC), and radiotherapy (RT) in one, two, and three patients, respectively. After a mean follow-up of 31 months (range 13-72 months), three patients are still alive. The predominant subtype was diagnosed in four patients, three of whom are alive at the time of writing, compared with the two patients in whom the focal subtype was diagnosed, both of whom are dead. Two of the living patients were treated with a bladder-preservation strategy. Our experiences suggest that RC may not be necessary in muscle invasive disease and that RT and chemotherapy may be reliable treatment options. The pathology report may be useful in selecting patients suitable for bladder-preservation treatment. PMID- 21815939 TI - Use of a combination of variables along with the PCA3 assay in better defining the "low risk" patient: a message from Pretoria to Kyoto. PMID- 21815942 TI - Editorial comment from Dr Chang to decompressive surgery in combination with preoperative transcatheter arterial embolization: successful improvement of ambulatory function in renal cell carcinoma patients with metastatic extradural spinal cord compression. PMID- 21815943 TI - Editorial comment from Dr Maeda to decompressive surgery in combination with preoperative transcatheter arterial embolization: successful improvement of ambulatory function in renal cell carcinoma patients with metastatic extradural spinal cord compression. PMID- 21815944 TI - Innate and adaptive antifungal immune responses: partners on an equal footing. AB - Adaptive immunity has long been regarded as the major player in protection against most fungal infections. Mounting evidence suggest however, that both innate and adaptive responses intricately collaborate to produce effective antifungal protection. Dendritic cells (DCs) play an important role in initiating and orchestrating antifungal immunity; neutrophils, macrophages and other phagocytes also participate in recognising and eliminating fungal pathogens. Adaptive immunity provides a wide range of effector and regulatory responses against fungal infections. Th1 responses protect against most forms of mycoses but they associate with significant inflammation and limited pathogen persistence. By contrast, Th2 responses enhance persistence of and tolerance to fungal infections thus permitting the generation of long-lasting immunological memory. Although the role of Th17 cytokines in fungal immunity is not fully understood, they can enhance proinflammatory or anti-inflammatory responses or play a regulatory role in fungal immunity all depending on the pathogen, site/phase of infection and host immunostatus. T regulatory cells balance the activities of various Th cell subsets thereby permitting inflammation and protection on the one hand and allowing for tolerance and memory on the other. Here, recent developments in fungal immunity research are reviewed as means of tracing the emergence of a refined paradigm where innate and adaptive responses are viewed in the same light. PMID- 21815945 TI - Cryptococcus gattii serotype-C strains isolated in Bangalore, Karnataka, India. AB - During a retrospective study on cryptococcosis carried out in Bangalore, Karnataka, India, four Cryptococcus gattii strains were isolated from one HIV positive and three HIV-negative patients, two of which had unknown predisposing conditions. Serotyping and genotyping showed that the isolates were C. gattii serotype C, mating-type alpha and genotype VGIV. All the isolates were identical by multilocus sequence typing, but presented a low similarity compared with a set of 17 C. gattii global control strains. The comparison with a larger number of previously reported C. gattii strains, including African isolates, revealed a close relationship between Indian and African serotype-C isolates. PMID- 21815946 TI - Transcription factor genes of Schizophyllum commune involved in regulation of mushroom formation. AB - Mushrooms represent the most conspicuous structures of fungi. Their development is being studied in the model basidiomycete Schizophyllum commune. The genome of S. commune contains 472 genes encoding predicted transcription factors. Of these, fst3 and fst4 were shown to inhibit and induce mushroom development respectively. Here, we inactivated five additional transcription factor genes. This resulted in absence of mushroom development (in the case of deletion of bri1 and hom2), in arrested development at the stage of aggregate formation (in the case of c2h2) and in the formation of more but smaller mushrooms (in the case of hom1 and gat1). Moreover, strains in which hom2 and bri1 were inactivated formed symmetrical colonies instead of irregular colonies like the wild type. A genome wide expression analysis identified several gene classes that were differentially expressed in the strains in which either hom2 or fst4 was inactivated. Among the genes that were downregulated in these strains were c2h2 and hom1. Based on these results, a regulatory model of mushroom development in S. commune is proposed. This model most likely also applies to other mushroom-forming fungi and will serve as a basis to understand mushroom formation in nature and to enable and improve commercial mushroom production. PMID- 21815947 TI - RNA processing in Bacillus subtilis: identification of targets of the essential RNase Y. AB - RNA processing and degradation is initiated by endonucleolytic cleavage of the target RNAs. In many bacteria, this activity is performed by RNase E which is not present in Bacillus subtilis and other Gram-positive bacteria. Recently, the essential endoribonuclease RNase Y has been discovered in B. subtilis. This RNase is involved in the degradation of bulk mRNA suggesting a major role in RNA metabolism. However, only a few targets of RNase Y have been identified so far. In order to assess the global impact of RNase Y, we compared the transcriptomes in response to the expression level of RNase Y. Our results demonstrate that processing by RNase Y results in accumulation of about 550 mRNAs. Some of these targets were substantially stabilized by RNase Y depletion, resulting in half lives in the range of an hour. Moreover, about 350 mRNAs were less abundant when RNase Y was depleted among them the mRNAs of the operons required for biofilm formation. Interestingly, overexpression of RNase Y was sufficient to induce biofilm formation. The results presented in this work emphasize the importance of RNase Y as the global acting endoribonuclease for B. subtilis. PMID- 21815948 TI - Combined experimental and computational strategies define an expansive regulon for GcvB small RNA. AB - The bacterial small RNA GcvB has been known as a translational repressor of mRNAs encoding amino acid transporters and has been postulated to limit uptake of unnecessary amino acids under nutrient-rich conditions. In this issue of Molecular Microbiology, Sharma et al. (2011) provide evidence for a much broader role for GcvB as a global regulator of amino acid metabolism. Using a unique combination of experimental and biocomputational approaches, the authors triple the size of the GcvB regulon, making it the largest sRNA regulon defined to date. PMID- 21815949 TI - Different routes to the same ending: comparing the N-glycosylation processes of Haloferax volcanii and Haloarcula marismortui, two halophilic archaea from the Dead Sea. AB - Recent insight into the N-glycosylation pathway of the haloarchaeon, Haloferax volcanii, is helping to bridge the gap between our limited understanding of the archaeal version of this universal post-translational modification and the better described eukaryal and bacterial processes. To delineate as yet undefined steps of the Hfx. volcanii N-glycosylation pathway, a comparative approach was taken with the initial characterization of N-glycosylation in Haloarcula marismortui, a second haloarchaeon also originating from the Dead Sea. While both species decorate the reporter glycoprotein, the S-layer glycoprotein, with the same N linked pentasaccharide and employ dolichol phosphate as lipid glycan carrier, species-specific differences in the two N-glycosylation pathways exist. Specifically, Har. marismortui first assembles the complete pentasaccharide on dolichol phosphate and only then transfers the glycan to the target protein, as in the bacterial N-glycosylation pathway. In contrast, Hfx. volcanii initially transfers the first four pentasaccharide subunits from a common dolichol phosphate carrier to the target protein and only then delivers the final pentasaccharide subunit from a distinct dolichol phosphate to the N-linked tetrasaccharide, reminiscent of what occurs in eukaryal N-glycosylation. This study further indicates the extraordinary diversity of N-glycosylation pathways in Archaea, as compared with the relatively conserved parallel processes in Eukarya and Bacteria. PMID- 21815950 TI - A seven-WD40 protein related to human RACK1 regulates mating and virulence in Ustilago maydis. AB - In mammalian cells RACK1 serves as a scaffold protein that has a role in integrating inputs from different signalling pathways and affects translation through association with ribosomes. Ustilago maydis contains a seven-WD40 repeat motif protein designated Rak1, which shows 68% identity to RACK1 and 51% identity to Asc1p of Saccharomyces cerevisiae. An asc1 mutant could be complemented by introduction of U. maydis rak1. The deletion of rak1 affected cell growth, cell wall integrity and specifically attenuated cell fusion. This latter defect was caused by reduced expression of prf1 encoding the regulator for pheromone (mfa) and pheromone-receptor genes. Rak1 interacts with a variety of ribosomal proteins and microarray analysis revealed that the deletion of rak1 led to severely reduced expression of rop1, a transcriptional activator of prf1. The constitutive expression of rop1 could rescue the defect of mfa1 expression as well as conjugation tube formation in response to pheromone induction in the rak1 mutant. Moreover, a solopathogenic rak1 mutant failed to respond to plant-derived stimuli, resulting in attenuated filamentation and pathogenicity. This could be partially rescued by constitutive expression of the b heterodimer. These data suggest that rak1 is a regulator of rop1 expression with additional roles after cell fusion. PMID- 21815951 TI - Differential and interactive effects of ligand-bound progesterone receptor A and B isoforms on tyrosine hydroxylase promoter activity. AB - The classical progesterone receptors (PRs) are expressed in some hypothalamic dopaminergic and brainstem noradrenergic neurones. Progesterone influences prolactin and luteinising hormone release from the anterior pituitary gland, in part by regulating the activity of these catecholaminergic neurones. The present study aimed to determine the effects of PRs on tyrosine hydroxylase (TH) promoter activity. When CAD, SK-N-SH and CV-1 cells were transfected with TH promoter constructs and PR-A or PR-B expression vectors, progesterone treatment caused three- to six-fold increases in TH-9.0 kb promoter activity in PR-B expressing cells, although only a modest increase or no change in PR-A expressing cells. Using CAD cells, deletional analysis mapped the site of PR action to the -1403 to -1304 bp region of the TH promoter. Mutational analysis of putative regulatory sequences in this region indicated that multiple DNA elements are required for complete PR-B transactivation. Electrophoretic mobility shift assays were unable to demonstrate direct PR-B binding to TH promoter DNA sequences. However, chromatin immunoprecipitation analysis indicated PR-B was recruited to the TH promoter. Two different PR-B DNA binding domain mutants had opposing effects on PR-B-mediated TH promoter activation. A GS to AA mutation located in the p-box of the first zinc finger of PR-B inhibited progesterone transactivation of the TH promoter, whereas a C to A mutation in the zinc finger increased transactivation. PR-A was able to inhibit PR-B transactivation in a dose-dependent manner, although the degree of PR-A inhibition was dependent on the TH promoter deletion construct. These data indicate that ligand-bound PR-B is recruited to DNA elements in the TH promoter and acts as a transcriptional activator of the TH gene, and also that changes in the ratio of PR-A to PR-B may affect the ability of progesterone to increase TH expression. PMID- 21815952 TI - Significant quantitative and qualitative transition in pituitary stem / progenitor cells occurs during the postnatal development of the rat anterior pituitary. AB - We reported recently that a pituitary-specific transcription factor PROP1 is present in SOX2-positive cells and disappears at the early stage of the transition from progenitor cell to committed cell during the embryonic development of the rat pituitary. In the present study, we examined the localisation and identification of SOX2-positive and PROP1/SOX2-positive cells in the neonatal and postnatal rat pituitaries by immunohistochemistry. Quantitative analysis of immunoreactive cells demonstrated that SOX2-positive pituitary stem/progenitor cells are not only predominantly localised in the marginal cell layer, but also are scattered in the parenchyma of the adult anterior lobe. In the marginal cell layer, the number of PROP1/SOX2-positive cells significantly decreased after postnatal day 15, indicating that a significant quantitative transition is triggered in the marginal cell layer during the first postnatal growth wave of the anterior pituitary. By contrast, other phenotypes of SOX2 positive stem/progenitor cells that express S100beta appeared in the postnatal anterior pituitary. These data suggested that quantitative and qualitative transition occurs by acquisition of a novel mechanism in terminal differentiation in the postnatal development of the anterior pituitary. PMID- 21815953 TI - Ultrastructural evidence of kisspeptin-gonadotrophin-releasing hormone (GnRH) interaction in the median eminence of female rats: implication of axo-axonal regulation of GnRH release. AB - The present study was conducted to determine the morphological and functional interaction between kisspeptin and gonadotrophin-releasing hormone (GnRH) neuronal elements at the median eminence in female rats to clarify a possibility that kisspeptin directly stimulates GnRH release at the nerve end. A dual immunoelectron microscopic study of kisspeptin and GnRH showed that the kisspeptin-immunoreactive nerve element directly abutted the GnRH-immunoreactive nerve element, although no obvious synaptic structure was found between kisspeptin and GnRH neurones in the median eminence. The current retrograde tracing study with FluoroGold (FG) indicates that kisspeptin neurones are not in contact with fenestrated capillaries because no FG signal was found in kisspeptin neurones when the FG was injected peripherally. This peripheral FG injection revealed the neuroendocrine neurones projecting to the median eminence because FG positive GnRH neuronal cell bodies were found in the preoptic area. Synthetic rat kisspeptin (1-52)-amide stimulated GnRH release from the median eminence tissues in a dose-dependent manner. Thus, the present results suggest that kisspeptin at least partly exerts stimulatory effects on GnRH release from the neuronal terminals of GnRH neurones by axo-axonal nonsynaptic interaction in the median eminence. PMID- 21815955 TI - Assessment of cavitated and active non-cavitated caries lesions in 3- to 4-year old preschool children: a field study. AB - BACKGROUND: The prevalence of early childhood caries (ECC) is high in developing countries; thus, sensitive methods for the early diagnosis of ECC are of prime importance to implement the appropriate preventive measures. AIM: To investigate the effects of the addition of early caries lesions (ECL) into WHO threshold caries detection methods on the prevalence of caries in primary teeth and the epidemiological profile of the studied population. DESIGN: In total, 351 3- to 4 year-old preschoolers participated in this cross-sectional study. Clinical exams were conducted by one calibrated examiner using WHO and WHO + ECL criteria. During the exams, a mirror, a ball-ended probe, gauze, and an artificial light were used. The data were analysed by Wilcoxon and Mc-Nemar's tests (alpha=0.05). RESULTS: Good intra-examiner Kappa values at tooth/surface levels were obtained for WHO and WHO+ECL criteria (0.93/0.87 and 0.75/0.78, respectively). The dmfs scores were significantly higher (P<0.05) when WHO+ECL criteria were used. ECLs were the predominant caries lesions in the majority of teeth. CONCLUSIONS: The results strongly suggest that the WHO+ECL diagnosis method could be used to identify ECL in young children under field conditions, increasing the prevalence and classification of caries activity and providing valuable information for the early establishment of preventive measures. PMID- 21815956 TI - Insertion of an intact CR1 retrotransposon in a cadherin gene linked with Bt resistance in the pink bollworm, Pectinophora gossypiella. AB - Three mutations in the Pectinophora gossypiella cadherin gene PgCad1 are linked with resistance to Bacillus thuringiensis (Bt) toxin Cry1Ac. Here we show that the r3 mutation entails recent insertion into PgCad1 of an active chicken repeat (CR1) retrotransposon, designated CR1-1_Pg. Unlike most other CR1 elements, CR1 1_Pg is intact, transcribed by a flanking promoter, contains target site duplications and has a relatively low number of copies. Examination of transcripts from the PgCad1 locus revealed that CR1-1_Pg disrupts both the cadherin protein and a long noncoding RNA of unknown function. Together with previously reported data, these findings show that transposable elements disrupt eight of 12 cadherin alleles linked with resistance to Cry1Ac in three lepidopteran species, indicating that the cadherin locus is a common target for disruption by transposable elements. PMID- 21815957 TI - Can observers link dream content to behaviours in rapid eye movement sleep behaviour disorder? A cross-sectional experimental pilot study. AB - Motor activity in rapid eye movement (REM) sleep behaviour disorder (RBD) has been linked to dream content. Systematic and controlled sleep laboratory studies directly assessing the relation between RBD behaviours and experienced dream content are, however, largely lacking. We aimed to investigate whether a link can be established between RBD behaviours and dream content when both are systematically sampled in a controlled setting. We investigated six patients with Parkinson syndrome and RBD who underwent 2-3 nights of video-polysomnographic recording during which they were awakened from REM sleep (10 min after the onset of the second and successive REM periods). Spontaneous free-worded dream reports and a structured dream questionnaire were obtained. Video recordings of motor manifestations were each combined with four dream reports, and seven judges had to match the video clip with the correctly reported dream content from a choice of four possibilities. Of the 35 REM sleep awakenings performed, a total of 17 (48.6%) motor-behavioural episodes with recalled dream content were obtained. The mean of correctly identified video-dream pairs was 39.5% (range 0-100%). Our data showed that reported dream content can be linked to motor behaviours above chance level. Matching accuracy was affected mainly by the clarity of dream reports and the specific nature of movements manifest in video recordings. PMID- 21815954 TI - Functional mapping of the neural circuitry of rat maternal motivation: effects of site-specific transient neural inactivation. AB - The present review focuses on recent studies from our laboratory examining the neural circuitry subserving rat maternal motivation across postpartum. We employed a site-specific neural inactivation method by infusion of bupivacaine to map the maternal motivation circuitry using two complementary behavioural approaches: unconditioned maternal responsiveness and choice of pup- over cocaine conditioned incentives in a concurrent pup/cocaine choice conditioned place preference task. Our findings revealed that, during the early postpartum period, distinct brain structures, including the medial preoptic area, ventral tegmental area and medial prefrontal cortex infralimbic and anterior cingulate subregions, contribute a pup-specific bias to the motivational circuitry. As the postpartum period progresses and the pups grow older, it is further revealed that maternal responsiveness becomes progressively less dependent on the medial preoptic area and medial prefrontal cortex infralimbic activity, and more distributed in the maternal circuitry, such that additional network components, including the medial prefrontal cortex prelimbic subregion, are recruited with maternal experience, and contribute to the expression of late postpartum maternal behaviour. Collectively, our findings provide strong evidence that the remarkable ability of postpartum females to successfully care for their developing infants is subserved by a distributed neural network that carries out efficient and dynamic processing of complex, constantly changing incoming environmental and pup-related stimuli, ultimately allowing the progression of appropriate expression and waning of maternal responsiveness across the postpartum period. PMID- 21815958 TI - Challenges of residential and community care: 'the times they are a-changin'. AB - This paper seeks to examine a number of issues which relate to the provision of appropriate and high-quality residential and community care for people with an intellectual disability. A number of key themes emerging from this Special Issue of the Journal of Intellectual Disability Research are identified and explored: (1) normalisation; (2) inclusion; (3) choice; and (4) regulation. It is concluded that the research community has an obligation to assume a higher profile at a time when the quality of life of people with an intellectual disability and their families is under threat. This can be done in a number of ways through: (1) the establishment of demonstration projects, either independently or in association with the voluntary and statutory sector, to explore innovative and practical approaches of enhancing the quality of services offered to people with an intellectual disability; (2) looking at ways of improving the quality of training programmes for care staff by moving away from current approaches that emphasise narrow instrumental competencies to strategies that develop essential expressive and relational aspects of care practice; and (3) offering a more considered and rigorous critique of current professional practice and assuming a leadership role at a time when leadership in this field is lacking. PMID- 21815959 TI - The effectiveness of interventions for reducing stigma related to substance use disorders: a systematic review. AB - AIMS: This study provides a systematic review of existing research that has empirically evaluated interventions designed to reduce stigma related to substance use disorders. METHODS: A comprehensive review of electronic databases was conducted to identify evaluations of substance use disorder related stigma interventions. Studies that met inclusion criteria were synthesized and assessed using systematic review methods. RESULTS: Thirteen studies met the inclusion criteria. The methodological quality of the studies was moderately strong. Interventions of three studies (23%) focused on people with substance use disorders (self-stigma), three studies (23%) targeted the general public (social stigma) and seven studies (54%) focused on medical students and other professional groups (structural stigma). Nine interventions (69%) used approaches that included education and/or direct contact with people who have substance use disorders. All but one study indicated their interventions produced positive effects on at least one stigma outcome measure. None of the interventions have been evaluated across different settings or populations. CONCLUSIONS: A range of interventions demonstrate promise for achieving meaningful improvements in stigma related to substance use disorders. The limited evidence indicates that self stigma can be reduced through therapeutic interventions such as group-based acceptance and commitment therapy. Effective strategies for addressing social stigma include motivational interviewing and communicating positive stories of people with substance use disorders. For changing stigma at a structural level, contact-based training and education programs targeting medical students and professionals (e.g. police, counsellors) are effective. PMID- 21815961 TI - The benefit of cardiac resynchronization therapy and QRS duration: a meta analysis. AB - BACKGROUND: Cardiac resynchronization therapy (CRT) improves outcomes in patients with heart failure (HF) because of reduced left ventricular systolic function and a wide QRS complex. Whether this benefit is consistent across all degrees of QRS widening is unclear. We performed a meta-analysis of randomized clinical trials to evaluate the impact of QRS duration on the efficacy of CRT. METHODS AND RESULTS: We searched MEDLINE and EMBASE databases for studies evaluating the efficacy of CRT in patients with HF. Only trials that reported subgroup data according to QRS duration were included. Hazard ratios (HR) with 95% confidence interval (CI) were calculated using a random effects model. Five trials involving 6,501 patients (4,437 with QRS >= 150 ms and 2,064 with QRS < 150 ms) were included. Three trials, enrolling patients with mild to moderate HF, compared CRT implantable cardioverter defibrillator with CRT, whereas CRT versus medical therapy was compared in the other 2 trials, which included patients with advanced HF. Based on the pooled estimate across the 5 studies, CRT significantly decreased the primary endpoint of death or hospitalization for HF in patients with QRS >= 150 ms (HR = 0.58, 95% CI: 0.50-0.68; P < 0.00001), but not in patients with QRS < 150 ms (HR = 0.95, 95% CI: 0.83-1.10; P = 0.51). These results were consistent across all degrees of HF severity. CONCLUSIONS: The benefit of CRT seems to be dependent on QRS duration. Available data suggest a significant benefit associated with CRT in patients with QRS >= 150 ms, but not in patients with QRS < 150 ms. Further studies are needed to identify patients with QRS < 150 ms who might benefit from CRT. PMID- 21815960 TI - Factors associated with injection cessation, relapse and initiation in a community-based cohort of injection drug users in Chennai, India. AB - AIMS: To characterize factors associated with injection cessation, relapse and initiation. DESIGN: The Madras Injection Drug User and AIDS Cohort Study (MIDACS) is a prospective cohort of injection drug users (IDUs) recruited in 2005-06 with semi-annual follow-up to 2009. Discrete-time survival models were used to characterize predictors of time to first injection cessation and relapse. SETTING: Chennai, India. PARTICIPANTS: A total of 855 IDUs who reported injecting in the 6 months prior to baseline and had >1 follow-up visit. MEASUREMENTS: Cessation was defined as the first visit where no injection drug use was reported (prior 6 months) and relapse as the first visit where drug injection (prior 6 months) was reported after first cessation. FINDINGS: All participants were male; median age was 35 years. Over 3 years, 92.7% reported cessation [incidence rate (IR): 117 per 100 person-years]. Factors associated positively with cessation included daily injection and incarceration and factors associated negatively with cessation included marriage, alcohol and homelessness. Of those who reported cessation, 23.6% relapsed (IR: 19.7 per 100 person-years). Factors associated positively with relapse included any education, injection in the month prior to baseline, sex with a casual partner, non-injection drug use, incarceration and homelessness. Alcohol was associated negatively with relapse. The primary reasons for cessation were medical conditions (37%) and family pressure (22%). The majority initiated with non-injection drugs, transitioning to injection after a median 4 years. CONCLUSIONS: Injection drug users in southern India demonstrate a high rate of injection cessation over 3 years, but relapse is not uncommon. Compensatory increases in alcohol use indicate that cessation of injection does not mean cessation of all substance use. Family pressure, concerns about general health, fear of human immunodeficiency virus infection and a history of non injection drug use are important correlates of cessation. PMID- 21815962 TI - Complex fractionated electrograms in the right atrial free wall and the superior/posterior wall of the left atrium are affected by activity of the autonomic nervous system. AB - BACKGROUND: Complex fractionated atrial electrograms (CFAEs) are supposed to be related to structural and electrical remodeling. Animal studies suggest a role of the autonomic nervous system (ANS). However, this has never been studied in humans. OBJECTIVE: The goal of this study was to investigate the influence of ANS on CFAEs in patients with idiopathic atrial fibrillation (AF). METHODS: Thirty six patients (28 men, 55 +/- 9 years) were included before undergoing catheter ablation. In the 24 hours preceding the procedure, 20 patients were in AF (group 1) and 16 were in sinus rhythm (SR, group 2). With 2 decapolar catheters, 1 in the right atrium (RA) and 1 in the left atrium (LA), 20 unipolar electrograms were simultaneously recorded during a 100-second AF-period (in group 2 after induction of AF). After atropine and metoprolol administration, a second 100 second AF-period was recorded 30 minutes later. Five patients of group 2 served as controls and did not receive atropine and metoprolol prior to the second recording. CFAEs were assessed and the prevalence of CFAEs was expressed as percentage of the recording time. RESULTS: The prevalence of CFAEs was greater in group 1 than in group 2 in both RA and LA (P = 0.026, P < 0.001, respectively). Atropine and metoprolol significantly reduced CFAEs in group 1 (P < 0.001) and prevented the time-dependent increase of CFAEs in group 2. CONCLUSION: The prevalence of CFAEs is greater in long-lasting AF episodes. Atropine and metoprolol administration reduces CFAEs in both atria. Thus, CFAEs are at least partly influenced by the ANS. PMID- 21815963 TI - Intravenous administration of magnesium and potassium solution lowers energy levels and increases success rates electrically cardioverting atrial fibrillation. AB - BACKGROUND: External biphasic electrical cardioversion (CV) is a standard treatment option for patients suffering from acute symptoms of atrial fibrillation (AF). Nevertheless, CV is not always successful, and thus strategies to increase the success rate are desirable. OBJECTIVE: The purpose of this study was to evaluate the effect of intravenously administered K/Mg solution on the biphasic CV energy threshold and success rate to restore sinus rhythm (SR) in patients with AF. METHODS: The study consisted of 170 patients with persistent AF. The patients were randomly assigned to undergo biphasic CV either with (n = 84) or without (n = 86) pretreatment with K/Mg solution. An energy step-up protocol of 75, 100, and 150 W (J) was used. RESULTS: Biphasic CV of AF was effective in 81 (96.4%) patients in the pretreatment and 74 (86.0%) patients in the control group (P = 0.005). The effective energy level required to achieve SR was significantly lower in the pretreated group (140.8 +/- 26.9 J vs 182.5 +/- 52.2 J, P = 0.02). No K/Mg-solution-associated side effects such as hypotension or bradycardia were observed. CONCLUSION: Administration of K/Mg solution positively influences the success rate of CV in patients with persistent AF. Furthermore, significantly less energy is required to successfully restore SR and therefore K/Mg pretreatment may facilitate SR restoration in patients undergoing CV for AF. PMID- 21815964 TI - Putative mechanism of a postpacing interval paradoxically shorter than the tachycardia cycle length. PMID- 21815965 TI - Subclavian steal syndrome like appearance resulting from a vertebral artery origin stenosis: a case report. AB - Partial steal has been regarded as a classic ultrasound appearance of subclavian steal syndrome. We report a case with the vertebral artery origin stenosis and intact subclavian artery, which showed the similar partial steal ultrasound features. The following computerized tomography angiography confirmed the stenosis. Therefore, when an alternating flow in the vertebral artery is detected, the investigation of its origin must be performed besides the ipsilateral subclavian artery. PMID- 21815966 TI - Influence of surface area and geometry of specimens on bond strength in a microtensile test: an analysis by the three-dimensional finite element method. AB - PURPOSE: This study employed three-dimensional (3D) finite element analysis to investigate the stress distribution patterns in a microtensile test with the goal of evaluating the effects of the bond surface area and geometry on bond strength. MATERIALS AND METHODS: Finite element models of six specimens were generated: three stick models and three hourglass models. All models simulated the bond strength between dentin and ceramic. The mechanical properties of the materials the modulus of elasticity and Poisson's coefficient-were defined according to a literature review. The base of each specimen was considered inserted (constrained area) and possessed nodes with displacements restricted in all directions. A traction load, which was calculated to generate a uniformly distributed stress of 20 N/mm(2) at the bond interface, was applied to the top of the specimen. The distribution pattern of the generated stress was qualitatively and quantitatively measured based on color scales ranging from blue to red, according to the von Mises equivalent stress. RESULTS: Specimens with similar shapes demonstrated similar stress distributions. Ceramic specimens had a higher stress value (30.35 MPa) compared to specimens consisting of resinous cement (23.59 MPa) and dentin (19.77 MPa). At the bond interface, the specimens with square sections demonstrated stress values ranging from 22.00 to 24.20 MPa. For the circular section, the stress values ranged from 23.40 to 27.00 MPa. CONCLUSION: The maximum stress values determined for the circular and square sections were similar among specimens with the same interface area. At the bond interface, the highest stress values were observed in hourglass-shaped specimens. PMID- 21815967 TI - Reduced oxygen stress promotes propagation of murine postnatal enteric neural progenitors in vitro. AB - BACKGROUND: Neural stem and progenitor cells of the Enteric Nervous System (ENS) are regarded as a novel cell source for applications in regenerative medicine. However, improvements to the current ENS cell culture protocols will be necessary to generate clinically useful cell numbers under defined culture conditions. Beneficial effects of physiologically low oxygen concentrations and/or the addition of anti-oxidants on propagation of various types of stem cells have previously been demonstrated. In this study, we tested the effects of such culture conditions on ENS stem and progenitor cell behavior. METHODS: Enteric neural progenitor cells were isolated from postnatal day 3 mouse intestine and propagated either as monolayers or neurosphere-like bodies. The influence of hypoxic culture conditions and/or anti-oxidants on enteric cell propagation were studied systematically using proliferation, differentiation and apoptosis assays, whereas effects on gene expression were determined by qRT-PCR, western blot, and immunocytochemistry. KEY RESULTS: Both hypoxic culture conditions and anti oxidants supported a significantly improved enteric cell propagation and the generation of differentiated neural cell types. Enteric neural progenitors were shown to be specifically vulnerable to persistent oxidative stress. CONCLUSIONS & INFERENCES: Our findings are consistent with previous reports of improved maintenance of brain stem cells cultured under reduced oxygen stress conditions and may therefore be applied to future cell culture protocols in ENS stem cell research. PMID- 21815969 TI - Evidence-based medicine and epistemological imperialism: narrowing the divide between evidence and illness. AB - Evidence-based medicine (EBM) has been rapidly and widely adopted because it claims to provide a method for determining the safety and efficacy of medical therapies and public health interventions more generally. However, as others have noted, EBM may be riven through with cultural bias, both in the generation of evidence and in its translation. We suggest that technological and scientific advances in medicine accentuate and entrench these cultural biases, to the extent that they may invalidate the evidence we have about disease and its treatment. This creates a significant ethical, epistemological and ontological challenge for medicine. PMID- 21815968 TI - Activation of innate immunity accelerates sialoadenitis in a mouse model for Sjogren's syndrome-like disease. AB - OBJECTIVE: Sjogren's syndrome is a chronic autoimmune disorder characterized by progressive lymphocytic infiltration within the salivary and lacrimal glands. This study was undertaken to investigate the effects of innate immunity activation on sialoadenitis in a mouse strain genetically susceptible for development of SS-like disease. METHODS: Female New Zealand Black X New Zealand White F1 mice were repeatedly treated with toll-like 3 receptor agonist poly(I:C). Submandibular glands were investigated at different time points for sialoadenitis by immunohistochemistry and for gene expression of different chemokines by quantitative PCR. Submandibular gland-infiltrating cells were characterized by flow cytometry. RESULTS: Poly(I:C) treatment significantly upregulated the expression of multiple chemokines within the submandibular glands. The severity and incidence of sialoadenitis was considerably higher in poly(I:C)-treated mice. There was a preponderance of dendritic cells and NK cells in the initial inflammatory cell infiltrates, and these were followed by CD4+ T cells. CONCLUSIONS: Our data clearly demonstrate that systemic activation of innate immunity accelerates sialoadenitis in a mouse model for SS-like disease. These findings suggest that chronic activation of innate immunity can influence certain features of SS. PMID- 21815970 TI - Four alternatives to a reductive view of knowledge (seeing with a squint). AB - Following my own involvement in the rise of evidence-based medicine in General Practice in the UK, and having seen how this tide has led to a relative devaluation of other kinds of knowing this paper sets out four alternative approaches to the problem of knowledge in a way which both undermines the predominance of a strictly evidence-based approach and re-emphasizes these other means through which we come to know the world. Philosophically, this brings together the works of Heidegger, Sebald, Bachelard and Gadamer and shows how these apparently disparate authors suggest that there is, underlying our empirical understanding of the world, a more primordial relationship between consciousness and world which supports empirical or evidence-based knowledge and without which evidence-based knowledge cannot be applied in practice. The implications for clinical practice of this kind of thinking should be a more cautious approach to the use of evidence and a greater emphasis and reliance on the discretion and judgement of clinical professionals. PMID- 21815971 TI - Mere anecdote: evidence and stories in medicine. AB - In evidence-based medicine, randomized controlled trials are said to be the highest evidence of what works, while anecdotes have low value or are not even considered to be medical evidence. Similar hierarchical views of evidence have infected other disciplines, including evidence-based education and evidence-based government. Here, I explore the artificial divisions of acceptable from unacceptable evidence, numbers from narrative and sciences from humanities. I challenge the deprecation of stories in medicine. Some stories are based on experiments while others are based on more or less plausible theories. Some stories offer vast and impressive statistics gathered from many observations while others present one noteworthy event. Published reports are themselves stories of what experimenters did. Systematic reviewers generate their own observations of collected stories of experiments. Reviewers of systematic reviews in turn report their observations of systematic reviews. All of these stories become evidence of what works in medicine. PMID- 21815972 TI - Virtuous acts as practical medical ethics: an empirical study. AB - RATIONALE, AIMS AND OBJECTIVES: To examine the nature, scope and significance of virtues in the biographies of medical practitioners and to determine what kind of virtues are at play in their ethical behaviour and reflection. METHODS: A case study involving 19 medical practitioners associated with the Sydney Medical School, using semi-structured narrative interviews. Narrative data were analysed using dialectical empiricism, constant comparison and iterative reformulation of research questions. RESULTS: Participants represented virtuous acts as centrally important in their moral assessments of both themselves and others. Acts appeared to be contextually virtuous, rather than expressions of stable character traits, and virtue was linked to acts that served to protect or enhance fundamental values attached to ontological security and human flourishing. Virtue ethics, in this sense, was the single most important ethical system for each of the participants. CONCLUSION: Virtue ethics, construed as the appraisal of acts in contexts of risk, danger or threat to foundational values, emerged as the 'natural' ethical approach for medical practitioners in this case study. Teaching medical ethics to students and graduates alike needs to accommodate the priority attached to virtuous acts. PMID- 21815973 TI - Signalling by the global regulatory molecule ppGpp in bacteria and chloroplasts of land plants. AB - The hyperphosphorylated guanine ribonucleotide ppGpp mediates the stringent response in bacteria. Biochemical and genetic studies of this response in Escherichia coli have shown that the biosynthesis of ppGpp is catalysed by two homologous enzymes, RelA and SpoT. RelA is activated in response to amino acid starvation, and SpoT responds to abiotic physical stress beside nutritional stress. All free-living bacteria, including Gram-positive firmicutes, contain RelA-SpoT homologues (RSH). Further, novel ppGpp biosynthetic enzymes, designated small alarmone synthetases (SASs), were recently identified in a subset of bacteria, including the Gram-positive organism Bacillus subtilis, and were shown to consist only of a ppGpp synthetase domain. Studies suggest that these SAS proteins contribute to ppGpp signalling in response to stressful conditions in a manner distinct from that of RelA-SpoT enzymes. SAS proteins currently appear to always occur in addition to RSH enzymes in various combinations but never alone. RSHs have also been identified in chloroplasts, organelles of photosynthetic eukaryotes that originated from endosymbiotic photosynthetic bacteria. These chloroplast RSHs are exclusively encoded in nuclear DNA and targeted into chloroplasts. The findings suggest that ppGpp may regulate chloroplast functions similar to those regulated in bacteria, including transcription and translation. In addition, a novel ppGpp synthetase that is regulated by Ca2+ as a result of the presence of two EF-hand motifs at its COOH terminus was recently identified in chloroplasts of land plants. This finding indicates the existence of a direct connection between eukaryotic Ca2+ signalling and prokaryotic ppGpp signalling in chloroplasts. The new observations with regard to ppGpp signalling in land plants suggest that such signalling contributes to the regulation of a wider range of cellular functions than previously anticipated. PMID- 21815974 TI - Identification of an Arabidopsis solute carrier critical for intracellular transport and inter-organ allocation of molybdate. AB - Plants represent an important source of molybdenum in the human diet. Recently, MOT1 has been identified as a transport protein responsible for molybdate import in Arabidopsis thaliana L.; however, the function of the homologous protein MOT2 has not been resolved. Interestingly, MOT2-GFP analysis indicated a vacuolar location of this carrier protein. By site directed mutagenesis at the N-terminal end of MOT2, we identified a di-leucine motif that is essential for driving the protein into the vacuolar membrane. Molybdate quantification in isolated vacuoles showed that this organelle serves as an important molybdate store in Arabidopsis cells. When grown on soil, leaves from mot2 T-DNA mutants contained more molybdate, whereas mot2 seeds contained significantly less molybdate than corresponding wild-type (Wt) tissues. Remarkably, MOT2 mRNA accumulates in senescing leaves and mot2 leaves from plants that had finished their life cycle had 15-fold higher molybdate levels than Wt leaves. Reintroduction of the endogenous MOT2 gene led to a Wt molybdate phenotype. Thus, mot2 mutants exhibit impaired inter-organ molybdate allocation. As total concentrations of the molybdenum cofactor (Moco) and its precursor MPT correlates with leaf molybdate levels, we present novel evidence for an adjustment of Moco biosynthesis in response to cellular MoO42- levels. We conclude that MOT2 is important for vacuolar molybdate export, an N-terminal di-leucine motif is critical for correct subcellular localisation of MOT2 and activity of this carrier is required for accumulation of molybdate in Arabidopsis seeds. MOT2 is a novel element in inter organ translocation of an essential metal ion. PMID- 21815975 TI - Transcriptional regulation of two RTE-like genes of carnation during flower senescence and upon ethylene exposure, wounding treatment and sucrose supply. AB - RTE1 (REVERSION-TO-ETHYLENE SENSITIVITY1) was identified as a positive regulator of ETR1 (ethylene resistant1) function in Arabidopsis; RTEs are a small gene family. Ethylene plays a crucial role in the senescence of carnation (Dianthus caryophyllus L.) flowers. Two cDNA clones encoding putative RTE-like protein (DCRTE1 and DCRTH1) were obtained from total RNA isolated from senescing carnation petals using RT-PCR and RACE techniques. The predicted proteins of DCRTE1 and DCRTH1 consist of 228 and 233 amino acids, respectively. Interestingly, the deduced DCRTE1 protein, like most other RTEs, includes two putative transmembrane domains, while the deduced DCRTH1 protein includes five putative transmembrane domains, according to the TMHMM database. Northern blots showed that the level of DCRTE1 mRNA in petals first decreased then increased remarkably after ethylene production started, and DCRTE1 expression showed an increasing trend in ovaries during natural flower senescence. The amount of DCRTH1 transcripts increased gradually in both petals and ovaries during natural senescence. Exogenous ethylene increased transcript abundance of DCRTE1 and DCRTH1 to various degrees in both petals and ovaries. STS treatment decreased the level of DCRTH1 mRNA in petals and ovaries compared with the control. DCRTE1 and DCRTH1 showed a rapid increase and then a decrease in mRNA accumulation in leaves after wounding. These results suggest that both DCRTE1 and DCRTH1 could play important roles in flower senescence-related signalling. Sucrose treatment did not remarkably affect the amount of DCRTE1 and DCRTH1 mRNAs. PMID- 21815976 TI - Plant U-box armadillo repeat proteins AtPUB18 and AtPUB19 are involved in salt inhibition of germination in Arabidopsis. AB - Plant U-box armadillo repeat (PUB-ARM) proteins represent a type of E3 ubiquitin ligase. PUB-ARM proteins have various functions in plant development, plant defence and plant stress responses. The so far uncharacterised PUB-ARM proteins AtPUB18 and AtPUB19 are highly homologous to each other and regulated on the transcript level by ABA and NaCl. To investigate their physiological function, we isolated and characterised two Arabidopsis mutants and named them pub18-1 and pub19-1. However, these single mutants did not show any ABA- or salt-dependent phenotype. In contrast, pub18-1/pub19-1 double mutant seeds were less sensitive to ABA and NaCl inhibition of seed germination compared to wild-type seeds, indicating that both PUB-ARM proteins may coordinately function as regulatory components in ABA or salt inhibition of germination. PMID- 21815977 TI - Influence of EARLI1-like genes on flowering time and lignin synthesis of Arabidopsis thaliana. AB - EARLI1 encodes a 14.7 kDa protein in the cell wall, is a member of the PRP (proline-rich protein) family and has multiple functions, including resistance to low temperature and fungal infection. RNA gel blot analyses in the present work indicated that expression of EARLI1-like genes, EARLI1, At4G12470 and At4G12490, was down-regulated in Col-FRI-Sf2 RNAi plants derived from transformation with Agrobacterium strain ABI, which contains a construct encoding a double-strand RNA targeting 8CM of EARLI1. Phenotype analyses revealed that Col-FRI-Sf2 RNAi plants of EARLI1 flowered earlier than Col-FRI-Sf2 wild-type plants. The average bolting time of Col-FRI-Sf2 and Col-FRI-Sf2 RNAi plants was 39.7 and 19.4 days, respectively, under a long-day photoperiod. In addition, there were significant differences in main stem length, internode number and rosette leaf number between Col-FRI-Sf2 and Col-FRI-Sf2 RNAi plants. RT-PCR showed that EARLI1-like genes might delay flowering time through the autonomous and long-day photoperiod pathways by maintaining the abundance of FLC transcripts. In Col-FRI-Sf2 RNAi plants, transcription of FLC was repressed, while expression of SOC1 and FT was activated. Microscopy observations showed that EARLI1-like genes were also associated with morphogenesis of leaf cells in Arabidopsis. Using histochemical staining, EARLI1-like genes were found to be involved in regulation of lignin synthesis in inflorescence stems, and Col-FRI-Sf2 and Col-FRI-Sf2 RNAi plants had 9.67% and 8.76% dry weight lignin, respectively. Expression analysis revealed that cinnamoyl-CoA reductase, a key enzyme in lignin synthesis, was influenced by EARLI1-like genes. These data all suggest that EARLI1-like genes could control the flowering process and lignin synthesis in Arabidopsis. PMID- 21815978 TI - Accumulation of human EGF in nectar of transformed plants of Nicotiana langsdorffii x N. sanderae and transfer to honey by bees. AB - Honey has been used successfully in wound healing for thousands of years. The peptide hormone human epidermal growth factor (hEGF) is also known to have a beneficial effect in various wound healing processes via mechanisms that differ from those for honey. In this study, we show that hEGF can be incorporated into honey via nectar. Plants of Nicotiana langsdorffii x N. sanderae were transformed with the gene for hEGF, equipped with a nectary-targeted promoter and a signal sequence for secretion to nectar. These plants accumulated hEGF in the nectar. The maximum hEGF concentration recorded with ELISA in these plants is 2.5 ng.ml 1. There is a significant linear relationship (P<0.001) between hEGF concentration and induction of hEGF-receptor phosphorylation. Since the flower morphology of these plants did not allow production of honey from their nectar, we used feeding solutions, spiked with synthetic hEGF, to study transfer of this peptide into honey through bee activity. Transfer of hEGF from a feeding solution to honey by bees occurred with retention of the hEGF concentration and the capacity to induce hEGF-receptor phosphorylation. These observations indicate that plants can function as a production platform for honey containing biologically active peptides, which may enhance wound healing and other biological processes. PMID- 21815979 TI - Are nitric oxide donors a valuable tool to study the functional role of nitric oxide in plant metabolism? AB - In the present work, we tested known nitric oxide (NO) modulators generating the NO+ (sodium nitroprusside, SNP) and NO forms (S-nitroso-N-acetyl-D-penicillamine, SNAP and nitrosoglutathione, GSNO). This allowed us to compare downstream NO related physiological effects on proteins found in leaves of pelargonium (Pelargonium peltatum L.). Protein modification via NO donors generally affects plant metabolism in a distinct manner, manifested by a lower thiobarbituric acid reactive substance (TBARS) content and lipoxygenase (LOX) activity in response to SNAP and GSNO. This is in contrast to the response observed for SNP treatment. Most changes in enzyme activity (GR, glutathione reductase; GST, glutathione-S transferase; GPX, glutathione peroxidase) are most spectacular and repeatable during the first 8 h of incubation, which is explained by the half-life of the applied donors. In particular, a close dependence was found between the time course of NO emission from the applied donors and the temporary inhibition of antioxidant enzymes, such as catalase (CAT) and ascorbate peroxidase (APX). The observed changes were accompanied by time-dependent alterations in protein accumulation as analysed by two-dimensional gel electrophoresis (2-DE) in pelargonium leaves treated with NO donors (SNP, SNAP and GSNO). Using proteomics, different proteins were found to be down- and up-regulated. However, no new protein spots characteristic of all three donors were found. These results indicate that the form of NO emitted from the donor structure plays a key role in switching on appropriate metabolic modifications. It has been noted that several NO-affected metabolomic changes induced by the used donors were not comparable, which confirms the need to maintain caution when interpreting results obtained using the pharmacological approach with different NO modulator compounds. PMID- 21815980 TI - Redox changes during cold acclimation affect freezing tolerance but not the vegetative/reproductive transition of the shoot apex in wheat. AB - Cold acclimation is necessary for winter wheat (Triticum aestivum L.) to achieve its genetically determined maximum freezing tolerance, and cold also fulfils the vernalisation requirement. Chromosome 5A is a major regulator of these traits. The aim of the present study was to discover whether changes in the half-cell redox potential of the glutathione/glutathione disulphide (GSH/GSSG) and ascorbate/dehydroascorbate (AA/DHA) couples induced by cold acclimation are related to freezing tolerance and vernalisation requirement in a specific genetic system including chromosome 5A substitution lines. The amounts of H2O2 and AA, and the AA/DHA ratio showed a rapid and transient increase in the crown of all genotypes during the first week of acclimation, followed by a gradual increase during the subsequent 2 weeks. The amount of GSH and its ratio compared to GSSG quickly decreased during the first day, while later these parameters showed a continuous slow increase. The H2O2, AA and GSH concentrations, AA/DHA and GSH/GSSG ratios and the half-cell reduction potential of the GSH/GSSG couple were correlated with the level of freezing tolerance after 22 days at 2 degrees C; hence these parameters may have an important role in the acclimation process. In contrast to H2O2 and the non-enzymatic antioxidants, the lipid peroxide concentration and activity of the four antioxidant enzymes exhibited a transient increase during the first week, with no significant difference between genotypes. None of the parameters studied showed any relationship with the vegetative/generative transition state monitored as apex morphology and vernalisation gene expression. PMID- 21815981 TI - Sugar ratios, glutathione redox status and phenols in the resurrection species Haberlea rhodopensis and the closely related non-resurrection species Chirita eberhardtii. AB - Because of their unique tolerance to desiccation, the so-called resurrection plants can be considered as excellent models for extensive research on plant reactions to environmental stresses. The vegetative tissues of these species are able to withstand long dry periods and to recover very rapidly upon re-watering. This study follows the dynamics of key components involved in leaf tissue antioxidant systems under desiccation in the resurrection plant Haberlea rhodopensis and the related non-resurrection species Chirita eberhardtii. In H. rhodopensis these parameters were also followed during recovery after full drying. A well-defined test system was developed to characterise the different responses of the two species under drought stress. Results show that levels of H2O2 decreased significantly both in H. rhodopensis and C. eberhardtii, but that accumulation of malondialdehyde was much more pronounced in the desiccation tolerant H. rhodopensis than in the non-resurrection C. eberhardtii. A putative protective role could be attributed to accumulation of total phenols in H. rhodopensis during the late stages of drying. The total glutathione concentration and GSSG/GSH ratio increased upon complete dehydration of H. rhodopensis. Our data on soluble sugars suggest that sugar ratios might be important for plant desiccation tolerance. An array of different adaptations could thus be responsible for the resurrection phenotype of H. rhodopensis. PMID- 21815982 TI - The betaI-galactosidase of Cicer arietinum is located in thickened cell walls such as those of collenchyma, sclerenchyma and vascular tissue. AB - We report localisation of the chickpea betaI-Gal, a member of the chickpea beta galactosidase family, which contains at least four members. After generation of specific antibodies, the distribution and cellular immunolocalisation of the protein in different organs and developmental stages of the plant was studied. betaI-Gal protein is much longer than the other chickpea beta-galactosidases because of the presence of a lectin-like domain in the carboxyl terminus of the protein. Western blot experiments indicated that the active betaI-Gal retains this lectin-like domain for its function in the plant. The betaI-Gal protein was mainly detected in cell walls of elongating organs, such as seedling epicotyls and stem internodes. An immunolocation study indicated a very good correlation between the presence of this betaIota-galactosidase and cells whose walls are thickening, not only in aged epicotyls and mature internodes in the final phase of elongation, but mostly in cells with a support function, such as collenchyma cells, xylem and phloem fibres and a layer of sclerenchyma cells surrounding the vascular cylinder (perivascular fibres). These results could suggest a function for the betaI-Gal in modification of cell wall polymers, leading to thicker walls than the primary cell walls. PMID- 21815983 TI - Gene expression profiling of Arabidopsis meiocytes. AB - Meiosis is a special type of cell division present in all organisms that reproduce by sexual reproduction. It ensures the transition between the sporophytic and gametophytic state and allows gamete production through meiotic recombination and chromosome number reduction. In this paper, we describe a technique for the isolation of Arabidopsis thaliana male meiocytes. From this cellular material, it was then possible to develop large-scale transcriptome studies using CATMA microarrays and thus to obtain an overview of genes expressed during Arabidopsis meiosis. The expression profiles were studied with either stringent statistical criteria or by performing clustering. Both methods resulted in gene clusters enriched in meiosis-specific genes (from 14- to 55-fold). Analysis of these data provided a unique set of genes that will be pivotal to further analysis aimed at understanding the meiotic process. PMID- 21815984 TI - Rhizobial Nod factors are required for cortical cell division in the nodule morphogenetic programme of the Aeschynomeneae legume Arachis. AB - Nod factors are among the best-studied molecules implicated in the signal exchange that leads to legume-rhizobia symbiosis. The role of these molecules in symbiosis development has been primarily studied in legumes invaded through infection threads. In these plants, Nod factors generate several responses required for nodulation, including the induction of cortical cell division to form the nodule primordium. Arachis hypogaea L. (peanut) exhibits a specific mode of rhizobial infection and nodule morphogenetic programme in which infection threads are never formed. The role of Nod factors in this particular mechanism is unknown. In this work, a peanut symbiont mutant strain unable to produce Nod factors was obtained and characterised. The strain Bradyrhizobium (Arachis) sp. SEMIA 6144 V2 is altered in the nodC gene, which encodes an N-acetylglucosaminyl transferase involved in the first step of the Nod factor biosynthetic pathway. Further research revealed that, although its ability to colonise peanut roots was unaffected, it is not capable of inducing the division of cortical cells. The results obtained indicate that rhizobial Nod factors are essential for the induction of cortical cell division that leads to nodule primordium formation. PMID- 21815985 TI - The life cycle of the amoeboid alga Synchroma grande (Synchromophyceae, Heterokontophyta)--highly adapted yet equally equipped for rapid diversification in benthic habitats. AB - Synchroma grande (Synchromophyceae, Heterokontophyta) is a marine amoeboid alga, which was isolated from a benthic habitat. This species has sessile cell stages (amoeboid cells with lorica and cysts) and non-sessile cell stages (migrating and floating amoebae) during its life cycle. The different cell types and their transitions within the life cycle are described, as are their putative functions. Cell proliferation was observed only in cells attached to the substrate but not in free-floating or migrating cells. We also characterised the phagotrophy of the meroplasmodium in comparison to other amoeboid algae and the formation of the lorica. The functional adaptations of S. grande during its life cycle were compared to the cell stages of other amoeboid algae of the red and green chloroplast lineages. S. grande was found to be highly adapted to the benthic habitat. One sexual and two asexual reproductive strategies (haplo-diploid life cycle) support the ability of this species to achieve rapid diversification and high adaptivity in its natural habitat. PMID- 21815986 TI - The FLOWERING LOCUS T orthologous gene of Platanus acerifolia is expressed as alternatively spliced forms with distinct spatial and temporal patterns. AB - The FLOWERING LOCUS T (FT) protein is a likely component of the 'florigen' signal that plays a crucial role in regulating the transition from vegetative to reproductive growth. Here, we report the isolation of full-length cDNAs and the corresponding genomic clones encoding orthologous FT proteins (PaFT) of London plane (Platanus acerifolia Willd). Two genes with high sequence identity were isolated (PaFT1-2), but 34 different transcript products were identified, comprising 21 splice forms produced by alternative splicing of the PaFT pre mRNAs. Expression of the alternative splicing forms of PaFT varied according to tissue type and developmental stage. PaFT transcripts were detected throughout adult trees, whereas in juvenile trees they were only detected in dormant sub petiolar buds. In adult trees, levels of the various alternative splicing PaFT forms were related to flower development stage and tree dormancy. Ectopic expression of the archetypal splice form of PaFT-A in tobacco and Arabidopsis developed multiple altered phenotypes, notably early flowering and attenuation of apical dominance. The evidence in this study indicates that complex alternative processing of PaFT transcripts in P. acerifolia may be associated with multiple regulatory roles, including initiation of flowering, flower development, apical dominance, tree dormancy and dormancy release. PMID- 21815987 TI - Persistence of sunflower crop traits and fitness in Helianthus petiolaris populations. AB - Transgenic plants have increased interest in the study of crop gene introgression in wild populations. Genes (or transgenes) conferring adaptive advantages persist in introgressed populations, enhancing competitiveness of wild or weedy plants. This represents an ecological risk that could increase problems of weed control. Introgression of cultivar alleles into wild plant populations via crop-wild hybridisations is primarily governed by their fitness effect. To evaluate this, we studied the second generation of seven wild-crop interspecific hybrids between weedy Helianthus petiolaris and cultivated sunflower, H. annuus var. macrocarpus. The second generation comprised open-pollinated progeny and backcrosses to the wild parent, mimicking crosses that occur in natural situations. We compared a number of morphological, life history and fitness traits. Multivariate analysis showed that the parental species H. annuus and H. petiolaris differed in a number of morphological traits, while the second hybrid generation between them was intermediate. Sunflower crop introgression lowered fitness of interspecific hybrids, but fitness parameters tended to recover in the following generation. Relative frequency of wild/weedy and introgressed plants was estimated through four generations, based on male and female parent fitness. In spite of several negative selection coefficients observed in the second generation, introgressed plants could be detected in stands of <100 weedy H. petiolaris populations. The rapid recovery of fecundity parameters leads to prediction that any trait conferring an ecological advantage will diffuse into the wild or weedy population, even if F1 hybrids have low fitness. PMID- 21815988 TI - The health implications of birth by Caesarean section. AB - Since the first mention of fetal programming of adult health and disease, a plethora of programming events in early life has been suggested. These have included intrauterine and postnatal events, but limited attention has been given to the potential contribution of the birth process to normal physiology and long term health. Over the last 30 years a growing number of studies have demonstrated that babies born at term by vaginal delivery (VD) have significantly different physiology at birth to those born by Caesarean section (CS), particularly when there has been no exposure to labour, i.e. pre-labour CS (PLCS). This literature is reviewed here and the processes involved in VD that might programme post-natal development are discussed. Some of the effects of CS are short term, but longer term problems are also apparent. We suggest that VD initiates important physiological trajectories and the absence of this stimulus in CS has implications for adult health. There are a number of factors that might plausibly contribute to this programming, one of which is the hormonal surge or "stress response" of VD. Given the increasing incidence of elective PLCS, an understanding of the effects of VD on normal development is crucial. PMID- 21815989 TI - Glucose-dependent insulinotropic polypeptide: from pathophysiology to therapeutic opportunities in obesity-associated disorders. AB - Glucose-dependent insulinotropic polypeptide (GIP) is a hormone secreted from the intestinal K-cells with established insulin-releasing actions. However, the GIP receptor is widely distributed in peripheral organs, including the adipose tissue, gut, bone and brain, where GIP modulates energy intake, cell metabolism and proliferation, and lipid and glucose metabolism, eventually promoting lipid and glucose storage. In diabetes and obesity, the incretin effect of GIP is blunted, while the extrapancreatic tissues keep a normal sensitivity to this hormone. As GIP levels are normal or elevated in obesity and diabetes, mounting evidence from chemical or genetic GIP deletion in animal models of obesity related diabetes suggests that GIP may have a pro-obesogenic action and that a strategy antagonizing GIP action may be beneficial in these conditions, clearing triglyceride deposits from adipose tissue, liver and muscle, and restoring normal insulin sensitivity. Emerging evidence also suggests that the metabolic benefits of bypass surgery are mediated, at least in part, by surgical removal of GIP secreting K-cells in the upper small intestine. PMID- 21815990 TI - Predictors of dropout in weight loss interventions: a systematic review of the literature. AB - Attendance and completion of weight loss intervention is associated with better weight loss outcomes; however, attrition is neither consistently reported nor comprehensively explored in the weight loss literature. A systematic review was undertaken to identify factors associated with attrition in weight loss interventions involving overweight or obese (body mass index >= 25) adults (18-65 years). Sixty-one studies published before May 2011 and addressing factors associated with weight loss programme attrition were identified. Conclusions were limited by the large number of variables explored, the small number of studies exploring each variable, the large variety of study settings and methodologies used, the inconsistent reporting of results, and the conflicting findings across studies. A consistent set of predictors has not yet been identified. The majority of studies relied on pre-treatment routinely collected data rather than variables selected because of their theoretical and/or empirical relationship with attrition. However, psychological and behavioural patient factors and processes associated with the treatment were more commonly associated with attrition than patient background characteristics. Future research should consider theoretically grounded social-psychological and behavioural processes as potential predictors of dropout. Identification of patients at risk of dropout will contribute to both the effectiveness and the cost-effectiveness of weight loss interventions. PMID- 21815991 TI - Single-tooth implants with different neck designs: a randomized clinical trial evaluating the aesthetic outcome. AB - AIM: To evaluate the aesthetic outcome of single-tooth implants in the aesthetic zone with different neck designs from a professional's and patient's perception. MATERIALS AND METHODS: Ninety-three patients with a missing anterior tooth in the maxilla were randomly assigned to be treated with an implant with a smooth neck, a rough neck with grooves or a scalloped rough neck with grooves. Implants were installed in healed sites. One year after definitive crown placement (18 months post-implant placement), photographs were taken and the aesthetic outcome was assessed according to two objective aesthetic indexes: pink esthetic score/white esthetic score (PES/WES) and implant crown aesthetic index (ICAI). A questionnaire was used to assess the aesthetic outcome and general satisfaction from a patient's perception. standardized radiographs were taken to measure marginal bone level changes. RESULTS: One implant was lost. Although there was a significant difference in marginal bone loss between the different implant neck designs (smooth neck 1.19+/-0.82mm, rough neck 0.90+/-0.57mm, scalloped neck 2.01+/-0.77mm), there were no differences in aesthetic outcome. According to the professional's assessments using PES/WES and ICAI, 79.3% and 62% of the cases showed acceptable crown aesthetics, and 59.8% and 56.5% of the cases showed acceptable mucosa aesthetics. Overall, patients were satisfied about the aesthetics of the mucosa (81.5%) and crown (93.3%), and general patient satisfaction was high (9.0+/-1.0 out of a maximum of 10). According to the professional's assessment, a pre-implant augmentation procedure was associated with less favorable aesthetics of the mucosa. CONCLUSION: This study shows that the aesthetics of single-tooth implants in the maxillary aesthetic zone appears to be independent of the implant neck designs applied but dependent on the need for pre-implant surgery. PMID- 21815992 TI - Bone regeneration using porous titanium particles versus bovine hydroxyapatite: a sinus lift study in rabbits. AB - AIM: The first objective of this study was to qualitatively and quantitatively assess the bone formation process, particularly the long-term behavior and three dimensional volume stability of subsinusal bone regeneration, using titanium (Ti) or bovine hydroxyapatite (BHA) granules, in a rabbit model. The second objective was to evaluate the effect of the hydration of the BHA particles with a therapeutic concentration of doxycycline solution on the osteogenesis and biomaterial resorption. MATERIALS AND METHODS: Rabbits underwent a double sinus lift procedure using one of three materials: grade 1 porous Ti particles, BHA, or BHA hydrated with doxycycline solution (0.1mg/ml) (BHATTC). Animals were sacrificed after 1 week, 5 weeks, or 6 months. Samples were analyzed using uCT and nondecalcified histology. RESULTS: The materials used in each of the three groups allowed an optimal bone formation; bone quantities and densities were not statistically different between the three groups. At 6 months, more stable three dimensional volume stability was found with Ti and BHATTC (p=.0033). At 5 weeks and 6 months, bone to material contact corroborating osteoconduction was significantly higher with BHA and BHATTC than with Ti (p<.0001). CONCLUSIONS AND CLINICAL IMPLICATIONS: Even though the studied biomaterials displayed different architectures, they are relevant candidates for sinus lift bone augmentation prior to dental implants because they allow adequate three-dimensional stability and osteogenesis. However, to recommend the clinical use of Ti, both an observation on the drilling effects of Ti particles and clinical trials are needed. PMID- 21815993 TI - Constant strain rate and peri-implant bone modeling: an in vivo longitudinal micro-CT analysis. AB - BACKGROUND: Strain, frequency, loading time, and strain rate, among others, determine mechanical parameters in osteogenic loading. We showed a significant osteogenic effect on bone mass (BM) by daily peri-implant loading at 1.600uepsilon.s(-1) after 4 weeks. PURPOSE: To study the peri-implant osteogenic effect of frequency and strain in the guinea pig tibia by in vivo longitudinal micro-computed tomography (CT) analysis. MATERIAL AND METHODS: One week after implant installation in both hind limb tibiae, one implant was loaded daily for 10' during 4 weeks, while the other served as control. Frequencies (3, 10, and 30Hz) and strains varied alike in the three series to keep the strain rate constant at 1.600uepsilon.s(-1) . In vivo micro-CT scans were taken of both tibiae: 1 week after implantation but before loading (v1) and after 2 (v2) and 4 weeks (v3) of loading as well as postmortem (pm). BM (BM (%) bone-occupied area fraction) was calculated as well as the difference between test and control sides (delta BM) RESULTS: All implants (n=78) were clinically stable at 4 weeks. Significant increase in BM was measured between v1 and v2 (p<.0001) and between v1 and v3 (p<.0001). A significant positive effect of loading on delta BM was observed in the distal peri-implant marrow 500 Region of Interest already 2 weeks after loading (p=.01) and was significantly larger (11%) in series 1 compared with series 2 (p=.006) and 3 (p=.016). CONCLUSIONS: Within the constraints of constant loading time and strain rate, the effect of early implant loading on the peri-implant bone is strongly dependent on strain and frequency. This cortical bone model has shown to be most sensitive for high force loading at low frequency. PMID- 21815994 TI - A comparative study of crestal bone loss and implant stability between osteotome and conventional implant insertion techniques: a randomized controlled clinical trial study. AB - PURPOSE: The aim of this prospective randomized controlled clinical study was to assess the crestal bone loss and the implant stability in implants that were placed by the osteotome technique compared with the conventional drilling technique. MATERIALS AND METHODS: Forty-six screw type Straumann SLA(r) oral implants (Straumann AG, Waldenburg, Switzerland) were inserted in the anterior segment of maxilla of 30 patients. The implant site was prepared randomly using either osteotome technique (test group) or the conventional drilling technique (control group). Radio frequency analysis (RFA) values at implant placement and after 3 months were recorded. The crestal bone loss was measured using digital subtraction radiography technique after 3, 6, and 12 months. RESULTS: RFA demonstrated a statistically significant higher primary stability for implants in the osteotome group than that of the conventional group (p=.026) at the time of implant insertion. However, there was no statistically significant difference between both groups 3 months after the surgery (p=.06). At month 3, the osteotome group caused significantly more crestal bone loss than the conventional group (p=.04). At months 6 and 12, both groups had comparable bone levels (p=.29). CONCLUSION: Osteotome technique yielded higher primary stability than conventional drilling technique. However, this technique was not superior to conventional technique after 3 months. PMID- 21815995 TI - Marginal bone-level alterations at implants installed in block versus particulate onlay bone grafts mixed with platelet-rich plasma in atrophic maxilla. a prospective 5-year follow-up study of 15 patients. AB - BACKGROUND: Extensive atrophy of the alveolar process may require a bone-grafting procedure prior to implant treatment. Autogenous bone grafts from the iliac crest, used as onlay block and particulate bone, have been used together with sinus-lift procedure in order to rehabilitate patients with extremely resorbed maxillae. However, there are to our knowledge no 5-year follow-up studies evaluating the extent of bone-level change in patients treated with respectively block and particulate autogenous bone grafts. PURPOSE: The purpose of this prospective clinical study was to conduct a 5-year follow-up analysis with focus on bone-level alteration in block versus particulate onlay bone grafts. MATERIAL AND METHODS: Fifteen out of originally 19 patients who were treated with iliac bone grafts and oral implants in the maxilla have been followed through the first 5 postoperative years. In a first study conducted on 19 patients, the role of platelet-rich plasma in conjunction with autogenous bone was evaluated. In this 5 year follow-up study, the marginal bone alterations have been documented at base line, 1 year and 5 years of loading to the nearest 0,1 mm at mesial and distal surfaces of the implants. Two implants were installed on each side of the midline in either block or particulate bone grafts giving test and control sides in each patient. Additionally, two implants on each side were installed in residual bone/grafted sinus floor. RESULT: Marginal bone alteration in the anterior maxilla appeared larger at the side augmented by block bone at baseline, and after 1 and 5 years of loading, but the change was not statistically significant. Moreover, there was a significantly higher degree of marginal alteration during the first year of loading, compared with the examinations after 5 years. CONCLUSION: The present follow-up study showed that there is no significant difference in the extension of resorption between block- and particulate autogenous bone grafts over a 5-year period. Most of the resorption occurred during the first year in function. PMID- 21815996 TI - Clinical outcomes of an osteotome technique and simultaneous placement of Neoss implants in the posterior maxilla. AB - BACKGROUND: Insufficient bone volume often hamper placement of dental implants in the posterior maxilla. PURPOSE: The aim of the present clinical study was to evaluate retrospectively the clinical outcome of implant placement in the resorbed posterior maxilla using an osteotome technique without adding any grafting material. MATERIALS AND METHODS: Twenty patients with 5 to 9 mm of residual alveolar bone height in the posterior maxilla received twenty-nine implants (Neoss Ltd., Harrogate, UK) using an osteotomy technique without bone grafts. Intraoral radiographs were taken before and after implant placement, at the time of loading and after 11 to 32 months of loading (mean 16.4 months), to evaluate bone formation below the sinus membrane and marginal bone loss. Implant stability measurements (Osstell(TM) , Gothenburg, Sweden) were performed after implant installation and at abutment connection 5 months later. All implants were installed with the prosthetic platform level with the bone crest. RESULTS: No implant was lost giving a survival rate of 100% after a mean follow-up time of 16.4 months. The average vertical bone height was 7.2 +/- 1.5 mm at placement and 10.0 +/- 1.0 mm after 11 to 32 months. The average increase of 2.8 +/- 1.1 mm was statistically significant. There was a statistically significant improvement in implant stability from 70.7 +/- 9.2 implant stability quotient (ISQ) at placement to 76.7 +/- 5.7 ISQ at abutment connection, 5 months later. The mean marginal bone loss amounted to 0.7 +/- 0.3 mm after 11 to 32 months of loading. CONCLUSION: It is concluded that the osteotome technique evaluated resulted in predictable intrasinus bone formation, firm implant stability, and good clinical outcomes as no implants were lost and minimal marginal bone loss was observed. PMID- 21815997 TI - CDH13 is associated with working memory performance in attention deficit/hyperactivity disorder. AB - Different analytic strategies, including linkage, association and meta-analysis support a role of CDH13 in the susceptibility to attention deficit/hyperactivity disorder (ADHD). CDH13 codes for cadherin 13 (or H-cadherin), which is a member of a family of calcium-dependent cell-cell adhesion proteins and a regulator of neural cell growth. We tested the association between CDH13 on three executive functioning tasks that are promising endophenotypes of ADHD. An adjusted linear regression analysis was performed in 190 ADHD-affected Dutch probands of the IMAGE project. Three executive functions were examined: inhibition, verbal and visuo-spatial working memory (WM). We tested 2632 single nucleotide polymorphisms (SNPs) within CDH13 and 20 kb up- and downstream of the gene (capturing regulatory sequences). To adjust for multiple testing within the gene, we applied stringent permutation steps. Intronic SNP rs11150556 is associated with performance on the Verbal WM task. No other SNP showed gene-wide significance with any of the analyzed traits, but a 72-kb SNP block located 446 kb upstream of SNP rs111500556 showed suggestive evidence for association (P-value range 1.20E 03 to 1.73E-04) with performance in the same Verbal WM task. This study is the first to examine CDH13 and neurocognitive functioning. The mechanisms underlying the associations between CDH13 and the clinical phenotype of ADHD and verbal WM are still unknown. As such, our study may be viewed as exploratory, with the results presented providing interesting hypotheses for further testing. PMID- 21815998 TI - Caries experience of institutionalized elderly and its association with dementia and functional status. AB - OBJECTIVES: The aim of this study was to assess the caries experience of the elderly residing in residential aged care facilities in Perth, Western Australia, and its association with dementia and functional status. METHODS: Oral examinations were conducted in a sample of institutionalized aged persons. This study was carried out over a period of 7 years, between 2002 and 2008. RESULTS: A total of 205 residents were examined. The mean decayed, missing and filled teeth index score was 25.9 for all residents. Residents with dementia did not have significantly different levels of caries experience than those without. The mean number of active caries and retained decayed roots, however, was higher among residents with dementia. There was a significant difference in the mean number of active decay and carious retained roots among residents based on their Activities of Daily Living Oral Health score and their status of assistance received with brushing. CONCLUSION: Caries experience among the institutionalized elderly is associated with disability, and oral care is lacking among the institutionalized elderly in this study. Appropriate preventive measures (as well as interventional activities) should be undertaken to control oral disease among residential aged care residents. PMID- 21815999 TI - Increased glucose concentration results in reduced proteasomal activity and the formation of glycogen positive aggresomal structures. AB - Recent studies indicate that glycogen, besides being a principal storage product, confers protection against cellular stress through an unknown physiological pathway. Abnormal glycogen inclusions have also been considered to underlie pathology in a few neurodegenerative disorders that are caused by proteolytic dysfunctions, although a link between proteolytic pathways and glycogen accumulation is yet to be established. In the present study, we investigated the subcellular localization of glycogen particles and report that their distribution is altered under physiological stress. Using a cellular model, we show that glycogen particles are recruited to the centrosomal aggresomal structures upon proteasomal or lysosomal blockade, and that this recruitment is dependent on the microtubule function. We also show that an increase in the glucose concentration leads to decreased cellular proteasomal activity and the formation of glycogen positive aggresomal structures. Proteasomal blockade also leads to the formation of diastase-resistant polyglucosan bodies. The glycogen particles in aggresomes might provide energy to the proteolytic process and/or function as a scaffold. Taken together, the findings of the present study suggest a functional link between proteasomal function and polyglucosan bodies, and also suggest that these two physiological processes could be linked in neurodegenerative disorders. PMID- 21816000 TI - Topical grape (Vitis vinifera) seed extract promotes repair of full thickness wound in rabbit. AB - In recent years, oxidative stress and free radicals have been implicated in impaired wound healing. Grape (Vitis vinifera) seed extract (GSE) possesses anti inflammatory and antioxidant properties. The present study was undertaken to assess the potential activity of grape seed hydroalcoholic extract in wound healing in rabbits. Rabbits of either sex were subjected to a 20 * 20 mm square excision made over the skin of the back. The animals were randomly divided into seven experimental groups, as negative and positive control, eucerin and treatments. Negative control group did not receive any treatment. Positive control and eucerin groups received phenytoin cream (1%) and topical eucerin, respectively, twice a day from the beginning of experiments to complete wound closure. Treatment groups were treated topically by cream of GSE (2, 5, 10 and 70% w/w) in eucerin base, twice daily. For evaluation of the percentage of wound healing, area of the wound was measured daily. Histological studies were performed on the 7th and 15th days of treatments. After complete healing, hydroxyproline content and tensile strength measurement of tissue samples were done. Results showed that there were statistically significant differences between GSE treatments groups and eucerin animals (P < 0.05) in most of the days. Rabbits treated with 2% GSE had best results (completed healing in 13 days, higher hydroxyproline content and higher tissue resistance). We concluded that the extract of 2% GSE administered topically has a good potential to promote wound healing in wound model of rabbits. PMID- 21816001 TI - Activated leukocyte cell adhesion molecule impacts on clinical wound healing and inhibits HaCaT migration. AB - Activated leukocyte cell adhesion molecule (ALCAM) is a glycoprotein of the immunoglobulin superfamily that has been implicated in the processes of cell adhesion and migration. The current study examines the importance of ALCAM in regulating HaCaT cell growth and migration and its potential to impact on wound healing. ALCAM levels were examined in a range of clinical wound and normal skin samples using Q-PCR and immunohistochemistry. ALCAM expression was targeted in HaCaT keratinocyte cells using a hammerhead ribozyme transgene system. Subsequently, the impact of ALCAM suppression on HaCaT migration and growth was assessed. ALCAM protein was detected mainly in keratinocytes. ALCAM transcript levels were found to be significantly higher in the non-healed chronic wound samples compared with healed samples (P = 0.026). In addition, targeting of ALCAM in HaCaT cells brought about a substantial increase in cellular migration and growth compared with HaCaT control cells.Our results suggest that ALCAM plays an important role in the migration of HaCaT keratinocyte cells. The data also suggests that higher levels of ALCAM may impair healing in chronic wounds. The impact of ALCAM in wound healing may thus be somewhat due to its impact on cell migration and growth. PMID- 21816002 TI - Distribution of human leucocyte antigen-A, -B and -DR alleles and haplotypes at high resolution in the population from Jiangsu province of China. AB - The frequencies of human leucocyte antigen (HLA)-A, -B and -DRB1 alleles and haplotypes were statistically analysed among 3238 donors from Chinese Marrow Donor Program (CMDP) Jiangsu Branch. All donors were typed using polymerase chain reaction-sequence-based typing (PCR-SBT) method or polymerase chain reaction reverse sequence-specific oligonucleotide probe (PCR-rSSOP) method. As a result, a total of 46 A, 85 B and 51 DRB1 alleles were found in Jiangsu population. The first three frequent alleles in HLA-A, -B and -DRB1 loci respectively were A*11:01(16.52%), A*24:02(15.10%) and A*02:01(13.02%); B*13:02(11.60%), B*46:01(8.89%) and B*58:01(7.12%); and DRB1*07:01(15.78%), DRB1*09:01(15.26%) and DRB1*15:01(9.76%). The top two frequent A-B-DRB1 haplotypes were A*30:01-B*13:02 DRB1*07:01(8.87%) and A*02:07-B*46:01-DRB1*09:01(2.79%); the top three A-B haplotypes were A*33:03-B*58:01-DRB1*03:01(2.59%), A*30:01-B*13:02(9.92%) and A*33:03-B*58:01(5.48%); the top two B-DRB1 haplotypes were B*13:02 DRB1*07:01(10.23%) and B*46:01-DRB1*09:01(4.61%); the top two A-DRB1 haplotypes were A*30:01-DRB1*07:01(8.96%) and A*33:03-DRB1*13:02(3.95%). These findings provided useful information in the study of genetics and anthropology in Chinese Han population. It also served as a basic guide for selection of future donors in CMDP Jiangsu Branch. PMID- 21816003 TI - Immunogenetics of hematopoietic stem cell transplantation: the contribution of microsatellite polymorphism studies. AB - Polymorphisms of short tandem repeats of <10 nucleotides, or microsatellites (Msat), are largely used for post-transplant chimerism analyses in clinical hematopoietic stem cell transplantation (HSCT). Compared to single nucleotide polymorphisms (SNP), they have the advantage of a higher degree of allelic polymorphism and thus a potentially larger degree of informativity. Msat markers contribute to approximately 3% of the human genome and have been highly informative in disease association studies, population genetics, forensic medicine and organ and HSC transplantation. They allowed to expand our knowledge of the haplotypic structure of the HLA complex, including the noncoding sequences in the MHC, and to reach a better characterization of immunological phenotypes. Among the different immunogenetic studies in HSCT patients reviewed here, four Msat loci linked to cytokine genes have been analysed by a number of laboratories as potential candidates markers for HSCT outcome: IFNG, TNFd, IL-10(-1064) and IL 1RN. The low patient numbers and high diversity of clinical parameters account for some heterogeneity of the results. Among the trends starting to emerge from these studies, specific TNFd Msat alleles seem to be associated with acute graft versus-host disease and mortality. Patient/donor Msat incompatibilities have also been used as surrogate markers to map biologically relevant polymorphisms, with a main focus on MHC-resident genetic variation. High throughput SNP typing and next generation sequencing technologies will allow acquisition of large-scale genomic data and should allow refined analyses of clinically relevant genotypes in the transplantation settting, although the heterogeneity of the study cohorts will remain an issue. The analysis of Msat polymorphisms may still have a place in functional studies on the impact of Msat diversity in the control of immune response gene expression. PMID- 21816004 TI - Synthesis and biological evaluation of biotinyl hydrazone derivatives of muramyl peptides. AB - Muramyl peptides derived from bacterial peptidoglycan have long been known for their ability to trigger host innate immune responses, including inflammation and antimicrobial defense. Muramyl peptides have also been widely studied for their role as immune adjuvants. In mammals, the nucleotide-binding oligomerization domain (Nod) proteins Nod1 and Nod2 detect distinct muramyl peptide structures and mediate their biological activity. Because of the poor immunogenicity of these small peptidoglycan derivatives, research in this field is currently limited by the lack of reagents to track or immobilize specific muramyl peptides. We present here the generation and initial biological characterization of synthetic muramyl peptides covalently coupled to dansyl or biotinyl derivatives and demonstrate that biotinyl coupling on the muramyl moiety results in derivatives that can be tracked by immunofluorescence and maintain full biological activity, as observed by their capacity to trigger Nod signaling. Moreover, using digitonin-mediated permeabilization techniques on live cells, we also demonstrate that biotinylated muramyl peptides efficiently reach the host cytosol, where they activate Nod signaling. Therefore, these derivatives represent useful probes to study the cell biology and the biochemistry of host responses to muramyl peptides. PMID- 21816005 TI - Design, synthesis, biological activities, and 3D-QSAR of new N,N' diacylhydrazines containing 2-(2,4-dichlorophenoxy)propane moiety. AB - A series of new N,N'-diacylhydrazine derivatives were synthesized efficiently under microwave irradiation. Their structures were characterized by (1) H NMR, MS, and elemental analysis. Various biological activities of these compounds were tested. Most of them exhibited higher herbicidal activities against dicotyledonous weeds than monocotyledonous weeds. In addition, favorable in vivo fungicidal activities were also found of these compounds against Cladosporium cucumerinum, Corynespora cassiicola, Sclerotinia sclerotiorum(Lib.)de Bary, Erysiphe cichoracearum, and Colletotrichum orbiculare (Berk aLMont) Arx. All compounds displayed excellent plant growth regulatory activities: 100% inhibition was achieved against the radicle growth of cucumber. To further investigate the structure-activity relationship, comparative molecular field analysis was performed on the basis of herbicidal activity data, resulting in a statistically reliable model with good predictive power (r(2) = 0.913, q(2) =0.556). Based on the calculation, five additional novel compounds were designed and synthesized. Satisfyingly, compound 4u displayed excellent herbicidal activity (94.7%) at 1500 g/ha, although it is less active than 2,4-D. Meanwhile, this compound also exhibited good fungicidal activity against C. orbiculare (Berk aLMont) Arx (82.16%). PMID- 21816006 TI - Bone-anchored hearing aids for people with bilateral hearing impairment: a systematic review. AB - BACKGROUND: Bone-anchored hearing aids (BAHAs) are indicated for people with conductive or mixed hearing loss who can benefit from amplification of sound. In resource limited health care systems, it is important that evidence regarding the benefit of BAHAs is critically appraised to aid decision-making. OBJECTIVE OF REVIEW: To assess the clinical effectiveness of BAHAs for people with bilateral hearing impairment. TYPE OF REVIEW: Systematic review. SEARCH STRATEGY: Nineteen electronic resources were searched from inception to November 2009. Additional studies were sought from reference lists, clinical experts and BAHA manufacturers. EVALUATION METHOD: Inclusion criteria were applied by two reviewers independently. Data extraction and quality assessment of full papers were undertaken by one reviewer and checked by a second. Studies were synthesised through narrative review with tabulation of results. RESULTS: Twelve studies were included. Studies suggested audiological benefits of BAHAs when compared with bone-conduction hearing aids or no aiding. A mixed pattern of results was seen when BAHAs were compared to air-conduction hearing aids. Improvements in quality of life with BAHAs were found by a hearing-specific instrument but not generic quality of life measures. Issues such as improvement of discharging ears and length of time the aid can be worn were not adequately addressed by the studies. Studies demonstrated some benefits of bilateral BAHAs. Adverse events data were limited. The quality of the studies was low. CONCLUSIONS: The available evidence is weak. As such, caution is indicated in the interpretation of presently available data. However, based on the available evidence, BAHAs appear to be a reasonable treatment option for people with bilateral conductive or mixed hearing loss. Further research into the benefits of BAHAs, including quality of life, is required to reduce the uncertainty. PMID- 21816007 TI - Emergence of 2009A/H1N1 cases in a tertiary care hospital in New Delhi, India. AB - OBJECTIVE: To determine virologic and epidemiologic characteristics of pandemic (H1N1) 2009 at All India Institute of Medical Sciences (AIIMS) a tertiary care hospital in New Delhi, India. METHODS: Nasal and throat swabs from patients with febrile acute respiratory illness (FARI) from August to December 2009 (n = 1401) were tested for 2009A/H1N1 and seasonal influenza A viruses by real-time RT-PCR. RESULTS: Of 1401 samples tested, 475 (33.9%) were positive for influenza A, of these majority (412; 87%) were 2009A/H1N1, whereas the remaining 63 (13%) were seasonal influenza A (49 were A/H3 and 14 were A/H1). While co-circulation of 2009A/H1N1 and A/H3 was observed in August-September, subsequent months had exclusive pandemic influenza activity (October-December 2009). Pandemic 2009A/H1N1 emergence did not follow typical seasonal influenza seasonality in New Delhi, which normally peaks in July-August, but instead showed bimodal peaks in weeks 39 and 48 in 2009. The percent of specimens testing positive for 2009A/H1N1 influenza virus was found to be highest in >5- to 18-year age group (41.2%; OR = 2.3; CI = 1.6-3.2; P = 0.00). CONCLUSIONS: Taken together, our data provide high prevalence of pandemic 2009A/H1N1 in urban New Delhi with bimodal peaks in weeks 39 and 48 and highest risk group being the children of school-going age (aged >5 18). PMID- 21816008 TI - Clinical features and disease outcomes of undifferentiated arthritis in Thailand. AB - BACKGROUND: Undifferentiated arthritis (UA) comprises arthritis not yet identifiable as a specific rheumatic disease. Few reports exist on the natural course of UA in Thai patients. OBJECTIVE: To study the clinical features and natural course of UA in Thai patients. METHOD: A retrospective, analytical study was performed among Thai patients diagnosed with UA seen at Srinagarind Hospital, Khon Kaen, Thailand, between January 2002 and December 2007. RESULTS: The medical records of 95 UA patients were reviewed. The mean age at onset was 40.7 +/- 14.7 years (range, 15-78). The female:male ratio was 1.25 : 1.00. Common presentations included asymmetrical oligoarthritis followed by polyarthritis. The knee was the most commonly affected joint, followed by the wrist and ankle. Complete remission occurred within 6 months of onset in 4.2% of cases. A diagnosis was specified in 29 patients (30.5%) during the follow-up period (which averaged 17.1 +/- 24.0 months [range, 6-84]), including reactive arthritis (in 9 patients), undifferentiated spondyloarthropathy (7), rheumatoid arthritis (6), psoriatic arthritis (4), ankylosing spondylitis (1), gout (1) and unclassified connective tissue disease (1). UA was the default diagnosis for 66 patients (69.5%) after 24 months of follow-up. Hyperglobulinemia was correlated with persistent arthritis (i.e., > 6 months, P = 0.045). The only predictive factor for RA development was old-age at onset (P = 0.038). CONCLUSION: The most common presentation of Thai UA was asymmetrical oligoarthritis and most patients had persistent arthritis correlated with hyperglobulinemia. Elderly-onset, without any radiographic changes or rheumatoid factor, was predictive of RA development during follow-up. PMID- 21816009 TI - Knowledge, attitude and practice regarding vitamin D deficiency among female students in Saudi Arabia: a qualitative exploration. AB - BACKGROUND: Vitamin D deficiency is associated with numerous chronic diseases including cancer, heart disease and diabetes type 1 and 2. It is currently estimated that one billion people suffer from vitamin D deficiency worldwide. A major cause is lack of sun exposure, and this is evident even in countries at mid and low latitudes. Although a high prevalence has been found in Saudi Arabia, little is known to date about the reasons for this and, consequently about, reduction methodologies. The study's aim was to investigate the knowledge, attitude and practice (KAP) towards vitamin D deficiency, sun exposure, supplementation and fortification in a sample of female Saudi Arabian students. METHODS: A focus group and eight in depth one-to-one semi-structured interviews were conducted and analysed using thematic analysis. RESULTS: Participants were limited in their knowledge about vitamin D and vitamin D deficiency. They reported limited sun exposure due to intense heat, cultural reasons for covering the body, and an infrastructure that makes sun exposure difficult. CONCLUSION: Important barriers for the prevention of vitamin D deficiency in Saudi Arabia were highlighted. Recommendations for more research in specific areas including the prevalence of vitamin D deficiency and recommended daily allowances of supplementation are made. Governmental actions including increasing awareness of the importance of vitamin D and guidelines on how to obtain it are necessary. Creating areas where women, particularly those of lower socio-economic status, can enjoy sun exposure as well as fortifying more foods would go some way towards tackling this problem. PMID- 21816010 TI - The Gouty Joseph in Giulio Romano's 'Holy Family'. AB - Joint diseases in antiquity and the Renaissance were generally known by the all encompassing term, gout (podagra or gotta). Only in later centuries was there a differentiation in the types of joint diseases, distinguishing gout in the modern sense from other arthritic and rheumatic disorders. The present article illustrates one pictorial representation of joint disease from the early sixteenth century, a case that seems typical of gouty tophi. PMID- 21816011 TI - Interleukin-1 inhibition by anakinra in refractory chronic tophaceous gout. AB - Since the discovery of the inflammasome, interleukin 1 production has been found to be integral in the pathophysiology of gout. Interleukin 1 inhibition by Anakinra has been shown to effective for the treatment of gout. We report three cases of resistant chronic tophaceous gout who responded to anakinra subcutaneous injections on an intermittent basis. PMID- 21816012 TI - Polymyositis associated with hepatitis B: management with entacavir and prednisolone. AB - We report a 57-year-old woman with a 20-year history of hepatitis B presenting with progressive proximal lower limb weakness for the previous 1 month. Previous medical history included a pericardial and pleural effusion, of which no cause was found and pulmonary tuberculosis which has been adequately treated. Examination revealed multiple telangiactasia over face and nail beds and bilateral proximal lower limb weakness of power 4/5. Biochemical investigation revealed a raised erythrocyte sedimentation rate of 36 mm/h, elevated creatinine kinase levels (14,363 IU/L) and raised liver enzymes (alanine aminotransferase 445 IU/L, aspartate aminotransferase 606 IU/L) with high hepatitis B virus DNA (1,021,158 copies/mL). Nerve conduction tests and muscle biopsy were consistent with polymyositis. She received entacavir for hepatitis B treatment. Despite treatment with entacavir for 10 weeks, her weakness persisted and prednisolone was added. Upon commencement of prednisolone, her symptoms and biochemical profiles returned to normal. PMID- 21816013 TI - A challenging case of gout and failure of anti-TNF therapy- are current treatments adequate? PMID- 21816014 TI - Preliminary report on class II histocompatibility (HLA-DR and DQ) antigens in a subpopulation of Arab patients with systemic lupus erythematosus. PMID- 21816015 TI - Lamotrigine-induced lupus: a case report. PMID- 21816016 TI - Rheumatoid factor isotypes in patients with erosive osteoarthritis of the hand. PMID- 21816017 TI - Glycolysis and rheumatoid arthritis. AB - Glucose metabolism not only provides energy for physical activity but also mediates a variety of physiological processes through the formation of complex signalling networks. Recent studies have indicated that glucose metabolism plays an important role in the pathogenesis of rheumatoid arthritis (RA), an autoimmune disease involving the inflammation of joints. Herein, we review recent progress in this area. Evidence indicates that RA synovial tissues have increased glycolytic activity, which leads to an acidic microenvironment that further induced the transformation of normal synovial cells. Enhanced glycolysis activity is related to hypoxia in RA synovial membranes. Glucose phosphate isomerase, enolase and aldolase and key enzymes of the glycolysis pathway promote RA autoimmunity by acting as autoantigens. Lactate and pyruvate, substrates of RA synovium metabolism, stimulate abnormal cell proliferation, angiogenesis and pannus formation. PMID- 21816018 TI - Consensus statements on osteoporosis diagnosis, prevention, and management in the Philippines. AB - OBJECTIVE: The consensus statements were developed to assist healthcare practitioners in providing optimal care to postmenopausal individuals at risk for osteoporosis and fragility fractures in the local setting. METHODOLOGY: The Technical Review Committee formed by the Osteoporosis Society of the Philippines Foundation Inc. in cooperation with the Philippine Orthopedic Association drafted, retrieved available published evidence, and appraised important issues on osteoporosis and fragility fractures. The Appraisal of Guidelines Research and Evaluation instrument was used to appraise published guidelines while a systematic way of validating the quality of evidence and the level of recommendation was done using the GRADE system. A multidisciplinary panel of experts and stakeholders in an en banc meeting conferred and approved the recommendations. RESULTS AND CONCLUSION: There were five key issues on preventive, seven on diagnostic, nine on therapeutic aspects of osteoporosis with four other surgical concerns on fragility fractures. All were approved by a panel of stakeholders through a majority vote. These statements will best inform the clinicians and the specialists including orthopedic surgeons and general care practitioners on issues of postmenopausal Filipino women at risk for osteoporosis and fragility fractures. PMID- 21816019 TI - Osteoporosis education improves osteoporosis knowledge and dietary calcium: comparison of a 4 week and a one-session education course. AB - BACKGROUND: Education is ideal for osteoporosis because many risk factors are modifiable. However, the efficacy of shortened education courses compared to a standard 4 week course for improving osteoporosis knowledge and healthy behaviours is not known. This study aimed to assess whether education changed knowledge and healthy behaviours over 3 months of follow-up; and whether changes in these outcomes were different between participants receiving the different education courses. METHODS: Adults aged >= 50 years presenting to Emergency with mild to moderate trauma fractures received either the Osteoporosis Prevention and Self-Management Course (OPSMC) (4 * 2.5 h) (n = 75) or a one-session course (1 * 2.5 h) (n = 71) in a non-randomised prospective study with single-blinded allocation. Participants completed questionnaires measuring osteoporosis knowledge, dietary calcium, physical activity, calcium and exercise self efficacy, and osteoporosis medications at baseline and 3 months. Data were analysed using mixed models and GEE regression models. RESULTS: Osteoporosis knowledge and calcium from food (% of RDI) increased from baseline to 3 months in both groups (P < 0.01). Use of osteoporosis medications increased between baseline and 3 months in the OPSMC group while decreasing in the one-session group (P = 0.039). There were no differences between the groups or over time in physical activity, calcium or exercise self-efficacy. CONCLUSIONS: Osteoporosis education (either the OPSMC or the one-session course) improved osteoporosis knowledge and calcium intake after 3 months. Participants attending the OPSMC maintained medication compliance. We were unable to determine other differences between the courses. This study confirms the value of osteoporosis education for improving osteoporosis knowledge. PMID- 21816020 TI - The frequency of metabolic syndrome in women with rheumatoid arthritis and in controls. AB - AIM: To compare the frequency of the metabolic syndrome and its components in a sample of patients with rheumatoid arthritis (RA) and controls. METHODS: This case control study was performed on 188 women over 18 years old: 92 RA patients and 96 healthy controls, from 2006 to 2008. Blood pressure, height, weight and waist circumference were measured. Blood was collected for the measurement of fasting glucose, lipid profile and insulin. The frequency of the metabolic syndrome was determined in case and control groups, using both WHO and National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) criteria. RESULTS: According to the NCEP criteria, the frequency of metabolic syndrome in RA patients and controls were 27.2% and 35.4%, respectively (P = 0.22). Based on WHO criteria, 19.6% of RA patients and 21.9% of the control group were subject to metabolic syndrome (P = 0.70). The proportion with hypertension was greater in RA patients than the control group. The duration of RA was significantly higher in patients with metabolic syndrome compared to those without metabolic syndrome using both the WHO and NCEP criteria. CONCLUSIONS: There was no evidence of a greater prevalence of metabolic syndrome in RA patients compared with controls in this study. The duration of RA was associated with metabolic syndrome, implicating the role of inflammation in metabolic syndrome development. PMID- 21816021 TI - A comparative study of renal dysfunction in patients with inflammatory arthropathies: strong association with cardiovascular diseases and not with anti rheumatic therapies, inflammatory markers or duration of arthritis. AB - AIMS: The aim of this study was to investigate the prevalence of chronic kidney disease (CKD) among comparable patients with rheumatoid arthritis (RA) and seronegative inflammatory arthritis, and to explore any predictive factors for renal impairment. METHODS: Consecutive patients with peripheral joint disease (oligo and polyarthritis) were recruited from our inflammatory arthritis clinics. We divided patients in two groups: RA group and seronegative inflammatory arthritis group. The cohort consisted of 183 patients (RA = 107, seronegative arthritis = 76 [psoriatic arthritis = 69, undifferentiated oligoarthritis = 7]). Estimated glomerular filtration rate (eGFR) was calculated using the established Modification of Diet in Renal Disease equation. Demographic details, disease specific characteristics, anti-rheumatic drugs and the presence of cardiovascular diseases were recorded. RESULTS: In total, 17.48% (n = 32) of the cohort had CKD. There was no statistically significant variation between the two groups as regards baseline demographics, disease characteristics, use of anti-rheumatic drugs and the presence of individual cardiovascular diseases. We found that eGFR and the presence of CKD were similar among these groups. Among patients with CKD, 72% had undiagnosed CKD. No association of statistical significance was noted between CKD and the use of corticosteroids, disease-modifying antirheumatic drugs and anti-tumor necrosis factor agents. The association of cardiovascular diseases with CKD remained significant after adjusting for confounders (age, gender, duration of arthritis, high C-reactive protein, use of anti-rheumatic drugs). CONCLUSIONS: Patients with inflammatory arthritis are more prone to have CKD. This could have serious implications, as the majority of rheumatology patients use non-steroidal anti-inflammatory drugs and different immunosuppressives, such as methotrexate. No association of kidney dysfunction was noted with inflammatory disease-specific characteristics; rather it appears to have a positive independent association with cardiovascular diseases. PMID- 21816022 TI - Decrease of CD68 and MMP-3 expression in synovium by treatment of adalimumab for rheumatoid arthritis. AB - AIMS: In order to investigate the histological change in the secondary non responder cases of adalimumab compared with methotrexate (MTX) treatment, we performed immunohistochemical examination of synovial tissue by seven different molecules to detect expression patterns of cytokines. METHODS: We histologically assessed synovial tissues from five MTX-treated rheumatoid arthritis (RA) patients as controls and five adalimumab plus MTX-treated RA patients after arthroscopic synovectomy in the knee joints. The synovium of both groups were assessed by hematoxylin and eosin (H&E) and analyzed the positive expression of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), matrix metalloproteinase-3 (MMP-3), B-cell precursor and mature B-cell transmembrane protein, CD20, macrophage marker, CD68, vascular endothelial growth factor (VEGF), receptor activator of nuclear (kappa) B ligand (RANKL) by immunohistochemical examination. RESULTS: H&E staining showed the increase of vascular and cell proliferations in the synovium of the RA patients who received adalimumab compared with the controls. TNF-alpha, IL-6 and CD20 were not significantly different in either group. On the other hand, MMP-3 and CD68 showed a significant decrease in the adalimumab group compared with controls (P < 0.05). VEGF and RANKL were weakly positive in both groups. CONCLUSION: Based on the histological analysis of synovium, the effect attenuation of adalimumab may be involved in vascular and cell proliferations; however, there was inhibition of the expression of CD68 and MMP-3 in synovium. These findings indicate CD68 and MMP-3 may have key roles in the mechanism of efficacy of adalimumab. PMID- 21816023 TI - Thickened carotid intima media thickness and carotid atherosclerosis among lupus nephritis patients: the role of traditional and lupus-specific factors. AB - AIM: The objectives of this study were to investigate the frequency of thickened carotid intima media thickness (CIMT) and atherosclerosis among lupus nephritis (LN) patients and to study their associated risk factors. METHOD: In this cross sectional study, carotid ultrasonography was performed on consecutive LN patients to determine CIMT and presence of carotid plaques. CIMT was considered to be abnormally thickened if it was more than the 75th percentile matched for age and sex from the 'Carotid Atherosclerosis Progression Study'. The association between thickened CIMT with traditional cardiovascular risk factors and lupus characteristics were examined. A total of 83 patients with the mean age of 33.6 +/- 10 years were recruited. RESULTS: Fourteen patients (16.9%) had thickened CIMT and three (3.6%) had carotid plaques. On univariate analysis, traditional risk factors significantly associated with thickened CIMT (P < 0.05) were patient's current age, diabetes mellitus and waist circumference. Meanwhile, a lower serum C4 levels and higher serum C-reactive protein levels were the lupus specific factors associated with thickened CIMT (P < 0.05, P < 0.05 and P < 0.01, respectively). In logistic regression analysis, the independent predictors of thickened CIMT were age of diagnosis, lower serum C4 levels and waist circumference (P < 0.05). CONCLUSION: More lupus specific factors were independently associated with thickened CIMT, suggesting that a multi-targeted approach of treatment addressing both the lupus and traditional cardiovascular risks are very important. Larger prospective studies of these special risk factors are indicated. PMID- 21816024 TI - Increased urotensin-II activity in patients with Raynaud's phenomenon and systemic lupus erythematosus. AB - AIM: Raynaud's phenomenon (RP) commonly co-exists with systemic lupus erythematosus (SLE). The obvious pathophysiological mechanism in RP is vasoconstriction. Although the roles of certain vasoconstrictor substances, like endothelin-1, have been identified in RP, underlying mechanisms remain unclear. METHODS: In this pilot study, we researched a relatively recently identified, very potent vasoconstrictor peptide, urotensin-II (U-II), in SLE patients versus those without RP. In addition to its vasoconstrictor effect, U-II has been implicated in cardiovascular events and atherosclerosis. Increased frequencies of atherosclerosis and cardiovascular events comprise another issue in SLE patients. To address these effects, we included 15 Raynaud's (+) and 15 Raynaud's (-) SLE patients and compared both cohorts against age and sex-matched controls. RESULTS: We found significantly elevated U-II activity in both RP (+) and RP (-) SLE patients, relative to controls (P < 0.0001); however, the difference among RP (+) SLE patients was more prominent. U-II was significantly elevated in RP (+) SLE patients when compared to RP (-) SLE patients (P < 0.001). CONCLUSIONS: The results of our study suggest that, either as a cause or by-product, U-II may have some role in Raynaud's-related vasoconstriction. It also might contribute to atherosclerosis and cardiovascular diseases in SLE patients. Further studies clearly are warranted. PMID- 21816025 TI - Prognostic factors of mortality and 2-year survival analysis of systemic sclerosis with pulmonary arterial hypertension in Thailand. AB - AIMS: Pulmonary arterial hypertension (PAH) is a major complication and cause of death in systemic sclerosis (SSc). Our objective was to identify the predictive factors of mortality and the 2-year survival rate among Thai sufferers of PAH SSc. METHODS: An historical cohort study was performed among PAH-SSc patients followed up at Srinagarind Hospital, Thailand, between January 2005 and December 2008. Kaplan-Meier and Cox regression analyses were used to estimate the probability of survival and to assess the significant factors associated with death. RESULTS: Pulmonary arterial hypertension was recognized in 60 patients using ECHO criteria, right ventricular systolic pressure (RVSP) > 35 mmHg. Two thirds of the patients were female, > 50 years of age, with the dSSc subtype. Twenty patients (33.3%) died: the mortality rate was 15.6% per 100 person-years. The respective 1-, 2-, 3- and 4-year survival rate was 86.1%, 71.3%, 64.6% and 53.9%. The majority (85%) died without any specific treatment for PAH. Using univariate analysis, the mortality risk was associated with: the WHO functional class (FC) III (HR = 27.82), visceral organ involvement (HR = 5.14), myositis (HR = 3.14), esophageal dysmotility (HR = 3.08) and pericarditis (HR = 2.84). Using Cox regression, the only predictor of death was FCIII. The causes of death in PAH SSc were related to PAH (60%), infection (30%) and acute renal failure (10%). CONCLUSION: Up to one-third of Thai sufferers of PAH-SSc died within 2 years of PAH diagnosis, without any specific treatment being given. Increased mortality risk was found in SSc patients who had FCIII and visceral organ involvement. PMID- 21816026 TI - Chondrocyte apoptosis determined by caspase-3 expression varies with fibronectin distribution in equine articular cartilage. AB - AIM: The purpose of this study was to investigate associations between the extent of chondrocyte apoptosis and expression of the articular cartilage (AC) extracellular matrix (ECM) molecules, cartilage oligomeric matrix protein (COMP) and fibronectin. METHOD: Cartilage from four sites (when available) on equine left middle carpal joints (n = 12) were used. Expression of COMP and fibronectin was determined using specific polyclonal antibodies and a biotin streptavidin/peroxidase method. The intensity of staining for matrix molecules was graded (none, mild, moderate, strong) in each cartilage zone. Apoptosis of chondrocytes in AC sections was assessed by their expression of active caspase-3 using immunohistochemistry. RESULTS: The intensity of fibronectin expression varied significantly according to cartilage depth, with greater expression in the deep zone than in either the superficial or middle layers (P < 0.001). A significant positive association was found overall between intensity of fibronectin expression and chondrocyte apoptosis (r = 0.44, P = 0.0187). The data were also significant for superficial and deep zones (r = 0.44, P = 0.0239 and r = 0.42, P = 0.0279 respectively). Conversely, intensity of COMP expression did not show zonal differences and was un-associated with degree of apoptosis. However, COMP expression was significantly more intense in cartilage than fibronectin (P = 0.0007), and the correlation between overall intensity of COMP and fibronectin was statistically significant (r = 0.56, P = 0.0018). CONCLUSION: The positive correlation between the incidence of apoptosis and expression of fibronectin, a key ECM molecule involved in communication between the chondrocyte and surrounding matrix, suggests that chondrocyte death by apoptosis may alter cartilage metabolism, supporting the role of this process in the pathogenesis of osteoarthritis. PMID- 21816027 TI - Investigation of bacterial and viral agents and immune status in Behcet's disease patients from Iran. AB - AIM: Behcet's disease (BD) is an autoimmune disorder associated with HLA-B51 positivity. Serologic/genomic findings have suggested microbes as possible causative agents and the geographical distribution suggests environmental influences. METHODS: We performed comparative analyses of 40 patients with BD or related symptoms not fulfilling BD criteria. Patients originating from different regions of Iran were tested by molecular/serological methods for human herpes viruses and parvovirus B19, two Chlamydiae species, as well as Coxiella, Listeria, Yersinia, Leptospira and Mycobacterium paratuberculosis. Human leukocyte antigen-typing was performed: testing of cytokine profiles and immune mediators representative for the cellular immune system, including neopterin/kynurenine production. RESULTS: No apparent differences in interleukin (IL)-4, 6, 8 and 10 were observed, whereas production of soluble IL-2-receptor and tumor necrosis factor (TNF)-alpha were more pronounced in the BD group. Neopterin/kynurenine production was comparable, although both groups showed twice the levels of healthy people. No significant differences of herpes simplex virus (HSV) antibody titres were observed but higher titres against Chlamydophila pneumoniae were found in the controls. In 20 BD patients and controls neither parvovirus B19 DNA was detected nor bacterial DNA. Viral DNA of Epstein-Barr virus (EBV), cytomegalovirus (CMV) and human herpes virus (HHV)8 was detected more frequently in the BD group, whereas HSV DNA was only found in the controls, indicating that stomatitis might be caused by HSV. CONCLUSION: Although no significant association of BD was detected with a single pathogen, our findings suggest that detection of HSV DNA or Chlamydiae would rather argue against classic BD. Whether there is a discriminative potential of the tested immune mediators/receptors has to be elucidated in further studies. PMID- 21816029 TI - Design of a phase III multicenter trial to evaluate the efficacy of the RTS,S/AS01 malaria vaccine in children across diverse transmission settings in Africa. AB - BACKGROUND: GlaxoSmithKline Biologicals and the PATH Malaria Vaccine Initiative are working in partnership to develop a malaria vaccine to protect infants and children living in malaria endemic regions of sub-Saharan Africa, which can be delivered through the Expanded Programme on Immunization. The RTS,S/AS candidate vaccine has been evaluated in multiple phase I/II studies and shown to have a favourable safety profile and to be well-tolerated in both adults and children. This paper details the design of the phase III multicentre efficacy trial of the RTS,S/AS01 malaria vaccine candidate, which is pivotal for licensure and policy decision-making. METHODS: The phase III trial is a randomized, controlled, multicentre, participant- and observer-blind study on-going in 11 centres associated with different malaria transmission settings in seven countries in sub Saharan Africa. A minimum of 6,000 children in each of two age categories (6-12 weeks, 5-17 months) have been enrolled. Children were randomized 1:1:1 to one of three study groups: (1) primary vaccination with RTS,S/AS01 and booster dose of RTS,S/AS01; (2) primary vaccination with RTS,S/AS01 and a control vaccine at time of booster; (3) primary vaccination with control vaccine and a control vaccine at time of booster. Primary vaccination comprises three doses at monthly intervals; the booster dose is administered at 18 months post-primary course. Subjects will be followed to study month 32. The co-primary objectives are the evaluation of efficacy over one year post-dose 3 against clinical malaria when primary immunization is delivered at: (1) 6-12 weeks of age, with co-administration of DTPwHepB/Hib antigens and OPV; (2) 5-17 months of age. Secondary objectives include evaluation of vaccine efficacy against severe malaria, anaemia, malaria hospitalization, fatal malaria, all-cause mortality and other serious illnesses including sepsis and pneumonia. Efficacy of the vaccine against clinical malaria under different transmission settings, the evolution of efficacy over time and the potential benefit of a booster will be evaluated. In addition, the effect of RTS,S/AS01 vaccination on growth, and the safety and immunogenicity in HIV infected and malnourished children will be assessed. Safety of the primary course of immunization and the booster dose will be documented in both age categories. CONCLUSIONS: This pivotal phase III study of the RTS,S/AS01 candidate malaria vaccine in African children was designed and implemented by the Clinical Trials Partnership Committee. The study will provide efficacy and safety data to fulfil regulatory requirements, together with data on a broad range of endpoints that will facilitate the evaluation of the public health impact of the vaccine and will aid policy and implementation decisions. TRIAL REGISTRATION: Clinicaltrials.gov NCT00866619. PMID- 21816030 TI - Statistical methodology for the evaluation of vaccine efficacy in a phase III multi-centre trial of the RTS, S/AS01 malaria vaccine in African children. AB - BACKGROUND: There has been much debate about the appropriate statistical methodology for the evaluation of malaria field studies and the challenges in interpreting data arising from these trials. METHODS: The present paper describes, for a pivotal phase III efficacy of the RTS, S/AS01 malaria vaccine, the methods of the statistical analysis and the rationale for their selection. The methods used to estimate efficacy of the primary course of vaccination, and of a booster dose, in preventing clinical episodes of uncomplicated and severe malaria, and to determine the duration of protection, are described. The interpretation of various measures of efficacy in terms of the potential public health impact of the vaccine is discussed. CONCLUSIONS: The methodology selected to analyse the clinical trial must be scientifically sound, acceptable to regulatory authorities and meaningful to those responsible for malaria control and public health policy. PMID- 21816031 TI - Assessment of severe malaria in a multicenter, phase III, RTS, S/AS01 malaria candidate vaccine trial: case definition, standardization of data collection and patient care. AB - BACKGROUND: An effective malaria vaccine, deployed in conjunction with other malaria interventions, is likely to substantially reduce the malaria burden. Efficacy against severe malaria will be a key driver for decisions on implementation. An initial study of an RTS, S vaccine candidate showed promising efficacy against severe malaria in children in Mozambique. Further evidence of its protective efficacy will be gained in a pivotal, multi-centre, phase III study. This paper describes the case definitions of severe malaria used in this study and the programme for standardized assessment of severe malaria according to the case definition. METHODS: Case definitions of severe malaria were developed from a literature review and a consensus meeting of expert consultants and the RTS, S Clinical Trial Partnership Committee, in collaboration with the World Health Organization and the Malaria Clinical Trials Alliance. The same groups, with input from an Independent Data Monitoring Committee, developed and implemented a programme for standardized data collection.The case definitions developed reflect the typical presentations of severe malaria in African hospitals. Markers of disease severity were chosen on the basis of their association with poor outcome, occurrence in a significant proportion of cases and on an ability to standardize their measurement across research centres. For the primary case definition, one or more clinical and/or laboratory markers of disease severity have to be present, four major co-morbidities (pneumonia, meningitis, bacteraemia or gastroenteritis with severe dehydration) are excluded, and a Plasmodium falciparum parasite density threshold is introduced, in order to maximize the specificity of the case definition. Secondary case definitions allow inclusion of co-morbidities and/or allow for the presence of parasitaemia at any density. The programmatic implementation of standardized case assessment included a clinical algorithm for evaluating seriously sick children, improvements to care delivery and a robust training and evaluation programme for clinicians. CONCLUSIONS: The case definition developed for the pivotal phase III RTS, S vaccine study is consistent with WHO recommendations, is locally applicable and appropriately balances sensitivity and specificity in the diagnosis of severe malaria. Processes set up to standardize severe malaria data collection will allow robust assessment of the efficacy of the RTS, S vaccine against severe malaria, strengthen local capacity and benefit patient care for subjects in the trial. TRIAL REGISTRATION: Clinicaltrials.gov NCT00866619. PMID- 21816032 TI - Development of standardized laboratory methods and quality processes for a phase III study of the RTS, S/AS01 candidate malaria vaccine. AB - BACKGROUND: A pivotal phase III study of the RTS,S/AS01 malaria candidate vaccine is ongoing in several research centres across Africa. The development and establishment of quality systems was a requirement for trial conduct to meet international regulatory standards, as well as providing an important capacity strengthening opportunity for study centres. METHODS: Standardized laboratory methods and quality assurance processes were implemented at each of the study centres, facilitated by funding partners. RESULTS: A robust protocol for determination of parasite density based on actual blood cell counts was set up in accordance with World Health Organization recommendations. Automated equipment including haematology and biochemistry analyzers were put in place with standard methods for bedside testing of glycaemia, base excess and lactacidaemia. Facilities for X-rays and basic microbiology testing were also provided or upgraded alongside health care infrastructure in some centres. External quality assurance assessment of all major laboratory methods was established and method qualification by each laboratory demonstrated. The resulting capacity strengthening has ensured laboratory evaluations are conducted locally to the high standards required in clinical trials. CONCLUSION: Major efforts by study centres, together with support from collaborating parties, have allowed standardized methods and robust quality assurance processes to be put in place for the phase III evaluation of the RTS, S/AS01 malaria candidate vaccine. Extensive training programmes, coupled with continuous commitment from research centre staff, have been the key elements behind the successful implementation of quality processes. It is expected these activities will culminate in healthcare benefits for the subjects and communities participating in these trials. TRIAL REGISTRATION: Clinicaltrials.gov NCT00866619. PMID- 21816033 TI - Effectiveness of the home-based alcohol prevention program "In control: no alcohol!": study protocol of a randomized controlled trial. AB - BACKGROUND: In the Netherlands, children start to drink at an early age; of the Dutch 12-year olds, 40% reports lifetime alcohol use, while 9.7% reports last month drinking. Starting to drink at an early age puts youth at risk of developing several alcohol-related problems later in life. Recently, a home-based prevention program called "In control: No alcohol!" was developed to delay the age of alcohol onset in children. The main aim of this project is to conduct a Randomized Controlled Trial (RCT) to evaluate the effectiveness of the program. METHODS/DESIGN: The prevention program will be tested with an RCT among mothers and their 6 grade primary school children (11-12 years old), randomly assigned to the prevention or control condition. The program consists of five printed magazines and an activity book designed to improve parental alcohol-specific socialization. Parent-child dyads in the control group receive a factsheet information brochure, which is the standard alcohol brochure of the Trimbos Institute (the Netherlands Institute for Mental Health and Addiction).Outcome measures are initiation of alcohol use (have been drinking at least one glass of alcohol), alcohol-specific parenting, susceptibility to drinking alcohol, alcohol expectancies, self-efficacy, and frequency and intensity of child alcohol use. Questionnaires will be administered online on secured Internet webpages, with personal login codes for both mothers and children. Mothers and children in both the experimental and control condition will be surveyed at baseline and after 6, 12, and 18 months (follow-ups). DISCUSSION: The present study protocol presents the design of an RCT evaluating the effectiveness of the home-based "In control: No alcohol!" program for 6 grade primary school children (11-12 years old). It is hypothesized that children in the prevention condition will be less likely to have their first glass of alcohol, compared to the control condition. When the prevention appears to be effective, it can easily and relatively quickly be implemented as a standard alcohol prevention program on a large scale. TRIAL REGISTRATION: Nederlands Trial Register NTR2564. PMID- 21816034 TI - The volatile compound BinBase mass spectral database. AB - BACKGROUND: Volatile compounds comprise diverse chemical groups with wide-ranging sources and functions. These compounds originate from major pathways of secondary metabolism in many organisms and play essential roles in chemical ecology in both plant and animal kingdoms. In past decades, sampling methods and instrumentation for the analysis of complex volatile mixtures have improved; however, design and implementation of database tools to process and store the complex datasets have lagged behind. DESCRIPTION: The volatile compound BinBase (vocBinBase) is an automated peak annotation and database system developed for the analysis of GC TOF-MS data derived from complex volatile mixtures. The vocBinBase DB is an extension of the previously reported metabolite BinBase software developed to track and identify derivatized metabolites. The BinBase algorithm uses deconvoluted spectra and peak metadata (retention index, unique ion, spectral similarity, peak signal-to-noise ratio, and peak purity) from the Leco ChromaTOF software, and annotates peaks using a multi-tiered filtering system with stringent thresholds. The vocBinBase algorithm assigns the identity of compounds existing in the database. Volatile compound assignments are supported by the Adams mass spectral-retention index library, which contains over 2,000 plant derived volatile compounds. Novel molecules that are not found within vocBinBase are automatically added using strict mass spectral and experimental criteria. Users obtain fully annotated data sheets with quantitative information for all volatile compounds for studies that may consist of thousands of chromatograms. The vocBinBase database may also be queried across different studies, comprising currently 1,537 unique mass spectra generated from 1.7 million deconvoluted mass spectra of 3,435 samples (18 species). Mass spectra with retention indices and volatile profiles are available as free download under the CC-BY agreement (http://vocbinbase.fiehnlab.ucdavis.edu). CONCLUSIONS: The BinBase database algorithms have been successfully modified to allow for tracking and identification of volatile compounds in complex mixtures. The database is capable of annotating large datasets (hundreds to thousands of samples) and is well suited for between-study comparisons such as chemotaxonomy investigations. This novel volatile compound database tool is applicable to research fields spanning chemical ecology to human health. The BinBase source code is freely available at http://binbase.sourceforge.net/ under the LGPL 2.0 license agreement. PMID- 21816035 TI - Lifestyle and self-rated health: a cross-sectional study of 3,601 citizens of Athens, Greece. AB - BACKGROUND: Self-rated health (SRH) is a popular health measure determined by multiple factors. International literature is increasingly focusing on health related behaviors such as smoking, dietary habits, physical activity, even religiosity. However, population-based studies taking into account multiple putative determinants of SRH in Greece are scarce. The aim of this study was to clarify possible determinants of SRH with an emphasis on the relationship between SRH and lifestyle variables in a large sample of urban citizens. METHODS: In this one-year cross-sectional study, a stratified random sample of 3,601 urban citizens was selected. Data were collected using an interview-based questionnaire about various demographic, socioeconomic, disease- and lifestyle related factors such as smoking, physical activity, dietary habits, sleep quality and religiosity. Multivariate logistic regression was used separately in three age groups [15-29 (N = 1,360), 30-49 (N = 1,122) and 50+ (N = 1,119) years old] in order to identify putative lifestyle and other determinants of SRH. RESULTS: Reporting of good SRH decreased with age (97.1%, 91.4% and 74.8%, respectively). Overall, possible confounders of the lifestyle-SRH relationship among age groups were sex, education, hospitalization during the last year, daily physical symptoms and disease status. Poor SRH was associated with less physical activity in the 15-29 years old (OR 2.22, 95%CI 1.14-4.33), with past or heavy smoking, along with no sleep satisfaction in the 30-49 years old (OR 3.23, 95%CI 1.35 7.74, OR 2.56, 95%CI 1.29-5.05, OR 1.79, 95%CI 1.1-2.92, respectively) and with obesity and no sleep satisfaction in the 50+ years old individuals (OR 1.83, 95%CI 1.19-2.81, OR 2.54, 95%CI 1.83-3.54). Sleep dissatisfaction of the 50+ years old was the only variable associated with poor SRH at the 0.001 p level of significance (OR 2.45, 99%CI 1.59 to 3.76). Subgroup analyses of the 15-19 years old individuals also revealed sleep dissatisfaction as the only significant variable correlated with SRH. CONCLUSIONS: Slight differences in lifestyle determinants of SRH were identified among age groups. Sleep quality emerged as an important determinant of SRH in the majority of participants. PMID- 21816036 TI - Innegligible musculoskeletal disorders caused by zoledronic acid in adjuvant breast cancer treatment: a meta-analysis. AB - BACKGROUND: Zoledronic acid (ZOL) is widely used for preventing bone loss in early breast cancer patients. However, the adverse effects caused by ZOL itself should not be neglected. Musculoskeletal disorders were common after ZOL administration and distressing to the patients. Up to now, no precise estimation of musculoskeletal disorders has been made. METHODS: Relevant randomized clinical trials were selected by searching the electronic database PubMed, and a meta analysis was conducted. RESULTS: Four trials reported musculoskeletal disorders of ZOL treatment versus no ZOL, including 2684 patients treated with ZOL and 2712 patients without ZOL treatment. Compared to patients without ZOL treatment, patients treated with ZOL had a significantly higher risk of arthralgia (risk ratio (RR): 1.162, 95% confidence interval (CI): 1.096-1.232, P = 0.466 for heterogeneity) and bone pain (RR: 1.257, 95% CI: 1.149-1.376, P = 0.193 for heterogeneity). Three clinical trials reported the complications of upfront versus delayed ZOL treatment, including 1091 patients with upfront ZOL and 1110 patients with delayed ZOL. The rate of bone pain in upfront group (119/824) was significantly higher than that in delayed group (74/836) (RR: 1.284, 95% CI: 1.135-1.453, P = 0.460 for heterogeneity). CONCLUSIONS: Our meta-analysis suggested that treatment with ZOL was significantly associated to the occurrence of arthralgia and bone pain. Moreover, higher rate of bone pain was observed in patients treated with upfront ZOL compared with delayed ZOL treatment. More attentions should be paid to patients treated with ZOL, especially for immediate ZOL. For patients with low risk of osteoporosis, immediate ZOL may be not needed due to additional musculoskeletal disorders and little benefit. Or it can be stopped after the occurrence of these adverse events. PMID- 21816037 TI - Strategies for aggregating gene expression data: the collapseRows R function. AB - BACKGROUND: Genomic and other high dimensional analyses often require one to summarize multiple related variables by a single representative. This task is also variously referred to as collapsing, combining, reducing, or aggregating variables. Examples include summarizing several probe measurements corresponding to a single gene, representing the expression profiles of a co-expression module by a single expression profile, and aggregating cell-type marker information to de-convolute expression data. Several standard statistical summary techniques can be used, but network methods also provide useful alternative methods to find representatives. Currently few collapsing functions are developed and widely applied. RESULTS: We introduce the R function collapseRows that implements several collapsing methods and evaluate its performance in three applications. First, we study a crucial step of the meta-analysis of microarray data: the merging of independent gene expression data sets, which may have been measured on different platforms. Toward this end, we collapse multiple microarray probes for a single gene and then merge the data by gene identifier. We find that choosing the probe with the highest average expression leads to best between-study consistency. Second, we study methods for summarizing the gene expression profiles of a co-expression module. Several gene co-expression network analysis applications show that the optimal collapsing strategy depends on the analysis goal. Third, we study aggregating the information of cell type marker genes when the aim is to predict the abundance of cell types in a tissue sample based on gene expression data ("expression deconvolution"). We apply different collapsing methods to predict cell type abundances in peripheral human blood and in mixtures of blood cell lines. Interestingly, the most accurate prediction method involves choosing the most highly connected "hub" marker gene. Finally, to facilitate biological interpretation of collapsed gene lists, we introduce the function userListEnrichment, which assesses the enrichment of gene lists for known brain and blood cell type markers, and for other published biological pathways. CONCLUSIONS: The R function collapseRows implements several standard and network based collapsing methods. In various genomic applications we provide evidence that both types of methods are robust and biologically relevant tools. PMID- 21816038 TI - Accumulation and aberrant composition of cholesteryl esters in Scrapie-infected N2a cells and C57BL/6 mouse brains. AB - OBJECTIVE: Cholesterol changes have been described in prion-cell models and in experimental rodent scrapie; yet, the pattern of this association is still controversial. METHODS: To shed light on the matter, we analysed and compared cholesterol variations in ScN2a cells and in brains of Scrapie-infected C57Bl/6 mice, using two different methods: a fluorimetric-enzymatic cholesterol assay, and high performance liquid chromatography-mass spectroscopy (HPLC-MS). RESULTS: Compared to uninfected controls, similar cholesterol metabolism anomalies were observed in infected cells and brains by both methods; however, only HPLC-MS revealed statistically significant cholesterol variations, particularly in the cholesteryl esters (CE) fraction. HPLC-MS analyses also revealed different fatty acid composition of the CE fraction in cells and brains. In N2a cells, their profile reflected that of serum, while in normal brains cholesteryl-linoleate only was found at detectable levels. Following prion infection, most CE species were increased in the CE pool of ScN2a cells, whereas a conspicuous amount of cholesteryl-arachidonate only was found to contribute to the cerebral increase of CE. Of interest, oral pravastatin administration to Scrapie-infected mice, was associated with a significant reduction of cerebral free cholesterol (FC) along with a concomitant further increase of the CE pool, which included increased amounts of both cholesteryl-linoleate and cholesteryl-arachidonate. CONCLUSION: Although mechanistic studies are needed to establish the pathophysiological relevance of changes in cerebral CE concentrations, to the best of our knowledge this is the first report to provide evidence of increased cholesterol esterification in brains of prion-infected mice, untreated and treated with pravastatin. PMID- 21816040 TI - RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome. AB - BACKGROUND: RNA-Seq is revolutionizing the way transcript abundances are measured. A key challenge in transcript quantification from RNA-Seq data is the handling of reads that map to multiple genes or isoforms. This issue is particularly important for quantification with de novo transcriptome assemblies in the absence of sequenced genomes, as it is difficult to determine which transcripts are isoforms of the same gene. A second significant issue is the design of RNA-Seq experiments, in terms of the number of reads, read length, and whether reads come from one or both ends of cDNA fragments. RESULTS: We present RSEM, an user-friendly software package for quantifying gene and isoform abundances from single-end or paired-end RNA-Seq data. RSEM outputs abundance estimates, 95% credibility intervals, and visualization files and can also simulate RNA-Seq data. In contrast to other existing tools, the software does not require a reference genome. Thus, in combination with a de novo transcriptome assembler, RSEM enables accurate transcript quantification for species without sequenced genomes. On simulated and real data sets, RSEM has superior or comparable performance to quantification methods that rely on a reference genome. Taking advantage of RSEM's ability to effectively use ambiguously-mapping reads, we show that accurate gene-level abundance estimates are best obtained with large numbers of short single-end reads. On the other hand, estimates of the relative frequencies of isoforms within single genes may be improved through the use of paired-end reads, depending on the number of possible splice forms for each gene. CONCLUSIONS: RSEM is an accurate and user-friendly software tool for quantifying transcript abundances from RNA-Seq data. As it does not rely on the existence of a reference genome, it is particularly useful for quantification with de novo transcriptome assemblies. In addition, RSEM has enabled valuable guidance for cost-efficient design of quantification experiments with RNA-Seq, which is currently relatively expensive. PMID- 21816041 TI - Bioprospecting metagenomics of decaying wood: mining for new glycoside hydrolases. AB - BACKGROUND: To efficiently deconstruct recalcitrant plant biomass to fermentable sugars in industrial processes, biocatalysts of higher performance and lower cost are required. The genetic diversity found in the metagenomes of natural microbial biomass decay communities may harbor such enzymes. Our goal was to discover and characterize new glycoside hydrolases (GHases) from microbial biomass decay communities, especially those from unknown or never previously cultivated microorganisms. RESULTS: From the metagenome sequences of an anaerobic microbial community actively decaying poplar biomass, we identified approximately 4,000 GHase homologs. Based on homology to GHase families/activities of interest and the quality of the sequences, candidates were selected for full-length cloning and subsequent expression. As an alternative strategy, a metagenome expression library was constructed and screened for GHase activities. These combined efforts resulted in the cloning of four novel GHases that could be successfully expressed in Escherichia coli. Further characterization showed that two enzymes showed significant activity on p-nitrophenyl-alpha-L-arabinofuranoside, one enzyme had significant activity against p-nitrophenyl-beta-D-glucopyranoside, and one enzyme showed significant activity against p-nitrophenyl-beta-D-xylopyranoside. Enzymes were also tested in the presence of ionic liquids. CONCLUSIONS: Metagenomics provides a good resource for mining novel biomass degrading enzymes and for screening of cellulolytic enzyme activities. The four GHases that were cloned may have potential application for deconstruction of biomass pretreated with ionic liquids, as they remain active in the presence of up to 20% ionic liquid (except for 1-ethyl-3-methylimidazolium diethyl phosphate). Alternatively, ionic liquids might be used to immobilize or stabilize these enzymes for minimal solvent processing of biomass. PMID- 21816039 TI - Alzheimer's disease - a neurospirochetosis. Analysis of the evidence following Koch's and Hill's criteria. AB - It is established that chronic spirochetal infection can cause slowly progressive dementia, brain atrophy and amyloid deposition in late neurosyphilis. Recently it has been suggested that various types of spirochetes, in an analogous way to Treponema pallidum, could cause dementia and may be involved in the pathogenesis of Alzheimer's disease (AD). Here, we review all data available in the literature on the detection of spirochetes in AD and critically analyze the association and causal relationship between spirochetes and AD following established criteria of Koch and Hill. The results show a statistically significant association between spirochetes and AD (P = 1.5 * 10-17, OR = 20, 95% CI = 8-60, N = 247). When neutral techniques recognizing all types of spirochetes were used, or the highly prevalent periodontal pathogen Treponemas were analyzed, spirochetes were observed in the brain in more than 90% of AD cases. Borrelia burgdorferi was detected in the brain in 25.3% of AD cases analyzed and was 13 times more frequent in AD compared to controls. Periodontal pathogen Treponemas (T. pectinovorum, T. amylovorum, T. lecithinolyticum, T. maltophilum, T. medium, T. socranskii) and Borrelia burgdorferi were detected using species specific PCR and antibodies. Importantly, co-infection with several spirochetes occurs in AD. The pathological and biological hallmarks of AD were reproduced in vitro by exposure of mammalian cells to spirochetes. The analysis of reviewed data following Koch's and Hill's postulates shows a probable causal relationship between neurospirochetosis and AD. Persisting inflammation and amyloid deposition initiated and sustained by chronic spirochetal infection form together with the various hypotheses suggested to play a role in the pathogenesis of AD a comprehensive entity. As suggested by Hill, once the probability of a causal relationship is established prompt action is needed. Support and attention should be given to this field of AD research. Spirochetal infection occurs years or decades before the manifestation of dementia. As adequate antibiotic and anti inflammatory therapies are available, as in syphilis, one might prevent and eradicate dementia. PMID- 21816043 TI - Medicinal plants used for traditional veterinary in the Sierras de Cordoba (Argentina): an ethnobotanical comparison with human medicinal uses. AB - BACKGROUND: This is a first description of the main ethnoveterinary features of the peasants in the Sierras de Cordoba. The aim of this study was to analyze the use of medicinal plants and other traditional therapeutic practices for healing domestic animals and cattle. Our particular goals were to: characterize veterinary ethnobotanical knowledge considering age, gender and role of the specialists; interpret the cultural features of the traditional local veterinary medicine and plant uses associated to it; compare the plants used in traditional veterinary medicine, with those used in human medicine in the same region. METHODS: Fieldwork was carried out as part of an ethnobotanic regional study where 64 informants were interviewed regarding medicinal plants used in veterinary medicine throughout 2001-2010. Based participant observation and open and semi-structured interviews we obtained information on the traditional practices of diagnosis and healing, focusing on the veterinary uses given to plants (part of the plant used, method of preparation and administration). Plants speciemens were collected with the informants and their vernacular and scientific names were registered in a database. Non-parametric statistic was used to evaluate differences in medicinal plant knowledge, use, and valorization by local people. A comparison between traditional veterinary medicine and previous human medicine studies developed in the region was performed by analyzing the percentages of common species and uses, and by considering Sorensen's Similarity Index. RESULTS: A total of 127 medicinal uses were registered, corresponding to 70 species of plants belonging to 39 botanic families. Veterinary ethnobotanical knowledge was specialized, restricted, in general, to cattle breeders (mainly men) and to a less degree to healers, and was independent of the age of the interviewees. Native plants were mostly used as skin cicatrizants, disinfectants or for treating digestive disorders. Together with a vast repertoire of plant pharmacopoeia, the therapies also involve religious or ritualistic practices and other popular remedies that evidence the influence of traditional Hispanic European knowledge. Although the traditional veterinary knowledge seems to be similar or else is inlcuded in the local human ethnomedicine, sharing a common group of plants, it has distinct traits originated by a constant assessment of new applications specifically destined to the treatment of animals. CONCLUSIONS: Veterinary medicine is a fountain of relevant vernacular knowledge, a permanent source for testing new applications with valuable ethnobotanical interest. Knowledge on medicinal applications of native plants will allow future validations and tests for new homeopathic or phytotherapeutic preparations. PMID- 21816042 TI - Complete genome sequence of Brachyspira intermedia reveals unique genomic features in Brachyspira species and phage-mediated horizontal gene transfer. AB - BACKGROUND: Brachyspira spp. colonize the intestines of some mammalian and avian species and show different degrees of enteropathogenicity. Brachyspira intermedia can cause production losses in chickens and strain PWS/AT now becomes the fourth genome to be completed in the genus Brachyspira. RESULTS: 15 classes of unique and shared genes were analyzed in B. intermedia, B. murdochii, B. hyodysenteriae and B. pilosicoli. The largest number of unique genes was found in B. intermedia and B. murdochii. This indicates the presence of larger pan-genomes. In general, hypothetical protein annotations are overrepresented among the unique genes. A 3.2 kb plasmid was found in B. intermedia strain PWS/AT. The plasmid was also present in the B. murdochii strain but not in nine other Brachyspira isolates. Within the Brachyspira genomes, genes had been translocated and also frequently switched between leading and lagging strands, a process that can be followed by different AT-skews in the third positions of synonymous codons. We also found evidence that bacteriophages were being remodeled and genes incorporated into them. CONCLUSIONS: The accessory gene pool shapes species-specific traits. It is also influenced by reductive genome evolution and horizontal gene transfer. Gene transfer events can cross both species and genus boundaries and bacteriophages appear to play an important role in this process. A mechanism for horizontal gene transfer appears to be gene translocations leading to remodeling of bacteriophages in combination with broad tropism. PMID- 21816044 TI - Kinetic targeting of pegylated liposomal doxorubicin: a new approach to reduce toxicity during chemotherapy (CARL-trial). AB - BACKGROUND: The therapeutic success of chemotherapeutic agents is often limited by severe adverse effects. To reduce toxicity of these drugs, nanoscale particle based drug delivery systems (DDS) are used. DDS accumulate to some extent in tumor tissues, but only a very small portion of a given dose reaches this target. Accumulation of DDS in tumor tissues is supposed to be much faster than in certain other tissues in which side effects occur ("Kinetic Targeting"). Once saturation in tumor tissue is achieved, most of the administered DDS still circulate in the plasma. The extracorporeal elimination of these circulating nanoparticles would probably reduce toxicity. METHODS: For the CARL-trial (Controlled Application and Removal of Liposomal chemotherapeutics), pegylated liposomal doxorubicin (PLD) was used as chemotherapeutic agent and double filtration plasmapheresis (DFPP) was performed for extracorporeal elimination of liposomes. PLD was given as 40 mg/m2 every 3 weeks in combination with vinorelbine 2 * 25 mg/m2 (neoadjuvant treatment of breast cancer, 12 patients), or as 40 mg/m2 every 4 weeks (recurrent ovarian cancer, 3 patients). Primary endpoints were the efficiency and safety profile of DFPP, and secondary endpoints were side effects and tumor response. RESULTS: DFPP eliminated ~62% of circulating PLD, corresponding to ~45% of the total dose (n = 57 cycles). AUC of doxorubicin was reduced by 50%. No leakage of doxorubicin was detected during elimination, and no relevant DFPP-related side effects occurred. Reduction in tumor size > 30% occurred in 10/12 (neoadjuvant) and in 1/3 patients (recurrent). Only five grade 2 events and one grade 3 event (mucositis, neutropenia or leucopenia) and a single palmar-plantar erythrodysesthesia grade 2 were reported. CONCLUSION: Extracorporeal elimination of PLD by DFPP is safe and efficient. CARL can diminish the main dose-limiting side effects of PLD, and probably many different DDS alike. TRIAL REGISTRATION: DRKS00000163. PMID- 21816045 TI - Validation of cross-cultural child mental health and psychosocial research instruments: adapting the Depression Self-Rating Scale and Child PTSD Symptom Scale in Nepal. AB - BACKGROUND: The lack of culturally adapted and validated instruments for child mental health and psychosocial support in low and middle-income countries is a barrier to assessing prevalence of mental health problems, evaluating interventions, and determining program cost-effectiveness. Alternative procedures are needed to validate instruments in these settings. METHODS: Six criteria are proposed to evaluate cross-cultural validity of child mental health instruments: (i) purpose of instrument, (ii) construct measured, (iii) contents of construct, (iv) local idioms employed, (v) structure of response sets, and (vi) comparison with other measurable phenomena. These criteria are applied to transcultural translation and alternative validation for the Depression Self-Rating Scale (DSRS) and Child PTSD Symptom Scale (CPSS) in Nepal, which recently suffered a decade of war including conscription of child soldiers and widespread displacement of youth. Transcultural translation was conducted with Nepali mental health professionals and six focus groups with children (n=64) aged 11-15 years old. Because of the lack of child mental health professionals in Nepal, a psychosocial counselor performed an alternative validation procedure using psychosocial functioning as a criterion for intervention. The validation sample was 162 children (11-14 years old). The Kiddie-Schedule for Affective Disorders and Schizophrenia (K-SADS) and Global Assessment of Psychosocial Disability (GAPD) were used to derive indication for treatment as the external criterion. RESULTS: The instruments displayed moderate to good psychometric properties: DSRS (area under the curve (AUC)=0.82, sensitivity=0.71, specificity=0.81, cutoff score >= 14); CPSS (AUC=0.77, sensitivity=0.68, specificity=0.73, cutoff score >= 20). The DSRS items with significant discriminant validity were "having energy to complete daily activities" (DSRS.7), "feeling that life is not worth living" (DSRS.10), and "feeling lonely" (DSRS.15). The CPSS items with significant discriminant validity were nightmares (CPSS.2), flashbacks (CPSS.3), traumatic amnesia (CPSS.8), feelings of a foreshortened future (CPSS.12), and easily irritated at small matters (CPSS.14). CONCLUSIONS: Transcultural translation and alternative validation feasibly can be performed in low clinical resource settings through task-shifting the validation process to trained mental health paraprofessionals using structured interviews. This process is helpful to evaluate cost-effectiveness of psychosocial interventions. PMID- 21816046 TI - Cardiovascular magnetic resonance of cardiomyopathy in limb girdle muscular dystrophy 2B and 2I. AB - BACKGROUND: Limb girdle muscular dystrophies (LGMD) are inclusive of 7 autosomal dominant and 14 autosomal recessive disorders featuring progressive muscle weakness and atrophy. Studies of cardiac function have not yet been well-defined in deficiencies of dysferlin (LGMD2B) and fukutin related protein (LGMD2I). In this study of patients with these two forms of limb girdle muscular dystrophy, cardiovascular magnetic resonance (CMR) was used to more specifically define markers of cardiomyopathy including systolic dysfunction, myocardial fibrosis, and diastolic dysfunction. METHODS: Consecutive patients with genetically-proven LGMD types 2I (n = 7) and 2B (n = 9) and 8 control subjects were enrolled. All subjects underwent cardiac magnetic resonance (CMR) on a standard 1.5 Tesla clinical scanner with cine imaging for left ventricular (LV) volume and ejection fraction (EF) measurement, vector velocity analysis of cine data to calculate myocardial strain, and late post-gadolinium enhancement imaging (LGE) to assess for myocardial fibrosis. RESULTS: Sixteen LGMD patients (7 LGMD2I, 9 LGMD2B), and 8 control subjects completed CMR. All but one patient had normal LV size and systolic function; one (type 2I) had severe dilated cardiomyopathy. Of 15 LGMD patients with normal systolic function, LGE imaging revealed focal myocardial fibrosis in 7 (47%). Peak systolic circumferential strain rates were similar in patients vs. controls: epsilonendo was -23.8 +/- 8.5vs. -23.9 +/- 4.2%, epsilonepi was -11.5 +/- 1.7% vs. -10.1 +/- 4.2% (p = NS for all). Five of 7 LGE positive patients had grade I diastolic dysfunction [2I (n = 2), 2B (n = 3)]. that was not present in any LGE-negative patients or controls. CONCLUSIONS: LGMD2I and LGMD2B generally result in mild structural and functional cardiac abnormalities, though severe dilated cardiomyopathy may occur. Long-term studies are warranted to evaluate the prognostic significance of subclinical fibrosis detected by CMR in these patients. PMID- 21816047 TI - Toxoplasmosis presenting as a swelling in the axillary tail of the breast and a palpable axillary lymph node mimicking malignancy: a case report. AB - INTRODUCTION: Lymphadenopathy is a common finding in toxoplasmosis. A breast mass due to toxoplasmosis is very rare, and only a few cases have been reported. We present a case of toxoplasmosis that presented as a swelling in the axillary tail of the breast with a palpable axillary lymph node which mimicked breast cancer. CASE PRESENTATION: A 45-year-old otherwise healthy Caucasian woman presented with a lump on the lateral aspect of her left breast. Her mother had breast cancer that was diagnosed at the age of 66 years. During an examination, we discovered that our patient had a discrete, firm lump in the axillary tail of her left breast and an enlarged, palpable lymph node in her left axilla. Her right breast and axilla were normal. The clinical diagnosis was malignancy in the left breast. Ultrasound and mammographic examinations of her breast suggested a pathological process but were not conclusive. She had targeted fine-needle aspiration cytology (FNAC) and core biopsy of the lesions. FNAC was indeterminate (C3) but suggested a possibility of toxoplasmosis. The core biopsy was not suggestive of malignancy but showed granulomatous inflammation. She had a wide local excision of the breast lump and an axillary lymph node biopsy. Histopathology and immunohistochemical studies excluded carcinoma or lymphoma but suggested the possibility of intramammary and axillary toxoplasmic lymphadenopathy. The results of Toxoplasma gondii IgM and IgG serology tests were positive, supporting a diagnosis of toxoplasmosis. CONCLUSIONS: Toxoplasmosis rarely presents as a pseudotumor of the breast. FNAC and histology are valuable tools for a diagnosis of toxoplasmosis, and serology is an important adjunct for confirmation. PMID- 21816048 TI - Rare recurrence of a rare ovarian stromal tumor with luteinized cells: a case report. AB - INTRODUCTION: Sex cord-stromal tumors of the ovary are uncommon. They behave unpredictably and often have a late recurrence, making counseling, management, and prediction of prognosis challenging. CASE PRESENTATION: A 52-year-old Moroccan woman with an sex cord-stromal tumors underwent a bilateral oophorectomy. The histology was unusual but was likely to be a luteinized thecoma with suspicious features for invasion. Seven years later, after a gastrointestinal bleed, a metastasis within the small bowel mucosa was detected. This represents probable isolated hematogenous or lymphatic spread, which is highly unusual, especially in the absence of concurrent peritoneal disease. CONCLUSIONS: To the best of our knowledge, this is the second reported case of an sex cord-stromal tumors recurring in small bowel mucosa and mimicking a primary colorectal tumor. This highlights the diverse nature and behavior of these tumors. PMID- 21816049 TI - Influence of in vitro supplementation with lipids from conventional and Alpine milk on fatty acid distribution and cell growth of HT-29 cells. AB - BACKGROUND: To date, the influence of milk and dairy products on carcinogenesis remains controversial. However, lipids of ruminant origin such as conjugated linoleic acids (CLA) are known to exhibit beneficial effects in vitro and in vivo. The aim of the present study was to determine the influence of milk lipids of different origin and varying quality presenting as free fatty acid (FFA) solutions on cellular fatty acid distribution, cellular viability, and growth of human colon adenocarcinoma cells (HT-29). METHODS: FAME of conventional and Alpine milk lipids (MLcon, MLalp) and cells treated with FFA derivatives of milk lipids were analyzed by means of GC-FID and Ag+-HPLC. Cellular viability and growth of the cells were determined by means of CellTiter-Blue(r)-assay and DAPI assay (4',6-diamidino-2-phenylindole dihydrochloride), respectively. RESULTS: Supplementation with milk lipids significantly decreased viability and growth of HT-29 cells in a dose- and time-dependent manner. MLalp showed a lower SFA/MUFA ratio, a 8 fold increased CLA content, and different CLA profile compared to MLcon but did not demonstrate additional growth-inhibitory effects. In addition, total concentration and fatty acid distribution of cellular lipids were altered. In particular, treatment of the cells yielded highest amounts of two types of milk specific major fatty acids (MUg FA/mg cellular protein) after 8 h of incubation compared to 24 h; 200 MUM of MLcon (C16:0, 206 +/- 43), 200 MUM of MLalp (C18:1 c9, (223 +/- 19). Vaccenic acid (C18:1 t11) contained in milk lipids was converted to c9,t11-CLA in HT-29 cells. Notably, the ratio of t11,c13 CLA/t7,c9-CLA, a criterion for pasture feeding of the cows, was significantly changed after incubation for 8 h with lipids from MLalp (3.6 - 4.8), compared to lipids from MLcon (0.3 - 0.6). CONCLUSIONS: Natural lipids from conventional and Alpine milk showed similar growth inhibitory effects. However, different changes in cellular lipid composition suggested a milk lipid-depending influence on cell sensitivity. It is expected that similar changes may also be evident in other cell lines. To our knowledge, this is the first study showing a varied impact of complex milk lipids on fatty acid distribution in a colon cancer cell line. PMID- 21816050 TI - Reduced perinatal mortality following enhanced training of birth attendants in the Democratic Republic of Congo: a time-dependent effect. AB - BACKGROUND: In many developing countries, the majority of births are attended by traditional birth attendants, who lack formal training in neonatal resuscitation and other essential care required by the newly born infant. In these countries, the major causes of neonatal mortality are birth asphyxia, infection, and low birth-weight/prematurity. Death from these causes is potentially modifiable using low-cost interventions, including neonatal resuscitation training. The purpose of this study was to evaluate the effect on perinatal mortality of training birth attendants in a rural area of the Democratic Republic of Congo (DRC) using two established programs. METHODS: This study, a secondary analysis of DRC-specific data collected during a multi-country study, was conducted in two phases. The effect of training using the WHO Essential Newborn Care (ENC) program was evaluated using an active baseline design, followed by a cluster randomized trial of training using an adaptation of a neonatal resuscitation program (NRP). The perinatal mortality rates before ENC, after ENC training, and after randomization to additional NRP training or continued care were compared. In addition, the influence of time following resuscitation training was investigated by examining change in perinatal mortality during sequential three-month increments following ENC training. RESULTS: More than two-thirds of deliveries were attended by traditional birth attendants and occurred in homes; these proportions decreased after ENC training. There was no apparent decline in perinatal mortality when the outcome of all deliveries prior to ENC training was compared to those after ENC but before NRP training. However, there was a gradual but significant decline in perinatal mortality during the year following ENC training (RR 0.73; 95% CI: 0.56 0.96), which was independently associated with time following training. The decline was attributable to a decline in early neonatal mortality. NRP training had no demonstrable effect on early neonatal mortality. CONCLUSION: Training DRC birth attendants using the ENC program reduces perinatal mortality. However, a period of utilization and re-enforcement of training may be necessary before a decline in mortality occurs. ENC training has the potential to be a low cost, high impact intervention in developing countries. TRIAL REGISTRATION: This trial has been registered at http://www.clinicaltrials.gov (identifier NCT00136708). PMID- 21816051 TI - Matched-pair analysis of patients with female and male breast cancer: a comparative analysis. AB - BACKGROUND: Male breast cancer (MBC) is a rare disease accounting for approximately 1% of all breast carcinomas. Presently treatment recommendations are derived from the standards for female breast cancer. However, those approaches might be inadequate because of distinct gender specific differences in tumor biology of breast cancer. This study was planned in order to contrast potential differences between female and male breast cancer in both tumor biological behavior and clinical management. METHODS: MBC diagnosed between 1995 2007 (region Chemnitz/Zwickau, Saxony, Germany) was retrospectively analyzed. Tumor characteristics, treatment and follow-up of the patients were documented. In order to highlight potential differences each MBC was matched with a female counterpart (FBC) that showed accordance in at least eight tumor characteristics (year of diagnosis, age, tumor stage, nodal status, grade, estrogen- and progesterone receptors, HER2 status). RESULTS: 108 male/female matched-pairs were available for survival analyses. In our study men and women with breast cancer had similar disease-free (DFS) and overall (OS) survival. The 5-years DFS was 53.4% (95% CI, range 54.1-66.3) in men respectively 62.6% (95% CI, 63.5-75.3) in women (p > 0.05). The 5-years OS was 71.4% (95% CI, 62.1-72.7%) and 70.3% (95% CI, 32.6-49.6) in women (p > 0.05). In males DFS analyses revealed progesterone receptor expression as the only prognostic relevant factor (p = 0.006). In multivariate analyses for OS both advanced tumor size (p = 0.01) and a lack of progesterone receptor expression were correlated (p = 0.01) with poor patients outcome in MBC. CONCLUSION: Our comparative study revealed no survival differences between male and female breast cancer patients and gives evidence that gender is no predictor for survival in breast cancer. This was shown despite of significant gender specific differences in terms of frequency and intensity of systemic therapy in favor to female breast cancer. PMID- 21816052 TI - Single cell transcriptomics of neighboring hyphae of Aspergillus niger. AB - Single cell profiling was performed to assess differences in RNA accumulation in neighboring hyphae of the fungus Aspergillus niger. A protocol was developed to isolate and amplify RNA from single hyphae or parts thereof. Microarray analysis resulted in a present call for 4 to 7% of the A. niger genes, of which 12% showed heterogeneous RNA levels. These genes belonged to a wide range of gene categories. PMID- 21816053 TI - An evaluation of ciprofloxacin pharmacokinetics in critically ill patients undergoing continuous veno-venous haemodiafiltration. AB - BACKGROUND: The study aimed to investigate the pharmacokinetics of intravenous ciprofloxacin and the adequacy of 400 mg every 12 hours in critically ill Intensive Care Unit (ICU) patients on continuous veno-venous haemodiafiltration (CVVHDF) with particular reference to the effect of achieved flow rates on drug clearance. METHODS: This was an open prospective study conducted in the intensive care unit and research unit of a university teaching hospital. The study population was seven critically ill patients with sepsis requiring CVVHDF. Blood and ultrafiltrate samples were collected and assayed for ciprofloxacin by High Performance Liquid Chromatography (HPLC) to calculate the model independent pharmacokinetic parameters; total body clearance (TBC), half-life (t1/2) and volume of distribution (Vd). CVVHDF was performed at prescribed dialysate rates of 1 or 2 L/hr and ultrafiltration rate of 2 L/hr. The blood flow rate was 200 ml/min, achieved using a Gambro blood pump and Hospal AN69HF haemofilter. RESULTS: Seventeen profiles were obtained. CVVHDF resulted in a median ciprofloxacin t1/2 of 13.8 (range 5.15-39.4) hr, median TBC of 9.90 (range 3.10 13.2) L/hr, a median Vdss of 125 (range 79.5-554) L, a CVVHDF clearance of 2.47+/ 0.29 L/hr and a clearance of creatinine (Clcr) of 2.66+/-0.25 L/hr. Thus CVVHDF, at an average flow rate of ~3.5 L/hr, was responsible for removing 26% of ciprofloxacin cleared. At the dose rate of 400 mg every 12 hr, the median estimated Cpmax/MIC and AUC0-24/MIC ratios were 10.3 and 161 respectively (for a MIC of 0.5 mg/L) and exceed the proposed criteria of >10 for Cpmax/MIC and > 100 for AUC0-24/MIC. There was a suggestion towards increased ciprofloxacin clearance by CVVHDF with increasing effluent flow rate. CONCLUSIONS: Given the growing microbial resistance to ciprofloxacin our results suggest that a dose rate of 400 mg every 12 hr, may be necessary to achieve the desired pharmacokinetic pharmacodynamic (PK-PD) goals in patients on CVVHDF, however an extended interval may be required if there is concomitant hepatic impairment. A correlation between ciprofloxacin clearance due to CVVHDF and creatinine clearance by the filter was observed (r2 = 0.76), providing a useful clinical surrogate marker for ciprofloxacin clearance within the range studied. TRIAL REGISTRATION: Current Controlled Trials ISRCTN52722850. PMID- 21816054 TI - Lung sonography and recruitment in patients with early acute respiratory distress syndrome: a pilot study. AB - INTRODUCTION: Bedside lung sonography is a useful imaging tool to assess lung aeration in critically ill patients. The purpose of this study was to evaluate the role of lung sonography in estimating the nonaerated area changes in the dependent lung regions during a positive end-expiratory pressure (PEEP) trial of patients with early acute respiratory distress syndrome (ARDS). METHODS: Ten patients (mean +/- standard deviation (SD): age 64 +/- 7 years, Acute Physiology and Chronic Health Evaluation II (APACHE II) score 21 +/- 4) with early ARDS on mechanical ventilation were included in the study. Transthoracic sonography was performed in all patients to depict the nonaerated area in the dependent lung regions at different PEEP settings of 5, 10 and 15 cm H2O. Lung sonographic assessment of the nonaerated lung area and arterial blood gas analysis were performed simultaneously at the end of each period. A control group of five early ARDS patients matched for APACHE II score was also included in the study. RESULTS: The nonaerated areas in the dependent lung regions were significantly reduced during PEEP increases from 5 to 10 to 15 cm H2O (27 +/- 31 cm2 to 20 +/- 24 cm2 to 11 +/- 12 cm2, respectively; P < 0.01). These changes were associated with a significant increase in arterial oxygen partial pressure (74 +/- 15 mmHg to 90 +/- 19 mmHg to 102 +/- 26 mmHg; P < 0.001, respectively). No significant changes were observed in the nonaerated areas in the dependent lung regions in the control group. CONCLUSIONS: In this study, we show that transthoracic lung sonography can detect the nonaerated lung area changes during a PEEP trial of patients with early ARDS. Thus, transthoracic lung sonography might be considered as a useful clinical tool in the management of ARDS patients. PMID- 21816055 TI - An accurate and efficient identification of children with psychosocial problems by means of computerized adaptive testing. AB - BACKGROUND: Questionnaires used by health services to identify children with psychosocial problems are often rather short. The psychometric properties of such short questionnaires are mostly less than needed for an accurate distinction between children with and without problems. We aimed to assess whether a short Computerized Adaptive Test (CAT) can overcome the weaknesses of short written questionnaires when identifying children with psychosocial problems. METHOD: We used a Dutch national data set obtained from parents of children invited for a routine health examination by Preventive Child Healthcare with 205 items on behavioral and emotional problems (n = 2,041, response 84%). In a random subsample we determined which items met the requirements of an Item Response Theory (IRT) model to a sufficient degree. Using those items, item parameters necessary for a CAT were calculated and a cut-off point was defined. In the remaining subsample we determined the validity and efficiency of a Computerized Adaptive Test using simulation techniques, with current treatment status and a clinical score on the Total Problem Scale (TPS) of the Child Behavior Checklist as criteria. RESULTS: Out of 205 items available 190 sufficiently met the criteria of the underlying IRT model. For 90% of the children a score above or below cut-off point could be determined with 95% accuracy. The mean number of items needed to achieve this was 12. Sensitivity and specificity with the TPS as a criterion were 0.89 and 0.91, respectively. CONCLUSION: An IRT-based CAT is a very promising option for the identification of psychosocial problems in children, as it can lead to an efficient, yet high-quality identification. The results of our simulation study need to be replicated in a real-life administration of this CAT. PMID- 21816057 TI - Improvement of pain and regional osteoporotic changes in the foot and ankle by low-dose bisphosphonate therapy for complex regional pain syndrome type I: a case series. AB - INTRODUCTION: Complex regional pain syndrome is characterized by pain, allodynia, hyperalgesia, edema, signs of vasomotor instability, movement disorders, joint stiffness, and regional osteopenia. It is recognized to be difficult to treat, despite various methods of treatment, including physiotherapy, calcitonin, corticosteroids, sympathetic blockade, and nonsteroidal anti-inflammatory drugs. Pathophysiologically, complex regional pain syndrome reveals enhanced regional bone resorption and high bone turnover, and so bisphosphonates, which have a potent inhibitory effect on bone resorption, were proposed for the treatment of complex regional pain syndrome. CASE PRESENTATION: A 48-year-old Japanese man with complex regional pain syndrome type I had severe right ankle pain with a visual analog scale score of 59 out of 100 regardless of treatment with physiotherapy and nonsteroidal anti-inflammatory drugs for five months. Radiographs showed marked regional osteoporotic changes and bone scintigraphy revealed a marked increase in radioactivity in his ankle. One month after the start of oral administration of risedronate (2.5 mg per day), his bone pain had fallen from a VAS score of 59 out of 100 to 18 out of 100. Bone scintigraphy at 12 months showed a marked reduction in radioactivity to a level comparable to that in his normal, left ankle. On the basis of these results, the treatment was discontinued at 15 months. At 32 months, our patient had almost no pain and radiographic findings revealed that the regional osteoporotic change had returned to normal.A second 48-year-old Japanese man with complex regional pain syndrome type I had severe right foot pain with a visual analog scale score of 83 out of 100 regardless of treatment with physiotherapy and nonsteroidal anti-inflammatory drugs for nine months. Radiographs showed regional osteoporotic change in his phalanges, metatarsals, and tarsals, and bone scintigraphy revealed a marked increase in radioactivity in his foot. One month after the start of oral administration of alendronate (35 mg per week), his bone pain had fallen from a visual analog scale score of 83 out of 100 to 30 out of 100 and, at nine months, was further reduced to 3 out of 100. The treatment was discontinued at 15 months because of successful pain reduction. At 30 months, our patient had no pain and the radiographic findings revealed marked improvement in regional osteoporotic changes. CONCLUSIONS: We believe low-dose oral administration of bisphosphonate is worth considering for the treatment of idiopathic complex regional pain syndrome type I accompanied by regional osteoporotic change. PMID- 21816056 TI - The ProPrems trial: investigating the effects of probiotics on late onset sepsis in very preterm infants. AB - BACKGROUND: Late onset sepsis is a frequent complication of prematurity associated with increased mortality and morbidity. The commensal bacteria of the gastrointestinal tract play a key role in the development of healthy immune responses. Healthy term infants acquire these commensal organisms rapidly after birth. However, colonisation in preterm infants is adversely affected by delivery mode, antibiotic treatment and the intensive care environment. Altered microbiota composition may lead to increased colonisation with pathogenic bacteria, poor immune development and susceptibility to sepsis in the preterm infant.Probiotics are live microorganisms, which when administered in adequate amounts confer health benefits on the host. Amongst numerous bacteriocidal and nutritional roles, they may also favourably modulate host immune responses in local and remote tissues. Meta-analyses of probiotic supplementation in preterm infants report a reduction in mortality and necrotising enterocolitis. Studies with sepsis as an outcome have reported mixed results to date.Allergic diseases are increasing in incidence in "westernised" countries. There is evidence that probiotics may reduce the incidence of these diseases by altering the intestinal microbiota to influence immune function. METHODS/DESIGN: This is a multi-centre, randomised, double blinded, placebo controlled trial investigating supplementing preterm infants born at < 32 weeks' gestation weighing < 1500 g, with a probiotic combination (Bifidobacterium infantis, Streptococcus thermophilus and Bifidobacterium lactis). A total of 1,100 subjects are being recruited in Australia and New Zealand. Infants commence the allocated intervention from soon after the start of feeds until discharge home or term corrected age. The primary outcome is the incidence of at least one episode of definite (blood culture positive) late onset sepsis before 40 weeks corrected age or discharge home. Secondary outcomes include: Necrotising enterocolitis, mortality, antibiotic usage, time to establish full enteral feeds, duration of hospital stay, growth measurements at 6 and 12 months' corrected age and evidence of atopic conditions at 12 months' corrected age. DISCUSSION: Results from previous studies on the use of probiotics to prevent diseases in preterm infants are promising. However, a large clinical trial is required to address outstanding issues regarding safety and efficacy in this vulnerable population. This study will address these important issues. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN012607000144415The product "ABC Dophilus Probiotic Powder for Infants(r)", Solgar, USA has its 3 probiotics strains registered with the Deutsche Sammlung von Mikroorganismen und Zellkulturen (DSMZ--German Collection of Microorganisms and Cell Cultures) as BB-12 15954, B-02 96579, Th-4 15957. PMID- 21816058 TI - Large infrapatellar ganglionic cyst of the knee fat pad: a case report and review of the literature. AB - INTRODUCTION: Large ganglionic cystic formations arising from the infrapatellar fat pad are quite uncommon and only a few are mentioned in the literature. An open excision in these cases is mandatory. CASE PRESENTATION: We report the case of a large infrapatellar fat pad ganglion in a 37-year-old Greek man with chronic knee discomfort. The ganglionic cyst originated from the infrapatellar fat pad and had no intrasynovial extension. The final diagnosis was determined with magnetic resonance imaging of the knee, and the lesion was treated with surgery. CONCLUSIONS: These lesions are asymptomatic in most cases but often are misdiagnosed as meniscal or ligamentous lesions of the knee joint. Nowadays, the therapeutic trend for such lesions is arthroscopic excision, but when there is a large ganglion, as in this case report, the treatment should be an open and thorough resection. This report is intended mostly but not exclusively for clinical physicians and radiologists. PMID- 21816059 TI - The lateral trauma position: what do we know about it and how do we use it? A cross-sectional survey of all Norwegian emergency medical services. AB - BACKGROUND: Trauma patients are customarily transported in the supine position to protect the spine. The Airway, Breathing, Circulation, Disability, and Exposure (ABCDE) principles clearly give priority to airways. In Norway, the lateral trauma position (LTP) was introduced in 2005. We investigated the implementation and current use of LTP in Norwegian Emergency Medical Services (EMS). METHODS: All ground and air EMS bases in Norway were included. Interviews were performed with ground and air EMS supervisors. Questionnaires were distributed to ground EMS personnel. RESULTS: Of 206 ground EMS supervisors, 201 answered; 75% reported that LTP is used. In services using LTP, written protocols were present in 67% and 73% had provided training in LTP use. Questionnaires were distributed to 3,025 ground EMS personnel. We received 1,395 (46%) valid questionnaires. LTP was known to 89% of respondents, but only 59% stated that they use it. Of the respondents using LTP, 77% reported access to written protocols. Flexing of the top knee was reported by 78%, 20% flexed the bottom knee, 81% used under head padding. Of 24 air EMS supervisors, 23 participated. LTP is used by 52% of the services, one of these has a written protocol and three arrange training. CONCLUSIONS: LTP is implemented and used in the majority of Norwegian EMS, despite little evidence as to its possible benefits and harms. How the patient is positioned in the LTP differs. More research on LTP is needed to confirm that its use is based on evidence that it is safe and effective. PMID- 21816060 TI - The direction of research into visual disability and quality of life in glaucoma. AB - BACKGROUND: Glaucoma will undoubtedly impact on a person's ability to function as they go about their day-to-day life. The purpose of this study is to investigate the amount of published knowledge in quality of life (QoL) and visual disability studies for glaucoma, and make comparisons with similar research in other chronic conditions. METHODS: A systematic literature search of the Global Health, EMBASE Psychiatry and MEDLINE databases. Title searches for glaucoma and six other example chronic diseases were entered alongside a selection of keywords chosen to capture studies focusing on QoL and everyday task ability. These results were further filtered during a manual search of resulting abstracts. Outcomes were the number of publications per year for each disease, number relating to QoL and type of glaucoma QoL research. RESULTS: Fifteen years ago there were no published studies relating to the impact of glaucoma on QoL but by 2009 this had risen to 1.2% of all glaucoma articles. The number of papers relating to QoL as a proportion of all papers in glaucoma in the past 10 years (0.6%) is smaller than for AMD and some other disabling chronic diseases. Most QoL studies in glaucoma (82%) involve questionnaires. CONCLUSION: QoL studies in glaucoma are increasing in number but represent a tiny minority of the total publications in glaucoma research. There are fewer QoL articles in glaucoma compared to some other disabling chronic conditions. The majority of QoL articles in glaucoma research use questionnaires; performance-based measures of visual disability may offer an additional method of determining how the disease impacts on QoL. PMID- 21816061 TI - Skin mucus of Cyprinus carpio inhibits cyprinid herpesvirus 3 binding to epidermal cells. AB - Cyprinid herpesvirus 3 (CyHV-3) is the aetiological agent of a mortal and highly contagious disease in common and koi carp. The skin is the major portal of entry of CyHV-3 in carp after immersion in water containing the virus. In the present study, we used in vivo bioluminescence imaging to investigate the effect of skin mucus removal and skin epidermis lesion on CyHV-3 entry. Physical treatments inducing removal of the mucus up to complete erosion of the epidermis were applied on a defined area of carp skin just before inoculation by immersion in infectious water. CyHV-3 entry in carp was drastically enhanced on the area of the skin where the mucus was removed with or without associated epidermal lesion. To investigate whether skin mucus inhibits CyHV-3 binding to epidermal cells, tail fins with an intact mucus layer or without mucus were inoculated ex vivo. While electron microscopy examination revealed numerous viral particles bound on the fins inoculated after mucus removal, no particle could be detected after infection of mucus-covered fins. Finally, anti-CyHV-3 neutralising activity of mucus extract was tested in vitro. Incubation of CyHV-3 with mucus extract reduced its infectivity in a dose dependent manner. The present study demonstrates that skin mucus removal and epidermal lesions enhance CyHV-3 entry in carp. It highlights the role of fish skin mucus as an innate immune protection against viral epidermal entry. PMID- 21816062 TI - Lamivudine plus adefovir is a good option for chronic hepatitis B patients with viral relapse after cessation of lamivudine treatment. AB - AIM: Currently, there is no consensus on the retreatment recommendation of chronic hepatitis B (CHB) patients with viral rebound after cessation of treatment. In the search of reasonable treatment, we compared the efficacy and safety of adefovir (ADV) plus lamivudine (LAM) and LAM alone for the retreatment of patients with viral relapse but without genotypic resistance after cessation of LAM. METHODS: This is a prospective controlled study, and a total of 53 hepatitis B e antigen (HBeAg)-positive patients with viral rebound but without resistance were received either LAM plus ADV or LAM alone treatment. RESULTS: After 1-year treatment, more patients who received LAM plus ADV than those who received LAM alone had ALT normalization (84% versus 53.6%, P = 0.018) or HBV DNA levels below 1000 copies/mL (80% versus 42.9%, P < 0.006). Seven patients receiving LAM plus ADV had HBeAg seroconversion, as compared with 0 in patients receiving ALM alone (28% versus 0%, P = 0.003). During 1-year retreatment, five patients receiving LAM alone had virological breakthrough and all of them had LAM resistance strains (rtM204V/I), while no LAM- or ADV- associated resistance strains were detected in patients receiving LAM plus ADV. All patients receiving LAM plus ADV were well tolerated, and no serious side effects were noted. CONCLUSIONS: Patients treated with LAM plus ADV exhibited significantly greater virological, biochemical and serological responses compared with LAM alone. These data suggested that combination of LAM plus ADV would be a good option for the retreatment of CHB patients with viral relapse after cessation of LAM. PMID- 21816063 TI - Serum uric acid level and its association with metabolic syndrome and carotid atherosclerosis in patients with type 2 diabetes. AB - OBJECTIVE: We aimed to investigate whether elevated serum uric acid concentrations are associated with higher risk of metabolic syndrome (MetS) and carotid atherosclerosis in patients with type 2 diabetes. METHODS: We conducted a population-based cross-sectional survey in Shanghai, with a total of 395 men and 631 women age 41 to 92 years. The carotid artery intima-media thickness (IMT) and carotid atherosclerotic plaques (PLQ) were measured by B-mode ultrasound. MetS was defined according to the updated National Cholesterol Education Program Adult Treatment Panel III criteria for Asian Americans. RESULTS: Uric acid levels were negatively associated with duration of diabetes, fasting plasma glucose, glycohemoglobin, eGFR, HDL-cholesterol (all P < 0.001) and positively with BMI, CRP, waist circumference, triglycerides, systolic blood pressure, ACR, HOMA-IR and IMT (all P < 0.05). In the highest quartile of uric acid levels, the risks were substantially higher for MetS [odds ratio 3.97, (95% confidence interval 2.58-6.13)] (P < 0.001 for trend) and PLQ [odds ratio 2.71 (95% confidence interval 1.62-4.47)] (p = 0.013 for trend) compared with that in the lowest quartile of uric acid levels after multiple adjustment. These associations remained significant after further adjustment for potential confounders. CONCLUSIONS: Serum uric acid level is associated with MetS and is an independent risk factor for carotid atherosclerosis in patients with type 2 diabetes. PMID- 21816064 TI - High glucose-induced apoptosis in human coronary artery endothelial cells involves up-regulation of death receptors. AB - BACKGROUND: High glucose can induce apoptosis in vascular endothelial cells, which may contribute to the development of vascular complications in diabetes. We evaluated the role of the death receptor pathway of apoptotic signaling in high glucose-induced apoptosis in human coronary artery endothelial cells (HCAECs). METHODS: HCAECs were treated with media containing 5.6, 11.1, and 16.7 mM of glucose for 24 h in the presence or absence of tumor necrosis factor (TNF)-alpha. For detection of apoptosis, DNA fragmentation assay was used. HCAEC expression of death receptors were analyzed by the PCR and flow cytometry methods. Also, using immunohistochemical techniques, coronary expression of death receptors was assessed in streptozotocin-nicotinamide-induced type 2 diabetic mice. RESULTS: Exposure of HCAECs to high glucose resulted in a significant increase in TNF-R1 and Fas expression, compared with normal glucose. High glucose increased TNF alpha production by HCAECs and exogenous TNF-alpha up-regulated TNF-R1 and Fas expression in HCAECs. High glucose-induced up-regulation of TNF-R1 and Fas expression was undetectable in the presence of TNF-alpha. Treatment with TNF-R1 neutralizing peptides significantly inhibited high glucose-induced endothelial cell apoptosis. Type 2 diabetic mice displayed appreciable expression of TNF-R1 and Fas in coronary vessels. CONCLUSIONS: In association with increased TNF-alpha levels, the death receptors, TNF-R1 and Fas, are up-regulated in HCAECs under high glucose conditions, which could in turn play a role in high glucose-induced endothelial cell apoptosis. PMID- 21816065 TI - Everyday episodic memory in amnestic mild cognitive impairment: a preliminary investigation. AB - BACKGROUND: Decline in episodic memory is one of the hallmark features of Alzheimer's disease (AD) and is also a defining feature of amnestic Mild Cognitive Impairment (MCI), which is posited as a potential prodrome of AD. While deficits in episodic memory are well documented in MCI, the nature of this impairment remains relatively under-researched, particularly for those domains with direct relevance and meaning for the patient's daily life. In order to fully explore the impact of disruption to the episodic memory system on everyday memory in MCI, we examined participants' episodic memory capacity using a battery of experimental tasks with real-world relevance. We investigated episodic acquisition and delayed recall (story-memory), associative memory (face-name pairings), spatial memory (route learning and recall), and memory for everyday mundane events in 16 amnestic MCI and 18 control participants. Furthermore, we followed MCI participants longitudinally to gain preliminary evidence regarding the possible predictive efficacy of these real-world episodic memory tasks for subsequent conversion to AD. RESULTS: The most discriminating tests at baseline were measures of acquisition, delayed recall, and associative memory, followed by everyday memory, and spatial memory tasks, with MCI patients scoring significantly lower than controls. At follow-up (mean time elapsed: 22.4 months), 6 MCI cases had progressed to clinically probable AD. Exploratory logistic regression analyses revealed that delayed associative memory performance at baseline was a potential predictor of subsequent conversion to AD. CONCLUSIONS: As a preliminary study, our findings suggest that simple associative memory paradigms with real-world relevance represent an important line of enquiry in future longitudinal studies charting MCI progression over time. PMID- 21816066 TI - Evolutionary history of Serpulaceae (Basidiomycota): molecular phylogeny, historical biogeography and evidence for a single transition of nutritional mode. AB - BACKGROUND: The fungal genus Serpula (Serpulaceae, Boletales) comprises several saprotrophic (brown rot) taxa, including the aggressive house-infecting dry rot fungus Serpula lacrymans. Recent phylogenetic analyses have indicated that the ectomycorrhiza forming genera Austropaxillus and Gymnopaxillus cluster within Serpula. In this study we use DNA sequence data to investigate phylogenetic relationships, historical biogeography of, and nutritional mode transitions in Serpulaceae. RESULTS: Our results corroborate that the two ectomycorrhiza-forming genera, Austropaxillus and Gymnopaxillus, form a monophyletic group nested within the saprotrophic genus Serpula, and that the Serpula species S. lacrymans and S. himantioides constitute the sister group to the Austropaxillus-Gymnopaxillus clade. We found that both vicariance (Beringian) and long distance dispersal events are needed to explain the phylogeny and current distributions of taxa within Serpulaceae. Our results also show that the transition from brown rot to mycorrhiza has happened only once in a monophyletic Serpulaceae, probably between 50 and 22 million years before present. CONCLUSIONS: This study supports the growing understanding that the same geographical barriers that limit plant- and animal dispersal also limit the spread of fungi, as a combination of vicariance and long distance dispersal events are needed to explain the present patterns of distribution in Serpulaceae. Our results verify the transition from brown rot to ECM within Serpulaceae between 50 and 22 MyBP. PMID- 21816067 TI - The prone 12 o'clock position reduces ileal intubation time during colonoscopy compared to the left lateral 6 o'clock (standard) position. AB - BACKGROUND: Ileal intubation is the gold standard for a complete colonoscopy. However, despite evidence of clinical benefit ileoscopy is not always attempted due to perceived technical difficulty. Our aim was to compare time taken for ileal intubation using a new position-the prone 12 o'clock position (PP) with the standard method (left lateral 6 o'clock position-LLP). METHODS: We performed a pilot study using fluoroscopy to determine the best patient position for ileal intubation. This was the prone 12 o'clock position. Patients were colonoscoped in the left lateral position and then randomized to ileal intubation in the 6 o'clock position(LL) or the 12 o'clock (PP) position. RESULTS: 202 consecutive patients were referred for colonoscopy. Colonoscopy was performed on 150 patients [82 females, mean (SD) age 53 (16) years]. 75 patients were randomized for ileal intubation in the PP and 75 patients in the LLP. Overall, the ileum was successfully intubated in 145 (96%) patients [74 (98.7%) in the PP and 71 (94.7%) in the LLP]. The median (Interquartile Range) ileal intubation time was 12 (10) seconds in the PP and 87 (82) seconds in the LLP (p < 0.0001; Mann-Whitney U test). The ileum was abnormal in 11 (7.5%) patients. CONCLUSIONS: During colonoscopy, the prone 12 o'clock position gives a more direct approach to the ileo-caecal valve and significantly reduces ileal intubation time. TRIAL REGISTRATION: TRIAL REGISTRY: Sri Lanka Clinical Trial Registry Clinical trial registry number: SLCTR/2009/002. PMID- 21816068 TI - Lipid-lowering drugs in ischaemic heart disease: a quasi-experimental uncontrolled before-and-after study of the effectiveness of clinical practice guidelines. AB - BACKGROUND: Cardiovascular diseases(CVD), specifically ischaemic heart disease(IHD), are the main causes of death in industrialized countries. Statins are not usually prescribed in the most appropriate way. To ensure the correct prescription of these drugs, it is necessary to develop, disseminate and implement clinical practice guidelines(CPGs), and subsequently evaluate them. The main objective of this study is to evaluate the effectiveness of the implementation of consensual Lipid-lowering drugs (LLD) prescription guidelines in hospital and primary care settings, to improve the control of Low-Density Lipoprotein Cholesterol (LDL-C) levels in patients with IHD in the Terres de l'Ebre region covered by the Catalonian Health Institute. Secondary objectives are to assess the improvement of the prescription profile of these LLDs, to assess cardiovascular morbimortality and the professional profile and participant centre characteristics that govern the control of LDL-C. METHODS/DESIGN: DESIGN: Quasi-experimental uncontrolled before and after study. The intervention consists of the delivery of training strategies for guideline implementation (classroom clinical sessions and on-line courses) aimed at primary care and hospital physicians. The improvement in the control of LDL-C levels in the 3,402 patients with IHD in our territory is then assessed. SCOPE: Primary care physicians from 11 basic health areas(BHAs) and two hospital services (internal medicine and cardiology). SAMPLE: 3,402 patients registered with IHD in the database of the Catalan Institute of Health(E-cap) before December 2008 and patients newly diagnosed during 2009-2010. VARIABLES: Percentage of patients achieving good control of LDL-C, measured in milligrams per decilitre. The aim of the intervention is to achieve levels of LDL-C < 100 mg/dl in patients with IHD. Secondary variables measure type and time of diagnosis of IHD, type and dose of prescribed cholesterol-lowering drugs, level of physician participation in training activities and their professional profile. DISCUSSION: The development of prescription guidelines previously agreed by various medical specialists involved in treating IHD patients have usually improved drug prescription. The guideline presented in this study aims to improve the control of LDL-C by training physicians through presential and on-line courses on the dissemination of this guideline, and by providing feedback on their personal results a year after this training intervention. PMID- 21816069 TI - Behaviour patterns preceding a railway suicide: explorative study of German Federal Police officers' experiences. AB - BACKGROUND: Constant high-level numbers of railway suicides indicate that prevention strategies against railway suicides are urgently needed. The main question of the present study was whether pre-crash railway suicide behaviour can be identified, using German Federal Police officers experience with suicidal events in railway related environments. METHODS: To collect information on pre crash railway suicide behaviour, a questionnaire was used and made available on the German Federal Police intranet. A total of 202 subjects (mean age: 41 years, sex: 84.9% male) were included in the analysis. Multivariate logistic regression analyses were performed to predict the prevention of suicide (first model) or demand for counselling (second model) as outcomes. Sex, age, years of service, number of experienced suicides, suicides personally observed, information on suicides obtained from witnesses and finally either counselling/debriefing (first model) or whether officers had prevented a suicide (second model) were used as predictors. RESULTS: A considerable proportion of police officers reported behavioural patterns preceding a suicide. Half of them observed the dropping or leaving behind of personal belongings or the avoidance of eye contact, more than a third erratic gesture, mimic or movement. Erratic communication patterns and general confusion were each reported by about one quarter. One fifth indicated the influence of alcohol. Less frequently observed behaviour was aimlessly wandering (14.3%) and out of the ordinary clothing (4%). About one third of all railway suicide victims committed suicide in stations. Of those, 70% had chosen an eminent spot. The multivariate logistic regression model using prevented suicides as the outcome identified the number of suicides experienced, counselling/debriefing and having personally observed a suicide as variables with significant impact. The model using counselling/debriefing as the outcome identified age and having prevented a suicide as variables with a significant association. CONCLUSIONS: Our results provide evidence that railway suicides are preceded by identifiable behavioural patterns. This emphasizes the importance of educational efforts, taking into account the knowledge and skills of experienced police officers. PMID- 21816070 TI - The prevalence of exposure to domestic violence and the factors associated with co-occurrence of psychological and physical violence exposure: a sample from primary care patients. AB - BACKGROUND: Since many health problems are associated with abuse and neglect at all ages, domestic violence victims may be considered as a group of primary care patients in need of special attention. METHODS: The aim of this multi-centre study was to assess the prevalence of domestic violence in primary care patients, and to identify those factors which influence the co-occurrence of psychological and physical violence exposure and their consequences (physical, sexual and reproductive and psychological) as obtained from medical records.A study was carried out in 28 family practices in Slovenia in 2009. Twenty-eight family physicians approached every fifth family practice attendee, regardless of gender, to be interviewed about their exposure to domestic violence and asked to specify the perpetrator and the frequency. Out of 840 patients asked, 829 individuals, 61.0% women (n = 506) and 39.0% men (n = 323) were assessed (98.7% response rate). They represented a randomised sample of general practice attendees, aged 18 years and above, who had visited their physician for health problems and who were given a physical examination. Visits for administrative purposes were excluded.Multivariate binary logistic regression analysis was used to determine the factors associated with exposure to both psychological and physical violence. RESULTS: Of 829 patients, 15.3% reported some type of domestic violence experienced during the previous five years; 5.9% reported physical and 9.4% psychological violence; of these 19.2% of men and 80.8% of women had been exposed to psychological violence, while 22.4% of men and 77.6% of women had been exposed to physical violence. The domestic violence victims were mostly women (p < 0.001) aged up to 35 years (p = 0.001). Exposure to psychological violence was more prevalent than exposure to physical violence. Of the women, 20.0% were exposed to either type of violence, compared to 8.0% of male participants, who reported they were rarely exposed to physical violence, while women reported often or constant exposure to physical violence. Their partners were mostly the perpetrators of domestic violence towards women, while amongst men the perpetrators were mostly other family members.In univariate analysis female gender was shown to be a risk factor for domestic violence exposure. Regression modelling, explaining 40% of the variance, extracted two factors associated with psychological and physical violence exposure: the abuse of alcohol in the patient (OR 4.7; 95% CI 1.54 14.45) and their unemployment (OR 13.3; 95% CI 1.53-116.45). CONCLUSIONS: As far as the study design permits, the identified factors associated with both psychological and physical violence exposure could serve as determinants to raise family physicians' awareness when exploring the prevalence of domestic violence. The results of previous research, showing at least 15% prevalence of exposure to domestic violence among primary care patients in Slovenia, and the female gender as a risk factor, were confirmed. PMID- 21816071 TI - Incorporation of n-3 PUFA and gamma-linolenic acid in blood lipids and red blood cell lipids together with their influence on disease activity in patients with chronic inflammatory arthritis--a randomized controlled human intervention trial. AB - BACKGROUND AND AIM: Marine n-3 fatty acids and gamma-linolenic acid both have anti-inflammatory effects and may be useful to help treat inflammatory diseases. The effects of these alone or combined were examined in patients with arthritis in a randomized controlled trial. DESIGN: Patients with rheumatoid arthritis or psoriatic arthritis were randomized into four groups in a double-blind, placebo controlled parallel designed study. Patients received the respective capsules (1: 3.0 g n-3 LC-PUFA/d; 2: 3.2 g gamma-linolenic acid/d; 3: 1.6 g n-3 LC-PUFA + 1.8 g gamma-linolenic acid/d; 4: 3.0 g olive oil) for a twelve week period. Clinical status was evaluated and blood samples were taken at the beginning and at the end of the period. Differences before and after intervention were tested with paired t-test or with Wilcoxon test for non-normal data distribution. RESULTS: 60 patients (54 rheumatoid arthritis, 6 psoriatic arthritis) were randomised, 47 finished per protocol. In group 1, the ratio of arachidonic acid (AA)/eicosapentaenoic acid (EPA) decreased from 6.5 +/- 3.7 to 2.7 +/- 2.1 in plasma lipids and from 25.1 +/- 10.1 to 7.2 +/- 4.7 in erythrocyte membranes (p <= 0.001). There was no significant influence on AA/EPA ratio due to interventions in group 2-4. In group 2, the intake of gamma-linolenic acid resulted in a strong rise of gamma-linolenic acid and dihomo-gamma-linolenic acid concentrations in plasma lipids, cholesteryl esters, and erythrocyte membranes. The combination of n-3 LC-PUFA and gamma-linolenic acid (group 3) led to an increase of gamma-linolenic acid and dihomo-gamma-linolenic acid concentrations in plasma lipids, cholesteryl esters, and erythrocyte mem-branes. This increase was only half of that in group 2. CONCLUSIONS: Incorporation of eicosanoid precursor FAs was influenced by an intake of n-3 LC-PUFA and gamma-linolenic acid suggesting a possible benefit for therapy of chronic inflammatory diseases. TRIAL REGISTRATION: ClinicalTrials NCT01179971. PMID- 21816074 TI - The contribution of dance to daily physical activity among adolescent girls. AB - BACKGROUND: Structured physical activity (PA) programs are well positioned to promote PA among youth, however, little is known about these programs, particularly dance classes. The aims of this study were to: 1) describe PA levels of girls enrolled in dance classes, 2) determine the contribution of dance classes to total moderate-to-vigorous physical activity (MVPA), and 3) compare PA between days with a dance class (program days) and days without a dance class (non-program days). METHODS: Participants were 149 girls (11-18 years) enrolled in dance classes in 11 dance studios. Overall PA was assessed with accelerometry for 8 consecutive days, and girls reported when they attended dance classes during those days. The percent contribution of dance classes to total MVPA was calculated, and data were reduced to compare PA on program days to non-program days. Data were analyzed using mixed models, adjusting for total monitoring time. RESULTS: Girls engaged in 25.0 +/- 0.9 minutes/day of MVPA. Dance classes contributed 28.7% (95% CI: 25.9%-31.6%) to girls' total MVPA. Girls accumulated more MVPA on program (28.7 +/- 1.4 minutes/day) than non-program days (16.4 +/- 1.5 minutes/day) (p < 0.001). Girls had less sedentary behavior on program (554.0 +/- 8.1 minutes/day) than non-program days (600.2 +/- 8.7 minutes/day) (p < 0.001). CONCLUSIONS: Dance classes contributed a substantial proportion (29%) to girls' total MVPA, and girls accumulated 70% more MVPA and 8% less sedentary behavior on program days than on non-program days. Dance classes can make an important contribution to girls' total physical activity. PMID- 21816072 TI - Nasal lavage natural killer cell function is suppressed in smokers after live attenuated influenza virus. AB - BACKGROUND: Modified function of immune cells in nasal secretions may play a role in the enhanced susceptibility to respiratory viruses that is seen in smokers. Innate immune cells in nasal secretions have largely been characterized by cellular differentials using morphologic criteria alone, which have successfully identified neutrophils as a significant cell population within nasal lavage fluid (NLF) cells. However, flow cytometry may be a superior method to fully characterize NLF immune cells. We therefore characterized immune cells in NLF by flow cytometry, determined the effects of live attenuated influenza virus (LAIV) on NLF and peripheral blood immune cells, and compared responses in samples obtained from smokers and nonsmokers. METHODS: In a prospective observational study, we characterized immune cells in NLF of nonsmokers at baseline using flow cytometry and immunohistochemistry. Nonsmokers and smokers were inoculated with LAIV on day 0 and serial nasal lavages were collected on days 1-4 and day 9 post LAIV. LAIV-induced changes of NLF cells were characterized using flow cytometry. Cell-free NLF was analyzed for immune mediators by bioassay. Peripheral blood natural killer (NK) cells from nonsmokers and smokers at baseline were stimulated in vitro with LAIV followed by flow cytometric and mediator analyses. RESULTS: CD45(+)CD56(-)CD16(+) neutrophils and CD45(+)CD56(+) NK cells comprised median 4.62% (range 0.33-14.52) and 23.27% (18.29-33.97), respectively, of non-squamous NLF cells in nonsmokers at baseline. LAIV did not induce changes in total NK cell or neutrophil percentages in either nonsmokers or smokers. Following LAIV inoculation, CD16(+) NK cell percentages and granzyme B levels increased in nonsmokers, and these effects were suppressed in smokers. LAIV inoculation enhanced expression of activating receptor NKG2D and chemokine receptor CXCR3 on peripheral blood NK cells from both nonsmokers and smokers in vitro but did not induce changes in CD16(+) NK cells or granzyme B activity in either group. CONCLUSIONS: These data are the first to identify NK cells as a major immune cell type in the NLF cell population and demonstrate that mucosal NK cell cytotoxic function is suppressed in smokers following LAIV. Altered NK cell function in smokers suggests a potential mechanism that may enhance susceptibility to respiratory viruses. PMID- 21816073 TI - Work related complaints of neck, shoulder and arm among computer office workers: a cross-sectional evaluation of prevalence and risk factors in a developing country. AB - BACKGROUND: Complaints of arms, neck and shoulders (CANS) is common among computer office workers. We evaluated an aetiological model with physical/psychosocial risk-factors. METHODS: We invited 2,500 computer office workers for the study. Data on prevalence and risk-factors of CANS were collected by validated Maastricht-Upper-extremity-Questionnaire. Workstations were evaluated by Occupational Safety and Health Administration (OSHA) Visual-Display Terminal workstation-checklist. Participants' knowledge and awareness was evaluated by a set of expert-validated questions. A binary logistic regression analysis investigated relationships/correlations between risk-factors and symptoms. RESULTS: Sample size was 2,210. Mean age 30.8 +/- 8.1 years, 50.8% were males. The 1-year prevalence of CANS was 56.9%, commonest region of complaint was forearm/hand (42.6%), followed by neck (36.7%) and shoulder/arm (32.0%). In those with CANS, 22.7% had taken treatment from a health care professional, only in 1.1% seeking medical advice an occupation-related injury had been suspected/diagnosed. In addition 9.3% reported CANS-related absenteeism from work, while 15.4% reported CANS causing disruption of normal activities. A majority of evaluated workstations in all participants (88.4%,) and in those with CANS (91.9%) had OSHA non-compliant workstations. In the binary logistic regression analyses female gender, daily computer usage, incorrect body posture, bad work-habits, work overload, poor social support and poor ergonomic knowledge were associated with CANS and its' severity In a multiple logistic regression analysis controlling for age, gender and duration of occupation, incorrect body posture, bad work-habits and daily computer usage were significant independent predictors of CANS. CONCLUSIONS: The prevalence of work-related CANS among computer office workers in Sri Lanka, a developing, South Asian country is high and comparable to prevalence in developed countries. Work-related physical factors, psychosocial factors and lack of awareness were all important associations of CANS and effective preventive strategies need to address all three areas. PMID- 21816075 TI - Seasonal variations of all-cause and cause-specific mortality by age, gender, and socioeconomic condition in urban and rural areas of Bangladesh. AB - BACKGROUND: Mortality exhibits seasonal variations, which to a certain extent can be considered as mid-to long-term influences of meteorological conditions. In addition to atmospheric effects, the seasonal pattern of mortality is shaped by non-atmospheric determinants such as environmental conditions or socioeconomic status. Understanding the influence of season and other factors is essential when seeking to implement effective public health measures. The pressures of climate change make an understanding of the interdependencies between season, climate and health especially important. METHODS: This study investigated daily death counts collected within the Sample Vital Registration System (VSRS) established by the Bangladesh Bureau of Statistics (BBS). The sample was stratified by location (urban vs. rural), gender and socioeconomic status. Furthermore, seasonality was analyzed for all-cause mortality, and several cause-specific mortalities. Daily deviation from average mortality was calculated and seasonal fluctuations were elaborated using non parametric spline smoothing. A seasonality index for each year of life was calculated in order to assess the age-dependency of seasonal effects. RESULTS: We found distinctive seasonal variations of mortality with generally higher levels during the cold season. To some extent, a rudimentary secondary summer maximum could be observed. The degree and shape of seasonality changed with the cause of death as well as with location, gender, and SES and was strongly age-dependent. Urban areas were seen to be facing an increased summer mortality peak, particularly in terms of cardiovascular mortality. Generally, children and the elderly faced stronger seasonal effects than youths and young adults. CONCLUSION: This study clearly demonstrated the complex and dynamic nature of seasonal impacts on mortality. The modifying effect of spatial and population characteristics were highlighted. While tropical regions have been, and still are, associated with a marked excess of mortality in summer, only a weakly pronounced secondary summer peak could be observed for Bangladesh, possibly due to the reduced incidence of diarrhoea-related fatalities. These findings suggest that Bangladesh is undergoing an epidemiological transition from summer to winter excess mortality, as a consequence of changes in socioeconomic conditions and health care provision. PMID- 21816076 TI - Antibody cross-linking and target elution protocols used for immunoprecipitation significantly modulate signal-to noise ratio in downstream 2D-PAGE analysis. AB - BACKGROUND: Immunoprecipitation and subsequent 2D-PAGE/mass spectrometry are powerful tools to study post-translational protein modifications. Often disregarded in this workflow is the impact of the chemical cross-linker upon antibody affinity, as well as incomplete elution of primary target protein in buffers commonly used in 2D-PAGE. This may impede detection of non-abundant protein isoforms. RESULTS: Here we have compared cross-linking of antibodies to Dynabeads(r) Protein A by using DMP or BS3, as well as the efficiency of various target elution buffers prior to 2D-PAGE separation. BS3 cross-linking generally resulted in less non-specific binding than DMP, whereas DMP cross-linking gave overall higher yield of target protein. Regardless of the cross-linker used, incomplete elution of target protein was observed with conventional glycine- or urea-based buffers. Conversely, complete elution was obtained with 2% hot SDS and subsequent dilution in urea buffer containing 4% CHAPS, to 0.2% final SDS yielded perfectly focused gels suitable for mass spectrometry analysis. CONCLUSION: Careful choice of Ig cross-linker as well as efficient elution of target protein in SDS prior to downstream 2D-PAGE may be key factors to analyze low-abundance proteins enriched by magnetic bead immunoprecipitation. PMID- 21816078 TI - Stink bug feeding induces fluorescence in developing cotton bolls. AB - BACKGROUND: Stink bugs (Hemiptera: Pentatomidae) comprise a critically important insect pest complex affecting 12 major crops worldwide including cotton. In the US, stink bug damage to developing cotton bolls causes boll abscission, lint staining, reduced fiber quality, and reduced yields with estimated losses ranging from 10 to 60 million dollars annually. Unfortunately, scouting for stink bug damage in the field is laborious and excessively time consuming. To improve scouting accuracy and efficiency, we investigated fluorescence changes in cotton boll tissues as a result of stink bug feeding. RESULTS: Fluorescent imaging under long-wave ultraviolet light showed that stink bug-damaged lint, the inner carpal wall, and the outside of the boll emitted strong blue-green fluorescence in a circular region near the puncture wound, whereas undamaged tissue emissions occurred at different wavelengths; the much weaker emission of undamaged tissue was dominated by chlorophyll fluorescence. We further characterized the optimum emission and excitation spectra to distinguish between stink bug damaged bolls from undamaged bolls. CONCLUSIONS: The observed characteristic fluorescence peaks associated with stink bug damage give rise to a fluorescence-based method to rapidly distinguish between undamaged and stink bug damaged cotton bolls. Based on the fluorescent fingerprint, we envision a fluorescence reflectance imaging or a fluorescence ratiometric device to assist pest management professionals with rapidly determining the extent of stink bug damage in a cotton field. PMID- 21816077 TI - Urine hepcidin has additive value in ruling out cardiopulmonary bypass-associated acute kidney injury: an observational cohort study. AB - INTRODUCTION: Conventional markers of acute kidney injury (AKI) lack diagnostic accuracy and are expressed only late after cardiac surgery with cardiopulmonary bypass (CPB). Recently, interest has focused on hepcidin, a regulator of iron homeostasis, as a unique renal biomarker. METHODS: We studied 100 adult patients in the control arm of a randomized, controlled trial http://www.clinicaltrials.gov/NCT00672334 who were identified as being at increased risk of AKI after cardiac surgery with CPB. AKI was defined according to the Risk, Injury, Failure, Loss, End-stage renal disease classification of AKI classification stage. Samples of plasma and urine were obtained simultaneously (1) before CPB (2) six hours after the start of CPB and (3) twenty-four hours after CPB. Plasma and urine hepcidin 25-isoforms were quantified by competitive enzyme-linked immunoassay. RESULTS: In AKI-free patients (N = 91), urine hepcidin concentrations had largely increased at six and twenty-four hours after CPB, and they were three to seven times higher compared to patients with subsequent AKI (N = 9) in whom postoperative urine hepcidin remained at preoperative levels (P = 0.004, P = 0.002). Furthermore, higher urine hepcidin and, even more so, urine hepcidin adjusted to urine creatinine at six hours after CPB discriminated patients who did not develop AKI (area under the curve (AUC) receiver operating characteristic curve 0.80 [95% confidence interval (95% CI) 0.71 to 0.87] and 0.88 [95% CI 0.78 to 0.97]) or did not need renal replacement therapy initiation (AUC 0.81 [95% CI 0.72 to 0.88] 0.88 [95% CI 0.70 to 0.99]) from those who did. At six hours, urine hepcidin adjusted to urine creatinine was an independent predictor of ruling out AKI (P = 0.011). Plasma hepcidin did not predict no development of AKI. The study findings remained essentially unchanged after excluding patients with preoperative chronic kidney disease. CONCLUSIONS: Our findings suggest that urine hepcidin is an early predictive biomarker of ruling out AKI after CPB, thereby contributing to early patient risk stratification. PMID- 21816079 TI - Cognition, behaviour and academic skills after cognitive rehabilitation in Ugandan children surviving severe malaria: a randomised trial. AB - BACKGROUND: Infection with severe malaria in African children is associated with not only a high mortality but also a high risk of cognitive deficits. There is evidence that interventions done a few years after the illness are effective but nothing is known about those done immediately after the illness. We designed a study in which children who had suffered from severe malaria three months earlier were enrolled into a cognitive intervention program and assessed for the immediate benefit in cognitive, academic and behavioral outcomes. METHODS: This parallel group randomised study was carried out in Kampala City, Uganda between February 2008 and October 2010. Sixty-one Ugandan children aged 5 to 12 years with severe malaria were assessed for cognition (using the Kaufman Assessment Battery for Children, second edition and the Test of Variables of Attention), academic skills (Wide Range Achievement Test, third edition) and psychopathologic behaviour (Child Behaviour Checklist) three months after an episode of severe malaria. Twenty-eight were randomised to sixteen sessions of computerised cognitive rehabilitation training lasting eight weeks and 33 to a non-treatment group. Post-intervention assessments were done a month after conclusion of the intervention. Analysis of covariance was used to detect any differences between the two groups after post-intervention assessment, adjusting for age, sex, weight for age z score, quality of the home environment, time between admission and post intervention testing and pre-intervention score. The primary outcome was improvement in attention scores for the intervention group. This trial is registered with Current Controlled Trials, number ISRCTN53183087. RESULTS: Significant intervention effects were observed in the intervention group for learning mean score (SE), [93.89 (4.00) vs 106.38 (4.32), P = 0.04] but for working memory the intervention group performed poorly [27.42 (0.66) vs 25.34 (0.73), P = 0.04]. No effect was observed in the other cognitive outcomes or in any of the academic or behavioural measures. CONCLUSIONS: In this pilot study, our computerised cognitive training program three months after severe malaria had an immediate effect on cognitive outcomes but did not affect academic skills or behaviour. Larger trials with follow-up after a few years are needed to investigate whether the observed benefits are sustained. TRIAL REGISTRATION: ISRCTN: ISRCTN53183087. PMID- 21816080 TI - Integration and fusion of standard automated perimetry and optical coherence tomography data for improved automated glaucoma diagnostics. AB - BACKGROUND: The performance of glaucoma diagnostic systems could be conceivably improved by the integration of functional and structural test measurements that provide relevant and complementary information for reaching a diagnosis. The purpose of this study was to investigate the performance of data fusion methods and techniques for simple combination of Standard Automated Perimetry (SAP) and Optical Coherence Tomography (OCT) data for the diagnosis of glaucoma using Artificial Neural Networks (ANNs). METHODS: Humphrey 24-2 SITA standard SAP and StratusOCT tests were prospectively collected from a randomly selected population of 125 healthy persons and 135 patients with glaucomatous optic nerve heads and used as input for the ANNs. We tested commercially available standard parameters as well as novel ones (fused OCT and SAP data) that exploit the spatial relationship between visual field areas and sectors of the OCT peripapillary scan circle. We evaluated the performance of these SAP and OCT derived parameters both separately and in combination. RESULTS: The diagnostic accuracy from a combination of fused SAP and OCT data (95.39%) was higher than that of the best conventional parameters of either instrument, i.e. SAP Glaucoma Hemifield Test (p < 0.001) and OCT Retinal Nerve Fiber Layer Thickness >= 1 quadrant (p = 0.031). Fused OCT and combined fused OCT and SAP data provided similar Area under the Receiver Operating Characteristic Curve (AROC) values of 0.978 that were significantly larger (p = 0.047) compared to ANNs using SAP parameters alone (AROC = 0.945). On the other hand, ANNs based on the OCT parameters (AROC = 0.970) did not perform significantly worse than the ANNs based on the fused or combined forms of input data. The use of fused input increased the number of tests that were correctly classified by both SAP and OCT based ANNs. CONCLUSIONS: Compared to the use of SAP parameters, input from the combination of fused OCT and SAP parameters, and from fused OCT data, significantly increased the performance of ANNs. Integrating parameters by including a priori relevant information through data fusion may improve ANN classification accuracy compared to currently available methods. PMID- 21816081 TI - Differential effects of a post-anthesis fertilizer regimen on the wheat flour proteome determined by quantitative 2-DE. AB - BACKGROUND: Mineral nutrition during wheat grain development has large effects on wheat flour protein content and composition, which in turn affect flour quality and immunogenic potential for a commodity of great economic value. However, it has been difficult to define the precise effects of mineral nutrition on protein composition because of the complexity of the wheat flour proteome. Recent improvements in the identification of flour proteins by tandem mass spectrometry (MS/MS) and the availability of a comprehensive proteome map of flour from the US wheat Butte 86 now make it possible to document changes in the proportions of individual flour proteins that result from the application of mineral nutrition. RESULTS: Plants of Triticum aestivum 'Butte 86' were grown with or without post anthesis fertilization (PAF) and quantitative 2-dimensional gel electrophoresis (2-DE) was used to analyze protein composition of the resulting flour. Significant changes in the proportions of 54 unique proteins were observed as a result of the treatment. Most omega-gliadins, high molecular weight glutenin subunits (HMW-GS) and serpins as well as some alpha-gliadins increased in proportion with PAF. In contrast, alpha-amylase/protease inhibitors, farinins, purinins and puroindolines decreased in proportion. Decreases were also observed in several low molecular weight glutenin subunits (LMW-GS), globulins, defense proteins and enzymes. The ratio of HMW-GS to LMW-GS in the flour increased from 0.61 to 0.95 and the ratio of gliadins to glutenins increased from 1.02 to 1.30 with PAF. Because flour protein content doubled with PAF from 7 to 14%, most protein types actually increased in absolute amount (MUg/mg flour protein). Data further suggest that flour proteins change with PAF according to their content of sulfur-containing amino acids Cys + Met. CONCLUSIONS: A 2-DE approach revealed changes in the wheat flour proteome due to PAF that are important for flour quality and immunogenic potential. The work forms a baseline for further studies of the effects of environmental variables on flour protein composition and provides clues about the regulation of specific flour protein genes. The study also is important for identifying targets for breeding programs and biotechnology efforts aimed at improving flour quality. PMID- 21816082 TI - rapmad: Robust analysis of peptide microarray data. AB - BACKGROUND: Peptide microarrays offer an enormous potential as a screening tool for peptidomics experiments and have recently seen an increased field of application ranging from immunological studies to systems biology. By allowing the parallel analysis of thousands of peptides in a single run they are suitable for high-throughput settings. Since data characteristics of peptide microarrays differ from DNA oligonucleotide microarrays, computational methods need to be tailored to these specifications to allow a robust and automated data analysis. While follow-up experiments can ensure the specificity of results, sensitivity cannot be recovered in later steps. Providing sensitivity is thus a primary goal of data analysis procedures. To this end we created rapmad (Robust Alignment of Peptide MicroArray Data), a novel computational tool implemented in R. RESULTS: We evaluated rapmad in antibody reactivity experiments for several thousand peptide spots and compared it to two existing algorithms for the analysis of peptide microarrays. rapmad displays competitive and superior behavior to existing software solutions. Particularly, it shows substantially improved sensitivity for low intensity settings without sacrificing specificity. It thereby contributes to increasing the effectiveness of high throughput screening experiments. CONCLUSIONS: rapmad allows the robust and sensitive, automated analysis of high-throughput peptide array data. The rapmad R-package as well as the data sets are available from http://www.tron-mz.de/compmed. PMID- 21816083 TI - Activation of human T-helper/inducer cell, T-cytotoxic cell, B-cell, and natural killer (NK)-cells and induction of natural killer cell activity against K562 chronic myeloid leukemia cells with modified citrus pectin. AB - BACKGROUND: Modified citrus pectin (MCP) is known for its anti-cancer effects and its ability to be absorbed and circulated in the human body. In this report we tested the ability of MCP to induce the activation of human blood lymphocyte subsets like T, B and NK-cells. METHODS: MCP treated human blood samples were incubated with specific antibody combinations and analyzed in a flow cytometer using a 3-color protocol. To test functionality of the activated NK-cells, isolated normal lymphocytes were treated with increasing concentrations of MCP. Log-phase PKH26-labeled K562 leukemic cells were added to the lymphocytes and incubated for 4 h. The mixture was stained with FITC-labeled active form of caspase 3 antibody and analyzed by a 2-color flow cytometry protocol. The percentage of K562 cells positive for PKH26 and FITC were calculated as the dead cells induced by NK-cells. Monosaccharide analysis of the MCP was performed by high-performance anion-exchange chromatography with pulse amperometric detection (HPAEC-PAD). RESULTS: MCP activated T-cytotoxic cells and B-cell in a dose dependent manner, and induced significant dose-dependent activation of NK-cells. MCP-activated NK-cells demonstrated functionality in inducing cancer cell death. MCP consisted of oligogalacturonic acids with some containing 4,5-unsaturated non reducing ends. CONCLUSIONS: MCP has immunostimulatory properties in human blood samples, including the activation of functional NK cells against K562 leukemic cells in culture. Unsaturated oligogalacturonic acids appear to be the immunostimulatory carbohydrates in MCP. PMID- 21816084 TI - Lower extremity fatigue increases complexity of postural control during a single legged stance. AB - BACKGROUND: Non-linear approaches to assessment of postural control can provide insight that compliment linear approaches. Control entropy (CE) is a recently developed statistical tool from non-linear dynamical systems used to assess the complexity of non-stationary signals. We have previously used CE of high resolution accelerometry in running to show decreased complexity with exhaustive exercise. The purpose of this study was to determine if complexity of postural control decreases following fatiguing exercise using CE. METHODS: Ten subjects (5 M/5 F; 25 +/- 3 yr; 169.4 +/- 11.7 cm; 79.0 +/- 16.9 kg) consented to participation approved by Western Oregon University IRB and completed two trials separated by 2-7 days. Trials consisted of two single-legged balance tests separated by two Wingate anaerobic tests (WAnT; PreFat/PostFat), or rest period (PreRest/PostRest). Balance tests consisted of a series of five single-legged stances, separated by 30 s rest, performed while standing on the dominant leg for 15-s with the participant crossing the arms over the chest and flexing the non dominant knee to 90 degrees. High resolution accelerometers (HRA) were fixed superficial to L3/L4 at the approximate center of mass (COM). Triaxial signals from the HRA were streamed in real time at 625 Hz. COM accelerations were recorded in g's for vertical (VT), medial/lateral (ML), and anterior/posterior (AP) axes. A newly developed statistic (R-test) was applied to group response shapes generated by Karhunen Loeve (KL) transform modes resulting from Control Entropy (CE) analysis. RESULTS: R-tests showed a significant mean vector difference (p < .05) within conditions, between axes in all cases, except PostFat, indicating the shape of the complexity response was different in these cases. R-test between conditions, within axis, differences were only present in PostFat for AP vs. PreFat (p < .05). T-tests showed a significantly higher overall CE PostFat in VT and ML compared to PreFat and PostRest (p < .0001). PostFat CE was also higher than PostRest in AP (p < .0001). CONCLUSIONS: These data indicate that fatiguing exercise eliminates the differential complexity response between axes, but increases complexity in all axes compared to the non fatigued condition. This has implications with regard to the effects of fatigue on strategies of the control system to maintain postural control. PMID- 21816085 TI - The architecture and effect of participation: a systematic review of community participation for communicable disease control and elimination. Implications for malaria elimination. AB - BACKGROUND: Community engagement and participation has played a critical role in successful disease control and elimination campaigns in many countries. Despite this, its benefits for malaria control and elimination are yet to be fully realized. This may be due to a limited understanding of the influences on participation in developing countries as well as inadequate investment in infrastructure and resources to support sustainable community participation. This paper reports the findings of an atypical systematic review of 60 years of literature in order to arrive at a more comprehensive awareness of the constructs of participation for communicable disease control and elimination and provide guidance for the current malaria elimination campaign. METHODS: Evidence derived from quantitative research was considered both independently and collectively with qualitative research papers and case reports. All papers included in the review were systematically coded using a pre-determined qualitative coding matrix that identified influences on community participation at the individual, household, community and government/civil society levels. Colour coding was also carried out to reflect the key primary health care period in which community participation programmes originated. These processes allowed exhaustive content analysis and synthesis of data in an attempt to realize conceptual development beyond that able to be achieved by individual empirical studies or case reports. RESULTS: Of the 60 papers meeting the selection criteria, only four studies attempted to determine the effect of community participation on disease transmission. Due to inherent differences in their design, interventions and outcome measures, results could not be compared. However, these studies showed statistically significant reductions in disease incidence or prevalence using various forms of community participation. The use of locally selected volunteers provided with adequate training, supervision and resources are common and important elements of the success of the interventions in these studies. In addition, qualitative synthesis of all 60 papers elucidates the complex architecture of community participation for communicable disease control and elimination which is presented herein. CONCLUSIONS: The current global malaria elimination campaign calls for a health systems strengthening approach to provide an enabling environment for programmes in developing countries. In order to realize the benefits of this approach it is vital to provide adequate investment in the 'people' component of health systems and understand the multi-level factors that influence their participation. The challenges of strengthening this component of health systems are discussed, as is the importance of ensuring that current global malaria elimination efforts do not derail renewed momentum towards the comprehensive primary health care approach. It is recommended that the application of the results of this systematic review be considered for other diseases of poverty in order to harmonize efforts at building 'competent communities' for communicable disease control and optimising health system effectiveness. PMID- 21816086 TI - Polyphosphate--an ancient energy source and active metabolic regulator. AB - There are a several molecules on Earth that effectively store energy within their covalent bonds, and one of these energy-rich molecules is polyphosphate. In microbial cells, polyphosphate granules are synthesised for both energy and phosphate storage and are degraded to produce nucleotide triphosphate or phosphate. Energy released from these energetic carriers is used by the cell for production of all vital molecules such as amino acids, nucleobases, sugars and lipids. Polyphosphate chains directly regulate some processes in the cell and are used as phosphate donors in gene regulation. These two processes, energetic metabolism and regulation, are orchestrated by polyphosphate kinases. Polyphosphate kinases (PPKs) can currently be categorized into three groups (PPK1, PPK2 and PPK3) according their functionality; they can also be divided into three groups according their homology (EcPPK1, PaPPK2 and ScVTC). This review discusses historical information, similarities and differences, biochemical characteristics, roles in stress response regulation and possible applications in the biotechnology industry of these enzymes. At the end of the review, a hypothesis is discussed in view of synthetic biology applications that states polyphosphate and calcium-rich organelles have endosymbiotic origins from ancient protocells that metabolized polyphosphate. PMID- 21816087 TI - Strict adherence to malaria rapid test results might lead to a neglect of other dangerous diseases: a cost benefit analysis from Burkina Faso. AB - BACKGROUND: Malaria rapid diagnostic tests (RDTs) have generally been found reliable and cost-effective. In Burkina Faso, the adherence of prescribers to the negative test result was found to be poor. Moreover, the test accuracy for malaria-attributable fever (MAF) is not the same as for malaria infection. This paper aims at determining the costs and benefits of two competing strategies for the management of MAF: presumptive treatment for all or use of RDTs. METHODS: A cost benefit analysis was carried out using a decision tree, based on data previously obtained, including a randomized controlled trial (RCT) recruiting 852 febrile patients during the dry season and 1,317 in the rainy season. Cost and benefit were calculated using both the real adherence found by the RCT and assuming an ideal adherence of 90% with the negative result. The main parameters were submitted to sensitivity analysis. RESULTS AND DISCUSSION: At real adherence, the test-based strategy was dominated. Assuming ideal adherence, at the value of 525 ? for a death averted, the total cost of managing 1,000 febrile children was 1,747 vs. 1,862 ? in the dry season and 1,372 vs. 2,138 in the rainy season for the presumptive vs. the test-based strategy. For adults it was 2,728 vs. 1,983 and 2,604 vs. 2,225, respectively. At the subsidized policy adopted locally, assuming ideal adherence, the RDT would be the winning strategy for adults in both seasons and for children in the dry season.At sensitivity analysis, the factors most influencing the choice of the better strategy were the value assigned to a death averted and the proportion of potentially severe NMFI treated with antibiotics in patients with false positive RDT results. The test based strategy appears advantageous for adults if a satisfactory adherence could be achieved. For children the presumptive strategy remains the best choice for a wide range of scenarios. CONCLUSIONS: For RDTs to be preferred, a positive result should not influence the decision to treat a potentially severe NMFI with antibiotics. In the rainy season the presumptive strategy always remains the better choice for children. PMID- 21816088 TI - Plasma concentrations of 25-hydroxyvitamin D among Jordanians: Effect of biological and habitual factors on vitamin D status. AB - BACKGROUND: Vitamin D is cutaneously synthesized following sun exposure (vitamin D3) as well as it is derived from dietary intake (vitamin D3 and D2). Vitamin D2 and D3 are metabolized in the liver to 25-hydroxyvitamin D (25(OH)D). This metabolite is considered the functional indicator of vitamin D stores in humans. Since Jordan latitude is 31 degrees N, cutaneous synthesis of vitamin D3 should be sufficient all year round. However, many indications reveal that it is not the case. Thus, this study was conducted to determine the 25(OH)D status among Jordanians. METHODS: Three hundred healthy volunteers were enrolled in a cross sectional study; 201 females and 99 males. 25(OH)D and calcium concentrations were measured by enzyme linked immunosorbent assay and spectroscopy techniques, respectively. All participants filled a study questionnaire that covered age, sex, height, weight, diet, and dress style for females. Females were divided according to their dress style: Western style, Hijab (all body parts are covered except the face and hands), and Niqab (all body parts are covered including face and hands). RESULTS: The average plasma 25(OH)D levels in males and females were 44.5 +/- 10.0 nmol/l and 31.1 +/- 12.0 nmol/l, respectively. However, when female 25(OH)D levels were categorized according to dress styles, the averages became 40.3, 31.3 and 28.5 nmol/l for the Western style, Hijab and Niqab groups, respectively. These 25(OH)D levels were significantly less than those of males (p < 0.05, 0.001, 0.001, respectively). In addition, the plasma 25(OH)D levels of the Western style group was significantly higher than those of Hijab and Niqab groups (p < 0.001). Furthermore, dairy consumption in males was a positive significant factor in vitamin D status. Even though calcium concentrations were within the reference range, the Hijab and Niqab-dressed females have significantly less plasma calcium levels than males (p < 0.01). CONCLUSIONS: Very low plasma 25(OH)D levels in females wearing Hijab or Niqab are highly attributed to low sunlight or UVB exposure. In addition, most of males (76%) and Western style dressed females (90%) have 25(OH)D concentrations below the international recommended values (50 nmol/l), suggesting that although sun exposure should be enough, other factors do play a role in these low concentrations. These findings emphasize the importance of vitamin D supplementation especially among conservatively dressed females, and determining if single nucleotide polymorphisms of the genes involved in vitamin D metabolism do exist among Jordanians. PMID- 21816089 TI - Pulmonary medium vessel vasculitis in an 11 year old boy: Hughes Stovin syndrome as a variant of polyarteritis nodosa? AB - We present the case of an 11-year-old boy presenting with haemoptysis, dyspnoea and weight loss as a manifestation of isolated pulmonary vasculitis, leading to pulmonary hypertension. He also appeared to have a longstanding dural venous sinus thrombosis. This rare presentation, especially in childhood, might represent a case of the seldomly reported Hughes-Stovin syndrome. The patient achieved remission after therapy with cyclophosphamide pulses and high-dose steroids. Based on the presented case and review of the literature, we propose that this syndrome might be a variant of polyarteritis nodosa. This report highlights diagnostic issues and describes a successful treatment regimen. PMID- 21816090 TI - Analysis of EpCAM positive cells isolated from sentinel lymph nodes of breast cancer patients identifies subpopulations of cells with distinct transcription profiles. AB - INTRODUCTION: The presence of tumor cells in the axillary lymph nodes is the most important prognostic factor in early stage breast cancer. However, the optimal method for sentinel lymph node (SLN) examination is still sought and currently many different protocols are employed. To examine two approaches for tumor cell detection we performed, in sequence, immunomagnetic enrichment and RT-PCR analysis on SLN samples from early stage breast cancer patients. This allowed us to compare findings based on the expression of cell surface proteins with those based on detection of intracellular transcripts. METHODS: Enrichment of EpCAM and Mucin 1 expressing cells from fresh SLN samples was achieved using magnetic beads coated with the appropriate antibodies. All resulting cell fractions were analyzed by RT-PCR using four chosen breast epithelial markers (hMAM, AGR2, SBEM, TFF1). Gene expression was further analyzed using RT-PCR arrays and markers for epithelial to mesenchymal transition (EMT). RESULTS: Both EpCAM and Mucin 1 enriched for the epithelial-marker expressing cells. However, EpCAM-IMS identified epithelial cells in 71 SLNs, whereas only 35 samples were positive with RT-PCR targeting breast epithelial transcripts. Further analysis of EpCAM positive but RT-PCR negative cell fractions showed that they had increased expression of MMPs, repressors of E-cadherin, SPARC and vimentin, all transcripts associated with the process of epithelial to mesenchymal transition. CONCLUSIONS: The EpCAM IMS-assay detected tumor cells with epithelial and mesenchymal-like characteristics, thus proving to be a more robust marker than pure epithelial derived biomarkers. This finding has clinical implications, as most methods for SLN analysis today rely on the detection of epithelial transcripts or proteins. PMID- 21816091 TI - Dyslipidaemia in HIV-infected women on antiretroviral therapy. Analysis of 922 patients from the Spanish VACH cohort. AB - BACKGROUND: Information concerning lipid disturbances in HIV-infected women on antiretroviral therapy (ART) is scarce. The objective of the study is to describe the lipid profile in a large cohort of HIV-infected women on contemporary ART and analyse differences between regimes and patient's characteristics. METHODS: Observational, multicentre, cross-sectional study from the Spanish VACH Cohort. 922 women on stable ART without lipid-lowering treatment were included. RESULTS: Median age was 42 years, median CD4 lymphocyte count was 544 cells/mm3, and 85.6% presented undetectable HIV-1 viral load. Median total cholesterol (TC) was 189 mg/dL (interquartile range, IQR, 165-221), HDL cholesterol 53 mg/dL (IQR, 44-64), LDL cholesterol 108 mg/dL (IQR, 86-134), and triglycerides 116 mg/dL (IQR, 85 163). Mean accumulated time on ART was 116 months; 47.4% were on NNRTI-based regimes, 44.7% on PI, and 6.7% on only-NRTI therapy. 43.8% were also hepatitis C (HCV) coinfected. Patients on PI treatment presented higher TC/HDL ratio than those on NNRTI (p < 0.001). Significantly higher HDL values were observed in NNRTI-treated patients. HCV-coinfected patients presented lower TC/HDL ratio than the non HCV-coinfected. In multivariate analysis, factors independently associated with TC/HDL ratio were age, triglyceride levels and HCV co-infection. PI treatment presented a non-significant association with higher TC/HDL ratio. CONCLUSIONS: In HIV-infected women, the NNRTI-based ART is associated with a better lipid profile than the PI-based. Factors unrelated to ART selection may also exert an independent, significant influence on lipids; in particular, age, and triglyceride levels are associated with an increased TC/HDL ratio while HCV co-infection is associated with a reduced TC/HDL ratio. PMID- 21816092 TI - Bifidobacterium pseudolongum are efficient indicators of animal fecal contamination in raw milk cheese industry. AB - BACKGROUND: The contamination of raw milk cheeses (St-Marcellin and Brie) from two plants in France was studied at several steps of production (raw milk, after addition of rennet - St-Marcellin - or after second maturation - Brie -, after removal from the mold and during ripening) using bifidobacteria as indicators of fecal contamination. RESULTS: Bifidobacterium semi-quantitative counts were compared using PCR-RFLP and real-time PCR. B. pseudolongum were detected in 77% (PCR-RFLP; 1.75 to 2.29 log cfu ml(-1)) and 68% (real-time PCR; 2.19 to 2.73 log cfu ml(-1)) of St-Marcellin samples and in 87% (PCR-RFLP; 1.17 to 2.40 log cfu ml(-1)) of Brie cheeses samples. Mean counts of B. pseudolongum remained stable along both processes. Two other populations of bifidobacteria were detected during the ripening stage of St-Marcellin, respectively in 61% and 18% of the samples (PCR-RFLP). The presence of these populations explains the increase in total bifidobacteria observed during ripening. Further characterization of these populations is currently under process. Forty-eight percents (St-Marcellin) and 70% (Brie) of the samples were B. pseudolongum positive/E. coli negative while only 10% (St-Marcellin) and 3% (Brie) were B. pseudolongum negative/E. coli positive. CONCLUSIONS: The increase of total bifidobacteria during ripening in Marcellin's process does not allow their use as fecal indicator. The presence of B. pseudolongum along the processes defined a contamination from animal origin since this species is predominant in cow dung and has never been isolated in human feces. B. pseudolongum was more sensitive as an indicator than E. coli along the two different cheese processes. B. pseudolongum should be used as fecal indicator rather than E. coli to assess the quality of raw milk and raw milk cheeses. PMID- 21816093 TI - A regression system for estimation of errors introduced by confocal imaging into gene expression data in situ. AB - BACKGROUND: Accuracy of the data extracted from two-dimensional confocal images is limited due to experimental errors that arise in course of confocal scanning. The common way to reduce the noise in images is sequential scanning of the same specimen several times with the subsequent averaging of multiple frames. Attempts to increase the dynamical range of an image by setting too high values of microscope PMT parameters may cause clipping of single frames and introduce errors into the data extracted from the averaged images. For the estimation and correction of this kind of errors a method based on censoring technique (Myasnikova et al., 2009) is used. However, the method requires the availability of all the confocal scans along with the averaged image, which is normally not provided by the standard scanning procedure. RESULTS: To predict error size in the data extracted from the averaged image we developed a regression system. The system is trained on the learning sample composed of images obtained from three different microscopes at different combinations of PMT parameters, and for each image all the scans are saved. The system demonstrates high prediction accuracy and was applied for correction of errors in the data on segmentation gene expression in Drosophila blastoderm stored in the FlyEx database (http://urchin.spbcas.ru/flyex/, http://flyex.uchicago.edu/flyex/). The prediction method is realized as a software tool CorrectPattern freely available at http://urchin.spbcas.ru/asp/2011/emm/. CONCLUSIONS: We created a regression system and software to predict the magnitude of errors in the data obtained from a confocal image based on information about microscope parameters used for the image acquisition. An important advantage of the developed prediction system is the possibility to accurately correct the errors in data obtained from strongly clipped images, thereby allowing to obtain images of the higher dynamical range and thus to extract more detailed quantitative information from them. PMID- 21816094 TI - Diagnostic value of circulating tumor cell detection in bladder and urothelial cancer: systematic review and meta-analysis. AB - BACKGROUND: The diagnostic value and prognostic significance of circulating tumor cell (CTC) detection in patients with bladder cancer is controversial. We performed a meta-analysis to consolidate current evidence regarding the use of CTC detection assays to diagnose bladder and other urothelial cancers and the association of CTC positivity with advanced, remote disease. METHODS: Studies that investigated the presence of CTCs in the peripheral blood of patients with bladder cancer and/or urothelial cancer were identified and reviewed. Sensitivities, specificities, and positive (LR+) and negative likelihood ratios (LR-) of CTC detection in individual studies were calculated and meta-analyzed by random effects model. Overall odds ratio of CTC positivity in patients with advanced disease versus those with organ-confined cancer was also calculated. RESULTS: Overall sensitivity of CTC detection assays was 35.1% (95%CI, 32.4-38%); specificity, LR+, and LR- was 89.4% (95%CI, 87.2-91.3%), 3.77 (95%CI, 1.95-7.30) and 0.72 (95%CI, 0.64-0.81). CTC-positive patients were significantly more likely to have advanced (stage III-IV) disease compared with CTC-negative patients (OR, 5.05; 95%CI, 2.49-10.26). CONCLUSIONS: CTC evaluation can confirm tumor diagnosis and identify patients with advanced bladder cancer. However, due to the low overall sensitivity, CTC detection assays should not be used as initial screening tests. PMID- 21816096 TI - Effects on the estimated cause-specific mortality fraction of providing physician reviewers with different formats of verbal autopsy data. AB - BACKGROUND: The process of data collection and the methods used to assign the cause of death vary significantly among different verbal autopsy protocols, but there are few data to describe the consequences of the choices made. The aim of this study was to objectively define the impact of the format of data presented to physician reviewers on the cause-specific mortality fractions defined by a verbal autopsy-based mortality-surveillance system. METHODS: Verbal autopsies were done by primary health care workers for all deaths between October 2006 and September 2007 in a community in rural Andhra Pradesh, India (total population about 180,162). Each questionnaire had a structured section, composed of a series of check boxes, and a free-text section, in which a narrative description of the events leading to death was recorded. For each death, a physician coder was presented first with one section and then the other in random order with a 20- to 40-day interval between. A cause of death was recorded for each data format at the level of ICD 10 chapter headings or else the death was documented as unclassified. After another 20- to 40-day interval, both the structured and free text sections of the questionnaire were presented together and an index cause of death was assigned. RESULTS: In all, 1,407 verbal autopsies were available for analysis, representing 94% of all deaths recorded in the population that year. An index cause of death was assigned using the combined data for 1,190 with the other 217 remaining unclassified. The observed cause-specific mortality fractions were the same regardless of whether the structured, free-text or combined data sources were used. At the individual level, the assignments made using the structured format matched the index in 1,012 (72%) of cases with a kappa statistic of 0.66. For the free-text format, the corresponding figures were 989 (70%) and 0.64. CONCLUSIONS: The format of the verbal autopsy data used to assign a cause of death did not substantively influence the pattern of mortality estimated. Substantially abbreviated and simplified verbal autopsy questionnaires might provide robust information about high-level mortality patterns. PMID- 21816095 TI - Population Health Metrics Research Consortium gold standard verbal autopsy validation study: design, implementation, and development of analysis datasets. AB - BACKGROUND: Verbal autopsy methods are critically important for evaluating the leading causes of death in populations without adequate vital registration systems. With a myriad of analytical and data collection approaches, it is essential to create a high quality validation dataset from different populations to evaluate comparative method performance and make recommendations for future verbal autopsy implementation. This study was undertaken to compile a set of strictly defined gold standard deaths for which verbal autopsies were collected to validate the accuracy of different methods of verbal autopsy cause of death assignment. METHODS: Data collection was implemented in six sites in four countries: Andhra Pradesh, India; Bohol, Philippines; Dar es Salaam, Tanzania; Mexico City, Mexico; Pemba Island, Tanzania; and Uttar Pradesh, India. The Population Health Metrics Research Consortium (PHMRC) developed stringent diagnostic criteria including laboratory, pathology, and medical imaging findings to identify gold standard deaths in health facilities as well as an enhanced verbal autopsy instrument based on World Health Organization (WHO) standards. A cause list was constructed based on the WHO Global Burden of Disease estimates of the leading causes of death, potential to identify unique signs and symptoms, and the likely existence of sufficient medical technology to ascertain gold standard cases. Blinded verbal autopsies were collected on all gold standard deaths. RESULTS: Over 12,000 verbal autopsies on deaths with gold standard diagnoses were collected (7,836 adults, 2,075 children, 1,629 neonates, and 1,002 stillbirths). Difficulties in finding sufficient cases to meet gold standard criteria as well as problems with misclassification for certain causes meant that the target list of causes for analysis was reduced to 34 for adults, 21 for children, and 10 for neonates, excluding stillbirths. To ensure strict independence for the validation of methods and assessment of comparative performance, 500 test-train datasets were created from the universe of cases, covering a range of cause-specific compositions. CONCLUSIONS: This unique, robust validation dataset will allow scholars to evaluate the performance of different verbal autopsy analytic methods as well as instrument design. This dataset can be used to inform the implementation of verbal autopsies to more reliably ascertain cause of death in national health information systems. PMID- 21816097 TI - Epidemiologic application of verbal autopsy to investigate the high occurrence of cancer along Huai River Basin, China. AB - BACKGROUND: In 2004, the media repeatedly reported water pollution and "cancer villages" along the Huai River in China. Due to the lack of death records for more than 30 years, a retrospective survey of causes of death using verbal autopsy was carried out to investigate cancer rates in this area. METHODS: An epidemiologic study was designed to compare numbers of deaths and causes of death between the study areas with water pollution and the control areas without water pollution in S County and Y District in 2005. The study areas were selected based on the distribution of the Huai River and its tributaries. Verbal autopsy was used to assist cause of death (COD) diagnoses and to verify mortality rates. The standard mortality rates (SMRs) of cancer in the study area were compared with those in the control areas. In order to verify the difference between mortality rates due to cancers in the study and the control areas, patients who reported having cancer in the survey received a second diagnosis by national and provincial oncologists with pathological and laboratory examinations. Comparisons were made to determine if differential cancer prevalence rates in the study and control areas were similar to the difference in mortality due to cancer in these study and control areas. Mortality rates of cancers in study and control areas were also compared with national statistics for the rural population of China. RESULTS: Over five years, 3,301 deaths were identified, including 1,158 cancer deaths. The annual average SMRs of cancer in the study areas of S County and Y District were 277.8/100,000 and 223.6/100,000, respectively, which is three to four times higher than those in the control areas. In addition, a total of 626 cases of cancer in the study and control areas were confirmed. The prevalence rates of cancer were 545/100,000 and 128.1/100,000 per year in the study and control areas in S County, respectively, and 440.9/100,000 and 200/100,000 per year in the study and control areas in Y District, respectively. The mortality and prevalence rates of digestive cancers were higher in the study areas than the control areas. In 2000, the SMR for cancer in rural areas nationwide was 120.9/100,000, and in study areas in S County and Y District, the excess rates of deaths were 184/100,000 and 138.8/100,000, respectively. CONCLUSIONS: The death rates of digestive cancers were much higher in the study areas of S County and Y District. The patterns for between-area differences in prevalence and mortality rates of cancer were similar. Verbal autopsy is shown to be a useful tool in retrospective mortality surveys in low-resource areas with limited access to health care. PMID- 21816098 TI - Direct estimation of cause-specific mortality fractions from verbal autopsies: multisite validation study using clinical diagnostic gold standards. AB - BACKGROUND: Verbal autopsy (VA) is used to estimate the causes of death in areas with incomplete vital registration systems. The King and Lu method (KL) for direct estimation of cause-specific mortality fractions (CSMFs) from VA studies is an analysis technique that estimates CSMFs in a population without predicting individual-level cause of death as an intermediate step. In previous studies, KL has shown promise as an alternative to physician-certified verbal autopsy (PCVA). However, it has previously been impossible to validate KL with a large dataset of VAs for which the underlying cause of death is known to meet rigorous clinical diagnostic criteria. METHODS: We applied the KL method to adult, child, and neonatal VA datasets from the Population Health Metrics Research Consortium gold standard verbal autopsy validation study, a multisite sample of 12,542 VAs where gold standard cause of death was established using strict clinical diagnostic criteria. To emulate real-world populations with varying CSMFs, we evaluated the KL estimations for 500 different test datasets of varying cause distribution. We assessed the quality of these estimates in terms of CSMF accuracy as well as linear regression and compared this with the results of PCVA. RESULTS: KL performance is similar to PCVA in terms of CSMF accuracy, attaining values of 0.669, 0.698, and 0.795 for adult, child, and neonatal age groups, respectively, when health care experience (HCE) items were included. We found that the length of the cause list has a dramatic effect on KL estimation quality, with CSMF accuracy decreasing substantially as the length of the cause list increases. We found that KL is not reliant on HCE the way PCVA is, and without HCE, KL outperforms PCVA for all age groups. CONCLUSIONS: Like all computer methods for VA analysis, KL is faster and cheaper than PCVA. Since it is a direct estimation technique, though, it does not produce individual-level predictions. KL estimates are of similar quality to PCVA and slightly better in most cases. Compared to other recently developed methods, however, KL would only be the preferred technique when the cause list is short and individual-level predictions are not needed. PMID- 21816099 TI - Simplified Symptom Pattern Method for verbal autopsy analysis: multisite validation study using clinical diagnostic gold standards. AB - BACKGROUND: Verbal autopsy can be a useful tool for generating cause of death data in data-sparse regions around the world. The Symptom Pattern (SP) Method is one promising approach to analyzing verbal autopsy data, but it has not been tested rigorously with gold standard diagnostic criteria. We propose a simplified version of SP and evaluate its performance using verbal autopsy data with accompanying true cause of death. METHODS: We investigated specific parameters in SP's Bayesian framework that allow for its optimal performance in both assigning individual cause of death and in determining cause-specific mortality fractions. We evaluated these outcomes of the method separately for adult, child, and neonatal verbal autopsies in 500 different population constructs of verbal autopsy data to analyze its ability in various settings. RESULTS: We determined that a modified, simpler version of Symptom Pattern (termed Simplified Symptom Pattern, or SSP) performs better than the previously-developed approach. Across 500 samples of verbal autopsy testing data, SSP achieves a median cause-specific mortality fraction accuracy of 0.710 for adults, 0.739 for children, and 0.751 for neonates. In individual cause of death assignment in the same testing environment, SSP achieves 45.8% chance-corrected concordance for adults, 51.5% for children, and 32.5% for neonates. CONCLUSIONS: The Simplified Symptom Pattern Method for verbal autopsy can yield reliable and reasonably accurate results for both individual cause of death assignment and for determining cause-specific mortality fractions. The method demonstrates that verbal autopsies coupled with SSP can be a useful tool for analyzing mortality patterns and determining individual cause of death from verbal autopsy data. PMID- 21816100 TI - Using verbal autopsy to assess the prevalence of HIV infection among deaths in the ART period in rural Uganda: a prospective cohort study, 2006-2008. AB - BACKGROUND: Verbal autopsy is important for detecting causes of death including HIV in areas with inadequate vital registration systems. Before antiretroviral therapy (ART) introduction, a verbal autopsy study in rural Uganda found that half of adult deaths assessed were in HIV-positive individuals. We used verbal autopsy to compare the proportion of HIV-positive adult deaths in the periods before and after ART introduction. METHODS: Between 2006 and 2008, all adult (>= 13 years) deaths in a prospective population-based cohort study were identified by monthly death registration, and HIV serostatus was determined through annual serosurveys. A clinical officer interviewed a relative of the deceased using a verbal autopsy questionnaire. Two clinicians independently reviewed the questionnaires and classified the deaths as HIV-positive or not. A third clinician was the tie-breaker in case of nonagreement. The performance of the verbal autopsy tool was assessed using HIV serostatus as the gold standard of comparison. We compared the proportions of HIV-positive deaths as assessed by verbal autopsy in the early 1990s and the 2006-2008 periods. RESULTS: Of 333 deaths among 12,641 adults of known HIV serostatus, 264 (79.3%) were assessed by verbal autopsy, of whom 59 (22.3%) were HIV-seropositive and 68 (25.8%) were classified as HIV-positive by verbal autopsy. Verbal autopsy had a specificity of 90.2% and positive predictive value of 70.6% for identifying deaths among HIV infected individuals, with substantial interobserver agreement (80.3%; kappa statistic = 0.69). The HIV-attributable mortality fraction estimated by verbal autopsy decreased from 47.0% (pre-ART period) to 25.8% (ART period), p < 0.001. CONCLUSIONS: In resource-limited settings, verbal autopsy can provide a good estimate of the prevalence of HIV infection among adult deaths. In this rural population, the proportion of deaths identified by verbal autopsy as HIV-positive declined between the early 1990s and the 2006-2008 period. Verbal autopsy findings can inform policy on HIV health care needs. PMID- 21816101 TI - Use of verbal autopsy in a national health information system: Effects of the investigation of ill-defined causes of death on proportional mortality due to injury in small municipalities in Brazil. AB - BACKGROUND: The Mortality Information System (MIS) in Brazil records mortality data in hospitals and civil registries with the responsibility of compiling underlying cause of death. Despite continuous improvements in the MIS, some areas still maintain a high proportion of deaths assigned to ill-defined causes. Deaths coded to this category have most likely been considered as miscoded deaths from communicable and noncommunicable diseases. However, some local studies have provided evidence of underreporting of injury in Brazil. The aim of this study was to investigate ill-defined causes of death using the verbal autopsy (VA) method to estimate injury-specific mortality fraction in small municipalities in northeastern Minas Gerais, Brazil. METHODS: A sample size of reported death certificates with ill-defined conditions in a random sample of 10 municipalities was obtained, and then trained interviewers questioned family members using a standardized VA questionnaire to elicit information on symptoms experienced by the deceased before death. All attempts were made to collect existing information about the disease or death using health facilities records. Probable causes of death were assigned by a physician after review of the completed questionnaires following rules of the 10th revision of the International Classification of Diseases (ICD-10). RESULTS: Of 202 eligible ill-defined deaths, 151 were investigated using the VA methodology, and 12.6% had injury as the underlying cause of death. The proportional mortality fraction from injury among all causes of death increases from 4.4% to 8.2% after investigation. Different specific injury category causes were observed between recorded injury causes and those detected by VA. Drowning was the top specific injury cause detected after investigation. CONCLUSIONS: This study provides evidence that the use of VA in the investigation of registered ill-defined conditions in an existing MIS can furnish information on the relevance of injury as a priority health problem in small municipalities of Minas Gerais. Local research with VA should be brought to the attention of regional health policymakers to improve the quality of data for their planning. PMID- 21816102 TI - An improved method for physician-certified verbal autopsy reduces the rate of discrepancy: experiences in the Nouna Health and Demographic Surveillance Site (NHDSS), Burkina Faso. AB - BACKGROUND: Through application of the verbal autopsy (VA) approach, trained fieldworkers collect information about the probable cause of death (COD) by using a standardized questionnaire to interview family members who were present at the time of death. The physician-certified VA (PCVA), an independent review of this questionnaire data by up to three physicians trained in VA coding, is currently recommended by the World Health Organization (WHO) and is widely used in the INDEPTH Network. Even given its appropriateness in these contexts, a large percentage of causes of death assigned by VAs remains undetermined. As physicians often do not agree upon a final COD classification, there remains substantial room to improve the standard VA method, potentially leading to a reduction in physician discordance in COD coding. METHODS: We present an extension of the current method of PCVA and compare it to the standard WHO-recommended procedure. We used VA data collected in the Nouna Health and Demographic Surveillance Site (NHDSS) between 2009 and 2010 using a locally-adapted version of an INDEPTH standard verbal autopsy questionnaire. Until 2009, physicians in the NHDSS followed the WHO method (Method 1). As an extension of Method 1, starting in 2010, the use of a panel of physicians was added to the coding process in the case where a third physician's final conclusions resulted in an undetermined COD (Method 2). Two independent samples of VA questionnaires were compared for the year 2009 (using Method 1) and the year 2010 (using Method 2). RESULTS: The WHO recommended method used for 2009 yielded a high level of undetermined CODs, where the final coding was "undetermined" in 50.8% of all questionnaires due to disagreement among participating physicians (Method 1). By introducing a panel of physicians in 2010 for cases where the principal physicians disagreed on the cause of death, the revised method significantly reduced the proportion of undetermined CODs to 1.5% (Method 2). CONCLUSIONS: As the extended method of PCVA significantly improved the accuracy of the VA procedure, we suggest the adoption of this method for those countries where alternatives like computer-based VA coding are not available. Based on the results of our study, further research should be pursued. PMID- 21816103 TI - Assessing quality of medical death certification: Concordance between gold standard diagnosis and underlying cause of death in selected Mexican hospitals. AB - BACKGROUND: In Mexico, the vital registration system relies on information collected from death certificates to generate official mortality figures. Although the death certificate has high coverage across the country, there is little information regarding its validity. The objective of this study was to assess the concordance between the underlying cause of death in official statistics obtained from death certificates and a gold standard diagnosis of the same deaths derived from medical records of hospitals. METHODS: The study sample consisted of 1,589 deaths that occurred in 34 public hospitals in the Federal District and the state of Morelos, Mexico in 2009. Neonatal, child, and adult cases were selected for causes of death that included infectious diseases, noncommunicable diseases, and injuries. We compared the underlying cause of death, obtained from medical death certificates, against a gold standard diagnosis derived from a review of medical records developed by the Population Health Metrics Research Consortium. We used chance-corrected concordance and accuracy as metrics to evaluate the quality of performance of the death certificate. RESULTS: Analysis considering only the underlying cause of death resulted in a median chance-corrected concordance between the cause of death in medical death certificates versus the gold standard of 54.3% (95% uncertainty interval [UI]: 52.2, 55.6) for neonates, 38.5% (37.0, 40.0) for children, and 66.5% (65.9, 66.9) for adults. The accuracy resulting from the same analysis was 0.756 (0.747, 0.769) for neonates, 0.683 (0.663, 0.701) for children, and 0.780 (0.774, 0.785) for adults. Median chance-corrected concordance and accuracy increased when considering the mention of any cause of death in the death certificate, not just the underlying cause. Concordance varied substantially depending on cause of death, and accuracy varied depending on the true cause specific mortality fraction composition. CONCLUSIONS: Although we cannot generalize our conclusions to Mexico as a whole, the results demonstrate important problems with the quality of the main source of information for causes of death used by decision-makers in settings with highly technological vital registration systems. It is necessary to improve death certification procedures, especially in the case of child and neonatal deaths. This requires an important commitment from the health system and health institutions. PMID- 21816104 TI - Performance of physician-certified verbal autopsies: multisite validation study using clinical diagnostic gold standards. AB - BACKGROUND: Physician review of a verbal autopsy (VA) and completion of a death certificate remains the most widely used approach for VA analysis. This study provides new evidence about the performance of physician-certified verbal autopsy (PCVA) using defined clinical diagnostic criteria as a gold standard for a multisite sample of 12,542 VAs. The study was also designed to analyze issues related to PCVA, such as the impact of a second physician reader on the cause of death assigned, the variation in performance with and without household recall of health care experience (HCE), and the importance of local information for physicians reading VAs. METHODS: The certification was performed by 24 physicians. The assignment of VA was random and blinded. Each VA was certified by one physician. Half of the VAs were reviewed by a different physician with household recall of health care experience included. The completed death certificate was processed for automated ICD-10 coding of the underlying cause of death. PCVA was compared to gold standard cause of death assignment based on strictly defined clinical diagnostic criteria that are part of the Population Health Metrics Research Consortium (PHMRC) gold standard verbal autopsy study. RESULTS: For individual cause assignment, the overall chance-corrected concordance for PCVA against the gold standard cause of death is less than 50%, with substantial variability by cause and physician. Physicians assign the correct cause around 30% of the time without HCE, and addition of HCE improves performance in adults to 45% and slightly higher in children to 48%. Physicians estimate cause-specific mortality fractions (CSMFs) with considerable error for adults, children, and neonates. Only for neonates for a cause list of six causes with HCE is accuracy above 0.7. In all three age groups, CSMF accuracy improves when household recall of health care experience is available. CONCLUSIONS: Results show that physician coding for cause of death assignment may not be as robust as previously thought. The time and cost required to initially collect the verbal autopsies must be considered in addition to the analysis, as well as the impact of diverting physicians from servicing immediate health needs in a population to review VAs. All of these considerations highlight the importance and urgency of developing better methods to more reliably analyze past and future verbal autopsies to obtain the highest quality mortality data from populations without reliable death certification. PMID- 21816105 TI - Random forests for verbal autopsy analysis: multisite validation study using clinical diagnostic gold standards. AB - BACKGROUND: Computer-coded verbal autopsy (CCVA) is a promising alternative to the standard approach of physician-certified verbal autopsy (PCVA), because of its high speed, low cost, and reliability. This study introduces a new CCVA technique and validates its performance using defined clinical diagnostic criteria as a gold standard for a multisite sample of 12,542 verbal autopsies (VAs). METHODS: The Random Forest (RF) Method from machine learning (ML) was adapted to predict cause of death by training random forests to distinguish between each pair of causes, and then combining the results through a novel ranking technique. We assessed quality of the new method at the individual level using chance-corrected concordance and at the population level using cause specific mortality fraction (CSMF) accuracy as well as linear regression. We also compared the quality of RF to PCVA for all of these metrics. We performed this analysis separately for adult, child, and neonatal VAs. We also assessed the variation in performance with and without household recall of health care experience (HCE). RESULTS: For all metrics, for all settings, RF was as good as or better than PCVA, with the exception of a nonsignificantly lower CSMF accuracy for neonates with HCE information. With HCE, the chance-corrected concordance of RF was 3.4 percentage points higher for adults, 3.2 percentage points higher for children, and 1.6 percentage points higher for neonates. The CSMF accuracy was 0.097 higher for adults, 0.097 higher for children, and 0.007 lower for neonates. Without HCE, the chance-corrected concordance of RF was 8.1 percentage points higher than PCVA for adults, 10.2 percentage points higher for children, and 5.9 percentage points higher for neonates. The CSMF accuracy was higher for RF by 0.102 for adults, 0.131 for children, and 0.025 for neonates. CONCLUSIONS: We found that our RF Method outperformed the PCVA method in terms of chance corrected concordance and CSMF accuracy for adult and child VA with and without HCE and for neonatal VA without HCE. It is also preferable to PCVA in terms of time and cost. Therefore, we recommend it as the technique of choice for analyzing past and current verbal autopsies. PMID- 21816106 TI - Robust metrics for assessing the performance of different verbal autopsy cause assignment methods in validation studies. AB - BACKGROUND: Verbal autopsy (VA) is an important method for obtaining cause of death information in settings without vital registration and medical certification of causes of death. An array of methods, including physician review and computer-automated methods, have been proposed and used. Choosing the best method for VA requires the appropriate metrics for assessing performance. Currently used metrics such as sensitivity, specificity, and cause-specific mortality fraction (CSMF) errors do not provide a robust basis for comparison. METHODS: We use simple simulations of populations with three causes of death to demonstrate that most metrics used in VA validation studies are extremely sensitive to the CSMF composition of the test dataset. Simulations also demonstrate that an inferior method can appear to have better performance than an alternative due strictly to the CSMF composition of the test set. RESULTS: VA methods need to be evaluated across a set of test datasets with widely varying CSMF compositions. We propose two metrics for assessing the performance of a proposed VA method. For assessing how well a method does at individual cause of death assignment, we recommend the average chance-corrected concordance across causes. This metric is insensitive to the CSMF composition of the test sets and corrects for the degree to which a method will get the cause correct due strictly to chance. For the evaluation of CSMF estimation, we propose CSMF accuracy. CSMF accuracy is defined as one minus the sum of all absolute CSMF errors across causes divided by the maximum total error. It is scaled from zero to one and can generalize a method's CSMF estimation capability regardless of the number of causes. Performance of a VA method for CSMF estimation by cause can be assessed by examining the relationship across test datasets between the estimated CSMF and the true CSMF. CONCLUSIONS: With an increasing range of VA methods available, it will be critical to objectively assess their performance in assigning cause of death. Chance-corrected concordance and CSMF accuracy assessed across a large number of test datasets with widely varying CSMF composition provide a robust strategy for this assessment. PMID- 21816107 TI - Performance of the Tariff Method: validation of a simple additive algorithm for analysis of verbal autopsies. AB - BACKGROUND: Verbal autopsies provide valuable information for studying mortality patterns in populations that lack reliable vital registration data. Methods for transforming verbal autopsy results into meaningful information for health workers and policymakers, however, are often costly or complicated to use. We present a simple additive algorithm, the Tariff Method (termed Tariff), which can be used for assigning individual cause of death and for determining cause specific mortality fractions (CSMFs) from verbal autopsy data. METHODS: Tariff calculates a score, or "tariff," for each cause, for each sign/symptom, across a pool of validated verbal autopsy data. The tariffs are summed for a given response pattern in a verbal autopsy, and this sum (score) provides the basis for predicting the cause of death in a dataset. We implemented this algorithm and evaluated the method's predictive ability, both in terms of chance-corrected concordance at the individual cause assignment level and in terms of CSMF accuracy at the population level. The analysis was conducted separately for adult, child, and neonatal verbal autopsies across 500 pairs of train-test validation verbal autopsy data. RESULTS: Tariff is capable of outperforming physician-certified verbal autopsy in most cases. In terms of chance-corrected concordance, the method achieves 44.5% in adults, 39% in children, and 23.9% in neonates. CSMF accuracy was 0.745 in adults, 0.709 in children, and 0.679 in neonates. CONCLUSIONS: Verbal autopsies can be an efficient means of obtaining cause of death data, and Tariff provides an intuitive, reliable method for generating individual cause assignment and CSMFs. The method is transparent and flexible and can be readily implemented by users without training in statistics or computer science. PMID- 21816108 TI - Enhanced inhibitory synaptic transmission in the spinal dorsal horn mediates antinociceptive effects of TC-2559. AB - BACKGROUND: TC-2559 is a selective alpha4beta2 subtype of nicotinic acetylcholine receptor (nAChR) partial agonist and alpha4beta2 nAChR activation has been related to antinociception. The aim of this study is to investigate the analgesic effect of TC-2559 and its underlying spinal mechanisms. RESULTS: 1) In vivo bioavailability study: TC-2559 (3 mg/kg) had high absorption rate in rats with maximal total brain concentration reached over 4.6 MUM within first 15 min after administration and eliminated rapidly with brain half life of about 20 min after injection. 2) In vivo behavioral experiments: TC-2559 exerts dose dependent antinociceptive effects in both formalin test in mice and chronic constriction injury (CCI) model in rats by activation of alpha4beta2 nAChRs; 3) Whole-cell patch-clamp studies in the superficial dorsal horn neurons of the spinal cord slices: perfusion of TC-2559 (2 MUM) significantly increased the frequency, but not amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs). The enhancement of sIPSCs was blocked by pre-application of DHbetaE (2 MUM), a selective alpha4beta2 nicotinic receptor antagonist. Neither the frequency nor the amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) of spinal dorsal horn neurons were affected by TC-2559. CONCLUSIONS: Enhancement of inhibitory synaptic transmission in the spinal dorsal horn via activation of alpha4beta2 nAChRs may be one of the mechanisms of the antinociceptive effects of TC-2559 on pathological pain models. It provides further evidence to support the notion that selective alpha4beta2 subtype nAChR agonist may be developed as new analgesic drug for the treatment of neuropathic pain. PMID- 21816109 TI - Behavioral evidence for the differential regulation of p-p38 MAPK and p-NF-kappaB in rats with trigeminal neuropathic pain. AB - BACKGROUND: We investigated the differential regulation of p-p38 MAPK or p-NF kappaB in male Sprague-Dawley rats with inferior alveolar nerve injury resulting from mal-positioned dental implants. For this purpose, we characterized the temporal expression of p-p38 MAPK or p-NF-kappaB in the medullary dorsal horn and examined changes in nociceptive behavior after a blockade of p-p38 MAPK or p-NF kappaB pathways in rats with trigeminal neuropathic pain. RESULTS: Under anesthesia, the left lower second molar was extracted and replaced with a mini dental implant to intentionally injure the inferior alveolar nerve. Western and immunofluorescence analysis revealed that p-p38 MAPK is upregulated in microglia following nerve injury and that this expression peaked on postoperative day (POD) 3 through 7. However, the activation of p-NF-kappaB in astrocyte peaked on POD 7 through 21. The intracisternal administration of SB203580 (1 or 10 MUg), a p38 MAPK inhibitor, on POD 3 but not on POD 21 markedly inhibits mechanical allodynia and the p-p38 MAPK expression. However, the intracisternal administration of SN50 (0.2 or 2 ng), an NF-kappaB inhibitor, on POD 21 but not on POD 3 attenuates mechanical allodynia and p-NF-kappaB expression. Dexamethasone (25 mg/kg) decreases not only the activation of p38 MAPK but also that of NF-kappaB on POD 7. CONCLUSIONS: These results suggest that early expression of p-p38 MAPK in the microglia and late induction of p-NF-kappaB in astrocyte play an important role in trigeminal neuropathic pain and that a blockade of p-p38 MAPK at an early stage and p-NF-kappaB at a late stage might be a potential therapeutic strategy for treatment of trigeminal neuropathic pain. PMID- 21816111 TI - Clinical significance of subepithelial growth patterns in non-muscle invasive bladder cancer. AB - BACKGROUND: We evaluated the clinical significance and prognostic value of histopathological features of bladder cancer, such as subepithelial growth patterns and tumor growth pattern at the invasion front. METHODS: In total, 130 patients newly diagnosed with non-muscle invasive bladder cancer and underwent transurethral resection between 1998 and 2009 were enrolled. Subepithelial growth patterns consisting of endophytic growth pattern (EGP) and von Brunn's nest involvement (VBNI) were investigated using hematoxylin and eosin-stained slides, and their frequency of occurrence, prognostic value, and correlation with other clinicopathological features was evaluated. RESULTS: EGP and VBNI were found in 40 (30.8%) and 5 (3.9%) of the 130 cases, respectively. Of the 26 pT1 tumors, the growth pattern at the invasion front was trabecular in 17 (65.4%) and infiltrative in 9 (34.6%). Although 8 (47.1%) of 17 trabecular tumors coexisted with EGP, no cases with infiltrative tumors had EGP (p = 0.023). VBNI correlated with high tumor grades (p = 0.006) and lymphovascular involvement (p = 0.026). The multivariate Cox proportional hazards analysis revealed that tumor diameter less than 3 cm (p = 0.04) and intravesical bacillus Calmette-Guerin therapy (p = 0.004) were independent favorable prognostic factors for recurrence-free survival, whereas tumor stage was an independent poor prognostic factor for disease progression (p = 0.006). CONCLUSIONS: Subepithelial growth patterns were not a significant prognostic factor in this study. Additionally, no tumors with an infiltrative growth pattern coexisted with EGP, suggesting that determining the presence of EGP might be helpful for managing non-muscle invasive bladder cancers. PMID- 21816110 TI - Syntenic relationships between cucumber (Cucumis sativus L.) and melon (C. melo L.) chromosomes as revealed by comparative genetic mapping. AB - BACKGROUND: Cucumber, Cucumis sativus L. (2n = 2 * = 14) and melon, C. melo L. (2n = 2 * = 24) are two important vegetable species in the genus Cucumis (family Cucurbitaceae). Both species have an Asian origin that diverged approximately nine million years ago. Cucumber is believed to have evolved from melon through chromosome fusion, but the details of this process are largely unknown. In this study, comparative genetic mapping between cucumber and melon was conducted to examine syntenic relationships of their chromosomes. RESULTS: Using two melon mapping populations, 154 and 127 cucumber SSR markers were added onto previously reported F(2)- and RIL-based genetic maps, respectively. A consensus melon linkage map was developed through map integration, which contained 401 co dominant markers in 12 linkage groups including 199 markers derived from the cucumber genome. Syntenic relationships between melon and cucumber chromosomes were inferred based on associations between markers on the consensus melon map and cucumber draft genome scaffolds. It was determined that cucumber Chromosome 7 was syntenic to melon Chromosome I. Cucumber Chromosomes 2 and 6 each contained genomic regions that were syntenic with melon chromosomes III+V+XI and III+VIII+XI, respectively. Likewise, cucumber Chromosomes 1, 3, 4, and 5 each was syntenic with genomic regions of two melon chromosomes previously designated as II+XII, IV+VI, VII+VIII, and IX+X, respectively. However, the marker orders in several syntenic blocks on these consensus linkage maps were not co-linear suggesting that more complicated structural changes beyond simple chromosome fusion events have occurred during the evolution of cucumber. CONCLUSIONS: Comparative mapping conducted herein supported the hypothesis that cucumber chromosomes may be the result of chromosome fusion from a 24-chromosome progenitor species. Except for a possible inversion, cucumber Chromosome 7 has largely remained intact in the past nine million years since its divergence from melon. Meanwhile, many structural changes may have occurred during the evolution of the remaining six cucumber chromosomes. Further characterization of the genomic nature of Cucumis species closely related to cucumber and melon might provide a better understanding of the evolutionary history leading to modern cucumber. PMID- 21816112 TI - Pregnant women's awareness of sensitivity to cold (hiesho) and body temperature observational study: A comparison of Japanese and Brazilian women. AB - BACKGROUND: Sensitivity to cold (hiesho) is a serious health problem in Japan, yet it is minimally understood within Western cultures. The purpose of this study was to clarify the divergence between pregnant Japanese woman living in Japan and pregnant Brazilian women living in Brazil in awareness of hiesho and differences between core body and peripheral temperatures. METHODS: The subjects of this study were 230 pregnant Japanese women living in Japan and 200 pregnant Brazilian women living in Brazil. Data was collected in June/July and November 2005 in Japan and from October 2007 to February 2008 in Brazil. The survey methods consisted of measurement of deep body temperatures and questionnaires. RESULTS: 67.0% of Japanese women and 57.0% of Brazilian women were aware of hiesho, which showed a significant difference between the Japanese and Brazilian women (p = 0.034). The difference between forehead and sole temperatures was 2.0 degrees C among Japanese and 2.8 degrees C among Brazilians in June-July (p = 0.01). But in November the difference between those temperatures was 5.2 degrees C among Japanese and 2.8 degrees C among Brazilians (p < 0.001). CONCLUSIONS: There are differences between Japanese and Brazilians both in awareness of hiesho and in body temperatures. PMID- 21816113 TI - Efficacy of interventions to increase the uptake of chlamydia screening in primary care: a systematic review. AB - BACKGROUND: As most genital chlamydia infections are asymptomatic, screening is the main way to detect and cases for treatment. We undertook a systematic review of studies assessing the efficacy of interventions for increasing the uptake of chlamydia screening in primary care. METHODS: We reviewed studies which compared chlamydia screening in the presence and the absence of an intervention. The primary endpoints were screening rate or total tests. RESULTS: We identified 16 intervention strategies; 11 were randomised controlled trials and five observational studies, 10 targeted females only, five both males and females, and one males only. Of the 15 interventions among females, six were associated with significant increases in screening rates at the 0.05 level including a multifaceted quality improvement program that involved provision of a urine jar to patients at registration (44% in intervention clinics vs. 16% in the control clinic); linking screening to routine Pap smears (6.9% vs. 4.5%), computer alerts for doctors (12.2% vs. 10.6%); education workshops for clinic staff; internet based continuing medical education (15.5% vs. 12.4%); and free sexual health consultations (16.8% vs. 13.2%). Of the six interventions targeting males, two found significant increases including the multifaceted quality improvement program in which urine jars were provided to patients at registration (45% vs. 15%); and the offering by doctors of a test to all presenting young male clients, prior to consultation (29 vs. 4%). CONCLUSIONS: Interventions that promoted the universal offer of a chlamydia test in young people had the greatest impact on increasing screening in primary care. PMID- 21816115 TI - Prestimulus vigilance predicts response speed in an easy visual discrimination task. AB - BACKGROUND: Healthy adults show considerable within-subject variation of reaction time (RT) when performing cognitive tests. So far, the neurophysiological correlates of these inconsistencies have not yet been investigated sufficiently. In particular, studies rarely have focused on alterations of prestimulus EEG vigilance as a factor which possibly influences the outcome of cognitive tests. We hypothesised that a low EEG-vigilance state immediately before a reaction task would entail a longer RT. Shorter RTs were expected for a high EEG-vigilance state. METHODS: 24 female students performed an easy visual discrimination task while an electroencephalogram (EEG) was recorded. The vigilance stages of 1-sec EEG-segments before stimulus presentation were classified automatically using the computer-based Vigilance Algorithm Leipzig (VIGALL). The mean RTs of each EEG vigilance stage were calculated for each subject. A paired t-test for the EEG vigilance main stage analysis (A vs. B) and a variance analysis for repeated measures for the EEG-vigilance sub-stage analysis (A1, A2, A3, B1, B2/3) were calculated. RESULTS: Individual mean RT was significantly shorter for events following the high EEG-vigilance stage A compared to the lower EEG-vigilance stage B. The main effect of the sub-stage analysis was marginal significant. A trend of gradually increasing RT was observable within the EEG-vigilance stage A. CONCLUSION: We conclude that an automatically classified low EEG-vigilance level is associated with an increased RT. Thus, intra-individual variances in cognitive test might be explainable in parts by the individual state of EEG-vigilance. Therefore, the accuracy of neuro-cognitive investigations might be improvable by simultaneously controlling for vigilance shifts using the EEG and VIGALL. PMID- 21816116 TI - Effect of sulfur concentration on the morphology of carbon nanofibers produced from a botanical hydrocarbon. AB - Carbon nanofibers (CNF) with diameters of 20-130 nm with different morphologies were obtained from a botanical hydrocarbon: Turpentine oil, using ferrocene as catalyst source and sulfur as a promoter by simple spray pyrolysis method at 1,000 degrees C. The influence of sulfur concentration on the morphology of the carbon nanofibers was investigated. SEM, TEM, Raman, TGA/DTA, and BET surface area were employed to characterize the as-prepared samples. TEM analysis confirms that as-prepared CNFs have a very sharp tip, bamboo shape, open end, hemispherical cap, pipe like morphology, and metal particle trapped inside the wide hollow core. It is observed that sulfur plays an important role to promote or inhibit the CNF growth. Addition of sulfur to the solution of ferrocene and turpentine oil mixture was found to be very effective in promoting the growth of CNF. Without addition of sulfur, carbonaceous product was very less and mainly soot was formed. At high concentration of sulfur inhibit the growth of CNFs. Hence the yield of CNFs was optimized for a given sulfur concentration. PMID- 21816117 TI - Linoleic acid intake, plasma cholesterol and 10-year incidence of CHD in 20,000 middle-aged men and women in the Netherlands. AB - We studied the associations of a difference in linoleic acid or carbohydrate intake with plasma cholesterol levels and risk of CHD in a prospective cohort study in the Netherlands. Data on diet (FFQ) and plasma total and HDL-cholesterol were available at baseline (1993-7) of 20,069 men and women, aged 20-65 years, who were initially free of CVD. Incidence of CHD was assessed through linkage with mortality and morbidity registers. During an average of 10 years of follow up, 280 CHD events occurred. The intake of linoleic acid ranged from 3.6 to 8.0 % of energy (en%), whereas carbohydrate intake ranged from 47.6 to 42.5 en% across quintiles of linoleic acid intake. Linoleic acid intake was inversely associated with total cholesterol and HDL-cholesterol in women but not in men. Linoleic acid intake was not associated with the ratio of total to HDL-cholesterol. No association was observed between linoleic acid intake and CHD incidence, with hazard ratios varying between 0.83 and 1.00 (all P>0.05) compared to the bottom quintile. We conclude that a 4-5 en% difference in linoleic acid or carbohydrate intake did not translate into either a different ratio of total to HDL cholesterol or a different CHD incidence. PMID- 21816118 TI - Alterations in microbiota and fermentation products in equine large intestine in response to dietary variation and intestinal disease. AB - We aimed to determine the effects of variations in dietary composition on equine gut microbiota and their fermentation products, and proposed that dietary modifications profoundly affect microbial ecosystems and their metabolites. Bacterial communities within the large intestine of three groups of horses were compared using oligonucleotide-RNA hybridisation methodology. Each group consisting of six horses was maintained on (1) a grass-only diet, (2) a concentrate diet (i.e. supplemented with hydrolysable carbohydrates) and (3) a concentrate diet but horses were affected by simple colonic obstruction and distension (SCOD), a prevalent form of dietary-induced intestinal disease. We show that in response to dietary change and intestinal disease, there is a progressive and significant increase in Lachnospiraceae, the Bacteroidetes assemblage and the lactic acid-producing, Bacillus-Lactobacillus-Streptococcus (BLS) group. In contrast, there is a corresponding decrease in the proportion of obligate fibrolytic, acid-intolerant bacteria, Fibrobacter and Ruminococcaceae. Assessment of monocarboxylic acids indicated that there are significantly higher concentrations of lactic acid in the colonic contents of horses maintained on a concentrate diet and those suffering from SCOD, correlating with the observed increase in the population abundance of the BLS group. However, the population size of the Veillonellaceae (lactate utilisers) remained constant in each study group. The inability of this group to respond to increased lactic acid may be a contributory factor to the build-up of lactic acid observed in horses fed a concentrate diet and those suffering from SCOD. PMID- 21816114 TI - Cruciform structures are a common DNA feature important for regulating biological processes. AB - DNA cruciforms play an important role in the regulation of natural processes involving DNA. These structures are formed by inverted repeats, and their stability is enhanced by DNA supercoiling. Cruciform structures are fundamentally important for a wide range of biological processes, including replication, regulation of gene expression, nucleosome structure and recombination. They also have been implicated in the evolution and development of diseases including cancer, Werner's syndrome and others.Cruciform structures are targets for many architectural and regulatory proteins, such as histones H1 and H5, topoisomerase IIbeta, HMG proteins, HU, p53, the proto-oncogene protein DEK and others. A number of DNA-binding proteins, such as the HMGB-box family members, Rad54, BRCA1 protein, as well as PARP-1 polymerase, possess weak sequence specific DNA binding yet bind preferentially to cruciform structures. Some of these proteins are, in fact, capable of inducing the formation of cruciform structures upon DNA binding. In this article, we review the protein families that are involved in interacting with and regulating cruciform structures, including (a) the junction-resolving enzymes, (b) DNA repair proteins and transcription factors, (c) proteins involved in replication and (d) chromatin-associated proteins. The prevalence of cruciform structures and their roles in protein interactions, epigenetic regulation and the maintenance of cell homeostasis are also discussed. PMID- 21816119 TI - Anticarcinogenic effect of probiotic fermented milk and chlorophyllin on aflatoxin-B1-induced liver carcinogenesis in rats. AB - The present investigation was carried out to evaluate the hepatoprotective effect of probiotic fermented milk (FM) containing Lactobacillus rhamnosus GG and Lactobacillus casei strain Shirota, alone as well as in combination with chlorophyllin (CHL) as an antioxidant agent in male Wistar rats administered aflatoxin-B1 (AFB1). AFB1 was injected intraperitoneally at the rate of 450 MUg/kg body weight per animal twice a week for 6 weeks, maintaining an equal time interval between the two consecutive AFB1 administrations. A total of 125 male Wistar rats were randomly allocated to five groups, each group having twenty-five animals. Group I was offered FM containing L. rhamnosus GG and L. casei strain Shirota. Group II was administered AFB1 and served as the control group; group III was administered FM-AFB1, in which besides administering AFB1, FM was also offered. Group IV was offered CHL and AFB1, and group V was offered both FM and CHL along with AFB1. The rats were euthanised at the 15th and 25th week of the experiment and examined for the biochemical and hepatopathological profile. A significant reduction in thiobarbituric acid-reactive substances (TBARS) was observed in the FM-CHL-AFB1 group compared with the AFB1 control group. FM alone or in combination with CHL was found to show a significant (P < 0.05) hepatoprotective effect by lowering the levels of TBARS and by enhancing the activities of antioxidant enzymes such as glutathione peroxidase, superoxide dismutase, catalase and glutathione-S-transferase, indicating that probiotic FM alone or in combination with CHL possesses a potent protective effect against AFB1-induced hepatic damage. PMID- 21816120 TI - Perialveolar bacterial microbiota and bacteraemia after dental alveolitis in adult rats that had been subjected to neonatal malnutrition. AB - The aim of the present study was to analyse the bacteriological factors during the process of dental alveolitis, relating it to a higher incidence of bacteraemia in adult rats subjected to neonatal malnutrition. We used forty male Wistar rats, suckled by mothers fed a diet during lactation containing 17 % protein in the nourished group (N) or 8 % protein in the undernourished group (UN). After weaning, the animals were given the Labina standard diet. After 90 d, these animals underwent upper right incisor extraction and induction of alveolitis. The oral microbiota was obtained using a swab and blood culture through venous blood. These procedures were performed before the extraction, 5 min after extraction, on the 21st day after alveolitis for groups N-21 and UN-21 and on the 28th day after alveolitis for groups N-28 and UN-28. Data were expressed as means and standard deviations for parametric data, and as medians and interquartile intervals for non-parametric data. Statistical significance was considered by assuming a critical level of 5 %. Before and after extraction, lower bacterial growth was observed per colony-forming unit (CFU) in the perialveolar region of the upper right incisors of undernourished animals, while the opposite was true after alveolitis, when a larger number of CFU was observed in these animals. The percentage of positive blood cultures obtained after alveolitis was greater in the undernourished animals. The present study thus demonstrated the influence of neonatal malnutrition in the perialveolar microbiota and in the development of bacteraemia after dental alveolitis. PMID- 21816121 TI - An unusual dark pigmentation on the tympanic membrane. AB - OBJECTIVE: To report an extremely rare case of dark pigmentation on the tympanic membrane due to alkaptonuria, and to discuss the probable association between this condition and hearing loss. CASE REPORT: A 58-year-old man with alkaptonuria was admitted with tinnitus and hearing loss in both ears. Physical examination showed bluish-black pigmentation on the helixes of both ears and both sclerae. Otoscopic examination revealed dark discolouration of both tympanic membranes. Audiological evaluation revealed mixed high frequency hearing loss in both ears. Tympanometric examination revealed type A tympanograms bilaterally, and absence of acoustic reflexes both ipsilaterally and contralaterally. Computed tomography of the temporal bones revealed no abnormality. CONCLUSION: Clinicians should consider alkaptonuria in the differential diagnosis of patients with abnormal tympanic membrane pigmentation and hearing loss. PMID- 21816122 TI - The parasitic nematodes Hysterothylacium sp. type MB larvae as bioindicators of lead and cadmium: a comparative study of parasite and host tissues. AB - Cadmium and lead concentrations were compared in tissues of cutlassfish, Trichiurus lepturus L., its intestinal nematode Hysterothylacium sp. type MB larvae, and in water from the same location in the Sea of Oman. Metal accumulation in hosts, parasites and sea water was measured by ICP-OES. Hysterothylacium larvae from the intestinal lumen and visceral cavity showed much higher metal concentrations than in host tissues or sea water. Statistical analyses revealed no significant differences in metal accumulation between infected and uninfected hosts. Cadmium concentration in the host muscle was lower than in intestine, liver and gonad tissues. The mean concentrations of lead and cadmium in nematodes were 289.03 and 81.5 times higher than in host intestine, 188.4 and 225 times higher than in host muscle, 108.6 and 65.3 times higher than in host gonads, 70.5 and 19.5 times higher than in host liver and 3351 and 148 times higher than in sea water. The results show the value of this and possibly related nematodes as bioindicators of heavy metals and their potential use in environmental studies. PMID- 21816123 TI - mGlu5 and adenosine A2A receptor interactions regulate the conditioned effects of cocaine. AB - Adenosine A2A receptors and metabotropic glutamate type 5 (mGlu5) receptors are co-localized in the striatum and can functionally interact to regulate drug seeking. We further explored this interaction using antagonism of mGlu5 receptors with 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine (MTEP) in combination with genetic deletion of A2A receptors. The conditioned rewarding and locomotor activating properties of cocaine were evaluated via conditioned place preference (CPP). Vehicle-treated mice of both genotypes expressed a CPP to cocaine while MTEP abolished cocaine CPP in wild-type, but not A2A knockout, mice. These results were mirrored when conditioned hyperactivity was assessed. In contrast, MTEP attenuated the acute locomotor-activating properties of cocaine similarly in both genotypes. These data provide evidence for a functional interaction between adenosine A2A and mGlu5 receptors in mediating the conditioned effects of cocaine but not direct cocaine-induced hyperactivity. This functional interaction is supported by modulation of 4-(2-[7-amino-2-[2-furyl][1,2,4]triazolol[2,3 a][1,3,5]triazin-5-yl-amino]ethyl)phenol ([125I]ZM241385) binding to the A2A receptor by MTEP. PMID- 21816124 TI - Conserved peptide sequences bind to actin and enolase on the surface of Plasmodium berghei ookinetes. AB - The description of Plasmodium ookinete surface proteins and their participation in the complex process of mosquito midgut invasion is still incomplete. In this study, using phage display, a consensus peptide sequence (PWWP) was identified in phages that bound to the Plasmodium berghei ookinete surface and, in selected phages, bound to actin and enolase in overlay assays with ookinete protein extracts. Actin was localized on the surface of fresh live ookinetes by immunofluorescence and electron microscopy using specific antibodies. The overall results indicated that enolase and actin can be located on the surface of ookinetes, and suggest that they could participate in Plasmodium invasion of the mosquito midgut. PMID- 21816126 TI - Radioembolization for hepatocellular carcinoma. AB - Radioembolization is a form of brachytherapy in which intra-arterially injected (90)Y-loaded microspheres serve as sources for internal radiation purposes. It produces average disease control rates above 80% and is usually very well tolerated. Main complications do not result from the microembolic effect, even in patients with portal vein occlusion, but rather from an excessive irradiation of non-target tissues including the liver. All the evidence that support the use of radioembolization in HCC is based on retrospective series or non-controlled prospective studies. However, reliable data can be obtained from the literature, particularly since the recent publication of large series accounting for nearly 700 patients. When compared to the standard of care for the intermediate and advanced stages (transarterial embolization and sorafenib), radioembolization consistently provides similar survival rates. Two indications seem particularly appealing in the boundaries of these stages for first-line radioembolization. First, the treatment of patients straddling between the intermediate and advanced stages (intermediate patients with bulky or bilobar disease that are considered poor candidates for TACE, and advanced patients with solitary tumors invading a segmental or lobar branch of the portal vein). Second, the treatment of patients that are slightly above the criteria for resection, ablation or transplantation, for which downstaging could open the door for a radical approach. Radioembolization can also be used to treat patients progressing to TACE or sorafenib. With a number of clinical trials underway, the available evidence shows that it adds a significant value to the therapeutic weaponry against HCC of tertiary care centers dealing with this major cancer problem. PMID- 21816127 TI - Shocks burden and increased mortality in implantable cardioverter-defibrillator patients. AB - BACKGROUND: Implantable cardioverter-defibrillator (ICD) shocks are associated with an increased risk of death. It is unclear whether ICD shocks are detrimental per se or a marker of higher risk patients. OBJECTIVE: We aimed to assess the association between ICD shocks and time to death after correction for baseline mortality based on the Seattle Heart Failure Model (SHFM). METHODS: The primary analysis compared time-to-death between patients receiving no shocks and patients receiving shocks of any type adjusted for SHFM score at time of implantation and other comorbidities. Subgroup analyses were performed to further describe the relationship between shocks and mortality risk. RESULTS: Over a median follow-up of 41 months (interquartile range 23-64), one or more shock episodes occurred in 59% of 425 patients and 40% of the patients died. Patients receiving shocks of any type had increased risk of death (hazard ratio 1.55; 95% confidence interval 1.07-2.23; P = .02) versus patients receiving no shocks. While patients with 1-5 days with shock (shock days) did not show evidence of increased risk of death (1.30 [0.88-1.94]; P = 0.19), those with 6-10 shock days (2.22 [1.21-4.08]; P <.01) and >10 shock days (3.66 [1.86-7.19]; P <.01) had increasingly higher risk. There was no increased hazard for death (0.73 [0.34-1.57]; P = .41) in patients treated only with antitachycardia pacing (ATP). CONCLUSION: ICD shocks were associated with increased mortality risk after adjustment for SHFM-predicted mortality, and the burden of shocks played a role in this association. ATP did not increase mortality risk, suggesting that shocks may themselves be detrimental. PMID- 21816128 TI - Echocardiographic predictors of frequency of paroxysmal atrial fibrillation (AF) and its progression to persistent AF in hypertensive patients with paroxysmal AF: results from the Japanese Rhythm Management Trial II for Atrial Fibrillation (J RHYTHM II Study). AB - BACKGROUND: Little is known about associations among echocardiographic variables, frequency of atrial fibrillation (AF), and progression from paroxysmal to persistent AF. OBJECTIVE: The purpose of this study was to investigate echocardiographic predictors of frequency of paroxysmal AF and its progression to persistent AF in hypertensive patients with paroxysmal AF. METHODS: We used data from 286 patients with paroxysmal AF and hypertension in the Japanese Rhythm Management Trial II for Atrial Fibrillation (J-RHYTHM II Study). Echocardiographic evaluation was performed at baseline. Endpoints were (1) percent of AF days measured daily by transtelephonic monitoring over 1 year and (2) development of persistent AF, defined as incidence of AF lasting for longer than 7 days and/or need for electrical cardioversion. Univariate and multivariate linear regression analysis was performed to evaluate the association between echocardiographic variables and percent of AF days. Cox proportional hazards analysis was used to examine the association between echocardiographic variables and development of persistent AF. RESULTS: Among echocardiographic variables, increased left atrial dimension (LAD) was associated with more AF days and development of persistent AF: a 10-mm increase in LAD was associated with a 6.5% increase in AF days (95% confidence interval 2.7%-10.3%) and an 84% increased risk of developing persistent AF (hazard ratio 1.84, 95% confidence interval 1.28 2.67). These associations remained significant after adjustment for age, sex, and other potential confounding factors. CONCLUSION: Increased LAD is associated with more AF days and progression from paroxysmal to persistent AF in patients with paroxysmal AF and hypertension. Increased LAD may be a good echocardiographic predictor of AF frequency and progression. PMID- 21816129 TI - Key role of the molecular autopsy in sudden unexpected death. AB - Sudden Cardiac Death (SCD) is a major and tragic complication of a number of cardiovascular diseases. While in the older populations, SCD is most frequently caused by underlying coronary artery disease and heart failure, in those aged under 40 years, the causes of SCD commonly include genetic disorders, such as inherited cardiomyopathies and primary arrhythmogenic diseases. As part of the evaluation of families in which SCD has occurred, the role of genetic testing has evolved as an important feature in both establishing an underlying diagnosis and in screening at-risk family relatives. Specifically, in cases where no definitive cause is identified at postmortem, i.e. Sudden Unexpected Death (SUD), the "molecular autopsy" has emerged as a key process in the investigation of the cause of death. The combination of clinical and genetic evaluation of families in which SUD has occurred provides a platform for early initiation of therapeutic and prevention strategies, with the ultimate goal to reduce sudden death among the young in our communities. PMID- 21816130 TI - Brugada syndrome and right ventricular conduction delay: what else? PMID- 21816131 TI - CD55 deficiency protects against atherosclerosis in ApoE-deficient mice via C3a modulation of lipid metabolism. AB - Atherosclerosis, the leading cause of death in the Western world, is driven by chronic inflammation within the artery wall. Elements of the complement cascade are implicated in the pathogenesis, because complement proteins and their activation products are found in the atherosclerotic plaque. We examined the role of CD55, a membrane inhibitor of the complement component 3 (C3) convertase, which converts C3 into C3a and C3b, in atherosclerosis. CD55-deficient (CD55(-/ )) mice were crossed onto the atherosclerosis-prone apolipoprotein E (apoE) deficient (apoE(-/-)) background. High fat-fed male apoE(-/-)/CD55(-/-) mice were strongly protected from developing atherosclerosis compared with apoE(-/-) controls. Lipid profiling showed significantly lower levels of triglycerides, nonesterified fatty acids, and cholesterol in apoE(-/-)/CD55(-/-) mice than that in controls after high-fat feeding, whereas body fat in apoE(-/-)/CD55(-/-) mice content was increased. Plasma levels of C3 fell, whereas concentrations of C3adesArg (alias acylation stimulating protein; ASP), produced by serum carboxypeptidase N-mediated desargination of C3a, increased in nonfasted high fat fed apoE(-/-)/CD55(-/-) mice, indicating complement activation. Thus, complement dysregulation in the absence of CD55 provoked increased C3adesArg production that, in turn, caused altered lipid handling, resulting in atheroprotection and increased adiposity. Interventions that target complement activation in adipose tissue should be explored as lipid-decreasing strategies. PMID- 21816132 TI - Competitive immunoassay for analysis of vitamin B(12). AB - In the current work, direct competitive enzyme-linked immunosorbent assay (ELISA) was developed for derivatized vitamin B(12) by generating chicken egg yolk immunoglobulins (IgY) against derivatized vitamin B(12) and purified using affinity chromatography. Checkerboard assay was performed with vitamin B(12) antibody and vitamin B(12)-alkaline phosphatase conjugate followed by its conjugate characterization using ultraviolet (UV) spectroscopy and high performance liquid chromatography (HPLC). The limit of detection was 10 ng/ml with a linear working range of 10 to 10,000 ng/ml. The affinity constant (K(a)) of the vitamin B(12) antibody was found to be 4.23*10(8) L/mol. Cross-reactivity with other water-soluble vitamins was found to be less than 0.01% except for analogs of vitamin B(12) that showed 12% to 35%. The intra- and interassay coefficients of variation were found to be in the ranges from 0.0005% to 1.2% and 0.009% to 1.03%, respectively. The assay was validated with the HPLC method in terms of sensitivity, specificity, precision, and recovery of vitamin B(12) with spiked multivitamin injections, tablets, capsules, and chocolates. The HPLC method had a detection limit of 500 ng/ml with a linear working range of 1000 to 10,000 ng/ml. After extraction of vitamin B(12) using Amberlite XAD, the developed ELISA method correlated well with the established HPLC method with a correlation coefficient of 0.90. PMID- 21816134 TI - Molecular organization of antibiotic amphotericin B in dipalmitoylphosphatidylcholine monolayers induced by K(+) and Na(+) ions: the Langmuir technique study. AB - The effect of potassium (K(+)) and sodium (Na(+)) ions on the self-association of antibiotic amphotericin B (AmB) in the lipid membrane was reported. Mixed Langmuir monolayers of AmB and dipalmitoylphosphatidylcholine (DPPC) were investigated by recording surface pressure-area isotherms spread on aqueous buffers containing physiological concentration of K(+) and Na(+) ions. The analyses of the pi-A isotherms and compressional modulus curves indicate the interactions in the AmB-DPPC system. The strength of the AmB-DPPC interactions and the stability of the mixed monolayers were examined on the basis of the excess free energy of mixing values. The obtained results proved a high affinity of AmB towards lipids induced by the presence of K(+) than Na(+) ions. The most stable monolayers in the presence of K(+) and Na(+) ions were formed by AmB and DPPC with the 1:1 and 2:1 stoichiometry. The understanding of the AmB aggregation processes at the molecular level should contribute to elucidate the mechanisms of action and toxicity of this widely used drug. The presented results are potentially valuable in respect to develop more efficient and less toxic AmB formulations. PMID- 21816133 TI - Outer membrane phospholipase A in phospholipid bilayers: a model system for concerted computational and experimental investigations of amino acid side chain partitioning into lipid bilayers. AB - Understanding the forces that stabilize membrane proteins in their native states is one of the contemporary challenges of biophysics. To date, estimates of side chain partitioning free energies from water to the lipid environment show disparate values between experimental and computational measures. Resolving the disparities is particularly important for understanding the energetic contributions of polar and charged side chains to membrane protein function because of the roles these residue types play in many cellular functions. In general, computational free energy estimates of charged side chain partitioning into bilayers are much larger than experimental measurements. However, the lack of a protein-based experimental system that uses bilayers against which to vet these computational predictions has traditionally been a significant drawback. Moon & Fleming recently published a novel hydrophobicity scale that was derived experimentally by using a host-guest strategy to measure the side chain energetic perturbation due to mutation in the context of a native membrane protein inserted into a phospholipid bilayer. These values are still approximately an order of magnitude smaller than computational estimates derived from molecular dynamics calculations from several independent groups. Here we address this discrepancy by showing that the free energy differences between experiment and computation become much smaller if the appropriate comparisons are drawn, which suggests that the two fields may in fact be converging. In addition, we present an initial computational characterization of the Moon & Fleming experimental system used for the hydrophobicity scale: OmpLA in DLPC bilayers. The hydrophobicity scale used OmpLA position 210 as the guest site, and our preliminary results demonstrate that this position is buried in the center of the DLPC membrane, validating its usage in the experimental studies. We further showed that the introduction of charged Arg at position 210 is well tolerated in OmpLA and that the DLPC bilayers accommodate this perturbation by creating a water dimple that allows the Arg side chain to remain hydrated. Lipid head groups visit the dimple and can hydrogen bond with Arg, but these interactions are transient. Overall, our study demonstrates the unique advantages of this molecular system because it can be interrogated by both computational and experimental practitioners, and it sets the stage for free energy calculations in a system for which there is unambiguous experimental data. This article is part of a Special Issue entitled: Membrane protein structure and function. PMID- 21816135 TI - Copy number variation of CCL3L1 influences asthma risk by modulating IL-10 expression. AB - BACKGROUND: Copy number of Chemokine ligand 3-like 1 (CCL3L1) is associated with various immune disorders. This study was conducted to assess the role of CCL3L1 in asthma by both association analyses of human subjects and in vitro functional analyses. METHODS: We analyzed the copy number of the CCL3L1 gene in 533 Korean subjects (372 controls and 161 asthma patients) by real-time PCR, and investigated the effect of recombinant CCL3L1 protein on THP-1 human monocytic cells that were stimulated with house dust mite extract. RESULTS: The mean copy number of CCL3L1 in asthma subjects was significantly lower than that of control subjects (3.18 vs. 3.75, p=0.001). A low copy number of <=1 was significantly associated with increased asthma risk with an odds ratio of 2.47, and a high copy number of >=5 was associated with decreased asthma risk with an odds ratio of 0.40. Subjects with <=1 copy of CCL3L1 had significantly lower mRNA levels of CCL3L1 in peripheral blood cells, and significantly higher serum IgE levels (p<0.05). In the house dust mite extract-simulated THP-1 monocytic cells, CCL3L1 protein dose-dependently up-regulated the expression of IL-10, an anti inflammatory cytokine. CONCLUSION: Copy number of CCL3L1 may influence asthma risk by modulating IL-10 expression. PMID- 21816136 TI - The diagnostic and prognostic significance of soluble urokinase plasminogen activator receptor in systemic inflammatory response syndrome. AB - OBJECTIVES: This study was intended to investigate the value of suPAR, C-reactive protein (CRP) and procalcitonin (PCT) in the determination and prognosis of systemic inflammatory response syndrome (SIRS) patients. METHODS: The study was performed among patients with at least two SIRS criteria. PCT, CRP and suPAR were analyzed from the blood specimens taken. RESULTS: Eighty-five patients were enrolled in the SIRS group (44 bacteremia, 20 urinary tract infection, 12 pneumonia and 9 non-infection), and 53 individuals in the control group. A significant correlation was determined between suPAR, PCT and CRP values in both groups (P<0.0001). A suPAR cutoff value of 2.8ng/mL was associated with an NPV of 87% and PPV of 91%, with 92% sensitivity and 85% specificity. A relatively high suPAR level that might predict fatality was also determined in fatal cases (P=0.001). CONCLUSION: suPAR possesses high sensitivity and specificity levels in terms of differential diagnosis, and high suPAR levels can predict fatality. PMID- 21816137 TI - Utility of imaging for nutritional intervention studies in Alzheimer's disease. AB - Alzheimer's disease (AD) is a multi-factorial neurodegenerative disorder and the leading cause of dementia, wherein synapse loss is the strongest structural correlate with cognitive impairment. Basic research has shown that dietary supply of precursors and co-factors for synthesis of neuronal membranes enhances the formation of synapses. Daily intake of a medical food containing a mix of these nutrients for 12 weeks in humans improved memory, measured as immediate and delayed verbal recall by the Wechsler Memory Scale-revised, in patients with very mild AD (MMSE 24-26). An improvement of immediate verbal recall was noted following 24 weeks of intervention in an exploratory extension of the study. These data suggest that the intervention may improve synaptic formation and function in early AD. Here we review emerging technologies that help identify changes in pathological hallmarks in AD, including synaptic function and loss of connectivity in the early stages of AD, before cognitive and behavioural symptoms are observable. These techniques include the detection of specific biomarkers in the cerebrospinal fluid, as well as imaging procedures such as fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET), amyloid PET, structural/functional magnetic resonance imaging, diffusion tensor imaging, magnetoencephalography (MEG) and electroencephalography (EEG). Such techniques can provide new insights into the functional and structural changes in the brain over time, and may therefore help to develop more effective AD therapies. In particular, nutritional intervention studies that target synapse formation and function may benefit from these techniques, especially FDG-PET and EEG/MEG employed in the preclinical or early stages of the disease. PMID- 21816139 TI - Non-nutritional uses of nutrients. AB - Nutrients are generally conceived as dietary substances which the body requires more-or-less continuously, within a particular dosage range, to protect against developing the characteristic syndromes that occur when they are deficient. However some nutrients - when given apart from their usual food sources or at higher doses than those obtained from the diet - can also exercise pharmacologic effects, particularly on the CNS. Some, like folic acid, can promote neuronal development; others, like the neurotransmitter precursors tryptophan, choline, and histidine, can modulate the rates at which their products are synthesized; yet others, like uridine and omega-3 fatty acids, can increase the production of synaptic membrane, and thus promote synaptogenesis. In order for the nutrient to produce such effects, its plasma levels must be allowed to increase substantially when larger amounts are consumed; an unsaturated or competitive system must exist for transporting the nutrient across the blood-brain barrier; and the enzymes that convert the nutrient to its pharmacologically-active form must also be unsaturated with substrate. Nutrient mixtures chosen for their pharmacologic effects (and general lack of serious side-effects) are presently used for ameliorating several conditions, and more such uses can be anticipated. PMID- 21816138 TI - Effect of treatment of high fat fed/low dose streptozotocin-diabetic rats with Ilepatril on vascular and neural complications. AB - We have previously shown that treating streptozotocin-induced diabetic rats, an animal model of type 1 diabetes, with Ilepatril (an inhibitor of neutral endopeptidase and angiotensin converting enzyme (ACE)) improves vascular and neural functions. In this study we sought to determine the effect of Ilepatril treatment of high fat fed/low dose streptozotocin-diabetic rats, a model for type 2 diabetes, on vascular and neural complications. Following 8 weeks on a high fat diet rats were treated with 30 mg/kg streptozotocin (i.p.) and after 4 additional weeks a group of these rats was treated for 12 weeks with Ilepatril followed by analysis of neural and vascular functions. Included in these studies were age matched control rats and rats fed a high fat diet and treated with or without Ilepatril. Diabetic and diet induced obese rats have characteristics of insulin resistance, slowing of nerve conduction velocity, thermal hypoalgesia, reduction in intraepidermal nerve fiber density in the hindpaw and impairment in vascular relaxation to acetylcholine and calcitonin gene-related peptide in epineurial arterioles of the sciatic nerve. Treatment with Ilepatril was efficacious in improving all of these endpoints although improvement of insulin resistance in diabetic rats was minimal. These studies suggest that dual inhibition of angiotensin converting enzyme and neutral endopeptidase activity of type 2 diabetic rats is an effective approach for treatment of diabetic neural and vascular complications. PMID- 21816140 TI - Functional foods and dietary supplements: products at the interface between pharma and nutrition. AB - It is increasingly recognized that most chronic diseases of concern today are multifactorial in origin. To combat such diseases and adverse health conditions, a treatment approach where medicines and nutrition complement each other may prove to be the most successful. Within nutrition, apart from (disease-related) dietetic regimes, an increasing number of functional foods and dietary supplements, each with their own health claim, are marketed. These food items are considered to be positioned between traditional foods and medicines at the so called 'Pharma-Nutrition Interface'. This paper encompasses aspects related to the regulatory framework and health claims of functional foods and dietary supplements. The use of functional foods or dietary supplements may offer opportunities to reduce health risk factors and risk of diseases, both as monotherapy and in combination with prescription drugs. Nevertheless, the potential caveats of these products should not be overlooked. These caveats include the increased risk for food-drug interactions due to the elevated amounts of specific functional ingredients in the diet, and the stimulation of self medication potentially resulting in lower adherence to drug therapy. Health technology assessments should be used more to compare the cost-effectiveness and benefit-risk ratios of drugs, functional foods and dietary supplements, and to evaluate the added value of functional foods or dietary supplements to drug therapy. PMID- 21816141 TI - Glycan recognition at the interface of the intestinal immune system: target for immune modulation via dietary components. AB - The intestinal mucosa is constantly exposed to the luminal content, which includes micro-organisms and dietary components. Prebiotic non-digestible oligosaccharides may be supplemented to the diet to exert modulation of immune responses in the intestine. Short chain galacto- and long chain fructo oligosaccharides (scGOS/lcFOS), functionally mimicking oligosaccharides present in human milk, have been reported to reduce the development of allergy through modulation of the intestinal microbiota and immune system. Nonetheless, the underlying working mechanisms of scGOS/lcFOS are unclear. Intestinal epithelial cells lining the mucosa are known to express carbohydrate (glycan)-binding receptors that may be involved in modulation of the mucosal immune response. This review aims to provide an overview of glycan-binding receptors, in particular galectins, which are expressed by intestinal epithelial cells and immune cells. In addition, their involvement in health and disease will be addressed, especially in food allergy and inflammatory bowel disease, diseases originating from the gastro-intestinal tract. Insight in the recognition of glycans in the intestinal tract may open new avenues for the treatment of intestinal inflammatory diseases by either nutritional concepts or pharmacological intervention. PMID- 21816142 TI - An intimate tete-a-tete - how probiotic lactobacilli communicate with the host. AB - Pharmaceutical agents are routinely used in the treatment of gastrointestinal disorders and their role as modulators of host cell responses is well characterized. In contrast, the understanding of the molecular mechanisms, which determine the role of probiotics, i.e. health-promoting bacteria, as host cell modulators is still in its infancy. Both in vitro and in vivo studies are just starting to reveal the capability of probiotic lactobacilli to modulate host cell signaling networks and the associated influences on downstream regulatory pathways, including modulation of mucosal cytokine profiles that dictate host immune functions. The communication between probiotic lactobacilli and intestinal host cells is multifactorial and involves an integrative repertoire of receptors on the host side that recognize multiple effector molecules on the bacterial side, of which most have been found to be cell wall- or cell surface-associated compounds and proteins. This review describes the discovery of these bacterial effector molecules and their role in strain- and species-specific modulation of host signaling pathways. Unraveling the mechanisms responsible for probiotic-host interactions will progress this research field towards molecular science and will provide markers for probiotic product quality control as well as host-response efficacy. These developments can ultimately lead to a more dedicated, personalized application of probiotics with strong molecular and scientific support for health promotion. PMID- 21816143 TI - Taurine chloramine inhibits osteoclastogenesis and splenic lymphocyte proliferation in mice with collagen-induced arthritis. AB - Taurine chloramine (TauCl) is produced by activated neutrophils in the inflammatory joint cavities of rheumatoid arthritis and is known to have anti inflammatory and anti-arthritic effects. However, the mechanisms underlying the anti-arthritic effect of TauCl have not been elucidated. Here, we investigated that mechanism using a collagen-induced arthritis (CIA) mouse model. DBA/1J mice were immunized with bovine type II collagen to induce CIA and were given daily subcutaneous injections of TauCl from the day of first collagen immunization. Severity of arthritis was scored by paw swelling and the arthritis score system. At the 8th week, mice were sacrificed for histological examination using hematoxylin and eosin, safranin-O and tartrate-resistant acid phosphatase (TRAP) staining. Effects of TauCl on osteoclastogenesis from bone marrow-derived preosteoclasts and proliferation of the lymphocytes obtained from spleens of CIA mice were determined. TauCl significantly attenuated the severity of paw swelling and reduced arthritis score in CIA mice. TauCl treated CIA mice showed significant reductions of synovial inflammation, cartilage damage and bone erosion. The number of TRAP-positive cells in the joints of TauCl treated CIA mice was reduced. TauCl inhibited osteoclastogenesis from the RANKL treated bone marrow-derived preosteoclasts in a dose-dependent manner. TauCl also inhibited the proliferation of splenic lymphocytes obtained from CIA mice. In conclusion, TauCl attenuated the severity of CIA by inhibiting lymphocyte proliferation and osteoclastogenesis. Combined our results suggest that TauCl produced endogenously in inflamed joints may suppress the development of rheumatoid arthritis and that TauCl may be used for therapeutic treatment of rheumatoid arthritis. PMID- 21816144 TI - In vitro pharmacology of aripiprazole, its metabolite and experimental dopamine partial agonists at human dopamine D2 and D3 receptors. AB - Aripiprazole is the first dopamine D(2)/D(3) receptor partial agonist successfully developed and ultimately approved for treatment of a broad spectrum of psychiatric and neurological disorders. Aripiprazole's dopamine D(2) and serotonin 5-HT(1A) receptor partial agonist activities have been postulated to confer clinical efficacy without marked sedation, and a relatively favorable overall side-effect profile. Using aripiprazole's unique profile as a benchmark for new dopamine partial agonist development may facilitate discovery of new antipsychotics. We conducted an in vitro comparative analysis between aripiprazole, and its human metabolite OPC-14857 (7-(4-[4-(2,3-dichlorophenyl)-1 piperazinyl)butoxy)-2(1H)-quinolinone)); RGH-188 (trans-1-[4-[2-[4-(2,3 dichlorophenyl)piperazine-1-yl]ethyl]cyclohexyl]-3,3-dimethylurea), and its metabolite didesmethyl-RGH-188 (DDM-RGH-188); as well as bifeprunox, sarizotan, N desmethylclozapine (NDMC; clozapine metabolite), and SDZ 208-912 (N-[(8alpha)-2 chloro-6-methylergolin-8-yl]-2,2-dimethylpropanamide). In vitro pharmacological assessment included inhibition of forskolin-stimulated cAMP accumulation and the reversal of dopamine-induced inhibition in clonal Chinese hamster ovary cell lines expressing D(2S), D(2L), D(3) Ser-9 and D(3) Gly-9 for human dopamine receptors. All test compounds behaved as dopamine D(2)/D(3) receptor partial agonists. Aripiprazole's intrinsic activity at dopamine D(2S) and D(2L) receptors was similar to that of OPC-14857 and RGH-188; lower than that of dopamine and bifeprunox; and higher than that of DDM-RGH-188, SDZ 208-912, sarizotan, and NDMC. Aripiprazole's intrinsic activity at dopamine D(3) Ser-9 and D(3) Gly-9 receptors was similar to that of OPC-14857 and sarizotan; lower than that of dopamine, bifeprunox, RGH-188 and DDM-RGH-188; and higher than that of SDZ 208 912 and NDMC. A consolidated assessment of these findings may help defining the most appropriate magnitude of intrinsic activity at dopamine D(2)/D(3) receptors for clinical efficacy and safety. PMID- 21816145 TI - Modulatory effects of fisetin, a bioflavonoid, on hyperglycemia by attenuating the key enzymes of carbohydrate metabolism in hepatic and renal tissues in streptozotocin-induced diabetic rats. AB - Fisetin (3, 7, 3', 4'-tetrahydroxyflavone) is a bioflavonoid found in fruits and vegetables. It exhibits a wide variety of pharmacological properties, including antioxidant, antiinflammatory and anticarcinogenic effects. Recently we have reported the hypoglycemic actions of fisetin. Oral administration of fisetin (10mg/kg body weight) to diabetic rats for 30 days established a significant (P<0.05) decline in blood glucose and glycosylated hemoglobin levels and a significant (P<0.05) increase in plasma insulin level. In the present study the activities of key enzymes of carbohydrate metabolism were assayed to establish the modulatory actions of fisetin in maintaining the glucose homeostasis. The altered activities of key enzymes of carbohydrate metabolism such as hexokinase, pyruvate kinase, lactate dehydrogenase, glucose-6-phosphatase, fructose-1,6 bisphosphatase, glucose-6-phosphate dehydrogenase, glycogen synthase and glycogen phosphorylase in liver and kidney tissues of diabetic rats were significantly (P<0.05) reverted to near normalcy by the administration of fisetin. Thus, fisetin regulates carbohydrate metabolism by modulating the key regulatory enzymes in the hepatic and renal tissues of diabetic rats. PMID- 21816146 TI - Fatty acids and inflammation: the cutting edge between food and pharma. AB - Inflammation underlies many common conditions and diseases. Fatty acids can influence inflammation through a variety of mechanisms, including acting via cell surface and intracellular receptors/sensors that control inflammatory cell signalling and gene expression patterns. Some effects of fatty acids on inflammatory cells appear to be mediated by, or at least are associated with, changes in fatty acid composition of cell membranes. Changes in these compositions can modify membrane fluidity, lipid raft formation, cell signalling leading to altered gene expression, and the pattern of lipid and peptide mediator production. Cells involved in the inflammatory response are typically rich in the n-6 fatty acid arachidonic acid, but the contents of arachidonic acid and of the n-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) can be altered through oral administration of EPA and DHA. Eicosanoids produced from arachidonic acid have roles in inflammation. EPA also gives rise to eicosanoids and these may have differing properties from those of arachidonic acid-derived eicosanoids. EPA and DHA give rise to resolvins which are anti-inflammatory and inflammation resolving. Thus, fatty acid exposure and the fatty acid composition of human inflammatory cells influences their function. As a result of their anti inflammatory actions marine n-3 fatty acids have therapeutic efficacy in rheumatoid arthritis, although benefits in other inflammatory diseases and conditions have not been unequivocally demonstrated. The anti-inflammatory effects of marine n-3 fatty acids may contribute to their protective actions towards atherosclerosis, plaque rupture and cardiovascular mortality. The therapeutic dose of n-3 fatty acids is not clear. PMID- 21816147 TI - Both alpha2B- and alpha2C-adrenoceptor subtypes are involved in the mediation of centrally induced gastroprotection in mice. AB - alpha(2)-adrenoceptors are known to mediate gastroprotective effect in both acid dependent and acid-independent ulcer models. The aim of the present study was to determine, which of the three alpha(2)-adrenoceptor subtypes (alpha(2A), alpha(2B) or alpha(2C)) is responsible for this protection. Various alpha(2) adrenoceptor agonists and antagonists were administered intracerebroventricularly (i.c.v.) to C57BL/6 mice with deletion of genes encoding the different subtypes. The gastric mucosal damage was induced by orally injected acidified ethanol. Both the non-selective alpha(2)-adrenoceptor agonist clonidine (0.3-2.8 nmol) and the alpha(2B/C)-adrenoceptor subtype preferring agonist ST-91 (0.5-11.5 nmol) induced dose-dependent gastroprotective effect in wild type, alpha(2A)-, alpha(2B)- and alpha(2C)-KO mice. In contrast, the alpha(2A)-adrenoceptor subtype agonist oxymetazoline (0.07-84 nmol i.c.v.) reduced only slightly the development of ethanol-induced ulcers. The effect of clonidine was antagonized by the non selective antagonist yohimbine (25 nmol) and the alpha(2B/C)-adrenoceptor antagonist ARC 239 (10.4 nmol), but not by the alpha(2A)-adrenoceptor antagonist BRL 44408 (7.5 nmol). ARC 239 also reversed the effect of clonidine in alpha(2A) , alpha(2B)- and alpha(2C)-KO mice, while the selective alpha(2C)-adrenoceptor antagonist JP 1302 (52 nmol) antagonized that only in alpha(2B)-KO, but not in alpha(2A)- and alpha(2C)-KO mice. These results suggest that alpha(2B)- and alpha(2C)-adrenoceptor subtypes can equally contribute to the mediation of gastroprotective effect induced by alpha(2)-adrenoceptor agonists in mice. PMID- 21816148 TI - Antihypertensive, insulin-sensitising and renoprotective effects of a novel, potent and long-acting angiotensin II type 1 receptor blocker, azilsartan medoxomil, in rat and dog models. AB - The pharmacological profile of a novel angiotensin II type 1 receptor blocker, azilsartan medoxomil, was compared with that of the potent angiotensin II receptor blocker olmesartan medoxomil. Azilsartan, the active metabolite of azilsartan medoxomil, inhibited the binding of [(125)I]-Sar(1)-I1e(8)-angiotensin II to angiotensin II type 1 receptors. Azilsartan medoxomil inhibited angiotensin II-induced pressor responses in rats, and its inhibitory effects lasted 24h after oral administration. The inhibitory effects of olmesartan medoxomil disappeared within 24h. ID(50) values were 0.12 and 0.55 mg/kg for azilsartan medoxomil and olmesartan medoxomil, respectively. In conscious spontaneously hypertensive rats (SHRs), oral administration of 0.1-1mg/kg azilsartan medoxomil significantly reduced blood pressure at all doses even 24h after dosing. Oral administration of 0.1-3mg/kg olmesartan medoxomil also reduced blood pressure; however, only the two highest doses significantly reduced blood pressure 24h after dosing. ED(25) values were 0.41 and 1.3mg/kg for azilsartan medoxomil and olmesartan medoxomil, respectively. In renal hypertensive dogs, oral administration of 0.1-1mg/kg azilsartan medoxomil reduced blood pressure more potently and persistently than that of 0.3-3mg/kg olmesartan medoxomil. In a 2-week study in SHRs, azilsartan medoxomil showed more stable antihypertensive effects than olmesartan medoxomil and improved the glucose infusion rate, an indicator of insulin sensitivity, more potently (>= 10 times) than olmesartan medoxomil. Azilsartan medoxomil also exerted more potent antiproteinuric effects than olmesartan medoxomil in Wistar fatty rats. These results suggest that azilsartan medoxomil is a potent angiotensin II receptor blocker that has an attractive pharmacological profile as an antihypertensive agent. PMID- 21816149 TI - Assessment of research models for testing gene-environment interactions. AB - Throughout the last century, possible effects of exposure to toxicants, nutrients or drugs were examined primarily by studies of groups or populations. Individual variation in responses was acknowledged but could not be analyzed due to lack of information or tools to analyze individual genetic make-ups and lifestyle factors such as diet and activity. The Human Genome, Haplotype Map, 1000Genomes, and Human Variome Projects are identifying and cataloging the variation found within humans. Advances in DNA sequencing technologies will soon permit the characterization of individual genomes in clinical and basic research studies, thus allowing associations to be made between an individual genotype and the response to a particular exposure. Such knowledge and tools have generated a significant challenge for scientists: to design and conduct research studies that account for individual genetic variation. However, before these studies are done in humans, they will be performed in various in vivo and in vitro models. The advantages and disadvantages of some of the model test systems that are being used or developed in relation to individual genetic make-up and responses to xenobiotics are discussed. PMID- 21816150 TI - The gut as communicator between environment and host: immunological consequences. AB - During human evolution, the mucosal immune system developed two anti-inflammatory mechanisms: immune exclusion by secretory antibodies (SIgA and SIgM) to control epithelial colonization of microorganisms and inhibit penetration of harmful substances; and immunosuppression to counteract local and peripheral hypersensitivity against innocuous antigens such as food proteins. The latter function is referred to as oral tolerance when induced via the gut. Similar mechanisms also control immunity to commensal bacteria. The development of immune homeostasis depends on "windows of opportunity" where adaptive and innate immunities are coordinated by antigen-presenting cells; their function is not only influenced by microbial products but also by dietary constituents, including vitamin A and lipids like polyunsaturated omega-3 fatty acids. These factors can in several ways exert beneficial effects on the immunophenotype of the infant. Also breast milk provides immune-modulating factors and SIgA antibodies - reinforcing the gut barrier. Mucosal immunity is most abundantly expressed in the gut, and the intestinal mucosa of an adult contains at least 80% of the body's activated B cells - terminally differentiated to plasmablasts and plasma cells (PCs). Most mucosal PCs produce dimeric IgA which is exported by secretory epithelia expressing the polymeric Ig receptor (pIgR), also called membrane secretory component (SC). Immune exclusion is therefore performed mainly by SIgA. Notably, pIgR knockout mice which lack SIgs show increased uptake of food and microbial antigens and they have a hyper-reactive immune system with disposition for anaphylaxis; but this untoward development is counteracted by cognate oral tolerance induction as a homeostatic back-up mechanism. PMID- 21816151 TI - Costs and health effects of adding functional foods containing phytosterols/ stanols to statin therapy in the prevention of cardiovascular disease. AB - The present modelling study aimed to evaluate if and by how much functional foods containing phytosterols/-stanols add to the benefits of statins in the prevention of cardiovascular disease in terms of cost-effectiveness. Long-term health effects, measured as quality-adjusted life-years gained, and costs for scenarios with additional phytosterol/-stanol use were compared to scenarios without extra use. Phytosterols/-stanols were given only to persons who were eligible for use according to their 10-year absolute risk of fatal cardiovascular disease (SCORE risk). Intake levels and discontinuation rates as observed in daily practice were included in the model. Two situations were compared: 1) A real-life situation in which persons at high SCORE-risk were identified through clinical case-finding and, 2) A theoretical maximum situation where universal screening was implemented resulting in known SCORE-risks for the whole Dutch population aged 35-75 years (8.4 million people). Sensitivity analyses were performed for variations in the cholesterol-lowering effect and intake level of phytosterols/-stanols, indirect health care costs, time horizon and discount rates. At the model's start year, a total of 1.0 (real-life situation) to 3.3 (maximum situation) million persons qualified for phytosterol/-stanol use based on their SCORE-risk (both statin users and statin non-users). Over the model's time horizon, this resulted in a gain of 2700 to 16,300 quality-adjusted life-years, and yielded cost effectiveness ratios that ranged between ?92,000 and ?203,000 per quality adjusted life-year. This simulation study showed that the cost-effectiveness of phytosterols/-stanols as monotherapy and as add-on to statins is above thresholds for cost-effectiveness, generally ranging between ?20,000 and ?50,000, and is thus a non-cost-effective strategy to reduce cardiovascular disease. PMID- 21816152 TI - Simple explant culture of the embryonic chicken retina with long-term preservation of photoreceptors. AB - Structurally stable in vitro-model systems are indispensible to analyse neural development during embryogenesis, follow cellular differentiation and evaluate neurotoxicological or growth factor effects. Here we describe a three dimensional, long-term in vitro-culture system of the embryonic chick retina which supports photoreceptor development. Retinal tissue was isolated from E6 chick eye, and cultured as explants by continuous orbital rotation to allow free floatation without any supporting materials. Young stage (E6) immature retinas were cultured for various time periods in order to follow the differentiation of cell types and plexiform layers by immunocytochemical methods. These explants could be cultured for at least 2-3 weeks with remarkable retention of retinal architecture. Interestingly, photoreceptors developed in the absence of pigment epithelium. Electron microscopic studies revealed formation of structures resembling photoreceptor outer segments, a feature not reported previously. Thus, the verification of photoreceptors, Muller cells, inner retinal cells and the inner plexiform layer described in our study establishes this explant culture as a valuable in vivo-like model system. PMID- 21816154 TI - Estradiol deficiency during development modulates the expression of circadian and daily rhythms in male and female aromatase knockout mice. AB - Gonadal steroids modify the phase, amplitude and period of circadian rhythms. To further resolve the role of estradiol, we examined daily patterns of activity, circadian free running period and behavioral responses to light pulses using aromatase deficient (ArKO) mice. These animals lack the enzyme necessary to produce estradiol. We hypothesized that circulating estrogens during development and adulthood modulate the amount of activity, the temporal relationship of activity patterns relative to a light:dark cycle, and the free running period. Intact and gonadectomized male and female ArKO and wildtype (WT) littermates were used. WT males, but not ArKO males, retained the ability to respond to steroid hormones; the time of activity onset, free running period in constant darkness, and total daily activity were significantly different in gonadectomized compared to intact males. In contrast, gonadectomy did not alter the expression of these variables in ArKO males. ArKO females had a longer free running period in constant darkness compared to WT females regardless of gonadal state. Ovariectomized ArKO females had a significantly delayed activity onset when compared to intact ArKO females and ovariectomized WT females, despite all 3 groups being estrogen deficient. Phase shifts in response to light pulses given at different times of the day revealed an interaction between genotype, sex, and circulating steroids. These results from ArKO animals strongly suggest an organizational effect of estradiol during a critical period of development on the expression of biological rhythms. PMID- 21816153 TI - The association between macular pigment optical density and CFH, ARMS2, C2/BF, and C3 genotype. AB - Age-related macular degeneration (AMD) is the most common cause of blindness in older people in developed countries, and risk for this condition may be classified as genetic or environmental, with an interaction between such factors predisposing to this disease. This study investigated the relationship between AMD risk genes, macular pigment optical density (MPOD), which may protect against AMD, and serum concentrations of the macular carotenoids, lutein (L) and zeaxanthin (Z). This was a cross-sectional study of 302 healthy adult subjects. Dietary intake of L and Z was assessed by food frequency questionnaire, and MPOD was measured by customized heterochromatic flicker photometry. We also calculated MPOD Area as the area of MP under the spatial profile curve, to reflect MP across the macula. Serum L and Z were measured by HPLC. Genotyping of tag SNPs in the genes CFH, ARMS2, C3, C2 and BF was undertaken with multiplex polymerase chain reaction (PCR) and primer extension methodology (ABI Snapshot, ABI Warrington UK) on DNA extracted from peripheral blood. The mean +/- SD (range) age of the subjects in this study was 48 +/- 11 (21-66) years. There was a statistically significant association between CFH genotype and family history of AMD, with subjects having two non-risk CFH haplotypes (n = 35), or one non-risk and one protective CFH haplotype (n = 33), being significantly more likely to have a negative family history of AMD (Pearson Chi square: p = 0.001). There was no significant association between the AMD risk genes investigated and either MPOD (One way ANOVA: p > 0.05) or serum concentrations of L or Z (One way ANOVA: p > 0.05, for both). Subjects who were homozygous for risk alleles of both CFH and ARMS2 (n = 4) had significantly lower MPOD at 0.5 degrees and 1 degrees retinal eccentricity (Independent samples t test: p < 0.05) and lower MPOD Area which approached statistical significance (Independent samples t test: p = 0.058), compared to other subjects (n = 291). In conclusion, this study did not detect an association between individual AMD risk genotypes and the putatively protective MP, or serum concentrations of its constituent carotenoids. However, the combination of homozygous risk alleles at both CFH and ARMS2 loci was associated with significantly lower MPOD centrally, despite comparable serum concentrations of the macular carotenoids. These findings suggest that the maculae of subjects at very high genetic risk of AMD represent a hostile environment for accumulation and/or stabilization of MP. PMID- 21816155 TI - Intracellular Energetic Units regulate metabolism in cardiac cells. AB - This review describes developments in historical perspective as well as recent results of investigations of cellular mechanisms of regulation of energy fluxes and mitochondrial respiration by cardiac work - the metabolic aspect of the Frank Starling law of the heart. A Systems Biology solution to this problem needs the integration of physiological and biochemical mechanisms that take into account intracellular interactions of mitochondria with other cellular systems, in particular with cytoskeleton components. Recent data show that different tubulin isotypes are involved in the regular arrangement exhibited by mitochondria and ATP-consuming systems into Intracellular Energetic Units (ICEUs). Beta II tubulin association with the mitochondrial outer membrane, when co-expressed with mitochondrial creatine kinase (MtCK) specifically limits the permeability of voltage-dependent anion channel for adenine nucleotides. In the MtCK reaction this interaction changes the regulatory kinetics of respiration through a decrease in the affinity for adenine nucleotides and an increase in the affinity for creatine. Metabolic Control Analysis of the coupled MtCK-ATP Synthasome in permeabilized cardiomyocytes showed a significant increase in flux control by steps involved in ADP recycling. Mathematical modeling of compartmentalized energy transfer represented by ICEUs shows that cyclic changes in local ADP, Pi, phosphocreatine and creatine concentrations during contraction cycle represent effective metabolic feedback signals when amplified in the coupled non equilibrium MtCK-ATP Synthasome reactions in mitochondria. This mechanism explains the regulation of respiration on beat to beat basis during workload changes under conditions of metabolic stability. This article is part of a Special Issue entitled "Local Signaling in Myocytes." PMID- 21816156 TI - Opposing actions of rosiglitazone and resveratrol on mineralization in human vascular smooth muscle cells. AB - Arteriosclerotic vascular disease is a major cardiac health problem in westernized countries and the primary cause of mortality in diabetic patients. Recent data have raised serious safety concerns with the antidiabetic rosiglitazone, a thiazolidinedione with peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonistic activity, in regard to cardiovascular risks. A common feature of atherosclerosis is vascular mineralization. The latter is formed by vascular smooth muscle cells (VSMC) through complex processes that are similar to mineralization in bone. The aim of the current study was to investigate the effect of rosiglitazone on mineralization in cultured human VSMCs. We found that rosiglitazone stimulated mineralization by, at least in part, induction of caspase-dependent apoptosis. Furthermore, rosiglitazone induced oxidative stress was correlated with stimulated osteoblast-like differentiation of VSMCs. Treatment of rosiglitazone-supplemented VSMC cultures with the caloric restriction mimetic and antioxidant resveratrol diminished rosiglitazone-induced oxidative stress, osteoblast-like differentiation and mineralization. In conclusion, this study reveals novel insights into the relationship of rosiglitazone and cardiovascular events by providing a model that links rosiglitazone-induced osteoblast-like differentiation, oxidative stress and apoptosis with mineralization in VSMCs. In addition, we position resveratrol in this model acting to reduce rosiglitazone-induced oxidative stress, osteoblast like VSMC differentiation and mineralization. PMID- 21816157 TI - Human embryonic stem cell-derived vascular smooth muscle cells in therapeutic neovascularisation. AB - Ischemic diseases remain one of the major causes of morbidity and mortality throughout the world. In recent clinical trials on cell-based therapies, the use of adult stem and progenitor cells only elicited marginal benefits. Therapeutic neovascularisation is the Holy Grail for ischemic tissue recovery. There is compelling evidence from animal transplantation studies that the inclusion of mural cells in addition to endothelial cells (ECs) can enhance the formation of functional blood vessels. Vascular smooth muscle cells (SMCs) and pericytes are essential for the stabilisation of nascent immature endothelial tubes. Despite the intense interest in the utility of human embryonic stem cells (ESCs) for vascular regenerative medicine, ESC-derived vascular SMCs have received much less attention than ECs. This review begins with developmental insights into a range of smooth muscle progenitors from studies on embryos and ESC differentiation systems. We then summarise the methods of derivation of smooth muscle progenitors and cells from human ESCs. The primary emphasis is on the inherent heterogeneity of smooth muscle progenitors and cells and the limitations of current in vitro characterisation. Essential transplantation issues such as the type and source of therapeutic cells, mode of cell delivery, measures to enhance cell viability, putative mechanisms of benefit and long-term tracking of cell fate are also discussed. Finally, we highlight the challenges of clinical compatibility and scaling up for medical use in order to eventually realise the goal of human ESC based vascular regenerative medicine. PMID- 21816158 TI - Structure, folding and stability of FimA, the main structural subunit of type 1 pili from uropathogenic Escherichia coli strains. AB - Filamentous type 1 pili are responsible for attachment of uropathogenic Escherichia coli strains to host cells. They consist of a linear tip fibrillum and a helical rod formed by up to 3000 copies of the main structural pilus subunit FimA. The subunits in the pilus interact via donor strand complementation, where the incomplete, immunoglobulin-like fold of each subunit is complemented by an N-terminal donor strand of the subsequent subunit. Here, we show that folding of FimA occurs at an extremely slow rate (half-life: 1.6 h) and is catalyzed more than 400-fold by the pilus chaperone FimC. Moreover, FimA is capable of intramolecular self-complementation via its own donor strand, as evidenced by the loss of folding competence upon donor strand deletion. Folded FimA is an assembly-incompetent monomer of low thermodynamic stability (-10.1 kJ mol(-1)) that can be rescued for pilus assembly at 37 degrees C because FimC selectively pulls the fraction of unfolded FimA molecules from the FimA folding equilibrium and allows FimA refolding on its surface. Elongation of FimA at the C terminus by its own donor strand generated a self-complemented variant (FimAa) with alternative folding possibilities that spontaneously adopts the more stable conformation (-85.0 kJ mol(-1)) in which the C-terminal donor strand is inserted in the opposite orientation relative to that in FimA. The solved NMR structure of FimAa revealed extensive beta-sheet hydrogen bonding between the FimA pilin domain and the C-terminal donor strand and provides the basis for reconstruction of an atomic model of the pilus rod. PMID- 21816159 TI - Structure-guided activity restoration of the silkworm glutathione transferase Omega GSTO3-3. AB - Glutathione transferases (GSTs) are ubiquitous detoxification enzymes that conjugate hydrophobic xenobiotics with reduced glutathione. The silkworm Bombyx mori encodes four isoforms of GST Omega (GSTO), featured with a catalytic cysteine, except that bmGSTO3-3 has an asparagine substitution of this catalytic residue. Here, we determined the 2.20-A crystal structure of bmGSTO3-3, which shares a typical GST overall structure. However, the extended C-terminal segment that exists in all the four bmGSTOs occupies the G-site of bmGSTO3-3 and makes it unworkable, as shown by the activity assays. Upon mutation of Asn29 to Cys and truncation of the C-terminal segment, the in vitro GST activity of bmGSTO3-3 could be restored. These findings provided structural insights into the activity regulation of GSTOs. PMID- 21816160 TI - Identification of intrinsic in vitro cellular mechanisms for glioma invasion. AB - Invasion of malignant glioma is a highly complex phenomenon involving molecular and cellular processes at various spatio-temporal scales, whose precise interplay is still not fully understood. In order to identify the intrinsic cellular mechanisms of glioma invasion, we study an in vitro culture of glioma cells. By means of a computational approach, based on a cellular automaton model, we compare simulation results to the experimental data and deduce cellular mechanisms from microscopic and macroscopic observables (experimental data). For the first time, it is shown that the migration/proliferation dichotomy plays a central role in the invasion of glioma cells. Interestingly, we conclude that a diverging invasive zone is a consequence of this dichotomy. Additionally, we observe that radial persistence of glioma cells in the vicinity of dense areas accelerates the invasion process. We argue that this persistence results from a cell-cell repulsion mechanism. If glioma cell behavior is regulated through a migration/proliferation dichotomy and a self-repellent mechanism, our simulations faithfully reproduce all the experimental observations. PMID- 21816161 TI - On the role of differential adhesion in gangliogenesis in the enteric nervous system. AB - A defining characteristic of the normal development of the enteric nervous system (ENS) is the existence of mesoscale patterned entities called ganglia. Ganglia are clusters of neurons with associated enteric neural crest (ENC) cells, which form in the simultaneously growing gut wall. At first the precursor ENC cells proliferate and gradually differentiate to produce the enteric neurons; these neurons form clusters with ENC scattered around and later lying on the periphery of neuronal clusters. By immunolabelling neural cell-cell adhesion molecules, we infer that the adhesive capacity of neurons is greater than that of ENC cells. Using a discrete mathematical model, we test the hypothesis that local rules governing differential adhesion of neuronal agents and ENC agents will produce clusters which emulate ganglia. The clusters are relatively stable, relatively uniform and small in size, of fairly uniform spacing, with a balance between the number of neuronal and ENC agents. These features are attained in both fixed and growing domains, reproducing respectively organotypic in vitro and in vivo observations. Various threshold criteria governing ENC agent proliferation and differentiation and neuronal agent inhibition of differentiation are important for sustaining these characteristics. This investigation suggests possible explanations for observations in normal and abnormal ENS development. PMID- 21816162 TI - Human cholesteryl ester transfer protein enhances insulin-mediated glucose uptake in adipocytes. AB - AIMS: Adipose tissue plays an important role in the pathogenesis of insulin resistance, obesity, and Type-2 diabetes. Human adipocytes express abundant cholesteryl ester transfer protein (CETP). However, the function and role of CETP in regulating lipoprotein metabolism are mostly unknown. In this study, we examined whether CETP affected the insulin-mediated responses in adipocytes. MAIN METHODS: Because mouse 3T3-L1 preadipocytes do not express CETP, we established a stable cell line expressing human CETP by transfecting the cells with pcDNA3.1/human CETP. We used a standard approach to differentiate the cells into mature adipocytes, and we examined the cholesterol balance and insulin responses. KEY FINDINGS: The human CETP stable cell line expressed stable levels of CETP without affecting the expression of either peroxisome proliferator-activated receptor-gamma (PPARgamma) or glucose transporter-4 (GLUT4) throughout cell differentiation. CETP expression significantly increased the level of both total and free cholesterol in the mature adipocytes. Upon insulin stimulation, CETP expressing cells had significantly higher protein kinase B (Akt) phosphorylation and 2-(3)H-deoxyglucose uptake, as compared with 3T3-L1 cells and cells transfected with control vector. SIGNIFICANCE: Human CETP expression increased cellular cholesterol levels and enhanced insulin-stimulated Akt phosphorylation and glucose uptake in adipocytes. Thus, CETP may modulate glucose metabolism and insulin action in addition to its effects on lipoprotein metabolism. PMID- 21816163 TI - In systemic sclerosis macrovascular damage of hands digital arteries correlates with microvascular damage. AB - OBJECTIVE: To assess morphology and blood flow of the proper palmar digital arteries (PPDA) by color Doppler ultrasonography (CDUS) and its relationship with nailfold videocapillaroscopy (NVC), skin blood perfusion and digital arteries pulsatility of hands in SSc patients and healthy controls. METHODS: CDUS, NVC, laser Doppler perfusion imaging (LDPI) and photoplethysmography (PPG) were performed in 36 systemic sclerosis (SSc) patients and 20 healthy controls. RESULTS: CDUS was pathologic in 69% of patients with SSc and in none of healthy controls (p<0.0001). SSc patients with low vascular damage (early capillaroscopic pattern) have a normal morphology of PPDA, but the blood flow, evaluated by peak systolic velocity (PSV) and end diastolic velocity (EDV), is reduced and vascular resistance, measured by resistive index (RI) and pulsatility index (PI), increased. At this stage the LDPI mean perfusion and digital artery pulsatility, evaluated by PPG, were reduced. The US changes appear with microvascular damage progression (active and late capillaroscopic patterns), while the PPDA blood flow progressively decreases (PSV and EDV decreased, RI and PI increased). The macrovascular damage correlates with disease duration. Anti-topoisomerase I represents an independent predictive factor for macrovascular damage. We not observed any association between digital ulcer history, pulmonary fibrosis and US findings. CONCLUSION: PPDA blood flow dysfunction is already present in early disease. Structural macrovascular damage progresses with worsening of SSc microangiopathy. PMID- 21816164 TI - The PDE10A inhibitor, papaverine, differentially activates ERK in male and female rat striatal slices. AB - The phosphodiesterase 10A (PDE10A) is highly expressed within dopaminoreceptive medium spiny neurons (MSNs) of the striatum, which are implicated in various neurodegenerative diseases and psychiatric disorders, such as Huntington's disease and schizophrenia. With its dual action on cAMP and cGMP, PDE10A has been proposed to affect several signaling cascades in the corticostriatothalamic circuits. In particular, papaverine, a selective PDE10A inhibitor has been shown to activate/phosphorylate ERK in striatum. We used acute rat striatal slices to further characterize the effects of papaverine on ERK activation/phosphorylation in D1- and D2-responsive striatal neurons. Incubation of striatal slices from male rats with papaverine increased the levels of phospho-ERK1/2 (p-ERK), an effect enhanced with a D1 agonist or a D2 antagonist, but decreased with a D1 receptor antagonist or a D2 receptor agonist. Papaverine-induced increase in p ERK was localized in striatal neurons receiving D1-enriched presynaptic terminals, as well as in postsynaptic D2-enriched neurons in striatal slices. Interestingly, papaverine had almost no stimulatory effects on ERK1/2 phosphorylation in slices prepared from female rats. In striatal slices prepared from ovariectomized female rats, papaverine treatment stimulated ERK1/2 phosphorylation to levels similar to those in slices from male rats. Moreover, estrogen was found to regulate the levels of D2 but not D1 receptors in striatum. These results indicate that circulating levels of female hormones, and in particular estrogen, regulate the effects of PDE10A inhibition on ERK1/2 phosphorylation in medium spiny neurons, an effect possibly linked to estrogen's regulation of D2 receptors. Considering the variety of events modulated by ERK1/2 activity, these findings suggest that sex difference needs to be taken into consideration for the further investigation of the effects of PDE10A inhibitors. PMID- 21816165 TI - Transcriptional up-regulation of cell surface Na V 1.7 sodium channels by insulin like growth factor-1 via inhibition of glycogen synthase kinase-3beta in adrenal chromaffin cells: enhancement of 22Na+ influx, 45Ca2+ influx and catecholamine secretion. AB - Insulin-like growth factor-1 (IGF-1) plays important roles in the regulation of neuronal development. The electrical activity of Na(+) channels is crucial for the regulation of synaptic formation and maintenance/repair of neuronal circuits. Here, we examined the effects of chronic IGF-1 treatment on cell surface expression and function of Na(+) channels. In cultured bovine adrenal chromaffin cells expressing Na(V)1.7 isoform of voltage-dependent Na(+) channels, chronic IGF-1 treatment increased cell surface [(3)H]saxitoxin binding by 31%, without altering the Kd value. In cells treated with IGF-1, veratridine-induced (22)Na(+) influx, and subsequent (45)Ca(2+) influx and catecholamine secretion were augmented by 35%, 33%, 31%, respectively. Pharmacological properties of Na(+) channels characterized by neurotoxins were similar between nontreated and IGF-1 treated cells. IGF-1-induced up-regulation of [(3)H]saxitoxin binding was prevented by phosphatydil inositol-3 kinase inhibitors (LY204002 or wortmannin), or Akt inhibitor (Akt inhibitor IV). Glycogen synthase kinase-3 (GSK-3) inhibitors (LiCl, valproic acid, SB216763 or SB415286) also increased cell surface [(3)H]saxitoxin binding by ~ 33%, whereas simultaneous treatment of IGF-1 with GSK-3 inhibitors did not produce additive increasing effect on [(3)H]saxitoxin binding. IGF-1 (100 nM) increased Ser(437)-phosphorylated Akt and Ser(9)-phosphorylated GSK-3beta, and inhibited GSK-3beta activity. Treatment with IGF-1, LiCl or SB216763 increased protein level of Na(+) channel alpha-subunit; it was prevented by cycloheximide. Either treatment increased alpha-subunit mRNA level by ~ 48% and accelerated alpha-subunit gene transcription by ~ 30% without altering alpha-subunit mRNA stability. Thus, inhibition of GSK-3beta caused by IGF-1 up-regulates cell surface expression of functional Na(+) channels via acceleration of alpha-subunit gene transcription. PMID- 21816167 TI - Attentional orienting towards emotion: P2 and N400 ERP effects. AB - Attention can be oriented to different spatial locations yielding faster processing of attended compared to unattended stimuli. Similarly attention can be oriented to a semantic category such as "animals" or "tools". Words from the attended category will also be recognized faster than words from an unattended category. Here, we asked whether it is possible to orient attention to an emotional category, for example, "negative emotional stimuli". Furthermore, we investigated which mechanisms facilitate processing of attended stimuli. In an attentional orienting paradigm in which cues are informative with regard to the spatial location, semantic category, or emotional category of subsequent target words, we found attention effects in all three cue conditions. Words at attended locations or of the attended semantic or emotional category were responded to faster than unattended categories. While spatial attention acted upon early visual processing and amplified occipital N1-P2 potentials, semantic cues modulated the N400 amplitude indexing semantic processing. Emotional cues also yielded an N400 modulation; however, in addition, a left anterior P2 effect was observed. The data clearly show that attention can be oriented to emotional categories. Emotional orienting yields facilitated processing of an attended emotional category through the modulation of early and late word processing stages. PMID- 21816166 TI - Premorbid expertise produces category-specific impairment in a domain-general semantic disorder. AB - For decades, category-specific semantic impairment - i.e., better comprehension of items from one semantic category than another - has been the driving force behind many claims about the organisation of conceptual knowledge in the brain. Double dissociations between patients with category-specific disorders are widely interpreted as showing that different conceptual domains are necessarily supported by functionally independent systems. We show that, to the contrary, even strong or classical dissociations can also arise from individual differences in premorbid expertise. We examined two patients with global and progressive semantic degradation who, unusually, had known areas of premorbid expertise. Patient 1, a former automotive worker, showed selective preservation of car knowledge, whereas Patient 2, a former botanist, showed selective preservation of information about plants. In non-expert domains, these patients showed the typical pattern: i.e., an inability to differentiate between highly similar concepts (e.g., rose and daisy), but retention of broader distinctions (e.g., between rose and cat). Parallel distributed processing (PDP) models of semantic cognition show that expertise in a particular domain increases the differentiation of specific-level concepts, such that the semantic distance between these items resembles non-expert basic-level distinctions. We propose that these structural changes interact with global semantic degradation, particularly when expert knowledge is acquired early and when exposure to expert concepts continues during disease progression. Therefore, category-specific semantic impairment can arise from at least two distinct mechanisms: damage to representations that are critical for a particular category (e.g., knowledge of hand shape and action for the category 'tools') and differences in premorbid experience. PMID- 21816168 TI - Development of pH-sensitive tamarind seed polysaccharide-alginate composite beads for controlled diclofenac sodium delivery using response surface methodology. AB - The present study deals with the development of novel pH-sensitive tamarind seed polysaccharide (TSP)-alginate composite beads for controlled diclofenac sodium delivery using response surface methodology by full 3(2) factorial design. The effect of polymer-blend ratio (sodium alginate:TSP) and cross-linker (CaCl(2)) concentration on the drug encapsulation efficiency (DEE, %) and drug release from diclofenac sodium loaded TSP-alginate composite beads prepared by ionotropic gelation was optimized. The observed responses were coincided well with the predicted values by the experimental design. The DEE (%) of these beads containing diclofenac sodium was within the range between 72.23+/-2.14 and 97.32+/-4.03% with sustained in vitro drug release (69.08+/-2.36-96.07+/-3.54% in 10 h). The in vitro drug release from TSP-alginate composite beads containing diclofenac sodium was followed by controlled-release pattern (zero-order kinetics) with case-II transport mechanism. Particle size range of these beads was 0.71+/-0.03-1.33+/-0.04 mm. The swelling and degradation of the developed beads were influenced by different pH of the test medium. The FTIR and NMR analyses confirmed the compatibility of the diclofenac sodium with TSP and sodium alginate used to prepare the diclofenac sodium loaded TSP-alginate composite beads. The newly developed TSP-alginate composite beads are suitable for controlled delivery of diclofenac sodium for prolonged period. PMID- 21816170 TI - Drug uptake transporters in antiretroviral therapy. AB - Current treatment of human immunodeficiency virus-1 (HIV-1) infection is effective, although it does not permanently suppress viral replication in all patients. Viral persistence, drug toxicity, and antiretroviral resistance are challenging barriers to successful treatment of HIV-1 infection. It has become increasingly apparent that the balance between drug influx and efflux transporter activity plays a critical role in the overall disposition of anti-HIV drugs in both cells and tissues. Thus, drug transporters directly influence the appearance of drug resistance and toxicity, and could also be related to persistence of HIV 1. We review the role of drug uptake transporters from the solute carrier (SLC) superfamily, their relation with specific antiretroviral drug disposition, and their efficacy in the tissues that absorb, metabolize, and eliminate anti-HIV drugs. Recent studies focusing on the role of drug uptake transporters in immune cells, key sites in the action of antiviral therapy, are highlighted. PMID- 21816169 TI - Structural insight into the low affinity between Thermotoga maritima CheA and CheB compared to their Escherichia coli/Salmonella typhimurium counterparts. AB - CheA-mediated CheB phosphorylation and the subsequent CheB-mediated demethylation of the chemoreceptors are important steps required for the bacterial chemotactic adaptation response. Although Escherichia coli CheB has been reported to interact with CheA competitively against CheY, we have observed that Thermotoga maritima CheB has no detectable CheA-binding. By determining the CheY-like domain crystal structure of T. maritima CheB, and comparing against the T. maritima CheY and Salmonella typhimurium CheB structures, we propose that the two consecutive glutamates in the beta4/alpha4 loop of T. maritima CheB that is absent in T. maritima CheY and in E. coli/S. typhimurium CheB may be one factor contributing to the low CheA affinity. PMID- 21816171 TI - Effects of freezing profile parameters on the survival of cryopreserved rat embryonic neural cells. AB - The ability to successfully cryopreserve neural cells would represent an important advance with benefits to neural tissue engineering, neural transplantation, and neuroscience research. We have examined key factors responsible for damage to rat embryonic neural cells during cryopreservation using a two-step temperature profile, with an emphasis on the effects of cooling rate and plunge temperature. Our results indicate that the initial addition of 8% dimethyl sulfoxide (DMSO) and seeding of extracellular ice do not significantly decrease viable cell yield. However, subsequent freezing resulted in significant cell losses for all profile parameter combinations examined. A maximum post-thaw survival of 56% (compared to unfrozen controls) was observed after cooling at 2 degrees C/min to -80 degrees C followed by direct immersion in liquid nitrogen. Single-step removal of DMSO after thawing was associated with an additional 40 70% loss of viable cells, and the number of viable cells was further reduced by approximately 70% after 2 days of cell culture (resulting in a net viable cell yield of 9.6+/-0.4%). Nonetheless, the cryopreserved neurons that did survive displayed a normal morphology, including formation of neurites. Trends in neuronal viability conformed with predictions of existing theoretical models of cell freezing, with reduced survival for rapid cooling rates or high plunge temperatures (attributable to intracellular ice formation), and decreasing viability with increasing profile duration (consistent with the known effects of cell dehydration at suboptimal cooling rates). These observations suggest that neural cells are good candidates for further refinement of freezing profile design using a physics-based approach to parameter optimization. PMID- 21816172 TI - Cognitive ability assessment by brain-computer interface validation of a new assessment method for cognitive abilities. AB - Brain-Computer Interfaces (BCIs) are systems which can provide communication and environmental control to people with severe neuromuscular diseases. The current study proposes a new BCI-based method for psychometric assessment when traditional or computerized testing cannot be used owing to the subject's output impairment. This administration protocol was based on, and validated against, a widely used clinical test (Raven Colored Progressive Matrix) in order to verify whether BCI affects the brain in terms of cognitive resource with a misstatement result. The operating protocol was structured into two phases: phase 1 was aimed at configuring the BCI system on the subject's features and train him/her to use it; during phase 2 the BCI system was reconfigured and the test performed. A step by-step checking procedure was adopted to verify progressive inclusion/exclusion criteria and the underpinning variables. The protocol was validated on 19 healthy subjects and the BCI-based administration was compared with a paper-based administration. The results obtained by both methods were correlated as known for traditional assessment of a similarly culture free and reasoning based test. Although our findings need to be validated on pathological participants, in our healthy population the BCI-based administration did not affect performance and added a further control of the response due to the several variables included and analyzed by the computerized task. PMID- 21816173 TI - Visualization of virus-infected brain regions using a GFP-illuminating flashlight enables accurate and rapid dissection for biochemical analysis. AB - Engineered viral vectors tagged with a fluorescent protein such as enhanced green fluorescent protein (EGFP) have been widely used to study neuronal function after intracranial injection into specific brain regions. A rapid dissection of the virus-expressing region is required for certain biochemical analyses. To improve the accuracy of the rapid dissection, we developed a method that employs a Bluestar flashlight in combination with barrier filter glasses to visualize the expression of EGFP lentivirus that has been microinjected into the nucleus accumbens. Processing of dissected tissue for EGFP immunoblotting further validated the approach. PMID- 21816174 TI - A novel method for analyzing images of live nerve cells. AB - Analysis of images from live-cell experiments is a central activity to studying the effects of stimulation on neuronal behavior. Image analysis techniques currently used to study these effects rely for the most part on the salience of the neuronal structures within the image. In both fluorescent and electron microscopy, neuronal structures are enhanced and therefore easy to distinguish in an image. Unlike images obtained via fluorescent or electron microscopy, however, images produced via transmission microscopy (e.g., bright field, phase contrast, DIC) are significantly more difficult to analyze because there is little contrast between the object-of-interest and the image background. This difficulty is amplified when a time-dependent sequence of images are to be analyzed, because of the corresponding large data sets. To address this problem, we introduce a novel approach to the analysis of images of live cells captured via transmission microscopy that takes advantage of commercially available software and the Fourier transform. Specifically, our approach utilizes several morphological functions in MATLAB to enhance the contrast of the cells with respect to the background, which is followed by 2-D Fourier analysis to generate a spectrum from which the orientation and alignment of cells and their processes can be measured. We show that this method can be used to simplify the interpretation of complex structure in images of live neurons obtained via transmission microscopy and consequently, discover trends in neurite development following different types of stimulation. This approach provides a consistent and reliable tool for analyzing changes in cell structure that occurs during live-cell experiments. PMID- 21816175 TI - Expression of an RSV-gag virus-like particle in insect cell lines and silkworm larvae. AB - Rous sarcoma virus group antigen protein-based virus-like particles (VLPs) are well known for their structural integrity and ease of handling. VLPs play an important role in drug delivery systems because they can be manipulated with ease. In this study, a new method was established for expressing Rous sarcoma virus group antigen protein based VLPs in silkworm larvae and establishing stably expressing insect cell lines. These VLPs have been isolated by ultracentrifugation using a sucrose step gradient of 10-60% (v/v), and their spherical structure has been confirmed using transmission electron microscopy (TEM). The spherical morphology is similar in both the silkworm larvae and in stably expressing cell lines. Silkworm larvae are better suited for producing Rous sarcoma virus group antigen protein-based VLPs on a large scale; yields from silkworm larvae were approximately 8.2-fold higher than yields from stable cell lines. These VLPs provide a new method for large-scale application in vaccine development and drug delivery systems. PMID- 21816176 TI - One-step RT-qPCR with an internal control system for the detection of turkey rotaviruses in faecal samples. AB - Turkey rotaviruses are one of the major pathogens responsible for the poult enteritis syndrome (PES). In this study a one step real-time reverse transcription polymerase chain reaction (RT-qPCR) assay targeting the rotaviral non-structural protein 4 (NSP4) was developed. The NSP4 is a highly conserved gene inside the turkey rotavirus genome and contains an internal control system to monitor any potential RT-qPCR inhibitors. The detection limit of the optimized NSP4-RT-qPCR assay ranged from 8.15 to 8.15 * 10(5) copy numbers. In total 149 faecal samples were collected from eight different flocks of commercial turkey farms. Faecal samples from hens and toms were collected separately at 2-week intervals from the 2nd week of age through the 16th and 20th week of age (age of slaughter for female and male, respectively) and tested. One farm reared only hens. The samples were tested previously using conventional RT-PCR targeting the same gene. When the conventional RT-PCR was compared with the developed NSP4-RT qPCR, the results revealed that 11% of the samples of the conventional RT-PCR were false negative. The results indicate that this NSP4-RT-qPCR is highly sensitive for the detection of turkey rotaviruses in faeces. In addition, it could be suitable for the development of high-throughput screening. PMID- 21816178 TI - Sensorimotor and cognitive functions in a SOD1(G37R) transgenic mouse model of amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a neurological disorder involving degeneration of motor neurons in brain and spinal cord, leading to progressive atrophy of skeletal muscles and, ultimately, paralysis and death. Copper-mediated oxidative damage is proposed to play a critical role in the pathogenesis of Cu/Zn superoxide dismutase (SOD1) - linked hereditary amyotrophic lateral sclerosis. To understand more clearly the pathogenesis of sensorimotor dysfunction and to find the most appropriate methods for early detection of symptoms and for monitoring them across time, a murine model was assessed at three time points (5, 8, and 11 months). Transgenic mice with the G37R mutation of human SOD1 exhibited earliest signs of dysfunction at 8 months in terms of a pathological hindpaw clasping reflex, as well as slowed movement time on a suspended bar, anomalies in footprint patterns, weaker grip strength, raised somatosensory thresholds, and deficits in passive avoidance learning, yielding a margin of 3-4 months before death to test experimental therapies. PMID- 21816179 TI - Behavioural deficits associated with maternal immune activation in the rat model of schizophrenia. AB - Schizophrenia is associated with changes in memory and contextual processing. As maternal infection is a risk factor in schizophrenia we tested for these impairments in a maternal immune activation (MIA) animal model. MIA rats displayed impaired object recognition memory, despite intact object discrimination, and a reduced reinstatement of rearing in response to a contextual manipulation. These results link MIA to contextual impairments in schizophrenia, possibly through changes in hippocampal function. PMID- 21816177 TI - Emerging, reemerging, and forgotten brain areas of the reward circuit: Notes from the 2010 Motivational Neural Networks conference. AB - On April 24-27, 2010, the Motivational Neuronal Networks meeting took place in Wrightsville Beach, North Carolina. The conference was devoted to "Emerging, re emerging, and forgotten brain areas" of the reward circuit. A central feature of the conference was four scholarly discussions of cutting-edge topics related to the conference's theme. These discussions form the basis of the present review, which summarizes areas of consensus and controversy, and serves as a roadmap for the next several years of research. PMID- 21816180 TI - Role of RPB7 in RNA pol I transcription in Trypanosoma brucei. PMID- 21816182 TI - Response to "Role of RPB7 in RNA pol I transcription in Trypanosoma brucei". PMID- 21816181 TI - Transcription by the multifunctional RNA polymerase I in Trypanosoma brucei functions independently of RPB7. AB - Trypanosoma brucei has a multifunctional RNA polymerase (pol) I that transcribes ribosomal gene units (RRNA) and units encoding its major cell surface proteins variant surface glycoprotein (VSG) and procyclin. Previous analysis of tandem affinity-purified, transcriptionally active RNA pol I identified ten subunits including an apparently trypanosomatid-specific protein termed RPA31. Another ortholog was identified in silico. No orthologs of the yeast subunit doublet RPA43/RPA14 have been identified yet. Instead, a recent report presented evidence that RPB7, the RNA pol II paralog of RPA43, is an RNA pol I subunit and essential for RRNA and VSG transcription in bloodstream form trypanosomes [18]. Revisiting this attractive hypothesis, we were unable to detect a stable interaction between RPB7 and RNA pol I in either reciprocal co-immunoprecipitation or tandem affinity purification. Furthermore, immunodepletion of RPB7 from extract virtually abolished RNA pol II transcription in vitro but had no effect on RRNA or VSG ES promoter transcription in the same reactions. Accordingly, chromatin immunoprecipitation analysis revealed cross-linking of RPB7 to known RNA pol II transcription units but not to the VSG ES promoter or to the 18S rRNA coding region. Interestingly, RPB7 did crosslink to the RRNA promoter but so did the RNA pol II-specific subunit RPB9 suggesting that RNA pol II is recruited to this promoter. Overall, our data led to the conclusion that RNA pol I transcription in T. brucei does not require the RNA pol II subunit RPB7. PMID- 21816183 TI - The impact of DNA topology on polyplex uptake and transfection efficiency in mammalian cells. AB - The effect of DNA vector topology when complexed to poly-l-lysine (PLL) and its quantification in transfection efficiency has not been fully addressed even though it is thought to be of importance from both production and regulatory viewpoints. This study investigates and quantifies cell uptake followed by transfection efficiency of PLL:DNA complexes (polyplexes) in Chinese hamster ovary (CHO) cells and their dependence on DNA topology. PLL is known for its ability to condense DNA and serve as an effective gene delivery vehicle. Characterization of PLL conjugated to a 6.9kb plasmid was carried out. Dual labeling of both the plasmid DNA (pDNA) and PLL enabled quantitative tracking of the complexed as well as dissociated elements, within the cell, and their dependence on DNA topology. Polyplex uptake was quantified by confocal microscopy and image analysis. Supercoiled (SC) pDNA when complexed with PLL, forms a polyplex with a mean diameter of 139.06nm (+/-0.84% relative standard error [RSE]), whereas open circular (OC) and linear-pDNA counterparts displayed mean diameters of 305.54 (+/-3.2% RSE) and 841.5nm (+/-7.2% RSE) respectively. Complexes containing SC-pDNA were also more resistant to nuclease attack than its topological counterparts. Confocal microscope images reveal how the PLL and DNA remain bound post transfection. Quantification studies revealed that by 1h post transfection 61% of SC-pDNA polyplexes were identified to be associated with the nucleus, in comparison to OC- (24.3%) and linear-pDNA polyplexes (3.5%) respectively. SC-pDNA polyplexes displayed the greatest transfection efficiency of 41% which dwarfed that of linear-pDNA polyplexes of 18.6%. Collectively these findings emphasize the importance of pDNA topology when complexed with PLL for gene delivery with the SC-form being a key pre-requisite. PMID- 21816184 TI - Limited effects of Muc1 deficiency on mouse adenovirus type 1 respiratory infection. AB - Muc1 (MUC1 in humans) is a membrane-tethered mucin that exerts anti-inflammatory effects in the lung during bacterial infection. Muc1 and other mucins are also likely to form a protective barrier in the lung. We used mouse adenovirus type 1 (MAV-1, also known as MAdV-1) to determine the role of Muc1 in the pathogenesis of an adenovirus in its natural host. Following intranasal inoculation of wild type mice, we detected increased TNF-alpha, a cytokine linked to Muc1 production, but no consistent changes in the production of lung Muc1, Muc5ac or overall lung mucus production. Viral loads were modestly higher in the lungs of Muc1(-/-) mice compared to Muc1(+/+) mice at several early time points but decreased to similar levels by 14 days post infection in both groups. However, cellular inflammation and the expression of CXCL1, CCL5, and CCL2 did not significantly differ between Muc1(-/-) and Muc1(+/+) mice. Our data therefore suggest that Muc1 may contribute to a physical barrier that protects against MAV-1 respiratory infection. However, our data do not reveal an anti-inflammatory effect of Muc1 that contributes to MAV-1 pathogenesis. PMID- 21816185 TI - Type-III interferon, not type-I, is the predominant interferon induced by respiratory viruses in nasal epithelial cells. AB - As an innate immune response against diverse viral infections, a host induces two types of interferon (IFN), type-I (IFN-beta/alpha) and type-III (IFN-lambda). We investigated IFN inductions by respiratory viruses, including respiratory syncytial virus (RSV), measles virus and mumps virus in human nasal epithelial cells (NECs). IFN-lambda, but not IFN-beta/alpha, was induced by respiratory virus infection in primary NECs and immortalized NECs through transfection with the human telomerase reverse transcriptase gene (hTERT-NECs). In contrast, both IFN-lambda and IFN-beta/alpha were induced by RSV infection in human bronchiolar carcinoma cell line A549. Suppression of retinoic acid-inducible gene-I (RIG-I) expression using siRNA significantly reduced IFN-lambda1 production in RSV infected hTERT-NECs, while suppression of melanoma differentiation-associated gene 5 (MDA5) expression did not. Exogenous IFN-lambda1 treatment suppressed RSV replication and chemokine induction in hTERT-NECs. These data indicate that IFN lambda, but not IFN-beta/alpha, contributes to the main first line defense via RIG-I-dependent pathway against respiratory virus infection in NECs. PMID- 21816186 TI - The importance of habits in eating behaviour. An overview and recommendations for future research. AB - There is ample evidence to suggest that a significant part of daily eating behaviours consists of habits. In line with this, the concept of habit is increasingly incorporated into studies investigating the behavioural and psychosocial determinants of food choice, yielding evidence that habit is one of the most powerful predictors of eating behaviour. Research shows that habitual behaviour is fundamentally different from non-habitual behaviour: when behaviour is habitual, people require little information to make decisions, intentions are poor predictors of behaviour, and behaviour is triggered by situational cues. These insights have vast implications for research in the food domain that are only just beginning to be addressed. Also, theorizing on habits has important implications for behaviour change interventions, yet few interventions that are based on habit theory have been tested in a food context. The present article provides an overview of habit research and discusses possibilities to increase our knowledge of the role of habits in eating behaviour. It is shown that interventions targeting habitual behaviour can try to (i) change the situation that triggers the habitual behaviour, (ii) promote or inhibit the habitual response and (iii) change relevant contingencies. These insights can act as a starting point for future intervention research. PMID- 21816187 TI - Regulation of C-type natriuretic peptide expression. AB - C-type natriuretic peptide (CNP) is a member of the small family of natriuretic peptides that also includes atrial natriuretic peptide (ANP) and brain, or B-type natriuretic peptide (BNP). Unlike them, it performs its major functions in an autocrine or paracrine manner. Those functions, mediated through binding to the membrane guanylyl cyclase natriuretic peptide receptor B (NPR-B), or by signaling through the non-enzyme natriuretic peptide receptor C (NPR-C), include the regulation of endochondral ossification, reproduction, nervous system development, and the maintenance of cardiovascular health. To date, the regulation of CNP gene expression has not received the attention that has been paid to regulation of the ANP and BNP genes. CNP expression in vitro is regulated by TGF-beta and receptor tyrosine kinase growth factors in a cell/tissue-specific and sometimes species-specific manner. Expression of CNP in vivo is altered in diseased organs and tissues, including atherosclerotic vessels, and the myocardium of failing hearts. Analysis of the human CNP gene has led to the identification of a number of regulatory sites in the proximal promoter, including a GC-rich region approximately 50 base pairs downstream of the Tata box, and shown to be a binding site for several putative regulatory proteins, including transforming growth factor clone 22 domain 1 (TSC22D1) and a serine threonine kinase (STK16). The purpose of this review is to summarize the current literature on the regulation of CNP expression, emphasizing in particular the putative regulatory elements in the CNP gene and the potential DNA-binding proteins that associate with them. PMID- 21816188 TI - Sequence variations of Env signal peptide alleles in different clinical stages of HIV infection. AB - The human immunodeficiency virus has been shown to increase its infectivity throughout the course of infection. This virus selection property has been associated with genome mutations and recombinations among virus variants, causing amino acid residue alterations in important viral proteins. In order to explore the contribution of Env signal peptide (Env-sp) to Env glycoprotein expression and its possible relationship to increased virus infectivity observed at late stages of infection, we characterized Env-sp sequences derived from twelve patients at "early" and "late" stages of HIV infection without antiretroviral therapy use. In spite of the remarkable overall similarity between both stages, we observed the deletion of a sequence of neutral and basic residues at the Env sp amino terminus in virus from early stage specimens and the insertion of basic residues in the hydrophobic region on late-stage viral isolates. The Env-sp sequence alterations may have viral adaptive functions during HIV infection. PMID- 21816190 TI - Development of a baited oral vaccine for use in reservoir-targeted strategies against Lyme disease. AB - Lyme disease is a major human health problem which continues to increase in incidence and geographic distribution. As a vector-borne zoonotic disease, Lyme disease may be amenable to reservoir targeted strategies for control. We have previously reported that a vaccinia virus (VV) based vaccine expressing outer surface protein A (OspA) of Borrelia burgdorferi, the causative agent of Lyme disease, protects inbred strains of laboratory mice against infection by feeding ticks and clears the ticks of infection when administered by gavage. Here we extend these studies to develop an effective bait formulation for delivery of the VV based vaccine and test its characteristics under simulated environmental conditions. We show that this vaccine is efficacious in decreasing acquisition of B. burgdorferi by uninfected larval ticks as well as in decreasing transmission from infected ticks to its natural reservoir, Peromyscus leucopus, when fed to mice in oral baits. Using live, in vivo imaging techniques, we describe the distribution of vaccinia virus infection after ingestion of the baited vaccines and establish the use of in vivo imaging technology for optimization of bait delivery. In summary, a VV based OspA vaccine is stable in an oral bait preparation and provides protection against infection for both the natural reservoir and the tick vector of Lyme disease. PMID- 21816191 TI - Transgenic Neospora caninum strains constitutively expressing the bradyzoite NcSAG4 protein proved to be safe and conferred significant levels of protection against vertical transmission when used as live vaccines in mice. AB - At present, there is no effective treatment or vaccine to prevent vertical transmission or abortion associated with Neospora caninum infection in cattle. Different vaccine formulations have been assayed, and live vaccines have shown the most promising results in terms of protection. Previously, transgenic N. caninum tachyzoites expressing the bradyzoite stage-specific NcSAG4 antigen in a constitutive manner (Nc-1 SAG4(c)) were obtained and showed a reduced persistence of parasite in inoculated mice. Thus, the present study evaluates the Nc-1 SAG4(c)1.1 and Nc-1 SAG4(c)2.1 transgenic strains and the Nc-1 wild-type (WT) strain to determine their protective efficacy against vertical transmission and cerebral neosporosis in mice. Consequently, dams were immunized twice with 5 * 10(5) tachyzoites of each strain and challenged with 2 * 10(6) tachyzoites of a heterologous and virulent isolate at 7-10 days of gestation. The Nc-1 SAG4(c)1.1 strain offered less protection than the other transgenic strain (Nc-1 SAG4(c)2.1) or their ancestor (Nc-1 WT). Indeed, 40%, 7% and 5.6% of the postnatal deaths corresponded to pups from dams vaccinated with Nc-1 SAG4(c)1.1, Nc-1 SAG4(c)2.1 and Nc-1 (WT) strains, respectively. In comparison, the non-immunized challenge group had a 100% mortality rate. In addition, mice were protected against congenital transmission; vertical transmission rates were 45%, 11.1% and 10.8% in the Nc-1 SAG4(c)1.1, Nc-1 SAG4(c)2.1 and Nc-1 WT immunized groups, respectively, vs. 94.9% in the non-vaccinated infected group. However, this protection against the postnatal mortality and the vertical transmission was not associated with a consistent Th1 or Th2-type immune response. Nonetheless, the Nc-1 SAG4(c)2.1 strain appears to be the best candidate for use as a live vaccine, as evidenced by results demonstrating its high levels of protection against vertical transmission and its lower persistence in mice, making this transgenic strain safer than Nc-1 WT. PMID- 21816192 TI - Modulation of Th1/Th2 immune responses to HIV-1 Tat by new pro-GSH molecules. AB - We have previously demonstrated that in Ova-immunized mice the increase in intra macrophage thiol pool induced by pro-GSH molecules modulates the Th1/Th2 balance in favour of a Th1-type immune response. We show now that the same molecules can support a Th1-type over Th2-type immunity against Tat, which is an early HIV-1 regulatory protein and a Th1 polarizing immunomodulator that is increasingly considered in new anti-HIV vaccination strategies. Our results indicate that Tat immunized mice pre-treated with the C4 (n-butanoyl) derivative of reduced glutathione (GSH-C4) or a pro-drug of N-acetylcysteine (NAC) and beta mercaptoethylamine (MEA) (I-152), have decreased levels of anti-Tat IgG1 as well as increased levels of anti-Tat IgG2a and IgG2b isotypes suggesting a Th1-type response. Moreover, Th1-(IFN-gamma and IL-2) Ag-specific cellular responses were detected by ELISPOT assay in splenocytes of the same animals as well as an increase of IL-12 levels in the plasma. These findings suggest that the Th1 immune response to HIV-1 Tat could be further polarized by these molecules. These results together with those previously reported suggest that pro-GSH molecules could be used to modulate the immune response towards different antigens and may be further exploited for inducing specific Th1 immune responses against other HIV antigens as well as other intracellular pathogens in new Tat-based vaccination protocols. PMID- 21816193 TI - The cost-effectiveness of male HPV vaccination in the United States. AB - INTRODUCTION: The objective of this study was to estimate the cost-effectiveness of adding human papillomavirus (HPV) vaccination of 12-year-old males to a female only vaccination program for ages 12-26 years in the United States. METHODS: We used a simplified model of HPV transmission to estimate the reduction in the health and economic burden of HPV-associated diseases in males and females as a result of HPV vaccination. Estimates of the incidence, cost-per-case, and quality of-life impact of HPV-associated health outcomes were based on the literature. The HPV-associated outcomes included were: cervical intraepithelial neoplasia (CIN); genital warts; juvenile-onset recurrent respiratory papillomatosis (RRP); and cervical, vaginal, vulvar, anal, oropharyngeal, and penile cancers. RESULTS: The cost-effectiveness of male vaccination depended on vaccine coverage of females. When including all HPV-associated outcomes in the analysis, the incremental cost per quality-adjusted life year (QALY) gained by adding male vaccination to a female-only vaccination program was $23,600 in the lower female coverage scenario (20% coverage at age 12 years) and $184,300 in the higher female coverage scenario (75% coverage at age 12 years). The cost-effectiveness of male vaccination appeared less favorable when compared to a strategy of increased female vaccination coverage. For example, we found that increasing coverage of 12-year-old girls would be more cost-effective than adding male vaccination even if the increased female vaccination strategy incurred program costs of $350 per additional girl vaccinated. CONCLUSIONS: HPV vaccination of 12 year-old males might potentially be cost-effective, particularly if female HPV vaccination coverage is low and if all potential health benefits of HPV vaccination are included in the analysis. However, increasing female coverage could be a more efficient strategy than male vaccination for reducing the overall health burden of HPV in the population. PMID- 21816194 TI - Live attenuated influenza vaccine (LAIV) impacts innate and adaptive immune responses. AB - Influenza A infection induces a massive inflammatory response in the lungs that leads to significant illness and increases the susceptibility to secondary bacterial pneumonia. The most efficient way to prevent influenza infection is through vaccination. While inactivated vaccines induce protective levels of serum antibodies to influenza hemaglutinin (HA) and neuraminidase (NA) surface proteins, these are strain specific and offer little protection against heterosubtypic influenza viruses. In contrast, live attenuated influenza vaccines (LAIVs) induce a T cell response in addition to antibody responses against HA and NA surface proteins. Importantly, LAIV vaccination induces a response in a mouse model that protects against illness due to heterosubtypic influenza strains. While it is not completely clear what is the mechanism of action of LAIV heterosubtypic protection in humans, it has been shown that LAIV induces heterosubtypic protection in mice that is dependent upon a Type 1 immune response and requires CD8 T cells. In this study, we show that LAIV-induced immunity leads to significantly reduced viral titers and inflammatory responses in the lungs of mice following heterosubtypic infection. Not only are viral titers reduced in LAIV vaccinated mice, the amounts of inflammatory cytokines and chemokines in lung tissue are significantly lower. Additionally, we show that LAIV vaccination of healthy adults also induces a robust Type 1 memory response including the production of chemokines and cytokines involved in T cell activation and recruitment. Thus, our results indicate that LAIV vaccination functions by inducing immune memory which can act to modulate the immune response to subsequent heterosubtypic challenge by influencing both innate and adaptive responses. PMID- 21816195 TI - Hospital-based surveillance of rotavirus gastroenteritis in the era of limited vaccine uptake through the private sector. AB - To investigate possible impact of limited vaccine uptake by the private sector since 2007, a prospective observational study included all children <5 years hospitalized for acute gastroenteritis (AGE) in a Tertiary Care Hospital between 09/2006 and 08/2010. Rotavirus (RV) antigen was detected in stools by a rapid immunochromatographic test and genotype analysis was performed on positive samples by RT-PCR. Compared to 2006-2008, the likelihood of rotavirus infection was significantly reduced among children hospitalized for AGE in 2008-2010 (OR 0.64; 95%CI: 0.49-0.84, p<0.001). This was mainly due to the reduction of RVGE cases in infants 0-11 months (p=0.035). Moreover, RVGE cases as well as the rate of RVGE/10,000 hospitalized children significantly decreased (p=0.009 and p=0.010 respectively). No children with rotavirus gastroenteritis (RVGE) had received any vaccine dose. G4P [8] was the most common genotype (64/90). In conclusion, this study indicates that even low RV vaccination coverage may have significant effect. PMID- 21816196 TI - Protection of mice from Mycobacterium tuberculosis by ID87/GLA-SE, a novel tuberculosis subunit vaccine candidate. AB - Tuberculosis is a major health concern. Non-living tuberculosis (TB) vaccine candidates may not only be safer than the current vaccine (BCG) but could also be used to boost BCG to enhance or elongate protection. No subunit vaccines, however, are currently available for TB. To address this gap and to improve the global TB situation, we have generated a defined subunit vaccine by genetically fusing the genes of 3 potent protein Mtb antigens, Rv2875, Rv3478 and Rv1886, into a single product: ID87. When delivered with a TLR4 agonist-based adjuvant, GLA-SE, ID87 immunization reduced Mtb burden in the lungs of experimentally infected mice. The reduction in bacterial burden of ID87/GLA-SE immunized mice was accompanied by an early and significant leukocyte infiltration into the lungs during the infectious process. ID87/GLA-SE appears to be a promising new vaccine candidate that warrants further development. PMID- 21816197 TI - Presence of immune memory and immunity to hepatitis B virus in adults after neonatal hepatitis B vaccination. AB - Neonatal vaccination against hepatitis B virus (HBV) infection was launched in the 1980s in Qidong, China, where HBV and hepatocellular carcinoma were highly prevalent. Presence of immune memory and immunity against HBV in adults needs to be clarified. From a cohort of 806 who received plasma-derived Hep-B-Vax as neonates and were consecutively followed at ages 5, 10, and 20 years, 402 twenty four-year-old adults were recruited for booster test. Among them 4 (1%) were found to be HBsAg(+), 27 (6.7%) were HBsAg(-)anti-HBc(+), 121 (30.2%) were HBsAg( )anti-HBc(-)anti-HBs(+), and 252 (62.4%) were HBsAg(-)anti-HBc(-)anti-HBs(-). Of them, 141 subjects with HBsAg(-)anti-HBc(-) were boosted with 10-MUg recombinant HBV vaccine on day-0 and 1-month. The conversion rates of anti-HBs >= 10 mIU/ml on D10-12 and 1-month post-booster were 71.4% and 87.3% respectively in the vaccinees who were anti-HBs(+) at age 5, higher than in those who were anti-HBs( ) at age 5, 57.5% and 80.0% respectively, but no statistically significant. After the second dose of booster, all subjects with anti-HBs(+) at age 5 had anti-HBs >500 mIU/ml. However, 6/40 subjects, with anti-HBs(-) at age 5, had anti-HBs <10 mIU/ml, geometric mean concentration was 3.6 (95% CI 2.0-7.7). Of the subjects received booster, 44 subjects were determined the presence of T cell immunity on D10-12, 41 had HBsAg-specific T cells detectable, including 7/10 subjects whose anti-HBs were <10 mIU/ml 10-12 days post-booster. Among 27 HBsAg(-)anti-HBc(+) subjects, 19 had detectable serum HBV-DNA, and an "a" epitope mutation was found in 1/5 HBV isolates. One subject who was anti-HBc(+) at age 20 converted into HBsAg(+) 4 years later. The adults received neonatal HBV vaccination had immune memory and immunity against HBV infection. However, 31.9% of neonatal HBV vaccinees who responded weakly at an early age might be susceptible to HBV infection after childhood. PMID- 21816198 TI - The immunogenicity of pneumococcal polysaccharides in infants and children: a meta-regression. AB - The immunogenicity of plain (not conjugated) pneumococcal polysaccharides in children and infants was reviewed using a systematic literature search. Immunogenicity was defined as the fold-increase in serotype specific antibody concentration after a single dose of plain polysaccharide vaccine in unprimed subjects. Meta-regression was used to calculate the influence of study treatments including subject age, sampling time, dosage, immunization route, vaccine composition and study location. Immunogenicity increased with age for all serotypes, and the increase was more rapid in the first 11 months of life. Study location was the next most significant study variable, with higher responses in countries with lower GDP. A flat dose-response curve was observed over a range from 5 to 50 MUg polysaccharide. Serotypes 6A, 6B, 14, 19F and 23F were significantly less immunogenic than serotypes 2, 3, 4, 7F, 8, 9N, 9V and 18C in 11 month old children, but continued to increase in immunogenicity with age until reaching similar levels at 6 years. Some proposed T-independent immune mechanisms could explain the differences in serotype immunogenicity. PMID- 21816199 TI - Safety and immunogenicity of a virus-like particle pandemic influenza A (H1N1) 2009 vaccine in a blinded, randomized, placebo-controlled trial of adults in Mexico. AB - Virus-like particles (VLPs) can be rapidly developed from influenza virus genetic sequences in order to supply vaccine after the onset of a pandemic. The safety and immunogenicity of one or two doses of a recombinant A (H1N1) 2009 influenza VLP vaccine was evaluated in a two-stage, Phase 2, randomized, double-blind, placebo-controlled study conducted in 4563 healthy adults, 18-64 years of age, during the H1N1 2009 pandemic in Mexico. In Part A, 1013 subjects were randomized into four treatment groups (5 MUg, 15 MUg, or 45 MUg hemagglutinin [HA] VLP vaccine or placebo) and vaccinated 21 days apart, with sera collected on Days 1, 14 and 36 for hemagglutination inhibition (HAI) testing. After review of safety and immunogenicity data from Part A, additional subjects were immunized with a single dose of 15 MUg VLP vaccine (N=2537) or placebo (N=1011) and assessed for safety in Part B. Results showed the H1N1 2009 VLP vaccine was safe and well tolerated. Systemic solicited events were similar between placebo and VLP vaccinated groups with no vaccine-related serious adverse events. Dose response trends for solicited local adverse events were observed, with higher incidences of local pain, swelling, tenderness, and redness reported in the higher VLP dose groups (15 MUg and 45 MUg) compared to the placebo and 5 MUg VLP groups following both vaccinations. Although the majority of local AEs were mild in severity, a dose trend in events of moderate or greater severity was also noted for these solicited events. The VLP vaccine groups demonstrated robust HAI immune responses after a single vaccination, with high rates of seroprotection (>= 40 HAI titer) in 82-92% of all subjects and in 64-85% of subjects who were seronegative at the time of immunization. HAI geometric mean titers (GMTs), geometric mean ratios (GMRs) and seroconversion rates were also all statistically higher in the VLP groups compared to placebo for both post-baseline time points. Based on these data, additional clinical trials are in development to evaluate influenza vaccine candidate antigens manufactured using Spodoptera frugiperda (Sf9)/baculovirus based VLP technology. PMID- 21816200 TI - A novel, broad spectrum therapeutic HPV vaccine targeting the E7 proteins of HPV16, 18, 31, 45 and 52 that elicits potent E7-specific CD8T cell immunity and regression of large, established, E7-expressing TC-1 tumors. AB - Persistent infection by high risk genotypes of human papillomavirus (HPV) is the cause of cervical cancer, which remains one of the most common cancers among women worldwide. In addition, there is a growing appreciation that high risk HPVs are associated with a number of other cancers including anogenital cancers as well as a subset of head and neck cancers. Recently, prophylactic HPV vaccines targeting the two most prevalent high risk HPVs (HPV16 and HPV18) have been deployed in large-scale vaccination campaigns. However, the extent to which these prophylactic vaccines confer protection against other high risk HPV genotypes is largely unknown and prophylactic vaccines have been shown to be ineffective against pre-existing infection. Thus there continues to be an urgent need for effective therapeutic vaccines against HPV. The E7 protein of HPV16 has been widely studied as a target for therapeutic vaccines in HPV-associated cancer settings because HPV16 is the most prevalent of the high risk HPV genotypes. However, HPV16 accounts for only about 50% of cervical cancers and there are at least 15 other high risk HPVs that are known to be oncogenic. We have developed a novel, broad-spectrum, therapeutic vaccine (Pentarix) directed at the E7 proteins from five of the most prevalent high-risk genotypes of HPV worldwide (HPV16, 18, 31, 45 and 52) that together account for more than 80% of all HPV-associated cancers. Pentarix is a recombinant protein-based vaccine that elicits strong, multi-genotype specific CD8 T cell immunity when administered to mice in combination with adjuvants comprised of agonists of the TLR3 or TLR9 family of innate immune receptors. Furthermore, large, established E7-expressing TC-1 tumors undergo rapid and complete regression after therapeutic vaccination of mice with Pentarix. Together, these data suggest that Pentarix may be of clinical value for patients with E7-positive, HPV-associated precancerous lesions or malignant disease. PMID- 21816201 TI - Influence of the drying method in the antioxidant potential and chemical composition of four shrubby flowering plants from the tribe Genisteae (Fabaceae). AB - Flowers from several common Mediterranean shrubs, such as those from the Cytisus genus and Genista genus (tribe Genisteae/Fabaceae) have long been used for medicinal purposes and seasoning in the northeastern Portuguese region. Despite, the shade-drying traditionally used to process these plants, freeze-drying is claimed to better preserve the quality of medicinal plants. Herein, the effects of drying process in the antioxidants composition and properties of Cytisus multiflorus, Cytisus scoparius, Cytisus striatus and Pterospartum tridentatum were evaluated. Freeze-dried P. tridentatum revealed the highest antioxidant properties (EC(50) values <= 0.15 mg/ml). Freeze-drying benefits were confirmed showing, the samples submitted to this process, higher antioxidant activity and higher concentrations of hydrophilic (phenolics, ascorbic acid and sugars) and lipophilic (tocopherols, chlorophylls and lycopene) compounds. This process could be applied in scale-up treatments of the studied plants for cosmetic or pharmaceutical applications. PMID- 21816202 TI - Two novel families of antimicrobial peptides from skin secretions of the Chinese torrent frog, Amolops jingdongensis. AB - The characterization of new natural antimicrobial peptides (AMPs) can help to solve the serious problem of bacterial resistance to currently used antibiotics. In the current study, we analyzed two families of AMPs from the Chinese torrent frog Amolops jingdongensis with a range of bioactivities. The first family of peptides, named jindongenin-1a, is 24 amino acids in length; a BLAST search of jindongenin-1a revealed no sequence similarity with other AMPs. The second family consists of two peptides containing 29 amino acid residues each. These peptides have high sequence similarity with the AMPs of palustrin-2 and are therefore designated palustrin-2AJ1 and palustrin-2AJ2. The cDNA sequences encoding these AMPs have been cloned and the deduced protein sequence of each AMP has been determined by protein sequencing. Sequence and structural analysis showed that each precursor is composed of a putative signal peptide, an N-terminal spacer, a processing site and a disulfide-bridged heptapeptide segment at the C-terminus. We synthesized jindongenin-1a and palustrin-AJ1 to test their antimicrobial, hemolytic, antioxidative and cytotoxic activities. These two peptides showed broad-spectrum antimicrobial activity to standard and clinically isolated strains of bacteria. In addition, they exhibited weak hemolytic activity to human and rabbit erythrocytes under our experimental conditions. Moreover, these peptides also displayed cytotoxic activity against the K562 and HT29 mammalian cell lines and low anti-oxidant activity. These findings provide helpful insight that will be useful in the design of anti-infective peptide agents. PMID- 21816203 TI - Dual-function RNA regulators in bacteria. AB - The importance of small RNA (sRNA) regulators has been recognized across all domains of life. In bacteria, sRNAs typically control the expression of virulence and stress response genes via antisense base pairing with mRNA targets. Originally dubbed "non-coding RNAs," a number of bacterial antisense sRNAs have been found to encode functional proteins. Although very few of these dual function sRNAs have been characterized, they have been found in both gram negative and gram-positive organisms. Among the few known examples, the functions and mechanisms of regulation by dual-function sRNAs are variable. Some dual function sRNAs depend on the RNA chaperone Hfq for base pairing-dependent regulation (riboregulation); this feature appears so far exclusive to gram negative bacterial sRNAs. Other variations can be found in the spatial organization of the coding region with respect to the riboregulation determinants. How the functions of encoded proteins relate to riboregulation is for the most part not understood. However, in one case it appears that there is physiological redundancy between protein and riboregulation functions. This mini review focuses on the two best-studied bacterial dual-function sRNAs: RNAIII from Staphylococcus aureus and SgrS from Escherichia coli and includes a discussion of what is known about the structure, function and physiological roles of these sRNAs as well as what questions remain outstanding. PMID- 21816204 TI - Functional evidence of post-transcriptional regulation by pseudogenes. AB - Pseudogenes have been mainly considered as functionless evolutionary relics since their discovery in 1977. However, multiple mechanisms of pseudogene functionality have been proposed both at the transcriptional and post-transcriptional level. This review focuses on the role of pseudogenes as post-transcriptional regulators. Two lines of research have recently presented strong evidence of their potential function as post-transcriptional regulators of the corresponding parental genes from which they originate. First, pseudogene genomic sequences can encode siRNAs. Second, pseudogene transcripts can act as indirect post transcriptional regulators decoying ncRNA, in particular miRNAs that target the parental gene. This has been demonstrated for PTEN and KRAS, two genes involved in tumorigenesis. The role of pseudogenes in disease has not been proven and seems to be the next research landmark. In this review, we chronicle the events following the initial discovery of the 'useless' pseudogene to its breakthrough as a functional molecule with hitherto unbeknownst potential to influence human disease. PMID- 21816205 TI - Controlling phospholipid self-assembly and film properties using highly fluorinated components--fluorinated monolayers, vesicles, emulsions and microbubbles. AB - Use of fluorinated components instead or along with standard phospholipids in film, vesicle, bubble and emulsion engineering, can cause drastic modifications of the formation processes, structure and dynamics, and functional behavior of these systems. Perfluoroalkyl chains provide a powerful driving force for self assembly and ordering. They allow, for example, obtainment of thermally stable vesicles from single-chain phosphocholine derivatives, tubules from non-chiral amphiphiles, faceted vesicles with fluid bilayer membranes, exceptionally stable and narrowly dispersed emulsions and microbubbles. Contact of a monolayer of DPPC with a fluorocarbon gas modifies the monolayer's phase behavior, suppressing the liquid expanded/liquid condensed transition. Phospholipid absorption kinetics at an air/water interface can be substantially accelerated, and the equilibrium interfacial tension reduced by exposure to a fluorocarbon gas. Perfluoroalkyl chains induce nanocompartmentation in films and membranes, allowing, for example, polymerization within vesicular membranes. Vesicles involving highly fluorinated components generally exhibit stability, permeability, fusion and recognition characteristics, different from those of their hydrogenated analogues. Drastic stabilization can be gained for phospholipid-coated emulsions through a co surfactant effect of (perfluoroalkyl)alkyl diblocks. Stable, size-controlled, narrowly dispersed populations of microbubbles have been obtained using fluorinated wall and/or internal gas components, allowing progress in the understanding of microbubble physics, and open new application perspectives. PMID- 21816206 TI - Ruthenium methylimidazole complexes induced apoptosis in lung cancer A549 cells through intrinsic mitochondrial pathway. AB - Ruthenium(II) methylimidazole complexes, with the general formula [Ru(MeIm)(4)(N?N)](2+) (N?N = tip (RMC1), iip (RMC2), dppz (RMC3), dpq (RMC4); MeIm = 1-methylimidazole, tip = 2-(thiophene-2-yl)-1H-imidazo [4,5-f] [1,10]phenanthroline, iip = 2-(1H-imidazol-4-yl)-1H-imidazo [4,5-f] [1,10]phenanthroline, dppz = dipyrido[3,2-a:2',3'-c]phenazine, dpq = pyrazino [2,3-f] [1,10]phenanthroline), were synthesized and characterized. As determined by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, these complexes displayed potent anti-proliferation activity against various cancer cells. RMC1 inhibited the growth of A549 (human lung adenocarcinoma) lung cells through induction of apoptotic cell death, as evidenced by the accumulation of cell population in sub-G1 phase. RMC1 also induced the depletion of mitochondrial membrane potential in A549 cells by regulating the expression of pro-survival and pro-apoptotic Bcl-2 family members. Another experiment showed that Bid protein was also activated by RMC1, which implied that RMC1 could existed two pathways crosstalk, namely, have exogenous death receptor signaling pathway. These results demonstrated that RMC1 induced cancer cell death by acting on both mitochondrial and death receptor apoptotic pathways, suggesting that RMC1 could be a candidate for further evaluation as a chemotherapeutic agent against human cancers. PMID- 21816207 TI - ALS genetic modifiers that increase survival of SOD1 mice and are suitable for therapeutic development. AB - Amyotrophic lateral sclerosis (ALS) is a frequently fatal motor neuron disease without any cure. To find molecular therapeutic targets, several studies crossed transgenic ALS murine models with animals transgenic for some ALS target genes. We aimed to revise the new discoveries and new works in this field. We selected the 10 most promising genes, according to their capability when down-regulated or up-regulated in ALS animal models, for increasing life span and mitigating disease progression: XBP-1, NogoA and NogoB, dynein, heavy and medium neurofilament, NOX1 and NOX2, MLC-mIGF-1, NSE-VEGF, and MMP-9. Interestingly, some crucial modifier genes have been described as being involved in common pathways, the most significant of which are inflammation and cytoskeletal activities. The endoplasmic reticulum also seems to play an important role in ALS pathogenesis, as it is involved in different selected gene pathways. In addition, these genes have evident links to each other, introducing the hypothesis of a single unknown, common pathway involving all of these identified genes and others to be discovered. PMID- 21816208 TI - Enhanced pain perception prior to smoking cessation is associated with early relapse. AB - Accumulated evidence suggests that nicotine induces analgesia, and endogenous pain regulatory mechanisms may be altered by chronic smoking. The extent to which individual differences in pain perception are related to smokers' ability to abstain from smoking has not been directly examined. Seventy-one smokers who were interested in quitting completed a pre-cessation laboratory session which included the cold pressor test (CPT). Pain ratings were collected during and after CPT. Also, mood changes, cardiovascular measures, and salivary cortisol samples were evaluated prior to, during, and after CPT. Participants attended 4 weekly follow-up assessment sessions after their quit day. Cox regression analysis revealed that higher pain ratings during and after CPT predicted greater risk for smoking relapse. These results remained significant after affective and physiological responses to CPT were controlled, suggesting that pain ratings prior to smoking cessation are potentially useful in identifying smokers who are at greater risk of early smoking relapse and may reflect underlying putative risk for nicotine dependence and relapse. PMID- 21816210 TI - Comparative pharmacokinetics of dehydroevodiamine and coptisine in rat plasma after oral administration of single herbs and Zuojinwan prescription. AB - Zuojinwan, which consists of Rhizoma coptidis-Evodia rutaecarpa powder (6:1,g/g), is a traditional Chinese medicine (TCM) prescription, clinically used for the treatment of gastro-intestinal disorders. This study compared the pharmacokinetics of dehydroevodiamine and coptisine, the main active ingredients in Zuojinwan, in rats administrated with whole prescription or single herbs. Multiple blood concentration peaks were observed in the mean plasma-concentration curves. The pharmacokinetic parameters were quite different between single herbs and Zuojinwan prescription. Moreover, the mean plasma concentration of dehydroevodiamine increased and the one of coptisine decreased after combining, which was in accord with the clinical principle of TCM. PMID- 21816209 TI - Alcohol induces synaptotagmin 1 expression in neurons via activation of heat shock factor 1. AB - Many synapses within the central nervous system are sensitive to ethanol. Although alcohol is known to affect the probability of neurotransmitter release in specific brain regions, the effects of alcohol on the underlying synaptic vesicle fusion machinery have been little studied. To identify a potential pathway by which ethanol can regulate neurotransmitter release, we investigated the effects of acute alcohol exposure (1-24 h) on the expression of the gene encoding synaptotagmin 1 (Syt1), a synaptic protein that binds calcium to directly trigger vesicle fusion. Syt1 was identified in a microarray screen as a gene that may be sensitive to alcohol and heat shock. We found that Syt1 mRNA and protein expression are rapidly and robustly up-regulated by ethanol in mouse cortical neurons, and that the distribution of Syt1 protein along neuronal processes is also altered. Syt1 mRNA up-regulation is dependent on the activation of the transcription factor heat shock factor 1 (HSF1). The transfection of a constitutively active Hsf1 construct into neurons stimulates Syt1 transcription, while transfection of Hsf1 small interfering RNA (siRNA) or a constitutively inactive Hsf1 construct into neurons attenuates the induction of Syt1 by ethanol. This suggests that the activation of HSF1 can induce Syt1 expression and that this may be a mechanism by which alcohol regulates neurotransmitter release during brief exposures. Further analysis revealed that a subset of the genes encoding the core synaptic vesicle fusion (soluble NSF (N-ethylmaleimide sensitive factor) attachment protein receptor; SNARE) proteins share this property of induction by ethanol, suggesting that alcohol may trigger a specific coordinated adaptation in synaptic function. This molecular mechanism could explain some of the changes in synaptic function that occur following alcohol administration and may be an important step in the process of neuronal adaptation to alcohol. PMID- 21816212 TI - In honor of Takeru Higuchi. PMID- 21816211 TI - Bioadhesion and enhanced bioavailability by wheat germ agglutinin-grafted lipid nanoparticles for oral delivery of poorly water-soluble drug bufalin. AB - Wheat germ agglutinin (WGA)-grafted lipid nanoparticles has been prepared and its in vitro association with Caco-2 cells has been studied previously. The purpose of this study was to further investigate the potential of WGA-grafted lipid nanoparticles for oral delivery of bufalin, a poorly water soluble drug, by evaluating its ex vivo bioadhesion with intestinal mucosal segments and in vivo bioavailability. A significant higher adhesion between WGA-grafted lipid nanoparticles and intestinal mucosa was found compared with that of WGA-free lipid nanoparticles (p<0.05). The in vivo pharmacodynamic studies were performed by oral administration of WGA-grafted lipid nanoparticles and suspensions to fasted rats. Compared with suspensions, WGA-grafted lipid nanoparticles showed much larger AUC and C(max), and a 2.7-fold improvement in oral bioavailability. These results illustrate the potential utility of WGA-grafted lipid nanoparticles for oral delivery of a poorly water-soluble drug such as bufalin. PMID- 21816213 TI - Inhibition of matrix metalloproteinases related to metastasis by diosgenyl and pennogenyl saponins. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Diosgenyl and pennogenyl saponins isolated from Rhizoma Paridis, showed pro-apoptosis and immunoregulation with antitumor activity in cultured cells and animal systems. AIM OF THE STUDY: To evaluate their anti-metastatic mechanism on cancer cells and discuss their structure activity relationship on anti-tumor effect. MATERIALS AND METHODS: This research used the wound healing and migration assay to detect their anti-invasive effect on B16 melanoma cells. Through the gelatin zymography assay, immunofluorescence analysis and western blot, saponins exhibited different levels of protein expression inhibition of MMP-1, -2, -3, -9 and -14. RESULTS: Through the analysis, diosgenyl and pennogenyl saponins inhibited the metastasis of B16 melanoma cells. Diosgenyl saponins also showed strong suppression of enzyme activity of MMP-2 and -9. Different saponins exhibited different levels of inhibition on MMP expression. CONCLUSIONS: 17-alpha OH increases the sensitivity of diosgenyl saponins to the membrane-bound protease which can stimulate proMMP-2 activation, but it also decreases the anti-metastatic activity of diosgenyl saponin. Furthermore, their combination might provide a potential therapeutic modality for metastasis. PMID- 21816214 TI - Wound repair and anti-inflammatory potential of essential oils from cones of Pinaceae: preclinical experimental research in animal models. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Ethnobotanical surveys revealed that Abies bornmulleriana, Abies cilicica, Abies nordmanniana and Cedrus libani have been used to promote wound healing in Turkish folk medicine. Four different fir species (Abies cilicica subsp. cilicica, Abies nordmanniana subsp. bornmulleriana, Abies nordmanniana subsp. equi-trojani, and Abies nordmanniana subsp. nordmanniana), Cedrus libani and Picea orientalis were assessed for their in vivo wound healing and anti-inflammatory activities. MATERIALS AND METHODS: The essential oils from six different coniferous cones were used. In vivo wound healing activity of the plants was evaluated by linear incision and circular excision experimental wound models subsequently histopathological analysis. The healing potential was comparatively assessed with a reference ointment Madecassol((r)), which contains 1% extract of Centella asiatica. Additionally acetic acid-induced capillary permeability test was used for the oils' anti inflammatory activity. RESULTS: The essential oils from Cedrus libani and Abies cilicica subsp. cilicica demonstrated the highest activities on the both wound models. Moreover, the oil from Abies nordmanniana subsp. bornmulleriana was found generally highly effective. On the other hand, the rest of the species did not show any remarkable wound healing effect. Results of the present study support the continued and expanded utilization of these plant species employed in Turkish folk medicine. CONCLUSION: The experimental study revealed that Cedrus libani and Abies cilicica subsp. cilicica display remarkable wound healing and anti inflammatory activities. PMID- 21816215 TI - Partially purified components of Nardostachys chinensis suppress melanin synthesis through ERK and Akt signaling pathway with cAMP down-regulation in B16F10 cells. AB - Ethnopharmacological relevance Nardostachys chinensis has been used in folk medicine to treat melasma and lentigines in Korea. We investigated the inhibitory activities of Nardostachys chinensis in melanogenesis and its related signaling pathway. MATERIALS AND METHODS: Bioassay-guided fractionation of Nardostachys chinensis using solvent partitioning and purification with octadecylsilane open column chromatography resulted in partial purification. The active 20% methanol chromatographic fraction from the ethyl acetate layer (PPNC) was used to investigate melanogenesis by melanin synthesis, tyrosinase activity assay, cAMP assay, Western blot and flow cytometric analyses in B16F10 mouse melanoma cells. RESULTS: PPNC markedly inhibits melanin synthesis and tyrosinase activity in a concentration-dependent manner. We also found that PPNC decreases microphthalmia associated transcription factor (MITF), tyrosinase, tyrosinase-related protein (TRP)-1, and dopachrome tautomerase (Dct) protein expressions and MITF and tyrosinase mRNA levels. Moreover, PPNC reduces intracellular cAMP levels and activates mitogen-activated protein kinase kinase (MEK)/extracellular signal regulated kinase (ERK) and phosphatidylinositol 3-kinase (PI3K)/Akt expression in B16F10 cells. The specific MEK/ERK inhibitor PD98059 and PI3K/Akt inhibitor LY294002, block the PPNC-induced hypopigmentation effect, and abrogate the PPNC suppressed expression of melanogenic proteins such as MITF, tyrosinase, TRP-1, and Dct. Using flow cytometry, we elucidated whether PPNC directly induces ERK phosphorylation at the level of an intact single cell. PPNC shows marked expression of phosphorylated ERK in live B16F10 cells and abrogates PPNC-induced phosphorylated ERK by PD98059 treatment. CONCLUSIONS: PPNC stimulates MEK/ERK phosphorylation and PI3K/Akt signaling with suppressing cAMP levels and subsequently stimulating MITF and TRPs down-regulation, resulting in melanin synthesis suppression. PMID- 21816216 TI - Treatment of leishmaniasis in the Oyapock basin (French Guiana): A K.A.P. survey and analysis of the evolution of phytotherapy knowledge amongst Wayapi Indians. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Cutaneous leishmaniasis is a neglected disease with a high incidence in French Guiana, mainly in the middle and upper Oyapock basin, where Amerindian and some Brazilian people live. The main goals of this work were (i) to assess the knowledge about leishmaniasis in the different populations of the middle and upper Oyapock basin, (ii) to study the therapeutic strategies adopted by people affected by leishmaniasis and (iii) to document the use of phytotherapeutic remedies for leishmaniasis. Knowledge, attitudes and practices (K.A.P.) related to this disease and its treatments have been studied according to cultural group and geographical settlement. Within the Wayapi group, the evolution of the knowledge of phytoremedies over the last 20 years has been characterised by literature-based comparisons. MATERIALS AND METHODS: A total of 144 questionnaires were administered in all the villages of the upper Oyapock and Camopi basins. Correspondence analyses were used for multivariate analysis. Plant species were identified at the Cayenne Herbarium (CAY). RESULTS: The biomedical concept of leishmaniasis correlates well with the Teko and Wayapi concepts of kalasapa and kalasapau. Although the vector of this disease was not correctly identified, the most commonly cited aetiology (74.5%) was vector-borne, and related epidemiological schemes correlate well with the one encountered in French Guiana. Theoretically and practically, health centres were the most commonly used resource for diagnostic in instances of leishmaniasis infection (65.9%), independently of the patient's cultural group, along with the use of pharmaceutical drugs (85.3%). Pharmaceuticals were commonly utilised despite the frequent (51.5%) use of phytotherapeutic remedies, alone or in combination with drugs. The most cited medicinal plant species for the treatment of leishmaniasis included Eleutherine bulbosa (Mill.) Urb. (Iridaceae, cited 14 times), Euterpe oleracea Mart. (Arecaceae, 9), Cecropia obtusa Trecul (Cecropiaceae, 8), Jatropha curcas L. (Euphorbiaceae, 7), Ceiba pentandra (L.) Gaertn. (Bombacaceae, 6) and Carica papaya L. (Caricaceae, 6). Multiple correspondence analyses demonstrated that the species used in leishmaniasis remedies are more prone to vary by the user's place of residence than by their cultural origin, which indicates that exchange of knowledge about leishmaniasis remedies has occurred across different cultural groups. Literature-based comparisons between the remedies for leishmaniasis used by the Wayapi during the 1980s showed a striking evolution, both in terms of diversity of species and number of plants used. The large number of species shared with other Guianese groups argues for intercultural exchange and may explain the majority (57.1%) of the newly used species highlighted in our study. CONCLUSIONS: Leishmaniasis is a well-known disease in the studied area. Phytotherapeutic treatments are still in use, although they are not the main source of remedies, and should undergo pharmacological studies to evaluate their potential therapeutic value. PMID- 21816217 TI - Autophagy regulates ROS-induced cellular senescence via p21 in a p38 MAPKalpha dependent manner. AB - Oxidative stress induces not only senescence but also autophagy in a variety of mammalian cells. However, the relationship between these two has not been well established and thus, was investigated in the present study using WI38 human diploid fibroblasts (WI38 cells) as a model system. Our results showed that exposure of WI38 cells to H2O2 induced both senescence and autophagy. Downregulation of autophagy protein 5 (Atg5) with Atg5 siRNA inhibited not only autophagy but also senescence induced by H2O2. Further studies showed that Atg5 regulates H2O2-induced senescence primarily by up-regulating the expression of p21 at the level of post-transcription. In addition, we examined the mechanisms by which H2O2 induces autophagy in WI38 cells. Our results revealed that H2O2 increases autophagy independent of the mammalian target of rapamycin (mTOR) negative feedback pathway. Instead, the induction of autophagy by H2O2 depends on the induction of intracellular production of reactive oxygen species (ROS) and activation of the p38 mitogen-activated protein kinase alpha (p38 MAPKalpha) pathway. PMID- 21816218 TI - Molecular identification of Bartonella quintana infection using species-specific real-time PCR targeting transcriptional regulatory protein (bqtR) gene. AB - We describe a SYBR Green I-based real-time PCR targeting Bartonella quintana transcriptional regulatory protein (bqtR) gene, recently found as invariant gene among different B. quintana strains. Melting curve analysis allowed us to discriminate between B. quintana and Bartonella henselae amplified products. We also show its usefulness in the management of a blood culture-negative patient affected by enlarged cervical lymphonodes and long-lasting fever. B. quintana DNA detection in patient whole blood samples and blood culture bottles was confirmed by sequencing and analyzing amplified products. PMID- 21816219 TI - Long-term intermittent feeding, but not caloric restriction, leads to redox imbalance, insulin receptor nitration, and glucose intolerance. AB - Calorie restriction is a dietary intervention known to improve redox state, glucose tolerance, and animal life span. Other interventions have been adopted as study models for caloric restriction, including nonsupplemented food restriction and intermittent, every-other-day feedings. We compared the short- and long-term effects of these interventions to ad libitum protocols and found that, although all restricted diets decrease body weight, intermittent feeding did not decrease intra-abdominal adiposity. Short-term calorie restriction and intermittent feeding presented similar results relative to glucose tolerance. Surprisingly, long-term intermittent feeding promoted glucose intolerance, without a loss in insulin receptor phosphorylation. Intermittent feeding substantially increased insulin receptor nitration in both intra-abdominal adipose tissue and muscle, a modification associated with receptor inactivation. All restricted diets enhanced nitric oxide synthase levels in the insulin-responsive adipose tissue and skeletal muscle. However, whereas calorie restriction improved tissue redox state, food restriction and intermittent feedings did not. In fact, long-term intermittent feeding resulted in largely enhanced tissue release of oxidants. Overall, our results show that restricted diets are significantly different in their effects on glucose tolerance and redox state when adopted long-term. Furthermore, we show that intermittent feeding can lead to oxidative insulin receptor inactivation and glucose intolerance. PMID- 21816221 TI - The effect of thiamin tetrahydrofurfuryl disulfide on behavior of juvenile DBA/2J mice. AB - Due to genetic defects or illness some individuals require higher amounts of thiamin than are typically provided by the diet. Lipid-soluble thiamin precursors can achieve high blood levels of thiamin and result in increased concentrations in the central nervous system. High intakes of thiamin have been reported as beneficial in children with autism and attention deficit/hyperactivity disorder. The current study examined the effect of thiamin tetrahydrofurfuryl disulfide (TTFD), a lipophilic precursor, on behavior in the juvenile male DBA/2J mouse. Mice given by oral gavage deionized water or deionized water providing 100 mg or 340 mg TTFD/kg body weight daily for 17 d, starting at postnatal day 18, were tested for effects on operant learning, social interaction, general activity level, and prepulse inhibition of acoustic startle, as well as effects on growth and select organ weights. Results indicate lower activity and altered social interaction at both treatment levels and decreased acoustic startle at the 100 mg/kg level. Compared to controls, percent weight gain was lower in the TTFD treatment groups, but percent body length increase was not affected by TTFD treatment. TTFD treatment did not influence percent organ weights as percentage of body weights. TTFD treatment resulted in increased whole brain thiamin concentrations. These results support the concept that lipophilic thiamin precursors provided during early development can affect a number of behavioral parameters. In clinical trials with children with behavior disorders, attention should be given to preventing possible adverse gastrointestinal irritant effects associated with TTFD therapy. PMID- 21816220 TI - Nuclear factor erythroid 2-related factor-2 activity controls 4-hydroxynonenal metabolism and activity in prostate cancer cells. AB - 4-Hydroxynonenal (HNE) is an end product of lipoperoxidation with antiproliferative and proapoptotic properties in various tumors. Here we report a greater sensitivity to HNE in PC3 and LNCaP cells compared to DU145 cells. In contrast to PC3 and LNCaP cells, HNE-treated DU145 cells showed a smaller reduction in growth and did not undergo apoptosis. In DU145 cells, HNE did not induce ROS production and DNA damage and generated a lower amount of HNE-protein adducts. DU145 cells had a greater GSH and GST A4 content and GSH/GST-mediated HNE detoxification. Nuclear factor erythroid 2-related factor-2 (Nrf2) is a regulator of the antioxidant response. Nrf2 protein content and nuclear accumulation were higher in DU145 cells compared to PC3 and LNCaP cells, whereas the expression of KEAP1, the main negative regulator of Nrf2 activity, was lower. Inhibition of Nrf2 expression with specific siRNA resulted in a reduction in GST A4 expression and GS-HNE formation, indicating that Nrf2 controls HNE metabolism. In addition, Nrf2 knockdown sensitized DU145 cells to HNE-mediated antiproliferative and proapoptotic activity. In conclusion, we demonstrated that increased Nrf2 activity resulted in a reduction in HNE sensitivity in prostate cancer cells, suggesting a potential mechanism of resistance to pro-oxidant therapy. PMID- 21816222 TI - 17beta-estradiol attenuates breakdown of blood-brain barrier and hemorrhagic transformation induced by tissue plasminogen activator in cerebral ischemia. AB - Tissue plasminogen activator (tPA) remains the only approved thrombolytic agent for the early treatment of ischemic stroke. However, treatment with tPA may lead to disruption of the blood-brain barrier and hemorrhagic transformation. 17beta estradiol (E2) has demonstrated efficacy in reduction of infarct volume in ischemic stroke models. The effects of acute administration of E2 on permeability of the blood-brain barrier and its ability to prevent hemorrhagic transformation in ischemic rats treated with tPA have not previously been studied. Here, we show that neurological deficits, brain water content, and Evan's blue extravasation were increased in ovariectomized female Wistar rats treated with tPA and attenuated in rats receiving E2+tPA. We also show that intracerebral hemoglobin and matrix metalloproteinase-9 activity were elevated with tPA treatment, and these increases were reduced by E2 treatment. Taken together, these data demonstrate that acute administration of E2 is capable of ameliorating some of the adverse effects of tPA administration, including the increase of matrix metalloproteinase-9 activity, blood-brain barrier permeability, and hemorrhagic transformation. These findings suggest a potential role for estrogen in thrombolytic treatment for ischemic stroke. PMID- 21816223 TI - Bioavailability and inter-conversion of sulforaphane and erucin in human subjects consuming broccoli sprouts or broccoli supplement in a cross-over study design. AB - Broccoli consumption may reduce the risk of various cancers and many broccoli supplements are now available. The bioavailability and excretion of the mercapturic acid pathway metabolites isothiocyanates after human consumption of broccoli supplements has not been tested. Two important isothiocyanates from broccoli are sulforaphane and erucin. We employed a cross-over study design in which 12 subjects consumed 40 g of fresh broccoli sprouts followed by a 1 month washout period and then the same 12 subjects consumed 6 pills of a broccoli supplement. As negative controls for isothiocyanate consumption four additional subjects consumed alfalfa sprouts during the first phase and placebo pills during the second. Blood and urine samples were collected for 48h during each phase and analyzed for sulforaphane and erucin metabolites using LC-MS/MS. The bioavailability of sulforaphane and erucin is dramatically lower when subjects consume broccoli supplements compared to fresh broccoli sprouts. The peaks in plasma concentrations and urinary excretion were also delayed when subjects consumed the broccoli supplement. GSTP1 polymorphisms did not affect the metabolism or excretion of sulforaphane or erucin. Sulforaphane and erucin are able to interconvert in vivo and this interconversion is consistent within each subject but variable between subjects. This study confirms that consumption of broccoli supplements devoid of myrosinase activity does not produce equivalent plasma concentrations of the bioactive isothiocyanate metabolites compared to broccoli sprouts. This has implications for people who consume the recommended serving size (1 pill) of a broccoli supplement and believe they are getting equivalent doses of isothiocyanates. PMID- 21816224 TI - In vivo analysis of protein sumoylation induced by a viral protein: Detection of HCMV pp71-induced Daxx sumoylation. AB - Small ubiquitin-like modifiers (SUMOs) are covalently conjugated to target proteins to regulate numerous biological processes, including subcellular localization, protein-protein interactions, and transactivational activities. While the majority of identified SUMO targets are cellular proteins, SUMO modified viral proteins have also been identified. In addition, there are a growing number of examples where viruses alter the sumoylation status of host cell proteins. Work from our laboratory has previously demonstrated that the human cytomegalovirus (HCMV) virion tegument protein pp71 binds to Daxx, a cellular transcriptional co-repressor, and promotes its sumoylation. Here we describe the in vivo techniques used to detect pp71-induced sumoylation of Daxx in a cotransfection system as well as the endogenous SUMO modified form of Daxx in HCMV-infected cells. The approaches we describe can be easily adapted to infections with other viruses and for the detection of sumoylation of other proteins. PMID- 21816225 TI - Occipital gamma-oscillations modulated during eye movement tasks: simultaneous eye tracking and electrocorticography recording in epileptic patients. AB - We determined the spatio-temporal dynamics of cortical gamma-oscillations modulated during eye movement tasks, using simultaneous eye tracking and intracranial electrocorticography (ECoG) recording. Patients with focal epilepsy were instructed to follow a target moving intermittently and unpredictably from one place to another either in an instantaneous or smooth fashion during extraoperative ECoG recording. Target motion elicited augmentation of gamma oscillations in the lateral, inferior and polar occipital regions in addition to portions of parietal and frontal regions; subsequent voluntary eye movements elicited gamma-augmentation in the medial occipital region. Such occipital gamma augmentations could not be explained by contaminations of ocular or myogenic artifacts. The degree of gamma-augmentation was generally larger during saccade compared to pursuit trials, while a portion of the polar occipital region showed pursuit-preferential gamma-augmentations. In addition to the aforementioned eye movement task, patients were asked to read a single word popping up on the screen. Gamma-augmentation was elicited in widespread occipital regions following word presentation, while gamma-augmentation in the anterior portion of the medial occipital region was elicited by an involuntary saccade following word presentation rather than word presentation itself. Gamma-augmentation in the lateral, inferior and polar occipital regions can be explained by increased attention to a moving target, whereas gamma-augmentation in the anterior-medial occipital region may be elicited by images in the peripheral field realigned following saccades. In functional studies comparing brain activation between two tasks, eye movement patterns during tasks may need to be considered as confounding factors. PMID- 21816227 TI - Reconstructing intraordinal relationships in Lepidoptera using mitochondrial genome data with the description of two newly sequenced lycaenids, Spindasis takanonis and Protantigius superans (Lepidoptera: Lycaenidae). AB - Lepidoptera is one of the largest insect orders, but the phylogenetic relationships within this order, have yet to be adequately described. Among these unresolved relationships include those regarding the monophyly of the Macrolepidoptera and interfamilial relationships of the true butterflies superfamily Papilionoidea. We present two new mitochondrial genomes (mitogenomes) belonging to the butterfly family Lycaenidae to explore the phylogenetic relationships existing among lepidopteran superfamilies and true butterfly families from a mitogenome perspective, and to evaluate the characteristics of the lepidopteran mitogenomes. Our consensus phylogeny of the Lepidoptera largely supported the superfamilial relationships (((((Bombycoidea+Geometroidea)+Noctuoidea)+Pyraloidea)+Papilionoidea)+Tortricoide ), signifying a lack of support for a traditionally defined Macrolepidoptera. The familial relationships of the true butterflies concordantly recovered the previously proposed phylogenetic hypothesis (((Lycaenidae+Nymphalidae)+Pieridae)+Papilionidae). The test for the effect of optimization schemes (exclusion and inclusion of third codon position of PCGs and two rRNA genes, with and without partitions) on the resolution and relationships within the Lepidoptera have demonstrated that the majority of analyses did not substantially alter the relevant topology and node support, possibly as the result of relatively strong signal in mitogenomes for intraordinal relationships in Lepidoptera. PMID- 21816226 TI - Expanding horizons in ergonomics research. PMID- 21816229 TI - Synapsins: from synapse to network hyperexcitability and epilepsy. AB - The synapsin family in mammals consists of at least 10 isoforms encoded by three distinct genes and composed by a mosaic of conserved and variable domains. Synapsins, although not essential for the basic development and functioning of neuronal networks, are extremely important for the fine-tuning of SV cycling and neuronal plasticity. Single, double and triple synapsin knockout mice, with the notable exception of the synapsin III knockout mice, show a severe epileptic phenotype without gross alterations in brain morphology and connectivity. However, the molecular and physiological mechanisms underlying the pathogenesis of the epileptic phenotype observed in synapsin deficient mice are still far from being elucidated. In this review, we summarize the current knowledge about the role of synapsins in the regulation of network excitability and about the molecular mechanism leading to epileptic phenotype in mouse lines lacking one or more synapsin isoforms. The current evidences indicate that synapsins exert distinct roles in excitatory versus inhibitory synapses by differentially affecting crucial steps of presynaptic physiology and by this mean participate in the determination of network hyperexcitability. PMID- 21816230 TI - [Disseminated tinea incognita mimicking pustular psoriasis]. PMID- 21816228 TI - Structured three-dimensional co-culture of mesenchymal stem cells with chondrocytes promotes chondrogenic differentiation without hypertrophy. AB - OBJECTIVE: This study investigated a novel approach to induce chondrogenic differentiation of human mesenchymal stem cells (hMSC). We hypothesized that a structured three-dimensional co-culture using hMSC and chondrocytes would provide chondroinductive cues to hMSC without inducing hypertrophy. METHOD: In an effort to promote optimal chondrogenic differentiation of hMSC, we created bilaminar cell pellets (BCPs), which consist of a spherical population of hMSC encased within a layer of juvenile chondrocytes (JC). In addition to histologic analyses, we examined proteoglycan content and expression of chondrogenic and hypertrophic genes in BCPs, JC pellets, and hMSC pellets grown in the presence or absence of transforming growth factor-beta (TGFbeta) following 21 days of culture in either growth or chondrogenic media. RESULTS: In either growth or chondrogenic media, we observed that BCPs and JC pellets produced more proteoglycan than hMSC pellets treated with TGFbeta. BCPs and JC pellets also exhibited higher expression of the chondrogenic genes Sox9, aggrecan, and collagen 2A1, and lower expression of the hypertrophic genes matrix metalloproteinase-13, Runx2, collagen 1A1, and collagen 10A1 than hMSC pellets. Histologic analyses suggest that JC promote chondrogenic differentiation of cells in BCPs without hypertrophy. Furthermore, when cultured in hypoxic and inflammatory conditions intended to mimic the injured joint microenvironment, BCPs produced significantly more proteoglycan than either JC pellets or hMSC pellets. CONCLUSION: The BCP co-culture promotes a chondrogenic phenotype without hypertrophy and, relative to pellet cultures of hMSCs or JCs alone, is more resistant to the adverse conditions anticipated at the site of articular cartilage repair. PMID- 21816232 TI - Estrella lausannensis, a new star in the Chlamydiales order. AB - Originally, the Chlamydiales order was represented by a single family, the Chlamydiaceae, composed of several pathogens, such as Chlamydia trachomatis, Chlamydia pneumoniae, Chlamydia psittaci and Chlamydia abortus. Recently, 6 new families of Chlamydia-related bacteria have been added to the Chlamydiales order. Most of these obligate intracellular bacteria are able to replicate in free living amoebae. Amoebal co-culture may be used to selectively isolate amoeba resisting bacteria. This method allowed in a previous work to discover strain CRIB 30, from an environmental water sample. Based on its 16S rRNA gene sequence similarity with Criblamydia sequanensis, strain CRIB 30 was considered as a new member of the Criblamydiaceae family. In the present work, phylogenetic analyses of the genes gyrA, gyrB, rpoA, rpoB, secY, topA and 23S rRNA as well as MALDI-TOF MS confirmed the taxonomic classification of strain CRIB 30. Morphological examination revealed peculiar star-shaped elementary bodies (EBs) similar to those of C. sequanensis. Therefore, this new strain was called "Estrella lausannensis". Finally, E. lausannensis showed a large amoebal host range and a very efficient replication rate in Acanthamoeba species. Furthermore, E. lausannensis is the first member of the Chlamydiales order to grow successfully in the genetically tractable Dictyostelium discoideum, which opens new perspectives in the study of chlamydial biology. PMID- 21816231 TI - Key aspects of the molecular and cellular basis of inhalational anthrax. AB - Bacillus anthracis is the etiologic agent of the disease inhalational anthrax, an acute systemic infection initiated by inhaling spores, which if not rapidly detected and treated, results in death. Decades of research have elucidated novel aspects of anthrax pathogenesis but there are many issues left unresolved. PMID- 21816233 TI - Estrogen upregulates hepatic apolipoprotein M expression via the estrogen receptor. AB - Apolipoprotein M (apoM) is present predominantly in high-density lipoprotein (HDL) in human plasma, thus possibly involved in the regulation of HDL metabolism and the process of atherosclerosis. Although estrogen replacement therapy increases serum levels of apoAI and HDL, it does not seem to reduce the cardiovascular risk in postmenopausal women. Therefore, we investigated the effects of estrogen on apoM expression in vitro and in vivo. HepG2 cells were incubated with different concentrations of estrogen with or without the estrogen receptor antagonist, fulvestrant, and apoM expression in the cells was determined. Hepatic apoM expression and serum levels of apoM were also determined in normal and in ovariectomized rats treated with either placebo or estradiol benzoate, using sham operated rats as controls. Estrogen significantly increased mRNA levels of apoM and apoAI in HepG2 cell cultures in a dose- and time dependent manner; the upregulation of both apolipoproteins was fully abolished by addition of estrogen receptor antagonist. In normal rats, estrogen treatment led to an increase in plasma lipid levels including HDL cholesterol, a marked upregulation of apoM mRNA and a significant increase in serum levels of apoM. The same pattern of regulation was found in ovariectomized rats treated with estrogen. Thus, estrogen upregulates apoM expression both in vivo and in vitro by mechanism(s) involving the estrogen receptor. PMID- 21816234 TI - Oxidative stress and histological alterations produced by dietary copper in the fresh water bivalve Diplodon chilensis. AB - The aim of this work was to study the oxidative stress effects and histological alterations caused by dietary copper on the filter-feeding freshwater mussel Diplodon chilensis. Bivalves were fed during 6 weeks with the green algae Scenedesmus vacuolatus previously exposed to copper. Metal concentration in algae cultures and bivalve digestive gland was measured by TXRF. A maximum accumulation of 0.49 MUg Cu/mg protein was detected at week 6. Also at this week, the hepatosomatic index (HSI) showed the highest decrease (50%) in response to Cu exposure. SOD and GST activities were significantly increased at weeks 4, 5 and 6, reaching an activity on average 50% higher than in controls for GST. CAT activity and GSH increased significantly at weeks 5 and 6. Despite this response, oxidative damage measured as TBARS and carbonyl groups contents increased significantly at weeks 4, 5 and 6, respectively. Digestive tubule and duct atrophy and cell-type replacement in treated mussels were observed by histological studies. The presence of intracellular rhodanine-positive granules, suggests copper accumulation in intracellular vacuoles of digestive cells. PMID- 21816235 TI - Residual oil fly ash worsens pulmonary hyperreactivity in chronic allergic mice. AB - BALB/c mice received saline (SAL groups) or ovalbumin (OVA groups) intraperitoneally (days 1, 3, 5, 7, 9, 11 and 13). After 27 days, a burst of intratracheal OVA or SAL (days 40, 43 and 46) was performed. Animals were then divided into four groups (N=8, each) and intranasally instilled with saline (SAL SAL and OVA-SAL) or residual oil fly ash (SAL-ROFA and OVA-ROFA). 24h later, total, initial and difference resistances (Rtot, Rinit, Rdiff) and static elastance (Est) were measured. Lung responsiveness to methacholine was assessed as slope and sensitivity of Est, Rtot, Rinit, and Rdiff. Lung morphometry (collapsed and normal areas and bronchoconstriction index) and cellularity (polymorphonuclear, mononuclear and mast cells) were determined. OVA or ROFA similarly impaired lung mechanics and increased the amount of polymorphonuclear cells and collapsed areas. OVA-ROFA showed even higher hyperresponsiveness, bronchoconstriction and mast cell infiltration. Thus, we concluded that ROFA exposure may add an extra burden to hyperresponsive lungs. PMID- 21816236 TI - Molecular mechanisms of the anomalous thermal aggregation of green fluorescent protein. AB - The peculiarities of thermal denaturation and interaction with water of the cycle 3 mutant of green fluorescent protein (GFP) were analyzed by NMR techniques and compared with those of bovine carbonic anhydrase II (BCA-II). Irreversible thermal denaturation was accompanied by massive GFP aggregation with no detectable accumulation of soluble denatured protein. Analysis of the spin diffusion data suggested that the internal part of the GFP beta-can is involved in intensive interactions with water molecules. As a result, at high temperatures, the GFP structure does not unfold but rather breaks, consequently leading to enhanced protein aggregation. This is very different from typical BCA II behavior. PMID- 21816237 TI - Histological and three-dimensional evaluation of osseointegration to nanostructured calcium phosphate-coated implants. AB - Nanostructures on implant surfaces have been shown to enhance osseointegration; however, commonly used evaluation techniques are probably not sufficiently sensitive to fully determine the effects of this process. This study aimed to observe the osseointegration properties of nanostructured calcium phosphate (CaP) coated implants, by using a combination of three-dimensional imaging and conventional histology. Titanium implants were coated with stable CaP nanoparticles using an immersion technique followed by heat treatment. Uncoated implants were used as the control. After topographical and chemical characterizations, implants were inserted into the rabbit femur. After 2 and 4weeks, the samples were retrieved for micro-computed tomography and histomorphometric evaluation. Scanning electron microscopy evaluation indicated that the implant surface was modified at the nanoscale by CaP to obtain surface textured with rod-shaped structures. Relative to the control, the bone-to-implant contact for the CaP-coated implant was significantly higher at 4weeks after the implant surgery. Further, corresponding 3-D images showed active bone formation surrounding the implant. 3-D quantification and 2-D histology demonstrated statistical correlation; moreover, 3-D quantification indicated a statistical decrease in bone density in the non-coated control implant group between 2 and 4weeks after the surgery. The application of 3-D evaluation further clarified the temporal characteristics and biological reaction of implants in bone. PMID- 21816238 TI - Ion reactivity of calcium-deficient hydroxyapatite in standard cell culture media. AB - Solution-mediated surface reactions occur for most calcium phosphate-based biomaterials and may influence cellular response. A reasonable extrapolation of such processes observed in vitro to in vivo performance requires a deep understanding of the underlying mechanisms. We therefore systematically investigated the nature of ion reactivity of calcium-deficient hydroxyapatite (CDHA) by exposing it for different periods of time to standard cell culture media of different chemical composition (DMEM and McCoy medium, with and without osteogenic supplements and serum proteins). Kinetic ion interaction studies of principal extracellular ions revealed non-linear sorption of Ca2+ (~50% sorption) and K+ (~8%) as well as acidification of all media during initial contact with CDHA (48h). Interestingly, inorganic phosphorus (P(i)) was sorbed from McCoy medium (~50%) or when using osteogenic media containing beta-glycerophosphate, but not from DMEM medium. Non-linear sorption data could be perfectly described by pseudo-first-order and pseudo-second-order sorption models. At longer contact time (21 days), and with frequent renewal of culture medium, sorption of Ca2+ remained constant throughout the experiment, while sorption of P(i) gradually decreased in McCoy medium. In great contrast, CDHA began to release P(i) slowly with time when using DMEM medium. Infrared spectra showed that CDHA exposed to culture media had a carbonated surface chemistry, suggesting that carbonate plays a key role in the ion reactivity of CDHA. Our data show that different compositions of the aqueous environment may provoke opposite ion reactivity of CDHA, and this must be carefully considered when evaluating the osteoinductive potential of the material. PMID- 21816239 TI - Clinical features and respiratory complications in Myhre syndrome. AB - We describe the clinical characteristics of 4 singleton cases, 3 males and 1 female, with Myhre Syndrome (OMIM 139210), who were born to non-consanguineous parents. Three cases had no family history of similarly affected individuals but 1 male's mother had short stature, some facial features suggestive of Myhre syndrome and evidence of skewed X-chromosome inactivation in her blood DNA. Short stature, deafness, learning difficulties, skeletal anomalies and facial dysmorphisms were evident in all cases. Arthralgia and stiff joints with limited movement were also present. The facial appearance, thickened skin, a 'muscular' habitus are memorable features. The female patient was least affected: this patient and one affected male displayed streaky skin with areas of patchy thickening, suggestive of genetic mosaicism. One patient developed sleep apnoea, a restrictive ventilatory defect and died following a choking episode. Another affected male developed recurrent, progressive, proximal, tracheal stenosis requiring partial tracheal resection, laser treatment and eventually tracheotomy. Review of Myhre syndrome patients in the literature and syndromes in the differential diagnosis, suggests heterogeneity in Myhre syndrome and clinical overlap with Laryngotracheal stenosis, Arthropathy, Prognathism and Short stature syndrome. PMID- 21816240 TI - Novel homozygous mutations in Desert hedgehog gene in patients with 46,XY complete gonadal dysgenesis and prediction of its structural and functional implications by computational methods. AB - Male to female sex reversal in patients with 46,XY karyotype results from the failure of development of testis which may be due to mutations in the SRY gene. Only 10-15% of cases of 46,XY gonadal dysgenesis are accounted for by different types of mutations in the SRY gene. Hence, majority of such patients may have mutations in other genes involved in the testicular differentiation pathway. Besides SRY, other autosomal and X-linked genes are also involved in sexual development during embryogenesis. We describe here the first report from India wherein, two cases of 46,XY complete gonadal dysgenesis that could be attributable to mutations in the Desert hedgehog (DHH) gene. The mutations found in these two patients were a homozygous deletion (c.271_273delGAG) that resulted in deletion of one amino acid (p.D90del) and a homozygous duplication (c.57 60dupAGCC) that resulted in premature termination resulting in non-functional DHH protein. The structure-function implications of the p.D90del mutation were predicted using computational tools. Structural studies on the p.D90del mutant revealed that the mutation could seriously perturb the interaction of DHH with its binding partners. This is the second report in literature showing homozygous mutation in cases with 46,XY complete gonadal dysgenesis. PMID- 21816241 TI - DFNB66 and DFNB67 loci are non allelic and rarely contribute to autosomal recessive nonsyndromic hearing loss. AB - We previously mapped the DFNB66 locus to an interval overlapping the DFNB67 region. Mutations in the LHFPL5 gene were identified as a cause of DFNB67 hearing loss (HL). However, screening of the coding exons of LHFPL5 did not reveal any mutation in the DFNB66 family. The objective of this study was to check whether DFNB66 and DFNB67 are distinctive loci and determining their contribution to HL. In the DFNB66 family, sequencing showed absence of mutations in the untranslated regions and the predicted promoter sequence of LHFPL5. Analysis of five microsatellites in the 6p21.31-22.3 region and screening of the LHFPL5 gene by DNA heteroduplex analysis in DHPLC revealed a novel mutation (c.89dup) in one out of 129 unrelated Tunisian families with autosomal recessive nonsyndromic (ARNS) HL. Our findings suggest that two distinct genes are responsible for DFNB66 and DFNB67 HL. These loci are likely to be a rare cause of ARNSHL. PMID- 21816242 TI - Leprosy epidemics during history increased protective allele frequency of PARK2/PACRG genes in the population of the Mljet Island, Croatia. AB - INTRODUCTION: Two regulatory polymorphisms (rs1040079 and rs9356058) shared by PARK2 and PACRG genes were identified as major risk variants for leprosy susceptibility. The aim of this study was to investigate if allele frequencies of these polymorphisms in the isolated population of the island of Mljet, which served as a quarantine for leprosy patients during past centuries, were different to allele frequencies in two control populations with no history of leprosy. SUBJECTS AND METHODS: This study included 88 unrelated Caucasian individuals from the island of Mljet while two control groups included 93 individuals from the island of Rab and 160 individuals from the region of Split. Genotyping for rs1040079 and rs9356058 was performed by "real-time" PCR analysis. We also compared the allele frequency of the rs9356058 polymorphism from the population of Mljet with allele frequencies derived from the existing genome wide association scans in two additional island populations, Vis (924 subjects) and Korcula (909 subjects). RESULTS: We found a significant increase in the frequency of rs9356058 allele C in the population of Mljet when compared to both control groups. We also observed a significant increase in the frequency of rs1040079 allele A in the population of Mljet when compared with the population of Rab, however this increase was not significant when compared with the population of Split. Allele frequencies of both examined polymorphisms did not differ between the two control populations. Protective haplotype rs9356058-rs1040079 CA was also more frequent in the population of Mljet compared with the Rab and Split populations. In addition, an increase of frequency of rs9356058 allele C was also observed in the population of Mljet when compared with the frequency in the Korcula population. CONCLUSION: The results of our study show the association of polymorphisms rs9356058 and rs1040079 in gene PARK2/PACRG with leprosy. The results of our study indicate that exposure to leprosy and mortality in the population caused by leprosy on Mljet resulted in the selection of rs9356058 "protective" C allele in the PARK2 gene, while this was not observed in the two control groups. This is the first study to assess the genetic susceptibility to leprosy in a European population. PMID- 21816245 TI - Evolution in surgical techniques and indications for corneal transplantation: past, present, and future. PMID- 21816246 TI - The need for "made in Canada" glaucoma epidemiology data. PMID- 21816244 TI - FoxO1, the transcriptional chief of staff of energy metabolism. AB - FoxO1, one of the four FoxO isoforms of Forkhead transcription factors, is highly expressed in insulin-responsive tissues, including pancreas, liver, skeletal muscle and adipose tissue, as well as in the skeleton. In all these tissues FoxO1 orchestrates the transcriptional cascades regulating glucose metabolism. Indeed, FoxO1 is a major target of insulin which inhibits its transcriptional activity via nuclear exclusion. In the pancreas, FoxO1 regulates beta-cell formation and function by a balanced dual mode of action that suppresses beta-cell proliferation but promotes survival. Hepatic glucose production is promoted and lipid metabolism is regulated by FoxO1 such that under insulin resistance they lead to hyperglycemia and dyslipidemia, two features of type 2 diabetes. In skeletal muscle FoxO1 maintains energy homeostasis during fasting and provides energy supply through breakdown of carbohydrates, a process that leads to atrophy and underlies glycemic control in insulin resistance. In a dual function, FoxO1 regulates energy and nutrient homeostasis through energy storage in white adipose tissue, but promotes energy expenditure in brown adipose tissue. In its most recently discovered novel role, FoxO1 acts as a transcriptional link between the skeleton and pancreas as well as other insulin target tissues to regulate energy homeostasis. Through its expression in osteoblasts it controls glucose metabolism, insulin sensitivity and energy expenditure. In a feedback mode of regulation, FoxO1 is also a target of insulin signaling in osteoblasts. Insulin suppresses activity of osteoblastic FoxO1 thus promoting beneficial effects of osteoblasts on glucose metabolism. The multiple actions of FoxO1 in all glucose regulating organs, along with clinical studies suggesting that its glycemic properties are conserved in humans, establish this transcription factor as a master regulator of energy metabolism across species. PMID- 21816247 TI - Laser trabeculoplasty: an investigation into factors that might influence outcomes. AB - OBJECTIVE: To examine the effectiveness of argon (ALT) or selective (SLT) laser trabeculoplasty (LTP) in lowering intraocular pressure (IOP) and to determine whether patient-related factors had any impact on outcome. DESIGN: Retrospective review. PARTICIPANTS: 500 patients treated with LTP over 14 years. METHODS: This study was conducted at Sunnybrook Health Sciences Centre, University of Toronto. Five patient-related characteristics were used as dependent variables-age, race, gender, pseudophakic status, and pseudoexfoliation. IOP decrease and treatment failure at 12 months were the main outcome variables. RESULTS: 500 eyes of 500 patients were included, 350 after ALT and 150 after SLT. The mean +/- standard deviation baseline IOP was significantly higher in the patients treated by ALT than in those treated by SLT (24.2 +/- 5.4 versus 22.2 +/- 4.6, p < 0.0001) at baseline but not at 1 year (19.6 +/- 5.1 versus 19.5 +/- 6.1, p = 0.41). When the final IOP was examined by multiple regression analysis, there was a significant effect in favor of ALT over SLT (p = 0.03) and for patients with higher baseline IOPs (p < 0.0001). No significant effect was found for any of the demographic subgroupings. However, when the outcome variable was success or failure, only the baseline IOP remained significant. CONCLUSIONS: Specific patient characteristics do not significantly influence LTP outcome after 12 months of follow-up. The most powerful predictor of either final IOP or clinical success was a higher baseline IOP, but ALT may have a better ability to lower IOP. PMID- 21816248 TI - The cost of vision loss in Canada. 1. Methodology. AB - OBJECTIVE: This paper outlines the methodology used to estimate the cost of vision loss in Canada. The results of this study will be presented in a second paper. DESIGN: The cost of vision loss (VL) in Canada was estimated using a prevalence-based approach. This was done by estimating the number of people with VL in a base period (2007) and the costs associated with treating them. The cost estimates included direct health system expenditures on eye conditions that cause VL, as well as other indirect financial costs such as productivity losses. Estimates were also made of the value of the loss of healthy life, measured in Disability Adjusted Life Years or DALY's. To estimate the number of cases of VL in the population, epidemiological data on prevalence rates were applied to population data. The number of cases of VL was stratified by gender, age, ethnicity, severity and cause. The following sources were used for estimating prevalence: Population-based eye studies; Canadian Surveys; Canadian journal articles and research studies; and International Population Based Eye Studies. Direct health costs were obtained primarily from Health Canada and Canadian Institute for Health Information (CIHI) sources, while costs associated with productivity losses were based on employment information compiled by Statistics Canada and on economic theory of productivity loss. Costs related to vision rehabilitation (VR) were obtained from Canadian VR organizations. CONCLUSIONS: This study shows that it is possible to estimate the costs for VL for a country in the absence of ongoing local epidemiological studies. PMID- 21816249 TI - The cost of vision loss in Canada. 2. Results. AB - OBJECTIVE: This study was conducted to provide the financial underpinnings necessary for effective planning for the provision of eye health services in Canada. Canada is facing an aging demographic and all the major eye diseases are diseases associated with aging. It is essential that we have information based on the best available data to support national and provincial vision health plans. DESIGN: The design associated with the prevalence-based approach used in this study was outlined previously in detail in The Cost of Vision Loss in Canada: Methodology. METHODS: The methods associated with the prevalence-based approach used in this study were previously outlined in detail in The Cost of Vision Loss in Canada: Methodology. RESULTS: The financial cost of VL in Canada in 2007 was estimated to be $15.8 billion per annum: $8.6 billion (54.6%) represents direct health system expenditure; $4.4 billion (28.0%) was productivity lost due to lower employment, higher absenteeism, and premature death of Canadians with VL; $1.8 billion (11.1%) was the dead weight losses (DWL) from transfers including welfare payments and taxation forgone; $0.7 billion (4.4%) was the value of the care for people with VL; $305 million (1.9%) was other indirect costs such as aids and home modifications and the bring forward of funeral costs. Additionally, the value of the lost well-being (disability and premature death) was estimated at a further $11.7 billion. In per capita terms, this amounts to a financial cost of $19370 per person with VL per annum. Including the value of lost well-being, the cost is $33704 per person per annum. CONCLUSIONS: There is a growing awareness in Canada and around the world of the impact of VL on health costs and on the economy in general. This awareness is supported by the growing number of independent studies on the cost of vision loss both nationally and globally. Because most of these studies are limited by the minimal amount of available data, the overall cost of vision loss is likely underestimated. Nevertheless, this study reports the cost of vision loss in Canada as being greater than previously reported, making the problem even more urgent to address. A comprehensive national vision health plan, that is a coordinated federal, provincial and territorial initiative dealing with all aspects of vision loss prevention, sight restoration, and vision rehabilitation is called for. PMID- 21816250 TI - Coaxially sighted intraocular lens light reflex for centration of the multifocal single piece intraocular lens. AB - Centration of multifocal Intraocular lenses (IOL) may be critical to ensure optimal function and prevent untoward side effects. Pharmacologic pupillary dilation and constriction may shift the physiologic location of the pupillary center rendering intraoperative positioning of multifocal IOL challenging. Similarly, the anterior capsular center is difficult to pinpoint and may not correspond to either the visual axis or the pupillary center. The visual axis is the only landmark that can be consistently identified prior, during and after cataract surgery. Centering diffractive multifocal IOL on the visual axis may allow more consistent placement and better outcome measures. In the following, we describe a simple technique to center multifocal single piece acrylic IOLs on the visual axis. PMID- 21816251 TI - Long-term daclizumab therapy for the treatment of noninfectious ocular inflammatory disease. AB - OBJECTIVE: Safety and efficacy of daclizumab during an 11-year period. DESIGN: Structured, retrospective chart review. PARTICIPANTS: Thirty-nine patients. METHODS: Patients with chronic, noninfectious intermediate and/or posterior uveitis. RESULTS: Thirty-nine patients (78 eyes) were treated for a mean of 40.3 months. Visual acuity improved by >=2 lines in the better eye in 7 patients (18.4%) and worsened by 2 lines in 6 patients (15.8%) with a mean of 2.8 Snellen lines of vision lost per eye. Six eyes with vitreous cell less than grade 2 lost 2 lines of vision and 7 eyes with less than grade 2 vitreous cell improved 2 lines. Mean number of immunosuppressive medications per patient decreased from 1.89 medications/patient to 1.17 medications/patient. The average number of periocular injections per patient was 1.46 (range, 0-9). The mean number of flares was 2.05/patient (range, 0-12), with the rate being 0.62 flares per patient-year. Four patients developed cancer during the course of this study. Mean time to onset of malignancy was 26 months and the mean age in this group was 49 years. CONCLUSIONS: Daclizumab demonstrated efficacy in the reduction of concomitant immunosuppressive medication, stabilization of visual acuity, and the prevention of uveitic flares in most cases. Dermatologic complications were the most frequently observed adverse event in our series. Four patients developed solid tumor malignancies during this 11-year period. PMID- 21816252 TI - Adjunctive globe magnetic resonance imaging in the diagnosis of posterior scleritis. AB - OBJECTIVE: To report 4 cases of posterior scleritis with unusually unremarkable ultrasonography findings in which diagnosis was based on magnetic resonance imaging (MRI) examination. DESIGN: Retrospective noncomparative case series. PARTICIPANTS: Four patients. METHODS: Patients suffering from suspected posterior scleritis and previously misdiagnosed with a range of conditions after an unremarkable B-scan ultrasonography. A new and thorough review of systems, including MRI examination of the eye/orbit, was carried out. RESULTS: All included patients were diagnosed with posterior scleritis based on MRI findings. Systemic treatment with immunosuppressors (2 patients), antibiotics (1 patient), or no treatment (1 patient) got their inflammatory condition under control. CONCLUSIONS: MRI may play a potential role in the diagnosis of posterior scleritis particularly in those clinically suspicious cases with nondefinitive ultrasonography. Further studies on this matter are warranted. PMID- 21816253 TI - Not only hard contact lens wear but also soft contact lens wear may be associated with blepharoptosis. AB - OBJECTIVE: The authors attempt to establish an association between prolonged hard and soft contact lens wear and ptosis. DESIGN: Single-center retrospective consecutive series. PARTICIPANTS: All patients between 18 and 50 years of age who were diagnosed with unilateral or bilateral ptosis between January 2002 and December 2005 (35 patients). METHODS: In a retrospective consecutive series, we included all patients between 18 and 50 years of age, with unilateral or bilateral ptosis between January 2002 and December 2005. Patients with congenital ptosis, ophthalmic surgery or disease, trauma, giant papillary conjunctivitis, unknown duration of contact lens wear, or muscular or neurologic disorders were excluded. We compared this study group to a Dutch reference population (the total underlying population from which the ptosis cases derive). RESULTS: The group included 35 patients: 20 (57%) (ages 18 to 50 years, average 37 years) had been wearing hard contact lenses for, on average, 17.6 years (range 6 to 27 years); 9 (26%) (ages 18 to 45 years, average 30 years) had been wearing soft contact lenses for, on average, 9 years (range 1.5 to 20 years); and 6 (17%) (ages 23 to 39 years, average 33 years) had no history of contact lens wear. The odds ratio for soft contact lenses was 14.7 (4.2 to 50.7; CI = 95) and for hard contact lenses 97.8 (22.5 to 424). CONCLUSIONS: This study suggests that not only hard contact lens wear but also soft contact lens wear may be associated with ptosis. PMID- 21816254 TI - Non-invasive anterior segment and posterior segment optical coherence tomography and phenotypic characterization of aniridia. AB - OBJECTIVE: To determine the value of optical coherence tomography (OCT) as a diagnostic tool in the critical evaluation of phenotypic variability seen in an aniridia family with a novel PAX6 mutation. DESIGN: Genetic and observational family study. PARTICIPANTS: Three-generation family segregating autosomal dominant aniridia. METHODS: Ophthalmic examination included best-corrected visual acuity, slit-lamp biomicroscopy, direct and indirect ophthalmoscopy, tonometry, and OCT. PAX6 gene mutation analysis was carried out by direct sequencing of gene specific PCR products and protein analysis by Western blot. RESULTS: Intrafamilial variable expressivity was seen between 4 affected family members. Phenotype differences between twin children suggested that this was due to modifier gene effects rather than environment. Anterior segment OCT demonstrated a range of iridocorneal angle abnormalities and corneal thickening in only 3, but ciliary body hypoplasia in all 4 affected patients. Posterior segment OCT demonstrated dome-shaped, hypoplastic macular profiles in the 2 affected children. Novel outer retinal changes were also seen, suggestive of a phototoxic retinopathy not previously recognized in aniridia. Ocular disease segregated with a novel PAX6 Q178X nonsense mutation with Western blot analysis suggesting that this led to haploinsufficiency of PAX6 protein. CONCLUSIONS: Non-contact OCT imaging allowed for a more detailed assessment of anterior and posterior segment disease in children and adults with aniridia plus nystagmus. This led to the identification of novel features and highlights a practical, non-contact strategy well suited to genotype/phenotype studies and the longitudinal management of aniridic glaucoma in children. PMID- 21816255 TI - Severe proliferative diabetic retinopathy treated with vitrectomy or panretinal photocoagulation: a monocenter randomized controlled clinical trial. AB - OBJECTIVE: Visual and anatomic results of pars plana vitrectomy were compared with panretinal photocoagulation in cases of severe proliferative diabetic retinopathy. DESIGN: Monocenter randomized controlled clinical trial; randomization and allocation to trial group were carried out by a central computer system. PARTICIPANTS: We studied 180 eyes of 180 patients with severe proliferative diabetic retinopathy, half with tractional retinal detachment not involving the macula (n = 90). Some were treated by pars plana vitrectomy (n = 90) and some by panretinal photocoagulation (n = 90). METHODS: Eyes were randomly divided into 2 groups. Group 1 was treated with pars plana vitrectomy, membrane and internal limited membrane peeling, panretinal photocoagulation, and focal or grid macular laser. Group 2 was treated with panretinal photocoagulation and focal or grid macular laser. Follow-up was at least 12 months. RESULTS: Mean preoperative visual acuities and ophthalmic fundus characteristics were compared across groups. A year postoperation, visual acuity (the primary endpoint) in group 1 improved in 30 eyes (33%); was unchanged in 22 eyes (25%); and decreased in 38 eyes (42%). In group 2, visual acuity improved in 32 eyes (35%); was unchanged in 42 eyes (47%); and decreased in 16 eyes (18%). The percentage of improvement in the 2 groups was not statistically significant (p = 0.75), whereas the stabilized (p = 0.002) and worsened eyes (p = 0.0003) in group 1 and group 2 were significantly different. CONCLUSION: In cases of severe proliferative diabetic retinopathy, even with tractional retinal detachment not involving macula, it is best to defer vitrectomy unless definite progression that threatens the vascular center is documented. PMID- 21816256 TI - The Toronto epidemiology glaucoma survey: a pilot study. AB - OBJECTIVE: To evaluate the prevalence of undetected glaucoma in a Toronto population. DESIGN: A cross-sectional survey. PARTICIPANTS: Toronto residents aged 50 years or older. METHODS: Telephone calls were randomly made to Toronto residents. Those who indicated they did not have glaucoma were invited to the Toronto Western Hospital for a comprehensive ophthalmic assessment, including best corrected visual acuity testing, applanation tonometry, pachymetry, gonioscopy, disc assessment, frequency doubling technology, and Heidelberg retinal tomography. Patient suspected to have glaucoma were asked to return for further evaluation, including a 24-2 Humphrey automated visual field test, repeat Heidelberg retinal tomography, repeat disc assessment, and possibly a diurnal tension curve. The diagnosis of glaucoma was made based on standardized criteria modified from those used by the Rotterdam Study and Foster and associates. RESULTS: Among 975 eligible respondents, 73 (7.5%) stated that they had glaucoma. Of the remaining 902 negative respondents, 271 booked clinical appointments, and 180 completed the clinical assessment; their mean age was 61.6 years. Of the participants, 7 (3.9%) were diagnosed with glaucoma: 5 (2.8%) had primary open angle glaucoma (3 with low-pressure and 2 with high-pressure glaucoma); 1 had (0.6%) chronic angle-closure glaucoma; and 1 (0.6%) had pseudoexfoliation glaucoma. A further 8 (4.4%) participants were classified as probably having open angle glaucoma and 33 (18.3%) as being suspected to have glaucoma. Narrow angles were found in 27 participants (15%), and 37 (20.6%) had family histories of glaucoma. CONCLUSION: The prevalence of undetected glaucoma appears to be high in Toronto. Further studies involving larger numbers of participants are required to confirm this finding. PMID- 21816257 TI - Anterior chamber air-fluid exchange for graft adhesion during Descemet stripping automated endothelial keratoplasty surgery. AB - One of the most important steps during Descemet stripping automated endothelial keratoplasty (DSAEK) is attaching the donor Descemet lenticule to the host's cornea. This is usually carried out by injecting air into the anterior chamber with a syringe and needle. We present an alternative technique using an air fluid exchange system connected to an anterior chamber maintainer used in 22 cases in our institute. This technique has proven to be simple and fast, thus facilitating the successful performance of DSAEK surgery. PMID- 21816258 TI - Evolving surgical techniques of and indications for corneal transplantation in Ontario from 2000 to 2009. AB - OBJECTIVE: To determine the changes in the leading indications for and the preferred surgical techniques of corneal transplantation in Ontario over a 9-year period. DESIGN: Retrospective review of Eye Bank of Canada (Ontario Division) records. PARTICIPANTS: Recipients of corneal transplants performed in Ontario between 2000 and 2009, totaling 6240 patients. METHODS: Records of all corneal tissues sent for transplantation in Ontario by the Eye Bank of Canada (Ontario Division) from July 1 2000 to June 30 2009 were reviewed. The records consist of recipient information forms completed by surgeons at the time of corneal transplant surgery. Of the 8186 available recipient information forms, 7755 (94.7%) were sufficiently complete to meet the inclusion criteria. RESULTS: The leading indications for corneal transplantation were pseudophakic corneal edema (28.3%), regraft (21.5%), Fuchs dystrophy (16.6%), and anterior keratoconus (13.8%). Beginning in 2006, there has been a shift in the proportion of corneal transplants performed using Descemet's stripping automated endothelial keratoplasty (DSAEK) and deep anterior lamellar keratoplasty, from 2.4% to 36.1% of all corneal transplants. Concomitantly, DSAEK has replaced penetrating keratoplasty (PKP) as the technique of choice when corneal transplantation is indicated for Fuchs' dystrophy (139 DSAEKs vs. 68 PKPs in 2009) and for pseudophakic corneal edema (118 DSAEKs vs. 115 PKPs in 2009). CONCLUSION: The indications for PKP in this study agree with the North American literature. In recent years, partial-thickness transplants have gained favor over PKP for select indications in Ontario. These changes reflect the future direction of corneal transplantation and will have implications on the supply of and demand for tissues. PMID- 21816259 TI - Orbital fibrosis syndrome associated with combined retinal hamartoma. PMID- 21816260 TI - Recurrent orbital cyst as a late complication of silastic implant for orbital floor fracture repair. PMID- 21816261 TI - Isolated conjunctival lymphangioma. PMID- 21816262 TI - Visual perception of a dislocated intraocular lens. PMID- 21816263 TI - An enlarging mass due to a retained gauze piece-an unusual complication of dacryocystorhinostomy. PMID- 21816264 TI - Utilitarian and lottery theory in age-related macular degeneration. PMID- 21816267 TI - Clinical outcomes with robotic surgery. PMID- 21816268 TI - Slick science: will new BP funds keep Gulf genomics afloat? AB - Funding injections by British Petroleum this summer are fueling studies in the Gulf Coast, raising hopes that the Deepwater Horizon oil spill might provide answers to long-standing questions on the nature of cellular toxicity. Rebecca Alvania investigates. PMID- 21816269 TI - Privileged signaling for brain growth. AB - When developing animals encounter nutrient restriction, most tissues stop growing. Some vital tissues, however, such as the brain, continue to grow. Now, Cheng et al. (2011) identify Alk as the kinase that allows the Drosophila brain to continue growing during nutrient restriction by bypassing the requirements for insulin receptor and TOR activation. PMID- 21816270 TI - A prion-like trigger of antiviral signaling. AB - The MAVS protein plays a critical role in the assembly of an antiviral signaling complex on mitochondrial membranes. Hou et al. (2011) now report that virus infection induces a conformational change in MAVS, leading to the prion-like formation of functional self-aggregates that provide a sensitive trigger for antiviral signaling. PMID- 21816271 TI - Regulatory revolution: evolving the "anti-LacI" repressor. AB - Much of adaptation is based upon changes in gene expression, but the emergence of new regulatory logic has not been observed directly. Now, Poelwijk et al. report evolving the lac repressor (LacI) to reverse its regulatory logic, resulting in an "anti-LacI" that represses transcription when bound to its "inducer." PMID- 21816272 TI - Directed conversion of Alzheimer's disease patient skin fibroblasts into functional neurons. AB - Directed conversion of mature human cells, as from fibroblasts to neurons, is of potential clinical utility for neurological disease modeling as well as cell therapeutics. Here, we describe the efficient generation of human-induced neuronal (hiN) cells from adult skin fibroblasts of unaffected individuals and Alzheimer's patients, using virally transduced transcription regulators and extrinsic support factors. hiN cells from unaffected individuals display morphological, electrophysiological, and gene expression profiles that typify glutamatergic forebrain neurons and are competent to integrate functionally into the rodent CNS. hiN cells from familial Alzheimer disease (FAD) patients with presenilin-1 or -2 mutations exhibit altered processing and localization of amyloid precursor protein (APP) and increased production of Abeta, relative to the source patient fibroblasts or hiN cells from unaffected individuals. Together, our findings demonstrate directed conversion of human fibroblasts to a neuronal phenotype and reveal cell type-selective pathology in hiN cells derived from FAD patients. PMID- 21816273 TI - Spo11-accessory proteins link double-strand break sites to the chromosome axis in early meiotic recombination. AB - Meiotic recombination between homologous chromosomes initiates via programmed DNA double-strand breaks (DSBs), generated by complexes comprising Spo11 transesterase plus accessory proteins. DSBs arise concomitantly with the development of axial chromosome structures, where the coalescence of axis sites produces linear arrays of chromatin loops. Recombining DNA sequences map to loops, but are ultimately tethered to the underlying axis. How and when such tethering occurs is currently unclear. Using ChIPchip in yeast, we show that Spo11-accessory proteins Rec114, Mer2, and Mei4 stably interact with chromosome axis sequences, upon phosphorylation of Mer2 by S phase Cdk. This axis tethering requires meiotic axis components (Red1/Hop1) and is modulated in a domain specific fashion by cohesin. Loss of Rec114, Mer2, and Mei4 binding correlates with loss of DSBs. Our results strongly suggest that hotspot sequences become tethered to axis sites by the DSB machinery prior to DSB formation. PMID- 21816274 TI - Structure of a key intermediate of the SMN complex reveals Gemin2's crucial function in snRNP assembly. AB - The SMN complex mediates the assembly of heptameric Sm protein rings on small nuclear RNAs (snRNAs), which are essential for snRNP function. Specific Sm core assembly depends on Sm proteins and snRNA recognition by SMN/Gemin2- and Gemin5 containing subunits, respectively. The mechanism by which the Sm proteins are gathered while preventing illicit Sm assembly on non-snRNAs is unknown. Here, we describe the 2.5 A crystal structure of Gemin2 bound to SmD1/D2/F/E/G pentamer and SMN's Gemin2-binding domain, a key assembly intermediate. Remarkably, through its extended conformation, Gemin2 wraps around the crescent-shaped pentamer, interacting with all five Sm proteins, and gripping its bottom and top sides and outer perimeter. Gemin2 reaches into the RNA-binding pocket, preventing RNA binding. Interestingly, SMN-Gemin2 interaction is abrogated by a spinal muscular atrophy (SMA)-causing mutation in an SMN helix that mediates Gemin2 binding. These findings provide insight into SMN complex assembly and specificity, linking snRNP biogenesis and SMA pathogenesis. PMID- 21816275 TI - The Min oscillator uses MinD-dependent conformational changes in MinE to spatially regulate cytokinesis. AB - In E. coli, MinD recruits MinE to the membrane, leading to a coupled oscillation required for spatial regulation of the cytokinetic Z ring. How these proteins interact, however, is not clear because the MinD-binding regions of MinE are sequestered within a six-stranded beta sheet and masked by N-terminal helices. minE mutations that restore interaction between some MinD and MinE mutants were isolated. These mutations alter the MinE structure leading to release of the MinD binding regions and the N-terminal helices that bind the membrane. Crystallization of MinD-MinE complexes revealed a four-stranded beta sheet MinE dimer with the released beta strands (MinD-binding regions) converted to alpha helices bound to MinD dimers. These results identify the MinD-dependent conformational changes in MinE that convert it from a latent to an active form and lead to a model of how MinE persists at the MinD-membrane surface. PMID- 21816276 TI - mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway. AB - The nutrient- and growth factor-responsive kinase mTOR complex 1 (mTORC1) regulates many processes that control growth, including protein synthesis, autophagy, and lipogenesis. Through unknown mechanisms, mTORC1 promotes the function of SREBP, a master regulator of lipo- and sterolgenic gene transcription. Here, we demonstrate that mTORC1 regulates SREBP by controlling the nuclear entry of lipin 1, a phosphatidic acid phosphatase. Dephosphorylated, nuclear, catalytically active lipin 1 promotes nuclear remodeling and mediates the effects of mTORC1 on SREBP target gene, SREBP promoter activity, and nuclear SREBP protein abundance. Inhibition of mTORC1 in the liver significantly impairs SREBP function and makes mice resistant, in a lipin 1-dependent fashion, to the hepatic steatosis and hypercholesterolemia induced by a high-fat and -cholesterol diet. These findings establish lipin 1 as a key component of the mTORC1-SREBP pathway. PMID- 21816277 TI - Recruitment of actin modifiers to TrkA endosomes governs retrograde NGF signaling and survival. AB - The neurotrophins NGF and NT3 collaborate to support development of sympathetic neurons. Although both promote axonal extension via the TrkA receptor, only NGF activates retrograde transport of TrkA endosomes to support neuronal survival. Here, we report that actin depolymerization is essential for initiation of NGF/TrkA endosome trafficking and that a Rac1-cofilin signaling module associated with TrkA early endosomes supports their maturation to retrograde transport competent endosomes. These actin-regulatory endosomal components are absent from NT3/TrkA endosomes, explaining the failure of NT3 to support retrograde TrkA transport and survival. The inability of NT3 to activate Rac1-GTP-cofilin signaling is likely due to the labile nature of NT3/TrkA complexes within the acidic environment of TrkA early endosomes. Thus, TrkA endosomes associate with actin-modulatory proteins to promote F-actin disassembly, enabling their maturation into transport-competent signaling endosomes. Differential control of this process explains how NGF but not NT3 supports retrograde survival of sympathetic neurons. PMID- 21816278 TI - Anaplastic lymphoma kinase spares organ growth during nutrient restriction in Drosophila. AB - Developing animals survive periods of starvation by protecting the growth of critical organs at the expense of other tissues. Here, we use Drosophila to explore the as yet unknown mechanisms regulating this privileged tissue growth. As in mammals, we observe in Drosophila that the CNS is more highly spared than other tissues during nutrient restriction (NR). We demonstrate that anaplastic lymphoma kinase (Alk) efficiently protects neural progenitor (neuroblast) growth against reductions in amino acids and insulin-like peptides during NR via two mechanisms. First, Alk suppresses the growth requirement for amino acid sensing via Slimfast/Rheb/TOR complex 1. And second, Alk, rather than insulin-like receptor, primarily activates PI3-kinase. Alk maintains PI3-kinase signaling during NR as its ligand, Jelly belly (Jeb), is constitutively expressed from a glial cell niche surrounding neuroblasts. Together, these findings identify a brain-sparing mechanism that shares some regulatory features with the starvation resistant growth programs of mammalian tumors. PMID- 21816279 TI - Role of the clathrin terminal domain in regulating coated pit dynamics revealed by small molecule inhibition. AB - Clathrin-mediated endocytosis (CME) regulates many cell physiological processes such as the internalization of growth factors and receptors, entry of pathogens, and synaptic transmission. Within the endocytic network, clathrin functions as a central organizing platform for coated pit assembly and dissociation via its terminal domain (TD). We report the design and synthesis of two compounds named pitstops that selectively block endocytic ligand association with the clathrin TD as confirmed by X-ray crystallography. Pitstop-induced inhibition of clathrin TD function acutely interferes with receptor-mediated endocytosis, entry of HIV, and synaptic vesicle recycling. Endocytosis inhibition is caused by a dramatic increase in the lifetimes of clathrin coat components, including FCHo, clathrin, and dynamin, suggesting that the clathrin TD regulates coated pit dynamics. Pitstops provide new tools to address clathrin function in cell physiology with potential applications as inhibitors of virus and pathogen entry and as modulators of cell signaling. PMID- 21816280 TI - SnapShot: mouse primitive streak. PMID- 21816281 TI - Geriatric trauma and the impact of nursing care. PMID- 21816282 TI - Patient transfer forms enhance key information between nursing homes and emergency department. AB - The purpose of this study was to determine whether the use of a transfer form increases the availability of essential information needed for patient care and to examine its effect on case resolution time and disposition status. A retrospective review was performed that included patients 65 years old or greater arriving from nursing homes to an academic Emergency Department from January to June 2009. Eighty randomly selected charts were reviewed. Sixteen items were deemed essential based on an expert-based rubric published in 2006. Each case was scored accordingly. Results indicate that the transfer form group had available, on average, 71% of the essential items as compared to 28% for cases without a transfer form (p < 0.001). There was no difference in the case resolution time (p = 0.94) or in disposition status (p = 0.12). In conclusion, essential information for providing emergency department patient care was significantly increased with the use of a transfer form. PMID- 21816283 TI - The challenge of discontinuing proton pump inhibitors. PMID- 21816284 TI - New regulation modifies civil money penalties process for nursing facilities. PMID- 21816285 TI - The Affordable Care Act: positive impact for quality improvement. PMID- 21816286 TI - Neurocognitive problems in critically ill older adults: the importance of history. PMID- 21816287 TI - Real-time elastography in the detection of prostate cancer in patients with raised PSA level. AB - The study was done to evaluate the role of real-time elastosonography (ES) in the detection of prostate cancer (PCa) in 50 consecutive patients with raised PSA level and to determine whether ES can be of use to perform a targeted biopsy. Fifty consecutive patients with raised PSA levels underwent transrectal ultrasound (TRUS) and ES examination. ES images with adequate compression and a quality factor of more than 50% were analyzed for areas of increased glandular stiffness. The ES findings were correlated with the targeted and 10-core biopsy and sensitivity, specificity calculated on per patient and per core basis. ES showed a sensitivity and specificity of 91.7% and 86.8% on per patient basis, respectively, with a false positive rate of 13%. The calculated sensitivity and specificity on per core basis of ES targeted biopsy was 72.5% and 100% compared with 100% and 81% of 10-core systematic biopsy group. The study concludes that combining ES with TRUS significantly improves the sensitivity to detect carcinoma prostate in patients with raised PSA, however, ES is unable to differentiate PCa from chronic prostatitis. The use of ES for targeted biopsy also improves the specificity over a 10-core systematic biopsy. PMID- 21816288 TI - Measurement of two-dimensional movement parameters of the carotid artery wall for early detection of arteriosclerosis: a preliminary clinical study. AB - The aim of this study was to clinically investigate the association between the risk factors of early-stage atherosclerosis and the two-dimensional (2-D) movement of the artery wall. To meet this objective, a speckle tracking approach for the estimation of the 2-D trajectory of the vessel wall was proposed and applied to B-mode ultrasound (US) sequences of the left common carotid artery (CCA). A deformable skeleton model was also introduced in the block matching scheme. Finally, the 2-D movements of both proximal and distal walls were investigated in three different local regions, with 1.5 * 0.3 mm(2) kernel blocks. A clinical study was conducted in which two different populations (26 young healthy volunteers and 26 older diabetic patients) were studied. The results show that the mean amplitude value of the diameter change DeltaD, of the longitudinal displacement of the proximal wall DeltaX(p) and of the longitudinal displacement of the distal wall DeltaX(d) were 0.65 +/- 0.17 vs. 0.41 +/- 0.12 mm (p < 0.001), 0.48 +/- 0.21 vs. 0.26 +/- 0.18 mm (p < 0.001) and 0.48 +/- 0.20 vs. 0.35 +/- 0.23 mm (p = 0.006) for the young healthy volunteers and the older diabetic patients, respectively. The results of the three dynamic parameters DeltaD, DeltaX(p) and DeltaX(d) were systematically and significantly lower for the diabetic subjects, respectively 37%, 46% and 27%. The method introduced in this feasibility study might constitute a pertinent approach to assess the presence of early-stage arteriosclerosis by the noninvasive estimation of the 2-D motion of the intima-media complex in the CCA. PMID- 21816289 TI - Dynamics of coated microbubbles adherent to a wall. AB - Molecular imaging with ultrasound is a promising noninvasive technique for disease-specific imaging, enabling for instance, the diagnosis of thrombus and inflammation. Selective imaging is performed by using ultrasound contrast agent microbubbles functionalized with ligands, which bind specifically to the target molecules. Here, we investigate in a model system, the influence of adherence at a wall on the dynamics of the microbubbles, in particular, on the frequency of maximum response, by recording the radial response of individual microbubbles as a function of the applied acoustic pressure and frequency. The frequency of maximum response of adherent microbubbles was found to be over 50% lower than for bubbles in the unbounded fluid and over 30% lower than that of a nonadherent bubble in contact with the wall. The change is caused by adhesion of the bubbles to the wall as no influence was found due solely to the presence of the targeting ligands on the bubble dynamics. The shift in the frequency of maximum response may prove to be important for molecular imaging with ultrasound as this application would benefit from an acoustic imaging method to distinguish adherent microbubbles from freely circulating microbubbles. PMID- 21816290 TI - Insulin-like growth factor-type 1 receptor inhibitor NVP-AEW541 enhances radiosensitivity of PTEN wild-type but not PTEN-deficient human prostate cancer cells. AB - PURPOSE: During the past decade, many clinical trials with both monoclonal antibodies and small molecules that target the insulin-like growth factor-type 1 receptor (IGF-1R) have been launched. Despite the important role of IGF-1R signaling in radioresistance, studies of such agents in combination with radiotherapy are lagging behind. Therefore, the aim of this study was to investigate the effect of the small molecule IGF-1R kinase inhibitor NVP-AEW541 on the intrinsic radioresistance of prostate cancer cells. METHODS AND MATERIALS: The effect of NVP-AEW541 on cell proliferation, cell viability, IGF-1R signaling, radiosensitivity, cell cycle distribution, and double strand break repair was determined in three human prostate cancer cell lines (PC3, DU145, 22Rv1). Moreover, the importance of the PTEN pathway status was explored by means of transfection experiments with constitutively active Akt or inactive kinase-dead Akt. RESULTS: NVP-AEW541 inhibited cell proliferation and decreased cell viability in a time-and dose-dependent manner in all three cell lines. Radiosensitization was observed in the PTEN wild-type cell lines DU145 and 22Rv1 but not in the PTEN-deficient PC3 cell line. NVP-AEW541-induced radiosensitization coincided with downregulation of phospho-Akt levels and high levels of residual double strand breaks. The importance of PTEN status in the radiosensitization effect was confirmed by transfection experiments with constitutively active Akt or inactive kinase-dead Akt. CONCLUSIONS: NVP-AEW541 enhances the effect of ionizing radiation in PTEN wild-type, but not in PTEN deficient, prostate cancer cells. Proper patient selection based on the PTEN status of the tumor will be critical to the achievement of optimal results in clinical trials in which the combination of radiotherapy and this IGF-1R inhibitor is being explored. PMID- 21816291 TI - Assessment of tumor radioresponsiveness and metastatic potential by dynamic contrast-enhanced magnetic resonance imaging. AB - PURPOSE: It has been suggested that gadolinium diethylene-triamine penta-acetic acid (Gd-DTPA)-based dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) may provide clinically useful biomarkers for personalized cancer treatment. In this preclinical study, we investigated the potential of DCE-MRI as a noninvasive method for assessing the radioresponsiveness and metastatic potential of tumors. METHODS AND MATERIALS: R-18 melanoma xenografts growing in BALB/c nu/nu mice were used as experimental tumor models. Fifty tumors were subjected to DCE-MRI, and parametric images of Ktrans (the volume transfer constant of Gd DTPA) and ve (the fractional distribution volume of Gd-DTPA) were produced by pharmacokinetic analysis of the DCE-MRI series. The tumors were irradiated after the DCE-MRI, either with a single dose of 10 Gy for detection of radiobiological hypoxia (30 tumors) or with five fractions of 4 Gy in 48 h for assessment of radioresponsiveness (20 tumors). The host mice were then euthanized and examined for lymph node metastases, and the primary tumors were resected for measurement of cell survival in vitro. RESULTS: Tumors with hypoxic cells showed significantly lower Ktrans values than tumors without significant hypoxia (p<0.0001, n=30), and Ktrans decreased with increasing cell surviving fraction for tumors given fractionated radiation treatment (p<0.0001, n=20). Tumors in metastasis-positive mice had significantly lower Ktrans values than tumors in metastasis-negative mice (p<0.0001, n=50). Significant correlations between ve and tumor hypoxia, radioresponsiveness, or metastatic potential could not be detected. CONCLUSIONS: R-18 tumors with low Ktrans values are likely to be resistant to radiation treatment and have a high probability of developing lymph node metastases. The general validity of these observations should be investigated further by studying preclinical tumor models with biological properties different from those of the R-18 tumors. PMID- 21816293 TI - Dose-volume histogram parameters and late side effects in magnetic resonance image-guided adaptive cervical cancer brachytherapy: in regard to Georg et al. (Int J Radiat Oncol Biol Phys 2011;79:356-362). PMID- 21816296 TI - The evaluation and treatment of children with brachial plexus birth palsy. AB - The Andrew J. Weiland Medal is presented by the American Society for Surgery of the Hand to a mid-career researcher dedicated to advancing patient care in the field of hand surgery. The Weiland Medal for 2010 was presented to the author at the annual meeting of the American Society for Surgery of the Hand. The purpose of this article is to present a decade of research directed at establishing and building evidence in support of effective treatment of adolescents and children impaired by nerve injury. The primary beneficiaries of this effort are children affected by brachial plexus injury. The research goals have been to better understand their underlying problems, improve their lives via advanced diagnostic and surgical techniques, and, by applying appropriate outcome measures, better appreciate the changes to their lives brought about by therapeutic interventions. PMID- 21816295 TI - In regard McDonald et al., to Pattern of failure after limited margin radiotherapy and temozolomide for glioblastoma (Int J Radiat Oncol Biol Phys 2011;79:130-136). PMID- 21816297 TI - Hand infections. AB - Hand infections are commonly seen by orthopedic surgeons as well as emergency room and primary care physicians. Identifying the cause of the infection and initiating prompt and appropriate medical or surgical treatment can prevent substantial morbidity. The most common bacteria implicated in hand infections remain Staphylococcus aureus and Streptococcus species. Methicillin-resistant S aureus infections have become prevalent and represent a difficult problem best treated with empiric antibiotic therapy until the organism can be confirmed. Other organisms can be involved in specific situations that will be reviewed. Types of infections include cellulitis, superficial abscesses, deep abscesses, septic arthritis, and osteomyelitis. In recent years, treatment of these infections has become challenging owing to increased virulence of some organisms and drug resistance. Treatment involves a combination of proper antimicrobial therapy, immobilization, edema control, and adequate surgical therapy. Best practice management requires use of appropriate diagnostic tools, understanding by the surgeon of the unique and complex anatomy of the hand, and proper antibiotic selection in consultation with infectious disease specialists. PMID- 21816298 TI - Indirect forearm pronation test. PMID- 21816299 TI - Coronary abscess in an adolescent with a structurally normal heart. PMID- 21816300 TI - Clinical characteristics of peripartum cardiomyopathy in the United States: diagnosis, prognosis, and management. AB - Peripartum cardiomyopathy is a pregnancy-associated myocardial disease characterized by the development of heart failure due to marked left ventricular systolic dysfunction. Although the disease is relatively uncommon, its incidence is increasing, and it can be associated with important and lasting morbidity and with mortality. Peripartum cardiomyopathy seems to affect women in different parts of the world but with considerable differences in clinical presentation. The purposes of this review are to describe the clinical profile of peripartum cardiomyopathy in the United States and to provide recommendations for the diagnosis and the management of this disease. PMID- 21816301 TI - International participation in cardiovascular randomized controlled trials sponsored by the National Heart, Lung, and Blood Institute. AB - OBJECTIVES: The aim of this study was to describe international enrollment and participation in National Institutes of Health (NIH)-sponsored cardiovascular randomized controlled trials (RCTs). BACKGROUND: RCTs provide the evidence base for major societal guidelines and profoundly influence patient care in the United States. Increased international involvement in clinical trials has been observed, but the rate of international enrollment in NIH-sponsored cardiovascular RCTs has not been described. METHODS: The NIH registry of clinical trials was searched for phase III or IV cardiovascular RCTs funded by the National Heart, Lung, and Blood Institute. Studies with outcomes of myocardial infarction, stroke, or death published between 1997 and 2009 were included. Rates of international enrollment were obtained from published data or personal communication with corresponding authors. RESULTS: Twenty-four studies met all inclusion criteria. Nineteen trials including 151,682 patients had international participation (IP), with median IP of 9.5% (range 0% to 100%). Coronary artery disease trials (11 studies) had nearly 50% international enrollment. High-risk trials and trials testing acute interventions tended to have higher rates of IP. CONCLUSIONS: Cardiovascular RCTs sponsored by the National Heart, Lung, and Blood Institute have substantial rates of international enrollment, particularly coronary artery disease trials. Given questions of applicability and ethical and financial considerations, IP in U.S. clinical trials deserves further scrutiny. PMID- 21816302 TI - American industry and the U.S. Cardiovascular Clinical Research Enterprise an appropriate analogy? PMID- 21816303 TI - Intracranial emboli associated with catheter ablation of atrial fibrillation: has the silence finally been broken? PMID- 21816304 TI - Culprit vessel only versus multivessel and staged percutaneous coronary intervention for multivessel disease in patients presenting with ST-segment elevation myocardial infarction: a pairwise and network meta-analysis. AB - OBJECTIVES: The purposes of this study were to investigate whether, in patients with ST-segment elevation myocardial infarction (STEMI) and multivessel disease (MVD), percutaneous coronary intervention (PCI) should be confined to the culprit or also nonculprit vessels and, when performing PCI for nonculprit vessels, whether it should take place during primary PCI or staged procedures. BACKGROUND: A significant percentage of STEMI patients have MVD. However, the best PCI strategy for nonculprit vessel lesions is unknown. METHODS: Pairwise and network meta-analyses were performed on 3 PCI strategies for MVD in STEMI patients: 1) culprit vessel only PCI strategy (culprit PCI), defined as PCI confined to culprit vessel lesions only; 2) multivessel PCI strategy (MV-PCI), defined as PCI of culprit vessel as well as >=1 nonculprit vessel lesions; and 3) staged PCI strategy (staged PCI), defined as PCI confined to culprit vessel, after which >=1 nonculprit vessel lesions are treated during staged procedures. Prospective and retrospective studies were included when research subjects were patients with STEMI and MVD undergoing PCI. The primary endpoint was short-term mortality. RESULTS: Four prospective and 14 retrospective studies involving 40,280 patients were included. Pairwise meta-analyses demonstrated that staged PCI was associated with lower short- and long-term mortality as compared with culprit PCI and MV-PCI and that MV-PCI was associated with highest mortality rates at both short- and long-term follow-up. In network analyses, staged PCI was also consistently associated with lower mortality. CONCLUSIONS: This meta-analysis supports current guidelines discouraging performance of multivessel primary PCI for STEMI. When significant nonculprit vessel lesions are suitable for PCI, they should only be treated during staged procedures. PMID- 21816305 TI - Prognostic impact of staged versus "one-time" multivessel percutaneous intervention in acute myocardial infarction: analysis from the HORIZONS-AMI (harmonizing outcomes with revascularization and stents in acute myocardial infarction) trial. AB - OBJECTIVES: The purpose of this study was to compare a one-time primary percutaneous coronary intervention (PCI) of the culprit and nonculprit lesions with PCI of only the culprit lesion and staged nonculprit PCI at a later date in patients with ST-segment elevation myocardial infarction (STEMI) and multivessel disease. BACKGROUND: In patients with STEMI and multivessel disease, it is unknown whether it is safe or even desirable to also treat the nonculprit vessel during the primary PCI procedure. METHODS: In the HORIZONS-AMI (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction) trial, 668 of the 3,602 STEMI patients enrolled (18.5%) underwent PCI of culprit and nonculprit lesions for multivessel disease. Patients were categorized into a single PCI strategy (n = 275) versus staged PCI (n = 393). The endpoints analyzed included the 1-year rates of major adverse cardiovascular events and its components, death, reinfarction, target-vessel revascularization for ischemia, and stroke. RESULTS: Single versus staged PCI was associated with higher 1-year mortality (9.2% vs. 2.3%; hazard ratio [HR]: 4.1, 95% confidence interval [CI]: 1.93 to 8.86, p < 0.0001), cardiac mortality (6.2% vs. 2.0%; HR: 3.14, 95% CI: 1.35 to 7.27, p = 0.005), definite/probable stent thrombosis (5.7% vs. 2.3%; HR: 2.49, 95% CI: 1.09 to 5.70, p = 0.02), and a trend toward greater major adverse cardiovascular events (18.1% vs. 13.4%; HR: 1.42, 95% CI: 0.96 to 2.1, p = 0.08). The mortality advantage favoring staged PCI was maintained in a subgroup of patients undergoing truly elective multivessel PCI. Also, the staged PCI strategy was independently associated with lower all-cause mortality at 30 days and at 1 year. CONCLUSIONS: A deferred angioplasty strategy of nonculprit lesions should remain the standard approach in patients with STEMI undergoing primary PCI, as multivessel PCI may be associated with a greater hazard for mortality and stent thrombosis. (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction [HORIZONS-AMI]; NCT00433966). PMID- 21816306 TI - Interventional Strategies for ST-Segment Elevation Myocardial Infarction and Multivessel Coronary Artery Disease. PMID- 21816307 TI - Transapical transcatheter aortic valve implantation in the presence of a mitral prosthesis. AB - OBJECTIVES: We review our experience with transapical transcatheter aortic valve implantation (AVI) in patients with functioning mitral prostheses, and describe the technical considerations. BACKGROUND: Transcatheter AVI for aortic stenosis in patients with mitral prostheses is technically challenging. METHODS: Ten patients (7 mechanical and 3 bioprosthetic mitral valves) received the Edwards SAPIEN balloon-expandable valve (Edwards Lifesciences, Irvine, California) during 2006 to 2010. All patients were declined conventional surgery and prospectively followed. The mean patient age was 77.6 +/- 7.1 years (range: 67 to 88 years). The logistic EuroSCORE and the Society of Thoracic Surgeons-predicted operative mortality were 30.3 +/- 18.6% (range: 11.4% to 70.4%), and 9.9 +/- 4.8% (range: 4.6% to 18.7%), respectively. RESULTS: All valves were successfully implanted, with no 30-day mortality or mitral prosthetic dysfunction. Nine patients had none to mild residual aortic paravalvular leak. The overall survival was 60% at a mean follow-up of 12.2 +/- 10.4 months (range: 2 to 33 months), with 4 nonvalve related deaths. Seven patients improved to New York Heart Association functional class I to II. The mean transvalvular gradient and effective orifice area improved from 40.0 +/- 17.4 mm Hg to 8.2 +/- 2.1 mm Hg, and 0.6 +/- 0.1 cm2 to 1.3 +/- 0.2 cm2, respectively (p < 0.0001). The mitral bioprosthetic strut predisposes to device "shift" during deployment. An "unfavorable" mechanical mitral prosthetic cage or pivot strut can also cause shifts. Balloon shifts during valvuloplasty warn of a high likelihood of prosthesis shift. CONCLUSIONS: This report details the technical lessons learned thus far from our first 10 patients. Excellent procedural success and early outcomes in patients with functioning mitral prosthesis can be achieved. PMID- 21816308 TI - Prevalence and characteristics of early repolarization in the CASPER registry: cardiac arrest survivors with preserved ejection fraction registry. AB - OBJECTIVES: We evaluated the prevalence and characteristics of early repolarization in patients in CASPER (Cardiac Arrest Survivors With Preserved Ejection Fraction Registry). BACKGROUND: Early repolarization has been implicated in a syndrome of polymorphic ventricular tachycardia and fibrillation in patients without organic heart disease. METHODS: One hundred patients with apparently unexplained cardiac arrest and preserved ejection fraction underwent extensive clinical and genetic testing to unmask subclinical electrical or structural disease. A blinded independent analysis of the 12-lead electrocardiogram (ECG) was performed. Early repolarization was defined as >=0.1 mV QRS-ST junction (J point) elevation with terminal QRS slurring or notching in at least 2 contiguous inferior and/or lateral leads. RESULTS: One hundred cardiac arrest patients were enrolled (40 females, age 43 +/- 14 years). Forty-four were diagnosed with an established cause for cardiac arrest. Significant early repolarization was found in 19 patients, including 6 with a primary diagnosis that explained their cardiac arrest (14%), compared with 23% of the 56 patients with idiopathic ventricular fibrillation (IVF) (p = 0.23). J-point elevation in IVF patients had higher amplitude (0.25 +/- 0.11 mV vs. 0.13 +/- 0.05 mV, p = 0.02) and wider distribution (4.3 +/- 1.3 leads vs. 2.8 +/- 0.8 leads; p = 0.01) than those with an established cause of cardiac arrest. J-wave amplitude was fluctuant on serial ECGs; at least 1 ECG failed to demonstrate early repolarization in 58% of patients. CONCLUSIONS: Early repolarization is present in a significant proportion of causally diagnosed and idiopathic VF. It is often intermittent and more pronounced in IVF patients. (Registry of Unexplained Cardiac Arrest; NCT00292032). PMID- 21816309 TI - Reduction of the risk of recurring heart failure events with cardiac resynchronization therapy: MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy). AB - OBJECTIVES: The evaluation of the risk of recurring heart failure events (HFEs) was a pre-specified substudy of MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy). BACKGROUND: There are limited data regarding the effect of cardiac resynchronization therapy with a defibrillator (CRT-D) on the occurrence of recurring heart failure episodes after a first post-implantation HFE. METHODS: Data with regard to recurring HFEs were prospectively collected for all 1,820 MADIT-CRT participants. The CRT-D versus defibrillator-only risk for nonfatal first- and subsequent-HFEs was assessed by Cox proportional hazards and Andersen-Gill proportional intensity regression modeling, respectively, in efficacy analyses recognizing active device-type during follow-up. RESULTS: Multivariate analysis showed that CRT-D was associated with a significant reduction in the risk of a first HFE (hazard ratio [HR]: 0.54, 95% confidence interval [CI]: 0.44 to 0.67, p < 0.001) and with a similar magnitude of reduction in the risk of HFEs subsequent to a first post-enrollment event (HR: 0.62, 95% CI: 0.45 to 0.85, p = 0.003). The benefit of CRT-D for the prevention of first and subsequent HFEs was pronounced among patients with left bundle branch block (HR: 0.38, 95% CI: 0.29 to 0.49, p < 0.001; and HR: 0.50, 95% CI: 0.33 to 0.76, p = 0.001, respectively) and nonsignificant in non-left bundle branch block patients (HR: 1.12, 95% CI: 0.77 to 1.64, p = 0.55; and HR: 0.99, 95% CI: 0.58 to 1.69, p = 0.96, respectively; p values for interaction: p < 0.001 and p = 0.06, respectively). The occurrences of first and second HFEs were associated with 7- and nearly 19-fold respective increases in the risk of subsequent mortality. CONCLUSIONS: In the MADIT-CRT trial, the benefit of cardiac resynchronization therapy for the reduction in recurring HFEs was maintained after the occurrence of a first post-enrollment event. The occurrence of HFEs greatly increased the risk of death. (Multicenter Automatic Defibrillator Implantation With Cardiac Resynchronization Therapy; NCT00180271). PMID- 21816310 TI - Fighting the malignancy of recurring heart failure events. PMID- 21816311 TI - Impaired myocardial flow reserve on rubidium-82 positron emission tomography imaging predicts adverse outcomes in patients assessed for myocardial ischemia. AB - OBJECTIVES: We evaluated the prognostic value of myocardial flow reserve (MFR) using rubidium-82 ((82)Rb) positron emission tomography (PET) in patients assessed for ischemia. BACKGROUND: The clinical value of MFR quantification using (82)Rb PET beyond relative myocardial perfusion imaging remains uncertain. METHODS: We prospectively enrolled 704 consecutive patients; 677 (96%) completed follow-up (median 387 days [interquartile range: 375 to 416 days]). Patients were divided into 4 groups: I, normal summed stress score (SSS) (<4) and normal myocardial flow reserve (MFR) (>2); II, normal SSS and MFR <2; III, SSS >=4 and MFR >=2; IV, SSS >=4 and MFR <2. RESULTS: For patients with a normal SSS and those with an abnormal SSS, there were significant differences in outcomes for hard events (cardiac death and myocardial infarction) between patients with MFR >=2 and those with MFR <2 (I: 1.3% vs. II: 2% [p = 0.029]; III: 1.1% vs. IV: 11.4% [p = 0.05]) and for major adverse cardiac events (MACE) (p = 0.003 and p < 0.001, respectively). In the adjusted Cox model, MFR was an independent predictor of hard events (hazard ratio: 3.3; 95% confidence interval: 1.1 to 9.5; p = 0.029) and MACE (hazard ratio: 2.4, 95% confidence interval: 1.4 to 4.4, p = 0.003). The incremental prognostic value of the MFR over the SSS was demonstrated by comparing the adjusted SSS model with and without the MFR for hard events (p = 0.0197) and MACE (p = 0.002). CONCLUSIONS: MFR quantified using (82)Rb PET predicts hard cardiac events and MACE independent of the SSS and other parameters. Routine assessment of (82)Rb PET-quantified MFR could improve risk stratification for patients being investigated for ischemia. PMID- 21816312 TI - Leaving relativity behind: quantitative clinical perfusion imaging. PMID- 21816313 TI - Aspirin extrusion from human platelets through multidrug resistance protein-4 mediated transport: evidence of a reduced drug action in patients after coronary artery bypass grafting. AB - OBJECTIVES: In this study we investigate: 1) the role of multidrug resistance protein-4 (MRP4), an organic anion unidirectional transporter, in modulating aspirin action on human platelet cyclooxygenase (COX)-1; and 2) whether the impairment of aspirin-COX-1 interaction, found in coronary artery bypass grafting (CABG) patients, could be dependent on MRP4-mediated transport. BACKGROUND: Platelets of CABG patients present a reduced sensitivity to aspirin despite in vivo and in vitro drug treatment. Aspirin is an organic anion and could be a substrate for MRP4. METHODS: Intracellular aspirin concentration and drug COX-1 activity, measured by thrombin-induced thromboxane B2 (TxB2) production, were evaluated in platelets obtained from healthy volunteers (HV) and hematopoietic progenitor cell cultures reducing or not reducing MRP4-mediated transport. Platelet MRP4 expression was evaluated, in platelets from HV and CABG patients, by dot-blot or by immunogold-electromicrographs or immunofluorescence-microscopy analysis. RESULTS: Inhibition of MRP4-mediated transport by dipyridamole or Mk 571 increases aspirin entrapment and its in vitro effect on COX-1 activity (142.7 +/- 34.6 pg/10(8) cells vs. 343.7 +/- 169.3 pg/108 cells TxB2-production). Platelets derived from megakaryocytes transfected with MRP4 small interfering ribonucleic acid have a higher aspirin entrapment and drug COX-1 activity. Platelets from CABG patients showed a high expression of MRP4 whose in vitro inhibition enhanced aspirin effect on COX-1 (349 +/- 141 pg/108 cells vs. 1,670 +/- 646 pg/108 cells TxB2-production). CONCLUSIONS: Aspirin is a substrate for MRP4 and can be extruded from platelet through its transportation. Aspirin effect on COX-1 is little-related to MRP4-mediated aspirin transport in HV, but in CABG patients with MRP4 over-expression, its pharmacological inhibition enhances aspirin action in an efficient way. PMID- 21816314 TI - Overexpression of the multidrug resistance protein-4 transporter in patients undergoing coronary artery bypass graft surgery a cause of aspirin resistance? PMID- 21816315 TI - Baroreflex activation therapy lowers blood pressure in patients with resistant hypertension: results from the double-blind, randomized, placebo-controlled rheos pivotal trial. AB - OBJECTIVES: We sought to determine the effect of baroreflex activation therapy (BAT) on systolic blood pressure (SBP) in patients with resistant hypertension. BACKGROUND: The Rheos Pivotal Trial evaluated BAT for resistant hypertension in a double-blind, randomized, prospective, multicenter, placebo-controlled Phase III clinical trial. METHODS: This was a double-blind randomized trial of 265 subjects with resistant hypertension implanted and subsequently randomized (2:1) 1 month after implantation. Subjects received either BAT (Group A) for the first 6 months or delayed BAT initiation following the 6-month visit (Group B). The 5 coprimary endpoints were: 1) acute SBP responder rate at 6 months; 2) sustained responder rate at 12 months; 3) procedure safety; 4) BAT safety; and 5) device safety. RESULTS: The trial showed significant benefit for the endpoints of sustained efficacy, BAT safety, and device safety. However, it did not meet the endpoints for acute responders or procedural safety. A protocol-specified ancillary analysis showed 42% (Group A) versus 24% (Group B) achieving SBP <=140 mm Hg at 6 months (p = 0.005), with both groups achieving over 50% at 12 months, at which point Group B had received 6 months of BAT. CONCLUSIONS: A clinically meaningful measure, those achieving a SBP of <=140 mm Hg, yielded a significant difference between the groups. The weight of the overall evidence suggests that over the long-term, BAT can safely reduce SBP in patients with resistant hypertension. Future clinical trials will address the limitations of this study and further define the therapeutic benefit of BAT. PMID- 21816316 TI - Free-floating thrombus in the left atrium. PMID- 21816317 TI - Circulating transforming growth factor-beta levels in acute aortic dissection. PMID- 21816319 TI - Limitations of gait speed as an independent predictor of mortality and morbidity in cardiac patients. PMID- 21816320 TI - Valve Academic Research Consortium Consensus report: the pharmaceutical and medical devices agency perspective. PMID- 21816321 TI - Lowering the triglyceride/high-density lipoprotein cholesterol and its association with the beneficial impact of pioglitazone on coronary atherosclerosis in the PERISCOPE study is likely due to lowering insulin resistance. PMID- 21816322 TI - Normal MRI anatomy from head to toe. PMID- 21816323 TI - Normal brain anatomy on magnetic resonance imaging. AB - The exquisite detail provided by brain magnetic resonance imaging scans can make interpretation simultaneously straightforward and complicated, particularly to the novice. For this reason, it is essential to become familiar with normal structures before describing the pathologic condition. This article serves as a practical reference point to further enhance knowledge of the intracranial anatomy. PMID- 21816324 TI - Skull base, orbits, temporal bone, and cranial nerves: anatomy on MR imaging. AB - Accurate delineation, diagnosis, and treatment planning of skull base lesions require knowledge of the complex anatomy of the skull base. Because the skull base cannot be directly evaluated, imaging is critical for the diagnosis and management of skull base diseases. Although computed tomography (CT) is excellent for outlining the bony detail, magnetic resonance (MR) imaging provides better soft tissue detail and is helpful for evaluating the adjacent meninges, brain parenchyma, and bone marrow of the skull base. Thus, CT and MR imaging are often used together for evaluating skull base lesions. This article focuses on the radiologic anatomy of the skull base pertinent to MR imaging evaluation. PMID- 21816325 TI - Neck MR imaging anatomy. AB - The normal MR imaging appearance of the neck can be confusing given the number and complexity of structures that pass through it. This article strives to simplify normal MR imaging anatomy of the neck using a spatial approach. We present the protocols used at our institution and provide tables with details. Magnetic resonance (MR) imaging anatomy and appearance of the deep spaces of the neck are described with extensive labeled imaging correlates. Pearls and common pitfalls encountered with MR imaging of the neck are discussed. Additional aspects of normal neck MR imaging are described including lymph node, brachial plexus, and vascular anatomy. PMID- 21816326 TI - Normal spinal anatomy on magnetic resonance imaging. AB - Over the past few decades, spinal magnetic resonance imaging (MR imaging) has largely replaced computed tomography (CT) and CT myelography in the assessment of intraspinal pathology at institutions where MR imaging is available. Given its high contrast resolution, MR imaging allows the differentiation of the several adjacent structures comprising the spine. This article illustrates normal spinal anatomy as defined by MR imaging, describes commonly used spinal MR imaging protocols, and discusses associated common artifacts. PMID- 21816327 TI - Normal magnetic resonance imaging of the thorax. AB - The soft tissue contrast properties of magnetic resonance (MR) allow excellent discrimination of most intrathoracic structures other than the lungs, and allow good insight into normal anatomy. Using MR imaging, the normal cardiorespiratory system, including portions of the lungs and pleural spaces, as well as the mediastinal, chest wall, and cardiac structures can be well depicted. In addition, using newer MR pulse sequences, dynamic ECG-gated imaging can also be achieved, which allows a window into the normal functional processes of these organs. PMID- 21816328 TI - Breast MR imaging: normal anatomy. AB - Dynamic contrast-enhanced magnetic resonance (MR) imaging of the breast is a useful tool for the assessment of both structural and functional anatomy. A basic approach to the interpretation of normal anatomy on breast MR imaging is reviewed in this article. PMID- 21816329 TI - Normal and variant abdominal anatomy on magnetic resonance imaging. AB - The diagnostic usefulness of abdominal magnetic resonance (MR) imaging lies in the improved contrast resolution and ability to qualify several tissue characteristics of a specific organ or lesion. Our institution uses organ specific protocols to facilitate technical reproducibility and optimize scan duration. These protocols are discussed individually in this article when applicable, noting that many build on a basic protocol with slight variations. Because most abdominal MR imaging studies are targeted toward an organ or area of interest, this article discusses the protocol strategies and relevant anatomy in a segmented/organ-specific manner. PMID- 21816330 TI - Normal and variant pelvic anatomy on MRI. AB - The superior tissue contrast and flexible imaging planes afforded by magnetic resonance imaging (MRI) versus competing technologies permit optimal depiction of the pelvic viscera. Targeted protocols developed for specific pelvic visceral organs highlight important anatomic features that may not be imaged by other modalities. Therefore, a solid understanding of normal and variant pelvic anatomy is crucial for appropriate interpretation of pelvic MRI studies. This article discusses the protocol strategies and relevant anatomy with commonly encountered anatomical variants in a segmented/organ-specific manner, using gender as a broad split given the substantial variance in relevant organs. PMID- 21816331 TI - Magnetic resonance imaging of the long bones of the upper extremity. AB - The long bones of the upper extremity are often overlooked in favor of addressing their intervening joints. However, there are a wide variety of pathologic processes that can involve these anatomic segments. To better understand the complex anatomy of the upper extremity, this article is divided into sections describing the osseous, muscular, and neurovascular anatomy of the arm and forearm using a compartmental approach. The discussion touches on a few common normal variants and their potential functional consequences. The upper extremity joints of the shoulder, elbow, and wrist are addressed separately. PMID- 21816332 TI - Normal and variant anatomy of the shoulder on MRI. AB - New developments in musculoskeletal magnetic resonance (MR) imaging, including improved spatial resolution and MR arthrography, have led to an increasing frequency in the performance of shoulder MR imaging. As a result, radiologists' understanding of the normal and variant anatomy of the shoulder visible on MR imaging has also become more important. In this article, the authors review the normal arrangement and appearance of osseous and soft-tissue structures in the shoulder, as well as nonpathologic osseous and nonosseous variants that should be recognized. PMID- 21816333 TI - Normal and variant anatomy of the wrist and hand on MR imaging. AB - Magnetic resonance imaging is the optimal modality for characterizing the ligaments, tendons, muscles, and neurovascular structures of the wrist and hand. Continued refinement in pulse sequence and coil design permits high-resolution examination of the many small structures and complex anatomy of this region. In this context, frequent anatomic variants and common false positives such as normal areas of high signal intensity in ligaments and tendons must be recognized to avoid misdiagnosis and improper treatment. This article discusses the osseous and soft tissue anatomy of the wrist and hand, as well as normal variants. PMID- 21816334 TI - Normal and variant anatomy of the elbow on magnetic resonance imaging. AB - Magnetic resonance imaging (MRI) provides excellent delineation of the bones of the elbow and the surrounding soft tissue structures. The components of the elbow can be divided into osseous structures, the joint capsule and ligaments, muscles and tendons, and nerves. In this article, the authors review the normal anatomy and appearance of these structures on MRI as well as the anatomic variants that should be recognized and distinguished from pathologic entities. PMID- 21816335 TI - Normal MR imaging anatomy of the thigh and leg. AB - Magnetic resonance (MR) imaging is the modality of choice for evaluating the soft tissues of the thigh and leg because of its superior soft tissue contrast resolution, multiplanar imaging capability, and lack of ionizing radiation. The superb image quality facilitates learning normal imaging anatomy, which ultimately forms the foundation of diagnostic interpretation. The purpose of this article is twofold: (1) depict normal MR anatomy throughout the thigh and leg using representative MR images, emphasizing a compartmental approach; and (2) describe and explain the rationale of standard imaging protocols. PMID- 21816336 TI - Normal MR imaging anatomy of the knee. AB - Magnetic resonance (MR) imaging is the preferred imaging modality for evaluating internal derangement of the knee, due to its superior soft tissue contrast resolution, multiplanar imaging capability, and lack of ionizing radiation. The superb image quality facilitates learning of normal imaging anatomy and conceptualizing spatial relationships of anatomic structures, leading to improved understanding of pathologic processes, mechanisms of injury, and injury patterns, and ultimately increased diagnostic accuracy. This article depicts normal MR imaging anatomy and commonly encountered anatomic variants using representative MR images of the knee, and describes and explains the rationale of routine knee MR imaging protocol. PMID- 21816337 TI - Normal magnetic resonance imaging anatomy of the ankle & foot. AB - This article discusses anatomic relationships, anatomic variants, and MRI protocols that pertain to the foot and ankle. MR images with detailed anatomic description form the cornerstone of this article. The superb image quality will facilitate learning normal imaging anatomy, as well as conceptualizing spatial relationships of anatomic structures. PMID- 21816338 TI - Part one: the vast majority of patients with renal artery stenoses require intervention. PMID- 21816339 TI - Part two: the vast majority of patients with atherosclerotic renal artery stenoses do not require intervention. PMID- 21816340 TI - UneCLIPsing HuR nuclear function. AB - The RNA-binding protein HuR, while known to stabilize cytoplasmic mRNAs, is largely nuclear. In this issue of Molecular Cell, Mukherjee et al. (2011) and Lebedeva et al. (2011) identify transcriptome-wide HuR-RNA interactions using PAR CLIP, unveiling HuR's nuclear role in pre-mRNA processing. PMID- 21816341 TI - CUL4B: trash talking at chromatin. AB - In this issue, Nakagawa and Xiong (2011) reveal a mechanism targeting WDR5 for proteolysis dependent on the X-linked mental retardation gene, CUL4B. This provides a link between the stability of a chromatin factor and gene expression implicated in neurological pathogenesis. PMID- 21816342 TI - The Ripoptosome: death decision in the cytosol. AB - In this issue of Molecular Cell, Tenev et al. and Feoktistova et al. describe the Ripoptosome, a cytosolic death-inducing RIP1-, FADD-, and caspase-8-containing complex that spontaneously assembles upon cIAP depletion, challenging the view that such complexes exclusively originate from receptor activation. PMID- 21816343 TI - The Ewing sarcoma protein regulates DNA damage-induced alternative splicing. AB - The Ewing sarcoma (EWS) protein is a member of the TET (TLS/EWS/TAF15) family of RNA- and DNA-binding proteins whose expression is altered in cancer. We report that EWS depletion results in alternative splicing changes of genes involved in DNA repair and genotoxic stress signaling, including ABL1, CHEK2, and MAP4K2. Chromatin and RNA crosslinking immunoprecipitation results indicate that EWS cotranscriptionally binds to its target RNAs. This association is reduced upon irradiation of cells with ultraviolet light, concomitant with transient enrichment of EWS in nucleoli and with alternative splicing changes that parallel those induced by EWS depletion and that lead to reduced c-ABL protein expression. Consistent with the functional relevance of EWS-mediated alternative splicing regulation in DNA damage response, EWS depletion reduces cell viability and proliferation upon UV irradiation, effects that are attenuated by restoring c-ABL expression. These results provide insights into posttranscriptional mechanisms of DNA damage response by a TET protein. PMID- 21816344 TI - Nonhistone Scm3 binds to AT-rich DNA to organize atypical centromeric nucleosome of budding yeast. AB - The molecular architecture of centromere-specific nucleosomes containing histone variant CenH3 is controversial. We have biochemically reconstituted two distinct populations of nucleosomes containing Saccharomyces cerevisiae CenH3 (Cse4). Reconstitution of octameric nucleosomes containing histones Cse4/H4/H2A/H2B is robust on noncentromere DNA, but inefficient on AT-rich centromere DNA. However, nonhistone Scm3, which is required for Cse4 deposition in vivo, facilitates in vitro reconstitution of Cse4/H4/Scm3 complexes on AT-rich centromere sequences. Scm3 has a nonspecific DNA binding domain that shows preference for AT-rich DNA and a histone chaperone domain that promotes specific loading of Cse4/H4. In live cells, Scm3-GFP is enriched at centromeres in all cell cycle phases. Chromatin immunoprecipitation confirms that Scm3 occupies centromere DNA throughout the cell cycle, even when Cse4 and H4 are temporarily dislodged in S phase. These findings suggest a model in which centromere-bound Scm3 aids recruitment of Cse4/H4 to assemble and maintain an H2A/H2B-deficient centromeric nucleosome. PMID- 21816345 TI - X-linked mental retardation gene CUL4B targets ubiquitylation of H3K4 methyltransferase component WDR5 and regulates neuronal gene expression. AB - CUL4B, encoding a scaffold protein for the assembly of Cullin4B-Ring ubiquitin ligase (CRL4B) complexes, is frequently mutated in X-linked mental retardation (XLMR) patients. Here, we show that CUL4B, but not its paralog, CUL4A, targets WDR5, a core subunit of histone H3 lysine 4 (H3K4) methyltransferase complexes, for ubiquitylation and degradation in the nucleus. Knocking down CUL4B increases WDR5 and trimethylated H3K4 (H3K4me3) on the neuronal gene promoters and induces their expression. Furthermore, CUL4B depletion suppresses neurite outgrowth of PC12 neuroendocrine cells, which can be rescued by codepletion of WDR5. XLMR linked mutations destabilize CUL4B and impair its ability to support neurite outgrowth of PC12 cells. Our results identify WDR5 as a critical substrate of CUL4B in regulating neuronal gene expression and suggest epigenetic change as a common pathogenic mechanism for CUL4B-associated XLMR. PMID- 21816346 TI - Alternative ubiquitin activation/conjugation cascades interact with N-end rule ubiquitin ligases to control degradation of RGS proteins. AB - Vertebrates express two enzymes for activation of ubiquitin-UBA1, which is responsible for activation of the vast majority of E2 conjugating enzymes, and UBA6, which uses the dedicated E2, USE1. However, targets and E3s for UBA6-USE1 are unknown. Here, we demonstrate that UBA6-USE1 functions with the UBR1-3 subfamily of N-recognin E3s to degrade the N-end rule substrates RGS4, RGS5, and Arg (R)-GFP. This pathway functions in the cytoplasm in parallel with the UBA1 UBE2A/B-UBR2 cascade, which promotes turnover of nuclear RGS4/5 proteins and an apparently phenotypically distinct pool of cytoplasmic RGS4/5. UBR2 promotes Lys48 (K48)-specific ubiquitin discharge from, and RGS4 ubiquitylation by, both USE1 and UBE2A in vitro. This work provides insight into the machinery employed by the UBA6-USE1 cascade to promote protein turnover and suggests that the UBA6 and UBA1 pathways can function in parallel with the same E3 to degrade the same targets in a spatially distinct manner. PMID- 21816347 TI - Quantitative proteomics reveals the basis for the biochemical specificity of the cell-cycle machinery. AB - Cyclin-dependent kinases comprise the conserved machinery that drives progress through the cell cycle, but how they do this in mammalian cells is still unclear. To identify the mechanisms by which cyclin-cdks control the cell cycle, we performed a time-resolved analysis of the in vivo interactors of cyclins E1, A2, and B1 by quantitative mass spectrometry. This global analysis of context dependent protein interactions reveals the temporal dynamics of cyclin function in which networks of cyclin-cdk interactions vary according to the type of cyclin and cell-cycle stage. Our results explain the temporal specificity of the cell cycle machinery, thereby providing a biochemical mechanism for the genetic requirement for multiple cyclins in vivo and reveal how the actions of specific cyclins are coordinated to control the cell cycle. Furthermore, we identify key substrates (Wee1 and c15orf42/Sld3) that reveal how cyclin A is able to promote both DNA replication and mitosis. PMID- 21816349 TI - Cordon-Bleu uses WH2 domains as multifunctional dynamizers of actin filament assembly. AB - Cordon-Bleu is, like Spire, a member of the growing family of WH2 repeat proteins, which emerge as versatile regulators of actin dynamics. They are expressed in morphogenetic and patterning processes and nucleate actin assembly in vitro. Here, we show that Cordon-Bleu works as a dynamizer of actin assembly by combining many properties of profilin with weak filament nucleating and powerful filament severing activities and sequestration of ADP-actin, which altogether generate oscillatory polymerization kinetics. A short lysine-rich sequence, N-terminally adjacent to the three WH2 domains, is required for nucleation and severing. In this context, nucleation requires only one WH2 domain, but filament severing requires two adjacent WH2 domains. A model integrating the multiple activities of Cordon-Bleu and quantitatively fitting the multiphasic polymerization curves is derived. Hence, with similar structural organization of WH2 repeats, Cordon-Bleu and Spire display different functions by selecting different sets of the multifunctional properties of WH2 domains. PMID- 21816348 TI - LGN/mInsc and LGN/NuMA complex structures suggest distinct functions in asymmetric cell division for the Par3/mInsc/LGN and Galphai/LGN/NuMA pathways. AB - Asymmetric cell division requires the establishment of cortical cell polarity and the orientation of the mitotic spindle along the axis of cell polarity. Evidence from invertebrates demonstrates that the Par3/Par6/aPKC and NuMA/LGN/Galphai complexes, which are thought to be physically linked by the adaptor protein mInscuteable (mInsc), play indispensable roles in this process. However, the molecular basis for the binding of LGN to NuMA and mInsc is poorly understood. The high-resolution structures of the LGN/NuMA and LGN/mInsc complexes presented here provide mechanistic insights into the distinct and highly specific interactions of the LGN TPRs with mInsc and NuMA. Structural comparisons, together with biochemical and cell biology studies, demonstrate that the interactions of NuMA and mInsc with LGN are mutually exclusive, with mInsc binding preferentially. Our results suggest that the Par3/mInsc/LGN and NuMA/LGN/Galphai complexes play sequential and partially overlapping roles in asymmetric cell division. PMID- 21816350 TI - Direct membrane binding by bacterial actin MreB. AB - Bacterial actin MreB is one of the key components of the bacterial cytoskeleton. It assembles into short filaments that lie just underneath the membrane and organize the cell wall synthesis machinery. Here we show that MreB from both T. maritima and E. coli binds directly to cell membranes. This function is essential for cell shape determination in E. coli and is proposed to be a general property of many, if not all, MreBs. We demonstrate that membrane binding is mediated by a membrane insertion loop in TmMreB and by an N-terminal amphipathic helix in EcMreB and show that purified TmMreB assembles into double filaments on a membrane surface that can induce curvature. This, the first example of a membrane binding actin filament, prompts a fundamental rethink of the structure and dynamics of MreB filaments within cells. PMID- 21816352 TI - Association of smoking and chronic pain syndromes in Kentucky women. AB - The objective of this project was to determine the relationship between cigarette smoking and the reporting of chronic pain syndromes among participants in the Kentucky Women's Health Registry. Data was analyzed on 6,092 women over 18 years of age who responded to survey questions on pain and smoking. The chronic pain syndromes included in the analysis were fibromyalgia, sciatica, chronic neck pain, chronic back pain, joint pain, chronic head pain, nerve problems, and pain all over the body. Analyses controlled for age, body mass index, and Appalachian versus non-Appalachian county of residence. Results showed that women who were daily smokers reported more chronic pain (defined as the presence of any reported chronic pain syndromes) than women who were never smokers (adjusted odds ratio [aOR] = 2.04 and 95% confidence interval [CI] 1.67, 2.49). An increased risk was also seen for "some-day" smokers (aOR 1.68, 95% CI 1.24, 2.27), and former smokers (aOR 1.20, 95% CI 1.06, 1.37), though with less of an association in the latter group. This study provides evidence of an association between chronic pain and cigarette smoking that is reduced in former smokers. PERSPECTIVE: This paper presents the association between smoking and musculoskeletal pain syndromes among Kentucky women. This finding may provide additional opportunities for intervention in patients with chronic pain. PMID- 21816351 TI - The TFIIH subunit Tfb3 regulates cullin neddylation. AB - Cullin proteins are scaffolds for the assembly of multisubunit ubiquitin ligases, which ubiquitylate a large number of proteins involved in widely varying cellular functions. Multiple mechanisms cooperate to regulate cullin activity, including neddylation of their C-terminal domain. Interestingly, we found that the yeast Cul4-type cullin Rtt101 is not only neddylated but also ubiquitylated, and both modifications promote Rtt101 function in vivo. Surprisingly, proper modification of Rtt101 neither correlated with catalytic activity of the RING domain of Hrt1 nor required the Nedd8 ligase Dcn1. Instead, ubiquitylation of Rtt101 was dependent on the ubiquitin-conjugating enzyme Ubc4, while efficient neddylation involves the RING domain protein Tfb3, a subunit of the transcription factor TFIIH. Tfb3 also controls Cul3 neddylation and activity in vivo, and physically interacts with Ubc4 and the Nedd8-conjugating enzyme Ubc12 and the Hrt1/Rtt101 complex. Together, these results suggest that the conserved RING domain protein Tfb3 controls activation of a subset of cullins. PMID- 21816353 TI - Factors affecting placebo acceptability: deception, outcome, and disease severity. AB - A burgeoning body of evidence supports the efficacy and elucidates the mechanisms of placebo analgesia. Debate persists, however, concerning their ethical use, with many of the present arguments being philosophically based. The present web based study empirically investigated the acceptability of an analgesic placebo treatment. Participants (103) responded to vignettes depicting patients receiving a placebo analgesic. We experimentally manipulated: 1) placebo treatment instructions (level of deception); 2) treatment outcome; and 3) patients' pain severity. Participants rated vignettes on outcome measures of deception, physician-patient relationship, and patient mood. Participants then characterized a range of placebo acceptability through ratings of deceptiveness, effectiveness, and negative consequences. Results showed that placebos described as "medication shown to be a powerful analgesic in some people" were equally deceptive as those described as "standard drug treatment." Ratings of patient mood and physician approval were determined as much by treatment instruction as by treatment outcome and an analgesic response mitigated the negative consequences of deceptive administration. Participants tolerated moderate effectiveness and considerable negative consequences in an acceptable placebo, although results suggest lay individuals may not have a sophisticated conceptualization of placebo effectiveness. Studies altering individuals' understanding of placebo effectiveness and mechanisms are needed to identify additional factors determining placebo acceptability. PERSPECTIVE: This study represents an empirical examination of analgesic placebo acceptability among lay individuals. This article is the first to systematically manipulate deception, treatment outcome, and disease severity to determine how these factors interact to differentially determine placebo acceptability-a highly relevant finding that informs the clinical use of placebo. PMID- 21816354 TI - Should the hot-plate test be reincarnated? PMID- 21816356 TI - Tolerance induction by allogeneic hematopoietic stem cells. AB - In this issue of Cell Stem Cell, Zheng et al. (2011) report that HSCs expressing PD-L1 display enhanced engraftment in irradiated allogeneic recipients. Independently in Nature, Fujisaki et al. (2011) observe allogeneic HSCs persisting in proximity to regulatory T cells in nonirradiated recipients, further connecting HSCs and immune tolerance. PMID- 21816357 TI - A simple code for installing hepatocyte function. AB - Forced lineage conversion of accessible cell types can supply scarce or inaccessible cells for research and therapy. Two papers in Nature now report the identification of transcription factors sufficient for inducing therapeutically effective hepatocyte function in fibroblasts (Huang et al., 2011; Sekiya and Suzuki, 2011). PMID- 21816358 TI - When BMP meets FGF. AB - Bone morphogenic proteins (BMPs) act as inducers of diverse cellular fates in human embryonic stem cells, but the mechanisms responsible remain poorly understood. In this issue of Cell Stem Cell, Bernardo et al. (2011) demonstrate that different BMP-induced differentiation programs may be orchestrated by similar key target genes. PMID- 21816359 TI - Gene editing in stem cells hits the target. AB - Two recent reports describe promising, highly efficient methods to modify genes in pluripotent stem cells using zinc finger nuclease (ZFN)-mediated (Soldner et al., 2011) or helper-dependent adenovirus (HDAdV)-mediated (Liu et al., 2011b) gene modification. These technical developments will have far ranging effects on the rapidly growing field of regenerative medicine. PMID- 21816360 TI - EPO and super-EPO: erythropoietins direct neoangiogenesis by cardiac progenitor cells. AB - Erythropoietin, the red blood cell-making cytokine, is also a potential cytoprotective agent in heart disease. In this issue of Cell Stem Cell, Hoch et al. (2011) use two heart failure models, including chemotherapeutic cardiotoxicity, to reveal a mechanistic connection between reduced cardiomyocyte production of erythropoietin and neoangiogenesis by cardiac progenitors. PMID- 21816361 TI - Large-scale analysis reveals acquisition of lineage-specific chromosomal aberrations in human adult stem cells. AB - In this study, we assessed the genetic integrity of over 400 samples of human multipotent stem cells using gene expression data sets. Our analysis reveals that neural and mesenchymal stem cells acquire characteristic large chromosomal aberrations at a similar, or somewhat lower, frequency to that seen in pluripotent stem cells, sometimes within a few passages in culture. Some of the identified chromosomal abnormalities can also be detected in human tumors of the respective tissues. PMID- 21816362 TI - Inducing iPSCs to escape the dish. AB - Induced pluripotent stem cells (iPSCs) hold great promise for autologous cell therapies, but significant roadblocks remain to translating iPSCs to the bedside. For example, concerns about the presumed autologous transplantation potential of iPSCs have been raised by a recent paper demonstrating that iPSC-derived teratomas were rejected by syngeneic hosts. Additionally, the reprogramming process can alter genomic and epigenomic states, so a key goal at this point is to determine the clinical relevance of these changes and minimize those that prove to be deleterious. Finally, thus far few studies have examined the efficacy and tumorigenicity of iPSCs in clinically relevant transplantation scenarios, an essential requirement for the FDA. We discuss potential solutions to these hurdles to provide a roadmap for iPSCs to "jump the dish" and become useful therapies. PMID- 21816363 TI - Ex vivo expanded hematopoietic stem cells overcome the MHC barrier in allogeneic transplantation. AB - The lack of understanding of the interplay between hematopoietic stem cells (HSCs) and the immune system has severely hampered the stem cell research and practice of transplantation. Major problems for allogeneic transplantation include low levels of donor engraftment and high risks of graft-versus-host disease (GVHD). Transplantation of purified allogeneic HSCs diminishes the risk of GVHD but results in decreased engraftment. Here we show that ex vivo expanded mouse HSCs efficiently overcame the major histocompatibility complex barrier and repopulated allogeneic-recipient mice. An 8-day expansion culture led to a 40 fold increase of the allograft ability of HSCs. Both increased numbers of HSCs and culture-induced elevation of expression of the immune inhibitor CD274 (B7-H1 or PD-L1) on the surface of HSCs contributed to the enhancement. Our study indicates the great potential of utilizing ex vivo expanded HSCs for allogeneic transplantation and suggests that the immune privilege of HSCs can be modulated. PMID- 21816364 TI - Erythropoietin preserves the endothelial differentiation capacity of cardiac progenitor cells and reduces heart failure during anticancer therapies. AB - Anticancer therapies, such as targeting of STAT3 or the use of anthracyclins (doxorubicin), can induce cardiomyopathy. In mice prone to developing heart failure as a result of reduced cardiac STAT3 expression (cardiomyocyte-restricted deficiency of STAT3) or treatment with doxorubicin, we observed impaired endothelial differentiation capacity of Sca-1(+) cardiac progenitor cells (CPCs) in conjunction with attenuated CCL2/CCR2 activation. Mice in both models also displayed reduced erythropoietin (EPO) levels in the cardiac microenvironment. EPO binds to CPCs and seems to be responsible for maintaining an active CCL2/CCR2 system. Supplementation with the EPO derivative CERA in a hematocrit-inactive low dose was sufficient to upregulate CCL2, restore endothelial differentiation of CPCs, and preserve the cardiac microvasculature and cardiac function in both mouse models. Thus, low-dose EPO treatment could potentially be exploited as a therapeutic strategy to reduce the risk of heart failure in certain treatment regimens. PMID- 21816365 TI - BRACHYURY and CDX2 mediate BMP-induced differentiation of human and mouse pluripotent stem cells into embryonic and extraembryonic lineages. AB - BMP is thought to induce hESC differentiation toward multiple lineages including mesoderm and trophoblast. The BMP-induced trophoblast phenotype is a long standing paradox in stem cell biology. Here we readdressed BMP function in hESCs and mouse epiblast-derived cells. We found that BMP4 cooperates with FGF2 (via ERK) to induce mesoderm and to inhibit endoderm differentiation. These conditions induced cells with high levels of BRACHYURY (BRA) that coexpressed CDX2. BRA was necessary for and preceded CDX2 expression; both genes were essential for expression not only of mesodermal genes but also of trophoblast-associated genes. Maximal expression of the latter was seen in the absence of FGF but these cells coexpressed mesodermal genes and moreover they differed in cell surface and epigenetic properties from placental trophoblast. We conclude that BMP induces human and mouse pluripotent stem cells primarily to form mesoderm, rather than trophoblast, acting through BRA and CDX2. PMID- 21816366 TI - Unexpected X chromosome skewing during culture and reprogramming of human somatic cells can be alleviated by exogenous telomerase. AB - Somatic tissues in female eutherian mammals are mosaic due to random X inactivation. In contrast to mice, X chromosome reactivation does not occur during the reprogramming of human female somatic cells to induced pluripotent stem cells (iPSCs), although this view is contested. Using balanced populations of female Rett patient and control fibroblasts, we confirm that all cells in iPSC colonies contain an inactive X, and additionally find that all colonies made from the same donor fibroblasts contain the same inactive X chromosome. Notably, this extreme "skewing" toward a particular dominant, active X is also a general feature of primary female fibroblasts during proliferation, and the skewing seen in reprogramming and fibroblast culture can be alleviated by overexpression of telomerase. These results have important implications for in vitro modeling of X linked diseases and the interpretation of long-term culture studies in cancer and senescence using primary female fibroblast cell lines. PMID- 21816368 TI - Standard therapy for patients with myelodysplastic syndromes. AB - The myelodysplastic syndromes (MDS) are a group of clonal hematopoietic stem cell disorders characterized by cytopenias, dysplastic changes in the hematopoietic precursors, and an increased risk of evolving into acute leukemia. Treatment for patients with MDS ranges from supportive care with blood products and/or growth factors up to allogeneic stem cell transplantation. Over the past decade, several novel therapeutic agents have been approved for clinical use. In this article, the current approach for the management of patients with MDS according to their risk category is described and mainly focuses on approved novel agents. PMID- 21816367 TI - Tet1 is dispensable for maintaining pluripotency and its loss is compatible with embryonic and postnatal development. AB - The Tet family of enzymes (Tet1/2/3) converts 5-methylcytosine (5mC) to 5 hydroxymethylcytosine (5hmC). Mouse embryonic stem cells (mESCs) highly express Tet1 and have an elevated level of 5hmC. Tet1 has been implicated in ESC maintenance and lineage specification in vitro but its precise function in development is not well defined. To establish the role of Tet1 in pluripotency and development, we have generated Tet1 mutant mESCs and mice. Tet1(-/-) ESCs have reduced levels of 5hmC and subtle changes in global gene expression, and are pluripotent and support development of live-born mice in tetraploid complementation assay, but display skewed differentiation toward trophectoderm in vitro. Tet1 mutant mice are viable, fertile, and grossly normal, though some mutant mice have a slightly smaller body size at birth. Our data suggest that Tet1 loss leading to a partial reduction in 5hmC levels does not affect pluripotency in ESCs and is compatible with embryonic and postnatal development. PMID- 21816369 TI - Consistency of FDG-PET accuracy and cost-effectiveness in initial staging of patients with Hodgkin lymphoma across jurisdictions. AB - INTRODUCTION: Two hundred ten patients with newly diagnosed Hodgkin's lymphoma (HL) were consecutively enrolled in this prospective trial to evaluate the cost effectiveness of fluorine-18 ((18)F)-fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET) scan in initial staging of patients with HL. METHODS: All 210 patients were staged with conventional clinical staging (CCS) methods, including computed tomography (CT), bone marrow biopsy (BMB), and laboratory tests. Patients were also submitted to metabolic staging (MS) with whole-body FDG PET scan before the beginning of treatment. A standard of reference for staging was determined with all staging procedures, histologic examination, and follow-up examinations. The accuracy of the CCS was compared with the MS. Local unit costs of procedures and tests were evaluated. Incremental cost-effectiveness ratio (ICER) was calculated for both strategies. RESULTS: In the 210 patients with HL, the sensitivity for initial staging of FDG-PET was higher than that of CT and BMB in initial staging (97.9% vs. 87.3%; P < .001 and 94.2% vs. 71.4%, P < 0.003, respectively). The incorporation of FDG-PET in the staging procedure upstaged disease in 50 (24%) patients and downstaged disease in 17 (8%) patients. Changes in treatment would be seen in 32 (15%) patients. Cumulative cost for staging procedures was $3751/patient for CCS compared to $5081 for CCS + PET and $4588 for PET/CT. The ICER of PET/CT strategy was $16,215 per patient with modified treatment. PET/CT costs at the beginning and end of treatment would increase total costs of HL staging and first-line treatment by only 2%. CONCLUSION: FDG PET is more accurate than CT and BMB in HL staging. Given observed probabilities, FDG-PET is highly cost-effective in the public health care program in Brazil. PMID- 21816371 TI - A retrospective study to evaluate the work-up and follow-up of patients with monoclonal gammopathy of undetermined significance. AB - BACKGROUND: Monoclonal gammopathy of undetermined significance (MGUS) is a plasma cell proliferative disorder that transforms into multiple myeloma and other serious B-cell disorders at an approximate rate of 1% per year; these patients are also at increased risk for fractures. PATIENTS AND METHODS: We conducted a retrospective, multicenter study of 100 patients from seven community health clinics to gain a better understanding of the work-up, follow-up, and treatment of these patients. RESULTS: MGUS patients appear to undergo inadequate work-up, follow-up, and treatment in the community setting. CONCLUSIONS: Physicians should adhere to recently established guidelines to ensure that MGUS patients receive optimal care for this condition. PMID- 21816370 TI - Primary bone lymphoma: evaluation of chemoimmunotherapy as front-line treatment in 21 patients. AB - BACKGROUND: We performed a retrospective investigation to assess the efficacy of chemotherapy and rituximab as front-line treatment for primary bone lymphoma (PBL). PATIENTS AND METHODS: Between 1999 and 2009, 21 previously untreated patients received a diagnosis of PBL. All the patients were treated with anthracycline-containing chemotherapeutic regimens, with the addition of rituximab; 11 patients received consolidative radiation therapy after induction treatment. RESULTS: Patients' median age was 34 years (range, 18-82 years); all presented with diffuse large B-cell lymphoma. Complete responses were seen in 95.2% of the patients treated. No relapses were observed at a median follow-up of 43.9 months. Eight-year overall survival and disease-free survival were 95.2% and 100.0%, respectively. CONCLUSION: These data indicate that the combined chemotherapy plus rituximab treatment may represent a suitable front-line approach in PBL, with a high rate of responses and an excellent long-term survival. PMID- 21816372 TI - Leukocytosis and circulating blasts in older adults with newly diagnosed acute myeloid leukemia: are they valuable factors for therapeutic decision-making? AB - BACKGROUND: The treatment of older adults with acute myeloid leukemia (AML) is associated with unsatisfactory rates of response and overall survival. Identification of valuable factors that can facilitate therapeutic decision making between intensive chemotherapy and investigational treatment strategies is warranted. METHODS: Analysis of proliferative (white blood cell [WBC] count) and invasive (percentage of blast cells in peripheral blood) characteristics of leukemic blasts at diagnosis is presented in a population of 432 promyelocytic leukemia AML patients who are older than than 60 years and have been selected for entering onto five successive clinical trials combining an anthracycline and cytarabine. RESULTS: Five groups of patients were defined according to these two relevant parameters used in clinical practice. Response rates were lower for the hyperproliferative groups (47% and 46%, respectively) and the nonproliferative groups displaying circulating blasts (56% and 59%, respectively) compared with those for the nonproliferative and noninvasive group (77%) (P = .0003). Median overall survivals were shorter for the hyperproliferative groups (5.7 and 5.8 months, respectively) compared with those observed for the nonproliferative groups (8.9 and12.6 months, respectively). CONCLUSIONS: This combination of basic characteristics helps estimate the outcome of elderly AML patients who are usually selected for intensive chemotherapy. Although these factors remain valuable for identifying leukemia behavior, our study demonstrated that results of intensive chemotherapy in elderly patients remained poor, whatever the prognostic group. Comparison with recent data from the literature requires investigators to study results differently and to consider investigational therapy as being the most appropriate treatment even for this highly selected population. PMID- 21816373 TI - Hematologic outcomes of myelodysplastic syndromes treatment with hypomethylating agents in community practice. AB - INTRODUCTION: Hypomethylating agents (HMAs) treat myelodysplastic syndromes (MDS) through suppression of abnormal clones that may cause low hemoglobin (Hgb), platelet (PLT) deficiencies, and reduced absolute neutrophil count (ANC). Our study examined hematologic outcomes in MDS among patients treated with HMAs in a large community hematology-oncology practice. MATERIALS AND METHODS: A retrospective study using electronic medical record data studied patients who received at least one cycle of a single HMA (decitabine [DAC] or azacitidine [AZA]) for MDS from June 1, 2006, to May 31, 2009, who had pretreatment and end of-treatment Hgb, PLT counts, and ANC available. Multivariate logistic regression assessed predictors of end-of-treatment response (Hgb >= 11 g/dL without transfusion or erythrocyte stimulating agent; PLT >= 100,000 cells/MUL without transfusion; ANC >= 1000 cells/mm(3) without colony stimulating factor) adjusting for baseline laboratory values, age, gender, and comorbidities. HMA choice was studied as a predictor of outcome. RESULTS: A total of 137 patients (mean age, 72.2 years; 57% male) met full inclusion criteria (DAC = 84, AZA = 53). Mean number of cycles was four (range, 1-16 cycles) for DAC and five (range, 1-23 cycles) for AZA. Total number of cycles significantly predicted Hgb, PLT, and ANC response (odds ratio [OR] 1.19, P = .029; OR 1.15, P = .031; OR 1.16, P = .047, respectively). Growth factor use at any point during HMA treatment was negatively associated with Hgb and ANC response (OR 0.85, P = .007; OR 0.96, P = .046). There was no difference between treatments in likelihood of PLT or ANC response. CONCLUSIONS: Patients treated with HMAs for MDS are more likely to achieve hematologic response when treated with a greater number of cycles. PMID- 21816374 TI - Pilot study of bortezomib for patients with imatinib-refractory chronic myeloid leukemia in chronic or accelerated phase. AB - BACKGROUND: Proteasome inhibitors are anticancer compounds that disrupt the proteolytic activity of the proteasome and lead to tumor cell growth arrest and apoptosis. Bortezomib is a proteasome inhibitor that is currently approved for use in multiple myeloma (MM) and mantle-cell lymphoma. It induces apoptosis of chronic myeloid leukemia (CML) cells in vitro, but the activity of bortezomib in patients with imatinib-resistant CML is unknown. METHODS: We conducted a pilot trial to evaluate the activity of single-agent bortezomib in CML. Seven patients with imatinib-refractory CML were treated with bortezomib at a dose of 1.5 mg/m2 on days 1, 4, 8, and 11 every 3 weeks. RESULTS: The median number of cycles received was 2. No patient had a hematologic or cytogenetic response. Three patients had a temporary decrease in basophil counts associated with therapy with bortezomib. Six patients experienced grade 3/4 nonhematologic toxicities. CONCLUSION: Bortezomib had minimal efficacy and considerable toxicity in patients with imatinib-refractory CML. Further studies should focus on alternative approaches to using proteasome inhibitors in the treatment of CML, such as in combination with tyrosine kinase inhibitors (TKIs) or as a strategy to eradicate leukemic stem cells. PMID- 21816375 TI - Patterns of molecular response to and relapse after combination of sorafenib, idarubicin, and cytarabine in patients with FLT3 mutant acute myeloid leukemia. AB - BACKGROUND: FMS-like tyrosine kinase 3 (FLT3) is a class III receptor tyrosine kinase involved in hematopoietic progenitor cell development. Mutations of FLT3 have been reported in about a third of patients with acute myeloid leukemia (AML), and inhibitors of FLT3 are of clinical interest. Sorafenib is an orally active multikinase inhibitor with potent activity against FLT3 and the Raf/ERK/MEK kinase pathway. METHODS: We studied the patterns of molecular response and relapse in 18 patients with mutated FLT3 treated with the combination of sorafenib, idarubicin, and cytarabine. RESULTS: The median follow up was 9 months. Sixteen patients achieved complete remission (CR), and the other 2 patients achieved CR but lacked platelet recovery for an overall response rate of 100%. Ten patients had their FLT3-mutated clone eradicated, with 6 patients who showed some residual FLT3-mutated cells, and 2 patients who showed persistent FLT3-mutated cells. The elimination of FLT3-mutated population at the time of morphologic CR, however, was not predictive of relapse. After a median follow-up of 9 months (range, 1-16 months), 10 (55%) patients had relapsed, with a median CR duration of 8.8 months (range, 1-9.5 months). By DNA sequencing, there was no evidence of an acquired FLT3 point mutation at the time of relapse in 7 patients tested, which suggested the presence of other mechanisms of sorafenib resistance. CONCLUSION: Sorafenib, combined with chemotherapy, is effective in attaining CR, but relapses still occur. PMID- 21816377 TI - Candida albicans cervical lymphadenitis in patients who have acute myeloid leukemia. AB - We describe two patients with acute myelogenous leukemia who developed cervical lymphadenitis and chronic disseminated infection due to Candida albicans. Candida albicans infection should be considered in leukemic patients with acute lymphadenitis. Evaluation for visceral dissemination is warranted even in the absence of fungemia. PMID- 21816376 TI - CD39 expression on T lymphocytes correlates with severity of disease in patients with chronic lymphocytic leukemia. AB - INTRODUCTION: Chronic lymphocytic leukemia (CLL) is a B-cell disorder, but it is also associated with abnormalities in T-lymphocyte function. In this study we examine changes in T-lymphocyte CD39 and CD73 expression in patients with CLL. METHODS: Blood samples were drawn from 34 patients with CLL and 31 controls. The cells were stained for CD3, CD4, CD8, CD19, CD39, and CD73 and analyzed by flow cytometry. RESULTS: Overall, patients with CLL had a higher percentage of CD39(+) T lymphocytes than did controls. The percentage of cells expressing CD39 was higher in both CD4(+) cells and CD8(+) cells. Higher CD3/CD39 expression was associated with a later disease stage. No correlations between T-lymphocyte CD39 levels and CD38 or Zap-70 expression were observed. In contrast, the percentage of T lymphocytes and B lymphocytes that expressed CD73 was decreased in patients with CLL. Average B-lymphocyte CD73 expression was decreased in CLL because the majority of CLL clones were CD73. However a minority of CLL clones were CD73(+), and patients with CD73(+) clones tended to have earlier stage disease. CONCLUSION: T-lymphocyte CD39 and CD73 expression may be useful prognostic markers in patients with CLL. Expression of CD73 on the malignant cell population in CLL may be a marker of better prognosis. PMID- 21816379 TI - Efficacy and safety of intensive antiplatelet therapy with prasugrel from TRITON TIMI 38 in a core clinical cohort defined by worldwide regulatory agencies. AB - TRITON-TIMI 38 showed that in patients with acute coronary syndrome undergoing percutaneous coronary intervention prasugrel decreased ischemic events compared to standard clopidogrel, but with more bleeding. The United States Food and Drug Administration and the European Medicines Agency approved prasugrel but provided contraindications in patients with previous stroke or transient ischemic attack and recommended limited use or reduced dose in patients >=75 years old and weighing <60 kg. This defined 3 clinically relevant groups of patients for use of prasugrel at the studied dose regimen: group I (core clinical cohort), group II (noncore cohort), and group III (contraindicated). We assessed clinical outcomes of patients within these cohorts in the TRITON-TIMI 38 trial. Survival analysis methods were used to compare outcomes by treatment assignment (prasugrel vs clopidogrel) and by cohort (groups I and II or III). Patients in group I (n = 10,804, 79%) treated with prasugrel had a clinically significant and robust decrease in the primary end point of cardiovascular death, myocardial infarction, or stroke (8.3 vs 11.0%, hazard ratio [HR] 0.74, 95% confidence interval 0.66 to 0.84, p <0.0001), whereas patients in group II (n = 2149, 16%) had limited efficacy (15.3% vs 16.3%, HR 0.94, 0.76 to 1.18, p = 0.61, p for interaction = 0.07). For Thrombolysis In Myocardial Infarction major bleeding not related to coronary artery bypass grafting, there were tendencies to higher rates with prasugrel in group I (1.9% vs 1.5%, HR 1.24, 0.91 to 1.69, p = 0.17) and group II (4.1% vs 3.4%, HR 1.23, 0.77 to 1.97, p = 0.40); however, the absolute difference was greater for group II. The net clinical outcome (all-cause death/myocardial infarction/stroke/Thrombolysis In Myocardial Infarction major bleeding) in group I patients was highly favorable (10.2% vs 12.5%, HR 0.80, 0.71 to 0.89, p <0.0001) and neutral in group II (19.5% vs 19.7%, HR 0.98, 0.81 to 1.20, p for interaction = 0.07). Patients in group III (n = 518, 4%) did poorly with regard to efficacy and safety. In TRITON-TIMI 38 patients without previous stroke, <75 years old, and weighing >60 kg had substantial decreases in ischemic events with prasugrel compared to clopidogrel. Although relative bleeding excess exists in this population, absolute rates and differences in bleeding were attenuated. In conclusion, these data indicate that use of prasugrel in a core clinical cohort that has been defined by regulatory action will maximize the benefit of prasugrel and limit the risk of adverse outcomes. PMID- 21816380 TI - National gender-specific trends in myocardial infarction hospitalization rates among patients aged 35 to 64 years. AB - In recent years, the prevalence of myocardial infarction (MI) has increased among women and decreased among men aged 35 to 54 years. To determine the extent to which changes in incidence account for recent variations in prevalence, we assessed the temporal trends in gender-specific hospitalization rates for MI. Using the Nationwide Inpatient Sample, we identified patients aged 35 to 64 years admitted to United States hospitals with a primary discharge diagnosis of MI from 1997 to 2006 (n = 2,824,615). The age-standardized MI hospitalization rates per 100,000 subjects were assessed for men and women aged 35 to 44, 45 to 54, and 55 to 64 years. The MI hospitalization rates per 100,000 subjects decreased by 26% from 168 to 126 for men and by 18% from 56 to 46 for women (both p <0.001). The reductions in the MI hospitalization rates were greatest among men aged 45 to 54, men aged 55 to 64, and women aged 55 to 64 years (standardized rates of change 3%, -4%, and -3% annually, p <0.001). The MI hospitalization rates decreased slightly for women aged 45 to 54 years and men aged 35 to 44 years (standardized rate of change -2% annually, p <0.001) and increased for women aged 35 to 44 years (standardized rate of change 2% annually, p = 0.008). In conclusion, from 1997 to 2006, men and women aged 35 to 64 years experienced an overall decrease in MI hospitalization rates; the reductions were more pronounced in men than in women. The slight increase in MI hospitalizations among women aged 35 to 44 years might have played a small role in the previously noted increases in MI prevalence among middle-age women. PMID- 21816381 TI - Outpatient management of primary hyperparathyroidism. AB - Primary hyperparathyroidism is the most common cause of hypercalcemia in an outpatient setting. Most patients are asymptomatic with mild hypercalcemia and only require periodic follow-up. Symptomatic patients and those with end-organ damage should undergo surgery according to the National Institutes of Health guidelines. No medical therapy has been approved for treatment of this disorder. Treatment with bisphosphonate, calcimimetic drugs, or alcohol ablation techniques has been used in select patients. PMID- 21816382 TI - Cutting-edge advances in the medical management of obstetrical hemorrhage. AB - Hemorrhagic shock is the most common form of shock encountered in obstetric practice. Interventions that may limit transfusion requirements include normovolemic hemodilution, use of recombinant activated factor VII, selective embolization of pelvic vessels by interventional radiology, and the use of the cell saver intraoperatively. Current understanding of the mechanisms of acute coagulopathy calls into question the current transfusion guidelines, leading to a tendency to apply massive transfusion protocols based on hemostatic resuscitation despite lack of prospective data. PMID- 21816384 TI - Performance skills for surgeons: lessons from sport. PMID- 21816385 TI - How can we know if Karydakis flap is a good solution for sacroccygeal pilonidal disease with laterally extended orifices? PMID- 21816383 TI - The use of psychosocial stress scales in preterm birth research. AB - Psychosocial stress has been identified as a potential risk factor for preterm birth. However, an association has not been found consistently, and a consensus on the extent to which stress and preterm birth are linked is still lacking. A literature search was performed with a combination of keywords and MeSH terms to detect studies of psychosocial stress and preterm birth. Studies were included in the review if psychosocial stress was measured with a standardized, validated instrument and if the outcomes included either preterm birth or low birthweight. Within the 138 studies that met inclusion criteria, 85 different instruments were used. Measures that had been designed specifically for pregnancy were used infrequently, although scales were sometimes modified for the pregnant population. The many different measures that have been used may be a factor that accounts for the inconsistent associations that have been observed. PMID- 21816386 TI - Does prehospital prolonged extrication (entrapment) place trauma patients at higher risk for venous thromboembolism? AB - BACKGROUND: The aim of this study was to determine if prolonged immobility and tissue injury from a prehospital entrapment would place patients at higher risk for in-hospital venous thromboembolism (VTE) complications. It was hypothesized that entrapment would increase in-hospital VTE. METHODS: All consecutive trauma admissions over a 10-year period were retrospectively reviewed. Patients were divided into those who were entrapped according to defined prehospital criteria for entrapment and those who were not entrapped. The complications of deep vein thrombosis and pulmonary embolism were noted. RESULTS: There were 15,159 patients admitted between 1999 and 2008. Of these, 1,176 met the criteria for prehospital entrapment. Those patients who met the criteria for entrapment had a significant risk for developing both deep vein thrombosis (P < .001, chi(2) test) and pulmonary embolism (P = .005, Fisher's exact test). Multiple logistic regression analysis revealed entrapment to be a significant contributing risk factor to the development of VTE (odds ratio, 1.54; P = .04). CONCLUSIONS: Patients with prehospital entrapment are at higher risk for VTE. These results mandate aggressive VTE prophylaxis in patients with histories of prehospital entrapment. PMID- 21816387 TI - Abnormal trajectories of neurodevelopment and behavior following in utero insult in the rat. AB - BACKGROUND: Environmental or genetic disturbances of early brain development are suggested to underlie the pathophysiology of several adult-onset neuropsychiatric disorders. We traced the developmental trajectories of brain structural and behavioral abnormalities from adolescence to young adulthood in rats born to mothers exposed to the viral mimic polyriboinosinic-polyribocytidylic acid (poly I:C) in pregnancy. METHODS: Pregnant rats were injected on gestational day 15 with poly-I:C (4 mg/kg) or saline. Volumes of lateral ventricles, hippocampus, striatum, and prefrontal cortex in male and female offspring were assessed longitudinally at postnatal days 35, 46, 56, 70, and 90 using in vivo magnetic resonance imaging. At parallel time windows, groups of offspring from the same litters underwent behavioral testing (latent inhibition and amphetamine-induced activity) and magnetic resonance imaging (cross-sectional assessment). RESULTS: The specific developmental trajectories of volumetric changes in both control and poly-I:C offspring were region-, age-, and sex-specific, but overall, poly-I:C offspring had smaller volumes of the hippocampus, striatum and prefrontal cortex, and larger ventricular volume. Structural pathology in different regions had different times of onset and was gradually accompanied by behavioral deficits, disrupted latent inhibition, and excessive amphetamine-induced activity. The onset of structural frontocortical and ventricular abnormalities and behavioral abnormalities was delayed in females. In both sexes, hippocampal and striatal volume reduction predated the appearance of behavioral abnormalities. CONCLUSIONS: Prenatal insult interferes with postnatal brain maturation, which in turn may result in behavioral abnormalities. PMID- 21816388 TI - Atrophy of the cholinergic Basal forebrain over the adult age range and in early stages of Alzheimer's disease. AB - BACKGROUND: The basal forebrain cholinergic system (BFCS) is known to undergo moderate neurodegenerative changes during normal aging as well as severe atrophy in Alzheimer's disease (AD). However, there is a controversy regarding how the cholinergic lesion in AD relates to early and incipient stages of the disease. In vivo imaging studies on the structural integrity of the BFCS in normal and pathologic aging are rare. METHODS: We applied automated morphometry techniques in combination with high-dimensional image warping and a cytoarchitectonic map of basal forebrain cholinergic nuclei to a large cross-sectional data set of high resolution magnetic resonance imaging scans, covering the whole adult age range (20-94 years; n = 211) as well as patients with very mild AD (Clinical Dementia Rating = .5; n = 69) and clinically manifest AD (AD; Clinical Dementia Rating = 1; n = 28). For comparison, we investigated hippocampus volume using automated volumetry. RESULTS: Volume of the BFCS declined from early adulthood on, and atrophy aggravated in advanced age. Volume reductions in very mild AD were most pronounced in posterior parts of the nucleus basalis of Meynert, whereas in AD, atrophy was more extensive and included the whole BFCS. In clinically manifest AD, the diagnostic accuracy of BFCS volume reached the diagnostic accuracy of hippocampus volume. CONCLUSIONS: Our findings indicate that cholinergic degeneration in AD occurs against a background of age-related atrophy and that exacerbated atrophy in AD can be detected at earliest stages of cognitive impairment. Automated in vivo morphometry of the BFCS may become a useful tool to assess BF cholinergic degeneration in normal and pathologic aging. PMID- 21816389 TI - Alpha-phenyl-N-tert-butylnitrone prevents oxidative stress in a haloperidol induced animal model of tardive dyskinesia: investigating the behavioural and biochemical changes. AB - Haloperidol (HP) is a widely prescribed antipsychotic drug used for the treatment of mental disorders. However, while providing therapeutic benefits, this drug also causes serious extrapyramidal side effects, such as tardive dyskinesia (TD). Upon chronic administration, HP causes behavioural supersensitivity to dopamine D2 receptor agonists, as well as the development of vacuous chewing movements (VCMs), in an animal model of human TD. Currently, a prevailing hypothesis to account for these behavioural abnormalities implicates oxidative stress. This study was undertaken to examine whether the free radical trapping agent, alpha phenyl-N-tert-butylnitrone (PBN), can prevent the development of behavioural supersensitivity to dopamine D2 receptor agonists and the development of VCMs. Additionally, the study examined whether increased synthesis of apoptosis inducing factor (AIF) can result from HP-induced oxidative stress. Male Sprague Dawley rats were treated with HP in conjunction with PBN, or its vehicle, for 4weeks. After a 24-hour washout period, behavioural observations were recorded along with the estimation of lipid peroxidation and antioxidant enzyme activities. The free radical trapping agent, PBN, prevented the development of behavioural supersensitivity, reduced lipid peroxidation and prevented the reduction of antioxidant enzyme activities. AIF concentrations at the mRNA and protein levels remained unchanged; therefore increased AIF gene expression is unlikely to be involved in HP-induced oxidative stress. The findings of the present study suggest the involvement of striatal free radicals in the development of behavioural supersensitivity, and free radical trapping agents, such as PBN, as possible options for the treatment of extrapyramidal side effects in humans. PMID- 21816390 TI - Neonatal alcohol exposure disrupts hippocampal neurogenesis and contextual fear conditioning in adult rats. AB - Developmental alcohol exposure can permanently alter brain structures and produce functional impairments in many aspects of behavior, including learning and memory. This study evaluates the effect of neonatal alcohol exposure on adult neurogenesis in the dentate gyrus of the hippocampus and the implications of such exposure for hippocampus-dependent contextual fear conditioning. Alcohol-exposed rats (AE) received 5.25g/kg/day of alcohol on postnatal days (PD) 4-9 (third trimester in humans), in a binge-like manner. Two control groups were included: sham-intubated (SI) and suckle-control (SC). Animals were housed in social cages (3/cage) after weaning. On PD80, animals were injected with 200mg/kg BrdU. Half of the animals were sacrificed 2h later. The remainder were sacrificed on PD114 to evaluate cell survival; separate AE, SI, and SC rats not injected with BrdU were tested for the context preexposure facilitation effect (CPFE; ~PD117). There was no difference in the number of BrdU+ cells in AE, SI and SC groups on PD80. On PD114, cell survival was significantly decreased in AE rats, demonstrating that developmental alcohol exposure damages new cells' ability to incorporate into the network and survive. Behaviorally tested SC and SI groups preexposed to the training context 24h prior to receiving a 1.5mA 2s footshock froze significantly more during the context test than their counterparts preexposed to an alternate context. AE rats failed to show the CPFE. The current study shows the detrimental, long-lasting effects of developmental alcohol exposure on hippocampal adult neurogenesis and contextual fear conditioning. PMID- 21816391 TI - Prenatal bystander stress induces neuroanatomical changes in the prefrontal cortex and hippocampus of developing rat offspring. AB - The rapid period of growth and development that occurs prenatally renders the brain vulnerable to experiences that may disrupt cortical plasticity. Although there is extensive literature examining anatomical changes in fully matured brain, there has been very little investigation of younger offspring. The current study used an indirect prenatal bystander stress and analyzed neuroanatomical changes in postnatal day 21 (P21) Long Evans rats. Dendritic architecture (dendritic length, branch order, and spine density) along with cell quantification (neuron and glia) was generated for layer 3 pyramidal cells of the medial prefrontal cortex (mPFC/Cg3), orbital prefrontal cortex (OFC/AID), and CA1 of the hippocampus. We found that prenatal bystander stress significantly altered the complexity and length of dendritic arbor, the density of excitatory spines and the actual volume of neuronal and glial cell numbers in the mPFC, OFC, and CA1 of developing rat offspring. Neuroanatomical changes of this extent occurring at such a critical time period will likely impact healthy maturation of the brain and long-term development. PMID- 21816392 TI - Low structural diversity of the O-polysaccharides of Photorhabdus asymbiotica subspp. asymbiotica and australis and their similarity to the O-polysaccharides of taxonomically remote bacteria including Francisella tularensis. AB - The O-polysaccharides were isolated from the lipopolysaccharides of emerging human pathogens Photorhabdus asymbiotica subsp. asymbiotica US-86 and US-87 and subsp. australis AU36, AU46, and AU92. Studies by sugar analysis and (1)H and (13)C NMR spectroscopy before and after O-deacetylation showed that the O polysaccharide structures are essentially identical within, and only slightly different between, the subspecies. The following structures of the repeating units of the O-polysaccharides were established: ->3)-beta-d-Quip4NGlyFo-(1->4) alpha-d-GalpNAcAN3Ac-(1->4)-alpha-d-GalpNAcA3R-(1->3)-alpha-d-QuipNAc-(1-> where GalNAcA stands for 2-acetamido-2-deoxygalacturonic acid, GalNAcAN for amide of GalNAcA, QuiNAc for 2-acetamido-2,6-dideoxyglucose, and Qui4NGlyFo for 4,6 dideoxy-4-(N-formylglycyl)aminoglucose; R=Ac in subsp. asymbiotica or H in subsp. australis. The structures established resemble those of a number of taxonomically remote bacteria including Francisella tularensis (Vinogradov, E. V.; Shashkov, A. S.; Knirel, Y. A.; Kochetkov, N. K.; Tochtamysheva, N. V.; Averin, S. P.; Goncharova, O. V.; Khlebnikov, V. S. Carbohydr. Res.1991, 214, 289-297), which differs in (i) the presence of a formyl group on Qui4N rather than the N formylglycyl group, (ii) the mode of the linkage between the repeating units (beta1->2 vs alpha1->3), (iii) amidation of both GalNAcA residues rather than one residue, and iv) the lack of O-acetylation. PMID- 21816393 TI - Phenylboronic acid esters of the common 2-deoxy-aldoses. AB - Phenylboronic acid esters are formed by the three common 2-deoxy aldoses: 2-deoxy d-erythro-pentose ('2-deoxy-d-ribose'), 2-deoxy-d-lyxo-hexose ('2-deoxy-d galactose'), and 2-deoxy-d-arabino-hexose ('2-deoxy-d-glucose'). The major species that was formed from equimolar quantities of boronic acid and the aldose, was the 3,4-monoester of the pentopyranose in a skew-boat conformation, and the 4,6-monoester in the case of the two hexopyranoses. A double molar quantity of boronic acid led, for both 2-deoxy-hexoses, to the diester of the open-chain aldehydo isomer as the major product: the 3,5:4,6-diester for the lyxo-configured deoxy-hexose, and the 3,4:5,6-diester of the arabino-configured isomer. Minor products of all reactions were identified by a combined NMR/DFT methodology. PMID- 21816394 TI - Investigation of the binding of roxatidine acetate hydrochloride with cyclomaltoheptaose (beta-cyclodextrin) using IR and NMR spectroscopy. AB - NMR chemical shift changes of the cyclomaltoheptaose (beta-cyclodextrin, beta-CD) cavity protons as well as roxatidine acetate hydrochloride aromatic ring protons revealed the formation of a RAH-beta-CD inclusion complex. Detailed FTIR and NMR spectroscopic ((1)H NMR, COSY, NOESY, ROESY) studies have been done. The stoichiometry of the complex was determined to be 1:1, and the overall binding constant was also determined by Scott's method. The NOESY spectrum confirmed the selective penetration of the aromatic ring of RAH into the beta-CD cavity in comparison to that of the piperidine ring. The mode of penetration of the guest into the CD cavity and structure of the complex has been established. PMID- 21816395 TI - Characterization of the binding profile of peptide to transporter associated with antigen processing (TAP) using Gaussian process regression. AB - Although MHC-peptide binding is the most selective event in epitope presentation process, the protein fragments generated by proteasomal cleavage require to be recognized by transporter associated with antigen processing (TAP) and translocated from cytosol to endoplasmic reticulum before they can be loaded into the ligand-binding groove of MHC. In this article, we report the use of a new and powerful machine learning tool called Gaussian process (GP) to model the linear and nonlinear relationships between the sequence pattern and binding affinity of peptide to TAP, and to explain the physicochemical properties and structural implications underlying the specific recognition and association of peptide with TAP. The resulting statistics are compared systematically with those obtained by sophisticated PLS, ANN and SVM. Results show that: (i) Nonlinear methods such as the ANN and GP perform much better than the linear PLS. (ii) GP is capable of handling both linearity- and nonlinearity-hybrid relationship and thus exhibits a good performance relative to other two nonlinear methods. (iii) Investigation of the GP model shows that the P1, P2, P3 and P9 of peptide are the most important positions that dominate TAP-peptide recognition, P5 contributes slightly to the peptide binding, whereas P4, P6, P7 and P8 can only exert very limited potency on the binding. (iv) Diverse properties cast remarkable effects on the interaction between TAP and peptide. In particular, hydrophobility, electronic property and hydrogen bond contribute most significantly to the binding affinity of TAP peptide association. PMID- 21816396 TI - Emergency ambulance dispatches and apparent temperature: a time series analysis in Emilia-Romagna, Italy. AB - INTRODUCTION: Increases in mortality associated with oppressive weather have been widely investigated in several epidemiological studies. However, to properly understand the full public health significance of heat-related health effects, as well as to develop an effective surveillance system, it is also important to investigate the impact of stressful meteorological conditions on non-fatal events. The objective of our study was to evaluate the exposure-response relationship of ambulance dispatch data in association with biometeorological conditions using time series techniques similar to those used in previous studies on mortality. METHODS: Daily data of emergency ambulance dispatches for people aged 35 or older in the summer periods from 2002 to 2006 were collected for the major towns in the Emilia-Romagna region. In the first stage of the analysis, the city-specific relationship between daily ambulance dispatches and increasing apparent temperature was explored using Generalized Additive Models while controlling for air pollution, seasonality, long-term trend, holidays and weekends. The relationship between ambulance dispatches and apparent temperature was approximated by linear splines. The effects of high temperatures on health were evaluated for respiratory and cardiovascular diseases as well as for all non traumatic conditions. In the second stage of the analysis, city-specific effects were combined in fixed or random effect meta-analyses. RESULTS: The percent change in the ambulance dispatches associated with every 1 degrees C increase in the mean apparent temperature between 25 and 30 degrees C was 1.45% (95% confidence interval: 0.95, 1.95) for non-traumatic diseases and 2.74% (95% CI: 1.34, 4.14) for respiratory diseases. The percent increase in risk was greater on days in which the mean apparent temperature exceeded 30 degrees C (8.85%, 95% CI: 7.12, 10.58 for non-traumatic diseases). In this interval of biometeorological conditions, cardiovascular diseases became positively associated with the apparent temperature. The risks increased with age. The increase in risk for the non-traumatic diseases reached 13.34% for people aged 75 or older compared to 4.75% for those aged 35-64. CONCLUSION: Time series analysis techniques were adopted for the first time to investigate emergency ambulance dispatches to evaluate the risks associated with biometeorological discomfort. Our findings show a strong relationship between biometeorological conditions and ambulance dispatches. PMID- 21816397 TI - [2010. What novelties are there in vascular risk?]. AB - This paper gathers the news concerning vascular risk in 2010. It summarizes five lectures, according to the order of presentation, at the annual meeting of the vascular risk working group of the Spanish Society of Internal Medicine (SEMI, Valencia 5(th) and 6(th) May 2011): arterial hypertension, antithrombosis, lipid disorders, diabetes mellitus and vascular risk stratification. The authors have made a depth revision of the more relevant research been published in 2010 with some data of 2011. PMID- 21816398 TI - A comparison of stress distributions for different surgical procedures, screw dimensions and orientations for a Temporomandibular joint implant. AB - Finite element analysis is a useful analytical tool for the design of biomedical implants. The aim of this study was to investigate the behavior of temporomandibular joint implants with multiple design variables of the screws used for fixation of the implant. A commercially available implant with full mandible was analyzed using a finite element software package. The effects of different design variables such as orientation, diameter and stem length of the screws on the stress distribution in bone for two different surgical procedures were investigated. Considering the microstrain in bone as a principal factor, the acceptable ranges for screw diameter and length were determined. Parallel orientation of the screws performed better from a stress point of view when compared to the zig-zag orientation. Sufficient contact between the implant collar and mandibular condyle was shown to reduce the peak stresses which may lead to long term success. The distance between screw holes in the parallel orientation was much closer when compared to the zig-zag orientation. However, the stresses in bone near the screw hole area for the parallel orientation were within acceptable limits. PMID- 21816399 TI - Using gas chromatography to characterize a direct coal liquefaction naphtha. AB - Speciation of oxygenated compounds in direct coal liquefaction naphthas is essential considering their important roles in coal conversion reactions. This study attempts to characterize them as fully as possible using gas chromatographic systems. Firstly, GC-MS was deployed allowing the identification of a few ketones, alcohols, and phenols. This conventional analysis was complemented by the application of GC-GC-FID aiming to overcome the coelutions highlighted when using one-dimensional gas chromatography. Heart-cutting and comprehensive two-dimensional gas chromatography were used and the comprehensive system led to better performances as expected considering the complexity of the matrix. In fact, it allowed the identification of more than a hundred of oxygenated compounds belonging to five chemical families: alcohols, ketones, furans, acids and phenols. Average response factors of each of these families were determined by GC*GC-FID using calibration curves and vary from 1 (hydrocarbons) to 2.50 (carboxylic acids). Thanks to a breakthrough columns set involving a trifluoropropyl stationary phase, alcohols and phenols which represent around 14% of the sample were fully identified. A detailed quantification of these species was carried out for the first time in such matrices using the determined response factors. It was concluded that 90% (w/w) of the alcohols are aromatic (phenols), 5% (w/w) are cyclic and 5% (w/w) are linear. A quantification of hydrocarbon families was also achieved and shows that the matrix is mostly naphthenic (56%, w/w), but also contains aromatics (22%, w/w) and paraffins (8%, w/w). This detailed characterization leads to a better understanding of coal conversion processes and is essential to convert them into synthetic fuels. PMID- 21816400 TI - Selective comprehensive multidimensional separation for resolution enhancement in high performance liquid chromatography. Part II: applications. AB - In this second paper of a two-part series, we demonstrate the utility of an approach to enhancing the resolution of select portions of conventional 1D-LC separations, which we refer to as selective comprehensive two-dimensional HPLC (sLC * LC), in three quite different example applications. In the first paper of the series we described the principles of this approach, which breaks the long standing link in online multi-dimensional chromatography between the timescales of sampling the first dimension (1D) separation and the separation of fractions of 1D effluent in the second dimension. In the first example, the power of the sLC * LC approach to significantly reduce the analysis time and method development effort is demonstrated by selectively enhancing the resolution of critical pairs of peaks that are unresolved by a one-dimensional separation (1D LC) alone. Transfer and subsequent 2D separations of multiple fractions of a particular 1D peak produces a two-dimensional chromatogram that reveals the coordinates of the peaks in the 2D separation space. The added time dimension of sLC * LC chromatograms also facilitates the application of sophisticated chemometric curve resolution algorithms to further resolve peaks that are otherwise chromatographically unresolved. This is demonstrated in this work by the targeted analysis of phenytoin in urban wastewater effluent using UV diode array detection. Quantitation by both standard addition and external calibration methods yielded results that were not statistically different from 2D-LC/MS/MS analysis of the same samples. Next, we demonstrate the utility of sLC * LC for reducing ion suppression due to matrix effects in electrospray ionization mass spectrometry through the analysis of cocaine in urban wastewater effluent. Finally, we explore the flexibility of the approach in its application to two select regions of a single 1D separation of triclosan and cocaine. The diversity of these applications demonstrates the power and versatility of the sLC * LC approach, which will benefit tremendously from further optimization and advances in valve technology that specifically address the needs of this new technique. PMID- 21816402 TI - Recombinant protein purification using gradient-assisted simulated moving bed hydrophobic interaction chromatography. Part I: selection of chromatographic system and estimation of adsorption isotherms. AB - The design of gradient simulated moving bed (SMB) chromatographic processes requires an appropriate selection of the chromatographic system followed by the determination of adsorption isotherm parameters in the relevant range of mobile phase conditions. The determination of these parameters can be quite difficult for recombinant target proteins present in complex protein mixtures. The first part of this work includes the estimation of adsorption isotherm parameters for streptokinase and a lumped impurity fraction present in an Escherichia coli cell lysate for a hydrophobic interaction chromatography (HIC) matrix. Perturbation experiments were carried out using a Butyl Sepharose matrix with purified recombinant protein on buffer equilibrated columns as well as with crude cell lysate saturated columns. The Henry constants estimated for streptokinase were found to exhibit in a wide range a linear dependence on the salt concentration in the mobile phase. These parameters were applied in subsequent investigations to design a simulated moving bed (SMB) process capable to purify in a continuous manner recombinant streptokinase from the E. coli cell lysate. PMID- 21816401 TI - Quest for organic polymer-based monolithic columns affording enhanced efficiency in high performance liquid chromatography separations of small molecules in isocratic mode. AB - The separations of small molecules using columns containing porous polymer monoliths invented two decades ago went a long way from the very modest beginnings to the current capillary columns with efficiencies approaching those featured by their silica-based counterparts. This review article presents a variety of techniques that have been used to form capillary formats of monolithic columns with enhanced separation performance in isocratic elutions. The following text first describes the traditional approaches used for the preparation of efficient monoliths comprising variations in polymerization conditions including temperature as well as composition of monomers and porogenic solvents. Encouraging results of these experiments fueled research of completely new preparation methods such as polymerization to an incomplete conversion, use of single crosslinker, hypercrosslinking, and incorporation of carbon nanotubes that are described in the second part of the text. PMID- 21816403 TI - Simultaneous enantioselective determination of fenbuconazole and its main metabolites in soil and water by chiral liquid chromatography/tandem mass spectrometry. AB - A novel and sensitive method was developed for the simultaneous determination of fenbuconazole and its main metabolites enantioselectively using chiral liquid chromatography coupled with tandem mass spectrometry. The separation and determination were performed using reversed-phase chromatography on a cellulose chiral stationary phase, a Chiralcel OD-RH (150 mm*4.6 mm) column, under isocratic conditions at 0.5 mL/min flow rate. The effects of three cellulose based columns and three amylose-based columns on the separation were also investigated. The elution orders of the eluting enantiomers were identified by an optical rotation detector. The QuEChERS (acronym for Quick, Easy, Cheap, Effective, Rugged and Safe) method and solid-phase extraction (SPE) were used for the extraction and clean-up of the soil and water samples, respectively. Parameters including the matrix effect, linearity, precision, accuracy and stability were evaluated. Under optimal conditions, the mean recoveries for all enantiomers from the soil samples were 82.5-104.1% with 2.7-9.5% intra-day relative standard deviations (RSD) and 5.7-11.2% inter-day RSD at 5, 25 and 50 MUg/kg levels; the mean enantiomer recoveries from the water samples were 81.8 104.6% with 2.6-11.4% intra-day RSD and 5.3-10.4% inter-day RSD at 0.25, 0.5 and 2.5 MUg/L levels. Coefficients of determination R2>=0.9991 were achieved for each enantiomer in the soil and water matrix calibration curves within the range of 1.0-125 MUg/L. The limits of detection (LOD) for all enantiomers in the soil and water were less than 0.8 MUg/kg, whereas the limit of quantification (LOQ) did not exceed 2.5 MUg/kg. The results of the method validation confirm that this proposed method is convenient and reliable for the enantioselective determination of the enantiomers of fenbuconazole and its main metabolites in soil and water. PMID- 21816404 TI - Preparation of phenyl-silica hybrid monolithic column with "one-pot" process for capillary liquid chromatography. AB - A phenyl-silica hybrid monolithic column for capillary liquid chromatography (cLC) was prepared through "one-pot" process by con-currently using benzyl methacrylate and alkoxysilanes. The effects of the molar ratio of tetramethoxysilane/vinyltrimethoxysilane (TMOS/VTMS), polycondensation temperature, content of supramolecule template (cetyltrimethylammonium bromide, CTAB), ratio of N,N'-dimethylformamide/methanol (v/v), the volume of benzyl methacrylate on the morphologies of the prepared phenyl-silica hybrid monolithic columns were investigated in detail. The permeability of the hybrid monolithic column was calculated as 3.23 * 10-13 m2, and the minimum plate height was determined as 8.38 MUm which corresponding to 119,000 theoretical plates per meter. Separation of various neutral, polar and basic analytes as well as small peptides on the hybrid monolithic column was achieved by cLC and showed high efficiency and satisfactory reproducibility. Moreover, the prepared hybrid monolithic column was also applied for the analysis of tryptic digests of bovine serum albumin (BSA), ovalbumin, alpha-casein, cytochrome C and myoglobin by cLC tandem mass spectrometry (cLC-MS/MS), and the results showed that the separation performance was close to that of the octadecylsilane (C18) packed capillary column which demonstrating its potential in proteome analysis. Moreover, since the prepolymerization system was mainly consisted of organic solvents (methanol and N,N'-dimethylformamide), various hydrophobic monomers could be potentially used to prepare organic-silica hybrid monolithic columns through "one-pot" approach. PMID- 21816405 TI - Preparation of methacrylate-based monolith for capillary hydrophilic interaction chromatography and its application in determination of nucleosides in urine. AB - A novel poly(N-acryloyltris(hydroxymethyl)aminomethane-co-pentaerythritol triacrylate) (NAHAM-co-PETA) monolith was prepared in the 100 MUm i.d. capillary and investigated for capillary liquid chromatography (cLC). The polymer monolith was synthesized by in situ polymerization of NAHAM and PETA in the presence of polyethylene glycol (PEG) in dimethyl sulfoxide (DMSO) as the porogen. The porous structure of monolith was optimized by changing the ratio of NAHAM to PETA, the molecular weight and amount of PEG. To evaluate the separation performance of the resultant polymer monolith, several groups of model compounds (including nucleosides, benzoic acids and anilines) were selected to perform cLC separation. Our results showed that these model compounds can be baseline separated on the resultant poly(NAHAM-co-PETA) monolithic column with the optimized mobile phases. The column efficiency was estimated to be 87,000 plates/m for acrylamide. In addition, this monolithic column was coupled with on-line solid-phase microextraction (SPME) for the analysis of four nucleosides (uridine, adenosine, cytidine, guanosine) in urine. The limit of detection of the proposed method was in the range from 40 to 52 ng/mL. The method reproducibility was obtained by evaluating the intra- and inter-day precisions with relative standard deviations (RSDs) less than 8.3% and 10.2%, respectively. Recoveries of the target analytes from spiked urine samples were ranged from 86.5% to 106.8%. PMID- 21816406 TI - Diagnosis of dengue infection using a modified gold electrode with hybrid organic inorganic nanocomposite and Bauhinia monandra lectin. AB - A sensitive and selective biosensor for dengue serotyping was successfully developed. The biosensor uses a novel gold nanoparticles-polyaniline hybrid composite (AuNpPANI) for the immobilization of Bauhinia monandra lectin (BmoLL). The nanocomposite was applied to a bare gold electrode surface by chemical adsorption, and BmoLL was subsequently electrostatically adsorbed to the nanocomposite-modified surface. Atomic force microscopy (AFM), cyclic voltammetry (CV) and electrochemical impedance (EI) techniques were applied to evaluate the immobilization of BmoLL on AuNpPANI. The AFM images for AuNpPANI-BmoLL-DEN systems indicate a homogenous, compact and dense film of the conjugate. In the EI analyses, an obvious difference of the electron transfer resistance between the AuNpPANI-modified electrode and the bare gold electrode was observed. Among three dengue serotypes studied, dengue serotype 2 (DEN2) has higher values for R(CT), and lower values for both n and Q. These are indications of a larger blocking effect and smaller capacitive dispersion, resulting from the higher agglutination of glycoproteins from the DEN2 sera. The selective BmoLL recognition for various dengue serotypes may be attributed to different patterns of glycoproteins in the sera produced by the glycoprotein immunoresponse from patients infected by the dengue virus. PMID- 21816407 TI - Gold nanoparticles modified ZnO nanorods with improved photocatalytic activity. AB - Well-aligned ZnO nanorods (NRs) were grown on indium-tin-oxide (ITO) slide by the hydrothermal method and used as templates for preparing ZnO/Au composite nanoarrays. The optical and morphological properties of ZnO/Au composites under various HAuCl(4) concentrations were explored via UV-vis absorption spectroscopy, photoluminescence (PL) and scanning electron microscopy (SEM). The density and size of gold nanoparticles (Au NPs) on ZnO NRs can be controlled by adjusting the concentration of HAuCl(4). The optimal ZnO/Au composites display complete photocatalytic degradation of methyl blue (MB) within 60 min, which is superior to that with pure ZnO NRs prepared by the same method. The reason of better photocatalytic performance is that Au NPs act as electron traps and it prevents the rapid recombination of electrons and holes, resulting in the improvement of photocatalytic efficiency. The photocatalytic performance of ZnO/Au composites is mainly controlled by the density of Au NPs formed on ZnO NRs. The application in rapid photodegradation of MB shows the potential of ZnO/Au composite as a convenient catalyst for the environmental purification of organic pollutants. PMID- 21816408 TI - Synthesis of zinc tin oxide (ZTO) nanocrystallites at room temperature through association with peptide-containing bolaamphiphile molecules. AB - Single crystalline zinc tin oxide (ZTO) nanocrystallites were prepared at room temperature through association with a peptide-containing bolaamphiphile molecule. The bolaamphiphile molecules self-assembled to form spherical structures with creation of ZTO nanocrystallites inside. ZTO nanocrystallite synthesis was achieved only when the bolaamphiphile molecule was present, while a mixture of amorphous Sn and Zn precipitates was formed in the absence of the bolaamphiphile molecule. The bolaamphiphile molecule is thought to stabilize the Zn(2+) and Sn(4+) precursor ions by ligation and to induce subsequent condensation forming crystalline ZTO. The ZTO formation was achieved only at a strong acidic condition that promotes dissociation and ionization of Zn and Sn precursors and represses formation of ZnO and H(2)SnO(3). The prepared ZTO nanocrystallites had almost the same band gap energy as ZTO nanoparticles prepared by the conventional hydrothermal process. The outcomes of this study indicate that the controlled mineralization of metal precursor ions in a peptide containing bolaamphiphile molecule suspension can be an alternative method to synthesize metal oxides at room temperature, while maintaining their crystalline structure and optoelectrical properties. PMID- 21816409 TI - Computer-based rhythm diagnosis and its possible influence on nonexpert electrocardiogram readers. AB - BACKGROUND: Systems providing computer-based analysis of the resting electrocardiogram (ECG) seek to improve the quality of health care by providing accurate and timely automatic diagnosis of, for example, cardiac rhythm to clinicians. The accuracy of these diagnoses, however, remains questionable. OBJECTIVES: We tested the hypothesis that (a) 2 independent automated ECG systems have better accuracy in rhythm diagnosis than nonexpert clinicians and (b) both systems provide correct diagnostic suggestions in a large percentage of cases where the diagnosis of nonexpert clinicians is incorrect. METHODS: Five hundred ECGs were manually analyzed by 2 senior experts, 3 nonexpert clinicians, and automatically by 2 automated systems. The accuracy of the nonexpert rhythm statements was compared with the accuracy of each system statement. The proportion of rhythm statements when the clinician's diagnoses were incorrect and the systems instead provided correct diagnosis was assessed. RESULTS: A total of 420 sinus rhythms and 156 rhythm disturbances were recognized by expert reading. Significance of the difference in accuracy between nonexperts and systems was P = .45 for system A and P = .11 for system B. The percentage of correct automated diagnoses in cases when the clinician was incorrect was 28% +/- 10% for system A and 25% +/- 11% for system B (P = .09). CONCLUSION: The rhythm diagnoses of automated systems did not reach better average accuracy than those of nonexpert readings. The computer diagnosis of rhythm can be incorrect in cases where the clinicians fail in reaching the correct ECG diagnosis. PMID- 21816410 TI - It's in the sample: the effects of sample size and sample diversity on the breadth of inductive generalization. AB - Developmental studies have provided mixed evidence with regard to the question of whether children consider sample size and sample diversity in their inductive generalizations. Results from four experiments with 105 undergraduates, 105 school-age children (M=7.2 years), and 105 preschoolers (M=4.9 years) showed that preschoolers made a higher rate of projections from large samples than from small samples when samples were diverse (Experiments 1 and 3) but not when samples were homogeneous (Experiment 4) and not when the task required a choice between two samples (Experiment 2). Furthermore, when a property occurred in large and diverse samples, preschoolers exhibited a broad pattern of projection, generalizing the property to items from categories not represented in the evidence. In contrast, adults followed a normative pattern of induction and never attributed properties to items from categories not represented in the evidence. School-age children showed a mixed pattern of results. PMID- 21816411 TI - An examination of the relation between combat experiences and combat-related posttraumatic stress disorder in a sample of Connecticut OEF-OIF Veterans. AB - BACKGROUND: Combat exposure is an important risk factor for posttraumatic stress disorder (PTSD). However, little research has examined specific combat experiences associated with PTSD and confirmatory factor analytically (CFA) derived re-experiencing, avoidance, dysphoria, and hyperarousal symptom clusters. METHODS: A total of 285 predominantly older National Guard/Reservist OEF-OIF Veterans completed an anonymous mail survey that assessed demographics and deployment history, a broad range of combat experiences, PTSD, and unit and postdeployment social support. RESULTS: Personally witnessing someone from one's unit or an ally unit being seriously wounded or killed (beta = 0.22), and being exposed to "friendly" fire (beta = 0.14) and land mines/traps (beta = 0.13) were the only three combat experiences associated with severity of combat-related PTSD symptoms, after adjustment for age, relationship status, unit support, postdeployment social support, and other combat experiences. Differential patterns of associations were observed for specific combat experiences in relation to CFA-derived symptom clusters (e.g., experiencing "friendly" fire was associated with re-experiencing and dysphoria symptoms, but not avoidance and hyperarousal symptoms). Personally witnessing someone from one's unit or an ally unit being seriously wounded or killed (odds ratio [OR] = 4.34; 95% confidence interval [CI] = 1.62-11.61) and being exposed to "friendly" fire (OR = 2.94; 95%CI = 1.16-7.47) emerged as independent predictors of a positive screen for probable PTSD. CONCLUSIONS: Results of this study suggest that witnessing someone in one's unit or ally unit being seriously wounded or killed while in a combat zone and being exposed to "friendly" fire are most strongly associated with combat-related PTSD in this sample of OEF/OIF Veterans. Examination of the relation between specific combat experiences and combat-related PTSD in OEF/OIF Veterans may help inform etiologic models of PTSD, and guide prevention and treatment approaches in this population. PMID- 21816412 TI - Erythropoietin ameliorates renal ischemia and reperfusion injury via inhibiting tubulointerstitial inflammation. AB - BACKGROUND: Tubulointerstitial inflammation is the characteristics of renal ischemia reperfusion injury (IRI) that is inevitable in kidney transplantation. Erythropoietin (EPO) has recently been shown to have protective effects on renal IRI by anti-apoptosis and anti-oxidation. Here, the effect and mechanism of EPO on renal IRI were further investigated, with a focus on tubulointerstitial inflammation. MATERIALS AND METHODS: Male Sprague-Dawley rats were administrated with saline or EPO prior to IRI induced by bilateral renal pedicle clamping. Twenty-four hours following reperfusion, the effects of EPO on renal IRI were assessed by renal function and structure, tubulointerstitial myeloperoxidase (MPO) positive neutrophils, and proinflammatory mediator gene expression. The translocation and activity of NF-kappaB in renal tissues were also evaluated. RESULTS: Compared with control groups, the EPO treated group exhibited lower serum urea and creatinine levels, limited tubular necrosis with a lower score of renal histological lesion. MPO positive cells in the tubulointerstitial area were greatly increased by IRI, but significantly reduced by the treatment of EPO. The gene expression of proinflammatory cytokines (IL-1beta, IL-6, IL-10, and TNF alpha) and chemokine (MCP-1) was also significantly decreased by EPO. In addition, less activation and nuclear-translocation of NF-kappaB was observed in the kidney treated by EPO as well. CONCLUSION: EPO improved renal function and structure in IRI rats via reducing neutrophils in the tubulointerstitium, the production of proinflammatory cytokines and chemokine, as well as the activation and nuclear-translocation of NF-kappaB. EPO may have potential clinical applications as an anti-inflammation agent clinically for a wide range of injury. PMID- 21816413 TI - Development of a porcine model of post-hepatectomy liver failure. AB - BACKGROUND: The aim of this study was to develop a porcine model of post operative liver failure (POLF) that could accurately reproduce all the neurological and metabolic parameters of the corresponding clinical syndrome that may develop after extensive liver resections. METHODS: In our model, we induced POLF by combining extended left hepatectomy and ischemia of the small liver remnant of 150 min duration. Subsequently, the remnant liver parenchyma was reperfused and the animals were closely monitored for 24 h. MATERIALS: Twelve Landrace pigs (weight 25-30 kg) were randomly assigned in two groups; eight of them constituted the experimental group, in which POLF was induced (POLF group, n = 8), whereas the rest of them (n = 4) were included in the control group (sham laparotomy without establishment of POLF). RESULTS (MEANS +/- SD): All POLF animals gradually developed neurological and biochemical signs of liver failure including, among many other parameters, elevated intracranial pressure (24.00 +/- 4.69 versus 10.17 +/- 0.75, P = 0.004) and ammonia levels (633.00 +/- 252.21 versus 51.50 +/- 9.49, P = 0.004) compared with controls. Histopathologic evaluation of the liver at the end of the experiment demonstrated diffuse coagulative necrosis and severe architectural distortion of the hepatic parenchyma in all POLF animals. CONCLUSION: Our surgical technique creates a reproducible porcine model of POLF which can be used to study the pathophysiology and possible therapeutic interventions in this serious complication of extensive hepatectomies. PMID- 21816414 TI - Real-time simultaneous near-infrared fluorescence imaging of bile duct and arterial anatomy. AB - BACKGROUND: We hypothesized that two independent wavelengths of near-infrared (NIR) fluorescent light could be used to identify bile ducts and hepatic arteries simultaneously, and intraoperatively. MATERIALS AND METHODS: Three different combinations of 700 and 800 nm fluorescent contrast agents specific for bile ducts and arteries were injected into N = 10 35-kg female Yorkshire pigs intravenously. Combination 1 (C-1) was methylene blue (MB) for arterial imaging and indocyanine green (ICG) for bile duct imaging. Combination 2 (C-2) was ICG for arterial imaging and MB for bile duct imaging. Combination 3 (C-3) was a newly developed, zwitterionic NIR fluorophore ZW800-1 for arterial imaging and MB for bile duct imaging. Open and minimally invasive surgeries were imaged using the fluorescence-assisted resection and exploration (FLARE) surgical imaging system and minimally invasive FLARE (m-FLARE) imaging systems, respectively. RESULTS: Although the desired bile duct and arterial anatomy could be imaged with contrast-to-background ratios (CBRs) >= 6 using all three combinations, each one differed significantly in terms of repetition and prolonged imaging. ICG injection resulted in high CBR of the liver and common bile duct (CBD) and prolonged imaging time (120 min) of the CBD (C-1). However, because ICG also resulted in high background of liver and CBD relative to arteries, ICG produced a lower arterial CBR (C-2) at some time points. C-3 provided the best overall performance, although C-2, which is clinically available, did enable effective laparoscopy. CONCLUSIONS: We demonstrate that dual-channel NIR fluorescence imaging provides simultaneous, real-time, and high resolution identification of bile ducts and hepatic arteries during biliary tract surgery. PMID- 21816415 TI - Hypertonic saline inhibits arachidonic acid priming of the human neutrophil oxidase. AB - BACKGROUND: Arachidonic acid (AA, and its leukotriene derivatives, e.g., LTB(4)) is an inflammatory mediator in post-shock mesenteric lymph that appears to act as an agonist on G-protein coupled receptors (GPCRs). These mediators prime neutrophils (PMNs) for an increased production of superoxide, implicated in the development of acute lung injury (ALI). Hypertonic saline (HTS) has also been shown to have immunomodulatory effects such as attenuation of PMN priming by precluding appropriate clathrin-mediated endocytosis of activated GPCRs, thereby potentially attenuating ALI. We hypothesize that HTS inhibits priming of the PMN oxidase by these lipid mediators. METHODS: After PMNs were isolated from healthy donors, incubation was done in either isotonic buffer (control) or HTS (180 mmol/L) for 5 min at 37 degrees C. The PMNs were then primed for 10 min with AA [5 MUM] or 5 min with LTB(4) [1 MUM] and the oxidase was activated with 200 ng/mL of phorbol 12-myristate 13-acetate (PMA), a non-GPCR activator, and superoxide anion generation was measured via reduction of cytochrome c. RESULTS: Both AA [5 MUM] and LTB(4) [1 MUM] significantly primed the PMA activated respiratory burst (P < 0.05, ANOVA, Newman-Keuls, n = 4). HTS inhibited both AA and LTB(4) priming of the respiratory burst. CONCLUSIONS: These data indicate that HTS reduces the cytotoxicity of PMNs stimulated by these lipid mediators in vitro and further support the immunomodulatory effects of HTS. PMID- 21816416 TI - Enhancing complement control on endothelial barrier reduces renal post-ischemia dysfunction. AB - BACKGROUND: Excessive complement activation is an integral part of ischemia and reperfusion (IR) injury (IRI) of organs. In kidney transplantation, the pathologic consequence of IRI and complement activation can lead to delayed graft function, which in turn is associated with acute rejection. Previous strategies to reduce complement-induced IRI required systemic administration of agents, which can lead to increased susceptibility to infections/immune diseases. The objective of this study was to determine whether an increase in complement control defenses of rat kidney endothelium reduces IRI. We hypothesized that increased complement control on the endothelial barrier reduces IR-mediated complement activation and reduces kidney dysfunction. MATERIALS AND METHODS: Fischer 344 rats underwent left kidney ischemia for 45 min and treatment with a novel fusogenic lipid vesicle (FLVs) delivery system to decorate endothelial cells with vaccinia virus complement control protein (VCP), followed by reperfusion for 24 h. Assessment included renal function by serum creatinine and urea, myeloperoxidase assay for neutrophil infiltration, histopathology, and quantification of C3 production in kidneys. RESULTS: Animals in which the kidney endothelium was bolstered by FLVs+VCP treatment had better renal function with a significant reduction in serum creatinine compared with vehicle controls (P < 0.05). Also, C3 production was significantly reduced (P < 0.05) in treated animals compared with vehicle controls. CONCLUSION: Increasing complement control at the endothelial barrier with FLVs+VCP modulates complement activation/production during the first 24 h, reducing renal dysfunction following IRI. PMID- 21816417 TI - Gentamicin promotes Staphylococcus aureus biofilms on silk suture. AB - BACKGROUND: Communities of bacteria, termed biofilms, develop on biotic and abiotic surfaces, including medical devices and surgical suture. Biofilm associated bacteria are typically recalcitrant to antibiotic therapy, and the effects of antibiotics on microbial biofilms are not clearly understood. There is emerging evidence that under specific conditions, aminoglycosides may actually promote biofilm development. Experiments were designed to study the effects of gentamicin on suture-associated Staphylococcus aureus biofilms. MATERIALS AND METHODS: S. aureus biofilms were formed after 24 h incubation of bacteria with silk suture. Susceptibility of planktonic S. aureus (from broth culture) to gentamicin was compared with the susceptibility of cells from mechanically dispersed S. aureus biofilms. Subinhibitory and inhibitory concentrations of gentamicin were subsequently incubated with intact suture-associated biofilms. S. aureus viability and metabolic capacity were assessed, and biofilm biomass was quantified with crystal violet (binds negatively charged surface molecules) and with the nucleic acid stain Syto 9. Scanning electron microscopy was used to assess the effect of gentamicin on the ultrastructure of suture-associated S. aureus biofilms. RESULTS: Planktonic cells and S. aureus cells from mechanically dispersed biofilms had similar susceptibility to gentamicin. However, after incubation of high concentrations of gentamicin with intact biofilms, high numbers of S. aureus remained both viable and metabolically active; biofilm biomass was increased and biofilm ultrastructure showed staphylococcal cells within copious amounts of extracellular material. CONCLUSION: Gentamicin does not effectively kill S. aureus within intact suture-associated biofilms, and gentamicin also promotes the biomass of S. aureus biofilms. PMID- 21816419 TI - Early post-discharge deaths following operative procedures--the untold story. PMID- 21816418 TI - The cytostatic effects of lovastatin on ACC-MESO-1 cells. AB - BACKGROUND: Malignant pleural mesothelioma is known to be widely resistant to therapy, and new treatment strategies are needed. Statins are small molecules that suppress the production of multiple hydrophobic substrates in the mevalonate pathway. Although still controversial, statins may decrease the risk of certain cancers such as colon cancer, lung cancer, and prostate cancer. Since the evaluations of the direct effect of statins on malignant mesothelioma are still few, the present study was done to evaluate the effects of lovastatin on ACC-MESO 1 cells in vivo and to investigate the potential mechanisms involved in vitro. MATERIALS AND METHODS: The in vivo effect of lovastatin was evaluated using an NOD/SCID/gammanull (NOG) mouse model of human malignant mesothelioma using ACC MESO-1 cells. Lovastatin was also applied to ACC-MESO-1 cells in vitro and the effects were observed. RESULTS: Lovastatin administration reduced primary tumor and metastasis in the NOG mouse model of human malignant mesothelioma. In vitro studies showed that lovastatin administration induced cytostatic effects as per reduced cell viability and cell migration in ACC-MESO-1 cells. These effects were suggested to be dependent on autophagic changes rather than apoptosis. Furthermore, induction of autophagic changes by lovastatin in ACC-MESO-1 cells was independent of mTOR, and was considered to be dependent at least in part on Rac/phospholipase C/ inositol 1,4,5-triphosphate axis. CONCLUSIONS: These results suggest that it may be possible to utilize statins, or other pharmacological agents that are known to induce mTOR-independent autophagy, as an adjunct to standard treatments in malignant mesothelioma. PMID- 21816420 TI - Effects of octreotide on activated pancreatic stellate cell-induced pancreas graft fibrosis in rats. AB - BACKGROUND: Of solid organ transplantations, pancreas transplantation is associated with the highest incidence of pancreatic fibrosis in the early post transplantation period. Activated pancreatic stellate cells (PSCs) are the main source of pancreatic fibrosis. Octreotide is widely used as a prophylactic for postoperative complications in pancreas transplant recipients. Recent studies have shown that it can inhibit liver fibrosis. This study investigated the effect of octreotide in pancreas graft fibrosis in rats. MATERIALS AND METHODS: Isolated PSCs from Sprague Dawley rats were co-cultured with different doses of octreotide (1.25, 2.5, 5, 10, 20, and 40 ng/mL). PSC proliferation was assessed by 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide at 48, 72, and 96 h. The alpha-smooth muscle actin (alpha-SMA) and collagen I expressions of PSCs were detected by immunohistochemistry and reverse-transcriptase polymerase chain reaction. Rat heterotopic pancreaticoduodenal transplantation was performed with and without octreotide treatment (0.01 mg/kg). Pancreas grafts were harvested at postoperative d 1, 3, 5, and 7. Hematoxylin-eosin staining, Masson's trichrome staining, and immunohistochemical staining for alpha-SMA, collagen I, and tumor growth factor-beta1 (TGF-beta1) were performed. RESULTS: Octreotide at a concentration of >20 ng/mL significantly inhibited PSC activation and proliferation in vitro. Inflammatory infiltration was reduced in the octreotide group in vivo, and the expression levels of alpha-SMA, collagen I, and TGF-beta1 were also lower, with statistic significant difference or not. Masson's trichrome staining showed a decrease in collagen deposition with octreotide treatment. CONCLUSIONS: Octreotide effectively inhibits PSC activation and proliferation in vitro, but has a limited inhibitory effect on the development of pancreas graft fibrosis. PMID- 21816421 TI - The effects of AEB071 (sotrastaurin) with tacrolimus on rat heterotopic cardiac allograft rejection and survival. AB - BACKGROUND: AEB071 (sotrastaurin) is a specific inhibitor of protein kinase C that prevents T-cell activation. Our previous study demonstrated that AEB071 monotherapy could prevent acute cardiac allograft rejection in rats. Herein, we investigated the effects of AEB071 combined with various doses of tacrolimus (Tac) on the allograft rejection and survival in a rat heart transplantation model. MATERIALS AND METHODS: Heterotopic cardiac transplantation from Brown Norway to Lewis rats was performed. Cardiac allograft survival was assessed by monitoring heartbeats in six recipients of each experimental group. Another four recipient rats were selectively sacrificed in each group at d 7 post transplantation for histologic examination. Serum transaminases, blood urea nitrogen, and creatinine concentrations were measured. RESULTS: AEB071 monotherapy prolonged allograft mean survival time (MST) compared with the untreated control group. Also a combination of AEB071 and Tac prolonged MST compared with monotherapy groups with higher dose of Tac. In the cardiac graft histology, AEB071 combined with Tac 0.6 mg/kg/d significantly decreased the rejection grade as indicative of decreased inflammatory cell infiltration into the graft. No experimental group was found with any abnormal histologic or serologic evidence of liver and kidney toxicity. CONCLUSION: AEB071 combined with a smaller dosage of Tac may be clinically possible to establish calcineurin inhibitor (CNI) minimization protocol in solid organ transplantation. PMID- 21816422 TI - Laparoscopic antireflux surgery for gastroesophageal reflux disease after lung transplantation. AB - BACKGROUND: Although gastroesophageal reflux disease (GERD) is highly prevalent in lung transplantation, the pathophysiology of GERD in these patients is unknown. We hypothesize that the pathophysiology of GERD after lung transplantation differs from that of a control population, and that the 30-d morbidity and mortality of laparoscopic antireflux surgery (LARS) are equivalent in both populations. METHODS: We retrospectively compared the pathophysiology of GERD and the 30-d morbidity and mortality of 29 consecutive lung transplant patients with 23 consecutive patients without lung transplantation (control group), all of whom had LARS for GERD between November 2008 and May 2010. RESULTS: Both groups had a similar prevalence of endoscopic esophagitis and Barrett's esophagus , comparable manometric profiles, and similar prevalence of abnormal peristalsis. However, hiatal hernia was more common in controls than in lung transplant patients (57% versus 24%; P = 0.04). Lung transplant patients had a higher prevalence and severity of proximal GERD (65% versus 33%; P = 0.04). The 30-d morbidity and mortality following LARS were similar in both groups regardless of the higher surgical risk of lung transplants (median ASA class: 3 versus 2 for controls, P < 0.001). CONCLUSIONS: These results show that despite similar manometric profiles, lung transplant patients are more prone to proximal reflux than the general population with GERD; the prevalence of endoscopic esophagitis and Barrett's esophagus is the same in both groups of patients; a hiatal hernia is uncommon after lung transplantation; and the morbidity and mortality of LARS are the same for lung transplant patients as the general population with GERD. PMID- 21816423 TI - Laparoscopic splenectomy for patients with immune thrombocytopenia and very low platelet count: is platelet transfusion necessary? AB - BACKGROUND: The safe level of platelet count (PC) and necessity for platelet transfusion during laparoscopic splenectomy (LS) remain uncertain in patients with immune thrombocytopenia (ITP). MATERIALS AND METHODS: From 2005 to 2010, 81 patients with ITP underwent LS by our surgical team. Of these patients, 10 (group Ia) with preoperative PC < 10 * 10(9)/L were administered platelet concentrates during surgery, whereas another 20 (group Ib) with PC < 10 * 10(9)/L, 24 (group II) with PC = 10-30 * 10(9)/L and 27 (group III) with PC >= 30 * 10(9)/L did not receive platelet transfusion. Recently, we carried out comparisons between groups in terms of demographic data and perioperative outcome. RESULTS: The demographic data were similar among groups. The operative outcome was comparable between group Ia and Ib. Patients in group Ib had significantly lower preoperative PC (P < 0.001) and hemoglobin concentration (P = 0.009), suffered relatively more blood loss (P = 0.151) and drainage exudates (P = 0.151), received more packed red blood cell (RBC) transfusions (P = 0.113) than patients in groups II or III. However, blood loss was not correlated with PC (r = -0.145, P = 0.195), but determined by operative time (r =0.610, P < 0.001); and packed RBC transfusion was significantly determined by lower preoperative hemoglobin and conversion to open surgery (OR = 7.2 and 46.7, P < 0.001 and P = 0.005, respectively). CONCLUSIONS: Very low platelet count should not be contraindicated for LS in ITP patients and perioperative platelet transfusion may be unnecessary. PMID- 21816424 TI - Renal transplant wound complications in the modern era of obesity. AB - BACKGROUND: Obesity is a known risk factor for wound complications following kidney transplantation (KTX), and obese transplant candidates are often encouraged to lose weight. The implications of this weight loss for post-KTX wound healing and morbidity have not been examined. Our aim was to study potential risk factors for post-KTX wound complications, with a specific focus on a history of significant weight loss. METHODS: Single-center retrospective review of all KTX recipients >= 18 y performed 04/2004-03/2009. We studied potential donor-, transplant-, and recipient-related risk factors for wound complications by univariate and multivariate analyses. Graft and patient survival comparisons were done by Kaplan-Meier curves and two-sided log-rank test. RESULTS: Overall wound complication incidence among the 487 study recipients was 6.4%. Significant independent risk factors for wound complications were BMI (odds ratio [OR] = 1.14 per 1 kg/m(2) increase), and history of significant weight loss (OR = 13.46), peri-KTX transfusion (OR = 5.42), and desensitization (OR = 60.34). Wound complications had no significant impact on graft and patient survival. CONCLUSIONS: Our study demonstrates for the first time that besides BMI, pre-KTX desensitization, and peri-KTX transfusion, a history of significant pre-KTX weight loss is also an independent risk factor for post-KTX wound complications (potentially at least in part due to body contour changes resulting in an unfavorable abdominal panniculus). Further study of KTX candidates who have lost a significant amount of weight is warranted to (1) identify the exact causes for their increased propensity for complications and (2) devise measures to minimize added cost and morbidity. Finally, our findings suggest that the impact of weight loss on the outcomes of non-transplant operations also warrants further investigation. PMID- 21816426 TI - Does BMI affect perioperative complications following total knee and hip arthroplasty? AB - BACKGROUND: Orthopedic surgeons are reluctant to perform total knee (TKA) or hip (THA) arthroplasty on patients with high body mass index (BMI). Recent studies are conflicting regarding the risk of obesity on perioperative complications. Our study investigates the effect of BMI on perioperative complications in patients undergoing TKA and THA using a national risk-adjusted database. METHODS: A retrospective analysis was performed using the 2005-2007 American College of Surgeons-National Surgical Quality Improvement Program ACS-NSQIP dataset. Inclusion criteria were patients between 18 and 90 y of age who underwent TKA or THA. Patients were stratified into five BMI categories: normal, overweight, obese class I, obese class II, and morbidly obese. Demographic characteristics, length of stay, co-morbidities, and complication rates were compared across the BMI categories. RESULTS: A total of 1731 patients met the inclusion criteria, with 66% and 34% undergoing TKA and THA, respectively. A majority were female (60%) and >60 y (70%) in age. Of the patients who underwent TKA, 90% were either overweight or obese, compared with 77% in those undergoing THA. The overall preoperative comorbidity rate was 73%. The complication and mortality rates were 7% and 0.4%, respectively. When stratifying perioperative complications by BMI categories, no differences existed in the rates of infection (P = 0.368), respiratory (P = 0.073), cardiac (P = 0.381), renal (P = 0.558), and systemic (P = 0.216) complications. CONCLUSIONS: Our study demonstrates no statistical difference in perioperative complication rates in patients undergoing TKA or THA across BMI categories. Performing TKA or THA on patients with high BMI may increase mobility leading to improved quality of life. PMID- 21816425 TI - ALCAM (CD166) expression as novel prognostic biomarker for pancreatic neuroendocrine tumor patients. AB - BACKGROUND: Activated leukocyte cell adhesion molecule (ALCAM, CD166) is a cell membrane protein that is aberrantly expressed in different tumors, including pancreatic neuroendocrine tumors (PNET). The aim of this study was to determine the expression of ALCAM in PNET to learn more about the prevalence and clinical significance of ALCAM expression in PNET. METHODS: Primary tumors (n = 38) and corresponding lymph node (n = 5) and liver metastases (n = 9) of patients with PNET, treated at the University Medical Center Hamburg-Eppendorf between 1993 and 2006, were analyzed via ALCAM immunohistochemistry in a tissue microarray format. The results were correlated with clinical and histopathologic data, including the WHO classification of PNET. RESULTS: The majority of primary (74%) and secondary (50%) lesions of PNET showed strong ALCAM expression. Immunohistochemistry of primary tumors revealed an association between high ALCAM expression and the hormone production status of the tumor (P = 0.037), and an inverse correlation with metastasis status (P = 0.041) and tumor size (cut off level 2 cm, P = 0.013). Elevated ALCAM expression was a significant positive prognostic factor for recurrence-free (P = 0.002) and disease-specific survival (P = 0.009) in Kaplan-Meier survival analysis (log rank test). CONCLUSIONS: ALCAM is abundantly expressed in PNET and decreased expression is significantly associated with poor prognosis. ALCAM may be a potential marker for risk prediction in patients diagnosed with PNET. Further studies with larger patient collectives are required to validate the results of this study and investigate the functional role of ALCAM in PNET. PMID- 21816427 TI - Hepatic differentiation from human embryonic stem cells using stromal cells. AB - OBJECTIVE: The derivation of hepatocytes from human embryonic stem (hES) cells is of value both in the study of early human liver organogenesis and in the creation of an unlimited source of donor cells for hepatocyte transplantation therapy. Here, we report the generation of hepatocyte-like cells derived from hES cells. METHODS: Hepatic endoderm cells were generated by adding activin A for 5 d- to 1 d-old embryoid bodies formed from hES cells. The hepatic endoderm cells were cocultured with mitomycin treated 3T3-J2 feeder cells. RESULTS: After co-culture with mitomycin treated 3T3-J2 feeder cells, these hepatic endodermal cells yielded hepatocyte-like cell colonies, which possessed the proliferation potential to be cultured for an extended period of more than 30 d. With extensive expansion, they co-expressed the hepatic marker AFP and albumin, indicating that they were hepatocyte-like cells. CONCLUSIONS: We report the generation of proliferative hepatocyte-like cells from hES cells. These hES cell derived hepatic cells can effectively be used as in vitro model for studying the mechanisms of hepatic stem/progenitor cell origin, self-renewal and differentiation. PMID- 21816429 TI - Medical education meets patient safety. PMID- 21816428 TI - Early myocardial dysfunction is not caused by mitochondrial abnormalities in a rat model of peritonitis. AB - BACKGROUND: Patients with complicated intra-abdominal infections are prone to develop multiple organ failure, including myocardial dysfunction. We hypothesized that early dysfunction during sepsis is associated with inflammation, mitochondrial injury, impaired mitochondrial function, and activation of mitochondrial biogenesis. MATERIALS AND METHODS: Rats received lipopolysaccharide (LPS, n = 11) intraperitoneally. Healthy rats (n = 6) served as controls. Myocardial function was measured ex vivo in an isolated Langendorff-perfused heart set-up. Myocardial vascular cell adhesion molecule-1 (VCAM-1) expression was determined by immunofluorescence microscopy. Cytochrome c release and cytochrome c oxidase (COX IV) activity were measured by immunohistochemistry and enzyme histochemistry, respectively. Protein expression of tumor necrosis factor alpha (TNF-alpha), B-cell lymphoma (Bcl)-2, peroxisome proliferator activated receptor gamma cofactor 1alpha (PGC-1alpha), and mitochondrial transcription factor A (TFAM) were analyzed by Western blot technique. Mitochondria were studied by electron microscopy. RESULTS: Two hours after LPS injection, developed pressure had decreased and after 4 h myocardial contractility (+dP/dt) and relaxation (-dP/dt) also had decreased. TNF-alpha protein expression was increased after 2 h and returned to normal at 4 h, whereas after 4 h VCAM-1 expression was higher in LPS-treated animals. At 2 h a substrate-dependent increase in COXIV-activity was seen, but no mitochondrial damage occurred as cytochrome c release, COX IV activity and Bcl-2, PGC-1alpha or TFAM expression were not changed. Electron microscopy did not reveal differences in myocardial mitochondrial characteristics between LPS-treated and control rats. CONCLUSIONS: Early myocardial dysfunction in sepsis is associated with myocardial inflammation but not with mitochondrial injury, impaired mitochondrial function, or activated mitochondrial biogenesis. PMID- 21816430 TI - Warm-ups, mental rehearsals and deliberate practice: adopting the strategies of elite professionals. PMID- 21816431 TI - A healthy dose of heavy metal: magnesium and acute lung injury. PMID- 21816432 TI - Glucose is an ineffective substrate for preservation of machine perfused donor hearts. AB - BACKGROUND: Machine perfusion with oxygenated preservation solution can support donor heart metabolism but the preservation solution should contain an oxidizable substrate to improve cellular energetics. We hypothesized that myocardial metabolism can be influenced by exogenous substrates in the preservation solution. METHODS: Eight groups of isolated rat hearts (n = 4/group) were perfused with University of Wisconsin Machine Perfusion Solution containing carbon 13 ((13)C) labeled glucose (2.5 mM, 5 mM, 10 mM, or 20 mM) or pyruvate (5 mM, 10 mM, 20 mM, or 40 mM). Hearts were perfused at 0.5 mL/min for 6 h at 8 degrees C, and myocardial oxygen consumption (MVO(2)) was measured. At end perfusion, magnetic resonance spectroscopy was performed on ventricular extracts to determine the contribution of exogenous, labeled substrate to glycolysis and oxidative metabolism by (13)C incorporation into metabolic intermediates. RESULTS: MVO(2) and perfusion conditions did not differ amongst groups. Exogenous glucose was metabolized by anaerobic glycolysis and contributed little to oxidative metabolism as measured by (13)C incorporation into metabolic intermediates. Pyruvate led to greater lactate enrichment via the lactate dehydrogenase reaction. Enrichment of tricarboxylic acid (TCA) cycle intermediates was also greater in all pyruvate groups compared with glucose containing groups (P < 0.05). Anaplerosis was increased in all pyruvate groups (P < 0.05). CONCLUSIONS: The preservation solution substrate composition influences myocardial substrate metabolism during machine perfusion preservation of donor hearts. Exogenous glucose is a minor substrate in machine perfused myocardium, is primarily metabolized by glycolysis and does not contribute appreciably to oxidative metabolism. Pyruvate appears more effective in supporting myocardial metabolism. Further experiments examining the influences of substrate modifications on reperfusion function are warranted. PMID- 21816433 TI - 415 patients with adenosquamous carcinoma of the pancreas: a population-based analysis of prognosis and survival. AB - BACKGROUND: Adenosquamous carcinoma of the pancreas is rare. Our understanding of the disease and its prognosis comes mainly from small retrospective studies. METHODS: Using the Surveillance, Epidemiology, and End Results (SEER) database (1988 to 2007), we identified patients with adenosquamous carcinoma (n = 415) or adenocarcinoma (n = 45,693) of the pancreas. The demographics, tumor characteristics, resection status, and survival were compared between the groups. RESULTS: Compared with patients with adenocarcinoma, patients with adenosquamous carcinoma were more likely to have disease located in the pancreatic body and tail (44.6% versus 53.5%, P < 0.0001). While the stage distribution was similar between the two groups, adenosquamous carcinomas were more likely to be poorly differentiated (71% versus 45%, P < 0.0001), node positive (53% versus 47%, P < 0.0001), and larger (5.7 versus 4.3 cm, P < 0.0001). For locoregional disease, resection increased over time from 26% in 1988 to 56% in 2007. The overall 2-y survival was 11% in both groups. Following resection, patients with adenosquamous carcinoma had worse 2-y survival (29% versus 36%, P < 0.0001). Resection was the strongest independent predictor of survival for patients with locoregional pancreatic adenosquamous carcinoma (HR 2.35, 95% CI = 1.47-3.76). CONCLUSIONS: This is the first population-based study to evaluate outcomes in adenosquamous carcinoma of the pancreas. Compared with pancreatic adenocarcinoma, adenosquamous carcinoma was more likely to occur in the pancreatic tail, be poorly differentiated, larger, and node positive. The long-term survival following surgical resection is significantly worse for adenosquamous cancers; however, patients with adenosquamous carcinoma can still benefit from surgical resection, which is the strongest predictor of survival. PMID- 21816434 TI - NSQIP reveals significant incidence of death following discharge. AB - BACKGROUND: The rates of post-discharge deaths after surgical procedures are unknown and may represent areas of quality improvement. The NSQIP database captures 30-d outcomes not included within normal administrative databases, and can thus differentiate between in-hospital and post-discharge deaths. METHODS: Retrospective analysis of NSQIP from 2005 through 2007. Inclusion criteria were procedures whose median length of stay was greater than 1 d (to exclude outpatient procedures), and whose overall death rate was greater than 2% (to include only procedures where mortality was a significant issue). Procedures where less than 25 deaths occurred were excluded (for sample size concerns). RESULTS: There were 363,897 patients with 2236 different CPT codes captured in NSQIP. There were 6395 deaths; among them, 1486 (23.2%) occurred after discharge. Thirty-eight CPT codes met the analysis threshold. In two of the CPT codes, there were no post-discharge deaths (repair of ruptured abdominal aortic aneurysm [AAA], repair of ruptured AAA involving iliacs). In the other 36 CPT codes, the proportion of deaths occurring after discharge ranged from 6.3% (repair of thoracoabdominal aneurysm) to 50.0% (femoral-distal bypass with vein). The highest percentage of post-discharge mortality occurs on d 1 after discharge. Fifty percent of post-discharge mortality occurs by d 7; 95% occurs by d 21. CONCLUSION: Approximately one-fourth of postoperative deaths occur after hospital discharge. There is significant variation across surgical procedures in the likelihood of postoperative deaths occurring after discharge. These data indicate a need for closer and more frequent monitoring of post-surgical patients. These data also call into question conclusions drawn from hospital-based outcomes analyses for at least some key diseases/procedures. This analysis demonstrates the power of the risk-adjusted 30-d follow-up NSQIP data, but perhaps more importantly, the responsibility of surgeons to monitor and optimize the discharge process. PMID- 21816435 TI - CT utilization in transferred trauma patients. AB - BACKGROUND: Trauma systems were designed to optimize care of critically injured patients. CT scanning and its duplication demonstrate waste, inefficiency, and harm to the patient. We define the frequency at which this occurs and identify areas of inefficiency within our system that may be present in other systems. MATERIALS AND METHODS: Patients transferred to a level I trauma center were prospectively identified at the time of transfer. All imaging completed at either the referring center or the level I center was recorded. The reason for CT scanning at the level I center was captured at the time of decision and recorded in one of four categories. RESULTS: A total of 207 transferred trauma patients with CT imaging were reviewed. Of these, 127 patients (61%) had CT scans obtained at both the referring and accepting facilities; 99 patients (48%) had one or more of the same body regions imaged at both centers; 28 (13%) patients did not have repeated body region scans, but received additional imaging at the Trauma Center. CT scans of the head (34%) and c-spine (35%) were most commonly obtained at both the referring center and the trauma center. The most common reason for repeat or additional imaging at the trauma center was improper image selection or poor image quality. CONCLUSION: Repeat and additional imaging of transferred trauma patients is a common practice. The reasons for this include image quality and selection. This provides necessary information for improvement in the quality of the trauma transfer process. PMID- 21816437 TI - Nutritional insight into preduodenal pouch reconstruction one year after total gastrectomy. AB - BACKGROUND: Various types of reconstructions have been developed to improve the quality of life of patients following total gastrectomy. In addition, to ensure larger food-intake reservoirs and extend meal transit times, different types of pouch reconstructions have been developed and described. Our opinion is that the most important factor in providing better physiologic regulation of ingested food is restoration of the duodenal passage and enlargement of the gastric substituent. MATERIALS AND METHODS: In the present study, we compared standard a Roux-en-Y reconstruction and a preduodenal pouch (PDP) reconstruction. We evaluated the quality of life (QoL) for 60 patients during the first postoperative year, comparing serum albumin, protein, hemoglobin, iron, body weight, body mass index, and QoL. QoL was defined according to Korenaga's score scale, which has 14 questions, for better understanding of subjective patient perceptions of digestive function. RESULTS: Our study population did not differ in iron and hemoglobin levels at a 1-y follow-up. The difference between total serum albumin level was significant in all observed patients in the follow-up period in favor of the PDP reconstruction group (P = 0.001). The PDP reconstruction group also had a significantly higher serum protein level after 12 mo. The higher score difference between the two groups generally confirm the improved QoL in the PDP group (P = 0.001). CONCLUSION: The most important aspects of improved QoL after gastrectomy due to gastric carcinoma are maintenance of the duodenal transit and the addition of a pouch. Jejunal preduodenal pouches provide a better QoL than Roux-en-Y reconstruction. Our study results suggest preduodenal pouch reconstruction should be used as the method of choice. PMID- 21816436 TI - Gene expression variations in microsatellite stable and unstable colon cancer cells. AB - BACKGROUND: Microsatellite instability (MSI) is a marker of chemoresistance, but it is associated with improved survival compared with microsatellite-stable (MSS) colon cancers. We hypothesized that MSI tumors overexpress chemoresistance associated genes and underexpress DNA damage/repair genes. We used ultra high throughput sequencing (UHTS) to assess the expression of representative genes in MSI and MSS colon cancer cell lines. METHODS: Solexa UHTS was used to examine gene expression in HCT116 (MSI) and HT29 (MSS) cells, and normal colonic mucosa (NCM). We compared expression of 40 genes involved in chemoresistance, DNA repair, DNA damage, and drug metabolism pathways. RESULTS: We observed gene expression differences between MSI and MSS cell lines in 8 out of 40 genes involved in mismatch repair (MMR), DNA repair, drug metabolism, and chemoresistance. MMR gene expression was lower in MSI cells, which is consistent with the MSI phenotype, whereas DNA repair genes were highly expressed in these cells. Genes associated with chemoresistance and drug metabolism also had increased expression in MSI cells. No difference in expression of DNA damage genes was observed between MSI and MSS cell lines. CONCLUSION: Using UHTS gene expression analysis, we identified differential expression of genes between MSI and MSS cell lines which may account for resistance to chemotherapy in MSI tumors. UHTS expression analysis has the potential to identify genome-wide predictors of response or resistance to chemotherapy. PMID- 21816438 TI - Indicators of complications and drain removal after pancreatoduodenectomy. AB - BACKGROUND: Significance and timing of drain removal after pancreatic surgery remain unclear. The aim of this study was to identify optimal indicators to predict severe intra-abdominal complications and determine the appropriate timing of prophylactic drain removal after pancreatoduodenectomy. MATERIALS AND METHODS: This study included 151 consecutive patients who underwent pancreatoduodenectomy. We investigated associations between postoperative intra-abdominal complications, drain amylase levels, and duration of postoperative inflammatory response. RESULTS: Patients who developed severe intra-abdominal complications showed re elevation of drain amylase levels after postoperative d 3 and prolonged postoperative inflammatory response, which were most pronounced in patients with severe pancreatic fistula and intra-abdominal abscess, respectively. In contrast, patients with a steady decline in drain amylase levels and short-term postoperative inflammatory response did not develop severe complications, and safe drain removal was possible even when the drain amylase value was more than three times the upper limit of normal serum amylase. CONCLUSION: A combination of trends in the drain amylase level and duration of the inflammatory response in the postoperative period may be optimal indicators for early detection of severe intra-abdominal complications and appropriate timing of drain removal. PMID- 21816440 TI - Preconditioning with hyperbaric oxygen induces tolerance against renal ischemia reperfusion injury via increased expression of heme oxygenase-1. AB - OBJECTIVE: Renal ischemia/reperfusion (I/R) injury occurs in both native and transplanted kidneys. Hyperbaric oxygen (HBO) has been shown to prevent I/R injury in different tissues. The aim of this study was to evaluate the effect of HBO on renal I/R injury in rats. MATERIALS AND METHODS: Male Sprague-Dawley rats were randomly assigned to three groups. The sham group (n = 8) received right nephrectomy. The I/R (n = 8) and HBO + I/R groups (n = 8) received 45 min left renal ischemia followed by 24 h of reperfusion after right nephrectomy. The HBO + I/R group (n = 8) received 100% oxygen at 2.5 atmosphere absolute (ATA), for 1 h at every 12 h interval for 2 d. Reperfusion was performed 24 h later after the last HBO exposure. RESULTS: In HBO + I/R group, blood urea nitrogen (BUN) and creatinine levels decreased significantly compared with the sham and I/R groups (P < 0.01). Activities of superoxide dismutase (SOD) were increased in renal tissue in the HBO + I/R groups. The content of malondialdehyde (MDA) were decreased in the HBO + I/R groups. Kidney samples from HBO + I/R group rats revealed markedly reduced histological damage under histopathological examination. The animals treated with HBO showed significantly elevated heme oxygenase-1 (HO-1) protein and mRNA levels expression compared with I/R group (P < 0.05). CONCLUSIONS: Hyperbaric oxygen preconditioning (HBO-PC) can protect renal I/R injury against oxidative stress, and the up-regulation of HO-1 expression plays an essential role in HBO induced preconditioning effect. PMID- 21816439 TI - Histone deacetylase inhibitor treatment attenuates MAP kinase pathway activation and pulmonary inflammation following hemorrhagic shock in a rodent model. AB - BACKGROUND: Hemorrhagic shock activates cellular stress signals and can lead to systemic inflammatory response, organ injury, and death. We have previously shown that treatment with histone deacetylase inhibitors (HDACIs) significantly improves survival in lethal models (60% blood loss) of hemorrhage. The aim of the current study was to examine whether these protective effects were due to attenuation of mitogen activated protein kinase (MAPK) signaling pathways, which are known to promote inflammation and apoptosis. METHODS: Wistar-Kyoto rats (250 300 g) were subjected to 40% blood loss and randomized to treatment with: (1) HDACI valproic acid (VPA 300 mg/kg i.v.; volume = 0.75 mL/kg), or (2) vehicle control (0.75 mL/kg of 0.9% saline). Animals were sacrificed at 1, 4, and 20 h (n = 3-4/group/timepoint), and lung samples were analyzed by Western blotting for expression of active (phosphorylated) and inactive forms of c-Jun N-terminal Kinase (JNK) and p38 MAPK. Myeloperoxidase (MPO) activity was measured in lung tissue 20 h after hemorrhage as a marker of neutrophil infiltration. Normal animals (n = 3) served as shams. RESULTS: Hemorrhaged animals demonstrated significant increases in phosphorylated p38 at 1 h, phosphorylated JNK at 4 h, and increased MPO activity at 20 h (P < 0.05 compared with sham). VPA treatment significantly (P < 0.05) attenuated all of these changes. CONCLUSIONS: Hemorrhagic shock activates pro-inflammatory MAPK signaling pathways and promotes pulmonary neutrophil infiltration, affects that are significantly attenuated by VPA treatment. This may represent a key mechanism through which HDACIs decrease organ damage and promote survival in hemorrhagic shock. PMID- 21816441 TI - Under mackerel skies. PMID- 21816443 TI - Effect of short-term low- and high-fat diets on low-density lipoprotein particle size in normolipidemic subjects. AB - High-fat, low-carbohydrate diets have been shown to raise plasma cholesterol levels, an effect associated with the formation of large low-density lipoprotein (LDL) particles. However, the impact of dietary intervention on time-course changes in LDL particle size has not been investigated. To test whether a short term dietary intervention affects LDL particle size, we conducted a randomized, double-blind, crossover study using an intensive dietary modification in 12 nonobese healthy men with normal plasma lipid profile. Participants were subjected to 2 isocaloric 3-day diets: high-fat diet (37% energy from fat and 50% from carbohydrates) and low-fat diet (25% energy from fat and 62% from carbohydrates). Plasma lipid levels and LDL particle size were assessed on fasting blood samples after 3 days of feeding on each diet. The LDL particles were characterized by polyacrylamide gradient gel electrophoresis. Compared with the low-fat diet, plasma cholesterol, LDL cholesterol, and high-density lipoprotein cholesterol were significantly increased (4.45 vs 4.78 mmol/L, P = .04; 2.48 vs 2.90 mmol/L, P = .005; and 1.29 vs 1.41 mmol/L, P = .005, respectively) following the 3-day high-fat diet. Plasma triglycerides and fasting apolipoprotein B-48 levels were significantly decreased after the high-fat diet compared with the low-fat diet (1.48 vs 1.01 mmol/L, P = .0003 and 9.6 vs 5.5 mg/L, P = .008, respectively). The high-fat diet was also associated with a significant increase in LDL particle size (255.0 vs 255.9 A;P = .01) and a significant decrease in the proportion of small LDL particle (<255.0 A) (50.7% vs 44.6%, P = .01). As compared with a low-fat diet, the cholesterol-raising effect of a high-fat diet is associated with the formation of large LDL particles after only 3 days of feeding. PMID- 21816442 TI - Inducible nitric oxide synthase deficiency ameliorates skeletal muscle insulin resistance but does not alter unexpected lower blood glucose levels after burn injury in C57BL/6 mice. AB - Burn injury is associated with inflammatory responses and metabolic alterations including insulin resistance. Impaired insulin receptor substrate-1 (IRS-1) mediated insulin signal transduction is a major component of insulin resistance in skeletal muscle following burn injury. To further investigate molecular mechanisms that underlie burn injury-induced insulin resistance, we study a role of inducible nitric oxide synthase (iNOS), a major mediator of inflammation, on burn-induced muscle insulin resistance in iNOS-deficient mice. Full-thickness third-degree burn injury comprising 12% of total body surface area was produced in wild-type and iNOS-deficient C57BL/6 mice. Insulin-stimulated activation (phosphorylation) of IR, IRS-1, and Akt was assessed by immunoblotting and immunoprecipitation. Insulin-stimulated glucose uptake by skeletal muscle was evaluated ex vivo. Burn injury caused induction of iNOS in skeletal muscle of wild-type mice. The increase of iNOS expression paralleled the increase of insulin resistance, as evidenced by decreased tyrosine phosphorylation of IR and IRS-1, IRS-1 expression, insulin-stimulated activation of phosphatidylinositol 3 kinase and Akt/PKB, and insulin-stimulated glucose uptake in mouse skeletal muscle. The absence of iNOS in genetically engineered mice significantly lessened burn injury-induced insulin resistance in skeletal muscle. In wild-type mice, insulin tolerance test revealed whole-body insulin resistance in burned mice compared with sham-burned controls. This effect was reversed by iNOS deficiency. Unexpectedly, however, blood glucose levels were depressed in both wild-type and iNOS-deficient mice after burn injury. Gene disruption of iNOS ameliorated the effect of burn on IRS-1-mediated insulin signaling in skeletal muscle of mice. These findings indicate that iNOS plays a significant role in burn injury-induced skeletal muscle insulin resistance. PMID- 21816444 TI - Metabolic syndrome in a Mediterranean pediatric cohort: prevalence using International Diabetes Federation-derived criteria and associations with adiponectin and leptin. AB - The aims of the study were to determine the prevalence of metabolic syndrome (MS) components and examine associations with adipokine concentrations in a healthy pediatric cohort. A cross-sectional study of 1138 children (53% girls; mean age of all participants, 11.2 +/- 0.7 years) was performed. Anthropometric and medical information was obtained; and a fasting blood sample was used to measure glucose, insulin, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, leptin, and adiponectin serum concentrations. Insulin resistance was assessed by the insulin resistance homeostasis model assessment. Body weight status (normal, overweight, and obese) was determined according to the International Obesity Task Force. Estimation of the MS was based on the International Diabetes Federation definition. The prevalence of the MS was 0.7% of children, all of whom were obese. Frequency of abdominal obesity, high fasting glucose, elevated triglycerides, low high-density-lipoprotein cholesterol, and elevated blood pressure was 4.8%, 4.7%, 0, 12.3%, and 33%, respectively. Body mass index (BMI) and z-BMI score increased significantly as the number of cardiometabolic risk factors increased. Regression analysis revealed that adiponectin (beta = -0.501, P = .003) and leptin (beta = 0.184, P < .0001) independently predicted the number of MS features. This finding was no longer significant after adjustment for BMI. In the present study, we provide the first estimate of the prevalence of the MS among healthy periadolescents in Greece using the International Diabetes Federation criteria. The MS prevalence was low, with elevated blood pressure being the most dominant feature. Finally, associations with adipokines are mediated by BMI. PMID- 21816445 TI - Mitochondrial regulators of fatty acid metabolism reflect metabolic dysfunction in type 2 diabetes mellitus. AB - The delicate homeostatic balance between glucose and fatty acid metabolism in relation to whole-body energy regulation is influenced by mitochondrial function. We determined expression and regulation of mitochondrial enzymes including pyruvate dehydrogenase kinase (PDK) 4, PDK2, carnitine palmitoyltransferase 1b, and malonyl-coenzyme A decarboxylase in skeletal muscle from people with normal glucose tolerance (NGT) or type 2 diabetes mellitus (T2DM). Vastus lateralis biopsies were obtained from NGT (n = 79) or T2DM (n = 33) men and women matched for age and body mass index. A subset of participants participated in a 4-month lifestyle intervention program consisting of an unsupervised walking exercise. Muscle biopsies were analyzed for expression and DNA methylation status. Primary myotubes were derived from biopsies obtained from NGT individuals for metabolic studies. Cultured skeletal muscle was exposed to agents mimicking exercise activation for messenger RNA (mRNA) expression analysis. The mRNA expression of PDK4, PDK2, and malonyl-coenzyme A decarboxylase was increased in skeletal muscle from T2DM patients. Methylation of the PDK4 promoter was reduced in T2DM and inversely correlated with PDK4 expression. Moreover, PDK4 expression was positively correlated with body mass index, blood glucose, insulin, C peptide, and hemoglobin A(1c). A lifestyle intervention program resulted in increased PDK4 mRNA expression in NGT individuals, but not in those with T2DM. Exposure to caffeine or palmitate increased PDK4 mRNA in a cultured skeletal muscle system. Our findings reveal that skeletal muscle expression of PDK4 and related genes regulating mitochondrial function reflects alterations in substrate utilization and clinical features associated with T2DM. Furthermore, hypomethylation of the PDK4 promoter in T2DM coincided with an impaired response of PDK4 mRNA after exercise. PMID- 21816446 TI - Treatment of genetically obese mice with the iminosugar N-(5-adamantane-1-yl methoxy-pentyl)-deoxynojirimycin reduces body weight by decreasing food intake and increasing fat oxidation. AB - Obesity and its associated conditions such as type 2 diabetes mellitus are major causes of morbidity and mortality. The iminosugar N-(5-adamantane-1-yl-methoxy pentyl)-deoxynojirimycin (AMP-DNM) improves insulin sensitivity in rodent models of insulin resistance and type 2 diabetes mellitus. In the current study, we characterized the impact of AMP-DNM on substrate oxidation patterns, food intake, and body weight gain in obese mice. Eight ob/ob mice treated with 100 mg/(kg d) AMP-DNM mixed in the food and 8 control ob/ob mice were placed in metabolic cages during the first, third, and fifth week of the experiment for measurement of substrate oxidation rates, energy expenditure, activity, and food intake. Mice were killed after 6 weeks of treatment. Initiation of treatment with AMP-DNM resulted in a rapid increase in fat oxidation by 129% (P = .05), a decrease in carbohydrate oxidation by 35% (P = .01), and a reduction in food intake by approximately 26% (P < .01) compared with control mice. Treatment with AMP-DNM decreased hepatic triglyceride content by 66% (P < .01) and, in line with the elevated fat oxidation rates, increased hepatic carnitine palmitoyl transferase 1a expression. Treatment with AMP-DNM increased plasma levels of the appetite regulating peptide YY compared with control mice. Treatment with AMP-DNM rapidly reduces food intake and increases fat oxidation, resulting in improvement of the obese phenotype. These features of AMP-DNM, together with its insulin-sensitizing capacity, make it an attractive candidate drug for the treatment of obesity and its associated metabolic derangements. PMID- 21816447 TI - Associations of urinary 6-sulfatoxymelatonin with biomarkers related to cardiovascular disease in Japanese women. AB - Melatonin's potential preventive effect against cardiovascular disease (CVD) remains hypothetical. No study has evaluated the relationships between endogenous melatonin and the established blood biomarkers related to CVD. The objective of the present study is to examine the association between the endogenous melatonin level and various established blood biomarkers of risk of CVD, including white blood cell (WBC) count and plasma concentrations of lipids, homocysteine, uric acid (UA), and high-sensitivity C-reactive protein (hs-CRP). This cross-sectional study included 181 Japanese women who attended a health checkup program provided by a general hospital between March 2005 and March 2006. All study subjects responded to a self-administered questionnaire and were measured for weight, height, and blood pressure. Venous fasting blood and first-void morning urine were obtained from all subjects. Statistically significant inverse correlations were observed between urinary 6-sulfatoxymelatonin (aMT6s), the major metabolite of melatonin in urine, and WBC count, UA, and hs-CRP after controlling for age, body mass index, menopausal status, smoking status, diet, sleeping habits, and exercise (r = -0.19, -0.21, and -0.24, respectively). There were no significant correlations between urinary aMT6s and plasma lipids and homocysteine. These data suggested that the urinary aMT6s level was inversely associated with established independent risk factors for CVD, such as WBC, UA, and hs-CRP. Endogenous melatonin may have implications for the risk of CVD. PMID- 21816448 TI - Exercise can induce temporary mitochondrial and contractile dysfunction linked to impaired respiratory chain complex activity. AB - Exercise is considered to elicit a physiological response of the heart. Previous studies investigated the influence of repetitive exercise only at the end of the training period. We assessed the impact of 2 exercise protocols, differing in their treadmill inclination, on cardiac and mitochondrial function at different times during the training period. Within 10 weeks, animals trained with 16% incline developed hypertrophy (left ventricular posterior wall thickness: 1.6 +/- 0.1 vs 2.4 +/- 0.1 mm; P < .05) with normal function (ejection fraction: 75.2% +/ 2.5% vs 75.6% +/- 2.1%). However, at 6 weeks, there was temporary impairment of contractile function (ejection fraction: 74.5% +/- 1.67% vs 65.8% +/- 2.3%; P < .05) associated with decreased mitochondrial respiratory capacity (state 3 respiration: 326 +/- 71 vs 161 +/- 22 natoms/[min mg protein]; P < .05) and a gene expression shift from the adult (alpha) to the fetal (beta) myosin heavy chain isoform. Although peroxisome proliferator-activated receptor gamma coactivator-1alpha expression was normal, nuclear respiratory factors (NRFs)-1 and -2 were significantly reduced (NRF-1: 1.00 +/- 0.16 vs 0.55 +/- 0.09; NRF-2: 1.00 +/- 0.11 vs 0.63 +/- 0.07; P < .05) after 6 weeks. These findings were associated with a reduction of electron transport chain complexes I and IV activity (complex I: 1016 +/- 67 vs 758 +/- 71 nmol/[min mg protein]; complex IV: 18768 +/- 1394 vs 14692 +/- 960 nmol/[min mg protein]; P < .05). Messenger RNA expression of selected nuclear encoded subunits of the electron transport chain was unchanged at all investigated time points. In contrast, animals trained with 10% incline showed less hypertrophy and normal function in echocardiography, normal maximal respiratory capacity, and unchanged complex activities at all 3 time points. Repetitive exercise may cause contractile and mitochondrial dysfunction characterized by impaired respiratory chain complex activities. This activity reduction is temporary and intensity related. PMID- 21816449 TI - PRNP haplotype and genotype frequencies in Brazilian sheep: issues for conservation and breeding programs. AB - Polymorphisms of PRNP gene have been strongly correlated to the susceptibility/resistance to scrapie in sheep. Variants at the coding positions 136, 154 and 171 have been the most frequently associated to susceptibility to classical scrapie. The aim of this study was to estimate PRNP haplotype and genotype frequencies in a sample of 1400 sheep from 13 different breeds that are representative of the main production regions in Brazil. A total of four different alleles (ARR, ARQ, AHQ and VRQ) and nine genotypes were observed at different frequencies among the investigated breeds. There were distinct patterns of allelic distribution between naturalized and commercial/specialized breeds and different geographic regions. These results will influence the development and management of breeding and conservation programs and will help to develop Brazilian efforts to avoid scrapie epidemics. PMID- 21816450 TI - Trihalomethane exposures in indoor swimming pools: a level III fugacity model. AB - The potential for generation of disinfection byproducts (DBPs) in swimming pools is high due to the concentrations of chlorine required to maintain adequate disinfection, and the presence of organics introduced by the swimmers. Health Canada set guidelines for trihalomethanes (THMs) in drinking water; however, no such guideline exists for swimming pool waters. Exposure occurs through ingestion, inhalation and dermal contact in swimming pools. In this research, a multimedia model is developed to evaluate exposure concentrations of THMs in the air and water of an indoor swimming pool. THM water concentration data were obtained from 15 indoor swimming pool facilities in Quebec (Canada). A level III fugacity model is used to estimate inhalation, dermal contact and ingestion exposure doses. The results of the proposed model will be useful to perform a human health risk assessment and develop risk management strategies including developing health-based guidelines for disinfection practices and the design of ventilation system for indoor swimming pools. PMID- 21816451 TI - Modelling nitrogen transformations in waters receiving mine effluents. AB - This paper presents a biogeochemical model developed for a clarification pond receiving ammonium nitrogen rich discharge water from the Boliden concentration plant located in northern Sweden. Present knowledge about nitrogen (N) transformations in lakes is compiled in a dynamic model that calculates concentrations of the six N species (state variables) ammonium-N (N(am)), nitrate N (N(ox)), dissolved organic N in water (N(org)), N in phytoplankton (N(pp)), in macrophytes (N(mp)) and in sediment (N(sed)). It also simulates the rate of 16 N transformation processes occurring in the water column and sediment as well as water-sediment and water-atmosphere interactions. The model was programmed in the software Powersim using 2008 data, whilst validation was performed using data from 2006 to 2007. The sensitivity analysis showed that the state variables are most sensitive to changes in the coefficients related to the temperature dependence of the transformation processes. A six-year simulation of N(am) showed stable behaviour over time. The calibrated model rendered coefficients of determination (R(2)) of 0.93, 0.79 and 0.86 for N(am), N(ox) and N(org), respectively. Performance measures quantitatively expressing the deviation between modelled and measured data resulted in values close to zero, indicating a stable model structure. The simulated denitrification rate was on average five times higher than the ammonia volatilisation rate and about three times higher than the permanent burial of N(sed) and, hence, the most important process for the permanent removal of N. The model can be used to simulate possible measures to reduce the nitrogen load and, after some modification and recalibration, it can be applied at other mine sites affected by N rich effluents. PMID- 21816453 TI - Lipoprotein lipase Ser447Ter polymorphism associated with the risk of ischemic stroke: a meta-analysis. AB - INTRODUCTION: Previous studies suggested lipoprotein lipase (LPL) Ser447Ter and Asn291Ser polymorphisms were associated with the risk of ischemic heart disease, however, their effects on ischemic stroke were controversial. A meta-analysis was performed to assess the associations between these two LPL polymorphisms and the risk of ischemic stroke. METHODS: The electronic databases PubMed and Embase were used to identify relevant studies by two interviews independently. The pooled odds ratios (ORs) and weighted mean differences (WMD) with 95% confidence interval (CI) were estimated for the risk of ischemic stroke and the plasma lipids in various Ser447Ter genotypes respectively. A fixed or random effect model was selected for pooling data based on homogeneity test. RESULTS: 13 studies including 4,681 ischemic stroke cases and 8,516 controls were involved in this meta-analysis. Overall, LPL Ter447 variant was associated with a significantly reduced risk for ischemic stroke (OR=0.79, 95% CI: 0.68-0.93) both in Caucasian (OR=0.87, 95% CI: 0.77-0.97) and East-Asian (OR=0.65, 95% CI: 0.43 0.99), whereas no significant association of Ser291 variant was observed (OR=1.25, 95% CI: 0.96-1.63). The Ser447Ter polymorphism may be more important in association with the decreased risk of atherosclerotic stroke (OR=0.44, 95% CI: 0.32-0.62) which derived from significantly increased high density lipoprotein cholesterol, decreased triglyceride and total cholesterol in Ter447 carriers compared with non-carriers. CONCLUSIONS: This meta-analysis indicated that LPL Ser447Ter polymorphism was associated with a significant reduction in the risk of ischemic stroke, especially atherosclerotic stroke subtype in both Caucasian and East-Asian. PMID- 21816452 TI - Comparison of wipe materials and wetting agents for pesticide residue collection from hard surfaces. AB - Different wipe materials and wetting agents have been used to collect pesticide residues from surfaces, but little is known about their comparability. To inform the selection of a wipe for the National Children's Study, the analytical feasibility, collection efficiency, and precision of Twillwipes wetted with isopropanol (TI), Ghost Wipes (GW), and Twillwipes wetted with water (TW), were evaluated. Wipe samples were collected from stainless steel surfaces spiked with high and low concentrations of 27 insecticides, including organochlorines, organophosphates, and pyrethroids. Samples were analyzed by GC/MS/SIM. No analytical interferences were observed for any of the wipes. The mean percent collection efficiencies across all pesticides for the TI, GW, and TW were 69.3%, 31.1%, and 10.3% at the high concentration, respectively, and 55.6%, 22.5%, and 6.9% at the low concentration, respectively. The collection efficiencies of the TI were significantly greater than that of GW or TW (p<0.0001). Collection efficiency also differed significantly by pesticide (p<0.0001) and spike concentration (p<0.0001). The pooled coefficients of variation (CVs) of the collection efficiencies for the TI, GW, and TW at high concentration were 0.08, 0.17, and 0.24, respectively. The pooled CV of the collection efficiencies for the TI, GW, and TW at low concentration were 0.15, 0.19, and 0.36, respectively. The TI had significantly lower CVs than either of the other two wipes (p=0.0008). Though the TI was superior in terms of both accuracy and precision, it requires multiple preparation steps, which could lead to operational challenges in a large scale study. PMID- 21816454 TI - Physician and patient perceptions of the route of administration of venous thromboembolism prophylaxis: results from an international survey. AB - INTRODUCTION: Acceptability of a prescribed treatment regimen is crucial to its clinical success, and the route of drug administration can play an important role in determining acceptability. This international survey explored physician and patient perceptions of injectable and oral treatments, and how these perceptions affect acceptability of treatments. Findings are discussed in the context of patient acceptance of treatments for venous thromboembolism (VTE) management. METHODS: Physicians who are regular prescribers of VTE prophylaxis and a randomly selected patient population were recruited to take part in a questionnaire. Patients had to answer 23 questions and physicians gave their predictions of patients' responses. RESULTS: In total, 568 physicians and 825 patients from 5 countries took part in the survey. More patients considered injectable treatments effective than considered oral treatments effective (87% versus 76%, respectively). This trend was well predicted by the physicians (98% and 61%, respectively). Additionally, 46% of patients would accept an injectable treatment program lasting >2months (rising to 67% for life-threatening diseases), a figure underestimated by physicians (11% and 46%, respectively). Overall, 73% of patients stated they would never miss an injection, where as 54% of physicians expected patients to miss one injection in a month of therapy. CONCLUSIONS: Physicians who are regular prescribers of VTE prophylaxis underestimate patients' ability to accept injectable treatments as an alternative to oral therapy. This survey suggests that injectable treatments may be an acceptable, and often preferred, option over oral administration of therapeutic and preventive medicines. PMID- 21816455 TI - High levels of platelet-monocyte aggregates after valve replacement for aortic stenosis: relation to soluble P-selectin and P-selectin glycoprotein ligand-1 genes. AB - BACKGROUND: Calcific aortic valve stenosis is linked to atherosclerosis. The latter is associated with increased levels of platelets adhering to monocytes (PMA). OBJECTIVE: The hemodynamic impairment in symptomatic aortic valve stenosis can be abated by valve replacement. We investigated the effect of valve replacement on PMA and receptor-ligand axis P-selectin - P-selectin glycoprotein ligand-1 (PSGL-1) in severe aortic valve stenosis. PATIENTS AND METHODS: PMA, plasma P-selectin (sP-selectin) and polymorphisms within the coding region for PSGL-1 (SELPLG) were determined in 42 patients with severe aortic valve stenosis before and 4 to 8 months after valve replacement. Ten patients suffered from significant coronary artery disease and received also a coronary artery bypass graft. Thirty-four patients received a bioprosthetic valve and 8 patients who were <65 years old received a mechanical valve. RESULTS: Before the intervention, PMA levels were significantly higher in patients with aortic valve stenosis than in two control cohorts, namely healthy indviduals and 88 age- and sex-matched patients with severe atherosclerosis, but without aortic valve stenosis (p<0.001). PMA decreased after surgery, but normalized in only 3 patients, while further increases were noted in 11 patients. sP-selectin was elevated in 3 and 4 patients before and after valve replacement, respectively. sP-selectin increased significantly after surgery, but remained within the normal range. There was no correlation between changes of PMA and sP-selectin or any of the polymorphisms within SELPLG. CONCLUSIONS: Exceedingly high PMA in aortic stenosis are independent of SELPLG polymorphisms, and largely of the hemodynamic compromise caused by the stenotic valve. PMID- 21816456 TI - Role of platelet glycoprotein receptor IIIa PI(A2) and traditional risk factors in the etiology of coronary thrombosis. PMID- 21816458 TI - Neurocognitive processing of the Chinese language. PMID- 21816457 TI - Nerve growth factor induces type III collagen production in chronic allergic airway inflammation. AB - BACKGROUND: Excessive extracellular matrix deposition occurs as a result of repetitive injury-repair cycles and plays a central role in the pathogenesis of chronic inflammatory diseases, such as allergic asthma. The molecular mechanism leading to aberrant collagen deposition is not fully understood. OBJECTIVE: We sought to test the hypothesis that increased nerve growth factor (NGF) production contributes to collagen deposition in the airways during chronic allergic airway inflammation. METHODS: Antibody-blocking experiments were performed in an in vivo model for chronic allergic airway inflammation (allergic asthma), which is accompanied by matrix deposition in the subepithelial compartment of the airways, to study the profibrotic effect of NGF. The signaling pathways were delineated with in vivo and in vitro studies in primary lung fibroblasts. RESULTS: Functional blocking of NGF in chronically affected mice markedly prevented subepithelial fibrosis. Transgenic overexpression of NGF in murine airways resulted in altered airway wall morphology with increased peribronchial collagen deposition and impaired lung physiology in the absence of inflammation. NGF exerted a direct effect on collagen expression in murine lung fibroblasts, which was mainly mediated through the activation of the receptor tropomyosin-related kinase A. NGF-induced collagen expression was dependent on downstream activation of p38 mitogen-activated protein kinase independent of the TGF-beta1/mothers against decapentaplegic homolog (SMAD) pathway. CONCLUSION: The results of this study demonstrate that NGF exerts profibrotic activities in the airways by inducing type III collagen production in fibroblasts independently of TGF-beta1. PMID- 21816459 TI - Acids with an equivalent taste lead to different erosion of human dental enamel. AB - OBJECTIVES: The consumption of acidic soft drinks may lead to demineralization and softening of human dental enamel, known as dental erosion. The aims of this in vitro study were to determine: (i) if different acids with a similar sensorial acidic taste lead to different hardness loss of enamel and (ii) if the fruit acids tartaric, malic, lactic or ascorbic acid lead to less hardness loss of enamel than citric or phosphoric acid when their concentration in solution is based on an equivalent sensorial acidic taste. METHODS: Enamel samples of non erupted human third molars were treated with acidic solutions of tartaric (TA), malic (MA), lactic (LA), ascorbic (AA), phosphoric (PA) and citric (CA) acids with a concentration that gave an equivalent sensorial acidic taste. The acidic solutions were characterized by pH value and titratable acidity. Atomic force microscopy (AFM) based nanoindentation was used to study the nano mechanical properties and scanning electron microscopy (SEM) was used to study the morphology of the treated enamel samples and the untreated control areas, respectively. RESULTS: The investigated acids fell into two groups. The nano hardnesses of MA, TA and CA treated enamel samples (group I) were statistically significantly greater (p<0.05) than the nano hardnesses of PA, AA and LA treated enamel samples (group II). Within each group the nano hardness was not statistically significantly different (p>0.05). The SEM micrographs showed different etch prism morphologies depending on the acid used. SIGNIFICANCE: In vitro, the acids investigated led to different erosion effects on human dental enamel, despite their equivalent sensorial acidic taste. This has not been reported previously. PMID- 21816460 TI - The influence of chemical structure on the properties in methacrylate-based dentin adhesives. AB - OBJECTIVES: The objective of this study was to investigate the influence of the chemical structure of methacrylate monomers used in dentin adhesives on degree of conversion (DC), water sorption, and dynamic mechanical properties. MATERIALS AND METHODS: Experimental adhesives containing 2,2-bis[4-(2-hydroxy-3 methacryloxypropoxy) phenyl]-propane (BisGMA), 2-hydroxyethyl methacrylate (HEMA), and co-monomer, 30/45/25 (w/w) were photo-polymerized. Ethyleneglycol dimethacrylate (EGDM), diethyleneglycol dimethacrylate (DEGDM), triethyleneglycol dimethacrylate (TEGDMA), 1,3-glycerol dimethacrylate (GDM), and glycerol trimethacrylate (GTM) were used as a co-monomer. The adhesives were characterized with regard to DC, water sorption, and dynamic mechanical analysis and compared to control adhesive [HEMA/BisGMA, 45/55 (w/w)]. RESULTS: DC and water sorption increased with an increase in the number of ethylene glycol units in the monomer. Experimental adhesive containing GDM showed significantly higher storage moduli (p<0.05) in both dry and wet samples than experimental adhesives containing EGDM or DEGDM. The rubbery moduli of adhesives containing GDM and GTM were found to be significantly greater (p<0.05) than that of the control. Adhesives containing GTM exhibited the widest tandelta curves, indicating the greatest structural heterogeneity. SIGNIFICANCE: The hydrophilicity, functionality and size of monomers in dentin adhesives affected the water sorption, solubility, crosslink density and heterogeneity of the polymer network. The experimental adhesives containing GDM and GTM showed higher rubbery moduli, indicating higher crosslink density accompanied by a decrease in the homogeneity of the polymer network structure. PMID- 21816461 TI - Zirconia-hydroxyapatite composite material with micro porous structure. AB - OBJECTIVES: Titanium plates and apatite blocks are commonly used for restoring large osseous defects in dental and orthopedic surgery. However, several cases of allergies against titanium have been recently reported. Also, sintered apatite block does not possess sufficient mechanical strength. In this study, we attempted to fabricate a composite material that has mechanical properties similar to biocortical bone and high bioaffinity by compounding hydroxyapatite (HAp) with the base material zirconia (ZrO(2)), which possesses high mechanical properties and low toxicity toward living organisms. METHODS: After mixing the raw material powders at several different ZrO(2)/HAp mixing ratios, the material was compressed in a metal mold (8 mm in diameter) at 5 MPa. Subsequently, it was sintered for 5 h at 1500 degrees C to obtain the ZrO(2)/HAp composite. The mechanical property and biocompatibility of materials were investigated. Furthermore, osteoconductivity of materials was investigated by animal studies. RESULTS: A composite material with a minute porous structure was successfully created using ZrO(2)/HAp powders, having different particle sizes, as the starting material. The material also showed high protein adsorption and a favorable cellular affinity. When the mixing ratio was ZrO(2)/HAp=70/30, the strength was equal to cortical bone. Furthermore, in vivo experiments confirmed its high osteoconductivity. SIGNIFICANCE: The composite material had strength similar to biocortical bones with high cell and tissue affinities by compounding ZrO(2) and HAp. The ZrO(2)/HAp composite material having micro porous structure would be a promising bone restorative material. PMID- 21816463 TI - Combined use of decellularized allogeneic artery conduits with autologous transdifferentiated adipose-derived stem cells for facial nerve regeneration in rats. AB - Natural biological conduits containing seed cells have been widely used as an alternative strategy for nerve gap reconstruction to replace traditional nerve autograft techniques. The purpose of this study was to investigate the effects of a decellularized allogeneic artery conduit containing autologous transdifferentiated adipose-derived stem cells (dADSCs) on an 8-mm facial nerve branch lesion in a rat model. After 8 weeks, functional evaluation of vibrissae movements and electrophysiological assessment, retrograde labeling of facial motoneurons and morphological analysis of regenerated nerves were performed to assess nerve regeneration. The transected nerves reconstructed with dADSC-seeded artery conduits achieved satisfying regenerative outcomes associated with morphological and functional improvements which approached those achieved with Schwann cell (SC)-seeded artery conduits, and superior to those achieved with artery conduits alone or ADSC-seeded artery conduits, but inferior to those achieved with nerve autografts. Besides, numerous transplanted PKH26-labeled dADSCs maintained their acquired SC-phenotype and myelin sheath-forming capacity inside decellularized artery conduits and were involved in the process of axonal regeneration and remyelination. Collectively, our combined use of decellularized allogeneic artery conduits with autologous dADSCs certainly showed beneficial effects on nerve regeneration and functional restoration, and thus represents an alternative approach for the reconstruction of peripheral facial nerve defects. PMID- 21816462 TI - The ROS scavenging and renal protective effects of pH-responsive nitroxide radical-containing nanoparticles. AB - The ultimate objective of nanoparticle-based therapy is to functionalize nanomedicines in a micro-disease environment without any side effects. Here, we reveal that our pH-responsive nitroxide radical-containing nanoparticles (RNP(pH)) disintegrate within the renal acidic lesion and act as scavengers of reactive oxygen species (ROS), leading to a relief of acute kidney injury (AKI). RNP(pH) was prepared using amphiphilic block copolymers possessing 2,2,6,6 tetramethylpiperidine-N-oxyl (TEMPO) moieties via amine linkage as a side chain of the hydrophobic segment. The self-assembled RNP(pH) disintegrated at pH below 7.0 because of a protonation of the amino groups in the hydrophobic core of the nanoparticles, thereby resulting in an improvement in ROS scavenging activity. Using a renal ischemia-reperfusion AKI model in mice, the therapeutic effect of RNP(pH) on ROS damage was evaluated. Unlike the RNP without pH-triggered disintegration (RNP(Non-pH)), the RNP(pH) showed extremely high ROS scavenging activity and renal protective effects. It is interesting to note that the side effect of nitroxide radicals was markedly suppressed due to the compartmentalization of nitroxide radicals in the core of RNP(pH) in untargeted area. The morphology changes in RNP(pH) were confirmed by analyzing electron spin resonance spectra, and these findings provide the evidence of the real therapeutic effect of the environment-sensitive specific disintegration of nanoparticles in vivo. PMID- 21816464 TI - Herceptin functionalized polyhedral oligomeric silsesquioxane - conjugated oligomers - silica/iron oxide nanoparticles for tumor cell sorting and detection. AB - Sorting and detection of circulating tumor cells (CTC) in peripheral blood as an efficient and non-invasive method to diagnose cancer have recently attracted much attention. In this article, we developed a multiply-engineered nanoparticle system for CTC sorting and detection, which consists of (1) conjugated oligomer (CO) as fluorescence signal source, (2) polyhedral oligomeric silsesquioxanes (POSS) scaffold for CO localization for better fluorescent effects, (3) silica nanoparticles (SiNPs) as formulation matrix of the POSS containing CO, (4) iron oxide (IO) layer on the silica nanoparticles (IO-SiNPs) for magnetic collection, and (5) herceptin surface functionalization of the IO-SiNPs to target cancer cells of HER2 overexpression. Such a multiply-engineered structure can be used for either traditional immunomagnetic methods or microfluidic devices for CTC sorting and detection. PMID- 21816465 TI - Engineering vessel-like networks within multicellular fibrin-based constructs. AB - Sufficient vascularization in engineered tissues can be achieved through coordinated application of improved biomaterial systems with proper cell types. In this study, we employed 3D fibrin gels alone or in combination with the synthetic poly(l-lactic acid) (PLLA)/polylactic-glycolic acid (PLGA) sponges to support in-vitro construct vascularization and to enhance neovascularization upon implantation. Two multicellular assays were embedded in these constructs: (a) co culture of endothelial (EC) and fibroblast cells, and (b) a tri-culture combination of ECs, fibroblasts and tissue specific skeletal myoblast cells. In vitro vessel network formation was examined under advanced confocal microscopy in various time points from cell seeding. Vessel network maturity levels and morphology were found to be highly regulated by fibrinogen concentrations in vitro. Combination of PLLA/PLGA sponges with fibrin matrices provided added mechanical strength and featured highly mature vessels-like networks. Implantation studies revealed that the implanted ECs developed into 3D interconnected vessel-like networks in-vivo. The PLLA/PLGA scaffold proved to be a key stimulator of neovascularization and perfusion of implanted grafts. Our findings demonstrate that complex biomaterial platform involving fibrin and PLLA/PLGA synthetic scaffold provide a way to enhancing vascularization in-vitro and in-vivo. PMID- 21816466 TI - Dual use of amphiphilic macromolecules as cholesterol efflux triggers and inhibitors of macrophage athero-inflammation. AB - Activated vascular wall macrophages can rapidly internalize modified lipoproteins and escalate the growth of atherosclerotic plaques. This article proposes a biomaterials-based therapeutic intervention for depletion of non-regulated cholesterol accumulation and inhibition of inflammation of macrophages. Macromolecules with high scavenger receptor (SR)-binding activity were investigated for SR-mediated delivery of agonists to cholesterol-trafficking nuclear liver-X receptors. From a diverse feature space of a family of amphiphilic macromolecules of linear and aromatic mucic acid backbones modified with varied aliphatic chains and conjugated with differentially branched poly(ethylene glycol), a key molecule (carboxyl-terminated, C12-derivatized, linear mucic acid backbone) was selected for its ability to preferentially bind scavenger receptor A (SR-A) as the key target. At a basal level, this macromolecule suppressed the pro-inflammatory signaling of activated THP-1 macrophages while competitively lowering oxLDL uptake in vitro through scavenger receptor SRA-1 targeting. To further deplete intracellular cholesterol, the core macromolecule structure was exploited to solubilize a hydrophobic small molecule agonist for nuclear Liver-X Receptors, which regulate the efflux of intracellular cholesterol. The macromolecule-encapsulated agonist system was found to reduce oxLDL accumulation by 88% in vitro in comparison to controls. in vivo studies were designed to release the macromolecules (with or without encapsulated agonist) to injured carotid arteries within Sprague Dawley rats fed a high fat diet, conditions that yield enhanced cholesterol accumulation and macrophage recruitment. The macromolecules lowered intimal levels of accumulated cholesterol (50% for macromolecule alone; 70% for macromolecule-encapsulated agonist) and inhibited macrophage retention (92% for macromolecule; 96% for macromolecule encapsulated agonist; 4 days) relative to non-treated controls. Thus, this study highlights the promise of designing bioactive macromolecule therapeutics based on scavenger receptor targeting, for potential management of vascular arterial disease. PMID- 21816467 TI - A pH-responsive mesoporous silica nanoparticles-based multi-drug delivery system for overcoming multi-drug resistance. AB - A type of pH-responsive nano multi-drug delivery systems (nano-MDDSs) with uniform particle size (100 +/- 13 nm) and excellent monodispersity was developed by in situ co-self-assembly among water-insoluble anti-cancer drug (doxorubicin, DOX), surfactant micelles (CTAB) as chemosensitiver and silicon species forming drugs/surfactant micelles-co-loaded mesoporous silica nanoparticles (drugs@micelles@MSNs or DOX@CTAB@MSNs) via a micelles-MSNs self-assembly mechanism. The nano-MDDS DOX@CTAB@MSNs had a highly precise pH-responsive drug release behavior both in vitro and in vivo, and exhibited high drug efficiencies against drug-resistant MCF-7/ADR cells as well as drug-sensitive MCF-7 cells by the MSNs-mediated transmembrane delivery, the sustained drug release and the high anti-cancer and multi-drug resistance (MDR)-overcoming efficiencies. The MDR overcoming mechanism was proved to be a synergistic cell cycle arrest/apoptosis inducing effect resulted from the chemosensitization of the surfactant CTAB. These results demonstrated a very promising nano-MDDS for the pH-responsive controlled drug release and the cancer MDR overcoming. PMID- 21816468 TI - Genistein upregulates placental corticotropin-releasing hormone expression in lipopolysaccharide-sensitized mice. AB - Genistein is a phytoestrogen isolated from soya beans. Although soy products are staple food of Asian, the potential effect of genistein on reproduction has not been fully addressed. Lipopolysaccharide (LPS) is an endotoxin found in the cell membrane of gram-negative bacteria. It may cause inflammation and other immune responses. Previous study has shown that LPS may induce pre-mature birth in rodents. In the present study, effect of genistein on LPS-induced preterm birth was investigated. Pregnant ICR mice were gavaged with genistein at 40, 200 and 400 mg/kg body weight/day during E13 to E16. LPS was injected i.p. on E16.5 and the animals were sacrificed at E17. Compared to the control group, an increased incidence of early delivery was observed in the pooled mice under LPS treatment. A rising trend of incidence was also demonstrated dose-dependently with genistein co-treatment. Real-time RT-PCR indicated that the placental crh expression was highly induced by the co-administration of 400 mg/kg genistein and LPS. By contrast, neither genistein nor LPS alone could alter the expression. Increased plasma CRH concentration was also seen in the co-treatment groups. In addition, the mRNA expression of placental CRH-binding protein and plasma progesterone concentration were reduced in these groups. These results indicated that genistein might exacerbate the undesirable effect of LPS on pregnant mice by altering hormonal regulations. PMID- 21816469 TI - Expression of HLA-G1 at the placental interface of HIV-1 infected pregnant women and vertical transmission of HIV. AB - OBJECTIVES: The ability of Human Leucocyte Antigen-G (HLA-G) to inhibit the cytolytic effect to immunocompetent cell types, suggests that HLA-G has an immunomodulatory role. In view of this concept the objective of the study was to assess whether the Major Histocompatibility Complex -coded molecule HLA-G mRNA is a risk factor at the placental barrier in HIV-1 positive pregnant women. DESIGN: Placental HLA-G1 levels in HIV-1 infected mothers and viral loads in both mothers and their babies were performed on fifty-five participants. METHODS: Synthesis of complementary deoxyribose nucleic acid (cDNA) was performed using ribose nucleic acid (RNA) extracted from placental tissue samples. Amplification of cDNA using specifically designed primers complementary to the full length HLA-G1 isoform was quantified using real time-polymerase chain reaction (RT-PCR). Viral load assays (Amplicor Version 1.5, Roche Diagnostics) were performed on all plasma samples. RESULTS: HLA-G1 primers detected the full length isoform HLA-G1 PCR product at 86.5 degrees C. Logistic regression calculations indicated that the risk of babies becoming infected increased by 1.3 with every 1 unit increase in HLA-G1 expression. Female babies were 3.7 times more likely to become infected than male. There was a positive correlation between mothers' log viral load and transmission of infection to the baby (p = 0.047; 95%CI 1.029-11.499). CONCLUSION: Maternal viral load was a strong predictor of viral transmission. Placental HLA-G1 expression was up-regulated 3.95 times more in placentas of HIV 1 infected mothers with infected babies when compared to uninfected babies. PMID- 21816470 TI - Expression, adverse prognostic significance and therapeutic small molecule inhibition of Polo-like kinase 1 in multiple myeloma. AB - The amplified myeloma centrosome has been identified as a therapeutic target. The present study explored the expression and prognostic significance of the centrosome-associated protein PLK1 in myeloma and the effect of BI 2536, a potent and selective inhibitor of PLK1, on myeloma cells. High plasma cell expression of PLK1 protein in myeloma patient bone marrow biopsies is an independent adverse prognostic factor (HR=2.3, p=0.003 unadjusted; HR=1.9, p=0.03 in multivariable model). BI 2536 inhibits myeloma cell lines at nanomolar concentrations, and is therapeutic for xenografts in NOD/SCID mice. PLK1 inhibition is a potential new strategy for the treatment of multiple myeloma. PMID- 21816471 TI - A case series of marijuana exposures in pediatric patients less than 5 years of age. PMID- 21816472 TI - Children exposed to child maltreatment and intimate partner violence: a study of co-occurrence among Hong Kong Chinese families. AB - OBJECTIVE: This study assessed the co-occurrence of child maltreatment and intimate partner violence (IPV) and examined the association between them. METHOD: The cross-sectional study recruited a population-based sample of 1,094 children aged 12-17 years in Hong Kong. Structured questionnaires were used to collect data from the children. The prevalence of occurrence of child abuse and neglect by parents and exposure to IPV in both the past year and lifetime was examined, and their correlates were assessed using univariate and multivariate logistic regression. RESULTS: The results show that 26% and 14.6% of child participants had been exposed to IPV physical assault, and 44.4% and 22.6% had been subjected to a parent's corporal punishment or to physical maltreatment from a parent in their lifetime and the year preceding the study, respectively. Among those families characterized by IPV, 54.4% and 46.5% were involved in child physical maltreatment over the child's lifetime and in the preceding year, respectively. CONCLUSIONS: Multivariate logistic regression analyses revealed that children exposed to IPV were at higher risk of being victims of neglect, corporal punishment, and physical maltreatment or severe physical maltreatment by their parents than children who were not exposed to IPV, even when child and parent demographic factors were controlled for. PRACTICAL IMPLICATIONS: The higher risk of child physical maltreatment associated with IPV highlights the need for an integrated assessment to screen for the presence of multiple forms of family violence within the family, and for intervention to assess effective responses to both IPV and child maltreatment by child protective service workers and domestic violence agencies. PMID- 21816473 TI - Prevalence and correlates of multiple victimization in a nation-wide adolescent sample. AB - OBJECTIVES: Adolescents often experience different types of victimization across a specified period of time in different situations. These multiple victimization experiences can have a number of deleterious effects on psychosocial well-being. To expand on research gathered primarily from US samples, the current study estimated the prevalence of multiple victimization in a nationally representative sample of Canadian adolescents. We also expanded on past research by adopting an ecological approach to identify correlates of multiple victimization. METHODS: Cross-sectional data from the 2000-2001 cycle of the National Longitudinal Survey of Children and Youth (NLSCY) were used to estimate the prevalence of multiple victimization (verbal harassment, threat of and actual physical assault, school social exclusion, discrimination) in 1,036 13-16 year olds. We also examined household (e.g., parental education), family (e.g., parenting practices), and adolescent (e.g., friendship quality) correlates of multiple victimization for the whole sample and separately by sex. RESULTS: Among the 6 in 10 adolescents who reported at least 1 victimization experience, 30.5% reported 2 types of victimization whereas 23.7% reported 3 or more types. There was an increased probability of multiple victimization (2 or more types) in adolescents who reported greater parental rejection, who engaged in more frequent out-of-school activities, and who experienced non-victimization adversity. The probability decreased if adolescents reported greater friendship quality. CONCLUSIONS: The clustering of different types of victimization is common among adolescents. For both males and females, a difficult parent-child relationship characterized as rejecting is important when considering risk for multiple victimization, as is the adolescent's functioning outside of the home in the context of friendship quality and involvement in out-of-school activities. Non-victimization adversity (e.g., death of a loved one) also emerged as a significant multiple victimization correlate. PRACTICE IMPLICATIONS: Non-physically invasive types of victimization (although adolescents also endorsed physical assault) are a reality for a number of adolescents. As such, we need to inquire about such experiences as school social exclusion, discrimination, and verbal threats in applied contexts. Moreover, in order to better identify adolescents who may be vulnerable to multiple forms of victimization, we need to adopt an ecological approach that considers individual, family, and household functioning. PMID- 21816475 TI - Identifying and predicting problem behavior trajectories among pre-school children investigated for child abuse and neglect. AB - OBJECTIVE: Young children involved with child welfare services are at high risk for behavior problems. This study aims to identify externalizing behavior paths that preschoolers in this high-risk population follow over a 6 year period, and the predictors of membership in normative and problematic pathways. METHODS: Using data from the National Study of Child and Adolescent Well-being (NSCAW), the sample included 246 4-year-olds who remained home after investigation. Latent class growth analysis (LCGA) was used to estimate the number, size, and shape of subgroups of preschoolers following distinct behavioral pathways. Early predictors of membership in the resulting groups were then examined. RESULTS: Four groups of preschool children following distinct behavior trajectories over 6 years were identified. Weighted results show that more than half (61%) of the children followed a low/normal problem behavior trajectory while just over one tenth (12%) were on a persistent high trajectory, remaining in the clinical range throughout the study. Improving (23%) and worsening (4%) problem behavior groups were also identified. Internalizing problems, attention problems, child ethnicity, and maltreatment type reported at age 4 predicted membership in the trajectory groups. CONCLUSIONS: Internalizing behavior problems and maltreatment type may distinguish preschool children who are more likely to experience worsening or persistent problematic externalizing behaviors from those likely to follow a normal behavior trajectory. PRACTICE IMPLICATIONS: Identifying early indicators of externalizing behavior problems and addressing them with evidence based interventions to reduce negative behaviors may avert long-term negative outcomes. PMID- 21816474 TI - Traumatic and stressful events in early childhood: can treatment help those at highest risk? AB - OBJECTIVE: This study involves a reanalysis of data from a randomized controlled trial to examine whether child-parent psychotherapy (CPP), an empirically based treatment focusing on the parent-child relationship as the vehicle for child improvement, is efficacious for children who experienced multiple traumatic and stressful life events (TSEs). METHODS: Participants comprised 75 preschool-aged children and their mothers referred to treatment following the child's exposure to domestic violence. Dyads were randomly assigned to CPP or to a comparison group that received monthly case management plus referrals to community services and were assessed at intake, posttest, and 6-month follow-up. Treatment effectiveness was examined by level of child TSE risk exposure (<4 risks versus 4+ TSEs). RESULTS: For children in the 4+ risk group, those who received CPP showed significantly greater improvements in PTSD and depression symptoms, PTSD diagnosis, number of co-occurring diagnoses, and behavior problems compared to those in the comparison group. CPP children with <4 risks showed greater improvements in symptoms of PTSD than those in the comparison group. Mothers of children with 4+ TSEs in the CPP group showed greater reductions in symptoms of PTSD and depression than those randomized to the comparison condition. Analyses of 6-month follow-up data suggest improvements were maintained for the high risk group. CONCLUSIONS: The data provide evidence that CPP is effective in improving outcomes for children who experienced four or more TSEs and had positive effects for their mothers as well. PRACTICE IMPLICATIONS: Numerous studies show that exposure to childhood trauma and adversity has negative consequences for later physical and mental health, but few interventions have been specifically evaluated to determine their effectiveness for children who experienced multiple TSEs. The findings suggest that including the parent as an integral participant in the child's treatment may be particularly effective in the treatment of young children exposed to multiple risks. PMID- 21816476 TI - Comparing responses in the performance of sentinel populations of stoneflies (Plecoptera) and slimy sculpin (Cottus cognatus) exposed to enriching effluents. AB - Programs in Canada that assess the effects of wastewater discharges on organisms, such as Environmental Effects Monitoring (EEM), primarily focus on fish populations and benthic invertebrate communities. Although these methods are widely accepted, there are many situations where fish monitoring is difficult and benthic community data is difficult to interpret; in these instances alternative approaches should be used. There are, however, few alternative methods available. One potential alternative is to use invertebrate population endpoints to determine effects in the receiving environment. In this study we examined effects of sewage and pulp mill effluents in the Saint John River, New Brunswick, on two stonefly genera (Plecoptera, Perlidae, Acroneuria spp. and Paragnetina spp.) and compared the responses to those of a small-bodied fish, the slimy sculpin (Cottus cognatus). Stonefly measurements included condition, developmental stage, gonad weight, and size upstream and downstream of sewage and a pulp mill discharge. Condition, developmental stage, and absolute gonad weight were greater in Paragnetina spp. downstream of the sewage discharge. Acroneuria spp. showed persistence of the late developmental stage downstream of the sewage inputs. Slimy sculpin exposed to sewage effluents also showed increased condition, but the impacts downstream of the pulp mill effluent were inconsistent in both sculpin and Paragnetina spp. Our findings suggest that stonefly populations and slimy sculpin respond to effluents in similar ways and that the responses of large long-lived invertebrate populations, such as stoneflies, may be a viable alternative to fish population monitoring in environmental assessments of point source discharges. PMID- 21816477 TI - Pitavastatin calcium: clinical review of a new antihyperlipidemic medication. AB - BACKGROUND: Pitavastatin calcium is a new addition to the class of 3-hydroxy-3 methylglutaryl coenzyme A reductase inhibitors ("statins") approved for use in the United States for the treatment of primary hyperlipidemia and mixed dyslipidemia. OBJECTIVE: The purpose of this review was to evaluate the literature related to the medicinal chemistry, pharmacology, pharmacokinetic properties, clinical efficacy, and tolerability of pitavastatin in the treatment of hyperlipidemia. METHODS: A search of MEDLINE, EMBASE, and the Journal Archive for English-language literature was conducted for articles published through January 2011 using the following search terms: itavastatin, Livalo, nisvastatin, NK 104, and pitavastatin. Articles were reviewed if they pertained to the clinical efficacy, pharmacology, pharmacokinetic properties, or tolerability of pitavastatin. Clinical trials were systematically included in the analysis of clinical efficacy if they used a randomized design to study the effects of the drug on hyperlipidemia, hypercholesterolemia, or heart disease. Trials were excluded if they did not signify the statin used, did not pertain to clinical efficacy, or enrolled <20 patients. RESULTS: A total of 16 studies were identified and reviewed for clinical efficacy. Based on findings from pharmacokinetic studies, pitavastatin may be given at any time of the day, with or without food. The drug had a mean plasma elimination t(1/2) of 12 hours, is expected to be associated with minimal drug-drug interactions because it is not metabolized by the cytochrome P450 3A4 isozyme, and is primarily excreted unchanged in the bile with little renal elimination. Clinical trials described the effects of pitavastatin on cholesterol, high-sensitivity C-reactive protein (hs-CRP), and progression of atherosclerosis. Pitavastatin at doses of 1 to 4 mg/d was reported to be associated with reductions in LDL-C of 38% to 44% and in triglycerides of 14% to 22%, and with increases in HDL-C of 5% to 8% (all, P < 0.05). Overall, the effect of pitavastatin on cholesterol was comparable to those of atorvastatin and simvastatin at low to intermediate doses. Studies on the effects of pitavastatin on cardiovascular outcomes were lacking. The adverse events (AE) profile of pitavastatin compared favorably with those of other available statins. AEs included gastrointestinal symptoms (0.7%-2.2%), myopathies (0.3%-1.1%), and elevated hepatic enzyme concentrations (0.0%-8.8%). CONCLUSIONS: Based on the findings from previously published clinical trials, pitavastatin is an effective lipid lowering agent and is another therapeutic option of currently available statins. PMID- 21816479 TI - Matching consequences to behavior: implications of failing to distinguish between noncompliance and nonresponsivity. AB - Neither punitive nor therapeutic approaches alone are effective at addressing the dual public health and public safety concerns associated with managing criminal behavior perpetrated by people who have psychiatric and substance use disorders. The optimal solution may instead require the integration of both criminal justice supervision and treatment. Using problem-solving courts (PSCs) as a model, we focus on one dimension of this integrated approach, distinguishing between behavior that stems from willful noncompliance with supervision and behavior that results from nonresponsivity to treatment. First, we discuss the public health and public safety consequences of using singular approaches to address the criminal behavior of this population. We then present lessons learned from PSCs that distinguish between noncompliant and nonresponsive behaviors in making treatment and supervision decisions. Finally, we consider how the concepts of nonresponsivity and noncompliance may be extended, via policy, to probation and parole settings as well as mental health and substance abuse treatment services outside the criminal justice setting in order to enhance public health and safety. PMID- 21816478 TI - Comparison of antiplatelet effect and tolerability of clopidogrel resinate with clopidogrel bisulfate in patients with coronary heart disease (CHD) or CHD equivalent risks: a phase IV, prospective, double-dummy, parallel-group, 4-week noninferiority trial. AB - BACKGROUND: Clopidogrel resinate is a resinate complex of (+)-clopidogrel optical isomer, wherein the (+)-clopidogrel isomer binds to a water-soluble cation exchange resin via sulfonic acid groups. It was approved by the Korean Food and Drug Administration on the basis of a Phase I study that demonstrated the bioequivalence of clopidogrel resinate and clopidogrel bisulfate. However, there are no available data regarding efficacy and tolerability in patients with vascular disease. OBJECTIVE: The goal of this study was to investigate the antiplatelet efficacy and tolerability of clopidogrel resinate in patients with coronary heart disease (CHD) or CHD-equivalent risks. METHODS: This study was a Phase IV, randomized, double-blind, double-dummy, parallel-group, noninferiority trial. We prospectively recruited patients in 10 centers between March 2008 and July 2008. Patients who had documented CHD or CHD-equivalent risks were randomly assigned to 1 of 3 groups: group A, aspirin (100 mg) + clopidogrel bisulfate placebo + clopidogrel resinate placebo; group B, aspirin (100 mg) + clopidogrel bisulfate placebo + clopidogrel resinate (75 mg); or group C, aspirin (100 mg) + clopidogrel bisulfate (75 mg) + clopidogrel resinate placebo. The primary outcome was the percent P2Y(12) inhibition after medication, assessed by using a point-of care assay. If the 1-sided 90% upper confidence limit for the difference was less than the prespecified delta value (-5.7), clopidogrel resinate would be considered noninferior to clopidogrel bisulfate. The secondary outcome, the prevalence of adverse events (AEs) associated with study medications, was assessed at each visit by direct interview. RESULTS: A total of 314 patients (mean [SD] age, 62.2 [9.0] years; male 63.7%; weight, 67.3 [13.6] kg [range, 45 102 kg]; all Asian) were enrolled, and 287 patients finished the study (group A, n = 97; group B, n = 90; and group C, n = 100). Eight patients took no study medications and were excluded from the tolerability and efficacy analyses. Nineteen patients discontinued the study because of protocol violation (n = 15), adverse events (n = 3), or voluntary withdrawal (n = 1) and were excluded from the efficacy analysis. There were no significant differences in baseline clinical characteristics among the groups except for the frequency of a history of CHD (group A, 85.4%; group B, 73.0%; and group C, 88.3%; P = 0.01). Patients treated with either type of clopidogrel showed significant inhibition (mean [SD]) of P2Y(12) (group A, -5.9% [15.1%]; group B, 23.4% [21.9%]; and group C, 19.5% [23.8%]; P < 0.001). Differences between clopidogrel resinate and clopidogrel bisulfate in the inhibition of P2Y(12) did not exceed the predetermined value for inferiority (P for noninferiority, 0.02; 90% CI, -0.9 to 10.3). In the tolerability analysis, there was no mortality during the study period and no significant differences between groups in the frequency of AEs and serious AEs (AEs: group A, 33.0%; group B, 26.0%; and group C, 23.3% [P = 0.27]; serious AEs: group A, 1.0%; group B, 3.0%; and group C, 1.0% [P = 0.42]). One patient in group B underwent coronary stent implantation for treatment of stable angina. CONCLUSIONS: In this small, selected Asian patient population, differences in the platelet inhibition efficacies of clopidogrel resinate and clopidogrel bisulfate did not exceed the predetermined limits for noninferiority. The differences in tolerability between the 2 drugs did not reach statistical significance. PMID- 21816480 TI - Perceiving onset clusters in infancy. AB - By 9-months infants are sensitive to native-language sound combinations. Our studies show that while younger infants discriminate clusters, they are not sensitive to differences in statistical frequency. Thus, the emergence of phonotactic knowledge is driven by experience with the frequency of occurrence of the sound combinations in one's language. PMID- 21816481 TI - Prevalence and features of panic disorder and comparison to posttraumatic stress disorder in VA primary care. AB - OBJECTIVE: Although panic disorder (PD) is a highly prevalent condition in both community and community primary care settings, little is known about PD in veteran populations, especially in comparison to posttraumatic stress disorder (PTSD). The present study investigated prevalence, comorbidity, physical and mental health impairment, and health care utilization of veterans with PD and PTSD. METHOD: A total of 884 veterans participated in a cross-sectional investigation in primary care clinics in four Veteran Affairs Medical Centers (VAMCs). Participants completed diagnostic interviews and self-report questionnaires, and a chart review was completed to assess their VAMC health care utilization. RESULTS: A large number of veterans (8.3%) met the diagnostic criteria for PD and reported significantly more severe physical health impairment (pain, general health), mental health impairment (emotional well-being, role limitations) and social functioning than veterans without PD. Veterans with PD also had increased health care utilization for mental health. Further, PD was highly comorbid with PTSD, with similar symptoms across all measures. CONCLUSIONS: These findings demonstrate the high prevalence and severe impairment associated with PD in veterans and highlight the need for improved recognition, assessment and specialized treatments for PD in VAMCs and other care settings. PMID- 21816482 TI - Factors affecting psychiatric inpatient hospitalization from a psychiatric emergency service. AB - OBJECTIVE: As a gateway to the mental health system, psychiatric emergency services (PES) are charged with assessing a heterogeneous array of short-term and long-term psychiatric crises. However, few studies have examined factors associated with inpatient psychiatric hospitalization following PES in a racially diverse sample. We examine the demographic, service use and clinical factors associated with inpatient hospitalization and differences in predisposing factors by race and ethnicity. METHOD: Three months of consecutive admissions to San Francisco's only 24-h PES (N = 1,305) were reviewed. Logistic regression was used to estimate the associations between demographic, service use, and clinical factors and inpatient psychiatric hospitalization. We then estimated separate models for Asians, Blacks, Latinos and Whites. RESULTS: Clinical severity was a consistent predictor of hospitalization. However, age, gender, race/ethnicity, homelessness and employment status were all significant related to hospitalization. Alcohol and drug use were associated with lower probability of inpatient admission, however specific substances appear particularly salient for different racial/ethnic groups. DISCUSSION: While clinical characteristics played an essential role in disposition decisions, these results point to the importance of factors external to PES. Individual and community factors that affect use of psychiatric emergency services merit additional focused attention. PMID- 21816483 TI - Psychiatric assessment of children with nonsyndromic cleft lip and palate. AB - OBJECTIVE: The aim of the study was to determine whether children with nonsyndromic cleft lip and palate (NSCLP) are more likely to be diagnosed with psychiatric disorders and whether cleft-related factors are related to psychopathology. METHOD: Twenty children from 6 to 16 years of age with NSCLP, attending the Plastic, Reconstructive and Aesthetic Surgery Department of Cerrahpasa Medical Faculty between January and October 2010, were included as the case group. Forty healthy children who were matched on age and sex with the case group served as controls. Children were assessed by psychiatric interviews and scales. RESULTS: Social anxiety disorder (SAD) (P=.003) and major depressive disorder (MDD) (P=.010) were more prevalent in children with NSCLP. The severity of dentofacial (P=.035) and cleft lip nose deformities (P=.002), appearance and competence of the lip (P=.008), dental alignment (P=.002), feeding (P=.044) and articulation problems (P<.001) were associated with clinical global functioning. CONCLUSIONS: Children with NSCLP are at risk of developing psychopathology, especially SAD and MDD. The above cleft-related factors and articulation problems may be the target of interventions to prevent and treat psychiatric disorders in these children. PMID- 21816484 TI - Ruminative response in clinical patients with major depressive disorder, bipolar disorder, and anxiety disorders. AB - BACKGROUND: There is a growing interest in the transdiagnostic trait of rumination. However, few studies have directly examined the ruminative response in the diagnosis of disorders other than major depression, such as anxiety disorders and bipolar disorders. Even fewer studies have done so in a large, clinical sample. METHOD: Patients with major depressive disorder (MDD), bipolar disorder (BPD), panic disorder with/without agoraphobia (PD), and generalized anxiety disorder or obsessive-compulsive disorder (GAD/OCD) were compared using the Ruminative Response Scale (RRS), Hamilton Rating Scale for Depression (HAM D), and Hamilton Rating Scale for Anxiety (HAM-A). RESULTS: The PD group displayed the lowest levels of rumination even when depression and anxiety symptoms were treated as a covariate. The BPD group displayed higher levels of rumination than the MDD group. CONCLUSIONS: A heightened ruminative response was not only found among individuals with MDD, but also among those with BPD and GAD/OCD; this might indicate ineffective thought control. PMID- 21816485 TI - Analysis of associations for candidate genes with anxiety disorders. PMID- 21816486 TI - The use of Mood Disorder Questionnaire, Hypomania Checklist-32 and clinical predictors for screening previously unrecognised bipolar disorder in a general psychiatric setting. AB - Bipolar disorder is often unrecognised and misdiagnosed in the general psychiatric setting. This study compared the psychometric properties of the Mood Disorder Questionnaire (MDQ) and the Hypomania Checklist-32 (HCL-32), examined the clinical predictors of bipolar disorder and determined the best approach for screening previously unrecognised bipolar disorder in a general psychiatric clinic. A random sample of 340 non-psychotic outpatients with no previous diagnosis of bipolar disorder completed the MDQ and HCL-32 during their scheduled clinic visits. Mood and alcohol/substance use disorders were reassessed using a telephone-based Structured Clinical Interview for DSM-IV. We found that the HCL 32 had better psychometric performance and discriminatory capacity than the MDQ. The HCL-32's internal consistency and 4-week test-retest reliability were higher. The area under the curve was also greater than that of the MDQ at various clustering and impairment criteria. The optimal cut-off of the MDQ was co occurrence of four symptoms with omission of the impairment criterion; for the HCL-32, it was 11 affirmative responses. Multivariable logistic regression found that bipolar family history was associated with an increased risk of bipolar disorder (odds ratio=4.93). The study showed that simultaneous use of the HCL-32 and bipolar family history was the best approach for detecting previously unrecognised bipolar disorder. PMID- 21816487 TI - A laboratory study of affectivity in schizotypy: subjective and lexical analysis. AB - Affective dysfunction is a defining schizotypy feature; yet the majority of studies examining affective dysfunction have largely relied on self-report of trait affect, which reflects only one dimension of emotional experience. Emerging research has explored a second dimension, state affect, using laboratory manipulation, with most finding that schizotypal participants report experiencing less positive/more negative affect than controls. This study expands upon this topic by examining patterns of state affect in psychometrically identified schizotypy through self-report and lexical expression in reaction to emotionally valenced photos. Overall, the schizotypy group reported less positive/more negative affect across affect induction conditions. Both schizotypy and control groups' affect ratings were similar following the unpleasant stimuli; but the schizotypy group's ratings remained significantly less positive/more negative than the control group following the pleasant stimuli. This pattern suggests that the schizotypy group experienced a deficit in emotional reactivity compared to controls in pleasant situations. The schizotypy group also used a higher percentage of negative words and a lower percentage of positive words in vocalized reactions during the pleasant, but not unpleasant, affect induction condition. These results reveal a specific pattern of "in-the-moment" affective dysfunction unique to pleasant situations that is consistent across both subjective experience and lexical expression. PMID- 21816488 TI - D-lactic acid interferes with the effects of platelet activating factor on bovine neutrophils. AB - D-lactic acidosis occurs in ruminants, such as cattle, with acute ruminal acidosis caused by ingestion of excessive amounts of highly fermentable carbohydrates. Affected animals show clinical signs similar to those of septic shock, as well as acute laminitis and liver abscesses. It has been proposed that the inflammatory response and susceptibility to infection could both be caused by the inhibition of phagocytic mechanisms. To determine the effects of d-lactic acid on bovine neutrophil functions, we pretreated cells with different concentrations of D-lactic acid and measured intracellular pH using 2',7'-bis-(2 carboxyethyl)-5-(and-6)-carboxyfluorescein acetoxymethyl ester (BCECF-AM) and calcium flux using FLUO-3 AM-loaded neutrophils. Reactive oxygen species (ROS) production was measured using a luminol chemiluminescence assay, and MMP 9/gelatinase-B granule release was measured by zymography. CD11b and CD62L/l selectin expression, changes in cell shape, superoxide anion production, phagocytosis of Escherichia coli-Texas red bioparticles, and apoptosis were all measured using flow cytometry. Our results demonstrated that D-lactic acid reduced ROS production, CD11b upregulation and MMP-9 release in bovine neutrophils treated with 100 nM platelet-activating factor (PAF). D-lactic acid induced MMP-9 release and, at higher concentrations, upregulated CD11b expression, decrease L-selectin expression, and induces late apoptosis. We concluded that D-lactic acid can interfere with neutrophil functions induced by PAF, leading to reduced innate immune responses during bacterial infections. Moreover, the increase of MMP-9 release and CD11b expression induced by 10mM D lactic acid could promote an nonspecific neutrophil-dependent inflammatory reaction in cattle with acute ruminal acidosis. PMID- 21816489 TI - Acute phase protein concentrations in colostrum-deprived pigs immunized with subunit and commercial vaccines against Glasser's disease. AB - Haemophilus parasuis is the etiological agent of Glasser's disease, which is characterized by fibrinous polyserositis, polyarthritis and meningitis in pigs. This study was focused on the characterization of the acute-phase response after immunization and infection of colostrum-deprived pigs with H. parasuis serovar 5, by measuring serum concentrations of three positive acute-phase proteins (APPs) (pig major acute-phase protein pig, MAP; haptoglobin, HPG; C-reactive protein, CRP) and one negative APP (apolipoprotein A-I, ApoA-I). Six experimental groups were established: a non-immunized but infected control group (CTL); two groups immunized with either a recombinant transferrin-binding protein (Tbp) A or TbpB fragment from H. parasuis Nagasaki strain (rTbpA and rTbpB, respectively); two groups immunized with native outer membrane proteins with affinity to porcine transferrin (NPAPT), one of them inoculated intramuscularly (NPAPTim) and the other intratracheally (NPAPTit), and the last group receiving a commercially available bacterin (PG). The greatest concentrations of the three positive APPs and the lowest concentration of the negative APP were detected in CTL group, as well as in those animals belonging to rTbpA or rTbpB groups that died in response to challenge. Significant differences (P<0.005) were found in these groups when comparing challenge with the following days after it. However, no significant differences were seen for the remaining vaccinated groups (NPAPTim, NPAPTit and PG), which were effectively protected against Glasser's disease. Therefore, APPs could be used as useful biomarkers for both evaluating disease progression and determining vaccination effectiveness. PMID- 21816490 TI - Measurements of normal upper airway assessed by 3-dimensional computed tomography in Chinese children and adolescents. AB - OBJECTIVE: To establish normative data of upper airway dimensions in Chinese children and adolescents by age and sex. METHODS: CT-scans of 281 Chinese children and adolescents (140 girls, 141 boys) aged from 6 to 18 years (yr) were selected among the patients who visited in Department of Oral and Maxillofacial Surgery from September 2009 to August 2010. Child was defined as 6-12 yr, and adolescent as 13-18 yr. All the subjects were divided into 4 groups according to age as 6-9, 10-12, 13-15 and 16-18. The upper airway was divided into four distinct anatomic regions: the nasopharynx, the palatopharynx, the glossopharynx and the epiglottic region. Using 3-dimension image processing software, the minimal cross-sectional area with its sagittal diameter and transversal diameter, length and volume of upper airway segmentations were measured. RESULTS: There was no difference in all parameters of segmentations between genders in children. In adolescents the differences of airway parameters were evident between genders. Male adolescents' upper airway were bigger and longer than female's. Volumes and lengths of segmentations were increased with age in male and female respectively. CONCLUSIONS: Norms for upper airway in Chinese children and adolescents assessed by 3-D reconstruction computed tomography have been established. Volume and other dimension of upper airway are increased with age. Significant sex dimorphisms in upper airway dimension are evident in adolescents. PMID- 21816491 TI - Changes in sleep apnea after supraglottoplasty in infants with laryngomalacia. AB - OBJECTIVE: To determine the clinical and polysomnography outcomes in infants with laryngomalacia undergoing supraglottoplasty. METHODS: Infants (<1 year old) who underwent polysomnography pre- and post-supraglottoplasty at our tertiary referral center between 2003 and 2009 were reviewed retrospectively. Outcome measures included changes in stridor, sleep disordered breathing, swallowing, and polysomnography parameters before and after surgery. Pre- and postoperative distributions were compared using a Wilcoxon signed-rank test. RESULTS: 20 children met inclusion criteria. Statistically significant improvements were found in pre- to postoperative median values for apnea-hypopnea index (AHI) (median change: -6.4 points, p=0.02) and obstructive apnea index (median change: 2.9 points, p=0.01) values. Obstructive AHI, O2 saturation nadir, and percentage of sleep spent with <90% O2 saturation improved, although not significantly. Postoperative AHI scores correlated with improvements in stridor in 80% of patients. Stratification showed similar improvements in AHI after supraglottoplasty regardless of reflux treatment, secondary airway lesions, age at supraglottoplasty, or time lag between supraglottoplasty and postoperative polysomnography. Secondary airway lesions are the only potential confounders shown to have significantly better improvements in O2 nadir. While the sleep study improved in patients with AHI >5, infants with AHI <5 had worse polysomnography parameter values postoperatively. Five patients had dysphagia that resolved within one month postoperatively; otherwise, supraglottoplasty resulted in no complications. CONCLUSION: Supraglottoplasty may be an effective and safe option to improve moderate to severe obstructive sleep apnea in infants with laryngomalacia. In addition, polysomnography may be useful in infants with laryngomalacia to identify obstructive sleep apnea and/or to objectively measure outcomes after supraglottoplasty. This pilot study warrants a larger, prospective, and controlled study to validate these findings. PMID- 21816492 TI - Role of high resolution ultrasound in parotid lesions in children. AB - PURPOSE: A pictorial review of the spectrum of sonographic abnormalities of the parotid gland in children is presented. METHODS: Two pediatric radiologists performed retrospective review of medical records and imaging findings of all parotid ultrasounds performed in 298 children in the age range of 24 days to 16 years, over a five-year period. RESULTS: The lesions varied from diffuse glandular abnormalities to discrete solid and cystic lesions. Of the 298 studies reviewed, 148 (49.6%) were normal results, while 150 (50.4%) had abnormalities of parotid gland identified at ultrasonography. These included acute parotitis in 54 (36%) cases, recurrent parotitis in 12 (8%), and intra-parotid abscess in 12 (8%) cases. Among the tumors, haemangioma was the commonest, identified in 16 (10.6%) cases, followed by lymphatic malformation in 3 (2%), Hodgkin's disease 2 (1.3%) and pleomorphic adenoma (1 case). Sialadenosis was identified in 4 (2.6%) cases. Abnormality of the superficial soft tissues was also seen in 25 cases. 12 cases had a lymphatic malformation of the neck, involving the parotid, while 11 cases had a vascular lesion of the cheek, but not involving the parotids directly. CONCLUSION: High resolution ultrasound remains the first-line imaging modality for evaluation of the parotid gland. It is sensitive in detection of salivary gland abnormalities. PMID- 21816494 TI - Prevalence of patent foramen ovale and its impact on oxygen desaturation in obstructive sleep apnea. AB - BACKGROUND: A possible association between patent foramen ovale (PFO) and obstructive sleep apnea has been suggested (OSA), whereby right-to-left shunting may exacerbate the severity of nocturnal oxygen desaturation. However, the interaction between these two conditions has not been well characterised. METHODS: A case-control study was conducted to evaluate the epidemiological association between PFO and OSA. Subjects were recruited prospectively from a sleep laboratory population, and 102 OSA subjects (mean age 51.5 +/- 13 years) were compared to 50 controls without OSA (mean age 49.9 +/- 12.4). The presence and size of right-to-left shunting were determined by contrast transcranial Doppler ultrasonography with Valsalva provocation. Using the 21,749 obstructive breathing events recorded at polysomnography from the OSA group, a mixed-effects linear regression model was developed to evaluate the impact of right-to-left shunting on nocturnal oxygen desaturation (DeltaSpO2). RESULTS: A higher prevalence of PFO was present in the OSA group compared to the control group (47.1% vs. 26.0%, OR 2.53, CI 1.20 to 5.31, p=0.014). From the regression model, right-to-left shunt size did not exert a significant influence on the severity of DeltaSpO2 (coefficient 0.85, CI -0.62 to 2.32, p=0.254); whereas sleep state, event type, body position, event duration, awake oxygen saturation, apnea hypopnea index and body mass index were all independent predictors of DeltaSpO2. CONCLUSION: A higher prevalence of PFO is found in OSA subjects. However, the degree of right-to-left shunting, characterised by Valsalva provocation, is not associated with an increased severity of nocturnal oxygen desaturation. PMID- 21816493 TI - Intrinsically photosensitive retinal ganglion cells: many subtypes, diverse functions. AB - For decades, rods and cones were thought to be the only photoreceptors in the mammalian retina. However, a population of atypical photoreceptive retinal ganglion cells (RGCs) expresses the photopigment melanopsin and is intrinsically photosensitive (ipRGCs). These ipRGCs are crucial for relaying light information from the retina to the brain to control circadian photoentrainment, pupillary light reflex, and sleep. ipRGCs were initially described as a uniform population involved solely in signaling irradiance for non-image forming functions. Recent work, however, has uncovered that ipRGCs are unexpectedly diverse at the molecular, cellular and functional levels, and could even be involved in image formation. This review summarizes our current understanding of the diversity of ipRGCs and their various roles in modulating behavior. PMID- 21816495 TI - Enzyme-assisted extraction of bioactives from plants. AB - Demand for new and novel natural compounds has intensified the development of plant-derived compounds known as bioactives that either promote health or are toxic when ingested. Enhanced release of these bioactives from plant cells by cell disruption and extraction through the cell wall can be optimized using enzyme preparations either alone or in mixtures. However, the biotechnological application of enzymes is not currently exploited to its maximum potential within the food industry. Here, we discuss the use of environmentally friendly enzyme assisted extraction of bioactive compounds from plant sources, particularly for food and nutraceutical purposes. In particular, we discuss an enzyme-assisted extraction of stevioside from Stevia rebaudiana, as an example of a process of potential value to the food industry. PMID- 21816496 TI - Egocentric or allocentric frameworks for the evaluation of other people's reachability. AB - The adoption of egocentric and allocentric frameworks in the perception of other people's reachability was investigated. In study 1, 24 adults (12 experienced and 12 inexperienced dealing with children) judged vertical reachability for themselves and for two children. In study 2, 37 parents judged vertical reachability for themselves and their children. Absolute errors (|estimate-actual reachability|), absolute percent errors (|1-judgement/actual reachability|*100), and error tendency (underestimations, right judgments, or overestimations) were calculated. Adults were quite accurate in perceiving their own reachability (absolute percent errors ranging from 2.20% in study 1 to 3.12% in study 2) and clearly less precise when estimating children's reachability. Results indicated a tendency for adults to overestimate reachability of the younger child (study 1) and a tendency for parents to overestimate their children's reachability (study 2). No correlation between judgement errors for the self and for the children in any of the studies was observed. Results support the existence of an allocentric and not an egocentric framework when evaluating other people's affordances. PMID- 21816497 TI - Individual differences in the biomechanical effect of loudness and tempo on upper limb movements during repetitive piano keystrokes. AB - The present study addressed the effect of loudness and tempo on kinematics and muscular activities of the upper extremity during repetitive piano keystrokes. Eighteen pianists with professional music education struck two keys simultaneously and repetitively with a combination of four loudness levels and four tempi. The results demonstrated a significant interaction effect of loudness and tempo on peak angular velocity for the shoulder, elbow, wrist and finger joints, mean muscular activity for the corresponding flexors and extensors, and their co-activation level. The interaction effect indicated greater increases with tempo when eliciting louder tones for all joints and muscles except for the elbow velocity showing a greater decrease with tempo. Multiple-regression analysis and K-means clustering further revealed that 18 pianists were categorized into three clusters with different interaction effects on joint kinematics. These clusters were characterized by either an elbow-velocity decrease and a finger-velocity increase, a finger-velocity decrease with increases in shoulder and wrist velocities, or a large elbow-velocity decrease with a shoulder-velocity increase when increasing both loudness and tempo. Furthermore, the muscular load considerably differed across the clusters. These findings provide information to determine muscles with the greatest potential risk of playing-related disorders based on movement characteristics of individual pianists. PMID- 21816498 TI - Age at menarche, menstrual cycle characteristics and risk of gestational diabetes. AB - AIMS: We examined associations of age at menarche and menstrual cycle characteristics with gestational diabetes mellitus (GDM) risk. METHODS: Study participants (N=3490) recruited prior to 16 weeks of gestation were followed until delivery. Menstrual history data were collected using questionnaires. GDM was diagnosed using the American Diabetes Association 2003 guidelines. Logistic regression was used to estimate odds-ratios (OR) and 95% confidence intervals (CI). RESULTS: Age at menarche was not associated with GDM risk. Women who had long menstrual cycles (>36 days) had higher risk of GDM compared with women who had normal cycle length (25-30 days) (OR=1.6; 95%CI0.98-2.67). Women who had long menstrual cycles and were either overweight or gained >5kg in adulthood had 4-5 fold higher GDM risk compared with women who had normal cycle length and were non obese or gained <5kg in adulthood, respectively (OR=4.03; 95%CI:2.08-7.81 and OR=4.62, 95%CI:2.65-8.07, respectively). CONCLUSION: Longer menstrual cycles are significantly associated with increased risk of GDM, particularly among women who were either overweight or obese pre-pregnancy, or had >=5kg weight gain in adult hood. Menstrual history may help identify women with increased risk of GDM. PMID- 21816500 TI - Influencing the future of the global diabetes and NCD response. PMID- 21816499 TI - Plasma coenzyme Q10 is increased during gestational diabetes. AB - OBJECTIVES: To determine plasma CoQ(10) concentration in the course of gestational diabetes mellitus. STUDY DESIGN: The assessment was provided longitudinally during the third trimester of pregnancy in 40 women with gestational diabetes mellitus (GDM) and 40 normal controls. CoQ(10) was measured with the HPLC method. CoQ(10) results were also normalized to plasma cholesterol concentration (nmoles/mmoles). Plasma samples were collected longitudinally throughout the third trimester. RESULTS: No statistically significant difference of plasma CoQ(10)/cholesterol levels between GDM patients and controls at 28-32 and 32-36 weeks of gestation, this difference was significant in late pregnancy (36-40 weeks), similarly, in the same gestational period, there was an increased level of HOMA-IR as index of insulin resistance ORAC as index of oxidative stress. CONCLUSIONS: Since coenzyme Q(10) is believed to be an important cellular antioxidant defence, higher levels of CoQ(10) in GDM patients may be a compensatory mechanism, in response to an activated oxidative stress, probably associated to hyperglycaemia and insulin resistance. PMID- 21816501 TI - Persistence despite action? Measuring the patterns of health inequality in England (1997-2007). AB - The persistence of socioeconomic inequalities in health is a major policy concern in England, which was addressed by the new labour government in 1997 which prioritised curtailing health inequalities as a policy goal. This paper addresses two related questions: first, it empirically examines the dynamic patterns of socioeconomic inequalities in health in England from 1997 to 2007 by estimating concentration indices over three measures of health, namely self-reported health, long standing illness and health limitations, calculated across different years of the Health Survey for England. Second, using regression based decomposition analysis, we explore whether specifically prioritised areas (spearhead local authority areas in the bottom fifth nationally on health indicators) exhibit a different pattern of inequality in the years following a (2005) targeted intervention. Results suggest that patterns of health inequalities in England exhibit no significant variation from 1997 to 2007, although importantly, some reduction on inequalities in health, measured through self-assessed health, is found. Patterns of socioeconomic inequalities in health in spearhead areas are not found to be significantly different than health inequalities in non-spearhead areas. PMID- 21816502 TI - Factors associated with adherence to chemotherapy guidelines in patients with non small cell lung cancer. AB - BACKGROUND: Evidence-based guidelines recommend chemotherapy for medically fit patients with stages II-IV non-small cell lung cancer (NSCLC). Adherence to chemotherapy guidelines has rarely been studied among large populations, mainly because performance status (PS), a key component in assessing chemotherapy appropriateness, is missing from claims-based datasets. Among a large cohort of patients with known PS, we describe first line chemotherapy use relative to guideline recommendations and identify patient factors associated with guideline concordant use. PATIENTS AND METHODS: Insured patients, ages 50+, with stages II IV NSCLC between 2000 and 2007 were identified via tumor registry (n=406). Chart abstracted PS, automated medical claims, Census tract information, and travel distance were linked to tumor registry data. Chemotherapy was considered appropriate for patients with PS 0-2. Multivariate logit models were fit to evaluate patient characteristics associated with chemotherapy over- and under-use per guideline recommendations. Tests of statistical significance were two sided. RESULTS: Overall compliance with first line chemotherapy guidelines was 71%. Significant (p<0.05) predictors of chemotherapy underuse (19%) included increasing age (odds ratio [OR], 1.09), higher income (OR, 1.02), diagnosed before 2003 (OR, 2.05), and vehicle access (OR, 6.96) in the patient's neighborhood. Significant predictors of chemotherapy overuse (10%) included decreasing age (OR, 0.92), diagnosed after 2003 (OR, 3.24), and higher income (OR, 1.05) in the patient's neighborhood. Among NSCLC patients 29% do not receive guideline recommended chemotherapy treatment missing opportunities for cure or beneficial palliation, or receiving chemotherapy with more risk of harm than benefit. Care concordant with guidelines is influenced by age, economic considerations such as income and transportation barriers. PMID- 21816503 TI - Safety and feasibility of a combined exercise intervention for inoperable lung cancer patients undergoing chemotherapy: a pilot study. AB - AIM: To investigate the safety and feasibility of a six-week supervised structured exercise and relaxation training programme on estimated peak oxygen consumption, muscle strength and health related quality of life (HRHRQOL) in patients with inoperable lung cancer, undergoing chemotherapy. METHODS: A prospective, single-arm intervention study of supervised, hospital based muscle and cardiovascular group training and individual home-based training. Peak oxygen consumption (VO(2peak)) was assessed using an incremental exercise test. Muscle strength was measured with one repetition maximum test (1RM). HRQOL was assessed using the Functional Assessment of Cancer Therapy-Lung (FACT-L) scale. RESULTS: Twenty-five patients with non-small cell cancer (NSCLC) stage III-IV and four patients with extensive disease small cell lung cancer (SCLC-ED) were recruited. Six patients (20.7%) dropped out leaving 23 patients for analysis. Exercise adherence in the group training was 73.0% and 8.7% in the home-based training. There were improvements in estimated VO(2peak) and six-minute walk distance (6 MWD) as well as increased muscle strength measurements (p<0.05). There was significant improvement in the "emotional well-being" parameter (FACT-L) while there were no significant changes in HRQOL. CONCLUSION: Exercise training produces significant improvements in physiological indices and emotional HRQOL and is safe and feasible in patients with advanced stage lung cancer, undergoing chemotherapy. No analysis on home-based training was done because of low adherence. PMID- 21816504 TI - Primary cutaneous diffuse large B-cell lymphoma, leg type and secondary cutaneous involvement by testicular B-cell lymphoma share identical clinicopathological and immunophenotypical features. AB - BACKGROUND: Primary cutaneous diffuse large B-cell lymphoma (PCDLBCL), leg type can eventually disseminate to extracutaneous sites including testes. In addition, patients with testicular lymphoma can develop specific skin involvement. OBJECTIVE: We sought to describe similarities between PCDLBCL, leg type and testicular B-cell lymphoma affecting the skin. METHODS: We report two cases with typical clinicopathological and immunophenotypical features of leg type lymphoma occurring simultaneously with a testicular B-cell lymphoma. We also report an additional case of PCDLBCL, leg type with secondary testicular involvement. RESULTS: All cases presented with typical red tumors exclusively located on the legs. Histologically, all cases showed a diffuse nonepidermotropic infiltrate composed of large blastic cells mainly centroblastic type. Phenotype showed strong positivity for Bcl-2, MUM-1, and FOXP1. Epstein-Barr virus stains and CD30 were negative in the 3 cases. In all cases the testicular infiltration showed the same pathological and phenotypical changes to those observed in the skin. LIMITATIONS: This was a retrospective case series study. CONCLUSION: Skin involvement by testicular B-cell lymphomas and PCDLBCL, leg type are indistinguishable on the basis of pathologic and immunophenotypical features, therefore specific investigation and clinic correlation are needed. PMID- 21816505 TI - Meta-analysis of randomized controlled trials using 5% benzoyl peroxide and clindamycin versus 2.5% benzoyl peroxide and clindamycin topical treatments in acne. PMID- 21816506 TI - An improved method of surgical pathology testing for onychomycosis. AB - BACKGROUND: Surgical pathology testing for onychomycosis using periodic acid Schiff staining is the "gold standard." However, routine histopathological methods of processing nail clippings can be limited by poor section quality, higher costs, and delayed turnaround times for some specimens because of tissue hardness. OBJECTIVE: We investigated the utility of sodium hydroxide (NaOH) pretreatment of nail specimens submitted for the histopathologic evaluation of onychomycosis. METHODS: We report our validation of a sodium hydroxide (NaOH) pretreatment protocol during a 7-month study period from 2009-2010. Nail clippings (n = 45) were divided into NaOH-treated and routine processing halves and submitted in separate tissue blocks for parallel processing, embedding, sectioning, and staining for hematoxylin-eosin and periodic acid-Schiff. Histologic sections were scored for section quality and statistical analysis performed. RESULTS: NaOH pretreatment yielded higher quality sections for both hematoxylin-eosin-stained (P < .001) and periodic acid Schiff-stained (P < .001) slides with reduced tissue folding and fragmentation, improved ease of cutting, and adherence of the tissue to glass slides. LIMITATIONS: Direct comparison of the proposed NaOH pretreatment protocol with other pretreatment techniques was not performed. CONCLUSION: NaOH pretreatment of nails submitted for a clinical suspicion of onychomycosis is a simple, rapid, and easily adopted method that leads to improved tissue section quality for optimal histopathologic evaluation and diagnosis. Improved tissue sections and adherence to glass slides can reduce the need for repeat sections, thereby reducing costs and preventing delays in turnaround time. PMID- 21816507 TI - H1N1 pandemic influenza impact on hand hygiene and specific precautions compliance among healthcare workers. PMID- 21816509 TI - Is progesterone therapy beneficial for acute traumatic brain injury? PMID- 21816508 TI - Understanding commonly encountered limitations in clinical research: an emergency medicine resident's perspective. PMID- 21816510 TI - Improving outcomes of elderly patients presenting to the emergency department. PMID- 21816511 TI - Successful control of a norovirus outbreak among attendees of a hospital teaching conference. AB - We report an outbreak of norovirus gastroenteritis after a hospital teaching conference, and describe the specific measures instituted by the infection control team. No secondary cases of norovirus infection were identified among hospital staff or patients. In a case-control study, we identified multiple food source contamination as the source of the outbreak. Our report highlights the potential success of a multifaceted infection control strategy in preventing the transmission of norovirus in health care settings. PMID- 21816512 TI - Neuroprotection by neuropeptide Y in cell and animal models of Parkinson's disease. AB - This study was aimed to investigate the potential neuroprotective effect of neuropeptide Y (NPY) on the survival of dopaminergic cells in both in vitro and in animal models of Parkinson's disease (PD). NPY protected human SH-SY5Y dopaminergic neuroblastoma cells from 6-hydroxydopamine-induced toxicity. In rat and mice models of PD, striatal injection of NPY preserved the nigrostriatal dopamine pathway from degeneration as evidenced by quantification of (1) tyrosine hydroxylase (TH)-positive cells in the substantia nigra pars compacta, levels of (2) striatal tyrosine hydroxylase and dopamine transporter, (3) dopamine and 3,4 dihydroxyphenylacetic acid (DOPAC) as well as (4) rotational behavior. NPY had no neuroprotective effects in mice treated with Y(2) receptor antagonist or in transgenic mice deficient for Y(2) receptor suggesting that NPY effects are mediated through this receptor. Stimulation of Y(2) receptor by NPY triggered the activation of both the ERK1/2 and Akt pathways but did not modify levels of brain derived neurotrophic factor (BDNF) or glial cell line-derived neurotrophic factor. These results open new perspectives in neuroprotective therapies using NPY and suggest potential beneficial effects in PD. PMID- 21816514 TI - [Prevention of HIV transmission (vertical, occupational and non-occupational)]. AB - In these almost thirty years since the epidemic of HIV infection strategies have been developed to decrease the transmission risk when a non-infected person comes into contact with HIV. One of the key landmarks was the use zidovudine was shown to reduce the risk of HIV infection by vertical transmission from 25% to 8% when given from the second trimester of pregnancy, during partum and for several weeks in the newborn. These strategies have been subsequently perfected until achieving vertical transmission rates less than 1%. Almost at the same time, strategies have been developed in an attempt to reduce the risk of transmission of infection after occupational accidents and, in the last few years prophylaxis after non occupational exposure has been a field of particular concern. Even in this past year several experiments on pre-exposure prophylaxis have been published, which are generating an intense debate on is applicability. In this article, we analyse the state of the art in the prevention of vertical transmission and occupational and non-occupational prophylaxis, from a perspective of applying this in the developed world. We also review the published data on pre-exposure prophylaxis. PMID- 21816515 TI - Synthesis and biological investigation of potential atypical antipsychotics with a tropane core. Part 1. AB - The synthesis, structure, in vitro and in vivo pharmacological activities of 3beta-acylamine derivatives of tropane (4a-n, 5a-g, 6a,b, 8a-c) are described. Among the investigated compounds, several displayed very high (in nM) affinity for the monoamine receptors 5-HT(1A), 5-HT(2A,) and D(2). The most interesting agent 6b revealed very high affinity for the 5-HT(2A) and D(2) receptors and high affinity for the 5-HT(1A) receptor. The in vivo head twitch model was used to demonstrate antagonism of the 5-HT(2A) receptor subtype by this compound. In another test, 6b caused hypothermia in mice, which was not attenuated by WAY 100635. In the climbing test, the compound did not significantly modify climbing behaviour following apomorphine administration. Moreover, 6b significantly reduced locomotor activity in mice. Molecular docking studies using a homology model of the 5-HT(1A) receptor revealed a significant role of the N-8 atom of the tropane core in stabilising the ligand-receptor complex due to strong hydrogen bonding with Asp116 located in the TMH 3 helix. Analogically, in a homology model of the 5-HT(2A) receptor, the N-8 atom formed a hydrogen bond with Gly369. In another homology model of the D(2) receptor, strong hydrogen bonding of the amide moiety in the 3beta position of the tropane nucleus with Asp85 was observed. Compound 6b displayed a favourable Meltzer index (1.21) which is a feature of atypical antipsychotic agents. PMID- 21816516 TI - Synthesis, pharmacological evaluation and docking studies of coumarin derivatives. AB - We synthesized coumarin derivatives using various aromatic and heterocyclic amines, and tested the target compound for its analgesic, anti-inflammatory, antimicrobial activities. Compounds 3l, 3m and 3n showed significant anti inflammatory, analgesic and antimicrobial activities. The synthesized compounds, then docked on COX-2 to predict the binding affinity and orientation at the active site of the receptor. It was found that the active compounds 3l, 3m and 3n intact mainly with Arg 44 amino acid, which may be involved in COX-2 inhibition. The compounds which bind with Arg 44 have significant anti-inflammatory activity. This could be due to the formation of more effective hydrogen bond with the receptor. Comparing pharmacological activity and docking results, we conclude that heterocyclic derivatives linked with nitrogen at 7-position of coumarin seem to be potentially active drug. PMID- 21816517 TI - Synthesis, molecular modeling and biological evaluation of chalcone thiosemicarbazide derivatives as novel anticancer agents. AB - A series of novel chalcone thiosemicarbazide derivatives (4a-4x) have been designed, synthesized, structurally determined, and their biological activities were also evaluated as potential EGFR kinase inhibitors. All the synthesized compounds are first reported. Among the compounds, compound 4r showed the most potent biological activity (IC(50) = 0.78 +/- 0.05 MUM for HepG2 and IC(50) = 0.35 MUM for EGFR), which is comparable to the positive controls. Docking simulation was also performed to position compound 4r into the EGFR active site to determine the probable binding model. Antiproliferative assay results demonstrated that some of these compounds possessed good antiproliferative activity against HepG2. Compound 4r with potent inhibitory activity in tumor growth inhibition may be a potential anticancer agent. PMID- 21816518 TI - Photodynamic efficacy of water-soluble Si(IV) and Ge(IV) phthalocyanines towards Candida albicans planktonic and biofilm cultures. AB - Water-soluble phthalocyanine complexes of silicon (SiPc1) and germanium (GePc1) were synthesized. The absorbance of SiPc1 in water was with minor aggregation while GePc1 strongly aggregated in water. The fluorescence data in water showed low quantum yields of 0.073 (SiPc1) and 0.01 (GePc1) and similar lifetimes of 4.07 ns and 4.27 ns. The uptake of SiPc1 into Candida albicans cells was two orders of magnitude lower as compared to GePc1 and for both was dependent on the cell density. Fungal cells in suspension were completely inactivated after SiPc1 (1.8 MUM) at soft light radiation (50 J cm(-2), 60 mW cm(-2)). The fungal biofilm formed on denture acrylic resin was inactivated with 3 log after fractionated light irradiation. PMID- 21816519 TI - Quinolinyl and quinolinyl N-oxide chalcones: synthesis, antifungal and cytotoxic activities. AB - A series of new 6-quinolinyl and quinolinyl N-oxide chalcones were efficiently prepared. All chalcones were tested by minimal inhibitory concentration (MIC) against three species of Candida, Cryptococcus gattii and Paracoccidioides brasiliensis. The effect of these compounds was also tested on the survival and growth of the human cancer cell lines UACC-62 (melanoma), MCF-7 (breast), TK-10 (renal) and leukemic cells, Jurkat and HL60. The compounds tested presented strong activity against P. brasiliensis, most importantly compound 4e. C. gattii also presented interesting susceptibility for compounds 5b and 5f. The cytotoxic activity showed that compounds 3c and 4e, presented the best activity against MCF 7 and TK-10. For leukemic cells the compounds 4f, 3g, 4g and 5g have shown the best activity. PMID- 21816520 TI - [Arthralgia and weight loss in an 84-year-old woman]. PMID- 21816521 TI - [Diffuse lymph nodes in a 70-year-old man]. PMID- 21816522 TI - Cesium isotope ratios as indicators of nuclear power plant operations. AB - There are multiple paths by which radioactive cesium can reach the effluent from reactor operations. The radioactive (135)Cs/(137)Cs ratios are controlled by these paths. In an effort to better understand the origin of this radiation, these (135)Cs/(137)Cs ratios in effluents from three power reactor sites have been measured in offsite samples. These ratios are different from global fallout by up to six fold and as such cannot have a significant component from this source. A cesium ratio for a sample collected outside of the plant boundary provides integration over the operating life of the reactor. A sample collected inside the plant at any given time can be much different from this lifetime ratio. The measured cesium ratios vary significantly for the three reactors and indicate that the multiple paths have widely varying levels of contributions. There are too many ways these isotopes can fractionate to be useful for quantitative evaluations of operating parameters in an offsite sample, although it may be possible to obtain limited qualitative information for an onsite sample. PMID- 21816523 TI - Effect of muscle loads and torque applied to the tibia on the strain behavior of the anterior cruciate ligament: an in vitro investigation. AB - BACKGROUND: Very little is known about the effects of applied torque about the long axis of the tibia in combination with muscle loads on anterior cruciate ligament biomechanics. The purpose of this study was to determine the effect of muscle contraction and tibial torques applied about the long axis of the tibia on anterior cruciate ligament strain behavior. METHODS: Six cadaver knee specimens were used to measure the strain behavior of the anterior cruciate ligament. Internal and external axial torques were applied to the tibia when the knee was between 30 degrees and 120 degrees of flexion in combination with the conditions of no muscle load, isolated quadriceps load, and simultaneous quadriceps and hamstring loading. FINDINGS: The highest anterior cruciate ligament strain values were measured when the muscles were not loaded, when the knee was at 120 degrees of flexion, and when internal tibial torques were applied to the knee. During muscle loading the highest anterior cruciate ligament strain values were measured at 30 degrees of flexion and then the strain values gradually decreased with increase in knee flexion. During co-contraction of the quadriceps and hamstring muscles the anterior cruciate ligament was unstrained or minimally strained at 60 degrees , 90 degrees and 120 degrees of knee flexion. INTERPRETATION: This study suggests that quadriceps and hamstring muscle co contraction has a potential role in reducing the anterior cruciate ligament strain values when the knee is in deep flexion. These results can be used to gain insight into anterior cruciate ligament injury mechanisms and to design rehabilitation regimens. PMID- 21816524 TI - Association of sleep-related problems with CKD in the United States, 2005-2008. AB - BACKGROUND: Sleep-related problems, which have been associated with poor health outcomes, have not been investigated thoroughly in people with chronic kidney disease (CKD). We examined the prevalence of a variety of sleep-related problems in persons with and without CKD. STUDY DESIGN: National cross-sectional survey (National Health and Nutrition Examination Survey 2005-2008). SETTING & PARTICIPANTS: Community-based survey of 9,110 noninstitutionalized US civilian residents 20 years or older. PREDICTOR: CKD, defined as estimated glomerular filtration rate (eGFR) of 15-59 mL/min/1.73 m(2) (stages 3 and 4) or eGFR >=60 mL/min/1.73 m(2) and albumin-creatinine ratio >=30 mg/g (stages 1 and 2). OUTCOME: Sleep quality, defined using self-report in a multi-item sleep questionnaire including items from previously validated instruments. MEASUREMENTS: Albuminuria and eGFR assessed from urine and blood samples; sleep, demographics, and comorbid conditions assessed using a standardized questionnaire. RESULTS: Inadequate sleep (<=6 hours per night) differed by CKD severity (37.4%, 43.0%, and 30.9% for no CKD, CKD stages 1 and 2, and CKD stages 3 and 4, respectively; P = 0.003). Frequent sleeping pill use (8.4%, 9.9%, and 16.6%), leg symptoms (39.2%, 48.0%, and 50.9%), and nocturia (20.9%, 35.2%, and 43.6%; P < 0.001 for all) also differed by CKD severity. After adjustment for age, sex, race/ethnicity, obesity, diabetes, and cardiovascular disease, the prevalence of these sleep-related problems remained higher in people with CKD stages 1 and 2 relative to no CKD. Most other measures of sleep quality, disorder, and functional outcomes did not differ by CKD. LIMITATIONS: Inability to establish causality and possible unmeasured confounding. CONCLUSION: Providers should be aware of early sleep-related CKD manifestations, including inadequate sleep, leg symptoms, and nocturia, and of the high rate of reported sleep medication use in this population. PMID- 21816525 TI - Low 25-hydroxyvitamin D levels and mortality in non-dialysis-dependent CKD. AB - BACKGROUND: Low 25-hydroxyvitamin D (25[OH]D) levels are common in patients with non-dialysis-dependent chronic kidney disease (CKD). The associations between low 25(OH)D levels and mortality in non-dialysis-dependent patients with CKD are unclear. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Patients with stages 3-4 CKD (estimated glomerular filtration rate, 15-59 mL/min/1.73 m(2); n = 12,673) who had 25(OH)D levels measured after the diagnosis of CKD in the Cleveland Clinic Health System. PREDICTOR: 25(OH)D levels categorized into 3 groups: <15, 15-29, and >=30 ng/mL. OUTCOMES: We examined factors associated with low 25(OH)D levels and associations between low 25(OH)D levels and all-cause mortality (ascertained using the Social Security Death Index and our electronic medical record) using logistic regression, Cox proportional hazard models, and Kaplan-Meier survival curves. MEASUREMENTS: 25(OH)D was measured using chemiluminescence immunoassay. RESULTS: Of 12,763 patients with CKD, 15% (n = 1,970) had 25(OH)D levels <15 ng/mL, whereas 45% (n = 5,749) had 25(OH)D levels of 15-29 ng/mL. Male sex, African American race, diabetes, coronary artery disease, and lower estimated glomerular filtration rate were associated significantly with 25(OH)D level <30 ng/mL. A graded increase in risk of 25(OH)D level <30 ng/mL was evident across increasing body mass index levels. Patients who had 25(OH)D levels measured in fall through spring had higher odds for 25(OH)D levels <30 ng/mL. After covariate adjustment, patients with CKD with 25(OH)D levels <15 ng/mL had a 33% increased risk of mortality (95% CI, 1.07 1.65). The group with 25(OH)D levels of 15-29 ng/mL did not show a significantly increased risk of mortality (HR, 1.03; 95% CI, 0.86-1.22) compared with patients with 25(OH)D levels >=30 ng/mL. LIMITATIONS: Single-center observational study, lack of data for albuminuria and other markers of bone and mineral disorders, and attrition bias. CONCLUSIONS: 25(OH)D level <15 ng/mL was associated independently with all-cause mortality in non-dialysis-dependent patients with CKD. PMID- 21816527 TI - Effect of pay for performance on hypertension in the United kingdom. PMID- 21816526 TI - Home hemodialysis and mortality risk in Australian and New Zealand populations. AB - BACKGROUND: There is a resurgence of interest in home hemodialysis (HD), especially frequent or extended forms involving unconventionally frequent (>3 times/wk) and/or long (>6 hours) treatments. This resurgence is driven by cost containment and experience suggesting lower mortality risk compared with facility HD and peritoneal dialysis (PD). STUDY DESIGN: We performed an observational cohort study using the Australia and New Zealand Dialysis and Transplant Registry, using marginal structural modeling to adjust for time-varying medical comorbidity as both a source of selection bias and an intermediary variable on the causal pathway to death. SETTING & PARTICIPANTS: All adult patients starting renal replacement therapy in Australia and New Zealand since March 31, 1996, followed up to December 31, 2007. PREDICTOR: The main predictor was dialysis modality (conventional facility HD, conventional home HD, frequent/extended facility HD, frequent/extended home HD, and PD). We adjusted for the confounding effects of patient demographics and comorbid conditions. OUTCOME: Patient mortality. RESULTS: We analyzed 26,016 patients with 856,007 patient-months of follow-up. Relative to conventional facility HD, adjusted mortality HRs were 0.51 (95% CI, 0.44-0.59) for conventional home HD, 1.16 (95% CI, 0.94-1.44) for frequent/extended facility HD, 0.53 (95% CI, 0.41-0.68) for frequent/extended home HD, and 1.10 (95% CI, 1.06-1.16) for PD. The apparent benefit of home HD on mortality risk was less for patients who were nonwhite, non-Asian, and older. LIMITATIONS: Potential for residual confounding from the limited collection of comorbid conditions (no collection of cognitive or motor impairment, depression, left ventricular volume or structure, or blood pressure/fluid volume status) and lack of socioeconomic, medication, and biochemical data in analyses. CONCLUSIONS: Our study supports a survival advantage of home HD without a difference between conventional and frequent/extended modalities. Suitably designed clinical trials of frequent/extended HD are needed to determine the presence and extent of mortality benefit with this modality. PMID- 21816528 TI - Albuminuria, kidney function, and the incidence of cognitive impairment among adults in the United States. AB - BACKGROUND: Albuminuria and estimated glomerular filtration rate (eGFR) are each associated with increased risk of cognitive impairment, but their joint association is unknown. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: A US national sample of 19,399 adults without cognitive impairment at baseline participating in the REGARDS (Reasons for Geographic and Racial Disparities in Stroke) Study. PREDICTORS: Albuminuria was assessed using urine albumin-creatinine ratio (UACR) and GFR was estimated using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation. OUTCOMES: Incident cognitive impairment was defined as score <=4 on the 6-Item Screener at the last follow-up visit. RESULTS: During a mean follow-up of 3.8 +/- 1.5 years, UACRs of 30-299 and >=300 mg/g were associated independently with 31% and 57% higher risk of cognitive impairment, respectively, relative to individuals with UACR <10 mg/g. This finding was strongest for those with high eGFRs and attenuated at lower levels (P = 0.04 for trend). Relative to eGFR >=60 mL/min/1.73 m(2), eGFR <60 mL/min/1.73 m(2) was not associated independently with cognitive impairment. However, after stratifying by UACR, eGFR <60 mL/min/1.73 m(2) was associated with a 30% higher risk of cognitive impairment in participants with UACR <10 mg/g, but not higher UACRs (P = 0.04 for trend). LIMITATIONS: Single measures of albuminuria and eGFR, screening test of cognition. CONCLUSIONS: When eGFR was preserved, albuminuria was associated independently with incident cognitive impairment. When albuminuria was <10 mg/g, low eGFR was associated independently with cognitive impairment. Albuminuria and low eGFR are complementary, but not additive, risk factors for incident cognitive impairment. PMID- 21816529 TI - Early life undernutrition and chronic diseases at older ages: the effects of the Dutch famine on cardiovascular diseases and diabetes. AB - Nutritional conditions in early life may causally affect health at older ages. This paper examines the effects of early life exposure to the Dutch famine (Winter 1944-45) on the prevalence of heart diseases, peripheral arterial diseases (PAD) and diabetes mellitus (DM) at ages 60-76. Analyses are performed using data from the fifth cycle of the Longitudinal Aging Study Amsterdam. Exposure to the famine is determined by reported place of residence during the Dutch famine, with those living in the cities in the West of the Netherlands defined as exposed (n = 278) and those living in the rural areas in the West or living in the North or East defined as non-exposed (n = 521). We successively compare the prevalence of heart diseases, PAD and DM at ages 60-76 of 370 males and 429 females exposed and non-exposed to the famine in early life. We distinguish four age classes of exposure in early life: gestation and infancy (ages 0-1), childhood (age 1-5), pre-adolescence (ages 6-10) and adolescence (ages 11-14). The analysis shows that exposure to severe undernutrition at ages 11-14 is significantly associated with a higher probability of developing DM and/or PAD at ages 60-76. The associations are found only in women, but not in men. If suggests that adolescence may be a critical period with respect to exposure to adverse (nutritional) conditions and that research should take this into account. These findings are relevant for children in developing countries who are exposed to severe nutritional deprivation. PMID- 21816530 TI - Agency versus structure or nature versus nurture: when the new twist on an old debate is not that new after all. A commentary on Angel. PMID- 21816531 TI - Agency versus structure: genetics, group membership, and a new twist on an old debate. AB - The decoding of the human genome and advances in genetic medicine promise great advances in the prevention and treatment of disease. These powerful methodologies, though, raise serious intellectual, ethical, and practical questions when they are employed in explanations of complex higher-order behavioral and social outcomes. There can be little doubt that all human behavior reflects complex gene/environment interactions, but isolating the unique contributions of genes and environment in the explanation of overdetermined behavioral and social outcomes may not in principle be possible. When dealing with groups that differ significantly in histories of discrimination and exclusion biological explanations must be employed with caution even as they promise great strides in dealing with specific diseases. PMID- 21816532 TI - Oral ulcers, a little known adverse effect of alendronate: review of the literature. AB - PURPOSE: To review the published data on a hitherto not widely known adverse effect of alendronate manifesting as mucosal ulcers in the oral cavity. MATERIALS AND METHODS: The electronic database PubMed was searched for reports of this adverse effect. Publications published up to August 2010 were included. This electronic search was combined with a manual search of the reference lists of the selected publications. RESULTS: A total of 47 publications were retrieved from the electronic and manual searches. Of these, 12 were selected for the review. Mostly, the ulcers were preceded by misuse of alendronate, but they also appeared after correct administration. The appearance of the ulcers varied from a few days to several months after the start of alendronate use. Effective treatment was withdrawal of the drug or revision of the dosing and administration instructions. CONCLUSIONS: Alendronate can cause mucosal ulcerations in the oral cavity, affecting patients with intense pain and causing severe morbidity. Successful treatment of this oral pathosis is achieved by aborting the use of alendronate. This adverse effect of alendronate is a rare entity in published reports but careful monitoring of patients at risk is recommended. PMID- 21816533 TI - A case of SAPHO syndrome with diffuse sclerosing osteomyelitis of the mandible treated successfully with prednisolone and bisphosphonate. PMID- 21816534 TI - Theoretical study of the excited states of the photosynthetic reaction center in photosystem II: electronic structure, interactions, and their origin. AB - The excited states of the chlorophyll 6-mer in the photosystem II (PSII) reaction center (RC) were investigated theoretically using ab initio quantum chemical calculations, and the results are compared with those of the bacterial reaction center (bRC). A significant difference in the peak at the lowest energy in the absorption spectra arises from the structural asymmetry of the special pair (SP). The origin can be traced back to the structural difference in the CD helix. The low-lying excited states are characterized as a linear combination of the excited states of the chlorophyll monomers, which verifies the applicability of exciton theory. Analysis of the molecular interactions clearly explains the cause of the constructive/destructive interferences in the state transition moment. The protein electrostatic potential (ESP) decreases the energy of the charge-transfer (Chl(D1)->Pheo(D1)) state. The ESP also localizes the HOMO distribution to the P(D1) moiety and increases the ionization potential. PMID- 21816535 TI - Target loads of atmospheric sulfur deposition for the protection and recovery of acid-sensitive streams in the Southern Blue Ridge Province. AB - An important tool in the evaluation of acidification damage to aquatic and terrestrial ecosystems is the critical load (CL), which represents the steady state level of acidic deposition below which ecological damage would not be expected to occur, according to current scientific understanding. A deposition load intended to be protective of a specified resource condition at a particular point in time is generally called a target load (TL). The CL or TL for protection of aquatic biota is generally based on maintaining surface water acid neutralizing capacity (ANC) at an acceptable level. This study included calibration and application of the watershed model MAGIC (Model of Acidification of Groundwater in Catchments) to estimate the target sulfur (S) deposition load for the protection of aquatic resources at several future points in time in 66 generally acid-sensitive watersheds in the southern Blue Ridge province of North Carolina and two adjoining states. Potential future change in nitrogen leaching is not considered. Estimated TLs for S deposition ranged from zero (ecological objective not attainable by the specified point in time) to values many times greater than current S deposition depending on the selected site, ANC endpoint, and evaluation year. For some sites, one or more of the selected target ANC critical levels (0, 20, 50, 100MUeq/L) could not be achieved by the year 2100 even if S deposition was reduced to zero and maintained at that level throughout the simulation. Many of these highly sensitive streams were simulated by the model to have had preindustrial ANC below some of these target values. For other sites, the watershed soils contained sufficiently large buffering capacity that even very high sustained levels of atmospheric S deposition would not reduce stream ANC below common damage thresholds. PMID- 21816536 TI - Are two resources really better than one? Some unexpected results of the availability of substitutes. AB - The possibility of exploiting multiple resources is usually regarded as positive from both the economic and the environmental point of view. However, resource switching may also lead to unsustainable growth and, ultimately, to an equilibrium condition which is worse than the one that could have been achieved with a single resource. We developed a dynamic model where users exploit multiple resources and have different levels of preference among them. In this setting, exploiting multiple resources leads to worse outcomes in both economic and ecological terms than the single resource case under a wide range of parameter configurations. Our arguments are illustrated using two empirical situations, namely oil drilling in the North Sea and whale hunting in the Antarctic. PMID- 21816537 TI - An exploratory assessment of the attitudes of Chinese wood products manufacturers towards forest certification. AB - Interviews with Chinese forest products manufacturers were conducted to explore their attitudes towards forest certification and related issues. Participants comprised owners, CEOs, and managers in 20 Chinese wood products companies, including producers of furniture, doors, flooring, and various engineered wood products. The interviews were used to analyze the extent to which participants were considering adopting forest certification and what might motivate such a decision. This was done by assessing their awareness and knowledge of certification. The results indicated that participants' understanding of forest certification was extremely low, despite major efforts in China to raise awareness of the issue. Potential economic benefits were the most frequently cited reason to adopt certification, including gaining or maintaining competitive advantage over their industry counterparts, improved access to both domestic and export markets, better customer recognition, and enhanced corporate responsibility practices. Some interviewees (3 out of 20) considered that certification would become a mandatory requirement or industry standard, and that this would be the only viable motivation for certification given that the financial benefits were potentially limited. According to the participants, the main differences between certified and uncertified wood products operations related to improved market access and public image. Interviewees felt that cooperation between and support from governments and the forest industry would enable the enhanced awareness of certification amongst manufacturers and the general public. This, in turn, could serve to stimulate demand for certified products. PMID- 21816538 TI - Examination of nitrate concentration, loading and isotope dynamics in subsurface drainage under standard agricultural cropping in Atlantic Canada. AB - Intensive agricultural farming practices have the potential to cause high levels of nitrate-nitrogen (NO(3)(-)-N) to be released from tile drainage systems. A better understanding of the temporal dynamics of NO(3)(-)-N loading, delta(15)N and delta(18)O from standard drainage systems is needed, in order to improve our understanding of NO(3)(-)-N transport and transformation processes; particularly, with regards to the imperfectly drained agricultural soils found within Atlantic Canada. Three conventional subsurface drainage plots (48 * 48 m) placed at a 0.80 m soil depth were monitored over a seven month period on sandy loam soil in Onslow, Nova Scotia. Each plot received similar applications of both organic and inorganic fertilizer. Water samples were obtained and analyzed for NO(3)(-)-N concentrations and isotopic signatures of delta(15)N and delta(18)O for NO(3)(-) N. Maximum NO(3)(-)-N loads were observed in the winter and fall, when both discharge and concentration of the NO(3)(-)-N were highest. Mean isotope values in NO(3)(-) ranged from 3.1 to 8.50/00 for delta(15)N and -3.2 to 17.70/00 for delta(18)O. Results suggest that NO(3)(-)-N from the drainage water was derived from organic sources (i.e. manure and soil organic matter) and that loss via denitrification does not impart an identifiable signature upon the NO(3)(-)-N pool. The dual isotope approach examined here provides insight into N source and transformation processes which may be contributing to the NO(3)(-)-N found within the drainage water. PMID- 21816539 TI - Greenhouse gas emissions control in integrated municipal solid waste management through mixed integer bilevel decision-making. AB - Recent studies indicated that municipal solid waste (MSW) is a major contributor to global warming due to extensive emissions of greenhouse gases (GHGs). However, most of them focused on investigating impacts of MSW on GHG emission amounts. This study presents two mixed integer bilevel decision-making models for integrated municipal solid waste management and GHG emissions control: MGU-MCL and MCU-MGL. The MGU-MCL model represents a top-down decision process, with the environmental sectors at the national level dominating the upper-level objective and the waste management sectors at the municipal level providing the lower-level objective. The MCU-MGL model implies a bottom-up decision process where municipality plays a leading role. Results from the models indicate that: the top down decisions would reduce metric tonne carbon emissions (MTCEs) by about 59% yet increase about 8% of the total management cost; the bottom-up decisions would reduce MTCE emissions by about 13% but increase the total management cost very slightly; on-site monitoring and downscaled laboratory experiments are still required for reducing uncertainty in GHG emission rate from the landfill facility. PMID- 21816540 TI - Autoimmunity against the beta2 adrenergic receptor and muscarinic-2 receptor in complex regional pain syndrome. AB - Complex regional pain syndrome (CRPS) is a painful condition affecting one or more extremities of the body, marked by a wide variety of symptoms and signs that are often difficult to manage because the pathophysiology is incompletely understood. Thus, diverse treatments might be ineffective. A recent report revealed the presence of autoantibodies against differentiated autonomic neurons in CRPS patients. However, it remained unclear how the antibodies act in the development of CRPS. We therefore aimed to characterize these antibodies and identify target antigens. Functional properties of affinity-purified immunoglobulin G of control subjects or CRPS patients were assessed using a cardiomyocyte bioassay. Putative corresponding receptors were identified using antagonistic drugs, and synthesized peptide sequences corresponding to segments of these receptors were used to identify the target epitopes. Chinese hamster ovary cells were transfected with putative receptors to ensure observed binding. Further, changes in the intracellular Ca(2+) concentration induced by agonistic immunoglobulin G were measured using the Ca(2+)-sensitive fluorescent dye fura-2 assay. Herein, we demonstrate the presence of autoantibodies in a subset of CRPS patients with agonistic-like properties on the beta(2) adrenergic receptor and/or the muscarinic-2 receptor. We identified these autoantibodies as immunoglobulin G directed against peptide sequences from the second extracellular loop of these receptors. The identification of functionally active autoantibodies in serum samples from CRPS patients supports an autoimmune pathogenesis of CRPS. Thus, our findings contribute to the further understanding of this disease, could help in the diagnosis in future, and encourage new treatment strategies focusing on the immune system. PMID- 21816541 TI - Temperature distribution in the upper airway after inhalation injury. AB - OBJECTIVE: The aim of the study was to establish an animal model of laryngeal burn and to investigate the temperature distribution of heated air in the upper airway. METHODS: The animal model was established by inhalation of dry heated air at 80, 160 and 320 degrees C in 18 healthy, male, adult hybrid dogs. Time for inducing injury was set at 20 min. The distribution of temperatures after heated air inhalation was examined at different locations including the epiglottis, laryngeal vestibule, vocal folds and trachea. RESULTS: The temperatures of the heated air decreased to 47.1, 118.4 and 193.8 degrees C at the laryngeal vestibule and to 39.3, 56.6 and 137.9 degrees C at the lower margin of vocal folds in the 80, 160 and 320 degrees C groups, respectively. CONCLUSION: Due to its special anatomy and functions, the larynx has different responses to dry heated air at different temperatures. The air temperature decreases markedly when the air arrives at the larynx. By contrast, the larynx has a low capacity for blocking high-temperature air and retaining heat. As a result, high-temperature air often causes more severe injury to the larynx and the lower airway. PMID- 21816542 TI - Safety and potential anticoagulant effects of nebulised heparin in burns patients with inhalational injury at Singapore General Hospital Burns Centre. AB - BACKGROUND: Nebulised heparin, N-acetylcysteine (NAC) and salbutamol were shown to decrease reintubation rates, incidence of atelectasis and mortality in paediatric patients and reduce lung injury scores in adult burns patients with inhalational lung injury (ILI). Nebulised heparin, NAC and salbutamol treatment protocol was introduced in Singapore General Hospital (SGH) Burns Centre in 2006. However, safety data on the use of nebulised heparin and NAC for burns patients with ILI is not well established. In this study, we investigated the safety and potential anticoagulant effects of nebulised heparin in burns patients with ILI. METHODS: A retrospective study with historical control was conducted. The treatment group consisted of 52 mechanically ventilated adult patients, with a diagnosis of ILI as confirmed by bronchoscopy, admitted to burn intensive care unit (BICU) from the year 2006 to 2009. The group was treated with nebulised heparin, NAC and salbutamol. The control group consists of 11 mechanically ventilated BICU ILI patients treated from year 2001 to 2005 before protocol initiation. Blood coagulation indices (prothrombin time (PT), activated partial thromboplastin time (APTT) and platelet count) were monitored and bleeding incidences were assessed. FINDINGS: Blood coagulation indices did not suggest an increase risk of bleeding with nebulised heparin. The APTT, PT and platelet count followed a similar trend for both groups over 7 days. No clinically significant increase in bleeding risk was found to be associated with nebulised heparin. CONCLUSION: Nebulised heparin was not found to potentiate the risk of bleeding in burns patients with ILI. PMID- 21816543 TI - Factors associated with smoking menthol cigarettes among treatment-seeking African American light smokers. AB - BACKGROUND: Smoking menthol cigarettes is more prevalent among African Americans (AA) compared to Whites. Menthol has been found to be inversely related to smoking cessation among AA, yet little is known about the factors associated with menthol smoking among AA light smokers. This study examines baseline demographic, psychological, and smoking factors associated with smoking menthol cigarettes among AA light smokers (<=10 cigarettes per day). METHODS: Participants (n=540) were enrolled in a double blind, placebo-controlled randomized trial of bupropion in combination with health education counseling for smoking cessation. Bivariate differences between menthol and non-menthol smokers were explored and baseline factors associated with smoking menthol cigarettes were identified. RESULTS: Participants averaged 46.5 years in age, predominantly female (66.1%), and smoked an average of 8.0 cpd (SD=2.5). The majority (83.7%) smoked menthol cigarettes. In bivariate analysis, menthol cigarette smokers were younger (mean age: 45 vs. 52 years p<0.0001), were more likely to be female (68% vs. 52% p=0.003) and had smoked for shorter duration (28 vs. 34 years p<0.0001) compared to non-menthol smokers. While depression and withdrawal scores were slightly higher and exhaled carbon monoxide values were lower among menthol smokers, the differences were not statistically significant. CONCLUSIONS: Among AA light smokers, younger individuals and females were more likely to smoke menthol cigarettes and may be more susceptible to the health effects of smoking. Appropriately targeted health education campaigns are needed to prevent smoking uptake in this high-risk population. PMID- 21816544 TI - Prediction of the intramuscular fat content in loin muscle of pig carcasses by quantitative time-resolved ultrasound. AB - A novel method for non-destructive intramuscular fat (IMF) estimation via spectral ultrasound backscatter analysis of signals obtained from pig carcasses early post mortem is described. A commercial hand-held ultrasound device (center frequency: 2.7 MHz) was modified to focus the sound beam to the longissimus muscle at the 2nd/3rd last rib. Time-resolved ultrasound backscatter signals of loin muscle were recorded 45 min p.m. on 82 pig carcass sides. Backfat width (d(BF)=18.9+/-3.8 mm) and muscle attenuation (alpha(muscle)=.77+/-.15 dB MHz(-1) cm(-1)) were assessed from the measured pulse echo data. Other propagation properties of skin, backfat and muscle tissue obtained in a previous investigation were incorporated into the signal pre-processing to minimize parameter estimation artifacts. Spectral and cepstral parameters were derived from time-gated backscattered signals measured in the central muscle region. The range of intramuscular fat (IMF) determined by ether extraction was representative for German pig populations (.7%<=IMF(chem)<=3.6%, coefficient of variation CV(IMF(chem))=44.8%). Variations of IMF were associated with variations of backfat width (CV(d(BF))=20.2%), muscle attenuation (CV(alpha(muscle))=19.3%), and slope of the backscattered amplitude spectrum (CV(m)=28.8%). A full cross validated multiple linear regression model using these parameters resulted in good predictability of IMF(chem) (R(2)=.76, RMSEP=.34%). Among all tested carcasses, 73% could be correctly classified into one of three IMF classes (LOW: <1%, MID: 1-2%, HIGH: >2%). Using a single threshold (2% IMF), about 92% of all carcasses were correctly classified. With respect to the inherent variability of IMF within a single muscle and the different tissue volumes used for the chemical and ultrasound based IMF estimations the remaining prediction errors are acceptable. Compared to previous ultrasound based studies, the number of acoustic parameters used for the IMF prediction could be reduced. Moreover, the used parameters are based on time-of-flight and spectral slope estimations, which are i) more robust with respect to measurement artifacts and ii) have a causal link to structural variations associated with IMF variations in pork loin. PMID- 21816545 TI - Reconstruction of digital nerves with collagen conduits. AB - PURPOSE: Digital nerve reconstruction with a biodegradable conduit offers the advantage of providing nerve reconstruction while providing a desirable environment for nerve regeneration. Many conduit materials have been investigated, but there have been few reports of human clinical trials of purified type I bovine collagen conduits. METHODS: We report a prospective study of 22 isolated digital nerve lacerations in 19 patients reconstructed with a bioabsorbable collagen conduit. The average nerve gap measured 12 mm. An independent observer performed the postoperative evaluation, noting the return of protective sensation, static 2-point discrimination, and moving 2-point discrimination, and recording the patient's pain level using a visual analog scale. Minimal follow-up was 12 months and mean follow-up was 20 months after surgery. RESULTS: All patients recovered protective sensation. The mean moving 2 point discrimination and static 2-point discrimination measured 5.0 and 5.2 mm, respectively, for those with measurable recovery at final follow-up visit. Excellent results were achieved in 13 of 22 digits, good results in 3 of 22 digits, and fair results in 6 of 22 digits, and there were no poor results. Reported pain scores at the last postoperative visit were measured universally as 0 on the visual analog scale. CONCLUSIONS: Our data suggest that collagen conduits offer an effective method of reconstruction for digital nerve lacerations. This study confirms that collagen conduits reliably provide a repair that restores nerve function for nerve gaps measuring less than 2 cm. PMID- 21816546 TI - Surgical technique for thumb-in-palm deformity in cerebral palsy. AB - The most common surgical procedure performed by hand surgeons in cerebral palsy for thumb-in-palm deformity is release of the adductor pollicis muscle from the middle metacarpal origin, with additional release of the thenar muscles or flexor pollicis longus, as indicated, to decrease the flexion adduction forces across the first ray. Tendon transfer to augment extension and abduction of the thumb metacarpal will help avoid recurrence, and it commonly includes rerouting of the extensor pollicis longus. Stabilization of the metacarpophalangeal joint might be necessary if hyperextension deformity exists. The assessment of the patient should occur over several visits to determine the correct combination of procedures that will best help the patient achieve a more functional upper extremity or improve hygiene. With appropriate planned procedure, meticulous surgical technique, and adherence to a postoperative rehabilitation regimen, patients can obtain substantial improvement with thumb-in-palm surgical re positioning. PMID- 21816547 TI - [Hepatitis B prevalence and risk factors in Morocco]. AB - AIM: The aim of this study was to determine the prevalence of hepatitis B and the risk factors in Morocco. STUDY DESIGN: A total number of 16,634 individuals were screened for HBsAg using the Murex HBsAg Version 3 assay and were interviewed using a structured standard questionnaire to collect information about risk factor. RESULTS: Two hundred seventy-six subjects were positive for HBsAg, the prevalence of HBV infection was 1.66%. Using a structured standard questionnaire we reported that sexual behaviours (43.84%) are among the main risk factors for HBV transmission. CONCLUSION: This study indicates that the prevalence of HBsAg in Morocco is currently estimated at 1.66% in the active population. The risk factors for HBV infection identified here indicate that prevention is the most cost-effective method for successfully controlling HBV infection, so vaccination remains the best way to control this infection and its related complications. PMID- 21816548 TI - Higher incidence of thyroid agenesis in Mexican newborns with congenital hypothyroidism associated with birth defects. AB - BACKGROUND: Congenital hypothyroidism (CH) is the most common endocrine system disorder in newborns. Ectopic thyroid and agenesis are the most frequent thyroid structural malformations. Several reports have shown that CH is associated with birth defects (BD) ranging from congenital heart disease to ocular and gastrointestinal anomalies. AIMS: We investigated how many and what types of BD were associated with CH in Mexican children. STUDY DESIGN: Cross-sectional study conducted in patients with confirmed CH. SETTING: Highly specialized government pediatric center in Mexico City. SUBJECTS: We included 212 patients with permanent CH identified by newborn screening. RESULTS: We found that 24% of patients with CH also had BD, and that there was a higher prevalence of thyroid agenesis in the group of patients with CH associated with BD (CH+BD) versus the isolated CH group (p=0.007). There were more females than males in both groups. The most common BD were congenital heart diseases, especially those of the atrial septum, followed by patent ductus arteriosus, found as a single malformation or as part of a complex congenital heart disease. In this study, we found Hirschsprung disease, Beckwith-Wiedemann syndrome, Pierre Robin sequence, Albright's osteodystrophy, VATER association, and frontonasal dysplasia associated with CH. CONCLUSIONS: In this study population, there was a high prevalence of BD in patients with permanent CH. Thyroid agenesis was the main etiological cause of CH in patients with associated congenital malformations. The high prevalence of CH+BD underlines the need for a comprehensive clinical diagnostic approach of the patients with CH. PMID- 21816549 TI - Effect of location and stage of development of dominant follicle on ovulation and embryo survival rate in alpacas. AB - This study was designed to determine the effect of location of the preovulatory dominant follicle and stage of ovarian follicle development on ovulation rate and embryo survival in alpacas. In Experiment 1, mature lactating alpacas were randomly assigned to one of two groups according to the location of the dominant follicle detected by ultrasonography: (a) Right ovary (RO, n=96) or (b) Left ovary (LO, n=108). All females were mated once by an intact adult male. Ovulation rate, CL diameter and embryo survival rate (heartbeat) were assessed by ultrasonography on Days 2 (Day 0=mating), 8 and 30, respectively. Ovulation rate (96.5 and 96.3% for RO and LO group, respectively), corpus luteum (CL) diameter (10.2 and 10.6 mm for RO and LO group, respectively) and pregnancy rate (60.2 and 56.7% for RO and LO group, respectively) did not differ among groups. In Experiment 2, lactating alpacas (n=116) were submitted to ultrasonic-guided follicle ablation to synchronize follicular wave emergence. Afterwards, daily ultrasonography examinations were performed and females were randomly assigned to the following groups according to the growth phase and diameter of the dominant follicle: (a) early growing (5-6 mm, n=27), (b) growing (7-12 mm, n=30); (c) static (7-12 mm, n=30), or (d) regressing phase (12-7 mm, n=29). All alpacas were mated with a proven intact male, except five alpacas from early growing group that rejected the male. Females were examined by ultrasonography on Day 2 (ovulation rate), Day 8 (CL diameter), and Days 15, 20, 25, 30 and 35 (embryo survival by the presence of embryo proper and heartbeat). No differences were detected in ovulation rate among groups (96%, 97%, 100%, and 97%) or in CL size (10.3, 11.7, 11.1, and 11.1 mm, for early growing, growing, early static and regressing, respectively). Although, embryo survival rate at Day 35 after mating was numerically greatest in growing (65.5%), intermediate in early growing (52.4%) and static (53.3%), and least in regressing phase (42.9%), there were no differences among groups. Results suggest that neither location nor stage of development of the dominant follicle has an influence on ovulation and embryo survival rate in alpacas. PMID- 21816550 TI - Therapeutic targets for premature ejaculation. AB - Premature ejaculation (PE) is the most common male sexual complaint, and may exert a profound negative impact on the man's life and partnership. Using currently available treatment alternatives (e.g., selective serotonin uptake inhibitor, agents acting locally on the penis), PE can be treated in most, but not all patients. However, since long term success rates have been disappointing, and the only approved treatment so far is the short-acting selective serotonin re uptake inhibitor dapoxetine, there is currently an intensive search for new treatment modalities. Selection of the most promising therapeutic targets from a host of current and potential candidates depends heavily on their roles in the pathophysiology of PE. Possible central nervous targets that will be discussed are serotonin transporters, and CNS receptors for 5-HT(IA) and 5-HT(1B), dopamine, oxytocin, opioids, neurokinin-1, and glutamate. Putative peripheral targets include alpha(1)-adrenoceptors, phosphodiestrase enzymes, Rho kinases, purinergic (P2X) receptors, and penile sensory nerves. It is clear that exploiting the full therapeutic potential of these targets will require additional basic and clinical research. PMID- 21816551 TI - Methods for detection and confirmation of HematideTM/peginesatide in anti-doping samples. AB - Since the 1990's, cheating athletes have abused substances to increase their oxygen transport capabilities; among these substances, recombinant EPO is the most well known. Currently, other investigational pharmaceutical products are able to produce an effect similar to EPO but without having chemical structures related to EPO; these are the synthetic erythropoiesis stimulating agents (ESAs). Peginesatide (also known as HematideTM) is being developed by Affymax and Takeda and, if approved by regulatory authorities, could soon be released on the international market. To detect potential athletic abuse of this product and deter athletes who consider cheating, we initiated a collaboration to implement a detection test for anti-doping purposes. Peginesatide is a synthetic, PEGylated, investigational, peptide-based erythropoiesis-stimulating agent that is designed and engineered to stimulate specifically the erythropoietin receptor dimer that governs erythropoiesis. It is undetectable using current anti-doping tests due to its lack of sequence homology to EPO. To detect and deter potential abuse of peginesatide, we initiated an industry/antidoping laboratory collaboration to develop and validate screening and confirmation assays so that they would be available before peginesatide reaches the market. We describe a screening ELISA and a confirmation assay consisting of immune-purification followed by separation with SDS-PAGE and revelation with Western double blotting. Both assays can detect 0.5 ng/mL concentrations of peginesatide in blood samples, enabling detection for several days after administration of a physiologically relevant dose. This initial report describes experimental characterization of these assays, including testing with a blinded set of samples from a clinical study conducted in healthy volunteers. PMID- 21816552 TI - Comparative study of Greulich and Pyle Atlas and Maturos 4.0 program for age estimation in a Portuguese sample. AB - Age estimation of living individuals has become one of the big issues of forensic anthropology. The increase of children and adolescents with no valid proof of their chronological age is a legal concern to many countries, especially in situations of illegal immigration, sub adult delinquency and juvenile work. For this purpose, the use of radiological methods for evaluation of skeletal maturation is particularly useful. In this study we compare the two of the most common methods applied in age estimation by hand/wrist radiographs: the Radiographic Atlas of Skeletal Development of the Hand and Wrist made by Greulich and Pyle (GP), 1959,and the Sempe method developed for computer--Maturos 4.0 (MT) program. These methods were applied to a sample of 230 radiographs of the hand and wrist from Portuguese children and adolescents of known sex age and age, aged between 12 and 20 years, who performed medical examination at the University of Coimbra Hospitals during 2005. The methods achieved different performances, depending on the age group. Between 12 and 15 years the bone age with the MT program is closer to the chronological age, whereas in older ages the GP Atlas method is more trustworthy. At the ages with legal consequences in Portugal (16 and 18 years) the GP Atlas method is most accurate, namely to decide whether an individual is younger or older than 18 years. Around 16 years old, although there are doubts in relation to the accuracy of both methods, GP Atlas seems to perform better. PMID- 21816553 TI - Inconsistency in 9 mm bullets measured with non-destructive X-ray computed tomography. AB - Fundamental to any ballistic armour standard is the reference projectile that is to be defeated. Typically, for certification, consistency of bullets is assumed. Therefore, practical variations in bullet jacket dimensions can have far reaching consequences. Traditionally, internal dimensions could only be analysed by cutting bullets which rules out any subsequent ballistic assessment. Therefore, the use of a non-destructive X-ray computed tomography (CT) method is explored in this paper. A set of 10 bullets (9 mm DM11) was taken for analysing both intra and inter bullet jacket thickness variation. CT measurements of jacket thickness were validated with high resolution scanning electron microscope (SEM) images. An image based analysis methodology has been developed to extract the jacket thickness map and the centre of gravity. Thickness variations of the order of 200 MUm were found commonly across all the bullets along the length and an angular variation of up to 100 MUm was found in a few bullets. Jacket thickness and centre of gravity were also calculated for the same bullets after impact and the variations between the pre- and post-impacted bullets were compared, by establishing a common physical reference. The results show that the proposed CT scanning approach and subsequent image analysis method can bring out the statistical variations in bullet geometry pre- and post impact effectively. PMID- 21816554 TI - SARM-S4 and metabolites detection in sports drug testing: a case report. AB - Recently, pharmaceutical industry developed a new class of therapeutics called Selective Androgen Receptor Modulator (SARM) to substitute the synthetic anabolic drugs used in medical treatments. Since the beginning of the anti-doping testing in sports in the 1970s, steroids have been the most frequently detected drugs mainly used for their anabolic properties. The major advantage of SARMs is the reduced androgenic activities which are the main source of side effects following anabolic agents' administration. In 2010, the Swiss laboratory for doping analyses reported the first case of SARMs abuse during in-competition testing. The analytical steps leading to this finding are described in this paper. Screening and confirmation results were obtained based on liquid chromatography tandem mass spectrometry (LC-MS/MS) analyses. Additional information regarding the SARM S-4 metabolism was investigated by ultra high-pressure liquid chromatography coupled to quadrupole time-of-flight mass spectrometer (UHPLC-QTOF MS). PMID- 21816555 TI - Purification of d-a-tocopheryl polyethylene glycol 1000 succinate (TPGS) by a temperature-modulated silica gel column chromatography: use of Taguchi method to optimize purification conditions. AB - The demand for high purity d-a-tocopheryl polyethylene glycol 1000 succinate (TPGS) is increasing with the exploitation of TPGS-related products. Previously, we synthesized a TPGS mixture by esterifying vitamin E succinate with polyethyleneglycol 1000. In this study, a temperature-modulated silica gel chromatographic column was used to purify the synthesized TPGS. Taguchi method was used to optimize purification conditions associated with column temperature, loading amount, feedstock concentration and flow rate of mobile phases. Purification efficacy under the Taguchi optimized conditions was predicted theoretically and the predicted results were verified experimentally. High performance liquid chromatography was used to quantify the unpurified and purified TPGS. The Taguchi-based analysis separately produced an optimum combination of purification conditions for TPGS purity and recovery. Under the optimized conditions, both the theoretical prediction and the confirmatory experiment yielded TPGS purity and recovery approximating to 98% each. Impressively, the study also found that column temperature had a considerable effect on purification efficacy, in particular on TPGS purity, although it was a less influential factor compared to loading amount and feedstock concentration. PMID- 21816556 TI - A high-throughput spectrophotometric approach for evaluation of precipitation resistance. AB - Many drugs that come out of discovery today are extremely challenging to formulate because of their high hydrophobicity and low water solubility. A kinetic, spectrophotometric approach for the rapid evaluation of precipitation resistance of multiple solubilized formulations that can be run on a very small scale is proposed. Using this high-throughput approach, multiple formulations are screened for inhibition of precipitation upon dilution into an aqueous environment. Data generated using the in vitro spectrophotometric approach is comparable to the traditional chromatographic approaches. Similar approaches have been previously attempted, but in this study, the focus is on pharmaceutical development of solubilized formulations by evaluation of the events post precipitation as opposed to determining the moment at which precipitation is observed, which is usually the case in kinetic solubility measurements. The information garnered thus offers insights not just into amount of precipitation, but also to the size and nature of the precipitate. Overall, this technique offers the potential to change the approach to the development of toxicology vehicles and solubilized clinical formulations for oral administration. PMID- 21816557 TI - Physician-child interaction: when children answer physicians' questions in routine medical encounters. AB - OBJECTIVE: The objective of the study is to examine predictors of children answering questions during primary care pediatric visits. METHODS: Relying on a sample of 322 video-taped community practice encounters, this study identifies predictors of when children answer physicians' questions. Multi-level multivariate regressions were used to model the relationships among communication and socio-demographic variables and whether or not children answered questions pediatricians asked them. RESULTS: Whereas race and education predict whether physicians select children to answer questions, these factors are not associated with whether children answer physicians' questions. Instead, a child's performance is associated with communication practices specific to physician child interaction such as the grammatical type of question and doctor gaze. CONCLUSION: Children are less responsive to physicians' questions than their parents but their failure to answer is predictable and thus can be improved. By increasing their participation in the visit, physicians may (a) secure more information about children's health and (b) socialize children to be more pro active patients. PRACTICE IMPLICATIONS: Physicians can improve the likelihood that children will answer their questions by (a) asking them social questions early in the visit, (b) phrasing their questions as yes-no questions, and (c) and directing their gaze at the children during each question. PMID- 21816558 TI - Blood alcohol concentration at 0.06 and 0.10% causes a complex multifaceted deterioration of body movement control. AB - Alcohol-related falls are recognized as a major contributor to the occurrence of traumatic brain injury. The control of upright standing balance is complex and composes of contributions from several partly independent mechanisms such as appropriate information from multiple sensory systems and correct feedback and feed forward movement control. Analysis of multisegmented body movement offers a rarely used option for detecting the fine motor problems associated with alcohol intoxication. The study aims were to investigate whether (1) alcohol intoxication at 0.06 and 0.10% blood alcohol concentration (BAC) affected the body movements under unperturbed and perturbed standing; and (2) alcohol affected the ability for sensorimotor adaptation. Body movements were recorded in 25 participants (13 women and 12 men, mean age 25.1 years) at five locations (ankle, knee, hip, shoulder, and head) during quiet standing and during balance perturbations from pseudorandom pulses of calf muscle vibration over 200s with eyes closed or open. Tests were performed at 0.00, 0.06, and 0.10% BAC. The study revealed several significant findings: (1) an alcohol dose-specific effect; (2) a direction specific stability decrease from alcohol intoxication; (3) a movement pattern change related to the level of alcohol intoxication during unperturbed standing and perturbed standing; (4) a sensorimotor adaptation deterioration with increased alcohol intoxication; and (5) that vision provided a weaker contribution to postural control during alcohol intoxication. Hence, alcohol intoxication at 0.06 and 0.10% BAC causes a complex multifaceted deterioration of human postural control. PMID- 21816559 TI - Interactions of the LIPG 584C>T polymorphism and alcohol consumption on serum lipid levels. AB - Both endothelial lipase gene (LIPG) 584C>T (rs2000813) polymorphism and alcohol consumption modulate serum lipid levels. But their interactions on serum lipid profiles are not well known. The present study was undertaken to detect the interactions of LIPG 584C>T polymorphism and alcohol consumption on serum lipid levels. Genotyping of the LIPG 584C>T was performed in 763 unrelated nondrinkers and 520 drinkers aged 15-85 years. The levels of serum total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), apolipoprotein (Apo) AI, and the ratio of ApoAI to ApoB were higher in drinkers than in nondrinkers (P<.01 for all). There were no significant differences in the genotypic and allelic frequencies between nondrinkers and drinkers. The levels of TC, HDL-C, and ApoAI in nondrinkers were different among the three genotypes (P<.05-.01), the subjects with CT genotype had higher TC, HDL-C, and ApoAI levels than the subjects with CC genotype. The levels of HDL-C and ApoAI in drinkers were different among the three genotypes (P<.001 and P<.05; respectively), the individuals with TT genotype had higher HDL-C and ApoAI levels than the individuals with CT and CC genotypes. The interactions between LIPG 584C>T genotypes and alcohol consumption on serum HDL-C (P<.01) and ApoAI levels (P<.05) were also detected by using a factorial regression analysis after controlling for potential confounders. The levels of TC in nondrinkers were correlated with LIPG 584C>T alleles (P<.05), whereas the levels of TG and HDL-C were associated with LIPG 584C>T alleles (P<.05) and genotypes (P<.05), respectively. These results suggest that the subjects with TT genotype benefit more from alcohol consumption than the subjects with CT and CC genotypes in increasing serum HDL-C and ApoAI levels. PMID- 21816560 TI - Place conditioning with ethanol in rats bred for high (UChB) and low (UChA) voluntary alcohol drinking. AB - The main goal of this study was to investigate the ability of an ethanol dose (1g/kg) administered intraperitoneally to induce conditioned place preference (CPP) and/or conditioned place aversion (CPA) in two lines of rats selectively bred for their high (UChB) or low (UChA) voluntary ethanol intake. It was found that five pairings with ethanol induced CPA in ethanol-naive rats of both lines, but the magnitude of avoidance was lower in the UChB relative to the UChA rats, indicating that ethanol was less aversive to naive rats bred for high alcohol drinking. After 2 months of high voluntary ethanol drinking (~6-7g/kg/day), in free choice between 10% ethanol and water, ethanol produced CPP in UChB rats, reflecting that ethanol had become rewarding to these rats. By contrast, the low voluntary ethanol intake (<1g/kg/day) displayed by UChA rats preexposed for 2 months in free choice did not change ethanol-induced CPA. However, preexposure of UChA rats to forced ethanol drinking (~5.7g/kg/day) and the later inhibition of ethanol-derived acetaldehyde by 4-methylpyrazole (10mg/kg intraperitoneal), an inhibitor of the enzyme alcohol dehydrogenase, not only increased their voluntary ethanol intake in free choice, but also had a facilitating effect on the development of CPP. Taken together, these results show that the expression of the reinforcing effects of ethanol required a period of voluntary ethanol intake in UChB rats, whereas in UChA rats, both prior exposure to forced ethanol drinking and reduction of high blood ethanol-derived acetaldehyde were required. PMID- 21816561 TI - Changes in magnetic resonance imaging signal intensity of transplanted meniscus allografts are not associated with clinical outcomes. AB - PURPOSE: To evaluate changes in intrameniscal signal intensity (IMSI) of transplanted allografts during the first year after meniscus allograft transplantation (MAT) by use of serial magnetic resonance imaging, as well as to analyze the relation between IMSI and clinical outcome. METHODS: This prospective study involved 43 patients who underwent MAT between 2006 and 2007 after diagnosis of total or subtotal meniscectomized knees. The mean patient age at the time of surgery was 35.8 years (range, 17 to 46 years). Allografts were assessed by conventional magnetic resonance imaging performed at 6 weeks and 3, 6, and 12 months after MAT. The ratio of the signal intensity of the transplanted meniscus allograft to that of the control normal meniscus in the ipsilateral knee was calculated to obtain a standardized signal intensity value. IMSI was assessed in terms of postoperative time and location (anterior v posterior horn). The Lysholm score was used to evaluate knee function. RESULTS: The IMSI of transplanted allograft menisci was higher than that for nontransplanted menisci at all 4 postoperative time points (P < .01). The anterior horn allograft IMSI was greater than the posterior horn allograft IMSI at all time points (P < .01). The allograft IMSI increased starting 3 months postoperatively for the anterior horn (F(3,40) = 7.5, P < .01) and 6 months postoperatively for the posterior horn (F(3,40) = 9.2, P < .01). These increases were maintained to the final assessment at 1 year postoperatively. No correlation was found between IMSI and postoperative Lysholm score. CONCLUSIONS: Transplanted allograft menisci had higher signal intensities than normal menisci. Signal intensity was higher for the anterior horn than the posterior horn throughout the first postoperative year. Signal intensity increased over time, and this increase was maintained at 1 year postoperatively. However, signal intensity was not related to clinical outcome. LEVEL OF EVIDENCE: Level II, development of diagnostic criteria based on analysis of consecutive patients, applying a universally recognized gold standard. PMID- 21816563 TI - [Diagnosis of crystal-induced arthritis]. AB - Crystal-induced arthritis (CIA) is easy to diagnose as soon as the physician might suspect the diagnosis. Indeed, CIA can be readily ascertained since one single gold standard is available: identification of microcrystals in synovial fluid or in other materials (tophus, synovial tissue biopsy, periarticular tissues). It is therefore mandatory to perform joint aspiration and to get synovial fluid sample for microscopic examination. Monosodium urate crystals are the key feature of gout, and calcium pyrophosphate (CPP) crystals are associated with CPP disease, also called "chondrocalcinosis" in France. Diagnosis of gout can be readily suspected when considering typical clinical presentations such as podagra, presence of tophi, cardiovascular comorbidities, and diuretics use. Plain radiographs, as long as technical quality is present, are an easy way to suspect and eventually to diagnose CPP disease or apatite deposits in any articular or periarticular site. Joint ultrasonography when performed by skilled physicians can easily help in displaying crystal deposits at the cartilage surface (gout) or within the cartilage (CPP), along with peri-tophaceous inflammatory reaction as evidenced by power Doppler. PMID- 21816562 TI - [Risk of accumulation of CO2 in the oxygen chamber in "HOOD" (Experimental study on test bed)]. AB - OBJECTIVES: Oxygen hood is largely used to deliver O2 to newborn infants with respiratory failure in the northern region of France. The oxygen flow is set to obtain the target arterial blood oxygen saturation. Thus, O2 flow delivers into the hood may be below the recommended gas flow of 6L/min. However, gas flow below 6L/min exposes to CO2 rebreathing. The aim of this study was to evaluate the effect of various rates of gas flows on the values of partial pressure of CO2 into the hood. MATERIAL AND METHODS: We measured CO2 and O2 partial pressure into hoods of two different volumes (4 and 10L) under two experimental bench test conditions. Protocol 1: gas flow was constant at 6L/min, while oxygen fraction varied from 0.21 to 1. Partial pressure of CO2 and O2 were recorded. Protocol 2: while O2 fraction was kept constant, oxygen flow varied from 0.5 to 7L/min (by step of 0.5L/min). Partial pressure of CO2 and O2 were recorded. RESULTS: Partial pressure of CO2 increases proportionally to the decrease in the gas flow delivered into the hood, and reached 14 mmHg at gas flow of 0.5L/min. CONCLUSION: Risk of CO2 rebreathing exists as soon as the gas is delivered into the hood at minimal flow rates below 6L/min. PMID- 21816564 TI - [Streptococcus pneumonia infection and positive blood culture with Francisella tularensis, in a renal transplant recipient]. PMID- 21816565 TI - [Watching the river flow]. PMID- 21816567 TI - The movement assessment battery in Greek preschoolers: the impact of age, gender, birth order, and physical activity on motor outcome. AB - Early identification of possible risk factors that could impair the motor development is crucial, since poor motor performance may have long-term negative consequences for a child's overall development. The aim of the current study was the examination of disorders in motor coordination in Greek pre-school aged children and the detection of differences in motor performance with regards to age, gender, participation in sports and order of birth in the family. Performance profiles on the movement ABC were used to classify 412 Greek children aged 4-6 years old. It appears from the results that the occurrence rate of probable developmental coordination disorders (DCD) was 5.4%. Significant differences were observed in all independent variables except the order of birth in the family. The findings reinforce the need for the evaluation of motor performance in preschool-aged children, in order specific individual motor profiles to be established for optimizing and adapting early intervention programs. PMID- 21816568 TI - Factors influencing the intention of students to work with individuals with intellectual disabilities. AB - Providing adequate care to individuals with intellectual disability (ID) requires the willingness of students in various health and social professions to care for this population upon completion of their studies. The aim of the current study was to examine the factors associated with the intentions of students from various fields to work with individuals with ID, using the framework of the Theory of Planned Behavior. A structured self-administered questionnaire was completed by 512 social work, occupational therapy, speech and language therapy, special education, and nursing students. The questionnaire measured students' attitudes toward individuals with ID and toward working with this population, as well as their perceptions of subjective norms, controllability, self-efficacy, prior acquaintance with individuals with ID, and subjective knowledge about ID. Structural equation modeling showed that the students' intentions to work with individuals with ID were predicted by their attitudes and perceptions of subjective norms. Field of study and subjective knowledge were also found to be predictive of behavioral intention. The TPB proved to be a useful framework for examining students' intentions to work with persons with ID. Given the lack of education in the field of ID, as well as the prevailing stigmatic attitudes toward this population, university departments should develop programs aimed at increasing knowledge, promoting positive contact, and reducing the fear attached to working with persons with intellectual disability. PMID- 21816569 TI - Laryngeal electromyography-guided hyaluronic acid vocal fold injection for unilateral vocal fold paralysis--preliminary results. AB - OBJECTIVES: The purpose of this study is to investigate the feasibility of using an injectable needle electrode to guide hyaluronic acid (HA) vocal fold injection (VFI) during laryngeal electromyography (LEMG) for unilateral vocal fold paralysis (UVFP). STUDY DESIGN: Prospective study. METHODS: From March to June 2010, 20 UVFP patients received LEMG examination at our clinic. Before completion of LEMG, 1.0 cc of HA (Restylane Perlane((r)); Q-Med, Uppsala, Sweden) was injected via a 26-gauge monopolar injectable needle electrode into paralyzed thyroarytenoid muscle. After injection, 20 patients completed 3-months follow-up and 16 patients completed 6-months follow-up. The data before, 1 week, 3 months, and 6 months after injection, including the normalized glottal gap area (NGGA) from videostroboscopy, maximal phonation time (MPT), mean airflow rate (MAFR), phonation quotient (PQ), perceptual evaluation of voice (grade, roughness, breathiness, asthenia, strain [GRBAS] scale), Voice Handicap Index (VHI), and self-grading of choking (grade 1-7), were analyzed by the Wilcoxon signed rank test. RESULTS: All of the patients completed the procedure without complications. After injection, mean NGGA was significantly reduced from 8.28 units to 0.52 units (1 week), 1.79 units (3 months), and 1.36 units (6 months). The mean MPT was prolonged from 5.66 seconds to 11.73, 11.25, and 11.93 seconds, respectively. VHI was reduced from 76.05 to 38.10, 37.40 and 35.00, respectively. Other analyzed data (PQ, MAFR, GRBAS scale, and choking severity) also showed statistically significant improvement. CONCLUSION: LEMG-guided HA VFI provides UVFP patients with neuromuscular function evaluation and treatment in one step. This clinical technique is feasible, and the short-term results are satisfactory. PMID- 21816570 TI - Normative values for the Voice Handicap Index-10. AB - OBJECTIVES: The objective of this study was to elucidate the normative values for the Voice Handicap Index-10 (VHI-10) questionnaire. METHODS: VHI questionnaires were completed by 190 subjects without voice complaints. The results were then analyzed for mean, standard error of the mean (SEM), and standard deviation (SD) for both the original VHI and VHI-10 subset questionnaires. Outliers were defined as being more than three standard deviations above the mean. RESULTS: Analysis of 156 VHI questionnaires revealed a mean of 6.86 (SEM=0.79, SD=9.88) for the normative values. One hundred fifty-eight VHI-10 questionnaires were analyzed to show a mean of 2.83 (SEM=0.31, SD=3.93) for the normative values. CONCLUSIONS: This study offers normative data for the VHI-10 that has been missing in the literature. A VHI-10 score >11 should be considered abnormal. PMID- 21816571 TI - A new method of reconstructing the human laryngeal architecture using micro-MRI. AB - OBJECTIVES/HYPOTHESIS: A realistic three-dimentional (3D) model of the larynx could be of value for the understanding of normal laryngeal motion and for studying pathological changes as well as in modeling potential therapy outcomes. The objective of this research was to present a new method of creating a computer model of the human larynx using data obtained through micro-magnetic resonance imaging (MRI) scanning. STUDY DESIGN: Prospective study. METHODS: A 7-T micro-MRI scanner was used to scan an excised larynx obtained postmortem from a 68-year-old woman. MRI data was manually segmented and compiled into 3D images using Mimics12.1 reconstruction software. Measurements of the reconstructed structures were also calculated using Mimics12.1. RESULTS: The 3D laryngeal model contained the thyroid, cricoid, and arytenoid cartilages. Nearly all of the intrinsic muscles could be segmented. Although the cricoarytenoid joint could be visualized, the features of the cricothyroid joint were not clear. Muscle and cartilage volumes and surface areas were calculated from the 3D model. CONCLUSIONS: The combination of MRI and 3D reconstruction generates promising results in the hopes of creating a highly realistic and detailed model of the human larynx. PMID- 21816572 TI - Pitch-matching in poor singers: human model advantage. AB - Previous studies on action imitation have shown an advantage for biological stimuli compared with nonbiological stimuli, possibly because of the role played by the mirror system. By contrast, little is known on whether such an advantage also takes place in the auditory domain, related to voice imitation. OBJECTIVES/HYPOTHESIS: In this study, we wanted to test the hypothesis that auditory stimuli could be more accurately reproduced when the timbre is human than when the timbre is synthetic. METHODS: Eighteen participants judged as poor singers and 14 controls were presented with vocal and synthetic singing models and had to reproduce them. RESULTS AND CONCLUSION: Results showed that poor singers were significantly helped by the human model. This effect of the human model on production might be linked to the preactivation of motor representations (auditory mirror system) during voice perception, which may in turn facilitate the imitative vocal gesture. PMID- 21816573 TI - Augmentation of vocal fold using a fat block implant following cordotomy through a minithyrotomy approach in a rabbit model. AB - OBJECTIVES: Minithyrotomy is a novel approach that provides direct access to the lamina propria and vocalis muscle without requiring incision of the vocal fold mucosa. The aim of this study was to demonstrate the efficacy of minithyrotomy vocal fold augmentation in a rabbit model by comparing the vocal fold total square amount and the density of scars between the cordotomy with minithyrotomy group and a cordotomy without minithyrotomy group. STUDY DESIGN: Animal study. METHODS: Twenty adult laboratory-conditioned female rabbits were used for this study. Minithyrotomy vocal fold augmentation was performed using a single fat block implant 3 months after cordotomy. To compare total square amount and density of vocal folds between the minithyrotomy and cordotomy group, hematoxylin and eosin, Masson's trichrome, and alcian blue staining was used. RESULTS: Histological examinations showed that minithyrotomy vocal fold augmentation postoperatively restored vocal fold bulkiness and maintained volume for up to 6 months, compared with the cordotomy group (P<0.05). In light of the surgical manipulation, the procedure also did not aggravate scarring of the cordectomized vocal fold. CONCLUSIONS: Minithyrotomy vocal fold augmentation using an autologous fat block may soon be feasible in humans undergoing rehabilitation for postcordotomy dysphonia without causing additional damage to the vocal folds. PMID- 21816574 TI - A technique for graphical recording of range of motion using an improvised paper goniometer. PMID- 21816575 TI - Case study: a patient-clinician collaboration that identified and prioritized evidence gaps and stimulated research development. AB - OBJECTIVE: To assess the effect of a research prioritization partnership that aimed to influence the research agenda relating to urinary incontinence (UI). STUDY DESIGN AND SETTING: Research often neglects important gaps in existing evidence so that decisions must be made about treatments without reliable evidence of their effectiveness. In 2007-2009, a United Kingdom partnership of eight patient and 13 clinician organizations identified and prioritized gaps in the evidence that affect everyday decisions about treatment of UI. The top 10 prioritized research questions were published and reported to research funders in 2009. A year later, new research or funding applications relating to the prioritized topics were identified through reviews of research databases and consultation with funding organizations, elements of the research community, and organizations that participated in the partnership. RESULTS: Since dissemination of the prioritized topics, five studies are known to have been funded, three in development; five new systematic reviews are under way, one is being updated; five questions are under consideration by a national research commissioning body. CONCLUSION: The partnership successfully developed and used a methodology for identification and prioritization of research needs through patient-clinician consensus. Prioritization through consensus can be effective in informing the development of clinically useful research. PMID- 21816576 TI - Number needed to treat is incorrect without proper time-related considerations. AB - The number needed to treat (NNT) is a simple measure of a treatment's impact, increasingly reported in randomized trials and observational studies. Its calculation in studies involving varying follow-up times or recurrent outcomes has been criticized. We discuss the NNT in these contexts, illustrating using several published studies. The computation of the NNT is founded on the cumulative incidence of the outcome. Instead, several published studies use simple proportions that do not account for varying follow-up times, or use incidence rates per person-time. We show that these approaches can lead to erroneous values of the NNT and misleading interpretations. For example, after converting the incidence rate to a cumulative incidence, we show that a trial reporting a NNT of 4 "to prevent one exacerbation in 1 year" should have reported a NNT of 9. A survey of all papers reporting NNT, published in four major medical journals in 2009, found that 6 out of all 10 papers involving varying follow-up times did not correctly estimate the NNT. As the "number needed to treat" becomes increasingly used in complex studies and in the comparative effectiveness of therapies, its accurate estimation and interpretation become crucial to avoid erroneous clinical and public health decisions. PMID- 21816577 TI - On the interaction of bovine serum albumin with ionic surfactants: temperature induced EPR changes of a maleimide nitroxide reflect local protein dynamics and probe solvent accessibility. AB - The interaction of bovine serum albumin (BSA) with the ionic surfactants sodium dodecylsulfate (SDS, anionic), cetyltrimethylammonium chloride (CTAC, cationic) and N-hexadecyl-N,N-dimethyl-3-ammonio-1-propanesulfonate (HPS, zwitterionic) was studied by electron paramagnetic resonance (EPR) spectroscopy of spin label covalently bound to the single free thiol group of the protein. EPR spectra simulation allows to monitor the protein dynamics at the labeling site and to estimate the changes in standard Gibbs free energy, enthalpy and entropy for transferring the nitroxide side chain from the more motionally restricted to the less restricted component. Whereas SDS and CTAC showed similar increases in the dynamics of the protein backbone for all measured concentrations, HPS presented a smaller effect at concentrations above 1.5mM. At 10mM of surfactants and 0.15 mM BSA, the standard Gibbs free energy change was consistent with protein backbone conformations more expanded and exposed to the solvent as compared to the native protein, but with a less pronounced effect for HPS. In the presence of the surfactants, the enthalpy change, related to the energy required to dissociate the nitroxide side chain from the protein, was greater, suggesting a lower water activity. The nitroxide side chain also detected a higher viscosity environment in the vicinity of the paramagnetic probe induced by the addition of the surfactants. The results suggest that the surfactant-BSA interaction, at higher surfactant concentration, is affected by the affinities of the surfactant to its own micelles and micelle-like aggregates. Complementary DLS data suggests that the temperature induced changes monitored by the nitroxide probe reflects local changes in the vicinity of the single thiol group of Cys-34 BSA residue. PMID- 21816578 TI - Silicon supported lipid-DNA thin film structures at varying temperature studied by energy dispersive X-ray diffraction and neutron reflectivity. AB - Non-viral gene transfection by means of lipid-based nanosystems, such as solid supported lipid assemblies, is often limited due to their lack of stability and the consequent loss of efficiency. Therefore not only a detailed thermo-lyotropic study of these DNA-lipid complexes is necessary to understand their interaction mechanisms, but it can also be considered as a first step in conceiving and developing new transfection biosystems. The aim of our study is a structural characterization of 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC)-dimethyl dioctadecyl-ammonium bromide (DDAB)-DNA complex at varying temperature using the energy dispersive X-ray diffraction (EDXD) and neutron reflectivity (NR) techniques. We have shown the formation of a novel thermo-lyotropic structure of DOPC/DDAB thin film self-organized in multi-lamellar planes on (100)-oriented silicon support by spin coating, thus enlightening its ability to include DNA strands. Our NR measurements indicate that the DOPC/DDAB/DNA complex forms temperature-dependent structures. At 65 degrees C and relative humidity of 100% DNA fragments are buried between single lamellar leaflets constituting the hydrocarbon core of the lipid bilayers. This finding supports the consistency of the hydrophobic interaction model, which implies that the coupling between lipid tails and hypo-hydrated DNA single strands could be the driving force of DNA lipid complexation. Upon cooling to 25 degrees C, EDXD analysis points out that full-hydrated DOPC-DDAB-DNA can switch in a different metastable complex supposed to be driven by lipid heads-DNA electrostatic interaction. Thermotropic response analysis also clarifies that DOPC has a pivotal role in promoting the formation of our observed thermophylic silicon supported lipids-DNA assembly. PMID- 21816579 TI - Structural and dynamical characterization of unilamellar AOT vesicles in aqueous solutions and their efficacy as potential drug delivery vehicle. AB - Sodium bis(2-ethylhexyl) sulfosuccinate (AOT) is well known to form nanometre sized aqueous droplets in organic solvents and used in several contemporary applications including templates of nanoparticle synthesis. However, the detailed structural characterization of AOT in aqueous media is relatively less attended. Here we have used dynamic light scattering technique for the structural characterization of AOT in aqueous solutions and found to have a monodispersed, unilamellar vesicles (~140 nm diameter). The efficacy of the vesicle to host both charged drugs like H258 (2'-(4-hydroxyphenyl)-5-[5-(4-methylpiperazine-1-yl) benzimidazo-2-yl-benzimidazole]), EtBr (ethidium bromide) and hydrophobic drug like DCM (4-(dicyanomethylene)-2-methyl-6-(p-dimethylamino-styryl)-4H-pyran) has also been investigated using Forster resonance energy transfer. Picosecond resolved and polarization gated spectroscopy have been used to study the solvation dynamics and microviscosity at the surface of the vesicles. We have also performed concentration and temperature dependent studies in order to confirm the stability of the vesicles in aqueous phase. The drug release profile of the vesicles has been studied through in vitro dialysis method. The non-toxic, monodispersed vesicles in aqueous media with a noteworthy stability in wide range of AOT concentration and temperature, capable of hosting drugs of various natures (both hydrophobic and charged) simultaneously for many codelivery applications with controlled drug release profile may find its applications in drug delivery. PMID- 21816580 TI - Preparation of active antibacterial LDPE surface through multistep physicochemical approach: I. Allylamine grafting, attachment of antibacterial agent and antibacterial activity assessment. AB - Low-density polyethylene (LDPE) samples were treated in air plasma discharge, coated by polyallyamine brush thought copolymeric grafting surface-from reaction and deposited four common antibacterial agents (benzalkonium chloride, bronopol, chlorhexidine and triclosan) to gain material with active antibacterial properties. Surface characteristics were evaluated by static contact angle measurement with surface energy evaluation ATR-FTIR, X-ray Photoelectron Spectroscopy (XPS) and SEM analysis. Inhibition zone on agar was used as in vitro test of antibacterial properties on two representative gram positive Staphylococcus aureus (S. aureus) and gram negative Escherichia coli (E. coli) strains. It was confirmed, that after grafting of polyallyamine, more antibacterial agent is immobilized on the surface. The highest increase of antibacterial activity was observed by the sample containing triclosan. Samples covered by bronopol did not show significant antibacterial activity. PMID- 21816581 TI - Determination of explosives based on novel type of sensor using porphyrin functionalized carbon nanotubes. AB - The hydroxide of meso-tetraphenylporphyrin derivatives functionalized carbon nanotubes (CNTs) was fabricated in our research to explore the interaction between porphyrin and explosive. It was turned out that in the formation of grid porphyrin film, carbon nanotubes as a cruciul base materials promoted the electron transfer rate. Most of important, the results also showed that the electrochemical response was enhanced through increasing the number of -OH substitution in porphyrin. Such information provides the platform for a practical strategy for rational design of the sensor of explosives. PMID- 21816582 TI - Hydrogel containing L-valine residues as a platform for cisplatin chemotherapy. AB - Two acrylic hydrogels, of low cross-linking content and carrying the L-valine residues, were synthesized and studied as a platform to load and release the chemotherapeutic agent cisplatin. The platinum(II)-complex species showed a well defined stoichiometric ratio in which two carboxylate groups of the collapsing gel coordinate a metal center; this was confirmed by FT-IR spectra. When loaded in water, a zero-order release rate of platinum(II)-species was shown in the physiologic solution (PBS, pH 7.40) for more than one week. Moreover, the amount of platinum(II)-species released from the hydrogel may be improved either by the cross-linking degree and by the temperature. Any increase of the cross-links results in a decreased slope of the straightline Pt(II)/gel (mg/g) versus time, whereas the increasing temperature results in a greater amount of platinum(II) species in solution. The chemical- and swelling-controlled release are the main mechanisms supervising the whole release process. On the other hand, the loading of cisplatin and temsirolimus in DMF showed a characteristic two phase releasing pattern; the initial burst effect was always followed by the zero-order release rate for a week. In this case only a swelling-controlled mechanism was mainly invoked. The cytotoxic activity towards Me665/2/21 human melanoma cell line, afforded by the cisplatin-loaded hydrogel, was close and in some cases higher compared to the native cisplatin at the same concentration; an interesting synergy in term of cytotoxicity was observed when a combined treatment of temsirolimus and cisplatin was used, although temsirolimus exerted only a moderate inhibition of cell proliferation. PMID- 21816583 TI - Electropolymerisation of L-arginine at carbon paste electrode and its application to the detection of dopamine, ascorbic and uric acid. AB - L-arginine was electropolymerised on a carbon paste electrode (CPE) to form the biopolymer by free radical formation in the electro oxidation process of the amino and carboxylic group containing compound by cyclic voltammetric technique. The modified electrode shows an excellent electrocatalytic activity towards the oxidation of both dopamine (DA) and ascorbic acid (AA). It was demonstrated that the deposited biopolymer has positive charges over the bare carbon electrode surface, which leads to the formation of electrical double layer made the fast electron transfer process could leads to the diffusion of dopamine, ascorbic acid and uric acid on their charge gradient by cyclic voltammetric technique. The response of the sensor was tested towards the different dopamine concentration. The catalytic peak current obtained was linearly related to DA concentrations in the ranges of 5*10(-5) to 1*10(-4)M L(-1) with correlation co-efficient of 0.9924 which reveals the adsorption controlled process. The detection limit for dopamine was 5*10(-7)M L(-1). The interference studies showed that the modified electrode exhibits excellent selectivity in the presence of large excess of ascorbic acid (AA) and response is fast stable, reliable, resistant to biofouling and can be applied for the real sample analysis in medical, pharmaceutical and biotechnological sectors. The adsorption-controlled process and kinetic parameters of the poly(L-arginine) were determined using electrochemical approaches. PMID- 21816584 TI - Antibacterial activity and cytocompatibility of chitosan-N-hydroxy-2,3-propyl-N methyl-N,N-diallylammonium methyl sulfate. AB - A water-soluble quaternary ammonium salt of chitosan, chitosan-N-hydroxy-2,3 propyl-N-methyl-N,N-diallylammonium methyl sulfate (MDAACS), was synthesized by reacting chitosan with methyl diallyl ammonium salt (MDAA). The results of water contact angle and swelling ratio showed that the membrane of MDAACS was more hydrophilic than chitosan. The antibacterial activities of MDAACS against Staphylococcus aureus and Klebsiella pneumoniae were evaluated with the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC). The results showed that the antibacterial activity of MDAACS was higher than that of chitosan. The cytocompatibility was evaluated in vitro with L929 fibroblast proliferation based on MTT colorimetric assay. The results showed that cell growth was much higher on MDAACS than on chitosan. PMID- 21816585 TI - Study on the interaction of CdTe quantum dots with coumaric acid and caffeic acid based on fluorescence reversible tune. AB - This paper describes the synthesis of CdTe quantum dots (QDs) together capped by glutathione and thioglycolic acid (GSH and TGA) in aqueous solution. The narrow photoluminescence (fwhm <= 40 nm) CdTe QDs, whose emission spans most of the visible spectrum from green through red, has a quantum yield (QY) of 68% at room temperature. GSH/TGA-CdTe QDs are characterized by various experimental techniques such as optical absorption, photoluminescence and AFM measurements. Coumaric acid and caffeic acid is able to quench the fluorescence of GSH/TGA-CdTe QDs, and the fluorescence intensity is linearly proportional to the concentration of quenchers. The addition of bovine serum albumin (BSA) restores the fluorescence intensity of GSH/TGA-CdTe QDs-coumaric acid system and GSH/TGA-CdTe QDs-caffeic acid system. The fluorescence recovery was due to the interaction of BSA with coumaric acid and caffeic acid, leading to the freeing of the GSH/TGA CdTe QDs. The fluorescence quenching mechanism of GSH/TGA-CdTe QDs was discussed. The binding constant and thermodynamics parameters of BSA-coumaric acid and BSA caffeic acid during the binding process were calculated in the paper. PMID- 21816587 TI - [Current events in sudden unexpected death in infancy in 2011]. AB - In 2011, questions raised in medicine, by the occurrence of the unexpected death of an infant (SUDI), are far from having found definitive answers. Explanations remain fragmented, statistics are fuzzy, research is unsystematic and care protocols are still highly varied in spite of recommendations by the HAS (Haute Autorite de sante, French National Authority for Health) in 2007, which are, in practice, difficult to follow. After 17 years, preventive measures should have given much better results but they continue to come up against strong resistance from the public and certain professionals, a lack of proper resources and numerous contradictory messages from business, advertising and even medicine. PMID- 21816586 TI - [Cryptosporidium infection in patients with major histocompatibility complex class II deficiency syndrome in Tunisia: description of five cases]. AB - BACKGROUND: In Tunisia, Cryptosporidium is frequently identified in diarrheic stools of children and immunocompromised patients. The infection is usually self limited in immunocompetent populations, but can be severe and life-threatening in immunocompromised individuals. Cryptosporidiosis is well-documented in patients with the human immunodeficiency virus; however, few data are available concerning children with primary immunodeficiencies (PIDs). PATIENTS AND METHODS: A retrospective study was conducted on 5 cryptosporidiosis cases diagnosed in 11 children with PIDs. Cryptosporidium was systematically investigated when patients presented chronic diarrhea. Stool samples were examined for the parasite oocysts by modified Ziehl-Neelsen staining, and DNA was systematically extracted for a nested polymerase chain reaction (PCR). The species were identified by the analysis of restriction patterns. Epidemiological and clinicobiological data were presented for each patient. RESULTS: All cryptosporidiosis cases presented a CMH class II deficiency syndrome. Chronic diarrhea was associated with failure to thrive in all cases. PCR provided the diagnosis in all patients, while Ziehl Neelsen staining revealed Cryptosporidium oocysts in only 3 cases. Species identification yielded Cryptosporidium hominis in 2 cases, Cryptosporidium meleagridis in 1 case, and Cryptosporidium parvum in 1 case; a C. hominis/C. meleagridis co-infection was observed in the last case. C. hominis was isolated in children from rural areas, suggesting that the infection could have been contracted in the hospital and thus a probability of nosocomial transmission. One of the C. hominis carriers developed sclerosing cholangitis with a high parasite load. CONCLUSION: Cryptosporidiosis with serious clinical symptoms is observed in PID patients, particularly those with CMH class II deficiency syndrome. Early, regular, and repeated screening, improved by PCR, is recommended in this group of patients. The predominance of C. hominis, the anthropophilic species, in children from rural areas should emphasize hygiene measures in care centers where PID cases are treated. PMID- 21816589 TI - [The Paris cell for collecting preoccupying information (la CRIP 75): an organization at the heart of child protection]. AB - Within the objective of coordinating actions of the different partners whose mission involves childhood protection measures, and to allow convergence of preoccupying information toward a centralized unit, law n(o) 2007-293 of 5 March 2007 reforming child protection requires the creation of a departmental cell for the collection, processing, and assessment of preoccupying information (cellule departementale, de recueil, de traitement, et d'evaluation des informations preoccupantes, CRIP) on the circumstances of a minor in danger or at risk of being so. The CRIP 75 is a multidisciplinary cell comprising an administrative pole, a socio-educational pole, and a medical health officer. Its mission is to participate in assessing preoccupying information and directing it appropriately, with a preference toward treating situations within an administrative framework and in accordance with the parents. The public prosecutor is only called in when the recommended measures have not provided an adequate response to the danger. Situations that are a matter for prosecution as a criminal offence are transmitted directly to the public prosecutor's office, as are situations for which the social or medico social services are unable to make an assessment. PMID- 21816590 TI - [Sclerosing cholangitis revealing Langerhans cell histiocytosis in a 15-month-old child]. AB - INTRODUCTION: Langerhans cell histiocytosis (LCH) is a rare disease that mainly affects young children. Sclerosing cholangitis may occur in 10-15% of patients with the multivisceral form. We report the case of a 15-month-old child who presented sclerosing cholangitis revealing LCH. OBSERVATION: A 15-month-old child was hospitalized for cholestatic jaundice. He was the son of consanguineous parents and had repeated ear infections. One month before his hospitalization, he developed febrile jaundice. Initial clinical examination showed hepatosplenomegaly, with cholestasis, bicytopenia, and biological inflammatory syndrome. The digestive radiological studies revealed hepatomegaly and a regular thickening of the intestinal wall with an extension to the biliary tree. During his hospitalization, the infant developed stubborn ascites, lymphadenopathy, and skin lesions. Skull radiographs revealed punched-out lesions. The skin biopsy confirmed the diagnosis of histiocytosis X. Chemotherapy was started. The child died after the first course of treatment as a consequence of liver failure. CONCLUSION: Sclerosing cholangitis may complicate LCH, mainly in its multivisceral form. On average, sclerosing cholangitis develops 2 years after diagnosis in children. It is rarely indicative of the diagnosis, which is mainly based on radiological examinations. Liver involvement is a factor of poor prognosis. It precipitates the occurrence of biliary cirrhosis. Usually, sclerosing cholangitis responds poorly to Langerhans histiocytosis treatment and liver transplantation must be considered. PMID- 21816591 TI - [Sweet syndrome revealing leukemia]. AB - Sweet syndrome is a neutrophilic dermatosis that can lead to various inflammatory and neoplastic pathologies. We report a case of Sweet syndrome revealing acute leukemia at a 13-year-old girl, who had no history of illness. The diagnosis was made in spite of atypical skin lesions and was confirmed by the skin biopsy and the bone marrow examination. In spite of corticosteroid therapy and chemotherapy, the patient died. Sweet syndrome's diagnosis requires an exhaustive etiologic survey. If there is no evidence of underlying disease, patients must be regularly monitored. PMID- 21816592 TI - The role of the final FRCR examination in specialist training in clinical oncology. PMID- 21816593 TI - Reduced levels of placental long chain polyunsaturated fatty acids in preterm deliveries. AB - Reports suggest that the placenta in preterm birth may provide clues to predicting the risk of individuals developing chronic diseases in later life. Placental delivery of long chain polyunsaturated fatty acids (LCPUFA) (constituents of the cell membrane and precursors of prostaglandins) is essential for the optimal development of the central nervous system of the fetus. The present study examines the levels of LCPUFA and their association with placental weight and birth outcome in 58 women delivering preterm and 44 women delivering at term. Docosahexaenoic acid (DHA) and arachidonic acid (ARA) levels were lower (p<0.01) in women delivering preterm. There was a positive association of placental DHA with placental weight (p=0.036) and nervonic acid with head circumference (p=0.040) in the preterm group. Altered placental LCPUFA status exists in Indian mothers delivering preterm, which may influence the birth outcome. PMID- 21816594 TI - Fatty acid transport into the brain: of fatty acid fables and lipid tails. AB - The blood-brain barrier formed by the brain capillary endothelial cells provides a protective barrier between the systemic blood and the extracellular environment of the central nervous system. Brain capillaries are a continuous layer of endothelial cells with highly developed tight junctional complexes and a lack of fenestrations. The presence of these tight junctions in the cerebral microvessel endothelial cells aids in the restriction of movement of molecules and solutes into the brain. Fatty acids are important components of biological membranes, are precursors for the biosynthesis of phospholipids and sphingolipids and are utilized for mitochondrial beta-oxidation. The brain is capable of synthesizing only a few fatty acids. Hence, most fatty acids must enter into the brain from the blood. Here we review current mechanisms of transport of free fatty acids into cells and describe how free fatty acids move from the blood into the brain. We discuss both diffusional as well as protein-mediated movement of fatty acids across biological membranes. PMID- 21816595 TI - A Promoter polymorphism (rs17222919, -1316T/G) of ALOX5AP is associated with intracerebral hemorrhage in Korean population. AB - To investigate whether single nucleotide polymorphisms (SNPs) of eicosanoid biosynthesis genes are associated with intracerebral hemorrhage (ICH) and ischemic stroke (IS), seven SNPs in the coding or promoter regions were selected: ALOX12 (rs434473, Asn322Ser), ALOX5 (rs2228064, Thr90Thr), ALOX5AP (rs17222919, 1316T/G), PTGES (rs7872802, -404A/G), PTGIS (rs5628, Leu256Leu), PTGS1 (rs3842788, Gln41Gln) and PTGS2 (rs5275, 3'UTR). A total of 398 control subjects and 196 stroke patients (79 ICH and 117 IS) were genotyped by direct sequencing. The rs17222919 SNP was associated with ICH in codominant 1 (P=0.008), dominant (P=0.003) and log-additive (P=0.004) models. Allele frequencies of rs17222919 were different between ICH and controls (P=0.007). However, the seven tested SNPs were not associated with clinical phenotypes (NIHSS, MBI and CRPS) in ICH and IS. These results suggest that the promoter SNP rs17222919 of ALOX5AP may be associated with the development of ICH in Korean population. PMID- 21816596 TI - Pneumococcal vaccination in adults: does it really work? AB - The universal burden of pneumococcal disease is high. As pneumococcal capsular antigens induce serotype specific antibodies, both the available vaccines (polysaccharide and polysaccharide conjugated) are able to produce serological response. However, there is reasonable skepticism about the effectiveness and efficacy of the 23-valent polysaccharide vaccine, especially in the elderly and in immunocompromised adults. Results from numerous studies are conflicting but the more recent data suggest that polysaccharide vaccine raises inadequate protection against non-bacteremic pneumonia, while the benefit against invasive pneumococcal disease in high-risk population is uncertain. On the contrary, conjugate vaccine, -originally indicated only for infants and young children- appears to be highly effective but it does not cover the tremendous diversity of pneumococcal serotypes being able to cause disease in adults. Despite this, there is growing evidence that conjugate vaccines, due to their superior immunogenicity, could also be offered for adult vaccination, but still there are certain issues that warrant further investigation. PMID- 21816597 TI - The problem of disposing of plaster waste from building sites: problem structuring based on value focus thinking methodology. AB - Plaster is a material which is widely used in Brazil on construction sites. However, its use in recent years has been limited by a legal resolution on the environment introduced in Brazil. One of the regions most affected by these restrictions is the Northeast where the strategic importance of plaster for the region is apparent from the extensive economic development, centered on the gypsum pole of Araripe in the state of Pernambuco. This problem has involved many interested parties, among whom are plaster producers, plastering companies, builders, unions (for plaster workers, and construction workers), Town Halls, and so forth. Therefore, there is a need to structure the problem with a view to obtaining a better understanding of the problem given the lack of information on the real decision problem. To reach this objective, value focus thinking (VFT), a methodology that addresses how values can be used to improve the decision making process, was applied and the problem was structured. Thus, it was possible for the parties involved to clarify their objectives, and specify more precisely the consequences and constraints for the decision problem. In addition, each party involved could get a better understanding of their own wishes. In conclusion, the VFT methodology application enables the parties involved to make more consistent decisions, and therefore to ensure that plaster will continue to be used in the construction industry. PMID- 21816598 TI - Simple detection of nucleic acids with a single-walled carbon-nanotube-based electrochemical biosensor. AB - We report for the first time a simple approach to fabricate an electrochemical DNA (E-DNA) biosensor by introducing the single-walled carbon nanotubes (SWNTs). The SWNTs combine with the electrochemical label (methyl blue, MB)-modified single-stranded DNA (ssDNA) probes to generate a nanomaterial-biomolecule composite, which functions as a signal amplification platform to facilitate the electron-transfer between the electrochemical label and the electrode. This SWNT based E-DNA biosensor produces a high square wave voltammetry (SWV) signal in the absence of target DNA. In the presence of target DNA, the MB-labeled ssDNA probes are removed from the SWNT-modified electrode due to the formation of a double stranded DNA (dsDNA), generating a relatively low SWV signal. This signal-off SWNT-based E-DNA biosensor exhibits improved sensitivity and large linear dynamic range with low detection limit; it can even distinguish 1-base mismatched target DNA. Further experiments demonstrate that the SWNT-based E-DNA biosensor is superior to the multi-walled carbon nanotube (MWNT)-based one for DNA detection. Moreover, the introduction of aptamer into the SWNT-based biosensor might be further extended to detect small biomolecules such as adenosine. PMID- 21816599 TI - The assessment of potentially interfering metabolites and dietary components in blood using an osmotic glucose sensor based on the concanavalin A-dextran affinity assay. AB - Continuous surveillance of blood glucose is a prerogative of maintaining a tight glycaemic control in people suffering from diabetes mellitus. Implantable sensor technology offers the potential of conducting direct long term continuous glucose measurements, but current size restrictions and operational challenges have limited their applications. The osmotic sensor utilises diffusion to create a hydrostatic pressure that is independent of sensor operation and power consumption. This permits ultra-low power architectures to be realized with a minimal start-up time in a package suitable for miniaturization. In contrast, osmotic sensors suffer from the inability of their membranes to discriminate between different constituents in blood or the interstitial fluid that are of comparable size to glucose. By implementing an affinity assay based on the competitive bonding between concanavalin A and dextran, the selectivity of the membrane can be transferred to the glucose specific recognition of the affinity assay. The osmotic effect from the physiological levels of several key metabolites and nutritional components has been addressed identifying in particular ethanol, lactate and amino acids as potential interfering constituents. Both ascorbic acid and mannose would have a normal physiological concentration that is too low to be detected. The studies shows that an osmotic glucose sensor equipped with the con A-dextran affinity assay, is able to filter out potential interfering constituents present in blood, plasma and the interstitial fluid yet retaining a pressure that is proportional to glucose only. PMID- 21816600 TI - Electrochemical endotoxin sensors based on TLR4/MD-2 complexes immobilized on gold electrodes. AB - Even low concentrations of endotoxins can be life-threatening. As such, continuous effort has been directed toward the development of sensitive and specific endotoxin detection systems. In this paper, we report the design and fabrication of a new electrochemical endotoxin sensor based on a human recombinant toll-like receptor 4 (rhTLR4) and myeloid differentiation-2 (MD-2) complex. The rhTLR4/MD-2 complex, which specifically binds to endotoxin, was immobilized on gold electrodes through a self-assembled monolayer (SAM) technique involving the use of dithiobis(succinimidyl undecanoate) (DSU). The surface topography of the electrodes at each fabrication stage was characterized with a nanosurface profiler and atomic force microscope (AFM). The electrochemical signals generated from interactions between the rhTLR4/MD-2 complex and the endotoxin were characterized by cyclic voltammetry (CV) and differential pulse voltammetry (DPV). A linear relationship between the peak current and endotoxin concentration was obtained in the range of 0.0005 to 5 EU/mL with a correlation coefficient (R(2)) of 0.978. The estimated limit of detection (LOD) was fairly low, 0.0002 EU/mL. The rhTLR4/MD-2 based sensors exhibited no current responses to dipalmitoylphosphatidylcholine (DPPC) bearing two lipid chains, which is structurally similar to endotoxin, indicating the high specificity of the sensors to endotoxin. PMID- 21816601 TI - An electrochemical biosensor for analysis of Fenton-mediated oxidative damage to BSA using poly-o-phenylenediamine as electroactive probe. AB - A sensitive electrochemical procedure based on bovine serum albumin (BSA)/poly-o phenylenediamine (PoPD)/carbon-coated nickel (C-Ni) nanobiocomposite film modified glassy carbon electrode (BSA/PoPD/C-Ni/GCE) has been developed to explore the electrochemical detection of BSA damage induced by hydroxyl radical. It is the first time that the electrochemical method has been applied for the analysis of Fenton-mediated oxidative damage to proteins. The hydroxyl radical was generated by Fenton reaction (Fe(2+)/H(2)O(2)), which was also validated by ultraviolet-visible (UV-vis) spectroscopy. The decrease in intensity of the PoPD oxidation signals was used as an indicator for the detection of BSA damage. Damage to BSA was also validated by horizontal Attenuation Total Reflection Fourier Transform Infra-red (ATR-FTIR) spectroscopy and the change of protein carbonyl group content achieved by UV-vis spectroscopy. Effects of H(2)O(2) concentration, the ratio of Fe(2+) and H(2)O(2) and incubation time on BSA damage were examined. Protections of BSA from damage by antioxidants were also investigated. These conclusions demonstrated that the proposed electrochemical method is expected to the further application for protein damage studies. PMID- 21816602 TI - Artificial antibodies for troponin T by its imprinting on the surface of multiwalled carbon nanotubes: its use as sensory surfaces. AB - A novel artificial antibody for troponin T (TnT) was synthesized by molecular imprint (MI) on the surface of multiwalled carbon nanotubes (MWCNT). This was done by attaching TnT to the MWCNT surface, and filling the vacant spaces by polymerizing under mild conditions acrylamide (monomer) in N,N' methylenebisacrylamide (cross-linker) and ammonium persulphate (initiator). After removing the template, the obtained biomaterial was able to rebind TnT and discriminate it among other interfering species. Stereochemical recognition of TnT was confirmed by the non-rebinding ability displayed by non-imprinted (NI) materials, obtained by imprinting without a template. SEM and FTIR analysis confirmed the surface modification of the MWCNT. The ability of this biomaterial to rebind TnT was confirmed by including it as electroactive compound in a PVC/plasticizer mixture coating a wire of silver, gold or titanium. Anionic slopes of 50 mV decade(-1) were obtained for the gold wire coated with MI-based membranes dipped in HEPES buffer of pH 7. The limit of detection was 0.16 MUg mL( 1). Neither the NI-MWCNT nor the MWCNT showed the ability to recognize the template. Good selectivity was observed against creatinine, sucrose, fructose, myoglobin, sodium glutamate, thiamine and urea. The sensor was tested successfully on serum samples. It is expected that this work opens new horizons on the design of new artificial antibodies for complex protein structures. PMID- 21816603 TI - Enhancing immunoassay detection of antigens with multimeric protein Gs. AB - This paper describes a method for the effective and self-oriented immobilization of antibodies on magnetic silica-nanoparticles using a multimeric protein G. Cysteine-tagged recombinant dimers and trimers of protein G were produced in Escherichia coli BL21 by repeated linking of protein G monomers with a flexible (GGGGS)(3) linker. Amino-functionalized silica-coated magnetic nanoparticles (SiO(2)-MNPs, Fe(3)O(4)@SiO(2)) were prepared and coupled to the protein G multimers, giving the final magnetic immunosensor. The optimal conditions for the reaction between the protein Gs and the SiO(2)-MNPs was a time of 60 min and a concentration of 100 MUg/mL, resulting in coupling efficiencies of 77%, 67% and 55% for the monomeric, dimeric and trimeric protein Gs, respectively. Subsequently, anti-hepatitis B surface antigen (HBsAg) was immobilized onto protein G-coupled SiO(2)-MNPs. The quantitative efficiency of antibody immobilization found the trimeric protein G to be the best, followed by the dimeric and monomeric proteins, which differs from the coupling efficiencies. Using all three protein constructs in an HBsAg fluoroimmunoassay, the lowest detectable concentrations were 500, 250 and 50 ng/mL for the monomeric, dimeric and trimeric protein G-coupled SiO(2)-MNPs, respectively. Therefore, multimeric protein Gs, particularly the trimeric form, can be employed to improve antibody immobilization and, ultimately, enhance the sensitivity of immunoassays. In addition, the multimeric protein Gs devised in this study can be utilized in other immunosensors to bind the antibodies at a high efficiency and in the proper orientation. PMID- 21816604 TI - Optical detection of choline and acetylcholine based on H2O2-sensitive quantum dots. AB - In this paper, we have constructed a simple, rapid and sensitive biosensor for detection of choline and acetylcholine (ACh) based on the hydrogen peroxide (H(2)O(2))-sensitive quantum dots (QDs). The detection limit for choline was 0.1 MUM and the linear range was 0.1-0.9 MUM and 5-150 MUM, respectively. The detection limit for ACh was found to be 10 MUM and the linear range was 10-5000 MUM. The wide linear ranges were shown to be suitable for routine analyses of choline and ACh. Possible mechanism of the fluorescence of QDs quenched by H(2)O(2) was an electron transfer (ET) process. The experimental conditions of biosensors were optimized, and anti-interference ability was also presented. We also detected the choline in milk samples and the linear range was 5-150 MUM. The detection linear range of ACh in serum was 10-140 MUM. Most importantly, the recovery of choline in milk and ACh in serum samples were both close to 99%. The excellent performance of this biosensor showed that the method can be used in practice detection of choline and ACh. PMID- 21816605 TI - Real-time detection of beta1 integrin expression on MG-63 cells using electrochemical impedance spectroscopy. AB - Beta 1 integrin is a membrane protein responsible for attachment and migration of osteosarcoma cells. In this study, expression of beta1 integrin on MG-63 cells, a human osteogenic sarcoma cell line, was monitored using electrochemical impedance spectroscopy (EIS). ITO-based biochips were developed using a semiconductor technique. Differences in electric resistance (DeltaR) were measured continuously when cells binding with anti-beta1 integrin antibody coagulated with nano-scale gold particles. The results of the EIS system were compared with traditional immunofluorescence staining. We found that sample chambers with higher cell densities had larger DeltaR values. When the cell densities increased from 5 * 10(4) cells/ml to 5 * 10(5) cells/ml, the DeltaR value dose-dependently increased from 14 Omega to 37 Omega. In addition, a highly linear relationship (correlation coefficient, 0.921) was found between the DeltaR values and the corresponding fluorescence intensities (p<0.05). These results suggest that electrochemical impedance spectroscopy can be a useful tool for evaluating beta1 integrin expression on cell membranes. PMID- 21816606 TI - P450-based porous silicon biosensor for arachidonic acid detection. AB - A porous silicon biosensor based on P450 enzyme for arachidonic acid detection was developed. A new transduction method is presented with a simultaneous measurement of refractive index and fluorescence intensity changes when the analyte is binding to an enzyme on the porous silicon surface. A fluorophore bound to a cysteine residue in an allosteric position of the haem domain (BMP) of cytochrome P450 BM3 enhances its fluorescence intensity upon interaction with its substrate arachidonic acid, involved in diseases such as Alzheimer's, liver cancer and cellular inflammation processes. BMP has been anchored on porous silicon surface and the new transduction method has been successfully exploited to develop a biosensor for arachidonic acid, reaching a detection limit of 10 MUM arachidonic acid in a dynamic range of 10-200 MUM. Moreover, the change of the refractive index has been also monitored at the same time, displaying a higher detection limit of 30 MUM. Preliminary test were also conducted in plasma proving the high specificity and selectivity of the sensor even in presence of interferents in the range of 50-100 MUM. Here we suggest these two detection systems could be used simultaneously to increase the accuracy and the dynamic range of the sensor avoiding a false positive response. PMID- 21816607 TI - Primary pancreatic cystic neoplasms of the pancreas revisited. Part IV: rare cystic neoplasms. AB - Primary pancreatic cystic neoplasms are being recognized with increasing frequency due to modern imaging techniques. In addition to the more common cystic neoplasms-serous cystadenoma, primary mucinous cystic neoplasm, and intraductal papillary mucinous neoplasm-there are many other less common neoplasms that appear as cystic lesions. These cystic neoplasms include solid pseudopapillary neoplasm of the pancreas (the most common rare cystic neoplasm), cystic neuroendocrine neoplasm, cystic degeneration of otherwise solid neoplasms, and then the exceedingly rare cystic acinar cell neoplasm, intraductal tubular neoplasm, angiomatous neoplasm, lymphoepithelial cysts (not true neoplasms), and few others of mesenchymal origin. While quite rare, the pancreatic surgeon should at the least consider these unusual neoplasms in the differential diagnosis of potentially benign or malignant cystic lesions of the pancreas. Moreover, each of these unusual neoplasms has their own natural history/tumor biology and may require a different level of operative aggressiveness to obtain the optimal outcome. PMID- 21816608 TI - Thermo-kinetics of lipase-catalyzed synthesis of 6-O-glucosyldecanoate. AB - Lipase-catalyzed synthesis of 6-O-glucosyldecanoate from d-glucose and decanoic acid was performed in dimethyl sulfoxide (DMSO), a mixture of DMSO and tert butanol and tert-butanol alone with a decreasing order of polarity. The highest conversion yield (> 65%) of decanoic acid was obtained in the blended solvent of intermediate polarity mainly because it could dissolve relatively large amounts of both the reactants. The reaction obeyed Michaelis-Menten type of kinetics. The affinity of the enzyme towards the limiting substrate (decanoic acid) was not affected by the polarity of the solvent, but increased significantly with temperature. The esterification reaction was endothermic with activation energy in the range of 60-67 kJ mol-1. Based on the Gibbs energy values, in the solvent blend of DMSO and tert-butanol the position of the equilibrium was shifted more towards the products compared to the position in pure solvents. Monoester of glucose was the main product of the reaction. PMID- 21816610 TI - Optimization of biodiesel supply chains based on small farmers: a case study in Brazil. AB - This article presents a methodology for conceiving and planning the development of an optimized supply chain of a biodiesel plant sourced from family farms and taking into consideration agricultural, logistic, industrial, and social aspects. This model was successfully applied to the production chain of biodiesel fuel from castor oil in the semi-arid region of Brazil. Results suggest important insights related to the optimal configuration of the crushing units, regarding its location, technology, and when it should be available, as well as the configuration of the production zones along the planning horizon considered. Moreover, a sensitivity analysis is performed in order to measure how possible variations in the considered conjecture can affect the robustness of the solutions. PMID- 21816609 TI - Evaluation of hemicellulose removal by xylanase and delignification on SHF and SSF for bioethanol production with steam-pretreated substrates. AB - Steam-pretreated sweet sorghum bagasse (SSB) and Douglas-fir (DF) were employed for SHF and SSF to evaluate the effects of xylanase supplementation and delignification on ethanol production. Results indicated final ethanol concentration in SHF could reach 28.4 g/L (SSB) and 20.4 g/L (DF) by xylanase supplementation with the increase of 46% and 61% in comparison with controls. The delignification could significantly enhance final ethanol concentration to 31.2g/L (SSB) and 30.2 g/L (DF) with the increase of 61% and 138%. In SSF, final ethanol concentration in the delignified SSB and DF arrived at 27.6 g/L and 34.3 g/L with the increase of 26% and 157% compared with controls. However, only 2.2 g/L (SSB) and 6.9 g/L (DF) ethanol were obtained with xylanase supplementation. According to these results, it could be concluded that delignification was beneficial to improve ethanol production of SHF and SSF. The xylanase supplementation (0.12 g protein/g glucan) was only positive to SHF while retarded SSF seriously. PMID- 21816611 TI - Dilute phosphoric acid-catalysed hydrolysis of municipal bio-waste wood shavings using autoclave parr reactor system. AB - The visibility of using municipal bio-waste, wood shavings, as a potential feedstock for ethanol production was investigated. Dilute acid hydrolysis of wood shavings with H3PO4 was undertaken in autoclave parr reactor. A combined severity factor (CSF) was used to integrate the effects of hydrolysis times, temperature and acid concentration into a single variable. Xylose concentration reached a maximum value of 17 g/100 g dry mass corresponding to a yield of 100% at the best identified conditions of 2.5 wt.% H3PO4, 175 degrees C and 10 min reaction time corresponding to a CSF of 1.9. However, for glucose, an average yield of 30% was obtained at 5 wt.% H3PO4, 200 degrees C and 10 min. Xylose production increased with increasing temperature and acid concentration, but its transformation to the degradation product furfural was also catalysed by those factors. The maximum furfural formed was 3 g/100 g dry mass, corresponding to the 24% yield. PMID- 21816613 TI - Removal of primary tumor improves survival in metastatic breast cancer. Does timing of surgery influence outcomes? AB - BACKGROUND: Resection of intact primary tumor is controversial in metastatic breast cancer patients. The aim of this study is to review the impact of surgical resection of primary tumor on overall survival and to assess the role of timing of surgery on survival rates. METHODS: 208 patients with metastatic breast cancer diagnosed between 1982 and 2005 in the Hospital Clinico of Valencia (Spain) were analysed. Exclusion criteria were age >80, PS 3-4, Charlson score 3 or follow-up < 90 days. 123 of these underwent surgery and 85 did not. In order to assess the role of timing, the "surgery" cohort was divided into two sub-groups: "before" (n = 78) or "after" (n = 45) diagnosis of disseminated disease. RESULTS: In the surgery group, patients underwent mastectomy with axillary dissection (82.9%), without axillary dissection (8.9%) and conservative surgery (8.1%). After a median follow-up of 29.68 months, median OS in the "surgery" and the "non surgery" groups were, 40.4 and 24.3 months. Removal of the primary tumor therefore had a significant positive impact on survival rates (p < 0.001). Benefits of surgery were observed mainly in patients with visceral disease (p = 0.005); no statistical differences were found in those with bone disease (p = 0.79). Univariate analysis for overall survival (OS) identified surgery, performance status, clinical T stage, hormone receptors and number and type of metastases as variables that impacted on survival. In the multivariate test, only resection of primary tumor and estrogen receptors maintained statistical significance, surgery having a protective effect with an HR 0.52 (95% CI 0.35 0.77). No differences in survival were found between the two sub-groups according to the timing of surgery: "before" vs "after"(p = 0.996). CONCLUSIONS: Resection of primary tumor should be considered not only as a palliative or preventive strategy but also as an approach that possibly contributes to the control of the disease in selected patients. PMID- 21816612 TI - Comparative data on effects of leading pretreatments and enzyme loadings and formulations on sugar yields from different switchgrass sources. AB - Dilute sulfuric acid (DA), sulfur dioxide (SO(2)), liquid hot water (LHW), soaking in aqueous ammonia (SAA), ammonia fiber expansion (AFEX), and lime pretreatments were applied to Alamo, Dacotah, and Shawnee switchgrass. Application of the same analytical methods and material balance approaches facilitated meaningful comparisons of glucose and xylose yields from combined pretreatment and enzymatic hydrolysis. Use of a common supply of cellulase, beta glucosidase, and xylanase also eased comparisons. All pretreatments enhanced sugar recovery from pretreatment and subsequent enzymatic hydrolysis substantially compared to untreated switchgrass. Adding beta-glucosidase was effective early in enzymatic hydrolysis while cellobiose levels were high but had limited effect on longer term yields at the enzyme loadings applied. Adding xylanase improved yields most for higher pH pretreatments where more xylan was left in the solids. Harvest time had more impact on performance than switchgrass variety, and microscopy showed changes in different features could impact performance by different pretreatments. PMID- 21816614 TI - Relationship between stair ambulation with and without a handrail and centre of pressure velocities during stair ascent and descent. AB - INTRODUCTION: Stair ambulation is one of the most challenging and hazardous types of locomotion for older adults and often requires the adoption of compensatory strategies such as increased handrail use to mitigate disability and increase stability. Centre of pressure velocity (VCOP) describes the neuromuscular response to shifts of the body's centre of mass and serves as an indicator of stability. Knowledge of VCOP may provide some understanding of strategies to improve measured and perceived stability during stair negotiation. The aim of this study was to compare VCOP during stair ascent and descent with and without a handrail in young, older and older adults with a fear of falling (FOF) populations. METHODS: COP velocities of 23 young adults (23.7+/-3.0 yrs), 26 older adults (66.4+/-8.3 yrs), and 3 older adults with FOF (80.2+/-8.0 yrs) were analyzed while they ascended and descended a custom 4-step staircase. VCOP were obtained using a force plate mounted on concrete blocks centered on the second step of the staircase. RESULTS: During stair ascent and descent with and without a handrail, the VCOP between young and older adults were comparable. The three adults with FOF demonstrated reduced VCOP during ascent and descent without the handrail and even slower VCOP when ascending and descending stairs with the handrail. These results suggest that handrail use does not increase biomechanical stability for healthy, older adults. However, in the presence of fear of falling the use of the handrail enhances dynamic stability, particularly during stair descent. CONCLUSIONS: This study provides the first detailed description of dynamic stability during stair ambulation with and without a handrail. Observations from those with FOF aid in understanding the nature of compensations to improve actual and perceived stability. PMID- 21816615 TI - Kinematic and kinetic analysis of static sitting of patients with neuropathic spine deformity. AB - Wheelchair dependent children with neuropathic and neuromuscular diseases have up to 90% risk for progressive spine deformities. An unbalanced sitting can induce progression of spinal and pelvic deformities. Many current clinical assessment methods of sitting of such patients are semi-quantitative, or questionnaire based. A 3D movement analysis offers quantitative and objective biomechanical analysis of sitting. The aim was to validate a method to describe quiet sitting and differences between patients and controls as well as to apply the methodology for pre- and post-operative comparison. The analysis was performed on 14 patients and 10 controls. Four patients were retested after spine surgery. Seat load asymmetry was up to 30% in the patient group comparing to maximum 7% in the control group. The asymmetric position of Ground Reaction Force vector between left and right sides was significant. Plumb line of cervical 7th vertebra over sacral 1st was different only in rotation. The location of Common Center of Pressure relative to inter-trochanteric midpoint was more anterior in controls than in patients. Pelvic inclination in patients was smaller, the obliquity and rotation was similar. There were no significant differences between patients and controls of the thorax position. Results with more changes in the seat-loading domain in comparison with posture indicate good postural control compensation of spinal deformity induced disequilibrium despite neuromuscular disease in the background. The comparison of the pelvic obliquity data from kinematics and X-ray showed good correlation. The four patients tested postoperatively improved after surgery. PMID- 21816616 TI - Mechanisms of meningococcal colonisation. AB - Despite advances against infectious diseases over the past century, Neisseria meningitidis remains a major causative agent of meningitis and septicaemia worldwide. Its adaptation for survival in the human nasopharynx makes the meningococcus a highly successful commensal bacterium. Recent progress has been made in understanding the mechanisms that enable neisserial colonisation, in terms of the role of type IV pili, the impact of other adhesins, biofilm formation, nutrient acquisition and resistance to host immune defences. Refinements in cell-based and in vivo models will lead to improved understanding of the colonisation process, and hopefully to more effective vaccines and therapeutic strategies. PMID- 21816618 TI - Determination of trace elements in some copper minerals by k0-neutron activation analysis. AB - Trace element contents in two copper minerals [brochantite [Cu(4)SO(4)(OH)(6)] and native Cu] using k(0)-NAA were determined before and after quantitative removal of copper. The distribution of 44 elements in the studied minerals was investigated. An important advantage of the proposed method is the possibility to determine the content of several elements (Al, Dy, Mg, Mn and V) via their short lived nuclides after the electrolytic removal of Cu due to the elimination of matrix interferences. PMID- 21816617 TI - RNA polymerase III under control: repression and de-repression. AB - The synthesis of tRNA by yeast RNA polymerase III (Pol III) is regulated in response to changing environmental conditions. This control is mediated by Maf1, the global negative regulator of Pol III transcription conserved from yeast to humans. Details regarding the molecular basis of Pol III repression by Maf1 are now emerging from recently reported structural and biochemical data on Pol III and Maf1. Efficient Pol III transcription, following the shift of cells from a non-fermentable carbon source to glucose, requires phosphorylation of Maf1. One of the newly identified Maf1 kinases is the chromatin-bound casein kinase II (CK2). Current studies have allowed us to propose an innovative mechanism of Pol III regulation. We suggest that CK2-mediated phosphorylation of Maf1, occurring directly on tDNA chromatin, controls Pol III recycling. PMID- 21816619 TI - A strategy for intensive production of molybdenum-99 isotopes for nuclear medicine using CANDU reactors. AB - Technetium-99m is an important medical isotope utilized worldwide in nuclear medicine and is produced from the decay of its parent isotope, molybdenum-99. The online fueling capability and compact fuel of the CANDU((r))(1) reactor allows for the potential production of large quantities of (99)Mo. This paper proposes (99)Mo production strategies using modified target fuel bundles loaded into CANDU fuel channels. Using a small group of channels a yield of 89-113% of the weekly world demand for (99)Mo can be obtained. PMID- 21816620 TI - Low energy prompt gamma-ray tests of a large volume BGO detector. AB - Tests of a large volume Bismuth Germinate (BGO) detector were carried out to detect low energy prompt gamma-rays from boron and cadmium-contaminated water samples using a portable neutron generator-based Prompt Gamma Neutron Activation Analysis (PGNAA) setup. Inspite of strong interference between the sample- and the detector-associated prompt gamma-rays, an excellent agreement has been observed between the experimental and calculated yields of the prompt gamma-rays, indicating successful application of the large volume BGO detector in the PGNAA analysis of bulk samples using low energy prompt gamma-rays. PMID- 21816621 TI - An Indian manufacturer's perspective for harmonization of guidelines for similar biotherapeutic products. AB - This review focuses on the scenario of Indian manufacturers, biotherapeutics approvals in India and important aspects which need to be precisely analyzed and resolved from the Indian perspective to facilitate implementation of global guidelines for the manufacture of these products, to best serve the public health needs of the developing countries. PMID- 21816622 TI - SEMG signal analysis at acupressure points for elbow movement. AB - Surface electromyography signals (SEMG) are the most common form of non-invasive measurement of muscle activities. To acquire proper SEMG for particular limb function, the placement of electrodes on the skin over respective active group of muscles becomes very important. Measurement of SEMG depends on a number of factors/parameters like amplitude, time and frequency domain properties. In the present investigation, analysis was carried firstly; to study the grip force vs. SEMG parameters at acupressure points on arm, using single channel approach. At all the selected acupressure points a linear increment of SEMG was observed. Secondly; to discriminate four elbow movements from different locations on arm using two channel approach with single parameter. The parameter for the analysis chosen was the root of mean of square (RMS) value of SEMG. Further; principal component analysis was used to verify the elbow movement discrimination. Extension and supination were the two operations which were observed to be easy to realize by prosthetic devices. The selection of these locations was done on the basis of acupressure points and anatomy of elbow. Matlab-softscope was used for acquiring the SEMG from line-in input port of PC-sound card. This study will also be helpful for the researchers in understanding the behavior of SEMG for elbow movement in development of prosthetic or exoskeleton devices. PMID- 21816623 TI - MR-guided portal vein delivery and monitoring of magnetocapsules: assessment of physiologic effects on the liver. AB - PURPOSE: The authors previously developed magnetic resonance (MR)-trackable magnetocapsules (MCs) that can simultaneously immunoprotect human islet cells and noninvasively monitor portal delivery and engraftment in real time with MR imaging. This study was designed to assess the physiologic effects of the delivery of a clinical dose of MCs (140,000 capsules) into the portal vein (PV) in swine over a 1-month period. MATERIALS AND METHODS: MCs were formed by using clinical-grade alginate mixed with a clinically applicable dosage of ferumoxide. Percutaneous access into the PV was obtained by using a custom-built, MR trackable needle, and 140,000 MCs were delivered under MR guidance in five swine. Portal pressures and liver function data were obtained over a 4-week period. RESULTS: A transient increase in portal pressure occurred immediately after MC delivery that returned to normal levels by 4 weeks after MC delivery. Liver function test results were normal during the entire period, and the appearance of the MCs on MR imaging did not change. CONCLUSIONS: A clinically applicable dose of 140,000 MCs has no adverse effects on portal pressures or liver function in this normal swine model during the first month after delivery. PMID- 21816624 TI - Bioresorbable hydrogel microspheres for transcatheter embolization: preparation and in vitro evaluation. AB - PURPOSE: To develop and evaluate a bioresorbable spherical material for embolization. MATERIALS AND METHODS: New bioresorbable hydrogel microspheres were prepared from carboxymethyl cellulose and chitosan by using an inverse emulsion method. Size distribution of the microspheres was determined with a microscope, and the colorability was tested with Evans blue dye. The compressibility was examined with a texture analyzer. After sieving, the suspendability of the microspheres was tested in saline solution/contrast agent mixture in different ratios, and then the injectability was tested with microcatheters (lumen sizes of 0.0165, 0.019, and 0.027 inches). The in vitro degradability tests were performed in a lysozyme solution. Cell culture study of the microspheres was performed with human fibroblasts. RESULTS: The microspheres exhibit diameters of 100-1,550 MUm with a transparent appearance. Their fracture force can reach 0.58-0.88 N, and fracture deformation varies from approximately 70% to 95% of their original size. These microspheres can be colored by Evans blue dye, and uniform subgroups of microspheres can be readily obtained by sieving. Within 3 minutes, the microspheres form a stable suspension in a 4:6 contrast agent/saline solution mixture, which can be easily injected through microcatheters without aggregating or clogging. These microspheres are biodegradable, with degradation times varying from 2 weeks to 1 month, depending on their composition. Cell culture studies reveal no adverse effect on the growth of human fibroblasts in the presence of the microspheres. CONCLUSIONS: A biodegradable and noncytotoxic microsphere was successfully prepared. It can be well suspended in the contrast solution and easily injected through a microcatheter. PMID- 21816626 TI - The role of pre-conversion glomerular filtration rate in predicting long-term renal function after conversion to proliferation signal inhibitors in long-term heart transplant recipients. PMID- 21816625 TI - A web-based pilot study of inter-pathologist reproducibility using the ISHLT 2004 working formulation for biopsy diagnosis of cardiac allograft rejection: the European experience. AB - BACKGROUND: The aim of this study was to assess, at the European level and using digital technology, the inter-pathologist reproducibility of the ISHLT 2004 system and to compare it with the 1990 system We also assessed the reproducibility of the morphologic criteria for diagnosis of antibody-mediated rejection detailed in the 2004 grading system. METHODS: The hematoxylin-eosin stained sections of 20 sets of endomyocardial biopsies were pre-selected and graded by two pathologists (A.A. and M.B.) and digitized using a telepathology digital pathology system (Aperio ImageScope System; for details refer to http://aperio.com/). Their diagnoses were considered the index diagnoses, which covered all grades of acute cellular rejection (ACR), early ischemic lesions, Quilty lesions, late ischemic lesions and (in the 2005 system) antibody-mediated rejection (AMR). Eighteen pathologists from 16 heart transplant centers in 7 European countries participated in the study. Inter-observer reproducibility was assessed using Fleiss's kappa and Krippendorff's alpha statistics. RESULTS: The combined kappa value of all grades diagnosed by all 18 pathologists was 0.31 for the 1990 grading system and 0.39 for the 2005 grading system, with alpha statistics at 0.57 and 0.55, respectively. Kappa values by grade for 1990/2005, respectively, were: 0 = 0.52/0.51; 1A/1R = 0.24/0.36; 1B = 0.15; 2 = 0.13; 3A/2R = 0.29/0.29; 3B/3R = 0.13/0.23; and 4 = 0.18. For the 2 cases of AMR, 6 of 18 pathologists correctly suspected AMR on the hematoxylin-eosin slides, whereas, in each of 17 of the 18 AMR-negative cases a small percentage of pathologists (range 5% to 33%) overinterpreted the findings as suggestive for AMR. CONCLUSIONS: Reproducibility studies of cardiac biopsies by pathologists in different centers at the international level were feasible using digitized slides rather than conventional histology glass slides. There was a small improvement in interobserver agreement between pathologists of different European centers when moving from the 1990 ISHLT classification to the "new" 2005 ISHLT classification. Morphologic suspicion of AMR in the 2004 system on hematoxylin-eosin-stained slides only was poor, highlighting the need for better standardization of morphologic criteria for AMR. Ongoing educational programs are needed to ensure standardization of diagnosis of both acute cellular and antibody-mediated rejection. PMID- 21816627 TI - Characterizing the inflammatory reaction in explanted Medtronic Freestyle stentless porcine aortic bioprosthesis over a 6-year period. AB - BACKGROUND: The Medtronic Freestyle valve is a stentless porcine valve with reportedly excellent clinical and hemodynamic results, but little has been reported about its long-term pathology. METHODS: Seventeen Freestyle valves were explanted (from 2003 to 2009) and reviewed to assess reasons for bioprosthesis failure. All valves were examined in detail, using histochemistry and immunohistochemistry to identify morphological changes, as well as cellular and humoral responses. RESULTS: One Freestyle valve, explanted for mitral valve endocarditis on the fifth postoperative day, was excluded from analysis. The average implant duration was 71.1+/-35.2 months. Six valves were explanted for infective endocarditis, six for aortic insufficiency, and four for aortic stenosis. Calcification was seen in 11 explants, pannus in 15, thrombus in 12, cusp tears in 9, and 10 explants showed needle tract-like injuries. A chronic inflammatory reaction involving the xenograft arterial wall was seen in 15 of 16 valves. The cells were composed of macrophages and lymphocytes, including T cells (CD8 positive) and B cells. Significant damage to the porcine aortic wall was seen in 15 cases, and cusp myocardial shelf damage in 7 cases. All cases stained positively for IgG and C4dpar. CONCLUSIONS: The porcine aortic tissue showed T cell-mediated rejection and significant aortic medial damage, consistent with dilatation of the porcine aortic root. The demonstration of IgG suggests the likelihood of humoral rejection, in addition to cellular rejection. One of the underlying possibilities is that the porcine aortic tissues are inadequately fixed, hence the retained antigenicity. PMID- 21816628 TI - Comparison of glenohumeral and subacromial steroid injection in primary frozen shoulder: a prospective, randomized short-term comparison study. AB - BACKGROUND: Glenohumeral (GH) joint steroid injection is one of the most well known treatments for frozen shoulder. However, the low accuracy of GH joint injections and the improvement of symptoms after subacromial (SA) steroid injections led us to design a study that compares the efficacy of a steroid injection for primary frozen shoulder according to the injection site. MATERIALS AND METHODS: Patients with primary frozen shoulder were randomly divided into 2 groups according to the location of the injection: a GH group of 37 for the glenohumeral joint and an SA group of 34 for the subacromial space. Injections were completed using ultrasonographic guidance. Evaluations using a visual analog scale (VAS) for pain, the Constant score, and passive range of motion (ROM) were completed at 3, 6, and 12 weeks after the injection. RESULTS: The GH group showed lower pain VAS at 3 weeks, but no statistical difference was found between the 2 groups at 6 and 12 weeks. Improvement in pain was evident at every follow-up visit compared with the preinjection evaluation. There was no significant difference between the 2 groups with respect to the Constant score or ROM at serial follow-up. CONCLUSIONS: The GH steroid injection was not superior to a SA injection for patients with primary frozen shoulder even though injection at the GH joint led to earlier pain relief compared with the SA injection. SA steroid injection along with a GH injection is an alternative modality, and the treatment should be individualized and tailored appropriately. PMID- 21816629 TI - Intra-articular changes precede extra-articular changes in the biceps tendon after rotator cuff tears in a rat model. AB - HYPOTHESIS: Biceps tendon pathology is common with rotator cuff tears. The mechanisms for biceps changes, and therefore its optimal treatment, are unknown. Our objective was to determine the effect of rotator cuff tears on regional biceps tendon pathology. We hypothesized that histologic and compositional changes would appear before organizational changes, both would appear before mechanical changes, and changes would begin at the tendon's insertion site. MATERIALS AND METHODS: Detachment of supraspinatus and infraspinatus tendons or sham surgery was done in 65 Sprague-Dawley rats. Rats were euthanized at 1, 4, or 8 weeks for regional measurements of histologic, compositional, organizational (1, 4 and 8 weeks), or mechanical properties (4 and 8 weeks only). RESULTS: One week after tendon detachments, decreased organization and more rounded cell shape were found in the intra-articular space of the biceps tendon. Aggrecan expression was increased along the entire length of the tendon, whereas all other compositional changes were only at the tendon's proximal insertion into bone. With time, this disorganization and more rounded cell shape extended the length of the tendon. Organizational and cell shape changes also preceded detrimental mechanical changes: decreased modulus in the intra-articular space was found after 8 weeks. CONCLUSIONS: Results support a degenerative component to pathology in the biceps tendon. In addition, changes resembling a tendon exposed to compressive loading occurring first in the intra-articular space indicate that the biceps tendon plays an increased role as a load-bearing structure against the humeral head in the presence of rotator cuff tears. PMID- 21816630 TI - Complete rupture through the short head of the biceps muscle belly: a case report. PMID- 21816631 TI - The superior capsule of the shoulder joint complements the insertion of the rotator cuff. AB - BACKGROUND: To date, there are no studies about the attachment of the articular capsule of the superior shoulder joint. The aim of this study was to measure the width of the attachment of the articular capsule on the humerus, and to clarify the anatomy and the relationship to the footprint of the rotator cuff. METHODS: The attachment of the articular capsule on the greater tuberosity was exposed. The width of the attachment of the capsule and the footprint of the rotator cuff were measured. RESULTS: The maximum capsular width was located at the border between the infraspinatus and the teres minor, and measured 9.1 mm. The minimum capsular width was 3.5 mm, and it was located at 10.9 mm posterior to the anterior margin of the greater tuberosity and 1.5 mm anterior to the posterior margin of the supraspinatus. CONCLUSION: Prior studies have overestimated the rotator cuff footprint width due to the lack of discrimination between the actual cuff insertion and capsule. The attachment of the articular capsule of the shoulder joint occupied a substantial area of the greater tuberosity. In particular, at the border between the infraspinatus and the teres minor, the very thick attachment of the articular capsule compensated for the lack of attachment of muscular components. The thinnest point of the articular capsule was 11 mm posterior to the anterior margin of the greater tuberosity and very close to the posterior edge of the tapered insertion of the supraspinatus, which could contribute to the etiology of degenerative rotator cuff tears. PMID- 21816632 TI - Influence of arm lengthening in reverse shoulder arthroplasty. AB - BACKGROUND: Reverse shoulder arthroplasty (RSA) can improve anterior active elevation (AAE) by lengthening of the deltoid and hence increasing its lever arm. However, evaluations of functional outcomes of RSA have shown variable improvements in the range of motion. The aim of our study was to correlate humeral and arm lengthening to postoperative AAE. METHODS: We reviewed 183 RSAs with a minimum follow-up of 1 year. Lengthening of the humerus and the arm was evaluated in relation to the contralateral side. RESULTS: We observed mean humeral lengthening of 0.2 +/- 1.4 cm (range, -4.7 to +5.2 cm) and mean arm lengthening of 1.6 +/- 1.9 cm (range, -5.1 to +5.4 cm). Postoperative AAE was 140 degrees +/- 27 degrees (range, 30 degrees to 180 degrees ). We found no significant correlation between lengthening or shortening of the humerus and AAE (P = .169). Shortening of the arm led to a mean AAE value of 122 degrees ; lengthening of 0 and 1 cm, mean AAE of 140 degrees ; lengthening of greater than 1 cm to 2.5 cm, mean AAE of 144 degrees ; and lengthening of greater than 2.5 cm, mean AAE of 147 degrees . When we compared patients with lengthening of the arm and those with shortening, the postoperative AAE was significantly greater after arm lengthening, 145 degrees versus 122 degrees , with a mean difference of 23 degrees (95% confidence interval, 13 degrees to 33 degrees ) (P < .001). CONCLUSION: This study shows that shortening of the arm reduced AAE. With respect to arm lengthening, a lengthening threshold was not found. An objective assessment of deltoid lengthening is possible preoperatively, intraoperatively, and postoperatively, and this measure seems to correlate with the functional outcome. PMID- 21816633 TI - Capitellar excision and hemiarthroplasty affects elbow kinematics and stability. AB - INTRODUCTION: Capitellar hemiarthroplasty is proposed as a reconstructive option for isolated capitellar deficiency, but there is limited data on its effect on elbow biomechanics. This study assessed the effect of capitellar excision with and without replacement on elbow kinematics and stability, and evaluated 2 different implant surface shapes. MATERIALS AND METHODS: Ten cadaveric arms were tested with an upper extremity joint simulator. Each arm underwent computer tomography scanning for implant sizing and computer-assisted implantation. Kinematic data were obtained using an electromagnetic tracking system during elbow flexion, with the arm oriented in the valgus, varus, and vertical positions. Implants were placed through an extended lateral epicondylar osteotomy using computer-assisted techniques. A repeated-measures design compared 2 implants (anatomical and spherical) to the native capitellum control and capitellar excision states. Outcomes were maximum varus-valgus laxity and rotation of the ulna with respect to the humerus. RESULTS: Excision of the capitellum increased the varus-valgus laxity up to 3.1 degrees in active elbow flexion, with the forearm in pronation but not in supination. Both capitellar implant designs maintained normal varus-valgus laxity in both active and passive elbow flexion. Excision of the capitellum increased external ulnar rotation during active flexion in the vertical and valgus positions up to 1.5 degrees , while both implants restored normal ulnar rotation. The kinematics and stability of the elbows were similar for both implant designs. CONCLUSION: The capitellum appears to have a role as a valgus and external rotational stabilizer of the ulnohumeral joint. This instability was corrected by both designs of capitellar hemiarthroplasty. PMID- 21816634 TI - Vacuum assist glenoid fixation: does this technique lead to a more durable glenoid component? AB - INTRODUCTION: This was a prospective random study to determine if suction applied to the glenoid vault through the coracoid process would facilitate deeper penetration of cement into the vault, and if deeper penetration would lead to a more durable glenoid component. MATERIALS AND METHODS: A group of 96 patients were randomly assigned to 1 of 2 pathways for glenoid fixation. One was cemented using modern "third generation" cementing techniques, while the second group utilizes these same steps as well as a vacuum assist (weep-hole) technique. We measured the "amount" of cement that penetrated the vault around either a pegged or keeled component as a function of the area of the cement noted on the fluoroscopic AP film that was taken 35.1 months postoperatively. We were able to determine the area of this irregular shape by using a program that was specifically written for the study. The films were evaluated by the senior author, as well as 2 musculoskeletal trained radiologists blind to the technique. RESULTS: The area of the cement mantle was found to be significantly larger (P < .005) in the group with the vacuum assist technique. There was a positive relationship between the durability of the cement mantle as determined by the presence and the extent of radiolucent lines and the size of the cement mantle (P < .001). CONCLUSION: If a cement technique is chosen to implant a glenoid component, the vacuum assist weep-hole technique is the most effective cementing technique to achieve durable fixation. PMID- 21816635 TI - Comparison between the acromion index and rotator cuff tears in the Brazilian and Japanese populations. AB - BACKGROUND: We compared the acromion index, a lateral tilt of the acromion described by Nyffeler et al as a possible cause of rotator cuff tears (RCTs), in 2 different populations: Brazilian and Japanese. METHODS: Patients with full thickness RCTs diagnosed by magnetic resonance imaging and corroborated by intraoperative findings were included in this study. Controls were patients with shoulder radiographs that indicated instability or adhesive capsulitis. The studied population was subdivided into 2 major racial groups: Brazilian and Japanese. We compared 83 Brazilian adults (mean age, 54 years) with RCTs with 28 individuals with intact rotator cuffs matched by sex, age, and race. Similarly, 112 Japanese individuals (mean age, 59 years) with RCTs were compared with 56 controls. The radiographic images were digitally scanned (HP DeskJet F4180; Hewlett-Packard, Palo Alto, CA, USA) and analyzed. RESULTS: The mean acromion index of the Brazilian patients with RCTs was 0.72; 0.68 was the result for the Japanese patients. When patients with RCTs were compared with those with intact rotator cuffs, a statistically significant difference was found in the Brazilian population (P = .001) but not in the Japanese population (P = .18). Therefore, Brazilian subjects with RCTs were found to have a greater lateral extension of the acromion than those with intact rotator cuffs. Such a difference, however, was not observed in the Japanese population. CONCLUSION: The acromion index can be used as a predictive factor for RCTs in the Brazilian population but not in the Japanese population. PMID- 21816636 TI - Longitudinal tears of peroneus longus and brevis tendons: a gouty infiltration. AB - The natural history of recurrent uric acid deposition includes joint destruction, as well as tendon weakening and rupture. Simultaneous rupture of the peroneus longus and brevis tendons secondary to tophaceous gout is very rare. In the present report, we describe the case of a 37-year-old man who had a history of recurrent ankle pain and 4 previous episodes of acute gout localized to his ipsilateral first metatarsophalangeal joint. The physical examination revealed the ankle pain to actually be localized to the peroneal tendons immediately distal to the fibular malleolar groove. Magnetic resonance imaging showed longitudinal tears in the peroneus longus and brevis. Surgical exploration and repair of the ruptured tendons revealed the presence of monosodium urate deposition within the substance of the tendons at the rupture sites. The tendons were debrided and repaired using longus to brevis tenodesis. The postoperative course was unremarkable and entailed referral to a rheumatologist for metabolic management. After more than a 1-year period of follow-up, the patient was ambulating without difficulties wearing regular shoe gear. PMID- 21816637 TI - Metal-reinforced cement augmentation for complex talar subsidence in failed total ankle arthroplasty. AB - There are limited options for failed total ankle arthroplasty (TAA) with major talar bone loss and component subsidence. Surgical options for this condition include revision arthroplasty, salvage arthrodesis, or amputation. Revision arthroplasty generally has been considered in situations of loose components with minimal bone loss or use of expensive custom-fabricated prosthetic components with elongated stems. Historically, failure that involves major talar bone loss has been considered resistant to reconstruction, and responsive only to complex arthrodesis or amputation. In this report, we describe a unique method of restoring talar support and preserving ankle function after failed TAA with major talar bone loss and component subsidence. Talar reconstruction using metal reinforced bone cement augmentation is combined with the Inbone (Wright Medical Technology, Inc., Arlington, TN) total ankle system to restore talar height and ligamentous support. This technique has been used successfully in the last 4 years for various patterns of talar bone loss and obviates the need for custom components. When successfully performed, the revision technique results in restoration of mechanical alignment, anatomic height, and component support, in addition to providing substantial symptomatic relief. PMID- 21816638 TI - On the significance of motion degradation in high-resolution 3D MUMRI of trabecular bone. AB - RATIONALE AND OBJECTIVES: Subtle subject movement during high-resolution three dimensional micro-magnetic resonance imaging of trabecular bone (TB) causes blurring, thereby rendering the data unreliable for quantitative analysis. In this work, the effects of translational and rotational motion displacements were evaluated qualitatively and quantitatively. MATERIALS AND METHODS: In experiment 1, motion was induced by applying various simulated and previously observed in vivo trajectories as phase shifts to k-space or rotation angles to k-space segments of a virtually motion-free data set. In experiment 2, images that were visually free of motion artifacts from two groups of 10 healthy individuals, differing in age, were selected to probe the effects of motion on TB parameters. In both experiments, images were rated for motion severity, and the scores were compared to a focus criterion, the normalized gradient squared. RESULTS: Strong correlations were observed between the motion quality scores and the corresponding normalized gradient squared values (R(2) = 0.52-0.64, P < .01). The results from experiment 1 demonstrated consistently lower image quality and alterations in structural parameters of 9% to 45% with increased amplitude of displacements. In experiment 2, the significant differences in structural parameter group means of the motion-free images were lost upon motion degradation. Autofocusing, a postprocessing correction method, partially recovered the sharpness of the original motion-free images in 13 of 20 subjects. CONCLUSIONS: Quantitative TB structural measures are highly sensitive to subtle motion-induced degradation, which adversely affects precision and statistical power. The results underscore the influence of subject movement in high resolution three-dimensional micro-magnetic resonance imaging and its correction for TB structure analysis. PMID- 21816639 TI - Impact of immediate TRUS rebiopsy in a patient cohort considering active surveillance for favorable risk prostate cancer. AB - INTRODUCTION AND OBJECTIVE: Active surveillance (AS) is an option for the management of favorable risk prostate cancer (CaP) in the PSA era. Published studies have reported variable inclusion criteria for cohort selection. Accurate assessment of individual patient risk in AS is dependent not only upon rigorous selection criteria, but also reliability of diagnosis at tissue biopsy. To date, the impact of immediate transrectal ultrasound (TRUS) rebiopsy in confirming candidates for AS has been incompletely defined. METHODS: From a total of over 567 men, 67 met criteria for AS (Gleason <7, PSA <10, PSAD <0.15, <3 cores with <50% involvement of any 1 core). Fifty-two men agreed to a 12-core TRUS rebiopsy within 6 months of first diagnosis performed in clinic. Statistical analysis was performed using Wilcoxon signed rank test and logistic regression to determine predictors of rebiopsy characteristics, histopathologic outcomes, and impact on treatment choice. RESULTS: Mean cohort age was 63.9 years (range 56-72 years), PSA 5.9 ng/ml (4.1-10), and PSA density 0.12 ng/ml/cc at initial biopsy. Tumor involved 1.1 cores and 3.2% (range 1%-5%) of the total tissue. Average time to rebiopsy was 2.7 months. Notably, 29 of 52 men (56%) demonstrated no evidence of CaP on repeat biopsy; 14 of 23 men with a positive repeat biopsy showed either an increase in cancer volume (2.8% mean increase) and 9 (18%) were upgraded to Gleason pattern 3+4 = 7. Rebiopsy demonstrated 9 (17%) patients exceeded AS criteria. Nine patients chose curative surgical intervention (radical prostatectomy) based on increased cancer volume or grade (4) or an elective desire for treatment (5). All had organ confined disease with negative margins on final pathologic analysis. Statistical review revealed that initial Gleason score, PSA density, and number of positive cores at first biopsy were not predictive of men with higher volume/grade on re-biopsy. CONCLUSIONS: Immediate TRUS repeat biopsy after diagnosis frequently fails to redemonstrate prostate cancer confirming the favorable-risk nature of disease burden in this group being considered for AS. A subset of patients are upgraded (17%) leading to reconsideration of AS. We conclude this clinic-based approach provides valuable additional information to discriminate appropriate AS candidates. PMID- 21816641 TI - Transcranial ultrasound in neurodegeneration with brain iron accumulation (NBIA). AB - NBIA/HSS is a neurodegenerative disorder associated with iron accumulation in specific brain regions. To date, the diagnosis is obtained by typical MRI changes followed by genetic mutation analysis. This procedure is laborious and limited to a few specially equipped medical centres. Since transcranial sonography (TCS) is widely used for the early diagnosis of PD in adults displaying parenchymal metal deposits, it is likely to be a reliable diagnostic tool for the early diagnosis of NBIA. In 7 patients with proven NBIA and 13 age-matched controls without record of neurological disease TCS was performed by an experienced ultrasound examiner. Data were analysed by two blinded investigators regarding hyperechogenicity and size of the substantia nigra (SN). SN size and hyperechogenicity was significantly increased in patients with NBIA compared to controls (students t-test: p < 0.001). TCS appears to be a non-invasive and inexpensive screening technique in patients with suspected NBIA. Performed by an experienced physician, it could enable an earlier diagnosis and pre-selection of patients for the MRI scan and genetic testing, which are still the diagnostic gold standard. PMID- 21816642 TI - Cavernous sinus syndrome from an internal carotid artery aneurysm in an infant with tuberous sclerosis. AB - Aneurysms are associated with tuberous sclerosis complex. We describe the first case of cavernous sinus syndrome from an intracavernous internal carotid artery aneurysm in a 9-month-old boy with tuberous sclerosis. The presence of an intracranial aneurysm should be considered in the differential diagnosis of children with tuberous sclerosis who develop cranial nerve deficits. PMID- 21816640 TI - A non-comparative randomized phase II study of 2 doses of ATN-224, a copper/zinc superoxide dismutase inhibitor, in patients with biochemically recurrent hormone naive prostate cancer. AB - OBJECTIVE: ATN-224 (choline tetrathiomolybdate) is an oral Cu(2+)/Zn(2+) superoxide dismutase 1 (SOD1) inhibitor with preclinical antitumor activity. We hypothesized that ATN-224 may induce antitumor effects as an antiangiogenic agent at low dose-levels while possessing direct antitumor activity at higher dose levels. The objective of this study was to screen its clinical activity in patients with biochemically recurrent hormone-naive prostate cancer. METHODS: Biochemically-recurrent prostate cancer patients with prostate specific antigen doubling times (PSADT) < 12 months, no radiographic evidence of metastasis, and no hormonal therapy within 6 months (with serum testosterone levels > 150 ng/dl) were eligible. ATN-224 was administered at 2 dose-levels, 300 mg (n = 23) or 30 mg (n = 24) daily, by way of randomization. PSA progression was defined as a >= 50% increase (and >5 ng/ml) in PSA from baseline or post-treatment nadir. Endpoints included the proportion of patients who were free of PSA progression at 24 weeks, changes in PSA slope/PSADT, and safety. The study was not powered to detect differences between the 2 treatment groups. RESULTS: At 24 weeks, 59% (95% CI 33%-82%) of men in the low-dose arm and 45% (95% CI 17%-77%) in the high-dose arm were PSA progression-free. Median PSA progression-free survival was 30 weeks (95% CI 21-40(+)) and 26 weeks (95% CI 24-39(+)) in the low-dose and high-dose groups, respectively. Pre- and on-treatment PSA kinetics analyses showed a significant mean PSA slope decrease (P = 0.006) and a significant mean PSADT increase (P = 0.032) in the low-dose arm only. Serum ceruloplasmin levels, a biomarker for ATN-224 activity, were lowered in the high-dose group, but did not correlate with PSA changes. CONCLUSIONS: Low-dose ATN-224 (30 mg daily) may have biologic activity in men with biochemically-recurrent prostate cancer, as suggested by an improvement in PSA kinetics. However, the clinical significance of PSA kinetics changes in this patient population remains uncertain. The absence of a dose-response effect also reduces enthusiasm, and there are currently no plans to further develop this agent in prostate cancer. PMID- 21816643 TI - Intraocular pressure and central corneal thickness in premature and full-term newborns. AB - PURPOSE: To evaluate the intraocular pressure (IOP) and central corneal thickness (CCT) in premature and full-term newborns. METHODS: IOP and CCT were determined in 33 premature (mean [+/- SD] gestational age 31 +/- 3 weeks, mean birth weight 1474 +/- 354 g) and in 33 full-term white newborns (mean gestational age 39 +/- 1 weeks, mean birth weight 2763 +/- 574 g). The mean age after birth at measurement was respectively 3 +/- 1 weeks and 1 +/- 1 weeks. Infants with any ocular abnormalities, such as corneal and iris alterations, congenital cataract, retinopathy, glaucomatous corneal and optic disk changes (horizontal corneal diameter >10 mm Hg, C/D >0.4), or familial congenital glaucoma were excluded. IOP was determined with the use of only topical anesthesia with a Tono-Pen XL tonometer and a wire lid retractor, and then CCT was determined by means of a portable pachymeter. RESULTS: Mean IOP was 18.9 +/- 3.7 mm Hg (range, 13-25) in premature and 17 +/- 2.6 mm Hg (range, 12-22) in full-term newborns (P = 0.018 after correction by age after birth). Mean CCT was 599 +/- 36 MUm (range, 524-720 MUm) in premature infants and 576 +/- 26 MUm (range, 489-650 MUm) in the full term group (P < 0.001 after correction by age after birth). Multivariate analysis showed that IOP increased with increasing CCT (P = 0.025) and that CCT declined with increasing birth weight (P = 0.026). CONCLUSIONS: In premature newborns, IOP measurements were slightly greater than in full-term newborns because of an increased CCT. PMID- 21816644 TI - Molecular modeling-based antioxidant arylidene barbiturates as urease inhibitors. AB - Previously we have reported arylidene barbiturates 1-18 as a novel class of antioxidants; however, their urease inhibitory potential has not yet been explored. In this communication, molecular docking studies were used to predict the potential ligands from compounds 1-18 which culminated in the identification of certain new urease inhibitors. Ligands were screened in vitro for their urease inhibitory potential. Compound 1, as deduced from modeling studies, was found to be the most active urease inhibitor (13.0 +/- 1.2 MUM), when compared with the standard thiourea (IC50=21.1 +/- 0.3 MUM). All of the compounds were found to be nontoxic to Artemia salina in brine shrimp lethality bioassay. PMID- 21816645 TI - Bezafibrate upregulates carnitine palmitoyltransferase II expression and promotes mitochondrial energy crisis dissipation in fibroblasts of patients with influenza associated encephalopathy. AB - Influenza-associated encephalopathy (IAE) is characterized by persistently high fever, febrile convulsions, severe brain edema and high mortality. We reported previously that a large proportion of patients with disabling or fatal IAE exhibit a thermolabile phenotype of compound variants for [1055T>G/F352C] and [1102G>A/V368I] of carnitine palmitoyltransferase II (CPT II) and mitochondrial energy crisis during high fever. In the present study, we studied the effect of bezafibrate, a hypolipidemic pan-agonist of peroxisome proliferator-activated receptor (PPAR), on CPT II expression and mitochondrial energy metabolism in fibroblasts of IAE patients and wild type (WT) fibroblasts from a healthy volunteer at 37 degrees C and 41 degrees C. Although heat stress markedly upregulated CPT II, CPT IA and PPAR-delta mRNA expression levels, CPT II activity, beta-oxidation and ATP levels in WT and IAE fibroblasts at 41 degrees C were paradoxically downregulated probably due to the thermal instability of the corresponding enzymes. Bezafibrate significantly enhanced the expression levels of the above mRNAs and cellular functions of these enzymes in fibroblasts at 37 degrees C. Bezafibrate-induced increase in CPT II activity also tended to restore the downregulated ATP levels, though moderately, and improved mitochondrial membrane potential even at 41 degrees C to the levels at 37 degrees C in fibroblasts of IAE patients. L-carnitine, a substrate of CPT II, boosted the effects of bezafibrate on cellular ATP levels in WT and IAE fibroblasts, even in severe IAE fibroblasts with thermolabile compound variations of F352C+V368I at 37 degrees C and 41 degrees C. The results suggest the potential usefulness of bezafibrate for the treatment of IAE. PMID- 21816646 TI - Effect of biofilm formation on the excretion of Salmonella enterica serovar Typhi in feces. AB - OBJECTIVES: We hypothesized that Salmonella enterica serovar Typhi (S. Typhi) with higher biofilm and capsule production capability are more able to survive continuously in typhoid patients/carriers, with subsequent prolonged shedding in feces. METHODS: Bacterial cell release from biofilm (produced in vitro and confirmed by specific staining and electron microscopy) and comparative cytotoxicity were studied on Caco2 cells. Functionality of the biofilm diffusion barrier was tested against ciprofloxacin. Biofilm production was graded and semi quantified as -, +, ++, +++, and ++++. RESULTS: Out of 30 isolates, 23 produced biofilm. The average post-treatment detection of S. Typhi in blood was 7-13 days and in stool was 13-32 days. A fall in cell count from 104 to approximately 101 over the course of 3 days as compared to total elimination of planktonic cells in 16 h after ciprofloxacin application substantiated the protective role of biofilm. Lactic dehydrogenase release ranged from 38% in non-biofilm producers to 97% in the highest biofilm producers, indicating increased pathogenic behavior. CONCLUSIONS: The period of S. Typhi clearance from typhoid patients after recovery was found to be directly related to biofilm production capability. PMID- 21816647 TI - Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease) and oligoarthritis. AB - A 24-year-old woman who had sinus histiocytosis with massive lymphadenopathy (SHML, Rosai-Dorfman disease) also had oligoarthritis. We found only four previously reported cases of SHML with clinical joint disease. The clinical picture may suggest rheumatoid arthritis or a spondylarthropathy with peripheral joint involvement. SHML should be considered routinely among the differential diagnoses in young patients with arthritis and large lymphadenopathies. There is no consensus regarding the treatment. In our patient, conventional disease modifying antirheumatic drugs followed by 3 months of adalimumab then 3 months of etanercept had no effect on the symptoms. PMID- 21816648 TI - Tigecycline option for the treatment of bone and joint infections caused by multidrug-resistant Staphylococcus epidermidis. PMID- 21816649 TI - Arthroscopic interposition arthroplasty of the trapeziometacarpal joint. AB - PURPOSE: In carpometacarpal (CMC) arthritis of the thumb, the use of interposition techniques (polylactic acid, pyrocarbon, dacron) has been increasing recently. These techniques are most often combined with open or arthroscopic complete or partial trapeziectomy. This article reports the results at one year of the arthroscopic interposition of an absorbable implant performed without trapeziectomy. METHODS: Our series included 25 patients aged 60.5 years on average, presenting with osteoarthritis of the trapeziometacarpal joint that had been medically treated for 18.5 months on average. All patients were operated using 1-ulnar (U) and 1-radial (R) portals. After joint debridement, a polylactic acid implant was inserted under arthroscopic control. Outcome evaluation consisted of the assessment of pain intensity, grip strength, pinch strength, opposition, thumb abduction and Dell radiological staging. RESULTS: The average follow-up was 14 months. Postoperative radiological data showed significant differences from baseline clinical data regarding all evaluated variables: 0.68 vs. 3.5 for pain, 24.76 Kg vs. 16.64 Kg for grip strength, 6.44 Kg vs. 3.64 Kg for pinch strength, 8.6 vs. 7.28 for opposition, 81.2 degrees vs. 69.6 degrees for thumb abduction, and 1.08 vs. 2.88 on the Dell stage. Eleven complications occurred, including a type 1 complex regional pain syndrome, one sepsis, and nine inflammatory reactions that resolved after an average of 3 weeks. CONCLUSIONS: Our technique is simple, rapid, cost-effective, and does not necessitate trapeziectomy, even partial. It has the same indications as other non-radical interventions. The follow-up duration of our study was too short for long-term evaluation but short-term outcome appeared superior to that in other published series. The regional inflammatory reactions that occurred in our series were transient and probably related to implant resorption. Our promising results suggest extending the indication of arthroscopic interposition to more advanced stages of proximal joint osteoarthritis. PMID- 21816650 TI - [Induced membrane technique for the reconstruction of bone defects in upper limb. A prospective single center study of nine cases]. AB - INTRODUCTION: Bone defect in the upper limb remain infrequent with few reported in the literature. Their reconstruction raises the problem of bone union of non weight-bearing segments as well as the function of adjacent joints. We report a monocentric continuous series of nine patients treated with the induced membrane technique (Masquelet technique). PATIENTS AND METHODS: Nine patients with a mean age of 39.2 years (17-69) presented with a bone defect of the humerus (six cases) or one of two bones (three cases). Diaphyseal (six cases) or metaphyseal (three cases) defects were secondary to trauma in three patients, to non-union in four others and following tumors for the other two. The mean defect was 5.1cm (2.5-9). Reconstruction was done by initial filling using a spacer in cement, followed by a cancellous bone graft within the induced membrane. BMP's growth factor was used in two cases. RESULTS: Bone union was achieved in eight out of nine cases with a follow-up of 23 months (8-52) after the first stage, and 17 months (6-49) following filling by the graft. One patient did not want the second stage done before one year. The failure was in a very non-compliant patient who had a bone substitute associated with aBMP. Two septic non-unions were cured. Shoulder and elbow functional outcomes were comparable to the controlateral side for humeral defects; pronosupination decreased by 17% for the cases of reconstruction of two bones. DISCUSSION: The technique of the induced membrane allows filling of a large bone defect, while avoiding vascularised bone autografts and their morbidity. It requires two procedures but can be used in emergency or after failure of other interventions. It is a reliable, and reproducible technique where the only limit is the cancellous bone stock. Following the series of Masquelet, Apard and Stafford in the lower limb, and the series of Flamans in the hand, this is the first report of reconstruction of defect in the upper limb using this technique. PMID- 21816651 TI - [Scaphotriquetral capsulodesis for scapholunate instability]. AB - OBJECTIVES: Scapholunate ligament injuries may lead to scapholunate instability and wrist osteoarthritis. Many surgical techniques have been described to repair these injuries. The goal of our study is to assess the clinical results after capsulodesis with the scaphotriquetral ligament for scapholunate instabilities. METHODS: Twenty-eight patients, 22 men and six women, were operated for scapholunate instability between January 2006 and December 2008. The average age was 37.8 years, and the average time between trauma and surgery was 9.9 months. The scaphoid shift test was present in 26 patients. All patients underwent static and dynamic X-rays of the wrist and scan. A capsulodesis with scaphotriquetral ligament was performed in all patients. RESULTS: At 24 months follow-up, a 13 degrees significant decreased of wrist range-of-motion was noted. The strength was significantly improved after surgery. The wrist stability was improved in 26 patients. Concerning pain, a significant reduction was noted with Analogical Visual Scale after surgery (p<0.005). Twenty-one patients returned to their previous work. Complications were reflex dystrophy in one patient and wrist infection in one patient. CONCLUSION: Many techniques were described for treatment of scapholunate injuries, from the simple scapholunate ligament suture to partial wrist arthrodesis. Capsulodesis with scaphotriquetral ligament improves grip strength, decreases wrist instability and pain with a slight lost of range-of-motion. PMID- 21816653 TI - Phase space analysis of myocardial coordination related to left ventricular ejection fraction by echocardiographic speckle-tracking radial strain. AB - Phase space reconstruction, which is performed by converting echocardiogram derived strain data from different ventricular regions into phase space trajectories, is applied in this study to describe nonlinear behaviour of myocardial coordination. A new method was developed to quantify patterns of phase space trajectories. Echocardiograms of 31 healthy individuals and 63 patients with left bundle branch block (LBBB) and different left ventricular ejection fractions (LVEFs) were used to evaluate this method. The LBBB patients were separated into two groups: LBBB with a LVEF>=50% and LBBB with a LVEF<50%. LVEF is used to represent levels of systolic function and disease severity. A classifying map was constructed to separate the reconstructed phase space into three zones and to acquire the parameters Pz1, Pz2 and Pz3 as percentiles of phase points related to the zones. The criteria used to define the zones were cross-tested. Based on these parameters, significant group-related differences in myocardial coordination were observed. Significantly smaller Pz1 and significantly larger Pz2 values were observed in the healthy group, as compared to the patient group, and similar, significant results were obtained for the patients with LVEF>=50%, as compared to the patients with LVEF<50% (p<.05). A significantly larger Pz3 was observed in patients with LVEF<50%, as compared to the other patients (p<.05). In addition, different inter-regional relationships among strain pairs (all, near-side, middle-side and opposite-wall) were examined to create phase space trajectories. Consistent group-related differences were observed when different inter-regional relationships were applied. Expanding the use of the proposed method to assess various pathological factors and therapeutic impacts is promising. PMID- 21816652 TI - [Rollover hands: classification of injuries and therapeutic strategy]. AB - The term Rollover hands (ROHs) corresponds to a loss of compound tissue from the back of the hand. Our aim was to specify the injuries associated with this type of accident and codify the therapeutic strategy. PATIENTS AND METHOD: Twenty-one ROHs were reviewed with an average follow-up of 38 months. Skin coverage included 15 pedicle flaps (two posterior interosseous, 13 pedicled groin flaps), and three free flaps (two external brachial or one parascapular). RESULTS: We identified: seven stage IA injuries where the extensor apparatus could be directly sutured; Seven stage IB injuries requiring a tendon graft; Stage II, like stage 1B but with bone and joint lesions or damage to the wrist extensors as well, and Stage III for which over 50% of the intrinsic muscles had been destroyed. All patients recovered their grasp. The mean active extension deficit for each finger was 20.9 degrees for the whole digital chain and a 194.4 degrees TAM. Palmo-digital grip strength was 51.3% on the controlateral side, and the mean DASH score was 16.1. DISCUSSION: Our study demonstrates the prognostic value of the proposed classification and importance of restoring high-quality skin covering. Reconstruction of the extensor apparatus must be envisaged once the condition of the bone and joints has become stable. Vascularised tendon grafts may be indicated when early mobilisation allowing restoration of a glliding surface around the tendon is impossible, or for loss of substance of over 5 cm. Damage to the intrinsic muscles is a very poor prognostic factor. PMID- 21816654 TI - Valosin-containing protein mutation and Parkinson's disease. PMID- 21816656 TI - Recreational physical activity facilities within walking and cycling distance: sociospatial patterning of access in Scotland. AB - To examine the sociospatial patterning of access to recreational physical activity facilities in Scotland, we used negative binomial multilevel models to investigate associations between income deprivation at datazone level and the number of facilities available within 10, 20 and 30 min walking and cycling thresholds, adjusting for datazone population size and local authority. Accessibility was significantly (p<0.01) lower in the most affluent quintile for most thresholds tested in urban areas and for some thresholds tested in small towns. In general, more affluent areas had less good access to recreational physical activity facilities within walking or cycling distance. PMID- 21816655 TI - Do interactions between SNCA, MAPT, and LRRK2 genes contribute to Parkinson's disease susceptibility? AB - BACKGROUND: Polymorphisms in SNCA, MAPT and LRRK2 genes have recently been confirmed as risk factors for Parkinson's disease (PD), although with small individual attributable risk. Here we investigated the association of PD with interactions between variants of these genes. METHODS: As part of a previous study of PD susceptibility genes 119 SNCA, MAPT, and LRRK2 haplotype tagging single nucleotide polymorphisms (SNPs) and two variable number tandem repeats (VNTRs) were genotyped in 1098 PD cases from the upper Midwest, USA and 1098 matched controls. Twenty-six of these SNPs were selected for SNP-SNP (or SNP-VNTR or VNTR-VNTR) interaction analysis (256 interaction pairs). Case-control analyses were performed to study association of pairwise SNP interactions with PD susceptibility. RESULTS: Out of the 256 interaction pairs investigated, 10 had uncorrected p-values <0.05. These represented six SNCA-LRRK2 pairs, three SNCA MAPT pairs, and one MAPT-LRRK2 pair. However, none of these pairwise interactions were significant after correction for multiple testing. Secondary analyses in strata defined by type of control (sibling or unrelated), sex, or age at onset of the case also did not reveal any significant interactions after accounting for multiple testing. CONCLUSIONS: This study provides no statistically significant evidence of gene-gene interaction effects for the three confirmed genetic susceptibility loci for PD. However, this does not exclude the possibility that other genomic loci or environmental risk factors interact with these genes. PMID- 21816657 TI - Social inequality and young pregnancy: the causal attributions of young parents in London, UK. AB - Although the association between young pregnancy and the socio-economic environment is globally recognised, little is understood about either the processes behind it or how young parents construe this relationship. Twenty-one semi-structured interviews were conducted in four London areas; two 'less deprived' and two 'more deprived' in order to solicit young parent's views. Thematic analysis uncovered three factors indicative of how young parents understand the social gradient in young pregnancy; the parental relationship status (openness and parental control); access to education and career; and acceptance of young pregnancy. It is suggested that differing representations of young parenthood across socio-economic subgroups correspond to differing representations, values and beliefs concerning sexual and reproductive behaviour, education and the social acceptability of young pregnancy. Further work is needed to build up a holistic picture of the influence place has on young people's sexual and reproductive health. PMID- 21816658 TI - The genetics of cognitive impairment in schizophrenia: a phenomic perspective. AB - Cognitive impairments are central to schizophrenia and could mark underlying biological dysfunction but efforts to detect genetic associations for schizophrenia or cognitive phenotypes have been disappointing. Phenomics strategies emphasizing simultaneous study of multiple phenotypes across biological scales might help, particularly if the high heritabilities of schizophrenia and cognitive impairments are due to large numbers of genetic variants with small effect. Convergent evidence is reviewed, and a new collaborative knowledgebase - CogGene - is introduced to share data about genetic associations with cognitive phenotypes, and enable users to meta-analyze results interactively. CogGene data demonstrate the need for larger studies with broader representation of cognitive phenotypes. Given that meta-analyses will probably be necessary to detect the small association signals linking the genome and cognitive phenotypes, CogGene or similar applications will be needed to enable collaborative knowledge aggregation and specify true effects. PMID- 21816659 TI - Corneal erosions in contact lens wear. AB - Contact lens wear continues to be the highest single risk factor for microbial keratitis, particularly when worn in the extended wear modality. For microbial keratitis to occur, the presence of at least a bacterial load as well as a break in the corneal surface is required. One such break occurs in the case of a corneal erosion. These well-circumscribed areas of full thickness epithelial loss can occur both with and without contact lens wear, however the risk of infection is greater in the presence of a lens due to its capacity to provide a vector for the entry of bacterial pathogens. While erosions in non-contact lens wearers are thought to result from defective epithelial basement membrane anchoring, the underlying causes during contact lens wear are yet unknown. This article sets out to review corneal erosions associated with contact lens wear, their associated risk factors such as extended wear, the mechanisms that may be responsible for their formation and the factors that differentiate them from other contact lens related adverse events. Appropriate diagnosis and understanding of the relevant pathophysiology is important to the effective treatment and an understanding of the aetiological factors responsible for erosions is critical to the development of preventative strategies and effective clinical care. PMID- 21816660 TI - Single-stranded DNA repeat synthesis by telomerase. AB - The eukaryotic ribonucleoprotein reverse transcriptase (RT) telomerase uses a template within its integral RNA subunit to extend chromosome ends by synthesis of single-stranded telomeric repeats. Telomerase is adapted to its unique cellular role by an ability to release product DNA in single-stranded form, regenerating free template from the product-template hybrid. Furthermore, by retaining a template-independent grip on the single-stranded product, telomerase can catalyze processive repeat synthesis. These specialized nucleic acid handling properties are dependent on the protein and RNA domain network within an active RNP. RNP domain architecture and mechanisms for single-stranded DNA handling have been a focus of recent studies highlighted here. PMID- 21816662 TI - Upstream and downstream signals of nitric oxide in pathogen defence. AB - Nitric oxide (NO) is now recognised as a crucial player in plant defence against pathogens. Considerable progress has been made in defining upstream and downstream signals of NO. Recently, MAP kinases, cyclic nucleotide phosphates, calcium and phosphatidic acid were demonstrated to be involved in pathogen induced NO-production. However, the search for inducers of NO synthesis is difficult because of the still ambiguous enzymatic source of NO. Accumulation of NO triggers signal transduction by other second messengers. Here we depict NON EXPRESSOR OF PATHOGENESIS-RELATED 1 and glyceraldehyde-3-phosphate dehydrogenase as central redox switches translating NO redox signalling into cellular responses. Although the exact position of NO in defence signal networks is unresolved at last some NO-related signal cascades are emerging. PMID- 21816663 TI - Antibiotics and the post-genome revolution. AB - The emergence of pathogenic bacteria resistant to multiple antimicrobial agents is turning into a major crisis in human and veterinary medicine. This necessitates a serious re-evaluation of our approaches toward antibacterial drug discovery and use. Concurrent advances in genomics including whole-genome sequencing, genotyping, and gene expression profiling have the potential to transform our basic understanding of antimicrobial pathways and lead to the discovery of novel targets and therapeutics. PMID- 21816661 TI - Human papillomavirus types 16 and 18 in epithelial dysplasia of oral cavity and oropharynx: a meta-analysis, 1985-2010. AB - Human papillomavirus (HPV) types 16 and 18 are causally related to a sub-set of oral cavity and oropharyngeal squamous cell cancers. However, a clear estimate of the prevalence of HPV-16/18 in oral cavity and oropharyngeal dysplasia (OOPD) is not available. This literature review and meta-analysis was conducted to provide a prevalence estimate for HPV-16/18 in OOPD. Twenty-two studies that reported prevalence of HPV-16 and/or 18 in 458 OOPD lesions were analyzed. Meta-analysis was used to evaluate the prevalence of HPV-16/18 and logistic regression was used for stratified analysis by age, gender, and histological grade. The overall prevalence of HPV-16/18 in OOPD lesions was 24.5% [95% confidence interval (CI), 16.4-36.7%)]. The individual prevalence for HPV-16 alone was 24.4%. The prevalence of HPV-16/18 in oral cavity lesions alone was 25.3% (95% CI, 14.2 45.2%). The odds of detection of HPV-16/18 in dysplastic lesions in males were twice that of females [odds ratio (OR), 2.44]. HPV-16/18 were 3 times more common in dysplastic lesions (OR, 3.29; 95% CI, 1.95-5.53%) and invasive cancers (OR, 3.43; 95% CI, 2.07-5.69%), when compared to normal biopsies. There was no significant difference in HPV-16/18 rates between dysplastic lesions and cancers or between mild, moderate or severe dysplastic lesions. This meta-analysis provides a quantification of the prevalence of HPV types 16/18 in OOPD lesions. These results also support the assumption that HPV-16/18 infection occurs during the early phase of the oral cavity and oropharyngeal carcinogenesis. PMID- 21816664 TI - Editorial overview. PMID- 21816665 TI - A chemical arms race at sea mediates algal host-virus interactions. AB - Despite the critical importance of viruses in shaping marine microbial ecosystems and lubricating upper ocean biogeochemical cycles, relatively little is known about the molecular mechanisms mediating phytoplankton host-virus interactions. Recent work in algal host-virus systems has begun to shed novel insight into the elegant strategies of viral infection and subcellular regulation of cell fate, which not only reveal tantalizing aspects of viral replication and host resistance strategies but also provide new diagnostic tools toward elucidating the impact of virus-mediated processes in the ocean. Widespread lateral gene transfer between viruses and their hosts plays a prominent role in host-virus diversification and in the regulation of host-virus infection mechanisms by allowing viruses to manipulate and 'rewire' host metabolic pathways to facilitate infection. PMID- 21816666 TI - A Raman spectroscopic study of the mono-hydrogen phosphate mineral dorfmanite Na2(PO3OH).2H2O and in comparison with brushite. AB - Aspects of the molecular structure of the mineral dorfmanite Na(2)(PO(3)OH).2H(2)O were determined by Raman spectroscopy. The mineral originated from the Kedykverpakhk Mt., Lovozero, Kola Peninsula, Russia. Raman bands are assigned to the hydrogen phosphate units. The intense Raman band at 949 cm(-1) and the less intense band at 866 cm(-1) are assigned to the PO(3) and POH stretching vibrations. Bands at 991, 1066 and 1141 cm(-1) are assigned to the nu(3) antisymmetric stretching modes. Raman bands at 393, 413 and 448 cm(-1) and 514, 541 and 570 cm(-1) are attributed to the nu(2) and nu(4) bending modes of the HPO(4) units, respectively. Raman bands at 3373, 3443 and 3492 cm(-1) are assigned to water stretching vibrations. POH stretching vibrations are identified by bands at 2904, 3080 and 3134 cm(-1). Raman spectroscopy has proven very useful for the study of the structure of the mineral dorfmanite. PMID- 21816667 TI - Molecular structure, vibrational spectroscopic, first hyperpolarizability, NBO and HOMO, LUMO studies of P-Iodobenzene sulfonyl chloride. AB - In this work, the experimental and theoretical vibrational spectra of P Iodobenzene sulfonyl chloride (P-IBSC) were studied. P-IBSC and its derivatives present in many biologically active compounds. Because of their spectroscopic properties and chemical significance in particular, sulfonyl chloride and its derivatives have been studied extensively by spectroscopic (FTIR and FT-Raman spectra) and theoretical methods. The infrared spectra of these compounds were recorded in condensed states, while the Raman spectra were measured without polarization using both parallel and perpendicular polarizations of scattered light. The molecular geometry, highest occupied molecular orbital (HOMO), lowest unoccupied molecular orbital (LUMO), first order hyperpolarizability and thermodynamic properties of P-IBSC have been computed with the help of density functional theory (B3LYP) and ab initio (HF) methods with the LanL2DZ basis set. The HOMO and LUMO energy gap explains the charge transfer interactions taking place within the molecule. NBO study explains charge delocalization of the molecule. The contributions of the different modes to each wave number were determined using potential energy distributions (PEDs). The experimental and calculated results were consistent with each other. PMID- 21816668 TI - A new hydrogen-bonded pseudo-dimer Mn(III) Schiff base complex. The synthesis, X ray structure and spectroscopic studies. AB - A new hydrogen-bonded pseudo-dimer, [Mn(III)L1(CH(3)CH(2)OH)](2)(ClO(4)) (1) (L1 = N,N'-bis(2-hydroxy-1-naphthalidenato)-1,2-diaminopropane) has been synthesized and characterized by UV-vis, IR, elemental analysis and crystal structure analysis. The single crystal X-ray diffraction reveals that the structure affords an elongated octahedral MnN(2)O(4) coordination environment, geometry with the four donor atoms of the tetradentate Schiff base in the equatorial plane and with two ethanol molecule in axial positions with Mn-O = 2.265(2) and 2.266(2) A. PMID- 21816669 TI - Control of fast squatting movements after stroke. AB - OBJECTIVE: Little is known about how residual motor impairments after stroke affect the motor control of fast movements, particularly those that combine postural control and limb movement. The purpose of this study was to examine the influence of stroke on the motor control of fast squatting movements. METHODS: Seventeen individuals with hemiparesis and seventeen age- and sex-matched controls performed fast squatting movements. Force platform data, knee acceleration, and electromyographic activity from rectus femoris, biceps femoris, tibialis anterior, soleus, were collected. RESULTS: Subjects after stroke performed the squats asymmetrically, with reduced velocity and acceleration compared to controls. Subjects with low motor recovery depended on the non paretic leg to compensate for poor paretic muscle activation whereas subjects with high motor recovery activated muscles in the paretic leg in an adaptive manner, making the movement more symmetrical. Difficulty with postural control was evident by reduced coupling of the timing of the knee movement with the center of pressure excursion. CONCLUSIONS: Slow performance of squatting movements was accompanied by altered muscle activation, coupled with impaired postural control. SIGNIFICANCE: Fast squatting movements in standing require appropriate muscle activation and postural control, the latter of which can be measured easily with force platform and accelerometer data. PMID- 21816670 TI - Mitochondrial development of the in vitro hepatic organogenesis model with simultaneous cardiac mesoderm differentiation from murine induced pluripotent stem cells. AB - Induced pluripotent stem (iPS) cells, resembling embryonic stem (ES) cells in many phenomena, including differentiation potential, colony morphology, and the expression of specific representative markers, were generated from differentiated somatic cells by exogenous expression of several transcriptional factors. In recent, the mitochondria of iPS cells were also reported to be rejuvenated to that of ES cells, however it is not known if the mitochondria have same potential for differentiation as ES cells. We have established the murine ES cell-derived in vitro hepatic organogenesis model, consisting of not only hepatocytes but also endothelial networks together with cardiac mesoderm differentiation, previously. By measuring oxygen concentration and pH in the culture medium, respectively corresponding to the oxygen consumption rate (OCR) and extracellular acidification rate (ECAR), we compared the metabolic patterns and bio-energetic profiles of both iPS and ES cells during the hepatic differentiation. The bio energetic profiles of the in vitro hepatic organogenesis from iPS cells accorded with each differentiation steps, from proliferation stage as the initiation, spontaneously beating cardiac differentiation in the next, and finally liver tissue-formation, as well as that from ES cells. Both iPS and ES cells were differentiated into liver-like tissue with similar mitochondrial development. PMID- 21816671 TI - Plastidic phosphoglycerate kinase from Phaeodactylum tricornutum: on the critical role of cysteine residues for the enzyme function. AB - Chloroplastidic phosphoglycerate kinase (PGKase) plays a key role in photosynthetic organisms, catalyzing a key step in the Calvin cycle. We performed the molecular cloning of the gene encoding chloroplastidic PGKase-1 in the diatom Phaeodactylum tricornutum. The recombinant enzyme was expressed in Escherichia coli, purified and characterized. Afterward, it showed similar kinetic properties than the enzyme studied from other organisms, although the diatom enzyme displayed distinctive responses to sulfhydryl reagents. The activity of the enzyme was found to be dependent on the redox status in the environment, determined by different compounds, including some of physiological function. Treatment with oxidant agents, such as diamide, hydrogen peroxide, glutathione and sodium nitroprusside resulted in enzyme inhibition. Recovery of activity was possible by subsequent incubation with reducing reagents such as dithiothreitol and thioredoxins (from E. coli and P. tricornutum). We determined two midpoint potentials of different regulatory redox centers, both values indicating that PGKase-1 might be sensitive to changes in the intracellular redox environment. The role of all the six Cys residues found in the diatom enzyme was analyzed by molecular modeling and site-directed mutagenesis. Results suggest key regulatory properties for P. tricornutum PGKase-1, which could be relevant for the functioning of photosynthetic carbon metabolism in diatoms. PMID- 21816672 TI - Evaluation of the adherence to follow-up care guidelines for women with breast cancer. AB - PURPOSE: To evaluate adherence with follow-up criteria as suggested by the national guideline for breast cancer patients. METHOD: Patients diagnosed with breast cancer in 2003 in two hospitals were identified from the Netherlands Cancer Registry (n = 198). Compliance with the guideline was assessed retrospectively by extracting follow-up care data from patient files for a period of five years. RESULTS: Follow-up data were available for 196 patients. In the first year of follow-up, fewer consultations were performed compared to guideline standards. In the second through the fifth year of follow-up, more consultations were performed, with nearly double the number of consultations in the third until the fifth year compared to the guideline (p < 0.05). This excess usage was mainly associated with the fact that women had received radiotherapy (p < 0.01). Physical examinations were performed during 97 percent of consultations. Mammograms were performed slightly less often than suggested. CONCLUSIONS: Among women receiving follow-up care after breast cancer, more consultations were provided compared to the guideline recommendations. Mammograms were performed slightly less often than recommended. With regard to the performance of physical examinations, the guideline was followed. PMID- 21816673 TI - Intestinal CD103+ dendritic cells: master regulators of tolerance? AB - CD103(+) dendritic cells (DCs) in the intestinal mucosa play a crucial role in tolerance to commensal bacteria and food antigens. These cells originate in the lamina propria (LP) and migrate to the mesenteric lymph nodes (MLNs), where they drive the differentiation of gut-homing FoxP3(+) regulatory T cells by producing retinoic acid from dietary vitamin A. Local 'conditioning' factors in the LP might also contribute to this tolerogenic profile of CD103(+) DCs. Considerably less is understood about the generation of active immunity or inflammation in the intestinal mucosa. This might require alterations in pre-existing CD103(+) DCs, arrival of new DCs, or the action of a distinct DC population. Here, we discuss our current knowledge of this as yet incompletely understood population. PMID- 21816674 TI - AMP kinase: the missing link between type 2 diabetes and neurodegenerative diseases? PMID- 21816675 TI - Energy balance regulation by endocannabinoids at central and peripheral levels. AB - Dysregulation of the endocannabinoid system (ECS) is a universal and, perhaps, causative feature of obesity. Central nervous system (CNS) circuits that regulate food intake were initially believed to be the targets for dysregulation. However, it is increasingly evident that endocannabinoids affect food intake, energy expenditure and substrate metabolism by acting on peripheral sites. Cannabinoid type 1 receptor (CB1r) antagonists can effectively treat obesity and associated metabolic alterations but, unfortunately, cause and exacerbate mood disorders. Drugs restricted to act on peripheral CB1rs might be safer and more effective, retaining the anti-obesity effects but lacking the adverse neurodepressive reactions. This review summarizes the emerging roles of the ECS in energy balance and discusses future pharmacological approaches for developing peripherally restricted CB1r antagonists. PMID- 21816676 TI - Neurocysticercosis in Qatari patients: case reports. AB - Neurocysticercosis is the most common parasitic infection of the central nervous system. It is a major cause of seizures in developing countries, especially in the Indian subcontinent and most of Asia, Latin America and Africa. It is increasing in prevalence in Muslim countries, especially in the Gulf region reflecting the demographics of these countries which rely heavily on labourers from highly endemic areas. Infections among Muslims in non-endemic regions are increasing. We describe one prospective case report of a Qatari male who presented with seizures and was found to have neurocysticercosis, and three retrospective cases of this infection among Qatari Muslims, who were admitted to a tertiary care hospital over the past 10 years. PMID- 21816678 TI - Clinical presentation and diagnosis of uterine sarcoma, including imaging. AB - Uterine sarcomas are uncommon tumours from mesenchymal elements. They are thought to arise primarily from endometrial stroma and uterine muscle, respectively. When endometrial stroma undergoes malignant transformation, it might be accompanied by a malignant epithelial component. Thus, malignant mesenchymal uterine tumours comprise leiomyosarcoma, endometrial stromal sarcoma, undifferentiated uterine sarcoma and carcinosarcoma. In this chapter, we discusses preoperative presentation, diagnosis and current progress in different imaging modalities, including ultrasonography, computed tomography, magnetic resonance image and positron emission tomography scan. We summarise advances in new technology, which might improve preoperative detection and enhance referral to gynaecologic oncologists for optimal staging surgery and treatment. PMID- 21816677 TI - Sarcoma of vulva, vagina and ovary. AB - Less than 5% of vulvar, vaginal and ovarian malignant diseases are sarcomas. Adequate knowledge of these particular malignant diseases is essential for accurate diagnosis and for choice of surgical treatment, adjuvant therapy and efficient medical treatment in relapse. A crucial aspect in the management of women with these diseases is a multidisciplinary approach. Globally, presenting signs and symptoms of these sarcomas are non-specific of histological type but linked to initial location. In view of this, management should be undertaken by clinicians experienced in these particular malignancies. Long-term side-effects, particularly in children with sarcoma, adversely affect quality of life. New treatment strategies require special attention. PMID- 21816679 TI - Ictal central apnea as a predictor for sudden unexpected death in epilepsy. AB - Epidemiological evidence associating ictal hypoventilation during focal seizures with a heightened risk for subsequent sudden unexpected death in epilepsy (SUDEP) is lacking. We describe a patient with temporal lobe epilepsy with two focal seizures recorded in the epilepsy monitoring unit that were associated with central apnea lasting 57 and 58 seconds. During these events, she demonstrated oxygen desaturation down to 68 and 62%. The patient subsequently died at home from autopsy-confirmed SUDEP. The family was not alerted of any seizure activity by the auditory alarm system in her room nor by sleeping in the adjacent room with open doors. This case emphasizes the fact that ictal hypoxia and SUDEP may occur in seizures without noticeable convulsive activity. The report gives credibility to the growing body of literature suggesting that epilepsies affecting the autonomic nervous system may predispose to SUDEP independent of the effects of a secondary generalized convulsion. PMID- 21816680 TI - Costs and ethical issues related to first-line treatment of metastatic non-small cell lung cancer: considerations from a public healthcare system perspective. AB - Metastatic non-small-cell lung cancer is generally not considered to be curable, and the overall 5-year survival rate is less than 1%. Despite this poor prognosis, palliative chemotherapy can increase time and quality of life in the advanced-disease setting. New chemotherapy treatments and targeted therapies are available for this stage of disease, but their high costs are an important issue. In this perspective article, we discuss the hospital costs of antitumor drug administration and the ethical principles involved, the roles of drug agencies and oncologists, and relevant current research on these topics. These considerations have been examined from the perspective of a national public healthcare system. PMID- 21816682 TI - Epidemiology of falls in residential aged care: analysis of more than 70,000 falls from residents of bavarian nursing homes. AB - OBJECTIVE: Falls and fall-related injuries are leading problems in residential aged care facilities. The objective of this study was to provide descriptive data about falls in nursing homes. DESIGN/SETTING/PARTICIPANTS: Prospective recording of all falls over 1 year covering all residents from 528 nursing homes in Bavaria, Germany. MEASUREMENTS: Falls were reported on a standardized form that included a facility identification code, date, time of the day, sex, age, degree of care need, location of the fall, and activity leading to the fall. Data detailing homes' bed capacities and occupancy levels were used to estimate total person-years under exposure and to calculate fall rates. All analyses were stratified by residents' degree of care need. RESULTS: More than 70,000 falls were recorded during 42,843 person-years. The fall rate was higher in men than in women (2.18 and 1.49 falls per person-year, respectively). Fall risk differed by degree of care need with lower fall risks both in the least and highest care categories. About 75% of all falls occurred in the residents' rooms or in the bathrooms and only 22% were reported within the common areas. Transfers and walking were responsible for 41% and 36% of all falls respectively. Fall risk varied during the day. Most falls were observed between 10 am and midday and between 2 pm and 8 pm. CONCLUSION: The differing fall risk patterns in specific subgroups may help to target preventive measures. PMID- 21816681 TI - Randomized multilevel intervention to improve outcomes of residents in nursing homes in need of improvement. AB - OBJECTIVES: A comprehensive multilevel intervention was tested to build organizational capacity to create and sustain improvement in quality of care and subsequently improve resident outcomes in nursing homes in need of improvement. DESIGN/SETTING/PARTICIPANTS: Intervention facilities (N = 29) received a 2-year multilevel intervention with monthly on-site consultation from expert nurses with graduate education in gerontological nursing. Attention control facilities (N = 29) that also needed to improve resident outcomes received monthly information about aging and physical assessment of elders. INTERVENTION: The authors conducted a randomized clinical trial of nursing homes in need of improving resident outcomes of bladder and bowel incontinence, weight loss, pressure ulcers, and decline in activities of daily living. It was hypothesized that following the intervention, experimental facilities would have higher quality of care, better resident outcomes, more organizational attributes of improved working conditions than control facilities, higher staff retention, similar staffing and staff mix, and lower total and direct care costs. RESULTS: The intervention did improve quality of care (P = .02); there were improvements in pressure ulcers (P = .05) and weight loss (P = .05). Organizational working conditions, staff retention, staffing, and staff mix and most costs were not affected by the intervention. Leadership turnover was surprisingly excessive in both intervention and control groups. CONCLUSION AND IMPLICATIONS: Some facilities that are in need of improving quality of care and resident outcomes are able to build the organizational capacity to improve while not increasing staffing or costs of care. Improvement requires continuous supportive consultation and leadership willing to involve staff and work together to build the systematic improvements in care delivery needed. Medical directors in collaborative practice with advanced practice nurses are ideally positioned to implement this low-cost, effective intervention nationwide. PMID- 21816683 TI - No difference in long-term trunk muscle strength, cross-sectional area, and density in patients with chronic low back pain 7 to 11 years after lumbar fusion versus cognitive intervention and exercises. AB - BACKGROUND CONTEXT: Reduced muscle strength and density observed at 1 year after lumbar fusion may deteriorate more in the long term. PURPOSE: To compare the long term effect of lumbar fusion and cognitive intervention and exercises on muscle strength, cross-sectional area, density, and self-rated function in patients with chronic low back pain (CLBP) and disc degeneration. STUDY DESIGN: Randomized controlled study with a follow-up examination at 8.5 years (range, 7-11 years). PATIENTS AND METHODS: Patients with CLBP and disc degeneration randomized to either instrumented posterolateral fusion of one or both of the two lower lumbar levels or a 3-week cognitive intervention and exercise program were included. Isokinetic muscle strength was measured by a Cybex 6000 (Cybex-Lumex, Inc., Ronkonkoma, NY, USA). All patients had previous experience with the test procedure. The back extension (E) flexion (F) muscles were tested, and the E/F ratios were calculated. Cross-sectional area and density of the back muscles were measured at the L3-L4 segment by computed tomography. Patients rated their function by the General Function Score. OUTCOME MEASURES: Trunk muscle strength, cross-sectional area, density, and self-rated function. RESULTS: Fifty-five patients (90%) were included at long-term follow-up. There were no significant differences in cross-sectional area, density, muscle strength, or self-rated function between the two groups. The cognitive intervention and exercise group increased trunk muscle extension significantly (p<.05), and both groups performed significantly better on trunk muscle flexion tests (p<.01) at long-term follow up. On average, self-rated function improved by 56%, cross-sectional area was reduced by 8.5%, and muscle density was reduced by 27%. CONCLUSION: Although this study did not assess the morphology of muscles likely damaged by surgery, trunk muscle strength and cross-sectional area above the surgical levels are not different between those who had lumbar fusion or cognitive intervention and exercises at 7- to 11-year follow-up. PMID- 21816684 TI - Monte Carlo calculations of AAPM Task Group Report No. 43 dosimetry parameters for the (125)I I-Seed AgX100 source model. AB - PURPOSE: The purpose of this study was to determine the dosimetric parameters of the AgX100, a new (125)I brachytherapy seed model, using Monte Carlo (MC) simulations according to the protocol specified by the updated American Association of Physicists in Medicine Task Group No. 43 Report (TG-43U1) and compare these parameters with those of the established brachytherapy (125)I seed models 6711 and I25.S06. METHODS AND MATERIALS: Independent verification of the new seed geometry was performed using high-resolution digital radiography and scanning electron microscopy. MCNPX v.2.5 MC simulations of the AgX100 seed were performed to derive its TG-43U1 parameters, the dose rate constant, the radial dose function, and the two- and one-dimensional anisotropy functions in liquid water. A dosimetric error propagation analysis was also performed to include uncertainty because of seed manufacturing tolerances and physics parameters. RESULTS: The MC-calculated dose rate constant for the AgX100 seed was 0.943cGy.h( 1).U(-1)+/-2.6% (k=1) based on the air kerma strength for a simulated point detector. Tabulated results of the radial dose function for line and point source approximations and the two-dimensional anisotropy function are also reported. CONCLUSIONS: The MC-predicted dose distribution of the AgX100 seed was found to be comparable with that of the model 6711 seed but much different from the dose distribution of the model I25.S06 seeds. However, at shallow distances, there were some dosimetric differences between the AgX100 and 6711 seed, which warrant separate TG-43U1 parameters for use in clinical treatment planning systems. PMID- 21816685 TI - Objective automated assessment of time trends in prostate edema after (125)I implantation. AB - PURPOSE: To present an objective automated method to determine time trends in prostatic edema resulting from iodine-125 brachytherapy. METHODS AND MATERIALS: We followed 20 patients, implanted with stranded seeds, with seven consecutive CT scans to establish a time trend in prostate edema. Seed positions were obtained automatically from the CT series. The change in seed positions was used as surrogate for edema. Two approaches were applied to model changes in volume. (1) A cylindrical model: seeds from the compared distribution were linked to the reference distribution of Day 28. After alignment, the compared distribution was scaled in cylindrical coordinates, leading to the changes in radial and craniocaudal directions. The volume changes were calculated using these scaling factors. (2) A spherical model: distances of seeds to the center of gravity of all seeds were used as a measure to model volume changes. RESULTS: With Day 28 as reference, the observed volume changes were smaller than 18% +/- 6% (1 standard deviation) for the cylindrical model and 12% +/- 7% for the spherical model. One day after implantation, the implanted prostate was less than 10% larger than in the reference scan for both models. Apart from Day 0, both models showed similar volume changes. CONCLUSIONS: We present an objective automated method to determine changes in the implanted prostate volume, eliminating the influence of an observer in the assessment of the prostate size. The implanted volume change was less than 18% +/- 7% for the studied group of 20 patients. Edema was 9% +/- 5% from 1 day after implantation onward. PMID- 21816686 TI - A comparison of brachytherapy techniques for partial breast irradiation. AB - Accelerated partial breast irradiation has emerged as an important treatment option for select patients with early-stage breast cancer. Numerous techniques for the delivery of accelerated partial breast irradiation have been developed involving both external beam and brachytherapy techniques. Brachytherapy techniques in general have the advantage of directly targeting the tumor bed and are not hampered by the requirement for large planning target volume margins needed with external beam techniques to account for uncertainties in targeting a very mobile organ, easily affected by patient and respiratory motion. We review established brachytherapy techniques and new emerging approaches. Technical considerations, available clinical data, advantages and shortcomings of each technique are reviewed. PMID- 21816687 TI - Case report: responses to cabazitaxel in metastatic castration-resistant prostate cancer after extensive docetaxel treatment. PMID- 21816688 TI - Managing refractory metastatic renal cell carcinoma: a RECORD spinning on a tilted AXIS. PMID- 21816689 TI - Development and validation of an enantioselective liquid-chromatography/tandem mass spectrometry method for the separation and quantification of eslicarbazepine acetate, eslicarbazepine, R-licarbazepine and oxcarbazepine in human plasma. AB - The purpose of this study was develop and validate a sensitive and specific enantioselective liquid-chromatography/tandem mass spectrometry (LC-MS/MS) method, for the simultaneous quantification of eslicarbazepine acetate (ESL), eslicarbazepine (S-Lic), oxcarbazepine (OXC) and R-licarbazepine (R-Lic) in human plasma. Analytes were extracted from human plasma using solid phase extraction and the chromatographic separation was achieved using a mobile phase of 80% n hexane and 20% ethanol/isopropyl alcohol (66.7/33.3, v/v). A Daicel CHIRALCEL OD H column (5 MUm, 50 mm * 4.6 mm) was used with a flow rate of 0.8 mL/min, and a run time of 8 min. ESL, S-Lic, R-Lic, OXC and the internal standard, 10,11 dihydrocarbamazepine, were quantified by positive ion electrospray ionization mass spectrometry. The method was fully validated, demonstrating acceptable accuracy, precision, linearity, and specificity in accordance with FDA regulations for the validation of bioanalytical methods. Linearity was proven over the range of 50.0-1000.0 ng/mL for ESL and OXC and over the range of 50.0 25,000.0 ng/mL for S-Lic and R-Lic. The intra- and inter-day coefficient of variation in plasma was less than 9.7% for ESL, 6.0% for OXC, 7.7% for S-Lic and less than 12.6% for R-Lic. The accuracy was between 98.7% and 107.2% for all the compounds quantified. The lower limit of quantification (LLOQ) was 50.0ng/mL for ESL, S-Lic, OXC and R-Lic in human plasma. The short-term stability in plasma, freeze-thaw stability in plasma, frozen long-term stability in plasma, autosampler stability and stock solution stability all met acceptance criteria. The human plasma samples, collected from 8 volunteers, showed that this method can be used for therapeutic monitoring of ESL and its metabolites in humans treated with ESL. PMID- 21816690 TI - The effects of hitchhiker antigens co-eluting with affinity-purified research antibodies. AB - The popularity of Protein G for the purification of antibodies has given rise to an entire industry that supplies scientists with research grade immunoreagents; however, many times the supplied product is contaminated with antigens bound to the antibody's complementarity-determining regions (CDRs). These "hitchhikers" are a category of host cell proteins that are elusive to detect due to their interaction with the antibody in the final product and yet their impact on an experiment or an entire field of study can be far reaching. In an earlier work, the role of hitchhikers on a human anti-histone antibody destined for clinical usage was explored and a stringent purification scheme developed. Here we use a murine monoclonal, which reflects the type of commercial antibody usually purchased for research. We evaluate three purification schemes: a traditional approach using a one-step, low pH elution buffer (pH 2.5); a gentler approach using a pH gradient elution scheme (pH 7 down to pH 2.5); and finally, a more stringent purification patterned on our earlier published method that uses a quaternary amine guard column and a high salt wash during antibody immobilization on the Protein G. We stress that the stringent purification incorporates the pH gradient scheme and is gentler than the low-pH approach. The resulting product from all three purifications is directly compared for binding potency, histone content (using an ELISA based assay) and residual DNA (using quantitative PCR). The results demonstrate that the first two methods are inadequate for hitchhiker removal. The traditional one-step, low pH approach produces a single elution peak containing histone contaminated antibody with picogram quantities of residual DNA, however, the trailing end of the same peak is loaded with antibody complexed to nanogram amounts of DNA, in some cases, over 100 ng. The pH gradient approach provided antibodies accompanied by only picograms of residual DNA and, on average, 1 out of every 10-20 CDRs occupied by a histone antigen. The more stringent approach, using the salt wash prior to elution with the pH gradient, has an average of 1 out of every 75 CDRs contaminated with a histone while the majority of the residual DNA is captured by the quaternary amine column placed in front of the Protein G. The consequences of these contaminants is illustrated by showing how they manifest themselves in unusual antibody potency values ranging from 558% for antibody bound to histone hitchhikers down to 15% for antibody contaminated with DNA hitchhikers. Those samples purified by the recommended stringent approach show potency values between 90 and 101%. Most importantly, we repeatedly demonstrate in a simulated chromatin immunoprecipitation (ChIP) assay the ability to precipitate clean plasmid DNA with histone contaminated antibody that had been purified using the traditional one-step, low pH elution approach. Expectedly, those antibodies stringently purified and showing 100% binding potency were unable to precipitate DNA in the absence of histone hitchhikers. PMID- 21816691 TI - Overweight and poor? On the relationship between income and the body mass index. AB - Contrary to conventional wisdom, NHANES data indicate that the poor have never had a statistically significant higher prevalence of overweight status at any time in the last 35 years. Despite this empirical evidence, the view that the poor are less healthy in terms of excess accumulation of fat persists. This paper provides evidence that conventional wisdom is reflecting important differences in the relationship between income and the body mass index. The first finding is based on distribution-sensitive measures of overweight which indicates that the severity of overweight has been higher for the poor than the nonpoor throughout the last 35 years. The second finding is from a newly introduced estimator, unconditional quantile regression (UQR), which provides a measure of the income gradient in BMI at different points on the unconditional BMI distribution. The UQR estimator indicates that the strongest relationship between income and BMI is observed at the tails of the distribution. There is a statistically significant negative income gradient in BMI at the obesity threshold and some evidence of a positive gradient at the underweight threshold. Both of these UQR estimates imply that for those at the tails of the BMI distribution, increases in income are correlated with healthier BMI values. PMID- 21816692 TI - [Benefits of a home-based physical exercise program in elderly subjects with type 2 diabetes mellitus]. AB - OBJECTIVE: To analyze the effects of a home-based physical exercise program on quality of life, metabolic control, and anthropometric and biochemical parameters in people over 60 years of age with type 2 diabetes mellitus. METHODS: Eighty four Spanish patients aged over 60 years were finally randomized to participate in a home-based, combined physical exercise program (aerobic and anaerobic exercises) or to receive conventional treatment for diabetes. At 6 months, effects on quality of life (EuroQoL questionnaire). HbA1c, fasting glucose, hypoglycemic events, weight, BMI, waist circumference, blood pressure, and biochemical parameters were assessed. RESULTS: Mean age of study participants was 66.7 (8.0) years. Patients in the exercise group showed an improved quality of life at six months based on EuroQol: 0.48 (0.38) vs 0.66 (0.35) and analogic scale 67.97 (18.92) vs 76.26 (20.14). An improved glycemic control was also seen: HbA1c 6.35 vs 6.0% and fasting glucose 151.2 (36.7) vs 137.6 (23.5) mg/dL, as well as a weight reduction by 1.7 kg. Hypoglycemic events did not increase. No benefits were seen in the control group. Ten subjects withdrew from the study before 6 months. CONCLUSIONS: A home-based physical exercise program improves quality of life, glycemic control, and weight in type 2 diabetic patients older than 60 years. PMID- 21816693 TI - [Large adrenal cavernous hemangioma as an unexpected finding after work-up of an abdominal mass]. PMID- 21816694 TI - The endocannabinoid system in cholestasis. PMID- 21816695 TI - Old and new antithrombotic drugs in neonates and infants. AB - Thromboembolic complications are becoming more frequent in children and the use of anticoagulation has increased considerably. The most widely used agents in children, heparin, low molecular weight heparin, and warfarin all have limitations which are exaggerated in children. This has led to the study of newer agents with improved pharmacologic properties such as bivalirudin, argatroban, and fondaparinux. Clinical trials are under way to assess several new oral anticoagulants that are in late phase studies or already licensed in adults. Based on the completed studies in children, several recommendations for the use of currently available agents (bivalirudin, argatroban, and fondaparinux) are suggested for clinical use today. Additional studies need to be conducted for the these agents, so that their use may be expanded in selected indications. New regulatory requirements are leading to a number of studies in the newer anticoagulants that are yet to be licensed in adults for treatment of venous thromboembolism. Pediatric thrombosis is entering a fruitful era of research in anticoagulation management, which is sure to lead to significant changes in how children are treated in the next 10 years. PMID- 21816696 TI - Inverted 'V--Y' advancement medial epicanthoplasty. AB - The presence of an epicanthal fold is a distinctive anatomic feature of the Asian population. Epicanthoplasty can be very helpful in resolving the above problematic anatomy and may produce a more aesthetic appearance. The goal of this report is to describe a modification in the traditional operative methods related to medial epicanthoplasty, to minimise scar appearance and maximise normal appearance. An inverse triangular flap of skin is based on the semilunar skin, which is elevated and retracted within the line of the normal eyelid. The design of four key points is crucial to this epicanthoplasty. A total of 62 patients were performed with this method; 42 of this group underwent simultaneous double eyelid plasty. Most of the patients obtained satisfactory results aesthetically followed from 6 months to 4 years postoperation. There was no recurrence of the epicanthal fold. As many as 38 patients were followed by interview and photographs were taken at the same time. The rest of the patients were followed up through telephone. No patients complained about visible scarring in the epicanthal area. As many as 60 patients obtained satisfactory results aesthetically, two patients complained about the median canthal asymmetry. The result indicates the reliability and feasibility of epicanthoplasty. PMID- 21816697 TI - Nocturnal asthma symptoms and poor sleep quality among urban school children with asthma. AB - OBJECTIVE: The aim of this study was to describe nocturnal asthma symptoms among urban children with asthma and assess the burden of sleep difficulties between children with varying levels of nocturnal symptoms. METHODS: We analyzed baseline data from 287 urban children with persistent asthma (aged 4-10 years) enrolled in the School-Based Asthma Therapy trial; Rochester, New York. Caregivers reported on nocturnal asthma symptoms (number of nights/2 weeks with wheezing or coughing), parent quality of life (Juniper's Pediatric Asthma Caregivers Quality of Life Questionnaire), and sleep quality by using the validated Children's Sleep Habits Questionnaire. We used bivariate and multivariate statistics to compare nocturnal asthma symptoms with sleep quality/quantity and quality of life. RESULTS: Most children (mean age, 7.5 years) were black (62%); 74% had Medicaid. Forty-one percent of children had intermittent nocturnal asthma symptoms, 23% mild persistent, and 36% moderate to severe. Children's average total sleep quality score was 51 (range, 33-99) which is above the clinically significant cutoff of 41, indicating pervasive sleep disturbances among this population. Sleep scores were worse for children with more nocturnal asthma symptoms compared with those with milder symptoms on total score, as well as several subscales, including night wakings, parasomnias, and sleep disordered breathing (all P < .03). Parents of children with more nocturnal asthma symptoms reported their child having fewer nights with enough sleep in the past week (P = .018) and worse parent quality of life (P < .001). CONCLUSIONS: Nocturnal asthma symptoms are prevalent in this population and are associated with poor sleep quality and worse parent quality of life. These findings have potential implications for understanding the disease burden of pediatric asthma. PMID- 21816698 TI - Anthropometric factors, physical activity, and risk of non-Hodgkin's lymphoma in the Women's Health Initiative. AB - BACKGROUND: Incidence rates of non-Hodgkin's lymphoma (NHL) increased substantially in the United States and worldwide during the latter part of the 20th century, but little is known about its etiology. Obesity is associated with impaired immune function through which it may influence the risk of NHL; other factors reflecting energy homeostasis (height, abdominal adiposity, and physical activity) may also be involved. METHODS: We examined the association of anthropometric factors and physical activity with risk of NHL and its major subtypes in a large cohort of women aged 50-79 years old who were enrolled at 40 clinical centers in the United States between 1993 and 1998. Over a mean follow up period of 11 years, 1123 cases of NHL were identified among 158,975 women. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: Height at baseline was positively associated with risk of all NHL and with that of diffuse large B-cell lymphoma (HRs(q4vs.q1) 1.19, 95% CI 1.00-1.43 and 1.43, 95% CI 1.01-2.03, respectively). Measures of obesity and abdominal adiposity at baseline were not associated with risk. Hazard ratios for NHL were increased for women in the highest quartile of weight and body mass index at age 18 (HRs(q4vs.q1) 1.29, 95% CI 1.01-1.65 and 1.27, 95% CI 1.01-1.59, respectively). Some measures of recreational physical activity were modestly associated with increased risk of NHL overall, but there were no clear associations with specific subtypes. CONCLUSION: Our findings regarding anthropometric measures are consistent with those of several previous reports, suggesting that early life influences on growth and immune function may influence the risk of NHL later in life. PMID- 21816700 TI - The second European evidence-based consensus on the diagnosis and management of Crohn's disease (part 3). PMID- 21816699 TI - Cystic duct remnant calculi after cholecystectomy. AB - Unrecognized lithiasis of the cystic duct (CDL) may be responsible for post cholecystectomy. This retrospective study looked at the incidence of CDL during cholecystectomy, as well as the context of its occurrence; recommendations for a practical surgical approach are offered. PATIENTS AND METHODS: Over a period of 30 months, 143 consecutive cholecystectomies (103 women, 40 men; mean age: 57 years) were performed by the same surgeon: 142 by laparoscopy, and one by laparotomy due to a history of previous gastrectomy. The cystic duct was always opened and milked upward in search of CDL before immediate clip occlusion or performance of cholangiography (106 times, 74.1%). In seven cases, cholangiography was impossible because the cystic duct was too narrow. RESULTS: There was no mortality. CDL was found in 21 cases (14.7%) and removed. This had not been identified by preoperative imaging (ultrasound or CT). Pain in the month preceding cholecystectomy occurred more frequently in cases of CDL (19/21[90.4%] vs 36/122 [29.5%]; P<0.001). Similarly, liver function tests were more often abnormal with CDL (10/21 [47.6%] vs 30/122 [24.5%]; P<0.05). However, neither jaundice nor gallbladder inflammation was predictive of CDL in this study. Echoendoscopy (EUS) was performed more often for suspected common duct lithiasis migration (CBDL) in patients with CDL than for those without (9/21 [42.8%] vs 26/122 [21.3%]; P<0.05). CBDL was present in 12 of 143 patients (8.3%). This was treated by preoperative endoscopic sphincterotomy in 10 cases, and twice by trans cystic stone extraction during the laparoscopic intervention. CBDL occurred more frequently in association with CDL (5/21 [23.8%] vs 7/122 [5.7%]; P<0.01). In addition, CDL was still present at cholecystectomy in the four patients who underwent preoperative endoscopic sphincterotomy. CONCLUSION: Cystic duct lithiasis is found frequently during cholecystectomy; CDL is often associated with preoperative pain, abnormal liver function tests and choledocholithiasis. It can persist despite preoperative sphincterotomy. The search for and treatment of CDL should be routinely performed during cholecystectomy. PMID- 21816701 TI - Anastomotic dehiscence during treatment with bevacizumab 5 years after colo-anal anastomosis with proposition for management without stopping chemotherapy. PMID- 21816702 TI - Improving the linkages between air pollution epidemiology and quantitative risk assessment. AB - BACKGROUND: Air pollution epidemiology plays an integral role in both identifying the hazards of air pollution as well as supplying the risk coefficients that are used in quantitative risk assessments. Evidence from both epidemiology and risk assessments has historically supported critical environmental policy decisions. The extent to which risk assessors can properly specify a quantitative risk assessment and characterize key sources of uncertainty depends in part on the availability, and clarity, of data and assumptions in the epidemiological studies. OBJECTIVES: We discuss the interests shared by air pollution epidemiology and risk assessment communities in ensuring that the findings of epidemiological studies are appropriately characterized and applied correctly in risk assessments. We highlight the key input parameters for risk assessments and consider how modest changes in the characterization of these data might enable more accurate risk assessments that better represent the findings of epidemiological studies. DISCUSSION: We argue that more complete information regarding the methodological choices and input data used in epidemiological studies would support more accurate risk assessments-to the benefit of both disciplines. In particular, we suggest including additional details regarding air quality, demographic, and health data, as well as certain types of data-rich graphics. CONCLUSIONS: Relatively modest changes to the data reported in epidemiological studies will improve the quality of risk assessments and help prevent the misinterpretation and mischaracterization of the results of epidemiological studies. Such changes may also benefit epidemiologists undertaking meta-analyses. We suggest workshops as a way to improve the dialogue between the two communities. PMID- 21816704 TI - [A therapeutic improvement: second generation tyrosine kinase inhibitors (TKI 2) in the treatment of chronic myelogenous leukemia]. AB - Second-generation tyrosine kinase inhibitors (TKI 2) represent a recent important improvement in the treatment of Philadelphia positive leukemias. These agents are a suitable major option if resistance or significant imatinib intolerance occurs in chronic and accelerated phase CML. They are now introduced as first line therapy in chronic phase CML where they induce cytogenetic and molecular response rates never seen to date, which is promising for long-term survival. We propose here an analysis of the main current data available for the use of TKI 2 in CML. PMID- 21816705 TI - Progress made in myeloma research through multiple efforts. PMID- 21816703 TI - Projecting future heat-related mortality under climate change scenarios: a systematic review. AB - BACKGROUND: Heat-related mortality is a matter of great public health concern, especially in the light of climate change. Although many studies have found associations between high temperatures and mortality, more research is needed to project the future impacts of climate change on heat-related mortality. OBJECTIVES: We conducted a systematic review of research and methods for projecting future heat-related mortality under climate change scenarios. DATA SOURCES AND EXTRACTION: A literature search was conducted in August 2010, using the electronic databases PubMed, Scopus, ScienceDirect, ProQuest, and Web of Science. The search was limited to peer-reviewed journal articles published in English from January 1980 through July 2010. DATA SYNTHESIS: Fourteen studies fulfilled the inclusion criteria. Most projections showed that climate change would result in a substantial increase in heat-related mortality. Projecting heat related mortality requires understanding historical temperature-mortality relationships and considering the future changes in climate, population, and acclimatization. Further research is needed to provide a stronger theoretical framework for projections, including a better understanding of socioeconomic development, adaptation strategies, land-use patterns, air pollution, and mortality displacement. CONCLUSIONS: Scenario-based projection research will meaningfully contribute to assessing and managing the potential impacts of climate change on heat-related mortality. PMID- 21816706 TI - Survivorship care guidelines for patients living with multiple myeloma: consensus statements of the International Myeloma Foundation Nurse Leadership Board. AB - Novel therapies approved over the past decade for the management of multiple myeloma have contributed to improved overall survival in patients with newly diagnosed and relapsed disease. Nurses play a key role in educating, advocating for, and supporting patients throughout the continuum of care. Identifying potential and actual comorbid conditions associated directly with multiple myeloma and its treatment is important, as is confirming those that are patient specific so that prompt intervention can take place; therefore, the International Myeloma Foundation Nurse Leadership Board identified the most significant needs of patients diagnosed with multiple myeloma as bone health, health maintenance, mobility and safety, sexual dysfunction, and renal health. The Nurse Leadership Board then developed a survivorship care plan to assist healthcare providers and patients with multiple myeloma, their partners, and their caregivers to identify these needs. PMID- 21816708 TI - Routine health maintenance in patients living with multiple myeloma: survivorship care plan of the International Myeloma Foundation Nurse Leadership Board. AB - Patients diagnosed with multiple myeloma are living longer because of new therapeutic options. Helping patients with multiple myeloma maintain a good state of health from the time of diagnosis and throughout their therapy leads to better quality of life. However, patients with multiple myeloma are at risk for illnesses experienced by the general population and at additional risk for illnesses related to multiple myeloma and its treatment. Therefore, the International Myeloma Foundation Nurse Leadership Board (NLB) has developed practice recommendations to meet the particular needs of adult patients with multiple myeloma using evidence-based recommendations for screening and disease prevention, as well as nursing experience. The NLB recommendations are designed to address and overcome barriers to health maintenance by educating and empowering nurses and their patients. PMID- 21816709 TI - Mobility and safety in the multiple myeloma survivor: survivorship care plan of the International Myeloma Foundation Nurse Leadership Board. AB - As in many other cancers, survivorship of multiple myeloma involves handling treatment, recovery from therapeutic interventions, the effects of the disease, and ongoing therapies. Although mobility challenges vary among survivors of multiple myeloma, these patients have an increased risk of impaired mobility because of side effects of therapy and the pathology of the disease, as well as other factors (e.g., increasing age). Health maintenance increasingly is becoming a part of the cancer control continuum, and nurses have the opportunity to help survivors of multiple myeloma optimize their functional mobility and safety, thereby preserving quality of life. The purpose of these practice recommendations is to provide the healthcare professional with information on mobility, fall risk, and planned activity as an integral part of the plan of care for patients with multiple myeloma. Tools for nurses and physicians for assessing and evaluating the newly diagnosed patient, the patient undergoing treatment, and the long-term survivor of multiple myeloma will be provided. PMID- 21816707 TI - Maintaining bone health in patients with multiple myeloma: survivorship care plan of the International Myeloma Foundation Nurse Leadership Board. AB - About 90% of individuals with multiple myeloma will develop osteolytic bone lesions from increased osteoclastic and decreased osteoblastic activity. Severe morbidities from pathologic fractures and other skeletal events can lead to poor circulation, blood clots, muscle wasting, compromised performance status, and overall poor survival. Supportive care targeting bone disease is an essential adjunct to antimyeloma therapy. In addition, the maintenance of bone health in patients with multiple myeloma can significantly improve quality of life. Oncology nurses and other healthcare providers play a central role in the management of bone disease and maintenance throughout the course of treatment. Safe administration of bisphosphonates, promotion of exercise, maintenance of adequate nutrition, vitamin and mineral supplementation, scheduled radiographic examinations, and monitoring of bone complications are among the important functions that oncology nurses and healthcare providers perform in clinical practice. PMID- 21816710 TI - Sexual dysfunction in multiple myeloma: survivorship care plan of the International Myeloma Foundation Nurse Leadership Board. AB - The World Health Organization describes sexuality as a "central aspect of being human throughout life and encompasses sex, gender identities and roles, sexual orientation, eroticism, pleasure, intimacy, and reproduction. Sexuality is influenced by the interaction of biological, psychological, social, economic, political, cultural, ethical, legal, historical, religious, and spiritual factors." Currently, no research has been conducted regarding sexual dysfunction in patients with multiple myeloma; therefore, information related to the assessment and evaluation of sexual dysfunction is gleaned from other malignancies and diseases. In this article, members of the International Myeloma Foundation's Nurse Leadership Board discuss the definition, presentation, and causes of sexual dysfunction; provide recommendations for sexual assessment practices; and promote discussion among patients with multiple myeloma, their healthcare providers, and their partners. PMID- 21816711 TI - Renal complications in multiple myeloma and related disorders: survivorship care plan of the International Myeloma Foundation Nurse Leadership Board. AB - Kidney dysfunction is a common clinical feature of symptomatic multiple myeloma. Some degree of renal insufficiency or renal failure is present at diagnosis or will occur during the course of the disease and, if not reversed, will adversely affect overall survival and quality of life. Chronic insults to the kidneys from other illnesses, treatment, or multiple myeloma itself can further damage renal function and increase the risk for additional complications, such as anemia. Patients with multiple myeloma who have light chain (Bence Jones protein) proteinuria may experience renal failure or progress to end-stage renal disease (ESRD) and require dialysis because of light chain cast nephropathy. Kidney failure in patients with presumed multiple myeloma also may result from amyloidosis, light chain deposition disease, or acute tubular necrosis caused by nephrotoxic agents; therefore, identification of patients at risk for kidney damage is essential. The International Myeloma Foundation's Nurse Leadership Board has developed practice recommendations for screening renal function, identifying positive and negative contributing risk and environmental factors, selecting appropriate therapies and supportive care measures to decrease progression to ESRD, and enacting dialysis to reduce and manage renal complications in patients with multiple myeloma. PMID- 21816712 TI - From Pauling's abzyme concept to the new era of hydrolytic anti-DNA autoantibodies: a link to rational vaccine design? - A review. AB - Specific entities of naturally-occurring DNA hydrolytic/cytotoxic antibodies (abzymes) are linked to autoimmune and lymphoproliferative disorders. Suggested sequence of underlying activities conform to such entities penetrating the living cells, trans-locating to nucleus and recognising specific binding sites within single- or double-stranded DNA. Their origin is unknown since corresponding immunogens are unidentified. These anti-DNA antibodies could be the organism's immune response to microbial attack. Their structure, function and pathogenicity were investigated in wet-lab and via bioinformatics in context of Rational Vaccine Designs. This paper offers a comprehensive critical review on the subject in the light of known and newly proposed concepts. PMID- 21816713 TI - Computation of entropy and energetics profiles of a single-stranded viral DNA. AB - The bioinformatic aspects of computing entropy and energetic profiles associated with a viral single-stranded DNA (ssDNA) are addressed. The analyses envisaged thereof determine the structural (stem and loop) features, identify the CpG motifs and delineate the boundaries of coding DNA segments along a test viral (B19) ssDNA. The analytical modelling and computational efforts conform to Shannon entropy and thermodynamic kinetics of the test genome. Results are presented toward validation against available data. Pertinent details are reviewed in the context of their possible uses in rational vaccine designs. PMID- 21816714 TI - CDS identification in a viral single-strand DNA (ssDNA) using Fisher linear discriminant. AB - In this paper, a novel discriminant algorithm based on Fisher linear discriminant that enables distinguishing the features of Codon DNA Segments (CDS) in a DNA sequence consistent with the underlying stochastic attributes is developed. It is specifically applied to a viral single-strand DNA (ssDNA). The Fisher discriminant adopted delineates judiciously, the codon and non-codon regions in the test ssDNA. With a complete description of the computational procedure, the efficacy of the algorithm is tested via simulated experiments on a real ssDNA of B19 virus. The results are validated against GenBank data available on the test viral sequence. Inferences with regard to CDS regions present in the test sequence are made indicating possible fuzzy transitions of codon/non-codon sections. PMID- 21816715 TI - Virus infection on Brain White Matter: statistical analysis of DT MRI scans. AB - Brain White Matter (BWM) is formed on nerve fibres (due to myelin coating) and it undergoes continuous changes with aging throughout the life of humans. This age related morphology, however, also gets further modified when a subject is infected by a viral disease such as HIV. In the present study, textural variations in BWM specific to a set of control images vs. images of a HIV + subject are assayed via an algorithm based on the Grey Level Co-occurrence Matrix (GLCM); and the associated Haralick features that are extracted from the GLCM. The clinical images of the brain used in the study are gathered from the noninvasive technique of Diffusion Tensor Magnetic Resonance Imaging (DT MRI). Results observed in the images of normal (nonpathogenic) subjects show progressive changes in the image parameters with aging; whereas, a wider variation is observed in the relevant parameters of the images pertinent to pathogenic subjects who exhibit cognitive (or motor impairments) due to HIV infection. The findings of the proposed method are reasonably correlated with clinical diagnosis in two HIV+ cases. PMID- 21816716 TI - B- and T-cell epitope mapping of human sapovirus capsid protein: an immunomics approach. AB - Human sapovirus is one of the major causes of viral gastroenteritis. Although the capsid protein (VP1) confers antigenic cross-reactivity, immunity against sapovirus is still unclear. Using immunoinformatics approach, we defined putative T- and B-cell epitopes of VP1 and mapped on to its predicted three-dimensional structure. Identified five putative T-cell epitopes also occupied the putative B cell epitope region. These putative epitopes were conserved in all existing serotypes. Predicted epitopes can be generated through proteasome cleavage and may be useful in designing peptide-based subunit vaccine to confer both humoral and cell-mediated immunity. PMID- 21816717 TI - Computer-aided vaccine design for liver cancer using epitopes of HBx protein isolates from HBV substrains. AB - Hepatitis B Virus encodes HBX, which is considered to be responsible for virus infection in mammals. The HBx modulates the signal transduction pathways toward the aetiological aspects of establishing liver cancer. In this context, to predict epitopes from three HBX protein (for vaccine designs), use of certain computational tools are indicated. Relevant study shows that seven binding peptides for MHC class I and 16 for MHC class II molecule bear significant binding affinity. Epitope LSAMSTTDL for MHC I and LRFTSARRM, HLSLRGLPV for MHC II have highest log-values of 0.746 and (0.8628, 0.8048), respectively. Vaccine model is designed using predicted epitopes. Such patterns characterise possible biological activity of the vaccine of interest. PMID- 21816718 TI - BioHCVKD: a bioinformatics knowledge discovery system for HCV drug discovery - identifying proteins, ligands and active residues, in biological literature. AB - Hepatitis C Virus (HCV) causes significant morbidity worldwide with restricted treatment options and lack of a universal cure which necessitate design of novel drugs. Researchers face an enormous growth of literature with very small portions of HCV knowledge accessible in structured way. This paper proposes the BioHCVKD that helps researchers to annotate relevant HCV information targeted to accelerate HCV drug discovery. BioHCVKD combines the dictionary based filtering and conditional random field (CRF) based gene mention tagger. BioHCVKD is supported by two modules, the Abstract Insertion module, and the Protein Insertion module. BioHCVKD achieves a recall of 73.25%, a precision of 70.5% and F-score of 71.85%, which improves the performance of the name entity tagger. PMID- 21816719 TI - NHS competition puts survival of social enterprises at risk, says think tank. PMID- 21816720 TI - Radiation protection issues for laser-based accelerators. AB - Radiation particles, besides their application to fundamental research, are widely applied in all fields of science (medicine, material science, chemistry, etc.). Up to today the radiations were produced by radiation sources such as accelerators, X-ray tubes, radioactive sources with the well-known problems of costs, parameters and safety. For the last few years, following the development of lasers able to focus ultra-short high-intensity pulses onto targets, the generation of ionising radiation by intense lasers has become possible. The paper will focus on some radiological protection aspects around the Frascati Laser for Acceleration and Multidisciplinary Experiments, 300 TW laser being commissioned at National Laboratories of Frascati. PMID- 21816721 TI - Estimated collective effective dose to the population from X-ray and nuclear medicine examinations in Finland. AB - The collective effective doses to the population from X-ray and nuclear medicine (NM) examinations in Finland in 2008 and 2009, respectively, were estimated. The estimated collective effective dose per inhabitant was 0.45 mSv from X-ray examinations and 0.03 mSv from NM examinations. The collective effective doses per inhabitant have not changed substantially during the last 10 y. However, proportional dose due to CT examinations has increased from 50 % in 2005 to 58 % in 2009 of the total collective effective dose from all X-ray examinations and proportional dose of PET examinations from 7 to 13 % of the total collective effective dose from NM examinations. The collective effective dose from conventional plain radiography was over 20 % higher when estimated using the new (ICRP 103) tissue weighting factors than that obtained using the old (ICRP 60) tissue weighting factors. PMID- 21816723 TI - Evaluation of patient dose in some mammography centres in Iran. AB - High diagnostic sensitivity and specificity while maintaining the least dose to the patient is the ideal mammography. The objective of this work was to evaluate patient dose and image quality of mammograms to propose corrective actions. The image quality for 1242 patient in 7 mammography facilities in Tehran city was evaluated based on selected image quality criteria using a three-point scale. Clinical image quality, the entrance surface air kerma, the average glandular dose and optical density of films for standard PMMA phantom of 4.5 cm thickness were evaluated. The results showed that up to 72 % of mammograms were in good condition to be diagnosed, and only about 3.4 % of the images were unacceptable or with suboptimal quality. The entrance surface air kerma values were in the range of 3.8-10.5 mGy, average glandular dose 0.5-1.8 mGy and optical density of films 0.74-2.03. The image quality evaluation after correction actions, periodic image quality evaluation and using the correct equipment certainly will improve patient dose. PMID- 21816722 TI - Dosimetric calculations for uranium miners for epidemiological studies. AB - Epidemiological studies on uranium miners are being carried out to quantify the risk of cancer based on organ dose calculations. Mathematical models have been applied to calculate the annual absorbed doses to regions of the lung, red bone marrow, liver, kidney and stomach for each individual miner arising from exposure to radon gas, radon progeny and long-lived radionuclides (LLR) present in the uranium ore dust and to external gamma radiation. The methodology and dosimetric models used to calculate these organ doses are described and the resulting doses for unit exposure to each source (radon gas, radon progeny and LLR) are presented. The results of dosimetric calculations for a typical German miner are also given. For this miner, the absorbed dose to the central regions of the lung is dominated by the dose arising from exposure to radon progeny, whereas the absorbed dose to the red bone marrow is dominated by the external gamma dose. The uncertainties in the absorbed dose to regions of the lung arising from unit exposure to radon progeny are also discussed. These dose estimates are being used in epidemiological studies of cancer in uranium miners. PMID- 21816724 TI - The development of fetal dosimetry and its application to A-bomb survivors exposed in utero. AB - The cohort of the atomic bomb survivors of Hiroshima and Nagasaki comprises the major basis for investigations of health effects induced by ionising radiation in humans. To study the health effects associated with radiation exposure before birth, fetal dosimetry is needed if significant differences exist between the fetal absorbed dose and the mother's uterine dose. Combining total neutron and gamma ray free-in-air fluences at 1 m above ground with fluence-to-absorbed dose conversion coefficients, fetal doses were calculated for various exposure orientations at the ground distance of 1500 m from the hypocentres in Hiroshima and Nagasaki. The results showed that the mother's uterine dose can serve as a good surrogate for the dose of the embryo and fetus in the first trimester. However, significant differences exist between doses of the fetus of different ages. If the mother's uterine dose were used as a surrogate, doses to the fetus in the last two trimesters could be overestimated by more than 20 % for exposure orientations facing towards and away from the hypocentre while significantly underestimated for lateral positions relative to the hypocentre. In newer fetal models, the brain is modelled for all fetal ages. Brain doses to the 3-month fetus are generally higher than those to an embryo and fetus of other ages. In most cases, brain absorbed doses differ significantly from the doses to the entire fetal body. In order to accurately assess radiation effects to the fetal brain, it is necessary to determine brain doses separately. PMID- 21816725 TI - The role of shielding in superficial X-ray therapy. AB - Superficial X-ray therapy is applicable in the kilovoltage range for the treatment of the cancer. Pb shielding is used to protect radiation-sensitive organs since the doses are high, however the question about shielding efficiency is still open. The role of shielding was investigated in this work based on the results of dose measurements performed using a set of pencil dosemeters and thermoluminescent dosimetries. According to the measured angular dose distributions on the phantom surface during X-ray irradiation, the area near the applicator exposed to the waste irradiation was evaluated and Pb shielding of a corresponding size was chosen. It has been shown that the dose in the area of interest decreases non-linearly, however high shielding efficiency (~90 %) remains almost stable in the whole area. No significant contribution of secondary scattered photons from Pb has been observed. The role of Pb shielding in superficial X-ray therapy is discussed on the basis of the obtained results. PMID- 21816726 TI - Organ and effective doses from verification techniques in image-guided radiotherapy. AB - The purpose of this work was an evaluation of organ doses and effective doses from three verification techniques in Image-Guided Radiotherapy: from kilovoltage (kV) cone beam computed tomography (CBCT) scans, from two orthogonal kV images and from two orthogonal megavoltage (MV) images for two different treatment sites: pelvis and head and neck (H&N). For comparison reasons, organ doses and effective doses from prostate and H&N radiotherapy were also evaluated. Measurements of organ doses were performed in a male anthropomorphic Rando phantom by means of thermoluminescent dosemeters. In this investigation, measured organ doses from one CBCT scan, from two MV images and from two kV images of pelvis represent typically 1-6, 1-10 and 0.05-1 %, respectively, of organ doses resulting from one fraction of prostate radiotherapy. The maximum effective doses from CBCT scans, kV images and MV images of pelvis are 5.6, 0.8 and 11.9 mSv, respectively. PMID- 21816727 TI - Areal dosimetry at research centres. AB - Radiation protection regulations apply to research centres and nuclear facilities alike. Radiological dose resulting from their activities is strictly limited by law; therefore, it has to be monitored. As a supplement to the personal dosimetry systems (mainly for the work force classified as occupationally exposed), areal dosimetry is an efficient surveillance tool. Serving as an example, the concept of areal dosimetry applied at the Paul Scherrer Institut is presented. PMID- 21816728 TI - Dose reduction using bismuth shielding during paediatric CT examinations in Slovakia. AB - Considering the massive increase of computer tomography (CT) examinations in Slovakia during the last 10 y, it can be expected that a higher radiation load may be observed in the Slovak population. Since child population is more sensitive to radiation than adult population, a monitoring has started to see how high the radiation dose is for paediatric patients during CT examinations in chosen departments in Slovakia. The CT examination of the head is one of the most frequently done examinations in Slovakian departments and that is why measurements were done to clarify how usage of bismuth shields for eyes and thyroid can affect the eye and thyroid doses. For simulation, 215 thermoluminescent dosimeters were exposed on anthropomorphic phantom of a child with and without usage of bismuth shields. The result was that only two of the three chosen departments confirmed a reduction. On the other hand, one of the departments confirmed that the reduction can be up to 56-65 %, which is significant. PMID- 21816729 TI - Assessment of personal exposures to optical radiation in large entertainment venues. AB - Workplace exposure to optical radiation from artificial sources is regulated in Europe under the Artificial Optical Radiation Directive 2006/25/EC implemented in the UK as The Control of Artificial Optical Radiation at Work Regulations 2010. The entertainment environment often presents an extremely complex situation for the assessment of occupational exposures. Multiple illumination sources, continuously changing illumination conditions and people moving during performances add further complexity to the assessment. This document proposes a methodology for assessing the risks arising from exposure to optical radiation and presents detailed case studies of practical assessment for two large entertainment venues. PMID- 21816730 TI - Transition from screen-film to computed radiography in a paediatric hospital: the missing link towards optimisation. AB - In paediatrics, the risks associated with ionising radiation should be a major concern, due to children's higher susceptibility to radiation effects. Measure entrance skin dose (ESD) in chest and pelvis X-ray projections and compare the results with the 'European guidelines on quality criteria for diagnostic radiographer images in paediatrics' in order to optimise radiological practice. ESD values were obtained using an ionisation chamber Diamentor M4 KDK (PTW) in 429 children, who underwent chest X-ray or pelvis X-ray in a Computed Radiography system. In the first phase of the study, data were collected according to protocols used in the department; in a second phase different tube voltage values were used according to patient weight. A third phase was carried out, only for chest X-ray, using the exposure parameters of phase 2, plus activating lateral ionisation chamber. Three paediatric radiologists blindly assessed image quality of chest X-ray, using a validated assessment available in the 'European guidelines on quality criteria for diagnostic radiographer images in paediatrics'. Considering all the patients submitted to chest X-ray, the average ESD was 0.22, 0.16 and 0.08 mGy, for phases 1, 2 and 3, respectively. For pelvis X-ray, the average ESD decreased from 1.18 mGy in phase 1 to 0.78 mGy in phase 2. Dose optimisation was achieved. ESD was reduced 63.6 and 33.9 % in chest and pelvis X-ray, respectively. PMID- 21816731 TI - Radiation protection of staff in 111In radionuclide therapy--is the lead apron shielding effective? AB - (111)In (Egamma = 171-245 keV, t1/2 = 2.83 d) is used for targeted therapies of endocrine tumours. An average activity of 6.3 GBq is injected into the liver by catheterisation of the hepatic artery. This procedure is time-consuming (4-5 min) and as a result, both the physicians and the technical staff involved are subjected to radiation exposure. In this research, the efficiency of the use of lead apron has been studied as far as the radiation protection of the working staff is concerned. A solution of (111)In in a cylindrical scattering phantom was used as a source. Close to the scattering phantom, an anthropomorphic male Alderson RANDO phantom was positioned. Thermoluminescent dosemeters were located in triplets on the front surface, in the exit and in various depths in the 26th slice of the RANDO phantom. The experiment was repeated by covering the RANDO phantom by a lead apron 0.25 mm Pb equivalent. The unshielded dose rates and the shielded photon dose rates were measured. Calculations of dose rates by Monte Carlo N-particle transport code were compared with this study's measurements. A significant reduction of 65 % on surface dose was observed when using lead apron. A decrease of 30 % in the mean absorbed dose among the different depths of the 26th slice of the RANDO phantom has also been noticed. An accurate correlation of the experimental results with Monte Carlo simulation has been achieved. PMID- 21816732 TI - The health risks and benefits of cycling in urban environments compared with car use: health impact assessment study. AB - OBJECTIVE: To estimate the risks and benefits to health of travel by bicycle, using a bicycle sharing scheme, compared with travel by car in an urban environment. DESIGN: Health impact assessment study. SETTING: Public bicycle sharing initiative, Bicing, in Barcelona, Spain. PARTICIPANTS: 181,982 Bicing subscribers. Main outcomes measures The primary outcome measure was all cause mortality for the three domains of physical activity, air pollution (exposure to particulate matter <2.5 um), and road traffic incidents. The secondary outcome was change in levels of carbon dioxide emissions. RESULTS: Compared with car users the estimated annual change in mortality of the Barcelona residents using Bicing (n = 181,982) was 0.03 deaths from road traffic incidents and 0.13 deaths from air pollution. As a result of physical activity, 12.46 deaths were avoided (benefit:risk ratio 77). The annual number of deaths avoided was 12.28. As a result of journeys by Bicing, annual carbon dioxide emissions were reduced by an estimated 9,062,344 kg. CONCLUSIONS: Public bicycle sharing initiatives such as Bicing in Barcelona have greater benefits than risks to health and reduce carbon dioxide emissions. PMID- 21816734 TI - Interpreting asymptomatic bacteriuria. PMID- 21816735 TI - How family friendly is the UK? PMID- 21816733 TI - Impact of CYP2C19 variant genotypes on clinical efficacy of antiplatelet treatment with clopidogrel: systematic review and meta-analysis. AB - OBJECTIVE: To evaluate the accumulated information from genetic association studies investigating the impact of variants of the cytochrome P450 (CYP) 2C19 genotype on the clinical efficacy of clopidogrel. DESIGN: Systematic review and meta-analysis with a structured search algorithm and prespecified eligibility criteria for retrieval of relevant studies; dominant genetic model assumptions and quantitative methods for calculating summary effect estimates from study level odds ratios; systematic assessment of bias within and between studies; and grading of the cumulative evidence by consensus criteria. DATA SOURCES: Medline, Embase, the Cochrane Library, online databases, contents pages and bibliographies of general medical, cardiovascular, pharmacological, and genetic journals. Eligibility criteria for selecting studies Original full length reports assessing the cumulative incidence of major adverse cardiovascular events or stent thrombosis over a follow-up period of at least a month in association with carrier status for the loss of function or gain of function CYP2C19 allele in adult patients with coronary artery disease and a clinical presentation of acute coronary syndrome or stable angina pectoris who were taking clopidogrel. RESULTS: 15 studies met the inclusion criteria. The random effects summary odds ratio for stent thrombosis in carriers of at least one CYP2C19 loss of function allele versus non-carriers combining nine studies was 1.77 (95% confidence interval 1.31 to 2.40; P < 0.001). This nominally significant odds ratio was subject to considerable bias across the studies (small study effect bias and replication diversity). The adjustment for these quality modifiers tended to abolish the association. The corresponding random effects summary odds ratio of major adverse cardiovascular events for 12 studies combined was 1.11 (0.89 to 1.39; P = 0.36). The random effects summary odds ratio of stent thrombosis in carriers versus non carriers of at least one CYP2C19*17 gain of function allele for three studies combined was 0.99 (0.60 to 1.62; P = 0.96), and the corresponding odds ratio of major adverse cardiovascular events in five studies was 0.93 (0.75 to 1.14; P = 0.48). The overall quality of epidemiological evidence was graded as low, which excludes reliable clinical assessments. CONCLUSIONS: Accumulated information from genetic association studies does not indicate a substantial or consistent influence of CYP2C19 gene polymorphisms on the clinical efficacy of clopidogrel. The current evidence does not support the use of individualised antiplatelet regimens guided by CYP2C19 genotype. PMID- 21816736 TI - Weight loss and nausea in a patient taking digoxin. PMID- 21816737 TI - Putting genomics into practice. PMID- 21816738 TI - Abdominal distension in a 4 year old. PMID- 21816739 TI - Stereotactic body radiotherapy. PMID- 21816740 TI - 10-Minute Consultation. Measles, mumps, and rubella vaccination in a child with suspected egg allergy. PMID- 21816743 TI - The management of superficial venous incompetence. PMID- 21816745 TI - We shouldn't fear social media. PMID- 21816746 TI - Very like a fish. PMID- 21816747 TI - Edzard Ernst: the prince and me. PMID- 21816748 TI - Potential withdrawal of bevacizumab for the treatment of breast cancer. PMID- 21816751 TI - France is set to radically overhaul its drug regulatory system. PMID- 21816752 TI - Government uses threat of flu pandemic to propose change to mental health act. PMID- 21816754 TI - Tolvaptan inhibits ERK-dependent cell proliferation, Cl- secretion, and in vitro cyst growth of human ADPKD cells stimulated by vasopressin. AB - In autosomal dominant polycystic kidney disease (ADPKD), arginine vasopressin (AVP) accelerates cyst growth by stimulating cAMP-dependent ERK activity and epithelial cell proliferation and by promoting Cl(-)-dependent fluid secretion. Tolvaptan, a V2 receptor antagonist, inhibits the renal effects of AVP and slows cyst growth in PKD animals. Here, we determined the effect of graded concentrations of tolvaptan on intracellular cAMP, ERK activity, cell proliferation, and transcellular Cl(-) secretion using human ADPKD cyst epithelial cells. Incubation of ADPKD cells with 10(-9) M AVP increased intracellular cAMP and stimulated ERK and cell proliferation. Tolvaptan caused a concentration-dependent inhibition of AVP-induced cAMP production with an apparent IC(50) of ~10(-10) M. Correspondingly, tolvaptan inhibited AVP-induced ERK signaling and cell proliferation. Basolateral application of AVP to ADPKD cell monolayers grown on permeable supports caused a sustained increase in short circuit current that was completely blocked by the Cl(-) channel blocker CFTR(inh 172), consistent with AVP-induced transepithelial Cl(-) secretion. Tolvaptan inhibited AVP-induced Cl(-) secretion and decreased in vitro cyst growth of ADPKD cells cultured within a three-dimensional collagen matrix. These data demonstrate that relatively low concentrations of tolvaptan inhibit AVP-stimulated cell proliferation and Cl(-)-dependent fluid secretion by human ADPKD cystic cells. PMID- 21816753 TI - Role of NKCC in BK channel-mediated net K+ secretion in the CCD. AB - Apical SK/ROMK and BK channels mediate baseline and flow-induced K secretion (FIKS), respectively, in the cortical collecting duct (CCD). BK channels are detected in acid-base transporting intercalated (IC) and Na-absorbing principal (PC) cells. Although the density of BK channels is greater in IC than PC, Na-K ATPase activity in IC is considered inadequate to sustain high rates of urinary K secretion. To test the hypothesis that basolateral NKCC in the CCD contributes to BK channel-mediated FIKS, we measured net K secretion (J(K)) and Na absorption (J(Na)) at slow (~1) and fast (~5 nl.min(-1).mm(-1)) flow rates in rabbit CCDs microperfused in vitro in the absence and presence of bumetanide, an inhibitor of NKCC, added to the bath. Bumetanide inhibited FIKS but not basal J(K), J(Na), or the flow-induced [Ca(2+)](i) transient necessary for BK channel activation. Addition of luminal iberiotoxin, a BK channel inhibitor, to bumetanide-treated CCDs did not further reduce J(K). Basolateral Cl removal reversibly inhibited FIKS but not basal J(K) or J(Na). Quantitative PCR performed on single CCD samples using NKCC1- and 18S-specific primers and probes and the TaqMan assay confirmed the presence of the transcript in this nephron segment. To identify the specific cell type to which basolateral NKCC is localized, we exploited the ability of NKCC to accept NH(4)(+) at its K-binding site to monitor the rate of bumetanide-sensitive cytosolic acidification after NH(4)(+) addition to the bath in CCDs loaded with the pH indicator dye BCECF. Both IC and PC were found to have a basolateral bumetanide-sensitive NH(4)(+) entry step and NKCC1-specific antibodies labeled the basolateral surfaces of both cell types in CCDs. These results suggest that BK channel-mediated FIKS is dependent on a basolateral bumetanide-sensitive, Cl-dependent transport pathway, proposed to be NKCC1, in both IC and PC in the CCD. PMID- 21816755 TI - Oncostatin M is a novel inhibitor of TGF-beta1-induced matricellular protein expression. AB - Matricellular proteins in the kidney have been associated with the development of tubulointerstitial fibrogenesis and the progression of renal disease. This study investigated potential antifibrotic effects of the cytokine oncostatin M (OSM) in human proximal tubule cells (PTC), particularly with regard to inhibition of profibrotic events initiated by TGF-beta1. In human PTC, OSM diminished transforming growth factor (TGF)-beta1-induced expression of the transcriptional epithelial-mesenchymal transition mediator FoxC2. Furthermore, exposure to OSM attenuated basal and TGF-beta1-induced expression of the matricellular proteins SPARC, TSP-1, TNC, and CTGF regardless of the sequence of ligand administration. OSM was shown to result in rapid and sustained phosphorylation of both Stat1 and Stat3 and also in transient phosphorylation of Smad2/3 in contrast to TGF-beta1, which demonstrated a gradually building phosphorylation of Smad2/3 and a brief phosphorylation of Smad1/5/8. Utilizing receptor-blocking molecules, we found the inhibitory effect of OSM on TGF-beta1-induced CTGF mRNA expression occurs independently of Smad2/3 signaling and present evidence that this effect may be partially driven by OSM receptor-mediated Stat1 and/or Stat3 signaling pathways, thereby providing a mechanism whereby OSM can contribute to tubulointerstitial protection. PMID- 21816756 TI - Inorganic phosphate homeostasis in sodium-dependent phosphate cotransporter Npt2b+/- mice. AB - An inorganic phosphate (P(i))-restricted diet is important for patients with chronic kidney disease and patients on hemodialysis. Phosphate binders are essential for preventing hyperphosphatemia and ectopic calcification. The sodium dependent P(i) (Na/P(i)) transport system is involved in intestinal P(i) absorption and is regulated by several factors. The type II sodium-dependent P(i) transporter Npt2b is expressed in the brush-border membrane in intestinal epithelial cells and transports P(i). In the present study, we analyzed the phenotype of Npt2b(-/-) and hetero(+/-) mice. Npt2b(-/-) mice died in utero soon after implantation, indicating that Npt2b is essential for early embryonic development. At 4 wk of age, Npt2b(+/-) mice showed hypophosphatemia and low urinary P(i) excretion. Plasma fibroblast growth factor 23 levels were significantly decreased and 1,25(OH)(2)D(3) levels were significantly increased in Npt2b(+/-) mice compared with Npt2b(+/+) mice. Npt2b mRNA levels were reduced to 50% that in Npt2b(+/+) mice. In contrast, renal Npt2a and Npt2c transporter protein levels were significantly increased in Npt2b(+/-) mice. At 20 wk of age, Npt2b(+/-) mice showed hypophosphaturia and reduced Na/P(i) cotransport activity in the distal intestine. Npt2b(+/+) mice with adenine-induced renal failure had hyperphosphatemia and high plasma creatinine levels. Npt2b(+/-) mice treated with adenine had significantly reduced plasma P(i) levels compared with Npt2b(+/+) mice. Intestinal Npt2b protein and Na(+)/P(i) transport activity levels were significantly lower in Npt2b(+/-) mice than in the Npt2b(+/+) mice. The findings of the present studies suggest that Npt2b is an important target for the prevention of hyperphosphatemia. PMID- 21816757 TI - Distinct cardiac and renal effects of ETA receptor antagonist and ACE inhibitor in experimental type 2 diabetes. AB - Diabetic nephropathy is associated with cardiovascular morbidity. Angiotensin converting enzyme (ACE) inhibitors provide imperfect renoprotection in advanced type 2 diabetes, and cardiovascular risk remains elevated. Endothelin (ET)-1 has a role in renal and cardiac dysfunction in diabetes. Here, we assessed whether combination therapy with an ACE inhibitor and ET(A) receptor antagonist provided reno- and cardioprotection in rats with overt type 2 diabetes. Four groups of Zucker diabetic fatty (ZDF) rats were treated orally from 4 (when proteinuric) to 8 mo with vehicle, ramipril (1 mg/kg), sitaxsentan (60 mg/kg), and ramipril plus sitaxsentan. Lean rats served as controls. Combined therapy ameliorated proteinuria and glomerulosclerosis mostly as a result of the action of ramipril. Simultaneous blockade of ANG II and ET-1 pathways normalized renal monocyte chemoattractant protein-1 and interstitial inflammation. Cardiomyocyte loss, volume enlargement, and capillary rarefaction were prominent abnormalities of ZDF myocardium. Myocyte volume was reduced by ramipril and sitaxsentan, which also ameliorated heart capillary density. Drug combination restored myocardial structure and reestablished an adequate capillary network in the presence of increased cardiac expression of VEGF/VEGFR-1, and significant reduction of oxidative stress. In conclusion, in type 2 diabetes concomitant blockade of ANG II synthesis and ET-1 biological activity through an ET(A) receptor antagonist led to substantial albeit not complete renoprotection, almost due to the ACE inhibitor. The drug combination also showed cardioprotective properties, which however, were mainly dependent on the contribution of the ET(A) receptor antagonist through the action of VEGF. PMID- 21816758 TI - Inflammatory neurological disease in patients treated with tumor necrosis factor alpha inhibitors. AB - BACKGROUND: TNF alpha inhibitor (TNFAI) therapy has been associated with inflammatory neurological syndromes. OBJECTIVES: To present 10 new cases of TNFAI associated neurological disease and a review of the literature. METHODS: The design and methods were based on case series collected from Oregon Health & Sciences University and the Department of Veterans Affairs Hospital in Portland, Oregon and PubMed review. RESULTS: We describe eight demyelinating central nervous system syndromes and two peripheral nervous system syndromes associated with TNFAI therapy. Characteristics from these cases are analyzed with data from 141 additional cases from the literature. Onset was between the ages of 36 and 65 years in 84% of CNS cases, distinguishing TNFAI-associated disease from sporadic multiple sclerosis. Symptoms occurred within one year of TNFAI therapy in 71%. Etanercept therapy was reported in the majority of cases of CNS syndromes and infliximab therapy in the majority of neuromuscular syndromes. Significant disability remained in 67% of cases although 82% had been followed for less than one year. CONCLUSIONS: Our case series and literature review demonstrates an association between TNFAI therapy and inflammatory neurological disease. While a causal relationship is suggested, this remains uncertain. TNFAI-associated neurological syndromes are associated with significant disability and longer follow-up is needed to better determine natural history and evaluate appropriate treatment interventions. PMID- 21816759 TI - Increased risk of multiple sclerosis among women with migraine in the Nurses' Health Study II. AB - BACKGROUND: The prospective Nurses' Health Study II (NHS-II), which enrolled over 116,000 female nurses, provides a unique opportunity to test the hypothesis of whether migraine is associated with multiple sclerosis (MS) and to explore the temporal aspects of the interrelationship. OBJECTIVES: To calculate relative risk of MS among NHS-II participants with and without migraine and to estimate odds ratio (OR) of being diagnosed with migraine in women with and without pre existing MS. METHODS: Cox proportional hazards regression was used to estimate rate ratios and 95% confidence intervals (CIs) of being diagnosed with MS in women with and without pre-existing migraine adjusted for potential confounders. Multivariate adjusted ORs of being diagnosed with migraine in women with and without pre-existing MS were estimated using logistic regression. RESULTS: The prevalence of migraine in women with MS at baseline (26%, p = 0.11) and those diagnosed with MS after enrolment (29%, p < 0.0001) was higher than in the non-MS cases (21%). The relative risk of developing MS in migraineurs was 1.39 times higher than in non-migraineurs (95% CI 1.10-1.77, p = 0.008). The absolute risk of developing MS in women migraineurs over a 15-year follow-up was 0.47% and among non-migraineurs 0.32%. The odds of being diagnosed with migraine was higher in women with pre-existing MS compared with those without MS, but did not reach statistical significance (OR = 1.57, 95% CI 0.97-2.52; p = 0.06). CONCLUSIONS: Using a large, cohort of women-nurses, history of migraine was associated with an increased risk of MS. However, the difference in absolute risk of MS in migraineurs and non-migraineurs was small. PMID- 21816760 TI - Potential association of vitamin D receptor polymorphism Taq1 with multiple sclerosis. AB - BACKGROUND: The environmental influence of sun exposure and vitamin D in particular and its implication with multiple sclerosis (MS) has recently received considerable attention. Current evidence based on genetic and epidemiological studies indicate that vitamin D is implicated in the aetiology of this disease. METHODS: We examined two common variants in the vitamin D receptor (VDR) gene in 1153 trio families and 726 cases and 604 controls. We also examined epistatic interactions between the VDR SNPs rs731236 and rs2228570 with the tagging single nucleotide polymorphism (SNP) rs3135388 for the HLA-DRB*1501 locus containing a highly conserved vitamin D responsive element within its promoter region. RESULTS: We found weak evidence for an association between the rs731236C allele and MS, while there was no direct association with rs2228570. When examining the interaction between the VDR gene variations and the DRB1*1501 tagging SNP a more complex relationship was observed. Although the interaction was not statistically significant, there appeared to be a trend of increasing risk of MS in participants who were homozygous for the HLA-DRB1*1501 allele in association with the more active form of the VDR (Fok1). CONCLUSION: We have identified weak evidence of an association between a common variation within the VDR gene and MS, in the largest study reported to date of this candidate gene. There appears to be a relationship between polymorphisms in the VDR and the risk of MS, which is potentially modified by HLA-DRB1*1501. PMID- 21816761 TI - A second case of Marburg's variant of multiple sclerosis with vasculitis and extensive demyelination. AB - Marburg's variant of multiple sclerosis is a rapidly progressive and malignant form of multiple sclerosis (MS) that usually leads to severe disability or death within weeks to months without remission. Few cases have been described in the literature since the original description by Marburg. The classic pathological findings usually include highly destructive zones of extensive demyelination, necrosis with dense cellular infiltrate, and giant reactive astrocytes. We report a case of a 31-year-old woman with Marburg's variant of MS who, over a period of eight months, became totally disabled, blind, and quadriplegic, with vocal cord paralysis, requiring a tracheostomy. The patient underwent diagnostic stereotactic brain biopsy. Clinical findings, magnetic resonance imaging (MRI), serologic and cerebrospinal fluid (CSF) findings, and neuropathology are discussed. MRI showed extensive white matter involvement in the brain and spinal cord that continuously progressed over time. A diagnostic stereotactic brain biopsy revealed extensive active demyelination with unexpected finding of active vasculitis and fibrinoid necrosis with a vascular inflammatory cell infiltrate, including polymorphonuclear neutrophils and rare eosinophils. Serologic work-up for vasculitis and neuromyelitis optica was unremarkable and the CSF showed only one oligoclonal band (OCB) not present in serum. This is the second case of Marburg's variant of MS that demonstrated both demyelination and vasculitis. In our case these features were demonstrated simultaneously, even though the demyelination was the predominant pathological finding. Since vasculitis is not a feature of classic MS, these findings pose the question as to whether Marburg's variant of MS is a true variant or different entity altogether. PMID- 21816762 TI - Autoimmunity against cardiac troponin I in ischaemia reperfusion injury. AB - AIMS: Autoimmunity against cardiac troponin I (cTnI) has deleterious effects on the infarcted myocardium early after onset of ischaemia. Here, we explored the impact of cTnI-autoimmunity in the long term. Furthermore, we studied the effects of cTnI-autoimmunity on the infarcted myocardium following revascularization measures in terms of ischaemia reperfusion injury (IRI), which resembles clinical reality more closely. METHODS AND RESULTS: After immunization with either cTnI (n= 10) or a control buffer (n= 14), A/J mice underwent chronic coronary artery ligation. Another group of mice immunized with cTnI (n= 13) underwent temporary coronary artery occlusion and were compared with non-immunized controls (n= 17). Left ventricular function was evaluated by echocardiography. Hearts were obtained for histological evaluation. Immunological responses were quantified by analysis of cytokine and chemokine patterns as well as anti-cTnI antibody titres. Myocardial inflammation and cardiac dysfunction were detectable as late as 180 days after myocardial infarction (MI). Previous cTnI-immunization enhanced myocardial inflammation and dysfunction. Mice subjected to cTnI-immunization before IRI exhibited a higher inflammation score, an upregulated expression of pro-inflammatory chemokines (IP-10, MIP-1, Ltn, RANTES, TCA-3) and chemokine receptors (CCR2, CCR5), increased interleukin (IL)-2, interferon (IFN)-g, and decreased IL-10 production along with a markedly reduced fractional shortening after IRI compared with the controls. CONCLUSION: Our results demonstrate for the first time that cTnI-induced autoimmune response not only leads to increased myocardial inflammation and impaired cardiac function 180 days after chronic coronary artery ligation, but also exacerbates ischaemia/reperfusion injury compared with non-immunized controls. Hence, the presence of cTnI-autoimmunity could render subjects more vulnerable to prospective myocardial injury, be it MI, or secondary revascularization measures. PMID- 21816763 TI - CONSENSUS to EMPHASIS: the overwhelming evidence which makes blockade of the renin-angiotensin-aldosterone system the cornerstone of therapy for systolic heart failure. AB - We will shortly celebrate the 25th anniversary of the publication of the Co operative North Scandinavian Enalapril Survival Study (CONSENSUS), a clinical trial which revolutionized the treatment of heart failure and highlighted the importance of the renin-angiotensin-aldosterone system (RAAS) in the pathophysiology of heart failure (Figure 1). In this article I will give a brief, historical overview of this exciting quarter-century of discovery related to the RAAS. My focus is on the treatment of heart failure in patients with a low left ventricular ejection fraction. PMID- 21816765 TI - Effect of applying the new CLSI imipenem susceptibility breakpoints for Enterobacteriaceae in Hong Kong. PMID- 21816764 TI - Antibiotic and antiseptic resistance genes are linked on a novel mobile genetic element: Tn6087. AB - OBJECTIVES: Tn916-like elements are one of the most common types of integrative and conjugative element (ICE). In this study we aimed to determine whether novel accessory genes, i.e. genes whose products are not involved in mobility or regulation, were present on a Tn916-like element (Tn6087) isolated from Streptococcus oralis from the human oral cavity. METHODS: A minocycline-resistant isolate was analysed using restriction fragment length polymorphism (RFLP) analysis on amplicons derived from Tn916 and DNA sequencing to determine whether there were genetic differences in Tn6087 compared with Tn916. Mutational analysis was used to determine whether the novel accessory gene found was responsible for an observed extra phenotype. RESULTS: A novel Tn916-like element, Tn6087, is described that encodes both antibiotic and antiseptic resistance. The antiseptic resistance protein is encoded by a novel small multidrug resistance gene, designated qrg, that was shown to encode resistance to cetyltrimethylammonium bromide (CTAB), also known as cetrimide bromide. CONCLUSIONS: This is the first Tn916-like element described that confers both antibiotic and antiseptic resistance, suggesting that selection of either antibiotic or antiseptic resistance will also select for the other and further highlights the need for prudent use of both types of compound. PMID- 21816766 TI - Bacteriophages as vehicles of the resistome in cystic fibrosis. AB - Environmental microbial communities and human microbiota represent a huge reservoir of mobilizable genes, the 'mobilome', including a pool of genes encoding antimicrobial resistance, the 'resistome'. Whole-genome sequencing of bacterial genomes from cystic fibrosis (CF) patients has demonstrated that bacteriophages contribute significantly to bacterial genome alterations, and metagenomic analysis of respiratory tract DNA viral communities has revealed the presence of genes encoding antimicrobial resistance in bacteriophages of CF patients. CF airways should now be considered as the site of complex microbiota, where bacteriophages are vehicles for the adaptation of bacteria to this specific environment and for the emergence and selection of multidrug-resistant bacteria with chimeric repertoires. As phages are already known to be mobilized during chronic infection of the lungs of patients with CF, it seems particularly important to improve the understanding of the mechanisms of phage induction to prevent the spread of virulence and/or antimicrobial resistance determinants within the CF population as well as in the community. Such a modern point of view may be a seminal reflection for clinical practice in the future since current antimicrobial therapy guidelines in the context of CF may lead to the emergence of genes encoding antimicrobial resistance. PMID- 21816767 TI - Bacteriophages and diffusion of genes encoding antimicrobial resistance in cystic fibrosis sputum microbiota. AB - OBJECTIVES: The cystic fibrosis (CF) airway is now considered the site of a complex microbiota, where cross-talking between microbes and lateral gene transfer are believed to contribute to the adaptation of bacteria to this specific environment and to the emergence of multidrug-resistant bacteria. The objective of this study was to retrieve and analyse specific sequences associated with antimicrobial resistance from the CF viromes database. METHODS: Specific sequences from CF metagenomic studies related to the 'antibiotic and toxic compound resistance' dataset were retrieved from the MG-RAST web site, assembled and functionally annotated for identification of the genes. Phylogenetic trees were constructed using a minimum parsimony starting tree topology search strategy. RESULTS: Overall, we found 1031 short sequences in the CF virome putatively encoding resistance to antimicrobials versus only 3 reads in the non CF virome dataset (P = 0.001). Among them, we could confidently identify 66 efflux pump genes, 15 fluoroquinolone resistance genes and 9 beta-lactamase genes. Evolutionary relatedness determined using phylogenetic information demonstrates the different origins of these genes among the CF microbiota. Interestingly, among annotated sequences within CF viromes, we also found matching 16S rDNA sequences from Escherichia, Cyanobacteria and Bacteroidetes. CONCLUSIONS: Our results suggest that phages in the CF sputum microbiota represent a reservoir of mobilizable genes associated with antimicrobial resistance that may spread in this specific niche. This phenomenon could explain the fantastic adaptation of CF strains to their niche and may represent a new potential therapeutic target to prevent the emergence of multidrug-resistant bacteria, which are responsible for most of the deaths in CF. PMID- 21816768 TI - Absolute asthenozoospermia and ICSI: what are the options? AB - BACKGROUND: Complete asthenozoospermia, i.e. 100% immotile spermatozoa in the ejaculate, is reported at a frequency of 1 of 5000 men. Its diagnosis implies a poor fertility prognosis even with ICSI. It is extremely important to distinguish between two different groups of patients with complete asthenozoospermia, i.e. virtual or absolute asthenozoospermia. With the former group having some motile spermatozoa after extensive processing of the semen, absolute asthenozoospermia can be associated with metabolic deficiencies, ultrastructural abnormalities of the sperm flagellum, necrozoospermia otherwise it can be idiopathic. In the management of persistent absolute asthenozoospermia, it is very important to elucidate its nature and whenever possible to correct the potential causes. METHODS: We reported data published in the literature on the aetiology of absolute asthenozoospermia and the different techniques to improve ICSI outcome. We propose an algorithm for diagnosis and treatment of this condition. RESULTS Different results regarding fertilization, cleavage and pregnancy rate have been published in patients with absolute asthenozoospermia undergoing ICSI. However, the results vary widely depending on the sperm origin and the technique applied for immotile sperm selection. The percentage of viable spermatozoa varies between 0 and 100%. CONCLUSIONS: Absolute immotile spermatozoa is one of the most important causes of reduced fertilization and pregnancy rates after ICSI and different techniques are used to improve ICSI outcomes. However, it still remains unclear which is the best technique to improve the pregnancy outcomes in these couples. PMID- 21816769 TI - Absence of haemodynamic refractory effects in patients with migraine without aura: an interictal fMRI study. AB - BACKGROUND: In healthy controls, haemodynamic refractory effects are observed with blood-oxygenation-level dependent (BOLD) functional MRI (fMRI): the haemodynamic response function (HRF) to the second stimulus in a pair of stimuli with short interstimulus interval (ISI) shows a decreased amplitude and an increased time-to-peak. We hypothesize that there may be interictal haemodynamic abnormalities in migraineurs. METHODS: An event-related fMRI design with paired face stimuli and varying ISIs was used to measure interictal HRFs in the face recognition area of patients with migraine without aura (MwoA) and controls. Net responses to the second stimulus in a pair were calculated and averaged per participant. Several characterizing parameters of the net responses were quantified and examined within each group. RESULTS: Refractory effects were not observed in our patient group. There are no changes in the net responses compared with the reference situation in patients, irrespective of the ISI, whereas in controls all HRF parameters are decreased or delayed for an ISI of 1 second. CONCLUSION: This is the first fMRI study investigating the haemodynamic refractory effects in MwoA patients. Unlike in controls, these effects are not observed in migraineurs. Although currently unclear, it is tempting to speculate that this observation reflects the neurovascular correlate of lack of habituation measured with evoked potentials in migraineurs. PMID- 21816770 TI - Occipital arteriovenous malformations and migraine. AB - BACKGROUND: Headache has been reported to be the first clinical presentation in several patients with cerebral arteriovenous malformations (AVMs). Headache associated with AVMs often shows characteristics of migraine with and without aura. Angiographic characteristics of AVMs, such as their location, could determine the 'migraine-like' features of attacks. METHODS: We performed an observational study of the clinical and angiographic characteristics of a cohort of 40 consecutive patients with AVMs who had been admitted to our institute for endovascular embolization over a 4-year period. Headache was characterized according to ICHD-II criteria. The relationship between headaches and the angioarchitectural features of AVMs was also analysed. RESULTS: Migraine-like headache was the first clinical manifestation in 22.5% of patients. The location of the malformation was significantly associated with migraine-like presentation (p=0.03) and the occipital lobe was the predominant site. CONCLUSIONS: An occipital location may be linked with spreading depression, a pathogenic mechanism of migraine. Headache associated with arteriovenous malformations in the occipital lobe, although secondary in nature, could have clinical features similar to migraine. PMID- 21816771 TI - Sodium MRI in a rat migraine model and a NEURON simulation study support a role for sodium in migraine. AB - INTRODUCTION: Increased lumbar cerebrospinal fluid (CSF) sodium has been reported during migraine. We used ultra-high field MRI to investigate cranial sodium in a rat migraine model, and simulated the effects of extracellular sodium on neuronal excitability. METHODS: Behavioral changes in the nitroglycerin (NTG) rat migraine model were determined from von Frey hair withdrawal response and photography. Central sensitization was measured by counting cFos-immunoreactive cells in the trigeminal nucleus caudalis (TNC). Sodium was quantified in vivo by ultra-high field sodium MRI at 21 Tesla. Effects of extracellular sodium on neuronal excitability were modeled using NEURON software. RESULTS: NTG decreased von Frey withdrawal threshold (p=0.0003), decreased eyelid vertical height:width ratio (p<0.0001), increased TNC cFos stain (p<0.0001), and increased sodium between 7.5 and 17% in brain, intracranial CSF, and vitreous humor (p<0.05). Simulated neurons exposed to higher sodium have more frequent and earlier spontaneous action potentials, and corresponding earlier sodium and potassium currents. CONCLUSIONS: In the rat migraine model, sodium rises to levels that increase neuronal excitability. We propose that rising sodium in CSF surrounding trigeminal nociceptors increases their excitability and causes pain and that rising sodium in vitreous humor increases retinal neuronal excitability and causes photosensitivity. PMID- 21816772 TI - Migraine and cognitive decline in the population-based EVA study. AB - BACKGROUND: Previous studies on migraine and cognition have shown mixed results. However, many could not assess the relationship between migraine and change in cognitive function or only used a limited number of cognitive tests. METHODS: Prospective cohort study among 1170 participants of the Epidemiology of Vascular Ageing Study who provided information about migraine status and completed cognitive testing. Participants were classified as having no severe headache, non migraine headache and migraine. Cognitive functioning was measured at up to four time points using nine different cognitive functioning tests. Linear mixed effects models were used to evaluate the relationship between migraine status and change in cognitive function. RESULTS: Of the 1170 participants, 938 had no severe headache, 167 had migraine, and 65 had non-migraine headache. After adjusting for age, gender, education and smoking status, people with migraine or non-migraine headache did not experience a greater rate of cognitive decline than those without headache or migraine in any domain (for the Mini Mental State Examination (MMSE), p-values were 0.68 for the non-migraine headache and time interaction and 0.85 for the migraine and time interaction) during 4-5 years of follow-up. For the Wechsler Adult Intelligence Scale-Revised, those with migraine declined less over time (p-value=0.02). CONCLUSION: Migraine was not associated with faster cognitive decline over time. PMID- 21816773 TI - The impact of a migraine attack and its after-effects on perceptual organization, attention, and working memory. AB - INTRODUCTION: Many migraine patients report cognitive complaints during the first hours or days following a migraine attack. The aim of this study was to assess whether and which cognitive (perceptual, attentional, or memory) processes are impaired during the first 48 hours after a migraine attack. METHODS: Three different cognitive tasks (global-local task, the attentional network task, and N back task) were administered to 16 migraine patients (13 migraine without aura; mean age 58 years, 15 female) and 18 controls (59 years, 15 female), matched on age, gender, and educational level. Tasks were administered at three time points; during the first headache free day following a migraine attack (first session), 24 hours later (second session), and 12 days after the attack (third session). RESULTS: The attentional network and N-back tasks showed no significant differences between migraineurs and controls. In the global-local task, controls showed faster reaction times to global than to local stimuli, which is the standard global-precedence effect. This effect was absent in the migraineurs in all three sessions, especially if they used prophylaxis. CONCLUSION: Migraineurs had no impaired attentional or working-memory functioning in the 2 days after an attack. They did show impairments in the processing of global visual features compared with controls, both between and immediately after an attack. PMID- 21816774 TI - Effectiveness of return-to-work interventions for disabled people: a systematic review of government initiatives focused on changing the behaviour of employers. AB - BACKGROUND: OECD countries over the past two decades have implemented a range of labour market integration initiatives to improve the employment chances of disabled and chronically ill individuals. This article presents a systematic review and evidence synthesis on effectiveness of government interventions to influence employers' employment practices concerning disabled and chronically ill individuals in five OECD countries. A separate paper reports on interventions to influence the behaviour of employees. METHODS: Electronic and grey literature searches to identify all empirical studies reporting employment effects and/or process evaluations of government policies aimed at changing the behaviour of employers conducted between 1990 and 2008 from Canada, Denmark, Norway, Sweden and the UK. RESULTS: Few studies provided robust evaluations of the programmes or their differential effects and selection of participants into programmes may distort the findings of even controlled studies. A population-level effect of legislation to combat discrimination by employers could not be detected. Workplace adjustments had positive impacts on employment, but low uptake. Financial incentives such as wage subsidies can work if they are sufficiently generous. Involving employers in return-to-work planning can reduce subsequent sick leave and be appreciated by employees, but this policy has not been taken up with the level of intensity that is likely to make a difference. Some interventions favour the more advantaged disabled people and those closer to the labour market. CONCLUSIONS: Future evaluations need to pay more attention to differential impact of interventions, degree of take-up, non-stigmatizing implementation and wider policy context in each country. PMID- 21816775 TI - Lower risk of Creutzfeldt-Jakob disease in pituitary growth hormone recipients initiating treatment after 1977. AB - CONTEXT: Creutzfeldt-Jakob disease (CJD) caused by contaminated cadaveric pituitary-derived human GH (hGH) has been responsible for hundreds of deaths worldwide. Studies of U.S. National Hormone and Pituitary Program (NHPP) hGH recipients have found CJD only in patients treated before 1977, when a new purification procedure with column chromatography was implemented for hGH extraction. OBJECTIVE: Our objective was to provide updated information on transmission of CJD to NHPP hGH recipients and determine whether recipients of hGH produced after 1977 had a significantly lower CJD risk than pre-1977 recipients. PATIENTS: A total of 5570 NHPP hGH recipients were included in the study: 2099 in the pre-1977 cohort and 3471 in the post-1977 cohort. MAIN OUTCOME MEASURE: We used probability distribution functions to determine whether the observed number of CJD cases in the post-1977 cohort was significantly fewer than expected if the CJD risk was equal to that of the pre-1977 cohort, controlling for treatment duration and follow-up time. RESULTS: All 22 CJD cases (diagnosed from 1984-2009) occurred in the pre-1977 hGH recipients. Almost half (47.9%) of pre-1977 recipients had a treatment duration of at least 5 yr compared with only 13.8% for post-1977 recipients. Based on the rates present in the pre-1977 cohort, the probability of observing no cases in the post-1977 cohort by chance alone was low (P = 0.0019). CONCLUSIONS: Risk of acquiring CJD was significantly lower for post-1977 NHPP hGH recipients than for pre-1977 recipients, suggesting that the new purification procedure in 1977 may have greatly reduced or eliminated CJD agent in hGH. PMID- 21816777 TI - Multiple loci in the HLA complex are associated with Addison's disease. AB - CONTEXT: A strong association between autoimmune Addison's disease (AAD) and major histocompatibility complex class II-encoded HLA-DRB1-DQA1-DQB1 haplotypes is well known. Recent evidence from other autoimmune diseases has suggested that class I-encoded HLA-A and HLA-B gene variants confer HLA-DRB1-DQA1-DQB1 independent effects on disease. OBJECTIVE: We aimed to explore AAD predisposing effects of HLA-A and -B and further investigate the role of MICA and HLA-DRB1 DQA1-DQB1 in a much larger material than has previously been studied. DESIGN: HLA A, -B, -DRB1, and -DQB1 and a microsatellite in MICA were genotyped in 414 AAD patients and 684 controls of Norwegian origin. RESULTS: The strongest association was observed for the DRB1 locus, in which the DRB1*03:01 and DRB1*04:04 conferred increased risk of AAD, particularly in a heterozygous combination [odds ratio 22.13; 95% confidence interval (11.39-43.98); P = 6 * 10(-20)]. After conditioning on DRB1, association with AAD was still present for HLA-B and MICA, suggesting the presence of additional risk factors. CONCLUSIONS: The major histocompatibility complex harbors multiple risk loci for AAD, in which DRB1 appears to represent the main risk factor. PMID- 21816776 TI - Clinical review: Endogenous testosterone and mortality in men: a systematic review and meta-analysis. AB - CONTEXT: Low testosterone levels have been associated with outcomes that reduce survival in men. OBJECTIVE: Our objective was to perform a systematic review and meta-analysis of published studies to evaluate the association between endogenous testosterone and mortality. DATA SOURCES: Data sources included MEDLINE (1966 to December 2010), EMBASE (1988 to December 2010), and reference lists. STUDY SELECTION: Eligible studies were published English-language observational studies of men that reported the association between endogenous testosterone and all cause or cardiovascular disease (CVD) mortality. A two-stage process was used for study selection. 1) Working independently and in duplicate, reviewers screened a subset (10%) of abstracts. Results indicated 96% agreement, and thereafter, abstract screening was conducted in singlicate. 2) All full-text publications were reviewed independently and in duplicate for eligibility. DATA EXTRACTION: Reviewers working independently and in duplicate determined methodological quality of studies and extracted descriptive, quality, and outcome data. DATA SYNTHESIS: Of 820 studies identified, 21 were included in the systematic review, and 12 were eligible for meta-analysis [n = 11 studies of all-cause mortality (16,184 subjects); n = 7 studies of CVD mortality (11,831 subjects)]. Subject mean age and testosterone level were 61 yr and 487 ng/dl, respectively, and mean follow-up time was 9.7 yr. Between-study heterogeneity was observed among studies of all-cause (P < .001) and CVD mortality (P = 0.06), limiting the ability to provide valid summary estimates. Heterogeneity in all-cause mortality (higher relative risks) was observed in studies that included older subjects (P = 0.020), reported lower testosterone levels (P = 0.018), followed subjects for a shorter time period (P = 0.010), and sampled blood throughout the day (P = 0.030). CONCLUSION: Low endogenous testosterone levels are associated with increased risk of all-cause and CVD death in community-based studies of men, but considerable between-study heterogeneity, which was related to study and subject characteristics, suggests that effects are driven by differences between cohorts (e.g. in underlying health status). PMID- 21816778 TI - GPIHBP1 C89F neomutation and hydrophobic C-terminal domain G175R mutation in two pedigrees with severe hyperchylomicronemia. AB - CONTEXT: GPIHBP1 is a new endothelial binding site for lipoprotein lipase (LPL), the key enzyme for intravascular lipolysis of triglyceride-rich lipoproteins (TGRL). We have identified two new missense mutations of the GPIHBP1 gene, C89F and G175R, by systematic sequencing in a cohort of 376 hyperchylomicronemic patients without mutations on the LPL, APOC2, or APOA5 gene. OBJECTIVE: Phenotypic expression and functional consequences of these two mutations were studied. DESIGN: We performed clinical and genotypic studies of probands and their families. GPIHBP1 functional alterations were studied in CHO pgsA-745 transfected cells. RESULTS: Probands are an adult with a homozygous G175R mutation and a child with a hemizygous C89F neomutation and a deletion of the second allele. C89F mutation was associated with a C14F signal peptide polymorphism on the same haplotype. Both patients had resistant hyperchylomicronemia, low LPL activity, and history of acute pancreatitis. In CHO pgsA-745 cells, both G175R and C14F variants reduce the expression of GPIHBP1 at the cell surface. C89F mutation is responsible for a drastic LPL-binding defect to GPIHBP1. C14F may further potentiate C89F effect. CONCLUSIONS: The emergence of hyperchylomicronemia in the generation after a neomutation further establishes a critical role for GPIHBP1 in TGRL physiopathology in humans. Our results highlight the crucial role of C65-C89 disulfide bond in LPL binding by GPIHBP1 Ly6 domain. Furthermore, we first report a mutation of the hydrophobic C-terminal domain that impairs GPIHBP1 membrane targeting. PMID- 21816779 TI - Type of dietary fat is associated with the 25-hydroxyvitamin D3 increment in response to vitamin D supplementation. AB - CONTEXT: Mono- and polyunsaturated fats may have opposing effects on vitamin D absorption. OBJECTIVE: The purpose of this study was to determine whether intakes of different dietary fats are associated with the increase in serum 25 hydroxyvitamin D (25OHD) after supplementation with vitamin D(3). DESIGN, SETTING, AND PARTICIPANTS: This analysis was conducted in the active treatment arm of a randomized, double-blind, placebo-controlled trial of vitamin D and calcium supplementation to prevent bone loss and fracture. Subjects included 152 healthy men and women age 65 and older who were assigned to 700 IU/d vitamin D(3) and 500 mg/d calcium. Intakes of monounsaturated fatty acids (MUFA), polyunsaturated fatty acids (PUFA), and saturated fatty acids (SFA) were estimated by food frequency questionnaire. MAIN OUTCOME MEASURE: The change in plasma 25OHD during 2 yr vitamin D and calcium supplementation was assessed. RESULTS: The change in plasma 25OHD (nanograms per milliliter) during vitamin D supplementation was positively associated with MUFA, (beta = 0.94; P = 0.016), negatively associated with PUFA, (beta = -0.93; P = 0.038), and positively associated with the MUFA/PUFA ratio (beta = 6.46; P = 0.014). CONCLUSION: The fat composition of the diet may influence the 25OHD response to supplemental vitamin D(3). Diets rich in MUFA may improve and those rich in PUFA may reduce the effectiveness of vitamin D(3) supplements in healthy older adults. More studies are needed to confirm these findings. PMID- 21816780 TI - Effects of nicotinic acid on gene expression: potential mechanisms and implications for wanted and unwanted effects of the lipid-lowering drug. AB - CONTEXT: Nicotinic acid (NA), or niacin, lowers circulating levels of lipids, including triglycerides, very low-density lipoprotein-cholesterol, and low density lipoprotein-cholesterol. The lipid-lowering effects have been attributed to its effect to inhibit lipolysis in adipocytes and thus lower plasma free fatty acid (FFA) level. However, evidence accumulates that the FFA-lowering effect may account for only a fraction of NA effects on plasma lipids, and other mechanisms may be involved. Recent studies have reported NA effects on gene expression in various tissues in vivo and in cultured cells in vitro. EVIDENCE ACQUISITION: We reviewed articles reporting NA effects on gene expression, identified by searching PubMed, focusing on potential underlying mechanisms and implications for unexplained NA effects. CONCLUSION: The effects of NA on gene expression may be mediated directly via the NA receptor in the affected cells, indirectly via changes in circulating FFA or hormone levels induced by NA, or by activating the transcription factor FOXO1 in insulin-sensitive tissues. NA effects on gene expression provide new insights into previously unexplained NA effects, such as FFA-independent lipid-lowering effects, FFA rebound, and insulin resistance observed in clinics during NA treatment. PMID- 21816781 TI - Endothelial progenitor cells in primary aldosteronism: a biomarker of severity for aldosterone vasculopathy and prognosis. AB - CONTEXT: Primary aldosteronism (PA) is associated with a higher incidence of cardiovascular events, probably through mineralocorticoid receptor (MR)-dependent endothelial cell dysfunction, in comparison with essential hypertension (EH). OBJECTIVE: Our objective was to investigate the number and function of endothelial progenitor cells (EPC) in PA and the relationship with arterial stiffness and disease progression. DESIGN AND SETTING: We conducted a prospective study of the change of EPC number and outcome of PA patients after treatment at a tertiary medical center. PRIMARY OUTCOMES: Changes in arterial stiffness and EPC number after treatment and the curability of hypertension were assessed. PATIENTS: A total of 113 PA patients (87 patients diagnosed with aldosterone producing adenoma, 26 with idiopathic hyperaldosteronism) and 55 patients with EH participated. RESULTS: PA patients had higher arterial stiffness than EH patients (P = 0.006), with a lower numbers of circulating EPC and endothelial colony forming units (P < 0.05). The differences were ameliorated at 6 months after unilateral adrenalectomy or treatment with spironolactone. Expression of MR was identified in the EPC. The number of circulating EPC was inversely correlated with the plasma aldosterone concentration (P = 0.021), arterial stiffness (P = 0.029) and serum high-sensitivity C-reactive protein (P = 0.03). High-dose aldosterone (10(-5) and 10(-6) m) attenuated EPC proliferation and angiogenesis in vitro. Among the 45 patients who underwent unilateral adrenalectomy, 32 (71%) were cured of hypertension. The preoperative number of EPC [log(EPC number percent) >-3.6] predicted the curability of hypertension after adrenalectomy (P = 0.003). CONCLUSIONS: The relative deficiency of EPC in PA patients may contribute to aldosterone vasculopathy, which can be reversed by adrenalectomy and spironolactone. High aldosterone levels attenuated EPC proliferation and angiogenesis. Circulating EPC number may be a valuable biomarker to identify PA patients with a high incidence of arterial stiffness and to predict postoperative residual hypertension of aldosterone-producing adenoma. PMID- 21816782 TI - A novel frame shift mutation in the GHRH receptor gene in familial isolated GH deficiency: early occurrence of anterior pituitary hypoplasia. AB - BACKGROUND: Mutations in the genes encoding for GHRH receptor (GHRHR) and GH (GH1) are the most common cause of familial isolated GH deficiency (IGHD). GHRHR mutations are often associated with anterior pituitary hypoplasia (APH), but this has been reported almost exclusively in children older than 8 yr. We analyzed the GHRHR and measured pituitary size in a consanguineous family with the father and three of the five siblings with IGHD. OBJECTIVE: The aim of the study was to find the mutated gene in a family with severe IGHD. METHODS: We sequenced the whole GHRHR coding regions and the intron-exon boundaries from peripheral DNA of the index patient. After identifying the novel mutation, we sequenced the region of interest in the other members of the family. We measured the anterior pituitary volume from magnetic resonance imaging (MRI). RESULTS: The father and the three affected children were homozygous for a new frame-shift mutation in the coding sequence of exon 4 (corresponding to the extracellular domain of the receptor) (c.340delG) that places the downstream sequence out of frame [corrected]. The mother and two unaffected siblings were heterozygous for the mutation. Two of the affected children had MRI evidence of APH before reaching 6 yr of age. CONCLUSIONS: We describe a new mutation in the GHRHR in a family with IGHD. The presence of frank APH before age 6 yr shows that MRI-evident reduced pituitary size can be present in GHRHR mutations even in children younger than 8 yr of age. PMID- 21816783 TI - NOS3 Glu298Asp polymorphism interacts with virgin olive oil phenols to determine the postprandial endothelial function in patients with the metabolic syndrome. AB - BACKGROUND: Glu298Asp polymorphism of the endothelial nitric oxide synthase (eNOS) gene (NOS3) has been characterized as a risk factor of hypertension and coronary artery disease. Previous studies suggest that the higher risk observed in T allele carriers is due to endothelial dysfunction associated with a lower eNOS activity and that acute consumption of phenol-rich olive oil ameliorates postprandial endothelial dysfunction by reducing oxidative stress and increasing nitric oxide bioavailability. Nevertheless, how these facts may interact in a population with altered endothelial function such as metabolic syndrome patients remains unknown. OBJECTIVE: The objective of the study was to evaluate whether the presence of NOS3 Glu298Asp polymorphism interacts with the phenol content of virgin olive oil (VOO) to influence postprandial endothelial function. DESIGN: Fifty-seven subjects with metabolic syndrome received three breakfasts based on VOO with different phenolic content. Baseline, incremental area under the curve, peak, and maximum parameters of postocclusive skin reactive hyperemia (PORH) were evaluated by laser Doppler, and the nitrate/nitrite [NO((x))] and eNOS concentrations were obtained during fasting and postprandially. RESULTS: A gene diet interaction was found on maximum PORH and NO((x)) (P = 0.039 and P = 0.043, respectively). TT subjects showed lower values of eNOS, NO((x)), and maximum PORH as compared with GG and GT subjects, especially in the postprandial measurements (all P < 0.05). However, most of these differences were attenuated when high phenol VOO was consumed. CONCLUSION: In a population with a compromised endothelial function, concentrations of phenols in dietary VOO interact with NOS3 Glu298Asp to ameliorate the endothelial dysfunction associated to the TT genotype. PMID- 21816784 TI - Nonalcoholic fatty liver disease is associated with low circulating levels of insulin-like growth factor-I. AB - CONTEXT: Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease and is associated with insulin resistance and cardiovascular disease. Among the potential factors that may account for the increased cardiometabolic risk, IGF-I is a plausible candidate because the liver is the main site of its production. OBJECTIVE: Our objective was to examine the relationship between NAFLD and IGF-I levels and to test the hypothesis that free fatty acids-induced insulin resistance might impair insulin-induced increase of GH receptor (GHR) expression in human hepatoma cells. SUBJECTS, DESIGN, AND SETTING: Five hundred three nondiabetic Caucasians participated in this ambulatory-care cross-sectional study. MAIN OUTCOME MEASURES: Cardiometabolic risk factors and liver ultrasound scanning were assessed. Insulin-induced expression of GHR in HuH7 human hepatoma cells exposed for 24 h to palmitate was determined by Western blotting and real-time PCR. RESULTS: After adjustment for age and gender, individuals with NAFLD had significantly higher body mass index, waist circumference, fasting insulin, triglycerides, homeostasis model assessment index, liver enzymes, and lower high-density lipoprotein cholesterol compared with control subjects. IGF-I levels were significantly lower in individuals with NAFLD (P = 0.001). Exposure of HuH7 hepatoma cells to palmitate caused a dose dependent reduction in the insulin-induced increase of GHR expression. CONCLUSIONS: These data show that IGF-I levels are reduced in subjects with NAFLD and suggest that hepatic insulin resistance may affect IGF-I levels by modulating GH-stimulated synthesis of hepatic IGF-I. PMID- 21816785 TI - Overt immune dysfunction after Cushing's syndrome remission: a consecutive case series and review of the literature. AB - CONTEXT: Autoimmune diseases frequently improve during active Cushing's syndrome. Several studies have reported new onset or exacerbation of these conditions upon cortisol normalization. OBJECTIVE: Our objective was to investigate the incidence and clinical characteristics of patients with autoimmune or allergic diseases after Cushing's syndrome remission. METHODS: Consecutive cases of confirmed Cushing's syndrome were characterized. A review of the literature was conducted to identify previous descriptions of immune dysfunction upon remission and evidence of the hypothalamic-pituitary-adrenal axis influence on the immune system. RESULTS: Among 66 patients who achieved Cushing's syndrome remission, the incidence of immune dysfunction was 16.7%, where eight cases (72.7%) were noted for the first time and three (27.3%) were exacerbated. All had an ACTH-dependent cause. Glucocorticoids reduce proinflammatory cytokines and interact with other transcription factors affecting T cell and mast cell survival. CONCLUSION: Hypercortisolism induces a state of immunosuppression. After Cushing's syndrome remission, rebound immunity frequently results in overt conditions extending beyond thyroid dysfunction. PMID- 21816786 TI - Mechanism of action of a peroxisome proliferator-activated receptor (PPAR)-delta agonist on lipoprotein metabolism in dyslipidemic subjects with central obesity. AB - CONTEXT: Dyslipidemia increases the risk of cardiovascular disease in obesity. Peroxisome proliferator-activated receptor (PPAR)-delta agonists decrease plasma triglycerides and increase high-density lipoprotein (HDL)-cholesterol in humans. OBJECTIVE: The aim of the study was to examine the effect of GW501516, a PPAR delta agonist, on lipoprotein metabolism. Design, Setting, and Intervention: We conducted a randomized, double-blind, crossover trial of 6-wk intervention periods with placebo or GW501516 (2.5 mg/d), with 2-wk placebo washout between treatment periods. PARTICIPANTS: We recruited 13 dyslipidemic men with central obesity from the general community. MAIN OUTCOME MEASURES: We measured the kinetics of very low-density lipoprotein (VLDL)-, intermediate-density lipoprotein-, and low-density lipoprotein (LDL)-apolipoprotein (apo) B-100, plasma apoC-III, and high-density lipoprotein (HDL) particles (LpA-I and LpA-I:A II). RESULTS: GW501516 decreased plasma triglycerides, fatty acid, apoB-100, and apoB-48 concentrations. GW501516 decreased the concentrations of VLDL-apoB by increasing its fractional catabolism and of apoC-III by decreasing its production rate (P < 0.05). GW501516 reduced VLDL-to-LDL conversion and LDL-apoB production. GW501516 increased HDL-cholesterol, apoA-II, and LpA-I:A-II concentrations by increasing apoA-II and LpA-I:A-II production (P < 0.05). GW501516 decreased cholesteryl ester transfer protein activity, and this was paralleled by falls in the triglyceride content of VLDL, LDL, and HDL and the cholesterol content of VLDL and LDL. CONCLUSIONS: GW501516 increased the hepatic removal of VLDL particles, which might have resulted from decreased apoC-III concentration. GW501516 increased apoA-II production, resulting in an increased concentration of LpA-I:A-II particles. This study elucidates the mechanism of action of this PPAR delta agonist on lipoprotein metabolism and supports its potential use in treating dyslipidemia in obesity. PMID- 21816787 TI - True and sham acupuncture produced similar frequency of ovulation and improved LH to FSH ratios in women with polycystic ovary syndrome. AB - CONTEXT: Acupuncture may represent a nonpharmaceutical treatment for women with polycystic ovary syndrome (PCOS), based on four studies. OBJECTIVE: The objective of the study was to determine whether true, as compared with sham, acupuncture normalizes pituitary gonadotropin hormones and increases ovulatory frequency in women with PCOS. DESIGN: This was a randomized, double-blind, sham-controlled clinical trial (5 month protocol). SETTING: The study was conducted in central Virginia. PARTICIPANTS: Eighty-four reproductive-aged women completed the intervention. Eligibility required a PCOS diagnosis and no hormonal intervention 60 d before enrollment. INTERVENTIONS: Intervention included 12 sessions of true or sham acupuncture (Park sham device) for 8 wk. MAIN OUTCOME MEASURES: Serum LH and FSH at baseline, after intervention, and 3 months later were measured. Ovulation was measured with weekly urine or blood samples. RESULTS: Both arms demonstrated a similar mean ovulation rate over the 5 months (0.37/month among n = 40 true acupuncture and 0.40/month among n = 44 sham participants, P = 0.6), similar LH to FSH ratio improvement (-0.5 and -0.8 true and sham, respectively, P < 0.04 after intervention vs. baseline) and a similar decline in LH over the 5 month protocol (P < 0.05). Neither arm experienced a change in FSH. There were seven pregnancies (no difference by intervention, P = 0.7). Lower fasting insulin and free testosterone were highly correlated with a higher ovulation rate within the true acupuncture group only (P = 0.03), controlling for prestudy menstrual frequency and body mass index. CONCLUSION: We were unable to discern a difference between the true and sham acupuncture protocols for these women with PCOS, and both groups had a similar improvement in their LH/FSH ratio. PMID- 21816788 TI - Sunitinib-induced hypothyroidism is due to induction of type 3 deiodinase activity and thyroidal capillary regression. AB - CONTEXT: Anticancer treatment with the tyrosine kinase inhibitor sunitinib causes thyroid dysfunction. OBJECTIVE: Our objective was to investigate the time course and underlying mechanisms of sunitinib-induced thyroid dysfunction. DESIGN: Thyroid function tests of 83 patients on sunitinib were collected retrospectively for their total treatment duration between January 2006 and November 2009 and prospectively in 15 patients on sunitinib for 10 wk. Additionally, thyroid function and histology were assessed in rats on sunitinib (8 d; n = 10) and after sunitinib withdrawal (11 d; n = 7) and compared with controls (n = 7). SETTING: Patients were seen at a university outpatient oncology clinic. Patients and Animals: Patients with metastatic renal cell carcinoma or gastrointestinal stromal tumors participated in the clinical study and Wistar Kyoto rats were used in the rat study. INTERVENTION: Sunitinib was taken according to a 4 wk "on," 2 wk "off" treatment regimen. Blood samples for measurement of thyroid function were collected at baseline and at wk 4 and 10. In rats, blood, liver, and thyroid were collected to assess thyroid hormones, deiodinase activity, and thyroid histology. MAIN OUTCOME MEASURES: TSH and free T(4) levels, deiodinase activity, and thyroid histology were assessed. RESULTS: Forty-two percent of patients in the retrospective study developed elevated TSH levels. Prospective analysis showed increased TSH levels within 10 wk of treatment, accompanied by a decreased T(3)/rT(3) ratio. In rats, serum T(4) and T(3) decreased, hepatic type 3 deiodinase activity increased, and thyroid histology showed marked capillary regression, which all but thyroid hormones reversed after sunitinib withdrawal. CONCLUSION: Sunitinib induces hypothyroidism due to alterations in T(4)/T(3) metabolism as well as thyroid capillary regression. PMID- 21816789 TI - Clinical review: Pseudohypoparathyroidism: diagnosis and treatment. AB - CONTEXT: The term pseudohypoparathyroidism (PHP) indicates a group of heterogeneous disorders whose common feature is represented by impaired signaling of various hormones (primarily PTH) that activate cAMP-dependent pathways via Gsalpha protein. The two main subtypes of PHP, PHP type Ia, and Ib (PHP-Ia, PHP Ib) are caused by molecular alterations within or upstream of the imprinted GNAS gene, which encodes Gsalpha and other translated and untranslated products. EVIDENCE ACQUISITION: A PubMed search was used to identify the available studies (main query terms: pseudohypoparathyroidism; Albright hereditary osteodystrophy; GNAS; GNAS1; progressive osseous heteroplasia). The most relevant studies until February 2011 have been included in the review. EVIDENCE SYNTHESIS AND CONCLUSIONS: Despite the first description of this disorder dates back to 1942, recent findings indicating complex epigenetic alterations beside classical mutations at the GNAS complex gene, pointed out the limitation of the actual classification of the disease, resulting in incorrect genetic counselling and diagnostic procedures, as well as the gap in our actual knowledge of the pathogenesis of these disorders. This review will focus on PHP type I, in particular its diagnosis, classification, treatment, and underlying molecular alterations. PMID- 21816791 TI - Patient Information Page. Medicines for hypothyroidism. PMID- 21816790 TI - Bone microarchitecture is impaired in adolescent amenorrheic athletes compared with eumenorrheic athletes and nonathletic controls. AB - CONTEXT: Bone mineral density (BMD) is lower in young amenorrheic athletes (AA) compared to eumenorrheic athletes (EA) and nonathletic controls and may contribute to fracture risk during a critical time of bone accrual. Abnormal bone microarchitecture is an independent determinant of fracture risk and has not been assessed in young athletes and nonathletes. OBJECTIVE: We hypothesized that bone microarchitecture is impaired in AA compared to EA and nonathletes despite weight bearing exercise. DESIGN AND SETTING: We conducted this cross-sectional study at the Clinical Research Center of Massachusetts General Hospital. SUBJECTS AND OUTCOME MEASURES: We assessed BMD and bone microarchitecture in 50 subjects [16 AA, 18 EA, and 16 nonathletes (15-21 yr old)] using dual-energy x-ray absorptiometry and high-resolution peripheral quantitative computed tomography. RESULTS: Groups did not differ for chronological age, bone age, body mass index, or vitamin D levels. Lumbar BMD Z-scores were lower in AA vs. EA and nonathletes; hip and femoral neck BMD Z-scores were highest in EA. At the weight-bearing tibia, athletes had greater total area, trabecular area, and cortical perimeter than nonathletes, whereas cortical area and thickness trended lower in AA. Trabecular number was lower and trabecular separation higher in AA vs. EA and nonathletes. At the non-weight-bearing radius, trabecular density was lower in AA vs. EA and nonathletes. Later menarchal age was an important determinant of impaired microarchitecture. After controlling for covariates, subject grouping accounted for 18-24% of the variability in tibial trabecular number and separation. CONCLUSION: In addition to low BMD, AA have impaired bone microarchitecture compared with EA and nonathletes. These are the first data to show abnormal bone microarchitecture in AA. PMID- 21816795 TI - Update on external beam radiation therapy in thyroid cancer. AB - Surgery is the mainstay of treatment for thyroid cancer. The role for external beam radiotherapy (EBRT) as an adjuvant to surgery or as the primary therapy is established in anaplastic thyroid cancer but is controversial in differentiated thyroid cancer and uncertain in medullary thyroid cancer. This update reviews the recent reported success of combining EBRT with taxanes in anaplastic thyroid cancer. Also discussed are the recent reports from large single institutions that support the recommendations of the American and British Thyroid Associations on the use of EBRT in high-risk differentiated thyroid cancer. Further evidence on the role of EBRT in MTC is discussed. The important advances in the delivery of EBRT using intensity-modulated radiation and image-guided radiation that result in more accurate and potentially more effective radiation therapy with less toxicity are also discussed. PMID- 21816796 TI - Approach to the thyroid cancer patient with bone metastases. PMID- 21816797 TI - Giant cystic pheochromocytoma containing high concentrations of catecholamines and metanephrines. PMID- 21816798 TI - Diabetic myonecrosis of the thigh. PMID- 21816799 TI - Increasing incidence of congenital hypothyroidism: some answers, more questions. PMID- 21816800 TI - Impact of insulin-sensitizing agents on risk for liver cancer and liver-related death in diabetic patients with compensated hepatitis C cirrhosis. PMID- 21816801 TI - Pediatric differentiated thyroid cancer: can the prescribed activity of I-131 be increased? PMID- 21816807 TI - Amphibian immune defenses against chytridiomycosis: impacts of changing environments. AB - Eco-immunology is the field of study that attempts to understand the functions of the immune system in the context of the host's environment. Amphibians are currently suffering devastating declines and extinctions in nearly all parts of the world due to the emerging infectious disease chytridiomycosis caused by the chytrid fungus, Batrachochytrium dendrobatidis. Because chytridiomycosis is a skin infection and remains confined to the skin, immune defenses of the skin are critical for survival. Skin defenses include secreted antimicrobial peptides and immunoglobulins as well as antifungal metabolites produced by symbiotic skin bacteria. Low temperatures, toxic chemicals, and stress inhibit the immune system and may impair natural defenses against B. dendrobatidis. Tadpoles' mouth parts can be infected by B. dendrobatidis. Damage to the mouth parts can impair growth, and the affected tadpoles maintain the pathogen in the environment even when adults have dispersed. Newly metamorphosing frogs appear to be especially vulnerable to infection and to the lethal effects of this pathogen because the immune system undergoes a dramatic reorganization at metamorphosis, and postmetamorphic defenses are not yet mature. Here we review our current understanding of amphibian immune defenses against B. dendrobatidis and the ability of the pathogen to resist those defenses. We also briefly review what is known about the impacts of temperature, environmental chemicals, and stress on the host-pathogen interactions and suggest future directions for research. PMID- 21816808 TI - Gliding flight in Chrysopelea: turning a snake into a wing. AB - Although many cylindrical animals swim through water, flying snakes of the genus Chrysopelea are the only limbless animals that glide through air. Despite a lack of limbs, these snakes can actively launch by jumping, maintain a stable glide path without obvious control surfaces, maneuver, and safely land without injury. Jumping takeoffs employ vertically looped kinematics that seem to be different than any other behavior in limbless vertebrates, and their presence in a closely related genus suggests that gap-crossing may have been a behavioral precursor to the evolution of gliding in snakes. Change in shape of the body by dorsoventral flattening and high-amplitude aerial undulation comprise two key features of snakes' gliding behavior. As the snake becomes airborne, the body flattens sequentially from head to vent, forming a cross-sectional shape that is roughly triangular, with a flat surface and lateral "lips" that protrude ventrally on each side of the body; these may diminish toward the vent. This shape likely provides the snake with lift coefficients that peak at high angles of attack and gentle stall characteristics. A glide trajectory is initiated with the snake falling at a steep angle. As the snake rotates in the pitch axis, it forms a wide "S" shape and begins undulating in a complex three-dimensional pattern, with the body angled upward relative to the glide path. The head moves side-to-side, sending traveling waves posteriorly toward the tail, while the body (most prominently, the posterior end) oscillates in the vertical axis. These active movements while gliding are substantially different and more dynamic than those used by any other animal glider. As the snake gains forward speed, the glide path becomes less steep, reaching minimally recorded glide angles of 13 degrees . In general, smaller snakes appear to be more proficient gliders. Chrysopelea paradisi can also maneuver and land either on the ground or on vegetation, but these locomotor behaviors have not been studied in detail. Future work aims to understand the mechanisms of production and control of force in takeoff, gliding, and landing, and to identify the musculoskeletal adaptations that enable this unique form of locomotion. PMID- 21816809 TI - Vitamin D and the social aspects of disease. AB - BACKGROUND: The strong association between socio-economic disadvantage and poor health in northern Europe and North America causes great public health concern but as the mechanism is not understood, government actions have been completely unsuccessful. The social gap continues to widen. AIM: I propose that an important mechanism involved is relative deficiency of vitamin D in the socio-economically disadvantaged people. DESIGN: The evidence is presented by explaining apparent paradoxes, together with the analogies of geography, season and ethnicity. Vitamin D studies are also demonstrated. METHOD: The picture is put together according to Hill's criteria of causation: strength of association, consistency of association, temporality, biological gradient, plausibility, coherence, experimentation and analogy. RESULTS: Hill's criteria of causation are met, acknowledging that they are pragmatic and not absolute. The associations between vitamin D deficiency and socio-economic deprivation are supported by analogies of geography, seasonality and ethnicity. There is also biological plausibility. The paradoxes of Albania and India show that health disadvantage and socio-economic disadvantage are not necessarily connected, if relative deficiency of vitamin D is the mediating biological factor. CONCLUSION: The poor health and average early death of the socio-economically disadvantaged in the UK, together with the widening social gap of health, can be explained by relative deficiency of vitamin D. At present there is no explanation and attempts by government to close the social gap have failed. The understanding presented gives an important opportunity to improve the health disadvantages of the socio-economically disadvantaged. PMID- 21816810 TI - A sticky situation. PMID- 21816812 TI - Letter to the Editor regarding the article 'The effect of applying NICE guidelines for the investigation of stable chest pain on out-patient cardiac services in the UK'. PMID- 21816813 TI - Pneumatosis cystoides intestinalis in dermatomyositis. PMID- 21816811 TI - Update on anti-coagulation in atrial fibrillation. AB - Atrial fibrillation (AF), the most common clinically relevant arrhythmia, affects 2.2 million individuals in the USA and 4.5 million in Europe, resulting in significant morbidity and mortality. Pharmacotherapy aimed at controlling both heart rate and rhythm is employed to relieve AF symptoms, though debate continues about which approach is preferable. AF prevalence rises with age from 0.4% to 1% in the general population to 11% in those aged >70 years. AF is associated with a pro-thrombotic state and other comorbidities; age, hypertension, heart failure and diabetes mellitus all play a key role in AF pathogenesis. Anti-coagulation is essential for stroke prevention in patients with AF and is recommended for patients with one or more risk factors for stroke. Used within the recommended therapeutic range, warfarin and other vitamin K antagonists decrease the incidence of stroke and mortality in AF patients. Warfarin remains under-used, however, because of the perceived high risk of haemorrhage, narrow therapeutic window and need for regular monitoring. Several novel anti-coagulants show promise in AF-related stroke prevention. In particular, the novel, oral, direct thrombin inhibitor, dabigatran etexilate, recently licensed by the US Food and Drug Administration (FDA) and Health Canada has shown improved efficacy and safety compared with warfarin for stroke prevention in AF, and has the potential to replace warfarin in this indication. The increasing number of new therapeutic options, including improved anti-arrhythmic agents, novel anti-coagulants and more accessible ablation techniques, are likely to deliver better care for AF patients in the near future. PMID- 21816814 TI - Whorton MD, Culver D, Sullivan FM, Wong O. Editorial Commentary regarding X:Y Sperm Ratio in Boron Exposed Men, by Robbins et al, 2008 [published online ahead of print December 30, 2010; retracted by Editors June 30, 2011]. J Androl. DOI:10.2164/jandrol.108.005082. Retraction. PMID- 21816815 TI - Disruption of IkappaB kinase (IKK)-mediated RelA serine 536 phosphorylation sensitizes human multiple myeloma cells to histone deacetylase (HDAC) inhibitors. AB - Post-translational modifications of RelA play an important role in regulation of NF-kappaB activation. We previously demonstrated that in malignant hematopoietic cells, histone deacetylase inhibitors (HDACIs) induced RelA hyperacetylation and NF-kappaB activation, attenuating lethality. We now present evidence that IkappaB kinase (IKK) beta-mediated RelA Ser-536 phosphorylation plays a significant functional role in promoting RelA acetylation, inducing NF-kappaB activation, and limiting HDACI lethality in human multiple myeloma (MM) cells. Immunoblot profiling revealed that although basal RelA phosphorylation varied in MM cells, Ser-536 phosphorylation correlated with IKK activity. Exposure to the pan-HDACIs vorinostat or LBH-589 induced phosphorylation of IKKalpha/beta (Ser-180/Ser-181) and RelA (Ser-536) in MM cells, including cells expressing an IkappaBalpha "super repressor," accompanied by increased RelA nuclear translocation, acetylation, DNA binding, and transactivation activity. These events were substantially blocked by either pan-IKK or IKKbeta-selective inhibitors, resulting in marked apoptosis. Consistent with these events, inhibitory peptides targeting either the NF-kappaB essential modulator (NEMO) binding domain for IKK complex formation or RelA phosphorylation sites also significantly increased HDACI lethality. Moreover, IKKbeta knockdown by shRNA prevented Ser-536 phosphorylation and significantly enhanced HDACI susceptibility. Finally, introduction of a nonphosphorylatable RelA mutant S536A, which failed to undergo acetylation in response to HDACIs, impaired NF-kappaB activation and increased cell death. These findings indicate that HDACIs induce Ser-536 phosphorylation of the NF-kappaB subunit RelA through an IKKbeta-dependent mechanism, an action that is functionally involved in activation of the cytoprotective NF-kappaB signaling cascade primarily through facilitation of RelA acetylation rather than nuclear translocation. PMID- 21816816 TI - Caspase-8-mediated cleavage inhibits IRF-3 protein by facilitating its proteasome mediated degradation. AB - Interferon regulatory factor 3 (IRF-3) plays a central role in inducing the expression of cellular antiviral genes, including the interferon-beta gene, in response to Pattern Recognition Receptors. IRF-3 is targeted for proteasome mediated degradation, which modulates the strength and duration of the innate immune responses that depend on it. We have found that caspase-8, which is activated by cytosolic RIG-I-dependent signaling, catalyzes an essential intermediate step in the ubiquitination and proteasome-mediated degradation of IRF-3. Mutation of a consensus cleavage site within IRF-3 generates a form that is not cleaved by caspase-8 and that is protected from ubiquitination and degradation. An in vitro assay confirms the direct action of caspase-8 cleavage on IRF-3. We also show that caspase-8-mediated cleavage of IRF-3 helps to modulate dsRNA-dependent gene induction. PMID- 21816817 TI - Functional role of two interhelical disulfide bonds in human Cox17 protein from a structural perspective. AB - Human Cox17 is the mitochondrial copper chaperone responsible for supplying copper ions, through the assistance of Sco1, Sco2, and Cox11, to cytochrome c oxidase, the terminal enzyme of the mitochondrial energy-transducing respiratory chain. It consists of a coiled coil-helix-coiled coil-helix domain stabilized by two disulfide bonds and binds one copper(I) ion through a Cys-Cys motif. Here, the structures and the backbone mobilities of two Cox17 mutated forms with only one interhelical disulfide bond have been analyzed. It appears that the inner disulfide bond (formed by Cys-36 and Cys-45) stabilizes interhelical hydrophobic interactions, providing a structure with essentially the same structural dynamic properties of the mature Cox17 state. On the contrary, the external disulfide bond (formed by Cys-26 and Cys-55) generates a conformationally flexible alpha helical protein, indicating that it is not able to stabilize interhelical packing contacts, but is important for structurally organizing the copper-binding site region. PMID- 21816819 TI - Insights into the molecular activation mechanism of the RhoA-specific guanine nucleotide exchange factor, PDZRhoGEF. AB - PDZRhoGEF (PRG) belongs to a small family of RhoA-specific nucleotide exchange factors that mediates signaling through select G-protein-coupled receptors via Galpha(12/13) and activates RhoA by catalyzing the exchange of GDP to GTP. PRG is a multidomain protein composed of PDZ, regulators of G-protein signaling-like (RGSL), Dbl-homology (DH), and pleckstrin-homology (PH) domains. It is autoinhibited in cytosol and is believed to undergo a conformational rearrangement and translocation to the membrane for full activation, although the molecular details of the regulation mechanism are not clear. It has been shown recently that the main autoregulatory elements of PDZRhoGEF, the autoinhibitory "activation box" and the "GEF switch," which is required for full activation, are located directly upstream of the catalytic DH domain and its RhoA binding surface, emphasizing the functional role of the RGSL-DH linker. Here, using a combination of biophysical and biochemical methods, we show that the mechanism of PRG regulation is yet more complex and may involve an additional autoinhibitory element in the form of a molten globule region within the linker between RGSL and DH domains. We propose a novel, two-tier model of autoinhibition where the activation box and the molten globule region act synergistically to impair the ability of RhoA to bind to the catalytic DH-PH tandem. The molten globule region and the activation box become less ordered in the PRG-RhoA complex and dissociate from the RhoA-binding site, which may constitute a critical step leading to PRG activation. PMID- 21816818 TI - Human Mre11/human Rad50/Nbs1 and DNA ligase IIIalpha/XRCC1 protein complexes act together in an alternative nonhomologous end joining pathway. AB - Recent studies have implicated a poorly defined alternative pathway of nonhomologous end joining (alt-NHEJ) in the generation of large deletions and chromosomal translocations that are frequently observed in cancer cells. Here, we describe an interaction between two factors, hMre11/hRad50/Nbs1 (MRN) and DNA ligase IIIalpha/XRCC1, that have been linked with alt-NHEJ. Expression of DNA ligase IIIalpha and the association between MRN and DNA ligase IIIalpha/XRCC1 are altered in cell lines defective in the major NHEJ pathway. Most notably, DNA damage induced the association of these factors in DNA ligase IV-deficient cells. MRN interacts with DNA ligase IIIalpha/XRCC1, stimulating intermolecular ligation, and together these proteins join incompatible DNA ends in a reaction that mimics alt-NHEJ. Thus, our results provide novel mechanistic insights into the alt-NHEJ pathway that not only contributes to genome instability in cancer cells but may also be a therapeutic target. PMID- 21816820 TI - Structures and oxygen affinities of crystalline human hemoglobin C (beta6 Glu >Lys) in the R and R2 quaternary structures. AB - Recent crystallographic studies suggested that fully liganded human hemoglobin can adopt multiple quaternary conformations that include the two previously solved relaxed conformations, R and R2, whereas fully unliganded deoxyhemoglobin may adopt only one T (tense) quaternary conformation. An important unanswered question is whether R, R2, and other relaxed quaternary conformations represent different physiological states with different oxygen affinities. Here, we answer this question by showing the oxygen equilibrium curves of single crystals of human hemoglobin in the R and R2 state. In this study, we have used a naturally occurring mutant hemoglobin C (beta6 Glu->Lys) to stabilize the R and R2 crystals. Additionally, we have refined the x-ray crystal structure of carbonmonoxyhemoglobin C, in the R and R2 state, to 1.4 and 1.8 A resolution, respectively, to compare precisely the structures of both types of relaxed states. Despite the large quaternary structural difference between the R and R2 state, both crystals exhibit similar noncooperative oxygen equilibrium curves with a very high affinity for oxygen, comparable with the fourth oxygen equilibrium constant (K(4)) of human hemoglobin in solution. One small difference is that the R2 crystals have an oxygen affinity that is 2-3 times higher than that of the R crystals. These results demonstrate that the functional difference between the two typical relaxed quaternary conformations is small and physiologically less important, indicating that these relaxed conformations simply reflect a structural polymorphism of a high affinity relaxed state. PMID- 21816821 TI - Role of net charge on catalytic domain and influence of cell wall binding domain on bactericidal activity, specificity, and host range of phage lysins. AB - The recombinant lysins of lytic phages, when applied externally to Gram-positive bacteria, can be efficient bactericidal agents, typically retaining high specificity. Their development as novel antibacterial agents offers many potential advantages over conventional antibiotics. Protein engineering could exploit this potential further by generating novel lysins fit for distinct target populations and environments. However, access to the peptidoglycan layer is controlled by a variety of secondary cell wall polymers, chemical modifications, and (in some cases) S-layers and capsules. Classical lysins require a cell wall binding domain (CBD) that targets the catalytic domain to the peptidoglycan layer via binding to a secondary cell wall polymer component. The cell walls of Gram positive bacteria generally have a negative charge, and we noticed a correlation between (positive) charge on the catalytic domain and bacteriolytic activity in the absence of the CBD (nonclassical behavior). We investigated a physical basis for this correlation by comparing the structures and activities of pairs of lysins where the lytic activity of one of each pair was CBD-independent. We found that by engineering a reversal of sign of the net charge of the catalytic domain, we could either eliminate or create CBD dependence. We also provide evidence that the S-layer of Bacillus anthracis acts as a molecular sieve that is chiefly size dependent, favoring catalytic domains over full-length lysins. Our work suggests a number of facile approaches for fine-tuning lysin activity, either to enhance or reduce specificity/host range and/or bactericidal potential, as required. PMID- 21816822 TI - Structures of Cryptococcus neoformans protein farnesyltransferase reveal strategies for developing inhibitors that target fungal pathogens. AB - Cryptococcus neoformans is a fungal pathogen that causes life-threatening infections in immunocompromised individuals, including AIDS patients and transplant recipients. Few antifungals can treat C. neoformans infections, and drug resistance is increasing. Protein farnesyltransferase (FTase) catalyzes post translational lipidation of key signal transduction proteins and is essential in C. neoformans. We present a multidisciplinary study validating C. neoformans FTase (CnFTase) as a drug target, showing that several anticancer FTase inhibitors with disparate scaffolds can inhibit C. neoformans and suggesting structure-based strategies for further optimization of these leads. Structural studies are an essential element for species-specific inhibitor development strategies by revealing similarities and differences between pathogen and host orthologs that can be exploited. We, therefore, present eight crystal structures of CnFTase that define the enzymatic reaction cycle, basis of ligand selection, and structurally divergent regions of the active site. Crystal structures of clinically important anticancer FTase inhibitors in complex with CnFTase reveal opportunities for optimization of selectivity for the fungal enzyme by modifying functional groups that interact with structurally diverse regions. A substrate induced conformational change in CnFTase is observed as part of the reaction cycle, a feature that is mechanistically distinct from human FTase. Our combined structural and functional studies provide a framework for developing FTase inhibitors to treat invasive fungal infections. PMID- 21816824 TI - Translocation of the Drosophila transient receptor potential-like (TRPL) channel requires both the N- and C-terminal regions together with sustained Ca2+ entry. AB - In Drosophila photoreceptors the transient receptor potential-like (TRPL), but not the TRP channels undergo light-dependent translocation between the rhabdomere and cell body. Here we studied which of the TRPL channel segments are essential for translocation and why the TRP channels are required for inducing TRPL translocation. We generated transgenic flies expressing chimeric TRP and TRPL proteins that formed functional light-activated channels. Translocation was induced only in chimera containing both the N- and C-terminal segments of TRPL. Using an inactive trp mutation and overexpressing the Na(+)/Ca(2+) exchanger revealed that the essential function of the TRP channels in TRPL translocation is to enhance Ca(2+)-influx. These results indicate that motifs present at both the N and C termini as well as sustained Ca(2+) entry are required for proper channel translocation. PMID- 21816823 TI - Deregulation of microRNAs by HIV-1 Vpr protein leads to the development of neurocognitive disorders. AB - Studies have shown that HIV-infected patients develop neurocognitive disorders characterized by neuronal dysfunction. The lack of productive infection of neurons by HIV suggests that viral and cellular proteins, with neurotoxic activities, released from HIV-1-infected target cells can cause this neuronal deregulation. The viral protein R (Vpr), a protein encoded by HIV-1, has been shown to alter the expression of various important cytokines and inflammatory proteins in infected and uninfected cells; however the mechanisms involved remain unclear. Using a human neuronal cell line, we found that Vpr can be taken up by neurons causing: (i) deregulation of calcium homeostasis, (ii) endoplasmic reticulum-calcium release, (iii) activation of the oxidative stress pathway, (iv) mitochondrial dysfunction and v- synaptic retraction. In search for the cellular factors involved, we performed microRNAs and gene array assays using human neurons (primary cultures or cell line, SH-SY5Y) that we treated with recombinant Vpr proteins. Interestingly, Vpr deregulates the levels of several microRNAs (e.g. miR-34a) and their target genes (e.g. CREB), which could lead to neuronal dysfunctions. Therefore, we conclude that Vpr plays a major role in neuronal dysfunction through deregulating microRNAs and their target genes, a phenomenon that could lead to the development of neurocognitive disorders. PMID- 21816825 TI - Maturation of thyroglobulin protein region I. AB - In vertebrates, the thyroglobulin (Tg) gene product must be exported to the lumen of thyroid follicles for thyroid hormone synthesis. In toto, Tg is composed of multiple type-1 repeats connected by linker and hinge (altogether considered as "region I," nearly 1,200 residues); regions II-III (~720 residues); and cholinesterase-like (ChEL) domain (~570 residues). Regions II-III and ChEL rapidly acquire competence for secretion, yet regions I-II-III require 20 min to become a partially mature disulfide isomer; stabilization of a fully oxidized form requires ChEL. Transition from partially mature to mature Tg occurs as a discrete "jump" in mobility by nonreducing SDS-PAGE, suggesting formation of at most a few final pairings of Cys residues that may be separated by significant intervening primary sequence. Using two independent approaches, we have investigated which portion of Tg is engaged in this late stage of its maturation. First, we demonstrate that this event is linked to oxidation involving region I. Introduction of the Tg-C1245R mutation in the hinge (identical to that causing human goitrous hypothyroidism) inhibits this maturation, although the Cys-1245 partner remains unidentified. Second, we find that Tg truncated after its fourth type-1 repeat is a fully independent secretory protein. Together, the data indicate that final acquisition of secretory competence includes conformational maturation in the interval between linker and hinge segments of region I. PMID- 21816827 TI - Biochemical impact of the host adaptation-associated PB2 E627K mutation on the temperature-dependent RNA synthesis kinetics of influenza A virus polymerase complex. AB - Most avian influenza A viruses, which preferentially replicate at the high temperatures found in the digestive tract of birds, have a glutamic acid at residue 627 of the viral RNA polymerase PB2 subunit (Glu-627), whereas the human viruses, which optimally replicate at the low temperatures observed in the human respiratory tract, have a lysine (Lys-627). The mechanism of action for this mutation is still not understood, although interaction with host factors has been proposed to play a major role. In this study, we explored an alternative, yet related, hypothesis that this PB2 mutation may alter the temperature-dependent enzymatic polymerase activity of the viral polymerase. First, the avian polymerase protein, which was purified from baculovirus expression system, indeed remained significantly active at higher temperatures (i.e. 37 and 42 degrees C), whereas the human E627K mutant drastically lost activity at these high temperatures. Second, our steady-state kinetics data revealed that the human E627K mutant polymerase is catalytically more active than the avian Glu-627 polymerase at 34 degrees C. Importantly, the E627K mutation elevates apparent K(cat) at low temperatures with little effect on K(m), suggesting that the E627K mutation alters the biochemical steps involved in enzyme catalysis rather than the interaction with the incoming NTP. Third, this temperature-dependent kinetic impact of the human E627K mutation was also observed with different RNA templates, with different primers and also in the presence of nucleoprotein. In conclusion, our study suggests that the amino acid sequence variations at residue 627 of PB2 subunit can directly alter the enzyme kinetics of influenza polymerase. PMID- 21816828 TI - Prevalence, characteristics, and risk factors of elevated triglyceride levels in US children. AB - Limited information is available on the epidemiology of hypertriglyceridemia (HTG; 150-499 mg/dL) and severe HTG (SHTG; >500 mg/dL) in children. This study estimates the prevalence of HTG and SHTG, evaluates factors that may be associated with these conditions, and describes the use of dyslipidemic agents in children. The sample included children 12 to 19 years old who participated in National Health and Nutrition Examination Survey (NHANES) 2001-2008 (n = 3248) and children 5 to 19 years of age who were part of a large managed-care claims database in the United States (n = 65 258). Results from NHANES confirm the rarity of SHTG in the US pediatric population (ie, 0.2%). Factors statistically significantly associated with having HTG or SHTG in the claims database were being male, 12 to 19 years old, having high low-density lipoprotein (LDL), having low high-density lipoprotein (HDL), diabetes, and psychological disorders. Fibrates were the most commonly prescribed triglyceride-lowering agent among children with SHTG, followed by statins and Lovaza. PMID- 21816826 TI - New insights into the mechanism of odorant detection by the malaria-transmitting mosquito Anopheles gambiae. AB - Anopheles gambiae mosquitoes that transmit Plasmodium falciparum malaria use a series of olfactory cues present in human sweat to locate their hosts for a blood meal. Recognition of these odor cues occurs through the interplay of odorant receptors and odorant-binding proteins (OBPs) that bind to odorant molecules and transport and present them to the receptors. Recent studies have implicated potential heterodimeric interactions between two OBPs, OBP1 and OBP4, as important for perception of indole by the mosquito (Biessmann, H., Andronopoulou, E., Biessmann, M. R., Douris, V., Dimitratos, S. D., Eliopoulos, E., Guerin, P. M., Iatrou, K., Justice, R. W., Krober, T., Marinotti, O., Tsitoura, P., Woods, D. F., and Walter, M. F. (2010) PLoS ONE 5, e9471; Qiao, H., He, X., Schymura, D., Ban, L., Field, L., Dani, F. R., Michelucci, E., Caputo, B., della Torre, A., Iatrou, K., Zhou, J. J., Krieger, J., and Pelosi, P. (2011) Cell. Mol. Life Sci. 68, 1799-1813). Here we present the 2.0 A crystal structure of the OBP4-indole complex, which adopts a classical odorant-binding protein fold, with indole bound at one end of a central hydrophobic cavity. Solution-based NMR studies reveal that OBP4 exists in a molten globule state and binding of indole induces a dramatic conformational shift to a well ordered structure, and this leads to the formation of the binding site for OBP1. Analysis of the OBP4-OBP1 interaction reveals a network of contacts between residues in the OBP1 binding site and the core of the protein and suggests how the interaction of the two proteins can alter the binding affinity for ligands. These studies provide evidence that conformational ordering plays a key role in regulating heteromeric interactions between OBPs. PMID- 21816829 TI - Complex regulation of human NKG2D-DAP10 cell surface expression: opposing roles of the gammac cytokines and TGF-beta1. AB - Natural killer (NK) cells help protect the host against viral infections and tumors. NKG2D is a vital activating receptor, also expressed on subsets of T cells, whose ligands are up-regulated by cells in stress. Ligation of NKG2D leads to phosphorylation of the associated DAP10 adaptor protein, thereby activating immune cells. Understanding how the expression of NKG2D-DAP10 is regulated has implications for immunotherapy. We show that IL-2 and TGF-beta1 oppositely regulate NKG2D-DAP10 expression by NK cells. IL-2 stimulation increases NKG2D surface expression despite a decrease in NKG2D mRNA levels. Stimulation with IL-2 results in a small increase of DAP10 mRNA and a large up-regulation of DAP10 protein synthesis, indicating that IL-2-mediated effects are mostly posttranscriptional. Newly synthesized DAP10 undergoes glycosylation that is required for DAP10 association with NKG2D and stabilization of NKG2D expression. TGF-beta1 has an opposite and dominant effect to IL-2. TGF-beta1 treatment decreases DAP10, as its presence inhibits the association of RNA polymerase II with the DAP10 promoter, but not NKG2D mRNA levels. This leads to the down regulation of DAP10 expression and, as a consequence, NKG2D protein as well. Finally, we show that other gamma(c) cytokines act similarly to IL-2 in up regulating DAP10 expression and NKG2D-DAP10 surface expression. PMID- 21816830 TI - BeEAM (bendamustine, etoposide, cytarabine, melphalan) before autologous stem cell transplantation is safe and effective for resistant/relapsed lymphoma patients. AB - We designed a phase 1-2 study to evaluate the safety and the efficacy of increasing doses of bendamustine (160 mg/m2, 180 mg/m2, and 200 mg/m2 given on days -7 and -6) coupled with fixed doses of etoposide, cytarabine, and melphalan (BeEAM regimen) as the conditioning regimen to autologous stem cell transplantation for resistant/relapsed lymphoma patients. Forty-three patients (median age, 47 years) with non-Hodgkin (n = 28) or Hodgkin (n = 15) lymphoma were consecutively treated. Nine patients entered the phase 1 study; no patients experienced a dose-limiting toxicity. Thirty-four additional patients were then treated in the phase 2. A median number of 6 * 106 CD34(+) cells/kg (range, 2.4 15.5) were reinfused. All patients engrafted, with a median time to absolute neutrophil count > 0.5 * 109/L of 10 days. The 100-day transplantation-related mortality was 0%. After a median follow-up of 18 months, 35 of 43 patients (81%) are in complete remission, whereas 6 of 43 relapsed and 2 of 43 did not respond. Disease type (non-Hodgkin lymphomas vs Hodgkin disease) and disease status at transplantation (chemosensitive vs chemoresistant) significantly influenced DFS (P = .01; P = .007). Remarkably, 4 of 43 (9%) patients achieved the first complete remission after receiving the high-dose therapy with autologous stem cell transplantation. In conclusion, the new BeEAM regimen is safe and effective for heavily pretreated lymphoma patients. The study was registered at European Medicines Agency (EudraCT number 2008-002736-15). PMID- 21816831 TI - Shiga toxin (Stx)1B and Stx2B induce von Willebrand factor secretion from human umbilical vein endothelial cells through different signaling pathways. AB - Diarrhea-associated hemolytic uremic syndrome (D(+)HUS) is caused by the ingestion of Escherichia coli that produce Shiga toxin (Stx), which is composed of a cytotoxic A subunit and pentameric B subunits that bind globotriaosylceramide on susceptible cells. Stx occurs in 2 types, Stx1 and Stx2. B subunits of either type stimulate von Willebrand factor (VWF) secretion from human umbilical vein endothelial cells (HUVECs), and Stx2B can cause thrombotic microangiopathy in Adamts13(-/-) mice. We have now determined that Stx1B and Stx2B activate different signaling pathways in HUVECs. VWF secretion induced by Stx1B is associated with a transient rise in intracellular Ca(2+) level that is blocked by chelation with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester, removal of extracellular Ca(2+), the phospholipase C inhibitor U73122, the protein kinase inhibitor staurosporine, or small interfering RNA knockdown of protein kinase Calpha. In contrast, Stx2B-induced VWF secretion is associated with activation of protein kinase A (PKA) and is blocked by the PKA inhibitor H89 or small interfering RNA knockdown of PKA. Stx2B does not increase cAMP levels and may activate PKA by a cAMP-independent mechanism. The activation of distinct signaling pathways may be relevant to understanding why E coli that express Stx2 are more likely to cause D(+)HUS than are E coli expressing only Stx1. PMID- 21816832 TI - Successful allogeneic hematopoietic stem cell transplantation for GATA2 deficiency. AB - We performed nonmyeloablative HSCT in 6 patients with a newly described genetic immunodeficiency syndrome caused by mutations in GATA2-a disease characterized by nontuberculous mycobacterial infection, monocytopenia, B- and NK-cell deficiency, and the propensity to transform to myelodysplastic syndrome/acute myelogenous leukemia. Two patients received peripheral blood stem cells (PBSCs) from matched related donors, 2 received PBSCs from matched-unrelated donors, and 2 received stem cells from umbilical cord blood (UCB) donors. Recipients of matched-related and -unrelated donors received fludarabine and 200 cGy of total body irradiation (TBI); UCB recipients received cyclophosphamide in addition to fludarabine and TBI as conditioning. All patients received tacrolimus and sirolimus posttransplantation. Five patients were alive at a median follow-up of 17.4 months (range, 10-25). All patients achieved high levels of donor engraftment in the hematopoietic compartments that were deficient pretransplantation. Adverse events consisted of delayed engraftment in the recipient of a single UCB, GVHD in 4 patients, and immune-mediated pancytopenia and nephrotic syndrome in the recipient of a double UCB transplantation. Nonmyeloablative HSCT in GATA2 deficiency results in reconstitution of the severely deficient monocyte, B-cell, and NK-cell populations and reversal of the clinical phenotype. Registered at www.clinicaltrials.gov as NCT00923364. PMID- 21816833 TI - B-cell receptor signaling in chronic lymphocytic leukemia. AB - The B-cell receptor (BCR) is a key survival molecule for normal B cells and for most B-cell malignancies. Recombinatorial and mutational patterns in the clonal immunoglobulin (Ig) of chronic lymphocytic leukemia (CLL) have revealed 2 major IgMD-expressing subsets and an isotype-switched variant, each developing from distinct B-cell populations. Tracking of conserved stereotypic features of Ig variable regions characteristic of U-CLL indicate circulating naive B cells as the likely cells of origin. In CLL, engagement of the BCR by antigen occurs in vivo, leading to down-regulated expression and to an unanticipated modulation of glycosylation of surface IgM, visible in blood cells, especially in U-CLL. Modulated glycoforms of sIgM are signal competent and could bind to environmental lectins. U-CLL cases express more sIgM and have increased signal competence, linking differential signaling responses to clinical behavior. Mapping of BCR signaling pathways identifies targets for blockade, aimed to deprive CLL cells of survival and proliferative signals. New inhibitors of BCR signaling appear to have clinical activity. In this Perspective, we discuss the functional significance of the BCR in CLL, and we describe strategies to target BCR signaling as an emerging therapeutic approach. PMID- 21816834 TI - Occlusive thrombi arise in mammals but not birds in response to arterial injury: evolutionary insight into human cardiovascular disease. AB - Mammalian platelets are small, anuclear circulating cells that form tightly adherent, shear-resistant thrombi to prevent blood loss after vessel injury. Platelet thrombi that form in coronary and carotid arteries also underlie common vascular diseases such as myocardial infarction and stroke and are the target of drugs used to treat these diseases. Birds have high-pressure cardiovascular systems like mammals but generate nucleated thrombocytes rather than platelets. Here, we show that avian thrombocytes respond to many of the same activating stimuli as mammalian platelets but are unable to form shear-resistant aggregates ex vivo. Avian thrombocytes are larger than mammalian platelets, spread less efficiently on collagen, and express much lower levels of the alpha(2b)beta3 integrin required for aggregate formation, features predicted to make thrombocyte aggregates less resistant than platelets are to the high fluid shear forces of the arterial vasculature. In vivo carotid vessel injury stimulates the formation of occlusive platelet thrombi in mice but not in the size- and flow-matched carotid artery of the Australian budgerigar. These studies indicate that unique physical and molecular features of mammalian platelets enable them to form shear resistant arterial thrombi, an essential element in the pathogenesis of human cardiovascular diseases. PMID- 21816836 TI - ED in APL: tip of the iceberg? PMID- 21816835 TI - Now you know your ABCs. PMID- 21816837 TI - Susceptibility to childhood leukemia. PMID- 21816838 TI - Platelet granules: surprise packages. PMID- 21816839 TI - c-Maf rules the island. PMID- 21816840 TI - CMV: when bad viruses turn good. PMID- 21816841 TI - Survivors after blood wars. PMID- 21816842 TI - Cambial activity related to tree size in a mature silver-fir plantation. AB - BACKGROUND AND AIMS: Our knowledge about the influences of environmental factors on tree growth is principally based on the study of dominant trees. However, tree social status may influence intra-annual dynamics of growth, leading to differential responses to environmental conditions. The aim was to determine whether within-stand differences in stem diameters of trees belonging to different crown classes resulted from variations in the length of the growing period or in the rate of cell production. METHODS: Cambial activity was monitored weekly in 2006 for three crown classes in a 40-year-old silver-fir (Abies alba) plantation near Nancy (France). Timings, duration and rate of tracheid production were assessed from anatomical observations of the developing xylem. KEY RESULTS: Cambial activity started earlier, stopped later and lasted longer in dominant trees than in intermediate and suppressed ones. The onset of cambial activity was estimated to have taken 3 weeks to spread to 90 % of the trees in the stand, while the cessation needed 6 weeks. Cambial activity was more intense in dominant trees than in intermediate and suppressed ones. It was estimated that about 75 % of tree-ring width variability was attributable to the rate of cell production and only 25 % to its duration. Moreover, growth duration was correlated to tree height, while growth rate was better correlated to crown area. CONCLUSIONS: These results show that, in a closed conifer forest, stem diameter variations resulted principally from differences in the rate of xylem cell production rather than in its duration. Tree size interacts with environmental factors to control the timings, duration and rate of cambial activity through functional processes involving source-sink relationships principally, but also hormonal controls. PMID- 21816843 TI - Cardiovascular risk markers and mechanisms in targeting the COX pathway for colorectal cancer prevention. AB - COX-2 inhibition reduces the incidence of colorectal neoplasia. The increased risk of thrombotic cardiovascular events produced by selective or nonselective COX-2 inhibitors, however, has confounded the consideration of employing them in cancer prevention. Developing a strategy for preventing colorectal cancer by inhibiting COX-2 depends on research advances in several key areas, including predictive biomarkers to identify people at the lowest risk for cardiovascular events, the molecular mechanisms whereby interdicting the COX-2 pathway produces thrombotic events, and the pharmacology of the widely divergent agents that act on COX-2 and its downstream pathway. PMID- 21816844 TI - Targeting the HER/EGFR/ErbB family to prevent breast cancer. AB - Preventing breast cancer is possible with selective estrogen receptor (ER) modulators and aromatase inhibitors, which reduce the risk of invasive disease by up to 65% (up to 73% for ER-positive and no effect for ER-negative cancer) and the risk of preinvasive disease [ductal carcinoma in situ (DCIS)] by up to 50%. Clearly, approaches for preventing ER-negative, and increased prevention of ER positive breast cancers would benefit public health. A growing body of work (including recent preclinical and clinical data) support targeting the HER family [epidermal growth factor receptor (EGFR), or human epidermal growth factor receptor (HER) 1 or ErbB1) and HER2, HER3, and HER4] for preventing ER-negative and possibly ER-positive breast cancer. Preclinical studies of HER family targeting drugs in mammary neoplasia show suppression of (i) ER-negative tumors in HER2-overexpressing mouse strains, (ii) ER-negative tumors in mutant Brca1/p53(+/-) mice, and (iii) ER-positive tumors in the methylnitrosourea (MNU) rat model; tumors arising in both the MNU and mutant Brca1/p53(+/-) models lack HER2 overexpression. Clinical trials include a recent placebo-controlled phase IIb presurgical trial of the dual EGFR HER2 inhibitor lapatinib that suppressed growth of breast premalignancy [including atypical ductal hyperplasia (ADH) and DCIS] and invasive cancer in patients with early-stage, HER2-overexpressing or amplified breast cancer. These results suggest that lapatinib can clinically suppress the progression of ADH and DCIS to invasive breast cancer, an effect previously observed in a mouse model of HER2-overexpressing, ER-negative mammary cancer. The preclinical and clinical signals provide a compelling rationale for testing HER-targeting drugs for breast cancer prevention in women at moderate-to high risk, leading perhaps to combinations that prevent ER-negative and ER positive breast cancer. PMID- 21816845 TI - C-reactive protein and risk of colorectal adenoma according to celecoxib treatment. AB - Inflammation, as measured by the circulating inflammatory marker high-sensitivity C-reactive protein (hsCRP), has been associated with cardiovascular disease. However, data about CRP and risk of colorectal cancer have been conflicting. The Adenoma Prevention with Celecoxib (APC) trial showed that the anti-inflammatory drug celecoxib prevents recurrence of colorectal adenoma but increases risk of cardiovascular events. We examined whether serum hsCRP modified these results. We measured hsCRP from serum specimens provided at study entry by patients enrolled in the APC trial. Patients were stratified according to use of low-dose aspirin, randomized to receive 3 years of treatment with placebo, 200-mg-bid celecoxib, or 400-mg-bid celecoxib, and underwent follow-up colonoscopies at years 1 and 3. Among 1,680 patients, the estimated 3-year cumulative incidence of adenoma was 42% for patients with hsCRP <1 mg/L, compared with 43% [relative risk (RR) = 1.02; 95% CI = 0.85-1.22] for hsCRP 1-3 mg/L, and 41% (RR = 1.10; 95% CI = 0.90 1.34) for hsCRP >3 mg/L. The effect of celecoxib on adenoma recurrence did not vary among patients with high (>3 mg/L) compared with low (<=3 mg/L) hsCRP. However, among patients with high hsCRP, the RR of cardiovascular events compared with placebo was 2.27 (95% CI = 0.72-7.14) for those randomized to celecoxib 200 mg-bid and 3.28 (95% CI = 1.09-9.91) for 400-mg-bid. In contrast, among patients with low hsCRP, the corresponding RRs were 0.99 (95% CI = 0.53-1.83) and 1.11 (95% CI = 0.61-2.02). hsCRP may predict risk of celecoxib-associated cardiovascular toxicity but not adenoma recurrence or celecoxib treatment efficacy. Patients with low hsCRP may be a subgroup with a favorable risk-benefit profile for celecoxib chemoprevention. PMID- 21816846 TI - Intracytoplasmic sperm injection with mouse spermatozoa preserved without freezing for six months can lead to full-term development. AB - Preservation of mammalian spermatozoa now plays an important role in fertility treatment, in generating hybrid animals, and in protecting endangered or extinct species. To date, the most common method of sperm preservation is freezing in liquid nitrogen (LN(2)). However, this method requires constant supplementation of the LN(2) and also involves some safety issues in transporting LN(2). Here we describe a new sperm preservation method that does not involve freezing. Mouse spermatozoa were cultured in four basic media (HEPES-CZB, potassium simplex optimization medium with amino acids [KSOMaa], K(+)-rich nuclear isolation medium [NIM], and PBS) with or without 10% bovine serum albumin (BSA) or 15% Ficoll as a protectant, and preserved in a refrigerator for up to 6 mo. These preserved sperm were then injected into fresh oocytes and cultured to the blastocyst stage in vitro or transferred into recipient females to demonstrate their genetic integrity. The results of sperm preservation for 1 mo suggested that NIM and PBS were better media than HEPES-CZB or KSOMaa and that BSA and Ficoll could improve either blastocyst or full-term development. Surprisingly, 18 pups were obtained using spermatozoa stored in these media for 6 mo. Moreover, this new method allowed easy production of healthy offspring even after transport of spermatozoa between two countries by aircraft at room temperature. In conclusion, this method allows for easy long-term preservation of mouse spermatozoa in a simple, modified medium at refrigerator temperature with very low cost and wide application. PMID- 21816847 TI - Gap junction-mediated communications regulate chromatin remodeling during bovine oocyte growth and differentiation through cAMP-dependent mechanism(s). AB - Oocyte development is characterized by impressive changes in chromatin structure and function in the germinal vesicle (GV) that are crucial in conferring to the oocyte meiotic and developmental competence. During oogenesis, oocyte and follicular cells communicate by paracrine and junctional mechanisms. In cow, cumulus-enclosed oocytes (CEOs) isolated from early antral follicles have uncondensed chromatin (GV0), functionally open gap junction (GJ)-mediated communications, and limited meiotic competence. The aim of the present study was to analyze the role of GJ communications on the chromatin remodeling process during the specific phase of folliculogenesis that coincides with the transcriptional silencing and the sequential acquisition of meiotic and developmental capability. CEOs were cultured in a follicle-stimulating hormone based culture system that sustained GJ coupling and promoted oocyte growth and transition from GV0 to higher stages of condensation. When GJ functionality was experimentally interrupted, chromatin rapidly condensed, and RNA synthesis suddenly ceased. These effects were prevented by the addition of cilostamide, a phosphodiesterase 3 inhibitor, indicating that the action of GJ-mediated communication on chromatin structure and function is mediated by cAMP. Prolonging GJ coupling during oocyte culture before in vitro maturation enhanced the ability of early antral oocytes to undergo meiosis and early embryonic development. Altogether, the evidence suggests that GJ-mediated communication between germinal and somatic compartments plays a fundamental role in the regulation of chromatin remodeling and transcription, which in turn are related to competence acquisition. PMID- 21816848 TI - Seasonal androgen cycles in adult male American alligators (Alligator mississippiensis) from a barrier island population. AB - The seasonal patterns of two primary plasma androgens, testosterone (T) and dehydroepiandrosterone (DHEA), were assessed in adult male alligators from the Merritt Island National Wildlife Refuge, a unique barrier island environment and home to the Kennedy Space Center in Florida. Samples were collected monthly from 2008 to 2009, with additional samples collected at more random intervals in 2007 and 2010. Plasma T concentrations peaked in April, coincident with breeding and courtship, and declined rapidly throughout the summer. Seasonal plasma T patterns in smaller though reproductively active adult males differed from those in their larger counterparts during the breeding season. Both size classes showed significant increases in plasma T concentration from February to March, at the beginning of the breeding season. However, smaller adults did not experience the peak in plasma T concentrations in April that were observed in larger adults, and their concentrations were significantly lower than those of larger males for the remainder of the breeding season. Plasma DHEA concentrations peaked in May and were significantly reduced by June. This is the first study to demonstrate the presence of DHEA in a crocodilian, and the high plasma DHEA concentrations that paralleled the animals' reproductive activity suggest a reproductive and/or behavioral role in adult male alligators. Similar to androgen variations in some birds, plasma DHEA concentrations in the alligators were considerably higher than T concentrations during the nonbreeding season, suggesting a potential role in maintaining nonbreeding seasonal aggression. PMID- 21816849 TI - The proximal promoter region of the zebrafish gsdf gene is sufficient to mimic the spatio-temporal expression pattern of the endogenous gene in Sertoli and granulosa cells. AB - The gonadal soma-derived factor (GSDF) is a new member of the transforming growth factor beta (TGF-beta) superfamily that regulates the proliferation of the primordial germ cells (PGC) in developing embryos and spermatogonia in juvenile male trout. The gsdf transcripts are expressed in the somatic cells supporting germ cell development. In zebrafish, we show that GSDF is encoded by a single copy gene that generates polymorphic transcripts and proteins. We determined that gsdf gene expression occurs before gonadal differentiation and is restricted to the gonads. Gene expression is maintained in adult granulosa cells and Sertoli cells but decreases in the cells that are in contact with meiotic and postmeiotic germ cells. Using zebrafish transgenic lines, we demonstrate that the 2-kb proximal promoter region of the gsdf gene targets high levels of transgene expression in the Sertoli and granulosa cells, and is sufficient to mimic the temporal expression pattern of the endogenous gsdf gene from 16 days postfertilization onward. We identified within the first 500 bp evolutionarily conserved DNA motifs that may be involved in Sertoli and granulosa cell-specific expression. However, the 2-kb proximal promoter region failed to drive efficient expression of the transgene in the gonads in four transgenic medaka lines. We propose that the proximal promoter region can be used to target candidate gene deregulation in zebrafish granulosa and Sertoli cells. Furthermore, the green fluorescent protein-expressing zebrafish lines produced in the present study are new valuable models for cell lineage tracing during sex differentiation and gametogenesis. PMID- 21816850 TI - Spermatogonial stem cell self-renewal requires ETV5-mediated downstream activation of Brachyury in mice. AB - Insight regarding mechanisms controlling gene expression in the spermatogonial stem cell (SSC) will improve our understanding of the processes regulating spermatogenesis and aid in treating problems associated with male infertility. In the present study, we explored the global gene expression profiles of the glial cell line-derived neurotrophic factor (GDNF)-regulated transcription factors Ets (E-twenty-six) variant gene 5 (Etv5); B-cell chronic lymphocytic leukemia (CLL)/lymphoma 6, member B (Bcl6b); and POU domain, class-3 transcription factor 1 (Pou3f1). We reasoned that these three factors may function as a core set of transcription factors, regulating genes responsible for maintaining the SSC population. Using transient siRNA oligonucleotides to individually target Etv5, Bcl6b, and Pou3f1 within mouse SSC cultures, we examined changes to the global gene expression profiles associated with these transcription factors. Only modest overlaps in the target genes regulated by the three factors were noted, but ETV5 was found to be a critical downstream regulator of GDNF signaling that mediated the expression of several known SSC self-renewal related genes, including Bcl6b and LIM homeobox 1 (Lhx1). Notably, ETV5 was identified as a regulator of Brachyury (T) and CXC chemokine receptor, type 4 (Cxcr4), and we showed that ETV5 binding to the Brachyury (T) gene promoter region is associated with an active state of transcription. Moreover, in vivo transplantation of SSCs following silencing of Brachyury (T) significantly reduced the number of donor cell-derived colonies formed within recipient mouse testes. These results suggest Brachyury is of biological importance and functions as part of GDNF/ETV5 signaling to promote self-renewal of mouse SSCs cultured in vitro. PMID- 21816851 TI - Oxytocin increases invasive properties of endometrial cancer cells through phosphatidylinositol 3-kinase/AKT-dependent up-regulation of cyclooxygenase-1, 2, and X-linked inhibitor of apoptosis protein. AB - Traditionally, oxytocin (OT) is well known to play a crucial role in the regulation of cyclic changes in the uterus, implantation of the embryo, and parturition. Recently, an additional role for OT has been identified in several types of cancer cells in which OT acts as a growth regulator. In endometrial cancer cells, OT is known to efficiently inhibit cellular proliferation. In the present study, we show that OT increases invasiveness of human endometrial carcinoma (HEC) cells, which are otherwise resistant to the growth-inhibiting effects of OT. Using pharmacological inhibitors, invasion assay, RNA interference, and immunofluorescence, we found that OT enhances the invasive properties of HEC cells through up-regulation of X-linked inhibitor of apoptosis protein (XIAP), matrix-metalloproteinase 2 (MMP2), and matrix-metalloproteinase 14 (MMP14). In addition, we show that OT-mediated invasion is both cyclooxygenase 1 (PTGS1) and cyclooxygenase-2 (PTGS2) dependent via the phosphatidylinositol 3 kinase/AKT (PIK3/AKT) pathway. PTGS2 knockdown by shRNA resulted in XIAP down regulation. We also show that OT receptor is overexpressed in grade I to III endometrial cancer. Taken together, our results describe for the first time a novel role for OT in endometrial cancer cell invasion. PMID- 21816852 TI - Neurons of the lateral preoptic area/rostral anterior hypothalamic area are required for photoperiodic inhibition of estrous cyclicity in sheep. AB - Photoperiod determines the timing of reproductive activity in many species, yet the neural pathways whereby day length is transduced to a signal influencing gonadotropin-releasing hormone (GnRH) release are not fully understood. Physical lesions of the lateral preoptic area (lPOA)/rostral anterior hypothalamic area (rAHA) in female sheep extend the period of estrous cyclicity during inhibitory photoperiods. In the present study we sought to determine whether destroying only neurons and not fibers of passage in this area would lead to similar resistance to photosuppression. Additionally, neural tract-tracing was used to map connectivity between the lPOA/rAHA and other hypothalamic areas implicated in photoperiodic regulation of reproduction. Progesterone secretion was monitored in six sheep to determine estrous cycles for 90 days during a short-day (permissive) photoperiod. Three sheep then received bilateral injections of the excitotoxic glutamate analog, n-methyl-aspartic acid, directed toward the lPOA/rAHA, whereas three others served as controls. All were then exposed to a long-day (suppressive) photoperiod for 120 days. Control sheep ceased cycling at 40 +/- 10 days (mean +/- SEM), whereas lesioned sheep continued cycling through the end of the study. The results of the tract-tracing study revealed both afferent and efferent projections to the medial POA, retrochiasmatic area, arcuate nucleus, and premammillary region. Furthermore, close proximal associations with GnRH neurons from efferent projections were observed. We conclude that neurons located within the lPOA/rAHA are important for timing cessation of estrous cycles during photosuppression and that this area communicates directly with GnRH neurons and other hypothalamic areas involved in the photoperiodic regulation of reproduction. PMID- 21816853 TI - Adrenomedullin 2/intermedin regulates HLA-G in human trophoblasts. AB - Adrenomedullin 2 (ADM2), also referred to as intermedin (IMD), is expressed in trophoblast cells in human placenta and enhances the invasion and migration of first-trimester HTR-8SV/neo cells. Further infusion of ADM2 antagonist in pregnant rat causes fetoplacental growth restriction, suggesting a role for ADM2 in maintaining a successful pregnancy. This study was undertaken to assess whether ADM2 protein is present in decidual tissue and colocalized with HLA-G positive cytotrophoblast cells and natural killer cells; to assess whether ADM2 regulates expression of HLA-G in trophoblast cells; and to identify whether mitogen-activated protein kinase (MAPK) signaling pathway is involved in ADM2 induced trophoblast cell invasion and migration. Using immunohistochemical methods and RT-PCR, this study shows that ADM2 protein is colocalized with HLA-G expressing cytotrophoblast cells as well as with NCAM1 (CD56) immunoreactivity in human first-trimester decidual tissue, and that ADM2 mRNA is expressed in peripheral blood natural killer cells. Further, ADM2 dose dependently increases the expression of HLA-G antigen in HTR-8SV/neo cells as well as in term placental villi explants, suggesting involvement of ADM2 in the regulation of HLA-G in trophoblast cells. In addition, interference with the activity of RAF and MAPK3/1 by their inhibitors, manumycin and U0126, respectively, reduces ADM2-induced HTR 8SV/neo cell invasion and migration. In summary, this study suggests a potential involvement for ADM2 in regulating HLA-G antigen at the maternal-fetal interface in human pregnancy and facilitating trophoblast invasion and migration via MAPK3/1 phosphorylation. PMID- 21816854 TI - Aldosterone promotes atrial fibrillation. AB - AIMS: Hyperaldosteronism is associated with an increased prevalence of atrial fibrillation (AF). However, it is unclear whether this is the consequence of altered haemodynamics or a direct aldosterone effect. It was the aim of the study to demonstrate load-independent effects of aldosterone on atrial structure and electrophysiology. METHODS: Osmotic mini-pumps delivering 1.5 ug/h aldosterone were implanted subcutaneously in rats (Aldo). Rats without aldosterone treatment served as controls. After 8 weeks, surface electrocardiogram, the inducibility of AF, and atrial pressures were recorded in vivo. In isolated working hearts, left ventricular function was measured, and conduction in the right atrium (RA) and the left atrium (LA) was mapped epicardially. The atrial effective refractory period (AERP) was determined. Atrial tissue was analysed histologically. RESULTS: Neither systolic nor diastolic ventricular function nor atrial pressures were altered in Aldo rats. All Aldo (11/11) showed inducible atrial arrhythmias vs. two of nine controls (P = 0.03). In Aldo, the P-wave duration and the total RA activation time were longer. Prolongation of local conduction times occurred more often in Aldo, whereas the AERP did not differ between both groups. In Aldo, atrial fibroblasts and interstitial collagen were increased, active matrix metalloproteinase 13 was reduced, and atrial myocytes were hypertrophied. The connexin 43 content was unaltered. CONCLUSIONS: Aldosterone causes a substrate for atrial arrhythmias characterized by atrial fibrosis, myocyte hypertrophy, and conduction disturbances. The described model imputes atrial proarrhythmia directly to aldosterone, since ventricular haemodynamics appeared unaltered in this model. This mechanism may have therapeutical impact for primary and secondary prevention of AF. PMID- 21816855 TI - Danon disease presenting as severe myocardial hypertrophy. PMID- 21816856 TI - Is activation of the renin-angiotensin system hazardous to your health? PMID- 21816857 TI - Psychometric assessment of the Mindful Attention Awareness Scale (MAAS) among Chinese adolescents. AB - The Mindful Attention Awareness Scale (MAAS) has the longest empirical track record as a valid measure of trait mindfulness. Most of what is understood about trait mindfulness comes from administering the MAAS to relatively homogenous samples of Caucasian adults. This study rigorously evaluates the psychometric properties of the MAAS among Chinese adolescents attending high school in Chengdu, China. Classrooms from 24 schools were randomly selected to participate in the study. Three waves of longitudinal data (N = 5,287 students) were analyzed. MAAS construct, nomological, and incremental validity were evaluated as well as its measurement invariance across gender using latent factor analyses. Participants' mean age was 16.2 years (SD = 0.7), and 51% were male. The 15-item MAAS had adequate fit to the one-dimensional factor structure at Wave 1, and this factor structure was replicated at Wave 2. A 6-item short scale of the MAAS fit well to the data at Wave 3. The MAAS maintained reliability (Cronbach's alpha = .89-.93; test-restest r = .35-.52), convergent/discriminant validity, and explained additional variance in mental health measures beyond other psychosocial constructs. Both the 15- and 6-item MAAS scales displayed at least partial factorial invariance across gender. The findings suggest that the MAAS is a sound measure of trait mindfulness among Chinese adolescents. To reduce respondent burden, the MAAS 6-item short-scale provides an option to measure trait mindfulness. PMID- 21816859 TI - Acute appendicitis masquerading as acute scrotum: a case report. AB - Acute appendicitis presents typically with periumbilical pain that in a few hours settles at the right lower quadrant of the abdomen. Atypical presentations are common but association with acute scrotum is an extreme rarity. A 30-year-old fisherman presented at a rural medical facility with a 2-day complaint of severe pain at the right hemiscrotum followed about 24 hours later with mild diffuse abdominal pain. There was associated mild fever and nausea but no vomiting. There were no urinary symptoms and no recent sexual exposure. Initial physical examination revealed mild generalized tenderness worse at the right lower quadrant but the scrotum was not remarkable, and cremasteric sign was negative. He was admitted as a case of acute abdomen for close observation. Abdominal and scrotal ultrasound scan were normal. By the second day of admission, pain became marked at the right lower abdomen with associated vomiting. There was also marked tenderness at the right lower quadrant with rebound. A diagnosis of acute appendicitis was thus made and appendicectomy done after proper workup. The abdominal and scrotal pain stopped after surgery and the patient was discharged on the seventh postoperative day. Patients with unusual abdominal and scrotal pain should be admitted and closely observed and evaluated to prevent unnecessary scrotal exploration or negative appendicectomy. PMID- 21816858 TI - On same-sex sexual behaviors among male bachelors in rural China: evidence from a female shortage context. AB - Using data from a survey conducted in the rural areas of Anhui Province, this study adopted the crosstabs and logistic regression model to analyze the same-sex sexual behaviors of forced male bachelors and the determinants when compared with married men with same ages. The prevalence of same-sex sexual behaviors among the unmarried men was reported as 17.2%, significantly higher than 8.9% among married men with same ages, indicating that same-sex sexual behaviors could be as a compensation for the absence of female sexual partners to some extent for those marriage squeezed or forced male bachelors. Among all groups, the occurrence of unprotected sexual behaviors were reported above 60%, regardless of marital status and the genders of sexual partners; the scores obtained on knowledge of acquired immune deficiency syndrome (AIDS) and sexually transmitted diseases (STDs) among bachelors (AIDS knowledge = 2.85; STDs knowledge = 2.38) are much poorer than those of married men (AIDS knowledge = 3.45; STDs knowledge = 2.79), which might exert potential negative impacts on men's health. PMID- 21816860 TI - It's not just about the french fry: avoidance as an idiom of distress among overweight and obese adolescent boys. AB - The purpose of this article is to explore idiom of distress and its application to overweight and obese adolescent boys. This case study suggests that avoidance, as an idiom of distress, offers self-protection from suffering among this population. Fieldwork included 55 face-to-face contact hours, 25 virtual contact hours (i.e., text messaging, e-mails, phone calls), and 16 person-centered interviews. The daily suffering experienced by this group of boys, and their collective enactment of avoidance as a self-protective strategy, offer an understanding of their lives beyond their obese bodies. Avoidance behaviors, however, can result in negative social consequences such as isolation. Recognizing avoidance as an idiom of distress permits parents, teachers, health professionals, and researchers to interact with overweight and obese adolescent boys in a profoundly different way. Attending to the personhood of these vulnerable boys was an important finding of this qualitative study. PMID- 21816861 TI - Addressing the challenge of informed decision making in prostate cancer community outreach to African American men. AB - African American men are disproportionately affected by prostate cancer. This project adopted a community-based participatory approach to design and pilot test an educational outreach strategy that promotes informed decision making about screening among African American men in community settings in St. Louis, Missouri. Interviews with local subject matter experts informed the design of the strategy. The revised curriculum was pilot tested in 2009 with 63 men who completed pre- and posttest surveys that measured knowledge, norms, beliefs, decision self-efficacy, and screening intention. The intervention resulted in statistically significant improvement in prostate cancer knowledge, decreased perceived risks and barriers, and increased screening decision self-efficacy. The educational outreach strategy offered in community settings was effective in improving knowledge, beliefs, and decision self-efficacy related to prostate cancer screening. This project sought to devise a screening outreach strategy that struck a balance between the imperatives of informed decision-making goals and the pragmatics of community settings. The findings suggest the need for further research to assess the effectiveness of community-based outreach efforts in enhancing engagement of men in decision making related to screening, diagnostics, and treatment. PMID- 21816862 TI - Emotional bonds and social support exchange between men living with HIV infection and their mothers. AB - Men infected with HIV are often faced with caregiving responsibilities of aging, ill parents, while simultaneously looking for support from their parents in dealing with their own health problems. Unfortunately, the reciprocal roles of HIV-positive adult sons and aging mothers as caregivers have not been examined. To address this gap in the literature, HIV-positive men (n = 118) answered open ended questions about the support they exchanged with their mothers, completed the Depth of Relationships Inventory, and rated the importance of health-related assistance between themselves and their mothers. The men viewed themselves as important providers of both instrumental and emotional support to their mothers. Men perceived their mothers to be significant providers of emotional support but only moderately important in providing instrumental support. About a third of the men responded that the help they provided and received from the mothers in managing each other's health and staying healthy was extremely important. Men regarded their relationships with their mothers as one of their most important social relationships. Non-White men rated the quality of their mother-son relationships more highly, exchanged more instrumental support, and provided more emotional support to their mothers than White men. Men who disclosed their HIV positive status to their mothers rated the importance of the help they received from their mothers in managing their illnesses higher than men who had not disclosed. PMID- 21816863 TI - Suicide from the perspectives of older men who experience depression: a gender analysis. AB - Depression can be a pathway to older men's suicide, yet the mechanisms by which this can occur are poorly understood. A qualitative study of 22 older men who self-identified or were formally diagnosed with depression was conducted to describe the connections between masculinity, depression, and suicide. Analyses of individual interviews revealed that cumulative losses around social bonds were central to older men's depression, apathy for living, and thoughts about suicide. Prominent were men's self-assessments of failing to fulfill breadwinner roles, judgments that led participants to ruminate on their shortcomings amid recognizing their older age as limiting opportunities for redemption. Stigma featured as a barrier for men acting on their suicidal thoughts, and guilt about the pain their suicide would evoke on family and friends was a strong deterrent for men's self-harm. Overall, participants' alignment to masculine ideals influenced both the connectedness and detachment between older men's depression and suicide. PMID- 21816864 TI - A limited role for gene duplications in the evolution of platypus venom. AB - Gene duplication followed by adaptive selection is believed to be the primary driver of venom evolution. However, to date, no studies have evaluated the importance of gene duplications for venom evolution using a genomic approach. The availability of a sequenced genome and a venom gland transcriptome for the enigmatic platypus provides a unique opportunity to explore the role that gene duplication plays in venom evolution. Here, we identify gene duplication events and correlate them with expressed transcripts in an in-season venom gland. Gene duplicates (1,508) were identified. These duplicated pairs (421), including genes that have undergone multiple rounds of gene duplications, were expressed in the venom gland. The majority of these genes are involved in metabolism and protein synthesis not toxin functions. Twelve secretory genes including serine proteases, metalloproteinases, and protease inhibitors likely to produce symptoms of envenomation such as vasodilation and pain were detected. Only 16 of 107 platypus genes with high similarity to known toxins evolved through gene duplication. Platypus venom C-type natriuretic peptides and nerve growth factor do not possess lineage-specific gene duplicates. Extensive duplications, believed to increase the potency of toxic content and promote toxin diversification, were not found. This is the first study to take a genome-wide approach in order to examine the impact of gene duplication on venom evolution. Our findings support the idea that adaptive selection acts on gene duplicates to drive the independent evolution and functional diversification of similar venom genes in venomous species. However, gene duplications alone do not explain the "venome" of the platypus. Other mechanisms, such as alternative splicing and mutation, may be important in venom innovation. PMID- 21816866 TI - Pre-conception inter-pregnancy interval and risk of schizophrenia. AB - It is hypothesised that the risk of schizophrenia may be elevated in children conceived following a short inter-pregnancy interval, when maternal folate stores are still being replenished. We examined the relationship between inter-pregnancy interval and schizophrenia risk in a longitudinal, population-based cohort. Risk of schizophrenia was increased by approximately 150% in those born following a pregnancy interval of <=6 months, but was not increased if the interval after birth of the participant, before conception of the subsequent sibling, was <=6 months. These findings support the hypothesis that folate (or other micronutrient) deficiency during fetal development may be an important risk factor for schizophrenia. PMID- 21816867 TI - Safety of antipsychotics in people with intellectual disability. AB - BACKGROUND: Despite frequent use, little is known about the metabolic and endocrine side-effects of antipsychotics in individuals with intellectual disability. AIMS: To compare indices of obesity, glucose, lipids and prolactin between antipsychotic-treated and antipsychotic-naive individuals with intellectual disability and also between participants with intellectual disability and controls from the general population. METHOD: Observational study comparing 138 antipsychotic-treated and 64 antipsychotic-naive participants with intellectual disability in one National Health Service trust with general population controls. RESULTS: Antipsychotic treatment comprised: risperidone 48%,olanzapine 18%, thioxanthenes 10%, other 24%; monotherapy 95% of participants; mean treatment duration 8 years;median daily chlorpromazine equivalent dose 108 mg(range 16-667). Metabolic indices were the same or more favourable in the intellectual disability group than the general population control group but overweight/obesity and type 2 diabetes were more prevalent in the women in the intellectual disability group than the control group. Metabolic indices were similar, statistically or clinically, between the antipsychotic treated and the antipsychotic-naive groups but there was a non-significant trend towards a higher rate of type 2 diabetes in the antipsychotic group. A total of 100%and 70% of participants on amisulpride/sulpiride and risperidone respectively had hyperprolactinaemia, with secondary hypogonadism in 77% and 4% of affected women and men. CONCLUSIONS: Antipsychotics, on average, did not increase metabolic risk,although the existence of a susceptible subgroup at risk of diabetes cannot be excluded. Some antipsychotics induced hyperprolactinaemic hypogonadism, requiring active management. However, our findings suggest that antipsychotics at the low doses routinely prescribed for people with intellectual disability are generally safe in relation to metabolic adverse effects, even if efficacy remains poorly defined. PMID- 21816865 TI - Crohn's disease and genetic hitchhiking at IBD5. AB - Inflammatory bowel disease 5 (IBD5) is a 250 kb haplotype on chromosome 5 that is associated with an increased risk of Crohn's disease in Europeans. The OCTN1 gene is centrally located on IBD5 and encodes a transporter of the antioxidant ergothioneine (ET). The 503F variant of OCTN1 is strongly associated with IBD5 and is a gain-of-function mutation that increases absorption of ET. Although 503F has been implicated as the variant potentially responsible for Crohn's disease susceptibility at IBD5, there is little evidence beyond statistical association to support its role in disease causation. We hypothesize that 503F is a recent adaptation in Europeans that swept to relatively high frequency and that disease association at IBD5 results not from 503F itself, but from one or more nearby hitchhiking variants, in the genes IRF1 or IL5. To test for evidence of recent positive selection on the 503F allele, we employed the iHS statistic, which was significant in the European CEU HapMap population (P=0.0007) and European Human Genome Diversity Panel populations (P<=0.01). To evaluate the hypothesis of disease-variant hitchhiking, we performed haplotype association tests on high density microarray data in a sample of 1,868 Crohn's disease cases and 5,550 controls. We found that 503F haplotypes with recombination breakpoints between OCTN1 and IRF1 or IL5 were not associated with disease (odds ratio [OR]: 1.05, P=0.21). In contrast, we observed strong disease association for 503F haplotypes with no recombination between these three genes (OR: 1.24, P=2.6*10(-8)), as expected if the sweeping haplotype harbored one or more disease-causing mutations in IRF1 or IL5. To further evaluate these disease-gene candidates, we obtained expression data from lower gastrointestinal biopsies of healthy individuals and Crohn's disease patients. We observed a 72% increase in gene expression of IRF1 among Crohn's disease patients (P=0.0006) and no significant difference in expression of OCTN1. Collectively, these data indicate that the 503F variant has increased in frequency due to recent positive selection and that disease-causing variants in linkage disequilibrium with 503F have hitchhiked to relatively high frequency, thus forming the IBD5 risk haplotype. Finally, our association results and expression data support IRF1 as a strong candidate for Crohn's disease causation. PMID- 21816869 TI - Is there a real benefit to zinc and prebiotic fortified ORS in children under the age of 3 years? PMID- 21816868 TI - Problem-solving therapy for people who present to hospital with self-harm: Zelen randomised controlled trial. AB - BACKGROUND: Presentations to hospital with self-harm are common, associated with suicide and have an increased mortality, yet there is no accepted effective intervention. AIMS: To investigate whether problem-solving therapy would improve outcomes in adults presenting to hospital with self-harm, compared with usual care. METHOD: A Zelen randomised controlled trial was conducted in four district health boards in New Zealand. A second hospital presentation with self-harm at 1 year for all episodes, plus separate comparisons of first-time and repeat presentations at the index episode, were the a priori primary outcomes. The trial registration number was ACTRN12605000337673. RESULTS: In an intention-to-treat analysis of all randomised patients (n = 1094) there was no significant difference at 12 months in the proportion of people who had presented again with self-harm when comparing all episodes (intervention 13.4%, usual care 14.1%; relative risk reduction RR = 0.05, 95% CI -0.28 to 0.30, P = 0.79) or where the index episode was the first episode (intervention 13.4%, usual care 9.4%, RR = 0.42, 95% CI -1.17 to 0.08, P = 0.37). Where the index episode was repeated self harm, those who received therapy were less likely to present again with self-harm (intervention 13.5%, usual care 22.1%, RR = 0.39, 95% CI 0.07 to 0.60, number needed to treat 12, P = 0.03). CONCLUSIONS: Problem-solving therapy is not recommended for everyone who presents to hospital with self-harm. Among adults with a history of self-harm it may be an effective intervention. PMID- 21816870 TI - Automated blood pressure readings in primary care demonstrate better correlation to the gold standard of ambulatory monitoring than manual assessment. PMID- 21816871 TI - Relationships between roles and mental states and role functional QOL in breast cancer outpatients. AB - OBJECTIVE: To evaluate the degrees of role accomplishment, the importance of and satisfaction with roles, and to assess their relationships with mental states and role functional quality of life, in breast cancer patients receiving treatment on an outpatient basis. METHODS: The study was designed as a cross-sectional study. Thirty patients with primary breast cancer were evaluated using the Self-Rating Frenchay Activities Index, the Role Checklist, the Profile of Mood States and the Medical Outcome Study Short-Form 36-Item Health Survey. Spearman's rank correlation coefficients were used to analyze the relationships between each role related item and each Profile of Mood States and Short-Form 36 subscale. RESULTS: A higher number of roles played was positively associated with the score for Vigor but was negatively associated with the score for physical quality of life. A higher degree of the importance of roles was negatively correlated with the score for Confusion and positively correlated with the score for mental quality of life. A higher degree of satisfaction with roles was negatively correlated with depression, tension-anxiety, confusion and the total mood disturbances score, and was positively correlated with both the physical and negative quality of life scores. No significant correlations were apparent between the degrees of role accomplishment (Self-Rating Frenchay Activities Index scores) and the Profile of Mood States and Short-Form 36 scores. CONCLUSIONS: The results indicated that qualitative and subjective factors (i.e. the degrees of importance of and satisfaction with roles) are associated more closely with emotional states and role functional quality of life in breast cancer outpatients than quantitative and objective factors (i.e. degree of role accomplishment and the number of roles). PMID- 21816872 TI - LKB1 mutations frequently detected in mucinous bronchioloalveolar carcinoma. AB - OBJECTIVE: LKB1 mutations are common in patients with Peutz-Jeghers syndrome, which is characterized by mucocutaneous pigmentation, intestinal polyps and a high incidence of cancers at variable sites. This study investigated the status of the LKB1 gene in mucinous bronchioloalveolar carcinoma with or without Peutz Jeghers syndrome. METHODS: Three mucinous bronchioloalveolar carcinoma tumors from two Peutz-Jeghers syndrome patients and seven tumors from sporadic mucinous bronchioloalveolar carcinoma patients were collected by surgery between 2002 and 2008, and high molecular weight genomic DNA was extracted from them. The nucleotide sequences in exons 1-9 of LKB1 were determined by genomic polymerase chain reaction-direct sequencing. The loss of heterozygosity was analyzed by high resolution fluorescent microsatellite analysis using two microsatellite markers that encompass the LKB1 locus, D19S886 and D19S565. The mutations of KRAS, EGFR and p53 were also evaluated. RESULTS: The germline mutation of LKB1 in the Peutz Jeghers syndrome patients was identified as G215D by analyzing genomic DNA from normal lung tissue specimens. Furthermore, two of the three mucinous bronchioloalveolar carcinomas from these Peutz-Jeghers syndrome patients exhibited additional somatic mutations. On the other hand, four of seven sporadic 'non-Peutz-Jeghers syndrome' mucinous bronchioloalveolar carcinomas had LKB1 mutations. Loss of heterozygosity analyses revealed allelic loss in two tumors with LKB1 mutations. As a result, 70% of the mucinous bronchioloalveolar carcinomas exhibited LKB1 mutations. KRAS, EGFR and p53 mutations were mutually exclusive and observed in four, two and one tumors, respectively. Among them, five mutations occurred concomitantly with LKB1 mutations. CONCLUSIONS: The relatively high frequency of LKB1 mutations in mucinous bronchioloalveolar carcinoma patients may therefore suggest its involvement in lung carcinogenesis, at least in mucinous bronchioloalveolar carcinoma. PMID- 21816874 TI - Geometry or function for the prediction of prognosis following revascularization in ischaemic cardiomyopathy: beyond the ejection fraction. PMID- 21816873 TI - Extensive chromosome homoeology among Brassiceae species were revealed by comparative genetic mapping with high-density EST-based SNP markers in radish (Raphanus sativus L.). AB - A linkage map of expressed sequence tag (EST)-based markers in radish (Raphanus sativus L.) was constructed using a low-cost and high-efficiency single nucleotide polymorphism (SNP) genotyping method named multiplex polymerase chain reaction-mixed probe dot-blot analysis developed in this study. Seven hundred and forty-six SNP markers derived from EST sequences of R. sativus were assigned to nine linkage groups with a total length of 806.7 cM. By BLASTN, 726 markers were found to have homologous genes in Arabidopsis thaliana, and 72 syntenic regions, which have great potential for utilizing genomic information of the model species A. thaliana in basic and applied genetics of R. sativus, were identified. By construction and analysis of the genome structures of R. sativus based on the 24 genomic blocks within the Brassicaceae ancestral karyotype, 23 of the 24 genomic blocks were detected in the genome of R. sativus, and half of them were found to be triplicated. Comparison of the genome structure of R. sativus with those of the A, B, and C genomes of Brassica species and that of Sinapis alba L. revealed extensive chromosome homoeology among Brassiceae species, which would facilitate transfer of the genomic information from one Brassiceae species to another. PMID- 21816875 TI - Parent-led, therapist-assisted, first-line treatment for young children after trauma: a case study. AB - Due to the prevalence of childhood posttraumatic stress disorder and barriers to treatment, novel service delivery approaches such as parent-led, therapist assisted, trauma-focused cognitive behavioral therapy (PTA-TF-CBT) within a stepped care model are needed. This case study presents the treatment of a 4-year old boy with posttraumatic stress symptoms whose parent led the treatment with therapist assistance and empirically supported materials. Findings from this case study indicated that: (a) PTA-TF-CBT was an acceptable and satisfactory treatment to the parent, (b) therapist time delivering the treatment was limited thereby conserving resources, and (c) clinically significant improvements in child and parent distress were reported posttreatment and at 5 weeks follow-up. Additional research on the feasibility and efficacy of PTA-TF-CBT within a stepped care model is warranted. PMID- 21816876 TI - Large-scale dynamic gene regulatory network inference combining differential equation models with local dynamic Bayesian network analysis. AB - MOTIVATION: Reverse engineering gene regulatory networks, especially large size networks from time series gene expression data, remain a challenge to the systems biology community. In this article, a new hybrid algorithm integrating ordinary differential equation models with dynamic Bayesian network analysis, called Differential Equation-based Local Dynamic Bayesian Network (DELDBN), was proposed and implemented for gene regulatory network inference. RESULTS: The performance of DELDBN was benchmarked with an in vivo dataset from yeast. DELDBN significantly improved the accuracy and sensitivity of network inference compared with other approaches. The local causal discovery algorithm implemented in DELDBN also reduced the complexity of the network inference algorithm and improved its scalability to infer larger networks. We have demonstrated the applicability of the approach to a network containing thousands of genes with a dataset from human HeLa cell time series experiments. The local network around BRCA1 was particularly investigated and validated with independent published studies. BRAC1 network was significantly enriched with the known BRCA1-relevant interactions, indicating that DELDBN can effectively infer large size gene regulatory network from time series data. AVAILABILITY: The R scripts are provided in File 3 in Supplementary Material. CONTACT: zheng.li@monsanto.com; jingdong.liu@monsanto.com SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 21816877 TI - A novel marsupial pri-miRNA transcript has a putative role in gamete maintenance and defines a vertebrate miRNA cluster paralogous to the miR-15a/miR-16-1 cluster. AB - Successful maintenance, survival and maturation of gametes rely on bidirectional communication between the gamete and its supporting cells. Before puberty, factors from the gamete and its supporting cells are necessary for spermatogonial stem cell and primordial follicle oocyte maintenance. Following gametogenesis, gametes rely on factors and nutrients secreted by cells of the reproductive tracts, the epididymis and/or oviduct, to complete maturation. Despite extensive studies on female and male reproduction, many of the molecular mechanisms of germ cell maintenance remain relatively unknown, particularly in marsupial species. We present the first study and characterisation of a novel primary miRNA transcript, pri-miR-16c, in the marsupial, the stripe-faced dunnart. Bioinformatic analysis showed that its predicted processed miRNA - miR-16c - is present in a wide range of vertebrates, but not eutherians. In situ hybridisation revealed dunnart pri miR-16c expression in day 4 (primordial germ cells) and day 7 (oogonia) pouch young, in primary oocytes and follicle cells of primordial follicles but then only in follicle cells of primary, secondary and antral follicles in adult ovaries. In the adult testis, pri-miR-16c transcripts were present in the cytoplasm of spermatogonial cells. The oviduct and the epididymis both showed expression, but not any other somatic tissues examined or conceptuses during early embryonic development. This pattern of expression suggests that pri-miR-16c function may be associated with gamete maintenance, possibly through mechanisms involving RNA transfer, until the zygote enters the uterus at the pronuclear stage. PMID- 21816878 TI - VisG is essential for biosynthesis of virginiamycin S, a streptogramin type B antibiotic, as a provider of the nonproteinogenic amino acid phenylglycine. AB - A streptogramin type B antibiotic, virginiamycin S (VS), is produced by Streptomyces virginiae, together with a streptogramin type A antibiotic, virginiamycin M1 (VM), as its synergistic counterpart. VS is a cyclic hexadepsipeptide containing a nonproteinogenic amino acid, Lphenylglycine (L pheGly), in its core structure. We have identified, in the left-hand extremity of the virginiamycin supercluster, two genes that direct VS biosynthesis with L pheGly incorporation. Transcriptional analysis revealed that visF, encoding a nonribosomal peptide synthetase, and visG, encoding a protein with homology to a hydroxyphenylacetyl-CoA dioxygenase, are under the transcriptional regulation of virginiae butanolide (VB), a small diffusing signalling molecule that governs virginiamycin production. Gene deletion of visG resulted in complete loss of VS production without any changes in VM production, suggesting that visG is required for VS biosynthesis. The abolished VS production in the visG disruptant was fully recovered either by the external addition of pheGly or by gene complementation, which indicates that VisG is involved in VS biosynthesis as the provider of an L pheGly molecule. A feeding experiment with L-pheGly analogues suggested that VisF, which is responsible for the last condensation step, has high substrate specificity toward L-pheGly. PMID- 21816879 TI - PcchiB1, encoding a class V chitinase, is affected by PcVelA and PcLaeA, and is responsible for cell wall integrity in Penicillium chrysogenum. AB - Penicillin production in Penicillium chrysogenum is controlled by PcVelA and PcLaeA, two components of the regulatory velvet-like complex. Comparative microarray analysis with mutants lacking PcVelA or PcLaeA revealed a set of 62 common genes affected by the loss of both components. A downregulated gene in both knockout strains is PcchiB1, potentially encoding a class V chitinase. Under nutrient-depleted conditions, transcript levels of PcchiB1 are strongly upregulated, and the gene product contributes to more than 50 % of extracellular chitinase activity. Functional characterization by generating PcchiB1-disruption strains revealed that PcChiB1 is responsible for cell wall integrity and pellet formation in P. chrysogenum. Further, fluorescence microscopy with a DsRed labelled chitinase suggests a cell wall association of the protein. An unexpected phenotype occurred when knockout strains were grown on media containing N acetylglucosamine as the sole C and N source, where, in contrast to the recipient, a penicillin producer strain, the mutants and an ancestral strain show distinct mycelial growth. We discuss the relevance of this class V chitinase for morphology in an industrially important fungus. PMID- 21816880 TI - Quantitative RNA-seq analysis of the Campylobacter jejuni transcriptome. AB - Campylobacter jejuni is the most common bacterial cause of foodborne disease in the developed world. Its general physiology and biochemistry, as well as the mechanisms enabling it to colonize and cause disease in various hosts, are not well understood, and new approaches are required to understand its basic biology. High-throughput sequencing technologies provide unprecedented opportunities for functional genomic research. Recent studies have shown that direct Illumina sequencing of cDNA (RNA-seq) is a useful technique for the quantitative and qualitative examination of transcriptomes. In this study we report RNA-seq analyses of the transcriptomes of C. jejuni (NCTC11168) and its rpoN mutant. This has allowed the identification of hitherto unknown transcriptional units, and further defines the regulon that is dependent on rpoN for expression. The analysis of the NCTC11168 transcriptome was supplemented by additional proteomic analysis using liquid chromatography-MS. The transcriptomic and proteomic datasets represent an important resource for the Campylobacter research community. PMID- 21816881 TI - Secretory nucleoside diphosphate kinases from both intra- and extracellular pathogenic bacteria are functionally indistinguishable. AB - Nucleoside diphosphate kinase (NDK), responsible for the maintenance of NTP pools, is an ATP-utilizing enzyme secreted by different pathogens. We found that NDK from Salmonella enterica serovar Typhimurium (S. Typhimurium) is also secretory in nature. Secretory NDK is known to play a crucial role in the survival of pathogenic microbes within host cells through their interaction with extracellular ATP. To elucidate this aspect, we assessed the contribution of secretory products containing NDK from intracellular (Mycobacterium tuberculosis and S. Typhimurium) and extracellular (Vibrio cholerae) pathogens to the process of ATP-induced J774 mouse macrophage cell lysis by monitoring lactate dehydrogenase (LDH) release in the culture medium. Compared with an untreated control, our results demonstrate that S. Typhimurium secretory products caused a greater than twofold decrease in LDH release from J774 macrophage cells treated with ATP. Furthermore, the secretory products from an ndk-deleted strain of S. Typhimurium did not display such behaviour. Contrary to this observation, the secretory products containing NDK of V. cholerae were found to be cytotoxic to J774 cells. At the amino acid level, the sequences of both the NDKs (S. Typhimurium and V. cholerae) exhibited 65 % identity, and their biochemical characteristics (autophosphorylation and phosphotransfer activities) were indistinguishable. However, to our surprise, the secretory product of an ndk deleted strain of S. Typhimurium, when complemented with V. cholerae ndk, was able to prevent ATP-induced cytolysis. Taken together, our results unambiguously imply that the intrinsic properties of secretory NDKs are identical in intra- and extracellular pathogens, irrespective of their mode of manifestation. PMID- 21816882 TI - Transcriptome analysis reveals that ClpXP proteolysis controls key virulence properties of Streptococcus mutans. AB - The ClpXP proteolytic complex is critical for maintaining cellular homeostasis, as well as expression of virulence properties. However, with the exception of the Spx global regulator, the molecular mechanisms by which the ClpXP complex exerts its influence in Streptococcus mutans are not well understood. Here, microarray analysis was used to provide novel insights into the scope of ClpXP proteolysis in S. mutans. In a DeltaclpP strain, 288 genes showed significant changes in relative transcript amounts (P<=0.001, twofold cut-off) as compared with the parent. Similarly, 242 genes were differentially expressed by a DeltaclpX strain, 113 (47 %) of which also appeared in the DeltaclpP microarrays. Several genes associated with cell growth were downregulated in both mutants, consistent with the slow-growth phenotype of the Deltaclp strains. Among the upregulated genes were those encoding enzymes required for the biosynthesis of intracellular polysaccharides (glg genes) and malolactic fermentation (mle genes). Enhanced expression of glg and mle genes in DeltaclpP and DeltaclpX strains correlated with increased storage of intracellular polysaccharide and enhanced malolactic fermentation activity, respectively. Expression of several genes known or predicted to be involved in competence and mutacin production was downregulated in the Deltaclp strains. Follow-up transformation efficiency and deferred antagonism assays validated the microarray data by showing that competence and mutacin production were dramatically impaired in the Deltaclp strains. Collectively, our results reveal the broad scope of ClpXP regulation in S. mutans homeostasis and identify several virulence-related traits that are influenced by ClpXP proteolysis. PMID- 21816883 TI - Comparison of tibialis anterior muscle electromyography, ankle angle, and velocity when individuals post stroke walk with different orthoses. AB - BACKGROUND: Ankle-foot orthoses (AFO) have been used to improve the gait of individuals post stroke, but their use has come into question secondary to increased understanding of motor re-learning. OBJECTIVES: The purpose of this study was to determine if there is a change in tibialis anterior muscle electromyography, ankle angle, or gait velocity when individuals post stroke walk with a posterior leaf-spring AFO (PLAFO) or a dynamic ankle orthosis (DAO). STUDY DESIGN: Repeated measures. METHODS: Fifteen participants post stroke walked without an orthosis, with a PLAFO, and with a DAO. Data were gathered using electromyography, force plates, and three-dimensional motion analysis cameras. A repeated measures ANOVA was used to test for statistical significance (p <= 0.05). RESULTS: Participants exhibited significantly less tibialis anterior muscle electromyography during the swing phase of gait with use of a DAO (p < 0.001). No change in velocity or ankle angle was exhibited with use of either orthosis. CONCLUSIONS: The results support therapists' notions that bracing can lead to a decline in tibialis anterior muscle activity during the swing phase of gait. The results also showed no improvement in gait velocity when either orthosis was used by participants who could walk without an orthosis. PMID- 21816887 TI - Comparison of modified Kessler tendon suture at different levels in the human flexor digitorum profundus tendon and porcine flexors and porcine extensors: an experimental biomechanical study. AB - This study compared the biomechanical behaviour of repairs in the human flexor digitorum profundus tendon in zones I, II and III with repairs of different segments of the porcine flexor tendon of the second digit and the extensor digiti quarti proprius tendon, in order to assess the validity of porcine tendons as models for human flexor tendon repairs. These porcine tendons were selected after comparing their size with the human flexor digitorum profundus tendon. The tendon repairs were done in three segments of each porcine tendon and repairs in the human tendons were done in zones I,II and III. Ten tendons in each group yielded a total of 90 specimens. A modified Kessler repair was done with 3-0 coated braided polyester suture and subjected to uniaxial tensile testing. In human flexor tendons, the ultimate force was higher in zones I and II than in zone III. The porcine flexor digitorum profundus tendon from the second digit and the proximal segment of the extensor digiti quarti proprius tendon behaved similarly to the human flexor tendon in zone III and can be considered as surrogates for the human flexor tendon. PMID- 21816888 TI - Outcome of corticosteroid injection versus physiotherapy in the treatment of mild trigger fingers. AB - We compared the effectiveness of physiotherapy and corticosteroid injection treatment in the management of mild trigger fingers. Mild trigger fingers are those with mild crepitus, uneven finger movements and actively correctable triggering. This is a single-centred, prospective, block randomized study with 74 patients; 39 patients for steroid injection and 35 patients for physiotherapy. The study duration was from Jun 2009 until August 2010. Evaluation was done at 6 weeks, 3 months and 6 months post-treatment. At 3 months, the success rate (absence of pain and triggering) for those receiving steroid injection was 97.4% and physiotherapy 68.6%. The group receiving steroid injection also had lower pain score, higher rate of satisfaction, stronger grip strength and early recovery to near normal function (findings were all significant, p < 0.05). At 6 months, only those who were successfully treated were further questioned on recurrence (presence of pain and triggering). Those who received corticosteroid injections had a significant recurrence rate of pain but not triggering. The physiotherapy group had no recurrence of pain or triggering due to the type of triggering responsive to physiotherapy or possibly due to awareness of physiotherapy exercises. Perhaps they were able to institute self-treatment on early onset of symptoms of trigger fingers. We conclude that corticosteroid injection has a better outcome compared to physiotherapy in the treatment of mild trigger fingers but physiotherapy may have a role in prevention of recurrence. PMID- 21816889 TI - Multiple regression analysis of factors influencing dominant hand grip strength in an adult Malaysian population. AB - Grip strength is an important measure used to monitor the progression of a condition, and to evaluate outcomes of treatment. We assessed how various physical and social factors predict normal grip strength in an adult Malaysian population of mixed Asian ethnicity (254 men, 246 women). Grip strength was recorded using the Jamar dynamometer. The mean grip strength for the dominant hand was 29.8 kg for men and 17.6 kg for women. Multiple regression analysis demonstrated that the dominant hand grip strength was positively associated with height and body mass index, and negatively associated with age for both sexes. Dominant hand grip strength was related to work status for men (p < 0.05) but not for women. However, there was no difference in grip strength among ethnic groups. PMID- 21816890 TI - Aseptic tissue necrosis and chronic inflammation after irrigation of penetrating hand wounds using Octenisept(r). AB - Penetrating hand wounds are common and these are managed by thorough debridement. However, stab wounds without evidence of divided structures are often treated with irrigation using antiseptic substances, antibiotic therapy, and immobilization. Octenisept(r) (Schulke & Mayr Ltd) is a widely used antiseptic agent for disinfection of acute or chronic wounds. It has a broad spectrum of antiseptic efficacy and has become an antiseptic of first choice in many hospitals. Within a few months, four patients presented to us with chronic inflammation and severe tissue necrosis after irrigation of penetrating hand wounds with Octenisept(r). Repeated surgery and debridement was required in all patients. Wound healing was prolonged and patients had persisting oedema. Penetrating hand wounds must not be irrigated with Octenisept(r). PMID- 21816891 TI - Effects of natural and recombinant hirudin on superoxide dismutase, malondialdehyde and endothelin levels in a random pattern skin flap model. AB - We have assessed the anti-inflammatory, anti-oxidative and anti-coagulant effects of locally applied natural and recombinant hirudin in a random skin flap rat model. Thirty Wistar rats with venous congested skin flaps were randomly divided into two treatment groups and a control group to receive subcutaneous injections of natural hirudin (6 U), recombinant hirudin (6 U) or physiological saline, respectively. Superoxide dismutase, malondialdehyde and endothelin levels as well as flap survival rates of the skin flaps were measured after surgery. Compared to the control group, the treatment groups had significant higher superoxide dismutase levels and lower malondialdehyde and endothelin levels in the skin flaps. The surviving areas of the flaps were larger in the treatment groups than the control group. Our results demonstrated that hirudin could improve skin flap survival through its anti-inflammatory, anti-oxidative and anti-coagulant activities. PMID- 21816893 TI - A prospective study of limited palmar and digital fasciectomy under local anaesthetic wrist block and upper arm tourniquet. PMID- 21816892 TI - Streptococcus milleri in hand infections. PMID- 21816894 TI - Wandering spleen with torsion and complete infarction. AB - Wandering spleen is rare and is associated with a high incidence of splenic torsion and infarction. Presenting symptoms range from an asymptomatic, incidentally palpated abdominal mass to an acutely ill patient. Because wandering spleen is uncommon in the pediatric population, a heightened awareness of the condition is required for accurate diagnosis and appropriate management. We present a case of a 4-year-old girl who presented with acute abdomen and was surgically confirmed to have a wandering spleen with torsion and complete infarction. PMID- 21816895 TI - Epistaxis in patients with hereditary hemorrhagic telangiectasia treated with selective arterial embolization. AB - BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is a rare systemic fibrovascular dysplasia also known as Rendu-Osler-Weber disease. Epistaxis is often the first and foremost symptom of the disease and recurrent epistaxis is the main complaint. PURPOSE: Evaluation of effectiveness and safety of endovascular treatment of epistaxis in HHT patients. MATERIAL AND METHODS: Between June 2004 and January 2008, 14 patients with HHT underwent embolization of external carotid artery (ECA) branches due to severe epistaxis. There were eight men and six women aged 27-42 years. Patients were referred for endovascular treatment when primary management with electrocautery and nasal packing was ineffective. Arteries suspected of bleeding were catheterized super-selectively with micro-catheters to perform embolization. Polyvinyl alcohol particles (PVA) or embospheres in diameter of 500-700-um were used as an embolic material. RESULTS: Embolization was technically successful in 11 (78.5%) patients. Immediate, complete control of bleeding was achieved in 12 (85%) patients. During long-term follow-up recurrent nasal bleeding occurred in six (43%) patients 6-24 months after treatment. There were no severe complications after embolization. Nine patients experienced mild facial pain which resolved within three days after the treatment. Three patients in whom arterial spasm was observed, suffered from facial paraesthesia lasting for 3-5 days after embolization. Out of 14 patients, 12 were available for 24-month follow-up evaluation. All except one claimed reduction in frequency and severity of epistaxis which had a positive impact on their quality of life. CONCLUSION: Endovascular embolization of epistaxis in patients with HHT is an effective and safe procedure although it cannot provide a long-term cure in most cases. Embolization reduces the frequency, severity and duration of nasal bleeding in patients with HHT, improving patients' quality of life. PMID- 21816896 TI - Evaluation of pneumonia in children: comparison of MRI with fast imaging sequences at 1.5T with chest radiographs. AB - BACKGROUND: Although there has been a study aimed at magnetic resonance imaging (MRI) evaluation of pneumonia in children at a low magnetic field (0.2T), there is no study which assessed the efficacy of MRI, particularly with fast imaging sequences at 1.5T, for evaluating pneumonia in children. PURPOSE: To investigate the efficacy of chest MRI with fast imaging sequences at 1.5T for evaluating pneumonia in children by comparing MRI findings with those of chest radiographs. MATERIAL AND METHODS: This was an Institutional Review Board-approved, HIPPA compliant prospective study of 40 consecutive pediatric patients (24 boys, 16 girls; mean age 7.3 years +/- 6.6 years) with pneumonia, who underwent PA and lateral chest radiographs followed by MRI within 24 h. All MRI studies were obtained in axial and coronal planes with two different fast imaging sequences: T1-weighted FFE (Fast Field Echo) (TR/TE: 83/4.6) and T2-weigthed B-FFE M2D (Balanced Fast Field Echo Multiple 2D Dimensional) (TR/TE: 3.2/1.6). Two experienced pediatric radiologists reviewed each chest radiograph and MRI for the presence of consolidation, necrosis/abscess, bronchiectasis, and pleural effusion. Chest radiograph and MRI findings were compared with Kappa statistics. RESULTS: All consolidation, lung necrosis/abscess, bronchiectasis, and pleural effusion detected with chest radiographs were also detected with MRI. There was statistically substantial agreement between chest radiographs and MRI in detecting consolidation (k = 0.78) and bronchiectasis (k = 0.72) in children with pneumonia. The agreement between chest radiographs and MRI was moderate for detecting necrosis/abscess (k = 0.49) and fair for detecting pleural effusion (k = 0.30). CONCLUSION: MRI with fast imaging sequences is comparable to chest radiographs for evaluating underlying pulmonary consolidation, bronchiectasis, necrosis/abscess, and pleural effusion often associated with pneumonia in children. PMID- 21816897 TI - Commentary: Children and predictive genomic testing: disease prevention, research protection, and our future. AB - Genetic testing offered by direct-to-consumer companies-herein referred to as "predictive genomic testing"--has come under federal scrutiny. Critics claim testing yields uninterpretable and potentially harmful information. Supporters assert individuals have a right to this information, which could catalyze preventive health actions. Despite contentions that predictive genomic testing is a tool of primary disease prevention, little discussion has focused on its use with children. This partly stems from concerns expressed in existing professional guidelines about the potential for psychological and behavioral harm to children engendered by predictive genetic tests for Mendelian diseases. Conducting research to understand the actual benefits and harms is important for policy development and practice guidance and can be ethically justified within the pediatric regulatory framework of research that offers a prospect of direct benefit. Child health psychologists are well poised to contribute to this research effort, and promote the translation of genomic discoveries to improve pediatric medicine. PMID- 21816899 TI - A TSH-CREB1-microRNA loop is required for thyroid cell growth. AB - MicroRNA (miRNA or miR) are an important class of regulators that participate in such biological functions as development, cell proliferation, differentiation, and apoptosis. The aim of this study was to elucidate the role of miRNA in cell proliferation using a unique cell system, namely thyroid cells that require thyrotropin for their growth. Here, we report the identification of a set of five specific miRNA (miR-1, miR-28-A, miR-290-5p, miR-296-3p, and miR-297a), whose down-regulation by thyrotropin is required for thyroid cell growth. In fact, overexpression of these miRNA negatively affects cell growth. We show that three of these miRNA target cAMP-responsive element binding protein (CREB)1, a thyrotropin-activated transcription factor, and that CREB1 binds the regulatory regions of the down-regulated miRNA. Hence, these data indicate that a synergistic loop involving thyrotropin, CREB1, and miRNA is required for thyroid cell proliferation. PMID- 21816898 TI - p38 and p42/44 MAPKs differentially regulate progesterone receptor A and B isoform stabilization. AB - Progesterone receptor (PR) isoforms (PRA and PRB) are implicated in the progression of breast cancers frequently associated with imbalanced PRA/PRB expression ratio. Antiprogestins represent potential antitumorigenic agents for such hormone-dependent cancers. To investigate the mechanism(s) controlling PR isoforms degradation/stability in the context of agonist and antagonist ligands, we used endometrial and mammary cancer cells stably expressing PRA and/or PRB. We found that the antiprogestin RU486 inhibited the agonist-induced turnover of PR isoforms through active mechanism(s) involving distinct MAPK-dependent phosphorylations. p42/44 MAPK activity inhibited proteasome-mediated degradation of RU486-bound PRB but not PRA in both cell lines. Ligand-induced PRB turnover required neosynthesis of a mandatory down-regulating partner whose interaction/function is negatively controlled by p42/44 MAPK. Such regulation strongly influenced expression of various endogenous PRB target genes in a selective manner, supporting functional relevance of the mechanism. Interestingly, in contrast to PRB, PRA stability was specifically increased by MAPK kinase kinase 1-induced p38 MAPK activation. Selective inhibition of p42/p44 or p38 activity resulted in opposite variations of the PRA/PRB expression ratio. Moreover, MAPK-dependent PR isoforms stability was independent of PR serine-294 phosphorylation previously proposed as a major sensor of PR down-regulation. In sum, we demonstrate that MAPK-mediated cell signaling differentially controls PRA/PRB expression ratio at posttranslational level through ligand-sensitive processes. Imbalance in PRA/PRB ratio frequently associated with carcinogenesis might be a direct consequence of disorders in MAPK signaling that might switch cellular responses to hormonal stimuli and contribute towards pathogenesis. PMID- 21816900 TI - Estrogen sulfotransferase inhibits adipocyte differentiation. AB - The estrogen sulfotransferase (EST) is a phase II drug-metabolizing enzyme known to catalyze the sulfoconjugation of estrogens. EST is highly expressed in the white adipose tissue of male mice, but the role of EST in the development and function of adipocytes remains largely unknown. In this report, we showed that EST played an important role in adipocyte differentiation. EST was highly expressed in 3T3-L1 preadipocytes and primary mouse preadipocytes. The expression of EST was dramatically reduced in differentiated 3T3-L1 cells and mature primary adipocytes. Overexpression of EST in 3T3-L1 cells prevented adipocyte differentiation. In contrast, preadipocytes isolated from EST knockout (EST-/-) mice exhibited enhanced differentiation. The inhibitory effect of EST on adipogenesis likely resulted from the sustained activation of ERK1/2 MAPK and inhibition of insulin signaling, leading to a failure of switch from clonal expansion to differentiation. The enzymatic activity of EST was required for the inhibitory effect of EST on adipogenesis, because an enzyme-dead EST mutant failed to inhibit adipocyte differentiation. In vivo, overexpression of EST in the adipose tissue of female transgenic mice resulted in smaller adipocyte size. Taken together, our results suggest that EST functions as a negative regulator of adipogenesis. PMID- 21816901 TI - HMGN2 inducibly binds a novel transactivation domain in nuclear PRLr to coordinate Stat5a-mediated transcription. AB - The direct actions of transmembrane receptors within the nucleus remain enigmatic. In this report, we demonstrate that the prolactin receptor (PRLr) localizes to the nucleus where it functions as a coactivator through its interactions with the latent transcription factor signal transducer and activator of transcription 5a (Stat5a) and the high-mobility group N2 protein (HMGN2). We identify a novel transactivation domain within the PRLr that is activated by ligand-induced phosphorylation, an event coupled to HMGN2 binding. The association of the PRLr with HMGN2 enables Stat5a-responsive promoter binding, thus facilitating transcriptional activation and promoting anchorage-independent growth. We propose that HMGN2 serves as a critical regulatory factor in Stat5a driven gene expression by facilitating the assembly of PRLr/Stat5a onto chromatin and that these events may serve to promote biological events that contribute to a tumorigenic phenotype. Our data imply that phosphorylation may be the molecular switch that activates a cell surface receptor transactivation domain, enabling it to tether chromatin-modifying factors, such as HMGN2, to target promoter regions in a sequence-specific manner. PMID- 21816902 TI - Skeletal muscle regeneration in mice is stimulated by local overexpression of V1a vasopressin receptor. AB - Skeletal muscle has a remarkable capacity to regenerate after mechanical or pathological injury. We show that the V1a receptor (V1aR) for vasopressin, a potent myogenic-promoting factor that stimulates differentiation and hypertrophy in vitro, is expressed in mouse skeletal muscle and modulated during regeneration after experimental injury. We used gene delivery by electroporation to overexpress the myc-tagged vasopressin V1aR in specific muscles, thus sensitizing them to circulating vasopressin. The correct localization on the surface of the fibers of the recombinant product was demonstrated by confocal immunofluorescence directed against the myc tag. V1aR overexpression dramatically enhanced regeneration. When compared with mock-transfected controls, V1aR overexpressing muscles exhibited significantly accelerated activation of satellite cells and increased expression of differentiation markers. Downstream of V1aR activation, calcineurin was strongly up-regulated and stimulated the expression of IL-4, a potent mediator of myogenic cell fusion. The central role of calcineurin in mediating V1aR-dependent myogenesis was also demonstrated by using its specific inhibitor, cyclosporine A. This study identifies skeletal muscle as a physiological target of hormones of the vasopressin family and reveals a novel in vivo role for vasopressin-dependent pathways. These findings unveil several steps, along a complex signaling pathway, that may be exploited as potential targets for the therapy of diseases characterized by altered muscle homeostasis and regeneration. PMID- 21816903 TI - Adenomatous polyposis coli (APC) is essential for maintaining the integrity of the seminiferous epithelium. AB - Sertoli cells provide the microenvironment necessary for germ cell development and spermatogenesis; disruption of Sertoli cell morphology or function can lead to germ cell aplasia, which is observed in testicular dysgenesis syndrome. Mutation of the adenomatous polyposis coli (APC) gene has been associated with various human cancers, including testicular cancer, but its involvement in nonmalignant testicular pathologies has not been reported. We have developed a mouse model (APC(cko)) that expresses a truncated form of APC in Sertoli cells. Despite normal embryonic and early postnatal testicular development in APC(cko) mice, premature germ cell loss and Sertoli cell-only seminiferous tubules were observed in mutant testes without affecting Sertoli cell quiescence, apoptosis, or differentiation, which were confirmed by the absence of both proliferating cell nuclear antigen, DNA strand breaks, and anti-Mullerian hormone, respectively. We show that mutant Sertoli cells lose their apical extensions, which would normally enclose germ cells during various stages of spermatogenesis, and were unable to maintain the blood-testis barrier because of disrupted expression of junctional proteins. We also observed an up-regulation of Snail and Slug, markers suggestive of epithelial-mesenchymal transition in the Sertoli cells, but tumorigenesis was not observed. No comparable phenotype was observed with Sertoli cell-specific loss-of-function mutations in beta-catenin, leading us to speculate that truncation of APC in Sertoli cells results in progressive degeneration of the seminiferous tubules by a mechanism that disrupts the integrity of Sertoli cell junctions independently of APC-regulated beta-catenin activities and leads to development of a Sertoli cell-only phenotype. PMID- 21816904 TI - p57(Kip2) and cancer: time for a critical appraisal. AB - p57(Kip2) is a cyclin-dependent kinase inhibitor belonging to the Cip/Kip family, which also includes p21(Cip1) and p27(Kip1). So far, p57(Kip2) is the least studied Cip/Kip protein, and for a long time its relevance has been related mainly to its unique role in embryogenesis. Moreover, genetic and molecular studies on animal models and patients with Beckwith-Wiedemann syndrome have shown that alterations in CDKN1C (the p57(Kip2) encoding gene) have functional relevance in the pathogenesis of this disease. Recently, a number of investigations have identified and characterized heretofore unexpected roles for p57(Kip2). The protein appears to be critically involved in initial steps of cell and tissue differentiation, and particularly in neuronal development and erythropoiesis. Intriguingly, p27(Kip1), the Cip/Kip member that is most homologous to p57(Kip2), is primarily involved in the process of cell cycle exit. p57(Kip2) also plays a critical role in controlling cytoskeletal organization and cell migration through its interaction with LIMK-1. Furthermore, p57(Kip2) appears to modulate genome expression. Finally, accumulating evidence indicates that p57(Kip2) protein is frequently downregulated in different types of human epithelial and nonepithelial cancers as a consequence of genetic and epigenetic events. In summary, the emerging picture is that several aspects of p57(Kip2)'s functions are only poorly clarified. This review represents an appraisal of the data available on the p57(Kip2) gene and protein structure, and its role in human physiology and pathology. We particularly focus our attention on p57(Kip2) changes in cancers and pharmacological approaches for modulating p57(Kip2) levels. PMID- 21816905 TI - Suppression of IRF4 by IRF1, 3, and 7 in Noxa expression is a necessary event for IFN-gamma-mediated tumor elimination. AB - IFN-gamma plays a critical role in tumor immunosurveillance by affecting either immune cells or tumor cells; however, IFN-mediated effects on tumor elimination are largely unknown. In this study, we showed that IFN regulatory factors (IRF) modulated by IFNs up- and downregulated Noxa expression, a prodeath BH3 protein, in various cancer cells. Inhibition of Noxa expression using short hairpin RNA in tumor cells leads to resistance against lipopolysaccharide (LPS)-induced tumor elimination, in which IFN-gamma is known as a critical effecter in mice. Chromatin immunoprecipitation analysis in both CT26 cells and SP2/0 cells, sensitive and resistant to LPS-induced tumor elimination, respectively, revealed that the responsiveness of IRF1, 3, 4, and 7 in the Noxa promoter region in response to IFN-gamma might be crucial in LPS-induced tumor elimination. IRF1, 3, and 7 were upregulated by IFN-gamma and activated Noxa expression, leading to the death of Noxa wild-type baby mouse kidney (BMK) cells but not of Noxa-deficient BMK cells. In contrast, IRF4 acts as a repressor for Noxa expression and inhibits cell death induced by IRF1, 3, or 7. Therefore, although IFN-gamma alone are not able to induce cell death in tumor cells in vitro, Noxa induction by IFN-gamma, which is regulated by the balance between its activators (IRF1, 3, and 7) and its repressor (IRF4), is crucial to increasing the susceptibility of tumor cells to immune cell-mediated cytotoxicity. PMID- 21816906 TI - MicroRNA-32 upregulation by 1,25-dihydroxyvitamin D3 in human myeloid leukemia cells leads to Bim targeting and inhibition of AraC-induced apoptosis. AB - 1,25-Dihydroxyvitamin D(3) (1,25D) used to treat human acute myeloid leukemia (AML) cells induces features of normal monocytes, but the mechanisms underlying this response are not fully understood. We hypothesized that one or more microRNAs (miRNA) known to control mouse hematopoiesis and lineage commitment might contribute to the ability of 1,25D to control the malignant phenotype. Here we report that 1,25D markedly induces expression of miR-32 in human myeloid leukemia cells, in which it targets the 3'-untranslated region of the mRNA encoding the proapoptotic factor Bim to reduce its expression. RNAi-mediated suppression of the miRNA-processing enzymes Drosha and Dicer increased Bim levels, in support of the concept that Bim is under miRNA control in AML cells. Antisense-mediated suppression of miR-32 was sufficient to upregulate Bim expression in AML cells. Conversely, ectopic expression of miR-32 downregulated Bim expression and increased the differentiation response to 1,25D treatment in a manner that was associated with increased cell survival. The positive effects of miR-32 on cell survival were confirmed by evidence of increased cell death in AML cells preexposed to antisense miR-32 before treatment with arabinocytosine, a chemotherapeutic drug used to treat human AML. Together, our findings indicate that miR-32 blockade is sufficient to elevate Bim expression and sensitize AML cells to chemotherapy-induced apoptosis. Thus, agents which can inhibit miR-32 expression may offer clinical utility by enhancing therapeutic efficacy in human AML. PMID- 21816907 TI - FLT3 ligand enhances the cancer therapeutic potency of naked RNA vaccines. AB - Intranodal immunization with antigen-encoding naked RNA may offer a simple and safe approach to induce antitumor immunity. RNA taken up by nodal dendritic cells (DC) coactivates toll-like receptor (TLR) signaling that will prime and expand antigen-specific T cells. In this study, we show that RNA vaccination can be optimized by coadministration of the DC-activating Fms-like tyrosine kinase 3 (FLT3) ligand as an effective adjuvant. Systemic administration of FLT3 ligand prior to immunization enhanced priming and expansion of antigen-specific CD8(+) T cells in lymphoid organs, T-cell homing into melanoma tumors, and therapeutic activity of the intranodal RNA. Unexpectedly, plasmacytoid DCs (pDC) were found to be essential for the adjuvant effect of FLT3 ligand and they were systemically expanded together with conventional DCs after treatment. In response to FLT3 ligand, pDCs maintained an immature phenotype, internalized RNA, and presented the RNA-encoded antigen for efficient induction of antigen-specific CD8(+) T-cell responses. Coadministration of FLT3 ligand with RNA vaccination achieved remarkable cure rates and survival of mice with advanced melanoma. Our findings show how to improve the simple and safe strategy offered by RNA vaccines for cancer immunotherapy. PMID- 21816908 TI - Wnt5a suppresses epithelial ovarian cancer by promoting cellular senescence. AB - Epithelial ovarian cancer (EOC) remains the most lethal gynecologic malignancy in the United States. Thus, there is an urgent need to develop novel therapeutics for this disease. Cellular senescence is an important tumor suppression mechanism that has recently been suggested as a novel mechanism to target for developing cancer therapeutics. Wnt5a is a noncanonical Wnt ligand that plays a context dependent role in human cancers. Here, we investigate the role of Wnt5a in regulating senescence of EOC cells. We show that Wnt5a is expressed at significantly lower levels in human EOC cell lines and in primary human EOCs (n = 130) compared with either normal ovarian surface epithelium (n = 31; P = 0.039) or fallopian tube epithelium (n = 28; P < 0.001). Notably, a lower level of Wnt5a expression correlates with tumor stage (P = 0.003) and predicts shorter overall survival in EOC patients (P = 0.003). Significantly, restoration of Wnt5a expression inhibits the proliferation of human EOC cells both in vitro and in vivo in an orthotopic EOC mouse model. Mechanistically, Wnt5a antagonizes canonical Wnt/beta-catenin signaling and induces cellular senescence by activating the histone repressor A/promyelocytic leukemia senescence pathway. In summary, we show that loss of Wnt5a predicts poor outcome in EOC patients and Wnt5a suppresses the growth of EOC cells by triggering cellular senescence. We suggest that strategies to drive senescence in EOC cells by reconstituting Wnt5a signaling may offer an effective new strategy for EOC therapy. PMID- 21816909 TI - microRNA-10b: a new marker or the marker of pancreatic ductal adenocarcinoma? AB - microRNA-10b (miR-10b) expression in pancreatic ductal adenocarcinoma (PDAC), as identified by in situ hybridization, is highly correlated with cancer diagnosis, therapy response, and prognosis. If these findings are further confirmed in prospective studies, miR-10b could be used to improve the management of PDAC and decrease the mortality rate of this deadly cancer. PMID- 21816910 TI - Synthetic spike-in standards for RNA-seq experiments. AB - High-throughput sequencing of cDNA (RNA-seq) is a widely deployed transcriptome profiling and annotation technique, but questions about the performance of different protocols and platforms remain. We used a newly developed pool of 96 synthetic RNAs with various lengths, and GC content covering a 2(20) concentration range as spike-in controls to measure sensitivity, accuracy, and biases in RNA-seq experiments as well as to derive standard curves for quantifying the abundance of transcripts. We observed linearity between read density and RNA input over the entire detection range and excellent agreement between replicates, but we observed significantly larger imprecision than expected under pure Poisson sampling errors. We use the control RNAs to directly measure reproducible protocol-dependent biases due to GC content and transcript length as well as stereotypic heterogeneity in coverage across transcripts correlated with position relative to RNA termini and priming sequence bias. These effects lead to biased quantification for short transcripts and individual exons, which is a serious problem for measurements of isoform abundances, but that can partially be corrected using appropriate models of bias. By using the control RNAs, we derive limits for the discovery and detection of rare transcripts in RNA seq experiments. By using data collected as part of the model organism and human Encyclopedia of DNA Elements projects (ENCODE and modENCODE), we demonstrate that external RNA controls are a useful resource for evaluating sensitivity and accuracy of RNA-seq experiments for transcriptome discovery and quantification. These quality metrics facilitate comparable analysis across different samples, protocols, and platforms. PMID- 21816911 TI - Extreme obesity and outcomes in critically ill patients. AB - BACKGROUND: Recent literature suggests that obese critically ill patients do not have worse outcomes than patients who are normal weight. However, outcomes in extreme obesity (BMI >= 40 kg/m(2)) are unclear. We sought to determine the association between extreme obesity and ICU outcomes. METHODS: We analyzed data from a multicenter international observational study of ICU nutrition practices that occurred in 355 ICUs in 33 countries from 2007 to 2009. Included patients were mechanically ventilated adults >= 18 years old who remained in the ICU for > 72 h. Using generalized estimating equations and Cox proportional hazard modeling with clustering by ICU and adjusting for potential confounders, we compared extremely obese to normal-weight patients in terms of duration of mechanical ventilation (DMV), ICU length of stay (LOS), hospital LOS, and 60-day mortality. RESULTS: Of the 8,813 patients included in this analysis, 3,490 were normal weight (BMI 18.5-24.9 kg/m(2)), 348 had BMI 40 to 49.9 kg/m(2), 118 had BMI 50 to 59.9 kg/m(2), and 58 had BMI >= 60 kg/m(2). Unadjusted analyses suggested that extremely obese critically ill patients have improved mortality (OR for death, 0.77; 95% CI, 0.62-0.94), but this association was not significant after adjustment for confounders. However, an adjusted analysis of survivors found that extremely obese patients have a longer DMV and ICU LOS, with the most obese patients (BMI >= 60 kg/m(2)) also having longer hospital LOS. CONCLUSIONS: During critical illness, extreme obesity is not associated with a worse survival advantage compared with normal weight. However, among survivors, BMI >= 40 kg/m(2) is associated with longer time on mechanical ventilation and in the ICU. These results may have prognostic implications for extremely obese critically ill patients. PMID- 21816913 TI - MR imaging of fetal goiter. PMID- 21816912 TI - Salivary cortisol can replace free serum cortisol measurements in patients with septic shock. AB - BACKGROUND: There is a renewed interest in adrenal function during severe sepsis. Most studies have used total serum cortisol levels; however, only free serum cortisol is biologically active. The aim of this study was to determine the validity of salivary cortisol levels as a surrogate for free serum cortisol levels during septic shock. METHODS: Fifty-seven patients with septic shock were studied to determine the correlation between total serum cortisol and salivary cortisol to free serum cortisol levels. Thirty-eight patients were included in the salivary to free serum cortisol correlation. Salivary cortisol level was tested by enzyme immunoassay. Serum total cortisol, free cortisol, and cortisol binding globulin (CBG) levels were determined by liquid chromatography-mass spectrometry, equilibrium analysis, and radioimmunoassay, respectively. RESULTS: The mean +/- SD age was 56.6 +/- 18.5 years. Fifty-seven percent were women. APACHE (Acute Physiology and Chronic Health Evaluation) II score median was 26, Simplified Acute Physiology Score II median was 61, and Sequential Organ Failure Assessment median was 13. The correlation between salivary and free serum cortisol levels was 0.79 (95% CI, 0.63-0.89; P < .0001). The correlation between free serum cortisol and total serum cortisol levels was 0.86 (95% CI, 0.78-0.92; P < .0001). The mean +/- SD free serum cortisol level was 2.27 +/- 1.64 MUg/dL. The mean +/- SD salivary cortisol level was 2.60 +/- 2.69 MUg/dL. The mean +/- SD total serum cortisol level was 21.56 +/- 8.71 MUg/dL. The mean +/- SD CBG level was 23.54 +/- 8.33 mg/dL. CONCLUSIONS: Salivary cortisol level can be used as a surrogate of free serum cortisol level in patients with septic shock with very good correlation. Salivary cortisol testing is noninvasive, easy to perform, and can be conducted daily. PMID- 21816914 TI - Trastuzumab (herceptin). AB - Herceptin (trastuzumab) is a human monoclonal antibody that interferes with the HER2 receptor. It is currently the only FDA-approved therapeutic antibody for HER2-positive breast cancer. This article will present the mechanism at action as well as the clinical role at this monoclonal antibody. PMID- 21816915 TI - Effect of lens-induced myopia on visual cortex activity: a functional MR imaging study. AB - BACKGROUND AND PURPOSE: Myopia is a type of refractive error that blurs retinal image and in turn can change neural signals transferred from retina to visual cortex. The purpose of this study was to evaluate the effect of induced myopia on occipital visual cortex activity by fMRI results. MATERIALS AND METHODS: BOLD fMRI was performed in 13 emmetropic volunteers (refractive error, <+/-0.50D) with normal visual acuity, good binocular vision, and no history of neurologic illness. Visual stimulus was counterphasing vertical luminance sinusoidal grating with spatiotemporal frequency of 1.84 cycles per degree/8 Hz and contrast of 60%. The functional images were acquired in block design, during normal refractive state and induced myopia produced by convex noncoating plastic lenses of +1D, +3D, +5D, by using an EPI gradient-echo sequence in a 1.5T MR imaging scanner. fMRI data were processed by using FSL software. RESULTS: fMRI responses to visual stimuli demonstrated that percentage of BOLD signal intensity change and number of activated voxels within occipital visual cortex were reduced remarkably in induced myopic states of 1D, 3D, and 5D in comparison with normal refractive state; the results did not show a significant and regular decreasing trend in number of activated voxels and BOLD signal intensity change in these 3 different values of induced myopia. CONCLUSIONS: The findings suggest that induced myopia has a considerable effect on visual cortex activity, because myopia induced by lens of +1D is sufficient to change fMRI results significantly. Accordingly, it is essential to correct myopia before visual fMRI studies, even if it is at low levels. PMID- 21816916 TI - Endovascular management of cerebral bypass graft problems: an analysis of technique and results. AB - BACKGROUND AND PURPOSE: Cerebral bypass grafts may develop generalized graft narrowing or focal stenosis during the perioperative period or later. Endovascular techniques such as PTA and stent placement of graft vessels are potential treatment options. Our objective was to review the safety, indications, technique, and results of endovascular management of graft problems. MATERIALS AND METHODS: All patients with cerebral bypass procedures by using graft vessels from 2005 to 2009 were identified from a prospective registry and were studied retrospectively. Patient characteristics, bypass procedures, indications for endovascular interventions, graft patency, and clinical outcomes were reviewed from medical charts and imaging records. RESULTS: A total of 79 patients underwent bypass procedures by using graft vessels. Seven patients of this group underwent endovascular interventions for the treatment of graft narrowing. Four of the 7 patients were treated for graft narrowing in the perioperative period (<1 month) with PTA; and 3 of the 7 patients, for late stenosis, 2 with PTA alone and 1 with PTA followed by stent placement. All procedures were immediately successful in improving flow through the graft. In late stenosis, PTA alone provided temporary improvement followed by recurrence, whereas PTA with a stent procedure was effective in the 1 patient long term. CONCLUSIONS: PTA is safe and effective in the management of graft spasm in the perioperative period. For late graft stenosis, PTA alone provides only temporary respite, while PTA with stent placement may be an effective solution. PMID- 21816917 TI - Discharge disposition following vertebroplasty. AB - BACKGROUND AND PURPOSE: A variety of factors, such as pain level at rest and with activity, have been used to assess outcome of the VP procedure. However, few studies have assessed discharge disposition as a reflection of VP efficacy in the inpatient population. The purpose of this study was to compare patient disposition status before and after VP and determine what relationship exists between the treatment and patient discharge status. MATERIALS AND METHODS: We performed a retrospective review of inpatients who underwent consultation for consideration of spinal augmentation for treatment of painful vertebral compression fractures. We gathered data concerning patients' demographics, living arrangements before hospitalization, discharge disposition, quantitative and qualitative pain levels, and length of hospital stay before and following VP. RESULTS: Ninety inpatients underwent VP, 73 (81%) of whom lived independently at home before hospitalization. Of these 73 patients, 31 (42%) returned home after discharge, 9 (12%) returned home with home health care assistance, and 32 (44%) were sent to skilled nursing facilities. Six (7%) of the 90 patients resided in assisted-living centers before hospitalization; all of these patients were discharged to assisted-living or skilled nursing facilities. Eight (9%) of the 90 patients resided at skilled nursing centers before hospitalization, and all returned to nursing centers after their hospital stay. Discharge disposition was not significantly associated with preoperative pain levels at rest or with activity (P = .76 and P = .23, respectively) or with postoperative pain levels at rest or with activity (P = .08 and P = .25, respectively). CONCLUSIONS: This study demonstrates that patients undergoing VP as inpatients are often discharged to rehabilitation centers rather than home, irrespective of their status before hospitalization or their pre- and postoperative pain levels. PMID- 21816918 TI - Parent vessel size and curvature strongly influence risk of incomplete stent apposition in enterprise intracranial aneurysm stent coiling. AB - BACKGROUND AND PURPOSE: Flexible microstents, such as the closed-cell EN, have facilitated adjunctive coiling of intracranial aneurysms. Little data are available on the ability of the stent struts to maintain vessel-wall apposition once deployed in the tortuous cerebral vasculature and the prevalence of ISA. The purpose of this study was to evaluate the relationship between geometric features of the parent vessel at the stent deployment site and prevalence of ISA. MATERIALS AND METHODS: Postprocedural 3T-MRA was performed in a cohort of 39 patients undergoing EN stent-assisted intracranial aneurysm coiling. 3T-MRA was analyzed for the presence of ISA and supplemented by angiographic C-arm FPCT (DynaCT). Parent vessel diameter, curvature radius, and stent-subtended arc angle were measured at the site of deployment and analyzed for prediction of ISA in the ICA. RESULTS: 3T-MRA uncovered a unique crescent flow pattern (CS) outside the EN struts, which was confirmed by FPCT to indicate ISA resulting from EN crimping. ISA was detected on 3T-MRA in 19/39 patients (49%). Univariate analysis revealed ISA in the ICA to correlate with a large stent-subtended angle, a small curvature radius, and a large diameter but not stent length or jailing versus a sequential technique. Multivariate analysis identified ISA to correlate with vessel curvature radius (OR, 253; P = .009), stent-subtended angle (OR, 225; P = .005), and parent vessel diameter (OR, 8.49; P = .044). CONCLUSIONS: In this study, ISA was detectable by 3T-MRA in a significant proportion of patients undergoing EN stent-assisted coiling of ICA aneurysms in a vessel geometry- and stent deployment location-dependent manner. This characteristic of EN coiling at this potentially tortuous location should be taken into account when selecting an endovascular strategy. PMID- 21816919 TI - CT perfusion in acute ischemic stroke: a comparison of 2-second and 1-second temporal resolution. AB - BACKGROUND AND PURPOSE: CT perfusion data sets are commonly acquired using a temporal resolution of 1 image per second. To limit radiation dose and allow for increased spatial coverage, the reduction of temporal resolution is a possible strategy. The aim of this study was to evaluate the effect of reduced temporal resolution in CT perfusion scans with regard to color map quality, quantitative perfusion parameters, ischemic lesion extent, and clinical decision-making when using DC and MS algorithms. MATERIALS AND METHODS: CTP datasets from 50 patients with acute stroke were acquired with a TR of 1 second. Two-second TR datasets were created by removing every second image. Various perfusion parameters (CBF, CBV, MTT, TTP, TTD) and color maps were calculated by using identical data processing settings for 2-second and 1-second TR. Color map quality, quantitative region-of-interest-based perfusion measurements, and TAR/NVT lesions (indicated by CBF/CBV mismatch) derived from the 2-second and 1-second processed data were statistically compared. RESULTS: Color map quality was similar for 2-second versus 1-second TR when using DC and was reduced when using MS. Regarding quantitative values, differences between 2-second and 1-second TR datasets were statistically significant by using both algorithms. Using DC, corresponding tissue-at-risk lesions were slightly smaller at 2-second versus 1-second TR (P < .05), whereas corresponding NVT lesions showed excellent agreement. With MS, corresponding tissue-at-risk lesions showed excellent agreement but more artifacts, whereas NVT lesions were larger (P < .001) compared with 1-second TR. Therapeutic decisions would have remained the same in all patients. CONCLUSIONS: CTP studies obtained with 2-second TR are typically still diagnostic, and the same therapy would have been provided. However, with regard to perfusion quantitation and image-quality-based confidence, our study indicates that 1 second TR is preferable to 2-second TR. PMID- 21816920 TI - Vascular geometry change because of endovascular stent placement for anterior communicating artery aneurysms. AB - BACKGROUND AND PURPOSE: Hemodynamics have been shown to play an important role in the initiation and progress of intracranial aneurysms, and are considered well related to vascular configuration. The purpose of this study was to quantify the vascular geometry change due to intracranial stent placement and to discuss its potential effects on hemodynamics. MATERIALS AND METHODS: Imaging data of patients with wide-neck AcomA aneurysms, treated with stent-assisted coiling between January 2005 and January 2010, were retrospectively analyzed. The angle between the afferent vessels (A1 segment) and the efferent vessels (ipsilateral or contralateral A2 segment) was calculated to determine the exact change in the angle after stent placement. RESULTS: In all 20 patients, the stent caused a distinct change in the geometry of the parent vessel. Stent-related vascular angle change ranged from 7.60 to 74.88 degrees , with an average of 29.95 degrees . In 10 cases, the angle changed by >30 degrees . In the 12 patients with the distal segment of the stent placed in the ipsilateral A2 segment, the mean postoperative A1-A2 angle increased by 27.71 +/- 13.17 degrees (from 7.60 degrees to 48.29 degrees ). In the other 8 patients with the distal segment of the stent placed in the contralateral A2 segment, the mean postoperative A1-AcomA A2 angle increased by 33.29 +/- 21.89 degrees (from 15.49 degrees to 74.88 degrees ). CONCLUSIONS: In addition to serving as a scaffold to contain coils, stent placement for AcomA aneurysms has a substantial effect on the vascular geometry, which may result in local hemodynamic changes. PMID- 21816921 TI - Altered microstructure in corticospinal tract in idiopathic normal pressure hydrocephalus: comparison with Alzheimer disease and Parkinson disease with dementia. AB - BACKGROUND AND PURPOSE: Previous neuropathologic studies in chronic hydrocephalus have suggested the presence of white matter damage, presumably from mechanical pressure due to ventricular enlargement and metabolic derangement. This study aimed to investigate the diffusional properties of the CST in patients with iNPH by using DTI and to determine whether this method could be used as a new diagnostic tool to differentiate patients with iNPH from those with AD and PDD and control subjects. MATERIALS AND METHODS: We enrolled 18 patients with iNPH, 11 patients with AD, 11 patients with PDD, and 19 healthy control subjects. Diffusion tensor metrics of the segmented CST, including FA values, axial eigenvalues, and radial eigenvalues, were evaluated by using tract-specific analysis. The anisotropy color-coding tractography of the CST was visually evaluated. The DTI findings were compared among groups. RESULTS: Tract-specific analysis of the CST showed that FA values and axial eigenvalues were significantly increased (P < .001), whereas radial eigenvalues were not significantly altered, in patients with iNPH compared with other subjects. The CST tractographic images in patients with iNPH was visually different from those in other subjects (P < .001). In discriminating patients with iNPH from other subjects, the CST FA values had a sensitivity of 94% and specificity of 80% at a cutoff value of 0.59. CONCLUSIONS: Our results suggest that patients with iNPH have altered microstructures in the CST. Quantitative and visual CST evaluation by using DTI may be useful for differentiating patients with iNPH from patients with AD or PDD or healthy subjects. PMID- 21816922 TI - miR-17~92 cooperates with RB pathway mutations to promote retinoblastoma. AB - The miR-17~92 cluster is a potent microRNA-encoding oncogene. Here, we show that miR-17~92 synergizes with loss of Rb family members to promote retinoblastoma. We observed miR-17~92 genomic amplifications in murine retinoblastoma and high expression of miR-17~92 in human retinoblastoma. While miR-17~92 was dispensable for mouse retinal development, miR-17~92 overexpression, together with deletion of Rb and p107, led to rapid emergence of retinoblastoma with frequent metastasis to the brain. miR-17~92 oncogenic function in retinoblastoma was not mediated by a miR-19/PTEN axis toward apoptosis suppression, as found in lymphoma/leukemia models. Instead, miR-17~92 increased the proliferative capacity of Rb/p107 deficient retinal cells. We found that deletion of Rb family members led to compensatory up-regulation of the cyclin-dependent kinase inhibitor p21Cip1. miR 17~92 overexpression counteracted p21Cip1 up-regulation, promoted proliferation, and drove retinoblastoma formation. These results demonstrate that the oncogenic determinants of miR-17~92 are context-specific and provide new insights into miR 17~92 function as an RB-collaborating gene in cancer. PMID- 21816923 TI - Crystal structure of the Gtr1p-Gtr2p complex reveals new insights into the amino acid-induced TORC1 activation. AB - The target of rapamycin (TOR) complex 1 (TORC1) is a central cell growth regulator in response to a wide array of signals. The Rag GTPases play an essential role in relaying amino acid signals to TORC1 activation through direct interaction with raptor and recruitment of the TORC1 complex to lysosomes. Here we present the crystal structure of the Gtr1p-Gtr2p complex, the Rag homologs from Saccharomyces cerevisiae, at 2.8 A resolution. The heterodimeric GTPases reveal a pseudo-twofold symmetric organization. Structure-guided functional analyses of RagA-RagC, the human homologs of Gtr1p-Gtr2p, show that both G domains (N-terminal GTPase domains) and dimerization are important for raptor binding. In particular, the switch regions of the G domain in RagA are indispensible for interaction with raptor, and hence TORC1 activation. The dimerized C-terminal domains of RagA-RagC display a remarkable structural similarity to MP1/p14, which is in a complex with lysosome membrane protein p18, and directly interact with p18, therefore recruiting mTORC1 to the lysosome for activation by Rheb. Our results reveal a structural model for the mechanism of the Rag GTPases in TORC1 activation and amino acid signaling. PMID- 21816924 TI - A cell-intrinsic role for CaMKK2 in granulocyte lineage commitment and differentiation. AB - Granulocytes serve a critical function in host organisms by recognizing and destroying invading microbes, as well as propagating and maintaining inflammation at sites of infection. However, the molecular pathways underpinning the development of granulocytes are poorly understood. Here, we identify a role for CaMKK2 in the restriction of granulocytic fate commitment and differentiation of myeloid progenitor cells. Following BMT, engraftment by Camkk2(-/-) donor cells resulted in the increased production of mature granulocytes in the BM and peripheral blood. Similarly, Camkk2(-/-) mice possessed elevated numbers of CMP cells and exhibited an accelerated granulopoietic phenotype in the BM. Camkk2(-/ ) myeloid progenitors expressed increased levels of C/EBPalpha and PU.1 and preferentially differentiated into Gr1(+)Mac1(+) granulocytes and CFU-G in vitro. During normal granulopoiesis in vivo or G-CSF-induced differentiation of 32D myeloblast cells in vitro, CaMKK2 mRNA and protein were decreased as a function of time and were undetectable in mature granulocytes. Expression of ectopic CaMKK2 in Camkk2(-/-) CMPs was sufficient to rescue aberrant granulocyte differentiation and when overexpressed in 32D cells, was also sufficient to impede granulocyte differentiation in a kinase activity-dependent manner. Collectively, our results reveal a novel role for CaMKK2 as an inhibitor of granulocytic fate commitment and differentiation in early myeloid progenitors. PMID- 21816925 TI - When will the News of the World moment arrive for medical journals? PMID- 21816926 TI - Health is global--what does that mean for the United Kingdom? PMID- 21816927 TI - Response to Antibiotic prophylaxis of endocarditis: the rest of the world and NICE. PMID- 21816928 TI - Work and ill-health. PMID- 21816929 TI - Lord Byron's first voyage in Greece (1810) and the neglected case of malaria. PMID- 21816930 TI - Reducing global health inequalities. Part 1. AB - This paper summarizes four UK reviews of socially stratified health inequalities that were undertaken during the past five decades. It describes the background of misplaced optimism and false hopes which characterized the UK's own record of health inequalities; the broken promises on debt cancellations which was the experience of developing countries. It describes why the UK's past leadership record in international health provides grounds for optimism for the future and for benefits for both developed and developing countries through the adoption of more collaborative approaches to global health than have characterized international relationships in the past. It recalls the enthusiasm generated in the UK, and internationally, by the establishment of the Global Commission on the Social Determinants of Health. It promotes the perception of health both as a global public good and as a developmental issue and why a focus on poverty is essential to the address of global health issues. It sees the designing of appropriate strategies and partnerships towards the achievement of the Millennium Development Goals as an important first step for achieving successful address to global public health issues. PMID- 21816931 TI - Mortality from pulmonary embolism is decreasing in hospital patients. AB - OBJECTIVES: Pulmonary embolism is believed to be a common cause of death of hospital inpatients. The aims of this study were to estimate the number of deaths caused by pulmonary embolism and the potential to reduce this by the use of caval filters according to accepted indications. DESIGN: Review of autopsy reports and death notification records from 2007 and 2008. When pulmonary embolism was given as cause of death (in the autopsy report or in section 1 a-c or part 2 of the Medical Certificate of the Cause of Death), hospital records were reviewed for evidence of pre-mortem diagnosis of pulmonary embolism or deep vein thrombosis (DVT) and for evidence of accepted indications for caval filter placement. SETTING: Large UK teaching hospital. PARTICIPANTS: Hospital inpatients whose deaths were attributed to pulmonary embolism. MAIN OUTCOME MEASURES: Proportion of deaths adjudged at autopsy to be due to pulmonary embolism; evidence of pre mortem diagnosis of DVT or pulmonary embolism; total number of hospital admission and deaths. RESULTS: From a total of 186,517 adult inpatient admissions there were 2583 (1.4%) adult inpatient deaths of which 696 (27%) underwent autopsy. Of those undergoing autopsy, 14 (2.0%, 95% CI 1.2-3.3%) deaths were caused by pulmonary embolism. Pulmonary embolism was recorded as a cause of death in a further 12 (0.7%) of 1773 patients who did not undergo autopsy. Of these, five had a pre-mortem diagnosis of DVT or pulmonary embolism. CONCLUSIONS: The proportion of deaths caused by pulmonary embolism appears to be considerably lower than the widely published rate, and of this small number, few have a pre mortem diagnosis of DVT or pulmonary embolism. There is little scope for further reduction of pulmonary embolism mortality through use of caval filters according to guidelines. Current policy on pulmonary embolism risk prevention appears to be based on an over-estimate of the level of risk. PMID- 21816932 TI - Orbital Wegener's granulomatosis as the initial presentation in a 9-year-old child. PMID- 21816933 TI - The Medical Research Council and clinical trial methodologies before the 1940s: the failure to develop a 'scientific' approach. PMID- 21816934 TI - Paediatric trainees and the quality improvement agenda: don't just do another audit. PMID- 21816936 TI - CXCL16 recruits bone marrow-derived fibroblast precursors in renal fibrosis. AB - Although fibroblasts are responsible for the production and deposition of extracellular matrix in renal fibrosis, their origin is controversial. Circulating fibroblast precursors may contribute to the pathogenesis of renal fibrosis, but the signaling mechanisms underlying the recruitment of bone marrow derived fibroblast precursors into the kidney in response to injury are incompletely understood. Here, in the unilateral ureteral obstruction model of renal fibrosis, tubular epithelial cells upregulated the chemokine CXCL16 in obstructed kidneys, and circulating fibroblast precursors expressed the CXCL16 receptor, CXCR6. Compared with wild-type mice, CXCL16-knockout mice accumulated significantly fewer bone marrow-derived fibroblast precursors in obstructed kidneys. CXCL16-knockout mice also exhibited significantly fewer CD45-, collagen I-, and CXCR6-triple-positive fibroblast precursors in injured kidneys. Furthermore, targeted deletion of CXCL16 inhibited myofibroblast activation, reduced collagen deposition, and suppressed expression of collagen I and fibronectin. In conclusion, CXCL16 contributes to the pathogenesis of renal fibrosis by recruiting bone marrow-derived fibroblast precursors. PMID- 21816937 TI - Targeted inhibition of beta-catenin/CBP signaling ameliorates renal interstitial fibrosis. AB - Because fibrotic kidneys exhibit aberrant activation of beta-catenin signaling, this pathway may be a potential target for antifibrotic therapy. In this study, we examined the effects of beta-catenin activation on tubular epithelial mesenchymal transition (EMT) in vitro and evaluated the therapeutic efficacy of the peptidomimetic small molecule ICG-001, which specifically disrupts beta catenin-mediated gene transcription, in obstructive nephropathy. In vitro, ectopic expression of stabilized beta-catenin in tubular epithelial (HKC-8) cells suppressed E-cadherin and induced Snail1, fibronectin, and plasminogen activator inhibitor-1 (PAI-1) expression. ICG-001 suppressed beta-catenin-driven gene transcription in a dose-dependent manner and abolished TGF-beta1-induced expression of Snail1, PAI-1, collagen I, fibronectin, and alpha-smooth muscle actin (alpha-SMA). This antifibrotic effect of ICG-001 did not involve disruption of Smad signaling. In the unilateral ureteral obstruction model, ICG-001 ameliorated renal interstitial fibrosis and suppressed renal expression of fibronectin, collagen I, collagen III, alpha-SMA, PAI-1, fibroblast-specific protein-1, Snail1, and Snail2. Late administration of ICG-001 also effectively attenuated fibrotic lesions in obstructive nephropathy. In conclusion, inhibiting beta-catenin signaling may be an effective approach to the treatment of fibrotic kidney diseases. PMID- 21816938 TI - Lower airway rhinovirus burden and the seasonal risk of asthma exacerbation. AB - RATIONALE: Most asthma exacerbations are initiated by viral upper respiratory illnesses. It is unclear whether human rhinovirus (HRV)-induced exacerbations are associated with greater viral replication and neutrophilic inflammation compared with HRV colds. OBJECTIVES: To evaluate viral strain and load in a prospective asthma cohort during a natural cold. METHODS: Adults were enrolled at the first sign of a cold, with daily monitoring of symptoms, medication use, and peak expiratory flow rate until resolution. Serial nasal lavage and induced sputum samples were assessed for viral copy number and inflammatory cell counts. MEASUREMENTS AND MAIN RESULTS: A total of 52 persons with asthma and 14 control subjects without atopy or asthma were studied for over 10 weeks per subject on average; 25 participants developed an asthma exacerbation. Detection of HRVs in the preceding 5 days was the most common attributable exposure related to exacerbation. Compared with other infections, those by a minor group A HRV were 4.4- fold more likely to cause exacerbation (P = 0.038). Overall, sputum neutrophils and the burden of rhinovirus in the lower airway were similar in control subjects without atopy and the asthma group. However, among HRV-infected participants with asthma, exacerbations were associated with greater sputum neutrophil counts (P = 0.005). CONCLUSIONS: HRV infection is a frequent cause of exacerbations in adults with asthma and a cold, and there may be group-specific differences in severity of these events. The absence of large differences in viral burden among groups suggests differential lower airway sensitization to the effects of neutrophilic inflammation in the patients having exacerbations. PMID- 21816939 TI - Role of growth arrest and DNA damage-inducible alpha in Akt phosphorylation and ubiquitination after mechanical stress-induced vascular injury. AB - RATIONALE: The stress-induced growth arrest and DNA damage-inducible a (GADD45a) gene is up-regulated by mechanical stress with GADD45a knockout (GADD45a(-/-)) mice demonstrating both increased susceptibility to ventilator-induced lung injury (VILI) and reduced levels of the cell survival and vascular permeability signaling effector (Akt). However, the functional role of GADD45a in the pathogenesis of VILI is unknown. OBJECTIVES: We sought to define the role of GADD45a in the regulation of Akt activation induced by mechanical stress. METHODS: VILI-challenged GADD45a(-/-) mice were administered a constitutively active Akt1 vector and injury was assessed by bronchoalveolar lavage cell counts and protein levels. Human pulmonary artery endothelial cells (EC) were exposed to 18% cyclic stretch (CS) under conditions of GADD45a silencing and used for immunoprecipitation, Western blotting or immunofluoresence. EC were also transfected with mutant ubiquitin vectors to characterize site-specific Akt ubiquitination. DNA methylation was measured using methylspecific polymerase chain reaction assay. MEASUREMENTS AND MAIN RESULTS: Studies exploring the linkage of GADD45a with mechanical stress and Akt regulation revealed VILI challenged GADD45a(-/-) mice to have significantly reduced lung injury on overexpression of Akt1 transgene. Increased mechanical stress with 18% CS in EC induced Akt phosphorylation via E3 ligase tumor necrosis factor receptor associated factor 6 (TRAF6)-mediated Akt K63 ubiquitination resulting in Akt trafficking and activation at the membrane. GADD45a is essential to this process because GADD45a silenced endothelial cells and GADD45a(-/-) mice exhibited increased Akt K48 ubiquitination leading to proteasomal degradation. These events involve loss of ubiquitin carboxyl terminal hydrolase 1(UCHL1), a deubiquitinating enzyme that normally removes K48 polyubiquitin chains bound to Akt thus promoting Akt K63 ubiquitination. Loss of GADD45a significantly reduces UCHL1 expression via UCHL1 promoter methylation resulting in increased Akt K48 ubiquitination and reduced Akt levels. CONCLUSIONS: These studies highlight a novel role for GADD45a in the regulation of site-specific Akt ubiquitination and activation and implicate a significant functional role for GADD45a in the clinical predisposition to VILI. PMID- 21816940 TI - Early-onset pneumonia after cardiac arrest: characteristics, risk factors and influence on prognosis. AB - RATIONALE: Although frequent, little is known about early-onset pneumonia that occurs in the postresuscitation period. Although induced hypothermia is recommended as a method of improving neurological outcome, its influence on the occurrence of early-onset pneumonia is not well defined. OBJECTIVES: To describe the incidence, risk factors, causative agents, and impact on outcome of early onset pneumonia occurring within 3 days after out-of-hospital cardiac arrest (OHCA). METHODS: Retrospective analysis of a large cohort study of all patients successfully resuscitated after OHCA and admitted from July 2002 to March 2008 in two medical intensive care units (ICUs). Patients who presented accidental hypothermia or a known pneumonia before OHCA, or patients who died within the first 24 hours, were excluded. MEASUREMENTS AND MAIN RESULTS: During this 6-year period, 845 patients were admitted after OHCA, and 641 consecutive patients were included. A total of 500 patients (78%) were treated with therapeutic hypothermia. In the first 3 days, 419 (65%) presented early-onset pneumonia. Multivariate analysis disclosed therapeutic hypothermia as the single independent risk factor of early-onset pneumonia (odds ratio, 1.90; 95% confidence interval, 1.28-2.80; P = 0.001). Early-onset pneumonia increased length of mechanical ventilation (5.7 +/- 5.9 vs. 4.7 +/- 6.2 d; P = 0.001) and ICU stay (7.9 +/- 7.2 versus 6.7 +/- 7.6 d; P = 0.001), but did not influence incidence of ventilator associated pneumonia (P = 0.25), favorable neurologic outcome (P = 0.35), or ICU mortality (P = 0.26). CONCLUSIONS: After OHCA, therapeutic hypothermia is associated with an increased risk of early-onset pneumonia. This complication was associated with prolonged respiratory support and ICU stay, but did not significantly influence ICU mortality. PMID- 21816941 TI - Loop gain as a means to predict a positive airway pressure suppression of Cheyne Stokes respiration in patients with heart failure. AB - RATIONALE: Patients with heart failure (HF) and Cheyne-Stokes respiration or periodic breathing (PB) often demonstrate improved cardiac function when treatment with continuous positive airway pressure (CPAP) resolves PB. Unfortunately, CPAP is successful in only 50% of patients, and no known factor predicts responders to treatment. Because PB manifests from a hypersensitive ventilatory feedback loop (elevated loop gain [LG]), we hypothesized that PB persists on CPAP when LG far exceeds the critical threshold for stable ventilation (LG = 1). OBJECTIVES: To derive, validate, and test the clinical utility of a mathematically precise method that quantifies LG from the cyclic pattern of PB, where LG = 2pi/(2piDR - sin2piDR) and DR (i.e., duty ratio) = (ventilatory duration)/(cycle duration) of PB. METHODS: After validation in a mathematical model of HF, we tested whether our estimate of LG changes with CPAP (n = 6) and inspired oxygen (n = 5) as predicted by theory in an animal model of PB. As a first test in patients with HF (n = 14), we examined whether LG predicts the first-night CPAP suppression of PB. MEASUREMENTS AND MAIN RESULTS: In lambs, as predicted by theory, LG fell as lung volume increased with CPAP (slope = 0.9 +/- 0.1; R(2) = 0.82; P < 0.001) and as inspired-arterial PO(2) difference declined (slope = 1.05 +/- 0.12; R(2) = 0.75; P < 0.001). In patients with HF, LG was markedly greater in 8 CPAP nonresponders versus 6 responders (1.29 +/- 0.04 versus 1.10 +/- 0.01; P < 0.001); LG predicted CPAP suppression of PB in 13/14 patients. CONCLUSIONS: Our novel LG estimate enables quantification of the severity of ventilatory instability underlying PB, making possible a priori selection of patients whose PB is immediately treatable with CPAP therapy. PMID- 21816942 TI - Novel variants of the qnrB gene, qnrB31 and qnrB32, in Klebsiella pneumoniae. AB - Quinolone resistance in the family Enterobacteriaceae is mostly attributed to the accumulation of mutations in the bacterial enzymes targeted by fluoroquinolones: DNA gyrase and DNA topoisomerase IV. Here we isolated the Klebsiella pneumoniae strains KP3606 and KP4707 from different specimens from 2008 to 2010 in Taizhou Municipal Hospital of China, and discovered a new subtype qnrB31, for which the GenBank accession number is HQ418999, and another new subtype qnrB32, for which the GenBank accession number is HQ704413. Susceptibility testing showed that KP3606 had a reduced susceptibility (MIC >=0.5 ug ml(-1)) to quinolones, while KP4707 was resistant to quinolones. Of all qnrB alleles, the novel variants the qnrB32 gene and qnrB31 gene have the highest amino acid identity. The results suggested that of all the various genes involved in resistance to quinolones, the qnrB gene is the most likely to be mutated, and plasmids might play a role in the dissemination and evolution of qnrB genes. PMID- 21816943 TI - Prevalence of plasmid-mediated quinolone resistance determinants in Citrobacter freundii isolates from Anhui province, PR China. AB - This study was conducted to detect and analyse the presence of plasmid-mediated quinolone resistance (PMQR) determinants [qnr, aac(6')-Ib-cr and qepA] among Citrobacter freundii isolates from patients in Anhui province, PR China. During 2009-2010, 31 C. freundii strains were collected from various hospital units and patient specimens. Using PCR, qnr genes were detected in eight isolates, but aac(6')-Ib-cr and qepA genes were not found. The genes qnrA1, qnrB1, qnrB2, qnrB4, qnrB10 and qnrB24 were present in 6.5, 3.2, 6.5, 3.2, 3.2 and 3.2% of C. freundii isolates, respectively. A new subgene of qnrB variant (qnrB24) was found and identified for what we believe to be the first time. PFGE after XbaI digestion of genomic DNA indicated that qnr-positive strains were not clonally related. Conjugation experiments were conducted to determine whether the qnr carrying plasmids were self-transferable, and plasmids of transconjugants were extracted and analysed. The qnr genes were transferred from three clinical isolates to their transconjugants. Two qnrA1 genes transferred quinolone resistance with a plasmid of ~11 kb, whilst the size of the plasmid carrying the qnrB4 gene was ~64 kb. The susceptibility of positive isolates and transconjugants was tested using an agar dilution method according to Clinical and Laboratory Standards Institute guidelines, and the MICs of ciprofloxacin and levofloxacin were determined using Etest strips. Most isolates with qnr genes were resistant to fluoroquinolones and other antimicrobial agents. The MICs of transconjugants showed reduced susceptibility to fluoroquinolones. PMID- 21816944 TI - Interleukin-1 alpha produced by human T-cell leukaemia virus type I-infected T cells induces intercellular adhesion molecule-1 expression on lung epithelial cells. AB - The pathogenic mechanism of human T-cell leukaemia virus type I (HTLV-I)-related pulmonary disease, which involves overexpression of intercellular adhesion molecule-1 (ICAM-1) in lung epithelial cells, was investigated. The supernatant of HTLV-I-infected Tax(+) MT-2 and C5/MJ cells induced ICAM-1 expression on A549 cells, a human tumour cell line with the properties of alveolar epithelial cells. Neutralization of ICAM-1 partially inhibited HTLV-I-infected T-cell adhesion to A549 cells. Analysis of the ICAM-1 promoter showed that the nuclear factor-kappa B-binding site was important for supernatant-induced ICAM-1 expression. Induction of interleukin (IL)-1 alpha (IL-1alpha) expression in MT-2 and C5/MJ cells was observed compared with uninfected controls and HTLV-I-infected Tax-negative cell lines. The significance of IL-1alpha as a soluble messenger was supported by blocking the biological activities of MT-2 supernatant with an IL-1alpha neutralizing mAb. Moreover, Tax and IL-1alpha expression was demonstrated in the bronchoalveolar lavage cells of patients with HTLV-I-related pulmonary disease. Immunohistochemistry confirmed ICAM-1 and IL-1alpha expression in lung epithelial cells and lymphocytes of patients with HTLV-I-related pulmonary diseases, and in a transgenic mouse model of Tax expression. These results suggest that IL-1alpha produced by HTLV-I-infected Tax(+) T cells is crucial for ICAM-1 expression in lung epithelial cells and subsequent adhesion of lymphocytes in HTLV-I-related pulmonary diseases. PMID- 21816945 TI - Rhodomyrtus tomentosa (Aiton) Hassk. ethanol extract and rhodomyrtone: a potential strategy for the treatment of biofilm-forming staphylococci. AB - The anti-staphylococcal activity of an ethanol extract of Rhodomyrtus tomentosa and its pure compound, rhodomyrtone, as well as their effects on staphylococcal biofilm formation and biofilm-grown cells were assessed. MIC and minimal bactericidal concentration values of the ethanol extract and rhodomyrtone against planktonic cultures and biofilms of five clinical strains each of Staphylococcus aureus and Staphylococcus epidermidis, and American Type Culture Collection (ATCC) strains of both species, were 32-512 and 0.25-2 ug ml(-1), respectively. Results from time-kill studies indicated that rhodomyrtone at a concentration of 4* MIC could reduce the number of Staphylococcus aureus ATCC 25923 and Staphylococcus epidermidis ATCC 35984 cells by 99.9% within 3 and 13 h, respectively. The ability of rhodomyrtone and the ethanol extract to prevent biofilm formation and kill mature biofilms was assessed: both demonstrated better activity than vancomycin at inhibiting staphylococcal biofilm formation. In addition, the viability of 24 h and 5-day staphylococcal biofilm-grown cells decreased after treatment with the ethanol extract and rhodomyrtone. The ability to reduce biofilm formation and kill mature biofilms occurred in a dose-dependent manner. Scanning electron microscopy clearly confirmed that treatment with rhodomyrtone at 16* MIC could reduce 24 h biofilm formation and the numbers of staphylococci, whilst at 64* MIC this compound destroyed the organisms in the 5 day established biofilm. These results suggest that rhodomyrtone has the potential for further drug development for the treatment of biofilm-forming staphylococcal infections. PMID- 21816946 TI - Changes in Toxoplasma diagnosis. AB - The serological laboratory workload in detecting toxoplasma infection may be expected to change with changes in the clinical profile of patient populations. We have examined the clinical information and laboratory results for patients referred to the Scottish Toxoplasma Reference Laboratory in April-March 1999-2000 and 2009-2010. Numbers of patient sera submitted for testing were similar (1624 and 1552) but there was a change in the clinical profile, with a significant fall in patients with symptoms of current infection (612 versus 335; P<0.0001) and a significant rise in immunocompromised patients (275 versus 531; P<0.0001). Although the percentage of patient samples with toxoplasma antibody decreased (53.9% versus 37.5%; P<0.0001), the number of positives increased with age, demonstrating the continuing risk of toxoplasma infection. More cases of current infection were identified in 2009-2010 than in 1999-2000 (48 versus 35). This increase was significant both for all females with current infection (P=0.0253) and also for those in the childbearing 20-39 years age group (P=0.0388). Our literature search did not find any published information on toxoplasma workload in the last decade. In summary, we have shown that there have been significant changes in the laboratory diagnosis of toxoplasma infection but it is as important as ever that effective diagnostic strategies are maintained. PMID- 21816947 TI - The ciliopathy gene cc2d2a controls zebrafish photoreceptor outer segment development through a role in Rab8-dependent vesicle trafficking. AB - Ciliopathies are a genetically and phenotypically heterogeneous group of human developmental disorders whose root cause is the absence or dysfunction of primary cilia. Joubert syndrome is characterized by a distinctive hindbrain malformation variably associated with retinal dystrophy and cystic kidney disease. Mutations in CC2D2A are found in ~10% of patients with Joubert syndrome. Here we describe the retinal phenotype of cc2d2a mutant zebrafish consisting of disorganized rod and cone photoreceptor outer segments resulting in abnormal visual function as measured by electroretinogram. Our analysis reveals trafficking defects in mutant photoreceptors affecting transmembrane outer segment proteins (opsins) and striking accumulation of vesicles, suggesting a role for Cc2d2a in vesicle trafficking and fusion. This is further supported by mislocalization of Rab8, a key regulator of opsin carrier vesicle trafficking, in cc2d2a mutant photoreceptors and by enhancement of the cc2d2a retinal and kidney phenotypes with partial knockdown of rab8. We demonstrate that Cc2d2a localizes to the connecting cilium in photoreceptors and to the transition zone in other ciliated cell types and that cilia are present in these cells in cc2d2a mutants, arguing against a primary function for Cc2d2a in ciliogenesis. Our data support a model where Cc2d2a, localized at the photoreceptor connecting cilium/transition zone, facilitates protein transport through a role in Rab8-dependent vesicle trafficking and fusion. PMID- 21816948 TI - Increased hedgehog signaling in postnatal kidney results in aberrant activation of nephron developmental programs. AB - Hedgehog (Hh) is a core signaling pathway implicated in fundamental processes during embryonic kidney development. We previously found that loss-of-function mutations in the transcription factor GLIS2, a putative vertebrate ortholog of Drosophila Ci, cause nephronophthisis type 7 in humans and mice. Kidney tubular cells in Glis2-knockout mice acquire mesenchymal phenotype, but the cellular mechanisms of this transition are unknown. Here, we demonstrate that Glis2 is a functional component of Hh signaling and is necessary to suppress this pathway in the postnatal kidney. In the epithelial compartment, Glis2 opposes Gli1 activity by binding cis-acting regulatory sequences in the 5' flanking regions of Snai1 and Wnt4, thereby inhibiting de-differentiation of tubular cells. We conclude that Glis2 is necessary to inhibit Hh signaling and to maintain the mature tubular epithelial phenotype in the adult kidney. This is the first description of a molecular mechanism that links the Hh signaling pathway to cystic kidney diseases and can open new avenues for the treatment of diverse ciliopathies. PMID- 21816949 TI - The in vivo contribution of motor neuron TrkB receptors to mutant SOD1 motor neuron disease. AB - Brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase B (TrkB) are widely expressed in the vertebrate nervous system and play a central role in mature neuronal function. In vitro BDNF/TrkB signaling promotes neuronal survival and can help neurons resist toxic insults. Paradoxically, BDNF/TrkB signaling has also been shown, under certain in vitro circumstances, to render neurons vulnerable to insults. We show here that in vivo conditional deletion of TrkB from mature motor neurons attenuates mutant superoxide dismutase 1 (SOD1) toxicity. Mutant SOD1 mice lacking motor neuron TrkB live a month longer than controls and retain motor function for a longer period, particularly in the early phase of the disease. These effects are subserved by slowed motor neuron loss, persistence of neuromuscular junction integrity and reduced astrocytic and microglial reactivity within the spinal cord. These results suggest that manipulation of BDNF/TrkB signaling might have therapeutic efficacy in motor neuron diseases. PMID- 21816950 TI - Abca12-mediated lipid transport and Snap29-dependent trafficking of lamellar granules are crucial for epidermal morphogenesis in a zebrafish model of ichthyosis. AB - Zebrafish (Danio rerio) can serve as a model system to study heritable skin diseases. The skin is rapidly developed during the first 5-6 days of embryonic growth, accompanied by expression of skin-specific genes. Transmission electron microscopy (TEM) of wild-type zebrafish at day 5 reveals a two-cell-layer epidermis separated from the underlying collagenous stroma by a basement membrane with fully developed hemidesmosomes. Scanning electron microscopy (SEM) reveals an ordered surface contour of keratinocytes with discrete microridges. To gain insight into epidermal morphogenesis, we have employed morpholino-mediated knockdown of the abca12 and snap29 genes, which are crucial for secretion of lipids and intracellular trafficking of lamellar granules, respectively. Morpholinos, when placed on exon-intron junctions, were >90% effective in preventing the corresponding gene expression when injected into one- to four-cell stage embryos. By day 3, TEM of abca12 morphants showed accumulation of lipid containing electron-dense lamellar granules, whereas snap29 morphants showed the presence of apparently empty vesicles in the epidermis. Evaluation of epidermal morphogenesis by SEM revealed similar perturbations in both cases in the microridge architecture and the development of spicule-like protrusions on the surface of keratinocytes. These morphological findings are akin to epidermal changes in harlequin ichthyosis and CEDNIK syndrome, autosomal recessive keratinization disorders due to mutations in the ABCA12 and SNAP29 genes, respectively. The results indicate that interference of independent pathways involving lipid transport in the epidermis can result in phenotypically similar perturbations in epidermal morphogenesis, and that these fish mutants can serve as a model to study the pathomechanisms of these keratinization disorders. PMID- 21816951 TI - The use of mouse models to understand and improve cognitive deficits in Down syndrome. AB - Remarkable advances have been made in recent years towards therapeutics for cognitive impairment in individuals with Down syndrome (DS) by using mouse models. In this review, we briefly describe the phenotypes of mouse models that represent outcome targets for drug testing, the behavioral tests used to assess impairments in cognition and the known mechanisms of action of several drugs that are being used in preclinical studies or are likely to be tested in clinical trials. Overlaps in the distribution of targets and in the pathways that are affected by these diverse drugs in the trisomic brain suggest new avenues for DS research and drug development. PMID- 21816952 TI - Executive function in 7-9-year-old children born extremely preterm or with extremely low birth weight: effects of biomedical history, age at assessment, and socioeconomic status. AB - Forty-five children born extremely preterm and/or with extremely low birth weight (ELBW), who were of average intelligence, were assessed at age 7-9 on a raft of measures of executive function (EF) designed to assess inhibition, set shifting, planning, fluency, and working memory. Relative to 45 full-term controls, the preterm/ELBW children showed reliable impairments of inhibition, fluency, and working memory. Among the 7-year olds, the preterm/ELBW group also showed significantly worse set shifting. After controlling for age and family socioeconomic status (SES), within-group analyses of the preterm/ELBW data revealed that higher birth weights were associated with better inhibition, whereas lower neurobiological risk (gauged by such aspects of neonatal medical history as a number of days on oxygen) was associated with better planning. Moreover, there were interactions between neurobiological risk and SES on the measures of inhibition, fluency, and working memory, indicating that the adverse effects of risk were greater among children from low-income households. These findings demonstrate that neonatal medical problems are associated with considerable variability in EF among normally developing preterm/ELBW children and implicate an important influence of the family environment on the maturation of EF. PMID- 21816953 TI - Application of homology modeling to generate CYP1A1 mutants with enhanced activation of the cancer chemotherapeutic prodrug dacarbazine. AB - The chemotherapeutic prodrug dacarbazine (DTIC) has limited efficacy in human malignancies and exhibits numerous adverse effects that arise from systemic exposure to the cytotoxic metabolite. DTIC is activated by CYP1A1 and CYP1A2 catalyzed N-demethylation. However, structural features of these enzymes that confer DTIC N-demethylation have not been characterized. A validated homology model of CYP1A1 was employed to elucidate structure-activity relationships and to engineer CYP1A1 enzymes with altered DTIC activation. In silico docking demonstrated that DTIC orientates proximally to Ser122, Phe123, Asp313, Ala317, Ile386, Tyr259, and Leu496 of human CYP1A1. The site of metabolism is positioned 5.6 A from the heme iron at an angle of 105.3 degrees . Binding in the active site is stabilized by H-bonding between Tyr259 and the N(2) position of the imidazole ring. Twenty-seven CYP1A1 mutants were generated and expressed in Escherichia coli in yields ranging from 9 to 225 pmol P450/mg. DTIC N demethylation by the E161K, E256K, and I458V mutants exhibited Michaelis-Menten kinetics, with decreases in K(m) (183-249 MUM) that doubled the catalytic efficiency (p < 0.05) relative to wild-type CYP1A1 (K(m), 408 +/- 43 MUM; V(max), 28 +/- 4 pmol . min(-1) . pmol of P450(-1)). The generation of enzymes with catalytically enhanced DTIC activation highlights the potential use of mutant CYP1A1 proteins in P450-based gene-directed enzyme prodrug therapy for the treatment of metastatic malignant melanoma. PMID- 21816954 TI - Dihydroxypentamethoxyflavone down-regulates constitutive and inducible signal transducers and activators of transcription-3 through the induction of tyrosine phosphatase SHP-1. AB - Because constitutive activation of signal transducers and activators of transcription-3 (STAT3) has been linked with cellular transformation, survival, proliferation, chemoresistance, and angiogenesis of various tumor cells, agents that can suppress STAT3 activation have potential as cancer therapeutics. In the present report, we identified a flavone from the leaves of a Thai plant, Gardenia obtusifolia, 5,3'-dihydroxy-3,6,7,8,4'-pentamethoxyflavone (PMF), that has the ability to inhibit STAT3 activation. PMF inhibited both constitutive and interleukin-6-inducible STAT3 activation in multiple myeloma (MM) cells, as indicated by suppression of STAT3 phosphorylation, nuclear translocation, DNA binding, and STAT3-regulated gene expression. The inhibition of STAT3 by PMF was reversible. We found that the activation of various kinases including Janus-like kinase (JAK)-1, JAK-2, c-Src, extracellular signal-regulated kinases 1 and 2, AKT, and epidermal growth factor receptor, implicated in STAT3 activation, were inhibited by the flavone. It is noteworthy that pervanadate suppressed the ability of PMF to inhibit the phosphorylation of STAT3, suggesting that protein tyrosine phosphatase was involved. PMF induced the expression of SHP-1 and was linked to the dephosphorylation of STAT3, because its deletion by small interfering RNA abolished the PMF-induced constitutive and inducible STAT3 inhibition. STAT3 inhibition led to the suppression of proteins involved in proliferation (cyclin D1 and c-myc), survival (survivin, Mcl-1, Bcl-xL, Bcl-2, and cIAP-2), and angiogenesis (vascular endothelial growth factor). Finally, PMF inhibited proliferation and induced apoptosis of MM cells. PMF also significantly potentiated the apoptotic effects of Velcade and thalidomide in MM cells. Overall, these results suggest that PMF is a novel blocker of STAT3 activation and thus may have potential in suppression of tumor cell proliferation and reversal of chemoresistance in MM cells. PMID- 21816956 TI - Antinociceptive and antihyperalgesic effects of tapentadol in animal models of inflammatory pain. AB - The novel analgesic tapentadol HCl [(-)-(1R,2R)-3-(3-dimethylamino)-1-ethyl-2 methyl-propyl)-phenol hydrochloride] combines MU-opioid receptor (MOR) agonism and noradrenaline reuptake inhibition (NRI) in a single molecule and shows a broad efficacy profile in various preclinical pain models. This study analyzed the analgesic activity of tapentadol in experimental inflammatory pain. Analgesia was evaluated in the formalin test (pain behavior, rat and mouse), carrageenan induced mechanical hyperalgesia (paw-pressure test, rat), complete Freund's adjuvant (CFA)-induced paw inflammation (tactile hyperalgesia, rat), and CFA knee joint arthritis (weight bearing, rat). Tapentadol showed antinociceptive activity in the rat and mouse formalin test with an efficacy of 88 and 86% and ED(50) values of 9.7 and 11.3 mg/kg i.p., respectively. Tapentadol reduced mechanical hyperalgesia in carrageenan-induced acute inflammatory pain by 84% with an ED(50) of 1.9 mg/kg i.v. In CFA-induced tactile hyperalgesia, tapentadol showed 71% efficacy with an ED(50) of 9.8 mg/kg i.p. The decrease in weight bearing after CFA injection in one knee joint was reversed by tapentadol by 51% with an ED(25) of 0.9 mg/kg i.v. Antagonism studies were performed with the MOR antagonist naloxone and the alpha(2)-noradrenergic receptor antagonist yohimbine in the carrageenan- and CFA-induced hyperalgesia model. In the CFA model, the serotonergic receptor antagonist ritanserin was also tested. The effect of tapentadol was partially blocked by naloxone and yohimbine and completely blocked by the combination of both, but it was not affected by ritanserin. In summary, tapentadol showed antinococeptive/antihyperalgesic analgesic activity in each model of acute and chronic inflammatory pain, and the antagonism experiments suggest that both MOR activation and NRI contribute to its analgesic effects. PMID- 21816955 TI - Molecular analysis and structure-activity relationship modeling of the substrate/inhibitor interaction site of plasma membrane monoamine transporter. AB - Plasma membrane monoamine transporter (PMAT) is a new polyspecific transporter that interacts with a wide range of structurally diverse organic cations. To map the physicochemical descriptors of cationic compounds that allow interaction with PMAT, we systematically analyzed the interactions between PMAT and three series of structural analogs of known organic cation substrates including phenylalkylamines, n-tetraalkylammonium (n-TAA) compounds, and beta-carbolines. Our results showed that phenylalkylamines with a distance between the aromatic ring and the positively charged amine nitrogen atom of ~6.4 A confer optimal interactions with PMAT, whereas studies with n-TAA compounds revealed an excellent correlation between IC(50) values and hydrophobicity. The five beta carbolines that we tested, which possess a pyridinium-like structure and are structurally related to the neurotoxin 1-methyl-4-phenylpyridinium, inhibited PMAT with high affinity (IC(50) values of 39.1-65.5 MUM). Cytotoxicity analysis further showed that cells expressing PMAT are 14- to 15-fold more sensitive to harmalan and norharmanium, suggesting that these two beta-carbolines are also transportable substrates of PMAT. We then used computer-aided modeling to generate qualitative and quantitative three-dimensional pharmacophore models on the basis of 23 previously reported and currently identified PMAT inhibitors and noninhibitors. These models are characterized by a hydrogen bond donor and two to three hydrophobic features with distances between the hydrogen bond donor and hydrophobic features ranging between 5.20 and 7.02 A. The consistency between the mapping results and observed PMAT affinity of a set of test compounds indicates that the models performed well in inhibitor prediction and could be useful for future virtual screening of new PMAT inhibitors. PMID- 21816957 TI - Point-of-care clinical documentation: assessment of a bladder cancer informatics tool (eCancerCareBladder): a randomized controlled study of efficacy, efficiency and user friendliness compared with standard electronic medical records. AB - OBJECTIVE: To compare the use of structured reporting software and the standard electronic medical records (EMR) in the management of patients with bladder cancer. The use of a human factors laboratory to study management of disease using simulated clinical scenarios was also assessed. DESIGN: eCancerCare(Bladder) and the EMR were used to retrieve data and produce clinical reports. Twelve participants (four attending staff, four fellows, and four residents) used either eCancerCare(Bladder) or the EMR in two clinical scenarios simulating cystoscopy surveillance visits for bladder cancer follow-up. MEASUREMENTS: Time to retrieve and quality of review of the patient history; time to produce and completeness of a cystoscopy report. Finally, participants provided a global assessment of their computer literacy, familiarity with the two systems, and system preference. RESULTS: eCancerCare(Bladder) was faster for data retrieval (scenario 1: 146 s vs 245 s, p=0.019; scenario 2: 306 vs 415 s, NS), but non-significantly slower to generate a clinical report. The quality of the report was better in the eCancerCare(Bladder) system (scenario 1: p<0.001; scenario 2: p=0.11). User satisfaction was higher with the eCancerCare(Bladder) system, and 11/12 participants preferred to use this system. LIMITATIONS: The small sample size affected the power of our study to detect differences. CONCLUSIONS: Use of a specific data management tool does not appear to significantly reduce user time, but the results suggest improvement in the level of care and documentation and preference by users. Also, the use of simulated scenarios in a laboratory setting appears to be a valid method for comparing the usability of clinical software. PMID- 21816958 TI - The NIAID Division of AIDS enterprise information system: integrated decision support for global clinical research programs. AB - The National Institute of Allergy and Infectious Diseases (NIAID) Division of AIDS (DAIDS) Enterprise Information System (DAIDS-ES) is a web-based system that supports NIAID in the scientific, strategic, and tactical management of its global clinical research programs for HIV/AIDS vaccines, prevention, and therapeutics. Different from most commercial clinical trials information systems, which are typically protocol-driven, the DAIDS-ES was built to exchange information with those types of systems and integrate it in ways that help scientific program directors lead the research effort and keep pace with the complex and ever-changing global HIV/AIDS pandemic. Whereas commercially available clinical trials support systems are not usually disease-focused, DAIDS ES was specifically designed to capture and incorporate unique scientific, demographic, and logistical aspects of HIV/AIDS treatment, prevention, and vaccine research in order to provide a rich source of information to guide informed decision-making. Sharing data across its internal components and with external systems, using defined vocabularies, open standards and flexible interfaces, the DAIDS-ES enables NIAID, its global collaborators and stakeholders, access to timely, quality information about NIAID-supported clinical trials which is utilized to: (1) analyze the research portfolio, assess capacity, identify opportunities, and avoid redundancies; (2) help support study safety, quality, ethics, and regulatory compliance; (3) conduct evidence-based policy analysis and business process re-engineering for improved efficiency. This report summarizes how the DAIDS-ES was conceptualized, how it differs from typical clinical trial support systems, the rationale for key design choices, and examples of how it is being used to advance the efficiency and effectiveness of NIAID's HIV/AIDS clinical research programs. PMID- 21816960 TI - Vitamin D inhibits proliferation and profibrotic marker expression in hepatic stellate cells and decreases thioacetamide-induced liver fibrosis in rats. AB - BACKGROUND AND AIM: Hepatic stellate cells (HSCs) are key participants in liver fibrosis development. 1,25(OH)(2)D(3), the active form of vitamin D, has antiproliferative properties and antifibrotic potential, as well as a role in extracellular matrix and matrix metalloproteinase (MMP) regulation in renal and lung fibrosis. Little is known about the role of 1,25(OH)(2)D(3) in liver and its involvement in liver fibrosis. Therefore, we investigated the antiproliferative and antifibrotic effects of 1,25(OH)(2)D(3) in primary cultured HSCs and in a rat model of liver fibrosis induced by thioacetamide (TAA). METHODS: Primary HSCs were isolated from rats' livers and treated with 1,25(OH)(2)D(3). Proliferation was examined by bromodeoxyuridine. Vitamin D receptor (VDR) expression and several fibrotic markers were detected by western blot analysis and real-time PCR. Collagen Ialpha1 and MMP-9 promoter activity were measured by luciferase assay. MMP-9 enzymatic activity was investigated by zymography. VDR silencing was performed by sh-RNA. An in vivo study was performed on TAA-induced liver fibrosis model in rats treated with or without 1,25(OH)(2)D(3). The fibrotic score and collagen deposition were determined by Masson and by Sirius red staining. RESULTS: While VDR was highly expressed in quiescent HSCs, its expression decreased up to 40% during activation. Addition of 1,25(OH)(2)D(3) to activated HSCs stimulated VDR expression. 1,25(OH)(2)D(3) suppressed HSC proliferation and cyclin D1 expression by ~50% and tissue inhibitor of metalloproteinase 1 (TIMP-1) by 60% and led to a 40% downregulation of collagen Ialpha1 expression. Moreover, 1,25(OH)(2)D(3) increased MMP-9 activity by 30%. Silencing VDR by sh-RNA demonstrated that suppression of cyclin D1 and collagen Ialpha1 protein expression was VDR dependent. Treatment with 1,25(OH)(2)D(3) significantly reduced extracellular matrix deposition and lowered the fibrotic score in TAA induced liver fibrosis. CONCLUSION: 1,25(OH)(2)D(3) has antiproliferative and antifibrotic effects on liver fibrosis in in vitro and in vivo models and may be considered as having potential therapeutic value. PMID- 21816961 TI - 'Why, why did you have me treated?': the psychotic experience in a literary narrative. AB - In this paper, the authors suggest an approach that may be helpful in teaching medical humanities to medical students. In the context of an honours class on medicine and literature, students (1) read a novel on an illness, (2) interviewed a patient with the medical condition described in the novel and (3) wrote an essay on the biomedical, narrative and literary aspects of these sources of information. The authors compared the story of Chekhov's literary protagonist Kovrin in The Black Monk with the personal story of patient H., who was diagnosed with schizophrenia. The narratives of the two patients were compared, based on Chekhov's literary narrative and the narrative of the patient. Both patients appeared to somehow regret losing their symptoms, following various psychiatric treatments. Both narratives show the ambivalence between the gain and loss that adequate psychiatric treatment may bring. Studying novels and other literary sources may help in understanding the story of the patient better, with associated improvements in various aspects of medical outcome. Reading literary fiction may help to increase an understanding of patients' emotions, experiences, cognitions and perspectives. It may also reduce the emotional distance between the self and the patient. The educational approach that was explored in the authors' honours class may be helpful to others when developing methods for teaching medical humanities to (medical) students. PMID- 21816962 TI - Impact of residency programs on professional socialization of newly licensed registered nurses. AB - Do Nurse Residency Programs (NRPs) reflect the professional socialization process? Residency facilitators in 34 Magnet hospitals completed Residency Program Questionnaires constructed to reflect the goals, themes, components, and strategies of the professional socialization process described in the literature. NRPs in 4 hospitals exemplified the complete two-stage (role transition and role/community integration) process. In 14 hospitals, NRPs were of sufficient length and contained components that reflected the professional socialization process. In 16 hospitals, NRPs exemplified the "becoming" role transition stage. What components are most effective in the professional socialization of new graduate nurses? A total of 907 new and experienced nurses, nurse managers, and educators working on clinical units with confirmed healthy work environments in 20 Magnet hospitals with additional "excellence designations" were interviewed. Components identified as most instrumental were precepted experience, reflective seminars, skill acquisition, reflective practice sessions, evidence-based management projects, and clinical coaching-mentoring sessions. Suggestions for improvement of NRPs are offered. PMID- 21816959 TI - Stem cell transplantation in neurodegenerative disorders of the gastrointestinal tract: future or fiction? AB - Current advances in our understanding of stem and precursor cell biology and in the protocols of stem cell isolation and transplantation have opened up the possibility of transplanting neural stem cells for the treatment of gastrointestinal motility disorders. This review summarises the current status of research in this field, identifies the major gaps in our knowledge and discusses the potential opportunities and hurdles for clinical application. PMID- 21816963 TI - Nutritional effects on sleep. AB - The purpose of this study was to examine the nutritional effects on sleep using actigraphy measures. A repeated-measures, counterbalanced, crossover study design was used to administer treatment diets to 44 adult participants. Participants served as their own control and consumed high-protein, high-fat, high carbohydrate, and control diets. The study participants wore Motionlogger Actigraph sleep watches while consuming weighed food intakes for 4 days over four different treatment periods. Demographic and laboratory data were also analyzed. Actigraph results showed that the wake episodes and sleep latencies were significantly different when comparing the macronutrient intakes of the participants. Post hoc test results showed that high-protein diets were associated with significantly fewer (p = .03) wake episodes and high-carbohydrate diets were associated with significantly shorter (p < .01) sleep latencies than control diets. Thus, consumption of specific macronutrient intakes may have a significant influence on sleep. PMID- 21816964 TI - S-nitrosoglutathione reductase in human lung cancer. AB - S-Nitrosoglutathione (GSNO) reductase regulates cell signaling pathways relevant to asthma and protects cells from nitrosative stress. Recent evidence suggests that this enzyme may prevent human hepatocellular carcinoma arising in the setting of chronic hepatitis. We hypothesized that GSNO reductase may also protect the lung against potentially carcinogenic reactions associated with nitrosative stress. We report that wild-type Ras is S-nitrosylated and activated by nitrosative stress and that it is denitrosylated by GSNO reductase. In human lung cancer, the activity and expression of GSNO reductase are decreased. Further, the distribution of the enzyme (including its colocalization with wild type Ras) is abnormal. We conclude that decreased activity of GSNO reductase could leave the human lung vulnerable to the oncogenic effects of nitrosative stress, as is the case in the liver. This potential should be considered when developing therapies that inhibit pulmonary GSNO reductase to treat asthma and other conditions. PMID- 21816965 TI - Genetic disruption of Fra-1 decreases susceptibility to endotoxin-induced acute lung injury and mortality in mice. AB - The activator protein-1 (AP-1) transcription factor, comprising Jun and Fos family proteins, distinctly regulates various cellular processes, including those involved in inflammation. FOS like antigen 1 (Fra-1), a member of the Fos family, dimerizes with members of the Jun family and regulates gene expression in a context-dependent manner. Although respiratory toxicants are known to stimulate the expression of Fra-1 in the lung, whether Fra-1 promotes or decreases susceptibility to the development and progression of toxicant-induced lung disease in vivo is not well established. To determine the role of Fra-1 in LPS induced acute lung injury and mortality, we administered LPS either intraperitoneally or intratracheally to Fra-1-sufficient (Fra-11(+/+)) and Fra-1 deficient (Fra-1(Delta/Delta)) mice. LPS-induced mortality, lung injury, inflammation, cytokine measurements, and AP-1 and NF-kappaB activities were then assessed in these mice. Fra-1(Delta/Delta) mice showed a greater resistance to LPS-induced mortality than did their Fra-1(+/+) counterparts. Consistent with this result, LPS-induced lung injury and inflammatory responses were markedly lower in Fra-1(Delta/Delta) mice than in Fra-1(+/+) mice. Compared with Fra 1(+/+) mice, Fra-1(Delta/Delta) mice showed a reduced influx of neutrophils into the lungs, accompanied by a decreased expression of proinflammatory cytokines in response to treatment with LPS. The decreased inflammatory responses in Fra 1(Delta/Delta) mice coincided with diminished and increased levels of NF-kappaB and c-Jun/AP-1 binding, respectively. These results demonstrate that Fra-1/AP-1 plays a key role in promoting LPS-induced injury and mortality in mice, and they suggest that targeting (i.e., inhibiting) this transcription factor may be a useful approach to dampening the adverse effects of exposure to endotoxins. PMID- 21816966 TI - Intermedin induces loss of coronary microvascular endothelial barrier via derangement of actin cytoskeleton: role of RhoA and Rac1. AB - AIMS: Intermedin (IMD) is a novel member of the calcitonin gene-related peptide family, which acts via calcitonin receptor-like receptors (CLRs), mediating activation of cAMP signalling. The main objective of the present study was to analyse the molecular mechanisms of the differential effects of IMD on the macromolecule permeability of endothelial cells of different vascular beds. METHODS AND RESULTS: Here we demonstrate that IMD increases permeability of rat coronary microvascular endothelial cells (RCECs) and reduces permeability of human umbilical vein endothelial cells (HUVECs) and rat aortic endothelial cells via CLRs and cAMP. Intermedin causes a derangement of the actin cytoskeleton accompanied by loss of vascular endothelial cadherin (VE-cadherin) in RCECs, while it causes a rearrangement of the actin cytoskeleton and VE-cadherin at cell cell junctions in HUVECs. Intermedin inactivates the RhoA/Rho-kinase (Rock) pathway in both cell types; however, it inactivates Rac1 in RCECs but not in HUVECs. Inhibition and rescue experiments demonstrate that both RhoA and Rac1 are required for the RCEC barrier stability, while in HUVECs the inhibition of RhoA/Rock signalling does not interfere with basal permeability. CONCLUSION: The opposite effects of IMD on permeability of RCECs and HUVECs are due to differential regulation of actin cytoskeleton dynamics via RhoA and Rac1. Moreover, Rac1 activity is regulated by the RhoA/Rock pathway in RCECs but not in HUVECs. PMID- 21816967 TI - Identification of adverse events in ground transport emergency medical services. AB - The purpose of this study was to develop a method to define and rate the severity of adverse events (AEs) in emergency medical services (EMS) safety research. They used a modified Delphi technique to develop a consensus definition of an AE. The consensus definition was as follows: "An adverse event in EMS is a harmful or potentially harmful event occurring during the continuum of EMS care that is potentially preventable and thus independent of the progression of the patient's condition." Physicians reviewed 250 charts from 3 EMS agencies for AEs. The authors examined physician agreement using kappa, Fleiss's kappa, and corresponding 95% confidence intervals (CIs). Overall physician agreement on presence of an AE per chart was fair (kappa = 0.24; 95% CI = 0.19, 0.29). These findings should serve as a basis for refining and implementing an AE evaluation instrument. PMID- 21816968 TI - Auger electron radioimmunotherapeutic agent specific for the CD123+/CD131- phenotype of the leukemia stem cell population. AB - Our aim was to construct and characterize (111)In-nuclear translocation sequence (NLS)-7G3, an Auger electron-emitting radioimmunotherapeutic agent that preferentially recognizes the expression of CD123 (interleukin-3 receptor [IL-3R] alpha-subchain) in the absence of CD131 (IL-3R beta-subchain) displayed by leukemia stem cells. METHODS: Monoclonal antibody 7G3 was modified with 13-mer peptides [CGYGPKKKRKVGG] harboring the NLS of SV-40 large T-antigen and with diethylenetriaminepentaacetic acid for labeling with (111)In. Immunoreactivity was evaluated in a competition radioligand binding assay and by flow cytometry. Nuclear localization of (111)In-NLS-7G3 was studied by cell fractionation in CD123(+)/CD131(-) acute myelogenous leukemia (AML)-3, -4, and -5 cells or in primary AML or normal leukocytes. Micro-SPECT was performed in nonobese diabetic (NOD)/severe combined immune deficient (SCID) mice engrafted subcutaneously with Raji-CD123 tumors or with disseminated AML-3 or -5 cells. The cytotoxicity of (111)In-NLS-7G3 on AML-5 cells was studied after 7 d in culture by trypan blue dye exclusion. DNA damage was assessed using the gamma-H2AX assay. RESULTS: NLS 7G3 exhibited preserved CD123 immunoreactivity (affinity, 4.6 nmol/L). Nuclear importation of (111)In-NLS-7G3 in AML-3, -4, or -5 cells was specific and significantly higher than unmodified (111)In-7G3 and was greater in primary AML cells than in normal leukocytes. Rapid elimination of (111)In-NLS-7G3 in NOD/SCID mice prevented imaging of subcutaneous Raji-CD123 tumors. This phenomenon was Fc dependent and IgG(2a) isotype-specific and was overcome by the preadministration of excess IgG(2a) or using (111)In-NLS-7G3 F(ab')(2) fragments. AML-3 and -5 cells were engrafted into the bone marrow or spleen or at extramedullary sites in NOD/SCID mice. Micro-SPECT/CT with (111)In-NLS-7G3 F(ab')(2) showed splenic involvement, whereas foci of disease were seen in the spine or femur or at extramedullary sites in the brain and lymph nodes using (111)In-NLS-7G3 IgG(2a). The viability of AML-5 cells was reduced by exposure in vitro to (111)In-NLS-7G3; this reduction was associated with an increase in unrepaired DNA double-strand breaks. CONCLUSION: (111)In-NLS-7G3 is a promising novel Auger electron-emitting radioimmunotherapeutic agent for AML aimed at the leukemia stem cell population. Micro-SPECT/CT was useful for visualizing the engraftment of leukemia in NOD/SCID mice. PMID- 21816969 TI - Incidental diagnosis of thrombus within an aneurysm on 18F-FDG PET/CT: frequency in 926 patients. AB - Our objective was to evaluate the incidence of aneurysm and the frequency of thrombus within an aneurysm on unenhanced (18)F-FDG PET/CT studies. METHODS: We reviewed 1,540 PET/CT scans from 926 patients. A log recorded whether each case of aneurysm had a suspected thrombus. The maximal standardized uptake value of the patent vessel was compared with the thrombus. Findings were confirmed using all available follow-up data. RESULTS: Aneurysm was found incidentally in 16 (1.7%) of the 926 patients, with 15 occurring in the abdominal aorta and 1 in the internal jugular vein. Seven of these 16 patients had shown suggestions of thrombus on unenhanced PET/CT, and in all 7, thrombi were confirmed on contrast enhanced CT. CONCLUSION: In 1.7% of patients, aneurysm was found incidentally on PET/CT, and thrombus was present in 44% of these cases. PMID- 21816970 TI - P-selectin imaging in cardiovascular disease: what you see is what you get? PMID- 21816971 TI - New players in apoptosis. PMID- 21816972 TI - The 2009 pandemic A/Wenshan/01/2009 H1N1 induces apoptotic cell death in human airway epithelial cells. AB - In 2009, a novel swine-origin H1N1 influenza virus emerged in Mexico and quickly spread to other countries, including China. This 2009 pandemic H1N1 can cause human respiratory disease, but its pathogenesis remains poorly understood. Here, we studied the infection and pathogenesis of a new 2009 pandemic strain, A/Wenshan/01/2009 H1N1, in China in human airway epithelial cell lines compared with contemporary seasonal H1N1 influenza virus. Our results showed that viral infection by the A/Wenshan H1N1 induced significant apoptotic cell death in both the human nasopharyngeal carcinoma cell line CNE-2Z and the human lung adenocarcinoma cell line A549. The A/Wenshan H1N1 virus enters both of these cell types more efficiently than the seasonal influenza virus. Viral entry in both cell lines was shown to be mediated by clathrin- and dynamin-dependent endocytosis. Therefore, we discovered that the 2009 pandemic H1N1 strain, A/Wenshan/01/2009, can induce apoptotic cell death in epithelial cells of the human respiratory tract, suggesting a molecular pathogenesis for the 2009 pandemic H1N1. PMID- 21816973 TI - Adiponectin and the incidence of type 2 diabetes in Hispanics and African Americans: the IRAS Family Study. AB - OBJECTIVE: A recent meta-analysis of 13 prospective studies reported that higher levels of adiponectin were significantly associated with lower risk of type 2 diabetes. Most previous studies, however, were limited in their ability to adjust for appropriate confounding variables. Our objective, therefore, was to study this association after adjustment for directly measured adiposity and insulin sensitivity, expressed as the insulin sensitivity index (S(I)). RESEARCH DESIGN AND METHODS: The study included 1,096 Hispanic and African American participants free of diabetes at baseline (2000-2002) who returned for follow-up after 5 years. S(I) was determined from frequently sampled intravenous glucose tolerance tests with minimal model analysis. Visceral adipose tissue (VAT) area was determined by computed tomography. Diabetes and impaired fasting glucose (IFG) were defined using American Diabetes Association criteria. Multivariate generalized estimating equation logistic regression models were used to account for correlations within families. RESULTS: A total of 82 subjects met criteria for incident diabetes. After adjustment for age, sex, ethnicity, and smoking, adiponectin was significantly inversely associated with diabetes (odds ratio [OR] 0.54 per 1 SD difference [95% CI 0.38-0.76]). The association remained significant after additional adjustment in individual models for BMI, homeostasis model assessment of insulin resistance, or VAT (all P < 0.05). However, adiponectin was no longer associated in separate models adjusted for S(I) or IFG (OR 0.81 [0.56-1.16] and 0.75 [0.53-1.06], respectively). CONCLUSIONS: Adiponectin was inversely associated with incident diabetes after adjustment for conventional anthropometric and metabolic variables or VAT. Adjustment for detailed measures of S(I) attenuated this relationship, however, suggesting that the link between adiponectin and diabetes may operate at least in part through insulin resistance. PMID- 21816974 TI - Surgical site infections after foot and ankle surgery: a comparison of patients with and without diabetes. AB - OBJECTIVE: This prospective study was designed to evaluate the rate of surgical site infection (SSI) after foot and ankle surgery in patients with and without diabetes. RESEARCH DESIGN AND METHODS: The study prospectively evaluated 1,465 consecutive foot and ankle surgical cases performed by a single surgeon. RESULTS: The overall SSI rate in this study was 3.5%, with significantly more infections occurring in individuals with diabetes than in those without (9.5 vs. 2.4%, P < 0.001). Peripheral neuropathy, Charcot neuroarthropathy, current or past smoking, and increasing length of surgery were significantly associated with SSI on multivariate analysis. CONCLUSIONS: This study demonstrates significant associations between the development of SSI and chronic complications of diabetes. We confirm previous findings that it is peripheral neuropathy and not diabetes itself that most strongly determines the development of postoperative infections in these surgical patients. PMID- 21816975 TI - Limited overlap between intermediate hyperglycemia as defined by A1C 5.7-6.4%, impaired fasting glucose, and impaired glucose tolerance. AB - OBJECTIVE: We compared the prevalences and overlap between intermediate hyperglycemia (IH), defined by a hemoglobin A(1c) (A1C) 5.7-6.4%, impaired fasting glucose (IFG), and impaired glucose tolerance (IGT). RESEARCH DESIGN AND METHODS: Oral glucose tolerance test results and A1C measurements were evaluated as markers of IH in an unselected cohort of 486 nondiabetic adults from Finland. RESULTS: The overall prevalence of IH was 34%. Prevalences of isolated A1C 5.7 6.4%, IGT, and IFG were 8.0, 13.2, and 4.5%, respectively. Overlap between these three markers was uncommon. Isolated A1C 5.7-6.4% was associated with a higher BMI compared with isolated IFG and IGT and with a more adverse lipid profile compared with isolated IFG. CONCLUSIONS: Prevalence of isolated IH was high, with limited overlap between the definitions. Differences in cardiovascular disease risk factors were observed among the groups. This study demonstrates that an A1C of 5.7-6.4% detects, in part, different individuals with IH compared with IFG and IGT. PMID- 21816977 TI - Prevalence of neuropathy and peripheral arterial disease and the impact of treatment in people with screen-detected type 2 diabetes: the ADDITION-Denmark study. AB - OBJECTIVE: There is limited evidence on how intensive multifactorial treatment (IT) improves outcomes of diabetes when initiated in the lead time between detection by screening and diagnosis in routine clinical practice. We examined the effects of early detection and IT of type 2 diabetes in primary care on the prevalence of diabetic peripheral neuropathy (DPN) and peripheral arterial disease (PAD) 6 years later in a pragmatic, cluster-randomized parallel group trial. RESEARCH DESIGN AND METHODS: A stepwise screening program in 190 general practices in Denmark was used to identify 1,533 people with type 2 diabetes. General practices were randomized to deliver either IT or routine care (RC) as recommended through national guidelines. Participants were followed for 6 years and measures of DPN and PAD were applied. RESULTS: We found no statistically significant effect of IT on the prevalence of DPN and PAD compared with RC. The prevalence of an ankle brachial index <=0.9 was 9.1% (95% CI 6.0-12.2) in the RC arm and 7.3% (5.0-9.6) in the IT arm. In participants tested for vibration detection threshold and light touch sensation, the prevalence of a least one abnormal test was 34.8% (26.7-43.0) in the RC arm and 30.1% (24.1-36.1) in the IT arm. CONCLUSIONS: In a population with screen-detected type 2 diabetes, we did not find that screening followed by IT led to a statistically significant difference in the prevalence of DPN and PAD 6 years after diagnosis. However, treatment levels were high in both groups. PMID- 21816976 TI - Prevalence and management of diabetes and metabolic risk factors in Thai adults: the Thai National Health Examination Survey IV, 2009. AB - OBJECTIVE: To determine the prevalence of impaired fasting glucose (IFG) and undiagnosed and diagnosed diabetes in Thai adults in 2009 and examine the extent of changes in proportions of diagnosis, treatment, and control for blood glucose, high blood pressure, and high total cholesterol between 2004 and 2009. RESEARCH DESIGN AND METHODS: Data from the multistage cross-sectional National Health Examination Survey (NHES) IV of 18,629 Thai adults aged >=20 years conducted in 2009 were used to analyze and compare with the data from NHES III in 2004. RESULTS: The prevalence of IFG and diabetes was 10.6 and 7.5%, respectively. Of all diabetes diagnoses, 35.4% were not previously diagnosed, and the proportion was higher in men than in women (47.3 vs. 23.4%, P < 0.05). Compared with those in year 2004, the proportions of individuals with diabetes and concomitant hypertension did not significantly decrease in 2009 in both sexes, but the proportions of women with diabetes who were abdominally obese or had high total cholesterol (>=5.2 mmol/L) significantly increased in 2009 by 18.0 and 23.5%, respectively (all P < 0.01). The rates of treatment and control of blood glucose, high blood pressure, and high total cholesterol were favorably improved in 2009. However, in substantial proportions of individuals with diabetes these concomitants were still controlled suboptimally. CONCLUSIONS: The prevalence of diabetes and IFG remained high in Thai adults. Improvement in detection and control of diabetes and associated metabolic risk factors, particularly obesity and high serum cholesterol, are necessary. PMID- 21816978 TI - Changes in altitude cause unintended insulin delivery from insulin pumps: mechanisms and implications. AB - OBJECTIVE: Children and adults with type 1 diabetes who receive insulin pump therapy have reported hypoglycemia during air travel. We studied the effects of atmospheric pressure on insulin pump delivery. RESEARCH DESIGN AND METHODS: Ten insulin pumps were connected to capillary tubes. The effects of changes in ambient pressure on insulin delivery, bubble formation, bubble size, and cartridge plunger movement were analyzed. RESULTS: During a flight (200 mmHg pressure decrease), excess insulin delivery of 0.623% of the cartridge volume occurred (P < 0.001, Student t test). In hypobaric chamber studies, bubbles developed in the insulin when the pressure decreased and displaced the insulin out of the cartridge. Pre-existing bubbles changed in size consistent with Boyle law. Cartridge plunger movement did not occur in normal flight conditions but did occur when catastrophic plane depressurization was mimicked. CONCLUSIONS: Atmospheric pressure reduction causes predictable, unintended insulin delivery in pumps by bubble formation and expansion of existing bubbles. PMID- 21816979 TI - Effects of the new dual PPAR alpha/delta agonist GFT505 on lipid and glucose homeostasis in abdominally obese patients with combined dyslipidemia or impaired glucose metabolism. AB - OBJECTIVE: We evaluated the metabolic effects and tolerability of GFT505, a novel dual peroxisome proliferator-activated receptor alpha/delta agonist, in abdominally obese patients with either combined dyslipidemia or prediabetes. RESEARCH DESIGN AND METHODS: The S1 study was conducted in 94 patients with combined dyslipidemia while the S2 study was conducted in 47 patients with prediabetes. Participants were randomly assigned in a double-blind manner to GFT505 at 80 mg/day or placebo for 28 (S1) or 35 (S2) days. Primary efficacy end points were changes from baseline at week 4 in both fasting plasma triglycerides and HDL cholesterol in the S1 group and 2-h glucose upon oral glucose tolerance test in the S2 group. RESULTS: In comparison with placebo, GFT505 significantly reduced fasting plasma triglycerides (S1: least squares means -16.7% [95% one sided CI -infinity to -5.3], P = 0.005; S2: -24.8% [-infinity to -10.5], P = 0.0003) and increased HDL cholesterol (S1: 7.8% [3.0 to infinity], P = 0.004; S2: 9.3% [1.7 to infinity], P = 0.009) in both studies, whereas LDL cholesterol only decreased in S2 (-11.0% [ -infinity to -3.5], P = 0.002). In S2, GFT505 did not reduce 2-h glucose (-0.52 mmol/L [-infinity to 0.61], P = 0.18) but led to a significant decrease of homeostasis model assessment of insulin resistance ( 31.4% [-infinity to 12.5], P = 0.001), fasting plasma glucose (-0.37 mmol/L [ infinity to -0.10], P = 0.01) and fructosamine (-3.6% [-infinity to -0.20], P = 0.02). GFT505 also reduced gamma glutamyl transferase levels in both studies (S1: -19.9% [-infinity to -12.8], P < 0.0001; S2: -15.1% [-infinity to -1.1], P = 0.004). No specific adverse safety signals were reported during the studies. CONCLUSIONS: GFT505 may be considered a new drug candidate for the treatment of lipid and glucose disorders associated with the metabolic syndrome. PMID- 21816980 TI - Dapagliflozin versus glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin: a randomized, 52-week, double-blind, active-controlled noninferiority trial. AB - OBJECTIVE: Although initially effective, sulfonylureas are associated with poor glycemic durability, weight gain, and hypoglycemia. Dapagliflozin, a selective inhibitor of sodium-glucose cotransporter 2 (SGLT2), reduces hyperglycemia by increasing urinary glucose excretion independent of insulin and may cause fewer of these adverse effects. We compared the efficacy, safety, and tolerability of dapagliflozin with the sulfonylurea glipizide in patients with type 2 diabetes inadequately controlled with metformin monotherapy. RESEARCH DESIGN AND METHODS: This 52-week, double-blind, multicenter, active-controlled, noninferiority trial randomized patients with type 2 diabetes (baseline mean HbA(1c), 7.7%), who were receiving metformin monotherapy, to add-on dapagliflozin (n = 406) or glipizide (n = 408) up-titrated over 18 weeks, based on glycemic response and tolerability, to <=10 or <=20 mg/day, respectively. RESULTS: The primary end point, adjusted mean HbA(1c) reduction with dapagliflozin (-0.52%) compared with glipizide ( 0.52%), was statistically noninferior at 52 weeks. Key secondary end points: dapagliflozin produced significant adjusted mean weight loss (-3.2 kg) versus weight gain (1.2 kg; P < 0.0001) with glipizide, significantly increased the proportion of patients achieving >=5% body weight reduction (33.3%) versus glipizide (2.5%; P < 0.0001), and significantly decreased the proportion experiencing hypoglycemia (3.5%) versus glipizide (40.8%; P < 0.0001). Events suggestive of genital infections and lower urinary tract infections were reported more frequently with dapagliflozin compared with glipizide but responded to standard treatment and rarely led to study discontinuation. CONCLUSIONS: Despite similar 52-week glycemic efficacy, dapagliflozin reduced weight and produced less hypoglycemia than glipizide in type 2 diabetes inadequately controlled with metformin. Long-term studies are required to further evaluate genital and urinary tract infections with SGLT2 inhibitors. PMID- 21816981 TI - Association between type 2 diabetes and exposure to persistent organic pollutants. AB - OBJECTIVE: The prevalence of type 2 diabetes is increasing alarmingly in both developed and developing countries. Recently, exposure to persistent organic pollutants (POPs) has been associated with the prevalence of type 2 diabetes. The purpose of this cross-sectional study is to examine the association between type 2 diabetes and POP exposure in the Helsinki Birth Cohort Study. RESEARCH DESIGN AND METHODS: The cohort consists of 8,760 people born in Helsinki during 1934 1944, before the global POP emission peak. In 2003, a clinical examination was performed, including blood sampling for laboratory analyses of serum lipids and POPs. Complete data from the examination were available for 1,988 participants. The concentrations of each POP were categorized into four groups on the basis of percentile intervals, and logistic regression was performed to examine diabetes prevalence across the POP categories, adjusting for sex, age, waist circumference, and mean arterial pressure and using the lowest category as the reference group. RESULTS: Among the participants with the highest exposure to oxychlordane, trans-nonachlor, 1,1-dichloro-2,2-bis-(p-chlorophenyl)-ethylene (p,p'-DDE, and polychlorinated biphenyl 153, the risk of type 2 diabetes was 1.64 2.24 times higher than that among individuals with the lowest exposure (P(lin) = 0.003-0.050, where P(lin) is the P value for linear trend across POP categories). In the stratified analysis, the associations between type 2 diabetes and oxychlordane and trans-nonachlor remained significant and were strongest among the overweight participants. Exposure to 2,2',4,4'-tetrabromodiphenyl ether (BDE 47) and 2,2',4,4',5,5'-hexabromodiphenyl ether (BDE 153) was not associated with type 2 diabetes. CONCLUSIONS: This study confirms the association between type 2 diabetes and adult-only exposure to organochlorine pesticides in a general urban population. PMID- 21816982 TI - PDZK1 regulates breast cancer resistance protein in small intestine. AB - Transporter adaptor protein PDZK1 regulates several influx transporters for xenobiotics and nutrients in small intestine, and their expression on the apical membrane is diminished in pdzk1 gene knockout [pdzk1(-/-)] mice. In the present study, we initially attempted to use pdzk1(-/-) mice to functionally identify influx transporters responsible for intestinal absorption of cimetidine. Contrary to our expectation, the plasma concentration of cimetidine after oral administration to pdzk1(-/-) mice was higher than that in wild-type mice, and the double peaks of plasma concentration found in wild-type mice were not observed in pdzk1(-/-) mice. Western blot analysis of intestinal brush-border membranes revealed that expression of breast cancer resistance protein (BCRP) but not of P glycoprotein is reduced in pdzk1(-/-) mice. This result was compatible with the reduction of apical localization of BCRP in pdzk1(-/-) mice assessed by immunohistochemical analysis. Transcellular transport of cimetidine in the basal to-apical direction in Madin-Darby canine kidney II (MDCKII) cells stably expressing both BCRP and PDZK1 (MDCKII/BCRP/PDZK1) was higher than that in MDCKII cells stably expressing BCRP (MDCKII/BCRP) cells. Moreover, MDCKII/BCRP/PDZK1 cells are more resistant than MDCKII/BCRP cells to the cytotoxicity of the anticancer agent 7-ethyl-10-hydroxycamptothecin (SN-38), which is a substrate of BCRP. These results were consistent with the higher expression of BCRP on apical membranes in MDCKII/BCRP/PDZK1 cells. Pull-down and immunoprecipitation studies revealed a physical interaction between BCRP and PDZK1. Taken together, these findings demonstrate that PDZK1 plays a pivotal role in the apical localization of BCRP. This is the first identification of a regulatory protein that physically interacts with and regulates BCRP in small intestine in vivo. PMID- 21816983 TI - A prospective, comparative, radiological, and clinical study of the influence of the "remplissage" procedure on shoulder range of motion after stabilization by arthroscopic Bankart repair. AB - BACKGROUND: Certain failures of arthroscopic Bankart repairs seem to be related to the presence of a Hill-Sachs defect. It has been suggested that Hill-Sachs lesions can be treated by "remplissage" (filling in) of the defect. The effect of this procedure on the mobility of the shoulder is not known. PURPOSE: To determine if filling in the Hill-Sachs defect with rotator cuff tendon would modify the range of motion of the operated shoulder. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: A prospective study of 2 patient populations (arthroscopic Bankart repair alone vs Bankart and remplissage) was undertaken after selecting patients using the Instability Severity Index Score (ISIS). Patients with a Hill-Sachs lesion seen on anteroposterior radiographs had a remplissage procedure if this procedure allowed them to obtain an ISIS lower than 4. The main clinical outcome was the range of motion (external rotation at the side [ER1], external rotation in abduction [ER2], internal rotation [IR], and forward elevation), assessed by the difference between each shoulder at 1 and 2 years' follow-up. Complications, recurrence, and the Walch-Duplay scores were noted at the same time. Minimum follow-up was 2 years. RESULTS: No significant statistical difference was noted in the range of motion between each group: ER1, difference of 4 degrees (P = .22); ER2, difference of 3 degrees (P = .49); anterior elevation, difference of 5 degrees (P = .35); and internal rotation, 2 vertebrae (P = .22). The rate of recurrence was identical in both groups (6.25%). For patients without redislocation, the Walch-Duplay score was excellent (14/17) or good (3/17) in the first group and excellent (12/15) or good (3/15) in the second group. Posterosuperior pain during forceful movements or when tired was noted in one third of patients having undergone remplissage. CONCLUSION: The remplissage technique did not alter the range of motion of the shoulder compared with Bankart procedure alone; however, one third of patients did experience posterosuperior pain. PMID- 21816984 TI - Acute injuries to the posterolateral corner of the knee in children: a case series of 6 patients. AB - BACKGROUND: Isolated avulsion fractures of the posterolateral structures (the popliteus tendon, the lateral collateral ligament, and the popliteofibular ligament) of the knee are rare. PURPOSE: To describe the outcome after an isolated avulsion fracture at the femoral attachment of the posterolateral structures in skeletally immature patients and to communicate our clinical experience concerning diagnosis and treatment. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Six skeletally immature patients (mean age, 13.3 years; range, 12.6-13.7 years; 5 boys, 1 girl) with an avulsion fracture of the femoral attachment of the posterolateral structures were evaluated on average 5.1 years (range, 2.7-8.3 years) after the injury. Five patients were treated with open reduction and fixation of the fragment. The sixth patient was treated nonoperatively with cast immobilization. The evaluation was based on reassessment of radiographs and magnetic resonance imaging (MRI scans), registration of activity level, and examination of objective and subjective knee function. RESULTS: The injury involved both the popliteus tendon and the lateral collateral ligament in 5 of the 6 cases. In the operated patients, the mean Lysholm knee score was 98 (range, 94-100) (0-100, with higher scores indicating a better outcome). The mean Knee injury and Osteoarthritis Outcome Score (KOOS) quality of life (QOL) was 80 (range, 50-100) (0-100, with higher scores indicating a better outcome). The range of motion and the KT-1000 arthrometer anterior laxity measurements were normal. The nonoperatively treated patient with involvement of both the popliteus tendon and the lateral collateral ligament suffered a bone bridge in the periphery of the femoral physis, causing a valgus deformity of the knee. An open wedge femoral osteotomy was performed. The Lysholm knee score was 80, and KOOS QOL was 25 at follow-up. The patient also had an extension deficit of 5 degrees and a flexion deficit of 10 degrees . CONCLUSION: An avulsion of the femoral attachment of the posterolateral structures in skeletally immature patients may involve both the popliteus tendon and the lateral collateral ligament. Open reduction and fixation of the fragment gave a satisfactory outcome. PMID- 21816989 TI - Activity promotion: a paradigm shift for chronic obstructive pulmonary disease therapeutics. AB - Many patients with chronic obstructive pulmonary disease (COPD) lead unsatisfying, sedentary existences, worn down by years of dyspnea and exacerbations. A downward spiral links progressive inactivity to accelerating disability and premature mortality. Indeed, cross-sectional COPD studies have demonstrated that inactivity is a potent predictor of early death. It should be considered a high priority for future COPD therapies to ameliorate inactivity. A necessary prerequisite to this endeavor is development of techniques to accurately assess activity levels. Development of questionnaires or, arguably more importantly, instrumentation for objective measurement of activity is a priority. There is a tendency to equate exercise intolerance with inactivity. Although, in a population, the two are correlated, higher exercise tolerance is only permissive of higher activity. It is plausible that, in reported correlations of measures of exercise tolerance with long-term outcomes, exercise tolerance is simply a proxy variable for activity level. Interventions have been identified that improve exercise tolerance in COPD. Do these interventions also increase activity levels? To date, evidence is mixed. No studies have appeared demonstrating that bronchodilator therapy or provision of lightweight ambulatory oxygen supplies increase activity level. Nine studies have appeared in which the ability of pulmonary rehabilitation to increase activity levels, objectively assessed by activity monitors; four of nine have demonstrated significantly increased activity levels. Future efforts should strive to isolate strategies that improve activity, perhaps coupling interventions permissive of improved exercise tolerance with behavior modification approaches that empower lifestyle modification. In particular, pulmonary rehabilitation seems ripe for augmentation with scientifically based strategies for activity promotion. PMID- 21816990 TI - Patient phenotyping and early disease detection in chronic obstructive pulmonary disease. AB - The traditional physiological definition of chronic obstructive pulmonary disease (COPD) is of practical use in encompassing the overlapping syndromes of COPD in routine clinical practice, and underpins the continued use of spirometry for diagnosis, screening, staging, and monitoring. However, the diagnostic criteria for COPD have not evolved in step with advances in understanding of pathogenesis, and this approach of including all the components of COPD under one umbrella is under question. The characterization of phenotypic variation is currently recognized to hold the key to better understanding of COPD pathogenesis and the identification of effective novel therapies. COPD demonstrates considerable heterogeneity, and, consequently, patient characterization requires a varied approach and the use of multiple modalities. This review discusses the methodologies that are currently used for patient phenotyping and the approaches that have been advocated for the identification of clinically meaningful phenotypes. PMID- 21816991 TI - Novel outcomes and end points: biomarkers in chronic obstructive pulmonary disease clinical trials. AB - Biomarker development in chronic obstructive pulmonary disease (COPD) is a nascent field, in part because of the complexity underlying COPD pathogenesis. The objective of this review is to provide examples of how biomarkers may be effectively applied in clinical trials of COPD by limiting their use to specific contexts and using them to answer well delineated questions. Types of novel outcomes or "biomarkers" that may be useful in clinical trials in COPD include analyses performed on bronchoscopically obtained samples, sputum, exhaled gases, blood, and urine and "ex vivo" assays performed using biological samples obtained from trial participants. These novel biological outcomes are rarely useful as primary end points in phase III clinical trials in COPD, because they are not typically recognized by the U.S. Food and Drug Administration or other regulatory agencies. More commonly, the applications of these outcomes include "proof-of concept" decisions, demonstration that the intervention had the intended pharmacologic or biological effect, identification of patient subgroups that benefit most, and safety monitoring. Examples given in this review include outcomes used in a phase IIA study of an inhaled small molecule inhibitor of epidermal growth factor receptor. Large observational studies of COPD, including the ECLIPSE, COPDGene, and SPIROMICS studies will further inform our use of biomarkers in COPD clinical trials. To encourage the application of novel biomarkers in clinical trials, the Food and Drug Administration has developed a new process for biomarker "qualification." This process has been designed to be more efficient and to promote consensus building and sharing of preclinical data. PMID- 21816993 TI - Chronic obstructive pulmonary disease overview: epidemiology, risk factors, and clinical presentation. AB - Chronic obstructive pulmonary disease (COPD) has been a major public health problem during the 20th century, and will remain a challenge for the foreseeable future. Worldwide, COPD is in the spotlight, because its high prevalence, morbidity, and mortality create formidable challenges for healthcare systems. However, there remain many ongoing, contentious issues in COPD, including the definition and staging of COPD itself. Similarly, it appears that there is no consensus as yet on how, when, and where spirometry and other tools (symptoms assessment, imaging, biomarkers, and so on) should be conducted and implemented to screen, label, and treat for COPD, if any. Our current knowledge on the epidemiology, risk factors, and clinical presentation of COPD has been reasonably well documented in several previous reviews. We aim to summarize new developments surrounding the epidemiology of COPD, both at the population and at the clinical level, in comparison with other major burden contributors, while debating old and novel risk factors. Cigarette smoking is the principal causal factor, but other factors play a role in causing and triggering COPD. Likely, the clinical presentation of COPD and its contributing phenotypes within the remainder of the 21st century will be different than the "blue bloaters" and "pink puffers" observed one or two generations ago. Hopefully, the COPD clinical course will shift to better outcomes and prognosis than in the past. PMID- 21816992 TI - Pharmacotherapeutic approaches to preventing acute exacerbations of chronic obstructive pulmonary disease. AB - The significance of acute exacerbations in chronic obstructive pulmonary disease (AECOPDs) is increasingly appreciated. AECOPDs result in significant morbidity and mortality and are a significant driver of health care costs. Frequent AECOPDs are associated with poor quality of life and more rapid decline in lung function. As such, reducing their frequency or severity is a key paradigm of COPD therapy. Bronchodilators alone and in combination with inhaled corticosteroids are the current standards of care and decrease AECOPDs. Prevention of infection with chronic macrolide antibiotics or pulsed quinolones has demonstrated some promise. Vaccination against Streptococcus pneumonia and influenza is likely beneficial. Therapeutics with antiinflammatory properties, including phosphodiesterase enzyme 4 inhibitors and HMG-CoA reductase inhibitors, may reduce AECOPD frequency. Inhibiting the formation of reactive oxidant species has also been studied, with varying results. Antioxidants, including N-acetylcysteine and S carbomethylcysteine, may reduce exacerbation frequency, but further investigation is needed. As new therapies are developed, it will be helpful to know in which patient phenotypes they are most effective and how they compare in efficacy and side-effect profiles with inhaled coricosteroids, bronchodilators, or their combination. PMID- 21816994 TI - Rationale and emerging approaches for targeting lung repair and regeneration in the treatment of chronic obstructive pulmonary disease. AB - Lung repair and regeneration are appropriate therapeutic targets for the treatment of chronic obstructive pulmonary disease (COPD). Abnormal repair results if fibrosis of the airways is a major contributor to fixed airflow limitation in airway disease. Inadequate repair in the face of tissue injury can contribute to the development of emphysema. With respect to the latter, acute exposure to cigarette smoke can impair repair responses of several cell types in the lung. Fibroblasts cultured from the lungs of patients with emphysema have persistent defects in repair that include modulation of extracellular matrix as well as production of growth factors that modulate other lung parenchymal cells. Some of the deficient repair functions appear to result from insensitivity to TGF beta and overproduction of prostaglandin E. Pharmacologic interventions targeting these pathways have the potential to at least partially reverse the abnormal repair. Alternate strategies that could modulate lung repair and regeneration could target resident or circulating stem/progenitor cells or potentially involve transplantation of new stem cells. Therapy directed at lung repair has the potential to restore lost lung function. In contrast to therapy designed to slow the progression of COPD, it may be much easier and less expensive to demonstrate efficacy for a therapy that restores lung function. PMID- 21816995 TI - Treating the systemic effects of chronic obstructive pulmonary disease. AB - Many patients with chronic obstructive pulmonary disease (COPD) also suffer from other disorders that are considered to be comorbidities and that may have a major impact on morbidity and mortality. So far, it is not clear if these diseases in the context of COPD need specific drugs or if patients diagnosed with COPD should receive certain medications to prevent the development of systemic effects of COPD. Cachexia may be caused by many contributing factors and thus may prove to be very difficult to reverse. For the treatment of osteoporosis in patients with COPD, treatment recommendations have been published. COPD is associated with reduced systemic levels of vitamin D, which has not only calcemic, but also extracalcemic effects that may play a role in the development of COPD and its consequences. Available evidence suggests that statins have a high potential, although definitive studies have not been published yet. Physical inactivity may be a major cause for systemic inflammation. In turn, exercise training may be an effective form of therapy. Although smoking cessation is very effective, it is not successful in the majority of cases. PMID- 21816996 TI - Dynamic splinting for postoperative hallux limitus: a randomized, controlled trial. AB - BACKGROUND: Hallux limitus (HL) is a pathology of degenerative arthritis in the first metatarsophalangeal joint (MTJ) of the great toe. Chief complaints of HL include inflammation, edema, pain, and reduced flexibility. The onset of HL commonly occurs after one of the two most common surgical procedures for foot pathologies, a bunionectomy or a cheilectomy. The purpose of this study is to determine the efficacy of dynamic splinting in treating patients with postoperative hallux limitus, in a randomized, controlled trial. METHODS: Fifty patients (ages 29 to 69) were enrolled after diagnosis of HL following surgery. The duration of this study was eight weeks, and all patients received nonsteroidal anti-inflammatory drugs, orthotics, and instructions for a home exercise program. Experimental patients were also treated with dynamic splinting for first MTJ extension (60 minutes, three times per day). The dependent variable was change in active range of motion (AROM). A repeated measures analysis of variance was used with independent variables of patient categories, surgical procedure (cheilectomy vs. bunionectomy) and duration since surgery. RESULTS: There was a significant difference in change of AROM for experimental vs. control patients (P < 0.001, T = 4.224, N = 48); there was also a significant difference for patient treated within 2 months of surgery (P = 0.0221). CONCLUSIONS: Dynamic splinting was effective in reducing contracture of postoperative hallux limitus in this study; experimental patients gained a mean 250% improvement in AROM. This modality should be considered for standard of care in treating postoperative hallux limitus. PMID- 21816997 TI - Variations in foot posture and mobility between individuals with patellofemoral pain and those in a control group. AB - BACKGROUND: We sought to determine whether foot posture and foot mobility were increased in individuals with patellofemoral pain syndrome compared with individuals in a control group. METHODS: A nested case-control design was used with two controls matched to each patient by sex and age (+/-1 year). Participants included 43 individuals with a history of unilateral or bilateral patellofemoral pain syndrome and 86 participants in a control group. Data collected included height, weight, and five different measures of foot height and width in weightbearing and nonweightbearing that have been previously shown to have high levels of reliability. RESULTS: Individuals with patellofemoral pain syndrome were found to be four times more likely (odds ratio, 4.04; 95% confidence interval, 1.45-11.32) to have a larger-than-normal difference between nonweightbearing and weightbearing arch height compared with those in the control group. The mean values for difference in arch height and foot mobility magnitude were also statistically significant between the patient and control groups. Foot posture, as determined using the arch height ratio, was not significant between groups (odds ratio, 0.94; 95% confidence interval, 0.34-2.61). CONCLUSIONS: Although foot posture may not be different between individuals with patellofemoral pain syndrome and controls, foot mobility assessed using difference in arch height and foot mobility magnitude is different between the two groups. PMID- 21816998 TI - Dorsal approach to transfer of the flexor digitorum brevis tendon. AB - BACKGROUND: Transposition of the flexor digitorum longus tendon has been widely reported for the correction of flexible claw and hammer toe deformities. Only transposition of the flexor digitorum brevis tendon has been reported in the literature in a cadaveric study that used the dorsal and plantar approach. A search of the literature revealed no reports of transposition of the flexor digitorum brevis tendon for treatment of these conditions through a unique dorsal cutaneous incision. We performed a cadaveric study to determine whether the flexor digitorum brevis tendon is long enough to be transferred to the dorsum of the proximal phalanx of the toe from its lateral or medial aspect through a unique dorsal cutaneous incision. METHODS: Transposition of the flexor digitorum brevis tendon was attempted in 156 toes of cadaveric feet (52 each second, third, and fourth toes) through a unique dorsal incision. RESULTS: The flexor digitorum brevis tendon was long enough to be successfully transposed in 100% of the second, third, and fourth toes by the dorsal incision approach. CONCLUSIONS: Transfer of the flexor digitorum brevis tendon to the dorsum of the proximal phalanx can be performed for the correction of claw and hammer toe deformities, especially in the second, third, and fourth toes. The meticulous longitudinal incision of the flexor tendon sheath to expose the flexor digitorum brevis tendon is essential to the success of the procedure. PMID- 21817000 TI - Postoperative infection after excisional toenail matrixectomy: a retrospective clinical audit. AB - BACKGROUND: Excisional toenail matrixectomies are performed on the area of the foot that has been reported to have the highest concentration of resident microorganisms. A retrospective infection audit was performed to identify whether this unique area of the foot was more susceptible to postoperative infection. METHODS: A retrospective audit reviewing the postoperative infection rate over a 6-year period after excisional nail matrixectomy in 111 patients was undertaken. RESULTS: The postoperative infection rate was found to be high (18.9%) relative to that of clean orthopedic foot and ankle surgery (0.5%-6.5%). CONCLUSIONS: The unique concentration of resident microbes found in the nail folds could help explain the high rate of postoperative infections identified in this study. This may provide some argument to classify excisional nail matrixectomy as clean contaminated surgery and, thus, warrant routine antibiotic prophylaxis. Further research is recommended to confirm the results of this study and to determine whether appropriately timed oral antibiotic prophylaxis will reduce the infection rate after nail surgery. PMID- 21816999 TI - Management of grade III open dislocated ankle fractures: combined internal fixation with bioabsorbable screws/rods and external fixation. AB - BACKGROUND: Isolated dislocation of the ankle with grade III open fracture has been scarcely reported. These ankle injuries usually involved mortise fractures, complete dislocation of the tibial astragaloid joint, capsuloligamentous structure disruption, and severe soft-tissue damage. There is no well-recognized regimen that would result in desirable outcomes. METHODS: Sixteen patients with grade III open dislocated ankle fractures were treated immediately with bioabsorbable implants and an external fixator between January 2003 and June 2007. According to the classification system of Gustilo and Anderson, five patients were grade IIIA, seven were grade IIIB, and four were grade IIIC. Surgical interventions included combined internal fixation with bioabsorbable screws/rods and external fixation. RESULTS: Patients underwent clinical and radiologic examination at an average of 18.1 months after surgery. Outcomes were excellent in seven patients (three IIIA, three IIIB, and one IIIC), good in four (one IIIA, two IIIB, and one IIIC), fair in three (one IIIA, one IIIB, and one IIIC), and poor in two (one IIIB, and one IIIC). In the two patients with poor outcomes, bone defect and cartilage exfoliating in the distal tibia were found during surgery. Painful osteoarthritis in the ankle was discovered 2 years after surgery. Another case had pin tract infections in the external fixator 3 months after surgery. There was no case of late deep infection. CONCLUSIONS: It may be a reasonable and desirable option that bioabsorbable implants combined with an external fixator be applied for treatment of severe open dislocated ankle fractures. PMID- 21817002 TI - The use of focused electronic medical record forms to improve health-care outcomes. AB - BACKGROUND: We tested the use of specifically designed electronic medical record forms, thereby demonstrating the ability to electronically capture, report, and compare clinical data. To that end, podiatric physicians can determine what constitutes the most effective program or treatment for specific conditions by documenting their treatment outcomes. METHODS: A prospective case series was initiated to determine the value of using focused electronic medical record forms to track walking programs in the practices of podiatric physicians. Three patients were observed for 48 weeks using focused electronic medical record forms to input data (body mass index, cholesterol level, hemoglobin A(1c) level, blood pressure, and other vital information). Patients were given pedometers so that they could log their mileage and their podiatric physicians could enter it into the medical record. Information was collected using an electronic medical record system with the ability to link multiple templates together and assign logic to create flexible entry completion requirements. The clinical data generated are captured in a common database, where the data offer future opportunity to compare statistics among a multitude of practices in various demographic regions. RESULTS: Focused electronic medical record forms were effectively used to track improvements and overall health benefits in a walking program supervised by podiatric physicians. CONCLUSIONS: Valuable information can be ascertained with focused electronic medical record forms to help determine treatment effectiveness. This information can later be compared with practices across many different demographics to ascertain the best evidence-based practice. PMID- 21817001 TI - Prevalence of podiatric medical problems in veterans versus nonveterans. AB - BACKGROUND: Lower-extremity pathologic abnormalities have been common in military recruits for many years. Many of these conditions can become chronic and persist even after retiring from military service. We hypothesized that certain foot abnormalities are more prevalent in veterans versus nonveterans. The purpose of this study was to evaluate what foot and ankle disorders are associated with veteran status while controlling for other demographic factors. METHODS: The National Health Interview Survey (Podiatry Supplement) from 1990 was used for this secondary data analysis. The data were divided into veterans and nonveterans, and the prevalence of podiatric medical problems, including callus, flatfoot deformity, bunion deformity, hammer toe deformity, arthritis, and sprain, was evaluated for each group. RESULTS: Flatfoot deformity and arthritis were significantly more prevalent in veterans versus nonveterans in the United States. Bunion deformity was significantly more prevalent in male veterans than in male nonveterans. Male veterans were less likely than male nonveterans to have sprains, and female veterans were more likely than their nonveteran counterparts to have sprains. CONCLUSIONS: These results may help us understand the potential risk factors for podiatric medical problems and may be used for formulating prevention programs. PMID- 21817003 TI - Freiberg's disease: quantitative assessment of osteonecrosis on three-dimensional CT. AB - BACKGROUND: The extent of necrosis is the main determining factor in the outcome of osteonecrosis. There is no method for measuring the extent of osteonecrosis of the metatarsal head in Freiberg's disease. The purpose of this study was to determine the reliability and prognostic ability of a new method for measurement of the extent of osteonecrosis in Freiberg's disease on three-dimensional computed tomography. METHODS: A retrospective review of 11 cases with symptomatic Freiberg's disease in ten patients (5 males and 5 females; mean age, 27 years) undergoing computed tomography between July 2005 and September 2007 was performed. Two investigators (K.A.C. and H.K.O.) used a new method to measure the necrotic extent of the metatarsal head: the necrotic angle ratio of necrotic arc angle to normal arc angle of the articular surface on the sagittal reconstruction image of computed tomography. The interobserver reliability was determined for computed tomography measurement. Correlation between the Smillie staging using radiographs and the necrotic angle ratio on computed tomography was also evaluated. RESULTS: One patient presented with stage I disease (Smillie staging), one with stage II, two with stage III, five with stage IV, and two with stage V, respectively. The necrotic angle ratio of the metatarsal head was 14% in stage I, 21% in stage II, 34% in stage III, 43% in stage IV, and 53% in stage V. The interobserver reliability for computed tomography measurement was high (Cronbach alpha=0.96). We found the increase of the necrotic extent in proportion to the Smillie stage. The Smillie staging using radiographs and the necrotic angle ratio on computed tomography were significantly correlated. (P<0.05) CONCLUSIONS: Three dimensional computed tomography measurement of the necrotic extent of the metatarsal head is a reliable and useful method in evaluating the staging of Freiberg's disease and may eventually help to optimize treatment. PMID- 21817004 TI - Foot orthoses: a review focusing on kinematics. AB - Orthoses have been broadly used by clinicians to treat mechanical misalignments, such as abnormal foot pronation. As such, the influences of orthoses on lower limb kinematics have been studied numerous times, with many articles reporting nonsystematic results; the aim of this review, therefore, was to examine the recognized effects of foot orthoses on lower-limb kinematics. The findings from this review suggest that foot orthoses seem to have certain generic and common effects on the lower limb when designed to control rearfoot pronation. We also discuss the possible reasons behind the lack of consistent results between studies. Based on the findings, a list of recommendations is presented for future research on foot orthoses to facilitate comparisons between studies and enable the scientific and clinical communities to better comprehend the effects that these variables might have on the kinematics and, possibly, the treatment outcomes. PMID- 21817005 TI - Charcot-Marie-Tooth disease complicating type 2 diabetes. AB - Although both conditions are relatively common, there are very few descriptions of type 2 diabetes mellitus coexisting with Charcot-Marie-Tooth disease (CMT). This case report and literature review describes a 53-year-old Irish man who presented with type 2 diabetes and significant neuropathy, and who was subsequently diagnosed with CMT type 1A. This case report will also discuss how to differentiate diabetic neuropathy from a progressive hereditary neuropathy and how coexistence aggravates the progression of neuropathy thus necessitating early diagnosis. PMID- 21817006 TI - Tungiasis in a beach volleyball player: a case report. AB - Tungiasis is an infestation caused by penetration of the skin by the gravid female of the flea Tunga penetrans Linnaeus 1758 (Insecta, Siphonaptera: Tungidae). Tunga penetrans is currently found in Central and South America, sub Saharan Africa, and Central Asia. Prevalence is very high in Brazil. We present a case of tungiasis in an Italian beach volleyball player who acquired the infestation in Brazil. PMID- 21817007 TI - The symptomatic os vesalianum as an uncommon cause of lateral foot pain: a case report. AB - The os vesalianum is an uncommon pedal accessory bone located lateral to the fifth metatarsal base. It may occasionally become symptomatic and require surgical excision, as in the case reported here in a 24-year-old woman. Simple excision of the ossicle, while effective in the present case, can be complicated by the attachment of fibers of the peroneus brevis tendon into the ossicle, thus requiring careful tenorraphy and sometimes tenodesis. PMID- 21817008 TI - Invasive cutaneous squamous cell carcinoma presenting as a nonhealing radiation wound: a case report. AB - Cutaneous squamous cell carcinoma is the second most common form of skin cancer and accounts for 20% of cutaneous malignancies. We report the case of a patient who presented with a complaint of nonhealing wounds following radiation therapy for the treatment of noninvasive squamous cell carcinoma of both lower extremities. Initial biopsies of the wounds were benign. However, a second biopsy performed approximately 2 months later was found to be positive for invasive squamous cell carcinoma. This case uniquely exemplifies that all nonhealing wounds should be viewed with a critical eye for possible malignancy even in the presence of previous negative biopsy. This is especially true for radiation wounds that may be prone to malignant transformation or recurrence. PMID- 21817011 TI - Determining current physical therapist management of hip fracture in an acute care hospital and physical therapists' rationale for this management. AB - BACKGROUND: Physical therapy has an important role in hip fracture rehabilitation to address issues of mobility and function, yet current best practice guidelines fail to make recommendations for specific physical therapy interventions beyond the first 24 hours postsurgery. OBJECTIVES: The aims of this study were: (1) to gain an understanding of current physical therapist practice in an Australian acute care setting and (2) to determine what physical therapists consider to be best practice physical therapist management and their rationale for their assessment and treatment techniques. DESIGN AND METHODS: Three focus group interviews were conducted with physical therapists and physical therapist students, as well as a retrospective case note audit of 51 patients who had undergone surgery for hip fracture. RESULTS: Beyond early mobilization and a thorough day 1 postoperative assessment, great variability in what was considered to be best practice management was displayed. Senior physical therapists considered previous clinical experience to be more important than available research evidence, and junior physical therapists modeled their behavior on that of senior physical therapists. The amount of therapy provided to patients during their acute inpatient stay varied considerably, and none of the patients audited were seen on every day of their admission. CONCLUSIONS: Current physical therapist management in the acute setting for patients following hip fracture varies and is driven by system pressures as opposed to evidence-based practice. PMID- 21817009 TI - Small blue round cell tumor: an unusual case presentation in the foot. AB - Small blue round cell tumors of childhood rarely present in the foot or ankle. The following is a case presentation of an 18-year-old male with a large soft tissue mass of the foot with associated lung metastasis. A definitive diagnosis could not be fully made, even with immunohistochemical and genetic testing. Diagnosis favored poorly differentiated synovial sarcoma. PMID- 21817012 TI - Building the rationale and structure for a complex physical therapy intervention within the context of a clinical trial: a multimodal individualized treatment for patients with hip osteoarthritis. AB - Evaluating the efficacy of complex interventions such as multimodal, impairment based physical therapy treatments in randomized controlled trials is essential to inform practice and compare relative benefits of available treatment options. Studies of physical therapy interventions using highly standardized intervention protocols, although methodologically rigorous, do not necessarily reflect "real world" clinical practice, and in many cases results have been disappointing. Development of a complex intervention that includes multiple treatment modalities and individualized treatment technique selection requires a systematic approach to designing all aspects of the intervention based on theory, evidence, and practical constraints. This perspective article outlines the development of the rationale and structure of a multimodal physical therapy program for painful hip osteoarthritis to be assessed in a clinical trial. The resulting intervention protocol comprises a semi-structured program of exercises and manual therapy, advice, physical activity, and optional prescription of a gait aid that is standardized, yet can be individualized according to physical assessment and radiographic findings. The program is evidence based and reflects contemporary physical therapist practice, while also being reproducible and reportable. This perspective article aims to encourage physical therapy researchers involved in evaluation of complex interventions to better document their own intervention development, as well as the outcomes, thus generating a body of knowledge about the development processes and protocols that is generalizable to the real-world complexity of providing physical therapy to individual patients. PMID- 21817013 TI - Mutations in CIC and FUBP1 contribute to human oligodendroglioma. AB - Oligodendrogliomas are the second most common malignant brain tumor in adults and exhibit characteristic losses of chromosomes 1p and 19q. To identify the molecular genetic basis for this alteration, we performed exomic sequencing of seven tumors. Among other changes, we found that the CIC gene (homolog of the Drosophila gene capicua) on chromosome 19q was somatically mutated in six cases and that the FUBP1 gene [encoding far-upstream element (FUSE) binding protein] on chromosome 1p was somatically mutated in two tumors. Examination of 27 additional oligodendrogliomas revealed 12 and 3 more tumors with mutations of CIC and FUBP1, respectively, 58% of which were predicted to result in truncations of the encoded proteins. These results suggest a critical role for these genes in the biology and pathology of oligodendrocytes. PMID- 21817014 TI - Control of local protein synthesis and initial events in myelination by action potentials. AB - Formation of myelin, the electrical insulation on axons produced by oligodendrocytes, is controlled by complex cell-cell signaling that regulates oligodendrocyte development and myelin formation on appropriate axons. If electrical activity could stimulate myelin induction, then neurodevelopment and the speed of information transmission through circuits could be modified by neural activity. We find that release of glutamate from synaptic vesicles along axons of mouse dorsal root ganglion neurons in culture promotes myelin induction by stimulating formation of cholesterol-rich signaling domains between oligodendrocytes and axons, and increasing local synthesis of the major protein in the myelin sheath, myelin basic protein, through Fyn kinase-dependent signaling. This axon-oligodendrocyte signaling would promote myelination of electrically active axons to regulate neural development and function according to environmental experience. PMID- 21817015 TI - Single-shot correlations and two-qubit gate of solid-state spins. AB - Measurement of coupled quantum systems plays a central role in quantum information processing. We have realized independent single-shot read-out of two electron spins in a double quantum dot. The read-out method is all-electrical, cross-talk between the two measurements is negligible, and read-out fidelities are ~86% on average. This allows us to directly probe the anticorrelations between two spins prepared in a singlet state and to demonstrate the operation of the two-qubit exchange gate on a complete set of basis states. The results provide a possible route to the realization and efficient characterization of multiqubit quantum circuits based on single quantum dot spins. PMID- 21817017 TI - Vacuum-induced transparency. AB - Photons are excellent information carriers but normally pass through each other without consequence. Engineered interactions between photons would enable applications as varied as quantum information processing and simulation of condensed matter systems. Using an ensemble of cold atoms strongly coupled to an optical cavity, we found that the transmission of light through a medium may be controlled with few photons and even by the electromagnetic vacuum field. The vacuum induces a group delay of 25 nanoseconds on the input optical pulse, corresponding to a light velocity of 1600 meters per second, and a transparency of 40% that increases to 80% when the cavity is filled with 10 photons. This strongly nonlinear effect provides prospects for advanced quantum devices such as photon number-state filters. PMID- 21817016 TI - Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. AB - The prevalent DNA modification in higher organisms is the methylation of cytosine to 5-methylcytosine (5mC), which is partially converted to 5 hydroxymethylcytosine (5hmC) by the Tet (ten eleven translocation) family of dioxygenases. Despite their importance in epigenetic regulation, it is unclear how these cytosine modifications are reversed. Here, we demonstrate that 5mC and 5hmC in DNA are oxidized to 5-carboxylcytosine (5caC) by Tet dioxygenases in vitro and in cultured cells. 5caC is specifically recognized and excised by thymine-DNA glycosylase (TDG). Depletion of TDG in mouse embyronic stem cells leads to accumulation of 5caC to a readily detectable level. These data suggest that oxidation of 5mC by Tet proteins followed by TDG-mediated base excision of 5caC constitutes a pathway for active DNA demethylation. PMID- 21817018 TI - Social science, spared again. PMID- 21817023 TI - Embryonic stem cells. NIH wins suit challenging legality of research. PMID- 21817024 TI - Newsmaker interview: Seiji Yasumura. Fukushima begins 30-year odyssey in radiation health. Interview by Dennis Normile. PMID- 21817025 TI - Newsmaker interview: Seiji Yasumura. Japan's electricity woes have researchers sweating. PMID- 21817026 TI - Marine biology. Marine census scrambles to fund a second phase with expanded focus. PMID- 21817027 TI - Alternative medicine. Scourge of snake oil salesmen bids an early farewell. PMID- 21817028 TI - Science education. Climate change sparks battles in classroom. PMID- 21817029 TI - Physics. Furtive approach rolls back the limits of quantum uncertainty. PMID- 21817030 TI - Newsmaker profile. Wayne Clough wants Smithsonian science to escape its shadow. PMID- 21817031 TI - Science-policy interface: scientific input limited. PMID- 21817032 TI - Fukushima research needs world's support. PMID- 21817033 TI - Science-policy interface: beyond assessments. PMID- 21817035 TI - Science policy. Changing incentives to publish. PMID- 21817036 TI - Biochemistry. Seeing a molecular motor at work. PMID- 21817037 TI - Microbiology. Exploiting malaria drug resistance to our advantage. PMID- 21817038 TI - Atmospheric science. Glacial cycles and Indian monsoon--a southern push. PMID- 21817039 TI - Evolution. Is bigger always better? PMID- 21817040 TI - Physics. Spotlight on plasmon lasers. PMID- 21817041 TI - Retrospective. Lennart Philipson (1929-2011). PMID- 21817042 TI - The future of seawater desalination: energy, technology, and the environment. AB - In recent years, numerous large-scale seawater desalination plants have been built in water-stressed countries to augment available water resources, and construction of new desalination plants is expected to increase in the near future. Despite major advancements in desalination technologies, seawater desalination is still more energy intensive compared to conventional technologies for the treatment of fresh water. There are also concerns about the potential environmental impacts of large-scale seawater desalination plants. Here, we review the possible reductions in energy demand by state-of-the-art seawater desalination technologies, the potential role of advanced materials and innovative technologies in improving performance, and the sustainability of desalination as a technological solution to global water shortages. PMID- 21817043 TI - Effects of working-memory training on striatal dopamine release. AB - Updating of working memory has been associated with striato-frontal brain regions and phasic dopaminergic neurotransmission. We assessed raclopride binding to striatal dopamine (DA) D2 receptors during a letter-updating task and a control condition before and after 5 weeks of updating training. Results showed that updating affected DA activity before training and that training further increased striatal DA release during updating. These findings highlight the pivotal role of transient neural processes associated with D2 receptor activity in working memory. PMID- 21817044 TI - Glacial-interglacial Indian summer monsoon dynamics. AB - The modern Indian summer monsoon (ISM) is characterized by exceptionally strong interhemispheric transport, indicating the importance of both Northern and Southern Hemisphere processes driving monsoon variability. Here, we present a high-resolution continental record from southwestern China that demonstrates the importance of interhemispheric forcing in driving ISM variability at the glacial interglacial time scale as well. Interglacial ISM maxima are dominated by an enhanced Indian low associated with global ice volume minima. In contrast, the glacial ISM reaches a minimum, and actually begins to increase, before global ice volume reaches a maximum. We attribute this early strengthening to an increased cross-equatorial pressure gradient derived from Southern Hemisphere high-latitude cooling. This mechanism explains much of the nonorbital scale variance in the Pleistocene ISM record. PMID- 21817046 TI - Nonreciprocal light propagation in a silicon photonic circuit. AB - Optical communications and computing require on-chip nonreciprocal light propagation to isolate and stabilize different chip-scale optical components. We have designed and fabricated a metallic-silicon waveguide system in which the optical potential is modulated along the length of the waveguide such that nonreciprocal light propagation is obtained on a silicon photonic chip. Nonreciprocal light transport and one-way photonic mode conversion are demonstrated at the wavelength of 1.55 micrometers in both simulations and experiments. Our system is compatible with conventional complementary metal-oxide semiconductor processing, providing a way to chip-scale optical isolators for optical communications and computing. PMID- 21817045 TI - Chemical genomic profiling for antimalarial therapies, response signatures, and molecular targets. AB - Malaria remains a devastating disease largely because of widespread drug resistance. New drugs and a better understanding of the mechanisms of drug action and resistance are essential for fulfilling the promise of eradicating malaria. Using high-throughput chemical screening and genome-wide association analysis, we identified 32 highly active compounds and genetic loci associated with differential chemical phenotypes (DCPs), defined as greater than or equal to fivefold differences in half-maximum inhibitor concentration (IC(50)) between parasite lines. Chromosomal loci associated with 49 DCPs were confirmed by linkage analysis and tests of genetically modified parasites, including three genes that were linked to 96% of the DCPs. Drugs whose responses mapped to wild type or mutant pfcrt alleles were tested in combination in vitro and in vivo, which yielded promising new leads for antimalarial treatments. PMID- 21817047 TI - A synthetic model of the Mn3Ca subsite of the oxygen-evolving complex in photosystem II. AB - Within photosynthetic organisms, the oxygen-evolving complex (OEC) of photosystem II generates dioxygen from water using a catalytic Mn(4)CaO(n) cluster (n varies with the mechanism and nature of the intermediate). We report here the rational synthesis of a [Mn(3)CaO(4)](6+) cubane that structurally models the trimanganese calcium-cubane subsite of the OEC. Structural and electrochemical comparison between Mn(3)CaO(4) and a related Mn(4)O(4) cubane alongside characterization of an intermediate calcium-manganese multinuclear complex reveals potential roles of calcium in facilitating high oxidation states at manganese and in the assembly of the biological cluster. PMID- 21817048 TI - Spectroscopic observation of dual catalytic sites during oxidation of CO on a Au/TiO2 catalyst. AB - The prevailing view of CO oxidation on gold-titanium oxide (Au/TiO(2)) catalysts is that the reaction occurs on metal sites at the Au/TiO(2) interface. We observed dual catalytic sites at the perimeter of 3-nanometer Au particles supported on TiO(2) during CO oxidation. Infrared-kinetic measurements indicate that O-O bond scission is activated by the formation of a CO-O(2) complex at dual Ti-Au sites at the Au/TiO(2) interface. Density functional theory calculations, which provide the activation barriers for the formation and bond scission of the CO-O(2) complex, confirm this model as well as the measured apparent activation energy of 0.16 electron volt. The observation of sequential delivery and reaction of CO first from TiO(2) sites and then from Au sites indicates that catalytic activity occurs at the perimeter of Au nanoparticles. PMID- 21817049 TI - Seasonal flows on warm Martian slopes. AB - Water probably flowed across ancient Mars, but whether it ever exists as a liquid on the surface today remains debatable. Recurring slope lineae (RSL) are narrow (0.5 to 5 meters), relatively dark markings on steep (25 degrees to 40 degrees ) slopes; repeat images from the Mars Reconnaissance Orbiter High Resolution Imaging Science Experiment show them to appear and incrementally grow during warm seasons and fade in cold seasons. They extend downslope from bedrock outcrops, often associated with small channels, and hundreds of them form in some rare locations. RSL appear and lengthen in the late southern spring and summer from 48 degrees S to 32 degrees S latitudes favoring equator-facing slopes, which are times and places with peak surface temperatures from ~250 to 300 kelvin. Liquid brines near the surface might explain this activity, but the exact mechanism and source of water are not understood. PMID- 21817050 TI - Reduced interannual rainfall variability in East Africa during the last ice age. AB - Interannual rainfall variations in equatorial East Africa are tightly linked to the El Nino Southern Oscillation (ENSO), with more rain and flooding during El Nino and droughts in La Nina years, both having severe impacts on human habitation and food security. Here we report evidence from an annually laminated lake sediment record from southeastern Kenya for interannual to centennial-scale changes in ENSO-related rainfall variability during the last three millennia and for reductions in both the mean rate and the variability of rainfall in East Africa during the Last Glacial period. Climate model simulations support forward extrapolation from these lake sediment data that future warming will intensify the interannual variability of East Africa's rainfall. PMID- 21817051 TI - A 10,000-year record of Arctic Ocean sea-ice variability--view from the beach. AB - We present a sea-ice record from northern Greenland covering the past 10,000 years. Multiyear sea ice reached a minimum between ~8500 and 6000 years ago, when the limit of year-round sea ice at the coast of Greenland was located ~1000 kilometers to the north of its present position. The subsequent increase in multiyear sea ice culminated during the past 2500 years and is linked to an increase in ice export from the western Arctic and higher variability of ice drift routes. When the ice was at its minimum in northern Greenland, it greatly increased at Ellesmere Island to the west. The lack of uniformity in past sea-ice changes, which is probably related to large-scale atmospheric anomalies such as the Arctic Oscillation, is not well reproduced in models. This needs to be further explored, as it is likely to have an impact on predictions of future sea ice distribution. PMID- 21817052 TI - Signal perception in frogs and bats and the evolution of mating signals. AB - Psychophysics measures the relationship between a stimulus's physical magnitude and its perceived magnitude. Because decisions are based on perception of stimuli, this relationship is critical to understanding decision-making. We tested whether psychophysical laws explain how female tungara frogs (Physalaemus pustulosus) and frog-eating bats (Trachops cirrhosus) compare male frog calls, and how this imposes selection on call evolution. Although both frogs and bats prefer more elaborate calls, they are less selective as call elaboration increases, because preference is based on stimulus ratios. Thus, as call elaboration increases, both relative attractiveness and relative predation risk decrease because of how receivers perceive and compare stimuli. Our data show that female cognition can limit the evolution of sexual signal elaboration. PMID- 21817053 TI - Extending the carbon chain: hydrocarbon formation catalyzed by vanadium/molybdenum nitrogenases. AB - In a small-scale reaction, vanadium-dependent nitrogenase has previously been shown to catalyze reductive catenation of carbon monoxide (CO) to ethylene, ethane, propylene, and propane. Here, we report the identification of additional hydrocarbon products [alpha-butylene, n-butane, and methane (CH(4))] in a scaled up reaction featuring 20 milligrams of vanadium-iron protein, the catalytic component of vanadium nitrogenase. Additionally, we show that the more common molybdenum-dependent nitrogenase can generate the same hydrocarbons from CO, although CH(4) was not detected. The identification of CO as a substrate for both molybdenum- and vanadium-nitrogenases strengthens the hypothesis that CO reduction is an evolutionary relic of the function of the nitrogenase family. Moreover, the comparison between the CO-reducing capacities of the two nitrogenases suggests that the identity of heterometal at the active cofactor site affects the efficiency and product distribution of this reaction. PMID- 21817054 TI - High-speed atomic force microscopy reveals rotary catalysis of rotorless F1 ATPase. AB - F(1) is an adenosine triphosphate (ATP)-driven motor in which three torque generating beta subunits in the alpha(3)beta(3) stator ring sequentially undergo conformational changes upon ATP hydrolysis to rotate the central shaft gamma unidirectionally. Although extensive experimental and theoretical work has been done, the structural basis of cooperative torque generation to realize the unidirectional rotation remains elusive. We used high-speed atomic force microscopy to show that the rotorless F(1) still "rotates"; in the isolated alpha(3)beta(3) stator ring, the three beta subunits cyclically propagate conformational states in the counterclockwise direction, similar to the rotary shaft rotation in F(1). The structural basis of unidirectionality is programmed in the stator ring. These findings have implications for cooperative interplay between subunits in other hexameric ATPases. PMID- 21817056 TI - Integrating what and when across the primate medial temporal lobe. AB - Episodic memory or memory for the detailed events in our lives is critically dependent on structures of the medial temporal lobe (MTL). A fundamental component of episodic memory is memory for the temporal order of items within an episode. To understand the contribution of individual MTL structures to temporal order memory, we recorded single-unit activity and local field potential from three MTL areas (hippocampus and entorhinal and perirhinal cortex) and visual area TE as monkeys performed a temporal-order memory task. Hippocampus provided incremental timing signals from one item presentation to the next, whereas perirhinal cortex signaled the conjunction of items and their relative temporal order. Thus, perirhinal cortex appeared to integrate timing information from hippocampus with item information from visual sensory area TE. PMID- 21817057 TI - EPO and HO-1 in cardiovascular and renal protection: just a common signaling pathway or a mechanistic link? PMID- 21817055 TI - Cartilage acidic protein-1B (LOTUS), an endogenous Nogo receptor antagonist for axon tract formation. AB - Neural circuitry formation depends on the molecular control of axonal projection during development. By screening with fluorophore-assisted light inactivation in the developing mouse brain, we identified cartilage acidic protein-1B as a key molecule for lateral olfactory tract (LOT) formation and named it LOT usher substance (LOTUS). We further identified Nogo receptor-1 (NgR1) as a LOTUS binding protein. NgR1 is a receptor of myelin-derived axon growth inhibitors, such as Nogo, which prevent neural regeneration in the adult. LOTUS suppressed Nogo-NgR1 binding and Nogo-induced growth cone collapse. A defasciculated LOT was present in lotus-deficient mice but not in mice lacking both lotus- and ngr1. These findings suggest that endogenous antagonism of NgR1 by LOTUS is crucial for normal LOT formation. PMID- 21817058 TI - Agreement between different parameters of dialysis dose in achieving treatment targets: results from the NECOSAD study. AB - BACKGROUND: The recommended parameter of dialysis dose differs between K-DOQI and the European Best Practice Guidelines. It is not well known to what extent an agreement exists between the different parameters, nor if target and delivered dialysis dose are prescribed according to the urea reduction rate (URR), single pool Kt/V (spKt/V) or equilibrated double-pool Kt/V (eKt/V) and which parameter is most strongly related to mortality. METHODS: In 830 haemodialysis patients from the NECOSAD cohort URR, spKt/V and eKt/V were calculated and compared according to a classification regarding the recommended treatment targets (70%, 1.4 and 1.2, respectively) as well as minimum delivered dialysis dose (65%, 1.2 and 1.05, respectively). Moreover, the relation between treatment dose and survival was assessed using Cox regression analysis. RESULTS: A spKt/V of >=1.4 and URR >=70% corresponded with eKt/V >=1.20 (as reference method) in, respectively, 98.0 and 90.6% of patients. spKt/V of >=1.2 and URR >=65% corresponded with eKt/V >=1.05 in, respectively, 95.5 and 91.2% of patients. Deviations from the reference method were significantly related to differences in urea distribution volume (spKt/V), treatment time (URR) and ultrafiltration volume (URR). The adjusted HR (95% CI) was 0.98 (0.96, 0.99) for URR, 0.51 (0.31, 0.84) for spKt/V and 0.46 (0.30, 0.80) for the eKt/V. CONCLUSION: The use of URR leads to larger disagreement with the reference method (eKt/V) treatment target as compared to spKt/V. Low urea distribution volume, short treatment time and low ultrafiltration volumes are predictive parameters for overestimation of dialysis dose when utilizing the alternative methods spKt/V and URR instead of eKt/V. Delivered eKt/V, spKt/V and URR were all positively related to survival. PMID- 21817059 TI - Novel oxysterols observed in tissues and fluids of AY9944-treated rats: a model for Smith-Lemli-Opitz syndrome. AB - Treatment of Sprague-Dawley rats with AY9944, an inhibitor of 3beta-hydroxysterol Delta(7)-reductase (Dhcr7), leads to elevated levels of 7-dehydrocholesterol (7 DHC) and reduced levels of cholesterol in all biological tissues, mimicking the key biochemical hallmark of Smith-Lemli-Opitz syndrome (SLOS). Fourteen 7-DHC derived oxysterols previously have been identified as products of free radical oxidation in vitro; one of these oxysterols, 3beta,5alpha-dihydroxycholest-7-en-6 one (DHCEO), was recently identified in Dhcr7-deficient cells and in brain tissues of Dhcr7-null mouse. We report here the isolation and characterization of three novel 7-DHC-derived oxysterols (4alpha- and 4beta-hydroxy-7-DHC and 24 hydroxy-7-DHC) in addition to DHCEO and 7-ketocholesterol (7-kChol) from the brain tissues of AY9944-treated rats. The identities of these five oxysterols were elucidated by HPLC-ultraviolet (UV), HPLC-MS, and 1D- and 2D-NMR. Quantification of 4alpha- and 4beta-hydroxy-7-DHC, DHCEO, and 7-kChol in rat brain, liver, and serum were carried out by HPLC-MS using d(7)-DHCEO as an internal standard. With the exception of 7-kChol, these oxysterols were present only in tissues of AY9944-treated, but not control rats, and 7-kChol levels were markedly (>10-fold) higher in treated versus control rats. These findings are discussed in the context of the potential involvement of 7-DHC-derived oxysterols in the pathogenesis of SLOS. PMID- 21817061 TI - Distension of the esophagogastric junction augments triggering of transient lower esophageal sphincter relaxation. AB - Patients with gastroesophageal reflux disease show an increase in esophagogastric junction (EGJ) distensibility and in frequency of transient lower esophageal sphincter relaxations (TLESR) induced by gastric distension. The objective was to study the effect of localized EGJ distension on triggering of TLESR in healthy volunteers. An esophageal manometric catheter incorporating an 8-cm internal balloon adjacent to a sleeve sensor was developed to enable continuous recording of EGJ pressure during distension of the EGJ. Inflation of the balloon doubled the cross-section of the trans-sphincteric portion of the catheter from 5 mm OD (round) to 5 * 11 mm (oval). Ten healthy subjects were included. After catheter placement and a 30-min adaptation period, the EGJ was randomly distended or not, followed by a 45-min baseline recording. Subjects consumed a refluxogenic meal, and recordings were made for 3 h postprandially. A repeat study was performed on another day with EGJ distension status reversed. Additionally, in one subject MRI was performed to establish the exact position of the balloon in the inflated state. The number of TLESR increased during periods of EGJ distension with the effect being greater after a meal [baseline: 2.0(0.0-4.0) vs. 4.0(1.0-11.0), P=0.04; postprandial: 15.5(10.0-33.0) vs. 22.0(17.0-58.0), P=0.007 for undistended and distended, respectively]. EGJ distension augments meal-induced triggering of TLESR in healthy volunteers. Our data suggest the existence of a population of vagal afferents located at sites in/around the EGJ that may influence triggering of TLESR. PMID- 21817060 TI - Altered lipid metabolism in Hfe-knockout mice promotes severe NAFLD and early fibrosis. AB - The HFE protein plays a crucial role in the control of cellular iron homeostasis. Steatosis is commonly observed in HFE-related iron-overload disorders, and current evidence suggests a causal link between iron and steatosis. Here, we investigated the potential contribution of HFE mutations to hepatic lipid metabolism and its role in the pathogenesis of nonalcoholic fatty liver disease. Wild-type (WT) and Hfe knockout mice (Hfe(-/-)) were fed either standard chow, a monounsaturated low fat, or a high-fat, high-carbohydrate diet (HFD) and assessed for liver injury, body iron status, and markers of lipid metabolism. Despite hepatic iron concentrations and body weights similar to WT controls, Hfe(-/-) mice fed the HFD developed severe hypoxia-related steatohepatitis, Tnf-alpha activation, and mitochondrial respiratory complex and antioxidant dysfunction with early fibrogenesis. These features were associated with an upregulation in the expression of genes involved in intracellular lipid synthesis and trafficking, while transcripts for mitochondrial fatty acid beta-oxidation and adiponectin signaling-related genes were significantly attenuated. In contrast, HFD-fed WT mice developed bland steatosis only, with no inflammation or fibrosis and no upregulation of lipogenesis-related genes. A HFD led to reduced hepatic iron in Hfe(-/-) mice compared with chow-fed mice, despite higher serum iron, decreased hepcidin expression, and increased duodenal ferroportin mRNA. In conclusion, our results demonstrate that Hfe(-/-) mice show defective hepatic intestinal iron and lipid signaling, which predispose them toward diet-induced hepatic lipotoxicity, accompanied by an accelerated progression of injury to fibrosis. PMID- 21817062 TI - Gut-derived factors promote neurogenesis of CNS-neural stem cells and nudge their differentiation to an enteric-like neuronal phenotype. AB - Recent studies have explored the potential of central nervous system-derived neural stem cells (CNS-NSC) to repopulate the enteric nervous system. However, the exact phenotypic fate of gut-transplanted CNS-NSC has not been characterized. The aim of this study was to investigate the effect of the gut microenvironment on phenotypic fate of CNS-NSC in vitro. With the use of Transwell culture, differentiation of mouse embryonic CNS-NSC was studied when cocultured without direct contact with mouse intestinal longitudinal muscle-myenteric plexus preparations (LM-MP) compared with control noncocultured cells, in a differentiating medium. Differentiated cells were analyzed by immunocytochemistry and quantitative RT-PCR to assess the expression of specific markers and by whole cell patch-clamp studies for functional characterization of their phenotype. We found that LM-MP cocultured cells had a significant increase in the numbers of cells that were immune reactive against the panneuronal marker beta-tubulin, neurotransmitters neuronal nitric oxide synthase (nNOS), choline acetyltransferase (ChAT), and neuropeptide vasoactive intestinal peptide (VIP) and showed an increase in expression of these genes, compared with control cells. Whole cell patch-clamp analysis showed that coculture with LM-MP decreases cell excitability and reduces voltage-gated Na(+) currents but significantly enhances A-current and late afterhyperpolarization (AHP) and increases the expression of the four AHP-generating Ca(2+)-dependent K(+) channel genes (KCNN), compared with control cells. In a separate experiment, differentiation of LM-MP cocultured CNS NSC produced a significant increase in the numbers of cells that were immune reactive against the neurotransmitters nNOS, ChAT, and the neuropeptide VIP compared with CNS-NSC differentiated similarly in the presence of neonatal brain tissue. Our results show that the gut microenvironment induces CNS-NSC to produce neurons that share some of the characteristics of classical enteric neurons, further supporting the therapeutic use of these cells for gastrointestinal disorders. PMID- 21817063 TI - DNA-induced narrowing of the gyrase N-gate coordinates T-segment capture and strand passage. AB - DNA gyrase introduces negative supercoils into DNA in an ATP-dependent reaction. DNA supercoiling is catalyzed by a strand-passage mechanism, in which a T-segment of DNA is passed through the gap in a transiently cleaved G-segment. Strand passage requires the coordinated closing and opening of three protein interfaces in gyrase, the N-gate, DNA-gate, and C-gate. We show here that DNA binding to the DNA-gate of gyrase and wrapping of DNA around the C-terminal domains of GyrA induces a narrowing of the N-gate. This half-closed state prepares capture of a T segment in the upper cavity of gyrase. Subsequent N-gate closure upon binding of ATP then poises the reaction toward strand passage. The N-gate reopens after ATP hydrolysis, allowing for further catalytic cycles. DNA binding, cleavage, and wrapping and N-gate narrowing are intimately linked events that coordinate conformational changes at the DNA and the N-gate. PMID- 21817064 TI - Retraction for Harland et al., "Phospholipid bilayers are viscoelastic". PMID- 21817066 TI - Joints are not lubricated in the way Greene et al. say they are. PMID- 21817067 TI - Time-resolved energy transduction in a quantum capacitor. AB - The capability to deposit charge and energy quantum-by-quantum into a specific atomic site could lead to many previously unidentified applications. Here we report on the quantum capacitor formed by a strongly localized field possessing such capability. We investigated the charging dynamics of such a capacitor by using the unique scanning tunneling microscopy that combines nanosecond temporal and subangstrom spatial resolutions, and by using Si(001) as the electrode as well as the detector for excitations produced by the charging transitions. We show that sudden switching of a localized field induces a transiently empty quantum dot at the surface and that the dot acts as a tunable excitation source with subangstrom site selectivity. The timescale in the deexcitation of the dot suggests the formation of long-lived, excited states. Our study illustrates that a quantum capacitor has serious implications not only for the bottom-up nanotechnology but also for future switching devices. PMID- 21817068 TI - 2011 Report of the Executive Vice President and Chief Executive Officer: ASHP: continually in pursuit of truth. PMID- 21817065 TI - The D-dopachrome tautomerase (DDT) gene product is a cytokine and functional homolog of macrophage migration inhibitory factor (MIF). AB - Macrophage migration inhibitory factor (MIF) is a pivotal regulator of the immune response. Neutralization or genetic deletion of MIF does not completely abrogate activation responses, however, and deletion of the MIF receptor, CD74, produces a more pronounced phenotype than MIF deficiency. We hypothesized that these observations may be explained by a second MIF-like ligand, and we considered a probable candidate to be the protein encoded by the homologous, D-dopachrome tautomerase (D-DT) gene. We show that recombinant D-DT protein binds CD74 with high affinity, leading to activation of ERK1/2 MAP kinase and downstream proinflammatory pathways. Circulating D-DT levels correlate with disease severity in sepsis or malignancy, and the specific immunoneutralization of D-DT protects mice from lethal endotoxemia by reducing the expression of downstream effector cytokines. These data indicate that D-DT is a MIF-like cytokine with an overlapping spectrum of activities that are important for our understanding of MIF-dependent physiology and pathology. PMID- 21817069 TI - Getting it started: a year to remember. PMID- 21817070 TI - 2011 Report of the ASHP treasurer: a strong and vibrant organization. PMID- 21817075 TI - Clinicians adjust to latest ESA recommendations. PMID- 21817076 TI - Oral direct factor Xa inhibitor gets FDA's OK. PMID- 21817077 TI - State funds medication reconciliation project at Virginia hospital. PMID- 21817078 TI - PTCB considers changes to certification, recertification. PMID- 21817079 TI - Dabigatran-induced rash. PMID- 21817080 TI - Pros and cons of dabigatran. PMID- 21817081 TI - Permission granted. PMID- 21817082 TI - Dabigatran etexilate: A novel oral direct thrombin inhibitor. AB - PURPOSE: The pharmacology, pharmacokinetics, clinical efficacy, tolerability, dosage and administration, and place in therapy of dabigatran etexilate are reviewed. SUMMARY: Dabigatran is a reversible direct thrombin inhibitor (DTI) that has rapid and predictable anticoagulant effects and does not require the anticoagulation monitoring seen with oral vitamin K antagonists. Dabigatran etexilate has demonstrated efficacy in several clinical studies in preventing venous thromboembolism (VTE) for patients undergoing total hip or knee replacement, in preventing strokes in patients with nonvalvular atrial fibrillation, and in treating acute VTE. Dabigatran etexilate is a prodrug that is orally absorbed and completely converted to the active form dabigatran by carboxylesterases. Neither the conversion of dabigatran etexilate nor the metabolism of active dabigatran involves the cytochrome P-450 isoenzyme system. Other than hemorrhage, dabigatran is generally well tolerated, with gastrointestinal effects being the most commonly reported adverse events. All dosages should be adjusted in patients with reduced renal function. Dabigatran is currently being investigated for several thromboembolic disorders. It was approved by the Food and Drug Administration in October 2010 for stroke and VTE prevention in adult patients with nonvalvular atrial fibrillation, and it was approved by the European Medicines Agency in March 2009 for the prevention of VTE in adult patients undergoing elective total hip or knee replacement. CONCLUSION: Dabigatran etexilate, the first oral DTI marketed in the United States, is indicated to reduce the risk of stroke and systemic embolism in patients with non valvular atrial fibrillation. Dabigatran may be a viable option for anticoagulation in some patients due to its oral administration, rapid onset of action, and predictable anticoagulant effects. PMID- 21817083 TI - Rationale and evidence for extended infusion of piperacillin-tazobactam. AB - PURPOSE: The pharmacodynamics and therapeutic effects of extended-infusion (EI) piperacillin-tazobactam therapy are reviewed, with an emphasis on growing evidence of its advantages over traditional infusion schemes. SUMMARY: EI beta lactam therapy is now considered a key aspect of antimicrobial stewardship, and published evidence indicates that i.v. infusion of piperacillin-tazobactam over extended periods (e.g., four hours) instead of the traditionally recommended 30 minutes may offer several advantages, including reduced mortality and length of hospital stay and lower treatment cost. A substantial body of evidence from in vitro and animal studies indicates that EI enhances the pharmacodynamic profile of piperacillin-tazobactam, particularly by extending the time the free drug level remains above the minimum inhibitory concentration. In one published study comparing the use of EI and traditional piperacillin-tazobactam infusion schemes in critically ill patients with Pseudomonas aeruginosa infection, EI therapy was associated with significantly improved 14-day mortality and significantly shorter hospital stays; a few other studies have yielded less favorable results. Pharmacoeconomic evaluations indicate that EI can offer significant cost benefits. However, evidence of the benefits of EI in actual clinical practice remains relatively weak, highlighting the need for large, controlled clinical trials to define its optimal role in patient care. CONCLUSION: The pharmacodynamic profile of EI piperacillin-tazobactam therapy; evidence of its benefits over traditional 30-minute infusions in terms of mortality, duration of hospitalization, clinical and microbiological cure rates, and reduction of fever; and EI's lower total treatment cost suggest that EI may be the superior mode of administration. PMID- 21817084 TI - Prolonged triple therapy for persistent multidrug-resistant Acinetobacter baumannii ventriculitis. AB - PURPOSE: A case of persistent multidrug-resistant (MDR) Acinetobacter baumannii ventriculitis successfully treated with a prolonged and novel combination of antimicrobials is reported. SUMMARY: A 38-year-old, 84-kg Caucasian woman with a recent history of craniotomy was admitted with nausea, fever, headache, photophobia, and drainage from her craniotomy incision. She underwent a repeat craniotomy on hospital day 4 with abscess debridement and repair of a cerebrospinal fluid leak. Cultures grew MDR A. baumannii, coagulase-negative Staphylococcus species, and methicillin-resistant Staphylococcus aureus. Based on the limited published pharmacokinetic and pharmacodynamic data for colistin, we determined a favorable outcome with i.v. colistin monotherapy was unlikely and decided to treat the patient with simultaneous i.v. and intraventricular colistin, as well as intraventricular tobramycin and i.v. rifampin. She was treated with a total of 36 days of intraventricular colistin, 40 days of intraventricular tobramycin, 51 days of i.v. colistin and rifampin, and 56 days i.v. vancomycin for infection that persisted despite multiple debridements. The patient had subsequent improvement in clinical manifestations and eradication of infection. She was subsequently discharged to an acute rehabilitation facility on hospital day 77 with posttreatment sequelae including mental impairment and renal failure requiring hemodialysis. Follow-up visits revealed significant improvement in her mental status, speech, and strength on the side not affected by the stroke. CONCLUSION: Prolonged combination therapy with intraventricular colistin and tobramycin plus i.v. colistin, rifampin, and vancomycin led to the resolution of a persistent central nervous system infection caused by MDR A. baumannii. PMID- 21817085 TI - Stability of diluted adenosine solutions in polyvinyl chloride infusion bags. AB - PURPOSE: The stability of diluted adenosine solutions in polyvinyl chloride infusion bags was studied. METHODS: Adenosine 50-, 100-, and 220-MUg/mL solutions were prepared in 50-mL polyvinyl chloride (PVC) infusion bags containing 0.9% sodium chloride injection or 5% dextrose injection and stored at room temperature (23-25 degrees C) or under refrigeration (2-8 degrees C). Each sample of every combination of concentration, diluent, and storage temperature was prepared in triplicate, yielding 36 samples. The samples were assayed using a stability indicating, reverse-phase high-performance liquid chromatographic method immediately after preparation (time zero) and at 24 hours, 48 hours, 7 days, and 14 days. pH was measured at time zero, 48 hours, 7 days, and 14 days. Time zero concentrations were calculated from the equation produced from a calibration curve of standards ranging from 10 to 500 MUg/mL. Samples were also visually inspected against a light background for clarity, color, and the presence of crystalline particulate matter. Stability was defined as retaining at least 90% of the initial adenosine concentration. RESULTS: After 14 days, all samples retained greater than 98% of the initial adenosine concentration, with no evidence of adsorption, visible precipitation, or considerable change in pH, suggesting minimal to no loss of product due to degradation or adsorption. CONCLUSION: Adenosine 50-, 100-, and 220-MUg/mL solutions in 50-mL PVC infusion bags containing 0.9% sodium chloride injection or 5% dextrose injection stored at room temperature and refrigerated conditions were stable for at least 14 days. PMID- 21817086 TI - Stability of midazolam hydrochloride injection 1-mg/mL solutions in polyvinyl chloride and polyolefin bags. AB - PURPOSE: The stability of midazolam hydrochloride injection 1-mg/mL solutions in polyvinyl chloride (PVC) and polyolefin bags under varying conditions was evaluated. METHODS: Triplicate solutions of midazolam hydrochloride 1-mg/mL were prepared in polyolefin and PVC i.v. bags by diluting midazolam hydrochloride injection 5 mg/mL with 5% dextrose injection. Bags were then stored under refrigeration (3-4 degrees C), exposed to light at room temperature (20-25 degrees C), or protected from light in amber bags at room temperature. Samples were taken immediately after preparation (day 0) and on days 1, 2, 3, 6, 13, 20, and 27 for analysis with a stability-indicating high-performance liquid chromatography assay in order to determine solution concentration. Stability was defined as retention of at least 90% of the initial drug concentration. The pH of each solution was also measured weekly. Sterility of the i.v. bags was determined at the end of the study by microbiological testing with culture in growth media. Differences in concentrations under the various storage conditions and bags used were analyzed using analysis of variance. RESULTS: All solutions retained over 98% of the initial midazolam hydrochloride concentration, with no statistically significant (p >= 0.05) change in concentration over the four-week period. Stability was not affected by temperature, exposure to light, or bag type. The pH of all solutions remained between 3.2 and 3.4 throughout the study. Sterility after 28 days was retained. CONCLUSION: Midazolam hydrochloride 1-mg/mL solutions diluted in 5% dextrose injection remained stable over 27 days in both polyolefin and PVC i.v. bags, regardless of storage condition. PMID- 21817087 TI - Pharmacy residency and the medical training model: is pharmacy at a tipping point? PMID- 21817088 TI - The significance of health anxiety and somatization in care-seeking for back and upper extremity pain. AB - BACKGROUND: Patients with musculoskeletal pain account for a large number of consultations in primary care. Improving our understanding of factors that make patients seek care could be of interest in decision making and prevention in the health care system. OBJECTIVES: Our objectives were to examine if health anxiety, somatization and fear-avoidance beliefs were of importance for care-seeking with either back pain or upper extremity pain and to look at possible differences between the two groups. METHODS: This is a prospective study with a baseline questionnaire and 18 months follow-up. Using the International Classification for Primary Care (ICPC), we identified care-seekers with either back pain or upper extremity pain among the potential patients of eight GPs. For analysis, we used Cox proportional hazards regression analysis. Analysis was stratified by gender. RESULTS: We found that previous regional pain was a strong predictor of care seeking. Somatization was associated with seeking care for back pain. Health anxiety was a predictor among women suffering from back pain. Only previous pain was a predictor of care-seeking for upper extremity pain. CONCLUSION: The study implies that prevention of back pain and upper extremity pain requires different strategies and that gender and health anxieties should be taken into account. PMID- 21817089 TI - Treatment of acute otitis media in general practice: quality variations across countries. AB - BACKGROUND: Recommendations for antibiotic treatment of acute otitis media (AOM) have changed over the years, and today many experts recommend initial observation. However, antibiotic prescribing should be considered in children aged <2 years or if AOM is accompanied by discharging ear. OBJECTIVES: To investigate the quality of treatment of AOM in general practice and to explore the influence of selected GP and patient characteristics on antibiotic prescribing. METHODS: During the winter 2008, a prospective registration of patients diagnosed with AOM was conducted in general practice in Lithuania, Kaliningrad, Spain, Argentina, Sweden and Denmark. Some 1175 patients diagnosed with AOM were registered. Information about age and sex of the patient, duration of symptoms (days), temperature >38.5 degrees C, ear discharge and the antibiotic treatment given was recorded. RESULTS: Danish GPs had the lowest antibiotic prescription rate for AOM [72.7% (95% confidence interval (CI) = 67.0-77.8)] and GPs in Kaliningrad had the highest [97.1% (95% CI = 89.8-99.6)]. Narrow-spectrum penicillin was almost exclusively prescribed in the two Nordic countries, while broad-spectrum penicillins, often in combination with clavulanic acid, were prescribed in the other four countries. Macrolides comprised 5-10% of prescriptions. Antibiotic prescribing was associated with the following characteristics of the patients: symptoms for >3 days, ear discharge and fever. CONCLUSION: The majority of patients with AOM were treated with antibiotics in all six countries, but considerable variations in both prescribing rate and choice of antibiotics were identified. PMID- 21817090 TI - Parental age effects on cortical morphology in offspring. AB - The age at which a parent has a child impacts the child's cognition and risk for mental illness. It appears that this risk is curvilinear, with both age extremes associated with lower intelligence and increased prevalence of some neuropsychiatric disorders. Little is known of the neural mechanisms underpinning this phenomenon. We extracted lobar volumes, surface areas, and cortical thickness from 489 neuroanatomic magnetic resonance images acquired on 171 youth. Using linear mixed model regression, we determined the association between parental age and offspring's neuroanatomy, adjusting for offspring's age, sex, intelligence, and parental socioeconomic class. For gray matter volumes, quadratic paternal and maternal age terms contributed significantly (maternal quadratic age effect: t = -2.2, P = 0.03; paternal quadratic age effect: t = 2.4, P = 0.02) delineating an inverted "U" relationship between parental age and gray matter volume. Cortical volume increased with both advancing paternal and maternal age until around the early 30s after which it fell. Paternal age effects were more pronounced on cortical surface area, whereas maternal age impacted more on cortical thickness. There were no significant effects of parental age on white matter volumes. These parental age effects on cerebral morphology may form part of the link between parental age extremes and suboptimal neurocognitive outcomes. PMID- 21817091 TI - Striatum-medial prefrontal cortex connectivity predicts developmental changes in reinforcement learning. AB - During development, children improve in learning from feedback to adapt their behavior. However, it is still unclear which neural mechanisms might underlie these developmental changes. In the current study, we used a reinforcement learning model to investigate neurodevelopmental changes in the representation and processing of learning signals. Sixty-seven healthy volunteers between ages 8 and 22 (children: 8-11 years, adolescents: 13-16 years, and adults: 18-22 years) performed a probabilistic learning task while in a magnetic resonance imaging scanner. The behavioral data demonstrated age differences in learning parameters with a stronger impact of negative feedback on expected value in children. Imaging data revealed that the neural representation of prediction errors was similar across age groups, but functional connectivity between the ventral striatum and the medial prefrontal cortex changed as a function of age. Furthermore, the connectivity strength predicted the tendency to alter expectations after receiving negative feedback. These findings suggest that the underlying mechanisms of developmental changes in learning are not related to differences in the neural representation of learning signals per se but rather in how learning signals are used to guide behavior and expectations. PMID- 21817092 TI - Compositionality of rule representations in human prefrontal cortex. AB - Rules are widely used in everyday life to organize actions and thoughts in accordance with our internal goals. At the simplest level, single rules can be used to link individual sensory stimuli to their appropriate responses. However, most tasks are more complex and require the concurrent application of multiple rules. Experiments on humans and monkeys have shown the involvement of a frontoparietal network in rule representation. Yet, a fundamental issue still needs to be clarified: Is the neural representation of multiple rules compositional, that is, built on the neural representation of their simple constituent rules? Subjects were asked to remember and apply either simple or compound rules. Multivariate decoding analyses were applied to functional magnetic resonance imaging data. Both ventrolateral frontal and lateral parietal cortex were involved in compound representation. Most importantly, we were able to decode the compound rules by training classifiers only on the simple rules they were composed of. This shows that the code used to store rule information in prefrontal cortex is compositional. Compositional coding in rule representation suggests that it might be possible to decode other complex action plans by learning the neural patterns of the known composing elements. PMID- 21817094 TI - Macrophage Elovl6 deficiency ameliorates foam cell formation and reduces atherosclerosis in low-density lipoprotein receptor-deficient mice. AB - OBJECTIVE: Elovl6, a long-chain fatty acid elongase, is a rate-limiting enzyme that elongates saturated and monounsaturated fatty acids and has been shown to be related to obesity-induced insulin resistance via modification of fatty acid composition. In this study, we investigated the roles of Elovl6 in foam cell formation in macrophages and atherosclerosis in mice. METHODS AND RESULTS: To investigate the roles of Elovl6 in macrophages in the progression of atherosclerosis, we transplanted bone marrow cells of wild-type or Elovl6(-/-) mice into irradiated LDL-R(-/-) mice that were fed a western diet. Aortic atherosclerotic lesion areas and infiltration of macrophages were significantly smaller in Elovl6(-/-) bone marrow cells-transplanted LDL-R(-/-) mice than in wild-type. Accumulation of esterified cholesterol on exposure to acetylated-LDL was less severe in peritoneal macrophages from Elovl6(-/-) mice than those from wild-type. Cholesterol efflux and expression of cholesterol efflux transporters were increased in Elovl6(-/-) macrophages, although no difference in uptake of acetylated-LDL was found between the two groups. On analysis of fatty acid composition of the esterified cholesterol fraction in macrophages, n-6 polyunsaturated fatty acids were decreased by absence of Elovl6. CONCLUSIONS: These findings suggest that Elovl6 in macrophages may contribute to foam cell formation and progression of atherosclerosis. PMID- 21817093 TI - Smooth muscle calponin: an unconventional CArG-dependent gene that antagonizes neointimal formation. AB - OBJECTIVE: Smooth muscle calponin (CNN1) contains multiple conserved intronic CArG elements that bind serum response factor and display enhancer activity in vitro. The objectives here were to evaluate these CArG elements for activity in transgenic mice and determine the effect of human CNN1 on injury-induced vascular remodeling. METHODS AND RESULTS: Mice carrying a lacZ reporter under control of intronic CArG elements in the human CNN1 gene failed to show smooth muscle cell (SMC)-restricted activity. However, deletion of the orthologous sequences in mice abolished endogenous Cnn1 promoter activity, suggesting their necessity for in vivo Cnn1 expression. Mice carrying a 38-kb bacterial artificial chromosome (BAC) harboring the human CNN1 gene displayed SMC- restricted expression of the corresponding CNN1 protein, as measured by immunohistochemistry and Western blotting. Extensive BAC recombineering studies revealed the absolute necessity of a single intronic CArG element for correct SMC-restricted expression of human CNN1. Overexpressing human CNN1 suppressed neointimal formation following arterial injury. Mice with an identical BAC carrying mutations in CArG elements that inhibit human CNN1 expression showed outward remodeling and neointimal formation. CONCLUSIONS: A single intronic CArG element is necessary but insufficient for proper CNN1 expression in vivo. CNN1 overexpression antagonizes arterial injury-induced neointimal formation. PMID- 21817095 TI - Proteasomal inhibition promotes ATP-binding cassette transporter A1 (ABCA1) and ABCG1 expression and cholesterol efflux from macrophages in vitro and in vivo. AB - OBJECTIVE: ATP-binding cassette transporter A1 (ABCA1) and ABCG1 are key molecules in an initial step of reverse cholesterol transport (RCT), a major antiatherogenic property of high-density lipoprotein (HDL). The ubiquitin proteasome system (UPS) mediates nonlysosomal pathways for protein degradation and is known to be involved in atherosclerosis. However, little is known about the effects of the UPS on these molecules and overall RCT. We therefore investigated whether UPS inhibition affects ABCA1/G1 expression in macrophages and RCT in vitro and in vivo. METHODS AND RESULTS: Various proteasome inhibitors increased ABCA1/G1 expression in macrophages, translating into enhanced apolipoprotein A-I- and HDL-mediated cholesterol efflux from macrophages. ABCA1 and ABCG1 were found to undergo polyubiquitination in the macrophages and HEK293 cells overexpressing these proteins, and pulse-chase analysis revealed that proteasome inhibitors inhibited ABCA1/G1 protein degradation. In in vivo experiments, the proteasome inhibitor bortezomib increased ABCA1/G1 protein levels in mouse peritoneal macrophages, and RCT assays showed that it significantly increased the fecal (54% increase compared with saline) and plasma (23%) appearances of the tracer derived from intraperitoneally injected (3)H cholesterol-labeled macrophages. CONCLUSIONS: The present study provided evidence that the UPS is involved in ABCA1/G1 degradation, thereby affecting RCT in vivo. Therefore, specific inhibition of the UPS pathway might lead to a novel HDL therapy that enhances RCT. PMID- 21817096 TI - Human neutrophil peptides mediate endothelial-monocyte interaction, foam cell formation, and platelet activation. AB - OBJECTIVE: Neutrophils are involved in the inflammatory responses during atherosclerosis. Human neutrophil peptides (HNPs) released from activated neutrophils exert immune modulating properties. We hypothesized that HNPs play an important role in neutrophil-mediated inflammatory cardiovascular responses in atherosclerosis. METHODS AND RESULTS: We examined the role of HNPs in endothelial leukocyte interaction, platelet activation, and foam cell formation in vitro and in vivo. We demonstrated that stimulation of human coronary artery endothelial cells with clinically relevant concentrations of HNPs resulted in monocyte adhesion and transmigration; induction of oxidative stress in human macrophages, which accelerates foam cell formation; and activation and aggregation of human platelets. The administration of superoxide dismutase or anti-CD36 antibody reduced foam cell formation and cholesterol efflux. Mice deficient in double genes of low-density lipoprotein receptor and low-density lipoprotein receptor related protein (LRP), and mice deficient in a single gene of LRP8, the only LRP phenotype expressed in platelets, showed reduced leukocyte rolling and decreased platelet aggregation and thrombus formation in response to HNP stimulation. CONCLUSIONS: HNPs exert proatherosclerotic properties that appear to be mediated through LRP8 signaling pathways, suggesting an important role for HNPs in the development of inflammatory cardiovascular diseases. PMID- 21817097 TI - Interleukin-10 released by CD4(+)CD25(+) natural regulatory T cells improves microvascular endothelial function through inhibition of NADPH oxidase activity in hypertensive mice. AB - OBJECTIVE: We previously demonstrated that a reduced number of CD(4+)CD(25+) regulatory T cells (Tregs) was associated with microvascular dysfunction in hypertension. However, the underlying mechanism by which Tregs regulate vascular endothelial function remains unknown. METHODS AND RESULTS: Control and interleukin (IL)-10(-/-) knockout mice were infused with angiotensin II (400 ng/kg/min) for 2 weeks (hypertensive [HT] and HT-IL-10(-/-)). Endothelium dependent relaxation (EDR) in response to acetylcholine was significantly reduced in mesenteric resistance artery (MRA) from HT and HT-IL-10(-/-) compared with control and IL-10(-/-) mice. Importantly, the incubation of MRA from HT mice with the conditioned media of cultured Tregs, isolated from control mice, reduced NADPH oxidase activity and improved EDR, whereas no effect was observed in MRA from control mice incubated with the same media. These effects were reversed when MRAs were preincubated with IL-10 antibody or IL-10 receptor antagonist, whereas incubation with transforming growth factor-beta receptor antagonist had no effect. The transfer of cultured Tregs, isolated from control mice, into HT-IL 10(-/-) mice reduced systolic blood pressure (SBP) and NADPH oxidase activity and improved EDR in MRA compared with untreated HT-IL-10(-/-) mice. In vivo treatment of HT mice with IL-10 (1000 ng/mouse) significantly reduced SBP and NADPH oxidase activity and improved EDR in MRA compared with untreated HT mice. The transfer of cultured Tregs, isolated from IL-10(-/-) mice, into HT mice did not reduce SBP or NADPH oxidase activity or improve EDR. The incubation of MRA from HT mice with apocynin improved EDR, whereas NADPH oxidase substrate attenuated EDR in MRA from control mice, which was reversed with exogenous IL-10. CONCLUSION: These data demonstrate that IL-10 released from Tregs attenuates NADPH oxidase activity, which is a critical process in the improvement of microvascular endothelial function in hypertension, suggesting that Tregs/IL-10 could be a therapeutic target for treatment of vasculopathy in hypertension. PMID- 21817098 TI - CD40L deficiency ameliorates adipose tissue inflammation and metabolic manifestations of obesity in mice. AB - OBJECTIVE: Obese adipose tissue shows hallmarks of chronic inflammation, which promotes the development of metabolic disorders. The mechanisms by which immune cells interact with each other or with metabolism-associated cell types, and the players involved, are still unclear. The CD40-CD40L costimulatory dyad plays a pivotal role in immune responses and in diseases such as atherosclerosis and may therefore be a mediator of obesity. Here we investigated whether CD40L is involved in adipose tissue inflammation and its associated metabolic changes. METHODS AND RESULTS: To assess a putative role of CD40L in obesity in vivo, we evaluated metabolic and inflammatory consequences of 18 weeks of high-fat feeding in CD40L(+/+) and CD40L(-/-) mice. In addition, C57Bl6 mice were injected with neutralizing anti-CD40L (alphaCD40L) antibody for 12 weeks while being fed a high fat diet. Genetic deficiency of CD40L attenuated the development of diet-induced obesity, hepatic steatosis, and increased systemic insulin sensitivity. In adipose tissue, it impaired obesity-induced immune cell infiltration and the associated deterioration of glucose and lipid metabolism. Accordingly, alphaCD40L treatment improved systemic insulin sensitivity, glucose tolerance, and CD4(+) T cell infiltration in adipose tissue with limited effects on adipose tissue weight. CONCLUSIONS: CD40L plays a crucial role in the development of obesity induced inflammation and metabolic complications. PMID- 21817099 TI - Cathepsin K deficiency reduces elastase perfusion-induced abdominal aortic aneurysms in mice. AB - OBJECTIVE: Cathepsin K (CatK) is one of the most potent mammalian elastases. We have previously shown increased expression of CatK in human abdominal aortic aneurysm (AAA) lesions. Whether this protease participates directly in AAA formation, however, remains unknown. METHODS AND RESULTS: Mouse experimental AAA was induced with aortic perfusion of a porcine pancreatic elastase. Using this experimental model, we demonstrated that absence of CatK prevented AAA formation in mice 14 days postperfusion. CatK deficiency significantly reduced lesion CD4(+) T-cell content, total lesion and medial cell proliferation and apoptosis, medial smooth muscle cell (SMC) loss, elastinolytic CatL and CatS expression, and elastin fragmentation, but it did not affect AAA lesion Mac-3(+) macrophage accumulation or CD31(+) microvessel numbers. In vitro studies revealed that CatK contributed importantly to CD4(+) T-cell proliferation, SMC apoptosis, and other cysteinyl cathepsin and matrix metalloproteinase expression and activities in SMCs and endothelial cells but played negligible roles in microvessel growth and monocyte migration. AAA lesions from CatK-deficient mice showed reduced elastinolytic cathepsin activities compared with those from wild-type control mice. CONCLUSIONS: This study demonstrates that CatK plays an essential role in AAA formation by promoting T-cell proliferation, vascular SMC apoptosis, and elastin degradation and by affecting vascular cell protease expression and activities. PMID- 21817100 TI - Inhibitor of apoptosis proteins as novel targets in inflammatory processes. AB - OBJECTIVE: Inhibitor of apoptosis proteins (IAPs), such as X-linked or cellular IAP 1/2 (XIAP, cIAP1/2), are important regulators of apoptosis. IAP antagonists are currently under clinical investigation as anticancer agents. Interestingly, IAPs participate in the inflammation-associated TNF receptor signaling complex and regulate NFkappaB signaling. This raises the question about the role of IAPs in inflammation. Here, we investigated the anti-inflammatory potential of IAP inhibitors and the role of IAPs in inflammatory processes of endothelial cells. METHODS AND RESULTS: In mice, the small molecule IAP antagonist A-4.10099.1 (ABT) suppressed antigen-induced arthritis, leukocyte infiltration in concanavalin A evoked liver injury, and leukocyte transmigration in the TNFalpha-activated cremaster muscle. In vitro, we observed an attenuation of leukocyte-endothelial cell interaction by downregulation of the intercellular adhesion molecule-1. ABT did not impair NFkappaB signaling but decreased the TNFalpha-induced activation of the TGF-beta-activated kinase 1, p38, and c-Jun N-terminal kinase. These effects are based on the proteasomal degradation of cIAP1/2 accompanied by an altered ratio of the levels of membrane-localized TNF receptor-associated factors 2 and 5. CONCLUSIONS: Our results reveal IAP antagonism as a profound anti inflammatory principle in vivo and highlight IAPs as important regulators of inflammatory processes in endothelial cells. PMID- 21817101 TI - Association of atherosclerosis with expression of the LILRB1 receptor by human NK and T-cells supports the infectious burden hypothesis. AB - OBJECTIVE: The contribution of human cytomegalovirus (HCMV) to vascular disease may depend on features of the immune response not reflected by the detection of specific antibodies. Persistent HCMV infection in healthy blood donors has been associated with changes in the distribution of NK cell receptors (NKR). The putative relationship among HCMV infection, NKR distribution, subclinical atherosclerosis, and coronary heart disease was assessed. METHODS AND RESULTS: NKR expression was compared in acute myocardial infarction (AMI) patients (n=70) and a population-based control sample (n=209). The relationship between NKR expression and carotid intima-media thickness (CIMT) in controls (n=149) was also studied. HCMV infection was associated with higher proportions of NKG2C+ and LILRB1+ NK and T-cells. In contrast, only LILRB1+ NK and CD56+ T-cells were found to be increased in AMI patients, independent of age, sex, conventional vascular risk factors, and HCMV seropositivity. Remarkably, LILRB1 expression in NK and T cells significantly correlated with CIMT in controls. CONCLUSIONS: The association of overt and subclinical atherosclerotic disease with LILRB1+ NK and T-cells likely reflects a relationship between the immune challenge by infections and cardiovascular disease risk, without attributing a dominant role for HCMV. Our findings may lead to the identification of novel biomarkers of vascular disease. PMID- 21817102 TI - Plaque rupture and thrombosis are reduced by lowering cholesterol levels and crystallization with ezetimibe and are correlated with fluorodeoxyglucose positron emission tomography. AB - OBJECTIVE: This study evaluated effects of lipid lowering with ezetimibe on plaque burden and associated cholesterol crystallization and inflammation in a rabbit model of plaque disruption and thrombosis. METHODS AND RESULTS: Atherosclerotic rabbits (Group I, n=10 without; Group II, n=12 with ezetimibe, 1 mg/kg per day) were pharmacologically triggered for plaque disruption. Fluorodeoxyglucose positron emission tomography, RAM 11 macrophage staining, and serum inflammatory markers detected arterial inflammation. Serum and aortic wall cholesterol levels were measured, and thrombus area was planimetered. Cholesterol crystal density on aortic surface was scored (0 to +3) by scanning electron microscopy. Serum and aortic wall cholesterol, plaque area, and thrombosis area were significantly lower in Group II versus Group I (83.4+/-106.4 versus 608+/ 386 mg/dL, P=0.002; 3.12+/-1.40 versus 9.39+/-5.60 mg/g, P=0.003; 10.84+/-1.6 versus 17.48+/-1.8 mm(2), P<0.001; and 0.05+/-0.15 versus 0.72+/-0.58 mm(2), P=0.01, respectively). There were significant correlations between crystal density and plaque area (r=0.75, P<0.003) and between crystal density and RAM 11 (r=0.82, P<0.001). Scanning electron microscopy demonstrated that there were fewer crystals in Group II versus Group I (+1.2+/-0.61 versus +2.4+/-0.63, P<0.001) and less inflammation detected by fluorodeoxyglucose positron emission tomography and RAM 11 (P<0.004 and P<0.04, respectively). CONCLUSIONS: Lowering cholesterol levels with ezetimibe reduced plaque burden, crystallization, and inflammation, preventing plaque disruption and thrombosis. PMID- 21817104 TI - Orally administered eicosapentaenoic acid induces rapid regression of atherosclerosis via modulating the phenotype of dendritic cells in LDL receptor deficient mice. AB - OBJECTIVE: Eicosapentaenoic acid (EPA) has been shown to have beneficial effects on cardiovascular diseases, although the precise mechanism is unknown. We investigated the effect of EPA on the regression of atherosclerosis. METHODS AND RESULTS: LDL-receptor-deficient mice were fed a high-cholesterol diet for 8 weeks to build up aortic sinus atherosclerotic lesions and then were fed a normal diet with or without 5% EPA for 4 weeks. Atherosclerotic lesions were histologically assessed, and immunologic assays were performed. EPA treatment significantly regressed atherosclerosis (-22.7%, P<0.05) and decreased the content of macrophages, CD4(+) T cells, and dendritic cells (DCs) in atherosclerotic lesions, though only changing the chow never induced the regression. Flow cytometric analysis revealed that EPA increased immature DCs (CD11c(+) CD80(-) CD86(-)), increased the indoleamine 2,3-dioxygenase (IDO) in DCs, and decreased the number of CD4(+) T cells. In the presence of the IDO inhibitor, the beneficial effects of EPA on regression were inhibited, suggesting that the effect of EPA was mainly mediated through IDO. CONCLUSIONS: In addition to lowering plasma cholesterol, EPA regressed atherosclerosis probably due to modulation of DC phenotype and reduction in T cell numbers. The present findings might partly explain the beneficial effects of EPA in clinics and support clinical evidence. PMID- 21817105 TI - Short-term exposure to exogenous lipids in premature infants and long-term changes in aortic and cardiac function. AB - OBJECTIVE: Intravenous lipid use is associated with an acute hyperlipidemia, but long-term consequences have not been studied. We investigated whether elevated lipids in humans during the critical period of preterm neonatal life have a long term impact on aortic and myocardial function relevant to adult disease. METHODS AND RESULTS: We followed up 102 subjects born prematurely and now aged 23 to 28 years. Eighteen received intravenous lipids as neonates and were matched to controls with equivalent perinatal characteristics. Global and regional aortic stiffness and left ventricular function were assessed by cardiovascular magnetic resonance. Those who received intravenous lipids had greater aortic stiffness in early adulthood (P=0.0002), with greater stiffness in the abdominal aorta (P=0.012). The relationship was graded according to the elevation in neonatal cholesterol induced by intravenous lipids (P<0.0001) but not other metabolic parameters altered by the infusion. Peak systolic circumferential strain was also reduced in the lipid group (P=0.006), which, again, was proportional to neonatal cholesterol level (P<0.01). CONCLUSIONS: Aortic and myocardial function in young adulthood is associated with intralipid exposure during neonatal life for preterm infants, in a graded manner related to the rise in cholesterol. Circulating cholesterol during critical developmental periods may have long-term impacts on the human cardiovascular system. PMID- 21817103 TI - Interactions between smoking, pulmonary surfactant protein B, and atherosclerosis in the general population: the Dallas Heart Study. AB - OBJECTIVE: Pulmonary surfactant protein B (SP-B), an alveolar protein normally detectable at only very low concentrations in blood, circulates at higher levels among smokers and those with alveolar injury and inflammation. We hypothesized that SP-B may serve as a marker of the vascular effects of smoking and would thus be associated with subclinical measures of atherosclerosis. METHODS AND RESULTS: Plasma levels of SP-B were measured in 3294 subjects, ages 30 to 65, enrolled in the Dallas Heart Study, a probability-based population sample of Dallas County adults. Coronary artery calcium (CAC) was measured by computed tomography and abdominal aortic plaque (AP) by magnetic resonance imaging. The cohort comprised 29% current and 17% former smokers. The overall prevalence of CAC was 22%, and that of AP was 39%. Median SP-B levels were 5-fold higher among current versus never smokers (P<0.0001) and were significantly correlated with estimated pack years smoked (Spearman rho=0.35, P<0.0001). Increasing levels of SP-B also associated with other traditional cardiac risk factors and higher levels of inflammatory biomarkers. In univariable analyses, increasing SP-B quartiles associated with higher prevalence of both CAC and AP (P(trend)<0.0001 for each). In multivariable analyses adjusting for traditional cardiovascular risk factors, SP-B remained associated with AP (OR 1.87 for the 4th versus 1st quartiles, 95% confidence interval 1.39 to 2.51; P<0.0001) but not CAC. An interaction was observed between SP-B, smoking status, and AP (P(interaction)=0.01), such that SP B associated with AP in current smokers (adjusted OR 2.15 for the 4th versus 1st quartile, 95% confidence interval 1.26 to 3.67; P=0.005) but not in former or never smokers. CONCLUSIONS: Circulating levels of SP-B increase with greater smoking burden and independently associate with abdominal AP among current smokers. Our findings support further investigation of the role of SP-B as a marker of the vascular effects of smoking. PMID- 21817106 TI - Oxidized low-density lipoprotein activates p66Shc via lectin-like oxidized low density lipoprotein receptor-1, protein kinase C-beta, and c-Jun N-terminal kinase kinase in human endothelial cells. AB - OBJECTIVE: Deletion of the mitochondrial gene p66(Shc) protects from endothelial dysfunction and atherosclerotic plaque formation in mice fed a high-fat diet. However, the molecular mechanisms underlying this beneficial effect have not yet been delineated. The present study was designed to elucidate the proatherogenic mechanisms by which p66(Shc) mediates oxidized low-density lipoprotein (oxLDL) uptake by the endothelium, a critical step in plaque formation. METHODS AND RESULTS: Incubation of human aortic endothelial cells with oxLDL led to phosphorylation of p66(Shc) at Ser36. Inhibition of lectin-like oxLDL receptor-1 prevented p66(Shc) phosphorylation, confirming that this effect is mediated by lectin-like oxLDL receptor-1. OxLDL also increased phosphorylation of protein kinase C beta(2) (PKCbeta(2)) at both Thr641 and Ser660, as well as c-Jun N terminal kinase (JNK). Furthermore, inhibition of PKCbeta(2) prevented the activation of JNK, suggesting that PKCbeta2 is upstream of JNK. Finally, p66(Shc) silencing blunted oxLDL-induced O(2)(-.) production, underscoring the critical role of p66(Shc) in oxLDL-induced oxidative stress in endothelial cells. CONCLUSIONS: In this study we provide the molecular mechanisms mediating the previously observed atherogenic properties of p66(Shc). Taken together, our data set the stage for the design of novel therapeutic tools to retard atherogenesis through the inhibition of p66(Shc). PMID- 21817107 TI - MicroRNA-21 regulates vascular smooth muscle cell function via targeting tropomyosin 1 in arteriosclerosis obliterans of lower extremities. AB - OBJECTIVE: The goal of this study was to determine the expression signature and the potential role of microRNAs in human arteries with arteriosclerosis obliterans (ASO). METHODS AND RESULTS: The expression profiles of microRNAs in human arteries with ASO and in normal control arteries were determined by quantitative reverse transcription-polymerase chain reaction array. Among the 617 detected microRNAs, multiple microRNAs were aberrantly expressed in arteries with ASO. Some of these dysregulated microRNAs were further verified by quantitative reverse transcription-polymerase chain reaction. Among them, microRNA-21 (miR-21) was mainly located in arterial smooth muscle cells (ASMCs) and was increased by more than 7-fold in ASO that was related to hypoxia inducible factor 1-alpha. In cultured human ASMCs, cell proliferation and migration were significantly decreased by inhibition of miR-21. 3'-Untranslated region luciferase assay confirmed that tropomyosin 1 was a target of miR-21 that was involved in miR-21 mediated cellular effects, such as cell shape modulation. CONCLUSION: The results suggest that miR-21 is able to regulate ASMC function by targeting tropomyosin 1. The hypoxia inducible factor-1 alpha/miR-21/tropomyosin 1 pathway may play a critical role in the pathogenesis of ASO. These findings might provide a new therapeutic target for human ASO. PMID- 21817108 TI - Long-term treadmill exercise induces neuroprotective molecular changes in rat brain. AB - Exercise enhances general health. However, its effects on neurodegeneration are controversial, and the molecular pathways in the brain involved in this enhancement are poorly understood. Here, we examined the effect of long-term moderate treadmill training on adult male rat cortex and hippocampus to identify the cellular mechanisms behind the effects of exercise. We compared three animal groups: exercised (30 min/day, 12 m/min, 5 days/wk, 36 wk), handled but nonexercised (treadmill handling procedure, 0 m/min), and sedentary (nonhandled and nonexercised). Moderate long-term exercise induced an increase in IGF-1 levels and also in energy parameters, such as PGC-1alpha and the OXPHOS system. Moreover, the sirtuin 1 pathway was activated in both the exercised and nonexercised groups but not in sedentary rats. This induction could be a consequence of exercise as well as the handling procedure. To determine whether the long-term moderate treadmill training had neuroprotective effects, we studied tau hyperphosphorylation and GSK3beta activation. Our results showed reduced levels of phospho-tau and GSK3beta activation mainly in the hippocampus of the exercised animals. In conclusion, in our rodent model, exercise improved several major brain parameters, especially in the hippocampus. These improvements induced the upregulation of sirtuin 1, a protein that extends life, the stimulation of mitochondrial biogenesis, the activation of AMPK, and the prevention of signs of neurodegeneration. These findings are consistent with other reports showing that physical exercise has positive effects on hormesis. PMID- 21817109 TI - Absence of heat shock transcription factor 1 retards the regrowth of atrophied soleus muscle in mice. AB - Effects of heat shock transcription factor 1 (HSF1) gene on the regrowth of atrophied mouse soleus muscles were studied. Both HSF1-null and wild-type mice were subjected to continuous hindlimb suspension for 2 wk followed by 4 wk of ambulation recovery. There was no difference in the magnitude of suspension related decrease of muscle weight, protein content, and the cross-sectional area of muscle fibers between both types of mice. However, the regrowth of atrophied soleus muscle in HSF1-null mice was slower compared with that in wild-type mice. Lower baseline expression level of HSP25, HSC70, and HSP72 were noted in soleus muscle of HSF1-null mice. Unloading-associated downregulation and reloading associated upregulation of HSP25 and HSP72 mRNA were observed not only in wild type mice but also in HSF1-null mice. Reloading-associated upregulation of HSP72 and HSP25 during the regrowth of atrophied muscle was observed in wild-type mice. Minor and delayed upregulation of HSP72 at mRNA and protein levels was also seen in HSF1-null mice. Significant upregulations of HSF2 and HSF4 were observed immediately after the suspension in HSF1-null mice, but not in wild-type mice. Therefore, HSP72 expression in soleus muscle might be regulated by the posttranscriptional level, but not by the stress response. Evidence from this study suggested that the upregulation of HSPs induced by HSF1-associated stress response might play, in part, important roles in the mechanical loading (stress) associated regrowth of skeletal muscle. PMID- 21817110 TI - Optimized murine lung preparation for detailed structural evaluation via micro computed tomography. AB - Utilizing micro-X-ray CT (MUCT) imaging, we sought to generate an atlas of in vivo and intact/ex vivo lungs from normal murine strains. In vivo imaging allows visualization of parenchymal density and small airways (15-28 MUm/voxel). Ex vivo imaging of the intact lung via MUCT allows for improved understanding of the three-dimensional lung architecture at the alveolar level with voxel dimensions of 1-2 MUm. MUCT requires that air spaces remain air-filled to detect alveolar architecture while in vivo structural geometry of the lungs is maintained. To achieve these requirements, a fixation and imaging methodology that permits nondestructive whole lung ex vivo MUCT imaging has been implemented and tested. After in vivo imaging, lungs from supine anesthetized C57Bl/6 mice, at 15, 20, and 25 cmH(2)O airway pressure, were fixed in situ via vascular perfusion using a two-stage flushing system while held at 20 cmH(2)O airway pressure. Extracted fixed lungs were air-dried. Whole lung volume was acquired at 1, 7, 21, and >70 days after the lungs were dried and served as validation for fixation stability. No significant shrinkage was observed: +8.95% change from in vivo to fixed lung (P = 0.12), -1.47% change from day 1 to day 7 (P = 0.07), -2.51% change from day 1 to day 21 (P = 0.05), and -4.90% change from day 1 to day 70 and thereafter (P = 0.04). MUCT evaluation showed well-fixed alveoli and capillary beds correlating with histological analysis. A fixation and imaging method has been established for MUCT imaging of the murine lung that allows for ex vivo morphometric analysis, representative of the in vivo lung. PMID- 21817111 TI - Exercise training increases mitochondrial biogenesis in the brain. AB - Increased muscle mitochondria are largely responsible for the increased resistance to fatigue and health benefits ascribed to exercise training. However, very little attention has been given to the likely benefits of increased brain mitochondria in this regard. We examined the effects of exercise training on markers of both brain and muscle mitochondrial biogenesis in relation to endurance capacity assessed by a treadmill run to fatigue (RTF) in mice. Male ICR mice were assigned to exercise (EX) or sedentary (SED) conditions (n = 16 19/group). EX mice performed 8 wk of treadmill running for 1 h/day, 6 days/wk at 25 m/min and a 5% incline. Twenty-four hours after the last training bout a subgroup of mice (n = 9-11/group) were euthanized, and brain (brain stem, cerebellum, cortex, frontal lobe, hippocampus, hypothalamus, and midbrain) and muscle (soleus) tissues were isolated for analysis of mRNA expression of peroxisome proliferator-activated receptor-gamma coactivator-1-alpha (PGC 1alpha), Silent Information Regulator T1 (SIRT1), citrate synthase (CS), and mitochondrial DNA (mtDNA) using RT-PCR. A different subgroup of EX and SED mice (n = 7-8/group) performed a treadmill RTF test. Exercise training increased PGC 1alpha, SIRT1, and CS mRNA and mtDNA in most brain regions in addition to the soleus (P < 0.05). Mean treadmill RTF increased from 74.0 +/- 9.6 min to 126.5 +/ 16.1 min following training (P < 0.05). These findings suggest that exercise training increases brain mitochondrial biogenesis, which may have important implications, not only with regard to fatigue, but also with respect to various central nervous system diseases and age-related dementia that are often characterized by mitochondrial dysfunction. PMID- 21817112 TI - The alpha7beta1-integrin increases muscle hypertrophy following multiple bouts of eccentric exercise. AB - Mechanical stimuli increase skeletal muscle growth in a mammalian target of rapamycin (mTOR)- and p70(S6K)-dependent manner. It has been proposed that costameric proteins at Z bands may sense and transfer tension to these initiators of protein translation, but few candidates have been identified. The purpose of this study was to determine whether a role exists for the alpha(7)-integrin in the activation of hypertrophic signaling and growth following eccentric exercise training. Five-week-old, wild-type (WT) and alpha(7)BX2-integrin transgenic (alpha(7)Tg) mice were randomly assigned to one of two groups: 1) sedentary (SED), or 2) exercise training (EX). Exercise training consisted of downhill running 3 sessions/wk for 4 wk (-20 degrees , 17 m/min, 30 min). Downhill running was used to induce physiological mechanical strain. Twenty-four hours following the final training session, maximal isometric hindlimb plantar flexor force was measured. Gastrocnemius-soleus complexes were collected for further analysis of signaling changes, which included AKT, mTOR and p70(S6K), and muscle growth. Despite increased p70(S6K) activity in WT/EX, no significant changes in cross sectional area or force were observed in WT/EX compared with WT/SED. AKT, mTOR, and p70(S6K) activation was higher, and whole muscle hypertrophy, relative muscle weight, myofibrillar protein, and force were significantly elevated in alpha(7)Tg/EX compared with alpha(7)Tg/SED. A marked increase in average myofiber cross-sectional area was observed in alpha(7)Tg/EX compared with all groups. Our findings demonstrate that the alpha(7)beta(1)-integrin sensitizes skeletal muscle to mechanical strain and subsequent growth. Thus the alpha(7)beta(1)-integrin may represent a novel molecular therapy for the treatment of disuse muscle atrophy. PMID- 21817113 TI - Mitochondrial-targeted antioxidants protect skeletal muscle against immobilization-induced muscle atrophy. AB - Prolonged periods of muscular inactivity (e.g., limb immobilization) result in skeletal muscle atrophy. Although it is established that reactive oxygen species (ROS) play a role in inactivity-induced skeletal muscle atrophy, the cellular pathway(s) responsible for inactivity-induced ROS production remain(s) unclear. To investigate this important issue, we tested the hypothesis that elevated mitochondrial ROS production contributes to immobilization-induced increases in oxidative stress, protease activation, and myofiber atrophy in skeletal muscle. Cause-and-effect was determined by administration of a novel mitochondrial targeted antioxidant (SS-31) to prevent immobilization-induced mitochondrial ROS production in skeletal muscle fibers. Compared with ambulatory controls, 14 days of muscle immobilization resulted in significant muscle atrophy, along with increased mitochondrial ROS production, muscle oxidative damage, and protease activation. Importantly, treatment with a mitochondrial-targeted antioxidant attenuated the inactivity-induced increase in mitochondrial ROS production and prevented oxidative stress, protease activation, and myofiber atrophy. These results support the hypothesis that redox disturbances contribute to immobilization-induced skeletal muscle atrophy and that mitochondria are an important source of ROS production in muscle fibers during prolonged periods of inactivity. PMID- 21817114 TI - 2-methoxy-5-amino-N-hydroxybenzamide sensitizes colon cancer cells to TRAIL induced apoptosis by regulating death receptor 5 and survivin expression. AB - TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis is a crucial event in the control of tumor growth. However, many cancer cells, including colon cancer cells, are resistant to TRAIL-driven cell death. We have recently shown that 2-methoxy-5-amino-N-hydroxybenzamide (herein termed 2-14), a novel derivative of mesalamine, induces endoplasmic reticulum stress in colon cancer cells. Because endoplasmic reticulum stress-induced signals regulate the expression of molecules involved in TRAIL-driven apoptosis, we examined whether 2 14 makes colon cancer cells sensitive to TRAIL. Colon cancer cells were cultured with 2-14 and/or TRAIL. Death receptor (DR) 4/DR5 were analyzed by real-time PCR and flow cytometry. TRAIL pathway-associated proteins and extracellular signal regulated kinase (ERK) were assessed by Western blotting. The in vivo capability of 2-14 to sensitize colon cancer cells to TRAIL-induced apoptosis was evaluated in a syngenic colon cancer model in which CT26-derived grafts were induced in mice. 2-14 promoted ERK-dependent induction of DR5, thereby enhancing TRAIL mediated caspase-8 activation and apoptosis. Analysis of TRAIL-related pro- and antiapoptotic factors and functional studies revealed that survivin is involved in the protection of colon cancer cells against TRAIL-driven apoptosis. Notably, 2-14 enhanced ubiquitination and proteasome-mediated degradation of survivin. These data were confirmed in a murine model of TRAIL-resistant colon cancer in which 2-14 upregulated DR5, reduced survivin expression, and synergized with TRAIL in inhibiting tumor growth. Similarly, intraperitoneal administration of 2 14 to mice upregulated DR5 and downregulated survivin in a model of colitis associated colon cancer. These findings indicate that 2-14 acts as a sensitizer for TRAIL-induced apoptosis and suggest that 2-14 can be useful in the therapy for TRAIL-resistant colon cancer. PMID- 21817115 TI - Dual-fluorescence isogenic high-content screening for MUC16/CA125 selective agents. AB - Most of the currently used cancer chemotherapies are based on compounds that inhibit general cellular mechanisms, such as DNA replication or tubulin function, and lack specificity in relation to features of the cancer cell. Recent advances in genomic studies have increased our knowledge of tumor cell biology, and a panoply of new targets have been postulated. This has provided an opportunity to develop and validate drugs that specifically target cancer cells through their unique genetic characteristics. Identification of MUC16/CA125 both as a marker and a driver of transformation led us to design a target-based high-content screen to identify and classify compounds that exhibit differential effect on MUC16-expressing cells. We developed a coculture assay in 384-well plate containing isogenic ovarian cancer cells that are positive or negative for the MUC16 protein. High-throughput screening of our small molecule pilot library led to the identification of compounds preferentially cytotoxic to MUC16(+) or MUC16( ) cells, using a Preferential Score analysis. We compared screening results in both A2780 and SK-OV-3 ovarian cancer cells in single and coculture settings. We also identified compounds that were cytotoxic for both types of ovarian cancer cells regardless of the MUC16 status. Compounds that were preferentially targeting MUC16 cells were subsequently confirmed by caspase-induction assays. The isogenic, dual-color fluorescence strategy is an innovative approach that can effectively identify novel drug candidates, selectively targeting cancer cells that have unique molecular properties. PMID- 21817117 TI - Bronchogenic squamous cell carcinoma mass with central photopenia on FDG-PET scan. PMID- 21817116 TI - Identification of a natural compound by cell-based screening that enhances interferon regulatory factor-1 activity and causes tumor suppression. AB - The transcription factor interferon regulatory factor-1 (IRF-1) is induced by many tumor-suppressive stimuli and can mediate antiproliferative and proapoptotic effects in cancer cells. Thus, identifying agents that enhance IRF-1 activity may be an effective approach to cancer therapy. A cell-based screening assay was developed to identify extracts and compounds that could enhance IRF-1 activity, using an IRF-1-dependent luciferase reporter cell line. Through this approach, we identified a natural product extract and a known active component of this extract, baicalein, which causes a marked increase in IRF-1-dependent reporter gene expression and IRF-1 protein, with modulation of known IRF-1 targets PUMA and cyclin D1. Baicalein causes suppression of growth in vitro in multiple cancer cell lines in the low micromolar range. IRF-1 plays a role in this growth suppression as shown by significant resistance to growth suppression in a breast cancer cell line stably transfected with short hairpin RNA against IRF-1. Finally, intraperitoneal administration of baicalein by repeated injection causes inhibition of growth in both xenogeneic and syngeneic mouse models of cancer without toxicity to the animals. These findings indicate that identifying enhancers of IRF-1 activity may have utility in anticancer therapies and that cell-based screening for activation of transcription factors can be a useful approach for drug discovery. PMID- 21817118 TI - Cardiovascular risk factor screening satisfaction in the Heart of New Ulm Project. AB - OBJECTIVE: Community-based cardiovascular disease (CVD) risk factor screening programs have been used successfully in rural health improvement initiatives. However, little is known about what consumers like or dislike about them, which is a barrier to the design of future process improvements. The objective of this study was to examine the degree to which health risks and participant characteristics predicted screening satisfaction. DESIGN: This study utilized a cross-sectional survey design. SETTING: Data was collected as part of the broader Heart of New Ulm Project, which is a community-based CVD prevention demonstration project based in rural Minnesota. PARTICIPANTS: There were 126 randomly invited individuals from the CVD risk factor screenings, with 118 individuals who agreed to participate and had complete data available for analyses. METHODS: A multivariate logistic regression analysis was used to examine the association between demographics, lifestyle, and biometric risk factors and screening satisfaction. RESULTS: Twenty percent of respondents indicated some level of dissatisfaction with the screening process. Satisfied participants were more likely to be female (OR=4.15), not have an optimal lifestyle (OR=3.47), and have an intention to improve their lifestyle habits (OR=3.26). Age, education, and CVD risk level were not significant predictors in the final model. CONCLUSION: Satisfaction was high in this screening program, with healthy males being least satisfied with their experience. This has implications for the design of future intervention efforts, as they may require specific programmatic features and more specialized, targeted marketing strategies to attract a broad spectrum of participants likely to benefit. PMID- 21817120 TI - Successful treatment of brainstem blastomycosis with fluconazole. AB - The lipid formulation of amphotericin B is the initial drug of choice for central nervous system blastomycosis, but it is costly and associated with significant toxicity. This case report details a patient with primary pulmonary blastomycosis with dissemination to the skin, one joint, and the brainstem that was successfully treated solely with high-dose fluconazole. PMID- 21817119 TI - Apical hypertrophic cardiomyopathy presenting as recurrent unexplained syncope. AB - Apical hypertrophic cardiomyopathy (AHC) is a rare variant of hypertrophic cardiomyopathy. Since its description by Sakamoto in 1976 in Japanese patients, our understanding of this entity has evolved. Although cardiac magnetic resonance imaging has emerged as the gold standard for diagnosing AHC, clinical attention must be drawn to the unique electrocardiographic features that provide the initial clues to making the diagnosis. In this case, we present a 47-year-old man with AHC who presented with recurrent syncope, but anomalies on his electrocardiogram went unnoticed on two clinical encounters. He was subsequently admitted to our service and rapidly diagnosed after we observed the very classical findings in the plain twelve lead electrocardiogram done at the time of admission. In a clinical encounter involving a patient presenting with recurrent syncope, special attention must be focused on the electrocardiogram to decipher the unique diagnostic features it might show. PMID- 21817121 TI - Drug rash with eosinophilia and systemic symptoms (DRESS) probably induced by cefotaxime: a report of two cases. AB - We report two cases, one of a 52-year-old man and one of a 32-year-old man, who were treated with cefotaxime. On day 23 and day 28 of the treatment, respectively, the patients manifested clinically with fever, pruriginous skin rash, and facial edema. Blood tests showed marked eosinophilia and atypical lymphocytosis for both patients, and hepatic cytolysis only in the second patient. Cefotaxime was discontinued in both patients; the clinico-biological picture improved gradually and completely disappeared approximately 4 weeks later. Six weeks after complete recovery, both patients underwent intradermal testing which was positive to cefotaxime (2 mg/ml) at the 48-hour reading and negative to benzylpenicillin, amoxicillin, and cefazolin at the 20-minute and 48 hour readings. These clinical pictures suggest drug rash with eosinophilia and systemic symptoms (DRESS) induced by cefotaxime. To the best of our knowledge, only one case of cefotaxime-induced DRESS has been reported in the medical literature. Thus, we add two new cases of cefotaxime-induced DRESS and emphasize the usefulness and safety of intradermal testing in establishing the diagnosis. PMID- 21817122 TI - Clinical and laboratory features of Streptococcus salivarius meningitis: a case report and literature review. AB - Streptococcus salivarius is a normal member of the human oral microbiome that is an uncommon cause of invasive infections. Meningitis is a rare but increasingly reported infection caused by S. salivarius. Despite the growing number of reported cases, a comprehensive review of the literature on S. salivarius meningitis is lacking. We sought to gain a better understanding of the clinical presentation, evaluation, management, and outcome of S. salivarius meningitis by analyzing previously reported cases. In addition to a single case reported here, 64 previously published cases of meningitis were identified for this review. The collected data confirm that most patients presented with classical signs and symptoms of bacterial meningitis with a predominance of neutrophils in the cerebrospinal fluid (CSF) and hypoglycorrhachia. The majority of cases followed iatrogenic or traumatic CSF contamination. Most cases were diagnosed by CSF culture within one day of symptom onset. There was no clear evidence of predisposing co-morbid conditions in patients with meningitis, although in most case reports, limited information was given on the medical history of each patient. Outcomes were generally favorable with antibiotic management. Clinicians should suspect S. salivarius meningitis in patients presenting acutely after medical or surgical procedures involving the meninges. PMID- 21817123 TI - Pelvic static magnetic stimulation to control urinary incontinence in older women: a randomized controlled trial. AB - OBJECTIVES: To determine the efficacy of non-invasive static magnetic stimulation (SMS) of the pelvic floor compared to placebo in the treatment of women aged 60 years and over with urinary incontinence for 6 months or more. SUBJECTS AND METHODS: A single-blinded randomized, placebo-controlled, parallel-group trial. Subjects were excluded if they had an implanted electronic device, had experienced a symptomatic urinary tract infection, or had commenced pharmacotherapy for the same in the previous 4 weeks, or if they were booked for pelvic floor or gynecological surgery within the next 3 months. Once written consent was obtained, subjects were randomly assigned to the active SMS group (n=50) or the placebo group (n=51). Treatment was an undergarment incorporating 15 static magnets of 800-1200 Gauss anterior, posterior, and inferior to the pelvis for at least 12 hours a day for 3 months. Placebo was the same protocol with inert metal disks replacing the magnets. Primary outcome measure was cessation of incontinence as measured by a 24-hour pad test. Secondary outcomes were frequency and severity of symptoms as measured by the Bristol Female Lower Urinary Tract Symptoms questionnaire (BFLUTS-SF), the Incontinence Severity Index, a Bothersomeness Visual Analog scale, and a 24-hour bladder diary. Data were collected at baseline and 12 weeks later. RESULTS: There were no statistically significant differences between groups in any of the outcome measures from baseline to 12 weeks. Initial evidence of subjective improvement in the treatment group compared to the placebo group was not sustained with sensitivity analysis. CONCLUSION: This study found no evidence that static magnets cure or decrease the symptoms of urinary incontinence. Additional work into the basic physics of the product and garment design is recommended prior to further clinical trials research. PMID- 21817124 TI - Sweet's syndrome: one disease, multiple faces. PMID- 21817125 TI - No evidence for human papillomavirus in the etiology of colorectal polyps. AB - BACKGROUND: While some studies have reported detection of oncogenic human papillomavirus (HPV) in colorectal tumors, others have not. METHODS: We examined the association between oncogenic HPV infection and colorectal polyps in a case control study of individuals with colorectal adenomas (n = 167), hyperplastic polyps (n = 87), and polyp-free controls (n = 250). We carried out real-time PCR for HPV-16 and -18 DNA, and SPF PCR covering 43 HPV types, on lesional and normal colorectal tissue samples. Plasma antibodies for oncogenic HPV types were assessed via a bead-based multiplex Luminex assay. RESULTS: HPV DNA was not found in any of the 609 successfully assayed colorectal tissue samples from adenomas, hyperplastic polyps, normal biopsies adjacent to polyps, or normal biopsies of the rectum of disease-free controls. Also, there was no association between HPV seropositivity for all oncogenic HPV types combined, for either polyp type, and for men or women. When analyses were restricted to participants without a history of polyps, among men [adenomas (n = 31), hyperplastic polyps (n = 28), and controls (n = 68)], there was an association between seropositivity and hyperplastic polyps when all oncogenic HPV types were combined (OR = 3.0; 95% CI: 1.1-7.9). CONCLUSIONS: Overall, our findings do not support an etiologic relationship between HPV and colorectal adenomas or hyperplastic polyps; however, our finding suggesting an association between HPV seropositivity and hyperplastic polyps in men may warrant further investigations. IMPACT: After stringent controls for contamination and three methods to assess HPV infection, we report no evidence for HPV in the etiology of colorectal neoplasia for either men or women. PMID- 21817128 TI - A new system for kidney allocation: the devil is in the details. PMID- 21817126 TI - Pancreatic beta-cell Raf-1 is required for glucose tolerance, insulin secretion, and insulin 2 transcription. AB - Regulation of glucose homeostasis by insulin depends on pancreatic beta-cell growth, survival, and function. Raf-1 kinase is a major downstream target of several growth factors that promote proliferation and survival of many cell types, including the pancreatic beta cells. We have previously reported that insulin protects beta cells from apoptosis and promotes proliferation by activating Raf-1 signaling in cultured human islets, mouse islets, and MIN6 cells. As Raf-1 activity is critical for basal apoptosis and insulin secretion in vitro, we hypothesized that Raf-1 may play an important role in glucose homeostasis in vivo. To test this hypothesis, we utilized the Cre-loxP recombination system to obtain a pancreatic beta-cell-specific ablation of Raf-1 kinase gene (RIPCre(+/+):Raf-1(flox/flox)) and a complete set of littermate controls (RIPCre(+/+):Raf-1(wt/wt)). RIPCre(+/+):Raf-1(flox/flox) mice were viable, and no effects on weight gain were observed. RIPCre(+/+):Raf-1(flox/flox) mice had increased fasting blood glucose levels and impaired glucose tolerance but normal insulin tolerance compared to littermate controls. Insulin secretion in vivo and in isolated islets was markedly impaired, but there was no apparent effect on the exocytosis machinery. However, islet insulin protein and insulin 2 mRNA, but not insulin 1 mRNA, were dramatically reduced in Raf-1-knockout mice. Analysis of insulin 2 knockout mice demonstrated that this reduction in mRNA was sufficient to impair in vivo insulin secretion. Our data further indicate that Raf-1 specifically and acutely regulates insulin 2 mRNA via negative action on Foxo1, which has been shown to selectively control the insulin 2 gene. This work provides the first direct evidence that Raf-1 signaling is essential for the regulation of basal insulin transcription and the supply of releasable insulin in vivo. PMID- 21817127 TI - Prognosis of CKD patients receiving outpatient nephrology care in Italy. AB - BACKGROUND AND OBJECTIVES: Prognosis in nondialysis chronic kidney disease (CKD) patients under regular nephrology care is rarely investigated. Design, setting, participants, & measurements We prospectively followed from 2003 to death or June 2010 a cohort of 1248 patients with CKD stages 3 to 5 and previous nephrology care >=1 year in 25 Italian outpatient nephrology clinics. Cumulative incidence of ESRD or death before ESRD were estimated using the competing-risk approach. RESULTS: Estimated rates (per 100 patient-years) of ESRD and death 8.3 (95% confidence interval [CI], 7.4 to 9.2) and 5.9 (95% CI 5.2 to 6.6), respectively. Risk of ESRD and death increased progressively from stages 3 to 5. ESRD was more frequent than death in stage 4 and 5 CKD, whereas the opposite was true in stage 3 CKD. Younger age, lower body mass index, proteinuria, and high phosphate predicted ESRD, whereas older age, diabetes, previous cardiovascular disease, ESRD, proteinuria, high uric acid, and anemia predicted death (P < 0.05 for all). Among modifiable risk factors, proteinuria accounted for the greatest contribution to the model fit for either outcome. CONCLUSIONS: In patients receiving continuity of care in Italian nephrology clinics, ESRD was a more frequent outcome than death in stage 4 and 5 CKD, but the opposite was true in stage 3. Outcomes were predicted by modifiable risk factors specific to CKD. Proteinuria used in conjunction with estimated GFR refined risk stratification. These findings provide information, specific to CKD patients under regular outpatient nephrology care, for risk stratification that complement recent observations in the general population. PMID- 21817129 TI - Symmetric dimethylarginine as a proinflammatory agent in chronic kidney disease. AB - BACKGROUND & OBJECTIVES: Chronic kidney disease (CKD) is characterized by chronic inflammation, considered a nontraditional risk factor for cardiovascular disease, the major cause of death in CKD. Symmetric dimethylarginine (SDMA) was recently demonstrated to induce reactive oxygen species in monocytes. The present study further investigates the inflammatory character of SDMA compared with its structural counterpart asymmetric dimethylarginine (ADMA). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In vitro, the effect of SDMA on intracellular monocytic expression of IL-6 and TNF-alpha was studied followed by an evaluation of nuclear factor (NF)-kappaB activation. Additionally, an association of SDMA with inflammatory parameters in consecutive stages of CKD was evaluated in vivo. RESULTS: Monocytes incubated with SDMA showed increased IL-6 and TNF-alpha expression and a rise in active NF-kappaB. N-acetylcysteine abrogated both these effects. No significant effects were observed with ADMA. In vivo, 142 patients (67 +/- 12 years) at different stages of CKD showed an inverse association between serum SDMA and ADMA and renal function. Correlations between SDMA and IL 6, TNF-alpha, and albumin were more significant than for ADMA, while multiple regression analysis only retained TNF-alpha at a high significance for SDMA (P < 0.0001). In receiver operating characteristic analysis for inflammation, defined as an IL-6 level above 2.97 pg/ml (median), the discriminative power of SDMA (area under the curve [AUC]: 0.69 +/- 0.05) directly followed that of C-reactive protein (AUC: 0.82 +/- 0.04) and albumin (AUC: 0.72 +/- 0.05; for all, P < 0.0001) and preceded that of ADMA (P = 0.002). CONCLUSIONS: The present study shows that SDMA is involved in the inflammatory process of CKD, activating NF kappaB and resulting in enhanced expression of IL-6 and TNF-alpha, which is corroborated by the clinical data pointing to an in vivo association of SDMA with inflammatory markers in CKD at different stages. PMID- 21817130 TI - A novel technique to optimize facility locations of new nephrology services for remote areas. AB - BACKGROUND AND OBJECTIVES: Travel distance to healthcare facilities affects healthcare access and utilization. Using the example of patients with kidney disease and nephrology services, we investigated the feasibility and utility of using geographic information system (GIS) techniques to identify the ideal location for new clinics to improve care for patients with kidney disease, on the basis of systematically minimizing travel time for remote dwellers. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Using a provincial laboratory database to identify patients with kidney disease and where they lived, we used GIS techniques of buffer and network analysis to determine ideal locations for up to four new nephrology clinics. Service-area polygons for different travel-time intervals were generated and used to determine the best locations for the four new facilities that would minimize the number of patients with kidney disease who were traveling >2 hours. RESULTS: We studied 31,452 adults with living in Alberta, Canada. Adding the four new facilities would increase the number of patients living <30 minutes from a clinic by 2.2% and reduce the number living >120 minutes away by 72.5%. Different two- and three-clinic scenarios reduced the number of people living >120 minutes away by as much as 65% or as little as 32%, emphasizing the importance of systematic evaluation. CONCLUSIONS: GIS techniques are an attractive alternative to the current practice of arbitrarily locating new facilities on the basis of perceptions about patient demand. Optimal location of new clinical services to minimize travel time might facilitate better patient care. PMID- 21817131 TI - Platelet activation in patients with atherosclerotic renal artery stenosis undergoing stent revascularization. AB - BACKGROUND AND OBJECTIVES: Soluble CD40 ligand (sCD40L) is a marker of platelet activation; whether platelet activation occurs in the setting of renal artery stenosis and stenting is unknown. Additionally, the effect of embolic protection devices and glycoprotein IIb/IIIa inhibitors on platelet activation during renal artery intervention is unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Plasma levels of sCD40L were measured in healthy controls, patients with atherosclerosis without renal stenosis, and patients with renal artery stenosis before, immediately after, and 24 hours after renal artery stenting. RESULTS: Soluble CD40L levels were higher in renal artery stenosis patients than normal controls (347.5 +/- 27.0 versus 65.2 +/- 1.4 pg/ml, P < 0.001), but were similar to patients with atherosclerosis without renal artery stenosis. Platelet-rich emboli were captured in 26% (9 of 35) of embolic protection device patients, and in these patients sCD40L was elevated before the procedure. Embolic protection device use was associated with a nonsignificant increase in sCD40L, whereas sCD40L declined with abciximab after the procedure (324.9 +/- 42.5 versus 188.7 +/- 31.0 pg/ml, P = 0.003) and at 24 hours. CONCLUSIONS: Atherosclerotic renal artery stenosis is associated with platelet activation, but this appears to be related to atherosclerosis, not renal artery stenosis specifically. Embolization of platelet-rich thrombi is common in renal artery stenting and is inhibited with abciximab. PMID- 21817133 TI - Letter by Gonzalez and Liebeskind regarding article, "remote ischemic limb preconditioning after subarachnoid hemorrhage: a phase Ib study of safety and feasibility". PMID- 21817132 TI - Referral patterns and outcomes in noncritically ill patients with hospital acquired acute kidney injury. AB - BACKGROUND AND OBJECTIVES: Despite modern treatment, the case fatality rate of hospital-acquired acute kidney injury (HA-AKI) is still high. We retrospectively described the prevalence and the outcome of HA-AKI without nephrology referral (nrHA-AKI) and late referred HA-AKI patients to nephrologists (lrHA-AKI) compared with early referral patients (erHA-AKI) with respect to renal function recovery, renal replacement therapy (RRT) requirement, and in-hospital mortality of HA-AKI. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Noncritically ill patients admitted to the tertiary care academic center of Lausanne, Switzerland, between 2004 and 2008 in the medical and surgical services were included. Acute kidney injury was defined using the Acute Kidney Injury Network (AKIN) classification. RESULTS: During 5 years, 4296 patients (4.12% of admissions) experienced 4727 episodes of HA-AKI during their hospital stay. The mean +/- SD age of the patients was 61 +/- 15 years with a 55% male predominance. There were 958 patients with nrHA-AKI (22.3%) and 2504 patients with lrHA-AKI (58.3%). RRT was required in 31% of the patients with lrHA-AKI compared with 24% of the patients with erHA-AKI. In the multiple risk factor analysis, compared with erHA-AKI, nrHA AKI and lrHA-AKI were significantly associated with worse renal outcome and higher in-hospital mortality. CONCLUSIONS: These data suggest that HA-AKI is frequent and the patients with nrHA-AKI or lrHA-AKI are at increased risk for in hospital morbidity and mortality. PMID- 21817134 TI - Prestroke glycemic control is associated with the functional outcome in acute ischemic stroke: the Fukuoka Stroke Registry. AB - BACKGROUND AND PURPOSE: Diabetes mellitus is an established risk factor for stroke. However, it is uncertain whether prestroke glycemic control (PSGC) status affects clinical outcomes of acute ischemic stroke. The aim of this study was to elucidate the association between PSGC status and neurological or functional outcomes in patients with acute ischemic stroke. METHODS: From the Fukuoka Stroke Registry (FSR), a multicenter stroke registry in Japan, 3627 patients with first ever ischemic stroke within 24 hours after onset were included in the present analysis. The patients were categorized into 4 groups based on their PSGC status: excellent (hemoglobin [Hb] A1c on admission<6.2%), good (6.2-6.8%), fair (6.9 8.3%) and poor (>=8.4%). Study outcomes were neurological improvement (>=4 points decrease in the National Institutes of Health Stroke Scale [NIHSS] score during hospitalization or 0 points on NIHSS score at discharge), neurological deterioration (>=1 point increase in NIHSS score) and poor functional outcome (death or dependency at discharge, modified Rankin Scale 2-6). RESULTS: The age- and sex-adjusted ORs for neurological improvement were lower, and those for neurological deterioration and a poor functional outcome were higher in patients with poorer PSGC status. After adjusting for multiple confounding factors, these trends were unchanged (all probability values for trends were <0.002). These findings were comparable in patients with noncardioembolic and cardioembolic infarctions. CONCLUSIONS: In ischemic stroke patients, HbA1c on admission was an independent significant predictor for neurological and functional outcomes. PMID- 21817136 TI - Advanced brain imaging studies should be performed in patients with suspected stroke presenting within 4.5 hours of symptom onset. PMID- 21817135 TI - Progression of magnetic resonance imaging-defined brain vascular disease predicts vascular events in elderly: the Cardiovascular Health Study. AB - BACKGROUND AND PURPOSE: To determine whether progression of MRI-defined vascular disease predicts subsequent vascular events in the elderly. METHODS: The Cardiovascular Health Study, a longitudinal cohort study of vascular disease in the elderly, allows us to address this question because its participants had 2 MRI scans~5 years apart and have been followed for ~9 years since the follow-up scan for incident vascular events. RESULTS: Both MRI-defined incident infarcts and worsened white matter grade were significantly associated with heart failure, stroke, and death, but not transient ischemic attacks, angina, or myocardial infarction. Strongest associations occurred when both incident infarcts and worsened white matter grade were present for heart failure (hazard ratio, 1.79; 95% confidence interval, 1.18-2.73), stroke (hazard ratio, 2.58; 95% confidence interval, 1.53-4.36), death (hazard ratio, 1.69; 95% confidence interval, 1.28 2.24), and cardiovascular death (hazard ratio, 1.97; 95% confidence interval, 1.24-3.14). CONCLUSIONS: Progression of MRI-defined vascular disease identifies elderly people at increased risk for subsequent heart failure, stroke, and death. Whether aggressive risk factor management would reduce risk is unknown. PMID- 21817138 TI - Self-reported atrial fibrillation and risk of stroke in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. AB - BACKGROUND AND PURPOSE: We compared the associations of self-reported atrial fibrillation (AF) and ECG-detected AF with incident stroke in the Risk of Stroke in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. METHODS: In this analysis, 27 109 participants aged 45 years or older without previous stroke were included. Stroke cases were identified and adjudicated during an average of 4.4 years of follow-up. Cox proportional hazards analysis was used to calculate hazard ratios (HR) of self-reported AF, ECG-detected AF, and AF detected by either method with incident stroke. We also examined the predictive ability of the Framingham Stroke Risk Score (FSRS) when the component AF was defined by different methods. RESULTS: After adjustment for components of the FSRS, self-reported AF, ECG-detected AF, and AF by either method were predictive of incident stroke (HR, 1.41; 95% CI, 1.05-1.88; HR, 1.90; 95% CI, 1.10-3.27; HR, 1.53; 95% CI, 1.16-2.01, respectively). When self-report, ECG, or either method, separately, were considered as the method of AF ascertainment in the FSRS, the HR per 1% increase in the FSRS were identical across AF ascertainment methods (HR, 1.04; 95% CI, 1.03-1.04; HR, 1.04; 95% CI, 1.04-1.05; HR, 1.04; 95% CI, 1.03-1.04; respectively). CONCLUSIONS: Self-reported AF is a strong predictor of stroke that can be used interchangeably or in combination with ECG-detected AF in stroke risk prediction models. PMID- 21817137 TI - Preclinical evidence toward the use of ketamine for recombinant tissue-type plasminogen activator-mediated thrombolysis under anesthesia or sedation. AB - BACKGROUND AND PURPOSE: Endovascular treatment of ischemic stroke usually involves recombinant tissue-type plasminogen activator (rtPA)-mediated thrombolysis in anesthetized patients. Paradoxically, differential influences of anesthetic agents on thrombolysis outcome remain unknown. METHODS: In situ thrombotic stroke was induced in mice by local injection of thrombin. Four hours after the ischemic onset, mice underwent rtPA-mediated thrombolysis either awake or subjected to different anesthetic regimens (propofol, isoflurane/N2O, ketamine). Infarct volume and arterial recanalization were assessed by MRI at 24 hours. RESULTS: Whatever the anesthetic regimen, infarct volumes measured at 24 hours were not affected. However, in contrast with other anesthetic agents tested, ketamine dramatically reduced infarct volume when combined with rtPA. CONCLUSIONS: Altogether these data suggest that ketamine significantly improves the benefit of rtPA-induced thrombolysis after stroke. PMID- 21817139 TI - Mechanical thrombectomy in acute embolic stroke: preliminary results with the revive device. AB - BACKGROUND AND PURPOSE: The purpose of this study was to evaluate the safety and technical feasibility of a new thrombectomy device (Revive; Micrus Endovascular) in the endovascular treatment of acute ischemic stroke. METHODS: Ten patients with acute large vessel occlusions were treated with the Revive device between October 2010 and December 2010. Mean National Institutes of Health Stroke Scale on admission was 19.0; mean duration of symptoms was 172 minutes. Recanalization was assessed using the Thrombolysis In Cerebral Infarction score. Clinical outcome (National Institutes of Health Stroke Scale) after thrombectomy was determined on Day 1, at discharge, and at Day 30. RESULTS: Vessel recanalization (Thrombolysis In Cerebral Infarction 2b or 3) was successful in all patients without device-related complications. Mean National Institutes of Health Stroke Scale 24 hours after the intervention, at discharge, and at Day 30 was 14.0, 11.5, and 5.1, respectively. At Day 30, 6 patients had a clinical improvement of >8 points or an National Institutes of Health Stroke Scale of 0 to 1, 1 patient showed minor improvement, and 3 patients had died. Symptomatic intracranial hemorrhage occurred in 2 patients, of which 1 was fatal. CONCLUSIONS: Thrombectomy with the Revive device in patients with stroke with acute large vessel occlusions demonstrated to be technically safe and highly effective. Clinical safety and efficacy have to be established in larger clinical trials. PMID- 21817140 TI - Socioeconomic differences in quality of care and clinical outcome after stroke: a nationwide population-based study. AB - BACKGROUND AND PURPOSE: The association among socioeconomic status, quality of care, and clinical outcome after stroke remains poorly understood. In a Danish nationwide follow-up study, we examined whether socioeconomic-related differences in acute stroke care occur and, if so, whether they explain socioeconomic differences in case-fatality and readmission risk. METHODS: Using population based public registries, we identified and followed all patients aged<=65 years admitted with stroke from 2003 to 2007 (n=14,545). We compared the proportion of patients receiving 7 specific processes of care according to income, educational attainment, and employment status. Furthermore, we computed 30-day and 1-year hazard ratios for death and readmission adjusted for patient characteristics and received processes of acute stroke care. RESULTS: For low-income patients and disability pensioners, the relative risk of receiving all of the relevant processes of care was 0.82 (95% CI, 0.78 to 0.86) and 0.83 (95% CI, 0.79 to 0.87), respectively, compared with high-income patients and employed patients. Adjusted 30-day and 1-year hazard ratios for death for unemployed patients were 1.57 (95% CI, 1.25 to 1.97) and 1.58 (1.32 to 1.88), respectively, compared with employed patients. Unemployed patients also had a higher risk of readmission. The differences in mortality and readmission risk remained after controlling for received processes of acute stroke care. CONCLUSIONS: Low socioeconomic status was associated with a lower chance of receiving optimal acute stroke care. However, the differences in acute care did not appear to explain socioeconomic differences in mortality and readmission risk. PMID- 21817141 TI - Advanced brain imaging studies should not be performed in patients with suspected stroke presenting within 4.5 hours of symptom onset. PMID- 21817142 TI - Letter by Nardi and Milia regarding article, "translational stroke research of the combination of thrombolysis and antioxidant therapy". PMID- 21817143 TI - Effect of dose and combination of antihypertensives on interindividual blood pressure variability: a systematic review. AB - BACKGROUND AND PURPOSE: Recent studies have shown that visit-to-visit blood pressure variability is a powerful risk factor for stroke, is reduced by calcium channel blockers and diuretics, and increased by beta-blockers. However, it is unknown whether these effects are dose-dependent and persist in combination with other drugs. METHODS: Cochrane and Medline databases were searched for systematic reviews and randomized controlled trials of antihypertensive drugs. Eligible trials randomized all patients to a combination of drug classes or different doses of the same drug. Baseline and follow-up data for mean (SD) systolic blood pressure (SBP) and diastolic blood pressure were extracted. Differences in interindividual variance (SD2) in blood pressure were expressed as a ratio (VR). Estimates were pooled by random-effects meta-analysis. RESULTS: Calcium channel blockers reduced interindividual variability in SBP when added to another agent (VR, 0.75; 95% CI, 0.64 to 0.87; P=0.0002; 12 trials; 1565 patients) with a smaller reduction with diuretics (VR, 0.85; 0.71 to 1.01; P=0.07; 17 trials; 3217 patients). Adding other agents to calcium channel blockers did not significantly affect SBP variability (VR, 1.06; 0.83 to 1.34; P=0.65; 12 trials; 1460 patients) despite a 5.8-mm Hg reduction in mean SBP. Randomization to a higher dose of calcium channel blockers reduced SBP variability (VR, 0.84; 0.74 to 0.94; P=0.004; 25 trials; 2179 patients), whereas randomization to a higher dose of beta-blockers increased SBP variability (VR, 1.31; 1.01 to 1.69; P=0.034; 6 trials; 486 patients). CONCLUSIONS: Effects of antihypertensive drugs on SBP variability are dose-dependent and persist when used in combinations. Use of a high dose of a calcium channel blocker alone or in combination with other agents is therefore likely to be particularly effective in prevention of stroke. PMID- 21817144 TI - Letter by Gaberel et Al regarding article, "dose effect of intraventricular fibrinolysis in ventricular hemorrhage". PMID- 21817145 TI - Patent foramen ovale may be causal for the first stroke but unrelated to subsequent ischemic events. AB - BACKGROUND AND PURPOSE: Studies with very long follow-up are scarce in patients with cryptogenic stroke and patent foramen ovale (PFO). Little is known about the etiology of recurrent cerebrovascular events (CVE) in PFO patients. METHODS: We collected information on recurrent CVE in 308 patients with cryptogenic stroke and PFO and sought to determine concurrent stroke causes that had emerged or been newly detected since the index event. One hundred fifty-eight patients received aspirin (48%), clopidogrel (2%), or oral anticoagulants (50%; medical group). One hundred fifty patients underwent percutaneous PFO closure (closure group). RESULTS: Mean age at index event was 50 years (SD 13). In 33% of patients, the index stroke or transient ischemic attack was preceded by at least 1 CVE. Mean follow-up was 8.7+/-4.0 years. During follow-up, 32 recurrent CVE (13 strokes and 19 transient ischemic attacks) occurred in the medical and 16 recurrent CVE (8 strokes and 8 transient ischemic attacks) in the closure group. Concurrent etiologies were identified for 12 recurrent CVE in the medical group (38%): large artery disease (9%), small artery disease (6%), cardioembolism (13%), cerebral vasculitis (3%), and antiphospholipid-antibody-syndrome (6%). In the closure group, 7 recurrent CVE had a concurrent etiology (44%): large artery disease (6%), small artery disease (19%), cardioembolism (13%), and thrombophilic disorder (6%). The frequency of concurrent etiologies did not differ between patients with recurrent CVE under medical treatment and those undergoing PFO closure (P=0.68). CONCLUSIONS: Concurrent etiologies are identified for more than one third of recurrent ischemic events in patients with cryptogenic stroke, casting doubt on the sole causal role of PFO. PMID- 21817146 TI - Intraventricular fibrinolysis versus external ventricular drainage alone in intraventricular hemorrhage: a meta-analysis. AB - BACKGROUND AND PURPOSE: The purpose of this study was to analyze the effect of intraventricular fibrinolysis (IVF) compared with external ventricular drainage alone on mortality and functional outcome in the management of intraventricular hemorrhage secondary to spontaneous supratentorial intracerebral hemorrhage. METHODS: The authors conducted a systematic review and performed a meta-analysis. They reviewed the PubMed, Cochrane Library, and Liliacs databases. In addition, they conducted a manual review of article bibliographies. RESULTS: Using a prespecified search strategy, 4 randomized and 8 observational studies were included in a meta-analysis. These studies involved a total of 316 patients with intraventricular hemorrhage at baseline, of whom 167 had IVF (52.8%). Pooled odds ratios of the impact of IVF on patient mortality, functional outcomes, and complications were calculated. The overall mortality risk decreased from 46.7% in the external ventricular drainage alone group to 22.7% in the external ventricular drainage+IVF group, corresponding to an overall pooled Peto OR of 0.32 (95% CI, 0.19 to 0.52). This result was highly significant with urokinase, not with recombinant tissue-type plasminogen activator. IVF was also associated with an increase in good functional outcome. There was no difference between the 2 groups in terms of shunt dependence and complications. CONCLUSIONS: The combination of IVF and external ventricular drainage in the management of severe intraventricular hemorrhage secondary to small intracerebral hemorrhage in young patients was associated with better survival and functional outcome results. Urokinase and recombinant tissue-type plasminogen activator could not have the same therapeutic effects. Well-designed randomized trials with special considerations to the fibrinolytic agents are needed. PMID- 21817147 TI - Graduating US neurology residents' experience with tissue-type plasminogen activator for acute stroke: a 10-year comparison. AB - BACKGROUND AND PURPOSE: A survey of graduating neurology residents conducted in 2000 showed that many residents had limited experience and comfort treating with tissue-type plasminogen activator (tPA). We examined changes in residents' experience during the past decade. METHODS: A 12-item survey was sent to US neurology residents in their final year of training. Items examined residents' experience and confidence with assessment of the acute stroke patient and use of tPA for treatment. Questions were worded identically in the 2000 and 2010 surveys, and responses were compared between the two. RESULTS: Of 491 residents, 286 (58%) responded. There was a significant increase from 2000 to 2010 in the percentage of residents who felt comfortable independently treating with tPA (73% versus 94%, P<0.001), who had observed administration of tPA (88% versus 99%, P<0.001), who had personally treated with tPA (80% versus 95%, P<0.001), and who had been involved in post-tPA care (89% versus 98%, P<0.001). There was a substantial increase in residents with formal training in using the National Institutes of Health Stroke Scale (65% versus 92%, P<0.001) and who had dedicated stroke teams at their institution (84% versus 93%, P=0.001). CONCLUSIONS: Neurology residents' experience and comfort treating acute ischemic stroke with tPA increased significantly between 2000 and 2010, as did resident exposure to stroke teams and formal training in the National Institutes of Health Stroke Scale. PMID- 21817148 TI - Conundra of the penumbra and acute stroke imaging. PMID- 21817149 TI - Patients with severe asymptomatic carotid artery stenosis do not have a higher risk of stroke and mortality after coronary artery bypass surgery. AB - BACKGROUND AND PURPOSE: Stroke development is a major concern in patients undergoing coronary artery bypass grafting (CABG). Whether asymptomatic severe carotid artery stenosis (CAS) contributes to the development of stroke and mortality in such patients remains uncertain. METHODS: A retrospective analysis of 878 consecutive patients with documented carotid duplex ultrasound who underwent isolated CABG in our institution from January 2003 to December 2009 was performed. Patients with severe CAS (n=117) were compared with those without severe CAS (n=761) to assess the rates of stroke and mortality during hospitalization for CABG. The 30-day mortality rate was also assessed. RESULTS: Patients with severe CAS were older and had a higher prevalence of peripheral arterial disease and heart failure. Patients with severe CAS had similar rates of in-hospital stroke (3.4% versus 3.6%; P=1.0) and mortality (3.4% versus 4.2%; P=1.0) compared with patients without severe CAS. The 30-day rate of mortality was also similar between the 2 cohorts (3.4% versus 2.9%; P=0.51). CONCLUSIONS: Severe CAS alone is not a risk factor for stroke or mortality in patients undergoing CABG. The decision to perform carotid imaging and subsequent revascularization in association with CABG must be individualized and based on clinical judgment. PMID- 21817150 TI - Ischemic stroke and transient ischemic attack after head and neck radiotherapy: a review. AB - BACKGROUND AND PURPOSE: Cerebrovascular disease can complicate head and neck radiotherapy and result in transient ischemic attack and ischemic stroke. Although the incidence of radiation vasculopathy is predicted to rise with improvements in median cancer survival, the pathogenesis, natural history, and management of the disease are ill defined. METHODS: We examined studies on the epidemiology, imaging, pathogenesis, and management of medium- and large-artery intra- and extra-cranial disease after head and neck radiotherapy. Controlled prospective trials and larger retrospective trials from the last 30 years were prioritized. RESULTS: The relative risk of transient ischemic attack or ischemic stroke is at least doubled by head and neck radiotherapy. Chronic radiation vasculopathy affecting medium and large intra- and extra-cranial arteries is characterized by increasing rates of hemodynamically significant stenosis with time from radiotherapy. Disease expression is the likely consequence of the combined radiation insult to the intima-media (accelerating atherosclerosis) and to the adventitia (injuring the vasa vasorum). Optimal medical treatment is not established. Carotid endarterectomy is confounded by the need to operate across scarred tissue planes, whereas carotid stenting procedures have resulted in high restenosis rates. CONCLUSIONS: Head and neck radiotherapy significantly increases the risk of transient ischemic attack and ischemic stroke. Evidence-based guidelines for the management of asymptomatic and symptomatic (medium- and large artery) radiation vasculopathy are lacking. Long-term prospective studies remain a priority, as the incidence of the problem is anticipated to rise with improvements in postradiotherapy patient survival. PMID- 21817151 TI - Loss of NB-3 aggravates cerebral ischemia by impairing neuron survival and neurite growth. AB - BACKGROUND AND PURPOSE: NB-3 is a member of the F3/contactin family of neural recognition molecules, which are crucial for cell morphogenesis and motility. NB 3 is expressed in neurons and plays an important role in axonal extension and neuronal survival. However, the role of NB-3 in cerebral ischemic injury remains unknown. METHODS: Adult male wild-type and NB-3 knockout mice were subjected to ischemic injury by unilateral middle cerebral carotid artery occlusion for 3 hours, 6 hours, and 12 hours. Ischemic infarction volumes were then determined by 2, 3, 5-triphenyltetrazolium chloride staining. Neurological dysfunction analysis was also performed. Primary culture of neuronal cells from wild-type and knockout animals was also used for analysis of neuronal survival and neurite outgrowth. RESULTS: NB-3 expression in the ischemic hemisphere was decreased after transient middle cerebral artery occlusion (MCAO). NB-3-knockout mice developed a 2.6-fold larger infarct volume and exhibited increased neurological deficit scores after transient middle cerebral artery occlusion compared with control mice. Substrate with NB-3 promoted neuronal survival and neurite outgrowth in vitro, whereas neurite outgrowth and neuronal survival were significantly reduced in NB-3 deficient neurons. In addition, NB-3 deficiency renders neurons more susceptible to oxygen-glucose deprivation-induced damage and NB-3 as substrate could partially through homophilic mechanisms. CONCLUSIONS: These data demonstrate that NB-3 deficiency may aggravate brain damage after middle cerebral artery occlusion by impairing neuronal survival and neurite growth. PMID- 21817152 TI - Predictors of early and late case-fatality in a nationwide Danish study of 26,818 patients with first-ever ischemic stroke. AB - BACKGROUND AND PURPOSE: Predictors of early case-fatality (3-day, 7-day, and 30 day) in first-ever ischemic stroke were identified and compared with predictors of late case-fatality (90-day and 1-year). METHODS: A registry designed to register hospitalized patients with stroke in Denmark 2000 to 2007 holds 26,818 patients with first-ever ischemic stroke with information on stroke severity (Scandinavian Stroke Scale), CT scan, cardiovascular risk factors, marital status, and fatality within 1 year. Multiple logistic regression was used in identifying predictors. RESULTS: Mean age was 71.2 years; 48.5% were women; mean Scandinavian Stroke Scale score was 43.9. Early case-fatality showed stroke severity and age were significant predictors of 3-day, 7-day, and 30-day case fatality (nonlinear effect). In addition, atrial fibrillation (OR, 1.56) predicted 30-day case-fatality. For late case-fatality, significant predictors of 90-day and 1-year case-fatality were age, stroke severity (nonlinear effect), atrial fibrillation (OR, 1.37 and 1.57), and diabetes (OR, 1.35 and 1.33), respectively. Male gender (OR, 1.28), previous myocardial infarction (OR, 1.40), and smoking (OR, 1.21) were also associated with 1-year case-fatality. Alcohol consumption, hypertension, intermittent arterial claudication, and marital state had no influence. All case-fatality rates accelerated with increasing age, but 3 day and 7-day case-fatality rates tended to level off or decline at the highest ages. CONCLUSIONS: Age and stroke severity were the only significant predictors of fatality within the first poststroke week; they were associated with late case fatality as well. Cardiovascular risk factors were associated with late case fatality; with the exception of atrial fibrillation, they were not significantly associated with early case-fatality rates. PMID- 21817153 TI - A unique microRNA signature associated with plaque instability in humans. AB - BACKGROUND AND PURPOSE: Atherosclerotic plaque rupture is considered the most important mechanism that underlies the onset of stroke, myocardial infarction, and sudden death. Several evidences demonstrated the pivotal role of inflammatory processes in plaque destabilization. MicroRNAs (miRNAs) are small endogenous RNAs and represent a new important class of gene regulators. Nevertheless, no data exist about the expression profile of miRNAs in atherosclerotic plaques. Thus, the aim of this study was to investigate the expression level of miRNAs in human plaques and to correlate it with clinical features of plaque destabilization. METHODS: Two separate groups of plaques were collected from patients who underwent carotid endarterectomy in Chieti (n=15) and Ancona (n=38) Hospitals. All the plaques were subdivided in symptomatic (n=22) and asymptomatic (n=31) according to the presence/absence of stroke. RESULTS: First, on the plaques collected at Chieti Hospital, we performed large-scale analysis of miRNA expression. Between the 41 miRNAs examined, we discovered profound differences in the expression of 5 miRNAs (miRNA-100, miRNA-127, miRNA-145, miRNA-133a, and miRNA-133b) in symptomatic versus asymptomatic plaques. Remarkably, when we repeated the analysis on the Ancona plaque subset, all these 5 miRNAs confirmed to be significantly more expressed in the symptomatic plaques. Finally, in vitro experiments on endothelial cells transfected with miRNA-145 and miRNA-133a confirmed the importance of these miRNAs in the modulation of stroke-related proteins. CONCLUSIONS: These results are the first to report alterations in the expression of specific miRNAs in human atherosclerotic plaques and suggest that miRNAs may have an important role in regulating the evolution of atherosclerotic plaque toward instability and rupture. Furthermore, by identifying the specific miRNA signature for stroke now, we are able to use computer algorithms to identify previously unrecognized molecular targets. PMID- 21817154 TI - Wars, war games, and dead bodies on the battlefield: variations on the theme of blood pressure variability. PMID- 21817155 TI - Growth dysregulation and ADHD: an epidemiologic study of children in France. AB - OBJECTIVE: A small literature suggests that ADHD may be associated with dysregulated growth, but this prior work primarily used clinically referred samples, so it faces difficulties of interpretation. The objective of this study is to sample the general French population for ADHD and evaluate if ADHD is associated with dysregulated growth. METHODS: Starting with 18 million telephone numbers, 7,912 were randomly called. Among 4,186 eligible families, 1,012 were recruited. The goal was for the final distribution of the sample to match the demographic background of the French population. A telephone interview was administered to all families to diagnose ADHD and assess other psychopathology and functioning variables. RESULTS: Medication-naive ADHD was associated with being taller, t(515) = 26.3, p < .001, and heavier, t(518) = 1.8, p = .03, for young children. In contrast, for older children, medication-naive ADHD participants were shorter and lighter. These results were stronger for weight than height. CONCLUSION: Although these data do not cast doubt on the well documented association of stimulant treatment with delays in growth, they provide some support for the idea that, in the absence of medication exposure, ADHD is associated with dysregulated growth. PMID- 21817156 TI - The Onodi cell: an obstacle to sellar lesions with a transsphenoidal approach. AB - OBJECTIVE: The Onodi cell is the posterior-most ethmoid air cell and an important anatomical variant because of the intimate spatial relationship with the optic nerve, internal carotid artery, and sellar floor during sphenoid sinus surgery. The authors evaluated the incidence of Onodi cells, their clinical importance, and the association between preoperative radiological findings and surgical findings. STUDY DESIGN: Case series with chart review. SETTING: Tertiary care medical center. METHODS: The authors retrospectively reviewed the medical records of 162 cases, including preoperative paranasal sinus computed tomography (PNS CT) findings and the findings with the endoscopic endonasal transsphenoidal approach (EETSA). They evaluated the prevalence of Onodi cells and the clinical manifestations in the patients with these cells. They also examined the clinical significance of these cells during EETSA. RESULTS: Onodi cells were identified in the preoperative PNS CT of 53 patients, whereas Onodi cells were observed in 54 (33.3%) of the 162 patients at EETSA. The Onodi cells were bilateral in 23 patients and unilateral in 31. In all cases, the Onodi cells limited the exposure of the sellar floor. Only after removing these cells was the entire sellar floor exposed so that the tumors could be removed completely. CONCLUSION: Onodi cells were observed more frequently than in previous studies, and 98.1% of them were identified on preoperative PNS CT. When reviewing PNS CT images preoperatively, one needs to identify the presence of Onodi cells. The Onodi cells must be removed to completely resect tumors located in the sellar region during EETSA. PMID- 21817157 TI - Simultaneous versus subsequent intratympanic dexamethasone for idiopathic sudden sensorineural hearing loss. AB - OBJECTIVE: The authors compared the efficacy of simultaneous and subsequent intratympanic dexamethasone injections for the treatment of idiopathic sudden sensorineural hearing loss. STUDY DESIGN: Prospective randomized controlled multicenter study. SETTING: Three tertiary university hospitals. SUBJECTS AND METHODS: In the simultaneous intratympanic dexamethasone group, intratympanic dexamethasone was given initially with systemic steroids. In the subsequent intratympanic dexamethasone group, intratympanic dexamethasone was given 7 days after systemic treatment. The authors compared hearing outcomes between the groups according to Siegel's criteria and frequency (0.25, 0.5, 1, 2, 3, 4, 6, and 8 kHz). RESULTS: A total of 88 patients were analyzed in this study. There was no difference between the groups in hearing recovery according to Siegel's criteria or frequencies. Neither recovery time nor early recovery differed between the groups. In the subsequent intratympanic dexamethasone group, 15 patients showed hearing recovery within 7 days and did not need intratympanic dexamethasone treatment. After intratympanic dexamethasone treatment, >28% (25/88) of the patients complained of otalgia, transient dizziness, ear fullness, and headache. Five percent of the patients showed small, transient perforations and otorrhea during intratympanic dexamethasone treatment. CONCLUSIONS: Simultaneous intratympanic dexamethasone did not confer an additional hearing gain or earlier recovery rate compared with subsequent intratympanic dexamethasone. A considerable number of patients did not need intratympanic dexamethasone for idiopathic sudden sensorineural hearing loss, and some patients experienced unnecessary side effects due to intratympanic dexamethasone. Therefore, the use of intratympanic dexamethasone is recommended only for subsequent or salvage treatment of idiopathic sudden sensorineural hearing loss after systemic steroid treatment. PMID- 21817158 TI - Stabilization of nasal tip support in nasal tip reduction surgery. PMID- 21817159 TI - Fibroblast growth factor homologous factor 13 regulates Na+ channels and conduction velocity in murine hearts. AB - RATIONALE: Fibroblast growth factor homologous factors (FHFs), a subfamily of fibroblast growth factors (FGFs) that are incapable of functioning as growth factors, are intracellular modulators of Na(+) channels and have been linked to neurodegenerative diseases. Although certain FHFs have been found in embryonic heart, they have not been reported in adult heart, and they have not been shown to regulate endogenous cardiac Na(+) channels or to participate in cardiac pathophysiology. OBJECTIVE: We tested whether FHFs regulate Na(+) channels in murine heart. METHODS AND RESULTS: We demonstrated that isoforms of FGF13 are the predominant FHFs in adult mouse ventricular myocytes. FGF13 binds directly to, and colocalizes with, the Na(V)1.5 Na(+) channel in the sarcolemma of adult mouse ventricular myocytes. Knockdown of FGF13 in adult mouse ventricular myocytes revealed a loss of function of Na(V)1.5-reduced Na(+) current density, decreased Na(+) channel availability, and slowed Na(V)1.5-reduced Na(+) current recovery from inactivation. Cell surface biotinylation experiments showed ~45% reduction in Na(V)1.5 protein at the sarcolemma after FGF13 knockdown, whereas no changes in whole-cell Na(V)1.5 protein or in mRNA level were observed. Optical imaging in neonatal rat ventricular myocyte monolayers demonstrated slowed conduction velocity and a reduced maximum capture rate after FGF13 knockdown. CONCLUSION: These findings show that FHFs are potent regulators of Na(+) channels in adult ventricular myocytes and suggest that loss-of-function mutations in FHFs may underlie a similar set of cardiac arrhythmias and cardiomyopathies that result from Na(V)1.5 loss-of-function mutations. PMID- 21817161 TI - CD34+ autologous human stem cells in treating refractory angina. PMID- 21817160 TI - Redox regulation of mitochondrial ATP synthase: implications for cardiac resynchronization therapy. AB - RATIONALE: Cardiac resynchronization therapy (CRT) is an effective clinical treatment for heart failure patients with conduction delay, impaired contraction, and energetics. Our recent studies have revealed that mitochondrial posttranslational modifications (PTM) may contribute to its benefits, motivating the present study of the oxidative regulation of mitochondrial ATP synthase. OBJECTIVES: We tested whether CRT alteration of ATP synthase function is linked to cysteine (Cys) oxidative PTM (Ox-PTM) of specific ATP synthase subunits. METHODS AND RESULTS: Canine left ventricular myocardium was collected under conditions to preserve Ox-PTM from control, dyssynchronous heart failure (DHF), or hearts that had undergone CRT. In-gel ATPase activity showed that CRT increased ATPase activity by approximately 2-fold (P<0.05) over DHF, approaching control levels, and this effect was recapitulated with a reducing agent. ATP synthase function and 3 Ox-PTM: disulfide bond, S-glutathionylation and S nitrosation were assessed. ATP synthase from DHF hearts contained 2 novel disulfide bonds, between ATP synthase alpha subunits themselves and between alpha and gamma subunits, both of which were decreased in CRT hearts (4.38 +/- 0.13- and 4.23 +/- 0.36-fold, respectively, P<0.01). S-glutathionylation of ATP synthase alpha subunit occurred in DHF hearts and was decreased by CRT (1.56 +/- 0.16-fold, P<0.04). In contrast, S-nitrosation of ATP synthase alpha subunit in DHF hearts was lower than in CRT hearts (1.53 +/- 0.19-fold, P<0.05). All modifications occurred at ATP synthase alpha subunit Cys294 and Cys to Ser mutation indicated that this residue is critical for ATP synthase function. CONCLUSIONS: A selective Cys in ATP synthase alpha subunit is targeted by multiple Ox-PTM suggesting that this Cys residue may act as a redox sensor modulating ATP synthase function. PMID- 21817162 TI - Circadian control of epigenetic modifications modulates metabolism. PMID- 21817163 TI - Modeling human disease phenotype in model organisms: "It's only a model!". PMID- 21817164 TI - Translational success stories: angiotensin receptor 1 antagonists in heart failure. AB - The title of the proposed series of reviews is Translational Success Stories. The definition of "translation" according to Webster is, "an act, process, or instance of translating as a rendering of one language into another." In the context of this inaugural review, it is the translation of Tigerstedt's and Bergman's(1) discovery in 1898 of the vasoconstrictive effects of an extract of rabbit kidney to the treatment of heart failure. As recounted by Marks and Maxwell,(2) their discovery was heavily influenced by the original experiments of the French physiologist Brown-Sequard, who was the author of the doctrine that "many organs dispense substances into the blood which are not ordinary waste products, but have specific functions." They were also influenced by Bright's(3) original observation that linked kidney disease with hypertension with the observation that patients dying with contracted kidneys often exhibited a hard, full pulse and cardiac hypertrophy. However, from Tigerstedt's initial discovery, there was a long and arduous transformation of ideas and paradigms that eventually translated to clinical applications. Although the role of the renin angiotensin system in the pathophysiology of hypertension and heart failure was suspected through the years, beneficial effects from its blockade were not realized until the early 1970s. Thus, this story starts with a short historical perspective that provides the reader some insight and appreciation into the long delay in translation. PMID- 21817166 TI - Status and prospects for discovery and verification of new biomarkers of cardiovascular disease by proteomics. AB - Despite unmet needs for cardiovascular biomarkers, few new protein markers have been approved by the US Food and Drug Administration for the diagnosis or screening of cardiovascular diseases. Mass spectrometry-based proteomics technologies are capable of identifying hundreds to thousands of proteins in cells, tissues, and biofluids. Proteomics may therefore provide the opportunity to elucidate new biomarkers and pathways without a prior known association with cardiovascular disease; however, important obstacles remain. In this review, we focus on emerging techniques that may form a coherently integrated pipeline to overcome present limitations to both the discovery and validation processes. PMID- 21817165 TI - Tear me down: role of calpain in the development of cardiac ventricular hypertrophy. AB - Cardiac hypertrophy develops most commonly in response to hypertension and is an independent risk factor for the development of heart failure. The mechanisms by which cardiac hypertrophy may be reversed to reduce this risk have not been fully determined to the point where mechanism-specific therapies have been developed. Recently, proteases in the calpain family have been implicated in the regulation of the development of cardiac hypertrophy in preclinical animal models. In this review, we summarize the molecular mechanisms by which calpain inhibition has been shown to modulate the development of cardiac (specifically ventricular) hypertrophy. The context within which calpain inhibition might be developed for therapeutic intervention of cardiac hypertrophy is then discussed. PMID- 21817167 TI - Profiling the humoral immune response of acute and chronic Q fever by protein microarray. AB - Antigen profiling using comprehensive protein microarrays is a powerful tool for characterizing the humoral immune response to infectious pathogens. Coxiella burnetii is a CDC category B bioterrorist infectious agent with worldwide distribution. In order to assess the antibody repertoire of acute and chronic Q fever patients we have constructed a protein microarray containing 93% of the proteome of Coxiella burnetii, the causative agent of Q fever. Here we report the profile of the IgG and IgM seroreactivity in 25 acute Q fever patients in longitudinal samples. We found that both early and late time points of infection have a very consistent repertoire of IgM and IgG response, with a limited number of proteins undergoing increasing or decreasing seroreactivity. We also probed a large collection of acute and chronic Q fever patient samples and identified serological markers that can differentiate between the two disease states. In this comparative analysis we confirmed the identity of numerous IgG biomarkers of acute infection, identified novel IgG biomarkers for acute and chronic infections, and profiled for the first time the IgM antibody repertoire for both acute and chronic Q fever. Using these results we were able to devise a test that can distinguish acute from chronic Q fever. These results also provide a unique perspective on isotype switch and demonstrate the utility of protein microarrays for simultaneously examining the dynamic humoral immune response against thousands of proteins from a large number of patients. The results presented here identify novel seroreactive antigens for the development of recombinant protein based diagnostics and subunit vaccines, and provide insight into the development of the antibody response. PMID- 21817169 TI - A user-assisted approach to visualizing multidimensional images. AB - We present a new technique for fusing together an arbitrary number of aligned images into a single color or intensity image. We approach this fusion problem from the context of Multidimensional Scaling (MDS) and describe an algorithm that preserves the relative distances between pairs of pixel values in the input (vectors of measurements) as perceived differences in a color image. The two main advantages of our approach over existing techniques are that it can incorporate user constraints into the mapping process and allows adaptively compressing or exaggerating features in the input in order to make better use of the output's limited dynamic range. We demonstrate these benefits by showing applications in various scientific domains and comparing our algorithm to previously proposed techniques. PMID- 21817168 TI - Peripheral blood monocyte-expressed ANXA2 gene is involved in pathogenesis of osteoporosis in humans. AB - Low bone mineral density (BMD) is a risk factor of osteoporosis and has strong genetic determination. Genes influencing BMD and fundamental mechanisms leading to osteoporosis have yet to be fully determined. Peripheral blood monocytes (PBM) are potential osteoclast precursors, which could access to bone resorption surfaces and differentiate into osteoclasts to resorb bone. Herein, we attempted to identify osteoporosis susceptibility gene(s) and characterize their function(s), through an initial proteomics discovery study on PBM in vivo, and multiscale validation studies in vivo and in vitro. Utilizing the quantitative proteomics methodology LC-nano-ESI-MS(E), we discovered that a novel protein, i.e. ANXA2, was up-regulated twofold in PBM in vivo in Caucasians with extremely low BMD (cases) versus those with extremely high BMD (controls) (n = 28, p < 0.05). ANXA2 gene up-regulation in low BMD subjects was replicated at the mRNA level in PBM in vivo in a second and independent case-control sample (n = 80, p < 0.05). At the DNA level, we found that SNPs in the ANXA2 gene were associated with BMD variation in a 3(rd) and independent case-control sample (n = 44, p < 0.05), as well as in a random population sample (n = 997, p < 0.05). The above integrative evidence strongly supports the concept that ANXA2 is involved in the pathogenesis of osteoporosis in humans. Through a follow-up cellular functional study, we found that ANXA2 protein significantly promoted monocyte migration across an endothelial barrier in vitro (p < 0.001). Thus, elevated ANXA2 protein expression level, as detected in low BMD subjects, probably stimulates more PBM migration through the blood vessel walls to bone resorption surfaces in vivo, where they differentiate into higher number of osteoclasts and resorb bone at higher rates, thereby decreasing BMD. In conclusion, this study identified a novel osteoporosis susceptibility gene ANXA2, and suggested a novel pathophysiological mechanism, mediated by ANXA2, for osteoporosis in humans. PMID- 21817170 TI - Spatiotemporal sampling of dynamic environment sequences. AB - Environment sampling is a popular technique for rendering scenes with distant environment illumination. However, the temporal consistency of animations synthesized under dynamic environment sequences has not been fully studied. This paper addresses this problem and proposes a novel method, namely spatiotemporal sampling, to fully exploit both the temporal and spatial coherence of environment sequences. Our method treats an environment sequence as a spatiotemporal volume and samples the sequence by stratifying the volume adaptively. For this purpose, we first present a new metric to measure the importance of each stratified volume. A stratification algorithm is then proposed to adaptively suppress the abrupt temporal and spatial changes in the generated sampling patterns. The proposed method is able to automatically adjust the number of samples for each environment frame and produce temporally coherent sampling patterns. Comparative experiments demonstrate the capability of our method to produce smooth and consistent animations under dynamic environment sequences. PMID- 21817171 TI - Partwise cross-parameterization via nonregular convex hull domains. AB - In this paper, we propose a novel partwise framework for cross-parameterization between 3D mesh models. Unlike most existing methods that use regular parameterization domains, our framework uses nonregular approximation domains to build the cross-parameterization. Once the nonregular approximation domains are constructed for 3D models, different (and complex) input shapes are transformed into similar (and simple) shapes, thus facilitating the cross-parameterization process. Specifically, a novel nonregular domain, the convex hull, is adopted to build shape correspondence. We first construct convex hulls for each part of the segmented model, and then adopt our convex-hull cross-parameterization method to generate compatible meshes. Our method exploits properties of the convex hull, e.g., good approximation ability and linear convex representation for interior vertices. After building an initial cross-parameterization via convex-hull domains, we use compatible remeshing algorithms to achieve an accurate approximation of the target geometry and to ensure a complete surface matching. Experimental results show that the compatible meshes constructed are well suited for shape blending and other geometric applications. PMID- 21817172 TI - [Gogi (word-meaning) aphasia]. AB - Gogi (word meaning) aphasia is an aphasic syndrome originally described by Tsuneo Imura in 1943. According to Imura, this syndrome is characterized by 4 symptoms: (1) difficulty in comprehending the meaning of a word despite perfect perception of the sound of the word; (2) presence of word amnesia and verbal paraphasia; (3) preservation of the ability to repeat spoken words; and (4) characteristic disturbances in reading and writing, in which Kana (Japanese syllabogram) can be correctly read and written, but Kanji (Japanese logogram) is read and transcribed in a peculiar way without comprehension, resulting in strange paragraphia. Gogi aphasia occupies a unique seat in the category of transcortical sensory aphasia. While the latter is grossly defined as fluent sensory aphasia with good repetition and without any specification about the linguistic level of deficit, the former is defined more specifically as fluent sensory aphasia with the deficit limited to the level of words. The characteristic Kana-Kanji dissociation aids in the diagnosis of this syndrome. Recently, it has been repeatedly confirmed that the temporal lobe type of Pick disease (known as semantic dementia in recent English literature) often presents the clinical picture of Gogi aphasia in its early course. Many Japanese physicians have contributed to the elucidation of this clinicopathological correlation. This is mainly because many neurologists and psychiatrists in Japan have long been familiar with the concept of Gogi aphasia and the nosology of Pick disease. PMID- 21817173 TI - [Dual neural circuit model of reading and writing]. AB - In the hypothetical neural circuit model of reading and writing that was initially proposed by Dejerine and subsequently confirmed by Geschwind, the left angular gyrus was considered as a unique center for processing letters. Japanese investigators, however, have repeatedly pointed out that this angular gyrus model cannot fully explain the disturbances observed in reading and writing Kanji letters in Japanese patients with various types of alexia with or without agraphia. In 1982, I proposed a dual neural circuit model of reading and writing Japanese on the basis of neuropsychological studies on the various types of alexia with or without agraphia without aphasia. This dual neural circuit model proposes that apart from the left angular gyrus which was thought to be a node for phonological processing of letters, the left posterior inferior temporal area, also acts as a node for semantic processing of letters. Further investigations using O15-PET activation on normal subjects revealed that the left middle occipital gyrus (area 19 of Brodmann) and the posterior portion of the left inferior temporal gyrus (area 37 of Brodmann) are the cortical areas responsible for reading Japanese letters; the former serving for phonological reading and the latter for semantic reading. This duality of the neural circuit in processing letters was later applied to explain disturbances in reading English, and was finally accepted as a valid model for other alphabetic letter systems too. PMID- 21817174 TI - [Agnosia for streets and defective root finding]. AB - Topographical disorientation is identified as a condition in which patients are unable to find their way in familiar surroundings, such as their home neighborhood or the admitting hospital after the onset of illness. I proposed to classify topographical disorientation into two categories: agnosia for streets (landmark agnosia) and defective root finding (heading disorientation). Patients with agnosia for streets are unable to identify familiar buildings and landscapes. They can, however, morphologically perceive them and remember their way around familiar areas. The lesions are located in the right posterior part of the parahippocampus gyrus, anterior half of the lingual gyrus and adjacent fusiform gyrus. Clinical findings and functional imaging studies suggest that these regions play a crucial role in the interaction between the visual information of streets and memories of them, which are thought to be retained in the right anterior part of the temporal lobe. In particular, the posterior part of the parahippocampus gyrus is critical for the acquisition of novel information. On the other hand, patients with defective root finding can identify familiar streets, but cannot remember their own location or positional relation between two points within a comparatively wide range not surveyable at one time. The lesions are located in the right retrosplenial cortex (Areas 29, 30), posterior cingulate cortex (Areas 23, 31) and precuneus. Clinical findings and functional imaging studies suggest that these regions are involved in the orientation function for navigating in wide spaces. In particular, the retrosplenial cortex is critical for encoding novel information. PMID- 21817175 TI - [Reverse Chaddock sign]. AB - It is widely accepted that the Babinski reflex is the most well-known and important pathological reflex in clinical neurology. Among many other pathological reflexes that elicit an upgoing great toe, such as Chaddock, Oppenheim, Gordon, Schaefer, and Stransky, only the Chaddock reflex is said to be as sensitive as the Babinski reflex. The optimal receptive fields of the Babinski and Chaddock reflexes are the lateral plantar surface and the external inframalleolar area of the dorsum, respectively. It has been said that the Babinski reflex, obtained by stroking the sole, is by far the best and most reliable method of eliciting an upgoing great toe. However, the Chaddock reflex, the external malleolar sign, is also considered sensitive and reliable according to the literature and everyday neurological practice. The major problems in eliciting the Babinski reflex by stroking the lateral part of the sole are false positive or negative responses due to foot withdrawal, tonic foot response, or some equivocal movements. On the other hand, according to my clinical experience, the external inframalleolar area, which is the receptive field of the Chaddock reflex, is definitely suitable for eliciting the upgoing great toe. In fact, the newly proposed method to stimulate the dorsum of the foot from the medial to the lateral side, which I term the "reversed Chaddock method," is equally sensitive to demonstrate pyramidal tract involvement. With the "reversed Chaddock method", the receptive field of the Chaddock reflex may be postulated to be in the territory of the sural nerve, which could be supported by the better response obtained on stimulation of the postero-lateral calf than the anterior shin. With regard to the receptive fields of the Babinski and Chaddock reflexes, the first sacral dermatome (S1) is also considered a reflexogenous zone, but since the dermatome shows marked overlapping, the zones vary among individuals. As upgoing toe responses are consistently observed in the case of pyramidal tract dysfunction by both the Chaddock reflex and the reversed Chaddock method, the external inframalleolar area of the dorsum as a reflexogenous zone is considered very important. In conclusion, this method, termed the "reversed Chaddock method," is not only effective but can also help avoid false positive results due to foot withdrawal or tonic foot responses elicited on stroking the sole. I would like to propose the "reverse Chaddock sign (Tashiro sign)" as one of the 15 pathological reflexes involving the foot. PMID- 21817176 TI - [Thumb/big-toe localizing test: examination for deficit of proprioception through the posterior column-medial lemniscal system]. AB - "Thumb localizing test" (TLT) and "big-toe localizing test" (BLT) are bedside examinations to detect abnormalities in proprioceptive afferent pathways from the limbs. In TLT, the patient is asked to close the eyes, one upper limb of the patient is placed in a fixed position by the examiner, and the patient is asked to localize the thumb of the fixed upper limb with the thumb and index finger of the other upper limb. In BLT, the patient is asked to close the eyes, a lower limb is passively immobilized by the examiner, and the patient is asked to locate the big toe with either index finger. Normal subjects can perform these tests quickly and accurately by the shortest spatial route, but some patients with neurological diseases show a deficit despite having normal sense of joint movement and position (JMP) for any of the joints of the fixed limb (so-called deep sensation). TLT/BLT deficits in such patients are caused by insufficient transmission or impaired integration of a proprioceptive sensation of the fixed limb that differs from discriminative sensation such as JMP and tactile cutaneous localization. TLT and BLT are more sensitive than the tests for JMP. BLT, in conjunction with TLT, is a more sophisticated bedside examination for determining the site of the lesion of the peripheral and central nervous systems. PMID- 21817177 TI - [Newly approved drugs for Alzheimer disease: effectiveness and limitation]. AB - In addition to donepezil, 2 other cholinesterase inhibitors galantamine and rivastigmine, and an N-methyl-D-aspartic acid receptor antagonist, memantine, have been recently approved for the treatment of Alzheimer disease patients at mild to moderately severe and moderately severe to severe stages of the disease, respectively, in Japan. These drugs were approved about a decade ago in Europe, US, and some other countries in Asia, and have been widely used since then. Many studies have been performed to evaluate the clinical effectiveness and cost effectiveness of these drugs for treating cognitive decline, deterioration of activity of daily living and behavior and mood disorders. Several systematic reviews of previous investigations of the effectiveness of these drugs suggest modest overall benefits for stabilizing and slowing decline in cognition and for reducing behavioral and psychological symptoms. Although these drugs may modulate various neurobiological aspects of Alzheimer disease and afford neuroprotection, in addition to improvement of impaired neurotransmission, limited evidence is available for the ability of these drugs to prevent or reverse the progression of the disease through disease-modifying action. In this article, we describe drugs profiles of the currently approved drugs for Alzheimer disease and discuss the effectiveness and limitations of these drugs. PMID- 21817178 TI - [Functional analysis of the thalamocortical pathways in eye movements]. AB - Although the roles of the thalamocortical pathways in somatic movements are well documented, their roles in eye movements have only recently been examined. The oculomotor-related areas in the frontal cortex receive inputs from the basal ganglia and the cerebellum via the thalamus. Consistent with this, neurons in the paralaminar part of the ventrolateral (VL), ventroanterior (VA), and mediodorsal (MD) nuclei and those in the intralaminar nuclei exhibit a variety of eye movement-related responses. To date, the thalamocortical pathways are known to play at least 2 roles in eye movements. First, they are involved in the generation of volitional, but not reactive, saccades. Thalamic neurons discharge during anti-saccades, which are known to be impaired in several neurological and psychiatric disorders, such as Parkinson's disease, attention deficit/hyperactivity disorder, and schizophrenia. In addition, neurons in the thalamus also exhibit a gradual increase in firing rate that predicts the timing of self-initiated saccades. Recent inactivation experiments have established the causal roles of these thalamic signals in the generation of volitional saccades. Second, the thalamocortical pathways transmit the efference copy signals for eye movements. During inactivation of the MD thalamus, which relays signals from the superior colliculus to the frontal eye field (FEF), the accuracy of the saccade is reduced in tasks requiring efference copy signals. In addition, inactivation of the same pathways reduces the predictive visual response associated with saccades in neurons in the FEF. Moreover the VL thalamus has been reported to play a role in monitoring smooth pursuit. While the functional analysis of thalamocortical pathways in eye movements is just a beginning, the anatomical data suggest their important roles. Analysis of eye movement control may shed light on the functions of the thalamocortical pathways in general, and may reveal the neural mechanisms of cerebro-cerebellar, cerebro-basal ganglia, and cerebro thalamic interactions. PMID- 21817179 TI - [A new rehabilitation strategy for patients with Parkinson disease: a proposal of mentality-orientated rehabilitation]. AB - Rehabilitation, a treatment strategy that involves group effort with multiple specialists, roles, and facilities, is widely offered to patients in need. The current rehabilitation strategy is mainly disability oriented, and, in principle, starts from the evaluation of motor function and aims to strengthen the deteriorated function/s. Therefore, this method is very effective for patients with acute diseases. However, the effect of such a rehabilitation strategy on gradually progressive neurodegenerative diseases is not well clarified. In particular, Disability-oriented Rehabilitation has not shown an adequate effect in Parkinson disease, which is associated with psychological stress. In this report, we provide an outline of a new rehabilitation strategy and introduce Mentality-oriented Rehabilitation for patients with Parkinson disease. PMID- 21817180 TI - [A 62-year-old woman presenting with progressive nonfluent aphasia, apraxia of eyelid opening, supranuclear gaze palsy, and asymmetric rigidity]. AB - A 62-year-old woman presented with difficulty in speaking and difficulty in opening her eyes. A neurological examination revealed progressive nonfluent aphasia (PNFA), apraxia of eyelid opening, supranuclear vertical gaze palsy, and mild asymmetric rigidity. The diagnosis was difficult to establish because of unusual clinical features, and progressive supranuclear palsy (PSP) was considered. The results from recent studies suggest a positive association between PNFA and a diagnosis of corticobasal degeneration (CBD) or PSP, even in mild parkinsonism cases. The overlapping clinical, genetic, and pathological features of CBD and PSP have also been recently recognized. However, in Japan, there have been few reports evaluating the clinical features of CBD or PSP accompanied by primary progressive aphasia. We report the case of our patient and compare the clinical features of our patient with those of Japanese patients with CBD or PSP accompanied by primary progressive aphasia; moreover we discuss clues that can lead to the correct clinical diagnosis of patients with primary progressive aphasia and parkinsonism comorbidities. PMID- 21817181 TI - [Successful treatment of brain stem and thalamic abscesses with high-dose meropenem]. AB - The incidence of brain abscess remains high, despite the development of novel antibiotics. Vancomycin or carbapenems, which are third-generation cephems, are recommended as standard therapy for bacterial meningitis or brain abscess. The effectiveness of the high-dose meropenem therapy on brain abscess has occasionally been reported. We experienced 2 consecutive cases of brain abscess in adults. The first patient was a 67-year-old man with diplopia, dizziness, and dysesthesia on the left upper and lower extremities. Images of T1-weighted magnetic resonance imaging (MRI) with contrast medium and diffusion-weighted MRI showed a ring enhancing cystic lesion and a high intensity lesion, respectively, in the right pons. The second patient was a 37-year-old man who complained of right hemiparesis. MRI revealed a ring-enhancing cystic mass in the left thalamus. On the basis of MRI findings, patients were diagnosed with brain abscess and were given high-dose meropenem (6g/day) continuously for 2 months. The abscess resolved completely after treatment with meropenem administered intravenously. Further, neurological deficits caused by abscess successfully improved. High-dose meropenem therapy should be considered as an effective treatment for brain abscess, even in the brain stem and basal ganglia, where it is quite difficult to achieve surgical access. PMID- 21817182 TI - [A case of asymptomatic takotsubo cardiomyopathy with intraventricular thrombus associated with epileptic seizure]. AB - A 69-year-old woman was admitted to our department for consciousness disturbance with generalized clonic seizure. She had a history of complex partial seizure with automatism 3 years previously, but had not received any antiepileptic drug therapy. On admission, she was unconscious with a Japan Coma Scale of 200. Physical examination demonstrated a blood pressure of 162/90 mm Hg and pulse of 126 beats/min. Neurological examination did not detect any focal findings. Four hours later, she was conscious and antiepileptic drug therapy was initiated. Twenty-six hours post admission, ECG monitoring showed giant T-wave inversion, but cardiac symptoms were absent. Echocardiography showed apical ballooning of the left ventricle. Echocardiography on day 6 demonstrated a thrombus at the apex of the left ventricle. Anticoagulant therapy was started immediately. Echocardiography on day 14 showed that the left ventricular apical asynergy had completely resolved, and the thrombus had disappeared. Takotsubo cardiomyopathy could be a complication of epilepsy. It occurs most often soon after epileptic seizure, rarely occurs with a time lag and is asymptomatic as in the present case. ECG monitoring after epileptic seizure is useful for prompt detection and treatment of takotsubo cardiomyopathy. PMID- 21817183 TI - Antiviral therapy for hepatitis B infection during pregnancy and breastfeeding. AB - It is estimated there are 350-400 million people worldwide chronically infected with HBV. Many of these are women and of reproductive age. As such, they may face therapeutic decisions regarding antiviral therapy and the implication this may have on future or current pregnancies. This article reviews the data of all antivirals licensed for use against hepatitis B infection regarding teratogenicity, carcinogenicity, clinical experience during pregnancy, placental transfer and excretion in breast milk. PMID- 21817184 TI - Effect of host and viral factors on hepatitis B e antigen-positive chronic hepatitis B patients receiving pegylated interferon-alpha-2a therapy. AB - BACKGROUND: Pegylated interferon (PEG-IFN)-alpha-2a improves the hepatitis B e antigen (HBeAg) seroconversion rate in HBeAg-positive chronic hepatitis B patients. However, baseline factors predicting favourable responses to PEG-IFN alpha-2a remain largely unknown. METHODS: A total of 115 HBeAg-positive chronic hepatitis B patients who had a pre-therapy serum alanine aminotransferase (ALT) level over two times the upper limit of normal and received PEG-IFN-alpha-2a for 6-12 months were consecutively enrolled according to the local reimbursed guidelines. HBeAg seroconversion and combined response defined as HBeAg seroconversion, HBV-DNA level <20,000 IU/ml as well as ALT normalization at 6 months off therapy were primary and secondary therapeutic end points, respectively. Baseline viral factors, including viral load, genotype and major sequences of precore stop codon/basal core promoter (BCP), and host factors, including three single nucleotide polymorphisms among the HLA-DPA1, HLA-DPB1 and IL28B regions, were determined to correlate with therapeutic end points. RESULTS: HBeAg seroconversion and combined response rates were 26.1% and 18.3%, respectively. By multivariate analysis, BCP mutation (OR 8.04, 95% CI 2.00-32.28) and rs3077 G/G genotype (OR 3.49, 95% CI 1.12-10.84) were associated with a higher HBeAg seroconversion rate; BCP mutation (OR 9.28, 95% CI 1.92-44.99) and baseline viral load <2 * 10(6) IU/ml (OR 4.78, 95% CI 1.37-16.69) were associated with a higher combined response rate. CONCLUSIONS: BCP mutation is associated with higher HBeAg seroconversion and combined response rates at 6 months off therapy in HBeAg-positive chronic hepatitis B patients treated with PEG-IFN-alpha 2a. Genetic variants in the HLA-DPA1 region may also affect treatment-induced HBeAg seroconversion. PMID- 21817185 TI - Antihypertensive and metabolic effects of telmisartan in hypertensive HIV positive patients. AB - BACKGROUND: Hypertension is more prevalent among HIV-infected individuals than in the general population and contributes to increased cardiovascular risk. The angiotensin II receptor blocker telmisartan is also a partial peroxisome proliferator activated receptor-gamma agonist with documented effects on glucose and lipid homeostasis. The aim of this study was to evaluate the antihypertensive and metabolic effects of telmisartan in hypertensive HIV-positive patients. METHODS: A total of 18 HIV-positive men treated with antiretroviral therapy and recently diagnosed with hypertension were administered 80 mg telmisartan daily. Systolic blood pressure (SBP) and diastolic blood pressure (DBP), viroimmunological and metabolic parameters, insulin resistance, C-reactive protein, microalbuminuria, cystatin C and plasma levels of interleukin-18 and endothelin-1 were measured at baseline (T0), 1 month (T1), 3 months (T3) and 6 months (T6). RESULTS: Treatment with telmisartan not only decreased SBP and DBP levels, but also improved insulin resistance and microalbuminuria by T1. Levels of triglycerides significantly decreased and high-density lipoprotein cholesterol increased at T1, whereas total and low-density lipoprotein cholesterol levels were statistically reduced at T3 and T6. Cystatin C and endothelin-1 showed a significant reduction at T1, whereas interleukin-18 decreased at both T3 and T6. CONCLUSIONS: Telmisartan was effective in reducing blood pressure and improving lipid metabolism and renal function. Reduction of endothelin-1 might be related to an endothelial protective effect. On the basis of these findings, and because of properties unrelated to blood pressure lowering, telmisartan might be the first choice antihypertensive drug for the treatment of HIV-positive patients. PMID- 21817186 TI - The lopinavir/ritonavir-associated rise in lipids is not related to lopinavir or ritonavir plasma concentration. AB - BACKGROUND: The relationship between lopinavir plasma concentration and the magnitude of lipid elevation after initiation of lopinavir/ritonavir-containing antiretroviral therapy is unclear. The aim of this study was to determine the relationship between drug concentration and lipid changes in two patient cohorts. METHODS: First, we analysed, in an outpatient cohort, the correlation between percentage lipid changes and lopinavir concentration, measured at least 2 weeks or more after initiation of lopinavir/ritonavir. Second, we analysed the correlation between lipid changes and lopinavir and ritonavir plasma concentrations in antiretroviral-naive patients enrolled in a trial comparing nevirapine plus lopinavir/ritonavir (533/133 mg twice daily) with zidovudine/lamivudine plus lopinavir/ritonavir (400/100 mg twice daily). RESULTS: In 82 outpatients with 215 lopinavir plasma measurements, we found no significant correlations between lopinavir concentration and changes in lipids a median of 522 days after lopinavir/ritonavir initiation in univariable regression analyses, nor in multivariable analyses adjusting for potential confounders. In 40 trial samples collected 24 months after treatment initiation, the mean (95% CI) percentage increase in low-density lipoprotein cholesterol (LDLc) was significantly greater in the nevirapine/lopinavir/ritonavir group (29.4% [16.8 43.3]) than in the zidovudine/lamivudine/lopinavir/ritonavir group (6.8% [-7.3 23.1]; P=0.03). However, the percentage LDLc change did not correlate with lopinavir or ritonavir concentration ratios (r=-0.25; P=0.17 and r=-0.06; P=0.75). Adding lopinavir or ritonavir concentrations into the multivariable regression analyses did not change the relation between LDLc change and randomized treatment. CONCLUSIONS: Neither in an HIV outpatient clinic cohort nor in a trial comparing two lopinavir/ritonavir-containing therapies did we find any relation between changes in lipids, and lopinavir and ritonavir concentration, after initiating lopinavir/ritonavir-containing treatment. PMID- 21817187 TI - Inhibition of primary effusion lymphoma engraftment in SCID mice by morpholino oligomers against early lytic genes of Kaposi's sarcoma-associated herpesvirus. AB - BACKGROUND: Kaposi's sarcoma-associated herpesvirus (KSHV) is associated with several malignant diseases, including Kaposi's sarcoma, primary effusion lymphoma (PEL) and multicentric Castleman's disease. The objectives of this study were to investigate the use of peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) against KSHV early lytic genes and to assess their efficacy in severe combined immunodeficiency disease (SCID) mice against PEL engraftment. PPMOs are short, single-stranded DNA analogues that contain a backbone of morpholine rings and phosphorodiamidate linkages and have high delivery efficiency into cells. METHODS: PEL cells were treated with PPMOs against viral interferon regulatory factor 1 (vIRF-1) and expression of vIRF-1 was analysed. PPMOs against vIRF-1 and viral interleukin-6 (vIL-6) were evaluated against PEL cell engraftment in SCID mice. The PPMOs were incubated with BCBL-1 cells and then introduced into the peritoneal cavities of SCID mice, followed by 9 more doses of PPMOs administered at 2-day intervals. At weeks 3 and 9 after BCBL-1 delivery, peritoneal lavage was collected and the ratio of PEL cells among total cells was determined by flow cytometry analysis. RESULTS: Treatment of PEL cells with PPMOs against vIRF-1 led to a reduction of vIRF-1 expression in a dose-dependent manner. Reduction of vIRF 1 expression resulted in higher levels of cellular interferon regulatory factor 3 and of signal transducer and activator of transcription 1. SCID mice receiving a PPMO against vIL-6 had no engraftment of PEL cells and remained healthy throughout the 120-day study. CONCLUSIONS: This study showed that PPMOs can be effective antiviral agents against KSHV. Blocking the expression of early lytic genes might be beneficial for the control of KSHV-associated malignant diseases. PMID- 21817188 TI - Hyaluronic acid levels predict increased risk of non-AIDS death in hepatitis coinfected persons interrupting antiretroviral therapy in the SMART Study. AB - BACKGROUND: In the SMART study, HIV-viral-hepatitis-coinfected persons were, compared with HIV-monoinfected persons, at higher risk of non-AIDS death if randomized to the antiretroviral therapy (ART) interruption strategy. We hypothesized that a marker of liver fibrosis, hyaluronic acid (HA), would be predictive of development of non-AIDS-related outcomes in coinfected participants in the SMART study. METHODS: All participants positive for HCV RNA or hepatitis B surface antigen (HBsAg) and with stored plasma samples were included (n=675). Plasma samples were tested for HA (normal range 0-75 ng/ml) at baseline and months 6, 12 and 24 during follow-up in the drug conservation (DC; interrupt ART until CD4(+) T-cell count <250) group and the viral suppression (VS; continued use of ART) group. Time to non-AIDS death was investigated using Kaplan-Meier analysis. RESULTS: Overall, 52 (31 in DC and 21 in VS) coinfected participants died during follow-up. Coinfected participants who were randomized to the DC group with baseline HA>75 ng/ml had a cumulative risk of non-AIDS death of 24.6% after 36 months of follow-up compared with 9.3% for participants randomized to the VS group (P=0.005), while the cumulative risk for coinfected participants with HA <= 75 ng/ml was 4.1% (DC) and 4.7% (VS; P=0.76). The change in HA from baseline to month 24 was 8.3 ng/ml and 4.7 ng/ml in the DC and VS group (P=0.56), respectively. CONCLUSIONS: Interruption of ART was particularly unsafe in HIV hepatitis-coinfected individuals if plasma HA was increased. HA changed very little during follow-up and was not influenced by differences in CD4(+) T-cell count or HIV viral load. PMID- 21817189 TI - The course of esophageal varices in patients with hepatitis C cirrhosis responding to interferon/ribavirin therapy. AB - BACKGROUND: Gastrointestinal haemorrhage from ruptured esophageal varices (EV) is a significant cause of morbidity and mortality in patients with HCV-related cirrhosis. The risk of developing EV and bleeding is influenced by hepatitis severity, which can be attenuated by successful interferon (IFN) therapy. Our aim was to prospectively assess whether a successful IFN therapy modifies development and/or progression of EV in patients with HCV-related compensated cirrhosis. METHODS: Child-Pugh A patients with either no or small (F1) EV underwent surveillance with repeated endoscopy during and after completion of IFN-based therapy. RESULTS: A total of 127 patients (59 years, 79 males, 65 HCV-1/4 and 17 F1 EV) received weight-based ribavirin (RBV) combined with either IFN-alpha2b 3 MU three times per week (n=36), weekly pegylated (PEG)-IFN-alpha2b 1.5 MUg/kg (n=68) or weekly PEG-IFN-alpha2a 180 MUg (n=23). Patients were followed-up for 18 108 months after treatment completion with a median endoscopic follow-up of 68 months for the 62 patients with a sustained virological response (SVR) and 57 months for the 65 non-SVR patients (P=0.3). De novo EV developed in 10 (9.1%) patients including 2/57 SVR and 8/53 non-SVR (3.5% versus 15.1%; P=0.047), whereas EV progressed in size in 3 patients, including 1/5 SVR and 2/12 non-SVR (P=0.87). Two non-SVR patients bled from EV and one died. CONCLUSIONS: A successful IFN therapy prevents or delays the de novo onset of EV in patients with compensated cirrhosis due to HCV, but does not abrogate the need for continued endoscopic surveillance. PMID- 21817190 TI - Relationship between polymorphisms of the inosine triphosphatase gene and anaemia or outcome after treatment with pegylated interferon and ribavirin. AB - BACKGROUND: A genome-wide association study revealed an association between variants of the inosine triphosphatase (ITPA) gene and ribavirin (RBV)-induced anaemia. The aim of this study was to replicate this finding in an independent Japanese cohort and to define a method to allow pretreatment prediction of anaemia in combination with other factors. METHODS: Genotype 1b chronic hepatitis C patients (n=132) treated with pegylated interferon (PEG-IFN)-alpha and RBV for 48 weeks were genotyped for ITPA rs1127354 and examined for anaemia and treatment outcome. RESULTS: Variants of the ITPA gene protected against severe anaemia throughout the 48-week treatment period and were associated with lower incidence of anaemia-related RBV dose reduction. A combination of the ITPA genotype with baseline haemoglobin (Hb) and creatinine clearance (CLcr) levels predicted severe anaemia with high accuracy (90% sensitivity and 62% specificity). Among a subset of patients with the IL28B genotype of TT at rs8099917, patients with variants of the ITPA gene were associated with a higher rate of receiving >80% of the expected RBV dose, a higher rate of sustained virological response (SVR), and a lower rate of relapse. CONCLUSIONS: The variants of the ITPA gene, which could protect against haemolytic anaemia and RBV dose reduction, were associated with a high rate of SVR by standard PEG-IFN and RBV therapy in a subset of Japanese patients with the favourable TT genotype at rs8099917 of IL28B. A combination of ITPA genetic polymorphisms with baseline Hb and CLcr levels further improves the predictive accuracy of severe anaemia. PMID- 21817191 TI - Impact of ribavirin on HCV replicon RNA decline during treatment with interferon alpha and the protease inhibitors boceprevir or telaprevir. AB - BACKGROUND: Ribavirin increases early and sustained virological response rates in patients chronically infected with HCV who receive pegylated interferon-alpha and novel HCV protease inhibitors. METHODS: To better characterize antiviral efficacies of these upcoming therapies, Huh7 cells harbouring a subgenomic HCV replicon system were cultivated with various doses and combinations of ribavirin, interferon-alpha, and the protease inhibitors boceprevir and telaprevir. Antiviral efficacy parameters were estimated from HCV RNA decay, and synergistic effects of combination therapies were analysed with the Bliss independency model. RESULTS: Single-drug antiviral activities showed dose-dependent HCV RNA reductions in replicon cells (50% inhibitory concentration of 386.16 MUM, 81.67 IU, 0.44 MUM and 0.81 MUM after 48 h for ribavirin, interferon-alpha, boceprevir and telaprevir, respectively). For the dual combination of ribavirin with either boceprevir or telaprevir, no deviation from additivity was observed whereas the reduction of HCV RNA was synergistic for ribavirin with interferon-alpha (P<0.001). Triple combinations with ribavirin, interferon-alpha and protease inhibitors showed the most profound HCV RNA decay. CONCLUSIONS: The beneficial in vitro antiviral effect of ribavirin with interferon-alpha and novel HCV protease inhibitors demonstrates that ribavirin may be required as an antiviral backbone in the near future. PMID- 21817192 TI - Development of a chimeric replicon system for phenotypic analysis of NS3 protease sequences from HCV clinical isolates. AB - BACKGROUND: To support clinical development of HCV non-structural protein (NS) 3 protease inhibitors (PIs), phenotypic monitoring of patient isolates is a prerequisite for understanding the emergence of resistance. HCV isolates typically fail to replicate in cell culture, necessitating the use of alternative phenotyping methods. METHODS: An NS3 protease chimeric replicon system was developed to monitor the phenotype of clinical isolates. The transfer of NS3 protease domain sequences from HCV-infected patients to the background of genotype (Gt) 1a-H77c, 1b-Con1 and 2a-JFH-1 lab strain replicons adapted to high level cell culture replication was investigated. RESULTS: NS3 protease sequences derived from HCV Gt 1a or Gt 1b infected patients were transferred into Gt 1a and 1b replicons, respectively. Replication was detected for 20% of Gt 1a and 75% of Gt 1b sequences. Incorporation of known cell culture adaptive change NS3-E176G improved replication of Gt 1b but not of Gt 1a sequences. Transfer of Gt 1a clinical sequences into the Gt 1b background enhanced replication and allowed phenotypic analysis of all sequences. A correlation was observed between clinical isolate sequence polymorphisms and reduced susceptibility to NS3 PI. In mixed populations containing known NS3 PI resistance changes NS3-R155K or D168E/V, sensitivity of resistance detection was >= 10%. CONCLUSIONS: An HCV replicon capable of supporting phenotypic characterization of patient-derived HCV NS3 protease sequences was developed. Pre-existence of amino acid changes associated with NS3 PI resistance highlights the need for combination therapies in the treatment of HCV. PMID- 21817193 TI - Mitochondrial assessment in asymptomatic HIV-infected paediatric patients on HAART. AB - BACKGROUND: HAART can cause mitochondrial DNA (mtDNA) depletion, which may lead to mitochondrial dysfunction. We aimed to determine whether mtDNA and mitochondrial function abnormalities are present in peripheral blood mononuclear cells from asymptomatic HIV-infected children. METHODS: A cross-sectional study in peripheral blood mononuclear cells was performed in 47 asymptomatic (free from any HIV- or AIDS-related active condition or HAART-related toxicity), HIV infected, HAART-treated children and adolescents and 27 uninfected healthy paediatric patients. We measured mtDNA and mitochondrial RNA (mtRNA) content by quantitative real-time PCR. Mitochondrial respiratory chain enzymatic activity of complex-IV (CIV) and mitochondrial mass (estimated by citrate synthase) were measured spectrophotometrically, and CIV protein subunit content was measured with western blot analysis. RESULTS: A reduction in mtDNA levels was observed in HIV-infected children compared with controls (mean +/- sem 4.47 +/- 0.31 and 5.82 +/- 0.48, respectively; 23% depletion; P=0.018), whereas similar levels of mtRNA, CIV protein subunit content and enzymatic activity were found in the two groups. These findings remained unaltered after considering mitochondrial abundance. Among HIV-infected children, mtDNA levels did not correlate with viral load, CD4(+) T-cell counts or lactataemia at the time of assessment. No differences were observed when current or past use of individual antiretroviral drugs or HAART regimens were taken into account. CONCLUSIONS: Depletion in mtDNA from asymptomatic HIV-infected children did not lead to differences in mtRNA levels or mitochondrially-encoded CIV proteins, nor to CIV dysfunction. This may be explained by homeostatic-compensatory mechanisms at the transcription level or by the mild depletion we observed. PMID- 21817194 TI - Single genome sequencing of HIV-1 gag and protease resistance mutations at virologic failure during the OK04 trial of simplified versus standard maintenance therapy. AB - BACKGROUND: Ritonavir-boosted lopinavir (LPV/RTV) alone has been evaluated as simplified maintenance therapy for HIV-1 infection, but there are concerns about greater potential for emergence of protease inhibitor (PI) resistance. The OK04 trial evaluated maintenance therapy with LPV/RTV alone versus standard therapy (ST) with two NRTIs plus LPV/RTV in 205 patients, of whom 15 had virological rebound by week 48 (11 versus 4 patients, respectively). We developed a single genome sequencing (SGS) assay of HIV-1 gag and protease to assess the emergence of low frequency drug-resistant variants during virological rebound. METHODS: Plasma samples from 15 subjects at virological rebound were analysed by SGS of HIV-1 gag and protease genes. A total of 45 SGS sequences were planned per sample, providing 90% power to detect variants comprising >5% of the virus population. RESULTS: Overall, 521 single sequences obtained from 13 patients (range 4-48 sequences/patient) revealed similar frequencies of major protease resistance mutations in samples from the LPV/RTV alone (3/11) and ST (3/4) arms (P=0.10), with a median number of minor protease resistance mutations of 3.0 versus 3.5, respectively (P=0.23). Median number of gag PI resistance mutations were similar between the LPV/RTV alone and ST arms at cleavage sites (3.0 versus 2.5; P=0.83), non-cleavage sites (21 versus 16.5; P=0.71) and the transframe protein-p6 pol region cleavage sites (4.0 versus 3.0; P=0.6). CONCLUSIONS: Although more subjects with simplified maintenance therapy with LPV/RTV alone had virological rebound compared to the ST arm, this was not associated with more frequent emergence of variants encoding PI resistance mutations in gag or protease detected by SGS. PMID- 21817195 TI - Single-centre experience with oral ribavirin in lung transplant recipients with paramyxovirus infections. AB - BACKGROUND: Paramyxovirus (PV) infections are increasingly recognized in lung transplant recipients and have been linked to subsequent graft failure and bronchiolitis obliterans syndrome (BOS). Ribavirin represents a possible treatment option although the outcome on graft function and BOS incidence is unknown. METHODS: We analysed outcomes of all PV infections in lung/heart-lung recipients between September 2006 and April 2009 in a single centre. PV-infected recipients treated with oral ribavirin were compared with those unable to receive ribavirin due to contraindications. Recovery of graft function, time to recovery and new development of BOS were compared. RESULTS: A total of 38 patients (ribavirin group) were treated with ribavirin for a median of 9 days (IQR 8-12), whilst 29 patients (non-ribavirin group) received best supportive care including corticosteroids. The median forced expiratory volume in 1 s dropped 20% (IQR 15 32) from baseline in the ribavirin group versus 18% (IQR 13-30) in the non ribavirin group during infection. In 84% of patients treated with ribavirin and 59% of the non-ribavirin group, graft function recovered within 30 days (P=0.02). New onset of BOS developed within 6 months in 5% of the ribavirin group versus 24% of the non-ribavirin group (P=0.02). CONCLUSIONS: Treatment of PV after lung/heart-lung transplantation with oral ribavirin seems to be associated with earlier recovery of graft function and to prevent BOS. PMID- 21817196 TI - Argonaute-2 enhances suppression of human cytomegalovirus replication by polycistronic short hairpin RNAs targeting UL46, UL70 and UL122. AB - BACKGROUND: Human cytomegalovirus (HCMV) is a common human pathogen that causes significant morbidity and mortality. The efficacy of anti-HCMV drugs such as ganciclovir, foscarnet and cidofovir is limited because of drug toxicities and frequent development of resistance. Here, we report an alternative anti-HCMV method using RNA silencing. METHODS: Combinatorial use of second-generation short hairpin RNAs (shRNA-miRs) targeting various transcripts of HCMV and an RNA silencing endonuclease Argonaute-2 (Ago2) expression vector were applied to inhibit replication of HCMV AD169. Normal human fetal lung MRC-5 fibroblasts were transfected with pSM30-shRNA-miRs harbouring single or multiple shRNA-miR cassettes with or without Ago2 and then infected with HCMV AD169. Production of small interfering RNA (siRNA) was quantified by reverse transcription PCR. Virus secretion was evaluated by plaque reduction assays. RESULTS: The use of shRNA miRs targeting a single HCMV gene suppressed HCMV AD169 viral titres by 50-70%. Polycistronic shRNA-miRs targeting UL46+UL122 and UL70+UL46+UL122 reached nearly 80% of inhibition. Coexpression of Ago2 with shRNA-miRs targeting UL46+UL122 and UL70+UL46+UL122 achieved a 95% reduction in viral maturation. CONCLUSIONS: Coexpression of Ago2 with shRNA-miRs enhanced the production of mature siRNAs and increased the efficiency of RNA silencing in the suppression of HCMV replication. This strategy may be universally applied to RNA interference-based therapies. PMID- 21817197 TI - Delivery with polycations extends the immunostimulant Ribomunyl into a potent antiviral Toll-like receptor 7/8 agonist. AB - BACKGROUND: Upper respiratory tract infection is a frequent cause of morbidity worldwide. Although the course of infection is usually mild, it is responsible for enormous social and economic costs. Immunostimulation with bacterial extracts consisting of ribosomal RNA and proteoglycans, such as Ribomunyl, was introduced into the clinic in the 1980s as a new treatment concept, but did not achieve widespread application. Ribomunyl has been proposed to activate innate immunity, but the contribution of its RNA content as well as its antiviral potential has not been studied. METHODS: Peripheral blood mononuclear cells from healthy donors and immune cells from adenoids were incubated with Ribomunyl either by itself or formulated in a complex with cationic polypeptides such as poly-l-arginine or protamine, and induction of cytokines was quantified by ELISA. RESULTS: Ribomunyl in complex with either poly-l-arginine or protamine, but not on its own, was able to strongly induce interferon-alpha (P<0.01) and interleukin-12 (P<0.01) in peripheral blood mononuclear cells, whereas induced tumour necrosis factor-alpha and interleukin-6 levels were independent of the formulation. Comparable results were obtained in immune cells from adenoids, suggesting efficacy also in virus affected tissue. Cell sorting, RNase digests and selective receptor expression show that the RNA in Ribomunyl acts as an agonist of Toll-like receptor (TLR)7 and TLR8. CONCLUSIONS: Ribomunyl is, in principle, able to potently induce antiviral interferon-alpha and interleukin-12 via TLR7 and TLR8, respectively, but only when formulated in a complex with cationic polypeptides. PMID- 21817198 TI - Efficacy and safety of nevirapine extended-release once daily versus nevirapine immediate-release twice-daily in treatment-naive HIV-1-infected patients. AB - BACKGROUND: This study (VERxVE) compared the efficacy and safety of the new nevirapine extended-release (NVP XR) formulation dosed once daily with NVP immediate release (IR) twice daily in treatment-naive patients. METHODS: Randomized, double-blind, double-dummy, parallel group study of HIV-1-infected adult patients with baseline viral load (VL) >= 1,000 copies/ml and CD4(+) T-cell count of >50-<400 (males) and >50-<250 cells/mm(3) (females). Patients stratified by baseline VL (<= 100,000/>100,000 copies/ml) were randomized 1:1 to NVP XR 400 mg once daily (plus placebo) or NVP IR 200 mg twice daily (plus placebo), both combined with tenofovir disoproxil fumarate (TDF) 300 mg and emtricitabine 200 mg once daily. Primary endpoint was sustained virological response (<50 copies/ml) through week 48 using the time to loss of virological response algorithm. Non inferiority of NVP XR to NVP IR was tested using Cochran's statistic incorporating baseline VL stratum with pre-specified, non-inferiority margin of 10%. RESULTS: Among 1,011 patients randomized and treated, virological response at week 48 was 81.0% (409/505) for NVP XR and 75.9% (384/506) for NVP IR with adjusted difference of 4.9% in favour of NVP XR (95% CI -0.1-10.0%), demonstrating non-inferiority of NVP XR to NVP IR. This finding was supported by secondary endpoints. The safety profile of NVP XR was similar to NVP IR, but showed numerically fewer treatment-related adverse events. CONCLUSIONS: NVP XR in combination with TDF and emtricitabine was shown to be non-inferior in efficacy to NVP IR with a similar safety and adverse event profile, with the potential for the added convenience of once-daily dosing. TRIAL REGISTRATION: ClinicalTrials (NCT): NCT00561925. PMID- 21817199 TI - Discordance between HCV RNA assays for week 24 HCV RNA determination during pegylated interferon-alpha/ribavirin treatment for chronic hepatitis C. AB - BACKGROUND: The development of more sensitive HCV RNA assays might necessitate re evaluation of the rules for stopping treatment (for example, HCV RNA negativity at week 24 during treatment with pegylated interferon-alpha and ribavirin for chronic hepatitis C). The aim of this study was to assess discordance between the week 24 HCV RNA test results of two PCR-based assays (Amplicor and TaqMan) and the transcription-mediated amplification (TMA) HCV RNA qualitative assay. METHODS: A total of 89 week 24 samples that were negative using PCR-based assays during treatment were retested with the TMA qualitative assay to investigate discordance between tests results. All week 24 samples were HCV RNA negative by Amplicor or by TaqMan. RESULTS: Of the 89 patients, 46 (52%) achieved sustained virological response (SVR). Viral breakthrough or relapse occurred in 43 patients (48%). All 89 HCV RNA negative week 24 samples were retested with the qualitative TMA assay. Eleven out of 89 samples had detectable HCV RNA (12%). All patients with detectable HCV RNA experienced breakthrough or relapse (negative predictive value 100%). Of the 78 patients with undetectable HCV RNA at week 24 using the TMA assay, 46 achieved SVR. This resulted in a positive predictive value (PPV) of 59% for the TMA assay compared with a PPV of 52% for the PCR-based assays. CONCLUSIONS: All patients with detectable HCV RNA at week 24 using the TMA assay eventually relapsed. On the basis of these results, the use of this more sensitive HCV RNA assay could lead to the prevention of unnecessary treatment. PMID- 21817200 TI - Reduced airborne transmission of oseltamivir-resistant pandemic A/H1N1 virus in ferrets. AB - BACKGROUND: The H275Y neuraminidase mutation conferring oseltamivir resistance has been reported in several pandemic A/H1N1 (pH1N1) isolates. We sought to evaluate transmission of this mutant virus through the direct contact and the airborne (aerosol and droplet) routes in the ferret model. METHODS: Groups of four ferrets were infected with either wild-type (WT) or oseltamivir-resistant pH1N1 (H275Y) strains. At 24 h following viral infection, a receptive ferret was introduced in the same cage as the infected animal to assess direct contact transmission. For the airborne transmission, naive ferrets were placed in a modified separate cage adjacent to that of their respective index ferret. RESULTS: The H275Y mutant virus was as efficiently transmitted as the WT strain by direct contact, as 100% (4/4) of contact ferrets in both groups seroconverted and shed virus. Mean peak viral titres were similar in both groups (4 * 10(4) and 2.63 * 10(4) plaque-forming units/ml after WT or H275Y mutant virus transmission, respectively). Peak viral shedding occurred on day 2 post-contact for the WT group and on day 4 post-contact for the H275Y mutant group. By contrast, airborne transmission of the mutant strain was less efficient, as only 25% (1/4) of contact ferrets seroconverted and shed virus, whereas 100% (4/4) of the WT ferrets did. Peak of viral replication was delayed compared to direct contact transmission and occurred on day 4 post-contact. CONCLUSIONS: Transmission of the H275Y pH1N1 mutant strain by the airborne route is somewhat compromised, which may limit its widespread dissemination. PMID- 21817202 TI - Exact mapping of the d(x(2)-y(2)) Cooper-pair wavefunction onto the spin fluctuations in cuprates: the Fermi surface as a driver for 'high T(c)' superconductivity. AB - We propose that the extraordinarily high superconducting transition temperatures in the cuprates are driven by an exact mapping of the d(x(2)-y(2)) Cooper-pair wavefunction onto the incommensurate spin fluctuations observed in neutron scattering experiments. This is manifested in the direct correspondence between the inverse of the incommensurability factor delta seen in inelastic neutron scattering experiments and the measured superconducting coherence length xi(0). Strikingly, the relationship between xi(0) and delta is valid for both La(2 x)Sr(x)CuO(4) and YBa(2)Cu(3)O(7-x), suggesting a common mechanism for superconductivity across the entire hole-doped cuprate family. Using data from recent quantum-oscillation experiments in the cuprates, we propose that the fluctuations responsible for superconductivity are driven by a Fermi-surface instability. On the basis of these findings, one can specify the optimal characteristics of a solid that will exhibit 'high T(c)' superconductivity. PMID- 21817201 TI - Predictors of having a resistance test following confirmed virological failure of combination antiretroviral therapy: data from EuroSIDA. AB - BACKGROUND: Guidelines suggest that patients on continuous antiretroviral therapy for >4 months with current viral load (VL)>1,000 copies/ml should be tested for resistance. There are limited data showing the frequency of resistance testing in routine clinical practice following these recommendations. METHODS: In EuroSIDA, virological failure (VF) was defined as confirmed VL>1,000 copies/ml after >= 4 months continuous use of any antiretroviral in a >= 3-drug regimen started during or after 2002. We assessed whether a resistance test was performed around VF (from 4 months before to 1 year after VF) and used logistic regression analysis to assess factors associated with having a resistance test. RESULTS: A total of 1,090 patients experienced VF a median 8.1 months (range 4 months to 6.3 years) after starting their regimen. There were 395 (36.2%; 95% CI 33.4-39.1) patients with a resistance test around the time of VF. Predictors of having a resistance test following VF include availability of a resistance test earlier than 4 months before VF (OR 2.20, 95% CI 1.77-2.75 for yes versus no; P<0.0001), region (OR 0.29, 95% CI 0.14-0.62 for Eastern Europe versus Northern Europe and OR 0.64, 95% CI 0.48-0.85 for Southern Europe versus Northern Europe; global P=0.0006) and current calendar year (OR 0.45, 95% CI 0.30-0.68 for >= 2007 versus 2004; global P=0.003). CONCLUSIONS: This analysis suggests a delay in genotypic testing after VF that seems longer than expected given current treatment guidelines. This delay is highly variable across Europe. PMID- 21817203 TI - High quality single crystals of the SrR(2)O(4) family of frustrated magnets. AB - Large high quality single crystals of several compounds of the new family of frustrated magnetic oxides SrR(2)O(4) where R = Dy, Er, Ho and their nonmagnetic analogues with R = Lu, Y have been synthesized by the floating zone technique. The magnetic rare earth ions in these compounds are linked to each other through a network of hexagons and triangles reminiscent of the honeycomb lattice. Initial characterization measurements show that geometrical frustration plays an important role in the formation of the magnetic ground states in these systems. The single crystals grown are suitable for more detailed investigations, especially those using neutron scattering techniques. PMID- 21817204 TI - Structural stability and decomposition of Mg(BH(4))(2) isomorphs-an ab initio free energy study. AB - We present the first comprehensive comparison between free energies, based on a phonon dispersion calculation within density functional theory, of theoretically predicted structures and the experimentally proposed alpha (P6(1)) and beta (Fddd) phases of the promising hydrogen storage material Mg(BH(4))(2). The recently proposed low-density [Formula: see text] ground state is found to be thermodynamically unstable, with soft acoustic phonon modes at the Brillouin zone boundary. We show that such acoustic instabilities can be detected by a macroscopic distortion of the unit cell. Following the atomic displacements of the unstable modes, we have obtained a new F 222 structure, which has a lower energy than all previously experimentally and theoretically proposed phases of Mg(BH(4))(2) and is free of imaginary eigenmodes. A new meta-stable high-density I4(1)/amd structure is also derived from the [Formula: see text] phase. Temperatures for the decomposition are found to be in the range of 400-470 K and largely independent of the structural complexity, as long as the primary cation coordination polyhedra are properly represented. This opens a possibility of using simple model structures for screening and prediction of finite temperature stability and decomposition temperatures of novel borohydride systems. PMID- 21817205 TI - 1.53 um photo- and electroluminescence from Er(3+) in erbium silicate. AB - Si-rich silicon oxide (SRO)/Er-Si-O/SRO multilayers were prepared on p-Si substrates using magnetron sputtering. X-ray diffraction measurements indicate that a mixture of silicates Er(2)Si(2)O(7) and Er(2)SiO(5) was formed after the multilayers were annealed at 1000 and 1150 degrees C. Strong Er(3+) 1.53 um photoluminescence (PL) at room temperature has been observed from these multilayers and the full width at half-maximum of the 1.53 um peak is less than 1.8 nm for the multilayers annealed at 1150 degrees C. Er(3+) 1.53 um electroluminescence has been observed from erbium silicate films for the first time. PMID- 21817206 TI - Observation of the room temperature magnetoelectric effect in Dy doped BiFeO(3). AB - Polycrystalline Bi(1-x)Dy(x)FeO(3) (x = 0.0, 0.03, 0.05, 0.07 and 0.1) ceramics have been prepared via a mixed oxide route. The effect of Dy substitution on the dielectric, ferroelectric, and magnetic properties of the BiFeO(3) multiferroic perovskite is studied. Experimental results suggest that in the Bi(1 x)Dy(x)FeO(3) system, increase of the Dy concentration leads to effective suppression of the spiral spin structure of BiFeO(3), resulting in the appearance of net magnetization. An anomaly in the dielectric constant (epsilon) was observed in the vicinity of the antiferromagnetic transition temperature. All compositions show saturated polarization-field (P-E) curves. As a result, improved multiferroic properties of Bi(0.9)Dy(0.1)FeO(3) ceramics with remnant polarization and magnetization (2P(r) and 2M(r)) of 7.98 uC cm(-2) and 0.024 emu g(-1), respectively, were established. An enhancement in remnant polarization after poling the samples in the magnetic field was evidence of magnetoelectric coupling at room temperature. PMID- 21817207 TI - Theoretical investigation of Hf and Zr defects in c-Ge. AB - The introduction of high-permittivity gate dielectric materials into complementary metal oxide semiconductor technology has reopened the interest in Ge as a channel material mainly due to its high hole mobility. Since HfO(2) and ZrO(2) are two of the most promising dielectric candidates, it is important to investigate if Hf and Zr may diffuse into the Ge channel. Therefore, using ab initio density functional theory calculations, we have studied substitutional and interstitial Hf and Zr impurities in c-Ge,looking for neutral defects. We find that (i) substitutional Zr and Hf defects are energetically more favorable than interstitial defects; (ii) under oxygen-rich conditions, neither Zr nor Hf migration towards the channel is likely to occur; (iii) either under Hf- or Zr rich conditions it is very likely, particularly for Zr, that defects will be incorporated in the channel. PMID- 21817208 TI - Statistical switching kinetics of ferroelectrics. AB - By assuming a more realistic nucleation and polarization reversal scenario we build a statistical switching model for polycrystalline ferroelectrics, which is different from both the Kolmogorov-Avrami-Ishibashi (KAI) model and the nucleation-limited-switching model. After incorporating a time-dependent depolarization field, this model gives a good explanation of the retardation behavior in polycrystalline thin films at medium or low fields, which cannot be described using the traditional KAI model. This model predicts n = 1 for polycrystalline thin films at high fields or ceramic bulks in the ideal case, in good agreement with the experimental data previously published. PMID- 21817209 TI - Superconductivity up to 29 K in SrFe(2)As(2) and BaFe(2)As(2) at high pressures. AB - We report the discovery of superconductivity at high pressure in SrFe(2)As(2) and BaFe(2)As(2). The superconducting transition temperatures are up to 27 K in SrFe(2)As(2) and 29 K in BaFe(2)As(2), the highest obtained for materials with pressure-induced superconductivity thus far. PMID- 21817210 TI - Elementary structural building blocks encountered in silicon surface reconstructions. AB - Driven by the reduction of dangling bonds and the minimization of surface stress, reconstruction of silicon surfaces leads to a striking diversity of outcomes. Despite this variety even very elaborate structures are generally comprised of a small number of structural building blocks. We here identify important elementary building blocks and discuss their integration into the structural models as well as their impact on the electronic structure of the surface. PMID- 21817211 TI - Vicinal surfaces for functional nanostructures. AB - Vicinal surfaces are currently the focus of research. The regular arrangements of atomic steps on a mesoscopic scale reveal the possibility to functionalize these surfaces for technical applications, e.g. nanowires, catalysts, etc. The steps of the vicinal surface are well-defined defect structures of atomic size for nucleation of low-dimensional nanostructures. The concentration and therefore the coupling between the nanostructures can be tuned over a wide range by simply changing the inclination angle of the substrate. However, the coupling of these nano-objects to the substrate is just as important in controlling their electronic or chemical properties and making a functionality useable. On the basis of stepped insulating films, these aspects are fulfilled and will be considered in the first part of this review. Recent results for the epitaxial growth of wide bandgap insulating films (CaF(2), MgO, NaCl, BaSrO) on metallic and semiconducting vicinal substrates (Si(100), Ge(100), Ag(100)) will be presented. The change of the electronic structure, the adsorption behavior as well as the kinetics and energetics of color centers in the presence of steps is discussed. The successful bridging of the gap between the atomic and mesoscopic world, i.e. the functionalization of vicinal surfaces by nanostructures, is demonstrated in the second part by metal adsorption on semiconducting surfaces. For (sub)monolayer coverage these systems have in common that the surface states do not hybridize with the support, i.e. the semiconducting surfaces are insulating. Here I will focus on the latest results of macroscopic transport measurements on Pb quantum wires grown on vicinal Si(111) showing indeed a one dimensional transport behavior. PMID- 21817212 TI - Surface-sensitive conductance measurements. AB - Several approaches for surface-sensitive conductance measurements are reviewed. Particular emphasis is placed on nanoscale multi-point probe techniques. The results for two model systems, which have given rise to some dispute, are discussed in detail: Si(111)(7 * 7) and ([Formula: see text])Ag-Si(111). Other recent examples are also given, such as phase transitions in quasi-one dimensional structures on semiconductor surfaces and the surface sheet conductivity of Bi(111), the surface of a semimetal. PMID- 21817213 TI - An ab initio study of the magnetic-metallic CoPt(3)-Au interfaces. AB - The new challenging field of fabrication and interconnection of inorganic nanostructures is giving new impetus to the study of solid-solid interfacial properties. In nanocrystals made of two domains of different chemical composition and sharing an interface, the interfacial behavior is indeed critical for the stability of such an interface, and also in determining the mutual interactions of the two domains. Following a recent study by our group on the growth of colloidal nanocrystal heterodimers made of a domain of Au and a domain of CoPt(3), we report here an ab initio density functional theory study of the structural and electronic properties of Au/CoPt(3) interfaces. We have investigated the structure of different bulk CoPt(3) facets and of Au atoms adsorbed on CoPt(3). We calculated CoPt(3) and Au surface energies, Au/CoPt(3) interfacial energies as well as adsorption energies of Au atoms on CoPt(3) and Au, and we can draw some important conclusions about the growth mechanism of gold on the magnetic alloy. Furthermore, we give here a detailed description of surface and interfacial electronic properties, which in turn determine the possibility of tuning conductivity and magnetic properties in the nanostructure. PMID- 21817214 TI - Formation of a coplanar O-Al bonding cluster: the effect of O impurity on a Sigma = 5 NiAl grain boundary from first-principles. AB - The site occupancy, structure, and bonding properties of O in an NiAl grain boundary (GB) have been investigated by employing a first-principles total energy method based on density functional theory with the generalized gradient approximation and ultrasoft pseudopotential. The Sigma5(310)/[001] tilt GB of NiAl has been chosen because (i) the Sigma = 5 GB has been observed to be a higher fraction in NiAl experimentally, and (ii) the Sigma5(310)/[001] is energetically favorable in comparison with the Sigma5(210)/[001]. The NiAl GB is shown to favor the O segregation with a segregation energy of -1.75 eV, indicating that most of the O impurity will distribute in the NiAl GB thermodynamically. Moreover, O is shown to prefer occupying the interstitial sites rather than the substitutional sites in the GB according to the calculated formation energies. The O-Al bond is energetically favorable as compared with the O-Ni bond due to different electronegativity of Al and Ni in reference to O. Charge distribution and the density of states further indicate the intrinsic bonding properties of O-Al that contain obvious covalent characteristics. It is interesting to find that O is coplanar with the surrounding Al atoms in both interstitial and substitutional cases with lower formation energies, forming stronger coplanar O-Al bonding clusters. Such stronger bonding clusters in the GB can embrittle the NiAl intermetallics and thus are not beneficial to the plasticity of NiAl. Our results will provide a useful reference for improving the mechanical properties and for understanding the oxidation effect of the NiAl intermetallics. PMID- 21817215 TI - Interfacial separation between elastic solids with randomly rough surfaces: comparison of experiment with theory. AB - We study the average separation between an elastic solid and a hard solid, with a nominally flat but randomly rough surface, as a function of the squeezing pressure. We present experimental results for a silicon rubber (PDMS) block with a flat surface squeezed against an asphalt road surface. The theory shows that an effective repulsive pressure acts between the surfaces of the form p~exp( u/u(0)), where u is the average separation between the surfaces and u(0) a constant of the order of the root-mean-square roughness, in good agreement with the experimental results. PMID- 21817216 TI - Directional photoelectric current across the bilayer graphene junction. AB - A directional photon-assisted resonant chiral tunneling through a bilayer graphene barrier is considered. An external electromagnetic field applied to the barrier switches the transparency T in the longitudinal direction from its steady state value T = 0 to the ideal T = 1 at no energy costs. The switch happens because the ac field affects the phase correlation between the electrons and holes inside the graphene barrier, changing the whole angular dependence of the chiral tunneling (directional photoelectric effect). The suggested phenomena can be implemented in relevant experiments and in various sub-millimeter and far infrared optical electronic devices. PMID- 21817217 TI - Effect of external electric field on the charge density waves in one-dimensional Hubbard superlattices. AB - We have studied the ground state of one-dimensional Hubbard superlattice structures with different unit-cell sizes in the presence of an electric field. A self-consistent Hartree-Fock approximation calculation is done in the weak- to intermediate-interaction regime. Studying the charge gap at the Fermi level and the charge density structure factor, we get an idea of how the charge modulation on the superlattice is governed by the competition between the electronic correlation and the external electric field. PMID- 21817218 TI - Resonance and phase shift in an open Aharonov-Bohm ring with an embedded quantum dot. AB - The transmission and phase properties of electron transport through a quantum dot (QD) with variable coupling to a third-terminal probe are investigated analytically for the case of the QD connected directly to source and drain reservoirs and when the QD is embedded in one arm of an Aharonov-Bohm (AB) ring. Using the tight-binding model, explicit analytical expressions of the transmission through the QD for each case are given. Expressions for the conductance with coupling to the third terminal, which breaks unitarity and phase locking, are also given. It is shown that in a three-terminal interferometer the zero of the Fano resonance in the transmission moves off the real energy axis for finite values of the coupling parameter. The zero orbits around the pole in the complex energy plane as a function of magnetic flux through the ring, and can be returned to the real energy axis unless the coupling parameter exceeds a critical value. With the QD embedded in one arm of the AB ring, the electron transmission and the transmission phase, and the phase of the AB oscillations, are described in relation to the degree of coupling to the third-terminal probe which opens the interferometer. By tuning the degree of coupling to the probe, it is shown that the phase of the AB oscillations can be made to match the intrinsic phase of the QD, facilitating experimental characterization of the phase response of the QD. PMID- 21817219 TI - Principal thermodynamic properties of quasi-two-dimensional carriers under in plane magnetic field. AB - An external magnetic field, H, applied parallel to a quasi-two-dimensional carrier system modifies quantitatively and qualitatively the density of states. We examine how this affects primary thermodynamic properties, namely, the entropy, S, the internal and free energy, U and F, the magnetization, M, and the magnetic susceptibility, chi(m), using a self-consistent numerical approach. Although M is mainly in the opposite direction to H, the system is not linear. Hence, surprisingly, [Formula: see text] swings between negative and positive values, i.e. a diamagnetic to paramagnetic transition of entirely orbital origin is predicted. This phenomenon is important compared to the ideal de Haas-van Alphen effect, i.e. the corresponding phenomenon under perpendicular magnetic field. By augmenting temperature, the diamagnetic to paramagnetic transition fades away. The overall behaviour of entropy is also foreseen and consistently interpreted. While the entropy contribution to the free energy is very small at low temperatures, entropy shows a clear dependence on the external magnetic field. PMID- 21817220 TI - The effect of Mg doping on the structural and physical properties of LuFe(2)O(4) and Lu(2)Fe(3)O(7). AB - The structural and physical properties of the recently discovered electronic ferroelectric materials LuFe(2)O(4) and Lu(2)Fe(3)O(7) have been investigated for Mg substitution of Fe. X-ray diffraction data demonstrate that the lattice parameters in both systems change progressively with increasing Mg content, with a smaller unit cell volume on replacing Fe(2+) by Mg(2+). X-ray absorption near edge spectroscopy experiments at the Fe K-edge show that the average Fe oxidation state is slightly increased along with Mg doping in Lu(2)Fe(3)O(7) materials, consistent with isomorphous replacement of Fe(2+) by Mg(2+). Measurements of dielectric properties demonstrate that Mg doping could have an effect on the electron hopping energy between Fe(2+) and Fe(3+) ions. Transmission electron microscopy and magnetization analysis reveal that Mg doping in LuFe(2)O(4) has a much greater influence than in Lu(2)Fe(3)O(7) on both the charge ordering and the low-temperature magnetic properties. PMID- 21817221 TI - Phonon and elastic instabilities in rocksalt calcium oxide under pressure: a first-principles study. AB - The lattice and elastic instabilities of rocksalt (RS) calcium oxide CaO under pressure are extensively studied to reveal the physically driven mechanism of the phase transition from RS to CsCl structure by using the pseudopotential plane wave method within density-functional theory. The predicted phase transition pressure is 66.38 GPa, employing the total energy method, which falls in the experimental transition pressure range of 60-70 GPa. A pressure-induced soft transverse acoustic (TA) phonon mode is identified at the zone boundary X point in the Brillouin zone, signifying a structural instability. A predicted charge transfer from Ca to O with pressure might be attributable to the phonon softening. Moreover, a softening behavior in the C(44) shear modulus with pressure is predicted. Analysis of the calculated results suggested that, with increasing pressure, the predicted TA phonon softening behavior, instead of C(44) shear modulus instability, is mainly responsible for the pressure-induced structural phase transition. We also find that the bond between Ca and O becomes more ionic under compression from Mulliken population analysis. PMID- 21817222 TI - Ab initio study of the elastic properties of single and polycrystal TiO(2), ZrO(2) and HfO(2) in the cotunnite structure. AB - In this work, we study theoretically the elastic properties of the orthorhombic (Pnma) high-pressure phase of IV-B group oxides: titania, zirconia and hafnia. By means of the self-consistent SIESTA code, pseudopotentials, density functional theory in the LDA and GGA approximations, the total energies, hydrostatic pressures and stress tensor components are calculated. From the stress-strain relationships, in the linear regime, the elastic constants C(ij) are determined. Derived elastic constants, such as bulk, Young's and shear modulus, Poisson coefficient and brittle/ductile behavior are estimated with the polycrystalline approach, using Voigt-Reuss-Hill theories. We have found that C(11), C(22) and C(33) elastic constants of hafnia and zirconia show increased strength with respect to the experimental values of the normal phase, P 2(1)/c. A similar situation applies to titania if these constants are compared with its normal phase, rutile. However, shear elastic constants C(44), C(55) and C(66) are similar to the values found in the normal phase. This fact increases the compound anisotropy as well as its ductile behavior. The dependence of unit-cell volumes under hydrostatic pressures is also analyzed. P-V data, fitted to third-order Birch-Murnaghan equations of state, provide the bulk modulus B(0) and its pressure derivatives B'(0). In this case, LDA estimations show good agreement with respect to recent measured bulk moduli of ZrO(2) and HfO(2). Thermo-acoustic properties, e.g. the propagation speed of transverse, longitudinal elastic waves together with associated Debye temperatures, are also estimated. PMID- 21817223 TI - Electronic band structure of Cu(2)O by spin density functional theory. AB - The band structure of Cu(2)O is calculated using density functional theory in the generalized gradient approximation. By taking spin-orbit coupling into account the split between the Gamma(7)(+) and the Gamma(8)(+) valence band states is obtained as 128 meV. The highest valence band shows a noticeable nonparabolicity close to the Gamma point. This is important for the quantitative description of excitons in this material, which is considered to be the best candidate for the confirmation that Bose-Einstein condensation also occurs in excitonic systems. PMID- 21817224 TI - Spontaneous emission near the band edge of a three-dimensional photonic crystal: a fractional calculus approach. AB - We suggest a better mathematical method, fractional calculus, for studying the behavior of the atom-field interaction in photonic crystals. By studying the spontaneous emission of an atom in a photonic crystal with a one-band isotropic model, we found that the long-time inducing memory of the spontaneous emission is a fractional phenomenon. This behavior could be well described by fractional calculus. The results show no steady photon-atom bound state for the atomic resonant transition frequency lying in the proximity of the allowed band edge which was encountered in a previous study (Woldeyohannes and John 2003 J. Opt. B: Quantum Semiclass. Opt. 5 R43). The correctness of this result is validated by the 'cut-off smoothing' density of photon states (DOS) with fractional calculus. By obtaining a rigorous solution without the multiple-valued problem for the system, we show that the method of fractional calculus has a logically concise property. PMID- 21817225 TI - Theoretical studies of defect states in GaTe. AB - Using first principle electronic structure calculations within density functional theory and the supercell model, we have investigated the nature and formation energies of defect states associated with Ga and Te vacancies and Ge and Sn substitutional impurities in GaTe. We have also calculated the band structure of pure GaTe for comparison with systems with defects and also to find out the importance of spin-orbit interaction (SOI) on its band structure. We find that the top valence band at the Gamma-point shifts up in energy by ~0.1 eV due to the mixing of Te p(x)-p(y) and p(z) bands, this splitting being considerably smaller than in atoms where it is ~0.8 eV. From an analysis of charge densities and band structures associated with the defect states, we find that most of them are strongly localized and lie deep in the band gap region. The calculated binding energy of the deep defect state and the epsilon(-1/-2) transition level associated with the Ga vacancy appears to be in good agreement with experiment. Formation energy calculations suggest that V(Ga) is the preferred intrinsic defect in GaTe. PMID- 21817226 TI - A unitary perturbation theory approach to real-time evolution problems. AB - We discuss a new analytical approach to real-time evolution in quantum many-body systems. Our approach extends the framework of continuous unitary transformations such that it amounts to a novel solution method for the Heisenberg equations of motion for an operator. It is our purpose to illustrate the accuracy of this approach by studying dissipative quantum systems on all timescales. In particular, we obtain results for non-equilibrium correlation functions for general initial conditions. We illustrate our ideas for the exactly solvable dissipative oscillator and, as a non-trivial model, for the dissipative two-state system. PMID- 21817227 TI - Spin ordering and enhancement of electronic heat capacity in an organic system of (DI-DCNQI)(2)(Ag(1-x)Cu(x)). AB - Thermodynamic measurements on the organic system of (DI-DCNQI)(2)(Ag(1-x)Cu(x)) (x = 0,0.05, 0.71, 0.90) were performed to study the change from the charge ordered (CO) insulating state to the pi-d hybridized metallic state. A thermal anomaly associated with the antiferromagnetic transition that occurred in the charge-ordered lattice was observed at 6.2 K from the temperature dependence of the heat capacity of (DI-DCNQI)(2)Ag. We have found that the magnetic entropy around the peak is only 1.5% of Rln2, corresponding to the full entropy expected for the formula unit of (DI-DCNQI)(2)Ag. This anomaly is suppressed down to about 3 K in the x = 0.05 sample owing to the disorders induced in the CO lattice. In the metallic concentration of x = 0.90, the low-temperature electronic heat capacity coefficient, gamma was found to be enhanced by up to about 63.6 mJ K(-2) mol(-1) probably owing to the cooperative effect of pi-d hybridization and intersite Coulomb interaction (V). PMID- 21817228 TI - LaBaNiO(4): a Fermi glass. AB - Polycrystalline samples of LaSr(1-x)Ba(x)NiO(4) show a crossover from a state with metallic transport properties for x = 0 to an insulating state as [Formula: see text]. The end member LaBaNiO(4) with a nominal nickel Ni 3d(7) configuration might therefore be regarded as a candidate for an antiferromagnetic insulator. However, we do not observe any magnetic ordering in LaBaNiO(4) down to 1.5 K, and despite its insulating transport properties several other physical properties of LaBaNiO(4) resemble those of metallic LaSrNiO(4). Based on an analysis of electrical and thermal-conductivity data as well as magnetic-susceptibility and low-temperature specific-heat measurements, we suggest that LaBaNiO(4) is a Fermi glass with a finite electron density of states at the Fermi level but these states are localized. PMID- 21817229 TI - Development of electron holes across the temperature-induced semiconductor-metal transition in Ba(1-x)Sr(x)Co(1-y)Fe(y)O(3-delta)(x, y = 0.2-0.8): a soft x-ray absorption spectroscopy study. AB - The x-ray absorption spectra of Ba(1-x)Sr(x)Co(1-y)Fe(y)O(3-delta) (BSCF) powders quenched in air from 623 and 1173 K were measured at the oxygen K and transition metal L(II,III) edges. All the samples show a predominantly Fe high spin ground state of 3d(5)L character, while the 3d(6)L Co ions are intermediate spin at 623 K and high spin at 1173 K. Further changes in the metal L(II,III) peaks caused by higher temperature quenching are attributed to changes in symmetry around the cations associated with oxygen loss. The oxygen K spectra show the development of unoccupied states just above the Fermi level for samples quenched from 1173 K. At 1173 K, Ba(1-x)Sr(x)Co(1-y)Fe(y)O(3-delta) shows metallic conductivity, while at 623 K it is a semiconductor; the states developed at high temperature with strong oxygen character are pathways for hole conductivity. Splitting of the transition metal 3d energy levels by the ligand field was observed in the oxygen K spectra, and the range for 10Dq is 1.6-1.8 eV, while the 3d bandwidth is 1.1-1.4 eV in samples quenched from 623 K. On the basis of the soft x-ray absorption results, the classification of Ba(1-x)Sr(x)Co(1-y)Fe(y)O(3-delta) as a material with a negative charge-transfer energy is proposed. PMID- 21817230 TI - Evidence for a vacancy-phosphorus-oxygen complex in silicon. AB - Low-energy (~0.5 MeV) electrons arising from (60)Co gamma-irradiation were used to create phosphorus-vacancy (PV) pairs and oxygen-vacancy pairs in Czochralski grown Si. Positron annihilation data show that PV pairs anneal in two stages: the commonly observed stage around 125 degrees C, where one third of the pairs disappear with an activation energy of 0.8 +/- 0.2 eV, and a new stage where none disappear, but form PV-oxygen complexes with an activation energy of 2.0 +/- 0.2 eV. PMID- 21817231 TI - Vacancies in wurtzite GaN and AlN. AB - Vacancies in wurtzite GaN and AlN are studied using a computational method which is based on the density functional theory (DFT) and takes into account the errors arising from use of finite-sized supercells and the DFT band gap underestimation. Negatively charged N vacancies in GaN and AlN are found to be stable, with formation energies similar to and higher than those of Ga and Al vacancies in n type material under Ga- and Al-rich growth conditions, respectively. The localization and energies of the defect levels close to the computational conduction band edge are considered in detail. PMID- 21817232 TI - Elastic anomalies associated with transformation sequences in perovskites: I. Strontium zirconate, SrZrO(3). AB - Elastic behaviour associated with the hierarchy of tilting transitions in SrZrO(3) has been examined using resonant ultrasound spectroscopy on a ceramic sample at temperatures between 153 and 1531 K. Changes in slope of the evolution of resonance frequencies with temperature indicate that phase transitions occur at 1038 K ([Formula: see text]), 1122 K ([Formula: see text]), and 1367 K ([Formula: see text]). Strain analysis of previously recorded neutron diffraction data shows that the [Formula: see text] and [Formula: see text] transitions are close to tricritical in character, and that [Formula: see text] is first order. Deviations from the form of the elastic behaviour predicted by Landau theory are found. In particular, elastic softening in the vicinity of the [Formula: see text] transition suggests that local dynamical fluctuations between individual tilt systems occur, rather than a discontinuous switch from one phase to another. Determinations of the mechanical quality factor, Q, show that SrZrO(3) in the [Formula: see text] phase is a classically high-Q (i.e. non-dissipating) cubic material. I4/mcm and Imma phases both have much greater dissipation (low Q), which is tentatively attributed to the mobility of twin walls. The room temperature Pnma phase is unexpectedly much stiffer than both I4/mcm and Imma phases and has high Q. It appears that when two separate tilt systems operate, as in Pnma, they can interact to reduce strain/order parameter relaxations. PMID- 21817233 TI - Elastic anomalies associated with transformation sequences in perovskites: II. The strontium zirconate-titanate Sr(Zr,Ti)O(3) solid solution series. AB - The sequence of phase transitions due to octahedral tilting across the Sr(Zr,Ti)O(3) solid solution series has been investigated by resonant ultrasound spectroscopy at high and low temperatures using ceramic samples. The elastic behaviour associated with phase transitions as a function of composition in Sr(Zr,Ti)O(3) at room temperature is proposed to be analogous to that as a function of temperature in SrZrO(3), with the [Formula: see text] transition at SrZr(0.57)Ti(0.43)O(3), [Formula: see text] at SrZr(0.35)Ti(0.65)O(3), and [Formula: see text] at SrZr(0.05)Ti(0.95)O(3). Changes in elastic constants and acoustic dissipation with temperature have been analysed for samples across the compositional range. The intermediate phases, I4/mcm and what is assumed to be Imma, appear to have stability fields across the full compositional range and both show large dissipation effects, most probably due to twin wall mobility. In contrast, the Zr-rich Pnma phase, which should contain transformation twin walls, is an unexpectedly stiff and non-dissipating material, similar to the high temperature and/or Ti-rich [Formula: see text] phase. In the case of Pnma, this is attributed to coupling between the two order parameters, which could impede relaxation responses to an applied stress. The [Formula: see text] structure is a classically stiff cubic perovskite and no transformation-related dissipation processes are expected. PMID- 21817234 TI - Crystal chemistry aspects of the magnetically induced ferroelectricity in TbMn(2)O(5) and BiMn(2)O(5). AB - The origin of magnetic frustration was stated and the ions, whose shift is accompanied by emerging magnetic ordering and ferroelectricity in TbMn(2)O(5) and BiMn(2)O(5), were determined on the basis of calculating the magnetic coupling parameters by using the structural data. The displacements accompanying the magnetic ordering are not polar, they just induce changes of bond valence (charge disordering) of Mn1 and Mn2, thus creating instability in the crystal structure. The approximation of the bond valence to the initial value (charge ordering) under magnetic ordering conditions is only possible again due to polar displacement of Mn2 (or O1) and O4 ions along the b axis which is the cause of the ferroelectric transition. PMID- 21817235 TI - Dielectric critical slowing down in pentakis(imidazolium) undecabromodibismuthate(III): (C(3)N(2)H(5))(5)Bi(2)Br(11). AB - Low frequency dielectric dispersion studies have been carried out for the ferroelectric pentakis(imidazolium) undecabromodibismuthate(III)- (C(3)N(2)H(5))(5)Bi(2)Br(11)-single crystal in the paraelectric phase in the radio-frequency region (100 Hz-1 MHz). The dielectric dispersion, observed for an electric field along the a-axis (P 2(1)/n space group), is characterized by a polydispersive nature close to the Curie temperature (T(c) = 155 K). The dielectric dispersion findings were analyzed accurately with the Cole-Cole formula. In the vicinity of the Curie temperature the process of the dielectric critical slowing down is clearly observed. Such a dynamic dielectric response is characteristic of ferroelectric crystals classified as 'order-disorder' type. PMID- 21817236 TI - Accurate determination of the anisotropy factors and the phase differences of Raman polarizabilities in some uniaxial crystals: the case of lithium niobate. AB - The present study highlights self-consistently helpful improvements dedicated to overcoming the difficulty resulting from the fitting procedure of integrated Raman intensities recorded according to the rotation crystal method described earlier. To this end, the anisotropy factors of Raman polarizabilities and the corresponding relative phases are determined within the framework of the exact mathematical derivation of the phase factors. These are the relevant parameters of the Raman efficiency relations which are numerically difficult to obtain from the fitting of the integrated areas. The present theoretical approach is then applied to the modes of the A(1) and Ey symmetry species of the lithium niobate (LN) crystal point group. All the expressions of the Raman absolute intensities of the A(1) and Ey irreducible representations initially imply three parameters to be determined from the fitting computations. However, from the derived analytical expressions of the phase differences, the number of parameters involved in the fitting procedure is reduced from 3 to 2, thus improving the statistics of the numerical treatment. PMID- 21817237 TI - Absorption cross sections and number densities of electron and hole polarons in congruently melting LiNbO(3). AB - The number densities and absorption cross sections of both optically generated and reduction-induced small electron and hole polarons in LiNbO(3) are determined by means of time-resolved pump-multiprobe spectroscopy. The data are obtained for free (Nb(Nb)(4+)) and bound (Nb(Li)(4+)) electron polarons, bound Nb(Li)(4+):Nb(Nb)(4+) electron bipolarons, and bound O(-) hole polarons. The peak absorption cross sections are in the range of sigma(pol)~(4-14) * 10(-22) m(2), comparable to that for Fe(2+). In all cases the ratio of occupied to unoccupied polaronic sites is less than 10(-2). PMID- 21817238 TI - Structural and magnetic properties of DyMn(2)D(6) synthesized under high deuterium pressure. AB - DyMn(2)D(6) has been prepared by applying high gaseous deuterium pressure on DyMn(2). This phase is isostructural with other RMn(2)D(6) (R = Y, Er) compounds and crystallizes with a K(2)PtCl(6) type structure having an ordered anion and a partially disordered cation arrangement because Dy and half the Mn atoms are randomly substituted in the same 8c site. The reverse susceptibility follows a Curie-Weiss law with an effective moment of 10 MU(B) similar to that of DyMn(2). Short range magnetic order, corresponding to ferromagnetic correlations, is observed in the neutron patterns up to 10 K and can be attributed to Dy-Dy interactions. The decomposition of the deuteride into Mn and DyD(2), studied by thermal gravimetric analysis, occurs between 470 and 650 K. A further deuterium desorption takes place above 920 K. PMID- 21817239 TI - XAS and XMCD study of the influence of annealing on the atomic ordering and magnetism in an NiMnGa alloy. AB - The proper annealing of Ni(51)Mn(28)Ga(21) ribbon alloy gives rise to an increase of the saturation magnetization and of the magnetic order T(C) (up to 20 K) and martensitic transition T(M) (up to 10 K) temperatures. The combined x-ray absorption spectroscopy (XAS) and x-ray magnetic circular dichroism (XMCD) studies indicate that the annealing treatment drives the alloy to a more ordered structure without significantly affecting the local structure in terms of interatomic distances and bonding geometry. By contrast, the annealing strongly affects the near-edge absorption at the Mn K-edge while no effect is observed at either the Ni or Ga K-edge. These results suggest that annealing leads to a modification of the electronic structure of the Mn atoms while that of Ni and Ga atoms remains unvaried. However, strong XMCD signals are detected at both Ni and Ga K-edges whose amplitude increases after annealing. These results point out that despite the change of the magnetic properties of the system being mainly associated with the modification of the electronic properties of the Mn atoms, both Ni and Ga may play a non-negligible role through the polarization of the conduction band. PMID- 21817240 TI - Magnetic-dipolar and electromagnetic vortices in quasi-2D ferrite discs. AB - Magnetic-dipolar-mode (MDM) oscillations in a quasi-2D ferrite disc show unique dynamical symmetry properties resulting in the appearance of topologically distinct structures. Based on the magnetostatic (MS) spectral problem solutions, in this paper we give evidence for eigen-MS power-flow-density vortices in a ferrite disc. Due to these circular eigen-power flows, the MDMs are characterized by MS energy eigenstates. It becomes evident that the reason for stability of the vortex configurations in saturated ferrite samples is completely different from the nature of stability in magnetically soft cylindrical dots. We found a clear correspondence between analytically derived MDM vortex states and numerically modeled electromagnetic vortices in quasi-2D ferrite discs. PMID- 21817241 TI - Magnetotransport properties in K(0.50)CoO(2) single crystals. AB - We have measured susceptibility and angle-dependent magnetoresistance (AMR) on K(0.50)CoO(2) single crystals. A possible magnetic structure similar to that of Na(0.5)CoO(2), a G-type anti-ferromagnetic (AF) structure (both in-plane and inter-plane are AF), is proposed. At ~20 K, a loop is observed between zero-field cooled (ZFC) and field-cooled (FC) susceptibility. The absolute value of magnetoresistance (MR) at 20 K is much larger than other cases with H applied within the ab plane. This could arise from the magnetic field being applied in the ab plane, leading to spin-flop of the small magnetic moment of Co(3.5-delta) sites at 20 K to form in-plane ferromagnetic ordering, as observed in Na(0.52)CoO(2). PMID- 21817242 TI - Spin waves in antiferromagnetically coupled bimetallic oxalates. AB - Bimetallic oxalates are molecule-based magnets with transition-metal ions M(II) and M(')(III) arranged on an open honeycomb lattice. Performing a Holstein Primakoff expansion, we obtain the spin-wave spectrum of antiferromagnetically coupled bimetallic oxalates as a function of the crystal-field angular momentum L(2) and L(3) on the M(II) and M(')(III) sites. Our results are applied to the Fe(II)Mn(III), Ni(II)Mn(III) and V(II)V(III) bimetallic oxalates, where the spin wave gap varies from 0 meV for quenched angular momentum to as high as 15 meV. The presence or absence of magnetic compensation appears to have no effect on the spin-wave gap. PMID- 21817243 TI - Insulator-metal phase transition of Pr(0.6)Ca(0.4)MnO(3) studied by x-ray absorption spectroscopy in pulsed magnetic fields. AB - Evolution of the Mn K-edge x-ray absorption near edge structure (XANES) in Pr(0.6)Ca(0.4)MnO(3) at pulsed magnetic fields has been investigated. A small enhancement of XANES spectra is detected across the magnetic-field-induced transition from the charge- and orbital-ordered (COO) insulator to ferromagnetic metal at 20 K. It is found that the magnetic-field dependence of the enhancement shows clear hysteresis, as seen in the magnetization with metamagnetic transition, suggesting a significant correlation between the change in the XANES and the field-induced collapse of the COO state. The enhancement of the absorption can be explained by an increase of the 4p density of states due to a reduction of hybridization between the 4p state of the central Mn ion with the core hole and the neighboring Mn 3d state. Local structural change around Mn ions is expected to modify the strength of the hybridization. PMID- 21817244 TI - Magnetic fluctuations in nanosized goethite (alpha-FeOOH) grains. AB - Mossbauer spectra of antiferromagnetic goethite (alpha-FeOOH) particles usually show an asymmetric line broadening, which increases with increasing temperature, although the magnetic anisotropy is expected to be so large that magnetic relaxation effects should be negligible. By use of high resolution transmission electron microscopy we have studied a sample of goethite particles and have found that the particles contain many defects such as low angle grain boundaries, in accordance with previous studies of other samples of goethite particles. Such defects can result in a magnetic mismatch at the grain boundaries between nanometer-sized grains, leading to a weakened magnetic coupling between the grains. We show that the Mossbauer data of goethite can be explained by fluctuations of the sublattice magnetization directions in such weakly coupled grains. It is likely that the influence of defects such as low angle grain boundaries also plays a role with regards to the magnetic properties in other antiferromagnetic nanograin systems. We discuss the results in relation to Mossbauer studies of alpha-Fe(2)O(3) and alpha-Fe(2)O(3)/NiO nanoparticles. PMID- 21817245 TI - Excited state properties of liquid water. AB - In this paper, we give an overview of the state of the art in calculations of the electronic band structure and absorption spectra of water. After an introduction to the main theoretical and computational schemes used, we present results for the electronic and optical excitations of water. We focus mainly on liquid water, but spectroscopic properties of ice and vapor phase are also described. The applicability and the accuracy of first-principles methods are discussed, and results are critically presented. PMID- 21817246 TI - Dynamical versus statistical mesoscopic models for DNA denaturation. AB - We recently proposed a dynamical mesoscopic model for DNA, which is based, like the statistical ones, on site-dependent finite stacking and pairing enthalpies. In the present paper, we first describe how the parameters of this model are varied to get predictions in better agreement with experimental results that were not addressed up to now, like mechanical unzipping, the evolution of the critical temperature with sequence length and temperature resolution. We show that the model with the new parameters provides results that are in quantitative agreement with those obtained from statistical models. Investigation of the critical properties of the dynamical model suggests that DNA denaturation looks like a first-order phase transition in a broad temperature interval, but that there necessarily exists, very close to the critical temperature, a crossover to another regime. The exact nature of the melting dynamics in this second regime still has to be elucidated. We finally point out that the descriptions of the physics of the melting transition inferred from statistical and dynamical models are not completely identical and discuss the relevance of our model from the biological point of view. PMID- 21817247 TI - Bubbles in DNA melting. AB - This paper presents a review of largely our own work on the DNA melting transition, and some new measurements of the elastic energy of sharp bends in single-stranded DNA and RNA. The purpose is to present the point of view that studying the transition of intermediate size oligomers leads to valuable tests of the models, in particular the ingredients most important for a reduced-degrees-of freedom description, such as the different role of base pairing and base stacking. We make the case that, with intermediate size oligomers, one can actually measure the bubble length, which exhibits a more interesting behavior than the fraction of dissociated bases alone. Here is where more work seems necessary, both on the experimental and the modeling side, to understand the differences between theory and experiments. We summarize our previous results on the cooperativity parameters, which suggest that the transition is never exactly two-state no matter how short the molecule, or in other words the nucleation size for bubbles opening at the ends of the molecule is essentially 1 base pair. We briefly discuss our own modification of the nearest-neighbor model which treats pairing and stacking separately, as a way to fit the experimental melting profiles in this intermediate length regime. Finally we go on to present some new measurements on the stability of DNA and RNA hairpins with very short loops. PMID- 21817248 TI - Experimental and theoretical studies of sequence effects on the fluctuation and melting of short DNA molecules. AB - Understanding the melting of short DNA sequences probes DNA at the scale of the genetic code and raises questions which are very different from those posed by very long sequences, which have been extensively studied. We investigate this problem by combining experiments and theory. A new experimental method allows us to make a mapping of the opening of the guanines along the sequence as a function of temperature. The results indicate that non-local effects may be important in DNA because an AT-rich region is able to influence the opening of a base pair which is about 10 base pairs away. An earlier mesoscopic model of DNA is modified to correctly describe the timescales associated with the opening of individual base pairs well below melting, and to properly take into account the sequence. Using this model to analyze some characteristic sequences for which detailed experimental data on the melting is available (Montrichok et al 2003 Europhys. Lett. 62 452), we show that we have to introduce non-local effects of AT-rich regions to get acceptable results. This brings a second indication that the influence of these highly fluctuating regions of DNA on their neighborhood can extend to some distance. PMID- 21817249 TI - Coupling between denaturation and chain conformations in DNA: stretching, bending, torsion and finite size effects. AB - We develop further a statistical model coupling denaturation and chain conformations in DNA (Palmeri et al 2007 Phys. Rev. Lett. 99 088103). Our discrete helical wormlike chain model takes explicitly into account the three elastic degrees of freedom, namely stretching, bending and torsion of the polymer. By integrating out these external variables, the conformational entropy contributes to bubble nucleation (opening of base-pairs), which sheds light on the DNA melting mechanism. Because the values of monomer length, bending and torsional moduli differ significantly in dsDNA and ssDNA, these effects are important. Moreover, we explore in this context the role of an additional loop entropy and analyze finite size effects in an experimental context, where polydA polydT is clamped by two G-C strands, as well as for free polymers. PMID- 21817251 TI - Thermal equivalence of DNA duplexes for probe design. AB - We present the theory of thermal equivalence in the framework of the Peyrard Bishop model and some of its anharmonic variants. The thermal equivalence gives rise to a melting index tau which maps closely the experimental DNA melting temperatures for short DNA sequences. We show that the efficient calculation of the melting index can be used to analyse the parameters of the Peyrard-Bishop model and propose an improved set of Morse potential parameters. With this new set we are able to calculate some of the experimental melting temperatures to +/- 1.2 degrees C. We review some of the concepts of sequencing probe design and show how to use the melting index to explore the possibilities of gene coverage by tuning the model parameters. PMID- 21817250 TI - Sequence effects in the melting and renaturation of short DNA oligonucleotides: structure and mechanistic pathways. AB - The renaturation/denaturation of DNA oligonucleotides is characterized in the context of expanded ensemble (EXE) and transition path sampling (TPS) simulations. Free energy profiles have been determined from EXE for DNA sequences of varying composition, chain length, and ionic strength. TPS simulations within a Langevin dynamics formalism have been carried out to obtain further information of the transition state for renaturation. Simulation results reveal that free energy profiles are strikingly similar for the various DNA sequences considered in this work. Taking intact double-stranded DNA to have an extent of reaction xi = 1.0, the maximum of the free energy profile appears at xi~0.15, corresponding to ~2 base pairs. In terms of chain length, the free energy barrier of longer oligonucleotides (30 versus 15 base pairs) is higher and slightly narrower, due to increased sharpness associated with the transition. Low ionic strength tends to decrease free energy barriers, whereby increasing strand rigidity facilitates reassociation. Two mechanisms for DNA reassociation emerge from our analysis of the transition state ensemble. Repetitive sequences tend to reassociate through a non-specific pathway involving molecular slithering. In contrast, random sequences associate through a more restrictive pathway involving the formation of specific contacts, which then leads to overall molecular zippering. In both random and repetitive sequences, the distribution of contacts suggests that nucleation is favored for sites located within the middle region of the chain. The prevalent extent of reaction for the transition state is xi~0.25, and the critical size of the nucleus as obtained from our analysis involves ~4 base pairs. PMID- 21817252 TI - Pre-melting dynamics of DNA and its relation to specific functions. AB - We discuss connections between the nonlinear dynamics of double-stranded DNA, experimental findings, and specific DNA functions. We begin by discussing how thermally induced localized openings (bubbles) of the DNA double strand are important for interpreting dynamic force spectroscopy data. Then we demonstrate a correlation between a sequence-dependent propensity for pre-melting bubble formation and transcription initiation and other regulatory effects in viral DNA. Finally, we discuss the possibility of a connection between DNA dynamics and the ability of repair proteins to recognize ultraviolet (UV) radiation damage sites. PMID- 21817253 TI - Genome wide application of DNA melting analysis. AB - Correspondences between functional and thermodynamic melting properties in a genome are being increasingly employed for ab initio gene finding and for the interpretation of the evolution of genomes. Here we present the first systematic genome wide comparison between biologically coding domains and thermodynamically stable regions. In particular, we develop statistical methods to estimate the reliability of the resulting predictions. Not surprisingly, we find that the success of the approach depends on the difference in GC content between the coding and the non-coding parts of the genome and on the percentage of coding base-pairs in the sequence. These prerequisites vary strongly between species, where we observe no systematic differences between eukaryotes and prokaryotes. We find a number of organisms in which the strong correlation of coding domains and thermodynamically stable regions allows us to identify putative exons or genes to complement existing approaches. In contrast to previous investigations along these lines we have not employed the Poland-Scheraga (PS) model of DNA melting but use the earlier Zimm-Bragg (ZB) model. The Ising-like form of the ZB model can be viewed as an approximation to the PS model, with averaged loop entropies included into the cooperative factor [Formula: see text]. This results in a speed up by a factor of 20-100 compared to the Fixman-Freire algorithm for the solution of the PS model. We show that for genomic sequences the resulting systematic errors are negligible compared to the parameterization uncertainty of the models. We argue that for limited computing resources, available CPU power is better invested in broadening the statistical base for genomic investigations than in marginal improvements of the description of the physical melting behavior. PMID- 21817254 TI - Segmentation of DNA sequences into twostate regions and melting fork regions. AB - The accurate prediction and characterization of DNA melting domains by computational tools could facilitate a broad range of biological applications. However, no algorithm for melting domain prediction has been available until now. The main challenges include the difficulty of mathematically mapping a qualitative description of DNA melting domains to quantitative statistical mechanics models, as well as the absence of 'gold standards' and a need for generality. In this paper, we introduce a new approach to identify the twostate regions and melting fork regions along a given DNA sequence. Compared with an ad hoc segmentation used in one of our previous studies, the new algorithm is based on boundary probability profiles, rather than standard melting maps. We demonstrate that a more detailed characterization of the DNA melting domain map can be obtained using our new method, and this approach is independent of the choice of DNA melting model. We expect this work to drive our understanding of DNA melting domains one step further. PMID- 21817255 TI - Dynamics of DNA melting. AB - The dynamics of loops at the DNA denaturation transition is studied. A scaling argument is used to evaluate the asymptotic behavior of the autocorrelation function of the state of complementary bases (either open or closed). The long time asymptotic behavior of the autocorrelation function is expressed in terms of the entropy exponent, c, of a loop. The validity of the scaling argument is tested using a microscopic model of an isolated loop and a toy model of interacting loops. This suggests a method for measuring the entropy exponent using single-molecule experiments such as fluorescence correlation spectroscopy. PMID- 21817256 TI - Single DNA denaturation and bubble dynamics. AB - While the Watson-Crick double-strand is the thermodynamically stable state of DNA in a wide range of temperature and salt conditions, even at physiological conditions local denaturation bubbles may open up spontaneously due to thermal activation. By raising the ambient temperature, titration, or by external forces in single molecule setups bubbles proliferate until full denaturation of the DNA occurs. Based on the Poland-Scheraga model we investigate both the equilibrium transition of DNA denaturation and the dynamics of the denaturation bubbles with respect to recent single DNA chain experiments for situations below, at, and above the denaturation transition. We also propose a new single molecule setup based on DNA constructs with two bubble zones to measure the bubble coalescence and extract the physical parameters relevant to DNA breathing. Finally we consider the interplay between denaturation bubbles and selectively single stranded DNA binding proteins. PMID- 21817257 TI - Assembly and melting of DNA nanotubes from single-sequence tiles. AB - DNA melting and renaturation studies are an extremely valuable tool to study the kinetics and thermodynamics of duplex dissociation and reassociation reactions. These are important not only in a biological or biotechnological context, but also for DNA nanotechnology which aims at the construction of molecular materials by DNA self-assembly. We here study experimentally the formation and melting of a DNA nanotube structure, which is composed of many copies of an oligonucleotide containing several palindromic sequences. This is done using temperature controlled UV absorption measurements correlated with atomic force microscopy, fluorescence microscopy and transmission electron microscopy techniques. In the melting studies, important factors such as DNA strand concentration, hierarchy of assembly and annealing protocol are investigated. Assembly and melting of the nanotubes are shown to proceed via different pathways. Whereas assembly occurs in several hierarchical steps related to the formation of tiles, lattices and tubes, melting of DNA nanotubes appears to occur in a single step. This is proposed to relate to fundamental differences between closed, three-dimensional tube-like structures and open, two-dimensional lattices. DNA melting studies can lead to a better understanding of the many factors that affect the assembly process which will be essential for the assembly of increasingly complex DNA nanostructures. PMID- 21817258 TI - Force induced DNA melting. AB - When pulled along the axis, double-strand DNA undergoes a large conformational change and elongates by roughly twice its initial contour length at a pulling force of about 70 pN. The transition to this highly overstretched form of DNA is very cooperative. Applying a force perpendicular to the DNA axis (unzipping), double-strand DNA can also be separated into two single-stranded DNA, this being a fundamental process in DNA replication. We study the DNA overstretching and unzipping transition using fully atomistic molecular dynamics (MD) simulations and argue that the conformational changes of double-strand DNA associated with either of the above mentioned processes can be viewed as force induced DNA melting. As the force at one end of the DNA is increased the DNA starts melting abruptly/smoothly above a critical force depending on the pulling direction. The critical force f(m), at which DNA melts completely decreases as the temperature of the system is increased. The melting force in the case of unzipping is smaller compared to the melting force when the DNA is pulled along the helical axis. In the case of melting through unzipping, the double-strand separation has jumps which correspond to the different energy minima arising due to sequence of different base pairs. The fraction of Watson-Crick base pair hydrogen bond breaking as a function of force does not show smooth and continuous behavior and consists of plateaus followed by sharp jumps. PMID- 21817259 TI - Y-DNA melting: a short tale of three scales. AB - We address some aspects of the thermal denaturation of Y-DNA-the three-way junction-on three different length scales: the effect of chain concentration on the extrinsic melting behaviour within a simple kinetic approach, the exponent of the loop entropy in intrinsic melting as it appears in statistical mechanics models, and the microscopics of stacking within the junction from molecular dynamics simulations. Our results suggest that a multiscale approach is needed to properly describe the denaturation properties of these systems. We propose experiments which can also shed light on the melting of short and long duplex DNA sequences. PMID- 21817260 TI - Depletion interactions in two-dimensional colloid-polymer mixtures: molecular dynamics simulations. AB - The depletion interactions acting between two hard colloids immersed in a bath of polymers, in which the interaction potentials include the soft repulsion/attraction, are extensively studied by using the molecular dynamics simulations. The collision frequencies and collision angle distributions for both incidental and reflection conditions are computed to study the dynamic properties of the colloidal mixtures. The depletion effect induced by the polymer-polymer and colloid-polymer interactions are investigated as well as the size ratio of the colloid and polymer. The simulated results show that the strong depletion interaction between two hard colloids appears for the highly asymmetric hard-disc mixtures. The attractive depletion force at contact becomes deeper and the repulsive barrier becomes wider as the asymmetry in size ratio increases. The strong polymer-polymer attraction leads to the purely attractive depletion interaction between two hard colloids, whereas the purely repulsive depletion interaction is induced by the strong colloid-polymer attraction. PMID- 21817261 TI - Orientational and structural properties of ferroelectric liquid crystal with a broad temperature range in the SmC(*) phase by (13)C NMR, x-ray scattering and dielectric spectroscopy. AB - Thermotropic liquid crystalline materials laterally substituted by a methyl group on the aromatic ring of the alkoxybenzoate unit far from the chiral centre exhibit a very broad temperature range in the ferroelectric smectic C* (SmC(*)) phase on cooling (including supercooling) with a very high spontaneous polarization (~210 nC cm(-2)) and tilt angle (~43 degrees ) at saturation. We are presenting a detailed study of the physical properties of a ferroelectric compound, representative of this category of liquid crystals, by means of solid state (13)C-NMR, small angle x-ray scattering, dielectric spectroscopy and optical methods of the tilted SmC(*). Values of the spontaneous tilt angle measured optically are compared to those determined from the x-ray data and discussed. In addition, the viscosity has been determined in the SmC(*) phase by different experimental methods. (13)C NMR data allowed us to get information about the degree of orientational order of the SmC(*) phase and revealed the complete unwinding of the helical axis at the magnetic field of 9.4 T. This result is discussed in the framework of recent publications on the effect of the magnetic field on the supra-molecular structure of the SmC(*) phase. PMID- 21817262 TI - Thermophoresis at a charged surface: the role of hydrodynamic slip. AB - By matching boundary layer hydrodynamics with slippage to the force-free flow at larger distances, we obtain the thermophoretic mobility of charged particles as a function of the Navier slip length b. A moderate value of b augments Ruckenstein's result by a term 2b/lambda, where lambda is the Debye length. If b exceeds the particle size a, the enhancement coefficient a/lambda is independent of b but proportional to the particle size. Similar effects occur for transport driven by a salinity gradient or by an electric field. PMID- 21817263 TI - Evaluation of viscoelastic master curves of filled elastomers and applications to fracture mechanics. AB - The viscoelastic response of filler-reinforced elastomers has been investigated by dielectric- and dynamic-mechanical spectroscopy. Horizontal and vertical shifting factors are evaluated, which are used for the construction of viscoelastic master curves. They are discussed in the framework of filler network effects and the slowed-down dynamics of a polymer layer close to the filler surface. The observed shifting behaviour is shown to be related to the superposition of two relaxation processes, i.e. that of the polymer matrix and the filler network, leading to a failure of the time-temperature superposition principle. While the matrix transforms according to the Vogel-Fulcher equation, the filler network exhibits an Arrhenius dependence, which results from the thermal activation of filler-filler bonds, i.e. glassy-like polymer bridges between adjacent filler particles. Based on the viscoelastic master curves relaxation time spectra are evaluated. By referring to a recently developed theory of crack propagation in viscoelastic solids it is demonstrated that the behaviour of the scaling exponent of the relaxation time spectra correlates fairly well with that of the crack propagation rates measured under moderate severity conditions. PMID- 21817264 TI - Intermolecular correlations in an ionic liquid under shear. AB - The behavior of a model room temperature ionic liquid under shear is explored using non-equilibrium molecular dynamics simulations. The external field reduces intermolecular structure in the liquid. However, orientational ordering of the molecules in the form of a nematic phase is observed under shear. PMID- 21817265 TI - Second order elasticity at hypersonic frequencies of reactive polyurethanes as seen by generalized Cauchy relations. AB - The non-equilibrium process of polymerization of reactive polymers can be accompanied by transition phenomena like gelation or the chemical glass transition. The sensitivity of the mechanical properties at hypersonic frequencies-including the generalized Cauchy relation-to these transition phenomena is studied for three different polyurethanes using Brillouin spectroscopy. As for epoxies, the generalized Cauchy relation surprisingly holds true for the non-equilibrium polymerization process and for the temperature dependence of polyurethanes. Neither the sol-gel transition nor the chemical and thermal glass transitions are visible in the representation of the generalized Cauchy relation. Taking into account the new results and combining them with general considerations about the elastic properties of the isotropic state, an improved physical foundation of the generalized Cauchy relation is proposed. PMID- 21817266 TI - Wicking with a yield stress fluid. AB - This work presents an experimental investigation of the flow of a model yield stress fluid (yield stresses between 5 and 21 Pa) driven by capillarity in horizontal glass tubes with diameters ranging from 0.46 to 1.5 mm. It is shown that the liquid penetration stops after typically a few centimeters. The results disagree with a simple model based on the balance between capillary and frictional forces, suggesting that the yield stress fluid constitutive equation may not be valid in the immediate vicinity of the wall. Scaling is proposed with respect to a dimensionless number comparing the yield stress with the capillary pressure. PMID- 21817267 TI - Luminescence properties of Sm(3+)-doped P(2)O(5)-PbO-Nb(2)O(5) glass under high pressure. AB - Samarium doped lead phosphate glass modified with niobium having a composition (in mol%) of 55P(2)O(5)+39.5PbO+5Nb(2)O(5)+0.5Sm(2)O(3) has been prepared by the conventional melt quenching technique. The emission spectra and the decay curves for the (4)G(5/2) level of Sm(3+) ions have been measured as a function of pressure up to 23.6 GPa at room temperature. A discontinuity in the observed shifts and crystal-field splittings as a function of pressure around 9-10 GPa suggests that a phase transition is taking place in the glass matrix. The [Formula: see text], (6)H(7/2) and (6)H(9/2) transitions are shifted towards the lower energy side with magnitudes of -7.1, -7.6 and -5.5 cm(-1) GPa(-1) up to 8.9 GPa (phase 1) and -5.6, -4.9 and -4.4 cm(-1) GPa(-1) beyond 10.3 GPa (phase 2), respectively. A much stronger increase in the splitting of the [Formula: see text] and [Formula: see text] Stark levels with pressure is observed in phase 1 than in phase 2. The lifetime of the (4)G(5/2) level decreases from 2.29 ms (0 GPa) to 0.64 ms (23.6 GPa) with pressure. The decay curves of the (4)G(5/2) level exhibit non-exponential behavior for all the pressures and were fitted by the generalized Yokota-Tanimoto model to probe the nature of the energy transfer process. The best fits with S = 6 indicate that the energy transfer between donor and acceptor is of dipole-dipole type. The crystal-field splitting experienced by the Sm(3+) ions in the title glass are found to be larger than those found in borate, K-Ba-Al phosphate and tellurite glasses. PMID- 21817268 TI - The structure of calcium metaphosphate glass obtained from x-ray and neutron diffraction and reverse Monte Carlo modelling. AB - The short range structure of (CaO)(0.5)(P(2)O(5))(0.5) glass has been studied using x-ray and neutron diffraction and modelled using the reverse Monte Carlo method. Using this combination of techniques has allowed six interatomic correlations to be distinguished and fitted to obtain a set of bond lengths and coordination numbers that describe the structure of the glass. The glass consists of metaphosphate chains of phosphate tetrahedra and each phosphate unit has two non-bridging oxygen atoms available for coordination with Ca. The Ca-O correlation was fitted with two peaks at 2.35 and 2.86 A, representing a broad distribution of bond lengths. The total Ca-O coordination is 6.9 and is consistent with distorted polyhedral units such as capped octahedra or capped trigonal prisms. It is found that most non-bridging oxygen atoms are bonded to two calcium atoms. All of these observations are consistent with Hoppe's model for phosphate glasses. Furthermore, the medium range order is revealed to consist of phosphate chains intertwined with apparently elongated clusters of Ca ions, and the Ca-O and Ca-P correlations contributed significantly to the first sharp diffraction peak in x-ray diffraction. PMID- 21817269 TI - A multi-timescale strength model of alpha-helical protein domains. AB - Here we report a constitutive model that characterizes the strength of an alpha helical protein domain subjected to tensile deformation, covering more than ten orders of magnitude in timescales. The model elucidates multiple physical mechanisms of failure in dependence on the deformation rate, quantitatively linking atomistic simulation results with experimental strength measurements of alpha-helical protein domains. The model provides a description of the strength of alpha-helices based on fundamental physical parameters such as the H-bond energy and the polypeptide's persistence length, showing that strength is controlled by energetic, nonequilibrium processes at high rates and by thermodynamical, equilibrium processes at low rates. Our model provides a novel perspective on the strength of protein domains at ultra-slow pulling speeds relevant under physiologic and experimental conditions. PMID- 21817270 TI - Crystallization of bismuth borate glasses. AB - Bismuth borate glasses with Bi(2)O(3) concentration of 20-66 mol% were prepared by melt quenching and devitrified by heat treatment above their glass transition temperatures. All glasses show a strong tendency towards crystallization on annealing that increases with Bi(2)O(3) concentration. The crystalline phases formed on devitrification were characterized by FTIR absorption spectroscopy and DSC measurements. Our studies reveal that phases produced in glasses are strongly determined by initial glass composition and the two most stable crystalline phases are: Bi(3)B(5)O(12) and Bi(4)B(2)O(9). The metastable BiBO(3) phase can also be formed by devitrification of glass with 50 mol% of Bi(2)O(3). This phase is, however, unstable and decomposes into Bi(3)B(5)O(12) and Bi(4)B(2)O(9) on prolonged heat treatment. PMID- 21817271 TI - Competition between two types of anti-Stokes emission in Ho(3+)-activated ZBLAN glass. AB - A competition between two anti-Stokes emissions has been observed and interpreted in ZBLAN glass activated by Ho(3+) ions. The first anti-Stokes emission intensity was seen to increase with temperature, whereas another, upconverted emission, was seen to decrease under the same conditions. Both observed tendencies are believed to be caused by the same effect: the multiphonon anti-Stokes excitation of the state responsible for the first emission. Analysis of the kinetics and fits of the theoretical model to experimental data are presented. PMID- 21817272 TI - Correlated small polaron hopping transport in 1D disordered systems at high temperatures: a possible charge transport mechanism in DNA. AB - Based on the generalized molecular crystal model (GMCM) and theoretical percolation arguments we investigate small polaron hopping transport in 1D disordered systems at high temperatures. Correlation (cr) effects are taken into account. An analytical expression for the temperature dependence of the electrical conductivity, lnsigma(h,cr)~T(-1/2), is obtained. This result reproduces satisfactorily the experimental data reported for lambda-DNA and for poly(dA)-poly(dT) DNA, considering DNA as a one-dimensional disordered molecular wire in which small polarons are the charge carriers. lnsigma(h,cr) versus T( 1/2) plots permit the evaluation of the maximum hopping distance. The results indicate that correlation effects are probably responsible for large hopping distances in DNA samples. PMID- 21817273 TI - Protein conformational changes revealed by optical spectroscopic reflectometry in porous silicon multilayers. AB - The protein-ligand molecular interactions imply strong geometrical and structural rearrangements of the biological complex which are normally detected by high sensitivity optical techniques such as time-resolved fluorescence microscopy. In this work, we have measured, by optical spectroscopic reflectometry in the visible-near-infrared region, the interaction between a sugar binding protein (SBP), covalently bound on the surface of a porous silicon (PSi) microcavity, and glucose, at different concentrations and temperatures. Variable-angle spectroscopic ellipsometric (VASE) characterization of protein-functionalized PSi layers confirms that the protein-ligand system has an overall volume smaller than the SBP alone. PMID- 21817274 TI - Theory of the low frequency mechanical modes and Raman spectra of the M13 bacteriophage capsid with atomic detail. AB - We present a theoretical study of the low frequency vibrational modes of the M13 bacteriophage using a fully atomistic model. Using ideas from electronic structure theory, the few lowest vibrational modes of the M13 bacteriophage are determined using classical harmonic analysis. The relative Raman intensity is estimated for each of the mechanical modes using a bond polarizability model. Comparison of the atomic mechanical modes calculated here with modes derived from elastic continuum theory shows that a much richer spectrum emerges from an atomistic picture. PMID- 21817275 TI - Glass transitions in one-, two-, three-, and four-dimensional binary Lennard Jones systems. AB - We investigate the calorimetric liquid-glass transition by performing simulations of a binary Lennard-Jones mixture in one through four dimensions. Starting at a high temperature, the systems are cooled to T = 0 and heated back to the ergodic liquid state at constant rates. Glass transitions are observed in two, three and four dimensions as a hysteresis between the cooling and heating curves. This hysteresis appears in the energy and pressure diagrams, and the scanning rate dependence of the area and height of the hysteresis can be described using power laws. The one-dimensional system does not experience a glass transition but its specific heat curve resembles the shape of the D>=2 results in the supercooled liquid regime above the glass transition. As D increases, the radial distribution functions reflect reduced geometric constraints. Nearest neighbor distances become smaller with increasing D due to interactions between nearest and next nearest neighbors. Simulation data for the glasses are compared with crystal and melting data obtained with a Lennard-Jones system with only one type of particle and we find that with increasing D crystallization becomes increasingly more difficult. PMID- 21817276 TI - Influence of Al(2)O(3) nanoparticles on the isothermal cure of an epoxy resin. AB - The influence of Al(2)O(3) nanoparticles on the curing of an epoxy thermoset based on diglycidyl ether of bisphenol A was investigated using temperature modulated differential scanning calorimetry (TMDSC) and rheology. Diethylene triamine was used as a hardener. TMDSC not only allows for a systematic study of the kinetics of cure but simultaneously gives access to the evolution of the specific heat capacities of the thermosets. The technique thus provides insight into the glass transition behaviour of the nanocomposites and hence makes it possible to shed some light on the interaction between the nanoparticles and the polymer matrix. The Al(2)O(3) fillers are shown to accelerate the growth of macromolecules upon isothermal curing. Several mechanisms which possibly could be responsible for the acceleration are described. As a result of the faster network growth chemical vitrification occurs at earlier times in the filled thermosets and the specific reaction heat decreases with increasing nanoparticle concentration. Rheologic measurements of the zero-shear viscosity confirm the faster growth of the macromolecules in the presence of the nanoparticles. PMID- 21817277 TI - Studies of Fe-Cu microwires with nanogranular structure. AB - We report on the fabrication, and structural and magnetic characterization of Cu(63)Fe(37) microwires with granular structure produced by rapid quenching, using the Tailor-Ulitovsky method, from the immiscible alloys. X-ray diffraction study demonstrated that the structure consists of small (6-45 nm) crystallites of Cu and body centred cubic alpha-Fe. Magnetic properties have been measured in the range of 5-300 K using a SQUID (superconducting quantum interference device) magnetometer. The temperature dependences of the magnetization measured in a cooling regime when no external magnetic field is applied (zero-field cooling) and in the presence of the field (field cooling) show considerable difference below 20 K. This difference could be related to the presence of small alpha-Fe grains embedded in the Cu matrix. Those alpha-Fe grains appear to be blocked at temperatures below that at which the maximum of the magnetization is observed in the low temperature range. Significant magnetoresistance (about 7%) has been found in the samples studied. The shape of the observed dependences is typical of a giant magnetoresistance effect. PMID- 21817278 TI - Ground-state phase diagram of Na(x)CoO(2): correlation of Na ordering with CoO(2) stacking sequences. AB - We have proposed a Hamiltonian that takes into account both Na-Na interactions and coupling between Na ions and CoO(2) layers. By a combination of the Monte Carlo and first-principles approaches, all the possible stacking sequences of CoO(2) layers together with the Na ordering have been obtained. In particular, an infinite series of ground states of Na ordering has been predicted in P3 Na(x)CoO(2). We have obtained the ground-state phase diagram with the variation of Na concentration, which explains well the complex variation of the CoO(2) stacking sequences. Our calculations show that the ordering of Na ions to minimize the Coulomb interaction is the main cause of the variation of the CoO(2) stacking sequences. PMID- 21817279 TI - Percolation limit and stability conditions for the spin glass state in the spinel families based on the two matrices CuCr(2)S(4) and CuCr(2)Se(4) doped by Sb ions. AB - The percolation limit of the appearance of the spin glass state in the compounds under study has been obtained experimentally. The conditions of stability of the spin glass state have been analyzed here on the basis of the de Almeida-Thouless theory for two spinels differing in the magnetic coupling constants. It turned out that for the higher value of the coupling constant the magnetic field influences the freezing temperature more strongly. Moreover, the greater the coupling constant the broader the range of the possible values of freezing temperatures, in other words the greater the temperature range of the appearance of the spin glass states. It was proved that for the stability of the spin glass state the existence of a small magnetic field is necessary. In our case the value of this field is equal to 3.46 * 10(-23)T(G). For the compounds under study the value of the magnetic coupling constant J cannot exceed 130 K for the spin glass state to appear. PMID- 21817280 TI - Itinerant ferromagnetism by e(g) and t(2g) states in the two-band Hubbard model. AB - Itinerant ferromagnetism derived from e(g) and t(2g) states has been studied by the Gutzwiller variational method based on the two-band Hubbard model. The analysis shows that the magnetization value that depends on the orbital reflects strength of renormalization for each band. As a result, the magnetization of the 3d(t(2g)) band, which is more strongly renormalized in the calculation, has a larger value than that of the 3d(e(g)) band. By changing the atomic interaction and projected orbital density of states (DOS), we have discussed general tendencies that the magnetizations by the e(g) and t(2g) states are determined by the relative intensities of the projected orbital DOS at the Fermi energy, the renormalized kinetic energies relative to U, and stability of atomic multielectron configuration states. The result indicates that increases in Coulomb interaction U and the portion of Hund's coupling J in the atomic interaction lead to balanced magnetizations between the two states. Variation in the above factors can generate a variety of spin-dependent electronic structures near the Fermi energy in 3d transition metal ferromagnets. PMID- 21817281 TI - Disorder-induced quantum bond percolation. AB - We investigate the effects of off-diagonal disorder on localization properties in quantum bond percolation networks on cubic lattices, motivated by the finding that the off-diagonal disorder does not always enhance the quantum localization of wavefunctions. We numerically construct a diagram of the 'percolation threshold', distinguishing extended states from localized states as a function of two degrees of disorder, by using the level statistics and finite-size scaling. The percolation threshold increases in a characteristic way on increasing the disorder in the connected bonds, while it gradually decreases on increasing the disorder in the disconnected bonds. Furthermore, the exchange of connected and disconnected bonds induced by the disorder causes a dramatic change of the percolation threshold. PMID- 21817282 TI - Supercurrent transferring through c-axis cuprate Josephson junctions with thick normal-metal bridge. AB - With a simple but exactly solvable model, we investigate the supercurrent transferring through the c-axis cuprate superconductor-normal metal superconductor junctions with the clean normal metal much thicker than its coherence length. It is shown that the supercurrent as a function of thickness of the normal metal decreases much slower than the exponential decaying expected by the proximity effect. The present result may account for the giant proximity effect observed in the c-axis cuprate SNS junctions. PMID- 21817283 TI - Domain boundary pinning and elastic softening in KMnF(3) and KMn(1-x)Ca(x)F(3). AB - Anelastic softening related to the movement of twin boundaries is observed in improper ferroelastic KMnF(3) and KMn(1-x)Ca(x)F(3). Wall movement in KMnF(3) shows a frequency dependence which is described in terms of an extended Debye relaxation with an extension exponent of 0.54. This exponent indicates a fairly narrow distribution of activation energies near 0.43 eV. Wall movements in Ca doped samples are best described in terms of Vogel-Fulcher (VF) relaxations with a VF energy of 0.23 eV. The activation energies are related to interaction between F vacancies or interstitials and the moving domain walls; Ca doping appears to increase the tendency to form glass-like states. No domain freezing occurs at temperatures above the subsequent phase transition I4/mcm-Pnma; the Pnma phase does not show any domain movement and anelastic behaviour. Elastic precursor softening is observed above the transition temperature between the cubic and the tetragonal phase. The softening can be described empirically using a power law: [(T-T(o))/T(o)](-K) with values of the exponent K around 0.5. PMID- 21817284 TI - Structural, magnetic, and electrical studies on polycrystalline transition-metal doped BiFeO(3) thin films. AB - We have synthesized a range of transition-metal-doped BiFeO(3) thin films on conducting silicon substrates using a spin-coating technique from metal-organic precursor solutions. Bismuth, iron and transition-metal-organic solutions were mixed in the appropriate ratios to produce 3% transition-metal-doped samples. X ray diffraction studies show that the samples annealed in a nitrogen atmosphere crystallize in a rhombohedrally distorted BiFeO(3) structure with no evidence for any ferromagnetic secondary phase formation. We find evidence for the disappearance of the 404 cm(-1) Raman mode for certain dopants indicative of structural distortions. The saturation magnetization of these BiFeO(3) films has been found to increase on doping with transition metal ions, reaching a maximum value of 8.5 emu cm(-3) for the Cr-doped samples. However, leakage current measurements find that the resistivity of the films typically decreases with transition metal doping. We find no evidence for any systematic variation of the electric or magnetic properties of BiFeO(3) depending on the transition metal dopant, suggesting that these properties are determined mainly by extrinsic effects arising from defects or grain boundaries. PMID- 21817285 TI - Theoretical study of the phonon spectra of multiferroic BiFeO(3) nanoparticles. AB - The phonon properties of multiferroic BiFeO(3) (BFO) nanoparticles are studied using a Green's function technique on the basis of the Heisenberg and the transverse Ising models, taking into account anharmonic spin-phonon and phonon phonon interaction terms. The phonon spectrum is obtained for different exchange, magnetoelectric, and spin-phonon interaction constants. The influence of temperature, surface and size effects on the phonon energy and damping is discussed. The phonon energy and damping in BFO nanoparticles are greater in comparison to those in bulk BFO. The strong spin-phonon interactions lead to anomalies in the phonon spectrum around the magnetic and ferroelectric phase transitions. The influence of an applied magnetic field is studied, too. The predictions are consistent with experimental results. PMID- 21817286 TI - Changes in the adsorbate dipole layer with changing d-filling of the metal (II) (Co, Ni, Cu) phthalocyanines on Au(111). AB - In combined photoemission and inverse photoemission spectroscopy studies, we observe changes in the metal phthalocyanine molecular orbital offsets with respect to the conducting gold substrate Fermi level, with the changing d electron filling of the metal (II) (Co, Ni, Cu) phthalocyanines. The implication is that the interfacial dipole layer depends upon the choice of metal (Co, Ni, Cu) centers within the metal (II) phthalocyanines adsorbed on Au(111). PMID- 21817287 TI - Spectroscopic manifestations of the Kondo effect on single adatoms. AB - The present topical review focuses on recent advances concerning an intriguing phenomenon in condensed matter physics, the scattering of conduction electrons at the localized spin of a magnetic impurity: the Kondo effect. Spectroscopic signatures of this effect have been observed in the past by high-resolution photoemission which, however, has the drawback of averaging over a typical surface area of 1 mm(2). By combining the atomic-scale spatial resolution of the scanning tunneling microscope (STM) with an energy resolution of a few tens of ueV achievable nowadays in scanning tunneling spectroscopy (STS), and by exposing the magnetic adatom to external magnetic fields, our understanding of the interaction of a single magnetic impurity with the conduction electrons of the nonmagnetic host has been considerably deepened. New insight has emerged by taking advantage of quantum size effects in the metallic support and by decoupling the magnetic adatom from the supporting host metal, for instance by embedding it inside a molecule or by separating it by an ultrathin insulating film from the metal surface. In this way, Kondo resonances and Kondo temperatures can be tailored and manipulated by changing the local density of states of the environment. In the weak coupling limit between a Kondo impurity and a superconductor only a convolution of tip and sample DOS is observed while for strongly coupled systems midgap states appear, indicating superconducting pair breaking. Magnetic impurities with co-adsorbed hydrogen on metallic surfaces show pseudo-Kondo resonances owing to very low-energy vibrational excitations detected by inelastic tunneling spectroscopy. One of the most recent achievements in the field has been the clarification of the role of magnetic anisotropy in the Kondo effect for localized spin systems with a spin larger than S = 1/2. PMID- 21817288 TI - Electronic structure of Sn/Cu(100)-[Formula: see text]. AB - We present measurements of the Fermi surface and underlying band structure of Sn/Cu(100)-[Formula: see text]. This phase is observed for a coverage of 0.60 0.65 monolayers. Its electronic structure is characterized by a free-electron like surface band folded with the reconstruction periodicity. At variance with other surface phases of Sn on Cu(100), no temperature-induced phase transition is observed for this phase from 100 K up to the desorption of Sn. PMID- 21817289 TI - Half-metallicity at the Heusler alloy Co(2)Cr(0.5)Fe(0.5)Al(001) surface and its interface with GaAs(001). AB - Electronic and magnetic properties of the Heusler alloy Co(2)Cr(0.5)Fe(0.5)Al(001) surfaces and its interfaces with GaAs(001) are studied within the framework of density functional theory by using the plane-wave pseudopotential approach. The phase diagram obtained by ab initio atomistic thermodynamics shows that the CrAl surface is the most stable (001) termination of this Heusler alloy. We discuss that, at the ideal surfaces and interfaces with GaAs, half-metallicity of the alloy is lost, although the CrAl surface keeps high spin polarization. The energy band profile of the stable interface is investigated and a negative p Schottky barrier of -0.78 eV is obtained for this system. PMID- 21817290 TI - Enhancing the hardness of Al/W nanostructured coatings. AB - Two-component multilayer thin films frequently show hardness enhancements at specific repeat periods above that of the constituent layers. This study of hardness enhancements in W/Al nanostructured coatings provides strong new evidence that hardness enhancements in this system arise not only from the presence of a layered structure, but also from the presence of defects introduced by changing the deposition conditions. Samples with well defined layers of W and Al were produced by sputtering to cover a wide range of periods from 10 to 200 nm. No evidence of enhanced hardness in these films was found by nanoindentation. On the other hand, samples deposited from cathodic arc sources showed strong hardness enhancement above that of pure W. However, the samples of highest hardness did not contain Al layers for much of their thickness. The hardening mechanism therefore could not be attributed to the presence of a multilayer structure. Examination of the microstructure showed that the interruptions to the W deposition caused by operation of the Al source introduced defects which acted as pinning sites for dislocations. The nanoindentation hardness data were well described using a modified Hall-Petch relation. PMID- 21817291 TI - Role of hydrogen adsorption on the carbon terminated beta-SiC(100)-c(2 * 2) surface structure: a theoretical approach. AB - The role of hydrogen adsorption on different clean surface models for the carbon terminated beta-SiC(100)-c(2 * 2) surface structure is investigated through the use of ab initio calculations. The structural and electronic effect of hydrogen atoms bonded to carbon and/or silicon dimers is specifically considered and compared with the results for a clean surface model. The presence of adsorbed hydrogen atoms affects the atomic equilibrium positions, as well as electronic properties, of the atoms of the clean structure. These last properties are altered in different directions if the adsorption occurs in one or the other of the two investigated models. The changes in both structural and electronic properties were evaluated and compared with those of the clean surface. From our obtained results, a possible metallization, as a result of hydrogen adsorption, is theoretically postulated to occur in a similar way to what occurs with the silicon terminated beta-SiC(100)(3 * 2) surface. PMID- 21817292 TI - Palladium interaction with CeO(2), Sn-Ce-O and Ga-Ce-O layers. AB - Using photoemission, we have studied the interaction of palladium with thin layers of stoichiometric ceria (Ce(4+) character) and two mixed oxides, Ga-Ce-O and Sn-Ce-O, where cerium in the Ce(3+) oxidation state is present. Palladium was found to partially reduce the CeO(2) layer by introducing oxygen vacancies most probably in the vicinity of the growing Pd particles. In mixed oxide systems palladium very strongly interacts with both added metals-gallium and tin-leading to a breaking of metal-ceria bonds and the establishment of Pd-Ga(Sn) intermetallic compounds. As a consequence the ceria reoxidizes back to a Ce(4+) oxidation state. PMID- 21817293 TI - Furan interaction with the Si(001)-(2 * 2) surface: structural, energetics, and vibrational spectra from first-principles. AB - In this work we employ the state of the art pseudopotential method, within a generalized gradient approximation to the density functional theory, to investigate the adsorption process of furan on the silicon (001) surface. A direct comparison of different adsorption structures with x-ray photoelectron spectroscopy (XPS), ultra-violet photoelectron spectroscopy (UPS), high resolution electron energy loss spectroscopy (HREELS), near edge x-ray absorption fine structure (NEXAFS), and high resolution spectroscopy experimental data allows us to identify the [4+2 ] cycloaddition reaction as the most probable adsorbate. In addition, theoretical scanning tunnelling microscopy (STM) images are presented, with a view to contributing to further experimental investigations. PMID- 21817294 TI - Final state interaction observed in M(2,3)VV Auger profile of Cu(110). AB - We have measured the M(2,3)VV Auger spectra of Cu(110) and studied the final state interaction following the Cu 3p core electron excitation. We have observed that the kinetic energy of the M(2,3)VV Auger electron shifts to an energy higher than that of the normal Auger electrons near the Cu 3p threshold, and it converges to the constant kinetic energy of the normal Auger electrons as the excitation energy increases above the Cu 3p threshold. In the excitation energy dependence of the kinetic energies of the M(2,3)VV Auger electrons, we observed step features at the excitation energies corresponding to the 3p core electron excitations to the L(1) and X(1) van Hove singularities in the valence states. The kinetic energy shifts of the M(2,3)VV Auger electrons are reasonably understood by considering the localization of the two-hole Auger final state and the hybridization between Cu 3d states and other valence states. PMID- 21817295 TI - How does an external electrical field affect adsorption patterns of thiol and thiolate on the gold substrate? AB - The responsive behavior of methanethiol and methylthiolate molecules on the Au(111) surface with an applied electrical potential is studied, and it is shown how the sulfur adsorption site, the S-H bond orientation and the interacting energy change with an external electric field strength. The electron charge density corresponding to an electric field minus that obtained in zero field, with zero-field optimal geometry, is calculated to explain the responsive behavior. The interacting energy for the intact methanethiol adsorption is larger than that for the dissociative one, showing that an external electric field cannot make the hydrogen dissociate from the sulfur. PMID- 21817296 TI - Adsorption sites on icosahedral quasicrystal surfaces: dark stars and white flowers. AB - From other work, two preferred sites have been suggested for metals and semimetals adsorbed on the fivefold surfaces of icosahedral, Al-based quasicrystals. Because of their appearance in scanning tunneling microscopy (STM) images, these sites are known as dark stars and white flowers. In this paper, we analyze four bulk structural models in physical space to determine the types, chemical decorations, and densities of the dark star-and, to a lesser extent, the white flower-adsorption sites for the fivefold planes of icosahedral Al-Pd-Mn. We find that the chemical decorations of these sites are heterogeneous, even within a single model. Both features are also structurally heterogeneous, according to STM measurements, and the structural variation is consistent with the bulk structure models. Finally, from the models, the density of dark stars in the planes correlates with the step height. This may explain previous experimental observations of different properties for different terraces. PMID- 21817297 TI - Separation and correlation of structural and magnetic roughness in a Ni thin film by polarized off-specular neutron reflectometry. AB - Diffuse (off-specular) neutron and x-ray reflectometry has been used extensively for the determination of interface morphology in solids and liquids. For neutrons, a novel possibility is off-specular reflectometry with polarized neutrons to determine the morphology of a magnetic interface. There have been few such attempts due to the lower brilliance of neutron sources, though magnetic interaction of neutrons with atomic magnetic moments is much easier to comprehend and easily tractable theoretically. We have obtained a simple and physically meaningful expression, under the Born approximation, for analyzing polarized diffuse (off-specular) neutron reflectivity (PDNR) data. For the first time PDNR data from a Ni film have been analyzed and separate chemical and magnetic morphologies have been quantified. Also specular polarized neutron reflectivity measurements have been carried out to measure the magnetic moment density profile of the Ni film. The fit to PDNR data results in a longer correlation length for in-plane magnetic roughness than for chemical (structural) roughness. The magnetic interface is smoother than the chemical interface. PMID- 21817298 TI - Atomic and electronic structure transformations of silver nanoparticles under rapid cooling conditions. AB - The structural evolution and dynamics of silver nanodrops Ag(2869) (4.4 nm in diameter) under rapid cooling conditions have been studied by means of molecular dynamics simulations and electronic density of state calculations. The interaction of silver atoms is modelled by a tight-binding semiempirical interatomic potential proposed by Cleri and Rosato. The pair correlation functions and the pair analysis technique are used to reveal the structural transition in the process of solidification. It is shown that Ag nanoparticles evolve into different nanostructures under different cooling processes. At a cooling rate of 1.5625 * 10(13) K s(-1) the nanoparticles preserve an amorphous like structure containing a large amount of 1551 and 1541 pairs which correspond to icosahedral symmetry. For a lower cooling rate (1.5625 * 10(12) K s(-1)), the nanoparticles transform into a crystal-like structure consisting mainly of 1421 and 1422 pairs which correspond to the face centred cubic and hexagonal close packed structures, respectively. The variations of the electronic density of states for the differently cooled nanoparticles are small, but in correspondence with the structural changes. PMID- 21817299 TI - Quantum mechanics-molecular dynamics approach to the interpretation of x-ray absorption spectra. AB - The quantum mechanics-molecular dynamics approach to the simulation of configuration-averaged EXAFS spectra is proposed, and its application is discussed for the example of the Ti K-edge EXAFS spectrum in cubic perovskite SrTiO(3). Proper use of ab initio quantum mechanics allows a number of empirical parameters, used in the molecular dynamics simulation, to be reduced, whereas the molecular dynamics allows us to account for temperature effects. All together, the approach provides a way of accounting for static and dynamic disorder in EXAFS signals from the coordination shells above the first one, where many-atom (multiple-scattering) effects are often important. PMID- 21817300 TI - Universality in the vibrational spectra of weakly-disordered two-dimensional clusters. AB - We numerically investigate the vibrational spectra of single-component clusters in two dimensions. Stable configurations of clusters at local energy minima are obtained, and for each the Hessian matrix is evaluated and diagonalized to obtain eigenvalues as well as eigenvectors. We study the density of states so obtained as a function of the width of the potential well describing the two-body interaction. As the width is reduced, as in three dimensions, we find that the density of states approaches a common form but the two-peak behavior survives. Further, calculations of the participation ratio show that most states are extended, although a smaller fraction of the degrees of freedom are involved in these modes compared to three dimensions. We show that the fluctuation properties of these modes converge to those of the Gaussian orthogonal ensemble of random matrices, in common with previous results on three-dimensional amorphous clusters and molecular liquids. PMID- 21817301 TI - Pressure effects on the phase stability of cubic BNC ternary alloys. AB - Pressure effects on the phase stability of cubic BNC alloys were examined by Monte Carlo simulations and the cluster expansion technique based on first principles calculations. At pressure P = 10 GPa, solution energy of neighboring B N and C-C atoms into diamond and cubic BN are both higher than those at P = 0 GPa, indicating a decrease of solubility in c-BNC under applied pressure. Monte Carlo statistical simulation reveal that the applied pressure decreases solubility limits by almost half of those at P = 0 GPa. This significant decrease can mainly be attributed to the increase of volume with the formation of a c-BNC solid solution. Formation of neighboring B-N bonds decreases volume, while that of second-neighboring B-N increases volume for c-BNC, which naturally increases the stability of c-BN and diamond in the c-BNC solid solution under external pressure. PMID- 21817302 TI - Direct observation of atomic scale surface relaxation in ortho twin structures in GaAs by XSTM. AB - We have studied the (110) GaAs surface of a structure containing ortho twins by cross-sectional scanning tunnelling microscopy and we have compared the experimental results with ab initio density functional theory calculations and STM simulations. Both experimentally and theoretically we find that the surface of different twin crystallites are significantly displaced with respect to each other, parallel to the twin boundary. This result is explained by a surface relaxation of the atoms in the (110) GaAs surface and the difference between the atomic configuration of the ortho twins. PMID- 21817303 TI - Charge qubit entanglement via conditional single-electron transfer in an array of quantum dots. AB - We propose a novel scheme to generate entanglement among quantum-dot-based charge qubits via sequential electron transfer in an auxiliary quantum dot structure whose transport properties are conditioned by qubit states. The transfer protocol requires the utilization of resonant optical pulses combined with an appropriate voltage gate pattern. As an example illustrating the application of this scheme, we examine the nine-qubit Shor code state preparation together with the error syndrome measurement. PMID- 21817304 TI - Subband anticrossing and the spin Hall effect in quantum wires. AB - We report on numerical simulations of the intrinsic spin Hall effect in semiconductor quantum wires as a function of the Rashba spin-orbit coupling strength, the electron density, and the width of the wire. We find that the strength of the spin Hall effect does not depend monotonically on these parameters, but instead exhibits a local maximum. This behavior is explained by considering the dispersion relation of the electrons in the wire, which is characterized by the anticrossing of adjacent subbands. These results lead to a simple estimate of the optimal wire width for spin Hall transport experiments, and simulations indicate that this optimal width is independent of disorder. The anticrossing of adjacent subbands is related to a quantum phase transition in momentum space, and is accompanied by an enhancement of the Berry curvature and subsequently in the magnitude of the spin Hall effect. PMID- 21817305 TI - Tunnelling spin current and spin diode behaviour in a bilayer system. AB - The coherent tunnelling spin current in the bilayer system with spin-orbit coupling is investigated. Based on the continuity-like equations, we discuss the definition of the tunnelling current and show that the overlaps between wavefunctions for different layers contribute to the tunnelling current. We study the linear response of the tunnelling spin current to an in-plane electric field in the presence of nonmagnetic impurities. The tunnelling spin conductivity we obtained presents a feature asymmetrical with respect to the gate voltage when the strengths of impurity potentials are different in each layer. PMID- 21817306 TI - Non-Markovian damping of Rabi oscillations in semiconductor quantum dots. AB - A systematic investigation is performed on the damping of Rabi oscillations induced by an external electromagnetic field interacting with a two-level semiconductor system. We have considered a coherently driven two-level system coupled to a dephasing reservoir and shown that, to explain the dependence of the dephasing rate on the driving intensity, it is essential to consider the non Markovian character of the reservoir. Moreover, we have demonstrated that intensity-dependent damping may be induced by various dephasing mechanisms due to stationary as well as non-stationary effects caused by coupling with the environment. Finally, present results are able to explain a variety of experimental measurements available in the literature. PMID- 21817307 TI - Theory of photo-magnetization of an interacting particle system: application to Hg(1-x)Mn(x)Te. AB - We derive a theory of light-induced magnetization of an interacting particle system, which describes a model diluted magnetic semiconductor. We set up a many body Hamiltonian that includes electron and hole kinetic energies, carrier-photon and carrier-local-moment interactions and all the Coulomb interactions. Using Heisenberg equations of motion and a mean-field approximation, we derive expressions for the carrier spin density and excitonic amplitudes. Non equilibrium relaxation is included phenomenologically. The interdependence of carrier spin density and the local-moment magnetization is calculated self consistently. We apply our theory of photo-magnetization to Hg(1-x)Mn(x)Te, choosing parameters of the model appropriate to this system. Our results for the photo-magnetization versus the input laser power agree qualitatively with the observed trends in this system. We also study the photo-magnetization as a function of temperature, manganese concentration and photon energy and the results obtained are along expected lines. PMID- 21817308 TI - Co and Al co-doping for ferromagnetism in ZnO:Co diluted magnetic semiconductors. AB - Co and Al co-doped ZnO diluted magnetic semiconductors are fabricated by a pulsed laser deposition and their electronic structure is investigated using x-ray absorption and emission spectroscopy. The Zn(0.895)Co(0.100)Al(0.005)O thin films grown under oxygen-rich conditions exhibit ferromagnetic behavior without any indication of Co clustering. The Co L-edge and O K-edge x-ray absorption and emission spectra suggest that most of the Co dopants occupy the substitutional sites and the oxygen vacancies are not responsible for free charge carriers. The spectroscopic results and first principles calculations reveal that the ferromagnetism in Co and Al co-doped ZnO semiconductors mainly arises from Al interstitial defects and their hybridization with Co substitutional dopants. PMID- 21817309 TI - Ultrasonic velocity studies in the vicinity of T(C) of bismuth doped manganites. AB - Materials with the compositional formula La(0.67-x)Bi(x)Sr(0.33)MnO(3) (where x = 0, 0.1, 0.2, 0.3) prepared by a citrate gel route were used with a view to investigating the elastic behaviour of manganites in the vicinity of their T(C). The structural characterization of the materials clearly indicates that all the samples have a rhombohedral structure with [Formula: see text] space group. The magnetic (T(C)) as well as the metal-insulator (T(P)) transition temperatures determined by AC susceptibility and resistivity measurements, respectively, are found to decrease continuously with increasing bismuth concentration. Finally, the ultrasonic longitudinal velocities of all the samples are found to exhibit considerable softening in the vicinity of their magnetic transition temperatures, and an effort has been made to explain the observed behaviour by mean field theory and the Jahn-Teller phenomenon. PMID- 21817310 TI - Understanding the inverse magnetocaloric effect in antiferro- and ferrimagnetic arrangements. AB - The inverse magnetocaloric effect occurs when a magnetic material cools down under applied magnetic field in an adiabatic process. Although the existence of the inverse magnetocaloric effect was recently reported experimentally, a theoretical microscopic description is almost nonexistent. In this paper we theoretically describe the inverse magnetocaloric effect in antiferro- and ferrimagnetic systems. The inverse magnetocaloric effects were systematically investigated as a function of the model parameters. The influence of the Neel and the compensation temperature on the magnetocaloric effect is also analyzed using a microscopic model. PMID- 21817311 TI - Multicritical behavior in a random-field Ising model under a continuous-field probability distribution. AB - A random-field Ising model that is capable of exhibiting a rich variety of multicritical phenomena, as well as a smearing of such behavior, is investigated. The model consists of an infinite-range-interaction Ising ferromagnet in the presence of a triple Gaussian random magnetic field, which is defined as a superposition of three Gaussian distributions with the same width sigma, centered at H = 0 and H = +/- H(0), with probabilities p and (1-p)/2, respectively. Such a distribution is very general and recovers, as limiting cases, the trimodal, bimodal and Gaussian probability distributions. In particular, the special case of the random-field Ising model in the presence of a trimodal probability distribution (limit [Formula: see text]) is able to present a rather nontrivial multicritical behavior. It is argued that the triple Gaussian probability distribution is appropriate for a physical description of some diluted antiferromagnets in the presence of a uniform external field, for which the corresponding physical realization consists of an Ising ferromagnet under random fields whose distribution appears to be well represented in terms of a superposition of two parts, namely a trimodal and a continuous contribution. The model is investigated by means of the replica method, and phase diagrams are obtained within the replica-symmetric solution, which is known to be stable for the present system. A rich variety of phase diagrams is presented, with one or two distinct ferromagnetic phases, continuous and first-order transition lines, tricritical, fourth-order, critical end points and many other interesting multicritical phenomena. Additionally, the present model carries the possibility of destroying such multicritical phenomena due to an increase in the randomness, i.e. increasing sigma, which represents a very common feature in real systems. PMID- 21817312 TI - Investigation of the effect of Ni substitution on the physical properties of Ce(Cu(1-x)Ni(x))(y)Sb(2). AB - Single crystals of Ce(Cu(1-x)Ni(x))(y)Sb(2) (x = 0, 0.25, 0.37, 0.46; y~0.7) were synthesized using a flux growth method and crystallize in the tetragonal P4/nmm space group with lattice parameters of a~4.4 A and c~9.8 A. The effects of Ni substitution on the magnetic and electrical transport properties are investigated. Three of the analogues (with x = 0, 0.37, and 0.46) show antiferromagnetic behavior while the x = 0.25 sample is paramagnetic down to 2 K. Field-dependent magnetization data as well as resistivities are presented. Positive magnetoresistance behaviors above 70% are observed for the analogues with x = 0, 0.37, and 0.46 at 3 K and up to 9 T. The La analogue La(Cu(0.2)Ni(0.8))(y)Sb(2), has been synthesized and large, positive magnetoresistance of ~300% is observed at 3 K and 9 T. PMID- 21817314 TI - Ferrimagnetism of MnV(2)O(4) spinel. AB - The spinel MnV(2)O(4) is a two-sublattice ferrimagnet, with site A occupied by the Mn(2+) ion and site B by the V(3+) ion. The magnon of the system, the transversal fluctuation of the total magnetization, is a complicated mixture of the sublattice A and B transversal magnetic fluctuations. As a result, the magnons' fluctuations suppress in a different way the manganese and vanadium sublattice magnetization and one obtains two phases. At low temperature (0,T(*)) the sublattice Mn magnetization and sublattice V magnetization contribute to the magnetization of the system, while at a high temperature (T(*),T(N)), the vanadium sublattice magnetization is suppressed by magnon fluctuations, and only the manganese ions have non-zero spontaneous magnetization. A modified spin-wave theory is developed to describe the two phases and to calculate the magnetization as a function of temperature. The anomalous M(T) curve reproduces the experimentally obtained zero-field-cooled (ZFC) magnetization. PMID- 21817313 TI - Electron transport and thermoelectric properties of layered perovskite LaBaCo(2)O(5.5). AB - We have investigated systematically the physical transport properties of layered 112-type cobaltite by means of electrical resistivity, magnetoresistance and thermopower measurements. In order to understand the complex transport mechanism of LaBaCo(2)O(5.5), the data have been analysed using different theoretical models. The compound shows an electronic transition between two semiconducting states around 326 K, which coincides with the ferromagnetic transition. Interestingly, the system also depicts a significant magnetoresistance (MR) effect near the ferro/antiferromagnetic phase boundary and the highest value of MR is close to 5% at 245 K under +/- 7 T. The temperature dependence of thermopower, S(T), exhibits p-type conductivity in the 60 K<=T<=320 K range and reaches a maximum value of around 303 uV K(-1) (at 120 K). In the low temperature antiferromagnetic region the unusual S(T) behaviour, generally observed for the cobaltite series LnBaCo(2)O(5.5) (Ln = rare earth), is explained by the electron magnon scattering mechanism. PMID- 21817315 TI - Correlation of morphology and charge transport in poly(3,4 ethylenedioxythiophene)-polystyrenesulfonic acid (PEDOT-PSS) films. AB - A wide variation in the charge transport properties of poly(3,4 ethylenedioxythiophene)-poly(styrenesulfonate) (PEDOT-PSS) films is attributed to the degree of phase segregation of the excess insulating polyanion. The results indicate that the charge transport in PEDOT-PSS can vary from hopping to the critical regime of the metal-insulator transition, depending on the subtle details of morphology. The extent of electrical connectivity in the films, directly obtained from a temperature-dependent high-frequency transport study, indicates various limiting factors to the transport, which are correlated with the phase separation process. The low temperature magnetotransport further supports this morphology-dependent transport scenario. PMID- 21817316 TI - Glass transition in soft-sphere dispersions. AB - The concept of dynamic equivalence among mono-disperse soft-sphere fluids is employed in the framework of the self-consistent generalized Langevin equation (SCGLE) theory of colloid dynamics to calculate the ideal glass transition phase diagram of model soft-sphere colloidal dispersions in the softness-concentration state space. The slow dynamics predicted by this theory near the glass transition is compared with available experimental data for the decay of the intermediate scattering function of colloidal dispersions of soft-microgel particles. Increasing deviations from this simple scheme occur for increasingly softer potentials, and this is studied here using the Rogers-Young static structure factor of the soft-sphere systems as the input of the SCGLE theory, without assuming a priori the validity of the equivalence principle above. PMID- 21817317 TI - A molecular dynamics model of the atomic structure of dysprosium alumino phosphate glass. AB - Molecular dynamics (MD) has been used to identify the relative distribution of dysprosium in the phosphate glass DyAl(0.30)P(3.05)O(9.62). The MD model has been compared directly with experimental data obtained from neutron diffraction to enable a detailed comparison beyond the total structure factor level. The MD simulation gives [Formula: see text] correlations at 3.80(5) and 6.40(5) A with relative coordination numbers of 0.8(1) and 7.3(5), thus providing evidence of minority rare-earth clustering within these glasses. The nearest neighbour Dy-O peak occurs at 2.30 A with each Dy atom having on average 5.8 nearest neighbour oxygen atoms. The MD simulation is consistent with the phosphate network model based on interlinked PO(4) tetrahedra where the addition of network modifiers Dy(3+) depolymerizes the phosphate network through the breakage of P-(O)-P bonds whilst leaving the tetrahedral units intact. The role of aluminium within the network has been taken into explicit account, and Al is found to be predominantly (78%) tetrahedrally coordinated. In fact all four Al bonds are found to be to P (via an oxygen atom) with negligible amounts of Al-O-Dy bonds present. This provides an important insight into the role of Al additives in improving the mechanical properties of these glasses. PMID- 21817318 TI - Static and thermodynamic properties of liquid and amorphous Fe(2)O(3) nanoparticles. AB - Molecular dynamics (MD) simulation of the structure and thermodynamic properties of liquid and amorphous Fe(2)O(3) nanoparticles, with different sizes ranging from 2 to 5 nm, has been carried out based on the Born-Mayer pair potentials under non-periodic boundary conditions. The partial radial distribution functions (PRDFs), coordination number distributions, bond-angle distributions and interatomic distances of liquid nanoparticles at 3500 K were calculated in detail. In addition, we show the radial density profile and stoichiometry in nanoparticles. The temperature dependence of the surface structure and surface energy of nanoparticles has been obtained and presented. Moreover, the size dependence of the glass transition temperature has been found and discussed. PMID- 21817319 TI - The structure of molten CuCl, CuI and their mixtures as investigated by using neutron diffraction. AB - The structure of molten CuCl, CuI and their mixtures (CuCl)(x)(CuI)(1-x) with x = 0.294, 0.576, 0.801 was studied by using neutron diffraction. The results are discussed by reference to the information that is available on the structure of CuCl and CuI from experiment, theory and computer simulation. The comparison points to a need for more realistic models for the CuCl-CuI system which should take into account the presence of chemical bonds that have been found in CuI by the application of ab initio molecular dynamics methods. PMID- 21817320 TI - Cooperative rearranging region size and free volume in As-Se glasses. AB - Glasses of the As-Se system have been used as model objects of the covalent disordered inorganic polymers to investigate the correlation between the cooperative rearranging region (CRR) size determined at the glass transition temperature and the free volume fraction in the glassy state. The CRR size has been determined using temperature modulated differential scanning calorimetry data according to Donth's approach, while the free volume fraction in the investigated materials has been estimated using positron annihilation lifetime spectroscopy data. The obtained results testify that the appearance of open volume defects greater than 80 A(3) leads to a significant decrease in the CRR size. PMID- 21817321 TI - Study of the physical properties of a mesogenic mixture showing induced smectic A(d) phase by refractive index, density and x-ray diffraction measurements. AB - The binary mixture of 4-n-pentyl phenyl 4-n'-hexyloxy benzoate (ME6O.5) and p cyanophenyl trans-4-pentyl cyclohexane carboxylate (CPPCC) shows the presence of an induced smectic A(d) phase in a certain concentration range 0.030.33, whereas there is a discontinuity in these values for mixtures with x<0.33, consistent with the density and transition entropy measurements done on this system. The orientational order parameter, measured from x-ray diffraction studies, are somewhat smaller than those obtained from refractive index measurement in the induced smectic phase for all the mixtures. In the smectic phase, the OOP values initially increases with molar concentration up to x = 0.24 and then decreases showing a broad minima around x = 0.4. The variation of layer thickness in the induced smectic phase with composition has been explained by assuming the formation of homo- and heterodimers. We conclude that the possible packing of molecules in the induced smectic A(d) phase stabilizes the layers but increases the orientational free volume, consistent with the lower orientational order parameter. PMID- 21817322 TI - An idealized polyhedral model and geometric structure for silicon nanotubes. AB - In this paper, we introduce an idealized model of silicon nanotubes comprising an exact polyhedral geometric structure for single-walled silicon nanotubes. The silicon nanotubes considered here are assumed to be formed by sp(3) hybridization and thus the nanotube lattice is assumed to comprise only squares or skew rhombi. Beginning with the three postulates that all bond lengths are equal, all adjacent bond angles are equal, and all atoms are equidistant from a common axis of symmetry, we derive exact formulae for the geometric parameters such as radii, bond angles and unit cell length. We present asymptotic expansions for these quantities to the first two orders of magnitude. Because of the faceted nature of the polyhedral model we may determine a perceived inner radius for the nanotube, from which an expression for the wall thickness emerges. We also describe the geometric properties of some ultra-small silicon nanotubes. Finally, the values of the diameters for the polyhedral model are compared with results obtained from molecular dynamics simulations and some limited numerical calculations are undertaken to confirm the meta-stability of the proposed structures. PMID- 21817323 TI - Distortion of Wigner molecules: a pair function approach. AB - We considered a two-dimensional three-electron quantum dot in a magnetic field in the Wigner limit. A unitary coordinate transformation decouples the Hamiltonian (with Coulomb interaction between the electrons included) into a sum of three independent pair Hamiltonians. The eigensolutions of the pair Hamiltonian provide a spectrum of pair states. Each pair state defines the distance of the two electrons involved in this state. In the ground state for given pair angular momentum m, this distance increases with increasing |m|. The pair states have to be occupied under consideration of the Pauli exclusion principle, which differs from that for one-electron states and depends on the total spin S and the total orbital angular momentum [Formula: see text] (the sum over all pair angular momenta). We have shown that the three electrons in the ground state of the Wigner molecule form an equilateral triangle (as might be expected) only if the state is a quartet (S = 3/2) and the orbital angular momentum is a magic quantum number (M(L) = 3m;m = integer). Otherwise the triangle in the ground state is isosceles. For M(L) = 3m+1 one of the sides is longer and for M(L) = 3m-1 one of the sides is shorter than the other two. PMID- 21817324 TI - Massive Dirac fermions in single-layer graphene. AB - Motivated by the results of recent photoemission and tunneling studies, we discuss potential many-body sources of a finite gap in the Dirac fermion spectrum of graphene. Specifically, we focus on the putative Peierls- and Cooper-like pairing instabilities, which can be driven by sufficiently strong Coulomb and electron-phonon interactions, respectively. Our results compare favorably with the available experimental and Monte Carlo data. PMID- 21817325 TI - Effects of dislocations on electron channeling. AB - The phenomenon of electron channeling in a crystal affected by dislocations is considered. Earlier we had considered the quantum aspects of the positron channeling in a crystal bent by dislocations where the effects of longitudinal motion of the particle were also considered along with the transverse motion. In this paper, the effective potential for the electron case is found for the two regions of dislocation-affected channel. There is considerable shift in the potential minima due to dislocations. The frequency and the corresponding spectrum of the channeling radiation due to electrons channeling through the perfect channel and the two regions of dislocation-affected channels are calculated. The spectral distribution of radiation intensity changes with the parameters of dislocation. The continuity of wavefunctions and their derivatives is used at the three boundaries and the reflection and transmission coefficients are found using these boundary conditions in the same way as in the positron case. PMID- 21817326 TI - Direct visualization of damage cascades in lithium niobate crystals caused by high-energy ions. AB - Congruently melting undoped lithium niobate crystals are irradiated with 20 MeV (3)He ions which penetrate the entire crystal volume. Radiation damage effects are directly visualized by transmission electron microscopy (TEM) where damage zones with diameters of 4 nm give rise to circular Fresnel fringe contrasts. These regions of modified material, appearing circular in cross-section, are interpreted as damage cascades inflicted by fast Nb and O atoms displaced in knock-on collisions with primary (3)He ions. This two-step displacement process results in local density changes manifested by the contrast behaviour of Fresnel fringes observed in TEM images. PMID- 21817327 TI - Derivation of the heat capacity anomaly at a first-order transition by using a semi-adiabatic relaxation technique. AB - This paper deals with the problem of determining the heat capacity anomaly associated with a first-order transition when using relaxation calorimetry. A method of data recording and analysis is proposed, which is shown to be well suited to investigate such a feature, including its hysteretical character. This technique is applied to spinel vanadates, allowing us to shed light on a recent controversy about the double-transition which takes place in these oxides. PMID- 21817328 TI - First-principles study of the electronic, vibrational, electron-phonon interaction and thermodynamics properties of ZrNi(2)Ga. AB - Using first-principles calculation, we investigate systematically the properties of ZrNi(2)Ga with fcc L 2(1) Heusler structure, including the electronic structure, phonon dispersion, electron-phonon interaction and thermodynamics. The calculated electron-phonon coupling constant lambda and the logarithmically averaged frequency [Formula: see text] are 0.747 and 68.48 cm(-1), respectively, giving the superconducting transition temperature T(c) = 3.15 K according to the Allen-Dynes formula. It is in good agreement with the corresponding experimental T(c) and ZrNi(2)Ga therefore can be explained as a conventional phonon-mediated superconductor. PMID- 21817329 TI - Proton momentum distribution and anomalous scattering intensities in a pseudo spherical ammonium ion: a neutron Compton scattering study of (NH(4))(2)PdCl(6) and (NH(4))(2)TeCl(6). AB - Neutron Compton scattering (NCS) measurements on ammonium hexachloropalladate and hexachlorotellurate were performed at room temperature. Proton scattering intensities and momentum distributions, as measured in the NCS experiment, have been compared with results expected from the impulse approximation (IA) for both systems. The measurement shows that scattering intensity from protons is anomalous even though their momentum distribution has a second moment that agrees very well with the ab initio calculation for an isolated pseudo-spherical NH(4)(+) ion in the ground vibrational state. Detailed data analysis shows that there is no extra (beyond the IA expected value) broadening or peak shift of proton momentum distribution due to ultra-fast kinetics of the Compton scattering process leading to anomalous scattering intensities. This is most probably due to highly symmetric local potential in the NH(4)(+). Presented results have interesting implications for further theoretical work in the field. PMID- 21817330 TI - Scattering-induced entanglement between spin qubits at remote two-state structures. AB - A theoretical scheme is presented for the entanglement of two-electron spin qubits bound in series within a quasi-one-dimensional mesoscopic structure at a distance beyond their normal range of interaction. A third electron is scattered from them, and full entanglement is achieved upon measurement of a transmitted electron in the correct spin state. Critically, each bound electron is trapped within an individual structure that has at least two spatial states. Two simple examples of such structures are discussed here. One is a 'stub', in which a quantum dot (for example) is coupled to one side of the quasi-one-dimensional structure. The other is a pair of degenerate, coupled quantum dots, with strong interdot Coulomb repulsion, placed within the one-dimensional superstructure. Both of these are shown to allow generation of entanglement with a significant probability of success. In contrast to the results of the authors' previous works, this allows for the generation of entanglement in a series, rather than in a parallel, configuration of the bound electrons with respect to the propagating electron. PMID- 21817331 TI - Structural transition, electrical and magnetic properties of the B-site Co doped Sr(14)Cu(24)O(41) compounds. AB - The effect of Co substitution for Cu on the structure and physical properties of Sr(14)(Cu(1-x)Co(x))(24)O(41) compounds was studied by analyzing the selected area electron diffraction and convergent-beam electron diffraction patterns, and by measuring the magnetic susceptibility, the electrical resistivity and Raman spectra. It is found that the space group of the CuO(2) chain is changed from Amma to Ammm upon Co doping, but the structure of the Cu(2)O(3) ladder remains unchanged. This indicates that the displacement between two neighboring CuO(2) chains has disappeared due to Co doping. Once a small amount of Co ions are doped into the compound, exceptional changes in the Weiss temperature and in the number of dimers occur. The remarkable increase in the absolute value of the Weiss temperature indicates that the antiferromagnetic interaction in CuO(2) chains becomes very strong due to Co doping. The increase in the Curie coefficient and the number of dimers implies that the Co doping causes Zhang-Rice singlets in the chains to be decoupled into free spins Cu(2+) and holes. Then, the free spins Cu(2+) are coupled into dimers, and the holes transfer from chains to ladders, which causes the resistivity to decrease when the Co dopant concentration is low (x<0.10). When the Co dopant concentration is high (x>0.10), some Co ions are directly substituted for the Cu ions in the ladders, which results in an increase in resistivity with increasing Co dopant content. PMID- 21817332 TI - Coulomb repulsion and correlation strength in LaFeAsO from density functional and dynamical mean-field theories. AB - The LDA+DMFT (local density approximation combined with dynamical mean-field theory) computation scheme has been used to calculate spectral properties of LaFeAsO-the parent compound of the new high-T(c) iron oxypnictides. The average Coulomb repulsion [Formula: see text] and Hund's exchange J parameters for iron 3d electrons were calculated using the first-principles constrained density functional theory scheme in the Wannier functions formalism. Resulting values strongly depend on the number of states taken into account in the calculations: when the full set of O-2p, As-4p and Fe-3d orbitals and the corresponding bands are included, the interaction parameters [Formula: see text] eV and J = 0.8 eV are obtained. In contrast, when the basis set is restricted to the Fe-3d orbitals and bands only, the calculation gives much smaller values of [Formula: see text] eV, J = 0.5 eV. Nevertheless, DMFT calculations with both parameter sets and the corresponding basis sets result in a weakly correlated electronic structure that is in agreement with the experimental x-ray and photoemission spectra. PMID- 21817333 TI - Photo-induced insulator-metal transition probed by Raman spectroscopy. AB - Strongly correlated electron systems give an opportunity to manipulate charge, orbital, magnetic and structural phases of matter. Here we show that the insulating phase where charges are localized can be delocalized through photo excitation which, in turn changes the structure locally, inducing an orthorhombic to rhombohedral phase transition. The I-M transition was witnessed for La(1 x)Sr(x)MnO(3) compounds in Raman spectra and photo-induced conduction simultaneously. A simple continuous argon ion laser source was used for optical excitation. The photon energy was 2.53 eV and the power can be chosen anywhere between 5 and 45 mW. Our studies clearly bring out the role of local disorder in the form of Jahn-Teller distortion in the localization of electrons. PMID- 21817334 TI - Comparison of different methods for analyzing MUSR line shapes in the vortex state of type-II superconductors. AB - A detailed analysis of muon-spin rotation (MUSR) spectra in the vortex state of type-II superconductors using different theoretical models is presented. Analytical approximations of the London and Ginzburg-Landau (GL) models, as well as an exact solution of the GL model were used. The limits of the validity of these models and the reliability for extracting parameters such as the magnetic penetration depth lambda and the coherence length xi from the experimental MUSR spectra were investigated. The analysis of the simulated MUSR spectra showed that at high magnetic fields there is a strong correlation between lambda and xi obtained for any value of the Ginzburg-Landau parameter kappa = lambda/xi. The smaller the applied magnetic field, the smaller the possibility of finding the correct value of xi. A simultaneous determination of lambda and xi without any restrictions is very problematic, regardless of the model used to describe the vortex state. It was found that for extreme type-II superconductors and low magnetic fields, the fitted value of lambda is practically independent of xi. The second-moment method frequently used to analyze MUSR spectra by means of a multi component Gaussian fit generally yields reliable values of lambda over the whole range of applied fields [Formula: see text] (H(c1) and H(c2) are the first and second critical fields, respectively). These results are also relevant for the interpretation of small-angle neutron scattering experiments on the vortex state in type-II superconductors. PMID- 21817335 TI - Spin glass behaviors compatible with a Zhang-Rice singlet within an effective model for cuprate superconductors. AB - To address the incompatibility of Zhang-Rice singlet formation and the observed spin glass behavior, an effective model is proposed for the electronic behavior of cuprate materials. The model includes an antiferromagnetic interaction between the spin of the hole in a Zhang-Rice orbital and the spin of the hole on the corresponding copper site. While in the large interaction limit this recovers the t-J model, in the low energy limit the Zhang-Rice singlets are deformed. It is also shown that such deformation can induce random defect ferromagnetic (FM) bonds between adjacent local spins, an effect herein referred to as unusual double exchange, and then spin glass behavior shall result in the case of localized holes. A derivation of the model is also presented. PMID- 21817336 TI - Point-contact spectroscopy of the heavy-fermion superconductor CePt(3)Si. AB - Differential resistance spectra (dV/dI-V characteristics) have been measured for point contacts between the heavy-fermion superconductor (HFS) CePt(3)Si and a normal metal. Some contacts show a peak at V = 0 that is characteristic of HFS coexisting with a magnetic order such as UPd(2)Al(3), UNi(2)Al(3) and URu(2)Si(2). The evolution of the peak occurs well above the antiferromagnetic transition temperature T(N)~2.2 K, so that the direct relationship with the magnetic transition is questionable. The half-width of the peak seems to reflect the crystal field splitting or the spin-wave gap as observed for the above mentioned HFSs, possibly suggesting that some common scattering process induces the zero-bias peaks in these materials. PMID- 21817337 TI - Effect of parallel transport currents on the d-wave Josephson junction. AB - In this paper, the non-local mixing of coherent current states in d-wave superconducting banks is investigated. The superconducting banks are connected via a ballistic point contact. The banks have mis-orientation and phase difference. Furthermore, they are subjected to a tangential transport current along the ab plane of d-wave crystals and parallel to the interface between the superconductors. The effects of mis-orientation and external transport current on the current-phase relations and current distributions are the subjects of this paper. It is observed that, at values of phase difference close to 0, pi and 2pi, the current distribution may have a vortex-like form in the vicinity of the point contact. The current distribution of the above-mentioned junction between d-wave superconductors is totally different from the junction between s-wave superconductors. The interesting result which this study shows is that spontaneous and Josephson currents are observed for the case of phi = 0. PMID- 21817338 TI - Temperature dependent pinning phenomenon in superconducting Nb films with triangular and honeycomb pinning arrays. AB - The pinning phenomena in superconducting Nb films with triangular and honeycomb pinning arrays were explored. Special temperature dependent phenomena were found for both films. For the film with a triangular pinning array, the pronounced matching peaks in the critical currents as a function of magnetic field reduce from six to three within a narrow temperature range. This temperature dependent matching effect is explained by considering the dramatic change of coherent length with temperature when the temperature is close to T(c). In order to compare with the film with a triangular pinning array, we fabricated a film with a honeycomb pinning array with similar pinning site spacing and pinning size. Special prominent matching peaks at H = 3.5H(1) were found for this film. Molecular dynamic simulations were made to study this phenomenon. The ground state distribution of vortices obtained from simulations reasonably explains the prominent matching peaks. Pronounced temperature dependent matching effects were also found for the film with a honeycomb pinning array. PMID- 21817339 TI - Structural stability of the sigma phase FeCr under pressure up to 77 GPa. AB - A tetragonal sigma phase of the equiatomic FeCr alloy was investigated by x-ray diffraction under pressure up to 77 GPa. The phase was found to be stable in the whole pressure range studied. The equation of state for the tetragonal phase was found to have a value of bulk modulus K(0) = 217(5) GPa and its pressure derivative was K(0)' = 5.8(2), which makes it less compressible than the constituent elements. Electronic factors governing the sigma phase stability are discussed in relation to the Hume-Rothery mechanism. PMID- 21817340 TI - Anomalous x-ray diffraction peak broadening and lattice strains in Zn(1-x)Co(x)O dilute magnetic semiconductors. AB - Nanocrystalline powders of Zn(1-x)Co(x)O synthesized by the coprecipitation technique show anomalous anisotropic broadening for x>0.05. This peak broadening is shown to be not only due to a reduction in the particle size but also due to a significant strain contribution, as confirmed by Williamson-Hall analysis. The presence of grouped Co(2+) ions, revealing the presence of clusters of high spin Co(2+) with antiferromagnetically coupled spins, as indicated by magnetization studies, seems to be responsible for the strain. PMID- 21817341 TI - Origins of bandgap bowing in compound-semiconductor common-cation ternary alloys. AB - We present an investigation into the existence and origins of bandgap bowing in compound-semiconductor common-cation ternary alloys. As examples, we consider CdSe(x)Te(1-x) and ZnSe(1-x)Te(x) alloys. A calculation, based on the sp(3)s(*) tight-binding method including spin-orbit coupling within the framework of the virtual crystal approximation, is employed to determine the bandgap energy, local density of states and atomic charge states versus composition and valence-band offset. The results show that (i) in the valence band, the top states are mainly contributed by Te atoms. The degree of ionicity of all atoms is found to vary linearly with mole fraction x. (ii) There is a strong competition between the anions (Se and Te) in trapping/losing charges and this competition is the main reason for the bandgap bowing character. (iii) There is a reasonable agreement between the calculated results and the available photoluminescence data. (iv) The bowing parameter is found to increase with increasing valence-band offset and increasing lattice mismatch. PMID- 21817342 TI - The donor nature of muonium in undoped, heavily n-type and p-type InAs. AB - The charge state of muonium has been investigated in p-type doped, nominally undoped (low n-type) and heavily n-type doped InAs. The donor Mu(+) state is shown to be the dominant defect in all cases. Consequently, muonium does not simply counteract the prevailing conductivity in this material. This is consistent with the charge neutrality level lying above the conduction band minimum in InAs. PMID- 21817343 TI - Computer modeling of Ba(2)RE(3+)NbO(6) (RE(3+) = rare-earth and Y) compounds. AB - In this work we have performed atomistic simulations in Ba(2)RE(3+)NbO(6) (RE(3+) = La, Ce, Nd, Pr, Pm, Sm, Eu, Gd, Tb, Dy, Y, Ho, Er, Tm, Yb and Lu) compounds in order to predict their physical properties and behavior under lanthanide substitutions. The potential model adopted describes very well the structural and dielectric properties of these materials. The dependence of the tolerance factor on their physical properties was investigated and the results indicate that the lattice energy, sound velocities and bulk modulus do not show morphotropic phase boundaries between the three phases in which these compounds crystallize. These observables have a linear dependence on the tolerance factor. Only the elastic constant shows morphotropic phase boundaries. PMID- 21817344 TI - Thermal expansion, polarization and phase diagrams of Ba(1-y)Bi(2y/3)Ti(1 x)Zr(x)O(3) and Ba(1-y)La(y)Ti(1-y/4)O(3) compounds. AB - The thermal expansion properties of the ceramic compositions Ba(1-y)La(y)Ti(1 y/4)O(3) (y = 0.0, 0.026, 0.036, 0.054) and Ba(1-y)Bi(2y/3)Ti(1-x)Zr(x)O(3) (y = 0.10; x = 0.0, 0.04, 0.05, 0.10, 0.15) were determined in the temperature range 120-700 K. We report the temperature-dependent measurements of the strain, thermal expansion coefficient and the magnitude of root mean square polarization. The results obtained are discussed together with the data on the structure and dielectric properties. PMID- 21817345 TI - Order-disorder nature of the antiferroelectric transition in Pb(2)MnWO(6). AB - The nature of the para-antiferroelectric phase transition in Pb(2)MnWO(6) was investigated by x-ray absorption spectroscopy. Extended x-ray absorption spectra (EXAFS) and x-ray absorption near-edge structure (XANES) at the Pb L(3)-edge, W L(3)-edge and Mn K-edge were measured at temperatures above and below the transition temperature, T(c)~445 K. The temperature dependence of the local geometrical and electronic structure around each of the three atoms was quantitatively determined. XANES spectra confirm the expected formal valence state as Pb(2+), W(6+) and Mn(2+) both above and below T(c). There are no significant changes of the local structure around the three atoms, which remains distorted in the whole temperature range. This indicates the existence of dynamic local distortions with a short-range order in the paraelectric phase. Below T(c), the local distortions (and the electrical dipoles) are static and their ordered arrangement gives rise to the orthorhombic crystallographic structure. Above T(c), these distortions are dynamically disordered, causing an average cubic crystallographic structure. Hence, the phase transition is of the order-disorder type. PMID- 21817346 TI - Jahn-Teller effect in BaTiO(3):Cr(5+): an electron paramagnetic resonance study. AB - Electron paramagnetic resonance (EPR) spectra of Cr(I)(5+) defects incorporated on Ti(4+) sites in single-crystal and powdered ceramics of BaTiO(3) were investigated in the temperature range 50-220 K at 34 GHz (Q band). Single-crystal and powder measurements allow the unambiguous determination of the full g tensor in the ferroelectric rhombohedral phase whereas in the orthorhombic phase only the determination of the principal values of the Cr(I)(5+) g tensor was successful. The [Formula: see text] Jahn-Teller effect stabilizes the vibronic ground state of the 3d(1) electron of the Cr(I)(5+) ion and leads to a tetragonally compressed defect-O(6) octahedron with the point symmetry D(4h). The spontaneous electrical polarization present in the ferroelectric phases of BaTiO(3) appears as a further perturbation. The quadratic field effect reduces the D(4h) symmetry of the Cr(I)(5+) defect centre and produces an additional g tensor breaking the tetragonal symmetry of the Zeeman term. For symmetry reasons one of the principal axes of the rhombic g tensor must be directed along one [Formula: see text] direction. The angles of the other two principal axes with respect to the [Formula: see text] axes are dependent on the absolute value of the spontaneous polarization. The difference in the temperature behaviour of the single-crystal and powder spectra can be explained by the presence of internal stress in the grains of the ceramic samples which increases the JT energy of the 3d(1) electron. PMID- 21817347 TI - Magnetic anisotropy in Ni-Fe-Ga-Co ferromagnetic shape memory alloys in the single-variant state. AB - The effects of the addition of Co on the magnetic anisotropy in Ni(55 x)Fe(18)Ga(27)Co(x) (x = 1-6) single-variant ferromagnetic shape memory alloys have been investigated. By the addition of Co from 1 to 6 at.%, the Curie temperature T(C) is increased from 318 to 405 K, keeping the martensitic transformation temperatures above room temperature. As a result, the value of the uniaxial magnetic anisotropy constant |K(u)| at 300 K increases with increasing x of the Co concentration and the martensite phase of Ni(49)Fe(18)Ga(27)Co(6) exhibits a relatively high value of |K(u)| = 1.15 * 10(5) J m(-3) at 300 K. With increasing Co concentration, on the other hand, the c axis changes from the magnetic easy axis to the hard axis at 4.2 K, that is, the sign of K(u) is reversed from positive to negative between 2 and 3 at.% Co. Furthermore, K(u) in Ni(53)Fe(18)Ga(27)Co(2) is positive below 100 K and negative above 100 K up to T(C), reducing the magnetic anisotropy around 200 K. From the present results, it is evident that the magnetic anisotropy of Ni(55-x)Fe(18)Ga(27)Co(x) (x = 1-6) single-variant ferromagnetic shape memory alloys is very sensitive to Co concentration and also temperature. PMID- 21817348 TI - Magnetism, transport, and specific heat of electronically phase-separated Pr(0.7)Pb(0.3)MnO(3) single crystals. AB - Magnetization, resistivity, and specific heat were studied systematically in the absence and presence of magnetic field in Pr(0.7)Pb(0.3)MnO(3) single crystals, in which electronic phase separation occurs near the ferromagnetic/metallic paramagnetic/insulating phase transition and the metal-insulator transition temperature is much higher than the Curie temperature. These measurements allow us to extract some fundamental physical parameters such as Fermi energy, density of states at the Fermi energy, Debye temperature, and interaction among electrons, phonons, and magnons. Furthermore, the magnetic entropy was studied around the phase transition temperature regime. It was found that a magnetic entropy change associated with the transition from the connected ferromagnetic phase to isolated superparamagnetic clusters appeared near the metal-insulator transition temperature following a large magnetic entropy change near the ferromagnetic-paramagnetic phase transition. PMID- 21817349 TI - Non-classical behaviour in an S = 5/2 chain with next nearest neighbour interactions observed from the inelastic neutron scattering of Mn(2)(OD)(2)(C(4)O(4)). AB - Low-dimensional and frustrated magnetic systems often show interesting quantum phenomena. The use of large moments such as S = 5/2 within such materials is uncommon, partly due to the evidence that the large manifold of states associated with these centres results in pseudo-classical behaviour. Here we report on the inelastic neutron scattering of Mn(2)(OD)(2)(C(4)O(4)), a well-isolated chain with next nearest neighbour interactions. We observe a magnetic excitation spectrum below 30 K whose characteristics resemble those of quantum spin singlets. Inelastic neutron scattering from a powdered sample is shown to yield a great deal of information about the nature of these effects. PMID- 21817350 TI - Magnetic behaviour of nickel-cyclam complexes in mesoporous silica: EPR investigations. AB - Electron paramagnetic resonance (EPR) investigations are carried out on mesoporous silica (SBA15) functionalized by Ni-cyclam complexes (1,4,8,11 tetraazacyclotetradecane groups chelating nickel ions). The magnetic behaviour of nickel-cyclam groups, their mutual interactions and dispersions in the mesoporous silica are compared with respect to the doping rates and the synthesis procedures. The spin-spin interactions and the relaxation processes were clarified from the thermal evolution in the temperature range (4 K, 300 K) of the paramagnetic spin susceptibilities and EPR line widths. Thus, the relaxation mechanisms seem marked by the Jahn-Teller effect on the nickel ions mediated by exchange interactions between nearest spins. Isolated Ni-cyclam molecules are involved in some samples while others show the formation of clusters where phonon assisted one-dimensional (1D) ferromagnetic ordering occurs below 45 K. The performed experiments point out the efficiency of the EPR technique to probe the degree of functionalization of mesoporous silica by Ni-cyclam molecules and to give valuable feedback to improve the synthesis routes. PMID- 21817351 TI - Comment on 'Particle size dependent exchange bias and cluster-glass states in LaMn(0.7)Fe(0.3)O(3) '. AB - Thakur et al (2008 J. Phys.: Condens. Matter 20 195215) have recently reported magnetization hysteresis loops shifted along the field axis of the cluster-glass compound LaMn(0.7)Fe(0.3)O(3), attributed there to exchange bias induced at ferromagnetic/spin-glass-like interfaces. The present comment affirms that their results are insufficient for assigning the phenomenon solely to exchange bias since the corresponding field shift, if any, cannot be separated from that of a minor hysteresis loop of a ferromagnet, naturally displaced from the origin. PMID- 21817352 TI - Reply to comment on 'Particle size dependent exchange bias and cluster-glass states in LaMn(0.7)Fe(0.3)O(3) '. AB - In reply to the comment by Geshev we emphasize that loop shift in the compounds is not a simplified phenomenon of minor loop effect of a ferromagnet rather, it is a genuine signature of exchange bias effect. The estimate of anisotropy field and the plot of exchange bias field at 5 K with the maximum field used for the measurement of hysteresis loop, in addition to the previously reported results such as temperature dependence of exchange bias field, training effect, etc, confirm the exchange bias effect. PMID- 21817353 TI - FLAPW: applications and implementations. AB - Modern material design involves a close collaboration between experimental and computational materials scientists. To be useful, the theory must be able to accurately predict the stability and properties of new materials, describe the physics of the experiments, and be applicable to new and complex structures-the all-electron full-potential linearized augmented plane wave (FLAPW) is one such method that provides the requisite level of numerical accuracy, albeit at the cost of complexity. Technical aspects and modifications related to the choice of basis functions (energy parameters, core-valence orthogonality, extended local orbitals) that affect the applicability and accuracy of the method are described, as well as an approach for obtaining k-independent matrix elements. The inclusion of external electric fields is illustrated by results for the induced densities at the surfaces of both magnetic and non-magnetic metals, and the relationship to image planes and to nonlinear effects such as second harmonic generation. The magnetic coupling of core hole excitations in Fe, the calculation of intrinsic defect formation energies, the concentration-dependent chemical potentials, entropic contributions, and the relative phase stability of Zr-rich Zr-Al alloys are also discussed. PMID- 21817354 TI - Transport and optical conductivity in dilute magnetic semiconductors. AB - A theory of transport in spin and charge disordered media is developed, with a particular emphasis on dilute magnetic semiconductors. The approach is based on the equation of motion for the current-current response function and considers both spin and charge disorder and electron-electron interaction on an equal footing. The formalism is applied to the specific case of Ga(1-x)Mn(x)As. Within the single parabolic band approximation it is shown that both spin (p-d exchange) and charge (Coulomb) scattering contributions to the resistivity are of the same order of magnitude and should be treated simultaneously. Positional correlations of charged impurities are shown to significantly increase the Coulomb scattering. In the magnetically ordered phase, the suppression of localized spin fluctuations leads to a sizable reduction of spin scattering, which may contribute to the experimentally observed drop in resistivity below the critical temperature. The developed model allows for a comprehensive treatment of electron-electron interaction, screening and correlation effects by means of time-dependent density functional theory. It is shown that collective modes and a dynamical treatment of electron-electron interaction are essential for an accurate description of the infrared absorption spectrum. PMID- 21817355 TI - A density functional for sparse matter. AB - Sparse matter is abundant and has both strong local bonds and weak nonbonding forces, in particular nonlocal van der Waals (vdW) forces between atoms separated by empty space. It encompasses a broad spectrum of systems, like soft matter, adsorption systems and biostructures. Density-functional theory (DFT), long since proven successful for dense matter, seems now to have come to a point, where useful extensions to sparse matter are available. In particular, a functional form, vdW-DF (Dion et al 2004 Phys. Rev. Lett. 92 246401; Thonhauser et al 2007 Phys. Rev. B 76 125112), has been proposed for the nonlocal correlations between electrons and applied to various relevant molecules and materials, including to those layered systems like graphite, boron nitride and molybdenum sulfide, to dimers of benzene, polycyclic aromatic hydrocarbons (PAHs), doped benzene, cytosine and DNA base pairs, to nonbonding forces in molecules, to adsorbed molecules, like benzene, naphthalene, phenol and adenine on graphite, alumina and metals, to polymer and carbon nanotube (CNT) crystals, and hydrogen storage in graphite and metal-organic frameworks (MOFs), and to the structure of DNA and of DNA with intercalators. Comparison with results from wavefunction calculations for the smaller systems and with experimental data for the extended ones show the vdW-DF path to be promising. This could have great ramifications. PMID- 21817356 TI - A grid-based Bader analysis algorithm without lattice bias. AB - A computational method for partitioning a charge density grid into Bader volumes is presented which is efficient, robust, and scales linearly with the number of grid points. The partitioning algorithm follows the steepest ascent paths along the charge density gradient from grid point to grid point until a charge density maximum is reached. In this paper, we describe how accurate off-lattice ascent paths can be represented with respect to the grid points. This improvement maintains the efficient linear scaling of an earlier version of the algorithm, and eliminates a tendency for the Bader surfaces to be aligned along the grid directions. As the algorithm assigns grid points to charge density maxima, subsequent paths are terminated when they reach previously assigned grid points. It is this grid-based approach which gives the algorithm its efficiency, and allows for the analysis of the large grids generated from plane-wave-based density functional theory calculations. PMID- 21817357 TI - Tailoring the reactivity of bimetallic overlayer and surface alloy systems. AB - Changing the composition and structure of a bimetallic surface system modifies its electronic properties and thus its catalytic activity. On the basis of density functional theory calculations, the electronic factors underlying the modified properties of bimetallic surfaces such as overlayer systems and, in particular, surface alloys will be discussed. It will be demonstrated that by mixing two metals a new metallic compound can result whose properties are not intermediate but beyond those of both constituents, so that for example by adding a relatively inert metal a more reactive surface can result. Besides the reactivity, the stability of the bimetallic systems will also be briefly discussed. PMID- 21817358 TI - Lattice instability and superconductivity in electron doped (3, 3) carbon nanotubes. AB - We investigated the effect of electron doping on the phonon dispersion and electron-phonon coupling of a small diameter (3, 3) carbon nanotube using first principles density functional perturbation theory. Electron doping increases the number of nesting features in the electronic band structure, which is reflected in a wealth of phonon anomalies. We found that the overall electron-phonon coupling is substantially enhanced with respect to the pristine tube, which improves superconductivity. At the same time, the intrinsic Peierls instability remains similar, but the Peierls temperature still remains larger than the superconducting transition temperature. PMID- 21817359 TI - Materials modeling by design: applications to amorphous solids. AB - In this paper, we review a host of methods used to model amorphous materials. We particularly describe methods which impose constraints on the models to ensure that the final model meets a priori requirements (on structure, topology, chemical order, etc). In particular, we review work based on quench from the melt simulations, the 'decorate and relax' method, which is shown to be a reliable scheme for forming models of certain binary glasses. A 'building block' approach is also suggested and yields a pleading model for GeSe(1.5). We also report on the nature of vulcanization in an Se network cross-linked by As, and indicate how introducing H into an a-Si network develops into a-Si:H. We also discuss explicitly constrained methods including reverse Monte Carlo (RMC) and a novel method called 'Experimentally Constrained Molecular Relaxation'. The latter merges the power of ab initio simulation with the ability to impose external information associated with RMC. PMID- 21817360 TI - Searching for low-energy structures of nanoparticles: a comparison of different methods and algorithms. AB - Nanoparticles can have unusual, low symmetry or non-crystalline shapes. Since structure determines nanoparticle physical and chemical properties, many efforts have been devoted to predict what are the most stable structural motifs depending on cluster size and composition. The global optimization of the 3N-dimensional potential energy surface of a nanocluster is nevertheless a very difficult computational problem. Here we depict the scenery of the global optimization strategies applied to the study of nanoclusters, focusing on genetic and Basin hopping approaches. Moreover, several strategies to improve Basin-hopping efficiency are discussed and compared through the optimization of test-systems with different size and composition. PMID- 21817361 TI - Diversity driven unbiased search of minimum energy cluster configurations. AB - The determination of the spatial distributions that atoms adopt to form condensed matter is a problem of crucial importance, since most physical properties depend on the atomic arrangement. This is especially relevant for clusters, where periodicity is nonexistent. Several optimization procedures have been implemented to tackle this problem, with ever increasing success. Here we put forward a search scheme which preserves as large a diversity as allowed by the use of phenomenological potentials, generating in an unbiased fashion a bank of configurations to be explored; a procedure we denominate diversity driven unbiased search (DDUS). It consists in the generation, using phenomenological potentials, of a data bank of putative minima rather than a single, or just a few, configurations which are based on the conformational space annealing method (CSA). All of the configurations in the bank are thereafter refined by means of DFT computations. Certainly, in spite of our efforts to generate a bank as diverse as possible, not all relevant structures might be included in it, since quantum effects are ignored. The procedure is applied to several examples of rhodium, palladium, silver, platinum and gold clusters, between 5 and 23 atoms in size. The main conclusion we reach is that unbiased search, among a significant number of candidates, quite often leads to rather unexpectedly low symmetry configurations, which turn out to be the lowest energy ones within our scheme. PMID- 21817362 TI - Finding mechanism of transitions in complex systems: formation and migration of dislocation kinks in a silicon crystal. AB - We demonstrate how a saddle point search method can be used to study dislocation mobility in a covalent material-a non-trivial transition mechanism in a complex system. Repeated saddle point searches have been carried out by using the minimum mode following algorithm and dimer method in combination with several empirical potential functions for silicon in order to determine the mechanisms for the creation and migration of kinks on a non-dissociated screw dislocation in a silicon crystal. For the environment-dependent interatomic potential, three possible kink migration processes have been identified with activation energies of 0.17, 0.25, and 0.33 eV. The Lenosky potential gives a single, low energy migration mechanism with an activation energy of 0.07 eV, in good agreement with density functional theory results. The kink formation mechanism determined using this potential has an activation barrier of 1.2 eV. Calculations were also carried out with the Tersoff potential, Stillinger-Weber potential and Bolding Andersen potential. The various potential functions give quite different results for the kink structure and the mechanism of transition. PMID- 21817363 TI - Atomistic studies of strain relaxation in heteroepitaxial systems. AB - We present a review of recent theoretical studies of different atomistic mechanisms of strain relaxation in heteroepitaxial systems. We explore these systems in two and three dimensions using different semi-empirical interatomic potentials of Lennard-Jones and many-body embedded atom model type. In all cases we use a universal molecular static method for generating minimum energy paths for transitions from the coherent epitaxial (defect free) state to the state containing an isolated defect (localized or extended). This is followed by a systematic search for the minimum energy configuration as well as self organization in the case of a periodic array of islands. In this way we are able to understand many general features of the atomic mechanisms and energetics of strain relaxation in these systems. Finally, for the special case of Pd/Cu(100) and Cu/Pd(100) heteroepitaxy we also use conventional molecular dynamics simulation techniques to compare the compressively and tensilely strained cases. The results for this case are in good agreement with the existing experimental data. PMID- 21817364 TI - Accelerated molecular dynamics simulation of thin-film growth with the bond-boost method. AB - We review the bond-boost method for accelerated molecular dynamics (MD) simulation and we demonstrate its application to kinetic phenomena relevant to thin-film growth. To illustrate various aspects of the method, three case studies are presented. We first illustrate aspects of the bond-boost method in studies of the diffusion of Cu atoms on Cu(001). In these studies, Cu interactions are described using a semi-empirical embedded-atom method potential. We recently extended the bond-boost method to perform accelerated ab initio MD (AIMD) simulations and we present results from preliminary studies in which we applied the bond-boost method in AIMD to uncover diffusion mechanisms of Al adatoms on Al(110). Finally, a problem inherent to many rare-event simulation methods is the 'small-barrier problem', in which the system resides in a group of states connected by small energy barriers and separated from the rest of phase space by large barriers. We developed the state-bridging bond-boost method to address this problem and we discuss its application for studying the diffusion of Co clusters on Cu(001). We discuss the outlook for future applications of the bond-boost method in materials simulation. PMID- 21817365 TI - Off-lattice self-learning kinetic Monte Carlo: application to 2D cluster diffusion on the fcc(111) surface. AB - We report developments of the kinetic Monte Carlo (KMC) method with improved accuracy and increased versatility for the description of atomic diffusivity on metal surfaces. The on-lattice constraint built into our recently proposed self learning KMC (SLKMC) (Trushin et al 2005 Phys. Rev. B 72 115401) is released, leaving atoms free to occupy 'off-lattice' positions to accommodate several processes responsible for small-cluster diffusion, periphery atom motion and heteroepitaxial growth. This technique combines the ideas embedded in the SLKMC method with a new pattern-recognition scheme fitted to an off-lattice model in which relative atomic positions are used to characterize and store configurations. Application of a combination of the 'drag' and the repulsive bias potential (RBP) methods for saddle point searches allows the treatment of concerted cluster, and multiple- and single-atom, motions on an equal footing. This tandem approach has helped reveal several new atomic mechanisms which contribute to cluster migration. We present applications of this off-lattice SLKMC to the diffusion of 2D islands of Cu (containing 2-30 atoms) on Cu and Ag(111), using the interatomic potential from the embedded-atom method. For the hetero-system Cu/Ag(111), this technique has uncovered mechanisms involving concerted motions such as shear, breathing and commensurate-incommensurate occupancies. Although the technique introduces complexities in storage and retrieval, it does not introduce noticeable extra computational cost. PMID- 21817366 TI - Parallel kinetic Monte Carlo simulations of Ag(111) island coarsening using a large database. AB - The results of parallel kinetic Monte Carlo (KMC) simulations of the room temperature coarsening of Ag(111) islands carried out using a very large database obtained via self-learning KMC simulations are presented. Our results indicate that, while cluster diffusion and coalescence play an important role for small clusters and at very early times, at late time the coarsening proceeds via Ostwald ripening, i.e. large clusters grow while small clusters evaporate. In addition, an asymptotic analysis of our results for the average island size S(t) as a function of time t leads to a coarsening exponent n = 1/3 (where S(t)~t(2n)), in good agreement with theoretical predictions. However, by comparing with simulations without concerted (multi-atom) moves, we also find that the inclusion of such moves significantly increases the average island size. Somewhat surprisingly we also find that, while the average island size increases during coarsening, the scaled island-size distribution does not change significantly. Our simulations were carried out both as a test of, and as an application of, a variety of different algorithms for parallel kinetic Monte Carlo including the recently developed optimistic synchronous relaxation (OSR) algorithm as well as the semi-rigorous synchronous sublattice (SL) algorithm. A variation of the OSR algorithm corresponding to optimistic synchronous relaxation with pseudo-rollback (OSRPR) is also proposed along with a method for improving the parallel efficiency and reducing the number of boundary events via dynamic boundary allocation (DBA). A variety of other methods for enhancing the efficiency of our simulations are also discussed. We note that, because of the relatively high temperature of our simulations, as well as the large range of energy barriers (ranging from 0.05 to 0.8 eV), developing an efficient algorithm for parallel KMC and/or SLKMC simulations is particularly challenging. However, by using DBA to minimize the number of boundary events, we have achieved significantly improved parallel efficiencies for the OSRPR and SL algorithms. Finally, we note that, among the three parallel algorithms which we have tested here, the semi-rigorous SL algorithm with DBA led to the highest parallel efficiencies. As a result, we have obtained reasonable parallel efficiencies in our simulations of room-temperature Ag(111) island coarsening for a small number of processors (e.g. N(p) = 2 and 4). Since the SL algorithm scales with system size for fixed processor size, we expect that comparable and/or even larger parallel efficiencies should be possible for parallel KMC and/or SLKMC simulations of larger systems with larger numbers of processors. PMID- 21817367 TI - Effects of impurities on surface morphology: some examples. AB - Small amounts of impurities are known to have remarkably great influence on surface morphology. We discuss three examples that arise in our research. First, we consider impurities codeposited during epitaxial growth, paying particular attention to Cu(100). After many layers of growth, the impurities can dramatically alter the surface morphology, changing the wavelength of the meandering instability and producing small square-base pyramids. Second, we consider the decoration of both island and vacancy island edges on Ag(111) with C(60). We use this system as a prototype to model how edge decoration with impurities can have a striking effect on the shape of the island as well as the dynamics of edge fluctuations. Finally, we show that about one per cent of pentacene quinone impurities alters the size of the critical nucleus in submonolayer pentacene deposition. This provides a platform on which to discuss our recent work characterizing the capture-zone distribution associated with the islands in terms of the generalized Wigner distribution, a simple one-parameter expression in which the characteristic exponent is the size of the smallest stable island. PMID- 21817368 TI - Formation of complex wedding-cake morphologies during homoepitaxial film growth of Ag on Ag(111): atomistic, step-dynamics, and continuum modeling. AB - An atomistic lattice-gas model is developed which successfully describes all key features of the complex mounded morphologies which develop during deposition of Ag films on Ag(111) surfaces. We focus on this homoepitaxial thin film growth process below 200 K. The unstable multilayer growth mode derives from the presence of a large Ehrlich-Schwoebel step-edge barrier, for which we characterize both the step-orientation dependence and the magnitude. Step dynamics modeling is applied to further characterize and elucidate the evolution of the vertical profiles of these wedding-cake-like mounds. Suitable coarse graining of these step-dynamics equations leads to instructive continuum formulations for mound evolution. PMID- 21817369 TI - A fast computational method for determining equilibrium concentration profiles in intermixed nanoislands. AB - An efficient computational method for finding the equilibrium concentration profiles which minimize the free energy of intermixed heteroepitaxial islands of assigned shape and average composition is described. A combination of a Monte Carlo method and continuum elasticity theory solved by a finite element method is shown to provide the desired profiles allowing for a significant computational gain with respect to atomistic approaches. The role played by dimensionality (ridges versus islands) and by entropy is discussed. PMID- 21817370 TI - Theory of Umklapp-assisted recombination of bound excitons in Si:P. AB - We present calculations for the oscillator strength of the recombination of excitons bound to phosphorus donors in silicon. We show that the direct recombination of the bound exciton cannot account for the experimentally measured oscillator strength of the no-phonon line. Instead, the recombination process is assisted by an Umklapp process of the donor electron state. We make use of the empirical pseudopotential method to evaluate the Umklapp-assisted recombination matrix element in second-order perturbation theory. Our result is in good agreement with experiment. Being potentially useful for quantum computing, the process of Umklapp-assisted recombination can be used to detect optically the spin state of the nucleus of a phosphorus donor, which requires that the energy levels of the nuclear spin are optically resolvable. We therefore present two methods to improve the optical resolution of the optical detection of the spin state of a single nucleus in Si:P. PMID- 21817371 TI - Thermal transport in polyethylene and at polyethylene-diamond interfaces investigated using molecular dynamics simulation. AB - The thermal conductances across covalently bonded interfaces between oriented single crystal diamond and completely aligned polyethylene chains are determined for the three principal orientations of diamond. The calculated thermal conductances, which range over 690-930 MW m(-2) K(-1), are consistent with those of other strongly bonded interfaces. These results suggest that the experimental interfacial conductances across hard-soft interfaces can be quite large if the bonding across the interface is strong, a conclusion that could have important implications for thermal management in bioelectromechanical systems and other inorganic-organic structures. The effects of defects and cross-linking on the thermal conductivity of polyethylene are also analyzed. PMID- 21817372 TI - Structural, vibrational and thermodynamic properties of Ag(n)Cu(34-n) nanoparticles. AB - We report results of a systematic study of structural, vibrational and thermodynamical properties of 34-atom bimetallic nanoparticles from the Ag(n)Cu(34-n) family using model interaction potentials as derived from the embedded atom method and invoking the harmonic approximation of lattice dynamics. Systematic trends in the bond length and dynamical properties can be explained largely from arguments based on local coordination and elemental environment. Thus an increase in the number of silver atoms in a given neighborhood introduces a monotonic increase in bond length, while an increase of the copper content does the reverse. Moreover, for the bond lengths of the lowest-coordinated (six and eight) copper atoms with their nearest neighbors (Cu atoms), we find that the nanoparticles divide into two groups with the average bond length either close to (~2.58 A) or smaller than (~2.48 A) that in bulk copper, accompanied by characteristic features in their vibrational density of states. For the entire set of nanoparticles, we find vibrational modes above the bulk bands of copper/silver. We trace a blue shift in the high-frequency end of the spectrum that occurs as the number of copper atoms increases in the nanoparticles, leading to shrinkage of the bond lengths from those in the bulk. The vibrational densities of states at the low-frequency end of the spectrum scale linearly with frequency as for single-element nanoparticles, with a more pronounced effect for these nanoalloys. The Debye temperature is found to be about one-third of that of the bulk for pure copper and silver nanoparticles, with a non-linear increase as copper atoms increase in the nanoalloy. PMID- 21817373 TI - The surface Rashba effect: a k.p perturbation approach. AB - For surface systems, the Rashba effect is studied by using a k.p perturbation method. It is shown that the velocity-operator term in the perturbation gives the generalized Rashba Hamiltonian, of which a group-theoretical analysis is given to explain variations in the spin splitting and spin structure expected for typical surface symmetry. The matrix elements of the velocity and spin-angular-momentum operators play a key role in determining the characteristic features of the surface Rashba effect. Whether a surface system shows isotropic spin splitting and vortical spin structure as given by the original Rashba Hamiltonian or not depends on the group of k appearing in the corresponding two-dimensional Brillouin zone. It is especially emphasized that the ideal Rashba effect may be realized even for a wavevector k without time reversal, which is usually believed to be a necessary condition. PMID- 21817374 TI - First-principles studies of the atomic reconstructions of CdSe (001) and (111) surfaces. AB - We have performed the first-principles total-energy calculations to investigate (2 * 1), (1 * 2), (2 * 2), (4 * 2) and (2 * 4) reconstructions of Cd- and Se terminated CdSe(001) and (111) surfaces as a function of the surface stoichiometry and the Cd chemical potential. We find that there exist Cd dimers on the (001) surface and Se tetramers on the (111) surface. Comparing surface formation energies as a function of the Cd chemical potential MU(Cd), we find the Cd-vacancy and Se-vacancy (2 * 2) structures to be energetically favorable for the Cd-terminated (001) surface at high MU(Cd) and Se-terminated (001) surface at low MU(Cd), respectively. In contrast, an Se-tetramer (2 * 4) structure is more favorable than the vacancy structure for the Se-terminated CdSe(111) surface almost in the whole region of allowed MU(Cd). PMID- 21817376 TI - Spin-polarized STM for a Kondo adatom. AB - We investigate the bias dependence of the tunneling conductance between a spin polarized (SP) scanning tunneling microscope (STM) tip and the surface conduction states of a normal metal with a Kondo adatom. Quantum interference between tip host metal and tip-adatom-host metal conduction paths is studied in the full range of the Fano parameter q. The spin-polarized STM gives rise to a splitting of the Kondo peak and asymmetry in the zero-bias anomaly, depending on the lateral tip-adatom distance. For increasing lateral distances, the Kondo peak splitting shows a strong suppression and the spin-polarized conductance exhibits the standard Fano-Kondo profile. PMID- 21817375 TI - Interaction potential for indium phosphide: a molecular dynamics and first principles study of the elastic constants, generalized stacking fault and surface energies. AB - Indium phosphide is investigated using molecular dynamics (MD) simulations and density-functional theory calculations. MD simulations use a proposed effective interaction potential for InP fitted to a selected experimental dataset of properties. The potential consists of two- and three-body terms that represent atomic-size effects, charge-charge, charge-dipole and dipole-dipole interactions as well as covalent bond bending and stretching. Predictions are made for the elastic constants as a function of density and temperature, the generalized stacking fault energy and the low-index surface energies. PMID- 21817377 TI - The role of steps in the dissociation of H(2) on Mg(0001). AB - The role of steps in the dissociation of molecules on metal surfaces has been extensively investigated in the past. In particular, both theoretical calculations and experimental results for H(2) dissociation on transition metal (TM) surfaces show that steps can significantly increase the reactivity, leading to higher metal-H binding energies and lower activation energies. Here we have used density functional theory (DFT) with the generalized gradient approximation (GGA) to investigate the role of steps on the Mg(0001) surface in the dissociation of H(2) and the binding of H to the metal surface. Our results follow those found for TM surfaces as far as H adsorption energies are concerned, namely that adsorption energies are higher near the steps. However, we find that the activation energy for the dissociation of hydrogen is hardly affected by the presence of steps, with a DFT-GGA value of 0.85 eV, only marginally lower than the value 0.87 eV found on the flat Mg(0001) surface. PMID- 21817378 TI - Core and valence exciton formation in x-ray absorption, x-ray emission and x-ray excited optical luminescence from passivated Si nanocrystals at the Si L(2,3) edge. AB - Resonant inelastic x-ray scattering (RIXS), x-ray absorption spectroscopy and x ray excited optical luminescence (XEOL) have been used to measure element specific filled and empty electronic states over the Si L(2,3) edge of passivated Si nanocrystals of narrow size distribution (diameter 2.2 +/- 0.4 nm). These techniques have been employed to directly measure absorption and luminescence specific to the local Si nanocrystal core. Profound changes occur in the absorption spectrum of the nanocrystals compared with bulk Si, and new features are observed in the nanocrystal RIXS. Clear signatures of core and valence band exciton formation, promoted by the spatial confinement of electrons and holes within the nanocrystals, are observed, together with band narrowing due to quantum confinement. XEOL at 12 K shows an extremely sharp feature at the threshold of orange luminescence (i.e., at ~1.56 eV (792 nm)) which we attribute to recombination of valence excitons, providing a lower limit to the nanocrystal band gap. PMID- 21817379 TI - Study of swift heavy-ion-induced modification in Ti/Si using x-ray standing waves. AB - Intermixing in a Si/Ti/Si tri-layer induced by 120 MeV Au ions has been studied. X-ray standing wave analysis combined with x-ray reflectivity has been used to get a depth profile of the Ti marker layer with an accuracy of a fraction of a nanometer. Two different thicknesses of the Ti marker layer have been used to study the possible effect of layer thickness on intermixing. In the case of a 2 nm thick Ti layer intermixing is stronger as compared to a 6 nm Ti film, which can be understood in terms of a stronger confinement of the dissipated energy in the Ti layer due to increased interface scattering of delta-electrons in the case of the 2 nm thick Ti layer. In the 6 nm thick Ti layer, intermixing is asymmetric at the two interfaces, which may be due to a possible asymmetry in the interface structure in the as-deposited film itself. PMID- 21817380 TI - Surface relaxation and stress for 5d transition metals. AB - Using the density functional theory, we present a systematic theoretical study of the layer relaxation and surface stress of 5d transition metals. Our calculations predict layer contractions for all surfaces, except for the (111) surface of face centered cubic Pt and Au, where slight expansions are obtained similarly to the case of the 4d series. We also find that the relaxations of the close packed surfaces decrease with increasing occupation number through the 5d series. The surface stress for the relaxed, most closely packed surfaces shows similar atomic number dependence as the surface energy. Using Cammarata's model and our calculated surface stress and surface energy values, we examine the possibility of surface reconstructions, which is in reasonable agreement with the experimental observations. PMID- 21817381 TI - Relative stability of low-index V(2)O(5) surfaces: a density functional investigation. AB - Ab initio density functional calculations of the structural and electronic properties of V(2)O(5) bulk and its low-index surfaces are presented. For the bulk oxide and the (010) surface (the natural cleavage plane) a good agreement with experiment and with earlier ab initio calculations is found. For the first time, the investigations are extended to other low-index surfaces: (001) and (100). On both surfaces, termination conserving a bulk-like stoichiometry is preferred, but-in contrast to the (010) surface-a strong structural relaxation takes place. Relaxation reduces the surface energy from 1.16 to 0.48 J m(-2) for the (001) and from 0.61 to 0.55 J m(-2) for the (100) surface. Although the relaxed surface energies are still one order of magnitude higher than calculated for the (010) surface (0.047 J m(-2)), the Wulff construction demonstrates that (001) and (100) surfaces contribute about 15% of the total surface area of a V(2)O(5) crystallite, indicating a non-negligible role in the catalytic activity of V(2)O(5). PMID- 21817382 TI - Electron-electron interaction effects on the photophysics of metallic single walled carbon nanotubes. AB - Single-walled carbon nanotubes are strongly correlated systems with large Coulomb repulsion between two electrons occupying the same p(z) orbital. Within a molecular Hamiltonian appropriate for correlated pi-electron systems, we show that optical excitations polarized parallel to the nanotube axes in the so-called metallic single-walled carbon nanotubes are excitons. Our calculated absolute exciton energies in twelve different metallic single-walled carbon nanotubes, with diameters in the range 0.8-1.4 nm, are in nearly quantitative agreement with experimental results. We have also calculated the absorption spectrum for the (21, 21) single-walled carbon nanotube in the E(22) region. Our calculated spectrum gives an excellent fit to the experimental absorption spectrum. In all cases our calculated exciton binding energies are only slightly smaller than those of semiconducting nanotubes with comparable diameters, in contradiction to results obtained within the ab initio approach, which predicts much smaller binding energies. We ascribe this difference to the difficulty of determining the behavior of systems with strong on-site Coulomb interactions within theories based on the density functional approach. As in the semiconducting nanotubes we predict in the metallic nanotubes a two-photon exciton above the lowest longitudinally polarized exciton that can be detected by ultrafast pump-probe spectroscopy. We also predict a subgap absorption polarized perpendicular to the nanotube axes below the lowest longitudinal exciton, blueshifted from the exact midgap by electron-electron interactions. PMID- 21817383 TI - Phase stabilization by rapid thermal annealing in amorphous hydrogenated silicon nitride film. AB - We have studied the effect of rapid thermal annealing (RTA) in the context of phase evolution and stabilization in hydrogenated amorphous silicon nitride (a SiN(x):H) thin films having different stoichiometries, deposited by an Hg sensitized photo-CVD (chemical vapor deposition) technique. RTA-treated films showed substantial densification and increase in refractive index. Our studies indicate that a mere increase in flow of silicon (Si)-containing gas would not result in silicon-rich a-SiN(x):H films. We found that out-diffusion of hydrogen, upon RTA treatment, plays a vital role in the overall structural evolution of the host matrix. It is speculated that less incorporation of hydrogen in as-deposited films with moderate Si content helps in the stabilization of the silicon nitride (Si(3)N(4)) phase and may also enable unreacted Si atoms to cluster after RTA. These studies are of great interest in silicon photonics where the post-treatment of silicon-rich devices is essential. PMID- 21817384 TI - Negative differential resistance in nanoscale transport in the Coulomb blockade regime. AB - Motivated by recent experiments, we have studied the transport behavior of coupled quantum dot systems in the Coulomb blockade regime using the master (rate) equation approach. We explore how electron-electron interactions in a donor-acceptor system, resembling weakly coupled quantum dots with varying charging energy, can modify the system's response to an external bias, taking it from normal Coulomb blockade behavior to negative differential resistance (NDR) in the current-voltage characteristics. PMID- 21817385 TI - Novel Andreev reflection and differential conductance of a ferromagnet/ferromagnet/superconductor junction on graphene. AB - Via numerical calculation of the spin-dependent Dirac-Bogoliubov-de Gennes equation, the differential conductance is obtained for a ferromagnet/ferromagnet/superconductor (F/F/S) junction on graphene where the two F layers are undoped. If the two F layers have noncollinear magnetizations, the spin-flipped scattering at the F/F interface leads to the novel Andreev reflection (AR), in which the spin directions of an incident electron and the reflected hole are opposite to each other. When the exchange energy is larger than the superconducting gap, this novel AR manifests itself as sub-gap differential conductance peaks because of the formation of spin-flipped Andreev bound states in the intermediate F layer, whereas for the parallel and anti parallel configurations no such peaks can be found. In the transitional regime with the exchange energy close to the gap, for noncollinear configurations, the round-trip path supporting the formation of those bound states is broken and a differential conductance dip can be found near the point where the external bias equals the exchange energy. PMID- 21817386 TI - Interference effect between superparamagnetic and spin glass correlated moments in a system of dispersed Co(3)O(4) nanocrystallites. AB - An inhomogeneous system of aggregates of Co(3)O(4) nanocrystallites dispersed in an amorphous SiO(2) matrix has been studied. X-ray diffraction and atomic force microscopy reveal a bimodal distribution of crystallite sizes, smaller nanocrystallites with dimension below 10 nm and larger nanocrystallites of about 20 nm. The Co(3)O(4) nanocrystallites enter the composition of nanograins with dimension 20-60 nm. The nanograins build aggregates with dimension 200-500 nm. A large value of the effective magnetic moment per Co(2+) ion obtained from the high-temperature susceptibility measurements indicates possible disturbance of the normal spinel structure in which a fraction of Co(3+) ions also possesses magnetic moment. An analysis based on the temperature dependence of the coercive field has shown that the smaller nanocrystallites behave as superparamagnetic particles with a blocking temperature of about 10 K. Simultaneous existence of two relaxation processes is observed in the frequency dependence of the imaginary part of the ac magnetic susceptibility in the vicinity of T = 15.8 K. The temperature dependence of the width of the distribution function of relaxation times obtained from the Cole-Cole diagrams exhibits behaviour characteristic for spin glass dynamics in a temperature range above 17.6 K and is temperature independent below 15.8 K, which is a property of superparamagnetic particles. The variation of the width of the distribution function between 17.6 and 15.8 K indicates that interference of the superparamagnetic and spin glass dynamics occurs. It has been found that average relaxation time increases with decreasing temperature from tau(c)<10(-4) s at 17.6 K to 1.5 * 10(-1) s at 15 K. The increase of the average relaxation time with decreasing temperature, the observed blocking temperature of the superparamagnetic moments at about 10 K and interference appearing between the two spin dynamics suggest that the magnetic moments in the smaller as well as in the larger nanocrystallites are subject to a thermally activated blocking process at low temperatures. PMID- 21817387 TI - A method for estimating the interactions in dissipative particle dynamics from particle trajectories. AB - We introduce a method for determining the functional form of the stochastic and dissipative interactions in a dissipative particle dynamics (DPD) model from projected phase space trajectories. The DPD model is viewed as a coarse graining of a detailed dynamics that displays a clear timescale separation. Based on the Mori-Zwanzig projection operator method we derive a consistency equation for the stochastic interaction in DPD. The consistency equation can be solved by an iterative bootstrapping procedure. Combined with standard techniques for estimating the conservative interaction, our method makes it possible to reconstruct all the forces in a coarse-grained DPD model. We demonstrate how the method works by recreating the interactions in a DPD model from its phase space trajectory. Furthermore, we discuss how our method can be used in realistic systems with finite timescale separation. PMID- 21817388 TI - Structural and vibrational properties of K(3)Fe(MoO(4))(2)(Mo(2)O(7))-a novel layered molybdate. AB - The new compound K(3)Fe(MoO(4))(2)(Mo(2)O(7)) was synthesized and characterized by a single-crystal x-ray structure determination, and IR and Raman spectroscopic studies. The crystal structure at room temperature and ambient pressure is monoclinic, space group C 2/c, with the unit cell dimensions a = 32.885(7), b = 5.7220(11), c = 15.852(3) A, beta = 91.11 degrees , Z = 8. The FeO(6) octahedra are joined by corners with MoO(4)(2-) tetrahedra and Mo(2)O(7)(2-) units. Some of the K(+) ions form layers in the b * c-plane. The origin of various Raman and IR vibrational modes is discussed. These results indicate that a clear energy gap exists between the stretching and remaining modes. High-pressure Raman scattering studies were also performed. These studies showed the onset of two reversible first-order phase transitions near 1.2 and 7.4 GPa, which are associated with strong distortion of the MoO(4)(2-) and Mo(2)O(7)(2-) units. PMID- 21817389 TI - Backscattering coefficients for low energy positrons and electrons impinging on bulk solid targets. AB - The backscattering coefficients (BSCs) for semi-infinite solids of normally incident 1-4 keV electrons and positrons are stochastically modeled and calculated by the Monte Carlo method. This paper aims at discussing the differences observed between the properties of electrons and positrons impinging on solid targets based on the use of the differential elastic scattering cross section which has been obtained using the Bentabet and Bouarissa approximation (2006 Phys. Lett. A 355 390). A new mathematical equation was developed for the adjustable parameter beta of the Bentabet et al approximation and seems to be valid for other elements. Both electron and positron BSC simulated results show good agreement with the experimental or computed data reported by other authors. PMID- 21817390 TI - FP-APW+lo calculations of the electronic and optical properties of alkali metal sulfides under pressure. AB - The electronic and optical properties of M(2)S (M = Li, Na, K and Rb) compounds in the cubic antifluorite structure have been calculated, using a full relativistic version of the full-potential augmented plane-wave plus local orbitals method based on density functional theory, within both the local density approximation (LDA) and the generalized gradient approximation (GGA). Moreover, the Engel-Vosko GGA formalism (EV-GGA) is applied so as to optimize the corresponding potential for band structure calculations. The calculated equilibrium lattices and bulk moduli are in good agreement with the available data. Band structure, density of states, electron charge density and pressure coefficients of energy gaps are given. Results obtained for band structure using EV-GGA are larger than those with LDA and GGA. It is found that the spin-orbit coupling lifts the triple degeneracy at the Gamma point and the double degeneracy at the X point. The analysis of the electron charge density shows that the M-S bonds have a significant ionic character. The complex dielectric functions epsilon(2)(omega) for alkali metal sulfides were calculated for radiation up to 30 eV and the assignment of the critical points to the band structure energy differences at various points of the Brillouin zone was made. The pressure and volume dependence of the static dielectric constant and the refractive index are calculated. PMID- 21817391 TI - Hyperfine interaction studies with (181)Ta and (111)Cd probes in the compound Ti(2)Ag. AB - By using the time-differential perturbed angular correlation technique, the electric field gradients (EFG) at (181)Hf/(181)Ta and (111)In/(111)Cd probe sites in the MoSi(2)-type compound Ti(2)Ag have been measured as a function of temperature in the range from 24 to 1073 K. Ab initio EFG calculations have been performed within the framework of density functional theory using the full potential augmented plane wave+local orbitals method as implemented in the WIEN2k package. These calculations allowed assignments of the probe lattice sites. For Ta, a single well-defined EFG with very weak temperature dependence was established and attributed to the [4(e)4mm] Ti site. For (111)Cd probes, two of the three measured EFGs are well defined and correlated with substitutional lattice sites, i.e. both the [4(e)4mm] Ti site and the [2(a)4/mmm] Ag site. PMID- 21817392 TI - Molecular dynamics simulation of the rotational order-disorder phase transition in calcite. AB - Molecular dynamics (MD) simulation of calcite was carried out with the interatomic potential model based on ab initio calculations to elucidate the phase relations for calcite polymorphs and the mechanism of the rotational order disorder transition of calcite at high temperature at the atomic scale. From runs of MD calculations with increasing temperature within a pressure range of 1 atm and 2 GPa, the transition of calcite with [Formula: see text] symmetry into a high-temperature phase with [Formula: see text] symmetry was reproduced. In the high-temperature [Formula: see text] phase, CO(3) groups vibrate with large amplitudes either around the original positions in the [Formula: see text] structure or around other positions rotated +/- 60 degrees , and their positions change continuously with time. Moreover, contrary to the suggestion of previous investigators, the motion of CO(3) groups is not two-dimensional. At 1 atm, the transition between [Formula: see text] and [Formula: see text] is first order in character. Upon increasing temperature at high pressure, however, first a first order isosymmetric phase transition between the [Formula: see text] phases occurs, which corresponds to the start of +/- 120 degrees flipping of CO(3) groups. Then, at higher temperatures, the transition of [Formula: see text] to [Formula: see text] phases happens, which can be considered second order. This set of two types of transitions at elevated pressure can be characterized by the appearance of an 'intermediate' [Formula: see text] phase between the stable region of calcite and the high-temperature [Formula: see text] phase, which may correspond to the CaCO(3)-IV phase. PMID- 21817393 TI - Evolution of internal stresses in the plain ferritic steel studied by neutron diffraction in situ upon tensile straining. AB - The present in situ neutron diffraction study aims to investigate the response of selected lattice planes in the polycrystalline material upon tensile loading. For this purpose, the 0.1C-0.4Mn construction steel was selected as a simple model material. The tensile deformation test was performed in the incremental mode in which each individual deformation step was followed by unloading. The neutron diffraction spectra were collected both upon loading and unloading and the behavior of the diffraction profiles in the elastic as well as in the plastic region of the deformation curve was examined in detail. Whereas the behavior of the lattice strains during straining and the evolution of the residual intergranular strains have already been described in other papers, the present work is focused mainly on profile broadening effects measured in the same deformation regime. The estimate of microstrain evolution was done by using the single-line profile analysis method. Comparison of microstrain values in the loaded/unloaded state and in the elastic and plastic regions offers an interesting possibility to estimate the contribution of the type II and type III microstrains. PMID- 21817394 TI - Ab initio refinement of the thermal equation of state for bcc tantalum: the effect of bonding on anharmonicity. AB - We report a detailed ab initio study for body-centered-cubic (bcc) Ta within the framework of the quasiharmonic approximation (QHA) to refine its thermal equation of state and thermodynamic properties. Based on the excellent agreement of our calculated phonon dispersion curve with experiment, the accurate thermal equations of state and thermodynamic properties are well reproduced. The thermal equation of state (EOS) and EOS parameters are considerably improved in our work compared with previous results by others. Furthermore, at high temperatures, the excellent agreement of our obtained thermal expansion and Hugoniot curves with experiments greatly verifies the validity of the quasiharmonic approximation at higher temperatures. It is known that pressure suppresses the vibrations of atoms from their equilibrium positions, i.e. the bondings among atoms are strengthened by pressure; for the same temperature, anharmonicity becomes less important at high pressure. Thus the highest valid temperature of the QHA can be reasonably extended to the larger range. PMID- 21817395 TI - An average atom code for warm matter: application to aluminum and uranium. AB - In astrophysics and in other sciences there is sometimes a need for information about the properties of matter, particularly equations of state, in extreme conditions of pressure and temperature. Global equation of state models, which represent solid, fluid and plasma states, typically consist of three parts: the cold curve, the ion-thermal contribution and the electron-thermal contribution. For the calculation of the latest part we present here an average atom embedded in a jellium code. We employ Liberman's relativistic and quantum model of matter which is a significant advance in complexity beyond the commonly used Thomas Fermi model. We have applied specific algorithms to deal with the highly oscillatory nature of the free wavefunctions at high temperatures and to capture resonances which form in the continuum when bound states are destroyed by pressure ionization. Also we use massive parallel computing to treat the huge number of free wavefunctions at high temperatures (up to 10(9) K). Densities of states of resonant states are shown for uranium. With our code, which we have called Paradisio, we obtain tables of electron-thermal entropies from which free energies and pressures are derived. Our results are compared with those calculated in the Thomas-Fermi approximation and with available experiments. In aluminum, with our quantum code, a shell structure appears on the Hugoniot and a first-order metallic-nonmetallic transition is created at low densities and temperatures. PMID- 21817396 TI - Vibrational properties of crystalline Sb(2)Te(3) from first principles. AB - Phonon dispersion relations and infrared and Raman spectra of crystalline Sb(2)Te(3) were computed within density functional perturbation theory. Overall good agreement with experiments is obtained, which allows us to assign the Raman and IR peaks to specific phonons. PMID- 21817397 TI - The phonon spectra and elastic constants of Pd(x)Fe(1-x): an understanding from inter-atomic interactions. AB - Understanding the role of the inter-atomic force constants in lattice dynamics of random binary alloys is a challenging problem. Addressing these inter-atomic interactions accurately is a necessity to obtain an accurate phonon spectrum and to calculate properties from them. Using a combination of ab initio density functional perturbation theory (DFPT) and the itinerant coherent potential approximation (ICPA), an analytic, self-consistent method for performing configuration averaging in random alloys, we model the inter-atomic force constants for Pd(0.96)Fe(0.04) and Pd(0.9)Fe(0.1) alloys based upon the ab initio results and intuitive arguments. The calculated phonon dispersion curves and elastic constants agree very well with the experimental results. Comparison of our results with those obtained in a model potential scheme is also done. The modeling of inter-atomic interactions in random alloys and their roles regarding the phonon-related properties are also discussed in light of these results. PMID- 21817398 TI - Scattering in one-dimensional heterostructures described by the Dirac equation. AB - We consider electronic transport across one-dimensional heterostructures described by the Dirac equation. We discuss the cases where both the velocity and the mass are position dependent. We show how to generalize the Dirac Hamiltonian in order to obtain a Hermitian problem for spatial dependent velocity. We solve exactly the case where the position dependence of both velocity and mass is linear. In the case of velocity profiles, it is shown that there is no backscattering of Dirac electrons. In the case of the mass profile, backscattering exists. In this case, it is shown that the linear mass profile induces less backscattering than the abrupt step-like profile. Our results are a first step towards the study of similar problems in graphene. PMID- 21817399 TI - Non-monotonic variation of the exchange energy in double elliptic quantum dots. AB - We study the properties of a few-electron system confined in coupled elongated quantum dots (QDs) using a model Gaussian potential and the numerical exact diagonalization technique. In the absence of magnetic fields, as the aspect ratio r between the QD extensions in the directions perpendicular and parallel to the coupling directions increases, the exchange energy exhibits a sharp variation at the specific value r = 3.9, before (after) which the exchange energy increases (declines). The sharp variation occurs because of a sudden change in the single particle configuration of the triplet state. The stability region with one electron in each of the QDs is found to shrink, and finally vanishes as it becomes progressively easier to localize both electrons into the QD with the lower electron potential energy. For r>3.9, the first singlet-triplet transition shifts to a small magnetic field. PMID- 21817400 TI - Direct calculation of 4f(3)-4f(3) transition intensities in Nd(3+)-doped YPO(4) system involving explicit effects of 4f(2)5d configuration. AB - The effects of the 4f(2)5d configuration on the intraconfigurational [Formula: see text] electric dipole transitions of Nd(3+) doped YPO(4) are taken into account by a 'direct' calculation. A simple model is applied to analyze the opposite-parity 4f(2)5d configuration admixing into 4f(3) transitional states. The matrix elements of the odd-rank crystal-field interaction and the interconfigurational electric dipole transition are directly expressed using a standard tensor operator method. A set of selection rules for f-d mixing and f-f electric dipole transitions is built up. The admixture effect is considered including both explicit 4f(2)5d configuration and other opposite-parity states such as the 4f(2)n(')g configuration which is treated by a closure procedure. Using this calculation method in combination with the experimental data from the absorption spectrum, a set of intensity parameters is obtained. The transition intensities originating from the high-lying (2)G(9/2)(2) level to the lower energy levels are then calculated, demonstrating a good agreement with the experimental results. The new calculation method is suitable for the electric dipole transitions within the 4f(N) configurations of trivalent lanthanide ions with more than two f-electrons. PMID- 21817401 TI - Magnetic properties of Ni(3)Al and Ni(3)Ga: emergent states and the possible importance of a tri-critical point. AB - We present a study of the magnetic properties of the itinerant-electron systems Ni(3)Al and Ni(3)Ga at ambient pressure. In both compounds the magnetization and susceptibility show a non-Fermi liquid form. We test these properties using a mean-field model of enhanced spin fluctuations on the border of ferromagnetism in three dimensions with no adjustable parameters. While Ni(3)Al is found to be explained well by the standard form of such a model, the data on Ni(3)Ga require us to extend the model to take into account the fact that this system lies close to a tri-critical point. We suggest that such a quantum tri-critical point may be a key feature in the understanding of quantum critical systems more generally. PMID- 21817402 TI - Andreev reflection and shot noise in a quantum dot with phonon modes. AB - Building on the nonequilibrium Green's function technique and a canonical transformation of the electron-phonon interaction, this paper focuses on the study of the Andreev reflection conductance and the shot noise in a single quantum dot coupling with local phonon modes. The effect of the intradot spin flip interaction on the transport properties is considered. We pay attention to the effects of the phonon on the Andreev reflection conductance and the shot noise. It is found that splits due to spin-flip scattering appear not only in the main Andreev reflection peaks but also in the new satellite peaks. The electron phonon interaction leads to new satellite resonant peaks that are located exactly on the integer number of the phonon frequency. Moreover, the peak height is sensitive to the electron-phonon coupling. Even if the electron-phonon coupling is weak, the shot noise spectrum shows the phonon mode peaks rather clearly, but in the Andreev reflection conductance the phonon mode peaks weakly. PMID- 21817403 TI - Pressure induced FFLO instability in multi-band superconductors. AB - Multi-band systems such as inter-metallic and heavy fermion compounds have quasi particles arising from different orbitals at their Fermi surface. Since these quasi-particles have different masses or densities, there is a natural mismatch of the Fermi wavevectors associated with different orbitals. This makes these materials potential candidates to observe exotic superconducting phases as Sarma or FFLO phases, even in the absence of an external magnetic field. The distinct orbitals coexisting at the Fermi surface are generally hybridized and their degree of mixing can be controlled by external pressure. In this work we investigate the existence of an FFLO type of phase in a two-band BCS superconductor controlled by hybridization. At zero temperature, as hybridization (pressure) increases we find that the BCS state becomes unstable with respect to an inhomogeneous superconducting state characterized by a single wavevector q. PMID- 21817404 TI - Conductance features in point contact Andreev reflection spectra. AB - Point contact Andreev reflection (PCAR) spectroscopy is a common technique for determining the spin polarization of a ferromagnetic sample. The polarization is extracted by measuring the bias dependence of the conductance of a metallic/superconducting point contact. Under ideal conditions, the conductance is dominated by Andreev reflection and the Blonder-Tinkham-Klapwijk (BTK) model can be used to extract a value for the polarization. However, PCAR spectra often exhibit unwanted features in the conductance that cannot be appropriately modelled with the BTK theory. In this paper we isolate some of these unwanted features and show that any further extraction of the spin polarization from these non-ideal spectra proves unreliable. Understanding the origin of these features provides an objective criterion for rejection of PCAR spectra unsuitable for fitting with the modified BTK model. PMID- 21817405 TI - The fcc-bcc Bain path in In-Sn and related alloys at ambient and high pressure. AB - Experimental high-pressure structural studies on an In-Sn alloy containing 8 at.% Sn reveal an isostructural transition of a face-centered tetragonal phase at pressures above 15 GPa with a switch of the axial ratio from c/a>1 to c/a<1. Such tetragonal phases in binary alloys based on In and Sn are analyzed in relation to the Bain path, i.e. a transformation between a face-centered cubic (fcc) and a body-centered cubic (bcc) structure. Variation of the axial ratio c/a in these phases correlates with the average number of valence electrons per atom in an alloy. A common Bain path from fcc to bcc is discussed within a nearly-free electron model of Brillouin-zone-Fermi-sphere interactions. PMID- 21817406 TI - Fluctuations and criticality in quantum paraelectrics. AB - The temperature dependence of the static dielectric susceptibility of a system with strongly coupled fluctuating dipoles is calculated within a self-consistent mean fluctuation field approximation. Results are qualitatively in good agreement with a quantum paraelectric SrTiO(3) in the low temperature regime. We identify this system as a gapped quantum paraelectric and suggest a possible experimental realization of a quantum critical paraelectric through the application of hydrostatic pressure or doping by impurity. PMID- 21817407 TI - The role of lattice distortions in determining the thermal properties of electron doped CaMnO(3). AB - We have investigated the thermal properties of electron doped perovskite manganite CaMnO(3), the end member ([Formula: see text]) of the Ruddlesden-Popper (RP) calcium manganates series with cation doping at the A-site. In this paper the functional relation between the lattice distortions and the thermal properties is determined and compared to available reports. The temperature dependence of the lattice specific heat (C(v(lattice))) of Ca(1-x)Ln(x)MnO(3) (x = 0.05, 0.10, 0.15, 0.20) with Ln(= La, Ce, Pr, Nd, Th, Bi) doping at the A-site has been studied as a function of temperature (10 K<=T<=500 K) by means of a rigid ion model (RIM) after modifying its framework to incorporate the van der Waals interactions. Strong electron-phonon interactions are present in these compounds, which are responsible for the variation of the lattice specific heat with cation doping of varying size and valency. We have found that the calculated thermal properties reproduce well the corresponding experimental data, implying that modified RIM represents properly the nature of these perovskite manganite systems. We demonstrate that the electron concentration, size mismatch and Jahn Teller (JT) effects are the dominant factors, whereas charge mismatch and buckling of Mn-O-Mn angle influence the thermal properties to a lesser degree in the ferromagnetic state. In the insulating paramagnetic state, JT distortions vary linearly and influence the thermal properties. These specific heat results can be further improved by including the ferromagnetic spin wave and charge order contributions to the specific heat. PMID- 21817408 TI - Phase transitions and rare-earth magnetism in hexagonal and orthorhombic DyMnO(3) single crystals. AB - The floating-zone method with different growth ambiences has been used to selectively obtain hexagonal or orthorhombic DyMnO(3) single crystals. The crystals were characterized by x-ray powder diffraction of ground specimens and a structure refinement as well as electron diffraction. We report magnetic susceptibility, magnetization and specific heat studies of this multiferroic compound in both the hexagonal and the orthorhombic structure. The hexagonal DyMnO(3) shows magnetic ordering of Mn(3+) (S = 2) spins on a triangular Mn lattice at T(N)(Mn) = 57 K characterized by a cusp in the specific heat. This transition is not apparent in the magnetic susceptibility due to the frustration on the Mn triangular lattice and the dominating paramagnetic susceptibility of the Dy(3+) (S = 9/2) spins. At T(N)(Dy) = 3 K, a partial antiferromagnetic order of Dy moments has been observed. In comparison, the magnetic data for orthorhombic DyMnO(3) display three transitions. The data broadly agree with results from earlier neutron diffraction experiments, which allows for the following assignment: a transition from an incommensurate antiferromagnetic ordering of Mn(3+) spins at T(N)(Mn) = 39 K, a lock-in transition at T(lock-in) = 16 K and a second antiferromagnetic transition at T(N)(Dy) = 5 K due to the ordering of Dy moments. Both the hexagonal and the orthorhombic crystals show magnetic anisotropy and complex magnetic properties due to 4f-4f and 4f-3d couplings. PMID- 21817409 TI - Si(+) ion irradiation in a Co/Pt multilayer system. AB - This paper deals with a study of the effect of Si(+) ion irradiation on a Co/Pt multilayer system irradiated at different temperatures. The as-deposited and irradiated samples have been characterized using x-ray reflectivity (XRR), x-ray diffraction (XRD) and the magneto-optical Kerr effect (MOKE). X-ray reflectivity shows clear intermixing at the interfaces. The x-ray diffraction pattern shows that Si(+) ion irradiation at higher temperatures results in the formation of the CoPt(3) fcc phase with a small fraction of L1(0) phase. The mixing process is discussed in terms of recoil displacements induced by energy transfers from ions. PMID- 21817410 TI - Quantum theory of the anisotropy of the magnetic properties of ferrimagnetic holmium iron garnet single crystals. AB - The pronounced anisotropy of the magnetization caused by the Ho(3+) ions in the ferrimagnetic holmium iron garnet has been investigated based on quantum theory. The strong anisotropy of the magnetization of the Ho(3+) ions originates mainly from the effect of the crystal field upon the Ho(3+) ions and the anisotropic Ho(3+)-Fe(3+) superexchange interaction. Following the expression of the Yb(3+) Fe(3+) exchange interaction used by Alben, the anisotropy of the Ho(3+)-Fe(3+) exchange interaction is defined by three principal values of the exchange tensor G. Because the six Ho(3+) sublattices are magnetically non-equivalent, we calculate the magnetic quantities of the Ho(3+) at the six sublattices and compare the average value of the so-obtained six quantities with the measured values. The calculated results are in good agreement with experiments. An interpretation on the anisotropy of the magnetic properties of HoIG is given. PMID- 21817411 TI - Comment on 'Anomalous dynamics of unbiased polymer translocation through a narrow pore' and other recent papers by D Panja, G Barkema and R Ball. AB - In a recent publication of Panja et al (2007 J. Phys.: Condens. Matter 19 432202) they suggested a new interpretation of the translocation problem of polymer chain threading through a narrow pore. Here we point out some contradictions and inconsistencies in this treatment which question the plausibility of the obtained results. PMID- 21817412 TI - Reply to the comment on 'Anomalous dynamics of unbiased polymer translocation through a narrow pore' and other recent papers by D Panja, G Barkema and R Ball. AB - We reply to the comment made by Dubbeldam et al (2009 J. Phys.: Condens. Matter 21 098001) on our paper 'Anomalous dynamics of unbiased polymer translocation through a narrow pore' and our other recent papers. PMID- 21817413 TI - Mesoscopic transport revisited. AB - Having driven a large part of the decade's progress in physics, nanoelectronics is now passing from today's realm of the extraordinary to tomorrow's commonplace. This carries the problem of turning proofs of concept into practical artefacts. Better and more sharply focused predictive modelling will be the ultimate guide to optimizing mesoscopic technology as it matures. Securing this level of understanding needs a reassessment of the assumptions at the base of the present state of the field. We offer a brief overview of the underlying assumptions of mesoscopic transport. PMID- 21817414 TI - Magnetic field induced confinement-deconfinement transition in graphene quantum dots. AB - Massless Dirac particles cannot be confined by an electrostatic potential. This is a problem for making graphene quantum dots but confinement can be achieved with a magnetic field and here general conditions for confined and deconfined states are derived. There is a class of potentials for which the character of the state can be controlled at will. Then a confinement-deconfinement transition occurs which allows the Klein paradox to be probed experimentally in graphene dots. A dot design suitable for this experiment is presented. PMID- 21817415 TI - Field modulation in bilayer graphene band structure. AB - Using an external electric field, one can modulate the band gap of Bernal stacked bilayer graphene by breaking the A-[Formula: see text] symmetry. We analyze strain effects on the bilayer graphene using the extended Huckel theory and find that reduced interlayer distance results in higher band gap modulation, as expected. Furthermore, above about 2.5 A interlayer distance, the band gap is direct, follows a convex relation with the electric field and saturates to a value determined by the interlayer distance. However, below about 2.5 A, the band gap is indirect, the trend becomes concave and a threshold electric field is observed, which also depends on the stacking distance. PMID- 21817416 TI - Evidence for coexistence of superconductivity and magnetism in single crystals of Co-doped SrFe(2)As(2). AB - In order to investigate whether magnetism and superconductivity coexist in Co doped SrFe(2)As(2), we have prepared single crystals of SrFe(2-x)Co(x)As(2), x = 0 and 0.4, and characterized them via x-ray diffraction, electrical resistivity in zero and applied field up to 9 T as well as at ambient and applied pressure up to 1.6 GPa, and magnetic susceptibility. At x = 0.4, there is both magnetic and resistive evidence for a spin density wave transition at 120 K, while T(c) = 19.5 K-indicating coexistent magnetism and superconductivity. A discussion of how these results compare with reported results, both in SrFe(2-x)Co(x)As(2) and in other doped 122 compounds, is given. PMID- 21817417 TI - Superfluid density in gapless superconductor CeCoIn(5). AB - Temperature dependence of the London penetration depth lambda measured in single crystals of CeCoIn(5) is interpreted as being caused by a strong pair-breaking scattering that makes the superconductivity in this compound gapless. For a gapless d-wave superconductor, we derive lambda = lambda(0)(1-T(2)/T(c)(2))(-1/2) caused by the combined effect of magnetic and non-magnetic scattering, in excellent agreement with the data in the full temperature range and with the gapless s-wave case of Abrikosov and Gor'kov. We also obtain the slope of the upper critical field at T(c) that compares well with the measured slope. PMID- 21817418 TI - Inertial rotation and matrix interaction effects on the EPR spectra of methyl radicals isolated in 'inert' cryogenic matrices. AB - The CW-EPR lineshapes of methyl and small methyl-like radicals trapped in noble gas matrices at liquid He temperatures are substantially different from the expected classical EPR spectra. At low temperatures they show small or negligible anisotropy in studies using different experimental techniques and have a temperature dependence that differs from systems whose motional dynamics is diffusion controlled. At liquid He temperatures, before the Boltzmann statistics take over in the classical high temperature realm, the spectral intensities are dominated by quantum statistics. These properties, which were obtained experimentally at temperatures about 5 K and lower, and up to about 20 K, can be attributed to quantum effects of inertial rotary motion and its coupling to the nuclear spin of the radical. Methyl-like radicals have nuclear-exchange symmetry and contain the lightest possible isotopes, protons, and deuterons. In the ideal case of absent radical-matrix interaction, the methyl rotation about the central heavier carbon atom guaranties minimal moments of inertia. However, the theoretical interpretation of the above effects and other related quantum effects, as well as recognition of the important physics which lead to them, is not a simple matter. The literature accumulated on the subject over the years is successful but contains several unresolved questions. Recently obtained spectra of methyl radicals in Kr, N(2) and CO matrices, which are less inert than the smaller noble gas Ar, were shown to exhibit greater, but certainly slight, overall anisotropic spectral features while in earlier experimental studies the anisotropy was practically absent. Even gases of smaller radii such as Ne and H(2) at liquid He temperatures show interesting differences as hosts of methyl radicals compared to Ar. Investigation of other possible causes of this difference, not excluding the experimentally controlled ones related to the sample preparation and the MW power saturation of the CW-EPR measurement, were conducted in this work. PMID- 21817419 TI - Magnetometry of low-dimensional electron and hole systems. AB - The high-magnetic-field, low-temperature magnetic properties of low-dimensional electron and hole systems reveal a wealth of fundamental information. Quantum oscillations of the thermodynamic equilibrium magnetization yield the total density of states, a central quantity in understanding the quantum Hall effect in 2D systems. The magnetization arising from non-equilibrium circulating currents reveals details, not accessible with traditional measurements, of the vanishingly small longitudinal resistance in the quantum Hall regime. We review how the technique of magnetometry has been applied to these systems, the most important discoveries that have been made, and their theoretical significance. PMID- 21817420 TI - Andreev reflection and order parameter symmetry in heavy-fermion superconductors: the case of CeCoIn(5). AB - We review the current status of Andreev reflection spectroscopy on the heavy fermions, mostly focusing on the case of CeCoIn(5), a heavy-fermion superconductor with a critical temperature of 2.3 K. This is a well-established technique to investigate superconducting order parameters via measurements of the differential conductance from nanoscale metallic junctions. Andreev reflection is clearly observed in CeCoIn(5) as in other heavy-fermion superconductors. Considering the large mismatch in Fermi velocities, this observation seemingly appears to disagree with the Blonder-Tinkham-Klapwijk (BTK) theory. The measured Andreev signal is highly reduced to the order of maximum ~13% compared to the theoretically predicted value (100%). The background conductance exhibits a systematic evolution in its asymmetry over a wide temperature range from above the heavy-fermion coherence temperature down to well below the superconducting transition temperature. Analysis of the conductance spectra using the extended BTK model provides a qualitative measure for the superconducting order parameter symmetry, which is determined to be the d(x(2)-y(2)) wave in CeCoIn(5). It is found that existing models do not quantitatively account for the data, which we attribute to the intrinsic properties of the heavy fermions. A substantial body of experimental data and extensive theoretical analysis point to the existence of two-fluid components in CeCoIn(5) and other heavy-fermion compounds. A phenomenological model is proposed employing a Fano interference effect between two conductance channels in order to explain both the conductance asymmetry and the reduced Andreev signal. This model appears plausible not only because it provides good fits to the data but also because it is highly likely that the electrical conduction occurs via two channels, one into the heavy-electron liquid and the other into the conduction electron continuum. Further experimental and theoretical investigations will shed new light on the mechanism of how the coherent heavy-electron liquid emerges out of the Kondo lattice, a prototypical strongly correlated electron system. Unresolved issues and future directions are also discussed. PMID- 21817421 TI - First-principles calculations of x-ray absorption near edge structure and energy loss near edge structure: present and future. AB - Computational methods for theoretical x-ray absorption near edge structure (XANES) and energy loss near edge structure (ELNES) are classified into a few groups. Depending on the absorption (or excitation) edge, required accuracy and desired information, one needs to select the most suitable method. In this paper, after providing a map of available computational methods, some examples of first principles calculations of XANES/ELNES for selected wide gap materials are given together with references. For ZnO, for example, experimental spectra at three edges, Zn K, L(3), and O K, including their orientation dependence, are well reproduced by the supercell calculations with a core hole. Good agreement between theoretical and experimental spectra of ZnO alloys can also be seen. Theoretical fingerprints are satisfactorily obtained in this way. However, there are remaining issues beyond 'good agreements' which need to be solved in the future. PMID- 21817422 TI - X-ray absorption near edge structure/electron energy loss near edge structure calculation using the supercell orthogonalized linear combination of atomic orbitals method. AB - Over the last eight years, a large number of x-ray absorption near edge structure (XANES) and/or electron energy loss near edge structure (ELNES) spectroscopic calculations for complex oxides and nitrides have been performed using the supercell-OLCAO (orthogonalized linear combination of atomic orbitals) method, obtaining results in very good agreement with experiments. The method takes into account the core-hole effect and includes the dipole matrix elements calculated from ab initio wavefunctions. In this paper, we describe the method in considerable detail, emphasizing the special advantages of this method for large complex systems. Selected results are reviewed and several hitherto unpublished results are also presented. These include the Y K edge of Y ions segregated to the core of a Sigma31 grain boundary in alumina, O K edges of water molecules, C K edges in different types of single walled carbon nanotubes, and the Co K edge in the cyanocobalamin (vitamin B(12)) molecule. On the basis of these results, it is argued that the interpretation of specific features of the calculated XANES/ELNES edges is not simple for complex material systems because of the delocalized nature of the conduction band states. The long-standing notion of the 'fingerprinting' technique for spectral interpretation of experimental data is not tenable. A better approach is to fully characterize the structure under study, using either crystalline data or accurate ab initio modeling. Comparison between calculated XANES/ELNES spectra and available measurements enables us to ascertain the validity of the modeled structure. For complex crystals or structures, it is necessary to use the weighted sum of the spectra from structurally nonequivalent sites for comparison with the measured data. Future application of the supercell-OLCAO method to complex biomolecular systems is also discussed. PMID- 21817423 TI - Core-level spectroscopy calculation and the plane wave pseudopotential method. AB - A plane wave based method for the calculation of core-level spectra is presented. We provide details of the implementation of the method in the pseudopotential density functional code CASTEP, including technical issues concerning the calculations, and discuss the applicability and accuracy of the method. A number of examples are provided for comparing the results to both experiment and other density functional theory techniques. PMID- 21817424 TI - First-principles calculation of spectral features, chemical shift and absolute threshold of ELNES and XANES using a plane wave pseudopotential method. AB - Spectral features, chemical shifts, and absolute thresholds of electron energy loss near-edge structure (ELNES) and x-ray absorption near-edge structure (XANES) for selected compounds, i.e. TiO(2) (rutile), TiO(2) (anatase), SrTiO(3), Ti(2)O(3), Al(2)O(3), AlN and beta-Ga(2)O(3), were calculated by a plane wave pseudopotential method. Experimental ELNES/XANES of those compounds were well reproduced when an excited pseudopotential, which includes a core hole, was used. In addition to the spectral features, it was found that chemical shifts among different compounds were also reproduced by correcting the contribution of the excited pseudopotentials to the energy of the core orbital. PMID- 21817425 TI - Near-edge structures from first principles all-electron Bethe-Salpeter equation calculations. AB - We obtain x-ray absorption near-edge structures (XANES) by solving the equation of motion for the two-particle Green's function for the electron-hole pair, the Bethe-Salpeter equation (BSE), within the all-electron full-potential linearized augmented plane wave method (FPLAPW). The excited states are calculated for the Li K-edge in the insulating solids LiF, Li(2)O and Li(2)S, and absorption spectra are compared with independent particle results using the random phase approximation (RPA), as well as supercell calculations using the core-hole approximation within density functional theory (DFT). The binding energies of strongly bound excitations are determined in the materials, and core-exciton wavefunctions are demonstrated for LiF. PMID- 21817426 TI - Full-potential multiple scattering for core electron spectroscopies. AB - We present a rigorous derivation of a real space full-potential multiple scattering theory (FP-MST), valid both for continuum and bound states, that is free from the drawbacks that up to now have impaired its development, in particular the need to use cell shape functions and rectangular matrices. In this connection we give a new scheme to generate local basis functions for the truncated potential cells that is simple, fast, efficient, valid for any shape of the cell and reduces to the minimum the number of spherical harmonics in the expansion of the scattering wavefunction. This approach provides a straightforward extension of MST in the muffin-tin (MT) approximation, with only one truncation parameter given by the classical relation l(max) = kR(b), where k is the photo-electron wavevector and R(b) the radius of the bounding sphere of the scattering cell. Some numerical applications of the theory are presented, both for continuum and bound states. PMID- 21817427 TI - The 1s x-ray absorption pre-edge structures in transition metal oxides. AB - We develop a general procedure to analyse the pre-edges in 1s x-ray absorption near edge structure (XANES) of transition metal oxides and coordination complexes. Transition metal coordination complexes can be described from a local model with one metal ion. The 1s 3d quadrupole transitions are calculated with the charge-transfer multiplet program. Tetrahedral coordination complexes have more intense pre-edge structures due to the local mixing of 3d and 4p states, implying a combination of 1s 3d quadrupole and 1s 4p dipole transitions. Divalent transition metal oxides can be described similar to coordination complexes, but for trivalent and tetravalent oxides, additional structures are visible in the pre-edge region due to non-local dipole transitions. The 1s 4p dipole transitions have large cross section at the 3d-band region due to the strong metal-metal interactions, which are oxygen mediated. This yields large intensity in the 3d band region but at a different energy than the local 1s 3d quadrupole transitions because of smaller core-hole effects due to the delocalization of the excited electron. PMID- 21817428 TI - Multiplet calculations of L(2,3) x-ray absorption near-edge structures for 3d transition-metal compounds. AB - The purpose of this work is to compare the two different procedures to calculate the L(2,3) x-ray absorption spectra of transition-metal compounds: (1) the semi empirical charge transfer multiplet (CTM) approach and (2) the ab initio configuration-interaction (CI) method based on molecular orbitals. We mainly focused on the difference in the treatment of ligand field effects and the charge transfer effects in the two methods. The reduction of multiplet interactions due to the solid state effects has been found by the ab initio CI approach. We have also found that the mixing between the original and the charge transferred configurations obtained by the ab initio CI approach is smaller than that obtained by the CTM approach, since charge transfer through the covalent bonding between metal and ligand atoms has been included by taking the molecular orbitals as the basis functions. PMID- 21817429 TI - All-electron CI calculations of 3d transition-metal L(2,3) XANES using zeroth order regular approximation for relativistic effects. AB - X-ray-absorption near-edge structures (XANES) at 3d transition-metal (TM) L(2,3) edges are computed using the all-electron configuration interaction (CI) method. Slater determinants for the CI calculations are composed of molecular orbitals obtained by density functional theory (DFT) calculations of model clusters. Relativistic effects are taken into account by the zeroth-order regular approximation (ZORA) using two-component wavefunctions. The theoretical spectra are found to be strongly dependent on the quality of the one-electron basis functions. On the other hand, a different choice of the exchange-correlation functionals for the DFT calculations does not exhibit visible changes in the spectral shape. Fine details of multiplet structures in the experimental TM L(2,3) XANES of MnO, FeO and CoO are well reproduced by the present calculations when the one-electron basis functions are properly selected. This is consistent with our previous report showing good agreement between theoretical and experimental TM L(2,3) XANES when four-component relativistic wavefunctions were used. PMID- 21817430 TI - Density functional theory simulations of B K and N K NEXAFS spectra of h BN/transition metal(111) interfaces. AB - The electronic structure and the corresponding B K and N K near-edge x-ray fine structure (NEXAFS) spectra of epitaxially grown h-BN on Ni(111), Pt(111), and Rh(111) surfaces are investigated by density functional theory. The calculations are carried out using the WIEN2k program package applying the augmented-plane wave+local orbitals (APW+lo) method. The NEXAFS spectra are simulated using a 3 * 3 * 1 super cell and considering the final state rule by means of a (partial) core hole for the corresponding atom. The influence of a full or partial core hole is shown for the h-BN/Ni(111) system, for which the best agreement with the experimental spectra is found when half a core hole is assumed. All characteristic features of the experimental spectra are well reproduced by theory, including the angular dependences. The bonding effects are investigated by comparing the spectra of bulk h-BN with those of the h-BN/Ni(111) system. An analysis of both the density of states and charge densities reveals strong N-p(z) Ni-d(z(2)) bonding/antibonding interactions. In the case of Pt(111) and Rh(111) surfaces, we discuss the effects of the nanomesh structures in terms of simple 1 * 1 commensurate models. PMID- 21817431 TI - Local environment analysis of dopants in ceramics by x-ray absorption near-edge structure with the aid of first-principles calculations. AB - Three types of functional ceramic materials, (1) dilute magnetic semiconductor, (2) phosphor and (3) electrolyte of a solid fuel cell, are fabricated by the conventional solid state reaction method. Local environments of dopants in these ceramic materials here synthesized are systematically investigated by using the x ray absorption near-edge structure (XANES) with the aid of first-principles calculations. Our present analytical method by combined use of XANES and first principles calculations has successfully explained the local environment of dopants in the above ceramic materials. PMID- 21817432 TI - First-principles calculation of oxygen K-electron energy loss near edge structure of HfO(2). AB - Oxygen K-electron energy loss near edge structures (ELNES) of monoclinic, tetragonal, and cubic HfO(2) were calculated by the first-principles full potential augmented plane wave plus local orbitals (APW+lo) method. By considering the relativistic effect as well as the core-hole effect in the calculation, the experimental oxygen K ELNES was successfully reproduced. The first, second, third, and fourth peaks originate from oxygen p components hybridized with Hf d-e(g), d-t(2g), s, and p components, respectively. It was found that the spectral differences among the polymorphs are mainly caused by the local structure of the Hf in the crystal. PMID- 21817433 TI - Local electronic structure analysis by site-selective ELNES using electron channeling and first-principles calculations. AB - In this paper, we review our recent analyses of electron energy loss near edge structure (ELNES) of particular crystalline sites, exploiting dynamical electron diffraction effects, or electron channeling, whereby the excitation weights of the Bloch waves propagating in a crystal can be controlled systematically by adjusting the diffraction conditions. A state-of-the-art data processing technique, multivariate curve resolution (MCR), can restore purely site-specific spectral profiles and their compositions from the experimental data set. Another technique, the Pixon deconvolution method, effectively removes the statistical noise, which enables us to compare the spectral fine structures with those calculated by first principles and discuss the site-specific local atomic and electronic structures. We demonstrate typical case studies in model materials and then an advanced chemical state analysis in a real material. Finally, some remarks toward further refinement of the method are made. PMID- 21817434 TI - Verification of the FEFF simulations to K-edge XANES spectra of the third row elements. AB - Availability of the FEFF simulations to K-edge x-ray absorption near-edge structure (XANES) spectra of the third row elements has been investigated. The FEFF simulations reproduce the spectra from simple substances (Al, Mg, Si, P and S) well, but do not always reproduce those from chemical compounds containing the third row elements. The FEFF simulation has a tendency to underestimate the white line intensity of the XANES spectra in these compounds. This situation is much improved by the Z+1 approach, in which the central atom is replaced by an atom with the atomic number larger by one. PMID- 21817435 TI - Overlap population diagram for ELNES and XANES: peak assignment and interpretation. AB - This article reviews overlap population (OP) diagrams for electron energy loss near-edge structure (ELNES) and x-ray absorption near-edge structure (XANES). By using the OP diagrams, peaks in ELNES and XANES of MgO, ZnO, AlN, GaN, InN, and YBa(2)Cu(3)O(7-x) are interpreted in terms of cation-anion and cation-cation interactions. Common features are found in the OP diagrams for different edges. A reconstruction of the unoccupied electronic structure is demonstrated by aligning the different edges with the common features in the OP diagrams. The OP diagram is also applied to the Cu/Al(2)O(3) hetero-interface to find the relationships among ELNES, atomic and electronic structures, and properties. PMID- 21817436 TI - High pressure evolution of YVO(4):Pr(3+) luminescence. AB - Photoluminescence and time-resolved photoluminescence spectra of YVO(4) doped with Pr(3+) obtained at high hydrostatic pressure up to 76 kbar applied in a diamond anvil cell are presented. At pressures lower than 60 kbar the steady state emission spectra consist of sharp lines related to the [Formula: see text] transition in Pr(3+). At pressures above 68 kbar the Pr(3+) emission intensity decreases and the corresponding bands are replaced by a broad band peaking at 19 500 cm(-1) attributed to perturbed VO(4)(3-) host luminescence. The quenching of the [Formula: see text] emission has been attributed to nonradiative transition to the charge transfer exciton trapped at Pr(3+) ion. The recovering of the VO(4)(3-) host luminescence at high pressure has been attributed to energy transfer from a Pr(3+) trapped exciton (PTE) to the host YVO(4). The kinetics of such a process is analyzed using the model of PTE considered as a Pr(4+) + electron bound by the Coulomb potential at the delocalized Rydberg states. PMID- 21817437 TI - Analysis of vacancy and interstitial nucleation kinetics in Si wafers during rapid thermal annealing. AB - The successful application of the rapid thermal annealing (RTA) process for creation of a magic denude zone in individual Czochralski silicon wafers is based on vacancy controlled oxygen precipitation. The kinetics of the vacancy and self interstitial processes in Si wafers are studied in this paper. Detailed insight into nucleation processes, out-diffusion and vacancy-interstitial recombination during the RTA leads to a new model of interaction between vacancies and oxygen. The calculation of the distribution function of these defects follows from modified Becker-Doring equations transformed for vacancies and interstitials and extended by diffusion and recombination terms. The new model, which includes the vacancy influence on oxygen nucleation and which follows from this theoretical analysis, corresponds very well to the experimental properties of formation of bulk micro-defects during RTA processes. PMID- 21817438 TI - Various ferroic orderings of triclinic tetrachloro-metallate dihydrate crystals. AB - In the triclinic crystals Rb(2)MnCl(4).2H(2)O, Cs(2)MnCl(4).2H(2)O and Cs(2)CaCl(4).2H(2)O the ferroelastic domain structure has been observed for temperatures from 100 K to the dehydration point. On heating at a few degrees before the dehydration point the structure has been found to reorganize. On heating in Rb(2)MnCl(4).2H(2)O and Cs(2)MnCl(4).2H(2)O (but not in Cs(2)CaCl(4).2H(2)O) a dielectric anomaly typical of a weak ferroelectric phase transition has been noted. The low-frequency dielectric dispersion in the low temperature phase is attributed to the oscillations of the domain walls. The activation energy of this motion is 73 and 67 kJ mol(-1) in Rb(2)MnCl(4).2H(2)O and Cs(2)MnCl(4).2H(2)O, respectively. In the phase transition region the complex permittivity has been found to show oscillations as a function of temperature. PMID- 21817439 TI - Cluster-glass behavior of a highly oxygen deficient perovskite, BaBi(0.28)Co(0.72)O(2.2). AB - A highly oxygen deficient perovskite, BaBi(0.28)Co(0.72)O(2.2), was synthesized by solid state reaction. The crystal structure was determined by means of neutron and x-ray powder diffraction. The material exhibits semiconducting behavior with an energy gap of 1.8 eV. The electron diffraction study does not reveal long range Bi:Co ordering; instead it shows the existence of short range ordering in this phase. The AC and DC magnetic susceptibility studies reveal cluster-glass behavior, which has its origin in the interacting ferromagnetic clusters present. PMID- 21817440 TI - Selective substitution in orbital domains of a low doped manganite: an investigation from Griffiths phenomenon and modification of glassy features. AB - An effort is made to study the contrast in magnetic behavior resulting from minimal disorder introduced by substitution of 2.5% Ga or Al in Mn site of La(0.9)Sr(0.1)MnO(3). It is considered that Ga or Al selectively create disorder within the orbital domains or on its walls, causing enhancement of Griffiths phase (GP) singularity for the former and disappearance of it in the latter case. It is shown that Ga replaces Mn(3+), which is considered to be concentrated within the domains, whereas Al replaces Mn(4+), which is segregated on the hole rich walls, without causing any significant effect on structure or ferromagnetic transition temperatures. Thus, it is presumed that the effect of disorder created by Ga extends across the bulk of the domain having correlation over a similar length scale, resulting in enhancement of the GP phenomenon. In contrast, the effect of disorder created by Al remains restricted to the walls, resulting in the modification of the dynamics arising from the domain walls and suppresses the GP. Moreover, contrasting features are observed in the low temperature region of the compounds; a re-entrant spin-glass-like behavior is observed in the Ga-doped sample, while the observed characteristics for the Al-doped sample are ascribed only to modified domain wall dynamics with the absence of any glassy phase. Distinctive features in third-order susceptibility measurements reveal that the magnetic ground state of the entire series comprises of orbital domain states. These observations bring out the role of the nature of disorder on the GP phenomenon and also reconfirms the character of self-organization in low doped manganites. PMID- 21817441 TI - Electron spin resonance observation of an interfacial Ge P(b 1)-type defect in SiO(2)/(100)Si(1-x)Ge(x)/SiO(2)/Si heterostructures. AB - Using electron spin resonance (ESR), we report on the observation of a first Ge dangling bond (DB)-type interface defect in the SiO(2)/(100)Ge(x)Si(1 x)/SiO(2)/(100)Si heterostructure manufactured by the condensation technique. The center, exhibiting monoclinic-I (C(2v)) symmetry with principal g values g(1) = 2.0338 +/- 0.0003, g(2) = 2.0386 +/- 0.0006, g(3) = 2.0054 is observed in maximum densities of ~6.8 * 10(12) cm(-2) of the Ge(x)Si(1-x)/SiO(2) interface for x~0.7, the signal disappearing for x outside the 0.45-0.93 range. The notable absence of interfering Si P(b)-type centers enables unequivocal spectral analysis. Collectively, the combination of all data leads to depicting the defect as a Ge P(b 1)-type center, i.e. not a trigonal basic Ge P(b(0))-type center ([Formula: see text]). Understanding the modalities of the defect's occurrence may provide an insight into the thus far elusive role of Ge DB defects at Ge/insulator interfaces, and widen our understanding of interfacial DB centers in general. PMID- 21817442 TI - Electron small polarons and bipolarons in LiNbO(3). AB - An overview of the properties of electron small polarons and bipolarons is given, which can occur in the congruently melting composition of LiNbO(3) (LN). Such polarons influence the performance of this important optical material decisively. Since coupling to the lattice strongly quenches the tunnelling of free small polarons in general, they are easily localized at one site even by weak irregularities of a crystal. The mechanism of their optical absorptions is thus shared with those of small polarons localized by binding to selected defects. It is shown that the optical properties of free electrons in LN as well as those bound to Nb(Li) antisite defects can be attributed consistently to small polarons. This is extended to electron pairs forming bipolarons bound to Nb(Li) Nb(Nb) nearest neighbours in the LN ground state. On the basis of an elementary phenomenological approach, relying on familiar concepts of defect physics, the peak energies, lineshapes, widths of the related optical absorption bands as well as the defect binding energies induced by lattice distortion are analysed. A criterion universally identifying small polaron absorption bands in oxide materials is pointed out. For the bipolarons, the dissociation energy, 0.27 eV, derived from a corresponding study of the mass action behaviour, is shown to be consistent with the data on isolated polarons. Based on experience with simple O( ) hole small polaron systems, a mechanism is proposed which explains why the observed small polaron optical absorptions are higher above the peak energies of the bands than those predicted by the conventional theory. The parameters characterizing the optical absorptions are seen to be fully consistent with those determining the electrical conductivity, i.e. the bipolaron dissociation energy and the positions of the defect levels as well as the activation energy of mobility. A reinterpretation of previous thermopower data of reduced LN on the basis of the bipolaron model confirms that the mobility of the free polarons is activated by 0.27 eV. On the basis of the level scheme of the bipolarons as well as the bound and free polarons the temperature dependence of the electronic conductivity is explained. The polaron/bipolaron concept also allows us to account for the concentrations of the various polaron species under the combined influence of illumination and heating. The decay of free and bound polarons dissociated from bipolarons by intense short laser pulses of 532 nm light is put in the present context. A critical review of alternative models, being proposed to explain the mentioned absorption features, is given. These proposals include: single free polarons in the (diamagnetic) LN ground state, oxygen vacancies in their various conceivable charge states, quadpolarons, etc. It is shown why these models cannot explain the experimental findings consistently. PMID- 21817443 TI - Neutron powder diffraction determination of the magnetic structure of Gd(3)Ag(4)Sn(4). AB - Natural gadolinium is the strongest neutron-absorbing element and neutron diffraction studies of Gd-containing materials rely on the use of either enriched Gd isotopes or short neutron wavelengths where the absorption is weaker but, unfortunately, the neutron flux is also weak. We have employed a new sample mounting technique to obtain neutron powder diffraction patterns from the intermetallic compound Gd(3)Ag(4)Sn(4) containing natural Gd, at a neutron wavelength of ~ 2.37 A where there is much greater flux. Here, we report the magnetic structure of Gd(3)Ag(4)Sn(4). The magnetic ordering temperature is 28.8(2) K. At 2.8 K the Gd(4e) sublattice is antiferromagnetically ordered along the crystal c-axis, commensurate with the crystal lattice. The Gd(2d) sublattice is also ordered along the c-axis but its magnetic structure is incommensurate with the crystal lattice. PMID- 21817444 TI - Magnetic particle hyperthermia: Neel relaxation in magnetic nanoparticles under circularly polarized field. AB - The mechanism of magnetization reversal in single-domain ferromagnetic particles is of interest in many applications, in most of which losses must be minimized. In cancer therapy by hyperthermia the opposite requirement prevails: the specific loss power should be maximized. Of the mechanisms of dissipation, here we study the effect of Neel relaxation on magnetic nanoparticles unable to move or rotate and compare the losses in linearly and circularly polarized fields. We present exact analytical solutions of the Landau-Lifshitz equation as derived from the Gilbert equation and use the calculated time-dependent magnetizations to find the energy loss per cycle. In frequencies lower than the Larmor frequency, linear polarization is found to be the better source of heat power, at high frequencies (beyond the Larmor frequency) circular polarization is preferable. PMID- 21817445 TI - An experimental investigation of dynamic behavior in FePt systems. AB - Magnetic relaxation experiments have been used to investigate the non-equilibrium dynamics of FePt nanoparticles. The system exhibits ageing at low temperatures, as well as a narrow energy distribution of the barrier to reversal. These properties were found susceptible to being affected by particle size, matrix and applied field strength. An analysis based on broad rate distributions is presented and compared with results obtained using energy barrier and viscosity interpretations. We find that a single broad distribution of relaxation times suggestive of cooperative effects is sufficient to explain the experimental results. PMID- 21817446 TI - Neutron diffuse scattering in deuterated para-terphenyl, C(18)D(14). AB - Neutron diffuse scattering is used to explore the short-range order (SRO) in deuterated para-terphenyl, C(18)D(14). The crystal shows SRO because the central of the three phenyl groups of each molecule can twist positively or negatively and these twists are correlated over the local scale. The presence of incipient Bragg peaks at [Formula: see text] at 200 K shows that these flips are negatively correlated along the a direction (nearest neighbour correlation coefficient of ~ 0.3) and b direction (nearest neighbour correlation coefficient of ~-0.87) and appear essentially uncorrelated along c. Diffuse peak anisotropy indicates that the range of the correlations along b is found to be ~3 times that along a. These correlations persist, although weaker, at room temperature. A Monte Carlo simulation was used to impose a correlation structure on the population of central ring twists that was deduced from Bragg scattering. By then allowing displacive relaxation of the structure, the observed diffuse scattering was well reproduced. Modelling the displacive motions of molecules showed that the positions of nearest ab-plane neighbour molecules are strongly positively correlated, particularly for motions approximately parallel to a, while the displacive correlations are weaker between molecules stacked along c. The apparent contradiction that the displacements are most strongly correlated along a while the occupancies are most strongly correlated along b is explained in terms of the connectivity of molecular interactions. PMID- 21817447 TI - Critical behaviour of structure factors at a quantum phase transition. AB - We review the theoretical behaviour of the total and one-particle structure factors at a quantum phase transition for temperature T = 0. The predictions are compared with exact or numerical results for the transverse Ising model, the alternating Heisenberg chain, and the bilayer Heisenberg model. At the critical wavevector, the results are generally in accord with theoretical expectations. Away from the critical wavevector, however, different models display quite different behaviours for the one-particle residues and structure factors. PMID- 21817448 TI - The crystal and magnetic structures of LaCa(2)Fe(3)O(8) and NdCa(2)Fe(3)O(8). AB - The crystal and magnetic structures of LaCa(2)Fe(3)O(8) and NdCa(2)Fe(3)O(8) have been established using a combination of x-ray, neutron and electron diffraction. It was already considered likely that LaCa(2)Fe(3)O(8) and NdCa(2)Fe(3)O(8) were made up of stacked perovskite-like layers of FeO(6) octahedra, with every third layer being replaced by a layer of tetrahedrally coordinated Fe, rather like a variation on the Brownmillerite (Ca(2)Fe(2)O(5)) structure type. We have gone further and determined a likely space group for this Grenier phase and determined the magnetic structure of the compounds at room temperature. The space group is found to be P 2(1)ma (b axis as the long axis), and the crystal structure has been refined, subject to the stacking faulting along the long axis that is apparent in electron diffraction patterns. The magnetic structure of LaCa(2)Fe(3)O(8) is shown to consist of antiferromagnetically ordered Fe(3+) ions on a collinear G-type antiferromagnetic structure, with the magnetic moments most likely (anti)parallel with the c axis, and of magnitude 3.4 +/- 0.2MU(B) (3.6 +/- 0.2MU(B) for NdCa(2)Fe(3)O(8)). The result is reasonable given the magnetic structures of the end members of the La(1-x)Ca(x)FeO(3) series, LaFeO(3) (x = 0) and Ca(2)Fe(2)O(5) (x = 1). PMID- 21817449 TI - Interlayer coupling in EuS/SrS, EuS/PbSe and EuS/PbTe magnetic semiconductor superlattices. AB - Neutron reflectivity studies of EuS/SrS, EuS/PbSe and EuS/PbTe all-semiconductor superlattices were carried out in a search for exchange interlayer coupling. A relatively weak antiferromagnetic coupling was found in EuS/SrS and EuS/PbSe systems but no interlayer coupling was detected in EuS/PbTe superlattices. In EuS/SrS, where the SrS spacer is an insulator (E(g)~4 eV), a very weak and short range interlayer coupling is in agreement with the earlier theoretical predictions that the interlayer coupling strength in EuS-based magnetic semiconductor superlattices depends strongly on the energy gap of the nonmagnetic layer and should decrease with an increase of the energy gap of the spacer material. A weak coupling in EuS/PbSe and no coupling in EuS/PbTe, where both PbSe and PbTe are narrow-gap semiconductors (E(g)~0.3 eV), is in disagreement not only with the theoretical expectations but also in stark contrast with earlier results for another narrow-gap spacer system, EuS/PbS, where pronounced antiferromagnetic coupling persists even in samples with PbS layer thicknesses as large as 200 A. A possible influence of the increasing lattice mismatch between EuS and the spacer materials (0.5%, 0.8%, 2.5% and 8.2% for PbS, SrS, PbSe and PbTe, respectively) on the magnetic ordering of the EuS layer near the interfaces and, consequently, on the interlayer coupling is discussed. PMID- 21817450 TI - Trevor Hicks and solid state neutron optics. AB - Following an idea of Trevor Hicks we built neutron polarizing benders with silicon wafers forming the bender channels. In the last decade a variety of neutron optical devices based on this idea were realized such as collimators with absorbing as well as reflecting walls, radial benders and collimators and focusing devices which are all much shorter than their classical counterparts. Their development will be reviewed here. PMID- 21817451 TI - Spin correlations in a simple cubic antiferromagnet L1(2)-type Pt(3)Fe. AB - Magnetic diffuse scattering of neutrons was studied for a simple cubic antiferromagnet L1(2)-type Pt(3)Fe alloy in a paramagnetic phase. In order to visualize the physics, the data were analyzed using a localized spin model and effective exchange coupling parameters were determined. The result shows a special feature of exchange couplings; the first neighbor coupling constant J(1) has almost the same value and the same sign as that of the second neighbor J(2). This fact explains well coexistence of the (1/2 1/2 0)-type and (1/2 0 0)-type magnetic structures in the low temperature phase of Pt(3)Fe alloy. PMID- 21817452 TI - Structural transitions in RNi(10)Si(2) intermetallics. AB - Intermetallic compounds of the type RFe(10)Si(2) and RCo(10)Si(2) crystallize in the ThMn(12) structure (space group I4/mmm) whilst the heavy rare earth series RNi(10)Si(2) crystallize in a maximal subgroup of I4/mmm, P4/nmm. Reported here are neutron powder diffraction investigations for TbNi(10)Si(2) and ErNi(10)Si(2) which show that the P4/nmm structure undergoes a high temperature order-disorder phase transition at approximately 930 degrees C above which the ordered Ni and Si fractions revert to a random distribution on 4d and 4e sites. The volume expansion has been tracked in detail via the temperature dependence of the lattice parameters, whilst the temperature dependence of the thermal expansion coefficients alpha(11), alpha(33) and alpha(volume) has been determined from the lattice parameters. Associated with the order-disorder transition is a transition associated with a displacement of the R ion along the c-axis. Both transitions are of second order and the critical exponent associated with the order-disorder and displacive transitions, beta = 0.31, is in excellent agreement with the exponent determined for the three-dimensional Ising model. PMID- 21817453 TI - On the interface magnetism of thin oxidized Co films: orbital and spin moments. AB - An x-ray magnetic circular dichroism study of a polycrystalline Co/CoO bilayer is presented. Using both the chemical specificity and surface sensitivity in the core level techniques, we find that uncompensated Co(2+) spin moments participate in the remanent ferromagnetic response of the bilayer that has oxygen nearest neighbors. These are likely located at the Co/CoO interface. As intermixing of magnetic species is not present in Co/CoO, it is concluded that the observed interface moments are due to interface roughness. Given their direction, these moments appear to not directly correlate to the exchange bias in these bilayers. PMID- 21817454 TI - Ferrimagnetism in the rare-earth iron garnets: a Monte Carlo study. AB - We investigate classical vector spin models of the rare-earth iron garnet ferrimagnets yttrium iron garnet (YIG) and gadolinium iron garnet (GdIG) using Monte Carlo simulations. Critical temperatures agree well with experiment. A compensation point is observed in GdIG, again in good agreement with experiment. PMID- 21817455 TI - Residual stress distribution in steel butt welds measured using neutron and synchrotron diffraction. AB - 70 keV synchrotron radiation and thermal neutrons have been employed to investigate the residual stress characteristics in a fully restrained, steel, butt weld. The focus is on the values of the subsurface and through-thickness strain/stress variation in the middle of the weld. The advantages and limitations of the techniques have been addressed, in relation to the gauge volume, the stress-free reference sample and positioning. The measurement of residual stress around the weld achieved in this work significantly improves the resolution at which residual stress in welded components has been determined. PMID- 21817456 TI - High energy excitations measured by neutron spectroscopy in FePS(3). AB - The quasi-two-dimensional antiferromagnet FePS(3) has been investigated using inelastic neutron spectroscopy with the time-of-flight spectrometer HET at the ISIS spallation neutron source. In the paramagnetic regime, two clearly resolved, high energy excitations were observed in the low scattering angle detector banks at 195(5) meV and 430(10) meV. The absence of these transitions from the high angle detector banks indicates that they are likely to be due to the crystal fields and magnetic in origin. The two transitions most probably represent electronic transitions in the Fe(2+) ion among the low lying crystal field and spin-orbit split levels raised from the ground state. It has not yet been determined why the energies are greater than those observed in a comparable Raman experiment. PMID- 21817457 TI - The crystal field interaction at the rare earth site in ErNiAl(4). AB - Inelastic neutron scattering spectra are reported for orthorhombic ErNiAl(4) at temperatures ranging from 2.1 to 280 K. The neutron transitions are interpreted in terms of three reliably identified excited crystal field (CF) levels and four tentative excited levels for the J = 7/2 ground term of Er(3+) at the single Er site. A shift in transition peak energy between 2.1 and 8.6 K is attributed to Zeeman splitting induced by magnetic order of the Er sub-lattice below T(N) = 5.8 K. With the aid of a suite of possible (155)Gd-Mossbauer spectroscopy derivations of the rank n = 2 CF parameters and a simple point charge model calculation of within-rank ratios for the higher rank (n = 4,6) parameters, estimates are made for all nine CF parameters required for the orthorhombic C(2v) (mm) Er-site symmetry. PMID- 21817458 TI - Magnetic short-range order in beta-Mn(1-x)Co(x). AB - We present a study of the magnetic ground state properties of beta-Mn metal alloyed with Co, using neutron polarization analysis of the diffuse neutron scattering cross-section. We analyse the magnetic structure obtained using a reverse Monte Carlo procedure to extract the Mn-Mn spin correlations. The addition of Co leads to a static disordered magnetic structure with medium-range correlations. Our analysis of the spin correlations indicates that both 8c and 12d non-equivalent lattice sites present in the beta-Mn structure contribute to the magnetic ground state, where previously it was thought that the 8c site was non-magnetic. PMID- 21817459 TI - Magnetic phase transitions in Pr(1-x)Lu(x)Mn(2)Ge(2) compounds. AB - The effects of replacing Pr by Lu on the magnetic behaviour and structures of Pr(1-x)Lu(x)Mn(2)Ge(2) (x = 0.2,x = 0.4) have been investigated using x-ray diffraction, Mossbauer spectroscopy, magnetization and neutron diffraction measurements. The substitution of Lu for Pr leads to a decrease in the lattice constants a, c and the unit cell volume V at room temperature with this contraction of the unit cell resulting in modifications of the Pr(1 x)Lu(x)Mn(2)Ge(2) magnetic structures. Four and five magnetic phase transitions linked primarily with temperature driven changes in the intralayer Mn-Mn separation distances-have been detected within the temperature range 4.5-550 K for Pr(0.8)Lu(0.2)Mn(2)Ge(2) and Pr(0.6)Lu(0.4)Mn(2)Ge(2), respectively, with re entrant ferromagnetism being detected around T(C)(Pr)~31 K for Pr(0.6)Lu(0.4)Mn(2)Ge(2). It was found that T(C)(inter) and T(C)(Pr) increase with increasing applied field while T(N)(inter) decreases for Pr(0.6)Lu(0.4)Mn(2)Ge(2), indicating that the canted antiferromagnetic AFmc region contracts with increasing field. The Debye temperatures for Pr(1 x)Lu(x)Mn(2)Ge(2) with x = 0.2 and 0.4 were evaluated as theta(D) = 320 +/- 40 K and theta(D) = 400 +/- 20 K respectively from the temperature dependence of the average isomer shift. The magnetic structures of both compounds have been determined by means of neutron diffraction measurements over the temperature range 3-300 K with formation of the Fmi magnetic state below T(c/c) = 192 K for Pr(0.8)Lu(0.2)Mn(2)Ge(2) and the occurrence of re-entrant ferromagnetism below T(C)(Pr) = 31 K for Pr(0.6)Lu(0.4)Mn(2)Ge(2) being confirmed. PMID- 21817460 TI - Crystal structures and phase transition in (Sr(0.8)Ce(0.2))(Mn(1-y)Co(y))O(3) (y = 0 and 0.2): the influence of Jahn-Teller distortion. AB - We have studied the crystal structures of (Sr(0.8)Ce(0.2))(Mn(1-y)Co(y))O(3) (y = 0 and 0.2) using neutron diffraction. Both (Sr(0.8)Ce(0.2))MnO(3) and (Sr(0.8)Ce(0.2))(Mn(0.8)Co(0.2))O(3) have a tetragonal structure in space group I4/mcm at room temperature, and the octahedral tilt angle around the c-axis is nearly the same. The only significant difference is the shape of the Mn(Co)O(6) octahedron: it is elongated in (Sr(0.8)Ce(0.2))MnO(3) due to the cooperative Jahn Teller (JT) effect, but essentially regular in (Sr(0.8)Ce(0.2))(Mn(0.8)Co(0.2))O(3) due to the absence of JT-active Mn(3+) ions. With increasing temperature, both compounds undergo a continuous phase transition at around 400 degrees C to a cubic structure in [Formula: see text], with no indication of a distinct transition in (Sr(0.8)Ce(0.2))MnO(3) from the removal of the static JT distortion. In addition, the temperature dependence of the octahedral tilt angle is very similar in the two samples, implying that the JT distortion has minimal effect on the octahedral tilting and the phase transition to cubic. X-ray absorption near-edge structure (XANES) analysis indicates that the Ce oxidation state is predominantly 4+ in both samples. The electrical conductivity is higher in (Sr(0.8)Ce(0.2))MnO(3) than in (Sr(0.8)Ce(0.2))(Mn(0.8)Co(0.2))O(3) in the temperature range studied (100-900 degrees C). PMID- 21817461 TI - A model for measurement of the states in a coupled-dot qubit. AB - We propose a quantum trajectory analysis of a scheme to measure the states of a coupled-dot device (qubit) where there is a fluctuating energy gap Delta between the two states. The system consists of the qubit and a readout dot coupled to source and drain leads. The tunnel rate through the detector is conditioned by the occupation number of the nearer quantum dot (target) of the qubit and therefore probes the states of the qubit. We derive a Lindblad-form master equation to calculate the unconditional evolution of the qubit and a conditional stochastic master equation calculating the conditional evolution for different tunneling rates. The results show the effects of various device parameters and provide the optimum selection and combination of the system structure. PMID- 21817462 TI - Crystal structure and physical properties of a novel Kondo antiferromagnet: U(3)Ru(4)Al(12). AB - A novel ternary compound U(3)Ru(4)Al(12) has been identified in the U-Ru-Al ternary diagram. Single-crystal x-ray diffraction indicates a hexagonal Gd(3)Ru(4)Al(12)-type structure for this uranium-based intermetallic. While this structure type usually induces geometrically a spin-glass behaviour, an antiferromagnetic ordering is observed at T(N) = 8.4 K in the present case. The reduced effective magnetic moment of U atoms (MU(eff) = 2.6 u(B)) can be explained by Kondo-like interactions and crystal field effects that have been identified by a logarithmic temperature dependence of the electrical resistivity, negative values of the magnetoresistivity and particular shape of the Seebeck coefficient. PMID- 21817463 TI - Generic properties of Mn spinels with an immiscibility induced by a Jahn-Teller distortion. AB - The generic properties are scrutinized in Mn spinels with an immiscibility induced by a Jahn-Teller distortion through the CoFe(2-x)Mn(x)O(4) system. The x ray diffraction experiment reveals that the immiscibility occurs at 1.120 K to be due to the polarization of the Nd magnetic moment by the field of Mn moments that order below T(N)~78 K. PMID- 21817476 TI - Ion beam triangulation based on electron detection for studies on the structure of 1 ML Mn on Cu(001). AB - Recent developments in studies on the structure of surfaces based on ion beam triangulation are discussed. We will outline recent experimental progress in the application of this method, which is closely related to the detection of the number of emitted electrons per incident ion during scattering under surface channeling conditions. Key features are the pronounced change of electron emission for the projectile beam aligned along a low index crystallographic direction in the surface plane ('axial surface channeling') and the interpretation of data in terms of classical trajectory computer simulations. As a representative example we will discuss here studies on the structure of the low temperature c(8 * 2) Mn/Cu(001) phase. PMID- 21817477 TI - Reactivity of periodically rippled graphene grown on Ru(0001). AB - We report here the reactivity of epitaxial graphene islands and complete monolayers on Ru(0001) towards molecular oxygen and air. The graphene is prepared by thermal decomposition of ethylene molecules pre-adsorbed on an Ru(0001) surface in an ultra-high vacuum chamber. The graphene layer presents a periodically rippled structure that is dictated by the misfit between graphene and Ru(0001) lattice parameters. The periodic ripples produce spatial charge redistribution in the graphene and modifies its electronic structure around the Fermi level. In order to investigate the reactivity of graphene we expose graphene islands to a partial pressure of oxygen and following the evolution of the surface by STM during the exposure. For the exposure to air we removed the sample from the UHV chamber and we re-introduce it after several hours, taking STM images before and after. The surface areas not covered by the graphene islands present a dramatic change but the graphene structure, even the borders of the islands, remain intact. In the case of a complete graphene monolayer the exposure to oxygen or to air does not affect or destroy the rippled structure of the graphene monolayer. PMID- 21817478 TI - The phase diagram of halogens on Pt(110): structure of the (4 * 1)-Br/Pt(110) phase. AB - When adsorbed on the strongly anisotropic Pt(110) surface Br forms a sequence of (n * 1) structures. In the present study we investigate the (4 * 1) structure by scanning tunneling microscopy, quantitative low-energy electron diffraction and density-functional calculations. We show that the optimal structural model contains essentially the same adsorption sites as the (3 * 1) structure, but with a different preference. The positions of the substrate atom are consistent with a frozen surface phonon of fourfold periodicity, suggesting that the phase diagram can be understood on the basis of a tunable charge density wave (Swamy et al 2001 Phys. Rev. B 86 1299). The structure could also be explained by assuming short range interactions only, but evidence is presented that adsorbate-adsorbate interactions mediated by quasi-one-dimensional surface resonances play a major role in both cases. PMID- 21817479 TI - Ferromagnetic Fe on Cu(001) throughout the fcc-like phase: arguing from the viewpoint of the electronic structure. AB - The scientific enthusiasm for ultrathin Fe films on Cu(001) has now lasted for more than 20 years. Is there ferromagnetic iron with a face-centred cubic (fcc) structure? Does ferromagnetism in Fe hinge on the body-centred cubic (bcc) structure? In this contribution, we try to establish that the electron system gives evidence of ferromagnetic behaviour with fcc-like electronic bands. We examine a crystal-induced surface state, which is characteristic of fcc surface order. Furthermore, we compare electronic signatures of fcc and bcc: the d-band exchange splitting, image-potential-state energies and the work function. We conclude that, from the viewpoint of the electronic structure, Fe on Cu(001) is found to be ferromagnetic throughout the fcc-like phase. This result raises a new question: how much deviation from the relaxed fcc order is acceptable without losing the electronic signature of fcc? PMID- 21817480 TI - A LEED study of NO superstructures on the Pd(111) surface. AB - We have examined two adsorption structures of NO on the Pd(111) surface and the transformation between them. Low-energy electron diffraction (LEED) I(V) curves of the Pd(111)-p(2 * 2)-NO and Pd(111)-c(4 * 2)-NO surface structures were acquired and analyzed using tensor LEED. Our structural models confirm a previous study by scanning tunneling microscopy and DFT (Hansen et al 2002 Surf. Sci. 496 1). In the c(4 * 2)-NO structure, which forms at an NO coverage of 0.5 monolayers (ML), the NO molecules occupy fcc and hcp hollow sites and are almost upright with only slight tilting, possibly related to NO-NO repulsion. In the p(2 * 2)-NO structure (0.75 ML), with two NO molecules in hollow sites and one in an on-top site, we find strong tilting of the on-top molecule. Upon heating, thermal desorption of NO leads to a transition from the p(2 * 2) to the c(4 * 2) structure, which leads to splitting of the diffraction spots and/or streaky spots. The transition is discussed in terms of domain walls. PMID- 21817481 TI - Electronic structure of CoSi(2) films on Si(111) studied using time-resolved two photon photoemission. AB - The occupied and unoccupied electronic structure of thin epitaxial CoSi(2) films grown on Si(111) substrates was studied using time-resolved two-photon photoemission and valence-band photoemission spectroscopy. The work function of the sample surfaces and the Schottky barrier height at the metal-semiconductor interface were measured as a function of annealing temperature. The photoemission data reveal several occupied and unoccupied electronic states which exhibit a high sensitivity to the annealing temperature. Time-resolved measurements show a behavior typical for a short-lived hot-electron gas and indications for an image potential resonance. PMID- 21817482 TI - Point defects in the NiAl(100) surface. AB - The stability of various point defects in NiAl(100) has been investigated by first-principles calculations. For Al-rich surfaces, Ni vacancies within the first Al layer are energetically most favourable. For Ni-rich surfaces, so-called double defects, consisting of both Ni-antisite atom in the first Al layer and a Ni vacancy within the second Ni layer, form the configuration of lowest energy, superior to singular Ni antisites. An additional and significant energy gain is found in both cases by mutual lateral interaction of the defects, when they are arranged in the diagonal direction. Respective [Formula: see text] ordered configurations were found as the most stable structures. A 50:50 mixture of both defect types turns out to be even lower in energy than the ideal Al-terminated NiAl(100) surface, proving the latter to be metastable only. This is in line with the often reported inability in experiments to prepare ideal NiAl(100) surfaces. PMID- 21817483 TI - Two-dimensional manganese oxide nanolayers on Pd(100): the surface phase diagram. AB - Two-dimensional manganese oxide layers have been grown on Pd(100) and have been characterized by means of scanning tunnelling microscopy, low energy electron diffraction and x-ray photoelectron spectroscopy (XPS). The complex surface phase diagram of MnO(x) on Pd(100) is reported, where nine different novel Mn oxide phases have been detected as a function of the chemical potential of oxygen MU(O). Three regions of the chemical potential of oxygen can be identified, in which structurally related oxide phases are formed, often in coexistence at the surface. The different regions of MU(O) are reflected in the oxidation states of the respective Mn oxide nanolayers as revealed by the Mn 2p and O 1s XPS binding energies. The MnO(x) nanolayers form two-dimensional wetting layers and it is speculated that they mediate the epitaxial growth of MnO on Pd(100) by providing structurally graded interfaces. PMID- 21817484 TI - O- and H-induced surface core level shifts on Ru(0001): prevalence of the additivity rule. AB - In previous work on adsorbate-induced surface core level shifts (SCLSs), the effects caused by O atom adsorption on Rh(111) and Ru(0001) were found to be additive: the measured shifts for first-layer Ru atoms depended linearly on the number of directly coordinated O atoms. Density-functional theory calculations quantitatively reproduced this effect, allowed separation of initial- and final state contributions, and provided an explanation in terms of a roughly constant charge transfer per O atom. We have now conducted similar measurements and calculations for three well-defined adsorbate and coadsorbate layers containing O and H atoms: (1 * 1)-H, (2 * 2)-(O+H) and (2 * 2)-(O+3H) on Ru(0001). As H is stabilized in fcc sites in the prior two structures and in hcp sites in the latter, this enables us to not only study coverage and coadsorption effects on the adsorbate-induced SCLSs, but also the sensitivity to similar adsorption sites. Remarkably good agreement is obtained between experiment and calculations for the energies and geometries of the layers, as well as for all aspects of the SCLS values. The additivity of the next-neighbor adsorbate-induced SCLSs is found to prevail even for the coadsorbate structures. While this confirms the suggested use of SCLSs as fingerprints of the adsorbate configuration, their sensitivity is further demonstrated by the slightly different shifts unambiguously determined for H adsorption in either fcc or hcp hollow sites. PMID- 21817485 TI - A LEED analysis of the clean surfaces of alpha-Fe(2)O(3)(0001) and alpha Cr(2)O(3)(0001) bulk single crystals. AB - We analyzed the (0001) surface structures of hematite and chromia bulk single crystals by low energy electron diffraction (LEED). The hematite crystal was annealed in an O(2) atmosphere, p(O(2))~3 * 10(-8) mbar, for several hours. The chromia crystal was sputtered with Ar(+) ions, E = 1 keV, and afterward heated up to 900 degrees C for 5 min under ultra-high-vacuum (UHV) conditions. I(V)-curve data sets of 12 symmetrically independent diffraction spots were measured at room temperature in the energy range E = 150-500 eV. Charging effects hindered measurements at lower energies. Our analysis of the hematite single crystal surface indicates that it is terminated by a single iron layer which is occupied at ~50%. Relaxation effects along the c-axis are quite large and involve several iron double layers. For the chromia surface the results indicate that termination with a single Cr seems not to hold. Most probably the surface is terminated by two partially occupied Cr sites or chromyl groups. Relaxations in deeper layers are small in contrast to alpha-Fe(2)O(3)(0001). PMID- 21817486 TI - Surface x-ray diffraction analysis using a genetic algorithm: the case of Sn/Cu(100)-[Formula: see text]. AB - The application of genetic algorithms to the analysis of surface x-ray diffraction data is discussed and the implementation of a genetic algorithm of evolutionary type is described in detail. The structure of Sn/Cu(100)-[Formula: see text] is determined on the basis of surface x-ray diffraction data analysed using this algorithm. The results are compared to previous findings using other techniques. PMID- 21817487 TI - Growth and structure of gold films on a Re([Formula: see text]) surface. AB - We have deposited Au films in ultra-high vacuum onto a rhenium ([Formula: see text]) surface in submonolayer and multilayer concentrations and studied them by means of low- and medium-energy electron diffraction in the temperature range between 300 and 800 K. In the submonolayer range, Au forms several low-energy electron diffraction (LEED) phases, namely, a (1 * 3), a (1 * 4), a (1 * 5) and a (1 * 6) phase, consisting of one-dimensionally ordered Au chains in the [[Formula: see text]] direction, until the formation of a complete pseudomorphic monolayer is indicated by a (1 * 1) LEED phase. In the multilayer regime, a (1 * 8) LEED phase appears over a surprisingly wide coverage range from about two to at least eight monolayers, which we interpret as a hexagonal uniaxially compressed reconstructed Au overlayer on pseudomorphically grown hexagonal close packed gold layers. In order to get access to absolute Au coverages, we have performed LEED (I,V) measurements and carried out a LEED structure determination for the (1 * 1) phase. We propose the formation of a full Au monolayer in which both the Re trough and top-row sites are being covered by Au atoms. The data are discussed and compared with those from previous studies on related systems. PMID- 21817488 TI - Collective diffusion in two-dimensional systems: exact analysis based on the kinetic lattice gas model. AB - Using a gradient expansion of the local microscopic particle current, in the long time and large-scale limit, we derive an exact analytical expression for the density and temperature dependence of the diffusivity in terms of the density dependence of correlation functions on a rectangular lattice. The latter are calculated by transfer matrix methods, generalized to an adsorbate with lateral interactions and subjected to an external field. This allows an examination of the effects of generalized hopping kinetics. Where both initial and final state interactions are involved, the Reed-Ehrlich factorization, commonly assumed, cannot apply. PMID- 21817489 TI - Structure of isolated biomolecules obtained from ultrashort x-ray pulses: exploiting the symmetry of random orientations. AB - Amongst the promised capabilities of fourth-generation x-ray sources currently under construction is the ability to record diffraction patterns from individual biological molecules. One version of such an experiment would involve directing a stream of molecules into the x-ray beam and sequentially recording the scattering from each molecule of a short, but intense, pulse of radiation. The pulses are sufficiently short that the diffraction pattern is that due to scattering from identical molecules 'frozen' in random orientations. Each diffraction pattern may be thought of as a section through the 3D reciprocal space of the molecule, of unknown, random, orientation. At least two algorithms have been proposed for finding the relative orientations from just the measured diffraction data. The 'common-line' method, also employed in 3D electron microscopy, appears not best suited to the very low mean photon count per diffraction pattern pixel expected in such experiments. A manifold embedding technique has been used to reconstruct the 3D diffraction volume and hence the electron density of a small protein at the signal level expected of the scattering of an x-ray free electron laser pulse from a 500 kD biomolecule. In this paper, we propose an alternative algorithm which raises the possibility of reconstructing the 3D diffraction volume of a molecule without determining the relative orientations of the individual diffraction patterns. We discuss why such an algorithm may provide a practical and computationally convenient method of extracting information from very weak diffraction patterns. We suggest also how such a method may be adapted to the problem of finding the variations of a structure with time in a time-resolved pump-probe experiment. PMID- 21817490 TI - The role of surface stress in structural transitions, epitaxial growth and magnetism on the nanoscale. AB - We review results on combined stress measurements by the crystal curvature technique and structural investigations on different nanoscale systems. It is shown that stress measurements offer highly sensitive and accurate data which identify even subtle structural changes in the sub-monolayer coverage regime. We discuss the unique potential of stress measurements to complement structural investigations of atomic layers and at surfaces. Our examples reveal that stress measurements enhance, support and clarify the interpretation of quantitative structural data. The role of surface stress and film stress for structural transitions in epitaxial growth, surfactant-mediated growth, surface reconstruction and adsorbate-induced spin reorientation transitions in monolayers is discussed. PMID- 21817491 TI - Epitaxial graphene on SiC(0001) and [Formula: see text]: from surface reconstructions to carbon electronics. AB - Graphene with its unconventional two-dimensional electron gas properties promises a pathway towards nanoscaled carbon electronics. Large scale graphene layers for a possible application can be grown epitaxially on SiC by Si sublimation. Here we report on the initial growth of graphene on SiC basal plane surfaces and its relation to surface reconstructions. The surfaces were investigated by scanning tunneling microscopy (STM), low energy electron diffraction (LEED), angle resolved ultraviolet photoelectron spectroscopy (ARUPS) and x-ray photoelectron spectroscopy (XPS). On SiC(0001) the interface is characterized by the so-called [Formula: see text] reconstruction. The homogeneity of this phase is influenced by the preparation procedure. Yet, it appears to be crucial for the quality of further graphene growth. We discuss the role of three structures with periodicities [Formula: see text], (6 * 6) and (5 * 5) present in this phase. The graphitization process can be observed by distinct features in the STM images with atomic resolution. The number of graphene layers grown can be controlled by the conical band structure of the pi-bands around the [Formula: see text] point of the graphene Brillouin zone as measured by laboratory-based ARUPS using UV light from He II excitation. In addition we show that the spot intensity spectra in LEED can also be used as fingerprints for the exact determination of the number of layers for the first three graphene layers. LEED data correlated to the ARUPS results allow for an easy and practical method for the thickness analysis of epitaxial graphene on SiC(0001) that can be applied continuously during the preparation procedure, thus paving the way for a large variety of experiments to tune the electronic structure of graphene for future applications in carbon electronics. On [Formula: see text] graphene grows without the presence of an interface layer. The initial graphene layer develops in coexistence with intrinsic surface reconstructions of the [Formula: see text] surface. In high resolution STM measurements we show atomically resolved graphene layers on top of the (3 * 3) reconstruction with a Moire type modulation by a large superlattice periodicity that indicates a weak coupling between the graphene layer and the substrate. PMID- 21817492 TI - Ab initio phase diagram of oxygen adsorption on W(110). AB - The phase diagram of oxygen adsorption on the W(110) surface is derived without any empirical parameters by a combination of density functional theory (DFT) calculations, the cluster expansion (CE) technique and Monte Carlo (MC) applications. Coverages up to 1 monolayer are considered corresponding to the range of oxygen concentrations, 0<=x(O)<=1. DFT results for single-site adsorption and in particular for full coverage reveal that adsorption at threefold hollow (H3) sites is by far the most stable one. Therefore, the CE is done for an atomic layer with the two H3 sublattices of the W(110) surface. Based on 60 DFT calculations with fully relaxed atomic geometries of lateral unit cells containing 12 atoms, and a ground state search for 80 394 structures, four ground state structures are found with the lateral unit cells (2 * 5) for x(O) = 0.20, (2 * 2) (a) for x(O) = 0.25, (2 * 1) for x(O) = 0.50 and (2 * 2) (b) for x(O) = 0.75. In agreement with experiments the most stable structures are (2 * 1) and (2 * 2) (b), which correspond to higher coverages. The thermodynamical stability of the two ground states at lower coverages is very weak. Detailed analysis of the relaxation of the (2 * 1) structure reveals sizeable lateral stresses acting on the surface tungsten atoms. On the basis of the effective cluster interactions MC simulations are performed in order to derive the critical temperatures by which the phase diagram is finally constructed. PMID- 21817493 TI - Site blocking and CO/sulfur site exchange processes on stepped Pt surfaces. AB - The influence of preadsorbed sulfur on the adsorption of CO on Pt(355) and Pt(322) is investigated systematically for sulfur precoverages between 0.02 and 0.30 ML by in situ x-ray photoelectron spectroscopy of the C 1s and S 2p core levels. The two surfaces have the same nominal terrace width of 5 atomic rows, but different step orientation. For both, at low temperatures (130 and 150 K), S preferentially adsorbs at the steps and passivates them for CO adsorption. The required S precoverage is significantly smaller for Pt(322), because of the lower number of steps as a result of the S-induced double-step formation. Upon heating, population of step sites with CO occurs due to irreversible CO/S site exchange. At low S precoverages, the characteristic transition temperatures of 165 K for Pt(355) and 245 K for Pt(322) are significantly different, indicating a higher activation barrier for the CO/S site exchange process for Pt(322). For medium to high S precoverages the transition temperature stays unchanged for Pt(322) but increases for Pt(355). The observed behavior is attributed to a kinetic passivation of the steps by sulfur at low temperatures, which is lifted upon heating. PMID- 21817494 TI - Morphology and CO adsorption on platinum supported on thin Fe(3)O(4)(111) films. AB - Nucleation, growth and thermal stability of Pt particles supported on well ordered Fe(3)O(4)(111) thin films grown on Pt(111) were studied by scanning tunnelling microscopy (STM) and temperature programmed desorption (TPD) of CO. STM studies showed that Pt grows through the formation of single-layer islands that coalesce at high coverage. Vacuum annealing at 600 K caused Pt sintering and the formation of extended two-dimensional (2D) islands one and two layers in thickness at sub-monolayer coverage. Well faceted, three-dimensional (3D) Pt nanoparticles formed by annealing to temperatures above 800 K were encapsulated by an FeO(111) monolayer. These results were rationalized in terms of the high adhesion energy for Pt on iron oxide surfaces. CO TPD studies showed that 2D structures, formed at 600 K, exhibit much lower CO adsorption capacity as compared to the Pt(111) single crystal surface. This effect has been tentatively assigned to lattice expansion in the Pt 2D islands leading to weakening of the Pt CO bond due to reduction of the [Formula: see text] back-donation. PMID- 21817495 TI - Thiolated chitosan nanoparticles: transfection study in the Caco-2 differentiated cell culture. AB - The aim of this study was to monitor the expression of secreted protein in differentiated Caco-2 cells after transfection with nanoparticles, in order to improve gene delivery. Based on unmodified chitosan and thiolated chitosan conjugates, nanoparticles with the gene reporter pSEAP (recombinant Secreted Alkaline Phosphatase) were generated at pH 4.0. Transfection studies of thiolated chitosan in Caco-2 cells during the exponential growth phase and differentiation growth phase of the cells led to a 5.0-fold and 2.0-fold increase in protein expression when compared to unmodified chitosan nanoparticles. The mean particle size for both unmodified chitosan and cross-linked thiolated chitosan nanoparticles is 212.2 +/- 86 and 113.6 +/- 40 nm, respectively. The zeta potential of nanoparticles was determined to be 7.9 +/- 0.38 mV for unmodified chitosan nanoparticles and 4.3 +/- 0.74 mV for cross-linked thiolated chitosan nanoparticles. Red blood cell lysis evaluation was used to evaluate the membrane damaging properties of unmodified and thiolated chitosan nanoparticles and led to 4.61 +/- 0.36% and 2.29 +/- 0.25% lysis, respectively. Additionally, cross-linked thiolated chitosan nanoparticles were found to exhibit higher stability toward degradation in gastric juices. Furthermore the reversible effect of thiolated chitosan on barrier properties was monitored by measuring the transepithelial electrical resistance (TEER) and is supported by immunohistochemical staining for the tight junction protein claudin. According to these results cross-linked thiolated chitosan nanoparticles have the potential to be used as a non-viral vector system for gene therapy. PMID- 21817496 TI - Folate-conjugated polymer micelles for active targeting to cancer cells: preparation, in vitro evaluation of targeting ability and cytotoxicity. AB - To obtain an active-targeting carrier to cancer cells, folate-conjugated stearic acid grafted chitosan oligosaccharide (Fa-CSOSA) was synthesized by 1-ethyl-3-(3 dimethylaminopropyl) carbodiimide (EDC)-mediated coupling reaction. The substitution degree is 22.1%. The critical micelle concentrations (CMCs) of Fa CSOSA were 0.017 and 0.0074 mg ml(-1) in distilled water and PBS (pH 7.4), respectively. The average volume size range of Fa-CSOSA micelles was 60-120 nm. The targeting ability of Fa-CSOSA micelles was investigated against two kinds of cell lines (A549 and Hela), which have different amounts of folate receptors in their surface. The results indicated that Fa-CSOSA micelles presented a targeting ability to the cells (Hela) with a higher expression of folate receptor during a short-time incubation (<6 h). As incubation proceeded, the special spatial structure of the micelles gradually plays a main role in cellular internalization of the micelles. Good internalization of the micelles into both Hela and A549 cells was shown. Then, paclitaxel (PTX) was encapsulated into the micelles, and the content of PTX in the micelles was about 4.8% (w/w). The average volume size range of PTX-loaded micelles was 150-340 nm. Furthermore, the anti-tumor efficacy in vitro was investigated by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) method. The IC(50) of Taxol (a clinical formulation containing PTX) on A549 and Hela cells was 7.0 and 11.0 ug ml(-1), respectively. The cytotoxicity of PTX-loaded micelles was improved sharply (IC(50) on A549: 0.32 ug ml(-1); IC(50) on Hela: 0.268 ug ml(-1)). This is attributed to the increased intracellular delivery of the drug. The Fa-CSOSA micelles that are presented may be a promising active-targeting carrier candidate via folate mediation. PMID- 21817498 TI - Preparation of a polymer surface coated with a gradient of quantum dots. AB - In the present study, we generated a polyethylene surface coated with a gradient of quantum dots for use in imaging experiments. The polyethylene surface was first treated with increasing coronal discharge along its length. Next, the surface was reacted with branched polyethyleneimine followed by biotin to produce a polyethylene surface with a gradient of biotin. Finally, the biotin-coated surface was reacted with streptavidin-coated quantum dots. Fluorescent imaging showed that the fluorescence intensity from the quantum dots gradually increased along its length. Such quantum-dot-modified gradient polyethylene surfaces may be useful in biomedical analyses. PMID- 21817497 TI - Measurement of immunotargeted plasmonic nanoparticles' cellular binding: a key factor in optimizing diagnostic efficacy. AB - In this study, we use polarized light scattering to study immunotargeted plasmonic nanoparticles which bind to live SK-BR-3 human breast carcinoma cells. Gold nanoparticles can be conjugated to various biomolecules in order to target specific molecular signatures of disease. This specific targeting provides enhanced contrast in scattering-based optical imaging techniques. While there are papers which report the number of antibodies that bind per nanoparticle, there are almost no reports of the key factor which influences diagnostic or therapeutic efficacy using nanoparticles: the number of targeted nanoparticles that bind per cell. To achieve this goal, we have developed a 'negative' method of determining the binding concentration of those antibody/nanoparticle bioconjugates which are targeted specifically to breast cancer cells. Unlike previously reported methods, we collected unbound nanoparticle bioconjugates and measured the light scattering from dilute solutions of these particles so that quantitative binding information can be obtained. By following this process, the interaction effects of adjacent bound nanoparticles on the cell membrane can be avoided simply by measuring the light scattering from the unbound nanoparticles. Specifically, using nanoshells of two different sizes, we compared the binding concentrations of anti-HER2/nanoshell and anti-IgG/nanoshell bioconjugates targeted to HER2-positive SK-BR-3 breast cancer cells. The results indicate that, for anti-HER2/nanoshell bioconjugates, there are approximately 800-1600 nanoshells bound per cell; for anti-IgG/nanoshell bioconjugates, the binding concentration is significantly lower at nearly 100 nanoshells bound per cell. These results are also supported by dark-field microscopy images of the cells labeled with anti-HER2/nanoshell and anti-IgG/nanoshell bioconjugates. PMID- 21817499 TI - Ru nanostructure fabrication using an anodic aluminum oxide nanotemplate and highly conformal Ru atomic layer deposition. AB - We fabricated metallic nanostructures directly on Si substrates through a hybrid nanoprocess combining atomic layer deposition (ALD) and a self-assembled anodic aluminum oxide (AAO) nanotemplate. ALD Ru films with Ru(DMPD)(EtCp) as a precursor and O(2) as a reactant exhibited high purity and low resistivity with negligible nucleation delay and low roughness. These good growth characteristics resulted in the excellent conformality for nanometer-scale vias and trenches. Additionally, AAO nanotemplates were fabricated directly on Si and Ti/Si substrates through a multiple anodization process. AAO nanotemplates with various hole sizes (30-100 nm) and aspect ratios (2:1-20:1) were fabricated by controlling the anodizing process parameters. The barrier layers between AAO nanotemplates and Si substrates were completely removed by reactive ion etching (RIE) using BCl(3) plasma. By combining the ALD Ru and the AAO nanotemplate, Ru nanostructures with controllable sizes and shapes were prepared on Si and Ti/Si substrates. The Ru nanowire array devices as a platform for sensor devices exhibited befitting properties of good ohmic contact and high surface/volume ratio. PMID- 21817500 TI - Controlled synthesis of InAs wires, dot and twin-dot array configurations by cleaved edge overgrowth. AB - We present experimental results on the controlled synthesis of InAs ordered nanostructures with three different grades of complexity: nanowires, quantum dot arrays, and double quantum dot arrays. A model for the diffusion of In adatoms on (110) surfaces explains the observed ordering and establishes general criteria for the optimized fabrication of the three different InAs nanostructure configurations, as a function of the growth conditions. These results are important for the use of ordered InAs nanostructures in future optoelectronic applications. PMID- 21817501 TI - Controlled positive and negative surface charge injection and erasure in a GaAs/AlGaAs based microdevice by scanning probe microscopy. AB - In this paper, we show that positive and negative charges can be injected into the surface of SiO(2)/Si(3)N(4)/SiO(2)/GaAs/AlGaAs heterostructure material by using a biased tip of a scanning probe microscope. Furthermore, the injected charges can be erased with the same tip once grounded, working in slow scan and contact mode. Surface potential measurements by quantitative analysis of Kelvin probe force microscopy after drawing and erasing charges at room temperature are presented and discussed. PMID- 21817502 TI - Multiwalled carbon nanotube film for strain sensing. AB - We have studied the possibility of using multiwalled carbon nanotube (MWCNT) films as strain sensors. The MWCNT films were prepared by a solution/filtration method and were bonded directly onto specimens by a nonconductive adhesive. For comparison, conventional foil strain gages were also bonded to the structure on the opposite side. The specimens then underwent a uniaxial tensile load-unload cycle to evaluate them as strain sensors. To ensure good electrical contact between carbon nanotube film and the wires, a thin layer of copper was thermally deposited on both ends of the film as electrodes, and the wires were connected to the electrodes by silver ink. Wheatstone bridges were used to convert the resistance changes of the MWCNTs to voltage output. Results indicated that the output voltages were proportional to the strain readings from the stain indicator. The effect of temperature on the resistance was measured and the MWCNT film resistance was found to be independent of temperature over the range 273-363 K. The optimal film dimension for strain sensing was evaluated as well. Dynamic tests suggest that the MWCNTs were able to extract the structural signature. Our results indicate that MWCNT film is potentially useful for structural health monitoring and vibration control applications. PMID- 21817503 TI - Gas phase sorting of fullerenes, polypeptides and carbon nanotubes. AB - We discuss the Stark deflectometry of micro-modulated molecular beams for the enrichment of biomolecular isomers as well as single-wall carbon nanotubes, and we demonstrate the working principle of this idea with fullerenes. The sorting is based on the species-dependent susceptibility-to-mass ratio chi/m. The device is compatible with a high molecular throughput, and the spatial micro-modulation of the beam permits one to obtain a fine spatial resolution and a high sorting sensitivity. PMID- 21817504 TI - Step-induced tip polarity reversal investigated by dynamic force microscopy on KBr(001). AB - We present atomic resolution images of monatomic step edges on the KBr(001) surface imaged by dynamic force microscopy operated in the non-contact mode. Under certain experimental conditions, we observe a systematic and reversible change of the atomic contrast when the tip crosses the step. This change is attributed to the reversal of the polarity of the ionic tip under the influence of the tip-substrate interaction in the immediate vicinity of the step edge. This polarity reversal is attributed to a change in the atomic structure of the tip and is described by a transition between the two potential wells of a two-level system localized near the tip apex. The case of two monatomic steps imaged in succession is also investigated in detail. The results indicate that the two level system associated with the reversal of the tip polarity involves the movement of a very limited number of ions on the tip. PMID- 21817505 TI - Ethylene glycol oxidation on Pt and Pt-Ru nanoparticle decorated polythiophene/multiwalled carbon nanotube composites for fuel cell applications. AB - A novel supporting material containing polythiophene (PTh) and multiwalled carbon nanotubes (MWCNTs) (PTh-CNTs) is prepared by in situ polymerization of thiophene on carbon nanotubes using FeCl(3) as oxidizing agent under sonication. The prepared polythiophene/CNT composites are further decorated with Pt and Pt-Ru nanoparticles by chemical reduction of the corresponding metal salts using HCHO as reducing agent at pH = 11 (Pt/PTh-CNT and Pt-Ru/PTh-CNT). The fabricated composite films decorated with nanoparticles were investigated towards the electrochemical oxidation of ethylene glycol (EG). The presence of carbon nanotubes in conjugation with a conducting polymer produces a good catalytic effect, which might be due to the higher electrochemically accessible surface areas, electronic conductivity and easier charge-transfer at polymer/electrolyte interfaces, which allows higher dispersion of Pt and Pt-Ru nanoparticles. Such nanoparticle modified PTh-CNT electrodes exhibit better catalytic behavior towards ethylene glycol oxidation. Results show that Pt/PTh-CNT and Pt-Ru/PTh-CNT modified electrodes show enhanced electrocatalytic activity and stability towards the electro-oxidation of ethylene glycol than the Pt/PTh electrodes, which shows that the composite film is more promising for applications in fuel cells. PMID- 21817506 TI - Calibration method for a carbon nanotube field-effect transistor biosensor. AB - An easy calibration method based on the Langmuir adsorption theory is proposed for a carbon nanotube field-effect transistor (NTFET) biosensor. This method was applied to three NTFET biosensors that had approximately the same structure but exhibited different characteristics. After calibration, their experimentally determined characteristics exhibited a good agreement with the calibration curve. The reason why the observed characteristics of these NTFET biosensors differed among the devices was that the carbon nanotube (CNT) that formed the channel was not uniform. Although the controlled growth of a CNT is difficult, it is shown that an NTFET biosensor can be easy calibrated using the proposed calibration method, regardless of the CNT channel structures. PMID- 21817507 TI - Tailoring of morphology and emission wavelength of AlGaInAs quantum dots. AB - We present a study of the growth, morphology and optical properties of Al(x)Ga(1 x-y)In(y)As quantum dots (QDs) for a wide range of Al and In concentrations (0<=x<=0.34 and 0.43<=y<=0.60). Short emission wavelengths between 660 and 940 nm and QD surface densities up to 1.1 * 10(11) cm(-2) have been achieved. Our results show that by varying both the Al concentration and the In concentration an independent adjustment of strain and QD band gap is possible. This additional degree of freedom can be employed for tailoring AlGaInAs QDs with the desired emission wavelength, surface density and average size. AlGaInAs QDs thus offer new possibilities for future QD device design. PMID- 21817508 TI - Assembly of CdS quantum dots onto mesoscopic TiO(2) films for quantum dot sensitized solar cell applications. AB - Colloidal cadmium sulfide (CdS) quantum dots (QDs) were prepared and surface modified by mercaptosuccinic acid (MSA) to render a surface with carboxylic acid groups (MSA-CdS). The MSA-CdS QDs were then assembled onto bare TiO(2) mesoporous films using the carboxylic groups/TiO(2) interaction. The TiO(2) film was also surface modified by 3-mercaptopropyl trimethoxysilane (MPTMS) or 3-aminopropyl methyl diethoxysilane (APMDS) to prepare, respectively, a thiol (-SH) or amino ( NH(2)) terminated surface for binding with the CdS QDs. The experimental results showed that the MPTMS-modified film has the highest adsorption rate and adsorption amount to the CdS QDs, attributable to the strong thiol/CdS interaction. In contrast, the adsorption rate and incorporated amount of the QDs on the bare TiO(2) film are much lower than for the silane-modified films. The incident photon-to-current conversion efficiency (IPCE) obtained for the CdS sensitized TiO(2) electrode was about 20% (at 400 nm) for the bare TiO(2), 13% for the MPTMS-TiO(2), and 6% for APMDS-TiO(2). The current-voltage measurement under dark conditions reveals a higher dark current on the MPTMS- and APMDS modified electrodes, indicating a lower coverage ratio of CdS on these TiO(2) films. This result is attributed to the fast adsorption rate of CdS QDs on the bottleneck of a mesopore which inhibits the transport of the QDs deep into the inner region of a pore. For the bare TiO(2) film, the lower incorporated amount of CdS but higher energy conversion efficiency indicates the formation of a better-covered CdS QDs monolayer. The moderate adsorption rate of MSA-CdS QDs using the carboxylic acid/TiO(2) interaction is responsible for the efficient assembly of QDs onto the mesoporous TiO(2) films. PMID- 21817509 TI - Microwave-assisted rapid synthesis of anisotropic Ag nanoparticles by solid state transformation. AB - Anisotropic silver nanoparticles (NPs) have been synthesized rapidly using microwave irradiation by the decomposition of silver oxalate in a glycol medium using polyvinyl pyrolidone (PVP) as the capping agent. The obtained Ag nanoparticles have been characterized by UV-visible spectroscopy, powder x-ray diffraction (XRD), transmission electron microscopy (TEM) and high-resolution TEM (HRTEM) studies. Anisotropic Ag nanoparticles of average size around 30 nm have been observed in the case of microwave irradiation for 75 s whereas spherical particles of a size around 5-6 nm are formed for 60 s of irradiation. The texture coefficient and particle size calculated from XRD patterns of anisotropic nanoparticles reveal the preferential orientation of (111) facets in the Ag sample. Ethylene glycol is found to be a more suitable medium than diethylene glycol. A plausible mechanism has been proposed for the formation of anisotropic Ag nanoparticles from silver oxalate. PMID- 21817510 TI - The effects of synthesis procedures on the morphology and photocatalytic activity of multi-walled carbon nanotubes/TiO(2) nanocomposites. AB - This study investigates the microstructures of multi-walled carbon nanotubes (MWNTs)/TiO(2) nanocomposites, obtained by sol-gel and hydrothermal processes. The synthesized nanocomposite materials were characterized by x-ray diffractometry (XRD), Brunauer-Emmett-Teller (BET) adsorption analysis, transmittance electron microscopy (TEM), scanning electron microscopy (SEM), photoluminescence (PL) spectroscopy, and x-ray photoelectron spectroscopy (XPS). The effects of the synthetic procedures and MWNTs on the morphology and photocatalytic activity of the nanocomposites were studied. The photocatalytic activity of the MWNTs/TiO(2) nanocomposite was elucidated based on the photooxidation of NO(x) under UV light illumination. A fleck-like and well dispersed TiO(2) microstructure on the surface of the MWNTs was observed in the sol-gel system, while compact and large aggregated particles were found in the hydrothermal procedure. The nanocomposite prepared by the sol-gel system exhibits better photocatalytic activity for NO oxidation (from 20.52 to 32.14%) than that prepared by the hydrothermal method (from 22.58 to 26.51%) with the same MWNT loading (from 0 to 8 wt%), respectively. The optimal MWNT content in the nanocomposite was considered at 8 wt%. Additionally, results confirm that the introduction of MWNTs will cause the NO(2) to be more consumed than NO in the photocatalytic experiments, leading to more complete NO(x) photooxidation. These observations indicate that the different TiO(2) distributions on the MWNT surfaces and MWNT contents in the materials would determine the morphology, the physicochemical and photocatalytic characteristics for the nanocomposite materials. PMID- 21817511 TI - Low-temperature synthesis and photocatalytic properties of ZnO nanotubes by thermal oxidation of Zn nanowires. AB - A low-cost and catalyst-free two-step approach has been developed to produce ZnO nanotubes (ZNTs) by simple thermal oxidation of Zn nanowires under 20 Pa at a low temperature of 400 degrees C. The growth mechanism of ZNTs is discussed in detail. The formation of these tubular structures is closely linked to the oxidation pressure and temperature, which involves a process consisting of the deposition of Zn nanowires, cracking of the Zn nanowires and sublimation of the Zn cores, and subsequent oxidation to ZNTs. The optical properties were studied by using Raman and photoluminescence spectra, where a strong green emission related to the single ionized oxygen vacancy appears. The photocatalytic activity measurement indicates an enhanced photocatalytic activity of the prepared ZNTs due to their high surface-to-volume ratios and abundant oxygen vacancies near the surfaces of the ZNTs. This type of high surface area structural ZNTs could find promising potential for optoelectronic and environmental applications. PMID- 21817512 TI - Effects of calcination temperature on microstructures and photocatalytic activity of titanate nanotube films prepared by an EPD method. AB - Titanate nanotube films are fabricated on F-doped SnO(2)-coated glass substrates via an electrophoretic deposition method using hydrothermally prepared titanate nanotubes as precursors. The effects of calcination temperature on the microstructures and photoactivity of as-prepared titanate nanotube films are investigated and discussed. The results indicate that the intercalated sodium ions (Na(+)) in the as-prepared titanate nanotubes are easily removed during the electrophoretic deposition. The phase transformation of titanate to anatase and diffusion of Na(+) ions from glass substrates into films occur at 400 degrees C. With increasing calcination temperature, the crystallization of anatase enhances and sodium content in the films increases. At 500 degrees C, the tubular structure still holds and the films show the highest photocatalytic activity probably due to their good crystallization, large specific surface areas and tubular structures. PMID- 21817513 TI - Synthesis of hollow silver nanostructures by a simple strategy. AB - Various silver nanostructures with hollow interiors, including nanoscaled cubic or quasi-cubic boxes, tubes, triangular rings, trapeziform rings and hybrid structures composed of tubes and cubic boxes, were synthesized via an extremely simple route. The method involved the modification of the solid silver nanocrystals by dithiol, and subsequent dissolving of the interior metal and assembly of the outer surface. In the whole process, only one simple step of pretreatment was needed before the transformation from Ag solid nanostructures to their corresponding hollow nanostructures. According to the morphological, spectral and structural changes in the evolution from silver solid nanostructures to their corresponding hollow nanostructures, a layer-by-layer assembly mechanism was proposed. The method is believed to open up a simple and versatile route to the fabrication of metallic hollow nanostructures with various morphologies according to the starting templates. PMID- 21817514 TI - The effect of nitrogen pressure during molecular beam epitaxy growth of InAsN quantum dots. AB - The influence of N flux during molecular beam epitaxy growth of InAsN quantum dots was studied. Growth of InAsN dots under high N flux was shown to give rise to an abnormal growth behaviour compared to InAs dots and InAsN dots with lower nitrogen content. Cubic In(x)Ga(1-x)N (x = 0.21 +/- 0.01) crystallites were found in samples grown with an excessive N flux. The crystallites are likely to form ~0.6 monolayers (MLs) after the quantum dots have nucleated, when the quantum dot changes growth mode. In addition, it is shown that a bimodal size distribution of InAsN quantum dots was generated in the wetting layer during the dot growth, as opposed to nucleation at N-induced dislocations at the substrate surface. The bimodal distribution may be explained by an increased energy barrier, in the presence of nitrogen, for atomic incorporation into the dots. PMID- 21817515 TI - Synthesis and alignment of Zn and ZnO nanoparticles by laser-assisted chemical vapor deposition. AB - A simple, versatile, and fast laser-assisted chemical vapor deposition (LCVD) technique that produces linear arrays of Zn and ZnO nanoparticles on a silicon substrate, covering an extended region, is described. A series of consecutive steps is involved in the synthesis and alignment of Zn/ZnO nanoparticles. First, a Lloyd's mirror arrangement is employed to produce two types of periodic nanostructure, i.e., nanoripples and nanoprotrusions. Next, the nanostructured substrate is laser irradiated at a fluence of 60 mJ cm(-2) in the presence of the metall-organic (MO) precursor gas diethylzinc (DEZn). The evolution of the Zn nanocrystals by LCVD processing was studied as a function of precursor gas pressure and laser fluence by ex situ high-resolution scanning electron microscopy (SEM). Laser irradiation fulfills a double role: it decomposes the adsorbed precursor and causes the evolution of resulting Zn into aligned aggregates of zinc nanoparticles. The Zn nanoparticles react with oxygen upon high-temperature thermal annealing to yield aligned assemblies of ZnO nanoparticles. The production of ZnO was confirmed by x-ray diffraction (XRD) and photoluminescence spectra. This technique is general and could be used in a large number of substrate/precursor combinations. PMID- 21817516 TI - Time and temperature dependence of multi-walled carbon nanotube growth on Inconel 600. AB - The growth kinetics of vertically aligned multi-walled carbon nanotubes (MWNTs) on conductive substrates is investigated by synthesizing MWNTs at different growth temperatures and measuring ex situ the length of the nanotubes as a function of growth duration. A typical 'root growth' mechanism (saturation of MWNT lengths with increasing growth duration) was observed. The value of the activation energy (E(a)~136 +/- 5 kJ mol(-1)) of the MWNT growth reaction is suggestive of carbon diffusion through the bulk of the iron catalyst particle versus diffusion on its surface. These findings will help in optimizing MWNT growth on conductive substrates for various applications. PMID- 21817517 TI - Control of ruthenium oxide nanorod length in reactive sputtering. AB - Ruthenium oxide nanorods have been grown on Si wafer substrates under a variety of pre-existing surface conditions by reactive radio frequency sputtering in an electron cyclotron resonant plasma process. Nanorod formation by this method is fast relative to that observed in other processes reported in the literature, with nucleation being the rate determining step. Growth in the axial direction is limited by the availability of ruthenium precursors which competes with their consumption in the lateral growth of the nanorods. The availability of Ru precursors at the top of the nanorods can be controlled by surface diffusion and therefore substrate temperature. The ultimate length of the nanorods is determined by the mole fraction of oxygen used in the reactor ambient through the production of mobile Ru hyperoxide precursors. The results of this investigation show the way to develop a process for producing a high density field of nanorods with a specified length. PMID- 21817518 TI - Coaxial stability of nano-bearings constructed by double-walled carbon nanotubes. AB - How to effectively control the coaxial stability of nano-bearings has an important influence on improving the quality of nano-bearings. Some relevant problems are studied in this paper. Firstly, we investigate basic non-coaxial modes in double-wall carbon nanotubes (DWCNTs). On the basis of analysis for these non-coaxial modes, a planar continuum model is established according to the principle of homogenization. By means of this model, a dynamic parameter lambda(*) characterizing the coaxial stability of nano-bearings is determined. lambda(*) is the explicit function of the angular velocity and interlayer spacing of DWCNTs. In terms of lambda(*), a criterion used to judge the coaxial stability of nano-bearings is given. Through discussing the influence of the angular velocity and interlayer spacing on the dynamic parameter lambda(*), some important conclusions are drawn. PMID- 21817519 TI - Ordered fullerene nanocylinders in large-diameter carbon nanotubes. AB - A new ordered fullerene phase encapsulated by large-diameter CNTs is systematically investigated by combining a growth technique by chemical vapour deposition, high-resolution transmission electron microscopy and molecular dynamics simulations. In contrast to fullerenes in smaller (1-2 nm) diameter CNTs, where fullerenes are packed in linear or helical chains, fullerenes form a nanoscale cylinder in double-walled CNTs with diameters of ~4 nm. The fullerenes were shown to form a nanocylinder with a side wall that resembled the (111) plane of solid C(60). This ordered phase is different from peapods or fullerene solids known so far, and a result of the interaction between the CNT wall and fullerenes. This finding will open up a new field of fullerene science. PMID- 21817520 TI - Temperature dependence of the energy dissipation in dynamic force microscopy. AB - The dissipation of energy in dynamic force microscopy is usually described in terms of an adhesion hysteresis mechanism. This mechanism should become less efficient with increasing temperature. To verify this prediction we have measured topography and dissipation data with dynamic force microscopy in the temperature range from 100 K up to 300 K. We used 3,4,9,10-perylenetetracarboxylic dianhydride (PTCDA) grown on KBr(001), both materials exhibiting a strong dissipation signal at large frequency shifts. At room temperature, the energy dissipated into the sample (or tip) is 1.9 eV/cycle for PTCDA and 2.7 eV/cycle for KBr, respectively, and is in good agreement with an adhesion hysteresis mechanism. The energy dissipation over the PTCDA surface decreases with increasing temperature, yielding a negative temperature coefficient. For the KBr substrate, we find the opposite behaviour: an increase of dissipated energy with increasing temperature. While the negative temperature coefficient in the case of PTCDA agrees rather well with the adhesion hysteresis model, the positive slope found for KBr points to a hitherto unknown dissipation mechanism. PMID- 21817521 TI - Stability analysis of optofluidic transport on solid-core waveguiding structures. AB - Optofluidic transport involves the use of electromagnetic energy to transport nanoparticles through the exploitation of scattering, adsorption and gradient (polarization) based forces. This paper presents a new approach to stability analysis for a system of broad applicability to such transport, namely the optical trapping of dielectric particles in the evanescent field of low index (polymer) and high index (silicon) solid-core waveguide structures integrated with microfluidics. Three-dimensional finite element based simulations are used to determine the electromagnetic and hydrodynamic field variables for the system of interest. The net force acting on particles is determined through evaluation of the full Maxwell and flow shear stress tensors, and a trapping stability number is obtained by comparing the work required to remove a particle from the waveguide with available random thermal energy. These forces are correlated to controllable experimental parameters such as particle size, fluid velocity, and channel height, and a series of trapping stability diagrams is produced which detail the conditions under which optofluidic transport is possible. PMID- 21817522 TI - Fluorescence properties of Dy(3+) doped La(3)Ga(5.5)Nb(0.5)O(14) nanocrystals. AB - The effects of Dy(3+) doping concentration and calcinations on the fluorescence properties of La(3)Ga(5.5)Nb(0.5)O(14) (Dy:LGN) nanocrystals were examined for the first time. High quality Dy:LGN nanocrystals were synthesized by the sol-gel method. The room temperature fluorescence spectra were measured; they showed a yellow emission, which can be attributed to the (4)F(9/2)-(6)H(13/2) transition. The relationship between the relative emission intensity and the doping concentration of the specimens, sintered at different temperatures, is consistent with a Gaussian distribution according a fitted and modified formula. The optimum value of the Dy(3+) doping concentration in LGN nanocrystals is in the range 2.0 2.5%. Moreover, in LGN bulk crystal for laser use, the optimum value, calculated through the obtained formula, is presumed in the range 1.5-2.0%. The fluorescent lifetime of a 2.0% Dy:LGN nanocrystal is quite short, only about 8.5 ns. PMID- 21817523 TI - Dominant dipolar interaction and glassy magnetic behaviour in polymer-coated magnetite nanoparticles. AB - The static and dynamic properties of magnetization have been investigated for polymer-coated magnetite nanoparticles with sizes from 5 to 15 nm. The analysis of the temperature dependence of zero-field-cooled magnetization indicates that the effective anisotropy constant is found to increase with the decrease of particle size, which is ascribed to the increase of surface anisotropy. The relaxation of the remanent magnetization clearly shows the signature of dominant dipolar interparticle interaction. The dynamics of magnetization also indicates the signature of glassy magnetic behaviour. The memory effect in the temperature dependence of field-cooled magnetization is noticed, which is inconsistent with the glassy magnetic behaviour. PMID- 21817524 TI - Spherical hexagonal tellurium nanocrystals: fabrication and size-dependent structural phase transition at high pressure. AB - Single-crystalline spherical nearly monodisperse tellurium (Te) nanocrystals (NCs) with average diameters of 20 and 90 nm, respectively, have been fabricated for the first time by a facile solution sonochemistry process. The structural characterizations show that the as-synthesized Te NCs have pure hexagonal structure, as revealed by x-ray diffraction (XRD), selected-area electron diffraction (SAED), energy-dispersive x-ray (EDX) spectroscopy, and high resolution transmission electron microscopy (HRTEM) methods. The size-dependent structural phase transition of Te NCs up to the high pressure of 20 GPa has been investigated in a diamond anvil cell using resistance measurement at room temperature, and compared with the behavior of bulk Te under identical conditions. The experimental results indicate that 20 nm Te NCs, 90 nm NCs, and bulk Te all undergo two phase transitions up to 20 GPa, their respective transition pressures being about 7.2 and 10.3 GPa, 5.9 and 8.8 GPa, and 4.0 and 6.8 GPa. This indicates that the phase transition pressures are higher for the smaller NCs. In this paper we discuss the size-dependent structural phase transitions, the sluggishness of the phase transition process, and the fluctuating properties of the phase transition products at high pressure. The present work might open an avenue to real-time detection of the dynamics of the phase transition in bulk and nanoscale materials at high pressure, and also could serve as a guide to tailoring the microscopic properties of materials. PMID- 21817525 TI - Reflectance spectra of individual single-walled carbon nanotubes. AB - We report backscattering spectroscopic measurements on individual single-walled carbon nanotubes (SWNTs). The reflectance spectra show geometry-dependent resonant peaks corresponding to optical transitions between Van Hove singularities in the SWNTs' joint density of states. All nanotubes display certain colours as their reflectance spectra demonstrate strong energy dependence. This approach was proved to be an effective tool for probing the geometric structures and optical properties of individual SWNTs. PMID- 21817526 TI - Surface energy of nanowires. AB - An analytical model is developed for calculation of the surface energy of a nanowire based on thermodynamics and continuum medium mechanics. The core-shell structure and the outer surface skin of the nanowire are considered for the one dimensional nanostructure and contributions from chemical and structural effects to the surface energy are discussed. It is found that the surface energy of nanowires decreases with the diameter reduction, which induces the melting temperature depression of nanowires. Theoretical results are in agreement with the results of experiments and simulations. PMID- 21817527 TI - Fabrication of ZnS nanoparticles and nanorods with cubic and hexagonal crystal structures: a simple solvothermal approach. AB - ZnS nanoparticles and nanorods with control over their crystal structure are fabricated through a solvothermal approach by changing the solvent used for the synthesis. The synthetic approach is suitable to fabricate ZnS nanoparticles with various sizes by varying the synthesis temperatures. Quantum confinement phenomena are studied by tailoring the particle sizes for both wurtzite and sphalerite polymorphs of ZnS. Photoluminescence studies reveal that the surface states greatly influence the emissions from the nanostructures. Wurtzite nanoparticles exhibit band-edge related UV emission owing to the effective surface passivation by the ethylene glycol molecules used as the solvent for the synthesis. On the other hand, the photoluminescence spectra of the cubic nanoparticles are mainly dominated by their surface states. Some of the nanorod samples exhibited Zn-vacancy related green emissions along with the surface defect related blue emission band. It is also demonstrated that ZnS nanostructures could be easily doped with useful impurities via this synthesis approach to tailor their luminescent properties. PMID- 21817528 TI - Electrical transport studies of individual IrO(2) nanorods and their nanorod contacts. AB - We have studied the electrical transport properties of individual single crystalline IrO(2) nanorods prepared by the metal-organic chemical vapour deposition method. With the help of the standard electron-beam lithographic technique, individual nanorods are contacted by Cr/Au submicron electrodes from above. Utilizing two-probe, three-probe and four-probe measurement configurations, not only the intrinsic electrical transport properties of the individual nanorods but also the electronic contact resistances, R(c)(T), have been determined from 300 K down to liquid-helium temperatures. Our measured resistivity behaviour of the nanorods is in close agreement with the current theoretical understanding of this rutile material. On the other hand, we found that the temperature behaviour of the electronic contact resistance obeys the law [Formula: see text] over an extremely wide temperature range, from approximately 100 K down to liquid-helium temperatures. This latter conduction process is ascribed to the hopping of electrons through nanoscale Cr granules and/or an amorphous coating incidentally formed at the interface between the submicron Cr/Au electrode and the nanorod. PMID- 21817529 TI - Characteristics of spray flames and the effect of group combustion on the morphology of flame-made nanoparticles. AB - Characteristics of burning and non-burning sprays generated by a coaxial air assist nozzle, previously used for the synthesis of ceramic nanoparticles by flame spray pyrolysis (FSP), are studied using phase Doppler anemometry. Also, the effect of droplet interaction on the overall combustion behavior of the spray (group combustion) and, consequently, on the characteristics of flame-made ceramic particles is investigated. A physical model is proposed which correlates the formation of inhomogeneous mixtures of micron-sized hollow particles and solid nanoparticles to the combustion mode: the precursor droplets which entirely evaporate in the hot flame are responsible for the formation of nanoparticles. The vapor species react, forming intermediate and product molecules and clusters that quickly grow to nanosized ceramic particles. On the other hand, under certain conditions, a small number of the droplets, particularly with large initial sizes, escape from the spray boundaries and become extinguished, producing large hollow ceramic particles. It is also possible that some of the large droplets, which lie within the spray core, do not entirely evaporate. These surviving droplets then form large particles which are usually hollow but can collapse to solid particles at sufficiently high temperatures. Also, a criterion for the formation of homogeneous ceramic nanoparticles is presented. PMID- 21817530 TI - The effect of the shape of nanorod arrays on the nanocarpet effect. AB - The bundling of densely packed free-standing nanorods/nanotubes in a liquid environment, or the 'nanocarpet effect', has a direct impact on the stability of nanostructures used for chemical and biological sensors. Using glancing angle deposition, we prepared four different structures: vertically aligned, tilted, zigzag, and square spring Si nanorod arrays, and compared their stabilities after water treatment. We found that although the tilted nanorods were bent in the nanorod tilting direction, they did not form nanorod bundles, and this structure was the most stable one. The larger the tilting angle, i.e., the more inclined the nanorod was to the surface, the more stable the structure. We also found that the quasi-vertical nanorod structures, the zigzag and square spring structures, showed improved stabilities compared to vertically aligned nanorods. Furthermore, by properly depositing a capping layer on top of the vertically aligned nanorods, the structure became mechanically very stable while the high porosity nature of the nanorod array was maintained. This work is helpful for designing stable nanostructures used in a liquid environment. PMID- 21817531 TI - High extractive single-photon emissions from InGaAs quantum dots on a GaAs pyramid-like multifaceted structure. AB - This work investigates the single-photon emissions from self-assembled InGaAs quantum dots that are grown on an apex plane of a GaAs pyramid-like multifaceted structure. The number of QDs on a multifaceted structure is estimated by scanning electron microscopy. Single-exciton emissions from individual quantum dots are examined by micro-photoluminescence and by making photon correlation measurements. This experiment demonstrates the improvement of the single-photon extraction efficiency as quantum dots are grown on a reduced apex plane of a multifaceted structure. PMID- 21817532 TI - Directed assembly of functional light harvesting antenna complexes onto chemically patterned surfaces. AB - We report the directed assembly of the photosynthetic membrane proteins LH1 and LH2 isolated from the purple bacterium Rhodobacter sphaeroides onto chemically patterned substrates. Nanoimprint lithography was used to pattern discrete regions of amino- and fluoro-terminated or poly(ethylene glycol) self-assembled monolayers onto a glass substrate. Densely packed layers of assembled protein complexes were observed with atomic force microscopy. The protein complexes attached selectively to the amino-terminated regions by electrostatic interactions. Spectral images generated with a hybrid scanning probe and fluorescence microscope confirmed that the patterned proteins retained their native optical signatures. PMID- 21817533 TI - Diffusion of nanoparticles into the capsule and cortex of a crystalline lens. AB - The purpose of this study is to determine the ability of fluorescent nanoparticles to diffuse into a crystalline lens. Intact porcine lenses from five month-old pigs, intact human lenses obtained from three donors aged 41, 42 and 45 years, and sections of human lens cortex obtained from four donors aged 11, 19, 32, and 34 years were incubated for 72 h at 7 degrees C in aqueous solutions of green (566 nm) and red (652 nm) fluorescent water soluble cadmium tellurium (CdTe) nanoparticles. As demonstrated by fluorescent and confocal microscopy, the CdTe nanoparticles diffused into the porcine and human lens capsule and into human cortical lens fibres; however, the nanoparticles did not pass through the intact lens capsule. Nanoparticles can be used as a method for studying intracellular structure and biochemical pathways within the lens capsule and cortical lens fibres to further understand cataractogenesis and may serve as a carrier for chemotherapeutic agents for the potential treatment of primary and secondary cataracts. PMID- 21817535 TI - Large complete bandgaps in a two-dimensional square photonic crystal with isolated single-atom dielectric rods in air. AB - It is well known that the square lattice of isolated single-atom dielectric rods in air does not give rise to complete bandgaps even when asymmetry is introduced to lift some degeneracy. However, in this paper, a new kind of two-dimensional square photonic crystal with isolated single-atom dielectric rods in air formed by holographic lithography is proposed, and the relation between their photonic bandgap properties and their specific holographic design are systematically analyzed. In addition to the large complete relative bandgap, namely 9.68% gap/midgap ratio for the dielectric constant contrast of 13.6:1, this structure has very large tolerance on the system parameters and fabrication conditions. This fact can greatly relax the experimental requirements. This work may demonstrate the unique feature and advantages of photonic crystals made by the holographic method and provide a guideline for their design and fabrication. PMID- 21817534 TI - Surface modified gold nanowires for mammalian cell transfection. AB - Aminothiol modified gold nanowires have been used as vectors for the delivery of plasmid DNA into two different types of mammalian cells: 3T3 and HeLa. It was measured that positively charged gold nanowires with a diameter of 200 nm and a length around 5 um were capable of carrying 1 pg of plasmid DNA per nanowire into cells. Compared with other transfection reagents, the gold nanowires exhibited the highest transfection efficiency while almost no cytotoxicity was observed. In addition, it has been shown that individual nanowires can be visualized with sub micrometer resolution, which may allow the use of functionalized multi-segment nanowires as local probes for the investigation of the microenvironment inside cells. PMID- 21817536 TI - Conductance oscillations in molecularly linked Au nanoparticle film superconductor systems. AB - Charge transport across a disordered normal-superconductor (DN-S) interface was studied using a macroscopic, molecularly linked Au nanoparticle film as the DN component. Low-temperature conductance versus voltage and magnetic field exhibit zero-bias and zero-field peaks, respectively. Importantly, the latter typically exhibit superimposed oscillations. Such oscillations are rarely seen in other DN S systems and are remarkable given their robustness in these macroscopic films and interfaces. A number of observations indicate that conductance peaks and oscillations arise due to a 'reflectionless tunnelling' process. Scattering length scales extracted from the data using a reflectionless tunnelling picture are consistent with literature values. Factors resulting in the observation of oscillations in this system are discussed. PMID- 21817537 TI - An electrostatic interaction model for frequency-dependent polarizability: methodology and applications to hydrocarbons and fullerenes. AB - We present an electrostatic interaction model for the calculation of frequency dependent electronic polarizability. The model is based on the representation of atoms by an induced electric charge and a dipole moment. The extension of the charge-dipole model to the interaction with oscillating electric fields requires us to account for the kinetics of the free moving charges and of the atomic dipoles. This step is achieved by first relating the oscillations of the atomic charges to the currents that flow through the atomic bonds. Adopting a classical description of this system of charges and dipoles, the time evolution of these quantities is determined from the principle that the action be minimized. As an application of this model, we compute the frequency-dependent molecular polarizability of hydrocarbons with different hybridization. We propose parameters for each chemical group, which provide an excellent agreement with reference data provided by current-density-functional theory. We finally study the frequency-dependent molecular polarizability of fullerenes ranging from C(60) to C(1500). PMID- 21817538 TI - Formation of dot arrays with a pitch of 20 nm * 20 nm for patterned media using 30 keV EB drawing on thin calixarene resist. AB - We studied the possibility of achieving very fine-pitch dot arrays with a pitch of 20 nm * 20 nm using 30 keV electron beam (EB) drawing on negative calixarene resist. In order to form such patterns, we studied the dependence on resist thickness of the dot size and the packing. We propose EB drawing on an extremely thin film for very highly packed dot-array formation. Our experimental results demonstrate the possibility of forming highly packed dot-array patterns with a pitch of 20 nm * 20 nm and a resist thickness of about 13 nm, which corresponds to about 1.6 Tbits in(-2). PMID- 21817539 TI - Covalent deposition of ferritin nanoparticles onto gold surfaces. AB - Ferritin nanoparticles have been deposited immobilized onto a properly modified gold surface by specific covalent bonding through lysine rests at the ferritin external surface. Atomic force microscopy (AFM) images confirmed the existence of a single ferritin monolayer. This is an easy and flexible route to form stable ferritin networks, which are covalently fixed to a gold substrate. PMID- 21817540 TI - High resolution radially symmetric nanostructures from simultaneous electron beam induced etching and deposition. AB - Electron beam induced etching (EBIE) and deposition (EBID) are promising fabrication techniques in which an electron beam is used to dissociate surface adsorbed precursor molecules to achieve etching or deposition. Spatial resolution is normally limited by the electron flux distribution at the substrate surface. Here we present simultaneous EBIE and EBID (EBIED) as a method for surpassing this resolution limit by using adsorbate depletion to induce etching and deposition in adjacent regions within the electron flux profile. Our simulation results indicate the possibility of growth control of radially symmetric nanostructures at the sub-1 nm length scale on bulk substrates. The technique is well suited to the fabrication of ring-shaped nanostructures such as those employed in plasmonics, sensing devices, magneto-optics and magnetoelectronics. PMID- 21817541 TI - Aligned nanowire growth using lithography-assisted bonding of a polycarbonate template for neural probe electrodes. AB - This research presents a fabrication method of vertically aligned nanowires on substrates using lithography-assisted template bonding (LATB) towards developing highly efficient electrodes for biomedical applications at low cost. A polycarbonate template containing cylindrical nanopores is attached to a substrate and the nanopores are selectively opened with a modified lithography process. Vertically aligned nanowires are grown by electrochemical deposition through these open pores on polyimide film and silicon substrates. The process of opening the nanopores is optimized to yield uniform growth of nanowires. The morphological, crystalline, and electrochemical properties of the resulting vertically aligned nanowires are discussed using scanning electron microscopy (SEM), x-ray diffraction (XRD), and electrochemical analysis tools. The potential application of this simple and inexpensive fabrication technology is discussed in the development of neural probe electrodes. PMID- 21817542 TI - Surface plasmon-based nanopatterning assisted by gold nanospheres. AB - A pulsed laser is used to produce surface plasmon excitation in a monolayer of gold (Au) spheres to nanopattern a silicon substrate. An electrodynamic model accompanies the experimental data, based on the numerical solution to the complete Maxwell's equations including near- and far-field effects and reflection from the substrate. The Drude-employing finite-difference time-domain method describes the deformation and enhancement of the laser pulse around the boundary of a Au sphere and the resulting distribution of intensity incident upon the substrate. The effect of the incident laser angle on the plasmon generation and lithographic potential is studied. PMID- 21817543 TI - In situ synthesis and photoluminescence of QD-CdS on silk fibroin fibers at room temperature. AB - A convenient room-temperature bioinspired technique has been developed to synthesize hybrid nanocomposites consisting of well-dispersed CdS quantum dots (QD) and the substrate silk fibroin fibers (SFF). The biomaterial SFF provides both a supporting substrate and functional sites for the in situ generation of QD CdS, which is supported by FTIR and PL measurements. The solid QD-CdS/SFF nanocomposites could be useful in photocatalyst, novel luminescence and photoelectron transfer devices. The QD-CdS/silk fibroin (SF) colloid, in which SF acts as both an inherent biocompatibilizer and an efficient passivator of trap sites on the QD-CdS surface, is also available for some potential applications in the biological fields. The bioinspired method and relevant ideas could extend to fabricating other functional hybrid materials. PMID- 21817544 TI - Bio-inspired fabrication of antireflection nanostructures by replicating fly eyes. AB - In this study, we examined the fine structure of the compound eyes of a household fly and precisely replicated its entire structure using a low-temperature atomic layer deposition technique. The surface of the fly eye is found to be covered by highly packed protuberances, which potentially increases visual efficiency through increased photon capture for a given stimulus. The alumina replica was achieved by removing the fly compound eye template at high temperature, and the alumina coating was crystallized simultaneously. Besides the morphology, the unique antireflection property was also inherited by the alumina replica. By measuring the reflective spectra of the replica, we demonstrated that the alumina replica of a fly eye was an efficient antireflection structure of visible light at an incident angle up to 80 degrees . Such a grating would be particularly useful on a cured corneal surface since it could increase the transmission of incident light through the cornea compared with a smooth surface. PMID- 21817545 TI - A preliminary investigation into the new class of lithium intercalating LiNiSiO(4) cathode material. AB - A unique attempt to exploit silicate chemistry for a possible enhancement of the electrochemical properties of a lithium ion system via exploration of the novel category lithium intercalating LiNiSiO(4) cathode has been made through the present study. A novel citric acid assisted modified sol-gel method (CAM sol-gel) has been adopted to synthesize the title compound with a formation temperature positioned well below 500 degrees C, as derived from thermal studies. A powder x ray diffraction (PXRD) pattern evidenced the absence of undesirable peaks and confirmed the formation of a hexagonal lattice structure with enhanced crystallinity and phase purity, and the presence of uniformly distributed particles of ~200 nm size with well defined grain boundaries is obvious from the scanning electron microscopy (SEM) image of LiNiSiO(4) material. Further, magic angle spinning (MAS) (7)Li nuclear magnetic resonance (NMR) results from LiNiSiO(4) confirmed the presence of a layered type of crystal arrangement. A cyclic voltammetry (CV) study performed on a LiNiSiO(4) cathode revealed an excellent reversibility without any change in the peak position upon extended cycling, thus substantiating the structural stability upon progressive cycling. PMID- 21817546 TI - Synthesis of fluorescent and photovoltaic Cu(2)O nanocubes. AB - Hollow and filled Cu(2)O nanocubes of about 28 +/- 5 nm in edge length with a band gap ~2.42 eV have been prepared from cupric nitrate in alkaline aqueous solutions containing fructose and ascorbic acid at room temperature. To the best of our knowledge, this simple strategy demonstrates the first example of preparing high-quality Cu(2)O nanocubes (yield>95%) with sizes smaller than 30 nm. By controlling several important experimental parameters such as pH, concentrations of fructose, and molar ratios of fructose/copper (II), different Cu(2)O nanostructures were prepared. The cubic nanostructures were evidenced by the metal shadowing and transmission electron microscope (TEM) images. We confirmed that the Cu(2)O nanocubes were formed from hollow to filled structures by conducting time-evolution TEM measurements. The thus-prepared Cu(2)O nanocubes possess size-dependence absorption and luminescence characteristics; they absorb light at wavelengths 360 and 454 nm and fluoresce at 493 nm (quantum yield 6.6 * 10(-2)%) when excited at 360 nm. A film of Cu(2)O nanocubes provided a photocurrent density of ~80 mA m(-2) at a biased voltage 3 V under sunlight illumination (100 mW cm(-2)). PMID- 21817547 TI - In situ synthesis and characterization of GaN nanorods through thermal decomposition of pre-grown GaN films. AB - Herein we describe a thermal treatment route to synthesize gallium nitride (GaN) nanorods. In this method, GaN nanorods were synthesized by thermal treatment of GaN films at a temperature of 800 degrees C. The morphology and structure of GaN nanorods were characterized by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The results show that GaN nanorods have a hexagonal wurtzite structure with diameters ranging from 30 to 50 nm. Additionally, GaN nanoplates are also founded in the products. The growth process of GaN nanostructures was investigated and a thermal decomposition mechanism was proposed. Our method provides a cost-effective route to fabricate GaN nanorods, which will benefit the fabrication of one-dimensional nanomaterials and device applications. PMID- 21817548 TI - Electron field emission of a nitrogen-doped TiO(2) nanotube array. AB - A nitrogen-doped titania nanotube array vertically aligned on a titanium substrate exhibits efficient electron field emission. Such a titania nanotube array shows very good stability at high field emission current (fluctuation <3% at field emission current of 160 uA within 4 h) and low turn-on and threshold fields (11.2 and 24.4 V um(-1), respectively) because of the coexistence of doped nitrogen and concomitant oxygen vacancies in titania nanotubes. This work demonstrates the possibility of converting pure titania nanotubes without field emission into a favorable and efficient one through the introduction of acceptor states and donor states both above the valence band maximum and below the conduction band minimum in the band gap of titania by the doped nitrogen and concomitant oxygen vacancies, respectively. Application of this doping concept to other transition metal oxides can be expected to broaden the scope of field emission materials. PMID- 21817549 TI - On-chip deposition of carbon nanotubes using CMOS microhotplates. AB - The direct deposition of carbon nanotubes on CMOS microhotplates is demonstrated in this paper. Tungsten microhotplates, fabricated on thin SOI membranes aside CMOS control circuitry, are used to locally grow carbon nanotubes by chemical vapour deposition. Unlike bulk heating of the entire chip, which could cause degradation to CMOS devices and interconnects due to high growth temperatures in excess of 500 degrees C, this novel technique allows carbon nanotubes to be grown on-chip in localized regions. The microfabricated heaters are thermally isolated from the rest of the CMOS chip as they are on the membranes. This allows carbon nanotubes to be grown alongside CMOS circuitry on the same wafer without any external heating, thus enabling new applications (e.g. smart gas sensing) where the integration of CMOS and carbon nanotubes is required. PMID- 21817550 TI - Electromechanical interactions in a carbon nanotube based thin film field emitting diode. AB - Carbon nanotubes (CNTs) have emerged as promising candidates for biomedical x-ray devices and other applications of field emission. CNTs grown/deposited in a thin film are used as cathodes for field emission. In spite of the good performance of such cathodes, the procedure to estimate the device current is not straightforward and the required insight towards design optimization is not well developed. In this paper, we report an analysis aided by a computational model and experiments by which the process of evolution and self-assembly (reorientation) of CNTs is characterized and the device current is estimated. The modeling approach involves two steps: (i) a phenomenological description of the degradation and fragmentation of CNTs and (ii) a mechanics based modeling of electromechanical interaction among CNTs during field emission. A computational scheme is developed by which the states of CNTs are updated in a time incremental manner. Finally, the device current is obtained by using the Fowler-Nordheim equation for field emission and by integrating the current density over computational cells. A detailed analysis of the results reveals the deflected shapes of the CNTs in an ensemble and the extent to which the initial state of geometry and orientation angles affect the device current. Experimental results confirm these effects. PMID- 21817551 TI - Synthesis of WO(3) nanoparticles using a biopolymer as a template for electrocatalytic hydrogen evolution. AB - Tungsten trioxide nanoparticles were prepared by a simple approach using chitosan biopolymer as a template. These nanoparticles were characterized using x-ray diffraction, Raman spectroscopy, transmission electron microscopy and high resolution transmission electron microscopy. The average size of the WO(3) nanoparticles is 42 nm, and they intercalate a larger amount of hydrogen than tungsten trioxide, which is prepared without chitosan. The materials are tested for their electrocatalytic hydrogen evolution in a sulfuric acid medium, where WO(3) nanoparticles show a fourfold higher activity than bulk tungsten trioxide. PMID- 21817552 TI - Understanding nanoparticle formation by a wire explosion process through experimental and modelling studies. AB - A wire explosion process (WEP) has been used to produce nano aluminium powder in nitrogen, argon and helium atmospheres. The impact of energy deposited into the exploding conductor on the size and shape of the particles was analysed using TEM analysis, which forms the first part of the study. It is observed that the higher the energy deposited, the smaller the particles formed. In the second part, modelling studies were carried out by solving the general dynamic equation through the nodal approach, and the particle size distributions were predicted. It is realized that, at the point of high saturation ratio and nucleation rate, the size of the critical nucleus formed is low. The particle size distribution predicted by the model correlates well with the experimental results. Time-series analysis of particle formation indicates that particles of lower dimensions form and, in the process of coagulation, larger particles are formed. It is realized that the plasma formed during the explosion plays a major role in the particle formation, and the modelling studies confirm that particle formation is not an instantaneous process but requires a certain time period to form stable sizes and shapes. PMID- 21817553 TI - Surface coating of carbon nanofibers/nanotubes by electrodeposition for multifunctionalization. AB - Carbon nanomaterials in the form of paper sheets have been used as platforms to achieve multifunctionality. Combined with electrochemical deposition, room temperature synthesis of magnetic Ni coatings on individual carbon nanofibers (CNF) and/or carbon nanotubes (CNT) has been realized through solution penetration and ion diffusion. In addition to significant electrical conductivity improvement, the magnetic responses of the Ni coated carbon nanopaper sheets can be tuned within large ranges in terms of saturation magnetic field, remnant magnetization and coercivity. After being re-suspended in liquids, the magnetized CNFs/CNTs can be aligned with small external magnetic fields. PMID- 21817554 TI - An atomic resolution scanning tunneling microscope that applies external tensile stress and strain in an ultrahigh vacuum. AB - We have developed an ultrahigh vacuum scanning tunneling microscope with an in situ external stress application capability in order to determine the effects of stress and strain on surface atomistic structures. It is necessary to understand these effects because controlling them will be a key technology that will very likely be used in future nanometer-scale fabrication processes. We used our microscope to demonstrate atomic resolution imaging under external tensile stress and strain on the surfaces of wafers of Si(111) and Si(001). We also successfully observed domain redistribution induced by applying uniaxial stress at an elevated temperature on the surface of a wafer of vicinal Si(100). We confirmed that domains for which an applied tensile stress is directed along the dimer bond become less stable and shrink. This suggests that it may be feasible to fabricate single domain surfaces in a process that controls surface stress and strain. PMID- 21817555 TI - A general aqueous sol-gel route to Ln(2)Sn(2)O(7) nanocrystals. AB - This paper describes a general aqueous sol-gel route for the synthesis of a series of rare earth stannates, Ln(2)Sn(2)O(7) (Ln = Y, La, Pr, Nd, Sm, Eu, Tb, Dy, Ho, Er, Tm, Yb and Lu), with pure pyrochlore phase via the assistance of a cetyltrimethyl ammonium bromide (CTAB) surfactant. The route involves first the formation of CTAB-inorganic lamellar structures and then their thermal decomposition at 800 degrees C to yield the pyrochlore Ln(2)Sn(2)O(7) nanocrystals. Techniques using a thermo-gravimetric/differential thermal analyzer (TG-DTA), x-ray diffraction (XRD) and transmission electron microscopy (TEM) as well as selected-area electron diffraction (SAED) have been employed to characterize the as-synthesized Ln(2)Sn(2)O(7) nanocrystals. Furthermore, photoluminescence (PL) of the 5% Eu(3+) activated Ln(2)Sn(2)O(7) nanocrystals and carbon monoxide catalytic oxidation over the as-obtained Ln(2)Sn(2)O(7) nanocrystals were investigated. The results indicate that the PL properties as well as the catalytic activity changes significantly with the ionic radii of the rare earth elements. PMID- 21817556 TI - Epitaxial Mn(5)Ge(3) nano-islands on a Ge(001) surface. AB - The growth behavior and atomic structure of Mn germanide, grown on Ge(001), is studied with x-ray diffraction and scanning probe microscopy. The amorphous clusters of as-deposited Mn are crystallized into Mn(5)Ge(3) nano-islands with a size of ~100 nm by solid phase epitaxy. At low coverage, the shape of the nano islands is plateau-like, while at increased coverage it becomes mound-like. At the flat top of the plateau-like nano-islands, the hexagonal atomic structure is resolved. It is interpreted, with the help of first-principles study, as a Mn terminated Mn(5)Ge(3)(0001) structure. PMID- 21817557 TI - Optical encoding of microbeads based on silica particle encapsulated quantum dots and its applications. AB - A novel method concerning the coding technology of polystyrene beads with Si encapsulated quantum dot (QD) particles (Si@QDs particles) is studied in this paper. In the reverse microemulsion system containing tetraethoxysilane (TEOS), water-soluble QDs (emission peak at 600 nm) were enveloped within the silica shell, forming Si@QDs particles. The Si@QDs particles were characterized by TEM, showing good uniform size, with an average diameter of about 167.0 nm. In comparison with the pure water-soluble QDs, the encapsulation of water-soluble QDs in the silica shell led to an enhancement in anti-photobleaching by providing inert barriers for the QDs. Images presented by SEM and confocal laser scanning microscopy demonstrated that the Si@QDs particles were equably coated on the surface of carboxyl functionalized polystyrene (PS) beads. Then, with the assistance of ethyl-3-(dimethyl aminopropyl) carbodiimide/N-hydroxysuccinimide (EDC/NHS), human IgG could be successfully crosslinked to Si@QDs particle coated PS-COOH beads. Furthermore, the Si@QDs coated PS-COOH beads with human IgG were examined in immunoassay experiments, and the results indicated that these beads could be applied in the specific recognition of goat-anti-human IgG in solution. This investigation is expected to provide a new route to bead coding in the field of suspension microarrays, based on the use of QDs. PMID- 21817558 TI - Behavior of a single nitrogen molecule on the pentagon at a carbon nanotube tip: a first-principles study. AB - Density functional theory (DFT) is used to investigate the adsorption properties of nitrogen on the pentagon at the tip of a capped (5, 5) single-walled carbon nanotube. The adsorption of N(2) outside the carbon nanotube with a parallel orientation with respect to the plane of the pentagon is found to be the most stable state of adsorption. Its binding energy of -0.318 eV is very small, with a large C-N equilibrium distance of 2.94 A. We have also investigated the number and the position of adsorption sites in the pentagon for the parallel configuration. This knowledge can lead to the precise control of adsorption states, and consequently may bring about a novel multistate monomolecular device. We find two stable configurations of the molecule that have only a small difference in energy, while the other configurations are energetically unfavorable. Our results support previous experimental predictions that the nitrogen molecule transits between two states with a small current pulse. The predicted position sites for the transient states are in reasonable agreement with experimental observations. PMID- 21817559 TI - Mechanical properties of microwave hydrothermally synthesized titanate nanowires. AB - In this investigation titanate nanowires were synthesized by a microwave hydrothermal process and their nanomechanical characterization was carried out by a compression experiment via buckling instability using a nanomanipulator inside a scanning electron microscope. Nanowires of diameters 120-150 nm and length tens of microns can be synthesized by keeping a commercial nanoparticle inside a microwave oven at 350 W and 210 degrees C for 5 h. The nanowire was clamped between two cantilevered AFM tips attached to two opposing stages of the manipulator for nanomechanical characterization. The elasticity coefficients of the titanate nanowires were measured by applying a continuously increasing load and observing the buckling instability of the nanowires. The buckling behavior of a nanowire was analyzed from the series of SEM images of displacement of the cantilever attached to the nanowire due to application of load. The critical loads for different sized titanate nanowires were determined and their corresponding Young's modulus was computed with the Euler pinned-fixed end model. The Young's modulus of these microwave hydrothermal process synthesized titanate nanowires were determined to be approximately in the range 14-17 GPa. This investigation confirms the capability of the nanomanipulator via the buckling technique as a constructive device for measuring the mechanical properties of nanoscale materials. PMID- 21817560 TI - Ab initio calculations of electron affinity and ionization potential of carbon nanotubes. AB - By combining ab initio all-electron localized orbital and pseudopotential plane wave approaches we report on calculations of the electron affinity (EA) and the ionization potential (IP) of (5, 5) and (7, 0) single-wall carbon nanotubes. The role played by finite-size effects and nanotube termination has been analysed by comparing several hydrogen-passivated and not passivated nanotube segments. The dependence of the EA and IP on both the quantum confinement effect, due to the nanotube finite length, and the charge accumulation on the edges, is studied in detail. Also, the EA and IP are compared to the energies of the lowest unoccupied and highest occupied states, respectively, upon increasing the nanotube length. We report a slow convergence with respect to the number of atoms. The effect of nanotube packing in arrays on the electronic properties is eventually elucidated as a function of the intertube distance. PMID- 21817561 TI - Characterization of nickel nanocones routed by electrodeposition without any template. AB - This work reports the synthesis of Ni nanocones by a one-step electrodeposition method without any template. With the addition of ethylenediamine dihydrochloride (EDA.2HCl) in the nickel plating solution, the novel Ni conical structure can be easily deposited onto different metal surfaces. The as-prepared nickel nanocones grow preferentially along [Formula: see text] directions with very sharp tips. The conical structures are single crystalline without any disruption of the lattice planes. In addition, the Ni nanocone structure is demonstrated to show magnetocrystalline anisotropy and enhance the magnetic properties when compared with other Ni nanostructures. PMID- 21817562 TI - The effect of local polarized domains of ferroelectric P(VDF/TrFE) copolymer thin film on a carbon nanotube field-effect transistor. AB - We produced local polarized domains of ferroelectric P(VDF/TrFE) copolymer thin films on a carbon nanotube field-effect transistor (CN-FET) channel by atomic force microscopy (AFM). The drain current versus gate voltage (I(d)-V(g)) curves measured after forming the local polarized domains showed a shift in the threshold voltages. We also found that the amount of the shifts in the threshold voltages gradually decreased during the measurement of this characteristic over 100 h after forming the polarized domains. The mechanisms of the shifts in the threshold voltages and their decreasing behaviour were explained in terms of the excessive charges that were induced upon the formation of the polarized domains. PMID- 21817563 TI - Organic memory using [6,6]-phenyl-C(61) butyric acid methyl ester: morphology, thickness and concentration dependence studies. AB - We report a simple memory device in which the fullerene-derivative [6,6]-phenyl C(61) butyric acid methyl ester (PCBM) mixed with inert polystyrene (PS) matrix is sandwiched between two aluminum (Al) electrodes. Transmission electron microscopy (TEM) images of PCBM:PS films showed well controlled morphology without forming any aggregates at low weight percentages (<10 wt%) of PCBM in PS. Energy dispersive x-ray spectroscopy (EDX) analysis of the device cross-sections indicated that the thermal evaporation of the Al electrodes did not lead to the inclusion of Al metal nanoparticles into the active PCBM:PS film. Above a threshold voltage of <3 V, independent of thickness, a consistent negative differential resistance (NDR) is observed in devices in the thickness range from 200 to 350 nm made from solutions with 4-10 wt% of PCBM in PS. We found that the threshold voltage (V(th)) for switching from the high-impedance state to the low impedance state, the voltage at maximum current density (V(max)) and the voltage at minimum current density (V(min)) in the NDR regime are constant within this thickness range. The current density ratio at V(max) and V(min) is more than or equal to 10, increasing with thickness. Furthermore, the current density is exponentially dependent on the longest tunneling jump between two PCBM molecules, suggesting a tunneling mechanism between individual PCBM molecules. This is further supported with temperature independent NDR down to 240 K. PMID- 21817564 TI - Real-time observation of FIB-created dots and ripples on GaAs. AB - We report a phenomenological study of Ga dots and ripples created by a focused ion beam (FIB) on the GaAs(001) surface. Real-time observation of dot diffusion and ripple formation was made possible by recording FIB movies. In the case of FIB irradiation with a 40 nA current of Ga(+) ions accelerated under 40 kV with an incidence angle of theta = 30 degrees , increasing ion dose gives rise to three different regimes. In Regime 1, dots with lateral sizes in the range 50-460 nm are formed. Dots diffuse under continuous sputtering. In Regime 2, dots self assemble into Bradley and Harper (BH) type ripples with a pseudo-period of lambda = 1150 +/- 25 nm. In Regime 3, ripples are eroded and the surface topology evolves into microplanes. In the case of normal incidence, FIB sputtering leads only to the formation of dots, without surface rippling. PMID- 21817565 TI - Controlled partial embedding of carbon nanotubes within flexible transparent layers. AB - Applications of carbon nanotubes (CNTs) like field emission displays, super capacitors, and cell growth scaffolds can benefit from controllable embedding of the CNTs in a material such that the CNTs are anchored and protrude a desired length. We demonstrate a simple method for anchoring densely packed, vertically aligned arrays of CNTs into silicone layers using spin-coating, CNT insertion, curing, and growth substrate removal. CNT arrays of 51 and 120 um in height are anchored into silicone layers of thickness 26 and 36 um, respectively. Scanning electron microscopy (SEM) and optical microscopy are used to characterize the sample morphology, a 5.5 m s(-1) impinging water jet is used to apply shear stress, and a tensile test shows that the silicone layer detaches from the substrate before the CNTs are ripped from the layer. The CNTs are thus well anchored in the silicone layers. The spin-coating process gives control over layer thickness, and the method should have general applicability to various nanostructures and anchoring materials. PMID- 21817566 TI - Controlled fabrication of patterned lateral porous alumina membranes. AB - Confined lateral alumina templates are fabricated with different pore sizes by changing the acid electrolyte and the anodization voltage. The control of the number of pore rows down to one dimension is also achieved, by controlling the thickness of the starting aluminum film as well as the anodization voltage. We observe that the mechanism of pore formation in the lateral regime is very similar to that in the classical vertical situation. PMID- 21817567 TI - Early stage of ripple formation on Ge(001) surfaces under near-normal ion beam sputtering. AB - We present a study of the early stage of ripple formation on Ge(001) surfaces irradiated by a 1 keV Xe(+) ion beam at room temperature and near-normal incidence. A combination of a grazing incidence x-ray scattering technique and atomic force microscopy allowed us to observe a variation of the symmetry of the surface nanopattern upon increase of the ion fluence. The isotropic dot pattern formed during the first minutes of sputtering evolves into an anisotropic ripple pattern for longer sputtering time. These results provide a new basis for further steps in the theoretical description of the morphology evolution during ion beam sputtering. PMID- 21817568 TI - A 100 nm thick InGaN/GaN multiple quantum-well column-crystallized thin film deposited on Si(111) substrate and its micromachining. AB - A 100 nm thick InGaN/GaN multiple quantum-well column-crystallized thin film was deposited on Si(111) substrate, with InN as the interlayer, by molecular beam epitaxy. The diameter of the column crystal is about 40 nm. Transmission electron microscopy images showed clear five-period well layers. Photoluminescence measurements demonstrated a wide emission wavelength from about 500 to 800 nm with the full width at half maximum of 107 nm at room temperature. An unusual photoluminescence peak position shift was observed from the optical measurement. The selected area electron diffraction image demonstrated the hexagonal wurtzite structure of the column crystal. A self-supported GaN-based active subwavelength grating was proposed, and the active subwavelength grating structure was fabricated from the InGaN/GaN quantum-well thin film by a Si micromachining process. PMID- 21817569 TI - Rapid and ultrahigh ethanol sensing based on Au-coated ZnO nanorods. AB - Rapid and ultrahigh sensing is realized from Au-coated ZnO rods with diameters down to 15 nm. Both the small diameters and the Au coating make the surface depletion effect more pronounced for gas sensing. Such enhanced surface depletion increases the sensitivity, lowers the operation temperature and decreases the response time. A sensitivity of 89.5-100 ppm ethanol is obtained with response time shorter than 2 s at 300 degrees C, and the operation temperature can be as low as 150 degrees C. It is found that the Au coating improves the sensitivity by three times; this is much higher than that of noble metal-doped metal oxide sensors controlled by a grain-boundary barrier. Our results imply that the surface-depletion model is very helpful in fabricating high performance gas sensors. PMID- 21817570 TI - Visual force sensing with flexible nanowire buckling springs. AB - A calibrated method of force sensing is demonstrated in which the buckled shape of a long flexible metallic nanowire, referred to as a 'nanoneedle', is interpreted to determine the applied force. An individual needle of 157 nm diameter by 15.6 um length is grown on an atomic force microscope (AFM) cantilever with a desired orientation (by the method of Yazdanpanah et al 2005 J. Appl. Phys. 98 073510). Using a nanomanipulator the needle is buckled in the chamber of a scanning electron microscope (SEM) and the buckled shapes are recorded in SEM images. Force is determined as a function of deflection for an assumed elastic modulus by fitting the shapes using the generalized elastica model (De Bona and Zelenika 1997 Proc. Inst. Mech. Eng. C 211 509-17). In this calibration the elastic modulus (68.3 GPa) was determined using an auxiliary AFM measurement, with the needle in the same orientation as in the SEM. Following this calibration the needle was used as a sensor in a different orientation than the AFM coordinates to deflect a suspended PLLA polymer fiber from which the elastic modulus (2.96 GPa) was determined. The practical value of the sensing method does depend on the reliability and ruggedness of the needle. In this study the same needle remained rigidly secured to the AFM cantilever throughout the entire SEM/AFM calibration procedure and the characterization of the nanofiber. PMID- 21817571 TI - Detection of bacteria based on the thermomechanical noise of a nanomechanical resonator: origin of the response and detection limits. AB - We have measured the effect of bacteria adsorption on the resonant frequency of microcantilevers as a function of the adsorption position and vibration mode. The resonant frequencies were measured from the Brownian fluctuations of the cantilever tip. We found that the sign and amount of the resonant frequency change is determined by the position and extent of the adsorption on the cantilever with regard to the shape of the vibration mode. To explain these results, a theoretical one-dimensional model is proposed. We obtain analytical expressions for the resonant frequency that accurately fit the data obtained by the finite element method. More importantly, the theory data shows a good agreement with the experiments. Our results indicate that there exist two opposite mechanisms that can produce a significant resonant frequency shift: the stiffness and the mass of the bacterial cells. Based on the thermomechanical noise, we analyse the regions of the cantilever of lowest and highest sensitivity to the attachment of bacteria. The combination of high vibration modes and the confinement of the adsorption to defined regions of the cantilever allows the detection of single bacterial cells by only measuring the Brownian fluctuations. This study can be extended to smaller cantilevers and other biological systems such as proteins and nucleic acids. PMID- 21817572 TI - Preparation of porous chromium oxide nanotubes using carbon nanotubes as templates and their application as an ethanol sensor. AB - Chromium oxide nanotubes were successfully prepared using multi-walled carbon nanotubes (MWCNTs) as a template via a supercritical fluid-mediated route. In this method, with chromium (III) nitrate nonahydrate as precursor, chromium oxide was first deposited on MWCNTs in supercritical ethanol in the presence of NH(4)HCO(3). The as-prepared chromium oxide/MWCNT nanocomposites were characterized by transmission electron microscopy, x-ray diffraction, infrared spectroscopy and thermogravimetric analysis. It was demonstrated that the MWCNTs were coated with a layer of amorphous Cr(2)O(3).xH(2)O. The thickness of the Cr(2)O(3).xH(2)O sheath on MWCNTs could be tuned by manipulating the ratio of precursor to MWCNTs. Calcining the composites at 550 degrees C, the MWCNTs were removed, producing polycrystalline alpha-Cr(2)O(3) nanotubes. The as-prepared alpha-Cr(2)O(3) sample was used as a sensor material to detect ethanol vapor, and it was demonstrated that the alpha-Cr(2)O(3) nanotubes exhibited good performance even at 400 degrees C. PMID- 21817573 TI - The interfacial behaviour of single poly(N,N-dimethylacrylamide) chains as a function of pH. AB - We have studied the pH-dependent conformational behaviour of poly(N,N dimethylacrylamide) (PDMAc) at silicon and gold surfaces using single-molecule force spectroscopy and a quartz crystal microbalance (QCM). Despite the pH dependence, nuclear magnetic resonance and titration experiments demonstrate that PDMAc is not a weak polybase. The interaction between single chains and a silicon surface (with native oxide layer intact) in aqueous solution was investigated using force spectroscopy. Single-molecule force measurements were performed using thiol-functionalized PDMAc and gold-coated AFM cantilevers. The forces of interaction between PDMAc and the native oxide-coated silicon surface vary with the pH. The shape of the retraction curve for low pH solution includes a greater number of 'train' conformations, which suggests a stronger interaction with the surface relative to the surrounding media at low pH. The adsorption behaviour of PDMAc, from liquid onto silicon surfaces, was monitored using a QCM, which shows greater PDMAc adsorption onto silicon at low pH. The force spectroscopy and QCM investigations confirm that the PDMAc chain is more extended and stiffer in low pH solution. We attribute the pH-dependent behaviour to an increased number of hydrogen bonding sites on the silicon surface at low pH. PMID- 21817574 TI - Nanomechanical and electrical characterization of a new cellular electret sensor actuator. AB - Electrically charged cellular polymers are known to display pseudo-piezoelectric effects that endow them with interesting mechano-electrical characteristics. When a film of such a polymer is compressed, charge is generated across its thickness, and conversely, applying an oscillatory or static potential elicits mechanical motions. This dual sensor-actuator behaviour can be embedded in one material and presents distinct advantages of functional integration. A novel electroactive foam is presented here that embeds such a sensor-actuator function. The foam has a sensitivity constant (d(33)) of 330 pC N(-1). Interestingly, the resonant behaviour of the cellular film can be altered by variation in the DC offset across the material. Such adaptive capacity could be of great advantage for tuning polymer-based mechanical devices to be either efficient sound radiators and mechanical actuators, or sensitive and coherent sensors. Possible applications in microfluidics are also discussed. PMID- 21817575 TI - A step towards length control of titanate nanotubes using hydrothermal reaction with sonication pretreatment. AB - It was experimentally confirmed that the average length of titanate nanotubes (TNTs) can be increased and controlled to a certain degree by applying sonication pretreatment to their titania precursors prior to hydrothermal synthesis. Without sonication, the average length of the TNTs synthesized by the hydrothermal process was much shorter due to constricted diffusion of the hydroxyl ion (OH(-)) and the sodium ion (Na(+)) through the narrow interparticle space of agglomerated titania precursors, thereby retarding the TNT formation mechanism. On the other hand, much longer TNTs with an average hydrodynamic size of 490-1760 nm were produced when the sonication pretreatment was applied. Based on microscopic observations on the transformation of the present precursors and the reported nanotube formation phenomena during the hydrothermal process, a mechanism contributing to length control is proposed. PMID- 21817576 TI - Large-scale preparation of CdS quantum dots by direct thermolysis of a single source precursor. AB - CdS quantum dots (QDs) have been synthesized on a large scale, based on the direct thermolysis of one single-source precursor, (Me(4)N)(4)[S(4)Cd(10)(SPh)(16)], in hexadecylamine (HDA). Transmission electron microscopy (TEM) observations show that the CdS QDs are well-defined, nearly spherical particles. The clear lattice fringes in high-resolution TEM (HRTEM) images confirm the crystalline nature of the QDs. The broad diffraction in the x ray diffraction (XRD) pattern and diffuse diffraction rings of the selected-area electron diffraction (SAED) pattern are typical of nanomeric-size particles and indicative of the hexagonal phase of CdS QDs. The absorption spectra confirm quantum confinement of CdS QDs. The synthesis process for CdS QDs was investigated by ultraviolet-visible (UV-vis) absorption spectroscopy. The results demonstrate that the nucleation and growth stages were separated automatically in a homogeneous system. PMID- 21817577 TI - Efficient field emission from vertically grown planar ZnO nanowalls on an ITO glass substrate. AB - Vertically grown planar ZnO nanowalls, with typical dimensions of 40-80 nm thickness and several micrometers wide, were electrodeposited on an indium-tin oxide (ITO)-glass substrate at 70 degrees C. X-ray photoelectron spectroscopy (XPS) studies reveal that the nanowalls consist of ZnO covered with a Zn(OH)(2) overlayer. An x-ray diffraction (XRD) study shows that these nanowalls have the wurtzite structure and are highly crystalline. The corresponding Raman and photoluminescence spectra further indicate the presence of oxygen deficiency. These ZnO nanowalls exhibit excellent field emission performance, with not only a considerably lower turn-on field of 3.6 V um(-1) (at 0.1 uA cm(-2)) but also a higher current density of 0.34 mA cm(-2) at 6.6 V um(-1) than most ZnO nanowires and other one-dimensional nanostructures reported to date. PMID- 21817578 TI - Shrunk lattice structure and interdiffusion characteristics of 5 nm thick Al(2)O(3) ultrathin films sputtered on silicon. AB - We report that a 5 nm thick Al(2)O(3) film grown on Si(100) directly by sputtering exhibits strong (110) texture, accompanied by a shrunk lattice structure (Deltad/d~-2.36%). The disordered nature of the film was confirmed by cross-sectional high-resolution transmission electron microscopy, implying the loosened microstructure responsible for enhanced interdiffusion. The oxygen deficient Al(2+delta)O(3-delta)(delta>0) interdiffusion region with complex interfacial chemical valences was formed between the Al(2)O(3) film and Si substrate, reducing the insulator properties. Using depth profiling in situ x-ray photoemission spectroscopy, we quantitatively reveal the non-stoichiometry deviation of the Al/O ratio at the interdiffusion region. A nominal thickness of 5 nm is required to obtain an actual barrier thickness of approximately 1 nm. PMID- 21817579 TI - Composition fluctuation induced growth of Al:ZnO rectangular nanorod arrays. AB - Arrays of single-crystalline Al doped ZnO rectangular nanorods were synthesized and nucleated from single-crystalline ZnO nanosheets by thermal chemical vapor deposition. The rectangular nanorods were grown from the periodic thicker regions of the nanosheets, associated with Al concentration fluctuation and evidenced from electron energy loss spectroscopy. High-resolution transmission electron microscopy also shows variations in the lattice constant and dislocations at the interface due to lattice strain. The composition modulation induced by doping may serve as a driving force for creating interesting nanostructures with tunable properties. PMID- 21817580 TI - Growth of Ag nanoparticles using plasma-modified multi-walled carbon nanotubes. AB - This study presents a novel method for preparing multi-walled carbon nanotubes (MWNTs) grafted with a poly(2-hydroxyethyl methacrylate) (HEMA)-silver complex (CNTs-HEMA-Ag complex) through plasma-induced grafting polymerization. The characteristics of the MWNTs after being grafted with HEMA polymer are monitored by Fourier transform infrared (FT-IR) spectroscopy. The chelating groups in the HEMA polymer grafted on the surface of the CNTs-HEMA are the coordination sites for chelating silver ions, and are further used as nanotemplates for the growing of Ag nanoparticles (quantum dots). Transmission electron microscopy (TEM) reveals that the particle size of Ag nanoparticles on the CNT surfaces increases with the Ag(+) chelating concentration, reaction time, and reaction temperature. Moreover, the crystalline phase of Ag nanoparticles is identified by using x-ray diffraction (XRD). In addition, high-resolution x-ray photoelectron spectroscopy (XPS) is used to characterize the functional groups on the surface of the MWNTs after chemical modification through plasma treatment; it demonstrates that the growing amount of the Ag nanoparticles on the nanotubes increases with the Ag(+) chelating concentration due to the blocking effect of the Ag particles forming on the MWNTs. PMID- 21817581 TI - Synthesis and field emission of single-crystalline copper vanadate nanobelts. AB - Single-crystalline nanobelts of a nonstoichiometric compound Cu(1.55)V(2)O(6.55), with a thickness of 40-60 nm, width of 50-300 nm and length of several micrometers, have been synthesized on a large scale by a hydrothermal method. The structures and morphologies of the nanobelts were characterized by x-ray powder diffraction, x-ray photoelectron spectroscopy, scanning electron microscopy, transmission electron microscopy and high-resolution transmission electron microscopy. A probable growth mechanism has also been discussed. The nanobelts exhibit a turn-on field of 11.0 V um(-1), which is defined as the macroscopic field required to produce a current density of 10 uA cm(-2). It is anticipated that the nanobelts can serve as a candidate material for future field emitters. PMID- 21817582 TI - Morphological and structural modulation of PbWO(4) crystals directed by dextrans. AB - A facile, dextran-directed solution route for the morphology- and structure controlled synthesis of PbWO(4) crystals, such as monoclinic raspite PbWO(4) nanobelts and tetragonal stolzite PbWO(4) crystals with penniform and wheat-ear like morphologies, has been demonstrated. Three differently charged dextrans were employed for the PbWO(4) crystallization and they turned out to be very effective in the morphological and structural modulation of PbWO(4) crystals, as evidenced by the scanning electron microscopy (SEM), transmission electron microscopy (TEM), x-ray diffraction (XRD) and Raman spectroscopy characterizations. In particular, novel monoclinic raspite PbWO(4) nanobelts were produced under the direction of anionic dextran with a suitable concentration, probably due to the specific interactions between SO(4)(2-) groups from anionic dextran molecules and Pb(2+) ions from PbWO(4) crystals. To the best of our knowledge, this is the first synthesis of monoclinic raspite PbWO(4) in the laboratory, which usually exists as a natural crystal. In addition, the photoluminescence properties of the obtained PbWO(4) crystals with different morphologies and crystal structures have been characterized and discussed, which provides useful information for the fundamental investigation and potential application of PbWO(4) crystals. PMID- 21817583 TI - Facile preparation of monodisperse ZnO quantum dots with high quality photoluminescence characteristics. AB - We report a new method that enables the facile synthesis of monodisperse zinc oxide (ZnO) quantum dots (QDs) with high quality photoluminescence (PL) characteristics. In the proposed method, ZnO QDs are grown on acid-treated multiwalled carbon nanotubes (a-MWCNTs) under remarkably mild reaction conditions (low temperature, short time, atmospheric pressure, and no need for subsequent thermal annealing). The ZnO QDs grown on the a-MWCNTs were monodisperse and highly crystalline, and had diameters of about 7 nm. Moreover, the a-MWCNT-grown ZnO QDs exhibited a definitive blue emission without defect-related blue-green emission, features that are indicative of definite quantum confinement effects and high quality. PMID- 21817584 TI - Multi-modal mesoporous TiO(2)-ZrO(2) composites with high photocatalytic activity and hydrophilicity. AB - Utilizing the amphiphilic triblock copolymer Pluronic P123 as the surfactant, and Ti(O(n)Bu)(4) and ZrOCl(2).8H(2)O as the inorganic sources, a series of multi modal mesoporous TiO(2)-ZrO(2) composites have been successfully synthesized through a one-step method. The resultant materials were characterized in detail by x-ray diffraction, atomic force microscopy, high resolution scanning electron microscopy, transmission electron microscopy, N(2) adsorption and water contact angle measurements. The effect of calcination temperatures on the physical parameters, hydrophilicity and photocatalytic activity of the obtained mesoporous TiO(2)-ZrO(2) composites was also investigated in this paper. PMID- 21817585 TI - Two- and three-dimensional micro/nanostructure patterning of CdS-polymer nanocomposites with a laser interference technique and in situ synthesis. AB - Two- and three-dimensional (2D and 3D) micro/nanostructures of CdS-polymer nanocomposites have been successfully patterned, combining photopolymerization via a laser four-beam interference technique with in situ synthesis of CdS nanoparticles in the patterned polymer matrix. The morphology and optical properties of CdS nanoparticles in polymer matrices have been confirmed using TEM, XRD, FTIR, UV-vis absorption and fluorescence spectroscopy. Laser irradiation time and film thickness are certified to be the key factors for the control of the micro/nanostructures. With thickening film, the fabricated microstructures of CdS-polymer nanocomposites were dramatically changed from 2D rods to 3D networks which were composed of nanofibres, nanometre-scale walls and micrometre-scale rods. These kinds of 2D and 3D micro/nanostructures could be expected as potential applications in the development of nanotechnology, such as nanomedical systems, micro-fluidic chips, nanoreactors and micro/nanopurification or separation systems. PMID- 21817586 TI - Photostability of quantum dots with amphiphilic polymer-based passivation strategies. AB - Quantum dots (QDs) have many appealing properties for biological fluorescence imaging, but exhibit photostabilities that are dependent upon surface passivation to minimize susceptibility to oxygen and light. Here, through spectroscopy and imaging techniques, we compare the photostability of micelle-encapsulated QDs with QDs passivated with either crosslinked amphiphilic polymers or crosslink free amphiphilic polymers. Both crosslinked and crosslink-free amphiphilic polymer passivation strategies produced QDs with high photoluminescence stability for exposure to light under ambient conditions. In contrast, micelle encapsulation resulted in QDs with photoluminescence emission levels that were highly sensitive to both light exposure and oxygen, exhibiting a reduction of up to 70% in photoluminescence intensity within twenty minutes of exposure. With the addition of reducing agents, the photoluminescence level of the micelle encapsulated QDs was significantly stabilized. We conclude that amphiphilic polymers provide coatings with considerably higher integrity and stability than micelle encapsulation, reducing the QDs' sensitivities to oxygen and light, both of which are relevant factors in biological imaging applications. PMID- 21817587 TI - Blue-shift and intensity enhancement of photoluminescence in lead-zirconate titanate-doped silica nanocomposites. AB - Transparent PbZr(0.52)Ti(0.48)O(3) (PZT)-doped silica nanocomposites were fabricated via a modified sol-gel process. The nanocomposites were annealed at different temperatures between 740 and 800 degrees C in order to produce PZT crystallites with different particle sizes. X-ray diffraction analysis indicated that the embedded PZT nanoparticles were crystallized with a perovskite structure while the SiO(2) matrix was still in an amorphous state. Transmission electron microscopy confirmed that the PZT particles were of nanosize with perovskite structure and dispersed within the SiO(2) matrix. Photoluminescence spectra of the samples were measured between 10 and 290 K. The pure silica matrix showed an emission band at 3.20 eV and a weak emission band at 2.65 eV. They were noticeably suppressed in the PZT/SiO(2) nanocomposites. An additional emission band at ~2.30 eV, due to transition within the PZT crystallites, was identified. This emission band showed a large blue-shift with decreasing PZT crystallite size and a substantially enhanced intensity as compared with that of bulk PZT ceramics. Our studies demonstrate the typical quantum size effect of ferroelectric-doped nanocomposites and the large influence of the silica matrix on the PL intensity of the embedded PZT particles. PMID- 21817588 TI - Chemical surface reactions by click chemistry: coumarin dye modification of 11 bromoundecyltrichlorosilane monolayers. AB - The functionalization of surfaces and the ability to tailor their properties with desired physico-chemical functions is an important field of research with a broad spectrum of applications. These applications range from the modification of wetting properties, over the alteration of optical properties, to the fabrication of molecular electronic devices. In each of these fields, it is of specific importance to be able to control the quality of the layers with high precision. The present study demonstrates an approach that utilizes the 1,3-dipolar cycloaddition of terminal acetylenes to prepare triazole-terminated monolayers on different substrates. The characterization of the precursor monolayers, the optimization of the chemical surface reactions as well as the clicking of a fluorescent dye molecule on such azide-terminated monolayers was carried out. A coumarin 343 derivative was utilized to discuss the aspects of the functionalization approach. Based on this approach, a number of potential surface reactions, facilitated via the acetylene-substituted functional molecules, for a broad range of applications is at hand, thus leading to numerous possibilities where surface modifications are concerned. These modifications can be applied on non-structured surfaces of silicon or glass or can be used on structured surfaces. Various possibilities are discussed. PMID- 21817589 TI - Substrate-free growth, characterization and growth mechanism of ZnO nanorod close packed arrays. AB - ZnO nanorod close-packed arrays are successfully fabricated in a substrate-free manner by a citric acid assisted annealing process at a low growth temperature of 400 degrees C. Each nanorod of ZnO nanorod close-packed arrays grows along the [0001] direction and is single crystalline with an average diameter of 50 nm, and an average length of 0.5 um. The aspect ratio is 10. The ZnO nanorod close-packed arrays show a strong exciton absorption peak at 372 nm in UV-visible absorption spectra, exhibiting a blue-shift relative to the bulk exciton absorption (387 nm). Finally, a new growth mechanism is proposed for the substrate-free preparation of ZnO nanorod close-packed arrays by a citric acid assisted annealing process. PMID- 21817590 TI - How nanoparticles encapsulating fluorophores allow a double detection of biomolecules by localized surface plasmon resonance and luminescence. AB - The paper shows how polysiloxane particles encapsulating fluorophores can be successfully used to detect biotin-streptavidin binding by two types of technique. After functionalization of the particles by streptavidin, the fixation of the biomolecule can indeed be detected by a shift of the localized surface plasmon resonance of the biotinylated gold dots used as substrate and by the luminescence of the fluorophores evidenced by scanning near-field optical microscopy. The development of particles allowing such a double detection opens a route for increasing the reliability of biological detection and for multi labelling strategies crossing both detection principles. PMID- 21817591 TI - Fluorescence blinking dynamics of silver nanoparticle and silver nanorod films. AB - Fluorescence blinking of silver nanoparticle films is observed when illuminated with red light (635 nm). The observed power-law off-time distribution is attributed to random surface diffusion and subsequent agglomeration of atomic Ag leading to the formation of photo-active Ag nanoclusters. These nanoclusters can in turn diffuse randomly to form non-emitting Ag clusters after aggregation with another Ag species. This is revealed in the power-law on-time distribution. Silver oxides found on the surfaces of Ag nanostructures are important for photoblinking to take place since nanostructures with a protective layer of polymeric citrate or cetyltrimethylammonium bromide (CTAB) against atmospheric O(2) do not display obvious emission intermittency. PMID- 21817592 TI - A nonlinear system model for electrospinning sub-100 nm polyacrylonitrile fibres. AB - Solutions of polyacrylonitrile (PAN) were electrospun using a range of process parameters, resulting in fibre diameters from 10 to 320 nm. A nonlinear neural network system model was used to analyse the dependence of the fibre diameter on the process parameters, and used to simulate conditions for electrospinning 40-60 nm diameter fibres. These results indicated that flow rate is most important for determining fibre diameter. It was not possible to find the appropriate conditions for electrospinning sub-25 nm fibres. Precise control of the ambient temperature and relative humidity will be critical to producing electrospun fibres that are sub-25 nm. Further, it is unlikely that sub-25 nm fibres will be produced without significant changes in the electrospinning apparatus, for example, by use of focusing and jet-steering fields, alternate carrier gases to modify the discharge characteristics, or patterned electrospinning. PMID- 21817593 TI - Unique electronic band structures of hydrogen-terminated [Formula: see text] silicon nanowires. AB - Band structure mutation from an indirect to a direct gap is a well-known character of small hydrogen-terminated [Formula: see text] and [Formula: see text] silicon nanowires (SiNWs), and suggests the possible emission of silicon. In contrast, we show that hydrogen-terminated [Formula: see text] SiNWs consistently present indirect band gaps even at an extremely small size, according to our calculations using density functional theory. Interestingly, the band gap of [Formula: see text] SiNWs shows a quasi-direct feature as the wire size increases, suggesting the possibility of using medium SiNWs in optoelectronic devices. This result also indicates that the electronic structures of SiNWs are strongly orientation dependent. PMID- 21817594 TI - Competition of elastic and adhesive properties of carbon nanotubes anchored to atomic force microscopy tips. AB - In this paper we address the mechanical properties of carbon nanotubes anchored to atomic force microscopy (AFM) tips in a detailed analysis of experimental results and exhaustive description of a simple model. We show that volume elastic and surface adhesive forces both contribute to the dynamical AFM experimental signals. Their respective weights depend on the nanotube properties and on an experimental parameter: the oscillation amplitude. To quantify the elastic and adhesive contributions, a simple analytical model is used. It enables analytical expressions of the resonance frequency shift and dissipation that can be measured in the atomic force microscopy dynamical frequency modulation mode. It includes the nanotube adhesive contribution to the frequency shift. Experimental data for single-wall and multi-wall carbon nanotubes compare well to the model predictions for different oscillation amplitudes. Three parameters can be extracted: the distance necessary to unstick the nanotube from the surface and two spring constants corresponding to tube compression and to the elastic force required to overcome the adhesion force. PMID- 21817595 TI - A resolution study for electrostatic force microscopy on bimetallic samples using the boundary element method. AB - Electrostatic force microscopy (EFM) is a special design of non-contact atomic force microscopy used for detecting electrostatic interactions between the probe tip and the sample. Its resolution is limited by the finite probe size and the long-range characteristics of electrostatic forces. Therefore, quantitative analysis is crucial to understanding the relationship between the actual local surface potential distribution and the quantities obtained from EFM measurements. To study EFM measurements on bimetallic samples with surface potential inhomogeneities as a special case, we have simulated such measurements using the boundary element method and calculated the force component and force gradient component that would be measured by amplitude modulation (AM) EFM and frequency modulation (FM) EFM, respectively. Such analyses have been performed for inhomogeneities of various shapes and sizes, for different tip-sample separations and tip geometries, for different applied voltages, and for different media (e.g., vacuum or water) in which the experiment is performed. For a sample with a surface potential discontinuity, the FM-EFM resolution expression agrees with the literature; however, the simulation for AM-EFM suggests the existence of an optimal tip radius of curvature in terms of resolution. On the other hand, for samples with strip- and disk-shaped surface potential inhomogeneities, we have obtained quantitative expressions for the detectability size requirements as a function of experimental conditions for both AM- and FM-EFMs, which suggest that a larger tip radius of curvature is moderately favored for detecting the presence of such inhomogeneities. PMID- 21817596 TI - From cobalt nitrate carbonate hydroxide hydrate nanowires to porous Co(3)O(4) nanorods for high performance lithium-ion battery electrodes. AB - We have developed a simple approach for the large-scale synthesis of cobalt nitrate carbonate hydroxide hydrate (Co(CO(3))(0.35)(NO(3))(0.2)(OH)(1.1).1.74H(2)O) nanowires via the hydrothermal process using sodium hydroxide and formaldehyde as mineralizers at 120 degrees C. The porous Co(3)O(4) nanorods 10-30 nm in diameter and hundreds of nanometres in length have been fabricated from the above-mentioned multicomponent nanowires by calcination at 400 degrees C. The morphology and structure of cobalt nitrate carbonate hydroxide hydrate nanowires and Co(3)O(4) nanorods have been characterized by transmission electron microscopy (TEM), field emission scanning electron microscopy (FESEM), high resolution transmission electron microscopy (HRTEM) and x-ray powder diffraction (XRD). Moreover, the porous Co(3)O(4) nanorods have been applied in the negative electrode materials for lithium ion batteries, which exhibit high electrochemical performance. PMID- 21817597 TI - Modulation effects on Landau levels in a monolayer graphene. AB - Magnetoelectronic properties of a single-layer graphene are studied by the Peierls tight-binding model. A new numerical technique is developed to obtain a band-like Hamiltonian matrix. A spatially modulated magnetic field B' could drastically alter the Landau levels due to a uniform magnetic field B. The modulation effects include enhancement in dimensionality, change of energy dispersions, destruction of state degeneracy and creation of band-edge states. The dispersionless Landau levels, those at the Fermi levels excepted, become the 1D parabolic bands. The density of states thus exhibits many pairs of asymmetric prominent peaks. The height, frequency and number of pronounced peaks strongly depend on the modulation strength. These characteristics are hardly affected by the period and direction when B' is much weaker than B. The predicted results could be verified by experimental measurements on magneto-optical absorption spectra. PMID- 21817598 TI - Visible cathodoluminescence of Er ions in beta-Ga(2)O(3) nanowires and microwires. AB - Erbium doped beta-Ga(2)O(3) nanowires and microwires have been obtained by a vapour-solid process from an initial mixture of Ga(2)O(3) and Er(2)O(3) powders. X-ray diffraction (XRD) analysis reveals the presence of erbium gallium garnet as well as beta-Ga(2)O(3) phases in the microwires. Scanning electron microscopy (SEM) images show that the larger microwires have a nearly rectangular cross section. Transmission electron microscopy (TEM) and high-resolution TEM (HRTEM) analysis show good crystal quality of the beta-Ga(2)O(3) nanowires. The nanostructures have been studied by means of the cathodoluminescence technique in the scanning electron microscope. Er intraionic blue, green and red emission lines are observed in luminescence spectra even at room temperature, which confirms the optical activity of the rare earth ions in the grown structures. Mapping of the main 555 nm emission intensity shows a non-homogeneous distribution of Er ions in the microstructures. PMID- 21817599 TI - Luminescence study on Eu(3+) doped Y(2)O(3) nanoparticles: particle size, concentration and core-shell formation effects. AB - Nanoparticles of Eu(3+) doped Y(2)O(3) (core) and Eu(3+) doped Y(2)O(3) covered with Y(2)O(3) shell (core-shell) are prepared by urea hydrolysis for 3 h in ethylene glycol medium at a relatively low temperature of 140 degrees C, followed by heating at 500 and 900 degrees C. Particle sizes determined from x ray diffraction and transmission electron microscopic studies are 11 and 18 nm for 500 and 900 degrees C heated samples respectively. Based on the luminescence studies of 500 and 900 degrees C heated samples, it is confirmed that there is no particle size effect on the peak positions of Eu(3+) emission, and optimum luminescence intensity is observed from the nanoparticles with a Eu(3+) concentration of 4-5 at.%. A luminescence study establishes that the Eu(3+) environment in amorphous Y (OH)(3) is different from that in crystalline Y(2)O(3). For a fixed concentration of Eu(3+) doping, there is a reduction in Eu(3+) emission intensity for core-shell nanoparticles compared to that of core nanoparticles, and this has been attributed to the concentration dilution effect. Energy transfer from the host to Eu(3+) increases with increase of crystallinity. PMID- 21817600 TI - Molecular ground hole state of vertically coupled GeSi/Si self-assembled quantum dots. AB - We study the ground state of a hole confined in two vertically coupled GeSi/Si quantum dots as a function of the interdot distance and dot composition within the sp(3) tight-binding approach. Both quantum-mechanical tunneling and inhomogeneous strain distribution are included. For pure Ge dots, the strain is found to have two effects on the hole binding energy: (i) reduction of the binding energy below the value of the single dot with increasing dot separation and (ii) molecular bond breaking for intermediate interdot distances and posterior bond restoration at larger distance. Both effects are smeared upon Ge Si intermixing. PMID- 21817601 TI - Memory effect in an ionic liquid matrix containing single-walled carbon nanotubes and polystyrene. AB - We report the use of an ionic liquid (IL) gel matrix containing a blend of single walled carbon nanotubes (SWNTs) and polystyrene (PS) as a memory device. SWNTs and PS beads were mixed in a room-temperature IL, 1-butyl-3-methyl hexafluorophosphate ([BMIM][PF(6)]). The composite gel was sandwiched between a bottom ITO glass and a top aluminium electrode. By merely changing the concentrations of SWNTs in the inert insulating PS matrix, we observed several distinct electrical properties of the device, such as an insulator, a memory in terms of switching and negative differential resistance (NDR), and a conductor. The electric bistable switching hops between a higher impedance (OFF) state and a lower impedance (ON) state which is approximately equal to five orders of current decays. PMID- 21817602 TI - Nonvolatile flexible organic bistable devices fabricated utilizing CdSe/ZnS nanoparticles embedded in a conducting poly N-vinylcarbazole polymer layer. AB - The bistable effects of CdSe/ZnS nanoparticles embedded in a conducting poly N vinylcarbazole (PVK) polymer layer by using flexible poly-vinylidene difluoride (PVDF) and polyethylene terephthalate (PET) substrates were investigated. Transmission electron microscopy (TEM) images revealed that CdSe/ZnS nanoparticles were formed inside the PVK polymer layer. Current-voltage (I-V) measurement on the Al/[CdSe/ZnS nanoparticles+ PVK]/ITO/PVDF and Al/[CdSe/ZnS nanoparticles+ PVK ]/ITO/PET structures at 300 K showed a nonvolatile electrical bistability behavior with a flat-band voltage shift due to the existence of the CdSe/ZnS nanoparticles, indicative of trapping, storing and emission of charges in the electronic states of the CdSe nanoparticles. A bistable behavior for the fabricated organic bistable device (OBD) structures is described on the basis of the I-V results. These results indicate that OBDs fabricated by embedding inorganic CdSe/ZnS nanoparticles in a conducting polymer matrix on flexible substrates are prospects for potential applications in flexible nonvolatile flash memory devices. PMID- 21817603 TI - Suppression of the internal electric field effects in ZnO/Zn(0.7)Mg(0.3)O quantum wells by ion-implantation induced intermixing. AB - Strong suppression of the effects caused by the internal electric field in ZnO/ZnMgO quantum wells following ion-implantation and rapid thermal annealing, is revealed by photoluminescence, time-resolved photoluminescence, and band structure calculations. The implantation and annealing induces Zn/Mg intermixing, resulting in graded quantum well interfaces. This reduces the quantum-confined Stark shift and increases electron-hole wavefunction overlap, which significantly reduces the exciton lifetime and increases the oscillator strength. PMID- 21817604 TI - Temperature sensing using individual single-walled carbon nanotubes. AB - Molecular dynamics simulations and quantum transport theory are employed to study the temperature-dependent electrical properties of individual (12,0) zigzag and (5,5) armchair carbon nanotubes deposited on silicon substrates. The results demonstrate that the magnitude of the leakage current depends on the length of the nanotube. Furthermore, the leakage current is generated periodically along the length of the nanotube. Finally, the results indicate that given an appropriate value of the applied bias voltage, the induced current varies linearly with the temperature over specific temperature ranges. As a result, the temperature can be inversely derived from the measured current signal. Overall, the results show that the (12,0) zigzag and (5,5) armchair carbon nanotubes are suitable for temperature sensing applications over temperature ranges of 200-420 K and 300-440 K, respectively. PMID- 21817605 TI - Optically controlled thermal management on the nanometer length scale. AB - The manipulation of polymers and biological molecules or the control of chemical reactions on a nanometer scale by means of laser pulses shows great promise for applications in modern nanotechnology, biotechnology, molecular medicine or chemistry. A controllable, parallel, highly efficient and very local heat conversion of the incident laser light into metal nanoparticles without ablation or fragmentation provides the means for a tool like a 'nanoreactor', a 'nanowelder', a 'nanocrystallizer' or a 'nanodesorber'. In this paper we explain theoretically and show experimentally the interaction of laser radiation with gold nanoparticles on a polymethylmethacrylate (PMMA) layer (one-photon excitation) by means of different laser pulse lengths, wavelengths and pulse repetition rates. To the best of our knowledge this is the first report showing the possibility of highly local (in a 40 nm range) regulated heat insertion into the nanoparticle and its surroundings without ablation of the gold nanoparticles. In an earlier paper we showed that near-infrared femtosecond irradiation can cut labeled DNA sequences in metaphase chromosomes below the diffraction-limited spot size. Now, we use gold as well as silver-enhanced gold nanoparticles on DNA (also within chromosomes) as energy coupling objects for femtosecond laser irradiation with single-and two-photon excitation. We show the results of highly localized destruction effects on DNA that occur only nearby the nanoparticles. PMID- 21817606 TI - Ion beam shaping and downsizing of nanostructures. AB - We report a new approach for progressive and well-controlled downsizing of nanostructures below the 10 nm scale. A low energetic ion beam (Ar(+)) is used for gentle surface erosion, progressively shrinking the dimensions with ~1 nm accuracy. The method enables shaping of the nanostructure geometry and polishing of the surface. The process is clean room/high vacuum compatible being suitable for various applications. Apart from technological advantages, the method enables the study of various size phenomena on the same sample between sessions of ion beam treatment. PMID- 21817607 TI - A novel method to obtain chitosan/DNA nanospheres and a study of their release properties. AB - Polysaccharides and other cationic polymers have recently been used in pharmaceutical research and industry for their properties to control the release of antibiotics, DNA, proteins, peptide drugs or vaccines, and they have also been extensively studied as non-viral DNA carriers for gene delivery and therapy. Among them, chitosan is the most used since it can promote long-term release of incorporated drugs. This work is focused on the preparation of chitosan and chitosan/DNA nanospheres by using a novel and simple osmosis-based method, recently patented. The morphology of chitosan/DNA particles is spherical (as observed by scanning electron microscopy, SEM) and the nanospheres' average diameter is 38 +/- 4 nm (obtained by dynamic light scattering, DLS). With this method, DNA is incorporated with high yield (up to 30%) and the release process is gradual and prolonged in time. The novelty of the reported method resides in the general applicability to various synthetic or natural biopolymers. Solvent, temperature and membrane cut-off are the physicochemical parameters that one is able to use to control the overall osmotic process, leading to several nanostructured systems with different size and shape that may be used in several biotechnological applications. PMID- 21817608 TI - Nonuniform shrinkage and stretching of polymerized nanostructures fabricated by two-photon photopolymerization. AB - We propose a method to measure the nonuniform shrinkage and stretching of polymerized nanostructures by marking them with periodical points. The method was tested, and the results showed that suspended lines themselves shrank after fabrication, but they were also stretched due to the shrinkage of their support anchors, a phenomenon that has not been investigated much before. The extension strain was measured from the change in the separation points, which reached 75% for a 2 um-long line with a width of 40 nm. PMID- 21817609 TI - Comparative study of the molecular aggregation state of alkyl organic monolayers prepared on Si and hydrogen-terminated Si substrates. AB - A comparative study of the molecular aggregation states of n octadecyltrichlorosilane (OTS) and octadecene monolayers was carried out based on water contact angle, x-ray reflectivity (XR), grazing incidence x-ray diffraction (GIXD), and Fourier transform infrared spectroscopy (FT-IR) measurements. Water contact angle, XR, and FT-IR measurements revealed that the packing density and orientational order of the OTS were higher than those of octadecene. The OTS monolayer was in a hexagonal crystalline state with (10) spacing of 0.417 nm, whereas the octadecene monolayer was in an amorphous state. The growth mechanisms of the OTS and octadecene monolayers are also proposed. The alkyl molecular aggregation states strongly depended on the chemical bonding state at the interface between the alkyl organic molecule and the substrate surface. PMID- 21817610 TI - Monodisperse magnetizable silica composite particles from heteroaggregate of carboxylic polystyrene latex and Fe(3)O(4) nanoparticles. AB - Monodisperse magnetizable silica composite particles were prepared from heteroaggregates of carboxylic polystyrene latex and Fe(3)O(4) nanoparticles. It was found that the heteroaggregation of the carboxylic latex and Fe(3)O(4) nanoparticles is dependent on the pH of the solution. At low pH value (pH = 2-4), the aggregation proceeds effectively due to opposite charges on the surfaces of the latex and the magnetic nanoparticles. At high pH value (pH>8), no aggregation was observed due to the negative charge on both the surface of the latex and the magnetic nanoparticles. The heteroaggregate of the latex and magnetic nanoparticles was found to be stable in a wide range of pH values, due to the existence of coordination interactions at the interface of the latex and magnetic nanoparticles. After silica layer coating on the heteroaggregate by the Stober process and removal of the latex by calcination, hollow monodisperse magnetizable silica composite particles are obtained. PMID- 21817611 TI - One-step synthesis of silver nanoparticles at the air-water interface using different methods. AB - Silver nanoparticles were synthesized in a one-step process at the air-AgNO(3) aqueous solution interface under Langmuir monolayers of 5,10,15,20-tetra-4-oxy(2 stearic acid) phenyl porphyrin (TSPP) at room temperature by using different methods including UV-light irradiation, ambient light irradiation, and formaldehyde gas reduction. It was found that parallel aligned one-dimensional (1D) chains composed of discrete silver nanoparticles with the size of 3-5 nm were formed under UV-light irradiation for a short time, while large areas of uniform silver spherical nanoparticles were formed under natural daylight illumination for several days or by formaldehyde gas treatment for several hours. The average size of the spherical nanoparticles ranges from 6.88 +/- 0.46 to 11.10 +/- 1.47 nm, depending on the experimental conditions. The 1D chains formed under UV-light irradiation result from the templating effect of parallel aligned linear supramolecular arrays formed by TSPP at the air-water interface, and rapid nucleation and growth of the nanoparticles. The formation of the uniform silver nanoparticles under daylight illumination or by formaldehyde gas treatment, however, should be ascribed to a kinetically controlled growth process of the nanoparticles. PMID- 21817612 TI - Well-defined nanoarrays from an n-type organic perylene-diimide derivative for photoconductive devices. AB - Well-defined one-dimensional (1D) perylene-diimide derivative (PDD) nanowire arrays were prepared via a simple electrophoretic deposition method by using anodic aluminum oxide (AAO) templates. The morphology of the as-deposited films was characterized by field emission scanning electron microscope and transmission electron microscopy. The highly ordered nanoarrays were free-standing after removing the AAO supports. Further studies revealed that the growth process of the nanowires in the AAO pores followed a 'bottom-up' growth model. A photoreceptor with PDD nanowire arrays as the charge generation layer was fabricated. It exhibited a better photoconductivity under light illumination when compared to that of its bulk counterpart. Our results suggested that electron accepting PDD nanowire arrays can be used as a potential candidate for photoconduction devices, which would facilitate further exploration of new technological applications of the photoimaging process. PMID- 21817613 TI - Real-time imaging of vertically aligned carbon nanotube array growth kinetics. AB - In situ time-lapse photography and laser irradiation are applied to understand unusual coordinated growth kinetics of vertically aligned carbon nanotube arrays including pauses in growth, retraction, and local equilibration in length. A model is presented which explains the measured kinetics and determines the conditions for diffusion-limited growth. Laser irradiation of the growing nanotube arrays is first used to prove that the nanotubes grow from catalyst particles at their bases, and then increase their growth rate and terminal lengths. PMID- 21817614 TI - Gold/boron core-shell nanocables synthesized from gold-boron eutectic droplets. AB - Metal/semiconductor core-shell coaxial nanocables are promising building blocks for nanoelectronic devices while in situ growth of these nanocables remains challenging due to the distinctly different synthesis temperature ranges required for metals and semiconductors. To overcome this difficulty, we have developed a vapor-liquid-solid and oxide-assisted bimodal competition growth strategy for in situ metal/semiconductor core-shell nanocable growth. Using this process, gold/boron core-shell nanocables were obtained. A core-shell Au-B/BO(x) eutectic droplet formed via hydrogen gas-assisted rapid cooling was found critical for initiation of the nanocable growth. In addition, the large difference in the boron nanowire growth rates in the vapor-liquid-solid and oxide-assisted mechanisms facilitates the layered growth in the nanocables. The compatibility of this method with the vapor-liquid-solid process applied widely for semiconductor nanowire growth allows in situ connection of metal/semiconductor nanocables with semiconductor nanowires. PMID- 21817616 TI - Coupling of ab initio density functional theory and molecular dynamics for the multiscale modeling of carbon nanotubes. AB - A multiscale technique is developed that couples empirical molecular dynamics (MD) and ab initio density functional theory (DFT). An overlap handshaking region between the empirical MD and ab initio DFT regions is formulated and the interaction forces between the carbon atoms are calculated based on the second generation reactive empirical bond order potential, the long-range Lennard-Jones potential as well as the quantum-mechanical DFT derived forces. A density of point algorithm is also developed to track all interatomic distances in the system, and to activate and establish the DFT and handshaking regions. Through parallel computing, this multiscale method is used here to study the dynamic behavior of single-walled carbon nanotubes (SWCNTs) under asymmetrical axial compression. The detection of sideways buckling due to the asymmetrical axial compression is reported and discussed. It is noted from this study on SWCNTs that the MD results may be stiffer compared to those with electron density considerations, i.e. first-principle ab initio methods. PMID- 21817615 TI - Magnetic SiO(2)/Fe(3)O(4) colloidal crystals. AB - We proposed a novel technique to fabricate colloidal crystals by using monodisperse SiO(2) coated magnetic Fe(3)O(4)(SiO(2)/Fe(3)O(4)) microspheres. The magnetic SiO(2)/Fe(3)O(4) microspheres with a diameter of 700 nm were synthesized in the basic condition with ferric sulfate, ferrous sulfate, tartaric acid and tetraethyl orthosilicate (TEOS) in the reaction system. Monodisperse SiO(2)/Fe(3)O(4) superparamagnetic microspheres have been successfully used to fabricate colloidal crystals under the existing magnetic field. PMID- 21817617 TI - Oscillation of absorption bands of Zn(1-x)Mn(x)S clusters: an experimental and theoretical study. AB - Electroporation of synthetic vesicles is utilized for the preparation of molecular size uncapped Zn(1-x)Mn(x)S clusters. The absence of caps permits (i) continued growth of the Zn(1-x)Mn(x)S clusters formed, (ii) the assessment of their true absorption spectra unaltered by stabilizing ligands, and (iii) the previously inaccessible live observation of the growth of the clusters in the molecular size regime. Upon cluster growth, the UV spectra exhibit novel, time dependent, oscillation of red and blue shifts of the characteristic absorption band. The structure and electronic properties of Zn(N-1)MnS(N) clusters with N = 1-9 are calculated using the first-principles DMol(3) package. On the basis of similarities between the oscillating trend of the experimentally observed absorption spectra and that of the calculated highest occupied molecular orbital lowest unoccupied molecular orbital (HOMO-LUMO) gap of Zn(N-1)MnS(N) clusters with N = 1-9, the wavelengths of the sequential spectral peaks can be assigned to Zn(2)MnS(3), Zn(3)MnS(4), Zn(4)MnS(5), Zn(6)MnS(7), and Zn(8)MnS(9), respectively. Our results demonstrate that both the cluster size and the composition can be used to tune the optical properties. PMID- 21817618 TI - Predicting the effective thermal conductivity of carbon nanotube based nanofluids. AB - Adding a small volume fraction of carbon nanotubes (CNTs) to a liquid enhances the thermal conductivity significantly. Recent experimental findings report an anomalously wide range of enhancement values that continue to perplex the research community and remain unexplained. In this paper we present a theoretical model based on three-dimensional CNT chain formation (percolation) in the base liquid and the corresponding thermal resistance network. The model considers random CNT orientation and CNT-CNT interaction forming the percolating chain. Predictions are in good agreement with almost all available experimental data. Results show that the enhancement critically depends on the CNT geometry (length), volume fraction, thermal conductivity of the base liquid and the nanofluid (CNT-liquid suspension) preparation technique. Based on the physical mechanism of heat conduction in the nanofluid, we introduce a new dimensionless parameter that alone characterizes the nanofluid thermal conductivity with reasonable accuracy (~ +/- 5%). PMID- 21817619 TI - Strain-dependent electrical resistance of multi-walled carbon nanotube/polymer composite films. AB - The strain-dependent electrical resistance characteristics of multi-walled carbon nanotube (MWCNT)/polymer composite films were investigated. In this research, polyethylene oxide (PEO) is used as the polymer matrix. Two representative volume fractions of MWCNT/PEO composite films were selected: 0.56 vol% (near the percolation threshold) and 1.44 vol% (away from the percolation threshold) of MWCNT. An experimental setup which can measure electrical resistance and strain simultaneously and continuously has been developed. Unique and repeatable relationships in resistance versus strain were obtained for multiple specimens with different volume fractions of MWCNT. The overall pattern of electrical resistance change versus strain for the specimens tested consists of linear and nonlinear regions. A resistance change model to describe the combination of linear and nonlinear modes of electrical resistance change as a function of strain is suggested. The unique characteristics in electrical resistance change for different volume fractions imply that MWCNT/PEO composite films can be used as tunable strain sensors and for application into embedded sensor systems in structures. PMID- 21817620 TI - An investigation of nanostructured rutile and anatase plates for improving the photosplitting of water. AB - Developing new semiconductor materials for improving photocatalytic reactivity is important for solving the challenging environmental and energy problems we are facing today. This work focuses on increasing the quantum efficiency in titania photocatalysts for photocatalytic (oxidation of acetaldehyde) and photosynthetic (photosplitting of water) reactions by synthesizing pure phase rutile and anatase nanostructures with well defined morphologies and investigating their photocatalytic performance compared to a commercial titania photocatalyst (Degussa P25). Nanostructured anatase is dominated by {100} surfaces with a small amount of {101} surfaces, whereas the rutile nanoplates consist of nanorods dominated by {110} and {111} crystal surfaces. In accordance with the signals from electron spin resonance (ESR) spectra, both nanostructured anatase and rutile phases have high photocatalytic activity for photosplitting of water compared to P25 titania. The anatase phase shows a high activity for photocatalytic oxidation (PCO) of acetaldehyde whereas the rutile phase shows a lower activity. The results of these experiments basically agree with previously published works that reported that the oxidation and reduction sites on rutile particles are on the {011} and {110} faces respectively, and on {001} and {011} faces respectively for anatase particles. The results have important implications for enhancing the photocatalytic activity of titania for environmental remediation, increasing the quantum efficiency in photo-voltaic (PV) solar cells and other photo-assisted processes. PMID- 21817621 TI - Fabrication of superhydrophobic surfaces by a Pt nanowire array on Ti/Si substrates. AB - Superhydrophobic surfaces were prepared on Ti/Si substrates via the fabrication of a platinum (Pt) nanowire array. The Pt nanowire array was obtained by dc electrodeposition of Pt into the pores of an anodic aluminium oxide (AAO) template on the substrate followed by the removal of the template. Transmission electron microscopy (TEM) examination demonstrated that all the nanowires have uniform diameter of about 30 nm. Field emission scanning electron microscopy (FE SEM) showed that the structures at both the micrometre scale and nanometre scale bestowed the prerequisite roughness on the surfaces. The chemical surface modification made the Pt nanowire array superhydrophobic. The surface modified Pt nanowire array exhibited superhydrophobicity even in corrosive solutions over a wide pH range, such as acidic or basic solutions. The results demonstrated that the Pt nanowire array will have good potential applications in the preparation of superhydrophobic surfaces. PMID- 21817622 TI - Orientation and the extent of exfoliation of clay on scratch damage in polyamide 6 nanocomposites. AB - The major objectives of this work are to understand the effects of organoclay, its extent of exfoliation and orientation, and indenter geometry on the scratch characteristics of polyamide 6/organoclay nanocomposites. Two different organically treated clays are used for this purpose and their structural parameters in a polyamide 6 matrix quantified. It is shown that, while the material properties are important for scratching resistance, they are not the only determinants of the scratch performance of materials. Further, despite proving beneficial to scratch resistance, in terms of residual depth, the presence (and exfoliation) of organoclay promotes the formation of brittle cracks during scratching. But with no organoclay layers, plastic flow controls the scratch damage in neat polyamide 6 with large residual depths. Factors such as orientation of clay layers and variations of indenter tip geometry also exert dominant effects on scratch penetration resistance and damage. Additionally, significant plastic flow and rotation of organoclay layers from the original configuration are observed underneath the sliding indenter. PMID- 21817623 TI - Myoglobin-loaded layer-by-layer films containing SiO(2) nanoparticles studied using electrochemistry. AB - In the present work, a new kind of protein-loaded layer-by-layer (LbL) film based on nanoparticles was fabricated on electrodes. First, oppositely charged SiO(2) nanoparticles and poly(diallyldimethylammonium) (PDDA) were alternately adsorbed on solid surfaces, forming {PDDA/SiO(2)}(n) LbL films. In the next step, the films were immersed in myoglobin (Mb) solution at pH 5.0 to load Mb, forming {PDDA/SiO(2)}(n)-Mb films. The loading behavior of {PDDA/SiO(2)}(n) films toward Mb was investigated by monitoring the cyclic voltammetric responses of the Mb heme Fe(III)/Fe(II) redox couple, and comparing them with those of {PDDA/PSS}(n) films, where PSS stands for poly(styrenesulfonate). Scanning electron microscopy (SEM) and electroactive probe tests demonstrated that the porosity of {PDDA/SiO(2)}(n) films assembled with 'hard' and rigid SiO(2) nanoparticles was much better than that of {PDDA/PSS}(n) films fabricated with just 'soft' polyelectrolytes, which led to the better electrochemical and electrocatalytic responses for the {PDDA/SiO(2)}(n)-Mb films. A series of comparative experiments showed that the main driving force for Mb to diffuse into the films was most probably electrostatic interaction between positively charged Mb and negatively charged SiO(2) components of the films, while the major force in stabilizing Mb in the {PDDA/SiO(2)}(n)-Mb films in blank buffers was more likely hydrophobic interaction. PMID- 21817624 TI - Silicon-induced oriented ZnS nanobelts for hydrogen sensitivity. AB - Oriented ZnS nanobelts were grown on an Si substrate using hydrogen-assisted thermal evaporation under moist gas conditions. It was found that these ZnS nanobelts had a single crystal hexagonal wurtzite structure growing along the [0001] direction. They had a rectangular cross section with lengths of up to tens of micrometres, a typical width of 50-150 nm, and a thickness of ~40 nm. A silicon-induced vapour-liquid-solid process was proposed for the formation of the ZnS nanobelts and their assembly. These oriented nanobelts have much faster response time to hydrogen gas than that of pure ZnO and Pd-sensitized ZnO, showing excellent hydrogen sensing properties. PMID- 21817625 TI - Enhanced emissions of Eu(3+) by energy transfer from ZnO quantum dots embedded in SiO(2) glass. AB - SiO(2):Eu(3+) based bulk composites containing ZnO quantum dots were synthesized by an in situ sol-gel process. The quantum dots homogeneously distributed among the SiO(2) glass matrix exhibited a broad ultraviolet emission band centered at 385 nm. The ZnO ultraviolet luminescence intensity decreased monotonically with increasing Eu(3+) doping concentration, while the Eu(3+) visible emission was intensified significantly by the precipitation of ZnO quantum dots, ascribed to the energy transfer from ZnO to Eu(3+). The Eu(3+) luminescence at 612 nm for the sample with 20 mol% ZnO was about ten times stronger than that for the sample without ZnO. The influence of ZnO or Eu(3+) concentration on the energy transfer process is discussed. PMID- 21817626 TI - A generally adoptable radiotracing method for tracking carbon nanotubes in animals. AB - Carbon nanotube (CNT) mediated drug delivery systems have currently aroused a great deal of interest. Such delivery systems for drugs, proteins and genes have been preliminarily studied using cellular and animal models. For the further study of the pharmacokinetics and related biological behaviours of CNTs in vivo, a fast and convenient tracing method is particularly demanded. In this paper, we developed a generally adoptable tracing method for the biodistribution study of functionalized CNTs in vivo. Taurine covalently functionalized multi-walled carbon nanotubes (tau-MWNTs) and Tween-80 wrapped MWNTs (Tween-MWNTs) were labelled with (125)I, and then their distribution in mice was determined. It is interesting that Tween-80 can reduce the RES uptake of MWNTs remarkably. The resulting distribution of (125)I-tau-MWNTs was very consistent with that using (14)C-taurine-MWNTs as the CNTs tracer, which means the easy (125)I labelling method is reliable and effective. PMID- 21817627 TI - Scalable fabrication of immunosensors based on carbon nanotube polymer composites. AB - In this work we present the fabrication and characterization of immunosensors based on polystyrene (PS)-multiwalled carbon nanotube (MWCNT) composites. The electrochemical properties of the sensors have been investigated and show that the surface area is increased upon addition of the MWCNT-PS layer. Furthermore, a plasma activation process is used to partially remove the PS and expose the MWCNTs. This results in a huge increase in the electrochemical area and opens up the possibility of binding biomolecules to the MWCNT wall. The MWCNTs have been functionalized covalently with a model antibody (rabbit IgG). The biosensors have been tested using amperometric techniques and show detection limits comparable to standard techniques such as ELISA. PMID- 21817628 TI - Green synthesis of highly stabilized nanocrystalline silver particles by a non pathogenic and agriculturally important fungus T. asperellum. AB - A controlled and up-scalable biosynthetic route to nanocrystalline silver particles with well-defined morphology using cell-free aqueous filtrate of a non pathogenic and commercially viable biocontrol agent Trichoderma asperellum is being reported for the first time. A transparent solution of the cell-free filtrate of Trichoderma asperellum containing 1 mM AgNO(3) turns progressively dark brown within 5 d of incubation at 25 degrees C. The kinetics of the reaction was studied using UV-vis spectroscopy. An intense surface plasmon resonance band at ~410 nm in the UV-vis spectrum clearly reveals the formation of silver nanoparticles. The size of the silver particles using TEM and XRD studies is found to be in the range 13-18 nm. These nanoparticles are found to be highly stable and even after prolonged storage for over 6 months they do not show significant aggregation. A plausible mechanism behind the formation of silver nanoparticles and their stabilization via capping has been investigated using FTIR and surface-enhanced resonance Raman spectroscopy. PMID- 21817629 TI - Implications of silver nanoparticle induced cell apoptosis for in vitro gene therapy. AB - The impact of manufactured nanomaterials on human health and the environment is a major concern for commercial use of nanotechnology based products. A judicious choice of selective usage, lower nanomaterial concentration and use in combination with conventional therapeutic materials may provide the best solution. For example, silver nanoparticles (Ag NPs) are known to be bactericidal and also cytotoxic to mammalian cells. Herein, we investigate the molecular mechanism of Ag NP mediated cytotoxicity in both cancer and non-cancer cells and find that optimum particle concentration leads to programmed cell death in vitro. Also, the benefit of the cytotoxic effects of Ag NPs was tested for therapeutic use in conjunction with conventional gene therapy. The synergistic effect of Ag NPs on the uracil phosphoribosyltransferase expression system sensitized the cells more towards treatment with the drug 5-fluorouracil. Induction of the apoptotic pathway makes Ag NPs a representative of a new chemosensitization strategy for future application in gene therapy. PMID- 21817630 TI - Design of novel polysaccharidic nanostructures for gene delivery. AB - The goal of the present work was to develop a new synthetic nanosystem for gene delivery. For this purpose, we chose two polysaccharides, hyaluronic acid (HA) and chitosan (CS), as the main components of the nanocarrier. Nanoparticles with different hyaluronate:chitosan (HA:CS) mass ratios (0.5:1 and 1:1) and different polymer molecular weights (hyaluronate 170 (HA) or <10 kDa (HAO) and chitosan 125 (CS) or 10-12 (CSO) kDa) could be obtained using an ionic crosslinking method. These nanoparticles were loaded with pDNA and characterized for their size, zeta potential and pDNA association efficiency. Moreover, their toxicity and ability to transfect the model plasmid pEGFP-C1 were evaluated in the cell line HEK 293, as well as their intracellular fate. The results showed that HA:CS nanoparticles have a small size in the range of 110-230 nm, a positive zeta potential of +10 to +32 mV and a very high pDNA association efficiency of 87-99% (w/w). On the other hand, nanoparticles exhibited low cell toxicity and transfection levels up to 25% GFP expressing HEK 293 cells, lasting for the whole observation period of 10 days. We also provide basic information about the role of both polymers, HA and CS, and the effect of their molecular weight on the effectiveness of the resulting DNA nanocarrier, being the highest transfection levels observed with HAO:CSO 1:1 nanoparticles. In conclusion, HA:CS nanoparticles are promising carriers for gene delivery. PMID- 21817631 TI - Photoinduced antiviral carbon nanohorns. AB - Nanocarbons, such as carbon nanohorns (CNH) and carbon nanotubes, are materials of interest in many fields of science and technology because of their remarkable physical properties. We report here a novel approach for using NIR laser-driven CNH as an antiviral agent. NIR laser-driven functional CNH complexes could open the way to a new range of antiviral materials. PMID- 21817632 TI - From particle self-assembly to functionalized sub-micron protein patterns. AB - Biologically relevant nanopatterns are useful platforms to address fundamental questions, for example, regarding protein-protein and cell-protein interactions. For the creation of nanopatterns, complex and expensive instrumentation is often needed. We present a simple but versatile patterning method using a combination of particle and subsequent molecular self-assembly to produce ordered structures in the micron and sub-micron range. Polystyrene particles were, in a first step, assembled via dip-coating or dried in a drying cell. Silicon wafers and glass slides coated with SiO(2) and a top layer of 11 nm of TiO(2) were used as substrates. Large hexagonally ordered particle monolayers were formed with high reproducibility. These were subsequently shrunk in a controlled manner by exposure to a O(2)/N(2) plasma and subsequently used as etching masks to transfer the particle pattern onto the substrate, creating TiO(2) features in an SiO(2) background. After removing the mask the oxide contrast was translated in three simple dip-and-rinse steps into a biochemical contrast of protein-coated features in an inert background. In short, alkane phosphates were first selectively adsorbed to the TiO(2) features. Then the SiO(2) background was backfilled using poly(L-lysine)-graft-poly(ethylene glycol) and finally streptavidin was adsorbed to the hydrophobic alkane phosphate SAMs, allowing subsequent binding and hybridization of biotinylated DNA. PMID- 21817633 TI - Fabrication and characterization of Si quantum dots and SiO(2) tunnel barriers grown by a controlled oxidation process. AB - The control of the growth of silicon dioxide (SiO(2)) and the formation of quantum dots (QDs) play an important role in the fabrication of single-electron transistors (SETs). In this work, SET structures were fabricated using a systematic oxidation technique known as the pattern-dependent oxidation (PADOX) process. For comparison, two oxidation processes using conventional furnace and rapid thermal processing (RTP) were used. The oxidation temperature for both oxidation processes was set at 1000 degrees C and the oxygen flow rate in the furnace was set at 1 l min(-1). The nanostructures were characterized using AFM, SEM and TEM to determine the quality and the stoichiometry of the Si QDs and the oxides. The oxidation rate using a furnace is 0.36 nm s(-1), significantly lower than the RTP value which is 2.16 nm s(-1). Meanwhile, the oxygen contents in SiO(2) grown by furnace and RTP are approximately the same. PMID- 21817634 TI - Iron-platinum-coated carbon nanocone probes on tipless cantilevers for high resolution magnetic force imaging. AB - High coercivity iron-platinum-coated carbon nanocones (CNCs) have been fabricated for magnetic force microscopy (MFM) by direct-current plasma-enhanced chemical vapor deposition growth of nanocones on tipless cantilevers followed by sputtering and annealing of the FePt film. The FePt-coated CNC probe has many localized magnetic stray fields due to the high-aspect-ratio geometry and small radius of the tip. The MFM imaging on magnetic recording media was performed using CNC probes and compared with the imaging by FePt-coated silicon probes. An image with 20 nm lateral resolution has been demonstrated. PMID- 21817635 TI - A lactate electrochemical biosensor with a titanate nanotube as direct electron transfer promoter. AB - Hydrogen titanate (H(2)Ti(3)O(7)) nanotubes (TNTs) have been synthesized by a one step hydrothermal processing. Lactate oxidase (LOx) enzyme has been immobilized on the three-dimensional porous TNT network to make an electrochemical biosensor for lactate detection. Cyclic voltammetry and amperometry tests reveal that the LOx enzyme, which is supported on TNTs, maintains their substrate-specific catalytic activity. The nanotubes offer the pathway for direct electron transfer between the electrode surface and the active redox centers of LOx, which enables the biosensor to operate at a low working potential and to avoid the influence of the presence of O(2) on the amperometric current response. The biosensor exhibits a sensitivity of 0.24 uA cm(-2) mM(-1), a 90% response time of 5 s, and a linear response in the range from 0.5 to 14 mM and the redox center of enzyme obviates the need of redox mediators for electrochemical enzymatic sensors, which is attractive for the development of reagentless biosensors. PMID- 21817636 TI - Numerical simulation of nano scanning in intermittent-contact mode AFM under Q control. AB - We investigate nano scanning in tapping mode atomic force microscopy (AFM) under quality (Q) control via numerical simulations performed in SIMULINK. We focus on the simulation of the whole scan process rather than the simulation of cantilever dynamics and the force interactions between the probe tip and the surface alone, as in most of the earlier numerical studies. This enables us to quantify the scan performance under Q control for different scan settings. Using the numerical simulations, we first investigate the effect of the elastic modulus of the sample (relative to the substrate surface) and probe stiffness on the scan results. Our numerical simulations show that scanning in an attractive regime using soft cantilevers with high effective Q factor (Q(eff)) results in a better image quality. We then demonstrate the trade-off in setting Q(eff) of the probe in Q control: low values of Q(eff) cause an increase in tapping forces while higher ones limit the maximum achievable scan speed due to the slow response of the cantilever to the rapid changes in surface profile. Finally, we show that it is possible to achieve higher scan speeds without causing an increase in the tapping forces using adaptive Q control (AQC), in which the Q factor of the probe is changed instantaneously depending on the magnitude of the error signal in oscillation amplitude. The scan performance of AQC is quantitatively compared to that of standard Q control using iso-error curves obtained from numerical simulations first and then the results are validated through scan experiments performed using a physical set-up. PMID- 21817637 TI - Organic nanocones fabricated by atmospheric plasma polymerization for immobilizing bioprobes. AB - Inspired by the formation process of natural thundershowers, we fabricated an organic nanocone matrix-like bamboo-shoot by using atmospheric plasma polymerization in the absence of any catalyst or template. The discharging characteristics affected the nanocone shape and distribution in an obvious way. The nanocones prepared by helium (He) plasma were about 120 nm in diameter and 80 nm high. The nanostructured surface acted as an adhesion layer immobilizing DNA probes for DNA hybridization assay. The density of NH(2)-DNA probes prepared by He, argon (Ar) and nitrogen (N(2)) plasma was confirmed by the dyed oligonucleotide and was found to be 3.2, 1.0 and 0.6 pM cm(-2), respectively. Each nanocone prepared by helium plasma contains nearly 4 * 10(2) amine groups. PMID- 21817638 TI - A single-step synthesis of gold nanochains using an amino acid as a capping agent and characterization of their optical properties. AB - We demonstrated a simple single-step synthesis of gold nanochains by reducing aqueous chloroaurate ions (AuCl(4)(-)) with sodiumborohydride (NaBH(4)) in the presence of an amino acid (glutamic acid and histidine) as a stabilizer. The structure and optical properties of gold nanochains and nanowires were characterized by transmission electron microscopy, UV-visible spectroscopy, infrared spectroscopy and femtosecond z-scan measurements. The results suggested that the gold nanochains and nanowires were formed via the nanospheres fusing into one another by an oriented attachment mechanism through dipole-dipole interactions. The z-scan measurements on Au nanowires showed a transition from saturable absorption to reverse saturable absorption as the pump intensity increased. PMID- 21817639 TI - Spherical CoS(2)@carbon core-shell nanoparticles: one-pot synthesis and Li storage property. AB - Well-defined spherical CoS(2)@carbon core-shell nanoparticles, with an average diameter of 40 nm and thin graphite shell of 4 nm, were synthesized by the one pot method in the presence of NaN(3) in supercritical CS(2) at 600 degrees C using cobaltocene as the cobalt source. The obtained product was characterized by XRD, Raman, FESEM, TEM and HRTEM and the possible formation mechanism was proposed here. Due to the good electronic conductivity and buffering matrix effect of graphitic carbon shells, the CoS(2)@carbon core-shell nanocomposite exhibited highly reversible capacity, good cycle performance and high Coulombic efficiency in lithium ion storage and retrieval, which makes it promising as an attractive anode material candidate for lithium ion batteries. PMID- 21817640 TI - Solvothermal synthesis of well-dispersed MF(2) (M = Ca,Sr,Ba) nanocrystals and their optical properties. AB - MF(2) (M = Ca,Sr,Ba) nanocrystals (NCs) were synthesized via a solvothermal process in the presence of oleic acid and characterized by x-ray diffraction (XRD), transmission electron microscopy (TEM), Fourier transform infrared (FT-IR) spectra, UV/vis absorption spectra, photoluminescence (PL) excitation and emission spectra, and lifetimes, respectively. In the synthetic process, oleic acid as a surfactant played a crucial role in confining the growth and solubility of the MF(2) NCs. The as-prepared CaF(2), SrF(2) and BaF(2) NCs present morphologies of truncated octahedron, cube and sheet in a narrow distribution, respectively. Possible growth mechanisms were proposed to explain these results. The as-prepared NCs are highly crystalline and can be well dispersed in cyclohexane to form stable and clear colloidal solutions, which demonstrate strong emission bands centred at 400 nm in photoluminescence (PL) spectra compared with the cyclohexane solvent. The PL properties of the colloidal solutions of the as-prepared NCs can be ascribed to the trap states of surface defects. PMID- 21817641 TI - The first biopolymer-wrapped non-carbon nanotubes. AB - DNA-wrapped halloysite nanotubes were obtained by a mechanochemical reaction in the solid state. The characterization by scanning electron microscopy showed that the nanotubes were cut into shorter lengths and were completely covered with DNA. This resulted in a high aqueous solubility of the product with stability of the solution for about 6 weeks. The nanotubes were cut to different fractions with lengths of 200-400 nm (30-40%), 400-600 nm (10-20%) and 600-800 nm (5-10%) after ball milling. FTIR spectroscopic analysis shows that the DNA in the product remained intact. This straightforward technique for obtaining water-soluble halloysite nanotubes by a solid-state reaction has great potential for biomedical applications of nanotubes. PMID- 21817642 TI - Synthesis of sealed sponge ZnO nanospheres through a novel NH(3)-evaporation method. AB - Sealed sponge ZnO nanospheres are prepared through a novel NH(3)-evaporation method. X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), atomic force microscopy (AFM) and N(2) physisorption analysis show that the samples obtained are ZnO nanospheres with hexagonal wurtzite structure. The particle size is in the range 80-130 nm and the pores inside are estimated to be in the range 2-35 nm. During the preparation process, the carboxyls derived from the polyacrylamide hydrolyzation tend to attach to the particle surface and bring about the interaction between particles by hydrogen bonding. Results show that the polyacrylamide and alcohol are crucial to the formation of the sealed sponge ZnO, by forming a diffusion layer around the particle. The formation mechanism is considered to be controlled by the diffusion of Zn(2+) through the diffusion layer, and the mass transmission between the initial particles. PMID- 21817643 TI - Hierarchical organization of Au nanoparticles in a poly(vinyl carbazole) matrix for hybrid electronic devices. AB - We report a novel one-step method for the preparation of hierarchically patterned Au nanoparticles in a conducting polymer matrix by controlling the interface properties between Au nanoparticles and the conducting polymer matrix. The terminal group of capping molecules for the Au nanoparticles was modified to change the interface properties, not to change the size of the Au nanoparticles which affects their intrinsic properties. By modulating the interface properties, it is possible to construct Au nanoparticle-conducting polymer composites with two different structures: one presents a triple layer in which the conducting polymer layer is sandwiched between Au nanoparticle layers at the top and bottom; the other exhibits a form like a raisin cake in which Au nanoparticles are homogeneously organized in the conducting polymer matrix. High-resolution transmission electron microscopy was used to study the morphology and patterning of Au nanoparticles in the conducting polymer matrix. PMID- 21817644 TI - Microstructural and optical characteristics of solution-grown Ga-doped ZnO nanorod arrays. AB - Highly oriented Ga-doped zinc oxide (ZnO) nanorod arrays have been prepared on a ZnO-buffered silicon substrate in an aqueous solution, which is a mixture of methenamine (C(6)H(12)N(4)), zinc nitrate hexahydrate (Zn(NO(3))(2).6H(2)O), and gallium nitrate hydrate (Ga(NO(3))(3).xH(2)O). The microstructure characteristics and optical properties of the nanorod arrays were analyzed using different characterization techniques including field-emission scanning electron microscopy (FESEM), x-ray photoelectron spectroscopy (XPS), and photoluminescence (PL). The experimental results show that the morphology, density, and surface compositions of ZnO nanorod arrays are sensitive to the concentration of gallium nitrate hydrate. The PL spectra of all ZnO nanorod arrays show three different emissions, including UV (ultraviolet), yellow, and NIR (near infrared) emissions. With the increase in the Ga doping level, the luminescence quality of ZnO nanorods has been improved. The peak of UV emission has a small redshift, which can be ascribed to the combined effect of size and Ga doping. Furthermore, Ga doping has caused defects that respond to NIR emission. PMID- 21817645 TI - A simple approach for large-area fabrication of Ag nanorings. AB - A simple and low-cost method based on a two-step heat treatment of AgNO(3)/SiO(2) film has been developed for fabricating metal Ag nanoring arrays. The as-prepared nanorings have an inner diameter of 70-250 nm and an average wall thickness (namely wire diameter) of approximately 30 nm with a number density of approximately 10(9) cm(-2) on the surface of the SiO(2) matrix. X-ray diffraction (XRD) results reveal that these nanorings exhibit a face-centered cubic crystal structure. Furthermore, a new growth mechanism, namely a molten metal bubble as a self-template, is tentatively proposed for Ag nanorings. PMID- 21817646 TI - Highly oriented carbon nanotube papers made of aligned carbon nanotubes. AB - Paper-like carbon nanotube (CNT) materials have many important applications such as in catalysts, in filtration, actuators, capacitor or battery electrodes, and so on. Up to now, the most popular way of preparing buckypapers has involved the procedures of dispersion and filtration of a suspension of CNTs. In this work, we present a simple and effective macroscopic manipulation of aligned CNT arrays called 'domino pushing' in the preparation of the aligned thick buckypapers with large areas. This simple method can efficiently ensure that most of the CNTs are well aligned tightly in the buckypaper. The initial measurements indicate that these buckypapers have better performance on thermal and electrical conductance. These buckypapers with controllable structure also have many potential applications, including supercapacitor electrodes. PMID- 21817647 TI - Magnetic sensitivity enhanced novel fluorescent magnetic silica nanoparticles for biomedical applications. AB - We synthesized novel fluorescent magnetic silica nanoparticles (FMSNPs) containing large magnetic components for biomedical application. By employing assemblies of magnetic nanoparticles as kernels against FMSNPs, both the saturation of magnetization and the magnetic resonance (MR) signal intensity were significantly enhanced. Furthermore, the cellular binding of FMSNPs was improved by introducing a positive charge on the surface of the FMSNPs, and fluorescent dyes on the surface of FMSNPs enable optical imaging of sub-cellular regions. PMID- 21817648 TI - Growth and characterization of well-aligned densely-packed rutile TiO(2) nanocrystals on sapphire substrates via metal-organic chemical vapor deposition. AB - Well-aligned densely-packed rutile TiO(2) nanocrystals (NCs) have been grown on sapphire (SA) (100) and (012) substrates via metal-organic chemical vapor deposition (MOCVD), using titanium-tetraisopropoxide (TTIP, Ti(OC(3)H(7))(4)) as a source reagent. The surface morphology as well as structural and spectroscopic properties of the as-deposited NCs were characterized using field-emission scanning electron microscopy (FESEM), transmission electron microscopy (TEM), selected-area electron diffractometry (SAED), x-ray diffraction (XRD) and micro Raman spectroscopy. FESEM micrographs reveal that vertically aligned NCs were grown on SA(100), whereas the NCs on the SA(012) were grown with a tilt angle of ~33 degrees from the normal to substrates. TEM and SAED measurements showed that the TiO(2) NCs on SA(100) with square cross section have their long axis directed along the [001] direction. The XRD results reveal TiO(2) NCs with either (002) orientation on SA(100) substrate or (101) orientation on SA(012) substrate. A strong substrate effect on the alignment of the growth of TiO(2) NCs has been demonstrated and the probable mechanism for the formation of these NCs has been discussed. PMID- 21817649 TI - Intercalating dye as an acceptor in quantum-dot-mediated FRET. AB - Fluorescence resonance energy transfer (FRET) is a popular tool to study intermolecular distances and characterize structural or conformational changes of biological macromolecules. We investigate a novel inorganic/organic FRET pair with quantum dots (QDs) as donors and DNA intercalating dyes, BOBO-3, as acceptors by using DNA as a linker. Typically, FRET efficiency increases with the number of stained DNA linked to a QD. However, with the use of intercalating dyes, we demonstrate that FRET efficiency at a fixed DNA:QD ratio can be further enhanced by increasing the number of dyes stained to a DNA strand through the use of an increased staining dye/bp ratio. We exploit this flexibility in the staining ratio to maintain a high FRET efficiency of >0.90 despite a sixfold decrease in DNA concentration. Having characterized this new QD-mediated FRET system, we test this system in a cellular environment using nanocomplexes generated by encapsulating DNA with commercial non-viral gene carriers. Using this novel FRET pair, we are able to monitor the configuration changes and fate of the DNA nanocomplexes during intracellular delivery, thereby providing an insight into the mechanistic study of gene delivery. PMID- 21817650 TI - Geometry dependence of the electrostatic and thermal response of a carbon nanotube during field emission. AB - In this paper we present an analysis to simulate heating within an isolated carbon nanotube (CNT) attached to an etched tungsten tip during field emission of an electron beam. The length, radius, wall thickness and shape of the tip (closed with a hemispherical shape or open and flat) of the CNT and its separation distance from the flat surface are considered as variables. Using a finite element method, we predict the field enhancement, emission current and temperature of the CNT as a function of these parameters. The electrostatic and transient thermal analyses are integrated with the field-emission models based on the Fowler-Nordheim approximation and heating/cooling due to emitting energetic electrons (the Nottingham effect). These simulations suggest that the main mechanism responsible for heating of the CNT is Joule heating, which is significantly larger than the Nottingham effect. Results also indicate that the electrostatic characteristics of CNTs are very sensitive to the considered parameters whereas the transient thermal response is only a function of the CNT radius and wall thickness. Further, the thermal response of the CNT is independent of its geometry, meaning that, as long as a given set of geometrical conditions are present that result in a given emission current, the maximum temperature a CNT attains will be the same. PMID- 21817651 TI - Analysis of nanometer vacuum gap formation in thermo-tunneling devices. AB - Combined thermionic emission and tunneling of hot electrons (thermo-tunneling) has emerged as a potential new solid-state cooling technology. Practical implementation of thermo-tunneling, however, requires the formation of a nanometer-sized gap spanning macroscopically significant surfaces. This paper describes a numerical and experimental investigation into the formation of a nanometer-sized tunneling gap based on the combined action of electrostatic, elastic and Lorentz forces. Experimental data reported here were used to tune the model and extract estimates for the size of the tunneling area and the gap size, respectively. The effect of changing the strength of the magnetic field was also investigated. The presented one-dimensional (1D) analysis of the relative magnitudes of these forces indicates possible stable operation. PMID- 21817652 TI - Junctions between a boron nitride nanotube and a boron nitride sheet. AB - For future nanoelectromechanical signalling devices, it is vital to understand how to connect various nanostructures. Since boron nitride nanostructures are believed to be good electronic materials, in this paper we elucidate the classification of defect geometries for combining boron nitride structures. Specifically, we determine possible joining structures between a boron nitride nanotube and a flat sheet of hexagonal boron nitride. Firstly, we determine the appropriate defect configurations on which the tube can be connected, given that the energetically favourable rings for boron nitride structures are rings with an even number of sides. A new formula E = 6+2J relating the number of edges E and the number of joining positions J is established for each defect, and the number of possible distinct defects is related to the so-called necklace and bracelet problems of combinatorial theory. Two least squares approaches, which involve variation in bond length and variation in bond angle, are employed to determine the perpendicular connection of both zigzag and armchair boron nitride nanotubes with a boron nitride sheet. Here, three boron nitride tubes, which are (3, 3), (6, 0) and (9, 0) tubes, are joined with the sheet, and Euler's theorem is used to verify geometrically that the connected structures are sound, and their relationship with the bonded potential energy function approach is discussed. For zigzag tubes (n,0), it is proved that such connections investigated here are possible only for n divisible by 3. PMID- 21817653 TI - A critical assessment of the elastic properties and effective wall thickness of single-walled carbon nanotubes. AB - This paper discusses the fundamental issues of the elastic properties and effective wall thickness of single-walled carbon nanotubes (SWCNTs). It provides an in-depth analysis based on the rationale of the nanoscale-to-macroscale deformation relationship of SWCNTs and carries out a critical assessment of the diverse theoretical predictions in the literature. It was found that the in-plane stiffness of SWCNTs is a mechanics quantity that has been consistently reflected by the majority of the existing models. However, a further systematic study is necessary to clarify the dilemma of the wall thickness of SWCNTs. PMID- 21817654 TI - Interaction between gallium atoms and the inner walls of single-walled carbon nanotubes. AB - The interaction between individual Ga atoms and the inner walls of both (8, 8) and (12, 0) carbon nanotubes (CNTs) is investigated using first principles calculations based on the density functional theory. We find that a single Ga atom favorably adsorbs at the center site (H) of a hexagonal ring and diffuses on the inner wall of a perfect CNT with very low energy barriers. In the case of CNTs containing monovacancies, a single Ga atom can heal the topological structure of a monovacancy in a (8, 8) CNT but not in a (12, 0) CNT. Our calculations show that the Ga atom adsorbed at the monovacancy in the CNT can alter the electronic structure of the tube significantly. PMID- 21817655 TI - Chemisorption of hydrogen molecules on carbon nanotubes: charging effect from first-principles calculations. AB - We report a systematic investigation of the charging effect on hydrogen molecule chemisorption on (3, 3), (5, 5), (5, 0), and (8, 0) carbon nanotubes by first principles calculations. The influence of injected charge on the chemisorption energy barriers is found to be sensitive to the nanotube diameter and chirality. The calculated results also indicate that electron injection is more effective in lowering the energy barrier for armchair carbon nanotubes while hole injection is more effective for zigzag nanotubes. The origin of these interesting trends and systematics can be understood by a close examination of the underlying electronic structure and the electron transfer between the hydrogen molecules and the nanotubes. PMID- 21817656 TI - Polymer-encapsulated metal nanoparticles: optical, structural, micro-analytical and hydrogenation studies of a composite material. AB - A single-step synthesis route is described for the preparation of a metal-polymer composite in which palladium acetate and meta-amino benzoic acid were used as the precursors for palladium nanoparticles and poly(meta-amino benzoic acid) (PABA). The palladium nanoparticles were found to be uniformly dispersed and highly stabilized throughout the macromolecule matrix. The resultant composite material was characterized by means of different techniques, such as IR and Raman spectroscopy, which provided information regarding the chemical structure of the polymer, whereas electron microscopy images yielded information regarding the morphology of the composite material and the distribution of the metal particles in the composite material. The composite material was used as a catalyst for the ethylene hydrogenation reaction and showed catalytic activity at higher temperatures. TEM studies confirmed the changed environment of the nanoparticles at these temperatures. PMID- 21817657 TI - Universal, geometry-driven hydrophobic behaviour of bare metal nanowire clusters. AB - A parallel array of isolated metal nanowires is expected to be hydrophilic. We show, however, that a clustering of such nanowires brought about by vacuum drying produces a 'dual-scale roughness' and confers a strongly hydrophobic property to the surface. The mean size of the nanowire clusters as well as the contact angle are both found to be related to the wire length, and the critical wire length above which the surface becomes hydrophobic is ~10 um. Surface roughness is generally known to enhance water-repellent properties, but this is the first report of roughness-induced hydrophobicity on a bare (uncoated) metallic surface. PMID- 21817658 TI - Size-dependent surface plasmon resonance in silver silica nanocomposites. AB - Silver silica nanocomposites were obtained by the sol-gel technique using tetraethyl orthosilicate (TEOS) and silver nitrate (AgNO(3)) as precursors. The silver nitrate concentration was varied for obtaining composites with different nanoparticle sizes. The structural and microstructural properties were determined by x-ray diffractometry (XRD), Fourier transform infrared spectroscopy (FTIR) and transmission electron microscopy (TEM). X-ray photoelectron spectroscopic (XPS) studies were done for determining the chemical states of silver in the silica matrix. For the lowest AgNO(3) concentration, monodispersed and spherical Ag crystallites, with an average diameter of 5 nm, were obtained. Grain growth and an increase in size distribution was observed for higher concentrations. The occurrence of surface plasmon resonance (SPR) bands and their evolution in the size range 5-10 nm is studied. For decreasing nanoparticle size, a redshift and broadening of the plasmon-related absorption peak was observed. The observed redshift and broadening of the SPR band was explained using modified Mie scattering theory. PMID- 21817659 TI - Fabrication of novel luminor Y(2)O(3):Eu(3+)@SiO(2)@YVO(4):Eu(3+) with core/shell heteronanostructure. AB - A novel polychromic phosphor with core-shell heteronanostructure has been prepared to improve the chromatic index of phosphors. As for the first example, Y(2)O(3):Eu(3+)@SiO(2)@YVO(4):Eu(3+), its synthetic route, structure and optical properties are presented in this paper. X-ray diffraction (XRD), field emission scanning electron microscopy (FE-SEM), high resolution transmission electron microscopy (HR-TEM), energy-dispersive x-ray spectra (EDS) and photoluminescence (PL) were all employed to characterize the composite core-shell phosphors. The XRD, FE-SEM and HR-TEM results indicate that the SiO(2) and YVO(4):Eu(3+) layers have been successfully coated on Y(2)O(3):Eu(3+) nanoparticles and SiO(2) layer, respectively: these layers were further verified by the EDS. The PL showed that the red-emitting phosphor Y(2)O(3):Eu(3+)@SiO(2)@YVO(4):Eu(3+) possessed the independent luminescent properties of both the core Y(2)O(3):Eu(3+) and the shell YVO(4):Eu(3+). The emissions were dominated by [Formula: see text] or [Formula: see text] transitions of Eu(3+) when excited with different wavelengths. Since this broad-band response to excitation in the range of 225-340 nm gave more red/dark red emissions found at 612, 616 and 620 nm, the novel phosphor Y(2)O(3):Eu(3+)@SiO(2)@YVO(4):Eu(3+) could have potential biological labeling applications with wide flexibility. PMID- 21817660 TI - Covered conduction of individual C(60) nanowhiskers. AB - We investigate the electronic properties of individual C(60) nanowhiskers by exploiting conductive atomic force microscopy at room temperature in ambient atmosphere. The pristine individual C(60) nanowhiskers exhibit conducting behavior. The outer C(60) oxide covering, confirmed by Auger electron spectroscopy, shelters the conductive properties of the C(60) nanowhiskers. It is proposed that the insulating outer C(60) oxide covering might be used as the dielectric layer in potential single C(60) nanowhisker-based field-effect transistors for nanoelectronics. PMID- 21817661 TI - Geometry dependence of coercivity in Ni nanowire arrays. AB - Magnetic properties of arrays of nanowires produced inside the pores of anodic alumina membranes have been studied by means of vibrating sample magnetometer techniques. In these systems the length of the wires strongly influences the coercivity of the array. A simple model for the coercivity as a function of the geometry is presented which exhibits good agreement with experimental results. Magnetostatic interactions between the wires are responsible for a decrease of the coercive field. PMID- 21817662 TI - A novel nanoscale catalyst system composed of nanosized Pd catalysts immobilized on Fe(3)O(4)@SiO(2)-PAMAM. AB - This study reports the syntheses of Fe(3)O(4)@SiO(2)-Gn-PAMAM-Pd(0) composites and their applications as magnetically recoverable catalysts for the hydrogenation of allyl alcohol. The controlled growth of polyamidoamine (PAMAM) dendrimers with different generations on Fe(3)O(4)@SiO(2) surfaces was monitored by FT-IR spectra. Subsequently, Pd nanoparticles with diameters of about 2.5 nm were stabilized homogeneously on the surface of Fe(3)O(4)@SiO(2)-Gn-PAMAM (n = 1 4), investigated by thermogravimetry (TG) and transmission electron microscopy (TEM) measurements. The Fe(3)O(4)@SiO(2)-Gn-PAMAM-Pd(0) have high catalytic activity for the hydrogenation of allyl alcohol and the rate of the reaction can be controlled by changing the generation of PAMAM. In particular, the composites made of superparamagnetic Fe(3)O(4) nanocrystals with diameters of about 10 nm are very suitable as catalyst supports for catalyst separation under a relatively low external magnetic field and catalyst re-dispersion after removing the external magnetic field. PMID- 21817663 TI - Photoacoustic tomography of joints aided by an Etanercept-conjugated gold nanoparticle contrast agent-an ex vivo preliminary rat study. AB - Monitoring of anti-rheumatic drug delivery in experimental models and in human diseases would undoubtedly be very helpful for both basic research and clinical management of inflammatory diseases. In this study, we have investigated the potential of an emerging hybrid imaging technology-photoacoustic tomography-in noninvasive monitoring of anti-TNF drug delivery. After the contrast agent composed of gold nanorods conjugated with Etanercept molecules was produced, ELISA experiments were performed to prove the conjugation and to show that the conjugated anti-TNF-alpha drug was biologically active. PAT of ex vivo rat tail joints with the joint connective tissue enhanced by intra-articularly injected contrast agent was conducted to examine the performance of PAT in visualizing the distribution of the gold-nanorod-conjugated drug in articular tissues. By using the described system, gold nanorods with a concentration down to 1 pM in phantoms or 10 pM in biological tissues can be imaged with good signal-to-noise ratio and high spatial resolution. This study demonstrates the feasibility of conjugating TNF antagonist pharmaceutical preparations with gold nanorods, preservation of the mechanism of action of TNF antagonist along with preliminary evaluation of novel PAT technology in imaging optical contrast agents conjugated with anti rheumatic drugs. Further in vivo studies on animals are warranted to test the specific binding between such conjugates and targeted antigen in joint tissues affected by inflammation. PMID- 21817664 TI - The structure and function of ribonuclease A upon interacting with carbon nanotubes. AB - Ribonucleic acid (RNA) is an important genetic material whose lifetime is most often determined by the rate of its enzymatic degradation. Our studies showed that multi-walled carbon nanotubes and single-walled carbon nanotubes functionalized with carboxylic groups interacted with ribonuclease A (RNase A) and caused the reduction of its activity by changing its conformation, thus protecting RNA from enzymatic cleavage. The results showed that RNase A was less active on the carbon nanotube surface than in free solution, and the activity was decreased further on larger carbon nanotubes, suggesting that carbon nanotubes with various surface modifications may be useful in RNA extraction, purification, and manipulation. PMID- 21817665 TI - Surface stress influences on nanopatterns formed in polystyrene films using a force-modulated nanohammer. AB - Two-dimensional lattices of nanodots can be reproducibly produced on polymer surfaces by a biaxial stress field generated using a force-modulated atomic force microscope tip as a nanohammer. Molecular sized super-lattice nanostructures were previously formed by a combination of fundamental and harmonic modulation of surface stress waves in different scanning directions. We find that similar super lattice structures can be formed in polystyrene films using only fundamental force modulation by taking advantage of elastic interactions between nearby nanoridges. Influences of the initial nanoridge size and the molecular weight of polystyrene on the formation of simple lattice patterns and complex nanometer scale super-lattice patterns were studied. PMID- 21817666 TI - Light-emitting nanocasts formed from bio-templates: FESEM and cathodoluminescent imaging studies of butterfly scale replicas. AB - Nanocasts comprising of red-light-emitting cubic Y(2)O(3):Eu phosphors were made from butterfly wing scale bio-templates. We report herein the first cathodoluminescent images made from such nanocasts and show that valuable insights into the nature of the internal structure of the casts can be gained by the use of this technique. The casts faithfully reproduced the fine sub micrometre size detail of the scales, as was made evident by both FESEM and cathodoluminescent images that were collected from the same sample areas using a hyphenated FESEM-CL instrument. There was excellent agreement between the FESEM and cathodoluminescent images, the image quality of the latter indicating that the Eu(3+) activator ions were evenly dispersed in the Y(2)O(3):Eu phosphor on a sub-micrometre scale. The casts were made by infilling the natural moulds with a Y(2)O(3):Eu precursor solution that was subsequently dried and fired to convert it into the phosphor material. This method provides a simple, low cost route for fabricating nanostructures having feature dimensions as small as 20 nm in size, and it has the potential to be applied to other metal oxide systems for producing nano-and micro-components for electronic, magnetic or photonic integrated systems. PMID- 21817667 TI - Massive assembly of ZnO nanowire-based integrated devices. AB - Although a directed assembly strategy has been utilized for the massive assembly of various nanowires and nanotubes (NWs/NTs), its application has usually been limited to rather small-diameter NWs/NTs prepared in solution. We report two complementary methods for the massive assembly of large-size ZnO nanowires (NWs). In the solution-phase method, ZnO NWs were assembled and aligned selectively onto negatively charged surface patterns in solution. In addition, the substrate bias voltage and capillary forces can be used to further enhance the adsorption rate and degree of alignment of ZnO NWs, respectively. In the direct-transfer method, a NW film grown on a solid substrate was placed in close proximity to a molecule patterned substrate, and ultrasonic vibration was applied so that the NWs were directly transferred and aligned onto the patterned substrate. The solution-phase and direct-transfer methods are complementary to each other and suitable for the assembly of NWs prepared in solution and on solid substrates, respectively. PMID- 21817668 TI - DNAzyme-based colorimetric sensing of lead (Pb(2+)) using unmodified gold nanoparticle probes. AB - Novel functional oligonucleotides, especially DNAzymes with RNA-cleavage activity, have been intensively studied due to their potential applications in therapeutics and sensors. Taking advantage of the high specificity of 17E DNAzyme for Pb(2+), highly sensitive and selective fluorescent, electrochemical and colorimetric sensors have been developed for Pb(2+). In this work, we report a simple, sensitive and label-free 17E DNAzyme-based sensor for Pb(2+) detection using unmodified gold nanoparticles (GNPs) based on the fact that unfolded single stranded DNA could be adsorbed on the citrate protected GNPs while double stranded DNA could not. By our method the substrate cleavage by the 17E DNAzyme in the presence of Pb(2+) could be monitored by color change of GNPs, thereby Pb(2+) detection was realized. The detection of Pb(2+) could be realized within 20 min, with a detection limit of 500 nM. The selectivity of our sensor has been investigated by challenging the sensing system with other divalent metal ions. Since common steps such as modification and separation could be successfully avoided, the sensor developed here could provide a simple, cost-effective yet rapid and sensitive measurement tool for Pb(2+) detection and may prove useful in the development of sensors for clinical toxicology and environmental monitoring in the future. PMID- 21817669 TI - Detection of neurotransmitters by a light scattering technique based on seed mediated growth of gold nanoparticles. AB - A simple light scattering detection method for neurotransmitters has been developed, based on the growth of gold nanoparticles. Neurotransmitters (dopamine, L-dopa, noradrenaline and adrenaline) can effectively function as active reducing agents for generating gold nanoparticles, which result in enhanced light scattering signals. The strong light scattering of gold nanoparticles then allows the quantitative detection of the neurotransmitters simply by using a common spectrofluorometer. In particular, Au-nanoparticle seeds were added to facilitate the growth of nanoparticles, which was found to enhance the sensing performance greatly. Using this light scattering technique based on the seed-mediated growth of gold nanoparticles, detection limits of 4.4 * 10(-7) M, 3.5 * 10(-7) M, 4.1 * 10(-7) M, and 7.7 * 10(-7) M were achieved for dopamine, L-dopa, noradrenaline and adrenaline, respectively. The present strategy can be extended to detect other biologically important molecules in a very fast, simple and sensitive way, and may have potential applications in a wide range of fields. PMID- 21817670 TI - The design of evanescent-field-coupled waveguide-mode sensors. AB - An evanescent-field-coupled waveguide-mode sensor with a multilayer structure consisting of a dielectric waveguide, a thin reflecting layer, and a glass substrate illuminated under the Kretschmann configuration operates as a sensor that is capable of detecting modifications in the dielectric environment near the waveguide surface with superior sensitivity by measuring the change in reflectivity. The sensitivity of the sensor is strongly dependent on the optical constants of the reflecting layer. Numerical simulations show that a sensor having a reflecting layer with a small value of the real part of the complex refractive index shows a good sensitivity for both S- and P-polarized light. Materials with values of the real and imaginary parts of the complex refractive index of >4 and ~0.5, respectively, are suitable for use as reflecting layers when S-polarized light excites only the lowest order waveguide mode. The simulations were experimentally confirmed using sensors with Au, Cu, Cr, W, a-Si, or Ge reflecting layers deposited by radiofrequency magnetron sputtering by observation of specific adsorption of streptavidin on biotinyl groups using an S polarized laser beam with a wavelength of 632.8 nm. From the results, guidelines are given for the fabrication of preferred sensor configurations. PMID- 21817671 TI - Nanopillar arrays on semiconductor membranes as electron emission amplifiers. AB - A new transmission-type electron multiplier was fabricated from silicon-on insulator (SOI) material by integrating an array of one-dimensional (1D) silicon nanopillars onto a two-dimensional (2D) silicon membrane. Primary electrons are injected into the nanopillar-membrane (NPM) system from the flat surface of the membrane, while electron emission from the nanopillars is probed by an anode. The secondary electron yield (SEY) from the nanopillars in the current device is found to be about 1.8 times that of the plain silicon membrane. This gain in electron number is slightly enhanced by the electric field applied from the anode. Further optimization of the dimensions of the NPM and an application of field emission promise an even higher gain for detector applications and allow for probing of electronic/mechanical excitations in an NPM system stimulated by incident particles or radiation. PMID- 21817672 TI - A ZnO nanowire vacuum pressure sensor. AB - In this study, we report the growth and characterization of lateral ZnO nanowires (NWs) on ZnO:Ga/glass templates. Using x-ray diffraction and micro-Raman spectroscopy, it was found that crystal quality of the as-grown ZnO NWs is good. It was also found that the average length and average diameter of the laterally grown ZnO NWs were 5 um and 30 nm, respectively. A vacuum pressure sensor was then fabricated using a single NW bridging across two electrodes. By measuring the current-voltage characteristics of the samples at low pressure, we found that the currents were of 17, 34.28, 57.37 and 96.06 nA for the ZnO NW measured at 1 * 10(-3) Torr, 1 * 10(-4) Torr, 3 * 10(-5) Torr and 5 * 10(-6) Torr, respectively. These values suggest that the laterally grown ZnO NWs prepared in this study are potentially useful for vacuum pressure sensing. PMID- 21817673 TI - A high sensitivity gas sensor for formaldehyde based on CdO and In(2)O(3) doped nanocrystalline SnO(2). AB - The gas-sensing characteristics of In(2)O(3) and CdO doped nanocrystalline SnO(2) compounds for formaldehyde were investigated in this study. The phases of the resulting materials and the morphologies of the sensing layers were characterized by x-ray diffraction (XRD) and scanning electron microscopy (SEM), respectively. Indirect-heating sensors using SnO(2)-In(2)O(3)-CdO compounds as sensitive materials were fabricated on an alumina tube with Au electrodes and platinum wires. All measurements were performed at several operating temperatures from 100 to 180 degrees C. Good gas-sensing responses to formaldehyde have been found for all the prepared samples. It is shown that the sensors exhibited high sensitivity at low operating temperature (133 degrees C), making them promising candidates for practical detectors for formaldehyde. PMID- 21817674 TI - Desorption kinetics of oxygen in plasma treated SWNTs by in situ thermoelectric power measurements. AB - The functionalization and defect formation of SWNTs caused by isotropic plasma treatments were studied using oxygen desorption/adsorption kinetics by measuring the time dependence of the in situ thermoelectric power (TEP). It is shown that the plasma treatments result in the formation of low binding energy sites for oxygen adsorption. Raman and x-ray photoelectron spectroscopy (XPS) data are in good agreement with the results. PMID- 21817675 TI - Novel fabrication of an SnO(2) nanowire gas sensor with high sensitivity. AB - We fabricated a nanowire-based gas sensor using a simple method of growing SnO(2) nanowires bridging the gap between two pre-patterned Au catalysts, in which the electrical contacts to the nanowires are self-assembled during the synthesis of the nanowires. The gas sensing capability of this network-structured gas sensor was demonstrated using a diluted NO(2). The sensitivity, as a function of temperature, was highest at 200 degrees C and was determined to be 18 and 180 when the NO(2) concentration was 0.5 and 5 ppm, respectively. Our sensor showed higher sensitivity compared to different types of sensors including SnO(2) powder based thin films, SnO(2) coating on carbon nanotubes or single/multiple SnO(2) nanobelts. The enhanced sensitivity was attributed to the additional modulation of the sensor resistance due to the potential barrier at nanowire/nanowire junctions as well as the surface depletion region of each nanowire. PMID- 21817676 TI - Fullerene-like WS(2) nanoparticles and nanotubes by the vapor-phase synthesis of WCl(n) and H(2)S. AB - Inorganic fullerene-like (IF) nanoparticles and nanotubes of WS(2) were synthesized by a gas phase reaction starting from WCl(n) (n = 4, 5, 6) and H(2)S. The effect of the various metal chloride precursors on the formation of the products was investigated during the course of the study. Various parameters have been studied to understand the growth and formation of the IF-WS(2) nanoparticles and nanotubes. The parameters that have been studied include flow rates of the various carrier gases, heating of the precursor metal chlorides and the temperature at which the reactions were carried out. The best set of conditions wherein maximum yields of the high quality pure-phase IF-WS(2) nanoparticles and nanotubes are obtained have been identified. A detailed growth mechanism has been outlined to understand the course of formation of the various products of WS(2). PMID- 21817677 TI - One-step solid state synthesis of capped gamma-Fe(2)O(3) nanocrystallites. AB - The thermally induced solid state synthesis of soluble organophilic maghemite (gamma-Fe(2)O(3)) nanocrystallites is described. The solvent-free one-step synthesis involves the reaction in the melt state of Fe(NO)(3).9H(2)O and RCOOH (R = C(11)H(23), C(15)H(31)) at 240 degrees C. The method yields well crystallized nanoparticles of gamma-Fe(2)O(3) functionalized with the corresponding aliphatic acid. Transmission electron microscopy (TEM) and atomic force microscopy (AFM) observations reveal composite particles with faceted magnetic cores and average size of 20 nm, which are well capped with the surrounding organic sheath. The Fourier transform infrared (FT-IR) spectra and thermal analysis suggest a bimodal configuration of the organic shell including chemically coordinated and physisorbed molecules of aliphatic acid. The chemical bonding of the carboxylate groups to the surface iron atoms is also indicated by a paramagnetic doublet with unchanged area in the variable temperature Mossbauer spectra. The spinel gamma-Fe(2)O(3) particles exhibit perfect structural and magnetic ordering, including the almost ideal ratio of octahedral to tetrahedral positions (5/3) and very low degree of spin canting, as confirmed by in-field Mossbauer spectroscopy. Magnetic measurements demonstrate the suitable properties required in various (bio)magnetic applications like superparamagnetic behavior at room temperature, high saturation magnetization achievable at low applied fields and suppressed magnetic interactions. PMID- 21817678 TI - Direct spectroscopic evidence of energy transfer from photo-excited semiconducting polymers to single-walled carbon nanotubes. AB - Single-walled carbon nanotubes have been efficiently dispersed in an organic solvent using the semiconducting polymers MEHPPV and PFO. It has been found that energy is transferred to the carbon nanotubes when the polymer is photo-excited across its minimum energy gap. This is shown using photoluminescence excitation mapping in the range of both the polymer's and the nanotube's optical absorbance. Possible mechanisms for the energy transfer are discussed. PMID- 21817679 TI - Growth mechanism of titanium dioxide nanowires for dye-sensitized solar cells. AB - Mesoporous films made of titanium dioxide nanowires are desirable for dye sensitized solar cells because nanowires provide direct conduction pathways for photogenerated electrons. Anatase titanium dioxide nanowires with polycrystalline microstructure were synthesized on titanium foil using a three-step process. First, the top surface of the titanium foil was transformed to Na(2)Ti(2)O(4)(OH)(2) nanotubes through hydrothermal oxidation in NaOH. Next, the Na(2)Ti(2)O(4)(OH)(2) nanotubes were converted to H(2)Ti(2)O(4)(OH)(2) nanotubes by ion exchange. Finally, the H(2)Ti(2)O(4)(OH)(2) nanotubes were converted to polycrystalline anatase nanowires through a topotactic transformation. The film morphology evolution, crystal structure transformations and growth mechanism are described in detail. Titanium foil reacts with NaOH to form Na(2)Ti(2)O(4)(OH)(2) sheets, which exfoliate and spiral into nanotubes. The Na(2)Ti(2)O(4)(OH)(2) nanotubes are immersed in HCl solution to replace the Na(+) ions with H(+) ions. During the topotactic transformation of H(2)Ti(2)O(4)(OH)(2) nanotubes to anatase TiO(2) nanowires, the sheets made of edge bonded TiO(6) octahedra in the H(2)Ti(2)O(4)(OH)(2) nanotubes dehydrate and move towards each other to form anatase crystals oriented along the nanotube axis which creates a polycrystalline nanowire. These mesoporous TiO(2) nanowire films were suitable for use as dye sensitized solar cell photoanodes. PMID- 21817680 TI - The fabrication of subwavelength anti-reflective nanostructures using a bio template. AB - This paper describes a paradigm, a simple, low-cost and conventional approach to the fabrication of large-area subwavelength anti-reflective nanostructures on films directly with a bio-template. Specifically, the nano-nipple arrays on the surface of cicada wings have been precisely replicated to a PMMA (polymethyl methacrylate) film with high reproducibility by a technique of replica molding, which mainly involves two processes: one is that a negative Au mold is prepared directly from the bio-template of the cicada wing by thermal deposition; the other is that the Au mold is used to obtain the replica of the nanostructures on the original cicada wing by casting polymer. The reflectance spectra measurement shows that the replicated PMMA film can considerably reduce reflectivity at its surface over a large wavelength range from 250 to 800 nm, indicating that the anti-reflective property has also been inherited by the PMMA film. PMID- 21817681 TI - Synthesis and performance of novel magnetically separable nanospheres of titanium dioxide photocatalyst with egg-like structure. AB - A magnetically separable photocatalyst TiO(2)/SiO(2)/NiFe(2)O(4) (TSN) nanosphere with egg-like structure was prepared by a unique process that combined a liquid catalytic phase transformation method, reverse micelle technique and chemical precipitation means. The prepared photocatalyst shows high photocatalytic activity for the degradation of methyl orange in water. The magnetic property measurements indicate that the photocatalyst possesses a superparamagnetic nature. It can be separated from water when an external magnetic field is added and redispersed into water solution after the external magnetic field is eliminated. It is one of the promising photocatalysts for wastewater treatment. A transmission electron microscope (TEM) and an x-ray diffractometer (XRD) were used to characterize the structure of the TSN photocatalyst. The results indicate that nickel ferrite core nanoparticles were completely encapsulated into monodisperse silica nanospheres as carrier, and titania nanoparticle aggregates were coated onto the surface of SN nanospheres, forming an imperfect TiO(2) shell for photocatalysis. The SiO(2) layer between the NiFe(2)O(4) core and the TiO(2) shell effectively prevents the injection of charges from TiO(2) particles to NiFe(2)O(4), which gives rise to an increase in photocatalytic activity. Moreover, the recycled TSN exhibits good repeatability of the photocatalytic activity. PMID- 21817682 TI - Growth of CNTs on Fe-Si catalyst prepared on Si and Al coated Si substrates. AB - In this paper we report the effect of Al interlayers on the growth characteristics of carbon nanotubes (CNTs) using as-deposited and plasma etched Fe-Si catalyst films as the catalysts. Al interlayers having various thicknesses ranging from 2 to 42 nm were deposited on Si substrates prior to the deposition of Fe-Si catalysts. It was found that the Al interlayer diffuses into the Fe-Si catalyst during the plasma etching prior to the CNT growth, leading to the swelling and amorphization of the catalyst. This allows enhanced carbon diffusion in the catalyst and therefore a faster growth rate of the resulting CNTs. It was also found that use of an Al interlayer having a thickness of ~3 +/- 1 nm is most effective. Due to the effectiveness of this, the normally required catalyst etching is no longer needed for the growth of CNTs. PMID- 21817683 TI - The effect of cetyl palmitate crystallinity on physical properties of gamma oryzanol encapsulated in solid lipid nanoparticles. AB - This present study was aimed at investigating the effect of the crystallinity of cetyl palmitate based solid lipid nanoparticles (SLNs) on the physical properties of gamma-oryzanol-loaded SLNs. SLNs consisting of varying ratios of cetyl palmitate and gamma-oryzanol were prepared. Their hydrodynamic diameters were in the range 210-280 nm and the zeta potentials were in the range -27 to -35 mV. The size of SLNs increased as the amount of cetyl palmitate decreased whereas no significant change of zeta potentials was found. Atomic force microscopy pictures indicated the presence of disc-like particles. The crystallinity of SLNs, determined by differential scanning calorimetry and powder x-ray diffraction, was directly dependent on the ratio of cetyl palmitate to gamma-oryzanol and decreased with decreasing cetyl palmitate content in the lipid matrix. Varying this ratio in the lipid mix resulted in a shift in the melting temperature and enthalpy, although the SLN structure remained unchanged as an orthorhombic lamellar lattice. This has been attributed to a potential inhibition by gamma oryzanol during lipid crystal growth as well as a less ordered structure of the SLNs. The results revealed that the crystallinity of the SLNs was mainly dependent on the solid lipid, and that the crystallinity has an important impact on the physical characteristics of active-loaded SLNs. PMID- 21817684 TI - Inkjet printing of single-walled carbon nanotubes and electrical characterization of the line pattern. AB - Single-walled carbon nanotubes (SWCNTs) were patterned using inkjet printing. To make the uniform networks of dropped SWCNTs, the effects of substrate heating, surface hydrophilicity of the substrate and the jetting process were investigated. Circuit diagrams including holes, lines and curves were printed on glass and polymer substrates, and the conductive lines were printed on a glass substrate to characterize their electrical properties by I-V curve and impedance measurements. Lines 75 mm long were printed along with the number of overwrites with 150 um linewidth and width change with five overwrites. As for the results, we confirmed that the dc resistance of the SWCNT line was proportionally changed according to the linewidth and the number of overwrites, and the line feature possessed ohmic characteristics to 2 MHz even after two overwrites. PMID- 21817685 TI - High resolution magnetic force microscopy of patterned L1(0)-FePt dot arrays by nanosphere lithography. AB - High resolution magnetic force microscopy (MFM) has been carried out on L1(0) FePt dot arrays patterned by plasma modified nanosphere lithography. An ex situ tip magnetization reversal experiment is carried out to determine the magnetic domains and verify the imaging stability of MFM and the mutual perturbations between the magnetic tip and the sample. We have identified that the critical size for the single domain region is about 90 nm across. Comparison with MFM image simulation also suggests that the magnetizations of the triangular dots in both single and double domain states are parallel to one edge of the dots, indicating the large uniaxial magnetocrystalline anisotropy of the L1(0)-FePt phase and the need for decreasing the magnetostatic energy. PMID- 21817686 TI - Pressure-induced transition-temperature reduction in ZnS nanoparticles. AB - The study of the structural transition in nanoscale materials is of particular interest for their potential applications. In the present study, we have observed a lower temperature T = 250 degrees C for the phase transition from the sphalerite structure to the wurtzite structure in ZnS nanoparticles under a pressure of 1 GPa, as compared to those, T = 400 and 1020 degrees C, for ZnS nanoparticles and bulk ZnS under normal pressure, respectively. The reduced transition temperature is attributed to the applied pressure leading to tight particle-particle contacts, which change the surface (or interfacial) environment of the nanoparticles and thus their surface (or interfacial) energy. PMID- 21817687 TI - Fabrication of a multi-scale nanostructure of TiO(2) for application in dye sensitized solar cells. AB - We propose a highly ordered multi-scale nanostructure of TiO(2) for applications as an anode in dye-sensitized solar cells (DSSCs). The structure is composed of a TiO(2) blocking layer, a TiO(2) inverse opal main body, regularly arranged transport channels between contacting spherical voids of the TiO(2) inverse opal, and TiO(2) nanoparticles coated on the spherical surfaces of the voids. The ordered and continuous backbone of the inverse opal serves as the fast electron transport pathways while the regularly arranged transport channels enable easy transport of dye and electrolyte within the structure. A multi-cycle procedure was developed to enable fabrication of thick inverse opals and easy adjustment of the inverse opal thickness. An example structure was constructed, involving a blocking layer of 90 nm thickness, an inverse opal of 100 nm voids, transport channels of 30-50 nm openings, and nanoparticles 10-15 nm in size. An open circuit voltage decay investigation showed a significant improvement in electron lifetime for the proposed multi-scale TiO(2) nanostructure based DSSC than that of a TiO(2) nanoparticle film based DSSC, revealing the superior electron recombination characteristic offered by the proposed TiO(2) nanostructure. The conversion efficiency of the DSSC assembled from such an anode structure can reach 4% with a short-circuit current density (J(sc)) of 8.7 mA cm(-2) and open circuit potential (V(oc)) of 0.76 V under AM 1.5 (100 mW cm(-2)) illumination. PMID- 21817688 TI - A study on adsorption of acetonitrile on gold nanorods by non-resonant Raman measurements and density functional theory calculations. AB - Adsorption of acetonitrile (Ac) molecules on gold (Au) nanorods has been investigated by Raman spectroscopic measurements and density functional theory (DFT) calculations. DFT calculations provide a valuable insight into the underlying structure of the metal-molecule complex. From the best agreement between the observed and the calculated Raman frequencies and also from other spectroscopic observations, we propose that Ac molecules interact with Au nanorods and form an [Ac+2Au](0)-like complex on the surface of nanostructures. The environmental effect has also been taken into consideration to explain the Raman activity of the complex. PMID- 21817689 TI - Boron nitride and carbon double-wall hetero-nanotubes: first-principles calculation of electronic properties. AB - First-principles calculations based on density functional theory with the generalized gradient approximation were carried out to investigate the electronic properties of boron nitride and carbon double-wall hetero-nanotubes of different chirality and size. The results show that the electronic structures of the double wall hetero-nanotubes near the Fermi level are dominated by the p electrons of carbon atoms, regardless of whether the carbon nanotube is inside or outside the boron nitride nanotube. Double-wall hetero-nanotubes consisting of semiconducting carbon and boron nitride nanotubes are semiconductors. An opening of a band gap is observed for armchair carbon and boron nitride double-wall hetero-nanotubes with small intertube spacing due to the intertube interaction and the changes of symmetry. PMID- 21817690 TI - Synthesis and optical properties of SnO(2) nanorods. AB - Well-crystalline SnO(2) nanorods have been synthesized successfully via a lithium assisted solution-phase method. The structural and optical properties of the SnO(2) nanorods were investigated using x-ray powder diffraction, transmission electron microscopy, high-resolution transmission electron microscopy, and infrared, Raman and photoluminescence spectroscopy. The experimental results show that lithium addition plays a critical role in the formation of SnO(2) nanorods, and the correlation between the surface energy change and morphological evolution of this material is also discussed. This approach provides an economically viable route for large-scale synthesis of this nanostructured material. PMID- 21817691 TI - Preparation and luminescence of nano-sized In(2)O(3) and rare-earth co-doped SiO(2) thin films. AB - The sol-gel method was used to prepare SiO(2) thin films co-doped with In(2)O(3) nano-particles and Eu(3+). The formation of nano-sized In(2)O(3) particles after annealing at 900 degrees C was confirmed by the x-ray diffraction technique. A novel phase transition from a hexagonal rhombic centered to a body centered cubic structure of In(2)O(3) nano-particles was observed at around 1100 degrees C. It is found that the particle size and the particle density of In(2)O(3) can be tuned by changing the annealing temperature and the indium doping concentration, respectively. The characteristic emission bands from Eu(3+) ions can be observed at room temperature and the luminescence intensity is increased 20 times by introducing In(2)O(3) nano-particles into Eu(3+)-doped silica films. The integrated luminescence intensity was gradually enhanced by increasing the In(3+) concentration, suggesting effective energy transfer from nano-sized In(2)O(3) to Eu(3+) ions. PMID- 21817692 TI - The effects of functional magnetic nanotubes with incorporated nerve growth factor in neuronal differentiation of PC12 cells. AB - In this in vitro study the efficiency of magnetic nanotubes to bind with nerve growth factor (NGF) and the ability of NGF-incorporated magnetic nanotubes to release the bound NGF are investigated using rat pheochromocytoma cells (PC12 cells). It is found that functional magnetic nanotubes with NGF incorporation enabled the differentiation of PC12 cells into neurons exhibiting growth cones and neurite outgrowth. Microscope observations show that filopodia extending from neuron growth cones were in close proximity to the NGF-incorporated magnetic nanotubes, at times appearing to extend towards or into them. These results show that magnetic nanotubes can be used as a delivery vehicle for NGF and thus may be exploited in attempts to treat neurodegenerative disorders such as Parkinson's disease with neurotrophins. Further neurite outgrowth can be controlled by manipulating magnetic nanotubes with external magnetic fields, thus helping in directed regeneration. PMID- 21817693 TI - Carbon nanotube based photocathodes. AB - This paper describes a novel photocathode which is an array of vertically aligned multi-walled carbon nanotubes (MWCNTs), each MWCNT being associated with one p-i n photodiode. Unlike conventional photocathodes, the functions of photon-electron conversion and subsequent electron emission are physically separated. Photon electron conversion is achieved with p-i-n photodiodes and the electron emission occurs from the MWCNTs. The current modulation is highly efficient as it uses an optically controlled reconfiguration of the electric field at the MWCNT locations. Such devices are compatible with high frequency and very large bandwidth operation and could lead to their application in compact, light and efficient microwave amplifiers for satellite telecommunication. To demonstrate this new photocathode concept, we have fabricated the first carbon nanotube based photocathode using silicon p-i-n photodiodes and MWCNT bunches. Using a green laser, this photocathode delivers 0.5 mA with an internal quantum efficiency of 10% and an I(ON)/I(OFF) ratio of 30. PMID- 21817694 TI - Fabrication of Cd(3)As(2) nanowires by direct vapor-solid growth, and their infrared absorption properties. AB - In this work the authors introduce and provide details of the synthesis and spectral characterization of single-crystal nanowires in less common, high performance, group II-V semiconductors such as Cd(3)As(2). The growth mechanism critically deviates from a known vapor-liquid-solid one by being completely non catalytic and involving only two states: vapor and solid. The resultant nanowires range from ~50 to 200 nm in diameter and reach lengths up to tens of micrometers, with their fast growth direction being normal to the (112) crystal planes. According to infrared (IR) optical absorption measurements, the nanowires have several IR active direct type light absorption transitions at 0.11, 0.28 and 0.54 eV, suggestive of their possible utility in low cost optoelectronic devices and photodetectors operating in the long wavelength range of the electromagnetic spectrum. PMID- 21817695 TI - Durable diamond-like carbon templates for UV nanoimprint lithography. AB - The interaction between resist and template during the separation process after nanoimprint lithography (NIL) can cause the formation of defects and damage to the templates and resist patterns. To alleviate these problems, fluorinated self assembled monolayers (F-SAMs, i.e. tridecafluoro-1,1,2,2,tetrahydrooctyl trichlorosilane or FDTS) have been employed as template release coatings. However, we find that the FDTS coating undergoes irreversible degradation after only 10 cycles of UV nanoimprint processes with SU-8 resist. The degradation includes a 28% reduction in surface F atoms and significant increases in the surface roughness. In this paper, diamond-like carbon (DLC) films were investigated as an alternative material not only for coating but also for direct fabrication of nanoimprint templates. DLC films deposited on quartz templates in a plasma enhanced chemical vapor deposition system are shown to have better chemical and physical stability than FDTS. After the same 10 cycles of UV nanoimprints, the surface composition as well as the roughness of DLC films were found to be unchanged. The adhesion energy between the DLC surface and SU-8 is found to be smaller than that of FDTS despite the slightly higher total surface energy of DLC. DLC templates with 40 nm features were fabricated using e-beam lithography followed by Cr lift-off and reactive ion etching. UV nanoimprinting using the directly patterned DLC templates in SU-8 resist demonstrates good pattern transfer fidelity and easy template-resist separation. These results indicate that DLC is a promising material for fabricating durable templates for UV nanoimprint lithography. PMID- 21817696 TI - Growth of a single-wall carbon nanotube film and its patterning as an n-type field effect transistor device using an integrated circuit compatible process. AB - This study presents the synthesis of a dense single-wall carbon nanotube (SWNT) network on a silicon substrate using alcohol as the source gas. The nanosize catalysts required are made by the reduction of metal compounds in ethanol. The key point in spreading the nanoparticles on the substrate, so that the SWNT network can be grown over the entire wafer, is making the substrate surface hydrophilic. This SWNT network is so dense that it can be treated like a thin film. Methods of patterning this SWNT film with integrated circuit compatible processes are presented and discussed for the first time in the literature. Finally, fabrication and characteristic measurements of a field effect transistor (FET) using this SWNT film are also demonstrated. This FET is shown to have better electronic properties than any other kind of thin film transistor. This thin film with good electronic properties can be readily applied in the processing of many other SWNT electronic devices. PMID- 21817697 TI - Solvent-mediated repair and patterning of surfaces by AFM. AB - A tip-based approach to shaping surfaces of soluble materials with nanometer scale control is reported. The proposed method can be used, for example, to eliminate defects and inhomogeneities in surface shape, repair mechanical or laser induced damage to surfaces, or perform 3D lithography on the length scale of an AFM tip. The phenomenon that enables smoothing and repair of surfaces is based on the transport of material from regions of high to low curvature within the solution meniscus formed in a solvent-containing atmosphere between the surface in question and an AFM tip scanned over the surface. Using in situ AFM measurements of the kinetics of surface remodeling on KDP (KH(2)PO(4)) crystals in humid air, we show that redistribution of solute material during relaxation of grooves and mounds is driven by a reduction in surface free energy as described by the Gibbs-Thomson law. We find that the perturbation from a flat interface evolves according to the diffusion equation, where the effective diffusivity is determined by the product of the surface stiffness and the step kinetic coefficient. We also show that, surprisingly, if the tip is instead scanned over or kept stationary above an atomically flat area of the surface, a convex structure is formed, with a diameter that is controlled by the dimensions of the meniscus, indicating that the presence of the tip and meniscus reduces the substrate chemical potential beneath that of the free surface. This allows one to create nanometer-scale 3D structures of arbitrary shape without the removal of substrate material or the use of extrinsic masks or chemical compounds. Potential applications of these tip-based phenomena are discussed. PMID- 21817698 TI - Fabrication of one-dimensional devices by a combination of AC dielectrophoresis and electrochemical deposition. AB - We demonstrate a hybrid process for fabricating one-dimensional wire devices. The process is a combination of an alignment procedure using dielectrophoresis and subsequent contact metal formation utilizing electrochemical deposition with non toxic organic-based Au electrolytes. Several devices have been successfully made from GaN nanowires or multi-walled carbon nanotubes (MWCNTs) using our hybrid technique. We demonstrate that rapid thermal annealing improves the ohmic characteristics by five orders of magnitude in the case of the GaN devices and ~300% in the case of the MWCNT devices. One of the reasons for this improvement is enhanced gold wetting due to the reduction of grain size at the annealing temperature. PMID- 21817699 TI - An energy conservation approach to adsorbate-induced surface stress and the extraction of binding energy using nanomechanics. AB - Surface stress induced by molecular adsorption in three different binding processes has been studied experimentally using a microcantilever sensor. A comprehensive free-energy analysis based on an energy conservation approach is proposed to explain the experimental observations. We show that when guest molecules bind to atoms/molecules on a microcantilever surface, the released binding energy is retained in the host surface, leading to a metastable state where the excess energy on the surface is manifested as an increase in surface stress leading to the bending of the microcantilever. The released binding energy appears to be almost exclusively channeled to the surface energy, and energy distribution to other channels, including heat, appears to be inactive for this micromechanical system. When this excess surface energy is released, the microcantilever relaxes back to the original state, and the relaxation time depends on the particular binding process involved. Such vapor phase experiments were conducted for three binding processes: physisorption, hydrogen bonding, and chemisorption. Binding energies for these three processes were also estimated. PMID- 21817700 TI - Tracking nanoparticles in an optical microscope using caustics. AB - An elegant method is proposed and demonstrated for tracking the location and movement of nanoparticles in an optical microscope using the optical phenomenon of caustics. A simple and reversible adjustment to the microscope generates caustics several orders of magnitude larger than the particles. The method offers a simple and relatively inexpensive method for visualizing such phenomena as the formation of self-assembled monolayers and the interaction of nanoparticles with chemically functionalized surfaces. PMID- 21817701 TI - An approach to fabricating chemical sensors based on ZnO nanorod arrays. AB - Vertically and laterally aligned ZnO nanorod arrays were synthesized on Pt-coated Si substrates by catalyst-free metal organic chemical vapor deposition. An approach to fabricating chemical sensors based on the nanorod arrays using a coating-and-etching process with a photo-resist is reported. Tests of the devices as oxygen gas sensors have been performed. Our results demonstrate that the approach holds promise for the realization of sensitive and reliable nanorod array chemical sensors. PMID- 21817702 TI - Long term storage of virus templated fluorescent materials for sensing applications. AB - Wild type, mutant, and chemically modified Cowpea mosaic viruses (CPMV) were studied for long term preservation in the presence and absence of cryoprotectants. Viral complexes were reconstituted and tested via fluorescence spectroscopy and a UV/vis-based RNase assay for structural integrity. When viruses lyophilized in the absence of cryoprotectant were rehydrated and RNase treated, UV absorption increased, indicating that the capsids were damaged. The addition of trehalose during lyophilization protected capsid integrity for at least 7 weeks. Measurements of the fluorescence peak maximum of CPMV lyophilized with trehalose and reconstituted also indicate that the virus remained intact. Microarray binding assays indicated that CPMV particles chemically modified for use as a fluorescent tracer were intact and retained binding specificity after lyophilization in the presence of trehalose. Thus, we demonstrate that functionalized CPMV nanostructures can be stored for the long term, enabling their use in practical sensing applications. PMID- 21817703 TI - Preparations of bifunctional polymeric beads simultaneously incorporated with fluorescent quantum dots and magnetic nanocrystals. AB - Bifunctional polystyrene beads simultaneously incorporated with fluorescent CdTe quantum dots (Q-dots) and superparamagnetic Fe(3)O(4) nanocrystals were prepared by a modified mini-emulsion polymerization method, in which polymerizable surfactants were used as both phase transfer agent for aqueous colloidal nanoparticles and emulsifier. In addition, silica coating was also introduced to Fe(3)O(4) nanocrystals for regulating the internal structure of the composite beads. Transmission electron microscopy, confocal fluorescence microscopy and conventional spectroscopy were used to characterize the composite beads, as well as the polymerizable surfactant-coated CdTe Q-dots and silica-coated Fe(3)O(4) nanoparticles. Different mixing methods were also attempted in order to vary the size of the resultant bifunctional beads. PMID- 21817704 TI - Aligned ultra-long single-crystalline alpha-Si(3)N(4) nanowires. AB - We report the synthesis of aligned ultra-long single-crystalline alpha-Si(3)N(4) nanowires by pyrolysis of a polymeric precursor without any template. The length of the wires is up to several centimeters, which is significantly longer than that of any Si(3)N(4) wires reported previously. Microscopy characterization reveals that the wires are single crystals, with a uniform diameter of ~200 nm. Intense visible photoluminescence was observed between 1.3 and 3.7 eV. The wires could be useful in the fabrication of optoelectronic nanodevices and nanocomposites. PMID- 21817705 TI - Preparation of AgX (X = Cl, I) nanoparticles using ionic liquids. AB - Nanoparticles of silver halides have been prepared by mixing silver halide powder with a single liquid phase consisting of an ionic liquid, isooctane, n-decanol and water. Much higher nanoparticle concentrations may be formed with ionic liquids using this new simple method than are found with conventionally applied surfactants. This method also emphasizes the applicability of ionic liquids as versatile components in microemulsions and as solvents for the synthesis of nanomaterials. The effect on the nanoparticles of changing the composition of the liquid mixtures and the nature of the ionic liquid is analysed. High nanoparticle concentrations were only found with chloride based ionic liquids, indicating the importance of the ionic liquid anion in the mechanism of the reaction. PMID- 21817706 TI - Facile fabrication of gold nanoparticle arrays for efficient surface-enhanced Raman scattering. AB - An effective and facile method for the fabrication of a surface-enhanced Raman scattering (SERS)-active film with closely packed gold nanoparticle (AuNP) arrays is proposed by self-assembly of different sizes (16, 25, 40 and 70 nm) of AuNPs at a toluene/water interface with ethanol as the inducer. The as-prepared AuNP arrays exhibit efficient Raman scattering enhancement, and the enhancement factors estimated using p-aminothiophenol as a probe molecule range from 10(5) to 10(7). This is attributed to the coupling electromagnetic SERS enhancement mechanism with additional localization field within closely packed AuNPs, which have greater SERS activity and reproducibility than that on aggregates and on self-assembled monolayers of isolated AuNPs on glass. PMID- 21817707 TI - Rod-shaped polyaniline-barium ferrite nanocomposite: preparation, characterization and properties. AB - Rod-shaped polyaniline (PANI)-barium ferrite nanocomposite was synthesized by in situ polymerization of aniline in the presence of BaFe(12)O(19) nanoparticles with diameters of 60-80 nm. The structure, morphology and properties of the nanocomposite were measured using powder x-ray diffraction, Fourier transform infrared spectroscopy, scanning electron microscopy, transmission electron microscopy and vibrating sample magnetometry. Different ferrite/PANI ratios were selected in order to study magnetic and conductive properties. The results indicated that there were some interactions between PANI chains and ferrite particles. The saturation magnetization and the coercivity varied with the ferrite content. The conductivity at room temperature decreased from 43.35 to 6.9 * 10(-2) S cm(-1) when the ferrite content changed from 0 to 50 wt%. The composite has excellent electromagnetic parameters which indicates potential application in high performance adsorbing materials in broadband and high frequency ranges. The polymerization mechanism and interactions in the nanocomposites were also studied. PMID- 21817708 TI - Nanoparticles with entrapped alpha-tocopherol: synthesis, characterization, and controlled release. AB - An emulsion evaporation method was used to synthesize spherical poly(DL-lactide co-glycolide) (PLGA) nanoparticles with entrapped alpha-tocopherol. Two different surfactants were used: sodium dodecyl sulfate (SDS) and poly(vinyl alcohol) (PVA). For SDS nanoparticles, the size of the nanoparticles decreased significantly with the entrapment of alpha-tocopherol in the PLGA matrix, while the size of PVA nanoparticles remained unchanged. The polydispersity index after synthesis was under 0.100 for PVA nanoparticles and around 0.150 for SDS nanoparticles. The zeta potential was negative for all PVA nanoparticles. The entrapment efficiency of alpha-tocopherol in the polymeric matrix was approximately 89% and 95% for nanoparticles with 8% and 16% alpha-tocopherol theoretical loading, respectively. The residual PVA associated with the nanoparticles after purification was approximately 6% ( w/w relative to the nanoparticles). The release profile showed an initial burst followed by a slower release of the alpha-tocopherol entrapped inside the PLGA matrix. The release for nanoparticles with 8% alpha-tocopherol theoretical loading (86% released in the first hour) was faster than the release for the nanoparticles with 16% alpha tocopherol theoretical loading (34% released in the first hour). PMID- 21817709 TI - The effect of temperature on the nanoscale adhesion and friction behaviors of thermoplastic polymer films. AB - Adhesion and friction tests were carried out in order to investigate the effect of temperature on the tribological characteristics of poly(methylmethacrylate) (PMMA) film using AFM. The pull-off and friction forces on the PMMA film were measured under a high vacuum condition (below 1 * 10(-4) Pa) as the temperature of the PMMA film was increased from 300 to 420 K (heating) and decreased to 300 K (cooling). Friction tests were also conducted in both high vacuum and air conditions at room temperature. When the temperature was 420 K, which is 25 K higher than the glass-transition temperature (T(g)) of PMMA, the PMMA film surface became deformable. Subsequently, the pull-off force increased in proportion to the maximum applied load during the pull-off force measurement. In contrast, when the temperature was under 395 K, the pull-off force did not depend on the maximum applied load. The friction force began to increase when the temperature rose above 370 K, which is 25 K lower than the T(g) of PMMA, and rapidly increased at 420 K. Decrease of the PMMA film stiffness and plastic deformation of the PMMA film were observed at 420 K in force-displacement curves. After the heating to 420 K, the coefficient of friction was measured under air condition at room temperature and was found to be lower than that measured before the heating. Additionally, the RMS roughness increased as a result of heating. PMID- 21817710 TI - Performance and electron transport properties of TiO(2) nanocomposite dye sensitized solar cells. AB - TiO(2) nanowire (NW)/nanoparticle (NP) composite films have been fabricated by hybridizing various ratios of hydrothermal anatase NWs and TiO(2) NPs for use in dye-sensitized solar cells (DSSCs). Scanning electron microscopy (SEM) images reveal that uniform NW/NP composite films were formed on fluorine-doped tin oxide (FTO) substrates by the dip-coating method. The NWs are randomly but neither vertically nor horizontally oriented within the composite film. The TiO(2) NP DSSC possesses superior performance to those of the NW/NP composite and the pure NW cells, and the efficiency of the NW/NP composite DSSC increases on increasing the NP/NW ratio in the composite anode. All types of DSSC possess the same dependence of performance on the anode thickness that the efficiency increases with the anode thickness to a maximum value, then it decreases when the anode is thickened further. Electrochemical impedance spectroscopy analyses reveal that the NP DSSCs possess larger effective electron diffusion coefficients (D(eff)) in the photoanodes and smaller diffusion resistances of I(3)(-) in electrolytes compared to those in the NW/NP and the NW DSSCs. D(eff) decreases when NWs are added into the photoanode. These results suggest that the vertical feature of the NWs within the anodes is crucial for achieving a high electron transport rate in the anode. PMID- 21817711 TI - Electronic properties of nanotube-ribbon hybrid systems. AB - In this work we use the tight-binding model to study the electronic properties of nanotube-ribbon hybrid systems. The nanotube-ribbon interactions will modify state energies, alter energy gaps, destroy state degeneracy, and create additional band-edge states. The bandstructures are asymmetric and symmetric about the Fermi energy when the interactions are turned on and off, respectively. The energy gap is found to vary sensitively with the nanotube location. Moreover, semiconductor-metal transition is predicted for nanotube-ribbon hybrid systems (I) and (III). For a zigzag ribbon, the partial flat bands at E(F) are almost unaffected by the nanotube-ribbon coupling although the bandstructures have been noticeably modified by such coupling; the energy gap of system (IV) is always zero. The effects of nanotube diameter and ribbon width on the energy gap and the density of states are also investigated. The semiconductor-metal transition can be accomplished by varying the nanotube location, the nanotube diameter or the ribbon width. The main features of the bandstructure are directly reflected in the density of states. The numbers, heights, and energies of the density of states peaks are strongly dependent on the nanotube-ribbon hoppings. PMID- 21817712 TI - Structure, wettability and photocatalytic activity of CO(2) laser sintered TiO(2)/multi-walled carbon nanotube coatings. AB - Nanocomposites of titanium dioxide (TiO(2)) and multi-walled carbon nanotubes (MWNTs) were prepared and deposited by sol-gel spin coating on borosilicate substrates and sintered in air at 300 degrees C for 15 min. Further irradiation of the films with different CO(2) laser intensities (4.3-17 W m(-2)) was carried out in order to crystallize TiO(2) in the anatase form while preserving the MWNT's structure. The laser irradiation changed the crystal structure of the coatings and also affected the wettability and photocatalytic activity of the films. The anatase phase was only observed when a minimum laser intensity of 12.5 W m(-2) was used. The contact angle decreased with the enhancement of the laser intensity. The photocatalytic activity of the films was determined from the degradation of a stearic acid layer deposited on the films. It was observed that the addition of carbon nanotubes themselves increases the photocatalytic activity of TiO(2) films. This efficiency is even improved when high CO(2) laser intensities are used during the sintering of the coatings. PMID- 21817713 TI - Nanomechanical and nanotribological characterization of noble metal-coated AFM tips for probe-based ferroelectric data recording. AB - Probe-based data recording is being developed as an alternative technology for ultrahigh areal density. In ferroelectric data storage, a conductive atomic force microscope (AFM) probe with a noble metal coating is placed in contact on lead zirconate titanate (PZT) film, which serves as the ferroelectric material. A crucial mechanical reliability concern is tip wear during contact of the ferroelectric material with the probe. To achieve high wear resistance, the mechanical properties (such as elastic modulus and hardness) of the metal-coated probe should be high. Nanoindentation experiments were performed in order to evaluate the mechanical properties of four commercial noble metal coatings, namely, Pt, Pt-Ni, Au-Ni and Pt-Ir, deposited on AFM probes. The effective hardness and elastic modulus were evaluated, using a contact mechanics model that accounts for the effect of the underlying silicon substrate. The Pt-Ir coating was found to exhibit the highest hardness, highest elastic modulus and lowest creep resistance. Nanoscratch studies reveal that the noble metal coatings are removed primarily by plastic deformation. The Pt-Ir and Pt coatings show the highest and lowest scratch resistance, respectively, which is consistent with results obtained from wear tests of the noble metal-coated AFM probes on a PZT surface. PMID- 21817714 TI - The glass transition and thermodynamics of liquid and amorphous TiO(2) nanoparticles. AB - The glass transition and thermodynamics of spherical liquid TiO(2) nanoparticles, with different sizes ranging from 2 to 5 nm, have been studied in a model under non-periodic boundary conditions. We use the pairwise interatomic potentials proposed by Matsui and Akaogi. Models have been obtained by cooling from the melt via molecular dynamics (MD) simulation. The structural properties of liquid nanoparticles at 3500 K have been analyzed in detail through the partial radial distribution functions (PRDFs), coordination number distributions, bond-angle distributions and interatomic distances. Moreover, we also show the radial density profile in nanoparticles. Calculations show that size effects on the structure of a model are significant and that liquid TiO(2) nanoparticles have a distorted pentahedral network structure with the mean coordination numbers Z(Ti O)~5.0 and Z(O-Ti)~2.5, while amorphous TiO(2) nanoparticles have an octahedral network structure. The temperature dependence of the surface structure and surface energy of the nanoparticles has been obtained and is presented. In addition, the size dependence of the glass transition temperature and the temperature dependence of the diffusion constant of atomic species have been found and are discussed. PMID- 21817715 TI - The fabrication and electrochemical properties of electrospun nanofibers of a multiwalled carbon nanotube grafted by chitosan. AB - Multiwalled carbon nanotubes (MWCNTs) were grafted by chitosan (CS); the product could disperse well in poly(vinyl alcohol) (PVA) aqueous solution with 2% (v/v) acetic acid solution. Because this product has potential in several biological fields, it was electrospun so as to enlarge the surface area. Raman spectra indicated that the electrospinning process did not severely alter the electron hybridization of carbon atoms within the nanotube framework. Moreover and interestingly, these nanofibers showed a novel sheath-core structure; the outer and inner diameters of these sheath-core nanofibers were about 200 nm and 100 nm, respectively. These nanofibers' electrochemical properties were characterized by detection of hydrogen peroxide and voltammetric responses of potassium ferricyanide. The electrospun fibers' web displayed faster electron transfer kinetics and better electrochemical properties than its cast film, which justified further applications in biological areas. PMID- 21817716 TI - Strong enhancement of Er(3+) 1.54 um electroluminescence through amorphous Si nanoparticles. AB - The roles of amorphous Si nanoparticles in light-emitting diodes (LEDs) based on Er-doped Si(1+x)O(2) films (x representing the degree of Si content, and varying widely from 0 to 4.50) have been investigated. In the aspect of the LEDs' electrical performance, it was found that the incorporation of Si nanoparticles facilitates the electrical conductivity of the films by improving the carrier mobility. With x increasing from 0 to 4.50, the mobility increases monotonically up to 5 times. The efficiency of Er(3+) electroluminescence (EL) at 1.54 um can be enhanced by as much as 160 times when the degree of Si content x is 2.00, coincident with the value at which the rate of mobility increasing versus x slows down. The fact that the maximum of EL efficiency and the slowing down of the rate of increase of mobility occur at the same x value can be explained by coalescence of Si nanoparticles starting at x = 2. PMID- 21817717 TI - Variations in properties of atomic force microscope cantilevers fashioned from the same wafer. AB - Variations in the mechanical properties of nominally identical V-shaped atomic force microscope (AFM) cantilevers sourced from the same silicon nitride wafer have been quantified by measuring the spring constants, resonant frequencies and quality factors of 101 specimens as received from the manufacturer using the thermal spectrum method of Hutter and Bechhoefer. The addition of thin gold coatings always lowers the resonant frequency but the corresponding spring constant can either increase or decrease as a result. The observed broad spread of spring constant values and the lack of correlations between the resonant frequency and spring constant can be attributed in part to the non-uniformity of composition and material properties in the thinnest dimension of such cantilevers which arise from the manufacturing process. The effects of coatings are dictated by the competing influence of differences in mass density and Young's modulus between the silicon nitride and the gold coating. An implication of this study is that cantilever calibration methods based on the assumption of uniformity of material properties of the cantilever in the thinnest dimension are unlikely to be applicable for such cantilevers. PMID- 21817718 TI - Random laser action of ZnO@mesoporous silicas. AB - ZnO@mesoporous silica nanocomposite was prepared by the impregnation method, and very efficient laser action was highlighted. As revealed by high-resolution transmission electron microscopy (HR-TEM), nanometric ZnO particles are confined inside the mesochannels of CMI-1 mesoporous silicas. Upon excitation at 3.6 eV of a femtosecond pulsed laser and at low pumping intensity, the ZnO@mesoporous silica showed a broad photoluminescence (PL) band corresponding to the excitonic recombination of ZnO. When the pumping intensity is increased up to a threshold (2.5 mJ cm(-2)), the excitonic emission turns to stimulated emission through a mechanism which will be discussed. The same threshold value was obtained with another excitation source and nanocomposites with different ZnO loadings inside the CMI-1 mesoporous silica. These results allow a better understanding of the random laser effect in ZnO@mesoporous silica and, consequently, a model has been proposed to explain this phenomenon. Based on these new observations, many new applications can be considered since short-wavelength devices are required by industry to design new information storage supports. PMID- 21817719 TI - Water permeation across nanochannels with defects. AB - Defects are common in fabricated nanochannels. In this paper, water permeation across a single-walled carbon nanotube with defects was studied using molecular dynamics simulations. It is found that the impact on water permeation is negligible when the density of the defects is small, while a significant reduction in water permeation is observed when the density of the defects is high. These findings should be helpful in both understanding water permeation across nanochannels and designing efficient artificial nanochannel. PMID- 21817720 TI - Surface deflection of a microtubule loaded by a concentrated radial force. AB - Microtubules are hollow cylindrical filaments of a eukaryotic cytoskeleton which are sensitive to externally applied radial forces due to their low circumferential elastic modulus. In this work, an orthotropic elastic shell model for microtubules is used to study the surface radial deflection of a microtubule loaded by a concentrated radial force generated by either a single molecular motor or a radial indentation tip. Our results show that the maximum surface radial deflection of a microtubule generated by a concentrated radial force of a few pN can be as large as a few nanometers (a significant fraction of the radius of microtubules), which could cause significant surface morphological non uniformity of the microtubule. In contrast, radial indentation under a much larger compressive force, which can be as large as a few hundreds of pN, will cause hardening of the circumferential elastic modulus almost equal to the longitudinal modulus of microtubules. In this case, our results show that a microtubule can withstand a concentrated radial compressive force as large as a few hundreds of pN, with a maximum radial deflection not more than a few nanometers, in good agreement with recent experiments on radial indentation of microtubules. These results offer useful data and new insights into the basic understanding of elastic interaction between microtubules and molecular motors and radial indentation of microtubules. PMID- 21817721 TI - Enzyme specific activity in functionalized nanoporous supports. AB - Here we reveal that enzyme specific activity can be increased substantially by changing the protein loading density (P(LD)) in functionalized nanoporous supports so that the enzyme immobilization efficiency (I(e), defined as the ratio of the specific activity of the immobilized enzyme to the specific activity of the free enzyme in solution) can be much higher than 100%. A net negatively charged glucose oxidase (GOX) and a net positively charged organophosphorus hydrolase (OPH) were entrapped spontaneously in NH(2)- and HOOC-functionalized mesoporous silica (300 A, FMS) respectively. The specific activity of GOX entrapped in FMS increased with decreasing P(LD). With decreasing P(LD), I(e) of GOX in FMS increased from<35% to>150%. Unlike GOX, OPH in HOOC-FMS showed increased specific activity with increasing P(LD). With increasing P(LD), the corresponding I(e) of OPH in FMS increased from 100% to>200%. A protein structure based analysis of the protein surface charges directing the electrostatic interaction-based orientation of the protein molecules in FMS demonstrates that substrate access to GOX molecules in FMS is limited at high P(LD), consequently lowering the GOX specific activity. In contrast, substrate access to OPH molecules in FMS remains open at high P(LD) and may promote a more favorable confinement environment that enhances the OPH activity. PMID- 21817722 TI - Stretching DNA in polymer nanochannels fabricated by thermal imprint in PMMA. AB - We present results regarding the fast and inexpensive fabrication of polymer biochips for investigating the statics and dynamics of DNA confined in nanochannels. The biochips have been fabricated by means of nanoimprint lithography (NIL) in low molecular weight polymethyl methacrylate (PMMA) using a 4 inch diameter two-level hybrid stamp. The fluidic structures were sealed using thermal polymer fusion bonding. The stamp has nanometer- and micrometer-sized protrusions defined in a thermally grown SiO(2) layer and the sol-gel process derived duromeric hybrid polymer Ormocomp, respectively. The stamp is compatible with molecular vapor deposition (MVD), used for applying a durable chlorosilane based antistiction coating, and allows for imprint up to a temperature of 270 degrees C. The extension of YOYO-1 stained T4 GT7 bacteriophage DNA inside the PMMA nanochannels has been experimentally investigated using epi-fluorescence microscopy. The measured average extension length amounts to 20% of the full contour length with a standard deviation of 4%. These results are in good agreement with results obtained by stretching DNA in conventional fused silica nanochannels. PMID- 21817723 TI - Charge dissipation in e-beam lithography with Novolak-based conducting polymer films. AB - Charging of common resist materials during electron beam (e-beam) writing leads to deflection of the electron beam path, which can result in significant pattern displacement. Here we report a new conducting polymer to eliminate charging. A common approach is to place the conducting layer underneath the e-beam resist layer. Conductivity equal or greater than 10(-4) S cm(-1) has been reported to prevent pattern displacement. Some other properties such as a flat surface layer, chemical inertness and insolubility in both the top resist solvent and the developer are also necessary. The way to achieve all these properties consisted in synthesizing a conducting polymer inside an insulating polymer to form an interpenetrating polymer network (IPN) which could combine their properties. Novolak was used as the host polymer and terthiophene (3T) as the monomer to polymerize. Cu(ClO(4))(2) initiates simultaneously the oxidative polymerization of the 3T and its subsequent doping inside Novolak during the bake step in a one step reaction. Solvent-resistant and homogeneous conducting films with smooth surfaces were achieved. The conductivity was of the order of 10(-2) S cm(-1). Patterning of the top resist was carried out without disturbing its lithographic performance. PMID- 21817724 TI - Growth and percolation of metal nanostructures in electrode gaps leading to conductive paths for electrical DNA analysis. AB - Metal nanostructures are promising novel labels for microarray-based biomolecular detection. Additional silver deposition on the surface-bound labels strongly enhances the sensitivity of the system and can lead to continuous metal areas, which enable an electrical readout especially for simple and robust point-of-care analyses. In this paper, atomic force microscopy (AFM) was used to study different routes of metal deposition on labelled DNA-DNA duplexes in electrode gaps. Besides the well-established metal-induced silver enhancement, a recently introduced enzymatic silver deposition was applied and proved highly specific. The in situ characterization was especially focused on the nanostructure percolation-the moment at which the nanoparticulate film becomes continuous and electrically conducting. The formation of conducting paths, continuous from one electrode to the other, was followed by complementary electrical measurements. Thereby, a percolation threshold was determined for the surface coverage with metal structures, i.e. the required metallized area to achieve conductance. Complementary graphic simulations of the growth process and graphic 'conductance measurements' were developed and proved suitable to model the metal deposition and electrical detection. This may help to design electrode arrays and identify optimum enhancement parameters (required seed concentration and shell growth) as well as draw quantitative conclusions on the existing label (i.e. analyte) concentration. PMID- 21817725 TI - Electrochemical deposition of polypyrrole nanolayers on discontinuous ultrathin gold films. AB - Ultrathin layers of polypyrrole (PPy) were electrochemically grown between microelectrodes on a Si/SiO(2) substrate. Conducting nanolayers of PPy are directly grown onto ultrathin discontinuous gold (Au) film between the microelectrodes, with thicknesses in the range 10-100 nm. The system therefore forms a novel (PPy/Au) nanocomposite conductor. Atomic force microscopy (AFM) imaging and conductivity measurements indicate that at all thicknesses a relatively uniform film is formed but with significant roughness that reflects the roughness of the metallic island layer. In PPy/Au films with thickness ~10 nm, the small barriers around the gold islands dominate the conduction, and as the film thickness increases to 100 nm the intrinsic conductivity of highly doped PPy dominates the charge transport. PMID- 21817726 TI - Quantitative characterizations of a nanopatterned bonded wafer: force determination for nanoimprint lithography stamp removal. AB - The nanoimprint lithography process consists of two mechanical steps: molding and stamp removal. While many publications dealing with anti-sticking layer properties or the understanding of polymer flow during imprinting have recently been published, only a few studies have been carried out to deeply characterize the demolding step. Regarding the small amount of theoretical work dedicated to this issue, in this paper both experimental and first theoretical approaches are proposed to characterize the demolding process in a peeling scheme. Full 200 mm stamp and imprinted wafers were used to identify the experimental limitation of such a full wafer peeling demolding scheme. A rectangular stamp and substrate samples with or without nanoscale features combined with an augmented beam theory are proposed to extract quantitative data for the required demolding force as well as the friction stress along the feature sidewall. Therefore both adhesion and friction forces were characterized on single stamp structures. PMID- 21817727 TI - Direct fabrication of nanoscale bio-adhesive patterns by electron beam surface modification of plasma polymerized poly ethylene oxide-like coatings. AB - In this study we present a method to produce nanostructured surfaces containing bio-adhesive features inside a non bio-adhesive matrix. The strategy is based on the combination of low pressure plasma polymerization and electron beam lithography processes and allows the fabrication of the structured materials in just two steps without using any solvents. In a first step, a thin protein-and cell-repelling coating (~10 nm) is obtained by plasma polymerization of Di-glyme. Then, in a second step, the bio-adhesive properties of the layer are tuned by monitoring the concentration of ether bonds of the film by irradiating it locally by different irradiation doses with an electron beam. Time-of-flight secondary ion mass spectroscopy and atomic force microscopy analysis have been used to characterize the produced surfaces. Experiments with a model protein (bovine serum albumin) on the patterned surfaces show preferential adhesion to the irradiated regions, indicating the potential of this simple technique for the development of highly compacted sensitive bio-sensing devices. PMID- 21817728 TI - Segmented metal nanowires as nanoscale thermocouples. AB - Segmented Au-Ni nanowires are demonstrated to be highly effective thermocouples with a spatial resolution of a few nanometers and a temporal resolution in the microsecond range. The performance of the devices is characterized by a self heating procedure in which an ac heating current with frequency omega is applied on the wires while monitoring the resulting thermoelectric voltage V(TH) at 2omega using a lock-in technique. An analytical model is developed that enables one to determine the time response of the thermocouples from plots of V(TH) as a function of omega. PMID- 21817729 TI - A single nanotrench in a palladium microwire for hydrogen detection. AB - The hydrogen sensing characteristics of a single nanotrench fabricated by focused ion beam milling (FIB) in an evaporated palladium microwire are presented. In situ atomic force microscopy (AFM) measurements proved that, in the presence of H(2), the trench closes and electrically connects the initially separated parts of the wire due to the increase in volume of the material. Therewith, an electrical current can be switched through the wire. With experiments under various H(2) concentrations and a mathematical model, we describe the closing mechanism of the trench with respect to various parameters, including the substrate material, film thickness, trench size and wire dimensions. Results have been compared with those from equivalent continuous wires. Thin SiO(2) and polyimide (PI) layers on silicon were used to study the effect of substrate elasticity. Sufficient lateral expansion of Pd to close trenches of up to 70 nm in width has only been observed on PI, which we attribute to its advantageous elastic properties. The scale of the response times allowed the observation of two superposing effects: the chemical conversion of Pd to PdH(x) and the mechanical closing of the trench. PMID- 21817730 TI - High-bandwidth control of a piezoelectric nanopositioning stage in the presence of plant uncertainties. AB - Inversion-based feedforward techniques have been known to deliver accurate tracking performance in the absence of plant parameter uncertainties. Piezoelectric stack actuated nanopositioning platforms are prone to variations in their system parameters such as resonance frequencies, due to changes in operating conditions like ambient temperature, humidity and loading. They also suffer from nonlinear effects of hysteresis, an inherent property of a piezoelectric actuator; charge actuation is applied to reduce the effects of hysteresis. In this work, we propose and test a technique that integrates a suitable feedback controller to reduce the effects of parameter uncertainties with the inversion-based feedforward technique. It is shown experimentally that the combination of damping, feedforward and charge actuation increases the tracking bandwidth of the platform from 310 to 1320 Hz. PMID- 21817731 TI - Nanostructured SnO(2) films prepared from evaporated Sn and their application as gas sensors. AB - This paper describes the morphology, stoichiometry, microstructure and gas sensing properties of nanoclustered SnO(x) thin films prepared by Sn evaporation followed by a rheotaxial growth and thermal oxidation process. Electron microscopy was used to investigate, in detail, the evolution of the films as the oxidation temperature was increased. The results showed that the contact angle, perpendicular height, volume and microstructure of the clusters all changed significantly as a result of the thermal oxidation processes. Electron diffraction and x-ray photoelectron spectroscopy measurements revealed that after oxidation at a temperature of 600 degrees C, the Sn clusters were fully transformed into porous three-dimensional polycrystalline SnO(2) clusters. On the basis of these results, a prototype SnO(2) sensor was fabricated and sensing measurements were performed with H(2) and NO(2) gases. At operating temperatures of 150-200 degrees C the film produced measurable responses to concentrations of H(2) as low as 600 ppm and NO(2) as low as 500 ppb. PMID- 21817732 TI - Polarity orientation of microtubules utilizing a dynein-based gliding assay. AB - The motor protein dynein was introduced into a nanotransport system. We oriented microtubules by their polarity, and immobilized them based on a dynein microtubule gliding assay system. This system achieved unidirectional transport of kinesin-coated microbeads. In contrast to conventional kinesin-based orientation systems, the dynein-based system allowed the reverse motion of microtubules, resulting in an inversion of the orientation of microtubule polarity and thus reverse transport of kinesin-coated microbeads. This combined kinesin- and dynein-based system constitutes a new means to facilitate the bidirectional orientation of microtubules and transport of cargos in a nanofluidic system. PMID- 21817733 TI - Monodisperse alpha-Fe(2)O(3)@SiO(2)@Au core/shell nanocomposite spheres: synthesis, characterization and properties. AB - A new hybrid spherical structure alpha-Fe(2)O(3)@SiO(2)@Au with a size of about 141 nm was designed, with a hematite cubic core surrounded by a thick silica shell and further decorated with gold nanoparticles. The monodisperse alpha Fe(2)O(3)@SiO(2) spheres were first prepared by a sol-gel process based on the modified Stober method. Subsequently, the surface of the alpha-Fe(2)O(3)@SiO(2) particles was functionalized by-NH(2) functional groups. The electrostatic attraction of -NH(2) groups will attach the negatively charged Au nanoparticles to the amino-functionalized alpha-Fe(2)O(3)@SiO(2) nanospheres in order to prepare alpha-Fe(2)O(3)@SiO(2) monodisperse hybrid spheres. The M(H) hysteresis loop for alpha-Fe(2)O(3)@SiO(2) and alpha-Fe(2)O(3)@SiO(2)@Au spheres indicates that the nanocomposite spheres exhibit superparamagnetic characteristics at room temperature. The optical properties and the application of these hybrid nanocomposites as catalysts for the conversion of CO to CO(2) have also been studied. PMID- 21817734 TI - Vertically standing Ge nanowires on GaAs(110) substrates. AB - The growth of epitaxial Ge nanowires is investigated on (100), (111) B and (110) GaAs substrates in the growth temperature range from 300 to 380 degrees C. Unlike epitaxial Ge nanowires on Ge or Si substrates, Ge nanowires on GaAs substrates grow predominantly along the [Formula: see text] direction. Using this unique property, vertical [Formula: see text] Ge nanowires epitaxially grown on GaAs(110) surface are realized. In addition, these Ge nanowires exhibit minimal tapering and uniform diameters, regardless of growth temperatures, which is an advantageous property for device applications. Ge nanowires growing along the [Formula: see text] directions are particularly attractive candidates for forming nanobridge devices on conventional (100) surfaces. PMID- 21817735 TI - Room-temperature preparation of ZnO nanosheets grown on Si substrates by a seed layer assisted solution route. AB - A facile route to prepare two-dimensional ZnO nanosheet structures on Si substrates was developed through the adoption of a ZnO seed-layer and suitable growth medium in this work. The characterization results showed that ZnO nanosheets could be grown on Si substrates with a pre-formed ZnO seed-layer at room temperature. The ZnO nanosheets, with thickness of 20-25 nm, were interwoven into networks to form a continuous nanosheet film. Room-temperature measurements of the photoluminescence (PL) spectra and water wettability for the resulting ZnO nanosheet structures showed high intensity ratio of the UV emission to the defect emissions and good hydrophilic property without UV illumination. The present work demonstrates that the adoption of a ZnO seed-layer is an effective approach for room-temperature growth of ZnO nanosheets grown on substrates. PMID- 21817736 TI - The growth mechanism for silicon oxide nanowires synthesized from an Au nanoparticle/polyimide/Si thin film stack. AB - During pyrolysis of polyimide (PI) thin film, amorphous silicon oxide nanowires (SiO(x)NWs) were produced on a large scale through heat treatment of an Au nanoparticle/PI/Si thin film stack at 1000 degrees C. It was shown that carbonization of the PI film preceded the nucleation of the SiO(x)NWs. The formation of the SiO(x)NWs was sustained by the oxygen derived from carbonization of the polyimide thin film while Si was provided from the substrate. Au nanoparticles promoted the SiO(x)NW growth by inducing localized melting of the Si substrate and by catalyzing the nanowire growth. PMID- 21817737 TI - High rate flame synthesis of highly crystalline iron oxide nanorods. AB - Single-step flame synthesis of iron oxide nanorods is performed using iron probes inserted into an opposed-flow methane oxy-flame. The high temperature reacting environment of the flame tends to convert elemental iron into a high density layer of iron oxide nanorods. The diameters of the iron oxide nanorods vary from 10 to 100 nm with a typical length of a few microns. The structural characterization performed shows that nanorods possess a highly ordered crystalline structure with parameters corresponding to cubic magnetite (Fe(3)O(4)) with the [100] direction oriented along the nanorod axis. Structural variations of straight nanorods such as bends, and T-branched and Y-branched shapes are frequently observed within the nanomaterials formed, opening pathways for synthesis of multidimensional, interconnected networks. PMID- 21817738 TI - Monodisperse hematite porous nanospheres: synthesis, characterization, and applications for gas sensors. AB - Monodisperse alpha-Fe(2)O(3) porous nanospheres with uniform shape and size have been synthesized via a facile template-free route. X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), high resolution TEM (HRTEM), and Raman spectroscopy were employed to characterize the product, showing the high quality of the as-prepared alpha-Fe(2)O(3) porous nanospheres. Furthermore, the alpha-Fe(2)O(3) porous nanospheres can selectively detect ethanol, formaldehyde and acetic acid, with a rapid response and high sensitivity, from a series of flammable and toxic/corrosive gases, indicating their potential applications for high sensitivity gas sensors. PMID- 21817739 TI - One-step functionalization of multi-walled carbon nanotubes with Ag/polymer under gamma-ray irradiation. AB - We reported an easy strategy of using gamma-ray irradiation to functionalize multi-walled carbon nanotubes (MWCNTs) without the use of aggressive acid treatment, all in a single processing step. In this paper, we tried to decorate MWCNTs with Ag nanoparticles relying on covalently bonded polymers, via one-step covalent grafting of the polymer to the surface of MWCNTs, and simultaneous reducing of Ag(+) ions to Ag which are then efficiently anchored onto the MWCNTs. Herein, the polymer involved was the commercially available polymer poly(vinyl alcohol) (PVA) and two of its derivatives, polyvinylacetone with ketalization degree D(H) = 0.22 and 0.53. It is envisioned that this simple but efficient method could be extended to fabricate other CNT-based hybrids for both theoretical study and applications in biological and technological fields. PMID- 21817740 TI - The growth of small diameter silicon nanowires to nanotrees. AB - In this work we have studied a way to control the growth of small diameter silicon nanowires by the vapour-liquid-solid (VLS) mode. We have developed a method to deposit colloids with good density control, which is a key point for control of the nanowire (NW) diameter. We also show the high dependence of the allowed growth diameter on the growth conditions, opening the door to the realization of as-grown 2 nm silicon NWs. Finally we have developed a smart way to realize nanotrees in the same run, by tuning the growth conditions and using gold on the sidewall of nanowires, without the need for two catalyst deposition steps. PMID- 21817741 TI - Composite droplets: evolution of InGa and AlGa alloys on GaAs(100). AB - We present a comparative study for the evolution of utilizing indium gallium (InGa) and aluminum gallium (AlGa) alloys fabricated on GaAs(100) by means of simultaneous and sequential droplet formation. The composite alloys reported using the sequential approach lack the ability to precisely determine the final alloy composition as well as consistency in the density of the droplets. Further, the composition of the InGa alloy is not uniform, as seen by the size distribution using an atomic force microscope (AFM). Although this approach may be acceptable for materials with similar surface kinetics, as in the case of AlGa, it is not acceptable for InGa. This investigation reveals that the simultaneous approach for fabricating composite alloys is the optimum approach for producing InGa alloys with better control on composition for plasmonic applications such as plasmonic waveguides. PMID- 21817742 TI - First-principles study of physisorption of nucleic acid bases on small-diameter carbon nanotubes. AB - We report the results of our first-principles study based on density functional theory on the interaction of the nucleic acid base molecules adenine (A), cytosine (C), guanine (G), thymine (T), and uracil (U), with a single-walled carbon nanotube (CNT). Specifically, the focus is on the physisorption of base molecules on the outer wall of a (5, 0) metallic CNT possessing one of the smallest diameters possible. Compared to the case for CNTs with large diameters, the physisorption energy is found to be reduced in the high-curvature case. The base molecules exhibit significantly different interaction strengths and the calculated binding energies follow the hierarchy G>A>T>C>U, which appears to be independent of the tube curvature. The stabilizing factor in the interaction between the base molecule and CNT is dominated by the molecular polarizability that allows a weakly attractive dispersion force to be induced between them. The present study provides an improved understanding of the role of the base sequence in deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) in their interactions with carbon nanotubes of varying diameters. PMID- 21817743 TI - Adhesion, friction and wear on the nanoscale of MWNT tips and SWNT and MWNT arrays. AB - The nanotribological characterization of carbon nanotubes is fundamental for the exploration of new sliding applications. In this study, a comprehensive investigation of adhesion, friction and wear of a multiwalled nanotube (MWNT) tip, and SWNT (single-walled nanotube) and MWNT arrays has been carried out. A nonlinear response of the MWNT tip is observed when the tip is brought into and out of contact with various surfaces. A nonlinear response occurs due to the buckling of the nanotube and its subsequent sliding on the surface. In addition to the role of surface chemistry, it can also explain the relatively high value of the coefficient of friction obtained on different surfaces, as compared to that of Si and Si(3)N(4) tips. The adhesion and friction studies carried out on SWNT and MWNT arrays using Si tips show that SWNT arrays, compared to MWNT arrays, exhibit lower values, possibly due to lower van der Waals forces as a result of lower packing density and higher flexibility. The wear tests conducted with the MWNT tip and a Si tip on a gold film, at two normal loads, show less damage of the surface when the MWNT tip is used because of the MWNT acting as a compliant spring, absorbing part of the load. Wear tests conducted with a Si tip on SWNT and MWNT arrays show that the arrays do not wear. The tip wear and the friction force in the SWNT array are lower, because of lower adhesion and higher flexibility of the SWNTs, which causes less opposition to the motion of the tip. PMID- 21817744 TI - Measurement of metal/carbon nanotube contact resistance by adjusting contact length using laser ablation. AB - A technique of measuring contact resistance between an individual nanotube and a deposited metallic film is described. Using laser ablation to sequentially shorten the contact length between a nanotube and the evaporated metallic film, the linear resistivity of the nanotube as well as the specific contact resistivity between the nanotube and metallic film can be determined. This technique can be generally used to measure the specific contact resistance that develops between a metallic film and a variety of different nanowires and nanotubes. PMID- 21817745 TI - A CdS-modified TiO(2) nanocrystalline photoanode for efficient hydrogen generation by visible light. AB - Cadmium sulfide (CdS) was in situ synthesized onto mesoporous TiO(2) films and used as a sensitizer to fabricate a photoelectrode for hydrogen generation in visible light. The incorporation of CdS extends the optical absorption threshold of a TiO(2) electrode to visible light, enhancing the visible-light-induced photocurrent. A maximum photoconversion efficiency of 3.67% was achieved for this CdS-sensitized TiO(2) electrode under visible light illumination of 100 mW cm( 2). The hydrogen generation rate obtained at conditions of maximum efficiency is 95.5 umol cm(-2) h(-1). To the best of our knowledge, the hydrogen generation rate is the highest among those reported for a photoelectrochemical cell under the illumination of visible light. PMID- 21817746 TI - Tailoring the microstructure and surface morphology of metal thin films for nano electro-mechanical systems applications. AB - Metallic structural components for micro-electro-mechanical/nano-electro mechanical systems (MEMS/NEMS) are promising alternatives to silicon-based materials since they are electrically conductive, optically reflective and ductile. Polycrystalline mono-metallic films typically exhibit low strength and hardness, high surface roughness, and significant residual stress, making them unusable for NEMS. In this study we demonstrate how to overcome these limitations by co-sputtering Ni-Mo. Detailed investigation of the Ni-Mo system using transmission electron microscopy and high-resolution transmission electron microscopy (TEM/HRTEM), x-ray diffraction (XRD), nanoindentation, and atomic force microscopy (AFM) reveals the presence of an amorphous-nanocrystalline microstructure which exhibits enhanced hardness, metallic conductivity, and sub nanometer root mean square (RMS) roughness. Uncurled NEMS cantilevers with MHz resonant frequencies and quality factors ranging from 200-900 are fabricated from amorphous Ni-Mo. Using a sub-regular solution model it is shown that the electrical conductivity of Ni-Mo is in excellent agreement with Bhatia's structural model of electrical resistivity in binary alloys. Using a Langevin type stochastic rate equation the structural evolution of amorphous Ni-Mo is modeled; it is shown that the growth instability due to the competing processes of surface diffusion and self-shadowing is heavily damped out due to the high thermal energies of sputtering, resulting in extremely smooth films. PMID- 21817747 TI - Tuning spin properties of excitons in single CdTe quantum dots by annealing. AB - Using polarization-resolved photoluminescence imaging in external magnetic fields we measure statistically significant distributions of exchange splitting, diamagnetic shift and effective g-factor of excitons in tens of single CdTe quantum dots. Comparison between the as-grown and annealed structures shows strong suppression of ensemble inhomogeneities, with the average exchange splitting reduced by half and significant narrowing of the g-factor distribution. Remarkably, the average value of the excitonic g-factor remains unchanged. This unique ability to yield highly uniform quantum dot ensembles without hampering the exciton Zeeman splitting makes annealing a highly attractive means for tuning the spin properties of quantum dot excitons. PMID- 21817748 TI - Nanofibrous membranes from aqueous electrospinning of carboxymethyl chitosan. AB - Carboxymethyl chitosan (CMCS) with varying molecular weights (M(v) = 40-405 kDa) and degrees of substitution (DS = 0.25-1.19) has been synthesized by alkalization of chitosan, followed by carboxymethylation with monochloroacetic acid. At DS up to 1.19, the locations where carboxymethylation took place were influenced by the alkalization temperature, i.e., both C2 and C6 substitution at ambient temperature (N,O-carboxymethylated) and mainly C6 substitution at the lower temperature, -15 degrees C (O-carboxymethylated). Generally, carboxymethylation was more favorable at the primary C6 hydroxyl than the C2 position with increasing DS. CMCS synthesized from 405 kDa CS was soluble in water at DS>=0.73 whereas those from 40 and 89 kDa became water-soluble at lower DS of 0.25 and 0.36, respectively. Electrospinning of aqueous solutions of CMCS was facilitated with the addition of water-soluble polymers, including PEO, PAA, PAAm and PVA. The optimal fiber formation was observed at equal mass composition of O-CMCS (89 kDa at 0.36 DS) and PVA, producing nanofibers with an average diameter of 130 nm. Heat-induced esterification (at 140 degrees C for 30 min) produced inter molecular covalent cross-links within and among fibers, rendering the fibrous membrane water-insoluble. Membranes containing higher CMCS carboxyl to PVA hydroxyl ratio retained better fiber morphology upon extended water exposure, indicating more favorable inter-molecular cross-links. The fibrous membranes generated with less substituted CMCS were more hydrophilic and retained a greater extent of the desirable amine functionality. PMID- 21817749 TI - Superconductivity of the bulk MgB(2)+nano(n)-SiC composite system: a high field magnetization study. AB - We study the effect of nano(n)-SiC addition on the crystal structure, critical temperature (T(c)), critical current density (J(c)) and flux pinning in MgB(2) superconductors. X-ray diffraction patterns show that all the samples have MgB(2) as the main phase with a very small amount of MgO; further, with n-SiC addition the presence of Mg(2)Si is also noted and confirmed by scanning electron microscopy (SEM) and energy-dispersive spectroscopy (EDS). The T(c) value for pure MgB(2) is 18.9 K under 8 T applied field, while it is 20.8 K for the 10 wt% n-SiC doped sample under the same field. This points towards the increment in the upper critical field value with n-SiC addition. The irreversibility field (H(irr)) for the 5% n-SiC added sample reached 11.3, 10 and 5.8 T, compared to 7.5, 6.5, and 4.2 T for the pure MgB(2) at 5, 10 and 20 K, respectively. The critical current density (J(c)) for the 5 wt% n-SiC added sample is increased by a factor of 35 at 10 K and 6.5 T field and by a factor 20 at 20 K and 4.2 T field. These results are understood on the basis of superconducting condensate (sigma band) disorder and ensuing intrinsic pining due to B-site C substitution clubbed with further external pinning due to available n-SiC/Mg(2)Si pins in the composite system. PMID- 21817750 TI - Quantitative modelling of the surface plasmon resonances of metal nanoclusters sandwiched between dielectric layers: the influence of nanocluster size, shape and organization. AB - The effects of size, shape and organization on the surface plasmon resonances of Ag nanoclusters sandwiched between Si(3)N(4) layers are studied by transmission electron microscopy and anisotropic spectroscopic ellipsometry. We present an easy-to-handle model that quantitatively links the nanostructure and optical response of the films, which are considered as dielectric/metal:dielectric/dielectric trilayers, with the central nanocomposite layer being an effective medium whose optical properties are described by an anisotropic dielectric tensor. The components of this tensor are calculated using a generalization of the Yamaguchi theory taking into account the real organization, size and shape distributions of ellipsoidal nanoclusters, whose electronic properties are assumed to reflect shape-dependent finite size effects. Using this model, it is shown that the optical response of the films in the visible range is dominated by the excitation of the surface plasmon resonance of the clusters along their in-plane long axis, while no surface plasmon resonance resulting from an excitation along their in-plane short axis can be observed due to damping effects. Moreover, the spectral position of this resonance appears to be mainly affected by the average shape of the clusters, and weakly by their size, their shape distribution and the electromagnetic interaction between them. PMID- 21817751 TI - Self-assembled nanoparticles of cholesterol-modified O-carboxymethyl chitosan as a novel carrier for paclitaxel. AB - Self-assembled nanoparticles of cholesterol-modified O-carboxymethyl chitosan (CCMC) were prepared to be used as a novel carrier for paclitaxel (PTX) in this study. CCMC-6.9 was synthesized by the covalent conjugation of cholesterol to O carboxymethyl chitosan with the succinyl linkage and the degree of substitution (DS) of the cholesterol moiety was 6.9%. CCMC-6.9 formed self-assembled nanoparticles with a size of 209.5 nm in aqueous media. Paclitaxel-loaded CCMC 6.9 self-assembled nanoparticles were prepared using a dialysis method and their characteristics were analyzed by dynamic laser light scattering (LLS), transmission electron microscopy (TEM) and ultraviolet spectroscopy (UV). PTX loaded CCMC-6.9 self-assembled nanoparticles were almost spherical in shape and their size increased from 245.6 to 355.3 nm with PTX-loading content increasing from 18.7% to 34.9%. In vitro release of PTX from CCMC-6.9 self-assembled nanoparticles was carried out by the dynamic dialysis method. PTX continuously released in phosphate buffered saline (PBS) solutions for 84 h at 37 degrees C and its release was sensitive to the pH of the release media. The biodistribution of PTX-loaded CCMC-6.9 self-assembled nanoparticles was studied in female Balb/c mice. Compared with PTX in the solution of Cremophor EL (polyethoxylated castor oil)/ethanol (PTX-Cre), CCMC-6.9 self-assembled nanoparticles significantly increased the uptake of PTX in plasma, liver and spleen, but decreased the uptake in heart and kidney. These results suggest that CCMC-6.9 self-assembled nanoparticles can effectively solubilize PTX and modify its tissue biodistribution, which may be advantageous in enhancing the therapeutic index and reducing the toxicity of PTX. PMID- 21817752 TI - The translocation of fullerenic nanoparticles into lysosome via the pathway of clathrin-mediated endocytosis. AB - Manufactured fullerene nanoparticles easily enter into cells and hence have been rapidly developed for biomedical uses. However, it is generally unknown which route the nanoparticles undergo when crossing cell membranes and where they localize to the intracellular compartments. Herein we have used both microscopic imaging and biological techniques to explore the processes of [C(60)(C(COOH)(2))(2)](n) nanoparticles across cellular membranes and their intracellular translocation in 3T3 L1 and RH-35 living cells. The fullerene nanoparticles are quickly internalized by the cells and then routed to the cytoplasm with punctate localization. Upon entering the cell, they are synchronized to lysosome-like vesicles. The [C(60)(C(COOH)(2))(2)](n) nanoparticles entering cells are mainly via endocytosis with time-, temperature- and energy-dependent manners. The cellular uptake of [C(60)(C(COOH)(2))(2)](n) nanoparticles was found to be clathrin-mediated but not caveolae-mediated endocytosis. The endocytosis mechanism and the subcellular target location provide key information for the better understanding and predicting of the biomedical function of fullerene nanoparticles inside cells. PMID- 21817753 TI - Flexible organic light-emitting diodes with a polymeric nanocomposite anode. AB - Flexible organic light-emitting diodes (FOLEDs) are facing mechanical issues arising from failure of the indium-tin oxide (ITO) films fabricated on flexible substrates. Polymeric nanocomposite anodes were fabricated by including single wall carbon nanotubes (SWCNTs) in aqueous poly(3,4 ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT:PSS). The conductivity, transmittance and flexibility of the polymeric nanocomposite anode were characterized. The polymeric nanocomposite anodes fabricated on a poly(ethylene terephthalate) (PET) substrate exhibited superior bending properties to ITO anodes on PET. The FOLEDs fabricated on the polymeric nanocomposite anodes had a low turn-on voltage and higher luminous intensity than those fabricated on ITO/PET anodes. This flexible nanocomposite polymeric anode is a very promising for fully FOLEDs and other optoelectronics. PMID- 21817754 TI - White light emitting diodes realized by using an active packaging method with CdSe/ZnS quantum dots dispersed in photosensitive epoxy resins. AB - White light emitting diodes (LEDs) have been realized using the active packaging (AP) method. The starting materials were bare InGaN LED chips and CdSe/ZnS core shell quantum dots (QDs) dispersed in photosensitive epoxy resins. Such hybrid LED devices were fabricated using QD mixtures with one ('single'), two ('dual') or four ('multi') emission wavelengths. The AP method allows for convenient adjustment of multiple parameters such as the CIE-1931 coordinate (x, y), color temperature, and color rending index (CRI). All samples show good white balance, and under a 20 mA working current the luminous efficacies of the single, dual, and multi hybrid devices were 8.1 lm W(-1), 5.1 lm W(-1), and 6.4 lm W(-1), respectively. The corresponding quantum efficiencies were 4.1%, 3.1%, and 3.1%; the CRIs were 21.46, 43.76, and 66.20; and the color temperatures were 12 000, 8190, and 7740 K. This shows that the CRI of the samples can be enhanced by broadening the QD emission band, as is exemplified by the 21.46 CRI of the single hybrid LED compared to the 66.20 value for the multi hybrid LED. In addition, we were able to increase the CRI of the single hybrid LED from 15.31 to 32.50 by increasing the working currents from 1 to 50 mA. PMID- 21817755 TI - Evaporative self-assembly assisted synthesis of polymeric nanoparticles by surface acoustic wave atomization. AB - We demonstrate a straightforward and rapid atomization process driven by surface acoustic waves that is capable of continuously producing spherical monodispersed submicron poly-epsilon-caprolactone particle aggregates between 150 and 200 nm, each of which are composed of nanoparticles of 5-10 nm in diameter. The size and morphologies of these particle assemblies were determined using dynamic light scattering, atomic force microscopy and transmission electron microscopy. Through scaling theory, we show that the larger particle aggregates are formed due to capillary instabilities amplified by the acoustic forcing whereas the smaller particulates that form the aggregates arise due to a nucleate templating process as a result of rapid spatially inhomogeneous solvent evaporation. Minimization of the free energy associated with the evaporative process yields a critical cluster size for a single nucleus in the order of 10 nm, which roughly corresponds with the dimensions of the sub-50 nm particulates. PMID- 21817756 TI - Fabrication of large area nanoprism arrays and their application for surface enhanced Raman spectroscopy. AB - This work demonstrates the fabrication of metallic nanoprism (triangular nanostructure) arrays using a low-cost and high-throughput process. In the method, the triangular structure is defined by the shadow of a pyramid during angle evaporation of a metal etching mask. The pyramids were created by nanoimprint lithography in polymethylmethacrylate (PMMA) using a mould having an inverse-pyramid-shaped hole array formed by KOH wet etching of silicon. Silver and gold nanoprism arrays with a period of 200 nm and an edge length of 100 nm have been fabricated and used as effective substrates for surface enhanced Raman spectroscopy (SERS) detection of rhodamine 6G (R6G) molecules. Numerical calculations confirmed the great enhancement of electric field near the sharp nanoprism corners, as well as the detrimental effect of the chromium adhesion layer on localized surface plasmon resonance. The current method can also be used to fabricate non-equilateral nanoprism and three-dimensional (3D) nanopyramid arrays, and it can be readily extended to other metals. PMID- 21817757 TI - Large-scale ultraflat nanopatterned surfaces without template residues. AB - Ultraflat surfaces are required for many studies of single molecules, and the need for both a wide choice of surface materials and the ability to pattern these surfaces has led to the development of different template-stripping approaches. The fabrication of nanopatterned ultraflat surfaces is particularly challenging, because more than one material is present in the surface. We demonstrate a new template-stripping strategy that allows us to fabricate large-area nanopatterned surfaces, solving the problem of incomplete template removal by introducing a sacrificial carbon layer and a sandwich structure for the template. The thin residual carbon film transferred from the template is removed from the nanopatterned surface by dry etching, as demonstrated by x-ray photoelectron spectroscopy and, for metal nanoparticles embedded in a glass surface, by a shift in the absorption of the localized surface plasmon resonance. We show that gold nanoparticles in a glass surface can be selectively functionalized with thiols yielding about 2 nm height increase. Atomic force microscopy and localized surface plasmon resonance spectroscopy both indicate that the nanoparticle shape is preserved well. PMID- 21817758 TI - Periodic arrays of deep nanopores made in silicon with reactive ion etching and deep UV lithography. AB - We report on the fabrication of periodic arrays of deep nanopores with high aspect ratios in crystalline silicon. The radii and pitches of the pores were defined in a chromium mask by means of deep UV scan and step technology. The pores were etched with a reactive ion etching process with SF(6), optimized for the formation of deep nanopores. We have realized structures with pitches between 440 and 750 nm, pore diameters between 310 and 515 nm, and depth to diameter aspect ratios up to 16. To the best of our knowledge, this is the highest aspect ratio ever reported for arrays of nanopores in silicon made with a reactive ion etching process. Our experimental results show that the etching rate of the nanopores is aspect-ratio-dependent, and is mostly influenced by the angular distribution of the etching ions. Furthermore we show both experimentally and theoretically that, for sub-micrometer structures, reducing the sidewall erosion is the best way to maximize the aspect ratio of the pores. Our structures have potential applications in chemical sensors, in the control of liquid wetting of surfaces, and as capacitors in high-frequency electronics. We demonstrate by means of optical reflectivity that our high-quality structures are very well suited as photonic crystals. Since the process studied is compatible with existing CMOS semiconductor fabrication, it allows for the incorporation of the etched arrays in silicon chips. PMID- 21817759 TI - Surface enhanced Raman scattering on long-range ordered noble-metal nanocrescent arrays. AB - Long-range ordered noble-metal nanocrescent arrays of different sizes and shapes have been successfully fabricated by using both nanoimprint lithography and e beam lithography techniques. Large surface enhanced Raman scattering (SERS) enhancements in the detection of rhodamine 6G (R6G) molecules on these arrays have been observed and attributed to the enhancement of the local electromagnetic (EM) fields near individual nanocrescents. Electromagnetic enhancement factors for crescents of different shapes are computed using the discrete dipole approximation and compared with experimental measurements of the R6G Raman intensities. It is found that the maximum values of SERS intensity appear at an intermediate value of the crescent eccentricity and the observed behaviour is related to the spatial distributions of the enhancement of the local EM field (hot spots). PMID- 21817760 TI - Variation of ZnO shell thickness and its effects on the characteristics of coaxial nanowires. AB - We have changed the thickness of the ZnO shell layers in SiO(x)/ZnO core-shell nanowires by increasing the atomic layer deposition (ALD) cycle, using diethylzinc (DEZn) and H(2)O as precursors of Zn and O, respectively. The samples were characterized by means of x-ray diffraction (XRD), scanning electron microscopy, transmission electron microscopy, and photoluminescence (PL) spectroscopy. While the thickness of the ZnO shell layers increased almost linearly with increase of the ALD cycle, their tubular morphologies were maintained. The variation in the thickness of the ZnO shell layers was accompanied by changes in the relative intensities of the characteristic ultraviolet (UV) and visible emission bands and by a shift of the UV peak position. On the basis of the observed relationship between the XRD shell grain size and the PL shift, we suggest that the PL shift is attributable to an exciton confinement effect. The findings in this study can be applied to a wide range of materials, and are expected to contribute to the development of potential applications of coaxial nanowires. PMID- 21817761 TI - Self-assembled palladium nanoparticles on carbon nanofibers. AB - Carbon nanofibers containing palladium nanoparticles were prepared simply by electrospinning a polymer solution containing palladium chloride and the subsequent thermal treatment in argon. It is demonstrated that palladium oxide formed in air stabilization transforms into nanoparticles through an interaction with carbon materials. Since the palladium nanoparticles covering the outer surface of nanofibers homogeneously are small enough to have high catalytic activity, this material could find applications as efficient catalysts and hydrogen sensors. PMID- 21817762 TI - Optical and electrical properties of indium tin oxide nanofibers prepared by electrospinning. AB - Indium tin oxide (ITO) nanofibers were successfully prepared via an electrospinning method, followed by annealing at 400 degrees C. Mixed solutions of ITO nanoparticle sol and polyethylene oxide (PEO) were used as precursors of the nanofibers. The PEO decomposed during annealing to yield ITO fibers. The fibers were characterized by scanning electron microscopy (SEM), x-ray diffraction (XRD), thermo-gravimetric/differential thermal analysis (TG/DTA), UV vis spectrophotometry and four-probe resistivity measurements. The diameter of the prepared fibers was controlled by adjusting the flow rate and the applied electric current. In(2)O(3) crystallized in the ITO nanofibers with a crystallite size of 27 nm. The optical transmittance in the visible region approached 90% in films deposited for 5 min, confirming that the nanofiber film is still transparent in the optical region. The sheet resistance of the nanofiber film was linearly dependent on the inverse of the deposition time and on the PEO/ITO ratio. PMID- 21817763 TI - The photoluminescence of SrS:Cu nanophosphor. AB - Strontium sulfide doped with copper has been regarded as one of the most promising inorganic materials for the blue-green color phosphor. A wet chemical precipitation method with post-annealing is presented for the synthesis of copper doped SrS nanoparticles. XRD studies revealed the phase purity of SrS particles with rocksalt structure. TEM images showed the formation of nanoparticles with an average size of 7 nm. Green photoluminescence emission (PL) at 535 nm was observed for an excitation wavelength of 356 nm, the intensity of which was greater than that of coarser phosphor particles synthesized by solid state reaction. Low temperature PL showed a redshift with decreasing temperature which is due to aggregated copper centers. Luminescent decay at room temperature was found to be faster than the reported values of the corresponding transition in thin film samples. A blueshift in the absorption edge was observed for the nanophosphor with respect to the bulk due to reduction in particle size. PMID- 21817764 TI - Phase-pure TiO(2) nanoparticles: anatase, brookite and rutile. AB - We report on the synthesis of phase-pure TiO(2) nanoparticles in anatase, rutile and brookite structures, using amorphous titania as a common starting material. Phase formation was achieved by hydrothermal treatment at elevated temperatures with the appropriate reactants. Anatase nanoparticles were obtained using acetic acid, while phase-pure rutile and brookite nanoparticles were obtained with hydrochloric acid at a different concentration. The nanomaterials were characterized using x-ray diffraction, UV-visible reflectance spectroscopy, dynamic light scattering, and transmission electron microscopy. We propose that anatase formation is dominated by surface energy effects, and that rutile and brookite formation follows a dissolution-precipitation mechanism, where chains of sixfold-coordinated titanium complexes arrange into different crystal structures depending on the reactant chemistry. The particle growth kinetics under hydrothermal conditions are determined by coarsening and aggregation recrystallization processes, allowing control over the average nanoparticle size. PMID- 21817765 TI - Fabrication of CuTAPc polymer nanowires and nanotubes by electropolymerization. AB - Poly-copper tetraaminophthalocyanine (CuTAPc) nanowires and nanotubes were successfully fabricated on porous alumina templates by electropolymerization and characterized using field-emission scanning electron microscopy (FE-SEM), energy dispersive x-ray spectroscopy (EDX), transmission electron microscopy (TEM) and Raman microscopy. The lengths of these nanostructures could be controlled by the number of cycles applied and the monomer concentrations, while their diameters are confined by the pore size of the template. The product of electropolymerization (whether as nanowires or nanotubes) is a function of the monomer concentrations. The morphology of electropolymerized nanowires was found to be sensitive to the changes in scan rates and monomer concentrations. These organometallic nanostructures may have applications in micro-electronics, chemical sensing, and catalysis. PMID- 21817766 TI - Synthesis, characterization and application in electrocatalysis of polyaniline/Au composite nanotubes. AB - Polyaniline (PANI) nanotubes were successfully synthesized using the hydrothermal method via an in situ polymerization. In the process, a fibrillar complex of FeCl(3) and methyl orange (MO), acting as the reactive self-degraded templates, directed the growth of PANI on its surface and promoted the assembly into nanotubular structures. By introducing PANI nanotubes into Au colloid, Au nanoparticles (NPs) could be decorated onto the PANI nanotube surface through the electrostatic effect. The morphology of the nanotubes and the number of decorated Au NPs could be controlled effectively by adjusting the experimental conditions. The resulting products were characterized by transmission electron microscopy (TEM), x-ray diffraction (XRD), x-ray photoelectron spectroscopy (XPS) and Fourier transform infrared spectroscopy (FTIR). In addition, the electrocatalytic activity of the composites towards the oxidation of NADH (nicotinamide adenine dinucleotide) was studied by immobilizing PANI/Au composites on the surface of a glassy carbon electrode (GCE). PMID- 21817767 TI - Experimental study on the surface modification of Y(2)O(3):Tm(3+)/Yb(3+) nanoparticles to enhance upconversion fluorescence and weaken aggregation. AB - In order to improve the solubility of doped nanoparticles in solutions, Y(2)O(3):Tm(3+)/Yb(3+) nanoparticles were synthesized using the Pechini-type sol gel method, and their surfaces were modified with amino or carboxylic functional groups using ligand-capped and ligand-exchanging methods. The nanoparticles with modified surfaces were characterized by transmission electron microscopy (TEM), Fourier transform infrared (FT-IR) spectroscopy and zeta potential (zeta), and their photoluminescence was studied by fluorescence spectrophotometry. The results indicate that the upconversion fluorescence of amine- and carboxyl modified nanoparticles was enhanced after the surfaces of nanoparticles were modified. Compared to the upconversion fluorescence intensity of non-modified nanoparticles, the upconversion fluorescence intensities of amine- and carboxyl modified nanoparticles were enhanced by 9.4 and 1.4 times, respectively. These results are attributed to the formation of the chemical bonds between Y(2)O(3):Tm(3+)/Yb(3+) core and non-crystalline SiO(2) shell via Y-O-Si bridges, which activate the 'dormant' Tm(3+)/Yb(3+) ions on the surfaces of nanoparticles. The results of the solubility investigations for amine- and carboxyl-modified nanoparticles indicate that severe aggregation can be weakened by adhering amino or carboxylic functional groups to the surfaces of nanoparticles. It is therefore concluded that the good hydrophilicity resulting from active functional groups in solutions and more intense upconversion fluorescence enable the doped core-shell nanoparticles to have great potential to be used as fluorescence biolabels in the future. PMID- 21817768 TI - Uniform and continuous silica nanocoatings on ZnS phosphors. AB - The penetration depth of the primary electrons into amorphous silica, anatase titania, Y(2)O(3), ZnO, In(2)O(3), indium and tin oxides is compared at lower voltages. It shows that amorphous silica has the largest penetration depth, thus the silica coatings will lead to minimal energy loss and maximal cathodoluminescence intensity. Almost uniform and continuous silica coatings on ZnS phosphors have successfully been obtained by a sol-gel method with the catalysis of ammonia. Zeta potential analysis shows that the ZnS phosphors are covered almost completely. An adsorption-catalysis-growth mechanism is suggested, and used to explain other ammonia-catalyzed coating processes. PMID- 21817769 TI - Band offsets and photocurrent spectroscopy of Si/Ge heterostructures with quantum dots. AB - Raman and lateral photoconductivity spectra of self-assembled SiGe nanoislands were studied with a height of ~2 nm and a base of ~20 nm formed at a temperature of 500 degrees C. It was estimated that the value of elastic deformation (epsilon(xx)) was -0.022 (epsilon(zz) = 0.017), while the germanium content in the islands (x) was 0.66. The obtained values of x and epsilon were used to calculate band offsets at the interfaces and the energy of interband transitions of structures under study. It was shown that the minimal energy of photocurrent observation is 0.52 eV, which is below the bandgap of the QDs under study. The first photocurrent component which began to contribute at 0.52 eV and had a peak at 0.68 eV is explained by optical transitions of electrons from the QD HH localized states of the valence band to the conduction band Delta(2) valley of the surrounding silicon matrix in which tensile strains are present. The second component with limiting energy of 0.73 eV can be caused by interband electron transitions from the HH valence band of the QDs to the Delta(4) valley of the QD conduction band. PMID- 21817770 TI - A density-functional study of the structures, binding energies and magnetic moments of the clusters Mo(N) (N = 2-13), Mo(12)Fe, Mo(12)Co and Mo(12)Ni. AB - We report the results of density-functional calculations of the structures, binding energies and magnetic moments of the clusters Mo(N) (N = 2-13), Mo(12)Fe, Mo(12)Co and Mo(12)Ni that were performed using the SIESTA method within the generalized gradient approximation for exchange and correlation. For pure Mo(N) clusters, we obtain collinear magnetic structures in all cases, even when the self-consistent calculations were started from non-collinear inputs. Our results for these clusters show that both linear, planar and three-dimensional clusters have a strong tendency to form dimers. In general, even-numbered clusters are more stable than their neighbouring odd-numbered clusters because they can accommodate an integer number of tightly bound dimers. As a consequence, the binding energies of pure Mo(N) clusters, in their lowest-energy states, exhibit an odd-even effect in all dimensionalities. Odd-even effects are less noticeable in the magnetic moments than in the binding energies. When comparing our results for pure Mo clusters with those obtained recently by other authors, we observe similarities in some cases, but striking differences in others. In particular, the odd-even effect in three-dimensional Mo clusters was not observed before, and our results for some clusters (e.g. for planar Mo(3) and Mo(7) and for three dimensional Mo(7) and Mo(13)) differ from those reported by other authors. For Mo(12)Fe and Mo(12)Ni, we obtain that the icosahedral configuration with the impurity atom at the cluster surface is more stable than the configuration with the impurity at the central site, while the opposite occurs in the case of Mo(12)Co. In Mo(12)Co and Mo(12)Ni, the impurities exhibit a weak magnetic moment parallely coupled to the total magnetic moment of the Mo atoms, whereas in Mo(12)Fe the impurity shows a high moment with antiparallel coupling. PMID- 21817771 TI - Surface photovoltage analysis of thin CdS layers on polycrystalline chalcopyrite absorber layers by Kelvin probe force microscopy. AB - An extensive Kelvin probe force microscopy study in an ultrahigh vacuum has been undertaken to examine the influence of growth modifications of a few nm thick CdS buffer layers in thin film chalcopyrite solar cells. In regions around the grain boundaries of the polycrystalline Cu(In,Ga)Se(2) substrate a lowering of the work function extending to about 200 nm away from this vertical interface was observed. This electrical inhomogeneity depends strongly on the Cu(In,Ga)Se(2) surface condition and is interpreted by a diffusion process along the substrate grain boundaries. Our results contribute to the understanding of the crucial role of the several nm thick CdS layer for improving the photovoltaic performance of chalcopyrite thin film solar cells. PMID- 21817772 TI - The preparation of copper fine particle paste and its application as the inner electrode material of a multilayered ceramic capacitor. AB - Well size-controlled copper fine particles (diameter: 100-300 nm) were used as the inner electrode material of multilayered ceramic capacitors (MLCCs). The particles were dispersed in terpineol to form a printing paste with 50 wt% copper particles. The MLCC precursor modules prepared by the layer-by-layer printing of copper and BaTiO(3) particles were cosintered. Detailed observation of the particles, paste, and MLCCs before and after sintering was carried out by electron microscopy. The sintering temperature of Cu-MLCC was as low as 960 degrees C. The permittivity of these MLCCs was successfully measured with the copper inner layers. PMID- 21817773 TI - Vibrational modes of nanolines. AB - Brillouin-light-scattering spectra previously have been shown to provide information on acoustic modes of polymeric lines fabricated by nanoimprint lithography. Finite-element methods for modeling such modes are presented here. These methods provide a theoretical framework for determining elastic constants and dimensions of nanolines from measured spectra in the low gigahertz range. To make the calculations feasible for future incorporation in inversion algorithms, two approximations of the boundary conditions are employed in the calculations: the rigidity of the nanoline/substrate interface and sinusoidal variation of displacements along the nanoline length. The accuracy of these approximations is evaluated as a function of wavenumber and frequency. The great advantage of finite-element methods over other methods previously employed for nanolines is the ability to model any cross-sectional geometry. Dispersion curves and displacement patterns are calculated for modes of polymethyl methacrylate nanolines with cross-sectional dimensions of 65 nm * 140 nm and rectangular or semicircular tops. The vibrational displacements and dispersion curves are qualitatively similar for the two geometries and include a series of flexural, Rayleigh-like, and Sezawa-like modes. PMID- 21817774 TI - Structure-dependent adhesion and friction on highly ordered metallic nanopore membranes. AB - Highly ordered metallic nanopore membranes are fabricated by direct deposition of nickel on typical porous anodic alumina (PAA) templates. The large-area uniform nanopore arrays of the PAA templates are accurately transferred to the metallic nanopore replicas, depending on the thickness of the deposited metal and the pore size of the base template. We demonstrate the ready tunability of the pore size and reproducibility of the metallic nanopore structure in a wide range of pore sizes. The adhesion and friction characteristics of the metallic replicas are studied according to the pore size using atomic force microscopy (AFM). As the pore diameter increases, the friction coefficients increase nonlinearly, and the adhesive forces scarcely change. These characteristics are understood in terms of the structural properties of the replicas, specifically the surface morphology and the real contact area. Initial pore formation from a flat thin film reduces the adhesive force by up to four times. PMID- 21817775 TI - Voltage-pulse-induced electromigration. AB - We propose and demonstrate a voltage-pulse-induced electromigration technique, in which electromigration in a gold nanowire is induced for a short period of about 10 us by applying a voltage pulse. A local temperature analysis and a controlled electromigration experiment in the presence of voltage pulses indicate successful control of this voltage-pulsed-induced electromigration. We also measured the current-voltage characteristics of the nanowire after the application of each single voltage pulse to investigate the stochastic behavior of electromigration. A pulse duration shorter than the thermal relaxation time of the nanowire would allow us to separately control the local temperature and driving force for electromigration. PMID- 21817776 TI - Particles and crystallites under electrical explosion of wires. AB - The data produced shed new light on particle formation under fast Joule heating: the particle size depends on the initial size of the crystallites of a metal. The size of crystallites has been determined by the x-ray diffraction method as the size of the region of coherent scattering d(RCS). Median-surface particle sizes d(S) of the powder have been evaluated from the specific surface area S (BET). Such different metals as Al, In, Cu, Ti have been investigated. For the given metals, d(RCS) varies from 25 to 77 nm, d(S) of the powder varies from 45 to 200 nm, and d(S) is the smaller, the smaller is d(RCS). On this evidence, from the beginning of heating, the power of Joule dissipation is higher at the boundaries of crystallites. As a result, even at the energy introduced in the wire equal to the sublimation energy, 'a gas of drops' is formed instead of 'a gas of atoms'. PMID- 21817777 TI - Selective optical pumping of charged excitons in unintentionally doped InAs quantum dots. AB - We have investigated the selective optical pumping of charged excitonic species in a sample containing quantum dots of different sizes and low areal density by photoluminescence and excitation of the photoluminescence microspectroscopy. We study the selective optical excitation of negatively charged excitons as an alternative to commonly used electrical methods. We demonstrate that under resonant excitation in impurity related bands, the selective pumping efficiency can be as high as 85% in small quantum dots having one electron shell and emitting at around 930 nm, and around 65% in big quantum dots having four electron shells and emitting at 1160 nm. PMID- 21817778 TI - sw-SVM: sensor weighting support vector machines for EEG-based brain-computer interfaces. AB - In many machine learning applications, like brain-computer interfaces (BCI), high dimensional sensor array data are available. Sensor measurements are often highly correlated and signal-to-noise ratio is not homogeneously spread across sensors. Thus, collected data are highly variable and discrimination tasks are challenging. In this work, we focus on sensor weighting as an efficient tool to improve the classification procedure. We present an approach integrating sensor weighting in the classification framework. Sensor weights are considered as hyper parameters to be learned by a support vector machine (SVM). The resulting sensor weighting SVM (sw-SVM) is designed to satisfy a margin criterion, that is, the generalization error. Experimental studies on two data sets are presented, a P300 data set and an error-related potential (ErrP) data set. For the P300 data set (BCI competition III), for which a large number of trials is available, the sw SVM proves to perform equivalently with respect to the ensemble SVM strategy that won the competition. For the ErrP data set, for which a small number of trials are available, the sw-SVM shows superior performances as compared to three state of-the art approaches. Results suggest that the sw-SVM promises to be useful in event-related potentials classification, even with a small number of training trials. PMID- 21817779 TI - Magnetic carbon nanotubes with particle-free surfaces and high drug loading capacity. AB - Open-ended, multi-wall carbon nanotubes (CNTs) with magnetic nanoparticles encapsulated within their graphitic walls (magCNTs) were fabricated by a combined action of templated growth and a ferrofluid catalyst/carbon precursor, and tested as drug hosts. The hybrid nanotubes are stable under extreme pH conditions due to particle protection provided by the graphitic shell. The magCNTs are promising for high capacity drug loading given that the magnetic functionalization did not block any of the active sites available for drug attachment, either from the CNT internal void or on the internal and external surfaces. This is in contrast to typical approaches of loading CNTs with particles that proceed through surface attachment or capillary filling of the tube interior. Additionally, the CNTs exhibit enhanced hydrophilic character, as shown by water adsorption measurements, which make them suitable for biological applications. The morphological and structural characteristics of the hybrid CNTs are evaluated in conjunction to their magnetic properties and ability for drug loading (diaminophenothiazine). The fact that the magnetic functionality is provided from 'inside the walls' can allow for multimode functionalization of the graphitic surfaces and makes the magCNTs promising for targeted therapeutic applications. PMID- 21817780 TI - One-step substrate nanofabrication and patterning of nanoparticles by lithographically controlled etching. AB - We propose an integrated top-down and bottom-up approach to single-step nanofabrication of complex nanostructures made of different materials. The process, termed lithographically controlled etching (LCE), starts with a drop of an etching solution cast on the surface to be patterned. By placing a polymeric mold on the substrate, the stamp protrusions come into contact with the surface, thus protecting it, whereas the surface beneath the mold recesses is exposed to a thin layer of etching solution, allowing the surface to be etched. By dispersing nanoparticles into the etching solution, these can be deposited and self-organize in the recesses on the substrate as these are excavated. We demonstrate here the fabrication of complex structures and nanowires 30 nm wide. Moreover, by exploiting capillary forces, it is possible to deposit nanoparticles at precise positions with respect to optically addressable microstructures, thus realizing a multiscale functional pattern. PMID- 21817781 TI - Quantitative in situ TEM tensile testing of an individual nickel nanowire. AB - In this paper, we have demonstrated the usage of a novel micro-mechanical device (MMD) to perform quantitative in situ tensile tests on individual metallic nanowires inside a transmission electron microscope (TEM). Our preliminary experiment on a 360 nm diameter nickel nanowire showed that the sample fractured at an engineering stress of ~ 1.2 GPa and an engineering strain of ~ 4%, which is consistent with earlier experiments performed inside a scanning electron microscope (SEM). With in situ high resolution TEM imaging and diffraction capabilities, this novel experimental set-up could provide unique opportunities to reveal the underlying deformation and damage mechanisms for metals at the nanoscale. PMID- 21817782 TI - Focused ion beam creation and templating of InAs and InAs/InP nanospikes. AB - Ion beam irradiation has been examined as a method for creating nanoscale semiconductor pillar and cone structures, but has the drawback of inaccurate nanostructure placement. We report on a method for creating and templating nanoscale InAs spikes by focused ion beam (FIB) irradiation of both homoepitaxial InAs films and heteroepitaxial InAs on InP substrates. These 'nanospikes' are created as In droplets, formed due to FIB irradiation, act as etch masks for the underlying InAs. By pre-patterning the InAs to influence In droplet movement, nanospike locations on homoepitaxial InAs may be controlled with limited accuracy. Creating nanospikes using an InAs/InP heterostructure provides an additional measure of control over where the spikes form because nanospikes will not form on exposed regions of InP. This effect may be exploited to accurately control nanospike placement by pre-patterning an InAs/InP heterostructure to control the location of the InAs/InP interface. Using this heterostructure templating method it is possible to accurately place nanospikes into regular arrays that may be useful for a variety of applications. PMID- 21817783 TI - Exceptional plasticity of silicon nanobridges. AB - The plasticity of covalently bonded materials is a subject at the forefront of materials science, bearing on a wide range of technological and fundamental aspects. However, covalent materials fracture in a brittle manner when the deformation exceeds just a few per cent. It is predicted that a macroscopically brittle material like silicon can show nanoscale plasticity. Here we report the exceptional plasticity observed in silicon nanocontacts ('nanobridges') at room temperature using a special experimental setup combining a transmission electron microscope and a microelectromechanical system. When accounting for surface diffusion, we succeeded in elongating the nanocontact into a wire-like structure, with a fivefold increase in volume, up to more than twenty times the original length. Such a large plasticity was caused by the stress-assisted diffusion and the sliding of the intergranular, amorphous-like material among the nanocrystals. PMID- 21817784 TI - Quantification of carbon nanotube induced adhesion of osteoblast on hydroxyapatite using nano-scratch technique. AB - This paper explores the nano-scratch technique for measuring the adhesion strength of a single osteoblast cell on a hydroxyapatite (HA) surface reinforced with carbon nanotubes (CNTs). This technique efficiently separates out the contribution of the environment (culture medium and substrate) from the measured adhesion force of the cell, which is a major limitation of the existing techniques. Nano-scratches were performed on plasma sprayed hydroxyapatite (HA) and HA-CNT coatings to quantify the adhesion of the osteoblast. The presence of CNTs in HA coating promotes an increase in the adhesion of osteoblasts. The adhesion force and energy of an osteoblast on a HA-CNT surface are 17 +/- 2 uN/cell and 78 +/- 14 pJ/cell respectively, as compared to 11 +/- 2 uN/cell and 45 +/- 10 pJ/cell on a HA surface after 1 day of incubation. The adhesion force and energy of the osteoblasts increase on both the surfaces with culture periods of up to 5 days. This increase is more pronounced for osteoblasts cultured on HA CNT. Staining of actin filaments revealed a higher spreading and attachment of osteoblasts on a surface containing CNTs. The affinity of CNTs to conjugate with integrin and other proteins is responsible for the enhanced attachment of osteoblasts. Our results suggest that the addition of CNTs to surfaces used in medical applications may be beneficial when stronger adhesion of osteoblasts is desired. PMID- 21817785 TI - Periodically porous top electrodes on vertical nanowire arrays for highly sensitive gas detection. AB - Nanowires of various materials and configurations have been shown to be highly effective in the detection of chemical and biological species. In this paper, we report a novel, nanosphere-enabled approach to fabricating highly sensitive gas sensors based on ordered arrays of vertically aligned silicon nanowires topped with a periodically porous top electrode. The vertical array configuration helps to greatly increase the sensitivity of the sensor while the pores in the top electrode layer significantly improve sensing response times by allowing analyte gases to pass through freely. Herein, we show highly sensitive detection to both nitrogen dioxide (NO(2)) and ammonia (NH(3)) in humidified air. NO(2) detection down to 10 parts per billion (ppb) is demonstrated and an order-of-magnitude improvement in sensor response time is shown in the detection of NH(3). PMID- 21817786 TI - Molecular absorption and photodesorption in pristine and functionalized large area graphene layers. AB - We studied the photodesorption behavior of pristine and nitric acid (HNO(3)) treated graphene layers fabricated by chemical vapor deposition (CVD). The decrease in electrical conductivity and a negative shift of the Dirac point in graphene layers illuminated with ultraviolet light are caused by molecular photodesorption, while the UV illumination does not degrade the carrier mobility of graphene layers. When graphene layers were treated with concentrated HNO(3), the photodesorption-induced current decrease became less significant than for pristine graphene layers. We suggest this is due to the passivation of oxygen bearing functionalities to CVD grown graphene structural defects by HNO(3) functionalization, which prevents the further absorption of gas molecules. Our results provide a new strategy for stabilizing the electrical performance of CVD grown large-area graphene layers for applications ranging from nanoelectronics to optoelectronics. PMID- 21817787 TI - Bio-synthesis of gold nanoparticles by human epithelial cells, in vivo. AB - Healthy epithelial cells, in vivo, have the ability to synthesize gold nanoparticles when aqueous tetrachloroauric acid is made to react with human skin. Neither a reducing agent nor a protecting chemical is needed for this bio synthesis method. The first indication of gold nanoparticle formation is the staining of the skin, which turns deep purple. Stereoscopic optical micrographs of human skin tissue in contact with aqueous tetrachloroauric acid clearly show the staining of the epithelial cells. The UV-Vis spectrum of these epithelial cells shows an absorption band with a maximum at 553 nm. This absorption peak is within the wavelength region where the surface plasmon resonance (SPR) band of aqueous colloidal gold exhibits a maximum. Transmission electron micrographs show that gold nanoparticles synthesized by epithelial cells have sizes between 1 and 100 nm. The electron diffraction pattern of these nanoparticles reveals a crystalline structure whose interplanar distances correspond to fcc metallic gold. Transmission electron micrographs of ultra-thin (70 nm thick) slices of epithelial cells clearly and undoubtedly demonstrate that gold nanoparticles are inside the cell. According to high resolution transmission electron micrographs of intracellular single gold nanoparticles, they have the shape of a polyhedron. PMID- 21817788 TI - Tetraaquabis(2,6-diamine-7H-purine-kappaN9)cobalt(II) benzene-1,2,4,5 tetracarboxylate tetrahydrate. AB - The title compound, [Co(C(5)H(7)N(6))(2)(H(2)O)(4)](C(10)H(2)O(8)).4H(2)O, is an ionic structure comprising a [Co(Hdap)(2)(H(2)O)(4)](4+) cation (dap is 2,6 diaminopurine) in a general position, two benzene-1,2,4,5-tetracarboxylate (btc(4 )) anions straddling two different inversion centres and four solvent water molecules. The structure presents a remarkable degree of pseudosymmetry, with the Co(II) cation lying almost exactly on a noncrystallographic pseudo-inversion centre. The overall spatial arrangement can be described in terms of cationic and anionic chains running along the [111] direction and linked into a three dimensional network by a very complex hydrogen-bonding scheme in which all the available N-H and O-H groups take part. PMID- 21817789 TI - The bis(acetonitrile-kappaN)bis[N,N-bis(diphenylphosphanyl)ethanamine kappa2P,P']iron(II) tetrabromidoferrate(II) and MU-oxido bis[tribromidoferrate(III)] complex salts. AB - Orange crystals of bis(acetonitrile-kappaN)bis[N,N bis(diphenylphosphanyl)ethanamine-kappa(2)P,P']iron(II) tetrabromidoferrate(II), [Fe(CH(3)CN)(2)(C(26)H(25)NP(2))(2)][FeBr(4)], (I), and red crystals of bis(acetonitrile-kappaN)bis[N,N-bis(diphenylphosphanyl)ethanamine kappa(2)P,P']iron(II) MU-oxido-bis[tribromidoferrate(III)], [Fe(CH(3)CN)(2)(C(26)H(25)NP(2))(2)][Fe(2)Br(6)O], (II), were obtained from the same solution after prolonged exposure to atmospheric oxygen, resulting in partial oxidation of the [FeBr(4)](2-) anion to the [Br(3)FeOFeBr(3)](2-) anion. The asymmetric unit of (I) consists of three independent cations, one on a general position and two on inversion centres, with two anions, required to balance the charge, located on general positions. The asymmetric unit of (II) consists of two independent cations and two anions, all on special positions. The geometric parameters within the coordination environments of the cations do not differ significantly, with the major differences being in the orientation of the phenyl rings on the bidentate phosphane ligand. The ethyl substituent in the cation of (II) and the Br atoms in the anions of (II) are disordered. The P-Fe-P bite angles represent the smallest angles reported to date for octahedral Fe(II) complexes containing bidentate phosphine ligands with MeCN in the axial positions, ranging from 70.82 (3) to 70.98 (4) degrees . The average Fe-Br bond distances of 2.46 (2) and 2.36 (2) A in the [FeBr(4)](2-) and [Br(3)FeOFeBr(3)](2 ) anions, respectively, illustrate the differences in the Fe oxidation states. PMID- 21817790 TI - A rare 'mesh of trees' (mot) net: poly[aquahemi[MU4-1,6-bis(1,2,4-triazol-1 yl)hexane](MU2-5-nitroisophthalato)cadmium(II)]. AB - In the title coordination compound, [Cd(C(8)H(3)NO(6))(C(5)H(8)N(3))(0.5)(H(2)O)](n), each Cd(II) atom is six coordinated in a distorted octahedral environment surrounded by three carboxylate O atoms from two different 5-nitroisophthalate (5-NIP(2-)) ligands, two N atoms from two distinct 1,6-bis(1,2,4-triazol-1-yl)hexane (bth) ligands and one water molecule. The Cd(II) centres are bridged by the bth ligands, which lie across centres of inversion, to give a honeycomb-like two-dimensional layer structure; the layers are further connected by the bridging 5-NIP(2-) ligands with a kappa(2);kappa(1)-MU(2) coordination mode to generate the final three-dimensional structure. Topologically, taking the the Cd(II) atoms and the bth ligands as different four-connected nodes and the 5-NIP(2-) ligands as linkers, the three dimensional structure can be simplified to a rare 'mesh of trees' (mot) net with the Schafli symbol (6(6))(6(4).8(2))(2). PMID- 21817791 TI - Five related N'-(2,2,2-trichloroethanimidoyl)benzene-1-carboximidamides. AB - In the solid state, 4-methoxy-N'-(2,2,2-trichloroethanimidoyl)benzene-1 carboximidamide, C(10)H(10)Cl(3)N(3)O, (I), N'-(2,2,2 trichloroethanimidoyl)benzene-1-carboximidamide, C(9)H(8)Cl(3)N(3), (II), 4 chloro-N'-(2,2,2-trichloroethanimidoyl)benzene-1-carboximidamide, C(9)H(7)Cl(4)N(3), (III), 4-bromo-N'-(2,2,2-trichloroethanimidoyl)benzene-1 carboximidamide, C(9)H(7)BrCl(3)N(3), (IV), and 4-trifluoromethyl-N'-(2,2,2 trichloroethanimidoyl)benzene-1-carboximidamide, C(10)H(7)Cl(3)F(3)N(3), (V), display strong intramolecular N-H...N hydrogen bonding across the chelate ring and also intramolecular N-H...Cl contacts. Additional intermolecular hydrogen bonds link the molecules into chains, double chains or sheets in all cases except for compound (V). For compound (II), there are three independent molecules per asymmetric unit. PMID- 21817792 TI - N-(tert-butoxycarbonyl)-L-valyl-L-valine methyl ester: a twisted parallel beta sheet in the crystal structure of a protected dipeptide. AB - The title compound, C(16)H(30)N(2)O(5), crystallizes with three molecules in the asymmetric unit, each adopting a beta-strand/polyproline II backbone conformation. The main-chain functional groups are hydrogen bonded into tapes having the characteristics of parallel beta-sheets. Each tape has a left-handed twist and thus forms a helix, with six peptide molecules needed to complete a full 360 degrees rotation. A comparison of hydrogen-bond lengths and twisting modes is made with other related structures of protected dipeptides and with a hexapeptide derived from amyloid-beta containing the Val-Val segment. Additionally, a comparison of the backbone conformation is made with that of the Val141-Val142 segment of the water channel aquaporin-4 (AQP4). PMID- 21817793 TI - N-(tert-butoxycarbonyl)-alpha-aminoisobutyryl-alpha-aminoisobutyric acid methyl ester: two polymorphic forms in the space group P2(1)/n. AB - The title compound (systematic name: methyl 2-{2-[(tert-butoxycarbonyl)amino]-2 methylpropanamido}-2-methylpropanoate), C(14)H(26)N(2)O(5), (I), crystallizes in the monoclinic space group P2(1)/n in two polymorphic forms, each with one molecule in the asymmetric unit. The molecular conformation is essentially the same in both polymorphs, with the alpha-aminoisobutyric acid (Aib) residues adopting phi and psi values characteristic of alpha-helical and mixed 3(10)- and alpha-helical conformations. The helical handedness of the C-terminal residue (Aib2) is opposite to that of the N-terminal residue (Aib1). In contrast to (I), the closely related peptide Boc-Aib-Aib-OBn (Boc is tert-butoxycarbonyl and Bn is benzyl) adopts an alpha(L)-P(II) backbone conformation (or the mirror image conformation). Compound (I) forms hydrogen-bonded parallel beta-sheet-like tapes, with the carbonyl groups of Aib1 and Aib2 acting as hydrogen-bond acceptors. This seems to represent an unusual packing for a protected dipeptide containing at least one alpha,alpha-disubstituted residue. PMID- 21817794 TI - Extensive hydrogen and halogen bonding, and absence of intramolecular hydrogen bonding between alcohol and nitro groups in a series of endo-nitronorbornanol compounds. AB - The influence of the substituent at the C2 position on the hydrogen-bonding patterns is compared for a series of five related compounds, namely (+/-)-3-exo,6 exo-dibromo-5-endo-hydroxy-3-endo-nitrobicyclo[2.2.1]heptane-2-exo-carbonitrile, C(8)H(8)Br(2)N(2)O(3), (II), (+/-)-3-exo,6-exo-dibromo-6-endo-nitro-5-exo phenylbicyclo[2.2.1]heptan-2-endo-ol, C(13)H(13)Br(2)NO(3), (III), (+/-)-methyl 3 exo,6-exo-dibromo-5-endo-hydroxy-3-endo-nitrobicyclo[2.2.1]heptane-2-exo carboxylate, C(9)H(11)Br(2)NO(5), (IV), (+/-)-methyl 3-exo,6-exo-dibromo-7 diphenylmethylidene-5-endo-hydroxy-3-endo-nitrobicyclo[2.2.1]heptane-2-exo carboxylate, C(22)H(19)Br(2)NO(5), (V), and (+/-)-methyl 3-exo,6-exo-dibromo-5 endo-hydroxy-3-endo-nitro-7-oxabicyclo[2.2.1]heptane-2-exo-carboxylate, C(8)H(9)Br(2)NO(6), (VI). The hydrogen-bonding motif in all five compounds is a chain, formed by O-H...O hydrogen bonds in (III), (IV), (V) and (VI), and by O H...N hydrogen bonds in (II). All compounds except (III) contain a number of Br...Br and Br...O halogen bonds that connect the chains to each other to form two-dimensional sheets or three-dimensional networks. None of the compounds features intramolecular hydrogen bonding between the alcohol and nitro functional groups, as was found in the related compound (+/-)-methyl 3-exo,6-exo-dichloro-5 endo-hydroxy-3-endo-nitrobicyclo[2.2.1]heptane-2-exo-carboxylate, (I) [Boeyens, Denner & Michael (1984b). J. Chem. Soc. Perkin Trans. 2, pp. 767-770]. The crystal structure of (V) exhibits whole-molecule disorder. PMID- 21817795 TI - (4aR,8aS,9aR,10aS)-8a,9a-difluoro-1,4,4a,5,8,8a,9,9a,10,10a-decahydroanthracene 4a,10a-diol hemihydrate. AB - The title compound, C(14)H(18)F(2)O(2).0.5H(2)O, a hemihydrate of a C(s) symmetric unsaturated difluorodiol, crystallizes in the centrosymmetric space group P2/m (Z = 4). The asymmetric unit contains two crystallographically independent difluorodiol half-molecules, occupying the mirror planes at (x, 0, z) and (x, 1/2, z), and half a molecule of water, lying on the twofold axis at (0, y, 0). Four difluorodiol molecules self-assemble around each solvent water molecule via O-H...O hydrogen bonds in a near tetrahedral symmetry to generate a cylindrical column-like architecture. PMID- 21817796 TI - Glycinium semi-malonate and a glutaric acid-glycine cocrystal: new structures with short O-H...O hydrogen bonds. AB - Glycinium semi-malonate, C(2)H(6)NO(2)(+).C(3)H(3)O(4)(-), (I), and glutaric acid glycine (1/1), C(2)H(5)NO(2).C(5)H(8)O(4), (II), are new examples of two component crystal structures containing glycine and carboxylic acids. (II) is the first example of a glycine cocrystal which cannot be classified as a salt, as glutaric acid remains completely protonated. In the structure of (I), there are chains formed exclusively by glycinium cations, or exclusively by malonate anions, and these chains are linked with each other. Two types of very short O H...O hydrogen bonds are present in the structure of (I), one linking glycinium cations with malonate anions, and the other linking malonate anions with each other. In contrast to (I), no direct linkages between molecules of the same type can be found in (II); all the hydrogen-bonded chains are heteromolecular, with molecules of neutral glutaric acid alternating with glycine zwitterions, linked by two types of short O-H...O hydrogen bonds. PMID- 21817797 TI - Concomitant polymorphism in the stereoselective synthesis of a beta-benzyl-beta hydroxyaspartate analogue. AB - Two concomitant polymorphs, (I) and (II), of a beta-benzyl-beta-hydroxyaspartate analogue [systematic name: dibenzyl 2-benzyl-2-hydroxy-3-(4 methylphenylsulfonamido)succinate], C(32)H(31)NO(7)S, crystallize from a mixture of ethyl acetate and cyclohexane at ambient temperature. The structure of (I) has triclinic (P-1) symmetry and that of (II) monoclinic (P2(1)/c) symmetry. Both crystal structures are made up of a stacking of homochiral racemic dimers (2S,3S and 2R,3R) which are internally connected by a similar R(2)(2)(9) hydrogen bonding pattern consisting of intermolecular N-H...O and O-H...O hydrogen bonds. The centroid of the racemic dimer lies on an inversion centre. The main structural difference between the two polymorphs is the conformational orientation of two of the four aromatic rings present in the molecule. Polymorph (II) is found to be twinned by reticular merohedry with twin index 3 and twin fractions 0.854 (1) and 0.146 (1). PMID- 21817798 TI - A 2:1 sulfamethazine-theophylline cocrystal exhibiting two tautomers of sulfamethazine. AB - In the title cocrystal, 4-amino-N-(4,6-dimethylpyrimidin-2-yl)benzenesulfonamide 4-amino-N-(4,6-dimethyl-1,2-dihydropyrimidin-2-ylidene)benzenesulfonamide-1,3 dimethyl-7H-purine-2,6-dione (1/1/1), C(7)H(8)N(4)O(2).2C(12)H(14)N(4)O(2)S, two sulfamethazine molecules cocrystallize with a single molecule of theophylline. Each molecule of sulfamethazine forms a hydrogen-bonded ribbon along the b axis crosslinked by further hydrogen bonding. The two sulfamethazine molecules exhibit a hydrogen-shift isomerization so that the crystal structure contains both tautomeric forms. Calculation of their relative energies showed that the tautomer protonated at the chain N atom is considerably more stable than the one where an N atom in the aromatic ring is protonated. The latter, here observed for the first time, is stabilized through strong intermolecular interactions with the theophylline molecules. PMID- 21817799 TI - Solvatomorphism in (E)-2-(2,6-dichloro-4 hydroxybenzylidene)hydrazinecarboximidamide. AB - The structures of orthorhombic (E)-4-(2-{[amino(iminio)methyl]amino}vinyl)-3,5 dichlorophenolate dihydrate, C(8)H(8)Cl(2)N(4)O.2H(2)O, (I), triclinic (E)-4-(2 {[amino(iminio)methyl]amino}vinyl)-3,5-dichlorophenolate methanol disolvate, C(8)H(8)Cl(2)N(4)O.2CH(4)O, (II), and orthorhombic (E)-amino[(2,6-dichloro-4 hydroxystyryl)amino]methaniminium acetate, C(8)H(9)Cl(2)N(4)O(+).C(2)H(3)O(2)(-), (III), all crystallize with one formula unit in the asymmetric unit, with the molecule in an E configuration and the phenol H atom transferred to the guanidine N atom. Although the molecules of the title compounds form extended chains via hydrogen bonding in all three forms, owing to the presence of different solvent molecules, those chains are connected differently in the individual forms. In (II), the molecules are all coplanar, while in (I) and (III), adjacent molecules are tilted relative to one another to varying degrees. Also, because of the variation in hydrogen-bond-formation ability of the solvents, the hydrogen bonding arrangements vary in the three forms. PMID- 21817800 TI - Iminopyrrole derivatives containing electron-withdrawing substituents: the formation of dimers and supramolecular arrangements. AB - The crystal structures of two p-substituted phenylformiminopyrrole derivatives, namely 2-[(4-fluorophenyl)iminomethyl]pyrrole, C(11)H(9)FN(2), (1), and 2-[(1H pyrrol-2-ylmethylidene)amino]benzonitrile, C(12)H(9)N(3), (2), bear F and C[triple-bond]N electron-withdrawing groups, respectively. Both structures feature two independent molecules in the asymmetric unit forming dimers via N H...N hydrogen bonds. In the case of (1), each dimer interacts with two other dimers via C-H...F contacts, thus forming one-dimensional chains in the b direction, whereas in the case of (2), a weak C-H...N interaction connects the dimers in one-dimensional chains in the (110) direction. PMID- 21817801 TI - Conformations of diester triphenylphosphonium ylides with an ylidic ester or keto and ester ylidic groups. AB - The structures of three related keto diester and diester ylides, namely diethyl 3 oxo-2-(triphenylphosphoranylidene)glutarate, C(27)H(27)O(5)P, (I), diethyl 3-oxo 2-(triphenylphosphoranylidene)glutarate acetic acid monosolvate, C(27)H(27)O(5)P.C(2)H(4)O(2), (II), and diethyl 2 (triphenylphosphoranylidene)succinate, C(26)H(27)O(4)P, (III), are presented. The syn-keto anti-ester conformations in the crystalline keto diesters are governed by electronic delocalization between the P-C and ylidic bonds and an acyl group, and by intra- and intermolecular interactions. There are also intramolecular attractive and repulsive interactions of different types (C-H...O and C-H...pi) controlling the molecular conformations. The mono-ylidic diester (III) has an anti-ester conformation, while those for (I) and (II) are related to pyrolytic formation of acetylene derivatives. The terminal nonylidic ester group in (I) was disordered over two sets of almost equally populated positions. PMID- 21817802 TI - Channel-forming solvate crystals and isostructural solvent-free powder of 5 hydroxy-6-methyl-2-pyridone. AB - Crystals of 5-hydroxy-6-methyl-2-pyridone, (I), grown from a variety of solvents, are invariably trigonal (space group R3); these are 5-hydroxy-6-methyl-2-pyridone acetone 0.1667-solvate, C(6)H(7)NO(2).0.1667C(3)H(6)O, (Ia), and 6-methyl-5 hydroxy-2-pyridone propan-2-ol 0.1667-solvate, C(6)H(7)NO(2).0.1667C(3)H(8)O, (Ib), and the forms from methanol, (Ic), water, (Id), benzonitrile, (Ie), and benzyl alcohol, (If). They incorporate channels running the length of the c axis that contain extensively disordered solvent molecules. A solvent-free sublimed powder of 5-hydroxy-6-methyl-2-pyridone microcrystals is essentially isostructural. Inversion-related host molecules interact via pairs of N-H...O hydrogen bonds to form R(2)(2)(8) dimers. Six of these dimers form large R(12)(6)(42) puckered rings, in which the O atom of each N-H...O hydrogen bond is also the acceptor in an O-H...O hydrogen bond that involves the 5-hydroxy group. The large R(12)(6)(42) rings straddle the -3 axes and form stacked columns via pi pi interactions between inversion-related molecules of (I) [mean interplanar spacing = 3.254 A and ring centroid-centroid distance = 3.688 (2) A]. The channels are lined by methyl groups, which all point inwards to the centre of the channels. PMID- 21817803 TI - 2,2'-(ethane-1,2-diyl)bis[2-(5-bromothiophen-2-yl)-1,3-dioxolane] at 100 K refined using a multipolar atom model. AB - The title compound, C(16)H(16)Br(2)O(4)S(2), which is a precursor for the synthesis of oligothiophenes and their substituted homologues, was synthesized and its X-ray crystal structure determined at 100 K. The experimental electron density parameters for the available atom types were transferred from the ELMAM2 database. The compound lies about an inversion centre, which coincides with the mid-point of a C-C bond. The molecules in the crystal are linked by several types of weak interactions; the largest contact surfaces are for H...H and H...Br. PMID- 21817804 TI - 2,3-dimethoxy-10-oxostrychnidinium 2-(2,4,6-trinitroanilino)benzoate monohydrate: a 1:1 proton-transfer salt of brucine with o-picraminobenzoic acid. AB - In the structure of the title 1:1 proton-transfer compound of brucine with 2 (2,4,6-trinitroanilino)benzoic acid, C(23)H(27)N(2)O(4)(+).C(13)H(7)N(4)O(8)( ).H(2)O, the brucinium cations form classic undulating ribbon substructures through overlapping head-to-tail interactions, while the anions and the three related partial solvent water molecules (having occupancies of 0.73, 0.17 and 0.10) occupy the interstitial regions of the structure. The cations are linked to the anions directly through N-H...O(COO(-)) hydrogen bonds and indirectly by the three water molecules, which form similar conjoint cyclic bridging units [graph set R(2)(4)(8)] through O-H...O(C=O) and O-H...O(COO(-)) hydrogen bonds, giving a two-dimensional layered structure. Within the anion, intramolecular N-H...O(COO( )) and N-H...O(nitro) hydrogen bonds result in the benzoate and picrate rings being rotated slightly out of coplanarity [inter-ring dihedral angle = 32.50 (14) degrees ]. This work provides another example of the molecular selectivity of brucine in forming stable crystal structures, and also represents the first reported structure of any form of the guest compound 2-(2,4,6 trinitroanilino)benzoic acid. PMID- 21817805 TI - Influence of platelet reactivity on outcome of patients with acute myocardial infarction undergoing primary angioplasty. PMID- 21817806 TI - Intensively lowering both low-density lipoprotein cholesterol and blood pressure does not reduce cardiovascular risk in Japanese coronary artery disease patients. AB - BACKGROUND: Despite mounting evidence of the benefit of intensive lowering of low density lipoprotein-cholesterol (LDL-C) in coronary artery disease (CAD) patients, it has not been shown that intensive lowering of both LDL-C and blood pressure (BP) reduces cardiovascular events in these patients. METHODS AND RESULTS: 498 patients with hypertension and hypercholesterolemia with >= 75% stenosis in at least one major coronary artery, were recruited from 17 cardiovascular centers in eastern Japan. Patients were randomly assigned to conventional therapy (CT) or intensive therapy (IT). CT aimed to reduce BP to < 140/90 mm Hg and LDL-C to <100mg/dl, and IT aimed for < 120/80 mm Hg and < 80 mg/dl, respectively. The primary endpoint was a composite of all deaths, non fatal myocardial infarction, unstable angina pectoris, coronary artery bypass graft surgery, non-fatal stroke, non-fatal major vascular disease, and peripheral artery disease. The mean follow-up period was 3.2 years. The achieved systolic BP was 126.8 mm Hg for the CT group, and 121.3 mm Hg for the IT group (P < 0.001). The achieved LDL-C was 92.1mg/dl for the CT group, and 79.6 mg/dl for the IT group (P < 0.001). We detected the primary endpoint in 18 (7.1%) patients in the CT group, and 26 (10.7%) in the IT group (hazard ratio 1.53, 95% confidence interval 0.84-2.80, P = 0.164). CONCLUSIONS: We could not show that intensively lowering both BP and LDL-C reduced cardiovascular risks in Japanese CAD patients with hypertension and hypercholesterolemia (UMIN-CTR UMIN000000571). PMID- 21817807 TI - Is human atrial natriuretic peptide (hANP) effective as an additive to cardioplegic solution during cardiac surgery? PMID- 21817808 TI - Can we stop warfarin after AF ablation? PMID- 21817809 TI - A unique warfarin therapy in Japan. PMID- 21817810 TI - Pulmonary artery distensibility index is a non-invasive useful marker of pulmonary arterial hypertension progression. PMID- 21817811 TI - Adipose tissue or bone marrow, store for purchasing mesenchymal stem cells? PMID- 21817812 TI - Heat shock proteins regulates cardiomyocytes via Toll-like receptors. PMID- 21817813 TI - Pregnancy-associated aortic dilatation or dissection in Japanese women with Marfan syndrome. AB - BACKGROUND: Aortic dilatation and dissection are severe complications of pregnancy that may cause maternal death. The purpose of the present study was to investigate risk factors for aortic dilatation or dissection in pregnant Japanese women with Marfan syndrome. METHODS AND RESULTS: A total of 28 patients with Marfan syndrome were investigated retrospectively during pregnancy and after delivery at 1 institution. These patients were divided into 2 groups: those who experienced aortic dilatation or dissection (group D, n=11) and those who did not (group ND, n = 17). In group D, aortic dilatation or dissection occurred in 7 cases during pregnancy (2 in the 2(nd) trimester, 5 in the 3(rd) trimester) and 4 cases after birth. The 2 cases in the 2nd trimester involved aortic dilatation > 60mm and those patients underwent hemiarch replacement and a David operation, respectively. Delivery by cesarean section (64% vs. 18%, P < 0.05), sinus of Valsalva >= 40mm (86% vs. 21%, P < 0.05), aortic size index (size of sinus of Valsalva/body surface area) >= 25 mm/m2 (7/7, 100% vs. 0/14, 0%, P < 0.0001), and faster growth of the sinus of the Valsalva (median, [interquartile range]: 0.41 mm/month [0.23-0.66 mm/month] vs. 0.05 mm/month [-0.13 to 0.22 mm/month]; P < 0.05) were significantly higher in group D than in group ND. CONCLUSIONS: A large sinus of Valsalva, increased aortic size index, and rapid growth of the sinus of Valsalva are risk factors for aortic dilatation or dissection in pregnant Japanese women with Marfan syndrome. PMID- 21817814 TI - Extracellular heat shock protein 70 induces cardiomyocyte inflammation and contractile dysfunction via TLR2. AB - BACKGROUND: Toll-like receptors (TLRs) are expressed on cardiomyocytes and recognize pathogen-associated molecular patterns. Whether endogenous molecules produced by tissue injury (damage associated molecular patterns, DAMPs) can induce cardiomyocyte inflammation via TLR signalling pathways and/or reduce cardiomyocyte contractility is unknown. METHODS AND RESULTS: Primary cardiomyocytes isolated from nuclear factor kappa B (NFkappaB)-luciferase knock in mice were used to assess NFkappaB signalling. DAMPs, HSP60, HSP70 and HMGB1, increased NFkappaB transcriptional activity compared to controls. HSP70 stood out compared to other DAMPs and even lipopolysaccharide (LPS). Subsequent experiments focused on HSP70. Cardiomyocytes exposed to HSP70 had a 58% decrease in contractility without a decrease in calcium flux. Exposure of cultured HL-1 cardiomyocytes to HSP70 resulted in increased expression of intercellular adhesion molecule 1 (ICAM-1), interleukin 6 (IL-6) and keratinocyte-derived chemokine (KC) compared to controls. Knock-out mice for TLR2, TLR4 and MyD88, plus background strain controls (C57BL/6) were used to assess induction of cardiomyocyte inflammation by HSP70. The cardiomyocyte expression of ICAM-1 induced by HSP70 was significantly reduced in TLR2 and MyD88 knock-out mice but not TLR4 knock-out mice; implicating the TLR2 signalling pathway. Furthermore, blocking antibodies to TLR2 were able to abrogate HSP70-induced contractile dysfunction and cell death. CONCLUSIONS: Extracellular HSP70 acting via TLR2 and its obligate downstream adaptor molecule, MyD88, activate NFkappaB. This causes cardiomyocyte inflammation and decreased contractility. PMID- 21817815 TI - Relationship between myocardial redox state and matrix metalloproteinase activity in patients on left ventricular assist device support. AB - BACKGROUND: Redox aminothiols have been reported to modulate the activity of recombinant metalloproteinases (MMP). The aim of the present study was to investigate the effects of myocardial redox state on the activities of MMP-2 and 9 implicated in cardiac remodeling in end-stage heart failure patients supported by left ventricular assist device (LVAD). METHODS AND RESULTS: During heart transplant (HT) surgery, myocardial specimens (MS) from right ventricular walls and LV walls were obtained from 7 LVAD recipients (LVAD group, MS n=35) and from 7 stable HT candidates on medical therapy (MT group, MS n=35). Myocardial MMP-2 and -9 activities and expression, tissue inhibitor of MMP (TIMP)-1 and -4, transforming growth factor (TGF)-beta1 and aminothiol concentrations were measured. MMP-2 and -9 activities were evaluated also by incubating MS with different amounts of reduced and oxidized glutathione (GSH). MMP-2 and -9 activities and expression were lower in the LVAD group, whereas myocardial TIMP-1 and -4 concentrations were comparable to those of MT patients. Higher GSH and TGF beta1 concentrations were found in LVAD-recipients. Only GSH concentrations were inversely related to MMP-2 and -9 activities. In vitro, GSH had an inhibitory effect on MMP-2 and -9 activities. CONCLUSIONS: LVAD recipients show reduced myocardial MMP-2 and -9 activities and expression when compared to medically treated patients. Changes of myocardial redox state, predominantly GSH-dependent, appear to modulate MMP-2 and -9 activities by an inhibitory effect dependent on thiol content. These data support a role of GSH cycle in modulating the extracellular matrix in end-stage heart failure patients supported by LVAD. PMID- 21817816 TI - Highly sensitive cardiac troponin-I in congenital heart disease. PMID- 21817818 TI - Careful echocardiographic analysis of right ventricular function as a long-term prognostic variable in systolic heart failure. PMID- 21817817 TI - How to treat stage D heart failure? - When to implant left ventricular assist devices in the era of continuous flow pumps?-. AB - The new classification of heart failure in the American College of Cardiology/American Heart Association guidelines includes stage D, which is refractory severe heart failure that does not respond to medical or resynchronization therapy. Among the many treatment strategies for stage D heart failure, only heart transplantation and ventricular assist devices have been established as improving prognosis. With the evolution in the mechanics of ventricular assist devices in recent years, the postoperative prognosis has improved, and less sick patients can now be candidates for these devices. In Japan, 2 continuous flow devices have been approved since April 2011, and now is the best time to consider the indications for their use. PMID- 21817819 TI - Coronary computed tomography in the evaluation of symptomatic patients with suspected coronary artery disease. - Coronary Calcium Scoring (CAC) and Computed Tomography Angiography (CTA)-. PMID- 21817820 TI - Effect of hydroxyethyl starch 130/0.4 on blood loss and coagulation in patients with recent exposure to dual antiplatelet therapy undergoing off-pump coronary artery bypass graft surgery. AB - BACKGROUND: Hydroxyethyl starch (HES) solutions are often used for maintaining intravascular volume and improving microperfusion, while a large amount of HES can cause adverse effects on coagulation. As the indications for clopidogrel expand, an increasing number of patients undergoing off-pump coronary artery bypass surgery (OPCAB) are also undergoing dual antiplatelet therapy (DAPT), with its higher risk of bleeding complications. The aim of the present study was to determine whether a moderate dose of 6% HES 130/0.4 significantly increases perioperative blood loss in patients with continued DAPT within 5 days of OPCAB. METHODS AND RESULTS: Patients who received clopidogrel and aspirin within 5 days of OPCAB were randomly allocated to receive HES 130/0.4 (<= 30 ml/kg) followed by crystalloid infusion (HES group, n=53), or crystalloid only (crystalloid group, n=53) perioperatively. The amount of perioperative blood loss (sum of bleeding during the intraoperative and postoperative 24-h period), transfusion requirements, modified thromboelastography and coagulation variables, hemodynamic parameters, and fluid balance were recorded. Perioperative blood loss and coagulation profiles were similar between the groups, but the postoperative hemoglobin level was higher in the crystalloid group. CONCLUSIONS: Up to 30 ml.kg 1.day-1 of 6% HES 130/0.4 did not increase the perioperative blood loss compared to crystalloid in patients with recent exposure to DAPT undergoing OPCAB. HES 130/0.4 caused a similar degree and duration of coagulation impairment as observed when only crystalloid was given. PMID- 21817821 TI - Clinical usefulness of additional treatment with ezetimibe in patients with coronary artery disease on statin therapy. - From the viewpoint of cholesterol metabolism.-. AB - BACKGROUND: Ezetimibe-plus-statin therapy has been reported to provide greater reduction in low-density lipoprotein cholesterol (LDL-C) level than statin monotherapy. The aim of the present study was to evaluate the relationship between LDL-C lowering effect and baseline cholesterol absorption and synthesis markers in patients with coronary artery disease (CAD). METHODS AND RESULTS: A total of 171 patients with CAD whose LDL-C level was >= 100 mg/dl after treatment with atorvastatin (10mg/day) or rosuvastatin (2.5 mg/day) for 4 weeks were assigned to additionally receive ezetimibe (10mg/day) plus a statin or a double dose of statin for 12 weeks. The decreases in LDL-C (-30.0 +/- 15.6 mg/dl vs. 19.2 +/- 14.2 mg/dl) and the ratio of campesterol, an absorption marker, to total cholesterol levels (-1.35 +/- 0.90 ug/mg vs. 0.33 +/- 0.74 ug/mg) were greater in the ezetimibe-plus-statin group (P<0.05, respectively). The decrease in LDL-C level in the ezetimibe-plus-statin group was greatest in patients with baseline levels of higher absorption and lower synthesis markers and smallest in patients with baseline levels of lower absorption and higher synthesis markers (-34.3 +/- 15.6 mg/dl vs. -21.5 +/- 16.7 mg/dl, P<0.05). The decrease in LDL-C did not differ, irrespective of baseline levels of cholesterol absorption and synthesis markers, in the double-dose statin group, and was similar to that in patients with lower absorption and higher synthesis markers in the ezetimibe-plus-statin group. CONCLUSIONS: Ezetimibe-plus-statin therapy may be useful for lowering LDL C level, irrespective of baseline levels of cholesterol absorption and synthesis markers. PMID- 21817822 TI - Elevated serum retinol-binding protein 4 concentrations are associated with chronic kidney disease but not with the higher carotid intima-media thickness in type 2 diabetic subjects. AB - To examine the association of serum retinol-binding protein 4 (RBP4) concentrations with carotid intima-media thickness (CIMT) in type 2 diabetic subjects with chronic kidney disease (CKD). A total of 239 type 2 diabetic patients (64 +/- 13 years, 154 males) were divided into two groups: one with CKD, defined as estimated glomerular filtration rate (eGFR) below 60 mL/min/1.73m(2) (n = 86), and one without (n = 153). We recorded clinical and biochemical data as well as CIMT. The patients with CKD were older, had had diabetes mellitus longer, and had higher incidence of hypertension, dyslipidemia and microalbuminuria than those without. They also had higher serum concentrations of RBP4 (44.8 +/- 6.4 vs 39.5 +/- 4.9 ug/mL, p < 0.001), higher mean CIMT (0.75 +/- 0.16 vs 0.69 +/- 0.14 mm, p = 0.0070), and higher incidence of carotid plaques (27.9 vs 11.8 %, p = 0.002). The RBP4 were negatively correlated with eGFR (r = -0.514, p < 0.001). However, the RBP4 were not correlated with mean CIMT (r = 0.065, p = 0.318). Moreover, when dividing the patients into two groups by the mean CIMT, those with mean CIMT above 0.71 mm did not have different RBP4 concentrations compared with those below (41.5 +/- 5.7 vs 41.3 +/- 6.3 ug/mL, p = 0.856). In conclusion, we observed an elevation of serum RBP4 concentrations and CIMT levels in type 2 diabetic subjects with CKD. However, the elevated RBP4 were not associated with the higher CIMT among these patients. PMID- 21817823 TI - PGC-1alpha mediates differentiation of mesenchymal stem cells to brown adipose cells. AB - AIM: Mesenchymal stem cells (MSCs) are a multipotent cell type that can differentiate into non-hematopoietic cells, such as adipocytes. Adipocyte tissue is central to the regulation of energy balance. Two functionally different types of fat are present in mammals. White adipose tissue is the primary site for triglyceride storage, while brown adipose tissue is specialized in energy expenditure. Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1alpha) controls several aspects of mitochondrial biogenesis. In this study, we hypothesized that PGC-1alpha plays a role in brown fat differentiation of MSCs. METHODS: Immortalized human MSCs were infected with adenovirus carrying PGC 1alpha cDNA to create PGC-1alpha-expressing MSCs. RESULTS: The genetic profiling of PGC-1alpha-expressing MSCs shows the significant increase of genes related to mitochondrial functions and lipid metabolism compared to that of MSCs. When expressed in MSCs, PGC-1alpha activates robust mitochondrial biogenesis and respiration. The increase of oxygen consumption and reactive oxygen species represents a cellular readout of increased activity of the respiratory chain. The expression of thermogenic markers, such as cytochrome C and complex II, was significantly increased in MSCs with treatment of adenovirus expressing PGC 1alpha. Moreover, PGC-1alpha markedly inhibited the osteogenesis of MSCs under osteogenic induction. During adipogenesis, PGC-1alpha-expressing MSCs showed a significant increase in brown fat markers and a decrease in white fat markers. Notably, PGC-1alpha knockdown inhibited adipocyte differentiation of MSCs. CONCLUSIONS: In summary, our data reveal an important role of PGC-1alpha in promoting brown fat differentiation of MSCs, and provide a new therapeutic approach for the treatment of obesity. PMID- 21817824 TI - Exposure of Candida to p-anisaldehyde inhibits its growth and ergosterol biosynthesis. AB - p-Anisaldehyde (4-methoxybenzaldehyde), an extract from Pimpinella anisum seeds, is a very common digestive herb of north India. Antifungal activity of p anisaldehyde was investigated on 10 fluconazole-resistant and 5 fluconazole sensitive Candida strains. Minimum inhibitory concentrations (MIC(90)) ranged from 250 ug/ml to 600 ug/ml for both sensitive and resistant strains. Ergosterol content was drastically reduced by p-anisaldehyde-62% in sensitive and 66% in resistant strains-but did not corelate well with MIC(90) values. It appears that p-anisaldehyde exerts its antifungal effect by decreasing NADPH routed through up regulation of putative aryl-alcohol dehydrogenases. Cellular toxicity of p anisaldehyde against H9c2 rat cardiac myoblasts was less than 20% at the highest MIC value. These findings encourage further development of p-anisaldehyde. PMID- 21817825 TI - Optimization of cryopreservation conditions for the unicellular red alga Cyanidioschyzon merolae. AB - Cryopreservation is essential for maintaining stable stocks of organisms. We report the development of a method for cryopreservation of the unicellular red alga Cyanidioschyzon merolae, a model organism for the investigation of the basic architecture of photosynthetic eukaryotes. Glycerol, dimethyl sulfoxide and methanol were examined for their ability to protect the cell from cryoinjury and/or cytotoxicity. It was found that methanol was the most effective as a cryoprotectant for C. merolae. After the optimized setting of parameters such as working concentration of cryoprotectant and the period of slow cooling, cultures were supplemented with 5% (v/v) methanol and frozen by slow cooling using a passive-freezing unit, followed by plunging into liquid nitrogen. We found C. merolae cells retained greater than 80% viability for at least 83 days in storage. PMID- 21817826 TI - Rhodovulum phaeolacus sp. nov. a phototrophic alphaproteobacterium isolated from a brown pond. AB - Two strains of oval-rod shaped, Gram-negative, phototrophic, purple non-sulfur bacteria designated JA580(T) and JA595 were isolated from a sediment sample collected from a brown pond. Strain JA580(T) was designated as the type strain, while strain JA595 as an additional strain has similar characteristics to the type strain. Strain JA580(T) was non-motile and grew photoheterotrophically with a number of organic compounds serving as carbon source/electron donor. Intracellular photosynthetic membranes were of the vesicular type. Bacteriochlorophyll a and carotenoids of the spheroidene series were present as the major photosynthetic pigments. Strain JA580(T) requires yeast extract for growth. Strain JA580(T) has an obligate requirement for sulfide or thiosulfate for growth. C(18:1)omega7c, C(18:0), C(18:1)omega9c were the predominant components of cellular fatty acids. Phylogenetic analysis on the basis of 16S rRNA gene sequences showed that strain JA580(T) clustered with species of the genus Rhodovulum of the family Rhodobacteraceae and is most closely related to the type strains of Rhodovulum adriaticum, Rhodovulum iodosum (96.5%), Rhodovulum robiginosum (96%), Rhodovulum imhoffii (95.6%) and other members of the genus Rhodovulum (<95%). On the basis of phenotypic and molecular genetic evidence, it is proposed that strain JA580(T) should be classified as a novel species of the genus Rhodovulum of the family Rhodobacteraceae, with the species name Rhodovulum phaeolacus sp. nov. The type strain of the species is JA580(T) (=NBRC 107612(T) =KCTC 5963(T)). PMID- 21817827 TI - Bacillus subtilis RNA polymerase incorporates digoxigenin-labeled nucleotide in vitro. PMID- 21817828 TI - Acetobacter farinalis sp. nov., an acetic acid bacterium in the alpha Proteobacteria. PMID- 21817829 TI - Exopolysaccharide produced by Bacillus licheniformis strains isolated from Kimchi. PMID- 21817830 TI - Safety and health in the petrochemical industry in Map Ta Phut, Thailand. AB - BACKGROUND: Petrochemical industries are known as sources of many toxic chemicals. Safety and health risks of the petrochemical workers employed at Map Ta Phut Industrial Estate, located in Rayong, Thailand, are potentially high. METHODS: The research materials consisted of documents emanating from statutory reports on safety in working with toxic chemicals and the results of interviews by questionnaire among 457 petrochemical workers regarding occupational health and safety issues. RESULTS: Most of workers who were working with toxic chemicals had knowledge and awareness of health risks and chemical hazards at work. We found that safe behavior at work through read the safety information among operational workers less than non-operational workers around 10%. Most of workers had perceived occupational health and safety management in their companies. Some companies revealed that they had not been performing biological monitoring of blood or urine for their health examination reports and that workplace exposure monitoring had not correlated well with health examination of workers. CONCLUSIONS: Our study suggested that occupational health and safety for petrochemical industries requires standards and guidelines for workers' health surveillance aimed at protection of workers. PMID- 21817831 TI - Changes in craniocervical and trunk flexion angles and gluteal pressure during VDT work with continuous cross-legged sitting. AB - OBJECTIVES: This study investigated changes in craniocervical and trunk flexion angles and gluteal pressure on both sides during visual display terminal (VDT) work with continuous cross-legged sitting. METHODS: The gluteal pressures of ten VDT workers, who were recruited from laboratories, were measured using a Teckscan system and videotaped using a single video camera to capture the craniocervical and trunk flexion angles during VDT work at 30 s, 10, 20 and 30 min. RESULTS: The craniocervical angle was significantly increased at 10 and 20 min compared with the initial angle (p<0.05). The trunk flexion angle was significantly decreased at 30 s, 10, 20 and 30 min (p<0.05). The gluteal pressure of the crossed-leg side significantly increased at 30 s, 10 and 20 min (p<0.05). The gluteal pressure of the uncrossed-leg side significantly decreased at 30 s (p<0.05). CONCLUSION: We found that cross-legged sitting during VDT work may exert disadvantageous postural effects resulting from craniocervical and trunk flexion angles and gluteal pressure. Therefore, this posture could not be recommended during long term VDT work. PMID- 21817832 TI - Assessments by HR and %HRR of occupational work exertion for alternating periods of rest and manual labor. AB - OBJECTIVES: Metabolic equivalents (METs) and relative metabolic rate (RMR) as calculated by oxygen uptake (VO(2)) are often used to assess physical exertion. In practice, accurate measurements of VO(2) are difficult; heart rate (HR) values represent an alternate index of physical exertion. We investigated whether one can assess physical exertion based on HR in the workplace, even if the physical task in question involves alternating periods of strenuous anaerobic activity and rest. We also examined the potential usefulness of assessments based on percentage of heart rate reserve (%HRR) and percentage of oxygen uptake reserve (% VO(2)R). METHODS: Six healthy men were asked to perform several physical movements. HR and VO(2) were recorded in real time. RESULTS: HR and VO(2) are significantly correlated even under conditions of various repeated intermittent movements including anaerobic exertion. Cumulative fatigue results in inadequate recovery in various parameters indicating sufficient rest times, whereas VO(2) values recover immediately. One movement may generate large differences in HR among individuals, but not in VO(2). We found no significant differences between dispersion for %HRR and VO(2)R. However, as with HR, %HRR values indicated insufficient recovery after strenuous exertion. CONCLUSIONS: VO(2) alone does not adequately reflect the exertion entailed by certain physical activities. HR is more useful than VO(2) in evaluating the exertion required by physical labor in individual workers. While we can use %HRR and % VO(2)R to compare physical exertion from individual to individual, %HRR is more valuable, since % VO(2)R can underestimate physical exertion in recovery periods for the same reasons as VO(2). PMID- 21817833 TI - Association between job stress and newly detected combined dyslipidemia among Chinese workers: findings from the SHISO study. AB - OBJECTIVES: Previous studies examining the association between job stress and blood lipids have produced mixed findings. We sought to investigate the association between job stress and blood lipids among Chinese workers. METHODS: A total of 544 subjects (367 men and 177 women) without known diseases from the Stress and Health in Shenzhen Workers (SHISO) cross-sectional study were analyzed. Job stress was evaluated by the effort-reward imbalance (ERI) model. The associations between job stress and blood lipids, such as for total cholesterol (TCHO), triglycerides (TG), high-density lipoprotein cholesterol (HDL C) and low-density lipoprotein cholesterol (LDL-C), were explored by multiple linear regression. The association between job stress and combined dyslipidemia was examined by multiple logistic regression. RESULTS: Compared with their corresponding low level groups, groups with high levels of effort, overcommitment and ERI had a significantly increased risk of combined dyslipidemia with adjusted odd ratios (ORs) of 3.5 (95% CI 1.8-6.7), 4.2 (95% CI 2.3-7.7) and 2.7 (95% CI 1.5-5.1), respectively, whereas high rewards significantly reduced the risk of combined dyslipidemia (adjusted OR 0.3, 95% CI 0.2-0.6) compared with low rewards. Effort, overcommitment and ERI were significantly positively related to TG and LDL-C, while rewards were inversely related to them. No significant associations were observed between job stress and TCHO and HDL-C. The results were similar for men and women. CONCLUSIONS: Effort, overcommitment, low reward and ERI increased the risk of dyslipidemia among Chinese workers, and they were significantly associated with TG and LDL-C rather than TCHO or HDL-C. Increasing blood lipids may be the possible link between job stress and coronary heart disease. PMID- 21817834 TI - Psychiatric knowledge and skills required of occupational physicians: priorities in the Japanese setting. AB - OBJECTIVE: To prioritize the educational content in psychiatry teaching materials for occupational physicians. METHODS: A preparatory investigation was performed that included interviews with 13 psychiatrists who were well acquainted with occupational health and practices. Brainstorming among the psychiatrists and 12 occupational physicians was used to develop a list of educational content related to psychiatric issues that should be required for occupational physicians. Using a questionnaire survey constructed based on the preparatory investigations, 135 specialists with extensive experience in occupational medicine were asked to prioritize the selected items. RESULTS: A total of 67 specialists responded to the questionnaire. The following were recommended as high educational priorities for occupational physicians to master: awareness and diagnosis of mood disorders, being able to appropriately deal with depressed workers, screening for depression, understanding cases that should be referred for special treatment, appropriate action for a suicidal person, understanding symptoms that require cooperation in an emergency with a specialist, acquisition of the attitude and skills used in active listening and awareness of diseases such as alcohol dependence, adjustment disorders and schizophrenia. CONCLUSIONS: What has been presented here is a consensus view of specialists in this field. The items included were those obtained from sitting in on the discussions of psychiatrists and occupational physicians. They represent indicators for the development of teaching materials. PMID- 21817835 TI - Cloned cows with short telomeres deliver healthy offspring with normal-length telomeres. AB - Dolly, the first mammal cloned from a somatic cell, had shorter telomeres than age-matched controls and died at an early age because of disease. To investigate longevity and lifetime performance in cloned animals, we produced cloned cows with short telomeres using oviductal epithelial cells as donor cells. At 5 years of age, despite the presence of short telomeres, all cloned cows delivered multiple healthy offspring following artificial insemination with conventionally processed spermatozoa from noncloned bulls, and their milk production was comparable to that of donor cows. Moreover, this study revealed that the offspring had normal-length telomeres in their leukocytes and major organs. Thus, cloned animals have normal functional germ lines, and therefore germ line function can completely restore telomere lengths in clone gametes by telomerase activity, resulting in healthy offspring with normal-length telomeres. PMID- 21817836 TI - Therapeutic and adverse effects of flunixin-meglumine in adult and young cats. AB - In this study, we elucidated the difference in nonsteroidal anti-inflammatory drug sensitivities between young and adult cats on therapeutic and adverse effects. In the prevention of lipopolysaccharide (LPS)-induced hyperthermia using flunixin-meglumine, young (<3 months old) and adult (>12 months old) cats of both sexes were given LPS (0.3 ug/kg, i.v.), and body temperature was measured 24 hr later. Flunixin (1 mg/kg, s.c.) was administered 30 min before the LPS injection. LPS-induced hyperthermia was almost completely inhibited by pre-treatment with flunixin in both adult and young cats. In addition, flunixin showed almost the same antipyretic effects in both young and adult cats. The animals were administered flunixin (1 mg/kg, s.c.) once a day for 3 days, and sacrificed 24 hr later to examine the gastrointestinal mucosal lesions. In adult cats, flunixin caused many severe lesions in the small intestine. In contrast, very few gastrointestinal lesions were produced by flunixin in young cats. In the pharmacokinetics of flunixin, plasma concentrations of flunixin were analysed using a high performance liquid chromatography. There were no significant differences in plasma concentration of flunixin between young and adult cats from 0.5 to 4 hr after the injection. These results demonstrated that NSAIDs could be used more safely in young than in adult cats from the points of gastrointestinal adverse effects. Furthermore, this difference in gastrointestinal lesions between adult and young cats was not related with the plasma concentration of flunixin. PMID- 21817837 TI - [Molecular pathogenesis of hepatocellular carcinoma]. PMID- 21817838 TI - [Search for molecular marker/target molecule useful for colorectal cancer treatment]. PMID- 21817839 TI - [Fibro-carcinogenic signaling via phospho-Smad during progression of chronic viral liver diseases]. PMID- 21817840 TI - [Role of inflammation in the development of gastrointestinal cancers]. PMID- 21817841 TI - The efficacy of ezetimibe on nonalcoholic fatty liver disease (NAFLD). AB - The usefulness of ezetimibe was examined in 297 patients with dyslipidemia who did not achieve LDL-C target levels set in JAS 2007 Guidelines by lifestyle modification. The mean period of administration was 178.2+/-295.4 days. Ezetimibe significantly improved serum lipid levels in the patients with and without non alcoholic fatty liver disease (NAFLD) (p<0.01). Significant improvement of AST, ALT and gamma GTP levels were also observed in the patients with NAFLD (p<0.01, p<0.05, and p<0.01, respectively). Seventy of the patients with NAFLD who underwent abdominal ultrasound before and after administration of ezetimibe were followed. Of those, 38.6% of the patients showed disappearance of steatosis, indicating that administration of ezetimibe is useful in patients with NAFLD. PMID- 21817842 TI - A case of candidal infection of gastric ulcers with characteristic endoscopic findings. AB - While Candida infection is a common opportunistic infection, Candida-associated gastric lesions are far less frequent. We report a case of gastric ulcers due to candidal infection. A 73-year-old woman had ulcers refractory to treatment with a proton pump inhibitor (PPI) and Helicobacter pylori eradication. Endoscopic findings showed that this case involved 2 gastric ulcers with thick exudate mainly located in the fornix. Biopsy specimens from gastric ulcers revealed numerous Candida forms. The patient was treated with antifungal drugs and the ulcers healed completely on endoscopy. We should draw attention to our observation in elderly patients with gastric ulcers, and if we find gastric ulcers with such characteristic endoscopic findings, candidal infection of gastric ulcers should be considered. PMID- 21817843 TI - A case of Helicobacter pylori-negative depressed type gastric adenoma. AB - A 75-year-old woman was referred to our hospital for further examination of gastric antral abnormal endoscopic findings. Endoscopic study of the stomach revealed a depressed lesion in the gastric antrum. Atrophic findings were not recognized in the background gastric mucosa, and Helicobacter pylori infection was not detected by histology, an urea breath test, a rapid urease test and serological test. A diagnosis of adenoma was given histopathologically from the resected specimens. As a result of immunohistological study, the phenotype of the tumor was not classified as either gastric type or intestinal type. CDX2 was positive in part of the tumor. PMID- 21817844 TI - A case of ulcerative colitis accompanied with myelodysplastic syndrome successfully treated by cyclosporine. AB - A 64-year-old man had been admitted to a previous hospital because of melena and a diagnosis of ulcerative colitis (UC, pancolitis type) had been made. He had received prednisolone and 5-ASA but steroid-induced hyperamylasemia had developed. Prednisolone had been tapered and halted, but it had resulted in UC relapse and thrombocytopenia. Then, he was referred to our hospital due to severe melena with hypovolemic shock. However, he was also positive for CMV antigen. Thus, we attempted to treat him with ganciclovir for CMV and intravenous cyclosporine (CsA) for UC. According to his clinical course, a reduction of CsA blood concentration induced leukocytopenia. Myelodysplastic syndrome (MDS, RAEB 1) was then revealed after bone marrow biopsy. A high blood CsA concentration may cause the improvement of UC and MDS conditions. PMID- 21817845 TI - A case of amoebic liver abscess complicated by a gastric fistula cured with oral medication only. AB - A 26-year-old man was admitted to our hospital because of a high-grade fever and abdominal pain. A blood test showed marked inflammation. Enhanced computed tomography (CT) showed an 8.0*6.0cm cystic lesion in the left hepatic lobe. Esophagogastroduodenoscopy showed a huge egg-yolk-like mass in the gastric submucosa in the lesser curvature of the gastric body from the gastric angle. There were 3 ulcers on the mass, out of which milky pus flowed. Trophozoites of Entamoeba histolytica were detected from cultures of the liver abscess and a biopsy of the gastric ulcers. The amoebic dysentery antibody titer was increased 1600 times. An amoebic liver abscess complicated by a gastric fistula was diagnosed. As therapy, oral metronidazole was administered for 2 weeks without percutaneous drainage. The systemic inflammatory findings improved immediately and the abscess decreased markedly in size. PMID- 21817846 TI - A case of splenic artery aneurysm simulating a pancreas tumor. AB - A 46-year-old man was admitted to our hospital for further evaluation of a hypoechogenic mass in the pancreatic body. He had no history of hypertension, pancreatitis, abdominal trauma, or portal hypertension. He had no abdominal symptoms. A contrast-enhanced CT scan demonstrated a hypodense, round shaped mass. EUS and MRI also showed it to be a pancreatic mass. Because of the tumor size of more than 30mm and the possibility of malignancy, distal pancreatectomy was performed. Microscopic findings showed the mass was the dissection of the proximal splenic artery. The true lumen of the dissecting aneurysm was occluded and the false lumen developed fusiform dilatation. Moreover, microscopic findings revealed the rupture of the false lumen complicated by pseudoaneurysm. We finally diagnosed the lesion simulating a pancreatic tumor as the pseudoaneurysm of the splenic artery. PMID- 21817847 TI - A case of spindle cell type anaplastic carcinoma of the pancreas -review of Japanese case report-. AB - We present a case of spindle cell type anaplastic carcinoma of the pancreas in a 63-year-old woman. A pancreatic mass was incidentally detected by routine abdominal ultrasonography examination for her hepatitis B infection, and she was admitted to our hospital for further examination. Computed tomography revealed a hypo-vascular mass measuring 25mm in maximal dimension at the pancreas body. Endoscopic ultrasonography showed a hypoechoic mass as the pancreas body and a swollen lymph node near the tumor. Endoscopic retrograde pancreatography revealed disruption of the main pancreatic duct, and carcinoma cells were detected in pancreatic juice obtained via an endoscopic nasopancreatic drainage tube. We diagnosed this case as an invasive ductal adenocarcinoma of the pancreas body, therefore the distal pancreatectomy with splenectomy (D1+alpha) was performed. The histopathological diagnosis for this case was a "spindle cell type anaplastic carcinoma of the pancreas". The patient has remained well with no evidence of recurrence for 9 months since her operation. PMID- 21817848 TI - Spontaneous bladder rupture occurred 17 years after radiation treatment for cervical cancer: a case report. PMID- 21817849 TI - Building medical ethics education to improve Japanese medical students' attitudes toward respecting patients' rights. AB - In medical education, it is important for medical students to develop their ethics to respect patients' rights. Some physicians might make light of patients' rights, because the increased awareness of such rights might make it more difficult for them to conduct medical practice. In the present study, predictors significantly associated with "a sense of resistance to patients' rights" were examined using anonymous self-administered questionnaires. For these predictors, we produced original items with reference to the concept of ethical development and the teachings of Mencius. The subjects were medical students at the Kitasato University School of Medicine, a private university in Japan. A total of 518 students were analyzed (response rate, 78.4%). The average age of enrolled subjects was 22.5 +/- 2.7 years (average age +/- standard deviation). The average age of 308 male subjects was 22.7 +/- 2.8 years, while that of 210 female subjects was 22.1 +/- 2.5 years. The item, "Excessive measures to pass the national examination for medical practitioners," was significantly associated with "a sense of resistance to patients' rights." However, other items, including basic attributes such as age and gender, were not significant predictors. If students spent their school time only focusing on the national examination, they would lose the opportunity to receive the ethical education that would allow them to respect patients' rights. That ethical development cannot easily be evaluated with written exams. Thus, along with the acquisition of medical knowledge, educational programs to promote medical students' ethics should be developed. PMID- 21817850 TI - Risk factors for deep-vein thrombosis and pulmonary thromboembolism in benign ovarian tumor. AB - Pulmonary thromboembolism (PE) is a serious postoperative complication. Reported rates of PE following gynecologic surgery are between 0.3% and 0.8%, with deep vein thrombosis (DVT) as the major cause (via seeding of the lungs). Benign ovarian tumors are treated principally by surgery. Possible risk factors for DVT and PE in patients with benign ovarian tumors include tumor size, patient age, and obesity. To date, however, there has been no report addressing the association of these risk factors in patients with benign ovarian tumors. This study offers a retrospective analysis of the incident of preoperative DVT by age, tumor size, and BMI in patients undergoing surgery for benign ovarian tumors. A total of 843 Japanese patients with a preoperative diagnosis of benign ovarian tumor who underwent tumorectomy or adnexectomy at our institution between July 2003 and December 2010 were enrolled. The incidence of preoperative DVT was monitored and statistically stratified by age (< 50 years and >= 50 years), largest tumor diameter (< 10 cm and >= 10 cm), and BMI (< 25 and >= 25). The result indicates that tumor diameter of >= 10 cm is not a risk factor for preoperative DVT in patients with benign ovarian tumor. On the other hand, age >= 50 years and BMI > 25 are independent risk factors for preoperative DVT in Japan. The patients with each risk factor should be treated with preoperative, intraoperative, and postoperative precautions against development of PE. PMID- 21817851 TI - Distinct features of second primary malignancies in head and neck cancer patients in Japan. AB - Second primary malignancies (SPMs) are one of the most critical problems in treating head and neck cancer patients. Our hospital had 742 patients with a diagnosis of malignant head and neck tumors during the five-year period from 2002 to 2006. In this study, we analyzed 360 of those patients who were assumed to have risk factors such as alcohol and tobacco use: 106 oral, 120 laryngeal, 50 oropharyngeal and 84 hypopharyngeal cancer patients. Synchronous SPMs are defined as second cancers diagnosed at the same time or within 6 months of the diagnosis of the index head and neck cancers. There were 4 (3.8%) and 11 (10.4%) oral cancer patients, 11 (8.3%) and 8 (5.8%) laryngeal cancer patients, 7 (14.0%) and 4 (8.0%) oropharyngeal cancer patients, and 30 (28.6%) and 7 (8.3%) hypopharyngeal cancer patients with synchronous and metachronous SPMs, respectively. The number of metachronous patients with synchronous SPMs tended to increase during this time period. The frequencies of SPMs in oropharyngeal and hypopharyngeal cancer patients are similar to those in oral and laryngeal cancer patients. Notably, the most frequent SPMs are upper gastrointestinal tract cancers in Japan, compared to lung cancers in Europe. The five-year overall survival rate of patients with synchronous SPMs was significantly poorer than that of patients without any other tumor except for the index cancer, according to the Kaplan-Meier analysis. In conclusion, searching for SPMs in the upper gastrointestinal tract is a critical issue in head and neck cancer patients in Japan. PMID- 21817852 TI - Insulin-dependent suppression of cholesterol 7alpha-hydroxylase is a possible link between glucose and cholesterol metabolisms. AB - Cholesterol 7alpha-hydroxylase (CYP7A1) regulates the balance between cholesterol supply and metabolism by catalyzing the rate-limiting step of bile acid biosynthesis. The transcriptional activity of CYP7A1 is tightly controlled by various nuclear receptors. A forkhead transcription factor O1 (FOXO1) plays a critical role in metabolism, and insulin inactivates FOXO1 through Akt-dependent phosphorylation and nuclear exclusion. We investigated the role of insulin- Akt FOXO1 signaling pathway in CYP7A1 transcriptional regulation since we found putative insulin-response elements, FOXO1 binding sequences, in both rat and human CYP7A1 promoters. However, ectopic expression of FOXO1 increased the rat CYP7A1-, but mildly reduced human CYP7A1-promoter activities in a dose-dependent manner. Similarly to bile acids, insulin treatment increased small heterodimer partner (SHP) mRNA rapidly and transiently, leading to the suppression of CYP7A1 transcription in both human and rodents. Chromatin immunoprecipitation showed that FOXO1 directly bound to rat CYP1A1 promoter in the absence of insulin. FOXO1 binding to the rat promoter was diminished by insulin treatment as well as by expression of SHP. Our results suggest that the stimulation of insulin- signaling pathway of Akt-FOXO1 and SHP expression may regulate cholesterol/bile acid metabolisms in liver, linking carbohydrate and cholesterol metabolic pathways. A prolonged exposure of insulin in hyperinsulinemic insulin resistance or diabetic status represses CYP7A1 transcription and bile acid biosynthesis through SHP induction and FOXO1 inactivation, leading to impairment of the hepatic cholesterol/bile acid metabolisms. PMID- 21817853 TI - A recombinant mutant abrin A chain expressed in Escherichia coli can be used as an effective vaccine candidate. AB - We used site-directed mutagenesis to mutate two key amino acid residues, Glu164 and Arg167, of abrin A chain (ABRA), creating a mutant ABRA(E164AR167L). The mutant ABRA(mABRA) encoded by mABRA(E164AR167L) was expressed in the cytoplasm of Escherichia coli, and used to develop an effective vaccine to protect mice against native abrin intoxication. The cytotoxicity of mABRA was dramatically reduced as compared to that of recombinant ABRA(rABRA) and native abrin, but the antigenicity and immunogenicity remained the same. Balb/c mice were vaccinated with purified mABRA, and survival was evaluated after challenge with native abrin. Mice that were given three vaccinations developed a protective immune response that was 100% protective against an intraperitoneal (i.p.) administration of 10*LD50 of native abrin. Furthermore, the sera from immunized mice provided complete passive protection for naive mice. This study describes the generation of a substantial amount of mABRA from E. coli and the potential application of mABRA as an effective vaccine candidate for humans, to protect against a high-dose of native abrin. PMID- 21817854 TI - Transcutaneous and intradermal vaccination. AB - Most vaccines are administered by intramuscular (i.m.) or subcutaneous (s.c.) routes, however, intradermal (i.d.) and transcutaneous (t.c.) techniques are regaining popularity. We will discuss in this review several factors that strongly justify the use of the cutaneous tissues and development of alternative methods for vaccination. That includes (1) our improved knowledge of skin physiology and better understanding of the barrier role of the horny layer, (2) the rationalization for targeting the different cutaneous layers, i.e. the epidermis, dermis, or hypodermis, (3) our advances in knowledge of the skin immune system, especially the plasticity of antigen-presenting cells (APCs) (i.e Langerhans cells (LC), dermal dendritic cells (DDC) and dermal macrophages) in the induction of immune responses, (4) the reduction of antigenic dose for some modes of cutaneous administration, (5) the increased need in needlefree vaccination strategies for developing countries to cope with blood contamination issues. Progress in skin immunization methods and better understanding of skin immunity allow proposing innovative and efficient vaccination strategies against infectious diseases. PMID- 21817855 TI - A highly specific antibody response after protein prime-peptide boost immunization with Eppin/B-cell epitope in mice. AB - Eppin seems to be a promising target for developing immunocontraceptives for males. In an attempt to develop a safer vaccine, the immune response should be specifically directed according to its fertility inhibition mechanism. The mechanism of Eppin as an immunocontraceptive agent is now assumed to be the inhibitory effect of Eppin-specific antibody on sperm motility. Hence, to make Eppin a successful immunocontraceptive, avid and specific antibody responses have to be elicited. We had employed the inoculation modality of protein prime-peptide boost with rhEppin and epitope-based peptide, which has previously showed a satisfying result of fertility inhibition with minimal adverse effects. We here further explored the immunological features and efficiency of a protein prime peptide boost strategy. The results of the present study showed that all the animals injected with rhEppin followed by epitope-based peptide boost, elicited enhanced specific anti-Eppin antibodies. The IgG subclasses of the antibodies generated by this regimen were primarily of IgG2b and IgG1 isotypes, and more importantly, the IgA level of epidydimis lavage was much higher, which correlated well with the results of cytokine profiles in spleen cell cultures. Furthermore, the results of peptide competition assays demonstrated that rhEppin alone prime boost vaccination lead to a broader B-cell response while protein prime-epitope peptide boosts directed the immune response mainly against the epitope. The results indicate that this immunization strategy may be advantageous in eliciting a highly specific humoral immune response. PMID- 21817856 TI - The first Research Consensus Summit of the Society for Simulation in Healthcare: conduction and a synthesis of the results. AB - INTRODUCTION: In this article, we describe the preparation and execution of the first Research Consensus Summit (Summit) of the Society for Simulation in Healthcare (SSH) held in January 2011 in New Orleans, Louisiana. The goals of the Summit were to provide guidance for better simulation-related research, to broaden the scope of topics investigated, and to highlight the importance of simulation-related research. METHOD: An international Core Group (the authors of this article) worked with the SSH Research Committee to identify 10 topic areas relevant for future research that would be examined by the 10 Topic Groups composed of Topic Chairs and Topic Group Members. Each Topic Group prepared a monograph and slide presentation on their topic which was presented at the 2-day Summit. The audience provided feedback on each presentation. Based on this feedback, the Topic Groups revised their presentations and monographs for publication in this supplement to Simulation in Healthcare. The Core Group has synthesized an overview of the key Summit themes in this article. RESULTS: In some groups, the agreement was that there is currently no consensus about the state of the science in certain topic aspects. Some key themes emerged from the Topic Groups. The conceptual and theoretical bases of simulation-related research, as well as the methods used and their methodological foundations, need to be more explicitly described in future publications. Although no single method is inherently better, the mix of research methods chosen should match the goal of each study. The impact of simulation, whether direct or indirect, needs to be assessed across different levels of training, and larger, more complex contexts need to be taken into account. When interpreting simulation-related research, the ecological validity of the results needs to be taken into consideration. The scope of simulation-related research can be widened from having simulation as the focus of research (research about simulation), to using simulation to investigate other research questions (research with simulation). Simulation-related research can benefit from an improved understanding of structural differences and similarities with other domains. The development of simulation equipment and concepts will benefit from applying known and available science-based design frameworks. Overall, the context of simulation-related research needs to be better understood. The progress of research depends on building overarching and sustainable research programs that relate individual studies with each other. DISCUSSION: The Summit was successful in taking a snapshot of the state of the science. Future summits might explore these topics further, monitor progress, and address new topics. PMID- 21817857 TI - Simulation for learning and teaching procedural skills: the state of the science. AB - INTRODUCTION: Simulation is increasingly used to support learning of procedural skills. Our panel was tasked with summarizing the "best evidence." We addressed the following question: To what extent does simulation support learning and teaching in procedural skills? METHODS: We conducted a literature search from 2000 to 2010 using Medline, CINAHL, ERIC, and PSYCHINFO databases. Inclusion criteria were established and then data extracted from abstracts according to several categories. Although secondary sources of literature were sourced from key informants and participants at the "Research Consensus Summit: State of the Science," they were not included in the data extraction process but were used to inform discussion. RESULTS: Eighty-one of 1,575 abstracts met inclusion criteria. The uses of simulation for learning and teaching procedural skills were diverse. The most commonly reported simulator type was manikins (n = 17), followed by simulated patients (n = 14), anatomic simulators (eg, part-task) (n = 12), and others. For research design, most abstracts (n = 52) were at Level IV of the National Health and Medical Research Council classification (ie, case series, posttest, or pretest/posttest, with no control group, narrative reviews, and editorials). The most frequent Best Evidence Medical Education ranking was for conclusions probable (n = 37). Using the modified Kirkpatrick scale for impact of educational intervention, the most frequent classification was for modification of knowledge and/or skills (Level 2b) (n = 52). Abstracts assessed skills (n = 47), knowledge (n = 32), and attitude (n = 15) with the majority demonstrating improvements after simulation-based interventions. Studies focused on immediate gains and skills assessments were usually conducted in simulation. DISCUSSION: The current state of the science finds that simulation usually leads to improved knowledge and skills. Learners and instructors express high levels of satisfaction with the method. While most studies focus on short-term gains attained in the simulation setting, a small number support the transfer of simulation learning to clinical practice. Further study is needed to optimize the alignment of learner, instructor, simulator, setting, and simulation for learning and teaching procedural skills. Instructional design and educational theory, contextualization, transferability, accessibility, and scalability must all be considered in simulation-based education programs. More consistently, robust research designs are required to strengthen the evidence. PMID- 21817858 TI - Simulation-based team training in healthcare. AB - INTRODUCTION: Simulation-based team training (SBTT) in healthcare is gaining acceptance. Guidelines for appropriate use of SBTT exist, but the evidence base remains limited. Insights from other academic disciplines with sophisticated models of team working may point to opportunities to build on current frameworks applied to team training in healthcare. The purpose of this consensus statement is threefold: (1) to highlight current best practices in designing SBTT in healthcare and to identify gaps in current implementation; (2) to explore validated concepts and principles from relevant academic disciplines and industries; and (3) to identify potential high-yield areas for future research and development. METHODS: We performed a selective review and critical synthesis of literature in healthcare simulation related to team learning as well as from other relevant disciplines such as psychology, business, and organizational behavior. We discuss appropriate use of SBTT and identify gaps in the literature. RESULTS: Healthcare educators should apply rigorous curriculum development processes and generate learning opportunities that address the interrelated conceptual levels of team working by addressing learning needs at the level of the individual, the team, the organization, and the healthcare system. The interplay between these conceptual levels and their relative importance to team based learning should be explored and described. Instructional design factors and contextual features that impact the effect of SBTT should be studied. Further development of validated assessment tools of team performance relevant to professional practice is a high priority and is essential to provide formative, summative, and diagnostic feedback and evaluation of SBTT. Standardized reporting of curriculum design and debriefing approaches, although difficult, would help move the field forward by allowing educators to characterize effective SBTT instruction. CONCLUSIONS: Much work is needed to establish a robust and defensible evidence base for SBTT. The complexity and expense of SBTT require that specific programs or interventions are appropriately designed, implemented, and evaluated. The healthcare sector needs to understand how team performance can be optimized through appropriate training methods. The specific role of simulation in team training needs to be more clearly articulated, and the training conditions that make SBTT in healthcare effective need to be better characterized. PMID- 21817859 TI - A path to better healthcare simulation systems: leveraging the integrated systems design approach. AB - This article addresses the necessary steps in the design of simulation-based instructional systems. A model for designing instructional systems is presented which stipulates that the outcome metrics be defined before the simulation system is designed. This ensures integration of educational objectives and measures of competency into the design and development process. The article ends with a challenge to simulator users and instructors: become involved in the integrated system design process by the daily collection of standardized data and working with the simulation engineers throughout the design process. PMID- 21817860 TI - The study of factors affecting human and systems performance in healthcare using simulation. AB - A large body of research using simulation in healthcare has focused on simulation itself as an object of research. However, simulation can also be used in research on human or system performance. It can be used to investigate the effects of performance shaping factors that would otherwise be difficult to study in the actual clinical setting due to practical constraints or ethical concerns. In this monograph, we illustrate various ways in which simulation has been used to study performance shaping factors. We also discuss possible directions for future research as well as methodological considerations for researchers engaging in this approach to study performance shaping factors. PMID- 21817861 TI - Literature review: instructional design and pedagogy science in healthcare simulation. AB - This article is a review of the literature focused on simulation as an educational intervention in healthcare. The authors examined the literature based on four key levels: (1) the validity and reliability of the simulator, (2) the validity and reliability of the performance evaluation tool, (3) the study design, and (4) the translational impact. The authors found that the majority of research literature in healthcare simulation does not address the validity and reliability of the simulator or the performance evaluation tool. However, there are well-designed research studies that address the translation into clinical settings and have positive patient safety outcomes. PMID- 21817862 TI - Research regarding debriefing as part of the learning process. AB - INTRODUCTION: Debriefing is a process involving the active participation of learners, guided by a facilitator or instructor whose primary goal is to identify and close gaps in knowledge and skills. A review of existing research and a process for identifying future opportunities was undertaken. METHODS: A selective critical review of the literature on debriefing in simulation-based education was done. An iterative process of analysis, gathering input from audience participants, and consensus-based synthesis was conducted. RESULTS: Research is sparse and limited in presentation for all important topic areas where debriefing is a primary variable. The importance of a format for reporting data on debriefing in a research context was realized and a "who, when, where, what, why" approach was proposed. Also, a graphical representation of the characteristics of debriefing studies was developed (Sim-PICO) to help guide simulation researchers in appropriate experimental design and reporting. CONCLUSION: A few areas of debriefing practice where obvious gaps that deserve study were identified, such as comparing debriefing techniques, comparing trained versus untrained debriefers, and comparing the effect of different debriefing venues and times. A model for publication of research data was developed and presented which should help researchers clarify methodology in future work. PMID- 21817863 TI - Simulation-based assessment and the regulation of healthcare professionals. AB - Although we still have much to learn about incorporating simulation into regulatory-based assessments, the authors believe that sufficient evidence exists to further advance the use of simulation-based assessments as part of the regulatory systems for healthcare professionals. This position article reviews the current use of simulation-based assessment for credentialing, licensing, and certification programs in medicine, nursing, and dentistry. The findings support the view that simulation-based assessments can make a meaningful and positive difference in credentialing, licensing, and certification programs now. PMID- 21817864 TI - Reporting inquiry in simulation. AB - The term "inquiry" covers the large spectrum of what people are currently doing in the nascent field of simulation. This monograph proposes appropriate means of dissemination for the many different levels of inquiry that may arise from the Summit or other sources of inspiration. We discuss various methods of inquiry and where they might fit in the hierarchy of reporting and dissemination. We provide guidance for deciding whether an inquiry has reached the level of development required for publication in a peer-reviewed journal and conclude with a discussion of what most journals view as inquiry acceptable for publication. PMID- 21817865 TI - Where do we come from? What are we? Where are we going? PMID- 21817867 TI - Infant asphyxia, soft mattresses, and the "trough" effect. AB - Although unexpected infant death in a cot has traditionally been attributed to sudden infant death syndrome, careful evaluation of death scenes and sleeping environments has increasingly identified deaths due to accidental asphyxia from so-called sleeping accidents. The case of a 5-month-old infant boy who was found facedown and unresponsive in a wooden portable cot with a sagging canvas base is reported to illustrate another potentially lethal situation. Although the autopsy revealed no specific findings, examination of the cot showed a significant depression caused by the sagging canvas base that was exacerbated by a soft-foam mattress and layers of bedding. Once in the trough, the infant would not have been able to extricate himself. Death was therefore attributed to accidental suffocation due to the infant's position resulting in contact of the mouth and face with soft bedding. In addition to again demonstrating the potential dangers of using old second-hand cots, this case clearly shows the problems that may exist when soft and sagging bedding forms a central trough that may entrap an infant. Death scene investigators should specifically comment on the presence of such troughs and measure of depth of the trough and/or cot base to provide some quantification of the degree of concavity present. PMID- 21817869 TI - Autopsy diagnosis of fat embolism syndrome. AB - The fat embolism syndrome (FES) is considered a clinical diagnosis. It typically occurs within several days following major traumatic injury, usually involving fractures of the pelvis and/or lower extremities. Fat embolism syndrome is characterized by the onset of respiratory, neurological, cutaneous, and hematologic manifestations and is thought to be related to intravascular embolization of fat, presumably arising from within the fractured bone marrow space. In its most severe form, FES can be lethal. The presence of fat emboli within the microvasculature of the lungs, brain, and sometimes other organs verifies the clinical impression of FES. Despite its relatively well-known clinical characterization, debate exists within the clinical literature regarding the most appropriate diagnostic criteria for FES. Given this fact, along with the fact that FES is a clinical diagnosis, it is not surprising that forensic pathologists may be somewhat reluctant to make a postmortem diagnosis of FES, especially in cases where insufficient clinical information is available. A case of fatal FES is presented in which rapid clinical deterioration occurred, followed by death, such that a clinical diagnosis of FES was never rendered. We propose that, given the correct circumstances, clinical scenario, and autopsy findings, it is appropriate and acceptable to make a postmortem diagnosis of FES. A multitiered approach to the postmortem diagnosis of FES is presented. PMID- 21817868 TI - Potentially lethal complications of tracheostomy: autopsy considerations. AB - Tracheostomy is widely used to facilitate respiration by protecting the airways. It may be performed to relieve upper airway obstruction from congenital stenoses or from acquired conditions such as foreign body impaction, swelling from neck trauma or anaphylaxis, benign or malignant tumors, and infection. Tracheostomy may also be performed in individuals with respiratory impairment who require suctioning for accumulated mucoid secretions and in those with obstructive sleep apnea. Review of autopsy files and the literature was undertaken to demonstrate the range of lethal circumstances that may involve tracheostomy. Unexpected death may result from incorrect positioning of an endotracheal tube with failure of oxygenation, tracheal perforation with pneumothorax, mucus plugging, accidental extubation, and hemorrhage from tracheovascular fistulas. Lethal tracheovascular fistulas usually involve the innominate artery and result from mural perforation by the tip of a tracheostomy tube, mural necrosis from a high-pressure cuff, prolonged intubation, radiotherapy, and low tracheal incisions. Increased movement of tubes in patients with impaired consciousness and excessive head movements may also increase the chances of hemorrhage, as may infiltrating tumors. Given the wide range of potential fatal mechanisms that may be found in such cases, careful autopsy evaluation and dissection will be required to demonstrate the exact nature and site of the lethal lesion in individuals who underwent tracheostomy and die unexpectedly. PMID- 21817870 TI - An unusual case of lead snowstorm caused by fragmentation of buckshot. AB - This article reports the unusual radiographic findings of 2 cases of a shotgun shooting incident involving the homicide of a plant manager and the subsequent suicide of the assailant. Radiologic examination of wounds produced by the no. 00 copper-plated buckshot used in the incident revealed images with striking similarity to the lead snowstorm appearance generally associated with high velocity, soft-point rifle bullets. PMID- 21817871 TI - Death of a 6-month-old due to a tracheal bronchus. AB - The death of an infant younger than 1 year requires a thorough scene investigation and autopsy. Most infant deaths investigated by forensic pathologists can be placed into 2 general categories: sudden infant death syndrome and accidental asphyxial deaths. Despite the fact that most infant deaths occur within these 2 categories, it is important to remember that other entities may be responsible for death. In this report, we present a developmental pulmonary abnormality that was ultimately responsible for the death of an infant. A 6-month-old male infant with a prior history of pneumonia was brought to an emergency department for evaluation of fever. Antibiotics were prescribed, and the child was discharged and sent home with instructions to his mother to follow up with his pediatrician. Later that evening, the infant seemed to be in respiratory distress. His mother again transported him to the emergency department, where, on arrival, he became apneic. Despite vigorous resuscitative efforts, the infant died. Of note at autopsy was the presence of low-set abnormal ears and bilateral inward-turning ankles. Internally, an abnormality of the tracheobronchial tree was evident, with the right upper lobe bronchus arising from the distal trachea, proximal to the carina. In addition, the right upper lobe was discolored and firm. Microscopically, pneumonia was present. The cause of death was pneumonia due to a right tracheal bronchus. Childhood pneumonia is a known cause of childhood hospitalization, morbidity, and mortality. Identifying the causes of recurrent pneumonia, be it structural, metabolic, or syndromic, aids in preventing recurrent infections and reducing the incidence of childhood mortality. A tracheal bronchus, also known as bronchus suis or "pig bronchus," is an anatomic variant of the tracheobronchial tree in which a bronchus arises proximal to the carina, most commonly on the right and predominantly in males. The incidence is around 0.2%. Although the tracheal bronchus is sometimes a clinically silent entity, some patients may exhibit certain signs and symptoms, including hemoptysis, coughing, stridor, wheezing, and pain. The typical consequences of the tracheal bronchus are recurrent pneumonias. The recurrent pneumonia is thought to be due to a stasis of secretions and an abnormal pulmonary clearing mechanism. Treatment for the condition varies, based on symptoms. For asymptomatic patients, conservative management is adequate. For symptomatic patients with persistent atelectasis or right upper lobe consolidation, surgical excision is advised. PMID- 21817872 TI - The effect of threat of litigation on forensic pathologist diagnostic decision making. AB - BACKGROUND: Recent litigation involving medical examiners has caused concern over certifying deaths. METHODS: We administered a survey of 716 medical examiners regarding the effects of the threat of litigation. RESULTS: Two hundred twenty two medical examiners responded (31%). Of those who responded, approximately 13.5% admitted to having modified their diagnostic findings due to threat of litigation, and approximately 32.5% stated these considerations would affect their decisions in the future. Physicians who indicated they had or would modify their diagnoses expressed more concern over the possibility of litigation. Chiefs of services were less likely than staff members to indicate changing diagnoses. Practitioners whose jurisdictions included rural areas were significantly more likely to indicate that litigation considerations would affect their diagnoses in the future, although this was not true with those who had already modified their diagnoses. No correlation was found with elected versus appointed positions, accreditation status, sex, race, geographic location, or board certification. CONCLUSIONS: Although very few medical examiners have actually been sued because of their diagnoses, a demonstrated threat of litigation has a substantial effect on diagnostic decision making. PMID- 21817873 TI - Is informed consent broken? AB - For as long as the federal regulations governing human subjects research have existed, the practice of informed consent has been attacked as culturally biased, legalistic, ritualistic and unevenly enforced. Its focus on meeting the regulatory requirements is seen as undermining a truly ethical process that produces informed and voluntary participation in medical research. Recent changes in the clinical translational research enterprise, with large scale genomic and other data sharing made possible by advanced bioinformatic technologies, may further challenge this goal. Study participants are asked to consent to future studies with unspecified aims, broad data sharing policies and ongoing uncertainties regarding confidentiality protections and the potential benefit of incidental genomic research findings. Because more research is conducted under these new conditions, the very nature of the researcher-subject relationship is shifting and will require new governance mechanisms to promote the original goals of informed consent. PMID- 21817874 TI - The use of nonhuman animals in biomedical research. AB - Opposition to the use of animals in biomedical research rests on diverse scientific and ethical arguments. Here I offer a response to key objections and argue that the responsible use of animals in biomedical research with the goal of advancing medical knowledge, science and human health, is scientifically and morally justified. My views are unlikely to be shared uniformly across the scientific community. Thus, I hope this personal perspective persuades other scientists, public health officials, scientific organizations and our academic leadership to join the debate and invites opponents of animal research to create an atmosphere where civil discourse can take place, free of threats and intimidation. The public deserves an open and honest debate on this important topic. PMID- 21817875 TI - Case report: storm and acid, together... ! AB - The authors discuss the case of a 32-year-old woman, with history of Graves' disease, who was noncompliant with her medications. She presented with thyroid storm and concomitant diabetic ketoacidosis. She had no history of diabetes, and this was the first presentation of diabetes. Type 1 diabetes mellitus and Graves' disease are both autoimmune diseases and can occur in concurrence, but such presentation wherein extremes of both disorders, namely thyroid storm and diabetic ketoacidosis occur together, is very rare and requires early diagnosis and management. PMID- 21817876 TI - Incessant ventricular tachycardia and cardiogenic shock: a common presentation of an uncommon diagnosis. AB - Giant cell myocarditis is a rare and highly lethal disease that is characterized by a rapidly progressive course of biventricular dysfunction. The authors present a case of giant cell myocarditis that presented with incessant ventricular tachycardia and cardiogenic shock in which clinical improvement was achieved with immunosuppressive therapy. PMID- 21817877 TI - Missed opportunities to counsel patients with malignant pleural mesothelioma about causation and potential compensation. AB - INTRODUCTION: Malignant pleural mesothelioma (MPM) is a lethal malignancy strongly associated with occupational exposure to asbestos. The aims of this study were to assess the quality of counseling provided to patients with MPM about the causation of MPM and the potential for compensation. METHODS: The authors conducted a structured retrospective chart review of patients with a diagnosis of MPM. They abstracted demographic data, occupational and environmental history and exposure data. They also searched for documentation of patient education and counseling. RESULTS: The authors identified 16 patients with a new diagnosis of MPM during the study period. A job title was documented at least once in the records of 12 (75%) patients. Documentation of occupational exposure to asbestos was found in the records of 12 (75%) patients. Two patients (13%) were presumed to have had bystander exposure to asbestos. Education about MPM causation and counseling about opportunities for compensation were documented in the record of 1 patient (6%). CONCLUSIONS: Among patients with MPM, documentation of some elements of an occupational history, including an occupational asbestos exposure history, was common. Advice to pursue compensation for potential occupation related MPM was rare. Physicians may be missing opportunities to provide beneficial information to patients with newly diagnosed MPM regarding potential legal redress and compensation. PMID- 21817878 TI - Financial incentives for research participation: empirical questions, available answers and the burden of further proof. PMID- 21817879 TI - Cocaine-induced thrombotic vasculopathy. AB - Cocaine has been associated with a number of cutaneous manifestations, and most reports in the literature have described cocaine-induced vasculitis. However, not all reactive patterns secondary to cocaine use are vasculitic in nature. Recently, there has been a disturbing trend of "cutting" cocaine with pharmacologically active substances, the most common being levamisole. This agent is known to cause serious adverse effects including agranulocytosis and cutaneous eruptions. The authors describe a 52-year-old woman who acutely developed an extensive bullous rash in the lower extremities after she snorted cocaine. The clinical, hematological and serological findings were suggestive of levamisole induced vasculitis, but histopathology of the skin showed thrombogenic vasculopathy with no inflammatory infiltrate. A skin biopsy is an essential component in the diagnosis of cocaine-related syndromes and can aid in the distinction from true autoimmune vasculitis. PMID- 21817880 TI - Impact of cardiovascular disease guideline dissemination on provider knowledge. AB - INTRODUCTION: Provider characteristics associated with higher cardiovascular disease (CVD) knowledge and learning through clinical practice guidelines (CPG) dissemination are not well understood. METHODS: A baseline knowledge survey was distributed to licensed primary care practitioners. A CPG was then distributed following 6-weeks later by a repeat survey to assess proportion reading the CPG and changes in an aggregate knowledge score. The authors examined provider characteristics as predictors of CPG review and knowledge. Changes in CVD knowledge and specific CVD knowledge deficits were assessed. RESULTS: Of 1415 providers, 59% (830) completed the initial survey, 46% (651) completed the survey after CPG dissemination and 37% (523) completed both. The weighted percentage of CPG review was 51% (95% CI: 47%-55%) and was higher among midlevel providers (63% versus 44%, P < 0.001) and those in practice >5 years (53% versus 40%, P=0.017). Overall, baseline knowledge score was 71.2% and improved to 72.2% (P=0.038). Improvement in knowledge score was greater among midlevel providers (mean increase 2.4%, 95% CI: 1.0%-4.0%). Paradoxically, those in practice >5 years exhibited a trend toward lower improvements (2.2% versus 1.1%, P=0.08). CONCLUSIONS: Direct dissemination of a CPG resulted in a moderate rate of review, yet only small improvements in knowledge. This suggests that CPG dissemination alone is inadequate to substantively improve provider knowledge, although midlevel providers were more likely to read the CPG and increase their knowledge score. Multicomponent education strategies tailored to provider characteristics may be more effective improving knowledge. PMID- 21817882 TI - Is methicillin-resistant Staphylococcus aureus pneumonia epidemiology and sensitivity changing? AB - INTRODUCTION: Methicillin-resistant Staphylococcus aureus (MRSA) pneumonia poses a deadly threat due to the pathogen's remarkable resistance and virulence factors. Evidence suggests that the epidemiology and sensitivity to antibiotics for MRSA pneumonia is changing extremely fast, creating the potential for it to become a "super bug." OBJECTIVE: To assess the incidence of community-acquired and hospital-acquired MRSA pneumonia in the community hospital at Christus Spohn during a period of 3 years and its reactivity to antibiotic therapy. METHODS: The retrospective study was performed using data collected from Christus Spohn Memorial Hospital Corpus Christi inpatient charts between 2006 and 2008. Patients were identified and selected based on positive sputum cultures for MRSA and using Center of Disease Control, American Thoracic Society and Infectious Diseases Society of America guidelines. Patients were then categorized into 2 groups: community-acquired MRSA (CA-MRSA) pneumonia and hospital acquired MRSA (HA-MRSA) pneumonia. RESULTS: Our results indicated increase resistance to clindamycin among both CA-MRSA and HA-MRSA, whereas the sensitivity to trimethoprim/sulfamethoxazole (TMP/SMX) is preserved for both CA-MRSA and HA MRSA. CONCLUSIONS: Resistance to clindamycin has increased over time, but TMP/SMX has preserved its sensitivity against MRSA. TMP/SMX should be revisited as a viable antibiotic option against CA-MRSA and HA-MRSA, specifically against CA MRSA. PMID- 21817881 TI - Acute kidney injury: the beginning of the end of the dark ages. AB - There has been enormous progress in the understanding of acute kidney injury (AKI) over the past 5 years. This article reviews some of the salient new findings, the challenges revealed by these findings and new insights into the pathogenesis of ischemic AKI. Clinical studies have demonstrated that even a small, transient rise in serum creatinine increases the risk of mortality in hospitalized patients and that a single event of AKI increases the risk for developing chronic kidney disease. Although the overall mortality rate from AKI has improved over the past 2 decades, it continues to be significant. Current treatment is focused on maintaining renal perfusion and avoiding volume overload. However, new therapeutic targets are emerging for the treatment of AKI as our understanding of the pathogenesis of ischemic injury and inflammation increases. Early diagnosis, however, continues to be challenging as the search continues for sensitive and specific biomarkers. PMID- 21817883 TI - Serum procalcitonin levels in patients with myeloperoxidase-antineutrophil cytoplasmic antibodies-associated glomerulonephritis. AB - INTRODUCTION: High serum procalcitonin (PCT) levels (>=0.5 ng/mL) commonly occur with systemic bacterial and fungal infections. Although several studies suggested that measuring serum PCT levels may serve as a useful marker to distinguish between active antineutrophil cytoplasmic antibodies (ANCA)-associated diseases and invasive infections, there is no information on PCT in myeloperoxidase (MPO) ANCA-associated glomerulonephritis. METHODS: The authors measured serum PCT concentrations before initiation of immunosuppressive therapy in 67 patients with biopsy-proven MPO-ANCA-associated glomerulonephritis. The authors compared complications and clinicopathological parameters between patients with serum PCT levels of <0.5 ng/mL (group A: 58 patients) and >=0.5 ng/mL (group B: 9 patients). RESULTS: All 58 patients in group A did not show any clinical sign of systemic infection. On the other hand, 3 of 9 patients in group B had bacterial or fungal infections of the respiratory or urinary tact. One patient had a history of chronic urinary tract infection. In the remaining 5 patients in group B, there were 3 patients with concurrent malignancies and 1 postoperative patient with malignancy. Another in group B had a long history of interstitial pneumonia of unknown origin and severe renal insufficiency. Serum levels of C-reactive protein and creatinine were significantly higher in group B than in group A. CONCLUSIONS: In patients with MPO-ANCA-associated glomerulonephritis, serum PCT levels of >=0.5 ng/mL are recommended as cutoff for consideration of bacterial and fungal infections. Elevated serum PCT levels could also be observed in some patients with severe injury of the kidneys and/or lungs in the absence of infection. PMID- 21817884 TI - Implementing National Institute of Clinical Excellence guidelines for venous thromboembolism prophylaxis. AB - INTRODUCTION: Venous thromboembolism (VTE) is a serious complication after lower limb injury and surgery. Pursuing prophylactic policies, particularly chemical prophylaxis, has been a debatable issue. In April 2007, the National Institute of Clinical Excellence recommended using chemical and/or mechanical prophylaxis for patients undergoing joint arthroplasty and other orthopedic operations. A list of risk factors predisposing patients to VTE was published. This article discusses the difficulties and methods of implementing the guidelines. METHODS AND MATERIAL: Patients undergoing lower limb arthroplasty or treatment for femoral neck fractures were included. In total, 9893 patients required prophylactic treatment for VTE. RESULTS: The maximum readmission rate within 3 months of lower limb arthroplasty with a deep vein thrombosis or pulmonary embolism was reduced from 70% in 2005 to 28% in 2009. CONCLUSION: The incidence of VTE was reduced to one fifth of that before implementing the National Institute of Clinical Excellence guidelines. Thus, it has been valuable to implement the guidelines. PMID- 21817886 TI - Breast enlargement with prednisone treatment. AB - A 17-year-old boy sought endocrine advice for an unusual gynecomastia that inexplicably recurred whenever he was treated with prednisone. This began at the age of 14, when the patient was diagnosed as having Addison's disease and was first treated with prednisone. An ensuing breast enlargement caused him to stop the medication and a regression of the gynecomastia was observed. Breast enlargement reappeared each time prednisone treatment resumed. Review of this problem led to the final diagnosis of congenital adrenal hyperplasia in a teenager who was genetically female but phenotypically male. PMID- 21817885 TI - Uncertainty and equipoise: at interplay between epistemology, decision making and ethics. AB - In recent years, various authors have proposed that the concept of equipoise be abandoned because it conflates the practice of clinical care with clinical research. At the same time, the equipoise opponents acknowledge the necessity of clinical research if there are unresolved uncertainties about the effects of proposed healthcare interventions. As equipoise represents just 1 measure of uncertainty, proposals to abandon equipoise while maintaining a requirement for addressing uncertainties are contradictory and ultimately not valid. As acknowledgment and articulation of uncertainties represent key scientific and moral requirements for human experimentation, the concept of equipoise remains the most useful framework to link the theory of human experimentation with the theory of rational choice. In this article, I show how uncertainty (equipoise) is at the intersection between epistemology, decision making and ethics of clinical research. In particular, I show how our formulation of responses to uncertainties of hoped-for benefits and unknown harms of testing is a function of the way humans cognitively process information. This approach is based on the view that considerations of ethics and rationality cannot be separated. I analyze the response to uncertainties as it relates to the dual-processing theory, which postulates that rational approach to (clinical research) decision making depends both on analytical, deliberative processes embodied in scientific method (system II), and good human intuition (system I). Ultimately, our choices can only become wiser if we understand a close and intertwined relationship between irreducible uncertainty, inevitable errors and unavoidable injustice. PMID- 21817887 TI - What would we do without metronidazole? AB - Metronidazole is a treatment of choice for several types of infections, but coexisting conditions or concomitant medications may preclude its use. Although tinidazole, a newer nitroimidazole, may be an option in cases where drug interactions make the use of metronidazole inadvisable, similar absolute contraindications exist. In situations where nitroimidazole use is contraindicated or inadvisable, clinicians may have difficulty deciding on efficacious treatment options. For the treatment of trichomoniasis, alternatives include furazolidone, clotrimazole, nonoxynol-9 or paromomycin. Alternatives for bacterial vaginosis include clindamycin topically or systemically. For giardiasis, alternative options include paromomycin, nitazoxanide or the antihelminthic benzimidazoles. Alternatives for Clostridium difficile are varied, including oral vancomycin, nitazoxanide and rifaximin. Although options are limited, alternative therapies for treatment of patients with absolute contraindications to the nitroimidazole antibiotics are available. PMID- 21817888 TI - Chasing zero: the drive to eliminate surgical site infections. AB - OBJECTIVES: It is estimated that healthcare associated infections (HAI) account for 1.7 million infections and 99,000 associated deaths each year, with annual direct medical costs of up to $45 billion. Surgical Site Infections (SSI) account for 17% of HAIs, an estimated annual cost of $3.5 to 10 billion for our country alone. This project was designed to pursue elimination of SSIs and document results. METHODS: Starting in 2009 a program to eliminate SSIs was undertaken at a nationally recognized academic health center. Interventions already outlined by CMS and IHI were utilized, along with additional interventions based on literature showing relationships with SSI reduction and best practices. Rapid deployment of multiple interventions (SSI Bundle) was undertaken. Tactics included standardized order sets, a centralized preoperative evaluation (POE) clinic, high compliance with intraoperative interventions, and widespread monthly reporting of compliance and results. Data from 2008 to 2010 were collected and analyzed. RESULTS: Between May 1, 2008 and June 30, 2010, all patients with Class I and Class II wounds were tracked for SSIs. Baseline data (May-June 2008) was obtained showing a Class I surgical site infection rate of 1.78%, Class II of 2.82% (total surgical volume: 4160 cases). As of the second quarter 2010, those rates have dropped to 0.51% and 1.44%, respectively (P < 0.001 and P = 0.013; total surgical cases: 2826). This represents a 57% decrease in the SSI rate with an estimated institution specific cost savings of nearly $1 million during the study period. CONCLUSION: Committed leadership, aggressive assurance of high compliance with multiple known interventions (SSI Bundle), transparency to achieve high levels of staff engagement, and centralization of critical surgical activities result in significant declines in SSIs with resulting substantial cost savings. PMID- 21817889 TI - Surgical site infection prevention: time to move beyond the surgical care improvement program. AB - OBJECTIVES: The objective of this study was to evaluate whether the Surgical Care Improvement Project (SCIP) improved surgical site infection (SSI) rates using national data at the patient level for both SCIP adherence and SSI occurrence. BACKGROUND: The SCIP was established in 2006 with the goal of reducing surgical complications by 25% in 2010. METHODS: National Veterans' Affairs (VA) data from 2005 to 2009 on adherence to 5 SCIP SSI prevention measures were linked to Veterans' Affairs Surgical Quality Improvement Program SSI outcome data. Effect of SCIP adherence and year of surgery on SSI outcome were assessed with logistic regression using generalized estimating equations, adjusting for procedure type and variables known to predict SSI. Correlation between hospital SCIP adherence and SSI rate was assessed using linear regression. RESULTS: There were 60,853 surgeries at 112 VA hospitals analyzed. SCIP adherence ranged from 75% for normothermia to 99% for hair removal and all significantly improved over the study period (P < 0.001). Surgical site infection occurred after 6.2% of surgeries (1.6% for orthopedic surgeries to 11.3% for colorectal surgeries). None of the 5 SCIP measures were significantly associated with lower odds of SSI after adjusting for variables known to predict SSI and procedure type. Year was not associated with SSI (P = 0.71). Hospital SCIP performance was not correlated with hospital SSI rates (r = -0.06, P = 0.54). CONCLUSIONS: Adherence to SCIP measures improved whereas risk-adjusted SSI rates remained stable. SCIP adherence was neither associated with a lower SSI rate at the patient level, nor associated with hospital SSI rates. Policies regarding continued SCIP measurement and reporting should be reassessed. PMID- 21817890 TI - Predictive index for long-term survival after retransplantation of the liver in adult recipients: analysis of a 26-year experience in a single center. AB - OBJECTIVE: To develop a prognostic scoring system for risk stratification of patients with hepatic graft failure (GF) undergoing retransplants of the liver (ReLT) and improve patient selection. SUMMARY OF BACKGROUND DATA: Retransplantation of the liver remains controversial because of inferior outcomes compared with the primary orthotopic liver transplantation (OLT) and raises concerns of inappropriate utilization of a scarce donor organ resource. Data on risk stratification of ReLT patients for long-term survival outcomes are limited. METHODS: We conducted an analysis from our prospective database of 466 adults' ReLT between February 1984 and September 2010. Mean follow-up was 3 years. Each independent predictor for allograft failure was assigned risk score (RS) points of 1 or 2, proportional to the corresponding parameter estimate under the Cox model: Predictive index category (PIC) 1, RS = 0; PIC II, RS = 1 to 2; PIC III, RS = 3 to 4; and PIC IV, RS = 5 to 12. RESULTS: Eight risk factors predictive for GF after ReLT included recipient age greater than 55 years, Model for End-Stage Liver Disease score greater than 27, history of prior OLT greater than 1, pre ReLT requirement for mechanical ventilation, serum albumin less than 2.5 g/dL, donor age greater than 45 years, intraoperative requirement of packed red blood cell transfusion greater than 30 units, and performance of ReLT between 15 and 180 days from the prior OLT. Five-year GF-free survival was significantly higher in PIC I (65%) than in PIC II (53%), PIC III (43%), and PIC IV (20%) groups (P < 0.001). CONCLUSIONS: This risk-stratification model was highly predictive of long term outcome after liver retransplantation in adult recipients. This formula provides a practical guide for selection of candidates for retransplantation of the liver that can lead to improved patient outcomes and optimal utilization of a scarce resource. PMID- 21817893 TI - Population-based analysis of 4113 patients with acute cholecystitis: defining the optimal time-point for laparoscopic cholecystectomy. AB - OBJECTIVE: To compare clinical outcomes after laparoscopic cholecystectomy (LC) for acute cholecystitis performed at various time-points after hospital admission. BACKGROUND: Symptomatic gallstones represent an important public health problem with LC the treatment of choice. LC is increasingly offered for acute cholecystitis, however, the optimal time-point for LC in this setting remains a matter of debate. METHODS: Analysis was based on the prospective database of the Swiss Association of Laparoscopic and Thoracoscopic Surgery and included patients undergoing emergency LC for acute cholecystitis between 1995 and 2006, grouped according to the time-points of LC since hospital admission (admission day (d0), d1, d2, d3, d4/5, d >=6). Linear and generalized linear regression models assessed the effect of timing of LC on intra- or postoperative complications, conversion and reoperation rates and length of postoperative hospital stay. RESULTS: Of 4113 patients, 52.8% were female, median age was 59.8 years. Delaying LC resulted in significantly higher conversion rates (from 11.9% at d0 to 27.9% at d >=6 days after admission, P < 0.001), surgical postoperative complications (5.7% to 13%, P < 0.001) and re-operation rates (0.9% to 3%, P = 0.007), with a significantly longer postoperative hospital stay (P < 0.001). CONCLUSIONS: Delaying LC for acute cholecystitis has no advantages, resulting in significantly increased conversion/re-operation rate, postoperative complications and longer postoperative hospital stay. This investigation-one of the largest in the literature-provides compelling evidence that acute cholecystitis merits surgery within 48 hours of hospital admission if impact on the patient and health care system is to be minimized. PMID- 21817894 TI - Polymyxin B-immobilized fiber hemoperfusion in a high school football player with septic shock caused by osteitis pubis. AB - A 17-year-old male high school football player treated by polymyxin B-immobilized fiber (PMX-F) hemoperfusion for mild-moderate septic shock caused by osteitis pubis is described in this study. He was admitted for inguinal pain, gait disturbance, and high fever (40.6 degrees C). His white blood cell (WBC) count and C-reactive protein (CRP), endotoxin, and procalcitonin (PCT) levels were significantly elevated. His blood pressure was 76/46 mm Hg. Magnetic resonance imaging showed bone and muscle injury at the pubic symphysis. Septic shock with high blood endotoxin and PCT concentrations was diagnosed, and the patient was treated with antibiotics, gamma-globulin, and dopamine on the admission day. However, the septic shock did not improve. On day 3, we performed direct hemoperfusion twice using a PMX-F column. After the second PMX-F treatment, the patient's temperature decreased to 37.0 degrees C, and his WBC count, CRP levels, blood endotoxin, and PCT levels decreased. The inguinal pain diminished, and the patient's blood pressure increased to 112/76 mm Hg. He was discharged on day 10 after admission. This case reflects association of PMX-F with decreased endotoxin, PCT, and CRP, suggesting the association of PMX-F with clinical improvement in mild-moderate sepsis in a young athlete. PMID- 21817895 TI - Dual percutaneous mechanical circulatory support as a bridge to recovery in fulminant myocarditis. PMID- 21817896 TI - Effective ventricular unloading by left ventricular assist device varies with stage of heart failure: cardiac simulator study. AB - Although the use of left ventricular assist devices (LVADs) as a bridge-to recovery (BTR) has shown promise, clinical success has been limited due to the lack of understanding the timing of implantation, acute/chronic device setting, and explantation. This study investigated the effective ventricular unloading at different heart conditions by using a mock circulatory system (MCS) to provide a tool for pump parameter adjustments. We tested the hypothesis that effective unloading by LVAD at a given speed varies with the stage of heart failure. By using a MCS, systematic depression of cardiac performance was obtained. Five different stages of heart failure from control were achieved by adjusting the pneumatic systolic/diastolic pressure, filling pressure, and systemic resistance. The Heart Mate II(r) (Thoratec Corp., Pleasanton, CA) was used for volumetric and pressure unloading at different heart conditions over a given LVAD speed. The effective unloading at a given LVAD speed was greater in more depressed heart condition. The rate of unloading over LVAD speed was also greater in more depressed heart condition. In conclusion, to get continuous and optimal cardiac recovery, timely increase in LVAD speed over a period of support is needed while avoiding the akinesis of aortic valve. PMID- 21817897 TI - Bioimpedance cardiac output measurement in hemodialysis patients. PMID- 21817898 TI - Sensitive determination of BRAF copy number in clinical samples by pyrosequencing. AB - Pilocytic astrocytoma is the most frequently occurring brain tumor during childhood. It is classified as grade I by the World Health Organization and may rarely evolve into higher-grade tumors. Frequent genetic abnormalities documented in astrocytomas in children are gains on chromosomal arm 7q. Duplications at 7q34 lead to a fusion between genes KIAA1549 and BRAF resulting in constitutive activation of the BRAF kinase. The BRAF gene is located on chromosome 7q34 and a pseudogene has been identified on chromosome Xq13. We have developed a simple and sensitive pyrosequencing method for the determination of the BRAF copy number in clinical samples. The approach is based on the simultaneous amplification of a DNA fragment contained in exon 11 of BRAF and the respective pseudogene that is used as an internal control. Three different bases in the PCR product allow precise sequence assessment of products originating from the BRAF gene and the respective pseudogene and a calculation of gene copy numbers. After the calibration of the assay on 78 control DNA samples, 42 clinical PA samples were analyzed for variation in copy numbers by pyrosequencing and for fusion gene expression by reverse transcription-polymerase chain reaction. The results obtained from tumor DNA by the developed assay and the established reverse transcription-polymerase chain reaction assays show a high concordance. In summary, we have established a pyrosequencing-based assay allowing precise detection of BRAF copy numbers in DNA extracted from clinical samples. PMID- 21817899 TI - VEGF expression is related to good response and long progression-free survival in gastrointestinal stromal tumor patients treated with Sunitinib. AB - We intended to find predictive markers in advanced gastrointestinal stromal tumor patients treated with sunitinib. Korean patients who received sunitinib after imatinib failure for advanced gastrointestinal stromal tumor were studied. Genotyping for KIT and PDGFRA were performed. An immunohistochemical stain for PDGFR-alpha, PDGFR-beta, and vascular endothelial growth factor (VEGF) was performed. A total of 22 patients were analyzed. Their median age was 55.1 years, and the male to female ratio was 12:10. The response rate of sunitinib was 30.4% and the median progression-free survival (PFS) was 10.1 months. In the sunitinib treatment, VEGF expression was related to a favorable response (P=0.002) and long PFS (P=0.020) in univariate analysis. CD34 (P=0.023) and PDGFR (P=0.022) expressions were also related to long sunitinib PFS in univariate analysis. However, the genotype did not affect either response rate or the PFS of sunitinib. In conclusion, expressions of VEGF, PDGFR, and CD34 may have predictive value in sunitinib treatments. PMID- 21817900 TI - Rapid In-situ hybridization for dematiaceous fungi using a broad-spectrum oligonucleotide DNA probe. AB - Dematiaceous fungi are a diverse group of "darkly" pigmented fungi, which contain melanin in their cell walls and are commonly found in soil worldwide. Although morphology and histochemical stains may aid identification in tissue sections, these means for species identification are not specific. In-situ hybridization (ISH) for abundant fungal rRNA sequences may provide a means for detecting dematiaceous fungi. In this study, a 24-base synthetic biotin-labeled oligonucleotide probe targeting rRNA sequences of a variety of dematiaceous fungi was developed. This probe was tested on a cohort of 29 patients with culture proven cases of dematiaceous fungal-associated rhinosinusitis (26 allergic fungal sinusitis, 2 fungal ball, and 1 acute invasive fungal sinusitis). Fungal cultures were positive for Alternaria species (10), Bipolaris species (5), Curvularia species (10), Cladosporium species (1), Scedosporium prolificans (1), Scopulariopsis species (1), and dematiaceous species, not otherwise specific (1). ISH showed positivity in fungal organisms in 24 of 29 specimens. ISH was negative in culture-proven examples of Rhizopus species, Aspergillus species, Fusarium species, Paecilomyces species, Histoplasmosis capsulatum, Candida species, and Blastomyces dermatitidis. ISH with a dematiaceous-specific fungal probe may be useful for differentiating dematiaceous fungi from other filamentous fungi in tissues, particularly those responsible for fungal rhinosinusitis. PMID- 21817901 TI - Validation of a TFE3 break-apart FISH assay for Xp11.2 translocation renal cell carcinomas. AB - Renal cell carcinomas (RCCs) with an Xp11.2 translocation predominantly affect young patients, and can present at an advanced stage. However, more cases in older patients and incidentally detected cancers at earlier stages are also being identified. As the histology of Xp11.2 RCCs overlaps with clear cell and papillary RCCs, it is not infrequent that Xp11.2 RCCs are overlooked and misdiagnosed. The objective of this study was to validate the use of fluorescence in-situ hybridization (FISH) for identifying Xp11.2 RCCs. One hundred fifty-eight consecutive, unselected renal tumors were evaluated in tissue microarrays, including 109 clear cell RCCs, 20 papillary RCCs, 3 RCCs with mixed papillary and clear cell features, 1 Xp11.2 translocation RCC, 8 chromophobe RCCs, 10 oncocytomas, and 7 angiomyolipomas. FISH evaluation was performed blinded to karyotype data, available in about two-thirds of cases. Furthermore, conventional sections of 4 Xp11.2 RCCs, 4 RCCs with mixed papillary and clear cell features, and 4 cases of alveolar soft part sarcoma (the latter for control purposes) were also assessed by FISH. Break-apart signals were homogeneously identified throughout tumor cells in 2 cases from the tissue microarrays including 1 known Xp11.2 RCC and 1 misdiagnosed Xp11.2 RCC. All conventional sections from the Xp11.2 RCC and alveolar soft part sarcoma cases were positive for the TFE3 rearrangement by FISH. All remaining cases were negative. Our study shows the clinical application of FISH in formalin-fixed, paraffin-embedded tissue for detection of Xp11.2 translocation RCCs and other tumors with this genetic aberration. PMID- 21817902 TI - Wobble-enhanced ARMS method for detection of KRAS and BRAF mutations. AB - Monoclonal antibodies targeting the epidermal growth factor receptor have expanded the range of treatment options for patients with metastatic colorectal cancer. However, somatic mutations in the KRAS and BRAF genes have proven to be molecular predictors of resistance to treatment with anti-epidermal growth factor receptor therapy in these patients. Thus, we have developed a sensitive mutation assay, wobble-enhanced amplification refractory mutation system, for detecting the 8 most commonly reported mutations of clinical importance in the KRAS and BRAF genes; KRAS g.34G>C (p.G12R), g.34G>A (p.G12S), g.34G>T (p.G12C), g.35G>A (p.G12D), g.35G>C (p.G12A), g.35G>T (p.G12V), g.38G>A (p.G13D), and BRAF g.1799T>A (p.V600E). A total of 28 candidate setups were designed based on bioinformatics and primer/probe design. Eight candidate setups were thus selected using a synthetic oligonucleotide model. The setups were further validated through several experiments using formalin-fixed paraffin-embedded tissue and cell lines. The results confirm that the wobble-enhanced amplification refractory mutation system method is quick, cost effective, and sensitive. The method is optimized to handle a typical template input of 1 to 20 ng DNA per polymerase chain reaction and can be implemented in any laboratory with ease with a real time polymerase chain reaction instrument capable of handling TaqMan techonology. The steps used to develop this method can be implemented to design assays for other mutations located in KRAS, BRAF, or other candidate genes. PMID- 21817903 TI - High-throughput genotyping robot-assisted method for mutation detection in patients with hypertrophic cardiomyopathy. AB - Hypertrophic cardiomyopathy (HCM) is the most frequent autosomal dominant genetic heart muscle disease and the most common cause of sudden cardiac death in young people (under 30 y of age), who are often unaware of their underlying condition. Genetic screening is now considered a fundamental tool for clinical management of HCM families. However, the high genetic heterogeneity of HCM makes genetic screening very expensive. Here, we propose a new high-throughput genotyping method based on a HCM 96-well sequencing plate for the analysis of 8 of the most frequent HCM-causing sarcomeric genes by automating several processes required for direct sequencing, using a commercially available robotic systems and routinely used instruments. To assess the efficiency of the robot-assisted method, we have analyzed the entire coding sequence and flanking intronic sequences of the 8 sarcomeric genes in samples from 18 patients affected by HCM and their relatives, which revealed 9 different mutations, 3 of which were novel. The automated, robot-assisted assembling of polymerase chain reaction, purification of polymerase chain reaction products, and assembly of sequencing reactions resulted in a substantial saving of time, reagent costs, and reduction of human errors, and can therefore be proposed as a primary strategy for mutation identification in HCM genetic screening in many medical genetic laboratories. PMID- 21817904 TI - Validation of multiplex ligation-dependent probe amplification for confirmation of array comparative genomic hybridization. AB - The American College of Medical Genetics recommends that each laboratory should confirm abnormal or ambiguous results detected by array comparative genomic hybridization (aCGH). At present, the gold standard method for aCGH confirmation is fluorescent in situ hybridization (FISH). However, FISH is not well suited for small tandem duplications or very small deletions that are detectable by oligonucleotide arrays. Therefore, we developed and validated multiplex ligation dependent probe amplification (MLPA) for aCGH confirmation. The method performance validation showed linearity through the expected analytical measurement range (0.05 to 2 genome equivalents). The interassay normalized coefficient of variation averaged 3.7% across 12 control and target probes. This low imprecision allowed detection of 20% mosaicism with exceptional confidence (P<0.006). Comparison with a combined gold standard of phenotype, aCGH, karyotype, and/ or FISH showed 100% concordance for 218 samples using an X/Y chromosome-specific probe set (95% confidence interval, 98.3%-100.0%). Patient specific probe sets also showed 100% concordance to the gold standard for 18 genomic targets. In conclusion, we have developed and validated an MLPA assay using a novel approach to accommodate the fact that positive controls would not be available at the time of testing. We initially validated the MLPA method using X/Y chromosome-specific probes and well-characterized samples and then validated new probe sets by comparision with reference populations. We have successfully incorporated aCGH confirmation using custom-designed MLPA into our normal workflow, and used it for confirmation of all abnormal or ambiguous results. PMID- 21817906 TI - Detection of p16INK4a promoter methylation status in non-small cell lung cancer by a fluorescence polarization assay. AB - The detection of the p16INK4a promoter methylation status has a good value for the prognosis, early detection, and individualized management of patients with non-small cell lung cancer. A novel method detecting the p16INK4a promoter methylation status of primary carcinoma tissue samples by a fluorescence polarization assay was developed in this research. A pair of general primers was used to amplify a 305-basepair fragment in the promoter region of p16INK4a. Two probes specific for either methylated p16INK4a or unmethylated p16INK4a DNA labeled with either tetramethyl 6-carboxyrhodamine or 6-carboxy-fluorescein hybridized, respectively, with their target amplicons, and the hybridization increased the fluorescence polarization values. The p16INK4a promoter methylation status was determined by the analysis of the fluorescence polarization values. One hundred and twenty-nine non-small cell lung cancer samples were analyzed in parallel with a fluorescence polarization assay and a gel-based methylation specific polymerase chain reaction (PCR) assay. There was no significant difference between the results of the p16INK4a promoter methylation status obtained with the fluorescence polarization assay and the results obtained with the gel-based methylation-specific PCR assay. The minimum detection level of the fluorescence polarization assay was 25 copies/MUL. The fluorescence polarization assay allowed the semiautomated detection of the methylated p16INK4a and unmethylated p16INK4a promoters directly in the solution with 1 PCR cycle, and it was much simpler than methylation-specific PCR and methylation-specific multiplex ligation-dependent probe amplification assays. PMID- 21817905 TI - Is there a clinical association of vancomycin MIC creep, agr group II locus, and treatment failure in MRSA bacteremia? AB - BACKGROUND: The association of vancomycin treatment failure with minimum inhibitory concentration (MIC) creep is concerning, as most isolates are still considered to be in the susceptible range. Several studies have suggested that the accessory gene regulator (agr) group II polymorphism is predictive of vancomycin treatment failure. We assessed the associations between increased vancomycin MIC, agr group II locus, and vancomycin treatment failure in Methicillin-resistant Staphylococcus aureus (MRSA) bacteremias. METHODS: MRSA isolates from 99 inpatient bacteremias were studied. Susceptibility testing was conducted by an automated method (MicroScan) and by the gradient diffusion method (E-test). Vancomycin MICs were stratified into 3 groups for analysis: MIC <= 1, MIC > 1 but <= 2, and MIC >2 MUg/mL. Strains were typed by repetitive-polymerase chain reaction analysis and the agr locus was identified by multiplex polymerase chain reaction. Failure of vancomycin treatment was defined as persistent bacteremia after 72 hours, death at 30 days, or treatment change due to clinical failure. RESULTS: Among 99 bacteremic patients, there were 82 agr group II and 15 agr group I isolates. There was no relationship between higher vancomycin MICs and isolate agr II loci (42 of 82) (P=0.59). Earlier vancomycin exposure was significantly associated with increased MIC (P=0.03). Vancomycin treatment failure was observed in 12 patients: 3 required an alternate regimen, 4 had persistent positive cultures, and 5 whose deaths were attributable to MRSA infection. Survival in agr group II was 57 of 82 (69%) versus agr group I in which it was 14 of 15 (93%), (P=0.06). CONCLUSIONS: We did not identify any significant association between MIC creep and vancomycin failure or between higher vancomycin MICs and agr group II. However, a higher mortality was seen in agr group II than agr group I. PMID- 21817907 TI - Carotid artery dissection: three cases and a review of the literature. AB - Carotid artery dissections are potentially disabling, probably underdiagnosed, and mainly affect young-aged and middle-aged people. We present three consecutive cases illustrating different clinical presentations and thereby emphasizing the diagnostic challenge of carotid artery dissections for the emergency physician. Neck and facial pain, headache, unilateral pulsatile tinnitus, partial Horner's syndrome (or oculosympathetic palsy), amaurosis fugax, retinal infarction, and anterior circulation brain ischemia may all occur in isolation or in various combinations. Medical imaging plays a pivotal role in making the right diagnosis. Clinical vigilance is of utmost importance as early diagnosis and timely treatment favor long-term prognosis and even prevent ischemic complications. We review the literature and discuss the pathophysiology, etiology, clinical presentation, diagnosis, imaging techniques, treatment, and prognosis of carotid dissections. PMID- 21817908 TI - Prehospital chest emergency sonography trial in Germany: a prospective study. AB - OBJECTIVES: To examine the feasibility and diagnostic value of a novel prehospital chest ultrasound algorithm in patients with dyspnea. METHODS: Sixty two patients (32 men, 30 women, mean 67.1 years, range 20-90 years) with acute dyspnea prospectively underwent chest sonography with a portable ultrasound device. The algorithm included five sectional views (four-chamber subxyphoidal view, left and right laterodorsal view, left and right anterior intercostal space two to four view) screening for pleural and pericardial effusion, right heart distension, and pneumothorax. The prehospital sonographic findings were confirmed by chest radiograph, ultrasonography, and clinical follow-up in the emergency department. RESULTS: Prehospital chest emergency sonography trial was completed in 56 patients. Mean examination time was 2 min, and no scan took longer than 5 min. Sonography was easily integrated in the prehospital workflow alongside paramedic treatment without delay of treatment or transport. The most common diagnoses associated with acute dyspnea were (a) acute coronary syndrome (n=12, 21%), (b) decompensated congestive heart failure (CHF) (n=11, 20%), and (c) chronic obstructive pulmonary disease (COPD) (n=10, 18%). Pleural effusion was detected in 100% of CHF, 17% of acute coronary syndrome, and 20% of COPD patients, constituting a highly significant parameter in the differential diagnosis (P<0.01). Ultrasonography provided a helpful tool in n=38 (68%), and additional therapeutic consequences were drawn in n=14 (25%). CONCLUSION: Prehospital chest emergency sonography trial is a novel prehospital ultrasound algorithm for patients with dyspnea. Pleural effusion may serve as a novel prehospital marker for patients with decompensated CHF, thus facilitating the often difficult differential diagnosis between CHF and COPD. PMID- 21817909 TI - Use of the TrachView videoscope as an adjunct to direct laryngoscopy for teaching orotracheal intubation. AB - The main objectives of this study were to assess the ease of the use of the TrachView videoscope and to compare it with direct laryngoscopy (DL) for teaching orotracheal intubation to emergency medicine (EM) medical students. Thirty-seven EM students with no earlier intubation experience were asked to intubate a manikin's trachea using DL alone and DL in combination with the TrachView. This investigation involved a randomized, cross-over study design and each trainee received a 10-min demonstration with each technique before the beginning of the study. The Percentage Of Glottic Opening (POGO) scores (%) were recorded and the ease of use of the device for intubation was evaluated by each student using a three-point rating scale. The median POGO score for the DL alone was 25% (range, 0-100%). However, the POGO score improved to 90% (range, 15-100%) with the addition of the TrachView device (P<0.001). The TrachView was considered easy to use by a majority of the EM students and improved visualization of the vocal cords compared with DL alone. The time to achieve successful intubation of the manikin's trachea was shorter when the TrachView was used as an adjunct to DL. PMID- 21817910 TI - Nonoperative management of anterior thoracoabdominal stab wounds in selected patients. AB - OBJECTIVES: Nowadays, use of selective nonoperative management has decreased the incidence of nontherapeutic laparotomies in patients with anterior thoracoabdominal stab wounds. The safety of selective nonoperative management was investigated in these patients, not requiring emergency laparotomy. PATIENTS AND METHODS: Patients referred to the Tabriz Imam Reza Hospital with anterior thoracoabdominal stab wounds were studied from August 2008 to 2010. The hemodynamically unstable patients, those with evidence of peritoneal irritation or with organ evisceration, underwent an emergency laparotomy. For other patients, diagnostic peritoneal lavage (DPL) was used and patients with positive results were operated. Patients with negative DPL results underwent serial physical and laboratory examinations. RESULTS: A total of 204 patients were studied. Sixty-two cases (30.4%) had emergency operations, with 12 (19.4%) cases of nontherapeutic laparotomies. On the basis of DPL results in 142 (69.6%) patients, laparotomy was carried out in another 18 (12.7%) cases with a nontherapeutic result in eight (5.6%) cases. Finally, 124 (60.8%) patients were left for further observation and serial physical and laboratory examinations. Accordingly, five (4%) patients needed delayed laparotomy without any serious complications due to the delayed operation. The length of hospital stay and nontherapeutic laparotomies in our study were lower than mandatory laparotomy management and also, there were no significant complications or mortalities within the 90 days follow-up period. CONCLUSION: This study showed that the proposed approach of selective nonoperative management in patients with anterior thoracoabdominal stab wounds is safe, feasible, and probably cost-effective. PMID- 21817911 TI - Small bowel entrapment associated with pelvic fracture: a case report with review of the literature and differentiation of clinical picture. PMID- 21817912 TI - Toxicology surveillance system of the Spanish Society of Paediatric Emergencies: first-year analysis. AB - We aim to describe the characteristics and the management of the paediatric poisonings registered in the Toxicology Surveillance System created by the Intoxications Working Group of the Spanish Society of Paediatric Emergencies. We reviewed 130 episodes registered during 1 year. The main involved substances were drugs (73, 56.2%), household products (24,18.5%) and ethanol (16, 12.3%). Most common mechanisms were accidental poisonings at home in children of less than 5 years (91, 70%; principally, paracetamol or anticatharrals) and patients of 12-18 years (24.6%), with recreational alcohol consumption or suicide attempt. Approximately 10% received prehospital treatment and 56.9% received treatment in the paediatric emergency department (PED), which mainly activated charcoal. Approximately 50% were managed as outpatients, and all did well. Although intoxications are infrequent in PED and the short-term prognosis is good, the consumption of healthcare resources is high. PMID- 21817913 TI - Idiopathic chylous ascites treated with total parenteral nutrition and octreotide. A case report and review of the literature. AB - Chylous ascites is the accumulation of lipid-rich lymph in the peritoneal cavity. The usual cause in adults is lymphatic obstruction or leakage caused by malignancy. Non-malignant causes include postoperative trauma, cirrhosis, tuberculosis, pancreatitis and filariasis. A variety of treatment options have been proposed for the management of chylous ascites; however, their effectiveness in idiopathic or primary form is unknown. Here we report a case of chylous acid rapidly resolved with the treatment of fasting, total parenteral nutrition and somatostatin analogue. PMID- 21817914 TI - Duration of methadone maintenance treatment during pregnancy and pregnancy outcome parameters in women with opiate addiction. AB - OBJECTIVES: Methadone maintenance treatment (MMT) is the standard treatment of choice for pregnant opiate addicts; however, data on newborn outcomes are contradictory. We studied the effect of the timing of starting MMT and of MMT related drug abstinence on the outcome of newborns of former and current opiate addicted pregnant women. METHODS: All babies (excluding repeated deliveries) of all pregnant women who were admitted to 1 MMT clinic between 1993 and 2008 were studied. Former opiate-addicted women who became pregnant while already on MMT (full-pregnancy MMT, FP-MMT) and opiate-addicted women who only started MMT during pregnancy (partial-pregnancy MMT, PP-MMT) were retrospectively compared for birth weight and gestational age of newborns. Abstinence was defined as negative urine sample results for opiates, cocaine, amphetamines, benzodiazepine and cannabis during the month before delivery. RESULTS: We examined 59 newborn babies: 14 in the FP-MMT group and 45 in the PP-MMT group. The mean birth weight was 2733.2 +/- 392.0 g versus 2240.0 +/- 680.4 g respectively (F[1] = 6.6, P = 0.01). Abstinence was determined among 73.3% of the FP-MMT and 28.6% of the PP MMT (P = 0.004). Gestational age was higher in the abstinence (37.9 +/- 2.8 weeks) versus no-abstinence group (35.8 +/- 4.6 weeks; F[1] = 4.4, P = 0.04). CONCLUSIONS: The best pregnancy outcome, characterized by a higher gestational and birth weight, was associated with a longer duration on MMT and substance abstinence, emphasizing the importance of MMT stabilization before and during pregnancy. PMID- 21817916 TI - Ethyl glucuronide for detecting alcohol lapses in patients with an alcohol use disorder. AB - Urine ethyl glucuronide (EtG) was screened in 75 patients during a hospital-based treatment for an alcohol use disorder. During follow-up, EtG was detected in 35 (14.6%) of the 239 urine samples. Positive screens were found in 22 patients (29%), of whom nine were outpatients (39.1% of all outpatients) and 13 inpatients (25.0% of all inpatients). Of the 22 patients with positive EtG, five (22%) also gave a positive breath alcohol test and 10 (45.5%) reported recent alcohol consumption; 12 (54.5%) gave a negative breath alcohol test and declared no alcohol lapse. Ethyl glucuronide has been found useful in detecting covered lapses. PMID- 21817915 TI - PATHOS: a brief screening application for assessing sexual addiction. AB - Sexual addiction is estimated to afflict up to 3% to 6% of the population. However, many clinicians lack clear criteria for detecting potential cases. OBJECTIVES: The present studies were conducted to assess the effectiveness of a brief sexual addiction screening instrument (ie, PATHOS Questionnaire) to correctly classify patients being treated for sex addiction and healthy volunteers. METHODS: In study 1, a 6-item questionnaire, which utilizes the mnemonic "PATHOS," was examined in regard to sensitivity and specificity using a sample combining patients being treated for sex addiction and healthy volunteers (970 men/80.2% patients; 938 women/63.8% patients). In study 2, a cross validation sample of 672 men (93% patients) and 241 women (35.3% patients) completed the PATHOS screener. RESULTS: Results of receiver operating characteristics analyses in study 1 demonstrated that the PATHOS captured 92.6% of the area under the curve and achieved 88.3% sensitivity and 81.6% specificity for classifying the male sample (n = 963) as patients and healthy subjects using a cutoff score of 3. Similarly, the PATHOS captured 90.2% of the area under the curve and, with a cutoff of 3, achieved 80.9% sensitivity and 87.2% specificity for the female sample (n = 808). In study 2, results of receiver operating characteristics analyses indicated that the PATHOS captured 85.1% of the area under the curve, with sensitivity of 70.7% and specificity of 86.9% for men (cutoff of 3). For women, the PATHOS captured 80.9% of the area under the curve and achieved 69.7% sensitivity and 85.1% specificity with the cutoff of 3. CONCLUSIONS: These studies provide support for the use of the PATHOS as a screening instrument to detect potential sexual addiction cases in clinical settings. PMID- 21817917 TI - Neuroleptic malignant syndrome-like reaction precipitated by antipsychotics in a patient with gamma-butyrolactone withdrawal. AB - We report the case of a patient with chronic abuse of gamma-butyrolactone (GBL, 3 bottles per week for 4 months), who in the course of the management of acute agitation and hallucinations developed symptoms compatible with both neuroleptic malignant syndrome and GBL withdrawal symptoms.Some GHB withdrawal symptoms are similar to those of neuroleptic malignant syndrome, and the administration of antipsychotics might worsen the neurological condition of patients. So, it seems important to rapidly detect drugs taken by patients with mental agitation, to optimize management and minimize complications related to drugs. PMID- 21817918 TI - A coincidence of addiction to "Kratom" and severe primary hypothyroidism. AB - Here we present a case of a coincidence of addiction to "Kratom" (botanically known as Mitragyna speciosa Korth) and developed severe primary hypothyroidism. We are discussing a possibility that high dose of indole alkaloid mitragynine (the major alkaloid identified from "Kratom") might reduce the normal response of the thyroid gland to thyroid-stimulating hormone resulting in primary hypothyroidism. Further experimental investigations of mitragynine as a possible suppressor of thyroid gland function would be a matter of interest. PMID- 21817919 TI - Is removal of asymptomatic cervical polyps necessary?: histologic findings in asymptomatic Israeli Jewish women. AB - OBJECTIVE: : The purpose of the present study was to assess the frequency of abnormal histologic findings in polyps of asymptomatic Israeli Jewish women who are known to have a low incidence of cervical neoplasia. MATERIALS AND METHODS: : The medical records of Israeli Jewish women with histologically proven cervical polyps treated during 2005 to 2009 in 2 Maccabi Health Service clinics that specialize in cervical pathology and colposcopy were retrieved from a computerized database. The records of asymptomatic women who underwent polypectomy were reviewed, and demographic information, clinical information, and the presence of abnormal colposcopic patterns, cervical intraepithelial neoplasia (CIN), and malignancy were abstracted. RESULTS: : The study included 228 asymptomatic women with cervical polyps who underwent colposcopy. Their median age was 49 +/- 10.9 years (range = 21-82 y). The highest percentage of patients was observed in the 40- to 49-year-old age group, was Israeli-born, and was married. The percentage of patients referred because of an abnormal cytology report (29.4%) was considerably higher than the percentage reported in Israeli Jewish women. Abnormal colposcopy patterns were seen in 9 polyps, and CIN was found in 6 of them. Despite the high frequency of abnormal cytologic smears, CIN 3 was detected in only 1 polyp (0.4 %). In none of the polyps was malignancy found. CONCLUSIONS: : The very low frequency of neoplasia in cervical polyps of asymptomatic patients seems to support the notion that there is no clear indication for polypectomy when cytology is normal. PMID- 21817920 TI - Chronic granulomatous inflammation of the vulva: an unusual presentation with diagnostic and therapeutic difficulties. AB - Inflammation of the vulva can present as a manifestation of a localized problem or as part of a systemic disorder. Granulomatous vulvitis is a rare inflammatory condition that has histologic similarities to Crohn disease. Clinically, it presents with painless, chronic relapsing erythema, and edema, typically affecting the genital area. We report a case of extensive granulomatous vulvitis in a patient with no gastrointestinal evidence of Crohn disease. We describe difficulties with diagnosis and limitations in the treatment of isolated vulval granulomatous disease and aim to promote earlier recognition of the disease. PMID- 21817921 TI - Iliac osteomyelitis in a newborn: a case report. AB - Pelvis is a rare location of the hematogeneous osteomyelitis during the newborn period. Successful cure of osteomyelitis during the newborn period is dependent on a fast and true diagnosis and on sufficient treatment. In this case report, iliac osteomyelitis of a newborn that was clinically suspected on the fifth day, was diagnosed radiologically and was found to be caused by methicillin-sensitive Staphylococcus aureus, is presented. According to our knowledge, this is the youngest osteomyelitis case in the literature and the third presented iliac osteomyelitis case of the newborn period. PMID- 21817922 TI - Genetics of clubfoot. AB - Modern advances in genetics have allowed investigators to identify the complex etiology of clubfoot. It has become increasingly apparent that clubfoot is a heterogeneous disorder with a polygenetic threshold model explaining its inheritance patterns. Several recent genetic studies have identified a key developmental pathway, the PITX1-TBX4 transcriptional pathway, as being important in clubfoot etiology. Both PITX1 and TBX4 are uniquely expressed in the hindlimb, which helps explain the foot phenotype seen with mutations in these transcription factors. Future studies are needed to develop animal models to determine the exact mechanisms by which these genetic abnormalities cause clubfoot and to test other hypotheses of clubfoot pathogenesis. PMID- 21817923 TI - Massive osteochondritis of the lateral femoral condyle associated with discoid meniscus: management with meniscoplasty, rim stabilization and bioabsorbable screw fixation. AB - Discoid menisci without tears and before surgical intervention may be an aetiological factor in the development of osteochondritis dissecans (OCD). We present the case of a massive OCD lesion in the lateral femoral condyle of a 12 year-old boy who presented with relatively few symptoms despite the size of the lesion. This was treated with meniscoplasty and rim stabilization, which has become established as the gold standard treatment for symptomatic discoid menisci. This was combined with bioabsorbable screw fixation of the OCD lesion, resulting in rapid resolution of symptoms and a return to normal magnetic resonance image appearances after 6 months. It is likely that instability of discoid menisci is a key causal component when present concurrently with OCD lesions. Therefore, stabilization of this is required as well as saucerization of the meniscus. OCD lesions which are of a sufficient size such that if they became unstable or dislocated would result in a significant defect should also be stabilized. We believe that bioabsorbable screw fixation presents a good solution for fixation in these cases and this combination of treatment should result in a satisfactory outcome. PMID- 21817924 TI - Effects of prism adaptation on motor-intentional spatial bias in neglect. AB - Prism adaptation may alleviate some symptoms of spatial neglect. However, the mechanism through which this technique works is still unclear. This study investigated whether prism adaptation differentially affects dysfunction in perceptual-attentional 'where' bias versus motor-intentional 'aiming' bias. Five neglect patients performed a line bisection task in which lines were viewed under both normal and right-left reversed viewing conditions, allowing for the fractionation of 'where' and 'aiming' spatial bias components. After two consecutive days of prism adaptation, participants demonstrated a significant improvement in 'aiming' spatial bias, with no effect on 'where' spatial bias. These findings suggest that prism adaptation may primarily affect motor intentional 'aiming' bias in poststroke spatial neglect patients. PMID- 21817925 TI - Anorexigenic action of nitric oxide synthase inhibition in the raphe nuclei. AB - The present report examined the effects of midbrain raphe nuclei injections of nitric oxide synthase inhibitors NG-nitro-L-arginine methyl ester (L-NAME) and 7 nitroindazole (7-NI) on eating behavior. L-NAME (5-500 pmol) and 7-NI (2-200 pmol) were administered into either the dorsal or median raphe nucleus. Both nitric oxide synthase inhibitors decreased food intake in adult male Sprague Dawley rats when injected into either raphe site. Further, eating elicited by dorsal and median raphe injections of the 5-HT1A agonist 8-OH-DPAT (0.8 nmol) was attenuated by L-NAME or 7-NI pretreatment. Our findings indicate that nitric oxide acts within the raphe to alter food intake. The inhibitory effects of L NAME and 7-NI on eating elicited by 8-OH-DPAT further suggest that nitric oxide and 5-HT systems interact in the control of food intake. PMID- 21817926 TI - The change in perceptual synchrony between auditory and visual speech after exposure to asynchronous speech. AB - Recent studies have shown that audiovisual synchrony is recalibrated after exposure to asynchronous auditory and visual signals. This temporal recalibration has been shown only under a dual-task situation for speech signals. Here we examined whether the temporal recalibration occurs for audiovisual speech in a single-task situation using an offline adaptation method. In the experiment, participants were exposed to synchronous or asynchronous audiovisual syllables (either congruent or incongruent) for 3 min. The adaptation phase was followed by test trials, in which participants judged whether the auditory or visual stimulus was presented first. Results showed shifts in the point of subjective simultaneity and the sensitivity. Our results suggest that attention to adaptation stimuli is necessary to induce temporal recalibration for speech. PMID- 21817927 TI - Anesthetic effects on fictive locomotion in the rat isolated spinal cord. AB - General anesthetic mechanisms are poorly understood. Anesthetic immobilizing effects occur in the spinal ventral horn. However, a detailed analysis of anesthetic effects on ventral motor networks is lacking. We delivered isoflurane, desflurane, or propofol during NMDA/5-HT-induced, or noxious tail stimulus evoked, fictive locomotion in neonatal rat isolated spinal cords. Anesthetics changed the frequency, amplitude, and regularity of fictive locomotion with little effect on phase-lag. Isoflurane abolished pharmacologically-induced versus noxious stimulus-induced motor output at similar concentrations. Propofol abolished pharmacologically-induced fictive locomotion through a gamma aminobutyric acid type A-receptor mechanism. Anesthetic effects on pharmacologically-elicted fictive locomotion appear clinically-relevant, and support a ventral horn immobilizing effect on locomotor rhythm generation. PMID- 21817928 TI - Direct skin-to-skin versus indirect touch modulates neural responses to stroking versus tapping. AB - It remains unclear whether direct interpersonal contact is processed differently from similar soft touch applied through inanimate objects. We performed a functional MRI experiment in healthy volunteers, whereby activity during gentle stroking or tapping was compared between stimuli delivered using the experimenter's hand or a velvet stick. Stroking with a hand elicited larger responses than the other three conditions in the contralateral primary and secondary somatosensory areas and in the posterior insula. The observed effects likely originate from a combination of perceptual differences and cognitive and emotional correlates of contact with another person. This empirical observation indicates that, to ensure ecological validity, studies of affective touch processing should be performed with stimuli delivered with direct interpersonal contact rather than inanimate objects. PMID- 21817929 TI - Violations of implicit rules elicit an early negativity in the event-related potential. AB - When participants are asked to learn letter strings, which were constructed on the basis of a complex rule system (an artificial grammar), they are able to classify novel letter strings as being grammatical or nongrammatical better than chance without explicit knowledge about the rules. We tested whether violations of such complex regularities can be detected by the brain, when strings were presented sequentially (i.e. letter by letter). Compared with regular letters, rule-violating letters elicited enlarged amplitudes of the N1 component in the event-related potential, indicating that violations are automatically detected by the brain. However, this effect occurred irrespective of the participants' classification of the strings, indicating that the brain's detection of regularity violations does not necessarily lead to correct classifications. PMID- 21817930 TI - Iliac screw fixation using computer-assisted computer tomographic image guidance: technical note. AB - BACKGROUND: Iliac screw fixation is a powerful tool used by spine surgeons to achieve fusion across the lumbosacral junction for a number of indications, including deformity, tumor, and pseudarthrosis. Complications associated with screw placement are related to blind trajectory selection and excessive soft tissue dissection. OBJECTIVE: To describe the technique of iliac screw fixation using computed tomographic (CT)-based image guidance. METHODS: Intraoperative registration and verification of anatomic landmarks are performed with the use of a preoperatively acquired CT of the lumbosacral spine. With the navigation probe, the ideal starting point for screw placement is selected while visualizing the intended trajectory and target on a computer screen. Once the starting point is selected and marked with a burr, a drill guide is docked within this point and the navigation probe re-inserted, confirming the trajectory. The probe is then removed and the high-speed drill reinserted within the drill guide. Drilling is performed to a depth measured on the computer screen and a screw is placed. RESULTS: Confirmation of accurate placement of iliac screws can be performed with standard radiographs. CONCLUSION: CT-guided navigation allows for 3-dimensional visualization of the pelvis and minimizes complications associated with soft tissue dissection and breach of the ilium during screw placement. PMID- 21817932 TI - Envelope versus fine structure speech coding strategy: a crossover study. AB - OBJECTIVE: The transmission of fine structure information to cochlear implant users is an expanding area of research. Previous studies comparing the fine structure processing (FSP) speech coding strategy to the envelope-based continuous interleaved sampling (CIS) strategy indicated improved speech perception when using the fine structure strategy. Those investigations were performed with an extended frequency spectrum in the low frequencies together with the fine structure strategy. The current study addresses the question whether these improvements are due to the presentation of fine structure per se or rather the extended frequency spectrum. Hence, this cross over study compares the two strategies using an identical frequency spectrum. STUDY DESIGN: Randomized crossover study. PATIENTS: 31 patients were randomly assigned to two groups. INTERVENTIONS: One group was fitted with a CIS map for 4 weeks, tested and subsequently fitted with a FSP map for 4 weeks. The other group followed the same pattern in reverse. MAIN OUTCOME MEASURES: Test material consisted of sentence tests in noise, monosyllables in quiet and melody recognition. RESULTS: No statistical significance was noted between the different speech coding strategies at an identical frequency spectrum. CONCLUSION: This study shows that there is no difference in speech perception with FSP compared to CIS at an extended frequency spectrum. Therefore, the extended frequency spectrum in the low frequencies might explain a benefit of FSP observed in previous studies. PMID- 21817933 TI - Inverting papilloma of the temporal bone: case report and meta-analysis of risk factors. AB - OBJECTIVE: To review the literature on inverting papilloma of the middle ear and mastoid with a focus on familiarizing clinicians with its presentation and cause and to discuss its epidemiologic, diagnostic, and therapeutic issues. STUDY DESIGN: Search of the English literature for cases of inverted papilloma of temporal bone in conjunction with 1 new case presenting at the UCSD Medical Center. SETTING: Academic, tertiary referral hospital. PATIENTS AND INTERVENTIONS: The patient underwent radical mastoidectomy with adjuvant therapy, revealing substantial tumor growth filling the external ear canal and middle ear space and obliterating much of the mastoid air cells. Histopathology confirmed inverted papilloma of the middle ear and mastoid. The patient underwent postoperative radiation and has been free of the disease at 6 months of follow up. RESULTS: A total of 25 inverted papillomas of the temporal bone cases from the English literature between 1987 and 2010 were reviewed. This tumor commonly presents with hearing loss and otorrhea. Although rare, temporal inverted papillomas display a higher incidence of malignancy (40%) compared with sinonasal papillomas. Secondary and recurrent temporal disease was frequently associated with carcinomatous changes. Although recurrence rate is higher in temporal inverted papillomas than that in sinonasal disease, this difference becomes magnified in cases with more aggressive surgical approaches. We present a case of multicentric inverted papillomas in the middle ear and the sinonasal cavities. CONCLUSION: Efforts to define the cause of middle ear papilloma have been challenging because of its exceeding rarity. Although published literature shows that middle ear papillomas differ from their sinonasal counterparts pathologically and epidemiologically, these papillomas parallel in the unique characteristics of local aggressiveness, tendency to recur, association with malignancy, and multicentricity. Surgical resection with adjuvant radiation therapy and long-term follow-up with magnetic resonance imaging is advocated in the successful management of middle ear inverted papillomas. PMID- 21817934 TI - Intracochlear schwannomas confined to the otic capsule. AB - OBJECTIVE: To determine the natural history and management for patients with intracochlear schwannomas. STUDY DESIGN: Retrospective case series of intracochlear schwannomas confined to the otic capsule. SETTING: Tertiary referral center. PATIENTS: Ten patients were found to have schwannomas limited to the cochlea from 1998 to 2009. INTERVENTIONS: All subjects underwent at least 1 magnetic resonance imaging (MRI) study and had at least 1 audiogram. Two patients underwent a transotic excision for intractable symptoms. MAIN OUTCOME MEASURES: Presenting symptoms, initial and follow-up MRI findings, audiometric testing results, and need for surgical intervention were recorded for each subject. RESULTS: Hearing loss was present in all 10 patients at their initial presentation. Tinnitus was present in 50% of patients, and vertigo was present in 30% of patients. No patient presented with aural fullness or facial weakness. The pattern of hearing loss seemed to correlate with the location of the lesion within the cochlea. Of the 9 patients that had follow-up MRIs, 3 patients showed tumor growth. Two of the 10 patients underwent surgical excision for intractable vertigo that resulted in resolution of symptoms. CONCLUSION: Hearing loss is the most common finding in patients with intracochlear schwannomas, followed by tinnitus and vertigo. If the patient does not have symptoms of intractable vertigo, observation with serial MRI scans is indicated. Surgical excision should be reserved for patients with intractable vertigo or with significant tumor growth. PMID- 21817935 TI - Cochlear coiling pattern and orientation differences in cochlear implant candidates. AB - BACKGROUND: Detailed studies of cochlear morphology can guide our approach to cochleostomy and electrode insertion to optimize neuronal and hair cell preservation and ultimate electrode location. METHODS: Normal developed cochleae from 124 cochlear implant candidates were studied. We performed morphometric analysis of the right cochleae in all subjects based on computed tomographic data. The length and width of the cochlear base, the angle between the first and second turn of the cochlea, and the cochlear orientation within the cranial base were measured and compared across age groups. In cochlear implant candidates with underdeveloped cochleae (n = 7), we performed similar measurements and assessed the modiolar inlet area on 3D volume rendered images. RESULTS: The birth to 1 year and 1- to 2-year age groups showed insignificant differences in the lengths and widths of the cochlear base, although variability was considerable, and a significantly wider angle (from the midsagittal line) than that of the older age groupings (p < 0.05). For underdeveloped cochleae, the length and width of the cochlear base were significantly smaller and angled between the first and second turn differed from the normal developed group. The modiolar inlet also was significantly smaller in the underdeveloped cochleae compared with normal cochleae. CONCLUSION: We observed that perspective 3D-volume rendering of the cochlea enables the determination of key features of cochlear morphology and orientation that may escape detection with routine computed tomographic scanning. Infants and young toddler candidates demonstrate greater variability in the dimensions of the cochlear base and in the orientation of the cochlea within the cranium. As evolving surgical techniques and device design enhance the ability of the surgeon to avoid cochlear damage and optimize electrode location, refined morphometric information may assist the surgeon in tailoring strategies of scala tympani implantation. PMID- 21817936 TI - Management of otogenic sigmoid sinus thrombosis. AB - OBJECTIVES: To analyze the demographics, presenting symptoms, diagnosis, and management of otogenic sigmoid sinus thrombosis and to propose an algorithm in diagnosis and treatment. METHODS: A retrospective chart review was performed. Six patients who were treated at the ENT University Hospital Graz between 2005 and 2010 were included. RESULTS: The mean age of the patients was 11.7 years. Patients were experiencing symptoms for 9.8 days on average. Presenting symptoms were headache, neck stiffness, fever, otalgia, postauricular pain, and erythema. One patient presented with sixth nerve palsy. The otoscopic findings were abnormal in all cases. Computed tomography with contrast enhancement was performed in all patients. It was possible to detect the thrombosis in all cases with computed tomographic scans after contrast administration. An additional magnetic resonance imaging was performed in 3 patients. One patient was treated completely conservatively. All other patients underwent surgical treatment consisting of mastoidectomy. Additional thrombectomy was performed in 3 patients, and ligation of the internal jugular vein was performed in 2 of these 3 patients. All patients were administered intravenous antibiotics and anticoagulants. There were no complications related to the therapy. Recanalization was found in all patients who were treated without thrombectomy or ligation of the internal jugular vein and in the patient with complete conservative treatment. CONCLUSION: Otogenic sigmoid sinus thrombosis is a rare complication of otitis media. Early treatment with broad-spectrum antibiotics combined with simple mastoidectomy is the standard treatment. Anticoagulants represent a safe treatment option if they are administered correctly. PMID- 21817937 TI - Longitudinal risk of meningitis after cochlear implantation associated with the use of the positioner. AB - OBJECTIVE: In 2002, the electrode combined with positioner was identified as a significant risk factor for postimplantation meningitis and was voluntarily discontinued by the manufacturer. The ongoing risk of meningitis with passage of time with the positioner remains unknown. The objective of this study was to determine the current risk of meningitis in patients implanted with the positioner. STUDY DESIGN: Data regarding the date of implantation, report of meningitis, and presence or absence of risk factors for meningitis (otitis media, inner ear malformation) were obtained from the clinical database maintained by the manufacturer. RESULTS: There were 8,329 devices implanted that may have used a positioner, yielding a cumulative postimplantation time of 74,976 patient years. The incidence of meningitis during the 3-year spans of 1999 to 2001, 2002 to 2004, 2005 to 2007, and 2008 to 2010 was 33, 40, 11, and 2, respectively; the risk of meningitis in cases per patient-years has decreased significantly from 0.0044 at its peak in 2001 to 0.0011 in 2010. Only a single case of positioner related meningitis 96 months or longer after implantation has been reported. More than 40% of children had otitis media within 1 week of developing meningitis; less than 10% had a history of meningitis or inner ear malformation. CONCLUSION: The risk of meningitis with the use of positioner is highest within the first 24 months after implantation and is frequently associated with otitis media. The risk of meningitis more than 96 months after implantation is significantly reduced. Thus, the prophylactic removal of the positioner is not recommended in patients who underwent implantation more than 8 years ago. PMID- 21817938 TI - Progression of endolymphatic hydrops in Meniere's disease as evaluated by magnetic resonance imaging. AB - OBJECTIVE: To evaluate the presence and the degree of endolymphatic hydrops (EHs) in patients with unilateral Meniere's disease (MD), as a function of duration of the disease, estimated using a 3-dimensional fluid-attenuated inversion recovery sequence in a 3-Tesla magnetic resonance imaging unit, after intratympanic gadolinium administration. PATIENTS: A total of 32 patients (21 male and 11 female subjects, aged 25-78 yr; median, 56 yr) participated in the investigation. The duration of the disease ranged from 2 months to 10 years (median, 3 yr), with a prevalence of vertigo spells in the last 6 months ranging from 0.5 to 8 per month (median, 2.5). INTERVENTION: A 0.6-ml solution of gadobutrol (1 mmol/ml) diluted 1:7 in saline was injected in the affected ear through the inferior posterior quadrant of the tympanic membrane, using a 22-gauge spinal needle. The patient was kept with the head rotated 45 degrees contralaterally for 30 minutes after each injection. Twenty-four hours later, a 3-dimensional fluid-attenuated inversion recovery magnetic resonance imaging was performed. MAIN OUTCOME MEASURE: Perilymphatic enhancement was evaluated in different portions of the labyrinth as a function of MD duration. RESULTS: Reduced or absence of enhancement of the vestibule occurred precociously and occurred in all subjects at long term. The prevalence of enhancement abnormalities in the cochlea and the semicircular canals was directly proportional to MD duration. At long term, the vestibule and the cochlea showed a more severe hydropic involvement compared with semicircular canals. A statistical significant correlation between enhancement abnormalities and MD duration was observed for most inner ear sites. CONCLUSION: The increased prevalence and severity of EH with the duration of MD indicates that hydrops is a progressive degenerative phenomenon. The frequent abnormality in the vestibule and, secondarily, in the cochlea is in line with some histopathologic investigations. It remains to be clarified whether hydropic changes are related to specific signs and symptoms of MD. PMID- 21817939 TI - Outcome of the bone-anchored hearing aid procedure without skin thinning: a prospective clinical trial. AB - OBJECTIVE: To evaluate the outcome of Bone-Anchored Hearing Aid surgery without skin thinning, a test group with direct implantation without such thinning was compared with a control group that underwent the traditional procedure. STUDY DESIGN: This was a single-center, prospective clinical trial designed to evaluate a novel approach to Bone-Anchored Hearing Aid implantation. Eligible patients were enrolled consecutively in the test group or selected to be age-matched controls. SETTING: University Hospital. PATIENTS: Eighteen adult patients, suffering from hearing loss, suitable for implantable hearing aid. METHODS: Single-step surgery was performed on 18 patients under local anesthesia. In 9 of these, a linear incision was made, a hole was punched through the skin above the bone-anchored implant, and a longer abutment (8.5-12 mm) was introduced, whereas the other 9 were subjected to the standard protocol, using a dermatome and skin thinning. All of the patients were followed for 12 months. RESULTS: The test group exhibited good preservation of the tissue, no increasing skin reactions and no adverse events. The time required for this surgery was reduced, as was their healing time. These patients also experienced less numbness and pain in the surrounding area and had an improved cosmetic outcome. MAIN OUTCOME AND CONCLUSION: This clinical trial indicates that introduction of the abutment to the osseointegrated screw directly through the skin, without skin thinning, could be beneficial. This approach had fewer negative effects than the conventional procedure during the 12- month follow-up period. PMID- 21817940 TI - Midmodiolar reconstruction as a valuable tool to determine the exact position of the cochlear implant electrode array. AB - HYPOTHESIS: A midmodiolar reconstruction with multislice computed tomography could potentially be used clinically to determine the cochlear implant electrode array position if the technique was validated with a cadaveric temporal bone study. BACKGROUND: Several radiologic studies using sophisticated techniques have been described. This study was designed to validate a standard multislice computed tomography scan technique to determine the electrode array position. METHODS: This ex vivo study was conducted on 18 cadaveric temporal bones without malformation. Cochlear electrode dummies were implanted by a single experimented surgeon with the Advance Off-Stylet technique. After randomization, the placement was processed through an anteroinferior or superior cochleostomy for respective scala tympani or vestibuli positioning with direct location of the basilar membrane. Cadaveric temporal bones were then scanned (Philips Brilliance 40 computed tomographic scan) and reconstructed into the midmodiolar computed tomography scan plane (+/- 45 degrees, z-axis in the cochlear coordinate system). Two independent neuroradiologists, who were unaware of the implanted scala, evaluated the electrode array position on a computed tomographic scan through the midmodiolar reconstruction. In the end, the microanatomic study was the criterion standard to determine the exact scala localization of the electrode array. RESULTS: Nine electrodes were inserted into the scala tympani, and 9 were inserted into the scala vestibuli. According to our anatomic criterion standard, the midmodiolar reconstruction sensitivity and the specificity for the scala tympani position were 0.875 (range, 0.722-1.0) and 1.0, respectively; the sensitivity and specificity for dislocation and the scala vestibuli position were both 1.0. The radioanatomic concordance was 0.94 (range, 0.89-0.98) for determining the electrode array position into scalae with midmodiolar reconstruction. CONCLUSION: Our cadaveric study validates midmodiolar reconstruction as a valuable tool to routinely determine the precise position of the cochlear implant electrode array. This study opens the field for further clinical studies. PMID- 21817941 TI - Evaluation of objective test techniques in cochlear implant users with inner ear malformations. AB - OBJECTIVE: The aim of the study was to compare results of objective test techniques in cochlear implant users with inner ear malformations and incomplete partition anomalies with types I and II and to show which techniques should be used in the evaluation and fitting of cochlear implant users with inner ear malformations. STUDY DESIGN: Retrospective clinical study. PATIENTS: The subjects in the control group were selected randomly from cochlear implant users with normal cochlea. Inclusion criteria for patients group were having inner ear malformation for the study group and at least 1 year cochlear implants use for both groups. INTERVENTIONS: For each individual subject, electrically evoked compound action potentials (ECAPs), electrically evoked stapedius reflex threshold (ESRT), and electrically evoked auditory brainstem response (EABR) thresholds were determined. These tests were applied after a normal cochlear implant fitting session. There were 20 subjects in inner ear malformation group and 15 subjects in the control group. For each subject, 6 intracochlear electrodes, representing apical, middle, and basal array of intracochlear electrode, were used. MAIN OUTCOMES: In the cochlear malformation group, percentage of acquired ECAP thresholds was 25%. However, in the control group, percentage of ECAP was 74%. Similarly with ECAP, percentage of ESRT in the cochlear malformation group was 17.5%, and that in the control group was 90%. The difference between these percentages was statistically significant. Both current levels and latencies of EABR wave V were significantly different from each other for the inner ear malformation group and the control group. RESULTS: For statistical analysis, Mann-Whitney U test for 2 independent samples, Kruskal Wallis analysis and Dunn's Z test were used. CONCLUSION: For the inner ear malformation group, EABR is a more applicable objective test technique when compared with ECAP and ESRT. PMID- 21817942 TI - Use of computed tomography to predict the possibility of exposure of the first genu of the facial nerve via the transmastoid approach. AB - HYPOTHESIS: The purpose of this study was to investigate whether computed tomography (CT) could predict the possibility of first genu exposure of the facial nerve via the transmastoid approach in patients with acute facial paralysis. BACKGROUND: Temporal bone CT is the best method for visualizing the intratemporal segment of the facial nerve canal, which is known to have diverse anatomic variations. METHODS: A prospective study was conducted on 11 patients who underwent facial nerve decompression via the transmastoid approach. Two groups of patients underwent surgery to expose the perigeniculate area via the transmastoid approach. One group included patients who had anatomic parameters of the temporal bone that met the CT criteria, including length of the labyrinthine segment, level of the geniculate ganglion, bony thickness of the lateral semicircular canal, and height interval between the tympanic and labyrinthine segments. The other group included patients with facial paralysis who required facial nerve exploration, especially distal to the geniculate ganglion. Facial nerve decompression was performed in all patients as far proximal in the transmastoid view as was possible without causing damage to the semicircular canals. RESULTS: We correlated the temporal bone CT images and surgical findings in 11 patients who underwent facial nerve decompression via the transmastoid approach. The facial nerves of 6 patients who had anatomic structures that met the CT criteria were successfully exposed to the proximal labyrinthine segment without labyrinthine damage. The facial nerves of another 4 patients who did not have anatomic structures that met the CT criteria could be decompressed only to the geniculate ganglion. CONCLUSION: CT scan can predict the possibility of first genu exposure of the facial nerve via the transmastoid approach based on the CT parameters suggested in this study. PMID- 21817943 TI - Resorbable plate cranioplasty after the translabyrinthine approach. AB - OBJECTIVE: To determine the safety of resorbable plate cranioplasty after translabyrinthine cerebellopontine angle tumor excision and to determine efficacy of this technique in the reduction of cerebrospinal fluid (CSF) leaks compared with fat grafting alone. STUDY DESIGN: Prospective clinical trial with matched, historic case controls. SETTING: University tertiary referral center. PATIENTS: Seventy-one patients with tumors of the cerebellopontine angle undergoing a translabyrinthine approach had the temporal bone defect repaired by a fat graft secured with a resorbable fixation plate. This cranioplasty technique was designed to improve pressure on the fat graft to block the egress of CSF. Historic controls included 149 consecutive patients undergoing a translabyrinthine approach who were closed with fat cranioplasty only. INTERVENTION: Resorbable plate cranioplasty versus fat graft cranioplasty. MAIN OUTCOME MEASURES: Wound complication rate, incidence of postoperative CSF leak, treatment required, and length of hospitalization. RESULTS: There were no surgical site infections in either group. The incidence of postoperative CSF leak was 12.7% (9/71) in the study group and 13.4% (20/149) in the controls (p = 0.88). There was no significant difference in the rate of lumbar drain placement or surgical revision requirement between the groups. There were no short- or long term complications attributable to the placement of the plate, and additional operative time for the procedure averaged 7 minutes. CONCLUSION: Cranioplasty with a resorbable plate after translabyrinthine craniotomy is safe. This technique results in a CSF leak rate equivalent to fat grafting alone. PMID- 21817944 TI - Management strategy of vestibular schwannoma in neurofibromatosis type 2. AB - OBJECTIVES: To discuss our management strategy of vestibular schwannoma in patients with neurofibromatosis type 2 (NF2). STUDY DESIGN: Retrospective study. SETTING: Quaternary referral skull base center. METHODS: Thirty-eight NF2 patients who had undergone 48 operations at the Gruppo Otologico between January 1988 and December 2008. The mean age at time of surgery was 36.3 years (range, 17 65 yr), and the average tumor size was 3.1 cm (range, 0.6-6 cm). There were 27 female and 21 male ears, and 25 cases were right side ears, whereas 23 were left sided. The average follow-up time was 3.7 years. Surgical approaches, hearing, and facial nerve functions, as well as hearing rehabilitation and facial nerve reconstruction outcomes, are discussed. RESULTS: Total tumor resection was achieved in 44 cases (92%). Facial nerve function was postoperatively House Brackmann grades I-III in 36 cases (77%); it was grade I in 17 cases (35%) and grade II in 8 cases (17%). In 7 cases, hearing preservation was attempted, and a measurable hearing has been recorded in 5 cases (71%). Auditory brainstem implant was inserted in 25 cases, and concomitant cochlear implants were inserted in 5 cases. CONCLUSION: Early diagnosis and treatment of bilateral vestibular schwannoma in patients with NF2 will achieve the best outcomes regarding facial nerve, hearing preservation, and postoperative complications. The watchful waiting policy will decrease the chance of reaching these goals. Cochlear implants and auditory brainstem implant have made hearing rehabilitation possible in NF2 patients who had bilateral sensorineural hearing loss. PMID- 21817945 TI - Otogenic lateral sinus thrombosis in children. AB - OBJECTIVE: To present the results and experience with diagnosis and treatment of lateral sinus thrombosis, as a complication of otitis media, in a pediatric population. PATIENTS: Five children, 2 girls and 3 boys, with age ranging from 3 to 9 years, identified as having otogenic lateral sinus thrombosis confirmed with clinical symptoms and radiologic findings. INTERVENTION: All patients underwent canal wall intact mastoidectomy with tympanostomic tube insertion. In all patients, granulation tissues from mastoids were removed and exploration of the lateral sinuses by needle aspiration was performed. All patients were treated with broad-spectrum antibiotics, and 4 of 5 patients were administered anticoagulants. MAIN OUTCOME MEASURES: Clinical improvement, resolution of symptoms. RESULTS: Patients with a diagnosis of otogenic lateral sinus thrombosis commonly presented with headache, nausea, and vomiting. Three patients had a bulging drum, 1 had otorrhea, and 1 had only retraction pocket. After surgery and pharmacologic treatment, clinical improvement was observed in all patients. Complication after anticoagulant administration was not observed. All patients were followed up from 12 to 36 months. All patients showed partial or complete recanalization on repeat imaging. CONCLUSION: Lateral sinus thrombosis is a rare complication of otitis media. In some cases, diagnosis is delayed because neurologic, rather than otologic, symptoms may dominate the presentation of the lateral sinus thrombosis. In our observation, the prognosis of lateral sinus thrombosis is better when surgical and pharmacologic treatments are instituted early. PMID- 21817946 TI - Atlantoaxial rotary subluxation after tympanoplasty. AB - OBJECTIVE: To describe a case of the atlantoaxial rotary subluxation (AARS) after tympanoplasty and discuss its mechanism and management. PATIENTS: A 10-year-old boy. INTERVENTIONS: Cervical spine plain radiography followed by cervical traction. MAIN OUTCOME MEASURES: Range of motion and radiologic follow-up. RESULTS: The patient showed painful torticollis and rotation and fixation of the head to the right side (cock robin sign). Increased atlantodens interval and asymmetry between facet joints were found on cervical plain radiography. Full functional recovery and reduction of subluxation were achieved by conservative cervical traction. CONCLUSION: Forced surgical positioning of head rotation to the contralateral ear down and restriction during otologic surgery under general anesthesia may complicate AARS, especially in pediatric otologic surgery patients. PMID- 21817947 TI - Treatment of acute vestibular neuronitis with glucocorticoids. AB - OBJECTIVE: To report the effects of glucocorticoid treatment of acute vestibular neuronitis on recovery of vestibular function and length of hospital stay. STUDY DESIGN: Prospective, consecutive case series compared with historic controls. SETTING: Secondary referral academic hospital. PATIENTS: Patients with acute vestibular neuronitis. One group treated with glucocorticoids within 3 days after symptom onset (n = 33) and 2 historic untreated control groups (n = 41 and n = 67). INTERVENTIONS: Oral prednisolone 50 mg/d for 5 days with tapering of doses for the next 5 days, alternatively with intravenous betamethasone 8 mg on the first 1 to 2 days if nauseated. MAIN OUTCOME MEASURES: Extent of unilateral vestibular paresis (%) in the caloric test at presentation and at 12 months of follow-up. Length of hospital stay (days). RESULTS: The initial vestibular paresis value did not differ between the treatment group and the control group. At follow-up, the treatment group showed a lower value (22.8% versus 47.2%, p = 0.0003) and greater improvement (53.4% versus 35.6%, p = 0.002). At follow-up, 70% of the treatment group had a normal caloric test result compared to only 34% of the control group. The mean hospital stay of the treatment group was significantly shorter than that of the control group (1.8 versus 3.0 d, p = 0.001). CONCLUSION: Glucocorticoids administered within 3 days after onset of vestibular neuronitis improves long-time recovery of vestibular function and reduces length of hospital stay. PMID- 21817948 TI - Respiratory syncytial virus-associated hospitalizations among infants and young children in the United States, 1997-2006. AB - BACKGROUND: Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract disease among young children in the United States. RSV associated hospitalization increased among children in the United States during 1980 through 1996. In this study, we updated national estimates of RSV hospitalization rates among US children through 2006. METHODS: We conducted a retrospective analysis of hospital discharges for lower respiratory tract illness (LRTI) in children <5 years old from the National Hospital Discharge Survey. LRTI hospitalizations were identified by using International Classification of Diseases, Ninth Revision, Clinical Modification codes. RSV-coded hospitalizations were International Classification of Diseases, Ninth Revision, Clinical Modification codes 466.11, 480.1, and 079.6. RSV-associated hospitalizations were the sum of RSV-coded hospitalizations and a proportion of hospitalizations coded as bronchiolitis and pneumonia during the RSV season. RESULTS: RSV-coded hospitalizations accounted for 24% of an estimated 5.5 million LRTI hospitalizations among children <5 years of age during the 10 study years, 1997 2006. The RSV-coded hospitalization rate in infants <1 year old was 26.0 per 1000, with no significant difference between study years. The hospitalization rate was highest among infants <3 months old (48.9 per 1000), followed by infants 3 to 5 months old (28.4 per 1000), and lower among those >1 year old (1.8 per 1000). An estimated 132,000 to 172,000 RSV-associated hospitalizations occurred annually in children <5 years of age. CONCLUSION: RSV hospitalization rates remained steady during 1997 to 2006 and were a substantial burden in the United States, especially among infants and young children. A safe and effective RSV vaccine is needed. PMID- 21817949 TI - Outcomes and duration of Pneumocystis jiroveci pneumonia therapy in infants with severe combined immunodeficiency. AB - This retrospective review of patients with severe combined immunodeficiency and Pneumocystis jiroveci pneumonia (PCP) evaluated the relationship between duration of therapy to treat PCP and overall survival. We found that 80% of patients receiving only 21 days of antibiotics survived to 12 months beyond hematopoietic cell transplant, whereas only 25% of patients who required longer treatment for PCP survived to stem cell engraftment. PMID- 21817950 TI - Trimethoprim-sulfamethoxazole therapy for children with acute osteomyelitis. AB - BACKGROUND: The emergence of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) has complicated the conventional management of osteomyelitis. While oral clindamycin is commonly used to treat acute CA-MRSA osteomyelitis, the emergence of inducible clindamycin resistance among CA-MRSA isolates has made alternative therapy necessary. The excellent oral bioavailability, susceptibility profile, favorable palatability, and low cost of trimethoprim-sulfamethoxazole (TMP-SMX) make this drug an attractive option for treating osteomyelitis, yet its clinical efficacy for osteomyelitis has not been established. METHODS: Between October 1998 and September 2009, 20 children who received a TMP-SMX-containing regimen for acute osteomyelitis at All Children's Hospital were identified from hospital records, and their cases reviewed for clinical outcome and drug safety. RESULTS: Patients ranged in age from 9 months to 17 years. Twelve (60%) of the patients were male. Causative pathogens were found in 8 (40%) cases of which 5 were CA-MRSA and 3 were methicillin-susceptible Staphylococcus aureus. Eleven patients (55%) received TMP-SMX as their primary therapy. The median dose of TMP-SMX was 16.4 mg/kg/d. During TMP-SMX therapy, 8 patients (40%) experienced adverse events; all were considered mild. Duration of total therapy was 26 to 59 days, with a median of 40 days. All 20 patients were considered cured of their infection at the end of therapy. CONCLUSION: Orally administered TMP-SMX appears to be a useful and well-tolerated therapy for treatment of acute osteomyelitis in children. Further prospective comparative studies will be needed to confirm this observation. PMID- 21817951 TI - Drug resistance among drug-naive and first-line antiretroviral treatment-failing children in Cameroon. AB - BACKGROUND: Scale-up to antiretroviral therapy (ART) requires surveillance for HIV drug resistance. With the goal of attaining 100% pediatric ART coverage in Cameroon, strategies to limit the spread of HIV resistance among children are very important. METHODS: From June 2009 through February 2011, 92 HIV-1-infected children (41 ART-naive, 51 failing first-line ART) living in Yaounde, Cameroon, were enrolled; HIV-1 Prot-RT genotypic resistance testing (GRT) was performed using an inhouse assay. Among 40 children failing first-line ART, treatment response was evaluated at weeks 24 and 48 after treatment was changed, based on GRT results. RESULTS: The mean age was 72 months both for children who were drug naive and those failing ART (range: 3-144 and 12-144, respectively), with a mean viremia of 5.59 log and 4.71 log RNA copies/mL, a median CD4 of 17% (588 cells/MUL) and 23% (719 cells/MUL), respectively. Median time-to-treatment failure was 610 days. A prevalence of 4.9% and 90% drug resistance was observed, respectively, among children who were drug-naive and those failing first-line ART, with circulating recombinant form CRF02_AG as the most prevalent clade (58.6% and 62%, respectively). After a change to GRT-based treatment, more than 90% of children had viremia <3 log RNA copies/mL at week 24 and confirmed at week 48, with 70% achieving undetectable viremia, although without correlation to immune response; 97.5% had switched to lopinavir/ritonavir-containing regimens. CONCLUSION: HIV-1 drug resistance was low among ART-naive children and very high among those failing first-line ART. Treatment change based on GRT was successful for most children, with lopinavir/ritonavir regimens being very promising for second-line use. PMID- 21817952 TI - Evolution of laboratory values in patients with Kawasaki disease. AB - BACKGROUND: As outlined in the 2004 American Heart Association guidelines, the diagnosis of Kawasaki disease (KD) is supported by results of clinical laboratory studies. However, detailed information regarding the evolution of these results during illness has not been previously reported. The goals of this project were to characterize the evolution of clinical laboratory values in KD before and after treatment with intravenous immunoglobulin (IVIG). METHODS: Laboratory values from 380 unselected, consecutive KD patients were analyzed at 3 times: acute (illness day, 2-10; illness day 1 = first day of fever and before IVIG), subacute (illness day, 11-21), and convalescent (illness day, 22-60). Results were stratified by IVIG response and coronary artery outcome. RESULTS: Although white blood cell count, percentage bands, erythrocyte sedimentation rate, and C reactive protein values were highest and age-adjusted hemoglobin was lowest in the acute phase before IVIG, platelet count was highest in the subacute phase, and percentage lymphocytes and eosinophils were highest in the convalescent phase after IVIG. KD patients with coronary artery aneurysms had a higher white blood cell count in the subacute phase and higher erythrocyte sedimentation rate in the subacute and convalescent phases compared with those with dilated or normal coronary arteries. CONCLUSIONS: A consistent evolution of laboratory values is associated with KD before and after treatment. Understanding the dynamic changes in laboratory values can assist physicians in using laboratory criteria to diagnose KD following the American Heart Association guidelines. PMID- 21817953 TI - Echocardiography in pediatric infective endocarditis. AB - Transesophageal echocardiography is more sensitive than transthoracic echocardiography (TTE) in detecting endocarditis in adults; however, pediatric data are limited. Retrospectively, 39 subjects with endocarditis were divided into adult-sized (>=60 kg) and pediatric-sized (<60 kg). TTE was 97% sensitive in pediatric-sized subjects but 70% in adult-sized subjects (P < 0.05). TTE is usually sufficient for detection of endocarditis in children <60 kg. PMID- 21817954 TI - Immunogenicity and safety of human papillomavirus-16/18 AS04-adjuvanted vaccine coadministered with tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine and/or meningococcal conjugate vaccine to healthy girls 11 to 18 years of age: results from a randomized open trial. AB - BACKGROUND: A combined immunization strategy for administration of human papillomavirus (HPV) vaccine with other routine vaccines may lead to better compliance. Reactions and immunologic interference with concomitantly administered vaccines are unpredictable, necessitating clinical evaluation. METHODS: This was a randomized, open study conducted at 48 centers in the United States (NCT00369824). Healthy girls 11 to 18 years of age were randomized equally to 1 of 6 groups to receive 3 doses of HPV-16/18 AS04-adjuvanted vaccine administered at 0, 1, and 6 or 1, 2, and 7 months, with or without 1 dose of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (Tdap) and/or 1 dose of meningococcal polysaccharide diphtheria toxoid conjugate vaccine (MCV4) in different coadministration regimens (1283 girls vaccinated). Coadministered vaccines were injected at separate sites. Antibodies were measured for all vaccine components. Reactogenicity and safety were monitored. RESULTS: The prespecified criteria for noninferiority were met for all primary and secondary immunogenicity end points, demonstrating similar immunogenicity of Tdap and MCV4 when given alone or coadministered with the HPV vaccine. Immunogenicity of the HPV vaccine (in terms of seroconversion rates and geometric mean antibody titers to HPV antigens) was similar, regardless of whether it was given alone or coadministered with Tdap and/or MCV4. No differences were observed in the reactogenicity profile of the HPV vaccine administered alone or coadministered with either Tdap and/or MCV4 in different regimens. CONCLUSIONS: Concomitant administration of HPV-16/18 AS04-adjuvanted vaccine with Tdap and/or MCV4 in different regimens did not interfere with the immune response to any of the vaccines and had an acceptable safety profile. PMID- 21817956 TI - Rotavirus vaccination in Germany: analysis of nationwide surveillance data 2006 to 2010. AB - BACKGROUND: Efficacy of rotavirus (RV) vaccination is difficult to assess outside of controlled clinical trials. In countries with low-to-moderate RV vaccination coverage, annual variation in RV outbreak might have a stronger influence on morbidity than RV vaccination. METHODS: We analyzed German RV surveillance data from 2006 to 2010 in the 16 federal states of Germany. To overcome the bias of annual variation of RV infections, we analyzed the effects of RV vaccination in Germany by comparing vaccination rate with morbidity as indicated by notification data. RESULTS: RV vaccination coverage in 0- to 1-year-old children in Germany increased from 3% in 2007 to 26% in 2010. The vaccination coverage varied highly between different federal states of Germany (2007, 1%-14%; 2008, 4%-35%, 2009, 8% 52%; and 2010, 17%-64%). There was a significant correlation between RV vaccination coverage and reduction in morbidity (r = -0.66, P = 0.0054) in 0- to <2-year-old children. The proportion of children vaccinated by one of the 2 vaccines, Rotarix and RotaTeq, was similar. Although we found a temporal delay of the epidemic RV seasons 2008 to 2010, those changes remained within the naturally occurring range. CONCLUSIONS: The overall RV vaccination coverage in Germany is still low as compared with other countries with vaccination-supporting policies. Initial data suggest an efficacy of the vaccination. PMID- 21817955 TI - Antibodies to Plasmodium falciparum erythrocyte-binding antigen-175 are associated with protection from clinical malaria. AB - BACKGROUND: Antibodies to blood-stage Plasmodium falciparum antigens have been associated with protection against clinical malaria in some studies but not others. Many of these studies have not assessed whether high-titer antibodies are associated with protection and have not adjusted for differences in malaria exposure. METHODS: The presence of high-titer antibodies to apical membrane antigen-1, erythrocyte-binding antigen-175 (EBA-175), and merozoite surface protein-119 (MSP-119) was assessed in 87 children living in a malaria holoendemic area of Kenya. The children were prospectively assessed during 1 year for clinical malaria. RESULTS: In unadjusted analyses, high-titer antibodies to MSP 119, but not EBA-175 or apical membrane antigen-1, were associated with protection from clinical malaria. However, after adjustment for exposure, only high-titer antibodies to EBA-175 were associated with protection from clinical malaria (hazard ratio, 0.48; 95% confidence interval [CI], 0.24, 0.95; P = 0.03), and with reduced episodes of clinical malaria (incidence rate ratio, 0.50; 95% CI, 0.31, 0.81; P = 0.005). A trend toward increased protection from clinical malaria in children was seen with antibodies to both EBA-175 and MSP-119 (hazard ratio, 0.26; 95% CI, 0.03, 1.94; P = 0.18). CONCLUSIONS: High-titer antibodies to EBA-175 are associated with protection from clinical malaria in children in a malaria holoendemic area of Kenya. Accurate estimates of antibody-associated protection from clinical malaria require adjustment for malaria exposure. PMID- 21817957 TI - Response to primary and booster vaccination with 10-valent pneumococcal nontypeable Haemophilus influenzae protein D conjugate vaccine in Korean infants. AB - BACKGROUND: This randomized single-blind study in Korea evaluated noninferiority of the 10-valent pneumococcal nontypeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) versus the 7-valent pneumococcal conjugate vaccine (7vCRM) when both were coadministered with H. influenzae type b (Hib) conjugate vaccine, as opposed to coadministration with diphtheria-tetanus-acellular pertussis-based combination vaccines in previous studies. METHODS: Infants received 3 primary doses at 2, 4, and 6 months and a booster dose at 12 to 18 months of PHiD-CV (N = 374) or 7vCRM (N = 129), both coadministered with Hib vaccine. Immune responses were measured 1 month postdose 3 and postbooster using 22F-inhibition enzyme-linked immunosorbent assay and functional opsonophagocytic activity assay. RESULTS: PHiD-CV-induced antibody responses against each of the vaccine pneumococcal serotypes and protein D. Noninferiority to 7vCRM was demonstrated for all 10 PHiD-CV serotypes in terms of percentages of subjects reaching an antibody concentration >=0.2 MUg/mL after primary vaccination. Postprimary and postbooster, percentages of subjects with antibody concentration >=0.2 MUg/mL or opsonophagocytic activity titer >=8 were generally consistent between groups for each pneumococcal serotype common to both vaccines. The safety and reactogenicity profiles of PHiD-CV and 7vCRM were generally comparable after both primary and booster vaccination. CONCLUSIONS: In this Korean study, 3-dose PHiD-CV priming followed by a booster dose was immunogenic for all 10 vaccine pneumococcal serotypes and protein D. Noninferiority to 7vCRM in terms of enzyme linked immunosorbent assay threshold responses postpriming was demonstrated. The safety and reactogenicity profiles of both vaccines when coadministered with Hib vaccine were generally comparable. PMID- 21817958 TI - Intravitreal anti-vascular endothelial growth factor therapy for choroidal neovascularization secondary to ocular histoplasmosis syndrome. AB - BACKGROUND: Intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy is beneficial in treating choroidal neovascularization from age-related macular degeneration, but few long-term studies have shown its efficacy in choroidal neovascularization from ocular histoplasmosis syndrome. Intravitreal anti-VEGF therapy may be effective in cases of choroidal neovascularization because of ocular histoplasmosis syndrome. METHODS: Retrospective chart review of 54 eyes treated with intravitreal anti-VEGF therapy for choroidal neovascularization in ocular histoplasmosis syndrome with >1 year of follow-up after initiation of anti-VEGF treatment was performed. Previous treatment and demographic information were recorded. Visual acuity was recorded for each injection treatment and at the last follow-up visit. The anti-VEGF agent was recorded for each injection treatment. Visual acuity was recorded at the last follow-up visit. RESULTS: Mean visual acuity improved from 20/53 to 20/26 over an average of 26.8 months. Either bevacizumab or ranibizumab were administered on an average of 4.5 injections per patient per year of follow-up. Vision loss was seen in only three eyes with loss limited to a single line of vision. Patients experienced no serious complications from treatment. CONCLUSION: Long-term intravitreal anti-VEGF therapy with bevacizumab or ranibizumab is beneficial in treatment of choroidal neovascularization in ocular histoplasmosis syndrome. PMID- 21817959 TI - Suprachoroidal drug infusion for the treatment of severe subfoveal hard exudates. AB - PURPOSE: To evaluate the safety, feasibility, and preliminary efficacy of suprachoroidal drug delivery with a microcatheter for the treatment of severe subfoveal hard exudates (SHE) in retinal vasculopathies. Definitive treatments for SHE have not yet been identified and prognosis is unfavorable. METHODS: In this prospective, interventional pilot study, six eyes of six patients with central or branch retinal vein occlusion or diffuse diabetic macular edema accompanied by massive refractory SHE underwent a single treatment with bevacizumab and triamcinolone administered to the submacular suprachoroidal space via a microcatheter introduced at the pars plana and advanced posteriorly. The main outcome measures included best-corrected visual acuity, vascular leakage, macular thickness, extent of SHE, and complications. RESULTS: Mean follow-up was 12 months. Three eyes had central retinal vein occlusion, one had branch retinal vein occlusion, and two had chronic diabetic macular edema. Best-corrected visual acuity improved by >=2 lines in 4 eyes and remained stable in 2 eyes. At 1 month to 2 months postprocedure, SHE was almost completely resolved in all eyes and macular edema was significantly reduced. There were no surgical or postoperative complications. CONCLUSION: Suprachoroidal infusion of drugs can be effective in reabsorbing massive SHE. PMID- 21817960 TI - A systematic review of the adverse events of intravitreal anti-vascular endothelial growth factor injections. AB - BACKGROUND: Intravitreal ranibizumab and pegaptanib are registered for neovascular age-related macular degeneration. No formal safety study has been conducted for intravitreal bevacizumab. These anti-vascular endothelial growth factor (anti-VEGF) drugs are being used on a large scale in daily practice for different ocular diseases. The objective of the present study was to systematically assess and compare the incidences of adverse events of anti-VEGFs. METHODS: A systematic search was conducted in April 2009 with no date restrictions in PubMed, Embase, Toxline, and the Cochrane library. We used the terms pegaptanib, bevacizumab, ranibizumab, intravitreal, and specific and general terms for adverse events. Studies describing adverse events after anti VEGF injections and the official safety data were included. RESULTS: Two hundred and seventy-eight articles were included, and the incidences of adverse events were calculated separately for effect, safety, and specific side effect studies. The incidences of serious ocular and nonocular adverse events were approximately below 1 per 100 injections for intravitreal bevacizumab, intravitreal ranibizumab, and intravitreal pegaptanib. Most mild ocular adverse events were below 5 per 100 injections. CONCLUSION: The reported rates of serious adverse events were low after anti-VEGF injections. There is no sufficient evidence to conclude that there is a difference in incidences between the anti-VEGFs. PMID- 21817962 TI - LOC387715/HTRA1 variants and the response to combined photodynamic therapy with intravitreal bevacizumab for polypoidal choroidal vasculopathy. AB - PURPOSE: To investigate whether there was an association with the LOC387715/HTRA1 variants and a response to combined photodynamic therapy with intravitreal bevacizumab for polypoidal choroidal vasculopathy. METHODS: Combined photodynamic therapy with intravitreal bevacizumab was repeated every 3 months until the disappearance of angiographic signs in the active lesions of 51 eyes with polypoidal choroidal vasculopathy who were followed-up for at least 12 months. Patients were genotyped for LOC387715 and HTRA1 polymorphisms. RESULTS: Although there was no significant difference in the baseline best-corrected visual acuity and fluorescein angiography-guided greatest linear dimension among the 3 genotypes in both genes, there was a significant difference at 12 months (P < 0.05, respectively). For LOC387715, the TT genotype showed greater fluorescein angiography-guided greatest linear dimension than the TG and GG genotypes (P = 0.035 and 0.006, respectively). The best-corrected visual acuity of the GG genotype was better than the TT and TG (P = 0.029 and 0.045, respectively). For HTRA1, the AA genotype showed greater fluorescein angiography-guided greatest linear dimension than AG and GG (P = 0.042 and 0.017, respectively). The best corrected visual acuity of GG genotype was better than AA and AG (P = 0.018 and 0.040, respectively). CONCLUSION: After combined photodynamic therapy with intravitreal bevacizumab treatment, LOC387715 TT and HTRA1 AA genotype had poorer outcomes at 12 months, suggesting a pharmacogenetic relationship. PMID- 21817963 TI - Three-year safety and visual acuity results of epimacular 90 strontium/90 yttrium brachytherapy with bevacizumab for the treatment of subfoveal choroidal neovascularization secondary to age-related macular degeneration. AB - PURPOSE: To evaluate the long-term safety and visual acuity outcomes associated with epimacular strontium 90 brachytherapy combined with intravitreal bevacizumab for the treatment of subfoveal choroidal neovascularization because of age related macular degeneration. METHODS: Thirty-four treatment-naive patients with predominantly classic, minimally classic, and occult subfoveal choroidal neovascularization lesions participated in this prospective, 2-year, nonrandomized multicenter study. Subjects from 1 center (n = 19) were reconsented and followed-up for 3 years. Each subject received a single 24-Gy beta irradiation treatment via an intraocular delivery device and 2 planned injections of bevacizumab at treatment and 1 month later. Additional bevacizumab therapy was permitted based on prespecified retreatment criteria. Adverse events were observed, and best-corrected visual acuity was measured using Early Treatment Diabetic Retinopathy Study vision charts. Subjects were evaluated every 3 months during the first year of follow-up and every 6 months during Years 2 and 3 of follow-up. RESULTS: All 34 subjects were followed-up for 24 months and 19 were followed-up through 36 months. With up to 24 months of follow-up, 12 of 24 phakic patients (50%) exhibited >= 2 grades of progression in Lens Opacification Classification System (LOCS) II lens classification; 5 eyes underwent cataract extraction before the Month 36 visit. There was 1 case of nonproliferative retinopathy identified at 36 months of follow-up that did not have an adverse effect on visual acuity, was stable at 43 months of follow-up, and was isolated to the parafoveal region. Mean best-corrected visual acuity demonstrated an average gain of +15.0 and -4.9 letters at 12 months and 24 months, respectively; the drop in mean gain at Month 24 was largely attributable to cataract formation. At 36 months (n = 19), the mean best-corrected visual acuity was +3.9, 90% (17 of 19) of eyes had lost <15 letters from baseline, 53% (10 of 19) had gained >= 1 letter, and 21% (4 of 19) had gained >= 15 letters. Through 36 months, 11 eyes required additional bevacizumab retreatment therapy and received a mean of 3.0 injections (range, 2-7 injections). CONCLUSION: Epimacular brachytherapy shows promise as a therapeutic option for subfoveal neovascular age-related macular degeneration. The procedure was safe and well tolerated, with a reasonable risk benefit profile that warrants further study in larger subject populations. The most common adverse event was cataract progression/formation. Surgical complications are similar to those expected from standard vitrectomy trials. This novel device is currently being evaluated in two prospective, randomized, controlled trials in treatment-naive subjects (CABERNET) and in subjects already treated with anti-vascular endothelial growth factor therapy (MERLOT). PMID- 21817964 TI - Vitreous hemorrhage complicating intravitreal tissue plasminogen activator and pneumatic displacement of submacular hemorrhage. AB - PURPOSE: To evaluate the clinical factors associated with vitreous hemorrhage (VH) complicating intravitreal tissue plasminogen activator and pneumatic displacement of submacular hemorrhage, and analyze visual outcomes. METHODS: In this retrospective, comparative study, 120 consecutive eyes underwent intravitreal tissue plasminogen activator (50 MUg) and perfluoropropane (0.3 mL) injection for submacular hemorrhage secondary to different causes. We recorded their demographic data, visual acuity, complications, and further treatment after VH. Two groups created according to the occurrence of VH were compared to identify possible risk factors. RESULTS: Breakthrough VH occurred in 18 eyes (15%). The size of submacular hemorrhage was significantly positively related to the occurrence of VH (P for trend <0.001). Among etiology, idiopathic polypoidal choroidal vasculopathy (IPCV) was associated with a significantly higher incidence of VH (odds ratio, 15.63; 95% confidence interval, 2.30-106.15; P = 0.005). Age-related macular degeneration was much less likely than other causes to result in VH (odds ratio, 0.121; 95% confidence interval, 0.023-0.642; P = 0.013). Best and final visual acuity improved significantly from initial visual acuity in both groups (P < 0.05). CONCLUSION: A large area of submacular hemorrhage (>=10 disk areas) and IPCV were risk factors for VH after injection. The occurrence of VH did not affect final visual outcome. PMID- 21817965 TI - The appearance of congenital hypertrophy of retinal pigment epithelium by high resolution optical coherence tomography. PMID- 21817966 TI - Delayed surgery for patients with femur and hip fractures-risk of deep venous thrombosis. AB - BACKGROUND: This prospective study explores the incidence of preoperative deep venous thrombosis (DVT) in a group of patients with hip and femur fracture who for various reasons experienced a delay of >24 hours from the time of injury until time of surgery. We also evaluated the results of preoperative treatment with inferior vena cava (IVC) filter. METHODS: There were 101 consecutive patients with a mean age of 75.8 years. The mean time to surgery from injury was 3.5 days. All patients were evaluated for signs and symptoms of DVT and underwent Doppler ultrasound before surgery. All patients received preoperative prophylactic anticoagulation. Those patients with DVT underwent IVC filter insertion before surgical intervention. RESULTS: No patient exhibited signs or symptoms of DVT; however, preoperative ultrasound detected DVT in 10 patients. Despite negative ultrasound, two additional patients developed pulmonary embolus preoperatively for an overall incidence of thromboembolic disease of 11.9%. The average delay in surgery was 5.7 days for patients with DVT versus 3.2 days for those without (p = 0.021). The incidence increased each day from 14.5% if surgery was delayed >1 day to 33.3% if surgery was delayed >7 days. Relative risk increased from 2.32 to 3.71 over the same period. There were no postoperative thromboembolic complications or complications related to IVC filter placement in these patients. DISCUSSION: In this prospective study, we observed that patients experiencing a delay in surgical care for an acute hip or femur fracture are at a relatively high risk for development of thromboembolic disease despite prophylactic anticoagulation. There was a direct correlation between the period of delay and the incidence of thromboembolism. Clinical examination in this setting is unreliable as none of these patients had signs or symptoms suggestive of DVT. We suggest that all patients with delayed (>24 hours) surgical intervention undergo preoperative Doppler ultrasound to rule out DVT. Appropriate measures such as placement of an IVC filter and aggressive postoperative anticoagulation should then be implemented for those with DVT and/or pulmonary embolus. PMID- 21817967 TI - Strengthening care for the injured globally. PMID- 21817968 TI - Emergency department length of stay is an independent predictor of hospital mortality in trauma activation patients. AB - BACKGROUND: The early resuscitation occurs in the emergency department (ED) where intensive care unit protocols do not always extend and monitoring capabilities vary. Our hypothesis is that increased ED length of stay (LOS) leads to increased hospital mortality in patients not undergoing immediate surgical intervention. METHODS: We examined all trauma activation admissions from January 2002 to July 2009 admitted to the Trauma Service (n = 3,973). Exclusion criteria were as follows: patients taken to the operating room within the first 2 hours of ED arrival, nonsurvivable brain injury, and ED deaths. Patients spending >5 hours in the ED were not included in the analysis because of significantly lower acuity and mortality. RESULTS: Patients spent a mean of 3.2 hours +/- 1 hour in the ED during their initial evaluation. Hospital mortality increases for each additional hour a patient spends in the ED, with 8.3% of the patients staying in the ED between 4 hours and 5 hours ultimately dying (p = 0.028). ED LOS measured in minutes is an independent predictor of mortality (odds ratio, 1.003; 95% confidence interval, 1.010-1.006; p = 0.014) when accounting for Injury Severity Score, Revised Trauma Score, and age. Linear regression showed that a longer ED LOS was associated with anatomic injury pattern rather than physiologic derangement. CONCLUSION: In this patient population, a longer ED LOS is associated with an increased hospital mortality even when controlling for physiologic, demographic, and anatomic factors. This highlights the importance of rapid progression of patients through the initial evaluation process to facilitate placement in a location that allows implementation of early goal directed trauma resuscitation. PMID- 21817969 TI - The impact of discharging minimally injured trauma patient: does age play a role in trauma admission? AB - BACKGROUND: Age is suggested as a triage criteria for transfer to a trauma center, despite poor outcomes after similar injury regardless of trauma center level. The effect of differential triage based on age to a trauma center has not been evaluated. We hypothesized that there would be a difference in the admission rates of geriatric patients compared with the rest of the adult trauma population independent of injury severity. METHODS: Records of 1,970 adult patients evaluated by the trauma team at a Level I trauma center and discharged directly from the emergency department were reviewed. Data abstracted included demographics, injuries, and physiologic information. These data were compared with 3,232 trauma patients admitted over the same time period who had similar information abstracted via record review. chi analysis of the admission rates of geriatric patients was performed, followed by a binomial logistic regression to determine factors that affected the odds of admission. RESULTS: A total of 451 (8.68%) patients were 65 years or older; 62.2% of the total population was admitted. Significantly more geriatric patients (82%) were admitted (chi = 126.24; p < 0.001). Multivariate analysis showed that age, head injury, Injury Severity Score, Glasgow Coma Scale, and initial blood pressure were significant independent factors in predicting hospital admission (p < 0.001). CONCLUSIONS: Age alone is associated with increased odds of being admitted to the hospital, independent of injury severity and other physiologic parameters. This has implications for trauma centers that see a significant proportion of geriatric trauma patients and for trauma systems that must prepare for the "aging of America." PMID- 21817970 TI - Screening for mental illness in a trauma center: rooting out a risk factor for unintentional injury. AB - BACKGROUND: Injury prevention and screening efforts have long targeted risk factors for injury recurrence. In a retrospective study, our group found that mental illness is an independent risk factor for unintentional injury and reinjury. The purpose of this study was to administer a standard validated screening instrument and psychosocial needs assessment to admitted patients who suffer unintentional injury. We aimed to prospectively measure the prevalence of mental illness. We hypothesize that systematic screening for psychiatric disorders in trauma patients is feasible and identifies people with preexisting mental illness as a high-risk group for unintentional injury. METHODS: In this prospective study, we recruited patients admitted to our Level I trauma center for unintentional injury for a period of 18 months. A bedside structured interview, including the Mini International Neuropsychiatric Interview, and a needs assessment were performed by lay research personnel trained by faculty from the Department of Psychiatry. The validated needs assessment questions were from the Camberwell Assessment of Need Short Appraisal Schedule instrument. Psychiatric screening and needs assessment results, as well as demographic characteristics are reported as descriptive statistics. RESULTS: A total of 1,829 people were screened during the study period. Of the 854 eligible people, 348 were able to be approached by researchers before discharge with a positive response rate of 63% (N = 219 enrolled). Interviews took 35 minutes +/- 12 minutes. Chi-squared analysis revealed no difference in mechanism in those with mental illness versus no mental illness. Men were significantly more likely to be found to have a mental health disorder but when substance abuse was excluded, no difference was found. Four-way diagnostic grouping revealed the prevalence of mental illness detected. CONCLUSIONS: This inpatient pilot screening program prospectively identified preexisting mental illness as a risk factor for unintentional injury. Implementation of validated psychosocial and mental health screening instruments is feasible and efficient in the acute trauma setting. Administration of a validated mental health screening instrument can be achieved by training college-level research assistants. This system of screening can lead to identification and treatment of mental illness as a strategy for unintentional injury prevention. PMID- 21817971 TI - Out-of-hospital decision making and factors influencing the regional distribution of injured patients in a trauma system. AB - BACKGROUND: The decision-making processes used for out-of-hospital trauma triage and hospital selection in regionalized trauma systems remain poorly understood. The objective of this study was to assess the process of field triage decision making in an established trauma system. METHODS: We used a mixed methods approach, including emergency medical services (EMS) records to quantify triage decisions and reasons for hospital selection in a population-based, injury cohort (2006-2008), plus a focused ethnography to understand EMS cognitive reasoning in making triage decisions. The study included 10 EMS agencies providing service to a four-county regional trauma system with three trauma centers and 13 nontrauma hospitals. For qualitative analyses, we conducted field observation and interviews with 35 EMS field providers and a round table discussion with 40 EMS management personnel to generate an empirical model of out-of-hospital decision making in trauma triage. RESULTS: A total of 64,190 injured patients were evaluated by EMS, of whom 56,444 (88.0%) were transported to acute care hospitals and 9,637 (17.1% of transports) were field trauma activations. For nontrauma activations, patient/family preference and proximity accounted for 78% of destination decisions. EMS provider judgment was cited in 36% of field trauma activations and was the sole criterion in 23% of trauma patients. The empirical model demonstrated that trauma triage is driven primarily by EMS provider "gut feeling" (judgment) and relies heavily on provider experience, mechanism of injury, and early visual cues at the scene. CONCLUSIONS: Provider cognitive reasoning for field trauma triage is more heuristic than algorithmic and driven primarily by provider judgment, rather than specific triage criteria. PMID- 21817972 TI - In a mature trauma system, there is no difference in outcome (survival) between Level I and Level II trauma centers. AB - BACKGROUND: The state of Pennsylvania (PA) has one of the oldest, most well established trauma systems in the country. The requirements for verification for Level I versus Level II trauma centers within PA differ minimally (only in the requirement for patient volume, residency, and research). We hypothesized that there would be no difference in outcome at Level I versus Level II trauma centers. METHODS: Odds of mortality for 16 Level I and 11 Level II hospitals in PA over a 5-year period (2004-2008) was computed using a random effects logistic regression model. Overall adjusted mortality rates at Level I versus Level II hospitals were compared using the nonparametric Wilcoxon's rank sum test. The crude mortality rates for 140,691 patients over the 5-year period were similar (5.07% Level II vs. 5.48% Level I), but statistically significant (odds ratio mortality at Level I = 1.084, p = 0.002 Fisher's exact test). RESULTS: Although Level I centers had on average crude mortality rates that were higher than those of Level II centers, median adjusted mortality rates were not different for the two types of centers (Wilcoxon's rank sum test). Performance of Level I versus Level II shows considerable variability among centers (basic random effects model, age, blunt/penetrating, and Injury Severity Score [ISS]). However, Level II centers seem no different from Level I. CONCLUSION: As trauma systems mature, the distinction between Level I and Level II trauma centers blurs. The hierarchal descriptors "Level I" or "Level II" in a mature trauma system is pejorative and implies in those hospitals labeled "Level II" as inferior, and as such should be replaced with nonhierarchal descriptors. PMID- 21817973 TI - Comparison of trauma mortality and estimated cancer mortality from computed tomography during initial evaluation of intermediate-risk trauma patients. AB - BACKGROUND: Computed tomography (CT) is the primary source of nontherapeutic medical radiation exposure. Radiation exposure is associated with an increased risk of cancer mortality. Although the risk of cancer mortality is negligible in comparison with that of trauma mortality in high-risk patients, the balance of risk versus benefit in patients with less severe mechanisms of injury is unknown. METHODS: This observational cohort study using a trauma center registry included blunt trauma patients prospectively triaged to an intermediate risk group (level II). Radiation dose was calculated using average dosage for each CT scan. Age adjusted attributable radiation risk for cancer mortality was calculated using Biological Effects of Ionizing Radiation VII data. RESULTS: Six hundred forty-two level II trauma patients were analyzed, with a mean age of 43.8 years and a median Injury Severity Score of 8. Patients received a median radiation effective dose of 24.7 mSv in the first 24 hours of medical evaluation. Higher Injury Severity Score was associated with greater total radiation dose. Of the four deaths, all were 80 years or older with intracranial injuries. The estimated risk of cancer death attributable to CT exposure was 0.1%. CONCLUSIONS: The risk of mortality from trauma is six times higher than the estimated risk of radiation induced cancer mortality in intermediate level trauma patients. The mortality due to trauma is greatest in older patients, suggesting lower clinical suspicion is needed to warrant CT studies in this population. Efforts to reduce radiation exposure to trauma patients should focus on young patients with minor injuries. PMID- 21817974 TI - Heart rate variability is an independent predictor of morbidity and mortality in hemodynamically stable trauma patients. AB - BACKGROUND: Reduced heart rate variability (HRV) reflects autonomic dysfunction and can triage patients better than routine trauma criteria or vital signs. However, there is questionable specificity and no consensus measurement technique. The purpose of this study was to analyze whether factors that alter autonomic function affect the specificity of HRV for assessing traumatic injury. METHODS: We evaluated 216 hemodynamically stable adults (3:1 M:F; 97:3 blunt:penetrating; age 49 years +/- 1 year, mean +/- standard error) undergoing computed axial tomography (CT) scan to rule out traumatic brain injury (TBI). All were prospectively instrumented with a Mars Holter system (GE Healthcare, Milwaukee, WI). HRV was determined offline using time domain (standard deviation of normal-normal intervals, root-mean-square successive difference) and frequency domain (very low frequency [VLF], LF, wideband frequency, high frequency [HF], low to HF index ratio) calculations from 15-minute electrocardiogram and correlated with routine vital signs, mortality, TBI, morbidity, length of stay (LOS), and comorbidities. Significance (p <= 0.05) was determined using nonparametric analysis, Student's t test, analysis of variance, or multiple logistic regression. RESULTS: VLF alone predicted survival, severity of TBI, intensive care unit LOS, and hospital LOS (all p < 0.05). Beta-blockers or diabetes had no effect, whereas age, sedation, mechanical ventilation, spinal cord injury, and intoxication influenced one or more of the variables with age being the most powerful confounder (all p < 0.05). Except for the Glasgow Coma Scale, no other routine trauma or hemodynamic criteria correlated with any of these outcomes. CONCLUSIONS: Decreased VLF is an independent predictor of mortality and morbidity in hemodynamically stable trauma patients. Other time and other frequency domain variables correlated with some, but not all, outcomes. All were heavily influenced by factors that alter autonomic function, especially patient age. PMID- 21817975 TI - Early lower extremity fracture fixation and the risk of early pulmonary embolus: filter before fixation? AB - BACKGROUND: Venous thromboembolism is a major cause of morbidity and mortality after injury. Prophylactic anticoagulation is often delayed as a result of injuries or required procedures. Those patients at highest risk in this early vulnerable window postinjury are not well characterized. We sought to determine those patients at highest risk for an early pulmonary embolism (PE) after injury. METHODS: A retrospective analysis using data derived from a large state wide trauma registry (1997-2007) was performed. Patients with a documented PE and time of occurrence were selected (n = 712). Patients with fat emboli and lower extremity vascular injuries were excluded. Patients with a PE within the first 72 hours of admission (EARLY, n = 122) were compared with those with DELAYED presentation. Kaplan-Meier survival analysis was used to characterize the timing of death between the two groups. Backward stepwise logistic regression was used to determine independent risk factors for EARLY PE relative to those with DELAYED PE. RESULTS: EARLY and DELAYED groups were similar in age, gender, Glasgow Coma Scale, emergency department systolic blood pressure, and injury mechanism. The EARLY PE group had a lower Injury Severity Score but injuries more commonly included femur fracture. Kaplan-Meier analysis revealed that EARLY PE patients have a significantly higher risk of early mortality relative to DELAYED PE patients (p = 0.012). Regression analysis revealed that the only independent risk factor for EARLY PE was lower extremity/pelvic orthopedic fixation (<48 hours from injury). The risk of EARLY PE was more than threefold higher (odds ratios, 3.85; 95% CI, 1.9-7.6; p < 0.001) for those who underwent early lower extremity orthopedic fixation versus those who did not. CONCLUSION: Early lower extremity/pelvis orthopedic fixation is the single independent predictor of EARLY PE in this patient cohort. Venous thromboembolism/PE prevention strategies should be made a priority in this group of patients, including early preoperative institution of anticoagulation prophylaxis. These results suggest that those with contraindications to early anticoagulation may benefit from insertion of retrievable inferior vena cava filters preoperatively. PMID- 21817976 TI - Venous thromboembolism in coagulopathic surgical intensive care unit patients: is there a benefit from chemical prophylaxis? AB - BACKGROUND: Coagulation abnormalities in critically ill surgical patients cause confusion in administration of venous thromboembolism (VTE) prophylaxis. Pharmaceutical VTE prophylaxis is often withheld because of presumed increased risk for bleeding and assumption that these patients would not benefit from it. Coagulopathic critically ill surgical patients are at risk for VTE and should be treated with chemical prophylaxis. METHODS: A retrospective review was performed of all coagulopathic patients (international normalized ration >1.5 or platelets <100,000 per MUL) admitted for at least 72 hours to the surgical intensive care units of a tertiary care center between January 2008 and January 2009. Patients were divided into two groups based on providing (group 1) or withholding (group 2) chemical prophylaxis. The incidence of VTE was then compared between the two groups. RESULTS: A total of 513 patients were included in the study: 241 patients in group 1 and 272 patients in group 2. The overall incidence of VTE was 16.4%. The incidence of VTE in the patients who received chemical prophylaxis was 17.0%, whereas the incidence in patients without chemical prophylaxis was 15.8% (p = 0.72). CONCLUSION: Coagulopathic critically ill surgical patients remain at significant risk for VTE. Unfortunately, chemical VTE prophylaxis does not seem to decrease this risk. Further research is warranted to investigate the nature of this increased risk of VTE and the reason chemical VTE prophylaxis has no benefit. PMID- 21817977 TI - New hemostatic dressing (FAST Dressing) reduces blood loss and improves survival in a grade V liver injury model in noncoagulopathic swine. AB - BACKGROUND: We performed this study to evaluate the hemostatic efficacy of the FAST Dressing in treating a grade V liver injury in noncoagulopathic swine. METHODS: Sixteen female splenectomized, noncoagulopathic swine underwent reproducible grade V liver injuries. The animals were blindly randomized to two treatment groups: (1) FAST Dressing (n = 8) or (2) IgG placebo dressing (n = 8). After 30 seconds of uncontrolled hemorrhage, dressings and manual compression were applied at 4-minute intervals. The number of dressings used, time to hemostasis, total blood loss, mean arterial pressure, blood chemistry, and total resuscitation fluid volume were monitored for 2 hours after injury. RESULTS: The mean total blood loss was 412.5 mL (SD 201.3) for the FAST Dressing group compared with 2296.6 mL (SD 1076.0) in the placebo group (p < 0.001). All animals in the FAST Dressing group achieved hemostasis and survived for the duration of the experiment (2 hours) after injury, whereas none of the animals in the placebo group attained hemostasis or survived to 2 hours after injury (p < 0.001). The mean time to hemostasis was 6.6 minutes (SD 2.5). A median of five dressings (mean absolute deviation 1.0, p = 0.007) was sufficient to control hemorrhage in the FAST Dressing group. CONCLUSION: The FAST Dressing reduced blood loss and improved survival compared with placebo in a noncoagulopathic, grade V liver injury swine model. PMID- 21817978 TI - Advanced hemostatic dressings are not superior to gauze for care under fire scenarios. AB - BACKGROUND: Advanced hemostatic dressings perform superior to standard gauze (SG) in animal hemorrhage models but require 2 minutes to 5 minutes application time, which is not feasible on the battlefield. METHODS: Twenty-four swine received a femoral artery injury, 30 seconds uncontrolled hemorrhage and randomization to packing with SG, Combat Gauze (CG), or Celox Gauze (XG) without external pressure. Animals were resuscitated to baseline mean arterial pressures with lactated Ringers and monitored for 120 minutes. Physiologic and coagulation parameters were collected throughout. Dressing failure was defined as overt bleeding outside the wound cavity. Tissues were collected for histologic and ultrastructural studies. RESULTS: All animals survived to study end. There were no differences in baseline physiologic or coagulation parameters or in dressing success rate (SG: 8/8, CG: 4/8, XG: 6/8) or blood loss between groups (SG: 260 mL, CG: 374 mL, XG: 204 mL; p > 0.3). SG (40 seconds +/- 0.9 seconds) packed significantly faster than either the CG (52 +/- 2.0) or XG (59 +/- 1.9). At 120 minutes, all groups had a significantly shorter time to clot formation compared with baseline (p < 0.01). At 30 minutes, the XG animals had shorter time to clot compared with SG and CG animals (p < 0.05). All histology sections had mild intimal and medial edema. No inflammation, necrosis, or deposition of dressing particles in vessel walls was observed. No histologic or ultrastructural differences were found between the study dressings. CONCLUSIONS: Advanced hemostatic dressings do not perform better than conventional gauze in an injury and application model similar to a care under fire scenario. PMID- 21817979 TI - How much free fluid can a pregnant patient have? Assessment of pelvic free fluid in pregnant patients without antecedent trauma. AB - BACKGROUND: The amount of free fluid that can normally be present in a pregnant patient is unknown. Evaluation of pelvic free fluid in a population of pregnant patients without early history of trauma would help determine what amount of free fluid should raise suspicion of intra-abdominal injury in those who have suffered trauma. METHODS: Patients presenting for routine obstetric ultrasound without an early history of trauma were offered participation in the study. Routine imaging of the cul de sac and ovaries was used for assessment of presence or absence of free fluid, with accompanying digitally recorded images. Depth of the fluid pocket was measured in millimeters. RESULTS: Six of 89 patients successfully scanned were found to have free fluid in to the cul de sac for an occurrence of 6.7%. Four patients had free fluid present during the first trimester with subsequent resolution by the late first trimester or early second trimester. Two of these patients had an identifiable cause for free fluid, one with right ovarian hyperstimulation and the second with idiopathic theca lutein cysts. Two patients had isolated free fluid appearing in the third trimester. CONCLUSIONS: These results suggest that the presence of pelvic free fluid in pregnant patients without antecedent trauma is very low. After blunt abdominal trauma, the presence of free fluid in the pelvis of a pregnant patient may not be physiologic, especially if there is >2 mm to 4 mm, and there is no history of ovarian hyperstimulation syndrome or other known associations. PMID- 21817980 TI - Closed suction drain after isolated hollow viscus injury: a friend or foe? AB - BACKGROUND: The objective of this study was to investigate associations between closed suction intra-abdominal drain placement in isolated hollow viscus injury (HVI) and intra-abdominal deep surgical site infections (DSSI). PATIENTS: Patients undergoing emergent trauma laparotomy at a Level I trauma center after isolated HVI from January 2006 to December 2008 were identified. Study variables extracted from institutional trauma registry and patient electronic medical records included demographics, clinical characteristics, abdominal injuries, drain placement, DSSI, septic events, intensive care unit and hospital length of stay, and mortality. Diagnosis of DSSI was based on abdominal computed tomography scan demonstrating an intra-abdominal collection combined with fever and increased white blood cell count. Patients were analyzed according to the HVI severity and the type of intervention performed: primary repair versus resection and primary reanastomosis. To identify independent associations between surgical management of HVI and DSSI, logistic regression analysis was used. RESULTS: Overall, 131 patients met the study criteria; 20% (n = 26) received an intra abdominal drain. The incidence of DSSI was significantly higher in patients who received a drain (31% vs. 9%, p = 0.001). No associated risk for development of DSSI in patients who underwent drain placement after primary repair versus resection and primary reanastomosis was demonstrated. Stepwise logistic regression analysis identified the following independent risk factors for development of DSSI: drain utilization (adjusted odds ratio, 3.7; 95% confidence interval, 1.15-11.9; p < 0.028), and Injury Severity Score >=16 (adjusted odds ratio, 5.6; 95% confidence interval, 1.9-16.9; p < 0.002). In-hospital survival was unchanged with respective interventions. CONCLUSION: Intra-abdominal drain placement after isolated HVI repair is associated with almost fourfold adjusted increased incidence of DSSI. Prospective validation of drain utilization in these instances is warranted. PMID- 21817981 TI - Current use of damage-control laparotomy, closure rates, and predictors of early fascial closure at the first take-back. AB - BACKGROUND: Damage-control laparotomy (DCL) is a lifesaving technique but carries significant morbidity. If DCL is over used and the factors that predict early fascial closure have not been fully evaluated. The purpose of the current study was to determine (1) the current rate of DCL, (2) the percentage of DCLs that are closed at first take-back, and (3) possible physiologic and resuscitative parameters predicting early fascial closure. METHODS: A retrospective review of all trauma laparotomies from a Level I trauma center between January 2004 and December 2008 was performed. Patients were excluded if they died before first take-back. Univariate and multivariate analyses were performed. RESULTS: Nine hundred thirty patients were eligible, 278 (30%) underwent DCL, 36 excluded for death before first take-back. Of the remaining 242 DCL patients, 83 (34%) were closed at first take-back and 159 (66%) were not closed at first take-back. These two groups were similar in injury severity, demographics, and prehospital and emergency department fluids and vitals. Median emergency department international normalized ratio (INR; 1.13 vs. 1.29, p = 0.010), post-op INR (1.4 vs. 1.5, p = 0.028), 24-hour fluids (11.9 L vs. 15.5 L, p = 0.006), peak post-op intra abdominal pressure (IAP; 15 vs. 18, p < 0.001), and mortality (1.2% vs. 8.2%, p = 0.027) were different between groups. Multivariate analysis noted vacuum-assisted closure at initial laparotomy (Odds ratio, 3.1; 95% confidence interval [CI], 1.42-6.63; p = 0.004) was an independent predictor of closure at first take-back. However, post-op INR (Odds ratio, 0.18; 95% CI, 0.03-0.97; p = 0.04) and post-op peak IAP (Odds ratio, 0.85; 95% CI, 0.76-0.95; p = 0.005) predicted failure to close fascia at first take-back. CONCLUSION: In similarly injured DCL patients, increased post-op INR and IAP predicted inability to achieve primary fascial closure on first take-back, while use of the vacuum-assisted closure was associated with increased likelihood of early fascial closure. At a busy academic Level I trauma center, the current rate of DCL among those undergoing emergent laparotomy is 30%. Whether this represents optimal use or overutilization of this technique still needs to be determined. PMID- 21817982 TI - Trauma healthcare providers' knowledge of alcohol abuse. AB - BACKGROUND: Brief alcohol interventions for patients in trauma settings have demonstrated significant reductions in drinking behaviors, injury related risk behaviors, and subsequent arrests for driving while intoxicated. However, although a number of surveys have examined the knowledge and attitudes of trauma center personnel regarding alcohol problems, the knowledge and attitudes toward alcohol misuse, screening, and intervention services among various trauma care personnel within an individual trauma center have not been investigated. The purpose of this study was to examine provider knowledge and attitudes related to screening and brief intervention for alcohol problems in a single Level-I trauma center. METHODS: A cross-sectional online survey was administered to employees of a Level-I trauma center with a screening and brief intervention program. Surveys were solicited from hospital staff responsible for the care of trauma patients. Topics covered in the survey included alcoholism, brief interventions in trauma centers, and motivational interviewing. RESULTS: Most trauma care staff members surveyed were white and held BS/BA degrees or Associates' degrees in nursing. The average years of professional practice were 8.6 years. Staff's attitudes regarding those who misuse alcohol was somewhat neutral, showing a weak understanding of the etiology of alcoholism and the effectiveness of brief intervention and referral for treatment. Staff members also struggled to correctly identify the components of brief interventions. CONCLUSIONS: This limited knowledge and the neutral attitudes regarding alcohol problems may indirectly influence metrics of program success. Trauma care staff will benefit from additional training regarding alcohol problems and brief interventions. PMID- 21817983 TI - Characterization of systemic and histologic injury after crush syndrome and intervals of reperfusion in a small animal model. AB - BACKGROUND: Prolonged compression of limb muscles and subsequent decompression are important in the development of crush syndrome (CS). We applied a simple rubber tourniquet to rat hind limbs to create a CS model. METHODS: Anesthetized rats were subjected to bilateral hind limb compression for 5 hours followed by decompression and reperfusion for 0 hour, 1 hour, 3 hours, and 24 hours under monitoring of arterial blood pressure and electrocardiography. Blood and tissue samples were collected for histology, biochemical analysis, and tissue myeloperoxidase activity assessment. RESULTS: The survival rates of the CS-model groups remained at 100% until 3 hours, however, dropped to 25% at 24 hours after reperfusion mainly because of hyperkalemia and consequent hypotension observed at 1 hour and deteriorated at 3 hours after reperfusion. Rhabdomyolysis evaluated by circulating and histologic markers of injury was found as early as 1 hour and more marked at 3 hours, resulting in impaired renal function 24 hours after reperfusion. Myeloperoxidase activities increased with incremental periods after reperfusion not only in injured limb muscles but also in kidney and lung, suggesting an abnormal interaction between the vascular endothelium and circulating leukocytes after rhabdomyolysis, possibly causing subsequent multiple organ dysfunction frequently encountered in CS. CONCLUSION: The findings from this study demonstrate the feasibility of a novel small animal model of extremity crush injury. By using this model, the impact of incremental periods of reperfusion on mortality and remote organ dysfunctions can be characterized. Future studies are necessary to better define a threshold for this injury pattern and the impact of other factors underlying this syndrome. PMID- 21817984 TI - Prolonged indwelling time of temporary vascular shunts is associated with increased endothelial injury in the porcine mesenteric artery. AB - BACKGROUND: Temporary intravascular shunts (TIVS) have been used as a damage control surgery (DCS) adjuncts in superior mesenteric artery (SMA) injuries, both experimentally and clinically. However, no study to date has evaluated the relationship between shunt indwelling time and resultant endothelial cell (EC) injury. We hypothesized that prolonged use of TIVS in SMA injuries would jeopardize EC integrity. METHOD: After laparotomy, the SMA was clamped and transected while pigs were hemorrhaged to 40 mm Hg for 30 minutes. A TIVS was inserted between transected ends of the SMA without systemic anticoagulation. Totally, 24 animals were resuscitated and randomized to different shunt indwelling time groups: A, 3 hours; B, 6 hours; C, 9 hours; and D, 12 hours. Patency of shunts was monitored and recorded. Continuous wave Doppler was used as a determinant of adequacy of flow through the shunts. Transmural SMA biopsies from areas of TIVS placement were examined with electron microscopy for histopathologic injury after staining with hematoxylin and eosin and immunofluorescence using a validated histopathologic injury score (minimum maximum score: 0-4). RESULTS: Severity of endothelial injury was observed to be directly related to shunt indwell time. SMA transmural biopsies harvested from group D animals showed the most profound injury, demonstrating extensive EC denudations and marked intimal rupture (injury grade, 3.4 +/- 0.2). Sections from group A animals revealed the mildest EC injury (1.3 +/- 0.3 vs. group D p < 0.01). No significant difference was detected between group A and B. EC injury grade in group C (2.7 +/- 0.6) was higher than that in group B (1.8 +/- 0.6) but did not reach statistical significance (p = 0.58). CONCLUSION: When possible, vascular reconstruction following use of shunts should include an interposition graft after debridement of the arterial edges having interfaced with the shunt. Finally, to minimize intimal injury to the native vessel, this model suggests that indwell times of shunts should be <9 hours. PMID- 21817985 TI - Effects of ketamine on endotoxin and traumatic brain injury induced cytokine production in the rat. AB - BACKGROUND: Endotoxemia from lipopolysaccharide (LPS) induces systemic cytokine production, whereas traumatic brain injury (TBI) increases intracerebral cytokine production. In anesthetic doses, ketamine has potent anti-inflammatory properties. However, its anti-inflammatory effects at subanesthetic doses and its effects on TBI-induced inflammation have not been fully investigated. We hypothesized that ketamine would attenuate both LPS- and TBI-induced inflammatory responses. METHODS: Male rats received intraperitoneal (i.p.) ketamine (70 mg/kg, 7 mg/kg, or 1 mg/kg) or saline 1 hour before LPS (20 mg/kg i.p.) or saline. Five hours after LPS, rats were killed. Serum was collected for cytokine analysis. In other experiments, male rats were given ketamine (7 mg/kg i.p.) or saline 1 hour before induction of TBI with controlled cortical impact (or sham). One hour and 6 hours after injury, brain was extracted for analysis of cerebral edema and cytokine production. RESULTS: LPS increased the serum concentrations of interleukin (IL)-1alpha, IL-1beta, IL-6, IL-10, tumor necrosis factor-alpha, and interferon-gamma. Ketamine dose dependently attenuated these changes. TBI caused cerebral edema and increased concentrations of cerebral IL-1alpha, IL-1beta, IL 6, IL-10, and tumor necrosis factor-alpha. However, ketamine had minimal effect on TBI-induced inflammation. CONCLUSIONS: Although ketamine did not seem to exert any beneficial effects against TBI in the rat, it did not exacerbate cytokine production or enhance cerebral edema as some studies have suggested. PMID- 21817987 TI - Early cardiac pacemaker placement for life-threatening bradycardia in traumatic spinal cord injury. AB - BACKGROUND: High cervical spinal cord injury (CSCI) can cause life-threatening bradycardia from autonomic instability that may be resistant to pharmacologic interventions. Placement of a cardiac pacemaker, traditionally reserved for patients refractory to drug therapy, may be lifesaving. METHODS: Our Level I trauma center registry found all patients with CSCI from 2003 to 2009. A retrospective chart review identified major events involving the circulatory system: those exhibiting bradycardia (minor, heart rate 40-60/min; major, heart rate <40/min), hypotension (systolic blood pressure <80 mm Hg), asystole, and cardiac arrest. Records of pharmacological interventions (e.g., atropine) and details of pacemaker placement (e.g., timing and any complications) were reviewed. Statistical differences were determined by Wilcoxon signed-rank test, with p < 0.05 as significant. RESULTS: Of the 106 patients with CSCI, 15 (14%) had bradycardia and 7 of those (47%) underwent cardiac pacemaker placement. Six of seven patients had reviewable data. A total of 35 events occurred in these six patients before pacemaker placement. Subsequent to placement, there were zero events of cardiovascular instability (p = 0.0135). Major bradycardic episodes were reduced from 9 to 0 (p = 0.0206) and incidents requiring atropine administration from 9 to 0 (p = 0.0197). Four survived; two patients died from pulmonary complications. There were no complications related to pacemaker insertion. CONCLUSIONS: Patients with CSCI life-threatening complications of bradycardia benefit from early placement of a cardiac pacemaker. Early stabilization may facilitate transfer out of the intensive care unit, mobilization, physical therapy, rehabilitation, and outcome. PMID- 21817986 TI - Dynamic changes of vascular endothelial growth factor and angiopoietin-1 in association with circulating endothelial progenitor cells after severe traumatic brain injury. AB - BACKGROUND: Vascular endothelial growth factor (VEGF) and angiopoietin-1 (Ang-1) can promote angiogenesis and vascular stability after brain injury. Circulating endothelial progenitor cells (EPCs) also play a crucial role in neovascularization and tissue repair after traumatic brain injury (TBI). We sought to compare the expression of VEGF and Ang-1 in serum and the circulating EPCs in patients after severe TBI with that of healthy control subjects. METHODS: We obtained peripheral blood and serum samples from 21 patients with severe TBI and 11 healthy control subjects. EPCs in blood samples from severe TBI patients and healthy controls were quantified by flow cytometry 1 day, 4 days, 7 days, 14 days, and 21 days after severe TBI. VEGF and Ang-1 were measured by enzyme linked immunosorbent assay at the same time points. RESULTS: Compared with control subjects, circulating EPCs in patients with severe TBI decreased 4 days (p < 0.05), but increased 7 days and 14 days (p < 0.05) after TBI. VEGF increased significantly during the follow-up period (p < 0.05). Ang-1 increased gradually and reached peak at 7 days and 14 days after TBI. The circulating EPCs were significantly correlated with VEGF and Ang-1 at 7 days and 14 days after severe TBI. CONCLUSIONS: Our results suggest that the increased VEGF and Ang-1 are closely related to increase in circulating EPCs in response to severe TBI, which may be needed for vascular repairs after severe TBI. PMID- 21817988 TI - Application of MPR in sacral nerve injury during sacral fracture. AB - BACKGROUND: To investigate the diagnostic and clinical value of multiplanar reconstruction (MPR) with spiral computed tomography for sacral nerve injury during sacral fracture. METHODS: From April 2007 to April 2009, 10 patients with sacral nerve injury during sacral fracture admitted to the Affiliated Shenjing Hospital of China Medical University were included in this study; of these, seven were men and three were women, aged around 30 years to 55 years. Hospital admission time from injury was around 1 day to 30 days for these patients. Causes of injury included six cases of car crashes, three cases of fallen heavy objects, and one case of crush injury. To evaluate fracture status of the sacral neuroforamen and relative position of fractured bone to the root of nerve, entire neuroforamen of sacral nerve was observed by MPR technique at double-oblique position (45-degree oblique coronary position and 30-degree oblique sagittal position), under which the fracture condition of sacral neuroforamen could be clearly displayed for further clinical verification. RESULTS: According to the 1990 standard classification for spinal injury by the National Spinal Cord Injury Association and the International Spinal Cord Society, with consideration of the clinical manifestations, clinical diagnosis of all patients were as follows: six cases of injury to S1 root, two cases of injury to S2 root, two cases of injury to both S1 and S2 roots, three cases of penetration of S1 neuroforamen by fractured bone after MPR at double-oblique position, one case of injury to S2 neuroforamen, and two cases of penetration of both S1 and S2 neuroforamen by fractured bone. Diagnosis of last six patients was confirmed by surgery (observed compression of S1 and S2 nerves by fractured bones). In addition, after removal of compression causes, symptoms of the patients were significantly improved, and patients completely recovered in an average of 12 weeks. After the MPR examination at double-oblique position, the remaining four patients (3 cases of injury to S1 and 1 case of injury to S2) did not show penetration of fractured bones to neuroforamen (thus considering the diagnosis of simple neural contusion). These patients recovered well after an average of 13-week conservative therapy. CONCLUSION: Sacral MPR at double-oblique position can be used as a routine examination for patient with sacral fracture, which is of great significance in determining the cause of injury to sacral nerve. Furthermore, it can also provide radiologic evidences to analyze the need for surgical therapy. PMID- 21817990 TI - Injury and health among children in vulnerable families. AB - BACKGROUND: Injury is the leading cause of death for children older than 1 year. The incidence of childhood injury varies greatly depending on social factors, including income, family violence, and other social stressors. This study reports the incidence of injury among children aged 5 years in a cohort of vulnerable families. METHODS: The Fragile Families and Child Wellbeing Study is a longitudinal cohort of approximately 5,000 at-risk families across the United States. Data from interviews with mothers conducted shortly after giving birth and follow-up surveys at 1 year, 3 years, and 5 years were used. Multivariate regression analysis was used to identify independent risk factors for injury in year 5. RESULTS: Five-year follow-up data on injury was complete for 2,397 families. Two hundred ninety-six children were injured at the age of 5 years (12.3%). Multivariate regression found that the strongest predictors of injury in year 5 were male gender (OR, 2.62; 95% CI, 1.02-6.75; p = 0.04) and being in the lowest income stratum (OR, 1.23; 95% CI, 1.01-1.49; p = 0.03). CONCLUSIONS: Children in vulnerable families are at higher risk for injury. The incidence of 12.3% found in this cohort is substantially higher than CDC risk for 5-year-old children, that is, overall 9.3%. This longitudinal cohort has demonstrated a persistently elevated risk of childhood injury, but risk factors for injury have changed with age. As these children reached school age, low household income and male gender were risk factors for injury. This suggests that recognition of gender differences and targeted interventions for caregivers and play environments may be useful. PMID- 21817989 TI - The use of fluorescence-labeled mesenchymal stem cells in poly(lactide-co glycolide)/hydroxyapatite/collagen hybrid graft as a bone substitute for posterolateral spinal fusion. AB - BACKGROUND: Posterolateral spinal fusion is used to treat patients with degenerative spinal disorders. In this study, we investigated the effectiveness of a mesenchymal stem cell (MSC)/hydroxyapatite/type I collagen hybrid graft for posterolateral spinal fusion in a rabbit model. METHODS: In vitro study, the hybrid graft was cultured in complete or osteogenic medium for 7 days and 14 days and examined by scanning electron microscopy. The alkaline phosphatase activity of the MSCs was assessed and the expression of osteogenic gene was determined by reverse transcription polymerase chain reaction. In vivo investigation, spinal fusion was examined using radiography, manual palpation, computed tomography, torsional loading tests, and histologic analysis. Furthermore, using a PKH fluorescence labeling system, we examined whether the newly formed bone was derived from the transplanted MSCs. RESULTS: Our data suggested that the MSCs differentiated into osteoblasts and produced extracellular matrix in the hybrid graft. Increased alkaline phosphatase activity was noted and mRNA of Cbfa-1 and osteopontin were detected. Radiographs and computed tomography images showed a continuous bone bridge and a satisfactory fusion mass incorporated into the transverse processes. The results of manual palpation and biomechanical data did not significantly differ between the two groups. Histologic examination of both groups revealed the presence of cartilage and endochondral ossification in the gaps between the grafted fragments. In situ tracing of the PKH 67-labeled MSCs indicated that the transplanted MSCs were partly responsible for the new bone formation. CONCLUSION: The hybrid graft could be effectively used to achieve posterolateral spinal fusion. PMID- 21817991 TI - Posttraumatic stress disorder in hospitalized terrorist bombing attack victims. AB - BACKGROUND: Posttraumatic stress disorder (PTSD) is a psychiatric disorder that results from exposure to a traumatic event and consists of intrusive and unwanted recollections; avoidance followed by emotional withdrawal; and heightened physiologic arousal. Hospitalized victims of suicide bombing attacks (SBAs) are unique because of the circumstances and severity of their injuries, which could affect the occurrence and delay the recognition of PTSD. Our objectives were to evaluate the prevalence and severity of PTSD among hospitalized SBA victims and to assess variables of physical injury as risk factors for the development of PTSD. METHODS: Forty-six hospitalized SBA victims were evaluated for PTSD using the PTSD symptom scale self-report questionnaire by phone. Demographic and medical data regarding the severity and type of injury and medical treatment were collected from medical files. Injury Severity Score was used to assess severity of physical injury. RESULTS: Twenty-four of 46 (52.2%) hospitalized SBA victims developed PTSD. Presence of blast lung injury was significantly higher in the PTSD group compared with the non-PTSD group (37.5% versus 9.1%, respectively; p < 0.04). There was no significant difference in Injury Severity Score between PTSD and non-PTSD groups. Blast lung injury and intracranial injury were found to be positive predictors of PTSD (odds ratio, 125 and 25, respectively). No correlation was found between the length of stay, length of intensive care unit stay, or severity of physical injuries and the severity of PTSD. CONCLUSIONS: Hospitalized victims of SBA are considerably vulnerable to develop PTSD. Victims should be monitored closely and treated in conjunction with their physical treatment. Blast lung injury and intracranial injury are predictors of PTSD. PMID- 21817992 TI - Evaluation and management of peripheral vascular injury. Part 1. Western Trauma Association/critical decisions in trauma. PMID- 21817993 TI - The trauma survivors network: Survive. Connect. Rebuild. AB - BACKGROUND: Despite substantial improvements in trauma care, severe injuries often result in significant long-term consequences for otherwise young, healthy individuals. Providing patient-centered care and extensive psychosocial support services is difficult for trauma centers. METHODS: In collaboration with researchers and clinicians, the American Trauma Society has developed the Trauma Survivors Network, a program incorporating self-management, peer support, timely access to information, and online social networking. RESULTS: Individually, these components have been proven effective in improving outcomes and quality of life and are widely used in nontrauma settings. To date, 70 representatives from 30 trauma centers have participated in training sessions conducted by the American Trauma Society. CONCLUSION: The Trauma Survivors Network provides a critical component of trauma care that can be adapted for local needs throughout the country. Implementation of these services is a necessary step in the development of comprehensive trauma systems that not only save lives but also reduce long term disability among survivors. PMID- 21817994 TI - Detection of central venous catheter insertion-related complication using bedside ultrasound: the CVC sono. PMID- 21817995 TI - A simple device to teach tube thoracostomy. AB - BACKGROUND: Chest tube insertion is an important component of medical and surgical education. This article reports a cost-effective and easily reproducible method for hands-on education of tube thoracostomy placement. METHODS: A wood base is constructed, and a large rack of ribs are secured to simulate the thorax. Partially inflated examination gloves and bagels are used to simulate the lung and diaphragm, respectively. RESULTS: A life-like, cost-efficient thoracostomy model is created allowing for proficiency training in chest tube insertion. According to Advanced Trauma Life Support criteria, 123 military personnel were satisfactory, 4 remedial, and 7 instructor potential using the described model. CONCLUSIONS: We have developed a simple, inexpensive training device for insertion of chest tubes and tested it on 134 military personnel. PMID- 21817996 TI - Orthopedic management of children with multiple injuries. PMID- 21817997 TI - Extraperitoneal bladder rupture communicating with the hip joint. PMID- 21817998 TI - Air in the spinal disc with dissecting into psoas muscle after trauma. PMID- 21817999 TI - Intraoperative sonography for detection of contralateral acute epidural or subdural hematoma after decompressive surgery. PMID- 21818000 TI - Excluding isolated hip fractures from the national trauma data bank would be a missed opportunity. PMID- 21818001 TI - The R.A.P.T.O.R. suite: resuscitation with angiography, percutaneous techniques, and operative repair. PMID- 21818003 TI - Base deficit: a better indicator for diagnosis and treatment of shock in trauma patients. PMID- 21818007 TI - Septic thrombophlebitis of the superior mesenteric vein caused by acute suppurative appendicitis. PMID- 21818008 TI - Life-threatening signs of ischemic bowel disease-portomesenteric venous gas. PMID- 21818009 TI - Western Trauma Association/critical decisions in trauma: operative management of adult blunt hepatic trauma. PMID- 21818010 TI - Liver dysfunction by model for end-stage liver disease score improves mortality prediction in injured patients with cirrhosis. AB - BACKGROUND: Cirrhosis is associated with poor outcomes in the trauma setting. We aimed to evaluate the utility of Model for End-Stage Liver Disease (MELD) in assessing additional mortality risk in trauma patients with cirrhosis. METHODS: Injured patients with liver dysfunction were identified by hospital and trauma registry query. Presence of cirrhosis was confirmed by laparotomy, biopsy, or imaging. MELD classification, Child-Turcotte-Pugh (CTP) classification, Injury Severity Score (ISS), and Trauma ISS (TRISS) were recorded, and the primary outcome variable was hospital mortality. We assessed the validity of the four scoring systems in prediction of mortality, individually and in combinations, by comparing the areas under receiver operating characteristic curves (AUC), which is the probability, for scores that increase with the risk of death that a randomly chosen deceased subject will score higher than a randomly chosen living subject. RESULTS: A total of 163 patients with confirmed cirrhosis were included. ISS (AUC = 0.849, p < 0.001) and TRISS (AUC = 0.826, p < 0.001) were the strongest predictors of mortality. MELD (AUC = 0.725) was not a significantly stronger predictor of mortality than CTP (AUC = 0.639; p = 0.38). ISS + MELD (AUC = 0.891) and ISS + CTP (AUC = 0.897) were stronger predictors than ISS alone (AUC = 0.849; p < 0.001) for both. The MELD score was more available from the records than the CTP score (91.4% vs. 75.5%). CONCLUSION: In trauma patients with cirrhosis, a score that evaluates the degree of liver dysfunction enhances the ability of ISS alone to predict mortality. The MELD score is more readily available than the CTP score for the prediction of mortality in trauma patients. PMID- 21818011 TI - Lyophilized plasma reconstituted with ascorbic acid suppresses inflammation and oxidative DNA damage. AB - BACKGROUND: Lyophilized plasma (LP) has been shown to be as effective as fresh frozen plasma (FFP) for resuscitation in polytrauma and hemorrhagic shock. LP reconstituted with ascorbic acid is associated with suppression of cytokines when compared with fresh frozen plasma. We aimed to determine the effect of using alternate LP reconstitution acids on physiologic parameters, blood loss, coagulation, oxidative DNA damage, and proinflammatory cytokines in a polytrauma and hemorrhagic shock model. METHODS: Thirty swine were anesthetized, subjected to polytrauma, hemorrhagic shock, and randomized to resuscitation with LP ascorbic acid (AA), LP-citric acid (CA), or LP-hydrochloric acid (HCL). Physiologic data were continuously monitored, blood loss measured, and serum collected at baseline, 2 hours, and 4 hours for enzyme-linked immunosorbent assays. Measured 8-OH-2'-deoxyguanosine (8-OHdG) was a biomarker of oxidative DNA damage. RESULTS: No differences were observed in physiologic measures, blood loss, or coagulation parameters. Interleukin-6 increased over time for all groups, but at 2 hours, the concentration in AA (median [minimum, maximum]: 113 ng/mL [0, 244]) was lower compared with CA (181 ng/mL [69, 314], p = 0.01) and HCL (192 ng/mL [41, 310], p = 0.03). Comparing 4 hours to baseline, a significant increase in oxidative DNA damage was observed in CA (22.9 ng/mL [16.3, 34.3] vs. 15.6 ng/mL [13.6, 26.7], p = 0.03) and HCL (19.6 ng/mL [15.7, 56.7] vs. 15.8 ng/mL [11.6, 21.4], p = 0.01) but not in AA (17.9 ng/mL [12.6, 26.9] vs. 17.1 ng/mL [11.8, 18.4], p = 0.24). CONCLUSIONS: Resuscitation with AA results in decreased interleukin-6 expression and oxidative DNA damage compared with CA and HCL. PMID- 21818012 TI - Risk factors associated with early reintubation in trauma patients: a prospective observational study. AB - BACKGROUND: After mechanical ventilation, extubation failure is associated with poor outcomes and prolonged hospital and intensive care unit (ICU) stays. We hypothesize that specific and unique risk factors exist for failed extubation in trauma patients. The purpose of this study was to identify the risk factors in trauma patients. METHODS: We performed an 18-month (January 2008-June 2009) prospective, cohort study of all adult (8 years or older) trauma patients admitted to the ICU who required mechanical ventilation. Failure of extubation was defined as reintubation within 24 hours of extubation. Patients who failed extubation (failed group) were compared with those who were successfully extubated (successful group) to identify independent risk factors for failed extubation. RESULTS: A total of 276 patients were 38 years old, 76% male, 84% sustained blunt trauma, with an mean Injury Severity Score = 21, Glasgow Coma Scale (GCS) score = 7, and systolic blood pressure = 125 mm Hg. Indications for initial intubation included airway (4%), breathing (13%), circulation (2%), and neurologic disability (81%). A total of 17 patients (6%) failed extubation and failures occurred a mean of 15 hours after extubation. Independent risk factors to fail extubation included spine fracture, airway intubation, GCS at extubation, and delirium tremens. Patients who failed extubation spent more days in the ICU (11 vs. 6, p = 0.006) and hospital (19 vs. 11, p = 0.002). Mortality was 6% (n = 1) in the failed group and 0.4% (n = 1) in the successful extubation group. CONCLUSIONS: Independent risk factors for trauma patients to fail extubation include spine fracture, initial intubation for airway, GCS at extubation, and delirium tremens. Trauma patients with these four risk factors should be observed for 24 hours after extubation, because the mean time to failure was 15 hours. In addition, increased complications, extended need for mechanical ventilation, and prolonged ICU and hospital stays should be expected for trauma patients who fail extubation. PMID- 21818013 TI - Training dedicated emergency physicians in surgical critical care: knowledge acquisition and workforce collaboration for the care of critically ill trauma/surgical patients. AB - BACKGROUND: The Leapfrog Group initiative has led to an increasing public demand for dedicated intensivists providing critical care services. The Acute Care Surgery training initiative promotes an expansion of trauma/surgical care and operative domain, redirecting some of our focus from critical care. Will we be able to train and enforce enough intensivists to care for critically ill surgical patients? METHODS: We have been training emergency physicians (EPs) alongside surgeons in our country's largest Trauma/Surgical Critical Care Fellowship Program annually for more than a decade. We reviewed our Society of Critical Care Medicine Multidisciplinary Critical Care Knowledge Assessment Program (MCCKAP, critical care in-training examination) scores from 2006 to 2009 (4 years). The MCCKAP, administered during the ninth month of a Critical Care Fellowship, is the only known standardized objective examination available in this country to compare critical care knowledge acquisition across different specialties. Subsequent workforce outcome for these Emergency Medicine Critical Care Fellowship graduates was analyzed. RESULTS: Over the 4-year period, we trained 42 Fellows in our Program who qualified for this study (30 surgeons and 12 EPs). Surgeons and EP performance scores on the MCCKAP examination were not different. The mean National Board Equivalent score was 419 +/- 61 (mean +/- standard deviation) for surgeons and 489 +/- 87 for EPs. The highest score was achieved by an EP. The lowest score was not achieved by an EP. Ten of 12 (83%) EP Critical Care Fellowship graduates are practicing inpatient critical care in intensive care units with attending physician level responsibilities. CONCLUSIONS: EPs training in a Surgical Critical Care Fellowship can acquire critical care knowledge equivalent to that of surgeons. EPs trained in a Surgical Critical Care paradigm can potentially expand the intensive care unit workforce for Surgical Critical Care patients. PMID- 21818014 TI - Telemedicine to a moving ambulance improves outcome after trauma in simulated patients. AB - BACKGROUND: Rural trauma victims often require prolonged transport by s with limited scopes of practice. We evaluated the impact of telemedicine (TM) to a moving ambulance on outcomes in simulated trauma patients. METHODS: This is an institutional review board approved, prospective double-blind study. Three trauma scenarios (blunt torso trauma, epigastric stab wound, and closed head injury) were created for a human patient simulator. Intermediate emergency medical technicians (EMTs; n = 20) managed the human patient simulator, in a moving ambulance. In the TM group, physicians (n = 12) provided consultation. In the non TM group, EMTs communicated with medical control by radio, as necessary. We tabulated the fraction of 13 key signs, 5 pathologic processes, and 12 key interventions that were performed. Vital signs and Sao2 (%) were recorded. Data were compared using the Wilcoxon rank-sum test. RESULTS: Lowest Sao2 (84 +/- 0.7 vs. 78 +/- 0), lowest systolic blood pressure (70 +/- 1 vs. 53 +/- 1), and highest heart rate (144 +/- 0.9 vs. 159 +/- 0.5) were significantly improved in the TM group (p < 0.001). Recognition rates for key signs (0.96 +/- 0.01 vs. 0.79 +/- 0.05), processes (0.98 +/- 0.02 vs. 0.75 +/- 0.05), and critical interventions (0.92 +/- 0.02 vs. 0.49 +/- 0.03) were higher in the TM group (p < 0.003). EMTs were successfully guided through needle decompression procedures in 22 of 24 cases (zero in the non-TM group). CONCLUSION: TM to a moving ambulance improved the care of simulated trauma patients. Furthermore, procedurally naive EMTs were able to perform needle thoracostomy and pericardiocentesis with TM guidance. PMID- 21818015 TI - Impact of the version of the abbreviated injury scale on injury severity characterization and quality assessment of trauma care. AB - BACKGROUND: The Abbreviated Injury Scale (AIS) was updated in 2008 (AIS 2008). We aimed to investigate the impact of AIS 2008 on the characterization of injury severity and quality assessment of trauma care. METHODS: We identified all blunt trauma patients in the Japan Trauma Data Bank. First, we converted AIS 98 codes to AIS 2008 codes using a mapping table. Next, we compared Injury Severity Scores (ISSs) and New ISSs (NISSs) based on AIS 98 and AIS 2008. We compared the proportion of major trauma (ISS >15) between the two AISs. We derived risk adjusted models using the two AISs and separately ranked hospitals according to the observed-to-expected death (OE) ratio. We counted the number of performance outliers for the two rankings. We analyzed the association between the percent change in OE ratios and the proportion of NISS outliers (change in NISS of <-12). RESULTS: There were 19,899 subjects. The ISSs and NISSs based on AIS 2008 were significantly less than those based on AIS 98. The proportion of major trauma was 46.3% and 38.9% for AIS 98 and AIS 2008, respectively (p < 0.001). The numbers of performance outliers were different between the two rankings. There was a significant positive linear relationship between the percent change in the OE ratio and the proportion of NISS outliers. CONCLUSION: The use of different AIS versions influenced the selection of major trauma patients and affected the quality assessment of the trauma care. Researchers should be aware of these findings when selecting the version of the AIS. PMID- 21818016 TI - Survival advantage for elderly trauma patients treated in a designated trauma center. AB - BACKGROUND: This article analyzes the effectiveness of designated trauma centers (DTCs) in Florida concerning reduction in the mortality risk of severely injured elderly trauma victims. METHODS: Inpatient hospital data collected by the Agency for Health Care Administration were used to identify elderly trauma patients. An instrumental variables method was used to adjust for prehospital selection bias in addition to the influence of age, gender, race, risk of mortality, comorbidities, and type of injury. The model was estimated using a bivariate probit full information maximum likelihood model to determine the impact of triage to a trauma center as opposed to a nontrauma hospital. RESULTS: After adjusting for confounding influences, treatment at a DTC was associated with a statistically significant reduction of 0.072, 0.040, and 0.036 in the probability of mortality for patients in the age groups 65 years to 74 years, 75 years to 84 years, and >= 85 years, respectively. CONCLUSIONS: Treatment of severely injured elderly trauma patients in DTCs is associated with statistically significant gains in the probability of survival. PMID- 21818017 TI - Minor trauma is an unrecognized contributor to poor fetal outcomes: a population based study of 78,552 pregnancies. AB - BACKGROUND: Fetal outcomes after minor injury (MI) to pregnant women are difficult to study because these patients are discharged after emergency room evaluation and not entered in trauma registries. The purpose of this study was to determine the association of both minor and severe injury on fetal demise and prematurity/low birth weight (LBW) in a large population-based study using robust state databases. METHODS: The Tennessee State Fetal Birth and Death Data Systems were merged with the Tennessee State Hospital Discharge Data System using patient identifiers. All women with an e-code requiring inpatient admission during their pregnancy were considered severely injured, whereas those discharged after emergency room evaluation were considered to have MI. The impact of trauma on unintended fetal demise and premature birth/LBW was assessed using multivariable logistic regression. RESULTS: In 2005, there were 376 fetal deaths and 78,176 viable deliveries of which 11,817 were premature/LBW. Severe injury was significantly associated with fetal demise and prematurity/LBW. Unexpectedly, first- and second-trimester MI was associated with both fetal demise and prematurity/LBW. CONCLUSIONS: As expected, fetal mortality and morbidity increased after severe injury. Surprisingly, MI was associated with fetal demise, premature delivery, and LBW. Pregnant women who sustain MI should be told that they are at increased risk for an adverse outcome. PMID- 21818018 TI - Can acute care surgeons perform emergency colorectal procedures with good outcomes? AB - BACKGROUND: Acute care surgeons (ACS) perform emergency colorectal procedures but may have lower case volumes when compared with their general surgical and colorectal colleagues, which may compromise outcomes. In the acute populations, the elderly may be at particular risk. METHODS: Records of all elderly patients (age >65 years) presenting to a tertiary center with a colorectal emergency requiring operation over a 7-year period were reviewed. Data abstracted included presenting characteristics, pre- and postoperative diagnosis, procedural details, surgeon, and outcomes. Surgeons were stratified based on the number of elective colorectal cases they performed over the same time period. Chi-square test, Fisher's exact test, and t test were used, and logistic regression models controlled for patient characteristics. p < 0.05 was significant. RESULTS: There were 293 emergent colorectal operations. Mortality before stratification for perioperative risk factors was 15% (43 of 293). ACS mortality was higher than other surgeons (23.2% versus 12.4%; odds ratio, 2.14; p = 0.034). Length of stay, intensive care unit length of stay, and ventilator days were longer for ACS although not significant. On risk stratification by multivariate analysis preoperative hypotension, American Society of Anesthesiology class, age, time to operating room, and management with an open abdominal technique predicted mortality but surgeon type did not. CONCLUSIONS: ACS caring for colorectal emergencies encounter critically ill patients with significant comorbidities, often from extended care facilities. If patient characteristics are considered when scrutinizing outcomes of emergency colorectal procedures, ACS perform as well as their colleagues who perform a higher volume of elective resections. PMID- 21818019 TI - Early VATS for blunt chest trauma: a management technique underutilized by acute care surgeons. AB - BACKGROUND: Retained hemothorax and/or empyema is a commonly recognized complication of penetrating chest injuries that may be treated by early video assisted thoracoscopy (VATS). However, the use of VATS in blunt chest trauma is less well defined. Our acute care surgeon (ACS) group aggressively treats complications of penetrating chest trauma with VATS, and our results suggested that the early use of VATS by ACS should be expanded. MATERIALS: A retrospective review of Trauma Center admissions between January 2007 and December 2009 was performed to identify patients with blunt thoracic injuries who underwent VATS. RESULTS: Eighty-three patients underwent VATS to manage thoracic complications arising from their blunt chest trauma. All operations were performed by ACS. The majority of patients (73%, 61 of 83) were treated with VATS for retained hemothorax, 18% for empyema (15 of 83), and 10% for persistent air leak (8 of 83). All (15) patients who developed empyema had chest tubes placed in the emergency department. No patient treated with VATS for a persistent air leak required further operation or conversion to thoracotomy. VATS performed <=5 days after injury was associated with a lower conversion to open thoracotomy (8% vs. 29.4%, p < 0.05). Hospital length of stay (LOS) was significantly lower for patients receiving VATS <=5 days after injury (11 +/- 6 vs. 16 +/- 8, p < 0.05). No patient treated with VATS <=5 days had persistent empyema; however, five patients treated with VATS for retained hemothorax or empyema >5 days after injury required further intervention for thoracic infection. Multivariate analysis demonstrated that both a diagnosis of empyema and VATS >5 days after injury were predictors of increased LOS and increased conversion to thoracotomy. CONCLUSIONS: Early VATS can decrease hospital LOS and thoracotomy rate in patient suffering blunt thoracic injuries. ACS can perform this procedure safely and effectively. PMID- 21818020 TI - Blunt cerebrovascular injury is poorly predicted by modeling with other injuries: analysis of NTDB data. AB - BACKGROUND: Traumatic blunt cerebrovascular injury (BCVI) may portend catastrophic complications if untreated. Who should be screened for BCVI is controversial. The purpose of this study was to develop and validate a prediction score (pBCVI) to identify those at sufficient risk to warrant dedicated screening. METHODS: We conducted a cohort study using data for years 2002-2007 from the National Trauma Data Bank. Blunt trauma patients aged 16 years and older were randomly divided into two groups for score creation and validation. Final prediction model included age, sex, Trauma Mortality Prediction Model p(death), traumatic intracranial hemorrhage, cerebellar/brain stem injury, malar/maxillary fracture, mandible fracture, cervical spine fracture, cervical spinal cord injury, thoracic spinal cord injury, and chest Abbreviated Injury Scale >=3. pBCVI was evaluated using receiver operating characteristic curve area and the Hosmer-Lemeshow statistic. The Youden Index estimated an optimal cut-point (J) of the pBCVI. RESULTS: The cohort numbered 1,398,310 patients, including 2,125 with BCVI. The overall incidence of BCVI was 0.15%. Cervical spine fracture had the strongest association with BCVI (odds ratio 4.82, p < 0.001). The receiver operating characteristic curve for pBCVI was 0.93 and the Hosmer-Lemeshow statistic was 206.3, p < 0.01. The optimal cut-point (J) of pBCVI was 0.0013 (sensitivity 0.91, specificity 0.82) and would miss 186 (8.8%) injuries in our cohort. To identify all BCVI using this model, an unrealistic 96% of the cohort would require screening. CONCLUSIONS: A model based on a pattern of other injuries cannot be used as a stand-alone instrument to determine screening for BCVI. "Optimal" model cut-points are not ideal for all injuries. Clinical suspicion that integrates energy of mechanism and associated injuries remains essential to effectively screen for BCVI and minimize patient risk for a catastrophic missed injury. PMID- 21818021 TI - Decompressive craniectomy in 14 children with severe head injury: clinical results with long-term follow-up and review of the literature. AB - BACKGROUND: Decompressive craniectomy (DC) is a controversial therapeutic measure used in patients with intractable intracranial hypertension after severe head injury. This study describes the morbidity and mortality of DC in 14 children with a mean follow-up of 3.2 years. We review published evidence from the past 10 years on the indications for DC in pediatric brain trauma. We also examine timing, surgical technique, and the results of this procedure. METHOD: We retrospectively reviewed patients who underwent DC from 2002 to 2010. Clinical data were collected at admission, as were data on the indication for craniectomy, timing, and surgical technique. Perioperative intracranial pressure (ICP), complications of craniectomy, and Glasgow Outcome Scale score at 2 years were recorded as outcome variables. RESULTS: Fourteen craniectomies were performed. The median presenting Glasgow Coma Scale score was 6.5 (range, 4-15). Ten patients were presented with anisocoria. In 13 patients, craniectomy initially decreased ICP to <25 mm Hg. Two patients (14%) had a poor prognosis on admission and died. The most frequent complications were hygroma (8 patients) and infections (3 patients). The mean Glasgow Outcome Scale score at the 2-year follow-up visit was 4.4 (range, 4-5). Behavioral and psychiatric abnormalities and poor academic performance were frequent (82%). CONCLUSIONS: DC reduces ICP in pediatric patients with traumatic brain injury. The mortality rate is low and long-term prognosis in survivors is good. Complications related to surgery are frequent. Wide craniectomy with duraplasty seems to be the most common technique. Defining the most appropriate indications and timing for DC in pediatric patients should be the objective of future prospective studies. PMID- 21818022 TI - Results of a computed tomography protocol evaluating distal third tibial shaft fractures to assess noncontiguous malleolar fractures. AB - BACKGROUND: Intra-articular tibia fractures are reported to occur in 1% to 25% of tibia diaphyseal fractures. The objective of this study was to create a standard protocol to evaluate noncontiguous malleolar fractures associated with distal third tibial diaphyseal fractures using computed tomography (CT). METHODS: Sixty six patients with 67 distal third tibia fractures were treated at a level one trauma center from December 2005 to November 2007. These patients were then evaluated using a CT protocol to assess the ankle joint. There were 45 men and 21 women with average age of 44 years (range 18-69 years). All films were independently examined by two orthopedic traumatologists and one musculoskeletal radiologist. RESULTS: Twenty-nine of 67 (43%) distal third tibial shaft fractures had associated intra-articular fractures determined by CT scan. There were 23 posterior malleolus fractures, 3 anterolateral fragments, and 3 medial malleolus fractures. Twenty-seven of 29 fractures (93%) were associated with spiral type fracture patterns (p = 0.001). Seventeen of 29 (59%) intra-articular fractures required operative fixation. Seventy-six percent were noncontiguous fractures. The radiologist detected 20 of 29 (69%) intra-articular fractures using high resolution monitors, and the orthopedic surgeons averaged 13 of 29 (45%) using initial injury radiographs in the emergency department. CONCLUSION: Plain radiographs are often insufficient for detecting posterior malleolus fractures in conjunction with ipsilateral distal third diaphyseal tibia fractures. Using a preoperative CT protocol for tibial shaft fractures can significantly improve the ability to diagnose associated intra-articular fractures that may not be evident on plain radiographs. Knowledge of these associated intra-articular fractures may prompt fracture stabilization and can prevent displacement during intramedullary nailing of tibia shaft fractures. PMID- 21818023 TI - The proximal femur nail antirotation: an identifiable improvement in the treatment of unstable pertrochanteric fractures? AB - BACKGROUND: The optimal surgical treatment of patients with an unstable extracapsular proximal femoral fracture is yet to be found. From the biomechanical point of view, the use of an intramedullary device in combination with a dynamic femoral head/neck stabilization implant seems an optimal technique. One of these intramedullary devices, the Proximal Femoral Nail (PFN), has several drawbacks in practice. The Proximal Femur Nail Antirotation (PFNA) has been designed to address these. We hypothesized that the placement of one femoral head/neck fixation device in the PFNA would improve positioning of the implant in the femoral head compared with the PFN and reduce the number of reoperations in both short and long term. METHODS: We followed 157 consecutive patients with unstable trochanteric fractures (Arbeitsgemeinschaft fur Osteosynthesefragen classification 31.A.2 and A.3) treated with a PFN or a PFNA for 1 year. The radiologic position of the implant was evaluated, and the postoperative local and systemic complications were registered. RESULTS: The position of the femoral head/neck stabilization implant was "good" in 39 (44.8%) patients in the PFN group and 23 (32.9%) patients in the PFNA group; the position was "acceptable" in 30 (34.5%) versus 33 (47.1%) patients, and in 18 (20.7%) versus 14 (20%) patients, the position was "poor" (p = 0.277). Because of implant related complications, three patients in the PFN group and four patients in the PFNA group needed an early reoperation (p = 0.136). A late reoperation because of implant-related complications was performed in 13 patients in the PFN group and in three in the PFNA group (p = 0.016). CONCLUSIONS: This study shows that osteosynthesis with the PFNA does not improve the position of the implant in the femoral head compared with the PFN. However, the risk of a secondary complication and the necessity of a late reoperation are significantly higher in patients treated with a PFN compared with patients treated with a PFNA. PMID- 21818024 TI - Risk factors for hip fracture sites and mortality in older adults. AB - BACKGROUND: Our study was designed to (1) investigate the risk factors associated with cervical or trochanteric hip fractures; and (2) identify the risk factors for increased mortality in the elderly population sustaining hip fractures, after adjusting the miscellaneous baseline prefracture conditions. METHODS: Two hundred seventeen elder patients with first-time, low-trauma hip fractures were enrolled. The follow-up time ranged from 35 months to 56 months. Potential risk factors for hip fracture types included (1) the 77 items on the self-reported questionnaire; (2) the body height, weight, and body mass index; (3) tests of coordination, handgrip strength, and peak expiratory flow rate; and (4) the bone mineral density variables. GTFN ratio was defined as the bone mineral density ratio between the greater trochanter and the femoral neck. Multivariate logistic regression and Cox regression models were used for analysis. The population attributable risk proportion of death to each significant factor was estimated. RESULTS: Risk factors for trochanteric fractures include a GTFN ratio <=0.81, being male, and an age >80 years. Risk factors for higher mortality after hip fracture included trochanteric fracture, body mass index <=20 (kg/m), poor self assessed health status, peak expiratory flow rate <=215 (L/min), being male, illiteracy, and coordination abnormality, in the declining order of population attributable risk proportion. Trochanteric fractures had a significantly higher cumulative mortality at 36 months, 48 months, and 60 months than cervical fractures. CONCLUSIONS: The novel GTFN ratio was associated with hip fracture sites. Clinically, cervical and trochanteric fractures represent different disease entities because of the difference in their mortality rates. PMID- 21818025 TI - Modified technique of percutaneous posterior columnar screw insertion and neutralization plate for complex acetabular fractures. AB - BACKGROUND: To overcome the complexity of acetabular fractures, several techniques, such as extensive surgical exposure, transtrochanteric osteotomy, and columnar screw fixation, were reported. However, all these techniques have their disadvantages and limitations. We report the surgical results of a modified technique with posterior columnar screw insertion and neutralization plate in a single Kocher-Langenbeck approach for complex acetabular fractures. METHODS: We identified 30 patients with 30 acetabular fractures who had been treated by this technique between 1995 and 2004. Demographic data, perioperative results, and complications were all recorded. The detail of surgical procedure was described and illustrated. RESULTS: There were 13 men and 17 women with mean age of 36.4 years (range, 19-66 years). Mean follow-up duration was 49.2 months (range, 24 112 months). All fractures achieved union, and there was no loss reduction and fixation during the follow-up period. There were five complications during hospital stay, including superficial and deep infection and transient sciatic nerve palsy. There was no loss of reduction during follow-up period. Five patients underwent total hip arthroplasty caused by posttraumatic osteoarthritis and preexisting osteoarthritis. The mean Harris Hip Score at 24-month follow-up was 79.7 (median, 92; range, 33-99). CONCLUSION: This study provided a modified surgical technique of percutaneous insertion of posterior columnar screw that appeared to be safe and reliably hold the column in place for healing. PMID- 21818026 TI - Iliosacral screw placement: are uniplanar changes realistic based on standard fluoroscopic imaging? AB - BACKGROUND: With the aim of improving the understanding of iliosacral screw placement, two hypotheses were tested: (1) standard intraoperative inlet and outlet images are not based on orthogonal coordinates, and (2) therefore making starting point and aim changes by moving perpendicular to the c-arm beam will displace the guide wire on the other intraoperative radiographic view. METHODS: This is a prospective case series with review of intraoperative data from consecutive patients treated at a University Level I trauma center. The study group included ten consecutive patients with nondysmorphic upper sacral segments and unstable posterior pelvic ring injuries that required surgical treatment. Posterior surgical stabilization included iliosacral screw placement using a standardized three- view technique in the supine position. The main outcome measurement included the angles from the perpendicular required to achieve what have been considered the ideal inlet and outlet views intraoperatively. The angle arc for each patient created by the recorded angles was then determined. RESULTS: The average sagittal plane tilt required to achieve the ideal inlet view was 25 degrees (range, 21-33 degrees). The average sagittal plane tilt required to achieve the ideal outlet view was 42 degrees (range, 30-50 degrees). The average arc between the ideal inlet and outlet views was 67 degrees (range, 62-76 degrees). These views never created an orthogonal system. CONCLUSION: We commonly work in orthogonal systems. Within these systems, it is possible to make a uniplanar correction by moving perpendicular to one plane or radiographic view. The ideal views to image the safe zone for iliosacral screw placement do not create an orthogonal system. When this average angle arc is placed on a graphic model of the pelvis, it becomes clear that the plane of the radiographic beam of the ideal inlet view is collinear with the anterior aspect of the upper two sacral bodies. The outlet view is oblique to the upper sacral bodies. Surgeons must keep this in mind when using fluoroscopic views to insert iliosacral screws. PMID- 21818027 TI - Modified posterior closing wedge osteotomy for the treatment of posttraumatic thoracolumbar kyphosis. AB - BACKGROUND: Posttraumatic thoracolumbar deformities can occur in patients after conservative or inadequate surgical treatment. Anterior, posterior, or combined anterior and posterior procedures of Smith-Peterson osteotomy technique have been developed to correct thoracolumbar kyphosis to various degrees. Recently, many reports have addressed the specific problem of local posttraumatic thoracolumbar deformity; however, there is significant controversy over the ideal management. The objectives are to illustrate the technique of modified closing wedge osteotomy for the treatment of posttraumatic kyphosis and to report the radiographic results and clinical outcome of patients treated with the technique. METHODS: Thirty-six patients with symptomatic posttraumatic thoracolumbar kyphosis treated with a posterior modified closing wedge osteotomy. All patients completed follow-up of at least 2 years. RESULTS: The mean surgical time was 224 minutes with a mean intraoperative blood loss of 611.5 mL. The average preoperative regional angle was 40.5 degrees, 4.8 degrees postoperatively, and 5.8 degrees at final follow-up. The average Cobb angle changed from 43.4 degrees preoperatively to 2.4 degrees after surgery. The mean visual analog scale back pain score decreased from 55.2 preoperatively to 19.6 at final follow up, and the mean Oswestry disability index score changed from 58.7 preoperatively to 21.8 at the last follow-up. All patients achieved bony anterior fusion based on radiographic evidence of the presence of trabecular bone bridging at the osteotomy site. CONCLUSIONS: The modified wedge closing osteotomy achieves satisfactory kyphosis correction and good fusion with less blood loss and complications than other approaches, implying an alternative method in patients with posttraumatic kyphosis. PMID- 21818028 TI - Long-term evaluation of a trauma center-based juvenile driving intervention program. AB - BACKGROUND: Motor vehicle-related trauma remains the leading cause of adolescent injury and death in the United States. We previously reported results from the Drive Alive (DA) program-a comprehensive juvenile prevention program that highlights risky driving behavior and consequences-and demonstrated a reduction in recidivism 6 months after its completion. We further evaluated the results of the original and subsequent participants on a long-term basis. METHODS: Bureau of Motor Vehicle records of all individuals who had completed the DA program were prospectively reviewed. This 4-week, Level I trauma center-based program provides 10 contact hours of exposure to mock trauma sessions, drug and alcohol education, former trauma patients and their families, state troopers and other pertinent driving safety, educational, and prevention topics. The County Juvenile Court ordered participation after driving-related convictions. The driving records were compared with a control group consisting of adolescents convicted of similar driving offenses in the same period, not referred to the DA program. Comparisons were made at 6 monthly intervals up to 60 months using Fischer's exact test. RESULTS: A total of 488 teens (346 male and 142 female) completed the DA program between May 2003 and October 2008. Mean participant age was 17.4 years. Speeding and driving under the influence of alcohol were the most frequent reasons for referral. CONCLUSION: Consistent with our prior results, this interactive intervention for juvenile driving offenders resulted in a statistically significant reduction in driving-related offenses for the 6-month periods after its completion. This effect is lost in the long term. The role of booster interventions at 6 months and beyond, as adjuncts to initial interventional prevention initiatives, needs to be explored to aid sustained positive effects in this population of drivers. PMID- 21818030 TI - Retrograde intramedullary multiple pinning through the deltoid "V" for valgus impacted four-part fractures of the proximal humerus. AB - BACKGROUND: The "palm tree-like wiring" introduced by Kapandji and its modifications for proximal humeral fractures should be given the generic name "retrograde intramedullary multiple pinning through the deltoid 'V'" (IMPV). IMPV is still preferable for treating valgus-impacted four-part fractures in which K wires have the advantage of working as an internal fixation material as well as a tool in fracture reduction. METHODS: Three 2.4-mm K-wires formed into the desired shape are used as the intramedullary pins and a 3.0- to 3.2-mm upwardly angled hole for each wire is opened in the deltoid "V." After the tips of two wires are introduced into the lateral aspect of the head, the valgus deformity of the head is gradually corrected by alternately tapping the two wires under fluoroscopy. When the head and metaphysis are strongly compressed together, open reduction is attempted. If required, the tuberosity fragments are surgically reduced and stabilized. We performed IMPV on one C2.1 fracture and nine C2.2 fractures with 1 year or more follow-up. RESULTS: No nonunion was observed, but avascular head necrosis with collapse was observed in two C2.2 fractures, of which constant score ratios to the normal side were 55% and 64%, respectively. The constant score ratios of the other eight patients were 92% +/- 8% (70-96%). CONCLUSIONS: IMPV is considered to be a preferable reducing and stabilizing method for valgus impacted four-part fractures regardless of patient age. Additionally beneficial is being able to use the intramedullary pins as a tool for bone fragment reduction. PMID- 21818029 TI - Brief violence interventions with community case management services are effective for high-risk trauma patients. AB - BACKGROUND: Currently there are few data that brief violence intervention (BVI) and community case management services (CCMS) are effective for trauma patients admitted for interpersonal violence in terms of recidivism, service utilization, or alcohol abuse. The objective of this study is to assess outcomes for a cohort of young trauma patients in a prospective, randomized trial comparing BVI with BVI + CCMS. METHODS: Intentionally injured patients, aged 10 years to 24 years, admitted to a Level I trauma center were randomized to receive a brief in hospital psychoeducational violence intervention alone (Group I) or in combination with a 6 months wraparound CCMS (Group II) that included vocational, employment, educational, housing, mental health, and recreational assistance. Recidivism, alcohol use, and hospital and community service utilization were assessed at 6 weeks (6W) and 6 months (6M). RESULTS: Seventy-five of 376 eligible injured patients were randomized into Group I and II. The two groups had similar demographics, injuries, and clinical outcomes. After discharge, percent clinic visits maintained was 57% in both the groups. Group II showed better hospital service utilization, CMS, and risk factor reduction at 6W and 6M. One patient in each group sustained a reinjury at 6M. CONCLUSIONS: In-hospital BVI with community wraparound case management interventions can improve hospital and community service utilization both short- and long-term for high-risk injured patients. Longer follow-up is needed to show sustained reduction. PMID- 21818031 TI - Clinical decision rules for adults with minor head injury: a systematic review. AB - BACKGROUND: There are many clinical decision rules for adults with minor head injury, but it is unclear how they compare in terms of diagnostic accuracy. This study aimed to systematically identify clinical decision rules for adults with minor head injury and compare the estimated diagnostic accuracies for any intracranial injury and injury requiring neurosurgical intervention. METHODS: Several electronic bibliographic databases covering biomedical, scientific, and gray literature were searched from inception to March 2010. At least two independent reviewers determined the eligibility of cohort studies that described a clinical decision rule to identify adults with minor head injury (Glasgow Coma Scale score, 13-15) at risk of intracranial injury or injury requiring neurosurgical intervention. RESULTS: Twenty-two relevant studies were identified. Differences existed in patient selection, outcome definition, and reference standards used. Nine rules stratified patients into high- and moderate-risk categories (to identify neurosurgical or nonsurgical intracranial lesions). The Canadian Computed Tomography Head Rule (CCHR) high-risk criteria have sensitivity of 99% to 100% with specificity of 48% to 77% for injury requiring neurosurgical intervention. Other rules such as New Orleans criteria, National Emergency X Radiography Utilization Study II, Neurotraumatology Committee of the World Federation of Neurosurgical Societies, Scandinavian, and Scottish Intercollegiate Guidelines Network produce similar sensitivities for injury requiring neurosurgical intervention but with lower and more variable specificity values. DISCUSSION: The most widely researched decision rule is the CCHR, which has consistently shown high sensitivity for identifying injury requiring neurosurgical intervention with an acceptable specificity to allow considered use of cranial computed tomography. No other decision rule has been as widely validated or demonstrated as acceptable results, but its exclusion criteria make it difficult to apply universally. PMID- 21818033 TI - Increase in fall-related hospitalizations in the United States, 2001-2008. AB - BACKGROUND: The objective was to determine secular trends in unintentional fall related hospitalizations in people aged 65 years and older in the United States. MATERIALS: Data were obtained from a nationally representative sample of emergency department visits from January 1, 2001, to December 31, 2008, available through the National Electronic Injury Surveillance System-All Injury Program. These data were weighted to estimate the number, incidence rates, and the annual percent change of fall-related hospitalizations. RESULTS: From 2001 to 2008, the estimated number of fall-related hospitalizations in older adults increased 50%, from 373,128 to 559,355 cases. During the same time period, the age-adjusted incidence rate, expressed per 100,000 population, increased from 1,046 to 1,368. Rates were higher in women compared with men throughout the study period. The age adjusted incidence rate showed an average annual increase of 3.3% (95% CI, 1.66 4.95). DISCUSSION: Both the number and rate of fall-related hospitalizations in the United States increased significantly over the 8-year study period. Unless preventive action is taken, rising hospitalization rates in combination with the aging US population over the next decades will exacerbate the already stressed healthcare system and may result in poorer health outcomes for older adults in the future. Further research is needed to determine the underlying causes for this rising trend. PMID- 21818032 TI - Multidrug-resistant chronic osteomyelitis complicating war injury in Iraqi civilians. AB - BACKGROUND: War-related orthopedic injury is frequently complicated by environmental contamination and delays in management, placing victims at increased risk for long-term infectious complications. We describe, among Iraqi civilians with war-related chronic osteomyelitis, the bacteriology of infection at the time of admission. METHODS: In the Medecins Sans Frontieres Reconstructive Surgery Project in Amman, Jordan, we retrospectively reviewed baseline demographics and results of initial intraoperative surgical cultures among Iraqi civilians with suspected osteomyelitis. RESULTS: One hundred thirty-seven patients (90% male; median age, 35 years [interquartile range {IQR}, 28-46]; median time since initial injury, 19 months [IQR, 10-35]) were admitted with suspected chronic osteomyelitis after war-related injury. One hundred seven patients had a positive intraoperative culture. Before arrival, patients had undergone a median of 4 (IQR, 2-6) surgical procedures in Iraq. Fifty-nine (55%) of 107 patients with confirmed osteomyelitis had a multidrug-resistant (MDR) organism isolated at admission: cefepime-resistant Enterobacteriaceae (n = 40), methicillin-resistant Staphylococcus aureus (n = 16), and MDR Acinetobacter baumannii (n = 3). An association of borderline significance existed between a history of more than two prior surgical procedures in Iraq and an MDR isolate at program entry (multivariate: odds ratio, 5.3; 95% confidence interval, 0.9-30.6; p = 0.064). CONCLUSION: Health care actors, including Iraqi health facilities and humanitarian medical organizations, must be aware of the link between chronic war injury and antimicrobial drug resistance in this region and should be prepared for the management challenges involved with the treatment of chronic drug resistant osteomyelitis. PMID- 21818034 TI - Penetrating cardiac wounds identified by three-dimensional transesophageal echocardiography. PMID- 21818035 TI - Blunt heart trauma. PMID- 21818036 TI - Physiologically relevant application of airway pressure release ventilation. PMID- 21818037 TI - Pitfalls in computed tomography evaluation for mild head injuries in children. PMID- 21818038 TI - The relationship between international normalized ratio and development of hemorrhage with placement of ventriculostomy. PMID- 21818040 TI - Tourniquets on the battlefield: could N-acetylcysteine be useful? PMID- 21818041 TI - Electronic scooters: sweet tooth for danger? PMID- 21818042 TI - Cervical spine immobilization in the tactical environment. PMID- 21818043 TI - Decompressive craniectomy for diffuse cerebral swelling after trauma. PMID- 21818044 TI - Trauma surgeon clinical judgment versus modern imaging technologies. PMID- 21818045 TI - Triage protocol modifications to reduce undertriage. PMID- 21818047 TI - Proximal splenic arterial embolization may also result in pancreatic necrosis. PMID- 21818048 TI - Emergency medical services and emergency department thoracotomy. PMID- 21818049 TI - Preliminary experience in acute pain control for nonoperated hip fracture. PMID- 21818050 TI - Revision internal fixation and nonvascular fibular graft for femoral neck nonunion. PMID- 21818053 TI - Bleeding after sphincterotomy in liver transplanted patients with biliary complications. AB - OBJECTIVE: To investigate the rate of immediate persistent bleeding requiring haemostasis and of delayed bleeding after endoscopic sphincterotomy in liver transplanted patients. METHODS: Clinical records of patients who underwent endoscopic sphincterotomy at our Center between January 2003 and December 2009 were reviewed. Platelets count, international normalized ratio, aminosalicylic acid use, presence of cholangitis and use of precut were evaluated as risk factors for bleeding. Crude and adjusted risk ratios (RR) with 95% confidence interval were calculated, using Poisson model. RESULTS: Forty-nine liver transplanted patients and 202 controls were studied. Rate of delayed bleeding, but not need of immediate haemostasis, was increased in liver transplanted patients, RRs of 11.0 (3.0-40.0) and 1.5 (0.7-3.4) respectively. The RR of delayed bleeding remained unchanged once adjusted for the other evaluated variables. CONCLUSION: In liver transplanted patients, the risk of bleeding after endoscopic sphincterotomy is markedly increased. Reasons for this increase still need to be elucidated. PMID- 21818054 TI - Common variation in the vitamin D receptor gene and risk of inflammatory bowel disease in an Irish case-control study. AB - OBJECTIVE: Vitamin D may protect against the development of inflammatory bowel disease (IBD). Several preliminary studies in separate geographical locations suggest that these effects may be partly mediated by genetic variants of the vitamin D receptor (VDR). The data, however, are yet to be confirmed in large European cohorts. This study aimed to determine if common VDR polymorphisms affected IBD risk in an Irish population. MATERIALS AND METHODS: The study was based on a cohort of 1359 Irish participants. Frequencies of the common VDR gene polymorphisms rs2228570 (FokI), rs1544410 (BsmI), rs7975232 (ApaI), and rs731236 (TaqI) were determined using allele-specific PCR in a case-control analysis of 660 patients with IBD and 699 controls. Unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between these variants and risk of IBD. RESULTS: There was no statistically significant effect observed on IBD risk for any of the four VDR polymorphisms tested. Furthermore, no significant differences were observed in susceptibility when the population was stratified by sex or IBD subtype (Crohn's disease or ulcerative colitis). Notably, however, there was an increased risk observed for both IBD and ulcerative colitis associated with heterozygote carriage of the FokI allele that approached significance (OR=1.21, 95% CI=0.95 1.53, P=0.12 and OR=1.36, 95% CI=0.98-1.89, P=0.06, respectively), this merits further investigation. CONCLUSION: This study indicates that there is no major effect for common variation in the VDR gene alone on predisposition to IBD in the Irish population. PMID- 21818055 TI - Impact of mycophenolic acid and tacrolimus on Th17-related immune response. AB - BACKGROUND: Little is known on the impact of immunosuppressive drugs on the development of the different T-cell subsets that compose the immune balance. We have explored the influence of mycophenolic acid (MPA) and tacrolimus on T cells response with a special focus on the Th17-cell subset. METHODS: In an in vitro model of human CD4 cells activation, we first compared the influence of MPA and tacrolimus on the transcription of different set of genes related to each of the main T-cell subsets and then investigated how these two drugs interfere with interleukin (IL)-17 production. We also studied, in stable kidney transplant patients, the relation between IL-17 serum concentration and systemic drug exposure. RESULTS: MPA and tacrolimus exhibited a comparable impact on T-cell response, dampening most Th1-related genes transcription and preserving regulatory T cells/Th2 molecular phenotypes. Although both MPA and tacrolimus decreased Th17-related transcripts after T-cell activation, MPA exerted a stronger inhibitory effect on IL-17 production than tacrolimus. Accordingly, renal transplant patients treated with MPA in combination with minimized dose of tacrolimus tended to have lower circulating IL-17 levels than patients treated with tacrolimus alone given at conventional dose. CONCLUSIONS: A treatment combining MPA and tacrolimus is susceptible to favorably tip the immune balance and might confer optimal allograft immunoprotection. Because of its ability to profoundly inhibit IL-17 production, MPA may help to better overcome Th17-related alloreactivity in the context of calcineurin inhibitor-minimizing protocol. PMID- 21818056 TI - Perfluoro Allyl fluorosulfate (FAFS): a versatile building block for new fluoroallylic compounds. AB - In this study we will present and discuss both the synthesis of CF(2) = CFCF(2)OSO(2)F (perfluoroallyl fluorosulfate, FAFS), focusing in particular on the important role of C(3)F(6)/SO(3) ratio, reaction temperature and boron catalyst/SO(3) ratio on FAFS' yield and selectivity, as well as a wide variety of ionic and radical reactions possible with FAFS. We focused our attention on reactions of FAFS with aliphatic and aromatic alcohols, acyl halides, halides, H(2)O(2), ketones and radicals whose synthesis and reaction mechanisms will be presented and discussed. Particular attention will be devoted to the novel diallyl-fluoroalkyl peroxide obtained. Factors such as pK(a) and Lowry and Pearson's Hard/Soft Acid-Base Theory which determine the selectivity between Addition/Elimination vs. Nucleophilic Substitution reaction mechanisms on FAFS will also be presented and discussed. PMID- 21818057 TI - Rauniticine-allo-oxindole B and rauniticinic-allo acid B, new heteroyohimbine type oxindole alkaloids from the stems of Malaysian Uncaria longiflora var. pteropoda. AB - Two new heteroyohimbine-type oxindole alkaloids, rauniticine-allo-oxindole B and rauniticinic-allo acid B, have been successfully isolated from the stems extract of Malaysian Uncaria longiflora var. pteropoda. The structures of the two new alkaloids were determined by spectroscopic analysis. PMID- 21818058 TI - Synthesis and antimicrobial activity of some new pyrazoles, fused pyrazolo[3,4-d] pyrimidine and 1,2-dihydroimidazo-[2,1-c][1,2,4]triazin-6-one derivatives. AB - A novel series of 7,7-diphenyl-1,2-dihydroimidazo[2,1-c][1,2,4]triazin-6(7H)-one 6a-h, were easily prepared via reactions of novel 2-hydrazinyl-4,4-diphenyl-1H imidazol-5(4H)-one (2) with hydrazonoyl halides 3a-h. In addition, we also examined the reaction of compound 2 with commercially available active methylene compounds to afford new pyrazoles containing an imidazolone moiety, expected to be biologically active. The structures of the synthesized compounds were assigned on the basis of elemental analysis, IR, 1H-NMR and mass spectral data. The antifungal and antibacterial activities of the newly synthesized compounds were evaluated. PMID- 21818059 TI - Synthesis of new pentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecane-8,11-dione (PCU) cyanosilylated derivatives using sulphated zirconia and hydrotalcite as catalysts in microwave-assisted reactions under solvent free conditions. AB - A comparison was made of the effectiveness of the functionalization reactions of pentacyclo[5.4.0.0(2,6).0(3,10).0(5,9)]undecane-8,11-dione (PCU) using sulphated zirconia in protection-deprotection reactions and Mg/Al hydrotalcite in a cyanosilylation reaction, under classical thermal conditions and imposing microwave radiation; improved yields and reaction times were considered. PMID- 21818060 TI - Isoconiferoside, a new phenolic glucoside from seeds of Panax ginseng. AB - A new phenolic glucoside, isoconiferoside (1), was isolated from the seeds of Panax ginseng (Araliaceae). The structure was determined to be 9-O-[beta-D glucopyranosyl-(1 --> 6)-beta-D-glucopyranosyl]-trans-coniferyl alcohol based on spectroscopic analyses (1H- and 13C-NMR, DEPT, COSY, HMQC, and HMBC) and acid hydrolysis. PMID- 21818061 TI - (+)-Kunstlerone, a new antioxidant neolignan from the Leaves of Beilschmiedia kunstleri gamble. AB - A new neolignan, 3,4-dimethoxy-3',4'-methylenedioxy-2,9-epoxy-6,7-cyclo-1,8 neolign-11-en-5(5H)-one, which has been named (+)-kunstlerone (1), together with six known alkaloids: (+)-norboldine (2), (+)-N-methylisococlaurine (3), (+) cassythicine (4), (+)-laurotetanine (5), (+)-boldine (6) and (-)-pallidine (7), were isolated from the leaves of Beilschmiedia kunstleri. The structures were established through various spectroscopic methods notably 1D- and 2D-NMR, UV, IR and LCMS-IT-TOF. (+)- Kunstlerone (1) showed a strong antioxidant activity, with an SC(50) of 20.0 ug/mL. PMID- 21818062 TI - Breast pump suction patterns that mimic the human infant during breastfeeding: greater milk output in less time spent pumping for breast pump-dependent mothers with premature infants. AB - OBJECTIVE: The objective of this study was to compare the effectiveness, efficiency, comfort and convenience of newly designed breast pump suction patterns (BPSPs) that mimic sucking patterns of the breastfeeding human infant during the initiation and maintenance of lactation. STUDY DESIGN: In total, 105 mothers of premature infants <=34 weeks of gestation were randomly assigned to 1 of 3 groups within 24 h post-birth. Each group tested two BPSPs; an initiation BPSP was used until the onset of lactogenesis II (OOL-II) and a maintenance BPSP was used thereafter. RESULT: Mothers who used the experimental initiation and the standard 2.0 maintenance BPSPs (EXP-STD group) demonstrated significantly greater daily and cumulative milk output, and greater milk output per minute spent pumping. CONCLUSION: BPSPs that mimic the unique sucking patterns used by healthy term breastfeeding infants during the initiation and maintenance of lactation are more effective, efficient, comfortable and convenient than other BPSPs. PMID- 21818063 TI - Covered skin transcutaneous bilirubin estimation is comparable with serum bilirubin during and after phototherapy. AB - OBJECTIVE: To determine whether transcutaneous bilirubin (TcB) from covered skin (TcB-C) during and after discontinuing phototherapy (PHT) is reliable in treating neonatal jaundice. STUDY DESIGN: In this prospective observational study, before starting PHT, part of the forehead was covered. TcB-C and TcB from exposed skin (TcB-E) to PHT were measured before starting PHT, on a 12-hourly basis while receiving PHT and 6 h after stopping PHT. We used ANOVA (analysis of variance) and Bonferroni's t-tests. RESULT: A total of 39 infants were enrolled (mean gestation 39 weeks, 51% males and 80% Hispanic). The mean TSB over all time periods was 10.9+/-2.4, TcB-C 10.9+/-2.4 and TcB-E 7.2+/-3.4. Before PHT, there were no significant differences in bilirubin by all three techniques. TcB-C was not significantly different from TSB at any time point. However, TcB-E was significantly lower during PHT and after stopping PHT. CONCLUSION: TcB-C is a reliable method in the management of neonatal jaundice. PMID- 21818064 TI - What happens when the patent ductus arteriosus is treated less aggressively in very low birth weight infants? AB - OBJECTIVE: It remains unclear whether indomethacin (INDO) and/or surgical ligation (LIGATE) are necessary to improve outcomes in premature infants with a patent ductus arteriosus (PDA). We have adopted a conservative approach to PDA management that emphasizes waiting for spontaneous closure unless certain cardiorespiratory distress criteria are met. STUDY DESIGN: This was a before after observational study in infants born 501 to 1,500 g in two distinct epochs. Era 1 (January 2005 to December 2007) featured traditional management with INDO and LIGATE used early to close all moderate and large PDAs in infants receiving any respiratory support. Era 2 (January 2008 to June 2009) emphasized modest fluid restriction, watchful waiting and limited INDO and LIGATE to only those infants with large PDAs who met certain cardiorespiratory distress criteria. RESULT: Era 1 included 139 infants with a PDA, mean (s.d.) gestational age 27.5 (2) weeks; Era 2 72 infants, mean (s.d.) gestational age 27.5 (2) weeks. In Era 2, INDO use significantly decreased (79% of infants to 26%, P<0.001), and 28 day total fluids decreased (140 vs. 130 ml kg(-1) day(-1), P<0.001). LIGATE rate was 45% in Era 1, 33% in Era 2 (P=0.11). There were no significant differences in supplemental oxygen, nasal continuous positive airway pressure, or mechanical ventilation days. There were no significant differences in mortality or individual morbidities. The combined outcome of chronic lung disease (CLD) or mortality after Day 7 significantly increased (Era 1, 40%, Era 2, 54%, P=0.04). More infants were discharged home with a PDA in Era 2, but most resolved spontaneously and the need for closure therapy after discharge from the neonatal intensive care unit (NICU) did not increase. Multiple regression analysis demonstrated Era 2 management did not predict an increased risk of one or more interlinked morbidities. CONCLUSION: Tolerance of the PDA with watchful waiting for spontaneous closure, modest fluid reduction, and less INDO use is a reasonable treatment strategy that is not associated with significant changes in NICU mortality or individual morbidities. We did note an increase in the combined outcome of CLD or mortality after Day 7, thus our investigation supports the urgency of a randomized controlled trial comparing traditional PDA management with a true control group similar to our Era 2 management to answer important questions of short and long-term outcomes. PMID- 21818065 TI - Difficult decisions. PMID- 21818066 TI - Exploratory grant scheme abandoned after failing to meet its goals. PMID- 21818067 TI - Overstretched medical mystery program takes a breather. PMID- 21818068 TI - Abuse-resistant painkillers get mixed FDA response. PMID- 21818070 TI - US switch to first-to-file patents could cause minor shake-up. PMID- 21818071 TI - New technologies aim to take shock out of treating irregular hearts. PMID- 21818072 TI - Combo antibody efforts up, despite regulatory uncertainties. PMID- 21818074 TI - Shuttle's end could spell a bumpy ride for biomedicine in space. PMID- 21818075 TI - Straight talk with... Maria Blasco. Interview by Elie Dolgin. PMID- 21818077 TI - Double-duty discovery. PMID- 21818078 TI - A ballsy search for cancer targets. PMID- 21818079 TI - It's time for a centralized registry of laboratory-acquired infections. PMID- 21818082 TI - To march in or not to march in. PMID- 21818083 TI - Immune response also connects autism and epilepsy. PMID- 21818084 TI - Carvedilol tweaks calcium release to ease arrhythmias. PMID- 21818085 TI - A step toward slaying the hydra of second cancers. PMID- 21818086 TI - A suPAR circulating factor causes kidney disease. PMID- 21818087 TI - Killing the messenger to maintain control of HIV. PMID- 21818088 TI - Treg cells: patrolling a dangerous neighborhood. PMID- 21818089 TI - A ribosomal tactic to halt cancer. PMID- 21818090 TI - Alzheimer's therapy: a BACE in the hand? PMID- 21818091 TI - miRNAs in the spotlight: Making 'silent' mutations speak up. PMID- 21818092 TI - miRNAs in the spotlight: Understanding cancer gene dependency. PMID- 21818095 TI - More knowledge of worldwide incidence and epidemiology of spinal cord injury: data from the United States military. PMID- 21818096 TI - Trauma and the wise baby. AB - This paper expands upon Ferenczi's concept of the wise baby and explores the dynamics of ignorance and compensatory ideals of wisdom as reactions to trauma and as manifestations of "double conscience," shame dynamics and Oedipal shame. Focusing on feelings of ignorance, of knowing and not knowing and their relation to trauma, the author elaborates on the dynamics of fantasies of wisdom, adumbrating implications for psychoanalytic technique. PMID- 21818097 TI - Corrective emotional experience remembered. AB - The paper examines on the one hand the influence of the Berlin Institute in the 1920s on Franz Alexander's training and on his later work, as it was a workshop aiming to test the possibilities of a large utilization of psychoanalytic therapy in an institutional framework. On the other hand, the spirit of experimentation of Sandor Ferenczi and the endeavor to enhance the effectiveness and efficiency of psychoanalysis by the use of countertransference and emotional exchange also became important for Alexander. A glimpse of recent researches on Freud's timetable gives background information with possible comparisons between Freud's technique and that of Alexander. PMID- 21818098 TI - The talking cure as action: Freud's theory of ritual revisited. AB - Freud made creative use of late Victorian theories of ritual as empty modes of behavior, using the idea of "seemingly meaningless" ritual to offer a compelling comparison with obsessive behavior. However, analytic hours, with their repetitive frame and repetition of unconscious conflicts, have stronger links with rituals than Freud admitted. Recent theories highlight the extensive power of rituals to organize and instantiate models of effective action, especially in terms of the multifunctionality of language. These new theories of ritual offer in turn new tools for understanding the therapeutic action of analytic hours. PMID- 21818099 TI - Deconstructing hermes: a critique of the hermeneutic turn in psychoanalysis. AB - In this brief essay, I attempt to critique some of the philosophical problematics inherent with the hermeneutic turn in psychoanalysis. The proposition that "there are only interpretations of interpretations" leads to an inescapable circularity because interpretation ultimately lacks a referent or criterion for which to anchor meaning. If we follow this proposition through to its logical end, this ultimately collapses into relativism because meaning is relative to its interpretive scheme, which further relies on other interpretative schemata for which there are no definitive definitions, conclusive consensus, or universal laws governing interpretation. How can hermeneutics escape the charge of circularity, infinite regress, disavowal of universals, its tacit relativism, and the failure to provide a consensus or criteria for interpretation? How is psychoanalysis able to philosophically justify interpretative truth claims when they potentially inhere to a recalcitrant subjectivism while claiming to be objectively valuative? PMID- 21818100 TI - Striving toward useful interpretation while managing countertransference enactments: encounters with a thick-skinned narcissistic person. AB - Narcissistic patients tend to push the analyst to work harder than usual to contain, understand, translate, and utilize their countertransference states. This is because of the unusually extreme reliance on denial, devaluation, projective identification, and control that these individuals exhibit. Defenses against loss, envy, greed, and dependence create difficult transference states in which symbolic or creative material is flattened, stripped, and neutralized. Feelings are out of the question. This clinical paper explores the narcissistic lack of connection to self and other that endures in the transference as well as in all aspects of these patients' lives. With thick-skinned narcissistic patients, there is a subtle lack of engagement, an underbelly of control, and a complete uncoupling of feeling or link between self and object. Envy is often a cornerstone of such difficult clinical problems and is part of an internal desolation that fuels an emotional firebombing of any awareness of interest in self or other. Detailed case material is used to show how confusing, alarming, and demanding such narcissistic patients can be, trying the very essence of the analytic process. They enter treatment looking for help, wanting a quick fix to their suffering, but resist the deeper understanding, learning, and change that psychoanalytic treatment offers. PMID- 21818101 TI - Defensive sexualization: a neurobiologically informed explanatory model. AB - Sexualization is a defense mechanism frequently referred to in clinical psychoanalytic literature. Despite this, there is no research linking the theoretical nature of this observed phenomenon to social or neurobiological theory. This discussion paper proposes an interaction between social learning and neural maturation in the development of sexualized tendencies. When anxiety within peer interactions is alleviated repeatedly through sexualized behavior, learned associations develop. This explanation allows understanding and empathy for individuals demonstrating a broad spectrum of sexualized responses since such learning is argued to be functional within their historic social climate. PMID- 21818102 TI - Groddeckian interventions in medical settings. AB - We present Groddeckian psychoanalytic psychosomatics in practice through two case studies. Groddeck pioneered the application of psychoanalysis to organic diseases, but his ideas have not been explored adequately. It is necessary to reappraise his concepts to develop their potential in psychoanalysis. We aim to demonstrate the efficacy of the Groddeckian approach by presenting two cases: a case of conversion of a boy who entered a semi-comatose state due to unattended emotional experiences and a man who developed a "sick role" resisting all medical interventions. In both histories, it is possible to see how disease and subjectivity intertwine in a complex unity of mind and body. PMID- 21818103 TI - Is psychoanalytic education effective?: comment on Damsa et al. (2010). AB - While a growing body of empirical data attests increasingly to the efficacy of psychoanalytic treatment, what data do we have that attests to the effectiveness of psychoanalytic education? In this comment on Damsa et al. (2010), I briefly address that question and suggest that-if we are to truly generate passionate interest in psychoanalysis among psychiatric residents and other mental health professionals in training-perhaps we need to begin by researching the largely unresearched process of psychoanalytic education and supervision. PMID- 21818107 TI - Antcin A contributs to anti-inflammatory effect of Niuchangchih (Antrodia camphorata). PMID- 21818108 TI - Vasorelaxant and antihypertensive effects of formononetin through endothelium dependent and -independent mechanisms. AB - AIM: To investigate the mechanisms underlying the vasorelaxant effect of formononetin, an O-methylated isoflavone, in isolated arteries, and its antihypertensive activity in vivo. METHODS: Arterial rings of superior mesenteric arteries, renal arteries, cerebral basilar arteries, coronary arteries and abdominal aortas were prepared from SD rats. Isometric tension of the arterial rings was recorded using a myograph system. Arterial pressure was measured using tail-cuff method in spontaneously hypertensive rats. RESULTS: Formononetin (1-300 MUmol/L) elicited relaxation in arteries of the five regions that were pre contracted by KCl (60 mmol/L), U46619 (1 MUmol/L) or phenylephrine (10 MUmol/L). The formononetin-induced relaxation was reduced by removal of endothelium or by pretreatment with L-NAME (100 MUmol/L). Under conditions of endothelium denudation, formononetin (10, 30, and 100 MUmol/L) inhibited the contraction induced by KCl and that induced by CaCl(2) in Ca(2+)-free depolarized medium. In the absence of extracellular Ca(2+), formononetin (10, 30, and 100 MUmol/L) depressed the constriction caused by phenylephrine (10 MUmol/L), but did not inhibit the tonic contraction in response to the addition of CaCl(2) (2 mmol/L). The contraction caused by caffeine (30 mmol/L) was not inhibited by formononetin (100 MUmol/L). Formononetin (10 and 100 MUmol/L) reduced the change rate of Ca(2+)-fluorescence intensity in response to KCl (50 mmol/L). In spontaneously hypertensive rats, formononetin (5, 10, and 20 mg/kg) slowly lowered the systolic, diastolic and mean arterial pressure. CONCLUSION: Formononetin causes vasodilatation via two pathways: (1) endothelium-independent pathway, probably due to inhibition of voltage-dependent Ca(2+) channels and intracellular Ca(2+) release; and (2) endothelium-dependent pathway by releasing NO. Both the pathways may contribute to its antihypertensive effect. PMID- 21818109 TI - Vasodilator efficiency of endogenous prostanoids, Ca2+-activated K+ channels and nitric oxide in rats with spontaneous, salt-dependent or NO-deficient hypertension. AB - Hypertension is associated with the imbalance of vasoconstrictor and vasodilator systems. Vasodilation is usually evaluated in isolated blood vessels, but except for nitric oxide (NO), relatively little attention is given to the in vivo efficiency of particular vasodilator mechanisms. The aim of our study was to evaluate the contribution of endogenous vasodilator prostanoids, Ca(2+)-activated K(+) channels and NO to blood pressure (BP) maintenance in rats with three different forms of experimental hypertension. Both principal vasopressor systems (the renin-angiotensin system and the sympathetic nervous system) were blocked by captopril and pentolinium in conscious spontaneously hypertensive rats (SHRs), Dahl salt-hypertensive (DS-HS) rats and rats with NO-deficient hypertension, as well as in their normotensive controls. Thereafter, we monitored BP changes in rats subjected to either a sequential or an isolated blockade of prostanoid synthesis by the non-selective cyclooxygenase inhibitor, indomethacin, of Ca(2+) activated K(+) channels by tetraethylammonium and of NO formation by N(G)-nitro-L arginine methyl ester. All three forms of experimental hypertension were characterized by augmented sympathetic vasoconstriction. The vasodilatation exerted by endogenous prostanoids and Ca(2+)-activated K(+) channels was enhanced in all forms of hypertension, almost proportionally to BP elevation. On the contrary, NO-dependent vasodilatation was not enhanced in any form of experimental hypertension, and there was a severe relative NO deficiency in both, SHRs and DS-HS rats. In conclusion, our data suggested that there is a compensatory activation of vasodilator prostanoids and Ca(2+)-activated K(+) channels in rats with experimental hypertension, whereas NO-dependent vasodilatation is not augmented. Thus, the overall activity of vasodilator systems failed to compensate for augmented sympathetic vasoconstriction in hypertensive animals. PMID- 21818112 TI - Dynamics of the emergence of dasatinib and nilotinib resistance in imatinib resistant CML patients. PMID- 21818111 TI - Limited clinical activity of nilotinib and sorafenib in FIP1L1-PDGFRA positive chronic eosinophilic leukemia with imatinib-resistant T674I mutation. PMID- 21818113 TI - Modern concepts in the biology, diagnosis, differential diagnosis and treatment of primary central nervous system lymphoma. AB - Recent studies addressing the molecular characteristics of PCNSL, which is defined as malignant B-cell lymphoma with morphological features of DLBCL, have significantly improved our understanding of the pathogenesis of this lymphoma entity, which is associated with an inferior prognosis as compared with DLBCL outside the CNS. This unfavorable prognosis stimulated intense efforts to improve therapy and induced recent series of clinical studies, which addressed the role of radiotherapy and various chemotherapeutic regimens. This review combines the discussion of diagnosis, differential diagnosis and recent progress in studies addressing the molecular pathogenesis as well as therapeutic options in PCNSL. PMID- 21818114 TI - Clinical value of flow cytometric immunophenotypic analysis for minimal residual disease detection in autologous stem-cell products of follicular and mantle cell lymphomas. PMID- 21818115 TI - Array-based DNA methylation analysis in classical Hodgkin lymphoma reveals new insights into the mechanisms underlying silencing of B cell-specific genes. PMID- 21818116 TI - Constitutive activation of STAT3 in Sezary syndrome is independent of SHP-1. AB - Constitutive and persistent activation of STAT3 has been implicated in the pathogenesis of many malignancies. Studies of CTCL cell lines have previously suggested that aberrant activation of STAT3 is mediated via silencing of the negative regulator SHP-1 by promoter methylation. In this study of ex vivo tumour cell populations from 18 Sezary syndrome (SS) patients, constitutive phosphorylation of STAT3, JAK1 and JAK2 was present in all patients, but was absent in comparative CD4+ T-cells from healthy controls. Furthermore, no loss or significant difference in SHP-1 expression was observed between patients and healthy control samples. Methylation-specific PCR analysis of the SHP-1 CpG island in 47 SS patients and 11 healthy controls did not detect any evidence of methylation. Moreover, small interfering RNA knockdown of SHP-1 had no effect on phosphorylation of STAT3. In contrast, treatment of SS tumour cells with the pan JAK inhibitor pyridone 6 led to downregulation of phosphorylated STAT3 (pSTAT3), its target genes and induction of apoptosis. No evidence for common JAK1/JAK2 activating mutations was found. These data demonstrate that constitutive activation of STAT3 in SS is not due to the loss of SHP-1, but is mediated by constitutive aberrant activation of JAK family members. PMID- 21818117 TI - Selective regulation of IP3-receptor-mediated Ca2+ signaling and apoptosis by the BH4 domain of Bcl-2 versus Bcl-Xl. AB - Antiapoptotic B-cell lymphoma 2 (Bcl-2) targets the inositol 1,4,5-trisphosphate receptor (IP(3)R) via its BH4 domain, thereby suppressing IP(3)R Ca(2+)-flux properties and protecting against Ca(2+)-dependent apoptosis. Here, we directly compared IP(3)R inhibition by BH4-Bcl-2 and BH4-Bcl-Xl. In contrast to BH4-Bcl-2, BH4-Bcl-Xl neither bound the modulatory domain of IP(3)R nor inhibited IP(3) induced Ca(2+) release (IICR) in permeabilized and intact cells. We identified a critical residue in BH4-Bcl-2 (Lys17) not conserved in BH4-Bcl-Xl (Asp11). Changing Lys17 into Asp in BH4-Bcl-2 completely abolished its IP(3)R-binding and inhibitory properties, whereas changing Asp11 into Lys in BH4-Bcl-Xl induced IP(3)R binding and inhibition. This difference in IP(3)R regulation between BH4 Bcl-2 and BH4-Bcl-Xl controls their antiapoptotic action. Although both BH4-Bcl-2 and BH4-Bcl-Xl had antiapoptotic activity, BH4-Bcl-2 was more potent than BH4-Bcl Xl. The effect of BH4-Bcl-2, but not of BH4-Bcl-Xl, depended on its binding to IP(3)Rs. In agreement with the IP(3)R-binding properties, the antiapoptotic activity of BH4-Bcl-2 and BH4-Bcl-Xl was modulated by the Lys/Asp substitutions. Changing Lys17 into Asp in full-length Bcl-2 significantly decreased its binding to the IP(3)R, its ability to inhibit IICR and its protection against apoptotic stimuli. A single amino-acid difference between BH4-Bcl-2 and BH4-Bcl-Xl therefore underlies differential regulation of IP(3)Rs and Ca(2+)-driven apoptosis by these functional domains. Mutating this residue affects the function of Bcl-2 in Ca(2+) signaling and apoptosis. PMID- 21818118 TI - HIF-1alpha is critical for hypoxia-mediated maintenance of glioblastoma stem cells by activating Notch signaling pathway. AB - Hypoxia induces the expansion of glioblastoma stem cells (GSCs), but the mechanism underlying it is still unclear. Here, we supply evidence that hypoxia inducible factor-1alpha (HIF-1alpha) induced activation of Notch pathway is essential for hypoxia-mediated maintenance of GSC. Either depletion of HIF-1alpha or inactivation of Notch signaling partly inhibits the hypoxia-mediated maintenance of GSC. Further data suggest a role for HIF-1alpha in the interaction and stabilization of intracellular domain of Notch (NICD), and activation of Notch signaling. The mRNA level of HIF-1alpha and Notch target gene FABP7 was elevated in GSC. And the STAT3 pathway responsible for the HIF-1alpha gene transcription, the phosphatidylinositol 3-kinase-Akt and ERK1/2, both of which are contributed to HIF-1alpha protein translation, are also preferentially activated in GSC. Inhibition of these pathways partly reduces the hypoxia-induced activation of the Notch pathway and subsequent GSC maintenance. Taken together, our findings suggest that HIF-1alpha requires Notch pathway to drive the maintenance of GSC. The activated regulation of HIF-1alpha makes GSC more sensitive to hypoxia-mediated maintenance. These findings enhance our understanding of mechanism of hypoxia-mediated GSC expansion and provide HIF 1alpha as an attractive target for glioblastoma therapy. PMID- 21818119 TI - Lanosterol induces mitochondrial uncoupling and protects dopaminergic neurons from cell death in a model for Parkinson's disease. AB - Parkinson's disease (PD) is a neurodegenerative disorder marked by the selective degeneration of dopaminergic neurons in the nigrostriatal pathway. Several lines of evidence indicate that mitochondrial dysfunction contributes to its etiology. Other studies have suggested that alterations in sterol homeostasis correlate with increased risk for PD. Whether these observations are functionally related is, however, unknown. In this study, we used a toxin-induced mouse model of PD and measured levels of nine sterol intermediates. We found that lanosterol is significantly (~50%) and specifically reduced in the nigrostriatal regions of 1 methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice, indicative of altered lanosterol metabolism during PD pathogenesis. Remarkably, exogenous addition of lanosterol rescued dopaminergic neurons from 1-methyl-4-phenylpyridinium (MPP+) induced cell death in culture. Furthermore, we observed a marked redistribution of lanosterol synthase from the endoplasmic reticulum to mitochondria in dopaminergic neurons exposed to MPP+, suggesting that lanosterol might exert its survival effect by regulating mitochondrial function. Consistent with this model, we find that lanosterol induces mild depolarization of mitochondria and promotes autophagy. Collectively, our results highlight a novel sterol-based neuroprotective mechanism with direct relevance to PD. PMID- 21818120 TI - The circadian mutation PER2(S662G) is linked to cell cycle progression and tumorigenesis. AB - Circadian oscillation and cell cycle progression are the two most essential rhythmic events present in almost all organisms. Circadian rhythms keep track of time and provide temporal regulation with a period of about 24 h. The cell cycle is optimized for growth and division, but not for time keeping. Circadian gated cell divisions are observed in nearly all organisms. However, the implications of this coupling to the physiology of mammals are unknown. A mutation (S662G) in the clock protein PERIOD2 (PER2) is responsible for familial advanced sleep phase syndrome in which sleep onset occurs in the early evening and wakefulness occurs in the early morning. Here, we provide evidence that the PER2(S662) mutation leads to enhanced resistance to X-ray-induced apoptosis and increased E1A- and RAS-mediated oncogenic transformation. Accordingly, the PER2(S662) mutation affects tumorigenesis in cancer-sensitized p53(R172H/+) mice. Finally, analyzing the clock-controlled cell cycle genes p21, c-Myc, Cyclin D1 and p27, we found that the relative phases between p21 and Cyclin D expression profiles have been changed significantly in these Per2 allele mutant mouse embryonic fibroblasts. This key role of the Per2-mediated phase alteration of p21 provides what we believe to be a novel mechanism in understanding cell cycle progression, its plasticity and its resistance to interference. PMID- 21818121 TI - Pancreatic beta-cell prosurvival effects of the incretin hormones involve post translational modification of Kv2.1 delayed rectifier channels. AB - Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are the major incretin hormones that exert insulinotropic and anti apoptotic actions on pancreatic beta-cells. Insulinotropic actions of the incretins involve modulation of voltage-gated potassium (Kv) channels. In multiple cell types, Kv channel activity has been implicated in cell volume changes accompanying initiation of the apoptotic program. Focusing on Kv2.1, we examined whether regulation of Kv channels in beta-cells contributes to the prosurvival effects of incretins. Overexpression of Kv2.1 in INS-1 beta-cells potentiated apoptosis in response to mitochondrial and ER stress and, conversely, co-stimulation with GIP/GLP-1 uncoupled this potentiation, suppressing apoptosis. In parallel, incretins promoted phosphorylation and acetylation of Kv2.1 via pathways involving protein kinase A (PKA)/mitogen- and stress-activated kinase-1 (MSK-1) and histone acetyltransferase (HAT)/histone deacetylase (HDAC). Further studies demonstrated that acetylation of Kv2.1 was mediated by incretin actions on nuclear/cytoplasmic shuttling of CREB binding protein (CBP) and its interaction with Kv2.1. Regulation of beta-cell survival by GIP and GLP-1 therefore involves post-translational modifications (PTMs) of Kv channels by PKA/MSK-1 and HAT/HDAC. This appears to be the first demonstration of modulation of delayed rectifier Kv channels contributing to the beta-cell prosurvival effects of incretins and of 7-transmembrane G protein-coupled receptor (GPCR) stimulated export of a nuclear lysine acetyltransferase that regulates cell surface ion channel function. PMID- 21818122 TI - Tankyrase-1 function at telomeres and during mitosis is regulated by Polo-like kinase-1-mediated phosphorylation. AB - Telomere length is critical for chromosome stability that affects cell proliferation and survival. Telomere elongation by telomerase is inhibited by the telomeric protein, TRF1. Tankyrase-1 (TNKS1) poly(ADP-ribosyl)ates TRF1 and releases TRF1 from telomeres, thereby allowing access of telomerase to the telomeres. TNKS1-mediated poly(ADP-ribosyl)ation also appears to be crucial for regulating the mitotic cell cycle. In searching for proteins that interact with polo-like kinase-1 (Plk1) by using complex proteomics, we identified TNKS1 as a novel Plk1-binding protein. Here, we report that Plk1 forms a complex with TNKS1 in vitro and in vivo, and phosphorylates TNKS1. Phosphorylation of TNKS1 by Plk1 appears to increase TNKS1 stability and telomeric poly(ADP-ribose) polymerase (PARP) activity. By contrast, targeted inhibition of Plk1 or mutation of phosphorylation sites decreased the stability and PARP activity of TNKS1, leading to distort mitotic spindle-pole assembly and telomeric ends. Taken together, our results provide evidence of a novel molecular mechanism in which phosphorylation of TNKS1 by Plk1 may help regulate mitotic spindle assembly and promote telomeric chromatin maintenance. PMID- 21818123 TI - The anti-inflammatory effects of exercise: mechanisms and implications for the prevention and treatment of disease. AB - Regular exercise reduces the risk of chronic metabolic and cardiorespiratory diseases, in part because exercise exerts anti-inflammatory effects. However, these effects are also likely to be responsible for the suppressed immunity that makes elite athletes more susceptible to infections. The anti-inflammatory effects of regular exercise may be mediated via both a reduction in visceral fat mass (with a subsequent decreased release of adipokines) and the induction of an anti-inflammatory environment with each bout of exercise. In this Review, we focus on the known mechanisms by which exercise - both acute and chronic - exerts its anti-inflammatory effects, and we discuss the implications of these effects for the prevention and treatment of disease. PMID- 21818125 TI - T cells: mTOR lullabies for naive T cells. PMID- 21818124 TI - Reciprocal regulation of the neural and innate immune systems. AB - Innate immune responses are regulated by microorganisms and cell death, as well as by a third class of stress signal from the nervous and endocrine systems. The innate immune system also feeds back, through the production of cytokines, to regulate the function of the central nervous system (CNS), and this has effects on behaviour. These signals provide an extrinsic regulatory circuit that links physiological, social and environmental conditions, as perceived by the CNS, with transcriptional 'decision-making' in leukocytes. CNS-mediated regulation of innate immune responses optimizes total organism fitness and provides new opportunities for therapeutic control of chronic infectious, inflammatory and neuropsychiatric diseases. PMID- 21818126 TI - T cell responses: Anger management for T(H)17 cells. PMID- 21818127 TI - Three horizontal muscle surgery for large-angle infantile esotropia: validation of a table of amounts of surgery. AB - PURPOSE: To validate a table of amounts of three horizontal muscle surgery in patients with large-angle infantile esotropia (>=60 prism dioptres, PD). METHODS: A prospective interventional case series reporting the postoperative alignment of 51 patients (27 male, 24 female) over a 15-year period was conducted. Surgery amounts were according to a published table developed on a previous patient cohort (n=49), using bilateral medial rectus recession with graded unilateral lateral rectus resection. Kaplan-Meier life-table survival curves were formulated for success to orthotropia (+/-10 PD) after one and subsequent horizontal muscle surgeries for up to 8 years follow-up. RESULTS: The median preoperative deviation was 65 PD (range 60-80 PD) and median age at surgery was 11.8 months (range 5.1 months-3.6 years). Surgical success to orthotropia (+/-10 PD) after one surgery was 100% at 2 months, 95.7% at 6 months, 91.3% at 12 months, 77.8% at 4 years, and 73.6% at 8 years. Postoperative failure requiring further horizontal surgery occurred in 17.6% (residual esotropia 4, consecutive exotropia 5). CONCLUSIONS: Our second cohort has reproduced the success rate of the previous cohort (77.8% vs 77.1% at 4 years). If the published table of surgical amounts is used, three horizontal muscle surgery in large-angle infantile esotropia (>=60 PD) appears to have a good long-term success rate, and does not lead to the high rates of either residual esotropia or consecutive exotropia reported by others in the literature. PMID- 21818128 TI - Reversible corneal epitheliopathy caused by vitamin B12 and folate deficiency in a vegan with a genetic mutation: a new disease. PMID- 21818129 TI - Hyperthyroid vs hypothyroid eye disease: the same severity and activity. AB - PURPOSE: To compare demographics, severity, and activity of thyroid eye disease (TED) in patients with hyperthyroidism (Hr-TED) vs primary hypothyroidism (Ho TED). PATIENTS AND METHODS: In a cross-sectional study, demographics, complete eye examination, severity score (NOSPECS, total hundred eye score), clinical activity score, and Rundle grading were recorded for patients with TED and different thyroid disorders referred from an endocrinology clinic from 2003 to 2006. RESULTS: TED was clinically found in 303 patients (303/851, 35.6%). The majority of them (280/303, 92.4%) had Graves' hyperthyroidism and 23 (23/303, 7.5%) had primary hypothyroidism. Mean age, gender, mean severity score, mean activity score, Rundle grade, unilateral presentation of TED, smoking habit, mean duration of eye disease, and mean interval time of thyroid to TED were not significantly different between the two groups (0.06=60 years, whose vitamin D levels were taken as part of routine examinations between 2000 and 2008. METHODS: All data for this study were obtained from MHS databases that include medical information on 1.8 million subscribers. MAIN OUTCOME MEASURES: Serum 25-OH vitamin D levels. RESULTS: The total study population comprised of 1045 members diagnosed as having AMD, and 8124 as non-AMD, for whom there was information on vitamin D levels. The mean+/-SD level of 25-OH vitamin D was 24.1+/-9.41 ng/ml (range 0.8-120) for the AMD patients and 24.13+/-9.50 ng/ml (range 0.0-120) for the controls (P=ns). One third (33.6%) of the AMD patients and 32.86% of the controls had a 25-OH vitamin D level <16 ng/ml, and the proportions of tests in which the 25-OH vitamin D level was >74 ng/ml were 0.19 and 0.14%, respectively (P=ns). CONCLUSIONS: No association was detected between vitamin D levels and the presence of AMD in this cross-sectional study. These results raise some doubt about an association between reduced vitamin D levels and the prevalence of AMD. PMID- 21818135 TI - Selective modification of HK peptides enhances siRNA silencing of tumor targets in vivo. AB - Our research has focused on systemic delivery of small interference RNA (siRNA) by branched peptides composed of histidine and lysine. After studying several histidine-lysine (HK) peptides, one four-branched peptide, H3K(+H)4b, with a predominant repeating pattern of -HHHK-, was found to be an effective carrier of siRNA. Although the unmodified H3K(+H)4b carrier of siRNA targeting an oncogene was previously shown to have promise in a tumor-bearing mouse model, we sought to develop a more effective HK carrier of siRNA in this study. Our primary goal was to determine whether different ligand (cyclic RGD)-pegylation patterns on the H3K(+H)4b peptide affect siRNA delivery in vitro and in vivo. We compared the unmodified H3K(+H)4b with two modified H3K(+H)4b peptides for their ability to deliver siRNA in a tumor-bearing mouse model; one modified HK peptide, (RGD PEG)(4)-H3K(+H)4b, had four cyclic RGD-polyethylene glycol (cRGD-PEG) conjugates per molecule, whereas the other peptide, (RGD-PEG)-H3K(+H)4b, had one cRGD-PEG per molecule. Although the modified HK peptides by themselves did not form stable nanoplexes with siRNA, combination of a highly charged unmodified HK peptide, H2K4b, with either of the modified HK peptides did form stable siRNA nanoparticles. For in vitro experiments with MDA-MB-435 cells that expressed luciferase (Luc), the H3K(+H)4b siRNA nanoplexes targeting Luc decreased its activity by 90% compared with negligible downregulation by the modified H3K(+H)4b nanoplexes (P<0.01). In contrast, the two modified H3K(+H)4b siRNA nanoplexes administered intravenously were more effective than the H3K(+H)4b nanoplexes in silencing Luc in a tumor xenograft model. The Luc activity in tumor lysates of mice administered H3K(+H)4b, (RGD-PEG)-H3K(+H)4b and (RGD-PEG)(4)-H3K(+H)4b nanoplexes decreased by 18, 35 and 75%, respectively. Thus, the siRNA nanoplex incorporating the highly modified peptide, (RGD-PEG)(4)-H3K(+H)4b, was the most effective at silencing its target in vivo (P<0.01). These studies demonstrate that selectively modified HK polymers are promising candidates for targeting oncogenes with siRNA. PMID- 21818137 TI - GERD: Modern antireflux therapy for chronic GERD achieves and maintains remission at 5 years. PMID- 21818136 TI - Deletion analysis of Ad5 E1a transcriptional control region: impact on tumor selective expression of E1a and E1b. AB - The regulatory sequences upstream of E1a, the first viral protein expressed upon infection of cells with adenovirus, have binding sites for multiple transcription factors including two binding sites for E2f and five binding sites for Pea3. We evaluated the impact of deletions, which remove one or more of these transcription factor-binding sites on the expression of E1a in a panel of tumor cells and non-transformed cells. We demonstrated that specific deletions in the E1a enhancer markedly reduced the expression of E1a in growth-arrested cells while having a minimal impact on the expression of E1a in a panel of tumor cells. In particular, deletion of a 50-bp region located from -305 to -255 upstream of the E1a initiation site resulted in marked reduction of E1a and E1b expression and cytolytic activity in growth-arrested cells, while retaining near wild-type of expression of E1a and E1b and cytolytic activity in tumor cells. This deletion removed two Pea3 sites and one E2f site. The characteristics of this vector, TAV 255, was compared with dl1520 (Onyx-015) and demonstrated restricted cytolytic activity in growth-arrested cells similar to dl1520 and superior cytolytic activity in a panel of tumor cell lines. In this current study, we demonstrate that TAV-255, an E1a enhancer deletion vector, possesses tumor selective expression of both E1a and E1b along with potent tumor-selective oncolytic activity. PMID- 21818139 TI - Helicobacter pylori: H. pylori infection might suppress allergy in children. PMID- 21818140 TI - Hepatitis: Hepatitis B averts liver steatosis. PMID- 21818141 TI - Upper gastrointestinal tract: Bile acids may have a role in GERD and related neoplasia. PMID- 21818142 TI - Viral hepatitis: Promising phase I trial results for TG4040 vaccine in patients with chronic hepatitis C. PMID- 21818143 TI - Cancer: Epithelial subtype influences the prognosis of invasive IPMN. PMID- 21818144 TI - Clinical trials: Trial design in NASH--realities and challenges. PMID- 21818146 TI - Obesity disparities in preventive care: findings from the National Ambulatory Medical Care Survey, 2005-2007. AB - Obesity and its consequences are a major health concern. There are conflicting reports regarding utilization of preventive health-care services among obese patients. Our objective was to determine whether obese patients receive the same preventive care as normal weight patients. Weighted patient clinic visit data from the National Ambulatory Medical Care Survey (NAMCS) were analyzed for all adult patient visits with height/weight data (N = 866,415,856) from 2005 to 2007. Preventive care practice patterns were compared among different weight groups of normal, obese, and morbidly obese. Obese patients received the least number of preventive exams with a clear gradient present by weight. Obese patients were significantly less likely to receive cancer screening including breast examination (normal weight, reference, obese, odds ratio (OR), 0.8), mammogram (obese OR, 0.7), pap smear (obese OR, 0.7), pelvic exam (obese OR, 0.8), and rectal exam (obese OR, 0.7). The obese population also received less tobacco (obese OR, 0.7) and injury prevention education (obese OR, 0.7), yet significantly more diet, exercise, and weight reduction education. Significant differences in clinic practice patterns relative to normal weight patients were also evident with more physician referral (obese OR, 1.2) and less likely to see physician at the index clinic visit (obese OR, 0.8) and less likely to receive psychotherapy referral (obese OR, 0.6). Significant gaps in preventive care exist for the obese including cancer screening, tobacco cessation and injury prevention counseling, and psychological referral. Although obese patients received more weight-related education, this emphasis may have the consequence of de emphasizing other needed preventive health measures. PMID- 21818147 TI - Body fat, abdominal fat, and body fat distribution is related to left atrial diameter in young children. AB - In adults, the size of the left atria (LA) has important prognostic information. In obese adults, adolescents and children enlargement of LA have been observed. This has not been investigated on a population-based level in young children. We therefore assessed if total body fat mass (TBF), abdominal fat, and body fat distribution were related to LA diameter. Cross-sectional study of 244 children (boys = 137 and girls n = 107) aged 8-11 years, recruited from an urban population-based cohort. Dual-energy X-ray absorptiometry (DXA) measured total lean body mass, TBF, and abdominal fat mass (AFM). Body fat was also calculated as a percentage of body mass (BF%). Body fat distribution (AFM/TBF) was calculated. Echocardiography was performed with two-dimensional guided M-mode. LA diameter was measured and left ventricular mass (LVM) was calculated. Systolic blood pressure and diastolic blood pressure were measured and maturity assessed according to Tanner. There were significant (P < 0.05) univariate correlations for all children between TBF (r = 0.40), BF% (r = 0.32), AFM (r = 0.41), and AFM/TBF (r = 0.41) vs. LA diameter. Multiple regression analyses with the inclusion of possible confounders such as lean body mass, blood pressure, gender, age, and Tanner stage revealed that TBF, AFM, and AFM/TBF were all independently related to LA diameter. Differences in the different body fat measurements explained 6-9% of the variance in LA size. These results demonstrated that both total body fat, AFM, and body fat distribution are already at a young age negatively and independently associated to LA diameter. PMID- 21818145 TI - New insights into gastrointestinal and hepatic granulomatous disorders. AB - Numerous diseases that involve the gastrointestinal tract reveal the presence of granulomas on histological analysis. Granulomatous diseases can be either primary or secondary to environmental factors. Granulomas are dynamic structures composed of organized collections of activated macrophages, including epithelioid and multinucleated giant cells, surrounded by lymphocytes. The formation of granulomas is usually in response to antigenic stimulation and is orchestrated through cytokines, immune cells and host genetics. In this Review, the pathogenesis and etiologies of granulomas of the gastrointestinal tract and liver are discussed, as are the available diagnostic tools to help differentiate their various underlying etiologies. In addition, the role of granulomas in harboring latent tuberculosis is reviewed. The effects of tumor necrosis factor antagonists and interferon-alpha on the development of granulomas are also discussed. PMID- 21818148 TI - The mRNA-binding protein Zfp36 is upregulated by beta-adrenergic stimulation and represses IL-6 production in 3T3-L1 adipocytes. AB - Obesity produces a chronic inflammatory state that contributes to the development of diabetes and atherosclerosis. In obese humans, fat depot adipocytes and macrophages produce inflammatory cytokines and other factors which exert unfavorable local and systemic immune responses. The expression of many cytokines is modulated at the post-transcriptional level by mRNA-binding proteins which recognize AU-rich elements (AREs) in the 3'-untranslated regions (3'-UTR) of these transcripts. One such protein, zinc finger protein 36 (Zfp36), is known to destabilize target mRNAs leading to decreased cytokine expression. Few regulators of Zfp36 expression in adipocytes have been described and mRNA targets of Zfp36 in adipocytes are largely unknown. We found that macrophage-derived inflammatory stimuli enhanced endogenous Zfp36 expression in 3T3-L1 adipocytes. Furthermore, the beta-adrenergic receptor agonist isoproterenol (Iso) and the glucocorticoid dexamethasone (Dex) each enhanced Zfp36 expression in adipocytes, the former most likely via a cyclic adenosine monophosphate (cAMP)-dependent pathway. By contrast, Zfp36 expression in murine macrophages (RAW 264.7) was not enhanced by exposure to Dex but was stimulated by retinoic acid (RA). Zfp36 inhibited basal and lipopolysaccharide (LPS)-stimulated interleukin-6 (IL-6) expression in adipocytes. These data reveal important and cell type-specific modulators of Zfp36 expression in adipocytes and macrophages and identify Zfp36 as a potent repressor of adipocyte-derived IL-6. Furthermore, this work identifies new factors that stimulate adipocyte Zfp36 expression that are neither classically inflammatory nor mitogenic. Upregulating an mRNA-binding protein for therapeutic purposes may provide a novel mechanistic approach with which to treat diverse inflammatory disorders including common conditions associated with obesity. PMID- 21818150 TI - Role of thrombospondin-2 in murine adipose tissue angiogenesis and development. AB - Expression of thrombospondin-2 (TSP-2), a matricellular protein with anti angiogenic properties, is modulated in developing adipose tissue. To investigate a potential functional role of TSP-2 in adipose tissue angiogenesis and growth, TSP-2 deficient (TSP-2(-/-)) and wild-type littermate (TSP-2(+/+)) mice were kept on normal chow (standard fat diet (SFD)) or on high fat diet (HFD) for 15 weeks. TSP-2(-/-) mice kept on HFD had a significantly lower total body weight throughout the experimental period. Subcutaneous (SC) and gonadal (GON) fat mass were, however, not different, and their composition in terms of size and density of adipocytes and blood vessels was also comparable in both genotypes. Macrophage infiltration in SC or GON adipose tissues was not affected by TSP-2 deficiency. TSP-2 deficiency had no effect on adipose tissue mRNA expression of gelatinase A (MMP-2), whereas gelatinase B (MMP-9) was downregulated in SC and GON adipose tissues of TSP-2(-/-) mice on HFD. Glucose tolerance and insulin resistance tests were comparable for TSP-2(+/+) and TSP-2(-/-) mice. TSP-2 deficiency was not compensated by increased expression of TSP-1 in the TSP-2(-/-) mice. These data suggest that TSP-2, despite its reported anti-angiogenic properties, does not play an important functional role in adipose tissue related angiogenesis or associated fat development in mice. PMID- 21818149 TI - Sex and type 2 diabetes: obesity-independent effects on left ventricular substrate metabolism and relaxation in humans. AB - Patients with type 2 diabetes (T2DM), particularly women, are at risk for heart failure. Myocardial substrate metabolism derangements contribute to cardiac dysfunction in diabetic animal models. The purpose of this study was to determine the effects of diabetes and sex on myocardial metabolism and diastolic function in humans, separate from those of obesity. Thirty-six diabetic subjects (22 women) and 36 nondiabetic, BMI-matched subjects (21 women) underwent positron emission tomography (myocardial metabolism) and echocardiography (structure, function). Myocardial blood flow and oxygen consumption (MVO(2)) were higher in women than men (P = 0.003 and <0.0001, respectively). Plasma fatty acid (FA) levels were higher in diabetics (vs. obese, P < 0.003) and sex and diabetes status interacted in its prediction (P = 0.03). Myocardial FA utilization, oxidation, and esterification were higher and percent FA oxidation lower in diabetics (vs. obese, P = 0.0004, P = 0.007, P = 0.002, P = 0.02). FA utilization and esterification were higher and percent FA oxidation lower in women (vs. men, P = 0.03, P = 0.01, P = 0.03). Diabetes and sex did not affect myocardial glucose utilization, but myocardial glucose uptake/plasma insulin was lower in the diabetics (P = 0.04). Left ventricular relaxation was lower in diabetics (P < 0.0001) and in men (P = 0.001), and diabetes and sex interacted in its prediction (P = 0.03). Sex, T2DM, or their interaction affect myocardial blood flow, MVO(2), FA metabolism, and relaxation separate from obesity's effects. Sexually dimorphic myocardial metabolic and relaxation responses to diabetes may play a role in the known cardiovascular differences between men and women with diabetes. PMID- 21818151 TI - Visceral fat thickness is associated with carotid atherosclerosis in peritoneal dialysis patients. AB - Visceral fat has been known to associate with atherosclerosis, inflammation, and insulin resistance. However, the influence of visceral fat on cardiovascular disease (CVD) in peritoneal dialysis (PD) patients has never been elucidated. We investigated whether visceral fat thickness (VFT) has a predictive role in carotid atherosclerosis determined by carotid intima-media thickness (cIMT) in PD patients. A cross-sectional study was undertaken in 88 prevalent PD patients. BMI and waist circumference (WC) were measured as anthropometric indexes of obesity. VFT and subcutaneous fat thickness (SFT) were determined by sonographic measurement of abdominal fat. Carotid atherosclerosis was defined as increased cIMT (>1.0 mm) or presence of plaque. Thirty-two (36.3%) patients had carotid atherosclerosis. Patients with carotid atherosclerosis showed significantly higher VFT, BMI, and WC. In univariate logistic analysis, BMI, WC, and VFT except SFT were significant risk factors of carotid atherosclerosis. However, multivariate analysis revealed VFT was an independent factor associated with carotid atherosclerosis after adjusting for demographic, biochemical parameters, and anthropometric indexes (per 1 mm increase, odds ratio (OR) = 2.294, 95% confidence interval: 1.048-5.021, P = 0.038). When the patients were divided into three groups according to VFT, log high sensitivity C-reactive protein (hs-CRP), and homeostasis model assessment-insulin resistance (HOMA(IR)) were both higher in the third tertile compared to other tertiles. In conclusion, VFT, not SFT, is independently associated with carotid atherosclerosis in PD patients. Therefore sonographic measurement of VFT could be useful to stratify the risk of cardiovascular disease in PD patients. PMID- 21818152 TI - Polymorphisms in the NPY2R gene show significant associations with BMI that are additive to FTO, MC4R, and NPFFR2 gene effects. AB - Neuropeptide Y (NPY) is an appetite hormone that acts centrally to control feeding behavior. The 5' and exon 2 regions of NPY2R, one of five NPY receptor genes, have been weakly and inconsistently implicated with obesity. With the ATG start site of the gene at the beginning of exon 2, single-nucleotide polymorphisms (SNPs) across intron 1 may show stronger associations with obesity than expected. Two 5' SNPs, three intron 1 SNPs, and one synonymous exon 2 SNP were genotyped on 2,985 white Utah subjects. Previously associated FTO, NPY, NPY1R, MC4R, PPARGC1A, OR7D4, and four NPFFR2 SNPs were also genotyped and related to BMI. One NPY2R 5' SNP (rs12649641, P = 0.008), an exon 2 SNP (rs2880415, P = 0.009), and an intron 1 SNP (rs17376826, P = 7 * 10(-6)) were each significantly associated with BMI. All three SNPs, plus FTO (rs9939609, P = 1.5 * 10(-6)) and two NPFFR2 SNPs (rs4129733, P = 3.7 * 10(-13) and rs11940196, 4.2 * 10(-10)) remained significant in a multiple regression additive model. Diplotypes using the estimated haplotypes of NPY2R, NPFFR2, and MC4R were significantly associated with BMI (P = 1.0 * 10(-10), 3.2 * 10(-8), and 1.1 * 10( 4), respectively). Haplotypes of NPY2R, NPFFR2, and MC4R, plus the FTO SNP, explained 9.6% of the BMI variance. SNP effect sizes per allele for the four genes ranged from 0.8 to 3.5 kg/m(2). We conclude that haplotypes containing the rs17376826 SNP in intron 1 of NPY2R have strong associations with BMI, some NPFFR2 haplotypes are strongly protective against or increase risk of obesity, and both NPY2R and NPFFR2 play important roles in obesity predisposition independent of FTO and MC4R. PMID- 21818153 TI - Epinephrine induces PDK4 mRNA expression in adipose tissue from obese, insulin resistant rats. AB - Thiazolidinediones (TZDs) are a commonly prescribed class of insulin sensitizing drugs that increase fatty acid re-esterification, in part through the induction of pyruvate dehydrogenase kinase 4 (PDK4). Owing to the deleterious side effects of TZDs the identification of alternative approaches with which to increase PDK4 is essential. We recently demonstrated that epinephrine increases PDK4 expression through p38 and peroxisome proliferator-activated receptor gamma (PPARgamma) dependent pathways in cultured adipose tissue from lean rats. The purpose of this study was to determine whether acute epinephrine treatment, in vivo, can induce PDK4 mRNA expression in adipose tissue from obese, insulin resistant rats and if the reputed signaling pathways mediating this effect are intact. To this end we fed male Wistar rats a chow or high-fat diet (HFD, 60% kcals from fat) for 6 weeks. Rats were then injected with a weight-adjusted bolus of epinephrine and tissue harvested. Despite a blunted activation of p38 epinephrine increased PDK4 mRNA expression to a similar extent in adipose tissue from chow and HFD rats. 5'AMP-activated protein kinase (AMPK) signaling was not altered by the HFD. Similar to epinephrine, 2 h of swim exercise, an intervention that increases plasma catecholamines, also increased PDK4 mRNA levels to a similar extent in adipose tissue from both lean and HFD rats. Collectively these findings demonstrate, for the first time, that acute elevations in catecholamines induce PDK4 in adipose tissue from HFD rats, that this effect is likely independent of p38, a reputed mediator of PDK4 expression and that exercise, similar to TZDs can induce PDK4 in adipose tissue from obese, insulin resistant rats. PMID- 21818154 TI - Perinephric and epididymal fat affect hepatic metabolism in rats. AB - The present study examined whether the perinephric and epididymal visceral fat (PEVF) depot under short-term excess nutrient protected the liver by trapping nutrient-derived nonesterified free fatty acids (NEFAs) or had deleterious effects on hepatic triglycerides (TGs) accumulation and insulin resistance due to adipokine secretion. Young rats pre-emptively underwent surgical PEVF removal or sham operations and were fed with either high-fat diet (HFD) (PEVF-HFD) or regular chow (RC) (PEVF-RC) for 3 days. Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp. Liver TG, serum NEFA, and fat-derived adipokines were assessed. Insulin and lipogenesis signaling were assessed by western blots. Pre-emptive PEVF removal significantly decreases insulin-induced suppression of hepatic glucose production (HGP) both in RC and in HFD-fed rats. In accordance with the clamp results, hepatic TG accumulation is also significantly reduced by PEVF excision both in RC and HFD-fed rats. These results are further validated by insulin signaling results, which show that pre-emptive PEVF removal increases phosphorylation of hepatic Akt, irrespective of diet. Notably, high levels of serum leptin induced by HFD are significantly reduced by pre-emptive PEVF excision. Additionally, expression of lipogenic enzyme p-acetyl CoA-carboxylase, denoting reduced lipogenesis, is increased in the PEVF-HFD rats. In conclusion, PEVF has a deleterious effect on the liver as a source of insulin resistance-inducing adipokines irrespective of diet, and does not serve as a buffer for excess nutrients. PMID- 21818155 TI - Relation of left ventricular mass to QTc in normotensive severely obese patients. AB - Prolongation of the corrected QT interval (QTc) has been described in obese subjects. This study assesses the relation of left ventricular (LV) mass to QTc in normotensive severely obese subjects. Fifty normotensive patients whose BMI was >=40 kg/m(2) (mean age: 38 +/- 7 years) were studied. QTc was derived using Bazett's formula. LV mass was calculated using the formula of Devereux et al. and was indexed to height(2.7). Mean QTc was 428.8 +/- 19.0 ms and was significantly longer in those with than in those without LV hypertrophy (P < 0.01) QTc correlated positively and significantly with BMI (r = 0.392, P < 0.025), LV mass/height(2.7) (r = 0.793, P < 0.0005), systolic blood pressure (r = 0.742, P < 0.001), LV end - systolic wall stress (r = 0.746, P < 0.001) and LV internal dimension in diastole (r = 0.788, P < 0.0005). Among five variables tested, LV mass/height(2.7) was identified as the sole predictor of QTc by multivariate analysis. In conclusion, LV mass and loading conditions that may affect LV mass are important determinants of QTc in normotensive severely obese subjects. PMID- 21818156 TI - Disparities in counseling for lifestyle modification among obese adults: insights from the Dallas Heart Study. AB - Clinician counseling is a catalyst for lifestyle modification in obesity. Unfortunately, clinicians do not appropriately counsel all obese patients about lifestyle modification. The extent of disparities in clinician counseling is not well understood. Obese participants (BMI >=30 kg/m(2), N = 2097) in the Dallas Heart Study (DHS), a probability-based sample of Dallas County residents ages 18 65, were surveyed regarding health-care utilization and lifestyle counseling over the year prior to DHS enrollment. Health-care utilization and counseling were compared between obese participants across three categories based on the presence of 0, 1, or 2+ of the following cardiovascular (CV) risk factors: hypertension, hypercholesterolemia, or diabetes. Logistic regression modeling was used to determine likelihood of counseling in those with 0 vs. 1+ CV risk factors, stratified by race, adjusting for age, sex, insurance status, and education. Among obese subjects who sought medical care, those with 0 CV risk factors, compared to those with 1 or 2+ CV risk factors, were less likely to report counseling about losing weight (41% vs. 67% vs. 87%, P trend <0.001), dietary changes (44% vs. 71% vs. 85%, P trend <0.001), and physical activity (46% vs. 71% vs. 86%, P trend <0.001). Blacks and Hispanics without CV risk factors had a lower odds of receiving counseling than whites without risk factors on weight loss (adjusted odds ratio (OR), 95% confidence interval (CI) for nonwhites 0.19, [0.13-0.28], whites 0.48, [0.26-0.87]); dietary changes (nonwhites 0.19, [0.13 0.27], whites 0.37, [0.21-0.64]); and physical activity (nonwhites 0.22, [0.16 0.32], whites 0.32, [0.18-0.57]). Lifestyle counseling rates by clinicians are suboptimal among obese patients without CV risk factors, especially blacks and Hispanics. Systematic education about and application of lifestyle interventions could capitalize on opportunities for primary CV risk prevention. PMID- 21818157 TI - The Things They Carry: Combat, Disability and Unemployment among US Men. AB - Sociologists have long recognized that historical events, such as wars, depressions, and natural disasters, can affect the trajectories of people's lives and can reproduce or alter social structure. The following paper examines the effect of a type of event, war, on a facet of people's lives, their ability to work. It uses data from the Panel Study of Income Dynamics to test three accounts regarding how wars affect men's lives. The direct cumulative disadvantage account sees wars as negatively affecting the service-men who see combat regardless of their pre-combat characteristics. The moderated cumulative disadvantage account suggests that combat most negatively affects those who, before they fought, had lower status. The turning point account suggests the reverse: combat most negatively affects those who, before they fought, had greater status. The evidence suggests that, with regard to disability and unemployment, the effects of combat are most consistent with the direct cumulative disadvantage account. PMID- 21818158 TI - Assessment Data-Informed Guidance to Individualize Kindergarten Reading Instruction: Findings from a Cluster-Randomized Control Field Trial. AB - The purpose of this cluster-randomized control field trial was to was to examine the extent to which kindergarten teachers could learn a promising instructional strategy, wherein kindergarten reading instruction was differentiated based upon students' ongoing assessments of language and literacy skills and documented child characteristic by instruction (CXI) interactions; and to test the efficacy of this differentiated reading instruction on the reading outcomes of students from culturally diverse backgrounds. The study involved 14 schools and included 23 treatment (n = 305 students) and 21 contrast teacher (n = 251 students). Teachers in the contrast condition received only a baseline professional development that included a researcher-delivered summer day-long workshop on individualized instruction. Data sources included parent surveys, individually administered child assessments of language, cognitive, and reading skills and videotapes of classroom instruction. Using Hierarchical Multivariate Linear Modeling (HMLM), we found students in treatment classrooms outperformed students in the contrast classrooms on a latent measure of reading skills, comprised of letter-word reading, decoding, alphabetic knowledge, and phonological awareness (ES = .52). Teachers in both conditions provided small group instruction, but teachers in the treatment condition provided significantly more individualized instruction. Our findings extend research on the efficacy of teachers using Individualized Student Instruction to individualize instruction based upon students' language and literacy skills in first through third grade. Findings are discussed regarding the value of professional development related to differentiating core reading instruction and the challenges of using Response to Intervention approaches to address students' needs in the areas of reading in general education contexts. PMID- 21818159 TI - Studies on the Biosynthesis of the Stephacidin and Notoamide Natural Products: A Stereochemical and Genetic Conundrum. AB - The stephacidin and notoamide natural products belong to a group of prenylated indole alkaloids containing a bicyclo[2.2.2]diazaoctane core. Biosynthetically, this bicyclic core is believed to be the product of an intermolecular Diels- Alder (IMDA) cycloaddition of an achiral azadiene. Since all of the natural products in this family have been isolated in enantiomerically pure form to date, it is believed that an elusive Diels-Alderase enzyme mediates the IMDA reaction. Adding further intrigue to this biosynthetic puzzle is the fact that several related Aspergillus fungi produce a number of metabolites with the opposite absolute configuration, implying that these fungi have evolved enantiomerically distinct Diels-Alderases. We have undertaken a program to identify every step in the biogenesis of the stephacidins and notoamides, and by combining the techniques of chemical synthesis and biochemical analysis we have been able to identify the two prenyltransferases involved in the early stages of the stephacidin and notoamide biosyntheses. This has allowed us to propose a modified biosynthesis for stephacidin A, and has brought us closer to our goal of finding evidence for, or against, the presence of a Diels-Alderase in this biosynthetic pathway. PMID- 21818160 TI - Stress in Childhood and Adulthood: Effects on Marital Quality Over Time. AB - We work from a stress and life course perspective to consider how stress affects trajectories of change in marital quality over time. Specifically, we ask whether stress is more likely to undermine the quality of marital experiences at different points in the life course. In addition, we ask whether the effects of adult stress on marital quality depend on childhood family stress experiences. Growth curve analysis of data from a national longitudinal survey (Americans' Changing Lives, N = 1,059 married individuals) reveals no evidence of age differences in the effects of adult stress on subsequent trajectories of change in marital experiences. Our results, however, suggest that the effects of adult stress on marital quality may depend on childhood stress exposure. Stress in adulthood appears to take a cumulative toll on marriage over time-but this toll is paid primarily by individuals who report a more stressful childhood. This toll does not depend on the timing of stress in the adult life course. PMID- 21818161 TI - Stability of Self-Assembled Polymeric Micelles in Serum. AB - The stability of polymeric nanoparticles in serum is critical to their use in drug delivery where dilution after intravenous injection often results in nanoparticle disassembly and drug unloading; however, few investigate this in biologically relevant media. To gain greater insight into nanoparticle stability in blood, the stability of self-assembled polymeric micelles of poly(d,l-lactide co-2-methyl-2-carboxytrimethylene carbonate)-g-poly(ethylene glycol), P(LA-co TMCC)-g-PEG, were tested in both serum and individual serum protein solutions. By encapsulating Forster resonance energy transfer pairs and following their release by fluorescence, these micelles demonstrated excellent thermodynamic and kinetic stability in the presence of serum. Further analyses by fast protein liquid chromatography and dynamic light scattering confirmed these data. Moreover, these micelles are compatible with red blood cells, as shown by a hemolysis assay. The stability and compatibility demonstrated in blood suggest that these micelles may be stable in vivo, which is critical for intravenous drug delivery applications. This comprehensive approach to understanding micelle stability and compatibility is broadly applicable. PMID- 21818162 TI - An Introduction to Propensity Score Methods for Reducing the Effects of Confounding in Observational Studies. AB - The propensity score is the probability of treatment assignment conditional on observed baseline characteristics. The propensity score allows one to design and analyze an observational (nonrandomized) study so that it mimics some of the particular characteristics of a randomized controlled trial. In particular, the propensity score is a balancing score: conditional on the propensity score, the distribution of observed baseline covariates will be similar between treated and untreated subjects. I describe 4 different propensity score methods: matching on the propensity score, stratification on the propensity score, inverse probability of treatment weighting using the propensity score, and covariate adjustment using the propensity score. I describe balance diagnostics for examining whether the propensity score model has been adequately specified. Furthermore, I discuss differences between regression-based methods and propensity score-based methods for the analysis of observational data. I describe different causal average treatment effects and their relationship with propensity score analyses. PMID- 21818163 TI - Literacy Gaps by Educational Attainment: A Cross-National Analysis. AB - Existing cross-national research on educational attainment does not fully address whether the same level of educational attainment generates the same level of literacy skills in different countries. We analyze literacy skills data for young adults from 19 countries in the 1994-1998 International Adult Literacy Survey and find that in all countries, individuals with a higher level of educational attainment tend to have greater literacy skills. However, there is substantial variation across countries in the size of literacy gaps by levels of educational attainment. In particular, young adults in the United States show the largest literacy gaps. Using two-level hierarchical linear models, we find that cross national differences in the literacy gap between more- and less-educated individuals are systematically linked to the degree of between-school inequality in school resources (instructional materials, class size, teachers' experience and certification). PMID- 21818164 TI - Simple, Efficient Protocols for the Pd-Catalyzed Cross-Coupling Reaction of Aryl Chlorides and Dimethylamine. AB - Simple and efficient procedures for the Pd-catalyzed cross-coupling reaction of aryl chlorides and dimethylamine are described. At room temperature with a strong base, t-BuXPhos is employed as the supporting ligand; at 110 degrees C with a weak base, XPhos is employed as the supporting ligand. In each of these cases, commercially available solutions constitute the source of the dimethylamine, and recently disclosed precatalysts constitute the source of the ligand and Pd. This work further expands the utility of these precatalysts in reactions that benefit from an easily activated source of L(1)Pd(0). PMID- 21818165 TI - Benzothiazines in organic synthesis. An approach to floresolide B. AB - The intramolecular conjugate addition of a sulfoximine carbanion to an alpha,beta unsaturated ester results in the formation of a benzothiaine bearing a benzylic stereocenter with extremely high fidelity. We have used this methodology to complete a formal total synthesis of the antitumor agent (+)-floresolide B. PMID- 21818166 TI - Welfare and Generational Equity in Sustainable Unfunded Pension Systems. AB - Using stochastic simulations we analyze how public pension structures spread the risks arising from demographic and economic shocks across generations. We consider several actual and hypothetical sustainable PAYGO pension structures, including: (1) versions of the US Social Security system with annual adjustments of taxes or benefits to maintain fiscal balance; (2) Sweden's Notional Defined Contribution system and several variants developed to improve fiscal stability; and (3) the German system, which also includes annual adjustments to maintain fiscal balance. For each system, we present descriptive measures of uncertainty in representative outcomes for a typical generation and across generations. We then estimate expected utility for generations based on simplifying assumptions and incorporate these expected utility calculations in an overall social welfare measure. Using a horizontal equity index, we also compare the different systems' performance in terms of how neighboring generations are treated.While the actual Swedish system smoothes stochastic fluctuations more than any other and produces the highest degree of horizontal equity, it does so by accumulating a buffer stock of assets that alleviates the need for frequent adjustments. In terms of social welfare, this accumulation of assets leads to a lower average rate of return that more than offsets the benefits of risk reduction, leaving systems with more frequent adjustments that spread risks broadly among generations as those most preferred. PMID- 21818167 TI - Cox Models With Smooth Functional Effect of Covariates Measured With Error. AB - We propose, develop, and implement a fully Bayesian inferential approach for the Cox model when the log hazard function contains unknown smooth functions of the variables measured with error. Our approach is to model nonparametrically both the log-baseline hazard and the smooth components of the log-hazard functions using low-rank penalized splines. Careful implementation of the Bayesian inferential machinery is shown to produce remarkably better results than the naive approach. Our methodology was motivated by and applied to the study of progression time to chronic kidney disease as a function of baseline kidney function and applied to the Atherosclerosis Risk in Communities study, a large epidemiological cohort study. This article has supplementary material online. PMID- 21818168 TI - Does Gender Moderate Factors Associated with Whether Spouses Are the Sole Providers of IADL Care to Their Partners? AB - We explored whether gender moderated the influence of other factors on solo spousal caregiving. The subsample (N = 452) from the AHEAD study included elderly care recipients (CRs) receiving IADL assistance and their spouses. Logistic regression modeled the likelihood of solo spousal IADL care. Gender moderation was tested by product terms between CRs' gender and measures of partners' health, potential helpers, and sociodemographic characteristics. As numbers of CRs' IADLs and couples' proximate daughters increased, wives less often received care solely from their husbands, but husbands' receipt of care from their wives was unaffected. Age differences between spouses and CRs affected solo spousal caregiving to wives and husbands in opposite ways. Regardless of gender, CRs' number of ADL limitations and spouses with IADL or ADL limitations reduced the likelihood of solo spouse care. Identifying circumstances influencing solo spouse caregiving differently among couples with frail wives and husbands facilitates gender sensitive services. PMID- 21818170 TI - Conformational Control of Polysilanes: Use of CH(2) Spacers in the Silicon Backbone. AB - By the reaction of a number of oligosilyl potassium compounds with (trimethylsilyl)chloromethane, derivatives containing the (trimethylsilyl)methyl substituent were prepared. Using X-ray single-crystal structure analysis and UV spectroscopy the conformational properties of some of the compounds were studied. It was found that the (trimethylsilyl)methylated examples exhibit UV absorption properties which correspond to lower energy transitions in comparison to those of analogous trimethylsilylated molecules. The influence of this effect decreases, however, with increasing chain lengths. PMID- 21818169 TI - Effects of Physical Activity on Children's Executive Function: Contributions of Experimental Research on Aerobic Exercise. AB - Executive function refers to the cognitive processes necessary for goal-directed cognition and behavior, which develop across childhood and adolescence. Recent experimental research indicates that both acute and chronic aerobic exercise promote children's executive function. Furthermore, there is tentative evidence that not all forms of aerobic exercise benefit executive function equally: Cognitively-engaging exercise appears to have a stronger effect than non-engaging exercise on children's executive function. This review discusses this evidence as well as the mechanisms that may underlie the association between exercise and executive function. Research from a variety of disciplines is covered, including developmental psychology, kinesiology, cognitive neuroscience, and biopsychology. Finally, these experimental findings are placed within the larger context of known links between action and cognition in infancy and early childhood, and the clinical and practical implications of this research are discussed. PMID- 21818171 TI - Rearrangement/Fragmentation Reactions of Oligosilanes with Aluminum Chloride. AB - Reinvestigation of the Lewis acid catalyzed rearrangement of some open-chain permethyloligosilanes with the Al(Fe)Cl(3) catalyst system exhibited several cases of additional reactivity: namely, a fragmentation/cyclization reaction. Introduction of (trimethylsilyl)methyl substituents into the oligosilane substrates strongly facilitated this reaction, yielding cyclic or bicyclic carbacyclosilanes. Investigations concerning the composition of the catalyst system indicated that the incorporation of about 0.1% FeCl(3) into the AlCl(3) lattice provided an effective catalyst. PMID- 21818172 TI - A Geography-Specific Approach to Estimating the Distributional Impact of Highway Tolls: An Application to the Puget Sound Region of Washington State. AB - This study contributes to the debate about tolls' equity impacts by examining the potential economic costs of tolling for low-income and non-low-income households. Using data from the Puget Sound metropolitan region in Washington State and GIS methods to map driving routes from home to work, we examine car ownership and transportation patterns among low-income and non-low-income households. We follow standard practice of estimating tolls' potential impact only on households with workers who would drive on tolled and non-tolled facilities. We then redo the analysis including broader groups of households. We find that the degree of regressivity is quite sensitive to the set of households included in the analysis. The results suggest that distributional analyses of tolls should estimate impacts on all households in the relevant region in addition to impacts on just users of roads that are currently tolled or likely to be tolled. PMID- 21818173 TI - EFFECT OF JOB SKILLS TRAINING ON EMPLOYMENT AND JOB SEEKING BEHAVIORS IN AN AMERICAN INDIAN SUBSTANCE ABUSE TREATMENT SAMPLE. AB - Employment difficulties are common among American Indian individuals in substance abuse treatment. To address this problem, the Southwest Node of NIDA's Clinical Trials Network conducted a single-site adaptation of its national Job Seekers Workshop study in an American Indian treatment program, Na'Nizhoozhi Center (NCI). 102 (80% men, 100% American Indian) participants who were in residential treatment and currently unemployed were randomized to (1) a three session, manualized program (Job seekers workshop: JSW) or (2) a 40-minute Job Interviewing Video: JIV). Outcomes were assessed at 3-month follow up: 1) number of days to a new taxed job or enrollment in a job-training program, and 2) total hours working or enrolled in a job-training program. No significant differences were found between the two groups for time to a new taxed job or enrollment in a job-training program. There were no significant differences between groups in substance use frequency at 3-month follow-up. These results do not support the use of the costly and time-consuming JSW intervention in this population and setting. Despite of the lack of a demonstrable treatment effect, this study established the feasibility of including a rural American Indian site in a rigorous CTN trial through a community-based participatory research approach. PMID- 21818174 TI - Collaborating With Physicians to Redesign a Sign-Out Tool: An iterative, multifaceted approach with users - even busy ones - can yield a satisfying and efficient product. AB - Physician sign-out is a mechanism for transferring patient information from one group of hospital care-givers to another at shift changes. Support tools are critical to the success of sign-out. To ensure that a tool is effective, designers must collaborate with end users, but collaboration can be difficult when working with users who are busy and have irregular schedules. In this article, we report on a collaborative effort between physicians and engineers to redesign a sign-out support tool. Strategies included focus groups, interviews, "on-the-fly" feedback, and an iterative design process, which engaged end users in the design process. Task analysis methods enabled us to quantify the differences in functionality between the original tool and the prototype. PMID- 21818175 TI - Acculturation and the Family: Core vs. Peripheral Changes among Korean Americans. AB - The traditional cultural characteristics are challenged and negotiated in the process of acculturation; some characteristics are discarded, others are maintained, still others may get strengthened, new characteristics from the new cultures are adopted, and possibly a new hybrid of a culture of family socialization may emerge. The focus group interviews conducted with Korean American parents and their children attest to the complexity of this process mixed with core and peripheral changes. The study findings show that Korean American families appear to live more distinctly in the Korean culture than the mainstream Western culture, and the parental cultural adaptation is, at least at this point, minimal. Korean immigrant parents show reluctance and resistance to change, except in some of the areas that they believe are necessary and potentially helpful to their children. Family values are core values that parents are eager to maintain and transmit to their children. Korean-American parents are also deeply concerned that their children are growing up as a racial and cultural minority, which, they believe, is likely to impede children's development and future prospects. To protect their children, parents focus quite intensely on ethnic socialization within the family - a pattern that is shared among many Asian subgroups, particularly among Chinese and Vietnamese immigrant families, because they strongly believe that a clear sense of ethnic identity and the deliberate preservation of the tradition helps buffer the risks and negativities derived from being an ethnic and cultural minority in the U.S. Youth, mostly second-generation immigrants, have internalized the Korean traditional family values and behaviors, probably more than their parents think that they have - a sign of successful enculturation. Unlike parents' fears, children do not seem to suffer greatly from identity confusion. The overall responses suggest that Korean American youth are aware of their minority status and cultural differences but have a positive and strong sense of ethnic identity as Korean-Americans, which also might be a sign of successful familial ethnic socialization. PMID- 21818176 TI - A nonlinear equation for ionic diffusion in a strong binary electrolyte. AB - The problem of the one dimensional electro-diffusion of ions in a strong binary electrolyte is considered. The mathematical description, known as the Poisson Nerst-Planck (PNP) system, consists of a diffusion equation for each species augmented by transport due to a self consistent electrostatic field determined by the Poisson equation. This description is also relevant to other important problems in physics such as electron and hole diffusion across semi-conductor junctions and the diffusion of ions in plasmas. If concentrations do not vary appreciably over distances of the order of the Debye length, the Poisson equation can be replaced by the condition of local charge neutrality first introduced by Planck. It can then be shown that both species diffuse at the same rate with a common diffusivity that is intermediate between that of the slow and fast species (ambipolar diffusion). Here we derive a more general theory by exploiting the ratio of Debye length to a characteristic length scale as a small asymptotic parameter. It is shown that the concentration of either species may be described by a nonlinear partial differential equation which provides a better approximation than the classical linear equation for ambipolar diffusion but reduces to it in the appropriate limit. PMID- 21818178 TI - Palliative Needs of Spousal Caregivers of Patients with Heart Failure Followed at Specialized Heart Failure Centers. PMID- 21818182 TI - Palladium-Catalyzed Aryl Amination Reactions of 6-Bromo- and 6-Chloropurine Nucleosides. AB - Palladium-catalyzed C-N bond forming reactions of 6-bromo- as well as 6 chloropurine ribonucleosides and the 2'-deoxy analogues with aryl amines are described. Efficient conversions were observed with Pd(OAc)(2)/Xantphos/Cs(2)CO(3), in PhMe at 100 degrees C. Reactions of the bromo nucleoside derivatives could be conducted at a lowered catalytic loading (5 mol % Pd(OAc)(2)/7.5 mol % Xantphos), whereas good product yields were obtained with a higher catalyst load (10 mol % Pd(OAc)(2)/15 mol % Xantphos) when the chloro analogue was employed. Among the examples evaluated, silyl protection for the hydroxyls appears better as compared to acetyl. The methodology has been evaluated via reactions with a variety of aryl amines and by synthesis of biologically relevant deoxyadenosine and adenosine dimers. This is the first detailed analysis of aryl amination reactions of 6-chloropurine nucleosides, and comparison of the two halogenated nucleoside substrates. PMID- 21818183 TI - Associations of BMI and its fat-free and fat components with blood lipids in children: Project HeartBeat! AB - AIM: This study aimed to distinguish between the roles of the two components of BMI, the fat mass (FM) index and the fat-free mass (FFM) index, in BMI's association with blood lipids in children and adolescents. METHODS: A total of 678 children (49.1% female, 79.9% non-black), initially aged 8, 11 and 14 years, were followed at 4-month intervals for up to 4 years (1991-1995). Total cholesterol (TC), LDL-C, HDL-C and triglycerides were determined in fasting blood samples. FFM index and FM index were calculated as FFM (kg)/height (m)(2) and FM (kg)/height (m)(2), respectively. Using a multilevel linear model, repeated measurements of blood lipids were regressed on concurrent measures of BMI or its components, adjusting for age, sex and race and, in a subsample, also for physical activity, energy intake and sexual maturity. RESULTS: Estimated regression coefficients for the relations of TC with BMI, FFM index and FM index were 1.539, -0.606 (p > 0.05) and 3.649, respectively. When FFM index and FM index were entered into the TC model simultaneously, regression coefficients were -0.855 and 3.743, respectively. An increase in BMI was related to an increase in TC; however, an equivalent increase in FM index was related to a greater increase in TC and, when FFM index was tested alone or with FM index, an increase in FFM index was related to a decrease in TC. Similar results were observed for LDL-C. FFM index and FM index were both inversely related to HDL-C and directly to triglycerides. Compared with FFM index, the equivalent increase in FM index showed a greater decrease in HDL-C. CONCLUSION: Greater BMI was related to adverse levels of blood lipids in children and adolescents, which was mainly attributable to BMI's fat component. It is important to identify weight management strategies to halt the childhood obesity epidemic and subsequently prevent heart disease in adulthood. PMID- 21818180 TI - Screening for HIV-associated tuberculosis and rifampicin resistance before antiretroviral therapy using the Xpert MTB/RIF assay: a prospective study. AB - BACKGROUND: The World Health Organization has endorsed the Xpert MTB/RIF assay for investigation of patients suspected of having tuberculosis (TB). However, its utility for routine TB screening and detection of rifampicin resistance among HIV infected patients with advanced immunodeficiency enrolling in antiretroviral therapy (ART) services is unknown. METHODS AND FINDINGS: Consecutive adult HIV infected patients with no current TB diagnosis enrolling in an ART clinic in a South African township were recruited regardless of symptoms. They were clinically characterised and invited to provide two sputum samples at a single visit. The accuracy of the Xpert MTB/RIF assay for diagnosing TB and drug resistance was assessed in comparison with other tests, including fluorescence smear microscopy and automated liquid culture (gold standard) and drug susceptibility testing. Of 515 patients enrolled, 468 patients (median CD4 cell count, 171 cells/ul; interquartile range, 102-236) produced at least one sputum sample, yielding complete sets of results from 839 samples. Mycobacterium tuberculosis was cultured from 81 patients (TB prevalence, 17.3%). The overall sensitivity of the Xpert MTB/RIF assay for culture-positive TB was 73.3% (specificity, 99.2%) compared to 28.0% (specificity, 100%) using smear microscopy. All smear-positive, culture-positive disease was detected by Xpert MTB/RIF from a single sample (sensitivity, 100%), whereas the sensitivity for smear-negative, culture-positive TB was 43.4% from one sputum sample and 62.3% from two samples. Xpert correctly identified rifampicin resistance in all four cases of multidrug-resistant TB but incorrectly identified resistance in three other patients whose disease was confirmed to be drug sensitive by gene sequencing (specificity, 94.1%; positive predictive value, 57%). CONCLUSIONS: In this population of individuals at high risk of TB, intensive screening using the Xpert MTB/RIF assay increased case detection by 45% compared with smear microscopy, strongly supporting replacement of microscopy for this indication. However, despite the ability of the assay to rapidly detect rifampicin-resistant disease, the specificity for drug-resistant TB was sub-optimal. PMID- 21818184 TI - PhD Thesis: burnout among Dutch medical residents. PMID- 21818185 TI - The same, but different. PMID- 21818186 TI - A new curriculum based on four pillars. PMID- 21818187 TI - Bologna in Medicine: the situation in Switzerland. PMID- 21818188 TI - A student's perspective from the Medical University of Innsbruck. PMID- 21818189 TI - 36 different ways to study medicine. PMID- 21818190 TI - Should the general curriculum of medical schools include teaching in 'alternative medicine'? PMID- 21818191 TI - Future medical doctors need to be informed about CAM to ensure safe and competent patient care. PMID- 21818192 TI - Quality assurance of medical education in the Netherlands: programme or systems accreditation? AB - Accreditation is an instrument that is used worldwide to monitor, maintain and improve the quality of medical education. International standards have been defined to be used in reviewing and evaluating the quality of education. The organization and the process of accreditation of medical education programmes in the Netherlands and in Flanders are described in some detail. Accreditation can be based on the results of a detailed assessment of an educational programme or on an evaluation of the educational system and the organization of the institution in question. The Flemish-Dutch accreditation organization (NAO) is moving from programme accreditation towards a combination of programme and systems accreditation. The pros and cons of these two approaches are discussed. PMID- 21818193 TI - Quality assurance of medical education: a case study from Switzerland. AB - In the light of ongoing changes and challenges in the European health systems which also have significant implications for undergraduate medical education, the present paper describes the accreditation of medical education programmes in Switzerland focussing on undergraduate medical education. A summary of the methodology used is provided and first experiences as well as future perspectives are discussed in the light of the aim to achieve continuous quality assurance and improvement in medical education. PMID- 21818194 TI - Dresden Faculty selection procedure for medical students: what impact does it have, what is the outcome? AB - Since 2004 German universities have been able to use a selection procedure to admit up to 60 percent of new students. In 2005, the Carl Gustav Carus Faculty of Medicine at Dresden introduced a new admission procedure. In order to take account of cognitive as well as non-cognitive competencies the Faculty used the following selection criteria based on the legal regulations for university admissions:the grade point average of the school-leaving exam (SSC, Abitur), marks in relevant school subjects; profession and work experience; premedical education; and a structured interview. In order to evaluate the effects of the Faculty admission procedures applied in the years 2005, 2006 and 2007, the results on the First National Medical Examination (FNME) were compared between the candidates selected by the Faculty procedures (CSF-group) and the group of candidates admitted by the Central Office for the Allocation of Places in Higher Education (the ZVS group, comprising the subgroups: ZVS best, ZVS rest and ZVS total). The rates of participation in the FNME within the required minimum time of 2 years of medical studies were higher in the CSF group compared to the ZVS total group. The FNME pass rates were lowest in the ZVS rest group and highest in the ZVS best group. The ZVS best group and the ZVS total group showed the best FMNE results, whereas the results of the CSF-group were equal or worse compared to the ZVS rest group. No correlation was found between the interview results and the FNME results. According to studies of the prognostic value of various selection instruments, the school leaving grade point average seems the best predictor of success on the FNME. In order to validate the non-cognitive selection instruments of the Faculty procedure, complementary instruments are needed to measure non-cognitive aspects that are not captured by the FNME results. PMID- 21818195 TI - How should ethnic diversity be represented in medical curricula? A plea for systematic training in cultural competence. AB - Ethnic diversity has become a common reality in European societies, including those of Germany and the Netherlands. Given that ethnic minority groups and immigrants are known to be especially vulnerable to inequalities in health, access to services and quality of care, the need for cultural competency training in medical education is widely acknowledged. This paper presents four key issues in providing medical students and physicians with the knowledge, attitudes and skills to adapt medical care to ethnically diverse populations. It then describes two educational programmes delivered by the University of Amsterdam (UvA Academic Medical Centre, the Netherlands) and Giessen University Medical School (Germany), respectively, to illustrate that translating theoretical educational objectives into educational practice can lead to different teaching programmes depending on specific local conditions. In the conclusions, emphasis is placed on the need for systematic approaches that do not limit their focus to patients and groups of specific ethnic or migration backgrounds. Issues of culture, communication and research in relation to ethnically diverse populations are magnifications of general problems in medicine and healthcare. Explicit attention to ethnic diversity thus offers a view through a 'magnifying glass' of subjects of much broader importance and can be a means for improving health care in general. PMID- 21818196 TI - Gender and sex: issues in medical education. AB - There is ample scientific evidence to support the importance of gender issues in health and illness. If we fail to take such sex and gender differences sufficiently into account, this will affect the quality of health care provided to men and women, and this is precisely what good medical education means to prevent. In this paper examples are given that show how knowledge, attitudes and skills relating to sex and gender can be implemented in both optional and compulsory courses. Next, factors that can facilitate or impede the implementation of gender specific medical education are described. Finally, the author discusses what needs to be done to educate future physicians that are equipped with appropriate expertise to deal with aspects of gender in medicine. PMID- 21818197 TI - Multiprofessional education to stimulate collaboration: a circular argument and its consequences. AB - The current developments in healthcare are unprecedented. The organization of health care is complex. Collaboration is essential to meet all the healthcare needs of patients and to achieve coordinated and unambiguous information. Multiprofessional education (MPE) or multidisciplinary training (MDT) seems a logical step to stimulate teamwork. However, collaboration and MPE are wrestling with the same problems: social identity and acceptance. PMID- 21818199 TI - Medical universities in Austria: impact of curriculum modernization on medical education. AB - During the last decade medical education in Austria has seen more changes than in the whole of the previous century, with a complete overhaul of the structure of undergraduate curricula. Curricula now are organized in thematic, integrated modules, students have early patient encounters, the number of examinations has been drastically reduced, objective examinations have been introduced throughout the entire course as has skills training, and quality management is assured. As a consequence of the judgement of the European Court in 2005 against discrimination and in favour of equal treatment of EU citizens, free enrolment was abandoned and admission tests were introduced. In postgraduate training, licensing examinations are now obligatory. Crucial results from the point of view of students as well as with regard to the supply of manpower to the health care system are a sharp decrease in the formerly extremely long mean duration of study programmes and a sharp fall in drop-out rates. The now fully autonomous medical universities have the opportunity to intensify collaboration and to embark on a process of continuous renewal. Structural reform of undergraduate and postgraduate curricula will eventually ensure full equality of Austrian and other European medical qualifications. PMID- 21818198 TI - Virtual medical campus: the increasing importance of E-learning in medical education. AB - In 2002, along with the integration of a new, integrated curriculum in human medicine, the Virtual Medical Campus Graz was installed. It accompanies the whole curriculum with electronic materials tailored to the needs of the students and the forthcoming examinations. To date, more than 15,000 learning objects have been developed, and students download up to 200,000 learning objects per month. Particular emphasis is placed on Web-Based Training materials, but video and simulations are also included. In part, transfer of basic knowledge is mediated by electronic learning materials, replacing several hours of classroom attendance. Face-to-face education, in turn, is focusing increasingly on small group clinical teaching. PMID- 21818200 TI - Two-cycle curriculum - bachelor-master structure according to the Bologna agreement: the Swiss experience in Basle. AB - In the autumn of 2006, the first cohort of students started with the bachelor programme in Basle. The whole curriculum had to be changed from the old system to the new two-cycle system. The implementation of the Bologna reform in Switzerland has been successful especially with regard to the very tight time schedule. Ongoing evaluation will detect fields for improvement which will of course arise in such a fundamental process of change. A major challenge for the future will be the sustainable consolidation of high quality in medical education. PMID- 21818201 TI - The Bologna agreement is not suitable for medical education: a German view. AB - Central elements of the Bologna declaration have been implemented in a huge variety of curricula in humanities, social sciences, natural sciences and engineering sciences at German universities. Overall the results have been nothing less than disastrous. Surprisingly, this seems to be the perfect time for German universities to talk about introducing a curriculum that is fully compatible with the Bologna declaration for medical education as well. However, German medical education does not have problems the Bologna declaration is intended to solve, such as quality, mobility, internationalization and employability. It is already in the Post-Bologna age. PMID- 21818202 TI - The bachelor-master structure (two-cycle curriculum) according to the Bologna agreement: a Dutch experience. AB - The Groningen Medical Curriculum is an example of a two-cycle curriculum with a course leading to the Bachelor's degree followed by a course at the end of which students receive a Master's degree in medicine. Moreover a third cycle is in the offing, in the form of a PhD trajectory for students who wish to pursue a career in research. The Groningen curriculum is based on the CanMEDS competency model. In addition to describing the Groningen curriculum, the author comments on the opportunities and threats offered by the bachelor-master structure. A plea is made for more vigorous collaboration in working towards a more uniform European medical curriculum with room for specific local features at the discretion of individual universities. PMID- 21818203 TI - Research in medical education: pratical impact on medical training and future challenges. AB - Medical education research has changed over the years from merely descriptive studies towards justification or curriculum comparison studies and, nowadays, towards a slow introduction of more clarification studies. In clarification studies quantitative and qualitative methods are used to explain why or how educational interventions work or do not work. This shift is described in this paper. In addition, it is explained how research into workplace learning and assessment has impacted developments in educational practice. Finally, it is argued that the participation of teachers within the medical domain in conducting and disseminating research should be cherished, because they play a crucial role in ensuring that medical education research is applied in educational practice. PMID- 21818204 TI - The 2009 framework for undergraduate medical education in the Netherlands. AB - The 2009 Framework defines the joint Dutch national learning outcomes to be attained by medical students after completing their three-year master programme in medicine. The Framework thus helps to guarantee to society at large and to patients in particular that medical graduates who are starting out as practitioners have attained a certain professional level. This level is the aggregate of the physicians' target profile, physicians' (sub-) competencies to be achieved and the list of issues relating to illness and health. In addition, the Framework also defines the profile of the bachelor and the learning outcomes of the bachelor programme in medicine. PMID- 21818205 TI - Medical education in Europe. PMID- 21818206 TI - The joint issue of the Tijdschrift voor Medisch Onderwijs and the GMS Zeitschrift fur Medizinische Ausbildung, Heft 02/2010. PMID- 21818207 TI - Culture and healthcare in medical education: migrants' health and beyond. AB - One of the main challenges for teaching programs on immigration, ethnic diversity and health is to transform the commonplace notion of "culture" into a helpful tool for medical training and practice. This paper presents the teaching approach of an interdisciplinary course on "migrants' health" established at the University of Giessen since 2004, which has recently been complemented by a thematically related collaboration with two universities in Latin America (Ecuador, Peru). The overall goal is to translate the abstract philosophy of "think global and teach local" into medical practice, and to provide students with the insights, attitudes and skills needed for a fruitful use of concepts like "culture", "ethnicity" and "migration background". A key feature of the course is the strong commitment to ethnography as an important means for looking under the surface of superficial attributions to culture, and for grasping the interplay of medicine and health with cultural, social, religious, economic and legal aspects in its particular local and/or individual shape. Three elements of the course are presented to illustrate this approach: First, a unit on Islam and Medicine, as important parts of the local immigrant community are Muslims. The second one deals with psychosomatic aspects, because in case of immigrants, complex symptoms and disease representations like somatisation are easily misinterpreted as "cultural". The third element consists of a unit with specialized social workers form outside the university, who provide direct insights into the living conditions and health problems of local immigrant communities. PMID- 21818208 TI - Criteria for the successful completion of medical dissertations - A multicenter study. AB - OBJECTIVE: In order to acquire the academic title "doctor" in Germany, it is essential to complete a dissertation. A high number of publications at German universities are based on medical dissertations. The reasons why some dissertations are successfully accomplished and why some are not completed - despite far-reaching consequences - have been barely investigated to date. METHODS: 467 students in the ninth semester at five German universities participated in this study in 2003. A questionnaire (return rate 93.5%) was used, asking details about the circumstances of a current or completed dissertation (Group A), an abandoned doctoral project (Group B), or one which was never started (Group C). RESULTS: Students in Group A referred significantly more often to their supervisor as being essential for choosing the topic of their dissertation project. Furthermore, students in Group A worked together with other students in self-organized support groups to debate methodological questions. They also discussed their project more frequently with a statistician. Students in Group C gave "interference with undergraduate studies" and "no time" as the most common reasons for not starting a dissertation. CONCLUSIONS: As the supervisor seems to play an important role for the successful completion of dissertations, universities should think about professional programs that would prepare supervisors for this educational task. Courses for doctoral candidates in scientific research methodology could also be a helpful tool toward successfully accomplishing a doctoral thesis or scientific projects in general. PMID- 21818209 TI - GMA Annual Conference 2010 in Bochum - A Review. PMID- 21818210 TI - GMA price for "teaching students" awarded for the first time. PMID- 21818211 TI - Exams at medical faculties - quality, responsibility and perspectives. PMID- 21818212 TI - Implementing the cross-disciplinary subject of palliative medicine (Q13) against the backdrop of recent changes of the legal framework using University Medical School Gottingen as an example. AB - Palliative care for patients with advanced and progressive diseases has recently become an integrated and compulsory part of undergraduate training in Germany. Up until now, undergraduate teaching in this cross-disciplinary medical field varied and therefore problems during the implementation process with regard to formal aspects and teaching content are to be expected. This contribution summarizes the new legislative framework for palliative care as an independent specialty in undergraduate medical training and describes format, content and problems of the current implementation process at the University Medical School Gottingen, in order to provide advice and support for other faculties. PMID- 21818213 TI - Review of multiple-choice-questions and group performance - A comparison of face to-face and virtual groups with and without facilitation. AB - BACKGROUND: Multiple choice questions (MCQs) are often used in exams of medical education and need careful quality management for example by the application of review committees. This study investigates whether groups communicating virtually by email are similar to face-to-face groups concerning their review process performance and whether a facilitator has positive effects. METHODS: 16 small groups of students were examined, which had to evaluate and correct MCQs under four different conditions. In the second part of the investigation the changed questions were given to a new random sample for the judgement of the item quality. RESULTS: There was no significant influence of the variables "form of review committee" and "facilitation". However, face-to-face and virtual groups clearly differed in the required treatment times. The test condition "face to face without facilitation" was generally valued most positively concerning taking over responsibility, approach to work, sense of well-being, motivation and concentration on the task. DISCUSSION: Face-to-face and virtual groups are equally effective in the review of MCQs but differ concerning their efficiency. The application of electronic review seems to be possible but is hardly recommendable because of the long process time and technical problems. PMID- 21818214 TI - Does the training of mentors increase the contact frequency and the quality of support in a portfolio-based teaching module? AB - INTRODUCTION: All over the world, mentors are employed more and more for portfolio-based training modules in order to support the learner's learning- and reflection process.Within the final year of medical education, tertial internal medicine, the University Hospital of Erlangen, Department of Medicine 1 offered trainings for mentors.In the framework of the student's evaluation of this training period it was asked whether and what kind of effect the mentor training has had on the contact frequency between mentor and student and whether it affects how students experience the mentor's support. METHODS: Since spring 2005, the Medizinische Klinik 1 held one-day-long mentor trainings, and in the following two years, about half of the medical staff attended. During the following four years, both trained and untrained mentors participated.At the end of the training section the students evaluated the contact to their mentor with a structured question form. The questions on the contact frequency and how the students experienced the support through the mentor were evaluated for the present study.186 question forms were evaluated; 67 of them related to trained mentors. RESULT: One year after the first training, the students rated the trained mentor's support significantly higher than the support by untrained mentors. There was a tendency noted, though not significant, for a higher contact frequency with the trained mentors.During the following three years, the measurable difference between the trained and untrained mentors regarding both items was not significant. In those years, a tendency towards a more intensive support of the students through all mentors was shown. DISCUSSION: The evaluation results one year after the intervention imply that trained mentors can intensify their support for the students without requiring more time. The positive development of the evaluation results for both mentor groups during the following three years can be interpreted as a result of the process of exchange between trained and untrained mentors and readjustment among staff. PMID- 21818215 TI - Using the Progress Test Medizin (PTM) for evaluation of the Medical Curriculum Munich (MeCuM). AB - AIMS: The Medical Curriculum Munich (MeCuM) has been implemented since 2004 and was completely established in 2007. In this study the clinical part of MeCuM was evaluated with respect to retention of the knowledge in internal medicine (learning objectives of the 6th/7th semester). METHODS: In summer of 2009 and winter of 2009/2010 1065 students participated in the Progress Test Medizin (PTM) from Charite Medical School Berlin. Additionally the students answered a questionnaire regarding the acceptance and rating of the progress test and basic demographic data. RESULTS: The knowledge of internal medicine continuously increases during the clinical part of the medical curriculum in Munich. However, significant differences between the sub-disciplines of internal medicine could be observed. The overall acceptance of the PTM was high and increased further with the study progress. Interestingly, practical experiences like clinical clerkships positively influenced the test score. CONCLUSIONS: The PTM is a useful tool for the evaluation of knowledge retention in a specific curriculum. PMID- 21818216 TI - Peer teaching in paediatrics - medical students as learners and teachers on a paediatric course. AB - BACKGROUND: Peer assisted learning is known as an effective educational strategy in medical teaching. We established a peer assisted teaching program by student tutors with a focus on clinical competencies for students during their practical training on paediatric wards. It was the purpose of this study to investigate the effects of a clinical skills training by tutors, residents and consultants on students evaluations of the teaching quality and the effects of a peer teaching program on self assessed clinical competencies by the students. METHODS: Medical student peers in their 6(th) year were trained by an intensive instruction program for teaching clinical skills by paediatric consultants, doctors and psychologists. 109 students in their 5(th) year (study group) participated in a peer assisted teaching program for training clinical skills in paediatrics. The skills training by student peer teachers were supervised by paediatric doctors. 45 students (control group) participated in a conventional paediatric skills training by paediatric doctors and consultants. Students from both groups, which were consecutively investigated, completed a questionnaire with an evaluation of the satisfaction with their practical training and a self assessment of their practical competencies. RESULTS: The paediatric skills training with student peer teachers received significantly better ratings than the conventional skills training by paediatric doctors concerning both the quality of the practical training and the support by the teaching medical staff. Self assessed learning success in practical skills was higher rated in the peer teaching program than in the conventional training. CONCLUSIONS: The peer assisted teaching program of paediatric skills training was rated higher by the students regarding their satisfaction with the teaching quality and their self assessment of the acquired skills. Clinical skills training by student peer teachers have to be supervised by paediatric doctors. Paediatric doctors seem to be more motivated for their own teaching tasks if they are assisted by student peer teachers. More research is needed to investigate the influence of peer teaching on the motivation of paediatric doctors to teach medical students und the academic performance of the student peers. PMID- 21818217 TI - Benefits and pitfalls of scientific research during undergraduate medical education. AB - OBJECTIVE: The integration of scientific research into medical education is a widely discussed topic. Most research training programs are offered on a voluntary basis. In Germany, it is mandatory to complete a doctoral thesis to obtain the academic title "doctor". The reasons why students start a dissertation project and the influence of this project on their undergraduate studies and later career choices are not well known. METHOD: This study was conducted at five German universities in 2003, with a total of 437 fifth-year students participating in it. A standardised questionnaire was used to ask participants about their current or finished dissertation (group A), a dissertation they had discontinued (group B) or why they had never started a dissertation project (group C). RESULTS: The two most important reasons for students from group A to start a dissertation were "interest in the topic" and "advantage for job applications". Compared with group B, they mentioned "improved ability to critically appraise scientific studies" and "doing scientific work independently" significantly more often as a result of working on their dissertation. Starting a dissertation project early during undergraduate studies was correlated with a less successful outcome. Moreover, working on a dissertation significantly reduced time spent on undergraduate studies. Students from group C named the "workload of undergraduate studies" and "no time" most frequently as reasons for not having started a dissertation. CONCLUSION: Students who have been working successfully on a dissertation rate items regarding the acquisition of scientific research skills significantly more positively, and participation in undergraduate studies seems to be negatively affected by working on a dissertation project. Therefore, basic training in scientific research methodology should become an integrated part of the medical undergraduate curriculum, while special programs should be offered for students with a particular interest in scientific research programs or an academic career. PMID- 21818218 TI - An approach towards problem-based learning in virtual space. AB - Problem-based learning (PBL) is an established and efficient approach to sustainable teaching. Here, we describe translation of PBL into the virtual classroom thereby offering novel teaching aspects in the field of Nuclear Medicine. Our teaching approach is implemented on a "moodle" platform and consists of 2 modules: complementary seminar teaching materials and a virtual PBL classroom, which can be attended via Skype.Over the course of 4 semesters 539 students have accessed our teaching platform. 21 students have participated in the PBL seminar (module 2). After resolving some minor technical difficulties our virtual seminars have evolved into a forum of intense studies, whereby the participating students have learned to become more independent along the workup of the teaching cases. This was reflected in the results of the intra-group presentations and discussions.Quantitative and qualitative evaluation of our moodle-based PBL platform indicates an increasing level of acceptance and enthusiasm by the students. This has initiated discussions about opening our PBL concept to a wider audience within the university and beyond the Nuclear Medicine specialty. PMID- 21818219 TI - Clinical externships within undergraduate studies in veterinary medicine. AB - The purpose of this study was to evaluate the benefits of checklists for clinical practical courses. Clinical externships are a component of the practical part of the veterinary medicine curriculum. The control is under the responsibility of the training centres. Guidelines and checklists for extramural clinical courses were developed in order to facilitate control mechanisms. The analysis of such checklists should give an overview over the actual situation to enable the setting of minimum standards for extramural courses. The guidelines list practical activities carried out by the students in the veterinary practices or clinics. Data of 360 checklists were assessed in this study to evaluate whether checklists constitute a useful tool to control extramural studies.The results show that checklists are useful to enhance the knowledge of the training centre about the training of students to be adapted. However, the advantage is not completely clear to students. The communication of the importance of the extramural training sessions has to be enhanced. PMID- 21818220 TI - Recommendations for reviewing a manuscript for the GMS Zeitschrift fur Medizinische Ausbildung. AB - The aim of this paper, written by the committee of educational research methodology of the "Society for Medical Education" of the German-speaking countries, will give recommendations for the review process of scientific papers in medical education. The recommendations are based on the results of a workshop in 2007 and on a survey among reviewers of the journal GMS Z Med Ausbild. It reflects on international standards and research in medical education in Germany. The paper describes reviewer's function concerning the journal of GMS Z Med Ausbild and specifies criteria for the review process with regard to the editors and reviewers; it also gives proposals for a feedback to the author. The catalogue of criteria for the reviewers is pictured in a checklist. The present recommendations shall help to increase the quality of the review process and to improve the national and international acceptance of the journal GMS Z Med Ausbild. Additionally, transparency of the review processes will support authors to submit a scientific article of high quality. PMID- 21818221 TI - Prize winner of the "GMA - Prize for young medical educators 2010" announced. PMID- 21818222 TI - Congress memorandum: day of teaching 2010 at the university heidelberg, medical faculty mannheim, 02.07.2010. PMID- 21818223 TI - A Summary and Commentary on Smith et al.'s "Why peer discussion improves student performance on in-class concept questions" (Science 2009). PMID- 21818224 TI - Comparative survey of educating doctors about communication - is ranking justified? PMID- 21818225 TI - Reducing common prescription errors - a modular lecture. PMID- 21818226 TI - Learning outcomes for health professions: the concept of the swiss competencies framework. AB - Modern conceptions of education are based on normative goals concerning learning outcomes in terms of competencies to acquire. The objective of the Swiss competencies framework was to define general and profession-specific learning outcomes for Bachelor's and Master's degree programmes in nursing, physiotherapy, occupational therapy (ergotherapy), midwifery, nutrition counselling, and technicians in medical radiology. In addition, national authorities needed an instrument that allowed the integration of the old professional trainings into a nationally-harmonised education system and that showed the specificities of the levels (higher vocational education; bachelor and master degree at university level). While the general learning outcomes were derived from legal bases, the profession-specific learning outcomes are elaborated according to the competency based CanMEDS framework. In the CanMEDS framework, knowledge, skills, and attitudes are condensed into meta-competencies which in turn are divided into seven roles, including the medical expert (central role). Taxonomic characteristics and indicators were elaborated in an iterative process that involved regulators, the universities of applied sciences and professional organisations. For the degree programmes mentioned above, the framework developed focuses not only on professional expertise, but also on collaboration with other health professions. Moreover, the interface-management in care taking processes is a critical success factor. Based on this conception, three levels of objectives were identified: general competencies, profession-specific learning outcomes and learning objectives to be implemented in the universities of applied sciences. The general competencies are composed of four dimensions and apply to all health professionals. The profession-specific learning outcomes for the Bachelor's and Master's degree programmes are outlined with 3 to 5 indicators each in all seven professions concerned. The definition and identification of these learning outcomes allows locating the different study programmes on the correct level of tertiary education. The resulting competency framework can be applied to all health professions. The general and job-specific learning outcomes are a coherent, coordinated set of standards, which represent the objectives of Bachelor's and Master's degree programmes in a differentiated way and promote inter-professional collaboration. PMID- 21818227 TI - Pilot project "Patient-Safety" in Medical Education. AB - Since the summer term 2009 the study project "Patientensicherheit - Der klinische Umgang mit Patienten- und Eingriffsverwechslungen sowie Medikationsfehlern" (Patient Safety - the clinical handling of patients - and mistaking of procedures as well as medication errors) is offered within the Modellstudiengang Medizin. Seminars on patient safety in Germany so far mainly address trained doctors and health economists. In contrast, this study project on patient safety should at an early stage contribute to a "culture of discussing and preventing mistakes" - an aspect that is little established in clinical medicine, but also in medical training. For this purpose, a broad variety of courses was developed, which - relying on problem-oriented learning - enables the students to analyse so-called adverse events (AE) and develop adequate prevention measures on the basis of the insights gained by this analysis. Therefore, theoretical lessons are complemented by discussing prototypical clinical cases. These discussions are moderated by experienced clinicians. After completing the seminar, students showed a significant increase (comparison of means) in the self-assessed qualifications "Wissen zu Patientensicherheit" (Knowledge of Patient Safety) and "Wahrnehmung von Risikosituationen" (Appreciation of Risk Situations). All in all, the students rated their training success with a grade of 1.5 (good). PMID- 21818228 TI - How high are the personnel costs for OSCE? A financial report on management aspects. AB - OBJECTIVE: The OSCE (objective structured clinical examination) was put to the test in order to assess the clinical practical skills of students in medical studies in the medical faculties. For the implementation of an OSCE, a large number of personnel is necessary. In particular for subjects with limited resources, therefore, efficient cost planning is required. In the winter semester 09/10, the Department of Neurology at the Medical Faculty of the University of Ulm introduced the OSCE as a pilot project. A financial report retrospectively shows the personnel expenses. The report is intended as an example for an insight into the resources needed for the OSCE with simulated patients. METHOD: Included in the calculation of the financial costs of the OSCE were: employment, status of staff involved in the OSCE, subject-matter and temporal dimension of the task. After the exam, acceptance of the examination format was reviewed by a focus group interview with the teachers and students. RESULT: The total expenses for the personnel involved in the OSCE amounted to 12,468 ?. The costing of the clinic's share was calculated at 9,576 ?. Tuition fees from the students have been used to the amount of 2.892 ?. For conversion of total expenditure to the number of examines the sum of 86 ? per student was calculated. Both students and teachers confirmed the validity of the OSCE and recognised the added value in the learning effects. CONCLUSION: The high acceptance of the OSCE in neurology by both students and teachers favours maintaining the test format. Against the background of the high financial and logistical costs, however, in individual cases it should be assessed how in the long-term efficient examination procedure will be possible. PMID- 21818229 TI - Starting a family during medical studies? Results of a pilot study on family friendliness in the study of medicine at the University of Ulm. AB - OBJECTIVE: The Ulm pilot study aimed to explore factors for a successful combination of medical education and starting a family. The empirical data derived from this study constitutes the foundation for an evidence-based reform of the medical curriculum in Ulm. METHODS: In 2009, qualitative interviews with 37 of the 79 medical students with children at University of Ulm were conducted and analyzed using content analysis. The detected problem areas were used to develop a quantitative questionnaire for studying parents and academic teaching members in medical education in Ulm. RESULTS: The parents were older, more often married and more likely to already have obtained a first training. One third of the students thought there was no ideal time to start a family during the years of medical education or specialist training. However, the majority of the students (61%) were convinced that parenthood is more compatible with medical studies than with specialist training. The interview data suggests that the end of medical school (4(th) to 6(th) year of studies), preferably during semester break, is especially suitable for child birth since it allows students to continue their studies without 'losing time'. CONCLUSION: The biography and career of studying parents in medicine have specific characteristics. Universities and teaching hospitals are required to no longer leave the compatibility of family and study responsibilities to the students themselves. Rather, flexible structures need to be implemented that enable students to start a family while continuing their education. This means providing more childcare and greater support regarding academic counselling and career development. PMID- 21818230 TI - Lectures based on cardinal symptoms in undergraduate medicine - effects of evaluation-based interventions on teaching large groups. AB - Despite critical voices lectures are still an important teaching format in current medical curricula. With the curricular reform at Hamburg Medical Faculty in the year 2004, all subject specific lectures were replaced by cardinal symptom oriented lectures (LSV) in the new clinical curriculum. LSVs are taught throughout all six thematic blocks in years three to five. Since regular student evaluations after each thematic block seemed to demand improvement of the LSVs, this study was carried out using evaluations of individual LSVs by the participating students and by trained auditors (final year students and academic staff). Based on these evaluations feedback containing the individual evaluation data was given in written form to the lecturers combined with information material on planning an LSV using modern didactic techniques. In a second evaluation period, the effects of this intervention were studied. Only small improvements in the LSVs' quality were noted regarding the level of marks achieved. When individual items were evaluated, especially the didactic quality, significant improvements were noticeable. Overall, on the basis of individual items students ranked the quality of the LSVs significantly higher than trained auditors during the first evaluation period. This effect was no longer seen after the second evaluation period. The inter rater reliability among the auditors was very good. This study shows that regular quality assurance is needed on the structural levels and for staff to accompany the process of embedding teaching formats into curricular concepts. Further investigation is needed to determine the adequate frequency of evaluation and the format of feedback to guarantee sustainable effects of the didactic quality of lectures. PMID- 21818231 TI - Attitudes of medical students towards general practice: Effects of gender, a general practice clerkship and a modern curriculum. AB - AIMS: Planning a career in general practice depends on positive attitudes towards primary care. The aim of this study was to compare attitudes of medical students of a Modern Curriculum at Hannover Medical School with those of the Traditional Curriculum before (pre) and after (post) a three-week clerkship in general practice. In parallel, we aimed to analyse several other variables such as age and gender, which could influence the attitudes. METHODS: Prospective survey of n=287 5th-year students. Attitudes (dependent variable, Likert-scale items) as well as socio-demographic characteristics (age, gender, rural/urban background), school leaving examination grades, former qualifications, experiences in general practice and career plans were requested. Attitudes were analysed separately according to these characteristics (e.g. career plans: general practitioner (GP)/specialist), curriculum type and pre/post the clerkship in general practice. Bi- and multivariate statistical analysis was used including a factor analysis for grouping of the attitude items. RESULTS: Most and remarkable differences of attitudes were seen after analysis according to gender. Women appreciated general practice more than men including a greater interest in chronic diseases, communication and psychosocial aspects. The clerkship (a total of n=165 students of the "post" survey could be matched) contributed to positive attitudes of students of both gender, whereas the different curricula did not show such effects. CONCLUSIONS: Affective learning goals such as a positive attitude towards general practice have depended more on characteristics of students (gender) and effects of a clerkship in general practice than on the curriculum type (modern, traditional) so far. For the development of outcomes in medical education research as well as for the evolution of the Modern Curriculum such attitudes and other affective learning goals should be considered more frequently. PMID- 21818232 TI - Prevention and health promotion in undergraduate medical education: Preferences, attitudes and previous knowledge of medical students - a cross-sectional study. AB - OBJECTIVE: The interdisciplinary topic "prevention and health promotion" (Q10) was introduced into the medical training in Germany by the new medical licensing regulations in 2004. For the conception of an effective curriculum, it is helpful to know student preferences concerning teaching-formats, attitudes and self estimated previous knowledge. Little is known concerning student perception of "prevention and health promotion" in Germany. Thus, this explorative cross sectional study aims to provide a first step for closing this gap. METHODS: Medical students (n=220) in the fifth academic year were asked to fill in a standardized questionnaire prior to the Q10 curriculum. Questions focused on preferences for teaching and testing formats and self-estimated previous knowledge as well as on rating the importance of prevention topics and health risks. The questions were multiple choice, five-point Likert scales and open ended questions. RESULTS: A total of 94 students filled questionnaires (42% response rate). Prevention and health promotion was rated as "important" or "very important" for their "own medical professionalism" by 68% of students. Ratings showed preferences for self-directed teaching and learning strategies, including case-based learning, and 78% wished for predominantly oral examinations. The self estimated knowledge about prevention and health promotion is rated as "rather poor". The most favored training aim was "decision making within the physician patient-relationship". Regarding medical health consultation, students frequently estimate "lifestyle factors" and "psychological disease" as being "very important". CONCLUSION: Students' self-estimated poor previous knowledge of prevention and health promotion creates special challenges for curriculum development. High ratings of relevance assigned to prevention-related topics point to a motivational potential which should be utilized through suitable selection of teaching and testing formats to achieve effective and practice relevant instructional content. PMID- 21818233 TI - GMA 800 plus. PMID- 21818234 TI - Students' performing of practical research tasks for their scientific qualification - an approach within the family practice internship in undergraduate education. AB - BACKGROUND: Future physicians should be educated in evidence-based medicine. So it is of growing importance for medical students to acquire both practical medical and basic research competencies. However, possibilities and concepts focusing on the acquisition of basic practical research competencies during undergraduate medical studies in Germany are rare. Therefore the aim of this article is to develop a didactic and methodological concept for research-based teaching and learning based on the initial results from the block placement in general practice. METHODS: Connecting medical didactic approaches with classic educational control measures (knowledge, acceptance and transfer evaluation, process evaluation, and outcome evaluation). RESULTS: We describe the steps for implementing a research task into the block placement in general practice. Also stressed is the need to develop didactic material and the introduction of structural changes. Furthermore, these steps are integrated with the individual educational control measures. A summary serves to illustrate the learning and teaching concept (Block Placement Plus). CONCLUSION: The conceptualisation of the Block Placement Plus leads to changes in the daily life routine of medical education during the undergraduate block placement in general practice. The concept can in principle be transferred to other courses. It may serve as an instrument for teachers within the framework of a longitudinal curriculum for the scientific qualification of medical students. PMID- 21818235 TI - The aimed or feared professional future of medical students at the Univesity of Witten/Herdecke. AB - The current challenges of educational policy seem to be associated to changes of the health care system, to counteract concerns regarding the lack of physicians, supply shortage and migration of specialists. Therefore, expectations, wishes and concerns relevant to the anticipated everyday life as a physician of medical students at the Witten/Herdecke University (UWH) were acquired with an online questionnaire. Useful for a direct comparison the results of the online survey 'Medical Study and Future' throughout Germany have been used. Findings from this survey are common characteristics regarding the choice of the profession and planning of an establishment as a general practitioner and clear differences in reflecting on future issues in the occupational field. PMID- 21818236 TI - A Novel Large-scale Mentoring Program for Medical Students based on a Quantitative and Qualitative Needs Analysis. AB - PURPOSE: Mentoring plays an important role in students' performance and career. The authors of this study assessed the need for mentoring among medical students and established a novel large-scale mentoring program at Ludwig-Maximilians University (LMU) Munich School of Medicine. METHODS: Needs assessment was conducted using a survey distributed to all students at the medical school (n=578 of 4,109 students, return rate 14.1%). In addition, the authors held focus groups with selected medical students (n=24) and faculty physicians (n=22). All students signing up for the individual mentoring completed a survey addressing their expectations (n=534). RESULTS: Needs assessment revealed that 83% of medical students expressed overall satisfaction with the teaching at LMU. In contrast, only 36.5% were satisfied with how the faculty supports their individual professional development and 86% of students voiced a desire for more personal and professional support. When asked to define the role of a mentor, 55.6% "very much" wanted their mentors to act as counselors, arrange contacts for them (36.4%), and provide ideas for professional development (28.1%). Topics that future mentees "very much" wished to discuss included research (56.6%), final year electives (55.8%) and experiences abroad (45.5%). CONCLUSIONS: Based on the strong desire for mentoring among medical students, the authors developed a novel two-tiered system that introduces one-to-one mentoring for students in their clinical years and offers society-based peer mentoring for pre-clinical students. One year after launching the program, more than 300 clinical students had experienced one-to-one mentoring and 1,503 students and physicians were involved in peer mentoring societies. PMID- 21818237 TI - Evidence-based Nursing Education - a Systematic Review of Empirical Research. AB - The project "Evidence-based Nursing Education - Preparatory Stage", funded by the Landesstiftung Baden-Wurttemberg within the programme Impulsfinanzierung Forschung (Funding to Stimulate Research), aims to collect information on current research concerned with nursing education and to process existing data. The results of empirical research which has already been carried out were systematically evaluated with aim of identifying further topics, fields and matters of interest for empirical research in nursing education. In the course of the project, the available empirical studies on nursing education were scientifically analysed and systematised. The over-arching aim of the evidence based training approach - which extends beyond the aims of this project - is the conception, organisation and evaluation of vocational training and educational processes in the caring professions on the basis of empirical data. The following contribution first provides a systematic, theoretical link to the over-arching reference framework, as the evidence-based approach is adapted from thematically related specialist fields. The research design of the project is oriented towards criteria introduced from a selection of studies and carries out a two-stage systematic review of the selected studies. As a result, the current status of research in nursing education, as well as its organisation and structure, and questions relating to specialist training and comparative education are introduced and discussed. Finally, the empirical research on nursing training is critically appraised as a complementary element in educational theory/psychology of learning and in the ethical tradition of research.This contribution aims, on the one hand, to derive and describe the methods used, and to introduce the steps followed in gathering and evaluating the data. On the other hand, it is intended to give a systematic overview of empirical research work in nursing education. In order to preserve a holistic view of the research field and methods, detailed individual findings are not included. PMID- 21818238 TI - Integrative vs. Traditional Learning from the Student Perspective. AB - BACKGROUND: The interdisciplinary surgery block of the reformed undergraduate curriculum HeiCuMed includes daily cycles of interactive case-based seminars, problem-based tutorials, case presentation by students, skills and communication training, and bedside teaching. The teaching doctors receive didactic training. In contrast, the previous traditional course was based on lectures with only two weekly hours of bedside teaching. Didactic training was not available. OBJECTIVE: The present work aims at analysing the importance of active participation of students and the didactic components of the reformed and traditional curricula, which contribute to successful learning as evaluated by the students. METHOD: Differentiated student evaluations of the undergraduate surgical courses between 1999 and 2008 were examined by correlation and regression analyses. RESULTS: The evaluation scores for organisation, dedication of the teaching staff, their ability to make lessons interesting and complex topics easily understandable, and the subjective gain of knowledge were significantly better in HeiCuMed than in the traditional curriculum. However, the dependence of knowledge gain on the didactic quality was the same in both curricula. The quality of discussions and the ability of the teaching doctors to promote active student participation were important to the subjective gain of knowledge in both seminars and practical courses of the reformed curriculum as well as for the overall evaluation of the practical courses but not the gain of knowledge in the traditional curriculum. CONCLUSION: The findings confirm psychological-educational perceptions, that competent implementation of integrative didactical methods is more important to successful teaching and the subjective gain of knowledge than knowledge transfer by traditional classroom teaching. PMID- 21818239 TI - A Model for Persistent Improvement of Medical Education as Illustrated by the Surgical Reform Curriculum HeiCuMed. AB - BACKGROUND: Heidelberg Medical School underwent a major curricular change with the implementation of the reform curriculum HeiCuMed (Heidelberg Curriculum Medicinale) in October 2001. It is based on rotational modules with daily cycles of interactive, case-based small-group seminars, PBL tutorials and training of sensomotor and communication skills. For surgical undergraduate training an organisational structure was developed that ensures continuity of medical teachers for student groups and enables their unimpaired engagement for defined periods of time while accounting for the daily clinical routine in a large surgery department of a university hospital. It includes obligatory didactic training, standardising teaching material on the basis of learning objectives and releasing teaching doctors from clinical duties for the duration of a module. OBJECTIVE: To compare the effectiveness of the undergraduate surgical reform curriculum with that of the preceding traditional one as reflected by students' evaluations. METHOD: The present work analyses student evaluations of the undergraduate surgical training between 1999 and 2008 including three cohorts (~360 students each) in the traditional curriculum and 13 cohorts (~150 students each) in the reform curriculum. RESULTS: The evaluation of the courses, their organisation, the teaching quality, and the subjective learning was significantly better in HeiCuMed than in the preceding traditional curriculum over the whole study period. CONCLUSION: A medical curriculum based on the implementation of interactive didactical methods is more important to successful teaching and the subjective gain of knowledge than knowledge transfer by traditional classroom teaching. The organisational strategy adopted in the surgical training of HeiCuMed has been successful in enabling the maintenance of a complex modern curriculum on a continuously high level within the framework of a busy surgical environment. PMID- 21818240 TI - The Questionnaire "SFDP26-German": a reliable tool for evaluation of clinical teaching? AB - AIMS: Evaluation of the effectiveness of clinical teaching is an important contribution for the quality control of medical teaching. This should be evaluated using a reliable instrument in order to be able to both gauge the status quo and the effects of instruction. In the Stanford Faculty Development Program (SFDP), seven categories have proven to be appropriate: Establishing the Learning Climate, Controlling a Teaching Session, Communication of Goals, Encouraging Understanding and Retention, Evaluation, Feedback and Self-directed Learning. Since 1998, the SFDP26 questionnaire has established itself as an evaluation tool in English speaking countries. To date there is no equivalent German-language questionnaire available which evaluates the overall effectiveness of teaching. QUESTION: Development and theoretical testing of a German-language version of SFDP26 (SFDP26-German),Check the correlation of subscale of SFDPGerman against overall effectiveness of teaching. METHODS: 19 anaesthetists (7 female, 12 male) from the University of Lubeck were evaluated at the end of a teaching seminar on emergency medical care using SFDP-German. The sample consisted of 173 medical students (119 female (68.8%) and 54 male (31.2%), mostly from the fifth semester (6.6%) and sixth semester (80.3%). The mean age of the students was 23+/ 3 years. RESULTS: The discriminatory power of all items ranged between good and excellent (r(it)=0.48-0.75). All subscales displayed good internal consistency (alpha=0.69-0.92) and significant positive inter-scale correlations (r=0.40 0.70). The subscales and "overall effectiveness of teaching" showed significant correlation, with the highest correlation for the subscale "communication of goals (p< 0.001; r = 0.61). CONCLUSION: The analysis of SFDP26-German confirms high internal consistency. Future research should investigate the effectiveness of the individual categories on the overall effectiveness of teaching and validate according to external criteria. PMID- 21818241 TI - Development of a questionnaire to assess medical competencies: Reliability and validity of the Questionnaire. AB - INTRODUCTION: While preparing a graduate survey for medical education in 2008 we realized that no instrument existed that would be suitable to evaluate whether the learning outcomes outlined in the Medical Licensure Act (AAppO) would be met. Therefore we developed the Freiburg Questionnaire to Assess Competencies in Medicine (Freiburger Fragebogen zur Erfassung von Kompetenzen in der Medizin, FKM)(1) which has been revised and extended several times since then.Currently the FKM includes 45 items which are assigned to nine domains that correspond to the CanMEDS roles: medical expertise, communication, team-work, health and prevention, management, professionalism, learning, scholarship, and personal competencies. METHODS: In order to test the reliability and validity of the questionnaire we have repeatedly surveyed medical students and residents since May 2008. In this article we report on the results of a cross-sectional study with 698 medical students from the preclinical and clinical years. In addition, we report the results of a survey of 514 residents who were up to two years into their residency. RESULTS AND CONCLUSIONS: In summary, results show that the scales of the FKM are reliable (Cronbach's alpha between .68 and .97). Significant differences in means between selected groups of students support the measure's construct validity. Furthermore, there is evidence that the FKM might be used as a screening tool e.g. in graduate surveys to identify weaknesses in the medical education curriculum. PMID- 21818242 TI - Archive of the Medical Education periodical. PMID- 21818243 TI - School based working memory training: Preliminary finding of improvement in children's mathematical performance. AB - Working memory is a complex cognitive system responsible for the concurrent storage and processing of information. Ggiven that a complex cognitive task like mental arithmetic clearly places demands on working memory (e.g., in remembering partial results, monitoring progress through a multi-step calculation), there is surprisingly little research exploring the possibility of increasing young children's working memory capacity through systematic school-based training. Tthis study reports the preliminary results of a working memory training programme, targeting executive processes such as inhibiting unwanted information, monitoring processes, and the concurrent storage and processing of information. Tthe findings suggest that children who received working memory training made significantly greater gains in the trained working memory task, and in a non trained visual-spatial working memory task, than a matched control group. Moreover, the training group made significant improvements in their mathematical functioning as measured by the number of errors made in an addition task compared to the control group. Tthese findings, although preliminary, suggest that school based measures to train working memory could have benefits in terms of improved performance in mathematics. PMID- 21818244 TI - The role of response modalities in cognitive task representations. AB - The execution of a task necessitates the use of a specific response modality. We examined the role of different response modalities by using a task-switching paradigm. In Experiment 1, subjects switched between two numerical judgments, whereas response modality (vocal vs. manual vs. foot responses) was manipulated between groups. We found judgment-shift costs in each group, that is irrespective of the response modality. In Experiment 2, subjects switched between response modalities (vocal vs. manual, vocal vs. foot, or manual vs. foot). We observed response-modality shift costs that were comparable in all groups. In sum, the experiments suggest that the response modality (combination) does not affect switching per se. Yet, modality-shift costs occur when subjects switch between response modalities. Thus, we suppose that modality-shift costs are not due to a purely motor-related mechanisms but rather emerge from a general switching process. Consequently, the response modality has to be considered as a cognitive component in models of task switching. PMID- 21818245 TI - Survival ensembles by the sum of pairwise differences with application to lung cancer microarray studies. AB - Lung cancer is among the most common cancers in the United States, in terms of incidence and mortality. In 2009, it is estimated that more than 150,000 deaths will result from lung cancer alone. Genetic information is an extremely valuable data source in characterizing the personal nature of cancer. Over the past several years, investigators have conducted numerous association studies where intensive genetic data is collected on relatively few patients compared to the numbers of gene predictors, with one scientific goal being to identify genetic features associated with cancer recurrence or survival. In this note, we propose high-dimensional survival analysis through a new application of boosting, a powerful tool in machine learning. Our approach is based on an accelerated lifetime model and minimizing the sum of pairwise differences in residuals. We apply our method to a recent microarray study of lung adenocarcinoma and find that our ensemble is composed of 19 genes while a proportional hazards (PH) ensemble is composed of nine genes, a proper subset of the 19-gene panel. In one of our simulation scenarios, we demonstrate that PH boosting in a misspecified model tends to underfit and ignore moderately-sized covariate effects, on average. Diagnostic analyses suggest that the PH assumption is not satisfied in the microarray data and may explain, in part, the discrepancy in the sets of active coefficients. Our simulation studies and comparative data analyses demonstrate how statistical learning by PH models alone is insufficient. PMID- 21818249 TI - The Barcode of Life Data Portal: bridging the biodiversity informatics divide for DNA barcoding. AB - With the volume of molecular sequence data that is systematically being generated globally, there is a need for centralized resources for data exploration and analytics. DNA Barcode initiatives are on track to generate a compendium of molecular sequence-based signatures for identifying animals and plants. To date, the range of available data exploration and analytic tools to explore these data have only been available in a boutique form--often representing a frustrating hurdle for many researchers that may not necessarily have resources to install or implement algorithms described by the analytic community. The Barcode of Life Data Portal (BDP) is a first step towards integrating the latest biodiversity informatics innovations with molecular sequence data from DNA barcoding. Through establishment of community driven standards, based on discussion with the Data Analysis Working Group (DAWG) of the Consortium for the Barcode of Life (CBOL), the BDP provides an infrastructure for incorporation of existing and next generation DNA barcode analytic applications in an open forum. PMID- 21818250 TI - Genomic regions identified by overlapping clusters of nominally-positive SNPs from genome-wide studies of alcohol and illegal substance dependence. AB - Declaring "replication" from results of genome wide association (GWA) studies is straightforward when major gene effects provide genome-wide significance for association of the same allele of the same SNP in each of multiple independent samples. However, such unambiguous replication is unlikely when phenotypes display polygenic genetic architecture, allelic heterogeneity, locus heterogeneity and when different samples display linkage disequilibria with different fine structures. We seek chromosomal regions that are tagged by clustered SNPs that display nominally-significant association in each of several independent samples. This approach provides one "nontemplate" approach to identifying overall replication of groups of GWA results in the face of difficult genetic architectures. We apply this strategy to 1 M SNP GWA results for dependence on: a) alcohol (including many individuals with dependence on other addictive substances) and b) at least one illegal substance (including many individuals dependent on alcohol). This approach provides high confidence in rejecting the null hypothesis that chance alone accounts for the extent to which clustered, nominally-significant SNPs from samples of the same racial/ethnic background identify the same sets of chromosomal regions. It identifies several genes that are also reported in other independent alcohol-dependence GWA datasets. There is more modest confidence in: a) identification of individual chromosomal regions and genes that are not also identified by data from other independent samples, b) the more modest overlap between results from samples of different racial/ethnic backgrounds and c) the extent to which any gene not identified herein is excluded, since the power of each of these individual samples is modest. Nevertheless, the strong overlap identified among the samples with similar racial/ethnic backgrounds supports contributions to individual differences in vulnerability to addictions that come from newer allelic variants that are common in subsets of current humans. PMID- 21818251 TI - The melanin-concentrating hormone (MCH) system modulates behaviors associated with psychiatric disorders. AB - Deficits in sensorimotor gating measured by prepulse inhibition (PPI) of the startle have been known as characteristics of patients with schizophrenia and related neuropsychiatric disorders. PPI disruption is thought to rely on the activity of the mesocorticolimbic dopaminergic system and is inhibited by most antipsychotic drugs. These drugs however act also at the nigrostriatal dopaminergic pathway and exert adverse locomotor responses. Finding a way to inhibit the mesocorticolimbic- without affecting the nigrostriatal-dopaminergic pathway may thus be beneficial to antipsychotic therapies. The melanin concentrating hormone (MCH) system has been shown to modulate dopamine-related responses. Its receptor (MCH1R) is expressed at high levels in the mesocorticolimbic and not in the nigrostriatal dopaminergic pathways. Interestingly a genomic linkage study revealed significant associations between schizophrenia and markers located in the MCH1R gene locus. We hypothesize that the MCH system can selectively modulate the behavior associated with the mesocorticolimbic dopamine pathway. Using mice, we found that central administration of MCH potentiates apomorphine-induced PPI deficits. Using congenic rat lines that differ in their responses to PPI, we found that the rats that are susceptible to apomorphine (APO-SUS rats) and exhibit PPI deficits display higher MCH mRNA expression in the lateral hypothalamic region and that blocking the MCH system reverses their PPI deficits. On the other hand, in mice and rats, activation or inactivation of the MCH system does not affect stereotyped behaviors, dopamine-related responses that depend on the activity of the nigrostriatal pathway. Furthermore MCH does not affect dizocilpine-induced PPI deficit, a glutamate related response. Thus, our data present the MCH system as a regulator of sensorimotor gating, and provide a new rationale to understand the etiologies of schizophrenia and related psychiatric disorders. PMID- 21818252 TI - DNA barcode libraries provide insight into continental patterns of avian diversification. AB - BACKGROUND: The causes for the higher biodiversity in the Neotropics as compared to the Nearctic and the factors promoting species diversification in each region have been much debated. The refuge hypothesis posits that high tropical diversity reflects high speciation rates during the Pleistocene, but this conclusion has been challenged. The present study investigates this matter by examining continental patterns of avian diversification through the analysis of large-scale DNA barcode libraries. METHODOLOGY AND PRINCIPAL FINDINGS: Standardized COI datasets from the avifaunas of Argentina, the Nearctic, and the Palearctic were analyzed. Average genetic distances between closest congeners and sister species were higher in Argentina than in North America reflecting a much higher percentage of recently diverged species in the latter region. In the Palearctic genetic distances between closely related species appeared to be more similar to those of the southern Neotropics. Average intraspecific variation was similar in Argentina and North America, while the Palearctic fauna had a higher value due to a higher percentage of variable species. Geographic patterning of intraspecific structure was more complex in the southern Neotropics than in the Nearctic, while the Palearctic showed an intermediate level of complexity. CONCLUSIONS AND SIGNIFICANCE: DNA barcodes can reveal continental patterns of diversification. Our analysis suggests that avian species are older in Argentina than in the Nearctic, supporting the idea that the greater diversity of the Neotropical avifauna is not caused by higher recent speciation rates. Species in the Palearctic also appear to be older than those in the Nearctic. These results, combined with the patterns of geographic structuring found in each region, suggest a major impact of Pleistocene glaciations in the Nearctic, a lesser effect in the Palearctic and a mild effect in the southern Neotropics. PMID- 21818253 TI - It costs to be clean and fit: energetics of comfort behavior in breeding-fasting penguins. AB - BACKGROUND: Birds may allocate a significant part of time to comfort behavior (e.g., preening, stretching, shaking, etc.) in order to eliminate parasites, maintain plumage integrity, and possibly reduce muscular ankylosis. Understanding the adaptive value of comfort behavior would benefit from knowledge on the energy costs animals are willing to pay to maintain it, particularly under situations of energy constraints, e.g., during fasting. We determined time and energy devoted to comfort activities in freely breeding king penguins (Aptenodytes patagonicus), seabirds known to fast for up to one month during incubation shifts ashore. METHODOLOGY/PRINCIPAL FINDINGS: A time budget was estimated from focal and scan sampling field observations and the energy cost of comfort activities was calculated from the associated increase in heart rate (HR) during comfort episodes, using previously determined equations relating HR to energy expenditure. We show that incubating birds spent 22% of their daily time budget in comfort behavior (with no differences between day and night) mainly devoted to preening (73%) and head/body shaking (16%). During comfort behavior, energy expenditure averaged 1.24 times resting metabolic rate (RMR) and the corresponding energy cost (i.e., energy expended in excess to RMR) was 58 kJ/hr. Energy expenditure varied greatly among various types of comfort behavior, ranging from 1.03 (yawning) to 1.78 (stretching) times RMR. Comfort behavior contributed 8.8-9.3% to total daily energy expenditure and 69.4-73.5% to energy expended daily for activity. About half of this energy was expended caring for plumage. CONCLUSION/SIGNIFICANCE: This study is the first to estimate the contribution of comfort behavior to overall energy budget in a free-living animal. It shows that although breeding on a tight energy budget, king penguins devote a substantial amount of time and energy to comfort behavior. Such findings underline the importance of comfort behavior for the fitness of colonial seabirds. PMID- 21818254 TI - Induction of stable drug resistance in human breast cancer cells using a combinatorial zinc finger transcription factor library. AB - Combinatorial libraries of artificial zinc-finger transcription factors (ZF-TFs) provide a robust tool for inducing and understanding various functional components of the cancer phenotype. Herein, we utilized combinatorial ZF-TF library technology to better understand how breast cancer cells acquire resistance to fulvestrant, a clinically important anti-endocrine therapeutic agent. From a diverse collection of nearly 400,000 different ZF-TFs, we isolated six ZF-TF library members capable of inducing stable, long-term anti-endocrine drug-resistance in two independent estrogen receptor-positive breast cancer cell lines. Comparative gene expression profile analysis of the six different ZF-TF transduced breast cancer cell lines revealed five distinct clusters of differentially expressed genes. One cluster was shared among all 6 ZF-TF transduced cell lines and therefore constituted a common fulvestrant-resistant gene expression signature. Pathway enrichment-analysis of this common fulvestrant resistant signature also revealed significant overlap with gene sets associated with an estrogen receptor-negative-like state and with gene sets associated with drug resistance to different classes of breast cancer anti-endocrine therapeutic agents. Enrichment-analysis of the four remaining unique gene clusters revealed overlap with myb-regulated genes. Finally, we also demonstrated that the common fulvestrant-resistant signature is associated with poor prognosis by interrogating five independent, publicly available human breast cancer gene expression datasets. Our results demonstrate that artificial ZF-TF libraries can be used successfully to induce stable drug-resistance in human cancer cell lines and to identify a gene expression signature that is associated with a clinically relevant drug-resistance phenotype. PMID- 21818255 TI - Immunodominance of HIV-1 specific CD8+ T-cell responses is related to disease progression rate in vertically infected adolescents. AB - BACKGROUND: HIV-1 vertically infected children in the USA are living into adolescence and beyond with the widespread use of antiretroviral drugs. These patients exhibit striking differences in the rate of HIV-1 disease progression which could provide insights into mechanisms of control. We hypothesized that differences in the pattern of immunodomination including breadth, magnitude and polyfunctionality of HIV-1 specific CD8+ T cell response could partially explain differences in progression rate. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we mapped, quantified, and assessed the functionality of these responses against individual HIV-1 Gag peptides in 58 HIV-1 vertically infected adolescents. Subjects were divided into two groups depending upon the rate of disease progression: adolescents with a sustained CD4%>=25 were categorized as having no immune suppression (NS), and those with CD4%<=15 categorized as having severe immune suppression (SS). We observed differences in the area of HIV-1-Gag to which the two groups made responses. In addition, subjects who expressed the HLA- B*57 or B*42 alleles were highly likely to restrict their immunodominant response through these alleles. There was a significantly higher frequency of naive CD8+ T cells in the NS subjects (p = 0.0066) compared to the SS subjects. In contrast, there were no statistically significant differences in any other CD8+ T cell subsets. The differentiation profiles and multifunctionality of Gag-specific CD8+ T cells, regardless of immunodominance, also failed to demonstrate meaningful differences between the two groups. CONCLUSIONS/SIGNIFICANCE: Together, these data suggest that, at least in vertically infected adolescents, the region of HIV 1-Gag targeted by CD8+ T cells and the magnitude of that response relative to other responses may have more importance on the rate of disease progression than their qualitative effector functions. PMID- 21818256 TI - Pyrosequencing for mini-barcoding of fresh and old museum specimens. AB - DNA barcoding is an effective approach for species identification and for discovery of new and/or cryptic species. Sanger sequencing technology is the method of choice for obtaining standard 650 bp cytochrome c oxidase subunit I (COI) barcodes. However, DNA degradation/fragmentation makes it difficult to obtain a full-length barcode from old specimens. Mini-barcodes of 130 bp from the standard barcode region have been shown to be effective for accurate identification in many animal groups and may be readily obtained from museum samples. Here we demonstrate the application of an alternative sequencing technology, the four-enzymes single-specimen pyrosequencing, in rapid, cost effective mini-barcode analysis. We were able to generate sequences of up to 100 bp from mini-barcode fragments of COI in 135 fresh and 50 old Lepidoptera specimens (ranging from 53-97 year-old). The sequences obtained using pyrosequencing were of high quality and we were able to robustly match all the tested pyro-sequenced samples to their respective Sanger-sequenced standard barcode sequences, where available. Simplicity of the protocol and instrumentation coupled with higher speed and lower cost per sequence than Sanger sequencing makes this approach potentially useful in efforts to link standard barcode sequences from unidentified specimens to known museum specimens with only short DNA fragments. PMID- 21818257 TI - Molecular sub-classification of renal epithelial tumors using meta-analysis of gene expression microarrays. AB - PURPOSE: To evaluate the accuracy of the sub-classification of renal cortical neoplasms using molecular signatures. EXPERIMENTAL DESIGN: A search of publicly available databases was performed to identify microarray datasets with multiple histologic sub-types of renal cortical neoplasms. Meta-analytic techniques were utilized to identify differentially expressed genes for each histologic subtype. The lists of genes obtained from the meta-analysis were used to create predictive signatures through the use of a pair-based method. These signatures were organized into an algorithm to sub-classify renal neoplasms. The use of these signatures according to our algorithm was validated on several independent datasets. RESULTS: We identified three Gene Expression Omnibus datasets that fit our criteria to develop a training set. All of the datasets in our study utilized the Affymetrix platform. The final training dataset included 149 samples represented by the four most common histologic subtypes of renal cortical neoplasms: 69 clear cell, 41 papillary, 16 chromophobe, and 23 oncocytomas. When validation of our signatures was performed on external datasets, we were able to correctly classify 68 of the 72 samples (94%). The correct classification by subtype was 19/20 (95%) for clear cell, 14/14 (100%) for papillary, 17/19 (89%) for chromophobe, 18/19 (95%) for oncocytomas. CONCLUSIONS: Through the use of meta-analytic techniques, we were able to create an algorithm that sub-classified renal neoplasms on a molecular level with 94% accuracy across multiple independent datasets. This algorithm may aid in selecting molecular therapies and may improve the accuracy of subtyping of renal cortical tumors. PMID- 21818258 TI - Two different template replicators coexisting in the same protocell: stochastic simulation of an extended chemoton model. AB - The simulation of complex biochemical systems, consisting of intertwined subsystems, is a challenging task in computational biology. The complex biochemical organization of the cell is effectively modeled by the minimal cell model called chemoton, proposed by Ganti. Since the chemoton is a system consisting of a large but fixed number of interacting molecular species, it can effectively be implemented in a process algebra-based language such as the BlenX programming language. The stochastic model behaves comparably to previous continuous deterministic models of the chemoton. Additionally to the well-known chemoton, we also implemented an extended version with two competing template cycles. The new insight from our study is that the coupling of reactions in the chemoton ensures that these templates coexist providing an alternative solution to Eigen's paradox. Our technical innovation involves the introduction of a two state switch to control cell growth and division, thus providing an example for hybrid methods in BlenX. Further developments to the BlenX language are suggested in the Appendix. PMID- 21818259 TI - Spherical harmonics coefficients for ligand-based virtual screening of cyclooxygenase inhibitors. AB - BACKGROUND: Molecular descriptors are essential for many applications in computational chemistry, such as ligand-based similarity searching. Spherical harmonics have previously been suggested as comprehensive descriptors of molecular structure and properties. We investigate a spherical harmonics descriptor for shape-based virtual screening. METHODOLOGY/PRINCIPAL FINDINGS: We introduce and validate a partially rotation-invariant three-dimensional molecular shape descriptor based on the norm of spherical harmonics expansion coefficients. Using this molecular representation, we parameterize molecular surfaces, i.e., isosurfaces of spatial molecular property distributions. We validate the shape descriptor in a comprehensive retrospective virtual screening experiment. In a prospective study, we virtually screen a large compound library for cyclooxygenase inhibitors, using a self-organizing map as a pre-filter and the shape descriptor for candidate prioritization. CONCLUSIONS/SIGNIFICANCE: 12 compounds were tested in vitro for direct enzyme inhibition and in a whole blood assay. Active compounds containing a triazole scaffold were identified as direct cyclooxygenase-1 inhibitors. This outcome corroborates the usefulness of spherical harmonics for representation of molecular shape in virtual screening of large compound collections. The combination of pharmacophore and shape-based filtering of screening candidates proved to be a straightforward approach to finding novel bioactive chemotypes with minimal experimental effort. PMID- 21818260 TI - Analyzing three-player quantum games in an EPR type setup. AB - We use the formalism of Clifford Geometric Algebra (GA) to develop an analysis of quantum versions of three-player non-cooperative games. The quantum games we explore are played in an Einstein-Podolsky-Rosen (EPR) type setting. In this setting, the players' strategy sets remain identical to the ones in the mixed strategy version of the classical game that is obtained as a proper subset of the corresponding quantum game. Using GA we investigate the outcome of a realization of the game by players sharing GHZ state, W state, and a mixture of GHZ and W states. As a specific example, we study the game of three-player Prisoners' Dilemma. PMID- 21818261 TI - Smoking is associated with, but does not cause, depressed mood in pregnancy--a mendelian randomization study. AB - Smokers have a higher prevalence of major depressive episodes and depressive symptoms than the general population, but whether this association is causal, or is due to confounding or reverse causation is uncertain because of the problems inherent in some epidemiological studies. Mendelian randomization, in which a genetic variant is used as a surrogate for measuring exposure, is an approach which may be used to better understand this association. We investigated the rs1051730 single nucleotide polymorphism in the nicotine acetylcholine receptor gene cluster (CHRNA5-CHRNA3-CHRNB4), associated with smoking phenotypes, to determine whether women who continued to smoke were also more likely to report a low mood during pregnancy. We found among women who smoked pre-pregnancy, those with the 1051730 T allele smoked more and were less likely to quit smoking during pregnancy, but were also less likely to report high levels of depressed mood at 18 weeks of pregnancy (per allele OR = 0.84, 95%CI 0.72 to 0.99, p = 0.034). The association between genotype and depressed mood was limited to women who were smokers prior to pregnancy, with weak evidence of an interaction between smoking status and genotype (p = 0.07). Our results do not support a causal role of smoking on depressed mood, but are consistent with a self-medication hypothesis, whereby smoking is used to alleviate symptoms of depression. A replication study using multiple genetic variants which influence smoking via different pathways is required to confirm these findings and provide evidence that the genetic variant is reflecting the effect of quitting smoking on depressed mood, and is not directly affecting mood. PMID- 21818262 TI - The use of research evidence in public health decision making processes: systematic review. AB - BACKGROUND: The use of research evidence to underpin public health policy is strongly promoted. However, its implementation has not been straightforward. The objectives of this systematic review were to synthesise empirical evidence on the use of research evidence by public health decision makers in settings with universal health care systems. METHODS: To locate eligible studies, 13 bibliographic databases were screened, organisational websites were scanned, key informants were contacted and bibliographies of included studies were scrutinised. Two reviewers independently assessed studies for inclusion, extracted data and assessed methodological quality. Data were synthesised as a narrative review. FINDINGS: 18 studies were included: 15 qualitative studies, and three surveys. Their methodological quality was mixed. They were set in a range of country and decision making settings. Study participants included 1063 public health decision makers, 72 researchers, and 174 with overlapping roles. Decision making processes varied widely between settings, and were viewed differently by key players. A range of research evidence was accessed. However, there was no reliable evidence on the extent of its use. Its impact was often indirect, competing with other influences. Barriers to the use of research evidence included: decision makers' perceptions of research evidence; the gulf between researchers and decision makers; the culture of decision making; competing influences on decision making; and practical constraints. Suggested (but largely untested) ways of overcoming these barriers included: research targeted at the needs of decision makers; research clearly highlighting key messages; and capacity building. There was little evidence on the role of research evidence in decision making to reduce inequalities. CONCLUSIONS: To more effectively implement research informed public health policy, action is required by decision makers and researchers to address the barriers identified in this systematic review. There is an urgent need for evidence to support the use of research evidence to inform public health decision making to reduce inequalities. PMID- 21818263 TI - The role of AGG interruptions in the transcription of FMR1 premutation alleles. AB - Fragile X associated disorders are caused by a premutation allele in the fragile X mental retardation 1 gene (FMR1) and are hypothesized to result from the toxic effect of elevated levels of expanded FMR1 transcripts. Increased levels of FMR1 mRNA have indeed been reported in premutation carriers; however the mechanism by which expanded alleles lead to elevated levels of FMR1 mRNA in premutation carriers is unknown. Within the CGG repeat tract AGG interruptions are found, generally 1-3 present in normal/intermediate alleles (6-54 CGG repeats) and usually 0-1 in premutation alleles (55-200 CGG repeats). They are present at specific locations, generally occurring after 9 or 10 uninterrupted CGG repeats [(CGG)(9)AGG(CGG)(9)AGG(CGG)(n)]. We evaluated both the number of AGG interruptions and the resulting length of the uninterrupted 3' CGG repeat pure tract in premutation alleles derived from two large cohorts of male and female carriers to determine whether the presence of AGG interruptions or the length of a pure stretch of CGG repeats influence the levels of FMR1 mRNA in blood. Our findings indicate that neither the number of AGG interruptions, nor their position along the CGG tract have a significant affect on mRNA levels in premutation carriers. We also, as expected based on previous findings, observed a highly significant correlation between CGG repeat number (as both total length and length of pure CGG stretch) and FMR1 mRNA expression levels, in both males and females. Importantly, we did not observe any significant difference in FMR1 mRNA levels in premutation carriers based on age. PMID- 21818264 TI - Predator-induced morphological plasticity across local populations of a freshwater snail. AB - The expression of anti-predator adaptations may vary on a spatial scale, favouring traits that are advantageous in a given predation regime. Besides, evolution of different developmental strategies depends to a large extent on the grain of the environment and may result in locally canalized adaptations or, alternatively, the evolution of phenotypic plasticity as different predation regimes may vary across habitats. We investigated the potential for predator driven variability in shell morphology in a freshwater snail, Radix balthica, and whether found differences were a specialized ecotype adaptation or a result of phenotypic plasticity. Shell shape was quantified in snails from geographically separated pond populations with and without molluscivorous fish. Subsequently, in a common garden experiment we investigated reaction norms of snails from populations' with/without fish when exposed to chemical cues from tench (Tinca tinca), a molluscivorous fish. We found that snails from fish-free ponds had a narrow shell with a well developed spire, whereas snails that coexisted with fish had more rotund shells with a low spire, a shell morphology known to increase survival rate from shell-crushing predators. The common garden experiment mirrored the results from the field survey and showed that snails had similar reaction norms in response to chemical predator cues, i.e. the expression of shell shape was independent of population origin. Finally, we found significant differences for the trait means among populations, within each pond category (fish/fish free), suggesting a genetic component in the determination of shell morphology that has evolved independently across ponds. PMID- 21818265 TI - Retention in care and connection to care among HIV-infected patients on antiretroviral therapy in Africa: estimation via a sampling-based approach. AB - INTRODUCTION: Current estimates of retention among HIV-infected patients on antiretroviral therapy (ART) in Africa consider patients who are lost to follow up (LTF) as well as those who die shortly after their last clinic visit to be no longer in care and to represent limitations in access to care. Yet many lost patients may have "silently" transferred and deaths shortly after the last clinic visit more likely represent limitations in clinical care rather than access to care after initial linkage. METHODS: We evaluated HIV-infected adults initiating ART from 1/1/2004 to 9/30/2007 at a clinic in rural Uganda. A representative sample of lost patients was tracked in the community to obtain updated information about care at other ART sites. Updated outcomes were incorporated with probability weights to obtain "corrected" estimates of retention for the entire clinic population. We used the competing risks approach to estimate "connection to care"--the percentage of patients accessing care over time (including those who died while in care). RESULTS: Among 3,628 patients, 829 became lost, 128 were tracked and in 111, updated information was obtained. Of 111, 79 (71%) were alive and 35/48 (73%) of patients interviewed in person were in care and on ART. Patient retention for the clinic population assuming lost patients were not in care was 82.3%, 68.9%, and 60.1% at 1, 2 and 3 years. Incorporating updated care information from the sample of lost patients increased estimates of patient retention to 85.8% to 90.9%, 78.9% to 86.2% and 75.8% to 84.7% at the same time points. CONCLUSIONS: Accounting for "silent transfers" and early deaths increased estimates of patient retention and connection to care substantially. Deaths soon after the last clinic visit (potentially reflecting limitations in clinical effectiveness) and disconnection from care among patient who were alive each accounted for approximately half of failures of retention. PMID- 21818266 TI - Computational reverse-engineering of a spider-venom derived peptide active against Plasmodium falciparum SUB1. AB - BACKGROUND: Psalmopeotoxin I (PcFK1), a protein of 33 aminoacids derived from the venom of the spider Psalmopoeus Cambridgei, is able to inhibit the growth of Plasmodium falciparum malaria parasites with an IC50 in the low micromolar range. PcFK1 was proposed to act as an ion channel inhibitor, although experimental validation of this mechanism is lacking. The surface loops of PcFK1 have some sequence similarity with the parasite protein sequences cleaved by PfSUB1, a subtilisin-like protease essential for egress of Plasmodium falciparum merozoites and invasion into erythrocytes. As PfSUB1 has emerged as an interesting drug target, we explored the hypothesis that PcFK1 targeted PfSUB1 enzymatic activity. FINDINGS: Molecular modeling and docking calculations showed that one loop could interact with the binding site of PfSUB1. The calculated free energy of binding averaged -5.01 kcal/mol, corresponding to a predicted low-medium micromolar constant of inhibition. PcFK1 inhibited the enzymatic activity of the recombinant PfSUB1 enzyme and the in vitro P. falciparum culture in a range compatible with our bioinformatics analysis. Using contact analysis and free energy decomposition we propose that residues A14 and Q15 are important in the interaction with PfSUB1. CONCLUSIONS: Our computational reverse engineering supported the hypothesis that PcFK1 targeted PfSUB1, and this was confirmed by experimental evidence showing that PcFK1 inhibits PfSUB1 enzymatic activity. This outlines the usefulness of advanced bioinformatics tools to predict the function of a protein structure. The structural features of PcFK1 represent an interesting protein scaffold for future protein engineering. PMID- 21818268 TI - Estimating trends of population decline in long-lived marine species in the Mediterranean Sea based on fishers' perceptions. AB - We conducted interviews of a representative sample of 106 retired fishers in Italy, Spain and Greece, asking specific questions about the trends they perceived in dolphin and shark abundances between 1940 and 1999 (in three 20 year periods) compared to the present abundance. The large marine fauna studied were not target species of the commercial fleet segment interviewed (trawl fishery). The fishers were asked to rank the perceived abundance in each period into qualitative ordinal classes based on two indicators: frequency of sightings and frequency of catches (incidental or intentional) of each taxonomic group. The statistical analysis of the survey results showed that both incidental catches and the sighting frequency of dolphins have decreased significantly over the 60+ years of the study period (except for in Greece due to the recent population increase). This shows that fishers' perceptions are in agreement with the declining population trends detected by scientists. Shark catches were also perceived to have diminished since the early 1940s for all species. Other long lived Mediterranean marine fauna (monk seals, whales) were at very low levels in the second half of the 20(th) century and no quantitative data could be obtained. Our study supports the results obtained in the Mediterranean and other seas that show the rapid disappearance (over a few decades) of marine fauna. We show that appropriately designed questionnaires help provide a picture of animal abundance in the past through the valuable perceptions of fishers. This information can be used to complement scientific sources or in some cases be taken as the only information source for establishing population trends in the abundance of sensitive species. PMID- 21818267 TI - Hypertension is associated with marked alterations in sphingolipid biology: a potential role for ceramide. AB - BACKGROUND: Hypertension is, amongst others, characterized by endothelial dysfunction and vascular remodeling. As sphingolipids have been implicated in both the regulation of vascular contractility and growth, we investigated whether sphingolipid biology is altered in hypertension and whether this is reflected in altered vascular function. METHODS AND FINDINGS: In isolated carotid arteries from spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats, shifting the ceramide/S1P ratio towards ceramide dominance by administration of a sphingosine kinase inhibitor (dimethylsphingosine) or exogenous application of sphingomyelinase, induced marked endothelium-dependent contractions in SHR vessels (DMS: 1.4+/-0.4 and SMase: 2.1+/-0.1 mN/mm; n = 10), that were virtually absent in WKY vessels (DMS: 0.0+/-0.0 and SMase: 0.6+/-0.1 mN/mm; n = 9, p<0.05). Imaging mass spectrometry and immunohistochemistry indicated that these contractions were most likely mediated by ceramide and dependent on iPLA(2), cyclooxygenase-1 and thromboxane synthase. Expression levels of these enzymes were higher in SHR vessels. In concurrence, infusion of dimethylsphingosine caused a marked rise in blood pressure in anesthetized SHR (42+/-4%; n = 7), but not in WKY (-12+/-10%; n = 6). Lipidomics analysis by mass spectrometry, revealed elevated levels of ceramide in arterial tissue of SHR compared to WKY (691+/-42 vs. 419+/-27 pmol, n = 3-5 respectively, p<0.05). These pronounced alterations in SHR sphingolipid biology are also reflected in increased plasma ceramide levels (513+/-19 pmol WKY vs. 645+/-25 pmol SHR, n = 6 12, p<0.05). Interestingly, we observed similar increases in ceramide levels (correlating with hypertension grade) in plasma from humans with essential hypertension (185+/-8 pmol vs. 252+/-23 pmol; n = 18 normotensive vs. n = 19 hypertensive patients, p<0.05). CONCLUSIONS: Hypertension is associated with marked alterations in vascular sphingolipid biology such as elevated ceramide levels and signaling, that contribute to increased vascular tone. PMID- 21818269 TI - Formin1 mediates the induction of dendritogenesis and synaptogenesis by neurogenin3 in mouse hippocampal neurons. AB - Neurogenin3, a proneural transcription factor controlled by Notch receptor, has been recently shown to regulate dendritogenesis and synaptogenesis in mouse hippocampal neurons. However, little is known about the molecular mechanisms involved in these actions of Ngn3. We have used a microarray analysis to identify Ngn3 regulated genes related with cytoskeleton dynamics. One of such genes is Fmn1, whose protein, Formin1, is associated with actin and microtubule cytoskeleton. Overexpression of the Fmn1 isoform-Ib in cultured mouse hippocampal neurons induced an increase in the number of primary dendrites and in the number of glutamatergic synaptic inputs at 4 days in vitro. The same changes were provoked by overexpression of Ngn3. In addition downregulation of Fmn1 by the use of Fmn1-siRNAs impaired such morphological and synaptic changes induced by Ngn3 overexpression in neurons. These results reveal a previously unknown involvement of Formin1 in dendritogenesis and synaptogenesis and indicate that this protein is a key component of the Ngn3 signaling pathway that controls neuronal differentiation. PMID- 21818270 TI - Toward a surrogate marker of malaria exposure: modeling longitudinal antibody measurements under outbreak conditions. AB - BACKGROUND: Biomarkers of exposure to Plasmodium falciparum would be a useful tool for the assessment of malaria burden and analysis of intervention and epidemiological studies. Antibodies to pre-erythrocytic antigens represent potential surrogates of exposure. METHODS AND FINDINGS: In an outbreak cohort of U.S. Marines deployed to Liberia, we modeled pre- and post-deployment IgG against P. falciparum sporozoites by immunofluorescence antibody test, and both IgG and IgM against the P. falciparum circumsporozoite protein by enzyme-linked immunosorbant assay. Modeling seroconversion thresholds by a fixed ratio, linear regression or nonlinear regression produced sensitivity for identification of exposed U.S. Marines between 58-70% and specificities between 87-97%, compared with malaria-naive U.S. volunteers. Exposure was predicted in 30-45% of the cohort. CONCLUSION: Each of the three models tested has merits in different studies, but further development and validation in endemic populations is required. Overall, these models provide support for an antibody-based surrogate marker of exposure to malaria. PMID- 21818271 TI - Evaluating patterns of a white-band disease (WBD) outbreak in Acropora palmata using spatial analysis: a comparison of transect and colony clustering. AB - BACKGROUND: Despite being one of the first documented, there is little known of the causative agent or environmental stressors that promote white-band disease (WBD), a major disease of Caribbean Acropora palmata. Likewise, there is little known about the spatiality of outbreaks. We examined the spatial patterns of WBD during a 2004 outbreak at Buck Island Reef National Monument in the US Virgin Islands. METHODOLOGY/PRINCIPAL FINDINGS: Ripley's K statistic was used to measure spatial dependence of WBD across scales. Localized clusters of WBD were identified using the DMAP spatial filtering technique. Statistics were calculated for colony- (number of A. palmata colonies with and without WBD within each transect) and transect-level (presence/absence of WBD within transects) data to evaluate differences in spatial patterns at each resolution of coral sampling. The Ripley's K plots suggest WBD does cluster within the study area, and approached statistical significance (p = 0.1) at spatial scales of 1100 m or less. Comparisons of DMAP results suggest the transect-level overestimated the prevalence and spatial extent of the outbreak. In contrast, more realistic prevalence estimates and spatial patterns were found by weighting each transect by the number of individual A. palmata colonies with and without WBD. CONCLUSIONS: As the search for causation continues, surveillance and proper documentation of the spatial patterns may inform etiology, and at the same time assist reef managers in allocating resources to tracking the disease. Our results indicate that the spatial scale of data collected can drastically affect the calculation of prevalence and spatial distribution of WBD outbreaks. Specifically, we illustrate that higher resolution sampling resulted in more realistic disease estimates. This should assist in selecting appropriate sampling designs for future outbreak investigations. The spatial techniques used here can be used to facilitate other coral disease studies, as well as, improve reef conservation and management. PMID- 21818272 TI - Facultative symbiont infections affect aphid reproduction. AB - Some bacterial symbionts alter their hosts reproduction through various mechanisms that enhance their transmission in the host population. In addition to its obligatory symbiont Buchnera aphidicola, the pea aphid Acyrthosiphon pisum harbors several facultative symbionts influencing several aspects of host ecology. Aphids reproduce by cyclical parthenogenesis whereby clonal and sexual reproduction alternate within the annual life cycle. Many species, including the pea aphid, also show variation in their reproductive mode at the population level, with some lineages reproducing by cyclical parthenogenesis and others by permanent parthenogenesis. While the role of facultative symbionts has been well studied during the parthenogenetic phase of their aphid hosts, very little is known on their possible influence during the sexual phase. Here we investigated whether facultative symbionts modulate the capacity to produce sexual forms in various genetic backgrounds of the pea aphid with controlled symbiont composition and also in different aphid genotypes from natural populations with previously characterized infection status and reproductive mode. We found that most facultative symbionts exhibited detrimental effects on their hosts fitness under sex-inducing conditions in comparison with the reference lines. We also showed that the loss of sexual phase in permanently parthenogenetic lineages of A. pisum was not explained by facultative symbionts. Finally, we demonstrated that Spiroplasma infection annihilated the production of males in the host progeny by inducing a male-killing phenotype, an unexpected result for organisms such as aphids that reproduce primarily through clonal reproduction. PMID- 21818273 TI - Feasibility of early infant diagnosis of HIV in resource-limited settings: the ANRS 12140-PEDIACAM study in Cameroon. AB - BACKGROUND: Early infant diagnosis (EID) of HIV is a key-point for the implementation of early HAART, associated with lower mortality in HIV-infected infants. We evaluated the EID process of HIV according to national recommendations, in urban areas of Cameroon. METHODS/FINDINGS: The ANRS12140 PEDIACAM study is a multisite cohort in which infants born to HIV-infected mothers were included before the 8(th) day of life and followed. Collection of samples for HIV DNA/RNA-PCR was planned at 6 weeks together with routine vaccination. The HIV test result was expected to be available at 10 weeks. A positive or indeterminate test result was confirmed by a second test on a different sample. Systematic HAART was offered to HIV-infected infants identified. The EID process was considered complete if infants were tested and HIV results provided to mothers/family before 7 months of age. During 2007-2009, 1587 mother-infant pairs were included in three referral hospitals; most infants (n = 1423, 89.7%) were tested for HIV, at a median age of 1.5 months (IQR, 1.4 1.6). Among them, 51 (3.6%) were HIV-infected. Overall, 1331 (83.9%) completed the process by returning for the result before 7 months (median age: 2.5 months (IQR, 2.4-3.0)). Incomplete process, that is test not performed, or result of test not provided or provided late to the family, was independently associated with late HIV diagnosis during pregnancy (adjusted odds ratio (aOR) = 1.8, 95%CI: 1.1 to 2.9, p = 0.01), absence of PMTCT prophylaxis (aOR = 2.4, 95%CI: 1.4 to 4.3, p = 0.002), and emergency caesarean section (aOR = 2.5, 95%CI: 1.5 to 4.3, p = 0.001). CONCLUSIONS: In urban areas of Cameroon, HIV-infected women diagnosed sufficiently early during pregnancy opt to benefit from EID whatever their socio economic, marital or disclosure status. Reduction of non optimal diagnosis process should focus on women with late HIV diagnosis during pregnancy especially if they did not receive any PMTCT, or if complications occurred at delivery. PMID- 21818274 TI - Characteristics and treatment preferences of people with symptoms of posttraumatic stress disorder: an internet survey. AB - BACKGROUND: Although Posttraumatic Stress Disorder (PTSD) is a severe and disabling anxiety disorder, relatively few people with this condition access evidence-based care. Barriers to treatment are multiple and complex, but the emerging field of Internet therapy for PTSD may improve access to evidence-based treatment. However, little is known about the characteristics of people with PTSD who seek online treatment, or whether they perceive internet treatment as an acceptable treatment option. METHODOLOGY: An online survey was used to collect information about the demographic and symptom characteristics of individuals with elevated levels of PTSD symptoms, and this was compared to data from corresponding sample from a national survey. Previous treatment experiences, perceived barriers to treatment and treatment preferences for Internet therapy and face-to-face treatment were also compared. PRINCIPAL FINDINGS: High levels of PTSD symptoms were reported by survey respondents. Psychological distress and disability was greater than reported by individuals with PTSD from a national survey. Half of the sample reported not having received treatment for PTSD; however, 88% of those who reported receiving treatment stated they received an evidence-based treatment. Primary barriers to treatment included cost, poor awareness of service availability, lack of prior treatment response and not perceiving personal distress as severe enough to warrant treatment. Most survey respondents indicated they were willing to try Internet treatment for PTSD. CONCLUSIONS: The Internet sample was symptomatically severe and multiple barriers existed to treatment. Internet therapy is an acceptable option for the treatment of PTSD in an internet sample. PMID- 21818275 TI - Efficient overproduction of membrane proteins in Lactococcus lactis requires the cell envelope stress sensor/regulator couple CesSR. AB - BACKGROUND: Membrane proteins comprise an important class of molecules whose study is largely frustrated by several intrinsic constraints, such as their hydrophobicity and added requirements for correct folding. Additionally, the complexity of the cellular mechanisms that are required to insert membrane proteins functionally in the membrane and to monitor their folding state makes it difficult to foresee the yields at which one can obtain them or to predict which would be the optimal production host for a given protein. METHODS AND FINDINGS: We describe a rational design approach to improve the lactic acid bacterium Lactococcus lactis as a producer of membrane proteins. Our transcriptome data shows that the two-component system CesSR, which senses cell envelope stresses of different origins, is one of the major players when L. lactis is forced to overproduce the endogenous membrane protein BcaP, a branched-chain amino acid permease. Growth of the BcaP-producing L. lactis strain and its capability to produce membrane proteins are severely hampered when the CesSR system itself or particular members of the CesSR regulon are knocked out, notably the genes ftsH, oxaA2, llmg_2163 and rmaB. Overexpressing cesSR reduced the growth defect, thus directly improving the production yield of BcaP. Applying this rationale to eukaryotic proteins, some of which are notoriously more difficult to produce, such as the medically-important presenilin complex, we were able to significantly diminish the growth defect seen in the wild-type strain and improve the production yield of the presenilin variant PS1Delta9-H6 more than 4-fold. CONCLUSIONS: The results shed light into a key, and perhaps central, membrane protein quality control mechanism in L. lactis. Modulating the expression of CesSR benefited the production yields of membrane proteins from different origins. These findings reinforce L. lactis as a legitimate alternative host for the production of membrane proteins. PMID- 21818276 TI - Increased expression of beta-defensin 1 (DEFB1) in chronic obstructive pulmonary disease. AB - On-going airway inflammation is characteristic for the pathophysiology of chronic obstructive pulmonary disease (COPD). However, the key factors determining the decrease in lung function, an important clinical parameter of COPD, are not clear. Genome-wide linkage analyses provide evidence for significant linkage to airway obstruction susceptibility loci on chromosome 8p23, the location of the human defensin gene cluster. Moreover, a genetic variation in the defensin beta 1 (DEFB1) gene was found to be associated with COPD. Therefore, we hypothesized that DEFB1 is differently regulated and expressed in human lungs during COPD progression. Gene expression of DEFB1 was assessed in bronchial epithelium and BAL fluid cells of healthy controls and patients with COPD and using bisulfite sequencing and ChIP analysis, the epigenetic control of DEFB1 mRNA expression was investigated. We can demonstrate that DEFB1 mRNA expression was significantly increased in bronchopulmonary specimen of patients with COPD (n = 34) vs. healthy controls (n = 10) (p<0.0001). Furthermore, a significant correlation could be detected between DEFB1 and functional parameters such as FEV(1) (p = 0.0024) and the FEV(1)/VC ratio (p = 0.0005). Upregulation of DEFB1 mRNA was paralleled by changes in HDAC1-3, HDAC5 and HDAC8 mRNA expression. Whereas bisulfite sequencing revealed no differences in the methylation state of DEFB1 promoter between patients with COPD and controls, ChIP analysis showed that enhanced DEFB1 mRNA expression was associated with the establishment of an active histone code. Thus, expression of human DEFB1 is upregulated and related to the decrease in pulmonary function in patients with COPD. PMID- 21818277 TI - Nucleoporin mediated nuclear positioning and silencing of HMR. AB - The organization of chromatin domains in the nucleus is an important factor in gene regulation. In eukaryotic nuclei, transcriptionally silenced chromatin clusters at the nuclear periphery while transcriptionally poised chromatin resides in the nuclear interior. Recent studies suggest that nuclear pore proteins (NUPs) recruit loci to nuclear pores to aid in insulation of genes from silencing and during gene activation. We investigated the role of NUPs at a native yeast insulator and show that while NUPs localize to the native tDNA insulator adjacent to the silenced HMR domain, loss of pore proteins does not compromise insulation. Surprisingly we find that NUPs contribute to silencing at HMR and are able to restore silencing to a silencing-defective HMR allele when tethered to the locus. We show that the perinuclear positioning of heterochromatin is important for the NUP-mediated silencing effect and find that loss of NUPs result in decreased localization of HMR to the nuclear periphery. We also show that loss of telomeric tethering pathways does not eliminate NUP localization to HMR, suggesting that NUPs may mediate an independent pathway for HMR association with the nuclear periphery. We propose that localization of NUPs to the tDNA insulator at HMR helps maintain the intranuclear position of the silent locus, which in turn contributes to the fidelity of silencing at HMR. PMID- 21818278 TI - Local field potential modeling predicts dense activation in cerebellar granule cells clusters under LTP and LTD control. AB - Local field-potentials (LFPs) are generated by neuronal ensembles and contain information about the activity of single neurons. Here, the LFPs of the cerebellar granular layer and their changes during long-term synaptic plasticity (LTP and LTD) were recorded in response to punctate facial stimulation in the rat in vivo. The LFP comprised a trigeminal (T) and a cortical (C) wave. T and C, which derived from independent granule cell clusters, co-varied during LTP and LTD. To extract information about the underlying cellular activities, the LFP was reconstructed using a repetitive convolution (ReConv) of the extracellular potential generated by a detailed multicompartmental model of the granule cell. The mossy fiber input patterns were determined using a Blind Source Separation (BSS) algorithm. The major component of the LFP was generated by the granule cell spike Na(+) current, which caused a powerful sink in the axon initial segment with the source located in the soma and dendrites. Reproducing the LFP changes observed during LTP and LTD required modifications in both release probability and intrinsic excitability at the mossy fiber-granule cells relay. Synaptic plasticity and Golgi cell feed-forward inhibition proved critical for controlling the percentage of active granule cells, which was 11% in standard conditions but ranged from 3% during LTD to 21% during LTP and raised over 50% when inhibition was reduced. The emerging picture is that of independent (but neighboring) trigeminal and cortical channels, in which synaptic plasticity and feed-forward inhibition effectively regulate the number of discharging granule cells and emitted spikes generating "dense" activity clusters in the cerebellar granular layer. PMID- 21818279 TI - Influence of FADS polymorphisms on tracking of serum glycerophospholipid fatty acid concentrations and percentage composition in children. AB - BACKGROUND: Tracking of fatty acid (FA) contribution to plasma or serum lipids over time was shown in children and adults. However, the potential role of FADS gene variants has not been investigated. METHODS AND PRINCIPAL FINDINGS: Serum GP FA composition of 331 children aged 2 and 6 years, participating in an ongoing birth cohort study, was analyzed. Correlation coefficients were estimated to describe FA tracking over 4 years and to assess the influence of FADS variants on tracking. We found low to moderate tracking (r = 0.12-0.49) of FA compositions and concentration between 2 and 6 years. Concentration changes of total monounsaturated FA and total saturated FA over time correlated closely (r = 0.79) but percentage values were unrelated (r = -0.02). Tracking for n-6 long chain polyunsaturated fatty acid (LC-PUFA) concentrations was lower in subjects homozygous for the major allele of FADS variants and higher in carriers of at least one minor allele, whereas for total n-3 LC-PUFA concentrations and compositions this was vice versa. For individual n-3 PUFA inconsistent results were found. CONCLUSIONS AND SIGNIFICANCE: Serum GP FA composition shows low to moderate tracking over 4 years with a higher tracking for LC-PUFA metabolites than for their precursor FA. Serum PUFA levels and their tracking seem to be more influenced by lipid and lipoprotein metabolism than by FA specific pathways. PMID- 21818280 TI - Hierarchical anatomical brain networks for MCI prediction: revisiting volumetric measures. AB - Owning to its clinical accessibility, T1-weighted MRI (Magnetic Resonance Imaging) has been extensively studied in the past decades for prediction of Alzheimer's disease (AD) and mild cognitive impairment (MCI). The volumes of gray matter (GM), white matter (WM) and cerebrospinal fluid (CSF) are the most commonly used measurements, resulting in many successful applications. It has been widely observed that disease-induced structural changes may not occur at isolated spots, but in several inter-related regions. Therefore, for better characterization of brain pathology, we propose in this paper a means to extract inter-regional correlation based features from local volumetric measurements. Specifically, our approach involves constructing an anatomical brain network for each subject, with each node representing a Region of Interest (ROI) and each edge representing Pearson correlation of tissue volumetric measurements between ROI pairs. As second order volumetric measurements, network features are more descriptive but also more sensitive to noise. To overcome this limitation, a hierarchy of ROIs is used to suppress noise at different scales. Pairwise interactions are considered not only for ROIs with the same scale in the same layer of the hierarchy, but also for ROIs across different scales in different layers. To address the high dimensionality problem resulting from the large number of network features, a supervised dimensionality reduction method is further employed to embed a selected subset of features into a low dimensional feature space, while at the same time preserving discriminative information. We demonstrate with experimental results the efficacy of this embedding strategy in comparison with some other commonly used approaches. In addition, although the proposed method can be easily generalized to incorporate other metrics of regional similarities, the benefits of using Pearson correlation in our application are reinforced by the experimental results. Without requiring new sources of information, our proposed approach improves the accuracy of MCI prediction from 80.83% (of conventional volumetric features) to 84.35% (of hierarchical network features), evaluated using data sets randomly drawn from the ADNI (Alzheimer's Disease Neuroimaging Initiative) dataset. PMID- 21818281 TI - Analysis of al-2 mutations in Neurospora. AB - The orange pigmentation of the fungus Neurospora crassa is due to the accumulation of the xanthophyll neurosporaxanthin and precursor carotenoids. Two key reactions in the synthesis of these pigments, the formation of phytoene from geranylgeranyl pyrophosphate and the introduction of beta cycles in desaturated carotenoid products, are catalyzed by two domains of a bifunctional protein, encoded by the gene al-2. We have determined the sequence of nine al-2 mutant alleles and analyzed the carotenoid content in the corresponding strains. One of the mutants is reddish and it is mutated in the cyclase domain of the protein, and the remaining eight mutants are albino and harbor different mutations on the phytoene synthase (PS) domain. Some of the mutations are expected to produce truncated polypeptides. A strain lacking most of the PS domain contained trace amounts of a carotenoid-like pigment, tentatively identified as the squalene desaturation product diapolycopene. In support, trace amounts of this compound were also found in a knock-out mutant for gene al-2, but not in that for gene al 1, coding for the carotene desaturase. The cyclase activity of the AL-2 enzyme from two albino mutants was investigated by heterologous expression in an appropriately engineered E. coli strain. One of the AL-2 enzymes, predictably with only 20% of the PS domain, showed full cyclase activity, suggesting functional independence of both domains. However, the second mutant showed no cyclase activity, indicating that some alterations in the phytoene synthase segment affect the cyclase domain. Expression experiments showed a diminished photoinduction of al-2 transcripts in the al-2 mutants compared to the wild type strain, suggesting a synergic effect between reduced expression and impaired enzymatic activities in the generation of their albino phenotypes. PMID- 21818282 TI - Discovering the impact of preceding units' characteristics on the wait time of cardiac surgery unit from statistic data. AB - INTRODUCTION: Prior research shows that clinical demand and supplier capacity significantly affect the throughput and the wait time within an isolated unit. However, it is doubtful whether characteristics (i.e., demand, capacity, throughput, and wait time) of one unit would affect the wait time of subsequent units on the patient flow process. Focusing on cardiac care, this paper aims to examine the impact of characteristics of the catheterization unit (CU) on the wait time of cardiac surgery unit (SU). METHODS: This study integrates published data from several sources on characteristics of the CU and SU units in 11 hospitals in Ontario, Canada between 2005 and 2008. It proposes a two-layer wait time model (with each layer representing one unit) to examine the impact of CU's characteristics on the wait time of SU and test the hypotheses using the Partial Least Squares-based Structural Equation Modeling analysis tool. RESULTS: Results show that: (i) wait time of CU has a direct positive impact on wait time of SU (beta = 0.330, p < 0.01); (ii) capacity of CU has a direct positive impact on demand of SU (beta = 0.644, p < 0.01); (iii) within each unit, there exist significant relationships among different characteristics (except for the effect of throughput on wait time in SU). CONCLUSION: Characteristics of CU have direct and indirect impacts on wait time of SU. Specifically, demand and wait time of preceding unit are good predictors for wait time of subsequent units. This suggests that considering such cross-unit effects is necessary when alleviating wait time in a health care system. Further, different patient risk profiles may affect wait time in different ways (e.g., positive or negative effects) within SU. This implies that the wait time management should carefully consider the relationship between priority triage and risk stratification, especially for cardiac surgery. PMID- 21818283 TI - Increased oxidative burden associated with traffic component of ambient particulate matter at roadside and urban background schools sites in London. AB - As the incidence of respiratory and allergic symptoms has been reported to be increased in children attending schools in close proximity to busy roads, it was hypothesised that PM from roadside schools would display enhanced oxidative potential (OP). Two consecutive one-week air quality monitoring campaigns were conducted at seven school sampling sites, reflecting roadside and urban background in London. Chemical characteristics of size fractionated particulate matter (PM) samples were related to the capacity to drive biological oxidation reactions in a synthetic respiratory tract lining fluid. Contrary to hypothesised contrasts in particulate OP between school site types, no robust size fractionated differences in OP were identified due high temporal variability in concentrations of PM components over the one-week sampling campaigns. For OP assessed both by ascorbate (OP(AA) m(-3)) and glutathione (OP(GSH) m(-3)) depletion, the highest OP per cubic metre of air was in the largest size fraction, PM(1.9-10.2). However, when expressed per unit mass of particles OP(AA) ug(-1) showed no significant dependence upon particle size, while OP(GSH) ug(-1) had a tendency to increase with increasing particle size, paralleling increased concentrations of Fe, Ba and Cu. The two OP metrics were not significantly correlated with one another, suggesting that the glutathione and ascorbate depletion assays respond to different components of the particles. Ascorbate depletion per unit mass did not show the same dependence as for GSH and it is possible that other trace metals (Zn, Ni, V) or organic components which are enriched in the finer particle fractions, or the greater surface area of smaller particles, counter-balance the redox activity of Fe, Ba and Cu in the coarse particles. Further work with longer-term sampling and a larger suite of analytes is advised in order to better elucidate the determinants of oxidative potential, and to fuller explore the contrasts between site types. PMID- 21818284 TI - Core proteome of the minimal cell: comparative proteomics of three mollicute species. AB - Mollicutes (mycoplasmas) have been recognized as highly evolved prokaryotes with an extremely small genome size and very limited coding capacity. Thus, they may serve as a model of a 'minimal cell': a cell with the lowest possible number of genes yet capable of autonomous self-replication. We present the results of a comparative analysis of proteomes of three mycoplasma species: A. laidlawii, M. gallisepticum, and M. mobile. The core proteome components found in the three mycoplasma species are involved in fundamental cellular processes which are necessary for the free living of cells. They include replication, transcription, translation, and minimal metabolism. The members of the proteome core seem to be tightly interconnected with a number of interactions forming core interactome whether or not additional species-specific proteins are located on the periphery. We also obtained a genome core of the respective organisms and compared it with the proteome core. It was found that the genome core encodes 73 more proteins than the proteome core. Apart of proteins which may not be identified due to technical limitations, there are 24 proteins that seem to not be expressed under the optimal conditions. PMID- 21818285 TI - Graph theoretical analysis of functional brain networks: test-retest evaluation on short- and long-term resting-state functional MRI data. AB - Graph-based computational network analysis has proven a powerful tool to quantitatively characterize functional architectures of the brain. However, the test-retest (TRT) reliability of graph metrics of functional networks has not been systematically examined. Here, we investigated TRT reliability of topological metrics of functional brain networks derived from resting-state functional magnetic resonance imaging data. Specifically, we evaluated both short term (<1 hour apart) and long-term (>5 months apart) TRT reliability for 12 global and 6 local nodal network metrics. We found that reliability of global network metrics was overall low, threshold-sensitive and dependent on several factors of scanning time interval (TI, long-term>short-term), network membership (NM, networks excluding negative correlations>networks including negative correlations) and network type (NT, binarized networks>weighted networks). The dependence was modulated by another factor of node definition (ND) strategy. The local nodal reliability exhibited large variability across nodal metrics and a spatially heterogeneous distribution. Nodal degree was the most reliable metric and varied the least across the factors above. Hub regions in association and limbic/paralimbic cortices showed moderate TRT reliability. Importantly, nodal reliability was robust to above-mentioned four factors. Simulation analysis revealed that global network metrics were extremely sensitive (but varying degrees) to noise in functional connectivity and weighted networks generated numerically more reliable results in compared with binarized networks. For nodal network metrics, they showed high resistance to noise in functional connectivity and no NT related differences were found in the resistance. These findings provide important implications on how to choose reliable analytical schemes and network metrics of interest. PMID- 21818286 TI - Location-specific epigenetic regulation of the metallothionein 3 gene in esophageal adenocarcinomas. AB - BACKGROUND: Metallothionein 3 (MT3) maintains intracellular metal homeostasis and protects against reactive oxygen species (ROS)-induced DNA damage. In this study, we investigated the epigenetic alterations and gene expression of the MT3 gene in esophageal adenocarcinomas (EACs). METHODS AND RESULTS: Using quantitative bisulfite pyrosequencing, we detected unique DNA methylation profiles in the MT3 promoter region. The CpG nucleotides from -372 to -306 from the transcription start site (TSS) were highly methylated in tumor (n = 64) and normal samples (n = 51), whereas CpG nucleotides closest to the TSS (-4 and +3) remained unmethylated in all normal and most tumor samples. Conversely, CpG nucleotides in two regions (from -139 to -49 and +296 to +344) were significantly hypermethylated in EACs as compared to normal samples [FDR<0.001, -log10(FDR)>3.0]. The DNA methylation levels from -127 to -8 CpG sites showed the strongest correlation with MT3 gene expression (r = -0.4, P<0.0001). Moreover, the DNA hypermethylation from -127 to 8 CpG sites significantly correlated with advanced tumor stages and lymph node metastasis (P = 0.005 and P = 0.0313, respectively). The ChIP analysis demonstrated a more repressive histone modification (H3K9me2) and less active histone modifications (H3K4me2, H3K9ace) in OE33 cells than in FLO-1 cells; concordant with the presence of higher DNA methylation levels and silencing of MT3 expression in OE33 as compared to FLO-1 cells. Treatment of OE33 cells with 5 Aza-deoxycitidine restored MT3 expression with demethylation of its promoter region and reversal of the histone modifications towards active histone marks. CONCLUSION: In summary, EACs are characterized by frequent epigenetic silencing of MT3. The choice of specific regions in the CpG island is a critical step in determining the functional role and prognostic value of DNA methylation in cancer cells. PMID- 21818287 TI - Comparative analysis of the volatile fraction of fruit juice from different Citrus species. AB - The volatile composition of fruit from four Citrus varieties (Powell Navel orange, Clemenules mandarine, and Fortune mandarine and Chandler pummelo) covering four different species has been studied. Over one hundred compounds were profiled after HS-SPME-GC-MS analysis, including 27 esters, 23 aldehydes, 21 alcohols, 13 monoterpene hydrocarbons, 10 ketones, 5 sesquiterpene hydrocarbons, 4 monoterpene cyclic ethers, 4 furans, and 2 aromatic hydrocarbons, which were all confirmed with standards. The differences in the volatile profile among juices of these varieties were essentially quantitative and only a few compounds were found exclusively in a single variety, mainly in Chandler. The volatile profile however was able to differentiate all four varieties and revealed complex interactions between them including the participation in the same biosynthetic pathway. Some compounds (6 esters, 2 ketones, 1 furan and 2 aromatic hydrocarbons) had never been reported earlier in Citrus juices. This volatile profiling platform for Citrus juice by HS-SPME-GC-MS and the interrelationship detected among the volatiles can be used as a roadmap for future breeding or biotechnological applications. PMID- 21818289 TI - Cytotoxic effect of poly-dispersed single walled carbon nanotubes on erythrocytes in vitro and in vivo. AB - Single wall Carbon Nanotubes (SWCNTs) are hydrophobic and do not disperse in aqueous solvents. Acid functionalization of SWCNTs results in attachment of carboxy and sulfonate groups to carbon atoms and the resulting acid functionalized product (AF-SWCNTs) is negatively charged and disperses easily in water and buffers. In the present study, effect of AF-SWCNTs on blood erythrocytes was examined. Incubation of mouse erythrocytes with AF-SWCNTs and not with control SWCNTs, resulted in a dose and time dependent lysis of erythrocyte. Using fluorescence tagged AF-SWCNTs, binding of AF-SWCNTs with erythrocytes could be demonstrated. Confocal microscopy results indicated that AF SWCNTs could enter the erythrocytes. Treatment with AF-SWCNTs resulted in exposure of hydrophobic patches on erythrocyte membrane that is indicative of membrane damage. A time and dose dependent increase in externalization of phosphatidylserine on erythrocyte membrane bilayer was also found. Administration of AF-SWCNTs through intravenous route resulted in a transient anemia as seen by a sharp decline in blood erythrocyte count accompanied with a significant drop in blood haemoglobin level. Administration of AF-SWCNTs through intratracheal administration also showed significant decline in RBC count while administration through other routes (gavage and intra-peritoneal) was not effective. By using a recently developed technique of a two step in vivo biotinylation of erythrocytes that enables simultaneous enumeration of young (age <10 days) and old (age>40 days) erythrocytes in mouse blood, it was found that the in vivo toxic effect of AF-SWCNTs was more pronounced on older subpopulation of erythrocytes. Subpopulation of old erythrocytes fell after treatment with AF-SWCNTs but recovered by third day after the intravenous administration of AF-SWCNTs. Taken together our results indicate that treatment with AF-SWCNTs results in acute membrane damage and eventual lysis of erythrocytes. Intravenous administration of AF-SWCNTs resulted in a transient anemia in which older erythrocytes are preferably lysed. PMID- 21818288 TI - Horizontal transmission of Candida albicans and evidence of a vaccine response in mice colonized with the fungus. AB - Disseminated candidiasis is the third leading nosocomial blood stream infection in the United States and is often fatal. We previously showed that disseminated candidiasis was preventable in normal mice by immunization with either a glycopeptide or a peptide synthetic vaccine, both of which were Candida albicans cell wall derived. A weakness of these studies is that, unlike humans, mice do not have a C. albicans GI flora and they lack Candida serum antibodies. We examined the influence of C. albicans GI tract colonization and serum antibodies on mouse vaccination responses to the peptide, Fba, derived from fructose bisphosphate aldolase which has cytosolic and cell wall distributions in the fungus. We evaluated the effect of live C. albicans in drinking water and antimicrobial agents on establishment of Candida colonization of the mouse GI tract. Body mass, C. albicans in feces, and fungal-specific serum antibodies were monitored longitudinally. Unexpectedly, C. albicans colonization occurred in mice that received only antibiotics in their drinking water, provided that the mice were housed in the same room as intentionally colonized mice. The fungal strain in unintentionally colonized mice appeared identical to the strain used for intentional GI-tract colonization. This is the first report of horizontal transmission and spontaneous C. albicans colonization in mice. Importantly, many Candida-colonized mice developed serum fungal-specific antibodies. Despite the GI tract colonization and presence of serum antibodies, the animals made antibodies in response to the Fba immunogen. This mouse model has potential for elucidating C. albicans horizontal transmission and for exploring factors that induce host defense against disseminated candidiasis. Furthermore, a combined protracted GI tract colonization with Candida and the possibility of serum antibody responses to the presence of the fungus makes this an attractive mouse model for testing the efficacy of vaccines designed to prevent human disseminated candidiasis. PMID- 21818290 TI - SPARC, FOXP3, CD8 and CD45 correlation with disease recurrence and long-term disease-free survival in colorectal cancer. AB - BACKGROUND: SPARC is a matricellular protein involved in tissue remodelling, cell migration and angiogenesis, while forkhead box P3 (FOXP3) protein functions as a transcription factor involved in immune cell regulation. Both SPARC and FOXP3 can play an anti-tumorigenic role in cancer progression. The aim was to determine if SPARC, FOXP3, CD8 and CD45RO expression levels are associated with colorectal cancer (CRC) stage, disease outcome and long-term cancer-specific survival (CSS) in stage II and III CRC. METHODS AND FINDINGS: SPARC expression was initially assessed in 120 paired normal and stage I-IV CRCs. Subsequently, approximately 1000 paired patient samples of stage II or III CRCs in tissue microarrays were stained for SPARC, FOXP3, CD8 or CD45RO. Proportional hazards modelling assessed correlations between these markers and clinicopathological data, including disease outcome and cancer specific survival (CSS). Both SPARC and FOXP3 expression were significantly greater in CRC than normal colon (p<0.0001). High SPARC expression correlated with good disease outcome (>=60 mths without disease recurrence, p = 0.0039) and better long-term CSS in stage II CRC (<0.0001). In stage III CRC, high SPARC expression correlated with better long-term CSS (p<0.0001) and less adjuvant chemotherapy use (p = 0.01). High FOXP3 correlated with a good disease outcome, better long-term CSS and less adjuvant chemotherapy use in stage II (p<0.0037, <0.0001 and p = 0.04 respectively), but not in stage III CRC. High CD8 and CD45RO expression correlated with better disease outcome in stage II CRC, and better CSS, but the differences were not as marked as for SPARC and FOXP3. CONCLUSIONS: These data suggest that high SPARC and FOXP3 are associated with better disease outcome in stage II CRC and may be prognostic indicators of CSS. Further assessment of whether these markers predict patients at high risk of recurrence with stage II CRC and functional studies of these effects are underway. PMID- 21818291 TI - Evolutionary history of Helicobacter pylori sequences reflect past human migrations in Southeast Asia. AB - The human population history in Southeast Asia was shaped by numerous migrations and population expansions. Their reconstruction based on archaeological, linguistic or human genetic data is often hampered by the limited number of informative polymorphisms in classical human genetic markers, such as the hypervariable regions of the mitochondrial DNA. Here, we analyse housekeeping gene sequences of the human stomach bacterium Helicobacter pylori from various countries in Southeast Asia and we provide evidence that H. pylori accompanied at least three ancient human migrations into this area: i) a migration from India introducing hpEurope bacteria into Thailand, Cambodia and Malaysia; ii) a migration of the ancestors of Austro-Asiatic speaking people into Vietnam and Cambodia carrying hspEAsia bacteria; and iii) a migration of the ancestors of the Thai people from Southern China into Thailand carrying H. pylori of population hpAsia2. Moreover, the H. pylori sequences reflect iv) the migrations of Chinese to Thailand and Malaysia within the last 200 years spreading hspEasia strains, and v) migrations of Indians to Malaysia within the last 200 years distributing both hpAsia2 and hpEurope bacteria. The distribution of the bacterial populations seems to strongly influence the incidence of gastric cancer as countries with predominantly hspEAsia isolates exhibit a high incidence of gastric cancer while the incidence is low in countries with a high proportion of hpAsia2 or hpEurope strains. In the future, the host range expansion of hpEurope strains among Asian populations, combined with human motility, may have a significant impact on gastric cancer incidence in Asia. PMID- 21818292 TI - A review of exotic animal disease in Great Britain and in Scotland specifically between 1938 and 2007. AB - BACKGROUND: Incursions of contagious diseases of livestock into disease-free zones are inevitable as long as the diseases persist elsewhere in the world. Knowledge of where, when and how incursions have occurred helps assess the risks, and regionalize preventative and reactive measures. METHODOLOGY: Based on reports of British governmental veterinary services, we review occurrence of the former OIE List A diseases, and of Aujeszky's disease, anthrax and bovine tuberculosis (bTB) in farm-animals in Great Britain (GB) between 1938 and 2007. We estimate incidence of each disease on GB agricultural holdings and fraction of susceptible farm-animals culled to control the disease each year. We then consider the frequency and incidence of the diseases in Scotland alone. The limitations of available data on historical disease occurrence and denominator populations are detailed in Text S2. CONCLUSIONS: The numbers of livestock and poultry farmed in GB grew over the years 1938-2007; the number of agricultural holdings decreased. An amalgamation of production on larger holdings took place from the 1940s to the 1980s. The maximum annual incidence of a reviewed disease in GB 1938-2007 was reported for bTB, 1.69% of holdings in 1961. This was followed by Newcastle disease, 1.50% of holdings in 1971, and classical swine fever, 1.09% of holdings in 1940. The largest fractional cull of susceptible livestock in a single year in each of the four decades 1950s-1980s was due to a viral disease primarily affecting swine. During the periods 1938-1949 and 2000-2007 this was due to outbreaks of foot and mouth disease. In the absence of incursions of the former OIE List A diseases in the 1990s, this was due to bTB. Over the 70 years, the diseases were reported with lower frequency and lower annual incidence in Scotland, as compared to when these statistics are considered for GB as a whole. PMID- 21818293 TI - A resource for discovering specific and universal biomarkers for distributed stem cells. AB - Specific and universal biomarkers for distributed stem cells (DSCs) have been elusive. A major barrier to discovery of such ideal DSC biomarkers is difficulty in obtaining DSCs in sufficient quantity and purity. To solve this problem, we used cell lines genetically engineered for conditional asymmetric self-renewal, the defining DSC property. In gene microarray analyses, we identified 85 genes whose expression is tightly asymmetric self-renewal associated (ASRA). The ASRA gene signature prescribed DSCs to undergo asymmetric self-renewal to a greater extent than committed progenitor cells, embryonic stem cells, or induced pluripotent stem cells. This delineation has several significant implications. These include: 1) providing experimental evidence that DSCs in vivo undergo asymmetric self-renewal as individual cells; 2) providing an explanation why earlier attempts to define a common gene expression signature for DSCs were unsuccessful; and 3) predicting that some ASRA proteins may be ideal biomarkers for DSCs. Indeed, two ASRA proteins, CXCR6 and BTG2, and two other related self renewal pattern associated (SRPA) proteins identified in this gene resource, LGR5 and H2A.Z, display unique asymmetric patterns of expression that have a high potential for universal and specific DSC identification. PMID- 21818294 TI - Broad-spectrum inhibition of HIV-1 by a monoclonal antibody directed against a gp120-induced epitope of CD4. AB - To penetrate susceptible cells, HIV-1 sequentially interacts with two highly conserved cellular receptors, CD4 and a chemokine receptor like CCR5 or CXCR4. Monoclonal antibodies (MAbs) directed against such receptors are currently under clinical investigation as potential preventive or therapeutic agents. We immunized Balb/c mice with molecular complexes of the native, trimeric HIV-1 envelope (Env) bound to a soluble form of the human CD4 receptor. Sera from immunized mice were found to contain gp120-CD4 complex-enhanced antibodies and showed broad-spectrum HIV-1-inhibitory activity. A proportion of MAbs derived from these mice preferentially recognized complex-enhanced epitopes. In particular, a CD4-specific MAb designated DB81 (IgG1Kappa) was found to preferentially bind to a complex-enhanced epitope on the D2 domain of human CD4. MAb DB81 also recognized chimpanzee CD4, but not baboon or macaque CD4, which exhibit sequence divergence in the D2 domain. Functionally, MAb DB81 displayed broad HIV-1-inhibitory activity, but it did not exert suppressive effects on T cell activation in vitro. The variable regions of the heavy and light chains of MAb DB81 were sequenced. Due to its broad-spectrum anti-HIV-1 activity and lack of immunosuppressive effects, a humanized derivative of MAb DB81 could provide a useful complement to current preventive or therapeutic strategies against HIV-1. PMID- 21818296 TI - The TNF-alpha-238 polymorphism and cancer risk: a meta-analysis. AB - BACKGROUND AND OBJECTIVES: Tumor necrosis factor-alpha (TNF-alpha) plays a very important role in the development and progress of cancer. Some TNF-alpha polymorphisms have been confirmed to increase cancer risks; however, the association between TNF-alpha-238 polymorphism and cancers remains controversial and ambiguous. The aim of this study is to explore a more precise estimation of its relationship with cancer using meta-analysis. METHODS: Electronic searches of several databases were conducted for all publications on the association between this variant and cancer through March 2011. Odds ratios (OR) with 95% confidence intervals (95% CI) were used to access the strength of this association in the random-effect model. RESULTS: Thirty four studies with 34,679 cancer patients and 41,186 healthy controls were included. This meta-analysis showed no significant association between TNF-alpha-238 polymorphism and cancers (AA+GA vs GG: OR = 1.09, 95%CI = 0.88-1.34). In Caucasian and Asian subgroups, OR values (95% CI) were 1.14 (0.91-1.43) and 0.97 (0.58-1.61), respectively. In the subgroups of cancer type, no significant association was detected. The sensitivity analysis further strengthened the validity of these negative associations. No publication bias was observed in this study. CONCLUSIONS: No significant association was found between the TNF-alpha-238 polymorphism and the risk for cancer. PMID- 21818295 TI - Information dynamics in living systems: prokaryotes, eukaryotes, and cancer. AB - BACKGROUND: Living systems use information and energy to maintain stable entropy while far from thermodynamic equilibrium. The underlying first principles have not been established. FINDINGS: We propose that stable entropy in living systems, in the absence of thermodynamic equilibrium, requires an information extremum (maximum or minimum), which is invariant to first order perturbations. Proliferation and death represent key feedback mechanisms that promote stability even in a non-equilibrium state. A system moves to low or high information depending on its energy status, as the benefit of information in maintaining and increasing order is balanced against its energy cost. Prokaryotes, which lack specialized energy-producing organelles (mitochondria), are energy-limited and constrained to an information minimum. Acquisition of mitochondria is viewed as a critical evolutionary step that, by allowing eukaryotes to achieve a sufficiently high energy state, permitted a phase transition to an information maximum. This state, in contrast to the prokaryote minima, allowed evolution of complex, multicellular organisms. A special case is a malignant cell, which is modeled as a phase transition from a maximum to minimum information state. The minimum leads to a predicted power-law governing the in situ growth that is confirmed by studies measuring growth of small breast cancers. CONCLUSIONS: We find living systems achieve a stable entropic state by maintaining an extreme level of information. The evolutionary divergence of prokaryotes and eukaryotes resulted from acquisition of specialized energy organelles that allowed transition from information minima to maxima, respectively. Carcinogenesis represents a reverse transition: of an information maximum to minimum. The progressive information loss is evident in accumulating mutations, disordered morphology, and functional decline characteristics of human cancers. The findings suggest energy restriction is a critical first step that triggers the genetic mutations that drive somatic evolution of the malignant phenotype. PMID- 21818297 TI - A role for strain differences in waveforms of ultrasonic vocalizations during male-female interaction. AB - Male mice emit ultrasonic vocalizations (USVs) towards females during male-female interaction. It has been reported that USVs of adult male mice have the capability of attracting females. Although the waveform pattern of USVs is affected by genetic background, differences among strains with respect to USV and the effects of these differences on courtship behavior have not been analyzed fully. We analyzed USV patterns, as well as actual social behavior during USV recording, in 13 inbred mouse strains, which included laboratory and wild-derived strains. Significant effects of strain were observed for the frequency of USV emission, duration, and frequency of the waveform category. Principal component (PC) analysis showed that PC1 was related to frequency and duration, and PC2-4 were related to each waveform. In the comparison of USV patterns and behaviors among strains, wild-derived KJR mice displayed the highest scores for PC2-4, and female mice paired with KJR males did not emit rejection-related click sounds. It is assumed that the waveforms emitted by KJR males have a positive effect in male female interaction. Therefore, we extracted waveforms in PC2-4 from the USV recordings of KJR mice to produce a sound file, "HIGH2-4". As a negative control, another sound file ("LOW2-4") was created by extracting waveforms in PC2-4 from strains with low scores for these components. In the playback experiments using these sound files, female mice were attracted to the speaker that played HIGH2-4 but not the speaker that played LOW2-4. These results highlight the role of strain differences in the waveforms of male USVs during male-female interaction. The results indicated that female mice use male USVs as information when selecting a suitable mate. PMID- 21818298 TI - Intracellular trafficking of the amyloid beta-protein precursor (APP) regulated by novel function of X11-like. AB - BACKGROUND: Amyloid beta (Abeta), a causative peptide of Alzheimer's disease, is generated by intracellular metabolism of amyloid beta-protein precursor (APP). In general, mature APP (mAPP, N- and O-glycosylated form) is subject to successive cleavages by alpha- or beta-, and gamma-secretases in the late protein secretory pathway and/or at plasma membrane, while immature APP (imAPP, N-glycosylated form) locates in the early secretory pathway such as endoplasmic reticulum or cis Golgi, in which imAPP is not subject to metabolic cleavages. X11-like (X11L) is a neural adaptor protein composed of a phosphotyrosine-binding (PTB) and two C terminal PDZ domains. X11L suppresses amyloidogenic cleavage of mAPP by direct binding of X11L through its PTB domain, thereby generation of Abeta lowers. X11L expresses another function in the regulation of intracellular APP trafficking. METHODOLOGY: In order to analyze novel function of X11L in intracellular trafficking of APP, we performed a functional dissection of X11L. Using cells expressing various domain-deleted X11L mutants, intracellular APP trafficking was examined along with analysis of APP metabolism including maturation (O glycosylation), processing and localization of APP. CONCLUSIONS: X11L accumulates imAPP into the early secretory pathway by mediation of its C-terminal PDZ domains, without being bound to imAPP directly. With this novel function, X11L suppresses overall APP metabolism and results in further suppression of Abeta generation. Interestingly some of the accumulated imAPP in the early secretory pathway are likely to appear on plasma membrane by unidentified mechanism. Trafficking of imAPP to plasma membrane is observed in other X11 family proteins, X11 and X11L2, but not in other APP-binding partners such as FE65 and JIP1. It is herein clear that respective functional domains of X11L regulate APP metabolism at multiple steps in intracellular protein secretory pathways. PMID- 21818299 TI - Higher height, higher ability: judgment confidence as a function of spatial height perception. AB - Based on grounded cognition theories, the current study showed that judgments about ability were regulated by the subjects' perceptions of their spatial height. In Experiment 1, we found that after seeing the ground from a higher rather than lower floor, people had higher expectations about their performance on a knowledge test and assigned themselves higher rank positions in a peer comparison evaluation. In Experiment 2, we examined the boundary conditions of the spatial height effects and showed that it could still occur even if we employed photos rather than actual building floors to manipulate the perceptions of spatial heights. In addition, Experiment 2 excluded processing style as an explanation for these observations. In Experiment 3, we investigated a potential mechanism for the spatial height effect by manipulating the scale direction in the questionnaire. Consequently, consistent with our representational dependence account, the effect of spatial heights on ability judgments was eliminated when the mental representation of ability was disturbed by a reverse physical representation. These results suggest that people's judgments about their ability are correlated with their spatial perception. PMID- 21818300 TI - MicroRNA-restricted transgene expression in the retina. AB - BACKGROUND: Gene transfer using adeno-associated viral (AAV) vectors has been successfully applied in the retina for the treatment of inherited retinal dystrophies. Recently, microRNAs have been exploited to fine-tune transgene expression improving therapeutic outcomes. Here we evaluated the ability of retinal-expressed microRNAs to restrict AAV-mediated transgene expression to specific retinal cell types that represent the main targets of common inherited blinding conditions. METHODOLOGY/PRINCIPAL FINDINGS: To this end, we generated AAV2/5 vectors expressing EGFP and containing four tandem copies of miR-124 or miR-204 complementary sequences in the 3'UTR of the transgene expression cassette. These vectors were administered subretinally to adult C57BL/6 mice and Large White pigs. Our results demonstrate that miR-124 and miR-204 target sequences can efficiently restrict AAV2/5-mediated transgene expression to retinal pigment epithelium and photoreceptors, respectively, in mice and pigs. Interestingly, transgene restriction was observed at low vector doses relevant to therapy. CONCLUSIONS: We conclude that microRNA-mediated regulation of transgene expression can be applied in the retina to either restrict to a specific cell type the robust expression obtained using ubiquitous promoters or to provide an additional layer of gene expression regulation when using cell-specific promoters. PMID- 21818301 TI - The transcriptional regulatory network of Mycobacterium tuberculosis. AB - Under the perspectives of network science and systems biology, the characterization of transcriptional regulatory (TR) networks beyond the context of model organisms offers a versatile tool whose potential remains yet mainly unexplored. In this work, we present an updated version of the TR network of Mycobacterium tuberculosis (M.tb), which incorporates newly characterized transcriptional regulations coming from 31 recent, different experimental works available in the literature. As a result of the incorporation of these data, the new network doubles the size of previous data collections, incorporating more than a third of the entire genome of the bacterium. We also present an exhaustive topological analysis of the new assembled network, focusing on the statistical characterization of motifs significances and the comparison with other model organisms. The expanded M.tb transcriptional regulatory network, considering its volume and completeness, constitutes an important resource for diverse tasks such as dynamic modeling of gene expression and signaling processes, computational reliability determination or protein function prediction, being the latter of particular relevance, given that the function of only a small percent of the proteins of M.tb is known. PMID- 21818302 TI - Collective emotions online and their influence on community life. AB - BACKGROUND: E-communities, social groups interacting online, have recently become an object of interdisciplinary research. As with face-to-face meetings, Internet exchanges may not only include factual information but also emotional information -how participants feel about the subject discussed or other group members. Emotions in turn are known to be important in affecting interaction partners in offline communication in many ways. Could emotions in Internet exchanges affect others and systematically influence quantitative and qualitative aspects of the trajectory of e-communities? The development of automatic sentiment analysis has made large scale emotion detection and analysis possible using text messages collected from the web. However, it is not clear if emotions in e-communities primarily derive from individual group members' personalities or if they result from intra-group interactions, and whether they influence group activities. METHODOLOGY/PRINCIPAL FINDINGS: Here, for the first time, we show the collective character of affective phenomena on a large scale as observed in four million posts downloaded from Blogs, Digg and BBC forums. To test whether the emotions of a community member may influence the emotions of others, posts were grouped into clusters of messages with similar emotional valences. The frequency of long clusters was much higher than it would be if emotions occurred at random. Distributions for cluster lengths can be explained by preferential processes because conditional probabilities for consecutive messages grow as a power law with cluster length. For BBC forum threads, average discussion lengths were higher for larger values of absolute average emotional valence in the first ten comments and the average amount of emotion in messages fell during discussions. CONCLUSIONS/SIGNIFICANCE: Overall, our results prove that collective emotional states can be created and modulated via Internet communication and that emotional expressiveness is the fuel that sustains some e-communities. PMID- 21818303 TI - A novel serum-free monolayer culture for orderly hematopoietic differentiation of human pluripotent cells via mesodermal progenitors. AB - Elucidating the in vitro differentiation of human embryonic stem (ES) and induced pluripotent stem (iPS) cells is important for understanding both normal and pathological hematopoietic development in vivo. For this purpose, a robust and simple hematopoietic differentiation system that can faithfully trace in vivo hematopoiesis is necessary. In this study, we established a novel serum-free monolayer culture that can trace the in vivo hematopoietic pathway from ES/iPS cells to functional definitive blood cells via mesodermal progenitors. Stepwise tuning of exogenous cytokine cocktails induced the hematopoietic mesodermal progenitors via primitive streak cells. These progenitors were then differentiated into various cell lineages depending on the hematopoietic cytokines present. Moreover, single cell deposition assay revealed that common bipotential hemoangiogenic progenitors were induced in our culture. Our system provides a new, robust, and simple method for investigating the mechanisms of mesodermal and hematopoietic differentiation. PMID- 21818304 TI - ENZO: a web tool for derivation and evaluation of kinetic models of enzyme catalyzed reactions. AB - We describe a web tool ENZO (Enzyme Kinetics), a graphical interface for building kinetic models of enzyme catalyzed reactions. ENZO automatically generates the corresponding differential equations from a stipulated enzyme reaction scheme. These differential equations are processed by a numerical solver and a regression algorithm which fits the coefficients of differential equations to experimentally observed time course curves. ENZO allows rapid evaluation of rival reaction schemes and can be used for routine tests in enzyme kinetics. It is freely available as a web tool, at http://enzo.cmm.ki.si. PMID- 21818305 TI - Antipredatory function of head shape for vipers and their mimics. AB - Most research into the adaptive significance of warning signals has focused on the colouration and patterns of prey animals. However, behaviour, odour and body shape can also have signal functions and thereby reduce predators' willingness to attack defended prey. European vipers all have a distinctive triangular head shape; and they are all venomous. Several non-venomous snakes, including the subfamily Natricinae, commonly flatten their heads (also known as head triangulation) when disturbed. The adaptive significance of this potential behavioural mimicry has never been investigated.We experimentally tested if the triangular head shape typical of vipers offers protection against predation. We compared the predation pressure of free-ranging predators on artificial snakes with triangular-shaped heads against the pressure on replicas with narrow heads. Snakes of both head types had either zigzag patterned bodies, typical of European vipers, or plain (patternless) bodies. Plain snakes with narrower Colubrid-like heads suffered significantly higher predation by raptors than snakes with triangular-shaped heads. Head shape did not, however, have an additive effect on survival in zigzag-patterned snakes, suggesting that species which differ from vipers in colouration and pattern would benefit most from behavioural mimicry. Our results demonstrate that the triangular head shape typical of vipers can act as a warning signal to predators. We suggest that head-shape mimicry may be a more common phenomenon among more diverse taxa than is currently recognised. PMID- 21818307 TI - Recurrent activity in higher order, modality non-specific brain regions: a Granger causality analysis of autobiographic memory retrieval. AB - It has been proposed that the workings of the brain are mainly intrinsically generated recurrent neuronal activity, with sensory inputs as modifiers of such activity in both sensory and higher order modality non-specific regions. This is supported by the demonstration of recurrent neuronal activity in the visual system as a response to visual stimulation. In contrast recurrent activity has never been demonstrated before in higher order modality non-specific regions. Using magneto-encephalography and Granger causality analysis, we tested in a paralimbic network the hypothesis that stimulation may enhance causal recurrent interaction between higher-order, modality non-specific regions. The network includes anterior cingulate/medial prefrontal and posterior cingulate/medial parietal cortices together with pulvinar thalami, a network known to be effective in autobiographic memory retrieval and self-awareness. Autobiographic memory retrieval of previous personal judgments of visually presented words was used as stimuli. It is demonstrated that the prestimulus condition is characterized by causal, recurrent oscillations which are maximal in the lower gamma range. When retrieving previous judgments of visually presented adjectives, this activity is dramatically increased during the stimulus task as ascertained by Granger causality analysis. Our results confirm the hypothesis that stimulation may enhance causal interaction between higher order, modality non-specific brain regions, exemplified in a network of autobiographical memory retrieval. PMID- 21818306 TI - The Vein Patterning 1 (VEP1) gene family laterally spread through an ecological network. AB - Lateral gene transfer (LGT) is a major evolutionary mechanism in prokaryotes. Knowledge about LGT--particularly, multicellular--eukaryotes has only recently started to accumulate. A widespread assumption sees the gene as the unit of LGT, largely because little is yet known about how LGT chances are affected by structural/functional features at the subgenic level. Here we trace the evolutionary trajectory of VEin Patterning 1, a novel gene family known to be essential for plant development and defense. At the subgenic level VEP1 encodes a dinucleotide-binding Rossmann-fold domain, in common with members of the short chain dehydrogenase/reductase (SDR) protein family. We found: i) VEP1 likely originated in an aerobic, mesophilic and chemoorganotrophic alpha proteobacterium, and was laterally propagated through nets of ecological interactions, including multiple LGTs between phylogenetically distant green plant/fungi-associated bacteria, and five independent LGTs to eukaryotes. Of these latest five transfers, three are ancient LGTs, implicating an ancestral fungus, the last common ancestor of land plants and an ancestral trebouxiophyte green alga, and two are recent LGTs to modern embryophytes. ii) VEP1's rampant LGT behavior was enabled by the robustness and broad utility of the dinucleotide binding Rossmann-fold, which provided a platform for the evolution of two unprecedented departures from the canonical SDR catalytic triad. iii) The fate of VEP1 in eukaryotes has been different in different lineages, being ubiquitous and highly conserved in land plants, whereas fungi underwent multiple losses. And iv) VEP1-harboring bacteria include non-phytopathogenic and phytopathogenic symbionts which are non-randomly distributed with respect to the type of harbored VEP1 gene. Our findings suggest that VEP1 may have been instrumental for the evolutionary transition of green plants to land, and point to a LGT-mediated 'Trojan Horse' mechanism for the evolution of bacterial pathogenesis against plants. VEP1 may serve as tool for revealing microbial interactions in plant/fungi-associated environments. PMID- 21818308 TI - Prevention of house dust mite induced allergic airways disease in mice through immune tolerance. AB - Allergic airways disease is a consequence of a Th2 response to an allergen leading to a series of manifestations such as production of allergen-specific IgE, inflammatory infiltrates in the airways, and airway hyper-reactivity (AHR). Several strategies have been reported for tolerance induction to allergens leading to protection from allergic airways disease. We now show that CD4 blockade at the time of house dust mite sensitization induces antigen-specific tolerance in mice. Tolerance induction is robust enough to be effective in pre sensitized animals, even in those where AHR was pre-established. Tolerant mice are protected from airways eosinophilia, Th2 lung infiltration, and AHR. Furthermore, anti-CD4 treated mice remain immune competent to mount immune responses, including Th2, to unrelated antigens. Our findings, therefore, describe a strategy for tolerance induction potentially applicable to other immunogenic proteins besides allergens. PMID- 21818309 TI - Identification of reproduction-specific genes associated with maturation and estrogen exposure in a marine bivalve Mytilus edulis. AB - BACKGROUND: While it is established that vertebrate-like steroids, particularly estrogens (estradiol, estrone) and androgens (testosterone), are present in various tissues of molluscs, it is still unclear what role these play in reproductive endocrinology in such organisms. This is despite the significant commercial shellfishery interest in several bivalve species and their decline. METHODOLOGY/PRINCIPAL FINDINGS: Using suppression subtraction hybridisation of mussel gonad samples at two stages (early and mature) of gametogenesis and (in parallel) following controlled laboratory estrogen exposure, we isolate several differentially regulated genes including testis-specific kinases, vitelline lysin and envelope sequences. CONCLUSIONS: The differentially expressed mRNAs isolated provide evidence that mussels may be impacted by exogenous estrogen exposure. PMID- 21818310 TI - Educational homogamy lowers the odds of reproductive failure. AB - Assortative mating based on education is a common phenomenon. We investigated whether it affected parameters of reproductive performance such as childlessness, offspring number and age at first marriage. On the basis of the US census from 1980 (n = 670,631 married US couples), we find that the proportion of childless individuals is usually minimal in women married to a husband of the same educational level. This holds particularly true in the highest and the lowest educated women. Educational homogamy is also associated with a lower average age at first marriage. No obvious effect of educational homogamy on a woman's average offspring number is found, where mean offspring number generally increases both with decreasing woman's and decreasing husband's educational attainment. We conclude that educational homogamy reduces the likelihood of reproductive failure. PMID- 21818311 TI - Film excerpts shown to specifically elicit various affects lead to overlapping activation foci in a large set of symmetrical brain regions in males. AB - While the limbic system theory continues to be part of common scientific parlance, its validity has been questioned on multiple grounds. Nonetheless, the issue of whether or not there exists a set of brain areas preferentially dedicated to emotional processing remains central within affective neuroscience. Recently, a widespread neural reference space for emotion which includes limbic as well as other regions was characterized in a large meta-analysis. As methodologically heterogeneous studies go into such meta-analyses, showing in an individual study in which all parameters are kept constant, the involvement of overlapping areas for various emotion conditions in keeping with the neural reference space for emotion, would serve as valuable confirmatory evidence. Here, using fMRI, 20 young adult men were scanned while viewing validated neutral and effective emotion-eliciting short film excerpts shown to quickly and specifically elicit disgust, amusement, or sexual arousal. Each emotion-specific run included, in random order, multiple neutral and emotion condition blocks. A stringent conjunction analysis revealed a large overlap across emotion conditions that fit remarkably well with the neural reference space for emotion. This overlap included symmetrical bilateral activation of the medial prefrontal cortex, the anterior cingulate, the temporo-occipital junction, the basal ganglia, the brainstem, the amygdala, the hippocampus, the thalamus, the subthalamic nucleus, the posterior hypothalamus, the cerebellum, as well as the frontal operculum extending towards the anterior insula. This study clearly confirms for the visual modality, that processing emotional stimuli leads to widespread increases in activation that cluster within relatively confined areas, regardless of valence. PMID- 21818312 TI - Functional hair cell mechanotransducer channels are required for aminoglycoside ototoxicity. AB - Aminoglycosides (AG) are commonly prescribed antibiotics with potent bactericidal activities. One main side effect is permanent sensorineural hearing loss, induced by selective inner ear sensory hair cell death. Much work has focused on AG's initiating cell death processes, however, fewer studies exist defining mechanisms of AG uptake by hair cells. The current study investigated two proposed mechanisms of AG transport in mammalian hair cells: mechanotransducer (MET) channels and endocytosis. To study these two mechanisms, rat cochlear explants were cultured as whole organs in gentamicin-containing media. Two-photon imaging of Texas Red conjugated gentamicin (GTTR) uptake into live hair cells was rapid and selective. Hypocalcemia, which increases the open probability of MET channels, increased AG entry into hair cells. Three blockers of MET channels (curare, quinine, and amiloride) significantly reduced GTTR uptake, whereas the endocytosis inhibitor concanavalin A did not. Dynosore quenched the fluorescence of GTTR and could not be tested. Pharmacologic blockade of MET channels with curare or quinine, but not concanavalin A or dynosore, prevented hair cell loss when challenged with gentamicin for up to 96 hours. Taken together, data indicate that the patency of MET channels mediated AG entry into hair cells and its toxicity. Results suggest that limiting permeation of AGs through MET channel or preventing their entry into endolymph are potential therapeutic targets for preventing hair cell death and hearing loss. PMID- 21818314 TI - Variance in centrality within rock hyrax social networks predicts adult longevity. AB - BACKGROUND: In communal mammals the levels of social interaction among group members vary considerably. In recent years, biologists have realized that within group interactions may affect survival of the group members. Several recent studies have demonstrated that the social integration of adult females is positively associated with infant survival, and female longevity is affected by the strength and stability of the individual social bonds. Our aim was to determine the social factors that influence adult longevity in social mammals. METHODOLOGY/PRINCIPAL FINDINGS: As a model system, we studied the social rock hyrax (Procavia capensis), a plural breeder with low reproductive skew, whose groups are mainly composed of females. We applied network theory using 11 years of behavioral data to quantify the centrality of individuals within groups, and found adult longevity to be inversely correlated to the variance in centrality. In other words, animals in groups with more equal associations lived longer. Individual centrality was not correlated with longevity, implying that social tension may affect all group members and not only the weakest or less connected ones. CONCLUSIONS/SIGNIFICANCE: Our novel findings support previous studies emphasizing the adaptive value of social associations and the consequences of inequality among adults within social groups. However, contrary to previous studies, we suggest that it is not the number or strength of associations that an adult individual has (i.e. centrality) that is important, but the overall configuration of social relationships within the group (i.e. centrality SD) that is a key factor in influencing longevity. PMID- 21818313 TI - Trypanosoma cruzi epimastigotes are able to store and mobilize high amounts of cholesterol in reservosome lipid inclusions. AB - BACKGROUND: Reservosomes are lysosome-related organelles found in Trypanosoma cruzi epimastigotes. They represent the last step in epimastigote endocytic route, accumulating a set of proteins and enzymes related to protein digestion and lipid metabolism. The reservosome matrix contains planar membranes, vesicles and lipid inclusions. Some of the latter may assume rectangular or sword-shaped crystalloid forms surrounded by a phospholipid monolayer, resembling the cholesterol crystals in foam cells. METHODOLOGY/PRINCIPAL FINDINGS: Using Nile Red fluorimetry and fluorescence microscopy, as well as electron microscopy, we have established a direct correlation between serum concentration in culture medium and the presence of crystalloid lipid inclusions. Starting from a reservosome purified fraction, we have developed a fractionation protocol to isolate lipid inclusions. Gas-chromatography mass-spectrometry (GC-MS) analysis revealed that lipid inclusions are composed mainly by cholesterol and cholesterol esters. Moreover, when the parasites with crystalloid lipid-loaded reservosomes were maintained in serum free medium for 48 hours the inclusions disappeared almost completely, including the sword shaped ones. CONCLUSIONS/SIGNIFICANCE: Taken together, our results suggest that epimastigote forms of T. cruzi store high amounts of neutral lipids from extracellular medium, mostly cholesterol or cholesterol esters inside reservosomes. Interestingly, the parasites are able to disassemble the reservosome cholesterol crystalloid inclusions when submitted to serum starvation. PMID- 21818315 TI - Suppression of jasmonic acid-dependent defense in cotton plant by the mealybug Phenacoccus solenopsis. AB - The solenopsis mealybug, Phenacoccus solenopsis, has been recently recognized as an aggressively invasive pest in China, and is now becoming a serious threat to the cotton industry in the country. Thus, it is necessary to investigate the molecular mechanisms employed by cotton for defending against P. solenopsis before the pest populations reach epidemic levels. Here, we examined the effects of exogenous jasmonic acid (JA), salicylic acid (SA), and herbivory treatments on feeding behavior and on development of female P. solenopsis. Further, we compared the volatile emissions of cotton plants upon JA, SA, and herbivory treatments, as well as the time-related changes in gossypol production and defense-related genes. Female adult P. solenopsis were repelled by leaves from JA-treated plant, but were not repelled by leaves from SA-treated plants. In contrast, females were attracted by leaves from plants pre-infested by P. solenopsis. The diverse feeding responses by P. solenopsis were due to the difference in volatile emission of plants from different treatments. Furthermore, we show that JA treated plants slowed P. solenopsis development, but plants pre-infested by P. solenopsis accelerated its development. We also show that P. solenopsis feeding inhibited the JA-regulated gossypol production, and prevented the induction of JA related genes. We conclude that P. solenopsis is able to prevent the activation of JA-dependent defenses associated with basal resistance to mealybugs. PMID- 21818316 TI - PRTFDC1 is a genetic modifier of HPRT-deficiency in the mouse. AB - Lesch-Nyhan disease (LND) is a severe X-linked neurological disorder caused by a deficiency of hypoxanthine phosphoribosyltransferase (HPRT). In contrast, HPRT deficiency in the mouse does not result in the profound phenotypes such as self injurious behavior observed in humans, and the genetic basis for this phenotypic disparity between HPRT-deficient humans and mice is unknown. To test the hypothesis that HPRT deficiency is modified by the presence/absence of phosphoribosyltransferase domain containing 1 (PRTFDC1), a paralog of HPRT that is a functional gene in humans but an inactivated pseudogene in mice, we created transgenic mice that express human PRTFDC1 in wild-type and HPRT-deficient backgrounds. Male mice expressing PRTFDC1 on either genetic background were viable and fertile. However, the presence of PRTFDC1 in the HPRT-deficient, but not wild-type mice, increased aggression as well as sensitivity to a specific amphetamine-induced stereotypy, both of which are reminiscent of the increased aggressive and self-injurious behavior exhibited by patients with LND. These results demonstrate that PRTFDC1 is a genetic modifier of HPRT-deficiency in the mouse and could therefore have important implications for unraveling the molecular etiology of LND. PMID- 21818317 TI - Development of a surface plasmon resonance biosensor for real-time detection of osteogenic differentiation in live mesenchymal stem cells. AB - Surface plasmon resonance (SPR) biosensors have been recognized as a useful tool and widely used for real-time dynamic analysis of molecular binding affinity because of its high sensitivity to the change of the refractive index of tested objects. The conventional methods in molecular biology to evaluate cell differentiation require cell lysis or fixation, which make investigation in live cells difficult. In addition, a certain amount of cells are needed in order to obtain adequate protein or messenger ribonucleic acid for various assays. To overcome this limitation, we developed a unique SPR-based biosensing apparatus for real-time detection of cell differentiation in live cells according to the differences of optical properties of the cell surface caused by specific antigen antibody binding. In this study, we reported the application of this SPR-based system to evaluate the osteogenic differentiation of mesenchymal stem cells (MSCs). OB-cadherin expression, which is up-regulated during osteogenic differentiation, was targeted under our SPR system by conjugating antibodies against OB-cadherin on the surface of the object. A linear relationship between the duration of osteogenic induction and the difference in refractive angle shift with very high correlation coefficient was observed. To sum up, the SPR system and the protocol reported in this study can rapidly and accurately define osteogenic maturation of MSCs in a live cell and label-free manner with no need of cell breakage. This SPR biosensor will facilitate future advances in a vast array of fields in biomedical research and medical diagnosis. PMID- 21818318 TI - Identification of host genes involved in geminivirus infection using a reverse genetics approach. AB - Geminiviruses, like all viruses, rely on the host cell machinery to establish a successful infection, but the identity and function of these required host proteins remain largely unknown. Tomato yellow leaf curl Sardinia virus (TYLCSV), a monopartite geminivirus, is one of the causal agents of the devastating Tomato yellow leaf curl disease (TYLCD). The transgenic 2IRGFP N. benthamiana plants, used in combination with Virus Induced Gene Silencing (VIGS), entail an important potential as a tool in reverse genetics studies to identify host factors involved in TYLCSV infection. Using these transgenic plants, we have made an accurate description of the evolution of TYLCSV replication in the host in both space and time. Moreover, we have determined that TYLCSV and Tobacco rattle virus (TRV) do not dramatically influence each other when co-infected in N. benthamiana, what makes the use of TRV-induced gene silencing in combination with TYLCSV for reverse genetic studies feasible. Finally, we have tested the effect of silencing candidate host genes on TYLCSV infection, identifying eighteen genes potentially involved in this process, fifteen of which had never been implicated in geminiviral infections before. Seven of the analyzed genes have a potential anti viral effect, whereas the expression of the other eleven is required for a full infection. Interestingly, almost half of the genes altering TYLCSV infection play a role in postranslational modifications. Therefore, our results provide new insights into the molecular mechanisms underlying geminivirus infections, and at the same time reveal the 2IRGFP/VIGS system as a powerful tool for functional reverse genetics studies. PMID- 21818319 TI - Glutamate-gated chloride channels of Haemonchus contortus restore drug sensitivity to ivermectin resistant Caenorhabditis elegans. AB - Anthelmintic resistance is a major problem in livestock farming, especially of small ruminants, but our understanding of it has been limited by the difficulty in carrying out functional genetic studies on parasitic nematodes. An important nematode infecting sheep and goats is Haemonchus contortus; in many parts of the world this species is resistant to almost all the currently available drugs, including ivermectin. It is extremely polymorphic and to date it has proved impossible to relate any sequence polymorphisms to its ivermectin resistance status. Expression of candidate drug-resistance genes in Caenorhabditis elegans could provide a convenient means to study the effects of polymorphisms found in resistant parasites, but may be complicated by differences between the gene families of target and model organisms. We tested this using the glutamate-gated chloride channel (GluCl) gene family, which forms the ivermectin drug target and are candidate resistance genes. We expressed GluCl subunits from C. elegans and H. contortus in a highly resistant triple mutant C. elegans strain (DA1316) under the control of the avr-14 promoter; expression of GFP behind this promoter recapitulated the pattern previously reported for avr-14. Expression of ivermectin-sensitive subunits from both species restored drug sensitivity to transgenic worms, though some quantitative differences were noted between lines. Expression of an ivermectin-insensitive subunit, Hco-GLC-2, had no effect on drug sensitivity. Expression of a previously uncharacterised parasite-specific subunit, Hco-GLC-6, caused the transgenic worms to become ivermectin sensitive, suggesting that this subunit also encodes a GluCl that responds to the drug. These results demonstrate that both orthologous and paralogous subunits from C. elegans and H. contortus are able to rescue the ivermectin sensitivity of mutant C. elegans, though some quantitative differences were observed between transgenic lines in some assays. C. elegans is a suitable system for studying parasitic nematode genes that may be involved in drug resistance. PMID- 21818320 TI - Do parents recognize autistic deviant behavior long before diagnosis? Taking into account interaction using computational methods. AB - BACKGROUND: To assess whether taking into account interaction synchrony would help to better differentiate autism (AD) from intellectual disability (ID) and typical development (TD) in family home movies of infants aged less than 18 months, we used computational methods. METHODOLOGY AND PRINCIPAL FINDINGS: First, we analyzed interactive sequences extracted from home movies of children with AD (N = 15), ID (N = 12), or TD (N = 15) through the Infant and Caregiver Behavior Scale (ICBS). Second, discrete behaviors between baby (BB) and Care Giver (CG) co occurring in less than 3 seconds were selected as single interactive patterns (or dyadic events) for analysis of the two directions of interaction (CG->BB and BB >CG) by group and semester. To do so, we used a Markov assumption, a Generalized Linear Mixed Model, and non negative matrix factorization. Compared to TD children, BBs with AD exhibit a growing deviant development of interactive patterns whereas those with ID rather show an initial delay of development. Parents of AD and ID do not differ very much from parents of TD when responding to their child. However, when initiating interaction, parents use more touching and regulation up behaviors as early as the first semester. CONCLUSION: When studying interactive patterns, deviant autistic behaviors appear before 18 months. Parents seem to feel the lack of interactive initiative and responsiveness of their babies and try to increasingly supply soliciting behaviors. Thus we stress that credence should be given to parents' intuition as they recognize, long before diagnosis, the pathological process through the interactive pattern with their child. PMID- 21818321 TI - The environment as an unrecognized reservoir for community-associated methicillin resistant Staphylococcus aureus USA300: a case-control study. AB - BACKGROUND: Community-associated methicillin-resistant Staphylococcus aureus (CA MRSA) infections are spreading, but the source of infections in non-epidemic settings remains poorly defined. METHODS: We carried out a community-based, case control study investigating socio-demographic risk factors and infectious reservoirs associated with MRSA infections. Case patients presented with CA-MRSA infections to a New York hospital. Age-matched controls without infections were randomly selected from the hospital's Dental Clinic patient population. During a home visit, case and control subjects completed a questionnaire, nasal swabs were collected from index respondents and household members and standardized environmental surfaces were swabbed. Genotyping was performed on S. aureus isolates. RESULTS: We enrolled 95 case and 95 control subjects. Cases more frequently reported diabetes mellitus and a higher number of skin infections among household members. Among case households, 53 (56%) were environmentally contaminated with S. aureus, compared to 36 (38%) control households (p = .02). MRSA was detected on fomites in 30 (32%) case households and 5 (5%; p<.001) control households. More case patients, 20 (21%) were nasally colonized with MRSA than were control indexes, 2 (2%; p<.001). In a subgroup analysis, the clinical isolate (predominantly USA300), was more commonly detected on environmental surfaces in case households with recurrent MRSA infections (16/36, 44%) than those without (14/58, 24%, p = .04). CONCLUSIONS: The higher frequency of environmental contamination of case households with S. aureus in general and MRSA in particular implicates this as a potential reservoir for recolonization and increased risk of infection. Environmental colonization may contribute to the community spread of epidemic strains such as USA300. PMID- 21818322 TI - Cat dilemma: too protected to escape trophy hunting? AB - Trophy hunting is one of the most controversial issues in the field of biodiversity conservation. In particular, proponents and opponents debate fiercely over whether it poses a threat to hunted populations. Here, we show that trophy hunting constitutes a greater menace to threatened species than previously realized. Because humans value rarity, targeted species that are threatened are likely to be disproportionately hunted, thereby becoming even more vulnerable, which could eventually push them to extinction. With the ten felid species currently hunted for their trophies, we present evidence that (1) the number of killed individuals increases with time, in several cases exponentially, despite population declines, (2) the price of trophies is strongly dependent on species protection status, (3) changes of protection status coincide with counter intuitive changes of hunting pressures: protection intensification with augmented hunting effort, and protection relaxation with lower effort. This suggests an over-exploitation of trophy-hunted felids and the necessity of a better quota system coupled with reconsidered protection methods. PMID- 21818323 TI - 17beta-Estradiol enhances breast cancer cell motility and invasion via extra nuclear activation of actin-binding protein ezrin. AB - Estrogen promotes breast cancer metastasis. However, the detailed mechanism remains largely unknown. The actin binding protein ezrin is a key component in tumor metastasis and its over-expression is positively correlated to the poor outcome of breast cancer. In this study, we investigate the effects of 17beta estradiol (E2) on the activation of ezrin and its role in estrogen-dependent breast cancer cell movement. In T47-D breast cancer cells, E2 rapidly enhances ezrin phosphorylation at Thr(567) in a time- and concentration-dependent manner. The signalling cascade implicated in this action involves estrogen receptor (ER) interaction with the non-receptor tyrosine kinase c-Src, which activates the phosphatidylinositol-3 kinase/Akt pathway and the small GTPase RhoA/Rho associated kinase (ROCK-2) complex. E2 enhances the horizontal cell migration and invasion of T47-D breast cancer cells in three-dimensional matrices, which is reversed by transfection of cells with specific ezrin siRNAs. In conclusion, E2 promotes breast cancer cell movement and invasion by the activation of ezrin. These results provide novel insights into the effects of estrogen on breast cancer progression and highlight potential targets to treat endocrine-sensitive breast cancers. PMID- 21818324 TI - Identification of inhibitors against Mycobacterium tuberculosis thiamin phosphate synthase, an important target for the development of anti-TB drugs. AB - Tuberculosis (TB) continues to pose a serious challenge to human health afflicting a large number of people throughout the world. In spite of the availability of drugs for the treatment of TB, the non-compliance to 6-9 months long chemotherapeutic regimens often results in the emergence of multidrug resistant strains of Mycobacterium tuberculosis adding to the precariousness of the situation. This has necessitated the development of more effective drugs. Thiamin biosynthesis, an important metabolic pathway of M. tuberculosis, is shown to be essential for the intracellular growth of this pathogen and hence, it is believed that inhibition of this pathway would severely affect the growth of M. tuberculosis. In this study, a comparative homology model of M. tuberculosis thiamin phosphate synthase (MtTPS) was generated and employed for virtual screening of NCI diversity set II to select potential inhibitors. The best 39 compounds based on the docking results were evaluated for their potential to inhibit the MtTPS activity. Seven compounds inhibited MtTPS activity with IC(50) values ranging from 20-100 ug/ml and two of these exhibited weak inhibition of M. tuberculosis growth with MIC(99) values being 125 ug/ml and 162.5 ug/ml while one compound was identified as a very potent inhibitor of M. tuberculosis growth with an MIC(99) value of 6 ug/ml. This study establishes MtTPS as a novel drug target against M. tuberculosis leading to the identification of new lead molecules for the development of antitubercular drugs. Further optimization of these lead compounds could result in more potent therapeutic molecules against Tuberculosis. PMID- 21818325 TI - Acidic environment leads to ROS-induced MAPK signaling in cancer cells. AB - Tumor micromilieu often shows pronounced acidosis forcing cells to adapt their phenotype towards enhanced tumorigenesis induced by altered cellular signalling and transcriptional regulation. In the presents study mechanisms and potential consequences of the crosstalk between extra- and intracellular pH (pH(e), pH(i)) and mitogen-activated-protein-kinases (ERK1/2, p38) was analyzed. Data were obtained mainly in AT1 R-3327 prostate carcinoma cells, but the principle importance was confirmed in 5 other cell types. Extracellular acidosis leads to a rapid and sustained decrease of pH(i) in parallel to p38 phosphorylation in all cell types and to ERK1/2 phosphorylation in 3 of 6 cell types. Furthermore, p38 phosphorylation was elicited by sole intracellular lactacidosis at normal pH(e). Inhibition of ERK1/2 phosphorylation during acidosis led to necrotic cell death. No evidence for the involvement of the kinases c-SRC, PKC, PKA, PI3K or EGFR nor changes in cell volume in acidosis-induced MAPK activation was obtained. However, our data reveal that acidosis enhances the formation of reactive oxygen species (ROS), probably originating from mitochondria, which subsequently trigger MAPK phosphorylation. Scavenging of ROS prevented acidosis-induced MAPK phosphorylation whereas addition of H(2)O(2) enhanced it. Finally, acidosis increased phosphorylation of the transcription factor CREB via p38, leading to increased transcriptional activity of a CRE-reporter even 24 h after switching the cells back to a normal environmental milieu. Thus, an acidic tumor microenvironment can induce a longer lasting p38-CREB-medited change in the transcriptional program, which may maintain the altered phenotype even when the cells leave the tumor environment. PMID- 21818326 TI - A non-synonymous mutation in the canine Pkd1 gene is associated with autosomal dominant polycystic kidney disease in Bull Terriers. AB - Polycystic Kidney Disease is an autosomal dominant disease common in some lines of Bull Terriers (BTPKD). The disease is linked to the canine orthologue of human PKD1 gene, Pkd1, located on CFA06, but no disease-associated mutation has been reported. This study sequenced genomic DNA from two Bull Terriers with BTPKD and two without the disease. A non-synonymous G>A transition mutation in exon 29 of Pkd1 was identified. A TaqMan(r) SNP Genotyping Assay was designed and demonstrated the heterozygous detection of the mutation in 47 Bull Terriers with BTPKD, but not in 102 Bull Terriers over one year of age and without BTPKD. This missense mutation replaces a glutamic acid residue with a lysine residue in the predicted protein, Polycystin 1. This region of Polycystin 1 is highly conserved between species, and is located in the first cytoplasmic loop of the predicted protein structure, close to the PLAT domain and the second transmembrane region. Thus, this change could alter Polycystin 1 binding or localization. Analytic programs PolyPhen 2, Align GVGD and SIFT predict this mutation to be pathogenic. Thus, BTPKD is associated with a missense mutation in Pkd1, and the application of this mutation specific assay could reduce disease transmission by allowing diagnosis of disease in young animals prior to breeding. PMID- 21818327 TI - Identification of candidate gene regions in the rat by co-localization of QTLs for bone density, size, structure and strength. AB - Susceptibility to osteoporotic fracture is influenced by genetic factors that can be dissected by whole-genome linkage analysis in experimental animal crosses. The aim of this study was to characterize quantitative trait loci (QTLs) for biomechanical and two-dimensional dual-energy X-ray absorptiometry (DXA) phenotypes in reciprocal F2 crosses between diabetic GK and normo-glycemic F344 rat strains and to identify possible co-localization with previously reported QTLs for bone size and structure. The biomechanical measurements of rat tibia included ultimate force, stiffness and work to failure while DXA was used to characterize tibial area, bone mineral content (BMC) and areal bone mineral density (aBMD). F2 progeny (108 males, 98 females) were genotyped with 192 genome wide markers followed by sex- and reciprocal cross-separated whole-genome QTL analyses. Significant QTLs were identified on chromosome 8 (tibial area; logarithm of odds (LOD) = 4.7 and BMC; LOD = 4.1) in males and on chromosome 1 (stiffness; LOD = 5.5) in females. No QTLs showed significant sex-specific interactions. In contrast, significant cross-specific interactions were identified on chromosome 2 (aBMD; LOD = 4.7) and chromosome 6 (BMC; LOD = 4.8) for males carrying F344mtDNA, and on chromosome 15 (ultimate force; LOD = 3.9) for males carrying GKmtDNA, confirming the effect of reciprocal cross on osteoporosis-related phenotypes. By combining identified QTLs for biomechanical-, size- and qualitative phenotypes (pQCT and 3D CT) from the same population, overlapping regions were detected on chromosomes 1, 3, 4, 6, 8 and 10. These are strong candidate regions in the search for genetic risk factors for osteoporosis. PMID- 21818328 TI - Plasticity in major ampullate silk production in relation to spider phylogeny and ecology. AB - Spider major ampullate silk is a high-performance biomaterial that has received much attention. However, most studies ignore plasticity in silk properties. A better understanding of silk plasticity could clarify the relative importance of chemical composition versus processing of silk dope for silk properties. It could also provide insight into how control of silk properties relates to spider ecology and silk uses. We compared silk plasticity (defined as variation in the properties of silk spun by a spider under different conditions) between three spider clades in relation to their anatomy and silk biochemistry. We found that silk plasticity exists in RTA clade and orbicularian spiders, two clades that differ in their silk biochemistry. Orbiculariae seem less dependent on external spinning conditions. They probably use a valve in their spinning duct to control friction forces and speed during spinning. Our results suggest that plasticity results from different processing of the silk dope in the spinning duct. Orbicularian spiders seem to display better control of silk properties, perhaps in relation to their more complex spinning duct valve. PMID- 21818329 TI - The enigma of number: why children find the meanings of even small number words hard to learn and how we can help them do better. AB - Although number words are common in everyday speech, learning their meanings is an arduous, drawn-out process for most children, and the source of this delay has long been the subject of inquiry. Children begin by identifying the few small numerosities that can be named without counting, and this has prompted further debate over whether there is a specific, capacity-limited system for representing these small sets, or whether smaller and larger sets are both represented by the same system. Here we present a formal, computational analysis of number learning that offers a possible solution to both puzzles. This analysis indicates that once the environment and the representational demands of the task of learning to identify sets are taken into consideration, a continuous system for learning, representing and discriminating set-sizes can give rise to effective discontinuities in processing. At the same time, our simulations illustrate how typical prenominal linguistic constructions ("there are three balls") structure information in a way that is largely unhelpful for discrimination learning, while suggesting that postnominal constructions ("balls, there are three") will facilitate such learning. A training-experiment with three-year olds confirms these predictions, demonstrating that rapid, significant gains in numerical understanding and competence are possible given appropriately structured postnominal input. Our simulations and results reveal how discrimination learning tunes children's systems for representing small sets, and how its capacity-limits result naturally out of a mixture of the learning environment and the increasingly complex task of discriminating and representing ever-larger number sets. They also explain why children benefit so little from the training that parents and educators usually provide. Given the efficacy of our intervention, the ease with which it can be implemented, and the large body of research showing how early numerical ability predicts later educational outcomes, this simple discovery may have far-reaching consequences. PMID- 21818330 TI - Shikonin increases glucose uptake in skeletal muscle cells and improves plasma glucose levels in diabetic Goto-Kakizaki rats. AB - BACKGROUND: There is considerable interest in identifying compounds that can improve glucose homeostasis. Skeletal muscle, due to its large mass, is the principal organ for glucose disposal in the body and we have investigated here if shikonin, a naphthoquinone derived from the Chinese plant Lithospermum erythrorhizon, increases glucose uptake in skeletal muscle cells. METHODOLOGY/PRINCIPAL FINDINGS: Shikonin increases glucose uptake in L6 skeletal muscle myotubes, but does not phosphorylate Akt, indicating that in skeletal muscle cells its effect is medaited via a pathway distinct from that used for insulin-stimulated uptake. Furthermore we find no evidence for the involvement of AMP-activated protein kinase in shikonin induced glucose uptake. Shikonin increases the intracellular levels of calcium in these cells and this increase is necessary for shikonin-mediated glucose uptake. Furthermore, we found that shikonin stimulated the translocation of GLUT4 from intracellular vesicles to the cell surface in L6 myoblasts. The beneficial effect of shikonin on glucose uptake was investigated in vivo by measuring plasma glucose levels and insulin sensitivity in spontaneously diabetic Goto-Kakizaki rats. Treatment with shikonin (10 mg/kg intraperitoneally) once daily for 4 days significantly decreased plasma glucose levels. In an insulin sensitivity test (s.c. injection of 0.5 U/kg insulin), plasma glucose levels were significantly lower in the shikonin-treated rats. In conclusion, shikonin increases glucose uptake in muscle cells via an insulin-independent pathway dependent on calcium. CONCLUSIONS/SIGNIFICANCE: Shikonin increases glucose uptake in skeletal muscle cells via an insulin independent pathway dependent on calcium. The beneficial effects of shikonin on glucose metabolism, both in vitro and in vivo, show that the compound possesses properties that make it of considerable interest for developing novel treatment of type 2 diabetes. PMID- 21818331 TI - Mechanisms of interference in vibrotactile working memory. AB - In previous studies of interference in vibrotactile working memory, subjects were presented with an interfering distractor stimulus during the delay period between the target and probe stimuli in a delayed match-to-sample task. The accuracy of same/different decisions indicated feature overwriting was the mechanism of interference. However, the distractor was presented late in the delay period, and the distractor may have interfered with the decision-making process, rather than the maintenance of stored information. The present study varies the timing of distractor onset, (either early, in the middle, or late in the delay period), and demonstrates both overwriting and non-overwriting forms of interference. PMID- 21818332 TI - Targeted sorting of single virus-infected cells of the coccolithophore Emiliania huxleyi. AB - Discriminating infected from healthy cells is the first step to understanding the mechanisms and ecological implications of viral infection. We have developed a method for detecting, sorting, and performing molecular analysis of individual, infected cells of the important microalga Emiliania huxleyi, based on known physiological responses to viral infection. Of three fluorescent dyes tested, FM 1-43 (for detecting membrane blebbing) gave the most unequivocal and earliest separation of cells. Furthermore, we were able to amplify the genomes of single infected cells using Multiple Displacement Amplification. This novel method to reliably discriminate infected from healthy cells in cultures will allow researchers to answer numerous questions regarding the mechanisms and implications of viral infection of E. huxleyi. The method may be transferable to other virus-host systems. PMID- 21818333 TI - Accelerated telomere attrition is associated with relative household income, diet and inflammation in the pSoBid cohort. AB - BACKGROUND: It has previously been hypothesized that lower socio-economic status can accelerate biological ageing, and predispose to early onset of disease. This study investigated the association of socio-economic and lifestyle factors, as well as traditional and novel risk factors, with biological-ageing, as measured by telomere length, in a Glasgow based cohort that included individuals with extreme socio-economic differences. METHODS: A total of 382 blood samples from the pSoBid study were available for telomere analysis. For each participant, data was available for socio-economic status factors, biochemical parameters and dietary intake. Statistical analyses were undertaken to investigate the association between telomere lengths and these aforementioned parameters. RESULTS: The rate of age-related telomere attrition was significantly associated with low relative income, housing tenure and poor diet. Notably, telomere length was positively associated with LDL and total cholesterol levels, but inversely correlated to circulating IL-6. CONCLUSIONS: These data suggest lower socio economic status and poor diet are relevant to accelerated biological ageing. They also suggest potential associations between elevated circulating IL-6, a measure known to predict cardiovascular disease and diabetes with biological ageing. These observations require further study to tease out potential mechanistic links. PMID- 21818334 TI - The world's rediscovered species: back from the brink? AB - Each year, numerous species thought to have disappeared are rediscovered. Yet, do these rediscoveries represent the return of viable populations or the delayed extinction of doomed species? We document the number, distribution and conservation status of rediscovered amphibian, bird, and mammal species globally. Over the past 122 years, at least 351 species have been rediscovered, most occurring in the tropics. These species, on average, were missing for 61 years before being rediscovered (range of 3-331 years). The number of rediscoveries per year increased over time and the majority of these rediscoveries represent first documentations since their original description. Most rediscovered species have restricted ranges and small populations, and 92% of amphibians, 86% of birds, and 86% of mammals are highly threatened, independent of how long they were missing or when they were rediscovered. Under the current trends of widespread habitat loss, particularly in the tropics, most rediscovered species remain on the brink of extinction. PMID- 21818335 TI - Control of gene expression by the retinoic acid-related orphan receptor alpha in HepG2 human hepatoma cells. AB - Retinoic acid-related Orphan Receptor alpha (RORalpha; NR1F1) is a widely distributed nuclear receptor involved in several (patho)physiological functions including lipid metabolism, inflammation, angiogenesis, and circadian rhythm. To better understand the role of this nuclear receptor in liver, we aimed at displaying genes controlled by RORalpha in liver cells by generating HepG2 human hepatoma cells stably over-expressing RORalpha. Genes whose expression was altered in these cells versus control cells were displayed using micro-arrays followed by qRT-PCR analysis. Expression of these genes was also altered in cells in which RORalpha was transiently over-expressed after adenoviral infection. A number of the genes found were involved in known pathways controlled by RORalpha, for instance LPA, NR1D2 and ADIPOQ in lipid metabolism, ADIPOQ and PLG in inflammation, PLG in fibrinolysis and NR1D2 and NR1D1 in circadian rhythm. This study also revealed that genes such as G6PC, involved in glucose homeostasis, and AGRP, involved in the control of body weight, are also controlled by RORalpha. Lastly, SPARC, involved in cell growth and adhesion, and associated with liver carcinogenesis, was up-regulated by RORalpha. SPARC was found to be a new putative RORalpha target gene since it possesses, in its promoter, a functional RORE as evidenced by EMSAs and transfection experiments. Most of the other genes that we found regulated by RORalpha also contained putative ROREs in their regulatory regions. Chromatin immunoprecipitation (ChIP) confirmed that the ROREs present in the SPARC, PLG, G6PC, NR1D2 and AGRP genes were occupied by RORalpha in HepG2 cells. Therefore these genes must now be considered as direct RORalpha targets. Our results open new routes on the roles of RORalpha in glucose metabolism and carcinogenesis within cells of hepatic origin. PMID- 21818336 TI - Expression of HA of HPAI H5N1 virus at US2 gene insertion site of turkey herpesvirus induced better protection than that at US10 gene insertion site. AB - Herpesvirus of turkey (HVT) is being widely used as a vector for development of recombinant vaccines and US2 and US10 genes are often chosen as insertion sites for targeted gene expression. However, the different effects of the two genes for generation of recombinant HVT vaccines were unknown. In order to compare the effects of inserted genes in the two sites on the efficacy of the recombinant vaccines, host-protective haemagglutinin (HA) gene of the highly pathogenic avian influenza virus (HPAIV) H5N1 was inserted into either US2 or US10 gene locus of the HVT. The resulting US2 (rHVT-US2-HA) or US10 (rHVT-US10-HA) recombinant HVT viruses were used to infect chicken embryo fibroblasts. Plaques and the growth kinetics of rHVT-US2-HA-infected chicken embryo fibroblasts were similar to those of parental HVT whereas rHVT-US10-HA infected chicken embryo fibroblasts had different growth kinetics and plaque formation. The viremia levels in rHVT-US10 HA virus-infected chickens were significantly lower than those of rHVT-US2-HA group on 28 days post infection. The vaccine efficacy of the two recombinant viruses against H5N1 HPAIV and virulent Marek's disease virus was also evaluated in 1-day-old vaccinated chickens. rHVT-US2-HA-vaccinated chickens were better protected with reduced mortality than rHVT-US10-HA-vaccinated animals following HPAIV challenge. Furthermore, the overall hemaglutination inhibition antibody titers of rHVT-US2-HA-vaccinated chickens were higher than those of rHVT-US10-HA vaccinated chickens. Protection levels against Marek's disease virus challenge following vaccination with either rHVT-US2-HA or rHVT-US10-HA, however, were similar to those of the parental HVT virus. These results, for the first time, indicate that US2 gene provides a favorable foreign gene insertion site for generation of recombinant HVT vaccines. PMID- 21818337 TI - Fast computing betweenness centrality with virtual nodes on large sparse networks. AB - Betweenness centrality is an essential index for analysis of complex networks. However, the calculation of betweenness centrality is quite time-consuming and the fastest known algorithm uses O(N(M + N log N)) time and O(N + M) space for weighted networks, where N and M are the number of nodes and edges in the network, respectively. By inserting virtual nodes into the weighted edges and transforming the shortest path problem into a breadth-first search (BFS) problem, we propose an algorithm that can compute the betweenness centrality in O(wDN2) time for integer-weighted networks, where w is the average weight of edges and D is the average degree in the network. Considerable time can be saved with the proposed algorithm when w < log N/D + 1, indicating that it is suitable for lightly weighted large sparse networks. A similar concept of virtual node transformation can be used to calculate other shortest path based indices such as closeness centrality, graph centrality, stress centrality, and so on. Numerical simulations on various randomly generated networks reveal that it is feasible to use the proposed algorithm in large network analysis. PMID- 21818338 TI - Spermidine promotes human hair growth and is a novel modulator of human epithelial stem cell functions. AB - BACKGROUND: Rapidly regenerating tissues need sufficient polyamine synthesis. Since the hair follicle (HF) is a highly proliferative mini-organ, polyamines may also be important for normal hair growth. However, the role of polyamines in human HF biology and their effect on HF epithelial stem cells in situ remains largely unknown. METHODS AND FINDINGS: We have studied the effects of the prototypic polyamine, spermidine (0.1-1 uM), on human scalp HFs and human HF epithelial stem cells in serum-free organ culture. Under these conditions, spermidine promoted hair shaft elongation and prolonged hair growth (anagen). Spermidine also upregulated expression of the epithelial stem cell-associated keratins K15 and K19, and dose-dependently modulated K15 promoter activity in situ and the colony forming efficiency, proliferation and K15 expression of isolated human K15-GFP+ cells in vitro. Inhibiting the rate-limiting enzyme of polyamine synthesis, ornithine decarboyxlase (ODC), downregulated intrafollicular K15 expression. In primary human epidermal keratinocytes, spermidine slightly promoted entry into the S/G2-M phases of the cell cycle. By microarray analysis of human HF mRNA extracts, spermidine upregulated several key target genes implicated e.g. in the control of cell adherence and migration (POP3), or endoplasmic reticulum and mitochondrial functions (SYVN1, NACA and SLC25A3). Excess spermidine may restrict further intrafollicular polyamine synthesis by inhibiting ODC gene and protein expression in the HF's companion layer in situ. CONCLUSIONS: These physiologically and clinically relevant data provide the first direct evidence that spermidine is a potent stimulator of human hair growth and a previously unknown modulator of human epithelial stem cell biology. PMID- 21818339 TI - Expression of transposable elements in neural tissues during Xenopus development. AB - Transposable elements comprise a large proportion of animal genomes. Transposons can have detrimental effects on genome stability but also offer positive roles for genome evolution and gene expression regulation. Proper balance of the positive and deleterious effects of transposons is crucial for cell homeostasis and requires a mechanism that tightly regulates their expression. Herein we describe the expression of DNA transposons of the Tc1/mariner superfamily during Xenopus development. Sense and antisense transcripts containing complete Tc1-2_Xt were detected in Xenopus embryos. Both transcripts were found in zygotic stages and were mainly localized in Spemann's organizer and neural tissues. In addition, the Tc1-like elements Eagle, Froggy, Jumpy, Maya, Xeminos and TXr were also expressed in zygotic stages but not oocytes in X. tropicalis. Interestingly, although Tc1-2_Xt transcripts were not detected in Xenopus laevis embryos, transcripts from other two Tc1-like elements (TXr and TXz) presented a similar temporal and spatial pattern during X. laevis development. Deep sequencing analysis of Xenopus tropicalis gastrulae showed that PIWI-interacting RNAs (piRNAs) are specifically derived from several Tc1-like elements. The localized expression of Tc1-like elements in neural tissues suggests that they could play a role during the development of the Xenopus nervous system. PMID- 21818340 TI - Broad-spectrum antiviral therapeutics. AB - Currently there are relatively few antiviral therapeutics, and most which do exist are highly pathogen-specific or have other disadvantages. We have developed a new broad-spectrum antiviral approach, dubbed Double-stranded RNA (dsRNA) Activated Caspase Oligomerizer (DRACO) that selectively induces apoptosis in cells containing viral dsRNA, rapidly killing infected cells without harming uninfected cells. We have created DRACOs and shown that they are nontoxic in 11 mammalian cell types and effective against 15 different viruses, including dengue flavivirus, Amapari and Tacaribe arenaviruses, Guama bunyavirus, and H1N1 influenza. We have also demonstrated that DRACOs can rescue mice challenged with H1N1 influenza. DRACOs have the potential to be effective therapeutics or prophylactics for numerous clinical and priority viruses, due to the broad spectrum sensitivity of the dsRNA detection domain, the potent activity of the apoptosis induction domain, and the novel direct linkage between the two which viruses have never encountered. PMID- 21818341 TI - The fat body transcriptomes of the yellow fever mosquito Aedes aegypti, pre- and post- blood meal. AB - BACKGROUND: The fat body is the main organ of intermediary metabolism in insects and the principal source of hemolymph proteins. As part of our ongoing efforts to understand mosquito fat body physiology and to identify novel targets for insect control, we have conducted a transcriptome analysis of the fat body of Aedes aegypti before and in response to blood feeding. RESULTS: We created two fat body non-normalized EST libraries, one from mosquito fat bodies non-blood fed (NBF) and another from mosquitoes 24 hrs post-blood meal (PBM). 454 pyrosequencing of the non-normalized libraries resulted in 204,578 useable reads from the NBF sample and 323,474 useable reads from the PBM sample. Alignment of reads to the existing reference Ae. aegypti transcript libraries for analysis of differential expression between NBF and PBM samples revealed 116,912 and 115,051 matches, respectively. De novo assembly of the reads from the NBF sample resulted in 15,456 contigs, and assembly of the reads from the PBM sample resulted in 15,010 contigs. Collectively, 123 novel transcripts were identified within these contigs. Prominently expressed transcripts in the NBF fat body library were represented by transcripts encoding ribosomal proteins. Thirty-five point four percent of all reads in the PBM library were represented by transcripts that encode yolk proteins. The most highly expressed were transcripts encoding members of the cathepsin b, vitellogenin, vitellogenic carboxypeptidase, and vitelline membrane protein families. CONCLUSION: The two fat body transcriptomes were considerably different from each other in terms of transcript expression in terms of abundances of transcripts and genes expressed. They reflect the physiological shift of the pre-feeding fat body from a resting state to vitellogenic gene expression after feeding. PMID- 21818342 TI - Prophylactic activated recombinant factor VII in liver resection and liver transplantation: systematic review and meta-analysis. AB - BACKGROUND AND AIM: Intraoperative blood loss is a frequent complication of hepatic resection and orthotopic liver transplantation. Recombinant activated coagulation factor VII (rFVIIa) is a coagulation protein that induces hemostasis by directly activating factor X. There is no clear information about the prophylactic value of rFVIIa in hepatobiliary surgery, specifically in liver resection and orthotopic liver transplantation. The aim of this study was to assess the effect of rFVIIa prophylaxis to prevent mortality and bleeding resulting from hepatobiliary surgery. METHODS: Relevant randomized trials were identified by searching The Cochrane Central Register of Controlled Trials in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index. Randomized clinical trials comparing different rFVIIa prophylactic schemas against placebo or no intervention to prevent bleeding in hepatobiliary surgery were included. Adults undergoing liver resection, partial hepatectomy, or orthotopic liver transplantation were included. Dichotomous data were analyzed calculating odds ratios (ORs) and 95% confidence intervals (CIs). Continuous data were analyzed calculating mean differences (MD) and 95% CIs. RESULTS: Four randomized controlled trials were included. There were no significant differences between rFVIIa and placebo for mortality (OR 0.96; 95% CI 0.35-2.62), red blood cell units (MD 0.32; 95% CI -0.08-0.72) or adverse events (OR 1.55; 95% CI 0.97-2.49). CONCLUSIONS: The available information is limited, precluding the ability to draw conclusions regarding bleeding prophylaxis in hepatobiliary surgery using rFVIIa. Although an apparent lack of effect was observed in all outcomes studied, further research is needed. PMID- 21818343 TI - Heterogeneous nucleation of protein crystals on fluorinated layered silicate. AB - Here, we describe an improved system for protein crystallization based on heterogeneous nucleation using fluorinated layered silicate. In addition, we also investigated the mechanism of nucleation on the silicate surface. Crystallization of lysozyme using silicates with different chemical compositions indicated that fluorosilicates promoted nucleation whereas the silicates without fluorine did not. The use of synthesized saponites for lysozyme crystallization confirmed that the substitution of hydroxyl groups contained in the lamellae structure for fluorine atoms is responsible for the nucleation-inducing property of the nucleant. Crystallization of twelve proteins with a wide range of pI values revealed that the nucleation promoting effect of the saponites tended to increase with increased substitution rate. Furthermore, the saponite with the highest fluorine content promoted nucleation in all the test proteins regardless of their overall net charge. Adsorption experiments of proteins on the saponites confirmed that the density of adsorbed molecules increased according to the substitution rate, thereby explaining the heterogeneous nucleation on the silicate surface. PMID- 21818344 TI - Social defeat: impact on fear extinction and amygdala-prefrontal cortical theta synchrony in 5-HTT deficient mice. AB - Emotions, such as fear and anxiety, can be modulated by both environmental and genetic factors. One genetic factor is for example the genetically encoded variation of the serotonin transporter (5-HTT) expression. In this context, the 5 HTT plays a key role in the regulation of central 5-HT neurotransmission, which is critically involved in the physiological regulation of emotions including fear and anxiety. However, a systematic study which examines the combined influence of environmental and genetic factors on fear-related behavior and the underlying neurophysiological basis is missing. Therefore, in this study we used the 5-HTT deficient mouse model for studying emotional dysregulation to evaluate consequences of genotype specific disruption of 5-HTT function and repeated social defeat for fear-related behaviors and corresponding neurophysiological activities in the lateral amygdala (LA) and infralimbic region of the medial prefrontal cortex (mPFC) in male 5-HTT wild-type (+/+), homo- (-/-) and heterozygous (+/-) mice. Naive males and experienced losers (generated in a resident-intruder paradigm) of all three genotypes, unilaterally equipped with recording electrodes in LA and mPFC, underwent a Pavlovian fear conditioning. Fear memory and extinction of conditioned fear was examined while recording neuronal activity simultaneously with fear-related behavior. Compared to naive 5 HTT+/+ and +/- mice, 5-HTT-/- mice showed impaired recall of extinction. In addition, 5-HTT-/- and +/- experienced losers showed delayed extinction learning and impaired recall of extinction. Impaired behavioral responses were accompanied by increased theta synchronization between the LA and mPFC during extinction learning in 5-HTT-/- and +/- losers. Furthermore, impaired extinction recall was accompanied with increased theta synchronization in 5-HTT-/- naive and in 5-HTT-/ and +/- loser mice. In conclusion, extinction learning and memory of conditioned fear can be modulated by both the 5-HTT gene activity and social experiences in adulthood, accompanied by corresponding alterations of the theta activity in the amygdala-prefrontal cortex network. PMID- 21818345 TI - Why does the giant panda eat bamboo? A comparative analysis of appetite-reward related genes among mammals. AB - BACKGROUND: The giant panda has an interesting bamboo diet unlike the other species in the order of Carnivora. The umami taste receptor gene T1R1 has been identified as a pseudogene during its genome sequencing project and confirmed using a different giant panda sample. The estimated mutation time for this gene is about 4.2 Myr. Such mutation coincided with the giant panda's dietary change and also reinforced its herbivorous life style. However, as this gene is preserved in herbivores such as cow and horse, we need to look for other reasons behind the giant panda's diet switch. METHODOLOGY/PRINCIPAL FINDINGS: Since taste is part of the reward properties of food related to its energy and nutrition contents, we did a systematic analysis on those genes involved in the appetite reward system for the giant panda. We extracted the giant panda sequence information for those genes and compared with the human sequence first and then with seven other species including chimpanzee, mouse, rat, dog, cat, horse, and cow. Orthologs in panda were further analyzed based on the coding region, Kozak consensus sequence, and potential microRNA binding of those genes. CONCLUSIONS/SIGNIFICANCE: Our results revealed an interesting dopamine metabolic involvement in the panda's food choice. This finding suggests a new direction for molecular evolution studies behind the panda's dietary switch. PMID- 21818346 TI - Adenovirus-vectored drug-vaccine duo as a rapid-response tool for conferring seamless protection against influenza. AB - Few other diseases exert such a huge toll of suffering as influenza. We report here that intranasal (i.n.) administration of E1/E3-defective (DeltaE1E3) adenovirus serotype 5 (Ad5) particles rapidly induced an anti-influenza state as a means of prophylactic therapy which persisted for several weeks in mice. By encoding an influenza virus (IFV) hemagglutinin (HA) HA1 domain, an Ad5-HA1 vector conferred rapid protection as a prophylactic drug followed by elicitation of sustained protective immunity as a vaccine for inducing seamless protection against influenza as a drug-vaccine duo (DVD) in a single package. Since Ad5 particles induce a complex web of host responses, which could arrest influenza by activating a specific arm of innate immunity to impede IFV growth in the airway, it is conceivable that this multi-pronged influenza DVD may escape the fate of drug resistance that impairs the current influenza drugs. PMID- 21818347 TI - Can oxygen set thermal limits in an insect and drive gigantism? AB - BACKGROUND: Thermal limits may arise through a mismatch between oxygen supply and demand in a range of animal taxa. Whilst this oxygen limitation hypothesis is supported by data from a range of marine fish and invertebrates, its generality remains contentious. In particular, it is unclear whether oxygen limitation determines thermal extremes in tracheated arthropods, where oxygen limitation may be unlikely due to the efficiency and plasticity of tracheal systems in supplying oxygen directly to metabolically active tissues. Although terrestrial taxa with open tracheal systems may not be prone to oxygen limitation, species may be affected during other life-history stages, particularly if these rely on diffusion into closed tracheal systems. Furthermore, a central role for oxygen limitation in insects is envisaged within a parallel line of research focussing on insect gigantism in the late Palaeozoic. METHODOLOGY/PRINCIPAL FINDINGS: Here we examine thermal maxima in the aquatic life stages of an insect at normoxia, hypoxia (14 kPa) and hyperoxia (36 kPa). We demonstrate that upper thermal limits do indeed respond to external oxygen supply in the aquatic life stages of the stonefly Dinocras cephalotes, suggesting that the critical thermal limits of such aquatic larvae are set by oxygen limitation. This could result from impeded oxygen delivery, or limited oxygen regulatory capacity, both of which have implications for our understanding of the limits to insect body size and how these are influenced by atmospheric oxygen levels. CONCLUSIONS/SIGNIFICANCE: These findings extend the generality of the hypothesis of oxygen limitation of thermal tolerance, suggest that oxygen constraints on body size may be stronger in aquatic environments, and that oxygen toxicity may have actively selected for gigantism in the aquatic stages of Carboniferous arthropods. PMID- 21818348 TI - Conformational plasticity of proNGF. AB - Nerve Growth Factor is an essential protein that supports neuronal survival during development and influences neuronal function throughout adulthood, both in the central and peripheral nervous system. The unprocessed precursor of NGF, proNGF, seems to be endowed with biological functions distinct from those of the mature protein, such as chaperone-like activities and apoptotic and/or neurotrophic properties. We have previously suggested, based on Small Angle X-ray Scattering data, that recombinant murine proNGF has features typical of an intrinsically unfolded protein. Using complementary biophysical techniques, we show here new evidence that clarifies and widens this hypothesis through a detailed comparison of the structural properties of NGF and proNGF. Our data provide direct information about the dynamic properties of the pro-peptide and indicate that proNGF assumes in solution a compact globular conformation. The N terminal pro-peptide extension influences the chemical environment of the mature protein and protects the protein from proteolytic digestion. Accordingly, we observe that unfolding of proNGF involves a two-steps mechanism. The distinct structural properties of proNGF as compared to NGF agree with and rationalise a different functional role of the precursor. PMID- 21818349 TI - An internal ribosome entry site directs translation of the 3'-gene from Pelargonium flower break virus genomic RNA: implications for infectivity. AB - Pelargonium flower break virus (PFBV, genus Carmovirus) has a single-stranded positive-sense genomic RNA (gRNA) which contains five ORFs. The two 5'-proximal ORFs encode the replicases, two internal ORFs encode movement proteins, and the 3'-proximal ORF encodes a polypeptide (p37) which plays a dual role as capsid protein and as suppressor of RNA silencing. Like other members of family Tombusviridae, carmoviruses express ORFs that are not 5'-proximal from subgenomic RNAs. However, in one case, corresponding to Hisbiscus chlorotic ringspot virus, it has been reported that the 3'-proximal gene can be translated from the gRNA through an internal ribosome entry site (IRES). Here we show that PFBV also holds an IRES that mediates production of p37 from the gRNA, raising the question of whether this translation strategy may be conserved in the genus. The PFBV IRES was functional both in vitro and in vivo and either in the viral context or when inserted into synthetic bicistronic constructs. Through deletion and mutagenesis studies we have found that the IRES is contained within a 80 nt segment and have identified some structural traits that influence IRES function. Interestingly, mutations that diminish IRES activity strongly reduced the infectivity of the virus while the progress of the infection was favoured by mutations potentiating such activity. These results support the biological significance of the IRES driven p37 translation and suggest that production of the silencing suppressor from the gRNA might allow the virus to early counteract the defence response of the host, thus facilitating pathogen multiplication and spread. PMID- 21818350 TI - Influenza vaccine effectiveness in the elderly based on administrative databases: change in immunization habit as a marker for bias. AB - BACKGROUND: Administrative databases provide efficient methods to estimate influenza vaccine effectiveness (IVE) against severe outcomes in the elderly but are prone to intractable bias. This study returns to one of the linked population databases by which IVE against hospitalization and death in the elderly was first assessed. We explore IVE across six more recent influenza seasons, including periods before, during, and after peak activity to identify potential markers for bias. METHODS AND FINDINGS: Acute respiratory hospitalization and all-cause mortality were compared between immunized/non-immunized community-dwelling seniors >=65 years through administrative databases in Manitoba, Canada between 2000-01 and 2005-06. IVE was compared during pre-season/influenza/post-season periods through logistic regression with multivariable adjustment (age/sex/income/residence/prior influenza or pneumococcal immunization/medical visits/comorbidity), stratification based on prior influenza immunization history, and propensity scores. Analysis during pre-season periods assessed baseline differences between immunized and unimmunized groups. The study population included ~140,000 seniors, of whom 50-60% were immunized annually. Adjustment for key covariates and use of propensity scores consistently increased IVE. Estimates were paradoxically higher pre-season and for all-cause mortality vs. acute respiratory hospitalization. Stratified analysis showed that those twice consecutively and currently immunized were always at significantly lower hospitalization/mortality risk with odds ratios (OR) of 0.60 [95%CI0.48-0.75] and 0.58 [0.53-0.64] pre-season and 0.77 [0.69-0.86] and 0.71 [0.66-0.77] during influenza circulation, relative to the consistently unimmunized. Conversely, those forgoing immunization when twice previously immunized were always at significantly higher hospitalization/mortality risk with OR of 1.41 [1.14-1.73] and 2.45 [2.21-2.72] pre-season and 1.21 [1.03-1.43] and 1.78 [1.61-1.96] during influenza circulation. CONCLUSIONS: The most pronounced IVE estimates were paradoxically observed pre-season, indicating bias tending to over-estimate vaccine protection. Change in immunization habit from that of the prior two years may be a marker for this bias in administrative data sets; however, no analytic technique explored could adjust for its influence. Improved methods to achieve valid interpretation of protection in the elderly are needed. PMID- 21818351 TI - Intestinal tumorigenesis is not affected by progesterone signaling in rodent models. AB - Clinical data suggest that progestins have chemopreventive properties in the development of colorectal cancer. We set out to examine a potential protective effect of progestins and progesterone signaling on colon cancer development. In normal and neoplastic intestinal tissue, we found that the progesterone receptor (PR) is not expressed. Expression was confined to sporadic mesenchymal cells. To analyze the influence of systemic progesterone receptor signaling, we crossed mice that lacked the progesterone receptor (PRKO) to the Apc(Min/+) mouse, a model for spontaneous intestinal polyposis. PRKO-Apc(Min/+) mice exhibited no change in polyp number, size or localization compared to Apc(Min/+). To examine effects of progestins on the intestinal epithelium that are independent of the PR, we treated mice with MPA. We found no effects of either progesterone or MPA on gross intestinal morphology or epithelial proliferation. Also, in rats treated with MPA, injection with the carcinogen azoxymethane did not result in a difference in the number or size of aberrant crypt foci, a surrogate end-point for adenoma development. We conclude that expression of the progesterone receptor is limited to cells in the intestinal mesenchyme. We did not observe any effect of progesterone receptor signaling or of progestin treatment in rodent models of intestinal tumorigenesis. PMID- 21818352 TI - Sh3pxd2b mice are a model for craniofacial dysmorphology and otitis media. AB - Craniofacial defects that occur through gene mutation during development increase vulnerability to eustachian tube dysfunction. These defects can lead to an increased incidence of otitis media. We examined the effects of a mutation in the Sh3pxd2b gene (Sh3pxd2b(nee)) on the progression of otitis media and hearing impairment at various developmental stages. We found that all mice that had the Sh3pxd2b(nee) mutation went on to develop craniofacial dysmorphologies and subsequently otitis media, by as early as 11 days of age. We found noteworthy changes in cilia and goblet cells of the middle ear mucosa in Sh3pxd2b(nee) mutant mice using scanning electronic microscopy. By measuring craniofacial dimensions, we determined for the first time in an animal model that this mouse has altered eustachian tube morphology consistent with a more horizontal position of the eustachian tube. All mutants were found to have hearing impairment. Expression of TNF-alpha and TLR2, which correlates with inflammation in otitis media, was up-regulated in the ears of mutant mice when examined by immunohistochemistry and semi-quantitative RT-PCR. The mouse model with a mutation in the Sh3pxd2b gene (Sh3pxd2b(nee)) mirrors craniofacial dysmorphology and otitis media in humans. PMID- 21818353 TI - Spatial and temporal profiles of growth factor expression during CNS demyelination reveal the dynamics of repair priming. AB - Demyelination is the cause of disability in various neurological disorders. It is therefore crucial to understand the molecular regulation of oligodendrocytes, the myelin forming cells in the CNS. Growth factors are known to be essential for the development and maintenance of oligodendrocytes and are involved in the regulation of glial responses in various pathological conditions. We employed the well established murine cuprizone model of toxic demyelination to analyze the expression of 13 growth factors in the CNS during de- and remyelination. The temporal mRNA expression profile during demyelination and the subsequent remyelination were analyzed separately in the corpus callosum and cerebral cortex using laser microdissection and real-time PCR techniques. During demyelination a similar pattern of growth factor mRNA expression was observed in both areas with a strong up-regulation of NRG1 and GDNF and a slight increase of CNTF in the first week of cuprizone treatment. HGF, FGF-2, LIF, IGF-I, and TGF-beta1 were up regulated mainly during peak demyelination. In contrast, during remyelination there were regional differences in growth factor mRNA expression levels. GDNF, CNTF, HGF, FGF-2, and BDNF were elevated in the corpus callosum but not in the cortex, suggesting tissue differences in the molecular regulation of remyelination in the white and grey matter. To clarify the cellular source we isolated microglia from the cuprizone lesions. GDNF, IGF-1, and FGF mRNA were detected in the microglial fraction with a temporal pattern corresponding to that from whole tissue PCR. In addition, immunohistochemical analysis revealed IGF-1 protein expression also in the reactive astrocytes. CNTF was located in astrocytes. This study identified seven different temporal expression patterns for growth factors in white and grey matter and demonstrated the importance of early tissue priming and exact orchestration of different steps during callosal and cortical de- and remyelination. PMID- 21818354 TI - The effect of repetitive transcranial magnetic stimulation on gamma oscillatory activity in schizophrenia. AB - BACKGROUND: Gamma (gamma) oscillations (30-50 Hz) have been shown to be excessive in patients with schizophrenia (SCZ) during working memory (WM). WM is a cognitive process that involves the online maintenance and manipulation of information that is mediated largely by the dorsolateral prefrontal cortex (DLPFC). Repetitive transcranial magnetic stimulation (rTMS) represents a non invasive method to stimulate the cortex that has been shown to enhance cognition and gamma oscillatory activity during WM. METHODOLOGY AND PRINCIPAL FINDINGS: We examined the effect of 20 Hz rTMS over the DLPFC on gamma oscillatory activity elicited during the N-back task in 24 patients with SCZ compared to 22 healthy subjects. Prior to rTMS, patients with SCZ elicited excessive gamma oscillatory activity compared to healthy subjects across WM load. Active rTMS resulted in the reduction of frontal gamma oscillatory activity in patients with SCZ, while potentiating activity in healthy subjects in the 3-back, the most difficult condition. Further, these effects on gamma oscillatory activity were found to be specific to the frontal brain region and were absent in the parieto-occipital brain region. CONCLUSIONS AND SIGNIFICANCE: We suggest that this opposing effect of rTMS on gamma oscillatory activity in patients with SCZ versus healthy subjects may be related to homeostatic plasticity leading to differential effects of rTMS on gamma oscillatory activity depending on baseline differences. These findings provide important insights into the neurophysiological mechanisms underlying WM deficits in SCZ and demonstrated that rTMS can modulate gamma oscillatory activity that may be a possible avenue for cognitive potentiation in this disorder. PMID- 21818355 TI - IRF4 is a suppressor of c-Myc induced B cell leukemia. AB - Interferon regulatory factor 4 (IRF4) is a critical transcriptional regulator in B cell development and function. We have previously shown that IRF4, together with IRF8, orchestrates pre-B cell development by limiting pre-B cell expansion and by promoting pre-B cell differentiation. Here, we report that IRF4 suppresses c-Myc induced leukemia in EMUMyc mice. Our results show that c-Myc induced leukemia was greatly accelerated in the IRF4 heterozygous mice (IRF4(+/-)Myc); the average age of mortality in the IRF4(+/-)Myc mice was only 7 to 8 weeks but was 20 weeks in the control mice. Our results show that IRF4(+/-)Myc leukemic cells were derived from large pre-B cells and were hyperproliferative and resistant to apoptosis. Further analysis revealed that the majority of IRF4(+/ )Myc leukemic cells inactivated the wild-type IRF4 allele and contained defects in Arf-p53 tumor suppressor pathway. p27(kip) is part of the molecular circuitry that controls pre-B cell expansion. Our results show that expression of p27(kip) was lost in the IRF4(+/-)Myc leukemic cells and reconstitution of IRF4 expression in those cells induced p27(kip) and inhibited their expansion. Thus, IRF4 functions as a classical tumor suppressor to inhibit c-Myc induced B cell leukemia in EMUMyc mice. PMID- 21818356 TI - Herpes simplex virus-induced epithelial damage and susceptibility to human immunodeficiency virus type 1 infection in human cervical organ culture. AB - Normal human premenopausal cervical tissue has been used to derive primary cell populations and to establish ex vivo organ culture systems to study infections with herpes simplex virus (HSV-1 or HSV-2) and human immunodeficiency virus type 1 (HIV-1). Infection with either HSV-1 or HSV-2 rapidly induced multinuclear giant cell formation and widespread damage in mucosal epithelial cells. Subsequent exposure of the damaged mucosal surfaces to HIV-1 revealed frequent co localization of HSV and HIV-1 antigens. The short-term organ culture system provides direct experimental support for the epidemiological findings that pre existing sexually transmitted infections, including primary and recurrent herpes virus infections at mucosal surfaces, represent major risk factors for acquisition of primary HIV-1 infection. Epithelial damage in combination with pre existing inflammation, as described here for overtly normal human premenopausal cervix, creates a highly susceptible environment for the initiation and establishment of primary HIV-1 infection in the sub-mucosa of the cervical transformation zone. PMID- 21818357 TI - Three-dimensional imaging of the mouse neurovasculature with magnetic resonance microscopy. AB - Knowledge of the three-dimensional (3D) architecture of blood vessels in the brain is crucial because the progression of various neuropathologies ranging from Alzheimer's disease to brain tumors involves anomalous blood vessels. The challenges in obtaining such data from patients, in conjunction with development of mouse models of neuropathology, have made the murine brain indispensable for investigating disease induced neurovascular changes. Here we describe a novel method for "whole brain" 3D mapping of murine neurovasculature using magnetic resonance microscopy (MUMRI). This approach preserves the vascular and white matter tract architecture, and can be combined with complementary MRI contrast mechanisms such as diffusion tensor imaging (DTI) to examine the interplay between the vasculature and white matter reorganization that often characterizes neuropathologies. Following validation with micro computed tomography (MUCT) and optical microscopy, we demonstrate the utility of this method by: (i) combined 3D imaging of angiogenesis and white matter reorganization in both, invasive and non invasive brain tumor models; (ii) characterizing the morphological heterogeneity of the vascular phenotype in the murine brain; and (iii) conducting "multi-scale" imaging of brain tumor angiogenesis, wherein we directly compared in vivo MRI blood volume measurements with ex vivo vasculature data. PMID- 21818358 TI - Predicting inactive conformations of protein kinases using active structures: conformational selection of type-II inhibitors. AB - Protein kinases have been found to possess two characteristic conformations in their activation-loops: the active DFG-in conformation and the inactive DFG-out conformation. Recently, it has been very interesting to develop type-II inhibitors which target the DFG-out conformation and are more specific than the type-I inhibitors binding to the active DFG-in conformation. However, solving crystal structures of kinases with the DFG-out conformation remains a challenge, and this seriously hampers the application of the structure-based approaches in development of novel type-II inhibitors. To overcome this limitation, here we present a computational approach for predicting the DFG-out inactive conformation using the DFG-in active structures, and develop related conformational selection protocols for the uses of the predicted DFG-out models in the binding pose prediction and virtual screening of type-II ligands. With the DFG-out models, we predicted the binding poses for known type-II inhibitors, and the results were found in good agreement with the X-ray crystal structures. We also tested the abilities of the DFG-out models to recognize their specific type-II inhibitors by screening a database of small molecules. The AUC (area under curve) results indicated that the predicted DFG-out models were selective toward their specific type-II inhibitors. Therefore, the computational approach and protocols presented in this study are very promising for the structure-based design and screening of novel type-II kinase inhibitors. PMID- 21818359 TI - Neotropical bats: estimating species diversity with DNA barcodes. AB - DNA barcoding using the cytochrome c oxidase subunit 1 gene (COI) is frequently employed as an efficient method of species identification in animal life and may also be used to estimate species richness, particularly in understudied faunas. Despite numerous past demonstrations of the efficiency of this technique, few studies have attempted to employ DNA barcoding methodologies on a large geographic scale, particularly within tropical regions. In this study we survey current and potential species diversity using DNA barcodes with a collection of more than 9000 individuals from 163 species of Neotropical bats (order Chiroptera). This represents one of the largest surveys to employ this strategy on any animal group and is certainly the largest to date for land vertebrates. Our analysis documents the utility of this tool over great geographic distances and across extraordinarily diverse habitats. Among the 163 included species 98.8% possessed distinct sets of COI haplotypes making them easily recognizable at this locus. We detected only a single case of shared haplotypes. Intraspecific diversity in the region was high among currently recognized species (mean of 1.38%, range 0-11.79%) with respect to birds, though comparable to other bat assemblages. In 44 of 163 cases, well-supported, distinct intraspecific lineages were identified which may suggest the presence of cryptic species though mean and maximum intraspecific divergence were not good predictors of their presence. In all cases, intraspecific lineages require additional investigation using complementary molecular techniques and additional characters such as morphology and acoustic data. Our analysis provides strong support for the continued assembly of DNA barcoding libraries and ongoing taxonomic investigation of bats. PMID- 21818360 TI - Stable panoramic views facilitate snap-shot like memories for spatial reorientation in homing pigeons. AB - Following spatial disorientation, animals can reorient themselves by relying on geometric cues (metric and sense) specified both by the macroscopic surface layout of an enclosed space and prominent visual landmarks in arrays. Whether spatial reorientation in arrays of landmarks is based on explicit representation of the geometric cues is a matter of debate. Here we trained homing pigeons (Columba livia) to locate a food-reward in a rectangular array of four identical or differently coloured pipes provided with four openings, only one of which allowed the birds to have access to the reward. Pigeons were trained either with a stable or a variable position of the opening on pipes, so that they could view the array either from the same or a variable perspective. Explicit mapping of configural geometry would predict successful reorientation irrespective of access condition. In contrast, we found that a stable view of the array facilitated spatial learning in homing pigeons, likely through the formation of snapshot-like memories. PMID- 21818361 TI - EEG correlates of attentional load during multiple object tracking. AB - While human subjects tracked a subset of ten identical, randomly-moving objects, event-related potentials (ERPs) were evoked at parieto-occipital sites by task irrelevant flashes that were superimposed on either tracked (Target) or non tracked (Distractor) objects. With ERPs as markers of attention, we investigated how allocation of attention varied with tracking load, that is, with the number of objects that were tracked. Flashes on Target discs elicited stronger ERPs than did flashes on Distractor discs; ERP amplitude (0-250 ms) decreased monotonically as load increased from two to three to four (of ten) discs. Amplitude decreased more rapidly for Target discs than Distractor discs. As a result, with increasing tracking loads, the difference between ERPs to Targets and Distractors diminished. This change in ERP amplitudes with load accords well with behavioral performance, suggesting that successful tracking depends upon the relationship between the neural signals associated with attended and non-attended objects. PMID- 21818362 TI - Outer membrane protein A (OmpA) of Shigella flexneri 2a, induces protective immune response in a mouse model. AB - BACKGROUND: In our earlier studies 34 kDa outer membrane protein (OMP) of Shigella flexneri 2a has been identified as an efficient immunostimulant. KEY RESULTS: In the present study MALDI-TOF MS analysis of the purified 34 kDa OMP of Shigella flexneri 2a shows considerable sequence homology (Identity 65%) with the OmpA of S. flexneri 2a. By using the specific primers, the gene of interest has been amplified from S. flexneri 2a (N.Y-962/92) genomic DNA, cloned in pET100/D TOPO(r) vector and expressed using induction with isopropyl thiogalactoside (IPTG) for the first time. Immunogenicity and protective efficacy of the recombinant OmpA has been evaluated in an intranasally immunized murine pulmonary model. The recombinant protein induces significantly enhanced protein specific IgG and IgA Abs in both mucosal and systemic compartments and IgA secreting cells in the systemic compartment (spleen). The mice immunized with OmpA have been protected completely from systemic challenge with a lethal dose of virulent S. flexneri 2a. Immunization with the protein causes mild polymorphonuclear neutrophil infiltration in the lung, without inducing the release of large amounts of proinflammatory cytokines. CONCLUSION: These results suggest that the OmpA of S. flexneri 2a can be an efficacious mucosal immunogen inducing protective immune responses. Our findings also demonstrate that antibodies and Th1 immune response may be associated with the marked protective efficacy of immunized mice after intranasal shigellae infection. PMID- 21818363 TI - Transmitters and pathways mediating inhibition of spinal itch-signaling neurons by scratching and other counterstimuli. AB - Scratching relieves itch, but the underlying neural mechanisms are poorly understood. We presently investigated a role for the inhibitory neurotransmitters GABA and glycine in scratch-evoked inhibition of spinal itch-signaling neurons in a mouse model of chronic dry skin itch. Superficial dorsal horn neurons ipsilateral to hindpaw dry skin treatment exhibited a high level of spontaneous firing that was significantly attenuated by cutaneous scratching, pinch and noxious heat. Scratch-evoked inhibition was nearly abolished by spinal delivery of the glycine antagonist, strychnine, and was markedly attenuated by respective GABA(A) and GABA(B) antagonists bicuculline and saclofen. Scratch-evoked inhibition was also significantly attenuated (but not abolished) by interruption of the upper cervical spinal cord, indicating the involvement of both segmental and suprasegmental circuits that engage glycine- and GABA-mediated inhibition of spinal itch-signaling neurons by noxious counterstimuli. PMID- 21818364 TI - Comparison of eight methods for the extraction of Bacillus atrophaeus spore DNA from eleven common interferents and a common swab. AB - Eight DNA extraction products or methods (Applied Biosystems PrepFiler Forensic DNA Extraction Kit; Bio-Rad Instagene Only, Bio-Rad Instagene & Spin Column Purification; EpiCentre MasterPure DNA & RNA Kit; FujiFilm QuickGene Mini80; Idaho Technologies 1-2-3 Q-Flow Kit; MoBio UltraClean Microbial DNA Isolation Kit; Sigma Extract-N-Amp Plant and Seed Kit) were adapted to facilitate extraction of DNA under BSL3 containment conditions. DNA was extracted from 12 common interferents or sample types, spiked with spores of Bacillus atropheaus. Resulting extracts were tested by real-time PCR. No one method was the best, in terms of DNA extraction, across all sample types. Statistical analysis indicated that the PrepFiler method was the best method from six dry powders (baking, biological washing, milk, plain flour, filler and talcum) and one solid (Underarm deodorant), the UltraClean method was the best from four liquids (aftershave, cola, nutrient broth, vinegar), and the MasterPure method was the best from the swab sample type. The best overall method, in terms of DNA extraction, across all sample types evaluated was the UltraClean method. PMID- 21818365 TI - Quantitative photo activated localization microscopy: unraveling the effects of photoblinking. AB - In this work we discuss how to use photophysical information for improved quantitative measurements using Photo Activated Localization Microscopy (PALM) imaging. We introduce a method that reliably estimates the number of photoblinking molecules present in a biological sample and gives a robust way to quantify proteins at the single-cell level from PALM images. We apply this method to determine the amount of beta2 adrenergic receptor, a prototypical G Protein Coupled Receptor, expressed on the plasma membrane of HeLa cells. PMID- 21818366 TI - ACE2-mediated reduction of oxidative stress in the central nervous system is associated with improvement of autonomic function. AB - Oxidative stress in the central nervous system mediates the increase in sympathetic tone that precedes the development of hypertension. We hypothesized that by transforming Angiotensin-II (AngII) into Ang-(1-7), ACE2 might reduce AngII-mediated oxidative stress in the brain and prevent autonomic dysfunction. To test this hypothesis, a relationship between ACE2 and oxidative stress was first confirmed in a mouse neuroblastoma cell line (Neuro2A cells) treated with AngII and infected with Ad-hACE2. ACE2 overexpression resulted in a reduction of reactive oxygen species (ROS) formation. In vivo, ACE2 knockout (ACE2(-/y)) mice and non-transgenic (NT) littermates were infused with AngII (10 days) and infected with Ad-hACE2 in the paraventricular nucleus (PVN). Baseline blood pressure (BP), AngII and brain ROS levels were not different between young mice (12 weeks). However, cardiac sympathetic tone, brain NADPH oxidase and SOD activities were significantly increased in ACE2(-/y). Post infusion, plasma and brain AngII levels were also significantly higher in ACE2(-/y), although BP was similarly increased in both genotypes. ROS formation in the PVN and RVLM was significantly higher in ACE2(-/y) mice following AngII infusion. Similar phenotypes, i.e. increased oxidative stress, exacerbated dysautonomia and hypertension, were also observed on baseline in mature ACE2(-/y) mice (48 weeks). ACE2 gene therapy to the PVN reduced AngII-mediated increase in NADPH oxidase activity and normalized cardiac dysautonomia in ACE2(-/y) mice. Altogether, these data indicate that ACE2 gene deletion promotes age-dependent oxidative stress, autonomic dysfunction and hypertension, while PVN-targeted ACE2 gene therapy decreases ROS formation via NADPH oxidase inhibition and improves autonomic function. Accordingly, ACE2 could represent a new target for the treatment of hypertension-associated dysautonomia and oxidative stress. PMID- 21818367 TI - Investigation of multiple susceptibility loci for inflammatory bowel disease in an Italian cohort of patients. AB - BACKGROUND: Recent GWAs and meta-analyses have outlined about 100 susceptibility genes/loci for inflammatory bowel diseases (IBD). In this study we aimed to investigate the influence of SNPs tagging the genes/loci PTGER4, TNFSF15, NKX2-3, ZNF365, IFNG, PTPN2, PSMG1, and HLA in a large pediatric- and adult-onset IBD Italian cohort. METHODS: Eight SNPs were assessed in 1,070 Crohn's disease (CD), 1,213 ulcerative colitis (UC), 557 of whom being diagnosed at the age of <=16 years, and 789 healthy controls. Correlations with sub-phenotypes and major variants of NOD2 gene were investigated. RESULTS: The SNPs tagging the TNFSF15, NKX2-3, ZNF365, and PTPN2 genes were associated with CD (P values ranging from 0.037 to 7*10(-6)). The SNPs tagging the PTGER4, NKX2-3, ZNF365, IFNG, PSMG1, and HLA area were associated with UC (P values 0.047 to 4*10(-5)). In the pediatric cohort the associations of TNFSF15, NKX2-3 with CD, and PTGER4, NKX2-3, ZNF365, IFNG, PSMG1 with UC, were confirmed. Association with TNFSF15 and pediatric UC was also reported. A correlation with NKX2-3 and need for surgery (P = 0.038), and with HLA and steroid-responsiveness (P = 0.024) in UC patients was observed. Moreover, significant association in our CD cohort with TNFSF15 SNP and colonic involvement (P = 0.021), and with ZNF365 and ileal location (P = 0.024) was demonstrated. CONCLUSIONS: We confirmed in a large Italian cohort the associations with CD and UC of newly identified genes, both in adult and pediatric cohort of patients, with some influence on sub-phenotypes. PMID- 21818368 TI - Native-state stability determines the extent of degradation relative to secretion of protein variants from Pichia pastoris. AB - We have investigated the relationship between the stability and secreted yield of a series of mutational variants of human lysozyme (HuL) in Pichia pastoris. We show that genes directly involved in the unfolded protein response (UPR), ER associated degradation (ERAD) and ER-phagy are transcriptionally up-regulated more quickly and to higher levels in response to expression of more highly destabilised HuL variants and those variants are secreted to lower yield. We also show that the less stable variants are retained within the cell and may also be targeted for degradation. To explore the relationship between stability and secretion further, two different single-chain-variable-fragment (scFv) antibodies were also expressed in P. pastoris, but only one of the scFvs gave rise to secreted protein. The non-secreted scFv was detected within the cell and the UPR indicators were pronounced, as they were for the poorly-secreted HuL variants. The non-secreted scFv was modified by changing either the framework regions or the linker to improve the predicted stability of the scFv and secretion was then achieved and the levels of UPR indicators were lowered Our data support the hypothesis that less stable proteins are targeted for degradation over secretion and that this accounts for the decrease in the yields observed. We discuss the secretion of proteins in relation to lysozyme amyloidosis, in particular, and optimised protein secretion, in general. PMID- 21818369 TI - Peptide substrates for Rho-associated kinase 2 (Rho-kinase 2/ROCK2). AB - Peptide substrates sensitive for a certain protein kinase could be important for new-drug development and to understand the mechanism of diseases. Rho-associated kinase (Rho-kinase/ROCK) is a serine/threonine kinase, and plays an important part in cardiovascular disease, migration and invasion of tumor cells, and in neurological disorders. The purpose of this study was to find substrates with high affinity and sensitivity for ROCK2. We synthesized 136 peptide substrates from protein substrates for ROCK2 with different lengths and charged peptides. Incorporation of (32)P [counts per minute (CPM)] for each peptide substrate was determined by the radiolabel assay using [gamma-(32)P]ATP. When the top five peptide substrates showing high CPMs (R4, R22, R133, R134, and R135) were phosphorylated by other enzymes (PKA, PKCalpha, and ERK1), R22, R133, and R135 displayed the highest CPM level for ROCK2 compared with other enzymes, whereas R4 and R134 showed similar CPM levels for ROCK2 and PKCalpha. We hypothesize that R22, R133, and R135 can be useful peptide substrates for ROCK2. PMID- 21818370 TI - Pathway of Toll-like receptor 7/B cell activating factor/B cell activating factor receptor plays a role in immune thrombocytopenia in vivo. AB - Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by anti platelet autoantibody-mediated platelet destruction. Antigen-presenting cell (APC) dysfunction is considered to play crucial roles in ITP. However, how APC affects autoreactive B cells in ITP is still unknown. Using a mouse model of immune thrombocytopenia, we demonstrated an increase in levels of TLR7 in splenic mononuclear cells (SMCs). Using both TLR7 agonist and TLR7 silencing lentivirus, we found stimulation of TLR7 decreased platelet counts and increased levels of platelet-associated IgG (PAIgG) in ITP mice, which correlates TLR7 with platelet destruction by autoantibodies. Levels of serum BAFF increased significantly in ITP mice and stimulation of TLR7 promoted secretion of BAFF. Among the three BAFF receptors, only BAFF receptor (BAFF-R) increased in ITP mice. However, activation of TLR7 showed no effect on the expression of BAFF receptors. These findings indicate that upregulation of TLR7 may augment BAFF secretion by APC and through ligation of BAFF-R promote autoreactive B cell survival and thus anti-platelet autoantibody production. The pathway of TLR7/BAFF/BAFF-R provides us with an explanation of how activation of APC affects autoantibody production by B cells in ITP and thus might provide a reasonable therapeutic strategy for ITP. PMID- 21818371 TI - Impaired cognitive function and altered hippocampal synapse morphology in mice lacking Lrrtm1, a gene associated with schizophrenia. AB - Recent genetic linkage analysis has shown that LRRTM1 (Leucine rich repeat transmembrane neuronal 1) is associated with schizophrenia. Here, we characterized Lrrtm1 knockout mice behaviorally and morphologically. Systematic behavioral analysis revealed reduced locomotor activity in the early dark phase, altered behavioral responses to novel environments (open-field box, light-dark box, elevated plus maze, and hole board), avoidance of approach to large inanimate objects, social discrimination deficit, and spatial memory deficit. Upon administration of the NMDA receptor antagonist MK-801, Lrrtm1 knockout mice showed both locomotive activities in the open-field box and responses to the inanimate object that were distinct from those of wild-type mice, suggesting that altered glutamatergic transmission underlay the behavioral abnormalities. Furthermore, administration of a selective serotonin reuptake inhibitor (fluoxetine) rescued the abnormality in the elevated plus maze. Morphologically, the brains of Lrrtm1 knockout mice showed reduction in total hippocampus size and reduced synaptic density. The hippocampal synapses were characterized by elongated spines and diffusely distributed synaptic vesicles, indicating the role of Lrrtm1 in maintaining synaptic integrity. Although the pharmacobehavioral phenotype was not entirely characteristic of those of schizophrenia model animals, the impaired cognitive function may warrant the further study of LRRTM1 in relevance to schizophrenia. PMID- 21818373 TI - The self in social interactions: sensory attenuation of auditory action effects is stronger in interactions with others. AB - The experience of oneself as an agent not only results from interactions with the inanimate environment, but often takes place in a social context. Interactions with other people have been suggested to play a key role in the construal of self agency. Here, we investigated the influence of social interactions on sensory attenuation of action effects as a marker of pre-reflective self-agency. To this end, we compared the attenuation of the perceived loudness intensity of auditory action effects generated either by oneself or another person in either an individual, non-interactive or interactive action context. In line with previous research, the perceived loudness of self-generated sounds was attenuated compared to sounds generated by another person. Most importantly, this effect was strongly modulated by social interactions between self and other. Sensory attenuation of self- and other-generated sounds was increased in interactive as compared to the respective individual action contexts. This is the first experimental evidence suggesting that pre-reflective self-agency can extend to and is shaped by interactions between individuals. PMID- 21818372 TI - Influence of climate on emergency department visits for syncope: role of air temperature variability. AB - BACKGROUND: Syncope is a clinical event characterized by a transient loss of consciousness, estimated to affect 6.2/1000 person-years, resulting in remarkable health care and social costs. Human pathophysiology suggests that heat may promote syncope during standing. We tested the hypothesis that the increase of air temperatures from January to July would be accompanied by an increased rate of syncope resulting in a higher frequency of Emergency Department (ED) visits. We also evaluated the role of maximal temperature variability in affecting ED visits for syncope. METHODOLOGY/PRINCIPAL FINDINGS: We included 770 of 2775 consecutive subjects who were seen for syncope at four EDs between January and July 2004. This period was subdivided into three epochs of similar length: 23 January-31 March, 1 April-31 May and 1 June-31 July. Spectral techniques were used to analyze oscillatory components of day by day maximal temperature and syncope variability and assess their linear relationship. There was no correlation between daily maximum temperatures and number of syncope. ED visits for syncope were lower in June and July when maximal temperature variability declined although the maximal temperatures themselves were higher. Frequency analysis of day by day maximal temperature variability showed a major non-random fluctuation characterized by a ~23-day period and two minor oscillations with ~3- and ~7-day periods. This latter oscillation was correlated with a similar ~7-day fluctuation in ED visits for syncope. CONCLUSIONS/SIGNIFICANCE: We conclude that ED visits for syncope were not predicted by daily maximal temperature but were associated with increased temperature variability. A ~7-day rhythm characterized both maximal temperatures and ED visits for syncope variability suggesting that climate changes may have a significant effect on the mode of syncope occurrence. PMID- 21818374 TI - Mechanisms underlying the bioindicator notion: spatial association between individual sexual performance and community diversity. AB - The bioindicator notion is an appealing concept that has received more support in applied than in basic ecology, mostly due to the difficulty in deriving general ecological rules applicable to all target organisms. However, recognizing the mechanisms that determine the association between a particular species and the well-being of many other species is important for understanding the functioning of ecosystems and the relationship among different biological levels. We examined here the processes at the individual level that cause an association between species performance and biodiversity value, by analyzing attributes that can be studied in a variety of animals with sexual reproduction, namely breeding site selection and condition-dependent sexual signals. Our study model was the Capercaillie, an indicator of forest functioning and diversity, and the associated bird community, used here as a surrogate of broader forest biodiversity. At a regional scale Capercaillie occurrence was not associated with the most diverse forest patches, but at the scale of male spring territories the sexual display grounds (arenas) were located in the oldest and less disturbed forest portions, which also hosted the richest local bird communities. Social mechanisms and conspecific cueing likely concurred with habitat-driven processes in determining the long-term persistence of traditional display grounds, which were appealing to many other species because of their structural composition. Characteristics of male vocal display that honestly advertize male quality (low frequencies and rapid song rates) were significantly correlated with high diversity values, resulting in a spatial association between individual and community performances. Costly or risky activities such as reproductive or social behaviors, which more than other attributes match gradients in habitat quality, are therefore contributing to functionally connect individuals with ecosystem health. PMID- 21818375 TI - piR_015520 belongs to Piwi-associated RNAs regulates expression of the human melatonin receptor 1A gene. AB - Piwi-associated RNAs (piRNAs) are a distinct class of 24- to 30-nucleotide-long RNAs produced by a Dicer-independent mechanism, and are associated with Piwi class Argonaute proteins. In contrast to the several hundred species of microRNAs (miRNAs) identified thus far, piRNAs consist of more than 30,000 different species in humans. Studies in flies, fish and mice implicate these piRNAs in regulating germ line development, the silencing of selfish DNA elements, and maintaining germ line DNA integrity. Most piRNAs map to unique sites in the human genome, including intergenic, intronic, and exonic sequences. However, the role of piRNAs in humans remains to be elucidated. Here, we uncover an unexpected function of the piRNA pathway in humans. We show for the first time, that the piRNA_015520, located in intron 1 of the human Melatonin receptor 1A (MTNR1A) gene, is expressed in adult human tissues (testes and brain) and in the human cell line HEK 293. Although the role of piR_015520 expression in brain tissue remains unknown, the testes-specific expression is consistent with previous findings in several species. Surprisingly, in contrast to the mechanism known for miRNA-mediated modulation of gene expression, piRNA_015520 negatively regulates MTNR1A gene expression by binding to its genomic region. This finding suggests that changes in individual piRNA levels could influence both autoregulatory gene expression and the expression of the gene in which the piRNA is located. These findings offer a new perspective for piRNAs functioning as gene regulators in humans. PMID- 21818376 TI - Effect of constitution on mass of individual organs and their association with metabolic rate in humans--a detailed view on allometric scaling. AB - Resting energy expenditure (REE)-power relationships result from multiple underlying factors including weight and height. In addition, detailed body composition, including fat free mass (FFM) and its components, skeletal muscle mass and internal organs with high metabolic rates (i.e. brain, heart, liver, kidneys), are major determinants of REE. Since the mass of individual organs scales to height as well as to weight (and, thus, to constitution), the variance in these associations may also add to the variance in REE. Here we address body composition (measured by magnetic resonance imaging) and REE (assessed by indirect calorimetry) in a group of 330 healthy volunteers differing with respect to age (17-78 years), sex (61% female) and BMI (15.9-47.8 kg/m(2)). Using three dimensional data interpolation we found that the inter-individual variance related to scaling of organ mass to height and weight and, thus, the constitution related variances in either FFM (model 1) or kidneys, muscle, brain and liver (model 2) explained up to 43% of the inter-individual variance in REE. These data are the first evidence that constitution adds to the complexity of REE. Since organs scale differently as weight as well as height the "fit" of organ masses within constitution should be considered as a further trait. PMID- 21818377 TI - Correlations among brain gray matter volumes, age, gender, and hemisphere in healthy individuals. AB - To determine the relationship between age and gray matter structure and how interactions between gender and hemisphere impact this relationship, we examined correlations between global or regional gray matter volume and age, including interactions of gender and hemisphere, using a general linear model with voxel based and region-of-interest analyses. Brain magnetic resonance images were collected from 1460 healthy individuals aged 20-69 years; the images were linearly normalized and segmented and restored to native space for analysis of global gray matter volume. Linearly normalized images were then non-linearly normalized and smoothed for analysis of regional gray matter volume. Analysis of global gray matter volume revealed a significant negative correlation between gray matter ratio (gray matter volume divided by intracranial volume) and age in both genders, and a significant interaction effect of age * gender on the gray matter ratio. In analyzing regional gray matter volume, the gray matter volume of all regions showed significant main effects of age, and most regions, with the exception of several including the inferior parietal lobule, showed a significant age * gender interaction. Additionally, the inferior temporal gyrus showed a significant age * gender * hemisphere interaction. No regional volumes showed significant age * hemisphere interactions. Our study may contribute to clarifying the mechanism(s) of normal brain aging in each brain region. PMID- 21818378 TI - Targeted ablation of oligodendrocytes triggers axonal damage. AB - Glial dysfunction has been implicated in a number of neurodegenerative diseases. In this study we investigated the consequences of glial and oligodendrocyte ablation on neuronal integrity and survival in Drosophila and adult mice, respectively. Targeted genetic ablation of glia was achieved in the adult Drosophila nervous system using the GAL80-GAL4 system. In mice, oligodendrocytes were depleted by the injection of diphtheria toxin in MOGi-Cre/iDTR double transgenic animals. Acute depletion of oligodendrocytes induced axonal injury, but did not cause neuronal cell death in mice. Ablation of glia in adult flies triggered neuronal apoptosis and resulted in a marked reduction in motor performance and lifespan. Our study shows that the targeted depletion of glia triggers secondary neurotoxicity and underscores the central contribution of glia to neuronal homeostasis. The models used in this study provide valuable systems for the investigation of therapeutic strategies to prevent axonal or neuronal damage. PMID- 21818379 TI - Synergistic interactions between HDAC and sirtuin inhibitors in human leukemia cells. AB - Aberrant histone deacetylase (HDAC) activity is frequent in human leukemias. However, while classical, NAD(+)-independent HDACs are an established therapeutic target, the relevance of NAD(+)-dependent HDACs (sirtuins) in leukemia treatment remains unclear. Here, we assessed the antileukemic activity of sirtuin inhibitors and of the NAD(+)-lowering drug FK866, alone and in combination with traditional HDAC inhibitors. Primary leukemia cells, leukemia cell lines, healthy leukocytes and hematopoietic progenitors were treated with sirtuin inhibitors (sirtinol, cambinol, EX527) and with FK866, with or without addition of the HDAC inhibitors valproic acid, sodium butyrate, and vorinostat. Cell death was quantified by propidium iodide cell staining and subsequent flow-cytometry. Apoptosis induction was monitored by cell staining with FITC-Annexin-V/propidium iodide or with TMRE followed by flow-cytometric analysis, and by measuring caspase3/7 activity. Intracellular Bax was detected by flow-cytometry and western blotting. Cellular NAD(+) levels were measured by enzymatic cycling assays. Bax was overexpressed by retroviral transduction. Bax and SIRT1 were silenced by RNA interference. Sirtuin inhibitors and FK866 synergistically enhanced HDAC inhibitor activity in leukemia cells, but not in healthy leukocytes and hematopoietic progenitors. In leukemia cells, HDAC inhibitors were found to induce upregulation of Bax, a pro-apoptotic Bcl2 family-member whose translocation to mitochondria is normally prevented by SIRT1. As a result, leukemia cells become sensitized to sirtuin inhibitor-induced apoptosis. In conclusion, NAD(+)-independent HDACs and sirtuins cooperate in leukemia cells to avoid apoptosis. Combining sirtuin with HDAC inhibitors results in synergistic antileukemic activity that could be therapeutically exploited. PMID- 21818380 TI - Imprint of the Atlantic multidecadal oscillation on tree-ring widths in northeastern Asia since 1568. AB - We present a new tree-ring reconstruction of the Atlantic Multidecadal Oscillation (AMO) spanning 1568-2007 CE from northeast Asia. Comparison of the instrumental AMO index, an existing tree-ring based AMO reconstruction, and this new record show strongly similar annual to multidecadal patterns of variation over the last 440 years. Warm phases of the AMO are related to increases in growth of Scots pine trees and moisture availability in northeast China and central eastern Siberia. Multi-tape method (MTM) and cross-wavelet analyses indicate that robust multidecadal (~64-128 years) variability is present throughout the new proxy record. Our results have important implications concerning the influence of North Atlantic sea surface temperatures on East Asian climate, and provide support for the possibility of an AMO signature on global multidecadal climate variability. PMID- 21818381 TI - TorsinA and the torsinA-interacting protein printor have no impact on endoplasmic reticulum stress or protein trafficking in yeast. AB - Early-onset torsion dystonia is a severe, life-long disease that leads to loss of motor control and involuntary muscle contractions. While the molecular etiology of the disease is not fully understood, a mutation in an AAA+ ATPase, torsinA, has been linked to disease onset. Previous work on torsinA has shown that it localizes to the endoplasmic reticulum, where there is evidence that it plays roles in protein trafficking, and potentially also protein folding. Given the high level of evolutionary conservation among proteins involved in these processes, the ability of human such proteins to function effectively in yeast, as well as the previous successes achieved in examining other proteins involved in complex human diseases in yeast, we hypothesized that Saccharomyces cerevisiae might represent a useful model system for studying torsinA function and the effects of its mutants. Since torsinA is proposed to function in protein homeostasis, we tested cells for their ability to respond to various stressors, using a fluorescent reporter to measure the unfolded protein response, as well as their rate of protein secretion. TorsinA did not impact these processes, even after co-expression of its recently identified interacting partner, printor. In light of these findings, we propose that yeast may lack an additional cofactor necessary for torsinA function or proteins required for essential post translational modifications of torsinA. Alternatively, torsinA may not function in endoplasmic reticulum protein homeostasis. The strains and assays we describe may provide useful tools for identifying and investigating these possibilities and are freely available. PMID- 21818382 TI - Molecular detection of vertebrates in stream water: a demonstration using Rocky Mountain tailed frogs and Idaho giant salamanders. AB - Stream ecosystems harbor many secretive and imperiled species, and studies of vertebrates in these systems face the challenges of relatively low detection rates and high costs. Environmental DNA (eDNA) has recently been confirmed as a sensitive and efficient tool for documenting aquatic vertebrates in wetlands and in a large river and canal system. However, it was unclear whether this tool could be used to detect low-density vertebrates in fast-moving streams where shed cells may travel rapidly away from their source. To evaluate the potential utility of eDNA techniques in stream systems, we designed targeted primers to amplify a short, species-specific DNA fragment for two secretive stream amphibian species in the northwestern region of the United States (Rocky Mountain tailed frogs, Ascaphus montanus, and Idaho giant salamanders, Dicamptodon aterrimus). We tested three DNA extraction and five PCR protocols to determine whether we could detect eDNA of these species in filtered water samples from five streams with varying densities of these species in central Idaho, USA. We successfully amplified and sequenced the targeted DNA regions for both species from stream water filter samples. We detected Idaho giant salamanders in all samples and Rocky Mountain tailed frogs in four of five streams and found some indication that these species are more difficult to detect using eDNA in early spring than in early fall. While the sensitivity of this method across taxa remains to be determined, the use of eDNA could revolutionize surveys for rare and invasive stream species. With this study, the utility of eDNA techniques for detecting aquatic vertebrates has been demonstrated across the majority of freshwater systems, setting the stage for an innovative transformation in approaches for aquatic research. PMID- 21818383 TI - Investing in threatened species conservation: does corruption outweigh purchasing power? AB - In many sectors, freedom in capital flow has allowed optimization of investment returns through choosing sites that provide the best value for money. These returns, however, can be compromised in countries where corruption is prevalent. We assessed where the best value for money might be obtained for investment in threatened species that occur at a single site, when taking into account corruption. We found that the influence of corruption on potential investment decisions was outweighed by the likely value for money in terms of pricing parity. Nevertheless global conservation is likely to get best returns in terms of threatened species security by investing in "honest" countries than in corrupt ones, particularly those with a high cost of living. PMID- 21818384 TI - Synaptic responses evoked by tactile stimuli in Purkinje cells in mouse cerebellar cortex Crus II in vivo. AB - BACKGROUND: Sensory stimuli evoke responses in cerebellar Purkinje cells (PCs) via the mossy fiber-granule cell pathway. However, the properties of synaptic responses evoked by tactile stimulation in cerebellar PCs are unknown. The present study investigated the synaptic responses of PCs in response to an air puff stimulation on the ipsilateral whisker pad in urethane-anesthetized mice. METHODS AND MAIN RESULTS: Thirty-three PCs were recorded from 48 urethane anesthetized adult (6-8-week-old) HA/ICR mice by somatic or dendritic patch-clamp recording and pharmacological methods. Tactile stimulation to the ipsilateral whisker pad was delivered by an air-puff through a 12-gauge stainless steel tube connected with a pressurized injection system. Under current-clamp conditions (I = 0), the air-puff stimulation evoked strong inhibitory postsynaptic potentials (IPSPs) in the somata of PCs. Application of SR95531, a specific GABA(A) receptor antagonist, blocked IPSPs and revealed stimulation-evoked simple spike firing. Under voltage-clamp conditions, tactile stimulation evoked a sequence of transient inward currents followed by strong outward currents in the somata and dendrites in PCs. Application of SR95531 blocked outward currents and revealed excitatory postsynaptic currents (EPSCs) in somata and a temporal summation of parallel fiber EPSCs in PC dendrites. We also demonstrated that PCs respond to both the onset and offset of the air-puff stimulation. CONCLUSIONS: These findings indicated that tactile stimulation induced asynchronous parallel fiber excitatory inputs onto the dendrites of PCs, and failed to evoke strong EPSCs and spike firing in PCs, but induced the rapid activation of strong GABA(A) receptor mediated inhibitory postsynaptic currents in the somata and dendrites of PCs in the cerebellar cortex Crus II in urethane-anesthetized mice. PMID- 21818385 TI - Interferon-alpha abrogates tolerance induction by human tolerogenic dendritic cells. AB - BACKGROUND: Administration of interferon-alpha (IFN-alpha) represents an approved adjuvant therapy as reported for malignancies like melanoma and several viral infections. In malignant diseases, tolerance processes are critically involved in tumor progression. In this study, the effect of IFN-alpha on tolerance induction by human tolerogenic dendritic cells (DC) was analyzed. We focussed on tolerogenic IL-10-modulated DC (IL-10 DC) that are known to induce anergic regulatory T cells (iTregs). METHODOLOGY/PRINCIPAL FINDINGS: IFN-alpha promoted an enhanced maturation of IL-10 DC as demonstrated by upregulation of the differentiation marker CD83 as well as costimulatory molecules. IFN-alpha treatment resulted in an increased capacity of DC to stimulate T cell activation compared to control tolerogenic DC. We observed a strengthened T cell proliferation and increased IFN-gamma production of CD4(+) and CD8(+) T cells stimulated by IFN-alpha-DC, demonstrating a restoration of the immunogenic capacity of tolerogenic DC in the presence of IFN-alpha. Notably, restimulation experiments revealed that IFN-alpha treatment of tolerogenic DC abolished the induction of T cell anergy and suppressor function of iTregs. In contrast, IFN alpha neither affected the priming of iTregs nor converted iTregs into effector T cells. CONCLUSIONS/SIGNIFICANCE: IFN-alpha inhibits the induction of T cell tolerance by reversing the tolerogenic function of human DC. PMID- 21818386 TI - Chinese and Korean characters engage the same visual word form area in proficient early Chinese-Korean bilinguals. AB - A number of recent studies consistently show an area, known as the visual word form area (VWFA), in the left fusiform gyrus that is selectively responsive for visual words in alphabetic scripts as well as in logographic scripts, such as Chinese characters. However, given the large difference between Chinese characters and alphabetic scripts in terms of their orthographic rules, it is not clear at a fine spatial scale, whether Chinese characters engage the same VWFA in the occipito-temporal cortex as alphabetic scripts. We specifically compared Chinese with Korean script, with Korean script serving as a good example of alphabetic writing system, but matched to Chinese in the overall square shape. Sixteen proficient early Chinese-Korean bilinguals took part in the fMRI experiment. Four types of stimuli (Chinese characters, Korean characters, line drawings and unfamiliar Chinese faces) were presented in a block-design paradigm. By contrasting characters (Chinese or Korean) to faces, presumed VWFAs could be identified for both Chinese and Korean characters in the left occipito-temporal sulcus in each subject. The location of peak response point in these two VWFAs were essentially the same. Further analysis revealed a substantial overlap between the VWFA identified for Chinese and that for Korean. At the group level, there was no significant difference in amplitude of response to Chinese and Korean characters. Spatial patterns of response to Chinese and Korean are similar. In addition to confirming that there is an area in the left occipito temporal cortex that selectively responds to scripts in both Korean and Chinese in early Chinese-Korean bilinguals, our results show that these two scripts engage essentially the same VWFA, even at the level of fine spatial patterns of activation across voxels. These results suggest that similar populations of neurons are engaged in processing the different scripts within the same VWFA in early bilinguals. PMID- 21818387 TI - Th17 cells and IL-17 in protective immunity to vaginal candidiasis. AB - BACKGROUND: Th17 cells play a major role in coordinating the host defence in oropharyngeal candidiasis. In this study we investigated the involvement of the Th17 response in an animal model of vulvovaginal candidiasis (VVC). METHODS: To monitor the course of infection we exploited a new in vivo imaging technique. RESULTS: i) The progression of VVC leads to a strong influx of neutrophils in the vagina soon after the challenge which persisted despite the resolution of infection; ii) IL-17, produced by vaginal cells, particularly CD4 T cells, was detected in the vaginal wash during the infection, reaching a maximum 14 days after the challenge; iii) The amount and kinetics of IL-23 in vaginal fluids were comparable to those in vaginal cells; iv) The inhibition of Th17 differentiation led to significant inhibition of IL-17 production with consequent exacerbation of infection; v) An increased production of betadefensin 2 was manifested in cells of infected mice. This production was strongly reduced when Th17 differentiation was inhibited and was increased by rIL-17 treatment. CONCLUSIONS: These results imply that IL-17 and Th17, along with innate antimicrobial factors, have a role in the immune response to vaginal candidiasis. PMID- 21818388 TI - The global burden of childhood coeliac disease: a neglected component of diarrhoeal mortality? AB - OBJECTIVES: Coeliac disease has emerged as an increasingly recognised public health problem over the last half-century, and is now coming to be seen as a global phenomenon, despite a profound lack of globally representative epidemiological data. Since children with coeliac disease commonly present with chronic diarrhoea and malnutrition, diagnosis is often overlooked, particularly in poorer settings where children often fail to thrive and water-borne infectious diarrhoeas are common. This is the first attempt to make global estimates of the burden of coeliac disease in childhood. METHODS: We built a relatively crude model of childhood coeliac disease, incorporating estimates of population prevalence, probability of non-diagnosis, and likelihood of mortality among the undiagnosed across all countries from 1970 to 2010, based around the few available data. All our assumptions are stated in the paper and the model is available as a supplementary file. FINDINGS: Our model suggests that in 2010 there were around 2.2 million children under 5 years of age living with coeliac disease. Among these children there could be 42,000 deaths related to coeliac disease annually. In 2008, deaths related to coeliac disease probably accounted for approximately 4% of all childhood diarrhoeal mortality. CONCLUSIONS: Although coeliac disease may only account for a small proportion of diarrhoeal mortality, these deaths are not preventable by applying normal diarrhoea treatment guidelines, which may even involve gluten-based food supplements. As other causes of diarrhoeal mortality decline, coeliac disease will become a proportionately increasing problem unless consideration is given to trying gluten-free diets for children with chronic diarrhoea and malnutrition. PMID- 21818389 TI - Therapeutic rescue of misfolded mutants: validation of primary high throughput screens for identification of pharmacoperone drugs. AB - BACKGROUND: Functional rescue of misfolded mutant receptors by small non-peptide molecules has been demonstrated. These small, target-specific molecules (pharmacological chaperones or "pharmacoperones") serve as molecular templates, promote correct folding and allow otherwise misfolded mutants to pass the scrutiny of the cellular quality control system (QCS) and be expressed at the plasma membrane (PM) where they function similarly to wild type (WT) proteins. In the case of the gonadotropin releasing hormone receptor (GnRHR), drugs that rescue one mutant typically rescue many mutants, even if the mutations are located at distant sites (extracellular loops, intracellular loops, transmembrane helices). This increases the value of these drugs. These drugs are typically identified, post hoc, from "hits" in screens designed to detect antagonists or agonists. The therapeutic utility of pharmacoperones has been limited due to the absence of screens that enable identification of pharmacoperones per se. METHODS AND FINDINGS: We describe a generalizable primary screening approach for pharmacoperone drugs based on measurement of gain of activity in stable HeLa cells stably expressing the mutants of two different model G-protein coupled receptors (GPCRs) (hGnRHR[E(90)K] or hV2R[L(83)Q]). These cells turn off expression of the receptor mutant gene of interest in the presence of tetracycline and its analogs, which provides a convenient means to identify false positives. CONCLUSIONS: The methods described and characterized here provide the basis of novel primary screens for pharmacoperones that detect drugs that rescue GPCR mutants of specific receptors. This approach will identify structures that would have been missed in screens that were designed to select only agonists or antagonists. Non-antagonistic pharmacoperones have a therapeutic advantage since they will not compete for endogenous agonists and may not have to be washed out once rescue has occurred and before activation by endogenous or exogenous agonists. PMID- 21818390 TI - An in vivo transfection approach elucidates a role for Aedes aegypti thioester containing proteins in flaviviral infection. AB - Mosquitoes transmit pathogens that cause infectious diseases of global importance. Techniques to easily introduce genes into mosquitoes, however, limit investigations of the interaction between microbes and their arthropod vectors. We now show that a cationic liposome significantly enhances delivery and expression of plasmid DNA in Aedes aegypti and Anopheles gambiae mosquitoes. We then introduced the genes for Ae. aegypti thioester-containing proteins (AeTEPs), which are involved in the control of flaviviral infection, into mosquitoes using this technique. In vivo transfection of AeTEP-1 into Ae. aegypti significantly reduced dengue virus infection, suggesting that the approach can further our understanding of pathogen-mosquito interactions. PMID- 21818391 TI - Respiratory paradoxical adverse drug reactions associated with acetylcysteine and carbocysteine systemic use in paediatric patients: a national survey. AB - OBJECTIVE: To report pediatric cases of paradoxical respiratory adverse drug reactions (ADRs) after exposure to oral mucolytic drugs (carbocysteine, acetylcysteine) that led to the withdrawal of licenses for these drugs for infants in France and then Italy. DESIGN: The study followed the recommendations of the European guidelines of pharmacovigilance for medicines used in the paediatric population. SETTING: Cases voluntarily reported by physicians from 1989 to 2008 were identified in the national French pharmacovigilance public database and in drug company databases. PATIENTS: The definition of paradoxical respiratory ADRs was based on the literature. Exposure to mucolytic drugs was arbitrarily defined as having received mucolytic drugs for at least 2 days (>200 mg) and at least until the day before the first signs of the suspected ADR. RESULTS: The non-exclusive paradoxical respiratory ADRs reported in 59 paediatric patients (median age 5 months, range 3 weeks to 34 months, 98% younger than 2 years old) were increased bronchorrhea or mucus vomiting (n = 27), worsening of respiratory distress during respiratory tract infection (n = 35), dyspnoea (n = 18), cough aggravation or prolongation (n = 11), and bronchospasm (n = 1). Fifty one (86%) children required hospitalization or extended hospitalization because of the ADR; one patient died of pulmonary oedema after mucus vomiting. CONCLUSION: Parents, physicians, pharmacists, and drug regulatory agencies should know that the benefit risk ratio of mucolytic drugs is at least null and most probably negative in infants according to available evidence. PMID- 21818393 TI - Sex-related effects of an immune challenge on growth and begging behavior of barn swallow nestlings. AB - Parent-offspring conflicts lead the offspring to evolve reliable signals of individual quality, including parasite burden, which may allow parents to adaptively modulate investment in the progeny. Sex-related variation in offspring reproductive value, however, may entail differential investment in sons and daughters. Here, we experimentally manipulated offspring condition in the barn swallow (Hirundo rustica) by subjecting nestlings to an immune challenge (injection with bacterial lipopolysaccharide, LPS) that simulates a bacterial infection, and assessed the effects on growth, feather quality, expression of morphological (gape coloration) and behavioral (posture) begging displays involved in parent-offspring communication, as well as on food allocation by parents. Compared to sham-injected controls, LPS-treated chicks suffered a depression of body mass and a reduction of palate color saturation. In addition, LPS treatment resulted in lower feather quality, with an increase in the occurrence of fault bars on wing feathers. The color of beak flanges, feather growth and the intensity of postural begging were affected by LPS treatment only in females, suggesting that chicks of either sex are differently susceptible to the immune challenge. However, irrespective of the effects of LPS, parents equally allocated food among control and challenged offspring both under normal food provisioning and after a short period of food deprivation of the chicks. These results indicate that bacterial infection and the associated immune response entail different costs to offspring of either sex, but a decrease in nestling conditions does not affect parental care allocation, possibly because the barn swallow adopts a brood-survival strategy. Finally, we showed that physiological stress induced by pathogens impairs plumage quality, a previously neglected major negative impact of bacterial infection which could severely affect fitness, particularly among long-distance migratory birds. PMID- 21818392 TI - Progressive reduction of its expression in rods reveals two pools of arrestin-1 in the outer segment with different roles in photoresponse recovery. AB - Light-induced rhodopsin signaling is turned off with sub-second kinetics by rhodopsin phosphorylation followed by arrestin-1 binding. To test the availability of the arrestin-1 pool in dark-adapted outer segment (OS) for rhodopsin shutoff, we measured photoresponse recovery rates of mice with arrestin 1 content in the OS of 2.5%, 5%, 60%, and 100% of wild type (WT) level by two flash ERG with the first (desensitizing) flash at 160, 400, 1000, and 2500 photons/rod. The time of half recovery (t(half)) in WT retinas increases with the intensity of the initial flash, becoming ~2.5-fold longer upon activation of 2500 than after 160 rhodopsins/rod. Mice with 60% and even 5% of WT arrestin-1 level recovered at WT rates. In contrast, the mice with 2.5% of WT arrestin-1 had a dramatically slower recovery than the other three lines, with the t(half) increasing ~28 fold between 160 and 2500 rhodopsins/rod. Even after the dimmest flash, the rate of recovery of rods with 2.5% of normal arrestin-1 was two times slower than in other lines, indicating that arrestin-1 level in the OS between 100% and 5% of WT is sufficient for rapid recovery, whereas with lower arrestin-1 the rate of recovery dramatically decreases with increased light intensity. Thus, the OS has two distinct pools of arrestin-1: cytoplasmic and a separate pool comprising ~2.5% that is not immediately available for rhodopsin quenching. The observed delay suggests that this pool is localized at the periphery, so that its diffusion across the OS rate-limits the recovery. The line with very low arrestin 1 expression is the first where rhodopsin inactivation was made rate-limiting by arrestin manipulation. PMID- 21818394 TI - The function of MoGlk1 in integration of glucose and ammonium utilization in Magnaporthe oryzae. AB - Hexokinases are conserved proteins functioning in glucose sensing and signaling. The rice blast fungus Magnaporthe oryzae contains several hexokinases, including MoHxk1 (hexokinase) and MoGlk1 (glucokinase) encoded respectively by MoHXK1 and MoGLK1 genes. The heterologous expression of MoGlk1 and MoHxk1 in Saccharomyces cerevisiae confirmed their conserved functions. Disruption of MoHXK1 resulted in growth reduction in medium containing fructose as the sole carbon source, whereas disruption of MoGLK1 did not cause the similar defect. However, the DeltaMoglk1 mutant displayed decreased proton extrusion and a lower biomass in the presence of ammonium, suggesting a decline in the utilization of ammonium. Additionally, the MoGLK1 allele lacking catalytic activity restored growth to the DeltaMoglk1 mutant. Moreover, the expression of MoPMA1 encoding a plasma membrane H(+)-ATPase decreased in the DeltaMoglk1 mutant that can be suppressed by glucose and G-6-P. Thus, MoGlk1, but not MoHxk1, regulates ammonium utilization through a mechanism that is independent from its catalytic activity. PMID- 21818395 TI - Distinctive left-sided distribution of adrenergic-derived cells in the adult mouse heart. AB - Adrenaline and noradrenaline are produced within the heart from neuronal and non neuronal sources. These adrenergic hormones have profound effects on cardiovascular development and function, yet relatively little information is available about the specific tissue distribution of adrenergic cells within the adult heart. The purpose of the present study was to define the anatomical localization of cells derived from an adrenergic lineage within the adult heart. To accomplish this, we performed genetic fate-mapping experiments where mice with the cre-recombinase (Cre) gene inserted into the phenylethanolamine-n methyltransferase (Pnmt) locus were cross-mated with homozygous Rosa26 reporter (R26R) mice. Because Pnmt serves as a marker gene for adrenergic cells, offspring from these matings express the beta-galactosidase (betaGAL) reporter gene in cells of an adrenergic lineage. betaGAL expression was found throughout the adult mouse heart, but was predominantly (89%) located in the left atrium (LA) and ventricle (LV) (p<0.001 compared to RA and RV), where many of these cells appeared to have cardiomyocyte-like morphological and structural characteristics. The staining pattern in the LA was diffuse, but the LV free wall displayed intermittent non-random staining that extended from the apex to the base of the heart, including heavy staining of the anterior papillary muscle along its perimeter. Three-dimensional computer-aided reconstruction of XGAL+ staining revealed distribution throughout the LA and LV, with specific finger-like projections apparent near the mid and apical regions of the LV free wall. These data indicate that adrenergic-derived cells display distinctive left-sided distribution patterns in the adult mouse heart. PMID- 21818397 TI - Visual exploration and object recognition by lattice deformation. AB - Mechanisms of explicit object recognition are often difficult to investigate and require stimuli with controlled features whose expression can be manipulated in a precise quantitative fashion. Here, we developed a novel method (called "Dots"), for generating visual stimuli, which is based on the progressive deformation of a regular lattice of dots, driven by local contour information from images of objects. By applying progressively larger deformation to the lattice, the latter conveys progressively more information about the target object. Stimuli generated with the presented method enable a precise control of object-related information content while preserving low-level image statistics, globally, and affecting them only little, locally. We show that such stimuli are useful for investigating object recognition under a naturalistic setting--free visual exploration- enabling a clear dissociation between object detection and explicit recognition. Using the introduced stimuli, we show that top-down modulation induced by previous exposure to target objects can greatly influence perceptual decisions, lowering perceptual thresholds not only for object recognition but also for object detection (visual hysteresis). Visual hysteresis is target-specific, its expression and magnitude depending on the identity of individual objects. Relying on the particular features of dot stimuli and on eye-tracking measurements, we further demonstrate that top-down processes guide visual exploration, controlling how visual information is integrated by successive fixations. Prior knowledge about objects can guide saccades/fixations to sample locations that are supposed to be highly informative, even when the actual information is missing from those locations in the stimulus. The duration of individual fixations is modulated by the novelty and difficulty of the stimulus, likely reflecting cognitive demand. PMID- 21818396 TI - Postnatal development of numbers and mean sizes of pancreatic islets and beta cells in healthy mice and GIPR(dn) transgenic diabetic mice. AB - The aim of this study was to examine postnatal islet and beta-cell expansion in healthy female control mice and its disturbances in diabetic GIPR(dn) transgenic mice, which exhibit an early reduction of beta-cell mass. Pancreata of female control and GIPR(dn) transgenic mice, aged 10, 45, 90 and 180 days were examined, using state-of-the-art quantitative-stereological methods. Total islet and beta cell volumes, as well as their absolute numbers increased significantly until 90 days in control mice, and remained stable thereafter. The mean islet volumes of controls also increased slightly but significantly between 10 and 45 days of age, and then remained stable until 180 days. The total volume of isolated beta-cells, an indicator of islet neogenesis, and the number of proliferating (BrdU-positive) islet cells were highest in 10-day-old controls and declined significantly between 10 and 45 days. In GIPR(dn) transgenic mice, the numbers of islets and beta-cells were significantly reduced from 10 days of age onwards vs. controls, and no postnatal expansion of total islet and beta-cell volumes occurred due to a reduction in islet neogenesis whereas early islet-cell proliferation and apoptosis were unchanged as compared to control mice. Insulin secretion in response to pharmacological doses of GIP was preserved in GIPR(dn) transgenic mice, and serum insulin to pancreatic insulin content in response to GLP-1 and arginine was significantly higher in GIPR(dn) transgenic mice vs. controls. We could show that the increase in islet number is mainly responsible for expansion of islet and beta-cell mass in healthy control mice. GIPR(dn) transgenic mice show a disturbed expansion of the endocrine pancreas, due to perturbed islet neogenesis. PMID- 21818398 TI - Assessing the validity of sexual behaviour reports in a whole population survey in rural Malawi. AB - BACKGROUND: Sexual behaviour surveys are widely used, but under-reporting of particular risk behaviours is common, especially by women. Surveys in whole populations provide an unusual opportunity to understand the extent and nature of such under-reporting. METHODS: All consenting individuals aged between 15 and 59 within a demographic surveillance site in northern Malawi were interviewed about their sexual behaviour. Validity of responses was assessed by analysis of probing questions; by comparison of results with in-depth interviews and with Herpes simplex type-2 (HSV-2) seropositivity; by comparing reports to same sex and opposite sex interviewers; and by quantifying the partnerships within the local community reported by men and by women, adjusted for response rates. RESULTS: 6,796 women and 5,253 men (83% and 72% of those eligible) consented and took part in sexual behaviour interviews. Probing questions and HSV-2 antibody tests in those who denied sexual activity identified under-reporting for both men and women. Reports varied little by sex or age of the interviewer. The number of marital partnerships reported was comparable for men and women, but men reported about 4 times as many non-marital partnerships. The discrepancy in reporting of non-marital partnerships was most marked for married women (men reported about 7 times as many non-marital partnerships with married women as were reported by married women themselves), but was only apparent in younger married women. CONCLUSIONS: We have shown that the under-reporting of non-marital partnerships by women was strongly age-dependent. The extent of under-reporting of sexual activity by young men was surprisingly high. The results emphasise the importance of triangulation, including biomarkers, and the advantages of considering a whole population. PMID- 21818399 TI - Laying the foundations for a human-predator conflict solution: assessing the impact of Bonelli's eagle on rabbits and partridges. AB - BACKGROUND: Predation may potentially lead to negative effects on both prey (directly via predators) and predators (indirectly via human persecution). Predation pressure studies are, therefore, of major interest in the fields of theoretical knowledge and conservation of prey or predator species, with wide ramifications and profound implications in human-wildlife conflicts. However, detailed works on this issue in highly valuable--in conservation terms- Mediterranean ecosystems are virtually absent. This paper explores the predator hunting conflict by examining a paradigmatic, Mediterranean-wide (endangered) predator-two prey (small game) system. METHODOLOGY/PRINCIPAL FINDINGS: We estimated the predation impact ('kill rate' and 'predation rate', i.e., number of prey and proportion of the prey population eaten, respectively) of Bonelli's eagle Aquila fasciata on rabbit Oryctolagus cuniculus and red-legged partridge Alectoris rufa populations in two seasons (the eagle's breeding and non-breeding periods, 100 days each) in SE Spain. The mean estimated kill rate by the seven eagle reproductive units in the study area was c. 304 rabbits and c. 262 partridges in the breeding season, and c. 237 rabbits and c. 121 partridges in the non-breeding period. This resulted in very low predation rates (range: 0.3 2.5%) for both prey and seasons. CONCLUSIONS/SIGNIFICANCE: The potential role of Bonelli's eagles as a limiting factor for rabbits and partridges at the population scale was very poor. The conflict between game profitability and conservation interest of either prey or predators is apparently very localised, and eagles, quarry species and game interests seem compatible in most of the study area. Currently, both the persecution and negative perception of Bonelli's eagle (the 'partridge-eating eagle' in Spanish) have a null theoretical basis in most of this area. PMID- 21818400 TI - Identification of human housekeeping genes and tissue-selective genes by microarray meta-analysis. AB - BACKGROUND: Categorizing protein-encoding transcriptomes of normal tissues into housekeeping genes and tissue-selective genes is a fundamental step toward studies of genetic functions and genetic associations to tissue-specific diseases. Previous studies have been mainly based on a few data sets with limited samples in each tissue, which restrained the representativeness of their identified genes, and resulted in low consensus among them. RESULTS: This study compiled 1,431 samples in 43 normal human tissues from 104 microarray data sets. We developed a new method to improve gene expression assessment, and showed that more than ten samples are needed to robustly identify the protein-encoding transcriptome of a tissue. We identified 2,064 housekeeping genes and 2,293 tissue-selective genes, and analyzed gene lists by functional enrichment analysis. The housekeeping genes are mainly involved in fundamental cellular functions, and the tissue-selective genes are strikingly related to functions and diseases corresponding to tissue-origin. We also compared agreements and related functions among our housekeeping genes and those of previous studies, and pointed out some reasons for the low consensuses. CONCLUSIONS: The results indicate that sufficient samples have improved the identification of protein-encoding transcriptome of a tissue. Comprehensive meta-analysis has proved the high quality of our identified HK and TS genes. These results could offer a useful resource for future research on functional and genomic features of HK and TS genes. PMID- 21818402 TI - The arouser EPS8L3 gene is critical for normal memory in Drosophila. AB - The genetic mechanisms that influence memory formation and sensitivity to the effects of ethanol on behavior in Drosophila have some common elements. So far, these have centered on the cAMP/PKA signaling pathway, synapsin and fas2 dependent processes, pumilio-dependent regulators of translation, and a few other genes. However, there are several genes that are important for one or the other behaviors, suggesting that there is an incomplete overlap in the mechanisms that support memory and ethanol sensitive behaviors. The basis for this overlap is far from understood. We therefore examined memory in arouser (aru) mutant flies, which have recently been identified as having ethanol sensitivity deficits. The aru mutant flies showed memory deficits in both short-term place memory and olfactory memory tests. Flies with a revertant aru allele had wild-type levels of memory performance, arguing that the aru gene, encoding an EPS8L3 product, has a role in Drosophila memory formation. Furthermore, and interestingly, flies with the aru(8-128) insertion allele had deficits in only one of two genetic backgrounds in place and olfactory memory tests. Flies with an aru imprecise excision allele had deficits in tests of olfactory memory. Quantitative measurements of aru EPS8L3 mRNA expression levels correlate decreased expression with deficits in olfactory memory while over expression is correlated with place memory deficits. Thus, mutations of the aru EPS8L3 gene interact with the alleles of a particular genetic background to regulate arouser expression and reveals a role of this gene in memory. PMID- 21818401 TI - Proteomic analysis shows synthetic oleanane triterpenoid binds to mTOR. AB - New multifunctional drugs that target multiple disease-relevant networks offer a novel approach to the prevention and treatment of many diseases. New synthetic oleanane triterpenoids (SO), such as CDDO (2-cyano-3,12-dioxooleana-1,9-dien-28 oic acid) and its derivatives, are multifunctional compounds originally developed for the prevention and treatment of inflammation and oxidative stress. However, the protein binding partners and mechanisms of action of these SO are not yet fully understood. Here we characterize the putative target profile of one SO, CDDO-Imidazolide (CDDO-Im), by combining affinity purification with mass spectroscopic proteomic analysis to identify 577 candidate binding proteins in whole cells. This SO pharmaco-interactome consists of a diverse but interconnected set of signaling networks; bioinformatic analysis of the protein interactome identified canonical signaling pathways targeted by the SO, including retinoic acid receptor (RAR), estrogen receptor (ER), insulin receptor (IR), janus kinase/signal transducers and activators of transcription (JAK/STAT), and phosphatase and tensin homolog (PTEN). Pull-down studies then further validated a subset of the putative targets. In addition, we now show for the first time that the mammalian target of rapamycin (mTOR) is a direct target of CDDO-Im. We also show that CDDO-Im blocks insulin-induced activation of this pathway by binding to mTOR and inhibiting its kinase activity. Our basic studies confirm that the SO, CDDO-Im, acts on a protein network to elicit its pharmacological activity. PMID- 21818403 TI - Molecular cloning and copy number variation of a ferritin subunit (Fth1) and its association with growth in freshwater pearl mussel Hyriopsis cumingii. AB - Iron is one of the most important minor elements in the shells of bivalves. This study was designed to investigate the involvement of ferritin, the principal protein for iron storage, in shell growth. A novel ferritin subunit (Fth1) cDNA from the freshwater pearl mussel (Hyriopsis cumingii) was isolated and characterized. The complete cDNA contained 822 bp, with an open reading frame (ORF) of 525 bp, a 153 bp 5' untranslated region (UTR) and a 144 bp 3' UTR. The complete genomic DNA was 4125 bp, containing four exons and three introns. The ORF encoded a protein of 174 amino acids without a signal sequence. The deduced ferritin contained a highly conserved motif for the ferroxidase center comprising seven residues of a typical vertebrate heavy-chain ferritin. It contained one conserved iron associated residue (Try27) and iron-binding region signature 1 residues. The mRNA contained a 27 bp iron-responsive element with a typical stem loop structure in the 5'-UTR position. Copy number variants (CNVs) of Fth1 in two populations (PY and JH) were detected using quantitative real-time PCR. Associations between CNVs and growth were also analyzed. The results showed that the copy number of the ferritin gene of in the diploid genome ranged from two to 12 in PY, and from two to six in JH. The copy number variation in PY was higher than that in JH. In terms of shell length, mussels with four copies of the ferritin gene grew faster than those with three copies (P<0.05), suggesting that CNVs in the ferritin gene are associated with growth in shell length and might be a useful molecular marker in selective breeding of H. cumingii. PMID- 21818404 TI - Fibroblast growth factor-2 primes human mesenchymal stem cells for enhanced chondrogenesis. AB - Human mesenchymal stem cells (hMSCs) are multipotent cells capable of differentiating into a variety of mature cell types, including osteoblasts, adipocytes and chondrocytes. It has previously been shown that, when expanded in medium supplemented with fibroblast growth factor-2 (FGF-2), hMSCs show enhanced chondrogenesis (CG). Previous work concluded that the enhancement of CG could be attributed to the selection of a cell subpopulation with inherent chondrogenic potential. In this study, we show that FGF-2 pretreatment actually primed hMSCs to undergo enhanced CG by increasing basal Sox9 protein levels. Our results show that Sox9 protein levels were elevated within 30 minutes of exposure to FGF-2 and progressively increased with longer exposures. Further, we show using flow cytometry that FGF-2 increased Sox9 protein levels per cell in proliferating and non-proliferating hMSCs, strongly suggesting that FGF-2 primes hMSCs for subsequent CG by regulating Sox9. Indeed, when hMSCs were exposed to FGF-2 for 2 hours and subsequently differentiated into the chondrogenic lineage using pellet culture, phosphorylated-Sox9 (pSox9) protein levels became elevated and ultimately resulted in an enhancement of CG. However, small interfering RNA (siRNA)-mediated knockdown of Sox9 during hMSC expansion was unable to negate the prochondrogenic effects of FGF-2, suggesting that the FGF-2-mediated enhancement of hMSC CG is only partly regulated through Sox9. Our findings provide new insights into the mechanism by which FGF-2 regulates predifferentiation hMSCs to undergo enhanced CG. PMID- 21818405 TI - Identification and differential expression of microRNAs during metamorphosis of the Japanese flounder (Paralichthys olivaceus). AB - BACKGROUND: MicroRNAs (miRNAs) are a class of endogenous small non-coding RNAs of 20-25 nucleotides that play a key role in diverse biological processes. Japanese flounder undergo dramatic metamorphosis in their early development. The metamorphosis is characterized by morphological transformation from a bilaterally symmetrical to an asymmetrical body shape concomitant with extensive morphological and physiological remodeling of organs. So far, only a few miRNAs have been identified in fish and there are very few reports about the Japanese flounder miRNA. METHODOLOGY/PRINCIPAL FINDINGS: Solexa sequencing technology was used to perform high throughput sequencing of the small RNA library from the metamorphic period of Japanese flounder. Subsequently, aligning these sequencing data with metazoan known miRNAs, we characterized 140 conserved miRNAs and 57 miRNA: miRNA* pairs from the small RNA library. Among these 57 miRNA: miRNA* pairs, twenty flounder miRNA precursors were amplified from genomic DNA. We also demonstrated evolutionary conservation of Japanese flounder miRNAs and miRNA* in the animal evolution process. Using miRNA microarrays, we identified 66 differentially expressed miRNAs at two metamorphic stages (17 and 29 days post hatching) of Japanese flounder. The results show that miRNAs might play a key role in regulating gene expression during Japanese flounder metamorphosis. CONCLUSIONS/SIGNIFICANCE: We identified a large number of miRNAs during flounder metamorphosis, some of which are differentially expressed at two different metamorphic stages. The study provides an opportunity for further understanding of miRNA function in the regulation of flounder metamorphosis and gives us clues for further studies of the mechanisms of metamorphosis in Japanese flounder. PMID- 21818406 TI - Matrix metalloproteinase 9 expression: new regulatory elements. AB - Retinal ganglion cells apoptosis is linked to matrix metalloproteinase 9 (MMP-9) controlled changes of extracellular matrix. Abnormal expression of MMP-9 is associated with glaucomatous alterations. Thus, the knowledge of MMP-9 regulation is important for the understanding the pathogenesis of glaucoma. Here, we investigated the role of 3'-untranslated regions (3'-UTR) and microRNAs in MMP-9 regulation. We used in vitro mutagenesis and Luc reporter system to identify regulatory elements in the 3'-UTR of MMP-9. microRNAs were analyzed by qRT-PCR, and their role was investigated with inhibitors and mimics. We identified targets for miRNAs in 3'-UTR of MMP-9 involved in the regulation of MMP-9 expression. We then isolated miRNAs from the optic nerve A7 astrocytes and 293 T cells and confirmed the role of mi340 in the regulation using specific inhibitors and mimics. The results obtained show a new miRNA-mediated mechanism of MMP-9 expression regulation. PMID- 21818407 TI - Integrating fMRI with psychophysiological measurements in the study of decision making. AB - Neuroimaging techniques have recently been used to examine the neural mechanism of decision-making. Nevertheless, most of the neuroimaging studies overlook the importance of emotion and autonomic response in modulating the process of decision-making. In this paper, we discussed how to integrating fMRI with psychophysiological measurements in studying decision-making. We suggested that psychophysiological data would complement with fMRI findings in providing a more comprehensive understanding about the physiological and neural mechanisms of decision-making. Also, this technique would yield valuable information in examining the interplay among emotions, autonomic response and decision-making. The discussion is presented in a tutorial format with concrete technical recommendations for researchers who may consider to adopt the technique in their study of decision-making. PMID- 21818408 TI - Gene expression, chromosome position and lamin A/C mutations. AB - The nuclear lamina is increasingly being appreciated for its epigenetic role in regulating gene expression. The nuclear lamina underlies the inner nuclear membrane and, in post mitotic cells, is composed of a latticework primarily formed by the intermediate filament protein, lamin A/C. Although not well defined, lamin-associated domains have been described, and these domains are determined by DNA sequence and chromatin conformation. Lamin-associated domains are positioned to mediate the interaction with the nuclear membrane, where they contribute to transcriptional regulation. Although lamin-associated domains are primarily considered to be repressive in nature, those nearer to nuclear pores may actually promote transcription. Mutations in LMNA, the gene encoding lamins A and C, are a relatively common cause of inherited cardiomyopathy. As substantial data supports a role for the lamina in its interaction with chromatin and gene regulation, we examined the role of a genetically disrupted lamina and the consequences thereof. A dominant LMNA mutation, E161K, that causes inherited cardiomyopathy was studied. Gene expression changes were profiled in a human cardiomyopathic E161K heart, and it was found that chromosome 13 had a high percentage of misexpressed genes. Chromosome 13 was also found to be less tightly associated with the nuclear membrane in E161K mutant cells, thereby linking abnormal gene expression and intranuclear position. These and other studies support a role for the nuclear membrane as an active regulator of gene expression and provide additional support that disrupting this regulation is a mechanism of human disease. PMID- 21818409 TI - Involvement of the nuclear pore complex in morphology of the plant nucleus. AB - Trafficking between the nucleoplasm and the cytoplasm occurs through the nuclear pore complex (NPC), which consists of large multiprotein complexes. Over the last several years, major progress has been made in both structural determination of the entire assembly of the NPC in yeast and animal cells. By contrast, the plant NPC has long been neglected. Components of the NPC in Arabidopsis thaliana have been identified recently using an interactive proteomic approach. The Arabidopsis nucleoporins are homologous to human nucleoporins, except for a single protein called Nup136. Nup136 is involved in flowering and pollen development, suggesting that Nup136 plays a physiological role in plant reproduction. Nup136 also regulates morphology of the nucleus. Overexpression of Nup136-GFP was found to induce elongation of nuclei in various tissues, whereas deficiency of Nup136 caused a reduction in the size of nuclei. Nup136 is thought to be a functional homolog to animal Nup153, although they have no sequence homology. The mechanism underlying the regulation of nuclear morphology by Nup136, which is thought to be unique to higher plants, is discussed. PMID- 21818410 TI - TAN lines: a novel nuclear envelope structure involved in nuclear positioning. AB - Nuclear position is actively controlled and can be adjusted according to the needs of a cell by nuclear movement. Microtubules mediate the majority of nuclear movements studied to date, although examples of nuclear movements mediated by the actin cytoskeleton have been described. One such actin-dependent nuclear movement occurs during centrosome orientation in fibroblasts polarizing for migration. Here, the centrosome is maintained at the cell center while the nucleus is moved to the cell rear by actin retrograde flow thus positioning the centrosome between the nucleus and the leading edge of the cell. We have explored the molecular mechanism for actin dependent movement of the nucleus during centrosome centration. We found that a novel linear array of nuclear envelope membrane proteins composed of nesprin-2G and SUN2, called transmembrane actin-associated nuclear (TAN) lines, couple the nucleus to moving actin cables resulting in the nucleus being positioned toward the cell rear. TAN lines are anchored by A-type lamins and this allows the forces generated by the actin cytoskeleton to be transmitted across the nuclear envelope to move the nucleus. Here we review the data supporting this mechanism for nuclear movement, discuss questions remaining to be addressed and consider how this new mechanism of nuclear movement may shed light on human disease. PMID- 21818411 TI - Where splicing joins chromatin. AB - There are numerous data suggesting that two key steps in gene expression transcription and splicing influence each other closely. For a long time it was known that chromatin modifications regulate transcription, but only recently it was shown that chromatin and histone modifications play a significant role in pre mRNA splicing. Here we summarize interactions between splicing machinery and chromatin and discuss their potential functional significance. We focus mainly on histone acetylation and methylation and potential mechanisms of their role in splicing. It seems that whereas histone acetylation acts mainly by alterating the transcription rate, histone methylation can also influence splicing directly by recruiting various splicing components. PMID- 21818412 TI - Assembly and disassembly of the nucleolus during the cell cycle. AB - The nucleolus is a large nuclear domain in which transcription, maturation and assembly of ribosomes take place. In higher eukaryotes, nucleolar organization in three sub-domains reflects the compartmentation of the machineries related to active or inactive transcription of the ribosomal DNA, ribosomal RNA processing and assembly with ribosomal proteins of the two (40S and 60S) ribosomal subunits. The assembly of the nucleoli during telophase/early G(1) depends on pre-existing machineries inactivated during prophase (the transcription machinery and RNP processing complexes) and on partially processed 45S rRNAs inherited throughout mitosis. In telophase, the 45S rRNAs nucleate the prenucleolar bodies and order the dynamics of nucleolar assembly. The assembly/disassembly processes of the nucleolus depend on the equilibrium between phosphorylation/dephosphorylation of the transcription machinery and on the RNP processing complexes under the control of the CDK1-cyclin B kinase and PP1 phosphatases. The dynamics of assembly/disassembly of the nucleolus is time and space regulated. PMID- 21818413 TI - Post-natal myogenic and adipogenic developmental: defects and metabolic impairment upon loss of A-type lamins. AB - A-type lamins are a major component of the nuclear lamina. Mutations in the LMNA gene, which encodes the A-type lamins A and C, cause a set of phenotypically diverse diseases collectively called laminopathies. While adult LMNA null mice show various symptoms typically associated with laminopathies, the effect of loss of lamin A/C on early post-natal development is poorly understood. Here we developed a novel LMNA null mouse (LMNA(GT-/-)) based on genetrap technology and analyzed its early post-natal development. We detect LMNA transcripts in heart, the outflow tract, dorsal aorta, liver and somites during early embryonic development. Loss of A-type lamins results in severe growth retardation and developmental defects of the heart, including impaired myocyte hypertrophy, skeletal muscle hypotrophy, decreased amounts of subcutaneous adipose tissue and impaired ex vivo adipogenic differentiation. These defects cause death at 2 to 3 weeks post partum associated with muscle weakness and metabolic complications, but without the occurrence of dilated cardiomyopathy or an obvious progeroid phenotype. Our results indicate that defective early post-natal development critically contributes to the disease phenotypes in adult laminopathies. PMID- 21818414 TI - Reversible aggregation of PABPN1 pre-inclusion structures. AB - Increased aggregation of misfolded proteins is associated with aging, and characterizes a number of neurodegenerative disorders caused by homopolymeric amino acid expansion mutations. PABPN1 is an aggregation-prone nuclear protein. Natural aggregation of wild-type (WT) PABPN1 is not known to be disease associated, but alanine-expanded PABPN1 (expPABPN1) accumulates in insoluble intranuclear inclusions in muscle of patients with oculopharyngeal muscular dystrophy (OPMD). We applied microscopic image quantification to study PABPN1 aggregation process in living cells. We identified transitional pre-inclusion foci and demonstrate that these structures significantly differ between WT- and expPABPN1-expressing cells, while inclusions of these proteins are indistinguishable. In addition to the immobile PABPN1 in inclusions, in the nucleoplasm of expPABPN1 expressing cells we also found a fraction of immobile proteins, representing pre-aggregated species. We found that pre-aggregated and pre-inclusion structures are reverted by a PABPN1 specific affinity binder while inclusion structures are not. Together our results demonstrate that the aggregation process of WT- and expPABPN1 differs in steps preceding inclusion formation, suggesting that pre-aggregated protein species could represent the cytotoxic structures. PMID- 21818415 TI - Fine structure of the "PcG body" in human U-2 OS cells established by correlative light-electron microscopy. AB - Polycomb group (PcG) proteins of the Polycomb repressive complex 1 (PRC1) are found to be diffusely distributed in nuclei of cells from various species. However they can also be localized in intensely fluorescent foci, whether imaged using GFP fusions to proteins of PRC1 complex, or by conventional immunofluorescence microscopy. Such foci are termed PcG bodies, and are believed to be situated in the nuclear intechromatin compartment. However, an ultrastructural description of the PcG body has not been reported to date. To establish the ultrastructure of PcG bodies in human U-2 OS cells stably expressing recombinant polycomb BMI1-GFP protein, we used correlative light electron microscopy (CLEM) implemented with high-pressure freezing, cryosubstitution and on-section labeling of BMI1 protein with immunogold. This approach allowed us to clearly identify fluorescent PcG bodies, not as distinct nuclear bodies, but as nuclear domains enriched in separated heterochromatin fascicles. Importantly, high-pressure freezing and cryosubstitution allowed for a high and clear-cut immunogold BMI1 labeling of heterochromatin structures throughout the nucleus. The density of immunogold labeled BMI1 in the heterochromatin fascicles corresponding to fluorescent "PcG bodies" did not differ from the density of labeling of heterochromatin fascicles outside of the "PcG bodies". Accordingly, an appearance of the fluorescent "PcG bodies" seems to reflect a local accumulation of the labeled heterochromatin structures in the investigated cells. The results of this study should allow expansion of the knowledge about the biological relevance of the "PcG bodies" in human cells. PMID- 21818416 TI - The dynamics of the alternatively spliced NOL7 gene products and role in nucleolar architecture. AB - Three alternatively spliced forms of the human NOL7 gene coding for relatively small proteins were identified. The two shorter forms were generated by intron retention events, and each isoform was differently localized within the cell. The NOL7-SP1 long form (29 kD) localized to the nucleolus, SP2 was nucleoplasmic, while SP3 was distributed throughout the whole cell. NOL7-SP1 was confined to the nucleolar granular component, and during cell division disassociated from the nucleolus. Knockdown of NOL7-SP1 levels abrogated nucleolar architecture, in particular the internal regions, and reduced cell proliferation. Analysis of the nucleolar dynamics of the SP1 protein during interphase showed nucleolar high binding affinity. Dissection of protein domains showed that nucleolar targeting was mediated by a unique C-terminal nucleolar localization sequence (NoLS). However, this sequence was not sufficient for conferring high binding affinity, which required additional regions of the protein. Our analysis shows that NOL7 is important for maintaining internal nucleolar structure and cell growth rates, and that while specific protein localization can be obtained by specific short localization motifs, nucleolar residency through binding must be mediated by a synergistic combination of protein modules. PMID- 21818417 TI - Review of semantically interoperable electronic health records for ubiquitous healthcare. AB - In order to provide more effective and personalized healthcare services to patients and healthcare professionals, intelligent active knowledge management and reasoning systems with semantic interoperability are needed. Technological developments have changed ubiquitous healthcare making it more semantically interoperable and individual patient-based; however, there are also limitations to these methodologies. Based upon an extensive review of international literature, this paper describes two technological approaches to semantically interoperable electronic health records for ubiquitous healthcare data management: the ontology-based model and the information, or openEHR archetype model, and the link to standard terminologies such as SNOMED-CT. PMID- 21818418 TI - A quality function deployment framework for the service quality of health information websites. AB - OBJECTIVES: This research was conducted to identify both the users' service requirements on health information websites (HIWs) and the key functional elements for running HIWs. With the quality function deployment framework, the derived service attributes (SAs) are mapped into the suppliers' functional characteristics (FCs) to derive the most critical FCs for the users' satisfaction. METHODS: Using the survey data from 228 respondents, the SAs, FCs and their relationships were analyzed using various multivariate statistical methods such as principal component factor analysis, discriminant analysis, correlation analysis, etc. Simple and compound FC priorities were derived by matrix calculation. RESULTS: Nine factors of SAs and five key features of FCs were identified, and these served as the basis for the house of quality model. Based on the compound FC priorities, the functional elements pertaining to security and privacy, and usage support should receive top priority in the course of enhancing HIWs. CONCLUSIONS: The quality function deployment framework can improve the FCs of the HIWs in an effective, structured manner, and it can also be utilized for critical success factors together with their strategic implications for enhancing the service quality of HIWs. Therefore, website managers could efficiently improve website operations by considering this study's results. PMID- 21818419 TI - An improved auto-generation system to obtain reference intervals for laboratory medicine. AB - OBJECTIVES: Reference values are highly required parameters for all tests in the clinical laboratory, and the supplementary provision of reliable reference intervals is an important task for both clinical laboratories and diagnostic test manufacturers. Despite the progress that has been made in the conceptual aspects of reference intervals, in practice their use is still not completely satisfactory. Most of the laboratories have used various methods to calculate statistic-based reference intervals, and they have mainly focused on extracted data, yet its use is considerably limited. We had to deal with the inconvenience of using a number of programs (SPSS or SAS, MS Excel) in order to calculate the results of reference intervals. METHODS: In order to obtain standardized reference intervals, we developed an integrated program that can calculate, by a nonparametric method, reference intervals with using the Clinical and Laboratory Standards Institute (CLSI) processes as its guideline. We also developed a grouping interface that enables users to customize classification of each group (age, gender, blood group, race, etc) when calculating reference intervals. RESULTS: To verify the developed program, we compared the reference intervals of the current data on 281 persons for 8 total areas, and the reference intervals were was already calculated beforehand with by using this new program. As a result, both results perfectly matched. CONCLUSIONS: This integrated program will be convenience for calculating reasonable values through continual datainspection at an inspection lab for calculating reference intervals. The newly developed program will improve the consistency and reliability of the statistics on reference intervals. PMID- 21818420 TI - A Selective Encryption Algorithm Based on AES for Medical Information. AB - OBJECTIVES: The transmission of medical information is currently a daily routine. Medical information needs efficient, robust and secure encryption modes, but cryptography is primarily a computationally intensive process. Towards this direction, we design a selective encryption scheme for critical data transmission. METHODS: We expand the advandced encrytion stanard (AES)-Rijndael with five criteria: the first is the compression of plain data, the second is the variable size of the block, the third is the selectable round, the fourth is the optimization of software implementation and the fifth is the selective function of the whole routine. We have tested our selective encryption scheme by C(++) and it was compiled with Code::Blocks using a MinGW GCC compiler. RESULTS: The experimental results showed that our selective encryption scheme achieves a faster execution speed of encryption/decryption. In future work, we intend to use resource optimization to enhance the round operations, such as SubByte/InvSubByte, by exploiting similarities between encryption and decryption. CONCLUSIONS: As encryption schemes become more widely used, the concept of hardware and software co-design is also a growing new area of interest. PMID- 21818421 TI - Electro-Mechanical Safety Testing of Portable ECG Devices for Home Healthcare Usage. AB - OBJECTIVES: This paper suggests the experimental guidelines to evaluate the electro-mechanical safety of belt type equipment. The electro-mechanical safety was determined by using the International Electrotechnical Commission guidelines, which are widely used as important factors for assessing the electro-mechanical safety of belt type equipment. However, the local guidelines on wearable healthcare sensors are currently not well-established. Therefore, safety guidelines suited for the actual circumstances in Korea are required, and this paper attempts to try a new experimental safety test procedure of the wearable healthcare sensor. METHODS: This belt type device measures the electrocardiogram (ECG) and heart rates by attaching to the chest. Examination lists were selected by analyzing the common standards ofelectro-mechanical safety (IEC 60601-1) and environment tests (IEC 60068-1, IEC 60068-2) of home-healthcare equipment. RESULTS: The essential electrical safety, which was required for the RS300G3 as a medical device, was evaluated, and most of the examination lists were selected by considering the circumstances of the users. The device passed all the selected examinable lists that are applicable to the Korean environment. CONCLUSIONS: This study has limitations to estimate and to conduct electro-mechanical safety experiments because our study focused on the belt type of heart-rates equipment. We are not taking into account the overall electro-mechanical home-healthcare measurements. According to industrial and technological development, there are infinite possibilities for the advancement of home-healthcare equipment, so more examination lists for safety are being added in addition to what we have done. PMID- 21818422 TI - Automatic Initialization Active Contour Model for the Segmentation of the Chest Wall on Chest CT. AB - OBJECTIVES: Snake or active contours are extensively used in computer vision and medical image processing applications, and particularly to locate object boundaries. Yet problems associated with initialization and the poor convergence to boundary concavities have limited their utility. The new method of external force for active contours, which is called gradient vector flow (GVF), was recently introduced to address the problems. METHODS: This paper presents an automatic initialization value of the snake algorithm for the segmentation of the chest wall. Snake algorithms are required to have manually drawn initial contours, so this needs automatic initialization. In this paper, our proposed algorithm is the mean shape for automatic initialization in the GVF. RESULTS: The GVF is calculated as a diffusion of the gradient vectors of a gray-level or binary edge map derived from the medical images. Finally, the mean shape coordinates are used to automatic initialize thepoint of the snake. The proposed algorithm is composed of three phases: the landmark phase, the procrustes shape distance metric phase and aligning a set of shapes phase. The experiments showed the good performance of our algorithm in segmenting the chest wall by chest computed tomography. CONCLUSIONS: An error analysis for the active contours results on simulated test medical images is also presented. We showed that GVF has a large capture range and it is able to move a snake into boundary concavities. Therefore, the suggested algorithm is better than the traditional potential forces of image segmentation. PMID- 21818423 TI - Non-linear Analysis of Single Electroencephalography (EEG) for Sleep-Related Healthcare Applications. AB - OBJECTIVES: Soft-computing techniques are commonly used to detect medical phenomena and to help with clinical diagnoses and treatment. The purpose of this paper is to analyze the single electroencephalography (EEG) signal with the chaotic methods in order to identify the sleep stages. METHODS: Data acquisition (polysomnography) was performed on four healthy young adults (all males with a mean age of 27.5 years). The evaluated algorithm was designed with a correlation dimension and Lyapunov's exponent using a single EEG signal that detects differences in chaotic characteristics. RESULTS: The change of the correlation dimension and the largest Lyapunov exponent over the whole night sleep EEG was performed. The results show that the correlation dimension and largest Lyapunov exponent decreased from light sleep to deep sleep and they increased during the rapid eye movement stage. CONCLUSIONS: These results suggest that chaotic analysis may be a useful adjunct to linear (spectral) analysis for identifying sleep stages. The single EEG based nonlinear analysis is suitable for u healthcare applications for monitoring sleep. PMID- 21818424 TI - Knowledge structure of korean medical informatics: a social network analysis of articles in journal and proceedings. AB - OBJECTIVES: This study aimed at exploring the knowledge structure of Korean medical informatics. METHODS: We utilized the keywords, as the main variables, of the research papers that were presented in the journal and symposia of the Korean Society of Medical Informatics, and we used, as cases, the English titles and abstracts of the papers (n = 915) published from 1995 through 2008. N-grams (bigram to 5-gram) were extracted from the corpora using the BiKE Text Analyzer, and their cooccurrence networks were generated via a cosine correlation coefficient, and then the networks were analyzed and visualized using Pajek. RESULTS: With the hub and authority measures, the most important research topics in Korean medical informatics were identified. Newly emerging topics by three year period units were observed as research trends. CONCLUSIONS: This study provides a systematic overview on the knowledge structure of Korean medical informatics. PMID- 21818425 TI - Ubiquitous-severance hospital project: implementation and results. AB - OBJECTIVES: The purpose of this study was to review an implementation of u Severance information system with focus on electronic hospital records (EHR) and to suggest future improvements. METHODS: Clinical Data Repository (CDR) of u Severance involved implementing electronic medical records (EMR) as the basis of EHR and the management of individual health records. EHR were implemented with service enhancements extending to the clinical decision support system (CDSS) and expanding the knowledge base for research with a repository for clinical data and medical care information. RESULTS: The EMR system of Yonsei University Health Systems (YUHS) consists of HP integrity superdome servers using MS SQL as a database management system and MS Windows as its operating system. CONCLUSIONS: YUHS is a high-performing medical institution with regards to efficient management and customer satisfaction; however, after 5 years of implementation of u-Severance system, several limitations with regards to expandability and security have been identified. PMID- 21818426 TI - Classification and sequential pattern analysis for improving managerial efficiency and providing better medical service in public healthcare centers. AB - OBJECTIVES: THIS STUDY SOUGHT TO FIND ANSWERS TO THE FOLLOWING QUESTIONS: 1) Can we predict whether a patient will revisit a healthcare center? 2) Can we anticipate diseases of patients who revisit the center? METHODS: For the first question, we applied 5 classification algorithms (decision tree, artificial neural network, logistic regression, Bayesian networks, and Naive Bayes) and the stacking-bagging method for building classification models. To solve the second question, we performed sequential pattern analysis. RESULTS: WE DETERMINED: 1) In general, the most influential variables which impact whether a patient of a public healthcare center will revisit it or not are personal burden, insurance bill, period of prescription, age, systolic pressure, name of disease, and postal code. 2) The best plain classification model is dependent on the dataset. 3) Based on average of classification accuracy, the proposed stacking-bagging method outperformed all traditional classification models and our sequential pattern analysis revealed 16 sequential patterns. CONCLUSIONS: Classification models and sequential patterns can help public healthcare centers plan and implement healthcare service programs and businesses that are more appropriate to local residents, encouraging them to revisit public health centers. PMID- 21818427 TI - Diagnostic analysis of patients with essential hypertension using association rule mining. AB - OBJECTIVES: The purpose of this study was to analyze the records of patients diagnosed with essential hypertension using association rule mining (ARM). METHODS: Patients with essential hypertension (ICD code, I10) were extracted from a hospital's data warehouse and a data mart constructed for analysis. Apriori modeling of the ARM method and web node in the Clementine 12.0 program were used to analyze patient data. RESULTS: Patients diagnosed with essential hypertension totaled 5,022 and the diagnostic data extracted from those patients numbered 53,994. As a result of the web node, essential hypertension, non-insulin dependent diabetes mellitus (NIDDM), and cerebral infarction were shown to be associated. Based on the results of ARM, NIDDM (support, 35.15%; confidence, 100%) and cerebral infarction (support, 21.21%; confidence, 100%) were determined to be important diseases associated with essential hypertension. CONCLUSIONS: Essential hypertension was strongly associated with NIDDM and cerebral infarction. This study demonstrated the practicality of ARM in co-morbidity studies using a large clinic database. PMID- 21818428 TI - Evaluation of the Clinical Data Dictionary (CiDD). AB - OBJECTIVES: The purpose of the study was to evaluate content coverage and data quality of the Clinical Data Dictionary (CiDD) developed by the Center for Interoperable EHR (CiEHR). METHODS: A total of 12,994 terms were collected from 98 clinical forms of a tertiary cancer center hospital with 500 beds. After data cleaning, 9,418 terms were mapped with the data items of the CiDD by the research team, and validated by 30 doctors and nurses at the research hospital. RESULTS: MAPPING RESULTS WERE CLASSIFIED INTO FIVE CATEGORIES: lexically mapped; semantically mapped; mapped to either a broader term or a narrower term; mapped to more than one term and not mapped. In terms of coverage, out of 9,418 terms, 6,750 (71.7%) terms were mapped; 4,319 (45.9%) terms were lexically mapped; 2,431 (25.8%) were semantically mapped; 281 (3.0%) terms were mapped to a broader term; 43 (0.5%) were mapped to a narrower term; and 550 (5.8%) were mapped to more than one term. In terms of data quality, the CiDD has problems such as errors in concept namingand representation, redundancy in synonyms, inadequate synonyms, and ambiguity in meaning. CONCLUSIONS: Although the CiDD has terms covering 72% of local clinical terms, the CiDD can be improved by cleaning up errors and redundancies, adding textual definitions or use cases of the concept, and arranging the concepts in a hierarchy. PMID- 21818429 TI - Analysis of information security management systems at 5 domestic hospitals with more than 500 beds. AB - OBJECTIVES: The information security management systems (ISMS) of 5 hospitals with more than 500 beds were evaluated with regards to the level of information security, management, and physical and technical aspects so that we might make recommendations on information security and security countermeasures which meet both international standards and the needs of individual hospitals. METHODS: The ISMS check-list derived from international/domestic standards was distributed to each hospital to complete and the staff of each hospital was interviewed. Information Security Indicator and Information Security Values were used to estimate the present security levels and evaluate the application of each hospital's current system. RESULTS: With regard to the moderate clause of the ISMS, the hospitals were determined to be in compliance. The most vulnerable clause was asset management, in particular, information asset classification guidelines. The clauses of information security incident management and business continuity management were deemed necessary for the establishment of successful ISMS. CONCLUSIONS: The level of current ISMS in the hospitals evaluated was determined to be insufficient. Establishment of adequate ISMS is necessary to ensure patient privacy and the safe use of medical records for various purposes. Implementation of ISMS which meet international standards with a long-term and comprehensive perspective is of prime importance. To reflect the requirements of the varied interests of medical staff, consumers, and institutions, the establishment of political support is essential to create suitable hospital ISMS. PMID- 21818430 TI - Analysis of Scientific Publication Networks among Medical Schools in Korea. AB - OBJECTIVES: This research was intended to analyze the special characteristics and structure of social networks among Korean medical schools for the purpose of providing knowledge regarding medical field structure, dynamics, and potential paradigm development. METHODS: A collaborative 12-year data set of 35,469 published articles in the SCOPUS(r) database was analyzed. Among ISI subcategories, 61 having more than 20 articles were scrutinized. Following identification of correspondence and co-authorship, centralization indices and Key Player analysis were run for each subcategory. Medical schools were grouped into uniform clusters with convergence of iterated correlation (CONCOR) for structural equivalence. Finally, multidimensional scaling was used to visualize similarities. RESULTS: All centralization indexes analyzed demonstrated a shift in the degree of centralization in the network of medical schools throughout the period examined. Betweenness centrality and eigenvector centrality in particular revealed a dramatic change indicating minimization of the role of a specific "gatekeeper". Key Player analysis confirmed Seoul National University as a constant 'key player' throughout the period evaluated and for the subcategories examined as well. CONCLUSIONS: This study provided insight into the scientific network among the medical schools of Korea. By understanding this network, a strategy to strengthen the basis of research may be developed. PMID- 21818431 TI - Evaluation of unpreparedness when issuing copies of medical records in tertiary referral hospitals. AB - OBJECTIVES: As a baseline study to aid in the development of proper policy, we investigated the current condition of unpreparedness of documents required when issuing copies of medical records and related factors. METHODS: The study was comprised of 7,203 cases in which copies of medical records were issued from July 1st, 2007 through June 30th, 2008 to 5 tertiary referral hospitals. Data from these hospitals was collected using their established electronic databases and included study variables such as unpreparedness of the required documents as a dependent variable and putative covariates. RESULTS: The rate of unpreparedness of required documents was 14.9%. Multiple logistic regression analysis revealed the following factors as being related to the high rate of unpreparedness: patient age (older patients had a higher rate), issuance channels (on admission > via out-patient clinic), type of applicant (others such as family members > for oneself > insurers), type of original medical record (utilization records on admission > other records), issuance purpose (for providing insurer > medical use), residential area of applicant (Seoul > Honam province and Jeju), and number of copied documents (more documents gave a lower rate). The rate of unpreparedness differed significantly among the hospitals; suggesting that they may have followed their own conventional protocols rather than legal procedures in some cases. CONCLUSIONS: The study results showed that the level of compliance to the required legal procedure was high, but that problems occurred in assuring the safety of the medical information. A proper legislative approach is therefore required to balance the security of and access to medical information. PMID- 21818432 TI - Implementation of single source based hospital information system for the catholic medical center affiliated hospitals. AB - OBJECTIVES: The objective of this research is to introduce the unique approach of the Catholic Medical Center (CMC) integrate network hospitals with organizational and technical methodologies adopted for seamless implementation. METHODS: The Catholic Medical Center has developed a new hospital information system to connect network hospitals and adopted new information technology architecture which uses single source for multiple distributed hospital systems. RESULTS: The hospital information system of the CMC was developed to integrate network hospitals adopting new system development principles; one source, one route and one management. This information architecture has reduced the cost for system development and operation, and has enhanced the efficiency of the management process. CONCLUSIONS: Integrating network hospital through information system was not simple; it was much more complicated than single organization implementation. We are still looking for more efficient communication channel and decision making process, and also believe that our new system architecture will be able to improve CMC health care system and provide much better quality of health care service to patients and customers. PMID- 21818433 TI - A new method for non-invasive measurement of skin in the low frequency range. AB - OBJECTIVES: The purpose of our study was to estimate skin structure and conductivity distribution in a cross section of local tissue using non-invasive measurement of impedance data. The present study was designed to evaluate the efficiency of skin depth information through computer simulations. The multilayer tissue model was composed of epidermis, dermis tissues, and subcutaneous. METHODS: In this study, electrical characteristics of skin models were used for conductivity of 0.13 S/m, 0.26 S/m, 0.52 S/m, permittivity of 94,000 F/m, and a frequency of 200 Hz. The effect of the new method was assessed by computer simulations using three-electrode methods. A non-invasive electrical impedance method has been developed for analysis using computer simulation and a skin electrical model with low frequency range. Using the three-electrode method differences through the potentials between measurement electrodes and reference electrodes can be easily detected. The Cole electrical impedance model, which is better suited for skin was used in this study. RESULTS: In this study, experiments using three-electrode methods were described by computer simulation based on a simple model. This electrical impedance model was fitted and developed in comparison with our model for measurement of skin impedance. CONCLUSIONS: The proposed electrical model for skin is suitable for use in interpretation of changes in impedance characterization of the skin. Using the computer simulation method, information on skin impedance depth can be more accurately developed and predicted. PMID- 21818434 TI - A meta-analysis on the effectiveness of computer-based education in nursing. AB - OBJECTIVES: The purpose of this study was to conduct a comparative analysis of education effectiveness between computer-based education and traditional education methods in nursing. METHODS: Medical and nursing literature databases were searched to identify studies regarding the effectiveness of computer-based education in nursing. Overall effect sizes for three outcome variables (knowledge, attitude, and practice level) were calculated. The effects of study characteristics on the outcome variables were analyzed. RESULTS: Twenty-seven studies published from 1990 to February 2009, which that met the inclusion criteria, were included in the analysis. The meta-analysis showed that computer based education generally had positive effects on knowledge, attitude, and practice, with overall effect sizes of 0.43, 0.35, and 0.34, respectively. This study also showed that the type of learner and the total education period had different effects on knowledge. CONCLUSIONS: This metaanalysis found that computer-based education in nursing had positive effects on knowledge, attitude, and practice. PMID- 21818435 TI - Prediction of Daily Patient Numbers for a Regional Emergency Medical Center using Time Series Analysis. AB - OBJECTIVES: To develop and evaluate time series models to predict the daily number of patients visiting the Emergency Department (ED) of a Korean hospital. METHODS: Data were collected from the hospital information system database. In order to develop a forecasting model, we used, 2 years of data from January 2007 to December 2008 data for the following 3 consecutive months were processed for validation. To establish a Forecasting Model, calendar and weather variables were utilized. Three forecasting models were established: 1) average; 2) univariate seasonal auto-regressive integrated moving average (SARIMA); and 3) multivariate SARIMA. To evaluate goodness-of-fit, residual analysis, Akaike information criterion and Bayesian information criterion were compared. The forecast accuracy for each model was evaluated via mean absolute percentage error (MAPE). RESULTS: The multivariate SARIMA model was the most appropriate for forecasting the daily number of patients visiting the ED. Because it's MAPE was 7.4%, this was the smallest among the models, and for this reason was selected as the final model. CONCLUSIONS: This study applied explanatory variables to a multivariate SARIMA model. The multivariate SARIMA model exhibits relativelyhigh reliability and forecasting accuracy. The weather variables play a part in predicting daily ED patient volume. PMID- 21818436 TI - Status and problems of adverse event reporting systems in korean hospitals. AB - OBJECTIVES: This study identifies the current status and problems of adverse event reporting system in Korean hospitals. The data obtained from this study will be used to raise international awareness and enable collaborative researches on patient safety. METHODS: We distributed the questionnaire developed by the Agency for Healthcare Research and Quality (AHRQ), USA to the 265 risk managers of hospitals by e-mail. Seventy-two percent of the risk managers responded to the inquiry. RESULTS: Eighty-five percent of the hospitals responded that they collect information regarding the event where harm has occurred or might have occurred to a patient. Seventy-five percent of the hospitals did not allow individuals to report occurrences without identifying themselves. Only 54% of the hospitals had an organized patient safety program that manages or coordinates all of the hospital's patient safety activities. The most frequent reason why errors were not reported was the fear of individuals being involved in the investigation and potential disadvantage resulting from it. Eighty-five percent of the hospitals produced reports of their adverse event data, but 68% of the hospitals did not distribute occurrence reports within the hospital. CONCLUSIONS: Lack of standardized reporting system, available information, procedures for protecting the reporting individuals, and mindlessness/indifference of the hospital employees are identified as the major problems. Therefore, it is crucial to address these problems to develop appropriate solutions, enable proactive involvement from the healthcare community, and change the overall patient safety culture, specifically protecting privacy, to increase the quality of service in the healthcare industry. PMID- 21818437 TI - Analysis of the korean emergency department syndromic surveillance system: mass type acute diarrheal syndrome. AB - OBJECTIVES: This study was designed to compare the data from the emergency department syndromic surveillance system of Korea in detection and reporting of acute diarrheal syndrome (mass type) with the data from the Korea Food and Drug Administration. And to offer fundamental materials for making improvements in current surveillance system was our purpose. METHODS: A study was conducted by reviewing the number of cases reported as acute diarrheal syndrome (mass type) from the Korean Center for Disease Control and Prevention between June, 2002 and July, 2008. And the data were compared with the number of mass food poisoning cases during the same period, reported from the Korea Food and Drug Administration. The difference between two groups was measured and their transitions were compared. RESULTS: The emergency department syndromic surveillance system's reports of the numbers of acute diarrheal syndrome (mass type) cases were different from the transition of mass food poisonings, reported by the Korea Food and Drug Administration. Their reports were not accurate and they could not follow the trends of increase in mass food poisonings since 2002. CONCLUSIONS: Current problems in the emergency department syndromic surveillance system in Korea are mostly related to inaccuracies of daily data reporting system. Manual data input by the reporters could play a big role in such inaccuracies. There need to be improvements in the ways of reporting data, such as automated information transport system linking electronic medical record. PMID- 21818438 TI - Proposed Algorithm with Standard Terminologies (SNOMED and CPT) for Automated Generation of Medical Bills for Laboratory Tests. AB - OBJECTIVES: In this study, we proposed an algorithm for mapping standard terminologies for the automated generation of medical bills. As the Korean and American structures of health insurance claim codes for laboratory tests are similar, we used Current Procedural Terminology (CPT) instead of the Korean health insurance code set due to the advantages of mapping in the English language. METHODS: 1,149 CPT codes for laboratory tests were chosen for study. Each CPT code was divided into two parts, a Logical Observation Identifi ers Names and Codes (LOINC) matched part (matching part) and an unmatched part (unmatched part). The matching parts were assigned to LOINC axes. An ontology set was designed to express the unmatched parts, and a mapping strategy with Systematized Nomenclature of Medicine Clinical Terms (SNOMED CT) was also proposed. Through the proceeding analysis, an algorithm for mapping CPT with SNOMED CT arranged by LOINC was developed. RESULTS: 75% of the 1,149 CPT codes could be assigned to LOINC codes. Two hundred and twenty-five CPT codes had only one component part of LOINC, whereas others had more than two parts of LOINC. The system of LOINC axes was found in 309 CPT codes, scale 555, property 9, method 42, and time aspect 4. From the unmatched parts, three classes, 'types', 'objects', and 'subjects', were determined. By determining the relationship between the classes with several properties, all unmatched parts could be described. Since the 'subject to' class was strongly connected to the six axes of LOINC, links between the matching parts and unmatched parts were made. CONCLUSIONS: The proposed method may be useful for translating CPT into concept oriented terminology, facilitating the automated generation of medical bills, and could be adapted for the Korean health insurance claim code set. PMID- 21818439 TI - Asan medical information system for healthcare quality improvement. AB - OBJECTIVES: This purpose of this paper is to introduce the status of the Asan Medical Center (AMC) medical information system with respect to healthcare quality improvement. METHODS: Asan Medical Information System (AMIS) is projected to become a completely electronic and digital information hospital. AMIS has played a role in improving the health care quality based on the following measures: safety, effectiveness, patient-centeredness, timeliness, efficiency, privacy, and security. RESULTS: AMIS CONSISTED OF SEVERAL DISTINCTIVE SYSTEMS: order communication system, electronic medical record, picture archiving communication system, clinical research information system, data warehouse, enterprise resource planning, IT service management system, and disaster recovery system. The most distinctive features of AMIS were the high alert-medication recognition & management system, the integrated and severity stratified alert system, the integrated patient monitoring system, the perioperative diabetic care monitoring and support system, and the clinical indicator management system. CONCLUSIONS: AMIS provides IT services for AMC, 7 affiliated hospitals and over 5,000 partners clinics, and was developed to improve healthcare services. The current challenge of AMIS is standard and interoperability. A global health IT strategy is needed to get through the current challenges and to provide new services as needed. PMID- 21818440 TI - Detailed clinical models: a review. AB - OBJECTIVES: Due to the increasing use of electronic patient records and other health care information technology, we see an increase in requests to utilize these data. A highly level of standardization is required during the gathering of these data in the clinical context in order to use it for analyses. Detailed Clinical Models (DCM) have been created toward this purpose and several initiatives have been implemented in various parts of the world to create standardized models. This paper presents a review of DCM. METHODS: Two types of analyses are presented; one comparing DCM against health care information architectures and a second bottom up approach from concept analysis to representation. In addition core parts of the draft ISO standard 13972 on DCM are used such as clinician involvement, data element specification, modeling, meta information, and repository and governance. RESULTS: SIX INITIATIVES WERE SELECTED: Intermountain Healthcare, 13606/OpenEHR Archetypes, Clinical Templates, Clinical Contents Models, Health Level 7 templates, and Dutch Detailed Clinical Models. Each model selected was reviewed for their overall development, involvement of clinicians, use of data types, code bindings, expressing semantics, modeling, meta information, use of repository and governance. CONCLUSIONS: Using both a top down and bottom up approach to comparison reveals many commonalties and differences between initiatives. Important differences include the use of or lack of a reference model and expressiveness of models. Applying clinical data element standards facilitates the use of conceptual DCM models in different technical representations. PMID- 21818441 TI - Development of a nursing practice guideline for pre and post-operative care of gastric cancer patients. AB - OBJECTIVES: The aim of this study was to develop nursing practice guidelines and algorithms for the pre- and postoperative care of gastric cancer patients. METHODS: The guidelines and algorithms were developed based on a literature review and subject-matter experts' knowledge. The usefulness and applicability of the developed guidelines and algorithms were evaluated by the expert group. RESULTS: The guidelines comprised 64 recommendations and algorithms for admission care, preoperative care on the day before the operation, preoperative care on the operation day, immediate postoperative assessment, postoperative care, and discharge care of gastric cancer patients. After appropriate evaluation, the experts declared the guidelines to be both useful and applicable. CONCLUSIONS: The guidelines developed in this study can be used for patient care and for training nursing students and novice nurses. In addition, these guidelines can be integrated into the electronic nursing record system for clinical decision support in the future. This will improve the quality of clinical nursing and the expertise of nurses. PMID- 21818442 TI - Support Vector Regression-based Model to Analyze Prognosis of Infants with Congenital Muscular Torticollis. AB - OBJECTIVES: Congenital muscular torticollis, a common disorder that refers to the shortening of the sternocleidomastoid in infants, is sensitive to correction through physical therapy when treated early. If physical therapy is unsuccessful, surgery is required. In this study, we developed a support vector regression model for congenital muscular torticollis to investigate the prognosis of the physical therapy treatent in infants. METHODS: Fifty-nine infants with congenital muscular torticollis received physical therapy until the degree of neck tilt was less than 5 degrees . After treatment, the mass diameter was reevaluated. Based on the data, a support vector regression model was applied to predict the prognoses. RESULTS: 10-, 20-, and 50-fold cross-tabulation analyses for the proposed model were conducted based on support vector regression and conventional multi-regression method based on least squares. The proposed methodbased on support vector regression was robust and enabled the effective analysis of even a small amount of data containing outliers. CONCLUSIONS: The developed support vector regression model is an effective prognostic tool for infants with congenital muscular torticollis who receive physical therapy. PMID- 21818443 TI - Development of a list of potentially inappropriate drugs for the korean elderly using the delphi method. AB - OBJECTIVES: This study aimed to develop a list of potentially inappropriate drugs for the elderly in Korea using the Delphi technique. METHODS: A Delphi evaluation with a two-round survey was used to reach a consensus on the criteria for inappropriate medications for the elderly in an outpatient setting. The expert panel consisted of 7 family medicine specialists, 3 psychiatrists, 1 neurologist and 3 clinical pharmacists. The level of inappropriateness was determined by considering clinical importance of the risk and availability of alternative therapy, and was rated on a scale of 1 (very low) to 4 (very high). The drugs were categorized into three groups. The first group (Group 1) was drugs that should be avoided. The second (Group 2) was for drugs that need to be monitored. And the third (Group 3) was for drugs with a low level of risk. RESULTS: We took a list of 60 ingredients for drugs and created a list of 57 potentially inappropriate ingredients for the elderly, independent of diagnosis. Forty-two drugs were classified as Group 1. 13 drugs were classified as Group 2. And 2 drugs were classified as Group 3. Ninety-three drugs were potentially inappropriate for the elderly with 29 diagnoses. Groups 1, 2, and 3 included 63, 28, and 3 drugs, respectively. CONCLUSIONS: This study is an important development of a list of drugs potentially inappropriate for the elderly in Korea. The application of this list may be useful for identifying potentially inappropriate medication uses and decreasing drug-related problems. PMID- 21818444 TI - Application of support vector machine for prediction of medication adherence in heart failure patients. AB - OBJECTIVES: Heart failure (HF) is a progressive syndrome that marks the end-stage of heart diseases, and it has a high mortality rate and significant cost burden. In particular, non-adherence of medication in HF patients may result in serious consequences such as hospital readmission and death. This study aims to identify predictors of medication adherence in HF patients. In this work, we applied a Support Vector Machine (SVM), a machine-learning method useful for data classification. METHODS: Data about medication adherence were collected from patients at a university hospital through self-reported questionnaire. The data included 11 variables of 76 patients with HF. Mathematical simulations were conducted in order to develop a SVM model for the identification of variables that would best predict medication adherence. To evaluate the robustness of the estimates made with the SVM models, leave-one-out cross-validation (LOOCV) was conducted on the data set. RESULTS: THE TWO MODELS THAT BEST CLASSIFIED MEDICATION ADHERENCE IN THE HF PATIENTS WERE: one with five predictors (gender, daily frequency of medication, medication knowledge, New York Heart Association [NYHA] functional class, spouse) and the other with seven predictors (age, education, monthly income, ejection fraction, Mini-Mental Status Examination Korean [MMSE-K], medication knowledge, NYHA functional class). The highest detection accuracy was 77.63%. CONCLUSIONS: SVM modeling is a promising classification approach for predicting medication adherence in HF patients. This predictive model helps stratify the patients so that evidence-based decisions can be made and patients managed appropriately. Further, this approach should be further explored in other complex diseases using other common variables. PMID- 21818445 TI - Integration and Evaluation of Clinical Decision Support Systems for Diagnosis Idopathics Pulmonary Fibrosis (IPF). AB - OBJECTIVES: The purpose of this study was to develop clinical decision support systems (CDSS) that are integrated with hospital information systems for the differential diagnosis of idiopathic pulmonary fibrosis (IPF). METHODS: The integrated CDSS were validated and evaluated by physicians. Knowledge modeling for diagnosing IPF was performed by knowledge working groups, composed of radiologists and respiratory specialists. In order to develop the model for CDSS diagnosis, the clinical cases were collected from 290 cases from Seoul National University Hospital and Sevrance Hospital of Yonsei University. For the evaluation of integrated CDSS, interviews were conducted with respiratory specialists and radiologist 2 weeks after applying CDSSs in clinical settings. The CDSS was integrated with the computer vision system (CVS) and diffuse parenchymal lung diseases (DPLD), CDSS developed in our previous project. RESULTS: Eighteen cases diagnosed as IPF were applied to the collection of diagnostic knowledge and the refined knowledge, the former diagnosed 1 case (6%) and the latter diagnosed 14 cases (78%). Therefore, the refined knowledge performed better than collected knowledge. The validation results of integrated CDSSs showed that 81 cases (74.3%) were diagnosed correctly. CONCLUSIONS: There were 109 cases of IPF diagnosed and initiated on treatment. The significance of this study is in developing integrated CDSS with PACS by acquiring and redefining the knowledge needed for IPF diagnosis. In addition, it is significant for the integration of CDSS to verification and clinical evaluation. PMID- 21818446 TI - Crossmapping of nursing problem and action statements in telephone nursing consultation documentations with international classification for nursing practice. AB - OBJECTIVES: This study is to cross-map telephone nursing consultation documentations with International Classification for Nursing Practice (ICNP; ver. 1.0 concepts). METHODS: The narrative telephone nursing consultation documentations of 170 ophthalmology nursing unit patients were analyzed. The nursing statements were examined and cross-mapped with the Korean version of the ICNP ver. 1.0. If all the concepts of a statement were mapped to ICNP concepts, it was classified as 'completely mapped'. If any concept of a statement wasnot mapped, it was classified as 'partially mapped'. If none of the concepts were mapped, it was classified as 'not mapped'. RESULTS: A total of 738 statements wereused for documenting telephone nursing consultations. These statements were divided into 3 groups according to their content: 1) 294 nursing phenomena related statements (72 unique statements), 2) 440 nursing actions-related statements (76 unique statements), and 3) 4 other statements (2 unique statements). In total, 189 unique nursing concepts extracted from 150 unique statements and 108 concepts (62.44%) were mapped onto ICNP concepts. CONCLUSIONS: This study demonstrated the feasibility of computerizing narrative nursing documentations for electronic telephone triagein the ophthalmology nursing unit. PMID- 21818447 TI - Implementation of Medical Information Exchange System Based on EHR Standard. AB - OBJECTIVES: To develop effective ways of sharing patients' medical information, we developed a new medical information exchange system (MIES) based on a registry server, which enabled us to exchange different types of data generated by various systems. METHODS: To assure that patient's medical information can be effectively exchanged under different system environments, we adopted the standardized data transfer methods and terminologies suggested by the Center for Interoperable Electronic Healthcare Record (CIEHR) of Korea in order to guarantee interoperability. Regarding information security, MIES followed the security guidelines suggested by the CIEHR of Korea. This study aimed to develop essential security systems for the implementation of online services, such as encryption of communication, server security, database security, protection against hacking, contents, and network security. RESULTS: The registry server managed information exchange as well as the registration information of the clinical document architecture (CDA) documents, and the CDA Transfer Server was used to locate and transmit the proper CDA document from the relevant repository. The CDA viewer showed the CDA documents via connection with the information systems of related hospitals. CONCLUSIONS: This research chooses transfer items and defines document standards that follow CDA standards, such that exchange of CDA documents between different systems became possible through ebXML. The proposed MIES was designed as an independent central registry server model in order to guarantee the essential security of patients' medical information. PMID- 21818448 TI - Impacts of Individual Innovativeness on the Acceptance of IT-based Innovations in Health Care Fields. AB - OBJECTIVES: The purpose of this study is to identify the role of individual innovation to demographic variables for determining IT adoption behaviors. This study also examines the effect of individual innovation on IT adoption behaviors across IT types. METHODS: To verify the invariant effect of individual innovativeness, two groups of persons working in the health care field were surveyed. The first study subject group was radiologists and their adoption of e purchasing the second group was emergency rescue crews and their adoption of GPS. RESULTS: Adopter categories in innovations (ACI) as the measurement of individual innovation were a significant variable in both studies. Innovative adopters were more likely to use new IT tools than the majority of early adopters, and the early majority was more likely to adopt IT than the laggards. After merging the two data sets into one for testing the role of IT types as a moderator, the significance of ACI did not change, compared to the two separate analyses. In the merged data set, innovative adopters were 2.34 times more likely to be adopters than the early majority. The early majority was 2.32 times more likely to be adopters than laggards. Moreover, there were no moderating effects of IT types. Thus, there were no reversed adoption rates according to levels of ACI and demographic variables. CONCLUSIONS: ACI has invariant effects on IT adoption behaviors regardless of IT types and demographic differences. To implement a new innovation, understanding individual innovativeness will provide more sophisticated implementation strategies for health care organizations and appropriate education programs for their employees. PMID- 21818449 TI - Implementation of Consolidated HIS: Improving Quality and Efficiency of Healthcare. AB - OBJECTIVES: Adoption of hospital information systems offers distinctive advantages in healthcare delivery. First, implementation of consolidated hospital information system in Seoul National University Hospital led to significant improvements in quality of healthcare and efficiency of hospital management. METHODS: THE HOSPITAL INFORMATION SYSTEM IN SEOUL NATIONAL UNIVERSITY HOSPITAL CONSISTS OF COMPONENT APPLICATIONS: clinical information systems, clinical research support systems, administrative information systems, management information systems, education support systems, and referral systems that operate to generate utmost performance when delivering healthcare services. RESULTS: Clinical information systems, which consist of such applications as electronic medical records, picture archiving and communication systems, primarily support clinical activities. Clinical research support system provides valuable resources supporting various aspects of clinical activities, ranging from management of clinical laboratory tests to establishing care-giving procedures. CONCLUSIONS: Seoul National University Hospital strives to move its hospital information system to a whole new level, which enables customized healthcare service and fulfills individual requirements. The current information strategy is being formulated as an initial step of development, promoting the establishment of next generation hospital information system. PMID- 21818451 TI - A frontline driver at crossroads. PMID- 21818450 TI - Implementation of Chest X-ray Observation Report Entry System. AB - OBJECTIVES: X-rays are widely used in medical examinations. In particular, chest X-rays are the most frequent imaging test. However, observations are usually recorded in a free-text format. Therefore, it is difficult to standardize the information provided to construct a database for the sharing of clinical data. Here, we describe a simple X-ray observation entry system that can interlock with an electronic medical record system. METHODS: We investigated common diagnosis indices. Based on the indices, we have designed an entry system which consists of 5 parts: 1) patient lists, 2) image selection, 3) diagnosis result entry, 4) image view, and 5) main menu. The X-ray observation results can be extracted in an Excel format. RESULTS: The usefulness of the proposed system was assessed in a study using over 500 patients' chest X-ray images. The data was readily extracted in a format that allowed convenient assessment. CONCLUSIONS: We proposed the chest X-ray observation entry system. The proposed X-ray observation system, which can be linked with an electronic medical record system, allows easy extraction of standardized clinical information to construct a database. However, the proposed entry system is limited to chest X-rays and it is impossible to interpret the semantic information. Therefore, further research into domains using other interpretation methods is required. PMID- 21818452 TI - History and Trends of "Personal Health Record" Research in PubMed. AB - OBJECTIVES: The purpose of this study was to review history and trends of personal health record research in PubMed and to provide accurate understanding and categorical analysis of expert opinions. METHODS: For the search strategy, PubMed was queried for 'personal health record, personal record, and PHR' in the title and abstract fields. Those containing different definitions of the word were removed by one-by-one analysis from the results, 695 articles. In the end, total of 229 articles were analyzed in this research. RESULTS: The results show that the changes in terms over the years and the shift to patient centeredness and mixed usage. And we identified history and trend of PHR research in some category that the number of publications by year, topic, methodologies and target diseases. Also from analysis of MeSH terms, we can show the focal interest in regards the PHR boundaries and related subjects. CONCLUSIONS: For PHRs to be efficiently used by general public, initial understanding of the history and trends of PHR research may be helpful. Simultaneously, accurate understanding and categorical analysis of expert opinions that can lead to the development and growth of PHRs will be valuable to their adoption and expansion. PMID- 21818453 TI - Hospital wireless local area network-based tracking system. AB - OBJECTIVES: The purpose of this study was to develop a prototype wireless local area network (LAN)-based tracking system and evaluate its efficacy. METHODS: A wireless LAN-based tracking system was developed with a personal digital assistant (PDA) having a simple text messaging function and a prototype stand alone tracking device. Evaluation of the effectiveness of the tracking system was performed in two ways. Twenty-five messages were sent to nurses by direct communication and 46 messages were sent by the wireless system. Thirty cases by nurses and 30 cases by the wireless system to locate hospital equipment were performed. The time required to transfer messages and to locate equipment was measured and analyzed with a Mann-Whitney test and a paired t-test, respectively. RESULTS: The mean time required to transfer messages by direct communication and by the wireless system were 37.92 +/- 19.19 seconds and 30.65 +/- 9.80 seconds, respectively which were not statistically different (p = 0.108). The mean time required to locate equipment by the nurses and by the wireless system was 234.00 +/- 59.99 and 23.97 +/- 6.17 seconds, respectively which was statistically different (p < 0.001). CONCLUSIONS: The wireless LAN-based tracking system can save time for nurses to communicate and to check for the location of equipment in wards which allows nurses to spend more time and attention to patient care and safety. PMID- 21818454 TI - Evaluation of Co-occurring Terms in Clinical Documents Using Latent Semantic Indexing. AB - OBJECTIVES: Measurement of similarities between documents is typically influenced by the sparseness of the term-document matrix employed. Latent semantic indexing (LSI) may improve the results of this type of analysis. METHODS: In this study, LSI was utilized in an attempt to reduce the term vector space of clinical documents and newspaper editorials. RESULTS: After applying LSI, document similarities were revealed more clearly in clinical documents than editorials. Clinical documents which can be characterized with co-occurring medical terms, various expressions for the same concepts, abbreviations, and typographical errors showed increased improvement with regards to a correlation between co occurring terms and document similarities. CONCLUSIONS: Our results showed that LSI can be used effectively to measure similarities in clinical documents. In addition, correlation between the co-occurrence of terms and similarities realized in this study is an important positive feature associated with LSI. PMID- 21818455 TI - High-Resolution Actigraphic Analysis of ADHD: A Wide Range of Movement Variability Observation in Three School Courses - A Pilot Study. AB - OBJECTIVES: This study was conducted to determine whether or not newly proposed high-resolution activity features could provide a superior analytic foundation compared to those commonly used to assess transitions in children's activities, under circumstances in which the types of courses attended exert different situational effects on activity levels. METHODS: From 153 children at a local elementary school, 10 subjects with attention deficit hyperactivity disorder (ADHD) and 7 controls were recruited. Their activity data was collected using an actigraph while they attended school. Ratios of partitioned activity ranges (0.5 2.8 G) during the entire activity were extracted during three classes: art, mathematics, and native language (Korean). Extracted activity features for each participant were compared between the two groups of children (ADHD and control) using graphs and statistical analysis. RESULTS: Activity distributions between ADHD and control groups for each class showed statistically significant differences spread through the entire range in art class compared to native language and mathematics classes. The ADHD group, but not the control group, experienced many significantly different intervals (> 50%) having low to very high activity acceleration regions during the art and languages courses. CONCLUSIONS: Class content appears to influence the activity patterns of ADHD children. Monitoring the actual magnitude and activity counts in a wide range of subjects could facilitate the examination of distributions or patterns of activities. Objective activity measurements made with an actigraph may be useful for monitoring changes in activities in children with ADHD in a timely manner. PMID- 21818456 TI - Development of data models for nursing assessment of cancer survivors using concept analysis. AB - OBJECTIVES: Sharing of cancer-related information among healthcare professionals is crucial to ensuring the quality of long-term care for cancer survivors. Appropriate distribution of the essential facts can be achieved using data models. The purpose of this study was to develop and validate suitable data models for use in the nursing assessment of cancer survivors. METHODS: The models developed in this study were based on a modification of concept analysis developed by Walker and Avant. Our approach involved determining the purpose of the analysis, identifying data elements, defining these elements and their uses, determining critical attributes, value sets, and cardinalities, and ultimately constructing data models which were examined externally by domain experts. RESULTS: We developed 112 data models with 112 data elements, 29 critical attributes, 102 value sets, and 6 data types for the assessment of cancer survivors. External validation revealed that the data elements, critical attributes, and value sets proposed were comprehensive, relevant, and sufficiently useful to encompass nursing issues related to cancer survivors. CONCLUSIONS: Data models developed in this study will contribute to ensuring the semantic consistency of data collected from cancer survivors, which will improve the quality of nursing assessments and in turn translate to improved long-term patient care. PMID- 21818457 TI - Statistical 3D Distribution Analysis of Prostate Cancers in Korean Using Digital Processing Techniques. AB - OBJECTIVES: Several researchers have shown that three dimensional (3D) distribution analysis of prostate cancer is helpful when initiating needle biopsy procedures. Knowledge regarding the distribution of prostate cancer could enhance understanding of the pathophysiology involved and improve detection of these malignancies. We propose utilizing digital processing techniques to analyze prostate cancer distribution in a 3D setting. METHODS: Pre-made radical prostatectomy sample slices were digitized with a resolution of 76 dpi. Slices of each sample were aligned and registered by deformation algorithm and interpolated for analysis of relative distribution statistics. We analyzed 80 samples saved in electronic medical record and compared the detection rate of preoperative needle biopsies and radical prostatectomies using our 3D analysis technique. RESULTS: The statistical 3D distribution of prostate cancer was evaluated using a 36 sector process. Results were represented in the following two ways: distribution of a single patient, and statistical distribution of prostate cancers of multiple patients. The overall concordance rate was 62.7% between the two methods; therefore a technique is needed which can raise this percentage. CONCLUSIONS: We suggest using the normalization method to develop a software tool which permits reconstruction of the 3D distribution of prostate cancer from 2D legacy images and reduces the loss of image quality as well. This application will facilitate detection of prostate cancer by aiding in the determination of the most effective clinical position via partial sampling with decreased patient inconvenience. PMID- 21818458 TI - Analysis of Relationship between Levofloxacin and Corrected QT Prolongation Using a Clinical Data Warehouse. AB - OBJECTIVE: The aim of this study was to examine whether or not levofloxacin has any relationship with QT prolongation in a real clinical setting by analyzing a clinical data warehouse of data collected from different hospital information systems. METHODS: Electronic prescription data and medical charts from 3 different hospitals spanning the past 9 years were reviewed, and a clinical data warehouse was constructed. Patients who were both administrated levofloxacin and given electrocardiograms (ECG) were selected. The correlations between various patient characteristics, concomitant drugs, corrected QT (QTc) prolongation, and the interval difference in QTc before and after levofloxacin administration were analyzed. RESULTS: A total of 2,176 patients from 3 different hospitals were included in the study. QTc prolongation was found in 364 patients (16.7%). The study revealed that age (OR 1.026, p < 0.001), gender (OR 0.676, p = 0.007), body temperature (OR 1.267, p = 0.024), and cigarette smoking (OR 1.641, p = 0.022) were related with QTc prolongation. After adjusting for related factors, 12 drugs concomitant with levofloxacin were associated with QTc prolongation. For patients who took ECGs before and after administration of levofloxacin during their hospitalization (n = 112), there was no significant difference in QTc prolongation. CONCLUSIONS: The age, gender, body temperature, cigarette smoking and various concomitant drugs might be related with QTc prolongation. However, there was no definite causal relationship or interaction between levofloxacin and QTc prolongation. Alternative surveillance methods utilizing the massive accumulation of electronic medical data seem to be essential to adverse drug reaction surveillance in future. PMID- 21818459 TI - New integrated information system for pusan national university hospital. AB - OBJECTIVES: This study presents the information system for Pusan National University Hospital (PNUH), evaluates its performance qualitatively, and conducts economic analysis. METHODS: Information system for PNUH was designed by component based development and developed by internet technologies. Order Communication System, Electronic Medical Record, and Clinical Decision Support System were newly developed. The performance of the hospital information system was qualitatively evaluated based on the performance reference model in order to identify problem areas for the old system. The Information Economics approach was used to analyze the economic feasibility of hospital information system in order to account for the intangible benefits. RESULTS: Average performance scores were 3.16 for input layer, 3.35 for process layer, and 3.57 for business layer. In addition, the cumulative benefit to cost ratio was 0.50 in 2011, 1.73 in 2012, 1.76 in 2013, 1.71 in 2014, and 1.71 in 2015. The B/C ratios steadily increase as value items are added. CONCLUSIONS: While overall performance scores were reasonably high, doctors were less satisfied with the system, perhaps due to the weak clinical function in the systems. The information economics analysis demonstrated the economic profitability of the information systems if all intangible benefits were included. The second qualitative evaluation survey and economic analysis were proposed to evaluate the changes in performance of the new system. PMID- 21818460 TI - Integrated Solution for Physical Activity Monitoring Based on Mobile Phone and PC. AB - OBJECTIVES: This study is part of the ongoing development of treatment methods for metabolic syndrome (MS) project, which involves monitoring daily physical activity. In this study, we have focused on detecting walking activity from subjects which includes many other physical activities such as standing, sitting, lying, walking, running, and falling. Specially, we implemented an integrated solution for various physical activities monitoring using a mobile phone and PC. METHODS: We put the iPod touch has built in a tri-axial accelerometer on the waist of the subjects, and measured change in acceleration signal according to change in ambulatory movement and physical activities. First, we developed of programs that are aware of step counts, velocity of walking, energy consumptions, and metabolic equivalents based on iPod. Second, we have developed the activity recognition program based on PC. iPod synchronization with PC to transmit measured data using iPhoneBrowser program. Using the implemented system, we analyzed change in acceleration signal according to the change of six activity patterns. RESULTS: We compared results of the step counting algorithm with different positions. The mean accuracy across these tests was 99.6 +/- 0.61%, 99.1 +/- 0.87% (right waist location, right pants pocket). Moreover, six activities recognition was performed using Fuzzy c means classification algorithm recognized over 98% accuracy. In addition we developed of programs that synchronization of data between PC and iPod for long-term physical activity monitoring. CONCLUSIONS: This study will provide evidence on using mobile phone and PC for monitoring various activities in everyday life. The next step in our system will be addition of a standard value of various physical activities in everyday life such as household duties and a health guideline how to select and plan exercise considering one's physical characteristics and condition. PMID- 21818461 TI - More powerful search engine invalidates anonymity guidelines for case reports. PMID- 21818462 TI - A new bio-nanochip sensor aids oral cancer detection. AB - A diagnostic cytology-on-a-chip technique rapidly detects pre-malignant and malignant cells with high sensitivity and specificity. PMID- 21818463 TI - Inorganic chiral 3-D photonic crystals with bicontinuous gyroid structure replicated from butterfly wing scales. AB - Three dimensional silica photonic crystals with the gyroid minimal surface structure have been synthesized. The butterfly Callophrys rubi was used as a biotemplate. This material represents a significant addition to the small family of synthetic bicontinuous photonic crystals. PMID- 21818464 TI - Propargyl/methyl furanosides as potential glycosyl donors. AB - Transfuranosylations are not well studied though many similar studies exist for transpyranosylation; herein, we report that propargyl/methyl D-ribf- and D-lyxf- give only 1,2-trans glycosides whereas D-araf- and D-xylf- result in a mixture of 1,2-trans and 1,2-cis glycosides; observed facts are rationalised by computational studies. PMID- 21818465 TI - Synthesis of a MUC1-glycopeptide-BSA conjugate vaccine bearing the 3'-deoxy-3' fluoro-Thomsen-Friedenreich antigen. AB - A novel MUC1-glycopeptide-BSA conjugate vaccine with a specifically fluorinated Thomsen-Friedenreich antigen side chain at Thr6 was prepared. Preliminary immunological experiments reveal specific binding of the tumor-associated glycopeptide antigen analog by anti-MUC1-mouse antibodies. PMID- 21818466 TI - Interfacial water on hydrophobic surfaces recognized by ions and molecules. AB - Recent spectrophotometric and molecular dynamics simulation studies have shown that the physicochemical properties and structures of water in the vicinity of hydrophobic surfaces differ from those of the bulk water. However, the interfacial water acting as a separation medium on hydrophobic surfaces has never been detected and quantified experimentally. In this study, we show that small inorganic ions and organic molecules differentiate the interfacial water formed on the surfaces of octadecyl-bonded (C(18)) silica particles from the bulk water and the chemical separation of these solutes in aqueous media with hydrophobic materials can be interpreted with a consistent mechanism, partition between the bulk water phase and the interfacial water formed on the hydrophobic surface. Thermal transition behaviour of the interfacial water incorporated in the nanopores of the C(18) silica materials and the solubility parameter of the water calculated from the distribution coefficients of organic compounds have indicated that the interfacial water may have a structure of disrupted hydrogen bonding. The thickness of the interfacial water or the limit of distance from the hydrophobic surface at which molecules and ions can sense the surface was estimated to be 1.25 +/- 0.13 nm from the volume of the interfacial water obtained by a liquid chromatographic method and the surface area, suggesting that the hydrophobic effect may extend beyond the first solvation shell of water molecules directly surrounding the surfaces. PMID- 21818467 TI - Design of magnetic coordination complexes for quantum computing. AB - A very exciting prospect in coordination chemistry is to manipulate spins within magnetic complexes for the realization of quantum logic operations. An introduction to the requirements for a paramagnetic molecule to act as a 2-qubit quantum gate is provided in this tutorial review. We propose synthetic methods aimed at accessing such type of functional molecules, based on ligand design and inorganic synthesis. Two strategies are presented: (i) the first consists in targeting molecules containing a pair of well-defined and weakly coupled paramagnetic metal aggregates, each acting as a carrier of one potential qubit, (ii) the second is the design of dinuclear complexes of anisotropic metal ions, exhibiting dissimilar environments and feeble magnetic coupling. The first systems obtained from this synthetic program are presented here and their properties are discussed. PMID- 21818469 TI - Traps and cages for universal SERS detection. AB - In this tutorial review, we provide an overview of the recent research toward surface functionalization of plasmonic nanoparticles for the generation of advanced optical sensors that make possible the analysis of various moieties by means of surface enhanced Raman scattering (SERS). Such moieties include atomic ions, low affinity target molecules, inorganic anions, biometabolites, pathogen markers and/or other analytes of interest even under very demanding circumstances such as those related to real life samples. We expect this review to be of interest to researchers in a broad diversity of fields that can take advantage of the unprecedented sensitivity of this type of molecular spectroscopy, in a wide variety of analytical and bioanalytical problems. PMID- 21818470 TI - (Zn, Mg)2GeO4:Mn2+ submicrorods as promising green phosphors for field emission displays: hydrothermal synthesis and luminescence properties. AB - (Zn(1-x-y)Mg(y))(2)GeO(4): xMn(2+) (y = 0-0.30; x = 0-0.035) phosphors with uniform submicrorod morphology were synthesized through a facile hydrothermal process. X-Ray diffraction (XRD), field emission scanning electron microscopy (FE SEM), photoluminescence (PL), and cathodoluminescence (CL) spectroscopy were utilized to characterize the samples. SEM and TEM images indicate that Zn(2)GeO(4):Mn(2+) samples consist of submicrorods with lengths around 1-2 MUm and diameters around 200-250 nm, respectively. The possible formation mechanism for Zn(2)GeO(4) submicrorods has been presented. PL and CL spectroscopic characterizations show that pure Zn(2)GeO(4) sample shows a blue emission due to defects, while Zn(2)GeO(4):Mn(2+) phosphors exhibit a green emission corresponding to the characteristic transition of Mn(2+) ((4)T(1)->(6)A(1)) under the excitation of UV and low-voltage electron beam. Compared with Zn(2)GeO(4):Mn(2+) sample prepared by solid-state reaction, Zn(2)GeO(4):Mn(2+) phosphors obtained by hydrothermal process followed by high temperature annealing show better luminescence properties. In addition, codoping Mg(2+) ions into the lattice to substitute for Zn(2+) ions can enhance both the PL and CL intensity of Zn(2)GeO(4):Mn(2+) phosphors. Furthermore, Zn(2)GeO(4):Mn(2+) phosphors exhibit more saturated green emission than the commercial FEDs phosphor ZnO:Zn, and it is expected that these phosphors are promising for application in field-emission displays. PMID- 21818468 TI - Misfolded proteins in Alzheimer's disease and type II diabetes. AB - This tutorial review presents descriptions of two amyloidogenic proteins, amyloid beta (Abeta) peptides and islet amyloid polypeptide (IAPP), whose misfolding propensities are implicated in Alzheimer's disease (AD) and type II diabetes, respectively. Protein misfolding diseases share similarities, as well as some unique protein-specific traits, that could contribute to the initiation and/or development of their associated conditions. Abeta and IAPP are representative amyloidoses and are used to highlight some of the primary considerations for studying misfolded proteins associated with human diseases in this review. Among these factors, their physiological formation, aggregation, interactions with metal ions and other protein partners, and toxicity are presented. Small molecules that target and modulate the metal-Abeta interaction and neurotoxicity are included to illustrate one of the current approaches for uncovering the complexities of protein misfolding at the molecular level. PMID- 21818480 TI - Solvent and hydrogen confinement in molecular capsules-Hirshfeld surface and molecular simulation analysis. AB - Hirshfeld surface analysis of the 'ordered' inner phase of the molecular capsule complex, [(chloroform)(6)@C-n-butylpyrogallol[4]arene)(6)], provides insight into the intermolecular contacts and orientation of the solvent molecules. Molecular simulations show that adding two or three hydrogen molecules to the six solvent molecules is energetically favoured, and this correlates with NMR studies. PMID- 21818481 TI - Synthesis and optical resolution of a Cu(I) double-stranded helicate with ketimine-bridged tris(bipyridine) ligands. AB - A tetranuclear Cu(I) double-stranded helicate was synthesized from ketimine bridged tris(bipyridine) ligands and Cu(I) ions, and the racemate was successfully resolved by diastereomeric salt formation using an optically pure phosphate anion followed by anion exchange with NaPF(6) without racemization. PMID- 21818482 TI - Rational design of boron dipyrromethene (BODIPY)-based photobleaching-resistant fluorophores applicable to a protein dynamics study. AB - We studied the photobleaching of a library of boron dipyrromethene (BODIPY) derivatives with a range of electron densities, and found that the photobleaching rate is influenced by the electron-withdrawing capacity of the substituents. Electron-deficient BODIPYs generated less singlet oxygen, were less reactive to singlet oxygen, and were highly resistant to photobleaching. We confirmed the utility of one of these fluorophores, 2,6-diCO(2)R-BDP, for visualizing EGF receptor dynamics in cells expressing an SNAP-tagged EGF receptor. PMID- 21818483 TI - Effects of various halogen anions and cations of alkali metals on energetics of excess charge recombination in stilbene donor-acceptor capped DNA hairpins. AB - DNA hairpin conjugates with a stilbenedicarboxamide (Sa) hole donor and a stilbenediether (Sd) hole acceptor are considered as model systems for studying charge recombination (CR) of excess charges in DNA. Using the method of thermodynamic integration, we estimated the relative free energies of this process in hairpins with three adenine:thymine pairs between Sa and Sd surrounded by 1 M aqueous solutions of ionic compounds M(+)Cl(-) (M = Li, Na, K) and Na(+)X( ) (X = F, Cl, Br, I). The values of this quantity were calculated with respect to the free energy for the same hairpin in the 1 M NaCl aqueous solution. Based on the results obtained, we conclude that halogen anions have no significant influence on the rate of the CR reaction. By contrast, cations of other alkali metals can considerably change the potential barrier of the process, thus affecting the reaction rate. Different results obtained for cations and anions were attributed to the fundamental distinction in the electrostatic interactions of M(+) and X(-) species with negatively charged phosphate groups of the hairpin. In addition, our results show that the relative free energy of CR is larger for cations that are able to be closer to Sd and Sa structural units. The latter correlation suggests that the replacement of Na(+) by cations of other alkali metals enables one to change the CR rate modifying it in either direction. PMID- 21818484 TI - The role of self-assembling polypeptides in building nanomaterials. AB - Polypeptides are functional biomolecules that play a key role in life science, where they can act as hormones and signaling molecules. They can self-assemble into a variety of nanostructures, including two dimensional (2D) lamellae, one dimensional (1D) nanofibrils and nanotubes, and zero dimensional (0D) nanospheres. The driving force behind these advanced nanomaterials involves weak non-covalent interactions that include hydrogen bonding, and hydrophobic and electrostatic interactions. Here we discuss each of the interactions in relation to self-assembly and provide examples of some novel applications in engineering materials, tissue engineering and nanoelectronics. The overall aim is to provide a comprehensive, yet easily accessible review of the known nanomaterials produced by self-assembling polypeptides, which may lead to the construction of more advanced polypeptide nanostructures for future applications. PMID- 21818485 TI - Chain-like and dinuclear coordination polymers in lanthanide (Nd, Eu) oxochloride complexes with 2,2':6',2''-terpyridine: synthesis, XRD structure and magnetic properties. AB - The solvothermal reactions (at 180 degrees C for 48 h) of a mixture of lanthanide chlorides (Nd, Eu) with the tridendate heterocyclic nitrogen ligand, 2,2':6',2''-terpyridine (terpy), in ethanol medium give rise to the formation of crystalline mixed chloro-hydroxo-aquo complex Ln(2)Cl(5)(OH)(H(2)O)(terpy). Its crystal structure consists of the connection of eight- and nine-fold coordinated lanthanide centers linked to each other via MU(2,3)-chloro and MU(3)-hydroxo species to form a tetranuclear unit, which are then further connected through chloro edges to generate infinite ribbons. Only one lanthanide cation in every two is chelated by terpy. Similar molar composition of the starting reactants led to the crystallization at room temperature of a second type of complex LnCl(3)(H(2)O)(terpy) (Ln = Nd, Eu). It is built up from the molecular assembly of dinuclear species containing two eight-fold coordinated lanthanide centers chelated by terpy and linked through a MU(2)-Cl edge. Luminescence spectra have been collected for the europium-based compound and indicates a strong red signal with the expected bands from the F-D transitions. The magnetic properties of the four compounds were investigated. Their behaviors correspond to that of the rare earth ions present in the structure. The magnetic susceptibility of the neodymium based compounds agrees with that of the Nd(III) ion with an (4)I(9/2) ground state split by crystal field. Concerning the Eu(III) derivatives, the term (7)F is split by spin-orbit coupling, the first excited states being thermally populated. Accordingly, the thermal dependence of the magnetic susceptibility was nicely reproduced by using appropriate analytical relations. The refined values of the spin-orbit coupling are consistent with the energies of the electronic levels deduced from the photoluminescence spectra. Unexpectedly, the magnetic susceptibility exhibits a hysteretic behavior in the range 45-75 K. PMID- 21818486 TI - Multi-ion detection by one-shot optical sensors using a colour digital photographic camera. AB - The feasibility and performance of a procedure to evaluate previously developed one-shot optical sensors as single and selective analyte sensors for potassium, magnesium and hardness are presented. The procedure uses a conventional colour digital photographic camera as the detection system for simultaneous multianalyte detection. A 6.0 megapixel camera was used, and the procedure describes how it is possible to quantify potassium, magnesium and hardness simultaneously from the images captured, using multianalyte one-shot sensors based on ionophore chromoionophore chemistry, employing the colour information computed from a defined region of interest on the sensing membrane. One of the colour channels in the red, green, blue (RGB) colour space is used to build the analytical parameter, the effective degree of protonation (1-alpha(eff)), in good agreement with the theoretical model. The linearization of the sigmoidal response function increases the limit of detection (LOD) and analytical range in all cases studied. The increases were from 5.4 * 10(-6) to 2.7 * 10(-7) M for potassium, from 1.4 * 10(-4) to 2.0 * 10(-6) M for magnesium and from 1.7 to 2.0 * 10(-2) mg L(-1) of CaCO(3) for hardness. The method's precision was determined in terms of the relative standard deviation (RSD%) which was from 2.4 to 7.6 for potassium, from 6.8 to 7.8 for magnesium and from 4.3 to 7.8 for hardness. The procedure was applied to the simultaneous determination of potassium, magnesium and hardness using multianalyte one-shot sensors in different types of waters and beverages in order to cover the entire application range, statistically validating the results against atomic absorption spectrometry as the reference procedure. Accordingly, this paper is an attempt to demonstrate the possibility of using a conventional digital camera as an analytical device to measure this type of one-shot sensor based on ionophore-chromoionophore chemistry instead of using conventional lab instrumentation. PMID- 21818487 TI - Swarm intelligence metaheuristics for enhanced data analysis and optimization. AB - The swarm intelligence (SI) computing paradigm has proven itself as a comprehensive means of solving complicated analytical chemistry problems by emulating biologically-inspired processes. As global optimum search metaheuristics, associated algorithms have been widely used in training neural networks, function optimization, prediction and classification, and in a variety of process-based analytical applications. The goal of this review is to provide readers with critical insight into the utility of swarm intelligence tools as methods for solving complex chemical problems. Consideration will be given to algorithm development, ease of implementation and model performance, detailing subsequent influences on a number of application areas in the analytical, bioanalytical and detection sciences. PMID- 21818488 TI - An ultra-sensitive DNA assay based on single-molecule detection coupled with hybridization accumulation and its application. AB - An ultra-sensitive assay for quantification of DNA based on single-molecule detection coupled with hybridization accumulation was developed. In this assay, target DNA (tDNA) in solution was accumulated on a silanized substrate blocked with ethanolamine and bovine serum albumin (BSA) through a hybridization reaction between tDNA and capture DNA immobilized on the substrate. The tDNA on the substrate was labeled with quantum dots which had been modified with detection DNA and blocked with BSA. The fluorescence image of single QD-labeled tDNA molecules on the substrate was acquired using total internal reflection fluorescence microscopy. The tDNA was quantified by counting the bright dots on the image from the QDs. The limit of detection of the DNA assay was as low as 6.4 * 10(-18) mol L(-1). Due to the ultra-high sensitivity, the DNA assay was applied to measure the beta-2-microglobulin messenger RNA level in single human breast cancer cells without a need for PCR amplification. PMID- 21818489 TI - Redox control of a polymerization catalyst by changing the oxidation state of the metal center. AB - The activity of cerium alkoxide complexes supported by a Schiff base ligand was controlled using redox reagents during the ring-opening polymerization of L lactide. The rate of L-lactide polymerization was modified by switching in situ between the cerium(III) and cerium(IV) species. PMID- 21818490 TI - Tuning ligand structure in chiral bis(phosphite) and mixed phosphite-phosphinite PCP-palladium pincer complexes. AB - A range of chiral resorcinol bis(phosphite) and phosphite-phosphinite ligands were produced and their propensity to form palladium PCP-pincer complexes examined. The ease of base-assisted C-H palladation of the ligands falls in the order bis(phosphinite) > phosphite-phosphinite > bis(phosphite). The catalytic activity of the complexes in the asymmetric allylation of benzaldehyde with allyl tributyltin was examined and it was found that, contrary to expectations, ligands with 3,3'-disubstituted BINOL residues show poorer activity and stereoselectivity than unsubstituted BINOL analogues. In addition the order of activity of the pincer complexes was established as bis(phosphite) > phosphite-phosphinite > bis(phosphinite). Crystal structures of representative examples of a 3,3' disubstituted BINOL, mono- and bis(phosphite) ligands based on 2,4-di-tert-butyl resorcinol and Pd complexes of two of the chiral complexes are presented. PMID- 21818491 TI - Chiral palladacycles based on resorcinol monophosphite ligands: the role of the meta-hydroxyl in ligand C-H activation and catalysis. AB - The reactions of a range of chiral resorcinol monophosphite ligands with [PdCl(2)(NCMe)(2)] was investigated in order to establish whether the meta hydroxyl function was involved in the orthometallation processes. These ligands underwent facile orthopalladation at room temperature in the presence of Et(3)N, whilst the equivalent hydroxyl-free analogues needed more forcing conditions to induce orthometallation. When the hydroxyl function was replaced by a similar sized methyl group no orthometallation occurred, even on heating. Furthermore the hydroxyl group influences both the structure and isomerism in the resultant palladacycles via hydrogen bonding to adjacent chloride ligands. Similarly, the hydroxyl function leads to higher enantiocontrol in the asymmetric allylation of benzaldehyde with allyl tributyltin. Representative examples of the ligands and the palladium complexes obtained were characterised by single crystal X-ray diffraction. PMID- 21818492 TI - Divacant polyoxotungstates: reactivity of the gamma-decatungstates [gamma XW10O36]8-(X = Si, Ge). AB - The dilacunary, Keggin-based gamma-decatungstate ions [gamma-XW(10)O(36)](8-) (X = Si, Ge) {XW(10)} exhibit an exciting and versatile solution chemistry, which is probably unmatched by any other lacunary polytungstate. The reactivity of {XW(10)} in the presence, and even absence, of electrophiles, includes loss/gain of tungsten, isomerization, and dimerization. Ever since the syntheses and structures of {XW(10)} were reported, many research groups around the world have investigated the reactivity of these polyanions towards nucleophiles (mostly d block metal ions) and different products with various shape, size and composition were obtained. Here we provide an overview of the state-of-the-art in this subarea of polyoxometalate chemistry, with a focus on synthetic and structural aspects. PMID- 21818493 TI - Double isotope dilution surface-enhanced Raman scattering as a reference procedure for the quantification of biomarkers in human serum. AB - Double isotope dilution surface-enhanced Raman scattering (double IDSERS) is qualified as a method for accurate and precise determination of biomarkers in human blood serum. Providing a full evaluation of the measurement uncertainty as well as traceability to a reference material sets the procedure in line with the requirements of a primary ratio method. Data evaluation is based on a partial least squares (PLS) model, whose prediction ability is validated from quantifying the uric acid concentration in both an artificial reference solution and a real human blood serum sample. With the proposed approach, the uric acid serum concentration can be determined with an uncertainty of 1.6% at a confidence level of 95%. PMID- 21818494 TI - High-throughput age synchronisation of Caenorhabditis elegans. AB - We present a passive microfluidic strategy for sorting adult C. elegans nematodes on the basis of age and size. The separation mechanism takes advantage of phenotypic differences between 'adult' and 'juvenile' organisms and their behaviour in microfluidic architectures. In brief, the microfluidic device allows worms to sort themselves in a passive manner. PMID- 21818495 TI - Unprecedented pi...pi interaction between an aromatic ring and a pseudo-aromatic ring formed through intramolecular H-bonding in a bidentate Schiff base ligand: crystal structure and DFT calculations. AB - A combination of a single crystal X-ray diffraction study and density functional theory calculations has been applied to a bidentate Schiff base compound to elucidate different cooperative non-covalent interactions involved in the stabilization of the keto form over the enol one in the solid state. The single crystal X-ray structure reveals a remarkable supramolecular assembly of the keto form through a cyclic hydrogen bonded dimeric motif. The most interesting feature in the supramolecular assembly is the formation of a 'dimer of dimer' motif by pi...pi, CH...pi and N...O/O...O interactions in which the pi...pi interaction involving the aromatic phenyl ring and the intramolecularly hydrogen bonded pseudo-aromatic ring of the keto form lying just above or below the phenyl ring of the other dimer seems to be unprecedented. The optimized geometry of the hydrogen bonded dimeric motif of the keto form of the organic molecule has been obtained by DFT calculations and agrees very well with that found within the crystalline state. The X-ray crystallographic geometry of the 'dimer of dimer' has also been computed, which shows that in the HOMO, the pi electrons are localized in the phenyl rings away from each other, while in the LUMO, there is a strong pi-pi interaction between the phenyl ring of one dimer with the pseudo aromatic ring of another dimer with an energy estimated to be 7.95 kJ mol(-1). Therefore, on HOMO -> LUMO excitation there is localization of pi electrons in the central part of the complex moiety which plays a stabilizing role of the dimer of dimer motif in the solid state. PMID- 21818496 TI - On the dimerization of chlorophyll in photosystem II. AB - In photosystem II, absorbed light energy is transferred to a reaction centre consisting of chlorophyll units. Release of an electron from the reaction centre is the starting point for the charge separation and electron transport chain in PSII. Crystal structures of the reaction centre have identified two chlorophyll monomers forming a dimer with a partial structural overlap, thus being stabilized by van der Waals interactions. However, the magnitude of this interaction is not accurately known. In this work, the structure of the chlorophyll dimer has been optimized for the first time using dispersion-corrected density functional theory (B3LYP-DCP) revealing the magnitude of dimerization to be approximately -17 kcal mol(-1). The dispersion interaction is shown to be of great significance for the chlorophyll dimer stabilization. In addition, the redox potential of the chlorophyll dimer is calculated to be 1283 mV in good agreement with recent experimental data. PMID- 21818497 TI - Trapping cold molecular hydrogen. AB - Translationally cold H(2) molecules excited to non-penetrating |M(J)| = 3 Rydberg states of principal quantum number in the range 21-37 have been decelerated and trapped using time-dependent inhomogeneous electric fields. The |M(J)| = 3 Rydberg states were prepared from the X (1)Sigma(+)(u)(v = 0, J = 0) ground state using a resonant three-photon excitation sequence via the B (1)Sigma(+)(u)(v = 3, J = 1) and I (1)Pi(g) (v = 0, J = 2) intermediate states and circularly polarized laser radiation. The circular polarization of the vacuum ultraviolet radiation used for the B <- X transition was generated by resonance-enhanced four-wave mixing in xenon and the degree of circular polarization was determined to be 96%. To analyse the deceleration and trapping experiments, the Stark effect in Rydberg states of molecular hydrogen was calculated using a matrix diagonalization procedure similar to that presented by Yamakita et al., J. Chem. Phys., 2004, 121, 1419. Particular attention was given to the prediction of zero-field positions of low-l states and of avoided crossings between Rydberg-Stark states with different values of |M(J)|. The calculated Stark maps and probabilities for diabatic traversal of the avoided crossings were used as input to Monte-Carlo particle-trajectory simulations. These simulations provide a quantitatively satisfactory description of the experimental data and demonstrate that particle loss caused by adiabatic traversals of avoided crossings between adjacent |M(J)| = 3 Stark states of H(2) is small at principal quantum numbers beyond n = 25. The main source of trap losses was found to be from collisional processes. Predissociation following the absorption of blackbody radiation is estimated to be the second most important trap-loss mechanism at room temperature, and trap loss by spontaneous emission is negligible under our experimental conditions. PMID- 21818498 TI - Expanded ring N-heterocyclic carbenes: a comparative study of ring size in palladium (0) catalysed Mizoroki-Heck coupling. AB - The synthesis and characterisation of a range of new 6- and 7-membered expanded ring N-heterocyclic carbene (NHC) complexes of zero valent palladium dvtms (divinyltetramethyldisiloxane) 8-14 is reported, with the first comparative catalytic study probing the effects of large ring N-heterocyclic carbene ligands (6-Mes and 7-Mes) with their analogous 5-membered derivative (IMes) on catalytic performance. The catalytic performances of the [Pd(NHC)(dvtms)] complexes are evaluated in the Mizoroki-Heck coupling of 4-bromoacetophenone and n-butyl acrylate, providing a ready and effective comparison into the influence of ring size and steric congestion on catalytic activity in carbon-carbon cross coupling reactions. PMID- 21818499 TI - Site regeneration in the Fischer-Tropsch synthesis reaction: a synchronized CO dissociation and C-C coupling pathway. AB - A critical issue in the Fischer-Tropsch synthesis reaction is the blocking of the active sites for low barrier CO dissociation by the C(1) adsorbed species generated from CO dissociation, which can hinder the further steps in the FT process. Here, we propose a synchronized pathway for low barrier CO dissociation and C-C coupling on a corrugated Ru surface. PMID- 21818500 TI - A water soluble vitamin B12-ReI fluorescent conjugate for cell uptake screens: use in the confirmation of cubilin in the lung cancer line A549. AB - A water soluble vitamin B(12)-rhenium conjugate was synthesized and used in concert with intrinsic factor to screen for cubilin receptor-mediated uptake in lung cancer cells. Internalization of the conjugate demonstrated that it could be used to rapidly screen for the cubilin receptor in living cells, subsequently confirmed with Western blotting and RT-PCR. PMID- 21818501 TI - A fluorescent turn-on probe for the detection of alkaline phosphatase activity in living cells. AB - Fluorescent probe 1, showing a high fluorescence turn-on signal ratio, enables the real-time imaging of endogenous alkaline phosphatase (ALP) activity in living cells, and the fast and quantitative analysis of enzyme activity at the single cell level. PMID- 21818502 TI - UV absorption cross sections between 230 and 350 nm and pressure dependence of the photolysis quantum yield at 308 nm of CF3CH2CHO. AB - Ultraviolet (UV) absorption cross sections of CF(3)CH(2)CHO were determined between 230 and 350 nm by gas-phase UV spectroscopy. The forbidden n -> pi* transition was characterized as a function of temperature (269-323 K). In addition, the photochemical degradation of CF(3)CH(2)CHO was investigated at 308 nm. The possible photolysis channels are: CF(3)CH(2) + HCO , CF(3)CH(3) + CO , and CF(3)CH(2)CO + H . Photolysis quantum yields of CF(3)CH(2)CHO at 308 nm, Phi(lambda=308nm), were measured as a function of pressure (25-760 Torr of synthetic air). The pressure dependence of Phi(lambda=308nm) can be expressed as the following Stern-Volmer equation: 1/Phi(lambda=308nm) = (4.65 +/- 0.56) + (1.51 +/- 0.04) * 10(-18) [M] ([M] in molecule cm(-3)). Using the absorption cross sections and the photolysis quantum yields reported here, the photolysis rate coefficient of this fluorinated aldehyde throughout the troposphere was estimated. This calculation shows that tropospheric photolysis of CF(3)CH(2)CHO is competitive with the removal initiated by OH radicals at low altitudes, but it can be the major degradation route at higher altitudes. Photodegradation products (CO, HC(O)OH, CF(3)CHO, CF(3)CH(2)OH, and F(2)CO) were identified and also quantified by Fourier transform infrared spectroscopy. CF(3)CH(2)C(O)OH was identified as an end-product as a result of the chemistry involving CF(3)CH(2)CO radicals formed in the OH + CF(3)CH(2)CHO reaction. In the presence of an OH scavenger (cyclohexane), CF(3)CH(2)C(O)OH was not detected, indicating that channel (R1c) is negligible. Based on a proposed mechanism, our results provide strong evidences of the significant participation of the radical-forming channel (R1a). PMID- 21818503 TI - Yin-yang strategy: proposing a new, effective, repeatable, sequential therapy for psoriasis. AB - Psoriasis is a chronic disease that exists in two phases: (1) the acute, flaring phase when psoriasis is highly inflamed, erythematous and pruritic and (2) the chronic, indolent phase after the acute manifestations are brought under control. Ideal therapies for psoriasis must focus on both of these phases. Therefore, a rapid and effective agent must be utilized to treat the acute phase, followed by safe long-term therapy for maintenance. This article proposes a new, effective sequential topical therapy for psoriasis using ongoing treatment with clobetasol (Clobex(r)) spray for one month followed by calcitriol (Vectical(r)) ointment for the next month. This strategy provides a highly effective, reliable and safe treatment option with minimal local and systemic adverse risks. PMID- 21818504 TI - Malignancy arising within cutaneous tattoos: case of dermatofibrosarcoma protuberans and review of literature. AB - BACKGROUND: Dermatofibrosarcoma protuberans (DFSP) is an uncommon tumor of the skin with high rates of local recurrence. Several reports describe a frequent history of local trauma. In one prior case, a DFSP arising in a tattoo site has been reported. Mohs micrographic surgery (MMS) has been used successfully for treatment. OBJECTIVE: To present a case of dermatofibrosarcoma protuberans arising in the site of a prior and current tattoo, and treated with Mohs micrographic surgery. METHODS: We present findings of a case of a DFSP arising in a tattoo and a review of Medline literature on the association between tattoos and cutaneous malignancy, and treatment of DFSP with MMS. RESULTS: Review of the literature confirms multiple reports of DFSP arising in sites of local trauma, as well as malignancies arising in sites of tattoos. The recurrence rate for MMS treatment of DFSP (0-6.6%) was found to be significantly lower than that for patients treated with wide local excision (13% to 95%). CONCLUSIONS: DFSP should be considered in the differential diagnosis of neoplasms arising within areas of tattoos. Sites of local trauma and tattoos may show predilection for benign and malignant changes and should be evaluated during regular skin exams. Review of the literature confirms MMS is an ideal treatment modality for DFSP as the tumor often extends far beyond clinical margins. PMID- 21818505 TI - Increased prevalence of psychiatric disorders and health care-associated costs among patients with moderate-to-severe psoriasis. AB - OBJECTIVE: To characterize the prevalence of psychiatric disorders in patients with moderate-to-severe psoriasis and compare health care costs between patients with and without psychiatric comorbidities. METHODS: In a retrospective, matched case-control study, data for services from nearly 75 health care plans in the United States (U.S.) were collected from PharMetrics Patient Centric Database using International Classification of Diseases, Ninth Revision Clinical Modification codes, identifying a total of 39,855 adults with moderate-to-severe psoriasis (n=7,971) and without (controls; n=31,884). Patients with psoriasis had at least one psoriasis health care claim and received at least one medical/prescription treatment claim within two consecutive years. Psychiatric comorbidities and treatments among patients and controls were determined by claims. Annual inpatient, outpatient, emergency room, and prescription costs for those with and without psoriasis and those with and without psychiatric disorders were compared. RESULTS: Patients had significantly higher prevalence of anxiety (6.9% versus 4.4%), depression (9.2% versus 5.3%), bipolar disorder (1.1% versus 0.5%), or delirium (0.3% versus 0.1%; P is less than 0.05) than controls (others P is less than 0.0001). Significantly higher proportions of patients with psoriasis received antidepressants (6.1% versus 0.9%), anxiolytics (5.0% versus 0.8%), or antipsychotics (5.9% versus 0.9%) compared with controls (each P is less than 0.0001). Total health care costs for patients with psoriasis (US $11, 369.47) were significantly higher than for controls ($3,427.60; P is less than 0.001). Psoriasis patients with psychiatric disorders had significantly higher health care costs ($17,637.66) than those without psychiatric disorders ($10,362.80; P is less than 0.001). CONCLUSION: The prevalence of psychiatric disorders is higher in patients with moderate-to-severe psoriasis than in controls. Annual health care costs are higher in psoriasis patients with psychiatric disorders than in those without psychiatric disorders. PMID- 21818506 TI - A randomized, double-blind, vehicle-controlled crossover study to determine the anti-pruritic efficacy, safety and local dermal tolerability of a topical formulation (srd174 cream) of the long-acting opiod antagonist nalmefene in subjects with atopic dermatitis. AB - OBJECTIVE: To investigate the efficacy, safety and tolerability of topical nalmefene (SRD174), a long acting opioid antagonist for the management of pruritus associated with atopic dermatitis (AD). DESIGN: Double-blind, vehicle controlled, randomized, cross-over trial. SETTING: Eleven dermatology outpatient clinics in the U.S. PATIENTS: Sixty-two out of 136 screened adult subjects with confirmed AD affecting is less than or equal to 20% of body surface area and with moderate-to-severe pruritus. INTERVENTIONS: SRD174 cream or matching vehicle cream applied as required during two 7-day periods separated by a wash-out period. MAIN OUTCOME MEASURE(S): The primary efficacy variable was the period mean of the sum of pruritus intensity difference (SPID) from 0 to 4 hours (SPID0 4) where pruritus was measured on a 0-100 scale Visual Analog Scale (VAS) at seven pre-specified time-points following study drug application. A range of secondary efficacy, safety and tolerance endpoints were included. RESULTS: The LS means for the SPID0-4 (+/- SD) for SRD174 cream and Vehicle were 210.7 (20.4) and 212.1 (20.2), respectively (Difference = -1.3 (95% CI: -25.9, 23.3). None of the secondary efficacy endpoints tested demonstrated a statistically significant or clinically important difference between the test product and the vehicle. Overall, the SRD174 cream was well tolerated although there was a higher incidence of AEs when subjects took SRD174 cream (22, 36.7 percent of subjects) compared with when they were taking vehicle (14, 23.3 percent of subjects). CONCLUSIONS: SRD174 cream did not demonstrate efficacy in the treatment of pruritus associated with atopic dermatitis raising questions on the role of peripheral opioid receptors as a target for the treatment of pruritus in this population. PMID- 21818507 TI - A retrospective study to investigate racial and ethnic variations in the treatment of psoriasis with etanercept. AB - OBJECTIVES: Psoriasis is a chronic inflammatory condition that occurs worldwide; however, few studies have examined this condition in non-Caucasian populations. The purpose of this study was to investigate racial/ethnic differences in demographics, psoriasis severity, efficacy, safety, and health-related quality of life in patients treated with etanercept using data from the Etanercept Assessment of Safety and Effectiveness (EASE) in Psoriasis trial. PATIENTS AND METHODS: This is an investigator-initiated evaluation of data from the EASE study. RESULTS: The study included 2511 patients (Caucasian n=2164; Hispanic/Latino n=173; African American n=98; Asian n=76). Although baseline Physicians' Global Assessment (PGA) scores were similar, we found significant baseline differences in patient characteristics, prior therapy, percentage of body surface area (%BSA) affected and Dermatology Life Quality Index (DLQI) scores between the groups. At baseline, the Caucasian group had the longest disease duration (19 years), but the lowest percentage of BSA involvement (28%). The Asian group had the highest percentage of BSA involvement (41%). Baseline DLQI score was lowest for Caucasians (12.0) and highest for Hispanic/Latinos (14.6). At week 12, response to therapy was similar in all ethnic/racial groups. The BSA involvement was reduced by more than 50 percent for all groups, but remained significantly higher for the Asian group (17%) than for the Caucasian (13%; P=0.0105) and African American groups (13%; P=0.0461). At week 12, the mean Asian DLQI score of 5.2 was significantly higher (worse) than scores for the Caucasian (3.5; P=0.0001) and Hispanic/Latino groups (3.8; P=0.028). For both percentage of BSA and DLQI, differences among racial/ethnic groups in the percentage improvement from baseline were not statistically significant. Adverse event rates were similar for the groups. CONCLUSIONS: Patient characteristics at enrollment differed among ethnic groups, but no significant racial/ethnic differences were found in safety or efficacy of etanercept. However, racial/ethnic differences in the impact of psoriasis on quality of life were observed. PMID- 21818508 TI - Acitretin for the treatment of psoriasis: an assessment of national trends. AB - BACKGROUND: Combination therapy is a common and appropriate treatment strategy for moderate-to-severe psoriasis, as it provides for enhanced efficacy and decreased toxicity compared to the use of a single agent. Acitretin is an effective oral retinoid for psoriasis that seems to find its greatest value when complemented by other topical and systemic treatments. OBJECTIVE: The primary aim of this study is to assess the use of acitretin in combination with other treatments for psoriasis. METHODS: We assessed the use of acitretin for the treatment of psoriasis using nationally representative survey data from the National Ambulatory Medical Care Survey (NAMCS). RESULTS: Among visits where acitretin was listed in the NAMCS, other psoriasis medications were co-prescribed in 62 percent of visits. The co-prescribed medications included topical corticosteroids (51%), calcipotriene (31%), biologics (6%), cyclosporine (5%), methotrexate (5%) and tazarotene (2%). CONCLUSION: The use of acitretin in combination with other psoriasis treatments, particularly topical corticosteroids and calcipotriene, is a common practice. Acitretin is co-prescribed with the biologics, likely because of the relative lack of overlapping effects on immune function. The immune-sparing method of action of acitretin makes combination treatment with the systemic agents an attractive treatment option, especially in patients where further immunosuppression is unwarranted. PMID- 21818509 TI - Topical calcipotriene 0.005% and betamethasone dipropionate 0.064% maintains efficacy of etanercept after step-down dose in patients with moderate-to-severe plaque psoriasis: results of an open label trial. AB - Etanercept is approved for the treatment of plaque psoriasis at a subcutaneous (SC) dosage of 50 mg twice-weekly for three months, followed by 50 mg SC once weekly thereafter. It is of note, however, that many patients experience loss of efficacy when they step down to etanercept 50 mg/week, often instigating a switch to another biological. The current pilot study investigated the adjunctive use of a topical calcipotriene 0.005% and betamethasone dipropionate 0.064% combination ointment, approved for the treatment of psoriasis, to sustain the original efficacy of etanercept by augmenting response to the 50 mg/week SC dose, thus stabilizing the disease. TRIAL DESIGN: In this single-center, open-label study, subjects (n=20) underwent 12 weeks treatment with etanercept 100 mg/week (50 mg, 2x week; weeks -12 to -1), followed by etanercept 50 mg/week maintenance therapy for 40 weeks (weeks 0 to 40). Subjects were followed at four-week intervals. Starting at week 4, subjects who demonstrated an increase from baseline (week 0) body surface area (BSA) of is greater than 2% initiated therapy with calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment for four weeks. The study is limited by its small sample size, open-label nature, and lack of blinding. FINDINGS: Mean BSA involvement decreased significantly from week -12 to 0 with etanercept 50 mg twice a week. At week 4, on the etanercept 50 mg/week dose, mean BSA increased to 9.42 +/- 9.39 compared to week 0. With introduction of calcipotriene 0.005%/betamethasone dipropionate 0.064% ointment at week 4, mean BSA decreased to 4.62 +/- 8.19 by week 24 and was relatively stable for the remainder of the study period. Similarly, mean PASI (Psoriasis Area and Severity Index) scores improved from week -12 to week 0, increased at week 4, then decreased significantly by week 24 with adjunctive topical treatment. CONCLUSION: Topical calcipotriene 0.005% and betamethasone dipropionate 0.064% ointment is a safe and effective adjunct to etanercept 50 mg/week maintenance therapy. PMID- 21818510 TI - Clobetasol propionate 0.05% spray for the management of moderate-to-severe plaque psoriasis of the scalp: results from a randomized controlled trial. AB - BACKGROUND: Clobetasol propionate 0.05% spray is available for treating moderate to-severe plaque psoriasis; however, there is limited information with plaque psoriasis of the scalp. OBJECTIVE: Evaluate the efficacy, safety, and quality-of life impact of clobetasol propionate 0.05% spray in patients with moderate to severe plaque psoriasis of the scalp. METHODS: Multicenter, randomized, double blind, vehicle-controlled study involving 81 men and women with moderate-to severe (Global Severity Score [GSS] = 3 or 4) plaque psoriasis of the scalp. Eligible patients were treated with clobetasol propionate 0.05% spray or vehicle spray, which was applied twice daily for up to four weeks. The primary efficacy end point was the GSS of psoriasis of the scalp after four weeks. Safety assessments included local tolerability, presence of Cushing's syndrome, and adverse events. RESULTS: At the end of treatment, 85 percent (35/41) of patients in the clobetasol propionate 0.05% spray group achieved success (GSS clear or almost clear), compared with 13 percent (5/40) in the vehicle spray group (P is less than .001). The proportion of patients treated with clobetasol propionate 0.05% spray who achieved a rating of clear (GSS = 0) after two weeks and at the end of treatment was 12 percent and 51 percent, respectively. Clobetasol propionate 0.05% spray was well tolerated, and there were no serious adverse events or reported cases of folliculitis or Cushing's syndrome. CONCLUSION: Treatment with clobetasol propionate 0.05% spray for up to four weeks is effective and well tolerated for moderate-to-severe plaque psoriasis of the scalp. PMID- 21818511 TI - An open-label study of the safety and efficacy of sertaconazole nitrate in the treatment of seborrheic dermatitis. AB - OBJECTIVES: To demonstrate the efficacy and evaluate the safety of sertaconazole nitrate cream 2% in the treatment of seborrheic dermatitis (SD). DESIGN: Single center, open-label study. SETTING: One academic medical center. PARTICIPANTS: Twenty adult male and female subjects aged 22 to 85 years (average, 56 years) with mild-to-severe seborrheic dermatitis of the face. MEASUREMENTS: The primary efficacy evaluation was the proportion of subjects with a score of 0 or 1 at the end of treatment (week 4) on the Investigator's Static Global Assessment scale. Secondary end points included percent change from baseline to week 4 in sum individual scores of erythema, scaling, induration, and pruritus at a preselected target lesion. Other end points included change in scores on Subject's Global Assessment scale and the Dermatology Life Quality Index. RESULTS: Success on the primary end point was achieved by 10 of 17 evaluable subjects (58.8%). Improvements in Investigator's Static Global Assessment score from baseline were statistically significant at each week. Significant improvements were also demonstrated in erythema, scaling, induration, and pruritus at week 4 compared to baseline. Improvement in Subject's Global Assessment scores compared to baseline were significant only at week 1 (P=0.031). Change in total mean SD Dermatology Life Quality Index scores from baseline to week 4 was 0.34 (+/- 0.62, P=0.039). CONCLUSION: The results of this preliminary study support the efficacy and safety of sertaconazole nitrate cream, 2%, for the treatment of seborrheic dermatitis. PMID- 21818512 TI - Assessor-blinded study of the metabolic syndrome and surrogate markers of increased cardiovascular risk in children with moderate-to-severe psoriasis compared with age-matched population of children with warts. AB - Adult patients with psoriasis have an increased prevalence of the metabolic syndrome (MetS) and cardiovascular disease (CVD) risk factors due to elevations of Tumor Necrosis Factor and other inflammatory cytokines.1,2 Recently, higher rates of hyperlipidemia, obesity, hypertension, and diabetes mellitus were seen in patients with juvenile psoriasis.3 Here, we report the interim results of an ongoing study of MetS and CVD risk factors in pediatric psoriasis patients. PMID- 21818513 TI - Fulminant dermatomyositis with flagellate erythema. PMID- 21818514 TI - Evaluation of clinical improvement in acne scars and active acne in patients treated with the 1540-nm non-ablative fractional laser. AB - INTRODUCTION: Acne is a characteristic condition of puberty; however, adults who continue to have acne outbreaks frequently attend dermatology clinics. Two conditions-active acne and residual scarring-often co-occur in these patients. The objective of the present study was to evaluate the improvement in scarring and active acne after treatment with a 1540-nm erbium: glass fractional laser. MATERIAL AND METHODS: The authors treated 20 patients with acne and scarring. Each patient received panfacial treatment in four sessions with a 1-month interval between sessions. Patients, the treating physician and a blinded observer evaluated the results in four areas: improvement in scars, improvement in pores, improvement in acne, and improvement in sebum secretion. Improvements were graded using the Global Aesthetic Improvement Scale. The evaluation was made 12 weeks after treatment finished. RESULTS: Patients presented an improvement in both acne and scars. In 80 percent of cases, patients felt that the appearance of the scars had improved, and the improvement was classified as very much improved in 40 percent. In 85 percent of cases, patients felt that active acne had improved, and the improvement was classified as very much improved in 45 percent. Pore size was evaluated as improved by 75 percent of patients. Sebum secretion improved in 80 percent of cases. CONCLUSION: A 1540-nm non-ablative fractional laser provides effective treatment of acne scars. Patient satisfaction is high and active acne lesions improve significantly. Treatment of this mixed condition (scarring and active acne) with a single device is reliable, with a favorable safety profile and a high degree of patient acceptance. PMID- 21818515 TI - Mycobacterium fortuitum infection following adalimumab treatment for psoriasis and subsequent complication-free treatment with alternate TNF-a blockers. AB - Tumor necrosis factor-a (TNF-a) inhibitors, such as adalimumab, are often used to treat psoriasis and psoriatic arthritis. While it is well known that these agents increase the risk of reactivation tuberculosis, recent evidence suggests that the risk of other nontuberculous mycobacterial (NTM) infections is on the rise. We report cutaneous Mycobacterium fortuitum in a 60-year-old woman with psoriasis who had been receiving adalimumab therapy for psoriatic arthritis for six months. No other risk factors were identified. M. fortuitum was cultured from a lesion on the right leg. Following resolution of the lesion, the patient has been successfully treated with infliximab infusions and subsequently certalizumab without complication for the past three years. To our knowledge, this is the first report of M. fortuitum occurring in a patient receiving adalimumab with successful subsequent treatment without complication while on another TNF-a inhibitor. PMID- 21818516 TI - Central serous chorioretinopathy associated with topical corticosteroids in a patient with psoriasis. AB - BACKGROUND: Central serous chorioretinopathy (CSC), also known as central serous retinopathy (CSR), is a visual impairment, often temporary, usually in a single eye, which mostly affects males in the age group of 20 to 50 but may also affect women. CSC occurring after prolonged use of topical steroids in a patient with psoriasis is a novel complication in the English literature. OBSERVATIONS: We describe a case of a 25-year-old male, with a 15-year history of corticoid ointment use for psoriasis, who presented with loss of vision secondary to CSR. CONCLUSIONS: All topical steroid treatments were discontinued and the patient recovered his vision completely. Although topical corticosteroids are frequently utilized for psoriasis management with a low rate of complication, clinicians should be familiar with this rare yet distressing condition. Furthermore, patients with increased production of endogenous corticosteroids (e.g., those with Cushing's syndrome, hypertension, or obstructive sleep apnea) should be warned of the potential of chorioretinopathy following prolonged use of topical corticosteroids. PMID- 21818517 TI - Alefacept therapy for nephrogenic systemic fibrosis: a case series. AB - Nephrogenic systemic fibrosis (NSF) is a recently described systemic fibrosing disorder that develops in the setting of renal insufficiency. Exposure to gadolinium has been implicated in its development. While the primary manifestations are cutaneous, systemic fibrosis can also occur. Several anecdotal reports of successful treatment have been reported, but there is no consistently efficacious therapy. We report the improvement or stabilization of cutaneous disease in three patients with NSF using alefacept therapy. PMID- 21818518 TI - Epidermolysis bullosa simplex with mottled pigmentation: a novel KRT14 mutation. PMID- 21818519 TI - A biopsy diagnosis? clinical clues and patterns to help distinguish cutaneous metastases: part II of II. AB - News, Views and Reviews provides focused updates, topic reviews and editorials concerning the latest developments in dermatologic therapy. PMID- 21818520 TI - On creating a patient-centric database from multiple Hospital Information Systems. AB - BACKGROUND: The information present in Hospital Information Systems (HIS) is heterogeneous and is used primarily by health practitioners to support and improve patient care. Conducting clinical research, data analyses or knowledge discovery projects using electronic patient data in secondary care centres relies on accurate data collection, which is often an ad-hoc process poorly described in the literature. OBJECTIVES: This paper aims at facilitating and expanding on the process of retrieving and collating patient-centric data from multiple HIS for the purpose of creating a research database. The development of a process roadmap for this purpose illustrates and exposes the constraints and drawbacks of undertaking such work in secondary care centres. METHODS: A data collection exercise was carried using a combined approach based on segments of well established data mining and knowledge discovery methodologies, previous work on clinical data integration and local expert consultation. A case study on prostate cancer was carried out at an English regional National Health Service (NHS) hospital. RESULTS: The process for data retrieval described in this paper allowed patient-centric data, pertaining to the case study on prostate cancer, to be successfully collected from multiple heterogeneous hospital sources, and collated in a format suitable for further clinical research. CONCLUSIONS: The data collection exercise described in this paper exposes the lengthy and difficult journey of retrieving and collating patient-centric, multi-source data from a hospital, which is indeed a non-trivial task, and one which will greatly benefit from further attention from researchers and hospital IT management. PMID- 21818521 TI - Gastrografin for uncomplicated adhesive small bowel obstruction in children. AB - PURPOSE: The risk of bowel injury during surgery for small bowel obstruction (SBO) has generated interest in conservative treatment modalities. Few data are available on conservative Gastrografin treatment for SBO in children. METHODS: We prospectively included patients with uncomplicated adhesive SBO managed at a pediatric center between March 2009 and September 2010. Patients who were unimproved after 48 h of conservative treatment received 50-100 ml of Gastrografin. If Gastrografin was seen in the cecum on the abdominal radiograph 4 6 h later, feeding was initiated and the patient was discharged on the same day. Each patient was matched to 2 controls on the number of previous SBO episodes. The primary outcome was length of hospital stay (>3 days), and the secondary outcome was time from admission to first feed (>2 days). Both were compared in the two groups using conditional logistic regression. RESULTS: The 8 patients admitted for SBO were matched to 16 controls. Gastrografin administration was associated with significantly lower risks of staying in the hospital longer than 3 days (P < 0.10) and waiting more than 2 days before the first feed. CONCLUSION: This preliminary study suggests that Gastrografin may be useful for managing adhesive SBO in children. PMID- 21818522 TI - Percutaneous sclerotherapy of peripheral venous malformations in pediatric patients. AB - PURPOSE: To report the efficacy of percutaneous puncture and sclerosis using polidocanol in the treatment of venous malformations (VMs) in pediatric patients. PATIENTS/METHODS: Between March 2007 and February 2011, a series of 19 patients with VMs on the upper and lower extremities had undergone a total of 89 sessions of intralesional sclerotherapy using polidocanol. All the procedures were performed in an angiographic suite under general anesthesia in order to maintain sedation for facilitating the procedure. For each injection, approximately 1 ml of 2% polidocanol was injected for each centimeter of the diameter of the lesion, with a maximum of 6 ml. Injection of the sclerosant was guided by real-time sonography and fluoroscopy. RESULTS: After the treatment, the symptoms completely resolved in four patients (21%). Clinical symptoms, such as bulging and pain were improved in 12 out of 19 patients (63%). They remained unchanged in three patients (16%). During the procedures, no major complications were encountered. The minor complications (65%) encountered were swelling and pain after treatment which were resolved by taking NSAID within a few days. CONCLUSION: In pediatric patients, sonographically guided percutaneous puncture and fluoroscopically guided sclerosis using 2% polidocanol is effective, less invasive and safe for the treatment of VMs, with a high success rate and minimal complications. PMID- 21818523 TI - [The White Paper on treating medical emergencies preclinically and at hospital : how can it be implemented?]. AB - Up-to-date management of medical emergencies implies primarily that definitive diagnoses and treatment are performed in a timely manner. These claims have been reconfirmed in 2007 by the leading German language medical associations in their "White Paper on Emergency Treatment". To actually realize the demands described in this paper a timely, transsectoral and close collaboration of all involved organizations is mandatory. To illustrate this race against cell death the phrase relay of survival is proposed and launched to replace the hitherto used but rigid concept of chain of survival. The tasks of each member of this relay of survival are critically scrutinized one after the other from a patient perspective. The paper presents tangible recommendations for improving the respective individual performance as well as, in particular, the cooperation and coordination between the team members which is comparable to handing over the baton in a relay race. PMID- 21818524 TI - Detection of human papillomavirus DNA in urine. A review of the literature. AB - The detection of human papillomavirus (HPV) DNA in urine, a specimen easily obtained by a non-invasive self-sampling method, has been the subject of a considerable number of studies. This review provides an overview of 41 published studies; assesses how different methods and settings may contribute to the sometimes contradictory outcomes; and discusses the potential relevance of using urine samples in vaccine trials, disease surveillance, epidemiological studies, and specific settings of cervical cancer screening. Urine sampling, storage conditions, sample preparation, DNA extraction, and DNA amplification may all have an important impact on HPV DNA detection and the form of viral DNA that is detected. Possible trends in HPV DNA prevalence in urine could be inferred from the presence of risk factors or the diagnosis of cervical lesions. HPV DNA detection in urine is feasible and may become a useful tool but necessitates further improvement and standardization. PMID- 21818525 TI - Improvement of MR cholangiopancreatography (MRCP) images after black tea consumption. AB - OBJECTIVE: Evaluation of the efficacy of black tea as the negative oral contrast agent in MRCP. MATERIALS AND METHODS: MRCP was performed before and 5 and 15 min after tea consumption for 35 patients. Depiction of the gall bladder (GB), cystic duct (CD), proximal and distal parts of the common bile duct (CBD), intrahepatic ducts (IHD), ampulla of vater (AV), main pancreatic duct (MPD) and signal loss of stomach and three different segments of the duodenum were investigated according to VAS and Likert scores. RESULTS: Twenty-one of the patients (60%) were female (mean age, 50.3 +/- 19.2 years). Regarding visibility of different anatomical parts of the pancreatobiliary tree, the post procedure images were better visualized in the distal part of CBD, AV and MPD in Likert and VAS scoring (all P <= 0.001). Regarding obliteration of high signal in the stomach and three different parts of the duodenum, all post procedure images showed significant disappearance of high signal in Likert and VAS scoring systems (all Ps <= 0.001). CONCLUSION: Black tea is a simple and safe negative oral contrast agent which reduces the signal intensity of gastrointestinal tract fluid and provides improved depiction of the MPD, the distal CBD and the ampulla during MRCP. Key Points *Tea is an effective negative oral contrast agent for gastrointestinal MRI *Ingestion of black tea improves conspicuity of the distal CBD in MRCP. PMID- 21818526 TI - Preliminary observations and clinical value of N-acetyl resonances in ovarian tumours using in-vivo proton MR spectroscopy at 3T. AB - OBJECTIVE: To retrospectively evaluate the clinical significance of N-acetyl resonances at 2 ppm in in-vivo proton magnetic resonance (MR) spectroscopy for distinguishing mucinous and non-mucinous tumours in patients with ovarian masses. METHODS: MR spectroscopy was performed in patients with pathologically diagnosed ovarian tumours at 3T-MR imaging. Single-voxel MR spectroscopy data were collected from a single square volume of interest that encompassed the ovarian masses. The metabolite resonance peak areas at 2 ppm were quantified relative to unsuppressed water using a software package (LCModel). RESULTS: A total of 32 ovarian lesions in 32 patients were evaluated in this study. High metabolite peak at 2 ppm was observed in all nine mucinous tumours (9.71 +/- 7.46 mM), whereas low peak was observed in 14 of 23 non-mucinous tumours (3.12 +/- 1.42 mM) (p < 0.001). Using a cut off value of 4.45 mM for mucinous tumours had a sensitivity of 89%, specificity of 86%, PPV of 80%, and NPV of 92%. CONCLUSION: Proton MR spectroscopy with quantitative evaluation of the metabolite at 2 ppm concentration, which may suggest the presence of mucinous material containing N acetyl mucinous compounds, can provide helpful information in distinguishing mucinous and non-mucinous ovarian tumours. Key Points * MR spectroscopy helps distinguish mucinous from non-mucinous ovarian tumours. * High N-acetyl resonance at 2 ppm is observed in ovarian mucinous tumours. * Thus MR spectroscopy could improve management of these patients. PMID- 21818527 TI - Evaluation of the relative effectiveness of three HIV testing strategies targeting African American men who have sex with men (MSM) in New York City. AB - BACKGROUND: African American men who have sex with men (MSM) are disproportionately affected by HIV and constitute more than half of all HIV infected MSM in the USA. PURPOSE: Data from the New York City location of a multi site study were used to evaluate the effectiveness of three HIV testing strategies for detecting previously undiagnosed, 18 to 64-year-old African American MSM. Effectiveness was defined as the identification of seropositive individuals. METHODS: Using a quasi-experimental design (N = 558), we examined HIV-positive test results for men tested via alternative venue testing, the social networks strategy, and partner counseling and referral services, as well as behavioral risk factors for 509 men tested through alternative venue testing and the social networks strategy. RESULTS: Detection rates of HIV-positives were: alternative venue testing-6.3%, the social networks strategy-19.3%, and partner services-14.3%. The odds for detection of HIV-positive MSM were 3.6 times greater for the social networks strategy and 2.5 times greater for partner services than alternative venue testing. Men tested through alternative venue testing were younger and more likely to be gay-identified than men tested through the social networks strategy. Men who tested through the social networks strategy reported more sexual risk behaviors than men tested through alternative venue testing. CONCLUSIONS: Findings suggest differential effectiveness of testing strategies. Given differences in the individuals accessing testing across strategies, a multi strategic testing approach may be needed to most fully identify undiagnosed HIV positive African American MSM. PMID- 21818529 TI - The relationship of physical activity and the built environment within the context of self-determination theory. AB - BACKGROUND: Evidence is emerging of the combined effects of psychosocial and environmental determinants on exercise. PURPOSE: This study aims to examine the moderating effects of convenience, facilities at places of worship, access, crime/safety, and neighborhood characteristics on the relationship between exercise and psychosocial needs satisfaction (autonomy, competence, and relatedness). METHODS: Adults from four cities enrolling in a weight loss program (N = 477; 72.1% White, BMI = 32.21 +/- 7.67) completed questionnaires on current exercise levels, perceptions of the environment for exercise, and autonomy, competence, and relatedness. RESULTS: There were significant interaction effects for neighborhood characteristics with all three psychological needs satisfaction, and for convenience with competence and relatedness, such that the relationship between psychosocial needs satisfaction and exercise is stronger for participants with better perceptions of convenience and neighborhood characteristics. CONCLUSIONS: Results indicate that the relationship between exercise and autonomy, competence, and relatedness is different for low and high perceptions of convenience to places for exercise and neighborhood characteristics. PMID- 21818528 TI - A closer look at depression and its relationship to HIV antiretroviral adherence. AB - BACKGROUND: Depression consistently predicts nonadherence to human immunodeficiency virus antiretroviral therapy, but which aspects of depression are most influential are unknown. Such knowledge could inform assessments of adherence readiness and the type of depression treatment to utilize. PURPOSE: We examined how depression severity, symptom type, and change over time relate to adherence. METHODS: Microelectronic adherence and self-reported depression data from 1,374 participants across merged studies were examined with cross-sectional and longitudinal analyses. Depression variables included a continuous measure, categorical measure of severity, cognitive and vegetative subscales, and individual symptoms. RESULTS: At baseline, mean adherence was 69%, and 25% had mild/moderate and 18% had severe depression. In cross-sectional multivariate analyses, continuous depression, cognitive depressive symptoms, and severe depression were associated with lower adherence. In longitudinal analysis, reductions in both continuous and categorical depression predicted increased adherence. CONCLUSIONS: The relationship between global continuous depression and nonadherence was statistically significant, but relatively weak compared to that of cognitive depressive symptoms and severe depression, which appear to pose strong challenges to adherence and call for the need for early detection and treatment of depression. PMID- 21818530 TI - Depression and smoking: mediating role of vagal tone and inflammation. AB - BACKGROUND: Depressed adults are more likely to become nicotine dependent and smokers are at increased risk for depression. Smoking and depression are each associated with inflammation and vagal tone. PURPOSE: The purpose of this study is to determine as to what extent the association between depression and smoking is mediated by inflammation and/or vagal tone. METHODS: We studied a cross sectional occupational sample (n = 647) with information on the number of cigarettes smoked per day and depression (as measured by the Hospital Anxiety and Depression Scale). Heart rate variability, an indicator of vagal tone, was measured by electrocardiographic recordings. Inflammatory markers included C reactive protein, white blood cells, and fibrinogen. Linear regression was employed along with the Freedman-Schatzkin test to assess mediation. RESULTS: We observed a positive association between depression and smoking (p < 0.05). Vagal tone and fibrinogen were found to weakly attenuate this association. CONCLUSION: These are the first data to demonstrate that the association between depression and smoking may partially be mediated by vagal tone and fibrinogen. PMID- 21818532 TI - A single camera photogrammetry system for multi-angle fast localization of EEG electrodes. AB - Photogrammetry has become an effective method for the determination of electroencephalography (EEG) electrode positions in three dimensions (3D). Capturing multi-angle images of the electrodes on the head is a fundamental objective in the design of photogrammetry system for EEG localization. Methods in previous studies are all based on the use of either a rotating camera or multiple cameras, which are time-consuming or not cost-effective. This study aims to present a novel photogrammetry system that can realize simultaneous acquisition of multi-angle head images in a single camera position. Aligning two planar mirrors with the angle of 51.4 degrees , seven views of the head with 25 electrodes are captured simultaneously by the digital camera placed in front of them. A complete set of algorithms for electrode recognition, matching, and 3D reconstruction is developed. It is found that the elapsed time of the whole localization procedure is about 3 min, and camera calibration computation takes about 1 min, after the measurement of calibration points. The positioning accuracy with the maximum error of 1.19 mm is acceptable. Experimental results demonstrate that the proposed system provides a fast and cost-effective method for the EEG positioning. PMID- 21818534 TI - Non-destructive evaluation of the effects of combined bisphosphonate and photodynamic therapy on bone strain in metastatic vertebrae using image registration. AB - Skeletal metastases most frequently affect the vertebral column and may lead to severe consequences including fracture. Clinical management of skeletal metastases often utilizes a multimodal treatment approach, including bisphosphonates (BPs). Previous work has demonstrated the synergistic potential of photodynamic therapy (PDT) in combination with BP in treating osteolytic disease through structural, histologic, and destructive mechanical testing analyses. Recent work has developed and validated image-based methods that may be used to non-destructively determine mechanical stability in whole bones, and enable their use for additional (i.e. histologic) analysis. In this work we use an intensity-based 3D image registration technique to compare the strain patterns throughout untreated control and BP + PDT treated rnu/rnu rat spinal motion segments with osteolytic metastases. It was hypothesized that the combination treatment will reduce average and maximum strain values and restore the pattern of strain to that of healthy vertebrae. Mean, median, and 90th percentile strains in the control group were significantly higher than the treatment group. High strain areas in both groups were observed around the endplates; in the control group, large areas of high strains were also observed around the lesions and adjacent to the dorsal wall. Absence of high strains adjacent to the dorsal wall (similar to healthy vertebrae) may correspond to a reduced risk of burst fracture following BP + PDT therapy. This study demonstrates the application of non destructive image analysis to quantify the positive mechanical effects of combined BP + PDT treatment in the metastatic spine. PMID- 21818535 TI - Murine cardiac hemodynamics following manganese administration under isoflurane anesthesia. AB - This study examines (a) the temporal stability of hemodynamic indices of systolic and diastolic function in C57BL/6 mice under 1.5% isoflurane (ISO) (v/v) anesthesia conditions in 50:50 O(2)/N(2)O (v/v) within 90 min post-induction, and (b) the effects of Mn(2+) on the mouse hemodynamic response in male C57BL/6 mice (n = 16). Left ventricular catheterizations allowed estimation of the hemodynamic indices. Hypertonic saline infusion (10%) allowed absolute volume quantification in conjunction with a separate series of aortic flow experiments (n = 3). In a separate cohort of mice (n = 6), MnCl(2) (190 nmoles/g/bw) was infused via the left jugular for 29-39 min, following 11 min of baseline recording, to assess temporal responses. Stable temporal hemodynamic responses were achieved in control mice under ISO anesthesia. Hemodynamic indices during control, time matched-control, baseline-Mn, and Mn-infused periods, were within normal expected ranges. No chronotropic changes were observed. Significant differences in systolic and diastolic cardiac indices of function (HR, EF, ESP, dP/dt (max), dP/dt (min), PAMP, tau(glantz), and tau(weiss)) resulted between baseline-Mn and Mn-infused time periods in Mn-treated mice at the 1% significance (p < 0.001). Transient positive, or negative, or positive followed by negative evoked pressure volume loop shifts were observed (exemplified through changes in the end-systolic pressure-volume relationship and dP/dt (max)) in Mn-infusion studies. It is concluded that Mn(2+) can be used safely for prolonged mouse imaging studies, however, the significant variations elicited in cardiovascular hemodynamics post manganese infusion, necessitate further investigations for its suitability and appropriateness for quantification of global cardiac function in image-based phenotyping. PMID- 21818536 TI - Re-challenge with etanercept in patients with etanercept-induced neutropenia. AB - TNF blockers have rarely been associated with haematological complications; however, there are scattered case reports of marked neutropenia with their use and necessitating in their withdrawal. We would like to report a series of five patients who developed neutropenia with etanercept use; however, all these patients were re-challenged with etanercept with a mean follow up of 30 months. These patients developed neutropenia within 2 months of starting etanercept. Two patients were eventually taken off etanercept; one of them needed switching to a different form of TNF blockers, and the second patient is in clinical remission with low-dose corticosteroids. All our patients continued to have mild-moderate degree of neutropenia; however, they are being monitored very closely and they are enjoying complete disease remission. It was interesting to note that none of our patients had increased infections during the re-challenge phase, even though they had grade 2 to grade 4 neutropenia. We have re-challenged these patients without any clinical complications, revealing that patients with mild to moderate neutropenia can be safely exposed to TNF blockers as long as they are monitored with regular cell count checks. Although largely noted to be clinically insignificant in our patient series, the potential of drug-induced neutropenia in causing higher rate of infections do exist. Careful clinical and hematologic monitoring is the best way to recognize this adverse event. PMID- 21818537 TI - Cilostazol determination by the enhancement of the green emission of Tb3+ optical sensor. AB - The efficiency of excited-state interaction between Tb(3+) and the industrial product Cilostazol (CIL) has been studied in different solvents. High luminescence intensity peak at 545 nm of terbium complex in acetonitrile was obtained. The photophysical properties of the green emissive Tb(3+) complex have been elucidated, the terbium was used as optical sensor for the assessment of CIL in the pharmaceutical tablets and body fluids at pH 3.1 and lambda(ex) = 320 nm with a concentration range 1.0 * 10(-9)-1.0 * 10(-6) mol L(-1) of CIL, correlation coefficient of 0.998 and detection limit of 7.5 * 10(-10) mol L(-1). PMID- 21818538 TI - The effects assessment of firm environmental strategy and customer environmental conscious on green product development. AB - The purpose of this study is to examine why both parties (industry and consumer market) have mutual interests in protecting the environment but they still are hesitant to act green. The study used two-stage sampling from consumer market to depict ideal green product characteristics and reliable toy companies, and visit these companies for the second sample collection to examine whether the organizational eco-innovation strategy with customer value has a positive effect on green product development. In other words, the customer's benefit is an important factor for new product development strategy for green toys. This research shows that the willingness to buy green toys increases if most people in society buy green toys. This represents that customers are environmentally conscious and care about protecting the environment, or buying green toys is the result of a new economic trend and childhood education. The willingness to buy green toys increases if customers think that green products implies an enhancement on new product development to toy manufacturers. Further, if manufacturers are able to manage the difficulty of cooperation with all parties in the supply chain and difficulties related to production, they are willing to adopt customers' perceived value on green toys for their new product development strategy. It is rare to find academic research discussing the perspectives of both consumers and manufacturers in the same study because the research topic is very broad and many conditions must be considered. This research aims to find the effect of consumer-perceived value and company eco-innovation on green product development. PMID- 21818539 TI - Multivariate statistical analysis of heavy metals in soils of a Pb-Zn mining area, India. AB - Surface soil samples collected from a Pb and Zn mining area in India were subjected to multi-elemental analysis by using inductively coupled plasma-atomic emission spectrometry. Multivariate statistical methods such as principal component analysis and cluster analysis, coupled with correlation coefficient analysis, were used to analyze the data and to apportion the possible sources of elements in soils of a metal mining area. Soils in this area have elevated heavy metal concentrations especially Pb, Zn, Mn, Cu, As, and Tl. Using principal component (PC) analysis, six components were extracted, out of which two PCs explaining 50.12% of total variance are more important. The first principal component with a high contribution of Ag, As, Be, Cd, Co, Cu, Mg, Mn, Ni, Pb, and Zn was deemed to be technogenic/anthropogenic component, and the second principal component, with high loadings for the five discerning variables (Al, Be, Cr, K, Li), was considered as lithogenic component. The third component having strong loadings of Ba, Ca, K, and Na is supposed to have a mixed origin (lithogenic as well as technogenic). Electrical conductivity and total organic matter were not correlated with any element and also have a strong loading in the fifth component which is probably the biomass and ions present in these soils. The findings of the principal component analysis were also substantiated by the cluster analysis. The present study would not only enhance our knowledge regarding the soil pollution status in the study area but would also provide us information to manage the sources of these elements in the study area. PMID- 21818540 TI - Regulation of the cardiovascular function by CO2 laser stimulation in anesthetized rats. AB - Physical stimulation of body surface points is known to affect various organ functions. In traditional Chinese medicine, so-called acupoints were defined. These points can be physically stimulated to effectively treat various diseases. Here we describe for the first time the effect of CO(2) laser stimulation at the acupoints Neiguan (PC-6), Quchi (LI-11), Zusanli (ST-36), and Taichong (LR-3) on heart rate and mean arterial blood pressure in anesthetized rats. CO(2) laser stimulation increased the skin surface temperature to 54 degrees C. Our results revealed that the laser stimulation at the left or right PC-6 and LR-3 increased heart rate and mean arterial pressure. There was no response of heart rate and mean arterial pressure during and after stimulation of the left LI-11, but laser stimulation at the right LI-11 slightly increased heart rate and mean arterial pressure. On the other hand, laser stimulation at the left and right ST-36 decreased heart rate and mean arterial pressure. The effects on mean arterial pressure were more pronounced than those on heart rate. After full spinal cord transection, all heart-rate and mean-arterial-pressure responses were attenuated or completely abolished. These results suggest that CO(2) laser stimulation at either the left or right PC-6, ST-36, and LR-3, as well as at the right LI-11 can modulate the cardiovascular functions in anesthetized rats, and its modulatory site might be supraspinal. PMID- 21818541 TI - The protective role of ascorbic acid (vitamin C) against chlorpyrifos-induced oxidative stress in Oreochromis niloticus. AB - Ability of ascorbic acid (vitamin C) to attenuate oxidative damage was evaluated in liver and brain tissues of Oreochromis niloticus (O. niloticus) experimentally exposed to sublethal concentrations of chlorpyrifos (CPF). O. niloticus was exposed to sublethal concentrations of CPF at 12 MUg/L (CPF1) and 24 MUg/L (CPF2) for 96 h. The fish of vitamin C (Vit C) and CPF2 + Vit C groups were fed with Vit C supplemented diet (200 mg Vit C/100 g feed). A significant increase in thiobarbituric acid-reactive substances (TBARS) level (P < 0.05) was observed in brain of CPF-exposed fish although liver TBARS level was not changed compared to control group. This result showed that lipid peroxidation (LPO) was elevated in brain of fish exposed to CPF. Glutathione peroxidase (GSH-Px) activity in liver and brain tissues was significantly elevated (P < 0.05) by exposure to CPF1 and CPF2. Catalase (CAT) activity was significantly increased (P < 0.05) in liver but decreased in brain of treated fish by CPF2 concentration. Superoxide dismutase (SOD) activity was decreased in liver, but increased in brain by exposure to CPF1 and CPF2 concentrations. Levels of TBARS were increased in brain of CPF-treated animals, but tended to decrease by the effect of Vit C. Vit C treatment for CPF intoxicated animals normalized the otherwise raised activities of GSH-Px, CAT, and SOD within normal limits. The results clearly indicate that exposure to CPF caused a dose-dependent increase in oxidative stress brain and to a lesser extend in liver of fish and the ability of Vit C to attenuate CPF-induced oxidative damage. PMID- 21818542 TI - Morphological and histochemical study of intestine in wild and reared European eel (Anguilla anguilla L.). AB - Diet-related differences between the ratio of intestine length to body size and the enzymatic activity in the intestinal tract of wild and reared European eel (Anguilla anguilla L.) were studied. Compared with reared eel, wild eel showed significantly shorter relative intestine length. For the purpose of histochemical examination, different parts (anterior, middle and posterior) of intestine proper were used. Activities of non-specific esterase, alkaline and acid phosphatase, and aminopeptidase were examined in each segment. All enzymes were present in the intestines of both wild and reared European eel. Fish from both groups showed similar enzyme distribution within the enterocytes, but distribution and intensity of enzyme activity along the intestine vary depending on the group. Generally, reared European eel showed highest enzymatic activity and wider distribution of enzymes throughout all parts of the intestine. These results suggest that different diets could be one of the reasons for observed changes. PMID- 21818543 TI - Effects of dissolved oxygen on glycolytic enzyme specific activities in liver and skeletal muscle of Fundulus heteroclitus. AB - Many aquatic habitats are characterized by variable concentrations of dissolved oxygen (DO), and fish that occur in these habitats respond to changes in DO through behavioral, physiological, and biochemical adjustments. The goal of the present study was to measure the effects of an ecologically relevant range of DO treatments, from severe hypoxia to moderate hyperoxia, on the maximal activities of nine glycolytic enzymes during chronic exposure of the mummichog, Fundulus heteroclitus. Over the 28 days of exposure period, specific activity was significantly affected by DO for three enzymes in liver and one enzyme in white skeletal muscle, although at specific times of exposure three other muscle enzymes were affected by DO. In general, exposure of fish to severe hypoxia led to higher specific activities in liver, but lower specific activities in skeletal muscle. Exposure to hyperoxia did not elicit changes in enzyme specific activities in either tissue. Surprisingly, exposure duration had strong effects on glycolytic enzyme specific activities in both liver and white skeletal muscle, with specific activities increasing with exposure duration regardless of DO treatment. The results demonstrate that the effects of DO on enzyme specific activities were restricted to a subset of the glycolytic enzymes in liver and white skeletal muscle of F. heteroclitus and that the directions of the changes were opposite in these two tissues. These observations suggest that the mechanisms resulting in these alterations are enzyme- and tissue specific, rather than applying uniformly to all enzymes within the glycolytic pathway. PMID- 21818545 TI - Circulating levels of soluble alpha-Klotho in patients with chronic kidney disease. PMID- 21818544 TI - Navigating breast cancer: axon guidance molecules as breast cancer tumor suppressors and oncogenes. AB - Slit, Netrin, Ephrin, and Semaphorin's roles in development have expanded greatly in the past decade from their original characterization as axon guidance molecules (AGMs) to include roles as regulators of tissue morphogenesis and development in diverse organs. In the mammary gland, AGMs are important for maintaining normal cell proliferation and adhesion during development. The frequent dysregulation of AGM expression during tumorigenesis and tumor progression suggests that AGMs also play a crucial role as tumor suppressors and oncogenes in breast cancer. Moreover, these findings suggest that AGMs may be excellent targets for new breast cancer prognostic tests and more effective therapeutic strategies. PMID- 21818546 TI - Significance of past history of renal failure for the detection of high-risk individuals for cardiovascular and end-stage renal disease: analysis of data from a nationwide health checkup. AB - BACKGROUND: Clinical information regarding risk factors may be helpful in the detection of various diseases. This cross-sectional study examined the characteristics of subjects with past history of renal failure, and assessed whether this information would be useful for the efficient detection of high-risk individuals for chronic kidney disease (CKD) and cardiovascular disease (CVD) at health checkup. METHODS: This study utilized data from a nationwide health checkup, "The Specific Health Check and Guidance in Japan," and data for 250,130 adult subjects were analyzed. Subjects with self-reported history of renal failure and receiving dialysis therapy were defined as having a history of renal failure. RESULTS: Among total participants, there were 1,400 (0.6%) with a history of renal failure. The prevalence of a history of renal failure was higher in subjects with CKD than in those without CKD (1.5 vs. 0.3%, P < 0.001) and increased with progression of the stage of CKD (0.9-43.5%). Subjects with a history of renal failure had a reduced estimated glomerular filtration rate (44.6 +/- 20.3 ml/min/1.73 m(2)) and a higher prevalence of CKD (50.5%) and CVD (31.9%), compared with subjects with hypertension, diabetes or metabolic syndrome. Multivariate logistic regression analysis showed an independent association between a history of CVD and renal failure (odds ratio 3.68, 95% confidence interval 3.26-4.15), after adjustment for confounding factors. CONCLUSIONS: A history of renal failure was strongly associated with advanced CKD and CVD. Information regarding history of renal failure could be utilized to efficiently detect high-risk individuals at health checkup. PMID- 21818547 TI - Safety and efficacy of administering the maximal dose of candesartan in renal transplant recipients. AB - BACKGROUND: The regular dose of an angiotensin II type-1 receptor blocker (ARB) in renal transplant patients for hypertension is shown to be safe and effective; however, information on the appropriate dosing of ARBs in renal transplant patients is limited. We evaluate the efficacy and safety of the maximal dose of candesartan administered to renal transplant patients. METHODS: Sixty-nine recipients were enrolled in this study. Patients were divided into three groups based on the basal dose of candesartan: patients not taking candesartan (Group A); patients taking a low to medium dose of candesartan (2-4 mg/day; Group B); and patients taking a high dose of candesartan (8 mg/day; Group C). During the course of the study, the dose of candesartan was gradually increased to a final dose of 12 mg/day. Physiological and biochemical parameters were measured before and after the 12-month study period. RESULTS: Ninety-one percent of patients succeeded in continuing their administration of candesartan for 1 year and 75% tolerated the administration of the maximal dose of candesartan. Significant differences in proteinuria, albuminuria, serum creatinine, and estimated glomerular filtration rate (eGFR) level among the groups were detected. In Group A, candesartan reduced systolic blood pressure, decreased the levels of proteinuria, albuminuria, eGFR, and hemoglobin and increased plasma potassium, creatinine level, and plasma renin activity. CONCLUSION: The gradual increase of an ARB to its maximal dose in renal transplant patients is safe when carefully monitored. We were able to demonstrate the impact of maximal renin-angiotensin system (RAS) blockade on both proteinuria and albuminuria, which indicates the need for future, long-term randomized prospective trials to further establish the impact of maximal RAS blockade on renal and cardiovascular protection in transplant patients. PMID- 21818549 TI - 1H, 13C and 15N chemical shift assignments for the human Pitx2 homeodomain in complex with a 22-base hairpin DNA. AB - As one of the most important eukaryotic DNA-binding motifs, the homeodomain has been identified in over one thousand proteins. Transcription factors containing homeodomains play critical roles in diverse biological processes and are often implicated in human genetic disorders. The human Pitx2 protein is a central downstream transcription factor in both the TGF-beta and Wnt/beta-catenin signaling pathways, and involved in the regulation of cell differentiation, cell pattern formation and tissue maintenance. To better understand how Pitx2 regulates its target genes, we are investigating the mechanisms that confer DNA binding specificity on its homeodomain. Here, we report complete (1)H, (13)C and (15)N protein chemical shift assignments of the human Pitx2 homeodomain in complex with a non-consensus DNA sequence. PMID- 21818548 TI - Diseases of the parathyroid gland in chronic kidney disease. AB - During the past few years, remarkable advances have been made in the understanding and the management of parathyroid diseases in patients with chronic kidney disease (CKD). One of the important insights is the identification of fibroblastic growth factor 23, which has greatly reshaped our understanding of secondary hyperparathyroidism (SHPT). The recent introduction of calcimimetic cinacalcet hydrochloride has led to a major breakthrough in the management of SHPT. Recognition of circulating molecular forms of parathyroid hormone (PTH) is also a major milestone in the accurate assessment of parathyroid function in CKD. Primary hyperparathyroidism should also be considered in patients with CKD, because it can cause various renal manifestations and can also occur as a sporadic disease in these patients. Hypoparathyroidism is occasionally seen in dialysis patients in the setting of diabetes mellitus and malnutrition inflammation complex syndrome, as well as after parathyroidectomy for advanced SHPT. For patients with adynamic bone disease due to hypoparathyroidism and/or skeletal resistance to PTH, teriparatide, a PTH analog, may have potential for improving bone metabolism and reducing the risk of fracture. In this review, we summarize our current knowledge on diseases of the parathyroid gland in CKD patients, with a particular focus on recent work in the field. PMID- 21818550 TI - Insulin-producing cells in the brain of adult Drosophila are regulated by the serotonin 5-HT1A receptor. AB - Insulin signaling regulates lifespan, reproduction, metabolic homeostasis, and resistance to stress in the adult organism. In Drosophila, there are seven insulin-like peptides (DILP1-7). Three of these (DILP2, 3 and 5) are produced in median neurosecretory cells of the brain, designated IPCs. Previous work has suggested that production or release of DILPs in IPCs can be regulated by a factor secreted from the fat body as well as by neuronal GABA or short neuropeptide F. There is also evidence that serotonergic neurons may regulate IPCs. Here, we investigated mechanisms by which serotonin may regulate the IPCs. We show that the IPCs in adult flies express the 5-HT(1A), but not the 5-HT(1B) or 5-HT(7) receptors, and that processes of serotonergic neurons impinge on the IPC branches. Knockdown of 5-HT(1A) in IPCs by targeted RNA interference (RNAi) leads to increased sensitivity to heat, prolonged recovery after cold knockdown and decreased resistance to starvation. Lipid metabolism is also affected, but no effect on growth was seen. Furthermore, we show that DILP2-immunolevels in IPCs increase after 5-HT(1A) knockdown; this is accentuated by starvation. Heterozygous 5-HT(1A) mutant flies display the same phenotype in all assays, as seen after targeted 5-HT(1A) RNAi, and flies fed the 5-HT(1A) antagonist WAY100635 display reduced lifespan at starvation. Our findings suggest that serotonin acts on brain IPCs via the 5-HT(1A) receptor, thereby affecting their activity and probably insulin signaling. Thus, we have identified a second inhibitory pathway regulating IPC activity in the Drosophila brain. PMID- 21818552 TI - NAD(P)H: quinone oxidoreductase 1 and its potential protective role in cardiovascular diseases and related conditions. AB - NAD(P)H: quinone oxidoreductase (NQO) represents a family of flavoproteins that catalyze the two-electron reduction of quinones and their derivatives. In mammalian systems, there are two members of NQO, namely, NQO1 and NQO2. NQO1 utilizes NAD(P)H, whereas NQO2 employs dihydronicotinamide riboside (NRH) as the electron donors. In addition to the well-documented action in reducing quinone compounds and preventing the formation of reactive oxygen species, NQO enzymes, especially NQO1 also possess other important biological activities. These include anti-inflammatory effects, direct scavenging of superoxide anion radicals, and stabilization of p53 and other tumor suppressors. Recently, multiple studies in animal models demonstrated a potential role for NQO1 in protecting against cardiovascular injury and related conditions, including atherogenesis, dyslipidemia, and insulin resistance. Functional gene polymorphisms have been identified in human NQO1 gene. Studies on the association between NQO1 gene polymorphisms and susceptibility to disease development also suggested a possible involvement of NQO1 in human cardiovascular diseases and metabolic syndrome. This review is intended to summarize the recent development regarding the biochemical properties and molecular regulation of NQO1 and its potential beneficial role in cardiovascular diseases and related conditions, including metabolic syndrome. PMID- 21818553 TI - Toxicological insight from AP-1 silencing study on proliferation, migration, and dedifferentiation of rat vascular smooth muscle cell. AB - There has an effective way to prevent intimal hyperplasia on vascular smooth muscle cell (VSMC) proliferation in grafted veins. The activator protein-1 (AP-1) transcription factor plays an important role in cardiovascular generation and angioplasty. Once activated, AP-1 binds its specific DNA sequence to promote the proliferation of VSMC, differentiation, and migration. The objectives of this study were to determine toxicological effects of AP-1 silencing study on proliferation, migration, and dedifferentiation of rat vascular smooth muscle cell. To suppress the expression of AP-1 gene, AP-1 siRNA was used to interfere post-transcription in rat primary VSMCs. To observe the expression of SM alpha actin and downstream genes of AP-1, the activity of cell matrix metal proteinases and the migration ability of VSMC was examined by a modified Boyden chamber assay. Effects of AP-1 siRNA on proliferation and differentiation in rat VSMCs were evaluated by cell cycle analysis, DNA synthesis, MTT-test, and immunofluorescence. The results showed that the level of SM alpha-actin protein expression was increased. AP-1 siRNA also significantly decreased the MTT extinction value, DNA synthesis, PCNA expression, and the cell migration velocity when compared to the control group. AP-1 siRNA also clearly arrested cell cycle of VSM at the G0/G1 phase. Zymographic and Western blotting analyses showed that AP-1 siRNA suppressed serum-induced MMP-2 expression. These data suggest that the AP-1 siRNA was able to effectively inhibit the proliferation, migration, and dedifferentiation of smooth muscle cells. Thus, AP-1 siRNA provides a novel method to prevent intimal hyperplasia in blood vessel angioplasty. PMID- 21818554 TI - Correlative BOLD MR imaging of stages of synovitis in a rabbit model of antigen induced arthritis. AB - BACKGROUND: Because of the ability of blood-oxygen-level-dependent (BOLD) MRI to assess blood oxygenation changes within the microvasculature, this technique holds potential for evaluating early perisynovial changes in inflammatory arthritis. OBJECTIVE: To evaluate the feasibility of BOLD MRI to detect interval perisynovial changes in knees of rabbits with inflammatory arthritis. MATERIALS AND METHODS: Rabbit knees were injected with albumin (n=9) or saline (n=6) intra articularly, or were not injected (control knees, n=9). Except for two rabbits (albumin-injected, n=2 knees; saline-injected, n=2 knees) that unexpectedly died on days 7 and 21 of the experiment, respectively, all other animals were scanned with BOLD MRI on days 0, 1, 7, 14, 21 and 28 after induction of arthritis. T2* weighted gradient-echo MRI was performed during alternate 30 s of normoxia/hyperoxia. BOLD MRI measurements were compared with clinical, laboratory and histological markers. RESULTS: Percentage of activated voxels was significantly greater in albumin-injected knees than in contralateral saline injected knees (P=0.04). For albumin-injected knees (P<0.05) and among different categories of knees (P=0.009), the percentage of activated BOLD voxels varied over time. A quadratic curve for on-and-off BOLD difference was delineated for albumin- and saline-injected knees over time (albumin-injected, P=0.047; saline injected, P=0.009). A trend toward a significant difference in synovial histological scores between albumin-injected and saline-injected knees was noted only for acute scores (P=0.07). CONCLUSION: As a proof of concept, BOLD MRI can depict perisynovial changes during progression of experimental arthritis. PMID- 21818551 TI - Advances in tenascin-C biology. AB - Tenascin-C is an extracellular matrix glycoprotein that is specifically and transiently expressed upon tissue injury. Upon tissue damage, tenascin-C plays a multitude of different roles that mediate both inflammatory and fibrotic processes to enable effective tissue repair. In the last decade, emerging evidence has demonstrated a vital role for tenascin-C in cardiac and arterial injury, tumor angiogenesis and metastasis, as well as in modulating stem cell behavior. Here we highlight the molecular mechanisms by which tenascin-C mediates these effects and discuss the implications of mis-regulated tenascin-C expression in driving disease pathology. PMID- 21818555 TI - Spondyloepimetaphyseal dysplasia, short limb-abnormal calcifications type: progressive radiological findings from fetal age to adolescence. AB - BACKGROUND: Spondyloepimetaphyseal dysplasia, short limb-abnormal calcifications type (SEMD, SL-AC) is a rare autosomal recessive condition with a grave prognosis. OBJECTIVE: We aimed to describe the progression of symptoms from fetal age to adolescence in SMED, SL-AC patients. MATERIALS AND METHODS: We retrospectively evaluated radiological findings on plain films, CT and MRI for eight children with genetically proven SEMD (male:female ratio 4:4, ages 30-week fetus to 18 years) and summarized findings from case reports and case series in the literature. RESULTS: Early and persistent radiological signs of SEMD were platyspondyly, chest narrowing, short ribs, and broad and short bones in the extremities and pelvis. In five children, we observed an unusually massive C2 vertebral body with narrowing of the spinal canal. Disease progression was characterized by anterior dislocation of C1, kyphoscoliosis, bowing of the limbs, metaphyseal and epiphyseal changes and abnormal calcifications. Earliest appearance of abnormal calcifications was 1.5 years; four children had no abnormal calcifications at diagnosis. There were persistent large open fontanelles in all children with skull radiographs, including a 17-year-old boy. Disease severity and progression were variable. Complications included cord compression and restrictive lung changes. CONCLUSION: Disease severity and progression vary. Absence of abnormal calcifications does not preclude the diagnosis. An unusual, massive C2 vertebral body may contribute to spinal cord compression. Persistent open fontanelles should be added to the clinical characteristics of SEMD, SL-AC. PMID- 21818556 TI - Introduction of pro-interleukin-16 inhibits T-lymphoblastic leukemia growth in mice. AB - PURPOSE: Pro-interleukin-16 (pro-IL-16) is the precursor to mature interleukin-16 (IL-16) protein. Previous studies have demonstrated that pro-IL-16 can function as a regulator of cell cycle. A number of human T-cell leukemia and lymphoma cell lines are pro-IL-16 deficient. Intracellular expression of pro-IL-16 causes these cell lines to become quiescent, implicating loss of pro-IL-16 as a contributory step in T-cell malignancy. Therefore, we tested whether or not reintroduction of pro-IL-16 into solid tumors in mice could halt tumor growth. METHODS: MOLT-4 lymphoblastic leukemia cells were stably transfected with a dsRed-tomato virus and were injected subcutaneously into NOD/SCID/gamma chain-knockout mice. Tumor growth was monitored with an in vivo imaging system. A pro-IL-16-GFP fusion virus or control GFP only virus was injected into the tumors, and mice were monitored for 1 week. RESULTS: Injection of the pro-IL-16-containing lentivirus inhibited growth of established MOLT-4 tumors in mice. Tumor explants exhibited diminished proliferative capacity. CONCLUSIONS: Our data support the concept that restoration of pro-IL-16 expression in malignant T cells may have therapeutic value. PMID- 21818557 TI - Interstitial lung disease associated with gemcitabine treatment in patients with non-small-cell lung cancer and pancreatic cancer. AB - PURPOSE: Although there are several reports concerning gemcitabine-induced interstitial lung disease (ILD), the risk factors for ILD are not well known. In addition, data comparing the incidence and pattern of ILD associated with gemcitabine treatment in patients with non-small-cell lung cancer (NSCLC) versus those with pancreatic cancer are scarce. METHODS: We reviewed clinical records of 118 patients treated with gemcitabine between November 2004 and November 2010. The radiographic findings and other relevant clinical data were reviewed to identify patients who had developed ILD associated with gemcitabine treatment. RESULTS: Out of these 118 patients, we identified 62 patients with NSCLC (group A) and 56 patients with pancreatic cancer (group B), which were then analysed. After gemcitabine administration, ILD was detected in 9 out of the total 118 patients (7.6%). Three patients had grade 2 ILD and 6 patients had grade 3 ILD. Multivariate analysis revealed that prior thoracic radiotherapy (odds ratio: 26.3) and pre-existing pulmonary fibrosis (PF) (odds ratio: 6.5) were correlated with ILD occurrence, but the incidence of ILD was not different between groups A and B. The median dose of gemcitabine administered till the manifestation of ILD tended to be lower in group A than in group B. CONCLUSIONS: Prior thoracic radiotherapy and pre-existing PF were correlated with higher ILD rate in gemcitabine-treated patients. ILD incidence did not differ between NSCLC and pancreatic cancer patients, which may be due to the differences in treatment strategy and tumour properties. PMID- 21818558 TI - Aquaporin 5 distribution pattern during development of the mouse sublingual salivary gland. AB - Aquaporin 5 (AQP5) is important in salivary fluid secretion, and has been found in acinar cells of salivary glands in several species. Recently, studies have shown the AQP5 transcript and protein expression patterns as well as the temporal spatial protein distribution during development of the mouse submandibular salivary gland. The AQP5 distribution pattern of the closely located sublingual gland (SLG) is, however, not well known. Thus, in this study, the Aqp5 RNA expression pattern and the temporal-spatial distribution of AQP5 protein in prenatal development and in adult mouse SLG was investigated. SLGs from embryonic day 14.5 (E14.5) to 18.5 and postnatal days 0 (P0), 25, and 60 were examined using real time PCR and immunohistochemistry. The Aqp5 transcript was detected from E13.5 and was found to increase towards birth and in young adults. The protein was first detected in a scattered pattern in the canalicular stage and became more organized in the luminal membrane of the acinar cells towards birth. During all postnatal developmental stages studied, AQP5 was localized in the luminal and lateral membrane of acinar cells. AQP5 was also detected in the intercalated duct and additional apical membrane staining in the entire intralobular duct was found in the terminal bud stage. These results indicate that AQP5 plays a role during embryonic salivary gland development. PMID- 21818559 TI - Assessment of Young Dong tributary and Imgok Creek impacted by Young Dong coal mine, South Korea. AB - An initial reclamation of the Young Dong coal mine site, located in northeastern South Korea, was completed in 1995. Despite the filling of the adit with limestone, acid rock drainage (ARD) enters Young Dong tributary and is then discharged to Imgok Creek. This ARD carries an average of 500 mg CaCO(3)/l of mineral acidity, primarily as Fe(II) and Al. Before spring runoff, the flow of Imgok Creek is 3.3-4 times greater than that of the tributary and has an alkalinity of 100 mg CaCO(3)/l, which is sufficient to eliminate the mineral acidity and raise the pH to about 6.5. From April through September 2008, there were at least two periods of high surface flow that affects the flow of ARD from the adit. Flow of ARD reaches 2.8 m(3)/min during spring runoff. This raised the concentrations of Fe and Al in the confluence with Imgok Creek. However, by 2 km downstream the pH of the Imgok Creek is 6.5 and only dissolved Fe is above the Korean drinking water criteria (0.30 mg/l). This suggests only a minor impact of Young Dong Creek water on Imgok Creek. Acid digestion of the sediments in Imgok Creek and Young Dong Tributary reveals considerable abundances of heavy metals, which could have a long-term impact on water quality. However, several water based leaching tests, which better simulate the bioavailable metals pool, released only Al, Fe, Mn, and Zn at concentrations exceeding the criteria for drinking water or aquatic life. PMID- 21818560 TI - Geochemical occurrences of arsenic and fluoride in bedrock groundwater: a case study in Geumsan County, Korea. AB - Bedrock groundwaters in Geumsan County, Korea, were surveyed to investigate the distribution and geochemical behaviors of arsenic and fluoride, mobilized through geogenic processes. The concentrations were enriched up to 113 MUg/L for arsenic and 7.54 mg/L for fluoride, and 16% of 150 samples exceeded World Health Organization drinking water guidelines for each element. Simple Ca-HCO(3) groundwater types and positive correlations with pH, Ca, SO(4), and HCO(3) were characteristics of high (>10 MUg/L) As groundwaters. The oxidation reaction of sulfide minerals in metasedimentary rocks and locally mineralized zones seems to be ultimately responsible for the existence of arsenic in groundwater. Desorption process under high pH conditions may also control the arsenic mobility in the study area. High (>1.5 mg/L) F groundwaters were found in the Na-HCO(3) type and with greater depth. Fluoride seemed to be enriched by deep groundwater interaction with granitic rocks, and continuous supply to shallow Ca-HCO(3)-type groundwater kept the concentration high. In the study area, drinking water management should include periodic As and F monitoring in groundwater. PMID- 21818561 TI - Association of PTPN22 gene polymorphism and systemic lupus erythematosus in a cohort of Egyptian patients: impact on clinical and laboratory results. AB - To assess the possible association between the protein tyrosine phosphatases non receptor 22 (PTPN22) gene 1858 CT polymorphism and the predisposition to systemic lupus erythematosus (SLE) in Egyptian patients and its influence on clinical and laboratory parameters. PTPN22 gene 1858 CT polymorphisms were analyzed in forty SLE patients and 20 normal controls by real-time polymerase chain reaction (PCR) technology, using the TaqMan 5-allele discrimination assay. Detailed history, clinical examination, and investigations were done to detect various organ involvement. The homozygous genotype TT was absent in both SLE and controls. The CC genotype was observed in 47.5% SLE and 80% controls; the CT genotype was found in 52.5% patients and 20% controls. The frequencies of the C and T alleles were 74 and 26% in SLE and 90 and 10% in controls, respectively. The presence of CT genotype increased the risk for developing SLE by 4.42. Renal involvement was significantly higher in SLE patients with CT (76.2%) compared to those with CC genotype (42.1%). PMID- 21818563 TI - Regulatory cross-talk of mouse liver polyamine and methionine metabolic pathways: a systemic approach to its physiopathological consequences. AB - Both polyamines and methionine derivatives are nitrogen compounds directly related to the regulation of gene expression. In silico predictions and experimental evidence suggest a cross-talk between polyamine and methionine metabolism in mammalian tissues. Since liver is the major organ that controls nitrogen metabolism of the whole organism, it is the best tissue to further test this hypothesis in vivo. In this work, we studied the effects of the chronic administration of a methionine-supplemented diet (0.5% Met in drinking water for 5 months) on the liver of mice (designated as MET-mice). Metabolic and proteomic approaches were performed and the data obtained were subjected to biocomputational analysis. Results showed that a supplemental methionine intake can indeed regulate biogenic amine metabolism in an in vivo model by multiple mechanisms including metabolic regulation and specific gene demethylation. Furthermore, putative systemic effects were investigated by molecular and cellular biology methods. Among other results, altered expression levels of multiple inflammation and cell proliferation/death balance markers were found and macrophage activation was observed. Overall, the results presented here will be of interest across a variety of biomedical disciplines, including nutrition, orphan diseases, immunology and oncology. PMID- 21818562 TI - Taurine enhances the anorexigenic effects of insulin in the hypothalamus of rats. AB - Taurine is known to modulate a number of metabolic parameters such as insulin secretion and action and blood cholesterol levels. Recent data have suggested that taurine can also reduce body adiposity in C. elegans and in rodents. Since body adiposity is mostly regulated by insulin-responsive hypothalamic neurons involved in the control of feeding and thermogenesis, we hypothesized that some of the activity of taurine in the control of body fat would be exerted through a direct action in the hypothalamus. Here, we show that the intracerebroventricular injection of an acute dose of taurine reduces food intake and locomotor activity, and activates signal transduction through the Akt/FOXO1, JAK2/STAT3 and mTOR/AMPK/ACC signaling pathways. These effects are accompanied by the modulation of expression of NPY. In addition, taurine can enhance the anorexigenic action of insulin. Thus, the aminoacid, taurine, exerts a potent anorexigenic action in the hypothalamus and enhances the effect of insulin on the control of food intake. PMID- 21818564 TI - Translational control of eIF5A in various diseases. AB - Translational control is a crucial component in the development and progression of different diseases. Translational control may involve selective translation of specific mRNAs, which promote cell proliferation or lead to alterations in translation factor levels and activities. Eukaryotic initiation factor 5A (eIF5A) is the only known protein to contain the unusual amino acid hypusine [N (epsilon) (4-amino-2-hydroxybutyl)-lysine], which is formed from the polyamine spermidine by two catalytic steps. eIF5A is involved in translation, elongation and stimulating peptide bond formation. Hypusination of eIF5A is essential for its activity in promoting cell proliferation. Meanwhile, there is evidence that eIF5A is a key protein in the pathogenicity of different diseases, such as diabetes, several human cancers, malaria and HIV-1 infections. Hitherto, the available data suggest that eIF5A has a role of a cell context-dependent function being more proliferative in the case of several human cancers and being involved under stress conditions in diabetes. Secondly, in HIV-1 infections and in diabetes, eIF5A also has a nuclear function by its sequence-specific binding of mRNAs as an mRNA-shuttle in conjunction with nuclear membrane export proteins. This binding may also influence the half-lives of mRNAs or their sequestration. Based on these data, there is a considerable therapeutic interest in eIF5A as a selective target for drug development through inhibition of hypusination. PMID- 21818565 TI - Polyamine flux analysis by determination of heavy isotope incorporation from 13C, 15N-enriched amino acids into polyamines by LC-MS/MS. AB - The study of polyamine flux, i.e. the circulating flow of polyamines through the interconnected biosynthetic and catabolic pathways, is of considerable interest because of the established links between the polyamine metabolism and many diseases, such as cancer and diabetes. To study polyamine flux in detail, a novel method based on following the label incorporation from the (13)C, (15)N-labeled polyamine precursors, arginine, methionine and ornithine, into polyamines by LC MS/MS was implemented. This methodology was tested on three distinct cell lines with different spermidine/spermine-N (1)-acetyltransferase (SSAT) expression levels, i.e. non-transgenic, transgenic and knockout. These trials allowed the identification of the critical conditions for the successful polyamine flux measurement, such as the functional time frame of label incorporation, until plateau phase with the selected precursor is reached. The novel LC-MS/MS-based method for polyamine flux overcame the limitations of previous existing methodologies, with baseline separation of the different polyamine species and the exact quantification of the incorporated label. Moreover, the obtained results clearly show that the increased SSAT expression is associated with accelerated polyamine flux. PMID- 21818566 TI - Polyamines and transglutaminase activity are involved in compatible and self incompatible pollination of Citrus grandis. AB - Pollination of pummelo (Citrus grandis L. Osbeck) pistils has been studied in planta by adding compatible and self-incompatible (SI) pollen to the stigma surface. The pollen germination has been monitored inside the pistil by fluorescent microscopy showing SI altered morphologies with irregular depositions of callose in the tube walls, and heavy callose depositions in enlarged tips. The polyamine (PA) content as free, perchloric acid (PCA)-soluble and -insoluble fractions and transglutaminase (TGase) activity have been analyzed in order to deepen their possible involvement in the progamic phase of plant reproduction. The conjugated PAs in PCA-soluble fraction were definitely higher than the free and the PCA-insoluble forms, in both compatible and SI pollinated pistils. In pistils, pollination caused an early decrease of free PAs and increase of the bound forms. The SI pollination, showed highest values of PCA-soluble and insoluble PAs with a maximum in concomitance with the pollen tube arrest. As TGase mediates some of the effects of PAs by covalently binding them to proteins, its activity, never checked before in Citrus, was examined with two different assays. In addition, the presence of glutamyl-PAs confirmed the enzyme assay data and excluded the possibility of a misinterpretation. The SI pollination caused an increase in TGase activity, whereas the compatible pollination caused its decrease. Similarly to bound PAs, the glutamyl-PAs and the enzyme activity peaked in the SI pollinated pistils in concomitance with the observed block of the pollen tube growth, suggesting an involvement of TGase in SI response. PMID- 21818567 TI - TG2, a novel extracellular protein with multiple functions. AB - TG2 is multifunctional enzyme which can be secreted to the cell surface by an unknown mechanism where its Ca(2+)-dependent transamidase activity is implicated in a number of events important to cell behaviour. However, this activity may only be transient due to the oxidation of the enzyme in the extracellular environment including its reaction with NO probably accounting for its many other roles, which are transamidation independent. In this review, we discuss the novel roles of TG2 at the cell surface and in the ECM acting either as a transamidating enzyme or as an extracellular scaffold protein involved in cell adhesion. Such roles include its ability to act as an FN co-receptor for beta integrins or in a heterocomplex with FN interacting with the cell surface heparan sulphate proteoglycan syndecan-4 leading to activation of PKCalpha. These different properties of TG2 involve this protein in various physiological processes, which if not regulated appropriately can also lead to its involvement in a number of diseases. These include metastatic cancer, tissue fibrosis and coeliac disease, thus increasing its attractiveness as both a therapeutic target and diagnostic marker. PMID- 21818569 TI - Evaluation of organ-specific glucose metabolism by 18F-FDG in insulin receptor substrate-1 (IRS-1) knockout mice as a model of insulin resistance. AB - OBJECTIVE: Insulin resistance (IR) is a physiological condition in which the body produces insulin but does not result in a sufficient biological effect. Insulin resistance is usually asymptomatic but is associated with health problems and is a factor in the metabolic syndrome. The aim of the present study is to clarify organ-specific insulin resistance in normal daily conditions using [(18)F]-2 fluoro-2-deoxy-D: -glucose ([(18)F]-FDG). METHODS: The biodistribution of [(18)F] FDG was examined in insulin receptor substrate-1 (IRS-1) knockout mice, an animal model of skeletal muscle insulin resistance, and C57BL/6J (wild-type) mice with and without insulin loading. Mice received 0.5 MBq of [(18)F]-FDG injected into the tail vein, immediately followed by nothing (control cohorts) or an intraperitoneal injection of 1.5 mU/g body weight of human insulin as an insulin loading test. Blood glucose concentrations for all of the experimental animals were assessed at 0, 20, 40, and 60 min post-injection. The mice were subsequently killed, and tissue was collected for evaluation of [(18)F]-FDG biodistribution. The radioactivity of each organ was measured using a gamma counter. RESULTS: In the absence of insulin, the blood glucose concentrations of wild-type mice (132 +/- 26 mg/dl) and IRS-1 knockout mice (134 +/- 18 mg/dl) were not significantly different. Blood glucose concentrations decreased following insulin administration, with lower concentrations in wild-type mice than in knockout mice at 20, 40, and 60 min. A statistically significant difference in [(18)F]-FDG uptake between wild-type mice and IRS-1 knockout mice was confirmed in the heart, abdominal muscle, and femoral muscle. With insulin loading, [(18)F]-FDG uptake in the heart, back muscle, and abdominal muscle was significantly increased compared to without insulin loading in both wild-type mice and knockout mice. CONCLUSION: Our results showed that IR significantly affected [(18)F]-FDG uptake in the heart in normal daily conditions. IR was associated with decreased [(18)F]-FDG uptake in the heart and was readily observed in the absence of insulin loading. [(18)F] FDG-positron emission tomography (PET) could be a useful tool for evaluating insulin resistance in images by investigating tissue-specific differences in [(18)F]-FDG uptake. PMID- 21818568 TI - Bisphosphonate-associated osteonecrosis of the mandible: reliable soft tissue reconstruction using a local myofascial flap. AB - For the treatment of bisphosphonate-associated osteonecrosis of the jaw (BP associated ONJ), poor cure rates are reported. In many cases, repeated osseous exposition and infection may occur. The currently recommended management of affected patients is antibiotic treatment and bony decortication, which is often complicated by soft tissue deficits due to chronic infection. In severe cases osteonecrosis can be managed often only by continuity resections of the mandible. For this purpose, we developed a new surgical procedure, which allows an effective closure of difficult jaw wounds in the lateral mandible. In the last 3 years, 20 patients with BP-associated osteonecrosis of the lower jaw were treated successfully with a modified defect-covering method using a myofascial flap. A mylohyoid muscle flap was detached from mylohyoid line and used to cover the bony defect. During 19 months mean follow-up, 90% of patients were asymptomatic, the oral mucosa was intact, and no exposed bone was observed. In consequence, we are able to demonstrate that a mylohyoid muscle flap provides a reliable wound closure in the lower jaw in patients treated with BPs. Although there are still no consensual therapy guidelines for patients affected by BP-associated ONJ, the results of the presented study provide evidence for an effective surgical therapy with long-term success. Covering compromised bone with well-vascularized tissue, a muscle flap, increased healing chances by enabling and supporting the necessary nutrition and defense against opportunistic infections. This therapy concept showed a good clinical outcome. PMID- 21818570 TI - Establishing a cGMP pancreatic islet processing facility: the first experience in Iran. AB - It has been predicted that one of the greatest increase in prevalence of diabetes will happen in the Middle East bear in the next decades. The aim of standard therapeutic strategies for diabetes is better control of complications. In contrast, some new strategies like cell and gene therapy have aimed to cure the disease. In recent years, significant progress has occurred in beta-cell replacement therapies with a progressive improvement of short-term and long term outcomes. In year 2005, considering the impact of the disease in Iran and the promising results of the Edmonton protocol, the funding for establishing a current Good Manufacturing Practice (cGMP) islet processing facility by Endocrinology and Metabolism Research Center was approved by Tehran University of Medical Sciences. Several islet isolations were performed following establishment of cGMP facility and recruitment of all required equipments for process validation and experimental purpose. Finally the first successful clinical islet isolation and transplantation was performed in September 2010. In spite of a high cost of the procedure it is considered beneficial and may prevent long term complications and the costs associated with secondary cares. In this article we will briefly describe our experience in setting up a cGMP islet processing facility which can provide valuable information for regional countries interested to establish similar facilities. PMID- 21818571 TI - Percent tumor volume predicts biochemical recurrence after radical prostatectomy: multi-institutional data analysis. AB - BACKGROUND: To investigate the prognostic significance of percent tumor volume (PTV) in relation to the surgical margin status in men with prostate cancer after radical prostatectomy (RP). METHODS: Clinical and pathological data from 1,567 patients treated with RP only between 1995 and 2007 at participating institutions were reviewed. PTV was determined by the sum of all visually estimated tumor foci on every section. Biochemical recurrence (BCR) was defined as 2 consecutive increases in prostate-specific antigen (PSA) > 0.2 ng/ml and various clinicopathological variables were tested for prognostication of recurrence-free survival. RESULTS: Serum PSA at surgery was 12.5 +/- 16.8 ng/ml and pathological stage was T2 in 899 (57.4%) patients. Surgical Gleason score was 7 in 842 patients (53.7%), higher than 7 in 250 (16%) patients, and in 32% of the patients, surgical margin was positive. Mean PTV was 15.7% and demonstrated a significant positive correlation with serum PSA, all pathological variables and BCR. On multivariate analysis, preoperative PSA (p = 0.012), surgical Gleason score (p < 0.0001, HR 2.183, 95% CI 1.778-2.681), and PTV (<=5, 5.1-15, >15%; p < 0.0001, HR 1.393, 95% CI 1.183-1.641) were independently prognostic of recurrence free survival. Pathological stage demonstrated a significant relationship with BCR but was not independently prognostic in the multivariate model. CONCLUSION: In men with prostate cancer, preoperative PSA, surgical Gleason score, and PTV are independent predictors of recurrence-free survival after RP. PMID- 21818572 TI - Extracellular ATP reduces tumor sphere growth and cancer stem cell population in glioblastoma cells. AB - Glioblastoma is the most aggressive tumor in the CNS and is characterized by having a cancer stem cell (CSC) subpopulation essential for tumor survival. The purinergic system plays an important role in glioma growth, since adenosine triphosphate (ATP) can induce proliferation of glioma cells, and alteration in extracellular ATP degradation by the use of exogenous nucleotidases dramatically alters the size of gliomas in rats. The aim of this work was to characterize the effect of the purinergic system on glioma CSCs. Human U87 glioma cultures presented tumor spheres that express the markers of glioma cancer stem cells CD133, Oct-4, and Nanog. Messenger RNA of several purinergic receptors were differently expressed in spheres when compared to a cell monolayer not containing spheres. Treatment of human gliomas U87 or U343 as well as rat C6 gliomas with 100 MUM of ATP reduced the number of tumor spheres when grown in neural stem cell medium supplemented with epidermal growth factor and basic fibroblast growth factor. Moreover, ATP caused a decline in the number of spheres observed in culture in a dose-dependent manner. ATP also reduces the expression of Nanog, as determined by flow cytometry, as well as CD133 and Oct-4, as analyzed by flow cytometry and RT-PCR in U87 cells. The differential expression of purinergic receptor in tumor spheres when compared to adherent cells and the effect of ATP in reducing tumor spheres suggest that the purinergic system affects CSC biology and that ATP may be a potential agonist for differentiation therapy. PMID- 21818573 TI - Three "hotspots" important for adenosine A(2B) receptor activation: a mutational analysis of transmembrane domains 4 and 5 and the second extracellular loop. AB - G protein-coupled receptors (GPCRs) are a major drug target and can be activated by a range of stimuli, from photons to proteins. Despite the progress made in the last decade in molecular and structural biology, their exact activation mechanism is still unknown. Here we describe new insights in specific regions essential in adenosine A(2B) receptor activation (A(2B)R), a typical class A GPCR. We applied unbiased random mutagenesis on the middle part of the human adenosine A(2B)R, consisting of transmembrane domains 4 and 5 (TM4 and TM5) linked by extracellular loop 2 (EL2), and subsequently screened in a medium-throughput manner for gain-of function and constitutively active mutants. For that purpose, we used a genetically engineered yeast strain (Saccharomyces cerevisiae MMY24) with growth as a read-out parameter. From the random mutagenesis screen, 12 different mutant receptors were identified that form three distinct clusters; at the top of TM4, in a cysteine-rich region in EL2, and at the intracellular side of TM5. All mutant receptors show a vast increase in agonist potency and most also displayed a significant increase in constitutive activity. None of these residues are supposedly involved in ligand binding directly. As a consequence, it appears that disrupting the relatively "silent" configuration of the wild-type receptor in each of the three clusters readily causes spontaneous receptor activity. PMID- 21818575 TI - Robotic-assisted sacrocolpopexy/sacrocervicopexy repair of pelvic organ prolapse: initial experience. AB - PURPOSE: To present the short-term surgical outcomes of robotic-assisted sacrocolpopexy and sacrocervicopexy. METHODS: Between January 2009 and September 2010, 12 patients underwent robotic-assisted pelvic organ prolapse repair including six sacrocolpopexy and six sacrocervicopexy. Patients' demographics, surgical procedures, operative and postoperative complications, hospital stay, conversion to laparotomy, time data including all operative times and estimated blood loss (EBL) were recorded. RESULTS: All surgeries were completed robotically with no conversion to laparotomy. The average operative time for the robotic assisted sacrocolpopexy (RASCP) was 150.5 +/- 29.6 min (range 114-189) and the mean console time was calculated as 123.6 +/- 34.2 min (range 84-166). The averages of the dissection and the suturation time were 34.8 +/- 24.3 min (range 13-72) and 63.3 +/- 21.8 min (range 28-95), respectively. The mean length of hospitalization was 2.8 +/- 0.7 days (range 2-4) and the mean EBL was calculated as 12.5 +/- 4.1 ml (range 10-20). There was one intraoperative complication. The mean age and body mass index of the patients underwent robotic-assisted sacrocervicopexy were 38.1 +/- 6.5 years (29-47) and 28.4 +/- 5.8 kg/m(2) (18.6 34.4), respectively. The mean operating times were calculated as follows: set-up time was 25.6 +/- 4.0 min, docking time was 3 +/- 0.8 min, dissection time was 28.6 +/- 7.7 min, suturation time was 70.8 +/- 10.9 min and console time was 123.1 +/- 23.6 min. There were no recurrences during the follow-up period (12 months) in both groups of the patients. CONCLUSION: The use of the robotic system during pelvic organ prolapse repair is feasible, safe and may support the surgeon during dissection and suturing at the level of sacral promontory. PMID- 21818574 TI - Expression of P2X(2) and P2X (3) receptors in the rat carotid sinus, aortic arch, vena cava, and heart, as well as petrosal and nodose ganglia. AB - With single- and double-labeling immunofluorescence techniques, the distribution patterns and morphological characteristics of P2X(2)- and P2X(3)-immunoreactive nerve fiber terminals and neuronal bodies have been studied in the main circulatory system baroreceptors and the nodose and petrosal ganglia of rats. A high density of P2X(2)- and P2X(3)-immunoreactive nerve fiber terminals was detected in the carotid sinus. P2X(2)- and P2X(3)-immunoreactive nerve fiber terminals were also distributed widely in the aortic arch, atrium, vena cava, and ventricles. Almost all the P2X(2)-immunoreactive nerve fiber terminals were immunoreactive for P2X(3) receptors. P2X(2)- and P2X(3)-immunoreactive neuronal bodies were also detected in the nodose and petrosal ganglia, which are the sources of the P2X(2)- and P2X(3)-immunoreactive nerve terminals. P2X(2) and P2X(3) receptors were expressed in the same ganglionic neurons. These data indicate that extracellular ATP, via the homomeric P2X(2) and P2X(3) receptors, and heteromeric P2X(2/3) receptor in the sensory receptors of carotid sinus, aortic arch, atrium, and vena cava, may be involved in the regulation of systematic circulation blood pressure. PMID- 21818576 TI - Effects of gabapentin on postoperative pain, nausea and vomiting after abdominal hysterectomy: a double blind randomized clinical trial. AB - PURPOSE: Gabapentin has demonstrated analgesic effects in some studies. This double blind randomized clinical trial (RCT) was conducted to evaluate whether the pre-emptive use of gabapentin 600 mg could reduce postoperative pain, nausea and vomiting, and meperidine consumption in patients after hysterectomy. METHODS: Between 2009 and 2010, a total of 170 patients who were candidates for abdominal hysterectomy were assessed for eligibility to enter the study. Thirty patients were excluded for different reasons; and 140 included patients were randomly assigned to one of two groups according to the method of treatment, gabapentin or placebo, in a double-blind manner before hysterectomy. Postoperatively, the pain was assessed on a visual analogue scale (VAS) at 1, 4, 8, 12 and 24 h at rest. Meperidine intramuscularly was used to treat postoperative pain on VAS score and patients demand. Total meperidine and anti emetic drug consumption in the first 24 h after surgery was also recorded. The trial is registered at irct.ir, number IRCT201106186829N1. RESULTS: Patients in the gabapentin group had significantly lower VAS scores at all time intervals, than those in the placebo group. The total meperidine consumed in the gabapentin group was significantly less than in the placebo group. Postoperative nausea and vomiting (PONV) and anti emetic drug consumption were significantly decreased in gabapentin group. CONCLUSION: Pre emptive use of gabapentin 600 mg orally, significantly decreases postoperative pain and PONV, and also rescues analgesic and anti emetic drug requirements in patients who undergo abdominal hysterectomy. PMID- 21818577 TI - Internalization of odorant-binding proteins into the mouse olfactory epithelium. AB - The detection of odorants in vertebrates is mediated by chemosensory neurons that reside in the olfactory epithelium of the nose. In land-living species, the hydrophobic odorous compounds inhaled by the airstream are dissolved in the nasal mucus by means of specialized globular proteins, the odorant-binding proteins (OBPs). To assure the responsiveness to odors of each inhalation, a rapid removal of odorants from the microenvironment of the receptor is essential. In order to follow the fate of OBP/odorant complexes, a recombinant OBP was fluorescently labeled, loaded with odorous compounds, and applied to the nose of a mouse. Very quickly, labeled OBP appeared inside the sustentacular cells of the epithelium. This uptake occurred only when the OBP was loaded with appropriate odorant compounds. A search for candidate transporters that could mediate such an uptake process led to the identification of the low density lipoprotein receptor Lrp2/Megalin. In the olfactory epithelium, megalin was found to be specifically expressed in sustentacular cells and the Megalin protein was located in their microvilli. In vitro studies using a cell line that expresses megalin revealed a rapid internalization of OBP/odorant complexes into lysosomes. The uptake was blocked by a Megalin inhibitor, as was the internalization of OBPs into the sustentacular cells of the olfactory epithelium. The results suggest that a Megalin-mediated internalization of OBP/odorant complexes into the sustentacular cells may represent an important mechanism for a rapid and local clearance of odorants. PMID- 21818578 TI - Complementary expression of EphB receptors and ephrin-B ligand in the pyloric and duodenal epithelium of adult mice. AB - Eph receptors and ephrin ligands are membrane-bound cell-cell communication molecules that regulate the spatial organisation of cells in various tissues by repulsive or adhesive signals arising from contact between EphB- and ephrin bearing cells. However, the expression and functions of Eph receptors in the gastric epithelium and Brunner's glands are virtually unknown. We detected several EphB receptors and ephrin-B ligands in the pyloric and duodenal mucosa of the adult mouse by RT-PCR amplification. Immunostaining showed complementary expression patterns, with ephrin-B1 being preferentially expressed in the superficial part and EphB receptors in the deeper part of both epithelia. In the gastric pylorus, ephrin-B1 was expressed in pit cells and proliferating cells of the isthmus. In contrast, EphB2, EphB3, and EphB4 were expressed in pyloric glandular cells and proliferating cells of the isthmus. In the duodenum, ephrin B1 was expressed in cells lining the ducts of Brunner's glands as well as those covering villi and the upper portion of the crypts of Lieberkuhn. In contrast, EphB2 and EphB3 were expressed in the gland segment of Brunner's glands and the lower portion of the crypts and EphB4, in the crypts. In both mucosae, EphB2, EphB3, and EphB4 were found to be tyrosine phosphorylated, suggesting that EphB/ephrin-B signalling might occur preferentially in the isthmus, crypts, and duct-gland transition of Brunner's glands, where the receptor and ligand expression overlaps. Based on these findings, we propose that EphB/ephrin-B signalling may regulate cell positioning within the pyloric and duodenal epithelium. PMID- 21818579 TI - Closer association of mitochondria with lipid droplets in hepatocytes and activation of Kupffer cells in resveratrol-treated senescence-accelerated mice. AB - Resveratrol has been extensively investigated because of its beneficial effects in delaying age-related diseases, thus extending the lifespan, possibly by mimicking calorie restriction. For this study, cell biological techniques were used to examine how resveratrol influenced hepatocytes in a senescence accelerated mouse P10 (SAMP10), treated from 35 to 55 weeks of age, with special emphasis on the relationship between mitochondria and lipid droplets. Survival ratio, body weight and food intake of SAMP10 did not differ significantly between the control and resveratrol-treated groups. Compared with the control, the treated livers were altered significantly, as follows. Lipid droplets were reduced and mitochondria were increased in number in hepatocytes. Phosphorylation of acetyl-CoA carboxylase and the expression of both the mitochondrial ATP synthase beta subunit and Mn superoxide dismutase (SOD2) were increased. Mitochondria, expressing more SOD2, were more tightly associated with lipid droplets, suggesting the enhancement of lipolysis through the activation of mitochondrial functions. Cathepsin D expression was less in hepatocytes but enhanced in Kupffer cells, which were increased in number and size with more numerous lysosome-related profiles. Together, resveratrol may activate mitochondria resulting in consuming lipids, and may also activate Kupffer cells by which a beneficial milieu for hepatocytes may be created. Both might be related to improvement in the functioning of the liver, which is the organ that is central to metabolic regulation. PMID- 21818580 TI - Functional haplotypes of Fc gamma (Fcgamma) receptor (FcgammaRIIA and FcgammaRIIIB) predict risk to repeated episodes of severe malarial anemia and mortality in Kenyan children. AB - Development of protective immunity against Plasmodium falciparum is partially mediated through binding of malaria-specific IgG to Fc gamma (gamma) receptors. Variations in human FcgammaRIIA-H/R-131 and FcgammaRIIIB-NA1/NA2 affect differential binding of IgG sub-classes. Since variability in FcgammaR may play an important role in severe malarial anemia (SMA) pathogenesis by mediating phagocytosis of red blood cells and triggering cytokine production, the relationship between FcgammaRIIA-H/R131 and FcgammaRIIIB-NA1/NA2 haplotypes and susceptibility to SMA (Hb < 6.0 g/dL) was investigated in Kenyan children (n = 528) with acute malaria residing in a holoendemic P. falciparum transmission region. In addition, the association between carriage of the haplotypes and repeated episodes of SMA and all-cause mortality were investigated over a 3-year follow-up period. Since variability in FcgammaR can alter interferon (IFN)-gamma production, a mediator of innate and adaptive immune responses, functional associations between the haplotypes and IFN-gamma were also explored. During acute malaria, children with SMA had elevated peripheral IFN-gamma levels (P = 0.006). Although multivariate logistic regression analyses (controlling for covariates) revealed no associations between the FcgammaR haplotypes and susceptibility to SMA during acute infection, the FcgammaRIIA-131H/FcgammaRIIIB NA1 haplotype was associated with decreased peripheral IFN-gamma (P = 0.046). Longitudinal analyses showed that carriage of the FcgammaRIIA-131H/FcgammaRIIIB NA1 haplotype was associated with reduced risk of SMA (RR 0.65, 95% CI 0.46-0.90; P = 0.012) and all-cause mortality (P = 0.002). In contrast, carriers of the FcgammaRIIA-131H/FcgammaRIIIB-NA2 haplotype had increased susceptibility to SMA (RR 1.47, 95% CI 1.06-2.04; P = 0.020). Results here demonstrate that variation in the FcgammaR gene alters susceptibility to repeated episodes of SMA and mortality, as well as functional changes in IFN-gamma production. PMID- 21818581 TI - Emerging roles of molecular chaperones and co-chaperones in selective autophagy: focus on BAG proteins. AB - Macroautophagy is a catabolic process by which the cell degrades cytoplasmic components through the lysosomal machinery. While initially acknowledged as a rather unspecific bulk degradation process, growing lines of evidence indicate the selectivity of macroautophagy pathways in the removal of misfolded or aggregated proteins. How such substrates are recognized and specifically targeted to the macroautophagy machinery has become a hotspot of investigation, and recent evidence suggests that here molecular chaperones and co-chaperones play a central role. One emerging pathway is mediated by the co-chaperone protein Bcl-2 associated athanogene 3 (BAG 3) which seems to utilize the specificity of molecular chaperones (heat-shock proteins) towards non-native proteins as basis for targeted macroautophagic degradation. In this short review, we focus on the molecular interplay between the macroautophagy system and molecular chaperones and highlight the relevance of the pathway mediated by BAG3 to aging and age associated protein-misfolding diseases. PMID- 21818582 TI - Spinophilin regulates central angiotensin II-mediated effect on blood pressure. AB - Central angiotensin II (AngII) plays an important role in the regulation of the sympathetic nervous system. The underlining molecular mechanisms are largely unknown. Spinophilin (SPL) is a regulator of G protein-coupled receptor signaling. Deletion of SPL induces sympathetically mediated arterial hypertension in mice. We tested the hypothesis that SPL restrains blood pressure (BP) by regulating AngII activity. We equipped SPL(-/-) and SPL(+/+) mice with telemetric devices and applied AngII (1.0 mg kg(-1) day(-1), minipumps) or the AngII subtype 1 receptor (AT1-R) blocker valsartan (50 mg kg(-1) day(-1), gavage). We assessed autonomic nervous system activity through intraperitoneal application of trimethaphan, metoprolol, and atropine. We also tested the effect of intracerebroventricular (icv) AngII on blood pressure in SPL(-/-) and in SPL(+/+) mice. Chronic infusion of AngII upregulates SPL expression in the hypothalamus of SPL(+/+) mice. Compared with SPL(+/+) mice, SPL(-/-) mice showed a greater increase in daytime BP with AngII (19.2 +/- 0.8 vs. 13.5 +/- 1.6 mmHg, p < 0.05). SPL(-/-) showed a greater depressor response to valsartan. BP and heart rate decreased more with trimethaphan and metoprolol in AngII-treated SPL(-/-) than in AngII-treated SPL(+/+) mice. SPL(-/-) mice responded more to icv AngII. Furthermore, brainstem AT1-R and AngII type 2 receptor (AT2-R) expression was reduced in SPL(-/-) mice. AngII treatment normalized AT1-R and AT2-R expression levels. In summary, our findings suggest that SPL restrains AngII-mediated sympathetic nervous system activation. SPL is a hitherto unrecognized molecule with regard to central blood pressure control and may pave the way to novel strategies for the treatment of hypertension. PMID- 21818583 TI - Recruitment and retention of Latino immigrant families in prevention research. AB - The development and testing of culturally competent interventions relies on the recruitment and retention of ethnic minority populations. Minority immigrants are a population of keen interest given their widespread growth, needs, and contributions to communities in which they settle, and particularly recent immigrants from Mexico and Central and South American countries. However, recruitment and retention strategies for entirely immigrant samples are rarely discussed in the literature. The current article describes lessons learned from two family-focused longitudinal prevention research studies of Latino immigrants in Oregon-the Adolescent Latino Acculturation Study (ALAS) and the Latino Youth and Family Empowerment Project-II (LYFE-II). Social, legal, economic, and political contexts are considered that shape Latino immigrants' experiences in their home countries as well as in the United States. The implications of these contexts for effective recruitment and retention strategies are discussed. PMID- 21818584 TI - Time trends and age-related etiologies of pediatric hydrocephalus: results of a groupwise analysis in a clinical cohort. AB - OBJECTIVE: The current study aimed at evaluating experience with pediatric hydrocephalus and reviewing time trends and age-related differences in etiology, management, and outcomes of pediatric hydrocephalus at a tertiary care center in a south Asian country. METHODS: We conducted a retrospective cohort study based on case note review of pediatric patients (age, 1 month to 15 years) with hydrocephalus managed at Aga Khan University Hospital Karachi, over an 18-year period (1988-2005). For analysis, the study period was divided into two epochs (period A, 1988-1996; period B, 1997-2005) and study population was divided into two age groups (0-12 months and 1-15 years). RESULTS: A total of 338 cases of pediatric hydrocephalus were identified. Most common etiology of pediatric hydrocephalus was meningitis (38.1%), followed by congenital hydrocephalus (20.4%) and brain tumors (8.3%). Shunt infection and blockage were seen in 38 (11.2%) and 54 (16.0%) children, respectively; 67 (19.8%) required shunt revision. Highest rates of shunt failure were seen in bacterial meningitis (35.3%) and aqueductal stenosis (29.2%). Neurological and/or cognitive deficits were observed more frequently in children under 1 year of age (P = 0.029). Duration of hospital stay in period A was significantly higher than in period B (P < 0.001). Mortality occurred in 38 (11.2%); it did not differ between two epochs and age groups (P = 0.059 and P = 0.865, respectively). Highest mortality was associated with intraventricular hemorrhage (23.1%) and brain tumors (21.4%). CONCLUSION: Despite recent advancements, hydrocephalus is still associated with high rate of shunt failure and mortality. Factors associated with poor outcome include younger age group and etiology of hydrocephalus. PMID- 21818585 TI - Inhibition of fumarase by bismuth(III): implications for the tricarboxylic acid cycle as a potential target of bismuth drugs in Helicobacter pylori. AB - Helicobacter pylori causes various gastric diseases, such as gastritis, peptic ulcerations and gastric cancer. Triple therapy combining bismuth compounds with two antibiotics is the cornerstone of the treatment of H. pylori infections. Up to now, the molecular mechanisms by which bismuth inhibits the growth of H. pylori are far from clear. In the bacterial tricarboxylic acid (TCA) cycle, fumarase catalyses the reversible hydration of fumarate to malic acid. Our previous proteomic work indicated that fumarase was capable of bismuth-binding. The interactions as well as the inhibitory effects of bismuth to fumarase have been characterized in this study. The titration of bismuth showed that each fumarase monomer binds one mol equiv of Bi(3+), with negligible secondary structural change. Bismuth-binding results in a near stoichiometric inactivation of the enzyme, leading to an apparent non-competitive mechanism as reflected by the Lineweaver-Burk plots. Our collective data indicate that the TCA cycle is a potential molecular target of bismuth drugs in H. pylori. PMID- 21818587 TI - Above- or below-elbow casts for distal third forearm fractures in children? A meta-analysis of the literature. AB - INTRODUCTION: Fractures of the distal third forearm are common fractures in childhood. Most of these fractures can be treated non-operatively by means of closed reduction and immobilization. The purpose of this meta-analysis is to investigate whether above- or below-elbow cast should be considered the first choice for conservative treatment. MATERIALS AND METHODS: A search was performed in multiple databases to identify all the studies comparing above- and below elbow cast for the treatment of distal third forearm fractures in children. All RCT's or CCT's were assessed for eligibility. Quality was assessed by the Cochrane Musculoskeletal Injuries Group assessment. Data were pooled using RevMan 5.0 RESULTS: Three trials involving a total of 300 participants were included. A total of 142 fractures were treated with a below-elbow cast (BEC) versus 158 with an above-elbow cast (AEC). Loss of reduction was encountered in 17 and 36 cases, respectively [odds ratio 0.44 (0.22-0.87)]. For combined radius and ulna fractures 15 of 97 in the BEC group and 34 out of 122 in the AEC group showed loss of reduction [odds ratio 0.55 (0.26-1.15)]. Children treated with BEC missed less school days [mean difference 1.12 (-1.52 to -0.59)], and encountered less difficulties in daily living [odds ratio 112.41 (6.58-1920.77)]. CONCLUSION: Due to heterogeneity, the trials are not fully compared. Based on the presented meta analysis, we conclude that BEC is not inferior to AEC so that this is a valid treatment option for distal third forearm fractures. PMID- 21818589 TI - Oncological and cosmetic outcome in breast cancer patients undergoing "moving window" operation. AB - An inappropriate skin incision on the breast reduces the cosmetic benefit of breast-conserving surgery (BCS). To improve the cosmetic outcome, we have performed "moving window" operation in which BCS can be performed via a periareolar incision (periareolar approach) and/or axillary incision (axillary approach) under direct visualization. Axillary lymph node dissection is also performed via an axillary incision. The periareolar and axillary approaches were used in 65 and 43 patients, respectively. Average operation time was 130 min in periareolar approach and 131 min in axillary approach. Average blood loss was 37 and 50 ml, respectively. Postoperatively, the surgical margin of breast tissue was histologically confirmed to be negative in 107 (99%) of 108 patients, one patients underwent subsequently reoperation because of positive surgical margin. Fifty-two patients (85%) in periareolar approach and 37 patients (86%) in axillary approach had excellent or good cosmetic results. With a mean follow-up of 36 months, four patients developed in-breast recurrence, but three of them had neoadjuvant chemotherapy before surgery. The moving window operation can improve cosmetic outcome of BCS without compromising oncological safety. Moreover, it can reduce operation time and blood loss in comparison to endoscope-assisted BCS. PMID- 21818590 TI - Inhibition of aldehyde dehydrogenase (ALDH) activity reduces chemotherapy and radiation resistance of stem-like ALDHhiCD44+ human breast cancer cells. AB - The majority of breast cancer deaths are because of ineffective treatment of metastatic disease. We previously identified a subpopulation of cells in human breast cancer cell lines that demonstrate high activity of aldehyde dehydrogenase (ALDH) and high expression of CD44. These ALDH(hi)CD44(+) cells displayed enhanced metastatic behavior in vitro and in vivo relative to ALDH(low)CD44(-) cells. The goal of this study was to test the hypothesis that ALDH(hi)CD44(+) breast cancer cells are more resistant to standard cancer therapy, and that inhibiting ALDH activity through all-trans retinoic acid (ATRA) or the specific ALDH inhibitor diethylaminobenzaldehyde (DEAB) sensitizes these cells to treatment. ALDH(hi)CD44(+) and ALDH(low)CD44(-) populations were isolated from MDA-MB-231 and MDA-MB-468 cells lines and exposed to chemotherapy (doxorubicin/paclitaxel) or radiotherapy +/- ATRA or DEAB. Cell populations were assessed for differences in survival, colony formation, and protein expression related to therapy resistance and differentiation. Significantly more ALDH(hi)CD44(+) cells survived chemotherapy/radiotherapy relative to ALDH(low)CD44(-) cells (P < 0.001). Glutathione-S-transferase pi, p-glycoprotein, and/or CHK1 were overexpressed in ALDH(hi)CD44(+) populations compared with ALDH(low)CD44(-) populations (P < 0.05). Pre-treatment of cell populations with DEAB or ATRA had no effect on ALDH(low)CD44(-) cells, but resulted in significant initial sensitization of ALDH(hi)CD44(+) cells to chemotherapy/radiotherapy. However, only DEAB had a long-term effect, resulting in reduced colony formation (P < 0.01). ATRA also significantly increased expression of CK8/18/19 in MDA-MB 468 ALDH(hi)CD44(+) cells compared with control (P < 0.05). Our novel findings indicate that ALDH(hi)CD44(+) breast cancer cells contribute to both chemotherapy and radiation resistance and suggest a much broader role for ALDH in treatment response than previously reported. PMID- 21818591 TI - Glucocorticoid receptor and breast cancer. AB - Stress enhances glucocorticoid (GC) synthesis, which alters inflammation and immune responses, as well as cellular proliferation and apoptosis in a number of tissues. Increasingly, stress has been associated with cancer progression, and in particular in breast cancer. Consequently, an operational glucocorticoid receptor system in breast tissue influences breast cancer development. In this review, we summarize the data on the GC/GR system in normal and tumoral breast tissue. We also review the molecular mechanisms by which GCs control apoptosis and proliferation in breast cancer models and how GCs alter the chemotherapy of breast cancer treatment when used in combination. Finally, we discuss the participation of GR in breast tumorigenesis under hormone replacement therapy. PMID- 21818594 TI - Expert's comment concerning Grand Rounds case entitled "The routine intra operative use of pulse oximetry for monitoring can prevent severe thromboembolic complications in anterior surgery" (by M.A. Konig, Y. Leung, S. Jurgens, S. MacSweeney and B.M. Boszczyk). AB - Routine monitoring of left extremity circulation with pulse oximetry during anterior lumbar surgery may help diagnose left iliac artery thrombosis and will lead to quick treatment of this potentially catastrophic complication. PMID- 21818595 TI - Sagittal balance of the spine: consequences for the treatment of the degenerative spine. PMID- 21818596 TI - Adult de novo lumbar scoliosis. Posterior instrumented fusion with Smith-Peterson osteotomy, decompression and management of postoperative infection. PMID- 21818597 TI - Thoracolumbar imbalance analysis for osteotomy planification using a new method: FBI technique. AB - INTRODUCTION: Treatment of spine imbalance by posterior osteotomy is a valuable technique. Several surgical techniques have been developed and proposed to redress the vertebral column in harmonious kyphosis in order to recreate correct sagittal alignment. Although surgical techniques proved to be adequate, preoperative planning still is mediocre. Multiple suggestions have been proposed, from cutting tracing paper to ingenious mathematical formulas and computerised models. The analysis of the pelvic parameters to try to recover the initial shape of the spine before the spine imbalance occurred is very important to avoid mistakes during the osteotomy planification. MATERIAL AND METHOD: The authors proposed their method for the osteotomy planning paying attention to the pelvic, and spine parameters and in accordance with Roussouly's classification. The pre operative planning is based on a full-body X-ray including the spine from C1 to the femoral head and the first 10 cm of the femur shaft. Using all the balance parameters provided, a formula name FBI is proposed. Calculation of the osteotomy is basic goniometry, the midpoint of the C7 inferior plateau (point a) is transposed horizontally on the projected future C7 plumb line (point b) crossing posterior S1 plateau on a sagittal X-ray. These are the first two reference points. A third reference point is made on the anterior wall of the selected vertebra for osteotomy at mid height of the pedicle (point c) mainly L4 vertebra. These three points form a triangle with the tip being the third reference point. The angle represented by this triangle is the theoretical angle of the osteotomy. Two more angles should be measured and eventually added. The femur angulation measured as the inclination of the femoral axis to the vertical. And a third angle named the compensatory pelvic tilt to integrate the type of pelvis. If the pelvic tilt is between 15 and 25 degrees or is higher than 25 degrees you must add 5 or 10 degrees , respectively. This compensatory tilt is based on a clinical analysis of operated patients. RESULTS: This planification was applied in a retrospective study of 18 patients and showed why in some cases improper correction was performed and prospectively in 8 cases with good clinical outcomes and correct spinal alignment. Sometimes it is necessary to find an acceptable compromise when rebalancing the spine paying attention to the general parameters of the patients like: age, osteoporosis, systemic disease etc. CONCLUSION: This FBI technique can be used even for small lordosis restoration: it gave a good evaluation of the amount of correction needed and then the surgeon had the choice to use the appropriate technique to obtain a good balance. PMID- 21818598 TI - Surgical management of recurrent thoracolumbar spinal sarcoma with 4-level total en bloc spondylectomy: description of technique and report of two cases. AB - INTRODUCTION: The descriptions of total spondylectomy and further development of the technique for the treatment of vertebral sarcomas offered for the first time the opportunity to achieve oncologically sufficient resection margins, thereby improving local tumor control and overall survival. Today, single level en bloc spondylectomies are routinely performed and discussed in the literature while only few data are available for multi-level resections. However, due to the topographic vicinity of the spinal cord and large vessels, the multisegmental resections are technically demanding, represent major surgery and only few case reports are available. Surgical options are even more limited in cases of revision surgery and local recurrences when en bloc spondylectomy was considered to be not feasible due to high risk of vital complications in expanding resection margins. Deranged anatomy, implants in situ and extensive intra-/paraspinal scar tissue formation resulting from previously performed approaches and/or radiation are considered the principal complicating factors that usually hold back spine surgeons to perform revision for resection leaving the patient to palliative treatment. METHODS: We present two patient cases with previously performed piecemeal vertebrectomy in the thoracic spine due to a solitary high-grade spinal sarcoma. After extensive re-staging, both patients underwent a multi (4)-level en bloc spondylectomy in our department (one patient with combined en bloc lung resection). Except a local wound disturbance, there was no severe intra- or postoperative complication. RESULTS: After multilevel en bloc spondylectomy both patients showed a good functional outcome without neurological deficits, except those resulting from oncologically scheduled resection of thoracic nerve roots. After a median follow-up of 13 months, there was no local recurrence or distant metastasis. The reconstruction using a posterior screw rod system that is interconnected to an anterior vertebral body replacement with a carbon composite cage showed no implant failure or loosening. In summary, the approach of a multilevel en bloc surgery for revision and oncologically sufficient resection in cases of spinal sarcoma recurrences seems possible. However, interdisciplinary decision making in a tumor board, realistic evaluation of surgical resectability to attain tumor free margins, advanced experiences in spinal reconstructions and involvement of vascular, visceral and thoracic surgical expertise are essential preconditions for acceptable oncological and functional outcome. PMID- 21818600 TI - Stress, uncertainty and decision confidence. AB - We successfully manipulated decision confidence in a probabilistic prediction task by means of stress as induced by excessive cognitive demands. In particular, our results indicate that decisions (based on high and low, but not intermediate levels of uncertainty) made under stress (confirmed by skin conductance measures) are associated with increased confidence when outcome probabilities are incompletely known (20% residual uncertainty). A different pattern was found when outcome probabilities were completely known (0% residual uncertainty). Here, stress led to decreased decision confidence when decisions were associated with intermediate levels of uncertainty but had no effect in case of high and low levels of uncertainty. In addition we provide evidence for ambiguity--(understood as implicit-risk) assessment being impaired under stress conditions. PMID- 21818599 TI - UV photography, masculinity, and college men's sun protection cognitions. AB - This study examined the impact of an ultraviolet (UV) photography intervention and masculinity on college men's sun protection cognitions, including: perceived vulnerability to skin damage, attitudes toward sun protection, willingness to engage in sun protection behaviors, and intentions to receive a skin cancer exam. After completing a baseline survey, participants (N = 152) viewed a black-and white photo of their face. Half also viewed a photo showing their UV damage. Participants then completed a second survey assessing sun protection cognitions. Regressions revealed that masculinity predicted lower sun protection cognitions, and men in the UV photograph condition reported higher sun protection cognitions. Masculinity by condition interactions showed that the positive effect of UV photography was stronger among masculine men. Negative associations between masculinity and sun protection cognitions were significant only among men who did not receive the intervention. Findings suggest that UV photography is a promising sun protection intervention among masculine men. PMID- 21818601 TI - Behavioural studies with a newly developed neuroprotective KYNA-amide. AB - The neuroactive properties and neuroprotective potential of endogenous L: kynurenine, kynurenic acid (KYNA) and its derivatives are well established. KYNA acts as an antagonist on the obligatory co-agonist glycine site, and has long been at the focus of neuroprotective trials. Unfortunately, KYNA is barely able to cross the blood-brain barrier. Accordingly, the development and synthesis of KYNA analogs which can readily cross the BBB have been at the focus of research interest with the aim of neuroprotection. Earlier we reported a new KYNA-amide crosses the BBB and proved neuroprotective in several experiments. In the present study, we investigated the locomotor activity, working memory performance, and also the long-lasting, consolidated reference memory of animals treated intraperitoneally (i.p.) with the novel analog. The effects of the novel analog on the spatial orientation and learning ability of rats were assessed in the Morris water maze (MWM) paradigm. The effects on locomotor activity of mice was assessed in the open field (OF) paradigm, and those on the spatial orientation and learning ability of mice were investigated in the radial arm maze (RAM) paradigm. It emerged that there is a dose of this KYNA-amide which is neuroprotective, but does not worsen the cognitive function of the brain. This result is significant in that a putative neuroprotectant without adverse cognitive side-effects is of great benefit. PMID- 21818602 TI - Clinical significance of salvage esophagectomy for remnant or recurrent cancer following definitive chemoradiotherapy. AB - BACKGROUND: The purpose of this study was to clarify the effect of preoperative chemoradiotherapy (CRT) for esophageal cancer on the postoperative course, and to determine the clinical significance of salvage esophagectomy after definitive CRT. METHODS: Based on their preoperative treatment, 477 patients with esophageal cancer were classified into three groups: 253 patients who received surgery alone (Group I), 197 who received planned CRT (30-45 Gy, Group II), and 27 who received a salvage esophagectomy (radiation >=60 Gy, Group III). RESULTS: Postoperative complications developed in 25, 40, and 59% of the patients in Groups I, II, and III, respectively, with pulmonary complications developing in 10, 15, and 30%, and anastomotic leakage developing in 13, 23, and 37%, respectively. Mortality rates were 2.4, 2.0, and 7.4%, respectively. Multivariate analysis revealed preoperative therapy to be an independent factor associated with postoperative risks: the odds ratios (ORs) of Groups II and III compared to Group I were 1.8 and 4.0 for pulmonary complications, while they were 1.9 and 2.8, respectively, for anastomotic leakage. No critical complications developed in the 14 patients who received salvage surgery performed with strict surgical indications after 2005. The survival of Group III was not significantly different from that of Groups I and II. Most patients who received an R1/R2 resection after definitive CRT died within 2 years after salvage surgery. CONCLUSIONS: Preoperative CRT is associated with postoperative complications especially in patients with R2 resection, while long-term survival can be achieved after R0 resections. Salvage surgery should be considered for carefully selected patients in whom R0 resection can be achieved. PMID- 21818603 TI - An assessment of radiation doses at an educational institution 57.8 km away from the Fukushima Daiichi nuclear power plant 1 month after the nuclear accident. AB - OBJECTIVES: On 11 March 2011, the Great East Japan Earthquake occurred. Due to this earthquake and subsequent tsunami, malfunctions occurred at the Fukushima Daiichi nuclear power plant. Radioactive material even reached the investigated educational institution despite being 57.8 km away from the power station. With the goal of ensuring the safety of our students, we decided to carry out a risk assessment of the premises of this educational institution by measuring radiation doses at certain locations, making it possible to calculate estimated radiation accumulation. METHODS: Systematic sampling was carried out at measurement points spaced at regular intervals for a total of 24 indoor and outdoor areas, with 137 measurements at heights of 1 cm and 100 cm above the ground surface. Radiation survey meters were used to measure environmental radiation doses. RESULTS: Radiation dose rates and count rates were higher outdoors than indoors, and higher 1 cm above the ground surface than at 100 cm. Radiation doses 1 cm above the ground surface were higher on grass and moss than on asphalt and soil. The estimated radiation exposure for a student spending an average of 11 h on site at this educational institution was 9.80 MUSv. CONCLUSIONS: Environmental radiation doses at our educational institution 57.8 km away from the Fukushima Daiichi nuclear power plant 1 month after the accident were lower than the national regulation dose for schools (3.8 MUSv/h) at most points. Differences in radiation doses depending on outdoor surface properties are important to note for risk reduction. PMID- 21818604 TI - Hallux valgus angle as a predictor of recurrence following proximal metatarsal osteotomy. AB - BACKGROUND: Postoperative recurrence of hallux valgus is a common complication. We hypothesized that patients who are at higher risk for recurrence of hallux valgus following a proximal metatarsal osteotomy could be recognized preoperatively and at the early follow-up on the basis of their radiographic evaluation. The purpose of this study was to clarify the relationship between the hallux valgus angle, intermetatarsal angle, and recurrence of hallux valgus. METHODS: We performed a case-control study of patients treated with a proximal metatarsal osteotomy for hallux valgus. Dorsoplantar weight-bearing radiographs of 72 feet were assessed preoperatively, at the early follow-up interval (mean 10 weeks), and at the most recent follow-up interval (mean 33 months). RESULTS: The rate of recurrence was 13.9% (ten feet). Risk factors for recurrence were preoperative hallux valgus angle >40 degrees [odds ratio (OR) = 5.1; 95% confidence interval (CI) 1.3-20.8]. Decreased risks of hallux valgus recurrence were a hallux valgus angle <= 15 degrees (OR = 0.036, 95% CI = 0.0056-0.24, p = 0.0005), and an intermetatarsal angle <10 degrees (OR = 0.083, 95% CI = 0.015 0.46, p = 0.0075) at the time of the early follow-up with the numbers available. CONCLUSIONS: Our radiographic results indicated that a preoperative hallux valgus angle >40 degrees can be a risk factor for hallux valgus recurrence. Decreased risk factors for recurrence included hallux valgus angle <= 15 degrees and an intermetatarsal angle <10 degrees at the early follow-up. These risk factors may be helpful for modifying surgical procedures, improving surgical outcome, and predicting hallux valgus recurrence. PMID- 21818605 TI - [Opening speech of the Congress President of the German Society for Pathology inc. Model roles in pathology]. PMID- 21818606 TI - [Pathology in Leipzig]. PMID- 21818607 TI - [Treatment of bulimia nervosa]. AB - Many young women and also men are constantly dissatisfied with their body. In some cases the discontent with one's own body and the resulting restrictive eating behaviour can predetermine the path to bulimia nervosa. This article summarizes the treatment options and their respective evidence for bulimia nervosa. Apart from the choice of treatment setting, psychotherapeutic treatment measures and the role of psychopharmacologic drugs for the treatment of bulimia nervosa are discussed. PMID- 21818608 TI - The abc1-/coq8- respiratory-deficient mutant of Schizosaccharomyces pombe suffers from glutathione underproduction and hyperaccumulates Cd2+. AB - The abc1(-)/coq8(-) gene deletion respiratory-deficient mutant NBp17 of fission yeast Schizosaccharomyces pombe displayed a phenotypic fermentation pattern with enhanced production of glycerol and acetate, and also possessed oxidative stress sensitive phenotypes to H(2)O(2), menadione, tBuOOH, Cd(2+), and chromate in comparison with its parental respiratory-competent strain HNT. As a consequence of internal stress-inducing mutation, adaptation processes to restore the redox homeostasis of mutant NBp17 cells were detected in minimal glucose medium. Mutant NBp17 produced significantly increased amounts of O(2)*- and H(2)O(2) as a result of the decreased internal glutathione concentration and the only slightly increased glutathione reductase activity. The Cr(VI) reduction capacity and hence the *OH production ability were decreased. The mutant cells demonstrated increased specific activities of superoxide dismutases and glutathione reductase (but not catalase) to detoxify at least partially the overproduction of reactive oxygen species. All these features may be explained by the decreased redox capacity of the mutant cells. Most notably, mutant NBp17 hyperaccumulated yellow CdS. PMID- 21818609 TI - KPC-2-producing Klebsiella pneumoniae isolated from a Czech patient previously hospitalized in Greece and in vivo selection of colistin resistance. AB - Carbapenemase-producing Gram-negative bacteria peak clinical interest due to their ability to hydrolyze most beta-lactams, including carbapenems; moreover, their genes spread through bacterial populations by horizontal transfer. Bacteria with acquired carbapenemase have sporadically been reported in the Czech Republic, so far only in Enterobacteriaceae and Pseudomonas aeruginosa. In this study, we described the first finding of a KPC-2-producing strain of Klebsiella pneumoniae, which was isolated from a surgical wound swab, decubitus ulcer, and urine of a patient previously hospitalized in Greece. The patient underwent various antibiotic therapies including a colistin treatment. However, after approximately 20 days of the colistin therapy, the strain developed a high-level resistance to this drug. All the isolates were indistinguishable by pulsed field gel electrophoretic analysis and belonged to the international clone ST258, which is typical of KPC-producing K. pneumoniae isolates. The bla (KPC-2) gene was located on a Tn4401a transposon variant. The OmpK35 and OmpK36 genes analysis performed due to the high resistance level of the strains to beta-lactams exhibited no changes in their sequence or in their expression when compared with carbapenem-susceptible isolates. PMID- 21818610 TI - Production of lipopeptides among Bacillus strains showing growth inhibition of phytopathogenic fungi. AB - The biological activity and the presence of genes sfp and ituD (surfactin and iturin A) among Bacillus strains isolated from the Amazon basin were determined. Bacillus spp. were tested for hemolytic activity and inhibition of fungal growth by agar plate assays in parallel with PCR for identification of sfp and ituD genes. All strains tested produced surface-active compounds, giving evidence by lysis of erythrocytes and emulsifying activity on mineral oil and soybean oil. These strains of Bacillus caused growth inhibition of several phytopathogenic fungi, including Fusarium spp., Aspergillus spp., and Bipolaris sorokiniana. The presence of genes ituD and sfp was confirmed by PCR and sequence analysis. The only exception was Bacillus sp. P34 that lacks sfp gene. Lipopeptides were isolated from culture supernatants and analyzed by mass spectrometry. Characteristic m/z peaks for surfactin and iturin were observed, and some strains also produced fengycin and bacillomycin. The remarkable antifungal activity showed by the strains could be associated with the co-production of three or more lipopeptide antibiotics. Screening for novel bacteria producing useful biosurfactants or biocontrol agents for agriculture is a topic of greatest importance to eliminate chemical pollutants. PMID- 21818611 TI - Biochemical and molecular characterization of wild-type and fused protoplasts of Beauveria bassiana and Metarhizium anisopliae. AB - Protoplasts were isolated from two isolates each of Beauveria bassiana and Metarhizium anisopliae using lysing enzymes. Intra- and intergeneric protoplast fusion has been carried out using 40% polyethylene glycol. The fused protoplasts of B. bassiana and M. anisopliae have been regenerated on Czapek-Dox agar media, and a total of four fusants were selected for further studies. An increase in proteinase and chitinase enzyme activity was recorded with all fusants as compared to the wild-type isolates. To understand the nature of recombination process, random amplification of polymorphic DNA (RAPD) and restriction fragment length polymorphism (RFLP) were carried out on genomic DNA of fused and wild-type isolates. The present study demonstrates the scope and significance of the protoplast fusion technique as a rapid consistent method for identification of B. bassiana and M. anisopliae fused and wild-type isolates based on the banding pattern of RAPD and RFLP that can be reliably used ahead for further applications on these species. PMID- 21818612 TI - Modulation of inv gene expression by the OmpR two-component response regulator protein of Yersinia enterocolitica. AB - To elucidate the physiological meaning of OmpR-dependent expression of invasin gene (inv) inhibition in Yersinia enterocolitica, the function of the EnvZ/OmpR regulatory pathway in osmoregulation of inv expression was analyzed in detail. The osmoregulation of inv expression was found to be a multifaceted process involving both OmpR-dependent and -independent mechanisms. Analysis of inv transcription in strains lacking OmpR or EnvZ proteins indicated that kinase EnvZ is not the only regulator of OmpR phosphorylation. Using the transcriptional inv::lacZ fusion in a heterologous system (Escherichia coli) we tried to clarify the role of OmpR in the inv regulatory circuit composed of negative (H-NS) and positive (RovA) regulators of inv gene transcription. We were able to show a significant increase in inv expression in E. coli ompR background under H-NS( Ecoli )-repressed condition. Moreover, H-NS-mediated inv repression was relieved when RovA of Y. enterocolitica was expressed from a plasmid. Furthermore, we showed that RovA may activate inv expression irrespective on the presence of H-NS protein. Using this strategy we showed that OmpR of Y. enterocolitica decrease RovA-mediated inv activation. PMID- 21818613 TI - The ciliate, Troglodytella abrassarti, contributes to polysaccharide hydrolytic activities in the chimpanzee colon. AB - Entodiniomorphid ciliates are intestinal protists inhabiting the colons of African great apes. The participation of intestinal entodiniomorphid ciliates in ape hindgut digestion has been proposed, but little data have been available to support the hypothesis. We measured the specific activities of carboxymethyl cellulase, xylanase, inulinase, and alpha-amylase against different polysaccharides in the feces of captive chimpanzees and evaluated the participation of the entodiniomorphid ciliate, Troglodytella abrassarti, in these activities. T. abrassarti contributed to the total fecal hydrolytic activities of CM-cellulase by 16.2%, alpha-amylase by 5.95%, and xylanase by 0.66%. Inulinase activity in T. abrassarti samples was not measurable at reaction conditions used. The ciliates, T. abrassarti, actively participate in the chimpanzee hindgut fermentation of fiber and starch. PMID- 21818614 TI - Hydroxylation modification and free radical scavenging activity of puerarin-7-O fructoside. AB - Puerarin-7-O-fructoside was transformed by Trichoderma harzianum CGMCC 1523 into 3'-hydroxypuerarin-7-O-fructoside; this was identified by MS and NMR. However, puerarin-7-O-glucoside was not directly hydroxylated but hydrolyzed back into puerarin, which was transformed into 3'-hydroxypuerarin by the same fungi. Comparative analysis of free radical scavenging activity of DPPH showed that the free radical scavenging activity of puerarin-7-O-glucoside was reduced to approximately 1/2 of that of puerarin, while the free radical scavenging activity of puerarin-7-O-fructoside was increased to approximately 1.5 times of that of puerarin. The free radical scavenging activity of 3'-hydroxypuerarin-7-O fructoside was further increased by 2.2 times of that of puerarin-7-O-fructoside, which was close to that of 3'-hydroxypuerarin. PMID- 21818615 TI - The importance of successful place integration for perceived health in very old age: a qualitative meta-synthesis. AB - OBJECTIVE: The aim of this study was to increase our understanding of the multifaceted phenomenon of home and health, by exploring processes underlying these dynamics when living at home in very old age. METHOD: A qualitative meta synthesis was used on four complementary qualitative studies, based on data from the Swedish ENABLE-AGE In-depth Study, focusing on very old, single-living people's experiences of home in relation to participation, independence and health (N = 40). RESULTS: Over time, very old people manage increased frailty by means of three intertwined processes concerning changes in everyday life: The turning points, The struggle and The negotiations. The findings show that these processes take place through the context of the Homelike functional home and a state of mind labelled, The awareness of frailty. CONCLUSION: The results can be useful in constructing and implementing guidelines for more holistic approaches to housing provision for senior citizens. Further, the study delivers a deeper understanding about how very old people live their lives, useful for practitioners as well as it contributes to theory development within the context of ageing and environments. PMID- 21818616 TI - Effects of sequential swallowing on drive to breathe in young, healthy adults. AB - Sequential swallowing is the act of swallowing multiple times, without pausing. Because sequential swallowing requires breath-holding, it seems likely that it could increase the drive to breathe. This study was designed to determine if sequential swallowing is accompanied by an increased drive to breathe in young, healthy adults. We predicted that sequential swallowing would be accompanied by prolonged breath-holding in most cases, and that this would be followed by a recovery phase during which ventilation would increase for a brief period. Results showed that not only did healthy participants increase ventilation after sequential swallowing, they also experienced breathing discomfort (dyspnea) despite the fact that they usually continued to breathe during the swallowing sequence. Given that these effects are observable in young, healthy adults, it seems reasonable to assume that individuals with respiratory and/or neurological compromise would also have an increased drive to breathe during sequential swallowing. PMID- 21818617 TI - Role of methylmercury exposure (from fish consumption) on growth and neurodevelopment of children under 5 years of age living in a transitioning (tin mining) area of the western Amazon, Brazil. AB - Human occupation of the Amazon region has recently increased, bringing deforestation for agriculture and open-cast mining, activities that cause environmental degradation and pollution. Families of new settlers in mining areas might have a diet less dependent on abundant fish and their children might also be impacted by exposures to mining environments. Therefore, there is compounded interest in assessing young children's nutritional status and neurobehavioral development with regard to family fish consumption. Anthropometric (z-scores, WHO standards) and neurologic [Gesell developmental scores (GDS)] development in 688 preschool children (1-59 months of age) was studied. Overall, the prevalence of malnutrition [i.e., moderate stunting (<=2 H/A-Z), underweight (<=2 W/A-Z), and wasting (<=2 W/H-Z) were respectively 0.3% (n = 2), 1.6% (n = 11), and 2.5% (n = 17). Children's mean hair Hg (HHg) concentration was 2.56 MUg/g (SD = 1.67); only 14% of children had HHg concentrations lower than 1 MUg/g and 1.7% had >=5 MUg/g. The biomarker of fish consumption was weakly but positively correlated with GDS (Spearman r = 0.080; p = 0.035). In the bivariate model, attained W/H-Z scores were not significantly correlated with GDS. A moderate level of GDS deficits (70 84%) was seen in 20% of children. There was significant correlation between family fish consumption and children's hair Hg (HHg) (Spearman r = 0.1756; p < 0.0001) but no significant correlation between children's HHg and W/H-Z scores. However, the multivariate model showed that breastfeeding, a fish consumption biomarker (HHg), maternal education, and child's age were statistically significant associated with specific domains (language and personal-social) of the Gesell scale. In this mining environment, family fish-eating did not affect children's linear growth, but it showed a positive influence (along with maternal variables) on neurodevelopment. Health hazards attendant on a high prevalence of moderate neurodevelopment delays coexisting with exposure to multiple neurotoxic substances merits further investigation in poor environmental settings of tin mining areas. PMID- 21818619 TI - Prospective assessment of out-of-pocket patient-related cost for ERCP at an urban tertiary care medical center. AB - BACKGROUND: When calculating differences between interventions, direct cost comparisons are typically based on Medicare reimbursement rates. The additional out-of-pocket costs of the patient have been little studied in endoscopy. AIM: To determine out-of-pocket costs for patients undergoing ERCP. METHODS: Between June and August 2009, all outpatients referred to our tertiary care university hospital for elective ERCP were prospectively interviewed regarding out-of-pocket costs for procedures. Patients were asked regarding any costs to undergo the procedure including co-pay, driving, parking, meals, child care or equivalent, and any additional expenses related to subsequent procedures or admissions related to the ERCP. RESULTS: Over the study period, 94 outpatients (mean age 57 +/- 16 years, 48% male) underwent ERCP. Mean/median out-of-pocket costs for the procedure were $177.97/72.54 and ranged from $0 to $2,033.54. The largest single expense for the procedure was related to copayment (median $75). Eleven patients required hospitalization for post-procedural complications resulting in additional median out-of-pocket costs of $25. Median hotel, food, and travel expenses were $171.00, $20.00, and $23.54, respectively. CONCLUSIONS: Out-of pocket ERCP costs are not insignificant from the patient's perspective and should be added to the direct costs to calculate true procedure costs. PMID- 21818620 TI - Measurement of the 3D geometry of the fascial arches in women with a unilateral levator defect and "architectural distortion". AB - INTRODUCTION AND HYPOTHESIS: The arcus tendineus fascia pelvis (ATFP) and arcus tendineus levator ani (ATLA) are elements of anterior vaginal support. This study describes their geometry in women with unilateral levator ani muscle defects and associated "architectural distortion." METHODS: Fourteen subjects with unilateral defects underwent MRI. 3D models of the arcus were generated. The locations of these relative to an ilial reference line were compared between the unaffected and affected sides. RESULTS: Pronounced changes occurred on the defect sides' ventral region. The furthest point of the ATLA lays up to a mean of 10 mm (p = 0.01) more inferior and 6.5 mm (p = 0.02) more medial than that on the intact side. Similarly, the ATFP lays 6 mm (p = 0.01) more inferior than on the unaffected side. CONCLUSIONS: The ventral arcus anatomy is significantly altered in the presence of levator defects and architectural distortion. Alterations of these key fixation points will change the supportive force direction along the lateral anterior vaginal wall, increasing the risk for anterior vaginal wall prolapse. PMID- 21818621 TI - Flash-lag effect: complicating motion extrapolation of the moving reference stimulus paradoxically augments the effect. AB - One fundamental property of the perceptual and cognitive systems is their capacity for prediction in the dynamic environment; the flash-lag effect has been considered as a particularly suggestive example of this capacity (Nijhawan in nature 370:256-257, 1994, Behav brain sci 31:179-239, 2008). Thus, because of involvement of the mechanisms of extrapolation and visual prediction, the moving object is perceived ahead of the simultaneously flashed static object objectively aligned with the moving one. In the present study we introduce a new method and report experimental results inconsistent with at least some versions of the prediction/extrapolation theory. We show that a stimulus moving in the opposite direction to the reference stimulus by approaching it before the flash does not diminish the flash-lag effect, but rather augments it. In addition, alternative theories (in)capable of explaining this paradoxical result are discussed. PMID- 21818622 TI - Early effects of erythropoietin on serum hepcidin and serum iron bioavailability in healthy volunteers. AB - Hepcidin regulates plasma iron bioavailability and subsequently iron availability for erythropoiesis. rHuEPO has been reported to decrease hepcidin expression in case of repeated subcutaneous injections. Thus, hepcidin level measurement could be a candidate marker for detection of rHuEPO abuse. However, when used for doping, rHuEPO can be injected intravenously and the scheme of injection is unknown. Our aim was to evaluate the early effects of a single intravenous rHuEPO injection on serum hepcidin levels. Fourteen male healthy volunteers received one intravenous injection of 50 U/Kg of rHuEPO during a placebo-controlled, randomized, double-blind, cross-over study. Serum hepcidin, quantified by a competitive ELISA method and iron parameters was then evaluated for 24 h. Serum levels of hepcidin were significantly increased 4 h after rHuEPO injection when compared with placebo injection (78.3 +/- 55.5 vs. 57.5 +/- 34.6 ng/ml, respectively; +36%, p < 0.05), whereas iron and transferrin saturation dramatically decreased 12 h after rHuEPO injection when compared with placebo injection (9.2 +/- 3.5 vs. 15.8 +/- 4.2 MUg/l, respectively; -42%, p < 0.05 and 14.8 +/- 5.0 vs. 26.3 +/- 6.4%, respectively; -44%, p < 0.05). In addition, 12 and 24 h after rHuEPO injection serum hepcidin levels were lower compared with placebo injection (41.6 +/- 27.4 vs. 56.6 +/- 28.1 ng/ml after 12 h; -27%, p < 0.05 and 26.0 +/- 29.6 vs. 81.2 +/- 29.4 ng/ml after 24 h; -68%, p < 0.05). Intravenous injection of recombinant EPO induces a precocious and transient increase of serum hepcidin leading to a transient decrease of iron bioavailability. The transitory increase and dynamics of its concentration make difficult the practical use of hepcidin to detect rHuEPO doping. PMID- 21818624 TI - Are the votes of ethics committees in Germany for the protection of clinical study trial subjects "sovereign acts?". AB - A sudden paradigm shift has resulted in governmental measures that greatly impact the scope in which the ethics committees in Germany can perform their task of providing expert opinions for clinical research. The so-called "revaluation" of the Medical Device Law Deutsches Medizinproduktegesetz-MPG) is, in our opinion, not based on sound political and professional judgment. In accordance with the changed regulations, ethics committees are now seen as being sub-organs of the state medical associations or the medical faculties and are therefore official authorities. It follows that the votes of ethics committees are then "sovereign acts" or authoritative measures! However, equality and justice speak against this misleading conclusion and its resulting consequence that an ethics committee's vote is a sovereign act. This has, in turn, resulted in the public ethics committees obtaining their long-sought goal of having a state-sanctioned monopoly. The private ethics committees are not recognized as being authoritative bodies, nor are they to be seen as such in the future (i.e. such a status has been denied the Freiburg Ethics Commission International (FEKI) in Baden Wurttemberg). This political mistake must be corrected, otherwise, conducting clinical research will become increasingly difficult. PMID- 21818623 TI - The spectral changes in EMG during a second bout eccentric contraction could be due to adaptation in muscle fibres themselves: a simulation study. AB - The mechanism of marked reduction in damage symptoms after repeated bout of similar eccentric contractions is still unknown. The neuronal adaptation leading to reduction of muscle fibre propagation velocity (MFPV) due to increased activation of slow-twitch motor units (MUs), decrease in activation of fast twitch MUs, and/or increase in MU synchronization was suggested as a cause for lower EMG frequency characteristics. However, the repeated bout effect could occur also after electrically stimulated exercise. Prolonged elevation of cytoplasmic Ca(2+) due to the increased membrane permeability after eccentric contractions was reported. Elevated Ca(2+) induced peripheral changes that included alteration of intracellular action potential and MFPV reduction. We simulated and compared changes in EMG frequency characteristics related to effects of central nervous system (CNS) or to peripheral changes. The simulations were performed for different electrode arrangements and positions. The results showed that the peripheral effects could be similar or even stronger than the effects related to CNS. We hypothesised that the repeated bout effect was a consequence of the adaptation in muscle fibres necessary for avoiding Ca(2+) induced protein and lipid degradation due to Ca(2+) overload resulting from the increased membrane permeability after eccentric contraction. The possibilities for noninvasive testing of this hypothesis were discussed. PMID- 21818625 TI - [Pneumatic dilation versus myotomy for achalasia: what do data from the new prospective randomized study tell us?]. PMID- 21818626 TI - The anabolic steroid methandienone targets the hypothalamic-pituitary-testicular axis and myostatin signaling in a rat training model. AB - There is increasing evidence that the biological activity of myostatin (MSTN), a negative regulator of muscle growth, is affected by training but also anabolic steroids. In this study, we analyzed the effects of the frequently abused anabolic steroid methandienone (Md) on the hypothalamic-pituitary-testicular axis and androgen-sensitive tissues in intact rats performing a treadmill training to simulate the situation of abusing athletes. The anabolic effects were correlated with the expression of members of the MSTN signaling cascade. Md treatment resulted in a significant stimulation of anabolic activity of the levator ani muscle, which was further increased by training, while prostate and seminal vesicle weights decreased in conformance with hormone concentrations of LH and testosterone. In gastrocnemius muscle, mRNA expression of genes of the MSTN signaling cascade (MSTN, Smad7 and MyoD) was reduced by training but not after Md treatment, in soleus muscle MSTN and its inhibitors, follistatin (FLST) and Smad 7 were only affected after training in combination with Md treatment. In summary, our data demonstrate that Md treatment of intact rats results in anabolic effects which are enhanced in combination with physical activity. Interestingly, the anabolic activity on the levator ani was increased in combination with training, although the levator ani muscle was not specifically stimulated by our training protocol. In the m. gastrocnemius and soleus, the anabolic effects correlate with changes in the expression patterns of genes involved in MSTN signaling. Our data provide evidence that the decrease in the weight of androgen-sensitive sexual glands, observed after Md treatment, is caused by a suppression of endogenous testosterone synthesis. These observations provide new insights into the molecular mechanisms of the interaction between anabolic steroids, training and MSTN signaling during skeletal muscle adaptation. PMID- 21818627 TI - Urban particulate matter activates Akt in human lung cells. AB - The normally picturesque Cache Valley in northern Utah is frequently reported to have the worst particulate (PM) air pollution in the United States. Numerous epidemiological studies conducted elsewhere have associated PM exposure to a variety of cardiovascular diseases and early mortality. We have previously shown that Cache Valley PM (CVPM) is pro-inflammatory, through a variety of mechanisms involving the release of inflammatory cytokines, unfolded protein response, ER stress, and C-reactive protein (CRP). This study was undertaken to determine whether Cache Valley PM (CVPM) would activate Akt, an upstream mechanism common to these events. Human lung (BEAS-2B) cells were treated with either fine (PM(2.5)) or coarse (PM(10)) particles (12.5 and 25 MUg/ml) for periods up to 24 h. PM-exposed cells exhibited Akt activation as evidenced by phosphorylation at Thr(308) and Ser(473). Events downstream of Akt activation such as NF-kappaB activation were observed at 1 and 24 h, but IkappaB phosphorylation occurred only at 24 h, indicating that mechanisms of PM-mediated NF-kappaB activation are time dependent. Akt and NF-kappaB related inflammatory cytokine IL-1alpha, and IL-6 and the chemokine IL-8 were upregulated in treated cells at 6 and 24 h. The calpain inhibitor leupeptin limited Akt phosphorylation to Ser(473) and reduced release of IL-1alpha, IL-6, and IL-8, indicating that calpain or similar protease(s) are involved in PM-induced activation of Akt and subsequent release of inflammatory cytokines. Our data indicate that PM activates Akt, which may play a role in the pro-inflammatory response to PM exposure. PMID- 21818628 TI - Longitudinal changes of fractional anisotropy in Alzheimer's disease patients treated with galantamine: a 12-month randomized, placebo-controlled, double blinded study. AB - Diffusion tensor imaging (DTI) demonstrates decline of fractional anisotropy (FA) as a marker of fiber tract integrity in Alzheimer's disease (AD). We aimed to assess the longitudinal course of white matter microstructural changes in AD and healthy elderly control (HC) subjects and to evaluate the effects of treatment with the cholinesterase inhibitor galantamine on white matter microstructure in AD patients. We enrolled 28 AD patients and 11 healthy elderly control subjects (HC). AD patients were randomly assigned to 6-month double-blind galantamine treatment or placebo, with a 6-month open-label extension phase. DTI was performed at baseline, as well as at 6 and 12-month follow-up in AD patients. The HC subjects underwent DTI at baseline and 12-month follow-up without treatment. We measured FA in regions of interest covering the posterior cingulate and corpus callosum. At 6-month follow-up, the AD group showed significant FA decline in the left posterior cingulate. FA decline was significantly preserved in the posterior body of the corpus callosum in AD group with treatment compared to placebo. At 12 month follow-up, the AD patients showed no differences in FA decline between initial treatment and placebo groups after the 6-month open-label extension phase. A significant FA decline occurred in the left posterior cingulate across the AD and HC groups without between-group differences. DTI demonstrated FA decline in intracortically projecting fiber tracts in aging and AD over 1 year. Galantamine had limited impact on regional FA decline, which was not preserved after additional 6-month open-label treatment. PMID- 21818629 TI - Diagnostic criteria for bipolarity based on an international sample of 5,635 patients with DSM-IV major depressive episodes. AB - To assess the clinical validity of individual DSM-IV criteria for hypomania. In an international sample of 5,635 patients with major depressive episodes (Bridge Study), DSM-IV criteria for hypomania (stem questions, number and quality of symptoms, duration and exclusion criteria) were systematically assessed and their validity analysed on the basis of clinical data including family history, course, and other clinical characteristics. Three stem questions for hypomania, irritability, elevated mood and the added question of increased activity, showed comparable validity. The results support the current DSM-IV requirement for a higher symptom threshold (4 of 7 hypomanic symptoms) in cases of irritable mood. Longer durations of hypomanic episodes were associated with higher scores on all validators. The results did not support the DSM-IV durational requirements for hypomanic episodes (4 days) and manic episodes (7 days). Brief hypomanic episodes of 1, 2 or 3 days were valid and would meet validity criteria for inclusion. The three exclusion criteria in DSM-IV (hypomania due to the use of antidepressants or of other substances, or to other medical conditions) were found to exclude patients with bipolar depression and should therefore not be retained. These results support several revisions of the DSM-IV concept of hypomanic episodes: specifically, the inclusion of increased activity as a gate question, the inclusion of 1 or 2 to 3-day episodes and the elimination of all exclusion criteria. PMID- 21818632 TI - Distance modulated neuronal activity in the cortical visual areas of cats. AB - During previous studies in cats and monkeys, it was found that in some neurons, responses to visual stimuli of the same angular size were dependent on the absolute distance to these stimuli. To study how widely this peculiarity of visual responses is distributed among cortical visual areas, we recorded activity of neurons in areas V4A, V2, V1, and frontal visual area on the lower bank of the cruciate sulcus. Neuronal activity was recorded at near (20 cm) or far (3 m) distances from a 3D stationary visual scene. Visual scenes were vertically corrugated light gray screens. Angular dimensions of the screens were the same at short and far distances. Eye movements were free during the test procedure. It was found that about 20% of neurons in areas V4A, V1, and frontal visual area had significantly different levels of activity, while animals were looking at the visual scenes located near or far from the eyes. No neurons with depth modulated activity were found in area V2. PMID- 21818631 TI - Illusory double flashes can speed up responses like physical ones: evidence from the sound-induced flash illusion. AB - When a single brief flash is accompanied by two auditory beeps, participants often report perceiving two flashes. The present experiment examined whether the perception of illusory redundant flashes can result in faster responses as compared to the perception of a single flash, because previous research has shown such a redundancy gain for physical stimuli. To this end, participants were asked to respond as rapidly as possible to the onset of any flash. Following their response, they additionally indicated whether they perceived a single flash or a double flash. Most importantly, we observed significant shorter reaction times in response to redundant flashes, irrespective of whether they were physically presented or illusorily perceived. Taken together, our results suggest that an illusory percept can affect simple reaction time in much the same manner as the corresponding physical stimulation. PMID- 21818633 TI - Spatial metaphor processing during temporal sequencing comprehension. AB - People all over the world use spatial metaphors to represent temporal sequencing, but so far the online stages during the comprehension of temporal sequencing still lack evidence. To explore this issue, the current EEG study constructed vertical anomaly and horizontal anomaly by exchanging spatial terms in vertical and horizontal temporal sequencing concepts in Mandarin. Both the vertical and the horizontal anomaly indicated an N400 effect (340 ms after stimulus onset) and a positive effect in a late time window (620 ms after stimulus onset). Additionally, the horizontal anomaly showed a reduced P2 effect (200-260 ms after stimulus onset) that might related to spatial processing. Direct comparison between the two anomaly effects revealed that the vertical anomaly evoked a stronger effect in an early N400 time window (from 360 to 440 ms), whereas the horizontal anomaly evoked a stronger effect in a late N400 time window (from 500 to 580 ms). These results indicate multiple stages during the comprehension of temporal sequencing. The relation between the current results and spatial metaphor differences is also discussed. PMID- 21818630 TI - Turner syndrome and sexual differentiation of the brain: implications for understanding male-biased neurodevelopmental disorders. AB - Turner syndrome (TS) is one of the most common sex chromosome abnormalities. Affected individuals often show a unique pattern of cognitive strengths and weaknesses and are at increased risk for a number of other neurodevelopmental conditions, many of which are more common in typical males than typical females (e.g., autism and attention-deficit hyperactivity disorder). This phenotype may reflect gonadal steroid deficiency, haploinsufficiency of X chromosome genes, failure to express parentally imprinted genes, and the uncovering of X chromosome mutations. Understanding the contribution of these different mechanisms to outcome has the potential to improve clinical care for individuals with TS and to better our understanding of the differential vulnerability to and expression of neurodevelopmental disorders in males and females. In this paper, we review what is currently known about cognition and brain development in individuals with TS, discuss underlying mechanisms and their relevance to understanding male-biased neurodevelopmental conditions, and suggest directions for future research. PMID- 21818634 TI - Apoptosis in lymphocytes of pancreatic cancer patients: influence of preoperative enteral immunonutrition and extensive surgery. AB - The mechanisms of correcting immune disorders in patients with pancreatic cancer requiring major surgery procedures by introducing perioperative immune-enhancing diet (immunonutrition) are still unclear. The purpose of our study was to investigate the effect of pancreatic cancer, extensive surgery and immunonutrition versus enteral standard nutrition on the apoptotic signaling pathways. The randomized studies were performed in 72 patients before and after pancreatic cancer resection with preoperative standard (Group I) or enteral immunonutrition (Group II). The expressions of Bcl-2, Bax, caspases-3, -9, NF kappaB, PARP-1/89 kDa, TNFR1/CD120a and Fas/CD95 in peripheral blood lymphocytes were assessed by western blot analysis and flow cytometry before and on day 1, 3 and 7 after surgery. In malnourished patients before and after surgery, the expression of Bcl-2, Bax, NF-kappaB, PARP-1 was significantly lower, whereas the expression of caspases, as well as the percentage of cells with death receptors were significantly higher when compared with the control group. There was no difference in Bcl-2, Bax and PARP-1 expression between the control group and the patients with normal nutritional status (Group III) before surgery. In comparison to the standard nutrition, the preoperative immunonutrition increased the Bcl-2 and Bax expression inconsiderably but significantly increased the percentage of CD95- and CD120a-positive lymphocytes after surgery. In malnourished patients with pancreatic cancer, the overwhelming expression of caspases and the decrease expression of anti-apoptotic proteins may lead to inappropriate lymphocyte apoptosis and higher cell depletion. The preoperative enteral immunonutrition prevents the postoperative decrease in lymphocyte subsets, but a higher level of lymphocyte susceptibility to undergo accelerated apoptosis can also be considered. PMID- 21818635 TI - Cytoglobin exhibits anti-fibrosis activity on liver in vivo and in vitro. AB - Cytoglobin, generated using genetic engineering method, is a kind of recombinant human stellate cell activation-associated protein. We speculate that it could influence the development of hepatic fibrosis like Sellate cell activation associated protein which was discovered by Kawada et al. Therefore, we investigated its anti-fibrosis effect on liver both in vivo and in vitro. During our research, we found that cytoglobin showed obvious effect compared with the control group on Thioacetamide-induced liver fibrosis in SD rats, including significantly decrease in aspartate aminotransferase, Hyaluronic acid, laminin and collagen I(Col I) levels in serum and hydroxyproline in livers, which are the important indices reflecting the degree of hepatic fibrosis. Meanwhile, the viability of rat hepatic stellate cell line T6 (HSC-T6) cells was inhibited by cytoglobin and the apoptosis induced by cytoglobin in HSC-T6 cells was detected by Annexin V/PI double staining. Activation of the caspase cascade including caspase-3 for the intrinsic pathways was demonstrated. The results also showed that the expression of Bcl-2 protein decreased whereas that of Bax protein increased, leading to an increase of the Bax/Bcl-2 ratio. Our results demonstrated that cytoglobin exhibited anti-fibrosis activity on livers in vivo and in vitro, involving apoptosis induction. PMID- 21818636 TI - Effects of wall shear stress and its gradient on tumor cell adhesion in curved microvessels. AB - Tumor cell adhesion to vessel walls in the microcirculation is one critical step in cancer metastasis. In this paper, the hypothesis that tumor cells prefer to adhere at the microvessels with localized shear stresses and their gradients, such as in the curved microvessels, was examined both experimentally and computationally. Our in vivo experiments were performed on the microvessels (post capillary venules, 30-50 MUm diameter) of rat mesentery. A straight or curved microvessel was cannulated and perfused with tumor cells by a glass micropipette at a velocity of ~1mm/s. At less than 10 min after perfusion, there was a significant difference in cell adhesion to the straight and curved vessel walls. In 60 min, the averaged adhesion rate in the curved vessels (n = 14) was ~1.5 fold of that in the straight vessels (n = 19). In 51 curved segments, 45% of cell adhesion was initiated at the inner side, 25% at outer side, and 30% at both sides of the curved vessels. To investigate the mechanical mechanism by which tumor cells prefer adhering at curved sites, we performed a computational study, in which the fluid dynamics was carried out by the lattice Boltzmann method , and the tumor cell dynamics was governed by the Newton's law of translation and rotation. A modified adhesive dynamics model that included the influence of wall shear stress/gradient on the association/dissociation rates of tumor cell adhesion was proposed, in which the positive wall shear stress/gradient jump would enhance tumor cell adhesion while the negative wall shear stress/gradient jump would weaken tumor cell adhesion. It was found that the wall shear stress/gradient, over a threshold, had significant contribution to tumor cell adhesion by activating or inactivating cell adhesion molecules. Our results elucidated why the tumor cell adhesion prefers to occur at the positive curvature of curved microvessels with very low Reynolds number (in the order of 10(-2)) laminar flow. PMID- 21818637 TI - Primary health risk analysis of metals in surface water of Taihu Lake, China. AB - The status and health risks of eight metals, Pb, Cd, Cr, Cu, Zn, Fe, Ni and Mn, in surface water from Taihu Lake (Jiangsu Province, China) were evaluated. The results showed that the maximum hazard quotients (HQ) value through ingestion pathway and dermal adsorption pathway was 2.74E-01 (Ni) and 2.57E-02 (Cd), respectively. However, the individual hazard quotient and total hazard index of eight metals through ingestion and dermal adsorption pathway was all lower than 1, indicating that the pollution situation in the surface water of Taihu Lake concerning these metals has no or low adverse health effects. PMID- 21818638 TI - Assessment of heavy metal pollution in urban soils of Havana city, Cuba. AB - Concentrations of Co, Ni, Cu, Zn, Pb and Fe in the top-soils (0-10 cm) from urbanized and un-urbanized areas of Havana city were measured by X-ray fluorescence analysis. The mean Co, Ni, Cu, Zn and Pb contents in the urban topsoil samples (13.9 +/- 4.1, 66 +/- 26, 101 +/- 51, 240 +/- 132 and 101 +/- 161 mg kg(-1), respectively) were compared with mean concentrations for other cities around the world. The results revealed the highest concentrations of metals in topsoil samples from industrial sites. Lowest metal contents were determined in the un-urbanized areas. The comparison with Dutch soil quality guidelines showed a slight contamination with Co, Ni Cu and Zn in all studied sites and with Pb in industrial soils. On the other hand, the metal-to-iron normalisation using Earth crust contents as background showed that soils from urbanized areas in Havana city (industrial sites, parks and school grounds) are moderately enriched with zinc, moderately to severe enriched (city parks and school grounds) and severe enriched (industrial sites) with lead. The values of integrated pollution index (IPI) indicated that industrial soils are middle and high contaminated by heavy metals (1.19 <= IPI <= 7.54), but enrichment index values (EI) shows that metal concentrations on the studied locations are not above the permissible levels for urban agriculture, except soils from power and metallurgical plants surroundings. PMID- 21818639 TI - Overexpression of Frat1 correlates with malignant phenotype and advanced stage in human non-small cell lung cancer. AB - Frat1 has been reported to be overexpressed in several human malignant tumors, including esophageal squamous, cervical, breast, and ovarian carcinoma, but the role of Frat1 in lung cancer is unknown. Our purpose is to investigate the expression of Frat1 and its correlation with clinicopathologic features and prognosis in lung cancer patients. Immunohistochemistry was performed on 137 cases of non-small cell lung cancer (NSCLC), including 78 cases with clinical follow-up, and Western blot and reverse transcription-polymerase chain reaction (RT-PCR) assays were performed to detect the protein and mRNA expression levels in 30 NSCLC and autologous matched normal tissues. In addition, lung cancer cell line A549 was transfected with Frat1-siRNA plasmids and Matrigel invasive assay was carried out to study the function of Frat1 in cancer cell invasiveness. The results showed that Frat1 was expressed in 85 (62.04%) cases of NSCLC by immunohistochemistry, while all 30 specimens of normal lung tissues were negative. Western blot and RT-PCR results for Frat1 mRNA were in agreement with immunohistochemical findings. Of interest, the expression of Frat1 was strongly correlated with tumor differentiation, TNM stage, and lymph node metastasis (P < 0.05). The Kaplan-Meier survival analysis demonstrated that the cases with Frat1 expression had significantly shorter survival than those without Frat1 (P < 0.001). In addition, down-regulation of Frat1 expression reduced the invasive ability in the A549 cell line, further supporting the idea that Frat1 may play a crucial role in carcinogenesis, tumor invasiveness and dissemination in human lung cancer. PMID- 21818640 TI - Inpatient oncology rehabilitation in Toronto: a descriptive 18-month retrospective record review. AB - PURPOSE: The purpose was twofold: (1) to develop a comprehensive profile of patients discharged from an inpatient oncology rehabilitation unit and (2) to explore the relationships between patient characteristics and functional status. METHODS: A retrospective review of electronic data from all patients discharged from oncology rehabilitation between November 1, 2008, and March 31, 2010, was conducted. Data elements included age, sex, primary language, living arrangements, cancer diagnosis, comorbidities, and admission and discharge Functional Independence Measure (FIM(TM)) scores. Descriptive statistics were compiled for all data elements. General linear regression was conducted to determine the descriptors independently associated with FIM(TM) discharge and FIM(TM) change scores. RESULTS: There were 153 eligible records. The patients' age ranged from 38 to 97 years (M = 72.6, SD = 12.9); 59.5% were women, and 39.3% lived alone prior to hospitalization. The most common diagnoses were colorectal cancer (n = 45, 28.8%), metastatic disease (n = 24, 15.7%), and cancer of the urinary organs (n = 14, 9.2%). Service goals were met for 77.1%. Patients improved an average of 17.1 (SD = 8.8) points on the FIM(TM). Being older and having a diagnosis of brain or uterine cancer were associated with lower FIMTM change scores. CONCLUSIONS: In this sample, the majority of patients were older women, and many lived alone. While the group as a whole made significant functional gains, those who were younger improved more. Having a diagnosis of uterine or brain cancer was associated with lower functional change scores. This study was limited by a small sample size and the retrospective design; however, the results provide a foundation for future prospective research. PMID- 21818641 TI - Incidence of febrile neutropenia among early-stage breast cancer patients receiving anthracycline-based chemotherapy. AB - OBJECTIVES: The aim of this study was to investigate the incidence of febrile neutropenia (FN) with adjuvant AC (doxorubicin and cyclophosphamide) chemotherapy among Asian early-stage breast cancer (ESBC) patients, to evaluate the impact of FN on chemotherapy delivery, and to identify specific risk factors that would predispose ESBC patients to FN. METHODS: This was a single-center, observational, retrospective cohort study conducted in Singapore. All ESBC patients who have received the AC regimen as adjuvant chemotherapy between January 2007 and July 2010 were included into the study. Patients did not receive granulocyte colony stimulating factors (G-CSF) as primary prophylaxis. RESULTS: One hundred and eighty-nine patients and 729 cycles of chemotherapy were analyzed in this study, of which, majority were Chinese (84%). Median age of the patients was 54 years old (IQR 49-58). In total, 26 patients (13.8%) manifested at least one episode of FN, of which 17 patients developed FN during the first cycle of treatment. Patients who manifested FN received similar dose intensities of chemotherapy, compared to those patients who did not manifest FN (100% versus 98%, p = 0.95). After adjusting for age, race, and presence of comorbidities, low body mass index (BMI) (<23 kg/m(2)) was found to be associated with a higher risk of FN (OR 4.4, 95% CI = 1.65-12.01, p = 0.003). CONCLUSIONS: Asian patients are at moderate risk for FN when they receive the AC regimen for treatment of ESBC. Further studies should evaluate the role of G-CSF to reduce the occurrence of FN in Asian patients with low BMI. PMID- 21818643 TI - Intraoperative monitoring of the visual function using cortical potentials after electrical epidural stimulation of the optic nerve. AB - BACKGROUND: Central skull base meningiomas commonly present with visual deficit, and their removal often leads to improvement of visual function. However, the incidence of postoperative visual deterioration has been reported to be up to 10%. Intraoperative monitoring using flash visual evoked potential has only recently been used with success. Cortical potentials (CP) after electrical epidural stimulation of the optic nerve (ON) were correlated with ON manipulation due to central skull base tumor removal to contribute to improvement of the intraoperative monitoring of the visual function. METHODS: Blunt needle stimulating electrodes were attached epidurally alongside ON in an unroofed optic canal and used for delivering a rectangular current pulse (intensity 0.2-5.0 mA; duration 0.1-0.3 ms; rate 2 Hz). CPs after electrical epidural stimulation of ON were recorded with corkscrew electrodes at O(z) with the reference electrode at F(z). RESULTS: P20 and N30 amplitudes were significantly lower (p < 0.05) during tumor removal associated with ON manipulation than in other phases of surgery; the amplitude reductions were reversible in all cases. There were no significant changes in P20, N30 and P40 latencies during the surgery. Immediate postoperative visual function was unchanged in all patients. CONCLUSIONS: P20 and N30 amplitude changes seem to reliably correspond with the manipulation of ON during anterior skull base tumor removal. Reversible reduction of P20 and N30 amplitude was associated with unchanged immediate postoperative visual function. No correlation between intraoperative variation of CP and newly acquired postoperative visual deficit can presently be made. PMID- 21818642 TI - Ginger (Zingiber officinale) reduces acute chemotherapy-induced nausea: a URCC CCOP study of 576 patients. AB - PURPOSE: Despite the widespread use of antiemetics, nausea continues to be reported by over 70% of patients receiving chemotherapy. METHODS: In this double blind, multicenter trial, we randomly assigned 744 cancer patients to four arms: 1) placebo, 2) 0.5 g ginger, 3) 1.0 g ginger, or 4) 1.5 g ginger. Nausea occurrence and severity were assessed at a baseline cycle and the two following cycles during which patients were taking their assigned study medication. All patients received a 5-HT(3) receptor antagonist antiemetic on Day 1 of all cycles. Patients took three capsules of ginger (250 mg) or placebo twice daily for 6 days starting 3 days before the first day of chemotherapy. Patients reported the severity of nausea on a 7-point rating scale ("1" = "Not at all Nauseated" and "7" = "Extremely Nauseated") for Days 1-4 of each cycle. The primary outcomes were to determine the dose and efficacy of ginger at reducing the severity of chemotherapy-induced nausea on Day 1 of chemotherapy. RESULTS: A total of 576 patients were included in final analysis (91% female, mean age = 53). Mixed model analyses demonstrated that all doses of ginger significantly reduced acute nausea severity compared to placebo on Day 1 of chemotherapy (p = 0.003). The largest reduction in nausea intensity occurred with 0.5 g and 1.0 g of ginger (p = 0.017 and p = 0.036, respectively). Anticipatory nausea was a key factor in acute chemotherapy-induced nausea (p < 0.0001). CONCLUSIONS: Ginger supplementation at a daily dose of 0.5 g-1.0 g significantly aids in reduction of the severity of acute chemotherapy-induced nausea in adult cancer patients. PMID- 21818644 TI - The fully endoscopic supraorbital trans-eyebrow keyhole approach to the anterior and middle skull base. AB - BACKGROUND: The purely endoscopic eyebrow supraorbital approach is an alternative to both the endoscopic endonasal and eyebrow microsurgical routes to the anterior and middle cranial base. It combines an enhanced visualization provided by the endoscope and the absence of cerebrospinal fluid (CSF) leaks and nasal complications. METHODS: A trans-eyebrow 2-cm craniotomy is designed to allow the placement of a straight endoscope and visualize the skull base from the cribriform plate to the mesiotemporal lobe. RESULT: Visualization is considerably improved, while the keyhole mini-invasive concept is respected. CONCLUSION: The purely endoscopic eyebrow supraorbital keyhole approach is a valuable and alternative minimally invasive route to anterior and middle skull base lesions. PMID- 21818645 TI - Incidence of Phlebiopsis gigantea large virus-1 in a collection of Phlebiopsis gigantea isolates. AB - Eighty six Phlebiopsis gigantea isolates from at least 9 different tree species from various locations in 12 different European countries and North America were screened for the presence of large molecular weight dsRNA >10 kbp in size. In 7 isolates, which contained large dsRNAs, the presence of Phlebiopsis gigantea large virus-1 (PgLV-1) was suggested following the sequencing of the RT-PCR amplicons generated with PgLV-1 specific oligonucleotide primers which also revealed little genetic diversity between the virus isolates. PMID- 21818646 TI - Our 1-year experience in laparoscopic sleeve gastrectomy. AB - Sleeve gastrectomy was conceived in 1988 both as a first step to the duodenal switch procedure and as an extension of anti-reflux surgery where patients lost significant weight. It is now a stand-alone laparoscopic bariatric procedure worldwide with two international consensus summits identifying it as a safe and feasible restrictive and appetite-suppressing procedure. In our centre, it is a key component in the surgical armamentarium and used as a first-line and revisional procedure for morbid obesity. The procedure is performed using standard five port technique. One year results are reviewed for its feasibility in our Asian patients. Twenty of 48 laparoscopic sleeve gastrectomies have a 1 year follow-up with four of them a revisional procedure for bands with complications. There were 11 males and 9 females (average age 43.6) and a representation of all four major ethnic groups. Average weight and BMI improved from 116.3 to 90.2 kg and 42.5 to 33.1 kg m(-2) after 1 year, respectively. Average weight loss was 26.1 kg and excess weight loss (in percent) was 49.6%. There was an improvement in diabetes mellitus, hypertension, obstructive sleep apnoea and asthma and three complications including two leaks and a gastro oesophageal spasm/stricture. Laparoscopic sleeve gastrectomy is safe and feasible as first-line surgery for morbid obesity and revisional procedures for band related complications in the short term. Further studies are required to elucidate the exact mechanisms of weight loss in the sleeve gastrectomy to answer the appropriateness of the variations in the technique and long-term weight loss and morbidity. PMID- 21818647 TI - Randomized clinical trial of laparoscopic Roux-en-Y gastric bypass versus laparoscopic sleeve gastrectomy for the management of patients with BMI < 50 kg/m2. AB - BACKGROUND: Laparoscopic Roux-en-Y gastric bypass (LRYGB) is currently the gold standard bariatric procedure for the treatment of morbid obesity. Laparoscopic sleeve gastrectomy (LSG) is a relatively innovative procedure which has been increasingly applied lately as a sole bariatric procedure. A randomized trial was conducted in a Greek population to evaluate perioperative safety and 3-years results. METHODS: Sixty patients with body mass index (BMI) <= 50 Kg/m(2) were randomized to LRYGB or LSG. Patients were monitored for 3 years postoperatively and throughout the study period weight loss, in terms of percent excess weight loss (%EWL), early and late complications, improvement of obesity related comorbidities and nutritional deficiencies were compared between groups. RESULTS: There was no death in either group and there was no significant difference in early (10% after LRYGB and 13% after LSG, P > 0.05) and late morbidity (10% in each group). Weight loss was significantly better after LSG in the first years of the study and at 3 years %EWL reached 62% after LRYGB and 68% after LSG (p = 0.13). There was no significant difference in the overall improvement of comorbidities. Nutritional deficiencies occurred at the same rate in the two groups except to vitamin B(12) deficiency which was more common after LRYGB (P = 0.05). CONCLUSION: LSG and LRYGB are equally safe and effective in the amelioration of comorbidities, while LSG is associated with fewer postoperative metabolic deficiencies, without the need of supplementation. Furthermore, LSG is a promising bariatric procedure, equally effective to LRYGB at 3 years follow up on weight reduction. PMID- 21818648 TI - Correlates of family health history discussions between college students and physicians: does family cancer history make a difference? AB - Effective communication between young adults and their healthcare providers can contribute to early detection of risk for developing cancer and establishment of lifelong habits for engagement in healthcare and health promotion behaviors. Our objectives were to examine factors influencing family health history discussions between college students and physicians and factors associated with perceptions about who is responsible for initiating such discussions. Data from an internet based study of 632 college students were analyzed. Approximately 60% of college student participants reported they had discussed their family health history with a physician. The perception that physicians are responsible for initiating family health history discussions was associated with being non-White and less than completely knowledgeable about cancer. Having a discussion with a physician was associated with being female, having a regular physician, perceiving genetics as a risk for developing cancer, and having a family member diagnosed with cancer. Understanding variation among college students' perceptions about their role in initiating health-history-related discussions and characteristics of those who have or have not discussed family health issues with physicians can inform healthcare practice to foster optimal healthcare interactions in early adulthood. PMID- 21818650 TI - Intrapericardial and retrocardial implantation of implantable cardioverter defibrillator lead in a child with type 3 long QT syndrome. AB - A 6-year-old girl with type 3 long QT syndrome was safely and successfully implanted with an implantable cardioverter-defibrillator (ICD) system. Prior to implantation, she had experienced uncontrollable life-threatening arrhythmia in spite of high-dose administration of mexiletine. An ICD coil lead for transvenous use was placed in the intrapericardial and retrocardial space and was connected to a generator placed in front of the posterior sheath of the right abdominal rectal muscle. Administration of a beta-blocker in addition to atrial pacing almost completely eliminated the patient's life-threatening arrhythmia attacks. Intrapericardial and retrocardial implantation of ICD coil leads might be useful for children. PMID- 21818649 TI - Clinical significance of thrombosis in an intracardiac blind pouch after a Fontan operation. AB - The univentricular heart after the Fontan operation may have a blind pouch formed by the pulmonary stump or rudimentary ventricle according to the anatomy before surgery. Thrombosis in an intracardiac blind pouch of patients with a univentricular heart is a hazardous complication. Because only a few reports have described this complication, the authors evaluated the clinical significance of thrombosis in an intracardiac blind pouch of a univentricular heart. They performed a retrospective review of medical records from August 1986 to December 2007. Four patients were confirmed as having thrombosis in a pulmonary artery stump and one patient as having thrombosis in a rudimentary ventricle shown by cardiac computed tomography (CT). This represents 1.85% (5/271) of patients with ongoing regular follow-up evaluation after the Fontan operation. The median age at diagnosis was 14.2 years. Two of the five patients were taking aspirin and one patient was taking warfarin when they were identified for the development of thrombosis. None of the patients demonstrated thrombosis in the Fontan tract or venous side of the circulation. Brain magnetic resonance imaging (MRI) showed that three patients had cerebral infarction and one patient had suggestive old ischemia. Three patients with thrombus in the pulmonary stump underwent pulmonary artery stump thrombectomy and pulmonary valve obliteration. One patient with thrombus in the rudimentary ventricle underwent ventricular septal defect (VSD) closure with thrombectomy. Thrombus in a blind pouch could cause systemic thromboembolism despite little blood communication. Therefore, surgical modification of the pulmonary stump and VSD closure of the rudimentary ventricle are required to reduce the risk of later thrombus formation. Clinicians should not overlook the possibility of thrombus in a ligated pulmonary artery stump or a rudimentary ventricle after the Fontan operation, which may increase the risk of embolic stroke for patients with single-ventricle physiology. PMID- 21818651 TI - Necrotizing pneumonia in adults: multidisciplinary management. PMID- 21818652 TI - The obesity paradox in surgical intensive care unit patients. AB - PURPOSE: To investigate the possible impact of obesity, as assessed by body mass index (BMI), on outcome in surgical intensive care unit (ICU) patients. METHODS: Prospectively collected data from all consecutive adult patients admitted to our ICU between January 2004 and January 2009 were analysed retrospectively. BMI was calculated using the formula: BMI = body weight/height(2) (kg/m(2)), and patients were grouped as underweight (<18.5 kg/m(2)), normal weight (18.5-24.9 kg/m(2)), overweight (25-29.9 kg/m(2)), obese (30-39.9 kg/m(2)) and very obese (>=40 kg/m(2)). RESULTS: Among the 12,938 patients who were admitted to our ICU during the study period, 9,935 (76.8%) had complete height and weight data and constituted the study group. The mean BMI was 27.1 +/- 5.0 kg/m(2). Overall, 34.4% of the study population had normal BMI, 1.8% were underweight, 41.2% were overweight, 20.8% were obese and 1.8% were very obese. The ICU mortality rate was similar among BMI subgroups, but hospital mortality was higher in underweight patients than in patients with normal BMI (17.8% versus 11.1%, P = 0.006). On multivariate Cox regression analysis, being overweight [hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.74-0.99, P = 0.047] or obese (HR = 0.83, 95% CI = 0.69-0.99, P = 0.047) was independently associated with lower 60-day in-hospital mortality, with normal BMI as the reference category. Risk of death increased in very obese patients, especially after neurosurgical procedures (HR = 0.3, 95% CI = 1.06-8.48, P = 0.039). CONCLUSION: In this cohort of surgical ICU patients, being overweight or obese was associated with decreased risk of 60-day in hospital mortality. PMID- 21818653 TI - Pairing words with syntactic frames: syntax, semantics, and count-mass usage. AB - Two experiments examined English speakers' choices of count or mass compatible frames for nouns varying in imageability (concrete, abstract) and noun class (count, mass). Pairing preferences with equative (much/many) and non-equative (less/fewer) constructions were compared for groups of teenagers, young adults, and older adults. Deviations from normative usage were, for all ages, larger for count than for mass nouns, for the non-equative than for the equative construction, and for abstract count than for concrete count nouns. These results indicate that mass syntax is not a developmental default, support proposals that mass syntax is more flexible than count syntax, verify the non-prescriptive use of less with count nouns, and extend the interaction of syntax and semantics in noun classification to older ages, with older adults showing a reduced reliance on semantics. Knowledge of frame compatibility and knowledge of noun class are also shown to be largely independent. PMID- 21818654 TI - Foster care history and HIV infection among drug-using African American female sex workers. AB - Foster care has been associated with increased HIV risk behaviors among youth, yet long-term association with HIV infection has not been examined. This study explored the associations between foster placement, victimization, mental health, onset of sex work and HIV infection among highly vulnerable female sex workers. 562 drug-involved African American women were enrolled into an intervention study to increase health services utilization and reduce HIV risk. Seventeen percent reported a history of foster placement. Foster history was associated with significantly lower educational attainment, higher victimization, and more severe mental health problems. Women with foster histories reported significantly earlier entry into paid sex work, with some 62% active in the sex trade before age 18. Multivariate analyses found that foster care was independently associated with HIV seropositivity, and that early sex work partially mediated this association. The potential long-term health vulnerabilities associated with foster placement are understudied and warrant additional research. PMID- 21818655 TI - Influence of habitat complexity and landscape configuration on pollination and seed-dispersal interactions of wild cherry trees. AB - Land-use intensification is a major cause for the decline in species diversity in human-modified landscapes. The loss of functionally important species can reduce a variety of ecosystem functions, such as pollination and seed dispersal, but the intricate relationships between land-use intensity, biodiversity and ecosystem functioning are still contentious. Along a gradient from forest to intensively used farmland, we quantified bee species richness, visitation rates of bees and pollination success of wild cherry trees (Prunus avium). We analysed the effects of structural habitat diversity at a local scale and of the proportion of suitable habitat around each tree at a landscape scale. We compared these findings with those from previous studies of seed-dispersing birds and mammals in the same model system and along the same land-use gradient. Bee species richness and visitation rates were found to be highest in structurally simple habitats, whereas bird species richness--but not their visitation rates--were highest in structurally complex habitats. Mammal visitation rates were only influenced at the landscape scale. These results show that different functional groups of animals respond idiosyncratically to gradients in habitat and landscape structure. Despite strong effects on bees and birds, pollination success and bird seed removal did not differ along the land-use gradient at both spatial scales. These results suggest that mobile organisms, such as bees and birds, move over long distances in intensively used landscapes and thereby buffer pollination and seed-dispersal interactions. We conclude that measures of species richness and interaction frequencies are not sufficient on their own to understand the ultimate consequences of land-use intensification on ecosystem functioning. PMID- 21818656 TI - Minimally invasive surgery for achalasia in patients >40 years: more favorable than anticipated. AB - PURPOSE: The efficacy of Heller myotomy in patients >40 years-a significant predictor suggesting a favorable response to pneumatic dilation-has been questioned. The aim of our study was to evaluate the results obtained in patients aged <40 and >40 years undergoing minimally invasive surgery (MIS) for achalasia. METHODS: In January 2008, we established the MIS technique for achalasia in our clinic. In the following period from January 2008 to March 2011, 74 patients underwent primary laparoscopic myotomy for achalasia. The procedure was accomplished with an anterior 180 degrees semifundoplication according to Dor in all patients. The Eckardt score and the Gastrointestinal Quality of Life Index (GQLI) served as outcome measures. RESULTS: The median age of patients was 45.5 years (range, 18-85 years) with a median duration of preoperative achalasia symptoms of 57 months (range, 2-468 months). There were no conversions to open surgery and-except for one patient with a sterile pleural effusion-no postoperative complications. At a median follow-up of 12 months, the preoperative Eckardt score of 7.0 (range, 3-12) was found to be significantly decreased to a median of 2 (range, 0-6; P < 0.001). With regard to patients <40 and >40 years, the postoperative Eckardt score obtained in the older patient population was not significantly lower (P = 0.074). There was no statistically significant difference between the two groups with respect to the postoperative GQLI (P = 0.860). Neither gender nor preoperative Botox injection or pneumatic dilation inserted a significant influence on the postoperative clinical outcome (P > 0.05). CONCLUSIONS: Laparoscopic Heller myotomy for achalasia is associated with a high success rate as the primary therapeutic option and after failure of endoscopic therapy. It can be performed safely and with favorable outcomes also in patients >40 years. However, the long-term durability of the procedure remains to be established. PMID- 21818657 TI - Reduced cell proliferation and neuroblast differentiation in the dentate gyrus of high fat diet-fed mice are ameliorated by metformin and glimepiride treatment. AB - We investigated the effects of a high-fat diet (HFD) and the subsequent treatment of metformin (met) and glimepiride (glim), which are widely prescribed for type 2 diabetes, on cell proliferation and neuroblast differentiation using Ki67 and doublecortin (DCX) immunohistochemistry, respectively. Animals were fed low-fat diet (LFD) or HFD for 8 weeks. After 5 weeks of the HFD treatment, met alone or met + glim was administered orally once a day for 3 weeks. Body weight and food intake were much higher in the HFD + vehicle-treated group than the LFD-treated group. The administration of met or met + glim to the HFD-treated group resulted in a decrease in weight gain and food intake. Ki67-immunoreactive ((+)) nuclei, DCX(+) neuroblasts and brain-derived neurotrophic factor (BDNF) protein levels were markedly decreased in the dentate gyrus (DG) of the HFD + vehicle-treated group compared to the LFD-treated group. The administration of met or met + glim to the HFD-treated group prevented the reduction of Ki67(+) nuclei, DCX(+) neuroblasts, BDNF levels in the DG. The intraventricular injection of K252a (a BDNF receptor blocker) to the HFD-treated group treated met or met + glim distinctively lowered the reduction of cell proliferation and neuroblast differentiation induced by HFD. These results suggest that a HFD significantly reduces cell proliferation and neuroblast differentiation by reducing BDNF levels and these effects are ameliorated by treatment with met or met + glim. PMID- 21818658 TI - Dopamine content in the striatum and expression changes of Bad and Bcl-2 in elderly rats with abnormal behavior. AB - To determine the dopamine (DA) content in the striatum and the expression changes of the apoptosis-associated proteins Bad and Bcl-2 in the substantia nigra compacta (SNc) in elderly rats with abnormal behavior. Fifty three Sprague-Dawley rats were divided into three groups: adult, age-motorplus (normal behavior) and aged-motorminus (abnormal behavior) using the hanger test. The DA content in the striatum and the expression of tyrosine hydroxylase (TH), Bad and Bcl-2 in the SNc were measured by HPLC/MS (high performance liquid chromatogram-mass spectra) and Western Blot. (1) The results from the hanger test demonstrated that the scores and latency of aged-motorminus group were lower than the age-motorplus group. (2) Results from HPLC-MS showed that, compared with the age-motorplus and adult group, the content of DA in elderly rat striata decreased significantly, with a statistically significant difference. (3) The Western Blot demonstrated that, compared with the adults, the expression of TH in elderly rats significantly decreased, but the difference was not significant between the aged motorminus group and the age-motorplus group. Compared with the age-motorplus and the adult group, the expression of Bad increased but Bcl-2 decreased in the aged motorminus group. The decrease in TH content in the SNc correlated with the aging of rats. The decrease in DA content in the striatum may correlate with the abnormal behavior in elderly rats, which could be ascribed to the variations in Bad and Bcl-2. PMID- 21818659 TI - The effects of single and repeated exposure to 2.45 GHz radiofrequency fields on c-Fos protein expression in the paraventricular nucleus of rat hypothalamus. AB - This study investigated the effects of microwave radiation on the PVN of the hypothalamus, extracted from rat brains. Expression of c-Fos was used to study the pattern of cellular activation in rats exposed once or repeatedly (ten times in 2 weeks) to 2.45 GHz radiation in a GTEM cell. The power intensities used were 3 and 12 W and the Finite Difference Time Domain calculation was used to determine the specific absorption rate (SAR). High SAR triggered an increase of the c-Fos marker 90 min or 24 h after radiation, and low SAR resulted in c-Fos counts higher than in control rats after 24 h. Repeated irradiation at 3 W increased cellular activation of PVN by more than 100% compared to animals subjected to acute irradiation and to repeated non-radiated repeated session control animals. The results suggest that PVN is sensitive to 2.45 GHz microwave radiation at non-thermal SAR levels. PMID- 21818661 TI - Plasticity and genotype * environment interactions for locomotion in Drosophila melanogaster larvae. AB - Locomotion is a primary means by which animals interact with the world. To understand the contribution of genotype * environment interactions to individual differences in D. melanogaster larval locomotion we investigated phenotypic sensitivity to environmental changes in four strains of this species and their F1 hybrids. We also investigated to what extent flexibility and plasticity of locomotion depend upon larval age. Specifically, we examined larval locomotion at 48 and 96 h of development on three different substrates. Locomotion was influenced by the structure of the substrate, but this depended on both the genotype and larval age. At 48 h of larval development phenotypic variation in locomotion was attributable to both genotype * environment interactions and genotypic differences among the larvae, while at 96 h of age, differences were mainly due to genotype * environment interactions. An analysis of variance of the 4 * 4 diallel cross made at 48 and 96 h of development showed, depending on the cross, either dominance to increase/decrease locomotion, overdominance to increase/decrease locomotion, or no dominance to increase/decrease locomotion. Furthermore, the diversity of behavioral responses in the F1 hybrids was greater at 96 than at 48 h of larval development. Our results demonstrate that genotype * environment interactions result in plasticity of D. melanogaster larval locomotion, which makes sense in light of the fact that larvae, in the wild, develop in heterogeneous and rapidly changing environments. PMID- 21818660 TI - Treatment of Peyronie's disease: 2012 update. AB - Peyronie's disease (PD) is the occurrence of a fibrous inelastic scar of the tunica albuginea of the penis. It is a relatively common disorder among men, with a reported prevalence of 3% to 8%. It is often associated with penile pain, anatomical deformities in the erect state, and difficulty with intromission. Because the exact pathophysiology of PD remains unknown and standards for evaluating or reporting treatment outcomes are unclear, research on effective therapies has been limited. The benefits of nonsurgical treatment options are conflicting and further controlled studies are required before any therapy can be fully recommended. The success of surgery has been well documented; however, surgery is invasive and costly and carries potential side effects. Patients who report stable disease that has been present for longer than 12 months and who experience penile deformity preventing satisfactory sexual intercourse are best suited for surgery. Additionally, failed conservative management and a patient's preference for definitive correction are important additional indications for surgical treatment. PMID- 21818662 TI - Stable genetic effects on symptoms of alcohol abuse and dependence from adolescence into early adulthood. AB - Relatively little is known about how genetic influences on alcohol abuse and dependence (AAD) change with age. We examined the change in influence of genetic and environmental factors which explain symptoms of AAD from adolescence into early adulthood. Symptoms of AAD were assessed using the four AAD screening questions of the CAGE inventory. Data were obtained up to six times by self report questionnaires for 8,398 twins from the Netherlands Twin Register aged between 15 and 32 years. Longitudinal genetic simplex modeling was performed with Mx. Results showed that shared environmental influences were present for age 15 17 (57%) and age 18-20 (18%). Unique environmental influences gained importance over time, contributing 15% of the variance at age 15-17 and 48% at age 30-32. At younger ages, unique environmental influences were largely age-specific, while at later ages, age-specific influences became less important. Genetic influences on AAD symptoms over age could be accounted for by one factor, with the relative influence of this factor differing across ages. Genetic influences increased from 28% at age 15-17 to 58% at age 21-23 and remained high in magnitude thereafter. These results are in line with a developmentally stable hypothesis that predicts that a single set of genetic risk factors acts on symptoms of AAD from adolescence into young adulthood. PMID- 21818663 TI - Genetic variance of body mass index from childhood to early adulthood. AB - Research has been conducted to determine genetic and environmental components of body mass index (BMI). The portion of phenotypic correlation attributed to genetic, and environmental effects, the effects of puberty stage on BMI means and variances, and consistency of parent/twin report remain largely unknown. The current study seeks to address these questions using four waves of data from 1480 twin pairs in the Swedish Twin Registry: Swedish Twin Study of Child and Adolescent Development. Two Cholesky decomposition models were fit (parental and twin report). For wave 2, a univariate model was fit allowing puberty stage moderation. Parent/twin concordance of reported BMI is high. Genetic factors are largely responsible for phenotypic correlation: puberty stage has a significant effect on BMI variance, with higher genetic variance at more advanced puberty stages. Results provide additional information about this phenotype and suggest early adolescent and parental reports for BMI are roughly equivalent. PMID- 21818665 TI - [Iris sutures]. AB - Iris defects can be congenital, traumatic or iatrogenic in origin and affect either the base of the iris or the stroma including the pupillary margin. A differentiation must be made between the occlusion of iridodialyses, by which the detached iris must be fixed on the sclera and defects of the stroma of the iris where parts of the iris are combined to cover the defect. A wide variety of suture techniques have been suggested over the years for iridoplasty to cover defects. Nowadays it is normal to use iris sutures with a closed anterior chamber, which have all the advantages of minimally invasive surgery. PMID- 21818664 TI - Immune tolerance induction for patients with severe hemophilia A: a critical literature review. AB - The development of inhibitors that neutralize the function of clotting factor VIII (FVIII) is currently the most challenging complication associated with the treatment of hemophilia A as it increases the disease-related morbidity and mortality. Immune tolerance induction (ITI) is the only documented strategy to eradicate persistent inhibitors in severe hemophilia A patients. Several studies have been conducted so far to identify patient- and treatment-related factors associated with greater ITI success. The currently available literature on ITI in hemophilia A will be critically reviewed in this article. In particular, we will focus on the role of the type of FVIII product on ITI outcome by analyzing the clinical and experimental data. PMID- 21818666 TI - [Reconstructive iris surgery : implants and techniques]. PMID- 21818667 TI - Comparative cellular and molecular analysis of cytotoxicity and apoptosis induction by doxorubicin and Baneh in human breast cancer T47D cells. AB - It is now widely accepted that dietary phytochemicals inhibit cancer progression and enhance the effects of conventional chemotherapy. In this report, we comparatively studied the cellular and molecular aspects of apoptosis induction by the methanolic extract of Baneh fruit skin in comparison to Doxorubicin (Dox), a well-known anticancer drug, in human breast cancer T47D cells. The MTT assay was used to determine the antiproliferative effects. The flow cytometric and microscopic analyses were done to evaluate the apoptosis induction. Furthermore, western blot analyses have been done to study the role of key molecular players of apoptosis including caspase 3 and PARP. The Baneh extract showed strong antiproliferative activity against T47D cells in a dose- and time-dependent manner that was comparable to and even stronger than Dox in certain concentrations. Analysis of Baneh-treated cells by flow cytometry and fluorescence microscopy indicated strong apoptosis induction and nuclear morphological alterations similar to or greater than Dox. Finally, molecular analysis of apoptosis by western blotting proved activation of caspase 3 followed by poly ADP ribose polymerase (PARP) cleavage more efficiently in Baneh than in Dox treated cancer cells. These findings indicate that Baneh extract contains phytochemicals which act as inhibitor of cell proliferation and inducer of apoptosis in human breast cancer T47D cells that makes it a potentially good candidate for new anticancer drug development. PMID- 21818669 TI - Solitary fibrous tumor of the thyroid gland: a report of two cases with an analysis of their clinical and pathological features. AB - Solitary fibrous tumors of the thyroid gland are rare soft-tissue neoplasms and only 24 cases have been reported in the literature to date. We describe two patients who underwent surgery for rapidly growing thyroid nodes of uncertain nature on cytology. At the final histological examination, they proved to be fibrous tumors of the thyroid gland that were CD-34, BCL2, CD-99, and Ki-67 positive, like other known cases. Neither of these two cases have recurred so far. PMID- 21818668 TI - Drivers of surgery for the degenerative hip, knee, and spine: a systematic review. AB - BACKGROUND: Surgical treatment for degenerative conditions of the hip, knee, and spine has an impact on overall healthcare spending. Surgical rates have increased dramatically and considerable regional variation has been observed. The reasons behind these increasing rates and variation across regions have not been well elucidated. QUESTIONS/PURPOSES: We therefore identified demographic (D), social structure (SS), health belief (HB), personal (PR) and community resources (CR), and medical need (MN) factors that drive rates of hip, knee, and spine surgery. METHODS: We conducted a systematic review to include all observational, population-based studies that compared surgical rates with potential drivers (D, SS, HB, PR, CR, MN). We searched PubMed combining key words focusing on (1) disease and procedure; (2) study methodology; and (3) explanatory models. Independent investigators selected potentially eligible studies from abstract review and abstracted methodological and outcome data. From an initial search of 256 articles, we found 37 to be potentially eligible (kappa 0.86) but only 28 met all our inclusion criteria. RESULTS: Age, nonminority, insurance coverage, and surgeon enthusiasm all increased surgical rates. Rates of arthroplasty were higher for females with higher education, income, obesity, rurality, willingness to consider surgery, and prevalence of disease, whereas spinal rates increased with male gender, lower income, and the availability of advanced imaging. CONCLUSIONS: Regional variation in these procedures exists because they are examples of preference-sensitive care. With strategies that may affect change in factors that are potentially modifiable by behavior or resources, extreme variation in rates may be reduced. PMID- 21818670 TI - Correlation between serum electrolytes and fasting glucose and Hb1Ac in Saudi diabetic patients. AB - In subjects with impaired insulin action, alterations of the serum sodium and potassium concentrations have been reported. The resulting cationic imbalance, along with the osmotic effect of the elevated sugar levels, could influence the course of diabetes mellitus management. Therefore, this study was conducted to compare the fasting blood glucose and HbA1c levels with those of the serum electrolytes. Blood samples were collected for assessment of HbA1c, fasting blood glucose (FBS), and electrolytes using different automated methods. A significant association between the serum sodium and FBS levels among types 1 and 2 insulin treated patients, and type 2 oral agent patients was observed. A total of 138 diabetic subjects were randomly selected from any gender aged between 25 and 65 years at the University Diabetes Center, King Saud University, Riyadh KSA. The subjects were classified into types 1 or 2 DM using ADA criteria. Blood samples were collected for assessment of HbA1c, FBS, and electrolytes using different automated methods. It showed a significant association between serum sodium, FBS among type 1, type 2 insulin treated, and type 2 oral agent groups. However, the association of sodium and HbA1c was insignificant when analyzed individually. A statistically significant association (P < 0.001) was observed between the levels of serum sodium and the fasting blood glucose levels. This study demonstrated significant reduction in serum sodium level among types 1 or 2 diabetic patients especially among insulin-treated patients. No significant association was demonstrated by serum potassium with FBS and degree of diabetes control. PMID- 21818671 TI - Impact of infliximab adherence on Crohn's disease-related healthcare utilization and inpatient costs. AB - INTRODUCTION: Few published reports have described the impact of adherence with biologic agents on hospitalizations and inpatient costs in Crohn's disease (CD). METHODS: A retrospective claims analysis using the IMS LifeLink Health Plan Claims Database between September 1, 2004 and June 30, 2009 was conducted. Continuous enrollment for 12 months before and 12 months after the index date was required. Patients were required to have >=2 claims with an International Classification of Diseases, 9th Edition, Clinical Modification diagnosis code for CD (555.xx) preindex, be >=18 years of age at index, and have >=4 infliximab infusions with a gap no greater than 12 weeks between each infusion. Patients with 7-9 infliximab infusions (12 months postindex) were considered adherent; patients with 4-6 infliximab infusions were considered nonadherent. RESULTS: In total, 638 patients were included in the analyses (mean age, 43 years; 58% female in the adherent group and 53% in the nonadherent group). The number of patients who met the definition of adherence was 466 (73%). A smaller proportion of adherent patients had a CD-related emergency room visit, compared with nonadherent patients (11% vs. 17%, P=0.029). A smaller proportion of adherent patients required CD-related hospitalization, compared with nonadherent patients (8% vs. 12%, P=0.117). Among those hospitalized, adherent patients had fewer mean [median] days in the hospital (5.9 [5] days), compared with nonadherent patients (12.8 [8] days, P=0.015). Mean [median] hospital costs were significantly lower for adherent patients ($13,427 [$9,352]), compared with nonadherent patients ($37,783 [$28,864], P=0.001). Multivariate analyses confirmed lower inpatient (P<0.001) costs for adherent versus nonadherent patients. CONCLUSION: Adherence with infliximab therapy during the first year of treatment in patients with CD was associated with a shorter hospital length of stay and lower inpatient costs compared with nonadherent patients. Strategies for increasing adherence rates to infliximab maintenance therapy may be valuable in reducing hospitalizations and inpatient costs in patients with CD. PMID- 21818672 TI - The human papillomavirus (HPV) vaccine and cervical cancer: uptake and next steps. AB - Infection with a high-risk type of the human papillomavirus (HPV) is a major contributing factor in the vast majority of cervical cancers. Dissemination of the HPV vaccine is critical in reducing the risk of the disease. This descriptive review of HPV vaccine uptake in papers published between 2006 and 2011 focuses on studies conducted in girls and young women. In the United States, rates of immunization as per the protocol for teens (age 13-17 years) range from 6% to 75% and those for young women (age 18-26 years) range from 4% to 79%, although the samples and data collection methods vary. The epidemiology of HPV, the mechanisms of action, protocols for vaccine immunization, rates of uptake, and barriers to vaccination at the policy, provider, and patient levels are reviewed. Various intervention techniques are described, and policy-level programs, such as legislation supporting mandates, subsidized public education, and cost-reduction initiatives, are also explored. Increased distribution of the HPV vaccine in school-based clinics, evidencebased scripts for provider counseling of young patients and their parents, concurrent immunizations to adolescents, prevention visits, greater patient education and outreach, and the dissemination of academic detailing can help to boost vaccine uptake, particularly in underresourced communities. Population-based surveillance is necessary for robust estimates of uptake over time. Additional research is needed to comprehensively examine socio demographic, psychosocial, and sociocultural factors that predict vaccine uptake according to the protocol. Increased study of the vaccine's long-term effectiveness, in both males and females and among extended age groups, is warranted. PMID- 21818673 TI - Febrile neutropenia in adjuvant docetaxel and cyclophosphamide (TC) with prophylactic pegfilgrastim in breast cancer patients: a retrospective analysis. AB - US Oncology Research Trial 9735 reported that TC improved overall survival when compared to doxorubicin and cyclophosphamide in early-stage breast cancer. Despite 61% grades 3-4 neutropenia in the TC arm, only 5% of patients developed febrile neutropenia (FN) without primary prophylactic GCSF (ppGCSF). TC has risen in popularity, particularly in older patients or in those where an anthracycline is contraindicated. Other studies examining the toxicity of TC without ppGCSF reported a higher incidence of FN between 23 and 46%. We reviewed our institutional experience with ppGCSF and the TC regimen. Women treated with adjuvant TC and pegfilgrastim at Roswell Park Cancer Institute were identified from the pharmacy database between 8/2006 and 11/2010. Patient characteristics and comorbidities were abstracted. Endpoints included incidence of FN, hematologic toxicities, relative dose intensity (RDI), and other acute complications. Docetaxel 75 mg/m(2) and cyclophosphamide 600 mg/m(2) were given every 21 day/cycle for a planned four cycles. All patients received pegfilgrastim 6 mg on day 3. One hundred and eleven women with median age of 56 years (27-79) were identified. Twenty-two percent of patients were >= 65 at diagnosis. Eight patients developed FN (7%). Ninety-five patients (86%) were able to complete four cycles. Completion rate was significantly lower in patients with age >= 65 (71% vs. 90%; P = 0.02). Incidence of hospitalization, delay, RDI <85%, and dose reduction were not significantly different between the age groups. The overall incidence of FN was 7%. Older patients were significantly less likely to complete four cycles of TC as planned. ppGCSF should be strongly considered in breast cancer patients receiving adjuvant TC chemotherapy. PMID- 21818674 TI - Sea-age variation in maiden Atlantic salmon spawners: phenotypic plasticity or genetic polymorphism? AB - Atlantic salmon exhibit a partially heritable polymorphism in which the morphs are distinguished by the duration and location of the sea-phase of their life cycle. These morphs co-occur, albeit in characteristically different proportions, in most Scottish rivers and in both the spring and autumn spawner runs; early running fish being generally associated with upland spawning locations while late running fish are associated with lowland spawning. Thus, differences in riverine and marine environment appear to be linked to differences in the relative abundance of the morphs, rather than to the specific morph which is optimally adapted. In this paper, we report a model-based synthetic study aimed at understanding the key dynamic elements which determine the long-term stability of this polymorphism, and thus determine the relative abundance of the various sea age morphs. Given the recent accumulation of evidence for a genetic basis for the polymorphism, we argue that the key dynamic mechanism which equalises the realized fitness of the sea-age morphs must be one or more morph-specific density dependencies in the riverine phase of the life-history. We explore a number of specific mechanisms, firmly based in known salmon biology, by which such morph specific density dependence could occur and investigate the robustness of the co existence which they imply. We conclude that the co-occurrence of multiple sea age morphs of Atlantic salmon in Scottish rivers is a stable genetic polymorphism, maintained by some combination of physical separation and asymmetric competition between spawners of different morphs or the riverine stages of their offspring or both. PMID- 21818675 TI - Case report: 16-Year-old male with autistic disorder with preoccupation with female feet. AB - This paper highlights clinical challenges faced when diagnosing and then treating an individual presenting to a child and adolescent psychiatry clinic because of unwelcome comments he made to female peers about their feet. Novel use of exposure therapy helped him effectively decrease his comments from 1 to 2 times per month to once every 6 months. Conceptualizing this case as the individual's failed attempts toward relationships with females instead of sexual harassment led to diminution of problematic behavior. Implications for diagnosis and treatment of individuals with Autistic Disorder displaying problematic behaviors are presented. PMID- 21818676 TI - Brief report: Hyperbaric oxygen therapy (HBOT) in children with autism spectrum disorder: a clinical trial. AB - We sought to determine whether HBOT leads to parental reported behavioral changes and alterations in cytokines in children with ASD. Ten children completed 80 sessions of HBOT and all improved by 2 points on the clinician-rated CGI-I scale (much improved) as well as several parent-completed measures of behavior. The lack of a control group limits the ability to determine if improvements were related to HBOT. Enrolled children did not exhibit abnormal cytokine levels at baseline and no significant changes in mean cytokine levels were observed. Although this study was limited by the small sample size and by the variable nature of cytokines, we found no evidence that HBOT affects cytokine levels or that cytokine levels were associated with behavioral changes. PMID- 21818677 TI - Assessment of the prerequisite skills for cognitive behavioral therapy in children with and without autism spectrum disorders. AB - The purpose of this study was to assess the cognitive skills of children with autism spectrum disorders (ASD) thought to be necessary for Cognitive Behavioral Therapy (CBT). Forty children with ASD and forty age-matched typically developing children between the ages of 7-12 years participated. Groups were comparable with regard to nonverbal IQ, but children with ASD had significantly lower verbal IQ. Children completed three CBT-related tasks requiring emotion recognition, discrimination among thoughts, feelings and behaviors, and cognitive mediation. With the exception of the emotion recognition task, children with ASD performed comparably to typically developing children and with a high rate of accuracy. PMID- 21818678 TI - [Resistance of Anopheles gambiae s.l. to pyrethroids and DDT at Tiassalekro, an irrigated rice-growing village in the southern forest of Ivory Coast]. AB - An assessment of the sensitivity of Anopheles gambiae s.l.to three pyrethroids (alphacypermethrin, permethrin, deltamethrin) and DDT has been carried out with a laboratory strain (Kisumu reference sensitive strain) and a wild strain (Tiassalekro strain) using larvae from an irrigated rice-growing area of Tiassalekro, located in the southern forest of Ivory Coast. The sensitivity tests were performed according to the standard WHO cylinder tests with adult female A. gambiae s.l. aged 2 to 4 days. The results showed that the strain of Tiassalekro is resistant to the three tested pyrethroids and DDT. The molecular forms M and S were identified, with a predominance of M form. The resistance mechanism involved is the Kdr mutation. In this region, control measures against malaria vectors by using bed nets impregnated with these insecticides or household sprays could be compromised. PMID- 21818679 TI - [Effect of intermittent presumptive treatment with sulfadoxine-pyrimethamine on the acquisition of anti-VAR2CSA antibodies in pregnant women living in a hypoendemic area in Senegal]. AB - The impact of intermittent presumptive treatment (IPT) on the immunity of pregnant women in Senegal is still not very well known. We conducted a prospective study at the Roi-Baudouin maternity of Guediawaye in Senegal to assess IgG antibodies production against MSP1, GLURP and DBL5 in pregnant women under IPT. Blood samples were collected from the participating women at inclusion and delivery. Samples were analyzed after centrifugation for the detection of IgG antibodies in sera by Elisa. Informed consent was given by each study participant prior to their inclusion. A total of 101 eligible women aged from 18 to 44 were included in this study. Multigravidae women represented 70.3% of the study population, whereas primigravidae accounted for 29.7%. The IgG level decreased slightly from inclusion to delivery for the women with regard to anti-MSP1 (83.1at inclusion versus 79.5 at delivery, p = 0.52) as well as anti-GLURP-R2 (84.1 at inclusion versus 75.9 at delivery, p = 0.16). After adjustment for number of pregnancies, there was a significant decrease in the production of anti VAR2CSA between inclusion and delivery (p < 0.05). By reducing the incidence of malaria during pregnancy, IPT reduced the acquisition of placental parasites antibodies suppressors which could delay the development of protective immunity against malaria. The application of IPT in pregnant women would thus be more appropriate in hypoendemic areas where malaria exposure is lower. PMID- 21818680 TI - [Comparison of efficacy of chloroquine versus sulfadoxine-pyrimethamine in malaria prevention in pregnant women in the Toamasina region (Madagascar)]. AB - Malaria still represents a great cause of death in sub-Saharan African areas, mainly among pregnant women. We conducted this prospective study during two years in a malaria-endemic stable region in the east of Madagascar (Toamasina) with an aim to compare the efficacy of weekly chloroquine (CQ) and the use of intermittent presumptive treatment by sulfadoxine-pyrimethamine (SP). 519 pregnant women were included in this study (CQ = 285; SP = 256). Socio demographical characteristics of each group were identical. We found more peripheral parasitemia (CQ = 8.07% vs SP = 2.73%; P = 0.0068) and severe malaria in the CQ group (CQ = 1.75% vs SP = 0%; P = 0.0332). Anemia was more frequent in the CQ group (CQ = 4.21% vs SP = 0.35%; P = 0.0038). Placental infestation rate was also higher in the CQ group (CQ = 7.01% vs SP = 0.39%; P = 0.00001). Low birth weight and fetal death were lower in the SP group respectively [(CQ = 4.21% vs SP = 0.78%; P = 0.0121) and (CQ = 1.75%vs SP = 0%; P = 0.0332)]. PMID- 21818681 TI - Heart failure with preserved ejection fraction in the elderly: scope of the problem. AB - Heart failure is an epidemic in the elderly and has become a leading cause for hospitalization and death. Heart failure with preserved ejection fraction (HFPEF) is more common than heart failure with reduced ejection fraction (HFREF) but disease identification remains challenging. Current criteria rely on symptoms of poor exercise tolerance, preserved ejection fraction and laboratory evidence for elevated filling pressures. Each of these clinical parameters is difficult to evaluate in the elderly and reduce the certainty of diagnosis. Aging is associated with changes in the peripheral vasculature, pulmonary function, oxygen transport and skeletal muscle function, all key determinants of exercise capacity. Furthermore, co-morbid conditions such as chronic obstructive pulmonary disease are common in the elderly and cloud the interpretation of symptoms. The choice of ejection fraction (EF) 45-50% as preserved appears arbitrary as there is evidence that the lower limit for EF in elderly women is much higher. B-type natriuretic peptide has emerged as a popular blood biomarker of heart failure and increased filling pressures but appears to have trouble discriminating HFPEF from normal elderly controls. Regardless of the difficulties in diagnosis, several population studies show that HFPEF incidence and prevalence are on the rise especially in those >70 years of age. Co-morbid diseases are common in HFPEF, and these patients often die from non-cardiac causes. Future studies need to emphasize a holistic approach to HFPEF and identify whether there are diagnostic or therapeutic targets outside of the heart. PMID- 21818682 TI - Potential analytical applications of lysenin channels for detection of multivalent ions. AB - Transmembrane protein transporters possessing binding sites for ions, toxins, pharmaceutical drugs, and other molecules constitute excellent candidates for developing sensitive and selective biosensing devices. Their attractiveness for analytical purposes is enhanced by the intrinsic amplification capabilities shown when the binding event leads to major changes in the transportation of ions or molecules other than the analyte itself. The large-scale implementation of such transmembrane proteins in biosensing devices is limited by the difficulties encountered in inserting functional transporters into artificial bilayer lipid membranes and by the limitations in understanding and exploiting the changes induced by the interaction with the analyte for sensing purposes. Here, we show that lysenin, a pore-forming toxin extracted from earthworm Eisenia foetida, which inserts stable and large conductance channels into artificial bilayer lipid membranes, functions as a multivalent ion-sensing device. The analytical response consists of concentration and ionic-species-dependent macroscopic conductance inhibition most probably linked to a ligand-induced gating mechanism. Multivalent ion removal by chelation or precipitation restores, in most cases, the initial conductance and demonstrates reversibility. Changes in lipid bilayer membrane compositions leading to the absence of voltage-induced gating do not affect the analytical response to multivalent ions. Microscopic current analysis performed on individual lysenin channels in the presence of Cu(2+) revealed complex open closed transitions characterized by unstable intermediate sub-conducting states. Lysenin channels provide an analytical tool with a built-in sensing mechanism for inorganic and organic multivalent ions, and the excellent stability in an artificial environment recommend lysenin as a potential candidate for single molecule detection and analysis. PMID- 21818684 TI - Novel regulation of endothelin-1 promoter activity by protein kinase C. AB - Endothelin-1 (ET-1) is produced in unusually large amounts by the renal collecting duct and acts locally to control renal salt and water excretion and arterial pressure; disorders of collecting duct ET-1 activity can cause marked hypertension. The mechanisms regulating collecting duct ET-1 synthesis are, however, poorly understood. In this study, we investigated the role of protein kinase C (PKC), a known regulator of ET-1 production in endothelial cells, in (1) the control of collecting duct ET-1 production; and (2) the modulation of ET-1 promoter region activity. Cultured rat inner medullary collecting duct (IMCD) cells were studied. Calphostin C, a PKC inhibitor, greatly reduced IMCD ET-1 release. Sustained exposure to phorbol myristate acetate (PMA) also decreased ET 1 secretion. PKC inhibition decreased steady-state ET-1 mRNA content. A brief exposure (15 min) to PMA augmented ET-1 mRNA levels, while prolonged PMA exposure (120 min) reduced ET-1 mRNA content, PKC inhibition did not affect ET-1 mRNA stability. Transfection of ET-1 promoter-luciferase reporter constructs into IMCD cells demonstrated that PKC inhibition reduced activity of only the larger promoter fragments (containing at least 1,725 bp 5' to the ET-1 gene transcription start site). Mutation of a previously identified AP-1 site at -186 in the ET-1 promoter greatly reduced activity of transfected ET-1 promoter reporter constructs (containing 366 or 1,725 bp 5' to the transcription start site); however, this region appears not to be regulated by PKC in IMCD cells. In summary, PKC stimulates collecting duct ET-1 synthesis via transcriptional activation of the ET-1 promoter. Such transcriptional activation occurs at a heretofore undescribed PKC-regulated region of the ET-1 promoter. PMID- 21818683 TI - RNA-seq discovery, functional characterization, and comparison of sesquiterpene synthases from Solanum lycopersicum and Solanum habrochaites trichomes. AB - Solanum lycopersicum and Solanum habrochaites (f. typicum) accession PI127826 emit a variety of sesquiterpenes. To identify terpene synthases involved in the production of these volatile sesquiterpenes, we used massive parallel pyrosequencing (RNA-seq) to obtain the transcriptome of the stem trichomes from these plants. This approach resulted initially in the discovery of six sesquiterpene synthase cDNAs from S. lycopersicum and five from S. habrochaites. Searches of other databases and the S. lycopersicum genome resulted in the discovery of two additional sesquiterpene synthases expressed in trichomes. The sesquiterpene synthases from S. lycopersicum and S. habrochaites have high levels of protein identity. Several of them appeared to encode for non-functional proteins. Functional recombinant proteins produced germacrenes, beta caryophyllene/alpha-humulene, viridiflorene and valencene from (E,E)-farnesyl diphosphate. However, the activities of these enzymes do not completely explain the differences in sesquiterpene production between the two tomato plants. RT qPCR confirmed high levels of expression of most of the S. lycopersicum sesquiterpene synthases in stem trichomes. In addition, one sesquiterpene synthase was induced by jasmonic acid, while another appeared to be slightly repressed by the treatment. Our data provide a foundation to study the evolution of terpene synthases in cultivated and wild tomato. PMID- 21818685 TI - Predictors of Asian American adolescents' suicide attempts: a latent class regression analysis. AB - Although suicide-related outcomes among Asian American adolescents are a serious public health problem in the United States, research in this area has been relatively sparse. To address this gap in the empirical literature, this study examined subgroups of Asian American adolescents for whom family, school, and peer relationships exerted differential effects on suicide attempts. Data were drawn from Waves 1 and 2 of the National Longitudinal Study of Adolescent Health dataset and included responses from a national sample of 959 Asian American adolescents (48.0% girls; average age at Wave 2 = 16.43). A latent class regression was used to assess the optimal number of latent classes (i.e., subgroups of participants) that explained the associations between family, school, and peer relationships and subsequent suicide attempts. Three latent classes were identified. Most participants belonged to a latent class in which family, school, and peer relationships were protective factors. However, stronger school relationships and peer relationships were found to be risk factors in two other latent classes. The three latent classes also differed significantly in terms of suicide attempts, gender, and acculturation. The practical implications of this study, particularly for educators and mental health professionals, are discussed. PMID- 21818686 TI - Effects of mutation number in interferon sensitivity determining region on peripheral blood CD4(+) T cell subsets (Th1, Th2) in chronic hepatitis C patients with hepatitis C virus genotype 1b and high viral load. AB - BACKGROUND/AIM: The number of amino acid (AA) mutations in the interferon sensitivity determining region (ISDR) of NS5A is reported to affect the response to interferon (IFN) therapy in patients with chronic hepatitis C (CHC). The aim of this study was to clarify whether host immunity is influenced by the number of AA mutations in the ISDR. PATIENTS AND METHODS: Subjects included 44 patients with CHC infected with genotype 1b and high viral load. The number of AA mutations in the ISDR was retrospectively determined using stored serum samples taken immediately before starting therapy. All patients received IFN-alpha 2b or pegylated-IFN (PEG-IFN)-alpha 2b and ribavirin. When serum hepatitis C virus ribonucleic acid (HCV-RNA) was negative at 4 or 12 weeks after starting therapy, the patient was defined as having rapid viral response (RVR) or early viral response (EVR), respectively. CD4(+) T cell (Th1 or Th2) in peripheral blood (PB) before and until day 56 of treatment was analyzed. RESULTS: Rates of RVR and EVR were 0 (0/21) and 14% (3/21), respectively, in patients with one or fewer AA mutations in the ISDR (ISDR0-1), and 30 (7/23), and 74% (17/23), respectively, with two or more AA mutations in the ISDR (ISDR > 2). Although the percentage of PB Th1 cells did not differ between the two groups during the study period, the percentage of PB Th2 cells was significantly lower in the ISDR0-1 group than in the ISDR > 2 group at baseline and on days 3, 7, 14, and 28 of treatment. CONCLUSION: The number of AA mutations in the ISDR influenced PB Th2 cells before and until day 28, and was associated with higher RVR and EVR rates. PMID- 21818687 TI - Hepatocyte growth factor overexpression ameliorates liver inflammation and fibrosis in a mouse model of nonalcoholic steatohepatitis. AB - BACKGROUND: Hepatocyte growth factor (HGF) is a potent growth factor involved in liver regeneration that has various effects on epithelial and nonepithelial cells. Although it has been demonstrated that HGF can reduce liver inflammation or fibrosis caused by pharmaceutical or chemical insult, no examination of its effect on liver injury in nonalcoholic steatohepatitis (NASH) has been reported. METHODS: To examine the effect of HGF on liver injury in NASH, we generated a murine steatohepatitis model on an HGF overexpression transgenic (Tg) background, and fed the mice a methionine- and choline-deficient diet (MCD). RESULTS: In mice fed the MCD diet, serum ALT levels and the inflammation score for the Tg mice were significantly lower than those for the wild-type (Wt) control mice (P < 0.01). The index of lipid peroxidation increased in the liver of the Wt mice as demonstrated by thiobarbituric acid-reactive substances. Furthermore, the liver fibrosis in Tg mice was dramatically suppressed in comparison to that in Wt mice. The gene expression of matrix metalloprotease-13 in the Tg mice was significantly increased in comparison to that of the Wt mice. Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay showed the apoptotic cells to significantly decrease in number in the Tg mice in comparison to the Wt mice fed the MCD diet (P < 0.01). CONCLUSION: Hepatocyte growth factor ameliorated liver inflammation and fibrosis in a murine model of NASH as a result of the anti oxidative and anti-apoptotic effect, and the induction of fibrinolysis. PMID- 21818688 TI - The pattern of cortical atrophy in Parkinson's disease with mild cognitive impairment according to the timing of cognitive dysfunction. AB - The density of Lewy bodies or the concurrent beta-amyloid pathology would act as modulators in the relative timing of dementia during the course of Parkinson's disease. Depending on the temporal relationship between the onset of parkinsonism and that of cognitive impairment, patients with Parkinson's disease with mild cognitive impairment were divided into two groups of earlier (<1 year) and later (>=1 year) cognitive decline, and cortical atrophy patterns and correlation of gray matter and timing of cognitive decline were analyzed using voxel-based morphometry. The morphometric analysis showed that patients with earlier cognitive decline demonstrated greater cortical atrophy in the inferior parietal and orbitofrontal areas than did those with later cognitive decline. Additionally, the anatomical bases of the timing of their cognitive decline differed in terms of correlation patterns. These data suggest that the pathological burden in Parkinson's disease with mild cognitive impairment may be more severe in patients with earlier cognitive decline than in those with later cognitive decline, and that the neural basis corresponding to the timing of cognitive decline may differ in these patients. PMID- 21818689 TI - The impact of motor and non motor symptoms on health state values in newly diagnosed idiopathic Parkinson's disease. AB - The aim of the study was to estimate health state utility values in newly diagnosed idiopathic Parkinson's disease (PD) for use in the assessment of health related quality-of-life (HRQL), and in the estimation of quality-adjusted life years (QALYs). Data from 162 patients enrolled in a community-based incidence study of PD were used to estimate health state utility values. Self-report data from the EQ-5D, a generic measure of HRQL, were used to derive preference-based health state utility values. The impact of motor and non motor symptoms, and other clinical and demographic factors, on the derived EQ-5D health state values was examined in univariate and multivariate analyses. The mean health state utility value for recently diagnosed PD patients was estimated at 0.65 +/- 0.27. Significant reductions in health state values were attributable to pain (-0.18), motor functioning (-0.16), depression (-0.12), and insomnia (-0.11). Depression had its greatest impact (-0.19) in patients in the less severe stages of PD (i.e. Hoehn Yahr stages <=2.5). This study shows, through the presentation of QALY values, that there is scope to achieve significant health gains in newly diagnosed idiopathic PD patients via improved management of pain, depression and insomnia, alongside the treatment of primary motor symptoms. PMID- 21818690 TI - Epigallocatechin-3-gallate has dual, independent effects on the cardiac sarcoplasmic reticulum/endoplasmic reticulum Ca2+ ATPase. AB - We determined the effects of epigallocatechin-3-gallate (EGCG) and epicatechin (EC), on pump turnover and Ca2+ transport by the cardiac form of the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA). Fluorescence spectroscopy was used to directly measure SERCA ATPase activity and to measure Ca2+ uptake into cardiac sarcoplasmic reticulum (SR) vesicles and microsomes derived from human embryonic kidney (HEK) cells expressing human cardiac SERCA2a. We found that EGCG reduces the maximum velocity of Ca2+ uptake into cardiac SR vesicles and increases the Ca2+-sensitivity of uptake in a concentration-dependent manner. EC is less potent than EGCG in increasing the Ca2+-sensitivity of uptake and does not affect maximum uptake velocity. The EGCG-dependent reduction in Ca2+ uptake velocity is well correlated with direct inhibition of SERCA. The effect of EGCG on the Ca2+-sensitivity of Ca2+ uptake into cardiac SR vesicles is affected by the phosphorylation status of phospholamban (PLB). When cardiac SERCA2a is expressed in HEK cells without PLB, EGCG reduces the maximum velocity of Ca2+ uptake but does not affect the Ca2+-sensitivity of uptake into microsomes derived from these cells indicating that the effect of EGCG on Ca2+-sensitivity requires the presence of PLB. Our results show that EGCG has dual effects on SERCA function in cardiac SR vesicles: it directly affects SERCA by reducing maximum uptake velocity; it increases the Ca2+-sensitivity of Ca2+ uptake in a manner that appears to depend on the interaction between SERCA and PLB. PMID- 21818691 TI - Toxicology, environmental health, and the "One Health" concept. AB - The One Health concept promotes collaboration among veterinarians, physicians, scientists, and other professions to promote human, animal, and ecosystem health. One Health illustrates the interconnectedness and interdependence of human, animal, and ecosystem health. This concept has traditionally focused on zoonoses that are infectious diseases, not on chemical- or poison-related illnesses in animals and their relationship to the detection and prevention of human illness. The purpose of this article is to describe key experiences of scientists in the Health Studies Branch within the National Center for Environmental of Health of the Centers for Disease Control and Prevention in which the study of animal illness facilitated a public health investigation into an outbreak of chemical associated human disease. The experiences highlight how utilizing the One Health approach may improve chemical-associated outbreak investigations and facilitate appropriate intervention strategies. An appropriate One Health approach in toxicology and environmental health in outbreak settings should include consideration of the common environments and food sources shared by humans and animals and consideration of the potential for contaminated animal products as food sources in human exposures. PMID- 21818692 TI - What toxicity may result from the xenobiotic responsible for the finding on this plain film? Answer: reduced iron, found in heating pads and instant hand warmers, may result in elevated serum iron concentrations and subsequent iron toxicity. AB - Disposable heating pads are commonly used products, with reduced iron as their active ingredient. Reduced iron is not expected to cause significant toxicity when ingested orally. We report a case of accidental heating pad ingestion seen on abdominal plain films that resulted in significantly elevated serum iron concentrations. PMID- 21818693 TI - Anticipating who will say what: the influence of speaker-specific memory associations on reference resolution. AB - Some accounts of common ground assume that successful communication requires detailed consideration of others' knowledge. In two studies, we provide evidence for an alternative account that views common ground as being mediated in part through domain-general memory mechanisms. On each trial, participants heard prerecorded instructions from one of two speakers indicating which of two displayed pictures to select. During an initial association phase, each speaker repeatedly referred to different sets of pictures. In Experiment 1, we contrasted a "between-speaker mapping" condition, in which each speaker referred to only one picture from critical item pairs (e.g., the cat drinking milk vs. the cat sitting up), and a "within-speaker mapping" condition, in which each speaker referred to both pictures within each pair, although item categories differed across speakers. On subsequent test trials, we recorded participants' eye fixations to critical displays that included both items from a category pair. Prior to the linguistic point of disambiguation, participants in the between-speaker mapping condition were more likely to fixate on the picture previously described by the current speaker, suggesting that knowledge associated with the speaker was prompting expectations for which picture would be the intended target. In Experiment 2, we used two prerecorded speakers of the same gender to strengthen the claim that the relevant implicit memory associations are speaker-specific. These results demonstrate how domain-general memory associations can be an important constraint upon language use. PMID- 21818694 TI - Differential metabolism of organic nitrates by aldehyde dehydrogenase 1a1 and 2: substrate selectivity, enzyme inactivation, and active cysteine sites. AB - Organic nitrate vasodilators (ORN) exert their pharmacologic effects through the metabolic release of nitric oxide (NO). Mitochondrial aldehyde dehydrogenase (ALDH2) is the principal enzyme responsible for NO liberation from nitroglycerin (NTG), but lacks activity towards other ORN. Cytosolic aldehyde dehydrogenase (ALDH1a1) can produce NO from NTG, but its activity towards other ORN is unknown. Using purified enzymes, we showed that both isoforms could liberate NO from NTG, isosorbide dinitrate (ISDN), and nicrorandil, while only ALDH1a1 metabolized isosorbide-2-mononitrate and isosorbide-5-mononitrate (IS-5-MN). Following a 10 min incubation with purified enzyme, 0.1 mM NTG and 1 mM ISDN potently inactivated ALDH1a1 (to 21.9% +/- 11.1% and 0.44% +/- 1.04% of control activity, respectively) and ALDH2 (no activity remaining and 4.57% +/- 7.92% of control activity, respectively), while 1 mM IS-5-MN exerted only modest inactivation of ALDH1a1 (reduced to 89% +/- 4.3% of control). Cytosolic ALDH in hepatic homogenates incubated at the vascular EC(50) concentrations of ORN was inactivated by NTG (to 45.1% +/- 8.1% of control activity) while mitochondrial ALDH was inactivated by NTG and nicorandil (to 68.2% +/- 10.0% and 78.7% +/- 19.8% of control, respectively). Via site-directed mutagenesis, the active sites of ORN metabolism of ALDH2 (Cys-319) and ALDH1a1 (Cys-303) were found to be identical to those responsible for their dehydrogenase activity. Cysteine-302 of ALDH1a1 and glutamate-504 of ALDH2 were found to modulate the rate of ORN metabolism. These studies provide further characterization of the substrate selectivity, inactivation, and active sites of ALDH2 and ALDH1a1 toward ORN. PMID- 21818695 TI - BDDCS applied to over 900 drugs. AB - Here, we compile the Biopharmaceutics Drug Disposition Classification System (BDDCS) classification for 927 drugs, which include 30 active metabolites. Of the 897 parent drugs, 78.8% (707) are administered orally. Where the lowest measured solubility is found, this value is reported for 72.7% (513) of these orally administered drugs and a dose number is recorded. The measured values are reported for percent excreted unchanged in urine, LogP, and LogD (7.4) when available. For all 927 compounds, the in silico parameters for predicted Log solubility in water, calculated LogP, polar surface area, and the number of hydrogen bond acceptors and hydrogen bond donors for the active moiety are also provided, thereby allowing comparison analyses for both in silico and experimentally measured values. We discuss the potential use of BDDCS to estimate the disposition characteristics of novel chemicals (new molecular entities) in the early stages of drug discovery and development. Transporter effects in the intestine and the liver are not clinically relevant for BDDCS class 1 drugs, but potentially can have a high impact for class 2 (efflux in the gut, and efflux and uptake in the liver) and class 3 (uptake and efflux in both gut and liver) drugs. A combination of high dose and low solubility is likely to cause BDDCS class 4 to be underpopulated in terms of approved drugs (N = 53 compared with over 200 each in classes 1-3). The influence of several measured and in silico parameters in the process of BDDCS category assignment is discussed in detail. PMID- 21818696 TI - Effect of pre-test genetic counseling for deaf adults on knowledge of genetic testing. AB - Empirical data on genetic counseling outcomes in the deaf population are needed to better serve this population. This study was an examination of genetics knowledge before and after culturally and linguistically appropriate pre-test genetic counseling in a diverse deaf adult sample. Individuals >=18 years old with early-onset sensorineural deafness were offered connexin-26/30 testing and genetic counseling. Participants completed questionnaires containing 10 genetics knowledge items at baseline and following pre-test genetic counseling. The effects of genetic counseling, prior beliefs about etiology, and participant's preferred language on genetics knowledge scores were assessed (n = 244). Pre-test genetic counseling (p = .0007), language (p < .0001), prior beliefs (p < .0001), and the interaction between counseling and beliefs (p = .035) were predictors of genetics knowledge. American Sign Language (ASL)-users and participants with "non genetic/unknown" prior beliefs had lower knowledge scores than English-users and participants with "genetic" prior beliefs, respectively. Genetics knowledge improved after genetic counseling regardless of participants' language; knowledge change was greater for the "non-genetic/unknown" beliefs group than the "genetic" beliefs group. ASL-users' lower knowledge scores are consistent with evidence that ethnic and cultural minority groups have less genetics knowledge, perhaps from exposure and access disparities. Culturally and linguistically appropriate pre-test genetic counseling significantly improved deaf individuals' genetics knowledge. Assessing deaf individuals' prior beliefs is important for enhancing genetics knowledge. PMID- 21818698 TI - Reducing the prevalence of inappropriate cardiac imaging tests. PMID- 21818699 TI - Stress-only myocardial perfusion imaging ... it is time for a change! PMID- 21818697 TI - Strategies for tissue engineering cardiac constructs to affect functional repair following myocardial infarction. AB - Tissue-engineered cardiac constructs are a high potential therapy for treating myocardial infarction. These therapies have the ability to regenerate or recreate functional myocardium following the infarction, restoring some of the lost function of the heart and thereby preventing congestive heart failure. Three key factors to consider when developing engineered myocardial tissue include the cell source, the choice of scaffold, and the use of biomimetic culture conditions. This review details the various biomaterials and scaffold types that have been used to generate engineered myocardial tissues as well as a number of different methods used for the fabrication and culture of these constructs. Specific bioreactor design considerations for creating myocardial tissue equivalents in vitro, such as oxygen and nutrient delivery as well as physical stimulation, are also discussed. Lastly, a brief overview of some of the in vivo studies that have been conducted to date and their assessment of the functional benefit in repairing the injured heart with engineered myocardial tissue is provided. PMID- 21818700 TI - Appropriateness of referrals for single-photon emission computed tomography myocardial perfusion imaging (SPECT-MPI) in a developing community: a comparison between 2005 and 2009 versions of ACCF/ASNC appropriateness criteria. AB - INTRODUCTION: Appropriateness of referrals for myocardial perfusion imaging (MPI) in developing countries has not been extensively studied. Our study was conducted to describe the ordering practices of physicians and appropriateness of MPI referrals in Iran. METHOD: We prospectively applied 2005 and 2009 versions of the Appropriateness Use Criteria published by the American College of Cardiology Foundation (ACCF) and the American Society of Nuclear Cardiology (ASNC) to 291 consecutive patients (age 55.3 +/- 10.3 years) who underwent SPECT-MPI. For this purpose, we convened a panel, consisting of two academic cardiologists, one academic clinician in internal medicine, and one academic clinician in nuclear medicine. The panelists were invited for a face-to-face meeting to judge appropriateness of SPECT-MPI and independently assign a specific indication (scenario), whenever possible, for each case in accordance with ACCF/ASNC appropriateness scenarios. RESULTS: Based on the 2005 ACCF/ASNC criteria, SPECT MPI studies were judged appropriate for 211 (72.5%), uncertain for 36 (12.4%), inappropriate for 32 (11.0%), and unclassifiable for 12 (4.1%) referrals. The same figures based on the 2009 version were 219 (75.3%), 15 (5.2%), 49 (16.8%), and 8 (2.7%) patients, respectively. Overall agreement between the 2005 and 2009 versions was good (kappa 0.63). Lack of chest pain and age below 60 years were significant indicators increasing the likelihood of inappropriate referrals by 2.9-3.4 fold. Absence of diabetes mellitus and hypertension, a normal lipid profile, lack of a past history of myocardial infarction or cardiovascular interventions (CABGs or PCI), as well as lack of application and exercise ECG stress test as the gate keeper (keeping abnormal ETT or inability of the patient to perform exercise as the appropriate indication for SPECT-MPI referral) were significant indicators, decreasing the odds of appropriate referrals. Generally a higher percentage of referrals with inappropriate indications had normal MPI. CONCLUSION: Our study provides an evidence for the fact that SPECT-MPI ordering practices in our developing community largely parallel the ACCF/ASNC recommendations. The implementation of appropriateness criteria is feasible in clinical settings and might provide an alternative to utilization management. PMID- 21818702 TI - Reconstructive osteotomy of fibular malunion: review of the literature. AB - The treatment of ankle fractures has a primary goal of restoring the full function of the injured extremity. Malunion of the fibula is the most common and most difficult ankle malunion to reconstruct. The most frequent malunions of the fibula are shortening and malrotation resulting in widening of the ankle mortise and talar instability, which may lead to posttraumatic osteoarthritis. The objective of this article is to review the literature concerning the results of osteotomies for correcting fibular malunions and to formulate recommendations for clinical practice. Based on available literature, corrective osteotomies for fibular malunion have good or excellent results in more than 75% of the patients. Reconstructive fibular osteotomy has been recommended to avoid or postpone sequela of posttraumatic degeneration, an ankle arthrodesis or supramalleolar osteotomy. The development of degenerative changes is not fully predictable; therefore, it is advisable to reconstruct a fibular malunion soon after the diagnosis is made and in presence of a good ankle function. Recommendations were made for future research because of the low level of evidence of available literature on reconstructive osteotomies of fibular malunions. PMID- 21818703 TI - The impact of physical and mental activity on cognitive aging. AB - With the aging of the population, there is continued emphasis on finding interventions that prevent or delay onset of cognitive disorders of aging. Pharmacological interventions have proven less effective than hoped in this capacity and a greater emphasis has therefore been placed on understanding behavioral interventions that will positively impact dementia risk. Building on a robust animal literature, a substantial volume of research has emerged, particularly over the last 5 years, to suggest that modifiable behaviors impact brain plasticity in both humans and animals. This chapter aims to provide a critical summary of this ever growing body of research, focusing specifically on participation in physical and cognitive activities among older adults and their impact on cognition, the brain, and cognitive aging outcomes. The animal literature on activity and cognition provides a series of hypotheses as to how exercise exerts its cognitive and brain benefits. Research in animals is briefly reviewed in the context of these hypotheses as it provides the groundwork for investigations in humans. The literature on physical and cognitive activity benefits to brain and cognition in humans is reviewed in more detail. The largely positive impact of physical and cognitive activities on cognition and brain health documented in epidemiological, cross sectional, and prospective randomized controlled studies are summarized. While most studies have targeted older adults in general, the implications of exercise and cognitive interventions in individuals with Alzheimer's disease (AD) or mild cognitive impairment (MCI) are also described as is the evidence supporting the ability for physical activity to modify genetic risk. The connection between activity levels and brain volume, white matter integrity, and improved functionality is reviewed. Practical recommendations regarding the nature, duration, intensity and age of onset of physical or mental activity necessary to reap cognitive and brain benefits are also detailed. Most studies have investigated a singular behavioral factor or intervention, but there is some research detailing the impact of combining both mental and physical activity to boost brain health; this emerging literature is also reviewed. Finally, we comment on the limitations of the extant literature and directions for future research, in particular the need for prospective trials of activity interventions in older adults. PMID- 21818704 TI - Adjuvant trials of targeted agents: the newest battleground in the war on cancer. AB - Two of the great successes in the many decades-long 'war on cancer' are the emergence of adjuvant chemotherapy regimens with lifesaving potential and the subsequent wave of 'targeted' therapies addressing the unique vulnerabilities of particular tumor types. The first intersection of adjuvant treatment and targeted treatment resulted in a spectacularly positive outcome as the addition of the anti-HER2 humanized monoclonal antibody trastuzumab to the standard adjuvant chemotherapy essentially halved the relapse rate among women with HER2+ tumors. Subsequent studies of adjuvant trastuzumab have confirmed its dramatic efficacy in a variety of chemotherapeutic contexts and have been instructive in elucidating some of the challenges ahead for newer targeted agents. The recent negative experience with bevacizumab in the adjuvant colon cancer setting suggests pitfalls and limitations of the current approach to developing adjuvant regimens. A change in thinking may be required to gain the substantial benefits implied by the trastuzumab experience in the broader context of the targeted treatments. The case for a revitalized industry/academia/government partnership to address these challenges is compelling, with the potential for enormous patient and societal benefit. In order to bring potentially lifesaving benefits of this new generation of cancer drugs to patients more rapidly, changes to our 'war strategy' appear necessary. PMID- 21818705 TI - Epigenetic biomarkers. AB - Profound changes in the epigenetic landscape of cancer cells underlie the development of human malignancies. These changes include large-scale DNA methylation changes throughout the genome as well as alterations in the compendium of post-translational chromatin modifications. Epigenetic aberrations impact multiple steps during tumorigenesis, ultimately promoting the selection of neoplastic cells with increasing pathogenicity. Identification of these alterations for use as predictive and prognostic biomarkers has been a highly sought after goal. Recent advances in the field have not only greatly expanded our knowledge of the epigenetic changes driving neoplasia but also demonstrated their significant clinical utility as cancer biomarkers. These biomarkers have proved to be useful for identifying patients whose malignancies are sensitive to specific cytotoxic chemotherapies and may hold promise for predicting which patients will benefit from newer targeted agents directed at oncogenes. The recent application of global analysis strategies has further accelerated our understanding of the epigenome and promises to enhance the identification of epigenomic programs underlying cancer progression and treatment response. PMID- 21818706 TI - Targeting oncogenic BRAF in human cancer. AB - Mitogen Activated Protein Kinase (MAPK) pathway activation is a frequent event in human cancer and is often the result of activating mutations in the BRAF and RAS oncogenes. BRAF missense mutations, the vast majority of which are V600E, occur in approximately 8% of human tumors. These kinase domain mutations, which are non overlapping in distribution with RAS mutations, are observed most frequently in melanoma but are also common in tumors arising in the colon, thyroid, lung, and other sites. Supporting its classification as an oncogene, (V600E)BRAF stimulates ERK signaling, induces proliferation, and is capable of promoting transformation. Given the frequent occurrence of BRAF mutations in human cancer and the continued requirement for BRAF activity in the tumors in which it is mutated, efforts are underway to develop targeted inhibitors of BRAF and its downstream effectors. These agents offer the possibility of greater efficacy and less toxicity than the systemic therapies currently available for tumors driven by activating mutations of MAPK pathway components. Early clinical results with the BRAF-selective inhibitors PLX4032 and GSK2118436 suggest that this strategy will prove successful in a select group of patients whose tumors are driven by oncogenic BRAF. PMID- 21818707 TI - Two wheat (Triticum aestivum) pathogenesis-related 10 (PR-10) transcripts with distinct patterns of abundance in different organs. AB - PR-10 genes encode small, acidic, intracellular proteins that respond to abiotic and biotic stimuli. Transgenic expression of PR-10 genes has been shown to enhance early seedling growth of dicots in saline environments. To identify candidate PR-10 genes in cereals for increasing stress tolerance, we conducted phylogenetic analyses and real-time polymerase chain reaction of representatives of the two major clades of putative PR-10 genes in wheat. We observed that the abundance of BQ752893 was generally greater than the abundance of CV778999, particularly when measured in roots across four wheat genotypes. However, CV778999 transcripts were more abundant than BQ752893 in flag leaves. These data suggest that the transcripts define two functionally divergent groups of PR-10 type genes in wheat, both of which may be suitable targets for biotechnological manipulation under different circumstances. PMID- 21818701 TI - Platelets: versatile effector cells in hemostasis, inflammation, and the immune continuum. AB - Platelets are chief effector cells in hemostasis. In addition, however, their specializations include activities and intercellular interactions that make them key effectors in inflammation and in the continuum of innate and adaptive immunity. This review focuses on the immune features of human platelets and platelets from experimental animals and on interactions between inflammatory, immune, and hemostatic activities of these anucleate but complex and versatile cells. The experimental findings and evidence for physiologic immune functions include previously unrecognized biologic characteristics of platelets and are paralleled by new evidence for unique roles of platelets in inflammatory, immune, and thrombotic diseases. PMID- 21818708 TI - Non-stationary influence of El Nino-Southern Oscillation and winter temperature on oak latewood growth in NW Iberian Peninsula. AB - The properties of El Nino-Southern Oscillation (ENSO), such as period, amplitude, and teleconnection strength to extratropical regions, have changed since the mid 1970s. ENSO affects the regional climatic regime in SW Europe, thus tree performance in the Iberian Peninsula could be affected by recent ENSO dynamics. We established four Quercus robur chronologies of earlywood and latewood widths in the NW Iberian Peninsula. The relationship between tree growth and the Southern Oscillation Index (SOI), the atmospheric expression of ENSO, showed that only latewood growth was correlated negatively with the SOI of the previous summer-autumn-winter. This relationship was non-stationary, with significant correlations only during the period 1952-1980; and also non-linear, with enhanced latewood growth only in La Nina years, i.e. years with a negative SOI index for the previous autumn. Non-linear relationship between latewood and SOI indicates an asymmetric influence of ENSO on tree performance, biassed towards negative SOI phases. During La Nina years, climate in the study area was warmer and wetter than during positive years, but only for 1952-1980. Winter temperatures became the most limiting factor for latewood growth since 1980, when mean regional temperatures increased by 1 degrees C in comparison to previous periods. As a result, higher winter respiration rates, and the extension of the growing season, would probably cause an additional consumption of stored carbohydrates. The influence of ENSO and winter temperatures proved to be of great importance for tree growth, even at lower altitudes and under mild Atlantic climate in the NW Iberian Peninsula. PMID- 21818709 TI - Theory of mind in dogs: is the perspective-taking task a good test? AB - Udell, Dorey, and Wynne (in press) have reported an experiment in which wolves, shelter dogs, and pet dogs all showed a significant preference for begging from a person who faced them (seer) over a person whose back was turned to them (blind experimenter). On tests with the blind person's eyes covered with a bucket, a book, or a camera, pet dogs showed more preference for the seer than did wolves and shelter dogs. We agree with the authors' position that most of these findings are best explained by preexperimental learning experienced by the subjects. We argue, however, that the perspective-taking task is not a good test of the domestication theory or of the theory of mind in dogs. The problem we see is that use of the perspective-taking task, combined with preexperimental learning in all the subjects, strongly biases the outcome in favor of a behavioral learning interpretation. Tasks less influenced by preexperimental training would provide less confounded tests of domestication and theory of mind. PMID- 21818710 TI - Investigations into the fate of inhaled salmon calcitonin at the respiratory epithelial barrier. AB - PURPOSE: The fate of inhaled salmon calcitonin (sCT) at the respiratory epithelial barrier was studied with particular emphasis on enzymatic degradation by trypsin, chymotrypsin, and neutrophil elastase. METHODS: Degradation of sCT was assessed by HPLC in cell homogenate, supernatant and intact monolayers of human respiratory epithelial cells (hBEpC, Calu-3, 16HBE14o-, A549) and Caco-2 as comparison at 37 degrees C for 2 h. Breakdown of sCT by trypsin, chymotrypsin and neutrophil elastase was investigated. The presence of enzymes in cell supernatant and homogenate was studied by immunoblot and enzyme activity by model substrate assay. Transport studies across Calu-3 monolayers were performed. RESULTS: sCT concentration remained unchanged over 2 h, when incubated in supernatant or with cell monolayers, independent of cell type studied. When cell homogenates were used, sCT concentrations were reduced to varying extents. sCT was degraded when incubated with enzymes alone. Western blot revealed abundance of all proteinases in cell homogenates and weaker expression in supernatants. Transport studies indicated net-absorptive sCT translocation; presence of bacitracin resulted in increased amount of sCT in receiver compartments. CONCLUSIONS: Epithelial proteases play a role in the disposition of sCT after pulmonary delivery. PMID- 21818711 TI - New fluorescent probes targeting the mitochondrial-located translocator protein 18 kDa (TSPO) as activated microglia imaging agents. AB - PURPOSE: To evaluate the utility of new Translocator protein 18 kDa (TSPO) targeted fluorescent probes for in vivo molecular imaging of activated microglia. METHODS: Compounds 2-4 were synthesized; their stability and affinity for TSPO were determined. Compounds 2-4 were incubated both with Ra2 cells in the presence of LPS, a potent activator of microglia, and with tissue sections of normal and chemically injured brains. Compounds 2-4 were injected into carotid artery or directly in striatum of mice. Cells and tissue sections from these in vitro and in vivo studies were observed by fluorescence microscopy after histochemical treatments. RESULTS: Compounds 2-4 are stable in both buffer and physiological medium and showed high affinity for TSPO and were found to stain live Ra2 microglial cells effectively. Double staining with Mito Tracker Red suggested that binding sites of compounds 2 and 3 may exist on mitochondria. In vivo studies showed that compounds 2-4 may penetrate in part into brain; moreover, cells in mouse striatum were stained with compounds 2-4 and microglial marker CD11b. CONCLUSION: Compounds 2-4 can fluorescently label activated microglia in vitro and in vivo. PMID- 21818715 TI - Retraction note to: Hemodynamics, intra-mucosal pH and regulators of circulation during perioperative epidural analgesia. PMID- 21818713 TI - The therapeutic potential of microRNAs: disease modulators and drug targets. AB - MiRNAs are a class of small, naturally occurring RNA molecules that play critical roles in modulating numerous biological pathways by regulating gene expression. The knowledge that miRNA expression is dysregulated in many pathological disease processes, including cancer, has led to a rapidly expanding body of literature as we try to unveil their mechanism of action. Their putative role as oncogenes or tumour suppressor genes presents a wonderful opportunity to provide targeted cancer treatment strategies. Additionally, their documented function in a host of benign diseases broadens the potential market for miRNA-based therapeutics. The present review outlines the underlying rationales for considering mi(cro)RNAs as therapeutic agents or targets. We highlight the potential of manipulating miRNAs for the treatment of many common diseases, particularly cancers. Finally, we summarize the challenges that need to be overcome to fully harness the potential of miRNA-based therapies so they become the next generation of pharmaceutical products. PMID- 21818714 TI - MicroRNA-101 inhibits growth of epithelial ovarian cancer by relieving chromatin mediated transcriptional repression of p21(waf1/cip1). AB - PURPOSE: MicroRNA-101 (miR-101) expression is negatively associated with tumor growth and proliferation in several solid epithelial cancers. Enhancer of zeste homolog 2 (EzH2) appears to be a functional target of miR-101. We explore the role of miR-101 and its interaction with EzH2 in epithelial ovarian carcinoma (EOC). METHODS: In situ hybridization (ISH) for miR-101 was performed on EOC patient tissues and normal controls. EOC cell lines were transfected with miR-101 and subjected to growth analysis and clonogenic assays. Cell motility was assessed by Boyden chamber and wound-healing assays. P21(waf1/cip1) and EzH2 interaction was assessed by Chromatin Immunoprecipitation (ChIP) assay in MDAH 2774 cells. SCID mice were assessed for tumor burden after injection with miR-101 or control vector-treated MDAH-2774 cells. RESULTS: ISH analysis revealed a decrease in miR-101 expression in EOC compared with normal tissue. MiR-101 re expression in EOC cell lines resulted in increased apoptosis, decreased cellular proliferation, invasiveness, and reduced growth of tumor xenografts. CHIP assays revealed that re-expression of miR-101 inhibited the interaction of EzH2 with p21(waf1/cip1) promoter. CONCLUSIONS: MiR-101 re-expression appears to have antitumor effects, providing a better understanding of the role of miR-101 in EOC. PMID- 21818712 TI - Hormetics: dietary triggers of an adaptive stress response. AB - A series of dietary ingredients and metabolites are able to induce an adaptive stress response either by generation of reactive oxygen species (ROS) and/or via activation of the Nrf2/Keap1 stress response network. Most of the molecules belong to activated Michael acceptors, electrophiles capable to S-alkylate redox sensitive cysteine thiols. This review summarizes recent advances in the (re)search of these compounds and classifies them into distinct groups. More than 60 molecules are described that induce the Nrf2 network, most of them found in our daily diet. Although known as typical antioxidants, a closer look reveals that these molecules induce an initial mitochondrial or cytosolic ROS formation and thereby trigger an adaptive stress response and hormesis, respectively. This, however, leads to higher levels of intracellular glutathione and increased expression levels of antioxidant enzymes such as glutathione peroxidase, thioredoxin reductase, and superoxide dismutase. According to this principle, the author suggests the term hormetics to describe these indirect antioxidants. PMID- 21818716 TI - [Without structure no quality!]. PMID- 21818717 TI - [Recommendations on classification of German pain treatment services]. AB - On behalf of the German chapter of the International Association for the Study of Pain (IASP) recommendations for German pain treatment services have been developed for the first time. The criteria were based on the IASP recommendations but adapted to the specific German situation. According to the structure and process criteria four different levels of pain treatment services can be distinguished. The aim of the recommendations is to serve as a guide for future development and implementation of pain therapy and quality assurance. PMID- 21818718 TI - [Neuropeptide effects on the trigeminal system: pathophysiology and clinical significance for migraine]. AB - Neuropeptides, such as calcitonin gene-related peptide (CGRP), substance P and vasoactive intestinal polypeptide (VIP) are considered important mediators in primary headaches. Increased concentrations of CGRP have been found in jugular venous plasma during attacks of migraine and, concomitant with VIP elevation, during cluster headache. Substance P and CGRP are produced from subsets of trigeminal afferents whereas VIP derives from parasympathetic efferents. Release of these neuropeptides in the meninges causes arterial vasodilatation, mast cell degranulation and plasma extravasation in animal experiments. Particularly CGRP seems to be important, as receptor antagonists have recently been shown to have a therapeutic effect on migraine. Animal models have confirmed the role of CGRP in meningeal nociception. The activity of spinal trigeminal neurons is a sensitive integrative measure of trigeminal activity and CGRP released from central terminals of trigeminal afferents in the spinal trigeminal nucleus has been shown to facilitate nociceptive transmission, most likely by a presynaptic action. The proposed CGRP functions are supported by the distribution of CGRP receptor components localized in the rat cranial dura mater, the trigeminal ganglion and the spinal trigeminal nucleus. The currently available data indicate multiple sites of CGRP action in trigeminal nociception and the pathogenesis of migraine but central CGRP receptors are probably the essential targets in the treatment of migraine using CGRP receptor antagonists. PMID- 21818719 TI - [Treatment and healthcare costs of fibromyalgia syndrome in Germany: analysis of the data of the Barmer health insurance (BEK) from 2008-2009]. AB - BACKGROUND: The data available on the types of treatment delivered and healthcare costs of fibromyalgia syndrome (FMS) patients in Germany are currently not representative. MATERIAL AND METHODS: The data from all 6,897,846 insured persons of the German statutory health insurance company Barmer Ersatzkasse (BEK) before the fusion with the Gmunder Ersatzkasse (GEK) were analyzed if more than 2 billing cases with the diagnosis M79.7 were found (FMS cases) in the 8 consecutive quarter years of 2007-2008. In these cases the types and costs of out patient treatment as well as the operation and procedure key (OPS) classification of in-patient treatment in cases of any discharge diagnosis of FMS were analyzed. RESULTS: A diagnosis of FMS was recorded in 14,870 insured persons in out-patient care and in 6130 in-patients from 1(st) January 2008 to 31(st) December 2009. The 1-year prevalence of FMS diagnosis was 19,592 of the patients (0.3%). Non steroidal agents were prescribed in 48%, weak opioids in 21% and strong opioids in 11% of the out-patients with FMS. Out-patient psychotherapy was conducted in 8% of the FMS cases. In 31% of the cases hospital treatment was carried out of which 14% received multicomponent therapy. The average healthcare costs were 4,331 per year. CONCLUSION: The data of the BEK document high healthcare costs and treatment which is mainly not in line with the recommendations of the German guidelines on the management of FMS. PMID- 21818720 TI - [Pediatric pain management: what do German nurses know?]. AB - BACKGROUND: In order to provide efficient pain treatment clinicians need to know the latest developments in pain management and to implement this knowledge into clinical practice. The knowledge of pediatric nursing staff with regards to pediatric pain management has not yet been investigated. In this study we therefore investigated nurses' knowledge of pediatric pain management strategies. METHODS: Nursing staff knowledge was analyzed using the German version of the PNKAS-Sr2002. This questionnaire was distributed to 310 pediatric nurses and the response rate was 51.3% (n=159). Analyses of variance (ANOVA) were conducted to examine whether educational level and work experience had an influence on knowledge. Independent from work experience the educational level of nurses is important for their knowledge in pediatric pain management. RESULTS: On average nurses obtained a mean individual test score of 69.3%. Nurses with advanced qualification and nurses with 6-10 years work experience obtained the highest scores. CONCLUSION: Pediatric nurses must be trained more efficiently in pediatric pain management so that an adequate pain management is available for children and adolescents. PMID- 21818721 TI - [Experience in treatment of patients with neuropathic facial pain using ziconotide]. AB - We report on the intrathecal use of ziconotide in three patients with idiopathic facial pain after surgery of the mouth, jaw or face and one patient with neuropathic pain after damage of the lingual nerve. The therapy was successful in three patients but one patient with idiopathic facial pain had pain relief only during the test phase of ziconotide with an external pump and not after implanting the Synchromed(r) pump. With intrathecal morphine therapy this patient achieved good pain relief. We recommend that patients with neuropathic facial pain should be treated with ziconotide after implementation of guideline-based therapy. In the test phase the ziconotide dose should be increased by 0.6 ug/day per week after an initial dose of 0.6-1.2 ug/day to avoid side-effects. PMID- 21818722 TI - [Prefrontal cortex mediated control of expectations in placebo analgesia]. AB - Expectations and beliefs modulate the experience of pain, which is particularly evident in placebo analgesia. The dorsolateral prefrontal cortex (DLPFC) has been associated with pain regulation and with the generation, maintenance and manipulation of cognitive representations. In a heat-pain paradigm, we employed non-invasive low-frequency repetitive transcranial magnetic stimulation (rTMS) to transiently disrupt left and right DLPFC function or used the TMS device itself as a placebo, before applying an expectation-induced placebo analgesia. The results demonstrated that placebo significantly increased pain threshold and pain tolerance. While rTMS did not affect pain experience, it completely blocked placebo analgesia. These findings suggest that expectation-induced placebo analgesia is mediated by symmetric prefrontal cortex function. Possible implications for medical practice and clinical trial research will be discussed in the article. PMID- 21818724 TI - [Relaxation techniques for chronic pain]. AB - Relaxation techniques are an integral part of the psychological therapy of chronic pain and follow very different objectives. These techniques lead to muscular and vegetative stabilization, serve as distraction from pain, to build up the internal focus of control and thus to improve self-efficacy. Additional targets are improvement of body awareness and stress management, shielding from sensory stimuli and recurrence prevention of migraine as well a sleeping aid. The most commonly used and best studied method is progressive muscle relaxation which has a good compliance because it is easy to learn and has a high plausibility for patients. PMID- 21818728 TI - Changing practice to improve patient safety and quality of care in perinatal medicine. AB - Despite an increased focus on the quality and safety of care, the United States health care system does not reliably deliver safe, high-quality care for all women and infants. In many cases, a gap still exists between best evidence and routine practice and pregnant women and neonates continue to experience preventable harm. Effective change strategies targeting individuals, groups or teams, organizations, and the larger system or environment have been used in the setting of perinatal care to improve quality and safety. In addition, strategies focused on aligning change efforts across multiple levels are increasingly being used to more effectively change practice in the context of the complex health care system. This review examines some of the single-level and multilevel approaches to changing practice that have been used in perinatal safety and quality improvement. Although progress has been slow, improvements in quality and safety measurement, widespread commitment to implementing effective practice change interventions, and advances in perinatal improvement and implementation research will help ensure that the dramatic improvements in perinatal quality and safety that have been anticipated will truly be realized. PMID- 21818727 TI - The effects of prenatal methamphetamine exposure on childhood growth patterns from birth to 3 years of age. AB - We examined the effects of prenatal methamphetamine (MA) exposure on growth parameters from birth to age 3 years. The 412 subjects included (n = 204 exposed) were enrolled at birth in the Infant Development, Environment and Lifestyle study, a longitudinal study assessing the effects of prenatal MA exposure on childhood outcomes. Individual models were used to examine the effects of prenatal MA exposure on weight, head circumference, height, and weight-for-length growth trajectories. After adjusting for covariates, height trajectory was lower in the exposed versus the comparison children (p = 0.021) over the first 3 years of life. Both groups increased height on average by 2.27 cm per month by age 3 years. In term subjects, MA exposure was also associated with a lower height trajectory (p = 0.034), with both the exposed and comparison groups gaining 2.25 cm per month by age 3 years. There was no difference in weight, head circumference, or weight-for-length growth trajectories between the comparison and the exposed groups. Children exposed prenatally to MA have a modest decrease in height growth trajectory during the first 3 years of life with no observed difference in weight, head circumference, or weight-for-length trajectories. PMID- 21818729 TI - Obstetric patient safety: an overview. AB - Patient safety, defined as "the absence of the potential for, or the occurrence of, health care associated injury to the patient," is a part of the larger concept of health care quality. Achieving safe patient care has become an increasing focus of the obstetric community, in part due to the realization of the number of preventable adverse events that occur as well as the pressures of the professional liability climate. Studies of obstetric care have revealed that multiple factors contribute to the occurrence of adverse obstetric events, although communication is one factor that consistently has been found to prominently contribute to these events. The data that exist also suggest that although most women who give birth on a labor and delivery unit do so without a significant safety incident, a notable minority does experience an event that may compromise their ability to achieve an optimal outcome. PMID- 21818730 TI - The significance of a positive fetal fibronectin in the setting of a normal cervical length in twin pregnancies. AB - To estimate the risk of preterm birth in asymptomatic women with twin pregnancies with a normal cervical length (CL) and a positive fetal fibronectin (fFN), we reviewed a retrospective cohort of twin pregnancies delivered in our practice from 2005 to 2010. Patients were screened from 22 to 32 weeks with CL and fFN at 2- to 4-week intervals. We examined 244 patients with twin pregnancies and a normal CL (>25 mm) between 22 and 32 weeks and compared outcomes based on the fFN result. Fourteen (5.7%) patients had a positive fFN and 230 (94.3%) patients had a negative fFN. Positive fFN was associated with an increased the risk of spontaneous preterm birth < 37 weeks (85.7% versus 38.3%, p = 0.001), < 35 weeks (50% versus 11.8%, p < 0.001), < 34 weeks (35.7% versus 6.9%, p < 0.001), and < 32 weeks (21.4% versus 2.2%, p < 0.001). On adjusted analysis, a positive fFN was independently associated with preterm birth < 32 weeks (odds ratio 6.8, 95% confidence interval 1.42, 32.2) and gestational age at delivery (p = 0.001). In the setting of a normal CL, a positive fFN is significantly associated with preterm birth in asymptomatic twin pregnancies. Contingency model screening of fFN in asymptomatic twin pregnancies solely based on CL evaluation may fail to identify a cohort of at-risk patients. PMID- 21818731 TI - Rapid diagnostic test for identifying group B streptococcus. AB - Neonatal infection with Streptococcus agalactiae (group B streptococcus [GBS]) causes significant morbidity and mortality. A truly rapid diagnostic test for identifying GBS would allow for more timely initiation of antibiotic prophylaxis and also reduce the administration of antibiotics for the prevention of early onset neonatal GBS infection. A stock culture was formed from a laboratory reference strain of GBS and was diluted from 10 (7) to 10 (1) bacteria/mL. Specific concentrations were used to inoculate nitrocellulose membranes (NCMs) that had been coated previously with polyclonal rabbit antibody against GBS. After specific times, the NCMs were removed from the sheep blood agar medium, and horseradish-peroxidase conjugate polyclonal antibody against GBS was added. Bound antibody was detected with diaminobenzidine. After 6 hours of incubation, GBS was detected at concentrations from 10 (7) through 10 (4) bacterial/mL. After 4 hours of incubation, GBS was detected at concentrations from 10 (7) through 10 (5) bacteria/mL. GBS was not detected at 2 hours of incubation. Rapid growth and detection of GBS can be performed, and the results can be reliably attained as early as 4 hours. This is in marked contrast to the 48 to 72 hours required by current methods. PMID- 21818732 TI - Impact of smoking during pregnancy on functional coagulation testing. AB - Compounds that are systemically absorbed during the course of cigarette smoking, and their metabolites, affect the coagulation system and cause endothelial dysfunction, dyslipidemia, and platelet activation leading to a prothrombotic state. In addition, smoking increases the activity of fibrinogen, homocysteine, and C-reactive protein. We hypothesize that smoking may affect functional coagulation testing during pregnancy. A secondary analysis of 371 women pregnant with a singleton pregnancy and enrolled in a multicenter, prospective observational study of complications of factor V Leiden mutation subsequently underwent functional coagulation testing for antithrombin III, protein C antigen and activity, and protein S antigen and activity. Smoking was assessed by self report at time of enrollment (<14 weeks). None of the functional coagulation testing results was altered by maternal smoking during pregnancy. Smoking does not affect the aforementioned functional coagulation testing results during pregnancy. PMID- 21818733 TI - Role of gender in morbidity and mortality of extremely premature neonates. AB - We investigated the effect of gender on survival and short-term outcomes of extremely premature infants (<=27 weeks) born in Canada. The records of infants admitted between 2000 and 2005 to a neonatal intensive care unit participating in the Canadian Neonatal Network were reviewed for infant gender, birth weight, gestational age, outborn status, Score for Neonatal Acute Physiology II, and antenatal corticosteroid exposure. The following outcomes were recorded: survival at final discharge, necrotizing enterocolitis, bronchopulmonary dysplasia (BPD), intraventricular hemorrhage grade >=3, retinopathy grade >=3, days on ventilation, and length of hospital stay. Among 2744 extremely premature infants, 1480 (54%) were male and 1264 (46%) were female. Mean birth weight of female neonates was significantly lower at each week of gestational age. Although no significant difference in survival at discharge was found between genders overall, the prevalence of BPD, combined adverse outcomes, and mortality for infants born between 24 and 26 weeks were significantly higher in males. This study suggests that, in the postsurfactant era, males remain at higher risk of respiratory complications and may have higher mortality when born between 24 and 26 weeks of gestation. PMID- 21818734 TI - Miami classification for probe-based confocal laser endomicroscopy. AB - An essential element for any new advanced imaging technology is standardization of indications, terminology, categorization of images, and research priorities. In this review, we propose a state-of-the-art classification system for normal and pathological states in gastrointestinal disease using probe-based confocal laser endomicroscopy (pCLE). The Miami classification system is based on a consensus of pCLE users reached during a meeting held in Miami, Florida, in February 2009. PMID- 21818735 TI - Complications in gastrointestinal endoscopy: a summary at the first international symposium in Hannover 2009. AB - Following the recent success of the Second International Symposium on Complications in Gastrointestinal Endoscopy (17-18 June 2011, Hannover, Germany), it would be worth reminding ourselves of the key points and highlights of the first symposium held in Hannover in June 2009. The congress, which is endorsed by the American Society for Gastrointestinal Endoscopy (ASGE) under the patronage of the European Society for Gastrointestinal Endoscopy (ESGE), is designed to bring together endoscopists and support staff to present and discuss the diagnosis, treatment, and prevention of complications associated with gastrointestinal endoscopy, including effective communication strategies and management in particular patient groups. This current report is a brief summary of topics discussed at the inaugural symposium in 2009. PMID- 21818736 TI - Endoscopic submucosal resection of esophageal subepithelial lesions using band ligation. AB - Subepithelial lesions (SELs) are occasionally found in the esophagus during upper endoscopy. Sometimes endoscopic resection is needed for accurate diagnosis or in the rare cases of malignant transformation of SELs. In this case series, we evaluated the usefulness of endoscopic submucosal resection with a ligation device (ESMR-L) in esophageal SELs. Twenty-three patients with 25 esophageal SELs that were no larger than 13 mm and were localized within the muscularis mucosae or submucosa were enrolled. ESMR-L was successfully performed in all 25 SELs. The en bloc resection rate was 100% (25/25), and histologically complete resection was achieved in 24 lesions (24/25, 96%). After resection of the lesion by snare, minor immediate bleeding occurred in four cases, but there was no delayed bleeding or perforation. PMID- 21818737 TI - [Prophylaxis and therapy of postdural puncture headache--a critical evaluation of treatment options]. AB - Since the first description of spinal and epidural anaesthesia, postdural puncture headache (PDPH) is a well known complication. Its prophylaxis and treatment has been studied and discussed for more than 100 years, but the evidence is still limited. Due to relatively low prevalence of PDPH, prospective RCTs are often missing, and the frequently self-limiting character of PDPH impedes an adequate interpretation of results from studies without a control group. Taking side effects and complications into account, a prophylactic treatment of PDPH cannot be recommended. In case of PDPH, non-opioid analgesics are the first choice treatment. The epidural blood patch remains the mainstay of severe PDPH therapy. Noninvasive therapies like theophylline, sumatriptan and ACTH can be an alternative. However, an evidence-based recommendation is lacking. The development of standard operating procedures for accidental dural punctures and PDPH is recommended. PMID- 21818738 TI - Radiological predictive factors in the healing of displaced intracapsular hip fractures. A clinical study of 404 cases. AB - BACKGROUND: Fracture healing complications occur in approximately a third of displaced intracapsular hip fractures treated by reduction and internal fixation. Various radiographic features of the fracture have been used to estimate the risk of fracture healing complications. AIMS: To determine which radiographic features of a displaced intracapsular hip fracture were the most reliable in predicting fracture re-displacement after internal fixation. METHODS: The pre-operative radiographs for 404 patients with a displaced intracapsular hip fracture treated by reduction and internal fixation were classified using five different variables. These were a direct measurement of trochanteric shortening and fracture shortening, a ratio of fracture displacement, the Garden grade and an alternative interpretation of the Garden grading. Inter-observer reliability of the various classifications was also studied. These observations were related to the later occurrence of fracture displacement or non-union. RESULTS: Only trochanteric shortening had an acceptable degree of inter-observer variation and this was also the most predictive of fracture re-displacement. The ratio method and fracture shortening were also related to fracture healing complications. Using the traditional Garden grading equal numbers of grade III and IV fractures healed but an alternative interpretation of the Garden grading showed some relationship to the development of non-union. CONCLUSIONS: A direct measurement of shortening of the femur is the most reliable predictor of failure of the fracture to heal. PMID- 21818739 TI - Acetabular impaction grafting in total hip replacement. AB - BACKGROUND AND PURPOSE: Acetabular impaction grafting has been shown to be very effective, but concerns regarding its suitability for larger defects have been highlighted. We report the use of this technique in a large cohort of patients, and address possible limitations of the technique. METHODS: We investigated a consecutive group of 339 cases of impaction grafting of the cup with morcellised impacted allograft bone for survivorship and mechanisms for early failure. RESULTS: Kaplan Meier survival was 89.1% (95% CI 83.2 to 95.0%) at 5.8 years for revision for any reason, and 91.6% (95% CI 85.9 to 97.3%) for revision for aseptic loosening of the cup. Of the 15 cases revised for aseptic cup loosening, nine were large rim mesh reconstructions, two were fractured Kerboull-Postel plates, two were migrating cages, one was a medial wall mesh failure and one had been treated by impaction alone. INTERPRETATION: In our series, results were disappointing where a large rim mesh or significant reconstruction was required. In light of these results, our technique has changed in that we now use predominantly larger chips of purely cancellous bone, 8-10 mm3 in size, to fill the cavity and larger diameter cups to better fill the aperture of the reconstructed acetabulum. In addition we now make greater use of i) implants made of a highly porous in-growth surface to constrain allograft chips and ii) bulk allografts combined with cages and morcellised chips in cases with very large segmental and cavitary defects. PMID- 21818740 TI - Developmental dysplasia in male infants: risk factors, instability and ultrasound screening. AB - OBJECTIVE: To evaluate the relationship between risk factors and presence of developmental dysplasia of the hip (DDH) in male infants, and to compare the efficiency of different ultrasound (US) screening protocols. MATERIALS AND METHODS: 1321 male infants were included in the study. Ultrasound examinations were performed by combining Graf's static method and Harcke's dynamic method. The relationship between the risk factors and DDH and the effect of risk factors on sonographic worsening in type 2a hips were assessed by the chi-square test and Fisher's exact test. RESULTS: The incidence of DDH was 1.4%. 13% of the cases had type 2a morphology, among whom in 3.1% sonographic deterioration occurred. The treatment rate was 1.8%. The rate of follow-up US was 17.5%. No risk factor was found to have a statistically significant influence on DDH (= type 2b morphology). Among the 32 cases with DDH, 23(72%) had a risk factor or positive clinical finding while 9(28%) did not (p:0.006). CONCLUSION: Risk factors do not have a statistically significant relationship with DDH in male cases. In our study 28% of the cases with DDH would be missed by a selective US screening protocol. We recommend assessment of all male infants with hip US. PMID- 21818741 TI - Total hip arthroplasty in developmental hip dysplasia using cementless tapered stem. Results after a minimum 10-year follow-up. AB - Acetabular and femoral abnormalities make total hip arthroplasty in developmental hip dysplasia a challenging procedure. We present details of long-term follow-up of a series of patients affected by developmental hip dysplasia treated with total hip arthroplasty using a cementless tapered stem. Thirty-five hips in 20 patients (18 women and 2 men) aged between 44 and 60 years (mean 51 years) were observed. Clinical evaluation was conducted using the Harris Hip Score (HHS). Radiographic evaluation consisted in standard anteroposterior and axial view radiographs of the hip. According to Crowe's classification, 25 hips had grade 2 and 10 hips grade 3 dysplasia. All patients were treated with total hip arthroplasty using a cementless tapered stem (Wagner Cone ProsthesisTM). After surgery the patients were clinically and radiographically evaluated at 1, 2, 3, 6 and 12 months and annually thereafter. The average follow-up was 12 years (range 10-14 years). The average HHS was 57+/-7 (range 45-66) preoperatively, 90+/-7 (range 81-100) 12 months after surgery and 90+/-6 (range 83-100) at last follow up. Radiographic evaluation demonstrated excellent osseointegration of the implants in most cases. Signs of bone resorption were present in 5 hips, but no evidence of loosening was observed and none of the implants have been revised. The tapered stem achieved adequate stability and orientation, and may be a suitable option for total hip arthroplasty for arthritis following developmental hip dysplasia. PMID- 21818742 TI - Pre-operative psychological distress does not adversely affect functional or mental health gain after primary total hip arthroplasty. AB - Preoperative psychological distress has been reported to predict poor outcome and patient dissatisfaction after total hip arthroplasty (THA). The purpose of this study was to investigate if pre-operative psychological distress was associated with adverse functional outcome after primary THR. We analysed the database of a prospective multi-centre study undertaken between January 1999 and January 2002. We recorded the Oxford Hip Score (OHS) and SF36 score preoperatively and up to five years after surgery for 1055 patients. We dichotomised the patients into the mentally distressed (Mental Health Scale score - MHS =56) and the not mentally distressed (MHS >56) groups based on their pre-operative MHS of the SF36. 762 (72.22%). Patients (595 not distressed and 167 distressed) were followed up at 5 years. Both pre and post-operative OHS and SF-36 scores were significantly worse in the distressed group (both p<0.001). However, both groups experienced statistically significant improvement in OHS and MHS, which was maximal at 1 year after surgery and was maintained over the follow up (p=0.00). There was a substantial improvement in mental distress in patients who reported mental distress prior to surgery. The results suggest that pre-operative psychological distress did not adversely compromise functional outcome gain after THA. Despite having worse absolute values both pre and post operatively, patients with mental distress did not have any less functional gain from THA as measured by improvement in OHS. PMID- 21818743 TI - Should the acetabular cup be medialised in total hip arthroplasty. AB - BACKGROUND: During total hip arthroplasty (THA), medialisation of the cup decreases the lever arm of body weight and is considered to be beneficial. Theoretically it should be compensated by an equivalent increase of the femoral offset in order to maintain global offset. GOAL OF THE STUDY: We investigated via a numerical model the forces on each bundle of the abductor muscles and the loading forces at the head-cup interface. We compared THA with and without medialisation of the cup and with and without restoration of the global offset. METHOD: A digital finite element model of the hip joint with THA was constructed. Monopodal weightbearing was simulated with the cup positioned so that the hip centre of rotation was left unchanged. Forces in the abductors and pressure on the prosthetic head were measured and then compared with three other configurations: 1. Medialisation of the cup by 5 to 15 mm with reproduction of the native femoral offset or; 2. with an increased femoral offset compensating for the cup medialisation and; 3. no medialisation of the cup with a femoral offset increased. RESULTS: Medialisation of the cup decreased stresses on the head-cup interface and on the abductor muscles, even when the global offset was not restored. Anatomical placement of the cup did not give the best results. The optimal outcome in terms of stress was observed when the cup was medialised but global offset restored. Any increase of global offset significantly increases the length and the tension in the anterior bundles of the abductor muscles. PMID- 21818744 TI - Influence of leg length discrepancy on clinical results after total hip arthroplasty--a prospective clinical trial. AB - The effect of leg length differences on early clinical outcome after total hip arthroplasty remains uncertain. We performed a prospective study on 94 patients who were evaluated preoperatively and one year after surgery for clinical leg length differences, which were then compared with radiological measurements. The effect of leg length differences on walking ability, limp, pain and patient satisfaction was studied. The mean clinical leg length difference after operation was 0.05 cm (-1.5 to 1.5, SD 0.5). Clinical and radiological measurements correlated poorly (omega =0.36 pre- and omega =0.186 postoperatively). Patients with a shorter operated leg on clinical assessment were more prone to limping (p<0.05), and patients with a longer leg had more pain compared to patients with equal leg lengths (p<0.05). Walking ability, Harris Hip Score and patient satisfaction were only marginally affected by leg length differences. Virtually equal leg length was achieved for most patients but small differences had a negative influence in relation to limping and pain. Patients should be counselled pre-operatively about possible leg length differences and associated symptoms. PMID- 21818745 TI - Radiological classification of hip arthropathy associated with long-term haemodialysis. AB - Various types of hip lesion associated with long-term haemodialysis have been observed. We present a new radiological classification system of haemodialysis related hip arthropathy. In total, 103 hip lesions were analyzed in 84 patients undergoing haemodialysis for more than ten years. The hip lesions were classified into 3 types; Type I--cystic type with further subdivisions based on cyst location, Type II--arthritic type, and Type III--deformity of the femoral head. Surgery was performed on 60 hips. We believe our classification system assists decision making on behalf of these patients. PMID- 21818746 TI - Supra acetabular bone mineral density measurements after hip resurfacing arthroplasty at short term follow up. AB - Implantation of a cementless press-fit acetabular cup during hip arthroplasty alters stress transfer to the periacetabular bone, resulting in stress shielding of cancellous bone and enhanced load transfer to cortical bone. Theoretically, the thicker, stiffer and larger acetabular cup of a hip resurfacing may increase periacetabular bone stress shielding. We attempted to assess the matter (at a minimum of 2 years after surgery) by measuring any difference in supra acetabular bone mineral density (BMD) between the side implanted with a thick monoblock cobalt-chromium (Co-Cr) acetabular component during hip resurfacing (HR) and the opposite non-operated side. We retrospectively recruited 44 patients who had undergone metal-on-metal hybrid hip resurfacing for unilateral osteoarthritis of the hip joint . BMD of the supra acetabular bone of both hips was measured using a dual energy X-ray absorptiometry (DEXA) scan. The BMD measured in Zone 2 was not different on the operated side (1.69 g/cm2 +/- 0.48) compared with the non operated side (1.70 g/cm2 +/-0.49) (p=0.904). Contrary to our expectations, implantation of a monoblock Co-Cr acetabular component during HR did not cause significant stress-shielding of supra acetabular cancellous bone. PMID- 21818747 TI - Arthroscopic grafting of chondral defects and subchondral cysts of the acetabulum. AB - We present a novel arthroscopic-assisted technique to graft chondral defects and subchondral cysts of the acetabular socket using a synthetic osteochondral plug. Four patients with groin pain,solitary cysts in the roof of the acetabulum and radiographic evidence of early osteoarthritis were treated. A bone tunnel was prepared from the region of the iliac crest to the acetabular articular surface.A synthetic osteochondral plug was inserted in an ante-grade fashion and positioned flush with the lunate articular cartilage. The minimum follow-up from surgery was 8 months (mean 10 months,range 8 to 11 months). There were no peri-operative complications related to the procedure. All patients reported an improvement in symptoms and function at the latest follow-up. One of the patients underwent a re look arthroscopy at 5 months for persistent dull groin and buttock pain. Capsular adhesions of the labrum were identified and released. The mean non-arthritic hip score improved from 53.8 (range 43.8 to 70) pre-operatively to 84.6 (range 78.8 to 87.5) at 6 months. Computed tomography and magnetic resonance imaging at 6 months confirmed the stability of the osteochondral plugs and on-going healing. This procedure offers an arthroscopic means to treat patients with solitary acetabular cysts and may prove effective for chondral grafting of denuded acetabular areas in early to moderate degenerative hip disease. PMID- 21818748 TI - Osteoid osteoma of the femoral neck causes deformity in children: a case report. AB - Intra-articular osteoid osteoma (IAOO) is rare and non-specific both in clinical and radiographic presentations, thus often associated with delayed diagnosis. Synovitis and muscle atrophy occur in adult IAOO. Bony deformity can occur in children and has been ascribed to muscle contractures. We report a case of a child with IAOO in the femoral neck. There was an absence of muscle contracture during surgery, and therefore the femoral deformity may have been induced directly by IAOO in the early stage of the disease. PMID- 21818749 TI - Bifocal cryptococcal osteomyelitis: management of a patient with concurrent femur and rib infections. AB - A case of Cryptococcus neoformans osteomyelitis involving both the femur and rib is reported. A 50-year-old male presented with a 1-month history of a persistently painful right hip. Radiography revealed an osteolytic area in the subcapital region of the right femoral neck and trochanteric region, and magnetic resonance imaging (MRI) revealed an intramedullary lesion in the peritrochanteric region. A Tc99m whole body bone scan showed significantly increased uptake in the posterior aspect of the right 7th rib as well as the right femoral region. Hemiarthroplasty with a bipolar prosthesis was performed. Because a permeative osteolytic lesion was identified intraoperatively, surgical resection was also performed. A culture from intraoperative specimens yielded C. neoformans. The rib infection was not treated surgically. Intravenous fluconazole was administered postoperatively. The patient became seronegative for cryptococcal antigen with no further illness over the next five years. PMID- 21818750 TI - Femoral artery injury during revision of a dislocated bipolar hemiarthroplasty: a case report. AB - Although rarely encountered, major vascular injury is a serious complication of total hip arthroplasty (THA). We report the case of an 85-year-old woman who sustained a deep femoral artery injury associated with a superficial femoral artery thrombosis during revision of a dislocated bipolar hemiarthroplasty to a THA. Altered anatomy due to migration of the femoral head was thought to be one of the factors leading to this complication. Following the revision procedure, no signs of vascular insufficiency were detected in the immediate postoperative period, but ischaemia was clinically evident 12 hours after surgery. The importance of careful preoperative and postoperative assessment is addressed. PMID- 21818751 TI - Assessment of mitochondrial toxicity in HepG2 cells cultured in high-glucose- or galactose-containing media. AB - Drug-induced mitochondrial toxicity has been recognized as contributing to a variety of organ toxicities, such as liver, heart, kidney, and CNS, and has been found to contribute to drug attrition and black box warnings. Here, we describe a cell-based assay that can detect direct drug-induced mitochondrial toxicity, providing protocols for screening in 96- and 384-well format. Cultured cells grown in glucose media produce their ATP by glycolysis, largely bypassing the mitochondria, and hence are fairly resistant to drugs that affect mitochondrial function. However, when growing the same cells in media supplemented with galactose as opposed to glucose, they are forced to produce ATP through oxidative phosphorylation, which then makes them vulnerable to mitochondrial insult. By measuring viability of cells grown in either glucose- or galactose-supplemented media, direct mitochondrial impairment can be detected. PMID- 21818752 TI - Measuring intracellular hsp70 in leukocytes by flow cytometry. AB - Heat shock or stress proteins are constitutively expressed redox-sensitive proteins, the synthesis of which is induced in almost all organisms exposed to a range of stressors, including heat shock, oxidative stress, free radicals, UV radiation, and heavy metals. This unit details a method, with supporting protocols, for the measurement of their expression in peripheral blood leukocytes by flow cytometry. PMID- 21818753 TI - Measurement of peroxiredoxin activity. AB - Peroxiredoxins are cysteine-dependent peroxidases that react with hydrogen peroxide, larger hydroperoxide substrates, and peroxynitrite. Protocols are provided to measure Prx activity with peroxide by (1) a coupled reaction with NADPH, thioredoxin reductase, and thioredoxin, (2) the direct monitoring of thioredoxin oxidation, (3) competition with horseradish peroxidase, and (4) peroxide consumption using the FOX assay. PMID- 21818756 TI - B lymphocytes that migrate to tuberculous pleural fluid via the SDF-1/CXCR4 axis actively respond to antigens specific for Mycobacterium tuberculosis. AB - B-cell biology has been largely uncharacterized in the field of tuberculosis (TB). In this study, we investigated the immunophenotypical and functional characteristics of B cells obtained from the pleural fluid (PF) and peripheral blood of patients with tuberculous pleuritis (TP). Our results indicated that the total numbers of B cells, CD27(+) memory B cells and plasmablasts were clearly lower in the PF than in peripheral blood. Furthermore, we found significantly higher expression of CXCR4 on B cells in the PF, and a chemotaxis assay showed that B cells in the PF were more responsive to stromal cell-derived factor-1 (SDF 1) than B cells from peripheral blood. In addition, SDF-1 levels in PF were remarkably high compared with SDF-1 levels in plasma, suggesting that the SDF 1/CXCR4 axis might facilitate the migration of circulating B cells into tuberculous pleural space. Importantly, we observed that significantly more antibodies were produced by B cells in the PF following stimulation with BCG, early secretory antigenic target (ESAT-6)/culture filtrate protein-10 (CFP-10) or ESAT-6 protein. Collectively, these data demonstrate that Mycobacterium tuberculosis-specific B cells exist at local sites of infection in TP patients and this localization might influence the immune response to M. tuberculosis. PMID- 21818755 TI - Intranasal but not intravenous delivery of the adjuvant alpha-galactosylceramide permits repeated stimulation of natural killer T cells in the lung. AB - Efficient induction of antigen-specific immunity is achieved by delivering multiple doses of vaccine formulated with appropriate adjuvants that can harness the benefits of innate immune mediators. The synthetic glycolipid alpha galactosylceramide (alpha-GalCer) is a potent activator of NKT cells, a major innate immune mediator cell type effective in inducing maturation of DCs for efficient presentation of co-administered antigens. However, systemic administration of alpha-GalCer results in NKT cell anergy in which the cells are unresponsive to subsequent doses of alpha-GalCer. We show here that alpha-GalCer delivered as an adjuvant by the intranasal route, as opposed to the intravenous route, enables repeated activation of NKT cells and DCs, resulting in efficient induction of cellular immune responses to co-administered antigens. We show evidence that after intranasal delivery,alpha-GalCer is selectively presented by DCs for the activation of NKT cells, not B cells. Furthermore, higher levels of PD-1 expression, a potential marker for functional exhaustion of the NKT cells when alpha-GalCer is delivered by the intravenous route, are not observed after intranasal delivery. These results support a mucosal route of delivery for the utility of alpha-GalCer as an adjuvant for vaccines, which often requires repeated dosing to achieve durable protective immunity. PMID- 21818754 TI - Overview of peroxiredoxins in oxidant defense and redox regulation. AB - Peroxiredoxins are important hydroperoxide detoxification enzymes, yet have only come to the fore in recent years relative to the other major players in peroxide detoxification, heme-containing catalases and peroxidases and glutathione peroxidases. These cysteine-dependent peroxidases exhibit high reactivity with hydrogen peroxide, organic hydroperoxides, and peroxynitrite and play major roles not only in peroxide defense, but also in regulating peroxide-mediated cell signaling. This overview focuses on important peroxiredoxin features that have emerged over the past several decades with an emphasis on catalytic mechanism, regulation, and biological function. PMID- 21818757 TI - Identification of stress and coping risk and protective factors associated with changes in adjustment to caring for an adult with mental illness. AB - There is a paucity of theory guided longitudinal research into how carers of an adult with mental illness adapt to caregiving. This study examined changes in carer adjustment over 12 months and identified risk and protective factors using stress/coping theory. Eighty-seven carers completed questionnaires at Time 1 and 12 months later (Time 2). The risk/protective factors were background variables, coping resources, appraisals, and coping strategies. Adjustment outcomes were stable over 12 months. Stress/coping variables were associated with one or more Time 2 adjustment outcomes when controlling for initial adjustment and the direction of these associations were consistent with predictions. Findings support the application of stress/coping theory to guide identification of modifiable risk and protective factors associated with caregiver adjustment. PMID- 21818758 TI - Multiple instrument translation for use with South Asian Indian immigrants. AB - The purpose of this study was to describe translation of five measures (physical activity, acculturation, discrimination, self-efficacy, and depression) from English into Hindi using the committee translation method, focus group, and think aloud interviews. Two South Asian Indian (SAI) immigrant bilingual translators and a moderator reached consensus on 93 of 102 items, using the committee method. Discrepancy in nine items was resolved with a focus group conducted with five bilingual SAI immigrants. Ten other bilingual SAI immigrants participated in think-aloud interviews to assess understanding and interpretation of the questions. More than 10 additional changes were made following the think-aloud interviews. Sequential use of multiple translation techniques improved translation with culturally acceptable language, thereby maintaining equivalence with original versions. PMID- 21818759 TI - Comparison of prevalence of toxoplasma and cytomegalovirus infection in cases with fetal ultrasound markers in the second trimester of pregnancy. AB - OBJECTIVES: To evaluate the prevalence of toxoplasma and cytomegalovirus (CMV) infections in cases of ultrasound anomalies detected in the second trimester of pregnancy. METHODS: Serological examinations for toxoplasma and CMV infection were carried out in 655 cases with sonographic findings suggestive of fetal infection, 612 cases with single ultrasound markers and 43 cases with two or more markers. RESULTS: In cases of single ultrasound markers, serological examination diagnosed recent toxoplasma infection in 107/612 cases (17.5%) and recent CMV infection in 75 cases (12.3%). Recent toxoplasma infection accounted for 13.8% (52/377) of the intracranial sonographic findings and 23.9% (45/188) of the abdominal findings, whereas recent CMV infections accounted for 12.2 (46/377) and 11.7% (22/188), respectively. Recent CMV infection with sonographic manifestations had higher rates of intracranial than intra-abdominal sonographic findings (46/75 or 61% vs 22/75 or 29%), whereas recent toxoplasma infection with sonographic manifestations had similar rates of intracranial (52/107 or 49%) and intra-abdominal (45/107 or 42%) findings. In cases of two or more ultrasound markers, serological examination diagnosed recent toxoplasma infection in 12/43 cases (27.9%) and recent CMV infection in 10/43 cases (23.3%). CONCLUSIONS: Ultrasound findings suspicious for toxoplasma and CMV infection are not pathognomonic for either pathologic entity. PMID- 21818760 TI - Ethyl pyruvate protects rats from phosgene-induced pulmonary edema by inhibiting cyclooxygenase2 and inducible nitric oxide synthase expression. AB - Phosgene is a poorly water-soluble gas penetrating the lower respiratory tract which can induce acute lung injury characterized by a latent phase of fatal pulmonary edema. Pulmonary edema caused by phosgene is believed to be a consequence of oxidative stress and inflammatory responses. Ethyl pyruvate (EP) has been demonstrated to have anti-inflammatory and anti-oxidative properties in vivo and in vitro. The potential therapeutic role of EP in phosgene-induced pulmonary edema has not been addressed so far. In the present study, we aim to investigate the protective effects of EP on phosgene-induced pulmonary edema and the underlying mechanisms. Rats were administered with EP (40 mg kg(-1)) and RAW264.7 cells were also incubated with it (0, 2, 5 or 10 um) immediately after phosgene (400 ppm, 1 min) or air exposure. Wet-to-dry lung weight ratio (W:D ratio), nitric oxide (NO) and prostaglandin E(2) (PGE(2)) production, cyclooxygenase2 (COX-2) and inducible nitric oxide synthase (iNOS) expression, and mitogen-activated protein kinases activities (MAPKs) were measured. Our results showed that EP treatment attenuated phosgene-induced pulmonary edema and decreased the level of NO and PGE(2) dose-dependently. Furthermore, EP significantly reduced COX-2 expression, iNOS expression and MAPK activation induced by phosgene. Moreover, specific inhibitors of MAPKs reduced COX-2 and iNOS expression induced by phosgene. These findings suggested that EP has a protective role against phosgene-induced pulmonary edema, which is mediated in part by inhibiting MAPK activation and subsequently down-regulating COX-2 and iNOS expression as well as decreasing the production of NO and PGE(2). PMID- 21818761 TI - A review of the logistic role of L-carnitine in the management of radiation toxicity and radiotherapy side effects. AB - Radiation therapy is a key modality in the treatment of different cancer types. Fatigue is the most common side effect of radiotherapy, while others include nausea, hair loss, skin irritation, anemia, infertility, cardiovascular disease, cognitive impairment and even the development of second cancers. Studies in experimental animals have shown protective effects of carnitine against exposure of various organs to ionizing radiation, whereas carnitine deficiency is known to enhance radiation-induced toxicity. This report summarizes the recent literature on the adverse effects of radiotherapy and the impact of radiation on carnitine homeostasis. Although some studies have demonstrated the prophylactic benefits of carnitine against the toxic effects of chemotherapy, the role of carnitine in the prognosis and management of cancer patients receiving radiotherapy is not clear and needs to be explored. PMID- 21818762 TI - Peripheral T cell lymphoma not otherwise specified with Reed Sternberg like cells. PMID- 21818763 TI - Treatment of vitamin D deficiency in transfusion-dependent thalassemia. PMID- 21818764 TI - Bone marrow aspirate in Chediak-Higashi syndrome. PMID- 21818765 TI - Pyrazinamide-induced sideroblastic anemia. PMID- 21818766 TI - Lenalidomide-associated pneumonitis in patients with plasma cell dyscrasias. PMID- 21818767 TI - Successful treatment with recombinant soluble thrombomodulin of two cases of sinusoidal obstructive syndrome/hepatic veno-occlusive disease after bone marrow transplantation. PMID- 21818768 TI - Inhibition of beta-catenin signaling in chondrocytes induces delayed fracture healing in mice. AB - Appropriate and controlled chondrogenesis and endochondral ossification play fundamental roles in the fracture healing cascade, a regenerative process involved in highly coordinated biological events, including the Wnt/beta-catenin signaling pathway. To examine the role and importance of this pathway in chondrocytes, we studied bone repair of closed tibias fractures in Col2a1-ICAT transgenic mice, in which the Wnt/beta-catenin signaling pathway is specially inhibited in chondrocytes. Radiological, histological, and histomorphometric analyses at 7, 9, 12, 14, 21, and 28 days after fracture demonstrated the bone repairs were retarded in Col2a1-ICAT transgenic mice, due to reduced and delayed cartilage formation, chondrocyte hypertrophy, and bone generation. In addition, at 5 weeks, Col2a1-ICAT transgenic mice exhibited a weak mechanical tolerance to four-point bending. Furthermore, quantitative-PCR analysis revealed that the expression of genes associated specifically with cartilage extracellular matrix formation (collagen II, collagen X, and mmp13), bone remodeling (alp, collagen I, and osteocalcin), and vascular extravagation (vegf), and transcriptional activators involved in cartilage generation and ossification (sox9 and runx2) was decreased and delayed in the fracture sites of Col2a1-ICAT transgenic mice during healing. Collectively, these results suggest that Wnt/beta-catenin signaling is critical for fracture healing, especially with respect to chondrogenesis and endochondral ossification. Thus, our study provides insight into the possible mechanisms of and therapeutic targets for improving normal facture repair and the healing of non-union fractures. PMID- 21818770 TI - Critical-size defect induces unicompartmental osteoarthritis in a stable ovine knee. AB - Animal models simulating osteoarthritis are frequently associated with irreversible changes in biomechanics. Although these models successfully induce osteoarthritis, results of experimental repair procedures are impaired by biomechanical problems. The aim of this study was to define the critical size of a chondral lesion to induce unicompartmental osteoarthritis in a stable joint. Sixteen sheep were randomly divided into four treatment groups. A cartilage defect (7- or 14-mm diameter) was created in the weight-bearing zone of the medial femoral condyle. The sheep were mobilized for 6 or 12 weeks. Osteoarthritis was determined by gross assessment, India ink staining, histology (Mankin score), and analysis of COMP in the serum. In the 6-week group, only minor osteoarthritis was registered for either defect size. After 12 weeks, the 14-mm defect induced minor osteoarthritis at the femoral condyle and caused significant degenerative changes at the tibial articular cartilage and the meniscus. The 7-mm defect created focal unicompartmental osteoarthritis at the medial femoral condyle and minor degenerative changes at the corresponding tibia. A 7-mm full-thickness chondral defect with a weight-bearing regimen of 12 weeks induced local osteoarthritis at the medial compartment in an otherwise stable joint as aimed. PMID- 21818769 TI - Notch signaling components are upregulated during both endochondral and intramembranous bone regeneration. AB - Previous studies have demonstrated that Notch signaling regulates endochondral and intramembranous bone formation by controlling cell proliferation and differentiation. Notch signaling has also been shown to regulate healing in a variety of tissues. The objective of this study was to characterize and compare activation of the Notch signaling pathway during endochondral and intramembranous bone healing using tibial fracture and calvarial defect injury models, respectively. Bilateral tibial fractures or bilateral 1.5 mm diameter calvarial defects were created in mice, and tissues were harvested at 0, 5, 10, and 20 days post-fracture. Gene expression of Notch signaling components was upregulated during both tibial fracture and calvarial defect healing, with expression generally higher during tibial fracture healing. The most highly expressed ligand and receptor during healing, Jag1 and Notch2 (specifically the activated receptor, known as NICD2), were similarly localized in mesenchymal cells during both modes of healing, with expression decreasing during chondrogenesis, but remaining present in osteoblasts at all stages of maturity. Results suggest that in addition to embryological bone development, Notch signaling regulates both endochondral and intramembranous bone healing. PMID- 21818771 TI - Visualization of protein digestion in the midgut of the acarid mite Lepidoglyphus destructor. AB - The ingestion of chromogenic or fluorescent substrates for protease detection enables the visualization of digestive processes in mites in vivo due to their transparent bodies. The substrates for protease detection were offered to Lepidoglyphus destructor, and the resulting signals were observed in specimens under a compound microscope. The protease activity was successfully localized using chromogenic substrates (azoalbumin, AAPpNA, SAAPFpNA, elastin-orcein, SA(3) pNA, ZRRpNA, ArgpNA, and MAAPMpNA) and fluorescent substrates (casein fluorescein, albumin-fluorescein, AAPAMC, BAAMC, ZRRAMC, ArgAMC, and AGPPPAMC). No activity was detected using the keratin azure and BApNA substrates. In the mesodeum, trypsin-like activity generated by hydrolysis of the BApNA substrate was not observed, but the BAAMC substrate allowed the visualization of trypsin like activity in food boli in the posterior mesodeum. The results indicate that cathepsins B, D, and G and cathepsin H or aminopeptidase-like activities are present in the midgut of L. destructor. Among these activities, cathepsin D-like activity was identified for the first time in the gut of L. destructor. All proteases mentioned are produced in the mesodeal lumen and form the food bolus together with ingested food, afterward passing through the gut to be defecated. The method used enables the visualization of protease activities in the gut of transparent animals. PMID- 21818772 TI - Kernel machine SNP-set analysis for censored survival outcomes in genome-wide association studies. AB - In this article, we develop a powerful test for identifying single nucleotide polymorphism (SNP)-sets that are predictive of survival with data from genome wide association studies. We first group typed SNPs into SNP-sets based on genomic features and then apply a score test to assess the overall effect of each SNP-set on the survival outcome through a kernel machine Cox regression framework. This approach uses genetic information from all SNPs in the SNP-set simultaneously and accounts for linkage disequilibrium (LD), leading to a powerful test with reduced degrees of freedom when the typed SNPs are in LD with each other. This type of test also has the advantage of capturing the potentially nonlinear effects of the SNPs, SNP-SNP interactions (epistasis), and the joint effects of multiple causal variants. By simulating SNP data based on the LD structure of real genes from the HapMap project, we demonstrate that our proposed test is more powerful than the standard single SNP minimum P-value-based test for association studies with censored survival outcomes. We illustrate the proposed test with a real data application. PMID- 21818773 TI - A comparison of strategies for analyzing dichotomous outcomes in genome-wide association studies with general pedigrees. AB - Genome-wide association studies (GWAS) have been frequently conducted on general or isolated populations with related individuals. However, there is a lack of consensus on which strategy is most appropriate for analyzing dichotomous phenotypes in general pedigrees. Using simulation studies, we compared several strategies including generalized estimating equations (GEE) strategies with various working correlation structures, generalized linear mixed model (GLMM), and a variance component strategy (denoted LMEBIN) that treats dichotomous outcomes as continuous with special attentions to their performance with rare variants, rare diseases, and small sample sizes. In our simulations, when the sample size is not small, for type I error, only GEE and LMEBIN maintain nominal type I error in most cases with exceptions for GEE with very rare disease and genetic variants. GEE and LMEBIN have similar statistical power and slightly outperform GLMM when the prevalence is low. In terms of computational efficiency, GEE with sandwich variance estimator outperforms GLMM and LMEBIN. We apply the strategies to GWAS of gout in the Framingham Heart Study. Based on our results, we would recommend using GEE ind-san in the GWAS for common variants and GEE ind fij or LMEBIN for rare variants for GWAS of dichotomous outcomes with general pedigrees. PMID- 21818774 TI - X chromosome association testing in genome wide association studies. AB - Genome wide association studies (GWAS) have revealed many fascinating insights into complex diseases even from simple, single-marker statistical tests. Most of these tests are designed for testing of associations between a phenotype and an autosomal genotype and are therefore not applicable to X chromosome data. Testing for association on the X chromosome raises unique challenges that have motivated the development of X-specific statistical tests in the literature. However, to date there has been no study of these methods under a wide range of realistic study designs, allele frequencies and disease models to assess the size and power of each test. To address this, we have performed an extensive simulation study to investigate the effects of the sex ratios in the case and control cohorts, as well as the allele frequencies, on the size and power of eight test statistics under three different disease models that each account for X-inactivation. We show that existing, but under-used, methods that make use of both male and female data are uniformly more powerful than popular methods that make use of only female data. In particular, we show that Clayton's one degree of freedom statistic [Clayton, 2008] is robust and powerful across a wide range of realistic simulation parameters. Our results provide guidance on selecting the most appropriate test statistic to analyse X chromosome data from GWAS and show that much power can be gained by a more careful analysis of X chromosome GWAS data. PMID- 21818775 TI - A test of Hardy-Weinberg equilibrium in structured populations. AB - Testing for Hardy-Weinberg equilibrium (HWE) is used routinely as an important initial step for genotype data quality checking. Departure from HWE can be caused by many factors, such as genotyping errors, population stratification, and disease association, if we use affected individuals only. In a structured population, even if a marker is in HWE in each subpopulation, data may show departure from HWE if allele frequencies are different in different subpopulations and such a departure can be misinterpreted as a potential problem in genotyping quality, resulting in false exclusion from future analysis. In this article, we propose a new HWE test, a test for HWE in structured populations (HWES) that can assess departure from HWE and take into account of population stratification at the same time. Our proposed test can distinguish departure from HWE caused by population stratification and departure from HWE caused by other factors. We use simulation studies as well as applications to real data sets to evaluate the performance of the proposed test. Results show that, for a wide range of population structures, our proposed test has correct type I error rates while the traditional chi(2) test will lead to false-positive results. In homogenous populations, our proposed test has comparable power with the traditional chi(2) test. PMID- 21818776 TI - A data-driven method for identifying rare variants with heterogeneous trait effects. AB - Collapsing multiple variants into one variable and testing their collective effect is a useful strategy for rare variant association analysis. Direct collapsing, however, is not valid or may significantly lose power when a group of variants to be collapsed have heterogeneous effects on target traits (i.e. some positive and some negative). This could be especially true for quantitative traits (such as blood pressure and body mass index), regardless of whether subjects are sampled randomly from a population or selectively from two extreme tails of the trait distribution. To deal with this problem, we propose a novel, data-driven method, the P-value Weighted Sum Test (PWST), which allows each variant to be individually weighted according to the evidence of association from the data itself. Specifically, both significance and direction of individual variant effects are used to calculate a single weighted sum score based on rescaled left-tail P-values from single-variant analysis, after which a permutation test of association is performed between the score and the trait. Our simulation under different sampling strategies shows that PWST significantly increases statistical power when there are heterogeneous variant effects. The appeal of the PWST approach is illustrated in an application to sequence data by detecting the collective effect of variants in the peroxisome proliferator activated receptor alpha (PPARalpha) gene on triglycerides (TG) response to fenofibrate treatment from 300 subjects in the Genetics of Lipid Lowering and Diet Network study. PMID- 21818777 TI - Method to detect differentially methylated loci with case-control designs using Illumina arrays. AB - It is now understood that many human cancer types are the result of the accumulation of both genetic and epigenetic changes. DNA methylation is a molecular modification of DNA that is crucial for normal development. Genes that are rich in CpG dinucleotides are usually not methylated in normal tissues, but are frequently hypermethylated in cancer. With the advent of high-throughput platforms, large-scale structure of genomic methylation patterns is available through genome-wide scans and tremendous amount of DNA methylation data have been recently generated. However, sophisticated statistical methods to handle complex DNA methylation data are very limited. Here, we developed a likelihood based Uniform-Normal-mixture model to select differentially methylated loci between case and control groups using Illumina arrays. The idea is to model the data as three types of methylation loci, one unmethylated, one completely methylated, and one partially methylated. A three-component mixture model with two Uniform distributions and one truncated normal distribution was used to model the three types. The mixture probabilities and the mean of the normal distribution were used to make inference about differentially methylated loci. Through extensive simulation studies, we demonstrated the feasibility and power of the proposed method. An application to a recently published study on ovarian cancer identified several methylation loci that are missed by the existing method. PMID- 21818778 TI - Stereochemical study of the sterically crowded phenylselanylalkenes by means of (77)Se-(1)H spin-spin coupling constants. AB - Stereochemical study of five sterically crowded phenylselanylalkenes obtained via the hydroselenation of either terminal or internal alkynes with benzeneselenol catalyzed by the nanosized Ni complexes has been carried out based on the experimental HMBC measurements and theoretical second order palarization propagator approach (SOPPA) calculations of their (77)Se-(1)H spin-spin coupling constants across double bond in combination with the energy-based theoretical conformational analysis performed at the MP2/6-311G** level. It has been found that studied phenylselanylalkenes adopt mainly skewed s-cis conformation with the noticeable out-of-plane deviations of the phenylselanyl and phenyl groups. PMID- 21818779 TI - hNCOcanH pulse sequence and a robust protocol for rapid and unambiguous assignment of backbone ((1)H(N), (15)N and (13)C') resonances in (15)N/(13)C labeled proteins. AB - A three-dimensional nuclear magnetic resonance (NMR) pulse sequence named as hNCOcanH has been described to aid rapid sequential assignment of backbone resonances in (15)N/(13)C-labeled proteins. The experiment has been derived by a simple modification of the previously described HN(C)N pulse sequence [Panchal et al., J. Biomol. NMR 20 (2001) 135-147]; t2 evolution is used to frequency label (13)C' rather than (15)N (similar trick has also been used in the design of hNCAnH pulse sequence from hNcaNH [Frueh et al., JACS, 131 (2009) 12880-12881]). The modification results in a spectrum equivalent to HNCO, but in addition to inter-residue correlation peaks (i.e. Hi , Ci-1), the spectrum also contains additional intra-residue correlation peaks (i.e. Hi-1 , Ci-1) in the direct proton dimension which has maximum resolution. This is the main strength of the experiment and thus, even a small difference in amide (1) H chemical shifts (5-6 Hz) can be used for establishing a sequential connectivity. This experiment in combination with the HNN experiment described previously [Panchal et al., J. Biomol. NMR 20 (2001) 135-147] leads to a more robust assignment protocol for backbone resonances ((1) H(N) , (15)N) than could be derived from the combination of HNN and HN(C)N experiments [Bhavesh et al., Biochemistry, 40 (2001) 14727 14735]. Further, this new protocol enables assignment of (13)C' resonances as well. We believe that the experiment and the protocol presented here will be of immense value for structural-and functional-proteomics research by NMR. Performance of this experiment has been demonstrated using (13)C/(15)N labeled ubiquitin. PMID- 21818780 TI - Isotopic effect on tautomeric behavior of 5-(2,6-disubstituted-aryloxy) tetrazoles. AB - Isotopic effect on tautomeric behaviors of the synthesized 5-phenoxy- (1a), 5 (2,6-dimethylphenoxy)-(1b), 5-(2,6-diisopropylphenoxy)-(1c), 5-(2,6 dimethoxyphenoxy)-(1d) and 5-(4-methylphenoxy)-tetrazole (1e) were investigated in DMSO-d6 by adding one drop of D2O. Among 1a-e, 1a, 1d and 1e show small rotational barrier around C5-O1 and O1-C6 while in 1b and 1c there are distinguishable rotational barrier about that bonds. The (1)H NMR spectra of 1b and 1c show slightly different chemical shifts for two methyl and isopropyl groups on those phenyl ring, respectively, while the chemical shifts difference (Deltadelta) between two methyl and two isopropyl groups were enhanced by adding D2O. The (13)C NMR spectra of 1b show two overlapped singlets for methyl groups after adding D2O. Representatively, the calculations of compound 1c were performed with GAUSSIAN-03 and the rotational barrier about C5-O1 and between isopropyl group and phenyl ring in 1c was calculated with B3LYP/6-31G(d) basis set. PMID- 21818781 TI - Induction of DNA damage signaling genes in benzidine-treated HepG2 cells. AB - We examined genotoxicity and DNA damage response in HepG2 cells following exposure to benzidine. Using the Comet assay, we showed that benzidine (50-200 MUM) induces DNA damage in HepG2 cells. DNA damage signaling pathway-based PCR arrays were used to investigate expression changes in genes involved in cell cycle arrest, apoptosis, and DNA repair and showed upregulation of 23 genes and downregulation of one gene in benzidine-treated cells. Induction of G2/M arrest and apoptosis was confirmed at the protein level. Real-time PCR and Western blots were used to demonstrate the expression of select DNA repair-associated genes from the PCR array. Upregulation of the p53 protein in benzidine-treated cells suggests the induction of the p53 DNA damage signaling pathway. Collectively, DNA damage response genes induced by benzidine indicate recruitment complex molecular machinery involved in DNA repair, cell-cycle arrest, and potentially, activation of the apoptosis. PMID- 21818782 TI - Tissue transglutaminase activity is involved in the differentiation of oligodendrocyte precursor cells into myelin-forming oligodendrocytes during CNS remyelination. AB - During normal brain development, axons are myelinated by mature oligodendrocytes (OLGs). Under pathological, demyelinating conditions within the central nervous system (CNS), axonal remyelination is only partially successful because oligodendrocyte precursor cells (OPCs) largely remain in an undifferentiated state resulting in a failure to generate myelinating OLGs. Tissue Transglutaminase (TG2) is a multifunctional enzyme, which amongst other functions, is involved in cell differentiation. Therefore, we hypothesized that TG2 contributes to differentiation of OPCs into OLGs and thereby stimulates remyelination. In vivo studies, using the cuprizone model for de- and remyelination in TG2(-/-) and wild-type mice, showed that during remyelination expression of proteolipid protein mRNA, as a marker for remyelination, in the corpus callosum lags behind in TG2(-/-) mice resulting in less myelin formation and, moreover, impaired recovery of motor behavior. Subsequent in vitro studies showed that rat OPCs express TG2 protein and activity which reduces when the cells have matured into OLGs. Furthermore, when TG2 activity is pharmacologically inhibited, the differentiation of OPCs into myelin-forming OLGs is dramatically reduced. We conclude that TG2 plays a prominent role in remyelination of the CNS, probably through stimulating OPC differentiation into myelin-forming OLGs. Therefore, manipulating TG2 activity may represent an interesting new target for remyelination in demyelinating diseases. PMID- 21818783 TI - Trauma and psychotic symptoms: data from a pediatric mental health inpatient unit. AB - This study describes differences in symptoms in young people with psychosis, with and without a history of trauma. The files of 118 mental health inpatients, aged 8 to 18 years, all reporting hallucinations and/or delusions, were reviewed for a history of trauma. Symptoms reported by inpatients with and without a history of trauma were compared. Variables found to be significantly associated with trauma in the univariate analysis were entered into a logistic regression analysis. Variables were entered if they met a significance of p < .05 or an adjusted odds ratio of < 2. Young people with a history of trauma reported a highly significant increase in disturbed behavior, particularly those with a history of sexual assault. This study illustrates the importance of obtaining an adequate assessment of children and adolescents with psychotic symptoms to ensure they receive the most effective treatment. PMID- 21818784 TI - Effect of transition home from combat on risk-taking and health-related behaviors. AB - Transition home following a combat deployment involves a period of adjustment. Exploratory and confirmatory factor analyses of a new 16-item transition scale were conducted with 2 samples and resulted in 4 factors (Benefit, Appreciation, Anger/Alienation, and Guilt/Remorse). In Study 1 (N = 1,651), the number of combat events was positively related to Anger/Alienation 4 months later even after controlling for posttraumatic stress disorder (PTSD) symptoms, partial r = .18, p < .001. In Study 2 (N = 647), after controlling for PTSD symptoms, Anger/Alienation assessed at 4 months postdeployment predicted more risk-taking behaviors 4 months later, partial r = .10, p = .01. Appreciation predicted fewer unhealthy habits, partial r = -.13, p = .001, whereas Anger/Alienation predicted more unhealthy habits, partial r = .09, p = .024. Results demonstrate the importance of broadening the conceptualization of adjustment in combat veterans. PMID- 21818785 TI - Prolonged grief among traumatically bereaved relatives exposed and not exposed to a tsunami. AB - Numerous studies on the mental health consequences of traumatic exposure to a disaster compare those exposed to those not exposed. Relatively few focus on the effect of the death of a close relative caused by the disaster-suffering a traumatic bereavement. This study compared the impact on 345 participants who lost a close relative in the 2004 Indian Ocean tsunami, but who were themselves not present, to 141 who not only lost a relative, but also were themselves exposed to the tsunami. The focus was on psychological distress assessed during the second year after the sudden bereavement. Findings were that exposure to the tsunami was associated with prolonged grief (B = 3.81) and posttraumatic stress reactions (B = 6.65), and doubled the risk for impaired mental health. Loss of children increased the risk for psychological distress (prolonged grief: B = 6.92; The Impact of Event Scale-Revised: B = 6.10; General Health Questionnaire 12: OR = 2.34). Women had a higher frequency of prolonged grief. For men, loss of children presented a higher risk for prolonged grief in relation to other types of bereavement (B = 6.36 vs. loss of partner). Further long-term follow-up could deepen the understanding of how recovery after traumatic loss is facilitated. PMID- 21818786 TI - A biographical sketch of Johannes Jessenius: 410th anniversary of his Prague dissection. AB - This article focuses on Johannes Jessenius (Jan Jesensky) (1566-1621), with particular attention paid to his famous Prague dissection and its publication (2011 marking its 410(th) anniversary). Jessenius was a physician, surgeon, anatomist, scholar, philosopher, and university authority. We focus on the life and main contribution of Jessenius based on his 1600 Prague dissection, the Anatomiae, Pragae (1601). Borovansky described Jessenius' book as "not as a textbook, but as a publication aiming at educated laymen with the purpose of advertising, filled with quotations of old classical authors." This work presents an important part of the Central European scientific, cultural, and political life of the late Renaissance period. PMID- 21818787 TI - Multilevel information storage in ferroelectric polymer memories. PMID- 21818789 TI - Shape-memory nanocomposites with magnetically adjustable apparent switching temperatures. PMID- 21818788 TI - Resistive switching phenomena in Li(x) CoO2 thin films. PMID- 21818792 TI - Experimental and theoretical evidence of aromatic behavior in heterobenzene-like molecules with metal-metal multiple bonds. AB - Binding two quadruply bonded dimolybdenum units [Mo(2)(DAniF)(3)](+) (DAniF=N,N' di-p-anisylformamidinate) with two chalcogen atoms generated two molecules with a central core composed of a cyclic six-membered [Mo(2)](2)(MU-EH)(2) species (E=S in 1 and O in 3, and [Mo(2)] is a quadruple-bonded [Mo(2)(formamidinate)(3)] unit). Aerobic oxidation of 1 and 3 followed by concomitant deprotonation gave rise to the corresponding [Mo(2)](2)(MU-E)(2) compounds 2 and 4. The latter show a striking coplanarity and near-bond equalization of the Mo/E cluster. The oxidized species 2 and 4 are diamagnetic in the measured temperature range of 5 to 300 K, which is somewhat unexpected for molecules that have dimetal units with a sigma(2)pi(4)delta(1) electronic configuration. This suggests there are strong interactions between the dimolybdenum units through the E atoms. The large electronic delocalization of the delta electrons over the entire Mo/E core is supported by the exceptionally large potential separation for the two successive one-electron reductions of the linked Mo(2)(5+) units from the oxidized species (DeltaE(1/2)=1.7 V for the sulfur analogue). This large electronic delocalization has an important effect on the NMR spectroscopic signals for the two sets of methine (N-(CH)-N) protons from the DAniF ligands. Those essentially parallel to the core, H(?), and those essentially perpendicular to the core, H(?), exhibit downfield and upfield chemical shifts, respectively, that are separated by delta=1.32 ppm. The structural, electronic, magnetic, and chemical behaviors for 2 and 4 are consistent with aromaticity, with the [Mo(2)E(2)Mo(2)] cores that resemble the prototypical benzene molecule. Theoretical studies, including DFT calculations, natural bond orbital (NBO) analyses, and gauge-independent atomic orbital (GIAO) NMR spectroscopic calculations, are also consistent with the aromaticity of the [Mo(2)](2)(MU-E)(2) units being promoted by d(delta)(Mo(2)) p(pi)(E) pi conjugation. The cyclic pi conjugation of the central moiety in 2 and 4 involves a total of six electrons with 2e from delta(Mo(2)) and 4e from p(pi)(E) orbitals, thereby conforming to Huckel's rule when electrons in the MOs with delta character are considered part of the delocalized system. PMID- 21818793 TI - alpha-Sulfonyl succinimides: versatile sulfinate donors in Fe-catalyzed, salt free, neutral allylic substitution. AB - Allyl sulfones are versatile intermediates in organic chemistry. The presence of two distinct functional groups sets the stage for a plethora of subsequent transformations. However, despite these advantages the preparation of regioisomerically enriched sulfones is not easy. The use of sulfinate salts as nucleophiles in substitutions is frequently accompanied by side reactions such as pi-bond migration, beta-elimination, and so on. Herein we present a preparatively simple way to synthesize a variety of different aryl or alkyl allyl sulfones starting from readily accessible allylic carbonates. By employing aryl or alkyl alpha-sulfonyl succinimides as sulfinate synthons, mild and regioselective ipso substitution of diverse allylic carbonates was realized. PMID- 21818794 TI - Single-molecule magnet behaviour in a tetrathiafulvalene-based electroactive antiferromagnetically coupled dinuclear dysprosium(III) complex. AB - The reactions between the [Ln(tta)(3)].2H(2)O precursors (tta(-)=2 thenoyltrifluoroacetonate anion) and the tetrathiafulvalene-3-pyridine-N-oxide ligands (L(1)) lead to dinuclear complexes of formula [{Ln(tta)(3)(L(1))}(2)].xCH(2)Cl(2) (x=0.5 for Ln=Dy(III) (1) and x=0 for Ln=Gd(III) (2)). The crystal structure reveals that two {Ln(tta)(3)} moieties are bridged by two donors through the nitroxide groups. The Dy(III) centre adopts a distorted square antiprismatic oxygenated polyhedron structure. The antiferromagnetic nature of the exchange interaction between the two Dy(III) ions has been determined by two methods: 1) an empirical method using the [Dy(hfac)(3)(L(2))(2)] mononuclear complex as a model (3) (hfac(-)=1,1,1,5,5,5 hexafluoroacetylacetonate anion, L(2)=tetrathiafulvaleneamido-2-pyridine-N-oxide ligand), and 2) assuming an Ising model for the Dy(III) ion giving an exchange energy of -2.30 cm(-1), g=19.2 in the temperature range of 2-10 K. The antiferromagnetic interactions have been confirmed by a quantitative determination of J for the isotropic Gd(III) derivative (J=-0.031 cm(-1), g=2.003). Compound 1 displays a slow magnetisation relaxation without applied external magnetic fields. Alternating current susceptibility shows a thermally activated behaviour with pre-exponential factors of 5.48(4)*10(-7) s and an energy barrier of 87(1) K. The application of an external field of 1.6 kOe compensates the antiferromagnetic interactions and opens a new quantum tunnelling path. PMID- 21818795 TI - Intramolecular oxidation of the alcohol functionalities in hydroxyalkyl-N heterocyclic carbene complexes of iridium and rhodium. AB - A series of hydroxyalkyl-functionalized imidazolium salts have been coordinated to Rh and Ir to afford the corresponding MCp*-(NHC) (Cp*=pentamethylcyclopentadienyl) complexes. The reactivity of the new complexes has been studied with special attention to the transformations that deal with the alcohol functionality. The metal-mediated intramolecular transformations allowed the formation of several products that resulted from the oxidation of the alcohols to aldehydes and esters. All the new complexes have been fully characterized, and the crystal structures of the most representative complexes have been resolved. PMID- 21818796 TI - Synthesis of isoreticular zinc(II)-phosphonocarboxylate frameworks and their application in the Friedel-Crafts benzylation reaction. AB - Three isoreticular zinc(II)-phosphonocarboxylate frameworks, namely {[Zn(3)(pbdc)(2)].2H(3)O}(n) (ZnPC-2), {[Zn(3)(pbdc)(2)].Hpd.H(3)O.4H(2)O}(n) (Hpd@ZnPC-2) and {[Co(1.5)Zn(1.5)(pbdc)(2)].2H(3)O}(n) (CoZnPC-2) (H(4)pbdc=5 phosphonobenzene-1,3-dicarboxylic acid, pd=pyrrolidine), were solvothermally synthesized. ZnPC-2 has a 3D structure based on trinuclear Zn(II) clusters (Zn(3) SBU) showing 3D interconnected channels. Hpd@ZnPC-2 contains an isoreticular framework of ZnPC-2 with small channels blocked by Hpd molecules. In CoZnPC-2, Zn(II) ions in ZnPC-2 are partially substituted by Co(II) ions. The Friedel Crafts benzylation reactions were carried out over these isoreticular porous materials. The catalytic results reveal that ZnPC-2 is an excellent heterogeneous Lewis acid catalyst with a high selectivity (>90%) towards less bulky para oriented products. The catalytic reaction has been proved to occur inside the pore of ZnPC-2, and the immobilized Zn(3)-SBUs are the active sites. PMID- 21818797 TI - Tris(bispyrene-bipyridine)iron(II): a supramolecular bridge for the biofunctionalization of carbon nanotubes via pi-stacking and pyrene/beta cyclodextrin host-guest interactions. PMID- 21818798 TI - Sulphur isotopes in animal hair track distance to sea. AB - Stable sulphur isotope ratios ((34)S/(32)S) in animal tissues have been suggested as a tracer of coastal residency of terrestrial animals, but data are lacking that quantify the inland range of the sulphur coastal signal and the effects of seasonality. Here, we present delta(34)S measurements of sheep wool collected seasonally on eight farms across Ireland and wool samples collected opportunistically along the west and east coasts. We observed large (>100/00) delta(34)S differences across the island and we show that wool delta(34)S values were negatively correlated with distance to the west coast. We propose that this is due to the predominantly (south-)westerly airflow, possibly combined with the influence of anthropogenic sulphur deposited from the east. While essentially all the sulphur contained in west-coast wool is of marine origin, relatively high delta(34)S values were still measured >100 km inland, suggesting that marine sulphur can be carried over long distances. Seasonal variations are small at the individual level for sedentary grazing animals. We conclude that sulphur isotopes ratios measured in archival keratinous tissues can be used to describe regional delta(34)S isoscapes primarily defined by distance to coasts and thus provide a tool to detect short-term movements of domestic, feral and wild animals within such isoscapes. PMID- 21818799 TI - Atmospheric identification of active ingredients in over-the-counter pharmaceuticals and drugs of abuse by atmospheric pressure glow discharge mass spectrometry (APGD-MS). AB - Atmospheric pressure glow discharge mass spectrometry was used to characterize the active ingredients in pharmaceutical over-the-counter (OTC) drug formulations (Tylenol Allergy, Alka-Seltzer Plus Nighttime, Sudafed, Aleve and Mucinex DM) and drugs of abuse (crack cocaine, methamphetamine, MDMA (ecstasy) and hydrocodone). Material was desorbed and directly ionized under atmospheric conditions by allowing the substance to come in direct contact with the plasma followed by mass spectrometric detection. With this technique, controlled substances and OTC medications were readily distinguished from one another. Characteristic mass spectra were identified for the active ingredients in the OTC and drugs of abuse. Importantly, all drug compounds studied here, both OTC and illicit, demonstrated signals for either molecular ions or protonated molecules as well as fragmentation patterns that are readily identified in the National Institute of Standards and Technology (NIST) electron ionization (EI) mass spectral library. It is believed that this technique holds promise for forensic and law enforcement communities for real-time atmospheric analysis of drugs with database-searchable spectra of controlled substances. PMID- 21818800 TI - Mass spectrometric characteristics and kinetics of iron release in visceral mass of Saccostrea cucullata. AB - Ferritins with electrophoretic homogeneity were prepared from the visceral mass of Saccostrea cucullata in batch. The native PAGE approach showed similar electrophoretic mobility among pig pancreatic ferritin, liver ferritin of Dasyatis akajei, and visceral mass ferritin of Saccostrea cucullata. SDS-PAGE indicated that the Saccostrea cucullata visceral ferritin (SCVF) consisted of a single subunit type and had a molecular weight (MW) of approximately 20 kDa, suggesting that the protein shell in SCVF was composed of a single subunit. In addition, peptide mass fingerprinting and transmission electron microscopy were used to identify SCVF further, and to observe its molecular structure. We found that the molecular structure in SCVF was similar to that of most mammalian ferritins, which are composed of a protein shell and an iron core. The results of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry under the assistance of an acidic matrix, sinapic acid, also showed that SCVF was composed of a single subunit type and its subunit MW was calculated to be 19871.042 Da in the absence of heme. Kinetics analysis revealed that the complete process of iron release fitted the law of a first-order reaction, which is similar to that of most ferritins in mammals. Similar to bacterial ferritin, studies indicated that the shell consisted of a single subunit type and showed similar kinetics of iron release, suggesting that this subunit plays two important roles in iron release and storage, and that it shows different stability and intensity of interaction in carrying out its physiological functions in SCVF. PMID- 21818801 TI - Compound-specific bromine isotope analysis of methyl bromide using gas chromatography hyphenated with inductively coupled plasma multiple-collector mass spectrometry. AB - Methyl bromide is the most important natural bromine contributor to stratospheric ozone depletion, yet there are still large uncertainties regarding quantification of its sources and sinks. The stable bromine isotope composition of CH(3)Br is potentially a powerful tool to apportion its sources and to study both its transport and its reactive fate. A novel compound-specific method to measure (81)Br/(79)Br isotope ratios in CH(3)Br using gas chromatography hyphenated with inductively coupled plasma multiple-collector mass spectrometry (GC/MCICPMS) was developed. Sample amounts of >40 ng could be measured with a precision of 0.10/00 (1sigma, n = 3). The method results are reproducible over the long term as shown with 36 analyses acquired over 3 months, yielding a standard deviation (1sigma) better than 0.40/00. This new method demonstrates for the first time Br isotope ratio determination in gaseous brominated samples. It is three orders of magnitude more sensitive than previously existing isotope ratio mass spectrometry methods for Br isotope determination of other organobromines, thus allowing applications towards ambient atmospheric samples. PMID- 21818803 TI - Chemical profiling of bioactive constituents in Sarcandra glabra and its preparations using ultra-high-pressure liquid chromatography coupled with LTQ Orbitrap mass spectrometry. AB - In this study, a fast and reliable method based on an ultra-high-pressure liquid chromatography coupled with photodiode-array detection (PDA) and a linear ion trap high-resolution mass spectrometer (LTQ-Orbitrap XL) has been developed for the identification of bioactive constituents in the whole plant of Sarcandra glabra and its related four preparations. By accurate mass measurements within 5 ppm error for each molecular ion and subsequent fragment ions in routine analysis, 50 compounds, including organic acids, caffeoyl derivatives, flavonoids, coumarins and terpenoids, were identified or tentatively characterized. Among them, 6,7,8-trihydroxycoumarin-O-rhamnopyranoside (17), (2R) naringenin-6-C-B-D-glucopyranosyl-(6->1)-apiose (25) and (2S)-naringenin-6-C-B-D glucopyranosyl-(6->1)-apiose (27) were tentatively identified as new compounds. Besides, 21 of these compounds were coexisting in four preparations of Sarcandra glabra. Fragmentation behaviors of the four major categories of compounds were also investigated. This established UPLC-PDA/ESI-MS(n) method was reliable and effective for the separation and identification of the major constituents and would be the basis for quality control of Sarcandra glabra and its related preparations. PMID- 21818802 TI - Can gas chromatography combustion isotope ratio mass spectrometry be used to quantify organic compound abundance? AB - Quantifying the concentrations of organics such as phospholipid fatty acids (PLFAs) and n-alkanes and measuring their corresponding (13)C/(12)C isotope ratios often involves two separate analyses; (1) quantification by gas chromatography flame ionisation detection (GC-FID) or gas chromatography/mass spectrometry (GC/MS), and (2) (13) C-isotope abundance analysis by gas chromatography/combustion/isotope ratio mass spectrometry (GC-C-IRMS). This requirement for two separate analyses has obvious disadvantages in terms of cost and time. However, there is a history of using the data output of isotope ratio mass spectrometers to quantify various components; including the N and C concentrations of solid materials and CO(2) concentrations in gaseous samples. Here we explore the possibility of quantifying n-alkanes extracted from sheeps' faeces and fatty acid methyl esters (FAMEs) derivatised from PLFAs extracted from grassland soil, using GC-C-IRMS. The results were compared with those from GC-FID analysis of the same extracts. For GC-C-IRMS the combined area of the masses for all the ions (m/z 44, 45 and 46) was collected, referred to as 'area all', while for the GC-FID analysis the peak area data were collected. Following normalisation to a common value for added internal standards, the GC-C-IRMS 'area all' values and the GC-FID peak area data were directly compared. Strong linear relationships were found for both n-alkanes and FAMEs. For the n-alkanes the relationships were 1:1 while, for the FAMEs, GC-C-IRMS overestimated the areas relative to the GC-FID results. However, with suitable reference material 1:1 relationships were established. The output of a GC-C-IRMS system can form the basis for the quantification of certain organics including FAMEs and n-alkanes. PMID- 21818804 TI - High-throughput walkthrough detection portal for counter terrorism: detection of triacetone triperoxide (TATP) vapor by atmospheric-pressure chemical ionization ion trap mass spectrometry. AB - With the aim of improving security, a high-throughput portal system for detecting triacetone triperoxide (TATP) vapor emitted from passengers and luggage was developed. The portal system consists of a push-pull air sampler, an atmospheric pressure chemical ionization (APCI) ion source, and an explosives detector based on mass spectrometry. To improve the sensitivity of the explosives detector, a novel linear ion trap mass spectrometer with wire electrodes (wire-LIT) is installed in the portal system. TATP signals were clearly obtained 2 s after the subject under detection passed through the portal system. Preliminary results on sensitivity and throughput show that the portal system is a useful tool for preventing the use of TATP-based improvised explosive devices by screening persons in places where many people are coming and going. PMID- 21818805 TI - Application of accelerator mass spectrometry to macromolecules: preclinical pharmacokinetic studies on a polybisphosphonate. AB - Data on the use of accelerator mass spectrometry (AMS) in conjunction with in vivo studies of macromolecular drugs are scarce. The present study shows the versatility of this technique when investigating the pharmacokinetics (PK) of a macromolecular drug candidate, a polybisphosphonate conjugate (ODX). The aforementioned is a polymer (molecular weight ~30 kDa) constituting a carbohydrate backbone with covalently linked ligands (aldendronate and aminoguanidine) and is intended for treatment of osteoporosis and the therapy of bone metastasis from prostate cancer. The conjugate is prepared through partial oxidation of the carbohydrate and sequential coupling of the ligands by reductive amination. (14)C was incorporated in the conjugate by means of coupling a commercially available (14)C-lysine in the conjugation sequence. Fifteen rats were injected intravenously with (14)C-labelled ODX (150 ug, 14 Bq/rat) and blood samples were collected at 1, 2, 4, 6, and 24 h post-injection (3 rats/time point). Liver, spleen and kidney samples were collected at 4 and 24 h post injection. Blood from each time point (triplicate) were collected for AMS measurement determining the isotopic ratio ((14)C/(12)C) and consequently the drug concentration in blood. ODX showed a transient presence in blood circulation; 93% of the total dose was cleared from the circulation within 1 h. The half-life after 1 h was estimated to be about 3 h; 0.7% of the administered (14)C dose of ODX remained in circulation after 24 h. The major (14)C accumulation was in the liver, the spleen and the kidneys indicating the probable route of metabolism and excretion. This study demonstrates the versatility of AMS for pharmacological in vivo studies of macromolecules. Labelling with (14)C is relatively simple, inexpensive and the method requires minimal radioactivity, eliminating the need for radioprotection precautions in contrast to methods using scintillation counting. PMID- 21818806 TI - Quantification of methyl thiocyanate in the headspace of Pseudomonas aeruginosa cultures and in the breath of cystic fibrosis patients by selected ion flow tube mass spectrometry. AB - Infection by Pseudomonas aeruginosa (PA) is a major cause of morbidity and mortality in patients with cystic fibrosis (CF). Breath analysis could potentially be a useful diagnostic of such infection, and analyses of volatile organic compounds (VOCs) emitted from PA cultures are an important part of the search for volatile breath markers of PA lung infection. Our pilot experiments using solid-phase microextraction, SPME and gas chromatography/mass spectrometric (GC/MS) analyses of volatile compounds produced by PA strains indicated a clear presence of methyl thiocyanate. This provided a motivation to develop a method for real-time online quantification of this compound by selected ion flow tube mass spectrometry, SIFT-MS. The kinetics of reactions of H(3)O(+), NO(+) and O(2)(+*) with methyl thiocyanate at 300 K were characterized and the characteristic product ions determined (proton transfer for H(3)O(+), rate constant 4.6 * 10(-9) cm(3) s(-1); association for NO(+), 1.7 * 10(-9) cm(3) s( 1) and nondissociative charge transfer for O(2)(+*) 4.3 * 10(-9) cm(3) s(-1)). The kinetics library was extended by a new entry for methyl thiocyanate accounting for overlaps with isotopologues of hydrated hydronium ions. Solubility of methyl thiocyanate in water (Henry's law constant) was determined using standard reference solutions and the linearity and limits of detection of both SIFT-MS and SPME-GC/MS methods were characterized. Thirty-six strains of PA with distinct genotype were cultivated under identical conditions and 28 of them (all also producing HCN) were found to release methyl thiocyanate in headspace concentrations greater than 6 parts per billion by volume (ppbv). SIFT-MS was also used to analyze the breath of 28 children with CF and the concentrations of methyl thiocyanate were found to be in the range 2-21 ppbv (median 7 ppbv). PMID- 21818807 TI - Disulfide bond decay during matrix-assisted laser desorption/ionization time-of flight mass spectrometry experiments. AB - In our laboratory, we have been studying the reductive processes that occur during matrix-assisted laser desorption/ionization (MALDI) experiments. Recently, we have finished an analysis of the DHB matrix effect on the azo group in cyclic peptides. However, deep understanding of disulfide bond behaviour during a mass spectrometry (MS) experiment is much more important in proteomics as its reduction can cause serious errors in protein spectra interpretation. Therefore, we have focused on intra- and intermolecular disulfide bonds as well as disulfide bonds connecting cysteine and 2-thio-5-nitrobenzoic acid (TNB, Ellman's reagent modification) in model peptides during MALDI MS measurements. While the reduction was not observed for intra- and intermolecular cysteine-cysteine disulfide bonds, the disulfide connection between cysteine and TNB was always affected. It was proved that TNB and Ellman's reagent can act as a matrix itself. The results obtained enabled us to propose a reaction mechanism model which is able to describe the phenomena observed during the desorption/ionization process of disulfide-containing molecules. PMID- 21818808 TI - Protein identification by accurate mass matrix-assisted laser desorption/ionization imaging of tryptic peptides. AB - The spatial distribution of proteins in tissue sections can be used to identify potential markers for pathological processes. Tissue sections are often subjected to enzymatic digestion before matrix-assisted laser desorption/ionization (MALDI) imaging. This study is targeted at improving the on-tissue identification of tryptic peptides by accurate mass measurements and complementary off-line liquid chromatography coupled to electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS) analysis. Two adjacent mouse brain sections were analyzed in parallel. The first section was spotted with trypsin and analyzed by MALDI imaging. Direct on-tissue MS/MS experiments of this section resulted in the identification of 14 peptides (originating from 4 proteins). The second tissue section was homogenized, fractionated by ultracentrifugation and digested with trypsin prior to LC/ESI-MS/MS analysis. The number of identified peptides was increased to 153 (corresponding to 106 proteins) by matching imaged mass peaks to peptides which were identified in these LC/ESI-MS/MS experiments. All results (including MALDI imaging data) were based on accurate mass measurements (RMS <2 ppm) and allow a confident identification of tryptic peptides. Measurements based on lower accuracy would have led to ambiguous or misleading results. MS images of identified peptides were generated with a bin width (mass range used for image generation) of Deltam/z = 0.01. The application of accurate mass measurements and additional LC/MS measurements increased both the quality and the number of peptide identifications. The advantages of this approach for the analysis of biological tissue sections are demonstrated and discussed in detail. Results indicate that accurate mass measurements are needed for confident identification and specific image generation of tryptic peptides in tissue sections. PMID- 21818809 TI - Quantitation of plasma 13C-galactose and 13C-glucose during exercise by liquid chromatography/isotope ratio mass spectrometry. AB - The utilisation of carbohydrate sources under exercise conditions is of considerable importance in performance sports. Incorporation of optimal profiles of macronutrients can improve endurance performance in athletes. However, gaining an understanding of the metabolic partitioning under sustained exercise can be problematical and isotope labelling approaches can help quantify substrate utilisation. The utilisation of oral galactose was investigated using (13)C galactose and measurement of plasma galactose and glucose enrichment by liquid chromatography/isotope ratio mass spectrometry (LC/IRMS). As little as 100 MUL plasma could readily be analysed with only minimal sample processing. Fucose was used as a chemical and isotopic internal standard for the quantitation of plasma galactose and glucose concentrations, and isotopic enrichment. The close elution of galactose and glucose required a correction routine to be implemented to allow the measurement, and correction, of plasma glucose delta(13)C, even in the presence of very highly enriched galactose. A Bland-Altman plot of glucose concentration measured by LC/IRMS against glucose measured by an enzymatic method showed good agreement between the methods. Data from seven trained cyclists, undergoing galactose supplementation before exercise, demonstrate that galactose is converted into glucose and is available for subsequent energy metabolism. PMID- 21818810 TI - Diagnostic cyclisation reactions which follow phosphate transfer to carboxylate anion centres for energised [M-H]- anions of pTyr-containing peptides. AB - The low-energy negative ion phosphoTyr to C-terminal -CO(2)PO(3)H(2) rearrangement occurs for energised peptide [M-H](-) anions even when there are seven amino acid residues between the pTyr and C-terminal amino acid residues. The rearranged C-terminal -CO(2)PO(2)H(O(-)) group effects characteristic S(N)i cyclisation/cleavage reactions. The most pronounced of these involves the electrophilic central backbone carbon of the penultimate amino acid residue. This reaction is aided by the intermediacy of an H-bonded intermediate in which the nucleophilic and electrophilic reaction centres are held in proximity in order for the S(N)i cyclisation/cleavage to proceed. The DeltaG(reaction) is +184 kJ mol(-1) with the barrier to the S(N)i transition state being +240 kJ mol(-1) at the HF/6-31 + G(d)//AM1 level of theory. A similar phosphate rearrangement from pTyr to side chain CO(2)(-) (of Asp or Glu) may also occur for energised peptide [M-H](-) anions. The reaction is favourable: DeltaG(reaction) is -44 kJ mol(-1) with a maximum barrier of +21 kJ mol(-1) (to the initial transition state) when Asp and Tyr are adjacent. The rearranged species R(1)-Tyr-NHCH(CH(2)CO(2)PO(3)H( ))COR(2) (R(1) = CHO; R(2) = OCH(3)) may undergo an S(N)i six-centred cyclisation/cleavage reaction to form the product anion R(1)-Tyr(NH(-)). This process has a high energy requirement [DeltaG(reaction) = +224 kJ mol(-1), with the barrier to the S(N)i transition state being +299 kJ mol(-1)]. PMID- 21818811 TI - Implementation of dipolar direct current (DDC) collision-induced dissociation in storage and transmission modes on a quadrupole/time-of-flight tandem mass spectrometer. AB - Means for effecting dipolar direct current collision-induced dissociation (DDC CID) on a quadrupole/time-of-flight in a mass spectrometer have been implemented for the broadband dissociation of a wide range of analyte ions. The DDC fragmentation method in electrodynamic storage and transmission devices provides a means for inducing fragmentation of ions over a large mass-to-charge range simultaneously. It can be effected within an ion storage step in a quadrupole collision cell that is operated as a linear ion trap or as ions are continuously transmitted through the collision cell. A DDC potential is applied across one pair of rods in the quadrupole collision cell of a QqTOF hybrid mass spectrometer to effect fragmentation. In this study, ions derived from a small drug molecule, a model peptide, a small protein, and an oligonucleotide were subjected to the DDC CID method in either an ion trapping or an ion transmission mode (or both). Several key experimental parameters that affect DDC CID results, such as time, voltage, low mass cutoff, and bath gas pressure, are illustrated with protonated leucine enkephalin. The DDC CID dissociation method gives a readily tunable, broadband tool for probing the primary structures of a wide range of analyte ions. The method provides an alternative to the narrow resonance conditions of conventional ion trap CID and it can access more extensive sequential fragmentation, depending upon conditions. The DDC CID approach constitutes a collision analog to infrared multiphoton dissociation (IRMPD). PMID- 21818812 TI - Identification of sulfoquinovosyldiacyglycerides from Phaeodactylum tricornutum by matrix-assisted laser desorption/ionization QTrap time-of-flight hybrid mass spectrometry. AB - The pharmaceutical industry is interested in identifying novel target compounds. Due to their versatile pharmacological activities (e.g. antiviral, anti carcinogen and immunosuppressive) sulfoquinovosyldiacylglycerides (SQDGs) are potential drug candidates. The present publication deals with the purification and structural characterization of SQDGs from three different strains of Phaeodactylum tricornutum. Besides detection of SQDGs (sn-1: C16:1/sn-2: C16:0 and sn-1: C20:5/sn-2: C16:0), two novel 2'-O-acylsulfoquinovosyldiacylglyerides (Ac-SQDGs, sn-1: C16:0/ sn-2: C16:0/2' C20:5 and sn-1: C20:5/sn-2: C16:0/2' C20:5) were identified by using matrix-assisted laser desorption/ionization (MALDI) QTrap time-of-flight (ToF) hybrid mass spectrometry (MS) with multistage MS(n). The analytical method enables the sn-position verification of fatty acids (MS(2)) as well as the confirmation of the regioposition of eicospentanoic acid at the sulfoquinovose (MS(3)). PMID- 21818814 TI - The use of multi-element stable isotope analysis to monitor the origin of chondroitin sulfates. AB - Continuous-flow isotope ratio mass spectrometry (CF-IRMS) of deuterium, carbon, nitrogen, oxygen and sulfur has been used to analyse samples of pure chondroitin sulfates from known animal sources (shark, squid, salmon, pig and bovine). There is a need to control the origin of this dietary supplement, which is extracted from several types of animals: for traditional, ethical, or economic reasons, a given source of natural products of animal origin can be preferred to another, and can therefore have a different price. Twenty-three samples collected in Europe and Asia were analysed by IRMS. The results, especially the isotopic deviations of sulphur, oxygen and deuterium, show a significant discrimination between marine and terrestrial origins of this compound which will provide a convenient and efficient way to control the declared sources in the market. The differences observed between origins are further discussed. PMID- 21818813 TI - Comparison of stable-isotope labeling with amino acids in cell culture and spectral counting for relative quantification of protein expression. AB - Protein quantification is one of the principal goals of mass spectrometry (MS) based proteomics, and many strategies exist to achieve it. Several approaches involve the incorporation of a stable-isotope label using either chemical derivatization, enzymatically catalyzed incorporation of (18)O, or metabolic labeling in a cell or tissue culture. These techniques can be cost or time prohibitive or not amenable to the biological system of interest. Label-free techniques including those utilizing integrated ion abundance and spectral counting offer an alternative to stable-isotope-based methodologies. Herein, we present the comparison of stable-isotope labeling of amino acids in cell culture (SILAC) with spectral counting for the quantification of human embryonic stem cells as they differentiate toward the trophectoderm at three time points. Our spectral counting experimental strategy resulted in the identification of 2641 protein groups across three time points with an average sequence coverage of 30.3%, of which 1837 could be quantified with more than five spectral counts. SILAC quantification was able to identify 1369 protein groups with an average coverage of 24.7%, of which 1027 could be quantified across all time points. Within this context we further explore the capacity of each strategy for proteome coverage, variation in quantification, and the relative sensitivity of each technique to the detection of change in relative protein expression. PMID- 21818816 TI - Host-enhanced pi-pi interaction for water-soluble supramolecular polymerization. AB - Host-enhanced pi-pi interaction based on anthracene derivatives and cucurbit[8]uril can be used as the driving force for constructing water-soluble supramolecular polymers. For this purpose, two anthracene moieties were encapsulated into one cucurbit[8]uril cavity, forming a ternary complex. After encapsulation in the host, the distance between the two anthracene moieties was shortened, and the pi-pi interaction between them was enhanced significantly. To realize supramolecular polymerization, a bifunctional monomer consisting of two anthracene moieties and a short linker in between was carefully designed. Cyclization was avoided in this way. Thus, host-enhanced pi-pi interaction can function as a new driving force for supramolecular polymerization. PMID- 21818815 TI - Thermal activation of methane and ethene by bare MO.+ (M=Ge, Sn, and Pb): a combined theoretical/experimental study. AB - The thermal ion/molecule reactions (IMRs) of the Group 14 metal oxide radical cations MO(.+) (M=Ge, Sn, Pb) with methane and ethene were investigated. For the MO(.+)/CH(4) couples abstraction of a hydrogen atom to form MOH(+) and a methyl radical constitutes the sole channel. The nearly barrier-free process, combined with a large exothermicity as revealed by density functional theory (DFT) calculations, suggests a fast and efficient reaction in agreement with the experiment. For the IMR of MO(.+) with ethene, two competitive channels exist: hydrogen-atom abstraction (HAA) from and oxygen-atom transfer (OAT) to the organic substrate. The HAA channel, yielding C(2)H(3.) and MOH(+) predominates for the GeO(.+)/ethene system, while for SnO(.+) and PbO(.+) the major reaction observed corresponds to the OAT producing M(+) and C(2)H(4)O. The DFT-derived potential-energy surfaces are consistent with the experimental findings. The behavior of the metal oxide cations towards ethene can be explained in terms of the bond dissociation energies (BDEs) of MO(+)-H and M(+)-O, which define the hydrogen-atom affinity of MO(+) and the oxophilicity of M(+), respectively. Since the differences among the BDEs(MO(+)-H) are rather small and the hydrogen-atom affinities of the three radical cations MO(.+) exceed the BDE(CH(3)H) and BDE(C(2)H(3)-H), hydrogen-atom abstraction is possible thermochemically. In contrast, the BDEs(M(+)-O) vary quite substantially; consequently, the OAT channel becomes energetically less favorable for GeO(.+) which exhibits the highest oxophilicity among these three group 14 metal ions. PMID- 21818817 TI - Predicting malignancy in thyroid nodules: molecular advances. AB - Over the last several years, a clearer understanding has developed of the genetic alterations underlying thyroid carcinogenesis. This knowledge can be used to tackle 1 of the challenges facing thyroidologists: management of the indeterminate thyroid nodule. Despite the accuracy of fine-needle aspiration cytology, many patients undergo surgery to diagnose malignancy and better diagnostic tools are required. A number of biomarkers have recently been studied and show promise in this setting. In particular, BRAF, RAS, PAX8-PPARgamma, microRNAs, and loss of heterozygosity have each been demonstrated as useful molecular tools for predicting malignancy and can potentially guide decisions regarding surgical management of nodular thyroid disease. This review summarizes the current literature surrounding each of these markers, highlights our institution's prospective analysis of these markers, and describes the subsequent incorporation of molecular markers into a management algorithm for thyroid nodules. PMID- 21818818 TI - Factors associated with recurrence and therapeutic strategies for sinonasal Rosai Dorfman disease. AB - BACKGROUND: The purpose of this study was to explore the factors associated with the recurrence of Rosai-Dorfman disease (RDD) in the nasal cavity and paranasal sinus. METHODS: In this study, we conducted a review of the English-language literature published between 1969 and 2010 on the recurrence of and treatment strategies for sinonasal RDD. RESULTS: To our knowledge, 126 cases of RDD have been reported to date. Of the 126 patients, 32 (25.4%) had no recurrence or were alive with no evidence of disease; remission occurred in only 1 patient (0.7%); 69 patients (54.8%) had a recurrent, persistent, or progressive course; and 6 patients (4.8%) died from the disease. In patients with recurrent, persistent, and progressive disease, there was no significant tendency for lymph node involvement. CONCLUSION: Sinonasal RDD is generally described as benign. However, recurrence and fatal outcome have been reported. Our results suggest that the initial modality may affect the recurrence of RDD. PMID- 21818819 TI - Efficacy of tissue autofluorescence imaging (VELScope) in the visualization of oral mucosal lesions. AB - BACKGROUND: Technology that highlights potentially malignant oral lesions in a highly sensitive and specific manner will aid clinicians in early diagnosis of these conditions. This study assessed the efficacy of direct tissue autofluorescence imaging Visually Enhanced Lesion Scope (VELScope) in the detection of oral mucosal lesions. METHODS: One hundred twelve patients referred with a potentially malignant oral mucosal lesion were examined under routine incandescent light, and then with VELScope, noting loss of autofluorescence and presence of blanching. Incisional biopsies were performed to provide definitive histopathological diagnoses. RESULTS: VELScope enhanced the visibility of 41 lesions and helped uncover 5 clinically undetected lesions. VELScope examination alone showed a sensitivity of 30% and a specificity of 63%. Its accuracy at identifying dysplasia was 55%. CONCLUSION: VELScope examination cannot provide a definitive diagnosis regarding the presence of epithelial dysplasia. Loss of autofluorescence is not useful in diagnosing epithelial dysplasia in its own right without relevant clinical interpretation. PMID- 21818820 TI - Five-year quality of life results of the randomized clinical phase III (RADPLAT) trial, comparing concomitant intra-arterial versus intravenous chemoradiotherapy in locally advanced head and neck cancer. AB - BACKGROUND: The purpose of this investigation was to present 5-years of quality of-life (QOL) results of a multicenter randomized phase III trial, assessing intra-arterial (IA) versus standard intravenous (IV) chemoradiation for inoperable stage IV head and neck cancer. METHODS: Evaluation of 71 patients through European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core Module (EORTC QLQ-C30) and Head and Neck Module (QLQ H&N35), and trial-specific questionnaires. Treatment consisted of standard radiotherapy with 4 weekly IA or 3 weekly IV cisplatin infusions. RESULTS: No significant differences in treatment-related QOL problems between 1 and 5 years posttreatment were observed, except for "dry mouth" (gradually improving; p = .004). Survivors have lower fatigue levels (p = .04), better voice (p = 0.3), and swallowing (p = .03) than patients who could not complete all subsequent follow up questionnaires. CONCLUSIONS: Most treatment-related QOL issues deteriorate during treatment, improve in the first year, and then remain stable, except xerostomia, improving up to the 5-year assessment point. Survivors show more positive scores for fatigue, voice, and swallowing. QOL issues at 1 year, thus, for most already represent those after 5-year follow-up. PMID- 21818821 TI - Nasopharyngectomy for locally advanced recurrent nasopharyngeal carcinoma: exploring the limits. AB - BACKGROUND: The purpose of this study was to present the outcome of nasopharyngectomy for locally advanced recurrent nasopharyngeal carcinoma (NPC). METHODS: Between 2000 and 2010, patients with locally advanced recurrent NPC were recruited. Surgical outcomes were analyzed retrospectively. RESULTS: Among the 22 patients recruited, all had extended resections via the maxillary swing approach, resulting in exposure of the petrosal part of the internal carotid artery (ICA). One patient required craniofacial approach for tumor removal. The curative resection rate was 81.8%. Free flap reconstruction was performed in all cases. The mean follow-up period was 38.8 months. All patients survived. Although 1 patient developed local and systemic tumor recurrence, the rest of the patients remained disease free. There was no carotid blowout or osteoradionecrosis of the skull base. CONCLUSION: Curative resections can be achieved for locally advanced recurrent NPC with good outcome. Microvascular free flap reconstruction is crucial to prevent carotid artery blowout and osteoradionecrosis of the skull base. PMID- 21818822 TI - The effect of retirement on cognitive functioning. AB - Cognitive impairment has emerged as a major driver of disability in old age, with profound effects on individual well-being and decision making at older ages. In the light of policies aimed at postponing retirement ages, an important question is whether continued labour supply helps to maintain high levels of cognition at older ages. We use data of older men from the US Health and Retirement Study to estimate the effect of continued labour market participation at older ages on later-life cognition. As retirement itself is likely to depend on cognitive functioning and may thus be endogenous, we use offers of early retirement windows as instruments for retirement in econometric models for later-life cognitive functioning. These offers of early retirement are legally required to be nondiscriminatory and thus, inter alia, unrelated to cognitive functioning. At the same time, these offers of early retirement options are significant predictors of retirement. Although the simple ordinary least squares estimates show a negative relationship between retirement duration and various measures of cognitive functioning, instrumental variable estimates suggest that these associations may not be causal effects. Specifically, we find no clear relationship between retirement duration and later-life cognition for white collar workers and, if anything, a positive relationship for blue-collar workers. PMID- 21818823 TI - Risk factors and posttraumatic stress disorder: are they especially predictive following exposure to less severe stressors? AB - BACKGROUND: The diagnosis of posttraumatic stress disorder (PTSD) requires exposure to a traumatic stressor, as defined by Criterion A in the DSM criteria for PTSD. Yet, over the course of successive revisions of the diagnostic manual, the range of qualifying stressors has expanded considerably (e.g., watching terrorist attacks on television). Moreover, stressors that fall short of qualifying for even an expanded Criterion A can produce apparent PTSD. Taken together, these findings imply that people who do satisfy symptomatic criteria for PTSD following exposure to less severe stressors carry a heavy burden of risk factors. METHOD: To test this hypothesis, we examined whether the association between the risk factor of lower intelligence and more severe PTSD and depression symptoms would be greater among women reporting less severe CSA (n = 15) relative to women who reported moderate (n = 54) or high (n = 31) severity CSA. RESULTS: The evidence was consistent with this hypothesis for subjects in the low and moderate severity groups, but less so for those in the high severity group. CONCLUSIONS: Lower intelligence was a more potent risk factor for posttraumatic distress among people exposed to less severe relative to moderately severe stressors. PMID- 21818824 TI - The urban brain: new directions in research exploring the relation between cities and mood-anxiety disorders. PMID- 21818825 TI - Prevalence and clinical characteristics of mental rituals in a longitudinal clinical sample of obsessive-compulsive disorder. AB - BACKGROUND: Obsessive-compulsive disorder (OCD) is a chronic and debilitating anxiety disorder associated with significant impairment in quality of life and functioning. Research examining the differences in clinical correlates and treatment response associated with different obsessions in OCD has yielded important findings underscoring the heterogeneous nature of this disorder. To date, most of this research has focused on differences associated with primary obsessions, and little attention has been paid to the clinical utility of studying how compulsive symptoms affect clinical course. Virtually no systematic research has explored the clinical characteristics of one understudied symptom presentation, mental rituals, and what impact this primary symptom has on severity and course of illness. Mental rituals, or compulsions without overt signs, represent unique clinical challenges but often go understudied for numerous methodological and clinical reasons. METHODS: In this study, we explored the impact of primary mental rituals on clinical severity and chronicity in a large, longitudinal sample of OCD patients (N = 225) over 4 years. RESULTS: Mental rituals were a primary presenting symptom for a sizable percentage of the sample (12.9%). Primary mental rituals were associated with greater clinical severity and lower functioning at intake, as well as a more chronic course of illness, as participants with primary mental rituals spent nearly 1 year longer in full DSM-IV criteria episodes over the 4-year follow-up interval than OCD patients without mental rituals. CONCLUSIONS: These results suggest that mental rituals are uniquely impairing and highlight the need for further empirical exploration and consideration in treatment. PMID- 21818826 TI - Role of anxiety sensitivity subfactors in suicidal ideation and suicide attempt history. AB - BACKGROUND: Anxiety along with anxiety-related risk factors has been increasingly implicated in suicidal ideation and suicide attempts. One such risk factor, anxiety sensitivity (AS), refers to fear of anxiety-related sensations. Subfactors of AS, notably physical and cognitive concerns, seem to be relevant to acquired capability, a risk factor for death by suicide from Joiner's (2005) Interpersonal-Psychological Theory of Suicide. METHODS: This study examined the effect of Anxiety Sensitivity Index (ASI) total score and subfactor scores on suicidal ideation and suicide attempt history in a very large, moderately severe outpatient sample (N = 1,378). RESULTS: Analyses were consistent with our a priori predictions about ASI cognitive concern and suicidal ideation. In contrast, ASI physical concerns did not predict previous suicide attempt as well as ASI cognitive or social concerns. However, ASI physical concerns did moderate the relationship between ASI social concerns and previous suicide attempt. CONCLUSIONS: These findings suggest that suicide potential may be related to cognitive risk factors for anxiety. PMID- 21818827 TI - The relationship between combat-related posttraumatic stress disorder and the 5 HTTLPR/rs25531 polymorphism. AB - BACKGROUND: Empirical evidence suggests that there is a significant genetic influence in the development of posttraumatic stress disorder (PTSD). The serotonin transporter (5-HTT) gene (SLC6A4) has been identified as a prime candidate for the development of the disorder, as 5-HTT is a working target for selective serotonin reuptake inhibitors (SSRIs), first line treatment agents for PTSD. Several studies have reported associations between 5-HTT-linked promoter region (5-HTTLPR) polymorphism variants and increased rates of PTSD in civilian samples. This study investigated the role of the 5-HTTLPR polymorphism, triallelically classified, in a sample of combat veterans with and without PTSD. METHODS: Rates of PTSD were examined across three genotypes in a sample of 388 combat veterans. The short/long polymorphism of 5-HTTLPR and the A-G polymorphism within the 5-HTTLPR (rs25531) were genotyped, and statistical analyses were conducted. RESULTS: There were significant intergroup (PTSD versus non-PTSD) differences in the genotype frequencies of 5-HTTLPR/rs25531 (chi(2) [1, n = 388] = 16.23, P = 5.62 * 10(-5) ). The 5-HTTLPR S'/S' (low transcriptionally efficient) genotype was also associated with the PTSD severity score in the 228 participants who had combat severity data (r = .15, P = 0.03). CONCLUSIONS: The findings are consistent with previous research among civilian populations that have indicated that the low transcriptionally efficient S'/S' genotype of 5 HTTLPR is a risk factor for the development of PTSD after trauma exposure. Our findings are the first to examine this polymorphism and PTSD in a military sample. Additional large-scale investigations are needed to replicate these findings. PMID- 21818828 TI - The importance of chemistry for the future of the pharma industry. PMID- 21818831 TI - Gold for C-C coupling reactions: a Swiss-Army-knife catalyst? AB - For organic chemists, the construction of C-C bonds is the most essential aspect of the assembly of molecules. Transition-metal-catalyzed coupling reactions have evolved as one of the key tools for this task. Lately, gold has also emerged as a catalyst for this kind of transformation. Gold, with its special properties as a mild carbophilic pi Lewis acid, its ability to insert into C-H bonds, and, as discovered recently, its ability to undergo redox transformations, offers the opportunity to apply all this potent proficiency for the construction of compounds in an efficient and economical way. This Minireview critically presents the C-C coupling reactions enabled by gold catalysts to encourage further research activities in this promising area of oxidation/reduction gold catalysts. PMID- 21818832 TI - Highly enantioselective synthesis of axially chiral biarylphosphonates: asymmetric Suzuki-Miyaura coupling using high-molecular-weight, helically chiral polyquinoxaline-based phosphines. PMID- 21818833 TI - High-sensitivity hydrogen detection: hydrogen-induced swelling of multiple cracked palladium films on compliant substrates. PMID- 21818836 TI - New insights into the band-gap narrowing of (N, P)-codoped TiO2 from hybrid density functional theory calculations. AB - The electronic properties of anatase-TiO(2) codoped by N and P at different concentrations have been investigated via generalized Kohn-Sham theory with the Heyd-Scuseria-Ernzerhof (HSE06) hybrid functional for exchange-correlation in the context of density functional theory. At high doping concentrations, we find that the high photocatalytic activity of (N, P)-codoped anatase TiO(2) vis-a-vis the N monodoped case can be rationalized by a double-hole-mediated coupling mechanism [Yin et al., Phys. Rev. Lett. 2011, 106, 066801] via the formation of an effective N-P bond. On the other hand, Ti(3+) and Ti(4+) ions' spin double exchange results in more substantial gap narrowing for larger separations between N and P atoms. At low doping concentrations, double-hole-coupling is dominant, regardless of the N-P distance. PMID- 21818837 TI - Tissue-specific alterations of methyl group metabolism with DNA hypermethylation in the Zucker (type 2) diabetic fatty rat. AB - BACKGROUND: Altered methyl group and homocysteine metabolism were tissue specific, persistent, and preceded hepatic DNA hypomethylation in type 1 diabetic rats. Similar metabolic perturbations have been shown in the Zucker (type 2) diabetic fatty (ZDF) rat in the pre-diabetic and early diabetic stages, but tissue specificity and potential impact on epigenetic marks are unknown, particularly during pathogenesis. METHODS: ZDF (fa/fa) and lean (+/?) control rats were killed at 12 and 21 weeks of age, representing early and advanced diabetic conditions. Blood and tissues were analysed with respect to methyl group and homocysteine metabolism, including DNA methylation. RESULTS: At 12 weeks, hepatic glycine N-methyltransferase (GNMT), methionine synthase, and cystathionine beta-synthase (CBS) activity and/or abundance were increased in ZDF rats. At 21 weeks, GNMT activity was increased in liver and kidney; however, only hepatic CBS protein abundance (12 weeks) and betaine-homocysteine S methyltransferase mRNA expression (21 weeks) were significantly elevated (78 and 100%, respectively). Hepatic phosphatidylethanolamine N-methyltransferase expression was also elevated in the ZDF rat. Homocysteine concentrations were decreased in plasma and kidney, but not in liver, at 12 and 21 weeks. In contrast to hepatic DNA hypomethylation in the type 1 diabetic rat, genomic DNA was hypermethylated at 12 and 21 weeks in the liver of ZDF rats, concomitant with an increase in DNA methyltransferase 1 expression at 21 weeks. CONCLUSIONS: The pathogenesis of type 2 diabetes in the ZDF rat was associated with tissue and disease stage-specific aberrations of methyl group and homocysteine metabolism, with persistent hepatic global DNA hypermethylation. PMID- 21818838 TI - First-trimester maternal vitamin D status and risk for gestational diabetes (GDM) a nested case-control study. AB - BACKGROUND: Vitamin D deficiency may contribute to impaired glucose metabolism. There are sparse data regarding vitamin D and the development of gestational diabetes (GDM). The objective of this study was to assess if first-trimester vitamin D deficiency is more prevalent in women later diagnosed with GDM compared with women with uncomplicated pregnancies. METHODS: We conducted a nested case control study of pregnant women who had previously given blood for routine genetic multiple marker screening and subsequently delivered at a tertiary hospital between November 2004 and July 2009. From an overall cohort of 4225 women, 60 cases of GDM were matched by race/ethnicity with 120 women delivering at term (>=37 weeks) with uncomplicated pregnancies. Banked maternal serum was used to measure maternal 25-hydroxyvitamin D [25(OH)D]. RESULTS: The prevalence of first-trimester maternal vitamin D deficiency (defined as 25(OH)D < 50 nmol/L) was comparable among women with GDM compared with controls (5/60 vs 8/120, p = 0.90). The median 25(OH)D level for all subjects was 89 nmol/L (interquartile range, 73-106 nmol/L). Seventy three percent (117/160) of the cohort had 25(OH)D levels >=75 nmol/L. CONCLUSIONS: In a cohort of pregnant women with mostly sufficient levels of serum 25(OH)D, vitamin D deficiency was not associated with GDM. Further studies are warranted with larger cohorts, especially in populations with lower levels of vitamin D. PMID- 21818839 TI - Role of phosphatidylcholine during neuronal differentiation. AB - Neuronal differentiation is characterized by neuritogenesis and neurite outgrowth, processes, which are critically dependent on membrane biosynthesis, and therefore, on the expression and regulation of enzymes involved in phospholipid biosynthesis. During the last decade a great effort was made to clarify where membrane lipids are synthesized, how the newly synthesized membrane components reach the membrane and are inserted during neuritogenesis and to elucidate the mechanism by which the supply of new membrane components is coordinated with the demand for growth. Phosphatidylcholine is the principal and essential component for mammalian membranes. This review updates the mechanism by which phosphatidylcholine biosynthesis takes place and how it is coordinately regulated during neuronal differentiation. PMID- 21818840 TI - Altered gene expression in rat cranial neural crest cells exposed to a teratogenic glucose concentration in vitro: paradoxical downregulation of antioxidative defense genes. AB - BACKGROUND: Diabetic pregnancy is associated with increased risk of malformation in the infant. Diabetes-induced anomalies of the face and heart are strongly correlated with neural crest cell (NCC) maldevelopment. We aimed to study glucose induced alterations of mRNA levels in cranial and trunk NCCs isolated from rat embryos with increased risk of developing mandibular and cardiac malformations in diabetic pregnancy. METHODS: Inbred Sprague-Dawley rat embryos were used for NCC isolation from neural tube explants. The migrating cells were exposed to 5.5 or 30 mmol/l glucose concentration for 48 hr, harvested, and prepared for gene expression measurement by RT-PCR or immunostaining with either distal-less (Dlx) or AP-2-alpha antibodies. RESULTS: Evaluation of the immunostained slides showed that approximately 75% of the cells were of NCC origin. Exposure to 30 mM glucose decreased mRNA levels of Copper-Zinc superoxide dismutase, manganese superoxide dismutase, extracellular superoxide dismutase, Catalase, Gpx-1, Nrf2, poly-ADP ribose polymerase, B-cell leukemia/lymphoma protein 2, and beta-Catenin genes in cranial neural crest explant cultures. In addition, Pax-3, Pax-6, Wnt3a, and Apc mRNA levels were decreased by high glucose exposure in both cranial and trunk neural crest explant cultures. CONCLUSION: Cranial NCCs diminish their mRNA levels of antioxidative enzymes and the Nrf2 response factor, as well as the antiapoptotic B-cell leukemia/lymphoma protein 2 gene, in response to increased ambient glucose concentration. Furthermore, both cranial and trunk NCC decrease the mRNA levels of the transcription factors Pax-3 and Pax-6, as well as key components of the Wnt pathway. These patterns of glucose-altered gene expression in a developmentally important cell population may be of etiological importance for NCC-associated malformations in diabetic pregnancy. PMID- 21818841 TI - Commentary on incidence and nature of testicular toxicity findings in pharmaceutical development survey: a pathologist's perspective. PMID- 21818842 TI - Toxicology and toxicokinetics of oral pantoprazole in neonatal and juvenile dogs. AB - BACKGROUND: Pantoprazole is an irreversible inhibitor of H(+) /K(+) adenosine triphosphatase proton pump. This study encompassed the period of postnatal stomach development to determine whether immature animals are uniquely sensitive to progression of PPI-induced enterochromaffin-like cell hyperplasia. METHODS: Pantoprazole was administered to beagle dogs at 3, 10, or 30 mg/kg/day (10/sex/group) from PND 1 for 13 weeks, subsets of animals had a 13-week recovery period. Clinical signs, body weights, growth, clinical chemistry, and neurobehavioral endpoints were assessed. Selected organs were weighed and histologically examined. RESULTS: There were no effects on body weights, growth, landmarks of physical and reproductive development, or sensory and neurobehavioral function. Cholesterol and triglyceride levels were increased at 10 and 30 mg/kg/day, but resolved during the recovery period. Stomach weight was increased at all doses, but after recovery the differences in stomach weights resolved for females although male stomach weights remained slightly increased. Pantoprazole-related microscopic findings in the stomach consisted of increased mucosal height, glandular necrosis, and glandular dilation at all doses; and ECL cell hyperplasia, parietal cell vacuolation, and atrophy of chief cells are noted at 10 and/or 30 mg/kg/day. There was a partial recovery of these microscopic changes indicated by a decreased incidence and/or severity of increased mucosal height, glandular necrosis, ECL cell hyperplasia, and chief cell atrophy, and complete resolution of other microscopic observations. CONCLUSION: Pantoprazole administered to beagles from PND 1 for 13 weeks resulted in findings similar to those in adult dogs and juvenile dogs, which showed no increase in severity or progression of ECL hyperplasia. PMID- 21818843 TI - Licorice extract increases cyclophosphamide teratogenicity by upregulating the expression of cytochrome P-450 2B mRNA. AB - BACKGROUND: Since cyclophosphamide is metabolically activated to teratogenic acrolein and cytotoxic phosphoramide mustard by cytochrome P-450 type 2B (CYP2B), we assessed the effects of licorice, a CYP2B inducer, on the fetal defects induced by cyclophosphamide. METHODS: Pregnant Sprague-Dawley rats were daily administered with licorice (100 mg/kg) by gavage for 7 days, from the 6th to 12th day of gestation, and intraperitoneally administered with cyclophosphamide (11 mg/kg) 1 hr after the final licorice treatment. On the 20th day of gestation, maternal and fetal abnormalities were determined by Cesarian section. RESULTS: Cyclophosphamide was found to reduce fetal and placental weights without increasing resorption or death. In addition, it induced malformations in live fetuses; 93.8, 41.1, and 100% of the external (skull and limb defects), visceral (cleft palate and ureteric dilatation), and skeletal (acrania, vertebral/costal malformations, and delayed ossification) abnormalities, respectively. When pre treated with licorice, cyclophosphamide-induced body weight loss and abnormalities of fetuses were remarkably aggravated. Moreover, repeated treatment with licorice greatly increased mRNA expression and activity of hepatic CYP2B. CONCLUSIONS: The results indicate that repeated intake of licorice may aggravate cyclophosphamide-induced body weight loss and malformations of fetuses by upregulating CYP2B. PMID- 21818844 TI - Differentially expressed miRNAs in cytogenetic and molecular subtypes of pediatric acute myeloid leukemia. AB - BACKGROUND: miRNAs regulate gene expression, and thus play an important role in critical cellular processes. Aberrant miRNA expression patterns have been found in various types of cancer. So far, information about the expression of miRNAs in pediatric acute myeloid leukemia is limited. PROCEDURE: We studied expression of miR-29a, -155, -196a, and -196b by stem-loop based RT-qPCR in 82 pediatric acute myeloid leukemia patients selected to represent relevant cytogenetic and molecular subgroups. RESULTS: High miR-196a and -b expression was observed in patients carrying MLL gene rearrangements (P < 0.001), NPM1 mutations (P < 0.001), or FLT3-ITD in a cytogenetically normal background (P <= 0.02), compared to all other patients. In contrast, CEBPA mutated cases had a low expression of miR-196a and -b (P <= 0.001). Expression of miR-196a and -b was correlated with expression of neighboring HOXA and HOXB genes (Spearman's r = 0.46-0.82, P < 0.01). Expression of miR-155 was not related to cytogenetic features but high expression of miR-155 was observed in FLT3-ITD (P = 0.001) and NPM1-mutated cases (P = 0.04). Lower miR-29a expression was mainly observed in MLL-rearranged pediatric acute myeloid leukemia, specifically in cases carrying t(10;11) (P < 0.001). CONCLUSIONS: We show aberrant expression of specific miRNAs in clinically relevant cytogenetic and molecular subgroups of pediatric acute myeloid leukemia, suggesting a role for these miRNAs in the underlying biology in these specific subgroups. PMID- 21818845 TI - The use of high frequency oscillatory ventilation in a pediatric oncology intensive care unit. AB - BACKGROUND: High frequency oscillatory ventilation (HFOV) has been successfully used in the management of acute respiratory distress syndrome (ARDS) in children. The aim of our study is to determine its effectiveness in pediatric patients with cancer or post hematopoietic stem cell transplantation (HSCT) diagnosed with ARDS. PROCEDURE: A retrospective case review, in a pediatric intensive care unit (PICU) in a tertiary-care oncology center in Amman, Jordan. Patients included were children with cancer and/or receiving allogeneic HSCT who were diagnosed with ARDS and placed on HFOV from January 2007 to February 2009. RESULTS: Data from 12 pediatric oncology patients on HFOV were analyzed for demographics, oncological diagnosis, PRISM III scores, ventilator settings before switching to HFOV and 24 hours after switching, complications, and outcomes. Alveolar-arterial oxygen (A-a) gradient and oxygen index (OI) were calculated, and pressure of arterial CO(2) (PaCO(2) ) was measured before and 24 hours after switching. Endpoints were successful extubation and discharge, or death while intubated. After 24 hours on HFOV, the A-a gradient decreased significantly in all patients (from a median of 564-267 torr; P=0.001). OI decreased in all but two patients who died (median 17); PaCO(2) decrease was not significant. Five patients died (two of them post-HSCT) and the 7 (58%) survivors were weaned from HFOV (median, 9 days) and discharged. CONCLUSIONS: HFOV improves gas exchange and is useful in managing critically ill children with cancer and post-HSCT patients who develop ARDS. PMID- 21818847 TI - Functionally decoupled soft lithography for patterning polymer brushes. AB - Easy soft imprint nanolithography (ESINL) is employed in the patterning of multiple olymer brushes. This new approach to soft lithography is found to be uniquely effective at patterning brushes both prior to and subsequent to grafting of the polymer chains. Silicon substrates are grafted with polystyrene, polymethylmethacrylate, and polyhydroxyethylmethacrylate using surface-initiated atom transfer radical polymerization assisted by activators generated by electron transfer (ARGET-ATRP) and characterized by contact angle measurements, infrared spectroscopy, and ellipsometry. Line grating features of 3 cm * 3 cm with critical dimensions in the range of 410-480 nm are imprinted directly over grafted brush layers or over assembled monolayers of initiator molecules and transferred to the active layer by reactive ion etching. In all cases the grating pattern is accurately reproduced in the brush layer as confirmed by atomic force microscopy, demonstrating the capability of the technique to generate large-area nanoscale patterns on a range of surface types and functionalities. PMID- 21818846 TI - Antioxidant deactivation on graphenic nanocarbon surfaces. AB - This article reports a direct chemical pathway for antioxidant deactivation on the surfaces of carbon nanomaterials. In the absence of cells, carbon nanotubes are shown to deplete the key physiological antioxidant glutathione (GSH) in a reaction involving dissolved dioxygen that yields the oxidized dimer, GSSG, as the primary product. In both chemical and electrochemical experiments, oxygen is only consumed at a significant steady-state rate in the presence of both nanotubes and GSH. GSH deactivation occurs for single- and multi-walled nanotubes, graphene oxide, nanohorns, and carbon black at varying rates that are characteristic of the material. The GSH depletion rates can be partially unified by surface area normalization, are accelerated by nitrogen doping, and suppressed by defect annealing or addition of proteins or surfactants. It is proposed that dioxygen reacts with active sites on graphenic carbon surfaces to produce surface bound oxygen intermediates that react heterogeneously with glutathione to restore the carbon surface and complete a catalytic cycle. The direct catalytic reaction between nanomaterial surfaces and antioxidants may contribute to oxidative stress pathways in nanotoxicity, and the dependence on surface area and structural defects suggest strategies for safe material design. PMID- 21818848 TI - Liquid-liquid interfacial nanomolding. PMID- 21818849 TI - Combined solid-phase extraction and gas chromatography-mass spectrometry used for determination of chloropropanols in water. AB - A sensitive and rapid derivatization method for the simultaneous determination of 1,3-dichloro-2-propanol (1,3-DCP) and 3-chloropropane-1,2-diol (3-MCPD) in water samples has been developed. The aim was to research the optimal conditions of the derivatization process for two selected reagents. A central composite design was used to determine the influence of derivatization time, derivatization temperature and reagent volume. A global desirability function was applied for multi-response optimization. The analysis was performed by gas chromatography mass spectrometry. During the optimization of the extraction procedure, four different types of solid-phase extraction (SPE) columns were tested. It was demonstrated that the Oasis HLB cartridge produced the best recoveries of the target analytes. The pH value and the salinity were investigated using a Doehlert design. The best results for the SPE of both analytes were obtained with 1.5 g of NaCl and pH 6. The proposed method provides high sensitivity, good linearity (R(2)>=0.999) and repeatability (relative standard deviations % between 2.9 and 3.4%). Limits of detection and quantification were in the range of 1.4-11.2 ng/mL and 4.8-34.5 ng/mL, respectively. Recoveries obtained for water samples were ca. 100% for 1,3-DCP and 3-MCPD. The method has been successfully applied to the analysis of different samples including commercially bottled water, an influent and effluent sewage. PMID- 21818850 TI - A comparison of Tris-glycine and Tris-tricine buffers for the electrophoretic separation of major serum proteins. AB - This paper compares different buffer systems for the electrophoretic separation of the five most abundant serum proteins on native-PAGE gel and cellulose membranes. A modified Tris-tricine system was shown to be superior for the separation of these serum proteins in a 7% m/v native-PAGE gel as compared with the traditionally used Tris-glycine and Tris-tricine methods. This modified Tris tricine buffer system was also employed for the separation of serum proteins using a cellulose acetate membrane and very effective separation was observed as compared with the traditionally used Tris-barbital and Tris-glycine buffer systems. PMID- 21818851 TI - Needle microextraction trap for on-site analysis of airborne volatile compounds at ultra-trace levels in gaseous samples. AB - Different capillary needle trap (NT) configurations are studied and compared to evaluate the suitability of this methodology for screening in the analysis of volatile organic compounds (VOCs) in air samples at ultra-trace levels. Totally, 22 gauge needles with side holes give the best performance and results, resulting in good sampling flow reproducibility as well as fast and complete NT conditioning and cleaning. Two different types of sorbent are evaluated: a graphitized carbon (Carbopack X) and a polymeric sorbent (Tenax TA). Optimized experimental conditions were desorption in the GC injector at 300 degrees C, no make-up gas to help the transport of the desorbed compounds to the GC column, 1 min splitless time for injection/desorption, and leaving the NT in the hot injector for about 20 min. Cross-contamination is avoided when samples containing high VOC levels (above likely breakthrough values) are evaluated. Neither carryover nor contamination is detected for storage times up to 48 h at 4 degrees C. The method developed is applied for the analysis of indoor air, outdoor air and breath samples. The results obtained are equivalent to those obtained with other thermal desorption devices but have the advantage of using small sample volumes, being simpler, more economical and more robust than conventional methodologies used for VOC analysis in air samples. PMID- 21818852 TI - Genetic, proteomic and metabolic analysis of the regulation of energy storage in rice seedlings in response to drought. AB - We used proteomic analysis to determine the response of rice plant seedlings to drought-induced stress. The expression of 71 protein spots was significantly altered, and 60 spots were successfully identified. The greatest down-regulated protein functional category was translation. Up-regulated proteins were mainly related to protein folding and assembly. Additionally, many proteins involved in metabolism (e.g. carbohydrate metabolism) also showed differences in expression. cDNA microarray and GC-MS analysis showed 4756 differentially expressed mRNAs and 37 differentially expressed metabolites. Once these data were integrated with the proteomic analysis, we were able to elucidate the metabolic pathways affected by drought-induced stress. These results suggest that increased energy consumption from storage substances occurred during drought. In addition, increased expression of the enzymes involved in anabolic pathways corresponded with an increase in the content of six amino acids. We speculated that energy conversion from carbohydrates and/or fatty acids to amino acids was increased. Analysis of basic metabolism networks allowed us to understand how rice plants adjust to drought conditions. PMID- 21818856 TI - PEGylated anti-MUC1 aptamer-doxorubicin complex for targeted drug delivery to MCF7 breast cancer cells. AB - Targeted drug delivery is especially important in cancer treatment as many anti cancer drugs are non-specific and highly toxic to both cancer and normal cells. The targeted drug delivery of DOX to the MUC1-expressing breast cancer cell line (MCF7) was obtained using APT as a carrier. Modification of the APT-DOX complex by PEG increases the survivability of the macrophage control (RAW 264.7) by about six-fold as compared to free DOX treatment without significantly affecting the cytotoxicity toward the target cell line. Thus, PEG-APT-DOX is potentially a new therapeutic agent for targeted drug delivery to MUC1-expressing cell lines. PMID- 21818855 TI - Self-assembled antimicrobial and biocompatible copolymer films on titanium. AB - Copolymers of 4-vinyl-N-hexylpyridinium bromide and dimethyl(2 methacryloyloxyethyl) phosphonate self-assemble to form ultrathin layers on titanium surfaces that show antimicrobial activity, and biocompatibility. The copolymer layers are characterized by contact angle measurements, ellipsometry and XPS. Antibacterial activity is assessed by investigation of adherence of S. mutans. Biocompatibility is rated based on human gingival fibroblast adhesion and proliferation. By balancing the opposing effects of the chemical composition on biocompatibility and antimicrobial activity, copolymer coatings are fabricated that are able to inhibit the growth of S. mutans on the surface but still show attachment of gingival fibroblasts, and therefore might prevent biofilm formation on implants. PMID- 21818857 TI - Doubly hydrophilic multiarm hyperbranched polymers with acylhydrazone linkages as acid-sensitive drug carriers. AB - A novel type of drug carrier capable of controlled drug release is proposed. It consists of an acid-sensitive doubly hydrophilic multiarm hyperbranched copolymer with a hyperbranched polyamidoamine core and many linear poly(ethylene glycol) arms. Using pH-sensitive acylhydrazone linkages, the polymer forms unimolecular micelles that can encapsulate hydrophobic drugs. Due to their amphiphilicity, the drug-loaded unimolecular micelles can self-assemble into multimolecular micelles that show acid-triggered intracellular delivery of the hydrophobic drugs. PMID- 21818859 TI - Butanol production from renewable biomass: rediscovery of metabolic pathways and metabolic engineering. AB - Biofuel from renewable biomass is one of the answers to help solve the problems associated with limited fossil resources and climate change. Butanol has superior liquid-fuel characteristics, with similar properties to gasoline, and thus, has the potential to be used as a substitute for gasoline. Clostridia are recognized as a good butanol producers and are employed in the industrial-scale production of solvents. Due to the difficulty of performing genetic manipulations on clostridia, however, strain improvement has been rather slow. Furthermore, complex metabolic characteristics of acidogenesis followed by solventogenesis in this strain have hampered the development of engineered clostridia strains with highly efficient and selective butanol-production capabilities. In recent years, the butanol-producing characteristics in clostridia have been further characterized and alternative pathways discovered. More recently, systems-level metabolic engineering approaches were taken to develop superior strains. Herein, we review recent discoveries of metabolic pathways for butanol production and the metabolic engineering strategies being developed. PMID- 21818860 TI - Insights into large-scale cell-culture reactors: I. Liquid mixing and oxygen supply. AB - In the pharmaceutical industry, it is state of the art to produce recombinant proteins and antibodies with animal-cell cultures using bioreactors with volumes of up to 20 m(3) . Recent guidelines and position papers for the industry by the US FDA and the European Medicines Agency stress the necessity of mechanistic insights into large-scale bioreactors. A detailed mechanistic view of their practically relevant subsystems is required as well as their mutual interactions, i.e., mixing or homogenization of the culture broth and sufficient mass and heat transfer. In large-scale bioreactors for animal-cell cultures, different agitation systems are employed. Here, we discuss details of the flows induced in stirred tank reactors relevant for animal-cell cultures. In addition, solutions of the governing fluid dynamic equations obtained with the so-called computational fluid dynamics are presented. Experimental data obtained with improved measurement techniques are shown. The results are compared to previous studies and it is found that they support current hypotheses or models. Progress in improving insights requires continuous interactions between more accurate measurements and physical models. The paper aims at promoting the basic mechanistic understanding of transport phenomena that are crucial for large-scale animal-cell culture reactors. PMID- 21818858 TI - Antimicrobial and hemolytic activities of copolymers with cationic and hydrophobic groups: a comparison of block and random copolymers. AB - Random and diblock copolymers of 2-(N,N-dimethylamino)ethyl methacrylate and butyl methacrylate are prepared by ATRP. As mimics of cationic antimicrobial peptides, the random and diblock copolymers show similar antimicrobial activities. In contrast, the diblock copolymers have much lower hemolytic activities than the random copolymers. The cell selectivity (HC(50)/MIC, where HC(50) is the concentration to lyse 50% of human red blood cells and MIC is the minimum concentration to inhibit bacterial growth) of the diblock copolymers are 150 to 27,500 times higher than that of random copolymers with similar compositions. PMID- 21818861 TI - Insights into large-scale cell-culture reactors: II. Gas-phase mixing and CO2 stripping. AB - Most discussions about stirred tank bioreactors for cell cultures focus on liquid phase motions and neglect the importance of the gas phase for mixing, power input and especially CO(2) stripping. Particularly in large production reactors, CO(2) removal from the culture is known to be a major problem. Here, we show that stripping is mainly affected by the change of the gas composition during the movement of the gas phase through the bioreactor from the sparger system towards the headspace. A mathematical model for CO(2)-stripping and O(2)-mass transfer is presented taking gas-residence times into account. The gas phase is not moving through the reactor in form of a plug flow as often assumed. The model is validated by measurement data. Further measurement results are presented that show how the gas is partly recirculated by the impellers, thus increasing the gas residence time. The gas-residence times can be measured easily with stimulus response techniques. The results offer further insights on the gas-residence time distributions in stirred tank reactors. PMID- 21818863 TI - Interdisciplinary studies: Seeking the right toolkit. PMID- 21818862 TI - Building the posterior lateral line system in zebrafish. AB - The posterior lateral line (pLL) in zebrafish has emerged as an excellent system to study how a sensory organ system develops. Here we review recent studies that illustrate how interactions between multiple signaling pathways coordinate cell fate,morphogenesis, and collective migration of cells in the posterior lateral line primordium. These studies also illustrate how the pLL system is contributing much more broadly to our understanding of mechanisms operating during the growth, regeneration, and self-organization of other organ systems during development and disease. PMID- 21818864 TI - Repetitive QRS axis shift: what is the cause? PMID- 21818865 TI - Modeling the thermostability of surface functionalisation by oxygen, hydroxyl, and water on nanodiamonds. AB - Understanding nanodiamond functionalisation is of great importance for biological and medical applications. Here we examine the stabilities of oxygen, hydroxyl, and water functionalisation of the nanodiamonds using the self-consistent charge density functional tight-binding simulations. We find that the oxygen and hydroxyl termination are thermodynamically favourable and form strong C-O covalent bonds on the nanodiamond surface in an O2 and H2 gas reservoir, which confirms previous experiments. Yet, the thermodynamic stabilities of oxygen and hydroxyl functionalisation decrease dramatically in a water vapour reservoir. In contrast, H2O molecules are found to be physically adsorbed on the nanodiamond surface, and forced chemical adsorption results in decomposition of H2O. Moreover, the functionalisation efficiency is found to be facet dependent. The oxygen functionalisation prefers the {100} facets as opposed to alternative facets in an O2 and H2 gas reservoir. The hydroxyl functionalisation favors the {111} surfaces in an O2 and H2 reservoir and the {100} facets in a water vapour reservoir, respectively. This facet selectivity is found to be largely dependent upon the environmental temperature, chemical reservoir, and morphology of the nanodiamonds. PMID- 21818867 TI - [Choice of urinary tract drainage in different age groups of patients with urolithiasis]. AB - Retro- and prospective analyses of 802 case histories of patients with nephrostomic drainage (n=272), ureteral catheter (n=27) and ureteral stent (n=503) treated for urolithiasis in the urological department of M.F. Vladimirsky Moscow Region Research Clinical Institute and Zhukovsky city hospital hospitalized in 1995 to 2009 made it possible to develop algorithms of choice of upper urinary tract drainage depending on clinical and laboratory indices. Nephrostomic drainage is preferable in a single functioning kidney, acute obstructive pyelonephritis, anuria, hyperthermia above 38 degrees C, marked supravesical urodynamic disorder, in renal failure, serum creatinine over 200 mcmol/l, urea over 10 mmol/l, blood potassium over 5 mmol/l, uric acid over 380 mcmol/l and leukocytosis over 8 x 10(9) l. Draining with ureteral stent was used primarily in elective surgery--extracorporeal shock-wave lithotripsy and transurethral operations. Stenting was better tolerated and entailed less frequent complications. In the rest cases choice of drain method should be made by the urologist. In active inflammation, before getting antibioticogram, the drain should be followed by antibiotic treatment with fluoroquinolones, cephalosporines of the third or forth generation, aminoglycosides, carbapenems in standard doses. PMID- 21818868 TI - [Dynamics of morphometric parameters of peripheral blood platelets as a criterion in assessing thrombogenicity of dialysis membranes]. AB - The study enrolled 45 patients with terminal chronic renal failure (CRF) aged 24 57 years on hemodialysis (a study group) and 30 healthy subjects of matched age (a control group). Morphofunctional condition of circulating platelets in situ was assessed by vital computer morphometry using computer phase-interference microscope, the analysis was made of opticogeometric parameters and morphological features of live platelets reflecting the degree of their activation. CRF patients' proportion of different platelet types in circulating population was 56.5, 34, 8.7 and 0.8% (platelets in situ, platelets with low, high activation, degenerative) versus 59.4, 28.1, 10.5 and 2% in the controls, respectively. Changes in morphological composition and opticogeometric parameters of circulating platelets were found in the dialysis membrane after a hemodialysis procedure. The changes were less or more pronounced depending on the dialysis membrane type. Thus, vital morphometric platelet parameters reflect condition of the platelets allowing quantitative assessment of impairment of the structure and functional activity of the cells in CRF progression. Hemodialysis procedure results in characteristic alterations of morphofunctional status of circulating platelets related, to a certain degree, to the material of extracorporeal outline. This dictates necessity of objective evaluation of such impact and prognosis of thrombogenic complications. Morphometric parameters of platelets can serve objective criteria of dialysis membrane thromboginicity. PMID- 21818869 TI - [Cefixim: clinical pharmacology and role in therapy of urogenital infections]. AB - Cefixim belongs to oral cephalosporins of the third generation and has the longest half-life period among all oral cephalosporins and, therefore can be taken once a day. Moreover, cefixim presents in high concentrations in the urine, kidneys and urinary tract. In vitro, this drug has high activity against basic pathogens of urogenital infection. A randomized clinical trial has found that cefixim has higher clinical and microbiological efficacy than ciprofloxacin in patients with acute uncomplicated cystitis. PMID- 21818870 TI - [What is done with a normal gut microbiota?]. PMID- 21818871 TI - [Why flowers . . . ?]. PMID- 21818872 TI - When patients suddenly become confused. Hospital delirium is common and often goes unrecognized. PMID- 21818873 TI - Food allergies and food intolerances. Both are on the rise--and it's important to know the difference. PMID- 21818874 TI - Culturally appropriate storytelling may help control blood pressure in African Americans. PMID- 21818875 TI - A device to prevent heart failure is twice as effective in women. PMID- 21818876 TI - Ask the doctor. I had my hair straightened six months ago. Is there any danger in getting these treatments twice a year? I hear they may contain formalin or formaldehyde. PMID- 21818877 TI - Lactococcin 972 : a homodimeric lactococcal bacteriocin whose primary target is not the plasma membrane. AB - Lactococcus lactis subsp. lactis IPLA 972 was shown to produce a bacteriocin which had a bactericidal effect on sensitive lactococci. Production of lactococcin 972 reached a maximum during the late-exponential phase of growth. The bacteriocinogenic activity was heat-sensitive, active in the pH range 40-9.0 and showed low susceptibility to proteases. Purification of the bacteriocin rendered a single polypeptide of 7.5 kDa (monomer) as shown by SDS-PACE. Gels overlaid with a lawn of sensitive bacteria showed inhibitory activity at a point corresponding t o 15 kDa. Changes in the electrophoretic conditions allowed the detection of a band at a position corresponding to that expected for a hypothetical dimer. Sequencing of the NH,-terminal end of lactococcin 972 revealed the sequence NH,-EGTWQHGYGV, which is not related to any other bacteriocin sequence present in the databases. Finally, lactococcin 972 did not induce the efflux of compounds previously incorporated into the cytoplasm of sensitive cultures nor did it inhibit macromolecular synthesis,suggesting that, in contrast to other bacteriocins, its primary target is not the plasma membrane. PMID- 21818879 TI - CQ sources/bibliography. PMID- 21818878 TI - Medicare program; inpatient rehabilitation facility prospective payment system for federal fiscal year 2012; changes in size and square footage of inpatient rehabilitation units and inpatient psychiatric units. Final rule. AB - This final rule will implement section 3004 of the Affordable Care Act, which establishes a new quality reporting program that provides for a 2 percent reduction in the annual increase factor beginning in 2014 for failure to report quality data to the Secretary of Health and Human Services. This final rule will also update the prospective payment rates for inpatient rehabilitation facilities (IRFs) for Federal fiscal year (FY) 2012 (for discharges occurring on or after October 1, 2011 and on or before September 30, 2012) as required under section 1886(j)(3)(C) of the Social Security Act (the Act). Section 1886(j)(5) of the Act requires the Secretary to publish in the Federal Register on or before the August 1 that precedes the start of each FY the classification and weighting factors for the IRF prospective payment system (PPS) case-mix groups and a description of the methodology and data used in computing the prospective payment rates for that fiscal year. We are also consolidating, clarifying, and revising existing policies regarding IRF hospitals and IRF units of hospitals to eliminate unnecessary confusion and enhance consistency. Furthermore, in accordance with the general principles of the President's January 18, 2011 Executive Order entitled "Improving Regulation and Regulatory Review," we are amending existing regulatory provisions regarding ''new'' facilities and changes in the bed size and square footage of IRFs and inpatient psychiatric facilities (IPFs) to improve clarity and remove obsolete material. PMID- 21818880 TI - Rationality and the genetic challenge revisited. PMID- 21818881 TI - Working practice of orthodontic therapists. PMID- 21818882 TI - [Private relationship between physician and patient]. PMID- 21818883 TI - Respiratory Medicine Symposium. A symposium held on 4 March 2011 at the Royal College of Physicians of Edinburgh. PMID- 21818884 TI - [The University Hospital of Children Queen Fabiola is twenty years old!]. AB - HUDERF is the only pediatric hospital autonomous in Belgium because the other academic pediatric departments are included in general hospitals. However, the model of the children hospital is the most common, both in the industrial nations and in the undeveloped countries and evolves in hospital "mother-child" for the optimaisation of cares in infants that often begin from before the birth, for example in the case of predictable genetic diseases. The children's first hospitals date of more than 150 years ago as that of London for example. Huderf considerably developed in 20 years: it is the topic of this article. Its future is shared with the academic Hospital today and St-Pierre Hospital through the Iris-ULB convention. PMID- 21818885 TI - [The Nursing department]. PMID- 21818886 TI - [New perspectives for pediatric surgery in the University of Brussels and the Brussels public health institutions, after 20 years of HUDERF (The University Hospital of Children Queen Fabiola)]. AB - A Convention signed by the academic and political Authorities of the University of Brussels and IRIS (Brussels public health institutions) allows the creation of an Interhospital Department of Pediatric Surgery. The pediatric surgeons of the different hospitals have now the opportunity to organise a large cooperation on a clinical, research and teaching basis. PMID- 21818887 TI - [Neuroprotection and sudden infant death. A robust Brussels--Paris collaboration and future perspectives]. AB - Queen Fabiola Hospital--Free University of Brussels (HUDERF) and Robert-Debre Hospital--Denis-Diderot University Paris 7 (HRD-P7) are born almost at the same time. They developed recently robust collaborations, especially for training of young pediatricians. In research, numerous results and papers have been produced, particularly in the fields of neuroprotection and sudden infant death. This article reviews also future perspectives and tools to expand joint programs between both institutions. PMID- 21818888 TI - [Inborn errors of metabolism: new developments and challenges]. AB - The recent evolution of hospital pediatrics in Western Europe results from the scientific progresses in preventive and curative medicine, from epidemiological changes related to environmental factors, from populations expectations about health and from the socioeconomical evolution. As a consequence, hospital pediatric activities have evolved toward the management of more chronic et complex diseases, requiring multidisciplinary approachs. In this context, the role of the "hospitalist" clinician, of family-oriented care, of coordination of inteventions and of minimization of complications during hospitalization need to be emphasized. The teaching of pediatrics has quickly evolved toward practical and interactive activities, organized in small groups. In a few years, EBM has spread like an epidemic in the scientific community. Clinical and epidemiological research remains underdeveloped in many European countries. This research needs to be boosted with the help of national European and private sponsors. European pediatric departments also have to develop their expertise in the field of research in developing countries. PMID- 21818889 TI - [Better medicines for children]. AB - The European Regulation incenting pharmaceutical companies to develop drugs in children will have substantial consequences for all partners involved. Children and parents will be asked to participate in clinical trials, paediatricians to monitor these investigations, industry to be creative and propose adapted formulations, ethical committees to deliver advices and public health authorities to assist the system in order to bring to a good end a full set of paediatric indications. PMID- 21818890 TI - [The laboratory of pediatrics]. AB - A medical department in a university hospital has 3 duties: care, teaching, and research. Partnership between the department of pediatrics and a laboratory of pediatrics is therefore essential; they are complementary. The development of the laboratory requires constructive collaboration with the medical department, clinicians addressing questions to the laboratory, and the laboratory developing tools in order to provide answers. This clearly supposes that the necessary human and material resources are made available to the laboratory. The Laboratory of Pediatrics of the ULB, through its basic activity, exists and functions, but possibilities and ambitions are broader. With the aid of the department of pediatrics and of the university, the Laboratory should be able to consolidate the diversification of its activities and financial resources, and to extent the panel of services offered. PMID- 21818891 TI - [A new framework for cerebral palsy]. AB - Cerebral palsy was recently redefined as a group of disorders of the development of movement and posture, causing activity limitation, that are attributed to non progressive disturbances that occurred in the developing fetal or infant brain. The motor disorders of cerebral palsy are often accompanied by disturbances of sensation, perception, cognition, communication or behaviour, by epilepsy or by secondary musculoskeletal problems (Bax et al. 2005). It has an estimated incidence of 0.2 %, i.e., 200 new cases per year in Belgium and a total of about 18,000 patients (in a population of 10 millions). Over the last few years, interest has risen in issues pertaining to learning, social participation, services, some assessment modalities (including gait analysis), some therapeutic modalities (including orthotics and antispastic treatment). The Department of Neurology of the H6pital Universitaire des Enfants Reine Fabiola has taken an active part in several aspects of these developments, including research on pathophysiology, neurophysiology, motor control and management (including intrathecal baclofen) as well as setting up the Interuniversity Reference Centre for Cerebral Palsy ULB-VUB-ULg. The 20th anniversary of the hospital offers an opportunity to review this important topic. PMID- 21818892 TI - [The future of pediatric intensive care]. AB - Paediatric intensive care is born 40 years ago. It has been shown that admission of critically ill children in intensive care (ICU) where no paediatric intensivists worked increased significantly the mortality and the length of stay. The recognition of Paediatric Intensive Care (PICU) does not exist in Belgium and children are admitted in both adult and paediatric intensive care units. It is mandatory to recognise the PICU specificity and the usefulness of a fellowship in paediatric intensive care. Development of molecular biology and genetics will permit in the near future to understand reversible and irreversible cellular processes of the majority of problems responsible for mortality in critical care and to allow the development of new diagnostic and therapeutic techniques. Rapid development of information will permit the creation of multicenter databases including all PICU's data. The final goal is an intelligent tool for making decision process. Telemedecine is born which permits a virtual consultation of the patient. Technological progress must not impair the wellbeing of the child and its family. The PICU of the future must be "parents admitted". PICU profile is progressively changing, the way of taking care of the critically ill child and its family is also changing and improving. An ethical reflexion among the health care providers' team and a dialogue with parents will blossom. PMID- 21818893 TI - [What glycemic control can be achieved in diabetic children and adolescents to avoid complications? Personal experience]. AB - The principal aims of therapeutic management of the child, adolescent and adult with type 1 diabetes are to allow good quality of life and to avoid long-term complications by maintaining blood glucose concentrations close to the normal range and an HbA1c level under 7%. The number of daily insulin injections, 2 or > or =4 or pumps, by itself does not necessarily give better results, but the 4 injection regimen allows greater freedom, taking into account that the proper insulin adjustment is difficult before adolescence. Successful glycaemic control in young patients depends mainly on the quality and intensity of diabetes education. Any dogmatism must be avoided. Dietary recommendations issued over the last few years are the same for diabetic and nondiabetic individuals in order to avoid degenerative diseases. In the twice-daily injection regimen, the allocation of carbohydrates throughout the day is essential. Due to their pharmakokinetic characteristics, fast-acting and long-acting insulin analogues have specific indications in both the twice-daily injection regimen and the basal-bolus insulin therapy. They improve quality of life, without necessarily reducing HbA1c. In the two daily insulin injection regimen, fast-acting analogues are very useful to rapidly correct hyperglycaemia, to allow sleeping in and eating something sweet. In the basal-bolus regimen, long-acting analogues reduce nocturnal hypoglycaemias and improve fasting blood glucose. Clinical studies, conducted since the 1970s by our team, have demonstrated that screening for subclinical retinopathy (fluorescein angiography), neuropathy (conduction velocities), nephropathy (microalbuminuria), should be started at puberty and at least 3 years after the diagnosis of diabetes. The goal is to detect early abnormalities responsible for subclinical disorders that can be reversed by improved metabolic control, thus preventing the occurrence of irreversible potentially incapacitating lesions. This motivates both the patient and the doctor in order to obtain good HbAlc levels. The mean HbAlc levels of our diabetic children and adolescents are among the lowest in the review of literature and in the international comparisons by the Hvidore Study Group on Childhood Diabetes. PMID- 21818894 TI - [Perinatology: an uncommon type of medicine]. AB - Perinatology is a developing medical field where decisions are particularly difficult and may be harmful in that they deal with the life of an infant and the future of the families. It deals with matters that are at cross boards of several medical specialties belonging to medicine and surgery but also relevant to psychology and ethics. Therefore, a collaborative approach is required. Interprofessional exchanges and a team organization are warranted in order to make handling consistent and allow a fruitful follow up. This holds true for the mother and the newborn throughout the pregnancy, delivery and early life. It seems important to us that the parents face with a couple obstetrician pediatrician. This couple will be able to help them in building their parenthood and considering their newborn as a full human being and not only a sum of several medical problems. PMID- 21818895 TI - [Neurogastroenterology: focus on pediatric digestive motility diseases]. AB - The enteric nervous system exercises a key role on the gastrointestinal tract (GIT) motility, sensibility, secretions and absorption. This "Little brain of the gut" consists of numerous autonomic neurones located in the GIT, influenced by luminal and intrinsic factors. A new science, the neurogastroenterology, explores the modulation of the GIT functions and the interactions between the central, autonomic and enteric nervous systems forming the brain-gut axis. It works to understand the role of the glial and Cajal's cells, of chemical mediators, hazards of the GIT ontology, influence of inflammation stress and early childhood environment. Motility disorders are congenital or acquired and can persist with more or less severe impairment of quality of life or be a life threatening condition. They are consequences of impaired embryonic development, genetic disorders, systemic diseases, toxic effects, normal or pathologic immunologic reactions acting on the nervous systems or the myocytes. Advances in the understanding of the pathogenesis of uncommon disorders (Hirschsprung disease, achalasia, chronic intestinal pseudo-obstruction) or more prevalent functional disorders (regurgitations, chronic constipation or diarrhoea, functional abdominal pain) contribute to improve the care of such patients. Multidisciplinary team is sometimes mandatory as a holistic approach and the use of sophisticated techniques are important. Improvement of the efficacy of the drugs could by obtained. For clinical works, we need a common language, for this purpose the paediatric Rome III classification of GIT functional disorders is proposed, we need also more consensus on paediatric GI motility exploration protocols. PMID- 21818896 TI - [The medico-surgical department of uro-nephrology, dialysis and renal transplantation in the Children's Hospital of Brussels]. AB - The department of pediatric uro-nephrology was created in 1977 in Brugmann hospital. Since then, various sectors have been developed including: hemodialysis and peritoneal dialysis, kidney transplantation, urological and genital surgery, antenatal screening and rapid management of uronephropathies, treatment of voiding dysfunction and neurogenic bladder, management of tubular and glomerular diseases. The progress in genetics, medical imaging, obstetrics, neonatology and surgery has allowed us to take care of our young patients within a multidisciplinary framework. The most original contributions of the department are related to the performance of combined liver-kidney transplantation in primary hyperoxaluria, to the determination of the natural history of several congenital anomalies of the kidney and urinary tract, to the assessment of the role of genetical mutations on tubular and glomerular diseases, to the usefulness of radioisotopic tracers in the measurement of renal function in infants, and to the study of experimental tolerization of PMID- 21818897 TI - [Inborn errors of metabolism: new developments and challenges]. AB - The concept "inborn error of metabolism" (IEM) arose from the observations of Sir A. Garrod at the beginning of the XXth century. The exponential development, during the last decades, of our knowledge in cellular biology and molecular genetics, and the availability of increasingly more precise diagnostic tools, allow the identification of a still growing number of inborn errors of metabolism. Their physiopathology is better understood. Treatments have considerably improved: more specific diets, new medical treatments, enzyme replacement therapy, organ transplantation, hepatocyte or stem cell transplantation... New techniques are under development, including various strategies of gene therapy. Improved therapeutic efficacy combined with earlier diagnosis have dramatically changed the prognosis of many disorders. As a consequence, new challenging questions have to be answered. Today, patients with an IEM, because of the extreme complexity of their management, need to be looked after by a multidisciplinary team of physicians (pediatricians and internists), dieticians, social workers, psychologists... It is essential, in this complex and rapidly expanding field, that experiences should be shared at national and international level, in order to provide the most adequate care for patients. PMID- 21818898 TI - [Diagnosis of congenital heart diseases]. AB - Most of the relevant congenital heart defects are recognized by the neonatal clinical screening or even in utero by fetal echocardiographic screening. Nevertheless, a substantial percentage of defects are missed in the early screening and are diagnosed after discharge from hospital during childhood or even during adulthood. Often, this delay in making the correct diagnosis affects the overall outcome of the cardiac children. In almost all patients, cardiac findings are present that should have alerted the physician. This article reviews the importance of history and physical examination in the early diagnosis of congenital heart disease. PMID- 21818899 TI - [Child food allergy: results of a Belgian cohort]. AB - INTRODUCTION: Food Allergy is a public health problem because of its increasingly prevalence, its severity and the difficulty of diagnosis. OBJECTIVE: to describe the responsible food allergens and the clinical features of food allergy in a large group of Belgian children. METHOD: 156 cases of food allergy observed between May 2002 and May 2005 were retrospectively reviewed. All patients have specific IgE. Unequivocal history, response to elimination diet, labial or oral food challenge confirmed the diagnostic. RESULTS: Median age is 26 months (range 1 months-14 years) and male to female ratio is 1.6. Fifty-nine percent of the cases are younger than 3 years. Family history of atopic disease is found in 80.3%. Foods most commonly involved are: eggs (31%), tree nuts (18.1% including hazelnuts 12.3%), cow's milk (16.1%), peanuts (13.2%), fish (4.5%), latex fruits (4.5%).The clinical manifestations are: atopic dermatitis (44.2%), urticaria (40.4%), angioedema (36.5%), gastrointestinal symptoms (21.8%), laryngeal edema (11.5%), asthma (9%), oral allergy syndrome (7.7%), systemic reactions (7.7%) and anaphylactic shock (3.8%). Multiple food allergies are rare: 78.9% of our population have one or two food allergies. CONCLUSION: This study confirms the usual distribution of food allergens in children. It shows that only four allergens (egg, tree nut, cow's milk, peanut) are responsible for 78.4% of the reactions and highlights the emergence of tree nuts allergy, particularly hazelnuts, in Belgium. PMID- 21818900 TI - [The genetic approaches of the disorders of the child]. AB - Genetics, which encompasses cytogenetic, molecular genetics, genetic of populations, pharmacogenetics and gene therapy, become as numerous and almost independent applications (fields). Deriving from the original questions on the origin and mechanisms of diseases, these represent essential tools to better understand physiopathogenesis. Cytogenetics (Chromosomes study, aberrations and their impact on the apparition of diseases) and genomics (the understand of the structure, organisation and DNA expression) are dedicated to clinical genetics as diagnostic and basic science improvements. The identification of new mechanisms of diseases were responsible for the creation of new tools which allow in turn to precise the intimate and underlying processes of diseases or syndromes. Due to the explosion of findings and research programs on fetal, embryologic and pediatric fields, laboratory and reference centers were build. Any child identified as carrier and/or affected from a pathogenic mutation became the primary step for the development of fetal, prenatal and preimplantatory medicines. Ethics came into play since responsibilities for 'do not harm', 'eugenism' temptations and 'individual life' with respect to medical laws should be guaranteed. These are part of the geneticist tasks and the reasons for professionalisation as for teaching genetics as part of medical traineeships that Paediatrics, among others, represents. The present review will systematically describe the principles of these different genetic fields. PMID- 21818901 TI - [Thoracoscopic surgery in children]. AB - Thoracoscopy offers numerous diagnostic and therapeutic options in pediatric surgery. This paper reviews some of the principal thoracoscpic procedures performed in children. Thoracoscopy for empyema, pectus excavatum, chylothorax, etc., will be discussed. Thoracoscpy has been postulated to offer similar results as conventional surgery with lower morbidity and reduced hospital stay. These assumptions still await systematic studies , however. PMID- 21818902 TI - [Dietetic and nutritional management in a university children's hospital]. AB - Dietetics and nutrition are new, expanding disciplines. Feeding man's cub to ensure the best physical, brain and psychic growth to reach the adult age in a "sane" state is the daily challenge of pediatric dieteticians. The role of dieteticians in a pediatric hospital is essential: optimizing sick children's nutrition. A child is highly vulnerable, above all when he is sick. Unappropriate feeding can put his growth and development, as well as his healing at stake. Numerous studies believe that denutrition in pediatric hospitals prevail by 7 to 45%. A survey has been carried out in two care units in the University Children's Hospital Queen Fabiola in Brussels. For one month, the nutritional hazard has been evaluated in every children admitted in these units. One observes that one third of these children shows a high nutritional hazard, and another third a moderate nutritional hazard. The tracking of the nutritional hazard and the appropriate nutritional care must be an integral part of the care given to any child admitted in hospital. A nutrition unit, with all the attending people involved (doctor, dietician, chemist, nurse), is necessary to improve the nutritional care of the patients. PMID- 21818903 TI - [Pediatric psychiatry: evolution and developments]. AB - Since 1986, the field of the child and adolescent clinics in the University Children Hospital Queen Fabiola is much developed. It is divided in five areas: the ambulatory sector, the medical psycho-psychiatry field, the day unit, the psychiatric hospitalisation and the ward. The population consists in babies (not yet born and born), children, adolescents. The clinical approach is multi and transdisciplinary including the child, his family and his life systems, caring staff included. Clinical research is centered on four axes: medical psychology, prevention, therapy and child psychiatry, somatic aspects included. PMID- 21818904 TI - [Ambulatory pediatrics: a challenge]. AB - Ambulatory paediatrics in University hospitals has remarkably evolved during the past decade, along with technological progress and the current need for undelayed information and attention; demand for hospital medical advice increases consequently, either directly in outpatients wards or indirectly by phone or e mails. Specific medico-social aspects linked essentially to populations' migration, poverty, chronic stress and family splitting are regularly encountered. Hospital architecture and adequacy of medical and nursing staff must both be adjusted to these changing medical demands including medical teaching. We now face the ever-growing challenge of providing an adequate management of actual medico-psycho-social aspects and integrating up-to-date paediatrics in our daily practices. PMID- 21818905 TI - [Belgian Kid's Fund for Pediatric Research]. PMID- 21818906 TI - [The Robert Dubois School and the sick child: psychological aspects]. AB - From an ethical and philosophic point of view, the school at the hospital is a determining link of the coverage of the sick child replacing the humanity in the center of the preoccupations and avoiding marginalizing the sick child by preventing him from losing foot in the school experiences. PMID- 21818907 TI - [To be a psychologist in a children's hospital: a privilege]. PMID- 21818908 TI - [The pediatric endocrinology unit: management of growth]. AB - The unit of pediatric endocrinology takes care of children and adolescents with disorders of growth, puberty, thyroid, adrenal, pituitary or gonadal function, and also anomalies of the calcium metabolism. We have a multidisciplinary approach, including the paediatrician and the other specialists. We analyse our results locally, but also at the national and international levels. Through special patients, we try to understand different concepts, at the level of physiology or at the molecular level. A few examples will be described here and can be found in more detail in the bibliography. PMID- 21818909 TI - [Pediatric physiotherapy]. PMID- 21818910 TI - [The University Hospital of Children Queen Fabiola and the Bordet Institute, two jewels of academic research]. PMID- 21818911 TI - [The University Hospital of Children Queen Fabiola, a superb human work ]. PMID- 21818912 TI - [Quantitative analysis of the change in neuronal numerical density of the human nucleus dentatus within development]. AB - BACKGROUND/AIM: The role of the dentate nucleus is to coordinate input information coming from the lower olivary complex and various parts of the brainstem of the spinal marrow with the output information from the cerebellar cortex. To better understand functions and relations of the dentate nucleus it is highly important to study its development process. The aim of this study was to determine a possible mathematical model of decrease in neuronal numerical density of the human nucleus dentatus at different stages of development. METHODS: This study included 25 fetal brains of different age (12.5-31 weeks of gestational age and one brain of a 6-day-old newborn). The brains were fixed in 10% formalin alcohol solution and embedded in paraffin. Sections were cut at a thickness of 6, 15, and 30 microm and stained with cresyl violet. Each fifth section was analyzed using a light microscope, and numerical density of dentate nucleus neurons was established using the M42 Weibel's grid system. RESULTS: The obtained results revealed a constant decrease in numerical density value. The changes of numerical densities at different stages of development correspond with Boltzmann function principles. The first, almost perpendicular part of Boltzmann function corresponds with the development of the dorsomedial lamina and the appearance of ventrolateral lamina primordium. The second, more or less horizontal part of Boltzmann function corresponds with the development of both laminae. CONCLUSION. The obtained results indicate that Boltzmann function can be considered a mathematical model of change in neuronal numerical density of dentate nucleus at different stage of development. PMID- 21818913 TI - [Effect of hysteroscopic examination on the outcome of in vitro fertilization]. AB - BACKGROUND/AIM: Implantation failure after embryo transfer is one of the main problems of in vitro fertilization (IVF) and intrauterine pathologies can lead to unsuccessful outcome. The aim of this study was to determine if hysteroscopic examination of uterine cavity and consequent treatment of intrauterine lesions prior to IVF could improve the pregnancy rate in women under 38. METHODS: This study included 480 patients under 38, who had undergone IVF or IVF?ICSI--embryo transfer cycles, in which one or more good quality embryos were transferred. By transvaginal sonography performed within the past 2 months, the uterus was found normal in all the patients enrolled in our IVF unit. The patients were divided into three groups: group A--with no hysteroscopic evaluation and no pathology, group B --with hysteroscopy but no pathology, and group C--with abnormal hysteroscopy finding and corresponding treatment. RESULTS: The obtained results revaled no difference in the mean age, duration of infertility, number of mature oocytes in either group (p > 0.05). Clinical pregnancy rates in the groups A, B and C were 36.9%, 58.75% and 32.7%, respectively, and delivery rates were 27.5%, 48.7% and 25.7%, respectively. There was a statistically significant difference among the groups concerning pregnancy and delivery rates. CONCLUSION: Considering the results of this study we could conclude that hysteroscopy, as a routine examination, should be performed before the first IVF-ET cycle in all patients thereby reducing the failures and then the costs of IVF-ET. PMID- 21818914 TI - [Assessment of memory in patients with rheumatoid arthritis]. AB - BACKGROUND/AIM. The diagnosis of emotional and cognitive dysfunction in patients with rheumatoid arthritis is often not noticed, regardless of their importance and frequency. The aim of this research was to assess memory function in patients with rheumatoid arthritis with respect to its emotional manifestation, pain intensity, the duration and degree of disease activity, and functional and anatomical stages of the disease. METHODS. The study involved 60 patients with rheumatoid arthritis and 30 healthy subjects of both sexes, aged up to 55, who were examined and tested in the Special Hospital for Rheumatic Diseases in Novi Sad. Depression was diagnosed by using the Beck's scale for depression (Beck Depression Inventory--BDI), anxiety by using the Spielberger Trait Anxiety Inventory--State and Traite; we evaluated the cognitive status (by the Wechsler scale-based memory -WBsp), the functional status (Health Assesment Questionnaire, HAQ) and disease activity by analyzing the index of disease activity (DAS 28). RESULTS: Depressive symptoms were registered in 38 (63.33%) patients, and anxiety symptoms in 22 (36.67%) patients. The average values of the memory coefficient were significantly lower in the group of patients with rheumatoid arthritis compared with the control group. CONCLUSION: High frequency of emotional dysfunction and damaged memory abilities in patients with rheumatoid arthritis requires in time diagnosis and adequate treatment. PMID- 21818915 TI - [Effects of use of riboflavin and ultraviolet light for pathogen inactivation on quality of platelet concentrates]. AB - BACKGROUND/AIM: Pathogen inactivation in blood and blood products is one of the major means to achieve a zero risk blood supply and improve transfusion safety. Riboflavin (vitamin B2) activated by ultraviolet (UV) light, produces active oxygen which damages cell membrane and prevents replication of the carrier of diseases (viruses, bacteria, protozoa) in all blood products. The aim of this study was to establish the influence of the process of pathogens photoinactivation using riboflavin and UV rays on the biochemical and functional characteristics of platelet concentrates prepared from "buffy coat". METHODS: The examination included 80 platelet concentrates prepared from "buffy coat", which was separated from whole blood donated by voluntary blood donors around 6 hours from the moment of collection. Concentrates were pooled, filtered and separated unton two groups: one consisted of 10 control units and the other of 10 examined units (pooled platelet concentrates). Examined units of the platelets were treated by riboflavin (35 mL) and UV rays (6.24 J/mL, 265-370 nm) on Mirasol aparature (Caridian BCT Biotechnologies, USA) in approximate duration of 6 min. A total of 35 mL of saline solution was added to the control units. The samples for examining were taken from the control and examined units initially (K0, I0), after the addition of saline (K1) and riboflavin (I1), after illumination (I2), first day of storage (K3, I3) and the fifth day of storage (K4, I4). The following parameters were measured: platelet count and platelet yield, residual erythrocyte and leukocyte count, pH, pO2, pCO2 and bacterial contamination. RESULTS: All the measured parameters showed a statistically significant decrease comparing to K0 and I0; all the results of the first day of platelet storage showed statistically significant decrease comparing to K1 and I1, and all the results of the fifth day of platelet storage (K4, I4) showed a statistically significant decrease comparing to K1 and K3 and to I1 and I3. There was no the mentioned difference in the measured parameters between K4 and I4 (the end of storage--the fifth day). All the platelet units were sterile till the seventh day, when the investigation ended. CONCLUSION: Platelet concentrates inactivated by riboflavin and UV rays (Mirasol PRT sistem, Caridian BCT, USA) keep all the characteristics assessed by the Guide to the preparation, use and quality assurance of blood components (Council of Europe), during the whole storage period (five days). The obtained data were correlated with existing up to date literature and demonstrated that Mirasol treated platelets were safe and could be incorporated effectively in the routine blood bank and transfusion setting. PMID- 21818916 TI - Therapeutic hypothermia and neurological outcome after cardiac arrest. AB - INTRODUCTION/AIM: The most important clinically relevant cause of global cerebral ischemia is cardiac arrest. Clinical studies showed a marked neuroprotective effect of mild hypothermia in resuscitation. The aim of this study was to evaluate the impact of mild hypothermia on neurological outcome and survival of the patients in coma, after cardiac arrest and return of spontaneous circulation. METHODS: The prospective study was conducted on consecutive comatose patients admitted to our clinic after cardiac arrest and return of spontaneous circulation, between February 2005 and May 2009. The patients were divided into two groups: the patients treated with mild hypothermia and the patients treated conservatively. The intravascular in combination with external method of cooling or only external cooling was used during the first 24 hours, after which spontaneous rewarming started. The endpoints were survival rate and neurological outcome. The neurological outcome was observed with Cerebral Performance Category Scale (CPC). Follow-up was 30 days. RESULTS: The study was conducted on 82 patients: 45 patients (age 57.93 +/- 14.08 years, 77.8% male) were treated with hypothermia, and 37 patients (age 62.00 +/- 9.60 years, 67.6% male) were treated conservatively. In the group treated with therapeutic hypothermia protocol, 21 (46.7%) patients had full neurological restitution (CPC 1), 3 (6.7%) patients had good neurologic outcome (CPC 2), 1 (2.2%) patient remained in coma and 20 (44.4%) patients finally died (CPC 5). In the normothermic group 7 (18.9%) patients had full neurological restitution (CPC 1), and 30 (81.1%) patients remained in coma and finally died (CPC 5). Between the two therapeutic groups there was statistically significant difference in frequencies of different neurologic outcome (p = 0.006), specially between the patients with CPC 1 and CPC 5 outcome (p = 0.003). In the group treated with mild hypothermia 23 (51.1%) patients survived, and in the normothermic group 30 (81.1%) patients died, while in the group of survived patients 23 (76.7%) were treated with mild hypothermia (p = 0.003). CONCLUSION: Mild therapeutic hypothermia applied after cardiac arrest improved neurological outcome and reduced mortality in the studied group of comatose survivors. PMID- 21818917 TI - [Comparison of the established definition criteria for diagnosing metabolic syndrome between overweight and obese children in Vojvodina]. AB - BACKGROUND/AIM: Metabolic syndrome is a clinical term which encompasses obesity, insulin resistance, dyslipidemia, hypertension, as well as an increased risk of the development of diabetes mellitus type 2 and cardiovascular disorders in early adulthood. The prevalence of metabolic syndrome is increasing and directly related to the obesity rate among children. The aim of the research was to compare the established definition of the criteria for diagnosing metabolic syndrome in a sample group consisting of overweight and obese children in Vojvodina. METHODS: The research was performed as a cross study analysis of 206 examinees. In terms of the sample group (25% children and 75% adolescents), 74% were obese and 26% overweight according to the body mass index (BMI). Two sets of criteria for diagnosing metabolic syndrome were applied in the sample of adolescents: the criteria for adults, specifically adapted for children, and the criteria defined by the International Diabetes Federation (IDF) for children and adolescents. The research included the analysis of the following criteria: BMI, waist circumference, blood pressure, triglycerides, HDL cholesterol, glycemia and insulinemia during the oral glucose tolerance test (OGTT). RESULTS: By applying the specific criteria for diagnosing the metabolic syndrome in children and adolescents on the whole sample, it was established that the metabolic syndrome was present in 41% of the examinees, while the application of the criteria defined by the IDF confirmed the diagnosis in 22% of the examinees. An analysis of the metabolic syndrome risk fac- tors established that among the defined specific criteria the most frequent factors present were elevated BMI and the pathological results of the OGTT, while the least frequent was low HDL cholesterol. Among the criteria listed by the IDF, the most frequent metabolic syndrome factors were waist circumference and increased blood pressure, while the least frequent was elevated fasting glucose. CONCLUSION: Metabolic syndrome in overweight and obese children in Vojvodina was diagnosed much more often when the specific criteria for children and adolescents were applied than it was the case when the criteria defined by the International Diabetes Federation were applied. PMID- 21818918 TI - [Assessment of the effectiveness of low level laser in the treatment of alveolar osteitis]. AB - BACKGROUND/AIM: Alveolar osteitis (AO) is the extraction wound healing disorder with a presence of severe pain. Low level laser therapy stimulates cell metabolism and microcirculation, have has pronounced analgesic, antiedematous and anti-inflammatory effect and speeds up wound healing process. The aim of this study was to present results of clinical research that examined the effectiveness of low level laser in pain relief and healing of extraction wounds with alveolar osteitis in the lower jaw which was formed on the second day after tooth extraction. METHODS: The study was conducted on 60 subjects divided into the study and the control group. In both groups extraction wounds were processed in similar way, except that in the study group was applied daily treatment of low level laser with a total of eight sessions of radiation, while in the control group extraction wounds were dressed with zinc oxide eugenol paste, which was changed every 48 hours up to the pain cessation. Measurement of pain intensity was done with a visual analogue scale (VAS) 10 min prior to processing of extraction wounds and daily for the next eight days. Assessment of the effectiveness of low level laser on healing of extraction wounds was performed on the day eight of the treatment. RESULTS: On the day five after beginning of the treatment of extraction wounds with alveolar osteitis in the patients of the study group a lower average value of pain as compared to the control group was registered. This difference was increased within the following days. Extraction wounds healing in the study group was more successful and faster than in the control group. CONCLUSION: This study suggested that the reduction of pain was more pronounced in the patients with alveolar osteitis whose extraction wounds were subjected to low level laser radiation in comparison to those in which extraction wounds were treated with zinc oxide eugenol paste. PMID- 21818919 TI - Prognostic value of apoptotic activity in muscle-invasive bladder cancer. PMID- 21818920 TI - Focal neuroendocrine differentiation in prostatic gland carcinoma with basaloid pattern. AB - INTRODUCTION: Prostatic gland basal cell proliferations exhibit morphological continuum ranging from basal cell hyperplasia to basal cell carcinoma. In the following report, we described clinical features, morphological spectrum, neuroendocrine differentiation and histogenesis of prostatic gland basal cell carcinoma in our patient. CASE REPORT: Hematoxylin-eosin (HE), Alcian blu periodic acid schiff (AB-PAS) at pH 2.5 stained sections and the avidin-biotin peroxidase complex (ABC), were performed on prostate gland paraffin-embedded tissue. Monoclonal antibodies directed against cytokeratin (34betaE12) which selectively stains basal cells, prostate specific antigen (PSA), chromogranine A, neuron-specific enolase (NSE), synaptophysin and CD56, were used. Basal cell proliferations exhibited a morphological continuum ranging from basal cell hyperplasia to prostatic gland carcinoma. In these prostatic lesions, positive reactivity was demonstrated for 34betaE12 and CD56. These findings indicate that the basaloid cells of basal cell hyperplasia, florid basal cell hyperplasia, atypical basal cell hyperplasia and basal cell carcinoma are derived from basal cells of the normal prostate gland suggesting a continuum in the progression of hyperplasia to benign and then malignant neoplasia. The presence of CD56 protein in the discovered lesions may be related to their neuroendocrine differentiation. CONCLUSION: The fact, that our patient was well six years after the radical prostatectomy supports the belief of some authors that basal cell carcinoma represents a low grade carcinoma with an excellent prognosis. PMID- 21818921 TI - Gastric adenomyoma. AB - BACKGROUND: Gastric adenomyoma is a rare, hamartomatous tumor localized most frequently in the gastric antrum. Review of the available literature shows only sporadic reports or smaller series. CASE REPORTS: We presented a 72-year-old woman admitted due to epigastric pain with dyspeptic difficulties. Biochemical parameters and tumor markers were within the referential limits. Diagnostic procedures (upper endoscopy, endoscopic ultrasonography and computerized tomography) revealed an intramural tumor prominence with intact mucosa on the posterior wall of gastric antrum, not accessible for biopsy. Surgical treatment was performed with total extirpation of the tumor. Histopathological examination verified adenomyoma with focal low grade epithelial dysplasia. Cytologic immunophenotype was consistent with smooth muscle stromal and epithelial tumor (CK7 and CK20 ++ immunophenotype). Stromal component revealed low proliferative index (Ki-67 protein immunoexpression level 3%), and p53 less than 0.1% in both epithelial and stromal components. Following the operation, the patient remained in good condition. CONCLUSION: Uncertain malignant potential of the gastric adenomyoma in the presented case indicates that timely diagnostics with adequate surgical treatment is crucial for an adequate treatment. PMID- 21818922 TI - Occupational contact allergic dermatitis in dentistry. AB - INTRODUCTION: Dental professionals may be at increased risk of developing occupational allergic diseases specially to methacrylates that can permeate protective disposable gloves. CASE REPORT: We presented a case of occupational allergic contact dermatitis in a 28-year-old dental technician. The patient had complained of itching and cracking of fingers for 6 months. The dermatitis improved over weekends. Skin erythema and scaling were present with primarily involvement of the fingertips. Patch testing with dental series gave positive vesicular reaction to methyl methacrylate. Follow-up after 6 months of allergen avoidance showed a complete regression of dermatitis. CONCLUSION: Methacrylates serve as bases for acrylic resins which are used in prosthetics. Methyl methacrylate as a small molecular acrylate can permeate thin protective disposable gloves. Using adequate personal protective equipment, like nitrile rubber gloves, is the most important preventive measure in this occupation. Health practitioners should recognize possible occupational hazards in dentistry and implement appropriate preventive measures to protect health of workers. PMID- 21818923 TI - Dilemmas in diagnostics and therapy of rolandic epilepsy. AB - INTRODUCTION: It is considered that around 20%-30% of patients of all ages and in all continents have wrong epilepsy diagnoses. Diagnostic and consequential therapeutic errors appear, most often, when an adequate diagnostics is not applied. Benign focal epilepsy of childhoods with centrotemporal spikes-rolandic epilepsy, brings very often to diagnostic and therapeutic problems because of persistence of epileptic-forms changes in an electroencephalography (EEG) recording, several years after establishment of good control over seizures. CASE REPORT: We presented 8.5 years-old girl, with the first and the only epileptic seizure at the age of 5, during her sleep. With a clear correlation of EEG record, benign rolandic epilepsy was diagnosed, so the therapy with valproate was introduced. There were no seizures after three years of its implementation. Because of epileptic-forms changes that still persisted in EEG record during her sleep, it was suggested to further use valproate. However, after reconsidering all circumstances it was concluded that the AED should bee slowly reduced up to its exclusion. After a complete stoppage of the therapy, the patient did not have any epileptic seizure for nine months, although EEG still remained pathologically changed during her sleep. CONCLUSION: A changed EEG record in a patient with rolandic epilepsy must not be a predictor of continuation of antiepileptic drugs therapy, after 2-3 years of successful seizures remission. PMID- 21818924 TI - More physicians in Congress! PMID- 21818925 TI - A valediction for medicine? I think not. PMID- 21818926 TI - Can a physician sue for online defamation? PMID- 21818927 TI - TM cover gave impression medical marijuana is a TMA priority. PMID- 21818928 TI - Work, family, health: maintaining life balance. PMID- 21818929 TI - Waiting for data can be critical! PMID- 21818930 TI - Timing is everything...is it time for concierge? PMID- 21818931 TI - Tips for a healthy cash flow in your practice. PMID- 21818932 TI - Catamenial pneumothorax: a rare cause of primary spontaneous pneumothorax. PMID- 21818933 TI - Economic justification for the Tennessee Lead Elimination Action Program. AB - Ingestion of lead by children can cause physical health issues and learning development issues. A primary source of lead as a hazard for children is found in deteriorating lead-based paint. The Tennessee Lead Elimination Action Program (TN LEAP) is a grant-funded initiative designed to identify and control lead poisoning hazards in Tennessee homes. TN LEAP conducted a study to evaluate the economic justification for the control of lead hazards through TN LEAP efforts. Using lead remediation cost information, the previously established relationship between child blood lead levels and loss of potential income, a loss-of-lifetime earnings was calculated for affected children. The economic Net Present Value (NPV) was calculated based on the expenses of lead hazard control and savings of lifetime earnings potential. Although blood lead levels for Tennessee children have significantly increased over the past 10 years, the current average for tested children is 2.51 microg/dL. The average remediation expense for houses affected by TN LEAP is $7,598 per unit. The NPV for the loss of lifetime income per housing unit is $17,035. Evaluating the total project yields a result of a positive NPV of $9,437. The study found that using an NPV analysis, there is a positive economic payback for reducing lead hazards in Tennessee homes. The future savings realized from lifetime income earnings will exceed the current remediation expenses. PMID- 21818934 TI - A look at membership and medical family health. PMID- 21818935 TI - [Progress and main points in treatment of acute foot and ankle injuries]. AB - OBJECTIVE: To give a review and commentary on the treatment of acute foot and ankle injuries. METHODS: Based on the treatment experience and recent literature, a commentary on acute foot and ankles injuries were given, included the basic and clinical research results, evaluation before operation, and treatment methods of the soft tissue and bone injuries. RESULTS: The treatment of acute foot and ankle injuries is still a hot point in orthopaedic surgery. Operative and non-operative treatment of fresh Achilles tendon rupture can achieve satisfactory results, and early weight-bearing do not increase the re-rupture rate. The time delay between first debridement and injury within 24 hours does not increase the infection rate. For the treatment of severe ankle fractures, attentions should be paid to the cartilage injury, and anatomic reduction, good realignment, and the congruity recovery are very important. The treatment determination of calcaneal fractures depends on the fully understanding injury mechanisms, classifications, and treatment method. Talus fractures should try to be treated by experienced surgeons. Operation and fixation methods of Lisfranc injury depends on different injury types. CONCLUSION: Acute foot and ankle injuries are common in clinical, to achieve a satisfactory result in evaluation and treatment, it is important to have a fully evaluation of the injury type, and choose best operation time and suitable treatment methods, as well as to fully understand the biomechanical characteristics of different regions. PMID- 21818936 TI - [Effectiveness of open reduction and internal fixation in treatment of posterior malleolus fractures]. AB - OBJECTIVE: To evaluate the operative procedure and the clinical effectiveness of open reduction and internal fixation in the treatment of posterior malleolus fractures. METHODS: Between June 2005 and December 2008, 46 patients with posterior malleolus fractures were treated with open reduction and internal fixation and followed up. There were 29 males and 17 females with an average age of 47.7 years (range, 19-76 years). Fractures were caused by sprain in 17 cases, by falling in 15 cases, by traffic accident in 12 cases, and by other reasons in 2 cases. The locations were left ankle in 25 cases and right ankle in 21 cases. There were 6 simple posterior malleolus fractures, 13 lateral and posterior malleolus fractures, and 22 trimalleolar fractures, and 5 lateral and posterior malleolus fractures accompanying by injury of deltoid ligament of ankle. According to Lauge-Hansen classification system, 13 cases and 9 cases were rated as supination-external rotation type III and type IV respectively, and 18 cases as pronation-external rotation type IV. According to Naoki's classification of posterior malleolus fractures, there were 29 cases of posterolateral-oblique type, 11 cases of medial-extension type, and 6 cases of small-shell type. Seven patients underwent emergency operation and 39 patients underwent selective operation. RESULTS: Two patients developed superficial infection, which was cured after dressing change, and the other incisions healed by first intention. Forty six patients were followed up 37 months on average (range, 18-63 months). All fractures healed after 3 to 6 months (mean, 4.3 months). One patient developed lateral sural cutaneous nerve injury, and 9 patients had mild weight-bearing pain or discomfort. The results of American Orthopaedic Foot and Ankle Society (AOFAS) ankle and hindfoot score were excellent in 17 cases, good in 21 cases, and fair in 8 cases with an excellent and good rate of 83%. The mean visual analogue scale (VAS) score was 1.9 (range, 0-5). CONCLUSION: The anatomic reduction and internal fixation can achieve the satisfactory results in the treatment of posterior malleolus fractures. The best treatment and fixation methods should be chosen based on different types of posterior malleolus fractures. PMID- 21818937 TI - [Arthroscopic therapy of ankle joint impingement syndrome after operation of ankle joint fracture dislocation]. AB - OBJECTIVE: To study the operative procedure and the effectiveness of arthroscopic therapy for ankle joint impingement syndrome after operation of ankle joint fracture dislocation. METHODS: Between March 2008 and April 2010, 38 patients with ankle joint impingement syndrome after operation of ankle joint fracture dislocation were treated. Among them, there were 28 males and 10 females with an average age of 28 years (range, 18 to 42 years). The time from internal fixation to admission was 12-16 months (mean, 13.8 months). There were pressing pain in anterolateral and anterior ankle. The dorsal extension ranged from -20 to -5 degrees (mean, -10.6 degrees), and the palmar flexion was 30-40 degrees (mean, 35.5 degrees). The total score was 48.32 +/- 9.24 and the pain score was 7.26 +/- 1.22 before operation according to American Orthopaedic Foot and Ankle Society (AOFAS) ankle and hindfoot score system. The X-ray films showed osteophyte formation in anterior tibia and talus; MRI showed cartilage injury in 22 cases. Arthroscopic intervention included removing osteophytes, debriding fabric scars and synovial membrane tissues, and removing osteochondral fragments. Arthroscopic microfracture technique was used in 22 patients with cartilage injury. RESULTS: All incisions healed primarily. Thirty-eight cases were followed up 10-26 months (mean, 16 months). At last follow-up, 26 patients had normal range of motion (ROM); the dorsal extension was 15-25 degrees (mean, 19.6 degrees) and the palmar flexion was 35-45 degrees (mean, 40.7 degrees). Eight patients had mild limited ROM; the dorsal extension was 5-15 degrees (mean, 7.2 degrees) and the palmar flexion was 35-45 degrees (mean, 39.5 degrees). Four patients had mild limited ROM and pain in posterior portion of the ankle after a long walking (3-4 hours); the dorsal extension was 0-5 degrees (mean, 2.6 degrees) and the palmar flexion was 35-40 degrees (mean, 37.5 degrees). The total score was 89.45 +/- 9.55 and the pain score was 1.42 +/- 1.26 after operation according to AOFAS ankle and hindfoot score system, showing significant differences when compared with preoperative ones (t=21.962, P=0.000; t=16.762, P=0.000). CONCLUSION: Arthroscopic treatment of ankle joint impingement syndrome after operation of ankle joint fracture dislocation is an effective, simple, and safe method. PMID- 21818938 TI - [Ankle arthrodesis by lateral malleolus osteotomy and internal fixation with locking proximal humeral plate]. AB - OBJECTIVE: To summarize the surgical technique of ankle arthrodesis using lateral malleolus osteotomy and locking proximal humeral plate internal fixation, and to evaluate the clinical effectiveness. METHODS: Between March 2009 and June 2010, 18 patients with ankle joint disease were treated, including 8 cases of post traumatic arthritis, 3 cases of rheumatoid arthritis, 5 cases of osteoarthritis, and 2 cases of post-traumatic necrosis of talus. There were 10 males and 8 females with an average age of 48 years (range, 36-67 years). The average disease duration was 3 years (range, 1-6 years). The main symptoms included swelling, pain, and a limited range of motion of the ankle. Four patients accompanied with ankle varus deformity and 2 patients with valgus deformity. According to American Orthopaedic Foot and Ankle Society (AOFAS) ankle and hindfoot score system, the preoperative score was 43.5 +/- 10.2. An ankle arthrodesis using lateral malleolus osteotomy and locking proximal humeral plate internal fixation was performed in all patients. RESULTS: Superficial wound infection and partial skin necrosis occurred in 1 case respectively, and were cured after symptomatic treatment; the other incisions healed by first intention without complications. Sixteen patients were followed up 16 months on average (range, 1-2 years). The X ray films showed that bone fusion was obtained at 8-16 weeks (mean, 12 weeks) after operation. The symptom was relieved completely in all patients at last follow-up without complication of implant failure, nonunion, and malunion. The postoperative AOFAS ankle and hindfoot score was 83.0 +/- 6.3, showing significant difference when compared with the preoperative score (t=26.20, P=0.00). CONCLUSION: Ankle arthrodesis using lateral malleolus osteotomy and locking proximal humeral plate internal fixation has the advantages of feasible technique, the rigid fixation, and high fusion rate, so it may obtain a good clinical effectiveness. PMID- 21818939 TI - [Treatment of occult Lisfranc injury with open reduction and internal fixation]. AB - OBJECTIVE: To evaluate the clinical effectiveness of open reduction and internal fixation in the treatment of occult Lisfranc injury. METHODS: Between July 2002 and July 2009, 47 patients with occult Lisfranc injuries underwent open reduction and internal fixation. There were 31 males and 16 females with an average age of 35.6 years (range, 19-66 years). Injuries were caused by traffic accident in 27 cases, falling from height in 11 cases, sport in 16 cases, and crush in 3 cases. The locations were left foot in 18 cases and right foot in 29 cases. Simple medial column was involved in 6 cases, medial and middle columns in 24 cases, middle and lateral columns in 13 cases, and three columns in 4 cases. Base fractures of metatarsal bone were identified in all cases. The time from injury to operation was 4-21 days (mean, 8.6 days). The unstable Lisfranc joints were reduced and fixed by plates, screws, staples, and Kirschner wire through 1 or 2 longitudinal dorsal incisions. RESULTS: One case had infection and wound was repaired with flap at 2 weeks after operation; the other wounds healed primarily. Thirty-two patients were followed up 28.3 months on average (range, 12-75 months). The mean time of fracture healing was 12.3 weeks (range, 9-15 weeks). Osteoarthritis at midfoot was found in 15 cases at last follow-up and arthrodesis was not needed. The results were excellent in 9 cases, good in 16 cases, fair in 4 case, and poor in 3 cases according to American Orthopaedic Foot and Ankle Society (AOFAS) midfoot score system; the excellent and good rate was 78.1%. No re-dislocation occurred during the follow-up. CONCLUSION: More attention should be paid to base fractures of metatarsal bone, operative exploration is conducive to diagnosis of occult Lisfranc injury. Suitable internal fixation should be selected according to injury type and concomitant injury. Anatomical reduction and stable fixation are the keys to reconstruct the joint stability in the initial treatment of occult Lisfranc injury. PMID- 21818940 TI - [Miniplate internal fixation and autogenous iliac bone graft in surgical treatment of old metatarsal fractures]. AB - OBJECTIVE: To summarize the experience of treating old metatarsal fractures with surgery methods of miniplate internal fixation and autogenous iliac bone. METHODS: Between May 2009 and July 2010, 7 patients with old metatarsal fractures were treated surgically, including 5 multi-metatarsal fractures and 2 single metatarsal fractures. There were 5 males and 2 females aged from 25 to 43 years (mean, 33 years). The time from fracture to operation was 4-12 weeks. The X-ray films showed that a small amount of callus formed at both broken ends with shortening, angulation, or rotation displacement. The surgical treatments included open reduction, internal fixation by miniplate, and autogenous iliac bone graft (1.5-2.5 cm(3)). The external plaster fixation was used in all patients for 4 to 6 weeks postoperatively (mean, 5 weeks). RESULTS: All incisions healed by first intention. The 7 patients were followed up 8-18 months (mean, 13.5 months). The clinical fracture healing time was 6 to 12 weeks postoperatively (mean, 8.4 weeks). No pain of planta pedis occurred while standing and walking. The American Orthopaedic Foot and Ankle Society (AOFAS) mesopedes and propodium score was 75-96 (mean, 86.4). CONCLUSION: It has the advantages of reliable internal fixation, high fracture healing rate, less complications to treat old metatarsal fractures with surgery methods of miniplate internal fixation and autogenous iliac bone graft, so it is an effective treatment method. PMID- 21818941 TI - [Treatment of mild or moderate hallux valgus by Austin osteotomy combined with lateral soft tissue release through a single medial incision]. AB - OBJECTIVE: To evaluate the primary clinical effectiveness of Austin metatarsal osteotomy combined with transection of adductor muscle and transverse metatarsal ligament for treating mild or moderate hallux valgus through a single medial incision. METHODS: Between May 2006 and January 2009, 41 patients (45 feet) with mild or moderate hallux valgus were treated. There were 9 males (10 feet) and 32 females (35 feet) with an average age of 45.3 years (range, 23-71 years). The hallux valgus angle (HVA) was (33.1 +/- 1.4) degrees, and the first and second inter-metatarsal angle was (20.4 +/- 1.1) degrees. The American Orthopaedic Foot and Ankle Society (AOFAS) ankle and hindfoot score of the affected foot's function was 47.2 +/- 3.7. A longitudinal medial incision was made at the first metatarsophalangeal joint. By the incision, Austin metatarsal osteotomy and lateral soft tissue release (including transection of adductor muscle and the transverse metatarsal ligament) were performed at the same time. RESULTS: During operation, 1 case had superficial peroneal nerve branch injury and suture repair was done microsurgically. All incisions healed by first intention postoperatively. All patients were followed up 16-36 months (mean, 26 months). Medial forefoot numbness occurred in 2 feet at 3 days after operation and relieved within 6 weeks. The X-ray films showed bone healing at osteotomy site within 8 weeks after operation. At last follow-up, the HVA was (10.7 +/- 1.7) degrees, showing significant difference when compared with preoperative value (t=22.32, P=0.00), and the first and second inter-metatarsal angle was (12.1 +/- 1.7) degrees, also showing significant difference when compared with preoperative value (t=21.17, P=0.03). The postoperative AOFAS ankle and hindfoot score of the affected foot's function was 84.9 +/- 4.5, showing significant difference when compared with preoperative score (t=20.75, P=0.01). No foot hallux varus, hallux valgus, or metatarsal necrosis occurred during follow-up. CONCLUSION: The Austin metatarsal osteotomy combined with transection of adductor muscle, transverse metatarsal ligament through a single medial incision can effectively correct the mild or moderate hallux valgus, and avoid the scar and injury of deep peroneal nerve branches by traditional lateral incision. PMID- 21818942 TI - [Reconstruction of chronic Achilles tendon rupture with flexor hallucis longus tendon harvested using a minimally invasive technique]. AB - OBJECTIVE: To evaluate the effectiveness of flexor hallucis longus tendon harvested using a minimally invasive technique in reconstruction of chronic Achilles tendon rupture. METHODS: Between July 2006 and December 2009, 22 patients (22 feet) with chronic Achilles tendon rupture were treated, including 16 males and 6 females with a median age of 48 years (range, 28-65 years). The disease duration was 27-1,025 days (median, 51 days). Twenty-one patients had hooflike movement's history and 1 patient had no obvious inducement. The result of Thompson test was positive in 22 cases. The score was 53.04 +/- 6.75 according to American Orthopedic Foot and Ankle Society (AOFAS) ankle and hindfoot score system. MRI indicated that the gap of the chronic Achilles tendon rupture was 4.2 8.0 cm. A 3 cm-long incision was made vertically in the plantar aspect of the midfoot and a 1 cm-long transverse incision was made in a plantar flexor crease at the base of the great toe to harvest flexor hallucis longus tendon. The flexor hallucis longus tendon was 10.5-13.5 cm longer from tuber calcanei to the end of the Achilles tendon, and then the tendon was fixed to the tuber calcanei using interface screws or anchor nail after they were woven to form reflexed 3-bundle and sutured. RESULTS: Wound healed by first intention in all patients and no early complication occurred. Twenty-two patients were followed up 12-42 months (mean, 16.7 months). At 12 months after operation, The AOFAS ankle and hindfoot score was 92.98 +/- 5.72, showing significant difference when compared with that before operation (t= -40.903, P=0.000). The results were excellent in 18 cases, good in 2 cases, and fair in 2 cases with an excellent and good rate of 90.9%. No sural nerve injury, posterior tibial nerve injury, plantar painful scar, medial plantar nerve injury, and lateral plantar nerve injury occurred. CONCLUSION: Chronic Achilles tendon rupture reconstruction with flexor hallucis longus tendon harvested using a minimally invasive technique offers a desirable outcome in operative recovery, tendon fixation, and complications. PMID- 21818943 TI - [Comparison study on different flaps in repairing defect caused by resection of cutaneous malignant melanoma in the heel region]. AB - OBJECTIVE: To compare the clinical effectiveness of the medial plantar flap, the retrograde posterior tibial vascular flap, and the reverse sural neurocutaneous flap in repairing defect caused by resection of cutaneous malignant melanoma (CMM) in the heel region. METHODS: The clinical data were retrospectively analysed from 24 patients with defect who had CMM in the heel region and were treated by radical excision and flap repairing between March 2007 and March 2010. Defects were repaired with the reverse sural neurocutaneous flaps of 8 cm x 7 cm 14 cm x 12 cm at size in 12 patients (group A), with the medial plantar flaps of 6 cm x 5 cm-8 cm x 7 cm at size in 7 patients (group B), and with the retrograde posterior tibial vascular flaps of 9 cm x 7 cm-15 cm x 13 cm at size in 5 patients (group C). There was no significant difference in gender, age, duration of illness, clinical stage, and size of CMM among 3 groups (P > 0.05). The donor site was sutured directly or by free skin graft. RESULTS: No significant difference was found in the operation time and the intraoperative blood loss among 3 groups (P > 0.05). All skin flaps or grafts survived and wounds healed by first intention. The patients were followed up 1-3 years. The flaps had normal texture and color with no ulcer in 3 groups. At 1 year after operation, the sensory recovery rates of the flaps were 0, 100%, and 20% in groups A, B, and C, respectively, showing significant difference among 3 groups (P=0.001). The patients had normal appearance of heel and pain-free walking [10 (83%) in group A, 6 (86%) in group B, and 4 (80%) in group C] of heel region, showing no significant difference among 3 groups (Chi(2)=40.000, P=0.135). Heel pain existed in weightbearing walking of 3 groups, and there were significant differences in visule analogue scale (VAS) score (P < 0.05). There was no significant difference in range of motion of ankle joint among 3 groups (P > 0.05). Except 1 patient of relapse in group A at 1 month after operation, no relapse was observed in the other patients during follow-up. CONCLUSION: The medial plantar flap, the retrograde posterior tibial vascular flap, and the reverse sural neurocutaneous flap can achieve the good clinical effectiveness in treating heel defect caused by the resection of CMM. And the medial plantar flap is the first choice in small skin defect of heel area. PMID- 21818944 TI - [Conservative dressing change method in treatment of skin necrosis after open reduction with internal fixation of calcaneal fracture]. AB - OBJECTIVE: To explore the effectiveness of conservative dressing change method in treating skin necrosis after open reduction with internal fixation (ORIF) of calcaneal fracture. METHODS: Between November 2007 and June 2010, 21 cases of skin necrosis after ORIF of calcaneal fracture were treated, including 18 cases of Sanders type II and 3 cases of Sanders type III. There were 20 males and 1 female with an average age of 33.1 years (range, 23-60 years). All fractures were close fractures and were treated by ORIF with plate. Skin necrosis occurred at 3 5 days (mean, 4 days) after internal fixation. The interval of internal fixation and conservative dressing change was 3-10 days (mean, 6 days). Of 21 cases, 10 cases had superficial skin necrosis with a size range of 1-10 cm in length and 0.5-1.5 cm in width, and 11 cases had deep skin necrosis with a size range of 1-8 cm in length and 0.5-1.5 cm in width. The conservative dressing change method was performed. Alcohol (75%) was used at the edge of the zone of skin necrosis, whereas saline in the central of the wound every 2-3 days. The necrosed tissue in the wound was reserved as more as possible. No patient was given antibiotic. RESULTS: Scab formed and subcrust healing was observed after 6-30 days (mean, 16 days) in 20 patients, 1 patient failed for discontinue treatment. No case had deep infection or osteomyelitis. The mean treatment time was 7.8 days (range, 6 14 days) in 10 cases of superficial skin necrosis, and was 23.1 days (range, 14 30 days) in 10 cases of deep skin necrosis. All cases were followed up 92 days on average (range, 54-123 days). The scar was usually dark red and hard, protruding from the normal skin. No patient had difficulty in weight bearing or walking. CONCLUSION: Skin necrosis after ORIF of calcaneal fracture can be cured by the conservative dressing change method, and this conservative method is effective and economic. PMID- 21818945 TI - [Clinical application of abductor digiti minimi muscle flap]. AB - OBJECTIVE: To discuss the surgery procedure and the clinical effectiveness of repairing skin and soft tissue defects in the lateral foot and the heel with the abductor digiti minimi muscle flap. METHODS: Between July 2002 and October 2010, 8 patients with skin and soft tissue defects in the lateral foot and the heel were treated. There were 6 males and 2 females with an average age of 42 years (range, 28-65 years). The locations were the left foot in 5 cases and the right foot in 3 cases. Defects were caused by ulcer of the heel in 2 cases, by poor healing of incision after calcaneus fracture surgery in 1 case, and by crushing in 5 cases. The defect size ranged from 1.5 cmx 1.0 cm x 8.0 cm x 2.6 cm. The disease duration was 30 minutes to 26 months. The result of bacterial culture was positive in 2 cases. After 9 to 15 days of debridement and dressing change, defects were repaired with the abductor digiti minimi muscle flap of 5.6 cm x 1.5 cm to 7.6 cm x 1.8 cm at size. The donor site were sutured directly. RESULTS: Partial necrosis of muscle flap occurred in 1 case at 4 days after operation, which was cured by symptomatic treatment, and the other muscle flaps survived. All incisions of the donor sites healed by first intention. The muscle flaps survived and the granulation grew well at 9-21 days after operation, and the muscle flap wounds were repaired by free leg edge thickness skin grafting. Wounds were repaired by one-stage free skin grafting in 1 case and by two-stage free skin grafting in 7 cases; all skin flaps survived and wounds healed by first intention. Seven patients were followed up 9-18 months (mean, 11 months). The appearance, texture, and sensation were satisfactory. The two-point discrimination was 16-23 mm (mean, 19.5 mm). Epidermal abrasion occurred in 1 case of heel ulcer after weigt-bearing walking. Hallux valgus and muscle weakness occurred in 1 case of necrosis of the peroneus length tendons; and the satisfactory results were achieved in the other patients. CONCLUSION: It has satisfactory effectiveness to use the abductor digiti minimi muscle flap for repairing skin and soft tissue defects in the lateral foot and the heel, which has the advantages of easy-to-operate, safe, less injury at donor site, good appearance and texture, and good recovery of sensation. PMID- 21818946 TI - [Modified retrograde rotative-type interlocking intramedullary nail for humeral shaft fractures]. AB - OBJECTIVE: To improve the retrograde rotative-type interlocking intramedullary nail based on humeral bone dissection and clinical application, and investigate the clinical values of modified retrograde rotative-type interlocking intramedullary nail for humeral shaft fracture. METHODS: Between March 2006 and March 2010, 146 patients with humeral shaft fractures were treated and fractures were fixed with the modified retrograde rotative-type interlocking intramedullary nail (the modified group, n=73) and with the retrograde rotative-type interlocking intramedullary nail (the original group, n=73). In the original group, there were 40 males and 33 females with an average age of 41 years; 41 cases were classified as transverse fracture, 18 as oblique fracture, 8 as spiral fracure, and 6 as comminuted fracture; the median disease duration was 11 days (range, 3 hours to 2 months); and close reduction fixation was performed in 27 cases and open reduction fixation in 46 cases. In the modified group, there were 39 males and 34 females with an average age of 40 years; 43 cases were classified as transverse fracture, 16 as oblique fracture, 10 as spiral fracure, and 4 as comminuted fracture; the median disease duration was 13 days (range, 3 hours to 3 months); and close reduction fixation was performed in 31 cases and open reduction fixation in 42 cases. There was no significant difference in sex, age, fracture type, and disease duration between 2 groups (P > 0.05). The fracture healing and functional recovery of affected limbs were compared between 2 groups after operation. RESULTS: The operation time and intraoperative blood loss in the modified group were significantly less than those in the original group (P < 0.05). Iatrogenic fracture occurred in 3 cases of the original group, which were cleavage fracture of supracondylar. No iatrogenic fracture occurred in the modified group. All incisions of 2 groups healed by first intention without complications of postoperative infections, metal fracture, and loosening of internal fixation, etc. A total of 116 patients were followed up more than 12 months in 2 groups with 58 patients in each group. The fracture healing time was (15 +/- 3) weeks (fresh fracture) and (30 +/- 12) weeks (old fracture and nonunion) in the modified group, and was (16 +/- 4) weeks (fresh fracture) and (35 +/- 14) weeks (old fracture) in the original group, showing significant differences between 2 groups (P < 0.05). The results of Neer shoulder score were excellent in 65 cases and good in 8 cases, and the results of Aitken and Rorabeck elbow function score were excellent in 61 cases and good in 12 cases in the original group; the results of Neer shoulder score were excellent in 67 cases and good in 6 cases, and the results of Aitken and Rorabeck elbow function score were excellent in 63 cases and good in 10 cases; and the excellent and good rates were 100% in 2 groups. CONCLUSION: The modified retrograde rotative-type interlocking intramedullary nail has the advantages of easy operation and less complication, which is an effective and reliable internal fixator. PMID- 21818947 TI - [Operation via anterior approach in treating pelvic crescent fracture]. AB - OBJECTIVE: To evaluate the effectiveness of operation via anterior approach in treating pelvic crescent fracture. METHODS: Between June 2007 and December 2009, 18 patients with pelvic crescent fracture were treated, including 11 males and 7 females with an average age of 32 years (range, 19-52 years). The locations were the right in 8 cases and the left in 10 cases. Fractures were caused by traffic accident in 10 cases, by falling from height in 5 cases, and by crushing with heavy weights in 3 cases. All patients suffered lateral compression injuries of the pelvis. The mean time from injury to operation was 7.8 days (range, 3-22 days). The preoperative mean displacement of the posterior pelvic ring was 13.7 mm (range, 5-24 mm) according to the method described by Matta et al. The operation time, intraoperative blood loss, displacement correction of the posterior pelvic ring, fracture healing time, and Hannover pelvic score were recorded. RESULTS: The average operation time was 175 minutes (range, 110-230 minutes); the average intraoperative blood loss was 561.7 mL (range, 300-1,100 mL); the postoperative mean displacement of the posterior pelvic ring was 1.2 mm (range, 0-3 mm); and the mean displacement correction of the posterior pelvic ring was 12.6 mm (range, 4-23 mm). No intraoperative lumbosacral nervous injury occurred. Superficial wound infection occurred in 2 cases and was cured after 1 week of wound drainage and application of antibiotic. The others achieved healing of incision by first intention. Fifteen patients were followed up 16.1 months on average (range, 13-22 months). The X-ray films showed fracture healing in all patients. The fracture healing time was 3.6 months on average (range, 3-4 months). No patient had loss of reduction or failure of internal fixation. The clinical outcome was excellent in 10 cases (66.7%) and good in 5 cases (33.3%) according to Hannover pelvic score; social reintegration was complete in 13 cases (86.7%) and incomplete in 2 cases (13.3%). CONCLUSION: Operation via anterior approach is a good choice in the treatment of pelvic crescent fracture. PMID- 21818948 TI - [Treatment of adult developmental dysplasia of the hip by rotational acetabular osteotomy combined with debridement under arthroscope]. AB - OBJECTIVE: To evaluate the results of rotational acetabular osteotomy (RAO) combined with debridement under arthroscope in the treatment of adult developmental dysplasia of the hip (DDH). METHODS: Between April 2002 and August 2007, 24 cases (29 hips) of DDH were treated with RAO combined with debridement under arthroscope. There were 2 males (2 hips) and 22 females (27 hips) with an average age of 37.7 years (range, 21-50 years). The locations were the left hip in 7 cases, the right hip in 12 cases, and both hips in 5 cases. The course of hip pain was 8-216 months (median, 30.5 months). According to Crowe DDH classification, there were 24 hips of type I and 5 hips of type II. According to Tonnis hip osteoarthritis classification, there were 20 hips of stage I and 9 hips of stage II. RESULTS: The mean operation time was 150 minutes (range, 120 180 minutes); the mean intraoperative blood loss was 600 mL (range, 500-700 mL); and the mean postoperative drainage volume was 200 mL(range, 50-400 mL). All incisions healed by first intention. Twenty-four cases were followed up 4.5 years on average (range, 3-8 years). At last follow-up, claudication disappeared in 16 hips and was improved in 8 hips. The Harris hip score was improved from 79.4 +/- 9.8 preoperatively to 95.1 +/- 8.6 postoperatively, showing significant difference (t=2.467, P=0.010). The visual analogue scale (VAS) score was improved from 5.1 +/- 0.8 preoperatively to 1.1 +/- 0.6 postoperatively, showing significant difference (t=2.118, P=0.011). The X-ray films showed union was achieved at 12-16 weeks (mean, 13.5 weeks). There were significant differences in the centre edge angle, Sharp angle, acetabular coverage rate, and acetabulum-head index between preoperation and postoperation (P < 0.05). Twenty hips at Tonnis stage I maintained after operation, among 9 hips at Tonnis stage II, 5 hips was improved to stage I and 4 hips maintained. CONCLUSION: It has a satisfactory result to treat adult DDH by RAO combined with debridement under arthroscope, which may increase the congruency of hip joint, delay or prevent the progression of hip osteoarthritis. PMID- 21818949 TI - [Repair of soft tissue defects of lower extremity by using cross-bridge contralateral distally based posterior tibial artery perforator flaps or peroneal artery perforator flaps]. AB - OBJECTIVE: To discuss the feasibility of repairing soft tissue defects of lower extremity with a distally based posterior tibial artery perforator cross-bridge flap or a distally based peroneal artery perforator cross-bridge flap. METHODS: Between August 2007 and February 2010, 15 patients with soft tissue defect of the legs or feet were treated. There were 14 males and 1 female with a mean age of 33.9 years (range, 25-48 years). The injury causes included traffic accident in 8 cases, crush injury by machine in 4 cases, and crush injury by heavy weights in 3 cases. There was a scar (22 cm x 8 cm at size) left on the ankle after the skin graft in 1 patient (after 35 months of traffic accident). And in the other 14 patients, the defect locations were the ankle in 1 case, the upper part of the lower leg in 1 case, and the lower part of the lower leg in 12 cases; the defect sizes ranged from 8 cm x 6 cm to 26 cm x 15 cm; the mean interval from injury to admission was 14.8 days (range, 4-28 days). Defects were repaired with distally based posterior tibial artery perforator cross-bridge flaps in 9 cases and distally based peroneal artery perforator cross-bridge flaps in 6 cases, and the flap sizes ranged from 10 cm x 8 cm to 28 cm x 17 cm. The donor sites were sutured directly, but a split-thickness skin graft was used in the middle part. The pedicles of all flaps were cut at 5-6 weeks postoperatively. RESULTS: Distal mild congestion and partial necrosis at the edge of the skin flap occurred in 2 cases and were cured after dressing change, and the other flaps survived. After cutting the pedicles, all flaps survived, and wounds of recipient sites healed by first intention. Incisions of the donor sites healed by first intention, and skin graft survived. Fifteen patients were followed up 7-35 months with an average of 19.5 months. The color and texture of the flaps were similar to these of the recipient site. According to American Orthopaedic Foot and Ankle Society (AOFAS) ankle and hindfoot score system, the mean score was 87.3 (range, 81-92). CONCLUSION: A distally based posterior tibial artery perforator cross-bridge flap or a distally based peroneal artery perforator cross-bridge flap is an optimal alternative for the reconstruction of the serious tissue defect of contralateral leg or foot because of no microvascular anastomosis necessary, low vascular crisis risk, and high survival rate. PMID- 21818950 TI - [Vancomycin-loaded bioactive borate glass for treatment of chronic osteomyelitis in rabbits]. AB - OBJECTIVE: Bioactive borate glass (BG) has good biocompatibility and biodegradation. To investigate the feasibility of bioactive borate glass as a carrier of the antibiotic controlled-releasing by implanting vancomycin-loaded BG (VBG) into the focus of tibia chronic osteomyelitis after debridement. METHODS: VBG and vancomycin-loaded calcium sulfate (VCS) were prepared with a vancomycin content of 80 mg/g. Sixty-five New Zealand white rabbits, weighing 2.12-3.91 kg (mean, 2.65 kg), were used. The tibia chronic osteomyelitis rabbit models were established by injecting methicillin-resistant Staphylococcus aureus (MRSA, 0.1 mL, 1 x 10(9) cfu/mL) into the right tibia of 65 rabbits. After 3 weeks of injection, 54 rabbits of successful models were randomly divided into groups A (n=11), B (n=11), C (n=16), and D (n=16). Simple debridement was performed in group A; BG, VCS, and VBG were implanted into the infection sites of groups B, C, and D respectively after thorough debridement. A sample of the debrided tissues was harvested for bacterial examination. The vancomycin serum levels were determined in groups C and D at 1, 2, 4, 10, 24, and 48 hours after operation. The boron serum levels were determined in groups B and D at 10, 24, 48, 72, and 120 hours after operation. After 8 weeks, the effectiveness was assessed radiographically, bacteriologically, and histopathologically. RESULTS: Ten rabbits died after operation. No vancomycin was detected in group C; the vancomycin level increased gradually, reached the highest level at 4 hours after operation, and then decreased rapidly in group D. No boron was detected in group B; the boron reached the highest serum level at 10 hours after operation, and then decreased gradually in group D. At 8 weeks, calcium sulfate degraded in group C; BG degraded partially in group D; and no obvious degradation was observed in group B. The repair effect was better in group D than in group C. There was no significant difference in radiograph scoring between groups A, B, C and D (P > 0.05) before operation, but there was significant difference between group D and groups A, B, C (P < 0.05) at 8 weeks after operation. The bacterial culture showed that all the MRSA results were positive in 4 groups. At 8 weeks, the negative rates of MRSA examination were 36.36%, 18.18%, 73.33%, and 81.25% respectively in groups A, B, C, and D, showing significant differences between group D and groups A, B (P < 0.05). The histopathological observation showed that a large number of new bones formed and no foreign body reaction occurred in group D. The histopathologic scores of groups A, B, C, and D were 6.45 +/- 3.62, 7.55 +/- 3.36, 4.27 +/- 2.91, and 3.81 +/- 3.04 respectively, showing significant differences between group D and groups A, B, and between group C and group B (P < 0.05). CONCLUSION: VBG can improve the repair of bone defect in the treatment of chronic osteomyelitis. PMID- 21818951 TI - [Effects of bone marrow mesenchymal stem cells transplantation on expression of vascular endothelial growth factor gene and angiogenesis after spinal cord injury in rats]. AB - OBJECTIVE: To investigate the effect of bone marrow mesenchymal stem cells (BMSCs) transplantation on the motor function recovery, the expression of vascular endothelial growth factor (VEGF) gene, and angiogenesis after spinal cord injury (SCI) in rats, and to explore the treatment mechanism of BMSCs in SCI. METHODS: BMSCs were isolated and cultured from the marrow of 5 Wistar rats (4 weeks old) and the 3rd-4th passage cells were prepared for the experiment. A total of 87 adult female Wistar rats (weighing 220-250 g) were randomly divided into 3 groups: sham-operated group (group A, n=21), DMEM group (group B, n=33), BMSCs group (group C, n=33). A laminectomy was only performed at T8-10 levels in group A. The SCI models were established by modified Nystrom's compression method in groups B and C, and BMSCs and DMEM were injected in groups B and C respectively at 30 minutes after SCI. Basso-Beattie-Bresnahan (BBB) score was used for the motor function recovery at 3, 7, 14, and 28 days, RT-PCR for the VEGF mRNA at 1, 3, and 5 days, and immunohistochemical staining for angiogenesis at 3, 7, 14, and 28 days. RESULTS: In groups B and C, the hindlimb locomotor function was improved at different degrees with time, showing significant difference in BBB score between groups B, C and group A (P < 0.05). At 28 days, the BBB score in group C was significantly higher than that in group B (P < 0.05) and there was no significant difference between groups B and C (P > 0.05) at 3, 7, and 14 days after transplantation. The numbers of microvessels in the ventral horns of gray matter around SCI in groups B and C were significantly lower than that in group C (P < 0.05) at 3 days, but there was no significant difference at 7, 14, and 28 days after transplantation (P > 0.05). There was no significant difference in the number of microvessels between group C and group B (P > 0.05) at 3 and 7 days, but the number of microvessels in group C was significantly higher than that in group B (P < 0.05) at 14 and 28 days after transplantation. However, there was no significant difference in the number of microvessels in the white matter around SCI in 3 groups at different time points after transplantation (P > 0.05). The RT-PCR results showed that VEGF mRNA expressed at a low level in group A. Compared with group A, the expression level of VEGF mRNA in groups B and C increased at 1 day and reached the peak at 3 days, then decreased at 5 days after transplantation; and the expression of VEGF mRNA was significantly higher in groups B and C than in group A (P < 0.05), and in group C than in group B (P < 0.05) at 1, 3, and 5 days. CONCLUSION: BMSCs may promote the motor function recovery by up-regulating VEGF mRNA expression and increasing angiogenesis in the spinal cord after SCI in rats. PMID- 21818952 TI - [Involvement of human amniotic fluid colony derived stem cells in regeneration of mouse injured muscle]. AB - OBJECTIVE: To study whether human amniotic fluid colony derived stem cells (hAFCSCs) are involved in regeneration of injured muscles in mice and to investigate the method and feasibility of hAFCSCs-based cytotherapy in the treatment of injured muscles. METHODS: s Human second-trimester amniotic fluid was collected through ultrasound-guided amniocentesis, hAFCSCs were isolated from second-trimester amniotic fluid and cultured, and the cells at 6th-8th passages were spared. The mRNA was extracted to identify the stem cell related genes by RT PCR. The muscular injury model of bilateral tibialis anterior muscle was established by cardiotoxin and X-ray irradiation in 16 Nod/Scid mice (aged 6-8 weeks, and weighing 20-24 g). The hAFCSCs (3.3 x 1(0)7/mL, 3 microIL) were injected into the right injured tibialis anterior muscles as the experimental group, while the same volume of complete medium (lphaa-MEM containing 15%FBS, 18%Chang B, 2%Chang C, 1% penicillin-streptomycin, and 1% L-glutamine) was injected into the left injured tibialis anterior muscles as the control group. At 2 and 4 weeks after cell transplantation, the immunofluorescence staining of tibialis anterior muscles was performed to detect hepatocyte growth factor receptor (c-Met), myogenic regulatory factor (Myf-5), Laminin, Desmin, and human specific nuclear mitotic apparatus protein (NuMa). RESULTS: s The clone formation was observed at 5-7 days of primary hAFCSCs culture; after 8-10 days, the clones with homogeneous morphology were selected for subculture. Adequate stem cells were available after 6th-8th subculture. RT-PCR analysis showed that hAFCSCs expressed mRNA of the stem cell related genes. The immunofluorescence double staining showed that NuMa expressed in tibialis anterior muscles of the experimental group and no myogenic phenotype expressed at 2 weeks after cell transplantation, and that single cell co-expressed NuMa and c-Met or Myf-5 at 4 weeks after cell transplantation. In some myofibers, NuMa and Laminin or Desmin were also co-expressed. No NuMa positive hAFCSCs were detected in the control group at 2 and 4 weeks after cell transplantation. CONCLUSION: n hAFCSCs can participate in the regeneration of injured mouse muscle. PMID- 21818953 TI - [Expression of human bone morphogenetic protein 7 gene in adipose-derived stem cells and its effects on osteogenic phenotype]. AB - OBJECTIVE: To construct the eukaryotic expression vector of human bone morphogenetic protein 7 (hBMP-7) gene so as to observe its expression in rabbit adipose-derived stem cells (ADSCs) and its effects on osteogenic phenotype. METHODS: Several healthy 3-month-old Japanese rabbits of clean grade were chosen, female or male and weighing 3-4 kg. ADSCs were isolated and cultured with collagenase digestion, then were detected and identified by CD44, CD49d, and CD106 immunofluorescence staining. The eukaryotic expression vector of hBMP-7 gene (pcDNA3.1-hBMP-7) was constructed, which was transfected into rabbit ADSCs (3rd passage) by Lipofectamine 2000 after identified, then the expression of hBMP 7 in transfected ADSCs was detected. The alkaline phosphatase (ALP) level and the collagen type I expression were detected by intracellular ALP spectrophotometry and immunofluorescence, respectively to assess the effect of hBMP-7 gene on the osteoblastic differentiation of ADSCs. RESULTS: ADSCs mostly presented fusiform and polygon shape with positive expressions of CD44 and CD49d and negative expression of CD106. The eukaryotic expression vector of pcDNA3.1-hBMP-7 gene was successfully constructed and the expression of hBMP-7 was confirmed in ADSCs by immunohistochemical staining. The intracellular ALP quantitative detection showed that the activity of ALP was significantly higher in pcNDA3.1-hBMP-7 transfected group (experimental group) than in pcDNA3.1 transfected group (control group) at 7, 10, and 14 days after transfection (P < 0.05). The expression of collagen type I was higher in experimental group than in control group at 7 and 14 days after transfection (P < 0.05). CONCLUSION: The eukaryotic expression vector of pcDNA3.1 hBMP-7 gene is successfully constructed, which can express in ADSCs. The expressions of collagen type I and ALP in experimental group are higher than those in control group, which lays a basis for the local gene therapy of skeletal regeneration. PMID- 21818954 TI - [Research and application progress of adipose-derived stem cells]. AB - OBJECTIVE: To review the biochemical characteristics, application progress, and prospects of the adipose-derived stem cells (ADSCs). METHODS: The recent original experimental and clinical literature about ADSCs was extensively reviewed and analyzed. RESULTS: ADSCs can be readily harvested in large numbers from adipose tissue with properties of stable proliferation and potential differentiation in vitro. Significant progress of ADSCs is made in the animal experiment and the clinical application. It has been widely used in the clinical treatment of cardiovascular disease, metabolic disease, encephalopathy, and tissue engineering repair. CONCLUSION: ADSCs have gradually replaced bone marrow mesenchymal stem cells and become the focused hot spot of regenerative medicine and stem cells. PMID- 21818955 TI - [Application of collagen composite scaffold in vascular tissue engineering]. AB - OBJECTIVE: To review the application of collagen and biodegradable polymer composite scaffolds in vascular tissue engineering, and describe the multi layering vascular scaffolds of collagen-based material in recent years. METHODS: The literature concerning collagen composite scaffold production for scaffold of vascular tissue engineering was extensively reviewed and summarized. RESULTS: As one of the structural proteins in natural blood vessel, collagen is widely used in vascular tissue engineering because of good biocompatibility, biodegradability, and cell recognition signal. The vascular scaffolds with biological activity and good mechanical properties can be made by collagen polymer composite materials. In addition, the structure and function of the natural blood vessel can be better simulated by multi-layering vascular scaffolds. CONCLUSION: Collagen-polymer composite material is the hot spot in the research of vascular scaffolds, and multi-layering vascular scaffolds have a brilliant future. PMID- 21818956 TI - [Vaginal reconstruction with tissue engineering technology]. AB - OBJECTIVE: To summarize the research and development of vaginal reconstruction with tissue engineering technology. METHODS: The recent literature concerning vaginal reconstruction with tissue engineering technology at home and abroad was extensively reviewed and the research and development were summarized. RESULTS: Tissue engineering provides an ideal material as the inner tissue in vaginoplasty. The reconstructed tissue closely resembles native vaginal tissue in the cellular organization and physical properties. The clinical use of the tissue engineered vagina in vaginoplasty can not be harmful to an organism, and the neovagina has sufficient length and depth. However, the long-term follow-up is needed. CONCLUSION: Vaginal reconstruction with tissue engineering technology may have good application prospects, but further research is required. PMID- 21818957 TI - [Research progress of nucleus pulposus cells phenotypic markers]. AB - OBJECTIVE: To review the research progress of nucleus pulposus cells phenotypic markers. METHODS: The domestic and international literature about nucleus pulposus cells phenotypic markers was reviewed extensively and summarized. RESULTS: Due to different biomechanical properties, nucleus pulposus cells and articular chondrocytes have differences in morphology and extracellular components such as the ratio of aggrecan to collagen type II alpha1. Nucleus pulposus cells can be identified by surface marker (CD24), gene markers (hypoxia inducible factor 1alpha, glucose-transporter protein 1, matrix metalloproteinase 2, vascular endothelial growth factor A, etc), and various markers (keratin 19 and glypican 3, paired box 1, forkhead box F1 and integrin-binding sialoprotein, etc). CONCLUSION: Nucleus pulposus cells and articular chondrocytes have different phenotypic markers, but nucleus pulposus cells are still lack of specific markers. PMID- 21818958 TI - [Effect of human hepatocyte growth factor gene-modified bone marrow mesenchymal stem cells on immunological rejection after allograft liver transplantation in rats]. AB - OBJECTIVE: To study the effect of recombinant lentiviral vector mediated human hepatocyte growth factor (hHGF) gene-modified bone marrow mesenchymal stem cells (BMSCs) on the immunological rejection after allograft liver transplantation in rats, and to reveal the mechanism of immune tolerance. METHODS: Eight male Sprague Dawley (SD) rats of clean grade (aged 3 to 4 weeks, weighing 75-85 g) were selected for the isolation and culture of BMSCs; 64 adult male SD rats of clean grade (weighing 200-250 g) were used as donors; and 64 adult male Wistar rats of clean grade (weighing 230-280 g) were used as receptors. After establishing a stable model of rat allogeneic liver transplantation, 1 mL saline, 2 x10(6)/mL of BMSCs 1 mL, 2 x 106/mL of BMSCs/green fluorescent protein 1 mL, and 2 x 10(6)/mL of BMSCs/hHGF 1 mL were injected via the portal vein in groups A, B, C, and D respectively. Then the survival time of the rats was observed. The hepatic function was determined and the histological observation of the liver was performed. The hHGF mRNA expression was detected by RT-PCR, the level of cytokine including hHGF, interleukin 2 (IL-2), IL-4, IL-10, and interferon gamma (IFN gamma) by ELISA assay, the level of apoptosis by TUNEL method, and the expression level of proliferating cell nuclear antigen (PCNA) by immunohistochemical method. RESULTS: The survival time of group D was significantly higher than that of groups A, B, and C (P < 0.01); the survival time of groups B and C was significantly higher than that of group A (P < 0.01), but there was no significant difference between group B and group C (P > 0.05). RT-PCR demonstrated the transcription of hHGF mRNA in the grafts of group D; the serum cytokine hHGF reached to (6.2 +/- 1.0) ng/mL. Compared with groups B and C, group D exhibited significant inhibitory effect, significantly improved liver function, and showed mild acute rejection. In addition, the levels of cytokine IL-2 and IFN gamma decreased; the levels of cytokine IL-4 and IL-10 increased; the level of apoptosis reduced; and the expression level of PCNA increased. Except for the expression of IL-4 (P > 0.05), there were significant differences in the other indexes between group D and groups B, C (P < 0.05). CONCLUSION: BMSCs/hHGF implanting to rat liver allograft via portal vein can induce immune tolerance. Compared with injection of BMSCs alone, BMSCs/hHGF treatment can alleviate acute rejection and prolong the survival time significantly. The immunosuppressive effect of BMSCs/hHGF is correlated with Th2 shifts up of Th1/Th2 shift, reduced apoptosis, promoted liver regeneration. PMID- 21818959 TI - [Comparative study on repairing rabbit radius segmental defects with two different proportions of chitosan combined with allogeneic morselized bone]. AB - OBJECTIVE: To give a preliminary experimental evidence and to prove chitosan and allogeneic morselized bone as potential bone substitutions in repairing rabbit radius segmental defect. METHODS: Chitosan and allogeneic morselized bone were mixed with various ratios (1:5, 1:10, 1:25, 1:50, and 1:100). After preparation, the physical and chemical properties of the composites were preliminary detected; the composites at the ratios of 1:50 and 1:25 had good physical and chemical properties and were used for the animal experiment. The radius segmental defects of 15 mm in length were made in 50 adult New Zealand white rabbits (weighing 2.5 3.0 kg), then the animals were divided into 2 groups. In groups A and B, chitosan/allogeneic morselized bone composites were implanted at the ratio of 1:50 and 1:25, respectively. After 1, 2, 4, 8, and 12 weeks of operation, the gross, histological, immunohistochemical observations were performed. Before the rabbits were sacrificed, X-ray films were taken; the serum calcium and alkaline phosphatase (ALP) concentration were measured; and the biomechanical measurement was carried out at 12 weeks. RESULTS: The results of gross observation were essentially consistent with those of the X-ray films. The histological observation showed that the bone formation was earlier in group A than in group B; the amount of new bone formation in group A was more than that in group B; and the bone forming area in group A was bigger than that in group B (P < 0.05) at 4 and 8 weeks after operation. The immunohistochemical staining showed that vascular endothelial growth factor and insulin-like growth factor receptor II proteins expressed in the cytoplasm of 2 groups after 4 and 8 weeks, and the expression in group A was higher than that in group B (P < 0.05). There was no significant difference in the serum calcium concentration between 2 groups at each time point (P > 0.05). After 4 and 8 weeks, the ALP concentration in group A was significantly higher than that in group B (P < 0.05). After 12 weeks, the radius maximum bending loads of groups A and B were (299.75 +/- 27.69) N and (278.54 +/- 17.09) N, respectively, showing significant difference (t=4.045, P=0.002). CONCLUSION: The composite of chitosan and allogeneic morselized bone has good osteogenic activity and can be used as a bone tissue engineering scaffold, and the optimum ratio of chitosan to allogeneic morselized bone was 1:50. PMID- 21818960 TI - [Porcine acellular dermal matrix for repair of abdominal wall defects in rabbit model]. AB - OBJECTIVE: To research the effect of porcine acellular dermal matrix in the reconstruction of abdominal wall defects in rabbits, and to investigate the application feasibility of xeno-transplantation of acellular dermal matrix. METHODS: The porcine acellular dermal matrix was prepared from a health white pig. Twenty-six Japanese white rabbits (weighing 2.2-2.3 kg, female or male) were randomly assigned to 2 groups: the control group (n=6) and the experimental group (n=20). In the control group, the full-thickness abdominal wall defect of 5.0 cm x 0.5 cm was made, and the defect was sutured directly; in the experimental group, the full-thickness abdominal wall defect of 5.0 cm x 2.5 cm was made, and the defect was repaired with porcine acellular dermal matrix patch at the same size as the defect. At 5 weeks after surgery, the incidence of hernia and the intra-abdominal adhesions were observed and the wound breaking strength was compared between the patch-fascia interface and the fascia-fascia interface. The graft vascularization was evaluated through histological analysis at 6 months after surgery in the experimental group. RESULTS: No hernia occurred in all rabbits of 2 groups. At 5 weeks after surgery, healing was observed between patch and the muscular fascia; the vascularization was seen in the porcine acellular dermal matrix patch. There was no significant difference in the adhesion grade (Z= -0.798, P=0.425) between the experimental group (grade 2 in 1 rabbit, grade 1 in 5, and grade 0 in 12) and the control group (grade 1 in 1 and grade 0 in 5). No significant difference was found (t= -0.410, P=0.683) in the breaking strength between the patch-fascia interface in the experimental group [(13.0 +/- 5.5) N] and the fascia-fascia interface in control group [(13.6 +/- 4.0) N]. In the experimental group, the small vessels and the infiltration of inflammatory cells were observed in the porcine acellular dermal matrix patch after 5 weeks through histological observations. The junctions of the patch-fascia interface healed with fibrous connective tissue. At 6 months after surgery, the inflammation was subsided and the collagen fiber of the patch was reconstructed. CONCLUSION: The porcine acellular dermal matrix patch has good results in repairing full thickness abdominal wall defect. The patch-fascia interface has similar breaking strength to the fascia-fascia interface. The collagen fibers of the patch are reconstructed. PMID- 21818961 TI - [Oryzalin-induced chromosome doubling of Scutellaria barbata]. AB - OBJECTIVE: To obtain polyploidy Scutellaria barbata. METHODS: Explants of stem segment of Scutellaria barbata were treated with oryzalin at various concentration and time duration in vitro. RESULTS: Comparing with the characteristics of diploid, mutant plants had significant changes in plant morphology inducing compact plant, darker leaf color, smaller leaf index, thicken stem, significantly larger stomata, guard cells and chloroplasts in stomata guard cells and significantly lower stomata density. Mutant plants were plant chimera of diploid and tetraploid assessed by chromosome counting and flow cytometry. CONCLUSION: The technique could be used for chromosome doubling in Scutellaria barbata. PMID- 21818962 TI - [The quality of Salvia miltforthiza from Beijing suburbs with different growing modes]. AB - OBJECTIVE: Study the yield and quality of Salvia miltforthiza in the poplars and apple trees intercropping system. METHODS: Assay the yield, heavy metals, organochlorine pesticides and active components of Salvia miltforthiza in different intercropping systems are different. RESULTS: The contents of Cd exceeds the allowed figure seriously though other heavy metals such as Pb, As, Hg, Cu fell in the standard range. The contents of organochlorine pesticides of different Salvia miltforthiza fell in the standard range. The active components of biennial Salvia miltforthiza intercropping with apple trees, including Tanshinone II A and Salvianolic acid B complied with the quality standards of Pharmacopoeia. CONCLUSION: Soil fertility, heavy metals of intercropping system and planting years should be considered in order to ensure the quality and stability of Chinese medicine. PMID- 21818963 TI - [Mixed infection caused by meloidogyne and pathogenic fungi on Siraitia grosvenorii]. AB - OBJECTIVE: To study the mixed infection caused by meloidogyne and pathogenic fungi on Siraitia grosvenorii,the result can provide basis for controltion. METHODS: The correlation of fungi, nematode with the disease was studied base on tissue-isolation, back-inoculation and morphological characters. RESULTS: The species of root-knot nematode was identified as Meloidogyne incognita. The main pathogens were Fusarium oxysporum, Fusarium solani, and Verticillium alboatrum. The three fungis and their mixture can infect the tubers of Siraitia. grosvenorii, and the disease incidence was 57.14%, 38.10%, 47.62% and 71.43% respectively. Inoculation tests showed that the three pathogens and the root-knot nematode could cause mixed infection, CONCLUSION: Meloidogyne and pathogenic fungi can infect Siraitia. grosvenorii together. The three pathogens and nematode should be controlled all together at the same time. PMID- 21818964 TI - [Identification of foliumn pyrrosiae from different habitats and species by HPLC fingerprint]. AB - OBJECTIVE: To establish HPLC fingerprint of Folium Pyrrosiae for identification. METHODS: The HPLC method was developed with Diamonsil C18 column (250 mm x 4.6 mm, 5 microm),and a mixture liquid of acetonitrile-0.8% acetic acid solution as mobile phase in a gradient elution. HPLC fingerprints of44 samples were analyzed by similarity, cluster and principal component analysis. RESULTS: The HPLC fingerprint common pattern of Pyrrosia petiolosa, Pyrrosia lingua and common pattern of Pyrrosia sheareri were set up separately. Samples from different species were classified based on the result of cluster and principal component analysis. Fingerprints of Pyrrosia sheareri and Pyrrosia lingua have high degree of similarity, but were different from Pyrrosia petiolosa, while Pyrrosia calvata and Pyrrosia assimlis were classified as adulterants with their dissimilar fingerprints. CONCLUSION: The method is stable and reliable with a good reproducibility and provides a reference standard for identifying Folium Pyrrosiae from different habitats and species. PMID- 21818965 TI - [Study of cajal interstitial cells in stomach and small intestine of rats with crude, honey-stir-baked radix polygalae and its saponins]. AB - OBJECTIVE: To observe the changes of interstitial cells of Cajal (ICC) in stomach and small intestine of rats with honey-stir-baked Radix Polygalae, crude Radix Polygalae and its saponins, so as to study mechanism of crude Radix Polygalae reducing the motility disorder in gastrointestinal tract. METHODS: Immunohistochemical staining was used to investigate the distribution of c-kit positive ICC in stomach and small intestine. RESULTS: Compared with control group, the c-kit positive ICC in stomach and small intestine of crude Radix Polygalae and its saponins groups were both markedly decreased in model group (both P < 0.01), while honey-stir-baked Radix Polygalae group can not (P > 0.05). CONCLUSION: The motility disorder in gastrointestinal tract caused by crude Radix Polygalae and its saponins may be associated with the changes of ICC number in stomach and small intestine. Honey-stir-baked Radix Polygalae can protect ICC in some extent. PMID- 21818966 TI - [Investigation on correlation between ratio of xylem to phloem of Radix Isatidis and efficacy, chemical composition]. AB - OBJECTIVE: Explore contribution of ratio of xylem to phloem(RXP) to evaluate the quality of Radix Isatidis. METHODS: Antivirus activity and chemical compositions of xylem, phloem and Radix Isatidis of different RXP were determined by RBC agglutination test and unique chromatogram. Meanwhile, correlation between RXP and bioactivity,components was investigated. RESULTS: the activity of medical material of Radix Isatidis whose RXP was 1:2 or 1:1 is equal to that of phloem sample, while is stronger than that of cylem sample. There was a good consistency among the chemical figureprints of three samples (Radix Isatidis, xylem and phloem). When the RXP was 2:1, the medical material of Radix Isatidi and its xylem had the same activity. But the activity of phloem was not obvious. Their consistency of chemical fingerprint was bad, and the activity of Radix Isatidis which had RXP of 1:2 or 1:1 was better than that formed by xylem and phloem of 2:1. The Radix Isatidis of RXP of 1:2 or 1:1 had less similarity of chemical figureprint with that having RXP of 2:1. CONCLUSION: The quality of Radix Isatidis made up by the various RXP had significant difference. Radix Isatidis whose RXP is less than 1:1 had good quality and better activity. As a characteristic parameter of biologic morpha, the RXP can be applied to identifying the quality of Radix Isatidis, and also provided a reference to evaluation of other medical material of roots. PMID- 21818967 TI - [Studies on fingerprints of Centella asiatica by HPLC]. AB - OBJECTIVE: To study the HPLC fingerprints and establish a sensitive and specific method for controlling the quality of Centella asiatica. METHODS: HPLC gradient elution was applied for the fingerprints of Centella asiatica. All 16 samples are collected from different habitats of China. The columni was Alltech C18 column (250 mm x 4.6 mm, 5 microm), mobile phase was acetonitrile-water, flow rate was 1.0 ml/min, wavelength was 205 nm. RESULTS: The fingerprint of Centella asiatica was established, 16 samples of different areas of Centella asiatica were detected. There were 15 common peaks in the HPLC fingerprints of Centella asiatica. By comparison with the reference standards and using LC-ESI-MS(n) to corroborate the structure, 5-10 peaks were identified as madecassoside, asiaticoside, quercetin, kaemperol, madecassic acid and asiatic acid respectively. After calculating the similarity of the HPLC fingerprints of 16 habitants, the similarity of different habitats has been bad quite. CONCLUSION: The method is accurate, reliable and good repeatability. This chromatographic fingerprint method can be used to controll the quality of Centella asiatica. PMID- 21818968 TI - [Studies on flavonoids from the leaves of Lindera aggregata]. AB - OBJECTIVE: To investigate the chemical constituents in the leaves of Lindera aggregate. METHODS: Compounds were separated by column chromatography with silica gel and ODS. The structures were identified by physicochemical properties and spectral analysis (1H-NMR, 13C-NMR). RESULTS: Eight compounds were isolated and identified as: quercetin-3-O-L-rhamnoside(1), kaempferol-3-O-L-rhamnoside(2), kaempferol(3), dihydrokaempferol-3-O-L-rhamnoside (4), quercetin (5), quercetin-3 O-alpha-D-arabinofuranoside (6), quercetin-3-O-alpha-D-glucopyranoside(7), kaempferol-3-O-D-glucopyranoside(8). CONCLUSION: Compounds 2,4 and 8 are obtained from Lindera aggregata for the first time. PMID- 21818969 TI - [Studies on the chemical constituents of Rubus parvifolius]. AB - OBJECTIVE: To study the chemical constituents of Rubus parvifoliu. METHODS: The constituents were isolated by column chromatography and their structures were elucidated through spectroscopic analysis such as 1H-NMR, 13C-NMR, FT-IR, et al. RESULTS: Seven compounds were isolated from the roots of Rubus parvifolius L., they were identified as p-sitosterol (I), lauric acid (II), O-nitrophenol (III), beta-daucosterol (IV), euscaphic acid (V), camelliagenin A (VI) and(+) -catech in (VII). CONCLUSION: Compounds III and VII are isolated from the plant for the first time. PMID- 21818970 TI - [Studies on the chemical constituents of Salicornia europaea]. AB - OBJECTIVE: To study the chemical constituents of Salicornia europaea. METHODS: The chemical constituents were isolated and purified by means of several chromatographic techniques and their structures were elucidated by spectroscopic methods. RESULTS: Five compounds were isolated and identified as syringaresinol 4 O-beta-D-glucopyranoside(1), icariside B2(2), erythro-1-(4-O-beta-D glucopyranosyl-3,5-dimethyoxyphenyl)-2-syringaresinoxyl-propane-1,3-diol(3), longifloroside B(4), 7-O-beta-D-glucopyranosyl-6-methoxychromone(5). CONCLUSION: Compounds 1-4 are obtained from this genus for the first time. PMID- 21818971 TI - [Tracking the active component of Tebatan medicine Meconopsis quintuplinervia from Gansu]. AB - OBJECTIVE: To study the active ingredients of analgesic and anti-inflammatory from Meconopsis quintuplinervia, Tracking the active ingredients of such medicines. METHODS: The compounds Meconopsis quintuplinervia,were separated with chromatography and its chemical structure was elucidated by means of MS, NMR spectroscopy methods respectively. RESULTS: Five compounds were obtaine as O methylflavinantine (I), flavinantin (II), tricin (III), quercitrin (IV) and methyl linoleate (V). CONCLUSION: Compounds I is obtained from the plant for the first time. PMID- 21818972 TI - [Study on yohimbine in positive mode by ion trap mass spectrometry]. AB - OBJECTIVE: The structure and fragmentation pathway of yohimbine were elucidated by electron spray ionization mass spectrometry( ESI-MS). METHODS: Quasi-molecular ion peak m/z 355 [M + H]+ was detected by ESI-MS, and the main fragment ions of m/z 212 and m/z 144 were detected by ESI-MS2. RESULTS: There are two main fragment pathway for m/z 355 [M + H]+ by ESI-MS2 and the fragment broken in pyridine ring. The full scan MS3 spectra of fragment m/z 212, and m/z 144 was obtained by ion trap mass spectrometry. The characteristic fragmentation was used to prove the structure of m/z 212, and m/z 144. The fragment routes of characteristic were discussed on the basis of ESI mass spectra. CONCLUSION: It can provide the experimental data for studying pharmacokinetics in vivo and modifying structure. PMID- 21818974 TI - [The influence of suoquan capsule on the mRNA expression of CYP11B2 in deficiency of the kidney and diuresis rats]. AB - OBJECTIVE: To explore the mechanism of nourishing kidney and reducing urine effect of suoquan capsule by discussing the adjusting action on ALD synthase. METHODS: Built the model of deficiency of the kidney and diuresis by adenine,inspectd the contents of Cort, ALD in blood and the mRNA expression of CYP11B2 with ELISA and RT-PCR technology of the mice. RESULTS: Compared with model group, Suoquan capsule could remarkedly increase the contents of Cort, ALD in blood and the mRNA expression of CYP1 1 B2 of model rats. CONCLUSIONS: Suoquan capsule can increase the contents of Cort, ALD in blood and the mRNA expression of CYP11B2 in deficiency of the kidney and diuresis rats. Promote the combining of ALD by adjusting the ALD synthase may be the mechanism of nourishing the kidney and reducing urine of Souquan capsule from ALD synthase approach. PMID- 21818973 TI - [Effect of Panax notoginseng saponins on APP gene transcription in the brain tissue of SAMP8]. AB - OBJECTIVE: To study the effect of Panax notoginseng saponins (PNS) on learning and memory ability and APP gene transcription in the brain tissue in senescence accelerated mouse prone 8 (SAMP8). METHODS: SAMP8 were randomly divided into high does PNS group, low-does PNS group, huperzin A group and model group,the treatment groups were treated with the designed drugs respectively by intragastric administration for 4 consecutive weeks. The same volume of double distilled water was given to model group. After treatment, the abilities of learning and memory of the mice were tested with morris water maze, the mRNA content of APP was assayed by reverse transcription (RT) and real-time polymerase chain reaction (RT-PCR). RESULTS: PNS could improve the abilities of learning and memory, high-does PNS could reduce the mRNA content of APP in the brain tissue of SAMP8. CONCLUSION: PNS can improve the abilities of learning and memory of SAMP8, the mechanism may be relevant to down-regulating the expression of APP gene at transcriptional level. PMID- 21818975 TI - [Experimental studies of therapeutic effect of Rheum officinale on acute pancreatitis]. AB - OBJECTIVE: To investigate the therapeutic effect of Rheum officinale on acute pancreatitis. METHODS: Buffered sodium taurocholate (3% m/V) was injected into the pancreatico-biliary duct to induce acute pancreatitis. Death rate,coefficient of pancreas, serum amylyse (AMY), hemocuprein (SOD), TNF-alpha and IL-1beta level were examined at 6, 12 and 24 hours after operations. Pathology analysis were also obtained. RESULTS: Compared with corresponding pancreatitis groups,death rate, coefficient of pancreas, serum TNF-alpha and IL-1beta level of drug groups decreased remarkably (P < 0.05), while serum SOD level significantly increased (P < 0.01). Serum AMY level of drug groups increased at 6 h (P < 0.01), decreased at 12 h (P < 0.01) and had no statistics disparity at 24 h (P > 0.05) compared with respective pancreatitis group. Although score points of all drug groups were lower than corresponding pancreatitis groups, the growth tendency of both were similar. CONCLUSION: Rheum officinale Baill has the effect of prevention to pancreas pathological changes in the animal pattern, but not able to reverse the tendency. PMID- 21818976 TI - [Comparative study on pharmacokinetics of curcumin extract of rhizoma curcumae longae and rhizoma wenyujin concisum in rats]. AB - OBJECTIVE: To compare the pharmacokinetics of curcumin extracted from Rhizoma Curcumae Longe and Rhizoma Wenyujin Concisum in rats. METHODS: Sprague Dawley rats were administrated extracts of Rhizoma Curcumae Longae and Rhizoma Wenyujin Concisum. The pharmacokinetic parameters were calculated with 3P97 program. RESULTS: The plasma concentration-time curves of curcumin that extracted from Rhizoma Curcumae Longae and Rhizoma Wenyujin Concisum were fitted with one compartment model respectively. The AUC and Cmax of curcumin extracted from Rhizoma Curcumae Longae were much greater than of extracted from Rhizoma Wenyujin Concisum. CONCLUSION: There were significantly difference in pharmacokinetic parameters of curcumin in Rhizoma Curcumae Longae and Rhizoma Wenyujin Concisum in rats. PMID- 21818977 TI - [Effects of polysaccharides isolated from Panax japonicus on immunosuppression mice]. AB - OBJECTIVE: To investigate the immunomodulatory effects of polysaccharides from Panax japonicus on immunosuppressed mice. METHODS: Immunosuppressed murine model were established in Kuming mice induced by cyclophosphamide (Cy) and splenic indexes were evaluated. The proliferation activities of splenic lymphocyte were assayed by MTT and levels of serum hemolysin were confirmed by spectrophotometry. The antibody-secreting capabilities of splenocytes were assayed by quan-titative haemolysis of SRBC (QHS). The percentage of NK cells were analysed by flow cytometry (FCM). RESULTS: Polysaccharides of Panax japonicus significantly increased the splenic indexes, promoted the proliferation of splenic lymphocytes, enhanced QHS reaction, elevated the production of serum hemolysin and percentages of peripheral blood NK cells in Cy-induced immunosuppressed mice. CONCLUSION: Panax japonicus polysaccharides can recover immune function in the Cy-induced immunosuppressed mice. PMID- 21818978 TI - [Preparation and physicochemical properties of vinorelbine liposomes]. AB - OBJECTIVE: To prepare the vinorelbine liposomes and investigate their physicochemical properties. METHODS: Vinorelbine liposomes were prepared by thin film ultrasonication method. The morphology of the liposomes was detected by transmission electron microscopy. The partical size distribution and zeta potential were investigated by laser scattering. Sephadex G-50 was applied to separate the free drug and liposomes in order to determine the entrapment efficiency and leakage efficiency of the liposomes. The release characteristics of vinorelbine liposomes were measured by dialysis method. RESULTS: The particle size of the liposome was 149.2 nm, the bilayer of the liposome was observed obviously. The zeta potential was 38.62 mv. The entrapment efficiency of vinorelbine liposomes was more than 85% (n=3), and the leakage efficiency was less than 9.0% preserved in refrigerator ( <4 degrees C). In vitro release test, it could sustain for 24 h and conform to the Higuchi model. CONCLUSION: The vinorelbine liposomes have uniform partical size, fine-looking, high entrapment efficiency and sustained releasing effect. PMID- 21818979 TI - [Optimal extraction of polysaccharide from Dioscorea nipponica by central composite design and response surface methodology]. AB - OBJECTIVE: To optimize the extracting technology for polysaccharides from Dioscorea nipponica by response surface methodology. METHODS: The independent variables were extraction temperature, reflux time and liquid-to-solid ratio, the dependent variable was extraction rate of polysaccharides in Dioscorea nipponica. Linear or nonlinear mathematic models were used to estimate the relationship between independent and dependent variables. Central composite design and response surface methodology were used to optimize the process of extraction. The prediction was carried out through comparing the observed and predicted values. RESULTS: The optimum technological parameters were as follows: extraction temperature 91.5 degrees C, reflux time 172.9 min, solid-to-liquid ratio 25.8:1 and 2 times for extraction. Bias between observed and predicted of rates was 1.3%. CONCLUSION: The extraction technology is simple, reliable and highly predictive. PMID- 21818980 TI - [Technology study on extraction and purification of alkaloid from Stemona japonica]. AB - OBJECTIVE: In order to obtain the optimal conditions for separating the alkaloids from the extract of Stemona japonica by selecting appropriate cation exchange resins. METHODS: Seven types of cation exchange resins were evaluated in separating efficiency with measuring the adsorption ratio and eluting ratio of total alkaloids as indices, and the content of total alkaloids from Stemona japonica was determined as an index by spectrophotometry to choose the optimal technological parameters. RESULTS: The optimal result of extraction was obtained as Stemona japonica shattered into thick powder, adding eight times amount of 90% alcohol and refluxing and extracting for 3 h (totally extracting for 3 times). Each gram of D004 cation exchange resin could absorb 0.5003 mg of the total alkaloid, and the desorption ratio was 68.45%. The transfer rate of total alkaloids was 58.70%. the product purity of alkaloids was up to 70%. CONCLUSION: The D004 cation exchange resin can be used for purificating total alkaloids from Stemona japonica and the established procedure is simple and feasible. PMID- 21818981 TI - [Study on the extraction of polyphenol from Scindapsus officinalis with ultrasonic wave technology optimized by central composite design-response surface method]. AB - OBJECTIVE: To optimize ultrasonic extraction technology process conditions of polyphenol from Scindapsus officinalis by the response surface method. METHODS: Based on ethanol concentration, ultrasonic time, the liquid-solid ratio of single factor experiment, the principle of design for 3 star factor 3 level response surface methodology was applied. With FC extraction method for determination of polyphenols, the response surface optimization extraction conditions were studied. RESULTS: The ethanol concentration of 61.14%, ultrasonic wave extracting time of 59.73 min and the ratio of solvent volume of 27.72:1 (Extract 3 times) were selected as the optimum conditions,the extraction yield of polyphenols was 1.352%, with the theoretical 1.361% for the relative error of -0.66%. CONCLUSION: Ultrasonic extraction is a good method for saving time, energy and material,and can be applied to the polyphenols extraction. Central composite design-response surface optimization can get better ecasting results. PMID- 21818982 TI - Why advertise...and why not? PMID- 21818983 TI - Building a brand--one patient at a time. PMID- 21818984 TI - Is social media a game changer, or just something else in your tool kit? PMID- 21818985 TI - Pregnancy education goes mobile. PMID- 21818986 TI - Care without compromise. PMID- 21818987 TI - Sealth care goes retail.olantic looks to retail marketing models to strengthen its brand. PMID- 21818988 TI - Prepare for the ambush! PMID- 21818989 TI - The quest for physician engagement. PMID- 21818990 TI - Protecting the heart of health care. PMID- 21818991 TI - History of diabetes: from ants to analogs. AB - The earliest description of diabetes was documented in the writings of Hindu scholars as long as in 1500 BC. In 1921 the Canadian scientists Fredrick G. Banting, Charles H. Best, J. J. R. Macleod and James B. Collip discovered insulin, a peptide (small protein hormone) which lowers blood sugar. They extracted insulin from the islets of animal pancreases. A year later, in January 1922, bovine insulin was first given to humans by injection. The co-discoverers, in particular James Collip, continued their work to purify the insulin extract to make it safer and more effective. In 1936, protamine, a low-weight protein, was used to develop a suspension. In 1951 the amorphous 'lente' insulins- semilente, lente and ultralente were developed. After several years of laboratory work during the years 1963-1966 human insulin was chemically synthesized. In 1975, fully synthetic insulin was synthesized. Since 1996, different insulin analogues have been introduced worldwide. Insulin therapy is undergoing a paradigm shift now a days and at this hour we need to focus on the cardinal principles of initiating, optimizing, and intensifying the treatment for achieving adequate control. PMID- 21818992 TI - Importance of controlling diabetes early--the concept of metabolic memory, legacy effect and the case for early insulinisation. AB - Most of the microvascular complications of diabetes are related to the degree and the length of exposure to hyperglycaemia. New data from the follow-up studies of the Diabetes Control and Complications Trial-the Epidemiology of Diabetes Intervention and Complications Study (DCCT-EDIC), and the United Kingdom Prospective Diabetes Study (UKPDS) emphasize the role of glycemic control early in the course of the disorder and its value in prevention of later complications. The phenomenon of ongoing beneficial effects on diabetic complications after a period of improved glycemic control even if followed by a return to usual (often poorer) metabolic control has been described as representing "metabolic memory" by the DCCT/EDIC investigators and as a "legacy effect" by the UKPDS investigators. This article reviews these concepts and explores the role of early use of insulin as a tool to achieve good glycemic control in type 2 diabetes. PMID- 21818993 TI - Insulin therapy at onset of type 2 diabetes mellitus--a new concept. AB - In this study, insulin therapy was initiated at onset of disease in patients whose fasting blood glucose was more than 250 mg/dl. All enrolled subjects were treated with human premixed insulin (30/70) administered subcutaneously twice daily before breakfast and before dinner. A total of 113 subjects entered the study fulfilling the inclusion criteria. Good glycaemic control was achieved in a few days. The dosage requirement of insulin came down gradually after control was achieved as manifest by hypoglycaemia--leading to withdrawal of insulin. Some of them were managed with diet and exercise alone. Others required small doses of oral antidiabetic agents (OAD). There were no cases of secondary failure to OADs. Ten cases are on average duration of follow-up of 10 years. Two cases are under good control with diet and exercise alone, seven on treatment with oral hypoglycemic agents and one of them requiring insulin to maintain HbAlc below 7%. Thus insulin therapy at onset provides an opportunity to correct all the underlying pathogenic mechanisms, i.e., glucotoxicity, lipotoxicity and prevents beta cell apoptosis and suppresses inflammation, leading to beta cell protection. Such timely intervention provides long term benefits, laying the foundation for the concept of beta cell preservation rather that only replacing beta cell function. Hence we propose that all patients with type 2 diabetes should be offered insulin therapy at the onset of their diabetes for a period of 2-4 weeks. PMID- 21818994 TI - Insulin initiation and intensification: insights from new studies. AB - Tight glycemic control is central to reducing the risk of long-term macrovascular and microvascular complications of type 2 diabetes and the associated morbidity and mortality. However majority of the patients do not achieve glycemic targets (HbA1c < 7%). Once insulin treatment has been initiated, each patient's regimen must be optimized and intensified to reach the target. In many guidelines, initial insulin therapy comprises a single dose of long-acting insulin or premixed insulin. Basal insulin will help to control fasting plasma glucose (FPG) level, but postprandial glucose excursions make a significant contribution to the overall daily hyperglycemia of type 2 diabetic patients. BIAsp 30 is the most prescribed analog premix and consequently has the largest evidence base in terms of randomized controlled trials (RCTs) and observational data. It follows that BIAsp 30 is therefore the analog premix most likely to be used for insulin intensification, both from basal insulin and from BIAsp 30 regimens: OD to BID and from BID to TID. PMID- 21818995 TI - Basal insulin analogues--a review of recent data on efficacy and safety. AB - Conventional basal insulin preparations have to be resuspended prior to injection and have low therapeutic efficacy and drawbacks like nocturnal hypoglycaemia. There is evidence supporting improved pharmacokinetic and pharmacodynamic profiles of basal insulin analogues, glargine and detemir as compared with NPH. Initiation and titration of basal insulin analogues helps patients to improve compliance due to low injection frequency compared to the conventional basal insulin. The unique protraction mechanism adds advantage to insulin detemir in terms of high predictability. Also these analogues have better patient adherence, improved quality of life and higher treatment satisfaction. So basal insulin analogues particularly are better treatment options for treatment of diabetes. PMID- 21818996 TI - Inpatient management of diabetes mellitus. AB - Inpatient hyperglycemia is associated with increased morbidity and mortality. The length of hospital stay and cost of care is higher for patients with diabetes than for others. Current evidence suggests that tight control of hyperglycemia in critically ill hospitalized patients with diabetes or acute hyperglycemia has been shown to reduce the risk of morbidity and mortality. In view of risk of severe hypoglycemia with near normal blood glucose target, latest consensus is to adopt a less stringent target of 140-180 mg/dl. The development of insulin analogs with more physiologic time-action profiles, improved insulin delivery systems, and standardized protocols for subcutaneous insulin administration and intravenous insulin infusion have improved the safety and convenience of insulin therapy for treating inpatients. PMID- 21818997 TI - Continuous insulin infusion systems in type 2 diabetes. AB - There are various delivery devices available for insulin like syringes, pens, and insulin pumps. Syringes have drawbacks like dosage errors and pain. Insulin pumps can be useful to mimic the physiological insulin secretion. Though the insulin pumps are launched in India a decade ago, they are not popular due to high price and thus there is limited experience and queries with its use. Use of insulin pumps can improve the quality of life for diabetic patients. Available evidence from recent studies is a compelling indication and not to deny the never before discovered benefits of continuous subcutaneous insulin infusion (CSII) in selective patients with type 2 diabetes mellitus. Pumps with continuous glucose monitoring (CGM) system helps as a therapeutic option enabling diabetic patients to restructure lifestyles based on glycemic patterns. PMID- 21818998 TI - Biosimilar peptides: need for pharmacovigilance. AB - Biosimilars or their copies are generic version of biopharmaceutical medicines which try to mimic products which are derived from recombinant technology. These are near or semi-identical products which use a separate process for its bioformulation and need to pass strict mandates of regulatory bodies like U.S. FDA and EMEA in Europe. As these compounds need for the process of manufacture requiring fermentation and not traditional reverse chemistry it is difficult to mimic bioidentical compounds. There are clear cut differences in the manufacture process and protein folding. However there is unclear data currently to know if these biosimilar have any clinically relevant impact. Due to the sophisticated nature of these biomolecules and their 3-D structure its a new area of research for pharmaceutical scientists and drug regulators. In India apart from Biogenerics a host of molecules especially have Biosimilar copies of compounds especially in endocrinology namely insulin, Exenatide, growth hormone, teriperatide like peptides are made in India. These need evidence based validation if they have clinically relevants effects or side effects and close pharmacovigliance. PMID- 21818999 TI - Facts of iodine supplementation. PMID- 21819000 TI - Management of hypothyroidism in adults. PMID- 21819001 TI - Thyrotoxicosis. PMID- 21819002 TI - Thyroid disorders in pregnancy. PMID- 21819003 TI - Thyroid function in children. PMID- 21819004 TI - Thyroiditis. PMID- 21819005 TI - Thyroid ophthalmopathy. PMID- 21819006 TI - Thyroid emergencies. PMID- 21819008 TI - [Significance and prospect of National Clinical Database]. PMID- 21819007 TI - [Fukushima nuclear power plant accident and disclosure of information]. PMID- 21819009 TI - [Current treatment strategies for pediatric surgical patients with severe congenital cardiac malformations]. PMID- 21819010 TI - [Optimal timing of pediatric surgery to prevent deleterious effects on associated cardiac defects]. AB - Although cardiac defects are thought to have deleterious effects on the outcome of general pediatric surgery due to low cardiac output syndrome and hypoxemia, both pediatric surgery and cardiac surgery can be performed at the optimal timing with good results. However, some conditions requiring pediatric surgery may have deleterious effects on the outcome of cardiac surgery. Airway obstructive diseases sometimes require concomitant repair of the associated cardiac defects. In particular, tracheal stenosis may be repaired in cooperation with not only general pediatric and cardiac surgeons but also with pediatric thoracic surgeons who work in other healthcare institutions. Low birth-weight infants with symptomatic patent ductal artery are at risk of poor outcome. For patients with right isomerism, midgut malrotation or sliding hernia should be diagnosed early and repaired at the optimal timing to prevent urgent surgical intervention. Pediatric surgery should be performed at the optimal timing to prevent any deleterious effects on cardiac defects. Moreover, respiratory infection and neurologic disease should be treated to reduce late deaths. PMID- 21819011 TI - [Influence of congenital heart defects on outcomes of noncardiac surgery in neonates]. AB - We reviewed our experience to examine the outcomes of noncardiac surgery in neonates with congenital cardiac defects and assess future changes in the management of noncardiac surgery in neonates for whom new cardiac surgical management strategies will develop based on current progress in prenatal diagnosis. Forty-five neonates with congenital cardiac defects underwent noncardiac surgery in our institution. Subsequent cardiac surgery was performed in 26 of those neonates. No patient underwent cardiac surgery before noncardiac surgery. However, rescue neonatal cardiac surgery, which is performed within 24 h after birth, has become more common because of the progress in prenatal diagnosis. Under these circumstances in neonatal cardiac surgery, the timing or approach of cardiac and noncardiac surgery should be reconsidered in the next few years. We emphasize the importance of cooperation among relevant specialists in the management of neonates with multiple disorders to increase the benefits offered by developments in prenatal diagnosis. PMID- 21819012 TI - [Treatment strategy for patients with extracardiac structural anomalies and congenital heart disease]. AB - The surgical treatment of patients with extracardiac structural anomalies and congenital heart disease often carries major risk and remains a challenging field. An appropriate, solid treatment plan should be developed during the early phase with interactive intelligence sharing between a pediatric surgery team and congenital heart surgery team. As the top of the chain of command, the role of a neonatologist is important. This article reviews the history of surgery for congenital heart disease and the progress of the Japan Congenital Cardiovascular Surgery Database. Finally, as an example of a combination of diseases, the clinical course and intelligence sharing during treatment of a patient with biliary atresia requiring living-donor liver transplantation and hypoplastic left heart syndrome is reported. The National Quality Forum provided structural measures, process measures, and outcome measures for congenital heart surgery. Structural measures provided by the National Quality Forum included participation in a preoperative multidisciplinary conference. To improve the outcome of surgical treatment of patients with congenital heart disease and extracardiac structural anomalies, the importance of a preoperative multidisciplinary conference involving not only pediatric surgeons, pediatric cardiologists, and pediatric cardiac surgeons but also neonatologists, anesthesiologists, and nurses cannot be overemphasized. PMID- 21819013 TI - [Surgical strategy and treatment for pediatric surgical diseases accompanied with congenital heart diseases]. AB - Advances in perinatal care in recent years have resulted in improved outcomes in both pediatric diseases treated surgically and congenital heart disease. However, aggressive surgical treatment is sometimes not performed because of a lack of knowledge of cardiac and pediatric surgeons. Lives may be saved if current pediatric surgical and pediatric cardiovascular surgical skills are combined. In complicated cases, a medical team is formed in our institution consisting of representatives of various departments, and the best treatment strategy tailored for individual patients is determined. We have treated 17 patients under this system, and 12 including 2 patients who had both severe pediatric diseases requiring surgery and congenital heart disease survived without major complications. Two patients died due to intestinal ischemia after cardiac surgery. To improve the survival rate of complicated cases, early detection or prevention of intestinal ischemia is required. PMID- 21819014 TI - [Strategy for surgery in neonates with coexisting congenital heart diseases]. AB - To determine the most appropriate treatment strategy for neonates with coexisting congenital heart diseases (CHD) requiring surgery, 408 neonates treated in our department between 2002 and 2009 were retrospectively reviewed. Of the 408 neonates, 37 (9.1%) had coexisting CHD. Among the pediatric diseases requiring surgery, esophageal atresia (46.7%), anorectal malformation (24.1%), and tracheobronchial anomalies (75.0%) were frequently associated with CHD, and the survival rate among patients with coexisting CDH was 24.3%, about 2-fold higher than among those without coexisting CHD. Clinical observations in the present series suggested that fatal conditions such as tracheoesophageal fistula should be repaired immediately after birth, followed by palliative cardiac surgery to stabilize the circulatory status if necessary. Thereafter, radical repair of cardiac and pediatric anomalies should be performed, taking into account the balance between surgical stress and cardiac reserve. For this purpose, proper assessment of surgical stress and cardiac function and collaboration among specialists in relevant fields are essential during the perinatal period to determine the treatment strategy for patients with multiple-organ anomalies. PMID- 21819016 TI - [Endoscopic surgical training system using virtual reality simulator]. PMID- 21819015 TI - [Management of gastrointestinal malformations in children with asplenia syndrome]. AB - Asplenia syndrome (AS) is a complex disorder that includes a variety of cardiovascular and gastrointestinal malformations (GMs), and its prognosis remains poor. We treated 40 AS patients between 2000 and 2010, 10 of whom underwent surgery to correct GMs. These comprised 7 hiatus hernias (HH), 1 intestinal malrotation (IM), 1 stomach volvulus, and 1 ompalocele. In this review, we consider the optimal surgical timing and methods of management, especially for HH and IM. Surgery was performed in 6 of 7 HH patients. Four of those underwent laparotomy, 1 thoracotomy, and 1 laparoscopy. The Toupet method or fixation of the His angle or hiatus closure was selected in each case. Because the stomach intruding into the mediastinum may cause pulmonary venous obstruction and respiratory impairment, surgical repair is preferably performed prior to Glenn surgery. Among the 9 IMs, 8 were nonrotational and required no treatment, and only 1 required surgical treatment. GMs in AS are difficult to manage because of the unique anatomy, meaning there are no fixed surgical techniques. Each patient must be carefully examined preoperatively, and the optimum surgical method selected. Close collaboration with cardiovascular surgeons is vital when determining the timing and method of surgery. PMID- 21819017 TI - [What we can learn from a case of medical malpractice--damages awarded for unsuccessful implant based on default under the medical service contract]. PMID- 21819018 TI - [Anatomical segmentectomy for clinical stage IA non-small cell lung cancer]. PMID- 21819020 TI - [International investigation of surgical training using human cadaver for clinical anatomy education and research]. PMID- 21819019 TI - [Draft of Guidelines for Human Body Dissection for Clinical Anatomy Education and Research and commentary]. AB - This article analyses the Draft of Guidelines for Human Body Dissection for Clinical Anatomy Education and Research drawn by the Study Group for Future Training Systems of Surgical Skills and Procedures established by the Fiscal Year 2010 research program of the Ministry of Health, Labor and Welfare. The purpose of the Draft of Guidelines is: First, to lay out the required basic guidelines for human cadaver usage to allow medical and dental faculty to conduct clinical education and research in accordance with existing regulations. Second, the guidelines are expected to give physicians a regulatory framework to carry out cadaver training in accordance with the current legal framework. This article explains the Draft of Guidelines in detail, outlines the future of cadaver training, and describes issues which must still be solved. PMID- 21819021 TI - [Physician assistant in Germany]. PMID- 21819022 TI - [A new milestone in Japanese medical practice: a Japanese nurse practitioner participates in Japan earthquake and tsunami relief]. PMID- 21819023 TI - [The experience of cooperating with Japanese nurse practitioner and physician assistant in the disaster-hit areas]. PMID- 21819024 TI - [Personal opinion on idea of (health care given by non physicians)]. PMID- 21819027 TI - Safety strategies in an academic radiation oncology department and recommendations for action. AB - BACKGROUND: Safety initiatives in the United States continue to work on providing guidance as to how the average practitioner might make patients safer in the face of the complex process by which radiation therapy (RT), an essential treatment used in the management of many patients with cancer, is prepared and delivered. Quality control measures can uncover certain specific errors such as machine dose miscalibration or misalignments of the patient in the radiation treatment beam. However, they are less effective at uncovering less common errors that can occur anywhere along the treatment planning and delivery process, and even when the process is functioning as intended, errors still occur. PRIORITIZING RISKS AND IMPLEMENTING RISK-REDUCTION STRATEGIES: Activities undertaken at the radiation oncology department at the Johns Hopkins Hospital (Baltimore) include Failure Mode and Effects Analysis (FMEA), risk-reduction interventions, and voluntary error and near-miss reporting systems. A visual process map portrayed 269 RT steps occurring among four subprocesses-including consult, simulation, treatment planning, and treatment delivery. Two FMEAs revealed 127 and 159 possible failure modes, respectively. Risk-reduction interventions for 15 "top-ranked" failure modes were implemented. Since the error and near-miss reporting system's implementation in the department in 2007, 253 events have been logged. However, the system may be insufficient for radiation oncology, for which a greater level of practice-specific information is required to fully understand each event. CONCLUSIONS: The "basic science" of radiation treatment has received considerable support and attention in developing novel therapies to benefit patients. The time has come to apply the same focus and resources to ensuring that patients safely receive the maximal benefits possible. PMID- 21819028 TI - Improving follow-up of high-risk psychiatry outpatients at resident year-end transfer. AB - BACKGROUND: Few studies have examined the safety risks of the annual outpatient clinic handoffthat occurs when residents either advance to a higher level of training or graduate ("year-end transfer"). A multifaceted intervention was designed and implemented to identify and improve followup of high-risk patients during academic year-end outpatient transfers in a psychiatry resident continuity clinic. METHODS: Departing residents identified "acute" patients, who were scheduled on a priority basis for longer appointments during the first month after the transfer. In addition, standardized written and face-to-face sign-outs occurred, incoming clinicians contacted every patient in the first week, and specialized didactics were provided. RESULTS: For the three intervention years combined, the odds ratio of hospitalization for acute patients compared to nonacute patients was 9.2 (95% confidence interval [CI]: 2.43, 34.7; p = .001). Compared to Year 1, the proportion of acute patients seen within 31 days in Years 2 and 3 increased by 32.2% (from 64.3% to 85.0%, p < .0001). The median time-to first visit for acute patients decreased by 42% (from 24 days in Year 1 to 14 days in Year 3, p = .001). Finally, resident perception of the quality of the handoffim-proved in all areas compared to baseline, including resident-to resident communication (2.8 to 3.0, p = .03), accuracy of caseload lists (2.8 to 4.1,p = .003), identification of high-risk patients (2.1 to 3.7, p < .0001), and usefulness of supervision during the transition (2.7 to 4.3, p < .0001). CONCLUSIONS: Categorical designation by the outgoing clinicians effectively identified patients at higher risk for hospitalization during the transition. Relatively low-cost interventions may significantly improve patient safety and resident training in not only psychiatry, but also other disciplines and specialties. PMID- 21819029 TI - The need for performance measures on testing for latent tuberculosis infection in primary care. AB - BACKGROUND: The millions of people living in the United States with latent tuberculosis infection (LTBI) represent a reservoir of potentially active tuberculosis (TB) disease. When LTBI is left to activate, the consequences may include intense suffering, permanent disability, and high economic costs for patients, their caretakers, and society at large as TB spreads. The introduction of performance measures would improve accountability for quality of care and to reduce disparities, especially if the measures are group-targeted. PERFORMANCE MEASURES PROPOSAL: One National Quality Forum-endorsed measure (#0408) calculates the rate of TB screening in persons with HIV. Using the measure as a model, a set of performance measures is proposed. Denominators will include all persons in a given high-risk category, and numerators will include those persons from the denominators with LTBI test results. National guidelines informed appropriate exclusions. IMPLEMENTATION CHALLENGES AND SOLUTIONS: Challenges to implementation include lack of TB knowledge among primary care providers, potential for overwhelming already burdened schedules, and stigma associated with TB. However, the new measures, along with publication of educational resources, would raise clinicians' awareness. Short checklists and electronic supports would minimize time pressures. The routinization of screening would help reduce stigma. Finally, new federal funding and political will for electronic health records would facilitate data collection and impact assessment. CONCLUSIONS: TB sits at the crossroads of health and economic inequity and is a huge public health problem. The proposed performance measures will address a neglected secondary prevention opportunity and will be consistent with national priorities and health reform. PMID- 21819030 TI - An inpatient fall prevention initiative in a tertiary care hospital. AB - BACKGROUND: In response to increasing inpatient fall rates, which reached 3.9 falls per 1000 inpatient-days in the last quarter of 2005, Staten Island University Hospital, a 714-bed, tertiary care hospital (Staten Island, New York), implemented a fall prevention initiative (FPI). The initiative was intended to decrease inpatient falls and associated injury by institutionalizing staff safety awareness; accountability, and critical thinking; eradicating historically acceptable system failures; and mandating a critical evaluation of safety precautions and application of fall prevention protocol. METHODS: The intervention included two phases (1) a review phase, in which existing fall prevention efforts were evaluated, and (2) the FPI implementation phase, in which systems were implemented to ensure fall risk assessments, fall incident investigations, identifying and confronting problem issues, planning and adherence to corrective action, and accountability for missed preventive opportunities. For all 1,098,471 inpatient-days of persons aged 18 years and older, with an admission lasting at least one day, between April 2006 and March 2010, data were collected for inpatient falls and fall-associated injuries per 1000 inpatient-days. RESULTS: Four-year inpatient fall rates decreased by 63.9% (p < .0001); the greatest reduction (72.3%) occurred between the first quarter (Q1) 2005 and Q4 2009. Minor and moderate fall-related injuries significantly decreased by 54.4% and 64.0%, respectively. Two falls with major injury occurred during the study. CONCLUSIONS: The FPI was associated with a significant reduction in fall and fall-related injury rates. The results suggest that increasing commitment to continuous quality improvement through enhanced safety awareness and accountability contributed to the initiative's success and led to a change of normative behavior and a culture of safety. PMID- 21819031 TI - Adopting real-time surveillance dashboards as a component of an enterprisewide medication safety strategy. AB - BACKGROUND: High-alert medications are frequently responsible for adverse drug events and present significant hazards to inpatients, despite technical improvements in the way they are ordered, dispensed, and administered. METHODS: A real-time surveillance application was designed and implemented to enable pharmacy review of high-alert medication orders to complement existing computerized provider order entry and integrated clinical decision support systems in a tertiary care hospital. The surveillance tool integrated real-time data from multiple clinical systems and applied logical criteria to highlight potentially high-risk scenarios. Use of the surveillance system for adult inpatients was analyzed for warfarin, heparin and enoxaparin, and aminoglycoside antibiotics. RESULTS: Among 28,929 hospitalizations during the study period, patients eligible to appear on a dashboard included 2224 exposed to warfarin, 8383 to heparin or enoxaparin, and 893 to aminoglycosides. Clinical pharmacists reviewed the warfarin and aminoglycoside dashboards during 100% of the days in the study period-and the heparinlenoxaparin dashboard during 71% of the days. Displayed alert conditions ranged from common events, such as 55% of patients receiving aminoglycosides were missing a baseline creatinine, to rare events, such as 0.1% of patients exposed to heparin were given a bolus greater than 10,000 units. On the basis of interpharmacist communication and electronic medical record notes recorded within the dashboards, interventions to prevent further patient harm were frequent. CONCLUSIONS: Even in an environment with sophisticated computerized provider order entry and clinical decision support systems, real-time pharmacy surveillance of high-alert medications provides an important platform for intercepting medication errors and optimizing therapy. PMID- 21819032 TI - The meaningful use regulations in information technology: what do they mean for quality improvement in hospitals? AB - If provider organizations are serious about improving quality and efficiency, they must advance their electronic health record capabilities far beyond just meeting the U.S. federal regulations. PMID- 21819033 TI - Atomic structure of interconnected few-layer graphene domains. AB - The atomic structure at the boundary interface between interconnected few-layer graphene (FLG) domains, synthesized by atmospheric pressure chemical vapor deposition (AP-CVD), is examined using aberration-corrected high-resolution transmission electron microscopy. Moire patterns in the HRTEM images reveal the presence of rotational stacking faults in the boundary region that extend over distances of ~100 nm. We show that FLG domains interconnect via two principle processes: graphene sheets from one domain grow over the top of a neighboring domain, while other graphene domains interconnect by direct atomic bonding. Differentiating between these two types of interconnects was found to be possible by examining the HRTEM contrast profiles produced at the interface. Graphene sheets that terminate were found to produce strong edge contrast with increasing defocus values, as well as a broader edge cross section, whereas atomically bonded interfaces were found to not exhibit any contrast, even under large defocus values. These findings are reinforced by correlating with multi-slice TEM image simulations of appropriate structures. PMID- 21819034 TI - Revelation of the molecular assembly of the nanoporous metal organic framework ZIF-8. AB - Crystalline nanoporous materials are one of the most important families of complex functional material. Many questions pertaining to the molecular assembly mechanism of the framework of these materials remain unanswered. Only recently has it become possible to answer definitively some of these questions by observation of growing nanoscopic surface features on metal organic frameworks (MOFs) through use of in situ atomic force microscopy (AFM). Here we reveal that a growth process of a MOF, zeolitic imidazolate framework ZIF-8, occurs through the nucleation and spreading of successive metastable unenclosed substeps to eventually form stable surface steps of the enclosed framework structure and that this process is reliant on the presence of nonframework species to bridge the developing pores during growth. The experiments also enable identification of some of the fundamental units in the growth process and the stable crystal surface plane. The former findings will be applicable to numerous nanoporous materials and support efforts to synthesize and design new frameworks and to control the crystal properties of these materials. PMID- 21819035 TI - Removal of hexavalent chromium by biosorption process in rotating packed bed. AB - Removal of hexavalent chromium ions from an aqueous solution by crude tamarind (Tamarindus indica) fruit shell was examined in a rotating packed bed contactor by continuously recirculating a given volume of solution through the bed. Reduction of Cr(VI) to Cr(III) within the biosorbent appeared to be the removal mechanism. Depletion rate of Cr(VI) from, and release of reduced Cr(III) ions into the aqueous phase, was influenced by mass transfer resistance besides pH and packing depth. A mathematical model considering the reduction reaction to be irreversible and incorporating intraparticle and external phase mass transfer resistances represented the experimental data adequately. The study indicated that the limitations of fixed bed contactor operating under terrestrial gravity in intensifying mass transfer rates for this system can be overcome with rotating packed bed due to liquid flow under centrifugal acceleration. PMID- 21819036 TI - Alkoxy radical cyclizations onto silyl enol ethers relative to alkene cyclization, hydrogen atom transfer, and fragmentation reactions. AB - This study examines the chemoselectivity of alkoxy radical cyclizations onto silyl enol ethers compared to competing cyclizations, 1,5-hydrogen atom transfers (1,5-HATs), and beta-fragmentations. Cyclization onto silyl enol ethers in a 5 exo mode is greatly preferred over cyclization onto a terminal alkene. The selectivity decreases when any alkyl substitution is present on the competing alkene radical acceptor. Alkoxy radical 5-exo cyclizations displayed excellent chemoselectivity over competing beta-fragmentations. Alkoxy radical 5-exo cyclizations onto silyl enol ether also outcompeted 1,5-HATs, even for activated benzylic hydrogen atoms. In tetrahydropyran synthesis, where 1,5-HAT has plagued alkoxy radical cyclization methodologies, 6-exo cyclizations were the dominant mode of reactivity. beta-Fragmentation still remains a challenge for tetrahydropyran synthesis when an aryl group is present in the beta position. PMID- 21819037 TI - Fast H/D exchange of B,B',B''-tribromoborazine in C6D6 in the presence of aluminum tribromide: first evidence for an electrophilic substitution reaction of borazines in solution. AB - A solution of B,B',B''-tribromoborazine (BrBNH)(3) in excess C(6)D(6) in a sealed NMR tube shows no changes for over 14 months at room temperature but undergoes fast (within minutes) H/D exchange in the presence of AlBr(3) as a Lewis acid, as evidenced by (1)H, (2)H, (11)B, and (27)Al NMR spectroscopy. The proposed electrophilic exchange mechanism is in agreement with the results of DFT computations. To our knowledge, this is the first example of the electrophilic substitution reaction of borazines in solution. PMID- 21819038 TI - Capture, store, and discharge. Shuttling photogenerated electrons across TiO2 silver interface. AB - UV irradiation of TiO(2) nanoparticles in the presence of Ag(+) ions results in the quantitative reduction and deposition of silver on its surface. Continued UV irradiation following the deposition of Ag on the TiO(2) surface causes a blue shift in the surface plasmon peak from 430 to 415 nm as these particles become charged with excess electrons. Under UV irradiation, both the charging and discharging of electrons occur at different rates, thus allowing the system to attain a steady state. Upon stopping the UV irradiation, a fraction of these electrons remain stored. The electron storage is dependent on the amount of Ag deposited on TiO(2) nanoparticles with maximum capacity seen at 8.6 MUM of Ag in a suspension containing 5.8 mM of TiO(2). Such electron charging and discharging processes in semiconductor-metal composites need to be taken into account while evaluating the plasmon resonance induced effects in photocatalysis and photoelectrochemistry. PMID- 21819040 TI - Aptamer modules as sensors and detectors. AB - Aptamers comprise a range of molecular recognition scaffolds that can be engineered to bind to a legion of different proteins and other targets with excellent specificity and affinity. Because these non-natural oligonucleotides are accessible entirely synthetically, aptamers can be equipped with all sorts of reporter groups and can be coupled to many different carriers, surfaces, nanoparticles, or other biomolecules. They can be used in a highly modular fashion and often recognize their targets by a mechanism in which the aptamer undergoes considerable structural rearrangement, which can be exploited for transducing a binding event into a signal. As a consequence, aptamers have been adapted to a huge variety of "read-out configurations" and are increasingly used as capture agents in many different bioanalytical methods. But despite considerable success with these applications, many remaining challenges must still be overcome for the more widespread incorporation of aptasensors in clinical and environmental biosensing and diagnostics to take place. Some particularly noteworthy progress on this front is currently being made with aptasensor configurations that can be used for the multiplexed sensing of many analytes in parallel. In this Account, we describe some of the concepts involved in transducing the binding of a ligand into a signal through various physico chemical interactions. Research in this area usually involves the combination of the molecular biology of proteins and nucleic acids with biotechnology, synthetic chemistry, physical chemistry, and surface physics. We begin with a brief introduction of the properties and characteristics that qualify aptamers as capture agents for many different analytes and their suitability as highly versatile biosensor components. We then address approaches that apply to surface acoustic wave configurations, drawing largely from our own contributions to aptasensor development, before moving on to describe previous and recent progress in multiplexed aptasensors. Obtaining proteome-wide profiles in cells, organs, organisms, or full populations requires the ability to accurately measure many different analytes in small sample volumes over a broad dynamic range. Multiplexed sensing is an invaluable tool in this endeavor. We discuss what we consider the biggest obstacles to the broader clinical use of aptasensor-based diagnostics and our perspective on how they can be surmounted. Finally,we explore the tremendous potential of aptamer-based sensors that can specifically discriminate between diseased and healthy cells. Progress in these areas will greatly expand the range of aptasensor applications, leading to enhanced diagnosis of diseases in clinical practice and, ultimately, improved patient care. PMID- 21819039 TI - Total synthesis of (+/-)-phomactin A. Lessons learned from respecting a challenging structural topology. AB - Our struggles and ultimate success in achieving a total synthesis of phomactin A are described. Our strategy features an intramolecular oxa-[3 + 3] annulation to construct its unique ABD-tricyclic manifold. Although the synthesis would constitute a distinctly new approach with the 12-membered D-ring of phomactin A being assembled simultaneously with the 1-oxadecalin at an early stage, the ABD tricycle represents a unique structural topology that would pose a number of unprecedented challenges. One challenge concerned elaborating this tricycle to have oxygenation at the proper carbon atoms. To overcome this, we would utilize a Kornblum-DeLaMare ring-opening of a peroxide bridge as well as a challenging late stage 1,3-allylic alcohol transposition. Further, the structural intricacies of the ABD-tricycle were uncovered by a conformational analysis that would be critical for the C5a-homologation. PMID- 21819041 TI - Prostanoid receptors. PMID- 21819042 TI - Impact of virus aggregation on inactivation by peracetic acid and implications for other disinfectants. AB - Viruses in wastewater and natural environments are often present as aggregates. The disinfectant dose required for their inactivation, however, is typically determined with dispersed viruses. This study investigates how aggregation affects virus inactivation by chemical disinfectants. Bacteriophage MS2 was aggregated by lowering the solution pH, and aggregates were inactivated by peracetic acid (PAA). Aggregates were redispersed before enumeration to obtain the residual number of individual infectious viruses. In contrast to enumerating whole aggregates, this approach allowed an assessment of disinfection efficiency which remains applicable even if the aggregates disperse in post-treatment environments. Inactivation kinetics were determined as a function of aggregate size (dispersed, 0.55 and 0.90 MUm radius) and PAA concentration (5-103 mg/L). Aggregation reduced the apparent inactivation rate constants 2-6 fold. The larger the aggregate and the higher the PAA concentration, the more pronounced the inhibitory effect of aggregation on disinfection. A reaction-diffusion based model was developed to interpret the experimental results, and to predict inactivation rates for additional aggregate sizes and disinfectants. The model showed that the inhibitory effect of aggregation arises from consumption of the disinfectant within the aggregate, but that diffusion of the disinfectant into the aggregates is not a rate-limiting factor. Aggregation therefore has a large inhibitory effect if highly reactive disinfectants are used, whereas inactivation by mild disinfectants is less affected. Our results suggest that mild disinfectants should be used for the treatment of water containing viral aggregates. PMID- 21819043 TI - Counterion-induced reversibly switchable transparency in smart windows. AB - Smart windows that can reversibly alternate between extreme optical characteristics via clicking counteranions of different hydration energies were developed on glass substrates through the facile spray-casting of poly[2 (methacryloyloxy)ethyltrimethylammonium chloride-co-3-(trimethoxysilyl)propyl methacrylate]. The optical transmittance was either 90.9% or 0% over the whole spectral range when alternately immersed in solutions containing thiocyanate (SCN(-)) or bis(trifluoromethane)sulfonimide (TFSI(-)) ions, respectively. The extreme optical transitions were attributed to formation of microporous structures via the molecular aggregation of polyelectrolyte chains bearing TFSI( ) ions in methanol. Because the smart windows were either highly transparent toward or completely blocking of incident light upon direct counterion exchange, this kind of nanotechnology may provide a new platform for efficiently conserving on energy usage in the interior of buildings. PMID- 21819044 TI - Enhanced specificity of the viral suppressor of RNA silencing protein p19 toward sequestering of human microRNA-122. AB - Tombusviruses express a 19 kDa protein (p19) that, as a dimeric protein, suppresses the RNAs silencing pathway during infection by binding short interfering RNA (siRNA) and preventing their association with the RNA-induced silencing complex (RISC). The p19 protein can bind to both endogenous and synthetic siRNAs with a high degree of size selectivity but with little sequence dependence. It also binds to other endogenous small RNAs such as microRNAs (miRNAs) but with lower affinity than to canonical siRNAs. It has become apparent, however, that miRNAs play a large role in gene regulation; their influence extends to expression and processing that affects virtually all eukaryotic processes. In order to develop new tools to study endogenous small RNAs, proteins that suppress specific miRNAs are required. Herein we describe mutational analysis of the p19 binding surface with the aim of creating p19 mutants with increased affinity for miR-122. By site-directed mutagenesis of a single residue, we describe p19 mutants with a nearly 50-fold increased affinity for miR-122 without altering the affinity for siRNA. Upon further mutational analysis of this site, we postulate that the higher affinity relies on hydrogen bonding interactions but can be sterically hindered by residues with bulky side chains. Finally, we demonstrate the effectiveness of a mutant p19, p19-T111S, at sequestering miR-122 in human hepatoma cell lines, as compared to wild-type p19. Overall, our results suggest that p19 can be engineered to enhance its affinity toward specific small RNA molecules, particularly noncanonical miRNAs that are distinguishable based on locations of base-pair mismatches. The p19-T111S mutant also represents a new tool for the study of the function of miR-122 in post transcriptional silencing in the human liver. PMID- 21819045 TI - Palladium-catalyzed synthesis of dibenzophosphole oxides via intramolecular dehydrogenative cyclization. AB - Dibenzophosphole oxides were obtained from secondary hydrophosphine oxides with a biphenyl group by dehydrogenation via phosphine-hydrogen and carbon-hydrogen bond cleavage in the presence of a catalytic amount of palladium(II) acetate, Pd(OAc)(2). By using this reaction, a ladder-type dibenzophosphole oxide could also be synthesized by double intramolecular dehydrogenative cyclization. PMID- 21819046 TI - Reduction-sensitive liposomes from a multifunctional lipid conjugate and natural phospholipids: reduction and release kinetics and cellular uptake. AB - The development of targeted and triggerable delivery systems is of high relevance for anticancer therapies. We report here on reduction-sensitive liposomes composed of a novel multifunctional lipidlike conjugate, containing a disulfide bond and a biotin moiety, and natural phospholipids. The incorporation of the disulfide conjugate into vesicles and the kinetics of their reduction were studied using dansyl-labeled conjugate 1 in using the dansyl fluorescence environmental sensitivity and the Forster resonance energy transfer from dansyl to rhodamine-labeled phospholipids. Cleavage of the disulfide bridge (e.g., by tris(2-carboxyethyl)phosphine (TCEP), dithiothreitol (DTT), l-cysteine, or glutathione (GSH)) removed the hydrophilic headgroup of the conjugate and thus changed the membrane organization leading to the release of entrapped molecules. Upon nonspecific uptake of vesicles by macrophages, calcein release from reduction-sensitive liposomes consisting of the disulfide conjugate and phospholipids was more efficient than from reduction-insensitive liposomes composed only of phospholipids. The binding of streptavidin to the conjugates did not interfere with either the subsequent reduction of the disulfide bond of the conjugate or the release of entrapped molecules. Breast cancer cell line BT-474, overexpressing the HER2 receptor, showed a high uptake of the reduction-sensitive doxorubicin-loaded liposomes functionalized with the biotin-tagged anti-HER2 antibody. The release of the entrapped cargo inside the cells was observed, implying the potential of using our system for active targeting and delivery. PMID- 21819047 TI - Detection of possible economically motivated adulterants in heparin sodium and low molecular weight heparins with a colorimetric microplate based assay. AB - Recently, we described a 96-well plate format assay for visual detection of oversulfated chondroitin sulfate A (OSCS) contamination in heparin samples based on a water-soluble cationic polythiophene polymer (3-(2-(N-(N' methylimidazole))ethoxy)-4-methylthiophene (LPTP)) and heparinase digestion of heparin. Here, we establish the specificity of the LPTP/heparinase test with a unique set of reagents that define the structural requirements for significant LPTP chemosensor color change. For example, we observed a biphasic behavior of larger shifts to the red in the UV absorbance spectra with decreasing average molecular weight of heparin chains with a break below 12-mer chain lengths. In addition, the oversulfation of chondroitin sulfate A (CSA) to a partially (PSCS) or fully (OSCS) sulfated form caused progressively less red shift of LPTP solutions. Furthermore, glycosaminoglycans (GAGs) containing glucuronic acid caused distinct spectral patterns compared to iduronic acid containing GAGs. We applied the LPTP/heparinase test to detection of OSCS (>=0.03% (w/w) visually or 0.01% using a plate reader) in 10 MUg amounts of low molecular weight heparins (LMWHs; i.e. dalteparin, tinzaparin, or enoxaparin). Furthermore, because other oversulfated GAGs are possible economically motivated adulterants (EMAs) in heparin sodium, we tested the capacity of the LPTP/heparinase assay to detect oversulfated dermatan sulfate (OSDS), heparin (OSH), and heparan sulfate (OSHS). These potential EMAs were visually detectable at a level of ~0.1% when spiked into heparin sodium. We conclude that the LPTP/heparinase test visually detects oversulfated GAGs in heparin sodium and LMWHs in a format potentially amenable to high-throughput screening. PMID- 21819048 TI - In situ preparation of highly fluorescent dyes upon photoirradiation. AB - Photoswitchable or photoactivatable fluorescent dyes are potentially applicable to ultrahigh density optical memory media as well as super-resolution fluorescence imaging when the dyes are highly fluorescent and have large absorption coefficients. Here, we report on highly fluorescent photochromic dyes, which are initially nonluminous in solution under irradiation with visible light but activated to emit green or red fluorescence upon irradiation with ultraviolet (UV) light. The dyes 5a-9a are sulfone derivatives of 1,2-bis(2-ethyl-6-phenyl(or thienyl)-1-benzothiophen-3-yl)perfluorocyclopentene. It was found that substitution of phenyl or thiophene rings at 6 and 6' positions of the benzothiophene-1,1-dioxide groups is effective to increase the fluorescence quantum yields of the closed-ring isomers over 0.7 and absorption coefficients over 4 * 10(4) M(-1) cm(-1). The phenyl-substituted derivatives 5a-7a undergo photocyclization reactions to produce yellow closed-ring isomers 5b-7b, which emit brilliant green fluorescence at around 550 nm (Phi(F) = 0.87-0.88) under irradiation with 488 nm light. Any absorption intensity change of the closed-ring isomers was not observed even after 100 h storage in the dark at 80 degrees C. The closed-ring isomers slowly returned to the initial open-ring isomers upon irradiation with visible (lambda > 480 nm) light. The ring-opening quantum yields (Phi(C->O)) were measured to be (1.6-4.0) * 10(-4). When the phenyl substituents are replaced with thiophene rings, such as compounds 8a and 9a, the absorption bands of the closed-ring isomers shift to longer than 500 nm. The closed-ring isomers exhibit brilliant red fluorescences at around 620 nm (Phi(F) = 0.61-0.78) under irradiation with 532 nm light. The ring-opening reactions are very slow (Phi(C->O) < 1 * 10(-5)). The fluorescence lifetimes of these sulfone derivatives were measured to be around 2-3 ns, which is much longer than the value of the closed-ring isomer of 1,2-bis(2-methyl-1-benzothiophen-3-yl)perfluorocyclopentene (tau(F) = 4 and 22 ps). The closed-ring isomer 8b in 1,4-dioxane exhibits excellent fatigue resistant property under irradiation with visible light (lambda > 440 nm) superior to the stability of Rhodamine 101 in ethanol. PMID- 21819049 TI - Dinuclear silylium-enolate bifunctional active species: remarkable activity and stereoselectivity toward polymerization of methacrylate and renewable methylene butyrolactone monomers. AB - Novel dinuclear silylium-enolate active species, consisting of an electrophilic silylium catalyst site and a nucleophilic silicon enolate initiating site that are covalently linked as single molecules, and their unique polymerization characteristics and kinetics are reported. Such unimolecular, bifunctional propagating species are conveniently generated from activation of ethyl- and oxo bridged disilicon enolate (i.e., disilyl ketene acetal, di-SKA) compounds with [Ph(3)C][B(C(6)F(5))(4)]. Both the ethyl- and oxo-bridged dinuclear species are much more active for the polymerization of methyl methacrylate (MMA) than the mononuclear SKA-based active species, exhibiting an approximate rate enhancement by a factor of 12 and 44, respectively. The oxo-bridged silylium-enolate species is considerably more active and controlled than the ethyl-bridged one, with their differences being even more pronounced in polymerizing a renewable monomer, gamma methyl-alpha-methylene-gamma-butyrolactone. The polymerization by the oxo-bridged silylium-enolate active species follows first-order kinetics in both monomer and silylium catalyst concentrations, indicating a unimolecular propagation mechanism which involves an intramolecular delivery of the polymeric enolate nucleophile to the monomer activated by the silylium ion electrophile being placed in proximity in the same catalyst molecule. Highly stereoregular poly(methyl methacrylate) (PMMA), with a syndiotacticity up to 92% rr, can be produced in quantitative yield using the oxo-bridged propagator at low temperature. PMID- 21819050 TI - S(T) = 22 [Mn10] supertetrahedral building-block to design extended magnetic networks. AB - The controlled organization of high-spin complexes, eventually single-molecule magnets, is a great challenge in molecular sciences to probe the possibility to design sophisticated magnetic systems to address a large quantity of magnetic information. The coordination chemistry is a tool of choice to make such materials. In this work, high-spin S(T) = 22 [Mn(10)] complexes, such as [Mn(III)(6)Mn(II)(4)(L(1))(6)(MU(4)-O)(4)(MU(3) N(3))(4)(CH(3)CN)(11)(H(2)O)].(ClO(4))(2).(CH(3)CN)(8.5) (1), have been assembled using (i) 1,3-propanediol derivatives as chelating ligands to form the [Mn(10)] core units and (ii) dicyanamide or azide anions as linkers to synthesize the first 2D and 3D [Mn(10)]-based networks: [Mn(III)(6)Mn(II)(4)(L(2))(6)(MU(3) N(3))(4)(MU(4)-O)(4)(CH(3)OH)(4)(dca)(2)] (2) and [Mn(III)(6)Mn(II)(4)(L(3))(6)(MU(3)-N(3))(4)(MU(4)-O)(4)(N(3))(2)].(CH(3)OH)(4) (3). The synthesis of these compounds is reported together with their single crystal X-ray structures and magnetic properties supported by DFT calculations. In the reported synthetic conditions, the stability of the [Mn(10)] complex is remarkably good that allows us to imagine many new materials combining these high spin moieties and other diamagnetic but also paramagnetic linkers to design for example ordered magnets. PMID- 21819051 TI - Single-stranded oligonucleotide adducts formed by Pt complexes favoring left handed base canting: steric effect of flanking residues and relevance to DNA adducts formed by Pt anticancer drugs. AB - Platinum anticancer drug binding to DNA creates large distortions in the cross link (G*G*) and the adjacent XG* base pair (bp) steps (G* = N7-platinated G). These distortions, which are responsible for anticancer activity, depend on features of the duplex (e.g., base pairing) and of the cross-link moiety (e.g., the position and canting of the G* bases). The duplex structure stabilizes the head-to-head (HH) over the head-to-tail (HT) orientation and right-handed (R) over left-handed (L) canting of the G* bases. To provide fundamental chemical information relevant to the assessment of such duplex effects, we examine (S,R,R,S)-BipPt(oligo) adducts (Bip = 2,2'-bipiperidine with S,R,R,S chiral centers at the N, C, C, and N chelate ring atoms, respectively; oligo = d(G*pG*) with 3'- and/or 5'-substituents). The moderately bulky (S,R,R,S)-Bip ligand favors L canting and slows rotation about the Pt-G* bonds, and the (S,R,R,S) BipPt(oligo) models provide more useful data than do dynamic models derived from active Pt drugs. All 5'-substituents in (S,R,R,S)-BipPt(oligo) adducts favor the normal HH conformer (~97%) by destabilizing the HT conformer through clashes with the 3'-G* residue rather than through favorable H-bonding interactions with the carrier ligand in the HH conformer. For all (S,R,R,S)-BipPt(oligo) adducts, the S pucker of the 5'-X residue is retained. For these adducts, a 5'-substituent had only modest effects on the degree of L canting for the (S,R,R,S)-BipPt(oligo) HH conformer. This small flanking 5'-substituent effect on an L-canted HH conformer contrasts with the significant decrease in the degree of R canting previously observed for flanking 5'-substituents in the R-canted (R,S,S,R)-BipPt(oligo) analogues. The present data support our earlier hypothesis that the distortion distinctive to the XG* bp step (S to N pucker change and movement of the X residue) is required for normal stacking and X.X' WC H bonding and to prevent XG* residue clashes. PMID- 21819052 TI - Properties, solution state behavior, and crystal structures of chelates of DOTMA. AB - The chemistry of polyamino carboxylates and their use as ligands for Ln(3+) ions is of considerable interest from the point of view of the development of new imaging agents. Of particular interest is the chemistry of the macrocyclic ligand 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and its derivatives. Herein we report that the tetramethylated DOTA derivative, DOTMA, possess several properties that, from an imaging agent development point of view, are more advantageous than those of the parent DOTA. In particular, the Ln(3+) chelates of DOTMA exhibit a marked preference for the monocapped twisted square antiprismatic coordination isomer which imparts more rapid water exchange kinetics on the chelates; tau(M)(298) was determined to be 85 ns for GdDOTMA. Differential analysis of the (17)O R(2rho) temperature profiles of both GdDOTA and GdDOTMA afforded the tau(M)(298) values for the square (SAP) and twisted square antiprismatic (TSAP) isomers of each chelate that were almost identical: 365 ns (SAP) and 52 ns (TSAP). The origin of this accelerated water exchange in the TSAP isomer appears to be the slightly longer Gd-OH(2) bond distance (2.50 A) that is observed in the crystal structure of GdDOTMA which crystallizes in the P(2) space group as a TSAP isomer. The Ln(3+) chelates of DOTMA also exhibit high thermodynamic stabilities ranging from log K(ML) = 20.5 for CeDOTMA, 23.5 for EuDOTMA and YbDOTMA comparable to, but a shade lower than, those of DOTA. PMID- 21819054 TI - Modeling structures and vibrational frequencies for dinitrosyl iron complexes (DNICs) with density functional theory. AB - The biochemical and physiological importance of nitric oxide (NO) in signaling and vasodilation has been studied for several decades. The discovery of both protein-bound and free low molecular weight dinitrosyl iron complexes (DNICs) suggests that such compounds might play roles in biological NO storage and transport. These complexes have important distinguishing spectroscopic features, including EPR and Mossbauer spectra, and NO vibrational frequencies (nu((NO))). The latter are particularly sensitive to modifications of the ligand environment and metal oxidation states. Examinations of functionals and basis sets delineate their effect on the NO vibrational frequencies and allow development of a methodology to calculate these frequencies in other DNICs. Three complexes of the form (L)(CO)Fe(NO)(2) (L = CO, N,N'-dimethyl-imidazol-2-ylidene (IMe) or 1 methylimidazole (MeImid)), where {Fe(NO)(2)}(10) is in its reduced form, have been used to calibrate the vibrational frequencies. The functional BP86 paired with a basis set of SDD/ECP on the metal and 6-311++G(d,p) on the ligand atoms exhibits the most accurate results, with deviations from experimental vibrational frequencies of no more than +/-40 cm(-1). Subsequent investigations were performed on a series of diiron trinitrosyl complexes of the form {Fe(NO)}(7) {Fe(NO)(2)}(9) bridged by sulfurs, namely, [(ON)Fe(MU-S,S-C(6)H(4))(2)Fe(NO)(2)]( ), [Fe(NO)(2){Fe(NS(3))(NO)}-MU-S,S'], and [(ON)Fe(bme-dach)Fe(NO)(2)-MU S,S'](+), with the ideal functional/basis set pair determined via the aforementioned test set. The ground state energetics (singlet/triplet/singlet, respectively), geometric parameters, and nitrosyl vibrational frequencies were calculated. The results for the former two complexes correlated well with the experimental work, and in contrast with what was reported in an earlier computational study, a stable triplet ground state structure was optimized for [Fe(NO)(2){Fe(NS(3))(NO)}-MU-S,S']. For [(ON)Fe(bme-dach)Fe(NO)(2)-MU-S,S'](+), whose synthesis and structure were recently reported, the geometric parameters, vibrational frequencies, and total energies compare well to experimental ones and favor a singlet ground state. PMID- 21819053 TI - Analysis of the conformational behavior and stability of the SAP and TSAP isomers of lanthanide(III) NB-DOTA-type chelates. AB - Controlling the water exchange kinetics of macrocyclic Gd(3+) chelates, a key parameter in the design of improved magnetic resonance imaging (MRI) contrast media, may be facilitated by selecting the coordination geometry of the chelate. The water exchange kinetics of the mono- capped twisted square antiprism (TSAP) being much closer to optimal than those of the mono capped square antiprism (SAP) render the TSAP isomer more desirable for high relaxivity applications. Two systems have been developed that allow for selection of the TSAP coordination geometry in 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-type Gd(3+) chelates, both based upon the macrocycle nitrobenzyl cyclen. In this paper we report investigations into the stability and formation of these chelates. Particular focus is given to the production of two regioisomeric chelates during the chelation reaction. These regioisomers are distinguished by having the nitrobenzyl substituent either on a corner or on the side of the macrocyclic ring. The origin of these two regioisomers appears to stem from a conformation of the ligand in solution in which it is hypothesized that pendant arms lie both above and below the plane of the macrocycle. The conformational changes that then result during the formation of the intermediate H(2)GdL(+) chelate give rise to differing positions of the nitrobenzyl substituent depending upon from which face of the macrocycle the Ln(3+) approaches the ligand. PMID- 21819055 TI - Doping of calcium in C(60) fullerene for enhancing CO(2) capture and N(2)O transformation: a theoretical study. AB - Recently, capturing or transforming greenhouse gases, such as CO(2) and N(2)O, have attracted considerable interest from the perspective of environmental protection. In the present work, by studying CO(2) and N(2)O adsorption on pristine and calcium (Ca)-decorated fullerenes (C(60)) with density functional theory (DFT) methods, we have evaluated the potential application of this C(60) based complex for the capture of CO(2) and transformation of N(2)O. The results indicate that the adsorptions of CO(2) and N(2)O molecules on the pristine C(60) are considerably weak accompanied by neglectable charge transfer. When C(60) is decorated with Ca atoms, however, it is found that CO(2) and N(2)O adsorptions on the C(60) are greatly enhanced. Up to five CO(2) molecules can be adsorbed on the CaC(60) system due to the electrostatic interaction. For N(2)O molecule, it is first molecularly adsorbed on the Ca atom with the adsorption energy of -0.534 eV, followed by the N(2) formation with a low barrier and high exothermicity. Moreover, when four Ca atoms are decorated on the surface of C(60), the maximum number of the adsorbed CO(2) molecules is 16. Our results might be useful not only to widen the potential applications of fullerene but also to provide an effective method to capture or transform greenhouse gases. PMID- 21819056 TI - Self-complementary quadruply hydrogen-bonded duplexes based on imide and urea units. AB - The quadruply hydrogen-bonded duplexes based on an imide-urea structure preorganized by three-center hydrogen bonds were found to associate via bifurcated hydrogen bonds. (1)H NMR dilution experiments revealed the high stability of the homodimer in apolar solvent (K(dim) > 10(5) M(-1) in CDCl(3)) and enhancement of association ability due to electron-withdrawing substituent effects. The ready synthetic availability and adjustable association affinity via electronic effects may render these association units potentially applicable in constructing supramolecular architectures. PMID- 21819057 TI - Synthesis of new metalloporphyrin triads: efficient and versatile tripod optical sensor for the detection of amines. AB - Zinc and manganese complexes of porphyrin triads have been synthesized and are shown to be efficient as highly sensitive and selective tripod optical sensors for amines at the picomolar level. PMID- 21819058 TI - Dual supramolecular photochirogenesis: ultimate stereocontrol of photocyclodimerization by a chiral scaffold and confining host. AB - In contrast to the brilliant success in thermal asymmetric synthesis, precise stereocontrol remains a great challenge in chiral photochemistry because of the lack of effective tools and methodologies for controlling the short-lived, weakly interacting, and highly reactive electronically excited species. In this work, we achieved this goal through the "dual-chiral, dual-supramolecular" photochirogenesis approach, which enabled us to realized dramatic acceleration and perfect stereocontrol in one of the most representative photoreactions. Thus, the [4 + 4] photocyclodimerization of 2-anthracenecarboxylate tethered to an alpha-cyclodextrin scaffold was accelerated by a gamma-cyclodextrin or cucurbit[8]uril host and gave a single enantiomeric cyclodimer (out of four possible chiral and achiral stereoisomers) in up to 98% chemical and 99% optical yield. PMID- 21819059 TI - Controlling the interplay of electric and magnetic modes via Fano-like plasmon resonances. AB - Assemblies of strongly coupled plasmonic nanoparticles can support highly tunable electric and magnetic resonances in the visible spectrum. In this Letter, we theoretically demonstrate Fano-like interference effects between the fields radiated by the electric and magnetic modes of symmetric nanoparticle trimers. Breaking the symmetry of the trimer system leads to a strong interaction between the modes. The near and far-field electromagnetic properties of the broken symmetry trimer are tunable across a large spectral range. We exploit this Fano like effect to demonstrate spatial and temporal control of the localized electromagnetic hotspots in the plasmonic trimer. PMID- 21819060 TI - Fulvenallene decomposition kinetics. AB - While the decomposition kinetics of the benzyl radical has been studied in depth both from the experimental and the theoretical standpoint, much less is known about the reactivity of what is likely to be its main decomposition product, fulvenallene. In this work the high temperature reactivity of fulvenallene was investigated on a Potential Energy Surface (PES) consisting of 10 wells interconnected through 11 transition states using a 1 D Master Equation (ME). Rate constants were calculated using RRKM theory and the ME was integrated using a stochastic kinetic Monte Carlo code. It was found that two main decomposition channels are possible, the first is active on the singlet PES and leads to the formation of the fulvenallenyl radical and atomic hydrogen. The second requires intersystem crossing to the triplet PES and leads to acetylene and cyclopentadienylidene. ME simulations were performed calculating the microcanonical intersystem crossing frequency using Landau-Zener theory convoluting the crossing probability with RRKM rates evaluated at the conical intersection. It was found that the reaction channel leading to the cyclopentadienylidene diradical is only slightly faster than that leading to the fulvenallenyl radical, so that it can be concluded that both reactions are likely to be active in the investigated temperature (1500-2000 K) and pressure (0.05-50 bar) ranges. However, the simulations show that intersystem crossing is rate limiting for the first reaction channel, as the removal of this barrier leads to an increase of the rate constant by a factor of 2-3. Channel specific rate constants are reported as a function of temperature and pressure. PMID- 21819061 TI - Synthesis of quinolines via Rh(III)-catalyzed oxidative annulation of pyridines. AB - Selective synthesis of quinolines has been achieved via oxidative annulation of functionalized pyridines with two alkyne molecules under Rh(III)-catalyzed cascade C-H activation of pyridines using Cu(OAc)(2) as an oxidant. The selectivity of this reaction is oxidant-dependent, particularly on the anion of the oxidant. PMID- 21819062 TI - Pressure-dependent OH yields in alkene + HO2 reactions: a theoretical study. AB - The major bimolecular product of alkyl + O(2) reactions is alkene + hydroperoxyl radical (HO(2)), but in the reverse direction, the reactants are reformed to a very limited extent only. The most important products of the alkene + HO(2) reactions are alkylperoxy radical (ROO(*)), hydroxyl radical (OH) + cyclic ether, and the corresponding hydroperoxyalkyl ((*)QOOH) species. Moreover, abstraction of allylic hydrogens can compete with the addition, further complicating the possible outcome of this reaction type and its effect on low-temperature combustion chemistry. In this paper, six alkene + HO(2) reactions and the reaction between an unsaturated oxygenate and HO(2) are studied based on previously established potential energy surfaces. The studied unsaturated compounds are ethene, propene, 1-butene, trans-2-butene, isobutene, cyclohexene, and vinyl alcohol. Using multiwell master equations, temperature- (300-1200 K) and pressure-dependent rate coefficients and branching fractions are calculated for these reactions. The importance of this reaction type for the combustion of unsaturated compounds is also assessed, and we show that, to get reliable results, it is important to include the pressure-dependence of the rate coefficients in the calculations. PMID- 21819063 TI - Additive-free clicking for polymer functionalization and coupling by tetrazine norbornene chemistry. AB - Herein we report the use of a tetrazine-norbornene inverse electron demand Diels Alder conjugation applied to polymer end-functionalization and polymer-polymer coupling. The reaction was found to be applicable to polymer-polymer coupling, as judged by SEC, DOSY NMR, and LCxSEC analyses, giving diblock copolymers by merely mixing the constituent homopolymers together under ambient conditions, using no catalyst, additive, or external stimulus. PMID- 21819064 TI - Porous siloxane-organic hybrid with ultrahigh surface area through simultaneous polymerization-destruction of functionalized cubic siloxane cages. AB - A novel hierarchically porous, hyper-cross-linked siloxane-organic hybrid (PSN-5) has been synthesized by Friedel-Crafts self-condensation of benzyl chloride terminated double-four-ring cubic siloxane cages as a singular molecular precursor. Simultaneous polymerization of the organic functional groups and destruction of the siloxane cages during synthesis yielded PSN-5, which has an ultrahigh BET surface area (~2500 m(2) g(-1)) and large pore volume (~3.3 cm(3) g(-1)) that to our knowledge are the highest values reported for siloxane-based materials. PSN-5 also shows a high H(2) uptake of 1.25 wt % at 77 K and 760 Torr. PMID- 21819065 TI - Anomalous thermal expansion in the square-net compounds RE4TGe8 (RE = Yb, Gd; T = Cr-Ni, Ag). AB - The family of materials RE(4)TGe(8) (RE = Yb, Gd; T = transition metal) exhibits directional zero thermal expansion (ZTE) via a process that is associated with the linking of planar square nets in the third dimension. The Ge square nets in these compounds exhibit commensurate long-range modulations similar to those observed in charge-density-wave compounds. The ZTE is manifested in the plane of the square nets from 10 to 300 K with negligible volume expansion below ~160 K. The specific atomic arrangement in RE(4)TGe(8) enables a Poisson-like mechanism that allows the structure to contract along one direction as it expands only slightly in the perpendicular direction. PMID- 21819066 TI - Hydrogen confinement in carbon nanopores: extreme densification at ambient temperature. AB - In-situ small-angle neutron scattering studies of H(2) confined in small pores of polyfurfuryl alcohol-derived activated carbon at room temperature have provided for the first time its phase behavior in equilibrium with external H(2) at pressures up to 200 bar. The data were used to evaluate the density of the adsorbed fluid, which appears to be a function of both pore size and pressure and is comparable to the density of liquid H(2) in narrow nanopores at ~200 bar. The surface-molecule interactions responsible for densification of H(2) within the pores create internal pressures that exceed the external gas pressure by a factor of up to ~50, confirming the benefits of adsorptive storage over compressive storage. These results can be used to guide the development of new carbon adsorbents tailored for maximum H(2) storage capacities at near-ambient temperatures. PMID- 21819067 TI - Influence of arsenate adsorption to ferrihydrite, goethite, and boehmite on the kinetics of arsenate reduction by Shewanella putrefaciens strain CN-32. AB - The kinetics of As(V) reduction by Shewanella putrefaciens strain CN-32 was investigated in suspensions of 0.2, 2, or 20 g L(-1) ferrihydrite, goethite, or boehmite at low As (10 MUM) and lactate (25 MUM) concentrations. Experimental data were compared with model predictions based on independently determined sorption isotherms and rates of As(V) desorption, As(III) adsorption, and microbial reduction of dissolved As(V), respectively. The low lactate concentration was chosen to prevent significant Fe(III) reduction, but still allowing complete As(V) reduction. Reduction of dissolved As(V) followed first order kinetics with a 3 h half-life of As(V). Addition of mineral sorbents resulted in pronounced decreases in reduction rates (32-1540 h As(V) half-life). The magnitude of this effect increased with increasing sorbent concentration and sorption capacity (goethite < boehmite < ferrihydrite). The model consistently underestimated the concentrations of dissolved As(V) and the rates of microbial As(V) reduction after addition of S. putrefaciens (~5 * 10(9) cells mL(-1)), suggesting that attachment of S. putrefaciens cells to oxide mineral surfaces promoted As(V) desorption and thereby facilitated As(V) reduction. The interplay between As(V) sorption to mineral surfaces and bacterially induced desorption may thus be critical in controlling the kinetics of As reduction and release in reducing soils and sediments. PMID- 21819068 TI - Formation mechanisms of gold-zinc oxide hexagonal nanopyramids by heterogeneous nucleation using microwave synthesis. AB - This work reports the development of a fast and simple "one-pot" route for the synthesis of hybrid Au-ZnO hexagonal nanopyramids by sequential homogeneous heterogeneous nucleation steps involving both Au and Zn ions using microwave irradiation (MWI). The rapid decomposition of zinc acetate by MWI in the presence of a mixture of oleic acid (OAc) and oleylamine (OAm) results in the formation of hexagonal ZnO nanopyramids. In the presence of Au ions, the initially formed Au nanocrystals act as heterogeneous nuclei for the nucleation and growth of the ZnO nanopyramids. The Au nanoparticles promote the heterogeneous nucleation of ZnO and the formation of the hexagonal base of the ZnO nanopyramids. Using preformed Au nanoparticles instead of Au ions results in a narrow size distribution of uniform Au-ZnO nanopyramids, each consisting of a gold nanoparticle embedded in the center of the hexagonal base of the ZnO nanopyramid. We study the factors that control the nucleation and growth of these complex structures, and provide new insights into the stepwise homogeneous-heterogeneous mechanism and the conventional heterogeneous nucleation on preformed Au nanoparticles. The formation of the hetero nanostructures Au-ZnO nanopyramids is strongly dependent on the molar ratios of OAc to OAm. The presence of OAc with a considerable dipole moment results in strong electrostatic interaction with the polar surfaces of the growing ZnO nanocrystals thus resulting in slowing the growth rate of the polar planes and allowing the formation of well-developed facets. In the absence of Au nanoparticles, a high concentration of zinc acetate and longer MWI times are required for the production of the nanopyramids. The gold nanoparticles could provide the metallic contact points within the hybrid nanopyramids which could facilitate the bottom-up assembly of Au-ZnO devices. Furthermore, the Au-ZnO nanopyramids could have improved performance in solar energy conversion and photocatalysis. PMID- 21819069 TI - Proton delivery to ferryl heme in a heme peroxidase: enzymatic use of the Grotthuss mechanism. AB - We test the hypothesized pathway by which protons are passed from the substrate, ascorbate, to the ferryl oxygen in the heme enzyme ascorbate peroxidase (APX). The role of amino acid side chains and bound solvent is demonstrated. We investigated solvent kinetic isotope effects (SKIE) for the wild-type enzyme and several site-directed replacements of the key residues which form the proposed proton path. Kinetic constants for H(2)O(2)-dependent enzyme oxidation to Compound I, k(1), and subsequent reduction of Compound II, k(3), were determined in steady-state assays by variation of both H(2)O(2) and ascorbate concentrations. A high value of the SKIE for wild type APX ((D)k(3) = 4.9) as well as a clear nonlinear dependence on the deuterium composition of the solvent in proton inventory experiments suggest the simultaneous participation of several protons in the transition state for proton transfer. The full SKIE and the proton inventory data were modeled by applying Gross-Butler-Swain-Kresge theory to a proton path inferred from the known structure of APX. The model has been tested by constructing and determining the X-ray structures of the R38K and R38A variants and accounts for their observed SKIEs. This work confirms APX uses two arginine residues in the proton path. Thus, Arg38 and Arg172 have dual roles, both in the formation of the ferryl species and binding of ascorbate respectively and to facilitate proton transfer between the two. PMID- 21819070 TI - Cavitation and pore blocking in nanoporous glasses. AB - In gas adsorption studies, porous glasses are frequently referred to as model materials for highly disordered mesopore systems. Numerous works suggest that an accurate interpretation of physisorption isotherms requires a complete understanding of network effects upon adsorption and desorption, respectively. The present article deals with nitrogen and argon adsorption at different temperatures (77 and 87 K) performed on a series of novel nanoporous glasses (NPG) with different mean pore widths. NPG samples contain smaller mesopores and significantly higher microporosity than porous Vycor glass or controlled pore glass. Since the mean pore width of NPG can be tuned sensitively, the evolution of adsorption characteristics with respect to a broadening pore network can be investigated starting from the narrowest nanopore width. With an increasing mean pore width, a H2-type hysteresis develops gradually which finally transforms into a H1-type. In this connection, a transition from a cavitation-induced desorption toward desorption controlled by pore blocking can be observed. Furthermore, we find concrete hints for a pore size dependence of the relative pressure of cavitation in highly disordered pore systems. By comparing nitrogen and argon adsorption, a comprehensive insight into adsorption mechanisms in novel disordered materials is provided. PMID- 21819073 TI - Innovation in analytical chemistry. PMID- 21819071 TI - 2H kinetic isotope effects and pH dependence of catalysis as mechanistic probes of rat monoamine oxidase A: comparisons with the human enzyme. AB - Monoamine oxidase A (MAO A) is a mitochondrial outer membrane-bound flavoenzyme important in the regulation of serotonin and dopamine levels. Because the rat is extensively used as an animal model in drug studies, it is important to understand how rat MAO A behaves in comparison with the more extensively studied human enzyme. For many reversible inhibitors, rat MAO A exhibits K(i) values similar to those of human MAO A. The pH profile of k(cat) for rat MAO A shows a pK(a) of 8.2 +/- 0.1 for the benzylamine ES complex and pK(a) values of 7.5 +/- 0.1 and 7.6 +/- 0.1 for the ES complexes with p-CF(3)-(1)H- and p-CF(3)-(2)H benzylamine, respectively. In contrast to the human enzyme, the rat enzyme exhibits a single pK(a) value (8.3 +/- 0.1) with k(cat)/K(m) for benzylamine versus pH and pK(a) values of 7.8 +/- 0.1 and 8.1 +/- 0.2 for the ascending limbs, respectively, of k(cat)/K(m) versus pH profiles for p-CF(3)-(1)H- and p CF(3)-(2)H-benzylamine and 9.3 +/- 0.1 and 9.1 +/- 0.2 for the descending limbs, respectively. The oxidation of para-substituted benzylamine substrate analogues by rat MAO A has large deuterium kinetic isotope effects on k(cat) and on k(cat)/K(m). These effects are pH-independent and range from 7 to 14, demonstrating a rate-limiting alpha-C-H bond cleavage step in catalysis. Quantitative structure-activity correlations of log k(cat) with the electronic substituent parameter (sigma) at pH 7.5 and 9.0 show a dominant contribution with positive rho values (1.2-1.3) and a pH-independent negative contribution from the steric term. Quantitative structure-activity relationship analysis of the binding affinities of the para-substituted benzylamine analogues for rat MAO A shows an increased van der Waals volume (V(w)) increases the affinity of the deprotonated amine for the enzyme. These results demonstrate that rat MAO A exhibits functional properties similar but not identical with those of the human enzyme and provide additional support for C-H bond cleavage via a polar nucleophilic mechanism. PMID- 21819075 TI - Net heterolytic cleavage of B-H and B-B bonds across the N-Pd bond in a cationic (PNP)Pd fragment. AB - The use of weakly coordinating anions BAr(F)(4) (where Ar(F) = 3,5 (CF(3))(2)C(6)H(3)) and CB(11)H(12) allows one to access clean reactions of the [(PNP)Pd](+) fragment (PNP = bis(2-(i)Pr(2)P4-Me-phenyl)amido) with the B-H bond in catecholborane (CatBH) and catecholdiboron (CatBBCat). In both cases, a net heterolytic cleavage of B-H or B-B takes place, with the nitrogen atom of PNP being a recipient of a boryl fragment. The resultant products [(PN(BCat)P)PdH](+) (2) and [(PN(BCat)P)PdBCat](+) (3) were isolated as either BAr(F)(4) or CB(11)H(12) salts and fully characterized. They are susceptible to hydrolysis, with the B-N bond hydrolyzing selectively and rapidly at RT to give [(PN(H)P)PdH](+) (1) and [(PN(H)P)PdBCat](+) (4). Notably, 4 and 2 are isomers, but they do not interconvert even under thermolysis at 90 degrees C. The Pd-B bond in 4 can be further hydrolyzed more slowly, to give 1. On the other hand, a Pd-B bond was formed from the Pd-H bond in 2 by reaction with excess CatBH (and evolution of H(2)), producing 3. PMID- 21819074 TI - Immuno-surface-enhanced coherent anti-stokes Raman scattering microscopy: immunohistochemistry with target-specific metallic nanoprobes and nonlinear Raman microscopy. AB - Immunohistochemistry (IHC) is one of the most widely used staining techniques for diagnostic purposes. The selective localization of target proteins in tissue specimens by conventional IHC is achieved with dye- or enzyme-labeled antibodies in combination with light microscopy. In this contribution, we demonstrate the proof-of-principle for IHC based on surface-enhanced coherent Raman scattering for contrast generation. Specifically, antibody-labeled metallic nanoshells in conjunction with surface-enhanced coherent anti-Stokes Raman scattering (SECARS) microscopy are employed for the selective, sensitive, and rapid localization of the basal cell protein p63 in normal prostate tissue. Negative control experiments were performed in order to confirm the selective binding of the target-specific metal nanoprobes and to disentangle the role of plasmonic (metal) and molecular (Raman reporter) resonances in this plasmon-assisted four-wave mixing technique. PMID- 21819076 TI - Magnetic ordering in three-dimensional metal-organic frameworks based on carboxylate bridged square-grid layers. AB - Three isomorphous metal-organic frameworks of formula [M(ppdc)(H(2)O)(2)](n) [M = Mn(II), Fe(II), and Co(II)] were synthesized from sodium p-phenylenediacrylic (Na(2)ppdc). Crystallographic studies revealed that the compounds are layer pillared 3D frameworks in which the square-grid M(II) layers with single carboxylate bridges are interlinked by long organic spacers with large interlayer separations of about 13 A. Magnetic investigations indicated that they all display intralayer antiferromagnetic interactions through the carboxylate bridges in the unusual skew-skew coordination mode but the bulk behaviors are quite different. The Co(II) compound, like most compounds containing similar M-O-C-O-M layers, shows no 3D magnetic ordering down to 2 K, while the Mn(II) and Fe(II) compounds exhibit spin-canted ordering, behaving as a weak ferromagnet (T(C) = 3.8 K) and a metamagnet (T(N) = 3.8 K, H(c) = 650 Oe), respectively. Spin-canted ordering is still a rarity in this series of materials. Magnetostructural comparisons with analogous compounds indicate that the occurrence of spin-canted ordering can be related to the uncommon skew-skew and anti-anti coordination modes of carboxylate bridges, which induce stronger antiferromagnetic interactions than the common syn-anti mode. PMID- 21819077 TI - Palladium-catalyzed intramolecular C(sp2)-H amidination by isonitrile insertion provides direct access to 4-aminoquinazolines from N-arylamidines. AB - An efficient method for the synthesis of 4-amino-2-aryl(alkyl)quinazolines from readily available N-arylamidines and isonitriles via palladium-catalyzed intramolecular aryl C-H amidination by isonitrile insertion has been developed. PMID- 21819078 TI - Saddle shaped hexaaryl[a,c,fg,j,l,op]tetracenes from 4,5,9,10-tetrafunctionalized pyrenes. AB - A new K-region functionalized pyrene is presented which was used as a building block for the straightforward synthesis of hexaaryl[a,c,fg,j,l,op]tetracene via fourfold Stille coupling and subsequent cyclodehydrogenation. Electronic properties and crystal structures are provided and reveal a saddle conformation for the curved hexaarylated tetracenes. PMID- 21819079 TI - Occurrence and toxicity of three classes of insecticides in water and sediment in two Southern California coastal watersheds. AB - The occurrence of chlorpyrifos, diazinon, pyrethroids, and fipronil was investigated in two watersheds along the southern California coast. Paired surface water and sediment samples were collected under dry and wet (after significant rain events) weather conditions. Insecticide concentrations in water and sediment were higher following rain events than during the dry season. Chlorpyrifos was the most frequently detected compound (>88%). Pyrethroids were detected in 74 and 100% of the water and sediment samples, respectively, with bifenthrin detected most frequently. Trans-permethrin was detected at the highest concentration followed by bifenthrin. Bifenthrin and trans-permethrin water concentrations were significantly correlated (P < 0.01) with the suspended solid level, suggesting transport facilitated by suspended particles. In 80% of the wet season samples with 100% of Ceriodaphnia dubia mortality, chlorpyrifos concentrations were >100 ng L(-1). Sediment pyrethroid levels (0.5-1100 ng g(-1)) were frequently higher than the respective Hyalella azteca LC(50) values, with bifenthrin as the primary contributor of H. azteca toxicity. PMID- 21819080 TI - Potential diffusion of doramectin into a soil amended with female pig manure. A field experiment. AB - Doramectin is a veterinary drug used as an antihelminthic and is excreted mainly in the feces as the nonmetabolized drug. This study investigated the time profile of doramectin excretion in pig feces and the potential transfer and persistence of doramectin in the soil when the pig manure is used as an organic amendment to the soil. The concentration of doramectin in feces peaked at 143.0 ng/g in the dry feces 4 days after treatment. On day 62, the drug was still detected in the pig feces. After the land application of pig manure, the maximum concentration of doramectin in soil (ppb level) was detected 6 days after treatment. Seven months after the manure application, traces of doramectin were detected in the soil from the surface to a depth of 90 cm. Successive applications of manure from pigs treated with doramectin in a specific area could produce an accumulation of this drug in the soil. PMID- 21819081 TI - Changes in phenolic content of tomato products during storage. AB - The effect of storage on the total polyphenol content and individual phenolic compounds as well as on the hydrophilic antioxidant capacity of ketchups and tomato juices was studied. The total polyphenol content was determined using the Folin-Ciocalteu assay, and the antioxidant capacity of the hydrophilic fraction was determined using DPPH and ABTS(+) assays. Individual polyphenols were identified and quantified using liquid chromatography/electrospray ionization tandem mass spectrometry on a triple quadrupole. All analyses were carried out for ketchups and tomato juices after storage for 3, 6, and 9 months. The total polyphenol content and antioxidant capacity of the hydrophilic fraction decreased during storage of ketchups and tomato juices. Ketchups, in general, showed a slightly greater stability during storage than tomato juices. The most significant decrease was observed for quercetin followed by caffeic and ferulic acids, whereas glycosilated polyphenols showed greater stability during storage. PMID- 21819084 TI - Pyrolysis of [14C]-chlorantraniliprole in tobacco. AB - The pyrolysis of [(14)C]-chlorantraniliprole {3-bromo-1-(3-chloro-2-pyridinal)-N [4-chloro-2-methyl-6-[(methylamino)carbonyl]phenyl]-1H-pyrazole-5-carboxamide} in tobacco was examined. Typically five commercially available cigarettes were treated separately with either [pyrazole carbonyl-(14)C] or [benzamide carbonyl (14)C]-chlorantraniliprole at a concentration of 20 ppm (MUg chlorantraniliprole equivalent/g cigarette weight; main study) to 40 ppm (for degradate identification only). All treated cigarettes were smoked using an apparatus designed to collect mainstream (MS) and sidestream (SS) smoke through a glass fiber filter and a series of liquid traps. The material balance for recovery of applied radiolabel ranged from 92.4 to 94.9%. Unchanged chlorantraniliprole was the major component found in butt and filter extracts, averaging a total of 17.4 17.9% of the applied radioactivity. A nonpolar degradation product, 2-[3-bromo-1 (3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-chloro-3,8-dimethyl-4(3H) quinazolinone, designated 1, represented an average of 10.1-15.9% of the applied radioactivity in the [pyrazole carbonyl-(14)C] or [benzamide carbonyl-(14)C] chlorantraniliprole cigarettes, respectively. (14)CO(2) was the major degradate, representing an average of 32.9 and 25.1% of the applied radioactivity in pyrazole and benzamide experiments, respectively. In the pyrazole carbonyl label a polar degradate, 5-bromo-N-methyl-1H-pyrazole-3-carboxamide (2) was present in the filter extracts at an average of 9.5% of the applied radioactivity. The most nonpolar degradate, 2,6-dichloro-4-methyl-11H-pyrido[2,1b]quinazolin-11-one (3), was present in [benzamide carbonyl-(14)C]-treated cigarettes only and represented an average of 14.7% of the applied radioactivity. PMID- 21819083 TI - proTeOn and proTeOff, new protein devices that inducibly activate bacterial gene expression. AB - Using an original workflow, we have modeled, constructed, and characterized two new molecular devices that inducibly activate gene expression in Escherichia coli. The devices, prokaryotic-TetOn and prokaryotic-TetOff, were built by fusing an inducible DNA-binding protein domain to a transcription activation domain and constructing a complementary synthetic promoter sequence through which they could control downstream gene expression. In particular, the transactivators were built using variants of the tetracycline repressor, TetR, and the transactivating domain of the LuxR activator. The complementary promoter sequence included TetR's operator, tetO, and elements of the lux promoter. These specific protein domains and their operator sites were chosen as they have been thoroughly studied and well characterized. First, our methodology began with optimizing the geometry of the molecular components using molecular modeling. We did so to achieve an unprecedented combination of controllable and transactivating function in bacterial organisms. The devices were then built to activate the expression of green fluorescent protein. Their unique function was found to be robustly tight and activating many-fold increases of expressed gene levels, as measured by flow cytometry experiments. The devices were further characterized with stochastic kinetic models. The new devices presented herein may become useful additions to the molecular toolboxes used by biologists to control bacterial gene expression. The methodology used may also be a foundation for the design, development, and characterization of a library of such devices and more complex gene regulatory networks. PMID- 21819082 TI - Discovery, synthesis, and biological evaluation of novel SMN protein modulators. AB - Spinal muscular atrophy (SMA) is an autosomal recessive disorder affecting the expression or function of survival motor neuron protein (SMN) due to the homozygous deletion or rare point mutations in the survival motor neuron gene 1 (SMN1). The human genome includes a second nearly identical gene called SMN2 that is retained in SMA. SMN2 transcripts undergo alternative splicing with reduced levels of SMN. Up-regulation of SMN2 expression, modification of its splicing, or inhibition of proteolysis of the truncated protein derived from SMN2 have been discussed as potential therapeutic strategies for SMA. In this manuscript, we detail the discovery of a series of arylpiperidines as novel modulators of SMN protein. Systematic hit-to-lead efforts significantly improved potency and efficacy of the series in the primary and orthogonal assays. Structure-property relationships including microsomal stability, cell permeability, and in vivo pharmacokinetics (PK) studies were also investigated. We anticipate that a lead candidate chosen from this series may serve as a useful probe for exploring the therapeutic benefits of SMN protein up-regulation in SMA animal models and a starting point for clinical development. PMID- 21819085 TI - Repellent constituents of essential oil of Cymbopogon distans aerial parts against two stored-product insects. AB - The screening for bioactive principles from several Chinese medicinal herbs showed that the essential oil of Cymbopogon distans aerial parts possessed strong repellency against the booklouse, Liposcelis bostrychophila , and the red flour beetle, Tribolium castaneum . A total of 36 components of the essential oil were identified by GC and GC-MS. trans-Geraniol (16.54%), (R)-citronellal (15.44%), (+)-citronellol (11.51%), and alpha-elemol (9.06%) were the main components of the essential oil followed by beta-eudesmol (5.71%) and (+)-limonene (5.05%). From the essential oil, four monoterpenes were isolated by bioassay-guided fractionation. The compounds were identified as limonene, citronellol, citronellal, and trans-geraniol. Geraniol and citronellol were strongly repellent against the booklouse, L. bostrychophila, whereas citronellal and limonene exhibited weak repellency against the booklouse. Geraniol and citronellol exhibited comparable repellency against the booklouse relative to the positive control, DEET. Moreover, geraniol and citronellol exhibited stronger repellency against the red flour beetle than DEET, whereas the two other compounds showed the same level of repellency against the red flour beetle compared with DEET. PMID- 21819086 TI - The quest for modular nanocages: tbo-MOF as an archetype for mutual substitution, functionalization, and expansion of quadrangular pillar building blocks. AB - A new blueprint network for the design and synthesis of porous, functional 3D metal-organic frameworks (MOFs) has been identified, namely, the tbo net. Accordingly, tbo-MOFs based on this unique (3,4)-connected net can be exclusively constructed utilizing a combination of well-known and readily targeted [M(R BDC)](n) MOF layers [i.e., supermolecular building layers (SBLs)] based on the edge-transitive 4,4 square lattice (sql) (i.e., 2D four-building units) and a novel pillaring strategy based on four proximal isophthalate ligands from neighboring SBL membered rings (i.e., two pairs from each layer) covalently cross linked through an organic quadrangular core (e.g., tetrasubstituted benzene). Our strategy permits the rational design and synthesis of isoreticular structures, functionalized and/or expanded, that possess extra-large nanocapsule-like cages, high porosity, and potential for gas separation and storage, among others. Thus, tbo-MOF serves as an archetypal tunable, isoreticular MOF platform for targeting desired applications. PMID- 21819088 TI - Heavy metal contents of road-deposited sediment along the urban-rural gradient around Beijing and its potential contribution to runoff pollution. AB - Understanding the contribution of road-deposited sediment (RDS) and its washoff process is essential for controlling urban runoff pollution. Ninety-seven RDS samples were collected along the urban-suburban-rural gradient from areas of five administrative units in the Beijing metropolitan region, including central urban (UCA), urban village (UVA), central suburban county (CSA), rural town (RTA), and rural village (RVA) areas. RDS washoff was evaluated with different particle sizes using a rainfall simulator. Heavy metal elements (i.e., Cr, Cu, Ni, Pb, and Zn) were estimated in both RDS and runoff samples. The RDS mass per unit area increased in the order UCA (21 +/- 24 g/m(2)) ~ CSA (20 +/- 16 g/m(2)) < RTA (59 +/- 63 g/m(2)) < RVA (147 +/- 112 g/m(2)) ~ UVA (147 +/- 198 g/m(2)). Compared to RDS from the other administrative units, RDS from the UCA and CSA had higher metal concentrations and higher proportions of smaller particles, whereas that from the RVA and UVA had larger quantities of metals per unit area. UCA and CSA had lower potential runoff pollution contributions per unit area. Our findings imply that controlling the first flush in the UCA and CSA, and improving existing street cleaning methods and road surface conditions in the TRA, UVA, and RVA will be appropriate strategies for controlling runoff pollution from RDS. PMID- 21819087 TI - Selective recognition of americium by peptide-based reagents. AB - The separation of lanthanides from minor actinides such as americium and curium is an important step during the recycling process in the treatment of nuclear waste. However, the similar chemistry and ionic size of lanthanide and actinide ions make the separation challenging. Here, we report that a peptide-based reagent can selectively bind trivalent actinides over trivalent lanthanides by means of introducing soft-donor atoms into a peptide known as a lanthanide binding tag (LBT). Fluorescence spectroscopy has been used to measure the dissociation constant of each metal/peptide complex. A 10-fold selectivity was obtained for Am(3+) over the similarly sized lanthanide cation, Nd(3+), when the asparagine on the fifth position of a LBT was mutated to a cysteine and further functionalized by a pyridine moiety. PMID- 21819089 TI - Heavy metal removal from sewage sludge ash by thermochemical treatment with gaseous hydrochloric acid. AB - Sewage sludge ash (SSA) is a suitable raw material for fertilizers due to its high phosphorus (P) content. However, heavy metals must be removed before agricultural application and P should be transferred into a bioavailable form. The utilization of gaseous hydrochloric acid for thermochemical heavy metal removal from SSA at approximately 1000 degrees C was investigated and compared to the utilization of alkaline earth metal chlorides. The heavy metal removal efficiency increased as expected with higher gas concentration, longer retention time and higher temperature. Equivalent heavy metal removal efficiency were achieved with these different Cl-donors under comparable conditions (150 g Cl/kg SSA, 1000 degrees C). In contrast, the bioavailability of the P-bearing compounds present in the SSA after thermal treatment with gaseous HCl was not as good as the bioavailability of the P-bearing compounds formed by the utilization of magnesium chloride. This disadvantage was overcome by mixing MgCO(3) as an Mg donor to the SSA before thermochemical treatment with the gaseous Cl-donor. A test series under systematic variation of the operational parameters showed that copper removal is more depending on the retention time than the removal of zinc. Zn-removal was declined by a decreasing ratio of the partial pressures of ZnCl(2) and water. PMID- 21819090 TI - High-pressure and -temperature ion exchange of aluminosilicate and gallosilicate natrolite. AB - The simultaneous application of high pressure and high temperature has been used to achieve direct ion exchange of large cesium cations for the small sodium cations found in the zeolite natrolite by putting it into a superhydrated state with increased pore size. The larger cations remain trapped upon pressure release, and thus, this method is a means of producing new cationic forms of zeolites. PMID- 21819091 TI - Tetrathiafulvalenylallene: a new class of donor molecules having strong chiroptical properties in neutral and doped states. AB - A chiral tetrathiafulvalene (TTF) dimer bridged by an allene framework (1) was synthesized. An X-ray analysis of 1 revealed an effective conjugation between TTF and the allene backbone. Allene 1 was resolved into both enantiomers, which showed strong chiroptical electrochromic properties. Absolute configuration of the allene was validated by theoretical study of the electronic circular dichroism (ECD) spectrum. ECD spectra of cationic species 1(2+) and 1(4+) exhibited intense Cotton Effects over the visible region. PMID- 21819092 TI - Strong guest binding by cyclodextrin hosts in competing nonpolar solvents and the unique crystalline structure. AB - 6-O-Modified beta-cyclodextrins, such as heptakis(6-O-triisopropylsilyl)-beta cyclodextrin (TIPS-beta-CD) and heptakis(6-O-tert-butyldimethylsilyl)-beta cyclodextrin (TBDMS-beta-CD), formed 2:1 inclusion complexes with pyrene in benzene and cyclohexane with high association constants. The X-ray crystalline structure of the TIPS-beta-CD-pyrene complex obtained from the benzene solution showed that one pyrene molecule was incorporated in the form of a sandwich-type complex with two benzene molecules within the cavity of the dimer formed by two TIPS-beta-CD molecules. PMID- 21819093 TI - Energy and lifetime of temporary anion states of uracil by stabilization method. AB - To investigate the temporary anion states of uracil, density functional theory with asymptotically corrected potentials is adopted. The stabilized Koopmans' theorem and stabilized Koopmans-based approximation are used in conjunction with an analytic continuation procedure to calculate its resonance energies and lifetimes. Results indicate the presence of several low-lying pi* and sigma* temporary anion states of uracil. The characteristics of these resonance orbitals are also analyzed. By comparing them with the experimental values and theoretical calculations, it is believed that the stabilization approach can provide more information on the resonance states. PMID- 21819094 TI - Mineralogy and geochemistry of Zn-rich mine-drainage precipitates from an MgO passive treatment system by synchrotron-based X-ray analysis. AB - Synchrotron radiation-induced micro-X-ray analysis were applied to characterize the newly formed phases that precipitate in a passive treatment system using magnesium oxide to remove high concentrations of zinc (ca. 440 mg/L) and other minor metals from neutral pretreated waters in the Iberian Pyrite Belt (SW Iberian Peninsula). Micro-X-ray fluorescence (MU-XRF) maps of polished samples were used to find spatial correlations among metals, pinpointing zones of interest where micro-X-ray diffraction (MU-XRD) data were exploited to identify the mineral phases responsible for metal retention. This coupled technique identified hydrozincite (Zn(5)(CO(3))(2)(OH)(6)) and minor loseyite ((Mn,Zn)(7)(CO(3))(2)(OH)(10)) as the mineral sinks for Zn and also other potentially toxic elements such as Co and Ni. Although hydrozincite retains traces of Mn, this metal is mainly retained by precipitation of loseyite. The precipitation of zinc hydroxy-carbonates and their ability to uptake other metals (Mn, Co, and Ni) is hence of potential interest not only for the treatment of contaminated waters but also for the generation of a solid waste that could be exploited as a new Zn economic resource. PMID- 21819095 TI - Nanoscale surface pattern evolution in heteroepitaxial bimetallic films. AB - Nanoscale self-assembly dynamics of submonolayer bimetallic films was studied through simulation of a coarse-grained mesoscopic model. Simulations predict a phase transition sequence (hexagonal->stripe->inverse hexagonal) consistent with experimental observations of Pb/Cu(111) heteroepitaxial growth. Post-transition ordering dynamics of hexagonal and inverse hexagonal patterns was simulated and quantified in order to predict pattern quality and evolution mechanisms. Correlation length scaling laws and nanoscale evolution mechanisms were predicted through simulation of experimentally relevant length (~1 MUm(2)) and time scales, with findings supporting evidence of universal pattern behavior with other hexagonal systems. Results provide detailed dynamics and structure of this novel self-assembly process applicable to the design and optimization of functional bimetallic materials, such as bimetallic catalysts. PMID- 21819096 TI - Accessing the structural diversity of pyridone alkaloids: concise total synthesis of rac-citridone A. AB - A unique route to the structural diversity of pyridone alkaloids is described based on the concept of a common synthetic strategy. Three different core structure analogues corresponding to akanthomycin, septoriamycin A, and citridone A have been prepared by using a highly selective and novel carbocyclization reaction. PMID- 21819097 TI - Copper-catalyzed beta-boration of alpha,beta-unsaturated carbonyl compounds with tetrahydroxydiborane. AB - The copper-catalyzed beta-boration of alpha,beta-unsaturated carbonyl compounds with tetrahydroxydiborane has been developed. This diboron reagent allows direct, efficient access to boronic acids and their derivatives. Primary, secondary, and tertiary alpha,beta-unsaturated amides are converted to the corresponding beta trifluoroboratoamides in good to excellent yields. The beta-boration of a variety of alpha,beta-unsaturated esters and ketones is also reported. PMID- 21819098 TI - Pitfalls in protein quantitation using acid-catalyzed O18 labeling: hydrolysis driven deamidation. AB - Proteolysis combined with O(18) labeling emerged recently as a powerful tool for quantitation of proteins for which suitable internal standards cannot be produced using molecular biology methods. Several recent reports suggested that acid catalyzed O(18) labeling may be superior to the commonly accepted enzymatic protocol, as it may allow more significant spacing between the isotopic clusters of labeled and unlabeled peptides, thereby eliminating signal interference and enhancing the quality of quantitation. However, careful examination of this procedure reveals that the results of protein quantitation assisted by acid catalyzed O(18) labeling are highly peptide-dependent. The inconsistency was found to be caused by deamidation of Asn, Gln, and carbamidomethylated Cys residues during prolonged exposure of the proteolytic fragments to the acidic environment of the labeling reaction, which translates into a loss in signal for these peptides. Taking deamidation into account leads to a significant improvement in the consistency of quantitation across a range of different proteolytic fragments. PMID- 21819100 TI - Nanosilver in consumer products and human health: more information required! AB - Commenting on "120 Years of Nanosilver History: Implications for Policy Makers" (Environ. Sci. Technol.2011, 45, 1177-1183). The title of the article seduces readers to the impression that we can look back at more than a century of safe use of nanosilver. In this context, colloidal silver and nanosilver have been sometimes used as synonyms. Historically, the term "colloidal silver" refers to dispersed silver particles encompassing a size range of 10-1000 nm. Following scientific definitions, "colloid" stands for freely dispersed particles in a fluid (heterogenic) phase irrespective of its size distribution, while the term "nanosilver" is used for categorization by size. Of course, just the labeling as such neither necessarily implies new hazard properties nor any specific risks; however, uncertainties and data gaps at many levels call for careful consideration and usually should take effect as alert signal for regulatory toxicologists all over the world. Within the frame of this short commentary, we would like to focus on some unclarified issues related to consumer products. PMID- 21819101 TI - Has the burden and distribution of PCBs and PBDEs changed in European background soils between 1998 and 2008? Implications for sources and processes. AB - Background soils were collected from 70 locations on a latitudinal transect in the United Kingdom and Norway in 2008, ten years after they had first been sampled in 1998. The soils were analyzed for polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), and organochlorine pesticides (OCs), to see whether there had been any change in the loadings or distributions of these persistent organic pollutants (POPs). The same transect has also been used to sample air between the mid-1990s and the present, so the air and soil spatial and temporal trends provide information on air-soil transfers, source-receptor relationships, long-range atmospheric transport (LRAT), and recycling phenomena. Comparisons of the 2008 and 1998 data sets show a general decline for PBDEs in surface soil, and a smaller averaged net decline of PCBs. Changes between the years were observed for total POP concentrations in soil and also for correlations with site and sample characteristics assumed to affect those concentrations. POP concentrations were correlated to distance and strength of possible sources, a relationship that became weaker in the 2008 data. Fractionation, a commonly discussed process for the global cycling of POPs was also lost in the 2008 data. As in 1998, soil organic matter content continues to have a strong influence on the loadings of POPs in surface soils, but changes in the PCB loads were noted. These factors indicate an approach to air-surface soil equilibrium and a lessening of the influence of primary sources on POP concentrations in soil between 1998 and 2008. PMID- 21819102 TI - Wet-chemical synthesis of palladium nanosprings. AB - We report a methodology for synthesis of palladium (Pd) nanospring structures using an anodic aluminum oxide (AAO) membrane template and facile electrochemical deposition. The hydroxyl-terminated surfaces of alumina nanochannels and localized hydrogen evolution contribute to the growth of Pd atoms at peripheral positions of the alumina nanochannels in the presence of an effectual electric potential and a plating solution consisting of PdCl(2), CuCl(2), and HCl. Structural characterization including EDS line analysis and element mapping revealed Pd nanodomains curling up on the Cu nanorods. A clear Pd nanospring shape was observed after selectively removing Cu. The lengths of the nanosprings were dictated by the charges transported through electrodeposition, and the diameters of the nanosprings were tunable by altering the diameter of the alumina nanochannels. Screw dislocation is the most probable crystallographic defect responsible for the formation of coiled Pd nanostructures. Pd nanosprings have potential applications in nanomachines, nanosensors, nanoinductors, and metamaterials. We anticipate that our synthesis method will motivate and inform the synthesis of more advanced nanomaterials. PMID- 21819103 TI - Efficient multigram synthesis of the repeating unit of gallic acid-triethylene glycol dendrimers. AB - A multigram synthesis of the repeating unit of GATG (gallic acid-triethylene glycol) dendrimers is described through an efficient and cost-effective route. These conditions overcome major problems precluding scaling up and afford product in excellent overall yield and purity. Special attention has been paid in this process to green chemistry principles: atom economy, safety, and waste reduction. This scheme could be easily adapted for the preparation of similar dendritic systems. PMID- 21819106 TI - Thermochemistry of the initial steps of methylaluminoxane formation. Aluminoxanes and cycloaluminoxanes by methane elimination from dimethylaluminum hydroxide and its dimeric aggregates. AB - Results are presented of ab initio studies at levels MP2(full)/6-31G* and MP2(full)/6-311G** of the hydrolysis of trimethylaluminum (TMA, 1) to dimethylaluminumhydroxide (DMAH, 2) and of the intramolecular 1,2-elimination of CH(4) from 2 itself to form methylaluminumoxide 3, from its dimeric aggregate 4 to form hydroxytrimethyldialuminoxane 5 and dimethylcyclodialuminoxane 6, and from its TMA aggregate 7 to form 8 and/or 9, the cyclic and open isomers of tetramethyldialuminoxane, respectively. Each methane elimination creates one new Lewis acid site, and dimethylether is used as a model oxygen-donor molecule to assess the most important effects of product stabilization by Lewis donor coordination. It is found that the irreversible formation of aggregate 4 (DeltaG(298) = -29.2 kcal/mol) is about three times more exergonic than the reversible formation of aggregate 7 (DeltaG(298) = -9.9 kcal/mol), that the reaction free enthalpies for the formations of 5 (DeltaG(298) = -9.0 kcal/mol) and 6 (DeltaG(298) = -18.8 kcal/mol) both are predicted to be quite clearly exergonic, and that there is a significant thermodynamic preference (DeltaG(298) = -7.2 kcal/mol) for the formation of 6 over ring-opening of 5 to hydroxytrimethyldialuminoxane 10. The mechanism for oligomerization is discussed based on the bonding properties of dimeric aggregates and involves the homologation of HO-free aluminoxane with DMAH (i.e., 9 to 13), and any initially formed hydroxydialuminoxane 10 is easily capped to trialuminoxane 13. Our studies are consistent with and provide support for Sinn's proposal for the formation of oligoaluminoxanes, and in addition, the results point to the crucial role played by the kinetic stability of 5 and the possibility to form cyclodialuminoxane 6. Dialuminoxanes 9 and 10 are reversed-polarity heterocumulenes, and intramolecular O->Al dative bonding competes successfully with Al complexation by Lewis donors. Intramolecular O->Al dative bonding is impeded in cyclodialuminoxane 6, and the dicoordinate oxygen in 6 is a strong Lewis donor. Ethylene polymerization catalysts contain highly oxophilic transition metals, and our studies suggest that these transition metal catalysts should discriminate strongly in favor of cycloaluminoxane-O donors even if these are present only in small concentrations in the methylaluminoxane (MAO) cocatalyst. PMID- 21819104 TI - Biosynthetic origin and mechanism of formation of the aminoribosyl moiety of peptidyl nucleoside antibiotics. AB - Several peptidyl nucleoside antibiotics that inhibit bacterial translocase I involved in peptidoglycan cell wall biosynthesis contain an aminoribosyl moiety, an unusual sugar appendage in natural products. We present here the delineation of the biosynthetic pathway for this moiety upon in vitro characterization of four enzymes (LipM-P) that are functionally assigned as (i) LipO, an L methionine:uridine-5'-aldehyde aminotransferase; (ii) LipP, a 5'-amino-5' deoxyuridine phosphorylase; (iii) LipM, a UTP:5-amino-5-deoxy-alpha-D-ribose-1 phosphate uridylyltransferase; and (iv) LipN, a 5-amino-5 deoxyribosyltransferase. The cumulative results reveal a unique ribosylation pathway that is highlighted by, among other features, uridine-5'-monophosphate as the source of the sugar, a phosphorylase strategy to generate a sugar-1 phosphate, and a primary amine-requiring nucleotidylyltransferase that generates the NDP-sugar donor. PMID- 21819107 TI - Wettability control of ZnO nanoparticles for universal applications. AB - Herein, a facile approach for the fabrication of a superhydrophobic nanocoating through a simple spin-coating and chemical modification is demonstrated. The resulting coated surface displayed a static water contact angle of 158 degrees and contact angle hysteresis of 1 degrees , showing excellent superhydrophobicity. The surface wettability could be modulated by the number of ZnO nanoparticle coating cycles, which in turn affected surface roughness. Because of its surface-independent characteristics, this method could be applicable to a wide range of substrates including metals, semiconductors, papers, cotton fabrics, and even flexible polymer substrates. This superhydrophobic surface showed high stability in thermal and dynamic conditions, which are essential elements for practical applications. Furthermore, the reversible switching of wetting behaviors from the superhydrophilic state to the superhydrophobic state was demonstrated using repeated chemical modification/heat treatment cycles of the coating films. PMID- 21819108 TI - Comment on "120 Years of nanosilver history: implications for policy makers". PMID- 21819105 TI - Choice of biological source material supersedes oxidative stress in its influence on DJ-1 in vivo interactions with Hsp90. AB - DJ-1 is a small but relatively abundant protein of unknown function that may undergo stress-dependent cellular translocation and has been implicated in both neurodegenerative diseases and cancer. As such, DJ-1 may be an excellent study object to elucidate the relative influence of the cellular context on its interactome and for exploring whether acute exposure to oxidative stressors alters its molecular environment. Using quantitative mass spectrometry, we conducted comparative DJ-1 interactome analyses from in vivo cross-linked brains or livers and from hydrogen peroxide-treated or naive embryonic stem cells. The analysis identified a subset of glycolytic enzymes, heat shock proteins 70 and 90, and peroxiredoxins as interactors of DJ-1. Consistent with a role of DJ-1 in Hsp90 chaperone biology, we document destabilization of Hsp90 clients in DJ-1 knockout cells. We further demonstrate the existence of a C106 sulfinic acid modification within DJ-1 and thereby establish that this previously inferred modification also exists in vivo. Our data suggest that caution has to be exerted in interpreting interactome data obtained from a single biological source material and identify a role of DJ-1 as an oxidative stress sensor and partner of a molecular machinery notorious for its involvement in cell fate decisions. PMID- 21819110 TI - Substrate-, wavelength-, and time-dependent plasmon-assisted surface catalysis reaction of 4-nitrobenzenethiol dimerizing to p,p'-dimercaptoazobenzene on Au, Ag, and Cu films. AB - In this article, we experimentally investigate the substrate, wavelength, and time dependence of the plasmon-assisted surface-catalyzed dimerization of 4 nitrobenzenethiol to form p,p'-dimercaptoazobenzene on Au, Ag, and Cu films. We provide direct experimental evidence that surface plasmon resonance plays the most important role in these surface-catalyzed reactions. It is found that the reaction is strongly dependent on the substrate, the wavelength of the laser, and the reaction timescales. Our experimental results revealed that optimal experimental conditions can be rationally chosen to control (accelerate or restrain) this reaction. The experimental results are also confirmed by theoretical calculations. PMID- 21819111 TI - Understanding optoelectronic properties of cyano-terminated oligothiophenes in the context of intramolecular charge transfer. AB - In this paper we have prepared a new series of oligothiophenes capped with hexyl groups and a variety of strong acceptors, mainly cyanovinyl moieties. An exhaustive analysis of the absorption, photophysical, electrochemical, solid state, nonlinear optical and vibrational properties has been presented guided by theoretical calculations. The investigation is centered on the efficiency of the intramolecular charge transfer (i.e., chain length and acceptor dependence) and its impact on all the relevant electronic, structural, optical, and vibrational properties. The most significant features imparted by the acceptors through the pi-conjugated oligothiophene path are (i) intense visible electronic absorptions, (ii) tuned fluorescence wavelength emissions, (iii) solid state pi-stacking, (iv) ambipolar redox behavior, (v) S(1) ? S(0) internal conversion as being the major route for the deactivation of the excited state, and (vi) large electronic and vibrational contributions to their nonlinear optical response (hyperpolarizability). The analysis establishes connections between the different properties of the materials and structure-function relationships useful in organic electronics. PMID- 21819109 TI - Exploring organosilane amines as potent inhibitors and structural probes of influenza a virus M2 proton channel. AB - We describe the use of organosilanes as inhibitors and structural probes of a membrane protein, the M2 proton channel from influenza A virus. Organosilane amine inhibitors were found to be generally as potent as their carbon analogues in targeting WT A/M2 and more potent against the drug-resistant A/M2-V27A mutant. In addition, intermolecular NOESY spectra with dimethyl-substituted organosilane amine inhibitors clearly located the drug binding site at the N-terminal lumen of the A/M2 channel close to V27. PMID- 21819112 TI - Structural and dynamical characteristics of peptoid oligomers with achiral aliphatic side chains studied by molecular dynamics simulation. AB - All-atom molecular dynamics simulations of N-substituted glycine peptoid oligomers with methyl and methoxyethyl side chains have been carried out for chain lengths of 5, 10, 20, and 50 residues in aqueous phase at room temperature. The (phi, psi) backbone dihedral angle distributions in the Ramachandran plots show that helical structures, similar to polyproline type I and type II helices, are the most favorable conformations in most peptoid oligomers studied. The left handed helical structures are shown to be increasingly favored as the oligomer chain length grows. A significant population of cis amide bond configurations has been identified in the peptoid oligomers. By combining the analysis of phi and omega backbone dihedral angles, we determined the relative composition of the four major conformations favored by the backbone dihedral angles. The trans alpha(D) conformation is found to be most favored for all peptoid oligomers studies. The time correlation functions of the end-to-end distance highlight a rigid backbone structure relative to side chains for peptoid oligomers. The transition between right-handed and left-handed helical conformations is found to be very rare and between cis and trans isomerism in the amide bond completely absent in the simulation time scale. The radii of gyration for all peptoid oligomers have been found to be consistently larger in comparison to the peptide counterparts, suggesting slightly open structures for peptoids relative to peptides, whereas the fluctuations in the radius of gyration support a rigid backbone structure of peptoids. PMID- 21819113 TI - Low-temperature frequency domain study of excitation energy transfer in ethynyl linked chlorophyll trefoils and aggregates. AB - Using hole-burning spectroscopy, we show that excitation energy transfer (EET) time in ethynyl-linked chlorophyll trefoil (ChlT1) monomer is very fast (~2.5 ps) at liquid helium temperature. This is consistent with data obtained by femtosecond transient spectroscopy experiments performed at room temperature, in which an EET time of 1.8 ps was observed (Kelley, R. F. et al. Angew. Chem. Int. Ed. 2006, 45, 7979). This finding further supports the importance of through-bond electronic coupling at low temperature. In addition, we show that ChlT1 (even at very low concentrations) in methyl tetrahydrofuran-ethanol glass (1:200 v/v; T ~ 5 K) forms different types of aggregates. It is demonstrated that the relative distribution of various types of aggregates (whose possible structures are briefly discussed) depends on the cooling rate and matrix composition. For example, the EET time in two types of ChlT1-based aggregates is slower by a factor of ~5-7 with respect to that observed for ChlT1 monomer. This indicates that ChlT1 aggregates can retain ultrafast energy transfer properties similar to those observed in natural photosynthetic antennas. It is anticipated that such building blocks could be utilized in future photovoltaic devices. PMID- 21819114 TI - Controlling the growth and differentiation of human mesenchymal stem cells by the arrangement of individual carbon nanotubes. AB - Carbon nanotube (CNT) networks on solid substrates have recently drawn attention as a means to direct the growth and differentiation of stem cells. However, it is still not clear whether cells can recognize individual CNTs with a sub-2 nm diameter, and directional nanostructured substrates such as aligned CNT networks have not been utilized to control cell behaviors. Herein, we report that human mesenchymal stem cells (hMSCs) grown on CNT networks could recognize the arrangement of individual CNTs in the CNT networks, which allowed us to control the growth direction and differentiation of the hMSCs. We achieved the directional growth of hMSCs following the alignment direction of the individual CNTs. Furthermore, hMSCs on aligned CNT networks exhibited enhanced proliferation and osteogenic differentiation compared to those on randomly oriented CNT networks. As a plausible explanation for the enhanced proliferation and osteogenic differentiation, we proposed mechanotransduction pathways triggered by high cytoskeletal tension in the aligned hMSCs. Our findings provide new insights regarding the capability of cells to recognize nanostructures smaller than proteins and indicate their potential applications for regenerative tissue engineering. PMID- 21819115 TI - Dynamic photocontrol of the gliding motility of a microtubule driven by kinesin on a photoisomerizable monolayer surface. AB - The gliding motility of microtubules driven by kinesin on the surface of an azobenzene monolayer presenting lysine terminal groups is reversibly and repeatedly altered upon photoisomerization of the monolayer. PMID- 21819117 TI - pH Responsivity and micelle formation of gradient copolymers of methacrylic acid and methyl methacrylate in aqueous solution. AB - A series of gradient copolymers of methacrylic acid (MAA)/methyl methacrylate (MMA) with four end-to-end composition profiles (uniform, linear gradient, triblock with linear gradient midblock, and diblock) but all having an average chain composition of F(MMA) ~ 0.5 and an average chain length of 200 were synthesized via model-based, computer-programmed, semibatch atom-transfer radical copolymerization (ATRcoP). These samples allowed us to investigate systematically the effects of the gradient composition profile on the pH responsivity and micelle formation of the copolymers in an aqueous solution. Measurements included light transmittance, TEM, AFM, DLS, (1)H NMR, and pH titration. It was found that linear gradient, triblock, and diblock copolymers formed spherical micelles at high pH. The micelles of the linear gradient copolymer contained MMA units in their hydrophilic shells, and those of the triblock and diblock copolymers had all of their MMA units residing in their cores. The composition profile showed a strong effect on the degree of acid dissociation at a given pH. The conformational transition of the copolymer chains was determined by both the pH value and composition profile. Copolymers having sharper gradients required a lower pH to trigger the conformational transition and a narrower pH range to complete the transition. PMID- 21819116 TI - Convergent synthesis of homogeneous Glc1Man9GlcNAc2-protein and derivatives as ligands of molecular chaperones in protein quality control. AB - A detailed understanding of the molecular mechanism of chaperone-assisted protein quality control is often hampered by the lack of well-defined homogeneous glycoprotein probes. We describe here a highly convergent chemoenzymatic synthesis of the monoglucosylated glycoforms of bovine ribonuclease (RNase) as specific ligands of lectin-like chaperones calnexin (CNX) and calreticulin (CRT) that are known to recognize the monoglucosylated high-mannose oligosaccharide component of glycoproteins in protein folding. The synthesis of a selectively modified glycoform Gal(1)Glc(1)Man(9)GlcNAc(2)-RNase was accomplished by chemical synthesis of a large N-glycan oxazoline and its subsequent enzymatic ligation to GlcNAc-RNase under the catalysis of a glycosynthase. Selective removal of the terminal galactose by a beta-galactosidase gave the Glc(1)Man(9)GlcNAc(2)-RNase glycoform in excellent yield. CD spectroscopic analysis and RNA-hydrolyzing assay indicated that the synthetic RNase glycoforms maintained essentially the same global conformations and were fully active as the natural bovine ribonuclease B. SPR binding studies revealed that the Glc(1)Man(9)GlcNAc(2)-RNase had high affinity to lectin CRT, while the synthetic Man(9)GlcNAc(2)-RNase glycoform and natural RNase B did not show CRT-binding activity. These results confirmed the essential role of the glucose moiety in the chaperone molecular recognition. Interestingly, the galactose-masked glycoform Gal(1)Glc(1)Man(9)GlcNAc(2)-RNase also showed significant affinity to lectin CRT, suggesting that a galactose beta 1,4-linked to the key glucose moiety does not significantly block the lectin binding. These synthetic homogeneous glycoprotein probes should be valuable for a detailed mechanistic study on how molecular chaperones work in concert to distinguish between misfolded and folded glycoproteins in the protein quality control cycle. PMID- 21819118 TI - Gas-phase spectroscopy of synephrine by laser desorption supersonic jet technique. AB - In our previous work, we found that synephrine has six conformers in the gas phase, while adrenaline, which is a catecholamine and has the same side chain as synephrine, has been reported to have only two conformers. To determine the conformational geometries of synephrine, we measured resonance enhanced multiphoton ionization, ultraviolet-ultraviolet hole burning, and infrared dip spectra by utilizing the laser desorption supersonic jet technique. By comparing the observed infrared spectra with theoretical ones, we assigned geometries except for the orientations of the phenolic OH group. Comparison between the determined structures of synephrine and those of 2-methylaminno-1-phenylethanol, which has the same side chain as synephrine but no phenol OH group, leads to the conclusion that the phenolic OH group in synephrine does not affect the conformational flexibility of the side chain. In the case of adrenaline, which is expected to have 12 conformers if there are no interactions between the catecholic OH groups and the side chain, some interactions possibly exist between them because only two conformations are observed. By estimation of the dipole dipole interaction energy between partial dipole moments of the catecholic OH groups and the side chain, it was concluded that the dipole-dipole interaction stabilizes specific conformers which are actually observed. PMID- 21819119 TI - Construction of a bFGF-tethered extracellular matrix using a coiled-coil helical interaction. AB - A novel method for construction of biomaterials for tissue engineering was developed. Noncovalent associations between extracellular matrix (ECM) and growth factors were achieved by engineering recombinant versions of both proteins that included helical peptides that could form a coiled-coil structure. The helix A peptide, which is capable of forming a coiled-coil helical structure, was fused with a matrix protein that contains a cell-adhesive RGD sequence. The helix B peptide, which is also capable of forming a coiled-coil helical structure, was fused with basic fibroblast growth factor (bFGF). Each protein retained its original activity of promoting cell adhesion and cell proliferation, respectively. These recombinant proteins associated noncovalently through coiled coil helix formation between helix A and helix B. The resulting complex combined the functions of both proteins, and this method of joining proteins with different functionalities could be used to develop biomaterials for tissue engineering. PMID- 21819120 TI - Evaluation of the effect of roasting on the structure of coffee galactomannans using model oligosaccharides. AB - The roasting process induces structural changes in coffee galactomannans. To know more about the reaction pathways that occur during the roasting of coffee, mannosyl and galactomannosyl oligosaccharides, having a degree of polymerization (DP) between 3 and 4, were used as models for galactomannans. These compounds were dry-heated under air atmosphere from room temperature to 200 degrees C, being maintained at 200 degrees C for different periods of time. The roasted materials were analyzed by mass spectrometry (ESI-MS, MALDI-MS, and ESI-MSn) and methylation analysis. In the MS spectra were identified several [M+Na]+ ions belonging to a series from a single hexose to 10 hexose residues ([Hex1-10+Na]+). The ions corresponding to their respective mono- and tridehydrated derivatives ([Hex2-10-H2O+Na]+ and [Hex2-10-3H2O+Na]+, respectively) were also identified. ESI-MSn as well as deuterium-labeling and alditol derivatization experiments showed that the tridehydrations occur at the reducing end of the oligosaccharides. The identification of (1->2)- and (1->6)-linked mannose residues and (1->4)-linked glucose residues by methylation analysis allowed the conclusion that transglycosylation and isomerization reactions occur during dry thermal processing. PMID- 21819121 TI - Identification of ethyl 2-sulfanylacetate as an important off-odor compound in white wines. AB - A number of Sauvignon blanc wines made from hard pressed juices in an inert atmosphere (nitrogen) or in contact with oxygen were identified as having heavy off-flavors to varying degrees. Samples were extracted and subjected to time based HPLC fractionation. The fractions were assessed by a sensory panel and those with unpleasant, irritating, off-odors were re-extracted. The extracts evaluated by gas chromatography coupled with olfactometry revealed a number of odoriferous zones, including one with an off-odor similar to the one perceived in two HPLC fractions. The odor was less intense in fractions previously supplemented with copper sulfate, suggesting that the compound(s) responsible were possibly thiol-related. A selective thiols extraction protocol and the analysis of the extract by gas chromatography coupled with mass spectrometry identified a new potent thiol in these wines. The compound responsible for the odoriferous zone, ethyl 2-sulfanylacetate (1), had an odor reminiscent of baked beans and Fritillaria meleagris bulbs. Its perception threshold was determined and sensory studies using graduated supplementation in dry white wines demonstrated its contribution to the off-odor observed in dry white wines. PMID- 21819122 TI - Retention and bioaccessibility of beta-carotene in blended foods containing orange-fleshed sweet potato flour. AB - The retention and bioaccessibility of beta-carotene (BC) in blended foods made with part orange-fleshed sweet potato (OFSP) flour (30%) were examined. Chapatis and porridges were prepared by local processors under field conditions (FC) in Uganda (n=10). While the retention of all-trans-BC in porridges (69 to 93%) and chapatis (70 to 97%) varied between the processors, there was no overall difference between the two products and this was probably because of the variability in FC. BC retention in mandazis was similar to that of chapatis and porridges. Processing in FC significantly increased the amount of cis-isomers, in particular 13-cis-BC. The bioaccessibility of the BC as measured by their transfer into micelles was evaluated using an in vitro digestion procedure in various OFSP-derived products. After in vitro digestion, the percentage of micellarized all-trans-BC was greater in products cooked with oil, chapati (73%) and mandazi (49%), as compared with the boiled ones, porridge (16%) and pureed from boiled root (10%). In all the products, the incorporation into micelles for 13-cis-BC was significantly higher to that of all-trans-BC. When taking into account the bioaccessibility of all-trans-BC and 13-cis-BC isomer, an edible portion of porridge (one mug), boiled root (half a root), mandazis (two), or chapati (one) could provide a significant part of the daily vitamin A requirements of a child under 6 years (respectively 20, 46, 75, or 100%). These data support the promotion/consumption of locally cooked OFSP food products to tackle vitamin A deficiency in sub-Saharan Africa. PMID- 21819123 TI - Biochemical and functional characterization of an albumin protein belonging to the hemopexin superfamily from Lens culinaris seeds. AB - The present paper reports the purification and biochemical characterization of an albumin identified in mature lentil seeds with high sequence similarity to pea PA2. These proteins are found in many edible seeds and are considered potentially detrimental for human health due to the potential allergenicity and lectin-like activity. Thus, the description of their possible presence in food and the assessment of the molecular properties are relevant. The M(r), pI, and N-terminal sequence of this protein have been determined. The work included the study of (i) the binding properties to hemine to assess the presence of hemopexin structural domains and (ii) the binding properties of the protein to thiamin. In addition, the structural changes induced by heating have been evaluated by means of spectroscopic techniques. Denaturation temperature has also been determined. The present work provides new insights about the structural molecular features and the ligand-binding properties and dynamics of this kind of seed albumin. PMID- 21819124 TI - Direct visualization and identification of biofunctionalized nanoparticles using a magnetic atomic force microscope. AB - Because of its outstanding ability to image and manipulate single molecules, atomic force microscopy (AFM) established itself as a fundamental technique in nanobiotechnology. (1) We present a new modality that distinguishes single nanoparticles by the surrounding magnetic field gradient. Diamagnetic gold and superparamagnetic iron oxide nanoparticles become discernible under ambient conditions. Images of proteins, magnetolabeled with nanoparticles, demonstrate the first steps toward a magnetic analogue to fluorescence microscopy, which combines nanoscale lateral resolution of AFM with unambiguous detection of magnetic markers. PMID- 21819125 TI - Mycobacterium tuberculosis NmtR harbors a nickel sensing site with parallels to Escherichia coli RcnR. AB - Mycobacterium tuberculosis NmtR is a Ni(II)/Co(II)-sensing metalloregulatory protein from the extensively studied ArsR/SmtB family. Two Ni(II) ions bind to the NmtR dimer to form octahedral coordination complexes with the following stepwise binding affinities: K(Ni1) = (1.2 +/- 0.1) * 10(10) M(-1), and K(Ni2) = (0.7 +/- 0.4) * 10(10) M(-1) (pH 7.0). A glutamine scanning mutagenesis approach reveals that Asp91, His93, His104, and His107, all contained within the C terminal alpha5 helix, and His3 as part of the conserved alpha-NH(2)-Gly2-His3 Gly4 motif at the N-terminus make significant contributions to the magnitude of K(Ni). In contrast, substitution of residues from the C-terminal region, His109, Asp114, and His116, previously implicated in Ni(II) binding and metalloregulation in cells, gives rise to wild-type K(Ni) and Ni(II)-dependent allosteric coupling free energies. Interestingly, deletion of residues 112-120 from the C-terminal region (Delta111 NmtR) reduces the Ni(II) binding stoichiometry to one per dimer and greatly reduces Ni(II) responsiveness. H3Q and Delta111 NmtRs also show clear perturbations in the rank order of metal responsiveness to Ni(II), Co(II), and Zn(II) that is distinct from that of wild-type NmtR. (15)N relaxation experiments with apo-NmtR reveal that both N-terminal (residues 2-14) and C- terminal (residues 110-120) regions are unstructured in solution, and this property likely dictates the metal specificity profile characteristic of the Ni(II) sensor NmtR relative to other ArsR family regulators. PMID- 21819126 TI - Supergrowth of nitrogen-doped single-walled carbon nanotube arrays: active species, dopant characterization, and doped/undoped heterojunctions. AB - We demonstrate the water-assisted supergrowth of vertically aligned single-walled carbon-nitrogen nanotubes (SWNNTs) using a simple liquid/gas-phase precursor system. In situ characterization of gas-phase nitrogen-containing precursors and their correlation to growth identifies HCN as the most active precursor for SWNNT growth, analogous to C(2)H(2) for single-walled carbon nanotubes (SWNTs). Utilizing Raman spectroscopy, combined with XPS and in situ mass spectrometry during growth, we demonstrate the ability to probe N atoms at low concentrations (10(-5) at. % N) in the SWNNT. Additionally, we demonstrate sensitivity of SWNNT optical transitions to N-doping through absorbance measurements, which appear to be a sensitive fingerprint for SWNNT doping. Finally, we demonstrate the fabrication of SWNT/SWNNT heterojunctions in the self-assembled carpet morphology that can be printed to arbitrary host substrates and facilitate potential emerging applications for this material. This work brings together new aspects regarding the growth, characterization, and materials processing that can yield advanced material architectures involving electronically tuned SWNNT array networks. PMID- 21819127 TI - Assembling and disassembling Ag clusters on Si(111)-(7*7) by vertical atomic manipulation. AB - Atomic manipulation has been rarely used in the studies of complex structures and a low temperature requirement usually limits its application. Herein we have demonstrated a vertical manipulation technique to reproducibly and reversibly manipulating Ag atoms on an Si(111)-(7*7) surface by a scanning tunneling microscope tip at room temperature. Simple and complex Ag nanoclusters were assembled and disassembled with a precise control of single Ag atoms, which provided critical information on the size of these nanoclusters. The manipulation showed the growth processes of these Ag clusters and even partly unveiled their atomic structures. This technique can form a fundamental basis for further studies of the Ag/Si(111)-(7*7) system and for fabricating functional nanodevices in various metal-semiconductor systems. PMID- 21819128 TI - Lithiation-induced embrittlement of multiwalled carbon nanotubes. AB - Lithiation of individual multiwalled carbon nanotubes (MWCNTs) was conducted in situ inside a transmission electron microscope. Upon lithiation, the intertube spacing increased from 3.4 to 3.6 A, corresponding to about 5.9% radial and circumferential expansions and ~50 GPa tensile hoop stress on the outermost tube wall. The straight tube walls became distorted after lithiation. In situ compression and tension tests show that the lithiated MWCNTs were brittle with sharp fracture edges. Such a failure mode is in stark contrast with that of the pristine MWCNTs which are extremely flexible and fail in a "sword-in-sheath" manner upon tension. The lithiation-induced embrittlement is attributed to the mechanical effect of a "point-force" action posed by the intertubular lithium that induces the stretch of carbon-carbon bonds in addition to that by applied strain, as well as the chemical effect of electron transfer from lithium to the antibonding pi orbital that weakens the carbon-carbon bond. The combined mechanical and chemical weakening leads to a considerable decrease of the fracture strain in lithiated MWCNTs. Our results provide direct evidence and understanding of the degradation mechanism of carbonaceous anodes in lithium ion batteries. PMID- 21819129 TI - Large enhancements in optoelectronic efficiencies of nano-plastically stressed conjugated polymer strands. AB - The photoluminescence (PL) of well dispersed molecules of a conjugated polymer, poly[2-methoxy-5-((2'-ethylhexyl)oxy)-1,4-phenylene-vinylene] (MEH-PPV), in an optically inert matrix manifested dramatic increases when the individual molecular strands were fully stretched. The PL increase rose with stretching and may reach several folds when the mechanical strain of the matrix polymer went beyond 550%. Strong polarization effects indicate that stretching individual polymer chains was responsible for the PL enhancement. This effect was attributed to suppression of electron-phonon interactions in the stress-rigidified polymer chain segments and may be useful for efficiency-enhanced polymer-based optoelectronic devices. PMID- 21819130 TI - Fruit quality of Redhaven and Royal Glory peach cultivars on seven different rootstocks. AB - Two peach cultivars, Redhaven and Royal Glory, grafted on seven different rootstocks (Adesoto, Barrier 1, GF 677, Ishtara, Monegro, Penta, and peach seedling) were analyzed for tree vigor and yield. Fruit of similar ripeness (fruit firmness) was analyzed in terms of pomological (fruit weight, soluble solids content) and biochemical parameters (individual sugars, organic acids, phenolic acids in the flesh and peel, as well as flavonols and anthocyanins in the peel). A uniform effect of rootstock on tree size was evident in the cases of both cultivars. The Ishtara rootstock induced weak tree growth; Adesoto, Penta and peach seedling semivigorous growth; and Barrier 1, GF 677, and Monegro vigorous tree growth. We recorded higher yields in the Redhaven cultivar, while no significant differences in yield in the fourth growing season were found among the rootstocks for each cultivar. Rootstock had no effect on soluble solids in the Redhaven cultivar, while in the Royal Glory it did. Penta yielded the highest soluble solids content levels, while Adesoto and Monegro were associated with low levels. In the fruit from both cultivars, the rootstock had a significant influence on individual sugars, organic acids, and phenolic acids in the pulp. We also found that phenolic acids in the pulp and skin were more affected by the rootstock than other secondary metabolites analyzed, regardless of the cultivar. PMID- 21819131 TI - Effects of lecithin and pectin on riboflavin-photosensitized oxidation of orange oil in a multilayered oil-in-water emulsion. AB - The effects of lecithin and pectin on riboflavin-photosensitized oxidation of orange oil in a multilayered oil-in-water emulsion are studied by response surface methodology. Lecithin and pectin contents are two variables studied. Mean oil droplet size, viscosity, and zeta-potential are investigated for evaluation of emulsion stability. Headspace oxygen depletion, increase of conjugated diene value, and released amounts of limonene and carvone are used as responses to evaluate the oxidative stability of orange oil in this emulsion. The results show that both lecithin and pectin contents have significant effects (p < 0.05) on the oxidative stability of orange oil in the multilayered emulsion during photosensitized oxidation. No interactive effect (p < 0.05) is found between the lecithin and pectin contents. To achieve optimal oxidative stability, the suggested values in ratio for lecithin and pectin contents are 14.1 +/- 0.5 and 19 +/- 0.7, respectively. PMID- 21819132 TI - Synthesis of cyclopentenols and cyclopentenones via nickel-catalyzed reductive cycloaddition. AB - Strategies for the reductive cycloaddition of enals or enoates with alkynes have been developed. The enal-alkyne cycloaddition directly affords cyclopentenols, whereas the enoate-alkyne cycloaddition affords the analogous cyclopentenones. The mechanism of these processes likely involves formation and protonation of a metallacyclic intermediate. The general strategy provides a straightforward entry to five-membered ring products from simple, stable pi-systems. PMID- 21819133 TI - Total synthesis of (-)-N-methylwelwitindolinone C isothiocyanate. AB - We report the first total synthesis of (-)-N-methylwelwitindolinone C isothiocyanate. Our route features a number of key transformations, including an indolyne cyclization to assemble the [4.3.1]-bicyclic scaffold, as well as a late stage intramolecular nitrene insertion to functionalize the C11 bridgehead carbon en route to the natural product. PMID- 21819134 TI - High-sensitivity strain gauge based on a single wire of gold nanoparticles fabricated by stop-and-go convective self-assembly. AB - High-sensitivity strain gauges based on single wires of close-packed 14 nm colloidal gold nanoparticles are obtained by a novel variant of convective self assembly (CSA). This CSA mode named stop-and-go CSA enables the fabrication of nanoparticle wires only a few micrometers wide, separated by distances that can be easily tuned over tens to hundreds of micrometers. Nanoparticle wires are obtained in a single step by direct deposition of nanoparticles from suspensions onto flexible polyethylene terephthalate films, without any lithographic prepatterning. When connected between two electrodes, such single nanoparticle wires function as miniature resistive strain gauges. The high sensitivity, repeatability, and robustness demonstrated by these single-wire strain gauges make them extremely promising for integration into micro-electromechanical systems or for high-resolution strain mapping. PMID- 21819135 TI - Minor groove binders and drugs targeting proteins cover complementary regions in chemical shape space. AB - DNA minor groove binders (MGBs) are known to influence gene expression and are therefore widely studied to explore their therapeutic potential. We identified shape-based virtual screening with ROCS as a highly effective computational approach to enrich known MGBs in top-ranked molecules. Discovery of ten previously unknown MGBs by shape-based screening further confirmed the relevance of ligand shape for minor groove affinity. Based on experimental testing we propose three simple rules (at least two positive charges, four nitrogen atoms, and one aromatic ring) as filters to reach even better enrichment of true positives in ROCS hit lists. Interestingly, shape-based ranking of MGBs versus FDA-approved drugs again leads to high enrichment rates, indicating complementary coverage of chemical shape space and indicating minor groove affinity to be unfavorable for approval of drugs targeting proteins. PMID- 21819136 TI - Enzymatically cross-linked tilapia gelatin hydrogels: physical, chemical, and hybrid networks. AB - This Article investigates different types of networks formed from tilapia fish gelatin (10% w/w) in the presence and absence of the enzymatic cross-linker microbial transglutaminase. The influence of the temperature protocol and cross linker concentration (0-55 U mTGase/g gelatin) was examined in physical, chemical, and hybrid gels, where physical gels arise from the formation of triple helices that act as junction points when the gels are cooled below the gelation point. A combination of rheology and optical rotation was used to study the evolution of the storage modulus (G') over time and the number of triple helices formed for each type of gel. We attempted to separate the final storage modulus of the gels into its chemical and physical contributions to examine the existence or otherwise of synergism between the two types of networks. Our experiments show that the gel characteristics vary widely with the thermal protocol. The final storage modulus in chemical gels increased with enzyme concentration, possibly due to the preferential formation of closed loops at low cross-linker amount. In chemical-physical gels, where the physical network (helices) was formed consecutively to the covalent one, we found that below a critical enzyme concentration the more extensive the chemical network is (as measured by G'), the weaker the final gel is. The storage modulus attributed to the physical network decreased exponentially as a function of G' from the chemical network, but both networks were found to be purely additive. Helices were not thermally stabilized. The simultaneous formation of physical and chemical networks (physical-co chemical) resulted in G' values higher than the individual networks formed under the same conditions. Two regimes were distinguished: at low enzyme concentration (10-20 U mTGase/g gelatin), the networks were formed in series, but the storage modulus from the chemical network was higher in the presence of helices (compared to pure chemical gels); at higher enzyme concentration (30-40 U mTGase/g gelatin), strong synergistic effects were found as a large part of the covalent network became ineffective upon melting of the helices. PMID- 21819138 TI - Hybrid genetic algorithm with an adaptive penalty function for fitting multimodal experimental data: application to exchange-coupled non-Kramers binuclear iron active sites. AB - A Genetic Algorithm (GA) is a stochastic optimization technique based on the mechanisms of biological evolution. These algorithms have been successfully applied in many fields to solve a variety of complex nonlinear problems. While they have been used with some success in chemical problems such as fitting spectroscopic and kinetic data, many have avoided their use due to the unconstrained nature of the fitting process. In engineering, this problem is now being addressed through incorporation of adaptive penalty functions, but their transfer to other fields has been slow. This study updates the Nanakorrn Adaptive Penalty function theory, expanding its validity beyond maximization problems to minimization as well. The expanded theory, using a hybrid genetic algorithm with an adaptive penalty function, was applied to analyze variable temperature variable field magnetic circular dichroism (VTVH MCD) spectroscopic data collected on exchange coupled Fe(II)Fe(II) enzyme active sites. The data obtained are described by a complex nonlinear multimodal solution space with at least 6 to 13 interdependent variables and are costly to search efficiently. The use of the hybrid GA is shown to improve the probability of detecting the global optimum. It also provides large gains in computational and user efficiency. This method allows a full search of a multimodal solution space, greatly improving the quality and confidence in the final solution obtained, and can be applied to other complex systems such as fitting of other spectroscopic or kinetics data. PMID- 21819137 TI - Single myosin cross-bridge orientation in cardiac papillary muscle detects lever arm shear strain in transduction. AB - Myosin motors transduce ATP free energy into mechanical work. Transduction models allocate specific functions to motor structural domains beginning with ATP hydrolysis in the active site and ending in a lever-arm rotating power-stroke. Myosin light chains, regulatory (RLC) and essential (ELC), bind IQ-domains on the lever-arm and track its movement. Strong evidence exists that light chains stabilize the lever-arm and that light chain mutation undermines stability. Human ventricular RLC tagged with photoactivatable GFP (HCRLC-PAGFP) replaces native RLC in porcine papillary muscle fibers, restores native contractility, and situates PAGFP for single molecule orientation tracking within the crowded fiber lattice. The spatial emission pattern from single photoactivated PAGFP tagged myosins was observed in z-stacks fitted simultaneously to maximize accuracy in estimated dipole orientation. Emitter dipole polar and azimuthal angle pair scatter plots identified an area where steric and molecular crowding constraints depopulated orientations unfavorable for actin interaction. Transitions between pre- and post-power-stroke states represent the lever-arm trajectory sampled by the data and quantify lever-arm shear strain in transduction at three tension levels. These data identify forces acting on myosin in the in situ fiber system due to crowding, steric hindrance, and actomyosin interaction. They induce lever arm shear strain observed with single molecule orientation detection. A single myosin work histogram reveals discretized power-stroke substates reminiscent of the Huxley-Simmons model for myosin based contraction [Huxley and Simmons ( 1971 ) Nature 233 , 533]. RLC or ELC mutation, should it impact lever-arm shear strain, will be detected as changes in single myosin shear strain or power-stroke substate distribution. PMID- 21819139 TI - Learning to predict chemical reactions. AB - Being able to predict the course of arbitrary chemical reactions is essential to the theory and applications of organic chemistry. Approaches to the reaction prediction problems can be organized around three poles corresponding to: (1) physical laws; (2) rule-based expert systems; and (3) inductive machine learning. Previous approaches at these poles, respectively, are not high throughput, are not generalizable or scalable, and lack sufficient data and structure to be implemented. We propose a new approach to reaction prediction utilizing elements from each pole. Using a physically inspired conceptualization, we describe single mechanistic reactions as interactions between coarse approximations of molecular orbitals (MOs) and use topological and physicochemical attributes as descriptors. Using an existing rule-based system (Reaction Explorer), we derive a restricted chemistry data set consisting of 1630 full multistep reactions with 2358 distinct starting materials and intermediates, associated with 2989 productive mechanistic steps and 6.14 million unproductive mechanistic steps. And from machine learning, we pose identifying productive mechanistic steps as a statistical ranking, information retrieval problem: given a set of reactants and a description of conditions, learn a ranking model over potential filled-to-unfilled MO interactions such that the top-ranked mechanistic steps yield the major products. The machine learning implementation follows a two-stage approach, in which we first train atom level reactivity filters to prune 94.00% of nonproductive reactions with a 0.01% error rate. Then, we train an ensemble of ranking models on pairs of interacting MOs to learn a relative productivity function over mechanistic steps in a given system. Without the use of explicit transformation patterns, the ensemble perfectly ranks the productive mechanism at the top 89.05% of the time, rising to 99.86% of the time when the top four are considered. Furthermore, the system is generalizable, making reasonable predictions over reactants and conditions which the rule-based expert does not handle. A web interface to the machine learning based mechanistic reaction predictor is accessible through our chemoinformatics portal ( http://cdb.ics.uci.edu) under the Toolkits section. PMID- 21819140 TI - Allergenicity assessment of the papaya ringspot virus coat protein expressed in transgenic rainbow papaya. AB - The virus-resistant, transgenic commercial papaya Rainbow and SunUp (Carica papaya L.) have been consumed locally in Hawaii and elsewhere in the mainland United States and Canada since their release to planters in Hawaii in 1998. These papaya are derived from transgenic papaya line 55-1 and carry the coat protein (CP) gene of papaya ringspot virus (PRSV). The PRSV CP was evaluated for potential allergenicity, an important component in assessing the safety of food derived from transgenic plants. The transgene PRSV CP sequence of Rainbow papaya did not exhibit greater than 35% amino acid sequence homology to known allergens, nor did it have a stretch of eight amino acids found in known allergens which are known common bioinformatic methods used for assessing similarity to allergen proteins. PRSV CP was also tested for stability in simulated gastric fluid and simulated intestinal fluid and under various heat treatments. The results showed that PRSV CP was degraded under conditions for which allergenic proteins relative to nonallergens are purported to be stable. The potential human intake of transgene-derived PRSV CP was assessed by measuring CP levels in Rainbow and SunUp along with estimating the fruit consumption rates and was compared to potential intake estimates of PRSV CP from naturally infected nontransgenic papaya. Following accepted allergenicity assessment criteria, our results show that the transgene-derived PRSV CP does not pose a risk of food allergy. PMID- 21819141 TI - A radical procedure for the anti-Markovnikov hydroazidation of alkenes. AB - A one-pot procedure for the efficient hydroazidation of alkenes involving hydroboration with catecholborane followed by reaction with benzenesulfonyl azide in the presence of a radical initiator is described. The regioselectivity is controlled by the hydroboration step and corresponds in most cases to an anti Markovnikov regioselectivity. This procedure is applicable to a wide range of alkenes and gives excellent results with 1,2-disubstituted and trisubstituted alkenes. PMID- 21819142 TI - Transgenic sorghum with altered kafirin synthesis: kafirin solubility, polymerization, and protein digestion. AB - Transgenic sorghum (TG) lines with altered kafirin synthesis, particularly suppression of gamma-kafirin synthesis, and improved protein quality have been developed. The proportion of kafirin extracted with 60% tert-butyl alcohol alone was greatly increased in the TG lines. However, the total amount of kafirin remained unchanged. Further, in the TG lines, the kafirin was much less polymerized by disulfide bonding. There was also evidence of compensatory synthesis of other kafirin proteins. Cooked protein digestibility was increased in the TG form, even after removal of interfering starch. The TG protein bodies were intermediate in appearance between the normal type and the invaginated high digestibility mutants. Hence, the increased protein digestibility of these TG lines is probably related to their lower levels of disulfide-bonded kafirin polymerization, allowing better access of proteases. This work appears to confirm that disulfide bond formation in kafirin is responsible for the reduced protein digestibility of cooked sorghum. PMID- 21819143 TI - Effect of modification of the kilning regimen on levels of free ferulic acid and antioxidant activity in malt. AB - Barley phenolic antioxidants change in response to the kilning regimen used to prepare malt. Green malt was kilned using four different regimens. There were no major differences among the finished malts in parameters routinely used by the malting industry, including, moisture, color, and diastatic activity. Ferulic acid esterase activity and free ferulic acid were higher in malts subjected to the coolest kilning regimen, but malt ethyl acetate extracts (containing ferulic acid) contributed only ~5% of the total malt antioxidant activity. Finished malt from the hottest kilning regimen possessed the highest antioxidant activity, attributed to higher levels of Maillard reaction products. Modifying kilning conditions leads to changes in release of bound ferulic acid and antioxidant activity with potential beneficial effects on flavor stability in malt and beer. PMID- 21819145 TI - NMR cross-correlated relaxation rates reveal ion coordination sites in DNA. AB - In this work, a novel NMR method for the identification of preferential coordination sites between physiologically relevant counterions and nucleic acid bases is demonstrated. In this approach, the NMR cross-correlated relaxation rates between the aromatic carbon chemical shift anisotropy and the proton-carbon dipolar interaction are monitored as a function of increasing Na(+), K(+), and Mg(2+) concentrations. Increasing the counterion concentration modulates the residence times of the counterions at specific sites around the nucleic acid bases. It is demonstrated that the modulation of the counterion concentration leads to sizable variations of the cross-correlated relaxation rates, which can be used to probe the site-specific counterion coordination. In parallel, the very same measurements report on the rotational tumbling of DNA, which, as shown here, depends on the nature of the ion and its concentration. This methodology is highly sensitive and easily implemented. The method can be used to cross-validate and/or complement direct but artifact-prone experimental techniques such as X-ray diffraction, NMR analysis with substitutionary ions, and molecular dynamics simulations. The feasibility of this technique is demonstrated on the extraordinarily stable DNA mini-hairpin d(GCGAAGC). PMID- 21819144 TI - Transformation of actoHMM assembly confined in cell-sized liposome. AB - To construct a simple model of a cellular system equipped with motor proteins, cell-sized giant liposomes encapsulating various amounts of actoHMM, the complexes of actin filaments (F-actin) and heavy meromyosin (HMM, an actin related molecular motor), with a depletion reagent to mimic the crowding effect of inside of living cell, were prepared. We adapted the methodology of the spontaneous transfer of water-in-oil (W/O) droplets through a phospholipid monolayer into the bulk aqueous phase and successfully prepared stable giant liposomes encapsulating the solution with a physiological salt concentration containing the desired concentrations of actoHMM, which had been almost impossible to obtain using currently adapted methodologies such as natural swelling and electro-formation on an electrode. We then examined the effect of ATP on the cytoskeleton components confined in those cell-sized liposomes, because ATP is known to drive the sliding motion for actoHMM. We added alpha hemolysin, a bacterial membrane pore-forming toxin, to the bathing solution and obtained liposomes with the protein pores embedded on the bilayer membrane to allow the transfer of ATP inside the liposomes. We show that, by the ATP supply, the actoHMM bundles inside the liposomes exhibit specific changes in spatial distribution, caused by the active sliding between F-actin and HMM. Interestingly, all F-actins localized around the inner periphery of liposomes smaller than a critical size, whereas in the bulk solution and also in larger liposomes, the actin bundles formed aster-like structures under the same conditions. PMID- 21819146 TI - Observation of intermolecular interactions in large protein complexes by 2D double difference nuclear Overhauser enhancement spectroscopy: application to the 44 kDa interferon-receptor complex. AB - NMR detection of intermolecular interactions between protons in large protein complexes is very challenging because it is difficult to distinguish between weak NOEs from intermolecular interactions and the much larger number of strong intramolecular NOEs. This challenging task is exacerbated by the decrease in signal-to-noise ratio in the often used isotope-edited and isotope-filtered experiments as a result of enhanced T(2) relaxation. Here, we calculate a double difference spectrum that shows exclusively intermolecular NOEs and manifests the good signal-to-noise ratio in 2D homonuclear NOESY spectra even for large proteins. The method is straightforward and results in a complete picture of all intermolecular interactions involving non exchangeable protons. Ninety-seven such (1)H-(1)H NOEs were assigned for the 44 KDa interferon-alpha2/IFNAR2 complex and used for docking these two proteins. The symmetry of the difference spectrum, its superb resolution, and unprecedented signal-to-noise ratio in this large protein/receptor complex suggest that this method is generally applicable to study large biopolymeric complexes. PMID- 21819148 TI - High-resolution 39K NMR spectroscopy of bio-organic solids. AB - We report the first implementation of the multiple-quantum magic-angle-spinning method to obtain high-resolution (39)K NMR spectra for bio-organic solids. The observed spectral resolution in the isotropic dimension is nearly at the sub-ppm level, which approaches the intrinsic resolution limit determined primarily by quadrupole relaxation. We show that high-resolution solid-state (39)K NMR spectroscopy can be used as a new means of probing K(+) ions in biomolecular systems. PMID- 21819147 TI - Probing conformational variations at the ATPase site of the RNA helicase DbpA by high-field electron-nuclear double resonance spectroscopy. AB - The RNA helicase DbpA promotes RNA remodeling coupled to ATP hydrolysis. It is unique because of its specificity to hairpin 92 of 23S rRNA (HP92). Although DbpA kinetic pathways leading to ATP hydrolysis and RNA unwinding have been recently elucidated, the molecular (atomic) basis for the coupling of ATP hydrolysis to RNA remodeling remains unclear. This is, in part, due to the lack of detailed structural information on the ATPase site in the presence and absence of RNA in solution. We used high-field pulse ENDOR (electron-nuclear double resonance) spectroscopy to detect and analyze fine conformational changes in the protein's ATPase site in solution. Specifically, we substituted the essential Mg(2+) cofactor in the ATPase active site for paramagnetic Mn(2+) and determined its close environment with different nucleotides (ADP, ATP, and the ATP analogues ATPgammaS and AMPPnP) in complex with single- and double-stranded RNA. We monitored the Mn(2+) interactions with the nucleotide phosphates through the (31)P hyperfine couplings and the coordination by protein residues through (13)C hyperfine coupling from (13)C-enriched DbpA. We observed that the nucleotide binding site of DbpA adopts different conformational states upon binding of different nucleotides. The ENDOR spectra revealed a clear distinction between hydrolyzable and nonhydrolyzable nucleotides prior to RNA binding. Furthermore, both the (13)C and the (31)P ENDOR spectra were found to be highly sensitive to changes in the local environment of the Mn(2+) ion induced by the hydrolysis. More specifically, ATPgammaS was efficiently hydrolyzed upon binding of RNA, similar to ATP. Importantly, the Mn(2+) cofactor remains bound to a single protein side chain and to one or two nucleotide phosphates in all complexes, whereas the remaining metal coordination positions are occupied by water. The conformational changes in the protein's ATPase active site associated with the different DbpA states occur in remote coordination shells of the Mn(2+) ion. Finally, a competitive Mn(2+) binding site was found for single-stranded RNA construct. PMID- 21819149 TI - Motion of a disordered polypeptide chain as studied by paramagnetic relaxation enhancements, 15N relaxation, and molecular dynamics simulations: how fast is segmental diffusion in denatured ubiquitin? AB - Molecular dynamics (MD) simulations have been widely used to analyze dynamic conformational equilibria of folded proteins, especially in relation to NMR observables. However, this approach found little use in the studies of disordered proteins, where the sampling of vast conformational space presents a serious problem. In this paper, we demonstrate that the latest advances in computation technology make it possible to overcome this limitation. The experimentally validated (calibrated) MD models allow for new insights into structure/dynamics of disordered proteins. As a test system, we have chosen denatured ubiquitin in solution with 8 M urea at pH 2. High-temperature MD simulations in implicit solvent have been carried out for the wild-type ubiquitin as well as MTSL-tagged Q2C, D32C, and R74C mutants. To recalibrate the MD data (500 K) in relation to the experimental conditions (278 K, 8 M urea), the time axes of the MD trajectories were rescaled. The scaling factor was adjusted such as to maximize the agreement between the simulated and experimental (15)N relaxation rates. The resulting effective length of the trajectories, 311 MUs, ensures good convergence properties of the MD model. The constructed MD model was validated against the array of experimental data, including additional (15)N relaxation parameters, multiple sets of paramagnetic relaxation enhancements (PREs), and the radius of gyration. In each case, a near-quantitative agreement has been obtained, suggesting that the model is successful. Of note, the MD-based approach rigorously predicts the quantities that are inherently dynamic, i.e., dependent on the motional correlation times. This cannot be accomplished, other than in empirical fashion, on the basis of static structural models (conformational ensembles). The MD model was further used to investigate the relative translational motion of the MTSL label and the individual H(N) atoms. The derived segmental diffusion coefficients proved to be nearly uniform along the peptide chain, averaging to D = 0.49-0.55 * 10(-6) cm(2)/s. This result was verified by direct analysis of the experimental PRE data using the recently proposed Ullman Podkorytov model. In this model, MTSL and H(N) moieties are treated as two tethered spheres undergoing mutual diffusion in a harmonic potential. The fitting of the experimental data involving D as a single adjustable parameter leads to D = 0.45 * 10(-6) cm(2)/s, in good agreement with the MD-based analyses. This result can be compared with the range of estimates obtained from the resonance energy transfer experiments, D = 0.2-6.0 * 10(-6) cm(2)/s. PMID- 21819150 TI - Attenuation of Slc27a5 gene expression followed by LC-MS measurement of bile acid reconjugation using metabolomics and a stable isotope tracer strategy. AB - The purpose of this study was to evaluate the use of high resolution LC-MS together with metabolomics and D(4)-cholic acid (D(4)-CA) as a metabolic tracer to measure the metabolism and reconjugation of bile acids (BAs) in vitro and in vivo. Metabolic tracers are very important because they allow for the direct detection (substrate-to-product) of small and significant biological perturbations that may not be apparent when monitoring "static" endogenous levels of particular metabolites. Slc27a5, also known as fatty acid transport protein 5 (FATP5), is the hepatic BA-CoA ligase involved in reconjugating BAs during enterohepatic BA recycling. Using Slc27a5-cKD mice, silencing of ~90% gene expression was achieved followed by reduction in the reconjugation of D(4)-CA to D(4)-taurocholic acid (D(4)-TCA), as well as other conjugated BA metabolites in plasma (p = 0.0031). The method described allowed a rapid measure of many D(4) and endogenous BA. Analysis of bile resulted in the detection of 39 BA metabolites from a 13 min analytical run. Finally, the utilization of a novel high resolution mass spectrometry method in combination with metabolomics and a stable isotope metabolic tracer allowed for the detection of targeted and untargeted BAs following silencing of the Slc27a5 gene in primary hepatocytes and in mice. PMID- 21819151 TI - G-quadruplex motifs arranged in tandem occurring in telomeric repeats and the insulin-linked polymorphic region. AB - To date, various G-quadruplex structures have been reported in the human genome. There are numerous studies focusing on quadruplex-forming sequences in general, but few studies have focused on two or more quadruplexes in the same molecule, which are most commonly found in telomeric DNA and other tandem repeats, e.g., insulin-linked polymorphic region (ILPR). Although the human telomere consists of a number of repeats, higher-order G-quadruplex structures are discussed less often because of the complexity of the structures. In this study, sequences consisting of 4-12 repeats of d(G(4)TGT), d(G(3)T(2)A), and/or d(G(4)T(2)A) have been studied by circular dichroism, ultraviolet spectroscopy, and temperature gradient gel electrophoresis. These sequences serve as a model for the arrangement of quadruplexes in the telomere and ILPR in solution. Our major findings are as follows. (i) The number of G-rich repeats has a great influence on G-quadruplex stability. (ii) The evidence of quadruplex-quadruplex interaction is confirmed. (iii) For the first time, we directly observed the melting behavior of different conformers in a single experiment. Our results agree with other calorimetric and spectroscopic data and data obtained by single-molecule studies, atomic force microscopy, and mechanical unfolding by optical tweezers. We propose that the end of telomeres can be formed by only a few tandem quadruplexes (fewer than three). Our findings improve our understanding of the mechanism of G quadruplex formation in long repeats in G-rich-regulating parts of genes and telomere ends. PMID- 21819152 TI - Opening an electrical band gap of bilayer graphene with molecular doping. AB - The opening of an electrical band gap in graphene is crucial for its application for logic circuits. Recent studies have shown that an energy gap in Bernal stacked bilayer graphene can be generated by applying an electric displacement field. Molecular doping has also been proposed to open the electrical gap of bilayer graphene by breaking either in-plane symmetry or inversion symmetry; however, no direct observation of an electrical gap has been reported. Here we discover that the organic molecule triazine is able to form a uniform thin coating on the top surface of a bilayer graphene, which efficiently blocks the accessible doping sites and prevents ambient p-doping on the top layer. The charge distribution asymmetry between the top and bottom layers can then be enhanced simply by increasing the p-doping from oxygen/moisture to the bottom layer. The on/off current ratio for a bottom-gated bilayer transistor operated in ambient condition is improved by at least 1 order of magnitude. The estimated electrical band gap is up to ~111 meV at room temperature. The observed electrical band gap dependence on the hole-carrier density increase agrees well with the recent density-functional theory calculations. This research provides a simple method to obtain a graphene bilayer transistor with a moderate on/off current ratio, which can be stably operated in air without the need to use an additional top gate. PMID- 21819153 TI - Expanding the genetic code of an animal. AB - Genetic code expansion, for the site-specific incorporation of unnatural amino acids into proteins, is currently limited to cultured cells and unicellular organisms. Here we expand the genetic code of a multicellular animal, the nematode Caenorhabditis elegans. PMID- 21819154 TI - Chemoselective surface immobilization of proteins through a cleavable peptide. AB - Surface immobilization of biomolecules is a fundamental step in several experimental techniques such as surface plasmon resonance analysis and microarrays. Oxime ligation allows reaching chemoselective protein immobilization with the retention of native-like conformation by proteins. Beside the need for chemoselective ligation of molecules to surface/particle, equally important is the controlled release of the immobilized molecules, even after a specific binding event. For this purpose, we have designed and assessed in an SPR experiment a peptide linker able to (i) anchor a given protein (enzymes, receptors, or antibodies) to a surface in a precise orientation and (ii) release the immobilized protein after selective enzymatic cleavage. These results open up the possibility to anchor to a surface a protein probe leaving bioactive sites free for interaction with substrates, ligands, antigens, or drugs and successively remove the probe-ligand complex by enzymatic cleavage. This peptide linker can be considered both an improvement of SPR analysis for macromolecular interaction and a novel strategy for drug delivery and biomaterial developments. PMID- 21819155 TI - Preferential solvation in alkan-1-ol/alkylbenzoate binary mixtures by solvatochromic probes. AB - The binary mixtures of methanol with (C(1)-C(4)) alkylbenzoates and of (C(1), C(3), C(5), C(7), C(9), C(11)) alkan-1-ols with methylbenzoate were used as solvents to look into the preferential solvation and intermolecular interactions of the solvatochromic indicators 2-nitroanisole, 4-nitroaniline, 4-nitrophenol, and Reichardt's dye by UV-vis measurements. The experimental data at 298.15 K have served to deduce the corresponding Reichardt and Kamlet-Taft parameters of the mixed solvents. The solvation effects exerted on the solvatochromic probes by the solvents used, either pure or binary mixed, were analyzed by means of the preferential solvation model. Likewise, the (1)H NMR, (13)C NMR, and IR spectroscopic parameters measured for the mixed solvents corroborate the structural effects. The sets of experimental data gathered shed abundant light on the underlying solute-solvent and solvent-solvent interactions. The alkanol/methylbenzoate mixtures display stronger solvation ability than the pure solvents. PMID- 21819156 TI - Structural requirements of strigolactones for germination induction of Striga gesnerioides seeds. AB - Strigolactones are highly potent germination stimulants for seeds of the parasitic weeds Striga and Orobanche spp. 4-Hydroxy-GR24 and 4-acetoxy-GR24 were prepared and their abilities to induce seed germination of Striga gesnerioides evaluated. Optically active (8bR,2'R)-isomers induced germination, although the racemic diastereomers were inactive. In contrast, the stereoisomer of GR24 with the same configuration induced negligible germination. Some stereoisomers of GR24 and its analogues acted as effective antagonists for induction of seed germination by cowpea root exudates. These results suggest that both an oxygenated substituent at C-4 and the configuration of the tricyclic lactone and the D-ring are essential structural requirements for induction of germination in S. gesnerioides seeds. PMID- 21819157 TI - SHAFTS: a hybrid approach for 3D molecular similarity calculation. 1. Method and assessment of virtual screening. AB - We developed a novel approach called SHAFTS (SHApe-FeaTure Similarity) for 3D molecular similarity calculation and ligand-based virtual screening. SHAFTS adopts a hybrid similarity metric combined with molecular shape and colored (labeled) chemistry groups annotated by pharmacophore features for 3D similarity calculation and ranking, which is designed to integrate the strength of pharmacophore matching and volumetric overlay approaches. A feature triplet hashing method is used for fast molecular alignment poses enumeration, and the optimal superposition between the target and the query molecules can be prioritized by calculating corresponding "hybrid similarities". SHAFTS is suitable for large-scale virtual screening with single or multiple bioactive compounds as the query "templates" regardless of whether corresponding experimentally determined conformations are available. Two public test sets (DUD and Jain's sets) including active and decoy molecules from a panel of useful drug targets were adopted to evaluate the virtual screening performance. SHAFTS outperformed several other widely used virtual screening methods in terms of enrichment of known active compounds as well as novel chemotypes, thereby indicating its robustness in hit compounds identification and potential of scaffold hopping in virtual screening. PMID- 21819158 TI - Polyphenolic composition of hazelnut skin. AB - Skins from different hazelnut samples were characterized for total polyphenol content, total antioxidant capacity (TAC), and their content in specific polyphenolic compounds. The main polyphenolic subclass, identified and quantified by means of HPLC-MS/MS, comprised monomeric and oligomeric flavan-3-ols, which accounted for more than 95% of total polyphenols. Flavonols and dihydrochalcones were 3.5% while phenolic acids were less than 1% of the total identified phenolics. The TAC values of the skin samples ranged between 0.6 and 2.2 mol of reduced iron/kg of sample, which is about 3 times the TAC of whole walnuts, 7-8 times that of dark chocolate, 10 times that of espresso coffee, and 25 times that of blackberries. By describing the profile of polyphenols present in hazelnut skins, this study provides the basis to further investigate the potential health effects of hazelnut byproduct. PMID- 21819159 TI - Newer generation fentanyl transmucosal products for breakthrough pain in opioid tolerant cancer patients. AB - Oral normal-release morphine has long been considered the gold-standard treatment for cancer breakthrough pain. However, its relatively long time to analgesic onset, delay in maximal analgesic effect and prolonged duration of action make it unsuitable for the management of breakthrough pain episodes. These limitations led to the development of an oral transmucosal formulation of the fast-acting opioid fentanyl (oral transmucosal fentanyl citrate [OTFC] lozenge on a plastic handle; Actiq(r)), which has been shown to produce more rapid and effective pain relief than oral morphine. However, the formulation itself has some limitations. Consequently, investigators have continued to develop other, newer generation, transmucosal formulations of fentanyl to further improve the management of breakthrough pain. Recently, five such compounds (Effentora(r)/Fentora(r), Abstral(r), Instanyl(r), Breakyl(r)/OnsolisTM and PecFent(r)) have been concurrently approved in Europe and/or the US, and have documented efficacy in quickly relieving breakthrough pain episodes. All of the available pivotal efficacy trials of these agents are randomized, double-blind comparisons with placebo. There are no head-to-head trials comparing any of the newer transmucosal formulations with each other. Only one non-pivotal study of intranasal fentanyl spray used a transmucosal preparation as an active comparator. However, that comparator was OTFC, not one of the newer transmucosal products. Close examination of the existing trials assessing these newer transmucosal preparations reveals significant variation in many study parameters, such as patient selection criteria, severity of breakthrough pain episodes, proportions of patients with a neuropathic pain component, titration protocols, choice of the primary endpoints, protocols for repeat dosing and rescue medication, the separation of treated episodes and the extent of the placebo response, all of which may have affected efficacy results. It is therefore difficult to evaluate the relative efficacies of these treatments on the basis of the available trials. Furthermore, given the differences in design between studies, the value of any potential meta-analyses including these trials would likely be limited. Blinded head-to-head comparisons of new transmucosal fentanyl preparations would be the only way to conclusively determine comparative effectiveness, but given the impracticalities of conducting such studies, these are unlikely. PMID- 21819160 TI - Bioequivalence of saxagliptin/metformin extended-release (XR) fixed-dose combination tablets and single-component saxagliptin and metformin XR tablets in healthy adult subjects. AB - BACKGROUND AND OBJECTIVES: As compared with individual tablets, saxagliptin/metformin extended-release (XR) fixed-dose combination (FDC) tablets offer potential for increased patient compliance with the convenience of once daily dosing. Two bioequivalence studies assessed the fed-state bioequivalence of saxagliptin/metformin XR 5 mg/500 mg FDC (study 1) and saxagliptin/metformin XR 5 mg/1000 mg FDC (study 2) relative to the same dosage strengths of individual component tablets administered concurrently. The effect of food on saxagliptin and metformin pharmacokinetics from the saxagliptin/metformin XR 5 mg/500 mg FDC and their steady-state pharmacokinetics from the saxagliptin/metformin XR 5 mg/1000 mg were also investigated. METHODS: These were randomized, open-label, single-dose, three-period, three-treatment, crossover studies in healthy subjects (n = 30 in each study). The treatments in study 1 were a saxagliptin/metformin XR 5 mg/500 mg FDC tablet in the fed and fasted states on separate occasions, and saxagliptin 5 mg and metformin XR 500 mg co-administered in the fed state. The treatments in study 2 were a saxagliptin/metformin XR 5 mg/1000 mg FDC tablet in the fed state, saxagliptin 5 mg and 2 * metformin XR 500 mg co-administered in the fed state, and saxagliptin/metformin XR 5 mg/1000 mg FDC once daily for 4 days in the fed state to assess steady-state pharmacokinetics. The safety and tolerability of each treatment were also evaluated. RESULTS: For both studies, saxagliptin and metformin in the FDCs were bioequivalent to the individual components as the limits of the 90% confidence interval of the ratio of adjusted geometric means for all key pharmacokinetic parameters were contained within 0.800 to 1.250. Compared with the fasted state, food did not have a meaningful effect on the pharmacokinetics of saxagliptin and metformin when administered as the saxagliptin/metformin XR 5 mg/500 mg FDC. The saxagliptin/metformin XR 5 mg/1000 mg FDC showed consistent pharmacokinetics at steady state without evidence of dose dumping. Co-administration of saxagliptin and metformin XR was generally safe and well tolerated as the FDCs or as individual tablets. CONCLUSION: Saxagliptin/metformin XR 5 mg/500 mg and saxagliptin/metformin XR 5 mg/1000 mg FDCs were bioequivalent to individual tablets of saxagliptin and metformin of the same strengths. Additionally, food had little effect on the pharmacokinetics of saxagliptin and metformin administered in the saxagliptin/metformin XR 5 mg/500 mg FDC and the steady-state pharmacokinetics of the saxagliptin/metformin XR 5 mg/1000 mg FDC was consistent over time. No unexpected safety findings were observed with saxagliptin/metformin XR administration. The tolerability of the FDC of saxagliptin/metformin XR was comparable to that of the co-administered individual components. These results indicate that the safety and efficacy profile of co-administration of saxagliptin and metformin can be extended to the saxagliptin/metformin XR FDC tablets. TRIALS REGISTRATION: ClinicalTrials.gov Identifiers: NCT01192139 and NCT01192152. PMID- 21819161 TI - Comparison of the efficacy and safety of pantoprazole magnesium and pantoprazole sodium in the treatment of gastro-oesophageal reflux disease: a randomized, double-blind, controlled, multicentre trial. AB - BACKGROUND: Proton pump inhibitors (PPIs) are well established as first-line agents for the treatment of moderate-to-severe gastro-oesophageal reflux disease (GORD). Although all PPIs heal oesophageal lesions and provide symptomatic relief, breakthrough symptoms may occur as acidity levels rebound. Pantoprazole magnesium (pantoprazole-Mg) has a longer elimination half-life than pantoprazole sodium (pantoprazole-Na), resulting in prolonged drug exposure. OBJECTIVE: This study compares the clinical efficacy and safety of once-daily pantoprazole-Mg 40 mg with that of once-daily pantoprazole-Na 40 mg in the management of GORD. METHODS: This was a randomized, double-blind, controlled, multicentre study of non-inferiority design in outpatients with GORD. The study was conducted in 53 centres in Germany from 12 May 2003 to 18 September 2003. Male or female outpatients (aged >=18 years) with endoscopically confirmed GORD stage I-III (according to the Savary-Miller classification modified by Siewert) were enrolled. Using a computer-generated randomization list, patients were randomized to treatment with pantoprazole-Mg 40 mg plus placebo or pantoprazole-Na 40 mg plus placebo, both given once daily for 4 or 8 weeks depending on healing of oesophagitis. The primary objective was endoscopic healing at 8 weeks. RESULTS: The intent-to-treat (ITT) group consisted of 636 patients (322 receiving pantoprazole-Mg and 314 receiving pantoprazole-Na). Endoscopically confirmed healing of reflux oesophagitis after 8 weeks occurred in 87.3% (95% CI 83.1, 90.7) of patients receiving pantoprazole-Mg and 85.0% (95% CI 80.6, 88.8) of patients receiving pantoprazole-Na (ITT population). The lower bound of the 95% CI for the between-group treatment difference was -1.3, which was within the predefined margin of non-inferiority of -10% to 0%. Healing rates after 4 weeks were superior in the pantoprazole-Mg group (72.7% [95% CI 67.5, 77.5]) compared with the pantoprazole-Na group (66.2% [95% CI 60.7, 71.5]), and the one-sided (lower bound) of the 95% CI for the difference between healing rates for the two treatments was within the predefined non-inferiority margin of -10% to 0%. Both treatments had a similar effect on GORD healing in subgroups of patients based on baseline oesophagitis grade and Helicobacter pylori status. Pantoprazole-Mg had similar efficacy to pantoprazole-Na in relieving a broad range of GORD-related symptoms across the course of the study, although symptomatic relief at 4 weeks was numerically higher in the pantoprazole-Mg group than in the pantoprazole-Na group (statistical analyses were not performed). Both treatments were well tolerated; most adverse events were of mild or moderate severity and unrelated to the study medication, and there were no unexpected safety concerns. CONCLUSION: Pantoprazole-Mg is clinically as effective and well tolerated as pantoprazole-Na in the treatment of GORD stages I-III, demonstrating non-inferiority for oesophageal healing at 8 weeks and superior healing rates at 4 weeks associated with high levels of symptomatic relief. PMID- 21819163 TI - Sharing area-specific information via an internet forum benefits rural clinicians: a lesson learned from a case with decompression sickness a remote island. PMID- 21819164 TI - Models of care for socially isolated older rural carers: barriers and implications. AB - INTRODUCTION: In response to population ageing, the numbers of older carers residing in rural areas are increasing. However, rural older carers are at risk of social isolation due to the decreased social networks associated with ageing and caring responsibilities, and the geographical isolation associated with rurality. This broad, systematic review of the literature was undertaken to: (1) identify barriers to social participation for rural older carers; and (2) summarise features of interventions that were effective in reducing social isolation for rural and/or older carers. METHODS: Literature was obtained through systematic searches of selected electronic databases; selected Australian and international government and research based websites and Google Scholar. Searches were limited to material published from 1999 to 2009, and literature was included which either identified barriers to social participation, or outlined interventions that were effective in reducing social isolation and increasing social support in rural and/or older carers. RESULTS: 67 articles, book chapters and reports identified which addressed the review objectives. Findings indicate that rural older carers experience considerable barriers to socialisation, and six dimensions are identified that are effective in reducing barriers, decreasing social isolation and increasing social participation. Interventions must address individual needs; incorporate a dual carer-care recipient focus and/or an educational component; facilitate informal social interaction; utilise existing networks and experienced personnel; and be both sustainable and long term. CONCLUSIONS: Reducing social isolation in rural older carers is a two-stage process. First, barriers to attendance, both logistical and perceived, must be addressed, and the focus of the intervention must be relevant to the carer. Second, opportunities for informal social interaction must be maximised within the intervention. However, a secondary focus may be necessary to ensure attendance, and the provision of education is also integral to achieving long term outcomes. Integration of service providers in an informal capacity is also important in providing long-term support options. Addressing these issues will assist in developing interventions for rural older carers that are both appropriate and sustainable. PMID- 21819162 TI - Comparative efficacy of vildagliptin and sitagliptin in Japanese patients with type 2 diabetes mellitus: a matching-adjusted indirect comparison of randomized trials. AB - BACKGROUND AND OBJECTIVE: Vildagliptin and sitagliptin are oral dipeptidyl peptidase 4 inhibitors approved in Japan for the treatment of type 2 diabetes mellitus when adequate glycaemic control is not achieved with diet, exercise or sulphonylureas. The aim of this study was to compare 12-week glycaemic control with vildagliptin 50 mg twice daily versus sitagliptin 50 or 100 mg once daily in Japanese patients with type 2 diabetes. METHODS: Randomized trials of vildagliptin or sitagliptin in Japanese patients were identified from the literature. Individual patient data were obtained for vildagliptin trials. In the absence of a head-to-head randomized trial, a matching-adjusted indirect comparison was conducted by weighting individual patients from vildagliptin trials to match average baseline characteristics published for sitagliptin trials, including age, sex, body mass index, glycosylated haemoglobin (HbA(1c)), fasting plasma glucose (FPG) and diabetes duration. After matching, HbA(1c) change from baseline to week 12, the primary endpoint in each trial, was compared between balanced populations treated with vildagliptin and sitagliptin. Separate comparisons were conducted for vildagliptin 50 mg twice daily versus sitagliptin 50 mg and 100 mg once daily. RESULTS: Two trials of vildagliptin and three trials of sitagliptin were identified for Japanese patients. Across all included trials, a total of 264 patients were treated with vildagliptin 50 mg twice daily, 235 were treated with sitagliptin 50 mg once daily and 145 were treated with sitagliptin 100 mg once daily. Mean baseline HbA(1c) ranged from 7.4% to 7.8% per trial. Before matching, significant (p < 0.05) cross-trial differences included lower mean HbA(1c) (by 0.2-0.3%) and higher FPG (by 5-13 mg/dL) in vildagliptin trials. After matching, all baseline characteristics were balanced between treatment groups. Combining matched trials, vildagliptin 50 mg twice daily was associated with significantly greater absolute HbA(1c) reduction by 0.28% compared with sitagliptin 50 mg once daily (95% CI 0.15, 0.41; p < 0.001) and by 0.35% compared with sitagliptin 100 mg once daily (95% CI 0.07, 0.62; p = 0.013). CONCLUSION: After adjusting for baseline differences among trials of vildagliptin and sitagliptin in Japanese patients with type 2 diabetes, vildagliptin 50 mg twice daily was associated with significantly greater HbA(1c) reduction than sitagliptin 50 mg or 100 mg once daily. PMID- 21819165 TI - Improving outcomes in patients at risk for venous thromboembolism following total knee and total hip replacement: implications for managed care. AB - An estimated 1 million Americans suffer from venous thromboembolism (VTE) annually and more than 600,000 experience symptomatic VTE events each year. Patients undergoing total knee replacement (TKR) and total hip replacement (THR) are at high risk for developing VTE (40%-60% risk without prophylaxis). The economic burden of post-TKR/THR VTE is very large, with the average length of stay more than double that of patients without VTE, and risk-adjusted overall costs 4 and 5 times greater among the TKR and THR populations, respectively, compared with non-VTE patients. Efforts are underway, however, in the public and private sectors to increase the rates of appropriate VTE thromboprophylaxis. Payers are experimenting with quality measurement and improvement programs to incentivize clinical behavior toward optimizing outcomes; the role of patient education in VTE prophylaxis is also evolving. There is an excellent opportunity to reshape the current patient education approach and develop appropriate, accessible materials, but, ultimately, a multipronged effort that targets as many variables related to VTE risk as possible is necessary in order to achieve success in lowering the burden of post-TKR/THR VTE. PMID- 21819166 TI - Cost-effectiveness of 21-gene assay in node-positive, early-stage breast cancer. AB - OBJECTIVE: To assess impact on health outcomes and healthcare expenditures of adopting a 21-gene assay for women with early-stage, minimally node-positive, estrogen receptor-positive (N (1-3)/ER) HER2-negative breast cancer. STUDY DESIGN: We adapted a deterministic decision-analytic model to estimate costs and quality-of-life outcomes associated with chemotherapy, adverse events, supportive care, recurrence, and second primary cancers for usual care compared with care determined by the 21-gene assay recurrence score, where 71% and 54% of women, respectively, were treated with adjuvant chemotherapy. Model input data were based on national statistics, published literature, physician surveys, and Medicare Part B prices. METHODS: Annual numbers of events were multiplied by quality-adjusted life-years (QALYs) lost and costs to estimate net health and economic impacts of each strategy. Analyses were from a managed care payer perspective for the US population. RESULTS: Patients receiving the assay were predicted to gain 0.127 QALY and save $4359 annually from avoiding chemotherapy, adverse events, supportive care, and secondary primary tumors. For a 2-million member plan, net gains were 4.44 QALYs/year and savings were $13,476/year. Cost savings were greater for the Medicare population. Although overall results were sensitive only to reduced impact of testing and chemotherapy costs, they were still highly cost-effective (incremental cost-effectiveness ratio <$20,000/QALY). CONCLUSIONS: Use of a 21-gene assay in patients with early-stage N (1-3)/ER HER2 negative breast cancer may improve health outcomes and add no incremental cost, thereby providing valuable insight for health plans, the Centers for Medicare and Medicaid Services, and clinicians regarding coverage policies and treatment decisions. PMID- 21819167 TI - Systolic blood pressure control after participation in a hypertension intervention study. AB - OBJECTIVE: To evaluate whether systolic blood pressure (SBP) control is maintained following participation in a multimodal hypertension intervention. STUDY DESIGN: This was a retrospective cohort of patients completing the Improving Blood Pressure in Colorado study, a randomized trial comparing a multimodal intervention with usual care for patients who had uncontrolled hypertension. Chart review assessed the first SBP measurement recorded as part of routine care after the study ended. Among patients who had controlled SBP at the final study visit, the proportions who had uncontrolled SBP during follow-up were compared for the intervention and usual care (UC) groups. Kaplan-Meier estimates assessed time to uncontrolled SBP by treatment arm. RESULTS: Of 283 patients completing the Improving Blood Pressure in Colorado study, 51.5% in the intervention and 46.9% in the UC group had controlled SBP at the final study visit. Of patients with controlled SBP, 37.0% and 46.4% of patients in the intervention and UC groups, respectively, had uncontrolled SBP at their initial measurement during follow-up (P = .32). There was no difference in median time to uncontrolled SBP (126 vs 114 days for the intervention and UC groups, respectively; P = .47). CONCLUSIONS: SBP control was not maintained in a significant proportion of patients in both groups following hypertension study participation. These findings suggest the need for interventions to focus on longer-term BP control in contrast to the short duration of most hypertension intervention trials. PMID- 21819168 TI - Colorectal cancer screening use among insured primary care patients. AB - OBJECTIVE: To compare colorectal cancer (CRC) screening use, including changes over time and demographic characteristics associated with screening receipt, between 2 insured primary care populations. STUDY DESIGN: Clinical and administrative records from 2 large health systems, one in New Mexico and the other in Michigan, were used to determine use of CRC screening tests between 2004 and 2008 among patients aged 51 to 74 years. METHODS: Generalized estimating equations were used to evaluate trends in CRC screening use over time and the association of demographic and other factors with screening receipt. RESULTS: Rates of CRC screening use ranged from 48.1% at the New Mexico site to 68.7% at the Michigan site, with colonoscopy being the most frequently used modality. Fecal occult blood test was used inconsistently by substantial proportions of patients who did not meet the definition of screening users. Screening use was positively and significantly associated with older age, male sex, and more periodic health examinations and other types of primary care visits; at the Michigan site, it was also associated with African American race, married status, and higher annual estimated household income. CONCLUSIONS: Among insured primary care patients, CRC screening use falls short. Further research is needed to determine what factors are barriers to routine fecal occult blood test or colonoscopy use among insured patients who have access to and regularly use primary care and how those barriers can be eliminated. PMID- 21819169 TI - Using medicare data for comparative effectiveness research: opportunities and challenges. AB - BACKGROUND: With the introduction of Part D drug benefits, Medicare began to collect information on diagnoses, treatments, and clinical events for millions of beneficiaries. These data are a promising resource for comparative effectiveness research (CER) on treatments, benefit designs, and delivery systems. OBJECTIVE: To explore the data available for researchers and approaches that could be used to enhance the value of Medicare data for CER. CHALLENGES AND OPPORTUNITIES: Using currently available Medicare data for CER is challenging; as with all administrative data, it is not possible to capture every factor that contributes to prescribing decisions and patients are not randomly assigned to treatments. In addition, Part D plan selection and switching may influence treatment decisions and contribute to selection bias. Exploiting certain program aspects could address these limitations. For example, ongoing changes in Medicare or plan policies and the random assignment of beneficiaries with Part D low-income subsidies into plans with different formularies could yield natural experiments. POLICY IMPLICATIONS: Refining policies for time to data release, provision of additional data elements, and linkage with more beneficiary level information would improve the value and usability of these data. Improving the transparency and reproducibility of findings, and potential open access for qualified stakeholders are also important policy considerations. Data needs must be reconciled with current policies and goals. CONCLUSIONS: Medicare data provide a rich resource for CER. Leveraging existing program elements, combined with some administrative changes in data availability, could create large data sets for evaluating treatment patterns, spending, and coverage decisions. PMID- 21819170 TI - Impact of Celecoxib restrictions in medicare beneficiaries with arthritis. AB - OBJECTIVE: To compare the incidence of serious gastrointestinal (GI) complications and associated medical costs in a population with either osteoarthritis (OA) or rheumatoid arthritis (RA) enrolled in Medicare plans with celecoxib formulary restrictions versus plans without such restrictions. METHODS: This study was a retrospective cohort analysis of Medicare members in plans with and without celecoxib restrictions. Members diagnosed with OA or RA were identified and followed for 1 year. RESULTS: The restricted group had higher levels of nonselective nonsteroidal anti-inflammatory drug use (51% vs 40%, p <.001), and celecoxib use was double in the unrestricted group (16% vs 8%, p <.001). The incidence of a serious GI complication was slightly higher in the restricted group (5.4% vs 4.6%, P <.001). The adjusted mean serious GI complication-related cost for the restricted group was more than 15 times higher than that for the nonrestricted group ($1559 [95% confidence interval (CI) $1341 $1811] vs $101 [95% CI $87-$117]), adjusted mean arthritis-related medical costs were $5733 per year (95% CI $5097-$6448) for the restricted group and $3170 (95% CI $2816-$3569) for the unrestricted group. CONCLUSIONS: The restricted group had significantly less use of celecoxib, indicating that restriction was effective at reducing celecoxib utilization. Although limitations exist when comparing populations from different health plans, and the underlying causes of serious GI complications are multifactorial, the restricted group had a higher incidence of serious GI complications and higher costs related to serious GI complications and arthritis. PMID- 21819171 TI - Effects of standardized outreach for patients refusing preventive services: a quasiexperimental quality improvement study. AB - OBJECTIVE: To determine the effect of standardized outreach on the receipt of preventive services for patients whose physicians record that the patient refused the service. STUDY DESIGN: Prospective observational study of a quality improvement intervention using a nonrandomly assigned comparator group. METHODS: Patients from a large internal medicine practice with recorded refusals to preventive services were included. A nonclinician care manager mailed plain language educational brochures, attempted telephone contact, and provided logistical assistance. The primary patient outcome was the time from refusal to first receipt of a refused service (colorectal cancer screening, breast cancer screening [mammography], cervical cancer screening, osteoporosis screening [bone density testing], or pneumococcal vaccination). We compared the time to completion of refused sevices during the period when outreach was performed (February 8, 2008, to November 25, 2008 [outreach cohort]), and during a subsequent period when refusals were recorded but no outreach was performed (November 26, 2008, to December 1, 2009 [nonintervention cohort]), using Cox proportional hazards regression models adjusted for patient characteristics. We recorded the time spent performing outreach. RESULTS: In total, 407 patients refused 520 preventive services in the outreach cohort, and 378 patients refused 510 services in the nonintervention cohort. After 6 months of follow-up, 6.1% of the outreach cohort and 4.8% of the nonintervention cohort had received a refused service (adjusted hazard ratio, 1.3; 95% confidence interval, 0.7-2.5). The care manager spent 214 hours performing the outreach. CONCLUSIONS: Standardized educational outreach was not a promising strategy for improving preventive services use among patients who have refused services recommended by their physician. The amount of time required to perform the outreach was substantial. PMID- 21819172 TI - Addressing healthcare inequities in Israel by eliminating prescription drug copayments. AB - OBJECTIVES: To determine whether subsidizing prescription drug copayments for patients with chronic illness and low socioeconomic status would increase their use of prescription drugs and improve their health. STUDY DESIGN: Prospective cohort study. METHODS: Enrolled were 355 patients with low socioeconomic status, as defined by the Israel National Insurance Institute, who were not regularly purchasing prescribed medications. Included were patients (mean age, 64.6 years) with diabetes mellitus, hypertension, or hypercholesterolemia, as these chronic illnesses have easily measurable surrogate end points. Patients were followed up for 24 months. Serum glycated hemoglobin level, blood pressure, and low-density lipoprotein cholesterol concentration were measured. Patients paid their copayments using a "credit card" covered by a donation. RESULTS: Two years after initiation of the subsidized copayment program, the mean (SD) values were significantly below those at the outset of the program for blood pressure (136.2 [16.7]/78.0 [8.7] vs 128.2 [13.3]/74.8 [8.1] mm Hg) and low-density lipoprotein cholesterol concentration (116.2 [38.0] vs 105.3 [38.0] mg/dL) (P <.001 for both). The mean glycated hemoglobin level showed no improvement in the first year, but a significant increase was noted by the second year of the program. CONCLUSIONS: When copayments for prescription drugs were eliminated, low-income patients demonstrated increased compliance with obtaining medications, better response to treatment, and improved blood pressure and low-density lipoprotein cholesterol concentrations. Glycemic control did not improve. PMID- 21819173 TI - Adherence to medication under mandatory and voluntary mail benefit designs. AB - OBJECTIVE: To compare adherence rates under voluntary and mandatory mail benefit designs. STUDY DESIGN: Matched retrospective cohort. METHODS: Adherence rates in the first year of therapy were compared between voluntary and mandatory mail cohorts composed of individuals who initiated statin, angiotensin-converting enzyme (ACE) inhibitor, angiotensin receptor blocker (ARB), platelet aggregation inhibitor, metformin, glitazone, or sulfonylurea therapy at a retail pharmacy between January 1 and March 31, 2009. Initiators in mandatory mail plans were matched on therapeutic class, age, sex, prospective risk, and cost of initial prescription with those in voluntary mail plans. Logistic regression models of optimal adherence were constructed to adjust for measured confounders. RESULTS: Persistence rates were similar through the first 60 days of therapy. The mandatory mail cohort had a notable drop in persistence by day 90 (63.3% vs 56.3%, P <.001), with a more pronounced drop among those without previous mail service pharmacy use (50.5%). Median medication possession ratio (49.2% vs 57.4%) and optimal adherence (33.6% vs 36.1) were also lower. In the multivariable models, mandatory mail participants were less likely to achieve optimal adherence overall (odds ratio [OR] 0.70; 95% confidence interval [CI] 0.67-0.74) and in the metformin (OR 0.55), sulfonylurea (OR 0.72), ACE inhibitor (OR 0.74), ARB (OR 0.69), and statin (OR 0.69) classes. Participants with no prior use of mail service pharmacy had significantly lower odds of achieving optimal adherence in all therapeutic classes. CONCLUSIONS: Mandatory mail appears to cause some members to discontinue therapy prematurely, particularly those without previous mail service pharmacy experience. PMID- 21819174 TI - Obtaining patient feedback at point of service using electronic kiosks. AB - BACKGROUND: Engaging patients in their healthcare is a goal of healthcare reform. Obtaining sufficient, reliable patient feedback about their experiences in an office encounter has been a challenge. OBJECTIVE: To determine the feasibility of collecting feedback from patients regarding their office encounter at the point of care using touch screen kiosk technology in an urban primary care clinic. METHODS: We analyzed response rate, ease of use, provider data, and condition specific data. The study was conducted over a 45-day period at 1 internal medicine academic teaching practice. Providers, staff, and a sponsor-supported monitor directed patients to use the kiosk after an office visit. RESULTS: A total of 1923 surveys were completed from 3850 office visits (50%). There was no appreciable impact on office flow in terms of wait time, checkout procedures, or visit with provider. Characteristics of patients completing the surveys were similar to practice demographics of patients with an office visit during the study period in terms of sex, but differed by age and race. Small but statistically significant differences were seen among patient ratings of resident versus attending physicians. Patients with depression were less likely than patients with diabetes, chronic low back pain, or asthma to report that they had set personal goals to manage their condition. CONCLUSION: This technology represents an important advance in our ability to capture the patient's opinion regarding quality and practice improvement initiatives, and has the potential for directly engaging patients in their care. PMID- 21819175 TI - Early clinical experience with networked system for promoting patient self management. AB - OBJECTIVE: To gain early experience with a networked system designed to assess a patient's adherence to oral medication and physiologic metrics in an ambulatory, at-home setting. STUDY DESIGN: Prospective, observational studies. MATERIALS AND METHODS: This networked system for patient self-management consists of ingestible markers and a wearable, personal monitor. When a marker is ingested, it communicates to a monitor that time-stamps the ingestion and identifies the marker as unique. The monitor also records heart rate and activity. Data from third-party monitoring equipment (eg, sphygmomanometer, weight scale) can be integrated into the system. Collected data are summarized for patient and physician review. Directly observed ingestion (DOI) of placebo tablet markers was used to assess the system's technical performance. Markers were also coencapsulated with drugs to capture at-home adherence. A performance criterion of <95% was set as the objective for system performance. RESULTS: A total of 111 subjects ingested 7144 ingestible markers; 3298 were DOIs. The system's positive detection accuracy and negative detection accuracy in detecting ingested markers were 97.1% and 97.7%, respectively. It differentiated 100% of multiple drugs and doses taken simultaneously by type and by dose. Medication adherence was >85%. The most common adverse effect was mild skin rash from the monitor's electrodes. No definitive marker-related adverse effects were reported. CONCLUSION: The system appears to be safe and effective in capturing and integrating adherence and physiologic data. Efforts are under way to enhance system functionalities and refine user interfaces. By providing context-rich information, this system may enhance patient-provider collaboration. PMID- 21819177 TI - Age-related changes in the appreciation of novel metaphoric semantic relations. AB - In the present study we tested the possibility that older adults differ from younger adults in their appreciation of metaphoric semantic relations, and that age-related changes occur due to the perception of novel metaphors. In the first experiment 35 younger (mean age?=?23.1) and 35 older adults (mean age?=?75.3) were asked to rate the plausibility of metaphoric, literal, and unrelated word pairs. Relative to young participants, older participants rated fewer expressions as metaphorically plausible. The second experiment was conducted to examine whether the findings of the first experiment could be accounted for by an age associated difference in the appreciation of metaphors with different levels of familiarity. In the second experiment, 25 younger (mean age?=?24.4) and 25 older adults (mean age?=?77.5) were asked to rate the familiarity level of the plausible metaphoric expressions. Relative to young participants, older participants rated fewer expressions as novel and more expressions as familiar. The results suggest that novelty plays an important role in appreciating the plausibility of semantic relationships, and age-related changes are associated with the appreciation of the novelty of expressions. PMID- 21819178 TI - Impact of youth injuries on the uninsured farm family's economic viability. AB - The objective of this study is to estimate the impact of youth injuries on the uninsured farm family's economic viability. Using farm prototypes, we compared farm profits with costs of farm youth injuries. We built profit models for two types of farms, dairy and soybean farms. Then we estimated the cost impact of farm youth injuries of different levels of severity on a farm family with no health insurance. A severe child injury that requires at least 10 days of hospitalisation would cost almost equal to the operating profit of the average dairy farm with no health insurance and would turn the operating profit of the average soybean farm into a severe loss of $99,499. Prevention of child agricultural injuries would significantly improve the financial situation for farm families that lack health insurance. PMID- 21819179 TI - Searching hospital discharge records for snow sport injury: no easy run? AB - When using hospital discharge data to shape sports injury prevention policy, it is important to correctly identify cases. The objectives of this study were to examine the ease with which snow-skiing and snowboarding injury cases could be identified from national hospital discharge data and to assess the suitability of the information obtained for shaping policy. Hospital discharges for 2000-2004 were linked to compensated claims and searched sequentially using coded and narrative information. One thousand three hundred seventy-six eligible cases were identified, with 717 classified as snowboarding and 659 as snow-skiing. For the most part, cases could not be identified and distinguished using simple searches of coded data; keyword searches of narratives played a key role in case identification but not in describing the mechanism of injury. Identification and characterisation of snow sport injury from in-patient discharge records is problematic due to inadequacies in the coding systems and/or their implementation. Narrative reporting could be improved. PMID- 21819180 TI - Developing injury prevention policy through a multi-agency partnership approach: a case study of a state-wide sports safety policy in New South Wales, Australia. AB - Sports injuries are an important public health issue. A multi-agency key stakeholder partnership was formed to develop a state-wide response to sports injury prevention in New South Wales, Australia. This study evaluated the partnership approach to injury prevention policy development. The partnership approach to policy development was evaluated pre- and post-partnership using semi structured telephone interviews and questionnaire data gathered from participants. Participants were satisfied with the partnership operation and outcomes. Challenges included: maintaining focus and efficiency; time constraints; sector diversity limiting the likelihood of addressing needs and reaching consensus; and ensuring commitment from all relevant organisations. Potential benefits included: a sense of policy ownership; a broad-based approach across the sector and savings from resource sharing. Policy resulted from a shared understanding of the injury problem, and of an appropriate response. A credible industry leader, investment in partnership management and a consultative approach facilitated the success of the partnership. PMID- 21819181 TI - Transcranial electrical stimulation (tES - tDCS; tRNS, tACS) methods. AB - Weak transcranial direct current stimulation (tDCS) with a homogenous DC field at intensities of around 1 mA induces long-lasting changes in the brain. tDCS can be used to manipulate brain excitability via membrane polarisation: cathodal stimulation hyperpolarises, while anodal stimulation depolarises the resting membrane potential, whereby the induced after-effects depend on polarity, duration and intensity of the stimulation. A variety of other parameters influence tDCS effects; co-application of neuropharmacologically active drugs may most impressively prolong or even reverse stimulation effects. Transcranial alternating stimulation (tACS) and random noise stimulation (tRNS) are used to interfere with ongoing neuronal oscillations and also finally produce neuroplastic effects if applied with appropriate parameters. PMID- 21819182 TI - Butterfly vertebra with lumbar intervertebral disc herniation. AB - A butterfly vertebra is a rare congenital anomaly that is usually asymptomatic. The authors, however, describe a novel case involving a butterfly vertebra overlapping with disc herniation that presented as radiculopathy. A butterfly vertebra is characterized by a symmetrical fusion defect resulting in a sagittal cleft vertebra. Only a few cases of butterfly vertebrae have been reported as incidental findings. This spinal anomaly may be associated with other congenital conditions such as Pfeiffer, Crouzon, Jarcho-Levin, and Alagille syndromes. Moreover, there is no previous report of a case associated with symptomatic disc herniation from the sagittal cleft. The authors excised the herniated disc fragment. They performed intraoperative discography after exposure of the corresponding intervertebral space via a conventional interlaminar approach. Histological examination of a tissue specimen showed scattered chondrocytes in the myxohyaline stroma, which indicated the nucleus pulposus. PMID- 21819183 TI - Letter to the Editor. PMID- 21819184 TI - Effect on clinical outcomes of patient pain expectancies and preoperative Mental Component Summary scores from the 36-Item Short Form Health Survey following anterior cervical discectomy and fusion. AB - OBJECT: The primary purpose of this study was to analyze what effect preoperative patient expectations and 36-Item Short Form Health Survey (SF-36) Mental Component Summary (MCS) scores have on clinical outcomes. To the authors' knowledge, there are no prospective studies that have examined the effects of both preoperative pain expectations and SF-36 MCS scores on clinical outcomes and satisfaction with results following anterior cervical discectomy and fusion (ACDF). METHODS: This study analyzed 79 patients (38 men, 41 women) undergoing 1- to 3-level ACDF surgery. Preoperatively, patients were divided into 2 groups for the expectation analyses: patients who expected complete resolution of pain postoperatively (44 total) and those who expected some residual pain (35 total) postoperatively. Preoperative SF-36 MCS scores were used to test the possible effects of mental health on clinical outcomes and satisfaction. Clinical outcomes were evaluated using visual analog scales (VASs) for neck/arm pain, Neck Disability Index (NDI), SF-36 Physical Component Summary (PCS)/MCS, and patient satisfaction with results scales. The mean follow-up duration was 38.8 months (range 7-59 months). RESULTS: All postoperative measures depicted significant improvement overall. Patients who expected no pain reported lower postoperative neck/arm pain scores (p < 0.02), higher SF-36 MCS scores (p = 0.04), and higher satisfaction with results scores (p = 0.01) compared with patients who expected some pain, after controlling for their respective preoperative scores. Higher preoperative SF-36 MCS scores predicted significantly lower postoperative neck pain (p = 0.003) and NDI (p = 0.004) scores, as well as higher postoperative SF 36 PCS (p = 0.002), SF-36 MCS (p = 0.001), and satisfaction (p = 0.03) scores, after controlling for their respective preoperative scores. CONCLUSIONS: Patients who expected no pain postoperatively reported better scores on the nonstandardized outcome measure scales (VAS arm/neck, satisfaction with results), and higher SF-36 MCS scores. Higher preoperative MCS scores were related to better overall (standardized and nonstandardized) clinical outcomes (VAS neck, NDI, SF-36 PCS/MCS, and satisfaction with results). The results suggest that optimism in patients' expectations as well as mental well-being are related to improved clinical outcomes and higher patient satisfaction. PMID- 21819185 TI - Combined endovascular and neurosurgical approach to the removal of an intraaortic pedicle screw. AB - Iatrogenic aortic injuries are a potentially devastating complication of spine surgery. In instrumented cases, injuries may occur in the perioperative period due to iatrogenic vessel injury, or they may occur years later as prominent implants erode or penetrate major vessels. The authors present a case of a 71 year-old man in whom a thoracic pedicle screw was found perforating the thoracic aorta during routine follow-up 6 months after surgery. Due to the risk of future complications, the screw was removed while simultaneously delivering an endovascular aortic stent to gain vascular control. Surgical considerations and potential technical limitations are discussed. PMID- 21819186 TI - Avoiding abdominal flank bulge after anterolateral approaches to the thoracolumbar spine: cadaveric study and electrophysiological investigation. AB - OBJECT: The thoracolumbar junction is frequently accessed through an anterolateral approach with the incision and muscle dissection extending from the lower thoracic region to the lateral border of the rectus abdominis muscle. This approach is frequently associated with the subsequent development of an unsightly and uncomfortable relaxation of the ipsilateral abdominal wall, or flank bulge, caused by denervation injury to the intercostal nerves. However, the etiology of this complication is not widely recognized by spine surgeons. The object of this study was to better define the relevant anatomy and innervation of the anterolateral abdominal wall musculature. METHODS: The authors performed 32 cadaveric dissections and 6 intraoperative electromyography (EMG) evaluations. RESULTS: The cadaveric dissection studies and intraoperative EMG evaluations provided detailed anatomy of the anterolateral abdominal wall and its innervation. Cadaveric dissections revealed that the most significant intercostal nerve contributions to the anterolateral abdominal wall arise from T11 and T12. Electrophysiological confirmation of these findings was accomplished through intraoperative stimulation in 6 patients undergoing anterolateral retroperitoneal approaches to the thoracolumbar junction. The authors confirmed T11 and T12 innervation of the anterolateral abdominal wall musculature by direct intraoperative EMG recording in all 6 patients. CONCLUSIONS: The authors classified the 3 potential zones of injury that can be affected during an anterolateral approach to the thoracolumbar junction. Modifications to the operative technique are suggested to avoid the complication of flank bulge. The most significant intercostal nerve contributions to the anterolateral abdominal wall arise from T11 and T12. PMID- 21819187 TI - An unusual and spectacular case of spindle cell lipoma of the posterior neck invading the spinal cervical canal and posterior cranial fossa. AB - The authors describe the first case of spindle cell lipoma of the posterior neck invading the upper cervical spinal canal and the posterior cranial fossa. Spindle cell lipoma is an extremely rare variant of benign lipoma. It usually occurs as a solitary subcutaneous well-circumscribed lesion in the posterior neck or shoulders of adult men. Local aggressiveness is unusual. This 61-year-old man presented with an increased left cerebellar syndrome and headaches. He also had a posterior neck tumefaction, which had been known about for a long time. Computed tomography and MR imaging studies revealed a voluminous mass extending to the upper cervical canal and posterior cranial fossa and eroding the neighboring bones. The lesion was well delimited, and contrast enhancement was intense and heterogeneous. The tumor, which had initially developed under the muscles of the posterior neck, was totally resected. Histological assessment revealed numerous fat cells with spindle cells secreting collagen. The large size of the tumor and the submuscular location, bone erosion, and compression of the CNS were unusual in this rare subtype of benign adipose tumor. Its presentation could simulate a sarcoma. PMID- 21819188 TI - Stridor and dysphagia associated with subthalamic nucleus stimulation in Parkinson disease. AB - Refractory symptoms in Parkinson disease show good response to deep brain stimulation (DBS). This procedure improves United Parkinson's Disease Rating Scale scores and reduces dyskinesias, whereas speech and swallowing dysfunction typically do not improve and may even worsen. Rarely, DBS can cause idiosyncratic dystonias of muscle groups, including those of the neck and throat. The authors describe a patient experiencing stridor and dysphagia with confirmed pulmonary restriction and aspiration following subthalamic nucleus deep brain stimulator adjustment, with a resolution of symptoms and signs when the stimulator was switched off. PMID- 21819190 TI - Deep brain stimulation for treatment of hemichorea-hemiballism after craniopharyngioma resection: long-term follow-up. AB - Hemichorea-hemiballism is a rare movement disorder that has various causes. In treatment-resistant cases, both thalamic and pallidal functional procedures have been shown to yield beneficial results. Until now it has not been clarified whether the thalamus or the pallidum would yield a superior outcome. After resection of a craniopharyngioma in this patient at the age of 49 years, hemichorea-hemiballism developed, with a latency of several weeks. Because the patient was greatly impaired by the movement disorder, she underwent implantation of deep brain stimulation (DBS) electrodes in the thalamic ventralis intermedius nucleus and the posteroventral lateral globus pallidus internus. Although both pallidal and thalamic stimulation could suppress the movement disorder, the voltage needed was clearly less with thalamic than with pallidal stimulation. At the last available follow-up 25 months postoperatively, complete subsidence of hemichorea-hemiballism was achieved with long-term thalamic stimulation. Long term DBS therapy is an efficient treatment modality for refractory hemichorea hemiballism in the long run (> 2 years). A bifocal (thalamic and pallidal) target paradigm allowed selection of the optimal stimulation site. Thalamic DBS was more favorable with regard to energy consumption. PMID- 21819189 TI - Epilepsy after subarachnoid hemorrhage: the frequency of seizures after clip occlusion or coil embolization of a ruptured cerebral aneurysm: results from the International Subarachnoid Aneurysm Trial. AB - OBJECT: The aim of this study was to determine the probability of seizures after treatment of a ruptured cerebral aneurysm by clip occlusion and coil embolization, and to identify the risks and predictors of seizures over the short and long-term follow-up period. METHODS: The study population included 2143 patients with ruptured intracranial aneurysms who were enrolled in 43 centers and randomly assigned to clip application or coil placement. Those patients suffering a seizure were identified prospectively at various time points after randomization, as follows: before treatment; after treatment and before discharge; after discharge to 1 year; and annually thereafter. RESULTS: Two hundred thirty-five (10.9%) of the 2143 patients suffered a seizure after randomization; 89 (8.3%) of 1073 and 146 (13.6%) of 1070 in the endovascular and neurosurgical allocations, respectively (p = 0.014). In 19 patients the seizure was associated with a rehemorrhage. Of those patients who underwent coil placement alone, without additional procedures, 52 suffered a seizure, and in the group with clip occlusion alone, 91 patients suffered a seizure. The risk of a seizure after discharge in the endovascular group was 3.3% at 1 year and 6.4% at 5 years. In the neurosurgical group it was 5.2% at 1 year and 9.6% at 5 years. The risk of seizure was significantly greater in the neurosurgical group at both 2 years and at up to 14 years (p = 0.005 and p = 0.013, respectively). The significant predictors of increased risk were as follows: neurosurgical treatment allocation, hazard ratio (HR) 1.64 (95% CI 1.19-2.26); younger age, HR 1.54 (95% CI 1.14-2.13); Fisher grade > 1 on CT scans, HR 1.34 (95% CI 0.62-2.87); delayed ischemic neurological deficit due to vasospasm, HR 2.10 (95% CI 1.49-2.94); and thromboembolic complication, HR 5.08 (95% CI 3.00-8.61). A middle cerebral artery (MCA) aneurysm location was also a significant predictor of increased risk in both groups; the HR was 2.23 (95% CI 1.57-3.17), with the probability of seizure at 6.1% and 11.5% at 1 year in the endovascular and neurosurgery groups, respectively. CONCLUSIONS: The risk of seizures after coil embolization is significantly lower than that after clip occlusion. An MCA aneurysm location increased the risk of seizures in both groups. PMID- 21819191 TI - Seizures and aneurysms. PMID- 21819192 TI - Emergency department predictors of tracheostomy in patients with isolated traumatic brain injury requiring emergency cranial decompression. AB - OBJECT: Patients with severe traumatic brain injury (TBI) frequently require a tracheostomy for prolonged mechanical ventilation and/or pulmonary toilet. It is now proven that the earlier the procedure is done, the more beneficial it is to the patient. The present study was carried out to determine if the requirement of a tracheostomy can be predicted on arrival of a patient to the emergency department. The prediction can potentially aid in combining the procedure with cranial decompression. In this study, the authors' aim was to determine the emergency department predictors of tracheostomy in patients with isolated TBI requiring emergency cranial decompression. METHODS: The authors performed a retrospective chart review of all patients who underwent surgery for isolated TBI and required more than 4 days of mechanical ventilation. Multivariate logistic regression analysis was used for predictive indicators. RESULTS: In patients with isolated severe TBI, a patient age of 31-50 years, the presence of preexisting medical comorbid conditions, a delay in emergency department arrival exceeding 1.5 hours, an abnormal pupil response on arrival, and a preoperative neurological worsening during hospital stay were independent predictors of the requirement for tracheostomy. These findings were validated in a small cohort of patients and were found to be significant. CONCLUSIONS: Requirement of a tracheostomy can be predicted in patients with severe TBI on arrival to the emergency department. These results were validated in a small cohort of patients, and it was found that the positive predictive value of requirement of tracheostomy was directly proportional to the number of predictors present. Larger prospective studies with appropriate control groups are further recommended to validate the authors' findings. PMID- 21819194 TI - Predictors of seizure freedom in the surgical treatment of supratentorial cavernous malformations. AB - OBJECT: Seizures are the most common presenting symptom of supratentorial cerebral cavernous malformations (CCMs) and progress to medically refractory epilepsy in 40% of patients. Predictors of seizure freedom in the resection of CCMs are incompletely understood. METHODS: The authors systematically reviewed the published literature on seizure freedom following the resection of supratentorial CCMs in patients presenting with seizures. Seizure outcomes were stratified across 12 potential prognostic variables. A total of 1226 patients with supratentorial CCMs causing seizures were identified across 31 predominantly retrospective studies; 361 patients had medically refractory epilepsy. RESULTS: Seventy-five percent of the patients were seizure free after microsurgical lesion removal, whereas 25% continued to have seizures. All patients had had preoperative seizures and > 6 months of postoperative follow-up. Modifiable predictors of postoperative seizure freedom included gross-total resection (OR 36.6, 95% CI 8.5-157.5) and surgery within 1 year of symptom onset (OR 1.83, 95% CI 1.30-2.58). Additional prognostic indicators of a favorable outcome were a CCM size < 1.5 cm (OR 15.4, 95% CI 5.2-45.4), the absence of multiple CCMs (OR 2.02, 95% CI 1.13-3.60), medically controlled seizures (OR 2.38, 95% CI 1.29-4.39), and the lack of secondarily generalized seizures (OR 3.33, 95% CI 2.09-5.30). Other factors, including extended resection of the hemosiderin ring, were not significantly predictive. CONCLUSIONS: In the surgical treatment of supratentorial CCMs, gross-total resection and early operative intervention may improve seizure outcome. While surgery should not be considered the first-line treatment for CCM-related epilepsy, it is important to understand the variables associated with seizure freedom in CCM resection given the considerable morbidity and diminished quality of life associated with epilepsy. PMID- 21819193 TI - Fibromatosis: a potential sequela of neuromuscular choristoma. AB - OBJECT: Neuromuscular choristoma (NMC) is a rare peripheral nerve lesion in which mature skeletal muscle fibers lie within the nerve and its fascicles. Given limited follow-up, its natural history is poorly understood. The occurrence of aggressive fibromatosis in one of the authors' patients and its occurrence in reported cases suggests an etiological relationship between the 2 lesions. This study attempts to explain the association and its frequency. METHODS: All cases of NMCs seen in consultation or treated at the Mayo Clinic were identified. Demographic and clinical data were reviewed in cases with coexistent aggressive fibromatosis. Pathology and neuroimaging studies were reexamined. In addition, an extensive literature review was performed to explore the association of NMC with aggressive fibromatosis, with special attention given to pathological and imaging characteristics and the development of aggressive fibromatosis. RESULTS: The authors identified 10 patients with a diagnosis of NMC who were treated at the Mayo Clinic between 1992 and 2010. Four of 5 with adequate follow-up had developed a definite or suspected aggressive fibromatosis. A review of the initial pathological specimens in these cases revealed no evidence of fibromatosis, but all of the lesions exhibited accompanying hypocellular collagenous tissue. On MR images, all cases showed areas of low signal intensity, which significantly differed from muscle, nerve, and NMC components. On available serial MR imaging studies, aggressive fibromatosis seemed to originate in such lower-intensity regions. In the 18 previously reported cases of NMC, 5 patients developed recurrent masses diagnosed as either definite (2 cases) or possible (3 cases) fibromatosis. Review of the published imaging studies in these cases suggests the presence of lower intensity areas similar to those observed in the 10 patients treated at the Mayo Clinic. CONCLUSIONS: This study confirms that the development of aggressive fibromatosis in patients with NMC has been underreported. A direct relationship between the NMC and the development of aggressive fibromatosis is suggested by pathological and neuroimaging evidence. PMID- 21819195 TI - Interobserver variability in the interpretation of computed tomography following aneurysmal subarachnoid hemorrhage. AB - OBJECT: Numerous abnormal findings may be evident on CT scans after aneurysmal subarachnoid hemorrhage (SAH). Here, the authors assess the interobserver variability in the radiological interpretation of the initial CT scan following SAH. METHODS: Two experienced reviewers, a neurosurgeon and a neuroradiologist, independently prospectively reviewed the initial CT scans of 413 patients enrolled in the CONSCIOUS-1 trial. Measured variables included SAH, intraventricular hemorrhage, intracerebral hemorrhage, subdural hematoma, chronic infarction, midline shift, and hydrocephalus. To assess interobserver variability, weighted kappa values and intraclass correlation coefficients (ICCs) were calculated and Bland-Altman analysis was performed. RESULTS: Moderate to substantial agreement was found for most of the CT scanning findings. There was fair to moderate interobserver agreement between reviewers when determining the extent of SAH based on a descriptive categorical classification (kappa 0.41; 95% CI 0.33-0.49), and better agreement when a semiquantitative scale was used (ICC 0.56; 95% CI 0.49-0.62). There was poor agreement between reviewers for the presence of hydrocephalus (kappa 0.34; 95% CI 0.20-0.48), but substantial to near perfect agreement on ventriculocranial ratio measurements (ICC 0.77; 95% CI 0.72 0.81). CONCLUSIONS: The authors' findings suggest that there is considerable interobserver variability in the interpretation of CT scans after SAH. Quantitative measures may reduce interobserver variability in comparison with qualitative or categorical scales. Variability in interpretation of CT scans has implications for patient care and conduct of clinical trials. It may be beneficial to develop standardized assessments to ensure consistent evaluation of measured variables. PMID- 21819196 TI - Hospital costs, incidence, and inhospital mortality rates of traumatic subdural hematoma in the United States. AB - OBJECT: This study provides the first US national data regarding frequency, cost, and mortality rate of traumatic subdural hematoma (SDH), and identifies demographic factors affecting morbidity and death in patients with traumatic SDH undergoing surgical drainage. METHODS: A retrospective analysis was conducted by querying the Nationwide Inpatient Sample, the largest all-payer database of nonfederal community hospitals. All cases of traumatic SDH were identified using ICD-9 codes. The study consisted of 2 parts: 1) trends data, which were abstracted from the years 1993-2006, and 2) univariate analysis and multivariate logistic regression of demographic variables on inhospital complications and deaths for the years 1993-2002. RESULTS: Admissions for traumatic SDH increased 154% from 17,328 in 1993 to 43,996 in 2006. Inhospital deaths decreased from 16.4% to 11.6% for traumatic SDH. Average costs increased 67% to $47,315 per admission. For the multivariate regression analysis, between 1993 and 2002, 67,864 patients with traumatic SDH underwent operative treatment. The inhospital mortality rate was 14.9% for traumatic SDH drainage, with an 18% inhospital complication rate. Factors affecting inhospital deaths included presence of coma (OR = 2.45) and more than 2 comorbidities (OR = 1.60). Increased age did not worsen the inhospital mortality rate. CONCLUSIONS: Nationally, frequency and cost of traumatic SDH cases are increasing rapidly. PMID- 21819197 TI - Current comprehensive management of cranial base chordomas: 10-year meta-analysis of observational studies. AB - OBJECT: The role of surgery and adjuvant radiation therapy for cranial base chordomas is not well established. This meta-analysis measures the relationship of complete resection and type of adjuvant radiation therapy to 5-year progression-free survival (PFS) and overall survival (OS) of cranial base chordomas. METHODS: A systematic MEDLINE search (1999-present) yielded 23 observational studies and 807 patients who fit inclusion criteria. The following analyses were performed: 1) Kaplan-Meier 5-year PFS and OS compared based on the extent of resection and type of adjuvant radiation therapy using the log-rank method; 2) a random-effects model comparing 5-year PFS with complete or incomplete resection; and 3) paired z-test comparisons of weighted average 5-year OS and PFS grouped by type of adjuvant radiation therapy. RESULTS: The weighted average follow-up was 53.6 months. The weighted average 5-year PFS and OS were 50.8% and 78.4%, respectively. Complete resection conferred a higher 5-year PFS than incomplete resection from the random effects model (mean difference in PFS 20.7%; 95% CI 6.57%-34.91%). Patients with incomplete resection were 3.83 times more likely to experience a recurrence (95% CI 1.63-9.00) and 5.85 times more likely to die (95% CI 1.40-24.5) at 5 years versus patients with complete resection. There was no difference in 5-year OS by type of adjuvant radiation, although 5-year PFS was lower in patients receiving Gamma Knife surgery relative to carbon ion radiotherapy (p = 0.042) on paired z-test. No survival difference occurred between radiation therapy techniques on Kaplan-Meier analysis of compiled patient data. CONCLUSIONS: Patients with complete resection of cranial base chordomas have a prolonged 5-year PFS and OS. Adjuvant proton-beam, carbon ion, and modern fractionated photon radiation therapy techniques offered a similar rate of PFS and OS at 5 years. PMID- 21819198 TI - Fracture resistance of cuspal coverage of endodontically treated maxillary premolars with combined composite-amalgam compared to other techniques. AB - This in vitro study investigated the fracture resistance of teeth restored with combined composite-amalgam for cuspal coverage compared to direct coverage with composite (with or without an amalgam base) and composite onlay. Seventy-two intact maxillary premolars were randomly divided into six groups (n=12). The two control groups were G1, intact teeth (negative control), and G2, mesio occlusodistal preparation only (positive control). Each of the four experimental groups used a different type of restoration for the prepared teeth: G3, direct composite cusp coverage; G4, composite onlay; G5, direct composite coverage with an amalgam base; and G6, combined composite-amalgam cuspal coverage. After thermocycling, fracture strength was tested. The data were analyzed with analysis of variance and the least significant differences post hoc tests (alpha=0.05). Mean fracture resistance in the six groups (in N) were G1, 1101 +/-1 86; G2, 228 +/- 38; G2, 699 +/- 161; G4, 953 +/- 185; G5, 859 +/- 146; and G6, 772 +/- 154. There were significant differences between G1 and all the other groups except for G4 and between G2 and all the other groups. Fracture strength in G3 also differed significantly compared to G4 and G5. The difference between G4 and G6 was statistically significant (p<0.05), but the difference between G3 and G6 was not (p>0.05). PMID- 21819199 TI - Efficacy of a novel at-home bleaching technique with carbamide peroxides modified by CPP-ACP and its effect on the microhardness of bleached enamel. AB - This study was designed to evaluate in vitro the efficacy of a novel at-home bleaching technique using 10% or 16% carbamide peroxide modified by casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) and its influence on the microhardness of bleached enamel. A total of 40 bovine incisors were divided into four groups (n=10) according to the bleaching agent used: 10% carbamide peroxide only; a blend of 10% carbamide peroxide and a CPP-ACP paste; 16% carbamide peroxide only; and a blend of 16% carbamide peroxide and a CPP-ACP paste. During the 14-day bleaching regimen, the samples were stored in artificial saliva. The Vickers microhardness and color of the teeth were assessed at baseline (T0) and immediately after the bleaching regimen (T14) using a microhardness tester and a spectrophotometer, respectively. The degree of color change was determined by the Commission Internationale de l'Eclariage (CIE) L*a*b* system (DeltaE, DeltaL*, Deltaa*, and Deltab*) and Vita shade guide parameters. The data were analyzed by analysis of variance and the Tukey test (p<0.05). The teeth that were bleached with a blend of peroxide (10% or 16%) and the CPP-ACP paste presented increased microhardness values at T14 compared with T0, whereas the samples that were bleached with peroxide only did not show any differences in their microhardness values. All of the bleaching agents were effective at whitening the teeth and did not show a statistically significant difference using the CIEL*a*b* system (DeltaE, DeltaL*, Deltaa*, and Deltab*) or the Vita shade guide parameters. The use of a CPP-ACP paste with carbamide peroxide bleaching agents increased the bleached enamel's microhardness and did not have an influence on whitening efficacy. PMID- 21819200 TI - The influence of surface standardization of lithium disilicate glass ceramic on bond strength to a dual resin cement. AB - In vitro studies to assess bond strength between resins and ceramics have used surfaces that have been ground flat to ensure standardization; however, in patients, ceramic surfaces are irregular. The effect of a polished and unpolished ceramic on bond strength needs to be investigated. Sixty ceramic specimens (20*5*2 mm) were made and divided into two groups. One group was ground with 220- to 2000-grit wet silicon carbide paper and polished with 3-, 1-, and 1/4-MUm diamond paste; the other group was neither ground nor polished. Each group was divided into three subgroups: treated polished controls (PC) and untreated unpolished controls (UPC), polished (PE) and unpolished specimens (UPE) etched with hydrofluoric acid, and polished (PS) and unpolished specimens (UPS) sandblasted with alumina. Resin cement cylinders were built over each specimen. Shear bond strength was measured, and the fractured site was analyzed. Analysis of variance (ANOVA) and Tukey post hoc tests were performed. PE (44.47 +/- 5.91 MPa) and UPE (39.70 +/- 5.46 MPa) had the highest mean bond strength. PS (31.05 +/- 8.81 MPa), UPC (29.11 +/- 8.11 MPa), and UPS (26.41 +/- 7.31 MPa) were statistically similar, and PC (24.96 +/- 8.17 MPa) was the lowest. Hydrofluoric acid provides the highest bond strength regardless of whether the surface is polished or not. PMID- 21819201 TI - Fluoride release, recharge and mechanical property stability of various fluoride containing resin composites. AB - AIM: To determine the fluoride release and recharge of three fluoride-containing resin composites when aged in deionized water (pH 6.5) and lactic acid (pH 4.0) and to assess mechanical properties of these composites following aging. METHODS: Three fluoride-containing resin composites were analyzed in this study; a new giomer material named Beautifil II, Gradia Direct X, and Tetric EvoCeram. A glass ionomer cement, Fuji IX Extra, was also analyzed for comparison. Specimens were fabricated for two test groups: group 1 included 10 disc specimens initially aged 43 days in deionized water (five specimens) and lactic acid (five specimens). The fluoride release from these specimens was measured using a fluoride-specific electrode on nine specific test days during the aging period. Following 49 days of aging, each specimen was recharged in 5000 ppm neutral sodium fluoride solution for 5 minutes. Specimen recharge was then repeated on a weekly basis for 3 weeks. The subsequent fluoride rerelease was measured at 1, 3, and 7 days after each recharge episode. Group 2 included six disc specimens aged for 3 months in deionized water (three specimens) and lactic acid (three specimens). The hardness and elastic modulus of each specimen was measured using nano-indentation at intervals of 24 hours, 1 month, and 3 months after fabrication. Two-way factorial analysis of variance (ANOVA) and post-hoc (Tukey) testing was used to assess the influence of storage media (two levels) and composite type (three levels) on the fluoride release, fluoride rerelease, hardness, and elastic modulus of the assessed materials. The level of significance was set at p=0.05. RESULTS: All three composites demonstrated fluoride release and recharge when aged in both deionized water and lactic acid. The cumulative fluoride released from Beautifil II into both media was substantially greater than the fluoride released from Gradia Direct X and Tetric EvoCeram after 43 days aging and was significantly (p<0.05, ANOVA, Tukey test) greater during several analysis periods. Beautifil II demonstrated the greatest recharge ability of the three composites over the 3 week recharge period in both media. Fuji IX Extra demonstrated a significantly (p<0.05) greater fluoride release and recharge compared with the three resin composites. The elastic modulus and hardness of the three composites did not decrease significantly (p<0.05) with fluoride release or fluid uptake over the 3 month aging period, in either media. CONCLUSION: The three composites in the present study demonstrated fluoride release (Beautiful II > Gradia Direct X > Tetric EvoCeram) and fluoride recharge (Beautiful II > Gradia Direct X > Tetric EvoCeram). This capability raises the possibility of fluoride-containing composites exhibiting a lower incidence of recurrent caries than non fluoride containing composites. The mechanical properties of each composite did not diminish with aging and fluoride release over the testing period. PMID- 21819202 TI - Bonding nano-filled resin-modified glass ionomer to dentin using different self etch adhesives. AB - OBJECTIVE: To investigate the shear bond strength of the nano-filled resin modified glass ionomer (RMGI) to dentin using different self-etch adhesives. MATERIALS AND METHODS: Two resin-based restorative materials, a nano-filled RMGI (Ketac Nano-100, 3M ESPE) and a restorative composite (Grandio, VOCO) were bonded to bovine dentin using four self-etch adhesives (Futurabond M, VOCO; Adper Easy Bond, 3M ESPE; G Bond, GC Corp; and One Coat, Coltene). One hundred bovine anterior teeth were used in this study. Subsequent to labial enamel removal, each adhesive was applied according to manufacturer instructions. Fifty teeth were restored with the nano-filled RMGI and the other 50 were restored with the resin composite. Cylinders of 3*2 mm from the two restorative materials were bonded to dentin, and the specimens were stored in distilled water for 24 hours. Shear bond strength testing was performed in a universal testing machine at a crosshead speed of 0.5 mm/min. Two randomly selected specimens from each group were chosen for evaluation by scanning electron microscopy (SEM). Failure modes were evaluated using the stereomicroscope. All data for shear bond strength in MPa were expressed as mean +/- standard deviation (SD). Statistical analysis was carried out using SAS program (SAS, 1988). RESULTS: Two-way analysis of variance revealed that the adhesives, the restorative materials, and their interactions (adhesives and restorative materials) had a significant effect on the shear bond strength to bovine dentin. CONCLUSIONS: Self-etch adhesives used in this study can adequately bond the nano-filled RMGI to dentin. PMID- 21819203 TI - Recent improvements in the SHIELD-HIT code. AB - PURPOSE: The SHIELD-HIT Monte Carlo particle transport code has previously been used to study a wide range of problems for heavy-ion treatment and has been benchmarked extensively against other Monte Carlo codes and experimental data. Here, an improved version of SHIELD-HIT is developed concentrating on three objectives, namely: Enhanced functionality, improved efficiency, and a modification of employed physical models. METHODOLOGICAL DEVELOPMENTS: SHIELD-HIT (currently at version '10A') is now equipped with an independent detector geometry, ripple filter implementations, and it is capable of using accelerator control files as a basis for the primaries. Furthermore, the code has been parallelized and efficiency is improved. The physical description of inelastic ion collisions has been modified. RESULTS: The simulation of an experimental depth-dose distribution including a ripple filter reproduces experimental measurements with high accuracy. CONCLUSIONS: SHIELD-HIT is now faster, more user friendly and accurate, and has an enhanced functionality with some features being currently unique to SHIELD-HIT. The possibility of data file exchange with existing treatment planning software for heavy-ion therapy allows for benchmarking under treatment conditions as well as extending the capabilities of treatment planning software. PMID- 21819204 TI - Breastfeeding protects against type 1 diabetes mellitus: a case-sibling study. AB - BACKGROUND: Some epidemiological studies have shown a protective effect of breastfeeding against type 1 diabetes mellitus (T1DM), whereas others have found opposite results. The role of early exposure to cow's milk protein and shorter duration of breastfeeding are still controversial. This study aimed to compare the frequency and duration of breastfeeding among siblings with and without T1DM. METHODS: A case-control study was conducted at the Prof. Fernando Figueira Institute of Integral Medicine, Recife, PE, Brazil, between June 2009 and August 2010. The case patients were children with T1DM, and the controls were their unaffected sibling. The World Health Organization criteria for T1DM were used. All T1DM cases had the diagnostic criteria confirmed by checking their medical records. Data on infant feeding during the first year of life, prenatal care, gestational age, delivery, birth weight, and immunization status were collected through information provided by the mothers. RESULTS: In total, 123 children with diabetes mellitus type 1 and their respective siblings were studied. There was no difference in breastfeeding rates among the two groups, but patients with diabetes had a shorter duration of breastfeeding (3.3 vs. 4.6 months, p < 0.001). The diabetic group was exposed earlier to cow's milk. After controlling for other associated variables it was shown that a longer duration of breastfeeding was associated with a protective effect against diabetes. CONCLUSIONS: Our data support the proposal that a shorter breastfeeding interval may contribute to T1DM in Brazilian children. PMID- 21819210 TI - Ceftiofur use in finishing swine barns and the recovery of fecal Escherichia coli or Salmonella spp. resistant to ceftriaxone. AB - The objective of this study was to investigate the association between ceftiofur use policy in finishing swine barns and recovery of fecal Escherichia coli or Salmonella spp. resistant to ceftriaxone. The study population included 54 finishing swine barns from three companies located in North Carolina. The barns were each classified according to their reported therapeutic ceftiofur use rates of "Rare," "Moderate," and "Common." Fecal samples from the barns were cultured for the presence of E. coli and Salmonella spp. resistant to ceftriaxone using selective media designed to recover rare organisms expressing the AmpC beta lactamase phenotype. A total of 1899 swine fecal samples yielded 1193 E. coli (63%) resistant to ceftriaxone. Recovery rates by ceftiofur use classification were 45% for Rare, 73% for Moderate, and 68% Common ceftiofur use groups. Barns reporting Rare ceftiofur use had a lower odds of recovery of E. coli (OR=0.32; p<0.001) resistant to ceftriaxone compared to Common use barns. The overall Salmonella spp. prevalence was 63.8% (n=714). Of these, 65 Salmonella were resistant to ceftriaxone with the highest rate (6%) found in the Common ceftiofur use group, followed by Rare (4.1%) and Moderate (0.15%). The odds of recovery of Salmonella resistant to ceftriaxone were similar for barns with ceftiofur use classified as Rare and Common. Samples from barns with ceftiofur use classified as Moderate had a lower odds (OR=0.02; p<0.01) of recovery of Salmonella resistant to ceftriaxone than barns classified as Common. Our result is consistent with the hypothesis that the use of ceftiofur in finishing swine barns, beyond its rare application, may influence the recovery of enteric E. coli with resistance to cephalosporin drugs, although other unmeasured factors appear to be important in the recovery of cephalosporin-resistant Salmonella. The dissemination of enteric bacteria with resistance to cephalosporins has the potential to impact both veterinary and human therapeutic treatment options. PMID- 21819211 TI - Effects of temperature abuse on the survival, growth, and inactivation of Salmonella typhimurium in goat milk. AB - The growth and survival of Salmonella typhimurium in goat milk samples at different shifting temperatures were evaluated. The growth of S. typhimurium at lower temperatures (5 degrees C, 10 degrees C, and 15 degrees C) exhibited bacteriostatic effects in milk, whereas at ambient temperature (25 degrees C) and at 45 degrees C, this pathogen luxuriantly grew throughout the 12-h stationary phase. At 50 degrees C this pathogen was found to be thermotolerant and could still thrive in the milk. Overall, shifting temperatures from 37 degrees C to 55 degrees C and 60 degrees C clearly indicated S. typhimurium to have reached complete elimination. The results demonstrated that the adaptation and survival of this pathogen directly depend on temperature stress. It is expected that the results will be useful to dairy industries for implementation of good manufacturing practices with a better hazard analysis critical control point approach to predict the microbial risk assessment and also benefit the consumers. PMID- 21819212 TI - Sorbitol-fermenting, beta-glucuronidase-positive, Shiga toxin-negative Escherichia coli O157:H7 in free-ranging red deer in South-Central Spain. AB - We investigated the prevalence of Escherichia coli O157:H7 in free-ranging red deer in south-central Spain, to assess their potential as reservoir hosts of sorbitol-fermenting (SF) E. coli O157:H7 strains, which are emerging causes of hemolytic uremic syndrome in Europe. Fecal samples from 264 hunter-harvested Iberian red deer (Cervus elaphus) were collected in 25 different game estates and examined for E. coli O157:H7 by culture and PCR. E. coli O157:H7 was detected and isolated in 4 of the 25 game estates sampled (16%) and the isolates obtained (four in total) were further phenogenotypically characterized. One of them was biochemically typical of E. coli O157:H7, that is, neither fermented sorbitol nor exhibited beta-glucuronidase (GUD) activity, and carried genes encoding Shiga toxins (Stx) 1 and 2, the intimin subtype gamma1, the enterohemorrhagic E. coli (EHEC)-hemolysin, and the ter gene cluster. The rest of the isolates (three of four) fermented sorbitol, exhibited GUD activity after 18-24 h incubation, and carried genes encoding the intimin subtype gamma1 and the EHEC-hemolysin, although no Stx-encoding genes were detected. All these atypical isolates carried the sfp gene cluster, lacked the ter gene cluster, and were unable to grow on cefixime tellurite sorbitol MacConkey agar, which are typical features of SF E. coli O157:H7 strains isolated from patients. In total, SF, GUD-positive, Stx negative E. coli O157:H7 strains were isolated in 3 of the 25 game estates sampled (12%), with an overall sample-level prevalence of 1.1% (3/264). Our findings indicate that free-ranging red deer may be one of the possible reservoir hosts of Stx-negative derivatives of SF E. coli O157:H7. PMID- 21819213 TI - Role of instruction method in novices' acquisition of minimally invasive surgical basic skills. AB - INTRODUCTION: We investigated the impact of instruction method on novices' acquisition of minimally invasive surgical (MIS) basic skills. MATERIALS AND METHODS: One hundred five novice medical students underwent text-based (TB), video-based (VB), or faculty-tutored (FT) single-session instruction in three basic MIS skill tasks on a box trainer. Pre- and postsession, participants completed a 12-item, 5-point Likert-type scale (1=Not confident at all, 5=Completely confident) of self-efficacy for performing basic MIS skills and had performances on each task recorded. Four raters evaluated every video performance of one task, a two-handed peg transfer, using a 16-cm visual analog measurement (VAM). Inter-rater reliability was good (intra-class correlation coefficient=0.82). The relationship between instruction method, self-efficacy mean score change, and mean VAM change was examined using ANOVA analysis. RESULTS: Eighty-five participants (TB=32, VB=24, FT=29) had valid matched data. Mean scores in self-efficacy and task performance increased from pre- to postsession for every instruction method: (1) Delta self-efficacy=1.04+/-0.64 (TB), 1.36+/-0.69 (VB), and 1.41+/-0.82 (FT); (2) Delta VAM=3.77+/-2.87 (TB), 3.82+/-2.35 (VB), and 2.57+/-2.60 (FT). Analysis of variance revealed no relationship between instruction method and self-efficacy (P=.10) or VAM mean score change (P=.14). CONCLUSIONS: Self-directed instruction methods (e.g., TB and VB) for novices' acquisition of MIS basic skills offer flexible, learner centered, and cost-effective alternatives to the more expensive FT method. PMID- 21819214 TI - Intraabdominal laparoscopy-assisted "open" vessel ligation of testicular vessels: a potential treatment for varicocele. AB - AIM: We tested our laparoscopy-assisted "open" ligation (LOL) technique on testicular vessels. METHODS: We ligated the left testicular artery and vein (TAV) in 8-week-old male Wister rats using LOL (LOL group; n=10) or laparotomy (open group; n=10). In LOL, a 0-degree laparoscope was introduced through a 5-mm epigastric trocar. A 3-mm grasper was used to expose the left TAV. A lapa-her closure (LHC) needle loaded with 3-0 SurgiPro was directly inserted into the left lower quadrant where the left TAV should be and advanced under the vessels, and the suture material was released leaving one end outside. The LHC was then withdrawn a little and advanced again over the vessels to grasp the end of the suture material just released to bring it outside. This was proximally repeated. The two ends of both sutures were conventionally tied outside, and the knot was passed through the insertion site and tightened around the vessels. In the open group, the left TAV were ligated using two 3-0 SurgiPro ties. In both groups, the right side was left intact. All rats were sacrificed 2 weeks postoperatively, and both testes were examined with hematoxylin and eosin. RESULTS: Treatment time was 5-7 minutes for LOL and 7-8 minutes for the open group. Postoperative recovery was uneventful. No adhesions were present between the ligated vessels and bowel in any rat. Histopathology of all left testes showed coagulative necrosis of germinal cells and seminiferous tubules; all right testes were normal. CONCLUSION: LOL appears to be as effective as open ligation and may find application for treating varicocele. PMID- 21819215 TI - Rectal diverticular perforation complicating diagnostic colonoscopy: a case report and review of the literature. AB - Abstract The presence of retroperitoneal, mediastinal, and subcutaneous emphysema due to rectal diverticular perforation during diagnostic colonoscopy has not been reported. Further, the management of colonoscopic perforation remains a controversial issue. In this case report, the authors discuss the importance of recognizing this rare complication after colonoscopy and its response to conservative treatment. PMID- 21819216 TI - The urachal pathology with umbilical manifestation: overview of laparoscopic technique. AB - BACKGROUND: The persistent patency of the urachus after birth is a rare anomaly, especially because most of the cases are asymptomatic. The guiding symptom for urachal-umbilical sinus and urachal cyst is the presence of umbilical discharge. Even if today we tend to laparoscopic treatment, in scientific literature there is still no evidence, because the reports are rare and often they are clinical cases. METHODS: Thirteen patients with a symptomatic urachal pathology were evaluated; 12 of these were affected by umbilical discharge and 1 by periumbilical discomfort. Five of 13 were prospectively treated by laparoscopy and the remaining 8 patients, who had been previously treated with conventional surgery, formed the control group. The authors report the laparoscopic technique used, which allowed the complete excision of the urachus. RESULTS: The operation time was lower for the patients treated by conventional surgery (71.9 minutes versus 101 minutes; P=.002), whereas the control pain (P=.05) and, above all, the excised urachus length (11.6 versus 8.7 cm; P=.03) were in favor of the patients treated by laparoscopic surgery. We registered only one recurrence in a patient treated by conventional surgery. CONCLUSION: In the rare international scientific literature, only one study report comparative data, as our study. The results that we obtained seem to be in favor of the laparoscopic procedure, although prospective, randomized trials are needed to get stronger evidence. PMID- 21819217 TI - Robotic Roux-en-Y duodenojejunostomy for superior mesenteric artery syndrome: operative technique. AB - BACKGROUND: Superior mesenteric artery (SMA) syndrome, also known as Wilkie's syndrome, is a rare condition characterized by vascular compression of the duodenum that leads to intestinal obstruction. While there have been a few recent case reports of laparoscopic duodenojejunostomy performed as an option for surgical treatment, the role of the da Vinci((r)) robot in superior mesenteric syndrome has been underestimated. The authors report a robotic Roux-en-Y duodenojejunostomy for the treatment of SMA syndrome. MATERIALS AND METHODS: A 39 year-old man with a history of Amyotrophic lateral sclerosis presented with an upper gastrointestinal obstruction with distended abdomen. A computed tomography scan showed a transition in the third portion of the duodenum where the SMA vessels crossed over, with a decompressed jejunum. He was identified as a candidate for a duodenojejunostomy. The da Vinci Surgical System was used to mobilize the colon and duodenum, and a Roux-en-Y duodenojejunostomy was performed with hand-sewn anastomosis. RESULTS: There were no intraoperative complications. The blood loss was minimal and operative time was 120 minutes. The postoperative course was uneventful with resolution of intestinal obstruction. CONCLUSION: Robotic Roux-en-Y duodenojejunostomy as a surgical option for treatment of SMA syndrome is safe, feasible, and a valid alternative to open surgery with the added benefits of a minimally invasive approach. PMID- 21819218 TI - Human T lymphotropic virus type 1 regulatory and accessory gene transcript expression and export are not rex dependent. AB - Human T lymphotropic virus type 1 (HTLV-1) requires regulated gene expression from unspliced and alternatively spliced transcripts for efficient replication and persistence. HTLV-1 Rex is known to facilitate cytoplasmic export of unspliced, gag/pol and incompletely spliced env mRNAs, but its contribution to the expression of other viral transcripts has not been experimentally assessed. In this study, we utilized HTLV-1 proviral clones, cellular fractionation, and real-time reverse transcriptase PCR to determine the role of Rex on the expression and export of all viral mRNAs. Our results indicate that the steady state levels of the different viral mRNAs are modulated by Rex, which we attribute to a redistribution of completely spliced mRNAs toward incompletely spliced mRNAs. Furthermore, we confirmed the positive effect of Rex on the unspliced gag/pol mRNA and singly spliced env mRNA, resulting in increased cytoplasmic expression. However, the cytoplasmic export of the alternatively spliced HTLV-1 mRNAs encoding the accessory proteins and the antisense Hbz mRNA are independent of direct Rex regulation. This is consistent with the conclusion that viral mRNAs that contain the cis-acting repressive sequence (CRS) and/or a fully functional splice donor site require a Rex/RxRE interaction for efficient cytoplasmic expression. PMID- 21819219 TI - Accumulation of HIV drug resistance mutations in patients failing first-line antiretroviral treatment in South Africa. AB - Patients failing antiretroviral treatment for extended periods of time are at risk of accumulating HIV drug resistance mutations (DRMs), which negatively influences second-line treatment. This retrospective study assessed the rate of DRM accumulation among South African patients with continued virological failure. Serial genotypic resistance testing was performed and DRMs were scored according to the 2009 IAS-USA list. Among 43 patients, 38 (88.4%) harbored >=1 DRM. The median time between two sequential resistance tests was 5 months (IQR: 3-10). Thymidine analogue mutations accumulated at a rate of 0.07 mutation per month of drug exposure, which is faster than previously reported. Routine virological monitoring should be implemented in resource-limited settings to preserve susceptibility to second-line regimens. PMID- 21819220 TI - Prevalence of metabolic syndrome components in a population of bank employees from St. Petersburg, Russia. AB - BACKGROUND: The aim of this study was to assess prevalence of metabolic syndrome and its components according to different criteria in the population of bank employees in St. Petersburg, Russia. METHODS: A total of 1,600 office workers were screened at their working places from the Sberbank state bank in St. Petersburg. All subjects were interviewed by a special questionnaire that included personal data, smoking status, physical activity, alcohol consumption, and medical history. Anthropometry measurements, vital signs, and fasting blood samples were obtained. Serum lipids and plasma glucose were measured. RESULTS: In all, 1,561 responders were included in the final analysis. Hypertension (HTN) was observed in 35.2% of subjects (64% in males and 25.4% in females), abdominal obesity (AO) according to Internation Diabetes Federation (IDF) criteria in 45.6% (51.5% in males and 44.0% in females), high triglyceride levels in 28.4%, low high-density lipoprotein cholesterol (HDL-C) levels in 23.9%, and elevated fasting glucose over 5.6 mmol/L in 28.4% of subjects. AO associated with HTN was observed in 24.3%. Metabolic syndrome according to IDF criteria was diagnosed in 21.5% (17.9% in females and 34.6% in males, P<0.01), and according to Adult Treatment Panel III (ATP III) (2005) criteria in 18.8% of subjects (16.2% in females and 28.4% in males, P<0.01). The correlation between criteria was rho(S)=0.79. Low physical activity, smoking, and alcohol abuse were associated with metabolic syndrome. CONCLUSIONS: Metabolic syndrome and its distinct components were very prevalent in Russian bank office workers. AO was most prevalent component for females with metabolic syndrome, whereas HTN was most prevalent for males. Coexistence of HTN and AO was the most frequent coupling of metabolic syndrome components. Unhealthy lifestyle characterized the selected group and was associated with metabolic syndrome, especially low physical activity. PMID- 21819221 TI - Prevalence of orthopedic complaints among endourologists and their compliance with radiation safety measures. AB - OBJECTIVES: To assess the compliance of endourologists with radiation safety measures and to determine the prevalence of orthopedic complaints among practicing endourologists. METHODS: An Internet-based survey was sent to all members of the Endourological Society. Baseline characteristics on practice patterns (geographical region, age, years of practice, days per week of endourology, and number of cases in the previous year), compliance with various radiation protection measures (thyroid, chest and pelvic shields, gloves, glasses, and dosimeters), and prevalence of various orthopedic complaints (neck, back, hand, and joint problems) were assessed. Furthermore, open-ended questions assessed reasons for noncompliance. RESULTS: Out of 160 surveys returned, 24 were excluded because of incomplete data. There was good compliance with chest and pelvic shields with 97% of endourologists reported wearing these. However, compliance with thyroid shields was only 68%. Furthermore, only 34.3%, 17.2%, and 9.7% of endourologists reported using dosimeters, lead-impregnated glasses, and gloves, respectively. Overall, 86 (64.2%) respondents complained of orthopedic problems. Specifically, 51 (38.1%) complained of back problems, 37 (27.6%) neck problems, 23 (17.2%) hand problems, and 19 (14.2%) complained of hip and knee problems. The prevalence of orthopedic complaints was significantly higher among African endourologists, older endourologists (>40 years), longer duration of practice (>10 years) and combined annual caseload of ureteroscopies (URS) and percutaneous nephrolithotomies (PCNL). CONCLUSIONS: Compliance in the use of thyroid shields, dosimeters, and lead-impregnated glasses and gloves could be improved. Orthopedic complaints among practicing endourologists are common and correlate with the annual caseload of combined URS and PCNL. PMID- 21819222 TI - Robot-assisted radical prostatectomy in patients with previous renal transplantation. AB - PURPOSE: To evaluate the outcomes of robot-assisted radical prostatectomy (RARP) in patients with previous renal transplantation. PATIENTS AND METHODS: We retrospectively identified all patients who had undergone RARP for localized prostate cancer between 2005 and 2008 at a single institution (N=228). Of these, three patients were renal transplant recipients. A four-arm robotic configuration was used in all patients. Port placement was modified in two of the three renal transplant recipients to avoid trauma to the renal allograft. Preoperative demographics, perioperative parameters, and postoperative outcomes were reviewed. RESULTS: RARP was completed successfully in all three renal transplant recipients. As expected, the American Society of Anesthesiologists score (3.3 vs 2.4) and Charlson weighted index of comorbidity (4.7 vs 2.4) were greater in previous transplant patients. There were no major differences in mean age, Gleason score, body mass index, estimated blood loss, operative time, complications, or oncologic outcomes between the two groups. Each of the patients with renal allografts had an undetectable prostate-specific antigen level and was continent (needing no pads) at 13 months of follow-up. CONCLUSIONS: RARP is feasible in patients with a previous renal transplant. Although technically more challenging, RARP can be performed in previous transplant patients with acceptable morbidity and oncologic outcomes similar to those of other prostate cancer patients. PMID- 21819224 TI - Balancing our approach to the insider threat. PMID- 21819223 TI - Micropatterned surfaces for reducing the risk of catheter-associated urinary tract infection: an in vitro study on the effect of sharklet micropatterned surfaces to inhibit bacterial colonization and migration of uropathogenic Escherichia coli. AB - BACKGROUND AND PURPOSE: Catheter-associated urinary tract infection (CAUTI) is the most common device-associated infection and can result in serious medical consequences. We studied the efficacy of a novel microscopic physical surface modification (Sharklet) for preventing bacterial colonization and migration of uropathogenic Escherichia coli on silicone elastomer. MATERIALS AND METHODS: In vitro growth assays evaluated E coli colonization using three variations of micropatterned silicone surfaces vs a smooth silicone control. Enumeration techniques included quantification of colonies on surfaces and analysis of bacterial area coverage and colony size. In vitro migration assays involved placement of micropatterned and smooth silicone rod segments between two agar islands to measure incidence of migration. RESULTS: All three variations of the Sharklet micropattern outperformed the control surfaces in inhibiting E coli colonization. On average, 47% reduction in colony-forming units (CFUs) and bacterial area coverage plus 77% reduction in colony size were achieved with the Sharklet surfaces in tryptic soy broth and artificial urine compared with the control nonpatterned surfaces. The incidence of E coli migration over the rod segments was reduced by more than 80% for the Sharklet transverse patterned rods compared with the unpatterned control rods. CONCLUSION: The Sharklet micropattern is effective at inhibiting colonization and migration of a common uropathogen. This performance is achieved through a physical surface modification without the use of any antimicrobial agents. Because deterrence of bacterial colonization and migration is a critical step to prevent CAUTI, the Sharklet micropattern offers a novel concept in addressing this important problem. PMID- 21819225 TI - Public response to an anthrax attack: reactions to mass prophylaxis in a scenario involving inhalation anthrax from an unidentified source. AB - An attack with Bacillus anthracis ("anthrax") is a known threat to the United States. When weaponized, it can cause inhalation anthrax, the deadliest form of the disease. Due to the rapid course of inhalation anthrax, delays in initiation of antibiotics may decrease survival chances. Because a rapid response would require cooperation from the public, there is a need to understand the public's response to possible mass dispensing programs. To examine the public's response to a mass prophylaxis program, this study used a nationally representative poll of 1,092 adults, supplemented by a targeted focus on 3 metropolitan areas where anthrax attacks occurred in 2001: New York City (n=517), Washington, DC (n=509), and Trenton/Mercer County, NJ (n=507). The poll was built around a "worst-case scenario" in which cases of inhalation anthrax are discovered without an identified source and the entire population of a city or town is asked to receive antibiotic prophylaxis within a 48-hour period. Findings from this poll provide important signs of public willingness to comply with public health recommendations for obtaining antibiotics from a dispensing site, although they also indicate that public health officials may face several challenges to compliance, including misinformation about the contagiousness of inhalation anthrax; fears about personal safety in crowds; distrust of government agencies to provide sufficient, safe, and effective medicine; and hesitation about ingesting antibiotic pills after receiving them. In general, people living in areas where anthrax attacks occurred in 2001 had responses similar to those of the nation as a whole. PMID- 21819226 TI - Modernizing confidence-building measures for the Biological Weapons Convention. AB - The Seventh Review Conference of the Biological Weapons Convention in December 2011 provides an opportunity to modernize the treaty to better address the challenges of the 21st century. The key to this modernization is to redesign the treaty's Confidence-Building Measures (CBMs), the only formal mechanism for increasing transparency and demonstrating compliance with the treaty, to address changes in the global scientific, health, and security environments since the end of the Cold War. The scope of the CBMs should be expanded beyond state-run biological warfare programs to encompass a broader array of threats to global security, such as biological terrorism, laboratory accidents, dual-use research, and disease pandemics. Modernizing the CBM mechanism to take into account these new risks would extend the transparency-enhancing benefits of CBMs to a range of new and important topics, such as biosafety, laboratory biosecurity, and dual-use research oversight; make the CBMs and the treaty itself more relevant to the concerns and priorities of more states; and build on progress made during the recent series of intersessional meetings. To accomplish this, the CBMs need to be revised to shift their focus from hardware, the dual-use capabilities relevant to the treaty, to software, the political and legal institutions that govern the development and use of these capabilities. A more modern CBM mechanism should encourage greater participation in the confidence-building process, improve international cooperation against the full spectrum of biological risks, and promote the goal of universal membership in the treaty. PMID- 21819227 TI - Carol Anne Bond v the United States of America: how a woman scorned threatened the Chemical Weapons Convention. AB - The case of Carol Anne Bond v the United States of America stemmed from a domestic dispute when Ms. Bond attempted to retaliate against her best friend by attacking her with chemical agents. What has emerged is a much greater issue--a test of standing on whether a private citizen can challenge the Tenth Amendment. Instead of being prosecuted in state court for assault, Ms. Bond was charged and tried in district court under a federal criminal statute passed as part of implementation of the Chemical Weapons Convention (CWC). Ms. Bond's argument rests on the claim that the statute exceeded the federal government's enumerated powers in criminalizing her behavior and violated the Constitution, while the government contends legislation implementing treaty obligations is well within its purview. This question remains unanswered because there is dispute among the lower courts as to whether Ms. Bond, as a citizen, even has the right to challenge an amendment guaranteeing states rights when a state is not a party to the action. The Supreme Court heard the case on February 22, 2011, and, if it decides to grant Ms. Bond standing to challenge her conviction, the case will be returned to the lower courts. Should the court decide Ms. Bond has the standing to challenge her conviction and further questions the constitutionality of the law, it would be a significant blow to implementation of the CWC in the U.S. and the effort of the federal government to ensure we are meeting our international obligations. PMID- 21819228 TI - Pulse wave analysis and cardiac autonomic neuropathy in type 1 diabetes: a report from the Pittsburgh Epidemiology of Diabetes Complications Study. AB - BACKGROUND: The cross-sectional associations of cardiac autonomic neuropathy (CAN) with pulse wave analysis (PWA) measures (both arterial stiffness and myocardial perfusion) have not been explored in type 1 diabetes, despite recognition of an association of CAN with coronary artery disease. METHODS: Both CAN and PWA measures were obtained from 144 participants of the Pittsburgh Epidemiology of Diabetes Complications Study of childhood-onset type 1 diabetes at the 18-year follow-up examination. CAN was measured as variability in the R-R interval during deep breathing, and PWA was performed using SphgymoCor Px (AtCor Medical, Sydney, Australia). Other clinical and demographic factors were also assessed. Univariate and multivariable analyses for associations with CAN were performed for arterial stiffness measures (augmentation index [AIx] and augmentation pressure [AP]) and a myocardial perfusion measure (subendocardial viability ratio [SEVR]). RESULTS: Presence of CAN was univariately associated with all three PWA measures: AIx (odds ratio [OR]=1.5, P=0.03), AP (OR=2.1, P=0.001), and SEVR (OR=0.4, P<0.001). These relationships persisted after adjustment for potential PWA confounders. Adjusting for age and diabetes-related factors (glycosylated hemoglobin, systolic blood pressure, and overt nephropathy), CAN only remained significantly associated with SEVR (OR=0.3, P=0.005). CONCLUSIONS: CAN is cross-sectionally associated with measures of both increased arterial stiffness and decreased myocardial perfusion in type 1 diabetes; however, only the association with decreased estimated myocardial perfusion persisted in fully adjusted models. These results provide potential insight into the CAN association with coronary artery disease. PMID- 21819229 TI - Methylenetetrahydrofolate reductase gene polymorphisms in Turkish children with attention-deficit/hyperactivity disorder. AB - Attention-deficit/hyperactivity disorder (ADHD) is a common, multifactorial genetic disorder. The aim of the present study was to evaluate a possible association between 5,10-methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and ADHD. There is evidence to suggest that MTHFR C677T and A1298C polymorphisms alter the function of the enzyme, causing reduced folate and increased homocysteine levels in plasma. Two polymorphisms of the MTHFR gene, C677T (rs1801133) and A1298C (rs1801131), were analyzed in a sample of 100 Diagnostic and Statistical Manual of Mental Disorders-IV-diagnosed ADHD and 300 healthy controls using a polymerase chain reaction-restriction fragment length polymorphism method. We did not find any association between MTHFR 677T allele, MTHFR 1298C allele, and ADHD. In addition, there was no genotype association between the MTHFR gene and ADHD (chi(2)=1.711; df=2; p=0.425; chi(2)=2.946; df=2; p=0.229). Our data suggest that neither the MTHFR C677T polymorphism nor the MTHFR A1298C polymorphism was associated with ADHD in Turkish children. Thus, the MTHFR gene does not seem to play a role in the etiopathogenesis of ADHD in the cohort studied. PMID- 21819230 TI - Genetic variants in fibrinolytic system-related genes in infertile women with and without endometriosis. AB - AIMS: The aim of this study was to evaluate urokinase-type plasminogen activator gene (uPA) and thrombin-activatable fibrinolysis inhibitor gene (TAFI) genotypes in a group of infertile women with and/or without endometriosis and controls. METHODS: A case-control study comprising 180 infertile women with endometriosis, 68 women with idiopathic infertility, and 152 fertile women as controls was carried out. Detection of uPA (C422T/rs2227564) and TAFI (G438A/rs2146881) polymorphisms was performed by TaqMan polymerase chain reaction. The results were statistically analyzed and a p-value of <0.05 was considered significant. RESULTS: We found no association among both uPA or TAFI polymorphisms and endometriosis-related infertility (p=0.920 and p=0.356, respectively) or idiopathic infertility (p=0.502 and p=0.392, respectively) comparing to controls, even considering minimal/mild and moderate/severe endometriosis separately. Both uPA and TAFI polymorphisms were in Hardy-Weinberg equilibrium for all studied groups. The combinatory analysis of both uPA and TAFI polymorphisms to endometriosis-related infertility, idiopathic infertility, and control group showed no statistical difference to any combination. CONCLUSION: The data suggest that, in the Brazilian population, genetic variations in both uPA and TAFI were not relevant to endometriosis and/or infertility. PMID- 21819231 TI - Toxins-antitoxins: diversity, evolution and function. AB - Genes for toxin-antitoxin (TA) complexes are widespread in prokaryote genomes, and species frequently possess tens of plasmid and chromosomal TA loci. The complexes are categorized into three types based on genetic organization and mode of action. The toxins universally are proteins directed against specific intracellular targets, whereas the antitoxins are either proteins or small RNAs that neutralize the toxin or inhibit toxin synthesis. Within the three types of complex, there has been extensive evolutionary shuffling of toxin and antitoxin genes leading to considerable diversity in TA combinations. The intracellular targets of the protein toxins similarly are varied. Numerous toxins, many of which are sequence-specific endoribonucleases, dampen protein synthesis levels in response to a range of stress and nutritional stimuli. Key resources are conserved as a result ensuring the survival of individual cells and therefore the bacterial population. The toxin effects generally are transient and reversible permitting a set of dynamic, tunable responses that reflect environmental conditions. Moreover, by harboring multiple toxins that intercede in protein synthesis in response to different physiological cues, bacteria potentially sense an assortment of metabolic perturbations that are channeled through different TA complexes. Other toxins interfere with the action of topoisomersases, cell wall assembly, or cytoskeletal structures. TAs also play important roles in bacterial persistence, biofilm formation and multidrug tolerance, and have considerable potential both as new components of the genetic toolbox and as targets for novel antibacterial drugs. PMID- 21819232 TI - Evaluation of syncope and palpitations in women. AB - Syncope and palpitations are common complaints that all physicians confront during daily clinical practice. Single center and multicenter cohort studies have found that syncope accounts for 1%-3% of emergency department evaluations and that palpitations are the primary symptom for approximately 16% of patients who arrive at an outpatient clinic with a cardiac complaint. For both conditions, women make up approximately 60% of the cohorts. In general, the evaluation of both syncope and palpitations can be challenging because of the heterogeneity of causes and, consequently, the variability of clinical outcomes, ranging from a single isolated event with no effect on morbidity and mortality to the first sign of a potentially life-threatening problem and sudden cardiac death. For all women with syncope or palpitations, the history, physical examination, and a baseline electrocardiogram (ECG) form the basis of the initial workup and focus on identifying patients with cardiovascular abnormalities who are at the highest risk for sudden cardiac death. More advanced tests must be chosen using a problem specific approach, but generally, documentation of the cardiac rhythm during symptoms is critical for all patients with syncope or palpitations. Although the diagnostic testing strategy is generally similar for men and women, gender related differences in treatment response have been identified. Antiarrhythmic medications, such as dofetilide and sotalol, that prolong the QT interval are more likely to be associated with proarrhythmia in women. In addition, higher complication rates for invasive cardiac procedures, such as device implantation, are observed in women. PMID- 21819233 TI - Clinical research enrolling pregnant women: a workshop summary. AB - Clinical research investigates mechanisms of human disease, interventions, or new technologies, but pregnant women are often excluded from clinical studies. Few studies, beyond research on pregnancy, are designed to address questions relevant to pregnant women. A recent National Institutes of Health workshop considered the barriers and opportunities in conducting clinical research studies enrolling pregnant women. PMID- 21819235 TI - Silver spoons and other personal reflections. AB - The intent is to tell a story-hopefully one that is at various times serious, light-hearted, or provocative-that describes my life in biomedical science, especially focusing on the 50 years from 1961 (as a college senior) to the present. PMID- 21819236 TI - Using genome-wide association studies to identify genes important in serious adverse drug reactions. AB - Genome-wide association (GWA) studies have detected novel associations for serious, idiosyncratic, adverse drug reactions including liver toxicity, hypersensitivity, skin rash, and myotoxicity. Human leukocyte antigen (HLA) genotype has been established as an important predictor of susceptibility to drug induced liver injury, including injury with some drugs where immune-related toxicity was not suspected previously. Similarly, GWA studies have shown a key role for HLA genotype in susceptibility to carbamazepine-related skin rash and hypersensitivity. HLA genotype is not a risk factor for all forms of drug-induced liver injury or for myotoxicity or cardiotoxicity. For simvastatin-related myotoxicity, a strong association with SLCO1B1, which encodes the hepatic statin uptake transporter, has been detected. Genome-wide studies have not yet found clear associations for drug-induced cardiotoxicity, but for bisphosphonate induced necrosis of the jaw, polymorphisms in the cytochrome P450 CYP2C8 may predict susceptibility. Larger GWA studies and whole-genome sequencing may provide additional insights into all these toxicities. PMID- 21819234 TI - Optogenetic control of cells and circuits. AB - The absorption of light by bound or diffusible chromophores causes conformational rearrangements in natural and artificial photoreceptor proteins. These rearrangements are coupled to the opening or closing of ion transport pathways, the association or dissociation of binding partners, the enhancement or suppression of catalytic activity, or the transcription or repression of genetic information. Illumination of cells, tissues, or organisms engineered genetically to express photoreceptor proteins can thus be used to perturb biochemical and electrical signaling with exquisite cellular and molecular specificity. First demonstrated in 2002, this principle of optogenetic control has had a profound impact on neuroscience, where it provides a direct and stringent means of probing the organization of neural circuits and of identifying the neural substrates of behavior. The impact of optogenetic control is also beginning to be felt in other areas of cell and organismal biology. PMID- 21819237 TI - Chemical genetics-based target identification in drug discovery. AB - Identification of novel, validated targets remains a top priority in modern drug discovery. Chemical genetics represents a powerful approach to the discovery of new targets. Unlike the traditional target-based screen that relies on a predefined, sometimes poorly validated target, a chemical genetics-based phenotypic screen probes the entire molecular signaling pathway in an efficient and unbiased manner for the most drug-sensitive node. The most significant obstacle associated with this approach is identification of the efficacy targets of small-molecule probes. The huge potential of chemical genetics cannot be realized without the establishment of reliable mechanisms for target identification. In this article, we describe each essential element of the chemical genetics process, discuss common challenges that the field is facing, and critically review various biochemical and genetics approaches recently developed for target deconvolution. We also attempt to summarize lessons that we have collectively learned and provide a practical perspective to facilitate the advancement of chemical genetics. PMID- 21819238 TI - Xenobiotic metabolomics: major impact on the metabolome. AB - Xenobiotics are encountered by humans on a daily basis and include drugs, environmental pollutants, cosmetics, and even components of the diet. These chemicals undergo metabolism and detoxication to produce numerous metabolites, some of which have the potential to cause unintended effects such as toxicity. They can also block the action of enzymes or receptors used for endogenous metabolism or affect the efficacy and/or bioavailability of a coadministered drug. Therefore, it is essential to determine the full metabolic effects that these chemicals have on the body. Metabolomics, the comprehensive analysis of small molecules in a biofluid, can reveal biologically relevant perturbations that result from xenobiotic exposure. This review discusses the impact that genetic, environmental, and gut microflora variation has on the metabolome, and how these variables may interact, positively and negatively, with xenobiotic metabolism. PMID- 21819239 TI - Old versus new oral anticoagulants: focus on pharmacology. AB - Since the discovery of heparin nearly a century ago, there have been large gaps in the development of anticoagulants. The discovery of warfarin was the first step toward using oral anticoagulants, but warfarin use has been associated with its own challenges from the perspectives of the prescribing physician and the patient. Warfarin, along with other coumarins, has a narrow therapeutic index, requires frequent monitoring, exhibits interindividual response variations, and is associated with several adverse effects. Frequent drug and food interactions contribute to potential safety and efficacy compromise. The indications for use of oral anticoagulants have increased, as these drugs are used not only for thrombosis management but also for cardiovascular indications, producing more challenges for oral anticoagulant use. Factor Xa and thrombin targeting has provided a rational approach to develop new oral anticoagulants with improvements over warfarin. In this review, the pharmacology of warfarin and the pharmacology of the newly developed oral anti-Xa and antithrombin agents are discussed. PMID- 21819240 TI - Axis formation in hydra. AB - A hydra has a simple structure consisting of a head, body column, and foot along a single axis called the oral-aboral axis. The tissue dynamics of a hydra consist of a steady state of production and loss of tissue involving the entire animal. Axis formation and its maintenance is controlled by the head organizer, which is located at the apex of the animal. The head organizer produces two signals, the head activator and head inhibitor, which are transmitted to, and are distributed in, descending gradients among the epithelial cells along the body column. The two gradients control axial patterning along the oral-aboral axis. In the context of the tissue dynamics of the adult hydra, these three elements controlling axis formation and axial patterning are in a steady state of production and loss. The canonical Wnt pathway plays a major role in setting up and maintaining the head organizer. PMID- 21819241 TI - Computer simulation of the static dielectric constant of systems with permanent electric dipoles. PMID- 21819242 TI - Community-based telemonitoring for hypertension management: practical challenges and potential solutions. AB - Older adults residing in rural areas often lack convenient, patient-centered, community-based approaches to facilitate receipt of routine care to manage common chronic conditions. Without adequate access to appropriate disease management resources, the risk of seniors' experiencing acute events related to these common conditions increases substantially. Further, poorly managed chronic conditions are costly and place seniors at increased risk of institutionalization and permanent loss of independence. Novel, telehealth-based approaches to management of common chronic conditions like hypertension may not only improve the health of older adults, but may also lead to substantial cost savings associated with acute care episodes and institutionalization. The aim of this report is to summarize practical considerations related to operations and logistics of a unique community-based telemonitoring pilot study targeting rural seniors who utilize community-based senior centers. This article reviews the technological challenges encountered during the study and proposes solutions relevant to future research and implementation of telehealth in community-based, congregate settings. PMID- 21819243 TI - New technologies and nursing: use and perception of primary healthcare nurses about electronic health record in Catalonia, Spain. AB - This study was aimed to analyze and assess the use and perception of electronic health records (EHRs) by nurses. The study sample included 113 nurses from different shifts of primary health facilities in Catalonia, Spain, devoted to adult as well as pediatric outpatients using EHRs throughout the year 2010. A majority of the sample (87.5%) were women and 12.5% were men. The average age was 44.27 years and the average time working in primary healthcare was 47.15 months. A majority (80.4%) received specific training on the use of the EHR and 19.6% did not. The use of the application required side technical support (mean: 3.42) and it is considered necessary to learn more about the performance of the application (mean: 3.50). The relationship between the average ratings that nurses have about the EHR and age shows that there is no statistically significant linear relationship (r=-0.002, p-value=0.984). As to how long they have used the EHRs, there are significant differences (r=-0.304, p-value=0.00), so the more time the nurse takes using the EHR, the greater degree of satisfaction is shown. In addition, there are significant differences between nurses' perceptions regarding the EHR and gender (t=-0.421, p-value=0.675). Nurses assessed as positive the contribution of the EHRs in their nursing care day work (average score: 2.55/5). Considering that the usability of the EHR device is assessed as satisfactory, the results of the perception of nurses show that we must also take into account the training and emphasize the need for a side technical support in the implementation process of the EHR. Doing so, the positive perception that nurses have in regard to information and communication technology in general and with respect to the EHR in particular may be increased. PMID- 21819244 TI - A health insurance portability and accountability act-compliant ocular telehealth network for the remote diagnosis and management of diabetic retinopathy. AB - In this article, we present the design and implementation of a regional ocular telehealth network for remote assessment and management of diabetic retinopathy (DR), including the design requirements, network topology, protocol design, system work flow, graphics user interfaces, and performance evaluation. The Telemedical Retinal Image Analysis and Diagnosis Network is a computer-aided, image analysis telehealth paradigm for the diagnosis of DR and other retinal diseases using fundus images acquired from primary care end users delivering care to underserved patient populations in the mid-South and southeastern United States. PMID- 21819245 TI - Apolipoprotein E gene polymorphism and the risk of intracerebral hemorrhage in the Chinese population. AB - Prior studies investigating the association between apolipoprotein E (APOE) gene polymorphism and the risk of intracerebral hemorrhage (ICH) have been inconsistent and limited to small sample sizes. The aim of this study was to test the hypothesis that APOE gene polymorphisms are associated with the risk of ICH in Chinese Han patients. We enrolled 180 ICH patients and 180 controls. APOE genotype was determined by using a polymerase chain reaction-restriction fragment length polymorphism assay. ICH patients had a significantly lower frequency E3/E3 [odds ratio (OR)=0.45, 95% confidence interval (CI)=0.28, 0.71; p=0.001] and E3 allele (OR=0.51, 95% CI=0.35, 0.76; p=0.001) than healthy controls. ICH patients also had a significantly higher frequency E3/E4 (OR=3.61, 95% CI=1.89, 6.88; p<0.001) and E4 allele (OR=3.00, 95% CI=1.76, 5.13; p<0.001) than healthy controls. This study suggests that the APOE genotype is associated with the risk of ICH in Chinese Han patients. PMID- 21819246 TI - Quality assessment of genetic counseling process in the context of presymptomatic testing for late-onset disorders: a thematic analysis of three review articles. AB - Presymptomatic testing (PST) is available for a range of late-onset disorders. Health practitioners generally follow guidelines regarding appropriate number of counseling sessions, involvement of multidisciplinary teams, topics for pretest discussion, and follow-up sessions; however, more understanding is needed about what helps consultands effectively and the impact of amount and quality of genetic counseling on the psychosocial sequelae of PST for late-onset disorders. We conducted a thematic analysis of three review articles on quality of the genetic counseling process, aiming at (1) exploring current evidence; (2) identifying quality assessment indicators; and (3) making recommendations for genetic counseling practice in late-onset disorders. We undertook a systematic search of 6 relevant databases: 38 articles were identified and 3 fitted our inclusion criteria; after quality appraisal, all were included in the review. The number of sessions, time spent, consultation environment, follow-up, and multidisciplinarity were identified as variables for quality assessment. Research on counseling in the context of genetic testing in familial cancer tends to be related to outcomes and indicators for quality assessment, while research concerning other late-onset diseases is mainly focused on the psychological impact of the test results. The quality and content of the overall process in noncancer late-onset diseases is insufficiently articulated. Despite the fact that PST for Huntington disease and other degenerative conditions has been offered for more than 20 years, good methodological approaches to assess quality of genetic counseling in that context remain elusive. This restricts improvement of the protocols for genetic services and, in general, healthcare for the at-risk population. PMID- 21819247 TI - Birth weight of infants of mothers with aggressive periodontitis. AB - BACKGROUND: It was hypothesized that if periodontal infections predispose low birth weights and premature birth, then such outcomes should be apparent when the mother has aggressive periodontitis (AgP). METHODS: Birth weight data were collected by questionnaire from females with AgP, their periodontally healthy siblings, and unrelated periodontally healthy women. Both prospective and retrospective birth outcome data were used. Because many of the periodontal evaluations were performed after the births, there were incomplete data regarding most of the risk factors for low birth weight. We determined associations between mothers' periodontal diagnoses and clinical variables and the reported birth weights. RESULTS: There were no significant differences in mean birth weights of babies born to control subjects or AgP patients. This was true whether all the births were considered or only those reported <1 or 2 years before periodontal examination. For periodontally healthy controls, 13.2% of babies born to siblings of AgP patients and 12.8% of babies born to unrelated mothers weighed <2,500 g, whereas 9.9% of those born to mothers with generalized AgP and 10.3% of those born to mothers with localized AgP weighed <2,500 g. CONCLUSIONS: Because of the relative rarity of AgP in the population, and attendant difficulties in performing a prospective study of its association with pregnancy outcomes, we used a compromised approach using prospective data as well as weaker retrospective data assuming that disease onset was likely before the births. Our results, within the limitations of this approach, indicate no evidence that AgP in the mother predisposes low birth weights. AgP has many unique biologic characteristics that differentiate it from chronic forms of periodontal disease, and the possible lack of its association with birth weight may be another such characteristic. PMID- 21819248 TI - The psychology of patient compliance: a focused review of the literature. AB - BACKGROUND: Excellent patient compliance to periodontal maintenance is absolutely necessary for successful long-term therapy. However, absolute (100%) compliance is rare, having been reported as low as 16%. Although social, behavioral, cultural, and economic factors have been implicated as determinants in patterns of compliance, the influence of personality characteristics on attitudes remains to be carefully explored. This focused review of the literature explores current research addressing psychologic factors associated with compliance to periodontal maintenance therapy. METHODS: A literature search of PubMed electronic database was conducted, inclusive of the years 1990 to 2011. The search used MeSH terminology such as periodontal maintenance, emotional intelligence, personality, patient compliance, etc. In addition, searches were conducted of reference lists from original research and review articles. Studies were assessed with respect to methodology and design, statistical analysis, and psychologic measurements. RESULTS: Non-compliant patients appear to have a higher frequency of stressful life events. Studies suggest that initial patient response to periodontal therapy may be related to emotional intelligence. Regarding personality factors, high neuroticism and low conscientiousness are most widely associated with non compliance. As such, increased knowledge of the "Big Five" personality factors (i.e., neuroticism, extraversion, openness to experience, agreeableness, and conscientiousness) could assist clinicians in potentially increasing compliance among patients. Clinicians could also incorporate a working knowledge of the Health Belief Model and Theory of Planned Behavior to develop individualized treatment strategies for patient compliance. CONCLUSION: Non-compliance to periodontal maintenance cannot be solely explained by one determinant but rather may involve an individual's health beliefs, emotional intelligence, psychologic stressors, and personality traits. PMID- 21819249 TI - Accuracy and complications of computer-designed selective laser sintering surgical guides for flapless dental implant placement and immediate definitive prosthesis installation. AB - BACKGROUND: Computer-aided dental implant placement seems to be useful for placing implants by using a flapless approach. However, evidence supporting such applications is scarce. The aim of this study is to evaluate the accuracy of and complications that arise from the use of selective laser sintering surgical guides for flapless dental implant placement and immediate definitive prosthesis installation. METHODS: Sixty implants and 12 prostheses were installed in 12 patients (four males and eight females; age range: 41 to 71 years). Lateral (coronal and apical) and angular deviations between virtually planned and placed implants were measured. The patients were followed up for 30 months, and surgical and prosthetic complications were documented. RESULTS: The mean +/- SD angular, coronal, and apical deviations were 6.53 degrees +/- 4.31 degrees , 1.35 +/- 0.65 mm, and 1.79 +/- 1.01 mm, respectively. Coronal and apical deviations of <2 mm were observed in 82.67% and 58.33% of the implants, respectively. The total complication rate was 34.41%; this rate pertained to complications such as pulling of the soft tissue from the lingual surface during drilling, insertion of an implant that was wider than planned, implant instability, prolonged pain, midline deviation of the prosthesis, and prosthesis fracture. The cumulative survival rates for implants and prostheses were 98.33% and 91.66%, respectively. CONCLUSIONS: The mean lateral deviation was <1.8 mm, and the mean angular deviation was 6.53 degrees . However, 41.67% of the implants had apical deviation >2 mm. The complication rate was 34.4%. Hence, computer-aided dental implant surgery still requires improvement and should be considered as in the developmental stage. PMID- 21819250 TI - Identifying and treating sexual dysfunction in postmenopausal women: the role of estrogen. AB - Sexual dysfunction is a common, but frequently overlooked, problem in postmenopausal women. At menopause, dramatic decreases in circulating estrogen concentrations cause physiologic changes that may affect sexual function, most notably the development of vulvovaginal atrophy. Vulvovaginal atrophy often leads to vaginal dryness, itching, irritation, reduced lubrication, dyspareunia, and vaginal bleeding associated with sexual activity. Estrogen deficiency also can affect other aspects of sexual function, including reduced vaginal blood flow and a reduced capacity for arousal and orgasm. As estrogen loss is a significant cause of sexual dysfunction in menopausal women, estrogen therapy is a logical treatment option in this population. Although both systemic and local estrogen therapy improve vaginal health and sexual functioning, local vaginal therapy with estrogen creams, rings, or tablets may be more appropriate for women without other indications for systemic estrogen therapy. These therapies are highly effective in reversing vaginal atrophy, improving vaginal symptomatology, and reducing dyspareunia, and may have effects on other dimensions of sexual function. Emerging treatments, such as ultra-low-dose vaginal estradiol tablets, new selective estrogen receptor modulators (SERMs), and intravaginal dehydroepiandrosterone (DHEA) are other promising options for postmenopausal women with vaginal atrophy and sexual dysfunction. PMID- 21819252 TI - Gynecologic oncologists and ovarian cancer treatment: avenues for improved survival. AB - Ovarian cancer is the deadliest gynecologic malignancy in the United States. Evidence-based interventions for the prevention and early detection of ovarian cancer do not currently exist. However, several treatment guidelines, including the receipt of treatment from a gynecologic oncologist, have been shown to result in improved survival from ovarian cancer. PMID- 21819251 TI - Cognitive function and fine motor speed in older women with diabetes mellitus: results from the women's health initiative study of cognitive aging. AB - BACKGROUND: We sought to determine if type 2 diabetes mellitus (T2DM) was associated with accelerated decline in domain-specific measures of cognitive function and fine motor speed. METHODS: Women aged 65-80 years who were enrolled in a clinical trial of postmenopausal hormone therapy were grouped as having T2DM (n=179) or not (n=1984) and followed for an average of 5 years with annual standardized assessments of domain-specific cognitive function. Mean patterns of cognitive measures over time were contrasted between groups using general linear models and Wald tests, with varying levels of covariate adjustment. The influences of age at onset, use of oral medications, and use of insulin were also examined. RESULTS: T2DM was associated with mean deficits of 0.2-0.4 standard deviations (SD) across follow-up in most cognitive domains. Consistent evidence that rates of decline were accelerated among women with T2DM was evident only for verbal knowledge and verbal memory (p<0.05). Decrements in fine motor speed, but no measure of cognitive function, were greater for women with earlier onset T2DM. Use of oral diabetes medications was associated with better relative cognitive function. CONCLUSIONS: In these women, T2DM was associated with cognitive deficits in most domains. Relative deficits in verbal knowledge and verbal memory may continue to increase after deficits in other domains have stabilized. Relative deficits in fine motor speed may be greater among women with earlier onsets of T2DM. Use of insulin, which may reflect greater T2DM severity, was associated with relatively greater cognitive deficits. PMID- 21819253 TI - Long-term outcome of transobturator tension-free vaginal tape: efficacy and risk factors for surgical failure. AB - PURPOSE: To assess the 5-year efficacy of the inside-out transobturator tension free vaginal tape (TVT-O) for the treatment of stress urinary incontinence (SUI) and to explore possible predictors for long-term failure. METHODS: Sixty-five consecutive patients who underwent TVT-O were prospectively enrolled. Patients who required concomitant anterior or apical pelvic organ prolapse repair or both and those with urodynamic occult SUI were excluded. Postoperatively, patients were scheduled for evaluation at 1, 3, 6, and 12 months and annually thereafter. Surgical failure was defined as positive stress test, daily episodes of SUI, and negative global satisfaction. Preoperative and interim clinical and urodynamic predictors for long-term failure were analyzed from a computerized database. RESULTS: Sixty-one patients (mean age at surgery 56.6+/-10.2 years) completed 5 years of follow-up. Of these, 11 (18%) patients were classified as surgical failure, 5 (8%) as improved, and 45 (74%) as cured. Any SUI (100% vs. 10%, p=0.001), daily SUI (100% vs. 0%, p=0.001), overactive bladder (OAB) (100% vs. 48%, p=0.001), and the use of antimuscarinic drugs (64% vs. 26%, p=0.03) were found to be significantly more common among failure cases. Preoperative detrusor overactivity (odds ratio [OR] 7.6, 95% confidence interval [CI] 1.7-32.9), interim 1-year OAB (OR 20.5, 95% CI 1.9-215.4), and interim 1-year SUI (OR 26.4, 95% CI 1.5-475.2) were found to be significant independent risk factors for long term surgical failure. CONCLUSIONS: An 18% rate of surgical failure was observed 5 years after TVT-O. Larger studies with longer follow-up periods may facilitate the identification of risk factors for failure and, thus, enable better preoperative consultation. PMID- 21819256 TI - Transmitted HIV resistance to first-line antiretroviral therapy in Lima, Peru. AB - Transmission of drug-resistant HIV (TDR) has been associated with virologic failure of "first-line," nonnucleoside reverse transcriptase inhibitor (NNRTI) based antiretroviral therapy (ART). A national ART program began in Peru in 2004. We evaluated the prevalence of TDR in individuals initiating ART and their virologic outcome during 2 years of ART. HIV-infected, ARV-naive subjects who met criteria to start ART in Lima, Peru were enrolled in a longitudinal observational study between July 2007 and February 2009. Blood plasma and cells obtained prior to ART initiation were assessed for antiretroviral (ARV) resistance by an oligonucleotide ligation assay (OLA) sensitive to 2% mutant at reverse transcriptase (RT) codons K103N, Y181C, G190A, and M184V and a subset by consensus sequencing. A total of 112 participants were enrolled; the mean CD4 was 134 +/- 89 cells/MUl and the median plasma HIV RNA was 93,556 copies/ml (IQR 62,776-291,364). Drug resistance mutations conferring high-level resistance to ARV were rare, detected in one of 96 (1%) evaluable participants. This subject had the Y181C mutation detected in both plasma and peripheral blood mononuclear cells (PBMCs) at a concentration of 100% by OLA and consensus sequencing; nevertheless nevirapine-ART suppressed her viral replication. Consensus sequencing of 37 (19%) participants revealed multiple polymorphisms that occasionally have been associated with low-level reductions in ARV susceptibility. A low prevalence of TDR was detected among Peruvians initiating ART. Given the increasing availability of ART, continuing surveillance is needed to determine if TDR increases and the mutant codons associated with virologic failure. PMID- 21819257 TI - Drug resistance and coreceptor usage in HIV type 1 subtype C-infected children initiating or failing highly active antiretroviral therapy in South Africa. AB - HIV-1 drug resistance monitoring in resource-poor settings is crucial due to limited drug alternatives. Recent reports of the increased prevalence of CXCR4 usage in subtype C infections may have implications for CCR5 antagonists in therapy. We investigated the prevalence of drug resistance mutations and CXCR4 coreceptor utilization of viruses from HIV-1 subtype C-infected children. Fifty one children with virological failure during highly active antiretroviral therapy (HAART) and 43 HAART-naive children were recruited. Drug resistance genotyping and coreceptor utilization assessment by phenotypic and genotypic methods were performed. At least one significant drug resistance mutation was present in 85.4% of HAART-failing children. Thymidine analogue mutations (TAMs) were detected in 58.5% of HAART-failing children and 39.0% had >=3 TAMs. CXCR4 (X4) or dual (R5X4)/mixed (R5, X4) (D/M)-tropic viruses were found in 54.3% of HAART-failing and 9.4% of HAART-naive children (p<0.0001); however, the HAART-failing children were significantly older (p<0.0001). In multivariate logistic regression, significant predictors of CXCR4 usage included antiretroviral treatment, older age, and lower percent CD4(+) T cell counts. The majority of genotypic prediction tools had low sensitivity (<=65.0%) and high specificity (>=87.5%) for predicting CXCR4 usage. Extensive drug resistance, including the high percentage of TAMs found, may compromise future drug choices for children, highlighting the need for improved treatment monitoring and adherence counseling. Additionally, the increased prevalence of X4/D/M viruses in HAART-failing children suggests limited use of CCR5 antagonists in salvage therapy. Enhanced genotypic prediction tools are needed as current tools are not sensitive enough for predicting CXCR4 usage. PMID- 21819258 TI - Topical curcumin for the healing of carbon dioxide laser skin wounds in mice. AB - OBJECTIVE: The purpose of this study was to evaluate the effect of topical curcumin on the healing of skin wounds produced by the CO(2) laser in an animal model. METHODS: A prospective, randomized study was made of 90 mice assigned to three groups (30 animals per group), with the creation of 6-mm incisions in the skin of the dorsal region by means of the CO(2) laser. A total of 270 wounds were made (3 wounds by animal). No product was applied to the resulting wound in group I (control group); vehicle was applied in group II (5 mg/day by wound); and topical curcumin was applied to the mice in group III (5 mg/day by wound). Re epithelialization and inflammation of the wounds were measured from histological sections of wounds, after 2, 7, and 14 days. RESULTS: Two days after production of the wounds, most of the latter showed incomplete re-epithelialization. After 7 days, 73.33% of the wounds treated with curcumin presented re-epithelialization covering the entire wound, with irregular thickness; nevertheless, only 37.50% of the wounds in control group and 41.67% in the vehicle group showed this degree ot re-epithelialization. After 14 days, all the wounds had completed re epithelization. No significant differences were observed regarding resolution of the inflammatory process in any of the study groups after 2, 7, and 14 days. CONCLUSIONS: This study shows that topical curcumin applied to CO(2) laser induced skin wounds may be useful, because improved re-epithelialization is observed after 7 days. PMID- 21819260 TI - Amorphous silica coatings on magnetic nanoparticles enhance stability and reduce toxicity to in vitro BEAS-2B cells. AB - BACKGROUND: Nanoparticles are being rapidly assimilated into numerous research fields and consumer products. A concurrent increase in human exposure to such materials is expected. Magnetic nanoparticles (MNPs) possess unique and beneficial features, increasing their functionality and integrative potential. However, MNP toxicity characterization is limited, especially in regards to the human respiratory system. This study aimed to assess the in vitro effects of airborne MNPs on BEAS-2B cells. Uncoated iron oxide was compared with two amorphous silica-coated MNPs, hypothesizing the coatings reduced toxicity and increased particle stability. METHOD: BEAS-2B cells were cultured at an air liquid interface and exposed to airborne MNPs using a fabricated exposure device. Indices of cytotoxicity, inflammatory response, oxidative stress, and iron homeostasis were monitored postexposure via cell viability assays and qRT-PCR. Concentrations of soluble iron-associated with different MNPs were also examined before and after contact with several aqueous organic and inorganic acids. RESULTS: The silica-coated MNPs had reduced soluble iron concentrations. This result indicates that the silica coating provides a barrier to and prevents the mobilization of soluble iron from the particle to the cell, thereby reducing the risk of oxidative stress or alterations of iron homeostasis. Cells exposed to MagSilica50 and MagSilica50-85(r) showed little to no indications of cytotoxicity or induction of inflammatory response/oxidative stress at the examined delivery concentrations. CONCLUSION: MNPs coated with amorphous silica are protected from acidic erosion. Correspondingly, the particle stability translates into reduced cytotoxicity and cellular influence on human airway epithelial cells. PMID- 21819262 TI - Antitumor efficacy and amelioration of oxidative stress by Trichosanthes dioica root against Ehrlich ascites carcinoma in mice. AB - CONTEXT: Trichosanthes dioica Roxb. (Cucurbitaceae) is a dioecious climber, traditionally used in India for several medicinal purposes. OBJECTIVE: The present study assessed the hydroalcoholic extract of T. dioica root (TDA) for antitumor effect and antioxidant influence against Ehrlich ascites carcinoma (EAC) in Swiss albino mice. METHODS: Twenty four hours after intraperitoneal inoculation of tumor (EAC) cells in mice, TDA was administered at 5 and 10 mg/kg body weight daily for 9 consecutive days. On the 10th day, half of the mice were sacrificed for estimation of tumor proliferation, hematological, and liver antioxidant parameters viz. lipid peroxidation, reduced glutathione (GSH), glutathione S-transferase (GST), superoxide dismutase (SOD) and catalase (CAT); and the rest were kept alive for assessment of increase in life span. The antitumor effect of TDA was assessed by evaluating tumor weight, tumor volume, packed cell volume, viable and non-viable tumor cell counts, median survival time and percentage increase in life span of EAC bearing mice. RESULTS AND DISCUSSION: TDA exhibited dose dependent and significant (p < 0.001) decrease in tumor weight, tumor volume, packed cell volume and viable cell count and extended the life span of EAC bearing hosts. Hematological profiles were significantly (p < 0.001) restored near to normal in TDA treated mice as compared to EAC control. TDA treatment significantly (p < 0.001) modulated the aforesaid liver antioxidant parameters as compared to EAC control. CONCLUSION: The present study demonstrated that TDA possessed promising antitumor efficacy in mice, plausibly mediated by amelioration of oxidative stress by multiple mechanisms. PMID- 21819261 TI - Relationship of pulmonary toxicity and carcinogenicity of fine and ultrafine granular dusts in a rat bioassay. AB - The current carcinogenicity study with female rats focused on the toxicity and carcinogenicity of intratracheally instilled fine and ultrafine granular dusts. The positive control, crystalline silica, elicited the greatest magnitude and progression of pulmonary inflammatory reactions, fibrosis and the highest incidence of primary lung tumors (39.6%). Addition of poly-2-vinylpyridine-N oxide decreased inflammatory responses, fibrosis, and the incidence of pulmonary tumors induced by crystalline quartz to 21.4%. After repeated instillation of soluble, ultrafine amorphous silica (15 mg) a statistically significant tumor response (9.4%) was observed, although, the inflammatory response in the lung was not as persistently severe as in rats treated with carbon black. Instillation of ultrafine carbon black (5 mg) caused a lung tumor incidence of 15%. In contrast to a preceding study using a dose of 66 mg coal dust, lung tumors were not detected after exposure to the same coal dust at a dose of 10 mg in this study. Pulmonary inflammatory responses to coal dust were very low indicating a mechanistic threshold for the development of lung tumors connected with particle related chronic inflammation. The animals treated with ultrafine carbon black and ultrafine amorphous silica showed significantly more severe lesions in non cancerous endpoints when compared to animals treated with fine coal dust. Furthermore, carbon black treated rats showed more severe non-cancerous lung lesions than amorphous silica treated rats. Our data show a relationship between tumor frequencies and increasing scores when using a qualitative scoring system for specific non-cancerous endpoints such as inflammation, fibrosis, epithelial hyperplasia, and squamous metaplasia. PMID- 21819263 TI - Is it possible to improve neurodevelopmental abnormalities in Down syndrome? AB - Down syndrome (DS) is a genetic pathology caused by the triplication of human chromosome 21. Although individuals with DS have various medical problems, intellectual disability is the most invalidating aspect of the pathology. Despite numerous efforts, the mechanisms whereby gene triplication leads to the DS phenotype have not been elucidated and there are, at present, no therapies to rescue brain developmental alterations and mental disability in individuals with DS. In this review, we focused on the major defects of the DS brain, comparing data regarding humans with DS and mouse models for DS, and therapeutic interventions attempted on animal DS models. Based on the promising results of pharmacotherapies in these models, we believe that it is possible to conclude that tools to improve brain development in DS are now almost at hand. We now know that it is possible to rescue and/or improve neurogenesis, neuron maturation, connectivity, neurodegeneration and behavior. We believe that the knowledge gained in DS mouse models provides a rational basis to start new clinical trials in infants, children and adults with DS, exploiting drugs that have proved able to rescue various facets of the DS neurologic phenotype. It is not unreasonable to consider that the results of these trials may provide a positive answer to the question: 'Is it possible to improve brain development in DS?'. PMID- 21819264 TI - Translational research in transcranial direct current stimulation (tDCS): a systematic review of studies in animals. AB - Recent therapeutic human studies testing transcranial direct current stimulation (tDCS) has shown promising results, although many questions remain unanswered. Translational research with experimental animals is an appropriate framework for investigating its mechanisms of action that are still undetermined. Nevertheless, animal and human studies are often discordant. Our aim was to review tDCS animal studies, examining and comparing their main findings with human studies. We performed a systematic review in Medline and other databases, screening for animal studies in vivo that delivered tDCS. Studies in vitro and using other neuromodulatory techniques were excluded. We extracted data according to Animal Research: Reporting In Vivo Experiments (ARRIVE) guidelines for reporting in vivo animal research. Thus, we collected data on sample characteristics (size, gender, weight and specimen) and methodology (experimental procedures, experimental animals, housing and husbandry, as well as analysis). We also collected data on methods for delivering tDCS (location, size, current and current density of electrodes and electrode montage), experimental effects (polarity-, intensity- and after-effects) and safety. Only 12 of 48 potentially eligible studies met our inclusion criteria and were reviewed. Quality assessment reporting was only moderate and studies were heterogeneous regarding tDCS montage methodology, position of active and reference electrodes, and current density used. Nonetheless, almost all studies demonstrated that tDCS had positive immediate and long-lasting effects. Vis-a-vis human trials, animal studies applied higher current densities (34.2 vs. 0.4 A/m(2), respectively), preferred extra-cephalic positions for reference electrodes (60% vs. 10%, respectively) and used electrodes with different sizes more often. Potential implications for translational tDCS research are discussed. PMID- 21819265 TI - Ageing populations, complex diseases and their challenge to 21st century healthcare: the focus of the European Society for Pharmacogenomics and Theranostics. PMID- 21819259 TI - Breast cancer medications and vision: effects of treatments for early-stage disease. AB - This review concerns the effects on vision and the eye of medications prescribed at three phases of treatment for women with early-stage breast cancer (BC): (1) adjuvant cytotoxic chemotherapy, (2) adjuvant endocrine therapy, and (3) symptomatic relief. The most common side effects of cytotoxic chemotherapy are epiphora and ocular surface irritation, which can be caused by any of several different regimens. Most notably, the taxane docetaxel can lead to epiphora by inducing canalicular stenosis. The selective-estrogen-receptor-modulator (SERM) tamoxifen, long the gold-standard adjuvant-endocrine-therapy for women with hormone-receptor-positive BC, increases the risk of posterior subcapsular cataract. Tamoxifen also affects the optic nerve head more often than previously thought, apparently by causing subclinical swelling within the first 2 years of use for women older than ~50 years. Tamoxifen retinopathy is rare, but it can cause foveal cystoid spaces that are revealed with spectral-domain optical coherence tomography (OCT) and that may increase the risk for macular holes. Tamoxifen often alters the perceived color of flashed lights detected via short wavelength-sensitive (SWS) cone response isolated psychophysically; these altered perceptions may reflect a neural-response sluggishness that becomes evident at ~2 years of use. The aromatase inhibitor (AI) anastrozole affects perception similarly, but in an age-dependent manner suggesting that the change of estrogen activity towards lower levels is more important than the low estrogen activity itself. Based on analysis of OCT retinal thickness data, it is likely that anastrozole increases the tractional force between the vitreous and retina. Consequently, AI users, myopic AI users particularly, might be at increased risk for traction-related vision loss. Because bisphosphonates are sometimes prescribed to redress AI-induced bone loss, clinicians should be aware of their potential to cause scleritis and uveitis occasionally. We conclude by suggesting some avenues for future research into the visual and ocular effects of AIs, particularly as relates to assessment of cognitive function. PMID- 21819266 TI - Clopidogrel pharmacogenetics: metabolism and drug interactions. AB - The thienopyridine, clopidogrel bisulfate (clopidogrel), is the most widely prescribed antiplatelet therapy in the world. Clopidogrel, alone or in conjunction with aspirin as part of a dual antiplatelet therapy regimen, is the standard of care for reducing ischemic events in patients with acute coronary syndrome, recent myocardial infarction, recent stroke, or established peripheral artery disease. Initially approved for use in 1997, the label was updated by both the USA Food and Drug Administration and the European Medicines Agency in 2009 to include information regarding cytochrome P450 (CYP) genotype status and concomitant proton pump inhibitor use. Labeling warns of reduced effectiveness in those with impaired CYP2C19 function and to avoid concomitant clopidogrel use with drugs that are strong or moderate CYP2C19 inhibitors, such as omeprazole. The interpretation of this warning and the implementation in clinical practice is not without controversy. The following review provides a summary of the published evidence regarding CYP2C19 function, both genotype status and drug inhibition from concomitant proton pump inhibitors use, and response to clopidogrel. PMID- 21819268 TI - Positive effect on bone fusion by the combination of platelet-rich plasma and a gelatin beta-tricalcium phosphate sponge: a study using a posterolateral fusion model of lumbar vertebrae in rats. AB - We developed a novel method for bone fusion by combining platelet-rich plasma (PRP) and a gelatin beta-tricalcium phosphate (beta-TCP) sponge. The PRP is an autologous concentration of platelets that includes several growth factors. The gelatin beta-TCP sponge comprises gelatin and beta-TCP, thus enabling the sustained release of growth factors and osteoconduction. To evaluate this method, we generated a posterolateral fusion model of lumbar vertebrae in rats and divided it into five groups by implanting the following materials between transverse processes of vertebrae, (1) the gelatin beta-TCP sponge with PRP (PRP sponge), (2) the gelatin beta-TCP sponge with platelet-poor plasma, (3) gelatin hydrogel with PRP, (4) autologous iliac bone (autograft), and (5) no material was implanted as a control. The assessment of bone fusion by a radiographic assessment, a biomechanical test, microcomputed tomography, and histological evaluations demonstrated that there were no significant differences between the PRP sponge and the autograft groups regarding the osteogenic effect. Subsequent examinations revealed that no significant differences existed between the PRP sponge and the autograft groups in either biomechanical stiffness or the bone volume over time; whereas the radiographic and histological composition underwent similar changes in the fusion process. These results indicate that the PRP sponge could, therefore, be potentially useful as an attractive and less invasive method for bone fusion. PMID- 21819269 TI - Wound degradomics - current status and future perspectives. AB - Proteases are pivotal modulators of extracellular matrix components and bioactive proteins at all phases of cutaneous wound healing and thereby essentially contribute to the successful reestablishment of skin integrity upon injury. As a consequence, disturbance of proteolytic activity at the wound site is a major factor in the pathology of chronic wounds. A large body of data acquired in many years of research provide a good understanding of how individual proteases may influence the repair process. The next challenge will be to integrate these findings and to elucidate the complex interactions of proteolytic enzymes, their inhibitors and substrates on a system-wide level. Here, we present novel approaches that might help to achieve this ambitious goal in cutaneous wound healing research. PMID- 21819270 TI - Disposition and metabolism of N,N-dimethylacetoacetamide in male F344 and Wistar Han rats and female B6C3F1 mice. AB - N,N-dimethylacetoacetamide (DMAAm) is a beta-dicarbonyl compound used as an industrial intermediate. This study investigated the disposition and metabolism of [14C]DMAAm in male rats and female mice. A single oral dose of [14C]DMAAm (target dose of 10 or 130 mg/kg) was administered to male F344 and Wistar-Han rats. [14C]DMAAm was almost completely absorbed and excreted in urine, with ca. 80-90% of the dose recovered within 24 h for both rat strains. Fecal excretion and CO2 exhalation were minimal (1 and 2%, respectively). Less than 3% of the dose remained in tissues at 24 h. There was no apparent dose- or strain-related difference in the disposition of [14C]DMAAm in rats. In female B6C3F1 mice administered 8 mg/kg [14C]DMAAm, 80% of the administered radioactivity was recovered in urine and cage rinse in 24 h. Urinary metabolites were isolated and characterized by liquid chromatography /mass spectrometry following oral administration of 435 mg/kg [(14C]DMAAm in male F344 rats. Metabolism occurred via reduction of the 3-keto group and oxidation of the N-methyl groups, to give N,N-dimethyl-3-hydroxybutanamide, N-methyl-N-hydroxymethyl-3-hydroxybutanamide, and N-hydroxymethyl-3-hydroxybutanamide, and N-demethylation to give N monomethylacetoacetamide (MMAAm). PMID- 21819271 TI - Migraine prophylactic drugs - something new under the sun? AB - INTRODUCTION: The development of preventive treatments for migraine has lagged behind, in part because of limited knowledge about the primum movens of attacks. AREAS COVERED: We aimed to make a status report about newer preventive drugs for migraine, mainly by reviewing ongoing studies and their potential mechanism of action. An overview of published and unpublished trials was obtained from electronic databases focusing on randomized controlled trials (RCTs) published or initiated during the last 3 years. Drugs inhibiting cortical spreading depression and calcitonin gene-related peptide antagonist, which mainly acts vasoconstrictive, seem promising, but need further exploration. The use of nitric oxide blockers and drugs modifying excitatory brain activity such as glutamate antagonists and newer antiepileptics have so far not been successful. Drugs such as melatonin, vitamin E and botulinum toxins aiming for other targets seem to have no or marginal effect. EXPERT OPINION: The results from Phase II studies with newer prophylactic drugs for migraine targeting binding sites in the brain are conflicting, but they may have potential for clinical use. No major breakthrough in migraine prevention can be expected from the ongoing trials, but further insight into the effect on migraine subtypes is anticipated. PMID- 21819272 TI - Vorapaxar: a novel protease-activated receptor-1 inhibitor. AB - INTRODUCTION: Platelet activation and reactivity are pivotal for both acute and chronic atherothrombotic event occurrences. AREAS COVERED: Only 20% relative risk (~ 2% absolute risk) reduction associated with newer P2Y(12) receptor blocker therapy such as prasugrel and ticagrelor compared with clopidogrel indicates that dual antiplatelet therapy may be associated with a ceiling effect in attenuating platelet-mediated ischemic event occurrence and that residual ischemic event occurrences are mediated by other pathways that are unblocked by current antiplatelet therapy. Therefore, inhibition of the thrombin-protease-activated receptor (PAR)-1 interaction may provide additional benefits in attenuating ischemic event occurrence in selected patients. There are two major PAR-1 blockers are under investigations - vorapaxar and atopaxar. In preclinical and Phase I - II studies, inhibition of thrombin-mediated platelet activation by a PAR-1 inhibitor, in general, has added to the antithrombotic efficacy of aspirin and clopidogrel without increasing bleeding. However, intracranial hemorrhage in patients with a history of stroke associated with vorapaxar and hepatic toxicity associated with atopaxar are important concerns. EXPERT OPINION: At this time, the specific role of PAR-1 inhibitor in the settings of percutaneous coronary intervention and acute coronary syndrome, both during the acute setting and as a long-term therapeutic agent, is not clear. Although the PAR-1 inhibitors are associated with less bleeding, its effectiveness as an antithrombotic agent and also side effects are major concerns. Future large-scale trials with goals addressing these concerns are needed to define the specific role of PAR-1 receptor inhibitor. PMID- 21819273 TI - New approaches to combining pharmacotherapy and psychotherapy for posttraumatic stress disorder. AB - INTRODUCTION: Posttraumatic stress disorder (PTSD) is a complex disorder associated with an intricate biological and psychological symptom profile and various common comorbidities. Despite an existing myriad of evidence-based and experimental treatments, PTSD is often difficult to treat. This reality necessitates a discussion of the potential of emerging treatments. AREAS COVERED: A literature search using PubMed and PsychInfo was done using the following keywords: randomized clinical trials, treatment guidelines, pharmacotherapy and psychotherapy, all in addition to PTSD. A comprehensive treatment review establishes that early intervention approaches have not yet been found to prevent PTSD in trauma survivors. However, psychotherapy research provides substantial support for cognitive behavioral therapies and eye movement desensitization and reprocessing for chronic PTSD, and psychopharmacological approaches are myriad - although at present there is FDA approval only for sertraline and paroxetine. However, the efficacy of these treatments varies and, unfortunately, not everyone will achieve remission. EXPERT OPINION: So far, the mental health field has tended to focus on either biological or psychological targets. We propose that maximizing treatment success may require an integrated approach that does not dichotomize biological and psychological aspects. Exciting new developments reflecting this perspective include psychopharmacologic augmentation strategies that enhance the mechanisms of psychotherapy. PMID- 21819274 TI - Vandetanib for the treatment of non-small-cell lung cancer. AB - INTRODUCTION: The use of targeted therapies in the treatment of advanced non small-cell lung cancer (NSCLC) is increasing, especially as conventional chemotherapy affords relatively small benefits at a cost of increased toxicity. Two of the more established therapeutic targets in NSCLC are the vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR). Vandetanib is an orally available inhibitor of VEGFR and EGFR signalling and is an attractive therapeutic agent owing to the simultaneous inhibition of both pathways. AREAS COVERED: This review encompasses the clinical efficacy, safety and tolerability of vandetanib in advanced NSCLC. Of particular interest are the randomized Phase III clinical trials, which did not show clinically significant overall survival benefit for vandetanib monotherapy or in combination with standard chemotherapy regimens. EXPERT OPINION: Vandetanib has anti-tumour activity in NSCLC, with improved objective responses and disease control. However, significant survival benefits were not demonstrated in Phase III clinical trials and at present vandetanib is not in further development for use in NSCLC. PMID- 21819275 TI - Varenicline for smoking cessation intervention in chronic obstructive pulmonary disease. AB - INTRODUCTION: In smoking-related chronic obstructive pulmonary disease (COPD), smoking cessation was previously demonstrated to reduce lung function decline and disease morbidity if it resulted in a sustained tobacco abstinence. Varenicline is a newer pharmacologic therapeutic agent able to reduce withdrawal symptoms in smokers, and this makes it particularly valuable in inducing abstinence in patients with significant addiction. AREAS COVERED: This paper discusses the results of a randomized, placebo-controlled study evaluating the effects of a smoking cessation intervention including varenicline in patients with COPD. EXPERT OPINION: Varenicline can be an appropriate aid to maintaining smoking abstinence in patients with COPD and heavier nicotine addiction, and the documentation of the long-term effects of a smoking cessation intervention that includes this pharmacologic therapeutic agent is necessary. PMID- 21819276 TI - Cognitive aging and flight performances in general aviation pilots. AB - Unlike professional pilots who are limited by the FAA's age rule, no age limit is defined in general aviation. Our overall goal was to examine how age-related cognitive decline impacts piloting performance and weather-related decision making. This study relied on three components: cognitive assessment (in particular executive functioning), pilot characteristics (age and flight experience), and flight performance. The results suggest that in comparison to chronological age, cognitive assessment is a better criterion to predict the flight performance, in particular because of the inter-individual variability of aging impact on cognitive abilities and the beneficial effect of flight experience. PMID- 21819277 TI - Factorial validity of the Behavior Rating Inventory of Executive Function (BRIEF) Teacher form. AB - Deficits in executive function (self-regulatory mechanisms) have been linked with many childhood disorders including attention deficit/hyperactivity disorder (ADHD), autism spectrum disorder, and conduct disorder. Executive functioning is typically assessed by individually administering performance-based measures in a clinical setting. However, performance-based methods are inefficient for school psychologists. A more feasibly implemented measure for applied settings is the Behavior Rating Inventory of Executive Function (BRIEF), but researchers have raised questions about the internal validity and the proposed factors. In this study, we examined the factor structure of the teacher form of the BRIEF in a sample of 2,044 general education elementary students and 131 teachers in a multilevel design. Results revealed support for a model with three factors at Level 1 and one general factor at Level 2. The results of our study do not support the current two-factor model of the published BRIEF protocol. PMID- 21819278 TI - On the joint effects of repetition and stimulus quality in lexical decision: looking to the past for a new way forward. AB - Two experiments investigated the joint effects of stimulus quality and repetition in the context of lexical decision. Experiment 1 yielded an interaction between repetition and stimulus quality for words (but additive effects for nonwords) when the lag was short, replicating previous reports. Experiment 2, with a much longer lag than Experiment 1, yielded main effects of stimulus quality and repetition, but these factors no longer interact. The joint effects of stimulus quality and repetition for words as a function of lag can be understood in terms of two loci for repetition effects: one short-term and one long-term. The transient effect of repetition is on activation levels in the lexicons (and in which the input lexicon, but not beyond, is affected by stimulus quality), whereas the long-term effect is on the strength of two-way connections between lexical-lexical and lexical-semantic modules. These data and others, taken together with the account, provide a new way of thinking about a 30-year-old conundrum. PMID- 21819279 TI - Prepotent response inhibition predicts treatment outcome in attention deficit/hyperactivity disorder. AB - OBJECTIVE: Inhibition deficits, including deficits in prepotent response inhibition and interference control, are core deficits in ADHD. The predictive value of prepotent response inhibition and interference control was assessed for outcome in a 10-week treatment trial with methylphenidate. METHODS: Thirty-four children with ADHD (ages 8-12) received 10 weeks of methylphenidate treatment. At pretest prepotent response inhibition was assessed using the Stop-Signal Task; interference control was assessed using the Stroop Color-Word task. Methylphenidate was individually titrated to an optimal dose. Treatment outcome was assessed by parent- and teacher-rated ADHD behavior. RESULTS: Only stop signal reaction time of the Stop-Signal Task was a significant predictor of parent-rated levels of inattention and hyperactivity/impulsivity at outcome. Children with lower levels of inhibition showed worse outcome after 10 weeks of treatment, independent of medication dose. CONCLUSIONS: Low levels of prepotent response inhibition are associated with worse response to treatment with methylphenidate. Prepotent response inhibition may be an intermediate phenotypical predictor of treatment outcome. PMID- 21819280 TI - The need to explain. AB - How do reasoners deal with inconsistencies? James (1907) believed that the rational solution is to revise your beliefs and to do so in a minimal way. We propose an alternative: You explain the origins of an inconsistency, which has the side effect of a revision to your beliefs. This hypothesis predicts that individuals should spontaneously create explanations of inconsistencies rather than refute one of the assertions and that they should rate explanations as more probable than refutations. A pilot study showed that participants spontaneously explain inconsistencies when they are asked what follows from inconsistent premises. In three subsequent experiments, participants were asked to compare explanations of inconsistencies against minimal refutations of the inconsistent premises. In Experiment 1, participants chose which conclusion was most probable; in Experiment 2 they rank ordered the conclusions based on their probability; and in Experiment 3 they estimated the mean probability of the conclusions' occurrence. In all three studies, participants rated explanations as more probable than refutations. The results imply that individuals create explanations to resolve an inconsistency and that these explanations lead to changes in belief. Changes in belief are therefore of secondary importance to the primary goal of explanation. PMID- 21819281 TI - The subjective visual vertical in patients with pusher behaviour: a pilot study with a psychophysical approach. AB - Pusher behaviour (PB) reflects some misrepresentation of verticality. However, its neural mechanisms are still unclear. The aim of this pilot study is to assess the perception of the subjective visual vertical in patients with PB using an orientation discrimination task relying on a psychophysical forced-choice procedure. A sample of eight patients with post-stroke hemiplegia, three of whom with (PB+ group) and five without (PB- group) a clear PB, and 10 matched healthy subjects, was selected. All participants were assessed with an orientation discrimination task based on the objective Two-Alternatives Forced Choice (2AFC) procedure, in which observers are forced to report whether an oriented stimulus that was tilted off-vertical by a varying amount (but never vertical) was tilted clockwise or counterclockwise from vertical. Participants' ability in detecting the visual vertical was estimated by calculation of bias and threshold, which represent deviations of the subjective vertical from the physical vertical and the sensitivity to orientation offsets away from vertical, respectively. While there were no significant differences between groups in terms of bias, statistical analysis showed a significantly higher threshold in the PB+ group compared to both PB- and control groups. Results suggest that vertical misrepresentation might be due to the presence, in patients with PB, of a lower signal-to-noise ratio in coding systems. Implications for clinical practice are discussed. PMID- 21819282 TI - Hyperemesis gravidarum: pathogenesis and the use of antiemetic agents. PMID- 21819283 TI - Current treatment for nonalcoholic fatty liver disease. PMID- 21819285 TI - Aluminum toxicokinetics in peritoneal dialysis patients. AB - CONTEXT: Despite the risk of aluminum (Al) toxicity in dialysis patients, little is known about its toxicokinetics (TK) in this population. A national contamination of dialysate solutions with Al provided the opportunity to study Al TK in peritoneal dialysis (PD) patients and to better understand the influence of covariates on its disposition. METHODS: Al levels in serum and dialysate as well as other laboratory values were collected prospectively from 83 PD patients after correction of Al contamination. Population TK analyses were conducted with NONMEM VI using standard model discrimination criteria. Covariate analyses were also performed using stepwise forward regression followed by backward deletion. RESULTS: After correction of Al exposure, serum levels declined in a biphasic manner, which was captured by the TK model. The TK of Al were best described by a 2-compartment model with linear elimination. Total creatinine clearance was a significant covariate for total clearance (CL). Mean parameter estimates for volume of central compartment (V1), CL, volume of peripheral compartment (V2), volume of distribution at steady-state (Vss), and intercompartmental clearance (Q) were 168 L, 8.99 L/day, 12 000 L, 12 168 L, and 4.93 L/day, respectively. Inter-individual variability for CL and V2 were 22.6 and 51.1%, respectively. Al distributional half-life was 8.5 days, while the terminal elimination half-life was 7.2 years. This model confirms that the large Vss reflects the widespread distribution of Al in bone, lungs, liver, and other tissues. CONCLUSION: This study describes the first population Al TK model in a large group of PD patients, which includes a covariate effect. The model confirms the extensive half-life and tissue distribution of Al in a dialysis-dependent population. PMID- 21819286 TI - Acetaminophen psi parameter: a useful tool to quantify hepatotoxicity risk in acute acetaminophen overdose. AB - CONTEXT: The risk of hepatotoxicity secondary to acute acetaminophen overdose is related to serum acetaminophen concentration and lag time from ingestion to N acetylcysteine (NAC) therapy. Psi (Greek letter psi) is a toxicokinetic parameter that takes the acetaminophen level at 4 h post-ingestion ([APAP](4 h)) and the time-to-initiation of NAC (tNAC) into account and was found to be significantly predictive of hepatotoxicity in Canadian patients with acetaminophen overdose treated with intravenous NAC. OBJECTIVE: We report the relationship of psi and hepatotoxicity in a Thai population with acute acetaminophen overdose. METHODS: This is a retrospective study of patients with acute paracetamol overdose during January 2004 to June 2009 at Siriraj Hospital. Patients were treated with the standard 21-h intravenous NAC regimen. Univariate analyses were performed with logistic regression to assess the relationships of psi, [APAP](4 h), and tNAC, and hepatotoxicity. RESULTS: A total of 127 patients were enrolled. The median (interquartile range; IQR) of [APAP](4 h) was 267.8 (196.0-380.0) mg/L. The median (IQR) of tNAC was 8.5 (6.2-12.0) h. Thirteen patients (10.2%) developed hepatotoxicity. Univariate analysis revealed [APAP](4 h), tNAC, and psi as statistically significant predictors of hepatotoxicity. DISCUSSION AND CONCLUSION: The psi parameter is a reliable prognostic tool to predict hepatotoxicity secondary to acute acetaminophen overdose treated with intravenous NAC. Our evidence shows that psi may be a more superior tool than either acetaminophen level or time-to-initiation of NAC at predicting hepatotoxicity. PMID- 21819287 TI - Review of the epidemiology and characteristics of intentional cyproheptadine overdose in Hong Kong. AB - OBJECTIVES: To identify the epidemiological characteristics and clinical outcome in patients who intentionally ingested cyproheptadine or cyproheptadine containing sleeping pills, and to investigate any association between dose ingested and reported adverse effects. METHOD: A retrospective study was performed based on data from the Hong Kong Poison Information Centre from July 2005 to December 2009. Fifty-seven eligible patients were recruited. Patients' epidemiological data, type and dose of cyproheptadine or cyproheptadine containing sleeping pills ingested, symptoms, clinical outcome, and length of stay in hospital were reviewed. RESULTS: The majority of patient with intentional overdose had no (42.1%) or mild (40.4%) sedative symptoms. Some 17% of patients developed anticholinergic symptoms, such as delirium, agitation, disorientation, and hallucination. The mean dose ingested was found to be significantly higher in patients who presented with delirium (188.6 mg) than those who were asymptomatic (49.8 mg) (p < 0.001). The time of symptom onset in all symptomatic patients was less than 6 h. CONCLUSIONS: The majority of patients with intentional cyproheptadine overdose had no or mild symptoms only. Patients who have ingested a significant amount of cyproheptadine are more prone to develop delirium. Patients who remain asymptomatic 6 h after exposure are unlikely to develop serious symptoms. PMID- 21819288 TI - Carbon monoxide poisoning associated with water pipe smoking. AB - The water pipe is a means of tobacco consumption widespread in Turkey and Arab countries. We present two patients brought to our emergency department due to a syncopal attack secondary to carbon monoxide toxicity following water pipe use. This rare form of poisoning should be borne in mind by emergency physicians as a differential diagnosis in water pipe smokers. Water pipes should be used where there is adequate ventilation. PMID- 21819289 TI - Intravenous fat emulsion therapy for intentional propafenone intoxication. PMID- 21819290 TI - Digital Holter measurement of QT prolongation in ziprasidone overdose. AB - OBJECTIVE: QT prolongation is an important complication in drug overdose, particularly with some antidepressants and antipsychotics. There are problems with the accurate measurement of the QT interval and determining for what QT interval patients should be monitored, because of the risk of torsades des pointes (TdP). We report a case of ziprasidone overdose with QT prolongation, demonstrating different methods of measuring the QT interval. CASE REPORT: A 47 year-old female presented after taking 1.2 g of ziprasidone and 250 mg of diazepam. She was taking propranolol and venlafaxine therapeutically. She developed bradycardia and QT prolongation (540 msec). She was transferred to a telemetry bed and observed for 48 h until her QT interval returned to normal (460 msec). QT intervals were extracted from (1) 12-lead digital Holter recordings (gold standard); (2) automated measurements on standard electrocardiograms (ECGs); and (3) manual measurements on standard ECGs, and compared on a QT versus time plot. An abnormal QT was determined based on the QT nomogram. Manual QT measurements showed a clear temporal association between ziprasidone overdose and a long QT, consistent with accurate QT measurements using continuous 12-lead Holter recordings with automatic QT measurements. However, standard automated measurements did not indicate an abnormal QT. CONCLUSIONS: Manual measurement of the QT interval appeared to be similar to the more accurate measurement of the QT by automated digital Holter recordings and better than standard automated measurements. Manual QT measurements would be more appropriate in clinical assessment of patients. PMID- 21819291 TI - High-dose insulin: a consecutive case series in toxin-induced cardiogenic shock. AB - CONTEXT: Cardiovascular medication overdoses can be difficult to treat. Various treatment modalities are currently recommended. OBJECTIVE: To describe patient outcomes and adverse events of high-dose insulin therapy in consecutive overdose patients in cardiogenic shock after implementation of a high-dose insulin protocol (1-10 U/kg/h, while avoiding or tapering off vasopressors). METHODS: This is an observational consecutive case series of patients identified from a registry. Data were collected by retrospective chart review of patients treated by our toxicology service with this protocol from February 2007 until March 2010. RESULTS: Twelve patients were treated with high-dose insulin. The mean age was 36.5 years (SD 11.7). Seven patients had pre-existing vasopressor therapy, and all were tapered off vasopressors while on insulin. Two patients experienced pulseless electrical activity cardiac arrest prior to high-dose insulin therapy. Intravenous fat emulsion was given to two patients. The mean maximum insulin infusion rate was 8.35 U/kg/h (mean = 8.35, SD 6.34). The mean duration of insulin infusion was 23.5 h (SD 19.7). The mean duration of glucose infusion post insulin was 25.2 h (SD 17.7). The primary toxins were beta-blocker in five, calcium channel blocker in two, combined beta-blocker/calcium channel blocker in two, tricyclic antidepressant in one, and polydrug in 2. CLINICAL OUTCOMES: Eleven of 12 patients survived. One patient expired 9 h into insulin therapy from cardiac arrest shortly after the insulin was stopped and a vasopressor re initiated (protocol deviation). ADVERSE EVENTS: Six patients experienced a total of 19 hypoglycemic events. Hypokalemia (defined as < 3.0 mEq/L) developed in eight patients. ADVERSE SEQUELAE: Necrotic digits occurred in one patient with known clotting disorder after receiving high-dose norepinephrine and INR reversal with fresh frozen plasma prior to insulin therapy. One patient was discharged with mild anoxic injury thought due to pulseless electrical activity arrest prior to insulin therapy. Three of these 12 patients have been previously described in published case reports. CONCLUSION: High-dose insulin therapy based on a 1-10 U/kg/h dosing guideline and recommending avoidance of vasopressors appears to be effective in the treatment of toxin-induced cardiogenic shock. Hypoglycemia was the most frequent adverse event, followed by hypokalemia. Adverse events did not lead to adverse sequelae. PMID- 21819292 TI - Dysgeusia following consumption of pine nuts: more than 3000 cases in France. AB - INTRODUCTION: In March 2008, French poison centres (PCs) recorded the first calls reporting persistent bitterness following the ingestion of pine nuts. METHODS: The French toxic exposure surveillance system (French-Tess) was searched and a descriptive analysis of cases was performed on data recorded from 13 March 2008 to 31 January 2010. RESULTS: Some 3111 cases of bitterness were reported to PCs. The number of cases rose sharply from May 2009 to reach a peak in August 2009 with 697 cases. The median time to onset of dysgeusia was 24 hours and it lasted less than 14 days in 95% of cases. Raw as well as cooked or processed pine nuts were implicated. DISCUSSION: The delayed onset and persistence of dysgeusia suggest that the toxin may act via an unknown toxic mechanism on the receptor. The aetiological agent could be an unidentified toxin present in some varieties of non-edible pine nuts. CONCLUSION: The high incidence of the event and the lack of understanding of the nature of the toxin and its pathophysiological mechanism require continued monitoring of poison cases, botanical and biochemical analysis, and experimental studies. PMID- 21819293 TI - A controlled evaluation of case clinical effect coding by poison center specialists for detection of WMD scenarios. AB - BACKGROUND: Many public health entities employ computer-based syndromic surveillance to monitor for aberrations including possible exposures to weapons of mass destruction (WMD). Often, this is done by screening signs and symptoms reported for cases against syndromic definitions. Poison centers (PCs) may offer significant contributions to public health surveillance because of their detailed clinical effect data field coding and real-time data entry. Because improper clinical effect coding may impede syndromic surveillance, it is important to assess this accuracy for PCs. METHODS: An AAPCC-certified regional PC assessed the accuracy of clinical effect coding by specialists in poison information (SPIs) listening to audio recordings of standard cases. Eighteen different standardized cases were used, consisting of six cyanide, six botulism, and six control cases. Cases were scripted to simulate clinically relevant telephone conversations and converted to audio recordings. Ten SPIs were randomly selected from the center's staff to listen to and code case information from the recorded cases. Kappa scores and the percentage of correctly coding a present clinical effect were calculated for individual clinical effects summed over all test cases along with corresponding 95% confidence intervals. The rate of the case coding by the SPIs triggering the PC's automated botulism and cyanide alerts was also determined. RESULTS: The kappa scores and the percentage of correctly coding a present clinical effect varied depending on the specific clinical effect, with greater accuracy observed for the clinical effects of vomiting and agitation/irritability, and poor accuracy observed for the clinical effects of visual defect and anion gap increase. Lack of correct coding resulted in only 60 and 86% of the cases that met the botulism and cyanide surveillance definitions, respectively, triggering the corresponding alert. There was no difference observed in the percentage of coding a present clinical effect between certified (9.0 years experience) and non-certified (2.4 years experience) specialists. There were no cases of coding errors that resulted in the triggering of a false positive alert. CONCLUSION: The success of syndromic surveillance depends on accurate coding of signs and symptoms. Although PCs generally contribute high quality data to public health surveillance, it is important to recognize this potential weak link in surveillance methods. PMID- 21819294 TI - Neuroprotective effects of Alpinia katsumadai against neuronal damage in the gerbil hippocampus induced by transient cerebral ischemia. AB - Alpinia katsumadai, one of the family Zingiberaceae, contains chalcone, flavonoids, diarylheptanoids, monoterpenes, sesquiterpenoids, stilbenes, and labdanes. It has been reported that the extract of Alpinia katsumadai seed (EAKS) has antiinflammatory effects, and enhances antioxidant activities. We observed the neuroprotective effects of EAKS against ischemic damage in gerbils received oral administrations of EAKS (50 mg/kg) once a day for 7 days before transient cerebral ischemia. In the EAKS-treated ischemia group, neuronal nuclei (NeuN, a marker for neurons)-immunoreactive pyramidal neurons were abundant (68.3% of the sham group) in the hippocampal CA1 region (CA1) 4 days after ischemia/reperfusion (I/R) compared to those in the vehicle-treated ischemia group (13.18%). We also observed that EAKS treatment significantly decreased the activation of astrocytes and microglia in the CA1 compared with the vehicle-treated ischemia group 4 days postischemia. In addition, protein levels of GFAP and Iba-1 in the EAKS-treated ischemia group were much lower than those in the vehicle-treated ischemia group 4 days after I/P. Our findings indicate that the repeated supplements of EAKS could protect neurons from an ischemic damage, showing that glial activation is markedly decreased in the ischemic area. PMID- 21819295 TI - Microscopic examination of stained cytospin preparations is a reliable method for the detection of calcium pyrophosphate crystals in synovial fluid. PMID- 21819296 TI - The identification of protein biomarkers for oxidative stress in Down syndrome. PMID- 21819298 TI - Glycopeptide microarray for autoantibody detection in cancer. AB - Evaluation of: Pedersen JW, Blixt O, Bennett EP et al. Seromic profiling of colorectal cancer patients with novel glycopeptide microarray. Int. J. Cancer 128(8), 1860-1871 (2011). Autoantibodies to cancer-associated antigens hold promise as sensitive biomarkers for cancer detection. Based on this hypothesis, and knowing that O-glycans on proteins constitute a source of possible epitopes recognized by autoantibodies, Pedersen and colleagues have generated a glycopeptide array displaying a comprehensive library of glycopeptides and glycoproteins derived from human mucins. The profiling of sera immunoreactivity of colon cancer patients allowed the identification of cancer-associated autoantibodies to various mucin (MUC)1 and MUC4 glycopeptides carrying aberrant glycosylation. This article provides evidence for the value of glycopeptides displaying cancer-associated glycans in diagnostic applications, and opens new avenues for the expansion to other protein glycoforms, as well as to further applications of such a microarray strategy for other post-translational modifications of proteins in the search for cancer biomarker. PMID- 21819299 TI - Identification and evaluation of a panel of serum biomarkers for predicting response to thalidomide in multiple myeloma patients. AB - Evaluation of: Rajpal R, Dowling P, Meiller J et al. A novel panel of protein biomarkers for predicting response to thalidomide-based therapy in newly diagnosed multiple myeloma patients. Proteomics 11(8), 1391-1402 (2011). Predicting response to thalidomide-based therapy remains a challenging task faced by clinicians in the treatment of multiple myeloma. The pioneering work reported by Rajpal et al. moves one step further towards solving this challenge. They developed a proteomics-based approach that combines immunodepletion, 2D difference gel electrophoresis analysis and mass spectrometry to search for serum proteins with expressions that show significant correlations to thalidomide treatment. This integrated approach allowed them to identify a panel of protein biomarkers. By using ELISA-based validation and strict statistical analysis, the authors have achieved an overall 84.0% predictive accuracy, with associated sensitivity and specificity values of 81.8 and 86.2%, respectively. Their methods and significant findings are reviewed within this article. This panel of biomarkers may not only guide initial therapy, but can also provide direct implications for personalized medicine in multiple myeloma patients. PMID- 21819300 TI - 'Proteomineering': has the mine been excavated? AB - Evaluation of: Di Girolamo F, Boschetti E, Chung MC, Guadagni F, Righetti PG. 'Proteomineering' or not? The debate on biomarker discovery in sera continues. J. Proteomics 74(5), 589-594 (2011). The combinatorial peptide ligand library in association with mass spectrometry can greatly enhance the dynamic range of the analysis of low- and very low-abundance proteins constituting the vast majority of species in any sample. When compared with untreated samples, the increment in detection of low-abundance species appears to be at least fourfold. Recently, the combinatorial peptide ligand library has been challenged; however, it has been clearly demonstrated in the evaluated paper that the protocols for elution of the captured polypeptides make the difference. Therefore, the solid-phase ligand library made of hexapeptides remains a promising and unique tool for biomarker discovery. PMID- 21819301 TI - Neurochemical dementia diagnostics in Alzheimer's disease: where are we now and where are we going? AB - Neurochemical dementia diagnostics (NDD) is a routine laboratory tool used in the diagnostic process for patients with neurodegenerative disorders, such as Alzheimer's disease. Currently, two groups of biomarkers analyzed in the cerebrospinal fluid are considered - namely amyloid-beta peptides and Tau proteins - along with the hyperphosphorylated forms of the latter (pTau). Current directions in the development of NDD include the following: search for novel biomarkers with improved analytical or diagnostic performance; optimization of the analysis of the biomarkers already available (e.g., by improved quality control and interlaboratory comparison of results); applications of novel technologies enabling better management of patient samples; and search for biomarkers in the blood. This article presents the state-of-the-art in the field of cerebrospinal fluid-based NDD, and also summarizes some of the hypotheses of how the future development of NDD tools might look. PMID- 21819302 TI - Proteomics to study the diversity and dynamics of proteasome complexes: from fundamentals to the clinic. AB - This article covers the latest contributions of proteomics to the structural and functional characterization of proteasomes and their associated proteins, but also to the detection of proteasomes as clinical biomarkers in diseases. Proteasomes are highly heterogenous supramolecular complexes and constitute important cellular proteases controlling the pool of proteins involved in key cellular functions. The comprehension of the structure/function relationship of proteasomes is therefore of major interest in biology. Numerous biochemical methods have been employed to purify proteasomes, and have led to the identification of complexes of various compositions - depending on the experimental conditions and the type of strategy used. In association with protein separation and enrichment techniques, modern mass spectrometry instruments and mass spectrometry-based quantitative methods, they have led to unprecedented breakthroughs in the in-depth analysis of the diversity and dynamics of proteasome composition and localization under various stimuli or pathological contexts. Proteasome inhibitors are now used in clinics for the treatment of cancer, and recent studies propose that the proteasome should be considered as a predictive biomarker for various pathologies. PMID- 21819303 TI - Challenges in plasma membrane phosphoproteomics. AB - The response to extracellular stimuli often alters the phosphorylation state of plasma membrane- associated proteins. In this regard, generation of a comprehensive membrane phosphoproteome can significantly enhance signal transduction and drug mechanism studies. However, analysis of this subproteome is regarded as technically challenging, given the low abundance and insolubility of integral membrane proteins, combined with difficulties in isolating, ionizing and fragmenting phosphopeptides. In this article, we highlight recent advances in membrane and phosphoprotein enrichment techniques resulting in improved identification of these elusive peptides. We also describe the use of alternative fragmentation techniques, and assess their current and future value to the field of membrane phosphoproteomics. PMID- 21819305 TI - Proteomics revisits the cancer metabolome. AB - Many cancer cells utilize aerobic glycolysis (also known as the 'Warburg effect'), instead of mitochondrial oxidative phosphorylation, to generate the energy necessary for diverse cellular processes. In tumor cells, mitochondria play more important roles in anabolism, for instance, de novo lipid biosynthesis and glutamine-dependent anaplerosis to fuel robust cell growth and proliferation. Proteomic analysis of tumor-related alterations of metabolism-associated proteins clearly indicates that such metabolic reprogramming contributes to cancer cell survival and cancer progression. Moreover, proteomics-based systems biology provides a powerful tool to re-evaluate the metabolic phenotype and regulatory mechanism associated with malignant cancer cells, and underscores their implications for cancer diagnosis and therapy. This article will address recent exciting advances in the understanding of cancer cell metabolism using proteomics based systems biology approaches. PMID- 21819304 TI - Unraveling pancreatic islet biology by quantitative proteomics. AB - The pancreatic islets of Langerhans play a critical role in maintaining blood glucose homeostasis by secreting insulin and several other important peptide hormones. Impaired insulin secretion due to islet dysfunction is linked to the pathogenesis underlying both Type 1 and Type 2 diabetes. Over the past 5 years, emerging proteomic technologies have been applied to dissect the signaling pathways that regulate islet functions and gain an understanding of the mechanisms of islet dysfunction relevant to diabetes. Herein, we briefly review some of the recent quantitative proteomic studies involving pancreatic islets geared towards gaining a better understanding of islet biology relevant to metabolic diseases. PMID- 21819306 TI - Differential proteomics in the search for biomarkers of radiotherapy resistance. AB - The individualization of radiotherapy treatment would be beneficial for cancer patients; however, there are no predictive biomarkers of radiotherapy resistance in routine clinical use. This article describes the body of work in this field where comparative proteomics methods have been used for the discovery of putative biomarkers associated with radiotherapy resistance. A large number of differentially expressed proteins have been reported, mostly from the study of novel radiotherapy-resistant cell lines. Here, we have assessed these putative biomarkers through the discovery, confirmation and validation phases of the biomarker pipeline, and inform the reader on the current status of proteomics based findings. Suggested avenues for future work are discussed. PMID- 21819308 TI - The effect of time, temperature and storage device on umbilical cord blood gas and lactate measurement: a randomized controlled trial. AB - OBJECTIVE: Umbilical cord blood gas analysis has a significant and growing role in early neonatal assessment. Factors often delay analysis of cord blood allowing values to change. Consequently, this study evaluates the impact of time, temperature and method of storage on umbilical blood gas and lactate analyses. METHODS: Umbilical cord segments from 80 singleton deliveries were randomized to: cords at room temperature (CR), cords stored on ice (CI), syringes at room temperature (SR) or syringes stored on ice (SI). Analysis occurred every 15 minutes for one-hour. Mixed model analysis of variance allowing for repeated measures was utilized. RESULTS: Cord arterial pH deteriorated in CR, CI, and SI within 15 minutes (p <= 0.001), with SR stable until 60 minutes (p = 0.002). Arterial pCO(2) remained stable in SR and CI, increased in SI (p = 0.002; 45 minutes) and decreased in CR (p < 0.001; 45 minutes). Arterial base excess deteriorated in CR and SI (p <= 0.009; 15 minutes), SR (p < 0.001; 30 minutes), and CI (p < 0.001; 45 minutes). Arterial lactate levels increased within 15 minutes in all groups (p < 0.001). CONCLUSIONS: Cord blood gas values change rapidly after delivery. Smallest changes were seen in SR group. Data suggest that analyses should be conducted as soon as possible after delivery. PMID- 21819309 TI - Associations between political/civic participation and HIV drug injection risk. AB - BACKGROUND: Participating in civic activities has been found to be related to positive health outcomes. OBJECTIVE: This study examines associations between injection drug use health variables (sharing paraphernalia, using shooting galleries) and political/civic engagement (identifying with any political party, attention paid to politics and being registered to vote). METHODS: Participants (N = 162) were recruited at 6 New York City (NYC) methadone programs as part of an HIV intervention (86% male). RESULTS: In the bivariate analysis, being registered to vote and political party identification were related to lower paraphernalia sharing; higher levels of attention paid to politics were associated with lower shooting gallery use. In the multivariate analysis, political party identification was associated with lower paraphernalia sharing and higher levels of attention paid to politics was related to lower shooting gallery use. CONCLUSIONS: Findings suggest that maintaining connections with mainstream civic activities can be related to reduced health risks, including HIV risk behaviors. SCIENTIFIC SIGNIFICANCE: This study contributes to understanding the relationships between involvement in civic/political participation and health, an area in which few studies have been conducted. PMID- 21819310 TI - A case study of haemoglobinopathy screening in the Netherlands: witnessing the past, lessons for the future. AB - OBJECTIVES: In 2007 neonatal screening (NNS) was expanded to include screening for sickle cell disease (SCD) and beta-thalassaemia. Up until that year no formal recommendations for haemoglobinopathy (carrier) screening existed in the Netherlands. Although it has been subject to debate in the past, preconceptional and prenatal haemoglobinopathy carrier screening are not part of routine healthcare in the Netherlands. This study aimed to explore the decision-making process of the past: why was the introduction of a screening programme for haemoglobinopathy considered to be untimely, and did ethnicity play a role given the history in other countries surrounding the introduction of haemoglobinopathy screening? DESIGN: A witness seminar was organised, inviting key figures to discuss the decision-making process concerning haemoglobinopathy screening in the Netherlands, thereby adding new perspectives on past events. The transcript was content-analysed. RESULTS: The subject of haemoglobinopathy screening first appeared in the 1970s. As opposed to a long history of neglect of African American health in the United States, the heritage of the Second World War influenced the decision-making process in the Netherlands. As a consequence, registration of ethnicity surfaced as an impeding factor. However, overall, official Dutch screening policy was restrained regarding reproductive issues caused by fear of eugenics. In the 1990s haemoglobinopathy screening was found to be 'not opportune' due to low prevalence, lack of knowledge and fear of stigmatisation. Currently the registration of ethnicity remains on the political agenda, but still proves to be a sensitive subject. DISCUSSION: Carrier screening in general never appeared high on the policy agenda. Registration of ethnicity remains sensitive caused by the current political climate. Complexities related to carrier screening are a challenge in Dutch healthcare. Whether carrier screening will be considered a valuable complementary strategy in the Netherlands, depends partly on participation of representatives of high-risk groups in policy making. PMID- 21819311 TI - Effect of Satureja khuzestanica essential oil on oxidative stability of sunflower oil during accelerated storage. AB - In this study, the application of various concentrations (0.02%, 0.04%, 0.06% and 0.08%) of Satureja khuzestanica essential oil (EO) was examined on the oxidative stability of sunflower oil and compared to butylated hydroxyanisole (BHA) during storage at 60 degrees C. Gas chromatography (GC) and GC-mass spectrometry analyses of the oils revealed that carvacrol (87.7%) was the major component of EO. Peroxide value and anisidine value measurements in sunflower oil showed that all concentrations of EO had antioxidant effects in comparison to BHA. Oil samples supplemented with EO concentration of 0.08% were the most stable during storage (p < 0.05). EO also was able to reduce the stable free radical 2, 2 diphenyl-1-picrylhydrazyl with a 50% inhibition concentration (IC50) of 31.5 +/- 0.6 ug mL-1. Therefore, the results indicate that EO could be used as a natural antioxidant in food lipids. PMID- 21819312 TI - Structural determination of two new triterpenoid saponins acylated with monoterpenic acid from Gymnocladus chinensis Baill. AB - Two new triterpenoid saponins acylated with monoterpenic acid, 2beta,23-dihydroxy 3-O-alpha-L-rhamnopyranosyl-21-O-{(6S)-2-trans-2,6-dimethyl-6-O-[3-O-(beta-D glucopyranosyl)-4-O-(2-methylbutanoyl)-beta-L-arabinopyranosyl]-2,7-octadienoyl) acacic acid 28-O-beta-D-xylopyranosyl-(1 -> 3)-beta-D-xylopyranosyl-(1 -> 4) [beta-D-glucopyranosyl-(1 -> 3)]-alpha-L-rhamnopyranosyl-(1 -> 2)-[alpha-L rhamnopyranosyl-(1 -> 6)]-beta-D-glucopyranosyl ester and 2beta,23-dihydroxy-3-O alpha-L-rhamnopyranosyl-21-O-{(6S)-2-trans-2,6-dimethyl-6-O-[4-O-((6S)-2-trans 2,6-dimethyl-6-O-(beta-L-arabinopyranosyl)-2,7-octadienoyl)]-beta-L arabinopyranosyl]-2,7-octadienoyl}-acacic acid 28-O-beta-D-xylopyranosyl-(1 -> 3) beta-D-xylopyranosyl-(1 -> 4)-[beta-D-glucopyranosyl-(1 -> 3)]-alpha-L rhamnopyranosyl-(1 -> 2)-[alpha-L-rhamnopyranosyl-(1 -> 6)]-beta-D-glucopyranosyl ester were isolated from the fruit of Gymnocladus chinensis Baill. and the structural elucidation of both the compounds was accomplished by extensive studies of their spectroscopic (1D and 2D NMR, TOF-MS, QFT-MS) and chemical methods. PMID- 21819313 TI - AIDS, religious enthusiasm and spiritual insecurity in Africa. AB - The connection between the AIDS epidemic and the efflorescence of religious 'enthusiasm' (construed in both classical and contemporary senses) in Africa in recent decades is best understood, this paper argues, by reference to a concept of 'spiritual insecurity'. The article offers a general description of the condition of spiritual insecurity and argues that it is best studied within a relational realist paradigm. The article presents a critique of the concept of 'belief' as commonly used in the social science of religion, arguing instead for an opening of the study of social relations to include the universe of relations within which people experience the world, including their relations with entities such as spiritual beings that might otherwise be considered virtual. PMID- 21819314 TI - Treatment of primary Sjogren's syndrome with anti-CD20 therapy (rituximab). A feasible approach or just a starting point? AB - INTRODUCTION: In vitro and in vivo experimental data have suggested new immunopathogenic mechanisms in primary Sjogren's syndrome (pSS). The availability of targeted treatment modalities has opened new ways to selectively target these mechanistic pathways in vivo. Amongst these new treatment modalities, monoclonal antibodies specific for the B-cell surface molecule CD20 have been shown to be the most promising treatment option to date. AREAS COVERED: A search of the Pubmed, MEDLINE, EMBASE, Cochrane and Ovid databases was performed to review literature on the efficacy and safety profile of anti-CD20 therapy in pSS patients. EXPERT OPINION: A single course of the chimeric humanized anti-CD20 antibody rituximab was effective in reducing disease activity in pSS patients for about six to nine months. Retreatment of responders resulted in a similar effect to initial treatment. When combined with corticosteroids during infusion, rituximab was shown to be a safe drug to administer. Thus, anti-CD20 therapy can be considered an effective treatment option in pSS patients. However, large randomized controlled trials with anti-CD20 therapy, for example rituximab, are warranted in order to: 1) assess long-term effects of such treatment, 2) determine which pSS patients will benefit most from anti-CD20 treatment and 3) assess which retreatment schedule should be followed. PMID- 21819315 TI - The influence of sunlight on the localized corrosion of UNS S31600 in natural seawater. AB - Tests were conducted on the performance of UNS S31600 stainless steel (SS) in a natural day/night cycle vs full darkness under conditions of natural marine biofilm accumulation. In quiescent flowing seawater tests in the laboratory as well as under natural immersion in the sea, diffuse sunlight (~10% of natural) counteracted the influence of marine biofilms and produced substantial inhibition of the corrosion of SS. Thus, the probabilities (percentage attack) and propagation rates (depths of attack) in multiple crevice tests were substantially lower in the day/night cycle than in the dark. A benefit was also observed for welded SS in terms of the time to corrosion initiation and the mass loss. SS in the passive state showed broader passive regions, well-defined breakdown potentials and markedly smaller anodic and cathodic current densities under the diurnal cycle. The overall reduction in corrosion is attributed to a combination of electrochemical photoinhibition and simultaneous photoinactivation of microbially mediated metal redox reactions linked to cathodic kinetics. These data offer fresh insights into the behaviour of SS under practical seawater situations and the proposed potential use of illumination in the mitigation of biologically influenced consequences. PMID- 21819316 TI - Preservation of residual renal function with limited water removal in hemodialysis patients. AB - Residual renal function (RRF) is of paramount importance for hemodialysis (HD) adequacy, morbidity, and mortality. Some studies have shown that overhydration is beneficial for preservation of RRF, but it can also increase the probability of adverse events such as hypertension and heart failure in HD patients. To determine the optimal amount of dehydration, we performed HD with limited water removal in HD patients. Eighteen HD patients included in this self-controlled study underwent HD with limited water removal. Water removal volume was determined by a previous volume as follows. Total water removal volume was divided into levels: <=3.0, 3.0-9.0, and >9.0 L per week. Water removal was performed to obtain dry weight in the last dialysis, and was performed three times with a ratio of 1:1:2 and 2:2:3, respectively. Urine volume, endogenous creatinine clearance rate, Kt/V, hemoglobin, and serum albumin were recorded before and after the study at 3, 6, 9, and 12 months. The follow-up period was 12 months. Ten patients withdrew from the study because of adverse events including hypertension (n = 3), heart failure (n = 3), angina (n = 1), polycystic kidney rupture (n = 1), obvious edema (n = 1), and one patient had too much interdialytic weight gain to continue. As a result, we stopped this study after 1 month. Our data suggest that the preservation of RRF with limited water removal in HD patients must be interpreted with caution. PMID- 21819317 TI - Takotsubo cardiomyopathy associated with peritonitis in peritoneal dialysis patient. AB - Takotsubo cardiomyopathy (TTC) is characterized by clinical and electrocardiographic features that mimic acute myocardial infarction, normal or mildly elevated cardiac enzymes, distinctive left ventricular wall motion abnormalities, and absence of significant obstructive coronary artery disease. Often there is a history of emotional stress and usually encountered in postmenopausal women. Excessive catecholamine stimulation plays an important role in the pathogenesis of TTC. Usually, this condition is reversible within several weeks to months. Only two cases of TTC were described in patients on hemodialysis. To our knowledge, we report the first case of TTC in peritoneal dialysis and the first case associated with peritonitis. PMID- 21819318 TI - Emerging pathways and future targets for the molecular therapy of pancreatic cancer. AB - INTRODUCTION: Pancreatic cancer treatment remains a challenge for clinicians and researchers. Despite undisputable advances in the comprehension of the molecular mechanisms underlying cancer development and progression, early disease detection and clinical management of patients has made little, if any, progress in the past 20 years. Clinical development of targeted agents directed against validated pathways, such as the EGF/EGF receptor axis, the mutant KRAS protein, MMPs, and VEGF-mediated angiogenesis, alone or in combination with gemcitabine-based standard chemotherapy, has been disappointing. AREAS COVERED: This review explores the preclinical rationale for clinical approaches aimed at targeting the TGF-beta, IGF, Hedgehog, Notch and NF-kappaB signaling pathways, to develop innovative therapeutic strategies for pancreatic cancer. EXPERT OPINION: Although some of the already clinically explored approaches (particularly EGFR and KRAS targeting) deserve further clinical consideration, by employing more innovative and creative clinical trial designs than the gemcitabine-targeted agent paradigm that has thus far invariably failed, the targeting of emerging and relatively unexplored signaling pathways holds great promise to increase our understanding of the complex molecular biology and to advance the clinical management of pancreatic cancer. PMID- 21819319 TI - Neonatal outcomes of successful VBAC among obese and super-obese mothers. AB - OBJECTIVE: We sought to evaluate neonatal morbidity and mortality among women who experienced successful vaginal births after previous cesarean delivery (VBAC) by obesity subtypes. METHODS: Missouri maternally linked cohort data files were utilized. Analyses were restricted to successful singleton VBACs. Main study outcomes were neonatal death and neonatal morbidity. Risk estimates were obtained using logistic and hazards regression modeling. RESULTS: A total of 30,017 singleton births met inclusion criteria. The prevalence of VBAC was 2.3%. The neonatal death rate (per 1000) by maternal obesity subtype was 4.1 for moderate, 3.2 for severe, 4.5 for extreme and 14.3 for super-obese. The overall risk for neonatal morbidity was 56% greater among obese women when compared with normal weight women, with risk estimates increased incrementally with ascending body mass index (BMI) (p for trend < 0.01). CONCLUSION: Infants of obese women undergoing successful VBAC are at elevated risk for neonatal morbidity, and the risk increases progressively with ascending BMI. PMID- 21819320 TI - Chronic hepatitis C infection and insulin resistance: two best friends. PMID- 21819321 TI - The BCG world atlas: a new, open-access resource for clinicians and researchers. PMID- 21819323 TI - Ceftaroline fosamil for treatment of community-acquired pneumonia: findings from FOCUS 1 and 2 and potential role in therapy. AB - Cephalosporins have been widely used over the last few decades (often as first line antibiotic therapy) for numerous infections, owing primarily to their broad spectrum of microbiologic activity and favorable safety profile. Current Infectious Diseases Society of America guidelines identify a third-generation cephalosporin in combination with a macrolide antibiotic as an option for treatment of hospitalized adult patients with community-acquired pneumonia (CAP) outside the intensive care unit setting. Although ceftriaxone is a frequently used agent for CAP, increasing incidence of multidrug-resistant Streptococcus pneumoniae and concerns regarding poor outcomes associated with ineffective therapy have prompted the search for a well-tolerated treatment alternative that is effective against bacteria that can cause CAP. Ceftaroline fosamil, the prodrug of ceftaroline, is a new extended-spectrum cephalosporin that exhibits time-dependant bactericidal activity against numerous Gram-negative and Gram positive organisms, including methicillin-resistant Staphylococcus aureus and penicillin-resistant S. pneumoniae. Notable exceptions include Pseudomonas spp. and Gram-negative organisms that produce extended-spectrum beta-lactamases or carbapenemases. Two large Phase III clinical trials (FOCUS 1 and 2) reported that ceftaroline fosamil was well tolerated, with a clinical cure rate of CAP that was noninferior to that with ceftriaxone in nonintensive care unit adult inpatients with moderately severe (Pneumonia Outcomes Research Team score of III or IV) community-acquired pneumonia. PMID- 21819324 TI - Pathogenesis of influenza: virus-host interactions. AB - Since their inception in March 1972, Keystone Symposia on Molecular and Cellular Biology have brought together scientists from across the globe to discuss key biological topics. Now in its 40th year, it is a completely independent, nonprofit organization devoted solely to providing outstanding scientific conferences in all areas of the biological and biomedical sciences. Towards the end of May 2011, over 200 virologists and immunologists came to Hong Kong, an appropriate setting given the emergence of H5N1, to discuss influenza virus and host interactions. The meeting, expertly organized by Siamon Gordon (University of Oxford, Oxofrd, UK), Malik Peiris (University of Hong Kong, Hong Kong, China) and Kanta Subbarao (NIAID, NIH, MD, USA), took place in the aftermath of the first pandemic in 40 years and provided great insight into both pandemic H1N1 and H5N1. This article focuses on some of the recurring themes that were discussed during the week. PMID- 21819325 TI - New insights into pathogen recognition. AB - The Society for General Microbiology (SGM) Spring Conference covers a range of topics of microbiology and comprises mixed sessions including symposia, workshops, debates, offered papers and invited presentations from international experts. This year the SGM Conference was held 11-14 April 2011 at the Harrogate Conference Centre in Harrogate, Yorkshire (UK). The main aim of the meeting is generally to provide a variety of programs that reflect current knowledge on different topics and introduce the recent advances in general and applied microbiology. Aspects of microbial recognition and interaction with the host immune response were addressed during a session of the meeting, where leaders in the field highlighted how the immune system is designed to recognize and destroy microorganisms by detecting microbial signature molecules (pathogen-associated molecular patterns) via interaction with specific receptors. This article focuses on the current research on pathogen recognition by the host through the interaction with surface structures present on microorganisms, with particular interest on the family of lectins, an emerging area in the understanding of infectious diseases. Discovering the mechanisms used by bacteria to survive in the host environment and at the same time elucidating the processes by which the immune system interacts with pathogens is vital for the development of vaccines and the design of new therapies. PMID- 21819326 TI - Guidelines for treatment of Helicobacter pylori in the East and West. AB - Infection with Helicobacter pylori remains a major healthcare burden, with persistently high prevalence rates, especially in less-developed countries. H. pylori infection is causally related to non-malignant and malignant gastroduodenal diseases, such as peptic ulcer diseases, gastric cancer and gastric mucosa-associated lymphoid tissue lymphoma. Current international guidelines recommend a standard triple therapy as first-line therapy, including a proton pump inhibitor and a combination of amoxicillin and clarithromycin. Standard triple therapy has shown a decreasing efficacy over the years. The main reason is the increasing antibiotic resistance, particular to clarithromycin of H. pylori strains. Several new treatment options or modifications of already established regimens have been introduced to overcome treatment failure. In this article, we intend to report the reasons for treatment failure, and furthermore we give an overview of new treatment options as alternatives to the current treatment regimens. Finally, the strategy for the future is considered. PMID- 21819327 TI - Screening strategies for discovery of antibacterial natural products. AB - Microbial-derived natural products have been a traditional source of antibiotics and antibiotic leads and continue to be effective sources of antibiotics today. The most important of these discoveries were made about 50 years ago. Chemical modifications of natural products discovered during those years continue to produce new clinical agents but their value is now, unfortunately, fading away owing to the exhaustion of opportunities of chemical modifications. The discovery of new natural antibiotics is directly linked to new screening technologies, particularly technologies that can help to eliminate the rediscovery of known antibiotics. In this article, we have reviewed the screening technologies from recent literature as well as originating from authors laboratories that were used for the screening of natural products. The article covers the entire spectrum of screening strategies, including classical empiric whole-cell assays to more sophisticated antisense based hypersensitive Staphylococcus aureus Fitness Test assays designed to screen all targets simultaneously. These technologies have led to the discovery of a series of natural product antibiotics, which have been summarized, including the discovery of platensimycin, platencin, nocathiacins, philipimycin, cyclothialidine and muryamycins. It is quite clear that natural products provide a tremendous opportunity to discover new antibiotics when combined with new hyper-sensitive whole-cell technologies. PMID- 21819328 TI - PCR for detection of respiratory viruses: seasonal variations of virus infections. AB - Real-time PCR and related methods have revolutionized the laboratory diagnosis of viral respiratory infections because of their high detection sensitivity, rapidness and potential for simultaneous detection of 15 or more respiratory agents. Results from studies with this diagnostic modality have significantly expanded our knowledge about the seasonality of viral respiratory diseases, pinpointed the difficulties to make a reliable etiologic diagnosis without the aid of an unbiased multiplex molecular assay for respiratory viruses, and revealed previously unknown details as to possible infections with multiple agents as aggravating factors. The scope of this article is to review and discuss this new knowledge and its implications for diagnostic strategies and other measures essential for the clinical management of respiratory viral infections and for epidemiological surveillance of seasonal respiratory infections. PMID- 21819329 TI - Primary prophylactic human papillomavirus vaccination programs: future perspective on global impact. AB - Of the 40 types of human papillomavirus that can infect the mucosal epithelium, four types can now be prevented using prophylactic vaccination. Two of these types (high-risk types 16 and 18) cause 70% of cervical cancers, a proportion of other genital cancers and a subset of head and neck cancers. The low-risk types 6 and 11 cause 90% of genital warts and the disease recurrent respiratory papillomatosis. Thus, if primary HPV vaccination programs can be implemented effectively, the potential for a reduction in global disease burden is great. This article considers the current issues and challenges in delivering primary HPV vaccination programs effectively and the likely impact of the vaccines in both the near and more distant future. PMID- 21819330 TI - Evaluation and management of hepatitis B virus infection in hematopoietic stem cell transplantation: before and after transplantation. AB - HBV infection remains a major global health problem and continues to be a common cause of liver-related morbidity and mortality in both immunocompetent and immunosuppressed individuals. Reactivation of HBV is a serious complication of chemotherapy/immunosuppressive therapy in patients with HBV infection. In this article, we aim to describe the diagnosis, prevention and management of HBV infection in allogeneic hematopoietic stem cell transplant candidates, from the pre- to post-transplant period. The data currently available suggest that all individuals with hemato-/onco-logical malignancies who undergo chemotherapy/immunosuppressive therapy should be screened for hepatotropic viruses such as HBV and HCV. HBV surface antigen-positive individuals who receive chemotherapy/immunosuppressive therapy are at considerable risk of HBV reactivation. Antiviral prophylaxis prevents HBV reactivation, decreases reactivation-related morbidity and mortality, and prevents interruptions in chemotherapy/immunosuppressive therapy in such individuals. The optimal duration of antiviral prophylaxis remains to be elucidated. The vaccination of HBV-naive recipients and their donors against HBV infection prior to transplantation plays an important role in preventing acquired HBV infection. The presence of hepatitis B surface antigen positivity is not an absolute contraindication for allogeneic hematopoietic stem cell transplantation. PMID- 21819331 TI - Surveillance and management of multidrug-resistant microorganisms. AB - Multidrug-resistant organisms are an established and growing worldwide public health problem and few therapeutic options remain available. The traditional antimicrobials (glycopeptides) for multidrug-resistant Gram-positive infections are declining in efficacy. New drugs that are presently available are linezolid, daptomicin and tigecycline, which have well-defined indications for severe infections, and talavancin, which is under Phase III trial for hospital-acquired pneumonia. Unfortunately the therapies available for multidrug-resistant Gram negatives, including carbapenem-resistant Pseudomonas aeruginosa, Acinetobacter baumannii and Enterobacteriaceae, are limited to only colistin and tigecycline. Both of these drugs are still not registered for severe infections, such as hospital acquired pneumonia. Consequently, as confirmed by scientific evidence, a multidisciplinary approach is needed. Surveillance, infection control procedures, isolation and antimicrobial stewardship should be implemented to reduce multidrug resistant organism diffusion. PMID- 21819332 TI - Progress and challenges in the discovery of macrofilaricidal drugs. AB - Control of human filarial infections currently depends on chemotherapeutic strategies predominantly directed at microfilariae. Doxycycline therapy in an extended daily dose regimen sterilizes and kills adult stages, but the utility of this drug for routine field use remains an issue of concern. No macrofilaricidal drugs with efficacy after one or two doses are available for use, delaying the achievement of the elimination or eradication of onchocerciasis and lymphatic filariasis. Moxidectin, a macrocyclic lactone, is currently in clinical trials for onchocerciasis. A few other drugs that have already been approved for use in veterinary practice or in human medicine for other indications are available for investigation. Early drug discovery pipelines are poorly populated and the process of macrofilaricide discovery and development remains highly challenging. In particular, the lack of convenient, validated animal models in an antifilarial drug discovery pathway is an unresolved issue. PMID- 21819337 TI - Unstimulated saliva 17beta-estradiol and xerostomia in menopause. AB - One of the most common oral manifestations of menopause is xerostomia. As gingival tissue is sensitive to changes in the female sex steroids; the aim of this study was to evaluate the relationship between saliva 17beta-estradiol and severity of xerostomia. A case-control study was carried out in 64 selected menopausal women aged 42-75 years with or without xerostomia (32 as case and 32 as control) conducted at the Clinic of Oral Medicine, Tehran university of medical sciences. Xerostomia inventory (XI) score was used as an index of xerostomia severity. The saliva 17beta-estradiol was measured by an enzyme immunoassay kit. The mean unstimulated saliva flow rate and concentration of 17beta-estradiol were significantly lower in case than control. There were significant negative correlation between XI score and unstimulated whole saliva flow rate and also concentration of 17beta-estradiol in menopausal women. It seems that there is a negative correlation between xerostomia severity and saliva 17beta-estradiol in menopausal women. PMID- 21819338 TI - Effects of obstructive sleep apnea and gastroesophageal reflux disease on asthma control in obesity. AB - BACKGROUND: Obesity is a risk factor for asthma. Obese asthmatics often have poor asthma control and respond poorly to therapy. It has been suggested that co morbidities associated with obesity, such as reflux and obstructive sleep apnea, could be important factors contributing to poor asthma control in obese patients. OBJECTIVES: The purpose of this study was to determine if (1) reflux and/or (2) symptoms of sleep apnea contribute to poor asthma control in obesity. METHODS: We studied asthmatic subjects participating in a trial of reflux treatment. Participants underwent baseline evaluation of asthma symptoms and lung function. Overall 304 participants underwent esophageal pH probe testing; 246 participants were evaluated for obstructive sleep apnea symptoms. RESULTS: Of 402 participants in this trial, 51% were obese. Role of reflux in asthma control. Those with higher body mass index (BMI) reported a higher prevalence of reflux symptoms, but the prevalence of pH probe acid reflux was similar in all groups. Reflux was not associated with measures of asthma control in obese patients. Role of obstructive sleep apnea in asthma control. Symptoms and self-report of obstructive sleep apnea were more common with increasing BMI and associated with worse asthma control as measured by the Juniper Asthma Control questionnaire and Asthma Symptom Utility Index. CONCLUSIONS: Our data suggest that obstructive sleep apnea, but not gastroesophageal reflux disease, may contribute significantly to poor asthma control in obese patients. PMID- 21819339 TI - Growth charts of fetal biometry: a longitudinal study. AB - OBJECTIVE: The aim of this study was to construct reference charts for fetal biometry in Karachi, Pakistan. METHODS: This was a prospective longitudinal study involving 1228 women with singleton pregnancies. Biparietal diameter, head circumference, abdominal circumference and femur length were measured repeatedly until delivery. Regression analysis and multilevel modeling was used to construct charts. RESULTS: The mean age of the women in this study was 28.0 years with standard deviation of 4.6. For each gestational age percentiles were calculated and charts were then constructed. CONCLUSION: Our reference percentiles for fetal biometry measurements are the first of their kind in Karachi, Pakistan. They will not only help us in the diagnosis and management of fetal growth restriction but will provide the basis to develop charts at the national level. PMID- 21819340 TI - Arriving now at the crossroads of technology: sex and gender differences in COPD. PMID- 21819341 TI - Separation anxiety disorder increases among neonatal intensive care unit graduates. AB - AIM: To evaluate whether separation anxiety disorder (SAD) develops in the later life of the infants, who were separated from their mothers in relation to being in neonatal intensive care unit (NICU). METHODS: A group of 57 children, ages over 6 years old who were cared in NICU has been evaluated retrospectively by using the SAD diagnostic scale which is adapted according to DSM-IV. Another age and sex matched 50 children who admitted to the outpatient unit were selected as control group. RESULTS: We found that the scores and incidence of SAD were increased among children who were cared in the NICU and both were correlated with the duration of stay in the NICU. CONCLUSION: The NICU should be arranged to support the development of the baby. Families should be informed about the necessity of sustaining an early mother-infant interaction. By supporting mother infant interaction, it will be provided that the baby will establish a more secure relation with his/her mother, develop more healthy and have less behavior problems in the future life. PMID- 21819342 TI - The impact of severe hyperemesis gravidarum on the triple test screening results. AB - OBJECTIVE: we aimed to determine the influence of severe hyperemesis gravidarum on the interpretation of the triple test screen results. METHODS: A retrospective, case control study. The study group included 73 women who were hospitalized due to severe hyperemesis gravidarum and data regarding triple screening test was available. Data was compared with a control group consisting of low-risk patients without hyperemesis gravidarum, who underwent the triple screening test in the same laboratory and matched to the study group by maternal age and gestational age at the time of screening in a 2:1 ratio. RESULTS: Overall, 219 gravid patients were included in the study, of whom 73 were diagnosed with severe hyperemesis gravidarum. Patients in the control group were characterized by higher weight at the time of triple test screen (53.7 +/- 10.9 vs. 59.7 +/- 14.3 years, p = 0.043). No difference was found in the level of Alpha-fetoprotein or unconjugated estriol (uE3) between the groups; however the level of hCG was significantly increased in women with severe hyperemesis gravidarum (1.2977 +/- 0.82 vs. 1.0662 +/- 0.53 MoM, p = 0.013). CONCLUSION: Increase in the level of hCG in women with severe hyperemesis gravidarum alter the results of triple test screen. This data should be incorporated when counseling patients regarding overall risk for chromosomal abnormalities. PMID- 21819343 TI - Image in toxicology: Pseudo-subarachnoid hemorrhage in a case of severe valproic acid poisoning. AB - Pseudo-subarachnoid hemorrhage (PSAH) is a false-positive finding on cranial computed tomography (CT) in patients with cerebral edema. Its appearance on CT resembles subarachnoid hemorrhage despite the absence of subarachnoid blood. We report the finding of PSAH in a case of massive valproic acid overdose. PMID- 21819344 TI - OxLDL-mediated survival of macrophages does not require LDL internalization or signalling by major pattern recognition receptors. AB - Macrophages play a key role in the pathogenesis of atherosclerosis, in part by destabilizing plaques. We and others have shown that low concentrations of oxidized LDL (oxLDL) inhibit macrophage apoptosis. As oxLDL is present in lesions, this may be a mechanism by which macrophage populations in the intima are expanded. We have previously shown that oxLDL activates prosurvival signalling pathways such as the phosphoinositide 3-kinase (PI3K) pathway in bone marrow derived macrophages (BMDMs). However, little is known about more upstream signalling events especially at the receptor level. The endocytic pattern recognition receptors (PRRs), scavenger receptor A (SR-A) and CD36, are the main receptors on macrophages for uptake of oxLDL and are therefore important in foam cell formation. The signalling PRRs such as toll-like receptor (TLR) 2 and 4 also bind some types of oxLDL. This study was done to determine if any of the known PRRs are required for the anti-apoptotic effects of oxLDL in BMDMs. To do this, we tested the effect of oxLDL on viability of BMDMs lacking both SR-A and CD36 or lacking TLR2, TLR4, CD14, FcgammaRIIb, or RAGE. Our results indicate that none of these receptors are essential for activating the oxLDL prosurvival pathway. Furthermore, we show that the anti-apoptotic effect is not dependent on the uptake of oxLDL. PMID- 21819345 TI - AIRE1A might be involved in cyclin B2 degradation in testicular lysates. AB - The autoimmune regulator gene Aire shows predominant expression in thymus and other immunologically relevant tissues, and is assigned the major function of programming autoreactive T-cell deletion. However, the expression of this gene in tissues outside the immune system raises a question about its possible function beyond the T-cell deletion dogma. We detected Aire in mouse testis, and the expression of AIRE protein was remarkably high in postmeiotic germ cells. Sequencing results indicate that testis expressed Aire variant 1a. AIRE could be detected in spermatozoa, with heavy localization on the principal acrosomal domains. Mouse oocytes stained negatively for AIRE before fertilization, but stained positively for AIRE 30 min after fertilization. In the zygote, the levels of AIRE correlated negatively with cyclin B2 levels. Goat testicular lysates spiked with recombinant human AIRE exhibited augmented cyclin B2 degradation in the presence of protease inhibitors, which was inhibited by MG-132, indicating the operation of proteasomal pathways. Thus, this study identifies a correlation between the presence of AIRE and proteasomal breakdown of cyclin B2, which leads us to speculate that cyclin B2 could be a target of AIRE's E3-ubiquitin ligase activity. PMID- 21819346 TI - The mitotic phosphorylation of p54(nrb) modulates its RNA binding activity. AB - The RNA-binding protein p54(nrb) is involved in many nuclear processes including transcription, RNA processing, and retention of hyperedited RNAs. In interphase cells, p54(nrb) localizes to the nucleoplasm and concentrates with protein partners in the paraspeckles via an interaction with the non-coding RNA Neat1. During mitosis, p54(nrb) becomes multiphosphorylated and the effects of this modification are not known. In the present study, we show that p54(nrb) phosphorylation does not affect the interactions with its protein partners but rather diminishes its general RNA-binding ability. Biochemical assays indicate that in vitro phosphorylation of a GST-p54(nrb) construct by CDK1 abolishes the interaction with 5' splice site RNA sequence. Site-directed mutagenesis shows that the threonine 15 residue, located N-terminal to the RRM tandem domains of p54(nrb), is involved in this inhibition. In vivo analysis reveals that Neat1 ncRNA co-immunoprecipitates with p54(nrb) in either interphase or mitotic cells, suggesting that p54(nrb)-Neat1 interaction is not modulated by phosphorylation. Accordingly, in vitro phosphorylated GST-p54(nrb) still interacts with PIR-1 RNA, a G-rich Neat1 sequence known to interact with p54(nrb). In vitro RNA binding assays show that CDK1-phosphorylation of a GST-p54(nrb) construct abolishes its interaction with homoribopolymers poly(A), poly(C), and poly(U) but not with poly(G). These data suggest that p54(nrb) interaction with RNA could be selectively modulated by phosphorylation during mitosis. PMID- 21819347 TI - Effect of birth season on circadian typology appearing in Japanese young children aged 2 to 12 years disappears in older students aged 18 to 25 years. AB - Several studies suggest that season of birth differentially affects the physiological characteristics of humans. Those living at relatively high latitude, such as Canada, Spain, and Italy (44 degrees N-45 degrees N), and born in the fall tended to be "morning-type" persons in comparison to those born in other seasons. There are relatively little data on the affect of season of birth on people residing at low latitude. Here the authors show that at low latitude, Kochi, Japan (33 degrees N), the effect of season of birth on the morningness chronotype is confined to young children aged 1-12 yrs, disappearing in elderly persons. Only female participants aged 2-12 yrs born in the fall, especially in November, were significantly morning-typed (p < .001) in comparison to those born in the other seasons, whereas there were no such significant season-of-birth differences in morningness-eveningness preference among male participants. Moreover, both female and male participants aged 13-25 yrs showed no significant seasonal differences in morningness-eveningness preference. The small effects detected in this study might be due to smaller seasonal change in day length at the relatively lower latitude of Kochi. PMID- 21819348 TI - Workplace-related smoking in New South Wales: extent of bans, public attitudes and relationships with relapse. AB - ISSUE ADDRESSED: Little research has examined issues surrounding employee smoking outside smoke-free workplaces. The study's aims were to: 1) document the proportion of NSW indoor employees covered by total workplace smoking bans; 2) examine community perceptions of employee smoking during working hours; 3) identify the characteristics of having a supportive attitude toward tobacco control in the workplace; and 4) describe relationships between smoking relapse and workplace-related smoking. METHODS: Two cross-sectional, computer-assisted telephone interview surveys of randomly selected adults were conducted. Consent rates were 49.1% in 2004 and 45.8% in 2006, with sample sizes of 1,158 and 2,393 respectively. RESULTS: Total workplace bans were reported by 92.9% of indoor employees. Community attitudes to smoking in working hours were highly negative: 77.7% agreed smoking breaks waste too much time and 85.1% opposed smoking near workplace doorways. Being female, born in Australia and a non-smoker were associated with more negative attitudes. A higher proportion of smokers (78.3%) perceived smoking was more common outside their place of work or study than at five other locations: rail/bus stop (60.2%), friends' houses (59.3%), own street (35.2%), parks (34.3%), and outside school (22.6%). Of smokers making a quit attempt in the past year, 42.1% relapsed at home, 22.1% at licensed premises and 18.7% at work. CONCLUSIONS: Findings emphasise the low support for smoking during or near work. Smoking outside workplaces is highly visible. Data on relapse suggest a modest relationship with workplace-related smoking. PMID- 21819349 TI - Tobacco and alcohol sponsorship of sporting events provide insights about how food and beverage sponsorship may affect children's health. AB - ISSUE ADDRESSED: Determining children's exposure to food and beverage company sponsorship, and the effect of this exposure, is important in establishing the extent to which there may be health and societal consequences. This paper aimed to provide preliminary evidence on the scope and potential effects on children of unhealthy food and beverage sponsorship. METHODS: A review of published literature and media and marketing reports was conducted to determine the types of food and beverage sponsorship campaigns that children are exposed to, and the effect of corporate sponsorship (including tobacco and alcohol) on children and adolescents. RESULTS: A large range of food and beverage sponsorship activities, in Australia and internationally, were identified for both school and sport settings. In particular, food and beverage companies have attempted to develop a marketing presence at all levels of professional and community sport. No information was identified measuring the effect of food and beverage company sponsorship on children and adolescents. However, empirical evidence from consumer studies relating to tobacco and alcohol sponsorship has repeatedly demonstrated that sponsorship has an impact on children's product recall and product-related attitudes and behavioural intentions. CONCLUSIONS: While there is no available research on the direct effect of food and beverage sponsorship, the demonstrated effects of tobacco and alcohol sponsorship on children's product awareness, preferences and consumption are likely to be applicable to food companies. PMID- 21819350 TI - Environmental sun protection and supportive policies and practices: an audit of outdoor recreational settings in NSW coastal towns. AB - ISSUES ADDRESSED: The results of a sun protection audit of outdoor recreational environments in three NSW coastal towns. METHODS: Thirty public swimming pools, beaches, sports grounds and skate parks were visited at two time points before and after summer (October 2009 and April 2010) and audited for the availability of sun protection, supportive polices and signage. RESULTS: There was insufficient shade in more than half (58%) of the observed sites at sports grounds, 49% of areas at beaches and 40% of areas at skate parks with most of these sites relying on natural shade (47-58%). Although pools were more likely to have shade available over most of the observed areas (36%) and permanent shade structures (75%), no shade was observed over any main outdoor pools. Similarly, there was only shade available over one of the main sporting grounds, one main beach and none of the main skate ramps. For other types of sun protection, sunscreen was the most popular product available either for free (nine sites) or for sale (eight sites). All pools had at least one supportive sun protection policy but only two of the total 30 sites had any related signage. CONCLUSIONS: This study demonstrates recent findings in relation to the accessibility of sun protection in these settings and the need for health promoting organisations to support and engage councils to invest in more sun protection strategies. The areas of focus should be shade provision particularly at beaches, skate parks and sports grounds; extending the availability of other types of sun protection; and introducing related policies and signage in more sites. PMID- 21819351 TI - Swimsuit issues: promoting positive body image in young women's magazines. AB - ISSUE ADDRESSED: This preliminary study reviews the promotion of healthy body image to young Australian women, following the 2009 introduction of the voluntary Industry Code of Conduct on Body Image. The Code includes using diverse sized models in magazines. METHOD: A qualitative content analysis of the 2010 annual 'swimsuit issues' was conducted on 10 Australian young women's magazines. Pictorial and/or textual editorial evidence of promoting diverse body shapes and sizes was regarded as indicative of the magazines' upholding aspects of the voluntary Code of Conduct for Body Image. RESULTS: Diverse sized models were incorporated in four of the seven magazines with swimsuit features sampled. Body size differentials were presented as part of the swimsuit features in three of the magazines sampled. Tips for diverse body type enhancement were included in four of the magazines. All magazines met at least one criterion. One magazine displayed evidence of all three criteria. CONCLUSION: Preliminary examination suggests that more than half of young women's magazines are upholding elements of the voluntary Code of Conduct for Body Image, through representation of diverse sized women in their swimsuit issues. PMID- 21819352 TI - An ethnographic process evaluation of a community support program with Sudanese refugee women in western Sydney. AB - ISSUE ADDRESSED: Through the humanitarian entrant program, a rapidly growing community of Sudanese refugees are resettling in Australia. Although the impact of pre-migration trauma upon refugee mental health is well established, there is a paucity of research exploring the impact of post-migration sociocultural factors. Women are often the most marginalised, which affects their mental health and ability to adjust in resettlement. METHODS: An ethnographic study was conducted to evaluate a Sudanese women's group exercise program designed from a community development strengths-based model. Qualitative analysis of a group interview and ethnographic process evaluation techniques enabled a deeper understanding of the perspectives of Sudanese women in Australia and their resettlement difficulties and needs. RESULTS: Participants (n=12) viewed the program positively due to educational components and the opportunity for respite. Transport and childminding support were seen as vital. Interview and evaluation processes were perceived as ineffectual. Key stressors raised include: acculturation, housing difficulties, developing language skills, lack of employment opportunities and family separation. CONCLUSION: It is vital that any attempts to address these issues are sustainable, aiming to empower the women and promote their existing strengths and resilience techniques. Research specific to cultural and ethnic groups of refugee women in an Australian context enables tailoring of appropriate support services, but can be tiresome for participants. PMID- 21819353 TI - Using an online service for breastfeeding support: what mothers want to discuss. AB - ISSUE ADDRESSED: There is little research on how the establishment and maintenance of breastfeeding and other early parenting skills is assisted by the use of electronic peer support groups. In what ways do parents use a popular peer moderated online resource and what topics do they choose to discuss? The objective of this study was to identify and quantify the main uses of an electronic discussion board hosted by a prominent Australian lay breastfeeding advocacy organisation. METHODS: Three consecutive days of conversations on the discussion board were followed. Using content analysis, the messages were coded and analysed statistically for the ways the board was used and which topics were and were not present. RESULTS: The discussion board almost universally gave emotional support to the participants and most users expressed their emotions in their messages. The giving of factual advice or opinions was a much less frequent use of the discussion board as was the clear seeking of emotional support and general facts or advice. The range of topics discussed was dominated by general parenting followed by various breastfeeding topics as well as much discussion related to general social support. CONCLUSIONS: The lay-moderated discussion board can be a worthwhile resource for parents in need of reassurance, information or general social support. It may also be useful to expand the amount of breastfeeding and parenting information available on the organisation's main website. PMID- 21819354 TI - Implications of participation and equality in the research process for health promotion practice: domestic violence as an example. AB - ISSUE ADDRESSED: Contemporary health promotion is underpinned by a philosophy of participation and working with communities to build strength and capacity. This article adds to literature, describing how this is operationalised in health promotion research. METHODS: The operationalisation of participation and equality in a participatory action research (PAR) project examining domestic violence in five communities from an African refugee background, post settlement in Perth (Ethiopia, Liberia, Sierra Leone, Somalia and Sudan) is described. The qualitative research undertaken included 78 participants: 54 from the five communities and 24 from health and support agency staff who provide services to them and utilised in-depth interviews and focus groups. RESULTS: Ongoing participation by community members and equality within stakeholder relationships was facilitated by the project being community-initiated, the crystallisation of strong stakeholder relationships, data collection by trained bicultural, bilingual interviewers from the five communities, and ongoing involvement of the communities through data analysis and report-writing phases. CONCLUSIONS: All stakeholders are able to learn from the perspectives and knowledge of others. Equality can supplant a subject-object relationship typical of much research and evident in some practice, with a subject-subject relationship. It can also transpose community members from the margins to the centre of research and practice. How community strength and capacity can be built through research is instructive for health promotion practice. PMID- 21819355 TI - Aggression and violence in the ED: issues associated with the implementation of restraint and seclusion. AB - A number of surveys have reported that those who work in emergency departments (EDs) experience high levels of violence and aggression. Some suggest that 100% of emergency department nurses have, at some time, experienced workplace violence. This report summarises those data and highlights the under-reporting of violent incidents occurring in emergency departments. Current responses to such incidents are reviewed, with particular focus on the use of both unambiguous and ambiguous restraint practices and also on seclusion. Those practices are evaluated in the context of current policy. This review suggests that rather than continue with discussions about whether or not restraint and seclusion are appropriate management procedures in the emergency room, efforts should be directed towards development of best practice for initiating and managing the use of restraint when it is implemented. PMID- 21819356 TI - Injuries across adolescence: an investigation using the extended adolescent injury checklist (E-AIC). AB - ISSUES ADDRESSED: Injuries are the leading cause of death among adolescents. The current research examined a measure of adolescent injury in terms of whether it encompasses the diverse injury experiences of Australian adolescents, including high-risk and normative adolescents, and thus determine its utility as a tool for health promotion research. METHODS: Grade 9 students from two Brisbane high schools (n=202, aged 13-14 years) and adolescents recruited from the Emergency Department waiting rooms of four Brisbane hospitals (n=98, aged 16-18 years) completed the Extended Adolescent Injury Checklist (E-AIC). RESULTS: The most common cause of injury among adolescents was a sports activity, followed by fights for all participants except school-based males, who experienced more bicycle injuries. Alcohol use was most frequently reported in association with interpersonal violence injuries. CONCLUSIONS: A broad variety of injuries, occurring in context of multiple risk as well as normative behaviours, were reported by adolescents in both school and ED settings, and were captured by the E-AIC. PMID- 21819357 TI - Australian health professionals' health website recommendation trends. AB - INTRODUCTION: This study was concerned with indentifying motivations and trends associated with a health website recommendation from eight of Australia's major health professions to the health consumer. Health professions included in this study are: psychiatrists, general practitioners, social workers, dietitians, chiropractors, physiotherapists, optometrists and pharmacists. METHODS: An online survey (www.limesurvey.org) was developed from a common set of questions negotiated between all eight health professions. Survey questions were constructed in an attempt to identify participants' reasons for or against recommending a health website to a patient. A 5-point scale (not, slightly, neutral, moderately, strongly) to measure influence was used throughout the question set. RESULTS: This study indicates that Australian general practitioners (GPs) were the highest Australian health professionals to undertake a health website recommendation (86%), followed by psychiatrists (80%), with the lowest being physiotherapists (42%) and optometrists (33%). A profile of the Australian health professional who recommends a health website is identified as male, aged above 50 years, has had more than 10 years experience, works in a major city, is in private practice and has patient numbers exceeding 500 in a 12-month period (2009). CONCLUSION: Recommendations from this study include the need to develop mechanisms that identify high-quality online medical information and the development and implementation of Continuing Professional Development (CPD) courses which up-skill health professionals concerning the recommendation of health websites for health care delivery. PMID- 21819358 TI - Lean people ... abundant food: memories of whanau health and food in mid-20th Century everyday life. AB - ISSUE ADDRESSED: This article reports the first phase of a project to develop, in participation with a Maori community, a model of health promotion to combat the impact of metabolic syndrome. METHODS: A series of hui (meetings and focus groups) were conducted with community elders to learn about the food they gathered, prepared and consumed in the mid-20th Century before diabetes became endemic. A participatory research approach was used. RESULTS: Three main themes emerged: food related work, self-sufficiency and the 'richness' of food. Most people were lean with diets rich in vegetables, fruit and sea food, while low in red meat and processed foods. The resources of the whole community were devoted to the growing, gathering, preparation and preservation of food. CONCLUSIONS: This first phase provides only a partial record; continued gathering of the stories to widen and deepen understanding of the changes to Maori communities and their health is recommended. Next is to collaboratively develop and test a Maori model of health promotion, using local knowledge to develop interventions relevant to the community. It is contended that the future of health promotion lies in the interface between medical science and the knowledge held by communities. PMID- 21819359 TI - Participation in cardiovascular risk factor and cancer screening among Australian Chinese. AB - ISSUE ADDRESSED: This study aimed to examine the participation of Australian Chinese in cardiovascular risk factor and cancer screening. METHODS: A telephone survey of a random sample of Chinese in New South Wales, Australia, was conducted. The presence of, and participation in screening for, hypertension, hyperlipidaemia and diabetes were ascertained. Additionally, women were surveyed regarding breast cancer and cervical cancer screening. RESULTS: Five hundred and fifty-five subjects were interviewed. Generally, Australian Chinese were as likely to participate in health screening activities as the general population. However, Chinese with poor English-speaking ability were less likely to have had recent lipid testing (85.4% vs 91.2%, p=0.01) or mammography (63.2% vs 92.6%, p=0.01) than those who were proficient in English (adjusted for age and gender). Those not in employment were less likely to have had lipid testing (86.9% vs 88.4%, p=0.04), mammography (61.1% vs 93.5%, p=0.04) or Pap tests (64.7% vs 85.0%, p<0.01) than those in employment. Chinese who had been in Australia for less than 10 years were also less likely to undergo Pap tests (68.7% vs 79%, p=0.03). CONCLUSIONS: Overall, participation of Australian Chinese in health screening is within the community norm. However, those with poor English-speaking skills, who are not employed, or who had been resident in Australia for a shorter duration are less likely to undergo some of these health activities. PMID- 21819360 TI - A qualitative study about smoking cessation with clients of community service organisations that work with disadvantaged families. AB - ISSUE ADDRESSED: To determine whether clients of community service organisations (CSOs) that work with disadvantaged families consider the organisation to be a suitable avenue for the delivery of smoking cessation assistance, and to explore clients' knowledge and attitudes on smoking, and barriers to quitting. METHODS: Seven focus groups were undertaken with clients from CSOs that work with disadvantaged families. Participants were asked questions on effects of smoking on health, barriers to quitting smoking and whether CSOs could provide smoking cessation support. Note-based analysis was undertaken to identify issues. RESULTS: Participants view CSOs as an acceptable avenue to provide support to quit smoking. Participants had misconceptions about the effects of smoking on health and the desire to quit smoking was not a priority among many participants. CONCLUSIONS: There is a need for smoking cessation support to be integrated into CSOs for disadvantaged families as clients are unlikely to seek support elsewhere. PMID- 21819361 TI - Workplace health promotion and pedometers: response to Hess, Borg and Rissel. PMID- 21819362 TI - Capacity building for evaluation of social connectedness. PMID- 21819363 TI - A model of volunteering for socio-disadvantaged people and its effect on their lives. PMID- 21819364 TI - Wicked problems and health promotion: reflections on learning. PMID- 21819365 TI - Nephrologists' perceptions of renal transplant as treatment of choice for end stage renal disease, preemptive transplant, and transplanting older patients: an international survey. AB - OBJECTIVES: To explore the relation between nephrologists' characteristics and their views of transplant as the treatment of choice for end-stage renal disease, preemptive transplant, and transplant of older patients. MATERIALS AND METHODS: A comprehensive international Web-based survey explored the relation between nephrologists' characteristics and their views of transplant as the treatment of choice for end-stage renal disease, preemptive transplant, and transplant of older patients. RESULTS: A total of 1448 nephrologists completed the survey. The majority of respondents agreed with transplant as the treatment of choice for end stage renal disease (75%), preemptive transplant (71%), and transplant for patients > 60 years of age (59%). The likelihood of agreement was higher among transplant and academic nephrologists, and practice at hospitals with >= 50 transplants per year. Urban location and >= 10 years in practice were associated with higher likelihood of viewing transplant as treatment of choice and favoring preemptive transplant. CONCLUSIONS: Demographic and practice characteristics influence nephrologists' attitudes about transplant as the treatment of choice for end-stage renal disease, preemptive transplant, and transplant as an option for older patients. Detailed studies exploring the determinants of nephrologists' attitudes are likely to identify sources of variations in perceptions of patient suitability for transplant. Our findings underscore the need for continuing educational programs addressing evolving aspects of transplant particularly targeting nephrologists practicing within nonacademic centers and in rural areas. PMID- 21819366 TI - Lipid disturbances before and after renal transplant. AB - OBJECTIVES: Hyperlipidemia is a significant metabolic disorder that is commonly encountered in renal transplant recipients. This study was conducted to investigate lipid disturbances and define its pattern in kidney recipients. MATERIALS AND METHODS: The records of 103 patients who had undergone a renal transplant between the years of 2004 and 2005 were retrospectively investigated. The lipid profile of these patients including total cholesterol, low-density lipoproteins, high-density lipoproteins, and triglyceride levels before and within 2 years' follow-up after transplant was evaluated. The demographics of the patients, cause of the end-stage renal failure, along with their immunosuppressive regimens were also considered. RESULTS: The study group included 43 women (41.8%) and 60 men (58.2%) (mean age, 39.25 +/- 13.9 y). After transplant, laboratory analyses yielded significantly increased levels of total cholesterol, low-density lipoproteins, triglyceride levels, and high-density lipoproteins despite statin therapy, and the most important predictor for developing hypercholesterolemia and hypertriglyceridemia-pre-existing dyslipidemia. The effects of the various drugs on lipid metabolism were not different. These effects seen on the lipid profiles also were independent of the patients' age, sex, and cause of end-stage renal failure. CONCLUSIONS: Despite statin treatment, renal transplants in our subjects were associated with a characteristic pattern of lipid disturbance with raised total cholesterol, low density lipoproteins, high-density lipoproteins, and a concomitant increase in triglycerides. A more-aggressive approach to managing posttransplant hypercholesterolemia is warranted, especially in patients with pre-existing dyslipidemia. PMID- 21819367 TI - Cyclophosphamide exposure pretransplant is associated with complications in the first year after kidney transplant. AB - OBJECTIVES: Some patients needing a kidney transplant have used cyclophosphamide before the transplant. Long-term bone marrow damage associated with cyclophosphamide could manifest with myelotoxic complications after transplant in the context of the immunosuppressant, but evidence for this has not been published. MATERIALS AND METHODS: We performed a retrospective, single-center analysis of renal transplant recipients with prior cyclophosphamide exposure and compared posttransplant short-term outcomes to a random control group (clinical outcomes identified by searching automated electronic databases). RESULTS: Sixteen recipients had taken cyclophosphamide before the transplant and were compared with a control group of 32 patients. Hospitalization rates were equal, and although there were 3 times more hospitalizations secondary to an infective course in the cyclophosphamide group, this did not achieve significance (0.63 vs 0.22; P = .147). There was no difference in rates of bacteriuria, cytomegalovirus, or Polyomavirus. The cyclophosphamide group was at significantly greater risk of needing a blood transfusion immediately after the transplant (average number of units of blood per patient, 0.44 vs 0.19; P = .038). Also, they were 3 times more likely to require anemia treatments 1 year after the transplant (average number of anemia treatment medications, 0.75 vs 0.25; P = .014). Full blood count parameters, graft function, and graft and patient survival at 1 year posttransplant were equal. CONCLUSIONS: Evidence suggests that pretransplant administration of cyclophosphamide is associated with adverse short term outcomes posttransplant. Further analyses are warranted to investigate these preliminary findings to determine whether myelosuppressive immunosuppressant should be modified in the context of prior cyclophosphamide exposure. PMID- 21819368 TI - Thiopurine S-methyltransferase polymorphism in Iranian kidney transplant recipients. AB - OBJECTIVES: Thiopurine S-methyltransferase is an enzyme that catalyzes S methylation of azathioprine as an immunosuppressive drug. Genetic polymorphisms influence thiopurine S-methyltransferase activity. There are 3 variant alleles: thiopurine S-methyltransferase*2, *3A, and *3C are responsible for more than 95% cases of low-enzyme activity. MATERIALS AND METHODS: We studied these polymorphisms and the occurrence of azathioprine adverse effects in 50 renal transplant recipients undergoing triple immunosuppressive therapy including azathioprine, cyclosporine, and prednisone. Thiopurine S-methyltransferase genetic polymorphism was determined by polymerase chain reaction restriction fragment length polymorphism assay and allele-specific polymerase chain reaction methods. Azathioprine dosage; leukocyte, erythrocyte, and platelet counts; and graft rejection episodes were analyzed during hospitalization. RESULTS: Two patients (2%) were heterozygous for thiopurine S-methyltransferase*3C, the remaining patients were thiopurine S-methyltransferase wild-type *1/*1 (98%). Thiopurine S-methyltransferase wild-type homozygous and heterozygous patients were administered similar azathioprine dosages at the beginning of treatment (2.42 +/- 0.50 and 2.52 +/- 0.40 mg/kg/24 h). During subsequent days, mean azathioprine dosage administered to thiopurine S-methyltransferase wild-type homozygous patients was similar to heterozygous patients, but with no statistical difference (P = .28). Three patients had an acute rejection episode during this time. Five patients (10%) had reduced azathioprine dosage owing to adverse effects. Adverse reactions consisted of hematotoxicity (n=2), hepatotoxicity (n=1), and gastrointestinal toxicity (n=2). All recipients were wild-type homozygotes. CONCLUSIONS: The frequency of thiopurine S-methyltransferase gene mutations is low among our patients. The incidence of adverse reactions to azathioprine was also low, even in patients carrying a variant of thiopurine S methyltransferase. We conclude that determining thiopurine S-methyltransferase genotype is not useful in our population to predict adverse reactions to azathioprine. PMID- 21819369 TI - Ten-year follow-up of basiliximab induction therapy for live-donor kidney transplant: a prospective randomized controlled study. AB - OBJECTIVES: The effect of basiliximab induction therapy on long-term patient and graft survival is not clear. We sought to evaluate if there is any advantage to routine basiliximab induction on the long-term outcome of living-related donor kidney transplants. MATERIALS AND METHODS: One hundred adult recipients with their first kidney allograft were randomized into 2 treatment groups; 1 group received basiliximab, and the second served as a control. All patients received a maintenance triple immunosuppressive therapy (steroids, cyclosporine, microemulsion, and azathioprine). We followed them for 10 years. RESULTS: Basiliximab reduced the proportion of patients who experienced an acute rejection in the first year (18/50) when compared with the control group (31/50) (P = .009), and in 10 years (28/50) when compared with controls (37/50) (P = .059). The cumulative steroid dosage used throughout the study was significantly lower in the basiliximab group. The overall incidence of posttransplant complications was comparable among the 2 groups. There was no significant difference in patient and graft survival; 10-year patient and graft survival were 92% and 76% for basiliximab and 90% and 68% for the control group. CONCLUSIONS: Routine basiliximab induction significantly reduces the incidence of acute rejection without any noticeable effects on the long-term renal transplant outcome. PMID- 21819370 TI - Lack of association of the polymorphism of the CCR5 gene in liver recipients with acute rejection from China. AB - OBJECTIVES: This study sought to investigate the associations between polymorphisms in the chemokine receptor 5 gene and acute rejection in liver transplant. MATERIALS AND METHODS: A total of 266 patients who underwent a liver transplant between January 2006 and March 2009 were enrolled in this study. Genomic DNA was extracted from whole blood, and chemokine receptor 5Delta32 was detected by polymerase chain reaction. Eight nucleotide polymorphism loci in the chemokine receptor 5 gene were detected by Applied Biosystems SNaPShot and TaqMan technologies. RESULTS: Chemokine receptor 5Delta32 mutation was not detected in all the individuals from China. There was no significant association between the single nucleotide polymorphism in chemokine receptor 5 gene and acute rejection. CONCLUSIONS: Single nucleotide polymorphisms in a single gene of the chemokine receptor 5 might not play a role in acute rejection after liver transplant. PMID- 21819371 TI - Heart allograft involvement by posttransplant lymphoproliferative disorders: report from the PTLD. Int survey. AB - OBJECTIVES: Owing to the rare incidence of posttransplant lymphoproliferative disorder of the heart, there is a paucity of data concerning it. In this study, we pooled data from posttransplant lymphoproliferative disorder patients from the existing literature. We sought to analyze and compare characteristics, predictors, and prognoses of patients with posttransplant lymphoproliferative disorder of the heart. MATERIALS AND METHODS: A comprehensive search was made to gather data by PubMed and Google for reports of lymphoproliferative disorders occurring in transplant patients occurring within the heart, the heart allograft, and surrounding tissues. Pooled data were reanalyzed. RESULTS: Overall, 206 patients were entered into the analysis. Transplant recipients with cardiac posttransplant lymphoproliferative disorders were significantly more likely to represent multivisceral and disseminated posttransplant lymphoproliferative disorder (P = .01 and P < .001). Posttransplant lymphoproliferative disorder in patients with heart involvement were more likely to involve the genitalia (P = .035), the adrenals (P = .035), the liver (P = .007), and the kidneys (P < .001). Patients with cardiac posttransplant lympho proliferative disorder had significantly shorter time from transplant to development of posttransplant lymphoproliferative disorder (P = .029). A log-rank test showed a significant inferior patient survival for transplant recipients with cardiac complications (P = .031). Patients with a cardiac allograft posttransplant lymphoproliferative disorder were significantly older at the time of transplant (55.3 +/- 8.4 vs 38.5 +/- 21.8 y; P = .002). CONCLUSIONS: Because cardiac posttransplant lymphoproliferative disorder is associated with multiorgan and disseminated posttransplant lymphoproliferative disorder, all transplant recipients who represent posttransplant lymphoproliferative disorder in the heart should be evaluated for other organs involvement most especially in the kidneys, liver, and adrenals. Further prospective studies with a larger patient population are needed to confirm our results. PMID- 21819372 TI - Aspergillus fumigatus spondylodiskitis in renal transplant patient: voriconazole experience. AB - The incidence of invasive aspergillosis has increased after solid organ transplant. However, aspergillus osteomyelitis in vertebrae is rare. We report a case of aspergillus spondylodiskitis after pulmonary aspergillosis in a renal transplant recipient. He was treated by antifungal therapy and surgical intervention. The transplantist should be alert for a diagnosis of aspergillus spondylodiskitis in recipients who developed back pain after aspergillosis infection in other sites. PMID- 21819373 TI - Flupirtine-induced hepatic failure requiring orthotopic liver transplant. AB - We present the case of a 48-year-old otherwise healthy man who required an urgent liver transplant owing to acute liver failure after flupirtine treatment. After 3 months of daily flupirtine intake as treatment for pseudoradicular pain syndrome, he presented at our institution with signs of jaundice and hepatic encephalopathy. Laboratory results showed elevated liver transaminases, and the liver histopathology supported the assumed drug-induced liver injury. After listing him for an urgent liver transplant, he was given a liver graft from a 21 year-old man. Despite a rejection episode on day 11 after the surgery (which was successfully treated by steroid pulse therapy), the postoperative course was uneventful and the patient recovered completely. To the best of our knowledge, this is the first report of a liver transplant for acute liver failure after taking flupirtine. PMID- 21819374 TI - Liver transplantation from an upper midline incision. AB - OBJECTIVES: To evaluate the minimally invasive incision to the recipient of a liver transplant. MATERIALS AND METHODS: A 55-year-old man with cirrhosis due to hepatitis B accompanied by hepatocellular carcinoma underwent a right lobe, living-donor liver transplant using an 18-cm long, upper midline incision. The recipient hepatectomy was performed from the left to the right side (from medial to lateral). Deep retractors and long surgical instruments were preferred. RESULTS: The surgical procedure was completed without problem. Both the recipient hepatectomy and implantation of the right liver took 8 hours. Postoperative recovery of the patient was rapid, and he was discharged 8 days after surgery, uneventfully. CONCLUSIONS: An upper midline incision can be preferred for liver transplant for selected cases. Minimally invasive surgery is an option for liver transplant recipients as well. PMID- 21819375 TI - Bilateral transversus abdominis plane block for managing pain after a pancreas transplant. AB - The authors report the first clinical application of a bilateral transversus abdominis plane block for treating pain after a pancreas transplant. In this case, a 36-year-old chronic opioid user presented postoperatively with severe incisional pain following a pancreas transplant. The pain was not ameliorated with opioids and was successfully treated with the administration of bilateral transversus abdominis plane blocks with 0.5% ropivicaine. Pain relief lasted for 6 hours. PMID- 21819376 TI - Combination antifungal therapy for invasive pulmonary aspergillosis in a heart transplant recipient. AB - Invasive pulmonary aspergillosis is a severe complication after solid organ transplant, with a high mortality rate. We present a 45-year-old male heart transplant recipient who developed fever, progressive worsening of dyspnea, and productive cough without response to antibiotics. Diagnosis of invasive pulmonary aspergillosis was made based on clinical, laboratory, and radiographic findings. The patient was treated successfully with combined antifungal therapy (voriconazole and micafungin). This case report highlights the importance of a high degree of clinical suspicion to allow curative treatment of invasive aspergillosis and the efficiency of new antifungal drugs. PMID- 21819377 TI - Ethical dilemma of recovering organs before donor death. AB - Organ transplant has had a momentous effect in improving global health over the years. However, there exists a sizeable discrepancy between the supply and demand of organs, especially in developing countries, where lack of expertise, financial constraints, and inadequate transplant facilities have been obstacles. According to current practice, donors must be dead before unpaired vital organs can be recovered. Equal health warrants needs-based health care for everyone. Recovering viable organs from donors while they are alive, but with death inevitable, may be significant to persons on waiting lists. Future policies in organ transplantation must be made after thorough consideration of all aspects of donation and dealing with the inequalities of health care. These pose a challenge for medicolegal and ethical organizations. PMID- 21819378 TI - The serine/threonine kinase ULK1 is a target of multiple phosphorylation events. AB - Autophagy is a cellular degradation process that is up-regulated upon starvation. Nutrition-dependent regulation of mTOR (mammalian target of rapamycin) is a major determinant of autophagy. RTK (receptor tyrosine kinase) signalling and AMPK (AMP activated protein kinase) converge upon mTOR to suppress or activate autophagy. Nutrition-dependent regulation of autophagy is mediated via mTOR phosphorylation of the serine/threonine kinase ULK1 (unc51-like kinase 1). In the present study, we also describe ULK1 as an mTOR-independent convergence point for AMPK and RTK signalling. We initially identified ULK1 as a 14-3-3-binding protein and this interaction was enhanced by treatment with AMPK agonists. AMPK interacted with ULK1 and phosphorylated ULK1 at Ser(555) in vitro. Mutation of this residue to alanine abrogated 14-3-3 binding to ULK1, and in vivo phosphorylation of ULK1 was blocked by a dominant-negative AMPK mutant. We next identified a high-stringency Akt site in ULK1 at Ser(774) and showed that phosphorylation at this site was increased by insulin. Finally, we found that the kinase-activation loop of ULK1 contains a consensus phosphorylation site at Thr(180) that is required for ULK1 autophosphorylation activity. Collectively, our results suggest that ULK1 may act as a major node for regulation by multiple kinases including AMPK and Akt that play both stimulatory and inhibitory roles in regulating autophagy. PMID- 21819379 TI - Peripheral insertion modulates the editing activity of the isolated CP1 domain of leucyl-tRNA synthetase. AB - A large insertion domain called CP1 (connective peptide 1) present in class Ia aminoacyl-tRNA synthetases is responsible for post-transfer editing. LeuRS (leucyl-tRNA synthetase) from Aquifex aeolicus and Giardia lamblia possess unique 20 and 59 amino acid insertions respectively within the CP1 that are crucial for editing activity. Crystal structures of AaLeuRS-CP1 [2.4 A (1 A=0.1 nm)], GlLeuRS CP1 (2.6 A) and the insertion deletion mutant AaLeuRS-CP1Delta20 (2.5 A) were solved to understand the role of these insertions in editing. Both insertions are folded as peripheral motifs located on the opposite side of the proteins from the active-site entrance in the CP1 domain. Docking modelling and site-directed mutagenesis showed that the insertions do not interact with the substrates. Results of molecular dynamics simulations show that the intact CP1 is more dynamic than its mutant devoid of the insertion motif. Taken together, the data show that a peripheral insertion without a substrate-binding site or major structural role in the active site may modulate catalytic function of a protein, probably from protein dynamics regulation in two respective LeuRS CP1s. Further results from proline and glycine mutational analyses intended to reduce or increase protein flexibility are consistent with this hypothesis. PMID- 21819380 TI - Vascular cell lines expressing SSAO/VAP-1: a new experimental tool to study its involvement in vascular diseases. AB - BACKGROUND INFORMATION: PrAO (primary amine oxidase), also known as SSAO (semicarbazide-sensitive amine oxidase)/VAP-1 (vascular adhesion protein-1), is an enzyme (EC 1.4.3.21) that is highly expressed in blood vessels and participates in many cell processes, including glucose handling or inflammatory leucocyte recruitment. High activity levels of this enzyme are associated with diabetes, atherosclerosis, AD (Alzheimer's disease) or stroke, among others, thus meaning that studies concerning SSAO as a therapeutic target are becoming more frequent. However, the study of this enzyme is difficult, owing to its loss of expression in cell cultures. RESULTS: We have developed an endothelial cell line that stably expresses the human SSAO/VAP-1 to be used as endothelial cell model for the study of this enzyme. The transfected protein is mainly expressed as a dimer in the membrane of these cells, and we demonstrate its specific localization in the lipid rafts of endothelial cells. The protein shows levels of enzymatic activity and kinetic parameters comparable with those observed in vivo by the same cell type. The transfected SSAO/VAP-1 is also able to mediate the adhesion of leucocytes to the endothelium, a known function of this protein under inflammatory conditions. This distinctive function is not exerted by the SSAO/VAP 1 transfected protein in a smooth muscle cell line that expresses 3-fold higher protein levels. These differences have been widely reported to exist in vivo. Furthermore, using this endothelial cell model, we describe for the first time the involvement of the leucocyte-adhesion activity of SSAO/VAP-1 in the Abeta (amyloid beta-peptide)-mediated pro-inflammatory effect. CONCLUSIONS: The characterization of this new cell line shows the correct behaviour of the transfected protein and endorses the use of these cellular models for the in depth study of the currently poorly understood functions of SSAO/VAP-1 and its involvement in the above-mentioned pathologies. This cellular model will be also useful for the evaluation of potential compounds that could modulate its activity for therapeutic purposes. PMID- 21819381 TI - The neural circadian system of mammals. AB - Humans and other mammals exhibit a remarkable array of cyclical changes in physiology and behaviour. These are often synchronized to the changing environmental light-dark cycle and persist in constant conditions. Such circadian rhythms are controlled by an endogenous clock, located in the suprachiasmatic nuclei of the hypothalamus. This structure and its cells have unique properties, and some of these are reviewed to highlight how this central clock controls and sculpts our daily activities. PMID- 21819382 TI - Circadian timekeeping in Drosophila melanogaster and Mus musculus. AB - The discovery of the period gene mutants in 1971 provided the first evidence that daily rhythms in the sleep-wake cycle of a multicellular organism, the fruit fly Drosophila melanogaster, had an underlying genetic basis. Subsequent research has established that the biological clock mechanism in flies and mammals is strikingly similar and functions as a bimodal switch, simultaneously turning on one set of genes and turning off another set and then reversing the process every 12 h. In this chapter, the current model of the clock mechanism in Drosophila will be presented. This relatively basic model will then be used to outline the general rules that govern how the biological clock operates in mammals. PMID- 21819383 TI - Circadian timekeeping in Neurospora crassa and Synechococcus elongatus. AB - At first, the saprophytic eukaryote Neurospora crassa and the photosynthetic prokaryote Synechococcus elongatus may seem to have little in common. However, in both organisms a circadian clock organizes cellular biochemistry, and each organism lends itself to classical and molecular genetic investigations that have revealed a detailed picture of the molecular basis of circadian rhythmicity. In the present chapter, an overview of the molecular clockwork in each organism will be described, highlighting similarities, differences and some as yet unexplained phenomena. PMID- 21819384 TI - Downstream of the plant circadian clock: output pathways for the control of physiology and development. AB - The plant circadian clock controls many aspects of growth and development, allowing an individual to adapt its physiology and metabolism in anticipation of diurnal and seasonal environmental changes. Circadian regulation of hormone levels and hormonal signalling modulates many features of development, including daily growth patterns and the breaking of seed dormancy. The clock also plays a role in seasonal day-length perception, allowing plants to optimally time key development transitions, such as reproduction. Moreover, the clock restricts (gates) the sensitivity of a plant's response to environmental cues, such as light and stress, to specific times of the day, ensuring that the plant can distinguish between normal fluctuations and longer-term changes. The central oscillator controls many of these output pathways via rhythmic gene expression, with several of the core clock components encoding transcription factors. Post transcriptional processes are also likely to make an important contribution to the circadian regulation of output pathways. The plant circadian clock plays a role in regulating fitness, hybrid vigour and numerous stress responses. Thus elucidating the complexities of the circadian output mechanisms and their regulation may provide new avenues for crop enhancement. PMID- 21819385 TI - The role of natural selection in circadian behaviour: a molecular-genetic approach. AB - Circadian rhythms (~24 h) in biochemistry, physiology and behaviour are found in almost all eukaryotes and some bacteria. The elucidation of the molecular components of the 24 h circadian clock in a number of model organisms in recent years has provided an opportunity to assess the adaptive value of variation in clock genes. Laboratory experiments using artificially generated mutants reveal that the circadian period is adaptive in a 24 h world. Natural genetic variation can also be studied, and there are a number of ways in which the signature of natural selection can be detected. These include the study of geographical patterns of genetic variation, which provide a first indication that selection may be at work, and the use of sophisticated statistical neutrality tests, which examine whether the pattern of variation observed is consistent with a selective rather than a neutral (or drift) scenario. Finally, examining the probable selective agents and their differential effects on the circadian phenotype of the natural variants provides the final compelling evidence for selection. We present some examples of how these types of analyses have not only enlightened the evolutionary study of clocks, but have also contributed to a more pragmatic molecular understanding of the function of clock proteins. PMID- 21819386 TI - Insect circadian clock outputs. AB - Insects display an impressive variety of daily rhythms, which are most evident in their behaviour. Circadian timekeeping systems that generate these daily rhythms of physiology and behaviour all involve three interacting elements: the timekeeper itself (i.e. the clock), inputs to the clock through which it entrains and otherwise responds to environmental cues such as light and temperature, and outputs from the clock through which it imposes daily rhythms on various physiological and behavioural parameters. In insects, as in other animals, cellular clocks are embodied in clock neurons capable of sustained autonomous circadian rhythmicity, and those clock neurons are organized into clock circuits. Drosophila flies spend their entire lives in small areas near the ground, and use their circadian brain clock to regulate daily rhythms of rest and activity, so as to organize their behaviour appropriately to the daily rhythms of their local environment. Migratory locusts and butterflies, on the other hand, spend substantial portions of their lives high up in the air migrating long distances (sometimes thousands of miles) and use their circadian brain clocks to provide time-compensation to their sun-compass navigational systems. Interestingly, however, there appear to be substantial similarities in the cellular and network mechanisms that underlie circadian outputs in all insects. PMID- 21819388 TI - Entrainment of circadian clocks in mammals by arousal and food. AB - Circadian rhythms in mammals are regulated by a system of endogenous circadian oscillators (clock cells) in the brain and in most peripheral organs and tissues. One group of clock cells in the hypothalamic SCN (suprachiasmatic nuclei) functions as a pacemaker for co-ordinating the timing of oscillators elsewhere in the brain and body. This master clock can be reset and entrained by daily LD (light-dark) cycles and thereby also serves to interface internal with external time, ensuring an appropriate alignment of behavioural and physiological rhythms with the solar day. Two features of the mammalian circadian system provide flexibility in circadian programming to exploit temporal regularities of social stimuli or food availability. One feature is the sensitivity of the SCN pacemaker to behavioural arousal stimulated during the usual sleep period, which can reset its phase and modulate its response to LD stimuli. Neural pathways from the brainstem and thalamus mediate these effects by releasing neurochemicals that inhibit retinal inputs to the SCN clock or that alter clock-gene expression in SCN clock cells. A second feature is the sensitivity of circadian oscillators outside of the SCN to stimuli associated with food intake, which enables animals to uncouple rhythms of behaviour and physiology from LD cycles and align these with predictable daily mealtimes. The location of oscillators necessary for food entrained behavioural rhythms is not yet certain. Persistence of these rhythms in mice with clock-gene mutations that disable the SCN pacemaker suggests diversity in the molecular basis of light- and food-entrainable clocks. PMID- 21819387 TI - In vitro circadian rhythms: imaging and electrophysiology. AB - In vitro assays have localized circadian pacemakers to individual cells, revealed genetic determinants of rhythm generation, identified molecular players in cell cell synchronization and determined physiological events regulated by circadian clocks. Although they allow strict control of experimental conditions and reduce the number of variables compared with in vivo studies, they also lack many of the conditions in which cellular circadian oscillators normally function. The present review highlights methods to study circadian timing in cultured mammalian cells and how they have shaped the hypothesis that all cells are capable of circadian rhythmicity. PMID- 21819389 TI - Mammalian clock output mechanisms. AB - In mammals many behaviours (e.g. sleep-wake, feeding) as well as physiological (e.g. body temperature, blood pressure) and endocrine (e.g. plasma corticosterone concentration) events display a 24 h rhythmicity. These 24 h rhythms are induced by a timing system that is composed of central and peripheral clocks. The highly co-ordinated output of the hypothalamic biological clock not only controls the daily rhythm in sleep-wake (or feeding-fasting) behaviour, but also exerts a direct control over many aspects of hormone release and energy metabolism. First, we present the anatomical connections used by the mammalian biological clock to enforce its endogenous rhythmicity on the rest of the body, especially the neuro endocrine and energy homoeostatic systems. Subsequently, we review a number of physiological experiments investigating the functional significance of this neuro anatomical substrate. Together, this overview of experimental data reveals a highly specialized organization of connections between the hypothalamic pacemaker and neuro-endocrine system as well as the pre-sympathetic and pre-parasympathetic branches of the autonomic nervous system. PMID- 21819390 TI - The importance of developing world haematology. PMID- 21819391 TI - Lymphocytes with crystalline inclusions in early chronic lymphocytic leukaemia. PMID- 21819392 TI - How the brain folds: a new genetic mechanism involving a laminin gene. PMID- 21819393 TI - Autism, mutations, and the environment: insights from exome sequencing. PMID- 21819394 TI - Same gene, surprising difference: adult neuronal ceroid lipofuscinosis linked to CLN6, mutated in variant late-infantile form. PMID- 21819395 TI - Genetic basis for tooth malformations: from mice to men and back again. AB - Teeth arise from sequential and reciprocal interactions between the oral epithelium and the cranial neural crest-derived mesenchyme. Their formation involves a precisely orchestrated series of molecular and morphogenetic events. Numerous regulatory genes that have been primarily found in organisms such as Drosophila, zebrafish, xenopus and mouse are associated with all stages of tooth formation (patterning, morphogenesis, cytodifferentiation and mineralization). Most of these genes belong to evolutionary conserved signaling pathways that regulate communication between epithelium and mesenchyme during embryonic development. These signaling molecules together with specific transcription factors constitute a unique molecular imprint for odontogenesis and contribute to the generation of teeth with various and function-specific shapes. Mutations in several genes involved in tooth formation cause developmental absence and/or defects of teeth in mice. In humans, the odontogenic molecular program is not as well known as that of mice. However, some insight can be obtained from the study of mutations in regulatory genes, which lead to tooth agenesis and/or the formation of defective dental tissues. PMID- 21819396 TI - A predictive model of avian natal dispersal distance provides prior information for investigating response to landscape change. AB - 1. Informative Bayesian priors can improve the precision of estimates in ecological studies or estimate parameters for which little or no information is available. While Bayesian analyses are becoming more popular in ecology, the use of strongly informative priors remains rare, perhaps because examples of informative priors are not readily available in the published literature. 2. Dispersal distance is an important ecological parameter, but is difficult to measure and estimates are scarce. General models that provide informative prior estimates of dispersal distances will therefore be valuable. 3. Using a world wide data set on birds, we develop a predictive model of median natal dispersal distance that includes body mass, wingspan, sex and feeding guild. This model predicts median dispersal distance well when using the fitted data and an independent test data set, explaining up to 53% of the variation. 4. Using this model, we predict a priori estimates of median dispersal distance for 57 woodland dependent bird species in northern Victoria, Australia. These estimates are then used to investigate the relationship between dispersal ability and vulnerability to landscape-scale changes in habitat cover and fragmentation. 5. We find evidence that woodland bird species with poor predicted dispersal ability are more vulnerable to habitat fragmentation than those species with longer predicted dispersal distances, thus improving the understanding of this important phenomenon. 6. The value of constructing informative priors from existing information is also demonstrated. When used as informative priors for four example species, predicted dispersal distances reduced the 95% credible intervals of posterior estimates of dispersal distance by 8-19%. Further, should we have wished to collect information on avian dispersal distances and relate it to species' responses to habitat loss and fragmentation, data from 221 individuals across 57 species would have been required to obtain estimates with the same precision as those provided by the general model. PMID- 21819397 TI - Female plumage coloration is sensitive to the cost of reproduction. An experiment in blue tits. AB - 1. A growing number of studies suggest that female ornaments are linked to maternal quality and influence male mate choice. These findings challenge the traditional male-biased view of sexual selection and the hypothesis that female ornaments are the outcome of a genetic correlation with male ornaments. To further test the hypothesis that female traits have a function, it is now essential to investigate their honesty and to determine how signalling and reproduction interact in females. If female traits are honest indicators of quality, then they are likely to have a specific signalling function. 2. We investigated whether carry-over effects of reproduction might ensure the honesty of plumage colour signalling of a bird species with conspicuous UV-blue and yellow coloration, the blue tit Cyanistes caeruleus. Reproductive effort was manipulated by removing clutches, thereby forcing both sexes to reproduce twice and to raise chicks later in the breeding season when food is less abundant. In the year following this manipulation, we investigated the change in plumage in experimental and control males and females. The change was measured in the two putative feather ornaments, the UV-blue cap and the yellow breast, and another feather trait probably less likely to be sexually selected: the wing length. We also tested whether higher-quality females had their coloration less affected by the experiment. 3. We found that control but not manipulated males and females increased their signal towards UV. In addition, in the manipulated group, females that were able to lay more eggs had their UV-blue coloration less affected by the treatment. For yellow coloration, we found that manipulated yearlings but not manipulated adults decreased their yellow chroma in comparison with control. Lastly, our results show that the condition of the manipulated females tended to be positively correlated with yellow chroma. 4. These results show that the trade offs between reproduction and signalling can ensure the honesty of conspicuous plumage traits in female and male blue tits. In addition, they suggest that female traits have the potential to evolve under sexual selection in this and other bird species. PMID- 21819398 TI - A longitudinal twin study on the association between ADHD symptoms and reading. AB - BACKGROUND: Attention deficit hyperactivity disorder (ADHD) and reading disability commonly co-occur because of shared genetic risk factors. However, the stability and change of these genetic influences and the predictive relationships underlying this association longitudinally remain unclear. METHODS: ADHD symptoms and reading were assessed as continuous dimensions in a UK general population sample of approximately 7,000 twin pairs. Parent ratings of ADHD symptoms and teacher ratings of reading were obtained at two ages: middle childhood (ages 7-8 years) and early adolescence (ages 11-12 years). Cross-lagged quantitative genetic analyses were applied. RESULTS: ADHD symptoms and reading significantly predicted each other over time. However, ADHD symptoms were a significantly stronger predictor of reading than vice versa. Inattentive and hyperactive impulsive symptoms of ADHD both contributed to the prediction of reading, but inattentiveness was a significantly stronger predictor. Furthermore, ADHD symptoms and reading were highly heritable, and their association was primarily attributable to shared genetic influences. Despite notable genetic innovation for each trait, genetic factors involved in the association of ADHD symptoms and reading over time were highly stable. CONCLUSIONS: ADHD symptoms may put children at increased risk for reading problems and vice versa. Moreover, enduring genetic mechanisms appear to be important in the association of ADHD symptoms and reading over time. PMID- 21819399 TI - A novel beta-glucosidase from Sporidiobolus pararoseus: characterization and application in winemaking. AB - For the first time, the production of an extracellular beta-glucosidase (Sp-beta gl) by a Sporidiobolus pararoseus yeast strain is reported. The Sp-beta-gl activity was quantified, characterized, and assessed for its efficiency in releasing aroma-enhancing compounds in wines. The maximum enzymatic synthesis was after 72 h of growth in a complex media with 20 g/L of cellobiose. The optimal pH and temperature were 5.5 and at 50 degrees C, respectively. It showed a wide range of pH stability and exhibited quite high thermostability at low temperatures. In addition, this beta-glucosidase revealed tolerance to wine associated inhibitory compounds (sugars and ethanol), showing suitable characteristics for all the stages of alcoholic fermentation. The hydrolysis of the glycosidic terpenes by Sp-beta-gl was studied by gas chromatography, and its ability to efficiently release free terpenols has been demonstrated. The concentrations of geraniol, linalool, alpha-terpineol, and nerol were significantly increased in treated wines. These results suggest the potential application of this new yeast beta-glucosidase as an aroma-enhancing enzyme in winemaking. PRACTICAL APPLICATION: The search for new beta-glucosidase from yeast sources is important to improve the quality of wines. In this work, an S. pararoseus yeast strain has shown to be capable to produce a beta-glucosidase with suitable combination of properties for functionality in wines and with potential to increase the concentration of free aroma compounds, showing good prospects for an industrial application. PMID- 21819400 TI - Quality of shell eggs pasteurized with heat or heat-ozone combination during extended storage. AB - The physical quality and functionality of shell eggs, pasteurized with heat or a combination of heat and ozone, were assessed during eight weeks of storage at 4 or 25 degrees C. Shell eggs were treated as follows: (1) immersion heating that mimics commercial pasteurization processes (egg internal temperature of 56 +/- 0.1 degrees C for 32 min), or (2) a newly developed combination process comprised of heating (56 +/- 0.1 degrees C, internal, for 10 min) followed by gaseous ozone treatment. Eggs were tested for yolk index, Haugh units, albumen pH, albumen turbidity, and percent overrun. Additionally, albumen samples were assayed for lysozyme activity and free sulfhydryl group content, and were analyzed using differential scanning calorimetry and Fourier transform infrared (FTIR) spectroscopy. Both processed and unprocessed eggs maintained superior quality when stored at 4 degrees C, as opposed to 25 degrees C. Pasteurization, regardless of method, led to superior maintenance of Haugh units during storage but also increased albumen opacity and decreased albumen overrun. Detrimental effects on quality markers were more severe in heat-pasteurized eggs than those treated with the ozone-based process. Pasteurization of shell eggs by either process did not affect lysozyme activity or sulfhydryl group content. Changes in protein secondary structure, as indicated by FTIR analysis, suggest that the ozone-based process is less damaging to albumen proteins than is the heat-alone process. In conclusion, heat-ozone pasteurization, by virtue of its less severe heat treatment, yields a safe final product that more closely resembles untreated shell eggs. PMID- 21819401 TI - Innovative composite films of chitosan, methylcellulose, and nanoparticles. AB - Plastic is readily available and inexpensive, so it is becoming the main material for packaging. Unfortunately plastics do not biodegrade and, if reduced in small pieces, contaminate soil and waterways. In the present work, natural films composed of chitosan, methylcellulose, and silica (SiO(2)) nanoparticles (NPs) were developed as new packaging materials. The effect of the incorporation of NPs into the polymeric film matrix was evaluated. An excellent improvement of the mechanical properties was obtained for nanostructured films with a composition of CH:MC 50:50 and NPs 1% w/v that make these materials able to replace plastics and derivatives, reducing environmental pollution. PMID- 21819402 TI - Desalination of fish sauce by electrodialysis: effect on selected aroma compounds and amino acid compositions. AB - Fish sauce is an ingredient that exhibits unique flavor and is widely used by people in Southeast Asia. Fish sauce, however, contains a significant amount of salt (sodium chloride). Recently, electrodialysis (ED) has been successfully applied to reduce salt in fish sauce; however, no information is available on the effect of ED on changes in compounds providing aroma and taste of ED-treated fish sauce. The selected aroma compounds, amino acids, and sensory quality of the ED treated fish sauce with various salt concentrations were then analyzed. The amounts of trimethylamine, 2,6-dimethylpyrazine, phenols, and all carboxylic acids except for hexanoic acid significantly decreased, whereas benzaldehyde increased significantly when the salt removal level was higher. The amounts of all amino acids decreased with the increased salt removal level. Significant difference in flavor and saltiness intensity among ED-treated fish sauce with various salt concentrations, as assessed by a discriminative test, were observed. PRACTICAL APPLICATION: Information obtained in this work can serve as a guideline for optimization of a process to produce low-sodium fish sauce by ED. It also forms a basis for further in-depth sensory analysis of low-sodium fish sauce. PMID- 21819403 TI - Changes in carotenoids, ascorbic acids, and quality characteristics by the pickling of paprika (Capsicum annuum l.) cultivated in Korea. AB - Paprika (Capsicum annuum L.) is widely used as a healthy vegetable having antitumor-promoting activity and reducing or preventing chronic disease. Paprika has been mostly consumed as fresh fruit, and as food colorants such as oleoresin or pigment powder. In this study, pickled paprika was produced and its quality characteristics were monitored during storage (35 degrees C for 42 d). Carotenoid composition, ascorbic acid, total phenolic contents, and antioxidant activities were also analyzed. Five carotenoid compounds were identified in the pickled paprika and after 42 d of storage, total carotenoid content was 2.44 +/- 0.69 mg/100g fresh weight(fw) and ascorbic acid content was 50.90 +/- 3.26 mg/100g dry weight (dw). 2,2'-azino-di-(3-ethylbenzthiazoline sulphonate (ABTS) radical-scavenging activity of the pickled paprika was maintained above 70% until 28 d of storage, and then decreased to 47% of the initial activity. pH increased from 2.78 +/- 0.06 to 3.10 +/- 0.03 at 14 d and was then maintained until 42 d. Soluble solids increased gradually and color values including L*, a*, and b* decreased during storage. Hardness also decreased from 6.17 +/- 0.18 kg force to 1.90 +/- 0.60 kg force during storage. The overall taste of the pickled paprika was deemed to be good until 28 d of storage. Pickled paprika showed a possibility as a new pickled product. We demonstrated that paprika could be processed as a new pickled product with extended storage. PRACTICAL APPLICATION: Pickled paprika was produced and its quality characteristics along with phytochemical contents were monitored during storage. Phytochemicals, including ascorbic acid and polyphenols in pickled paprika were considerably retained and visual color was satisfactory during storage. Texture was deemed to be satisfactory for 4 wk. Considering that our experiment was performed at a relatively high temperature and without the addition of calcium for the improvement of texture, our results are quite promising in order to produce new pickled products with extended shelf life along with conserving nutritional and functional components and satisfying consumer needs. PMID- 21819404 TI - Phenolics and antioxidant capacity of table grape (Vitis vinifera L.) cultivars grown in Chile. AB - Grapes (Vitis vinifera L.) possess health-promoting effects attributed to their supply of a wide variety of bioactive phenolics. Juice and skin fractions of 4 varieties of table grapes: Red Globe, Crimson Seedless, Autumn Royal, and Ribier were prepared to determine and compare their total phenolics content, antioxidant capacity (DPPH, FRAP, and ORAC), anthocyanins, and specific phenolics (caffeic acid, gallic acid, resveratrol, and catechin) content, since a series of positive health benefits are expected from the intake of any of these fractions. Higher amounts of total phenolics and antioxidant capacity were observed in the skin fractions (P < 0.05). Blue grapes (Autumn Royal and Ribier) exhibited higher phenolics content and antioxidant capacity (P < 0.05) than red grapes. The most abundant phenolic compound observed was catechin (P < 0.05). Significant correlations between the antioxidant capacity and total phenolics were observed in grape juice and skin fractions. Autumn Royal juice provides a very high amount of phenolics, anthocyanins, and exhibits the highest antioxidant capacity, offering the best health promoting properties compared with the other grape varieties studied. PRACTICAL APPLICATION: Grapes possess health-promoting effects attributed to their supply of a wide variety of bioactive phenolics. Grape juice made with blue grapes (Autumn Royal, Ribier) exhibit higher phenolics content and antioxidant capacity than juice elaborated with red grapes (Red Globe, Crimson Seedless). The skin is a good source of phenolics and has a high antioxidant capacity. Specific health-promoting phenolics are more abundant in blue grapes, mainly in their skin fraction, which should not be discarded. PMID- 21819405 TI - Kynurenine metabolism predicts cognitive function in patients following cardiac bypass and thoracic surgery. AB - Cardiac surgery involving extra-corporeal circulation can lead to cognitive dysfunction. As such surgery is associated with signs of inflammation and pro inflammatory mediators activate tryptophan oxidation to neuroactive kynurenines which modulate NMDA receptor function and oxidative stress, we have measured blood concentrations of kynurenines and inflammatory markers in 28 patients undergoing coronary arterial graft surgery and, for comparison, 28 patients undergoing non-bypass thoracic surgery. A battery of cognitive tests was completed before and after the operations. The results show increased levels of tryptophan with decreased levels of kynurenine, anthranilic acid and 3 hydroxyanthranilic acid associated with bypass, and a later increase in kynurenic acid. Levels of neopterin and lipid peroxidation products rose after surgery in non-bypass patients whereas tumour necrosis factor-alpha and S100B levels increased after bypass. Changes of neopterin levels were greater after non-bypass surgery. Cognitive testing showed that the levels of tryptophan, kynurenine, kynurenic acid and the kynurenine/tryptophan ratio, correlated with aspects of post-surgery cognitive function, and were significant predictors of cognitive performance in tasks sensitive to frontal executive function and memory. Thus, anaesthesia and major surgery are associated with inflammatory changes and alterations in tryptophan oxidative metabolism which predict, and may play a role in, post-surgical cognitive function. PMID- 21819407 TI - Pyrrolizidine alkaloid variation in shoots and roots of segregating hybrids between Jacobaea vulgaris and Jacobaea aquatica. AB - Hybridization can lead to novel qualitative or quantitative variation of secondary metabolite (SM) expression that can have ecological and evolutionary consequences. We measured pyrrolizidine alkaloid (PA) expression in the shoots and roots of a family including one Jacobaea vulgaris genotype and one Jacobaea aquatica genotype (parental genotypes), two F(1) hybrid genotypes, and 102 F(2) hybrid genotypes using liquid chromatography-tandem mass spectrometry (LC-MS/MS). We detected 37 PAs in the roots and shoots of J. vulgaris, J. aquatica and the hybrids. PA concentrations and compositions differed between genotypes, and between roots and shoots. Three otosenine-like PAs that only occurred in the shoots of parental genotypes were present in the roots of F(2) hybrids; PA compositions were sometimes novel in F(2) hybrids compared with parental genotypes, and in some cases transgressive PA expression occurred. We also found that PAs from within structural groups covaried both in the roots and in the shoots, and that PA expression was correlated between shoots and roots. Considerable and novel variation present among F(2) hybrids indicates that hybridization has a potential role in the evolution of PA diversity in the genus Jacobaea, and this hybrid system is useful for studying the genetic control of PA expression. PMID- 21819406 TI - Tissue-specific expression of Populus C19 GA 2-oxidases differentially regulate above- and below-ground biomass growth through control of bioactive GA concentrations. AB - * Here, we studied the poplar C(19) gibberellin 2-oxidase (GA2ox) gene subfamily. We show that a set of paralogous gene pairs differentially regulate shoot and root development. * PtGA2ox4 and its paralogous gene PtGA2ox5 are primarily expressed in aerial organs, and overexpression of PtGA2ox5 produced a strong dwarfing phenotype characteristic of GA deficiency. Suppression of PtGA2ox4 and PtGA2ox5 led to increased biomass growth, but had no effect on root development. By contrast, the PtGA2ox2 and PtGA2ox7 paralogous pair was predominantly expressed in roots, and when these two genes were RNAi-suppressed it led to a decrease of root biomass. * The morphological changes in the transgenic plants were underpinned by tissue-specific increases in bioactive GAs that corresponded to the predominant native expression of the targeted paralogous gene pair. Although RNAi suppression of both paralogous pairs led to changes in wood development, they were much greater in the transgenics with suppressed PtGA2ox4 and PtGA2ox5. The degree of gene suppression in independent events was strongly associated with phenotypes, demonstrating dose-dependent control of growth by GA2ox RNA concentrations. * The expression and transgenic modifications reported here show that shoot- and leaf-expressed PtGA2ox4 and PtGA2ox5 specifically restrain aerial shoot growth, while root-expressed PtGA2ox2 and PtGA2ox7 promote root development. PMID- 21819408 TI - NKp46+ cells express granulysin in multiple cutaneous adverse drug reactions. AB - BACKGROUND: The spectrum of cutaneous adverse drug reactions (cADRs) ranges from benign presentations to severe life-threatening forms such as toxic epidermal necrolysis (TEN). In TEN, granulysin has been shown to be the key cytotoxic molecule. Still, little is known about the expression of granulysin in other cADRs. As an important source of granulysin, natural killer (NK) cells are of major interest in cADRs. Recently, NKp46 has been identified as the most selective NK-cell marker. However, the role of NKp46(+) cells in cADRs and their contribution to granulysin expression remain to be elucidated. METHODS: Immunohistochemical and immunofluorescence staining of tissue sections from multiple cADRs were quantitatively and qualitatively evaluated. Further, in vivo and in vitro drug-stimulation tests were performed. RESULTS: Granulysin is expressed at different levels in multiple cADRs both by NKp46(+) cells and by CD8(+) T cells. Even in mild forms of cADRs, granulysin can be induced in vivo and in vitro in a drug-specific manner. NKp46(+) cells were found to infiltrate the dermal/epidermal junction particularly in TEN. CONCLUSION: The impressive clinical differences of cADRs may not be uniquely explained by the expression of granulysin. Additional factors such as drug-specific activation and recruitment of NKp46(+) cells to the epidermis may play a role in determining the severity of cADRs. Therefore, unraveling the effects of drugs on NK-cell activation and trafficking may help to better understand the cytotoxic mechanisms behind cADRs. PMID- 21819410 TI - Dose-dependent systemic exposure of albendazole metabolites in lambs. AB - The gastrointestinal absorption of most drugs follows a first-order kinetics, whereby a constant fraction of the total drug is absorbed in each equal time interval. Although this related absorption principle is applicable to the most of the therapeutically used drugs, it remains unclear for poorly water-soluble compounds such as the benzimidazole anthelmintics in ruminants. The goal of the current work was to characterize the albendazole (ABZ) metabolites plasma disposition kinetics after ABZ administration at different dosages to nematode infected lambs. Eighteen Corriedale lambs artificially infected with a resistant Haemonchus contortus strain were allocated into three groups and intraruminally treated with ABZ at either 5 (ABZ(5)), 15 (ABZ(15)) or 45 (ABZ(45)) mg/kg. Blood samples were collected up to 120 h post-treatment, and the collected plasma was analysed by high-performance liquid chromatography. The estimated pharmacokinetic parameters were statistically compared using parametric and nonparametric tests. None of the animals involved in the current trial showed any adverse events during the study. While ABZ parent drug was not recovered in the bloodstream, the area under the concentration vs time curve (AUC) of the active ABZ-sulphoxide (ABZSO) metabolite increased significantly (P<0.05) from 21.0 (ABZ(5)) up to 158.6 (ABZ(15)) and 389.7 MUg.h/mL (ABZ(45)), which indicates some type of nonproportionality in the relationship between dose level and drug systemic exposure. The overall kinetic disposition of the inactive sulphone metabolite did not change after treatment at threefold the therapeutic ABZ dosage. However, significantly (P<0.05) higher AUC, C(max) and mean residence time values were observed after the administration of the highest dosage level. The higher dosages accounted for a significantly (P<0.05) enhancement of the ABZSO peak plasma concentration, which were obtained at delayed times post-treatment. High correlations between AUC(0-LOQ) and C(max) and nematode counts were observed, with Spearman's coefficients of -0.83 and -0.84, respectively. The results obtained in the current experiment show that increasing the dose of ABZ in sheep is clearly associated with enhanced plasma ABZ metabolites exposure. The data showed a nonproportionality on the gastrointestinal absorption of ABZ in nematode infected lambs. PMID- 21819411 TI - Changes in leaf optical properties associated with light-dependent chloroplast movements. AB - We surveyed 24 plant species to examine how leaf anatomy influenced chloroplast movement and how the optical properties of leaves change with chloroplast position. All species examined exhibited light-dependent chloroplast movements but the associated changes in leaf absorptance varied considerably in magnitude. Chloroplast movement-dependent changes in leaf absorptance were greatest in shade species, in which absorptance changes of >10% were observed between high- and low light treatments. Using the Kubelka-Munk theory, we found that changes in the absorption (k) and chlorophyll a absorption efficiency (k*) associated with chloroplast movement correlated with cell diameter, such that the narrower, more columnar cells found in sun leaves restricted the ability of chloroplasts to move. The broader, more spherical cells of shade leaves allowed greater chloroplast rearrangements and in low-light conditions allowed efficient light capture. Across the species tested, light-dependent chloroplast movements modulated leaf optical properties and light absorption efficiency by manipulating the package (sieve or flattening) effect but not the detour (path lengthening) effect. PMID- 21819409 TI - Gene-vitamin D interactions on food sensitization: a prospective birth cohort study. AB - BACKGROUND: It has been hypothesized that vitamin D deficiency (VDD) contributes to the development of food sensitization (FS) and then food allergy. However, the epidemiological evidence is conflicting. We aim to examine whether cord blood VDD is associated with FS and whether such association can be modified by genetic variants in a prospective birth cohort. METHODS: This study included 649 children who were enrolled at birth and followed from birth onward at the Boston Medical Center. We defined VDD as cord blood 25(OH)D < 11 ng/ml, and FS as specific IgE >= 0.35 kUA/l to any of eight common food allergens in early childhood. We genotyped potentially functional single-nucleotide polymorphisms (SNPs) in 11 genes known to be involved in regulating IgE and 25(OH)D concentrations. Logistic regressions were used to test the effects of VDD on FS individually and jointly with SNPs. RESULTS: Among the 649 children, 44% had VDD and 37% had FS. When examined alone, VDD was not associated with FS. When examined jointly with SNPs, a significant interaction between IL4 gene polymorphism (rs2243250) and VDD (p(interaction) = 0.003, p(FDR) = 0.10) was found: VDD increased the risk of FS among children carrying CC/CT genotypes (OR = 1.79, 95%CI: 1.15-2.77). Similar but weaker interactions were observed for SNPs in MS4A2 (rs512555), FCER1G (rs2070901), and CYP24A1 (rs2762934). When all four SNPs were simultaneously considered, a strong gene-VDD interaction was evident (p(interaction) = 9 * 10( 6) ). CONCLUSIONS: Our data demonstrate that VDD may increase the risk of FS among individuals with certain genotypes, providing evidence of gene-vitamin D interaction on FS. PMID- 21819412 TI - Dinitrogen-fixing Acacia species from phosphorus-impoverished soils resorb leaf phosphorus efficiently. AB - Nitrogen (N) and phosphorus (P) resorption from senescing leaves were studied, and the contribution of N and P cycling through litterfall to soil nutrient patchiness was investigated for four Acacia species in the Great Sandy Desert in north-western Australia. N and P concentrations of mature and recently shed leaves were analysed and compared; soils under the canopies of the shrubs and soils in gaps (open areas) between the shrubs were also analysed and compared for N and P concentrations. Mature leaf P concentrations of the plants were considerably lower than the global average values, and N : P ratios of mature leaves were high. Plants derived 0-75% of their leaf N from symbiotic N(2) fixation. N-resorption efficiency was between 0 and 43%, and P-resorption efficiency was between 32 and 79%; all plants were more efficient at P resorption than at N resorption, and litter N : P ratios were significantly higher than mature leaf N : P ratios. Soils of the study sites were P-impoverished. Total soil N and P concentrations were higher under the canopy than in gaps, but bicarbonate-extractable P concentration was higher in gaps. Nutrient cycling through litterfall results in soil nutrient patchiness and forms 'islands of fertility' under the canopies of the shrubs. PMID- 21819413 TI - Physiological characterization of cadmium-exposed Chlamydomonas reinhardtii. AB - Chlamydomonas reinhardtii is a common model organism for investigation of metal stress. This green alga produces phytochelatins in the presence of metal ions. The influence of cadmium is of main interest, because it is a strong activator of phytochelatin synthase. Cell wall bound and intracellular cadmium content was determined after exposition to 70 um CdCl(2), showing the main portion of the metal outside the cell. Nevertheless, imported cadmium was sufficient to cause significant changes in thiolpeptide metabolism and its transcriptional regulation. Modern analytical approaches enable new insights into phytochelatin (PC) distribution. A new rapid and precise UPLC-MS method allowed high-throughput PC quantification in algal samples after 1, 4, 24 and 48 h cadmium stress. Initially, canonic PCs were synthesized in C. reinhardtii during cadmium exposition, but afterwards CysPCs became the major thiolpeptides. Thus, after 48 h the concentration of the PC-isoforms CysPC(2-3) and CysGSH attained between 105 and 199 nmol g(-1) fresh weight (FW), whereas the PC(2-3) concentrations were only 15 nmol g(-1) FW. The relative quantification of gamma-glutamyl transpeptidase (gamma-GT) mRNA suggests the generation of CysPCs by glutamate cleavage from canonic PCs by gamma-GT. Furthermore, a homology model of C. reinhardtii phytochelatin synthase was constructed to verify the use of crystal structures from Anabaena sp. phytochelatin synthase (PCS) for docking studies with canonical PCs and CysPCs. From the difference in energy scores, we hypothesize that CysPC may prevent the synthesis of canonical PCs by blocking the binding pocket. Finally, possible physiological reasons for the high abundance of CysPC compared with their canonic precursors are discussed. PMID- 21819414 TI - Leaf gas films of Spartina anglica enhance rhizome and root oxygen during tidal submergence. AB - Gas films on hydrophobic surfaces of leaves of some wetland plants can improve O(2) and CO(2) exchange when completely submerged during floods. Here we investigated the in situ aeration of rhizomes of cordgrass (Spartina anglica) during natural tidal submergence, with focus on the role of leaf gas films on underwater gas exchange. Underwater net photosynthesis was also studied in controlled laboratory experiments. In field experiments, O(2) microelectrodes were inserted into rhizomes and pO(2) measured throughout two tidal submergence events; one during daylight and one during night-time. Plants had leaf gas films intact or removed. Rhizome pO(2) dropped significantly during complete submergence and most severely during night. Leaf gas films: (1) enhanced underwater photosynthesis and pO(2) in rhizomes remained above 10 kPa during submergence in light; and (2) facilitated O(2) entry from the water into leaves so that rhizome pO(2) was about 5 kPa during darkness. This study is the first in situ demonstration of the beneficial effects of leaf gas films on internal aeration in a submerged wetland plant. Leaf gas films likely contribute to submergence tolerance of S. anglica and this feature is expected to also benefit other wetland plant species when submerged. PMID- 21819415 TI - Never too many? How legumes control nodule numbers. AB - Restricted availability of nitrogen compounds in soils is often a major limiting factor for plant growth and productivity. Legumes circumvent this problem by establishing a symbiosis with soil-borne bacteria, called rhizobia that fix nitrogen for the plant. Nitrogen fixation and nutrient exchange take place in specialized root organs, the nodules, which are formed by a coordinated and controlled process that combines bacterial infection and organ formation. Because nodule formation and nitrogen fixation are energy-consuming processes, legumes develop the minimal number of nodules required to ensure optimal growth. To this end, several mechanisms have evolved that adapt nodule formation and nitrogen fixation to the plant's needs and environmental conditions, such as nitrate availability in the soil. In this review, we give an updated view on the mechanisms that control nodulation. PMID- 21819416 TI - Potassium channel-oxidative phosphorylation relationship in durum wheat mitochondria from control and hyperosmotic-stressed seedlings. AB - Durum wheat mitochondria (DWM) possess an ATP-inhibited K(+) channel, the plant mitoK(ATP) (PmitoK(ATP) ), which is activated under environmental stress to control mitochondrial ROS production. To do this, PmitoK(ATP) collapses membrane potential (DeltaPsi), thus suggesting mitochondrial uncoupling. We tested this point by studying oxidative phosphorylation (OXPHOS) in DWM purified from control seedlings and from seedlings subjected both to severe mannitol and NaCl stress. In severely-stressed DWM, the ATP synthesis via OXPHOS, continuously monitored by a spectrophotometric assay, was about 90% inhibited when the PmitoK(ATP) was activated by KCl. Contrarily, in control DWM, although PmitoK(ATP) collapsed DeltaPsi, ATP synthesis, as well as coupling [respiratory control (RC) ratio and ratio between phosphorylated ADP and reduced oxygen (ADP/O)] checked by oxygen uptake experiments, were unaffected. We suggest that PmitoK(ATP) may play an important defensive role at the onset of the environmental/oxidative stress by preserving energy in a crucial moment for cell and mitochondrial bioenergetics. Consistently, under moderate mannitol stress, miming an early stress condition, the channel may efficiently control reactive oxygen species (ROS) generation (about 35-fold from fully open to closed state) without impairing ATP synthesis. Anyway, if the stress significantly proceeds, the PmitoK(ATP) becomes fully activated by decrease of ATP concentration (25-40%) and increase of activators [free fatty acids (FFAs) and superoxide anion], thus impairing ATP synthesis. PMID- 21819417 TI - Ictal asystole: an indication for pacemaker implantation and emerging cause of sudden death. AB - Ictal asystole is being recognized as a potential mechanism of sudden unexplained death in epilepsy (SUDEP). We report a case of a patient without known cardiac disease presenting with ictal asystole resulting in syncope, trauma, and need for pacemaker implantation. The management of ictal asystole is also briefly reviewed. This case is notable for the asystolic episode wholly captured on video electroencephalogram/electrocardiogram, the serious risk of trauma and death posed to the patient, and its implications for the mechanism of ictal asystole. This report will alert physicians to the possibility of ictal arrhythmias as a cause of syncope and SUDEP in vulnerable patients. PMID- 21819418 TI - Intercostal muscle twitching from right ventricular apical pacing. AB - A patient with a dilated cardiomyopathy underwent successful implantation of a cardiac resynchronization therapy defibrillator. The device system included an active fixation lead placed at the right ventricular (RV) apex. Pacing from the RV apex unexpectedly led to left-sided intercostal muscle stimulation and twitching. This intercostal muscle twitching resolved completely with movement of the lead to the RV outflow tract. PMID- 21819419 TI - Tachycardia during coronary computed tomography angiography. PMID- 21819420 TI - An apparent way of achieving proof of pulmonary vein disconnection during cryoballoon ablation. AB - Pulmonary vein isolation (PVI) has established itself as a standard therapy for paroxysmal atrial fibrillation (AF). Still, the most widely performed procedure of point-by-point distal-tip ablation using a 3-dimensional mapping system and a circular catheter to validate PVI remains a complex, elaborative, and time consuming procedure. This explains the many efforts being made over the recent years to simplify and shorten PVI procedures without compromising the efficacy or the safety. The cryoballoon (Ablation Frontiers, Medtronic, Inc., Minneapolis, MN, USA) is a recently introduced "single shot ablation tool" to facilitate PVI. Initial studies on efficacy and safety of this device are encouraging in patients with paroxysmal AF. However, several controversies remain, such as the need for an additional circular mapping catheter to validate PVI and the lack of on-line PV recording during freezes. One of the most recent developments in this field is the Achieve circular mapping catheter (Ablation Frontiers, Medtronic, Inc.). We describe an apparent case in which this tool is used in conjunction with the cryoballoon. PMID- 21819421 TI - Methodology. PMID- 21819422 TI - Practical and analytical aspects of using friend controls in case-control studies: experience from a case-control study of childhood cancer. AB - We report empirical data on the use of friend controls, specifically response rates, case-control concordance and analytical approaches. The data derive from a North American multi-institutional study of childhood cancer that was conducted in 2002-07 and that focused on paternal exposures. Case parents nominated friends as potential controls; up to three controls participated per case. For 137 (69%) of the 199 case families, at least one control parent participated. Of 374 potential controls contacted, 247 (66%) participated. Case fathers with controls were markedly more likely to be non-Hispanic White, college graduates and non smokers compared with case fathers without controls. Odds ratios adjusted for demographic characteristics were generally similar but occasionally differed between analyses that included only members of matched sets and those that included all participants, i.e., controls and cases with and without controls. For demographic characteristics, simulations demonstrated that the observed concordance of cases and controls within matched sets exceeded that expected under random ascertainment, indicating probable overmatching. However, the observed concordance of smoking and other exposures was similar to the expectation under random ascertainment, suggesting little overmatching on exposures. Although not ideal, friend controls were convenient, had a reasonably high response rate and provided controls closely matched on race/ethnicity, education and age. PMID- 21819423 TI - Designing prospective cohort studies for assessing reproductive and developmental toxicity during sensitive windows of human reproduction and development--the LIFE Study. AB - The relationship between the environment and human fecundity and fertility remains virtually unstudied from a couple-based perspective in which longitudinal exposure data and biospecimens are captured across sensitive windows. In response, we completed the LIFE Study with methodology that intended to empirically evaluate a priori purported methodological challenges: implementation of population-based sampling frameworks suitable for recruiting couples planning pregnancy; obtaining environmental data across sensitive windows of reproduction and development; home-based biospecimen collection; and development of a data management system for hierarchical exposome data. We used two sampling frameworks (i.e., fish/wildlife licence registry and a direct marketing database) for 16 targeted counties with presumed environmental exposures to persistent organochlorine chemicals to recruit 501 couples planning pregnancies for prospective longitudinal follow-up while trying to conceive and throughout pregnancy. Enrolment rates varied from <1% of the targeted population (n = 424,423) to 42% of eligible couples who were successfully screened; 84% of the targeted population could not be reached, while 36% refused screening. Among enrolled couples, ~ 85% completed daily journals while trying; 82% of pregnant women completed daily early pregnancy journals, and 80% completed monthly pregnancy journals. All couples provided baseline blood/urine samples; 94% of men provided one or more semen samples and 98% of women provided one or more saliva samples. Women successfully used urinary fertility monitors for identifying ovulation and home pregnancy test kits. Couples can be recruited for preconception cohorts and will comply with intensive data collection across sensitive windows. However, appropriately sized sampling frameworks are critical, given the small percentage of couples contacted found eligible and reportedly planning pregnancy at any point in time. PMID- 21819425 TI - The GABRIEL Advanced Surveys: study design, participation and evaluation of bias. AB - Exposure to farming environments has been shown to protect substantially against asthma and atopic disease across Europe and in other parts of the world. The GABRIEL Advanced Surveys (GABRIELA) were conducted to determine factors in farming environments which are fundamental to protecting against asthma and atopic disease. The GABRIEL Advanced Surveys have a multi-phase stratified design. In a first-screening phase, a comprehensive population-based survey was conducted to assess the prevalence of exposure to farming environments and of asthma and atopic diseases (n = 103,219). The second phase was designed to ascertain detailed exposure to farming environments and to collect biomaterial and environmental samples in a stratified random sample of phase 1 participants (n = 15,255). A third phase was carried out in a further stratified sample only in Bavaria, southern Germany, aiming at in-depth respiratory disease and exposure assessment including extensive environmental sampling (n = 895). Participation rates in phase 1 were around 60% but only about half of the participating study population consented to further study modules in phase 2. We found that consenting behaviour was related to familial allergies, high parental education, wheeze, doctor diagnosed asthma and rhinoconjunctivitis, and to a lesser extent to exposure to farming environments. The association of exposure to farm environments with asthma or rhinoconjunctivitis was not biased by participation or consenting behaviour. The GABRIEL Advanced Surveys are one of the largest studies to shed light on the protective 'farm effect' on asthma and atopic disease. Bias with regard to the main study question was able to be ruled out by representativeness and high participation rates in phases 2 and 3. The GABRIEL Advanced Surveys have created extensive collections of questionnaire data, biomaterial and environmental samples promising new insights into this area of research. PMID- 21819424 TI - Stillbirth Collaborative Research Network: design, methods and recruitment experience. AB - The Stillbirth Collaborative Research Network (SCRN) has conducted a multisite, population-based, case-control study, with prospective enrollment of stillbirths and livebirths at the time of delivery. This paper describes the general design, methods and recruitment experience. The SCRN attempted to enroll all stillbirths and a representative sample of livebirths occurring to residents of pre-defined geographical catchment areas delivering at 59 hospitals associated with five clinical sites. Livebirths <32 weeks gestation and women of African descent were oversampled. The recruitment hospitals were chosen to ensure access to at least 90% of all stillbirths and livebirths to residents of the catchment areas. Participants underwent a standardised protocol including maternal interview, medical record abstraction, placental pathology, biospecimen testing and, in stillbirths, post-mortem examination. Recruitment began in March 2006 and was completed in September 2008 with 663 women with a stillbirth and 1932 women with a livebirth enrolled, representing 69% and 63%, respectively, of the women identified. Additional surveillance for stillbirths continued until June 2009 and a follow-up of the case-control study participants was completed in December 2009. Among consenting women, there were high consent rates for the various study components. For the women with stillbirths, 95% agreed to a maternal interview, chart abstraction and a placental pathological examination; 91% of the women with a livebirth agreed to all of these components. Additionally, 84% of the women with stillbirths agreed to a fetal post-mortem examination. This comprehensive study is poised to systematically study a wide range of potential causes of, and risk factors for, stillbirths and to better understand the scope and incidence of the problem. PMID- 21819426 TI - Realignment and multiple imputation of longitudinal data: an application to menstrual cycle data. AB - Reproductive hormone levels are highly variable among premenopausal women during the menstrual cycle. Accurate timing of hormone measurement is essential, especially when investigating day- or phase-specific effects. The BioCycle Study used daily urine home fertility monitors to help detect the luteinising hormone (LH) surge in order to schedule visits with biologically relevant windows of hormonal variability. However, as the LH surge is brief and cycles vary in length, relevant hormonal changes may not align with scheduled visits even when fertility monitors are used. Using monitor data, measurements were reclassified according to biological phase of the menstrual cycle to more accurate cycle phase categories. Longitudinal multiple imputation methods were applied after reclassification if no visit occurred during a given menstrual cycle phase. Reclassified cycles had more clearly defined hormonal profiles, with higher mean peak hormones (up to 141%) and reduced variability (up to 71%). We demonstrate the importance of realigning visits to biologically relevant windows when assessing phase- or day-specific effects and the feasibility of applying longitudinal multiple imputation methods. Our method has applications in settings where missing data may occur over time, where daily blood sampling for hormonal measurements is not feasible, and in other areas where timing is essential. PMID- 21819427 TI - Clustering of fecundability within women. AB - Adverse pregnancy outcomes have long been observed to cluster within women resulting in the inclusion of past reproductive history in clinical assessments and perinatal scoring systems. However, limited study has focused on the clustering of fecundability as measured by time to pregnancy (TTP), despite growing evidence suggestive of a possible association with adverse pregnancy outcomes known to cluster within women. We sought to empirically evaluate the clustering of conception delay, and TTP more globally, in one of the few existing prospective pregnancy cohort studies that captured women's successive pregnancies. The study cohort comprised 544 women who contributed 1119 pregnancies in the U.S. Collaborative Perinatal Project. We used a discrete Cox frailty model to estimate the degree and significance of within-woman clustering of TTP. Women with an initial conception delay (TTP > 6 months) were older, less educated and had higher body mass indices than women not experiencing delays (TTP <= 6 months). Our analysis indicates that there is significant within-woman clustering of TTP (variance of the frailty = 0.80, [95% confidence interval 0.49, 1.11]) after adjusting for baseline maternal age, body mass index and education level. Similar to many other reproductive and perinatal outcomes, our findings suggest that TTP clusters within women. Identifying exposures or behaviours that affect TTP may offer strategies for reducing conception delay in future pregnancy attempts. PMID- 21819428 TI - Infertility, infertility treatment and behavioural problems in the offspring. AB - Behavioural patterns in children of infertile couples may be influenced by both the underlying causes of infertility and stress in the couples. Treatment procedures, such as culture media and manipulation of gametes and embryos, may also result in developmental problems. We examined behavioural problems in children as a function of infertility and infertility treatment, using data from three population-based birth cohorts in Denmark (Aalborg-Odense Birth Cohort, Aarhus Birth Cohort and Danish National Birth Cohort). Information on time to pregnancy and infertility treatment was collected during pregnancy. Children aged between 7 and 21 years were assessed using the Strengths and Difficulties Questionnaire (SDQ). The SDQ was completed by mothers in all cohorts and, in addition, by teachers in the Aarhus cohort and by children themselves in the Aalborg-Odense cohort. Children born after a time to pregnancy of >12 months and no infertility treatment had a behavioural pattern similar to children of fertile parents. Teachers reported a higher total difficulties score for children born after infertility treatment, but no significant differences were seen on any subscales of the teachers' report, and neither the mothers nor the children reported any differences on the total difficulties score and the prosocial behaviour score. Our results are thus overall reassuring regarding behavioural problems in children born to infertile couples, regardless of infertility treatment. PMID- 21819429 TI - Physical violence between intimate partners during pregnancy and postpartum: a prediction model for use in primary health care facilities. AB - This article offers a simple predictive model of physical intimate partner violence (PIPV) to be used by primary health care (PHC) professionals. The sample comprised 811 mothers of children <5 months old attending PHC facilities in Rio de Janeiro, Brazil. A multinomial logit model was used. Measured by the Revised Conflict Tactics Scales, PIPV was classified in three levels (absence, at least one episode during pregnancy or postpartum, and presence in both periods). Socio economic, demographic and life style variables were considered as potential predictors. Maternal age <20 years, an education of <8 years of schooling, raising >2 children under 5, tobacco smoking, alcohol misuse and illicit drug use by the mother and/or partner, and perception of baby's ill-health were identified as predictors of PIPV. The model-projected prevalence of PIPV for pregnancy and/or postpartum was just 10.1% in the absence of these characteristics, whereas this increased to 96.4% when all the seven characteristics were present. Child, maternal and family characteristics greatly increase the likelihood of PIPV and could be used together as screening indicators. PMID- 21819430 TI - Maternal injuries during the periconceptional period and the risk of birth defects, National Birth Defects Prevention Study, 1997-2005. AB - Maternal injuries during pregnancy are common (~7% prevalence). However, few studies have examined the association between maternal injuries and birth defects. The National Birth Defects Prevention Study is a population-based case control study of birth defects in 10 U.S. states. Cases were ascertained through surveillance; controls were randomly selected from infants delivered without major birth defects in the study regions. Mothers completed a telephone interview on exposures before and during pregnancy, including injuries. We assessed associations between periconceptional (month before until the end of the third month of pregnancy) maternal injuries and birth defects. We used logistic regression to estimate adjusted odds ratios (AORs) and 95% confidence intervals (CI). Periconceptional injuries were associated with interrupted aortic arch type B [AOR = 5.2, 95% CI 1.2, 23.2]; atrioventricular septal defect [AOR = 2.2, 95% CI 1.1, 4.4]; pulmonary atresia [AOR = 3.2, 95% CI 1.6, 6.4]; tricuspid atresia [AOR = 2.8, 95% CI 1.2, 6.7]; hypoplastic left heart syndrome [AOR = 2.0, 95% CI 1.1, 3.4]; anorectal atresia/stenosis [AOR = 1.7, 95% CI 1.0, 2.7]; longitudinal limb deficiency [AOR = 2.1, 95% CI 1.1, 3.9]; and gastroschisis [AOR = 1.8, 95% CI 1.2, 2.8]. Associations with longitudinal limb deficiency, gastroschisis and hypoplastic left heart syndrome were stronger for intentional injuries. Our results suggest maternal injury during the periconceptional period, particularly those inflicted intentionally, may be associated with select birth defects. This analysis was hypothesis-generating, with many associations tested. Further research is warranted. PMID- 21819431 TI - Wide complex tachycardia with a unique mode of termination: what is the mechanism? PMID- 21819432 TI - The importance of tricuspid regurgitation and right ventricular overload in ICD/CRT recipients: beside the left, beyond the left. AB - Device therapy for advanced heart failure has become increasingly employed in the last 10 years. Several retrospective studies have postulated a harmful effect of implantable cardioverter-defibrillator (ICD) lead placement on tricuspid valve function and right heart hemodynamics, in particular among patients with preexisting pulmonary vascular overload and both left and right ventricular remodeling/dysfunction. This functional hypothesis is also supported by long-term clinical follow-up analyses of ICD and cardiac resynchronization therapy recipients. In this viewpoint, we propose that the possibility of worsening tricuspid regurgitation and consequent hemodynamic deterioration following device implantation should be considered in future studies, as well as in the preimplant evaluation of individual candidates among other clinical factors. PMID- 21819433 TI - Predictors of axillary vein location for vascular access during pacemaker and defibrillator lead implantation. AB - BACKGROUND: The axillary vein is a commonly used extrathoracic access site for cardiac rhythm device lead implantation. We sought to describe variation in axillary vein location and identify predictors of a more cranial or caudal radiographic location to facilitate blind venous cannulation. METHODS: This was a single-center, retrospective study of patients undergoing lead implantation between 2006 and 2010. The cranial-caudal location of the axillary vein lateral and medial to the rib cage border was determined by reviewing peripheral contrast venograms. Multivariate linear regression was performed. RESULTS: Of 155 patients, the majority were men (62%) and White (53%). The most frequent position of the lateral and medial axillary vein was over the third rib (40%) and top of the third rib (15%), respectively. In multivariate analysis, whites had a more caudal location of both the lateral (0.56 rib spaces lower, 95% confidence interval [CI] 0.22-0.91, P = 0.002) and medial axillary vein (0.50 rib spaces lower, 95% CI 0.85-0.91, P = 0.019). Other independent predictors included an approximate 3-4% higher rib space location for every digit increase in body mass index (BMI) (P = 0.049 for the lateral location and P = 0.016 for the medial location) and an approximate half rib space higher location for males (P = 0.015 for the lateral location and P = 0.013 for the medial location). CONCLUSIONS: The most common radiographic position of the axillary vein was over the third rib. Whites have a more caudal axillary vein location while men and patients with higher BMI have a more cranial position of the axillary vein. PMID- 21819434 TI - The influence of atrial and ventricular pacing on the incidence of atrial fibrillation: a meta-analysis. AB - BACKGROUND: The effect of atrial pacing on the incidence of atrial fibrillation (AF) is unknown. Furthermore, the threshold of ventricular pacing that is associated with a higher incidence of AF has yet to be determined. Thus, we set out to determine the optimal pacing modality in patients with sinus node dysfunction (SND) for the prevention of AF. METHODS: Individual patient data from four contemporary pacemaker studies were gathered and analyzed. Since AF would inherently lead to a reduction in atrial pacing, percent atrial and ventricular pacing (%AP and %VP) were determined at the first follow-up visit and then used as a surrogate for all endpoints. Patients with >5 minutes of AF at the first visit were excluded. The primary endpoint was defined as 7 consecutive days of AF. RESULTS: A total of 1,507 patients were included. During a mean follow-up of 14.3 +/- 8.7 months, 77 patients developed AF (annual rate of 4.3%). The incidence of AF in the first (0-32%), second (32-66%), third (66-89%), and fourth (89-100%) quartiles of %AP was 1.3%, 5.3%, 5.8%, and 8.0%, respectively (P < 0.001). A multivariable analysis found that pacing above the first quartile was associated with a relative risk of 2.93 (95% confidence interval 1.16-7.39, P = 0.023). The grouping of %VP into first (0-2%), second (2-7%), third (7-84%), and fourth (84-100%) quartiles yielded an AF incidence of 2.4%, 3.4%, 6.6%, and 8.0%, respectively (P = 0.001). CONCLUSION: We demonstrated that in patients with SND both atrial and ventricular pacing are associated with a higher incidence of AF. PMID- 21819435 TI - Novel surface modifications of carbon fiber-reinforced polyetheretherketone hip stem in an ovine model. AB - A carbon fiber-reinforced polymer (CFRP) is theoretically a suitable material for use in an uncemented hip prosthesis considering it can provide isoelastic environment with the surrounding bone, adequate fatigue strength, and a metal free radiographic evaluation. To date, the selection of polymer material and optimization of both design and surface finish of the prostheses for osseointegration has not been accomplished. This study examined radiographic and histologic results of an uncemented CFRP stem manufactured from carbon fiber reinforced polyetheretherketone (CFR/PEEK) with a roughened surface and a bioactive treatment in an adult ovine model following a 12-month implantation period. A unilateral hemiarthroplasty of the hip was performed using the CFRP stem or a titanium stem as a control. Four cases with the CFRP stem and five cases with titanium stem were evaluated. Bone on-growth fixation was achieved in two cases with the CFRP stem and in all the cases with the titanium stem. The CFRP cases showed minimal stress shielding while three of five cases with the titanium stem demonstrated typical osteopenia associated with stiff metal stems. Bone on-growth to the uncemented CFRP stem was achieved by using the CFR/PEEK for the material and modifying the surface design and the bioactive surface finish. Bone resorption and osteopenia observed with the Ti stems was not found with the CFRP design. PMID- 21819436 TI - In vitro comparison of support capabilities of intra-aortic balloon pump and Impella 2.5 left percutaneous. AB - The Impella 2.5 left percutaneous (LP), a relatively new transvalvular assist device, challenges the position of the intra-aortic balloon pump (IABP), which has a long record in supporting patients after myocardial infarction and cardiac surgery. However, while more costly and more demanding in management, the advantages of the Impella 2.5 LP are yet to be established. The aim of this study was to evaluate the benefits of the 40 cc IABP and the Impella 2.5 LP operating at 47,000 rpm in vitro, and compare their circulatory support capabilities in terms of cardiac output, coronary flow, cardiac stroke work, and arterial blood pressure. Clinical scenarios of cardiogenic preshock and cardiogenic shock (CS), with blood pressure depression, lowered cardiac output, and constant heart rate of 80 bpm, were modeled in a model-controlled mock circulation, featuring a systemic, pulmonary, and coronary vascular bed. The ventricles, represented by servomotor-operated piston pumps, included the Frank-Starling mechanism. The systemic circulation was modeled with a flexible tube having close-to-human aortic dimensions and compliance properties. Proximally, it featured a branch mimicking the brachiocephalic arteries and a physiological correct coronary flow model. The rest of the systemic and pulmonary impedance was modeled by four element Windkessel models. In this system, the enhancement of coronary flow and blood pressure was tested with both support systems under healthy and pathological conditions. Hemodynamic differences between the IABP and the Impella 2.5 LP were small. In our laboratory model, both systems approximately yielded a 10% cardiac output increase and a 10% coronary flow increase. However, since the Impella 2.5 LP provided significantly better left ventricular unloading, the circulatory support capabilities were slightly in favor of the Impella 2.5 LP. On the other hand, pulsatility was enhanced with the IABP and lowered with the Impella 2.5 LP. The support capabilities of both the IABP and the Impella 2.5 LP strongly depended on the simulated hemodynamic conditions. Maximum hemodynamic benefits were achieved when mechanical circulatory support was applied on a simulated scenario of deep CS. PMID- 21819437 TI - The influence of membrane molecular weight cutoff on a novel bioartificial liver. AB - Given the xenogeneic immune reaction relevant to the molecular weight cutoff of the membrane of a bioartificial liver (BAL) system, we investigated the influence of membrane molecular weight cutoff in our BAL system in this study. Acute liver failure in beagles was induced by d-galactosamine administration. Eight beagles were divided into two groups by the membrane molecular weight cutoff of the plasma component separator. Group 1 beagles were treated with BAL containing 200 kDa retention rating membrane. Group 2 beagles were treated with BAL containing 1200 kDa retention rating membrane. Each group underwent two 6-h BAL treatments that were performed on day 1 and day 21. The hemodynamic and hematologic response, humoral immune responses, and cytotoxic immune response to BAL therapy were studied before and after treatments. All beagles remained hemodynamically and hematologically stable during BAL treatments. BAL treatment was associated with a significant decline in levels of complement; however, a longer time of level maintenance was observed in Group 2. Group 2 beagles experienced a significant increase in levels of IgG and IgM after two BAL treatments. Significant levels of canine proteins were detected in BAL medium from Group 2; only trace levels of canine proteins were detected in BAL medium from Group 1. The posttreatment viability of co-culture cells in Group 2 was lower compared with Group 1, and the viability of co-culture cells after treatments was associated with deposition of canine proteins on the cells. Xenogeneic immune response was influenced by membrane molecular weight cutoff in the BAL. PMID- 21819438 TI - Reduced growth hormone secretion in obesity is associated with smaller LDL and HDL particle size. AB - OBJECTIVE: Reduced growth hormone (GH) secretion is observed in obesity and may contribute to increases in cardiovascular disease (CVD) risk. Lipoprotein characteristics including increased small dense low-density lipoprotein (LDL) particles are known independent risk factors for CVD. We hypothesized that reduced GH secretion in obesity would be associated with a more atherogenic lipid profile including increased small dense LDL particles. DESIGN: To evaluate this hypothesis, we studied 102 normal weight and obese men and women using standard GH stimulation testing to assess GH secretory capacity and performed comprehensive lipoprotein analyses including determination of lipoprotein particle size and subclass concentrations using proton NMR spectroscopy. RESULTS: Obese subjects were stratified into reduced or sufficient GH secretion based on the median peak-stimulated GH (<=6.25 MUg/l). Obese subjects with reduced GH secretion (n = 35) demonstrated a smaller mean LDL and HDL particle size in comparison to normal weight subjects (n = 33) or obese subjects with sufficient GH (n = 34) by ANOVA (P < 0.0001). Univariate analyses demonstrated peak stimulated GH was positively associated with LDL (r = 0.50; P < 0.0001) and HDL (r = 0.57; P < 0.0001), but not VLDL (P = 0.06) particle size. Multivariate regression analysis controlling for age, gender, race, ethnicity, tobacco, use of lipid-lowering medication, BMI and HOMA demonstrated peak-stimulated GH remained significantly associated with LDL particle size (beta = 0.01; P = 0.01; R(2) = 0.42; P < 0.0001 for overall model) and HDL particle size (beta = 0.008; P = 0.001; R(2) = 0.44; P < 0.0001 for overall model). CONCLUSIONS: These results suggest reduced peak-stimulated GH in obesity is independently associated with a more atherogenic lipoprotein profile defined in terms of particle size. PMID- 21819439 TI - Preference for dentist's home visits among older people. AB - OBJECTIVES: To investigate factors associated with older people's preference for a dentist's home visit. METHODS: This is a report on 321 home-dwelling participants (mean age 81.6) in the population-based Geriatric Multidisciplinary Strategy for Good Care of the Elderly (GeMS) study, conducted in 2004-2005 in the city of Kuopio in eastern Finland. The information about sociodemographic and general health-related factors and the use of social and health services was collected by two study nurses using a structured interview. Each study subject was given a clinical oral examination and an interview about oral health and the use of dental health care services by one of two dentists. Logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Of the study subjects, 25.9% preferred a dentist's home visit. The preference for choosing a dentist's home visit was associated with a low score (<=24) in the Mini-Mental State Examination, OR 6.1 (CI: 2.9-13.6), and a low score (<8) on the scale of Instrumental Activities of Daily Living, OR 8.0 (CI: 3.6-18.6). It was also associated with living alone, OR 5.9 (CI: 2.7-13.0), and high use of home care services, OR 9.3 (CI: 4.6-19.0). CONCLUSIONS: The findings of this study emphasize the need to organize dentists' home visits in order to increase equality in the use of dental health care services among the older people with disabilities. PMID- 21819440 TI - Fluoride content of ready-to-feed (RTF) infant food and drinks in the UK. AB - BACKGROUND: The level of Fluoride exposure needed to cause dental fluorosis is not known precisely. An awareness of total F intake from all sources, especially during the critical stages of dental development during infancy and early childhood, is important in preventing the development of dental fluorosis. OBJECTIVES: The aim of the study was to measure F content of ready-to-feed (RTF) infant drinks and foods in the UK. METHODS: In total, 122 infant foods were analysed for F concentrations, in triplicate, indirectly by an acid diffusion method and 25 infant drinks analysed directly using an F-ion-selective electrode after addition of TISABIII. RESULTS: The median (range) F concentration was 0.110 (0.030-0.221) MUg/g for breakfast cereals, 0.112 (0.040-1.200) MUg/g for savoury meals, 0.056 (0.030-0.379) MUg/g for desserts, 0.044 (0.020-0.191) MUg/g for fruits, 0.196 (0.040-0.397) MUg/g for baked goods, 0.069 (0.050-0.148) MUg/ml for juices, 0.016 (0.009-0.030) MUg/ml for milks and 0.041 (0.022-0.069) MUg/ml for waters. The median (range) F concentration of all RTF infant foods and drinks by recommended age of consumption was 0.029 (0.010-0.245), 0.088 (0.020-0.500), 0.108 (0.100-0.510) and 0.108 (0.060-1.200) MUg/g for infants from birth, 4+ month, 6+ month and 10+ month, respectively. CONCLUSION: The results suggest that the F concentrations of UK-marketed RTF infant foods, drinks and formula milk are not sufficiently high to be a risk factor for dental fluorosis, if consumption is within the limits recommended for infants and young children. PMID- 21819441 TI - Childhood socioeconomic position, adult sense of coherence and tooth retention. AB - OBJECTIVE: To explore the role of sense of coherence (SOC) as a mediator in the relationship between childhood socioeconomic position (SEP) and tooth retention in adulthood. METHODS: Data from 5401 dentate adults aged 30 and over who participated in the nationally representative Finnish Health 2000 Survey were analysed. Participants provided information on demographic characteristics (sex and age), childhood SEP (parental education), adulthood SEP (years of education and household income), the SOC scale and oral health-related behaviours (dental attendance, toothbrushing frequency, sugar intake frequency and daily smoking). They also had a clinical oral health examination. Structural equation modelling was used to test a model including adulthood SEP, SOC and oral health-related behaviours as mediators of the relationship between childhood SEP and tooth retention. Multigroup comparison was also conducted to test the hypothesized model within each sex and age group (<45 years, 45-59 years and 60+ years). RESULTS: The relationship between childhood SEP and tooth retention in adulthood was to a large extent mediated by adulthood SEP and to a much lesser extent by SOC. There was only a weak association between childhood SEP and adult SOC, but favourable oral health-related behaviours appeared to link a strong SOC with greater tooth retention. The model was invariant across sexes and age groups. CONCLUSIONS: SOC is associated with tooth retention through oral health-related behaviours, but contributes little to the relationship between childhood SEP and tooth retention. PMID- 21819442 TI - Distinctive eosinophilic cytoplasmic inclusion bodies in melanocytic nevi: an immunohistochemical and ultrastructural study. AB - BACKGROUND: We sought to further determine the histochemical, immunohistochemical and ultrastructural properties of eosinophilic cytoplasmic inclusion bodies in melanocytic nevi. METHODS: Skin specimens from four patients with a known diagnosis of conventional melanocytic nevus (3) or Spitz nevus (1) and containing intracytoplasmic eosinophilic inclusion bodies were selected. In addition, melanomas (25), Spitz nevi (10) and blue nevi (4) were examined to determine the frequency of the inclusions. RESULTS: Inclusions tended to be located in multinucleated melanocytes with abundant vacuolated cytoplasm. In conventional (hematoxylin and eosin-stained) sections, the degree of density and eosinophilia of intracytoplasmic inclusions varied with size. Periodic acid-Schiff, Fontana and Congo red stains showed no reactivity. All bodies were immunoreactive for ubiquitin but negative for tyrosinase, keratin and vimentin. Ultrastructurally, inclusion bodies were non-membrane bound, ranged from 4 to 7 um, and were comprised of radiating filamentous structures with or without an electron-dense core. Electron probe x-ray microanalysis revealed no significant peaks. None of additional melanomas, Spitz nevi and blue nevi that were evaluated showed similar inclusions. CONCLUSIONS: The inclusion bodies described herein bear no resemblance to other cytoplasmic inclusion bodies previously described in melanocytic lesions. There is no discernible relationship to melanosomes by ultrastructural analysis. We postulate a relationship with dysfunction of ubiquitin-mediated protein degradation occurring in melanocytes. PMID- 21819443 TI - A physiological concentration of glucocorticoid inhibits the pro-inflammatory cytokine-induced proliferation of adult rat cardiac fibroblasts: roles of extracellular signal-regulated kinase 1/2 and nuclear factor-kappaB. AB - 1. Inflammation-induced proliferation of cardiac fibroblasts plays an important role in cardiac remodelling. Pharmacological doses of exogenous glucocorticoids (GC) are the most effective therapy for inflammatory diseases. Similarly, physiological concentrations of endogenous GC have recently been shown to have anti-inflammatory effects. Therefore, the aim of the present study was to determine whether a physiological concentration of GC could inhibit pro inflammatory cytokine-stimulated proliferation of cardiac fibroblasts and to explore the mechanisms involved. 2. Cardiac fibroblasts were isolated from adult male Sprague-Dawley rats and cell proliferation was measured using a CCK-8 kit. Western blotting was used to detect protein expression of extracellular-regulated kinase (ERK) 1/2 and nuclear factor (NF)-kappaB. 3. Cardiac fibroblast proliferation was significantly increased by tumour necrosis factor-alpha, interleukin (IL)-1beta and angiotensin II and was accompanied by upregulated protein expression of ERK1/2 and NF-kappaB. A physiological concentration of hydrocortisone (127 ng/mL) not only inhibited the proliferation of cardiac fibroblasts, but also suppressed activation of ERK1/2 and NF-kappaB. These effects of hydrocortisone were abrogated by the glucocorticoid receptor (GR) antagonist RU-486 (100 nmol/L). Furthermore, inflammation-induced cardiac fibroblast proliferation was also blocked by the mitogen-activated protein kinase kinase 1/2 inhibitor U0126 (100 nmol/L) and the NF-kappaB inhibitor pyrrolidine dithiocarbamate (1 MUmol/L). Cytokine-induced ERK1/2 phosphorylation and cyclin D1 expression were attenuated by U0126, suggesting that the ERK1/2 and NF-kappaB signalling pathways were involved in cardiac fibroblast proliferation. 4. In conclusion, the results of the present study indicate that a physiological concentration of hydrocortisone can inhibit inflammation-induced proliferation of cardiac fibroblasts by preventing the activation of ERK1/2 and NF-kappaB. PMID- 21819444 TI - Captopril and telmisartan treatments attenuate cadmium-induced testicular toxicity in rats. AB - The possible protective effect of captopril, an angiotensin-converting enzyme inhibitor, vs. telmisartan, an angiotensin II-receptor antagonist, was investigated in rats with testicular injury induced by a single i.p. injection of cadmium chloride (2 mg/kg). Captopril (60 mg/kg/day, p.o.) and telmisartan (10 mg/kg/day, p.o.) were given for five consecutive days, starting 3 days before cadmium administration. Both agents significantly increased serum testosterone level, which was reduced by cadmium, suppressed lipid peroxidation, restored the depleted reduced glutathione, decreased the elevations of nitric oxide, tumor necrosis factor-alpha, and cadmium ion levels, and attenuated the reductions of selenium and zinc ions in testicular tissue resulted from cadmium administration. Immunohistochemical analysis revealed that both captopril and telmisartan significantly reduced the cadmium-induced expression of inducible nitric oxide synthase, nuclear factor-kappaB, Fas ligand, and caspase-3 in testicular tissue. The differences between the results obtained with captopril and telmisartan were insignificant, suggesting that both drugs equally protected the testicular tissue from the detrimental effects of cadmium. PMID- 21819445 TI - Physical activity level in Achilles tendinosis is associated with blood levels of pain-related factors: a pilot study. AB - Physical activity affects the pain symptoms for Achilles tendinosis patients. Brain-derived neurotrophic factor (BDNF), tumor necrosis factor-alpha (TNF-alpha) and their receptors have been detected in human Achilles tendon. This pilot study aimed to compare serum BDNF and soluble tumor necrosis factor receptor I (sTNFRI) levels in Achilles tendinosis patients and healthy controls and to examine the influence of physical activity, and BMI and gender, on these levels. Physical activity was measured with a validated questionnaire, total physical activity being the parameter analyzed. Physical activity was strongly correlated with BDNF among tendinosis women [Spearman's rho (rho)=0.90, P<0.01] but not among control women (rho=-0.08, P=0.83), or among tendinosis and control men. Physical activity was significantly correlated with sTNFRI in the entire tendinosis group and among tendinosis men (rho=0.65, P=0.01), but not in the entire control group or among control men (rho=0.04, P=0.91). Thus, the physical activity pattern is related to the TNF and BDNF systems for tendinosis patients but not controls, the relationship being gender dependent. This is new information concerning the relationship between physical activity and Achilles tendinosis, which may be related to pain for the patients. This aspect should be further evaluated using larger patient materials. PMID- 21819446 TI - Whole-body vibration does not influence knee joint neuromuscular function or proprioception. AB - This study examined the acute effects of whole-body vibration (WBV) on knee joint position sense and indices of neuromuscular function, specifically strength, electromechanical delay and the rate of force development. Electromyography and electrically evoked contractions were used to investigate neural and contractile responses to WBV. Fourteen healthy males completed two treatment conditions on separate occasions: (1) 5 * 1 min of unilateral isometric squat exercise on a synchronous vibrating platform [30 Hz, 4 mm peak-to-peak amplitude] (WBV) and (2) a control condition (CON) of the same exercise without WBV. Knee joint position sense (joint angle replication task) and quadriceps neuromuscular function were assessed pre-, immediately-post and 1 h post-exercise. During maximum voluntary knee extensions, the peak force (PF(V)), electromechanical delay (EMD(V)), rate of force development (RFD(V)) and EMG of the quadriceps were measured. Twitch contractions of the knee extensors were electrically evoked to assess EMD(E) and RFD(E). The results showed no influence of WBV on knee joint position, EMD(V), PF(V) and RFD(V) during the initial 50, 100 or 150 ms of contraction. Similarly, electrically evoked neuromuscular function and neural activation remained unchanged following the vibration exercise. A single session of unilateral WBV did not influence any indices of thigh muscle neuromuscular performance or knee joint proprioception. PMID- 21819447 TI - Promoting the Swedish method of physical education throughout France for the benefit of public health (1868-1954). AB - This article examines the cultural and public health challenges associated with the dissemination of the Swedish approach and methods of physical education throughout France and illustrates the two main methods of influence, both direct through research and study visits and indirect through the creation of an international network entitled the International Federation of Physical Education. More particularly, it studies the roles of Philippe Tissie in 1898 and Pierre Seurin in 1946, and shows how these two major players of French physical education contributed actively to strengthening Swedish influence throughout France. It also highlights their equally essential role in the successful implementation of a pro-Swedish network in France, intended to serve their public health aims. This analysis forms part of the geopolitical and socio-cultural history of foreign physical education models, whose exemplarity was mainly dependent on Franco-Swedish relations and the models' social representations. Using archives from the French Physical Education League, travel logs and the Revue des jeux scolaires et d'hygiene sociale (Journal for School Games and Social Hygiene), it has been shown why the myth of the Swedish Eldorado contributed to creating, in France, "a work of art and of science that was, at the same time, both national and practical." PMID- 21819448 TI - Instrumental emotion regulation in sport: relationships between beliefs about emotion and emotion regulation strategies used by athletes. AB - This study examined relationships between beliefs about emotions (meta-emotion beliefs), emotion regulation strategies, and pre-competition emotional states using an instrumental model of emotion regulation. Three hundred and sixty runners reported meta-beliefs about the influence of anxiety and/or anger on performance, completed a short emotion scale, and reported their use of emotion regulation strategies. Results indicated that 55 runners (15%) reported meta emotion beliefs that strategies aimed at increasing anxiety and/or anger would help performance while 305 runners (85%) reported beliefs that strategies intended to reduce the same emotions before competition would help performance. Multivariate analysis of variance indicated that people who believe that anxiety or anger is good for performance reported high anger, but not anxiety, before performance. They also reported using strategies to increase unpleasant emotions. We suggest that further research is needed to examine relationships between meta emotion beliefs and the use of emotion regulation strategies in sport. PMID- 21819449 TI - Clinical and prognostic reports from 270 patients with multiple primary melanomas: a 34-year single-institution study. AB - BACKGROUND: Development of more than one primary melanoma in a sole patient is frequent, accounting for 1.2-8.2% of melanoma patients in most recent series. OBJECTIVE AND METHODS: Clinical, histological and epidemiological characteristics of 270 multiple primary melanomas patients were reviewed. RESULTS: Two-hundred and seven patients (76.7%) had two melanomas, whereas in the remaining 63 the number of primary ranged from three to eight; on the whole, 639 multiple primary melanomas were identified. Synchronous melanomas developed more frequently in patients with three or more lesions; median age was significantly lower in the group of patients with more than three melanomas than in the others. Mean Breslow's thickness significantly decreases (P<0.001) from the first (1.77+/-1.76 mm) to subsequent primaries (0.85+/-1.25 mm for the second and 0.66+/-0.48 mm for the third melanoma). Percentage of 'in situ' melanomas was 5.6% as first diagnosis, but increased to 24.8% for the second melanoma; number of nodular melanomas was significantly lower for succeeding diagnosis. AJCC stage at diagnosis showed a statistical prognostic significance, whereas outcome and survival did not depend on the number of primary lesions. Multivariate analysis confirmed the prognostic role of Breslow's thickness, ulceration, gender and patient age, and the better prognosis of patients with multiple melanomas, respect to those with single primary melanoma. CONCLUSIONS: Skin examination and long-term follow-up are mandatory for patients affected by melanoma, with the intent to promptly diagnose not only a disease progression but also possible new primary melanomas. PMID- 21819450 TI - Psodisk, a new visual method for assessing the burden of psoriasis on patients. AB - BACKGROUND: The last decades have witnessed an increasing interest for the psychosocial aspects of chronic skin diseases, such as psoriasis. Nonetheless, systematic assessments of the impact of psoriasis on patients' lives are rarely done in daily clinical practice. The existing instruments are mostly meant to be completed by patients alone, and rarely comprise a graphical representation of the results. OBJECTIVE: To develop a questionnaire allowing both a quick assessment of the impact of psoriasis on patients and, at the same time, an intuitive graphic visualization of the outcome of the test. METHODS: A preliminary version of an Italian questionnaire aimed to assess the global impact of psoriasis on patients, meant to be filled in together by the patient and the dermatologist and to produce visual, intuitive results, was developed through focus groups. The instrument was then the object of a Delphi survey addressed to a panel of experts, to assess both the need of possible improvements of the questionnaire (in terms of the formulations of the questions and of the domains to be explored) and the usefulness of the questionnaire. RESULTS: A 10-item questionnaire in Italian, taking into account different aspects of the burden of psoriasis on the patient, was developed. The answers are given on a 10-point visual analogue scale and graphically represented on a disc as a polygon. CONCLUSIONS: A formal validation of the questionnaire and a study to assess potential clinical and psychological benefits of a systematic implementation of the instrument in daily practice are planned. PMID- 21819451 TI - Treatment of epidermolysis bullosa acquisita with intravenous immunoglobulin in patients non-responsive to conventional therapy: clinical outcome and post treatment long-term follow-up. AB - BACKGROUND: Epidermolysis bullosa acquisita (EBA) is a chronic subepidermal blistering disease that is caused by antibodies binding to type VII collagen within anchoring fibrils. It is rare disease with an incidence of 0.25 cases per 1,000,000 population. OBJECTIVE: The objective of this study is to report the treatment outcomes with intravenous immunoglobulin (IVIg) therapy in 10 patients with severe and widespread EBA non-responsive to conventional therapy. METHODS: Patients were treated according to a protocol published in a Consensus Statement to treat autoimmune mucocutaneous blistering diseases, including EBA with IVIg. A dose of 2 g/kg/cycle was used. RESULTS: Ten patients: four males and six females, all were North American Caucasian. The age at onset varied from 37 to 75 years (mean 57.4). A satisfactory clinical response was observed in all 10 patients. The patients received 16-31 cycles (mean 23.1) of IVIg over a period of 30-52 months (mean 38.8). Once IVIg was initiated, earlier drugs (prednisone, dapsone and others) were gradually withdrawn over a 5-9 month period (mean 7.2). Thereafter, IVIg was used as monotherapy. No serious side-effects were observed. The follow-up period since discontinuation of IVIg varied from 29 to 123 months (mean 53.9). During this follow-up period, recurrence of disease was not observed. CONCLUSION: The data suggest that IVIg can produce a long-term sustained clinical remission in patients with EBA. In the patients, of this study concomitant therapy could be discontinued and IVIg was used as monotherapy. PMID- 21819452 TI - Biomarkers for skin involvement and fibrotic activity in scleroderma. AB - Systemic sclerosis (scleroderma, SSc) is characterized as a severe and very heterogeneous disease with a bright variation of skin and organ manifestations in individual patients. The pathogenesis is still not fully elucidated; however, it is known that this disease starts with an initial vascular damage, which then leads to an inflammatory process and finally promotes the development of an accumulation of collagen and other extracellular matrix (ECM) components. As a result of the heterogeneous characteristics of this multisystem, autoimmune disease, it is always a challenge to identify high-risk patients and to monitor the fibrotic activity also in response to therapies. This can be achieved by several physical methods including the mRSS, the durometer and ultrasound determination of skin thickness. However, this also requires the use of laboratory biomarkers, which are easily detectable and that reflect the inflammatory and/or fibrotic activity. As skin correlates well with the extent of fibrosis also in other organs, we focused in this review on biomarkers which reflect skin involvement of scleroderma patients. These include growth factors, cytokines and proteases as well as their inhibitors. Moreover, several ECM proteins, especially the collagens have been determined in skin biopsies and in blood/serum samples. Determination of proteins has been supported by mRNA levels using PCR techniques and expression analysis of gene expression patterns. This review summarizes all non-invasive physical and laboratory examinations, which permit a better understanding of the fibrotic activity of the disease, can be effectively used to assess potential therapeutic response and help to find better treatment options. PMID- 21819453 TI - Critical comment on: 'In vitro susceptibility of Aspergillus spp. to dithiocarbamate organoruthenium compounds'. PMID- 21819454 TI - Accidental Trichophyton mentagrophytes fungemia during the course of kerion celsi. PMID- 21819455 TI - The Mycobacterium tuberculosis Ag85A is a novel diacylglycerol acyltransferase involved in lipid body formation. AB - Mycobacterium tuberculosis accumulates large amounts of triacylglycerol (TAG) which acts as storage compounds for energy and carbon. The mycobacterial triacylglycerols stored in the form of intracellular lipid droplets are essential for long-term survival of M. tuberculosis during a dormant state. We report here that when the M. tuberculosis mycolytransferase Ag85A is overexpressed in Mycobacterium smegmatis mc(2)155, cell morphology was changed and the cells became grossly enlarged. A massive formation of lipid bodies and a change in lipid pattern was observed simultaneously. We suspected a possible role of Ag85A in the acyl lipid metabolism and discovered that the enzyme possesses acyl CoA:diacylglycerol acyltransferase (DGAT) activity in addition to its well-known function as mycolyltransferase. Ag85A mediates the transesterification of diacylglycerol using long-chain acyl-CoA as acyl donors. The K(m) and K(cat) values for palmitoleoyl-coenzyme A were 390 uM and 55.54 min(-1) respectively. A docking model suggests that palmitoleoyl-coenzyme A and 1,2-dipalmitin occupy the same active site as trehalose 6,6'-dimycolate and trehalose 6'-monomycolate. The site-directed Ser126Ala mutation of the active site proved that this residue is involved in the catalytic activity of this enzyme. Although not proven conclusively for dormant stage of M. tuberculosis, our novel finding about the synthesis of TAGs by Ag85A strongly suggests that Ag85A may play a significant role in the formation of lipid storage bodies and thus also in the establishment and maintenance of a persistent tuberculosis infection. PMID- 21819456 TI - The copper regulon of the human fungal pathogen Cryptococcus neoformans H99. AB - Cryptococcus neoformans is a human fungal pathogen that is the causative agent of cryptococcosis and fatal meningitis in immuno-compromised hosts. Recent studies suggest that copper (Cu) acquisition plays an important role in C. neoformans virulence, as mutants that lack Cuf1, which activates the Ctr4 high affinity Cu importer, are hypo-virulent in mouse models. To understand the constellation of Cu-responsive genes in C. neoformans and how their expression might contribute to virulence, we determined the transcript profile of C. neoformans in response to elevated Cu or Cu deficiency. We identified two metallothionein genes (CMT1 and CMT2), encoding cysteine-rich Cu binding and detoxifying proteins, whose expression is dramatically elevated in response to excess Cu. We identified a new C. neoformans Cu transporter, CnCtr1, that is induced by Cu deficiency and is distinct from CnCtr4 and which shows significant phylogenetic relationship to Ctr1 from other fungi. Surprisingly, in contrast to other fungi, we found that induction of both CnCTR1 and CnCTR4 expression under Cu limitation, and CMT1 and CMT2 in response to Cu excess, are dependent on the CnCuf1 Cu metalloregulatory transcription factor. These studies set the stage for the evaluation of the specific Cuf1 target genes required for virulence in C. neoformans. PMID- 21819457 TI - Lactobacillus brevis responds to flavonoids through KaeR, a LysR-type of transcriptional regulator. AB - The ability of transcription factors to respond to flavonoids as signal molecules was investigated in Lactobacillus brevis. Through in vitro screening of a small library of flavonoids, LVIS1989 (KaeR), a LysR-type transcriptional regulator (LTTR), was identified as responsive to kaempferol. The modulation of KaeR activity by flavonoids was characterized in vivo and in vitro. DNase I footprint assays identified the binding of KaeR at two distinctive sites, one in the intergenic region between LVIS1988 and kaeR (-39 to +2) and another within LVIS1988 (-314 to -353, from kaeR translational start point). EMSA assays revealed that both binding sites are required for KaeR binding in vitro. Furthermore, KaeR-DNA interactions were stabilized by the addition of kaempferol (20 uM). In vivo qRT-PCR experiments performed in L. brevis confirmed that the divergently transcribed genes LVIS1988, LVIS1987 and LVIS1986 and kaeR are upregulated in the presence of kaempferol, indicating the role of KaeR as a transcriptional activator. Transcriptional lacZ fusions using Bacillus subtilis as a surrogate host showed that expression of kaeR and LVIS1988 were induced by the presence of the flavonoid. These results indicate that KaeR belongs to a small and poorly understood group of LTTRs that are positively autoregulated in the presence of a ligand. PMID- 21819458 TI - FraC/FraD-dependent intercellular molecular exchange in the filaments of a heterocyst-forming cyanobacterium, Anabaena sp. AB - The filamentous, heterocyst-forming cyanobacteria are multicellular organisms in which two different cell types, the CO2-fixing vegetative cells and the N2-fixing heterocysts, exchange nutrients and regulators. In Anabaena sp. strain PCC 7120, inactivation of sepJ or genes in the fraC operon (fraC, fraD and fraE) produce filament fragmentation. SepJ, FraC and FraD are cytoplasmic membrane proteins located in the filament's intercellular septa that are needed for intercellular exchange of the fluorescent tracer calcein (622 Da). Transmission electron microscopy showed an alteration in the heterocyst cytoplasmic membrane at the vegetative cell-heterocyst septa in DeltafraC and DeltafraD mutants. Immunogold labelling of FraD confirmed its localization in the intercellular septa and clearly showed the presence of part of the protein between the cytoplasmic membranes of the adjacent cells. This localization seemed to be affected in the DeltafraC mutant but was not impaired in a DeltasepJ mutant. Intercellular transfer of a smaller fluorescent tracer, 5-carboxyfluorescein (374 Da), was largely impaired in DeltafraC, DeltafraD and double DeltafraC-DeltafraD mutants, but much less in the DeltasepJ mutant. These results show the existence in the Anabaena filaments of a FraC/FraD-dependent intercellular molecular exchange that does not require SepJ. PMID- 21819459 TI - The Leishmania nicotinamidase is essential for NAD+ production and parasite proliferation. AB - NAD+ is a central cofactor that plays important roles in cellular metabolism and energy production in all living cells. Genomics-based reconstruction of NAD+ metabolism revealed that Leishmania protozoan parasites are NAD+ auxotrophs. Consequently, these parasites require assimilating NAD+ precursors (nicotinamide, nicotinic acid, nicotinamide riboside) from their host environment to synthesize NAD+ by a salvage pathway. Nicotinamidase is a key enzyme of this salvage pathway that catalyses conversion of nicotinamide (NAm) to nicotinic acid (Na), and that is absent in higher eukaryotes. We present here the biochemical and functional characterizations of the Leishmania infantum nicotinamidase (LiPNC1). Generation of Lipnc1 null mutants leads to a decrease in NAD+ content, associated with a metabolic shutdown-like phenotype with an extensive lag phase of growth. Both phenotypes could be rescued by an add-back construct or by addition of exogenous Na. In addition, Lipnc1 null mutants were unable to establish a sustained infection in a murine experimental model. Altogether, these results illustrate that NAD+ homeostasis is a fundamental component of Leishmania biology and virulence, and that NAm constitutes its main NAD+ source in the mammalian host. The crystal structure of LiPNC1 we solved allows now the design of rational inhibitors against this new promising therapeutic target. PMID- 21819460 TI - Cluster analysis and food group consumption in a national sample of Australian girls. AB - BACKGROUND: Food preferences develop early in life and track into later life. There is limited information on food consumption and dietary patterns in Australian girls. The present study aimed to: (i) determine the frequency of food groups consumed over 1day; (ii) identify dietary clusters based on food group consumption; and (iii) compare dietary intakes and activity variables between clusters. METHODS: A cross-sectional analysis of 9-16-year-old girls (n=1114) from the 2007 Australian National Children's Nutrition and Physical Activity Survey was performed. RESULTS: Over the whole day, 30% of all girls consumed carbonated sugar drinks, 46% consumed take-away food, 56% consumed fruit, 70% consumed at least one vegetable, and 19% and 30% consumed white and/or red meat, respectively. K-means cluster analysis derived four clusters. Approximately one third of girls were identified in a Meat and vegetable cluster; these girls had the highest intakes of red meat and vegetables, and tended to have higher intakes of fruit, whole grain breads, low fat yoghurt, and lower intakes of take-away foods and soft drinks. They also had the highest intakes of protein, fibre and micronutrients; and tended to perform more physical activity, compared to girls in the remaining clusters. CONCLUSIONS: Girls identified in the Meat and vegetable cluster, on average, consumed more lean red meat, vegetables, fruits, and low-fat dairy products, and had a higher intakes of many nutrients. The high percentage of girls not identified in this cluster suggests the need to inform them on how to make healthy, nutrient dense food choices, and why they require increased nutrient intakes at this time. PMID- 21819461 TI - Weaning infants with phenylketonuria: a review. AB - Careful weaning is particularly important in phenylketonuria (PKU). Dietary phenylalanine intake is severely restricted, and the diet is supplemented with phenylalanine-free amino acids and special low protein foods. In PKU, there are no evidence-based weaning guidelines and no studies assessing the introduction of solid foods. We critically review the literature and examine current UK weaning practices. Ideally, weaning in PKU should closely reflect the 'model' for healthy infants. However, the requirement for optimal blood phenylalanine control and the demands of diet therapy overshadow the social aspects of weaning. Solid food intake is established with very low protein foods first, and then 50 mg phenylalanine exchanges (equivalent to 1 g of intact protein) gradually replace breast/formula feeds. Introducing solids before the recommended 6 months of age may be advantageous because there is a less persistent neophobic food response, possibly leading to better food acceptance. Infants with PKU also require a special phenylalanine-free protein substitute. Between 6 and 12 months, a second concentrated source of phenylalanine-free protein substitute is required. This is commonly given as an additional liquid, although the prescribed volume may adversely affect appetite. Alternatively, a second-stage protein substitute administered as a paste may better suit feeding development. Further research aiming to examine the weaning process in PKU with a focus on biological, maternal, infant, social and environmental factors is required. This will help provide evidence for the effect of protein substitute on appetite and help in the development of evidence-based guidelines. PMID- 21819462 TI - Sniffing shapes the dynamics of olfactory bulb gamma oscillations in awake behaving rats. AB - Mammals actively sample the environment for relevant olfactory objects. This active sampling is revealed by rapid changes in respiratory rate that influence the olfactory input. Yet the role of sniffing in shaping the neural responses to odorants has not been elucidated. In the olfactory bulb (OB), odorant-evoked gamma oscillations reflect the synchronous activity of mitral/tufted cells, a proposed mechanism for odorant representation. Here we examined the effect of sniffing frequency on the odorant-evoked gamma oscillations in the OB. We simultaneously recorded the respiratory rate and the local field potential while rats performed a lick/no-lick olfactory discrimination task with low odorant concentrations. High-frequency sniffing (HFS) augmented the power of gamma oscillations, suggesting an increase in the sensitivity to odorants. By contrast, coupling of the gamma oscillations to the sniff cycle and the amplitude of individual bursts were not modified by the respiratory rate. However, HFS prolonged the overall response to odorants and increased the frequency of the gamma oscillations, indicating that HFS reduces the adaptation to continuous odorant stimulation. Therefore, the increase in gamma power during HFS is the result of more frequent gamma bursts and the extended response to odorants. As odorant discrimination can be performed in a single sniff, a reduction in the adaptation mediated by HFS of novel odorants may facilitate odorant memory formation for subsequent odorant identification. Finally, these results corroborate that olfactory sampling should be integrated to the study of odorant coding in behaving animals. PMID- 21819463 TI - Synaptic transmission of graded membrane potential changes and spikes between identified visual interneurons. AB - Several physiological mechanisms allow sensory information to be propagated in neuronal networks. According to the conventional view of signal processing, graded changes of membrane potential at the dendrite are converted into a sequence of spikes. However, in many sensory receptors and several types of mostly invertebrate neurons, graded potential changes have a direct impact on the cells' output signals. The visual system of the blowfly Calliphora vicina is a good model system to study synaptic transmission in vivo during sensory stimulation. We recorded extracellularly from an identified motion-sensitive neuron while simultaneously measuring and controlling the membrane potential of individual elements of its presynaptic input ensemble. The membrane potential in the terminals of the presynaptic neuron is composed of two components, graded membrane potential changes and action potentials. To dissociate the roles of action potentials and graded potential changes in synaptic transmission we used voltage-clamp-controlled current-clamp techniques to suppress the graded membrane potential changes without affecting action potentials. Our results indicate that both the graded potential and the action potentials of the presynaptic neuron have an impact on the spiking characteristics of the postsynaptic neuron. Although a tight temporal coupling between pre- and postsynaptic spikes exists, the timing between these spikes is also affected by graded potential changes. We propose that the control of synaptic transfer of a dynamically complex signal by graded changes in membrane potential and spikes is useful to enable a temporally precise coupling of spikes in response to sudden transitions in stimulus intensity. PMID- 21819465 TI - Pharmacogenetic profiling might meet the challenge. PMID- 21819467 TI - Barrett's oesophagus in Asians--are ethnic differences due to genes or the environment? PMID- 21819464 TI - Corticotropin-releasing factor and urocortin I activate CREB through functionally selective Gbetagamma signaling in hippocampal pyramidal neurons. AB - Stress is a perceived perturbation in the environment of the organism that affects numerous extrahypothalamic brain regions including the hippocampus, a limbic structure critical for learning, spatial memory and the regulation of stress hormones. Though many effects of stress on the hippocampus are mediated via local glucocorticoid action, there is now ample evidence for the contributions of the stress peptides corticotropin-releasing factor (CRF) and urocortin I (UCN). Thus, understanding the intracellular signaling pathways activated by stress peptides is required to fully understand the mechanisms by which stress influences the hippocampus. Here we elucidate molecular mechanisms by which CRF and UCN induce phosphorylation of the activity-dependent transcription factor CREB, a molecule critical for numerous forms of neuronal plasticity. We report that nanomolar concentrations of both CRF and UCN lead to a rapid, CRF receptor 1 (CRFR1)- and Gbetagamma-dependent increase in CREB phosphorylation in rat hippocampal pyramidal neurons. Interestingly, CRF- and UCN induced signaling pathways diverge downstream of Gbetagamma, with UCN, but not CRF, signaling to CREB via a MEK/MAPK-dependent pathway. These data suggest novel molecular mechanisms by which stress can directly impact hippocampal neurons, as well as highlight an emerging role for Gbetagamma signaling in mediating the effects of stress peptides in extrahypothalamic stress-responsive brain regions. PMID- 21819468 TI - Caspase-3/caspase-8, bax and bcl2 in pulps of human primary teeth with physiological root resorption. AB - OBJECTIVE. Physiological root resorption is a programmed event that takes place in primary teeth leading to elimination of all root structures. The mechanism behind pulp elimination indicates apoptosis, but its pathway has not been well characterised yet. To better understand this event, we evaluated the gene expression of bax, bcl-2, caspase-3 and caspase-8 through real-time polymerase chain reaction (PCR) and immunohistochemistry expression of Caspase-8 and Bax in pulps. METHODS. Samples were split into two groups: pulps from primary teeth with physiological root resorption (n = 40) and control (n =40), pulps from permanent teeth. Samples of each group were split into PCR (n = 20) and immunohistochemistry (n = 20). RESULTS. Pulps from primary teeth showed a higher caspase-3 mRNA level than pulps from permanent teeth. The expression of bax gene was more intense than caspase-8 but both did not show difference between groups. The bcl-2 mRNA level was incipient and similar between groups. Histopath slides did not show any evidence of inflammatory infiltration, which implies that extrinsic via is not likely to be involved. Immunohistochemistry reaction to Bax and Caspase-8 supported PCR results. CONCLUSIONS. Pulp apoptosis is likely to occur via caspase-3 activation through the mitochondrial pathway. PMID- 21819469 TI - Landscape genetics highlights the role of bank vole metapopulation dynamics in the epidemiology of Puumala hantavirus. AB - Rodent host dynamics and dispersal are thought to be critical for hantavirus epidemiology as they determine pathogen persistence and transmission within and between host populations. We used landscape genetics to investigate how the population dynamics of the bank vole Myodes glareolus, the host of Puumala hantavirus (PUUV), vary with forest fragmentation and influence PUUV epidemiology. We sampled vole populations within the Ardennes, a French PUUV endemic area. We inferred demographic features such as population size, isolation and migration with regard to landscape configuration. We next analysed the influence of M. glareolus population dynamics on PUUV spatial distribution. Our results revealed that the global metapopulation dynamics of bank voles were strongly shaped by landscape features, including suitable patch size and connectivity. Large effective size in forest might therefore contribute to the higher observed levels of PUUV prevalence. By contrast, populations from hedge networks highly suffered from genetic drift and appeared strongly isolated from all other populations. This might result in high probabilities of local extinction for both M. glareolus and PUUV. Besides, we detected signatures of asymmetric bank vole migration from forests to hedges. These movements were likely to sustain PUUV in fragmented landscapes. In conclusion, our study provided arguments in favour of source-sink dynamics shaping PUUV persistence and spread in heterogeneous, Western European temperate landscapes. It illustrated the potential contribution of landscape genetics to the understanding of the epidemiological processes occurring at this local scale. PMID- 21819470 TI - Fine-scale population structure and riverscape genetics of brook trout (Salvelinus fontinalis) distributed continuously along headwater channel networks. AB - Linear and heterogeneous habitat makes headwater stream networks an ideal ecosystem in which to test the influence of environmental factors on spatial genetic patterns of obligatory aquatic species. We investigated fine-scale population structure and influence of stream habitat on individual-level genetic differentiation in brook trout (Salvelinus fontinalis) by genotyping eight microsatellite loci in 740 individuals in two headwater channel networks (7.7 and 4.4 km) in Connecticut, USA. A weak but statistically significant isolation-by distance pattern was common in both sites. In the field, many tagged individuals were recaptured in the same 50-m reaches within a single field season (summer to fall). One study site was characterized with a hierarchical population structure, where seasonal barriers (natural falls of 1.5-2.5 m in height during summer base flow condition) greatly reduced gene flow and perceptible spatial patterns emerged because of the presence of tributaries, each with a group of genetically distinguishable individuals. Genetic differentiation increased when pairs of individuals were separated by high stream gradient (steep channel slope) or warm stream temperature in this site, although the evidence of their influence was equivocal. In a second site, evidence for genetic clusters was weak at best, but genetic differentiation between individuals was positively correlated with number of tributary confluences. We concluded that the population-level movement of brook trout was limited in the study headwater stream networks, resulting in the fine-scale population structure (genetic clusters and clines) even at distances of a few kilometres, and gene flow was mitigated by 'riverscape' variables, particularly by physical barriers, waterway distance (i.e. isolation-by-distance) and the presence of tributaries. PMID- 21819471 TI - Alcohol consumption and non-communicable diseases: epidemiology and policy implications. AB - AIMS: This paper summarizes the relationships between different patterns of alcohol consumption and various on non-communicable disease (NCD) outcomes and estimates the percentage of NCD burden that is attributable to alcohol. METHODS: A narrative review, based on published meta-analyses of alcohol consumption disease relations, together with an examination of the Comparative Risk Assessment estimates applied to the latest available revision of Global Burden of Disease study. RESULTS: Alcohol is causally linked (to varying degrees) to eight different cancers, with the risk increasing with the volume consumed. Similarly, alcohol use is related detrimentally to many cardiovascular outcomes, including hypertension, haemorrhagic stroke and atrial fibrillation. For other cardiovascular outcomes the relationship is more complex. Alcohol is furthermore linked to various forms of liver disease (particularly with fatty liver, alcoholic hepatitis and cirrhosis) and pancreatitis. For diabetes the relationship is also complex. Conservatively, of the global NCD-related burden of deaths, net years of life lost (YLL) and net disability adjusted life years (DALYs), 3.4%, 5.0% and 2.4%, respectively, can be attributed to alcohol consumption, with the burden being particularly high for cancer and liver cirrhosis. This burden is especially pronounced in countries of the former Soviet Union. CONCLUSIONS: There is a strong link between alcohol and non-communicable diseases, particularly cancer, cardiovascular disease, liver disease, pancreatitis and diabetes, and these findings support calls by the World Health Organization to implement evidence-based strategies to reduce harmful use of alcohol. PMID- 21819472 TI - Positive impact of hepatitis C virus (HCV) treatment on antiretroviral treatment adherence in human immunodeficiency virus-HCV coinfected patients: one more argument for expanded access to HCV treatment for injecting drug users. AB - AIMS: Treatment for the hepatitis C virus (HCV) may be delayed significantly in human immunodeficiency virus (HIV)/HCV coinfected patients on antiretroviral treatment (ART) for fear that its burden could compromise ART adherence. However, the effect such treatment has on ART adherence in observational settings remains largely unknown. Longitudinal data were used to investigate the relationship between initiating HCV treatment and adherence to ART in HIV/HCV coinfected patients. DESIGN: The French national prospective cohort of patients coinfected with HIV and HCV (ANRS-CO-13-HEPAVIH) is a multi-centre cohort. SETTING: Seventeen out-patient hospital services delivering HIV and HCV care in France. PARTICIPANTS: HIV/HCV coinfected patients on ART (n = 593 patients, 976 visits). MEASUREMENTS: Self-administered questionnaires and medical records. A mixed logistic regression model based on generalized estimates equations (GEE) to identify factors associated with non-adherence to ART. FINDINGS: Among the 593 patients, 36% were classified as non-adherent to ART at the enrolment visit and 12% started HCV treatment during follow-up. ART adherence was not associated statistically with HCV treatment initiation. The proportion of patients maintaining adherence or becoming adherent to ART for those starting HCV treatment was higher than in the rest of the sample (P = 0.07). After multiple adjustment for known correlates, such as poor housing conditions, binge drinking, recent drug use and depressive symptoms, patients who initiated HCV treatment were less likely to be non-adherent to ART [odds ratio (95% confidence interval) = 0.41 (0.24-0.71)]. CONCLUSIONS: Engaging human immunodeficiency virus/hepatitis C virus coinfected individuals in hepatitis C virus treatment is associated with high adherence to antiretroviral treatment. Physicians should prioritize hepatitis C virus treatment as part of a multi-disciplinary approach. PMID- 21819474 TI - A restorative home care intervention in New Zealand: perceptions of paid caregivers. AB - Paid caregivers possess an essential role in home care services. However, recruitment and retention issues are extensive within this workforce, largely in relation to poor working conditions. This article primarily focuses on the qualitative data extracted from a large randomised controlled trial in New Zealand and is supported by some quantitative findings. The aim was to explore paid caregiver perceptions of a restorative home care intervention in comparison with usual home care. The purpose of the qualitative exploration was to gather rich descriptive data that highlight differences between the two services with an emphasis on the workforce viewpoint. Four focus groups were undertaken with paid caregivers, two at baseline (4 and 5 participants in the control and intervention groups, respectively) and two at 14 months (eight participants in each focus group). Focus group data were collected in December 2005 and February 2007. A general inductive approach was used to analyse focus group transcripts. Two themes emerged from both the control and intervention focus groups: relationship with older people and issues with home care service delivery. A further two themes were pertinent to the intervention group: job satisfaction and preintervention. Findings revealed the intervention had a substantial positive impact on paid caregiver job satisfaction in comparison with usual care. This appeared to be due to improved training, increased support and supervision, and more flexibility. The intervention resulted in positive changes from the paid caregiver perspective and substantially reduced turnover in comparison with usual home care. However, both groups identified the need for further improvements to their working conditions. In addition, the need to regulate this vulnerable workforce is discussed. PMID- 21819473 TI - Prevention of mother-to-child transmission of human immunodeficiency virus among pregnant women using injecting drugs in Ukraine, 2000-10. AB - AIMS: To compare clinical status, mother-to-child transmission (MTCT) rates, use of prevention of (PMTCT) interventions and pregnancy outcomes between HIV infected injecting drug users (IDUs) and non-IDUs. DESIGN AND SETTING: Prospective cohort study conducted in seven human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) Centres in Ukraine, 2000-10. PARTICIPANTS: Pregnant HIV-infected women, identified before/during pregnancy or intrapartum, and their live-born infants (n = 6200); 1028 women followed post-partum. MEASUREMENTS: Maternal and delivery characteristics, PMTCT prophylaxis, MTCT rates, preterm delivery (PTD) and low birth weight (LBW). FINDINGS: Of 6200 women, 1111 (18%) reported current/previous IDU. The proportion of IDUs diagnosed with HIV before conception increased from 31% in 2000/01 to 60% in 2008/09 (P < 0.01). Among women with undiagnosed HIV at conception, 20% of IDUs were diagnosed intrapartum versus 4% of non-IDUs (P < 0.01). At enrolment, 14% of IDUs had severe/advanced HIV symptoms versus 6% of non-IDUs (P < 0.001). IDUs had higher rates of PTD and LBW infants than non-IDUs, respectively, 16% versus 7% and 22% versus 10% (P < 0.001). IDUs were more likely to receive no neonatal or intrapartum PMTCT prophylaxis compared with non-IDUs (OR 2.81, p < 0.001). MTCT rates were 10.8% in IDUs versus 5.9% in non-IDUs; IDUs had increased MTCT risk (adjusted odds ratio 1.32, P = 0.049). Fewer IDUs with treatment indications received HAART compared with non-IDUs (58% versus 68%, P = 0.03). CONCLUSIONS: Pregnant human immunodeficiency virus-infected injecting drug users in Ukraine have worse clinical status, poorer access to prevention of mother-to-child transmission prophylaxis and highly active antiretroviral therapy, more adverse pregnancy outcomes and higher risk of mother-to-child transmission than non injecting drug user women. PMID- 21819475 TI - The characteristics of residents in extra care housing and care homes in England. AB - Extra care housing aims to meet the housing, care and support needs of older people, while helping them to maintain their independence in their own private accommodation. It has been viewed as a possible alternative, or even a replacement for residential care. In 2003, the Department of Health announced capital funding to support the development of extra care housing and made the receipt of funding conditional on participating in an evaluative study. This paper presents findings on the characteristics of the residents at the time of moving in, drawing on information collected from the 19 schemes in the evaluation, and a recent comparable study of residents who moved into care homes providing personal care. Overall, the people who moved into extra care were younger and much less physically and cognitively impaired than those who moved into care homes. However, the prevalence of the medical conditions examined was more similar for the two groups, and several of the schemes had a significant minority of residents with high levels of dependence on the Barthel Index of Activities of Daily Living. In contrast, levels of severe cognitive impairment were much lower in all schemes than the overall figure for residents of care homes, even among schemes designed specifically to provide for residents with dementia. The results suggest that, although extra care housing may be operating as an alternative to care homes for some individuals, it is providing for a wider population, who may be making a planned move rather than reacting to a crisis. While extra care supports residents with problems of cognitive functioning, most schemes appear to prefer residents to move in when they can become familiar with their new accommodation before the development of more severe cognitive impairment. PMID- 21819476 TI - Maternal neutrophil toll-like receptor mRNA expression is down-regulated in preeclampsia. AB - PROBLEM: There are many immunological changes in preeclampsia. For example, TLR-4 expression is increased in the placenta during preeclampsia. However, data on TLR expression in other tissues during preeclampsia are lacking. This study aimed to determine whether TLR mRNA expression in maternal neutrophils is altered in preeclampsia. METHOD OF STUDY: A case-control study using standard quantitative real-time PCR techniques was performed to assess TLR-2 and TLR-4 mRNA expression in 12 patients with mild preeclampsia and 18 normal pregnant controls at similar gestational ages. RESULTS: Compared to normal pregnant controls, there was a significant decrease in TLR-2 and TLR-4 expression in women with mild preeclampsia. CONCLUSION: TLR-2 and TLR-4 expression in maternal neutrophils is decreased in preeclampsia. Given the many immunological changes in preeclampsia, this may represent an adaptation to the increased inflammatory signals present in preeclampsia. Further study is needed to clarify the role of the TLR in preeclampsia. PMID- 21819478 TI - Early-pregnancy cytokines in mothers to children developing multiple, persistent islet autoantibodies, type 1 diabetes, or both before 7 years of age. AB - PROBLEM: Increased levels of serum cytokines in early pregnancy may increase the risk of type 1 diabetes in the offspring. METHOD OF STUDY: Early-pregnancy (between 10 and 16 gestational weeks) serum samples from non-diabetic index mothers (n = 48) of children who developed islet autoimmunity, type 1 diabetes, or both before 7 years of age were analyzed for IFN-gamma, IL-10, IL-12, IL-13, IL-1beta, IL-2, IL-4, IL-5, CXCL8, and TNF. Control mothers (n = 93) were matched for age, sampling date, and HLA-DQ genotypes. RESULTS: IFN-gamma (P = 0.02) and IL-1beta (P = 0.04) were elevated in the index mothers. All cytokines except IL-4 were highly correlated (P < 0.0001). IFN-gamma [OR 1.39 (1.04, 1.85), P = 0.026] and possibly IL-2 [OR 1.21 (0.99, 1.48), P = 0.057] in early pregnancy were associated with an increased risk of multiple, persistent islet autoantibodies, type 1 diabetes, or both before 7 years of age in the offspring. However, the statistical significance for IL-2 was lost in the logistic regression when adjusted for gestational length at delivery and parity. CONCLUSION: Increased Th1 cytokine levels during early pregnancy might contribute to an increased risk of islet autoimmunity, type 1 diabetes, or both in the offspring. PMID- 21819477 TI - Modulation and recruitment of inducible regulatory T cells by first trimester trophoblast cells. AB - PROBLEM The specialized regulatory T-cells (Treg) population, essential for maternal tolerance of the fetus, performs its suppressive actions in the critical peri-implantation phase of pregnancy. In the present work, we investigated whether trophoblast cells are able to induce Treg recruitment, differentiation, and whether these mechanisms are modified by a bacterial or viral infection. METHOD OF STUDY Human T-regulatory cells were differentiated from naive CD45RA(+) CCR7(+) cells obtained from peripheral blood mononuclear cells cultured with IL-2 and TGFbeta over 5 days. Induction of iTregs (CD4(+) Foxp3(+) cells) was evaluated using low serum conditioned media (LSCM), obtained from two first trimester trophoblast cell lines, Swan-71 and HTR8. Coculture experiments were carried out using transwell assays where trophoblast cells were in the absence or presence of PGN, LPS, or Poly [I:C]. Cytokine production was measured by multiplex analysis. RESULTS Trophoblast cells constitutively secrete high levels of TGFbeta and induced a significant increase of Foxp3 expression accompanied by a specific T-reg cytokine profile. Moreover, trophoblast cells were able to recruit iTregs in a specific manner. CONCLUSION We demonstrate that trophoblast cells have an active role on the recruitment and differentiation of iTregs, therefore, contributing to the process of immune regulation at the placental maternal interface. PMID- 21819479 TI - Desensitization of thermal hyperemia in the skin is reproducible. AB - OBJECTIVE: Local heating increases skin blood flow SkBF (thermal hyperemia). In a previous study, we reported that a first local thermal stimulus could attenuate the hyperemic response to a second one applied later on the same skin spot, a phenomenon that we termed desensitization. However, other studies found no evidence for desensitization in similar conditions. The aim of the present work was to test whether it was related to differences in instrumentation. METHODS: Twenty-eight healthy young males were studied. Two pairs of heating chambers, one custom-made (our study) and one commercial (other groups), were affixed to forearm skin. SkBF was measured with single-point laser-Doppler flowmetry (LDF) (780nm) in one pair, and laser-Doppler imaging (LDI) (633nm) in the other. A temperature step from 34 to 41 degrees C, was applied for 30minutes and repeated after two hours. RESULTS: During the second thermal challenge, the plateau SkBF was lower than during the first thermal and was observed with each of the four combinations of SkBF measurement techniques and heating equipment (p<0.05 for all conditions, range -9% to -16% of the initial value). CONCLUSION: Desensitization of thermal hyperemia is not specific to peculiar operating conditions. PMID- 21819480 TI - Can the rat be used as a valid model of human esophageal adenocarcinoma? AB - Animal models of Barrett's metaplasia and esophageal adenocarcinoma are important to further characterize the disease and test potential therapies. This paper reviews the development of the surgical model of esophageal adenocarcinoma in the rat and considers whether this model provides a biologically accurate representation of Barrett's esophagus and esophageal adenocarcinoma in humans. PMID- 21819481 TI - Prevention of gastroduodenal content reflux and delayed gastric emptying after esophagectomy: gastric tube reconstruction with duodenal diversion plus Roux-en-Y anastomosis. AB - Reflux of gastroduodenal contents and delayed gastric emptying are the most common and serious problems after esophagectomy with gastric reconstruction. However, attempts to reduce the above symptoms, surgically as well as non surgically, had no or limited effect. To address this issue, we performed retrosternal gastric reconstruction with duodenal diversion plus Roux-en-Y anastomosis (RY) in eight patients with thoracic esophageal cancer and compared the outcomes with control patients who underwent standard reconstruction. The procedure is simple, safe, and not associated with any postoperative complications. The pancreatic amylase concentrations in the gastric juice samples on postoperative day 2 were slightly lower in the non-RY group than in the RY group (1884 +/- 2152 vs. 25,790 +/- 23,542IU/mL, respectively, P= 0.07). Postoperative endoscopic examination showed neither reflux esophagitis nor residual gastric content in the RY group. Quality of life assessed by the Dysfunction After Upper Gastrointestinal Surgery-32 questionnaire postoperatively was significantly better in the RY group than in the non-RY group for 'decreased physical activity,''symptoms of reflux,''nausea and vomiting,' and 'pain.' The results of this pilot study suggest that gastric reconstruction with duodenal diversion plus RY seems effective in improving both the reflux and delayed gastric emptying. The benefits of this procedure need to be further assessed in a large-scale, randomized controlled trial. PMID- 21819482 TI - Markers of tyrosine kinase activity in eosinophilic esophagitis: a pilot study of the FIP1L1-PDGFRalpha fusion gene, pERK 1/2, and pSTAT5. AB - The pathogenesis of eosinophilic esophagitis (EoE) is incompletely understood. In certain eosinophilic diseases, activation of tyrosine kinase after fusion of the Fip1-like-1 and platelet-derived growth factor receptor-alpha genes (F-P fusion gene) mediates eosinophilia via downstream effectors such as extracellular regulated kinase (ERK1/2) and signal transducers and activators of transcription (STAT5). This mechanism has not been examined in EoE. Our aim was to detect the F P fusion gene, pERK1/2, and pSTAT5 in esophageal tissue from patients with EoE, gastroesophageal reflux disease (GERD), and normal controls. We performed a cross sectional pilot study comparing patients with steroid-responsive and steroid refractory EoE, to GERD patients and normal controls. EoE cases were defined by consensus guidelines. Fluorescence in situ hybridization (FISH) was performed to detect the F-P fusion gene and immunohistochemistry (IHC) was performed to detect pERK1/2 and pSTAT5 in esophageal biopsies. Twenty-nine subjects (median age 30 years [range 1-59]; 16 males; 24 Caucasians) were included: eight normal, six GERD, and 15 EoE (five steroid-refractory). On FISH, 98%, 99%, and 99% of the nuclei in the normal, GERD, and EoE groups, respectively, were normal (P= 0.42). On IHC, a median of 250, 277, and 479 nuclei/mm(2) stained for pERK 1/2 in the normal, GERD, and EoE groups, respectively (P= 0.07); the refractory EoE patients had the highest degree pERK 1/2 staining (846 nuclei/mm(2); P= 0.07). No trend was seen for pSTAT5. In conclusion, the F-P fusion gene was not detected with increased frequency in EoE. Patients with EoE had a trend toward higher levels of pERK 1/2, but not STAT5, in the esophageal epithelium, with highest levels in steroid-refractory EoE patients. PMID- 21819483 TI - Beneficial effects of Ankaferd Blood Stopper on caustic esophageal injuries: an experimental model. AB - Ankaferd Blood Stopper (ABS) is an herbal extract that enhances mucosal healing. The aim of this study was to investigate the efficacy of ABS on the healing of the esophagus and prevention of stricture development after esophageal caustic injuries in rats. The study included 50 rats. Rats were divided into five groups: group 1 (no injury, sham surgery), group 2 (injury + no ABS + study after 2 weeks of injury), group 3 (injury + ABS + study after 2 weeks of injury), group 4 (injury + no ABS + study after 4 weeks of injury), and group 5 (injury + ABS + study after 4 weeks of injury). Standard esophageal burn injury was created by applying 50% NaOH solution to distal esophagus of about 1.5 cm. To rats in the sham group, isotonic solution was given instead of NaOH. ABS (2 mL/day) was given via oral route to group 3 and 5 rats. Fourteen days (group 2 and 3) and 28 days (group 4 and 5) later, all the live rats were killed. The distal esophageal segments of all rats were removed and divided into two equal parts for biochemical and histopathological examination. Mortality rate, weight changes, inflammation, stenosis index (SI), and biochemical measurements were evaluated. The SI was found as 0.31 +/- 0.03 in group 1, 0.533 +/- 0.240 in group 2, 0.568 +/- 0.371 in group 3, 0.523 +/- 0.164 in group 4, and 0.28 +/- 0.03 in group 5. The SI and inflammation in ABS-treatment group 5 was significantly lower than that in non-treatment group 4 (P= 0.005). There were no significant differences between inflammation and SI among other groups. The mortality rate was 14.2% in group 1, 37.5% in untreated group 2, 14.2% in ABS-treated group 3, 80% in untreated group 4, and 33.3% in ABS-treated group 5. The mortality rate in group 4 was significantly higher than other groups (P= 0.025). Decrease rates in mean body weights of the groups were as follows: group 1, 1%; group 2, 15%; group 3, 14%; group 4, 46%; and group 5, 15%. Biochemical tests other than albumin and creatinine were comparable among the groups. Treatment with ABS prevents inflammation, scar formation, weight loss, and mortality in esophageal caustic injuries. Additional studies to evaluate the clinical benefits of ABS in esophageal caustic injury are recommended. PMID- 21819484 TI - Safe esophageal reconstruction by ileocolic interposition. AB - Many techniques have been proposed for esophageal reconstruction after esophagectomy when a gastric tube cannot be employed. There are two essential criteria for such a substitute: substitute length and sufficient blood supply. We propose ileocolic interposition as an easy and safe option. Two technical aspects contributing to the high success rate of this method are the preservation of an intact arterial network allowing normal blood flow to the ileocolic area, and the ability to quantify blood flow using a Doppler pulse flow meter in six cases. These are enabled by a long (up to 20cm) ileocolic segment. The preservation of the right colic artery is important, because its interruption would reduce blood supply to the long ileum segment. Between July 2003 and October 2008, we used this method in six patients in whom a gastric tube was not an option. We assessed perioperative morbidity and swallowing difficulties in each patient, quantifying dysphagia on scale of 0 to 4. There was no mortality and no anastomotic leak. There was one wound infection, and in one patient, recurrent nerve paralysis was observed. The postoperative hospital stay was 29.5 +/- 10.8 days. The average dysphagia score for the six patients was 0.17 +/- 0.41 after the operation. All patients can eat normally, without any dietary limitations. Ileocolonic interposition after esophagectomy requires careful assessment of the vascular supply. In this small series, morbidity was low and there was no perioperative mortality. We believe that this is an easy and safe method of reconstruction after esophagectomy in cases in whom a gastric tube cannot be used as a substitute. PMID- 21819485 TI - Psychological distress among survivors of esophageal cancer: the role of illness cognitions and coping. AB - Leventhal's common sense model has provided a useful framework for explaining psychological distress in several chronic illnesses. The model indicates that a person's perception of their illness and their coping strategies are the key determinants of their experience of psychological distress. The present research examines whether illness perceptions and coping strategies are related to levels of psychological distress among survivors of esophageal cancer. Everyone registered with the Oesophageal Patients' Association in the UK was mailed a questionnaire booklet, which included the Illness Perception Questionnaire Revised, the Cancer Coping Questionnaire, and the Hospital Anxiety and Depression Scale. Complete responses were received from 484 people. Regression models indicated that the variables measured could explain 51% of the variance in anxiety and 42% of the variance in depression. Perceptions of esophageal cancer explained the majority of this variance. Positive focus coping strategies were also found to be important in explaining psychological distress. The results of this study are consistent with previous research demonstrating that illness perceptions are stronger correlates of adaptive outcomes than coping strategies. The findings suggest that cognition-based interventions could potentially be most effective in minimizing emotional distress among survivors of esophageal cancer. PMID- 21819486 TI - Correlation of mutant menin stability with clinical expression of multiple endocrine neoplasia type 1 and its incomplete forms. AB - Germline mutations of the tumor suppressor gene MEN1 are found not only in typical multiple endocrine neoplasia type 1 (MEN1) but also in its incomplete forms such as familial isolated hyperparathyroidism (FIHP) and apparently sporadic parathyroid tumor (ASPT). No definitive genotype-phenotype correlation has been established between these clinical forms and MEN1 gene mutations. We previously demonstrated that mutant menin proteins associated with MEN1 are rapidly degraded by the ubiquitin-proteasome pathway. To examine whether the intracellular stability of mutant menin is correlated with clinical phenotypes, we developed a method of evaluating menin stability and examined 20 mutants associated with typical MEN1 (17 missense, two in-frame deletion, one nonsense) and 21 mutants associated with FIHP or ASPT (19 missense, two in-frame deletion). All tested mutants associated with typical MEN1 showed reduced stability. Some missense and in-frame deletion mutants (G28A, R171W, T197I, E255K, E274A, Y353del and E366D) associated with FIHP or ASPT were almost as stable as or only slightly less stable than wild-type menin, while others were as unstable as those associated with typical MEN1. Some stable mutants exhibited substantial biological activities when tested by JunD-dependent transactivation assay. These findings suggest that certain missense and in-frame mutations are fairly stable and retain intrinsic biological activity, and might be specifically associated with incomplete clinical phenotypes. The menin stability test will provide useful information for the management of patients carrying germline MEN1 mutations especially when they have missense or in-frame variants of ambiguous clinical significance. PMID- 21819487 TI - Efficacy, safety and tolerability of rasagiline as adjunctive therapy in elderly patients with Parkinson's disease. AB - BACKGROUND: Rasagiline, an MAO-B inhibitor, is indicated for the treatment of Parkinson's disease (PD). In this post hoc analysis, the efficacy, safety and tolerability of rasagiline as an adjunct to levodopa were compared with placebo in elderly (>=70 years) and younger (<70 years) patients with PD. METHODS: Data were pooled from the Parkinson's Rasagiline: Efficacy and Safety on the Treatment of 'OFF' and Lasting effect in Adjunct therapy with Rasagiline Given Once daily randomized, double-blind, placebo-controlled trials with the primary efficacy end point being the reduction from baseline in daily OFF time. Secondary efficacy end points included scores for Clinical Global Improvement (CGI)-Examiner during ON time, Unified Parkinson's Disease Rating Scale (UPDRS)-ADL during OFF time, UPDRS Motor during ON time and total daily ON time with and without troublesome dyskinesia. Tolerability was evaluated from adverse events (AEs) in the two age groups. RESULTS: Rasagiline decreased daily OFF time versus placebo (P<0.01) and improved CGI-Examiner score (P=0.001) and UPDRS-Motor ON score (P<0.05). Changes in UPDRS-ADL OFF score and total daily ON time without dyskinesia also favoured rasagiline but were not significant. Between-group comparisons (>=70 vs. <70 years) showed that efficacy was unaffected by age for all end-points (P>0.1), and rasagiline was well tolerated amongst both groups of patients with a comparable incidence of total and dopaminergic AEs (P>0.1). CONCLUSIONS: Adjunct rasagiline is efficacious and well tolerated in elderly non-demented patients (>=70 years) with moderate to advanced PD. Confirmation of the efficacy and safety of rasagiline in the elderly patient subgroup is especially relevant because of the increasing number of elderly patients with PD. PMID- 21819488 TI - Isolated lateral thalamic infarction: the role of posterior cerebral artery disease. AB - BACKGROUND AND PURPOSE: Lateral thalamic infarction (LTI) is usually caused by small vessel disease (SVD), i.e., occlusion of the deep perforator. However, focal atherosclerotic posterior cerebral artery disease (PCAD) may produce LTI via thrombotic occlusion of the perforator. We aimed to investigate the prevalence of PCAD in LTI and differences in clinical and imaging findings between LTIs associated with PCAD and SVD. METHODS: We retrospectively evaluated 58 consecutive patients with isolated LTI who underwent diffusion-weighted imaging (DWI) and MR angiography (MRA) within 7 days after stroke onset. Patients were divided into two groups: those with PCAD and those with SVD. Clinical syndromes were divided into pure sensory stroke (PSS) and sensory stroke plus (SS plus), i.e., the concomitant presence of motor dysfunction or ataxia. Clinical and imaging findings were compared between these two groups. RESULTS: Of the 58 patients, 13 (22.4%) had PCAD. PSS was more frequently associated with SVD than with PCAD (57.8% vs. 23.1%, P=0.032). Initial DWI lesion volume (cm3) was significantly larger in PCAD than in patients with SVD (0.38+/-0.13 vs. 0.33+/ 0.22, P=0.025). Among the 23 patients (39.7%) who underwent follow-up DWI, patients with PCAD showed a significantly greater increase in subacute lesion volume than those with SVD (P=0.019). Although National Institutes of Health Stroke Scale scores did not differ at admission (P=0.185), they were significantly higher at discharge in PCAD than in patients with SVD (P=0.012). CONCLUSIONS: Our data suggest that PCAD is an important cause of LTI, being related to SS-plus, larger lesion volume, and worse clinical outcomes. PMID- 21819490 TI - Sleep disturbances in chronic progressive external ophthalmoplegia. AB - BACKGROUND: Chronic progressive external ophthalmoplegia (CPEO) is a relatively common mitochondrial disorder. In addition to extraocular muscle weakness, various other organs can typically be affected, including laryngeal and limb muscles, cerebrum, cerebellum, and peripheral nerves. Given this multi-organ involvement, patients are likely to be prone to sleep disturbances. Here, we determined the nature, prevalence, and determinants of sleep disturbances in CPEO. METHODS: We used validated questionnaires for various sleep disorders and possible determinants such as mood and anxiety, and we performed ambulant polysomnography (PSG) in 20 patients with genetically confirmed CPEO. RESULTS: Three quarters of patients reported nocturnal sleep dysfunction. Thirty-five percent of patients fulfilled the criteria for restless legs syndrome, 30% excessive daytime sleepiness, and 70% significant periodic limb movements. PSG recordings revealed several indicators of a disrupted sleep architecture. Obstructive sleep disordered breathing was present in only one patient. However, four patients had an increased central sleep apnea index, all of whom had a polymerase gamma-1 mutation and a SANDO phenotype (sensoric atactic neuropathy, dysarthria, ophthalmoplegia). Physical examination and questionnaire outcomes were poor predictors of PSG results. CONCLUSION: Several specific sleep disturbances are part of the phenotype of CPEO. Given that the disease is otherwise incurable, symptomatic treatment of sleep disturbances may be an important tool to improve quality of life. Therefore, patients with CPEO should be actively screened for sleep disorders, with a low threshold to perform PSG. PMID- 21819489 TI - Immunosuppressive treatment in refractory chronic inflammatory demyelinating polyradiculoneuropathy. A nationwide retrospective analysis. AB - BACKGROUND AND PURPOSE: There are other options open to patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) who are non-responders to conventional treatment, including immunosuppressive and immunomodulatory agents (IA). The aim of this study was to assess whether the use of IA is able to increase the number of responders. METHODS: Clinical and electrophysiological data of patients with refractory CIDP, followed at 10 Italian centres, were collected, and the clinical outcome (Rankin Scale) and drug side effects (SE) for the different therapies were analysed. RESULTS: A total of 110 patients were included. These patients underwent 158 different therapeutic procedures with IA. Seventy-seven patients were treated with azathioprine, 18 rituximab, 13 cyclophosphamide, 12 mycophenolate mofetil, 12 cyclosporine, 12 methotrexate, 11 interferon-alpha and three interferon beta-1a. The percentage of patients who responded to azathioprine (27%) was comparable to the percentage of responders to other therapies, after the exclusion of interferon beta-1a that was not effective in any of the three patients treated. The percentage of SE ranges from 8% (methotrexate) to 50% (cyclosporine). CONCLUSIONS: One-fourth of patients, refractory to conventional treatment, showed an improvement in their disability with IA. Methotrexate had the lowest SE; cyclosporine was associated with severe SE and often led to drug discontinuation. PMID- 21819491 TI - Joint protection in haemophilia. AB - Haemarthroses (intra-articular haemorrhages) are a frequent finding typically observed in patients with haemophilia. Diagnosis and treatment of these bleeding episodes must be delivered as early as possible. Additionally, treatment should ideally be administered intensively (enhanced on-demand treatment) until the resolution of symptoms. Joint aspiration plays an important role in acute and profuse haemarthroses as the presence of blood in the joint leads to chondrocyte apoptosis and chronic synovitis, which will eventually result in joint degeneration (haemophilic arthropathy). Ultrasonography (US) is an appropriate diagnostic technique to assess the evolution of acute haemarthrosis in haemophilia, although magnetic resonance imaging remains the gold standard as far as imaging techniques are concerned. Some patients experience subclinical haemarthroses, which eventually tend to result in some degree of arthropathy, especially in the ankles. Nowadays, the most effective way of protecting these patients is primary prophylaxis, which in practice changes severe haemophilia into moderate haemophilia, preventing or at least minimizing the occurrence of haemarthrosis. If primary prophylaxis is, for whatever reason not an option, secondary prophylaxis and enhanced on demand treatment should be considered. Two alternatives are available for inhibitor patients: (i) control of haemostasis using by-passing agents (rFVIIa or aPCCs) either as enhanced on demand treatment or secondary prophylaxis, as appropriate, following the same basic principles used for non-inhibitor patients and (ii) immune tolerance induction (ITI) to eradicate the inhibitor. PMID- 21819492 TI - Microarray analysis of sexually dimorphic gene expression in human minor salivary glands. AB - OBJECTIVE: We hypothesized that differential mRNA transcription between the sexes may be linked to the 9:1 female-to-male gender-related relative risk for the development of Sjogren's syndrome (SS), an autoimmune disease that leads to inflammation and dysfunction in the lachrymal and salivary glands. SUBJECTS AND METHODS: RNA from minor salivary glands was collected from nine healthy volunteers (four men and five women) and analyzed using the Agilent 4 * 44K human microarray platform. Differential expression was confirmed by qRT-PCR. RESULTS: Comparison of the transcriptome of minor salivary glands from normal male and female volunteers with that of salivary glands and secretory epithelia identified a number of gender, species, and tissue-specific gene expression patterns. These differences include, but are not limited to, a diverse set of genes involved in immune modulation, chemotactic control, inhibition of complement, metabolism, and neurogenesis. CONCLUSION: Analysis of these changes provides insight into the protective and predisposing molecular factors that may be involved in the development of Sjogren's syndrome. Some of the gene changes observed in this study correlate with previously observed sexual dimorphisms in salivary gland function and also illustrate several new targets for further investigation. PMID- 21819493 TI - Are oral and dental diseases linked to cancer? AB - OBJECTIVE: Infection and inflammation play a role in carcinogenesis, and highly prevalent oral and dental diseases have been significantly linked to some types of cancer. This article reviews current literature in this area. MATERIALS AND METHODS: Open literature review using the PubMed database and focused on publications from 2000 to 2010. RESULTS: Numerous potential mechanisms are implicated in the oral disease/carcinogenesis paradigm, including infection- and inflammation-associated cell pathology and microbial carcinogen metabolism. Poor oral hygiene is associated with oral cancer, but there is also evidence of a possible link between oral or dental infections and malignancies in general. CONCLUSION: Oral infections may trigger malignant transformation in tissues of the mouth and other organs. However, scientific evidence to date remains weak and further well-conducted studies are warranted before cancer can be properly added to the list of oral infection-related systemic diseases. PMID- 21819494 TI - Hypermethylation of RUNX3 but not WIF1 gene and its association with stage and nodal status of tongue cancers. AB - OBJECTIVES: Recent studies indicate various molecular abnormalities in oral squamous cell carcinomas (OSCC), including DNA methylation of tumor-associated genes. Although promoter hypermethylation of Wnt pathway antagonists RUNX3 (Runt related transcription factor 3) and Wnt inhibitory factor 1 (WIF1) has been identified as a common event in a number of carcinomas, methylation status and the role of RUNX3 as a possible tumor suppressor in oral and head and neck cancer are yet controversial. The aim of our study is to determine the occurrence of RUNX3 and WIF1 genes hypermethylation and correlation with tumor and host-related factors and prognosis in tongue carcinomas. MATERIAL AND METHODS: In 76 patients with tongue carcinoma, RUNX3 and WIF1 genes promoter hypermethylation analysis was assessed by nested methylation-specific PCR method. RESULTS: Hypermethylation of WIF1 and RUNX3 genes promoters was observed in 35% and 25% of carcinomas, respectively. RUNX3 gene promoter hypermethylation was significantly associated with lymph node involvement (P = 0.013) and tumor stage (P = 0.006), but not with the overall survival. Occurrence of RUNX3 and WIF1 genes comethylation was associated with nodal status (P = 0.058) and tumor stage (P = 0.055). CONCLUSIONS: Our findings indicate that RUNX3 and WIF1 are frequently aberrantly methylated and that RUNX3 promoter methylation could be considered as a potential prognostic marker in tongue carcinoma. PMID- 21819495 TI - Expression of fatty acid synthase (FASN) in oral nevi and melanoma. AB - OBJECTIVE: The aim of this study was to determine the expression of fatty acid synthase (FASN) in oral nevi and melanomas, comparing the results with correspondent cutaneous lesions. MATERIALS AND METHODS: Expression of FASN was evaluated by immunohistochemistry in 51 oral melanocytic lesions, including 38 intramucosal nevi and 13 primary oral melanomas, in 10 cutaneous nevi and in 14 melanomas. RESULTS: Fatty acid synthase was strongly expressed only in melanomas, either of the oral mucosa or cutaneous. On the other hand, most oral and cutaneous nevi were negative, with a few oral cases showing focal and weak expression. CONCLUSION: Fatty acid synthase is expressed in malignant melanocytes, and it can be a helpful marker to distinguish oral melanomas from oral melanocytic nevi. PMID- 21819497 TI - Identification of Stenotrophomonas maltophilia strains isolated from environmental and clinical samples: a rapid and efficient procedure. AB - AIMS: Aim of the study is to identify accurately Stenotrophomonas maltophilia isolates recovered from environmental and clinical samples. METHODS AND RESULTS: Recovery of Sten. maltophilia-like isolates from soil samples using the vancomycin, imipenem, amphotericin B (VIA) selective agar medium enabled distinction of various morphotype colonies. A set of soil and clinical isolates was tested for species identification using different methods. 16S rDNA analyses showed the dark green with a blue halo morphotype to be typical Sten. maltophilia strains. The API-20NE, Vitek-2 and Biolog phenotypic analyses typically used for the identification of clinical isolates did not perform well on these soil isolates. The species-specific PCR screening targeting Sten. maltophilia 23S rDNA and the multiplex smeD/ggpS PCR, differentiating Sten. maltophilia from Stenotrophomonas rhizophila, were tested for improvement of these identification schemes. The latter multiplex PCR identified all isolates tested in this study, whatever be their origin. CONCLUSIONS: Isolation on VIA medium and confirmation of Sten. maltophilia species membership by smeD PCR is proposed to identify environmental and clinical isolates of Sten. maltophilia. SIGNIFICANCE AND IMPACT OF THE STUDY: The proposed approach enables isolation and identification of Sten. maltophilia from different environments in an easy and rapid way. This approach will be useful to accurately manage studies on the abundance and distribution of Sten. maltophilia in hospital and nonhospital environments. PMID- 21819498 TI - The sterol-binding protein Kes1/Osh4p is a regulator of polarized exocytosis. AB - Oxysterol-binding protein (OSBP)-related protein Kes1/ Osh4p is implicated in nonvesicular sterol transfer between membranes in Saccharomyces cerevisiae. However, we found that Osh4p associated with exocytic vesicles that move from the mother cell into the bud, where Osh4p facilitated vesicle docking by the exocyst tethering complex at sites of polarized growth on the plasma membrane. Osh4p formed complexes with the small GTPases Cdc42p, Rho1p and Sec4p, and the exocyst complex subunit Sec6p, which was also required for Osh4p association with vesicles. Although Osh4p directly affected polarized exocytosis, its role in sterol trafficking was less clear. Contrary to what is predicted for a sterol transfer protein, inhibition of sterol binding by the Osh4p Y97F mutation did not cause its inactivation. Rather, OSH4(Y97F) is a gain-of-function mutation that causes dominant lethality. We propose that in response to sterol binding and release Osh4p promotes efficient exocytosis through the co-ordinate regulation of Sac1p, a phosphoinositide 4-phosphate (PI4P) phosphatase, and the exocyst complex. These results support a model in which Osh4p acts as a sterol-dependent regulator of polarized vesicle transport, as opposed to being a sterol-transfer protein. PMID- 21819499 TI - A weak base-generating system suitable for selective manipulation of lysosomal pH. AB - pH varies widely among the different intracellular compartments. The establishment and maintenance of a particular pH appears to be critical for proper organellar function. This has been deduced from experiments where intraorganellar pH was altered by means of weak acids or bases, ionophores or inhibitors of the vacuolar H(+)-ATPase (V-ATPase). These manipulations, however, are not specific and simultaneously alter the pH of multiple compartments. As a result, it is difficult to assign their effect to a defined organelle. To circumvent this limitation, we designed and implemented a procedure to selectively manipulate the pH of a compartment of choice, using lysosomes as a model organelle. The approach is based on the targeted and continuous enzymatic generation of weak electrolyte, which enabled us to overcome the high buffering capacity of the lysosomal lumen, without altering the pH of other compartments. We targeted jack-bean urease to lysosomes and induced the localized generation of ammonia by providing the membrane-permeant substrate, urea. This resulted in a marked, rapid and fully reversible alkalinization that was restricted to the lysosomal lumen, without measurably affecting the pH of endosomes or of the cytosol. The acute alkalinization induced by urease-urea impaired the activity of pH-dependent lysosomal enzymes, including cathepsins C and L, without altering endosomal function. This approach, which can be extended to other organelles, enables the analysis of the role of pH in selected compartments, without the confounding effects of global disturbances in pH or vesicular traffic. PMID- 21819500 TI - The rising tide of diabetic retinopathy in indigenous Australians. PMID- 21819501 TI - Optic disc haemorrhage: the more we look the more we find. PMID- 21819502 TI - Prevalence of self-reported diabetes and diabetic retinopathy in indigenous Australians: the National Indigenous Eye Health Survey. AB - BACKGROUND: To assess the prevalence of diabetes and diabetic retinopathy in indigenous Australians aged >=40 years. DESIGN: The National Indigenous Eye Health Survey used a stratified, multistage cluster probability sampling frame to provide a representative sample of the indigenous Australian population. PARTICIPANTS: One thousand one hundred and eighty-nine eligible indigenous adults were examined using standardized procedures. METHODS: Each participant underwent a comprehensive eye examination included presenting and best corrected visual acuity, visual field, fundus and lens photography. MAIN OUTCOME MEASURES: Diabetic retinopathy. RESULTS: The prevalence of diabetes in the 1189 eligible indigenous adults was 37.3% (95% confidence interval: 34.6-40.2%). The prevalence of diabetic retinopathy among 394 people with diabetes was 29.7% (95% confidence interval: 25.2-34.2%), and 17.8% (95% confidence interval: 14.0-21.6%), 8.9% (95% confidence interval: 6.1-11.7%) and 3.1% (95% confidence interval: 1.3-4.7%) for mild or moderate diabetic retinopathy, clinically significant macular oedema and severe or proliferative diabetic retinopathy, respectively. Diabetic retinopathy was presented in 6.3% in those who did not report diabetes. The risk of diabetic retinopathy increased with duration of diabetes (the adjusted odds ratios were 3.4 for 10-19 years, 6.1 for 20-29 years and 25.8 for >=30 years). CONCLUSIONS: The prevalence of self-reported diabetes in indigenous Australians is more than eight times higher than that in non-indigenous Australians. The prevalence of diabetic retinopathy in people with diabetes is similar to that of non-indigenous Australians. PMID- 21819503 TI - Assessing the diagnostic validity of a blind register. AB - BACKGROUND: To validate the accuracy of clinical ophthalmic information held on the West Australian blind register. DESIGN: Community-based cross-sectional study. PARTICIPANTS: Legally blind or severely vision-impaired people were selected randomly from the Association for the Blind of Western Australia register. METHODS: Individuals were reviewed by one of two consultant ophthalmologists. MAIN OUTCOME MEASURES: The positive predictive value (ppv), sensitivity and specificity for legal blindness status and diagnostic causes of vision loss were calculated using data extracted from the Association for the Blind of Western Australia blind register. RESULTS: 273 blind or near blind people were reviewed from the register total of 4271 individuals. There were more women (57%) than men, median age 81 years. For legal blindness status the ppv was 0.88 (95% confidence interval [CI] 0.82-0.92), sensitivity 0.75 (95% CI 0.74 0.84) and specificity 0.6 (95% CI 0.46-0.73). The ppv for the diagnostic causes of blindness were: age-related macular degeneration = 0.95 (95% CI 0.91-0.97), retinitis pigmentosa ppv = 1 (95% CI 0.81-1.0), diabetic retinopathy ppv = 0.9 (95% CI 0.57-0.99), optic neuropathies ppv = 0.77 (95% CI 0.51-0.92) and glaucoma ppv = 0.87 (95% CI 0.7-0.96). Forty individuals (15%) had treatable conditions contributing to their vision loss. CONCLUSIONS: The blind register diagnoses and legal blindness status are of high accuracy. This information allows useful linkages to other databases for studies of blindness interactions. A regular updating mechanism would improve the future accuracy of this valuable regional asset. The presence of untreated cataract suggests that regular follow up and appropriate treatment may help optimize vision in blind patients. PMID- 21819504 TI - Use of the electroretinogram in a paediatric hospital. AB - BACKGROUND: To review the use of electroretinography and identify common reasons for referral and diagnoses at a tertiary paediatric hospital. DESIGN: Retrospective cohort study. PARTICIPANTS: Three hundred and eighteen patients (male 195, female 123) aged <18 years with 388 electroretinograms were included. METHODS: All electroretinograms performed at the Royal Children's Hospital, Brisbane from 1998 to 2005 were reviewed. Normative data and electroretinograms from patients aged >=18 years were excluded. MAIN OUTCOME MEASURES: Reasons for referral and diagnoses were determined from each patient's first electroretinogram. Concordance between the first electroretinogram diagnosis and clinical referral was reviewed to determine whether the electroretinogram was normal, inconclusive, confirmed, excluded, or changed the clinical diagnosis or provided a new diagnosis. RESULTS: The median age at the time of the first investigation was 3.78 years (range 2.6 weeks to 17.5 years). The most common reasons for referral were nystagmus (n = 93), decreased vision (n = 33) and sensorineural deafness (n = 29). After one electroretinogram, 51% were normal (n = 162) and 15% were inconclusive (n = 49). The most common electroretinography diagnosis was cone rod dystrophy. The first electroretinogram for each patient confirmed the clinical suspicion in 17.6% (n = 56) and excluded it in 23% (n = 73) of cases. The electroretinogram resulted in a changed diagnosis in 0.9% (n = 3) and provided a new diagnosis in 15.1% (n = 48). Overall, the first electroretinogram was considered useful in 85% cases (n = 269). CONCLUSIONS: Electroretinography is a valuable investigation for evaluating paediatric eye disease and in this series confirmed, excluded, changed or provided a new diagnosis in 85% of cases. PMID- 21819505 TI - Corneal transplantation in Hungary (1946-2009). AB - BACKGROUND: To identify changing trends in indications for corneal transplantation in Debrecen, Hungary over the past 64 years. DESIGN: Retrospective study, at the Department of Ophthalmology, University of Debrecen, Hungary. PARTICIPANTS: Four thousand seven hundred and seventy-eight patients who underwent keratoplasty. METHODS: The analysis was based on medical charts, surgical descriptions and eye bank records. MAIN OUTCOME MEASURES: Keratoplasty indications between January 1946 and December 2009. For an easier overview, the 64-year interval was divided into seven time periods (1946-1955, I; 1956-1965, II; 1966-1975, III; 1976-1985, IV; 1986-1995, V; 1996-2005, VI; 2006-2009, VII). RESULTS: Over the 64 years, clinical indications for keratoplasty were corneal scarring (24.9%), regraft (18.6%), keratoconus (18.6%), pseudophakic/aphakic corneal oedema (12%), stromal corneal dystrophies (6%), non-infectious keratitis (4.7%), chemical injuries (3.3%), corneal degenerations (3%), mechanical trauma (1.7%), infectious keratitis (1.4%), endothelial corneal dystrophies (1.3%) and others (4.5%). During periods I-IV, corneal scarring was the most common indication for corneal transplantation. In period V, corneal ectasia became the leading clinical indication. Regraft was the most frequent indication in period VI. In the most recent years, an emerging tendency in pseudophakic/aphakic corneal oedema as the indication for keratoplasty was observed. CONCLUSIONS: In Hungary, the number of grafts has increased greatly in the past 64 years, the transplantation rates are similar to those of industrial countries. Indications for corneal transplantation have changed considerably over the last half decade from corneal scarring to corneal ectasia, regraft and pseudophakic/aphakic corneal oedema. PMID- 21819506 TI - Management of upper eyelid cicatricial entropion. AB - PURPOSE: There is a paucity of published data on the management of upper eyelid cicatricial entropion. We report on our results using such techniques as lamella repositioning, recession or augmentation and terminal tarsal rotation. DESIGN: Observational retrospective case series. PARTICIPANTS: Consecutive cases of upper eyelid cicatricial entropion of two specialist oculoplastic centres (Corneoplastic Unit, East Grinstead, UK and South Australian Institute of Ophthalmology, Adelaide, Australia) were reviewed over a 7-year period. METHODS: All patients underwent anterior lamellar repositioning or terminal tarsal rotation. MAIN OUTCOME MEASURES: Success was defined by two definitions: anatomical success was defined where the lid margin was restored to its normal position. Complete success was defined where there were no eyelashes touching the globe. Gain or loss (<= or >=2 Snellen lines) in best corrected visual acuity using a Snellen chart and resolution of any corneal epitheliopathy at final follow-up were also recorded (as graded by experienced oculoplastic consultants). RESULTS: Fifty-two procedures were performed on 41 patients (11 bilateral). All patients underwent either an anterior lamellar repositioning or a terminal tarsal rotation. Trachoma, previous upper lid surgery, Stevens-Johnson syndrome and meibomian gland dysfunction were the commonest underlying diagnoses. Ninety-eight per cent of the group had a normal anatomical lid position at follow-up. Nine eyelids (17%) of the group had recurrence of trichiasis. CONCLUSION: This large case series demonstrates that upper eyelid cicatricial entropion is managed effectively utilizing procedures that involve recession and reposition. We recommend that excision of tissue is avoided, especially in pathology that has a progressive immunological cicatricial drive. PMID- 21819507 TI - Aqueous humour levels of vascular endothelial growth factor and erythropoietin in patients with diabetic macular oedema before and after intravitreal erythropoietin injection. AB - BACKGROUND: To determine the aqueous humour levels of vascular endothelial growth factor (VEGF) and erythropoietin (EPO) in eyes with diabetic macular oedema before and after intravitreal EPO injection. DESIGN: Prospective interventional case series. PARTICIPANTS: Eleven eyes of 11 patients with diabetic macular oedema, and 10 eyes of 10 patients with cataract surgery as controls. MAIN OUTCOMES MEASURES: EPO and VEGF levels in aqueous humour before and after intravitreal EPO injection in patients and compared with controls. METHODS: Eyes with diabetic macular oedema received an intravitreal injection of EPO (1000 IU/0.05 mL), followed by various intraocular procedures at different intervals (1 54 days) after injection. An aqueous humour sample was obtained and aqueous humour levels of EPO and VEGF were measured using enzyme-linked immunosorbent assay. RESULTS: The aqueous levels of EPO and VEGF were significantly elevated in diabetic macular oedema eyes compared to control eyes (P < 0.05). EPO levels in patients correlated with VEGF levels (r = 0.816, P = 0.002) and central macular thickness at baseline (r = 0.618, P = 0.043). After intravitreal EPO injection, aqueous EPO levels were significantly elevated, whereas aqueous VEGF levels were varied according to the time interval since injection. Visual acuity and central macular thickness were not different after injection, compared to before injection. Aqueous EPO levels did not correlate with serum EPO levels(r = 0.299, P = 0.371). CONCLUSIONS: EPO is locally expressed and is correlated with VEGF in eyes with diabetic macular oedema. The role of EPO and the effect of intravitreal EPO in patients with diabetic macular oedema need to be further defined. PMID- 21819508 TI - Changes in tarsal plate fibrillar collagens and elastic fibre phenotype in floppy eyelid syndrome. AB - BACKGROUND: The aims of this study are to investigate the expression of the main structural components of the tarsal extracellular matrix (ECM) in floppy eyelid syndrome (FES) focusing on elastic fibres and collagen types I and III, and also to identify possible cell-mediated inflammatory mechanisms in the pathogenesis of this condition. METHODS: A histopathological case control study was conducted using 30 upper lid specimens from patients with FES and 15 undiseased upper lid control specimens. Structural ECM components were assessed using a combination of immunctorial ataining ohistochemical and techniques including antibodies to collagens I and III, Verhoeff's iron haematoxylin, Gomori's aldehyde fuchsin and Lillie's oxidised aldehyde fuchsin. The contribution of different cellular components of the inflammatory response was investigated by immunohistochemical techniques using antibodies to CD3, CD20, CD68. Slide scoring was performed using a semiquantitative technique on an ordinal scale. Statistical analysis was performed using matched ordinal regression analysis. RESULTS: FES tarsal plate tissue demonstrated a decreased abundance of mature elastic fibres (P <= 0.001) and an increased abundance of oxytalan fibres (P = 0.006). Intensity of staining for collagens I (P = 0.012) and III (P < 0.001) was increased. No significant difference in the abundance of CD3, CD20 and CD68 expressing cells was identified. CONCLUSIONS: The findings of altered elastic fibre phenotype and collagen accumulation are consistent with an adaptive response to cyclic mechanical loading of the tarsal plate, rather than an aetiological feature. These findings are important in understanding how the tarsal ECM responds to mechanical loading. PMID- 21819511 TI - Relationship between aggression, interpersonal style, and therapeutic alliance during short-term psychiatric hospitalization. AB - Aggression during psychiatric hospitalization is frequent, problematic, and a major challenge for nurses and mental health services more generally. The strength of the therapeutic alliance between nursing staff and patients has been posited as an important protective factor that can limit the likelihood of aggression. This study examined the relationship between interpersonal style, perceived coercion, and psychiatric symptoms on the therapeutic alliance between patients and staff, and how each, in turn, is related to aggression. Participants in this study were 79 patients admitted to an acute psychiatric hospital. Each participant was interviewed to determine perceived coercion, symptoms of psychiatric illness, interpersonal style, and therapeutic alliance. Incidents of aggression were recorded at discharge through a review of incident forms, file review, and interviews with unit nursing staff. The results showed that a hostile dominant interpersonal style and symptoms of paranoia predicted poor therapeutic alliance, contributing 14% of the variance in therapeutic alliance scores. A dominant interpersonal style predicted aggression towards staff. Therapeutic alliance, perceived coercion, and symptoms of psychiatric illness did not predict aggression. Implications for engagement in treatment and the prevention of aggression are discussed. PMID- 21819510 TI - Young, gifted, and caring: a project narrative of young carers, their mental health, and getting them involved in education, research and practice. AB - Young carers are a global phenomenon. The UK estimates it has in excess of 175 000 young carers, the onset of their caring role often occurring between 8 and 10 years of age. Of these, 17 000 are caring for a parent who has severe mental illness, a significant factor for children entering the health and social care system, as up to 60% experience mental health difficulties themselves. This paper reports on the outcome of a participatory project aimed at better understanding the needs of young people. A World Cafe event was hosted, bringing together those involved in promoting the mental health of young people in a partnership consortium. The event was led by young service users and carers. Important issues raised by the young carers were being excluded from being included; stuck in the here and now, ignoring the future; a hole in the net; and ensuring the hidden is on the agenda. The World Cafe gave the university the privilege of insight into what local young carers need to improve their mental health, and more importantly, how we can utilize our skills to help them achieve their goals. PMID- 21819512 TI - Outer membrane continuity and septosome formation between vegetative cells in the filaments of Anabaena sp. PCC 7120. AB - Anabaena sp. PCC 7120 is a prototype filamentous nitrogen-fixing cyanobacterium, in which nitrogen fixation and photosynthesis are spatially separated. Recent molecular and cellular studies have established the importance of molecular exchange between cells in the filament, but the routes involved are still under investigation. Two current models propose either a continuous periplasm or direct connections between adjacent cells whose integrity requires the protein SepJ. We used electron tomography to analyze the ultrastructure of the septum between vegetative cells in the Anabaena filament and were able to visualize intercellular connections that we term 'SEPTOSOMES'. We observed that, whereas the existence of the septosome does not depend on the presence of SepJ, the spacing between the two plasma membranes of the septum was significantly decreased in a DeltasepJ mutant. In addition, we observed that the peptidoglycan layer of each cell enters the septum but the outer membrane does not. Thus, each cell in the filament is individually surrounded by a plasma membrane and a peptidoglycan layer, and physical cell-cell contacts are mediated by the septosome. PMID- 21819513 TI - A systematic analysis of the early transcribed membrane protein family throughout the life cycle of Plasmodium yoelii. AB - The early transcribed membrane proteins (ETRAMPs) are a family of small, highly charged transmembrane proteins unique to malaria parasites. Some members of the ETRAMP family have been localized to the parasitophorous vacuole membrane that separates the intracellular parasite from the host cell and thus presumably have a role in host-parasite interactions. Although it was previously shown that two ETRAMPs are critical for rodent malaria parasite liver-stage development, the importance of most ETRAMPs during the parasite life cycle remains unknown. Here, we comprehensively identify nine new etramps in the genome of the rodent malaria parasite Plasmodium yoelii, and elucidate their conservation in other malaria parasites. etramp expression profiles are diverse throughout the parasite life cycle as measured by RT-PCR. Epitope tagging of two ETRAMPs demonstrates protein expression in blood and liver stages, and reveals differences in both their timing of expression and their subcellular localization. Gene targeting studies of each of the nine uncharacterized etramps show that two are refractory to deletion and thus likely essential for blood-stage replication. Seven etramps are not essential for any life cycle stage. Systematic characterization of the members of the ETRAMP family reveals the diversity in importance of each family member at the interface between host and parasite throughout the developmental cycle of the malaria parasite. PMID- 21819514 TI - Leishmania-host interactions: what has imaging taught us? AB - Leishmania parasites are well adapted to initiate infection, resist the onslaught of innate immunity and achieve a state of long-lived persistence. In recent years, the tools available to study these interactions have developed enormously and have become much more widely available. Confocal microscopy, live cell imaging, whole animal imaging and intra-vital 2-photon now complement and extend the classical light and electron microscopical techniques. Coupled with approaches to generate transgenic parasites that express imaging friendly reporter proteins, these tools are making the full breadth of the life cycle accessible to imaging studies. New insights into the life history of these highly successful parasites are emerging with increasing frequency, and often with startling clarity and visual drama. In this short review, we focus on how this new generation of imaging-based research tools has augmented our understanding of the complex interplay that occurs between Leishmania and the cells that it infects in mammalian hosts. PMID- 21819515 TI - Entry of oomycete and fungal effectors into plant and animal host cells. AB - Fungal and oomycete pathogens cause many destructive diseases of plants and important diseases of humans and other animals. Fungal and oomycete plant pathogens secrete numerous effector proteins that can enter inside host cells to condition susceptibility. Until recently it has been unknown if these effectors enter via pathogen-encoded translocons or via pathogen-independent mechanisms. Here we review recent evidence that many fungal and oomycete effectors enter via receptor-mediated endocytosis, and can do so in the absence of the pathogen. Surprisingly, a large number of these effectors utilize cell surface phosphatidyinositol-3-phosphate (PI-3-P) as a receptor, a molecule previously known only inside cells. Binding of effectors to PI-3-P appears to be mediated by the cell entry motif RXLR in oomycetes, and by diverse RXLR-like variants in fungi. PI-3-P appears to be present on the surface of animal cells also, suggesting that it may mediate entry of effectors of fungal and oomycete animal pathogens, for example, RXLR effectors found in the oomycete fish pathogen, Saprolegnia parasitica. Reagents that can block PI-3-P-mediated entry have been identified, suggesting new therapeutic strategies. PMID- 21819516 TI - Characteristic features of intracellular pathogenic Leptospira in infected murine macrophages. AB - Leptospira interrogans is a spirochaete responsible for a zoonotic disease known as leptospirosis. Leptospires are able to penetrate the abraded skin and mucous membranes and rapidly disseminate to target organs such as the liver, lungs and kidneys. How this pathogen escape from innate immune cells and spread to target organs remains poorly understood. In this paper, the intracellular trafficking undertaken by non-pathogenic Leptospira biflexa and pathogenic L. interrogans in mouse bone marrow-derived macrophages was compared. The delayed in the clearance of L. interrogans was observed. Furthermore, the acquisition of lysosomal markers by L. interrogans-containing phagosomes lagged behind that of L. biflexa containing phagosomes, and although bone marrow-derived macrophages could degrade L. biflexa as well as L. interrogans, a population of L. interrogans was able to survive and replicate. Intact leptospires were found within vacuoles at 24 h post infection, suggesting that bacterial replication occurs within a membrane-bound compartment. In contrast, L. biflexa were completely degraded at 24 h post infection. Furthermore, L. interrogans but not L. biflexa, were released to the extracellular milieu. These results suggest that pathogenic leptospires are able to survive, replicate and exit from mouse macrophages, enabling their eventual spread to target organs. PMID- 21819517 TI - Comparison of insulin lispro protamine suspension versus insulin glargine once daily in basal-bolus therapies with insulin lispro in type 2 diabetes patients: a prospective randomized open-label trial. AB - AIMS: To compare the efficacy and safety of insulin lispro protamine suspension (ILPS) versus insulin glargine once daily in a basal-bolus regimen in type 2 diabetes mellitus (T2DM) patients. METHODS: Three hundred eighty-three insulin treated patients were randomized to either ILPS plus lispro or glargine plus lispro in this open-label 24-week European study. Insulin doses were titrated to predefined blood glucose (BG) targets. Non-inferiority of ILPS versus glargine was assessed by comparing the upper limit of the 95% confidence interval (CI) for the change of HbA1c from baseline to week 24 (adjusted for country and baseline HbA1c) with the non-inferiority margin of 0.4%. Secondary endpoints included HbA1c categories, BG profiles, insulin doses, hypoglycaemic episodes, adverse events and vital signs. RESULTS: Non-inferiority of ILPS versus glargine in the change of HbA1c from baseline was shown: least-square mean between-treatment difference (95% CI) was 0.1% (-0.11; 0.31). Mean changes at week 24 were -1.05% (ILPS) and -1.20% (glargine). HbA1c <7.0% was achieved by 21.7 versus 29.4% of patients. Mean basal/mealtime insulin doses at week 24 were 29.6/36.2 IU/day (ILPS) versus 32.8/42.2 IU/day (glargine); the difference was not statistically significant for total dose (p = 0.7). In both groups, 56.1/25.7% versus 63.6/19.3% of patients experienced any/nocturnal hypoglycaemia (p = 0.2 for both). No relevant differences were noted in any other variables. CONCLUSIONS: A basal-bolus regimen with ILPS once daily resulted in non-inferior glycaemic control compared to a similar regimen with glargine, without statistically significant or clinically relevant differences in hypoglycaemia. ILPS-based regimens can be considered an alternative to basal-bolus regimens with glargine for T2DM patients. PMID- 21819518 TI - Management of diverticulitis: results of a survey among gastroenterologists and surgeons. AB - AIM: The study aimed to investigate current management strategies for left-sided diverticulitis and compare them with current international guidelines. Differences between surgeons and gastroenterologists and between gastrointestinal and nongastrointestinal surgeons were assessed. METHOD: A web-based survey of treatment options for uncomplicated and complicated diverticulitis was carried out among surgeons and gastroenterologists in the Netherlands. Only surgeons were asked about surgical strategy. RESULTS: A total of 292 surgeons and 87 gastroenterologists responded, representing 92% of all surgical and 46% of all gastroenterology departments. Ninety per cent of respondents treated mild diverticulitis without antibiotics. About one-fifth (18% gastroenterologists; 19% surgeons) regarded a CT scan as mandatory in the initial assessment. Most surgeons and gastroenterologists used some form of bowel rest, would consider outpatient treatment and would perform a colonoscopy on follow up. For Hinchey Stage 3, 78% of surgeons would consider resection and primary anastomosis and laparoscopic lavage was viewed as a valid alternative by 30% of gastrointestinal and 2% of nongastrointestinal surgeons. For Hinchey stage 4, 46% of gastrointestinal and 72% of nongastrointestinal surgeons would always perform Hartmann's procedure. CONCLUSION: The treatment of diverticulitis in the Netherlands shows major differences when compared with guidelines for all stages of disease. PMID- 21819519 TI - Efficacy and safety of dalcetrapib in type 2 diabetes mellitus and/or metabolic syndrome patients, at high cardiovascular disease risk. AB - AIMS: Mixed dyslipidaemia, characterized by low levels of high-density lipoprotein cholesterol (HDL-C) and high levels of triglycerides, is common in patients with type 2 diabetes mellitus (T2DM) and/or metabolic syndrome. Dalcetrapib effectively increases HDL-C levels by modulating cholesteryl ester transfer protein (CETP) activity. The aim of this analysis was to investigate the lipid modifying efficacy and safety of dalcetrapib in patients with T2DM and/or metabolic syndrome. METHODS: Post hoc analysis of dalcetrapib therapy in five placebo-controlled, Phase II trials (4-48 weeks of duration) involving T2DM and/or metabolic syndrome, in dyslipidaemic patients with coronary heart disease (CHD) or CHD risk equivalent. RESULTS: Both in patients with and without T2DM and/or metabolic syndrome, dalcetrapib decreased CETP activity by 26-58% and increased HDL-C levels by 23-34%, depending on dose and duration of treatment. Dalcetrapib did not significantly affect low-density lipoprotein cholesterol (LDL C) or apolipoprotein B levels. Treatment with dalcetrapib was generally well tolerated with a similar number of adverse events reported between patient groups and between those receiving dalcetrapib compared with placebo. CONCLUSIONS: Dalcetrapib similarly decreased CETP activity and increased HDL-C levels in patients with and without T2DM or metabolic syndrome; the ongoing Phase III dal OUTCOMES study will help to determine if dalcetrapib's improvement in lipid levels also reduces cardiovascular morbidity and mortality. PMID- 21819520 TI - Urethro-anastomotic fistula caused by manual digital dilatation of low rectal anastomotic stricture successfully managed by prostatectomy: a case report. PMID- 21819521 TI - Reply to Dr Filik. PMID- 21819522 TI - Long-term results of surgery plus fibrin sealant for anal fistula. AB - AIM: The long-term recurrence rate of fibrin glue treatment was analysed in patients with trans-sphincteric cryptoglandular fistula operated by a two-phase procedure: (i) fistulectomy with seton placement; (ii) fibrin sealant (Tissucol Duo(r), Baxter) insertion in the track. METHOD: Clinical data were collected prospectively for all patients operated between 2004 and 2010. The statistical association of clinical variables and recurrence was analysed and a disease-free curve was constructed using the Kaplan-Meier method. RESULTS: Twenty-eight consecutive patients (mean age 48.3 +/- 13.3 years; 22 men) were enrolled in the study. Middle and high trans-sphincteric fistulae were diagnosed in 20 (71.4%) and eight (28.6%) patients. Seven (25%) had secondary track formation. The mean interval between the first operation and the fibrin sealant treatment was 12.5 +/ 7.6 months. There were no complications related to the procedure. Nine (32.1%, 95% CI 17.9-50.7%) patients developed recurrence between 3 and 27 months after fibrin sealant treatment. Disease-free curves showed that the highest probability of recurrence occurred in the first 2 years. No incontinence was found at a mean follow-up of 20.6 (3-60) months among the 67.8% patients with no evidence of recurrence. CONCLUSION: Fibrin sealant is safe and simple. The healing rate is satisfactory without the risk of incontinence. PMID- 21819523 TI - Nervous system abscess: a rare complication of diverticulitis. PMID- 21819524 TI - An unusual case of small intestine evisceration through a transverse loop colostomy. PMID- 21819525 TI - Heterotopic mesenteric ossification. PMID- 21819526 TI - Major but differential decline in the incidence of Staphylococcus aureus bacteraemia in HIV-infected individuals from 1995 to 2007: a nationwide cohort study*. AB - OBJECTIVES: Incidence rates (IRs) of Staphylococcus aureus bacteraemia (SAB) are known to be higher in HIV-infected individuals than in the general population, but have not been assessed in the era of highly active antiretroviral therapy. METHODS: From 1 January 1995 to 31 December 2007, all Danish HIV-infected individuals (n=4871) and population controls (n=92 116) matched on age and sex were enrolled in a cohort and all cases of SAB were registered. IRs and risk factors were estimated using time-updated Poisson regression analysis. RESULTS: We identified 329 cases of SAB in 284 individuals, of whom 132 individuals were infected with HIV and 152 were not [crude IR ratio (IRR) 24.2; 95% confidence interval (CI) 19.5-30.0, for HIV-infected vs. non-HIV-infected individuals]. Over time, IR declined for HIV-infected individuals (IRR 0.40). Injecting drug users (IDUs) had the highest incidence and the smallest decline in IR, while men who have sex with men (MSM) had the largest decline over time. Among HIV-infected individuals, a latest CD4 count <100 cells/MUL was the strongest independent predictor of SAB (IRR 10.2). Additionally, HIV transmission group was associated with risk of SAB. MSM were more likely to have hospital-acquired SAB, a low CD4 cell count and AIDS at the time of HIV acquisition compared with IDUs. CONCLUSIONS: We found that the incidence of SAB among HIV-infected individuals declined during the study period, but remained higher than that among HIV uninfected individuals. There was an unevenly distributed burden of SAB among HIV transmission groups (IDU>MSM). Low CD4 cell count and IDU were strong predictors of SAB among HIV-infected individuals. PMID- 21819527 TI - Does use of antiretroviral therapy regimens with high central nervous system penetration improve survival in HIV-infected adults? AB - OBJECTIVES: The aim of the study was to determine whether combination antiretroviral therapy (cART) with high central nervous system penetration effectiveness (CPE) rank (neurocART) is associated with increased survival benefit compared with non-neurocART. METHODS: Prospective data were examined for HIV-positive patients in the Asia Pacific HIV Observational Database who had commenced cART. CPE rank was calculated using the 2010 rankings process. NeurocART status was assigned to regimens with a CPE rank of 8 or more. Survival was analysed using Cox proportional hazards models with covariates updated at changes in cART regimen and with deaths up to 90 days after regimen cessation attributed to that regimen. Sensitivity analyses were conducted to examine the robustness of analysis assumptions. RESULTS: Among 5882 patients, 308 deaths occurred. The hazard ratio (HR) for neurocART use was 0.89 (P=0.35) when data were stratified by cohort and adjusted for age, mode of HIV exposure, hepatitis B virus coinfection, AIDS-defining illness, CD4 count (cells/MUL) and regimen count. Sensitivity analyses showed similar nonsignificant results. We also examined a composite endpoint of AIDS-defining illness or death (HR=0.93; P=0.61), baseline regimen as neurocART (HR=0.95; P=0.69), CPE category (P=0.71) and prior neurocART duration (P=0.16). No association between CD4 cell count and neurocART use was observed (P=0.52). CONCLUSIONS: Our findings do not show a significant overall survival benefit associated with neurocART compared with cART. The potential benefit associated with neurocART in terms of prevention of neurocognitive impairment did not translate into an improvement in overall survival in this population. These findings were limited by the low incidence of associated mortality. Further studies and more extensive data are needed to address these limitations. PMID- 21819528 TI - Cervical intraepithelial neoplasia and invasive cancer risks in women infected with HIV in the French West Indies. AB - OBJECTIVE: The aim of the study was to assess whether HIV infection is associated with a higher risk of invasive cervical cancer (ICC). METHODS: We conducted a region-wide, population-based observational cohort study of 1232 HIV-infected women over the age of 15 years in Guadeloupe, a French Caribbean archipelago, during the period 1999-2006. The observed numbers of incident cases of cervical intraepithelial neoplasia (CIN) and ICC were compared with the expected numbers of cases based on the incidence rates for the general population, and the standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were calculated. RESULTS: The incidence rate of CIN was higher in the HIV-infected women than in the general population for all grades (SIR 10.1, 95% CI 6.8-14.6 for CIN grade 1; SIR 9.9, 95% CI 6.1-15.3 for CIN grade 2; and SIR 5.2, 95% CI 3.4-7.7 for CIN grade 3). However, no increase in the risk of ICC was observed (SIR 1.7, 95% CI 0.3-4.9). CONCLUSIONS: Despite an increase in the occurrence of cervical cancer precursors, no increase in the risk of cervical cancer was found in a population of HIV-infected women who receive treatment for their infection and have access to ICC prevention services. PMID- 21819529 TI - The effect of injecting drug use history on disease progression and death among HIV-positive individuals initiating combination antiretroviral therapy: collaborative cohort analysis. AB - BACKGROUND: We examined whether determinants of disease progression and causes of death differ between injecting drug users (IDUs) and non-IDUs who initiate combination antiretroviral therapy (cART). METHODS: The ART Cohort Collaboration combines data from participating cohort studies on cART-naive adults from cART initiation. We used Cox models to estimate hazard ratios for death and AIDS among IDUs and non-IDUs. The cumulative incidence of specific causes of death was calculated and compared using methods that allow for competing risks. RESULTS: Data on 6269 IDUs and 37 774 non-IDUs were analysed. Compared with non-IDUs, a lower proportion of IDUs initiated cART with a CD4 cell count <200 cells/MUL or had a prior diagnosis of AIDS. Mortality rates were higher in IDUs than in non IDUs (2.08 vs. 1.04 per 100 person-years, respectively; P<0.001). Lower baseline CD4 cell count, higher baseline HIV viral load, clinical AIDS at baseline, and later year of cART initiation were associated with disease progression in both groups. However, the inverse association of baseline CD4 cell count with AIDS and death appeared stronger in non-IDUs than in IDUs. The risk of death from each specific cause was higher in IDUs than non-IDUs, with particularly marked increases in risk for liver-related deaths, and those from violence and non-AIDS infection. CONCLUSION: While liver-related deaths and deaths from direct effects of substance abuse appear to explain much of the excess mortality in IDUs, they are at increased risk for many other causes of death, which may relate to suboptimal management of HIV disease in these individuals. PMID- 21819530 TI - Randomized comparison of metabolic and renal effects of saquinavir/r or atazanavir/r plus tenofovir/emtricitabine in treatment-naive HIV-1-infected patients. AB - OBJECTIVES: The aim of the study was to compare the effects on lipids, body composition and renal function of once-daily ritonavir-boosted saquinavir (SQV/r) or atazanavir (ATV/r) in combination with tenofovir/emtricitabine (TDF/FTC) over 48 weeks. METHODS: An investigator-initiated, randomized, open-label, multinational trial comparing SQV/r 2000/100 mg and ATV/r 300/100 mg once daily, both in combination with TDF/FTC, in 123 treatment-naive HIV-1-infected adults was carried out. The primary endpoint was to demonstrate noninferiority of SQV/r compared with ATV/r with respect to the change in fasting cholesterol after 24 weeks. Secondary outcome measures were changes in metabolic abnormalities, body composition, renal function, and virological and immunological efficacy over 48 weeks. Patients who had used at least one dose of trial drug were included in the analysis. RESULTS: Data for 118 patients were analysed (57 patients on SQV/r and 61 on ATV/r). At week 24, changes in lipids were modest, without increases in triglycerides, including a significant rise in high-density lipoprotein (HDL) cholesterol and a nonsignificant decrease in the total:HDL cholesterol ratio in both arms with no significant difference between arms. Lipid changes at week 48 were similar to the changes observed up to week 24, with no significant change in the homeostasis model assessment (HOMA) index. Adipose tissue increased regardless of the regimen, particularly in the peripheral compartment and to a lesser extent in the central abdominal compartment, with an increase in adipose tissue reaching statistical significance in the ATV/r arm. A slight decline in the estimated glomerular filtration rate (eGFR) was observed in both arms during the first 24 weeks, with no progression thereafter. The immunological and virological responses were similar over the 48 weeks. CONCLUSIONS: Combined with TDF/FTC, both SQV/r 2000/100 mg and ATV/r 300/100 mg had comparable modest effects on lipids, had little effect on glucose metabolism, conserved adipose tissue, and similarly reduced eGFR. The virological efficacy was similar. PMID- 21819531 TI - Hepatitis E virus coinfection in patients with HIV infection. AB - OBJECTIVES: Hepatitis E virus (HEV) infection is an emerging infection in developed countries and is thought to be a porcine zoonosis. HEV can cause chronic infection and cirrhosis in the immunosuppressed, including patients with HIV infection. Little is known about HEV and HIV coinfection. The aim of the study was to document the incidence of chronic HEV coinfection in patients with HIV infection and to determine the anti-HEV seroprevalence and compare it with that of a control population. METHODS: A cohort/case-control study was carried out in two teaching hospitals in southwest England. A total of 138 patients with HIV infection were tested for HEV using an immunoassay for anti-HEV immunoglobulin M (IgM) and IgG and reverse transcriptase-polymerase chain reaction (RT-PCR), and 464 control subjects were tested for anti-HEV IgG. Demographic, lifestyle and laboratory data were prospectively collected on each patient with HIV infection. The anti-HEV IgG seroprevalence in patients with HIV infection was compared with that in controls and demographic risk factors for HEV exposure were explored using logistic regression models. RESULTS: There was no difference in anti-HEV IgG seroprevalence between the HIV-infected patients and controls. The only risk factor predictive of anti-HEV seropositivity was the consumption of raw/undercooked pork; sexual risk factors were unrelated. No patient with HIV infection had evidence of chronic coinfection with HEV CONCLUSIONS: Anti-HEV seroprevalence is similar in controls and patients with HIV infection. Risk factor analysis suggests that HEV is unlikely to be transmitted sexually. Chronic coinfection with HEV was absent, indicating that chronic HEV/HIV coinfection is not a common problem in this cohort. PMID- 21819532 TI - Comparison of real-time elastography with grey-scale ultrasonography for detection of organ-confined prostate cancer and extra capsular extension: a prospective analysis using whole mount sections after radical prostatectomy. AB - OBJECTIVE: *To evaluate whether transrectal real-time elastography (RTE) improves the detection of intraprostatic prostate cancer (PCa) lesions and extracapsular extension (ECE) compared with conventional grey-scale ultrasonography (GSU). PATIENTS AND METHODS: *In total, 229 patients with biopsy-proven PCa were prospectively screened for cancer-suspicious areas and ECE using GSU and RTE. *The largest tumour focus detected by RTE was defined as the index lesion. *The prostate gland was stratified into six sectors on GSU and RTE, which were compared with histopathological whole mount sections after radical prostatectomy. RESULTS: *Histopathologically, PCa was confirmed in 894 out of 1374 (61.8%) evaluated sectors and ECE was identified in 47 (21%) patients. *Of these 894 sectors, RTE correctly detected 594 (66.4%) and GSU 215 (24.0%) cancer suspicious lesions. *Sensitivity was 51% and specificity 72% using RTE compared to 18% and 90% for GSU. *RTE identified the largest side specific tumour focus in 68% of patients. *ECE was identified with a sensitivity of 38% and specificity of 96% using RTE compared to 15% and 97% using GSU. CONCLUSIONS: *Compared with GSU, RTE provides a statistically significant improvement in detection of PCa lesions and ECE. *RTE enhances GSU, although improvement is still needed to achieve a clinically meaningful sensitivity. PMID- 21819533 TI - Regulation of basal resistance by a powdery mildew-induced cysteine-rich receptor like protein kinase in barley. AB - The receptor-like protein kinases (RLKs) constitute a large and diverse group of proteins controlling numerous plant physiological processes, including development, hormone perception and stress responses. The cysteine-rich RLKs (CRKs) represent a prominent subfamily of transmembrane-anchored RLKs. We have identified a putative barley (Hordeum vulgare) CRK gene family member, designated HvCRK1. The mature putative protein comprises 645 amino acids, and includes a putative receptor domain containing two characteristic 'domain 26 of unknown function' (duf26) domains in the N-terminal region, followed by a rather short 17 amino-acid transmembrane domain, which includes an AAA motif, two features characteristic of endoplasmic reticulum (ER)-targeted proteins and, finally, a characteristic putative protein kinase domain in the C-terminus. The HvCRK1 transcript was isolated from leaves inoculated with the biotrophic fungal pathogen Blumeria graminis f.sp. hordei (Bgh). HvCRK1 transcripts were observed to accumulate transiently following Bgh inoculation of susceptible barley. Transient silencing of HvCRK1 expression in bombarded epidermal cells led to enhanced resistance to Bgh, but did not affect R-gene-mediated resistance. Silencing of HvCRK1 phenocopied the effective penetration resistance found in mlo resistant barley plants, and the possible link between HvCRK1 and MLO was substantiated by the fact that HvCRK1 induction on Bgh inoculation was dependent on Mlo. Finally, using both experimental and in silico approaches, we demonstrated that HvCRK1 localizes to the ER of barley cells. The negative effect on basal resistance against Bgh and the functional aspects of MLO- and ER localized HvCRK1 signalling on Bgh inoculation are discussed. PMID- 21819534 TI - Differential N-glycosylation of a monoclonal antibody expressed in tobacco leaves with and without endoplasmic reticulum retention signal apparently induces similar in vivo stability in mice. AB - Plant cells are able to perform most of the post-translational modifications that are required by recombinant proteins to achieve adequate bioactivity and pharmacokinetics. However, regarding N-glycosylation the processing of plant N glycans in the Golgi apparatus displays major differences when compared with that of mammalian cells. These differences in N-glycosylation are expected to influence serum clearance rate of plant-derived monoclonal antibodies. The monoclonal antibody against the hepatitis B virus surface antigen expressed in Nicotiana tabacum leaves without KDEL endoplasmic reticulum (ER) retention signal (CB.Hep1(-)KDEL) and with a KDEL (Lys-Asp-Glu-Leu) fused to both IgG light and heavy chains (CB.Hep1(+)KDEL) were tested for in vivo stability in mice. Full characterization of N-glycosylation and aggregate formation in each monoclonal antibody batch was determined. The mouse counterpart (CB.Hep1) was used as control. Both (CB.Hep1(-)KDEL) and (CB.Hep1(+)KDEL) showed a faster initial clearance rate (first 24 h) compared with the analogous murine antibody while the terminal phase was similar in the three antibodies. Despite the differences between CB.Hep1(+)KDEL and CB.Hep1(-)KDEL N-glycans, the in vivo elimination in mice was indistinguishable from each other and higher than the murine monoclonal antibody. Molecular modelling confirmed that N-glycans linked to plantibodies were oriented away from the interdomain region, increasing the accessibility of the potential glycan epitopes by glycoprotein receptors that might be responsible for the difference in stability of these molecules. PMID- 21819535 TI - Apoptosis-related genes confer resistance to Fusarium wilt in transgenic 'Lady Finger' bananas. AB - Fusarium wilt, caused by Fusarium oxysporum f. sp. cubense (Foc), is one of the most devastating diseases of banana (Musa spp.). Apart from resistant cultivars, there are no effective control measures for the disease. We investigated whether the transgenic expression of apoptosis-inhibition-related genes in banana could be used to confer disease resistance. Embryogenic cell suspensions of the banana cultivar, 'Lady Finger', were stably transformed with animal genes that negatively regulate apoptosis, namely Bcl-xL, Ced-9 and Bcl-2 3' UTR, and independently transformed plant lines were regenerated for testing. Following a 12-week exposure to Foc race 1 in small-plant glasshouse bioassays, seven transgenic lines (2 * Bcl-xL, 3 * Ced-9 and 2 * Bcl-2 3' UTR) showed significantly less internal and external disease symptoms than the wild-type susceptible 'Lady Finger' banana plants used as positive controls. Of these, one Bcl-2 3' UTR line showed resistance that was equivalent to that of wild-type Cavendish bananas that were included as resistant negative controls. Further, the resistance of this line continued for 23-week postinoculation at which time the experiment was terminated. Using TUNEL assays, Foc race 1 was shown to induce apoptosis-like features in the roots of wild-type 'Lady Finger' plants consistent with a necrotrophic phase in the life cycle of this pathogen. This was further supported by the observed reduction in these effects in the roots of the resistant Bcl-2 3' UTR-transgenic line. This is the first report on the generation of transgenic banana plants with resistance to Fusarium wilt. PMID- 21819536 TI - Biliary atresia with associated structural malformations in Canadian infants. AB - BACKGROUND: Biliary atresia (BA) is associated with extrahepatic congenital malformations in a minority of affected infants. The term commonly applied to this subgroup is 'BASM' for biliary atresia splenic malformation syndrome, as spleen abnormalities are prominent. AIMS AND METHODS: To examine clinical outcome in Canadian BA patients with extrahepatic congenital malformations in the Canada wide BA database of patients born between 1985 and 2002, and additionally, to recharacterized the syndrome. Patients had >=1 of the following: a/polysplenia, abnormal abdominal situs, intestinal malrotation, abdominal vascular anomaly or congenital heart disease. RESULTS: Among 328 BA patients, 44 (13%) had associated congenital abnormalities. Intra-abdominal anomalies included polysplenia (n=25), abnormal abdominal situs (n=9), intestinal malrotation (n=19), portal vein anomaly (n=12), hepatic artery anomaly (n=3) and inferior vena cava interruption (n=20). Twenty-six patients had cardiac malformations including pulmonary stenosis (n=11), ventricular septal defect (n=10), atrial septal defect (n=7), total anomalous pulmonary venous return (n=3), double outlet right ventricle (n=3), tetralogy of Fallot (n=2), atrioventricular canal (n=2), dextrocardia (n=2), bicuspid aortic valve (n=2), hypoplastic left heart (n=1) and partial anomalous pulmonary venous return (n=1). Age at Kasai operation, performance of liver transplant, overall survival, post-Kasai native liver survival and transplant survival were comparable to isolated BA. Presence of polysplenia or complex cardiac disease did not reduce post-Kasai native liver survival. Three patients had >=2 typical abnormalities without polysplenia: thus, splenic malformations are not essential to this BA subgroup. Hierarchical cluster analysis demonstrated characteristic abnormalities grouped in a multiplicity of combinations, consistent with a spectrum of defective lateralization. CONCLUSION: We suggest that the acronym 'BASM' be redefined as 'biliary atresia structural malformation'. PMID- 21819537 TI - Management of patients with recently implanted coronary stents on dual antiplatelet therapy who need to undergo major surgery. AB - About 5% of patients undergoing coronary stenting need to undergo surgery within the next year. The risk of perioperative cardiac ischemic events, particularly stent thrombosis (ST), is high in these patients, because surgery has a prothrombotic effect and antiplatelet therapy is often withdrawn in order to avoid bleeding. The clinical and angiographic predictors of ST are well known, and the proximity to an acute coronary syndrome adds to the risk. The current guidelines recommend delaying non-urgent surgery for at least 6 weeks after the placement of a bare metal stent and for 6-12 months after the placement of a drug eluting stent, when the risk of ST is reduced. However, in the absence of formal evidence, these recommendations provide little support with regard to managing urgent operations. When surgery cannot be postponed, stratifying the risk of surgical bleeding and cardiac ischemic events is crucial in order to manage perioperative antiplatelet therapy in individual cases. Dual antiplatelet therapy should not be withdrawn for minor surgery or most gastrointestinal endoscopic procedures. Aspirin can be safely continued perioperatively in the case of most major surgery, and provides coronary protection. In the case of interventions at high risk for both bleeding and ischemic events, when clopidogrel withdrawal is required in order to reduce perioperative bleeding, perioperative treatment with the short-acting intravenous glycoprotein IIb-IIIa inhibitor tirofiban is safe in terms of bleeding, and provides strong antithrombotic protection. Such surgical interventions should be performed at hospitals capable of performing an immediate percutaneous coronary intervention at any time in the case of acute myocardial ischemia. PMID- 21819538 TI - Relationship between paraoxonase Q192R gene polymorphism and on-clopidogrel platelet reactivity over time in patients treated with percutaneous coronary intervention. PMID- 21819539 TI - No accumulation of the peak anti-factor Xa activity of tinzaparin in elderly patients with moderate-to-severe renal impairment: the IRIS substudy. AB - BACKGROUND: In the elderly, concerns have been raised regarding the risk of accumulation of low molecular weight heparins, owing to their renal elimination. Although data exist for tinzaparin, they are observational. OBJECTIVES: To assess whether: (i) there was an accumulation of anti-factor Xa activity; and (ii) there was any relationship between anti-FXa activity and age, weight, creatinine clearance or clinical outcomes in patients with moderate-to-severe renal impairment receiving tinzaparin (175 IU kg(-1) per 24 h) for acute venous thromboembolism. METHODS: In 38 centers participating in the Innohep in Renal Insufficiency Study (IRIS), peak plasma anti-FXa activity was measured on day 2/day 3 and on day 5 or at visit S (VS) (end of tinzaparin treatment). There was considered to be absence of accumulation if the 90% confidence interval (CI) of the (anti-FXa day 5/VS)/(anti-FXa day 2/3) ratio did not exceed the predefined limit of 1.25. RESULTS: Eighty-seven patients, with a mean age of 83 +/- 5 years (range: 75-99 years) and a mean creatinine clearance (CrCl) of 40.8 mL min(-1) , 24.1% of whom had severe renal impairment, were included. The mean duration of tinzaparin treatment was 8.4 days. No significant accumulation was detected: the mean accumulation ratio was 1.06 (90% CI 1.01-1.11). There was no correlation between the accumulation ratio and age, weight, or CrCl. The mean anti-FXa activity did not differ significantly between the eight patients who experienced clinically relevant bleeding and those who did not. CONCLUSIONS: No accumulation of anti-FXa activity was observed in elderly patients with renal impairment receiving therapeutic doses of tinzaparin, suggesting that there is no need for systematic anti-FXa monitoring in these patients. The high proportion of high molecular weight moieties in tinzaparin may account for its reduced dependence on renal elimination. PMID- 21819540 TI - Comparison of two prognostic models for acute pulmonary embolism: clinical vs. right ventricular dysfunction-guided approach. AB - BACKGROUND: Recently, some prognostic models for acute pulmonary embolism (PE) have been proposed. We investigated whether the Pulmonary Embolism Severity Index (PESI) and the European Society of Cardiology (ESC) prognostic approaches result in different prognoses. METHODS: Consecutive adult patients with acute PE were included. According to the ESC guidelines, high-risk patients were identified by the presence of shock/hypotension, intermediate-risk patients by elevated troponin I or right ventricular dysfunction as assessed by echocardiography, and low-risk patients by the absence of any of the above. In the PESI model, 11 clinical variables, easily accessible at the bedside, were used to generate three risk classes. The main outcomes were all-cause and PE-related in-hospital mortality. RESULTS: Forty-one patients (8%, 95% confidence interval [CI] 5.8 10.8) of 510 died. According to the ESC model, 40% were at low risk of short-term mortality, 54% at intermediate risk, and 6% at high risk. The distribution according to the PESI model was 31% (P < 0.05 vs. ESC), 49% and 20% (P < 0.05 vs. ESC), respectively. Mortality increased through the risk classes (P < 0.01), without significant differences between the models. The ESC model identified with higher accuracy than the PESI model both high-risk and low-risk patients (P < 0.05 for both). When patients with shock/hypotension were excluded, the PESI model stratified patients into classes with increasing PE-related mortality (0.7%, 4.3%, and 11.6%, P < 0.05). Troponin I and right ventricular dysfunction added incremental prognostic value to the PESI model, particularly in normotensive patients at intermediate risk. CONCLUSIONS: The ESC model showed higher accuracy than the PESI model in identifying high-risk and low-risk patients. In normotensive patients, the PESI model could guide clinical management as well as troponin I and echocardiography testing. PMID- 21819541 TI - Isolation and characterization of type I antifreeze proteins from cunner, Tautogolabrus adspersus, order Perciformes. AB - Antifreeze proteins (AFPs) are produced by many species of teleost fish that inhabit potentially lethal ice-laden seawater and afford them protection from freezing. To date type I AFPs have been fully characterized in two teleost orders: Pleuronectiformes and Scorpaeniformes. In this study, we report the isolation and complete characterization of a type I AFP present in fish from a third order: cunner (Tautogolabrus adspersus), order Perciformes (family Labridae). This protein was purified from blood plasma and found to belong to what is now known as classical type I AFP with their small size (mass 4095.16 Da), alanine richness (> 57 mol%), high alpha-helicity (> 99%) with the ability to undergo reversible thermal denaturation, 11 amino acid (ThrX(10)) repeat regions within the primary structure, the capacity to impart a hexagonal bipyramidal shaping to ice crystals and the conservation of an ice-binding site found in many of the other type I AFPs. Partial de novo sequencing of the plasma AFP accounted for approximately half of the peptide mass. Sequencing of a combined liver and skin cDNA library indicated that the protein is produced without a signal sequence. In addition the translated product of the AFP cDNA suggests that it codes for the AFP isolated from plasma. These results further solidify the hypothesis that type I AFPs are multiphyletic in origin and suggest that they represent remarkable examples of convergent evolution within three orders of teleost fish. PMID- 21819542 TI - Hatching enzyme of Japanese eel Anguilla japonica and the possible evolution of the egg envelope digestion mechanism. AB - We purified eel hatching enzyme (EHE) from the hatching liquid of Japanese eel Anguilla japonica belonging to Elopomorpha to a single band on SDS/PAGE. TOF-MS analysis revealed that the purified EHE contained several isozymes with similar molecular masses. Comparison of the egg envelope digestion specificities of the purified EHE and of recombinant EHE4, one of the EHE isozymes, suggested that the isozymes contained in the purified EHE were functionally the same in terms of egg envelope digestion. By electron microscopy, the egg envelope became swollen after treatment with the purified EHE. The EHE cleavage sites on the zona pellucida (ZP) protein of the egg envelope were located in the N-terminal repeat regions. In previous phylogenetic analysis, we suggested that fishes included in Elopomorpha, as basal teleosts, possess a single type of hatching enzyme genes, and that fishes in Otocephala and Euteleostei gain two types of hatching enzyme genes called clade I and II genes by duplication. Further, the clade I enzymes, zebrafish hatching enzyme (ZHE1) and medaka high choriolytic enzyme (HCE), swell the egg envelope by cleaving the N-terminal regions of ZP proteins, while the clade II enzyme, medaka low choriolytic enzyme (LCE), solubilizes the swollen envelope by cleaving the site at the middle region on the ZP domain. In this evolutionary scenario, our findings support that hatching of Japanese eel conserves the ancestral mechanism of fish egg envelope digestion. The clade I enzymes inherit the ancestral enzyme function, and the clade II enzymes gain a new function during evolution to Otocephala and Euteleostei. PMID- 21819543 TI - Up-regulation of VEGF by small activator RNA in human corpus cavernosum smooth muscle cells. AB - INTRODUCTION: Functional failure of smooth muscle cells and endothelial cells in corpus cavernosum contributes to erectile dysfunction (ED) in aging men. Given that vascular endothelial growth factor (VEGF) may improve the function of smooth muscle cells and endothelial cells through different mechanisms, it is thus expected that increasing the expression of VEGF may have beneficial effects on erectile function. AIM: The aim of this article is to explore the possibility that VEGF can be induced by ribonucleic acid activation (RNAa) technology, and VEGF induction by RNAa has the potential of treating ED. METHODS: Primary human corpus cavernosum smooth muscle cells (CCSMCs) were isolated and cultured in vitro. The expression of alpha-smooth muscle actin was detected by immunohistochemistry to identify CCSMCs. A previously identified VEGF promoter targeted small activator RNA (saRNA, double-stranded [ds]VEGF-706) and a negative control dsRNA were chemically synthesized. Cultured human CCSMCs were transfected with the saRNAs. The expression of VEGF messenger RNA (mRNA) and protein in transfected CCSMCs was evaluated by real-time polymerase chain reaction (RT-PCR) and Western blotting assay, respectively. Immunofluorescent staining was also used to confirm VEGF protein expression in cultured CCSMCs. MAIN OUTCOME MEASURE: The expression of VEGF was assessed by RT quantitative PCR, Western blotting, and immunofluorescence assays. RESULTS: After transfection, RT quantitative PCR analysis showed that the expression of VEGF mRNA was significantly induced in dsVEGF-706 transfected cells compared with cells receiving control treatments (P < 0.05). Consistent with mRNA induction, Western blotting and immunofluorescence analysis showed that VEGF protein expression was also induced by dsVEGF-706. CONCLUSION: VEGF expression can be activated by RNAa in primary human CCSMCs, suggesting a potential application of RNAa-mediated VEGF activation for the treatment of ED. PMID- 21819544 TI - Human acellular matrix graft of tunica albuginea for penile reconstruction. AB - INTRODUCTION: Penile curvature is one of the most common male conditions, affecting nearly 10% of men, and can impair sexual intercourse. Tunica albuginea (hTA) plays a key role in penile curvature, and reconstructive procedures may be necessary for its substitution. Although several grafts have been proposed for hTA repair, the ideal graft is not yet available. AIM: The aim of this article is to evaluate a new human tunica albuginea acellular matrix (hTAAM) as potential graft for penile reconstructive procedures. METHODS: Twelve penises were obtained during sex reassignment surgeries from male-to-female transsexual patients. After dissection, hTAs were assigned into two groups according to the decellularization methods: polyethylene glycol (PEG) 1000 method following ultraviolet-C radiation, and Triton X-100 modified method. MAIN OUTCOME MEASURES: Structural analyses were assessed by hematoxilin and eosin, Masson's trichrome, Weigert's, and picrosirius polarization staining methods. Total protein, total glycosaminoglycan (GAG), and nucleic acid (DNA and RNA) concentrations were assessed by specific biochemical analyses. Uniaxial strength tests were performed to evaluate biomechanical properties. RESULTS: All hTAAMs presented no nuclear or cellular remnants. Total protein concentration was significantly higher in PEG 1000 hTAAM. Despite GAG concentration decreased significantly in hTAAM, Triton X-100 hTAAM retained the highest GAG concentration (1.0 +/- 0.42 ug HexUr/mg dry tissue, P > 0.05). All decellularization methods were efficacious to remove nucleic acids. The maximal break point presented no difference between hTA and hTAAM groups (P > 0.05). CONCLUSIONS: PEG 1000 and Triton X-100 decellularization methods provide equally successful hTAAMs, preserving original structural and biochemical properties. PMID- 21819545 TI - Comparing effects of a low-energy diet and a high-protein low-fat diet on sexual and endothelial function, urinary tract symptoms, and inflammation in obese diabetic men. AB - INTRODUCTION: Abdominal obesity and type 2 diabetes mellitus are associated with sexual and endothelial dysfunction, lower urinary tract symptoms (LUTS), and chronic systemic inflammation. AIM: To determine the effects of diet-induced weight loss and maintenance on sexual and endothelial function, LUTS, and inflammatory markers in obese diabetic men. MAIN OUTCOME MEASURES: Weight, waist circumference (WC), International Index of Erectile Function (IIEF-5) score, Sexual Desire Inventory (SDI) score, International Prostate Symptom Scale (IPSS) score, plasma fasting glucose and lipids, testosterone, sex hormone binding globulin (SHBG), inflammatory markers (high-sensitivity C-reactive protein [CRP] and interleukin-6 [IL-6]) and soluble E-selectin, and brachial artery flow mediated dilatation (FMD) were measured at baseline, 8 weeks, and 52 weeks. METHODS: Over 8 weeks, 31 abdominally obese (body mass index >= 30 kg/m(2) , WC >= 102 cm), type 2 diabetic men (mean age 59.7 years) received either a meal replacement-based low-calorie diet (LCD) ~1,000 kcal/day (N = 19) or low-fat, high-protein, reduced-carbohydrate (HP) diet (N = 12) prescribed to decrease intake by ~600 kcal/day. Subjects continued on, or were switched to, the HP diet for another 44 weeks. RESULTS: At 8 weeks, weight and WC decreased by ~10% and ~5% with the LCD and HP diet, respectively. Both diets significantly improved plasma glucose, low-density lipoprotein (LDL), SHBG, IIEF-5, SDI and IPSS scores, and endothelial function (increased FMD, reduced soluble E-selectin). Erectile function, sexual desire, and urinary symptoms improved by a similar degree with both diets. CRP and IL-6 decreased with the HP diet. At 52 weeks, reductions in weight, WC, and CRP were maintained. IIEF-5, SDI, and IPSS scores improved further. CONCLUSIONS: Diet-induced weight loss induces rapid improvement of sexual, urinary, and endothelial function in obese diabetic men. A high-protein, carbohydrate-reduced, low-fat diet also reduces systemic inflammation and sustains these beneficial effects to 1 year. PMID- 21819546 TI - Discovery of two novel HLA-B alleles, B*46:13:03 and B*15:189, in two Taiwanese volunteer bone marrow donors by sequence-based typing. AB - We report here two novel HLA-B alleles, B*46:13:03 and B*15:189, discovered in two Taiwanese volunteer bone marrow donors. The sequence of B*15:189 has a nucleotide sequence possibly derived from a recombination event between HLA B*39:01:01 and B*15:01:01:01, while the origin of the sequence B*46:13:03 was less obvious to postulate, considering the low frequency of B*46:13 in the general population and the silent mutations involved. Our report here adds further HLA polymorphism to the growing lists of HLA-B*46 and HLA-B*15 and provides an additional HLA information for donor search programme for patients undergoing transplant. PMID- 21819548 TI - B- and T-cell memory elicited by a seasonal live attenuated reassortant influenza vaccine: assessment of local antibody avidity and virus-specific memory T-cells using trogocytosis-based method. AB - PURPOSE: The main purpose of vaccination is to generate immunological memory providing enhanced immune responses against infectious pathogens. The standard and most commonly used assay for influenza vaccine immunogenicity evaluation is a hemagglutination inhibition assay (HAI). It is clear now that HAI assay is unable to properly assess the proven protective immunity elicited by live attenuated influenza vaccines (LAIV). New methods need to be developed for more accurate LAIV immunogenicity assessment and prediction of vaccine efficacy among target populations. OBJECTIVE: Randomized placebo-controlled study of memory B- and T cell responses to intranasal LAIV in young adults. METHODS: A total of 56 healthy young adults 18-20 years old received seasonal monovalent LAIV. Mucosal memory B cell responses were measured by IgA avidity assessment in nasal swabs. CD4 memory T cells in peripheral blood were examined by the expression of CD45RO marker and in functional test by the ability of virus-specific T cells to maintain the trogocytosis with antigen-loaded target cells. RESULTS: Intranasal LAIV immunization enhances mucosal IgA avidity even without reliable increases in antibody titers. At the day 21 after vaccination, up to 40% of subjects demonstrated significant increases in both total and virus-specific CD4 memory T cells that were observed regardless of seroconversion rate measured by HAI assay. CONCLUSION: The data suggest that immunogenicity of LAIV vaccines should be evaluated on the mucosal and cellular immunity basis. The assays applied could be used to support influenza clinical trials through preliminary screening of volunteers and subsequent measurement of anti-influenza in immunity. PMID- 21819549 TI - Histone H1 interphase phosphorylation becomes largely established in G1 or early S phase and differs in G1 between T-lymphoblastoid cells and normal T cells. AB - BACKGROUND: Histone H1 is an important constituent of chromatin, and is involved in regulation of its structure. During the cell cycle, chromatin becomes locally decondensed in S phase, highly condensed during metaphase, and again decondensed before re-entry into G1. This has been connected to increasing phosphorylation of H1 histones through the cell cycle. However, many of these experiments have been performed using cell-synchronization techniques and cell cycle-arresting drugs. In this study, we investigated the H1 subtype composition and phosphorylation pattern in the cell cycle of normal human activated T cells and Jurkat T lymphoblastoid cells by capillary electrophoresis after sorting of exponentially growing cells into G1, S and G2/M populations. RESULTS: We found that the relative amount of H1.5 protein increased significantly after T-cell activation. Serine phosphorylation of H1 subtypes occurred to a large extent in late G1 or early S phase in both activated T cells and Jurkat cells. Furthermore, our data confirm that the H1 molecules newly synthesized during S phase achieve a similar phosphorylation pattern to the previous ones. Jurkat cells had more extended H1.5 phosphorylation in G1 compared with T cells, a difference that can be explained by faster cell growth and/or the presence of enhanced H1 kinase activity in G1 in Jurkat cells. CONCLUSION: Our data are consistent with a model in which a major part of interphase H1 phosphorylation takes place in G1 or early S phase. This implies that H1 serine phosphorylation may be coupled to changes in chromatin structure necessary for DNA replication. In addition, the increased H1 phosphorylation of malignant cells in G1 may be affecting the G1/S transition control and enabling facilitated S-phase entry as a result of relaxed chromatin condensation. Furthermore, increased H1.5 expression may be coupled to the proliferative capacity of growth-stimulated T cells. PMID- 21819547 TI - Improving influenza vaccine virus selection: report of a WHO informal consultation held at WHO headquarters, Geneva, Switzerland, 14-16 June 2010. AB - * For almost 60 years, the WHO Global Influenza Surveillance and Response System (GISRS) has been the key player in monitoring the evolution and spread of influenza viruses and recommending the strains to be used in human influenza vaccines. The GISRS has also worked to continually monitor and assess the risk posed by potential pandemic viruses and to guide appropriate public health responses. * The expanded and enhanced role of the GISRS following the adoption of the International Health Regulations (2005), recognition of the continuing threat posed by avian H5N1 and the aftermath of the 2009 H1N1 pandemic provide an opportune time to critically review the process by which influenza vaccine viruses are selected. In addition to identifying potential areas for improvement, such a review will also help to promote greater appreciation by the wider influenza and policy-making community of the complexity of influenza vaccine virus selection. * The selection process is highly coordinated and involves continual year-round integration of virological data and epidemiological information by National Influenza Centres (NICs), thorough antigenic and genetic characterization of viruses by WHO Collaborating Centres (WHOCCs) as part of selecting suitable candidate vaccine viruses, and the preparation of suitable reassortants and corresponding reagents for vaccine standardization by WHO Essential Regulatory Laboratories (ERLs). * Ensuring the optimal effectiveness of vaccines has been assisted in recent years by advances in molecular diagnosis and the availability of more extensive genetic sequence data. However, there remain a number of challenging constraints including variations in the assays used, the possibility of complications resulting from non-antigenic changes, the limited availability of suitable vaccine viruses and the requirement for recommendations to be made up to a year in advance of the peak of influenza season because of production constraints. * Effective collaboration and coordination between human and animal influenza networks is increasingly recognized as an essential requirement for the improved integration of data on animal and human viruses, the identification of unusual influenza A viruses infecting human, the evaluation of pandemic risk and the selection of candidate viruses for pandemic vaccines. * Training workshops, assessments and donations have led to significant increases in trained laboratory personnel and equipment with resulting expansion in both geographical surveillance coverage and in the capacities of NICs and other laboratories. This has resulted in a significant increase in the volume of information reported to WHO on the spread, intensity and impact of influenza. In addition, initiatives such as the WHO Shipment Fund Project have facilitated the timely sharing of clinical specimens and virus isolates and contributed to a more comprehensive understanding of the global distribution and temporal circulation of different viruses. It will be important to sustain and build upon the gains made in these and other areas. * Although the haemagglutination inhibition (HAI) assay is likely to remain the assay of choice for the antigenic characterization of viruses in the foreseeable future, alternative assays - for example based upon advanced recombinant DNA and protein technologies - may be more adaptable to automation. Other technologies such as microtitre neuraminidase inhibition assays may also have significant implications for both vaccine virus selection and vaccine development. * Microneutralization assays provide an important adjunct to the HAI assay in virus antigenic characterization. Improvements in the use and potential automation of such assays should facilitate large-scale serological studies, while other advanced techniques such as epitope mapping should allow for a more accurate assessment of the quality of a protective immune response and aid the development of additional criteria for measuring immunity. * Standardized seroepidemiological surveys to assess the impact of influenza in a population could help to establish well-characterized banks of age-stratified representative sera as a national, regional and global resource, while providing direct evidence of the specific benefits of vaccination. * Advances in high-throughput genetic sequencing coupled with advanced bioinformatics tools, together with more X-ray crystallographic data, should accelerate understanding of the genetic and phenotypic changes that underlie virus evolution and more specifically help to predict the influence of amino acid changes on virus antigenicity. * Complex mathematical modelling techniques are increasingly being used to gain insights into the evolution and epidemiology of influenza viruses. However, their value in predicting the timing and nature of future antigenic and genetic changes is likely to be limited at present. The application of simpler non-mechanistic statistical algorithms, such as those already used as the basis of antigenic cartography, and phylogenetic modelling are more likely to be useful in facilitating vaccine virus selection and in aiding assessment of the pandemic potential of avian and other animal influenza viruses. * The adoption of alternative vaccine technologies - such as live-attenuated, quadrivalent or non HA-based vaccines - has significant implications for vaccine virus selection, as well as for vaccine regulatory and manufacturing processes. Recent collaboration between the GISRS and vaccine manufacturers has resulted in the increased availability of egg isolates and high-growth reassortants for vaccine production, the development of qualified cell cultures and the investigation of alternative methods of vaccine potency testing. WHO will continue to support these and other efforts to increase the reliability and timeliness of the global influenza vaccine supply. * The WHO GISRS and its partners are continually working to identify improvements, harness new technologies and strengthen and sustain collaboration. WHO will continue in its central role of coordinating worldwide expertise to meet the increasing public health need for influenza vaccines and will support efforts to improve the vaccine virus selection process, including through the convening of periodic international consultations. PMID- 21819550 TI - Differential gene expression in Schistosoma japonicum schistosomula from Wistar rats and BALB/c mice. AB - BACKGROUND: More than 46 species of mammals can be naturally infected with Schistosoma japonicum in the mainland of China. Mice are permissive and may act as the definitive host of the life cycle. In contrast, rats are less susceptible to S. japonicum infection, and are considered to provide an unsuitable micro environment for parasite growth and development. Since little is known of what effects this micro-environment has on the parasite itself, we have in the present study utilised a S. japonicum oligonucleotide microarray to compare the gene expression differences of 10-day-old schistosomula maintained in Wistar rats with those maintained in BALB/c mice. RESULTS: In total 3,468 schistosome genes were found to be differentially expressed, of which the majority (3,335) were down regulated (<= 2 fold) and 133 were up-regulated (>= 2 fold) in schistosomula from Wistar rats compared with those from BALB/c mice. Gene ontology (GO) analysis revealed that of the differentially expressed genes with already established functions or close homology to well characterized genes in another organisms, many are related to important biological functions or molecular processes. Among the genes that were down-regulated in schistosomula from Wistar rats, some were associated with metabolism, signal transduction and development. Of these genes related to metabolic processes, areas including translation, protein and amino acid phosphorylation, proteolysis, oxidoreductase activities, catalytic activities and hydrolase activities, were represented. KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis of differential expressed genes indicated that of the 328 genes that had a specific KEGG pathway annotation, 324 were down regulated and were mainly associated with metabolism, growth, redox pathway, oxidative phosphorylation, the cell cycle, ubiquitin-mediated proteolysis, protein export and the MAPK (mitogen-activated protein kinases) signaling pathway. CONCLUSIONS: This work presents the first large scale gene expression study identifying the differences between schistosomula maintained in mice and those maintained in rats, and specifically highlights differential expression that may impact on the survival and development of the parasite within the definitive host. The research presented here provides valuable information for the better understanding of schistosome development and host-parasite interactions. PMID- 21819551 TI - Early and late mortality in elderly patients after hip fracture: a cohort study using administrative health databases in the Lazio region, Italy. AB - BACKGROUND: Hip fractures represent one of the most important causes of morbidity and mortality in elderly people. We evaluated the risk and the potential determinants of early, mid and long term mortality, in a population-based cohort of subjects aged >= 65 years old. METHODS: Using hospital discharge database we identified all hospitalized hip fracture cases of 2006, among residents in Lazio Region aged >= 65 years old. The mortality follow-up was performed through a deterministic record-linkage between the cohort and the death registry for the years 2006 and 2007. Kaplan-Meier method was used to calculate cumulative survival probability after admission. Shared frailties Cox regression model was used to estimate adjusted hazard ratios (HRs) for early (within 1 month), mid (1 6 months) and long term (6-24 months) mortality. As possible cofactors we considered age, gender, marital status, education degree, comorbidities, surgical intervention, and hospital volume of surgical treatment for hip fracture. RESULTS: We identified 6,896 patients; 78% were females, median age was 83 and 9% had two or more comorbidities. Five percent died during hospital stay; the cumulative probability of dying at 30, 180 days, and at 2 years was 7%, 18% and 30%. In the first month following admission, we found a significantly increased HR with older age, male sex, not married status, history of hearth disease, chronic pulmonary and renal disease; for those who had surgery there was a significantly increased HR within two days after surgical intervention and a significantly decreased HR thereafter compared to those who received a conservative management. Between 1 and 6 months significantly increased HRs were for older age, male sex and higher hospital volume of surgical treatment. After six months, significantly increased HRs were for older age, male sex, presence of dementia and other low prevalence diseases. CONCLUSION: In Lazio region the risk of dying after hip fracture is similar to that found in high-income countries. Both clinical and organizational factors of acute care are associated with the risk of early mortality. As time passes, some of these factors tend to become less important while older age, male gender, the presence of cognitive problems and the presence of other comorbidities remain significant. PMID- 21819552 TI - Confidence and quality in managing CKD compared with other cardiovascular diseases and diabetes mellitus: a linked study of questionnaire and routine primary care data. AB - BACKGROUND: Much of chronic disease is managed in primary care and chronic kidney disease (CKD) is a recent addition. We are conducting a cluster randomised study of quality improvement interventions in CKD (QICKD) - Clinical Trials Registration: ISRCTN56023731. CKD registers have a lower than expected prevalence and an initial focus group study suggested variable levels of confidence in managing CKD. Our objective is to compare practitioner confidence and achievement of quality indicators for CKD with hypertension and diabetes. METHOD: We validated a new questionnaire to test confidence. We compared confidence with achievement of pay-for-performance indicators (P4P) and implementation of evidence-based guidance. We achieved a 74% (148/201) response rate. RESULTS: 87% (n = 128) of respondents are confident in managing hypertension (HT) compared with 59% (n = 87) in managing HT in CKD (HT+CKD); and with 61% (n = 90) in HT, CKD and diabetes (CKD+HT+DM). 85.2% (P4P) and 62.5% (National targets) of patients with hypertension are at target; in patients with HT and CKD 65.1% and 53.3%; in patients with HT, CKD and DM 67.8% and 29.6%. Confidence in managing proteinuria in CKD is low (42%, n = 62). 87% of respondents knew BP treatment thresholds in CKD, but only 53% when proteinuria is factored in. Male GPs, younger (< 35 yrs), and older (> 54 yrs) clinicians are more confident than females and 35 to 54 year olds in managing CKD. 84% of patients with hypertension treated with angiotensin modulating drugs achieve achieved P4P targets compared to 67% of patients with CKD. CONCLUSIONS: Practitioners are less likely to achieve management targets where their confidence is low. PMID- 21819553 TI - How the gene ontology evolves. AB - BACKGROUND: Maintaining a bio-ontology in the long term requires improving and updating its contents so that it adequately captures what is known about biological phenomena. This paper illustrates how these processes are carried out, by studying the ways in which curators at the Gene Ontology have hitherto incorporated new knowledge into their resource. RESULTS: Five types of circumstances are singled out as warranting changes in the ontology: (1) the emergence of anomalies within GO; (2) the extension of the scope of GO; (3) divergence in how terminology is used across user communities; (4) new discoveries that change the meaning of the terms used and their relations to each other; and (5) the extension of the range of relations used to link entities or processes described by GO terms. CONCLUSION: This study illustrates the difficulties involved in applying general standards to the development of a specific ontology. Ontology curation aims to produce a faithful representation of knowledge domains as they keep developing, which requires the translation of general guidelines into specific representations of reality and an understanding of how scientific knowledge is produced and constantly updated. In this context, it is important that trained curators with technical expertise in the scientific field(s) in question are involved in supervising ontology shifts and identifying inaccuracies. PMID- 21819554 TI - A novel inhibitor of hypoxia-inducible factor-1alpha P3155 also modulates PI3K pathway and inhibits growth of prostate cancer cells. AB - BACKGROUND: Hypoxia-inducible factor-1 (HIF-1) is a master regulator of the transcriptional response to hypoxia. It is essential for angiogenesis and is associated with tumor progression and overexpression of HIF-1alpha has been demonstrated in many common human cancers. Therefore, HIF-1alpha is one of the most compelling anticancer targets. METHODS: To identify HIF-1alpha inhibitors, luciferase reporter gene assay under hypoxia and normoxia was used. Detailed studies such as western blotting, RT-PCR, immunofluorescence were carried out to elucidate its mechanism of action. Antiangiogenic activity of P3155 was demonstrated by migration assay and tube formation assay. Efficacy study of P3155 was performed on PC-3 xenograft model. RESULTS: P3155 showed specific HIF-1alpha inhibition with IC50 of 1.4 MUM under hypoxia. It suppressed HIF-1alpha expression as well as PI3K/Akt pathway and abrogated expression of HIF-1 inducible gene viz. vascular endothelial growth factor (VEGF). P3155 in combination with HIF-1alpha siRNA showed significant synergistic effect. In addition, it demonstrated significant in vivo efficacy and antiangiogenic potential in prostate cancer cell lines. CONCLUSION: We have identified a novel HIF-1alpha inhibitor P3155 that also modulates PI3K/Akt pathway, which may contribute to its significant in vitro and in vivo antitumor activity. PMID- 21819555 TI - Reliability and validity of the Spanish version of the 10-item Connor-Davidson Resilience Scale (10-item CD-RISC) in young adults. AB - BACKGROUND: The 10-item Connor-Davidson Resilience Scale (10-item CD-RISC) is an instrument for measuring resilience that has shown good psychometric properties in its original version in English. The aim of this study was to evaluate the validity and reliability of the Spanish version of the 10-item CD-RISC in young adults and to verify whether it is structured in a single dimension as in the original English version. FINDINGS: Cross-sectional observational study including 681 university students ranging in age from 18 to 30 years. The number of latent factors in the 10 items of the scale was analyzed by exploratory factor analysis. Confirmatory factor analysis was used to verify whether a single factor underlies the 10 items of the scale as in the original version in English. The convergent validity was analyzed by testing whether the mean of the scores of the mental component of SF-12 (MCS) and the quality of sleep as measured with the Pittsburgh Sleep Index (PSQI) were higher in subjects with better levels of resilience. The internal consistency of the 10-item CD-RISC was estimated using the Cronbach alpha test and test-retest reliability was estimated with the intraclass correlation coefficient.The Cronbach alpha coefficient was 0.85 and the test retest intraclass correlation coefficient was 0.71. The mean MCS score and the level of quality of sleep in both men and women were significantly worse in subjects with lower resilience scores. CONCLUSIONS: The Spanish version of the 10 item CD-RISC showed good psychometric properties in young adults and thus can be used as a reliable and valid instrument for measuring resilience. Our study confirmed that a single factor underlies the resilience construct, as was the case of the original scale in English. PMID- 21819556 TI - A single-blinded trial of methotrexate versus azathioprine as steroid-sparing agents in generalized myasthenia gravis. AB - BACKGROUND: Long-term immunosuppression is often required in myasthenia gravis (MG). There are no published trials using methotrexate (MTX) in MG. The steroid sparing efficacy of azathioprine (AZA) has been demonstrated after 18-months of starting therapy. However, AZA is considered expensive in Africa. We evaluated the steroid-sparing efficacy of MTX (17.5 mg weekly) compared with AZA (2.5 mg/kg daily) in subjects recently diagnosed with generalized MG by assessing their average monthly prednisone requirements. METHODS: The primary outcome was the average daily prednisone requirement by month between the two groups. Prednisone was given at the lowest dose to manage MG symptoms and adjusted as required according to protocol. Single-blinded assessments were performed 3-monthly for 2 years to determine the quantitative MG score and the MG activities of daily living score in order to determine those with minimal manifestations of MG. RESULTS: Thirty-one subjects (AZA n = 15; MTX n = 16) satisfied the inclusion criteria but only 24 were randomized. Baseline characteristics were similar. There was no difference between the AZA- and MTX-groups in respect of prednisone dosing (apart from months 10 and 12), in quantitative MG Score improvement, proportions in sustained remission, frequencies of MG relapses, or adverse reactions and/or withdrawals. The MTX-group received lower prednisone doses between month 10 (p = 0.047) and month 12 (p = 0.039). At month 12 the prednisone dose per kilogram bodyweight in the MTX-group (0.15 mg/kg) was half that of the AZA-group (0.31 mg/kg)(p = 0.019). CONCLUSIONS: This study provides evidence that in patients with generalized MG methotrexate is an effective steroid-sparing agent 10 months after treatment initiation. Our data suggests that in generalized MG methotrexate has similar efficacy and tolerability to azathioprine and may be the drug of choice in financially constrained health systems. TRIAL REGISTRATION: SANCTR:DOH-27-0411-2436. PMID- 21819557 TI - Overproduction of Bacillus amyloliquefaciens extracellular glutamyl-endopeptidase as a result of ectopic multi-copy insertion of an efficiently-expressed mpr gene into the Bacillus subtilis chromosome. AB - BACKGROUND: Plasmid-less, engineered Bacillus strains have several advantages over plasmid-carrier variants. Specifically, their stability and potential ecological safety make them of use in industrial applications. As a rule, however, it is necessary to incorporate many copies of a key gene into a chromosome to achieve strain performance that is comparable to that of cells carrying multiple copies of a recombinant plasmid. RESULTS: A plasmid-less B. subtilis JE852-based strain secreting glutamyl-specific protease (GSP-the protein product of the mpr gene from B. amyloliquefaciens) was constructed that exhibits decreased levels of other extracellular proteases. Ten copies of an mprB.amy cassette in which the GSP gene was placed between the promoter of the B. amyloliquefaciens rplU-rpmA genes and the Rho-independent transcription terminator were ectopically inserted into designated (3 copies) and random (7 copies) points in the recipient chromosome. The resulting strain produced approximately 0.5 g/L of secreted GSP after bacterial cultivation in flasks with starch-containing media, and its performance was comparable to an analogous strain in which the mprB.amy cassette was carried on a multi-copy plasmid. CONCLUSION: A novel strategy for ectopically integrating a cassette into multiple random locations in the B. subtilis chromosome was developed. This new method is based on the construction of DNA fragments in which the desired gene, marked by antibiotic resistance, is sandwiched between "front" and "back" portions of random chromosomal DNA restriction fragments. These fragments were subsequently inserted into the targeted sites of the chromosome using double-cross recombination. The construction of a marker-free strain was achieved by gene conversion between the integrated marked gene and a marker-less variant carried by plasmid DNA, which was later removed from the cells. PMID- 21819558 TI - Awareness of health risks related to body art practices among youth in Naples, Italy: a descriptive convenience sample study. AB - BACKGROUND: Body art practices have emerged as common activities among youth, yet few studies have investigated awareness in different age groups of possible health complications associated with piercing and tattooing. METHODS: We investigated perceptions of and knowledge about health risks. To highlight differences among age groups, we gathered data from students at high schools and universities in the province of Naples. RESULTS: Of 9,322 adolescents, 31.3% were pierced and 11.3% were tattooed. Of 3,610 undergraduates, 33% were pierced and 24.5% were tattooed (p < 0.05). A higher number of females were pierced in both samples, but there were no gender differences among tattooed students. Among high school students, 79.4% knew about infectious risks and 46% about non-infectious risks; the respective numbers among university students were 87.2% and 59.1%. Only 3.5% of students in high school and 15% of university undergraduates acknowledged the risk of viral disease transmission; 2% and 3% knew about allergic risks. Among adolescents and young adults, 6.9% and 15.3%, respectively, provided signed informed consent; the former were less knowledgeable about health risks (24.7% vs. 57.1%) (p < 0.05). Seventy-three percent of the high school students and 33.5% of the university students had body art done at unauthorized facilities. Approximately 7% of both samples reported complications from their purchased body art. CONCLUSIONS: Results indicate a need for adequate information on health risks associated with body art among students in Naples, mainly among high school students. Therefore, adolescents should be targeted for public health education programs. PMID- 21819559 TI - Hypoxia-inducible factor-1 alpha/platelet derived growth factor axis in HIV associated pulmonary vascular remodeling. AB - BACKGROUND: Human immunodeficiency virus (HIV) infected patients are at increased risk for the development of pulmonary arterial hypertension (PAH). Recent reports have demonstrated that HIV associated viral proteins induce reactive oxygen species (ROS) with resultant endothelial cell dysfunction and related vascular injury. In this study, we explored the impact of HIV protein induced oxidative stress on production of hypoxia inducible factor (HIF)-1alpha and platelet derived growth factor (PDGF), critical mediators implicated in the pathogenesis of HIV-PAH. METHODS: The lungs from 4-5 months old HIV-1 transgenic (Tg) rats were assessed for the presence of pulmonary vascular remodeling and HIF 1alpha/PDGF-BB expression in comparison with wild type controls. Human primary pulmonary arterial endothelial cells (HPAEC) were treated with HIV-associated proteins in the presence or absence of pretreatment with antioxidants, for 24 hrs followed by estimation of ROS levels and western blot analysis of HIF-1alpha or PDGF-BB. RESULTS: HIV-Tg rats, a model with marked viral protein induced vascular oxidative stress in the absence of active HIV-1 replication demonstrated significant medial thickening of pulmonary vessels and increased right ventricular mass compared to wild-type controls, with increased expression of HIF 1alpha and PDGF-BB in HIV-Tg rats. The up-regulation of both HIF-1alpha and PDGF B chain mRNA in each HIV-Tg rat was directly correlated with an increase in right ventricular/left ventricular+septum ratio. Supporting our in-vivo findings, HPAECs treated with HIV-proteins: Tat and gp120, demonstrated increased ROS and parallel increase of PDGF-BB expression with the maximum induction observed on treatment with R5 type gp-120CM. Pre-treatment of endothelial cells with antioxidants or transfection of cells with HIF-1alpha small interfering RNA resulted in abrogation of gp-120CM mediated induction of PDGF-BB, therefore, confirming that ROS generation and activation of HIF-1alpha plays critical role in gp120 mediated up-regulation of PDGF-BB. CONCLUSION: In summary, these findings indicate that viral protein induced oxidative stress results in HIF 1alpha dependent up-regulation of PDGF-BB and suggests the possible involvement of this pathway in the development of HIV-PAH. PMID- 21819560 TI - Pseudomonas aeruginosa toxin ExoU induces a PAF-dependent impairment of alveolar fibrin turnover secondary to enhanced activation of coagulation and increased expression of plasminogen activator inhibitor-1 in the course of mice pneumosepsis. AB - BACKGROUND: ExoU, a Pseudomonas aeruginosa cytotoxin with phospholipase A2 activity, was shown to induce vascular hyperpermeability and thrombus formation in a murine model of pneumosepsis. In this study, we investigated the toxin ability to induce alterations in pulmonary fibrinolysis and the contribution of the platelet activating factor (PAF) in the ExoU-induced overexpression of plasminogen activator inhibitor-1 (PAI-1). METHODS: Mice were intratracheally instilled with the ExoU producing PA103 P. aeruginosa or its mutant with deletion of the exoU gene. After 24 h, animal bronchoalveolar lavage fluids (BALF) were analyzed and lung sections were submitted to fibrin and PAI-1 immunohistochemical localization. Supernatants from A549 airway epithelial cells and THP-1 macrophage cultures infected with both bacterial strains were also analyzed at 24 h post infection. RESULTS: In PA103-infected mice, but not in control animals or in mice infected with the bacterial mutant, extensive fibrin deposition was detected in lung parenchyma and microvasculature whereas mice BALF exhibited elevated tissue factor-dependent procoagulant activity and PAI-1 concentration. ExoU-triggered PAI-1 overexpression was confirmed by immunohistochemistry. In in vitro assays, PA103-infected A549 cells exhibited overexpression of PAI-1 mRNA. Increased concentration of PAI-1 protein was detected in both A549 and THP-1 culture supernatants. Mice treatment with a PAF antagonist prior to PA103 infection reduced significantly PAI-1 concentrations in mice BALF. Similarly, A549 cell treatment with an antibody against PAF receptor significantly reduced PAI-1 mRNA expression and PAI-1 concentrations in cell supernatants, respectively. CONCLUSION: ExoU was shown to induce disturbed fibrin turnover, secondary to enhanced procoagulant and antifibrinolytic activity during P. aeruginosa pneumosepsis, by a PAF-dependent mechanism. Besides its possible pathophysiological relevance, in vitro detection of exoU gene in bacterial clinical isolates warrants investigation as a predictor of outcome of patients with P. aeruginosa pneumonia/sepsis and as a marker to guide treatment strategies. PMID- 21819561 TI - Sequence analysis reveals mosaic genome of Aichi virus. AB - Aichi virus is a positive-sense and single-stranded RNA virus, which demonstrated to be related to diarrhea of Children. In the present study, phylogenetic and recombination analysis based on the Aichi virus complete genomes available in GenBank reveal a mosaic genome sequence [GenBank: FJ890523], of which the nt 261 852 region (the nt position was based on the aligned sequence file) shows close relationship with AB010145/Japan with 97.9% sequence identity, while the other genomic regions show close relationship with AY747174/German with 90.1% sequence identity. Our results will provide valuable hints for future research on Aichi virus diversity.Aichi virus is a member of the Kobuvirus genus of the Picornaviridae family 12 and belongs to a positive-sense and single-stranded RNA virus. Its presence in fecal specimens of children suffering from diarrhea has been demonstrated in several Asian countries 3456, in Brazil and German 7, in France 8 and in Tunisia 9. Some reports showed the high level of seroprevalence in adults 710, suggesting the widespread exposure to Aichi virus during childhood.The genome of Aichi virus contains 8,280 nucleotides and a poly(A) tail. The single large open reading frame (nt 713-8014 according to the strain AB010145) encodes a polyprotein of 2,432 amino acids that is cleaved into the typical picornavirus structural proteins VP0, VP3, VP1, and nonstructural proteins 2A, 2B, 2C, 3A, 3B, 3C and 3D 211. Based on the phylogenetic analysis of 519-bp sequences at the 3C-3D (3CD) junction, Aichi viruses can be divided into two genotypes A and B with approximately 90% sequence homology 12. Although only six complete genomes of Aichi virus were deposited in GenBank at present, mosaic genomes can be found in strains from different countries. PMID- 21819562 TI - A mental health training program for community health workers in India: impact on knowledge and attitudes. AB - BACKGROUND: Unmet needs for mental health treatment in low income countries are pervasive. If mental health is to be effectively integrated into primary health care in low income countries like India then grass-roots workers need to acquire relevant knowledge and skills to be able to recognise, refer and support people experiencing mental disorders in their own communities. This study aims to provide a mental health training intervention to community health workers in Bangalore Rural District, Karnataka, India, and to evaluate the impact of this training on mental health literacy. METHODS: A pre-test post-test study design was undertaken with assessment of mental health literacy at three time points; baseline, completion of the training, and three month follow-up. Mental health literacy was assessed using the interviewer-administered Mental Health Literacy Survey. The training intervention was a four day course based on a facilitator's manual developed specifically for community health workers in India. RESULTS: 70 community health workers from Doddaballapur, Bangalore Rural District were recuited for the study. The training course improved participants' ability to recognize a mental disorder in a vignette, and reduced participants' faith in unhelpful and potentially harmful pharmacological interventions. There was evidence of a minor reduction in stigmatizing attitudes, and it was unclear if the training resulted in a change in participants' faith in recovery following treatment. CONCLUSION: The findings from this study indicate that the training course demonstrated potential to be an effective way to improve some aspects of mental health literacy, and highlights strategies for strengthening the training course. PMID- 21819563 TI - Limiting worker exposure to highly pathogenic avian influenza a (H5N1): a repeat survey at a rendering plant processing infected poultry carcasses in the UK. AB - BACKGROUND: Current occupational and public health guidance does not distinguish between rendering plant workers and cullers/poultry workers in terms of infection risk in their respective roles during highly pathogenic avian influenza poultry outbreaks. We describe an operational approach to human health risk assessment decision making at a large rendering plant processing poultry carcasses stemming from two separate highly pathogenic avian influenza A (H5N1) outbreaks in England during 2007. METHODS: During the first incident a uniform approach assigned equal exposure risk to all rendering workers in or near the production line. A task based exposure assessment approach was adopted during the second incident based on a hierarchy of occupational activities and potential for infection exposure. Workers assessed as being at risk of infection were offered personal protective equipment; pre-exposure antiviral prophylaxis; seasonal influenza immunisation; hygiene advice; and health monitoring. A repeat survey design was employed to compare the two risk assessment approaches, with allocation of antiviral prophylaxis as the main outcome variable. RESULTS: Task based exposure assessment during the second incident reduced the number of workers assessed at risk of infection from 72 to 55 (24% reduction) when compared to the first incident. No cases of influenza like illness were reported in workers during both incidents. CONCLUSIONS: Task based exposure assessment informs a proportionate public health response in rendering plant workers during highly pathogenic avian influenza H5N1 outbreaks, and reduces reliance on extensive antiviral prophylaxis. PMID- 21819565 TI - Violence witnessing, perpetrating and victimization in Medellin, Colombia: a random population survey. AB - BACKGROUND: The burden of injury from violence and the costs attributable to violence are extremely high in Colombia. Despite a dramatic decline in homicides over the last ten years, homicide rate in Medellin, Colombia second largest city continues to rank among the highest of cities in Latin America. This study aims to estimate the prevalence and distribution of witnesses, victims and perpetrators of different forms of interpersonal violence in a representative sample of the general population in Medellin in 2007. METHODS: A face-to-face survey was carried out on a random selected, non-institutionalized population aged 12 to 60 years, with a response rate of 91% yielding 2,095 interview responses. RESULTS: We present the rates of prevalence for having been a witness, victim, or perpetrator for different forms of violence standardized using the WHO truncated population pyramid to allow for cross-national comparison. We also present data on verbal aggression, fraud and deception, yelling and heavy pranks, unarmed aggression during last year, and armed threat, other severe threats, robbery, armed physical aggression, and sexual aggression during the lifetime, by age, sex, marital and socioeconomic status, and education. Men reported the highest prevalence of being victims, perpetrators and witnesses in all forms of violence, except for robbery and sexual violence. The number of victims per perpetrator was positively correlated with the severity of the type of violence. The highest victimization proportions over the previous twelve months occurred among minors. Perpetrators are typically young unmarried males from lower socio economic strata. CONCLUSIONS: Due to very low proportion of victimization report to authorities, periodic surveys should be included in systems for epidemiological monitoring of violence, not only of victimization but also for perpetrators. Victimization information allows quantifying the magnitude of different forms of violence, while data on factors associated with aggression and perpetrators are necessary to estimate risk and protective factors that are essential to sound policies for violence prevention formulation. PMID- 21819564 TI - Rationale and methods of the multicenter randomised trial of a heart failure management programme among geriatric patients (HF-Geriatrics). AB - BACKGROUND: Disease management programmes (DMPs) have been shown to reduce hospital readmissions and mortality in adults with heart failure (HF), but their effectiveness in elderly patients or in those with major comorbidity is unknown. The Multicenter Randomised Trial of a Heart Failure Management Programme among Geriatric Patients (HF-Geriatrics) assesses the effectiveness of a DMP in elderly patients with HF and major comorbidity. METHODS/DESIGN: Clinical trial in 700 patients aged >= 75 years admitted with a primary diagnosis of HF in the acute care unit of eight geriatric services in Spain. Each patient should meet at least one of the following comorbidty criteria: Charlson index >= 3, dependence in >= 2 activities of daily living, treatment with >= 5 drugs, active treatment for >= 3 diseases, recent emergency hospitalization, severe visual or hearing loss, cognitive impairment, Parkinson's disease, diabetes mellitus, chronic obstructive pulmonary disease (COPD), anaemia, or constitutional syndrome. Half of the patients will be randomly assigned to a 1-year DMP led by a case manager and the other half to usual care. The DMP consists of an educational programme for patients and caregivers on the management of HF, COPD (knowledge of the disease, smoking cessation, immunizations, use of inhaled medication, recognition of exacerbations), diabetes (knowledge of the disease, symptoms of hyperglycaemia and hypoglycaemia, self-adjustment of insulin, foot care) and depression (knowledge of the disease, diagnosis and treatment). It also includes close monitoring of the symptoms of decompensation and optimisation of treatment compliance. The main outcome variables are quality of life, hospital readmissions, and overall mortality during a 12-month follow-up. DISCUSSION: The physiological changes, lower life expectancy, comorbidity and low health literacy associated with aging may influence the effectiveness of DMPs in HF. The HF Geriatrics study will provide direct evidence on the effect of a DMP in elderly patients with HF and high comorbidty, and will reduce the need to extrapolate the results of clinical trials in adults to elderly patients. TRIAL REGISTRATION: (ClinicalTrials.gov number, NCT01076465). PMID- 21819566 TI - Evaluation of movements of lower limbs in non-professional ballet dancers: hip abduction and flexion. AB - BACKGROUND: The literature indicated that the majority of professional ballet dancers present static and active dynamic range of motion difference between left and right lower limbs, however, no previous study focused this difference in non professional ballet dancers. In this study we aimed to evaluate active movements of the hip in non-professional classical dancers. METHODS: We evaluated 10 non professional ballet dancers (16-23 years old). We measured the active range of motion and flexibility through Well Banks. We compared active range of motion between left and right sides (hip flexion and abduction) and performed correlation between active movements and flexibility. RESULTS: There was a small difference between the right and left sides of the hip in relation to the movements of flexion and abduction, which suggest the dominant side of the subjects, however, there was no statistical significance. Bank of Wells test revealed statistical difference only between the 1st and the 3rd measurement. There was no correlation between the movements of the hip (abduction and flexion, right and left sides) with the three test measurements of the bank of Wells. CONCLUSION: There is no imbalance between the sides of the hip with respect to active abduction and flexion movements in non-professional ballet dancers. PMID- 21819567 TI - Case-control study for colorectal cancer genetic susceptibility in EPICOLON: previously identified variants and mucins. AB - BACKGROUND: Colorectal cancer (CRC) is the second leading cause of cancer death in developed countries. Familial aggregation in CRC is also important outside syndromic forms and, in this case, a polygenic model with several common low penetrance alleles contributing to CRC genetic predisposition could be hypothesized. Mucins and GALNTs (N-acetylgalactosaminyltransferase) are interesting candidates for CRC genetic susceptibility and have not been previously evaluated. We present results for ten genetic variants linked to CRC risk in previous studies (previously identified category) and 18 selected variants from the mucin gene family in a case-control association study from the Spanish EPICOLON consortium. METHODS: CRC cases and matched controls were from EPICOLON, a prospective, multicenter, nationwide Spanish initiative, comprised of two independent stages. Stage 1 corresponded to 515 CRC cases and 515 controls, whereas stage 2 consisted of 901 CRC cases and 909 controls. Also, an independent cohort of 549 CRC cases and 599 controls outside EPICOLON was available for additional replication. Genotyping was performed for ten previously identified SNPs in ADH1C, APC, CCDN1, IL6, IL8, IRS1, MTHFR, PPARG, VDR and ARL11, and 18 selected variants in the mucin gene family. RESULTS: None of the 28 SNPs analyzed in our study was found to be associated with CRC risk. Although four SNPs were significant with a P-value < 0.05 in EPICOLON stage 1 [rs698 in ADH1C (OR = 1.63, 95% CI = 1.06-2.50, P-value = 0.02, recessive), rs1800795 in IL6 (OR = 1.62, 95% CI = 1.10-2.37, P-value = 0.01, recessive), rs3803185 in ARL11 (OR = 1.58, 95% CI = 1.17-2.15, P-value = 0.007, codominant), and rs2102302 in GALNTL2 (OR = 1.20, 95% CI = 1.00-1.44, P-value = 0.04, log-additive 0, 1, 2 alleles], only rs3803185 achieved statistical significance in EPICOLON stage 2 (OR = 1.34, 95% CI = 1.06 1.69, P-value = 0.01, recessive). In the joint analysis for both stages, results were only significant for rs3803185 (OR = 1.12, 95% CI = 1.00-1.25, P-value = 0.04, log-additive 0, 1, 2 alleles) and borderline significant for rs698 and rs2102302. The rs3803185 variant was not significantly associated with CRC risk in an external cohort (MCC-Spain), but it still showed some borderline significance in the pooled analysis of both cohorts (OR = 1.08, 95% CI = 0.98 1.18, P-value = 0.09, log-additive 0, 1, 2 alleles). CONCLUSIONS: ARL11, ADH1C, GALNTL2 and IL6 genetic variants may have an effect on CRC risk. Further validation and meta-analyses should be undertaken in larger CRC studies. PMID- 21819568 TI - The PPAR-gamma agonist pioglitazone modulates inflammation and induces neuroprotection in parkinsonian monkeys. AB - BACKGROUND: Activation of the peroxisome proliferator-activated receptor gamma (PPAR-gamma) has been proposed as a possible neuroprotective strategy to slow down the progression of early Parkinson's disease (PD). Here we report preclinical data on the use of the PPAR-gamma agonist pioglitazone (Actos(r); Takeda Pharmaceuticals Ltd.) in a paradigm resembling early PD in nonhuman primates. METHODS: Rhesus monkeys that were trained to perform a battery of behavioral tests received a single intracarotid arterial injection of 20 ml of saline containing 3 mg of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP). Twenty-four hours later the monkeys were assessed using a clinical rating scale, matched accordingly to disability, randomly assigned to one of three groups [placebo (n = 5), 2.5 (n = 6) or 5 (n = 5) mg/kg of pioglitazone] and their treatments started. Three months after daily oral dosing, the animals were necropsied. RESULTS: We observed significant improvements in clinical rating score (P = 0.02) in the animals treated with 5 mg/kg compared to placebo. Behavioral recovery was associated with preservation of nigrostriatal dopaminergic markers, observed as higher tyrosine hydroxylase (TH) putaminal optical density (P = 0.011), higher stereological cell counts of TH-ir (P = 0.02) and vesicular monoamine transporter-2 (VMAT-2)-ir nigral neurons (P = 0.006). Stereological cell counts of Nissl stained nigral neurons confirmed neuroprotection (P = 0.017). Pioglitazone-treated monkeys also showed a dose dependent modulation of CD68-ir inflammatory cells, that was significantly decreased for 5 mg/kg treated animals compared to placebo (P = 0.018). A separate experiment to assess CSF penetration of pioglitazone revealed that 5 mg/kg p.o. induced consistently higher levels than 2.5 mg/kg and 7.5 mg/kg. p.o. CONCLUSIONS: Our results indicate that oral administration of pioglitazone is neuroprotective when administered early after inducing a parkinsonian syndrome in rhesus monkeys and supports the concept that PPAR-gamma is a viable target against neurodegeneration. PMID- 21819569 TI - A comprehensive evaluation of the impact of telemonitoring in patients with long term conditions and social care needs: protocol for the whole systems demonstrator cluster randomised trial. AB - BACKGROUND: It is expected that increased demands on services will result from expanding numbers of older people with long-term conditions and social care needs. There is significant interest in the potential for technology to reduce utilisation of health services in these patient populations, including telecare (the remote, automatic and passive monitoring of changes in an individual's condition or lifestyle) and telehealth (the remote exchange of data between a patient and health care professional). The potential of telehealth and telecare technology to improve care and reduce costs is limited by a lack of rigorous evidence of actual impact. METHODS/DESIGN: We are conducting a large scale, multi site study of the implementation, impact and acceptability of these new technologies. A major part of the evaluation is a cluster-randomised controlled trial of telehealth and telecare versus usual care in patients with long-term conditions or social care needs. The trial involves a number of outcomes, including health care utilisation and quality of life. We describe the broad evaluation and the methods of the cluster randomised trial DISCUSSION: If telehealth and telecare technology proves effective, it will provide additional options for health services worldwide to deliver care for populations with high levels of need. TRIAL REGISTRATION: Current Controlled Trials ISRCTN43002091. PMID- 21819570 TI - Alcohol misuse, drinking contexts and intimate partner violence in St. Petersburg, Russia: results from a cross-sectional study. AB - BACKGROUND: Alcohol misuse has been linked to intimate partner violence (IPV). However, this association is not usually examined in Russia. Moreover, more investigation is required as to whether specific drinking contexts are also associated with IPV. The objectives of this study are: to investigate whether alcohol misuse is associated with IPV and to further examine whether specific drinking contexts among drinkers are associated with IPV. METHODS: A questionnaire was used to collect information on demographics, health status, alcohol use, and violence involving sexual partners among 440 participants who were recruited from an STI (sexually transmitted infection) clinic center in St. Petersburg, Russia for a cross-sectional study from 2008 to 2009. Multivariate logistic regression was used for analysis. RESULTS: Overall, 47.0% participants were classified as misusing alcohol and 7.2% participants perpetrated IPV in the past three months. Participants with alcohol misuse were 3.28 times (OR: 3.28; 95% CI: 1.34-8.04) as likely as those without alcohol misuse to perpetrate IPV. Among participants who had consumed alcohol in the past three months, those who usually drank on the streets or in parks (OR: 5.62; 95% CI: 1.67-18.90) were more likely to perpetrate IPV. CONCLUSIONS: Both alcohol misuse and certain drinking contexts (e.g., drinking on the streets or at parks) were associated with IPV. The association between drinking contexts and IPV needs further investigation, as do the underlying mechanisms for this association. IPV prevention initiatives might benefit from reducing alcohol misuse. Drinking contexts such as drinking on the streets or at parks as well as the factors related to the use of alcohol in these contexts may also need to be addressed. PMID- 21819571 TI - Evaluation of real-time PCR of patient pleural effusion for diagnosis of tuberculosis. AB - BACKGROUND: Pleural tuberculosis (TB) diagnosis often requires invasive procedures such as pleural biopsy. The aim of this study was to evaluate the role of real-time polymerase chain reaction (PCR) for the IS6110 sequence of M. tuberculosis in pleural fluid specimens as a rapid and non-invasive test for pleural TB diagnosis. FINDINGS: For this cross-sectional study, 150 consecutive patients with pleural effusion diagnosed by chest radiography, who were referred for diagnostic thoracocentesis and pleural biopsy and met eligibility criteria, had a pleural fluid specimen submitted for real-time PCR testing. Overall, 98 patients had pleural TB and 52 had pleural effusion secondary to other disease. TB diagnosis was obtained using acid-fast bacilli (AFB) smear or culture for mycobacteria and/or histopathologic examination in 94 cases and by clinical findings in 4 cases. Sensitivity, specificity, positive and negative predictive values of PCR testing for pleural TB diagnosis were 42.8% (95% CI 38.4 - 44.8), 94.2% (95% CI 85.8 - 98.0), 93.3% (95% CI 83.6 - 97.7), and 48.5% (95% CI 44.2 - 50.4), respectively. The real-time PCR test improved TB detection from 30.6% to 42.9% when compared to AFB smear and culture methods performed on pleural fluid specimens, although the best sensitivity was achieved by combining the results of culture and histopathology of pleural tissue specimens. CONCLUSION: The real-time PCR test of pleural fluid specimens is a useful and non-invasive additional assay for fast diagnosis of pleural TB. PMID- 21819572 TI - A galU mutant of Francisella tularensis is attenuated for virulence in a murine pulmonary model of tularemia. AB - BACKGROUND: A number of studies have revealed that Francisella tularensis (FT) suppresses innate immune responses such as chemokine/cytokine production and neutrophil recruitment in the lungs following pulmonary infection via an unidentified mechanism. The ability of FT to evade early innate immune responses could be a very important virulence mechanism for this highly infectious bacterial pathogen. RESULTS: Here we describe the characterization of a galU mutant strain of FT live vaccine strain (LVS). We show that the galU mutant was highly attenuated in a murine model of tularemia and elicited more robust innate immune responses than the wild-type (WT) strain. These studies document that the kinetics of chemokine expression and neutrophil recruitment into the lungs of mice challenged with the galU mutant strain are significantly more rapid than observed with WT FT, despite the fact that there were no observed differences in TLR2 or TLR4 signaling or replication/dissemination kinetics during the early stages of infection. We also show that the galU mutant had a hypercytotoxic phenotype and more rapidly induced the production of IL-1beta following infection either in vitro or in vivo, indicating that attenuation of the galU mutant strain may be due (in part) to more rapid activation of the inflammasome and/or earlier death of FT infected cells. Furthermore, we show that infection of mice with the galU mutant strain elicits protective immunity to subsequent challenge with WT FT. CONCLUSIONS: Disruption of the galU gene of FTLVS has little (if any) effect on in vivo infectivity, replication, or dissemination characteristics, but is highly attenuating for virulence. The attenuated phenotype of this mutant strain of FT appears to be related to its increased ability to induce innate inflammatory responsiveness, resulting in more rapid recruitment of neutrophils to the lungs following pneumonic infection, and/or to its ability to kill infected cells in an accelerated fashion. These results have identified two potentially important virulence mechanisms used by FT. These findings could also have implications for design of a live attenuated vaccine strain of FT because sublethal infection of mice with the galU mutant strain of FTLVS promoted development of protective immunity to WT FTLVS. PMID- 21819574 TI - Gold nanoparticles administration induced prominent inflammatory, central vein intima disruption, fatty change and Kupffer cells hyperplasia. AB - BACKGROUND: Advances in nanotechnology have identified promising candidates for many biological, biomedical and biomedicine applications. They are being increasingly exploited for medical uses and other industrial applications. The aim of the present study was to investigate the effects of administration of gold nanoparticles (GNPs) on inflammatory cells infiltration, central vein intima disruption, fatty change, and Kupffer cells hyperplasia in the hepatic tissue in an attempt to cover and understand the toxicity and the potential threat of their therapeutic and diagnostic use. METHODS: A total of 70 healthy male Wistar-Kyoto rats were exposed to GNPs received 50 or 100 MUl of GNPs infusion of 10, 20 and 50 nm GNPs for 3 or 7 days. Animals were randomly divided into groups, 12 GNPs treated rats groups and one control group (NG). Groups 1, 2 and 3 received infusion of 50 MUl GNPs of size 10 nm (3 or 7 days), size 20 nm (3 or 7 days) and 50 nm (3 or 7 days), respectively; while groups 4, 5 and 6 received infusion of 100 MUl GNPs of size 10 nm, size 20 nm and 50 nm, respectively. RESULTS: In comparison with respective control rats, exposure to GNPs doses has produced alterations in the hepatocytes, portal triads and sinusoids. The alterations in the hepatocytes were mainly vacuolar to hydropic degeneration, cytopasmic hyaline vacuolation, polymorphism, binucleation, karyopyknosis, karyolysis, karyorrhexis and necrosis. In addition, inflammatory cell infiltration, Kupffer cells hyperplasia, central veins intima disruption, hepatic strands dilatation and occasional fatty change together with a loss of normal architechiture of hepatic strands were also seen. CONCLUSIONS: The alterations induced by the administration of GNPs were size-dependent with smaller ones induced more affects and related with time exposure of GNPs. These alterations might be an indication of injured hepatocytes due to GNPs toxicity that became unable to deal with the accumulated residues resulting from metabolic and structural disturbances caused by these NPs. These histological alterations may suggest that GNPs interact with proteins and enzymes of the hepatic tissue interfering with the antioxidant defense mechanism and leading to reactive oxygen species (ROS) generation which in turn may induce stress in the hepatocytes to undergo necrosis. PMID- 21819573 TI - Domain architecture conservation in orthologs. AB - BACKGROUND: As orthologous proteins are expected to retain function more often than other homologs, they are often used for functional annotation transfer between species. However, ortholog identification methods do not take into account changes in domain architecture, which are likely to modify a protein's function. By domain architecture we refer to the sequential arrangement of domains along a protein sequence.To assess the level of domain architecture conservation among orthologs, we carried out a large-scale study of such events between human and 40 other species spanning the entire evolutionary range. We designed a score to measure domain architecture similarity and used it to analyze differences in domain architecture conservation between orthologs and paralogs relative to the conservation of primary sequence. We also statistically characterized the extents of different types of domain swapping events across pairs of orthologs and paralogs. RESULTS: The analysis shows that orthologs exhibit greater domain architecture conservation than paralogous homologs, even when differences in average sequence divergence are compensated for, for homologs that have diverged beyond a certain threshold. We interpret this as an indication of a stronger selective pressure on orthologs than paralogs to retain the domain architecture required for the proteins to perform a specific function. In general, orthologs as well as the closest paralogous homologs have very similar domain architectures, even at large evolutionary separation.The most common domain architecture changes observed in both ortholog and paralog pairs involved insertion/deletion of new domains, while domain shuffling and segment duplication/deletion were very infrequent. CONCLUSIONS: On the whole, our results support the hypothesis that function conservation between orthologs demands higher domain architecture conservation than other types of homologs, relative to primary sequence conservation. This supports the notion that orthologs are functionally more similar than other types of homologs at the same evolutionary distance. PMID- 21819576 TI - Complex problems require complex solutions: the utility of social quality theory for addressing the Social Determinants of Health. AB - BACKGROUND: In order to improve the health of the most vulnerable groups in society, the WHO Commission on Social Determinants of Health (CSDH) called for multi-sectoral action, which requires research and policy on the multiple and inter-linking factors shaping health outcomes. Most conceptual tools available to researchers tend to focus on singular and specific social determinants of health (SDH) (e.g. social capital, empowerment, social inclusion). However, a new and innovative conceptual framework, known as social quality theory, facilitates a more complex and complete understanding of the SDH, with its focus on four domains: social cohesion, social inclusion, social empowerment and socioeconomic security, all within the same conceptual framework. This paper provides both an overview of social quality theory in addition to findings from a national survey of social quality in Australia, as a means of demonstrating the operationalisation of the theory. METHODS: Data were collected using a national random postal survey of 1044 respondents in September, 2009. Multivariate logistic regression analysis was conducted. RESULTS: Statistical analysis revealed that people on lower incomes (less than $45000) experience worse social quality across all of the four domains: lower socio-economic security, lower levels of membership of organisations (lower social cohesion), higher levels of discrimination and less political action (lower social inclusion) and lower social empowerment. The findings were mixed in terms of age, with people over 65 years experiencing lower socio-economic security, but having higher levels of social cohesion, experiencing lower levels of discrimination (higher social inclusion) and engaging in more political action (higher social empowerment). In terms of gender, women had higher social cohesion than men, although also experienced more discrimination (lower social inclusion). CONCLUSIONS: Applying social quality theory allows researchers and policy makers to measure and respond to the multiple sources of oppression and advantage experienced by certain population groups, and to monitor the effectiveness of interventions over time. PMID- 21819575 TI - Neutralizing activities of caprine antibodies towards conserved regions of the HCV envelope glycoprotein E2. AB - Anti HCV vaccine is not currently available and the present antiviral therapies fail to cure approximately half of the treated HCV patients. This study was designed to assess the immunogenic properties of genetically conserved peptides derived from the C-terminal region of HVR-1 and test their neutralizing activities in a step towards developing therapeutic and/or prophylactic immunogens against HCV infection. Antibodies were generated by vaccination of goats with synthetic peptides derived from HCV E2. Viral neutralizing capacity of the generated anti E2 antibodies was tested using in vitro assays. Goats immunized with E2 synthetic peptides termed p412 [a.a 412-419], p430 [a.a 430 447] and p517 [a.a 517-531] generated high titers of antibody responses 2 to 4.5 fold higher than comparable titers of antibodies to the same epitopes in chronic HCV patients. In post infection experiments of native HCV into cultured Huh7.5 cells anti p412 and anti p 517 were proven to be neutralizing to HCV genotype 4a from patients' sera (87.5% and 75% respectively). On the contrary anti p430 exhibited weak viral neutralization capacity on the same samples (31.25%). Furthermore Ab mixes containing anti p430 exhibited reduced viral neutralization properties. From these experiments one could predict that neutralization by Abs towards different E2-epitopes varies considerably and success in the enrichment of neutralization epitope-specific antibodies may be accompanied by favorable results in combating HCV infection. Also, E2 conserved peptides p517 and p412 represent potential components of a candidate peptide vaccine against HCV infection. PMID- 21819577 TI - LXR agonist increases apoE secretion from HepG2 spheroid, together with an increased production of VLDL and apoE-rich large HDL. AB - BACKGROUND: The physiological regulation of hepatic apoE gene has not been clarified, although the expression of apoE in adipocytes and macrophages has been known to be regulated by LXR. METHODS AND RESULTS: We investigated the effect of TO901317, a LXR agonist, on hepatic apoE production utilizing HepG2 cells cultured in spheroid form, known to be more differentiated than HepG2 cells in monolayer culture. Spheroid HepG2 cells were prepared in alginate-beads. The secretions of albumin, apoE and apoA-I from spheroid HepG2 cells were significantly increased compared to those from monolayer HepG2 cells, and these increases were accompanied by increased mRNA levels of apoE and apoA-I. Several nuclear receptors including LXRalpha also became abundant in nuclear fractions in spheroid HepG2 cells. Treatment with TO901317 significantly increased apoE protein secretion from spheroid HepG2 cells, which was also associated with the increased expression of apoE mRNA. Separation of the media with FPLC revealed that the production of apoE-rich large HDL particles were enhanced even at low concentration of TO901317, and at higher concentration of TO901317, production of VLDL particles increased as well. CONCLUSIONS: LXR activation enhanced the expression of hepatic apoE, together with the alteration of lipoprotein particles produced from the differentiated hepatocyte-derived cells. HepG2 spheroids might serve as a good model of well-differentiated human hepatocytes for future investigations of hepatic lipid metabolism. PMID- 21819578 TI - Durability associated efficacy of long-lasting insecticidal nets after five years of household use. AB - BACKGROUND: Long-lasting insecticidal nets (LLINs) have been strongly advocated for use to prevent malaria in sub-Saharan Africa and have significantly reduced human-vector contact. PermaNet(r) 2.0 is among the five LLINs brands which have been given full approval by the WHO Pesticide Evaluation Scheme (WHOPES). The LLINs are expected to protect the malaria endemic communities, but a number of factors within the community can affect their durability and efficacy. This study evaluated the durability, efficacy and retention of PermaNet(r) 2.0 after five years of use in a Tanzanian community. METHOD: Two to three day- old non blood fed female mosquitoes from an insectary susceptible colony (An. gambiae s.s, this colony was established at TPRI from Kisumu, Kenya in 1992) and wild mosquito populations (An. arabiensis and Culex quinquefasciatus) were used in cone bioassay tests to assess the efficacy of mosquito nets. FINDINGS: The knockdown effect was recorded after three minutes of exposure, and mortality was recorded after 24 hours post-exposure. Mortality of An. gambiae s.s from insectary colony was 100% while An. arabiensis and Cx.quinquefasciatus wild populations had reduced mortality. Insecticide content of the new (the bed net of the same brand but never used before) and used PermaNet(r) 2.0 was determined using High Performance Liquid Chromatography (HPLC). CONCLUSION: The results of this study suggest that, in order to achieve maximum protection against malaria, public health education focusing on bed net use and maintenance should be incorporated into the mass distribution of nets in communities. PMID- 21819579 TI - Preventing malaria in pregnancy through community-directed interventions: evidence from Akwa Ibom State, Nigeria. AB - BACKGROUND: Despite massive anti-malaria campaigns across the subcontinent, effective access to intermittent preventive treatment (IPTp) and insecticide treated nets (ITNs) among pregnant women remain low in large parts of sub-Saharan Africa. The slow uptake of malaria prevention products appears to reflect lack of knowledge and resistance to behavioural change, as well as poor access to resources, and limited support of programmes by local communities and authorities. METHODS: A recent community-based programme in Akwa Ibom State, Nigeria, is analysed to determine the degree to which community-directed interventions can improve access to malaria prevention in pregnancy. Six local government areas in Southern Nigeria were selected for a malaria in pregnancy prevention intervention. Three of these local government areas were selected for a complementary community-directed intervention (CDI) programme. Under the CDI programme, volunteer community-directed distributors (CDDs) were appointed by each village and kindred in the treatment areas and trained to deliver ITNs and IPTp drugs as well as basic counseling services to pregnant women. FINDINGS: Relative to women in the control area, an additional 7.4 percent of women slept under a net during pregnancy in the treatment areas (95% CI [0.035, 0.115], p value < 0.01), and an additional 8.5 percent of women slept under an ITN after delivery and prior to the interview (95% CI [0.045, 0.122], p-value < 0.001). The effects of the CDI programme were largest for IPTp adherence, increasing the fraction of pregnant women taking at least two SP doses during pregnancy by 35.3 percentage points [95% CI: 0.280, 0.425], p-value < 0.001) relative to the control group. No effects on antenatal care attendance were found. CONCLUSION: The presented results suggest that the inclusion of community-based programmes can substantially increase effective access to malaria prevention, and also increase access to formal health care access in general, and antenatal care attendance in particular in combination with supply side interventions. Given the relatively modest financial commitments they require, community-directed programmes appear to be a cost-effective way to improve malaria prevention; the participatory approach underlying CDI programmes also promises to strengthen ties between the formal health sector and local communities. PMID- 21819580 TI - Performance of InterVA for assigning causes of death to verbal autopsies: multisite validation study using clinical diagnostic gold standards. AB - BACKGROUND: InterVA is a widely disseminated tool for cause of death attribution using information from verbal autopsies. Several studies have attempted to validate the concordance and accuracy of the tool, but the main limitation of these studies is that they compare cause of death as ascertained through hospital record review or hospital discharge diagnosis with the results of InterVA. This study provides a unique opportunity to assess the performance of InterVA compared to physician-certified verbal autopsies (PCVA) and alternative automated methods for analysis. METHODS: Using clinical diagnostic gold standards to select 12,542 verbal autopsy cases, we assessed the performance of InterVA on both an individual and population level and compared the results to PCVA, conducting analyses separately for adults, children, and neonates. Following the recommendation of Murray et al., we randomly varied the cause composition over 500 test datasets to understand the performance of the tool in different settings. We also contrasted InterVA with an alternative Bayesian method, Simplified Symptom Pattern (SSP), to understand the strengths and weaknesses of the tool. RESULTS: Across all age groups, InterVA performs worse than PCVA, both on an individual and population level. On an individual level, InterVA achieved a chance-corrected concordance of 24.2% for adults, 24.9% for children, and 6.3% for neonates (excluding free text, considering one cause selection). On a population level, InterVA achieved a cause-specific mortality fraction accuracy of 0.546 for adults, 0.504 for children, and 0.404 for neonates. The comparison to SSP revealed four specific characteristics that lead to superior performance of SSP. Increases in chance-corrected concordance are attained by developing cause-by-cause models (2%), using all items as opposed to only the ones that mapped to InterVA items (7%), assigning probabilities to clusters of symptoms (6%), and using empirical as opposed to expert probabilities (up to 8%). CONCLUSIONS: Given the widespread use of verbal autopsy for understanding the burden of disease and for setting health intervention priorities in areas that lack reliable vital registrations systems, accurate analysis of verbal autopsies is essential. While InterVA is an affordable and available mechanism for assigning causes of death using verbal autopsies, users should be aware of its suboptimal performance relative to other methods. PMID- 21819582 TI - Classifying perinatal mortality using verbal autopsy: is there a role for nonphysicians? AB - BACKGROUND: Because of a physician shortage in many low-income countries, the use of nonphysicians to classify perinatal mortality (stillbirth and early neonatal death) using verbal autopsy could be useful. OBJECTIVE: To determine the extent to which underlying perinatal causes of deaths assigned by nonphysicians in Guatemala, Pakistan, Zambia, and the Democratic Republic of the Congo using a verbal autopsy method are concordant with underlying perinatal cause of death assigned by physician panels. METHODS: Using a train-the-trainer model, 13 physicians and 40 nonphysicians were trained to determine cause of death using a standardized verbal autopsy training program. Subsequently, panels of two physicians and individual nonphysicians from this trained cohort independently reviewed verbal autopsy data from a sample of 118 early neonatal deaths and 134 stillbirths. With the cause of death assigned by the physician panel as the reference standard, sensitivity, specificity, positive and negative predictive values, and cause-specific mortality fractions were calculated to assess nonphysicians' coding responses. Robustness criteria to assess how well nonphysicians performed were used. RESULTS: Causes of early neonatal death and stillbirth assigned by nonphysicians were concordant with physician-assigned causes 47% and 57% of the time, respectively. Tetanus filled robustness criteria for early neonatal death, and cord prolapse filled robustness criteria for stillbirth. CONCLUSIONS: There are significant differences in underlying cause of death as determined by physicians and nonphysicians even when they receive similar training in cause of death determination. Currently, it does not appear that nonphysicians can be used reliably to assign underlying cause of perinatal death using verbal autopsy. PMID- 21819581 TI - Manual hyperinflation partly prevents reductions of functional residual capacity in cardiac surgical patients--a randomized controlled trial. AB - INTRODUCTION: Cardiac surgery is associated with post-operative reductions of functional residual capacity (FRC). Manual hyperinflation (MH) aims to prevent airway plugging, and as such could prevent the reduction of FRC after surgery. The main purpose of this study was to determine the effect of MH on post operative FRC of cardiac surgical patients. METHODS: This was a randomized controlled trial of patients after elective coronary artery bypass graft and/or valve surgery admitted to the intensive care unit (ICU) of a university hospital. Patients were randomly assigned to a "routine MH group" (MH was performed within 30 minutes after admission to the ICU and every 6 hours thereafter, and before tracheal extubation), or a "control group" (MH was performed only if perceptible (audible) sputum was present in the larger airways causing problems with mechanical ventilation, or if oxygen saturation (SpO2) dropped below 92%). The primary endpoint was the reduction of FRC from the day before cardiac surgery to one, three, and five days after tracheal extubation. Secondary endpoints were SpO2 (at similar time points) and chest radiograph abnormalities, including atelectasis (at three days after tracheal extubation). RESULTS: A total of 100 patients were enrolled. Patients in the routine MH group showed a decrease of FRC on the first post-operative day to 71% of the pre-operative value, versus 57% in the control group (P = 0.002). Differences in FRC became less prominent over time; differences between the two study groups were no longer statistically significant at Day 5. There were no differences in SpO2 between the study groups. Chest radiographs showed more abnormalities (merely atelectasis) in the control group compared to patients in the routine MH group (P = 0.002). CONCLUSIONS: MH partly prevents the reduction of FRC in the first post-operative days after cardiac surgery. TRIAL REGISTRATION: Netherlands Trial Register (NTR): NTR1384. http://www.trialregister.nl. PMID- 21819583 TI - Feasibility of using a World Health Organization-standard methodology for Sample Vital Registration with Verbal Autopsy (SAVVY) to report leading causes of death in Zambia: results of a pilot in four provinces, 2010. AB - BACKGROUND: Verbal autopsy (VA) can be used to describe leading causes of death in countries like Zambia where vital events registration does not produce usable data. The objectives of this study were to assess the feasibility of using verbal autopsy to determine age-, sex-, and cause-specific mortality in a community based setting in Zambia and to estimate overall age-, sex-, and cause-specific mortality in the four provinces sampled. METHODS: A dedicated census was conducted in regions of four provinces chosen by cluster-sampling methods in January 2010. Deaths in the 12-month period prior to the census were identified during the census. Subsequently, trained field staff conducted verbal autopsy interviews with caregivers or close relatives of the deceased using structured and unstructured questionnaires. Additional deaths were identified and respondents were interviewed during 12 months of fieldwork. After the interviews, two physicians independently reviewed each VA questionnaire to determine a probable cause of death. RESULTS: Among the four provinces (1,056 total deaths) assessed, all-cause mortality rate was 17.2 per 1,000 person-years (95% confidence interval [CI]: 12.4, 22). The seven leading causes of death were HIV/AIDS (287, 27%), malaria (111, 10%), injuries and accidents (81, 8%), diseases of the circulatory system (75, 7%), malnutrition (58, 6%), pneumonia (56, 5%), and tuberculosis (50, 5%). Those who died were more likely to be male, have less than or equal to a primary education, and be unmarried, widowed, or divorced compared to the baseline population. Nearly half (49%) of all reported deaths occurred at home. CONCLUSIONS: The 17.2 per 1,000 all-cause mortality rate is somewhat similar to modeled country estimates. The leading causes of death -- HIV/AIDS, malaria, injuries, circulatory diseases, and malnutrition -- reflected causes similar to those reported for the African region and by other countries in the region. Results can enable the targeting of interventions by region, disease, and population to reduce preventable death. Collecting vital statistics using standardized Sample Vital Registration with Verbal Autopsy (SAVVY) methods appears feasible in Zambia. If conducted regularly, these data can be used to evaluate trends in estimated causes of death over time. PMID- 21819584 TI - Verbal autopsy completion rate and factors associated with undetermined cause of death in a rural resource-poor setting of Tanzania. AB - BACKGROUND: Verbal autopsy (VA) is a widely used tool to assign probable cause of death in areas with inadequate vital registration systems. Its uses in priority setting and health planning are well documented in sub-Saharan Africa (SSA) and Asia. However, there is a lack of data related to VA processing and completion rates in assigning causes of death in a community. There is also a lack of data on factors associated with undetermined causes of death documented in SSA. There is a need for such information for understanding the gaps in VA processing and better estimating disease burden. OBJECTIVE: The study's intent was to determine the completion rate of VA and factors associated with assigning undetermined causes of death in rural Tanzania. METHODS: A database of deaths reported from the Ifakara Health and Demographic Surveillance System from 2002 to 2007 was used. Completion rates were determined at the following stages of processing: 1) death identified; 2) VA interviews conducted; 3) VA forms submitted to physicians; 4) coding and assigning of cause of death. Logistic regression was used to determine factors associated with deaths coded as "undetermined." RESULTS: The completion rate of VA after identification of death and the VA interview ranged from 83% in 2002 and 89% in 2007. Ninety-four percent of deaths submitted to physicians were assigned a specific cause, with 31% of the causes coded as undetermined. Neonates and child deaths that occurred outside health facilities were associated with a high rate of undetermined classification (33%, odds ratio [OR] = 1.33, 95% confidence interval [CI] (1.05, 1.67), p = 0.016). Respondents reporting high education levels were less likely to be associated with deaths that were classified as undetermined (24%, OR = 0.76, 95% CI (0.60, 0.96), p = 0.023). Being a child of the deceased compared to a partner (husband or wife) was more likely to be associated with undetermined cause of death classification (OR = 1.35, 95% CI (1.04, 1.75), p = 0.023). CONCLUSION: Every year, there is a high completion rate of VA in the initial stages of processing; however, a number of VAs are lost during the processing. Most of the losses occur at the final step, physicians' determination of cause of death. The type of respondent and place of death had a significant effect on final determination of the plausible cause of death. The finding provides some insight into the factors affecting full coverage of verbal autopsy diagnosis and the limitations of causes of death based on VA in SSA. Although physician review is the most commonly used method in ascertaining probable cause of death, we suggest further work needs to be done to address the challenges faced by physicians in interpreting VA forms. There is need for an alternative to or improvement of the methods of physician review. PMID- 21819586 TI - Right pulmonary artery agenesis presenting with uncontrolled asthma in an adult: a case report. AB - INTRODUCTION: Unilateral absence of the pulmonary artery (UAPA) or pulmonary artery agenesis is a rare congenital disorder presenting with a wide spectrum of symptoms. The clinical presentation is variable and many patients can be asymptomatic for many years and even throughout their lives. CASE PRESENTATION: We report the case of a 53-year-old African-American woman who was diagnosed with right pulmonary artery agenesis after presenting with uncontrolled asthma and recurrent bronchopulmonary infections. CONCLUSION: In an unexplained case of recurrent respiratory infections and shortness of breath, the possibility of a rare congenital anomaly like UAPA should be considered and an appropriate evaluation should be done. PMID- 21819585 TI - Nef-mediated enhancement of cellular activation and human immunodeficiency virus type 1 replication in primary T cells is dependent on association with p21 activated kinase 2. AB - BACKGROUND: The HIV-1 accessory protein Nef is an important determinant of lentiviral pathogenicity that contributes to disease progression by enhancing viral replication and other poorly understood mechanisms. Nef mediates diverse functions including downmodulation of cell surface CD4 and MHC Class I, enhancement of viral infectivity, and enhancement of T cell activation. Nef interacts with a multiprotein signaling complex that includes Src family kinases, Vav1, CDC42, and activated PAK2 (p21-activated kinase 2). Although previous studies have attempted to identify a biological role for the Nef-PAK2 signaling complex, the importance of this complex and its constituent proteins in Nef function remains unclear. RESULTS: Here, we show that Nef mutants defective for PAK2-association, but functional for CD4 and MHC Class I downmodulation and infectivity enhancement, are also defective for the ability to enhance viral replication in primary T cells that are infected and subsequently activated by sub-maximal stimuli (1 MUg/ml PHA-P). In contrast, these Nef mutants had little or no effect on HIV-1 replication in T cells activated by stronger stimuli (2 MUg/ml PHA-P or anti-CD3/CD28-coated beads). Viruses bearing wild-type Nefs, but not Nef mutants defective for PAK2 association, enhanced NFAT and IL2 receptor promoter activity in Jurkat cells. Moreover, expression of wild-type Nefs, but not mutant Nefs defective for PAK2 association, was sufficient to enhance responsiveness of primary CD4 and CD8 T cells to activating stimuli in Nef expressing and bystander cells. siRNA knockdown of PAK2 in Jurkat cells reduced NFAT activation induced by anti-CD3/CD28 stimulation both in the presence and absence of Nef, and expression of a PAK2 dominant mutant inhibited Nef-mediated enhancement of CD25 expression. CONCLUSION: Nef-mediated enhancement of cellular activation and viral replication in primary T cells is dependent on PAK2 and on the strength of the activating stimuli, and correlates with the ability of Nef to associate with PAK2. PAK2 is likely to play a role in Nef-mediated enhancement of viral replication and immune activation in vivo. PMID- 21819587 TI - Bullet embolization to the external iliac artery after gunshot injury to the abdominal aorta: a case report. AB - INTRODUCTION: Abdominal vascular trauma is fairly common in modern civilian life and is a highly lethal injury. However, if the projectile is small enough, if its energy is diminished when passing through the tissue and if the arterial system is elastic enough, the entry wound into the artery may close without exsanguination and therefore may not be fatal. A projectile captured may even travel downstream until it is arrested by the smaller distal vasculature. The occurrence of this phenomenon is rare and was first described by Trimble in 1968. CASE PRESENTATION: Here we present a case of a 29-year-old Albanian man who, due to a gunshot injury to the back, suffered fracture of his twelfth thoracic and first lumbar vertebra, injury to the posterior wall of his abdominal aorta and then bullet embolism to his left external iliac artery. It is interesting that the signs of distal ischemia developed several hours after the exploratory surgery, raising the possibility that the bullet migrated in the interim or that there was a failure to recognize it during the exploratory surgery. CONCLUSION: In all cases where there is a gunshot injury to the abdomen or chest without an exit wound and with no projectile in the area, there should be a high index of suspicion for possible bullet embolism, particularly in the presence of the distal ischemia. PMID- 21819588 TI - Peritoneal dissemination of prostate cancer due to laparoscopic radical prostatectomy: a case report. AB - INTRODUCTION: Peritoneal dissemination with no further metastases of prostate cancer is very rare, with only three cases reported in the available literature. We report the first case of iatrogenic peritoneal dissemination due to laparoscopic radical prostatectomy. CASE PRESENTATION: A 59-year-old Japanese man underwent laparoscopic radical prostatectomy for clinical T2bN0M0 prostate cancer, and the pathological diagnosis was pT3aN0 Gleason 3+4 adenocarcinoma with a negative surgical margin. Salvage radiation therapy was performed since his serum prostate-specific antigen remained at a measurable value. After the radiation, he underwent castration, followed by combined androgen blockade with estramustine phosphate and dexamethasone as each treatment was effective for only a few months to a year. Nine years after the laparoscopic radical prostatectomy, computed tomography revealed a peritoneal tumor, although no other organ metastasis had been identified until then. He died six months after the appearance of peritoneal metastasis. An autopsy demonstrated peritoneal dissemination of the prostate cancer without any other metastasis. CONCLUSION: Physicians should take into account metastasis to unexpected sites. Furthermore, we suggest that meticulous care be taken not to disseminate cancer cells to the peritoneum during laparoscopic radical prostatectomy. PMID- 21819590 TI - Rectal hemangiopericytoma in a 37-year-old woman: a case report and review of the literature. AB - INTRODUCTION: Hemangiopericytoma is an uncommon perivascular tumor. Rectal Hemangiopericytomas are extremely rare. To the best of our knowledge, only two cases have been reported in the literature. CASE PRESENTATION: We report the case of a 37-year-old Asian woman with an Hemangiopericytoma rising from the anterior wall of her rectum. Abdominopelvic computed tomography showed a 7.4 cm solid mass between her uterus and her rectum. Heterogeneous gradual enhancement after intravenous injection of contrast material was noted with several tortuous vessels around her tumor. Intra-operative findings indicated a capsule and well circumscribed solid tumor connecting with the anterior wall of her rectum by a small pedicle. With immunohistochemical stains, her tumor cells reacted positive for Bcl-2, CD34, and ki67 and negative for CD10, CD117, S100, and Desmin. Follow up computed tomography scans have shown no tumor recurrence or metastasis signs. CONCLUSIONS: Rectal Hemangiopericytoma is a rare tumor with non-specific imaging findings. Hemangiopericytomas should be included in the differential list when a massive tumor with heterogeneously gradual enhancement in the regions of the rectum is encountered. PMID- 21819589 TI - A review of Brucella infection in marine mammals, with special emphasis on Brucella pinnipedialis in the hooded seal (Cystophora cristata). AB - Brucella spp. were isolated from marine mammals for the first time in 1994. Two novel species were later included in the genus; Brucella ceti and Brucella pinnipedialis, with cetaceans and seals as their preferred hosts, respectively. Brucella spp. have since been isolated from a variety of marine mammals. Pathological changes, including lesions of the reproductive organs and associated abortions, have only been registered in cetaceans. The zoonotic potential differs among the marine mammal Brucella strains. Many techniques, both classical typing and molecular microbiology, have been utilised for characterisation of the marine mammal Brucella spp. and the change from the band-based approaches to the sequence-based approaches has greatly increased our knowledge about these strains. Several clusters have been identified within the B. ceti and B. pinnipedialis species, and multiple studies have shown that the hooded seal isolates differ from other pinniped isolates. We describe how different molecular methods have contributed to species identification and differentiation of B. ceti and B. pinnipedialis, with special emphasis on the hooded seal isolates. We further discuss the potential role of B. pinnipedialis for the declining Northwest Atlantic hooded seal population. PMID- 21819591 TI - Association between physical activity and metabolic syndrome in middle-aged Japanese: a cross-sectional study. AB - BACKGROUND: Although many studies have reported an association between self reported physical activity and metabolic syndrome (MetS), there is limited information on the optimal level of physical activity required to prevent MetS. This study aimed to determine the association between objectively measured physical activity and MetS in middle-aged Japanese individuals. We also determined the optimal cutoff value for physical activity required to decrease the risk of developing MetS. METHODS: A total of 179 men and 304 women, aged between 30 and 64 years, participated in this study. Participants were divided into two groups using the Japanese criteria for MetS as those with MetS or pre MetS, and those without MetS. Participants were considered to be physically active if they achieved a physical activity level of 23 metabolic equivalents (METs) h/week, measured using a triaxial accelerometer. The association between physical activity and MetS was analyzed using logistic regression with the following covariates: sex, age, sedentary time, low intensity activity, calorie intake, smoking, menopause and body mass index. We also evaluated the factors that determined the association between the prevalence of MetS and pre-MetS and the physical activity cutoff value using classification and regression tree (CART) analysis. RESULTS: The odds ratio for MetS and pre-MetS was 2.20 for physically inactive participants (< 23 METs h/week), compared with physically active participants (>= 23 METs h/week). The corresponding odds ratios for men and women were 2.27 (P < 0.01) and 1.95 (not significant), respectively. CART analyses revealed that moderate-vigorous physical activity of > 26.5 METs h/week was sufficient to decrease the prevalence of MetS and pre-MetS in middle-aged Japanese men and women. CONCLUSIONS: The results of this cross-sectional study indicate that the Exercise and Physical Activity Reference for Health Promotion 2006 is inversely associated with the prevalence of MetS in men. Our results also suggest that moderate physical activity of > 26.5 METs h/week may decrease the risk of developing MetS and pre-MetS in middle-aged Japanese individuals. PMID- 21819592 TI - Cloning and expression profiling of the VLDLR gene associated with egg performance in duck (Anas platyrhynchos). AB - BACKGROUND: The very low density lipoprotein receptor gene (VLDLR), a member of the low density lipoprotein receptor (LDLR) gene family, plays a crucial role in the synthesis of yolk protein precursors in oviparous species. Differential splicing of this gene has been reported in human, rabbit and rat. In chicken, studies showed that the VLDLR protein on the oocyte surface mediates the uptake of yolk protein precursors into growing oocytes. However, information on the VLDLR gene in duck is still scarce. METHODS: Full-length duck VLDLR cDNA was obtained by comparative cloning and rapid amplification of cDNA ends (RACE). Tissue expression patterns were analysed by semi-quantitative reverse transcription polymerase chain reaction (RT-PCR). Association between the different genotypes and egg performance traits was investigated with the general linear model (GLM) procedure of the SAS(r) software package. RESULTS: In duck, two VLDLR transcripts were identified, one transcript (variant-a) containing an O linked sugar domain and the other (variant-b) not containing this sugar domain. These transcripts share ~70 to 90% identity with their counterparts in other species. A phylogenetic tree based on amino acid sequences showed that duck VLDLR proteins were closely related with those of chicken and zebra finch. The two duck VLDLR transcripts are differentially expressed i.e. VLDLR-a is mainly expressed in muscle tissue and VLDLR-b in reproductive organs. We have localized the duck VLDLR gene on chromosome Z. An association analysis using two completely linked SNP sites (T/C at position 2025 bp of the ORF and G/A in intron 13) and records from two generations demonstrated that the duck VLDLR gene was significantly associated with egg production (P < 0.01), age of first egg (P < 0.01) and body weight of first egg (P < 0.05). CONCLUSIONS: Duck and chicken VLDLR genes probably perform similar function in the development of growing oocytes and deposition of yolk lipoprotein. Therefore, VLDLR could be a candidate gene for duck egg performance and be used as a genetic marker to improve egg performance in ducks. PMID- 21819593 TI - A novel synthetic quantification standard including virus and internal report targets: application for the detection and quantification of emerging begomoviruses on tomato. AB - BACKGROUND: Begomovirus is a genus of phytopathogenic single-stranded DNA viruses, transmitted by the whitefly Bemisia tabaci. This genus includes emerging and economically significant viruses such as those associated with Tomato Yellow Leaf Curl Disease, for which diagnostic tools are needed to prevent dispersion and new introductions. Five real-time PCRs with an internal tomato reporter gene were developed for accurate detection and quantification of monopartite begomoviruses, including two strains of the Tomato yellow leaf curl virus (TYLCV; Mld and IL strains), the Tomato leaf curl Comoros virus-like viruses (ToLCKMV like viruses) and the two molecules of the bipartite Potato yellow mosaic virus. These diagnostic tools have a unique standard quantification, comprising the targeted viral and internal report amplicons. These duplex real-time PCRs were applied to artificially inoculated plants to monitor and compare their viral development. RESULTS: Real-time PCRs were optimized for accurate detection and quantification over a range of 2 * 10(9) to 2 * 10(3) copies of genomic viral DNA/MUL for TYLCV-Mld, TYLCV-IL and PYMV-B and 2 * 10(8) to 2 * 10(3) copies of genomic viral DNA/MUL for PYMV-A and ToLCKMV-like viruses. These real-time PCRs were applied to artificially inoculated plants and viral loads were compared at 10, 20 and 30 days post-inoculation. Different patterns of viral accumulation were observed between the bipartite and the monopartite begomoviruses. Interestingly, PYMV accumulated more viral DNA at each date for both genomic components compared to all the monopartite viruses. Also, PYMV reached its highest viral load at 10 dpi contrary to the other viruses (20 dpi). The accumulation kinetics of the two strains of emergent TYLCV differed from the ToLCKMV-like viruses in the higher quantities of viral DNA produced in the early phase of the infection and in the shorter time to reach this peak viral load. CONCLUSIONS: To detect and quantify a wide range of begomoviruses, five duplex real-time PCRs were developed in association with a novel strategy for the quantification standard. These assays should be of a great interest for breeding programs and epidemiological surveys to monitor viral populations. PMID- 21819594 TI - Effectiveness of the back school and mckenzie techniques in patients with chronic non-specific low back pain: a protocol of a randomised controlled trial. AB - BACKGROUND: Chronic low back pain is a highly prevalent condition, which is associated with high direct and indirect costs to the society. Although this condition is highly prevalent, it is still extremely difficult to treat. Two potentially useful treatments for patients with chronic low back pain are called the McKenzie and Back School treatment programs. These programs have good biological plausibility, are widely available and have a modest cost. Although these treatments are already available for patients, the evidence that supports their use is largely based on low quality methodological studies. Therefore, a high-quality randomised controlled trial is required to compare, for the first time, the effectiveness of these treatments in patients with chronic low back pain. METHODS/DESIGN: One hundred and forty-eight patients will be randomly allocated to a four-week treatment program based upon the McKenzie or Back School principles. Clinical outcomes (pain intensity, disability, quality of life, and trunk flexion range of motion) will be obtained at follow-up appointments at 1, 3 and 6 months after randomisation. The data will be collected by an assessor who will be blinded to the group allocation. DISCUSSION: This will be the first study aimed to compare the McKenzie and Back School approaches in patients with chronic low back pain. The results of this trial may help in the decision-making process of allied health providers for the treatment of chronic low back pain and reduce the health-related costs of this condition. TRIAL REGISTRATION: ACTRN12610000435088. PMID- 21819596 TI - Could peak proteinuria determine whether patient with dengue fever develop dengue hemorrhagic/dengue shock syndrome?--a prospective cohort study. AB - BACKGROUND: Worldwide there is a need to develop simple effective predictors that can distinguish whether a patient will progress from dengue fever (DF) to life threatening dengue hemorrhagic (DHF) or dengue shock syndrome (DSS). We explored whether proteinuria could be used as such a marker. METHODS: We included patients admitted to hospital with suspected dengue fever. Starting at enrollment until discharge, each patient's daily spot urine protein creatinine ratio (UPCR) was measured. We classified those with confirmed dengue infection as DF or DHF (including DSS) based on WHO criteria. Peak and day of onset of proteinuria was compared between both groups. RESULTS: Compared to those with DF, patients with DHF had significantly higher median peak proteinuria levels (0.56 versus 0.08 g/day; p < 0.001). For patients with DHF, the median day of onset of proteinuria was at 6 days of defervescence, with a range of -2 to +3 days after defervescence. There were three patients with DF who did not have proteinuria during their illness; the five remaining patients with DF had a median day of onset of proteinuria of was at 6 days of defervescence with a range of 0 to +28 days. CONCLUSIONS: Peak UPCR could potentially predict DHF in patients with dengue requiring close monitoring and treatment. PMID- 21819595 TI - A retrosynthetic biology approach to metabolic pathway design for therapeutic production. AB - BACKGROUND: Synthetic biology is used to develop cell factories for production of chemicals by constructively importing heterologous pathways into industrial microorganisms. In this work we present a retrosynthetic approach to the production of therapeutics with the goal of developing an in situ drug delivery device in host cells. Retrosynthesis, a concept originally proposed for synthetic chemistry, iteratively applies reversed chemical transformations (reversed enzyme catalyzed reactions in the metabolic space) starting from a target product to reach precursors that are endogenous to the chassis. So far, a wider adoption of retrosynthesis into the manufacturing pipeline has been hindered by the complexity of enumerating all feasible biosynthetic pathways for a given compound. RESULTS: In our method, we efficiently address the complexity problem by coding substrates, products and reactions into molecular signatures. Metabolic maps are represented using hypergraphs and the complexity is controlled by varying the specificity of the molecular signature. Furthermore, our method enables candidate pathways to be ranked to determine which ones are best to engineer. The proposed ranking function can integrate data from different sources such as host compatibility for inserted genes, the estimation of steady-state fluxes from the genome-wide reconstruction of the organism's metabolism, or the estimation of metabolite toxicity from experimental assays. We use several machine-learning tools in order to estimate enzyme activity and reaction efficiency at each step of the identified pathways. Examples of production in bacteria and yeast for two antibiotics and for one antitumor agent, as well as for several essential metabolites are outlined. CONCLUSIONS: We present here a unified framework that integrates diverse techniques involved in the design of heterologous biosynthetic pathways through a retrosynthetic approach in the reaction signature space. Our engineering methodology enables the flexible design of industrial microorganisms for the efficient on-demand production of chemical compounds with therapeutic applications. PMID- 21819597 TI - Is race medically relevant? A qualitative study of physicians' attitudes about the role of race in treatment decision-making. AB - BACKGROUND: The role of patient race in medical decision-making is heavily debated. While some evidence suggests that patient race can be used by physicians to predict disease risk and determine drug therapy, other studies document bias and stereotyping by physicians based on patient race. It is critical, then, to explore physicians' attitudes regarding the medical relevance of patient race. METHODS: We conducted a qualitative study in the United States using ten focus groups of physicians stratified by self-identified race (black or white) and led by race-concordant moderators. Physicians were presented with a medical vignette about a patient (whose race was unknown) with Type 2 diabetes and untreated hypertension, who was also a current smoker. Participants were first asked to discuss what medical information they would need to treat the patient. Then physicians were asked to explicitly discuss the importance of race to the hypothetical patient's treatment. To identify common themes, codes, key words and physician demographics were compiled into a comprehensive table that allowed for examination of similarities and differences by physician race. Common themes were identified using the software package NVivo (QSR International, v7). RESULTS: Forty self-identified black and 50 self-identified white physicians participated in the study. All physicians - regardless of their own race - believed that medical history, family history, and weight were important for making treatment decisions for the patient. However, black and white physicians reported differences in their views about the relevance of race. Several black physicians indicated that patient race is a central factor for choosing treatment options such as aggressive therapies, patient medication and understanding disease risk. Moreover, many black physicians considered patient race important to understand the patient's views, such as alternative medicine preferences and cultural beliefs about illness. However, few white physicians explicitly indicated that the patient's race was important over-and-above medical history. Instead, white physicians reported that the patient should be treated aggressively regardless of race. CONCLUSIONS: This investigation adds to our understanding about how physicians in the United States consider race when treating patients, and sheds light on issues physicians face when deciding the importance of race in medical decision-making. PMID- 21819598 TI - Insulin glycation by methylglyoxal results in native-like aggregation and inhibition of fibril formation. AB - BACKGROUND: Insulin is a hormone that regulates blood glucose homeostasis and is a central protein in a medical condition termed insulin injection amyloidosis. It is intimately associated with glycaemia and is vulnerable to glycation by glucose and other highly reactive carbonyls like methylglyoxal, especially in diabetic conditions. Protein glycation is involved in structure and stability changes that impair protein functionality, and is associated with several human diseases, such as diabetes and neurodegenerative diseases like Alzheimer's disease, Parkinson's disease and Familiar Amyloidotic Polyneuropathy. In the present work, methylglyoxal was investigated for their effects on the structure, stability and fibril formation of insulin. RESULTS: Methylglyoxal was found to induce the formation of insulin native-like aggregates and reduce protein fibrillation by blocking the formation of the seeding nuclei. Equilibrium-unfolding experiments using chaotropic agents showed that glycated insulin has a small conformational stability and a weaker dependence on denaturant concentration (smaller m-value). Our observations suggest that methylglyoxal modification of insulin leads to a less compact and less stable structure that may be associated to an increased protein dynamics. CONCLUSIONS: We propose that higher dynamics in glycated insulin could prevent the formation of the rigid cross-beta core structure found in amyloid fibrils, thereby contributing to the reduction in the ability to form fibrils and to the population of different aggregation pathways like the formation of native-like aggregates. PMID- 21819599 TI - Adaptation of a probabilistic method (InterVA) of verbal autopsy to improve the interpretation of cause of stillbirth and neonatal death in Malawi, Nepal, and Zimbabwe. AB - BACKGROUND: Verbal autopsy (VA) is a widely used method for analyzing cause of death in absence of vital registration systems. We adapted the InterVA method to extrapolate causes of death for stillbirths and neonatal deaths from verbal autopsy questionnaires, using data from Malawi, Zimbabwe, and Nepal. METHODS: We obtained 734 stillbirth and neonatal VAs from recent community studies in rural areas: 169 from Malawi, 385 from Nepal, and 180 from Zimbabwe. Initial refinement of the InterVA model was based on 100 physician-reviewed VAs from Malawi. InterVA indicators and matrix probabilities for cause of death were reviewed for clinical and epidemiological coherence by a pediatrician-researcher and an epidemiologist involved in the development of InterVA. The modified InterVA model was evaluated by comparing population-level cause-specific mortality fractions and individual agreement from two methods of interpretation (physician review and InterVA) for a further 69 VAs from Malawi, 385 from Nepal, and 180 from Zimbabwe. RESULTS: Case by-case agreement between InterVA and reviewing physician diagnoses for 69 cases from Malawi, 180 cases from Zimbabwe, and 385 cases from Nepal were 83% (kappa 0.76 (0.75 - 0.80)), 71% (kappa 0.41(0.32-0.51)), and 74% (kappa 0.63 (0.60 0.63)), respectively. The proportion of stillbirths identified as fresh or macerated by the different methods of VA interpretation was similar in all three settings. Comparing across countries, the modified InterVA method found that proportions of preterm births and deaths due to infection were higher in Zimbabwe (44%) than in Malawi (28%) or Nepal (20%). CONCLUSION: The modified InterVA method provides plausible results for stillbirths and newborn deaths, broadly comparable to physician review but with the advantage of internal consistency. The method allows standardized cross-country comparisons and eliminates the inconsistencies of physician review in such comparisons. PMID- 21819600 TI - Trends in causes of death among children under 5 in Bangladesh, 1993-2004: an exercise applying a standardized computer algorithm to assign causes of death using verbal autopsy data. AB - BACKGROUND: Trends in the causes of child mortality serve as important global health information to guide efforts to improve child survival. With child mortality declining in Bangladesh, the distribution of causes of death also changes. The three verbal autopsy (VA) studies conducted with the Bangladesh Demographic and Health Surveys provide a unique opportunity to study these changes in child causes of death. METHODS: To ensure comparability of these trends, we developed a standardized algorithm to assign causes of death using symptoms collected through the VA studies. The original algorithms applied were systematically reviewed and key differences in cause categorization, hierarchy, case definition, and the amount of data collected were compared to inform the development of the standardized algorithm. Based primarily on the 2004 cause categorization and hierarchy, the standardized algorithm guarantees comparability of the trends by only including symptom data commonly available across all three studies. RESULTS: Between 1993 and 2004, pneumonia remained the leading cause of death in Bangladesh, contributing to 24% to 33% of deaths among children under 5. The proportion of neonatal mortality increased significantly from 36% (uncertainty range [UR]: 31%-41%) to 56% (49%-62%) during the same period. The cause-specific mortality fractions due to birth asphyxia/birth injury and prematurity/low birth weight (LBW) increased steadily, with both rising from 3% (2%-5%) to 13% (10%-17%) and 10% (7%-15%), respectively. The cause-specific mortality rates decreased significantly due to neonatal tetanus and several postneonatal causes (tetanus: from 7 [4-11] to 2 [0.4-4] per 1,000 live births (LB); pneumonia: from 26 [20-33] to 15 [11-20] per 1,000 LB; diarrhea: from 12 [8 17] to 4 [2-7] per 1,000 LB; measles: from 5 [2-8] to 0.2 [0-0.7] per 1,000 LB; injury: from 11 [7-17] to 3 [1-5] per 1,000 LB; and malnutrition: from 9 [6-13] to 5 [2-7]). CONCLUSIONS: Pneumonia remained the top killer of children under 5 in Bangladesh between 1993 and 2004. The increasing importance of neonatal survival is highlighted by the growing contribution of neonatal deaths and several neonatal causes. Notwithstanding the limitations, standardized computer based algorithms remain a promising tool to generate comparable causes of child death using VA data. PMID- 21819601 TI - Using verbal autopsy to track epidemic dynamics: the case of HIV-related mortality in South Africa. AB - BACKGROUND: Verbal autopsy (VA) has often been used for point estimates of cause specific mortality, but seldom to characterize long-term changes in epidemic patterns. Monitoring emerging causes of death involves practitioners' developing perceptions of diseases and demands consistent methods and practices. Here we retrospectively analyze HIV-related mortality in South Africa, using physician and modeled interpretation. METHODS: Between 1992 and 2005, 94% of 6,153 deaths which occurred in the Agincourt subdistrict had VAs completed, and coded by two physicians and the InterVA model. The physician causes of death were consolidated into a single consensus underlying cause per case, with an additional physician arbitrating where different diagnoses persisted. HIV-related mortality rates and proportions of deaths coded as HIV-related by individual physicians, physician consensus, and the InterVA model were compared over time. RESULTS: Approximately 20% of deaths were HIV-related, ranging from early low levels to tenfold-higher later population rates (2.5 per 1,000 person-years). Rates were higher among children under 5 years and adults 20 to 64 years. Adult mortality shifted to older ages as the epidemic progressed, with a noticeable number of HIV-related deaths in the over-65 year age group latterly. Early InterVA results suggested slightly higher initial HIV-related mortality than physician consensus found. Overall, physician consensus and InterVA results characterized the epidemic very similarly. Individual physicians showed marked interobserver variation, with consensus findings generally reflecting slightly lower proportions of HIV-related deaths. Aggregated findings for first versus second physician did not differ appreciably. CONCLUSIONS: VA effectively detected a very significant epidemic of HIV-related mortality. Using either physicians or InterVA gave closely comparable findings regarding the epidemic. The consistency between two physician coders per case (from a pool of 14) suggests that double coding may be unnecessary, although the consensus rate of HIV-related mortality was approximately 8% lower than by individual physicians. Consistency within and between individual physicians, individual perceptions of epidemic dynamics, and the inherent consistency of models are important considerations here. The ability of the InterVA model to track a more than tenfold increase in HIV-related mortality over time suggests that finely tuned "local" versions of models for VA interpretation are not necessary. PMID- 21819602 TI - Verbal autopsy-based cause-specific mortality trends in rural KwaZulu-Natal, South Africa, 2000-2009. AB - BACKGROUND: The advent of the HIV pandemic and the more recent prevention and therapeutic interventions have resulted in extensive and rapid changes in cause specific mortality rates in sub-Saharan Africa, and there is demand for timely and accurate cause-specific mortality data to steer public health responses and to evaluate the outcome of interventions. The objective of this study is to describe cause-specific mortality trends based on verbal autopsies conducted on all deaths in a rural population in KwaZulu-Natal, South Africa, over a 10-year period (2000-2009). METHODS: The study used population-based mortality data collected by a demographic surveillance system on all resident and nonresident members of 12,000 households. Cause of death was determined by verbal autopsy based on the standard INDEPTH/WHO verbal autopsy questionnaire. Cause of death was assigned by physician review and the Bayesian-based InterVA program. RESULTS: There were 11,281 deaths over 784,274 person-years of observation of 125,658 individuals between Jan. 1, 2000 and Dec. 31, 2009. The cause-specific mortality fractions (CSMF) for the population as a whole were: HIV-related (including tuberculosis), 50%; other communicable diseases, 6%; noncommunicable lifestyle related conditions, 15%; other noncommunicable diseases, 2%; maternal, perinatal, nutritional, and congenital causes, 1%; injury, 8%; indeterminate causes, 18%. Over the course of the 10 years of observation, the CSMF of HIV-related causes declined from a high of 56% in 2002 to a low of 39% in 2009 with the largest decline starting in 2004 following the introduction of an antiretroviral treatment program into the population. The all-cause age-standardized mortality rate (SMR) declined over the same period from a high of 174 (95% confidence interval [CI]: 165, 183) deaths per 10,000 person-years observed (PYO) in 2003 to a low of 116 (95% CI: 109, 123) in 2009. The decline in the SMR is predominantly due to a decline in the HIV-related SMR, which declined in the same period from 96 (95% CI: 89, 102) to 45 (95% CI: 40, 49) deaths per 10,000 PYO.There was substantial agreement (79% kappa = 0.68 (95% CI: 0.67, 0.69)) between physician coding and InterVA coding at the burden of disease group level. CONCLUSIONS: Verbal autopsy based methods enabled the timely measurement of changing trends in cause-specific mortality to provide policymakers with the much-needed information to allocate resources to appropriate health interventions. PMID- 21819603 TI - Validating physician-certified verbal autopsy and probabilistic modeling (InterVA) approaches to verbal autopsy interpretation using hospital causes of adult deaths. AB - BACKGROUND: The most common method for determining cause of death is certification by physicians based either on available medical records, or where such data are not available, through verbal autopsy (VA). The physician certification approach is costly and inconvenient; however, recent work shows the potential of a computer-based probabilistic model (InterVA) to interpret verbal autopsy data in a more convenient, consistent, and rapid way. In this study we validate separately both physician-certified verbal autopsy (PCVA) and the InterVA probabilistic model against hospital cause of death (HCOD) in adults dying in a district hospital on the coast of Kenya. METHODS: Between March 2007 and June 2010, VA interviews were conducted for 145 adult deaths that occurred at Kilifi District Hospital. The VA data were reviewed by a physician and the cause of death established. A range of indicators (including age, gender, physical signs and symptoms, pregnancy status, medical history, and the circumstances of death) from the VA forms were included in the InterVA for interpretation. Cause specific mortality fractions (CSMF), Cohen's kappa (kappa) statistic, receiver operating characteristic (ROC) curves, sensitivity, specificity, and positive predictive values were applied to compare agreement between PCVA, InterVA, and HCOD. RESULTS: HCOD, InterVA, and PCVA yielded the same top five underlying causes of adult deaths. The InterVA overestimated tuberculosis as a cause of death compared to the HCOD. On the other hand, PCVA overestimated diabetes. Overall, CSMF for the five major cause groups by the InterVA, PCVA, and HCOD were 70%, 65%, and 60%, respectively. PCVA versus HCOD yielded a higher kappa value (kappa = 0.52, 95% confidence interval [CI]: 0.48, 0.54) than the InterVA versus HCOD which yielded a kappa (kappa) value of 0.32 (95% CI: 0.30, 0.38). Overall, (kappa) agreement across the three methods was 0.41 (95% CI: 0.37, 0.48). The areas under the ROC curves were 0.82 for InterVA and 0.88 for PCVA. The observed sensitivities and specificities across the five major causes of death varied from 43% to 100% and 87% to 99%, respectively, for the InterVA/PCVA against the HCOD. CONCLUSION: Both the InterVA and PCVA compared well with the HCOD at a population level and determined the top five underlying causes of death in the rural community of Kilifi. We hope that our study, albeit small, provides new and useful data that will stimulate further definitive work on methods of interpreting VA data. PMID- 21819604 TI - Social autopsy: INDEPTH Network experiences of utility, process, practices, and challenges in investigating causes and contributors to mortality. AB - BACKGROUND: Effective implementation of child survival interventions depends on improved understanding of cultural, social, and health system factors affecting utilization of health care. Never the less, no standardized instrument exists for collecting and interpreting information on how to avert death and improve the implementation of child survival interventions. OBJECTIVE: To describe the methodology, development, and first results of a standard social autopsy tool for the collection of information to understand common barriers to health care, risky behaviors, and missed opportunities for health intervention in deceased children under 5 years old. METHODS: Under the INDEPTH Network, a social autopsy working group was formed to reach consensus around a standard social autopsy tool for neonatal and child death. The details around 434 child deaths in Iganga/Mayuge Health and Demographic Surveillance Site (HDSS) in Uganda and 40 child deaths in Dodowa HDSS in Ghana were investigated over 12 to 18 months. Interviews with the caretakers of these children elicited information on what happened before death, including signs and symptoms, contact with health services, details on treatments, and details of doctors. These social autopsies were used to assess the contributions of delays in care seeking and case management to the childhood deaths. RESULTS: At least one severe symptom had been recognized prior to death in 96% of the children in Iganga/Mayuge HDSS and in 70% in Dodowa HDSS, yet 32% and 80% of children were first treated at home, respectively. Twenty percent of children in Iganga/Mayuge HDSS and 13% of children in Dodowa HDSS were never taken for care outside the home. In both countries most went to private providers. In Iganga/Mayuge HDSS the main delays were caused by inadequate case management by the health provider, while in Dodowa HDSS the main delays were in the home. CONCLUSION: While delay at home was a main obstacle to prompt and appropriate treatment in Dodowa HDSS, there were severe challenges to prompt and adequate case management in the health system in both study sites in Ghana and Uganda. Meanwhile, caretaker awareness of danger signs needs to improve in both countries to promote early care seeking and to reduce the number of children needing referral. Social autopsy methods can improve this understanding, which can assist health planners to prioritize scarce resources appropriately. PMID- 21819605 TI - Social autopsy for maternal and child deaths: a comprehensive literature review to examine the concept and the development of the method. AB - "Social autopsy" refers to an interview process aimed at identifying social, behavioral, and health systems contributors to maternal and child deaths. It is often combined with a verbal autopsy interview to establish the biological cause of death. Two complementary purposes of social autopsy include providing population-level data to health care programmers and policymakers to utilize in developing more effective strategies for delivering maternal and child health care technologies, and increasing awareness of maternal and child death as preventable problems in order to empower communities to participate and engage health programs to increase their responsiveness and accountability.Through a comprehensive review of the literature, this paper examines the concept and development of social autopsy, focusing on the contributions of the Pathway Analysis format for child deaths and the Maternal and Perinatal Death Inquiry and Response program in India to social autopsy's success in meeting key objectives. The Pathway Analysis social autopsy format, based on the Pathway to Survival model designed to support the Integrated Management of Childhood Illness approach, was developed from 1995 to 2001 and has been utilized in studies in Asia, Africa, and Latin America. Adoption of the Pathway model has enriched the data gathered on care seeking for child illnesses and supported the development of demand- and supply-side interventions. The instrument has recently been updated to improve the assessment of neonatal deaths and is soon to be utilized in large-scale population-representative verbal/social autopsy studies in several African countries. Maternal death audit, starting with confidential inquiries into maternal deaths in Britain more than 50 years ago, is a long-accepted strategy for reducing maternal mortality. More recently, maternal social autopsy studies that supported health programming have been conducted in several developing countries. From 2005 to 2009, 10 high-mortality states in India conducted community-based maternal verbal/social autopsies with participatory data sharing with communities and health programs that resulted in the implementation of numerous data-driven maternal health interventions.Social autopsy is a powerful tool with the demonstrated ability to raise awareness, provide evidence in the form of actionable data and increase motivation at all levels to take appropriate and effective actions. Further development of the methodology along with standardized instruments and supporting tools are needed to promote its wide-scale adoption and use. PMID- 21819607 TI - A codon substitution model that incorporates the effect of the GC contents, the gene density and the density of CpG islands of human chromosomes. AB - BACKGROUND: Developing a model for codon substitutions is essential for the analyses of protein sequences. Recent studies on the mutation rates in the non coding regions have shown that CpG mutation rates in the human genome are negatively correlated to the local GC content and to the densities of functional elements. This study aimed at understanding the effect of genomic features, namely, GC content, gene density, and frequency of CpG islands, on the rates of codon substitution in human chromosomes. RESULTS: Codon substitution rates of CpG to TpG mutations, TpG to CpG mutations, and non-CpG transitions and transversions in humans were estimated by comparing the coding regions of thousands of human and chimpanzee genes and inferring their ancestral sequences by using macaque genes as the outgroup. Since the genomic features are depending on each other, partial regression coefficients of these features were obtained. CONCLUSION: The substitution rates of codons depend on gene densities of the chromosomes. Transcription-associated mutation is one such pressure. On the basis of these results, a model of codon substitutions that incorporates the effect of genomic features on codon substitution in human chromosomes was developed. PMID- 21819606 TI - Drug therapy for hereditary cancers. AB - Tumors arising in patients with hereditary cancer syndromes may have distinct drug sensitivity as compared to their sporadic counterparts. Breast and ovarian neoplasms from BRCA1 or BRCA2 mutation carriers are characterized by deficient homologous recombination (HR) of DNA, that makes them particularly sensitive to platinum compounds or inhibitors of poly (ADP-ribose) polymerase (PARP). Outstandingly durable complete responses to high dose chemotherapy have been observed in several cases of BRCA-related metastatic breast cancer (BC). Multiple lines of evidence indicate that women with BRCA1-related BC may derive less benefit from taxane-based treatment than other categories of BC patients. There is virtually no reports directly assessing drug response in hereditary colorectal cancer (CRC) patients; studies involving non-selected (i.e., both sporadic and hereditary) CRC with high-level microsatellite instability (MSI-H) suggest therapeutic advantage of irinotecan. Celecoxib has been approved for the treatment of familial adenomatous polyposis (FAP). Hereditary medullary thyroid cancers (MTC) have been shown to be highly responsive to a multitargeted tyrosine kinase inhibitor vandetanib, which exerts specific activity towards mutated RET receptor. Given the rapidly improving accessibility of DNA analysis, it is foreseen that the potential predictive value of cancer-associated germ-line mutations will be increasingly considered in the future studies. PMID- 21819608 TI - An evidence-based health workforce model for primary and community care. AB - BACKGROUND: The delivery of best practice care can markedly improve clinical outcomes in patients with chronic disease. While the provision of a skilled, multidisciplinary team is pivotal to the delivery of best practice care, the occupational or skill mix required to deliver this care is unclear; it is also uncertain whether such a team would have the capacity to adequately address the complex needs of the clinic population. This is the role of needs-based health workforce planning. The objective of this article is to describe the development of an evidence-informed, needs-based health workforce model to support the delivery of best-practice interdisciplinary chronic disease management in the primary and community care setting using diabetes as a case exemplar. DISCUSSION: Development of the workforce model was informed by a strategic review of the literature, critical appraisal of clinical practice guidelines, and a consensus elicitation technique using expert multidisciplinary clinical panels. Twenty-four distinct patient attributes that require unique clinical competencies for the management of diabetes in the primary care setting were identified. Patient attributes were grouped into four major themes and developed into a conceptual model: the Workforce Evidence-Based (WEB) planning model. The four levels of the WEB model are (1) promotion, prevention, and screening of the general or high risk population; (2) type or stage of disease; (3) complications; and (4) threats to self-care capacity. Given the number of potential combinations of attributes, the model can account for literally millions of individual patient types, each with a distinct clinical team need, which can be used to estimate the total health workforce requirement. SUMMARY: The WEB model was developed in a way that is not only reflective of the diversity in the community and clinic populations but also parsimonious and clear to present and operationalize. A key feature of the model is the classification of subpopulations, which gives attention to the particular care needs of disadvantaged groups by incorporating threats to self care capacity. The model can be used for clinical, health services, and health workforce planning. PMID- 21819609 TI - Spring cleaning as a safety risk: results of a population-based study in two consecutive years. AB - BACKGROUND: Spring cleaning is a popular tradition in Iran as well as in many other countries. The purpose of our study was to determine the pattern and compare the incidence of spring cleaning related injuries in Tehran, in the years 2007 and 2008. METHODS: In the year 2007, a household survey was performed in Tehran by random cluster sampling. The survey was repeated in May 2008 with the same clusters and starting points, but different households. The incidence of spring cleaning related injuries, the age and sex of injured person(s), the mechanism, type and cost of injuries were recorded through semi-structured interviews. The incidence rates of injuries and injuries leading to health visits (severe) according to sex and age groups were calculated. Data were analyzed using SPSS and STATA statistical softwares. RESULTS: The incidence of all and severe spring cleaning related injuries were 3.8 (3.0 - 4.8) and 1.6 (1.1-2.3) per 1000, respectively. The most common mechanisms of injuries were falls, followed by cutting and lifting heavy objects or overexertion. Falls were also the main mechanism of severe injuries. The most common injuries were open wounds, followed by superficial injuries (including contusions) and sprain and strain. Among severe injuries, the most frequent injuries were open wounds and contusions, followed by dislocations. The injuries were most common among women with an incidence of about 8.4 per 1000 in women older than 18 years of age (severe injuries: 3.4 per 1000 (2.2-5.1)). CONCLUSION: The incidence of spring cleaning related injuries is high enough to raise concern in health system authorities. It could be estimated that about 23,927 to 38,283 persons get injured during the spring cleaning in Tehran at the beginning of every Persian new year. In addition, about 8,773-18,344 of these cases are expected to be severe enough to lead to medical attention (considering 7,975,679 as the population of Tehran at the time of study). Improving awareness of families, especially young women, regarding the scope and importance of spring cleaning safety can be suggested as the first population-based strategy to decrease the incidence of these injuries. PMID- 21819610 TI - Comparison of the antibody responses to Plasmodium vivax and Plasmodium falciparum antigens in residents of Mandalay, Myanmar. AB - BACKGROUND: The aim of this study was to investigate the profile of antibodies against several antigens of Plasmodium vivax and Plasmodium falciparum in Mandalay, Myanmar. METHODS: Malaria parasites were identified by microscopic examination. To test the antibodies against P. vivax and P. falciparum in sera, an indirect immunofluorescence antibody test (IFAT) was performed using asexual blood parasite antigens. An enzyme-linked immunosorbent assay (ELISA) was performed with circumsporozoite protein (CSP), Pvs25 and Pvs28 recombinant proteins of transmission-blocking vaccine candidates for P. vivax, and liver stage specific antigen-1 and -3 (PfLSA-1, PfLSA-3) for P. falciparum. RESULTS: Fourteen patients among 112 were found to be infected with P. vivax and 26 with P. falciparum by thick smear examination. Twenty-three patients were found to be infected with P. vivax, 19 with P. falciparum and five with both by thin smear examination. Blood samples were divided into two groups: Group I consisted of patients who were positive for infection by microscopic examination, and Group II consisted of those who showed symptoms, but were negative in microscopic examination. In P. falciparum, IgG against the blood stage antigen in Group I (80.8%) was higher than in Group II (70.0%). In P. vivax, IgG against the blood stage antigen in Group I (53.8%) was higher than in Group II (41.7%). However, the positivity rate of the PvCSP VK210 subtype in Group II (40.0%) was higher than in Group I (23.1%). Similarly for the PvCSP VK247 subtype, Group II (21.7%) was higher than that for Group I (9.6%). A similar pattern was observed in the ELISA using Pvs25 and Pvs28: positive rates of Group II were higher than those for Group I. However, those differences were not shown significant in statistics. CONCLUSIONS: The positive rates for blood stage antigens of P. falciparum were higher in Group I than in Group II, but the positive rates for antigens of other stages (PfLSA-1 and -3) showed opposite results. Similar to P. falciparum, the positive rate of pre-blood stage (CSP VK210 and 247 subtype) and post-blood stage (Pvs25 and 28) antigens of P. vivax were higher in Group II than in Group I. Therefore, sero-diagnosis is not helpful to discriminate between malaria patients and symptomatic individuals during the epidemic season in Myanmar. PMID- 21819611 TI - Perceived social approval and condom use with casual partners among youth in urban Cameroon. AB - BACKGROUND: HIV prevention programs targeting youth often emphasize the role of peers, and assume that youths will model their behavior after their peers'. We challenge this view; we argue that adopting a given behavior requires social approval, and that youths do not necessarily turn to peers for such approval. This study analyzes survey data on youths in urban Cameroon to 1) identify which type of persons youths look to for social approval, and 2) establish how important social approval by these persons is for condom use among youths. METHODS: We analyzed data from three survey waves (2000, 2002, and 2003) of a reproductive health survey conducted among urban Cameroonian youth (aged 15-24). Only respondents who reported having at least one casual partner in the past year were retained for the analysis. Bivariate analyses and structural equation modeling were used to examine relationships among perceived social approval, attitudes towards condoms and condom use. RESULTS: The data show that only 3% of youths named their friends as people whose opinion they valued, while 93% mentioned family members. The perceived approval of condom use by these persons had a significant positive effect on the frequency of condom use among youths. The frequency of condom use was also affected by the respondents' attitudes toward condom use, the range of persons with whom they discussed reproductive health matters, whether they were enrolled in school, socioeconomic status, their self-efficacy, perceived severity of AIDS, risk perception and sexual risk behavior. The perceived social approval of condom use and the respondents' own condom attitudes were correlated. CONCLUSIONS: Our analysis demonstrates that perceived social approval facilitates the adoption of condom use among urban Cameroonian youth. However, youths tend to value the opinions of family members much more than the opinions of their peers. These results suggest that interventions targeting youths should not focus exclusively on peers but should also include other groups, such as parents and community leaders. PMID- 21819612 TI - Impact of severity, duration, and etiology of hyperthyroidism on bone turnover markers and bone mineral density in men. AB - BACKGROUND: Hyperthyroidism is accompanied by osteoporosis with higher incidence of fracture rates. The present work aimed to study bone status in hyperthyroidism and to elucidate the impact of severity, duration, and etiology of hyperthyroidism on biochemical markers of bone turnover and bone mineral density (BMD). METHODS: Fifty-two male patients with hyperthyroidism, 31 with Graves' disease (GD) and 21 with toxic multinodular goiter (TNG), with an age ranging from 23 to 65 years were included, together with 25 healthy euthyroid men with matched age as a control group. In addition to full clinical examination, patients and controls were subjected to measurement of BMD using dual-energy X ray absorptiometery scanning of the lower half of the left radius. Also, some biochemical markers of bone turnover were done for all patients and controls. RESULTS: Biochemical markers of bone turnover: included serum bone specific alkaline phosphatase, osteocalcin, carboxy terminal telopeptide of type l collagen also, urinary deoxypyridinoline cross-links (DXP), urinary DXP/urinary creatinine ratio and urinary calcium/urinary creatinine ratio were significantly higher in patients with GD and TNG compared to controls (P < 0.01). However, there was non-significant difference in these parameters between GD and TNG patients (P > 0.05). BMD was significantly lower in GD and TNG compared to controls, but the Z-score of BMD at the lower half of the left radius in patients with GD (-1.7 +/- 0.5 SD) was not significantly different from those with TNG ( 1.6 +/- 0.6 SD) (>0.05). There was significant positive correlation between free T3 and free T4 with biochemical markers of bone turnover, but negative correlation between TSH and those biochemical markers of bone turnover. The duration of the thyrotoxic state positively correlated with the assessed bone turnover markers, but it is negatively correlated with the Z-score of BMD in the studied hyperthyroid patients (r = -0.68, P < 0.0001). CONCLUSION: Men with hyperthyroidism have significant bone loss with higher biochemical markers of bone turnover. The severity and the duration of the thyrotoxic state are directly related to the derangement of biochemical markers of bone turnover and bone loss. PMID- 21819613 TI - Selective intraarterial radionuclide therapy with Yttrium-90 (Y-90) microspheres for unresectable primary and metastatic liver tumors. AB - BACKGROUND: The aim of this study was to evaluate the success of selective intraarterial radionuclide therapy (SIRT) with Yttrium-90 (Y-90) microspheres in liver metastases of different tumors. We also interpreted the contribution of SIRT to survival times according to responder- non responder and hepatic- extra hepatic disease. METHODS: The clinical and follow-up data of 124 patients who were referred to our department for SIRT between June 2008 [corrected] and October 2010 were evaluated retrospectively. SIRT has been applied to 78 patients who were suitable for treatment. All the patients had primary liver tumor or unresectable liver metastasis of different malignancies. The treatment was repeated at least one more time in 5 patients to the same or other lobes. Metabolic treatment response evaluated by fluorine-18 fluorodeoxyglucose (F18 FDG) positron emission tomography/computed tomography (PET/CT) in the 6th week after treatment. F18-FDG PET/CT was repeated in per six weeks periods. The response criterion had been described as at least 20% decrease of SUV value. Also in patients with neuroendocrine tumor serial Gallium-68 (Ga-68) PET/CT was used for evaluation of response. Patients were divided into 2 groups according to their treatment response. RESULTS: 68 patients received treatment for the right lobe, seven patients received treatment for the left lobe and 3 patients for both lobes. The mean treatment dose was estimated at 1.62 GBq. In the evaluation of treatment response; 43(55%) patients were responder (R) and 35 (45%) patients were non-responder (NR) in the sixth week F18-FDG PET/CT. Mean pretreatment SUVmax value of R group was 11.6 and NR group was 10.7. While only 11 (31%) out of 35 NR patients had H disease, 30 (69%) out of 43 R patients had H disease (p < 0.05). The mean overall survival time of R group was calculated as 25.63 +/- 1.52 months and NR group's 20.45 +/- 2.11 (p = 0.04). The mean overall survival time of H group was computed as 25.66 +/- 1.52 months and EH group's 20.76 +/- 1.97 (p = 0.09). CONCLUSIONS: SIRT is a useful treatment method which can contribute to the lengthening of survival times in patients with primary or metastatic unresectable liver malignancies. Also F18-FDG PET/CT is seen to be a successful imaging method in evaluating treatment response for predicting survival times in this patient group. PMID- 21819614 TI - A new adaptive testing algorithm for shortening health literacy assessments. AB - BACKGROUND: Low health literacy has a detrimental effect on health outcomes, as well as ability to use online health resources. Good health literacy assessment tools must be brief to be adopted in practice; test development from the perspective of item-response theory requires pretesting on large participant populations. Our objective was to develop a novel classification method for developing brief assessment instruments that does not require pretesting on large numbers of research participants, and that would be suitable for computerized adaptive testing. METHODS: We present a new algorithm that uses principles of measurement decision theory (MDT) and Shannon's information theory. As a demonstration, we applied it to a secondary analysis of data sets from two assessment tests: a study that measured patients' familiarity with health terms (52 participants, 60 items) and a study that assessed health numeracy (165 participants, 8 items). RESULTS: In the familiarity data set, the method correctly classified 88.5% of the subjects, and the average length of test was reduced by about 50%. In the numeracy data set, for a two-class classification scheme, 96.9% of the subjects were correctly classified with a more modest reduction in test length of 35.7%; a three-class scheme correctly classified 93.8% with a 17.7% reduction in test length. CONCLUSIONS: MDT-based approaches are a promising alternative to approaches based on item-response theory, and are well-suited for computerized adaptive testing in the health domain. PMID- 21819615 TI - Association between statin therapy and outcomes in critically ill patients: a nested cohort study. AB - BACKGROUND: The effect of statin therapy on mortality in critically ill patients is controversial, with some studies suggesting a benefit and others suggesting no benefit or even potential harm. The objective of this study was to evaluate the association between statin therapy during intensive care unit (ICU) admission and all-cause mortality in critically ill patients. METHODS: This was a nested cohort study within two randomised controlled trials conducted in a tertiary care ICU. All 763 patients who participated in the two trials were included in this study. Of these, 107 patients (14%) received statins during their ICU stay. The primary endpoint was all-cause ICU and hospital mortality. Secondary endpoints included the development of sepsis and severe sepsis during the ICU stay, the ICU length of stay, the hospital length of stay, and the duration of mechanical ventilation. Multivariate logistic regression was used to adjust for clinically and statistically relevant variables. RESULTS: Statin therapy was associated with a reduction in hospital mortality (adjusted odds ratio [aOR] = 0.60, 95% confidence interval [CI] 0.36-0.99). Statin therapy was associated with lower hospital mortality in the following groups: patients >58 years of age (aOR = 0.58, 95% CI 0.35-0.97), those with an acute physiology and chronic health evaluation (APACHE II) score >22 (aOR = 0.54, 95% CI 0.31-0.96), diabetic patients (aOR = 0.52, 95% CI 0.30-0.90), patients on vasopressor therapy (aOR = 0.53, 95% CI 0.29-0.97), those admitted with severe sepsis (aOR = 0.22, 95% CI 0.07-0.66), patients with creatinine <= 100 MUmol/L (aOR = 0.14, 95% CI 0.04-0.51), and patients with GCS <= 9 (aOR = 0.34, 95% CI 0.17-0.71). When stratified by statin dose, the mortality reduction was mainly observed with statin equipotent doses >= 40 mg of simvastatin (aOR = 0.53, 95% CI 0.28-1.00). Mortality reduction was observed with simvastatin (aOR = 0.37, 95% CI 0.17-0.81) but not with atorvastatin (aOR = 0.80, 95% CI 0.84-1.46). Statin therapy was not associated with a difference in any of the secondary outcomes. CONCLUSION: Statin therapy during ICU stay was associated with a reduction in all-cause hospital mortality. This association was especially noted in high-risk subgroups. This potential benefit needs to be validated in a randomised, controlled trial. PMID- 21819616 TI - Polymorphic variability in the 3' untranslated region (UTR) of IL12B is associated with susceptibility to severe anaemia in Kenyan children with acute Plasmodium falciparum malaria. AB - BACKGROUND: Plasmodium falciparum malaria remains a leading cause of morbidity and mortality among African children. Innate immunity provides the first line of defence against P. falciparum infections, particularly in young children that lack naturally-acquired malarial immunity, such as the population examined here. Consistent with the fact that elevated interleukin (IL)-12 is an important component of the innate immune response that provides protective immunity against malaria, we have previously shown that suppression of IL-12 in African children is associated with the development of severe malarial anaemia (SMA). Since the role of IL12B variants in conditioning susceptibility to SMA remains largely unexplored, the association between a single nucleotide polymorphism (1188A->C, rs3212227), SMA (Hb<6.0 g/dL), circulating IL-12p40/p70 levels, and longitudinal clinical outcomes in Kenyan children (n = 756) residing in a holoendemic falciparum malaria transmission area were investigated. RESULTS: Multivariate logistic regression analysis in children with acute malaria (n = 544) demonstrated that carriers of the C allele had increased susceptibility to SMA (CC: OR, 1.674; 95% CI, 1.006-2.673; P = 0.047, and AC: OR, 1.410; 95% CI, 0.953 2.087; P = 0.086) relative to wild type (AA). Although children with SMA had lower IL-12p40/p70 levels than the non-SMA group (P = 0.037), levels did not differ significantly according to genotype. Longitudinal analyses in the entire cohort (n = 756) failed to show any significant relationships between rs3212227 genotypes and either susceptibility to SMA or all-cause mortality throughout the three year follow-up. CONCLUSION: The rs3212227 is a marker of susceptibility to SMA in children with acute disease, but does not appear to mediate functional changes in IL-12 production or longitudinal outcomes during the acquisition of naturally-acquired malarial immunity. PMID- 21819617 TI - Prognostic significance of CD44s expression in resected non-small cell lung cancer. AB - BACKGROUND: CD44s is a cell adhesion molecule known to mediate cellular adhesion to the extracellular matrix, a prerequisite for tumor cell migration. CD44s plays an important role in invasion and metastasis of various cancers. In the present study, we sought to determine whether CD44s is involved in clinical outcomes of patients with resected non-small cell lung cancer (NSCLC). METHODS: Using immunohistochemical staining, we investigated CD44s protein expression using tissue array specimens from 159 patients with resected NSCLC (adenocarcinoma (AC; n=82) and squamous cell carcinoma (SCC; n=77). Additionally, the immunoreactivity of cyclooxygenase (COX)-2 was also studied. The clinicopathological implications of these molecules were analyzed statistically. RESULTS: High CD44s expression was detected more frequently in NSCLC patients with SCC (66/72; 91.7%) than in those with AC histology (P<0.001). Additionally, high CD44s expression was significant correlated with more advanced regional lymph node metastasis (P=0.021). In multivariate analysis of survival in NSCLC patients with AC histology, significant predictors were lymph node metastasis status (P<0.001), high-grade tumor differentiation (P=0.046), and high CD44s expression (P=0.014). For NSCLC patients with SCC histology, the significant predictor was a more advanced tumor stage (P=0.015). No significant association was found between CD44s and clinical outcome (P=0.311). CONCLUSIONS: High CD44s expression was a negative prognostic marker with significance in patients with resected NSCLC, particularly those with AC histology, and was independent of tumor stage. PMID- 21819618 TI - The Chinese version of the Pediatric Quality of Life InventoryTM (PedsQLTM) 3.0 Asthma Module: reliability and validity. AB - BACKGROUND: Health-related quality of life (HRQOL) has been recognized as an important health outcome measurement for pediatric patients. One of the most promising instruments in measuring pediatric HRQOL emerged in recent years is the Pediatric Quality of Life Inventory (PedsQLTM). The PedsQLTM 3.0 Asthma Module, one of the PedsQLTMdisease-specific scales, was designed to measure HRQOL dimensions specifically tailored for pediatric asthma. The present study is aimed to evaluate the psychometric properties of the Chinese version of the PedsQLTM 3.0 Asthma Module. METHODS: The PedsQLTM 3.0 Asthma Module was translated into Chinese following the PedsQLTM Measurement Model Translation Methodology. The Chinese version scale was administered to 204 children with asthma and 337 parents of children with asthma from four Triple A hospitals. The psychometric properties were then evaluated. RESULTS: The percentage of missing value for each item of the scale ranged from 0.00% to 8.31%. All child self-report subscales and parent proxy-report subscales approached or exceeded the minimum reliability standard of 0.70 for alpha coefficient, except 3 subscales of Young Child (aged 5 7) self-report (alphas ranging from 0.59 to 0.68). Test-retest reliability was satisfactory with intraclass correlation coefficients (ICCs) which exceeded the recommended standard of 0.80 in all subscales. Correlation coefficients between items and their hypothesized subscales were higher than those with other subscales. The PedsQLTM 3.0 Asthma Module distinguished between outpatients and inpatients. Patients with mild asthma reported higher scores than those with moderate/severe asthma in majority of subscales. The intercorrelations among the PedsQLTM 3.0 Asthma Module subscales and the PedsQLTM 4.0 Generic Core Scales were in medium to large effect size. The child self-report scores were consistent with the parent proxy-report scores. CONCLUSIONS: The Chinese version of the PedsQLTM 3.0 Asthma Module has acceptable psychometric properties, except the internal consistency reliability for Young Child (aged 5-7) self-report. Further studies should be focused on testing responsiveness of the Chinese version scale in longitudinal studies, evaluating the reliability and validity of the scale for the patients with severe asthma or teens independently, and assessing HRQOL of children with asthma in other areas. PMID- 21819620 TI - Decoding complex biological networks - tracing essential and modulatory parameters in complex and simplified models of the cell cycle. AB - BACKGROUND: One of the most well described cellular processes is the cell cycle, governing cell division. Mathematical models of this gene-protein network are therefore a good test case for assessing to what extent we can dissect the relationship between model parameters and system dynamics. Here we combine two strategies to enable an exploration of parameter space in relation to model output. A simplified, piecewise linear approximation of the original model is combined with a sensitivity analysis of the same system, to obtain and validate analytical expressions describing the dynamical role of different model parameters. RESULTS: We considered two different output responses to parameter perturbations. One was qualitative and described whether the system was still working, i.e. whether there were oscillations. We call parameters that correspond to such qualitative change in system response essential. The other response pattern was quantitative and measured changes in cell size, corresponding to perturbations of modulatory parameters. Analytical predictions from the simplified model concerning the impact of different parameters were compared to a sensitivity analysis of the original model, thus evaluating the predictions from the simplified model. The comparison showed that the predictions on essential and modulatory parameters were satisfactory for small perturbations, but more discrepancies were seen for larger perturbations. Furthermore, for this particular cell cycle model, we found that most parameters were either essential or modulatory. Essential parameters required large perturbations for identification, whereas modulatory parameters were more easily identified with small perturbations. Finally, we used the simplified model to make predictions on critical combinations of parameter perturbations. CONCLUSIONS: The parameter characterizations of the simplified model are in large consistent with the original model and the simplified model can give predictions on critical combinations of parameter perturbations. We believe that the distinction between essential and modulatory perturbation responses will be of use for sensitivity analysis, and in discussions of robustness and during the model simplification process. PMID- 21819619 TI - Septic arthritis of the knee: presentation of a novel irrigation-suction system tested in a cadaver study. AB - BACKGROUND: The established treatment for bacterial arthritis of the knee joint is arthroscopic surgery with irrigation and debridement. The aim of this article is to summarize the relevant data in treating bacterial arthritis of the knee joint, and based on these findings to present a novel irrigation suction system, tested in a cadaver study, as an additional tool in the postoperative treatment phase of arthroscopic surgery for knee joint infections. METHOD: The novel automated irrigation-suction system presented here was compared to conventional continuous suction irrigation in a total of six knee joints. All knee joints were filled with 80 ml methylene blue stain and rinsed by two different methods. Fluid specimens were taken after ten and twenty minutes to be compared by photometric extinction measurement at a wave length of 500 nm. RESULTS: After ten minutes, the average extinction was e(1C) = 0.8 for the continuous suction irrigation and e(1N) = 0.4 for the novel irrigation-suction system. After twenty minutes, we recorded an average extinction of e(2C) = 0.3 for continuous suction irrigation and e(2N) = 0.001 for the novel irrigation-suction system. The students t-test revealed superior results after ten and twenty minutes of washing out the knee joints with a p < 0.001 for the novel irrigation-suction system. CONCLUSION: A novel irrigation-suction system may be an effective tool for postoperative knee joint irrigation in arthroscopic therapy for bacterial arthritis of the knee. Further animal studies are needed to verify the effects in vivo. PMID- 21819621 TI - Analysis of MEFV exon methylation and expression patterns in familial Mediterranean fever. AB - BACKGROUND: MEFV mutations and decreased expression level of the gene are related to FMF pathology. DNA methylation at CpG islands is a well-known mechanism for transcriptional silencing. MEFV has a CpG island, spanning a part of the first intron and the whole of the second exon of the gene covering 998 bp region. Here, we tested the hypothesis that the MEFV transcript level in FMF patients correlates with its methylation level, and methylation, by allowing transcription silencing, has a role in FMF ethiopathogenesis. METHODS: The study group was composed of pediatric FMF patients (N = 51) and age-gender matched healthy controls (N = 21). The relative expression level of MEFV was assessed via quantitative real-time PCR (qRT-PCR) and bisulfite sequencing (BS) was performed to analyse the methylation level quantitatively. RESULTS: MEFV expression in FMF patients were decreased compared to healthy controls (P = 0.031). Methylation level of exon 2 of MEFV was found to be slightly higher in FMF patients compared to healthy controls (76% versus 74%) (P = 0.049). The expression level of the MEFV was negatively correlated with the methylation level of the CpG island in both FMF and healthy controls groups (cor = -0.29, P = 0.041) but more so in the FMF only group (cor = -0.36, P = 0.035). CONCLUSIONS: In this study, the relation between reduced MEFV expression level and FMF was confirmed. Observed slight increase in methylation in FMF patients, and correlation of methylation with expression might be indicative of its role in FMF, however a larger dataset is needed to confirm our preliminary findings. PMID- 21819623 TI - Children's hospitalizations with a mood disorder diagnosis in general hospitals in the united states 2000-2006. AB - BACKGROUND: Mood disorders including depression and bipolar disorders are a major cause of morbidity in childhood and adolescence, and hospitalizations for mood disorders are the leading diagnosis for all hospitalizations in general hospitals for children age 13 to 17. We describe characteristics of these hospitalizations in the U.S. focusing on duration of stay, charges, and geographic variation. METHODS: The Kids' Inpatient Database was analyzed to calculate hospitalization rates for 2000, 2003, and 2006. For each year, information was available for over 2 million hospitalizations, representing 6.3 to 6.5 million hospital stays annually in acute care, non-psychiatric hospitals. RESULTS: The rate of pediatric hospitalizations with a principal diagnosis of a mood disorder was 12.4/10,000 in 2000, 13.0 in 2003, and 12.1 in 2006. In the same period, the incidence of hospitalizations for depressive disorders decreased from 9.1 to 6.4/10,000 children while the incidence of hospitalizations for bipolar disorders increased from 3.3 to 5.7/10,000 children. The mean length of stay increased from 7.1 to 7.7 days, while inflation-adjusted hospital charges increased from $10,600 in 2000, to $13,700 in 2003, to $16,300 in 2006. The proportion of mood disorder stays paid by government increased from 35.3% to 45.2%. The Western region experienced the lowest rates (9.9/10,000, 11.6 and 10.2 in 2000, 2003 and 2006) while the Midwest had the highest rates (26.4, 27.6, and 25.4). CONCLUSIONS: Mood disorders are a major reason for hospitalization during development, especially in adolescence. Mood disorder hospitalizations remained relatively constant from 2000-2006, but diagnoses of depressive disorders decreased while diagnoses of bipolar disorders increased. Hospitalization rates vary widely by region of the country. PMID- 21819622 TI - Ki67 proliferation in core biopsies versus surgical samples - a model for neo adjuvant breast cancer studies. AB - BACKGROUND: An increasing number of neo-adjuvant breast cancer studies are being conducted and a novel model for tumor biological studies, the "window-of opportunity" model, has revealed several advantages. Change in tumor cell proliferation, estimated by Ki67-expression in pre-therapeutic core biopsies versus post-therapeutic surgical samples is often the primary end-point. The aim of the present study was to investigate potential differences in proliferation scores between core biopsies and surgical samples when patients have not received any intervening anti-cancer treatment. Also, a lack of consensus concerning Ki67 assessment may raise problems in the comparison of neo-adjuvant studies. Thus, the secondary aim was to present a novel model for Ki67 assessment. METHODS: Fifty consecutive breast cancer cases with both a core biopsy and a surgical sample available, without intervening neo-adjuvant therapy, were collected and tumor proliferation (Ki67, MIB1 antibody) was assessed immunohistochemically. A theoretical model for the assessment of Ki67 was constructed based on sequential testing of the null hypothesis 20% Ki67-positive cells versus the two-sided alternative more or less than 20% positive cells.. RESULTS: Assessment of Ki67 in 200 tumor cells showed an absolute average proliferation difference of 3.9% between core biopsies and surgical samples (p = 0.046, paired t-test) with the core biopsies being the more proliferative sample type. A corresponding analysis on the log-scale showed the average relative decrease from the biopsy to the surgical specimen to be 19% (p = 0.063, paired t-test on the log-scale). The difference was significant when using the more robust Wilcoxon matched-pairs signed-ranks test (p = 0.029). After dichotomization at 20%, 12 of the 50 sample pairs had discrepant proliferation status, 10 showed high Ki67 in the core biopsy compared to two in the surgical specimen (p = 0.039, McNemar's test). None of the corresponding results for 1000 tumor cells were significant - average absolute difference 2.2% and geometric mean of the ratios 0.85 (p = 0.19 and p = 0.18, respectively, paired t-tests, p = 0.057, Wilcoxon's test) and an equal number of discordant cases after dichotomization. Comparing proliferation values for the initial 200 versus the final 800 cancer cells showed significant absolute differences for both core biopsies and surgical samples 5.3% and 3.2%, respectively (p < 0.0001, paired t-test). CONCLUSIONS: A significant difference between core biopsy and surgical sample proliferation values was observed despite no intervening therapy. Future neo-adjuvant breast cancer studies may have to take this into consideration. PMID- 21819624 TI - Adult attention deficit hyperactivity disorder is associated with asthma. AB - BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is increasingly recognized as a common disorder not only in children, but also in the adult population. Similarly, asthma also has a substantial prevalence among adults. Previous studies concerning a potential relationship between ADHD and asthma have not presented consistent results. METHODS: A cross-sectional study of 594 adult patients diagnosed with ADHD, compared with 719 persons from the general population. Information was collected between 1997 and 2005 using auto questionnaires rating past and present symptoms of ADHD, co-morbid conditions, including asthma, and work status. RESULTS: The prevalence of asthma was significantly higher in the ADHD patient group compared to the controls, 24.4% vs. 11.3% respectively (OR = 2.54, 95% CI 1.89-3.44), and controls with asthma scored higher on ratings of both past and present symptoms of ADHD. Female ADHD patients had a significantly higher prevalence of asthma compared to male ADHD patients (30.9% vs. 18.2%, OR = 2.01, CI 1.36-2.95), but in controls a slight female preponderance was not statistically significant. In both ADHD patients and controls, having asthma was associated with an increased prevalence of symptoms of mood- and anxiety disorders. CONCLUSIONS: The present findings point to a co morbidity of ADHD and asthma, and these patients may represent a clinical and biological subgroup of adult patients with ADHD. PMID- 21819625 TI - Transcription analysis on response of swine lung to H1N1 swine influenza virus. AB - BACKGROUND: As a mild, highly contagious, respiratory disease, swine influenza always damages the innate immune systems, and increases susceptibility to secondary infections which results in considerable morbidity and mortality in pigs. Nevertheless, the systematical host response of pigs to swine influenza virus infection remains largely unknown. To explore it, a time-course gene expression profiling was performed for comprehensive analysis of the global host response induced by H1N1 swine influenza virus in pigs. RESULTS: At the early stage of H1N1 swine virus infection, pigs were suffering mild respiratory symptoms and pathological changes. A total of 268 porcine genes showing differential expression (DE) after inoculation were identified to compare with the controls on day 3 post infection (PID) (Fold change >= 2, p < 0.05). The DE genes were involved in many vital functional classes, mainly including signal transduction, immune response, inflammatory response, cell adhesion and cell-cell signalling. Noticeably, the genes associated with immune and inflammatory response showed highly overexpressed. Through the pathway analysis, the significant pathways mainly concerned with Cell adhesion molecules, Cytokine cytokine receptor interaction, Toll-like receptor signaling pathway and MAPK signaling pathway, suggesting that the host took different strategies to activate these pathways so as to prevent virus infections at the early stage. However, on PID 7, the predominant function classes of DE genes included signal transduction, metabolism, transcription, development and transport. Furthermore, the most significant pathways switched to PPAR signaling pathway and complement and coagulation cascades, showing that the host might start to repair excessive tissue damage by anti-inflammatory functions. These results on PID 7 demonstrated beneficial turnover for host to prevent excessive inflammatory damage and recover the normal state by activating these clusters of genes. CONCLUSIONS: This study shows how the target organ responds to H1N1 swine influenza virus infection in pigs. The observed gene expression profile could help to screen the potential host agents for reducing the prevalence of swine influenza virus and further understand the molecular pathogenesis associated with H1N1 infection in pigs. PMID- 21819626 TI - Assessment and histological analysis of the IPRL technique for sequential in situ liver biopsy. AB - BACKGROUND: The isolated perfused rat liver (IPRL) is a technique used in a wide range of liver studies. Typically livers are assessed at treatment end point. Techniques have been described to biopsy liver in the live rat and post hepatectomy. RESULTS: This paper describes a technique for obtaining two full and one partial lobe biopsies from the liver in situ during an IPRL experiment. Our approach of retaining the liver in situ assists in minimising liver capsule damage, and consequent leakage of perfusate, maintains the normal anatomical position of the liver during perfusion and helps to keep the liver warm and moist. Histological results from sequential lobe biopsies in control perfusions show that cytoplasmic vacuolation of hepatocytes is a sign of liver deterioration, and when it occurs it commences as a diffuse pattern which tends to develop a circumscribed, centrilobular pattern as perfusion progresses. CONCLUSIONS: Liver lobe biopsies obtained using this method can be used to study temporal effects of drug treatments and are suitable for light and electron microscopy, and biochemical analyses. PMID- 21819627 TI - Disparities exist between National food group recommendations and the dietary intakes of women. AB - BACKGROUND: Preconception and pregnancy dietary intakes can influence the health of future generations. In this study we compared the food intakes of reproductive aged women by pregnancy status, to current Australian recommendations. METHODS: Data are from the Australian Longitudinal Study on Women's Health, younger cohort aged 25-30 years in 2003, with self-reported status as pregnant (n = 606), trying to conceive (n = 454), given birth in the last 12 months (n = 829) or other (n = 5597). Diet was assessed using a validated 74-item food frequency questionnaire. Food group servings and nutrient intakes were compared to the Australian Guide to Healthy Eating (AGHE) and Australian Nutrient Reference Values (NRVs). RESULTS: No women met all AGHE food group recommendations. Highest adherence rates [mean (95% CI) servings/day] were for meat [85%, 1.9(1.8-1.9)], fruit [44%, 2.1(2.1 2.2)] and dairy [35%, 1.8(1.8-1.9)], with < 14% meeting remaining recommendations. Women who achieved NRVs (folate, iron, calcium, zinc, fibre) for pregnancy, breastfeeding and adult life stages were 1.5%, 3.3% and 13.7%, respectively. Compared to AGHE, women consumed more servings of fruit (4.9 vs 4.0;P = 0.034) and dairy (3.4 vs 2.0;P = 0.006) to achieve pregnancy NRVs; more dairy (2.9 vs 2.0;P = 0.001), less fruit (3.9 vs 5.0;P < .001) and vegetables (3.4 vs 7.0;P < .001) to achieve breastfeeding NRVs; more fruit (3.6 vs 3.0;P < .001), dairy (2.5 vs 2.0;P < .001), meat (1.8 vs 1.5;P = 0.015), less vegetables (3.6 vs 5.0;P < .001) to achieve adult NRVs. CONCLUSIONS: The AGHE does not align with contemporary diets of Australian women or enable them to meet all NRVs. Current tools to guide food consumption by women during pregnancy require revision. PMID- 21819628 TI - The effects of stem length and core placement on shRNA activity. AB - BACKGROUND: Expressed short hairpin RNAs (shRNA) used in mammalian RNA interference (RNAi) are often designed around a specific short interfering RNA (siRNA) core. Whilst there are algorithms to aid siRNA design, hairpin-specific characteristics such as stem-length and siRNA core placement within the stem are not well defined. RESULTS: Using more than 91 hairpins designed against HIV-1 Tat and Vpu, we investigated the influence of both of these factors on suppressive activity, and found that stem length does not correspond with predictable changes in suppressive activity. We also detected multiple processed products for all stem lengths tested. However, the entire length of the hairpin stem was not equally processed into active products. As such, the placement of the siRNA core at the base terminus was critical for activity. CONCLUSION: We conclude that there is no fixed correlation between stem length and suppressive activity. Instead, core selection and placement likely have a greater influence on the effectiveness of shRNA-based silencing. PMID- 21819629 TI - C-Jun N-terminal kinase controls TDP-43 accumulation in stress granules induced by oxidative stress. AB - BACKGROUND: TDP-43 proteinopathies are characterized by loss of nuclear TDP-43 expression and formation of C-terminal TDP-43 fragmentation and accumulation in the cytoplasm. Recent studies have shown that TDP-43 can accumulate in RNA stress granules (SGs) in response to cell stresses and this could be associated with subsequent formation of TDP-43 ubiquinated protein aggregates. However, the initial mechanisms controlling endogenous TDP-43 accumulation in SGs during chronic disease are not understood. In this study we investigated the mechanism of TDP-43 processing and accumulation in SGs in SH-SY5Y neuronal-like cells exposed to chronic oxidative stress. Cell cultures were treated overnight with the mitochondrial inhibitor paraquat and examined for TDP-43 and SG processing. RESULTS: We found that mild stress induced by paraquat led to formation of TDP-43 and HuR-positive SGs, a proportion of which were ubiquitinated. The co localization of TDP-43 with SGs could be fully prevented by inhibition of c-Jun N terminal kinase (JNK). JNK inhibition did not prevent formation of HuR-positive SGs and did not prevent diffuse TDP-43 accumulation in the cytosol. In contrast, ERK or p38 inhibition prevented formation of both TDP-43 and HuR-positive SGs. JNK inhibition also inhibited TDP-43 SG localization in cells acutely treated with sodium arsenite and reduced the number of aggregates per cell in cultures transfected with C-terminal TDP-43 162-414 and 219-414 constructs. CONCLUSIONS: Our studies are the first to demonstrate a critical role for kinase control of TDP-43 accumulation in SGs and may have important implications for development of treatments for FTD and ALS, targeting cell signal pathway control of TDP-43 aggregation. PMID- 21819631 TI - MiR-106b promotes cell proliferation via targeting RB in laryngeal carcinoma. AB - MiR-106b is frequently up-regulated in various types of human cancer including laryngeal carcinoma. However the underlying mechanism of miR-106b involved in laryngeal carcinoma remains elusive. Here we showed that reduction of miR-106b induced cell cycle G0/G1 arrest by targeting tumor suppressor RB in human laryngeal carcinoma cells. Further, Introducing RB cDNA without 3'UTR abrogated miR-106b-induced cell proliferation. Finally, there was an inverse relationship between RB and miR-106b expression in laryngeal carcinoma tissues. To our knowledge, these data indicate for the first time that miR-106b directly regulate cell cycle by targeting RB in laryngeal carcinoma and that miR-106b could be potential therapeutic approaches for laryngeal carcinoma. PMID- 21819630 TI - Pure seminoma: a review and update. AB - Pure seminoma is a rare pathology of the young adult, often discovered in the early stages. Its prognosis is generally excellent and many therapeutic options are available, especially in stage I tumors. High cure rates can be achieved in several ways: standard treatment with radiotherapy is challenged by surveillance and chemotherapy. Toxicity issues and the patients' preferences should be considered when management decisions are made. This paper describes firstly the management of primary seminoma and its nodal involvement and, secondly, the various therapeutic options according to stage. PMID- 21819632 TI - Breaking up is hard to do: the economic impact of provisional funding contingent upon evidence development. AB - Funding contingent upon evidence development (FED) has recently been the subject of some considerable debate in the literature but relatively little has been made of its economic impact. We argue that FED has the potential to shorten the lag between innovation and access but may also (i) crowd-out more valuable interventions in situations in which there is a fixed dedicated budget; or (ii) lead to a de facto increase in the funding threshold and increased expenditure growth in situations in which the programme budget is open-ended. Although FED would typically entail periodic review of provisional or interim listings, it may prove difficult to withdraw funding even at cost/QALY ratios well in excess of current listing thresholds. Further consideration of the design and implementation of FED processes is therefore required to ensure that its introduction yields net benefits over existing processes. PMID- 21819633 TI - Pharmaceutical lobbying under postcommunism: universal or country-specific methods of securing state drug reimbursement in Poland? AB - This paper aims to fill in the gap in research on the effect of pharmaceutical lobbying on drug reimbursement policy, particularly in Poland, a post-communist country. To this end, we conducted in-depth, semi-structured, anonymous, elite interviews in Poland, supplemented by a review of legislation, policy documents, official reports and press articles, as well as observations. Overall, 109 representatives of stakeholders involved in reimbursement policy were interviewed. We identified two key lobbying methods: informal persuasion and third-party endorsements. These methods are coupled with two supplementary ones: lobbying through parliament and ministries, as well as diplomatic pressure. Pharmaceutical lobbying methods in Poland clearly resemble those used in other European countries. What is notable about the Polish case is extensive reliance on informal lobbying and diplomatic pressure. PMID- 21819634 TI - Social preferences for the inclusion of indirect benefits in the evaluation of publicly funded health services: results from an Australian survey. AB - The inclusion of both monetary and non-monetary indirect benefits in economic evaluations of public health programmes and services can have significant distributive effects between patient groups. As a result, some patients may be advantaged and others disadvantaged for reasons not directly related to health outcomes or (direct) treatment costs. In pluralistic democracies, there is a case for consulting the community on the fairness of policies that have such distributive implications. This paper reports the results of two pilot studies aimed at uncovering the preferences of the Australian public for the inclusion of indirect benefits in the evaluation of services for its national health scheme, Medicare. The initial survey found some support for taking account of non monetary indirect benefits - for example, the social contribution made by parents of young children and carers of elderly relatives. By contrast, there was little support for giving high taxpayers priority access to general Medicare services, to life-saving organ transplants, or to very costly drugs, despite the indirect social benefits of doing so. However, such support increased significantly in the follow-up study when the outcomes were characterised as certain, identifiable and health related, and the opportunity costs of failing to take account of indirect benefits were made very clear. The follow-up survey provided evidence of public scepticism about the willingness or ability of government to use additional tax receipts for socially beneficial purposes, and/or a preference for programmes and services that focus on health rather than welfare more generally. PMID- 21819635 TI - Anaemia in Ugandan preschool-aged children: the relative contribution of intestinal parasites and malaria. AB - Anaemia is a severe public health issue among African preschool-aged children, yet little effective progress has been made towards its amelioration, in part due to difficulties in unravelling its complex, multifactorial aetiology. To determine the current anaemia situation and assess the relative contribution of malaria, intestinal schistosomiasis and infection with soil-transmitted helminths, two separate cross-sectional epidemiological surveys were carried out in Uganda including 573 and 455 preschool-aged children (<=6 years) living along the shores of Lake Albert and on the islands in Lake Victoria, respectively. Anaemia was found to be a severe public health problem in Lake Albert, affecting 68.9% of children (ninety-five percent confidence intervals (95% CI) 64.9-72.7%), a statistically significant higher prevalence relative to the 27.3% detected in Lake Victoria (95% CI: 23.3-31.7%). After multivariate analysis (controlling for sex and age of the child), the only factor found to be significantly associated with increased odds of anaemia in both lake systems was malaria (Lake Albert, odds ratio (OR)=2.1, 95% CI: 1.4-3.2; Lake Victoria, OR=1.9, 95% CI: 1.2-2.9). Thus intervention strategies primarily focusing on very young children and combating malaria appear to represent the most appropriate use of human and financial resources for the prevention of anaemia in this age group and area. Looking to the future, these activities could be further emphasised within the National Child Health Days(PLUS) agenda. PMID- 21819636 TI - Seroprevalence of Toxoplasma gondii and Neospora caninum in slaughtered pigs in the Czech Republic. AB - In the Czech Republic, sera from 551 clinically healthy adult slaughtered pigs (females, 6-8 months old) were collected during the first half of June in 2010. Sera were tested for Toxoplasma gondii-specific IgG antibodies by an enzyme linked immunosorbent assay; samples with more than 50% S/P were considered as positive. The same samples were also analysed for Neospora caninum antibodies using a commercial competitive-inhibition enzyme-linked immunosorbent assay; samples with more than 30% inhibition were considered as positive. Antibodies against T. gondii were found in 198 pigs (36%) in all districts with prevalences ranging from 18% to 75%. Antibodies against N. caninum were found in 16 pigs (3%); positive animals were found in 4 districts with prevalences ranging from 1% to 20%. Indication of mixed infections (concurrent presence of both N. caninum and T. gondii antibodies) was found in 8 (1.5%) pigs. The results of our study indicate that pigs in the Czech Republic have a relatively high seroprevalence for T. gondii, while they have only a low seroprevalence for N. caninum. Therefore, natural infection with T. gondii seems to be very common in Czech pigs. It is the first evidence of N. caninum antibodies in pigs in the Czech Republic. These results complete data about N. caninum infection in pigs in Europe. PMID- 21819637 TI - The loading of labelled antibody-engineered nanoparticles with Indinavir increases its in vitro efficacy against Cryptosporidium parvum. AB - There is much evidence to indicate the ability of Indinavir (IND) to reduce Cryptosporidium parvum infection in both in vitro and in vivo models. However, there are limitations to the administration of IND as such, due to its renal toxicity and the high rate of metabolism and degradation. We aimed to encapsulate IND in biodegradable poly (D,L-lactide-co-glycolide) nanoparticles (Np) and to engineer their surface by conjugation with an anti-Cryptosporidium IgG polyclonal antibody (Ab). Tetramethylrhodamine-labelled Np were loaded with IND and modified by conjugation with an Ab. The IND-loaded modified Np (Ab-TMR-IND-Np) did not show any change, as demonstrated by chemical analysis studies. Simultaneous addition of 50MUM Ab-TMR-IND-Np and excysted oocysts to the cell culture resulted in complete inhibition of the infection. In C. parvum-infected cells, the extent to which the infection decreased depended on the duration of treatment with the Ab-TMR-IND-Np. The antibody-engineered Np loaded with IND were able to target C. parvum in infected cells and therefore might represent a novel therapeutic strategy against Cryptosporidium sp. infection. Moreover, the use of Np as an IND delivery device, allows the development of a more appropriate dose formulation thereby reducing the IND side effects. PMID- 21819638 TI - Increased metacyclogenesis of antimony-resistant Leishmania donovani clinical lines. AB - Mathematical models predict that the future of epidemics of drug-resistant pathogens depends in part on the competitive fitness of drug-resistant strains. Considering metacyclogenesis (differentiation process essential for infectivity) as a major contributor to the fitness of Leishmania donovani, we tested its relationship with pentavalent antimony (SbV) resistance in clinical lines. Different methods for the assessment of metacyclogenesis were cross-validated: gene expression profiling (META1 and SHERP), morphometry (microscopy and FACS), in vitro infectivity to macrophages and resistance to complement lysis. This was done on a model constituted by 2 pairs of reference strains cloned from a SbV resistant and -sensitive isolate. We selected the most adequate parameter and extended the analysis of metacyclogenesis diversity to a sample of 20 clinical lines with different in vitro susceptibility to the drug. The capacity of metacyclogenesis, as measured by the complement lysis test, was shown to be significantly higher in SbV-resistant clinical lines of L. donovani than in SbV sensitive lines. Together with other lines of evidence, it is concluded that L. donovani constitutes a unique example and model of drug-resistant pathogens with traits of increased fitness. These findings raise a fundamental question about the potential risks of selecting more virulent pathogens through massive chemotherapeutic interventions. PMID- 21819639 TI - Sir2-Related Protein 1 from Leishmania amazonensis is a glycosylated NAD+ dependent deacetylase. AB - Sirtuin proteins form a family of NAD+-dependent protein deacetylases that are considered potential drug targets against parasites. Here, we present the first characterization of a sirtuin orthologue from Leishmania amazonensis, an aetiological agent of American tegumentary leishmaniasis that has been the subject of many studies focused in the development of therapeutic approaches. The protein has high sequence identity with other Kinetoplastid Silent information regulator 2 Related Protein 1 (Sir2RP1) and was named LaSir2RP1. The gene exists as a single copy, encoding a monomeric protein (LaSir2RP1) of approximately 41 kDa that has NAD+-dependent deacetylase activity. LaSir2RP1 was immunodetected in total protein extracts, in cytoplasmic granules, and in the secreted material of both promastigotes and lesion-derived amastigotes. Analysis of both lectin affinity purified promastigote and amastigote extracts revealed the presence of a major enriched protein of approximately 66 kDa that was recognized by an anti LaSir2RP1 serum, suggesting that a parasite sirtuin could be glycosylated in vivo. PMID- 21819641 TI - Thermodynamics of cercarial survival and metabolism in a changing climate. AB - Cercariae are non-feeding free-living stages in the life cycles of trematodes, highly influenced by temperature. Their life span is brief, limited by the depletion of a non-renewable glycogen store. Warmer temperatures under the influence of climate change may promote the transmission of parasites and therefore understanding their thermobiology forms an important step in discerning the future dynamics of parasite populations. An empirical relationship exists between cercarial mean expected life span and the half-life of the population (t0.5) and therefore t0.5 is a good indicator of glycogen utilization. In this study experimental data on the effects of temperature on cercarial survival is compiled from the scientific literature and evaluated in terms of metabolism using Q10 and Arrhenius activation energy (E* or MU), common measures of temperature-mediated reaction rates. Cercariae have a variable response to temperature, which does not appear to be influenced by their life-history attributes or size. There were little differences in Q10 and E* values between most temperature ranges. In almost half the studies examined (7 of 16) cercariae demonstrated a discrete zone of thermostability over a range equivalent to typical individual mean summer temperatures. Distinct intraspecific differences in temperature responses between 3 laboratory strains of Schistosoma mansoni and 2 natural strains of Echinoparyphium recurvatum sensu stricto were apparent. The importance of these results for cercarial biology under global climate change is discussed. PMID- 21819640 TI - Rates and intensity of re-infection with human helminths after treatment and the influence of individual, household, and environmental factors in a Brazilian community. AB - This study quantifies the rate and intensity of re-infection with human hookworm and Schistosoma mansoni infection 12 months following successful treatment, and investigates the influence of socio-economic, geographical and environmental factors. A longitudinal study of 642 individuals aged over 5 years was conducted in Minas Gerais State, Brazil from June 2004 to March 2006. Risk factors were assessed using interval censored regression for the rate and negative binomial regression for intensity. The crude rate and intensity of hookworm re-infection was 0.21 per year (95% confidence interval (CI) 0.15-0.29) and 70.9 epg (95% CI 47.2-106.6). For S. mansoni the rate was 0.06 per year (95% CI 0.03-0.10) and intensity 6.51 epg (95% CI 3.82-11.11). Rate and intensity of re-infection with hookworm were highest among males and positively associated with previous infection status, absence of a toilet and house structure. Rate and intensity of S. mansoni re-infection were associated with previous infection status as well as geographical, environmental and socio-economic factors. The implications of findings for the design of anti-helminth vaccine trials are discussed. PMID- 21819642 TI - Variation in growth and drug susceptibility among Giardia duodenalis assemblages A, B and E in axenic in vitro culture and in the gerbil model. AB - This study investigated the molecular and biological variation among different Giardia duodenalis assemblages. In vitro growth and susceptibility to albendazole, fenbendazole, flubendazole, metronidazole, tinidazole and furazolidone was studied for laboratory (AI: WB, AII: G1 and B: GS/M-83-H7) and 6 field isolates of assemblage subtype AI, AII, B and EIII. Additionally, isolates of the 3 assemblages were evaluated in the gerbil upon 3-day oral treatment with albendazole (6 mg/kg), flubendazole (5 mg/kg) and metronidazole (20 mg/kg). Assemblage AI grew significantly faster than all other assemblage subtypes, which showed comparable generation times. The assemblage A laboratory strains displayed altered in vitro drug susceptibilities compared to their matching AI or AII field isolate. No variation in drug susceptibility was observed between field isolates of assemblages A and E. However, assemblage A laboratory strains were more susceptible to the benzimidazoles and less susceptible to the nitro-imidazoles and furazolidone than the assemblage B laboratory strain. In the gerbil, no markedly different drug susceptibilities were observed. In conclusion, the Giardia assemblage subtype can be associated with differences in growth characteristics rather than in drug susceptibility. PMID- 21819643 TI - A qualitative study exploring why people do not participate in cardiac rehabilitation and coronary heart disease self-help groups, and their rehabilitation experience without these resources. AB - BACKGROUND: Secondary prevention and self-management of coronary heart disease (CHD) are of major importance to people who survive myocardial infarction (MI). This can be facilitated by cardiac rehabilitation (CR; the formal health service programme) and informal CHD self-help groups. Non-participation is an important issue, yet it is poorly understood. Rehabilitation difficulties and prevention challenges have been identified among people following MI, but the particular experience and perspective of CR and CHD group non-participants are largely unknown. AIM: The study aimed to understand non-participation in CR and CHD self help groups from the perspectives of the non-participants and to provide insight into their experience and that of their 'significant others' in rehabilitating in the absence of these resources. METHODS: In-depth interviews were conducted with 27 people who had not participated in either hospital-based CR or a CHD group, 6 14 months post-MI, and 17 'significant others' in Lothian, Scotland. FINDINGS: Factors influencing non-participation fell into three broad themes 'No need/no point', 'Not worth it', and 'Not possible'. In the latter two categories, non participation in these resources was often considered a 'missed opportunity' and needs had remained unmet. Shifts between categories could occur over time. Non participation was linked to rehabilitation difficulties for some people and family members. Recommendations to enhance post-MI support are made. PMID- 21819644 TI - Political or dental power in private and public service provision: a study of municipal expenditures for child dental care. AB - Both professionals and politicians may affect expenditures for highly professional services provided in the public and private sector. We investigated Danish publicly financed child dental care with a special focus on the influence of politicians and dentists on the expenditure level. By studying spatial patterns in expenditure levels across municipalities, we are able to test the influences of these two main actors and the networks through which learning is achieved. Four hypotheses on the existence of different spatial spillover effects are tested. The empirical analysis is based on annual data from 1996 to 2001 for 226 Danish municipalities, thus allowing for the control for heterogeneity between municipalities and for intra-municipal correlations across time. The results point to differences in expenditures between municipalities with privately and publicly produced dental care. Furthermore, dentists appear to be the most important actors for the spatial spillover effects, and these effects are especially strong for municipalities situated in the same county that use private dental clinics. There is no evidence of political spatial spillover effects between municipalities. PMID- 21819645 TI - Protease inhibitor-containing antiretroviral treatment and tuberculosis: can rifabutin fill the breach? AB - OBJECTIVE: To assess how to best manage co-administration of rifabutin (RFB) and human immunodeficiency virus 1 (HIV-1) protease inhibitor (PI) containing antiretroviral treatment (ART). Recommended for initial anti-tuberculosis treatment, rifampicin (RMP) lowers PI concentrations below therapeutic levels, posing significant challenges for ART. As RFB has little effect on PI concentrations, it could be an alternative to RMP. METHODS: A review of the scientific literature on the safety and efficacy of RFB for adult tuberculosis (TB) treatment was conducted, focusing on ART-TB co-therapy. A cost comparison was performed between treatment regimens, and estimates of the burden of TB disease in patients on ART were used to model RFB demand in low- and middle income countries (LMICs). RESULTS: Eleven clinical studies were identified, comprising 1543 TB patients treated with RFB; 980 (64%) were living with HIV. RFB was as safe and effective as RMP, including in 313 patients receiving co administered ART (unboosted PIs included indinavir, nelfinavir or saquinavir; a minority received ritonavir [RTV] boosted amprenavir or saquinavir). The total cost for 6 months of all HIV and TB treatment containing RTV-boosted lopinavir (LPV) and RFB is US$410, compared to US$455 if RMP is used with LPV super-boosted with RTV. Our model suggests that demand for RFB in LMICs could be between 10,000 and 18,000 courses by 2012. CONCLUSION: RFB is effective and safe in combination with the PIs studied, cost-saving for co-therapy with currently recommended boosted PIs, and may have a pivotal role in the roll-out of ART. Further research into a daily dose of RFB to simplify dosing regimens and developing fixed-dose combinations can enhance the public sector roll-out of ART. PMID- 21819646 TI - Meeting the challenges of paediatric cochlear implantation. PMID- 21819647 TI - Identification of the cellular location of internalized Escherichia coli O157:H7 in mung bean, Vigna radiata, by immunocytochemical techniques. AB - Escherichia coli O157:H7 has been associated with numerous outbreaks involving fresh produce. Previous studies have shown that bacteria can be internalized within plant tissue and that this can be a source of protection from antimicrobial chemicals and environmental conditions. However, the types of tissue and cellular locations the bacteria occupy in the plant following internalization have not been addressed. In this study, immunocytochemical techniques were used to localize internalized E. coli O157:H7 expressing green fluorescent protein in germinated mung bean (Vigna radiata) hypocotyl tissue following contamination of intact seeds. An average of 13 bacteria per mm(3) were localized within the sampled tissue. The bacteria were found to be associated with every major tissue and corresponding cell type (cortex, phloem, xylem, epidermis, and pith). The cortical cells located on the outside of the vascular bundles contained the majority of the internalized bacteria (61%). In addition, the bacteria were localized primarily to the spaces between the cells (apoplast) and not within the cells. Growth experiments were also performed and demonstrated that mung bean plants could support the replication of bacteria to high levels (10(7) CFU per plant) following seed contamination and that these levels could be sustained over a 12-day period. Therefore, E. coli O157:H7 can be internalized in many different plant tissue types after a brief seed contamination event, and the bacteria are able to grow and persist within the plant. PMID- 21819649 TI - Microbiological quality of fresh-squeezed orange juice and efficacy of fruit surface decontamination methods in microbiological quality. AB - The aims of this study were to evaluate the microbiological quality of fresh squeezed orange juice and to reduce the microbial population by using various chemical and physical fruit surface decontamination methods. In the first step of the study, polyethylene-bottled fresh-squeezed orange juice samples purchased in Ankara, Turkey, were examined. The average aerobic plate count (APC) and coliform count (CC) varied within the ranges of 3 to 5 log CFU/ml and 1 to 4 log MPN/ml, respectively. Ten of 60 samples contained various levels of Escherichia coli, while Salmonella spp. and E. coli O157:H7 were not detected in any of the samples. Comparing the efficacy of various fruit surface decontamination methods on microbial population of oranges, the best results were obtained following two applications of submersion in boiling water and 5% H(2)O(2) solution for both the uninoculated and inoculated samples. Orange juice samples obtained from surface inoculated and decontaminated oranges were also examined. We showed that about 17.4% of the E. coli population was transferred to orange juice after extraction, indicating the separation of microbial contaminants from fruit peel during extraction. Finally, the levels of microbial contamination occurred throughout the extraction process on the inner surfaces of a commercial juice extractor at one of the sale points investigated. Significant (P < 0.05) increases in the APC and CC were determined in surface samples of the extractor after the extraction. Surface decontamination and extraction are critical steps in fresh juice production for preventing microbial contamination. Immersion in boiling water for 0.5 min, without using any chemicals, can be offered as an effective method to reduce microbial population on orange surfaces. PMID- 21819648 TI - Thermal resistance parameters for Shiga toxin-producing Escherichia coli in apple juice. AB - The purpose of the present study was to determine the heat resistance of six non O157 Shiga toxin-producing Escherichia coli (STEC) serotypes in comparison to E. coli O157:H7 in single-strength apple juice without pulp. The thermal parameters for stationary-phase and acid-adapted cells of E. coli strains from serogroups O26, O45, O103, O111, O121, O145, and O157:H7 were determined by using an immersed coil apparatus. The most heat-sensitive serotype in the present study was O26. Stationary-phase cells for serotypes O145, O121, and O45 had the highest D(56 degrees C)-value among the six non-O157 serotypes studied, although all were significantly lower (P < 0.05) than that of E. coli O157:H7. At 60 degrees C E. coli O157:H7 and O103 demonstrated the highest D-values (1.37 +/- 0.23 and 1.07 +/- 0.03 min, respectively). The D(62 degrees C) for the most heat-resistant strain belonging to the serotype O145 was similar (P > 0.05) to that for the most resistant O157:H7 strain (0.61 +/- 0.17 and 0.60 +/- 0.09 min, respectively). The heat resistance for stationary-phase cells was generally equal to or higher than that of acid-adapted counterparts. Although E. coli O157:H7 revealed D-values similar to or higher than the individual six non-O157 STEC serotypes in apple juice, the z-values for most non-O157 STEC tested strains were greater than those of E. coli O157:H7. When data were used to calculate heat resistance parameters at a temperature recommended in U.S. Food and Drug Administration guidance to industry, the D(71.1 degrees C) for E. coli O157:H7 and non-O157 STEC serotypes were not significantly different (P > 0.05). PMID- 21819650 TI - Antimicrobial resistance in Campylobacter, Salmonella, and Escherichia coli isolated from retail grain-fed veal meat from Southern Ontario, Canada. AB - This study estimated the prevalence of Salmonella, Campylobacter, and Escherichia coli isolates in fresh retail grain-fed veal obtained in Ontario, Canada. The prevalence and antimicrobial resistance patterns were examined for points of public health significance. Veal samples (n = 528) were collected from February 2003 through May 2004. Twenty-one Salmonella isolates were recovered from 18 (4%) of 438 samples and underwent antimicrobial susceptibility testing. Resistance to one or more antimicrobials was found in 6 (29%) of 21 Salmonella isolates; 5 (24%) of 21 isolates were resistant to five or more antimicrobials. No resistance to antimicrobials of very high human health importance was observed. Ampicillin chloramphenicolstreptomycin-sulfamethoxazole-tetracycline resistance was found in 5 (3%) of 21 Salmonella isolates. Campylobacter isolates were recovered from 5 (1%) of 438 samples; 6 isolates underwent antimicrobial susceptibility testing. Resistance to one or more antimicrobials was documented in 3 (50%) of 6 Campylobacter isolates. No Campylobacter isolates were resistant to five or more antimicrobials or category I antimicrobials. E. coli isolates were recovered from 387 (88%) of 438 samples; 1,258 isolates underwent antimicrobial susceptibility testing. Resistance to one or more antimicrobials was found in 678 (54%) of 1,258 E. coli isolates; 128 (10%) of 1,258 were resistant to five or more antimicrobials. Five (0.4%) and 7 (0.6%) of 1,258 E. coli isolates were resistant to ceftiofur and ceftriaxone, respectively, while 34 (3%) of 1,258 were resistant to nalidixic acid. Ciprofloxacin resistance was not detected. There were 101 different resistance patterns observed among E. coli isolates; resistance to tetracycline alone (12.7%, 161 of 1,258) was most frequently observed. This study provides baseline prevalence and antimicrobial resistance data and highlights potential public health concerns. PMID- 21819651 TI - Identification of bacteriocin genes in enterococci isolated from game animals and saltwater fish. AB - Bacteriocins produced by enterococci, referred to as enterocins, possess great interest for their potential use as biopreservatives in food and feed, as well as alternative antimicrobials in humans and animals. In this context, the aim of the present study was to determine the antimicrobial activity and the presence of bacteriocin structural genes in fecal enterococcal isolates from animal origins. Evaluation of the direct antimicrobial activity of 253 isolates from wild boars (Sus scrofa, n = 69), mullets (Liza ramada, n = 117), and partridges (Perdix perdix, n = 67) against eight indicator bacterial strains (including Listeria monocytogenes, Pediococcus pentosaceus, and Enterococcus spp.) showed that 177 (70%) exerted antimicrobial activity against at least one indicator microorganism. From these isolates, 123 were further selected on the basis of their inhibition group, and 81 were found to be producers of bacteriocins active against Listeria monocytogenes. Analysis of the presence of enterocin structural genes in a subset of 36 isolates showed that 70% harbored one or more of the evaluated genes, those of enterocin P and hiracin JM79 being the most prevalent. These results show that wild animals constitute an appropriate source for the isolation of bacteriocinogenic enterococci. PMID- 21819652 TI - A predictive model for the inactivation of Listeria innocua in cooked poultry products during postpackage pasteurization. AB - Contamination of Listeria monocytogenes in ready-to-eat poultry products poses potential risk of listeriosis to the public. To control the level of Listeria contamination, attention has been focused on the postpackage pasteurization of fully cooked poultry products. In this study, we sought to develop a model to predict the thermal inactivation of L. monocytogenes in chicken drumettes during postpackage hot water pasteurization. Fully cooked chicken drumettes were inoculated with Listeria innocua as a surrogate microorganism for Listeria monocytogenes, vacuum packaged, and treated in hot water baths at 60, 70, 80, and 90 degrees C for different heating times. Experimental results showed that a 7 log CFU/g reduction of L. innocua occurred at 54, 28, 18, and 10 min at 60, 70, 80, and 90 degrees C, respectively. The Weibull model was used to fit the survival curves of L. innocua at each heating temperature. The root mean square errors and residual plots indicated good agreements between the predicted and observed values. The predictive model was further validated by predicting a new data set generated in the pilot-plant tests. Model performance was evaluated by the acceptable prediction zone method, and the results indicated that the percentages of acceptable prediction errors were 100, 100, 82.4, and 87.5% at 60, 70, 80 and 90 degrees C, respectively, which were all greater than the threshold acceptable value of 70% , indicating good performance of the model. The developed predictive model can be used as a tool to predict thermal inactivation behaviors of L. monocytogenes in ready-to-eat chicken drumettes products. PMID- 21819653 TI - Quantitative risk assessment of listeriosis due to consumption of raw milk. AB - The objectives of this study were to estimate the risk of illness for raw milk consumers due to Listeria monocytogenes in raw milk sold by permitted dealers, and the risk for people on farms who consume raw milk. Three scenarios were evaluated for raw milk sold by dealers: raw milk purchased directly from bulk tanks, from on-farm stores, and from retail. To assess the effect of mandatory testing of raw milk by regulatory agencies, the number of listeriosis cases per year was compared where no raw milk testing was done, only a screening test to issue a permit was conducted, and routine testing was conducted and milk was recalled if it was L. monocytogenes positive. The median number of listeriosis cases associated with consumption of raw milk from bulk tanks, farm stores, and retail for an intermediate-age population was 6.6 * 10(-7), 3.8 * 10(-5), and 5.1 * 10(-5) cases per year, respective ly. In populations with high susceptibility, the estimated median number of cases per year was 2.7 * 10(-7) (perinatal, i.e., pregnant women and their fetuses or newborns) and 1.4 * 10(-6) (elderly) for milk purchased from bulk tanks, 1.5 * 10(-5 ) (perinatal) and 7.8 * 10(-5) (elderly) for milk from farm stores, and 2.1 * 10(-5) (perinatal) and 1.0 * 10(-4) (elderly) for milk from retail. For raw milk consumed on farms, the median number of listeriosis cases was 1.4 * 10(-7) cases per year. A greater risk of listeriosis was associated with consumption of raw milk obtained from retail and farm stores as compared with milk obtained from bulk tanks. This was likely due to additional time-temperature combination steps in the retail and farm store models, which increased the chances for growth of L. monocytogenes in raw milk. A close relationship between prevalence of L. monocytogenes in raw milk and the values of disease incidence was observed. Hence, a reduction in the number of cases per year in all populations was observed when a raw milk-testing program was in place, especially when routine testing and recalling of milk was conducted. PMID- 21819654 TI - Reduced detectability of Listeria monocytogenes in the presence of Listeria innocua. AB - Recent foodborne crises have demonstrated the importance of monitoring food safety. In terms of microbiological criteria, food safety requires the reliable detection of pathogens such as Listeria monocytogenes along the food chain by appropriate analytical methods. However, indications exist that accompanying Listeria innocua strains suppress the growth of L. monocytogenes during selective enrichment, which may cause reduced or even inhibited detection. To study these effects, the limit of detection of L. monocytogenes was investigated in the presence of L. innocua using the International Organization for Standardization standard method ISO 11290-1 and the VIDAS LDUO system, an automated method based on enzyme-linked fluorescence technology. The challenge was to provide low initial Listeria concentrations at sufficient precision to quantify the influence on the probability of detection of L. monocytogenes. The application of reference materials appropriate for quantitative test methods and a standardized dilution procedure were necessary to ensure accurate CFU levels of defined proportions of mixtures of both Listeria species. During selective enrichment, overgrowth of L. monocytogenes by L. innocua could be confirmed, leading to high rates of false negative results. Moreover, with both methods, a significant decrease in the detectability of L. monocytogenes could be quantified at ratios of 2:1 at very low concentrations representative of natural contamination levels often found in foods and environments. It is concluded that there is a need to improve existing procedures with respect to selective enrichment, as well as the detection techniques. PMID- 21819655 TI - Abiotic and biotic factors affect efficacy of chlorfenapyr for control of stored product insect pests. AB - Laboratory bioassays were conducted to assess pyrole chlorfenapyr as a potential grain protectant against adults of Rhyzopertha dominica, Sitophilus oryzae, Prostephanus truncatus, Tribolium confusum, and Liposcelis bostrychophila. Factors such as dose (0.01, 0.1, 0.5, 1, 5, and 10 ppm), exposure interval (7 and 14 days), temperature (20, 25, and 30 degrees C), relative humidity (RH; 55 and 75%), and commodity (wheat, maize, barley, and paddy rice) were evaluated. Progeny production was assessed after 74 days of exposure. For L. bostrychophila and T. confusum the increase of dose increased mortality. After 7 or 14 days of exposure, mortality was low at doses of <= 1 ppm and did not exceed 23 or 36%, respectively, for L. bostrychophila or 13 or 58%, respectively, for T. confusum. After 14 days of exposure, mortality of S. oryzae at 30 degrees C and 75% RH was 82.2%. Mortality of P. truncatus was considerably higher than that of the other species. At 0.5 ppm, mortality exceeded 81% after 7 days of exposure and 91% after 14 days of exposure. Progeny production of L. bostrychophila was extremely high. Very few progeny were found for T. confusum. For S. oryzae, offspring emergence was high, except at 20 degrees C and 55% RH. For P. truncatus, progeny production in the treated maize was not avoided, even at 10 ppm. In the case of S. oryzae, at 0.1 ppm and after 14 days of exposure, mortality in wheat was higher than in the other three commodities. For R. dominica, mortality was low at 0.1 and 1 ppm for paddy rice but reached 74.4% in barley after 14 days of exposure. For T. confusum, mortality was low at 0.1 and 1 ppm in all commodities. For progeny production counts, for S. oryzae or R. dominica, adult emergence was higher in paddy rice than in the other three commodities. Finally, overall T. confusum progeny was low. Chlorfenapyr efficacy varied remarkably among the combinations tested, and it may be a viable grain protectant in combination with other insecticides. PMID- 21819656 TI - Detection of banned ruminant-derived material in industrial feedstuffs by TaqMan real-time PCR Assay. AB - A ruminant-specific real-time PCR system was designed and applied for the detection of processed animal protein from ruminants in industrial feedstuffs. The assay includes a primer pair and a TaqMan probe selectively targeting mitochondrial 16S rRNA gene sequences from the ruminant group and another primer probe set based on the eukaryotic nuclear 18S rRNA gene (positive amplification control). Both ruminant and eukaryotic PCR systems generated short PCR amplicons of 79 and 77 bp, respectively. To evaluate the suitability of the real-time PCR assay for the detection of banned by-products of ruminant origin, 126 feed samples subjected to rendering under current European legislation regulations were analyzed. The assay achieved 100% success in classifying the samples as positive or negative in terms of qualitative ruminant composition, with a detection limit of 0.1%. The quantitative ability of the assay is however restricted by variations in the composition and treatment of the feeds, which affect the amount and quality of amplifiable DNA. PMID- 21819657 TI - Molecular cloning, heterologous expression, and characterization of Ornithine decarboxylase from Oenococcus oeni. AB - Ornithine decarboxylase (ODC) is responsible for the production of putrescine, the major biogenic amine found in wine. Oenococcus oeni is the most important lactic acid bacterium in the winemaking process and is involved in malolactic fermentation. We report here the characterization of ODC from an O. oeni strain isolated from wine. Screening of 263 strains isolated from wine and cider from all over the world revealed that the presence of the odc gene appears to be strain specific in O. oeni. After cloning, heterologous expression in Escherichia coli, and characterization, the enzyme was found to have a molecular mass of 85 kDa and a pI of 6.2 and revealed maximal activity at pH 5.5 and an optimum temperature of 35 degrees C. Kinetic studies showed that O. oeni ODC is specific for L-ornithine with a K(m) value of 1 mM and a V(max) of 0.57 U.mg(-1). The hypothesis that cadaverine, which results from lysine decarboxylation, may be linked to putrescine production is not valid since O. oeni ODC cannot decarboxylate L-lysine. As no lysine decarboxylase was detected in any of the O. oeni genomes sequenced, cadaverine synthesis may result from another metabolic pathway. This work is the first characterization of an ODC from a lactic acid bacterium isolated from a fermented product. PMID- 21819658 TI - Multistate outbreak of multidrug-resistant Salmonella newport infections associated with ground beef, October to December 2007. AB - In late October 2007, an outbreak of multidrug-resistant Salmonella Newport infections affected 42 case patients in California, Arizona, Idaho, and Nevada. A case-control study implicated ground beef from one chain store. Despite detailed ground beef purchase histories--including shopper card information for several case patients--traceback efforts by both the U.S. Department of Agriculture, Food Safety and Inspection Service and the California Department of Public Health were unable to identify the source of contamination. Case patients consumed multiple types of ground beef products purchased at numerous chain store A retail locations. These stores had received beef products for grinding from multiple beef slaughter-processing establishments. Detailed retail grinding logs and grinding policies that prevent cross-contamination between batches of ground beef products are crucial in the identification of contaminated beef products associated with foodborne illness. PMID- 21819659 TI - Prevalence of foodborne pathogens in grilled chicken from street vendors and retail outlets in Reynosa, Tamaulipas, Mexico. AB - We analyzed a total of 70 grilled chicken samples bought randomly from street vendors and retail outlets in the city of Reynosa, Mexico, to determine the prevalence of Escherichia coli (Shiga toxin producing and enterotoxin producing), Salmonella spp., Staphylococcus aureus, Listeria spp., and Campylobacter spp. using microbiological methods and PCR detection of bacterial sequences. Of the 70 samples, 27 (38.5%) were from retail outlets and 43 (61.4%) from street vendors. All specimens were negative by both microbiological and molecular methods for Listeria monocytogenes, Shiga toxin 2 of Shiga toxin-producing E. coli, lt of enterotoxin-producing E. coli, and st enterotoxin, and all were negative for Salmonella spp. and Campylobacter jejuni by PCR. Of the samples studied, 49 (70%) had undetectable levels of the foodborne pathogens studied with the methods used. In the remaining 21 (30%) specimens, at least one pathogen was isolated or detected, with E. coli being the pathogen most frequently isolated and with two samples bearing the hlyA gene. We found no statistical difference in bacterial prevalence between retail and street vendor samples. The presence of pathogens in grilled chicken is an important public health risk because of the great demand for and daily consumption of this product in this region. PMID- 21819660 TI - Emergence of enterohemorrhagic Escherichia coli serovar O157 strains in clade 8 with highly similar pulsed-field gel electrophoresis patterns. AB - Enterohemorrhagic Escherichia coli serovar O157 (O157) strains with highly similar pulsed-field gel electrophoresis (PFGE) patterns were isolated in Japan during 2007 and 2008. Several genetic features related to O157 evolution were investigated to indicate whether homoplasy might have contributed to the highly similar PFGE patterns in these strains. The O157 strains were classified in lineage I/II, as defined by a lineage-specific polymorphism assay-6 with an atypical allele in Z5935 (code: 231111). Analysis of the insertion sites of stx(2) phage in these strains showed that the sites were "occupied" in yehV and "intact" in wrbA, indicating that the strains were derived from "Cluster 1" of "Subgroup C." When a specific single-nucleotide polymorphism in ECs2357 in clade 8 strains was investigated, all of the strains in the present study were confirmed to be clade 8 strains. These results indicated that the O157 strains in this study had common genetic features, suggesting that the highly similar PFGE patterns of these strains were not due to homoplasy. Because no common source of these strains could be identified in 2007 to 2008 in Japan, these strains may have emerged from a unique O157 clade 8 clone and then spread by dissemination in Japan. PMID- 21819661 TI - Antimicrobial resistance in Escherichia coli isolated from retail milk-fed veal meat from Southern Ontario, Canada. AB - This study estimated the prevalence of Escherichia coli isolates in fresh retail milk-fed veal scallopini pieces obtained from grocery stores in Ontario, Canada. In addition, the prevalence and antimicrobial resistance patterns were examined for points of public health significance. One hundred fifty-three milk-fed veal samples were collected over the course of two sampling phases, January to May 2004 and November 2004 to January 2005. E. coli isolates were recovered from 87% (95% confidence interval, 80.54 to 91.83%) of samples, and antimicrobial susceptibility testing was conducted on 392 isolates. The prevalence of resistance to one or more antimicrobials was 70% (274 of 392), while the resistance to five or more antimicrobials was 33% (128 of 392). Resistance to ceftiofur (2.8%), ceftriaxone (3.6%), nalidixic acid (12%), and ciprofloxacin (3.8%) alone or in combination was observed. Eighty-five resistance patterns were observed; resistance to tetracycline only (7.4%) was observed most frequently. Individual antimicrobial resistance prevalence levels were compared with grain fed veal and retail beef data from samples collected in Ontario. In general, resistance to individual antimicrobials was observed more frequently in E. coli isolates from milk-fed veal than in isolates from grain-fed veal and beef. Resistance to one or more antimicrobials and to five or more antimicrobials in E. coli isolates was more frequent in isolates from milk-fed veal than in isolates from grain-fed veal and beef. This study provides baseline data on the occurrence of resistance in E. coli isolates from milk-fed veal that can be compared with data for other commodities. Additionally, E. coli resistance patterns may serve as an indicator of antimicrobial exposure. PMID- 21819662 TI - Translocation of surface-inoculated Escherichia coli into whole muscle nonintact beef striploins following blade tenderization. AB - Translocation of Escherichia coli among beef loins processed with a mechanical tenderizer was evaluated. Two beef striploins were inoculated on the lean side with 6.4 to 7.2 ml of a nalidixic acid-resistant E. coli at 8.2 to 10.1 log CFU/ml. Total E. coli inoculated onto striploins ranged from 1.12 * 10(9) to 9.10 * 10(10) CFU. Striploins were passed once (lean side up, anterior end first) through a mechanical blade tenderizer. After the inoculated striploins had been tenderized, uninoculated beef striploins (n = 5) were passed once (lean side up, anterior end first) through the same mechanical tenderizer. This procedure was repeated twice for a total of 12 striploins. Six core samples were taken from each striploin starting with the anterior end. Each core was cut into six sections; sections 1 through 4 represented the top 4 cm of the core sample, and sections 5 and 6 represented the remaining part of the core split in half. After tenderization, E. coli levels were highest (P < 0.05) in loin 1. Loin 2 had higher levels (P < 0.05) than did loins 4, 5, and 6. No differences in E. coli levels (P > 0.05) were found among loins 3, 4, 5, and 6, for which levels were below the limit of detection. Levels of E. coli from section 1 were higher than those for all other sections. Section 2 had higher levels (P < 0.05) than did sections 3, 4, 5, and 6. E. coli recovery from section 6 was higher (P < 0.05) than that from sections 3, 4, and 5. No differences in E. coli recovery (P > 0.05) were found among sections 3, 4, and 5. Data indicate that even after inoculation of E. coli a high initial levels, contamination from one loin to another is quickly reduced to < 10 CFU/g. PMID- 21819663 TI - Microbiological and sensory effects of the combined application of hot-cold organic acid sprays and steam condensation at subatmospheric pressure for decontamination of inoculated pig tissue surfaces. AB - We studied microbiological and sensory effects of treating pig tissue for 15 s with 55 and 10 degrees C sprays of acetic acid (AA; 0.15 to 0.3 M) and lactic acid (LA; 0.1 to 0.2 M) solutions prior to the tissue being subjected to steam condensation (18 s at 65 degrees C or 10 s at 75 degrees C). LA or AA spraying and then steam treatment resulted in 3- to 4-log average reductions of Pseudomonas fragi and Yersinia enterocolitica inocula (6 to 7 log CFU/cm(2)), regardless of acid temperature or concentration. Buffered LA or 1:1 mixtures of AA:LA and then steam treatment yielded similar reductions. Most of the acid-steam treated samples had microbial counts below the limit of detection (2 log CFU/cm(2)); thus, the results likely underestimate the potential of this procedure. When the period between inoculation and acid-steam treatment was extended from 0.5 to 24 h, up to a 1-log-higher microbial reduction was observed, due to a 1- to 2-log-greater initial contamination. Increasing the LA contact time to 6 min increased the microbial reduction by 0.8 log. Acid-steam treatment effected lower L* values (darker color) on pigskin, but higher L* values on muscle and fat tissue (paler color). Many muscle samples exhibited lower a* values and off-color brown hues. Off-odors were observed immediately after treatment, but with the exception of fat tissue and AA-treated samples, they largely disappeared during further storage. Off-flavors were only detected in AA treated muscle samples. PMID- 21819664 TI - Occurrence of Vibrio spp. in fish and shellfish collected from the Swiss market. AB - The genus Vibrio includes gram-negative bacteria that inhabit estuarine ecosystems. V. cholerae, V. parahaemolyticus, and V. vulnificus pose a considerable public health threat as agents of sporadic and epidemic foodborne infections associated with the consumption of raw or undercooked contaminated fish or shellfish. In this study, we analyzed 138 fish and shellfish samples collected from the Swiss market (fish fillets [n = 102], bivalves [n = 34], and squid [n = 2]). Microbiological analysis was done according to International Organization for Standardization method 21872-1/21872-2:2007, using thiosulfate citrate bile sucrose agar and chromID Vibrio agar as selective agar. Presumptive positive colonies on thiosulfate citrate bile sucrose agar or chromID Vibrio agar were picked and were identified by the API 20E and species-specific PCR systems. V. cholerae isolates were tested further by PCR for the presence of the cholera toxin A subunit gene (ctxA). V. parahaemolyticus isolates were tested by PCR for genes encoding for thermostable direct hemolysin (tdh) and TDH-related hemolysin (trh). V. cholerae was isolated from three samples and V. parahaemolyticus from eight samples. None of these strains harbored species-specific virulence factors. Further, V. alginolyticus was isolated from 40 samples, and V. fluvialis was isolated from 1 sample. Our study provides, for the first time, data for the assessment of exposure to Vibrio spp. in raw fish and bivalves consumed in Switzerland. PMID- 21819665 TI - Survival of Listeria innocua in rainbow trout protein recovered by isoelectric solubilization and precipitation with acetic and citric acids. AB - During mechanical fish processing, a substantial amount of protein is discarded as by-products. Isoelectric solubilization and precipitation (ISP) is a process that uses extreme pH shifts to solubilize and precipitate protein from by products to recover previously discarded protein. Typically, strong acids are used for pH reduction, but these acids do not have a pasteurization effect (6 log reduction) on bacterial load; therefore, organic acids were used during ISP processing to test the impact on Listeria innocua concentrations. Headed and gutted rainbow trout (Oncorhynchus mykiss) were inoculated with L. innocua, homogenized, and brought to the target pH with granular citric acid (pH 2.0 and 2.5) or glacial acetic acid (pH 3.0 and 3.5). Proteins were solubilized for 10 min at 4 degrees C, and insoluble components (e.g., skin and insoluble protein) were removed by centrifugation. The remaining solution was pH shifted to the protein isoelectric point (pH 5.5) with sodium hydroxide, and precipitated protein was separated from the water. Microbial cells for each component (proteins, insolubles, and water) were enumerated on modified Oxford agar (MOX) and tryptic soy agar with 6% yeast extract (TSAYE). The sums of the surviving cells from each component were compared with the initial inoculum levels. No significant differences were observed between results obtained from TSAYE and from MOX (P > 0.05). Significant reductions in microbial populations were detected, regardless of pH or acid type (P < 0.05). The greatest reduction was at pH 3.0 with glacial acetic acid, resulting in a mean reduction of 6.41 log CFU/g in the recovered protein and 5.88 log CFU/g in the combined components. These results demonstrate the antimicrobial potential of organic acids in ISP processing. PMID- 21819666 TI - Characterization of Staphylococcus aureus strains isolated from raw milk utilized in small-scale artisan cheese production. AB - Staphylococcus aureus is an important agent of bacterial mastitis in milking animals and of foodborne intoxication in humans. The purpose of this study was to examine the genetic and phenotypic diversity, enterotoxigenicity, and antimicrobial resistance of S. aureus strains isolated from raw milk used for the production of artisan cheese in Vermont. Cross-tabulations revealed that the 16 ribotypes identified among the 90 milk isolates examined were typically associated with a specific animal species and that more than half of these ribotypes were unique to individual farms. In general, specific EcoRI ribotypes were commonly associated with specific phenotypical characteristics, including staphylococcal enterotoxin production or the lack thereof. Limited antimicrobial resistance was observed among the isolates, with resistance to ampicillin (12.51%) or penicillin (17.04%) most common. Two isolates of the same ribotype obtained from the same farm were resistant to oxacillin with 2% NaCl. More than half (52.22%) of isolates produced toxin, and 31 of the 32 isolates solely produced staphylococcal enterotoxin type C. Although these data demonstrate that S. aureus strains found in raw milk intended for artisan cheese manufacture are capable of enterotoxin production, staphylococcal enterotoxin C is not typically linked to foodborne illness. Because S. aureus is a common contaminant of cheese, an understanding of the ecology of this pathogen and of the antimicrobial susceptibility and toxigenicity of various strains will ultimately contribute to the development of control practices needed to enhance the safety of artisan and farmstead cheese production. PMID- 21819667 TI - Surface roughness of stainless steel influences attachment and detachment of Escherichia coli O157. AB - Determining the influence of surface roughness on Escherichia coli O157 attachment to and detachment from stainless steel (SS) is important for controlling this foodborne pathogen. The aim of this study was to evaluate the interactions of six E. coli strains (four O157:H7, one O157:H12, and one O1:H7) with SS type 304 finishes of various surface roughness: 2B (unpolished surface), 4 (common food grade SS), and 8 (polished smooth surface). In attachment assays (exposure to cell suspensions with periodic swirling), bacteria were enumerated by epifluorescence microscopy, and in detachment assays a blotting technique and atomic force microscopy (AFM) were used. Attachment data suggest that E. coli attach in greater numbers to significantly smoother SS8; however, detachment assays and AFM data suggest cells are more easily removed from this finish. Conversely, attachment to SS2B was lower, and AFM data suggest that E. coli O157 may adhere more strongly to this finish. Attachment and detachment data for SS4 was variable, suggesting complex attachment mechanisms to this type of SS. SS4 is the most common material used in food processing facilities. The data from this study indicate that bacterial interactions with SS4 are complex and less easily predicted than those with SS of other finishes, including 2B and 8. These differences in bacterial attachment may be of concern to the food industry and warrant further investigation. PMID- 21819668 TI - Differences in the binding of human norovirus to and from romaine lettuce and raspberries by water and electrolyzed waters. AB - Food contamination by human norovirus (hNoV) is a major cause of gastrointestinal disease. We evaluated the effectiveness of removing inoculated hNoV from the surfaces of raspberries and romaine lettuce by a simple wash in tap water and in different forms of electrolyzed water (EW), including acidic EW (AEW), neutral EW (NEW), and basic EW (BEW). A simple rinsing or soaking in water was able to remove >95% of hNoV from surface-inoculated raspberries. In contrast, only 75% of hNoV was removed from surface-inoculated romaine lettuce by rinsing in tap water. An AEW wash enhanced the binding of hNoV to raspberries and lettuce. Only 7.5% (+/-10%) and 4% (+/-3.1%) of hNoV were removed by AEW wash from surface inoculated raspberries and lettuce, respectively. When raspberries and lettuce were prewashed with NEW or BEW prior to surface inoculation, an AEW wash likewise resulted in significantly less removal of hNoV compared with untreated samples. A prewash with AEW significantly decreased the removal of hNoV from raspberries and lettuce when they were washed with NEW, from 90.6 to 51% and from 76 to 51.3% , respectively. There are minimal or no improvements gained by use of any of the EWs instead of a regular tap water wash in removal of hNoV from produce. However, use of AEW shows a significant decrease in the removal of hNoV from contaminated produce compared with other water rinses. The ability to remove hNoV from different types of produce varies, possibly due to differences among types of ligand-like molecules that bind hNoV. The distribution of hNoV on raspberries and lettuce was studied using recombinant Norwalk-like particles (rNVLP). By immunofluorescence microscopy, we were able to observe binding of rNVLP only to vein areas of romaine lettuce, suggesting that the virus was binding to specific molecules in these areas. Random binding of rNVLP occurred only with raspberries prewashed with AEW or washed with AEW. PMID- 21819669 TI - Recovery of alicyclobacillus from inhibitory fruit juice concentrates. AB - Growth of Alicyclobacillus in low-pH fruit juices may result in off-odors and off flavors due to the production of compounds such as guaiacol (2-methoxy phenol). An important step in preventing Alicyclobacillus contamination of fruit juices is the screening of incoming ingredients. Many fruit juice concentrates contain compounds that inhibit Alicyclobacillus growth, but beverages produced from the concentrates may not contain sufficient amounts of the active component to prevent spoilage. Therefore, accurate screening of juice concentrates is essential to prevent false-negative test results and product spoilage. The objective of this study was to evaluate isolation methods for detection of Alicyclobacillus in inhibitory juice concentrates. Recovery of Alicyclobacillus spores from inoculated and naturally contaminated concentrates was compared by using pour plate, spread plate, and filtration methods. Pour plates consistently recovered the lowest number of spores from inoculated concentrates. Spread plating was the most effective method used to recover spores from inoculated apple and pomegranate juice concentrates, while filtration resulted in the highest recovery from cranberry concentrate. When tested on naturally contaminated concentrates, the pour plate method failed to detect Alicyclobacillus in many samples. Filtration was much more effective. The filtration method increased the likelihood of detecting Alicyclobacillus contamination of fruit juice concentrates containing inhibitory compounds. PMID- 21819670 TI - Natural occurrence of fumonisins b1 and b2 in corn from three main production provinces in China. AB - A total of 255 corn samples collected in 2010 from three main corn production provinces of China (Liaoning, Shandong, and Henan) were analyzed for contamination with fumonisins (FB(1) and FB(2)). The incidence of contamination was significantly higher in samples from Liaoning than in samples from the other two provinces. Approximately 80.0% of the samples from Liaoning were contaminated with fumonisins, with a mean total fumonisin concentration of 3,990 ng/g. In contrast, the mean total fumonisin concentrations were 845 and 665 ng/g in samples from Shandong and Henan, respectively. The probable daily intake of fumonisins (0.3 MUg/kg of body weight) is within the provisional maximum tolerable daily intake of 2.0 MUg/kg of body weight set by the Joint Food and Agriculture Organization and World Health Organization Expert Committee on Food Additives. PMID- 21819671 TI - Characterization of certain bacterial strains for potential use as starter or probiotic cultures in dairy products. AB - The present work was aimed at characterizing 12 strains of lactic acid bacteria (LAB) to obtain improved potential starter or probiotic cultures that could be used for making dairy products from ewe's milk and cow's milk. Eight strains with antimicrobial properties, isolated from ewe's milk and from cheese made from ewe's and/or cow's milk, were studied. They were identified as Enterococcus faecalis (five strains), Lactococcus lactis subsp. cremoris, Leuconostoc mesenteroides, and Lactobacillus paracasei subsp. paracasei (one strain of each species). Additionally, four strains were obtained from the American Type Culture Collection: Lactobacillus casei 393 (isolated from cheese), L. lactis subsp. lactis 11454 (origin nonspecified and a producer of nisin), and two strains isolated from human feces (L. paracasei subsp. paracasei 27092 and Lactobacillus rhamnosus 53103, antibacterial agent producer). All E. faecalis strains showed at least one virulence factor (either hemolysin or gelatinase), which emphasizes the importance of these studies in this species. Both L. lactis strains and most Lactobacillus spp. were good acidifiers in ewe's milk and cow's milk at 30 degrees C. High beta-galactosidase activity, as well as aminopeptidase activities that favor the development of desirable flavors in cheese, were detected in all Lactobacillus spp. strains. Furthermore, L. rhamnosus ATCC 53103 showed alpha fucosidase activity (thought to help colonization of the intestine) and lack of alpha-glucosidase activity (a trait considered positive for diabetic and obese humans). This last enzymatic activity was also lacking in L. lactis ATCC 11454. L. mesenteroides was the only strain D(2)-lactic acid producer. The selection of any particular strain for probiotic or dairy cultures should be performed according to the technological and/or functional abilities needed. PMID- 21819672 TI - Indicator organisms in meat and poultry slaughter operations: their potential use in process control and the role of emerging technologies. AB - Measuring commonly occurring, nonpathogenic organisms on poultry products may be used for designing statistical process control systems that could result in reductions of pathogen levels. The extent of pathogen level reduction that could be obtained from actions resulting from monitoring these measurements over time depends upon the degree of understanding cause-effect relationships between processing variables, selected output variables, and pathogens. For such measurements to be effective for controlling or improving processing to some capability level within the statistical process control context, sufficiently frequent measurements would be needed to help identify processing deficiencies. Ultimately the correct balance of sampling and resources is determined by those characteristics of deficient processing that are important to identify. We recommend strategies that emphasize flexibility, depending upon sampling objectives. Coupling the measurement of levels of indicator organisms with practical emerging technologies and suitable on-site platforms that decrease the time between sample collections and interpreting results would enhance monitoring process control. PMID- 21819674 TI - The AALAS journals: 2010 in review. PMID- 21819675 TI - Left ventricular hypertrophy is prevalent in sprague-dawley rats. PMID- 21819677 TI - Association between hair-induced oronasal inflammation and ulcerative dermatitis in C57BL/6 mice. AB - Ulcerative dermatitis (UD) is a genetically linked syndrome that affects the neck, torso, and facial regions of C57BL/6 mice and strains with C57BL/6 background. In this study, 96 mice with skin ulcerations in 3 different regions of the body and 40 control animals without ulcerated lesions were evaluated histologically for the presence of hair-induced inflammation in the oronasal cavity. We found that 73.5% (100 of 136) of the mice had hair-induced periodontitis, glossitis, or rhinitis regardless of the presence or absence of UD. Of those mice with UD, 93.9% had hair-induced oronasal inflammation. The mandibular incisors were the most commonly affected site (64.6%), followed by the maxillary molars (20.8%), maxillary incisors (16.7%), tongue (16.7%), nasal cavity (10.4%), and mandibular molars (7.3%). In addition, oronasal hair-induced inflammation occurred in 25% (10 of 40) of the control mice. Here we show a significant association between UD and hair-induced inflammatory lesions of the oronasal cavities. PMID- 21819678 TI - Paternal experience and stress responses in California mice (Peromyscus californicus). AB - Paternal behavior greatly affects the survival, social development, and cognitive development of infants. Nevertheless, little research has been done to assess how paternal experience modifies the behavioral characteristics of fathers, including fear and stress responses to a novel environment. We investigated long-term behavioral and physiologic effects of parental experience in mice (Peromyscus californicus) and how this response activates the hypothalamic-pituitary-adrenal axis (as measured by corticosterone and dehydroepiandrosterone [DHEA] levels) and interacts with anxiety-related behaviors. Three groups of adult males were tested -fathers exposed to pups, virgins exposed to pups, and virgins never exposed to pups--in 2 environments designed to elicit anxiety response: an open field with a novel object placed in the center and a closed cage containing a sample of a component of fox feces. Behavioral responses were measured by using traditional methods (duration and frequency) and behavioral-chain sequences. Results indicated that paternal experience significantly modifies a male mouse's behavioral and physiologic responses to stress-provoking stimuli. Compared with inexperienced male mice, experienced male mice had a significant decrease in the occurrence of incomplete behavioral chains during the exposure to the novel object, an index of reduced stress. Further, even moderate pup exposure induced behavioral modifications in virgin male mice. These behavioral responses were correlated with changes in corticosterone and DHEA levels. Together, these data provide evidence that interactions between male mice and offspring may have mutually beneficial long-term behavioral and physiologic effects. PMID- 21819679 TI - The effects of diet composition on body fat and hepatic steatosis in an animal (Peromyscus californicus) model of the metabolic syndrome. AB - The objective of this research was to determine body composition, total fat content, fat distribution, and serum leptin concentration in hyperlipidemic (high responder, HR) and normolipidemic (low responder, LR) California mice (Peromyscus californicus). In our initial experiments, we sought to determine whether differences in regional fat storage were associated with hyperlipidemia in this species. To further characterize the hepatic steatosis in the mice, we performed 2 additional experiments by using a diet containing 45% of energy as fat. The body fat content of mice fed a low fat-diet (12.3% energy as fat) was higher than that of mice fed a moderate-fat diet (25.8% energy as fat). Total body fat did not differ between HR and LR mice. There was no significant difference between intraabdominal, gonadal, or inguinal fat pad weights. Liver weights of HR mice fed the moderate-fat diet were higher than those of LR mice fed the same diet, and the moderate-fat diet was associated with nonalcoholic fatty liver (NAFL). Mice fed the 45% diet had higher histologic score for steatosis but very little inflammatory response. Chemical analysis indicated increased lipid in the livers of mice fed the high-fat diet compared with those fed the low-fat diet. HR and LR mice had similar serum leptin concentrations. California mice develop NAFL without excess fat accumulation elsewhere. NAFL was influenced by genetic and dietary factors. These mice may be a naturally occuring model of partial lipodystrophy. PMID- 21819680 TI - Protective effect of inositol hexaphosphate against UVB damage in HaCaT cells and skin carcinogenesis in SKH1 hairless mice. AB - UVB radiation damages keratinocytes, potentially inducing chronic skin damage, cutaneous malignancy, and suppression of the immune system. Naturally occurring agents have been considered for prevention and treatment of various kinds of cancer, including skin cancer. Inositol hexaphosphate (IP6), an antioxidant, is a naturally occurring polyphosphorylated carbohydrate that has shown a strong anticancer activity in several experimental models. We assessed the protective effects of IP6 against UVB irradiationinduced injury and photocarcinogenesis by using HaCaT cells (human immortalized keratinocytes) and SKH1 hairless mice. We found that IP6 counteracts the harmful effects of UVB irradiation and increases the viability and survival of UVB-exposed cells. Treatment with IP6 after UVB irradiation (30 mJ/cm(2)) arrested cells in the G(1) and G(2) M phases while decreasing the S phase of the cell cycle. Treatment with IP6 also decreased UVB induced apoptosis and caspase 3 activation. Topical application of IP6 followed by exposure to UVB irradiation in SKH1 hairless mice decreased tumor incidence and multiplicity as compared with control mice. Our results suggest that IP6 protects HaCaT cells from UVB-induced apoptosis and mice from UVB-induced tumors. PMID- 21819681 TI - Pneumocystis carinii infection causes lung lesions historically attributed to rat respiratory virus. AB - Idiopathic lung lesions characterized by dense perivascular cuffs of lymphocytes and a lymphohistiocytic interstitial pneumonia have been noted in research rats since the 1990s. Although the etiology of this disease has remained elusive, a putative viral etiology was suspected and the term 'rat respiratory virus' (RRV) has been used in reference to this disease agent. The purpose of this study was to determine whether Pneumocystis carinii infection in immunocompetent rats can cause idiopathic lung lesions previously attributed to RRV. In archived paraffin embedded lungs (n = 43), a significant association was seen between idiopathic lung lesions and Pneumocystis DNA detected by PCR. In experimental studies, lung lesions of RRV developed in 9 of 10 CD rats 5 wk after intratracheal inoculation with P. carinii. No lung lesions developed in CD rats (n = 10) dosed with a 0.22 MUm filtrate of the P. carinii inoculum, thus ruling out viral etiologies, or in sham-inoculated rats (n = 6). Moreover, 13 of 16 CD rats cohoused with immunosuppressed rats inoculated with P. carinii developed characteristic lung lesions from 3 to 7 wk after cohousing, whereas no lesions developed in rats cohoused with immunosuppressed sham-inoculated rats (n = 7). Both experimental infection studies revealed a statistically significant association between lung lesion development and exposure to P. carinii. These data strongly support the conclusion that P. carinii infection in rats causes lung lesions that previously have been attributed to RRV. PMID- 21819682 TI - Diabetes enhances dental caries and apical periodontitis in caries-susceptible WBN/KobSlc rats. AB - Many epidemiologic studies have suggested that diabetes may be an important risk factor for periodontal disease. To determine whether diabetes induces or enhances periodontal disease or dental caries, dental tissue from diabetic male and nondiabetic female WBN/KobSlc rats and male and female age-matched nondiabetic F344 rats was analyzed morphologically and morphometrically for these 2 types of lesions. Soft X-ray examination revealed that the incidence and severity of both molar caries and alveolar bone resorption were much higher in male WBN/KobSlc rats with chronic diabetes than in nondiabetic female rats of the same strain. Histopathologic examination showed that dental caries progressed from acute to subacute inflammation due to bacterial infections and necrosis in the pulp when the caries penetrated the dentin. In the most advanced stage of dental caries, inflammatory changes caused root abscess and subsequent apical periodontitis, with the formation of granulation tissue around the dental root. Inflammatory changes resulted in resorption of alveolar bone and correlated well with the severity of molar caries. Our results suggest that diabetic conditions enhance dental caries in WBN/KobSlc rats and that periodontal lesions may result from the apical periodontitis that is secondary to dental caries. PMID- 21819683 TI - Longitudinal patterns of viremia and oral shedding of rhesus rhadinovirus and retroperitoneal fibromatosis herpesviruses in age-structured captive breeding populations of rhesus Macaques (Macaca mulatta). AB - Rhesus rhadinovirus (RRV) and retroperitoneal fibromatosis herpesvirus (RFHV), 2 closely related gamma2 herpesviruses, are endemic in breeding populations of rhesus macaques at our institution. We previously reported significantly different prevalence levels, suggesting the transmission dynamics of RRV and RFHV differ with regard to viral shedding and infectivity. We designed a longitudinal study to further examine the previously observed differences between RRV and RFHV prevalence and the potential influence of age, season, and housing location on the same 90 rhesus macaques previously studied. Virus- and host-genome-specific real-time PCR assays were used to determine viral loads for both RRV and RFHV in blood and saliva samples collected at 6 time points over an 18-mo period. Proportions of positive animals and viral load in blood and saliva were compared between and within viruses by age group, location, and season by using 2-part longitudinal modeling with Bayesian inferences. Our results demonstrate that age and season are significant determinants, with age as the most significant factor analyzed, of viremia and oral shedding for both RRV and RFHV, and these pathogens exhibit distinctly different patterns of viremia and oral shedding over time within a single population. PMID- 21819684 TI - Use of an implantable loop recorder in the investigation of arrhythmias in adult captive chimpanzees (Pan troglodytes). AB - Cardiovascular disease in general, and cardiac arrhythmias specifically, is common in great apes. However, the clinical significance of arrhythmias detected on short-duration electrocardiograms is often unclear. Here we describe the use of an implantable loop recorder to evaluate cardiac rhythms in 4 unanesthetized adult chimpanzees (Pan troglodytes), 1 with a history of possible syncope and 3 with the diagnosis of multiform ventricular ectopy (ventricular premature complexes) and cardiomyopathy. The clinical significance of ventricular ectopy was defined further by using the implantable loop recorder. Arrhythmia was ruled out as a cause of collapse in the chimpanzee that presented with possible syncope because the implantable loop recorder demonstrated normal sinus rhythm during a so-called syncopal event. This description is the first report of the use of an implantable loop recorder to diagnose cardiac arrhythmias in an unanesthetized great ape species. PMID- 21819685 TI - Comparative bone anatomy of commonly used laboratory animals: implications for drug discovery. AB - To accommodate functional demands, the composition and organization of the skeleton differ among species. Microcomputed tomography has improved our ability markedly to assess structural parameters of cortical and cancellous bone. The current study describes differences in cortical and cancellous bone structure, bone mineral density, and morphology (geometry) at the proximal femur, proximal femoral diaphysis, lumbar vertebrae, and mandible in mice, rats, rabbits, dogs, and nonhuman primates. This work enhances our understanding of bone gross and microanatomy across lab animal species and likely will enable scientists to select the most appropriate species and relevant bone sites for research involving skeleton. We evaluated the gross and microanatomy of the femora head and neck, lumbar spine, and mandible and parameters of cancellous bone, including trabecular number, thickness, plate separation, and connectivity among species. The skeletal characteristics of rabbits, including a very short femoral neck and small amounts of cancellous bone at the femoral neck, vertebral body, and mandible, seem to make this species the least desirable for preclinical research of human bone physiology; in comparison, nonhuman primates seem the most applicable for extrapolation of data to humans. However, rodent (particularly rat) models are extremely useful for conducting basic research involving the skeleton and represent reliable and affordable alternatives to dogs and nonhuman primates. Radiology and microcomputed tomography allow for reliable evaluation of bone morphology, microarchitecture, and bone mineral density in preclinical and clinical environments. PMID- 21819686 TI - Pulmonary embolization of fat and bone marrow in cynomolgus Macaques (Macaca fascicularis). AB - Fat embolization (FE), the introduction of bone marrow elements into circulation, is a known complication of bone fractures. Although FE has been described in other animal models, this study represents the first reported cases of FE and bone marrow embolism in nonhuman primates. Histopathologic findings from cynomolgus macaques (Macaca fascicularis) indicated that in all 5 cases, fat and bone marrow embolization occurred subsequent to multiple bone marrow biopsies. In the most severe case, extensive embolization was associated pulmonary damage consistent with acute respiratory distress syndrome. Fat embolism syndrome (FES) is an infrequent clinical outcome of FE and is triggered by systemic biochemical and mechanical responses to fat in circulation. Although clinical criteria diagnostic of FES were not investigated at the time of death, this severe case may represent the fulminant form of FES, which occurs within 12 h after trauma. Bone marrow biopsy as an etiology of FES has been reported only once in humans. In addition, the association of embolization with bone marrow biopsies suggests that nonhuman primates may be a useful animal model of FE. FE and FES represent important research confounders and FES should be considered as a differential diagnosis for clinical complications subsequent to skeletal trauma. PMID- 21819687 TI - AALAS journals reader survey: survey conducted from 02 to 17 February 2011 survey results reported to AALAS on 18 February 2011. PMID- 21819688 TI - Association between hair-induced oronasal inflammation and ulcerative dermatitis in C57BL/6 mice. PMID- 21819690 TI - Minimizing animal numbers: the variable-criteria sequential stopping rule. AB - The variable-criteria sequential stopping rule (SSR) allows an investigator to use a few subjects at a time to determine whether a planned experiment is worth pursuing without increasing the rate of false discoveries (type I errors). The SSR is appropriate whenever testing a null hypothesis if the experiment can be conducted in stages. The investigator adds a predetermined number of subjects at each stage and tests repeatedly for significance until the experiment is stopped because: (1) a significant effect is detected; (2) the effect is clearly not going to be significant; or (3) the predetermined maximal number of subjects has been reached. Two crucial features of the SSR are that it holds the probability of a type I error constant and maintains excellent power. The method is more efficient than is performing a typical significance test after a power analysis because SSR can require 30% fewer subjects to achieve the same power. The variable-criteria SSR provides a formal method for assuring the use of a minimal number of animals. This article provides practical examples of how to use the SSR in combination with a t test, one-way ANOVA, one-way ANOVA with a planned contrast as the focus of the stopping rule, or, in limited circumstances, multifactorial ANOVA. PMID- 21819691 TI - Lack of effect of murine norovirus infection on a mouse model of bacteria-induced colon cancer. AB - Murine norovirus (MNV) is endemic in mouse research facilities in the United States and Europe, with a prevalence as high as 58% to 64%. Because of MNV's orofecal route of infection, clinically silent persistent infections in some mouse strains, and proclivity for macrophage and dendritic cells, its presence in mouse colonies has potential to alter phenotypes in experimental mouse models, particularly those involving inflammation and immunologic responses. Although MNV is subclinical, not causing overt disease in immunocompetent mice, we found that MNV infection can accelerate bacteria-induced inflammatory bowel disease (IBD) progression in Mdr1a(-/-) mice. The studies presented here examined whether MNV infection also affects the phenotype of a bacterially driven mouse model of inflammation-associated colon cancer in genetically susceptible Smad3(-/-) mice. In vitro culture of bone-marrow-derived macrophages (BMDM) was used to determine whether MNV4 influenced macrophage cytokine production. For in vivo studies, Smad3(-/-) mice were infected with MNV4 one week prior to infection with Helicobacter. Mice were monitored for 17 to 32 wk for development of IBD and colon cancer, and tissues were analyzed histopathologically. Although in vitro infection of BMDM with MNV4 led to increased inflammatory cytokine production, infection with MNV4 in vivo did not result in any statistically significant differences in survival, IBD scores, tumor incidence, or tumor phenotype in Smad3(-/-) mice. In addition, MNV infection alone did not result in IBD or colon cancer. Therefore MNV infection alone or in conjunction with Helicobacter does not alter the development or progression of IBD or colon cancer in Smad3(-/-) mice. PMID- 21819692 TI - Spontaneous nonthymic tumors in SCID mice. AB - SCID mice provide an excellent platform for cancer research. Because of their lack of immunity, SCID mice readily succumb to infectious pathogens and therefore must be maintained in an SPF, barrier-protected environment. Although SPF and barrier facilities prevent infection, SCID mice remain prone to premature death due in part to a high prevalence of spontaneous thymic lymphomas. However, little is known about spontaneous nonthymic tumors in SCID mice. We therefore analyzed the incidence of nonthymic tumor in our defined-flora C.B-17/Icr-SCID/Sed mice and examined their histopathologic characteristics. We necropsied 1060 retired SCID breeders (506 males, 554 females; average ages of 325 and 320 d, respectively) and found that 24 mice had developed nonthymic tumors, yielding an incidence of 2.26% (1.78% in males; 2.71% in females). The incidence of nonthymic tumors was substantially lower than that of thymic lymphomas in our retired SCID breeders (12.3% in males; 4.15% in females). Based on histopathology, 9 nonthymic tumors in male SCID mice consisted of 4 salivary gland myoepiteliomas, 2 rhabdomyosarcomas, and 3 cases of leukemia involving multiple organs. Female SCID mice had 15 nonthymic tumors consisting of 8 mammary adenocarcinomas, 4 salivary gland myoepitheliomas, and 1 case each of leukemia, rhabdomyosarcoma, and fibrosarcoma. In addition, we tested in vivo transplantability and characterized the growth behavior of several of these tumors. To our knowledge, this report is the first comprehensive description of spontaneous nonthymic tumors, including 8 myoepitheliomas and 3 rhabdomyosarcomas, from the same SCID mouse colony. PMID- 21819693 TI - An alternative in vivo method to refine the mouse bioassay for botulinum toxin detection. AB - Botulism is a rare, life-threatening paralytic disease of both humans and animals that is caused by botulinum neurotoxins (BoNT). Botulism is confirmed in the laboratory by the detection of BoNT in clinical specimens, contaminated foods, and cultures. Despite efforts to develop an in vitro method for botulinum toxin detection, the mouse bioassay remains the standard test for laboratory confirmation of this disease. In this study, we evaluated the use of a nonlethal mouse toe-spread reflex model to detect BoNT spiked into buffer, serum, and milk samples. Samples spiked with toxin serotype A and nontoxin control samples were injected into the left and right extensor digitorum longus muscles, respectively. Digital photographs at 0,8, and 24 h were used to obtain objective measurements through effective paralysis scores, which were determined by comparing the width to-length ratio between right and left feet. Both objective measurements and clinical observation could accurately identify over 80% of animals injected with 1 LD(50) (4.3 pg) BoNT type A within 24 h. Half of animals injected with 0.5 LD(50) BoNT type A and none injected with 0.25 LD(50) demonstrated localized paralysis. Preincubating the toxin with antitoxin prevented the development of positive effective paralysis scores, demonstrating that (1) the effect was specific for BoNT and (2) identification of toxin serotype could be achieved by using this method. These results suggest that the mouse toe-spread reflex model may be a more humane alternative to the current mouse bioassay for laboratory investigations of botulism. PMID- 21819694 TI - Heterogeneity of the tumorigenic phenotype expressed by Madin-Darby canine kidney cells. AB - The mechanisms by which cells spontaneously immortalized in tissue culture develop the capacity to form tumors in vivo likely embody fundamental processes in neoplastic development. The evolution of Madin-Darby canine kidney (MDCK) cells from presumptively normal kidney cells to immortalized cells that become tumorigenic represents an example of neoplastic development in vitro. Studies of the mechanisms by which spontaneously immortalized cells develop the capacity to form tumors would benefit from quantitative in vivo assays. Most mechanistic correlations are evaluated by using single-dose tumor-induction experiments, which indicate only whether cells are or are not tumorigenic. Here we used quantitative tumorigenicity assays to measure dose-and time-dependent tumor development in nude mice of 3 lots of unmodified MDCK cells. The results revealed lot-to-lot variations in the tumorigenicity of MDCK cells, which were reflected by their tumor-inducing efficiency (threshold cell dose represented by mean tumor producing dose; log(10) 50% endpoints of 5.2 for vial 1 and 4.4 for vial 2, and a tumor-producing dose of 5.8 for vial 3) and mean tumor latency (vial 1,6.6 wk; vial 2,2.9 wk; and vial 3,3.8 wk). These studies provide a reference for further characterization of the MDCK cell neoplastic phenotype and may be useful in delineating aspects of neoplastic development in vitro that determine tumor forming capacity. Such data also are useful when considering MDCK cells as a reagent for vaccine manufacture. PMID- 21819695 TI - Removal of potentially confounding phenotypes from a Siamese-derived feline glaucoma breeding colony. AB - Feline breeding colonies face genetic constraints involving founder effects. A Siamese-founded colony used to study primary congenital glaucoma displayed coat colors additional to the Siamese coat. Genes affecting pigment can exhibit pleiotropy on ocular development and function. To remove potentially confounding phenotypes from our colony, we documented the source and frequency of the Siamese allele at the gene for tyrosinase (TYR), the dilution allele at melanophilin (MLPH), and the brown allele at tyrosinase-related protein 1 (TYRP1). We used PCR RFLP diagnostics to genotype cats in our colony for the published alleles. A commercially acquired phenotypically normal tom was the source of the dilute allele. A founding Siamese queen was the source of the brown allele. Founders also were blood-typed and screened for disease-associated alleles segregating in Siamese cats at 3 loci (ASB, GLB1, and CEP290). Siamese founders were normal at all loci except ASB, at which both animals carried the hypomorpic allele. Current stock is being managed to limit production of glaucomatous cats with brown, dilute, or Siamese phenotypes or homozygosity for the ASB hypomorphic allele. Genotyping will aid in the elimination of these alleles. The clinical effect of these phenotypes and alleles on the glaucoma phenotype is uncertain, but their elimination will remove potentially confounding effects. In conclusion, when founding a colony, stock should be selected or screened to limit potentially confounding phenotypes. When studying the immune, nervous, and visual systems, screening stock for alleles known to be associated with coat color may be warranted. PMID- 21819696 TI - Hemodynamic and histologic characterization of a swine (Sus scrofa domestica) model of chronic pulmonary arterial hypertension. AB - The purpose of this work was to develop and characterize an aortopulmonary shunt model of chronic pulmonary hypertension in swine and provide sequential hemodynamic, angiographic, and histologic data by using an experimental endoarterial biopsy catheter. Nine Yucatan female microswine (Sus scrofa domestica) underwent surgical anastomosis of the left pulmonary artery to the descending aorta. Sequential hemodynamic, angiographic, and pulmonary vascular samples were obtained. Six pigs (mean weight, 22.4+/-5.3 kg; mean age, 7.3+/-2.7 mo at surgery) survived long-term (6 mo) and consistently developed marked pulmonary arterial hypertension. Angiography showed characteristic central pulmonary arterial enlargement and peripheral tortuosity and pruning. The biopsy catheter was safe and effective in obtaining pulmonary endoarterial samples for histologic studies, which showed neointimal and medial changes. Autopsy confirmed severe pulmonary vascular changes, including concentric obstructive neointimal and plexiform-like lesions. This swine model showed hemodynamic, angiographic, and histologic characteristics of chronic pulmonary arterial hypertension that mimicked the arterial pulmonary hypertension of systemic-to-pulmonary arterial shunts in humans. Experimental data obtained using this and other models and application of an in vivo endoarterial biopsy technique may aid in understanding mechanisms and developing therapies for experimental and human pulmonary arterial hypertension. PMID- 21819697 TI - Psychogenic alopecia in rhesus macaques presenting as focally extensive alopecia of the distal limb. AB - Focally extensive alopecia affecting the distal limbs is a common clinical finding in rhesus macaque (Macaca mulatta) colonies and is both a regulatory and colony-health concern. We performed diagnostic examinations including physical exams, bloodwork, skin scrapes, surface cytology, and surface bacterial-fungal cultures on 17 rhesus macaques with this presentation of alopecia. Skin biopsies from alopecic skin obtained from each macaque were compared with those of normal skin from the same animal. Immunohistochemistry and metachromatic staining for inflammatory cells were performed to compare alopecic and normal skin. In addition, we compared these biopsies with those previously obtained from macaques with generalized alopecia and dermal inflammatory infiltrates consistent with cutaneous hypersensitivity disorders and with those from animals with normal haircoats. Bacterial and fungal cultures, skin scrapes, surface cytology, and bloodwork were unremarkable. Affected skin showed only mild histologic alteration, with rare evidence of trichomalacia and follicular loss. Numbers of mast cells and CD3+ lymphocytes did not differ between alopecic and normally haired skin from the same animal. The number of mast cells in alopecic skin from animals in the current cohort was significantly lower than that in skin of animals previously diagnosed with a cutaneous hypersensitivity disorder. Numbers of both mast cells and CD3+ lymphocytes in alopecic skin from the current cohort were similar to those from biopsies of animals with normal haircoats. Together, the clinical findings and pathology are consistent with a psychogenic origin for this pattern of alopecia in rhesus macaques. PMID- 21819698 TI - Alterations in peripheral blood B-cell populations in SHIV89.6P-infected macaques (Macacca fascicularis). AB - In addition to CD4+ T cell depletion, the B cell compartment of HIV-infected patients exhibits abnormalities, including deficits and diminished responses to ex vivo antigenic stimulation and in vivo vaccination. We used chimeric simian human immunodeficiency virus (SHIV) infection of cynomolgus macaques to determine the dynamics of peripheral blood B cell alterations in this model of HIV infection. During the course of infection, we observed progressive loss of total and memory (CD27+) B cells, increased percentages of activated (CD95+) B cells, hypergammaglobulinemia, and deficits in the CD21+ B cell population. In addition, we noted declines in subsets of memory B cells, including both IgM+ and class switched (IgD-IgM- CD27+) cells, with sustained deficits in the IgM+ memory (IgM+CD27+) B cell population. The similarity of the B cell alterations in these studies to those observed in HIV+ subjects supports the utility of the SHIV macaque model for examination of HIV-related B cell dysfunction. PMID- 21819700 TI - Skewing the balance of regulatory T-cells and T-helper 17 cells in breast cancer patients. AB - This study investigated the distribution of interleukin (IL)-17-producing CD4(+) T-cells (T-helper [Th17] cells) in relation to CD4(+)CD25(+)CD127(-) cells (regulatory T-cells [T(reg)]) in tumour-infiltrating lymphocytes (TILs) and peripheral blood mononuclear cells (PBMCs) from breast cancer patients. The Th17 and T(reg) cells were evaluated by flow cytometry and reported as a percentage of total CD4(+) cells. In TILs from early breast cancer patients (n = 12), the frequency of Th17 cells was significantly higher than in PBMCs (14.5 +/- 7.2% versus 6.9 +/- 2.1%). In TILs from patients with advanced breast cancer (n = 15), the frequency of Th17 cells was also significantly higher than that in PBMCs (9.1 +/- 5.7% versus 3.2 +/- 2.3%) but lower compared with early disease. The Th17/T(reg) ratio in TILs was markedly increased in early versus advanced disease. In conclusion, Th17 and T(reg) cell accumulation in the tumour microenvironment of breast cancer occurred in early disease; Th17 cell infiltration gradually decreased and T(reg) cells accumulated with disease progression. PMID- 21819699 TI - Colonization with nontuberculous mycobacteria is associated with positive tuberculin skin test reactions in the common marmoset (Callithrix jacchus). AB - Mycobacterium tuberculosis infections can result in significant morbidity and mortality in nonhuman primate colonies. Preventative health programs designed to detect infection routinely include tuberculin skin testing (TST). Because Mammalian Old Tuberculin used for TST contains antigens common to a variety of mycobacterial species, false-positive results can occur in animals sensitized to nontuberculous mycobacteria (NTM). Over 11 mo, a large colony of common marmosets (Callithrix jacchus) demonstrated a 3.6% prevalence of equivocal or positive TST reactions (termed 'suspect reactions'). Culture of gastric aspirates, bronchoalveolar lavage fluid, and feces revealed a single animal with a positive fecal culture for Mycobacterium gordonae. PCR amplification of M. gordonae DNA in feces collected from animals with suspect TST reactions (demonstrating a 66.7% colonization rate) and colony controls (demonstrating a 14.3% colonization rate) revealed a significant association between suspect TST reactions and intestinal colonization. Gross and histopathologic evaluation revealed a multifocal lymphadenopathy and granulomatous lymphadenitis in 2 of 4 TST-positive marmosets examined. Counter to expectations, granulomatous lymphoid tissue was culture positive for M. kansasii rather than M. gordonae. Detection of M. gordonae in the feces of TST-suspect animals likely represents an apathogenic intestinal colonization that may serve as an indicator of NTM exposure, whereas evidence of histopathologic disease is associated with the more pathogenic M. kansasii. Although a high index of suspicion for M. tuberculosis should always be maintained, colonization with NTM organisms represents a cause of suspect TST reactions in common marmosets. PMID- 21819701 TI - Expression of aquaglyceroporins in epithelial ovarian tumours and their clinical significance. AB - Protein levels of aquaglyceroporins AQP3, AQP7 and AQP9 were measured by immunohistochemistry and Western blotting in epithelial ovarian tumour tissue from 98 patients and in normal ovary tissue from 20 persons with uterine myoma. AQP3 and AQP9 proteins were detected immunohistochemically in the basolateral membranes of benign and borderline tumour cells and were found to be distributed throughout the plasma membranes of malignant tumour cells. AQP7 protein was localized in the plasma membranes of benign tumour cells but, in borderline and malignant tumour cells, it was selectively stained in the nuclear membrane. Western blotting showed significantly higher AQP7 and AQP9 protein expression in malignant and borderline tumours than in benign tumour and normal ovarian tissue. AQP9 expression level was positively and significantly correlated with tumour grade and histological type. It was concluded that a high level of aquaglyceroporin expression may be an important factor in ovarian carcinogenesis. PMID- 21819702 TI - Identification of high-risk human papillomavirus (hrHPV)-associated genes in early stage cervical squamous cell carcinomas. AB - This retrospective study investigated gene expression in tumour samples from 38 patients with early stage human papillomavirus (HPV)-associated cervical squamous cell carcinoma (CSCC). The patients were divided into two groups based on the presence of viral markers of HPV16 or HPV18 infection. Gene expression profiles of tumour samples and the corresponding normal cervical epithelium were analysed using cDNA microarrays. Several genes showed differential expression between the two groups of HPV-infected CSCC patients, although seven genes showed similar changes in both groups. The four genes encoding cyclin-dependent kinase inhibitor 2A, matrix metallopeptidase 9, laminin gamma-1, and epidermal growth factor receptor were up-regulated, and the three genes encoding transforming growth factor beta receptor 1, interleukin-1alpha and insulin-like growth factor-binding protein 6 were down-regulated, in both HPV16(+) and HPV18(+) CSCC. These proteins are involved in cell proliferation, cell structure and cell attachment, so their expression might be involved in the mechanism of HPV-induced carcino genesis. A clearer understanding of HPV type-specific gene expression might aid diagnosis and treatment. PMID- 21819703 TI - Silencing of the GnRH type 1 receptor blocks the antiproliferative effect of the GnRH agonist, leuprolide, on the androgen-independent prostate cancer cell line DU145. AB - This study investigated the mechanism of action of a gonadotropin-releasing hormone (GnRH) agonist, leuprolide, on proliferation of the hormone-refractory prostate cancer cell line DU145, transfected with short hairpin RNA (shRNA), to reduce expression of the GNRHR1 gene (which encodes the GnRH type 1 receptor). DU145 cell proliferation in the presence of leuprolide (10(-9) and 10(-7) M) or control medium was measured before and after GnRHR1 knockdown. Reverse transcription-polymerase chain reaction and Western blot analysis were used to measure the degree of GNRHR1 silencing. DU145 cells treated with leuprolide (10( 9) and 10(-7) M) showed significant growth inhibition compared with control treated DU145 cells. Transfection with GNRHR1 -shRNA significantly decreased GNRHR1 expression at 48 h. DU145 cells transfected with silencing GNRHR1 -shRNA showed normal growth patterns; however, there was no significant inhibition of proliferation of DU145 cells transfected with GNRHR1 -shRNA compared with cells transfected with control-shRNA in response to leuprolide. These data demonstrated that the antiproliferative effect of leuprolide was mediated by the GnRHR1. PMID- 21819704 TI - Antileukaemia immunity: effect of exosomes against NB4 acute promyelocytic leukaemia cells. AB - Exosomes are a family of bioactive vesicles and play important roles in antigen presentation. A recent phase I clinical trial with an exosome vaccine derived from colorectal cancer has shown minor clinical benefit. Exosomes derived from leukaemia cell lines have been little studied so, in the present study, the immunoprotective effect of exosomes secreted by NB4 cells, a human acute promyelocytic leukaemia cell line, was investigated. NB4-derived exosomes expressed the proteins retinoic acid receptor alpha and interstitial cell adhesion molecule 1 and contained heat shock protein 70, as demonstrated by transmission electron microscopy and Western blotting. Cytotoxicity assay demonstrated that cytotoxic T lymphocytes (CTLs) induced by dendritic cells (DCs) pulsed with exosomes were significantly more effective in killing target NB4 cells than CTLs induced by DCs alone. Exosome-based vaccines may be a promising means of prolonging disease-free survival in acute promyelocytic leukaemia patients after induction therapy. PMID- 21819705 TI - Comparison of the predictability, uniformity and stability of a laser in situ keratomileusis corneal flap created with a VisuMax femtosecond laser or a Moria microkeratome. AB - This prospective study compared the predictability, uniformity and stability of laser in situ keratomileusis corneal flap thickness created by a femtosecond laser or a classic microkeratome. Twenty-five femtosecond laser (VisuMax, Carl Zeiss Meditec) flaps and 38 microkeratome (Moria M3) flaps were measured using anterior segment optical coherence tomography at 1 week, 1 month and 6 months postoperatively. Flap thickness at seven points on each of the four meridians was calculated. At 6 months, VisuMax flaps showed better prediction than Moria flaps for central flap thickness. The standard deviation within individual flaps was smaller for VisuMax flaps and their index of symmetry was better. The mean thicknesses among the four eccentricities in the VisuMax flaps were the same, while Moria flaps were thicker at the 3-mm radius compared with the centre. The VisuMax femtosecond laser created corneal flaps with better predictability and uniformity, and similar reproducibility and stability, compared with the microkeratome. PMID- 21819706 TI - Restless legs syndrome in Behcet's disease. AB - The prevalence of restless legs syndrome (RLS) and its association with the clinical features of Behcet's disease (BD) has not previously been elucidated. The inflammatory character, central nervous system involvement and neuropathies of BD led to this investigation of RLS risk in BD patients. A total of 116 BD patients and 104 healthy control subjects were included; seven BD patients were excluded because of concurrent diseases, pregnancy or alcohol misuse that might cause RLS symptoms, and the remaining 109 BD patients were included in the analysis. The prevalence of RLS was significantly higher in patients with BD (32/109; 29.4%) than in controls (5/104; 4.8%). No significant differences were found between BD patients with and without RLS with regard to the clinical features of BD. RLS severity positively correlated with age in BD patients. In conclusion, BD-related RLS should be considered in symptomatic RLS secondary to rheumatological disorders and BD patients should be examined for RLS. Further studies are needed to clarify the pathogenetic mechanisms underlying BD-related RLS. PMID- 21819707 TI - Use of a new type of trocar for the surgical treatment of hydrocephalus: a simple and effective technique. AB - This study compared the use of a new type of peritoneocentesis trocar with conventional laparotomy for the placement of the distal catheter in the treatment of hydrocephalus with ventriculoperitoneal shunt. A total of 376 patients with hydrocephalus were recruited to the study and were assigned randomly to undergo insertion of the distal catheter by conventional laparotomy (n = 195) or using the new peritoneal trocar (n = 181). The time taken for the surgical procedure and the complication rate over the following 1-year period were compared between the two groups. The mean length of the procedure to place the distal catheter was significantly shorter in the trocar group compared with the laparotomy group. Infection and obstruction rates were significantly higher in the laparotomy group than in the trocar group. In conclusion, the use of the new trocar was associated with lower rates of surgically induced trauma and complications compared with conventional laparotomy. PMID- 21819708 TI - Differences in left ventricular diastolic dysfunction between eccentric and concentric left ventricular hypertrophy in hypertensive patients with preserved systolic function. AB - Left ventricular (LV) hypertrophy (LVH) may be eccentric or concentric (2 * LV posterior wall thickness relative to LV end-diastolic dimension <= 0.42 or > 0.42, respectively). The LV diastolic function between age-matched hypertensive patients with eccentric and concentric LVH was compared in the present study. Echocardiography was used to measure LV mass index (LV mass/body surface area; LVMI) as an index of LVH. LV diastolic function was assessed by measurements of peak early transmitral flow velocity (E)/peak late transmitral flow velocity (A) (the E/A ratio), peak early diastolic mitral annular velocity (e') and the E/e' ratio. Although LVMI, E/A and e' did not differ between the two groups, E/e' was significantly higher (worse) in patients with concentric LVH (13.4 +/- 5.4) than in those with eccentric LVH (11.1 +/- 3.6). Among hypertensive patients with LVH, those with concentric LVH may, therefore, have more severe LV diastolic dysfunction than those with eccentric LVH even if their LVMIs, which reflect the degree of LVH, are similar. PMID- 21819709 TI - The role of serum osteoprotegerin and S-100 protein levels in patients with acute ischaemic stroke: determination of stroke subtype, severity and mortality. AB - This study investigated correlations between mortality, stroke subtype and stroke severity with serum osteoprotegerin (OPG) and S-100 protein levels prior to the treatment of patients admitted to the emergency department and diagnosed with ischaemic stroke. Pretreatment serum samples were collected from patients (n = 90) to determine OPG and S-100 protein levels. Age- and sex-matched healthy individuals (n = 16) served as controls. Compared with controls, OPG and S-100 protein levels were significantly higher in the cardioembolic and atherothrombotic stroke groups. Within the stroke group, OPG levels were significantly higher in the cardioembolic and atherothrombotic stroke groups compared with the transient ischaemic attack (TIA) group. S-100 protein levels were significantly higher in the atherothrombotic stroke group than in the lacunar stroke and TIA groups, and in the cardioembolic stroke group compared with the lacunar stroke group. Serum OPG and S-100 protein levels were significantly higher in patients who died compared with survivors. In predicting stroke subtype and severity, although both OPG and S-100 protein levels were indicators, S-100 protein was more valuable for mortality prediction. PMID- 21819710 TI - Prevalence of femoroacetabular impingement in asymptomatic contralateral hips in patients with unilateral idiopathic osteoarthritis. AB - Radiographic findings of femoroace tabular impingement in the contralateral asymptomatic hip of patients who had undergone total hip arthroplasty because of primary osteoarthritis (n = 44) were compared with controls (n = 40). The centre edge angle and caput-collum-diaphyseal angle were measured and the presence of crossover sign and a prominent ischial spine noted on anteroposterior radiographs of the pelvis. The alpha-angle and offset ratio were measured on cross-table lateral radiographs of the hip. The centre-edge angle and offset ratio were significantly lower and the alpha-angle significantly higher in the study group compared with controls. While the number of cases with an abnormal centre-edge angle was similar in both groups, the numbers with an alpha-angle > 50 degrees and the number with an offset ratio <= 15 were significantly higher in the study group. It was concluded that morphological anomalies associated with femoroacetabular impingement are seen more frequently in the asymptomatic contralateral hip of patients who have undergone hip replacement for primary osteoarthritis than in controls. PMID- 21819711 TI - Low-dose captopril inhibits wear debris-induced inflammatory osteolysis. AB - The role of captopril in titanium alloy particle-induced inflammatory osteolysis was investigated. BALB/c mice (n = 32) were divided into four groups, an untreated control group and three treatment groups given 12.5, 25 or 50 mg/kg per day captopril. Intraperitoneal injections of either 0.9% saline (control) or captopril began 2 days before the introduction of titanium alloy particles and calvaria bone from a syngeneic mouse into established air pouches. Mice were sacrificed 10 days after bone/titanium alloy implantation, and pouch membranes and implants were collected for histological and molecular analysis. Low-dose captopril (12.5 mg/kg per day) was found to inhibit titanium particle-induced tissue inflammation and inflammatory osteolysis. Pouch membrane thickness and inflammatory cellular infiltration were significantly reduced relative to controls. Captopril also inhibited production of the inflammatory cytokines tumour necrosis factor-alpha, interleukin-1beta and receptor activator of nuclear factor-kappaB ligand compared with controls. This study provides evidence that a low-dose of captopril can inhibit titanium particle-induced inflammatory osteolysis. PMID- 21819712 TI - Effects of a single dose of methylprednisolone versus three doses of rosiglitazone on nerve growth factor levels after spinal cord injury. AB - Acute spinal cord lesions result in dramatic changes in neuronal function. Studies have shown that the peroxisome proliferator-activated receptor-gamma agonist, rosiglitazone, has neuroprotective properties. The effect of rosiglitazone after acute spinal cord injury was examined in the present study. Rats were subjected to laminectomy only; laminectomy with spinal cord contusion injury; laminectomy with contusion injury plus 30 mg/kg body weight methylprednisolone administered 5 min after surgery; or laminectomy with contusion injury plus 2 mg/kg body weight rosiglitazone administered intraperitoneally 5 min, 6 h and 24 h after surgery. Both drugs increased neurotrophin gene and protein expression 24 h after injury compared with injured rats without drug treatment. Rosiglitazone increased neurotrophin expression at 7 days to a greater extent than methylprednisolone. Early functional recovery was observed in rats treated with rosiglitazone. The greater increase in rosiglitazone-induced nerve growth factor expression soon after injury could explain, at least in part, the improved recovery of motor function compared with methylprednisolone or saline. PMID- 21819713 TI - Polycythaemia in infants of diabetic mothers: beta-hydroxybutyrate stimulates erythropoietic activity. AB - This study tested whether elevated maternal beta-hydroxybutyrate (beta-OHB) levels contribute to polycythaemia in infants of diabetic mothers. Pregnant diabetic women (n = 27) and non-diabetic controls (n = 20) and their singleton infants were included. Maternal glycosylated haemoglobin and beta-OHB levels were studied at 34-36 weeks' gestation; levels were significantly higher in mothers with diabetes than in controls. Birth weights and cord blood levels of insulin and fetal haemoglobin were significantly higher in infants from diabetic mothers compared with control infants, as were haematocrit levels in venous blood samples taken from each infant at 4 h following delivery. Cord blood erythropoietin levels were similar in both groups. There was a positive strong correlation between maternal beta-OHB levels and polycythaemia in newborn infants, indicating that beta-OHB could activate erythropoiesis independently from intrauterine hyperinsulinaemia and/or erythropoietin levels, and may be important in the pathogenesis of polycythaemia in infants born to diabetic mothers. PMID- 21819714 TI - Biochemical markers comparison of dynamic hip screw and Gamma nail implants in the treatment of stable intertrochanteric fracture: a prospective study of 60 patients. AB - This prospective study compared the extent of surgical trauma following dynamic hip screw (DHS) or Gamma nail (GN) implantation in 60 patients (>= 60 years old) with stable intertrochanteric fracture. Levels of the biochemical markers creatinine kinase (CK) and C-reactive protein (CRP) were measured pre- and postoperatively. CRP levels were statistically significantly lower on postoperative days 1 and 2 in patients in the DHS versus the GN group; no other differences were observed. Surgical procedures for DHS implantation were considered less invasive than those for GN implantation, although the degree of muscle damage was similar in both groups. The degree of bone and bone marrow damage, rather than muscle tissue damage, may be crucial for determining the CRP response during the operative period. It is concluded that DHS implantation may be described as a more 'systemically' minimally invasive procedure than GN implantation. PMID- 21819715 TI - Vascular endothelial growth factor (VEGF) and the VEGF soluble receptor-1 (sFlt 1) in chorionic villus tissue from Chinese women with early recurrent spontaneous abortion. AB - This case-control study explored the relationship between early recurrent spontaneous abortion (RSA) and the expression of two genes: VEGFA, the gene encoding vascular endothelial growth factor (VEGF); and fms-related tyrosine kinase 1 (FLT1), the gene encoding the soluble VEGF receptor-1 (sFlt-1). Women experiencing RSA or undergoing induced abortions in the early stage of normal pregnancy were recruited to the study (n = 30 per group). There were no significant between-group differences in maternal age or duration of pregnancy. The levels of VEGF and sFlt-1 mRNA in chorionic villus tissue samples were examined by quanti tative reverse transcription-polymerase chain reaction. Levels of sFlt-1 and VEGF mRNA in the chorionic villus tissue of women with RSA were significantly higher than levels in the control group. This study demonstrated that there is a relationship between early RSA and VEGF and sFlt-1 levels, suggesting that over-expression of the FLT1 and VEGFA genes may be associated with the pathogenesis of RSA. PMID- 21819716 TI - Circulating antibodies to carcinoembryonic antigen related to improved recurrence free survival of patients with colorectal carcinoma. AB - This prospective study evaluated the prognostic value of antibodies to carcinoembryonic antigen (anti-CEA), detected by indirect immunosorbent assay, in the serum of colorectal carcinoma patients. Serum carcinoembryonic antigen (CEA) concentrations, measured by electrochemiluminescence immunoassay, were elevated in 26 (37.7%) of 69 patients with colorectal cancer and could not be detected among the 28 patients with benign intestinal conditions or 37 healthy individuals who comprised the control groups. Anti-CEA immuno globulin (Ig)G or IgM was detected by immunonephelometry in 44 (63.8%) patients with colorectal cancer, three (10.7%) with benign intestinal conditions and four (10.8%) healthy blood donors. Differences in antibody detection frequencies between the cancer patient group and the control groups were statistically significant. Titres of anti-CEA correlated significantly with CEA levels and Dukes' cancer stage. Antibody titre was an independent, significant, favourable predictor for 5-year recurrence-free survival. It is concluded that measurement of serum anti-CEA combined with CEA might be useful as a tumour marker and to assess prognosis. These results need to be confirmed in large, well-controlled, randomized clinical trials. PMID- 21819717 TI - Documented intraoperative hypotension according to the three most common definitions does not match the application of antihypotensive medication. AB - This observational study investigated which of the three most common definitions of intraoperative hypotension (IOH), reported in a published systematic literature review, were associated best with anaesthetists' administration of antihypo tensive medication (AHM). IOH and AHM use in anaesthetic procedures in a mixed surgical population (n = 2350) were also reviewed. The definitions were: arterial systolic blood pressure (SBP) < 100 mmHg or a fall in SBP of > 30% of the preoperative SBP baseline; arterial SBP < 80 mmHg; a fall in SBP of > 20% of the preoperative SBP. Accuracy of predicting AHM using these three definitions was 67%, 54% and 65%, respectively. Prediction by a new fourth definition, using an optimal threshold of minimal SBP falling to < 92 mmHg or by > 24% of preoperative baseline, was 68% accurate. In multivariate logistic analysis, age, volatile versus intravenous anaesthetics, medical history of arterial hypertension and all four definitions of IOH were associated with intraoperative AHM, however IOH was not associated with postoperative in-patient stay. The three original definitions correlated poorly with the anaesthetist's judgement about applying AHM. Anaesthetists make complex decisions regarding the relevance of IOH, considering various perioperative factors in addition to SBP. Age, physical status and duration and type of surgery showed better correlations with postoperative in-patient stay than IOH. PMID- 21819718 TI - Effect of osteoporosis on clinical outcomes in intertrochanteric hip fractures treated with a proximal femoral nail. AB - The effect of osteoporosis on clinical outcomes following surgical treatment of intertrochanteric hip fractures was investigated. A total of 80 patients aged 65 97 years with intertrochanteric hip fractures underwent insertion of a proximal femoral nail. Osteoporosis severity was measured using the Singh index in the unaffected hip. Screw cut-out occurred in four patients, reverse Z-effect in three patients and Z-effect in one patient. Four patients were lost to follow up. Clinical results were evaluated according to the Harris hip scoring system. The mean Harris hip score was 73.58 (range 25-100). When divided according to Singh index grade (I-II versus III-V), there were no significant differences in mean age, type of fracture, American Society of Anesthesiologists classification or frequency of technical failures between the two groups. The mean Harris hip score, however, was significantly lower in patients with grades I-II compared with grades III-V, suggesting that the presence of osteoporosis had a negative effect on clinical outcome after hip fracture. PMID- 21819719 TI - Otitis media with effusion in primary schools in Princes' Islands, Istanbul: prevalence and risk factors. AB - The prevalence of otitis media with effusion (OME) and environmental risk factors were investigated in 423 children aged 7-12 years at three primary schools in Princes' Islands, Istanbul, Turkey. An ear, nose and throat examination, including tympanometry, was performed in April (end of the school year) and the families completed a questionnaire about potential risk factors. Type B or C2 tympanograms were taken as indicating OME. The overall prevalence of OME was 16%. OME was significantly associated with numbers of episodes of upper respiratory tract infections (URTI) and acute otitis media (AOM) during the previous year, class size and snoring, but not with allergic symptoms, kindergarten years, breast-feeding duration, parental smoking, domestic animals at home, numbers of siblings and family members, type of home heating, parents' educational level or monthly income. Four or more URTIs and two or more AOM episodes in a year, snoring and class size larger than 20 were risk factors for OME. PMID- 21819720 TI - The epidemiology, management, outcomes and areas for improvement of burn care in central Malawi: an observational study. AB - This report describes the epidemiology of burn injuries and quantifies the appropriateness of use of available interventions at Kamuzu Central Hospital, Malawi, between July 2008 and June 2009 (370 burn patients). Burns accounted for 4.4% of all injuries and 25.9% of all burns presenting to the hospital were admitted. Most patients (67.6%) were < 15 years old and 56.2% were male. The most frequent cause was scalding (51.4%). Burns occurred most frequently in the cool, dry season and in the evening. The mean burn surface area (second/third degree) was 14.1% and most burns (74%) presented within 8 h. The commonest procedure was debridement and/or amputation. The mean hospital stay was 21.1 days, in-hospital mortality was 27% and wound infection rate was 31%. Available interventions (intravenous fluids, nutrition therapy, physiotherapy) were misapplied in 59% of cases. It is concluded that primary prevention should address paediatric and scald burns, and secondary prevention should train providers to use available interventions appropriately. PMID- 21819721 TI - Significance of plasma levels of pigment epithelium-derived factor as determined by multidetector row computed tomography in patients with mild chronic kidney disease and/or coronary artery disease. AB - Little is known about the association between plasma levels of pigment epithelium derived factor (PEDF), coronary artery disease (CAD) and/or chronic kidney disease (CKD). This study evaluated 289 consecutive patients with chest pain or at least one coronary risk factor who underwent coronary angiography using multidetector row computed tomography (MDCT). Presence of CAD and CKD, CAD severity (i.e. number of significantly stenosed coronary vessels, described as vessel disease [VD]), coronary calcification scores, visceral fat area (VFA), subcutaneous fat area on MDCT, and metabolic biomarkers were recorded. PEDF levels correlated significantly with sex, VFA, CKD presence/hyperuricaemia and high-density lipoprotein cholesterol levels. PEDF levels were closely associated with CKD and were significantly higher in CKD patients than in non-CKD patients, regardless of the presence of CAD. CKD patients with two-VD or three-VD had higher plasma PEDF levels than non-CKD patients with two-VD or three-VD. It is concluded that PEDF may be associated with CKD regardless of the presence of CAD. PMID- 21819722 TI - Multiple intraoperative monitoring-assisted microneurosurgical treatment for anterior circulation cerebral aneurysm. AB - This study investigated the efficacy of multiple intraoperative monitoring techniques including indocyanine green angiography (ICGA), somatosensory evoked potential (SSEP) and motor evoked potential (MEP) in the clinical outcome of microneurosurgical treatment for anterior circulation cerebral aneurysm. Fifty two anterior circulation cerebral aneurysms (Hunt and Hess [H&H] grades 0, 1 or 2) from 45 Chinese in-patients were completely clipped. In one patient, ICGA directed neurosurgeons to readjust aneurysmal clips in order to eliminate a residual aneurysm and restore patency of a branching artery. SSEP/MEP directed neurosurgeons to implement intervention measures in 12 patients for recovery of SSEP/MEP changes, and SSEP/MEP changes partially/totally recovered in 11 of these 12 patients (91.6%). Postoperative motor deficits were observed in three patients, two of which were Glasgow Outcome Scale level 3 (4.4%). In conclusion, for patients with anterior circulation cerebral aneurysm (H&H grade < 3), multiple intraoperative monitoring was beneficial for finding residual aneurysms, detecting ischaemic events in the perforating arteries and reducing severe postoperative motor deficiency. PMID- 21819723 TI - Modified thoracoscopic versus minimally invasive oesophagectomy in curative resection of oesophageal cancer. AB - Conventional thoracoscopic oesophagectomy is time-consuming and requires sophisticated endoscopic skills. To reduce these problems we have modified the operating procedure, first by anastomosis of the oesophagus with the tubular stomach pulled up via the retrosternal route, followed by thoracoscopic oesophagectomy (modified thoracoscopic oesophagectomy). Outcomes were compared between the modified procedure and minimally invasive oesophagectomy. There were no significant differences in general preoperative clinical characteristics between the two patient groups. The modified thoracoscopic oesophagectomy group had significantly lower hospitalization expenses, significantly shorter operation times and significantly more lymph nodes removed compared with the minimally invasive oesophagectomy group, but there were no significant group differences in lengths of hospital and intensive care unit stays, morbidity and mortality. These results indicate that modified thoracoscopic oesophagectomy is feasible, simplifies operating procedures and reduces hospitalization expenses with acceptable morbidity. PMID- 21819724 TI - Value of diffusion-weighted imaging in grading tumours localized in the fourth ventricle region by visual and quantitative assessments. AB - This study investigated visual and quantitative assessment of diffusion-weighted imaging (DWI) for grading tumours localized in the fourth ventricle region. Patients were diagnosed histopathologically and classified into two groups: those with high-grade (World Health Organization [WHO] grades III and IV) and those with low-grade tumours (benign, WHO grades I and II). DWI signal intensity was described using a five-point scale. Minimum apparent diffusion coefficient (ADC) values were obtained from areas with the lowest signal. The mean signal intensity was significantly higher in high-grade than in low-grade tumours. The mean minimum ADC value was significantly lower in high-grade than low-grade tumours. Marked hyperintensity had sensitivity, specificity, positive predictive value and negative predictive value of 89.7%, 100%, 100% and 94.2%, respectively, when used as a diagnostic tool for high-grade tumours compared with 96.6%, 97.9%, 96.6% and 97.9%, respectively, when using a minimum ADC of 0.9 * 10(-3) mm(2)/s as a diagnostic marker. It was concluded that DWI is helpful in predicting the grades of tumours in the fourth ventricle region. PMID- 21819725 TI - Contrast-enhanced ultrasound for the diagnosis of hepatic adenoma. AB - Nine hepatic adenomas (HA) diagnosed by contrast-enhanced ultrasound (CEUS) among 123 liver lesions (89 patients) were evaluated retrospectively; five were confirmed through pathological diagnosis. Time-intensity curves (TIC), contrast medium arriving time (AT), peak time (PT) and retrogression time (RT) for HA were compared with 30 hepatocellular carcinomas (HCC) and six focal nodular hyperplasias (FNH). Significant differences existed between HA and poorly differentiated HCC in AT, PT and RT, and between HA and well-differentiated HCC in AT. Differential diagnosis between HA and FNH was determined only through their different perfusion and arterial morphological features: HA showed typical perfusion characteristic of 'fast-in, slow-out', with a centripetal or mixed filling pattern in the arterial phase, while FNH showed a centrifugal filling pattern. In conclusion, CEUS was helpful for identifying HA but it may be relatively difficult to distinguish between HA and some well-differentiated HCC or FNH. PMID- 21819726 TI - Association between ABO blood groups and osteoporosis severity in Chinese adults aged 50 years and over. AB - This study investigated whether the ABO blood groups contributed to the severity of osteoporosis in 1452 community-dwelling Chinese adults aged 50-85 years. Osteoporosis severity was scored as: F(0), no osteoporosis; F(1), osteopenia; F(2), osteoporosis; and F(3), severe osteoporosis. The proportions of adults with a non-O blood group were 55.0%, 62.0%, 70.8% and 72.6% for the groups with F(0), F(1), F(2) and F(3) osteoporosis scores, respectively. Having a non-O blood group was associated with an increased severity of osteoporosis, even after adjustment for gender, age and cigarette consumption (odds ratio 1.8; 95% confidence interval 1.0, 2.9). This study demonstrated that having a non-O blood group was an independent risk factor for the progression of osteoporosis in Chinese adults with osteoporosis aged >= 50 years. PMID- 21819727 TI - Comparative evaluation of the microcolumn gel card test and the conventional tube test for measurement of titres of immunoglobulin G antibodies to blood group A and blood group B. AB - The conventional tube test (CTT) and microcolumn gel card test (MG) were used to measure immunoglobulin G (IgG) antibody titres to blood group A (anti-A) and blood group B (anti-B) in 288 serum samples. Diagnostic concordance and correlations between the two methods were analysed. MG was more sensitive than CTT in the detection of both anti-A and anti-B IgG. Correlation coefficients for the two methods for the titration of anti-A and anti-B were 0.8470 and 0.8336, respectively. The regression equation representing the relationship between the two methods was calculated and used to convert critical values for anti-A and anti-B IgG antibodies determined by CTT to critical values for MG titration. Analyses showed 86.8% and 89.9% diagnostic concordant rates for the detection of anti-A and anti-B IgG, respectively. It was concluded that titration results obtained by MG correlate well with those obtained by CTT, but critical values determined by CTT need to be converted into corresponding MG values. PMID- 21819728 TI - Bronchopulmonary infection with Lophomonas blattarum: a case report and literature review. AB - Human infection with Lophomonas blattarum is extremely rare. The clinical manifestations of 45 cases of bronchopulmonary L. blattarum infection occurring in China, including one case diagnosed and treated at the authors' hospital, are described. The most common manifestations included fever, cough with expectoration, chest stuffiness or shortness of breath, bronchiectasis and pulmonary abscess. A course of metronidazole treatment lasting 14-38 days was effective in controlling the disease. The diagnosis of L. blattarum infection should be based on one or more of bronchoscopic brush smear, bronchoscopic biopsy smear and bronchoalveolar lavage. PMID- 21819729 TI - Haploidentical allogeneic haematopoietic stem cell transplantation as salvage therapy for engraftment failure after unrelated and autologous stem cell transplantation: a case report and review of the literature. AB - Engraftment failure is a rare but life-threatening complication of haematopoietic stem cell transplantation (HSCT) and treatment of this condition is often challenging. This case report describes a patient with acute myeloid leukaemia and engraftment failure after unrelated donor allogeneic stem cell transplantation. Rescue treatment with granulocyte-colony stimulating factor and reinfusion of autologous 'back-up' stem cells failed, but transplantation of haploidentical donor stem cells following a fludarabine and antithymocyte globulin (ATG)-based conditioning regimen resulted in haematological reconstitution and long-term disease-free survival. The use of haploidentical donor stem cell transplantation as salvage therapy after engraftment failure in adult patients has not, to the authors' knowledge, been previously reported. Additionally, a review of the relevant literature is presented. This case report and literature review suggest that reinfusion of cryopreserved 'back-up' haematopoietic stem cells is a safe and effective salvage therapy for engraftment failure after allogeneic HSCT. Haploidentical donor stem cell transplantation after a fludarabine and ATG-based conditioning regimen could provide effective second-line therapy in adult patients. PMID- 21819730 TI - Extracranial skeletal metastasis in anaplastic oligodendroglioma: case report and review of the literature. AB - A case of anaplastic oligodendroglioma with femoral metastasis is presented in a 37-year old male with a 2-year history of progressive headaches and dizziness associated with a 2-month history of epilepsy and right hemiparesis. Magnetic resonance imaging (MRI) demonstrated a solid temporoparietal tumour and the patient underwent a left temporal craniotomy and subtotal resection followed by limited-field radiation therapy. The pathological diagnosis was anaplastic oligodendroglioma. The patient presented with left hip pain 3 years later. Radiography and computed tomography demonstrated osteosclerosis of the left proximal femur, and MRI revealed an intramedullary metastatic lesion. Total body (99m)Tc-methylene diphosphonate bone scan showed hyperactivity in the lesion and open biopsy confirmed it was a metastasis from the cerebral oligodendroglioma. The patient was treated with temozolomide and, to date, there is no sign of recurrence or progression in either the brain or the femur. Seven previously reported cases of extracranial skeletal metastasis from anaplastic oligodendroglioma are reviewed. Co-deletion of chromosome arms 1p and 19q and O(6)-methylguanine DNA methyltransferase status remain the most important prognostic and predictive markers. PMID- 21819731 TI - Diagnosis of pulmonary disease caused by Mycobacterium abscessus: a case report. AB - Mycobacterium abscessus (M. abscessus) is a non-tuberculous mycobacterium and an important emerging pathogen causing skin, soft tissue and pulmonary infections. The case of a 59-year-old man with a history of pulmonary tuberculosis (TB) and current pulmonary infection due to M. abscessus, complicated with pneumocardial disease and bronchiectasis, is described. Zhiel-Neelsen stain and acid Lowenstein Jensen culture were both positive for acid-fast bacillus. The patient was initially misdiagnosed and ineffectively treated for pulmonary TB. Antimycobacterial susceptibility tests found the isolate to be resistant to four first-line and seven second-line antituberculosis drugs. The isolate was finally identified as M. abscessus using 16S ribosomal RNA and hsp65 and rpoB gene sequence analysis. Species of mycobacterium should be included in the differential diagnosis when patients do not respond to standard antituberculosis therapy. Molecular methods are useful for rapid and species-specific identification. PMID- 21819732 TI - Total parathyroidectomy with forearm autotransplantation as the treatment of choice for secondary hyperparathyroidism. AB - Chronic kidney disease-mineral and bone disease (CKD-MBD) is associated with uraemic bone disease, vascular calcification, reduced quality of life and reduced survival. This study evaluated the efficacy of parathyroidectomy (PTX) with autotransplantation in improving short-term and long-term outcomes. Dialysis patients who underwent PTX showed significantly more favourable biochemical parameters after PTX. These changes were accompanied by a lower coronary artery calcification score, reduced thickness of the intimae media and comparable bone mineral density measures compared with control dialysis patients who did not undergo PTX. Despite the risk of a substantially lower intact parathyroid hormone level postoperatively that might lead to adynamic bone disease, none of the patients reported clinical signs of this disease, such as bone pain or fractures. In conclusion, PTX with autotransplantation led to improvement of CKD-MBD so may be considered in patients with secondary hyperparathyroidism that is resistant to treatment with vitamin D analogues and calcimimetics. PMID- 21819733 TI - Intelligent data analysis for the diagnosis of alcohol dependence syndrome. AB - Alcohol dependence syndrome is hard to diagnose because none of the existing laboratory markers alone has sufficient specificity and sensitivity. This study investigated whether combinations of markers would improve the identification of patients with alcohol dependence syndrome. Intelligent data analysis was carried out using the decision tree induction method with training and test data from 244 healthy volunteers and 238 patients with alcohol dependence syndrome. The results showed that a combination of two or three laboratory markers can identify alcohol dependence syndrome with almost 85% accuracy. It must be noted that induced decision trees offer a qualitatively different diagnostic evaluation of laboratory findings that varies from common practice, because they set up their own new borders and criteria that are different to generally accepted or set reference values. Tests for all of the selected laboratory markers are widely available, inexpensive to perform and usually form part of a routine laboratory examination. PMID- 21819734 TI - Anatomical variations of the posterior intercostal arteries and the thoracic vertebral artery. AB - This study evaluated the occurrence and frequency of the anatomical variations of the origin and course of the posterior intercostal arteries (PIA) in 44 human cadavers. During a classical anatomical dissection of each cadaver an anomalous course of the PIA, defined as a thoracic vertebral artery, was found in six (14%) individuals. Every dorsally coursing PIA was taken into account, regardless of its origin, and their different origins and course were described. A specific dorsal course for the PIA was found in nine cases, which was bilateral in two cases. The variations that were found and that have been schematically presented will provide new information about the anatomical variations of the PIA. Consideration of the potential for anatomical variation of the PIA is important in vascular and thoracic surgery and in diagnostic and interventional radiology such as spinal angiography. PMID- 21819735 TI - Comparison of coronary artery calcification and some coronary artery calcification risk factors in patients on haemodialysis and in patients with type 2 diabetes. AB - Patients on haemodialysis (HD) and patients with type 2 diabetes are at high-risk for coronary artery calcification (CAC). The coronary artery calcium score (CACS), quantified by computed tomography, cannot be completely explained by traditional cardiovascular disease risk factors. CAC was measured in 45 non diabetic chronic kidney disease patients on HD and in 45 matched type 2 diabetes patients without diabetic nephropathy. Serum calcium, phosphate, 25 hydroxyvitamin D (25[OH]D), alkaline phosphatase, intact parathyroid hormone (iPTH), fetuin-A, high-sensitivity C-reactive protein (hsCRP), albumin, homocysteine, total cholesterol, low-density lipoprotein cholesterol, high density lipoprotein cholesterol, triglycerides and femoral neck bone mineral density were also measured. No differences were observed in patient distribution across the CACS risk categories between the two groups. Significant differences were observed in serum calcium, phosphate, 25(OH)D, alkaline phosphatase, iPTH, fetuin-A, hsCRP, homocysteine and triglycerides between the two patient groups. Further research into the diverse, numerous and often interlinked factors that influence CAC in different groups of patients is warranted. PMID- 21819736 TI - Upper gastrointestinal haemorrhage: predictive factors of in-hospital mortality in patients treated in the medical intensive care unit. AB - This prospective, cohort study assessed the independent predictors of in-hospital mortality in patients with acute upper gastrointestinal haemorrhage admitted to the medical intensive care unit (MICU) at the University Clinical Centre Maribor, Slovenia. Using univariate, multivariate and logistic regression methods the predictors of mortality in 54 upper gastrointestinal haemorrhage patients (47 men, mean +/- SD age 61.6 +/- 14.2 years) were investigated. The mean +/- SD duration of treatment in the MICU was 2.8 +/- 2.9 days and the mortality rate was 31.5%. Significant differences between nonsurvivors and survivors were observed in haemorrhagic shock, heart failure, infection, diastolic blood pressure at admission, haemoglobin and red blood cell count at admission, and lowest haemoglobin and red blood cell count during treatment. Heart failure (odds ratio 59.13) was the most significant independent predictor of in-hospital mortality. Haemorrhagic shock and the lowest red blood cell count during treatment were also important independent predictive factors of in-hospital mortality. PMID- 21819737 TI - Anxiety and depression during hospital treatment of exacerbation of chronic obstructive pulmonary disease. AB - This study investigated the prevalence, risk factors and rate of recognition of anxiety and depression in 50 patients hospitalized for exacerbation of chronic obstructive pulmonary disease (COPD). Using the Primary Care Evaluation of Mental Disorders questionnaire, 13 patients were identified as having depression, four had anxiety and eight had a combination of the two. Patients with anxiety and/or depression had a significantly higher partial pressure of oxygen and pH, and a lower partial pressure of carbon dioxide, in arterial blood on admission, more severe dyspnoea after a 6-min walk test and less improvement of dyspnoea from admission to discharge than COPD patients without anxiety and/or depression. Two patients were referred to a mental health specialist during their hospitalization, indicating a low rate of recognition. The results suggest that patients with mental disorders are referred and admitted to hospital earlier in the course of a COPD exacerbation due to earlier and more intense perception of dyspnoea. PMID- 21819738 TI - The size of the papilla of Vater and its relation to its height in comparison with the visibility of the sphincter of Oddi before and after cholecystectomy. AB - This study investigated the changes in the surface area and height of the papilla of Vater (PV) and the visibility of the sphincter of Oddi complex (SOK) using endoscopic ultrasound (EUS) examinations of 80 patients with symptomatic gallstones before and at 3 and 6 months after cholecystectomy. Following surgery, 50 patients experienced early atypical symptoms characteristic of postcholecystectomy syndrome (PCS) and 30 patients were asymptomatic. The PV measurements were greater in all patients compared with normal reference values and increased significantly from before surgery to 3 months postsurgery. At 6 months postsurgery, both the surface area and height of the PV had significantly decreased to preoperative values but remained higher than normal. The proportion of patients with a visible SOK had increased by 3 months postsurgery but had reduced again by 6 months. There were no significant differences between symptomatic and asymptomatic patients, suggesting that the changes observed in the PV and SOK do not explain the presence of the atypical symptoms of PCS. PMID- 21819739 TI - Dynamic changes of echogenicity and the size of the papilla of Vater before and after cholecystectomy. AB - This study investigated the changes in echogenicity, as measured by endoscopic ultrasound, and the surface area of the papilla of Vater (PV) and their relationship with postoperative symptoms in a group of 80 patients with symptomatic gallstones before and at 3 and 6 months after cholecystectomy. After cholecystectomy, 50 patients experienced early atypical symptoms characteristic of postcholecystectomy syndrome (PCS) and 30 patients were asymptomatic. The surface area of the PV was larger than normal prior to surgery and increased after surgery. The healthy PV is isoechogenic, but 48% of all patients were anisoechogenic preoperatively, increasing to 61% at 3 months after surgery, and decreasing to 25% at 6 months postsurgery. There was no significant difference between the two patient groups, suggesting that the changes observed in the PV do not explain the presence of the atypical symptoms of PCS. PMID- 21819740 TI - Lipids, waist circumference and body mass index in haemodialysis patients. AB - In the general population, dyslipidaemia and abdominal obesity are risk factors for cardiovascular disease, but less is known about their roles in patients on maintenance haemodialysis (HD). This study investigated the association between blood lipids and abdominal obesity, as determined by waist circumference (WAC), and body mass index (BMI) in 72 HD patients (32 women). Blood lipid levels were measured using routine laboratory methods. Abdominal obesity, based on the WAC measurement, was found in 62.5% of HD patients (75.0% of women; 52.5% of men). Triglyceride levels were higher in abdominally obese compared with abdominally non-obese men. According to BMI measurements, 34.7% of HD patients were overweight/obese and 9.7% were underweight. In men, WAC and BMI were positively correlated with triglyceride levels. In women, WAC was negatively correlated with high-density lipoprotein (HDL) cholesterol and apolipoprotein A levels. The results indicated that there was a negative association of abdominal obesity and BMI with HDL cholesterol in HD patients. PMID- 21819741 TI - Diagnosing mitral valve prolapse by improving the predictive power of classifiers. AB - Mitral valve prolapse (MVP) has been described as one of the most common cardiac valvular abnormalities in industrialized countries, and can result in sudden death. This study focused on various feature selection mechanisms that might improve the predictive power of a classifier to diagnose MVP. The experiment included selection mechanisms using classical greedy feature selection approaches (forward selection and backward elimination), a genetic algorithm (GA) approach and a cellular automaton (CA) approach. The main aim of this latest approach is to use CA with GA for the data transformation phase of the knowledge discovery process. The CA-GA approach produced better results than the classical greedy approaches. The subsets of features produced by the GA and CA approaches were most appropriate for the decision tree classifier, for diagnosing MVP with the highest overall class accuracy. More importantly, the CA and GA approaches were also capable of generalizing some important knowledge concerning MVP diagnosis. PMID- 21819742 TI - The influence of the Trendelenburg position on haemodynamics: comparison of anaesthetized patients with ischaemic heart disease and healthy volunteers. AB - This study compared the influence of the Trendelenburg position on haemodynamics in non-anaesthetized spontaneously breathing healthy volunteers and anaesthetized, mechanically ventilated patients with ischaemic heart disease scheduled for coronary artery bypass graft (CABG) surgery. Placing the anaesthetized patients scheduled for CABG surgery in the Trendelenburg position resulted in a significant increase in cardiac output and mean arterial pressure and a non-significant decrease in heart rate. In contrast, in the non anaesthetized healthy volunteers, heart rate increased significantly but both cardiac output and mean arterial pressure changed non-significantly. Further studies will be needed to evaluate the haemodynamics of the Trendelenburg position. PMID- 21819743 TI - Non-cirrhotic and non-malignant acute extrahepatic portal vein thrombosis (PVT): short- and long-term results. AB - This observational cohort study reports the short- and long-term clinical outcomes of 31 patients admitted for acute non-malignant, non-cirrhotic portal vein thrombosis (PVT) over a 10-year period. Patients had a mean age of 43 years at admission and a mean duration of follow-up of 84 months. All patients were initially treated with anticoagulants. Complete recanalization occurred within 30 days after admission in 18 patients (58%), partially in nine patients (29%), and failed in four patients (13%). During follow-up, 10 patients (32%) had at least one episode of gastrointestinal bleeding. The probability of remaining bleed-free was 0.93 at 24 months and 0.61 at 48 months. Fundal varices were not controlled by endoscopic sclerotherapy, so all four patients underwent portosystemic shunt construction. To date, there has been no mortality. In conclusion, using a combination of different treatment options reduces the risk of death and late complications in patients with non-malignant, non-cirrhotic PVT. PMID- 21819744 TI - High-dose cholecalciferol supplementation for vitamin D deficiency in haemodialysis patients. AB - Vitamin D deficiency, which is a recognized problem in haemodialysis (HD) patients, has been associated with higher all-cause mortality. There are no guidelines concerning vitamin D supplementation in HD patients. This study aimed to assess the effects of once-monthly supplementation with high-dose cholecalciferol (vitamin D(3)) in HD patients. Patients with 25-hydroxy vitamin D (25[OH]D) levels of < 75 nmol/l received 40,000 IU of cholecalciferol oncemonthly for 3 months in succession. Every 4 months, 25(OH)D levels were measured and, based on the findings, cholecalciferol therapy was continued for another cycle if necessary. Six cycles were completed in the 24-month study period. The majority of HD patients had mild or severe vitamin D deficiency at baseline. Monthly supplementation with cholecalciferol at 40,000 IU was well tolerated, safe and inexpensive. The treatment regime was effective for vitamin D insufficiency but did not prove to be enough to restore 25(OH)D levels in HD patients with mild or severe vitamin D deficiency. PMID- 21819745 TI - Intravenous thrombolysis with recombinant tissue plasminogen activator (rt-PA) in acute lower limb ischaemia. AB - For various reasons some patients are unable to undergo intra-arterial thrombolysis for acute limb ischaemia. This interventional case series study prospectively evaluated the effect of thrombolytic treatment with 100 mg recombinant tissue plasminogen activator (rt-PA), administered intravenously, in patients with acute thrombosis of the lower limb arteries and onset of symptoms within 12 h prior to treatment. During a 3-year period (2007-2009), 18 of 86 patients satisfied the inclusion criteria and were included in the study (age range 65-80 years; 11 women). Complete and partial thrombolysis was observed in eight (44.4%) and six (33.3%) patients, respectively. All patients experienced clinical improvement. There were no amputations during the 36-month follow-up period and no haemorrhagic complications in the first 30 days post-treatment. Five patients died (27.8%) during follow-up from unrelated causes. This small study demonstrated that thrombolytic treatment with intravenous rt-PA in selected patients with acute limb ischaemia is feasible. PMID- 21819746 TI - Influence of cataract surgery on macular thickness--a 3-month follow-up. AB - This prospective follow-up study evaluated the longer term changes to macular thickness and volume following cataract surgery. The study included 23 patients (23 eyes) who underwent ambulatory cataract surgery with phacoemulsification and intraocular lens implantation, followed by a scheduled optical coherence tomography measurement of macular thickness and volume after 3 months. Results were compared with preoperative data and measurements taken at 1 month after surgery, which were recorded in a previous study. A comparison of preoperative macular thickness values with those at 3 months after surgery demonstrated that the latter values remained greater in all macular regions except the superior outer macula, and that the differences were significant in the fovea, nasal inner macula and inferior outer macula. When macular thickness at 3 months after surgery was compared with that measured at 1 month, decreases were observed in all perifoveal areas, suggesting the reversible nature of cataract surgery related macular thickness changes. PMID- 21819747 TI - Effects of methotrexate on vascular endothelial growth factor, angiopoietin 1, and angiopoietin 2 in nasal polyps. AB - BACKGROUND: Methotrexate (MTX) is a very effective treatment for chronic inflammatory diseases, which are often associated with increased angiogenesis. Angiogenesis is dependent on a perfectly coordinated balance between endogenous positive and -negative regulatory factors, including vascular endothelial growth factor (VEGF) and the angiopoietins (Ang). The aim of this study was to investigate the effects of MTX on levels of VEGF, Ang-1, and Ang-2 in organ cultured nasal polyps (NPs). METHODS: To determine the effects of MTX, NP tissues were cultured using an air-liquid interface method. Cultures were maintained in the absence or presence of MTX (10 or 100 micromoles) for 24 hours. Hematoxylin and eosin, and TUNEL (terminal deoxynucleotidyl transferase [Tdt]-mediated dUTP biotin nick-end labeling) staining were performed to observe apoptosis. Enzyme linked immunosorbent assay was used to quantify tissue concentrations of VEGF, Ang-1, and Ang-2. RESULTS: MTX treatment resulted in marked alterations in inflammatory cells, especially eosinophils. In contrast, the mucosal epithelium, microvessels including arterioles, veins and capillaries, and fibroblasts maintained their structure. TUNEL(+) cells (apoptotic cells) were seen in the MTX treated specimens. The more induction of TUNEL(+) cells was observed 100 micromolar MTX-treated specimens. VEGF and Ang-1 levels were significantly lower, and Ang-2 levels were significantly higher in NPs treated with 100-micromolar MTX than in nontreated NPs (p < 0.01). CONCLUSION: MTX may inhibit the growth of NPs via local regulation of VEGF, Ang-1, and Ang-2 protein levels. We suggest that MTX can be used to treat NPs. PMID- 21819748 TI - Characterization of bacterial community diversity in chronic rhinosinusitis infections using novel culture-independent techniques. AB - BACKGROUND: Chronic rhinosinusitis (CRS) with or without polyps is a common chronic upper airway condition of multifactorial origin. Fundamental to effective treatment of any infection is the ability to accurately characterize the underlying cause. Many studies have shown that only a small fraction of the total range of bacterial species present in CRS is detected through conventional culture-dependent techniques. Consequently, culture data are often unrepresentative of the true diversity of the microbial community within the sample. These drawbacks, along with the length of time required to complete the analysis, strongly support the development of alternative means of assessing which bacterial species are present. As such, molecular microbiological approaches that assess the content of clinical samples in a culture-independent manner could significantly enhance the range and quality of data obtained routinely from such samples. We aimed to characterize the bacterial diversity present in tissue and mucus samples taken from the CRS setting using molecular nonculture-dependent techniques. METHODS: Through 16S ribosomal RNA (rRNA) gene clone sequencing and terminal restriction fragment length polymorphism (T-RFLP) analysis, the bacteria present in 70 clinical samples from 43 CRS patients undergoing endoscopic sinus surgery were characterized. RESULTS: Bacterial T-RFLP profiles were generated for 70 of 73 samples and a total of 48 separate bands were detected. Species belonging to 34 genera were identified as present by clone sequence analysis. Of the species detected, those within the genera Pseudomonas, Citrobacter, Haemophilus, Propionibacterium, Staphylococcus, and Streptococcus were found numerically dominant, with Pseudomonas aeruginosa the most frequently detected species. CONCLUSION: This study has validated the use of the culture independent technique T-RFLP in sinonasal samples. Preliminary characterization of the microbial diversity in CRS suggests a complex range of common and novel bacterial species within the upper airway in CRS, providing further evidence for the polymicrobial etiology of CRS. PMID- 21819749 TI - Comparison of the effect of corticosteroid therapy and decongestant on reducing rhinoplasty edema. AB - BACKGROUND: Comparison of the two methods of decongestant and three doses of dexamethasone on reducing edema and ecchymosis after septorhinoplasty. METHODS: Seventy-four patients who were candidates for rhinoplasty were randomly divided into three groups. Group A received 8 mg of i.v. dexamethasone preoperatively and again after 24 and 48 hours after surgery, group B received three pseudoephedrine tablets (60 mg) per day for 1 week, and group C received three pseudoephedrine tablets (60 mg) per day for 2 weeks. Finally, their effects on the eye, tip and dorsal edema, and ecchymosis were evaluated. RESULTS: Our findings showed that both decongestant and corticosteroid had significant short-term effects on edema and ecchymosis, but only continuation of pseudoephedrine could reduce the evaluated variables after 1 week. CONCLUSION: Pseudoephedrine can be effective for reducing eyelid edema and ecchymosis after rhinoplasty. Also, administration of three doses of dexamethasone in the postoperative care of nasal plastic surgery harmlessly diminished postsurgical edema. PMID- 21819750 TI - The Candy Smell Test in clinical routine. AB - BACKGROUND: The "Candy Smell Test" (CST) has been introduced as a new testing method for the evaluation of the human sense of smell. In contrast to other established orthonasal smell tests, the CST addresses the retronasal application of odors, typical for food aroma effects during mastication and swallowing. The aim of this study was to evaluate the CST in a clinical setting in patients with olfactory dysfunction and normal controls against the Sniffin' Sticks test. Furthermore, cutoff points for normal and pathological results in the CST should be determined. METHODS: The olfactory performance of 96 patients presenting with olfactory disorders and 71 healthy controls was evaluated with the CST-comprised of 23 different aromatized smell candies and the extended Sniffin' Sticks test (threshold, discrimination, and identification). The control group was gender matched but included also younger persons. RESULTS: The tested subjects could easily understand the procedures and were motivated to participate. The CST correlated well with the Sniffin' Sticks for all tested subjects and for patients (n = 96) and controls (n = 71). The proposed cutoff value to differentiate normosmia from hyposmia in the CST was a score of <16 (i.e., 16 correctly identified odors) of 23. A score below 13 in the CST was the cutoff value for anosmia. CONCLUSION: The CST is an easy-to-handle reliable tool to investigate retronasal olfaction suited for clinical determination of normosmia, hyposmia, and ansomia. In addition, it can be used for investigation where self-application is necessary such as in large survey studies. PMID- 21819751 TI - Olopatadine 0.6% nasal spray protects from vasomotor challenge in patients with severe vasomotor rhinitis. AB - BACKGROUND: Vasomotor rhinitis (VMR) is a hypersensitivity syndrome with heightened reactivity to environmental triggers. METHODS: Twenty-two patients with severe VMR were treated nasally with either normal saline or 0.6% olopatadine and challenged nasally with a hyperosmolar mannitol solution. RESULTS: Treatment with 0.6% olopatadine resulted in an improvement in instantaneous nasal symptom scores at 5 and 30 minutes (p < 0.01) compared with baseline and at 30 minutes after hyperosmolar challenge compared with saline pretreated individuals (p < 0.01). There was also an improvement in nasal peak inspiratory flow rate at 30 minutes after hyperosmolar challenge compared with saline-pretreated individuals (p < 0.01). CONCLUSION: In this patient population 0.6% olopatadine appears to be efficacious in symptom reduction in VMR and protects from hyperosmolar challenge. PMID- 21819752 TI - Comparison study between MAST CLA and OPTIGEN. AB - BACKGROUND: The MAST-CLA system (Hitachi Chemical Diagnostics, Inc., Mountain View, CA) is an in vitro diagnostic test for the simultaneous determination of specific IgE to different allergens. Recently, a new generation of MAST-CLA was developed (OPTIGEN; Hitachi Chemical Diagnostics). The purpose of this study was to determine the performance of these two tests for the diagnosis of allergic rhinitis. METHODS: Suspicious allergic rhinitis patients were divided into four groups and their medical records were reviewed: group 1 patients were tested with the MAST-CLA and skin-prick tests (251 patients), group 2 patients were tested with the OPTIGEN and skin-prick tests (319 patients), group 3 patients were tested with the MAST-CLA and CAP (104 patients) tests, and group 4 patients were tested with the OPTIGEN and CAP tests (270 patients). The correlation between MAST-CLA and OPTIGEN to skin-prick and CAP tests was determined. RESULTS: The positivity percentage of MAST-CLA results was higher than with skin-prick and CAP tests, and the results for the OPTIGEN test were comparable with skin-prick test and CAP. This suggests that the MAST-CLA test might have a slightly higher rate of giving false positive results. The OPTIGEN test correlated better with the skin-prick test and CAP. CONCLUSION: The OPTIGEN test performed better than the MAST-CLA test for diagnosing allergic rhinitis. PMID- 21819753 TI - Outcomes after endonasal septoplasty using caudal septal batten grafting. AB - BACKGROUND: This study evaluated surgical outcomes after endonasal septoplasty using caudal septal batten grafting for caudal septal deviation. METHODS: Fifty six patients completed questionnaires to assess nasal obstruction by telephone interviews 8-63 months postoperatively (12.2 months on the average). In addition, patients assessed the severity of nasal symptoms (i.e., mouth breathing, mouth dryness, hyposmia, rhinorrhea, epistaxis, trouble sleeping, snoring, and being concerned about nasal problems) preoperatively and postoperatively using a visual analog scale (VAS). These VAS scores were compared with those of patients who underwent endonasal septoplasty using the cutting and suture technique. Complications were analyzed. RESULTS: Thirty-four (60.7%) patients reported their nasal obstruction was much improved, 17 (30.3%) reported their condition was improved, and 5 (8.9%) reported no change postoperatively. Patients reported a decrease in severity of all nasal symptoms (p < 0.05 for each). Their nasal obstruction improvement was not significantly different from that of patients managed by the cutting and suture technique. Complications after surgery included hyposmia in two cases, small septal perforation in one case, chondritis in one case, and septal abscess in one case, and all were managed successfully. No patient required revision septoplasty due to recurrence during the follow-up period. CONCLUSION: Endonasal septoplasty using caudal septal batten grafting for caudal septal deviation resulted in improvement in nasal obstruction and nasal symptoms and was associated with an acceptable complication rate. PMID- 21819754 TI - Association between severity of asthma and degree of chronic rhinosinusitis. AB - BACKGROUND: There is a clinical association between asthma and chronic rhinosinusitis (CRS). This study was designed to determine whether severity of coexistent asthma affects the clinical presentation of CRS. METHODS: Cross sectional analysis was performed of prospectively collected data in 187 patients with CRS who were evaluated in a large, tertiary academic nasal and sinus center. Patients were stratified into three groups based on asthma status using National Institutes of Health criteria: (1) nonasthmatic, (2) intermittent/mild asthma, (3) or moderate/severe asthma. RESULTS: Mean Lund-Mackay scores were 9.7, 11.6, and 15.6, respectively. ANOVA testing with post-hoc Tukey analysis revealed that Lund-MacKay scores were significantly greater in group 3 than either group 1 (p < 0.05) or group 2 (p < 0.01). The prevalence of allergic sensitization was 72.4, 82.8, and 100% in groups 1, 2, and 3, respectively (p = 0.03). The prevalence of nasal polyposis was 31.4% in group 1, 48.3% in group 2, and 94.4% in group 3 (p < 0.0001). No differences were observed regarding demographic factors or the incidence of the triad of aspirin sensitivity, asthma, and nasal polyposis among those with different severities of asthma. CONCLUSION: Increasing severity of asthma is associated with advancing radiological severity of CRS and a greater prevalence of allergic sensitization and nasal polyposis. This large adult series shows that asthma severity may have a significant correlation with the presentation of CRS. This study adds to the growing support for the unified airway theory. PMID- 21819756 TI - The natural history of epistaxis in patients with hereditary hemorrhagic telangiectasia in the Norwegian population: a cross-sectional study. AB - BACKGROUND: Epistaxis is usually the first and most common symptom in hereditary hemorrhagic telangiectasia (HHT), which is known also as Rendu-Osler-Weber syndrome. The severity of HHT-associated epistaxis is highly variable and can affect the patient's quality of life. In the literature, the natural history of epistaxis in HHT patients has been described in a few countries but not from the Norwegian population. OBJECTIVE: This work focused on the natural history of epistaxis in the Norwegian population in a cross-sectional study. MATERIAL AND METHODS: Ninety-eight patients with three or four Curacao criteria were included. The severity of epistaxis was graded depending on epistaxis intensity, frequency, and the amount of blood transfusion during a period of 4 weeks. The epistaxis grades were studied in association with age, gender, gene mutation, age of onset, and whether the patient had or had not been treated for epistaxis during the last 2 years. RESULTS: Most of the HHT patients (90%) complained of mild-to-moderate epistaxis. Seventy-seven percent of the patients started epistaxis by or before the age of 20 years. The progression of HHT-associated epistaxis with age could not be proved statistically in this study. There was no statistically significant difference in the grades of epistaxis between HHT1 and HHT2 type, neither between female and male patients. Most of the patients started epistaxis by or before the age of 20 years. There was a significant difference in the grade of epistaxis between non-ENG, non-ALK1 carrier patients, and ENG or ALK1 carrier patients. CONCLUSION: Compared with other populations, the grading of epistaxis in Norwegian patients with HHT gave generally similar results. A multicenter epidemiological study is required to get a larger study population. A common internationally accepted grading or classification system for epistaxis in HHT is highly recommended. PMID- 21819755 TI - Inherent differences in nasal and tracheal ciliary function in response to Pseudomonas aeruginosa challenge. AB - BACKGROUND: Sinonasal mucosal biofilms are recognized as contributors to the pathogenesis of chronic rhinosinusitis (CRS). Attachment of bacteria to the sinonasal surface is an initial step in biofilm formation. A critical defense against this occurrence is mucociliary clearance (MCC). To ascertain whether the ciliary component of MCC is uniform throughout the airway we compared ciliary beat frequency (CBF) in the murine nasal septum and trachea at baseline and after challenge with Pseudomonas aeruginosa, a common pathogen of CRS. METHODS: Murine septal and tracheal air-liquid interface cultures were evaluated for basal and stimulated CBF after exposure to control or conditioned media from Pseudomonas. Additionally, the attachment of Pseudomonas to nasal and tracheal cultures was assessed after pretreatment with control or conditioned media. RESULTS: Basal CBF is significantly slower in primary nasal airway cultures compared with tracheal airway cultures. Tracheal airway cultures show resistance to Pseudomonas secreted ciliotoxins not evident in nasal septal cultures. Furthermore, after challenge with viable Pseudomonas, significantly more bacteria attach to the nasal cultures compared with the tracheal cultures. CONCLUSION: Using primary murine nasal and tracheal airway cultures we show inherent differences in cilia function and increased susceptibility of the upper airway to attachment by Pseudomonas. Understanding the differences between upper and subglottic airway mucociliary clearance should lead to novel approaches in the management of upper airway infection. PMID- 21819757 TI - Aspergillus fumigatus biofilm on primary human sinonasal epithelial culture. AB - BACKGROUND: Bacterial biofilms have been implicated in chronic rhinosinusitis (CRS). However, direct evidence in support of fungal biofilms in sinus disease is lacking in the literature. This study was designed to develop and characterize an in vitro Aspergillus fumigatus biofilm model on primary human sinonasal epithelial cell culture. METHODS: Sinonasal biopsy specimens harvested during endoscopic sinus surgery of six CRS patients and three pituitary tumor (control) patients were cultured in Dulbecco's modified Eagle media (DMEM; Invitrogen)/Hams F12 airway media to encourage epithelial cell proliferation. Epithelial cells separated by immunomagnetic beads were seeded in tissue culture-treated Y-shaped microslides. At confluence the primary cultures were inoculated with A. fumigatus spores. Fungus was allowed to germinate and form biofilms under two in vitro conditions: (1) static (no flow through of media) and (2) continuous flow coculture (continuous flow movement of media). At regular intervals cocultures were stained with FUN-1, concanavalin A-alexa fluor 488, and examined by confocal scanning laser microscopy. Comstat software was used to assess biomass and thickness. RESULTS: A. fumigatus formed three-dimensional biofilm structures with parallel-packed, cross-linked hyphae and channels/passages. Metabolically active hyphae showed orange-red fluorescing intravacuolar structures. Extracellular matrix (ECM) between/around the hyphae fluoresced intense green. A. fumigatus biofilms development occurred in five stages: (1) conidial attachment to epithelial cells, (2) hyphal proliferation, (3) ECM production, (4) hyphal parallel packing and cross-linking, and (5) channel/pores formation. Mature biofilms showed basal conidial, middle hyphal, and superficial ECM layers. Biofilms formed under flow conditions displayed more robust and faster growth kinetics when compared with that under static conditions, with a thick, stocky, wrinkly/undulating hyphal growth and extensive ECM production. The differences in biomass and average thickness of the cocultures under static and flow conditions were statistically significant after similar periods of incubation (p = 0.0002; p < 0.0001, respectively). CONCLUSION: To our knowledge, this is the first article of an in vitro model characterizing A. fumigatus biofilm formation using primary human sinonasal epithelium under different growth conditions. PMID- 21819758 TI - The effect of passive smoking on the levels of matrix metalloproteinase 9 in nasal secretions of children. AB - BACKGROUND: Matrix metalloproteinase (MMP) 9 is a gelatinase associated with tissue remodeling. It is thought to play a part in the pathogenesis of allergy. Increased levels of MMP-9 have been shown to increase in the acute allergic response in the nose, lungs, and skin. Exposure to passive tobacco smoke is associated with an increase in sneezing, nasal blockage, and a decreased sense of smell. The aim of this study was to study the effect of passive smoking on the levels of MMP-9 in nasal secretions of children. METHODS: A prospective descriptive study was performed. Thirty-nine children aged between 7 and 16 years were enrolled in the study. They were selected based on attendance at the Otorhinolaryngology Outpatients Clinic with a primary complaint unrelated to the nose or paranasal sinuses. Children with allergic rhinitis, sinusitis, or a recent cold were excluded. The study was performed at a tertiary pediatric referral center. Exposure to passive smoking was determined by measuring the urinary cotinine to creatinine ratio. Nasal fluid was obtained by using a Rhino Probe curette (Arlington Scientific, Inc., Springville, UT). The concentration of MMP-9 was determined by ELISA. MMP-9 activity was determined by gelatin zymography. Data were tabulated on Microsoft Excel (Microsoft Corp., Redmond, WA) and analyzed using SPSS (SPSS Inc., Chicago, IL). RESULTS: Using a cutoff urinary cotinine/creatinine ratio of 0.025 ng/mg, 15 children were found to be exposed to passive smoking. Both the MMP-9 concentration and the activity were significantly higher in nasal secretions of children exposed to passive smoking. There was a distinct difference between the two cohorts with regard to the level of enzyme activity per weight of protein. The lowest level of enzyme activity recorded in the "exposed" cohort was over twice that of the level in the "not exposed" cohort. CONCLUSION: MMP-9 activity and concentration is higher in nasal secretions of children exposed to passive smoking. This suggests that passive smoking might alter the inflammatory response within the nasal mucosa in a similar way to allergy. PMID- 21819759 TI - Transforming growth factor beta: a role in the upper airway and rhinosinusitis Dermatophagoides pteronyssinus-induced apoptosis with pulmonary alveolar cells. AB - BACKGROUND: There is a link with the upper and lower airway and disruption of alveolar epithelial cells, which is a potential trigger for the reactivation of the epithelial-mesenchymal trophic unit (EMTU) and induced characteristic airway changes associated with allergic asthma. Dermatophagoides pteronyssinus is a common inhalant indoor allergen and is known for causing allergic rhinitis and airway inflammation. Transforming growth factor beta 1 (TGF-beta1) is a major participant in the airway remodeling of asthma, a component of cellular stress response pathways, and enhanced epithelial immunoreactivity is known to occur in allergic rhinitis. METHODS: In this study, we show the ability of D. pteronyssinus allergens from dialyzed standardized immunotherapy extract to induce apoptosis and increase TGF-beta1 secretion in a confluent A549 cell line model. A549 cells were treated with either 600 AU/mL dialyzed D. pteronyssinus immunotherapy extract (eDp) or Ctl media (Ctl) for 24 hours. Cells and supernatants were collected, washed, and treated with Annexin V-FITC Apoptosis Detection Kit II (BD Pharmingen, La Jolla, CA) and then analyzed by flow cytometry. TGF-beta1 secretion was determined by ELISA using cell culture supernatants. RESULTS: The eDp group showed a fourfold increase in early apoptotic cells with a twofold increase in late apoptotic cells versus the Ctl group, along with a 1.65-fold increase of TGF-beta1. CONCLUSION: eDp induced viable A549 cells to undergo apoptosis determined by flow cytometry analysis with a significant increase in TGF-beta1 secretion compared with Ctl. PMID- 21819761 TI - The drainage system of the paranasal sinuses: a review with possible implications for balloon catheter dilation. AB - BACKGROUND: Intersinus connections and accessory ostia of the maxillary sinus are well known to rhinologic surgeons but are less known for the remaining paranasal sinuses. Probing and dilatation of the natural ostia of diseased sinuses is being popularized currently by the clinical value of balloon catheter dilation (BCD). Although short-term high success rates with treatment of the dilated ostia/duct have been reported with this technique, the potential impact of fractures of adjacent bony septae on accessory sinus ostia, on mucosally lined surfaces, and on intersinus drainage pathways still has not been considered. The aim of this study was to review the literature on accessory sinus ostia, intersinus connections, and mucociliary drainage pathways for the entire sinus system that are relevant to BCD. METHODS: A literature review was performed. RESULTS: Accessory sinus ostia exist for each paranasal sinus. Many sinuses drain not only directly into the nasal cavity but also indirectly through adjacent sinuses. Of note, one major drainage pathway of the frontal sinus is over the ethmoid sinuses and via the ethmoids into the maxillary sinus and subsequently into the nose. Drainage of the sphenoid sinus exists both through posterior ethmoidal cells and directly into the nasopharynx. CONCLUSION: Accessory ostia are not only common for the maxillary sinus but also for the entire paranasal sinus system. BCD may potentially inadvertently impair mucociliary clearance of the sinuses through effects on secondary drainage pathways. PMID- 21819760 TI - Characterization of specific antibody deficiency in adults with medically refractory chronic rhinosinusitis. AB - BACKGROUND: Specific antibody deficiency may predispose patients to recurrent respiratory tract infections. There is limited literature assessing specific antibody deficiency in chronic rhinosinusitis (CRS). This study evaluated the role of specific antibody deficiency in patients with CRS who have failed medical therapy. METHODS: We performed a retrospective chart review of patients with CRS who underwent functional endoscopic sinus surgery and had prior assessment for humoral immunodeficiency. Each patient's record was reviewed for serum quantitative immunoglobulin G (IgG) and IgA and anti-Streptococcus pneumoniae antibody titers measured at baseline and 6 weeks postvaccination with the 23 valent unconjugated pneumococcal vaccine. Clinical characteristics, including asthma, atopy, and nasal polyps, were recorded. RESULTS: Of the 129 CRS patients who met inclusion criteria, 93 (72%) had low baseline antipneumococcal titers. Fifteen (11.6%) patients were diagnosed with specific antibody deficiency based on an inadequate response to the pneumococcal polysaccharide vaccine. The group of patients with specific antibody deficiency had significantly lower serum IgA levels when compared with those patients with normal preimmunization titers (138 +/- 67.3 versus 330 +/- 356; p < 0.05). Patients with specific antibody deficiency had a significantly lower number of preimmunization protective antipneumococcal titers when compared with vaccine responders (1.41 versus 2.72; p < 0.0005). CONCLUSION: This retrospective study indicates that patients with medically refractory CRS may have a high prevalence of low preimmunization antipneumococcal titers and specific antibody deficiency. Furthermore, lower serum IgA levels identified in these specific antibody deficiency patients suggests that a prospective study to further characterize this relationship is warranted. PMID- 21819762 TI - Stenting the nasal airway for maximizing inspiratory airflow: internal Max-Air Nose Cones versus external Breathe Right strip. AB - BACKGROUND: Several nasal dilator devices designed to stent the anterior nasal airway to increase peak nasal inspiratory flow (PNIF) currently exist; however, comparisons of such devices are limited. This study was designed to compare the efficacy of two different nasal dilator devices, an internal device (Max-Air Nose Cones; Sanostec Corp., Beverly Farms, MA) and an external device (Breathe Right nasal strip; GlaxoSmithKline, Brentford, Middlesex, U.K.) on stenting of the anterior nasal airway to maximize PNIF. METHODS: Repeated measurements of PNIF were obtained in 30 individuals noting complaints of sleep-disordered breathing due to nasal breathing discomfort and nasal airway obstruction, both with and without the two different nasal dilator devices. RESULTS: A one-within analysis of variance (ANOVA) was performed among the three conditions (control, Max-Air Nose Cones, and Breathe Right nasal strip), and a statistically significant effect was found (F[2,58] = 298.13; p< 0.00001). Tukey post hoc contrasts revealed that the control condition PNIF (66.07 L/min) was significantly lower than both the Max-Air Nose Cones (138.73 L/min) and the Breathe Right nasal strip (102.17 L/min) conditions. The Max-Air Nose Cone increased inspiratory airflow by 73 L/min, or a 110% improvement over baseline. In addition, the Max-Air Nose Cone condition PNIF was significantly higher than both the control condition and the nasal strip condition. CONCLUSION: Although both the Max-Air Nose Cones and the Breathe Right nasal strips increased PNIF from baseline, the Max-Air Nose Cones showed significantly greater efficacy at stenting the anterior nasal airway, providing twice the improvement in PNIF over baseline than did the Breathe Right nasal strips. PMID- 21819763 TI - Dog allergen levels in homes with hypoallergenic compared with nonhypoallergenic dogs. AB - BACKGROUND: Despite the public interest in hypoallergenic dogs, few scientific, including epidemiological studies have attempted to evaluate claims of hypoallergenicity. This study was designed to determine whether dog breeds reported as hypoallergenic correspond to lower dog allergen in the home versus nonhypoallergenic dogs. METHODS: A web search was conducted to identify breeds cited as hypoallergenic. Four separate classification schemes using combinations of purebred and mixed breed dogs were used to compare the levels of Canis familiaris 1 in dust samples collected from homes with hypoallergenic versus nonhypoallergenic dogs from an established birth cohort. RESULTS: No classification scheme showed that the level of dog allergen in homes with hypoallergenic dogs differed from other homes. CONCLUSION: Dog-allergic individuals should have access to scientifically valid information on the level of allergen shedding of different breeds of dogs. PMID- 21819764 TI - Outcomes research in rhinoplasty: body image and quality of life. AB - BACKGROUND: Although hundreds of quality-of-life (QOL) studies are available in the literature, very few were designed that include both a global and a procedure specific evaluation of QOL and an inventory for the assessment of body image. The purpose of this study was to use condition-specific and global measures as well as psychological evaluations in a case series of rhinoplasties for a more comprehensive assessment of patient-reported outcomes. METHODS: Records of 225 patients aged 18-57 years who underwent rhinoplasty were prospectively included in the study. Study participants completed both a baseline questionnaire before the rhinoplasty operation and a postsurgical patient questionnaire 12 months after the operation, including the European QOL Questionnaire (EQ), Rhinoplasty Outcomes Evaluation Questionnaire (ROE), and the Multidimensional Body-Self Relations Questionnaire (MBSRQ). RESULTS: Mean values corresponding to the EQ VAS results except for discomfort and anxiety domains increased after treatment compared with baseline. Both male and female patients experienced significant improvement in ROE scores, with larger differences between pre- and postoperative ROE scores in male patients compared with female patients. The analyses of variance in the MBSRQ results revealed significant postsurgical improvements on the appearance orientation subscale. CONCLUSION: The development, standardization, and use of validated procedure-specific QOL tools are essential components for accurately measuring patient-reported outcomes of facial plastic surgery procedures. To measure patient satisfaction in a more objective and standardized manner, specific questionnaires or instruments should be used that can determine the QOL changes associated with each procedure of interest. PMID- 21819765 TI - Microporous polysaccharide hemospheres do not increase synechiae after sinus surgery: randomized controlled study. AB - BACKGROUND: Many surgeons use absorbable packing materials after endoscopic sinus surgery (ESS). Despite their popularity, some of these agents have been shown to contribute to synechiae formation. Microporous polysaccharide hemospheres (MPH) is a plant-based hemostatic powder that does not interfere with regenerating sinus mucosa in the animal model. The goal of this study was to examine the impact of MPH on healing and synechiae formation after ESS in human subjects. METHODS: A prospective, randomized, controlled, double-blind study was performed. Forty consenting adult patients with chronic sinusitis requiring symmetric ESS were randomized to receive MPH unilaterally at the conclusion of surgery. The opposite side was untreated. Standard postoperative care was performed bilaterally. Outcomes measured included blinded observer ratings for synechiae formation, edema, and infection. Each side was examined endoscopically and scored at postoperative days 7, 14, and 30. RESULTS: Twenty men and 20 women with an average age of 48.2 years were included. There were no complications and all patients were discharged home the same day. There was no significant difference in synechiae formation at any point postoperatively. The rate of synechiae formation was determined to be 10% (4/40) on the MPH-treated side versus 7.5% (3/40) on the untreated side (p = 0.7639). In addition, there were no significant differences observed in edema (p = 0.7480) or infection (p = 0.5533). CONCLUSION: The use of MPH after sinus surgery does not increase synechiae formation and does not appear to deleteriously affect the healing of postoperative sinus cavities. PMID- 21819766 TI - Paranasal sinus mucoceles with ophthalmologic manifestations: a 17-year review of 96 cases. AB - BACKGROUND: The purpose of this study was to assess the characteristics of paranasal sinus mucoceles with ophthalmologic manifestations with a focus on optic neuropathy. METHODS: From January 1993 to May 2010, 96 consecutive patients diagnosed with paranasal sinus mucoceles with ophthalmologic manifestations were investigated. Clinical and therapeutic factors and demographics were reviewed from medical records. Statistical associations between clinical and therapeutic factors and visual outcomes after surgery were also analyzed. RESULTS: A total of 352 patients were diagnosed with paranasal sinus mucoceles and underwent surgical treatment. Ninety-six of them presented with ophthalmologic symptoms, and periorbital swelling and pain were the most common symptoms (36.4%) in those patients. Among the 96 patients with ophthalmologic manifestations, 18 (18.8%) were diagnosed with optic neuropathy based on the deterioration of their visual acuity and unilateral relative afferent papillary defect. Ten of these 18 patients showed improvements in their vision after surgical intervention. The statistical analysis of the association between clinical and therapeutic factors and visual outcomes showed that the presence of infection was the only significant factor (p = 0.023). CONCLUSION: Paranasal sinus mucoceles present various ophthalmologic manifestations. Among them, optic neuropathy may be one of the most devastating conditions. In treating optic neuropathy caused by mucoceles, the presence of infection was the only factor that had any influence on postoperative visual outcomes. Therefore, we conclude that not only surgical drainage and ventilation of the sinus are necessary, but infection control is also a vital factor in treating mucoceles with optic neuropathy. PMID- 21819767 TI - Sphenoid sinus fungus ball: our experience. AB - BACKGROUND: Fungal rhinosinusitis is a common disease of the paranasal sinuses. The fungus ball (FB) is defined as an extramucosal mycotic proliferation that fills one or more paranasal sinuses. Sphenoid sinus is an uncommon localization of this disease, as reported in the literature. This study describes our experience in the diagnosis and treatment of sphenoid sinus FB (SSFB), with a particular focus on the surgical approach to the sphenoid sinus. METHODS: We retrospectively analyzed the clinical records of patients affected by FB of the sphenoid sinus, who underwent endoscopic sinus surgery (ESS) in our institutions between 1995 and 2009. We described the surgical technique, the methods of mycological and histopathological evaluation, as well as the perioperative and postoperative management. RESULTS: From 1995 to 2009, 226 patients affected by sinonasal FB underwent ESS in our institutions. A sphenoid localization was found in 56 patients (24.78%; mean age, 62 years). Cephalea was the most common symptom, and 14.3% of patients complained of ocular symptoms. We performed a direct paraseptal sphenoidotomy in 31 patients (55.4%) and a transethmoidal sphenoidotomy in 25 patients (44.6%). Histology unveiled fungal hyphae with absent mucosal invasion in all cases. Cultural results revealed positivity for mycotic colonization in 26 cases (46.4%, most commonly Aspergillus fumigatus). Follow-up ranged from 12 to 181 months with a mean of 70.7 months. CONCLUSION: The description of our experience in the diagnosis and treatment of SSFB underlines the importance of a precise diagnostic pathway in case of sphenoidal disease. Nowadays, in our opinion, the paraseptal direct sphenoidotomy represents the less invasive, fastest and most anatomically conservative approach to the sphenoid sinus in case of SSFB. PMID- 21819771 TI - Surface-enhanced Raman scattering (SERS) and surface-enhanced resonance Raman scattering (SERRS): a review of applications. AB - Surface-enhanced Raman scattering (SERS) and surface-enhanced resonance Raman scattering (SERRS) can provide positive identification of an analyte or an analyte mixture with high sensitivity and selectivity. Better understanding of the theory and advances in the understanding of the practice have led to the development of practical applications in which the unique advantages of SERS/SERRS have been used to provide effective solutions to difficult analytical problems. This review presents a basic theory and illustrates the way in which SERS/SERRS has been developed for practical use. PMID- 21819772 TI - Surface-enhanced spectra on D-gluconic acid coated silver nanoparticles. AB - Coated silver (Ag) colloids synthesized with D-glucose permit the observation of surface-enhanced fluorescence (SEF) and surface-enhanced resonance Raman scattering (SERRS) of the rhodamine B (RhB) molecule. The organic coating formed during the synthesis of the Ag nanostructures was identified by its surface enhanced Raman scattering (SERS) spectrum as D-gluconic acid. The RhB molecule is used to exemplify the distance dependence of SEF and SERRS on the coated Ag nanostructures. The fluorescence enhancement factor for RhB on D-gluconic acid coated silver nanoparticles was determined experimentally and estimated using a simple model. Further support for the plasmon enhancement is obtained from the fact that the measured fluorescence lifetime of RhB on the silver coated with D gluconic acid is shorter than that found on a glass surface. A very modest enhancement factor is obtained, as expected for very short distance between RhB and the metal surface. Given the very thin metal-fluorophore separation, estimated from the size of the D-gluconic acid, the energy transfer or fluorescence quenching is still efficient and the SEF enhancement is just overcoming the energy transfer. Therefore, both SEF and SERRS are observed. Notably, the aggregation of coated nanoparticles also increases the enhancement factor for SEF. PMID- 21819773 TI - Noninvasive subsurface analysis using multiple miniaturized Raman probes, part I: basic study of thin-layered transparent models of biomedical tissues. AB - This study describes a basic theory for reconstructing pure Raman signals of materials composing a multilayer sample from Raman spectra obtained using two types of miniaturized Raman probes. An illustrative example is demonstrated using a multilayer system of samples composed of the transparent plastics polymethylmethacrylate (PMMA) and polyethylene (PE) as a model of thin-layered biomedical tissues. When the same region of an object is measured using Raman probes with different focal properties, the Raman spectra provide different depth profile information depending on the level of light penetration. Thus, a detailed comparison of the spectra can provide an interesting opportunity to probe the differences between the layers. A simple analytic form is presented for reconstructing the pure Raman spectra of the embedded layer. The method applies an understanding of the Raman sampling volume in layered transparent materials to the interpretation of Raman spectra experimentally measured by multiple probes. The basic theory described here is necessary for the expansion of the technique to turbid media, such as biological samples, where light-scattering effects must be considered. The potential applications of the proposed method include material and catalyst subsurface probing through different embedded materials, such as assessment of silicon wafers, effective noninvasive screening for catalyst synthesis, and biomedical tissue research. PMID- 21819774 TI - Raman spectroscopy using a spatial heterodyne spectrometer: proof of concept. AB - The use of a spatial heterodyne interferometer-based spectrometer (SHS) for Raman spectroscopy is described. The motivation for this work is to develop a small, rugged, high-resolution ultraviolet (UV) Raman spectrometer that is compatible with pulsed laser sources and that is suitable for planetary space missions. UV Raman is a particular technical challenge for space applications because dispersive (grating) approaches require large spectrographs and very narrow slits to achieve the spectral resolution required to maximize the potential of Raman spectroscopy. The heterodyne approach of the SHS has only a weak coupling of resolution and throughput, so a high-resolution UV SHS can both be small and employ a wide slit to maximize throughput. The SHS measures all optical path differences in its interferogram simultaneously with a detector array, so the technique is compatible with gated detection using pulsed lasers, important to reject ambient background and mitigate fluorescence (already low in the UV) that might be encountered on a planetary surface where samples are uncontrolled. The SHS has no moving parts, and as the spectrum is heterodyned around the laser wavelength, it is particularly suitable for Raman measurements. In this preliminary report we demonstrate the ability to measure visible wavelength Raman spectra of liquid and solid materials using an SHS Raman spectrometer and a visible laser. Spectral resolution and bandpass are also discussed. Separation of anti-Stokes and Stokes Raman bands is demonstrated using two different approaches. Finally spectral bandpass doubling is demonstrated by forming an interference pattern in both directions on the ICCD detector followed by analysis using a two-dimensional Fourier transform. PMID- 21819775 TI - Molecular orientation evolution and solvent evaporation during electrospinning of atactic polystyrene using real-time Raman spectroscopy. AB - Real-time Raman spectroscopy was successfully utilized to monitor solvent evaporation and molecular orientation during electrospinning of atactic polystyrene (a-PS). The use of a binary solvent system of N,N-dimethyl formamide (DMF) and tetrahydrofuran (THF) provided a stable, straight jet during the experiment. The prominent Raman bands centered at 866 cm(-1), 914 cm(-1), and 1004 cm(-1), unique to DMF, THF, and a-PS, respectively, were used to monitor solvent concentration changes along the electrospinning jet for two different a PS solutions. In addition, the changes in relative intensity for the radial skeletal ring vibration of the aromatic group of a-PS at 623 cm(-1) in two different polarization geometries, ZZ and YY, were monitored for orientation information. This study reports the first quantitative vibrational spectroscopic measurement during the electrospinning process. A significant change in concentration and orientation was observed during the process. The changes are explained in relation to the electrospinning process. PMID- 21819777 TI - Coating effects on mid-infrared reflection spectra of fabrics. AB - Polymer films of varying thicknesses were deposited onto cotton and polyester fabric samples by dip-coating from solution. Scanning electron microscopy (SEM) images of the coated fabric samples were used to evaluate the quality of the polymer coating. The samples were analyzed by infrared diffuse reflection spectroscopy to determine the relationship between film thickness and the effect of the coating on the spectroscopy of the two fabrics. Effects observed in four limiting cases are examined: (Case I) weak coating absorption on a fabric with weak absorption at the same frequency; (Case II) strong coating absorption in a spectral region of weak fabric absorption; (Case III) weak coating absorption in a spectral region of strong fabric absorption; and (Case IV) strong coating absorption in a spectral region of strong fabric absorption. In the first case, effects were dominated by reduced scattering as the coating is added. In the second case, the strong coating absorption that was observed at low coverages plateaus at higher coverage due to depth of penetration effects. In the third and fourth cases, reduced Fresnel diffuse reflection is measured as the coating is added, consistent with the reduction of scattering observed in the first case. PMID- 21819776 TI - In situ surface-etched bacterial spore detection using dipicolinic acid-europium silica nanoparticle bioreporters. AB - A basic approach was optimized for the synthesis of highly selective and sensitive in situ mesoporous (MCM) type imprinted silica polymers for the detection of dipicolinic acid (DPA) using europium as a reporter. DPA is a ubiquitous biochemical marker available during the germination event of endospore forming bacteria such as Bacillus . Additionally, an MCM-MIP (molecularly imprinted polymeric phenomena) detector and a companion MCM-non-surface-MIP detector were synthesized using europium reporters for the sensing of DPA under optimized laboratory conditions. Our results showed that the in situ molecular imprinting process enabled rapid, selective detection of DPA with high sensitivity compared to MCM-MIP (imprinted for DPA; no DPA present), MCM-Non-MIP (no imprint present), and MCM-SR-MIP (imprinted with DPA present) detectors. The lower detection limit observed for DPA concentration is 5.49 * 10(-10) mol dm(-3) for MCM-MIP. The performance of the sensor in high-salt-water conditions, under photo-bleaching, and its reusability were also evaluated. The synthesized in situ MCM-MIP material should permit the detection of DPA for field assays related to suspect bacterial sporulation events. PMID- 21819778 TI - A modified golden gate attenuated total reflection (ATR) cell for monitoring phase transitions in multicomponent fluids at high temperatures. AB - A new continuous flow method using attenuated total reflection infrared (ATR-IR) spectroscopy has been developed for monitoring phase transitions in multicomponent fluids at high pressures and temperatures. Our approach uses Fourier transform infrared (FT-IR) and a modified Golden Gate attenuated total reflection (ATR) cell and exploits the fact that the absorbance of a vapor is much lower than that of the corresponding liquid to monitor the phase transition between vapor and liquid. We demonstrate that this method can provide quantitative measurements on both the dew point and the bubble point. We have validated our approach using three single-component systems (EtOH, MeOH, and H(2)O) and a binary system of EtOH + H(2)O, monitoring phase transitions at temperature up to 300 degrees C and pressure up to 10 MPa. PMID- 21819779 TI - Solvent interactions in methanol/N, N-dimethylamide binary systems studied by Fourier transform infrared-attenuated total reflection (FT-IR/ATR) and two dimensional correlation spectroscopy (2D-COS). AB - The interaction of N,N-dimethyl formamide (DMF) and N,N-dimethyl acetamide (DMA) with methanol in solution mixtures was studied using Fourier transform infrared attenuated total reflection (FT-IR/ATR) spectroscopy. The concentration-dependent FT-IR/ATR spectra of DMF/methanol and DMA/methanol mixtures were recorded in the wavenumber range 4000-650 cm(-1) to investigate wavenumber shifts as a consequence of hydrogen bonding interactions. In combination with two-dimensional correlation spectroscopy (2D-COS), the positional fluctuations observed in the nu(C=O) and nu(O-H) regions of DMF/DMA and methanol, respectively, have been discussed in terms of changing populations of differently hydrogen-bonded and interacting species of the same and different component molecules. PMID- 21819781 TI - Method of spectral subtraction of gas-phase Fourier transform infrared (FT-IR) spectra by minimizing the spectrum length. AB - A new method of spectral subtraction for gas-phase Fourier transform infrared (FT IR) spectra was developed for long-path gas measurements. The method is based on minimization of the length of the spectrum that results from subtracting the spectrum of an individual component of a gas mixture (water, CO(2), etc.) from the experimental spectrum of the mixture. For this purpose a subtraction coefficient (k(min)) is found for which the length of the resulting spectrum is minimized. A mathematical simulation with two Lorentzian absorption bands was conducted and the limits of application for the proposed method were determined. Two experimental examples demonstrate that a successful result could be achieved in the case when the subtrahend spectrum contains a number of narrow absorption bands (such as the spectrum of water vapor). PMID- 21819780 TI - Asynchronous orthogonal sample design scheme for two-dimensional correlation spectroscopy (2D-COS) and its application in probing intermolecular interactions from overlapping infrared (IR) bands. AB - This paper introduces a new approach to analysis of spectra called asynchronous orthogonal sample design (AOSD). Specifically designed concentration series are selected according to mathematical analysis of orthogonal vectors. Based on the AOSD approach, the interfering portion of the spectra arising strictly from the concentration effect can be completely removed from the asynchronous spectra. Thus, two-dimensional (2D) asynchronous spectra can be used as an effective tool to characterize intermolecular interactions that lead to apparent deviations from the Beer-Lambert law, even if the characteristic peaks of two compounds are substantially overlapped. A model solution with two solutes is used to investigate the behavior of the 2D asynchronous spectra under different extents of overlap of the characteristic peaks. Simulation results demonstrate that the resulting spectral patterns can reflect subtle spectral variations in bandwidths, peak positions, and absorptivities brought about by intermolecular interaction, which are barely visualized in the conventional one-dimensional (1D) spectra. Intermolecular interactions between butanone and dimethyl formamide (DMF) in CCl(4) solutions were investigated using the proposed AOSD approach to prove the applicability of the AOSD method in real chemical systems. PMID- 21819782 TI - Extended range near-infrared imaging of water and oil in facial skin. AB - Recently, near-infrared (NIR) imaging has been applied to detecting changes in skin hydration using the water OH band centered near 1460 nm. However, assigning changes in the intensity of the OH band near 1460 nm to changes in the skin's water content is complicated. Consequently, detection of small changes in facial skin water content is difficult. For highly sensitive imaging of facial skin water and oil, a near-infrared unit with a large detection range that includes the CH(3) and CH(2) stretching vibration modes at 1700-1800 nm and the strongest water bands centered near 1920 nm is required. In this study, an extended range indium gallium arsenide near-infrared camera was combined with a diffuse illumination unit specifically developed for facial skin analysis. Images of water and oil in facial skin were obtained in real time using a combination of interference filters, such as 1950 +/- 56 nm for water OH, 1775 +/- 50 nm for oil CH, and 1300 +/- 40 nm for background reflections. Clear near-infrared images were obtained with little mirror reflection. The water and oil content of facial skin could be evaluated even around the eyes, nose, and sides of the cheeks, which are areas that are difficult to analyze using current commercial devices. Differences were detected in the time-dependent changes of water and oil content in facial skin images obtained after the application of different types of moisturizer. The distribution of both water and oil in the facial skin could be visualized at the same time, and the images could be used to evaluate skin type and skin conditions. PMID- 21819783 TI - In situ determination of growing stages and harvest time of tomato (Lycopersicon esculentum ) fruits using fiber-optic visible-near-infrared (Vis-NIR) spectroscopy. AB - Nondestructive in situ measurement of tomato fruits is essential to determine growing stages and to assist in automatic picking of fruits. This study evaluates the applicability of visible and near-infrared (Vis-NIR) spectroscopy for in situ determination of growing stages and harvest time of three cultivars of tomato fruits. A mobile fiber-type AgroSpec Vis-NIR spectrophotometer (Tec5 Co., Germany) with a spectral range of 350-2200 nm was used to measure tomato spectra in reflection mode. A new growing stage (GS) index defined as the ratio of the current growing age in days to the on-vine duration before harvest in days was proposed. After dividing spectra into a calibration set (70%) and an independent prediction set (30%), spectra in the calibration set were subjected to a partial least squares regression (PLSR) with leave-one-out cross-validation to establish calibration models relating GS to the spectra of tomato fruits. Separate models were developed for each tomato cultivar and compared with a general model that used combined spectra of all three cultivars. The results show that PLSR based on the new GS is successful and robust in predicting the growing stages and harvest time of tomato fruits. Validation of calibration models on the independent prediction set indicates that successful prediction of GS can be achieved using the three models developed separately for each cultivar with a coefficient of determination (R(2)) of 0.91-0.92, root mean square error of prediction (RMSEP) of 0.081-0.097, and residual prediction deviation (RPD) of 3.29-3.70. General calibration using the combined spectra produces good prediction performance, although less accurate than that for the three individual cultivar models. The analysis of regression coefficient plots resulting from PLSR analysis indicates consistent assignment of important wavelengths for individual cultivar spectra and combined spectra. It is concluded that the Vis-NIR PLSR based on GS index can be adopted successfully for in situ determination of growing stages and harvest time of on-vine tomato fruits, which allows for automatic picking of fruits by a horticultural robot. PMID- 21819784 TI - Near-infrared luminescence of cadmium pigments: in situ identification and mapping in paintings. AB - A comprehensive study of the luminescence properties of cadmium pigments was undertaken to determine whether these properties could be used for in situ identification and mapping of the pigments in paintings. Cadmium pigments are semiconductors that show band edge luminescence in the visible range and deep trap luminescence in the red/infrared range. Emission maxima, quantum yields, and excitation spectra from the band edge and deep trap emissions were studied for sixty commercial cadmium pigments that span the color range from yellow to red (reflectance transition 470 to 660 nm). For paints containing cadmium pigments, luminescence from deep traps was more readily observable than that from the band edge, although the yield varied widely from zero to around 4.5%. Optimal excitation for emission is found to be in the visible for both pigments in powder form and mixed with a medium. The maxima of the deep trap emission shift with the band gap energy, providing a potentially useful way to assign pigment type even when used in pigment mixtures. The usefulness of the results of the study on mockups was demonstrated by the mapping of cadmium pigments of different hues with the aid of calibrated luminescence imaging spectroscopy in a painting by Edward Steichen, entitled Study for 'Le Tournesol' (1920). Analysis of the luminescence image cube reveals at least six unique spectral components, associated with emission from white pigments, paint binder, and cadmium red and yellow pigments. The results were compared with those from X-ray fluorescence spectrometry (XRF) and fiber-optic reflection spectroscopy (FORS) and the results obtained on paint samples containing cadmium pigments. These results show that, when present, the emission from traps can be used as an analytical tool to identify cadmium pigments, to distinguish among cadmium sulfide, cadmium zinc sulfide, and cadmium sulfoselenide, and to map cadmium pigments, even in mixtures. PMID- 21819785 TI - Effective laser-induced breakdown spectroscopy (LIBS) detection using double pulse at optimum configuration. AB - A short laser pulse is irradiated on a sample to create a highly energetic plasma that emits light of a specific peak wavelength according to the material. By identifying different peaks for the analyzed samples, their chemical composition can be rapidly determined. The characteristics of the laser-induced breakdown spectroscopy (LIBS) plasma are strongly dependent on the ambient conditions. Research aimed at enhancing LIBS intensity is of great benefit in advancing LIBS for the exploration of harsh environments. By using double-pulse LIBS, the signal intensity of Al and Ca lines was enhanced by five times compared to the single pulse signal. Also, the angles of the target and detector are adjusted to simulate samples of arbitrary shape. We verified that there exists an optimal angle at which specific elements of a test sample may be detected with stronger signal intensity. We provide several optimum configurations for the LIBS system for maximizing the signal intensity for the analysis of a nonstandard aluminum sample. PMID- 21819787 TI - A comparison of the validity of gas chromatography-mass spectrometry and liquid chromatography-tandem mass spectrometry analysis of urine samples II: amphetamine, methamphetamine, (+/-)-3,4-methylenedioxyamphetamine, (+/-)-3,4 methylenedioxymethamphetamine, (+/-)-3,4-methylenedioxyethylamphetamine, phencyclidine, and (+/-)-11-nor-9-carboxy-Delta9-tetrahydrocannabinol. AB - On November 25, 2008, the U.S. Department of Health and Human Services posted a final notice in the Federal Register authorizing the use of liquid chromatography tandem mass spectrometry (LC-MS-MS) and other technologies in federally regulated workplace drug testing (WPDT) programs. To support this change, it is essential to explicitly demonstrate that LC-MS-MS, as a technology, can produce results at least as valid as gas chromatography (GC)-MS, the long-accepted standard in confirmatory analytical technologies for drugs of abuse. A series of manufactured control urine samples (n = 10 for each analyte) containing amphetamine, methamphetamine, (+/-)-3,4-methylenedioxyamphetamine, (+/-)-3,4 methylenedioxymethamphetamine, (+/-)-3,4-methylenedioxyethylamphetamine, phencyclidine, and (+/-)-11-nor-9-carboxy-Delta9-tetrahydrocannabinol at concentrations ranging from 10% to 2000% of federal cutoffs were analyzed with replication by five federally regulated laboratories using GC-MS and at RTI International using LC-MS-MS. Interference samples as described in the National Laboratory Certification Program 2009 Manual were analyzed by GC-MS and LC-MS-MS as well as previously confirmed urine specimens of WPDT origin. Matrix effects were assessed for LC-MS-MS. Results indicated that LC-MS-MS analysis produced results at least as precise, accurate, and specific as GC-MS for the analytes investigated in this study. Matrix effects, while evident, could be controlled by the use of matrix-matched controls and calibrators with deuterated internal standards. PMID- 21819788 TI - Urine drug testing of chronic pain patients. III. Normetabolites as biomarkers of synthetic opioid use. AB - Opioids are important therapeutic agents available to patients with moderate to severe pain. The synthetic opioids, buprenorphine, fentanyl, meperidine, methadone, and propoxyphene have been utilized for decades as analgesics. One of the major biotransformation pathways of these drugs occurs through N demethylation leading to the formation and excretion of normetabolites. Normetabolites generally exhibit longer half-lives than the parent drug leading to accumulation with prolonged use. As part of continuing research efforts to improve monitoring programs of chronic pain patients undergoing opioid treatment, we evaluated the prevalence and relative abundance of normetabolites of buprenorphine, fentanyl, meperidine, methadone, and propoxyphene in patients? urine specimens. Selected sets of specimens were analyzed without prior immunoassay screening by liquid chromatography-tandem mass spectrometry for buprenorphine, fentanyl, meperidine, methadone, propoxyphene, and their respective normetabolites. Limits of quantitation (LOQ) were as follows: buprenorphine, 1 ng/mL; fentanyl, 0.5 ng/mL; meperidine, 50 ng/mL; methadone, 50 ng/mL; and propoxyphene, 50 ng/mL. LOQs for normetabolites were equal to the parent drug with the exception of norbuprenorphine (2.5 ng/mL). The percentage of positive specimens that contained normetabolite (only) ranged from 8.0% for EDDP (2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine) to 53.1% for norpropoxyphene. Inclusion of the five normetabolites in the test panel produced an increase in detection rates for parent drug use as follows: buprenorphine, 10.0%; fentanyl, 42.1%; meperidine, 98.7%; methadone, 8.7%; and propoxyphene, 113.2%. The authors conclude that testing for synthetic opioid normetabolites enhances the effectiveness of monitoring programs for pain patients. PMID- 21819789 TI - Determination of tapentadol (Nucynta(r)) and N-desmethyltapentadol in authentic urine specimens by ultra-performance liquid chromatography-tandem mass spectrometry. AB - Urine specimens from pain management patients dosed with Nucynta (Tapentadol) were confirmed for the presence of tapentadol and N-desmethyltapentadol using ultra-performance liquid chromatography-tandem mass spectrometry to minimize sample preparation and urine volume requirements. The linearity of the method for both tapentadol and N-desmethyltapentadol demonstrated correlation coefficients (R2) above 0.99 and linear ranges from 50 to 500,000 ng/mL for tapentadol and 100 to 500,000 ng/mL for N-desmethyltapentadol. The intraday precision of the assay for both analytes ranged from 2.2 to 6.9% over three concentrations; the interday precision for both analytes ranged from 1.2 to 8.4%. The limits of quantitation were 50 and 100 ng/mL for tapentadol and N-desmethyltapentadol, respectively, and the upper limit of linearity for both analytes was determined to be 500,000 ng/mL. Urine samples were collected within 24 h of dosing with tapentadol and shipped overnight to the laboratory. Samples were hydrolyzed with acid prior to analysis to measure total (unconjugated and conjugated) tapentadol and N desmethyltapentadol. Further investigation into characterization of metabolites was performed by using a hybrid quadrupole-time-of-flight mass spectrometer in lieu of suitable analytical reference standards. The presence of significant N desmethyltapentadol glucuronide was demonstrated for the first time. PMID- 21819790 TI - Determination of tapentadol and its metabolite N-desmethyltapentadol in urine and oral fluid using liquid chromatography with tandem mass spectral detection. AB - An analytical procedure for the determination of the new pain medication tapentadol and its main metabolite N-desmethyltapentadol (DMT), in urine and oral fluid has been developed and validated using liquid chromatography with tandem mass spectral detection (LC-MS-MS). Oral fluid was collected using QuantisalTM devices, and drugs present were quantified using solid-phase extraction followed by LC-MS-MS. For confirmation, two transitions were monitored and one ratio determined which had to be within 20% of that of the known calibration standard. For tapentadol, 222.1 > 107 was used as the quantifying transition; 222.1 > 121 for the qualifier. For DMT, 208.1 > 107 was used for quantification; 208.1 > 121 as the qualifier. For saliva, the linear range was 10-100 ng/mL; the lower limit of quantitation (LLOQ) was 10 ng/mL; the intraday precision was 3.6% (n = 6) and interday precision was 13.6% (n = 24). The recovery of tapentadol and DMT from the oral fluid collection pad was > 99%. For urine, the specimens were diluted and injected directly into the LC-MS-MS. The LLOQ was 50 ng/mL; the intraday and interday precisions were 2.1% and 4.4%, respectively, for tapentadol and 2.9% and 5.7%, respectively, for DMT. This is the first analytical procedure for tapentadol and DMT in urine and oral fluid. PMID- 21819791 TI - Detection of 1-benzylpiperazine, 1-(3-trifluoromethylphenyl)-piperazine, and 1-(3 chlorophenyl)-piperazine in 3,4-methylenedioxymethamphetamine-positive urine samples. AB - Historically, ecstasy tablets contained 3,4-methylenedioxymethamphetamine (MDMA) as the psychoactive component. In recent years, the Drug Enforcement Administration (DEA) and other law enforcement agencies have seized ecstasy tablets that are comprised of psychoactive drugs or drug mixtures other than MDMA. Many jurisdictions have reported the presence of piperazine derivatives including 1-benzylpiperazine (BZP), 1-(3-trifluoromethylphenyl)-piperazine (TFMPP), and 1-(3-chlorophenyl)-piperazine (mCPP) in ecstasy tablets. These piperazine derivatives produce stimulant and psychoactive effects similar to those produced by MDMA, amphetamine, and methamphetamine. In many countries, their use is not controlled, and therefore they have become a legal alternative to MDMA. For this study, a targeted population of 251 MDMA-positive urine samples were analyzed for designer drugs, including the piperazine derivatives. A basic liquid-liquid extraction followed by pentafluoropropionic anhydride (PFPA) derivatization and a full scan (m/z 42-550) gas chromatography-mass spectrometry analysis was used to screen the urine samples for 33 designer drugs. Overall, in 36% of the specimens analyzed, a stimulant or psychoactive compound other than MDMA and 3,4-methylenedioxyamphetamine (MDA) was detected. BZP, TFMPP, and mCPP were detected in 15%, 7%, and 1% of the samples, respectively. PMID- 21819792 TI - Automated solid-phase extraction-liquid chromatography-tandem mass spectrometry analysis of 6-acetylmorphine in human urine specimens: application for a high throughput urine analysis laboratory. AB - An automated solid-phase extraction-liquid chromatography- tandem mass spectrometry (SPE-LC-MS-MS) method using the Spark Holland Symbiosis Pharma SPE LC coupled to a Waters Quattro Micro MS-MS was developed for the analysis of 6 acetylmorphine (6-AM) in human urine specimens. The method was linear (R2 = 0.9983) to 100 ng/mL, with no carryover at 200 ng/mL. Limits of quantification and detection were found to be 2 ng/mL. Interrun precision calculated as percent coefficient of variation (%CV) and evaluated by analyzing five specimens at 10 ng/mL over nine batches (n = 45) was 3.6%. Intrarun precision evaluated from 0 to 100 ng/mL ranged from 1.0 to 4.4%CV. Other opioids (codeine, morphine, oxycodone, oxymorphone, hydromorphone, hydrocodone, and norcodeine) did not interfere in the detection, quantification, or chromatography of 6-AM or the deuterated internal standard. The quantified values for 41 authentic human urine specimens previously found to contain 6-AM by a validated gas chromatography (GC)-MS method were compared to those obtained by the SPE-LC-MS-MS method. The SPE-LC-MS-MS procedure eliminates the human factors of specimen handling, extraction, and derivatization, thereby reducing labor costs and rework resulting from human error or technique issues. The time required for extraction and analysis was reduced by approximately 50% when compared to a validated 6-AM procedure using manual SPE and GC-MS analysis. PMID- 21819793 TI - The role of dihydrocodeine (DHC) metabolites in dihydrocodeine-related deaths. AB - The focus of this study was to report the blood and urine concentrations of dihydrocodeine (DHC) and its metabolites, dihydrocodeine-6-glucuronide (DHC6G), dihydromorphine (DHM), dihydromorphine-3-glucuronide (DHM3G), and dihydromorphine 6-glucuronide (DHM6G) in deaths involving DHC, and to report the range of concentrations detected in real cases in order to understand their contribution to DHC intoxication. Twenty-six positive postmortem cases were involved in the current study. Five cases were attributed solely to DHC intoxication, 13 cases to polydrug intoxication, and the remainder of the cases were unrelated to DHC (DHC has been detected but is unrelated to the cause of death). DHC and its glucuronide were detected in all cases investigated in blood and urine matrices. Unchanged parent drug is the most abundant analyte detected in blood samples mean and median of DHC/total DHC (DHC plus DHC6G) percentages were 63% and 72%, and DHC6G is the most abundant DHC metabolite in urine with a mean and median DHC6G/TDHC of 69% and 70%, respectively. Blood DHC concentrations ranged from 40 to 166,000 ng/mL and 200 to 159,000 ng/mL in urine. DHC6G concentrations in these cases ranged from 20 to 62,180 ng/mL in blood and 40 to 500,000 ng/mL in urine. However, DHM and its glucuronide were present at lower concentrations than DHC and its glucuronide. In the current study, it can be concluded that concentrations of DHC that cause death may be lower in polydrug intoxication. Concentrations found at autopsy overlapped between toxic and therapeutic concentrations because of the presence of other harmful substances, and death can occur with concentrations below lethal concentrations as reported in Case 1 (500 ng/mL). It has been suggested that DHM and DHM6G may play a major role in assessing the cause of death in cases where DHC is not detected and when it is detected in low concentrations. The current study does not support this hypothesis, and it can be seen clearly from the data reported here that DHM and its glucuronide were not detected where DHC was not detected. Toxic concentrations of DHM and DHM6G were identified in some of these cases; however, the concentration of DHC was enough to cause death on its own. It seems that DHM and DHM6G have less influence in causing death than the parent drug itself. PMID- 21819794 TI - Evaluating the relationship between postmortem and antemortem morphine and codeine concentrations in whole blood. AB - The purpose of this study was to examine the relationship between antemortem (AM) and postmortem (PM) morphine and codeine concentrations in whole blood. In addition, the effects of antemortem to death interval as well as the postmortem interval were considered during the interpretive process. The cases of seven human subjects are presented here with an average postmortem interval of 28 h (13.5-48 h) and an average antemortem to death interval of 97 min (ranging from 9 to 300 min). Drug concentrations were obtained from AM blood collected from local hospitals in Miami, FL, and postmortem blood was obtained from the Miami-Dade County Medical Examiner Department in Miami, FL. The results obtained for this study indicated that factors such as metabolism and postmortem interval can affect postmortem drug concentrations in an unpredictable manner. Four out of seven morphine cases appeared to be affected by postmortem redistribution, and five of seven codeine and two of two 6-monoacetylmorphine cases were affected as well. PMID- 21819795 TI - Umbilical cord monitoring of in utero drug exposure to buprenorphine and correlation with maternal dose and neonatal outcomes. AB - Buprenorphine is under investigation in the U.S. as pharmacotherapy for opioid dependent pregnant women. Buprenorphine and metabolites were quantified in umbilical cord specimens from women receiving daily buprenorphine doses. Correlations between maternal buprenorphine dose, buprenorphine and metabolite umbilical cord concentrations, and neonatal outcomes were investigated, as well as the ability to identify heroin and cocaine relapse during pregnancy. Umbilical cord concentrations were compared to those of matched umbilical cord plasma and meconium. Buprenorphine metabolites were detected in all cords, but buprenorphine itself was absent. Concentration ranges were 1.2-5.1 ng/g norbuprenorphine, 1.7 4.2 ng/g buprenorphine-glucuronide, and 8.3-23 ng/g norbuprenorphine-glucuronide. Cord concentrations were similar to those in plasma, and lower (16-210-fold), although statistically correlated, than those in meconium. Significant positive correlations were observed for buprenorphine-glucuronide concentrations in umbilical cord and mean maternal BUP daily dose throughout pregnancy and third trimester, but buprenorphine biomarker concentrations did not predict neonatal outcomes. Opiate concentrations were lower (200-fold) in umbilical cord than in meconium, and when cocaine was present in meconium, it was not identified in cord. Umbilical cord can serve as an alternative matrix for identifying prenatal drug-exposure, but is much less sensitive than meconium. Buprenorphine provided a controlled drug administration model for evaluating drug disposition in the maternal-fetal dyad. PMID- 21819796 TI - Tissue distribution of newer anticonvulsant drugs in postmortem cases. AB - Levetiracetam, hydroxycarbazepine (the primary product of oxcarbazepine use), and topiramate were quantified using the acid/neutral drug screening procedure employed by this laboratory. Briefly, blood or tissue homogenate spiked with an internal standard (cyclopentobarbital) was buffered to pH 5 and applied to Chem Elut(r) columns. The columns were washed with methylene chloride, collected, and evaporated to dryness. The residue was reconstituted with 0.033 M trimethylanilinium hydroxide and injected into a gas chromatograph equipped with a DB-5 analytical column (25 m * 0.32-mm i.d.) and a nitrogen-phosphorus detector. A calibration curve using four calibrators ranging in concentration from 2 to 20 mg/L was used for quantification. Despite the limited number of cases for each drug, there were some trends suggested by the data. None of the drugs displayed significant differences in concentration between the heart blood and peripheral (subclavian) blood specimens. Only the hydroxycarbazepine quantifications in one case (case 5) showed significant differences between the two blood sites. This is consistent with other acid/neutral drugs such as acetaminophen and meprobamate. It also appears that the liver and kidney concentrations of the three drugs are on the same order of magnitude as the blood concentrations. Only the levetiracetam concentration in one case (case 3) reflected a liver or kidney concentration greater than 5 times the blood concentration. PMID- 21819797 TI - Relative distribution of drugs in decomposed skeletal tissue. AB - Skeletal tissues from a domestic pig exposed to amitriptyline, diazepam, and pentobarbital were analyzed to determine the relative distribution of these drugs in bone. Following drug exposure and euthanasia, remains were allowed to decompose outdoors to complete skeletonization between summer 2007 and fall 2009. Remains were recovered and separated according to bone type. Twelve different bone types were pulverized and sampled in triplicate. Each bone sample underwent methanolic extraction (96 h, 50 degrees C), followed by solid-phase extraction and gas chromatography-mass spectrometry in the selected ion monitoring mode. Mass-normalized assay responses underwent ANOVA with post-hoc testing, revealing bone type as a main effect for all three drugs, but not for the diazepam metabolite (nordiazepam). The assay response varied with respect to bone type by factors of 27, 39, and 20 for pentobarbital, diazepam, and amitriptyline, respectively. The relative distribution between bone type was qualitatively similar for the three administered drugs analyzed for, with the largest response obtained from rib for all three drugs. This is the first study, to the authors' knowledge, of the distribution of different drugs in various decomposed skeletal tissues in a controlled experiment using an animal model of comparable physiology to humans. These data have implications for the interpretive value of forensic drug measurements in skeletal tissues. PMID- 21819798 TI - An overdose death involving the insufflation of extended-release oxymorphone tablets. AB - Two cases are reported involving the abuse of extended-release oxymorphone hydrochloride tablets (Opana(r) ER) in combination with alprazolam (Xanax(r)). Two juvenile females were discovered unresponsive and hypoxic by a male acquaintance. The trio had reportedly crushed and snorted Opana ER tablets and consumed Xanax for recreational purposes. Emergency personnel were able to stabilize one female. The second female was pronounced dead at the scene. Blood and urine samples from the surviving female were collected at the trauma center between 48 and 96 h post incident. Toxicology results showed the presence of oxymorphone, doxylamine, dextromethorphan, alprazolam, alpha-hydroxyalprazolam, oxazepam, and temazepam in her urine. No drugs were detected in her blood. Toxicology on the deceased female revealed the presence of 0.13 mg/L oxymorphone and 0.04 mg/L alprazolam in her blood. Gastric contents contained 0.25 and 0.93 mg/L of oxymorphone and alprazolam, respectively. Oxymorphone, alprazolam, and alpha-hydroxyalprazolam were present in her urine. Quantitative results were achieved by gas chromatography-mass spectrometry monitoring selected ions for the oxime-oxymorphone-trimethylsilyl derivative, alprazolam, and the alpha hydroxyalprazolam tert-butyldimethylsilyl derivative. The established linearity ranges for the opiate and benzodiazepine methods were 0.050-3.000 and 0.025-1.000 mg/L, respectively. The cause of death was reported as multiple drug toxicity, and the manner of death was accidental. PMID- 21819799 TI - Fatality involving the ingestion of phenazepam and poppy seed tea. AB - Phenazepam is a benzodiazepine derivative that has been in clinical use in Russia since 1978 and is not available by prescription in the United States; however, it is attainable through various internet websites, sold either as tablets or as a reference grade crystalline powder. Presented here is the case of a 42-year old Caucasian male who died as the result of combined phenazepam, morphine, codeine, and thebaine intoxication. A vial of white powder labeled "Phenazepam, Purity 99%, CAS No. 51753-57-2, Research Sample", a short straw, and several poppy seed pods were found on the scene. Investigation revealed that the decedent had a history of ordering medications over the internet and that he had consumed poppy seed tea prior to his death. Phenazepam, morphine, codeine, and thebaine were present in the blood at 386, 116, 85, and 72 ng/mL, respectively. PMID- 21819802 TI - [Evidence-based therapeutic drug monitoring for nevirapine]. AB - Nevirapine, a HIV non nucleosidic reverse transcriptase inhibitor, displays an inter-individual variability in its pharmacokinetics parameters, related to its hepatic metabolism. Based on literature, is the nevirapine therapeutic drug monitoring relevant? In naive and pre-treated HIV infected patients, the probability of achieving and maintaining an undetectable HIV viral load was significantly associated with a nevirapine plasma trough concentration (C(trough)) > 4 000 ng/mL. The probability of virologic failure was significantly associated with a C(trough) < 3 000 ng/mL. Concerning the exposure-toxicity relationship, the emergence of hepatotoxicity was more frequently associated with high C(trough), especially in case of HCV coinfection. Non-randomized studies have reported the interest of nevirapine therapeutic drug monitoring to optimize the virologic response and, to a lesser extent, to prevent hepatotoxicity. Therefore, the level of evidence of the interest of nevirapine therapeutic drug monitoring is "recommended". PMID- 21819803 TI - [Evidence-based therapeutic drug monitoring for efavirenz]. AB - The efavirenz, a non nucleoside reverse transcriptase inhibitor of HIV-1, presents a marked pharmacokinetics variability related to an intense hepatic metabolism. Efavirenz is also a potent inducer. Central nervous system (CNS) toxicity associated with efavirenz therapy is a major cause of non adherence and therefore treatment failure. The literature has been analyzed to evaluate the level of evidence of the interest of a therapeutic drug monitoring for efavirenz. Several studies have reported that an efavirenz plasma concentration >1 000 ng/mL is a predictive factor of the viral response. Efavirenz plasma concentrations >4 000 ng/mL were associated to an increase frequency of CNS side effects. CNS toxicity was also more frequent in patients carrying the 516G > T mutation (CYP2B6*6 allele), associated with a significantly greater efavirenz plasma exposure. Non-randomized studies have reported the interest of efavirenz therapeutic drug monitoring to optimize viral response and prevent CNS toxicity, allowing to suggest a level of evidence "recommended" for efavirenz. PMID- 21819804 TI - [Evidence-based therapeutic drug monitoring for saquinavir]. AB - The human immunodeficiency virus (HIV) protease inhibitor saquinavir displays a large inter-individual variability in its pharmacokinetic parameters, related to a low absorption rate and an important hepatic metabolism. Based on literature, is the saquinavir therapeutic drug monitoring relevant? In naive HIV-infected patients, the probability of achieving an undetectable HIV viral load at W48 was significantly associated with a saquinavir plasma trough concentration >100 ng/mL. Two studies in HIV-infected pre-treated patients reported that the genotypic inhibitory quotient was a predictive factor of virologic response with a threshold value around 40 ng/mL/mutation. Concerning the exposure-toxicity relationship, the risk of occurrence of grade 3-4 abdominal pains was more frequently associated with high concentrations of saquinavir, but without threshold value determination. Several studies, one of which was randomized, have reported the interest of saquinavir therapeutic drug monitoring to optimize the virologic response. Therefore, the level of evidence of the interest of saquinavir therapeutic drug monitoring is "recommended". PMID- 21819805 TI - [Evidence-based therapeutic drug monitoring of atazanavir]. AB - The HIV protease inhibitor atazanavir presents a wide inter-individual variability related to an intense hepatic metabolism. Dose-dependent elevations of bilirubin have been frequently reported with atazanavir. Relative to literature, the atazanavir therapeutic drug monitoring can it be proposed? In naive HIV-infected patients, the probability of achieving an undetectable HIV viral load at W48 was significantly associated with a plasma trough concentration (C(min)) of atazanavir >200 ng/mL. Studies in HIV-infected pre-treated patients reported that the genotypic inhibitory quotient was a predictive factor of the virologic response with a threshold value around 200 ng/mL/mutation. Concerning the exposure-toxicity relationship, the risk of occurrence of grade 3-4 hyperbilirubinemia was more frequently associated with C(min) > 750-800 ng/mL. Non-randomized studies have reported the interest of atazanavir therapeutic drug monitoring to optimize the virologic response and prevent severe bilirubin elevations. Therefore, the level of evidence of the interest of atazanavir therapeutic drug monitoring is recommended. PMID- 21819806 TI - [Evidence-based therapeutic drug monitoring for ribavirine]. AB - Ribavirin in combination with pegylated interferon alpha is the current treatment for chronic hepatitis C (HCV). Ribavirin presents a wide inter-individual pharmacokinetic variability and adequate exposure seems crucial for achieving sustained virologic response. Severe anaemia frequently occurred under ribavirin treatment and is a dose-dependent limiting side effect. Several studies have been carried out in HVC-infected or HIV-HCV co-infected patients to evaluate the pharmacokinetic-pharmacodynamic relationships of ribavirin. Achievement of a sustained virologic response, defined as undetectable HCV-RNA six months after the end of treatment, have been significantly associated with ribavirin concentration. A cut-off for the trough concentration of ribavirin ranging between 2-3 MUg/ml at week 4 has been proposed. A significant correlation has also been reported between ribavirin concentration and the extent of haemoglobin decline. A ribavirin concentration >2 MUg/ml is significantly associated to an increase risk of severe anaemia. Non randomized studies have shown that therapeutic drug monitoring of ribavirin improve the management of therapeutic response and haematologic toxicity. Therefore, the level of evidence of the therapeutic drug monitoring of ribavirin is recommended. PMID- 21819807 TI - [Evidence-based therapeutic drug monitoring of lopinavir]. AB - The HIV protease inhibitor lopinavir presents a wide inter-individual variability related to liver and intestinal metabolism involving CYP3A. Published studies were analyzed to establish whether there is evidence that therapeutic drug monitoring of lopinavir could improve patient care. In naive or pretreated HIV infected patients, no relationship could be evidenced between virological efficacy and trough lopinavir concentration, most likely because concentrations are above inhibitory concentrations. Although data are limited, patients with elevated triglycerides and cholesterol had trough lopinavir concentrations >8 000 ng/mL. These data suggest that the level of evidence of interest of lopinavir therapeutic drug monitoring is may be recommended in some situations such as children, pregnant women, pretreated patients if the number of mutations is <5, when coadministration with drug with metabolizing enzyme inducing properties is warranted and toxicity. PMID- 21819808 TI - [Evidence-based therapeutic drug monitoring for indinavir]. AB - The HIV protease inhibitor indinavir presents a wide inter-individual variability related to an intense hepatic metabolism. Published studies were analyzed to establish whether there is evidence that therapeutic drug monitoring of indinavir could improve patient care. It was reported that indinavir virological efficacy in HIV-infected patients with wild-type virus was significantly associated with trough concentrations > 100-150 ng/mL. Concerning the exposure-toxicity relationship, the risk of occurrence of nephrotoxicity was more frequently associated with trough concentrations > 500-1 000 ng/mL. Studies with concentration-controlled indinavir therapy suggest that therapeutic drug monitoring allows to achieve safe and effective concentrations, therefore, the level of evidence of the interest of indinavir therapeutic drug monitoring is highly recommended when indinavir is not associated with ritonavir and recommended when ritonavir is combined with ritonavir. PMID- 21819809 TI - [Modeling of antiretroviral response from taxonomy of CD4 cells count trajectories in profound immunodeficiency setting]. AB - Modeling of CD4 cells counts response was performed through a Non-Hierarchical descendant process with profoundly immunocompromised symptomatic patients under nevirapine or efavirenz-based antiretroviral regimen in Abidjan. Similar CD4 cells count trajectories have been modelled in meta-trajectories linked to patients' classes. Global immunological response is similar between "nevirapine group" and "efavirenz group" but the model showed an internal variation of this response in each group. In the both groups, some variables presented a significant variation between classes: average CD4, CD4 Nadir, CD4 peak and average gain of CD4. In "nevirapine group", these following parameters vary significantly between classes: mean weight, mean haemoglobin count and mean increase in haemoglobin count and sex. It's also important to note that, all meta trajectories began with distinctive categories of baseline CD4 cells counts. Other explanatory factors must be sought because the characteristics we have chosen to describe patients'classes, are not exhaustive. PMID- 21819810 TI - [Post-marketing surveillance systems for psychoactive prescription drug abuse]. AB - Drugs affecting the central nervous system form a unique group of products for surveillance because they could be misused, abused or diverted. Considering the characteristics of this behaviour that is often concealed, specific post marketing surveillance systems have been developed to monitor abuse of prescription drugs in some countries. The purpose of this review is to list and to describe post-marketing surveillance systems, according their methodology, in France and in foreign countries. These programs are based on adverse effect notifications, medical or legal consequences of abuse, general or specific population-based survey, professional networks or medication databases. Some programs use simultaneously several information sources. In conclusion, the multifaceted nature, the diversity and the inventiveness of post-marketing surveillance systems reflects the complexity of the abuse issue. PMID- 21819811 TI - [H1N1 influenza vaccines in Tunisia: efficiency and safety]. AB - OBJECTIVE: We carried out this study in order to evaluate the effectiveness and the safety of the two H1N1 vaccines available in Tunisia: Focetria((r)) and Panenza((r)). METHODS: It's a prospective epidemiological study including 601 vaccinated subjects. The vaccine effectiveness was based on the occurrence of flu clinical symptoms after vaccination. The safety was based on the occurrence of unexpected events after vaccines administration. The vaccines imputability was established according to Begaud et al. method. RESULTS: The number of subjects vaccinated by Focetria((r)) is more important than Panenza((r)). The efficiency of vaccines would be 93.6%. Neither the medical statue nor the type of the vaccine used influence the occurrence of a flu episode after vaccination. We recorded 406 adverse effects (32.4%) with a high score of imputability (I3). Focetria((r)) adverse effects were more frequent than Panenza((r)) ones (p = 0.009). Almost all adverse events disappeared within few days. CONCLUSION: The two vaccines used in Tunisia remain enough efficient to face the influenza (H1N1) pandemia and are well tolerated independently of the demographic and pathological statue of the vaccinated person as well as nature of the vaccine used. PMID- 21819812 TI - Threat engagement, disengagement, and sensitivity bias in worry-prone individuals as measured by an emotional go/no-go task. AB - BACKGROUND AND OBJECTIVES: The goal of the present study was to investigate a threat engagement, disengagement, and sensitivity bias in individuals suffering from pathological worry. METHODS: Twenty participants high in worry proneness and 16 control participants low in worry proneness completed an emotional go/no-go task with worry-related threat words and neutral words. RESULTS: Shorter reaction times (i.e., threat engagement bias), smaller omission error rates (i.e., threat sensitivity bias), and larger commission error rates (i.e., threat disengagement bias) emerged only in the high worry group when worry-related words constituted the go-stimuli and neutral words the no-go stimuli. Also, smaller omission error rates as well as larger commission error rates were observed in the high worry group relative to the low worry group when worry-related go stimuli and neutral no-go stimuli were used. LIMITATIONS: The obtained results await further replication within a generalized anxiety disorder sample. Also, further samples should include men as well. CONCLUSIONS: Our data suggest that worry-prone individuals are threat-sensitive, engage more rapidly with aversion, and disengage harder. PMID- 21819813 TI - Examining the effects of thought records and behavioral experiments in instigating belief change. AB - OBJECTIVE: While the efficacy and effectiveness of CBT protocols are well established, much less is known about the comparative contribution of the various techniques within CBT. The present study examined the relative efficacy, in comparison to a control condition, of two central techniques in CBT: thought records (TRs) and behavioral experiments (BEs). METHOD: A mixed within and between participants design was used to compare the efficacy of a single session TR and a single session BE intervention with a control intervention, in a non clinical sample. Ninety one participants were randomly allocated to one of the three conditions. RESULTS: The overall pattern of results suggests that both TR and BE had a beneficial therapeutic impact in comparison to the control condition on beliefs, anxiety, behavior and a standardized measure of symptoms. There was evidence of a small advantage of the BE over the TR intervention in that the target belief changed earlier and change generalized to beliefs about others as well as the self. CONCLUSIONS: The findings confirm the utility of both TR and BE interventions and point to BEs as more useful in effecting belief change in that the change in the BE condition occurred sooner and generalized further. PMID- 21819814 TI - Phase-II conjugation ability for PAH metabolism in amphibians: characteristics and inter-species differences. AB - The present study examines amphibian metabolic activity - particularly conjugation - by analysis of pyrene (a four ring, polycyclic aromatic hydrocarbon) metabolites using high-performance liquid chromatography (HPLC) with fluorescence detector (FD), a mass spectrometry detector (MS) system and kinetic analysis of conjugation enzymes. Six amphibian species were exposed to pyrene (dissolved in water): African claw frog (Xenopus laevis); Tago's brown frog (Rana tagoi); Montane brown frog (Rana ornativentris); Wrinkled frog (Rana rugosa); Japanese newt (Cynops pyrrhogaster); and Clouded salamander (Hynobius nebulosus); plus one fish species, medaka (Oryzias latipes); and a fresh water snail (Clithon retropictus), and the resultant metabolites were collected. Identification of pyrene metabolites by HPLC and ion-trap MS system indicated that medaka mainly excreted pyrene-1-glucuronide (PYOG), while pyrene-1-sulfate (PYOS) was the main metabolite in all amphibian species. Pyrene metabolites in amphibians were different from those in invertebrate fresh water snails. Inter-species differences were also observed in pyrene metabolism among amphibians. Metabolite analysis showed that frogs relied more strongly on sulfate conjugation than did Japanese newts and clouded salamanders. Furthermore, urodelan amphibians, newts and salamanders, excreted glucose conjugates of pyrene that were not detected in the anuran amphibians. Kinetic analysis of conjugation by hepatic microsomes and cytosols indicated that differences in excreted metabolites reflected differences in enzymatic activities. Furthermore, pyrenediol (PYDOH) glucoside sulfate was detected in the Japanese newt sample. This novel metabolite has not been reported previously to this report, in which we have identified unique characteristics of amphibians in phase II pyrene metabolism. PMID- 21819815 TI - Effects of lifetime chemical inhibition of aromatase on the sexual differentiation, sperm characteristics and fertility of medaka (Oryzias latipes) and zebrafish (Danio rerio). AB - The deleterious effects of tributyltin (TBT) on spermiation in fish have been attributed to its role in inhibiting aromatisation of androgens to estrogens, and the critical role of the latter in sperm development. We test this hypothesis by examining sperm parameters, fertilisation and hatching success in males of two fish species exposed throughout life to doses of Fadrozole, a non-steroidal aromatase inhibitor (AI), provided in their diets. AI-treatment caused 100% male development in zebrafish, but only partial masculinisation in medaka, in both cases supporting previous studies and suggesting different roles of estrogen in sexual differentiation in the two species. Milt volume, initial sperm motility, maximum sperm swimming duration and sperm morphology did not differ significantly between Control and AI-dosed fish in either species, after excluding low milt volumes in sex-changed females in medaka. Fertilisation rates were also unaffected by the aromatase inhibition, but hatching success in medaka was 31% lower than in Control males, suggesting a previously unreported effect of aromatase on sperm quality. The slight effect of aromatase inhibition on sperm parameters in general contrasts with the marked effect of TBT on fish sperm, and suggests that a mechanism other than depressed estrogen levels is involved. PMID- 21819816 TI - Motorcycle protective clothing: protection from injury or just the weather? AB - BACKGROUND: Apart from helmets, little is known about the effectiveness of motorcycle protective clothing in reducing injuries in crashes. The study aimed to quantify the association between usage of motorcycle clothing and injury in crashes. METHODS AND FINDINGS: Cross-sectional analytic study. Crashed motorcyclists (n=212, 71% of identified eligible cases) were recruited through hospitals and motorcycle repair services. Data was obtained through structured face-to-face interviews. The main outcome was hospitalization and motorcycle crash-related injury. Poisson regression was used to estimate relative risk (RR) and 95% confidence intervals for injury adjusting for potential confounders. RESULTS: Motorcyclists were significantly less likely to be admitted to hospital if they crashed wearing motorcycle jackets (RR=0.79, 95% CI: 0.69-0.91), pants (RR=0.49, 95% CI: 0.25-0.94), or gloves (RR=0.41, 95% CI: 0.26-0.66). When garments included fitted body armour there was a significantly reduced risk of injury to the upper body (RR=0.77, 95% CI: 0.66-0.89), hands and wrists (RR=0.55, 95% CI: 0.38-0.81), legs (RR=0.60, 95% CI: 0.40-0.90), feet and ankles (RR=0.54, 95% CI: 0.35-0.83). Non-motorcycle boots were also associated with a reduced risk of injury compared to shoes or joggers (RR=0.46, 95% CI: 0.28-0.75). No association between use of body armour and risk of fracture injuries was detected. A substantial proportion of motorcycle designed gloves (25.7%), jackets (29.7%) and pants (28.1%) were assessed to have failed due to material damage in the crash. CONCLUSIONS: Motorcycle protective clothing is associated with reduced risk and severity of crash related injury and hospitalization, particularly when fitted with body armour. The proportion of clothing items that failed under crash conditions indicates a need for improved quality control. While mandating usage of protective clothing is not recommended, consideration could be given to providing incentives for usage of protective clothing, such as tax exemptions for safety gear, health insurance premium reductions and rebates. PMID- 21819817 TI - Potential Risk Estimation Drowning Index for Children (PREDIC): a pilot study from Matlab, Bangladesh. AB - Childhood drowning is a major public health problem that has been neglected in many low- and middle-income countries. In Matlab, rural Bangladesh, more than 40% of child deaths aged 1-4 years are due to drowning. AIM: The main objective of this paper was to develop and evaluate a childhood drowning risk prediction index. METHODOLOGY: A literature review was carried out to document risk factors identified for childhood drowning in Bangladesh. The Newacheck model for special health care needs for children was adapted and applied to construct a childhood drowning risk index called "Potential Risk Estimation Drowning Index for Children" (PREDIC). Finally, the proposed PREDIC Index was applied to childhood drowning deaths and compared with the comparison group from children living in Matlab, Bangladesh. This pilot study used t-tests and Receiver Operating Characteristic (ROC) curve to analyze the results. RESULTS: The PREDIC index was applied to 302 drowning deaths and 624 children 0-4 years old living in Matlab. The results of t-test indicate that the drowned children had a statistically (t= 8.58, p=0.0001) significant higher mean PREDIC score (6.01) than those in comparison group (5.26). Drowning cases had a PREDIC score of 6 or more for 68% of the children however, the comparison group had 43% of the children with score of 6 or more which was statistically significant (t=-7.36, p<0.001). The area under the curve for the Receiver Operating Characteristic curve was 0.662. CONCLUSION: Index score construction was scientifically plausible; and the index is relatively complete, fairly accurate, and practical. The risk index can help identify and target high risk children with drowning prevention programs. PREDIC index needs to be further tested for its accuracy, feasibility and effectiveness in drowning risk reduction in Bangladesh and other countries. PMID- 21819818 TI - Outline for a causal model of traffic conflicts and crashes. AB - Road crashes tend to be infrequent but with nontrivial consequences, leading to a long-running interest in identifying surrogate events, such as traffic conflicts, that can support a timely recognition and correction of safety deficiencies. Although a variety of possible surrogates have been suggested, questions remain regarding how crashes and surrogates are related. Using recent developments in causal analysis we propose a simple model which represents crashes and conflicts as resulting from interactions between initiating conditions and evasive actions, and then use this model to identify relationships between these types of events. Our first set of results expresses the probability of a crash as a mixture of probabilities over different sets of initiating conditions, where the mixing probabilities are governed by the evasive action. Our second set of results considers situations where sampling is restricted to non-crash events, and gives conditions where these truncated probabilities can serve as proxies for crash probabilities. We then illustrate how trajectory-based reconstruction can be used to classify initiating events with respect to severity, and to estimate a proxy for the crash probability from a set of incompletely observed non-crash events. PMID- 21819819 TI - Drugs related to motor vehicle crashes in northern European countries: a study of fatally injured drivers. AB - The aim of this study was to find which drugs and drug combinations were most common in drivers who died, in particular, in single vehicle crashes where the responsibility for the crash would be referred to the driver killed. The study included all available blood samples from drivers, who died within 24h of the accident, in the years 2001 and 2002 in the five Nordic countries (total population about 24 million inhabitants). The samples were analysed for more than 200 different drugs in addition to alcohol, using a similar analytical programme and cut-off limits in all countries. In three countries (Finland, Norway and Sweden) blood samples were available for more than 70% of the drivers, allowing representative prevalence data to be collected. 60% of the drivers in single vehicle crashes had alcohol and/or drug in their blood samples, compared with 30% of drivers killed in collisions with other vehicles. In single vehicle accidents, 66% of the drivers under 30 years of age had alcohol and/or drugs in their blood (alcohol only - 40%; drugs only - 12%; alcohol and drugs - 14%). The drugs found were mostly illicit drugs and psychoactive medicinal drugs with warning labels (in 57% and 58% respectively of the drivers under 30 with drugs present). Similar findings were obtained for drivers 30-49 years of age (63% with alcohol and/or drugs). In drivers aged 50 years and above, killed in single vehicle crashes (48% with alcohol and/or drugs) illicit drugs were found in only one case, and psychoactive medicinal drugs were detected less frequently than in younger age groups. In 75% of single vehicle crashes, the driver was under 50 years. Thus, the majority of accidents where the drivers must be considered responsible, occurred with drivers who had recently used alcohol, or drugs, alone or in combination. The drugs involved were often illicit and/or psychoactive drugs with warning labels. Therefore a large proportion of single vehicle accidents appear to be preventable, if more effective measures against driving after intake of alcohol and drugs can be implemented. PMID- 21819820 TI - Pedestrians' crossing behaviors and safety at unmarked roadway in China. AB - Pedestrians' crossing out of crosswalks (unmarked roadway) contributed to many traffic accidents, but existing pedestrian studies mainly focus on crosswalk crossing in developed countries specifically. Field observation of 254 pedestrians at unmarked roadway in China showed that 65.7% of them did not look for vehicles after arriving at the curb. Those who did look and pay attention to the traffic did so for duration of time that followed an exponential distribution. Pedestrians preferred crossing actively in tentative ways rather than waiting passively. The waiting time at the curb, at the median, and at the roadway all followed exponential distributions. During crossing, all pedestrians looked at the oncoming vehicles. When interacting with these vehicles, 31.9% of them ran and 11.4% stepped backwards. Running pedestrians usually began running at the borderline rather than within the lanes. Pedestrians preferred safe to short paths and they crossed second half of the road with significantly higher speed. These behavioral patterns were rechecked at an additional site with 105 pedestrians and the results showed much accordance. In terms of safety, pedestrians who were middle aged, involved in bigger groups, looked at vehicles more often before crossing or interacted with buses rather than cars were safer while those running were more dangerous. Potential applications of these findings, including building accurate simulation models of pedestrians and education of drivers and pedestrians in developing countries were also discussed. PMID- 21819821 TI - Spatial and temporal visualisation techniques for crash analysis. AB - Understanding the underlying structure of single vehicle crashes (SVCs) is essential for improving safety on the roads. Past research has found that SVCs tend to cluster both spatially and temporally. However, limited research has been conducted to investigate the interaction between the location of SVCs and the time they occur, especially at different levels of scales or spatial extents. This paper applied spatial, temporal and spatio-temporal techniques to investigate patterns of SVCs in Western Australia between 1999 and 2008, at different levels of scale. Spider graphs were adapted to identify temporal patterns of vehicle crashes at two different levels of scales: daily and weekly with respect to their causes. The spatial structures of vehicle crashes were analysed using Kernel Density Estimation analysis at three different scales: West Australia, Metropolitan area, and Perth Local Government Area (LGA). These are illustrated using spatial zooming theory. Comap was then used to demonstrate the spatio-temporal interaction effect on vehicle crashes. The results show significant differences in spatio-temporal patterns of SVCs for various crash causes. The techniques used here have the potential to help decision makers in developing effective road safety strategies. PMID- 21819822 TI - Effects of transverse rumble strips on safety of pedestrian crosswalks on rural roads in China. AB - The primary objective of this study is to evaluate the impacts of transverse rumble strips in reducing crashes and vehicle speeds at pedestrian crosswalks on rural roads in China. Using crash data reported at 366 sites, the research team conducted an observational before-after study using a comparison group and the Empirical Bayesian (EB) method to evaluate the effectiveness of transverse rumble strips in reducing crashes at pedestrian crosswalks. It was found that transverse rumble strips may reduce expected crash frequency at pedestrian crosswalks by 25%. The research team collected more than 15,000 speed observations at 12 sites. The speed data analysis results show that transverse rumble strips significantly reduce vehicle speeds in vicinity of pedestrian crosswalks on rural roads with posted speed limits of 60 km/h and 80 km/h. On average, the mean speed at pedestrian crosswalks declined 9.2 km/h on roads with a speed limit of 60 km/h; and 11.9 km/h on roads with a speed limit of 80 km/h. The 85th percentile speed declined 9.1 km/h on roads with a speed limit of 60 km/h; and 12.0 km/h on roads with a speed limit of 80 km/h. However, the speed reduction impacts were not found to be statistically significant for the pedestrian crosswalk on the road with a speed limit of 40 km/h. The study also looked extensively at the influence area of transverse rumble strips on rural roads. Speed profiles developed in this study show that the influence area of transverse rumble strips is generally less than 0.3 km. PMID- 21819823 TI - Is the TMPM-ICD9 revolution in trauma risk-adjustment compatible with imperfect administrative coding? AB - BACKGROUND: TMPM-ICD9 is the latest injury-severity measure based on empirical estimation from ICD-9-CM codes. It is candidate to replace expert-based AIS measures worldwide because of easier accessibility and better predictive performances. In Italy and other countries administrative ICD coding is generally less complete than dedicated AIS coding. We attempted to ascertain how this affects TMPM performances. METHODS: Discrimination (c statistics) and calibration (calibration curves, Akaike's criterion) of hierarchical logistic regression models for hospital mortality comprising TMPM or ISS were compared using trauma registry data on 3570 patients of years 2007-2009. The completeness of AIS vs. ICD-9-CM coding was also investigated through the ratio of the respective numbers of codes per patient. Model discrimination was further analyzed after stratification according to the above ratio (>1 and <= 1). RESULTS: The models with TMPM showed worse performances. The differences, concerned calibration (graphical evidence) in univariate models and discrimination (-1.2% of area under the ROC curve, p<0.05) in models completed with age, gender, mechanism of injury, motor GCS and systolic pressure. In parallel, ICD coding was less complete than AIS, as expected: 68% of patients had a ratio >1. The discrimination of TMPM vs. ISS models improved when the ratio changed from >1 to <= 1. CONCLUSIONS: The predictive performances of TMPM-ICD9 vs. ISS were lower than in the previous studies; the sub-optimal quality of ICD coding was a main cause. Imperfect administrative coding may hence hamper the TMPM-ICD9 revolution, although in our setting the negligible differences and the ready availability of administrative data may still give reason for adopting TMPM-ICD9. PMID- 21819825 TI - Exposure to lateral collision in signalized intersections with protected left turn under different traffic control strategies. AB - This paper proposes an original definition of the exposure to lateral collision in signalized intersections and discusses the results of a real world experiment. This exposure is defined as the duration of situations where the stream that is given the right-of-way goes through the conflict zone while road users are waiting in the cross-traffic approach. This measure, obtained from video sensors, makes it possible to compare different operating conditions such as different traffic signal strategies. The data from a real world experiment is used, where the adaptive real-time strategy CRONOS (ContRol Of Networks by Optimization of Switchovers) and a time-plan strategy with vehicle-actuated ranges alternately controlled an isolated intersection near Paris. Hourly samples with similar traffic volumes are compared and the exposure to lateral collision is different in various areas of the intersection and various traffic conditions for the two strategies. The total exposure under peak hour traffic conditions drops by roughly 5 min/h with the CRONOS strategy compared to the time-plan strategy, which occurs mostly on entry streams. The results are analyzed through the decomposition of cycles in phase sequences and recommendations are made for traffic control strategies. PMID- 21819824 TI - The effects of closer monitoring on driver compliance with interlock restrictions. AB - This randomized controlled trial of 2168 DWI multiple offenders assigned to a state-wide ignition interlock program in Maryland compared non-compliance with interlock requirements among drivers who were closely monitored (by Westat staff) and drivers who received standard monitoring (by the Motor Vehicle Administration). Compliance comparisons relied on datalogger data from MVA's interlock providers plus driver records that contained demographic information, prior alcohol-related traffic violations, their dispositions, and interlock duration. Measures for quantifying non-compliance included rates per 1000 engine starts for initial breath test failures at varying BAC levels and time periods, retest failures, retest refusals, interlock disconnects, startup violations, and summation measures. Regression analysis estimated the effects of closer monitoring on non-compliance, using linear mixed models that included random driver effects and fixed effects for study-group assignment, prior alcohol related traffic violations, and months of continuous datalogger data with a quadratic function that assessed changes and rates of change in interlock non compliance over time. All the separate non-compliance rates and summary measures derived from them were lower for closer monitored than control drivers for continuous data series of at least 6, 12, or 24 months. The differences for initial test failures and the two summary measures were statistically significant. Most measures of non-compliance decreased significantly as continuous time on the interlock increased. Parallel trends in each study group indicated that drivers learned to improve their compliance over time. Thus, this study convincingly demonstrates that closer monitoring substantially enhanced compliance with requirements of the ignition interlock and that regardless of group assignment, compliance increased over time. PMID- 21819826 TI - Predicting accident frequency at their severity levels and its application in site ranking using a two-stage mixed multivariate model. AB - Accident prediction models (APMs) have been extensively used in site ranking with the objective of identifying accident hotspots. Previously this has been achieved by using a univariate count data or a multivariate count data model (e.g. multivariate Poisson-lognormal) for modelling the number of accidents at different severity levels simultaneously. This paper proposes an alternative method to estimate accident frequency at different severity levels, namely the two-stage mixed multivariate model which combines both accident frequency and severity models. The accident, traffic and road characteristics data from the M25 motorway and surrounding major roads in England have been collected to demonstrate the use of the two-stage model. A Bayesian spatial model and a mixed logit model have been employed at each stage for accident frequency and severity analysis respectively, and the results combined to produce estimation of the number of accidents at different severity levels. Based on the results from the two-stage model, the accident hotspots on the M25 and surround have been identified. The ranking result using the two-stage model has also been compared with other ranking methods, such as the naive ranking method, multivariate Poisson-lognormal and fixed proportion method. Compared to the traditional frequency based analysis, the two-stage model has the advantage in that it utilises more detailed individual accident level data and is able to predict low frequency accidents (such as fatal accidents). Therefore, the two-stage mixed multivariate model is a promising tool in predicting accident frequency according to their severity levels and site ranking. PMID- 21819827 TI - Modeling animal-vehicle collisions considering animal-vehicle interactions. AB - Animal-Vehicle Collisions (AVCs) have been a major safety problem in the United States over the past decades. Counter measures against AVCs are urgently needed for traffic safety and wildlife conservation. To better understand the AVCs, a variety of data analysis and statistical modeling techniques have been developed. However, these existing models seldom take human factors and animal attributes into account. This paper presents a new probability model which explicitly formulates the interactions between animals and drivers to better capture the relationship among drivers' and animals' attributes, roadway and environmental factors, and AVCs. Findings of this study show that speed limit, rural versus urban, and presence of white-tailed deer habitat have an increasing effect on AVC risk, whereas male animals, high truck percentage, and large number of lanes put a decreasing effect on AVC probability. PMID- 21819828 TI - Modeling improvements in booster seat use: a discrete choice conjoint experiment. AB - Automobile crashes are the leading cause of death in children aged 1-14 years. Many children, however, are not properly restrained in safety seats that reduce serious injury and death. This study used a discrete choice conjoint experiment to study factors influencing the decision to use booster seats. Parents of 1714 children aged 4-9 years from nine Canadian provinces completed choice tasks presenting experimentally varied combinations of 15 4-level booster seat promotion attributes. Latent class analysis yielded three segments of parents. The choices of the Benefit Sensitive segment (50%) were most sensitive to the injury prevention benefits of booster seats. The choices of parents in the Context Sensitive segment (33.5%) were more likely to be influenced by installation complexity, oppositional behavior, and the prospect that their child may be teased for riding in booster seats. Parents in the High Risk segment (16.5%) were younger, less educated, and less knowledgeable about vehicle safety legislation. They anticipated fewer benefits, expected more barriers and were less likely to use booster seats. Simulations suggest that consistent enforcement coupled with advertising focusing on injury prevention and the use of booster seats by other parents would increase adoption. PMID- 21819829 TI - Traffic light compliance by civilians, soldiers and military officers. AB - Military officers, particularly those in the chain of command, are expected to provide "a good example of virtue, honor, patriotism, and subordination" (Snider, 2008). The aim of the present study was to examine the extent to which these values are reflected in the behavior that military officers exhibit crossing roads, as compared with soldiers' and civilians' road-crossing behavior. One thousand two hundred pedestrians were observed while crossing the street at an urban intersection in the center of Israel. Of these pedestrians, 594 (49.5%) were soldiers, 112 (9.33%) were officers and 488 (40.66%) were civilians. An observation grid was constructed to register pedestrians' crossing behavior. The independent variables encoded were gender, military status and military rank. The dependent variables encoded were crossing the road at a red light; crossing a busy road; running across the road; crossing the road diagonally; crossing the road without looking both ways; and crossing without first stopping at the sidewalk edge. To compare the crossing behaviors of each group of pedestrians, a summation was made for the six parameters of safe crossing. An ANOVA compared the means of unsafe road-crossing behaviors of males and females, on the one hand, and of civilians, soldiers and officers, on the other. A post hoc Scheffe test conducted on the means showed that the mean of the unsafe road-crossing behaviors of the civilians (M=1.55, SE=.04) was higher than that of the soldiers (M=1.35, SE=.04) and of the officers (M=1.21, SE=.08) p<.05. No significant difference was found between the means of the unsafe road-crossing behaviors of soldiers and officers, although the means of the officers' unsafe behaviors was lower than that of the soldiers. That is, both soldiers and officers exhibited road-crossing behavior that was significantly safer than that of civilians. Generally, more females waited for the green light (54.1%) than males (45.9%). No main effect of gender or interaction with belonging to the military was found. PMID- 21819830 TI - Mind the gap: training road users to use speed and distance when making gap acceptance decisions. AB - Accurate gap-acceptance decisions require individuals to take into account both the distance to and the speed of an oncoming vehicle. The aim of the present studies was to develop an intervention that could successfully teach road users to focus on speed as well as distance. Across three studies, participants judged whether it was safe to cross the road or not when an oncoming vehicle was approaching from different distances and at different speeds. Study 1 trialed two techniques ("standard feedback" versus "three-look") aimed at improving gap judgments. Standard feedback involved telling participants what the actual speed of a car was after they had made an estimate, whereas the three-look technique required participants to make timed and controlled head movements when scanning the road environment. Only standard feedback increased the participants' mean gap acceptance accuracy (assessed using both verbal and behavioral response measures). Study 2 also trialed two techniques, the standard feedback intervention used in Study 1, and a "two-response" intervention in which participants judged whether the oncoming vehicle was traveling at an atypical or normal speed. Study 2 found the two-response intervention to be more promising than the standard feedback procedure. Finally, Study 3 used video footage of oncoming vehicles to train younger (18-27 years) and older (60-80 years) adults and found the two-response intervention to be successful at improving gap acceptance accuracies for both age groups. However, the intervention also resulted in more conservative gap judgments from participants in the older population independent of improvements in accuracy. PMID- 21819831 TI - Older drivers' attitudes about instrument cluster designs in vehicles. AB - Little is known about older drivers' preferences and attitudes about instrumentation design in vehicles. Yet visual processing impairments are common among older adults and could impact their ability to interface with a vehicle's dashboard. The purpose of this study is to obtain information from them about this topic, using focus groups and content analysis methodology. A trained facilitator led 8 focus groups of older adults. Discussion was stimulated by an outline relevant to dashboard interfaces, audiotaped, and transcribed. Using multi-step content analysis, a trained coder placed comments into thematic categories and coded comments as positive, negative, or neutral in meaning. Comments were coded into these categories: gauges, knobs/switches, interior lighting, color, lettering, symbols, location, entertainment, GPS, cost, uniformity, and getting information. Comments on gauges and knobs/switches represented half the comments. Women made more comments about getting information; men made more comments about uniformity. Positive and negative comments were made in each category; individual differences in preferences were broad. The results of this study will be used to guide the design of a population based survey of older drivers about instrument cluster format, which will also examine how their responses are related to their visual processing capabilities. PMID- 21819832 TI - Ship collision risk assessment for the Singapore Strait. AB - The Singapore Strait is considered as the bottleneck and chokepoint of the shipping routes connecting the Indian and the Pacific Ocean. Therefore, the ship collision risk assessment is of significant importance for ships passing through the narrow, shallow, and busy waterway. In this paper, three ship collision risk indices are initially proposed to quantitatively assess the ship collision risks in the Strait: index of speed dispersion, degree of acceleration and deceleration, and number of fuzzy ship domain overlaps. These three risk indices for the Singapore Strait are estimated by using the real-time ship locations and sailing speeds provide by Lloyd's MIU automatic identification system (AIS). Based on estimation of these three risk indices, it can be concluded that Legs 4W, 5W, 11E, and 12E are the most risky legs in the Strait. Therefore, the ship collision risk reduction solutions should be prioritized being implemented in these four legs. This study also finds that around 25% of the vessels sail with a speed in excess of the speed limit, which results in higher potentials of ship collision. Analysis indicates that the safety level would be significantly improved if all the vessels follow the passage guidelines. PMID- 21819833 TI - Driving performance impairments due to hypovigilance on monotonous roads. AB - Drivers' ability to react to unpredictable events deteriorates when exposed to highly predictable and uneventful driving tasks. Highway design reduces the driving task mainly to a lane-keeping manoeuvre. Such a task is monotonous, providing little stimulation and this contributes to crashes due to inattention. Research has shown that driver's hypovigilance can be assessed with EEG measurements and that driving performance is impaired during prolonged monotonous driving tasks. This paper aims to show that two dimensions of monotony - namely road design and road side variability - decrease vigilance and impair driving performance. This is the first study correlating hypovigilance and driver performance in varied monotonous conditions, particularly on a short time scale (a few seconds). We induced vigilance decrement as assessed with an EEG during a monotonous driving simulator experiment. Road monotony was varied through both road design and road side variability. The driver's decrease in vigilance occurred due to both road design and road scenery monotony and almost independently of the driver's sensation seeking level. Such impairment was also correlated to observable measurements from the driver, the car and the environment. During periods of hypovigilance, the driving performance impairment affected lane positioning, time to lane crossing, blink frequency, heart rate variability and non-specific electrodermal response rates. This work lays the foundation for the development of an in-vehicle device preventing hypovigilance crashes on monotonous roads. PMID- 21819834 TI - A framework for a critical assessment of the quality of epidemiological studies of driver health and accident risk. AB - A large number of studies have tried to assess how various aspects of driver health influence driver involvement in accidents. The objective of this paper is to provide a framework for a critical assessment of the quality these studies from a methodological point of view. Examples are given of how various sources of bias and confounding can produce study findings that are highly misleading. Ten potential sources of error and bias in epidemiological studies of the contribution of driver health impairments to road accidents are discussed: (1) Poor description of the medical conditions whose effects are studied (measurement error). (2) Inadequate control for the effects of exposure on accident rate. (3) Sampling endogeneity with respect to assessment for fitness to drive (outcome based sampling; self-selection bias). (4) Combined exposure to several risk factors. (5) Poor control for potentially confounding factors. (6) Failure to specify potentially moderating factors (interaction effects). (7) Failure to consider a severity gradient with respect to the effect of health impairments. (8) Failure to specify the compliance of drivers with medical treatments or treatment effectiveness. (9) No data on the population prevalence of various health conditions. (10) The use of multiple study approaches and methods making the comparison and synthesis of findings difficult. Examples are given of how all these items may influence the findings of a single study or make synthesising findings from multiple studies difficult. A checklist for assessing study quality is provided. PMID- 21819835 TI - Underreporting of maritime accidents to vessel accident databases. AB - Underreporting of maritime accidents is a problem not only for authorities trying to improve maritime safety through legislation, but also to risk management companies and other entities using maritime casualty statistics in risk and accident analysis. This study collected and compared casualty data from 01.01.2005 to 31.12.2009, from IHS Fairplay and the maritime authorities from a set of nations. The data was compared to find common records, and estimation of the true number of occurred accidents was performed using conditional probability given positive dependency between data sources, several variations of the capture recapture method, calculation of best case scenario assuming perfect reporting, and scaling up a subset of casualty information from a marine insurance statistics database. The estimated upper limit reporting performance for the selected flag states ranged from 14% to 74%, while the corresponding estimated coverage of IHS Fairplay ranges from 4% to 62%. On average the study results document that the number of unreported accidents makes up roughly 50% of all occurred accidents. Even in a best case scenario, only a few flag states come close to perfect reporting (94%). The considerable scope of underreporting uncovered in the study, indicates that users of statistical vessel accident data should assume a certain degree of underreporting, and adjust their analyses accordingly. Whether to use correction factors, a safety margin, or rely on expert judgment, should be decided on a case by case basis. PMID- 21819836 TI - The impact of compulsory cycle helmet legislation on cyclist head injuries in New South Wales, Australia. AB - The study aimed to assess the effect of compulsory cycle helmet legislation on cyclist head injuries given the ongoing debate in Australia as to the efficacy of this measure at a population level. We used hospital admissions data from New South Wales, Australia, from a 36 month period centred at the time legislation came into effect. Negative binomial regression of hospital admission counts of head and limb injuries to cyclists were performed to identify differential changes in head and limb injury rates at the time of legislation. Interaction terms were included to allow different trends between injury types and pre- and post-law time periods. To avoid the issue of lack of cyclist exposure data, we assumed equal exposures between head and limb injuries which allowed an arbitrary proxy exposure to be used in the model. As a comparison, analyses were also performed for pedestrian data to identify which of the observed effects were specific to cyclists. In general, the models identified a decreasing trend in injury rates prior to legislation, an increasing trend thereafter and a drop in rates at the time legislation was enacted, all of which were thought to represent background effects in transport safety. Head injury rates decreased significantly more than limb injury rates at the time of legislation among cyclists but not among pedestrians. This additional benefit was attributed to compulsory helmet legislation. Despite numerous data limitations, we identified evidence of a positive effect of compulsory cycle helmet legislation on cyclist head injuries at a population level such that repealing the law cannot be justified. PMID- 21819837 TI - Simulator evaluation of drivers' speed, deceleration and lateral position at rural intersections in relation to different perceptual cues. AB - Aim of the study was to investigate, by means of a driving simulator experiment, drivers' behaviour in terms of speed, deceleration, and lateral position on major approaches of rural intersections in relation to different perceptual cues. In the experiment, ten different design conditions with and without speed-reducing treatments along the approach to the intersection were tested. Twenty-three drivers drove a test route two times and data from the second drive were used for comparison. The order of the ten design conditions was counterbalanced for all the drivers to minimize the presentation order effect. Three different data analysis techniques were used: (a) cluster analysis of speed and lateral position data, (b) statistical tests of speed and lateral position data, and (c) categorical analysis of deceleration behaviour patterns. The most effective treatments were the dragon teeth markings (based on the principle of optical road narrowing), the colored intersection area (based on the principle of intersection highlighting), and the raised median island (based on the principle of physical road narrowing). These measures, in comparison to the base intersection, produced: (1) a significant speed reduction starting from 250 m before the intersection in the range between 13 and 23 km/h, (2) a significant change in the deceleration behaviour with a reduction in the proportion of drivers which did not decelerate, and (3) a shift away from the intersection of the deceleration beginning. Given the significant effects on drivers' behaviour, the dragon teeth markings, the colored intersection area, and the raised median island are strongly recommended for real world implementation. PMID- 21819838 TI - Incidence, severity and correlates of bicycling injuries in a sample of cyclists in Queensland, Australia. AB - Bicycle injuries, particularly those resulting from single bicycle crashes, are underreported in both police and hospital records. Data on cyclist characteristics and crash circumstances are also often lacking. As a result, the ability to develop comprehensive injury prevention policies is hampered. The aim of this study was to examine the incidence, severity, cyclist characteristics, and crash circumstances associated with cycling injuries in a sample of cyclists in Queensland, Australia. A cross-sectional study of Queensland cyclists was conducted in 2009. Respondents (n=2056) completed an online survey about their cycling experiences, including cycling injuries. Logistic regression modelling was used to examine the associations between demographic and cycling behaviour variables with experiencing cycling injuries in the past year, and, separately, with serious cycling injuries requiring a trip to a hospital. Twenty-seven percent of respondents (n=545) reported injuries, and 6% (n=114) reported serious injuries. In multivariable modelling, reporting an injury was more likely for respondents who had cycled <5 years, compared to >= 10 years (p<0.005); cycled for competition (p=0.01); or experienced harassment from motor vehicle occupants (p<0.001). There were no gender differences in injury incidence, and respondents who cycled for transport did not have an increased risk of injury. Reporting a serious injury was more likely for those whose injury involved other road users (p<0.03). Along with environmental and behavioural approaches for reducing collisions and near-collisions with motor vehicles, interventions that improve the design and maintenance of cycling infrastructure, increase cyclists' skills, and encourage safe cycling behaviours and bicycle maintenance will also be important for reducing the overall incidence of cycling injuries. PMID- 21819839 TI - Developing effective professional bus driver health programs: an investigation of self-rated health. AB - The health of professional bus drivers is a critical factor in their driving performance; any impairment may lead to undesired consequences. In an attempt to develop and prioritize health and wellness programs, this study investigates the factors significantly affecting the health conditions of professional bus drivers, as well as the strength of these factors. This study uses self-rated health as the examination measurement. This simple assessment is an inclusive measure of health status for judging health trajectory, and is highly associated with changes in functional ability, including perceived control over driving. This study evaluates driver responses of self-rated health with ordered response models that consider factors such as the driver reported health problems, physical and psychological conditions, demographic factors, driving experience, and working environment. Analysis of a sample of 785 drivers shows that age, body mass index, depression, daily working hours, perceived company safety culture, and health problems are the factors significantly affecting self-rated health. Depression has the greatest effect among all factors except health problems. Unlike the linear relationships for the other factors, the relationships between depression levels and perceived health are S-shaped. The results of ordered response models suggest that these influential factors have distinct effects on the self-rated health of individual drivers and on the different levels of self rated health. PMID- 21819840 TI - A note on modeling road accident frequency: a flexible elasticity model. AB - Count data models and their variants have been widely applied in accident modeling. The traditional log-linear function is used to represent the relationship between explanatory variables and the dependent variable (accident frequency). However, this function assumes constant elasticity for the estimation parameters, which is a limitation in the analysis of the effects of explanatory variables on accident risk. Although interaction effects between explanatory variables have been studied in the road safety context (where they are normally assessed by logistic regression), no one has yet examined the possibility of using a flexible function form allowing non-constant elasticity values. This paper seeks to explore the use of the translog function usually used in the economics context to allow the elasticity to vary with the values of other explanatory variables. Therefore, the objective of this study was to evaluate the application of the translog function to accident modeling and to compare the results with those of the traditional log-linear function negative binomial (NB) model. The results show that, in terms of goodness-of-fit statistics and residual analysis, the NB model with the translog function performs better than the traditional NB model. Additional evaluations in terms of predictive performance, hotspot identification and uncertainty associated with the estimated values were taken into account. Although this study is exploratory in nature, it suggests that the translog function has considerable potential for modeling accident observations. It is hoped that this novel accident modeling methodology will open the door to the reliable interpretation and evaluation of the influence of explanatory variables on accident frequency. PMID- 21819841 TI - Required length of guardrails before hazards. AB - One way to protect against impacts during run-off-road accidents with infrastructure is the use of guardrails. However, real-world accidents indicate that vehicles can leave the road and end up behind the guardrail. These vehicles have no possibility of returning to the lane. Vehicles often end up behind the guardrail because the length of the guardrails installed before hazards is too short; this can lead to a collision with a shielded hazard. To identify the basic speed for determining the necessary length of guardrails, we analyzed the speed at which vehicles leave the roadway from the ZEDATU (Zentrale Datenbank Todlicher Unfalle) real-world accidents database. The required length of guardrail was considered the length that reduces vehicle speed at a maximum theoretically possible deceleration of 0.3g behind the barrier based on real-world road departure speed. To determine the desired length of a guardrail ahead of a hazard, we developed a relationship between guardrail length and the speed at which vehicles depart the roadway. If the initial elements are flared away from the carriageway, the required length will be reduced by up to an additional 30% The ZEDATU database analysis showed that extending the current length of guardrails to the evaluated required length would reduce the number of fatalities among occupants of vehicles striking bridge abutments by approximately eight percent. PMID- 21819842 TI - Older drivers' insight into their hazard perception ability. AB - Even though the driving ability of older adults may decline with age, there is evidence that some individuals attempt to compensate for these declines using strategies such as restricting their driving exposure. Such compensatory mechanisms rely on drivers' ability to evaluate their own driving performance. This paper focuses on one key aspect of driver ability that is associated with crash risk and has been found to decline with age: hazard perception. Three hundred and seven drivers, aged 65-96, completed a validated video-based hazard perception test. There was no significant relationship between hazard perception test response latencies and drivers' ratings of their hazard perception test performance, suggesting that their ability to assess their own test performance was poor. Also, age-related declines in hazard perception latency were not reflected in drivers' self-ratings. Nonetheless, ratings of test performance were associated with self-reported regulation of driving, as was self-rated driving ability. These findings are consistent with the proposal that, while self assessments of driving ability may be used by drivers to determine the degree to which they restrict their driving, the problem is that drivershave little insight into their own driving ability. This may impact on the potential road safety benefits of self-restriction of driving because drivers may not have the information needed to optimally self-restrict. Strategies for addressing this problem are discussed. PMID- 21819843 TI - Roadway crash risks in recent immigrants. AB - Adult immigrants are sometimes characterized as unsafe drivers and responsible for excess road crashes. We analyzed Canada's largest and most ethnically diverse province to assess whether recent immigrants had an increased risk of involvement as drivers in serious motor vehicle crashes. Overall, the study included 4,238,222 individuals followed for a median duration of 8.0 years. In total, 10,975 individuals were subsequently admitted to hospital as drivers involved in a crash, with a rate per 100,000 significantly lower among recent immigrants compared to long-term residents (158 vs 289, p<0.001). This difference was equal to a 45% relative reduction in the incidence of a crash (odds ratio=0.55, 95% confidence interval 0.52-0.58), persisted after adjustment for baseline characteristics (hazard ratio=0.61, 95% confidence interval 0.58-0.65), extended to extremes of crash severity, and was accentuated during initial years following immigration. These findings suggest that, contrary to popular opinion, recent immigrants are less prone to be drivers in serious motor vehicle crashes. PMID- 21819844 TI - Measuring driver responses at railway level crossings. AB - Railway level crossings are amongst the most complex of road safety control systems, due to the conflicts between road vehicles and rail infrastructure, trains and train operations. Driver behaviour at railway crossings is the major collision factor. The main objective of the present paper was to evaluate the existing conventional warning devices in relation to driver behaviour. The common conventional warning devices in Australia are a stop sign (passive), flashing lights and a half boom-barrier with flashing lights (active). The data were collected using two approaches, namely: field video recordings at selected sites and a driving simulator in a laboratory. This paper describes and compares the driver response results from both the field survey and the driving simulator. The conclusion drawn is that different types of warning systems resulted in varying driver responses at crossings. The results showed that on average driver responses to passive crossings were poor when compared to active ones. The field results were consistent with the simulator results for the existing conventional warning devices and hence they may be used to calibrate the simulator for further evaluation of alternative warning systems. PMID- 21819845 TI - Effect of shoulder width, guardrail and roadway geometry on driver perception and behavior. AB - Roadway design is one of the most significant factors that affect driving behavior and perceived safety. The current study tests the combined effects of three roadway design elements - shoulders width, guardrail existence and roadway geometry (curvature) - on objective driving measures (speed and lane position), and subjective measures (perceived safe driving speed and estimated road safety). Twenty two drivers participated in an experiment with a driving simulation. In the first part objective driving data were collected, and in the second part subjective paper-pencil evaluations were requested of the perceived safety of 30 different scenarios that were previously experienced in the simulator. The scenarios consisted of the various combinations of the three roadway design elements. The results showed a significant effect of roadway geometry on both objective and subjective measures. The shoulders width had a significant effect on actual speed, on lane position, and on perceived safe driving speed, but only when a guardrail was present. These findings illustrate the perceptual role of a guardrail in defining the perceived safety margins that various shoulder widths provide. When a guardrail is absent, the width of the shoulder loses much of its benefits and effects on driving behavior. The results also demonstrate that roadway geometry can be used to reduce driving speeds, but at the same time it can have a negative effect on maintaining a stable lane position in sharp curves. Thus, controlling the width of road shoulders and the placement of guardrails seems to be a safer approach to speed and lane position control. PMID- 21819846 TI - Developing safety performance functions incorporating reliability-based risk measures. AB - Current geometric design guides provide deterministic standards where the safety margin of the design output is generally unknown and there is little knowledge of the safety implications of deviating from these standards. Several studies have advocated probabilistic geometric design where reliability analysis can be used to account for the uncertainty in the design parameters and to provide a risk measure of the implication of deviation from design standards. However, there is currently no link between measures of design reliability and the quantification of safety using collision frequency. The analysis presented in this paper attempts to bridge this gap by incorporating a reliability-based quantitative risk measure such as the probability of non-compliance (P(nc)) in safety performance functions (SPFs). Establishing this link will allow admitting reliability-based design into traditional benefit-cost analysis and should lead to a wider application of the reliability technique in road design. The present application is concerned with the design of horizontal curves, where the limit state function is defined in terms of the available (supply) and stopping (demand) sight distances. A comprehensive collision and geometric design database of two-lane rural highways is used to investigate the effect of the probability of non-compliance on safety. The reliability analysis was carried out using the First Order Reliability Method (FORM). Two Negative Binomial (NB) SPFs were developed to compare models with and without the reliability-based risk measures. It was found that models incorporating the P(nc) provided a better fit to the data set than the traditional (without risk) NB SPFs for total, injury and fatality (I+F) and property damage only (PDO) collisions. PMID- 21819847 TI - The development and application of a proxy measure of alcohol-related traffic crashes for rural communities. AB - CONTEXT: To date, no studies have adequately examined whether community-level, rather than individual-level, characteristics, are associated with high rates of alcohol-related traffic crashes (ARTC). OBJECTIVE: This study aims to identify a proxy measure of ARTC most appropriate to rural communities in New South Wales (NSW), Australia, and to identify community characteristics that predict higher rates of ARTC. METHODS: ARTC (2001-2007) incident data from 20 rural communities in NSW were obtained. Cost data were applied to take account of ARTCs of different severity. RESULTS: The method used to define a proxy measure of ARTCs for NSW generally was found to be inadequate when applied to local communities within NSW: specifically, two time periods were found to be alcohol-related for local communities only and seven time periods were found to be non-alcohol related for local communities only. Applying a community-specific proxy measure of ARTCs to 20 communities identified substantial variation in ARTC cost-ratios, ranging from 1.20 to 0.15. Higher cost-ratios were statistically significantly predicted by the proportion of residents who were male and less than 25 years. CONCLUSIONS: Proxy measures of ARTCs represent an ideal method of utilising routinely collected data to identify specific types of ARTCs that are most relevant to a defined community, identify community-specific factors associated with higher rates of ARTCs and measure the impact of interventions tailored to those risk factors. Such measures ought to be community-specific because these results suggest national or provincial-level definitions are not necessarily directly applicable to local communities. These results show substantial variability between communities in their rates of ARTC and identify communities with higher proportions of young males as being at increased risk. PMID- 21819848 TI - The dark side of stimulus control--associations between contradictory stimulus configurations and pedestrians' and cyclists' illegal street crossing behavior. AB - Since illegal pedestrian behavior represents a major source of accidents, research investigating possible reasons and risk factors for crossing against the lights is pivotal for enhancing safety in traffic. The present approach regards behavior at signalized intersections as a result of multiple stimulus discrimination. Hence, it is expected that at crossings divided by a median refuge the excitatory potential of a "consecutive green light" or "oncoming pedestrians" (S+*) attenuates the inhibition of crossing behavior induced by the relevant red light (S-). Standardized observations at critical intersections in Braunschweig, Germany, were conducted to investigate these hypotheses. Comparing outside traffic participants' behavior in the presence of different stimulus configurations identified the assumed S+* as substantial risk factors for illegal crossings. Moreover, the presented model of stimulus control integrates past risk factor research and may help develop future prevention measures. PMID- 21819849 TI - Equine road user safety: public attitudes, understandings and beliefs from a qualitative study in the United Kingdom. AB - Horse riders represent a significant group of vulnerable road user and are involved in a number of accidents and near misses on the road. Despite this horse riders have received little attention both in terms of academic research and transport policy. Based on literature on vulnerable road user safety, including attitudes to road user safety and behaviour of drivers and their relationship with cyclists and motorcyclists, this paper examines the attitudes and reported behaviour of drivers and horse riders. A total of 46 participants took part in six focus groups divided into four groups of drivers with little or no horse riding experience and two groups of frequent horse riders. Each group investigated five key topic areas stemming from the literature review on vulnerable road users including hazard perception, risk perception, emotion, attitudes to sharing the road and empathy. It was found that drivers and horse riders are not always aware of the same hazards in the road and that this may lead drivers to under-estimate the risk when encountering horses. Drivers often had good intentions to overtake horses safely, but were unaware of how vulnerable passing very wide and slow made them feel until they had begun the manoeuvre and hence quickly reduced such feelings either by speeding up or cutting in too soon. However, other than this, drivers had good skills when encountering horses. But these skills could be impeded by frustration when encountering a slow moving horse which was further compounded by a feeling, mainly by younger drivers, that horse riding was for leisure and as such should not get in the way of necessary work journeys. There is a need for drivers to be more aware of the potential hazards a horse rider faces on the road and these could be achieved through inducing empathy amongst drivers for horse riders, creating nudges for drivers in the environment and better education for drivers. PMID- 21819850 TI - The role of parental alcohol consumption on driving under the influence of alcohol: results from a longitudinal, nationally representative sample. AB - PURPOSE: Many studies have examined the role of peer and parental alcohol use on drinking behaviors among adolescents. Few studies, however, have examined parental influences on driving under the influence (DUI) of alcohol. The current study uses data from a longitudinal study to examine the role of parental alcohol use during adolescence on the risk for DUI among young adult men and women. METHODS: Data were derived from 9559 adolescents and young adults who participated in the National Longitudinal Study of Adolescent Health (Add Health) Waves I and III. Survey logistic regression was used to examine the relationship between multilevel risk and protective factors and self-reported DUI. Analyses were stratified by gender and frequency of parental alcohol consumption to understand the role of parental alcohol use on risk for DUI among their youth. RESULTS: Risk and protective factors for DUI were very similar among men and women. Parental alcohol use significantly predicted DUI among women (OR=1.39, p<0.01) and men (OR=1.33, p<0.05). When parents did not report alcohol use, peer alcohol use significantly increased risk for DUI for both women (OR=1.26, p<0.05) and men (OR=1.31, p<0.001). When parents reported alcohol use, however, peer alcohol use was not a significant independent predictor. CONCLUSIONS: Findings suggest remarkable similarities in risk and protective factors for DUI across gender groups. For men and women, parental alcohol consumption was a risk factor for DUI. Peers' alcohol use predicted DUI only when parents did not use alcohol. PMID- 21819851 TI - An analysis of alcohol breath tests results with portable and desktop breath testers as surrogates of blood alcohol levels. AB - There is a perceived tradeoff between the ease of measuring alcohol in the body and the accuracy of the result. Direct tests of blood alcohol concentrations are considered the most accurate, desktop stationary breath testers based on electro chemical infra-red technology are slightly less accurate, but accepted for evidentiary purposes in most jurisdictions, and quick portable breath testers based on fuel-cell technology are the easiest to administer but not acceptable in many courts. This study compared the accuracy of an evidentiary portable breath tester and an evidentiary desktop breath tester relative to blood alcohol concentrations. Inverse regressions were used to obtain confidence limits for the alcohol levels as read by the breath testers that would provide tradeoffs of false positives and false negatives for three levels of confidence: 95%, 96%, and 98%; corresponding to false positive values of 2.5%, 2%, and 1%, respectively. A decision tree model is offered for the optimal use of the three measures, so that portable breath testers can be sufficient for high level BrAC, stationary breath testers can be sufficient for medium level BrAC, and blood tests are recommended for still lower BrACs. The model provides quantitative BrAC threshold levels for the two most common BAC levels used to imply DWI: 50mg/dl and 80 mg/dl. PMID- 21819852 TI - Restraint use and seating position among child car passengers: an observational study in Shanghai. AB - Child passenger restraint practices in China are poorly characterized and few direct observational studies have been performed. This study aims to describe child passenger restraint use and to investigate factors influencing the restraint practices. A cross-sectional observational study was conducted at toll gates in Shanghai during an 11-day period in June in 2009. A pro-forma observation checklist was used to collect data related to restraint use by child passengers aged <= 12 years, restraint use by drivers, and the number of child passengers traveling in passenger cars registered in Shanghai. Adjusted risk ratios (RR) comparing those children who were properly rear seated with those in other positions (front seat, on adult's lap) and any restraint use with no restraint use were evaluated using multivariate binomial regression with robust variance estimation. Among 967 children observed, 44.1% of children were in suboptimal seating positions (i.e., 12.2% in the front seat and 31.9% in adult laps) and 93.9% were unrestrained. Children aged <= 4 years (RR: 0.35, 95% Confidence Interval: 0.28-0.44), and those who were the only child in a car (RR: 0.84, 95% confidence interval: 0.74-0.96) had a lower likelihood of being properly rear seated. Children traveling with unrestrained drivers (RR: 0.09, 95% confidence interval: 0.01-0.60) were less likely to be restrained. This study demonstrates low restraint use and common suboptimal seating positions for child passengers in China and relates these to driver restraint use. These findings support the need for targeted programs to improve child restraint practices in China. PMID- 21819853 TI - "Teaching them a lesson?" A qualitative exploration of underlying motivations for driver aggression. AB - Aggressive driving is increasingly a concern for drivers in highly motorised countries. However, the role of driver intent in this behaviour is problematic and there is little research on driver cognitions in relation to aggressive driving incidents. In addition, while drivers who admit to behaving aggressively on the road also frequently report being recipients of similar behaviours, little is known about the relationship between perpetration and victimisation or about how road incidents escalate into the more serious events that feature in capture media attention. The current study used qualitative interviews to explore driver cognitions and underlying motivations for aggressive behaviours on the road. A total of 30 drivers aged 18-49 years were interviewed about their experiences with aggressive driving. A key theme identified in responses was driver aggression as an attempt to manage or modify the behaviour of other road users. Two subthemes were identified and appeared related to separate motivations for aggressive responses: 'teaching them a lesson' referred to situations where respondents intended to convey criticism or disapproval, usually of unintended behaviours by the other driver, and thus encourage self-correction; and 'justified retaliation' which referred to situations where respondents perceived deliberate intent on the part of the other driver and responded aggressively in return. Mildly aggressive driver behaviour appears to be common. Moreover such behaviour has a sufficiently negative impact on other drivers that it may be worth addressing because of its potential for triggering retaliation in kind or escalation of aggression, thus compromising safety. PMID- 21819854 TI - Roadwise Review has limited congruence with actual driving performance of aging drivers. AB - The Roadwise Review (RR) CD-ROM has been proposed as one way for older drivers to self-evaluate the skills that support safe driving. To better gauge the utility of RR for that purpose, further validation of RR vis-a-vis measures of driving performance is needed. We carried out this study to provide such validation. We correlated the results of the standard Useful Field of View subtest 2 (UFOV-2) and Trail Making Test (TMT) parts A and B to the corresponding RR subsections on visual information processing and visual search. We further examined the correlations between on-road performance (based on demerit points) and RR results (absolute scores and number of problems identified). The correlations between UFOV-2, TMT and the relevant RR sections ranged from .46 to .61. The correlations between demerit points and RR absolute values ranged from -.40 to .50. The correlations between demerit points and the number of problems identified by RR ranged from -.24 to .45. Using a "pass/fail" approach we also failed to find a relationship with the number of problems. These results indicate limited convergence between findings obtained with RR and actual performance using standardized approaches. Such results emphasize the importance of developing a rigorous data synthesis process before attempting knowledge translation of material aimed at older drivers. PMID- 21819855 TI - Ambient ionization mass spectrometry: a tutorial. AB - Ambient ionization is a set of mass spectrometric ionization techniques performed under ambient conditions that allows the direct analysis of sample surfaces with little or no sample pretreatment. Using combinations of different types of sample introduction systems and ionization methods, several novel techniques have been developed over the last few years with many applications (e.g., food safety screening; detection of pharmaceuticals and drug abuse; monitoring of environmental pollutants; detection of explosives for antiterrorism and forensics; characterization of biological compounds for proteomics and metabolomics; molecular imaging analysis; and monitoring chemical and biochemical reactions). Electrospray ionization and atmospheric pressure chemical ionization are the two main ionization principles most commonly used in ambient ionization mass spectrometry. This tutorial paper provides a review of the publications related to ambient ionization techniques. We describe and compare the underlying principles of operation, ionization processes, detecting mass ranges, sensitivity, and representative applications of these techniques. PMID- 21819856 TI - Review of analytical methods for the quantification of iodine in complex matrices. AB - Iodine is an essential element of human nutrition. Nearly a third of the global population has insufficient iodine intake and is at risk of developing Iodine Deficiency Disorders (IDD). Most countries have iodine supplementation and monitoring programs. Urinary iodide (UI) is the biomarker used for epidemiological studies; only a few methods are currently used routinely for analysis. These methods either require expensive instrumentation with qualified personnel (inductively coupled plasma-mass spectrometry, instrumental nuclear activation analysis) or oxidative sample digestion to remove potential interferences prior to analysis by a kinetic colorimetric method originally introduced by Sandell and Kolthoff ~75 years ago. The Sandell-Kolthoff (S-K) method is based on the catalytic effect of iodide on the reaction between Ce(4+) and As(3+). No available technique fully fits the needs of developing countries; research into inexpensive reliable methods and instrumentation are needed. There have been multiple reviews of methods used for epidemiological studies and specific techniques. However, a general review of iodine determination on a wide ranging set of complex matrices is not available. While this review is not comprehensive, we cover the principal developments since the original development of the S-K method. PMID- 21819857 TI - Comparison of theoretical and experimental models for characterizing solvent properties using reversed phase liquid chromatography. AB - Theoretical and experimental quantitative structure-retention relationships (QSRR) models are useful for characterizing solvent properties and column selectivity in reversed phase liquid chromatography (RPLC). The chromatographic behavior of a model analyte, the herbicide atrazine, in a system derived from nine organic solvents and three chromatographic columns was used for developing QSRR models. Multiple linear regression (MLR) and partial least squares regression (PLSR) were used as statistical approaches. The similarities and differences between linear solvation energy relationships (LSER), and semi empirical and theoretical molecular models were demonstrated. QSRR models show high predictive power, and can successfully predict retention factor (log k) for new solvents. The models are useful for solvent optimization and reducing time for method development in RPLC. The herbicide atrazine can be readily analyzed at a low level, and all three columns provided good resolution, high-performance and symmetrical peaks. The method is suitable for analysis of atrazine in water samples. PMID- 21819858 TI - Immunoassay of C-reactive protein by hot electron induced electrochemiluminescence using integrated electrodes with hydrophobic sample confinement. AB - C-reactive protein (CRP) was determined in the concentration range 0.01-10 mg L( 1) using hot electron induced electrochemiluminescence (HECL) with devices combining both working and counter electrodes and sample confinement on a single chip. The sample area on the electrodes was defined by a hydrophobic ring, which enabled dispensing the reagents and the analyte directly on the electrode. Immunoassay of CRP by HECL using integrated electrodes is a good candidate for a high-sensitivity point-of-care CRP-test, because the concentration range is suitable, miniaturisation of the measurement system has been demonstrated and the assay method with integrated electrodes is easy to use. High-sensitivity CRP tests can be used to monitor the current state of cardiovascular disease and also to predict future cardiovascular problems in apparently healthy people. PMID- 21819859 TI - Speciation analysis of mercury in water samples using dispersive liquid-liquid microextraction combined with high-performance liquid chromatography. AB - A novel approach for preconcentration and speciation analysis of trace amount of mercury from water samples was proposed by dispersive liquid-liquid microextraction (DLLME) coupled to high performance liquid chromatography with diode array detection (HPLC-DAD). Mercury species (Hg(2+), methylmercury (MeHg(+)) and phenylmercury (PhHg(+))) were complexed with dithizone (DZ) to form hydrophobic chelates and then extracted into the fine drops of extraction solvent dispersed in the aqueous sample by dispersive solvent. After extraction, the sedimented phase was analyzed by HPLC-DAD. Some important parameters affecting the DLLME such as extraction solvent and dispersive solvent type and volume, concentration of dithizone solution, sample pH, extraction time and salt effect were investigated. Ionic liquid 1-hexyl-3-methylimidazolium hexafluorophosphate ([HMIM][PF(6)]) was found to be a suitable extractant for the chelates. Under the optimized conditions (extraction solvent: 70 MUL of ionic liquid 1-hexyl-3 methylimidazolium hexafluorophosphate ([HMIM][PF(6)]); dispersive solvent: 0.75 mL of methanol containing dithizone (0.02%, m/v); pH: 4; extraction time: 5 min; and without salt addition), the limits of detection for Hg(2+), MeHg(+) and PhHg(+) were 0.32, 0.96 and 1.91 MUg L(-1) (SN(-1)=3) respectively, and the relative standard deviation (RSD) was between 4.1 and 7.3% (n=5). Three real water samples (tap water, river water and lake water) spiked with mercury species were detected by the developed method, and the relative recoveries obtained for Hg(2+), MeHg(+) and PhHg(+) were 89.6-101.3%, 85.6-102.0% and 81.3-97.6%, respectively. PMID- 21819860 TI - Using an on-line microdialysis/HPLC system for the simultaneous determination of melamine and cyanuric acid in non-dairy creamer. AB - The recent revelation of melamine (MEL) contamination in foodstuffs in China has rocked the international public health community. Many food categories have been involved in this scandal, including non-dairy creamer (NDC). In this study, we investigated the use of hollow-fiber microdialysis (MD) sampling coupled on-line with high-performance liquid chromatography (HPLC) as an alternative to sample pretreatment for the direct determination of MEL and its analogue cyanuric acid (CYA) in NDC. After MD sampling, the dialysate was injected on-line into the chromatographic system for analysis of MEL and CYA with UV detection at 203 nm. We monitored the effects of various parameters affecting the MD efficiency, namely the characteristics of the MD probe membrane, the flow-rate and the nature of the polarity modifier in the perfusion stream, and the addition of salt in the sample solution. The optimal enrichment efficiency for collecting MEL and CYA from aqueous NDC samples occurred with MD sampling using a hollow polysulfone MD fiber and MeOH as the perfusate at a flow rate of 10 MUL min(-1). The optimized chromatographic conditions involved using a reversed-phase phenyl column and a mobile phase of 5 mM phosphate buffer in 10% (v/v) MeOH, buffered at pH 6.5. Detection was linear in the concentration range from 0.02 to 5 ppm for MEL and from 2 to 100 ppm for CYA, with detection limits of 1 ppb for MEL and 30 ppb for CYA. The volume of perfusate required to extract MEL and CYA from the NDC solution was only 21 MUL. The total MD sampling time was 2.1 min. This method allows the sensitive, eco-friendly, and rapid determination of MEL and CYA in NDC a risk food for economically motivated adulteration. PMID- 21819861 TI - Determination of eight nitrosamines in water at the ng L(-1) levels by liquid chromatography coupled to atmospheric pressure chemical ionization tandem mass spectrometry. AB - In this work, we have developed a sensitive method for detection and quantification of eight N-nitrosamines, N-nitrosodimethylamine (NDMA), N nitrosomorpholine (NMor), N-nitrosomethylethylamine (NMEA), N-nitrosopirrolidine (NPyr), N-nitrosodiethylamine (NDEA), N-nitrosopiperidine (NPip), N-nitroso-n dipropylamine (NDPA) and N-nitrosodi-n-butylamine (NDBA) in drinking water. The method is based on liquid chromatography coupled to tandem mass spectrometry, using atmospheric pressure chemical ionization (APCI) in positive mode with a triple quadrupole analyzer (QqQ). The simultaneous acquisition of two MS/MS transitions in selected reaction monitoring mode (SRM) for each compound, together with the evaluation of their relative intensity, allowed the simultaneous quantification and reliable identification in water at ppt levels. Empirical formula of the product ions selected was confirmed by UHPLC-(Q)TOF MS accurate mass measurements from reference standards. Prior to LC-MS/MS QqQ analysis, a preconcentration step by off-line SPE using coconut charcoal EPA 521 cartridges (by passing 500 mL of water sample) was necessary to improve the sensitivity and to meet regulation requirements. For accurate quantification, two isotope labelled nitrosamines (NDMA-d(6) and NDPA-d(14)) were added as surrogate internal standards to the samples. The optimized method was validated at two concentration levels (10 and 100 ng L(-1)) in drinking water samples, obtaining satisfactory recoveries (between 90 and 120%) and precision (RSD<20%). Limits of detection were found to be in the range of 1-8 ng L(-1). The described methodology has been applied to different types of water samples: chlorinated from drinking water and wastewater treatment plants (DWTP and WWTP, respectively), wastewaters subjected to ozonation and tap waters. PMID- 21819862 TI - Determination of relative rate of spectral events by novel modification of two dimensional correlation spectroscopy. AB - Sign of two-dimensional (2D) correlation peaks provides information on sequence of spectral events. This information is related to molecular mechanism of changes in a given system. Recently, few papers addressing the problems with interpretation of the sign of 2D correlation peaks have been published. To overcome these problems, a modification of the generalized 2D correlation method has been proposed. This method compares variations in the dynamic spectrum with a linear change at a reference point. The rates of spectral responses at individual wavenumbers are proportional to magnitudes of the peaks in the slice of asynchronous spectrum at the reference point. This way, analysis of complex 2D contour plots is replaced by a simple examination of one-dimensional (1D) slice spectrum. In spite of reduced ability of the resolution enhancement, in special cases the proposed method provides information not accessible from the classical 2D correlation analysis. At first, the principles of this method are shown with the synthetic data. Next, the influence of spectral separation, band width and position changes on the slice spectrum is evaluated. Finally, the proposed approach is applied to the experimental spectra of two hydrogen-bonded systems. PMID- 21819863 TI - A new coumarin-based fluorescence turn-on chemodosimeter for Cu2+ in water. AB - A highly selective and sensitive coumarin-based chemodosimeter 1 for Cu(2+) in water is reported in this work. 1 was designed and facilely synthesized by a one step reaction with coumarin as a fluorophore and 2-picolinic acid as the binding moiety, which showed very week fluorescence in buffer solution, and its fluorescence was considerably enhanced by the addition of Cu(2+) at room temperature in 5 min. Mechanism study suggested that Cu(2+) promoted the hydrolysis of 1 via the catalytic sensing cycle, generating a highly fluorescent product 7-hydroxycoumarin with fluorescence signal greatly amplified. The probe exhibited remarkably selective fluorescence enhancement to Cu(2+) over other metal ions at 454 nm, with a detection limit of 35 nM Cu(2+). Under optimal condition, 1 was successfully used for the determination of Cu(2+) in fetal equine serum and two water samples. PMID- 21819864 TI - Development of fluorescence imaging-based assay for screening cardioprotective compounds from medicinal plants. AB - Medicinal plants have been widely recognized as a renewable resource for the discovery of novel leads and drug. In this study, an approach for screening and identification compounds with cardioprotective activity from medicinal plant extracts by cellular-fluorescence imaging technique was developed. It is a cell based assay for measuring mitochondrial membrane potential changes in H9c2 cardiac muscle cells exposed to H(2)O(2) by using a fluorescence automatic microscopy screening platform. Rhodamine 123 was used as the fluorescent dye to indicate the change of mitochondrial membrane potential. The sensitivity and linear range of the proposed approach were evaluated and validated using vitamin C, an antioxidative compound. The method was applied to screen active components with potent cardioprotective effects from a traditional Chinese formula. The potential cardioprotective components were identified by liquid chromatography coupled with mass spectrometry (LC/MS). Moreover, the utility of the proposed approach was further validated by three compounds (salvianolic acid B, protocatechuic aldehyde, and tanshinone II A) identified from the formula which showed cardioprotective effects in a dose-dependent manner. These applications suggested that the proposed rapid and sensitive screening approach offers an efficient way to discover active components or compounds from medicinal plants. PMID- 21819865 TI - An optical sensor based on H-acid/layered double hydroxide composite film for the selective detection of mercury ion. AB - A novel optical chemosensor was fabricated based on 1-amino-8-naphthol-3,6 disulfonic acid sodium (H-acid) intercalated layered double hydroxide (LDH) film via the electrophoretic deposition (EPD) method. The film of H-acid/LDH with the thickness of 1 MUm possesses a well c-orientation of the LDH microcrystals confirmed by X-ray diffraction (XRD) and scanning electron microscopy (SEM). The fluorescence detection for Hg(II) in aqueous solution was performed by using the H-acid/LDH film sensor at pH 7.0, with a linear response range in 1.0 * 10(-7) to 1.0 * 10(-5) mol L(-1) and a detection limit of 6.3 * 10(-8) mol L(-1). Furthermore, it exhibits excellent selectivity for Hg(II) over a large number of competitive cations including alkali, alkaline earth, heavy metal and transitional metals. The specific fluorescence response of the optical sensor is attributed to the coordination between Hg(II) and sulfonic group in the H-acid immobilized in the LDH matrix, which was verified by NMR spectroscopy and UV-vis spectra. In addition, density functional theory (DFT) calculation further confirms that the coordination occurs between one Hg(2+) and two O atoms in the sulfonic group, which is responsible for the significant fluorescence quenching of the H-acid/LDH film. The results indicate that the H-acid/LDH composite film can be potentially used as a chemosensor for the detection of Hg(2+) in the environmental and biomedical field. PMID- 21819866 TI - Development of two highly sensitive immunoassays for detection of copper ions and a suite of relevant immunochemicals. AB - Availability of highly sensitive assays for metal ions can help monitor and manage the environmental and food contamination. In the present study, a monoclonal antibody against Copper(II)-ethylenediaminetetraacetic acid was used to develop two sensitive ELISAs for Cu(II) analysis. Cobalt(II)-EDTA-BSA was the coating antigen in a heterologous indirect competitive ELISA (hicELISA), whereas Co(II)-EDTA-BSA-horseradish peroxidase (HRP) was the enzyme tracer in a heterologous direct competitive ELISA (hdcELISA). Both ELISAs were validated for detecting the content of Cu(II) in environmental waters. The ELISA data agreed well with those from graphite furnace atomic absorption spectroscopy. The methods of developing the Cu(II) hicELISA and hdcELISA are potentially applicable for developing ELISAs for other metals. The chelator-protein complexes such as EDTA BSA and EDTA-BSA-HRP can form a suite of metal complexes having the consistent hapten density, location and orientation on the conjugates except the difference of the metal core, which can be used as ideal reagents to investigate the relationship between assay sensitivity and antibody affinities for the haptens and the analytes. The strategy of conjugating a haptenated protein directly with HRP can reduce the loss of HRP activity during the conjugation reaction and thus can be applicable for the development of ELISAs for small molecules. PMID- 21819867 TI - Application of 3,4,9,10-perylenetetracarboxylic diimide microfibers as a fluorescent sensing platform for biomolecular detection. AB - In this paper, we report on the use of 3,4,9,10-perylenetetracarboxylic diimide microfibers (PDIMs) as an effective fluorescent sensing platform for DNA detection for the first time. This sensing system exhibits a detection limit as low as 15 nmol L(-1) and has a high selectivity down to single-base mismatch. The general concept used in this approach is based on adsorption of fluorescently labeled single-stranded DNA (ssDNA) probe by PDIM due to the strong pi-pi stacking between unpaired DNA bases and PDIM. As a result, the fluorophore is brought into close proximity of PDIM, leading to substantial fluorescence quenching. In the presence of the target, the specific hybridization of the probe with its complementary DNA sequence generates a double stranded DNA (dsDNA) which detaches from PDIM, leading to fluorescence recovery. Its generality of this sensing platform for protein detection is also demonstrated. PMID- 21819868 TI - Universal optical assays based on multi-component nanoprobes for genomic deoxyribonucleic acid and proteins. AB - In this report, we developed a universal assay method for both genomic DNA and proteins by using enzyme-based multi-component optical nanoprobes. The nanoprobes are gold nanoparticles assembled with bio-recognizing and signaling elements. We firstly demonstrated that the nanoprobes could detect unpurified asymmetric polymerase chain reaction (PCR) product from genomic DNA of Escherichia coli, with the sensitivity approximately 10 times higher than that of quantitative real time PCR assay. The limit of detection (LOD) of our nanoprobe-based method is less than 10 pg template DNA (target DNA). Using DNA aptamers as recognition elements, we also showed that as few as 0.1 nM thrombin could be colorimetrically detected with high specificity. These results indicated that the enzyme-based multi-component nanoprobes have the capability to work with real biological samples, and have the potential in various biological and clinical applications. PMID- 21819869 TI - Characterization of a novel particle into liquid sampler for analysis of single fluorescent aerosol particles through capillary electrophoresis. AB - An approach to sample and analyze single aerosolized droplets (<10 nL) of solutions containing fluorescein isothiocyanate (FITC) labeled glycine (GLY) and glutamic acid (GLU) is demonstrated. The sampling approach is based on inertial impaction in which the sample particle is accelerated through a nozzle and directly into a small drop of buffered solution (20 mM borate, pH=10) suspended at the end of a coaxial tube of stainless steel and a fused silica capillary. A spherical light scattering cell and laser (lambda=532 nm) is used to detect the arrival of particles at the buffered droplet. Upon dissolution and/or mixing, a portion of the sample is injected onto the fused silica capillary for subsequent chemical analysis by capillary electrophoresis (CE) and detection by laser induced fluorescence (LIF). It was found that the inertial impaction approach sampled particles >1 MUm diameter with an efficiency of 80% or greater. At 15 kV applied potential, the FITC conjugates of GLY and GLU could be resolved in less than 120 s allowing qualitative analysis of the contents of single dispersed particles. However, the extent to which the sample is diluted into the buffer droplet varied significantly on a per-particle basis that caused >80% R.S.D. in fluorescence peak heights. This aspect of the method would necessitate the use of internal standards for quantitative analysis of materials present within the particles. It is envisaged that further improvements to the device described may ultimately lead to analysis of the contents of single particles dispersed in earth's atmosphere. PMID- 21819870 TI - Enantioselective determination of triazole fungicide simeconazole in vegetables, fruits, and cereals using modified QuEChERS (quick, easy, cheap, effective, rugged and safe) coupled to gas chromatography/tandem mass spectrometry. AB - A rapid and effective method for enantioselective determination of simeconazole enantiomers in food products (cucumber, tomato, apple, pear, wheat and rice) has been developed. The enantiomers were resolved by capillary gas chromatography (GC) using a commercial chiral column (BGB-172) and a temperature program from 150 degrees C (held for 1 min) and then raised at 10 degrees C min(-1) to 240 degrees C (held for 10 min). This enantioselective gas chromatographic separation was combined with a clean-up/enrichment procedure based on the modification of QuEChERS (quick, easy, cheap, effective, rugged and safe) method. Co-extractives were removed with graphitized carbon black/primary secondary amine (GCB/PSA) solid-phase extraction (SPE) cartridges using acetonitrile:toluene (3:1, v/v) as eluent. Gas chromatography/ion trap mass spectrometry (GC-ITMS) with electron ionization (EI) was then used for qualitative and quantitative determination of the simeconazole enantiomers. Two precursor-to-product ion transitions (m/z 121 101 and 195-153) with the best signal intensity were chosen to build the multiple reaction monitoring (MRM) acquisition method. The limits of detection for each enantiomer of simeconazole in six food products ranged between 0.4 and 0.9 MUg kg(-1), which were much lower than maximum residue levels (MRLs) established by Japan. The methodology was successfully applied for the enantioselective analysis of simeconazole enantiomers in real samples, indicating its efficacy in investigating the environmental stereochemistry of simeconazole in food matrix. PMID- 21819871 TI - High temperature-high efficiency liquid chromatography using sub-2 MUm coupled columns for the analysis of selected non-steroidal anti-inflammatory drugs and veterinary antibiotics in environmental samples. AB - A high efficiency HPLC method was developed by coupling three sub-2 MUm columns in series and operating them at high temperature for the separation of selected non-steroidal anti-inflammatory drugs and veterinary antibiotics in environmental samples. The separation was performed at 80 degrees C to reduce the solvent viscosity, thus reducing the column backpressure. The chromatographic performance of high temperature-extended column length HPLC method was used to determine the most widely used non-steroidal anti-inflammatory drugs and veterinary antibiotics such as sulphonamides in wastewater samples. The method could simultaneously determine 24 pharmaceuticals in short analysis time with high efficiency. The method involved pre-concentration and clean-up by solid phase extraction (SPE) using Oasis HLB extraction cartridges. It was validated based on linearity, precision, detection and quantification limits, selectivity and accuracy. Good recoveries were obtained for all analytes ranging from 72.7% to 98.2% with standard deviations not higher than 6%, except for acetaminophen and acetyl salicylic acid, for which low recovery was obtained. The detection limits of the studied pharmaceuticals ranged from 2 to 16 MUg L(-1), while limits of quantification were in the range from 7 to 54 MUg L(-1) with UV detection. PMID- 21819872 TI - Comment on "Application of a superoxide (O2-) thermal source (SOTS-1) for the determination and calibration of O2- fluxes in seawater" by Heller and Croot. PMID- 21819874 TI - Skull base: meeting place for multidisciplinary collaboration. PMID- 21819875 TI - Spontaneous CSF Leaks. AB - Spontaneous cerebrospinal fluid rhinorrhea represents a distinct clinic entity that is likely a variant of idiopathic intracranial hypertension (IIH). Patients with spontaneous cerebrospinal fluid (CSF) leaks are generally middle-aged obese women with radiographic evidence of skull base defects, associated meningoencephaloceles, and empty sella syndrome, a common sign of increased intracranial pressure. Significant overlap exists in the characteristics of patients with spontaneous CSF leak and IIH. Endoscopic repair of the CSF fistula is the gold standard treatment for this condition, but emerging evidence supports the reduction of CSF pressure as an important adjuvant treatment in this patient population. PMID- 21819876 TI - Traumatic cerebrospinal fluid leaks. AB - This article discusses the epidemiology, diagnosis, and management of traumatic cerebrospinal fluid (CSF) leaks. An overview of traumatic CSF leaks is presented, and both conservative and operative therapies are reviewed. Management decisions are discussed based on the current literature. Controversial clinical topics are addressed, including the use of prophylactic antibiotics and the timing of surgical repair. PMID- 21819877 TI - Osteoma of the skull base and sinuses. AB - Osteomata of the frontal and ethmoid sinuses have traditionally been surgically removed via external approaches. However, endoscopic techniques have increasingly been used for the surgical management of selected cases. Advances in visualization and instrumentation, as well as the excellent access provided by the Draf type 3 procedure, expanded the reach of endoscopes. We describe current limits of endoscopic approaches in the removal of osteomata from the frontal sinus and our algorithms for their management. We believe that the vast majority of frontal sinus osteomata can be managed endoscopically, and that only significant anterior or extreme infero-lateral extension constitute major limiting factors. PMID- 21819878 TI - Fibrous dysplasia of the sphenoid and skull base. AB - This article reviews the current literature and level-1 evidence of the natural history and the medical and surgical treatment of skull base fibrous dysplasia. The high rate of optic nerve (ON) involvement and the potential risk of visual impairment as a result of nerve compression have led many surgeons to suggest prophylactic decompression of the ON in asymptomatic patients. However, review of the cases reported in the literature reveals that ON decompression surgery is indicated only for patients with visual deficits, whereas asymptomatic patients with radiologic evidence of ON compression are better managed conservatively. PMID- 21819879 TI - Orbit and orbital apex. AB - Pathology affecting the orbit and orbital apex is diverse and heterogeneous. Many of the differential pathologies require management in a multidisciplinary team involving both otolaryngology and ophthalmology. This article discusses the differential pathologies. Emphasis has been placed on Graves orbitopathy, traumatic optic neuropathy, and the indications for decompression in each. The differential diagnosis for a lesion within the orbit and orbital apex is diverse. The presentation, investigation, and appropriate management of these conditions is discussed with emphasis on traumatic optic neuropathy and Graves orbitopathy. PMID- 21819880 TI - Endoscopic surgery of pituitary tumors. AB - Endoscopic pituitary surgery has been gaining wide acceptance as the first-line treatment of most functional pituitary adenomas. This technique has many advantages over traditional procedures, and growing evidence supports its use for endocrine control of functioning tumors. This article reviews data on the different modalities of treatment of functioning pituitary adenomas and compares the results. Endoscopic pituitary surgery controls tumor growth and endocrinopathy as well as or better than other treatment modalities. Complication rates are low and patient recovery is fast. Furthermore, surgery provides a means of achieving prompt decompression of neurologic structures and endocrine remission. PMID- 21819881 TI - Craniopharyngioma. AB - Craniopharyngiomas are rare epithelial tumors arising along the path of the craniopharyngeal duct; therefore, they occur in the sellar or suprasellar regions. These tumors commonly lead to neurologic, endocrinological, or visual symptoms. Radical surgery is the treatment of choice in craniopharyngiomas. The transnasal/transsphenoidal endoscopic approach offers the possibility of removing the tumor without retracting brain and optic pathways, with good results. The rate of cerebrospinal fluid fistula has improved due to the use of vascularized mucosal flaps for cranial base reconstruction. PMID- 21819882 TI - Tuberculum sella meningioma. AB - Tuberculum sellae (TS) meningiomas represent a distinct subgroup of anterior cranial fossa meningiomas with distinctive features. Early visual deterioration with optic canal infiltration occurs because of the site of dural origin. The expanded endonasal transsphenoidal approach and the eyebrow supraorbital craniotomy have been advocated as minimally invasive techniques for TS meningiomas. The authors review the current literature on minimally invasive techniques for TS meningiomas to define visual outcomes, extent of resection, and operative morbidity associated with each approach and highlight pertinent features of individual tumors, which favor either a cranial or an endonasal approach to achieve optimal outcomes. PMID- 21819883 TI - Olfactory groove meningioma. AB - Meningiomas are slow-growing benign tumors believed to originate from arachnoidal cap cells. This article discusses the surgical approaches for resection, especially the transnasal endoscopic approach. Alternative treatment options are primarily used where patients are not surgical candidates or location of recurrence precludes additional surgery. These options include radiotherapy, stereotactic radiosurgery, and chemotherapy. In addition, we discuss the current on going research in molecular targeting agents for meningioma treatment. PMID- 21819884 TI - Endoscopic endonasal surgery for nasal dermoids. AB - Midline congenital lesions are rare and commonly comprise nasal dermoids (NDs), encephaloceles, and gliomas. This article discusses the epidemiology of NDs. Management is also discussed, as well as prognosis. PMID- 21819885 TI - Juvenile nasopharyngeal angiofibroma. AB - Juvenile nasopharyngeal angiofibromas (JNAs) are rare, benign, highly vascular, locally aggressive tumors that primarily affect male adolescents. Historical treatment of these neoplasms has been primarily surgical. In the past decade, endoscopic resection of JNAs has become a viable and promising surgical treatment option. Endoscopic resection has many advantages over traditional open techniques, including better cosmesis, decreased blood loss, shortened hospital stays, and equivalent or improved recurrence rates. Emerging endoscopic technology continues to push the boundaries of resection of skull base tumors and will no doubt become the surgical treatment of choice for most JNAs in the near future. PMID- 21819886 TI - Hypothalamic/pituitary morbidity in skull base pathology. AB - In this article the epidemiology, pathophysiology, clinical presentation, investigation, management, and prognosis of hypopituitarism and hypothalamic dysfunction, arising from skull base pathologies and treatment of these conditions, are reviewed and discussed. The clinical question: "What is the consequence of pituitary hypofunction in young patients (ie, craniopharyngioma)?" is answered based on information provided in the review. PMID- 21819887 TI - From the road: lessons from the troops in the field. PMID- 21819889 TI - Unusual or unavailable? PMID- 21819888 TI - Unusual or unavailable? PMID- 21819891 TI - Perfect view. PMID- 21819894 TI - Unusual or unavailable? PMID- 21819895 TI - Up at Night? An EMS manager's concerns, from safety to politics. PMID- 21819896 TI - Lung sound assessment: the lost art of using a stethoscope. PMID- 21819897 TI - Three good rules: do we transfer too many patients at night? PMID- 21819898 TI - In over his head swift: EMS response saves surfer's life. PMID- 21819900 TI - Conquering clots: diagnostic use of ultrasound in stroke treatment. PMID- 21819901 TI - Elevation imposters: when the classic approach to ECG interpretation isn't enough. PMID- 21819902 TI - Keeping patients SAFE. PMID- 21819903 TI - Stop the pain: fentanyl is a viable alternative to morphine. PMID- 21819904 TI - Bath salt abuse: new designer drug keeps EMS crews busy nationwide. PMID- 21819905 TI - Too young to stop: recognize the warning signs of sudden pediatric cardiac death. PMID- 21819906 TI - [Interventional radiology is an unavoidable fact]. PMID- 21819907 TI - [Imaging features and evaluation of liver lesions after non-surgical therapy]. AB - The main non-surgical treatments for liver lesions include chemotherapy, targeted treatments, chemoembolization and radiofrequency ablation. The post-treatment imaging features are variable and depend on the initial appearance of the lesion, the type of treatment and the imaging modality. Evaluation of tumour response to treatment is important. RECIST criteria based on unidimensional lesion measurements may not always be appropriate. Other evaluation criteria (Choi for GIST, EASL for HCC or Chun criteria.) may be more relevant. PMID- 21819908 TI - [Periprocedural management of hemostasis risk in interventional radiology]. AB - Given the increasing demand for interventional image-guided procedures, radiologists are increasingly sollicited by clinicians to participate in the management of patients prior to and after the interventional procedure, especially with regards to hemostasis. Therefore, radiologists should be familiar with the risk of procedure related hemorrhage. Based on consensus guidelines published by the Society of Interventional Radiology (SIR), the risk of hemorrhage for each interventional procedure will be classified. Recommendations for preprocedure testing based on the type of procedure planned will be reviewed. Finally, limitations of hemostasis parameters will be discussed along with management of anticoagulants and antiplatelet agents before the procedure. PMID- 21819909 TI - [Imaging features of osseous and extra-osseous involvement in Erdheim-Chester disease]. AB - Erdheim-Chester disease is a rare form of systemic non-Langerhans cell histiocytosis characterized by infiltration by lipid-laden or foamy histiocytes. Osseous involvement, major diagnostic criteria, is constant and characteristic. It presents as metaphyseal and diaphyseal osteosclerosis, mainly affecting the long bones of the lower limbs. A few cases with axial skeleton involvement have been reported. Extra-osseous lesions may affect the retroperitoneum, lungs, skin, heart, brain and orbits. Prognosis depends mainly on the extra-osseous disease, mainly heart and lung involvement. Diagnosis is based on the combination of radiographic features, nuclear medicine features and nearly pathognomonic immunohistochemical profile. PMID- 21819910 TI - [Evaluation of the knowledge of physicians prescribing CT examinations on the radiation protection of patients]. AB - PURPOSE: To evaluate the knowledge of physicians prescribing CT examinations on the radiation protection of patients. MATERIALS AND METHODS: A questionnaire was distributed to all clinicians on medical staff who prescribe CT examinations. Several questions related to their prescription pattern and their knowledge of radiation protection. RESULTS: Forty-four questionnaires were analyzed. While 70% of physicians claimed that they considered the risks from exposure to ionizing radiation when prescribing a CT examination, only 25% informed their patients about those risks. Knowledge of the radiation dose delivered during CT evaluation of the abdomen and pelvis was poorly understood and the risks related to small doses of radiation were grossly underestimated. Finally, only a third of clinicians had received training with regards to radiation protection. CONCLUSION: While most clinicians claim that they consider the risks from exposure to ionizing radiation when prescribing a CT examination, the risks are either not well known or not known at all. Increased formation of clinicians with regards to the radiation protection of patients, maybe through a dedicated clinical rotation while in medical school, could be a solution to improve the knowledge of hospital clinicians with regards to radiation protection. PMID- 21819911 TI - [Evaluation of noninvasive diagnostic criteria for hepatocellular carcinoma on pretransplant MRI (2010): correlation between MR imaging features and histological features on liver specimen]. AB - PURPOSE: To validate the 2010 diagnostic criteria from the American Association for the Study of Liver Diseases (AASLD) for hepatocellular carcinoma (HCC) on MRI using the surgical liver specimen as a gold standard. PATIENTS AND METHODS: A total of 21 liver transplant recipients were retrospectively included. Each underwent surgery because of HCC between January 2007 and January 2008. Pre transplant MRI was performed on a 1.5 Tesla MR unit. The T1W and T2W signal and kinetic contrast enhancement were correlated for each lesion with the surgical specimen. Lesion diameters between MRI and specimen were compared (Spearman). A multivariate model was created (R statistics software package) to predict the presence and grade of tumor differentiation (WHO, Edmonson Steiner). RESULTS: A total of 71 nodules were detected at histology, including 54 HCC (mean size: 25.3mm) compared to 68 on MRI. There was moderate agreement (r=0.58, P<0.001) between the maximum lesion diameters measured on MRI and at histology. Wash-out on MRI provided an accuracy of 75 % for the detection of HCC (sensitivity=75 %, specificity=76 %). Adding T2W hyperintensity to the AASLD criteria increased the sensitivity of MRI from 70.3 % to 77.7 % for the diagnosis of HCC and from 67.6 % to 79 % for nodules less than 20mm in diameter, without affecting specificity. On multivariate analysis, wash out as a single variable was significantly associated with a diagnosis of HCC (P<0.01, odds ratio 12.0, CI 95 % [2.6-55.5]). T1W hyperintensity (P=0.04, odds ratio 5.4) and loss of signal on opposed-phase images (P=0.02, odds ratio 9.2) were predictive of good differentiation. CONCLUSION: On MRI, the AASLD criteria or presence of wash out within a liver nodule in patients with underlying chronic hepatocellular disease are suggestive of tumoral transformation. The addition of T2W hyperintensity to the AASLD criteria increases the detection of HCC, especially nodules smaller than 20mm. PMID- 21819912 TI - [The Thyroid Imaging Reporting and Data System (TIRADS) for ultrasound of the thyroid]. AB - PURPOSE: To develop a standardized system for analyzing and reporting thyroid ultrasound, or Thyroid Imaging Reporting and Data System (TIRADS), in order to improve the management of patients with thyroid nodules. MATERIALS AND METHODS: An atlas of imaging features, a standardized vocabulary, a report template and TIRADS categories 0 to 6 were defined, based on the BI-RADS system used for mammography. The diagnostic efficacy of the system was tested by a retrospective review of 500 nodules (159 cancers and 341 benign nodules) and comparing US imaging features to histological findings. RESULTS: Five signs allow accurate detection of 90% of thyroid cancers. The score of a nodule can be easily defined by using an organigram. Sensitivity, specificity and odds-ratio of the score were respectively 95%, 68% and 40. CONCLUSION: TIRADS is a quality assurance tool for thyroid ultrasound. It contains an image atlas, a standardized report and categories to evaluate thyroid nodules to easily assess the risk of individual nodules being cancers and facilitate patient management. PMID- 21819913 TI - [MR imaging features of tuberculosis of the sellar region]. AB - PURPOSE: Tuberculosis of the sellar region, especially the pituitary gland, is rare. The purpose of this article is to demonstrate through a review of five clinical cases the value of imaging, especially MR imaging, in the evaluation of this pathology. PATIENTS AND METHODS: CT and MRI of the brain were obtained in all cases along with a chest radiograph. RESULTS: Four patterns were detected on MRI: pituitary tuberculoma mimicking adenoma; pituitary abscess, extending to the cavernous sinus in one case and associated with infundibulum thickening in another; hypophysitis with suprasellar extension in association with tuberculous meningoencephalitis; and infundibular thickening associated with tuberculous meningoencephalitis. Diagnosis was based on biopsy in two cases and combination of imaging and clinical data in three cases. Outcome was favorable with anti tuberculosis drugs. CONCLUSION: Irrespective of the imaging features, a history of travel to an endemic region combined to other findings such as infundibular thickening should raise concern for the possibility of tuberculosis even in the absence of signs of systemic infection. PMID- 21819914 TI - [Heterotopic nasopharyngeal neuroglial tissue]. PMID- 21819916 TI - [Solitary hepatic lymphangioma of the adult: MRI findings]. PMID- 21819915 TI - [Uterine necrosis complicating embolization with resorbable material for postpartum hemorrhage]. PMID- 21819917 TI - [Rare lumbar spine localization of a giant cell tumor]. PMID- 21819918 TI - [Spontaneous rupture of a hydatid cyst and anaphylactic shock]. PMID- 21819919 TI - [Metastatic paraganglioma. Answer to May e-quid]. PMID- 21819921 TI - Invited commentary. PMID- 21819924 TI - Invited commentary. PMID- 21819922 TI - Aortic remodeling, volumetric analysis, and clinical outcomes of endoluminal exclusion of acute complicated type B thoracic aortic dissections. AB - OBJECTIVE: Structural changes within the aorta after thoracic endovascular aortic repair (TEVAR) for acute complicated type B thoracic aortic dissections (ABAD) remain unknown. This study reviewed and analyzed morphologic changes, volumetric data, and clinical outcomes of patients with ABAD. METHODS: Forty-one consecutive patients with ABAD, all with the volumetric analysis of aortic luminal changes and >=1 year of follow-up, were treated as a part of a single-center U.S. Food and Drug Administration (FDA)-approved investigational device exemption (IDE) trial from 2002 to 2009. Indications were malperfusion in 17, rupture in 12, chest pain in 6, acute enlargement in 4, and uncontrolled hypertension in 2. Duration of symptoms was <=14 days. Three-dimensional M2S computed tomography reconstructions (Medical MetRx Solutions, West Lebanon, NH) were analyzed for aortic volume and diameter changes, regression of the false lumen, and expansion of the true lumen. RESULTS: Emergent surgery was required in 17 (42%) patients, excluding one death at induction. Procedural success rate was 92.5%. The 30-day mortality was 4.9% for malperfusion, 4.9% for rupture, and 0% for all others, with late mortality of 0%, 9.8%, and 7.3%, respectively. Mean follow-up was 12.4 months. Permanent stroke and paraplegia rates were 4.9% (n = 2) and 0%. Ten of 12 secondary interventions were performed for 6 proximal endoleaks, 1 distal cuff endoleak, and 3 distal reperfusions. For the 33 patients without endoleaks, the true lumen volume increased by 29% at 1 month, 51% at 1 year, and 80% at 5 years. Volume regression of the false lumen was 69%, 76%, and 86%, respectively. The true lumen volume did not change at 1 month or 1 year in the endoleak group (n = 7) but increased 50% at 2 years after secondary intervention. A 10% reduction of abdominal aortic volume distal to endograft occurred over 5 years in the absence of endoleaks. CONCLUSIONS: TEVAR offers a promising solution to patients with ABAD. Aortic morphologic changes occur shortly after TEVAR and remain predictable up to 5 years with continuous expansion of the true lumen and regression of the false lumen. A lack of increase in the true lumen volume is associated with endoleaks or distal reperfusion. PMID- 21819925 TI - Association between polymorphisms of the renin angiotensin system and carotid stenosis. AB - OBJECTIVE: Carotid stenosis is a common manifestation of systemic atherosclerosis. Apart from traditional risk factors, genetic determinants, such as polymorphisms of the renin angiotensin system (RAS), may be relevant in modulating the atherosclerotic process leading to carotid stenosis. In this study, we investigated the role of angiotensin-converting enzyme (ACE) I/D and 240A>T, angiotensinogen (AGT) M235T, and angiotensin type 1 receptor (AGTR1) 1166A > C polymorphisms in modulating the susceptibility to the disease. METHODS: Eight hundred twenty-one consecutive patients with severe carotid stenosis (>=70%) and 847 control subjects were investigated. RESULTS: A significant difference in genotype distribution (P < .0001) and allele frequency (P < .0001) between patients and controls for the ACE I/D polymorphism, but not for the other single-nucleotide polymorphisms investigated, was observed. The ACE D allele frequency was significantly higher in patients without traditional risk factors in comparison with that observed in those with at least one risk factor (0.71 vs 0.61; P = .04). The ACE D allele significantly influenced carotid stenosis under dominant, recessive, and additive model of inheritance at both univariate (P < .0001) and multivariate analysis (P < .0001). When the combined effect of RAS unfavorable alleles was considered, patients carrying less than three alleles had a lower risk of carotid stenosis (odds ratio [OR], 0.79 [0.63-0.99]; P = .05), while carriers of more than four unfavorable alleles had an increased risk (OR, 1.44 [1.12-1.84]; P = .004), in comparison with subjects carrying three or four unfavorable alleles. ACE D allele frequency was similar in patients with and without additional atherosclerotic localizations (0.61 vs 0.62, respectively). CONCLUSIONS: Our findings evidence a role for ACE I/D polymorphism in influencing the susceptibility to carotid stenosis, even in the absence of traditional risk factors. Interestingly, our findings provided further information concerning the role of this polymorphism in modulating the atherosclerotic process apart from its different localizations. PMID- 21819926 TI - Is carotid artery stenting a fair alternative to carotid endarterectomy for symptomatic carotid artery stenosis? A commentary on the AHA/ASA guidelines. AB - The recent guidelines by the American Heart Association/American Stroke Association (AHA/ASA) and several other associations recommended carotid artery stenting (CAS) as an alternative to carotid endarterectomy (CEA) for symptomatic patients (Class I; LEVEL OF EVIDENCE: B). The term "alternative" may easily be misinterpreted as "equivalent" to justify the widespread use of CAS. However, current evidence indicates that for symptomatic patients, CAS produces inferior outcomes compared with CEA. It is likely that with technical improvements, better patient selection, and better physician experience, CAS outcomes will improve in the future. CAS may then become a fair alternative to CEA, at least in certain patient subgroups. Based on current evidence, however, we are not there yet and it seems unfair to spin the AHA/ASA guidelines to conclude that we are. PMID- 21819928 TI - Role of interventions for atherosclerotic renal artery stenoses. AB - The role of and indications for interventions for renal artery stenosis have long been a hot topic of debate. Despite numerous reports and studies over the years, there remain many unanswered questions. Among them are: Who should be intervened upon? What should be the objectives of intervention? What is the optimal mode of intervention? More recently, several randomized studies have attempted to answer some of these basic questions, but unfortunately have left many unanswered questions. In the following debate, the authors consider the existing literature and attempt to convince us that the majority, or the minority, of patients with renal artery stenoses should be intervened upon. PMID- 21819932 TI - Regarding "creating functional autogenous vascular access in older patients". PMID- 21819933 TI - In some patients with small abdominal aortic aneurysms, an attitude of "watchful waiting" may result in loss of suitability for endovascular repair. PMID- 21819934 TI - Abnormal plasma peptide YY(3-36) levels in patients with liver cirrhosis. AB - OBJECTIVE: Peptide YY(3-36) (PYY(3-36)) is a gut hormone with anorectic action that also affects energy expenditure. Anorexia and malnutrition are often observed in patients with decompensated liver cirrhosis (LC), whereas patients with LC after insertion of transjugular portosystemic stent shunts (TIPS) show normal eating behavior. The underlying mechanism of anorexia in decompensated LC and its resolution in patients with TIPS is still unclear. We thus investigated fasting and postprandial PYY(3-36) serum levels in patients with decompensated LC, patients with compensated LC with in situ TIPS, and healthy controls. METHODS: We analyzed fasting PYY(3-36) levels in six patients with decompensated LC (four men and two women, 55 +/- 11 y of age), nine patients with TIPS (seven men and two women, 48 +/- 11 y of age), and 10 controls (eight men and two women, 43 +/- 9 y of age) postprandially after a standardized meal of 300 kcal and during 1-h continuous parenteral nutrition. Energy expenditure was determined by indirect calorimetry. RESULTS: At baseline PYY(3-36) was comparable in controls and patients with TIPS (91 +/- 10 and 89 +/- 25 ng/L) but was increased in patients with decompensated LC (165 +/- 44 ng/L, P < 0.01). Although the cumulative postprandial PYY(3-36) increase was similar in controls (mean 2089 ng/240 min per liter) and patients with decompensated LC (mean 1735 ng/240 min per liter), no postprandial PYY(3-36) increase was observed in patients with TIPS (mean -579 ng/240 min per liter). Parenteral nutrition did not significantly affect PYY(3-36) levels in any group. Fasting PYY(3-36) values were negatively related to resting energy expenditure (r = -0.443, P = 0.030). PYY(3-36) was not associated to liver parameters (e.g., bilirubin, alanine aminotransferase). CONCLUSION: Our results demonstrate an abnormal neuroendocrine regulation of PYY(3-36) in patients with decompensated LC and those with TIPS. PMID- 21819936 TI - Foreword. PMID- 21819937 TI - Ten years of the Genolevures Consortium: a brief history. AB - We report the early phase of yeast comparative genomics conducted by a group of seven French CNRS laboratories: the Genolevures Consortium. This first multispecies comparison of Hemiascomycetes (now called Saccharomycotina) opened the way to yeast evolutionary genomics. This analysis indicates that yeasts are powerful organisms to decipher the different mechanisms acting to reshape the genome of eukaryotes during long evolution periods. This initial DNA approach reveals how biodiversity could be characterized with robust data. PMID- 21819938 TI - The Genolevures database. AB - The Genolevures online database (URL: http://www.genolevures.org) stores and provides the data and results obtained by the Genolevures Consortium through several campaigns of genome annotation of the yeasts in the Saccharomycotina subphylum (hemiascomycetes). This database is dedicated to large-scale comparison of these genomes, storing not only the different chromosomal elements detected in the sequences, but also the logical relations between them. The database is divided into a public part, accessible to anyone through Internet, and a private part where the Consortium members make genome annotations with our Magus annotation system; this system is used to annotate several related genomes in parallel. The public database is widely consulted and offers structured data, organized using a REST web site architecture that allows for automated requests. The implementation of the database, as well as its associated tools and methods, is evolving to cope with the influx of genome sequences produced by Next Generation Sequencing (NGS). PMID- 21819939 TI - New perspectives in hemiascomycetous yeast taxonomy. AB - DNA sequencing has revolutionized yeast taxonomy. Although initially rDNA sequences proved to be universal and convenient for assigning phylogenetic relationships, it was eventually supplanted by multigene analysis, which provided more discriminating and robust results. This led to a new classification of the major yeast clades, which is still used as a reference today. More recently, the availability of a large number of complete genome sequences has given a new perspective on the molecular taxonomy of yeasts by providing a high number of genes to compare. It also highlighted an unexpected aspect of yeast genome evolution: the existence of interspecific hybrids outside of the industrial Saccharomyces clade. Together with the loss of heterozygosity in interspecific hybrids and a reduced sexuality leading to clonal propagation, this observation obliges us to reexamine the present concept of species. In parallel, the ongoing challenge is to find a universal molecular marker, to improve fast authentication and, if possible, phylogeny of yeasts. The future of yeast taxonomy will involve the sequencing of more genomes, thorough analysis of populations to obtain a good representation of the biodiversity and integration of these data into dedicated databases. PMID- 21819940 TI - Yeast cell morphology and sexual reproduction--a short overview and some considerations. AB - Over the decades, basic research in life sciences has profited greatly from the study of the small unicellular fungal species Saccharomyces cerevisiae. This yeast turned out to be key for the identification and understanding of molecular mechanisms that underlay the basic functions of all eukaryotic cells. These include, but are not limited to, the regulatory mechanisms behind cellular reproduction (cell cycle control), cellular morphogenesis (cell polarity, cytoskeleton and membrane trafficking) and the management of cellular information (chromosome biology, transcription and translation). Rapid access to genomic information of many yeast species, combined with bioinformatics analyses, provide information on the evolutionary history of yeasts and the molecular ancestry of their constituents. The availability of a comprehensive list of experimental procedures for these organisms presents now a unique opportunity to learn about variations of molecular processes on an evolutionary scale. Yeast cell morphology is another interesting factor, since cellular shapes influence the interactions with the environment on all levels. In this overview article I provide a short summary of the relevant aspects of yeast cell morphology, in particular in relation to one of the most influencing processes, cellular reproduction by mating and meiosis. PMID- 21819941 TI - The genetic code of the fungal CTG clade. AB - Genetic code alterations discovered over the last 40 years in bacteria and eukaryotes invalidate the hypothesis that the code is universal and frozen. Mitochondria of various yeast species translate the UGA stop codon as tryptophan (Trp) and leucine (Leu) CUN codons (N = any nucleotide) as threonine (Thr) and fungal CTG clade species reassigned Leu CUG codons to serine and translate them ambiguously in their cytoplasms. This unique sense-to-sense genetic code alteration is mediated by a Ser-tRNA containing a Leu 5'-CAG-3'anticodon (ser tRNA(CAG)), which is recognized and charged with Ser (~97%) by the seryl-tRNA synthetase (SerRS) and with Leu (~3%) by the leucyl-tRNA synthetase (LeuRS). This unusual tRNA appeared 272 +/- 25 million years ago and had a profound impact on the evolution of the CTG clade species. Here, we review the most recent results and concepts arising from the study of this codon reassignment and we highlight how its study is changing our views of the evolution of the genetic code. PMID- 21819942 TI - The rise of yeast population genomics. AB - Genome sequences of multiple individuals are essential to determine the forces shaping sequence variation as well as to understand the relationship between genotype and phenotype. Because of their wide ecological, geographical and genetic diversity, yeast species represent an ideal model system for population genomics. Recently, there has been a renewed interest in characterizing the genetic diversity within yeast species such as Saccharomyces cerevisiae and Saccharomyces paradoxus. Here, we review recent progress in the exploration of the intraspecific diversity using large collections of yeast isolates. These recent large-scale polymorphism surveys have increased our understanding of the population structures as well as the evolutionary history of the species. In addition, these resources represent a powerful framework for dissecting the relationship between genotype and phenotype. PMID- 21819943 TI - Yeasty clocks: dating genomic changes in yeasts. AB - Calibration of clocks to date evolutionary changes is of primary importance for comparative genomics. In the absence of fossil records, the dating of changes during yeast genome evolution can only rely on the properties of the genomes themselves, given the uncertainty of extrapolations using clocks from other organisms. In this work, we use the experimentally determined mutational rate of Saccharomyces cerevisiae to calculate the numbers of successive generations corresponding to observed sequence polymorphism between strains or species of other yeasts. We then examine synteny conservation across the entire subphylum of Saccharomycotina yeasts, and compare this second clock based on chromosomal rearrangements with the first one based on sequence divergence. A non-linear relationship is observed, that interestingly also applies to insects although, for equivalent sequence divergence, their rate of chromosomal rearrangements is higher than that of yeasts. PMID- 21819944 TI - Comparative study on synteny between yeasts and vertebrates. AB - We studied synteny conservation between 18 yeast species and 13 vertebrate species in order to provide a comparative analysis of the chromosomal plasticity in these 2 phyla. By computing the regions of conserved synteny between all pairwise combinations of species within each group, we show that in vertebrates, the number of conserved synteny blocks exponentially increases along with the divergence between orthologous protein and that concomitantly; the number of genes per block exponentially decreases. The same trends are found in yeasts but only when the mean protein divergence between orthologs remains below 36%. When the average protein divergence exceeds this threshold, the total number of recognizable synteny blocks gradually decreases due to the repeated accumulation of rearrangements. We also show that rearrangement rates are on average 3-fold higher in vertebrates than in yeasts, and are estimated to be of 2 rearrangements/Myr. However, the genome sizes being on average 200 times larger in vertebrates than in yeasts, the normalized rates of chromosome rearrangements (per Mb) are about 50-fold higher in yeast than in vertebrate genomes. PMID- 21819945 TI - Tandem gene arrays, plastic chromosomal organizations. AB - This short article presents an overview of tandem gene arrays (TGAs) in hemiascomycete yeasts. In silico and in vivo analyses are combined to address structural, functional and evolutionary aspects of these particular chromosomal structures. Genomic instability of TGAs is discussed. We conclude that TGAs are generally dynamic regions of the genome in that they are the seats of chromosomal rearrangement events. In addition, they are often breeding grounds of new genes for a rapid adaptation of cells to demands of the environment. PMID- 21819946 TI - A genomic view of mRNA turnover in yeast. AB - The steady-state mRNA level is the result of two opposing processes: transcription and degradation; both of which can provide important points to regulate gene expression. In the model organism yeast Saccharomyces cerevisiae, it is now possible to determine, at the genomic level, the transcription and degradation rates, as well as the mRNA amount, using DNA chip or parallel sequencing technologies. In this way, the contribution of both rates to individual and global gene expressions can be analysed. Here we review the techniques used for the genomic evaluation of the transcription and degradation rates developed for this yeast, and we discuss the integration of the data obtained to fully analyse the expression strategies used by yeast and other eukaryotic cells. PMID- 21819947 TI - The evolution of gene expression regulatory networks in yeasts. AB - Gene regulation is a major source of phenotypic diversity between and within species. This aspect of evolution has long been addressed from the sole point of view of the genome sequence. The incredible development of transcriptomics approaches now allows one to actually study the topology and the properties of regulatory networks on an evolutionary perspective. This new discipline is called comparative functional genomics or comparative transcriptomics. This article reviews some of the main advances made in this field, using yeast species, and especially the species sequenced in the frame of the Genolevures program, as a model. PMID- 21819948 TI - The intronome of budding yeasts. AB - Whatever their abundance in genomes, spliceosomal introns are the signature of eukaryotic genes. The sequence of Saccharomyces cerevisiae, achieved fifteen years ago, revealed that this yeast has very few introns, but conserved intron boundaries typical for an intron definition mechanism. With the improvement and the development of new sequencing technologies, yeast genomes have been extensively sequenced during the last decade. We took advantage of this plethora of data to compile and assess the intron content of the protein-coding genes of 13 genomes representative of the evolution of hemiascomycetous yeasts. We first observed that intron paucity is a general rule and that the fastest evolving genomes tend to lose their introns more rapidly (e.g. S. cerevisiae versus Yarrowia lipolytica). Noticeable differences were also confirmed for 5' splice sites and branch point sites (BP) as well as for the relative position of the BP. These changes seemed to be correlated with the lineage specific evolution of splicing factors. PMID- 21819949 TI - Identification and annotation of noncoding RNAs in Saccharomycotina. AB - The importance of ncRNAs in biological processes makes their annotation an essential component of any genome-sequencing project. The identification of ncRNAs in genomes requires specific expertise and tools that are distinct from the traditional protein gene annotation tools. Here, we describe the assembly of two automatic annotation pipelines, integrating publicly available tools, for homology and de novo ncRNA search in genomes. We applied both pipelines to 10 Saccharomycotina genomes and were able to find and annotate 693 ncRNA genes, corresponding to 81% of the ncRNAs expected for those genomes assuming the number of ncRNAs in Saccharomyces cerevisiae (86) as a reference. Several new ncRNAs, not yet known in the Saccharomycotina clade, were also detected. The results show the feasibility of automatic search for ncRNAs in full genomes and the utility of such approaches in large multi-genome sequencing and annotation projects. PMID- 21819950 TI - Transposable elements in yeasts. AB - With the development of new sequencing technologies in the past decade, yeast genomes have been extensively sequenced and their structures investigated. Transposable elements (TEs) are ubiquitous in eukaryotes and constitute a limited part of yeast genomes. However, due to their ability to move in genomes and generate dispersed repeated sequences, they contribute to modeling yeast genomes and thereby induce plasticity. This review assesses the TE contents of yeast genomes investigated so far. Their diversity and abundance at the inter- and intraspecific levels are presented, and their effects on gene expression and genome stability is considered. Recent results concerning TE-host interactions are also analyzed. PMID- 21819951 TI - The genomes of fermentative Saccharomyces. AB - Many different yeast species can take part in spontaneous fermentations, but the species of the genus Saccharomyces, including Saccharomyces cerevisiae in particular, play a leading role in the production of fermented beverages and food. In recent years, the development of whole-genome scanning techniques, such as DNA chip-based analysis and high-throughput sequencing methods, has considerably increased our knowledge of fermentative Saccharomyces genomes, shedding new light on the evolutionary history of domesticated strains and the molecular mechanisms involved in their adaptation to fermentative niches. Genetic exchange frequently occurs between fermentative Saccharomyces and is an important mechanism for generating diversity and for adaptation to specific ecological niches. We review and discuss here recent advances in the genomics of Saccharomyces species and related hybrids involved in major fermentation processes. PMID- 21819952 TI - How to detect side effects of chest compressions? PMID- 21819953 TI - Oktoberfest binge drinking and acute pancreatitis: is there really no relationship? PMID- 21819954 TI - Understanding the multidimensional nature of illness severity as measured by patient-reported outcome measures in irritable bowel syndrome. PMID- 21819955 TI - Foreword. The international centers of excellence for malaria research. PMID- 21819956 TI - Defective myofibroblast formation from mesenchymal stem cells in the aging murine heart rescue by activation of the AMPK pathway. AB - Aged mice in a murine model of myocardial infarction exhibit less effective myocardial repair. We hypothesized that the deficiency arises from altered lineage choice of endogenous mesenchymal stem cells (MSCs) and faulty maturation of myofibroblasts. Examination of cardiac MSCs revealed a substantial reduction in the pluripotency marker Nanog in cells from aged mice. In addition, the aged MSCs demonstrated a redirected lineage choice that favored adipocytic commitment over fibroblast or myofibroblast differentiation. Fibroblasts derived from aged MSCs demonstrated reduced expression of transforming growth factor-beta (TGF beta) receptors I and II and diminished SMAD3 phosphorylation, associated with attenuated contractility and migration. Overexpression of constitutively active TGF-beta receptor I in aged cardiac fibroblasts ameliorated their defective motility but did not improve their contractility. Culturing of MSCs and fibroblasts with AICAR (5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside) to activate adenosine monophosphate-activated kinase resulted in TGF-beta dependent development of myofibroblasts with markedly enhanced contractility despite no reduction in adipocytic commitment or increased expression of TGF-beta receptors and SMAD3 phosphorylation. The data suggest an adenosine monophosphate activated kinase-dependent gain of function as mediated by phosphorylation of TGF beta-activated kinase 1 and p38 mitogen-activated protein kinase, which amplifies the response to TGF-beta1 via a non-canonical pathway, thus compensating for the reduced expression of TGF-beta receptors. PMID- 21819957 TI - Phosphatase and tensin homolog on chromosome 10 is phosphorylated in primary effusion lymphoma and Kaposi's sarcoma. AB - Primary effusion lymphoma (PEL) is a non-Hodgkin's B-cell lymphoma driven by Kaposi's sarcoma-associated herpesvirus. It is uniquely sensitive to mTOR, PI3K, and Akt inhibitors; however, the basis of this requirement for the mTOR pathway remains to be elucidated. The phosphatase and tensin homolog gene (PTEN) on chromosome 10 controls the first step in the phosphatidylinositol 3 kinase (PI3K) Akt-mammalian target of rapamycin (mTOR) pathway and is genetically inactivated in many solid tumors. We find an absence of PTEN deletions, mutations, or protein mislocalization in PEL. However, we find consistent hyperphosphorylation at serine 380 of PTEN, which is an inactivating modification, in PEL cell lines and in tumor xenografts. We also evaluated a large tissue microarray of Kaposi's sarcoma biopsies and observed concordant high levels of phospho-PTEN, phospho Akt, and phospho-S6 ribosomal protein. Reintroduction of PTEN into PEL inhibited colony formation in soft agar, verifying the functional dependence of PEL on PI3K signaling. This was also true for PEL cell lines that carried mutant p53 and for KS-like cell lines. Activating PTEN in these cancers may yield a new treatment strategy for PEL, KS, and similar PTEN wild-type lymphomas. PMID- 21819958 TI - Mast cell function and death in Trypanosoma cruzi infection. AB - Although the roles of mast cells (MCs) are essential in many inflammatory and fibrotic diseases, their role in Trypanosoma cruzi-induced cardiomyopathy is unexplored. In this study, we treated infected CBA mice with cromolyn, an MC stabilizer, and observed much greater parasitemia and interferon-gamma levels, higher mortality, myocarditis, and cardiac damage. Although these data show that MCs are important in controlling acute infection, we observed MC apoptosis in the cardiac tissue and peritoneal cavity of untreated mice. In the heart, pericardial mucosal MC die, perhaps because of reduced amounts of local stem cell factor. Using RT-PCR in purified cardiac MCs, we observed that infection induced transcription of P2X(7) receptor and Fas, two molecules reportedly involved in cell death and inflammatory regulation. In gld/gld mice (FasL(-/-)), apoptosis of cardiac, but not peritoneal, MCs was decreased. Conversely, infection of P2X(7)( /-) mice led to reduced peritoneal, but not cardiac, MC death. These data illustrate the immunomodulatory role played by MCs in T. cruzi infection and the complexity of molecular interactions that control inflammatory pathways in different tissues and compartments. PMID- 21819960 TI - Contribution of K99 and D319 to substrate binding and catalysis in the saccharopine dehydrogenase reaction. AB - Saccharopine dehydrogenase catalyzes the NAD-dependent oxidative deamination of saccharopine to l-lysine and alpha-ketoglutarate. Lysine 99 is within hydrogen bond distance to the alpha-carboxylate of the lysine substrate and D319 is in the vicinity of the carboxamide side chain of NADH. Both are conserved and may be important to the overall reaction. Replacing K99 with M gives decreases of 110-, 80- and 20-fold in the V(2)/K(m) values for lysine, alpha-ketoglutarate and NADH, respectively. Deuterium isotope effects on V and V/K(Lys) increase, while the solvent deuterium isotope effects decrease compared to the C205S mutant enzyme. Data for K99M suggest a decreased affinity for all reactants and a change in the partition ratio of the imine intermediate to favor hydrolysis. A change in the bound conformation of the imine and/or the distance of the imine carbon to C4 of the nicotinamide ring of NADH is also suggested. Changing D319 to A decreases V(2)/K(NADH) by 33-fold. Primary deuterium and solvent deuterium isotope effects decrease compared to C205S suggesting a non-isotope sensitive step has become slower. NADH binds to enzyme first, and sets the site for binding of lysine and alpha-ketoglutarate. The slower step is likely the conformational change generated upon binding of NADH. PMID- 21819959 TI - Lung gene expression in a rhesus allergic asthma model correlates with physiologic parameters of disease and exhibits common and distinct pathways with human asthma and a mouse asthma model. AB - Experimental nonhuman primate models of asthma exhibit multiple features that are characteristic of an eosinophilic/T helper 2 (Th2)-high asthma subtype, characterized by the increased expression of Th2 cytokines and responsive genes, in humans. Here, we determine the molecular pathways that are present in a house dust mite-induced rhesus asthma model by analyzing the genomewide lung gene expression profile of the rhesus model and comparing it with that of human Th2 high asthma. We find that a prespecified human Th2 inflammation gene set from human Th2-high asthma is also present in rhesus asthma and that the expression of the genes comprising this gene set is positively correlated in human and rhesus asthma. In addition, as in human Th2-high asthma, the Th2 gene set correlates with physiologic markers of allergic inflammation and disease in rhesus asthma. Comparison of lung gene expression profiles from human Th2-high asthma, the rhesus asthma model, and a common mouse asthma model indicates that genes associated with Th2 inflammation are shared by all three species. However, some pathophysiologic aspects of human asthma (ie, subepithelial fibrosis, angiogenesis, neural biology, and immune host defense biology) are better represented in the gene expression profile of the rhesus model than in the mouse model. Further study of the rhesus asthma model may yield novel insights into the pathogenesis of human Th2-high asthma. PMID- 21819961 TI - Fluorescence methods for lipoplex characterization. AB - Since the first reported transfection studies using cationic liposomes in 1987, significant advances have been made on the understanding of the physical properties of DNA/cationic liposome complexes (lipoplexes) in order to improve their transfection efficiencies. In this review a critical survey of the biophysical techniques used in their characterization is presented, with an emphasis on fluorescence methodologies, namely FRET. It is shown that the use of FRET combined with state-of-the-art modeling and data analysis allows detailed structural information in conditions close to the in vivo utilization of these non-viral based vectors. We describe in detail the use of fluorescence-based methods in (i) the assessment of DNA-lipid interaction and kinetics of lipoplex formation; (ii) membrane mixing studies; (iii) characterization of lipoplex molecular structure through the determination of interlamellar distances; and (iv) qualitative and quantitative evaluation of DNA condensation by cationic liposomes. This review aims at providing a framework for future characterization studies of novel liposomal formulations as gene delivery carriers, taking advantage of more sensitive nucleic acid and lipid dyes concomitantly with increasingly sophisticated fluorescence techniques. PMID- 21819963 TI - Mechanistic insights into the translocation of full length HIV-1 Tat across lipid membranes. AB - The mechanism of how full length Tat (aa 1-86) crosses artificial lipid membranes was elucidated by means of fluorescence spectroscopy and fluorescence microscopy. It was shown that full length Tat (aa 1-86) neither forms pores in large unilamellar vesicles (LUVs) nor in giant unilamellar vesicles (GUVs) composed of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC). In contrast, an N terminally truncated Tat protein (aa 35-86) that lacks the structurally defined proline- and cysteine-rich region as well as the highly conserved tryptophan residue at position 11 generates pores in artificial POPC-membranes, through which a water-soluble dye up to a size of 10kDa can pass. By means of fluorescence microscopy, the transfer of fluorescently labeled full length Tat across POPC-bilayers was unambiguously visualized with a concomitant accumulation of the protein in the membrane interface. However, if the dye was attached to the protein, also pore formation was induced. The size of the pores was, however smaller than the protein size, i.e. the labeled protein with a mass of 11.6kDa passed the membrane, while a fluorescent dye with a mass of 10kDa was excluded from the vesicles' interior. The results demonstrate that pore formation is not the prime mechanism by which full length Tat crosses a membrane. PMID- 21819962 TI - Connexin43 phosphorylation in brain, cardiac, endothelial and epithelial tissues. AB - Gap junctions, composed of proteins from the connexin family, allow for intercellular communication between cells in essentially all tissues. There are 21 connexin genes in the human genome and different tissues express different connexin genes. Most connexins are known to be phosphoproteins. Phosphorylation can regulate connexin assembly into gap junctions, gap junction turnover and channel gating. Given the importance of gap junctions in development, proliferation and carcinogenesis, regulation of gap junction phosphorylation in response to wounding, hypoxia and other tissue insults is proving to be critical for cellular response and return to homeostasis. Connexin43 (Cx43) is the most widely and highly expressed gap junction protein, both in cell culture models and in humans, thus more research has been done on it and more reagents to it are available. In particular, antibodies that can report Cx43 phosphorylation status have been created allowing temporal examination of specific phosphorylation events in vivo. This review is focused on the use of these antibodies in tissue in situ, predominantly looking at Cx43 phosphorylation in brain, heart, endothelium and epithelium with reference to other connexins where data is available. These data allow us to begin to correlate specific phosphorylation events with changes in cell and tissue function. This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and characteristics. PMID- 21819964 TI - Characterization of a potent antimicrobial lipopeptide via coarse-grained molecular dynamics. AB - The prevalence of antibiotic-resistant pathogens is a major medical concern, prompting increased interest in the development of novel antimicrobial compounds. One such set of naturally occurring compounds, known as antimicrobial peptides (AMPs), have broad-spectrum activity, but come with many limitations for clinical use. Recent work has resulted in a set of antimicrobial lipopeptides (AMLPs) with micromolar minimum inhibitory concentrations and excellent selectivity for bacterial membranes. To characterize a potent, synthetic lipopeptide, C16-KGGK, we used multi-microsecond coarse-grained simulations with the MARTINI forcefield, with a total simulation time of nearly 46MUs. These simulations show rapid binding of C16-KGGK, which forms micelles in solution, to model bacterial lipid bilayers. Furthermore, upon binding to the surface of the bilayer, these lipopeptides alter the local lipid organization by recruiting negatively charged POPG lipids to the site of binding. It is likely that this drastic reorganization of the bilayer has major effects on bilayer dynamics and cellular processes that depend on specific bilayer compositions. By contrast, the simulations revealed no association between the lipopeptides and model mammalian bilayers. These simulations provide biophysical insights into lipopeptide selectivity and suggest a possible mechanism for antimicrobial action. This article is part of a Special Issue entitled: Membrane protein structure and function. PMID- 21819965 TI - Recognition of polyunsaturated acyl chains by enzymes acting on membrane lipids. AB - Polyunsaturated acyl chains play an important role in human biology. These lipids cannot be synthesized de novo and they are selectively distributed to certain organs and are found predominantly only in certain lipid classes. Their selective distribution is a consequence of the specificity of the binding of these lipids by certain proteins. Lipoxygenases are a group of well studied enzymes that specifically oxidize polyunsaturated fatty acids. We propose that certain features of the interaction of lipoxygenases with polyunsaturated acyl chains are also found in other unrelated proteins that act on lipids with these moieties. The features common to several of the enzymes that specifically interact with polyunsaturated acyl chains include the fact that the polyunsaturated chain is drawn out of the membrane to bind to a hydrophobic channel within the protein and that a similar pattern of required amino acids residues comprises part of the binding site for the polyunsaturated chain. This article is part of a Special Issue entitled: Protein Folding in Membranes. PMID- 21819967 TI - Protein palmitoylation and subcellular trafficking. AB - Protein S-palmitoylation, the covalent lipid modification of the side chain of Cys residues with the 16-carbon fatty acid palmitate, is the most common acylation of proteins in eukaryotic cells. This post-translational modification provides an important mechanism for regulating protein subcellular localization, stability, trafficking, translocation to lipid rafts, aggregation, interaction with effectors and other aspects of protein function. In addition, N-terminal myristoylation and C-terminal prenylation, two well-studied post-translational modifications, frequently precede protein S-palmitoylation at a nearby spot of the polypeptide chain. Whereas N-myristoylation and prenylation are considered essentially irreversible attachments, S-palmitoylation is a tightly regulated, reversible modification. In addition, the unique reversibility of protein palmitoylation also allows proteins to rapidly shuttle between intracellular membrane compartments in a process controlled, in some cases, by the DHHC family of palmitoyl transferases. Recent cotransfection experiments using the DHHC family of protein palmitoyl transferases as well as RNA interference results have revealed that these enzymes, frequently localized to the Golgi apparatus, tightly control subcellular trafficking of acylated proteins. In this article we will give an overview of how protein palmitoylation regulates protein trafficking and subcellular localization. PMID- 21819968 TI - Fluid phase lipid areas and bilayer thicknesses of commonly used phosphatidylcholines as a function of temperature. AB - The structural parameters of fluid phase bilayers composed of phosphatidylcholines with fully saturated, mixed, and branched fatty acid chains, at several temperatures, have been determined by simultaneously analyzing small angle neutron and X-ray scattering data. Bilayer parameters, such as area per lipid and overall bilayer thickness have been obtained in conjunction with intrabilayer structural parameters (e.g. hydrocarbon region thickness). The results have allowed us to assess the effect of temperature and hydrocarbon chain composition on bilayer structure. For example, we found that for all lipids there is, not surprisingly, an increase in fatty acid chain trans-gauche isomerization with increasing temperature. Moreover, this increase in trans-gauche isomerization scales with fatty acid chain length in mixed chain lipids. However, in the case of lipids with saturated fatty acid chains, trans-gauche isomerization is increasingly tempered by attractive chain-chain van der Waals interactions with increasing chain length. Finally, our results confirm a strong dependence of lipid chain dynamics as a function of double bond position along fatty acid chains. PMID- 21819969 TI - Negative regulation by Ser/Thr phosphorylation of HadAB and HadBC dehydratases from Mycobacterium tuberculosis type II fatty acid synthase system. AB - The type II fatty acid synthase system of mycobacteria is involved in the biosynthesis of major and essential lipids, mycolic acids, key-factors of Mycobacterium tuberculosis pathogenicity. One reason of the remarkable survival ability of M. tuberculosis in infected hosts is partly related to the presence of cell wall-associated mycolic acids. Despite their importance, the mechanisms that modulate synthesis of these lipids in response to environmental changes are unknown. We demonstrate here that HadAB and HadBC dehydratases of this system are phosphorylated by Ser/Thr protein kinases, which negatively affects their enzymatic activity. The phosphorylation of HadAB/BC is growth phase-dependent, suggesting that it represents a mechanism by which mycobacteria might tightly control mycolic acid biosynthesis under non-replicating condition. PMID- 21819970 TI - Unusual adult-onset Leigh syndrome presentation due to the mitochondrial m.9176T>C mutation. AB - Leigh syndrome (LS) is an incurable, nearly always fatal, neurodegenerative, pediatric disorder that results from respiratory chain failure. The most common mitochondrial DNA (mtDNA) mutations that result in LS are m.8993T->C/G and m.9176T->C/G, which were previously found in several patients with early-onset Leigh syndrome. Here, we describe clinical and molecular features of a novel pedigree, where LS developed in two siblings. The proband was a young woman with an unusual adult-onset LS. She harbored a homoplasmic m.9176T->C mutation, based on analysis of a muscle biopsy. In contrast, the brother died at a young age. This novel case report and literature review highlights the variability of phenotypic expression of the m.9176T->C mutation. PMID- 21819966 TI - Biophysics of alpha-synuclein membrane interactions. AB - Membrane proteins participate in nearly all cellular processes; however, because of experimental limitations, their characterization lags far behind that of soluble proteins. Peripheral membrane proteins are particularly challenging to study because of their inherent propensity to adopt multiple and/or transient conformations in solution and upon membrane association. In this review, we summarize useful biophysical techniques for the study of peripheral membrane proteins and their application in the characterization of the membrane interactions of the natively unfolded and Parkinson's disease (PD) related protein, alpha-synuclein (alpha-syn). We give particular focus to studies that have led to the current understanding of membrane-bound alpha-syn structure and the elucidation of specific membrane properties that affect alpha-syn-membrane binding. Finally, we discuss biophysical evidence supporting a key role for membranes and alpha-syn in PD pathogenesis. This article is part of a Special Issue entitled: Membrane protein structure and function. PMID- 21819971 TI - Circadian Clock genes Per2 and clock regulate steroid production, cell proliferation, and luteinizing hormone receptor transcription in ovarian granulosa cells. AB - Circadian Clock genes are associated with the estrous cycle in female animals. Treatment with Per2 and Clock siRNAs decreased the number of granulosa cells and LHr expression in follicle-stimulating hormone FSH-treated granulosa cells. Per2 siRNA treatment did not stimulate the production of estradiol and expression of P450arom, whereas Clock siRNA treatment inhibited the production of estradiol and expression of P450arom mRNA. Per2 and Clock siRNA treatment increased and unchanged, respectively, progesterone production in FSH-treated granulosa cells. Similarly, expression of StAR mRNA was increased by Per2 siRNA and unchanged by Clock siRNA. Our data provide a new insight that Per2 and Clock have different action on ovarian granulosa cell functions. PMID- 21819973 TI - Proteasome inhibitor MG132-induced apoptosis via ER stress-mediated apoptotic pathway and its potentiation by protein tyrosine kinase p56lck in human Jurkat T cells. AB - Exposure of human Jurkat T cells to MG132 caused apoptosis along with upregulation of Grp78/BiP and CHOP/GADD153, activation of JNK and p38MAPK, activation of Bak, mitochondrial membrane potential (Deltapsim) loss, cytochrome c release, activation of caspase-12, -9, -3, -7, and -8, cleavage of Bid and PARP, and DNA fragmentation. However, these MG132-induced apoptotic events, with the exceptions of upregulation of Grp78/BiP and CHOP/GADD153 and activation of JNK and p38MAPK, were abrogated by overexpression of Bcl-xL. Pretreatment with the pan-caspase inhibitor z-VAD-fmk prevented MG132-induced apoptotic caspase cascade, but allowed upregulation of Grp78/BiP and CHOP/GADD153 levels, activation of JNK and p38MAPK, Deltapsim loss, and cleavage of procaspase-9 (47kDa) to active form (35kDa). Further analysis using selective caspase inhibitors revealed that caspase-12 activation was required for activation of caspase-9 and -3 to the sufficient level for subsequent activation of caspase-7 and -8. MG132-induced cytotoxicity, apoptotic sub-G(1) peak, Bak activation, and Deltapsim loss were markedly reduced by p38MAPK inhibitor, but not by JNK inhibitor. MG132-induced apoptotic changes, including upregulation of Grp78/BiP and CHOP/GADD153 levels, activation of caspase-12, p38MAPK and Bak, and mitochondria-dependent activation of caspase cascade were more significant in p56(lck)-stable transfectant JCaM1.6/lck than in p56(lck)-deficient JCaM1.6/vector. The cytotoxicity of MG132 toward p56(lck)-positive Jurkat T cell clone was not affected by the Src-like kinase inhibitor PP2. These results demonstrated that MG132-induced apoptosis was caused by ER stress and subsequent activation of mitochondria-dependent caspase cascade, and that the presence of p56(lck) enhances MG132-induced apoptosis by augmenting ER stress-mediated apoptotic events in Jurkat T cells. PMID- 21819972 TI - Activation of mitogen-activated protein kinases by 5,6-dimethylxanthenone-4 acetic acid (DMXAA) plays an important role in macrophage stimulation. AB - The small molecule anti-tumor agent, 5,6-dimethylxanthenone-4-acetic acid (DMXAA, now called Vadimezan) is a potent macrophage and dendritic cell activating agent that, in the murine system, results in the release of large amounts of cytokines and chemokines. The mechanisms by which this release is mediated have not been fully elucidated. The mitogen-activated protein kinase (MAPK) pathways play an important role in the regulation of proinflammatory cytokines, such as TNF-alpha, IL-1beta, as well as the responses to extracellular stimuli, such as lipopolysaccharide (LPS). The results of this study demonstrate that DMXAA activates three members of mitogen-activated protein kinase (MAPK) superfamily, namely p38 MAPK, extracellular signal-regulated kinases 1 and 2 (ERK1 and ERK2), and c-Jun N-terminal kinases (JNKs) via a RIP2-independent mechanism in murine macrophages. By using selective inhibitors of MAPKs, this study confirms that both activated p38/MK2 pathways and ERK1/2 MAPK play a significant role in regulation of both TNF-alpha and IL-6 protein production induced by DMXAA at the post-transcriptional level. Our findings also show that interferon-gamma priming can dramatically augment TNF-alpha protein secretion induced by DMXAA through enhancing activation of multiple MAPK pathways at the post-transcriptional level. This study expands current knowledge on mechanisms of how DMXAA acts as a potent anti-tumor agent in murine system and also provides useful information for further study on the mechanism of action of this potential anti-tumor compound in human macrophages. PMID- 21819974 TI - Association of plasma and synovial fluid interferon-gamma inducible protein-10 with radiographic severity in knee osteoarthritis. AB - OBJECTIVES: The objective of this study was to investigate interferon-gamma inducible protein-10 (IP-10) concentrations in plasma and synovial fluid of patients with knee osteoarthritis (OA) and to analyze their relationship with disease severity. DESIGN AND METHODS: Forty OA patients and 15 healthy controls were enrolled in this study. OA grading was performed according to the Kellgren Lawrence criteria. IP-10 levels in plasma and synovial fluid were assessed using enzyme-linked immunosorbent assay. RESULTS: Plasma IP-10 levels in the knee OA patients were significantly lower than those of controls (P=0.006). IP-10 levels in plasma were markedly higher with regard to paired synovial fluid (P<0.001). Furthermore, IP-10 concentrations in plasma and synovial fluid displayed significant inverse correlation with radiographic severity (r=-0.713, P<0.001 and r=-0.561, P<0.001, respectively). Subsequent analysis revealed that plasma IP-10 levels were positively correlated with synovial fluid IP-10 levels (r=0.424, P=0.006). CONCLUSIONS: IP-10 levels in both plasma and synovial fluid were inversely associated with the severity of knee OA. Accordingly, IP-10 could serve as a biomarker for determining disease severity and might play a possible role in the pathophysiology of osteoarthritis. PMID- 21819975 TI - C-reactive protein level is decreased in patients with Alzheimer's disease and related to cognitive function and survival time. AB - BACKGROUND: Previous studies have observed decreased serum CRP levels in patients with established Alzheimer's disease (AD) compared to controls or other diagnostic groups of elderly patients with mental illness. METHODS: We have investigated the relation between CRP level and the severity of AD as assessed by cognitive function, brain imaging and survival time. RESULTS: Patients with AD showed overall lower CRP levels than other patients with mental illness, but elevated CRP levels in these patients were associated with lower cognitive function and shorter survival time. CONCLUSION: The reason for an overall low CRP level is not obvious. Elevated CRP level in patients with AD suggests the presence of inflammatory activity in this subgroup of patients that may benefit from anti-inflammatory administration. PMID- 21819976 TI - Brassinosteroids regulate pectin methylesterase activity and AtPME41 expression in Arabidopsis under chilling stress. AB - Pectin methylesterases (PMEs) are important cell wall enzymes that may play important roles in plant chilling/freezing tolerance. We investigated the possible roles of brassinosteroids (BRs) in regulation of PMEs under chilling stress. Chilling stress or 24-epibrassinolide (eBL) treatments induced significant increases in PME activity in wild type (Col-0) seedlings of Arabidopsis. The chilling-stress-induced increases in PME activity were also found in bzr1-D mutant, a BZR1 stabilized mutant with a constitutively active BR signaling pathway, but not in bri1-116, a BR insensitive null allele of the BR receptor BRI1. The results suggest that the regulation of PME activity in Arabidopsis under chilling stress depends on the BR signaling pathway. Furthermore, we showed that the effect of chilling stress on PME activity was impaired in pme41, a knockout mutant of AtPME41. Semi-quantitative RT-PCR results showed that expression of AtPME41 was induced by chilling stress in wild type plants but not in the bri1-116 mutant. The expression of AtPME41 increased in bzr1-D and eBL treated wild type seedlings, but decreased in bri1-116 seedlings. Furthermore, ion leakage induced by low temperature were dramatically increased in both bri1-116 and pme41, while lipid peroxidation was increased in bri1-116 only. The results suggest that BRs may modulate total PME activity in Arabidopsis under chilling stress by regulating AtPME41 expression. Regulation of PME activity may serve as one of the mechanisms that BR participates in chilling tolerance of plants. PMID- 21819977 TI - P2X7 receptors contribute to the currents induced by ATP in guinea pig intestinal myenteric neurons. AB - The whole-cell configuration, several pharmacological tools, and single-cell RT PCR were used to investigate the contribution of P2X7 subunits to the ATP-induced currents (I(ATP)) in guinea pig myenteric neurons. I(ATP) was recorded in the great majority of tested neurons. ATP concentration-response curve (0.01-10mM) showed two phases, the first mediated by high-sensitive P2X receptors (hsP2X receptors), observed between 0.01-0.3mM and the second mediated by low-sensitive P2X receptors (lsP2X receptors). The calculated EC(50) values of these phases were 38 and 1759 MUM, respectively. 2'-3'-O-(4-benzoylbenzoyl)-ATP (BzATP) concentration-response curve was monophasic (0.01-1mM), and less potent (EC(50) 142 MUM) than ATP to activate hsP2X receptors. A strong inward rectification was noticed when hsP2X receptors were activated with ATP (0.1mM) and for BzATP induced currents (0.1mM; I(BzATP)) but a significant lower rectification was noticed when lsP2X receptors were activated (5mM). Brilliant blue G (BBG) at a concentration of 0.3 MUM (known to inhibit only P2X7 receptors) reduced I(ATP) when lsP2X receptors contributed to it but neither affect hsP2X receptors nor I(BzATP). However, hsP2X receptors and I(BzATP) were both inhibited by concentrations >= 1 MUM of this antagonist. BzATP inhibited hsP2X receptors and therefore, it behaves as partial agonist on these receptors. Using the single cell RT-PCR technique P2X7 mRNA was detectable in 7 out of 13 myenteric neurons exhibiting P2X2 mRNA. Altogether, our results show that low-sensitive P2X receptors are likely P2X7, whereas, the high-sensitive P2X channels are probably constituted, at least in part, by P2X2 subunits. PMID- 21819979 TI - WITHDRAWN: Reprint of: Variations in the rheostat model of apoptosis: What studies of retinal ganglion cell death tell us about the functions of the Bcl2 family proteins. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published, doi:10.1016/j.exer.2010.03.004. The duplicate article has therefore been withdrawn. PMID- 21819980 TI - WITHDRAWN: Reprint of: Mitochondria: Their role in ganglion cell death and survival in primary open angle glaucoma. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published, doi:10.1016/j.exer.2010.03.008. The duplicate article has therefore been withdrawn. PMID- 21819978 TI - Antibodies to cell surface proteins redirect intracellular trafficking pathways. AB - Antibody-mediated intracellular delivery of therapeutic agents has been considered for treatment of a variety of diseases. These approaches involve targeting cell-surface receptor proteins expressed by tumors or viral proteins expressed on infected cells. We examined the intracellular trafficking of a viral cell-surface-expressed protein, rabies G, with or without binding a specific antibody, ARG1. We found that antibody binding shifts the native intracellular trafficking pathway of rabies G in an Fc-independent manner. Kinetic studies indicate that the ARG1/rabies G complex progressively co-localized with clathrin, early endosomes, late endosomes, and lysosomes after addition to cells. This pathway was different from that taken by rabies G without addition of antibody, which localized with recycling endosomes. Findings were recapitulated using a cellular receptor with a well-defined endogenous recycling pathway. We conclude that antibody binding to cell-surface proteins induces redirection of intracellular trafficking of unbound or ligand bound receptors to a specific degradation pathway. These findings have broad implications for future developments of antibody-based therapeutics. PMID- 21819981 TI - WITHDRAWN: Reprint of: Mechanisms of retinal ganglion cell injury and defense in glaucoma. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published, doi:10.1016/j.exer.2010.04.002. The duplicate article has therefore been withdrawn. PMID- 21819982 TI - 5-HT(1A) receptor stimulation and L-DOPA-induced dyskinesia in Parkinson's disease: bridging the gap between serotonergic and glutamatergic mechanisms. PMID- 21819983 TI - Chronic stress induces changes in the structure of interneurons and in the expression of molecules related to neuronal structural plasticity and inhibitory neurotransmission in the amygdala of adult mice. AB - Chronic stress in experimental animals, one of the most accepted models of chronic anxiety and depression, induces structural remodeling of principal neurons in the amygdala and increases its excitation by reducing inhibitory tone. These changes may be mediated by the polysialylated form of the neural cell adhesion molecule (PSA-NCAM), a molecule related to neuronal structural plasticity and expressed by interneurons in the adult CNS, which is downregulated in the amygdala after chronic stress. We have analyzed the amygdala of adult mice after 21 days of restraint stress, studying with qRT-PCR the expression of genes related to general and inhibitory neurotransmission, and of PSA synthesizing enzymes. The expression of GAD67, synaptophysin and PSA-NCAM was also studied in specific amygdaloid nuclei using immunohistochemistry. We also analyzed dendritic arborization and spine density, and cell activity, monitoring c-Fos expression, in amygdaloid interneurons. At the mRNA level, the expression of GAD67 and of St8SiaII was significantly reduced. At the protein level there was an overall reduction in the expression of GAD67, synaptophysin and PSA-NCAM, but significant changes were only detected in specific amygdaloid regions. Chronic stress did not affect dendritic spine density, but reduced dendritic arborization in interneurons of the lateral and basolateral amygdala. These results indicate that chronic stress modulates inhibitory neurotransmission in the amygdala by regulating the expression of molecules involved in this process and by promoting the structural remodeling of interneurons. The addition of PSA to NCAM by St8SiaII may be involved in these changes. PMID- 21819984 TI - Redundancy of interleukin-6 in the differentiation of T cell and monocyte subsets during cutaneous leishmaniasis. AB - Leishmania (L.) major is a protozoan parasite that infects mammalian hosts and causes a spectrum of disease manifestations that is strongly associated with the genetic background of the host. Interleukin (IL)-6 is an acute phase proinflammatory cytokine, known in vitro to be involved in the inhibition of the generation of regulatory T cells. IL-6-deficient mice were infected with L. major, and T cell and monocyte subsets were analyzed with flow cytometry. Our data show that at the site of infection in the footpad and in the draining popliteal lymph node, numbers of regulatory T cells remain unchanged between WT and IL-6-deficient mice. However, the spleens of IL-6(-/-) mice contained fewer regulatory T cells after infection with L. major. The development of cutaneous lesions is similar between WT and IL-6-deficient mice, while parasite burden in IL-6(-/-) mice is reduced compared to WT. The development of IFN-gamma or IL-10 producing T cells is similar in IL-6(-/-) mice. Despite a comparable adaptive T cell response, IL-6-deficient mice develop an earlier peak of some inflammatory cytokines than WT mice. This data indicate that the role of IL-6 in the differentiation of regulatory T cells is complex in vivo, and the effect of an absence of this cytokine can be counter-intuitive. PMID- 21819985 TI - Structural insights into the dual substrate specificities of mammalian and Dictyostelium dihydropteridine reductases toward two stereoisomers of quinonoid dihydrobiopterin. AB - Up to now, d-threo-tetrahydrobiopterin (DH(4), dictyopterin) was detected only in Dictyostelium discoideum, while the isomer L-erythro-tetrahydrobioterin (BH(4)) is common in mammals. To elucidate the mechanism of DH(4) regeneration by D. discoideum dihydropteridine reductase (DicDHPR), we have determined the crystal structure of DicDHPR complexed with NAD(+) at 2.16 A resolution. Significant structural differences from mammalian DHPRs are found around the coenzyme binding site, resulting in a higher K(m) value for NADH (K(m)=46.51+/-0.4 MUM) than mammals. In addition, we have found that rat DHPR as well as DicDHPR could bind to both substrates quinonoid-BH(2) and quinonoid-DH(2) by docking calculations and have confirmed their catalytic activity by in vitro assay. PMID- 21819986 TI - Cytokine components and mucosal immunity in the oviduct of Xenopus laevis (amphibia, pipidae). AB - Most studies on the mucosal immunity in female reproductive tissues have been performed in mammals. In all species, apart from their reproductive strategies, immunity in the genital mucosa is required to defend the host against luminal pathogens. In this study we investigated the role of the innate immunity of the oviductal mucosa of Xenopus laevis, an amphibian characterized by external fertilization. In particular we examined the expression and localization of Interleukin-1beta (IL1B), Macrophage migration inhibitory factor (MIF) and Interleukin-1 receptor type 1 (IL1R1) in different oviductal portions including an upper glandular region, an intermediate and a lower aglandular region (the ovisac). Tissues were examined by immunohistochemistry and western blot using polyclonal antibodies against human molecules. IL1B, MIF and IL1R1 were all shown in the three oviductal regions examined, albeit with a general increase towards the external environment. A substantial difference among the cytokine components was also observed mainly in the epithelium of the glandular and intermediate regions. Specifically, all three molecules were expressed by the luminal ciliated cells while only IL1R1 was present in the unciliated cells at the bottom of the epithelial ingrowths. The expression of IL1R1 in these cells appeared as a continuous layer separating the epithelium from the underlying tissues. While supporting the role of the innate immune system for host's defense against pathogens, the peculiar distribution of the cytokine components in the oviduct of X. laevis suggests novel immunologic strategies useful to assure gland secretion essential for egg formation and fertilization. PMID- 21819987 TI - The effects of brood size on growth and steroid hormone concentrations in nestling eastern bluebirds (Sialia sialis). AB - Birds in multi-nestling broods often experience reduced growth and elevated nutritional and social stress as a result of competition for parental resources. While responses are often species-specific, experimentally increasing brood size has been shown to decrease growth and increase production of both testosterone and corticosterone in nestling passerines. To investigate the relationship between brood size, growth, and steroid hormone production in eastern bluebirds, we cross-fostered nestlings to small, medium, and large broods. Body mass, skeletal size, serum testosterone, and baseline serum corticosterone concentration were measured prior to fledging. Bluebird nestlings raised in large broods weighed less than nestlings in small and medium-sized broods and secreted elevated concentrations of testosterone. Nestling corticosterone concentrations did not vary in response to brood size or body condition, but concentrations were higher in males compared to females. Our results suggest that nestling bluebirds experiencing nutritional and social stress increase testosterone production. Elevated concentrations may enhance begging and competitive abilities in smaller young. Higher concentrations of corticosterone in males may be related to sex biased provisioning. Further experimental work is needed to ascertain the effects of elevated testosterone concentrations in nestling bluebirds, as well as the causes and consequences of elevated corticosterone for male nestlings. PMID- 21819988 TI - Effects of androgen and leptin on behavioral and cellular responses in female rats. AB - The causes of anxiety and depression in women with polycystic ovary syndrome (PCOS) remain elusive. To identify steps linking androgen signaling to the regulation of affective symptoms in vivo, we compared behavioral responses in female rats continuously exposed to DHT from puberty (a model of DHT-induced PCOS) and in rats exposed to DHT for 1week. Continuous and 1week of DHT exposure resulted in a general decrease in locomotor activity and time spent on the open arms in the elevated plus maze, indicating anxiety-like behavior. Rats with DHT induced PCOS have increases in adiposity and circulating leptin levels accompanied by leptin resistance. One week of DHT exposure decreased androgen receptor (AR) expression in the hypothalamus and leptin synthesis and function in adipocytes; it also inhibited signal transducer and activator of transcription 3 (STAT3) and attenuated leptin activity by increasing levels of soluble leptin receptor, a leptin-binding protein, in the hypothalamus. This may affect the androgen-induced anxiety-related behavior in female rats. In conclusion, our results highlight the central role of androgens in behavioral function in female rats and suggest that androgens directly regulate the AR by decreasing its hypothalamic expression. Androgens also increase leptin synthesis in adipocytes, which drives central leptin signaling, and may regulate anxiety-related behaviors. Elucidating mechanisms by which androgens modulate female anxiety-like behavior may uncover useful approaches for treating women with PCOS who have symptoms of anxiety. PMID- 21819989 TI - IrCL1 - the haemoglobinolytic cathepsin L of the hard tick, Ixodes ricinus. AB - Intracellular proteolysis of ingested blood proteins is a crucial physiological process in ticks. In our model tick, Ixodes ricinus, cathepsin L (IrCL1) is part of a gut-associated multi-peptidase complex; its endopeptidase activity is important in the initial phase of haemoglobinolysis. We present the functional and biochemical characterisation of this enzyme. We show, by RNA interference (RNAi), that cathepsin L-like activity that peaks during the slow feeding period of females is associated with IrCL1. Recombinant IrCL1 was expressed in bacteria and yeast. Activity profiling with both peptidyl and physiological protein substrates (haemoglobin and albumin) revealed that IrCL1 is an acidic peptidase with a very low optimum pH (3-4) being unstable above pH 5. This suggests an endo/lysosomal localisation that was confirmed by indirect fluorescence microscopy that immunolocalised IrCL1 inside the vesicles of digestive gut cells. Cleavage specificity determined by a positional scanning synthetic combinatorial library and inhibition profile indicated that IrCL1 has the ligand-binding characteristics of the cathepsin L subfamily of cysteine peptidases. A non redundant proteolytic function was demonstrated when IrCL1-silenced ticks had a decreased ability to feed compared with controls. The data suggest that IrCL1 may be a promising target against ticks and tick-borne pathogens. PMID- 21819990 TI - Peroxidase catalysed cross-linking of an intrinsically unstructured protein via dityrosine bonds in the oocyst wall of the apicomplexan parasite, Eimeria maxima. AB - Apicomplexan parasites such as Eimeria maxima possess a resilient oocyst wall that protects them upon excretion in host faeces and in the outside world, allowing them to survive between hosts. The wall is formed from the contents of specialised organelles - wall-forming bodies - found in macrogametes of the parasites. The presence of dityrosine in the oocyst wall suggests that peroxidase catalysed dityrosine cross-linking of tyrosine-rich proteins from wall-forming bodies forms a matrix that is a crucial component of oocyst walls. Bioinformatic analyses showed that one of these tyrosine-rich proteins, EmGAM56, is an intrinsically unstructured protein, dominated by random coil (52-70%), with some alpha-helix (28-43%) but a relatively low percentage of beta-sheet (1-11%); this was confirmed by nuclear magnetic resonance and circular dichroism. Furthermore, the structural integrity of EmGAM56 under extreme temperatures and pH indicated its disordered nature. The intrinsic lack of structure in EmGAM56 could facilitate its incorporation into the oocyst wall in two ways: first, intrinsically unstructured proteins are highly susceptible to proteolysis, explaining the several differently-sized oocyst wall proteins derived from EmGAM56; and, second, its flexibility could facilitate cross-linking between these tyrosine-rich derivatives. An in vitro cross-linking assay was developed using a recombinant 42kDa truncation of EmGAM56. Peroxides, in combination with plant or fungal peroxidases, catalysed the rapid formation of dityrosine cross linked polymers of the truncated EmGAM56, as determined by western blotting and HPLC, confirming this protein's propensity to form dityrosine bonds. PMID- 21819991 TI - Effect of larval host food substrate on egg load dynamics, egg size and adult female size in four species of braconid fruit fly (Diptera: Tephritidae) parasitoids. AB - Life history theory predicts that individuals will allocate resources to different traits so as to maximize overall fitness. Because conditions experienced during early development can have strong downstream effects on adult phenotype and fitness, we investigated how four species of synovigenic, larval pupal parasitoids that vary sharply in their degree of specialization (niche breadth) and life history (Diachasmimorpha longicaudata, Doryctobracon crawfordi, Opius hirtus and Utetes anastrephae), allocate resources acquired during the larval stage towards adult reproduction. Parasitoid larvae developed in a single host species reared on four different substrates that differed in quality. We measured parasitoid egg load at the moment of emergence and at 24 h, egg numbers over time, egg size, and also adult size. We predicted that across species the most specialized would have a lower capacity to respond to changes in host substrate quality than wasps with a broad host range, and that within species, females that emerged from hosts that developed in better quality substrates would have the most resources to invest in reproduction. Consistent with our predictions, the more specialized parasitoids were less plastic in some responses to host diet than the more generalist. However, patterns of egg load and size were variable across species. In general, there was a remarkable degree of reproductive effort-allocation constancy within parasitoid species. This may reflect more "time-limited" rather than "egg-limited" foraging strategies where the most expensive component of reproductive success is to locate and handle patchily-distributed and fruit-sequestered hosts. If so, egg costs, independent of degree of specialization, are relatively trivial and sufficient resources are available in fly larvae stemming from all of the substrates tested. PMID- 21819993 TI - Reprint of: inhibition of Escherichia coli RNAp by T7 Gp2 protein: role of negatively charged strip of amino acid residues in Gp2. AB - Gp2, a 7 kDa protein encoded by T7 bacteriophage, is a potent inhibitor of Escherichia coli RNA polymerase (RNAp), the enzyme responsible for transcription of all bacterial genes and early viral genes. A prominent feature in the structure of Gp2 is a contiguous strip of seven negatively charged amino acid residues (negatively charged strip or NCS), located along one side of the molecule. The role of the NCS in Gp2 function is not known. Here, the in vivo and in vitro properties of altered forms of Gp2 with amino acid substitutions in the NCS are described. While mutations in the NCS do not compromise the folding or the ability of Gp2 to bind to the RNAp beta' subunit, disruption of the NCS significantly attenuates Gp2 function in vivo and its ability to inhibit RNAp in vitro. Efficient inhibition of the RNAp by Gp2 also involves the amino terminal region 1 domain of the RNAp promoter specificity subunit sigma(70), located in the vicinity of the primary Gp2 binding site in beta'. The results are discussed in the context of hypothetical molecular mechanisms of RNAp inhibition by Gp2. PMID- 21819994 TI - Phylogeny-based design of a B-subunit of DNA gyrase and its ATPase domain using a small set of homologous amino acid sequences. AB - We have developed a phylogeny-based design method that has been used to produce mutated proteins with enhanced thermal stabilities. We previously validated the predictive worth of the method by producing and characterizing mutants in which one original residue or a small number of the original residues had been replaced with the one or the ones found in the phylogenetically predicted "ancestral" sequence. For the current study, this method was used to design a sequence for the deepest nodal position of a phylogenic tree composed of 16 gyrase B-subunit sequences, which was then synthesized and characterized. The sequence was inferred from the sequences of 16 extant DNA gyrases and 3 extant type VI DNA topoisomerases. Genes encoding the inferred sequence and its N-terminal ATPase domain were PCR constructed and expressed in Escherichia coli. The full-length designed protein is slightly less thermally stable than is subunit B from the extant thermophilic Thermus thermophilus DNA gyrase, whereas the thermal stability of the designed ATPase domain is more similar to that of the T. thermophilus ATPase domain. Moreover, the designed ATPase domain has significant catalytic activity. Therefore, even a small set of homologous amino acid sequences contains sufficient information to design a thermally stable and functional protein. Because the isolated designed ATPase domain is more thermally stable and catalytically active than is the sequence containing the most frequently occurring amino acids among the 16 gyrases, the phylogenetic approach was superior (in this case, at least) to the consensus approach when the same data set was used to predict the two sequences. PMID- 21819992 TI - CaMKII-dependent SR Ca leak contributes to doxorubicin-induced impaired Ca handling in isolated cardiac myocytes. AB - Doxorubicin (DOX) is one of the most effective chemotherapeutic agents, but cardiotoxicity limits DOX therapy. Although the mechanisms are not entirely understood, reactive oxygen species (ROS) appear to be involved in DOX cardiotoxicity. Ca/calmodulin dependent protein kinase II (CaMKII) can be activated by ROS through oxidation and is known to contribute to myocardial dysfunction through Ca leakage from the sarcoplasmic reticulum (SR). We hypothesized that CaMKII contributes to DOX-induced defects in intracellular Ca ([Ca](i)) handling. Cardiac myocytes were isolated from wild-type (WT) adult rat hearts and from mouse hearts lacking the predominant myocardial CaMKII isoform (CaMKIIdelta(-/-), KO) vs. WT. Isolated cardiomyocytes were investigated 30 min after DOX (10 MUmol/L) superfusion, using epifluorescence and confocal microscopy. Intracellular ROS-generation ([ROS](i)) and [Ca](i) handling properties were assessed. In a subset of experiments, KN-93 or AIP (each 1 MUmol/L) were used to inhibit CaMKII. Melatonin (Mel, 100 MUmol/L) served as ROS scavenger. Western blots were performed to determine the amount of CaMKII phosphorylation and oxidation. DOX increased [ROS](i) and led to significant diastolic [Ca](i) overload in rat myocytes. This was associated with reduced [Ca](i) transients, a 5.8-fold increased diastolic SR Ca leak and diminished SR Ca content. ROS-scavenging partially rescued Ca handling. Western blots revealed increased CaMKII phosphorylation, but not CaMKII oxidation after DOX. Pharmacological CaMKII inhibition attenuated diastolic [Ca](i) overload after DOX superfusion and led to partially restored [Ca](i) transients and SR Ca content, presumably due to reduced Ca spark frequency. In line with this concept, isoform specific CaMKIIdelta-KO attenuated diastolic [Ca](i) overload and Ca spark frequency. DOX exposure induces CaMKII-dependent SR Ca leakage, which partially contributes to impaired cellular [Ca](i) homeostasis. Pharmacological and genetic CaMKII inhibition attenuated but did not completely abolish the effects of DOX on [Ca](i). In light of the clinical relevance of DOX, further investigations seem appropriate to determine if CaMKII inhibition could reduce DOX-induced cardiotoxicity. PMID- 21819996 TI - Escaping the tragedy of the commons via directed investments. AB - Cooperation is ubiquitous in the world surrounding us, from bacteria to Human interactions. In Humans, cooperation is often associated with various group decisions, resulting from their complex web of interrelated interests, associations or preferences. The existence of such social structures not only opens the opportunity of having diverse behaviors depending on the individuals' social position, but also for a dynamical allocation of contributions depending on the returns obtained from each group. Here, we address these issues by studying the evolution of cooperation under Public Goods Games in the framework of Evolutionary Game Theory where cooperative players are able to distribute their donations to their liking. As a result, cooperation is greatly enhanced when the community structure is described by homogeneous graphs, as cooperators become able to support cooperative groups and retaliate against those with poor achievements by withdrawing donations from them. Whenever the underlying network becomes complex enough to add diversity to the distribution of group sizes, directed investments do not optimize the emergence of cooperation, but they do enhance its robustness against the invasion of a minority of free-riders. We define a robustness index and show that directed investments expand the robustness of cooperation by about 50%. PMID- 21819997 TI - Efficacy of propiverine, an anticholinergic agent, in young and old rats. AB - AIMS: We examined the influence of propiverine hydrochloride, an anticholinergic agent, on the micturition reflex, blood pressure, and plasma catecholamine levels in young rats and old rats. MAIN METHOD: Male F344/DuCrlCrlj Fischer rats (young rats aged 2 months and old rats aged 26 months) were divided into the following 4 groups: a young sham group, an old sham group, a young propiverine group, and an old propiverine group. Rats from the young (body weight: 215+/-7g) or old propiverine groups (body weight: 414+/-22g) were administered propiverine hydrochloride (5 or 10mg, respectively) dissolved in distilled water (0.5mL) into the stomach through a fine catheter once daily. Rats from the young and old sham groups were administered the same volume of distilled water. After 2 weeks of treatment, continuous cystometry was done with physiological saline and 0.1% acetic acid, and measurement of plasma catecholamines, blood pressure, and heart rate was performed. KEY FINDINGS: The old rats had a longer interval between bladder contractions and higher plasma catecholamine levels than the young rats. Bladder stimulation by 0.1% acetic acid induced frequency in both young and old rats. Administration of propiverine inhibited the induction of frequency in the old rats, but not in the young rats. Propiverine increased plasma catecholamine levels in the young rats, but not in the old rats. SIGNIFICANCE: These findings show that bladder activity varies with aging, and the response to propiverine also changes in an age-related manner. PMID- 21819995 TI - Exploring the roles of nucleobase desolvation and shape complementarity during the misreplication of O(6)-methylguanine. AB - O(6)-methylguanine (O(6)-MeG) is a miscoding DNA lesion arising from the alkylation of guanine. This report uses the bacteriophage T4 DNA polymerase as a model to probe the roles of hydrogen-bonding interactions, shape/size, and nucleobase desolvation during the replication of this miscoding lesion. This was accomplished by using transient kinetic techniques to monitor the kinetic parameters for incorporating and extending natural and nonnatural nucleotides. In general, the efficiency of nucleotide incorporation does not depend on the hydrogen-bonding potential of the incoming nucleotide. Instead, nucleobase hydrophobicity and shape complementarity appear to be the preeminent factors controlling nucleotide incorporation. In addition, shape complementarity plays a large role in controlling the extension of various mispairs containing O(6)-MeG. This is evident as the rate constants for extension correlate with proper interglycosyl distances and symmetry between the base angles of the formed mispair. Base pairs not conforming to an acceptable geometry within the polymerase's active site are refractory to elongation and are processed via exonuclease proofreading. The collective data set encompassing nucleotide incorporation, extension, and excision is used to generate a model accounting for the mutagenic potential of O(6)-MeG observed in vivo. In addition, kinetic studies monitoring the incorporation and extension of nonnatural nucleotides identified an analog that displays high selectivity for incorporation opposite O(6)-MeG compared to unmodified purines. The unusual selectivity of this analog for replicating damaged DNA provides a novel biochemical tool to study translesion DNA synthesis. PMID- 21819998 TI - Short-term effects of palmitate and 2-bromopalmitate on the lipolytic activity of rat adipocytes. AB - AIMS: Fatty acids are involved in the regulation of lipolysis in adipocytes; however, this regulatory action is unclear. The present study aimed to determine the short-term influence of palmitate and its non-metabolisable analogue, 2 bromopalmitate, on the lipolytic activity of adipocytes. MAIN METHODS: Freshly isolated rat adipocytes were exposed to lipolytic modulators with or without palmitate or 2-bromopalmitate. Glycerol released from cells was determined as an indicator of lipolysis. Moreover, cAMP, ATP and changes in mitochondrial membrane potential were measured in cells treated with 2-bromopalmitate. KEY FINDINGS: It was demonstrated that glycerol release from adipocytes incubated with epinephrine alone or epinephrine with insulin was unchanged by palmitate. However, 2 bromopalmitate was found to significantly decrease lipolysis stimulated by epinephrine or dibutyryl-cAMP. The inhibitory effect of 2-bromopalmitate on lipolysis was accompanied by reduced cAMP in adipocytes. Moreover, 2 bromopalmitate diminished hyperpolarisation of the inner mitochondrial membrane. Adipocyte exposure to 2-bromopalmitate also resulted in a substantial ATP depletion. The effects of 2-bromopalmitate on lipolysis and on ATP content were prevented neither by high glucose nor by alanine in the incubation medium. SIGNIFICANCE: These findings demonstrate that short-term adipocyte exposure to palmitate disturbs neither the lipolytic action of epinephrine nor the antilipolytic action of insulin. However, 2-bromopalmitate significantly decreases lipolysis probably due to impaired metabolic activity of mitochondria. PMID- 21819999 TI - Neurobehavioral and metabolic long-term consequences of neonatal maternal deprivation stress and adolescent olanzapine treatment in male and female rats. AB - Early maternal deprivation (MD), 24h of dam-litter separation on postnatal day (PND) 9, has been proposed as a suitable animal model to investigate some neuropsychiatric disorders with a base in neurodevelopment that also compromises metabolic and endocrine homeostasis. Atypical antipsychotics are frequently prescribed to children and adolescents as first-line treatment for several mental disorders despite the adverse metabolic effects frequently reported. However, persistent long-term effects after adolescent drug therapy have been scarcely investigated. In the present study we aimed to investigate the long-lasting metabolic and behavioral effects of MD in combination with the administration of an atypical antipsychotic, i.e. olanzapine, during adolescence. For that purpose, male and female Wistar rats not exposed (control group, Co) and exposed to the MD protocol were administered with oral olanzapine (Olan, 7.5mg/kg/day) or vehicle (Vh, 1mM acetic acid) in drinking water from PND 28 to PND 49. Body weight gain, glycaemia and plasma triglyceride (TG) levels were evaluated as relevant metabolic parameters. MD significantly diminished body weight gain, while Olan administration only induced a subtle decrease in body weight gain among female animals in the long-term. Olan discontinuation decreased plasma TG levels in adult rats, an effect that was counteracted by neonatal exposure to the MD protocol. Both MD and Olan treatment impaired cognitive function in the novel object recognition test, although no interaction between treatments was observed. Neither MD nor Olan administration affected psychotic-related symptoms evaluated in the prepulse inhibition task, although animals treated with Olan showed an increased reactivity to the first acoustic stimulus. MD diminished the corticosterone stress-induced response among females, and reduced the expression of CB1 receptors in the hippocampus of both male and female rats. Notably, Olan administration tended to counterbalance these two MD-induced effects (i.e. corticosterone response and CB1 receptor expression). Present findings provide evidence for the long-lasting effects of neonatal MD and Olan administration during adolescence, and suggest some sex-dependent interactions between these two protocols. Further research on the interactions between early life stress and antipsychotic drugs is urgently needed, and sex differences should be consistently considered both in animal models and in translation to human studies. PMID- 21820000 TI - Vestibular information is necessary for maintaining metric properties of representational space: evidence from mental imagery. AB - The vestibular system contributes to a wide range of functions, from postural and oculomotor reflexes to spatial representation and cognition. Vestibular signals are important to maintain an internal, updated representation of the body position and movement in space. However, it is not clear to what extent they are also necessary to mentally simulate movement in situations that do not involve displacements of the body, as in mental imagery. The present study assessed how vestibular loss can affect object-based mental transformations (OMTs), i.e., imagined rotations or translations of objects relative to the environment. Participants performed one task of mental rotation of 3D-objects and two mental scanning tasks dealing with the ability to build and manipulate mental images that have metric properties. Meniere's disease patients were tested before unilateral vestibular neurotomy and during the recovery period (1 week and 1 month). They were compared to healthy participants tested at similar time intervals and to bilateral vestibular-defective patients tested after the recovery period. Vestibular loss impaired all mental imagery tasks. Performance varied according to the extent of vestibular loss (bilateral patients were frequently the most impaired) and according to the time elapsed after unilateral vestibular neurotomy (deficits were stronger at the early stage after neurotomy and then gradually compensated). These findings indicate that vestibular signals are necessary to perform OMTs and provide the first demonstration of the critical role of vestibular signals in processing metric properties of mental representations. They suggest that vestibular loss disorganizes brain structures commonly involved in mental imagery, and more generally in mental representation. PMID- 21820001 TI - The effects of Lonomin V, a toxin from the caterpillar (Lonomia achelous), on hemostasis parameters as measured by platelet function. AB - Platelets play a central role in hemostasis during vascular injury. Patients affected with the hemorrhagic syndrome caused by contact with Lonomia achelous caterpillars (Lac) Lepidoptera distributed in various South American countries, show digestive, pulmonary and intraperitoneal bleeding in combination with hematomas and echymosis. In the present study, we have evaluated the effects of Lonomin V (serine protease isolated from Lac hemolymph) on some functional properties of platelets, evaluating its importance in primary hemostasis. Platelet adhesion to fibrinogen was reduced by 19, 20, 36, and 37% after pre treated with 0.2, 2, 20 and 40 nM of Lonomin V, respectively. Pre-incubation of the platelets with 408 nM of Lonomin V, for 4 min at 37 degrees C, resulted in complete inhibition of the collagen-induced platelet aggregation, in contrast to 56% inhibition of the ADP - induced platelet aggregation. Lonomin V also inhibited anti-alpha(IIb)beta(3) integrin binding to platelets by 56, 57, 52 and 54% at concentrations of 0.2, 2, 20 and 40 nM respectively. Additionally, Lonomin V inhibited anti-P-selectin binding to platelets by 28, 37, 33 and 33% at the same concentrations. The platelets tested with Lonomin V did not modify their viability. In summary, Lonomin V inhibited platelet aggregation, probably caused by the degradation of collagen. The anti-platelet activity of Lonomin V has been shown to be unique and a potentially useful tool for investigating cell-matrix and cell-cell interactions and for the development of antithrombotic agents in terms of their anti-adhesive activities. PMID- 21820002 TI - Distinct cortical responses to 2D figures defined by motion contrast. AB - Motion contrast contributes to the segregation of a two-dimensional figure from its background, yet many questions remain about its neural mechanisms. We measured steady-state visual evoked potential (SSVEP) responses to moving dot displays in which figure regions emerged from and disappeared into the background at a specific temporal frequency (1.2Hz, F1), based on regional differences of dot direction and global direction coherence. The goal was to measure the cortical response function across a range of motion contrast magnitudes. In two experiments using both a low channel count electrode array (Experiment 1) and a high density array (Experiment 2), we observed two distinct phase-locked evoked responses that were similar across motion contrast type. A response at 1.2Hz (1F1) increased in amplitude with increasing magnitudes of direction or coherence contrast. A response at 2.4Hz (2F1) increased in amplitude, but saturated at low levels of direction or coherence contrast. The two components showed different scalp distributions - the 1F1 was strongest along medial occipital channels, while the 2F1 was bilaterally distributed. Taken together, the studies suggest that figures defined by different types of motion contrast are processed by cortical systems with similar dynamics, and that there are separable neural systems devoted to (i) signaling the absolute magnitude of motion contrast and (ii) detecting when a figure defined by motion contrast appears and disappears from view. PMID- 21820003 TI - Decisions about objects in real-world scenes are influenced by visual saliency before and during their inspection. AB - Evidence from eye-tracking experiments has provided mixed support for saliency map models of inspection, with the task set for the viewer accounting for some of the discrepancies between predictions and observations. In the present experiment viewers inspected pictures of road scenes with the task being to decide whether or not they would enter a highway from a junction. Road safety observations have concluded that highly visible road users are less likely to be involved in crashes, suggesting that saliency is important in real-world tasks. The saliency of a critical vehicle was varied in the present task, as was the type of vehicle and the preferred vehicle of the viewer. Decisions were influenced by saliency, with more risky decisions when low saliency motorcycles were present. Given that the vehicles were invariably inspected, this may relate to the high incidence of "looked-but-failed-to-see" crashes involving motorcycles and to prevalence effects in visual search. Eye-tracking measures indicated effects of saliency on the fixation preceding inspection of the critical vehicle (as well as effects on inspection of the vehicle itself), suggesting that high saliency can attract an early fixation. These results have implications for recommendations about the conspicuity of vulnerable road users. PMID- 21820004 TI - Task relevancy and demand modulate double-training enabled transfer of perceptual learning. AB - Location-specific perceptual learning can be rendered transferrable to a new location with double training, in which feature training (e.g., contrast) is accompanied by additional location training at the new location even with an irrelevant task (e.g. orientation). Here we investigated the impact of relevancy (to feature training) and demand of location training tasks on double training enabled learning transfer. We found that location training with an irrelevant task (Gabor vs. letter judgment, or contrast discrimination) limited transfer of Vernier learning to the trained orientation only. However, performing a relevant suprathreshold orthogonal Vernier task prompted additional transfer to an untrained orthogonal orientation. In addition, the amount of learning transfer may depend on the demand of location training as well as the double training procedure. These results characterize how double training potentiates the functional connections between a learned high-level decision unit and visual inputs from an untrained location to enable transfer of learning across retinal locations. PMID- 21820005 TI - 3rd International Genome Dynamics in Neuroscience Conference: "DNA repair and neurological disease". PMID- 21820006 TI - Two incretin hormones GLP-1 and GIP: comparison of their actions in insulin secretion and beta cell preservation. AB - Gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are the two primary incretin hormones secreted from the intestine upon ingestion of glucose or nutrients to stimulate insulin secretion from pancreatic beta cells. GIP and GLP-1 exert their effects by binding to their specific receptors, the GIP receptor (GIPR) and the GLP-1 receptor (GLP-1R), which belong to the G-protein coupled receptor family. Receptor binding activates and increases the level of intracellular cAMP in pancreatic beta cells, thereby stimulating insulin secretion glucose-dependently. In addition to their insulinotropic effects, GIP and GLP-1 have been shown to preserve pancreatic beta cell mass by inhibiting apoptosis of beta cells and enhancing their proliferation. Due to such characteristics, incretin hormones have been gaining mush attention as attractive targets for treatment of type 2 diabetes, and indeed incretin-based therapeutics have been rapidly disseminated worldwide. However, despites of plethora of rigorous studies, molecular mechanisms underlying how GIPR and GLP-1R activation leads to enhancement of glucose-dependent insulin secretion are still largely unknown. Here, we summarize the similarities and differences of these two incretin hormones in secretion and metabolism, their insulinotropic actions and their effects on pancreatic beta cell preservation. We then try to discuss potential of GLP-1 and GIP in treatment of type 2 diabetes. PMID- 21820007 TI - Perception of environmental obstacles to commuting physical activity in Brazilian elderly. AB - OBJECTIVE: To evaluate the association between perceived environmental attributes and commuting physical activity (PA) in a population-based sample of elderly persons. METHODS: Cross-sectional study was performed in 2009/2010, including 1652 elderly individuals aged 60 years or greater living in Florianopolis-SC, Brazil. Physical activity was measured using the long version of the International Physical Activity Questionnaire. Perceived environmental variables were assessed using a modified version of the Neighborhood Environment Walkability Scale. Multinomial logistic regression was used and a 5% significance level was taken into account. RESULTS: 36.8% and 35.2% of the subjects were inactive or did not reach 150 min/week on transport-related physical activity, respectively. Physical and social environmental characteristics, such as the absence of parks and athletic courts (OR(Inactive):1.75; 95% CI:1.22-2.51); presence of garbage (OR(Low-active):1.55; 1.04-2.30); street lighting (OR(Low active):2.51; 95% CI:1.36-4.64; OR(Low-active):2.43; 95% CI:1.43-4.15); not walking with the dog (OR(Inactive): 3.08; 95% CI:1.42-6.69) and don't have a dog (OR(Inactive):2.45; 95% CI:1.06-5.66) were associated with lower levels of commuting PA. CONCLUSIONS: Results showed that poor physical and social environmental characteristics were related to lower commuting. Building public facilities and promoting physical activity in groups are likely to impact in active commuting among the elderly in Brazil. PMID- 21820008 TI - Tracking of children's body-mass index, television viewing and dietary intake over five-years. AB - OBJECTIVE: To examine the tracking of children's body mass index, television viewing, and dietary intake over five-years. METHODS: In 2002/3 (T1) parents of children aged 5-6 years (n=175) and 10-12 years (n=121), from Victoria, Australia, completed measures assessing their child's frequency of fruit, vegetable, and energy-dense sweet and savory snack consumption, and their child's television (TV) viewing. Children's height and weight were measured by researchers and sex-age adjusted body mass index (BMI) calculated. All measures were repeated in 2006 (T2) and 2008 (T3). Generalized estimating equations (GEE) (standardized stability coefficients, beta) were used to assess tracking and were interpreted as: beta <0.3=low, 0.3-0.6=moderate, and >0.6=high. RESULTS: High standardized stability coefficients were found for BMI (beta=0.74-0.92), TV viewing (beta=0.65-0.73), and frequency of fruit consumption (beta=0.73-0.89) among younger and older children. Moderate-to-high standardized stability coefficients were found for frequency of vegetable (beta=0.52-0.86), energy-dense sweet (beta=0.41-0.65), and savory snack consumption (0.40-0.67) among younger and older children. CONCLUSIONS: BMI, TV viewing and dietary intake patterns are moderate-highly stable throughout childhood and into adolescence. Further research that identifies and targets high risk groups to prevent increased BMI, reduce TV viewing and promote healthy dietary behaviors may be justified. PMID- 21820009 TI - Activity compensation and activity synergy in British 8-13 year olds. AB - OBJECTIVES: To examine whether children compensate for participating in physically active behaviors by reducing activity at other times (the 'activitystat' hypothesis); or alternatively become more active at other times (activity synergy). METHODS: In 2002-2006, 345 British children (8-13 years) completed activity diaries and wore accelerometers. This generated 1077 days of data which we analyzed between-children (comparing all days) and within-child (comparing days from the same child). RESULTS: On week and weekend days, each extra 1% of time in PE/games, school breaks, school active travel, non-school active travel, structured sports and out-of-home play predicted a 0.21 to 0.60% increase in the proportion of the day in moderate-to-vigorous physical activity (MVPA). None of these behaviors showed evidence of reduced MVPA at other times, i.e. activity compensation (all p>0.15). Moreover, each 1% increase in weekday non-school active travel predicted 0.38% more time in MVPA at other times (95% CI 0.18, 0.58). This activity synergy reflected children using active travel for playing and visiting friends. CONCLUSIONS: Contrary to the 'activitystat' hypothesis, we found no evidence of activity compensation. This suggests that interventions increasing activity in specific behaviors may increase activity overall. The activity synergy of non-school active travel underlines the need for further research into this neglected behavior. PMID- 21820010 TI - A novel telemetry system for recording EEG in small animals. AB - It has become increasingly evident that continuous EEG monitoring is necessary to observe the development of epilepsy in animals, and to determine the effect of drugs on spontaneous seizures. Telemetric recording systems have been increasingly used to monitor EEG in freely moving animals. One challenge faced by such systems is to monitor frequencies above 80Hz continuously for weeks. We present an implantable, 2.4-ml, telemetric sensor that can monitor EEG at 512 samples per second for eight weeks in a freely moving animal. With minor modifications, the same transmitter can operate at higher sample rates with a proportional decrease in operating life. Signal transmission is through bursts of 915-MHz radio power. The burst transmission and several other novel techniques reduce the transmitter's power consumption by two orders of magnitude while allowing 8 transmitters to share the same recording system. The use of radio frequency transmission permits digitization within the sensor to sixteen-bit resolution, thus eliminating transmission-generated signal noise. The result is a signal with dynamic range 9mV, bandwidth 160Hz, input noise 12MUV, and AC power interference less than 1MUV. All circuit diagrams are open-source. Data acquisition takes place over the Internet using open-source software that works on multiple operating systems. The resulting system permits long-term, continuous, monitoring of EEG signals, therefore providing continuous and reliable data upon which to base studies of epilepsy in freely moving animals. PMID- 21820011 TI - Amplification-free detection of grapevine viruses using an oligonucleotide microarray. AB - A single-colour microarray hybridization system was designed and evaluated for the detection of viruses infecting grapevine. Total RNA (>=0.5MUg) from infected plants was converted to cDNA and labelled with Cy3 using two different strategies. While amine-modified and labelled cDNA was adequate for the detection of nepoviruses, the 3DNA technique, a post-hybridization detection method that uses intensely fluorescent dendrimer reagents, was required for the detection of closteroviruses in infected plants. Threshold detection levels were based on the ratio between viral specific and 18S rRNA positive control signal intensities. Oligonucleotides between 27 and 75 nucleotides in length were evaluated and compared. Viruses detected include eight nepoviruses, two vitiviruses, and one each of closterovirus, foveavirus, ampelovirus, maculavirus and sadwavirus. Results of this work demonstrate the potential of microarray technique to detect viral pathogens without sequence bias amplification of template RNA. PMID- 21820012 TI - The amphetamine-chlordiazepoxide mixture, a pharmacological screen for mood stabilizers, does not enhance amphetamine-induced disruption of prepulse inhibition. AB - In rodents, administration of a mixture of the psychostimulant d-amphetamine and the benzodiazepine chlordiazepoxide results in supra-additive hyperlocomotion, a phenomenon used to identify mood stabilizers. In an attempt to determine whether the d-amphetamine/chlordiazepoxide assay could extend to other behaviors that are affected in mania, we evaluated the effects of the mixture on prepulse inhibition. In addition, we combined chlordiazepoxide with the selective dopamine reuptake inhibitor GBR 12909 or the noradrenergic stimulant (-) ephedrine, and tested these alternative mixtures in locomotor activity and prepulse inhibition tests. Chlordiazepoxide (3mg/kg) robustly potentiated amphetamine-induced hyperactivity, but did not change the amphetamine-induced disruption of prepulse inhibition. This indicates that the d-amphetamine-chlordiazepoxide-induced hyperlocomotion does not extend to other dopamine-driven behaviors. GBR 12909 (16mg/kg) and (-) ephedrine (50mg/kg) both enhanced locomotor activity and disrupted PPI, but combined treatment of either of these compounds with chlordiazepoxide had no significant additive effect on locomotor activity or prepulse inhibition. These findings suggest that the effect of the d amphetamine/chlordiazepoxide mixture cannot be accounted for by the dopamine enhancing properties of amphetamine alone. Last, valproic acid (120-240mg/kg) did not reduce the GBR-induced hyperactivity. Therefore, further pharmacological evaluation of GBR 12909-induced hyperactivity is warranted to determine its pharmacological potential to model mania-like behavior. Based on the current results, it is concluded that the utility of the pharmacological d amphetamine/chlordiazepoxide assay as a tool to study brain mechanisms relevant to mania is limited. PMID- 21820013 TI - Butyrylcholinesterase inhibitors ameliorate cognitive dysfunction induced by amyloid-beta peptide in mice. AB - The cholinesterase inhibitor, rivastigmine, ameliorates cognitive dysfunction and is approved for the treatment of Alzheimer's disease (AD). Rivastigmine is a dual inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE); however, the impact of BuChE inhibition on cognitive dysfunction remains to be determined. We compared the effects of a selective BuChE inhibitor, N1-phenethyl norcymserine (PEC), rivastigmine and donepezil (an AChE-selective inhibitor) on cognitive dysfunction induced by amyloid-beta peptide (Abeta(1-40)) in mice. Five week-old imprinting control region (ICR) mice were injected intracerebroventricularly (i.c.v.) with either Abeta(1-40) or the control peptide Abeta(40-1) on Day 0, and their recognition memory was analyzed by a novel object recognition test. Treatment with donepezil (1.0mg/kg), rivastigmine (0.03, 0.1, 0.3mg/kg) or PEC (1.0, 3.0mg/kg) 20min prior to, or immediately after the acquisition session (Day 4) ameliorated the Abeta(1-40) induced memory impairment, indicating a beneficial effect on memory acquisition and consolidation. In contrast, none of the investigated drugs proved effective when administrated before the retention session (Day 5). Repeated daily administration of donepezil, rivastigmine or PEC, on Days 0-3 inclusively, ameliorated the cognitive dysfunction in Abeta(1-40) challenged mice. Consistent with the reversal of memory impairments, donepezil, rivastigmine or PEC treatment significantly reduced Abeta(1-40) induced tyrosine nitration of hippocampal proteins, a marker of oxidative damage. These results indicate that BuChE inhibition, as well as AChE inhibition, is a viable therapeutic strategy for cognitive dysfunction in AD. PMID- 21820014 TI - Proteasomal AAA-ATPases: structure and function. AB - The 26S proteasome is a chambered protease in which the majority of selective cellular protein degradation takes place. Throughout evolution, access of protein substrates to chambered proteases is restricted and depends on AAA-ATPases. Mechanical force generated through cycles of ATP binding and hydrolysis is used to unfold substrates, open the gated proteolytic chamber and translocate the substrate into the active proteases within the cavity. Six distinct AAA-ATPases (Rpt1-6) at the ring base of the 19S regulatory particle of the proteasome are responsible for these three functions while interacting with the 20S catalytic chamber. Although high resolution structures of the eukaryotic 26S proteasome are not yet available, exciting recent studies shed light on the assembly of the hetero-hexameric Rpt ring and its consequent spatial arrangement, on the role of Rpt C-termini in opening the 20S 'gate', and on the contribution of each individual Rpt subunit to various cellular processes. These studies are illuminated by paradigms generated through studying PAN, the simpler homo hexameric AAA-ATPase of the archaeal proteasome. The similarities between PAN and Rpts highlight the evolutionary conserved role of AAA-ATPase in protein degradation, whereas unique properties of divergent Rpts reflect the increased complexity and tighter regulation attributed to the eukaryotic proteasome. PMID- 21820015 TI - Microbial DNA extraction from intestinal biopsies is improved by avoiding mechanical cell disruption. AB - Currently, standard protocols for microbial DNA extraction from intestinal tissues do not exist. We assessed the efficiency of a commercial kit with and without mechanical disruption. Better quality DNA was obtained without mechanical disruption. Thus, it appears that bead-beating is not required for efficient microbial DNA extraction from intestinal biopsies. PMID- 21820016 TI - Psychophysiology and brain imaging of cognition and affect following traumatic brain injury: an overview of the special issue. PMID- 21820017 TI - Stimulus appraisal modulates cardiac reactivity to briefly presented mutilation pictures. AB - Emotional reactions to threatening situations can be either advantageous for human adaptation or unfavorable for physical and mental health if sustained over prolonged periods of time. These contrasting effects mostly depend on the individual's capacity for emotion regulation. It has been shown, for example, that changing appraisal can alter the course of emotional processing. In the present study, the influence of stimulus appraisal over cardiac reactivity to briefly presented (200ms) mutilation pictures was tested in the context of an affective classification task. Heart rate and reaction time of twenty-four undergraduate students were monitored during the presentation of pictures (neutral or mutilated bodies) in successive blocks. In one condition (real), participants were told that the pictures depicted real events. In the other condition (fictitious), they were told that the pictures were taken from movie scenes. As expected, the results showed a more pronounced bradycardia to mutilation pictures, in comparison to neural pictures, in the real context. In the fictitious context, a significant attenuation of the emotional modulation (defensive bradycardia) was observed. However, this attenuation seemed to be transient because it was only observed in the first presentation block of the fictitious context. Reaction time to classify mutilation pictures, compared to neutral pictures, was slower in both contexts, reflecting the privileged processing of emotionally laden material. The present findings show that even briefly presented mutilation pictures elicit a differential cardiac reactivity and modulate behavioral performance. Importantly, changing stimulus appraisal attenuates the emotional modulation of cardiac reactivity (defensive bradycardia). PMID- 21820018 TI - Levansucrases from Pseudomonas syringae pv. tomato and P. chlororaphis subsp. aurantiaca: substrate specificity, polymerizing properties and usage of different acceptors for fructosylation. AB - Levansucrases of Pseudomonas syringae pv. tomato DC3000 (Lsc3) and Pseudomonas chlororaphis subsp. aurantiaca (also Pseudomonas aurantiaca) (LscA) have 73% identity of protein sequences, similar substrate specificity and kinetic properties. Both enzymes produce levan and fructooligosaccharides (FOS) of varied length from sucrose, raffinose and sugar beet molasses. A novel high-throughput chip-based nanoelectrospray mass spectrometric method was applied to screen alternative fructosyl acceptors for levansucrases. Lsc3 and LscA could both transfructosylate D-xylose, D-fucose, L- and D-arabinose, D-ribose, D-sorbitol, xylitol, xylobiose, D-mannitol, D-galacturonic acid and methyl-alpha-D glucopyranoside and heterooligofructans with degree of polymerization up to 5 were detected. The ability of D-sorbitol, xylobiose, D-galacturonic acid, D mannitol, xylitol and methyl-alpha-D-glucopyranoside to serve as fructosyl acceptors for levansucrases is shown for the first time. Expectedly, site directed mutagenesis of His321 in Lsc3 to Arg, Lys, Leu and Ser resulted in proteins with decreased catalytic activity, affinity for sucrose and polymerizing ability. Random mutagenesis yielded a Lsc3 mutant Thr302Pro with reduced synthesis of levan and long-chain FOS. Thr302 is located in conserved DQTERP region of levansucrases adjacent to predicted acid-base catalyst Glu303. Thr302 and His321 are predicted to belong to +1 subsite of the substrate binding region of Lsc3. PMID- 21820019 TI - An RNA-DNA hybridization assay chip with electrokinetically controlled oil droplet valves for sequential microfluidic operations. AB - A novel RNA-DNA hybridization microfluidic chip for detecting pathogens was developed. The on-chip sequential operations of reagent delivery and washing processes in the hybridization assay were performed by gravity-based pressure driven flow controlled by a pair of electrokinetically controlled oil-droplet sequence valves (ECODSVs). Numerical method was used to simulate the fluidic processes of reagents in the complex microchannel network. Based on the parameters determined from the numerical simulations, a reasonable hybridization assay microfluidic chip was developed. The application of this on-chip assay to detect Salmonella was demonstrated. Significantly shortened assay time (25 min) and a 3-20-fold reduction in reagent/sample consumption were achieved. The detection limit was 103 CFU/mL which is comparable to the conventional assay. With further development of automatic control and the improvement of the detection strategy, this microfluidic RNA-DNA hybridization assay technique has a potential for point-of-testing applications. PMID- 21820020 TI - In vivo tropisms and kinetics of rat theilovirus infection in immunocompetent and immunodeficient rats. AB - Rat theilovirus (RTV) is a cardiovirus related to Theiler's murine encephalomyelitis virus. While RTV is a prevalent viral pathogen of rats used in biomedical research, the pathogenesis and characterization of RTV infections is not well understood. In the studies reported herein, we used immunohistochemistry to identify viral antigens in enterocytes of the small intestines of Sprague Dawley (SD) rats. Fecal viral shedding in immunocompromised and immunocompetent rats following oral gavage with RTV1 was high for the first 2 weeks of infection with persistent shedding of high viral loads being observed in immunocompromised nude rats but not in immunocompetent rats. RTV was also detected in mesenteric lymph nodes and spleen of immunocompromised rats but not immunocompetent rats. In addition, the magnitude of serum antibody responses differed between immunocompetent rat strains with Brown Norway and SD rats having a significantly higher antibody response than CD or Fischer 344 rats. These data suggest that RTV1 has a tropism for the epithelial cells of the small intestine, immunocompetent rats have differing serum antibody responses to RTV infection, and sustained fecal shedding and extraintestinal dissemination of RTV1 occurs in rats deficient in T cell-dependent adaptive immunity. RTV infection in immunocompromised and immunocompetent rats has merit as a model for further studies of theilovirus pathogenesis following oral viral exposure. PMID- 21820021 TI - Comparison of innate immune responses to pathogenic and putative non-pathogenic hantaviruses in vitro. AB - Hantaviruses are human pathogens that cause hemorrhagic fever with renal syndrome or hantavirus cardiopulmonary syndrome. The mechanisms accounting for the differences in virulence between pathogenic and non-pathogenic hantaviruses are not well known. We have examined the pathogenesis of different hantavirus groups by comparing the innate immune responses induced in the host cell following infection by pathogenic (Sin Nombre, Hantaan, and Seoul virus) and putative non pathogenic (Prospect Hill, Tula, and Thottapalayam virus) hantaviruses. Pathogenic hantaviruses were found to replicate more efficiently in interferon competent A549 cells than putative non-pathogenic hantaviruses. The former also suppressed the expression of the interferon-beta and myxovirus resistance protein genes, while the transcription level of both genes increased rapidly within 24 h post-infection in the latter. In addition, the induction level of interferon correlated with the activation level of interferon regulatory factor-3. Taken together, these results suggest that the observed differences are correlated with viral pathogenesis and further indicate that pathogenic and putative non pathogenic hantaviruses differ in terms of early interferon induction via activation of the interferon regulatory factor-3 in infected host cells. PMID- 21820022 TI - Preparation of polyion complex micelles from poly(ethylene glycol)-block polyions. AB - Polyion complex micelles (PICMs) arise from the spontaneous self-assembly of ionic polymers of opposite charges to form a condensate that is dispersed in aqueous media by a hydrophilic segment, usually poly(ethylene glycol) (PEG), present on at least one of the two ionic polymers. PICMs are used for many applications, especially drug delivery. This protocol paper describes the preparation by atom transfer radical polymerization (ATRP) of diblock copolymers of PEG bearing either positive or negative charges, both of which have been shown to form PICMs. Furthermore, methods of preparation and characterization of PICMs loaded with nucleic acid drugs are presented. PMID- 21820023 TI - Circulation kinetics and biodistribution of dual-labeled polymersomes with modulated surface charge in tumor-bearing mice: comparison with stealth liposomes. AB - Polymersomes (Ps) based on poly(ethylene glycol)-b-poly(D,L-lactide) (PEG-PDLLA), with similar sizes (90-100 nm), but different zeta potentials (-7.6 to -38.7 mV) were prepared to investigate the effect of surface charge on blood circulation time and tissue distribution in tumor-bearing mice. For the in vivo studies dual labeled Ps were applied, which were obtained by encapsulating (3)H-dextran 70k in the aqueous core of Ps and by post-coupling of (14)C-thioglycolic acid onto acrylated PEG chains of the Ps. Stealth liposomes (103 nm, -6 mV) were used as a control. A substantial longer half lifetime (tau(1/2)) (47.3h) and a reduced liver uptake (27.9% of injected dose (% ID)) of Ps with a zeta potential of -7.6 mV were observed as compared to those of stealth liposomes (10.6h, 39.8% ID) most probably due to the presence of a relatively thicker and denser PEG brush of the Ps as compared to the liposomes. As a result of their longer circulation times a high tumor accumulation of 18.6% ID was obtained for these Ps after 3d circulation in mice while only 11.2% ID of stealth liposomes accumulated in the tumors as a result of their relatively short tau(1/2) in blood. By increasing the zeta potential on Ps, more rapid clearance of Ps from the blood circulation was found due to an enhanced uptake by the liver. Importantly, co-localization of the two labels of Ps was observed during circulation indicating that dual labeled Ps were colloidally stable in blood without leakage of (3)H-dextran. In conclusion, the results show that Ps with a slightly negative surface charge (zeta potential 7.6 mV) are stable in the circulation and have longer circulation times and a higher tumor accumulation in mice than Ps with more negative zeta potentials or the stealth liposomes used as a control. PMID- 21820025 TI - Characterization of the CDR3 structure of the Vbeta21 T cell clone in patients with P210(BCR-ABL)-positive chronic myeloid leukemia and B-cell acute lymphoblastic leukemia. AB - The clonally expanded T cells identified in most cancer patients that respond to tumor-associated antigen such as P210(BCR-ABL) protein have definite, specific antitumor cytotoxicity. T cell receptor (TCR) Vbeta CDR3 repertoire diversity was analyzed in patients with chronic myeloid leukemia (CML) and BCR-ABL(+) B-cell acute lymphoblastic leukemia (B-ALL) by GeneScan. A high frequency of oligoclonal expansion of the TCR Vbeta21 subfamily was observed in the peripheral blood of CML and B-ALL patients. These clonally expanded Vbeta21 T cells were correlated with the pathophysiologic process of CML. A conserved amino acid motif (SLxxV) was observed within the CDR3 region in only 3 patients with CML. Preferential usage of the Jbeta segments was also observed in a minority of patients. The 3 dimensional structures of the CDR3 region containing the same motif or using the same Jbeta segment displayed low similarity; on the contrary, the conformation of the CDR3 region containing no conserved motif in some T cell clones was highly similar. In conclusion, our findings indicate a high frequency of TCR Vbeta21 subfamily expansion in p210(BCR-ABL)-positive CML and B-ALL patients. The characterization of the CDR3 structure was complex. Regrettably, at this time it was not possible to confirm that the Vbeta21 T cell clones were derived from the stimulation of p210(BCR-ABL) protein. PMID- 21820026 TI - A toxicologic and dermatologic assessment of cinnamyl phenylpropyl materials when used as fragrance ingredients. AB - The cinnamyl phenylpropyl fragrance ingredients are a diverse group of chemical structures that have similar metabolic and toxicity profiles. A toxicological and dermatological review of these fragrance ingredients is presented. The common characteristic structural element of cinnamyl phenylpropyl materials is an aryl substituted primary alcohol/aldehyde/ester. For high end users, calculated maximum dermal exposures vary from 0.14% to 0.72%; systemic exposures vary from 0.0002 to 0.0280 mg/kg/day. Human dermatological studies show that these materials are not generally irritants or sensitizers at lower exposures from consumer products. Reactions (0.9%) in fragrance sensitive patients were observed with 3-phenyl-1-propanol at 5% in petrolatum. The cinnamyl phenylpropyl materials had low acute toxicity and no significant toxicity in repeat dose oral or dermal toxicity studies. No mutagenic or genotoxic activity in bacteria and mammalian cell line assays was observed. The cinnamyl phenylpropyl alcohol materials participate in the same beta oxidation pathways as their parent cinnamic acid derivatives, including common routes of absorption, distribution, and metabolic detoxification, and exhibit similar toxicological endpoints. Based on the review of available data, it is concluded that these materials would not present a safety concern at current levels of use as fragrance ingredients. PMID- 21820027 TI - Oxidative stress induced apoptosis of human lung carcinoma (A549) cells by a novel copper nanorod formulation. AB - This study elucidates the process of synthesis of copper (Cu) nanorods using almond skin extract as stabilizing cum capping agent. These nanorods were (about 200 nm long and 40 nm wide) characterized by transmission electron microscopy (TEM). Further, cytotoxicity potential of these nanorods was evaluated in A549 cells (Human lung carcinoma cell line) via cell viability assay and extracellular lactate dehydrogenase (LDH) release. Also, reduced glutathione (GSH), lipid peroxidation (LPO), cellular oxidative stress (Rhodamine 123 florescence) and apoptosis (Annexin V FITC/Propidium iodide staining) were also investigated in control and treated cells. Results indicated that Cu nanorods induced apoptotic death of cancer cells by induction of oxidative stress, depletion of cellular antioxidants and mitochondrial dysfunction. This study reports a novel process of synthesis of almond skin extract capped Cu nanorods and its potential as an anticancer agent against A549 lung carcinoma cells. PMID- 21820024 TI - Robust IgG responses to nanograms of antigen using a biomimetic lipid-coated particle vaccine. AB - New subunit vaccine formulations with increased potency are of interest to improve immune responses against poorly immunogenic antigens, to avoid vaccine shortages in pandemic situations, and to promote dose-sparing of potent adjuvant molecules that can cause unacceptable side effects in prophylactic vaccination. Here we report strong class-switched, high avidity humoral immune responses elicited by a vaccine system based on poly(lactide-co-glycolide) micro- or nano particles enveloped by PEGylated phospholipid bilayers, with protein antigens covalently anchored to the lipid surface and lipophilic adjuvants inserted in the bilayer coating. Strikingly, these particles elicited high endpoint antigen specific IgG titers (>10(6)) sustained for over 100 days after two immunizations with as little as 2.5 ng of antigen. At such low doses, the conventional adjuvant alum or the molecular adjuvants monophosphoryl lipid A (MPLA) or alpha galactosylceramide (alphaGC) failed to elicit responses. Co-delivery of antigen with MPLA or alphaGC incorporated into the particle bilayers in a pathogen mimetic fashion further enhanced antibody titers by ~12-fold. MPLA provided the highest sustained IgG titers at these ultra-low antigen doses, while alphaGC promoted a rapid rise in serum IgG after one immunization, which may be valuable in emergencies such as disease pandemics. The dose of alphaGC required to boost the antibody response was also spared by particulate delivery. Lipid-enveloped biodegradable micro- and nano-particles thus provide a potent dose-sparing platform for vaccine delivery. PMID- 21820028 TI - Chlorella vulgaris restores bone marrow cellularity and cytokine production in lead-exposed mice. AB - Chlorella vulgaris (CV) was examined for its modulating effects on the reduction induced by lead (Pb) on the numbers of marrow hematopoietic stem cells (HSCs) (c Kit(+)Lin(-)), granulocyte-macrophage progenitors (Gr1(+)Mac1(+)) and total bone marrow cellularity. In mice gavage-treated daily with 50mg/kg dose of CV for 10 days, concomitant to a continuous offering of 1300 ppm lead acetate in drinking water, the treatment with the algae recovered the significantly reduced numbers of these cell populations to control values. As CV may have a myelostimulating effect through the induction of cytokines, we evaluated its modulating effects on the production of IL-1alpha, TNF-alpha, IFN-gamma, IL-10 and IL-6. Our results demonstrated that lead significantly impairs the production of IFN-gamma, IL 1alpha and TNF-alpha and increases the production of IL-10 and IL-6 and that these effects are successfully modulated by the CV treatment. The activity of NK cells, reduced in Pb-exposed animals, was raised to levels higher than those of controls in the exposed group treated with CV. Treatment with the algae also stimulated the production of IFN-gamma, IL-1alpha, TNF-alpha and NK cells activity in normal mice. In addition, zinc bone concentrations, reduced in lead exposed mice, were partially, but significantly, reversed by the treatment with CV. PMID- 21820029 TI - A toxicological and dermatological assessment of macrocyclic lactone and lactide derivatives when used as fragrance ingredients. AB - The Macrocyclic Lactone and Lactide derivative (ML) group of fragrance ingredients was critically evaluated for safety following a complete literature search. For high end users, calculated maximum dermal exposures vary from 0.47% to 11.15%; systemic exposures vary from 0.0008 to 0.25mg/kg/day. The MLs had low acute toxicity and no significant toxicity in repeat dose oral or dermal toxicity studies. Effects on blood biochemistry were reversible after 2 weeks of no treatment. No mutagenic or genotoxic activity in bacteria and mammalian cell line assays was observed. Reproductive and developmental toxicity was not observed. Human dermatological studies show MLs are generally not irritating after one application. Minor irritation was observed in a few individuals following multiple applications. At rates consistent with reported levels for current human exposure, no phototoxicity or photosensitization was observed. In animal studies, the MLs are not sensitizers at lower exposures from consumer products. Eleven ML materials were evaluated for human sensitization. Of these, only ethylene brassylate showed evidence of sensitization in 2/27 studies (sensitization frequency 4/2059 total). Based on these findings, the Panel is of the opinion that there are no safety concerns for the MLs at reported levels of use and exposure as fragrance ingredients. PMID- 21820030 TI - Differences in neonatal neurotoxicity of brominated flame retardants, PBDE 99 and TBBPA, in mice. AB - Flame retardants such as polybrominated diphenyl ethers (PBDE) and tetrabromobisphenol A are used as flame retardants and detected in the environmental, wildlife species and human tissues. Exposure to PBDEs during the neonatal development of the brain has been shown to affect behavior and learning and memory in adult mice, while neonatal exposure to TBBPA (another brominated flame retardant) did not affect behavioral variables in the adult. In this study, we hypothesized that the effects of these compounds could be reflected by changes in biochemical substrates and cholinergic receptors and have examined the levels of four proteins involved in maturation of the brain, neuronal growth and synaptogenesis and the densities of both muscarinic and nicotinic cholinergic receptors. We measured the levels of radioactivity in the brain after administration of (14)C-labelled TBBPA at different time points and saw that levels of TBBA peaked earlier and decreased faster than the earlier reported levels of PBDE 99. The protein analysis in the neonatal brain showed changes in the levels of calcium/calmodulin-dependent protein kinase II (CaMKII), growth associated protein-43 (GAP-43) and synaptophysin following neonatal exposure to PBDE 99 (21 MUmol/kg body weight), but not following exposure TBBPA. Furthermore, neonatal exposure to PBDE 99 and TBBPA caused a decrease in binding sites of the nicotinic ligand cytisine in frontal cortex. These results confirm earlier reported data that PBDE 99 can act as a developmental neurotoxicant, possibly due to its different uptake and retention in the brain compared to TBBPA. In addition, the changes in protein levels are interesting leads in the search for mechanisms behind the developmental neonatal neurotoxicity of PBDEs in general and PBDE 99 in particular, since also other compounds inducing similar adult behavioral disturbances as PBDE 99, affect these proteins during the period of rapid brain development. PMID- 21820031 TI - Deciphering the molecular structure of cryptolepain in organic solvents. AB - Solvent composition plays a major role in stabilizing/destabilizing the forces that are responsible for the native structure of a protein. Often, the solvent composition drives the protein into non-native conformations. Elucidation of such non-native structures provides valuable information about the molecular structure of the protein, which is unavailable otherwise. Inclusion of methanol (non fluorinated alcohol) or TFE (fluorinated alcohol) in the solvent composition drove cryptolepain, a serine protease and an all-beta-protein, into a non-native structure with an enhanced beta-sheet or induction of alpha-helix. These solvents did not much affect cryptolepain under neutral conditions, even at higher concentrations, but the effects were predominant at lower pH, when the protein molecule is under stress. The organic solvent-induced state is partially unfolded with similar characteristics to the molten globule state seen with protein under a variety of conditions. Chemical- or temperature-induced unfolding of cryptolepain in the presence of organic solvent is distinctly different from that in the absence of organic solvent. Such different unfolding provided evidence of two structural variants in the molecular structure of the protein as well as the differential stabilization/destabilization of such structural variants and their sequential unfolding. PMID- 21820032 TI - Structural determinants of ligand binding to the mineralocorticoid receptor. AB - The first and critical step in the mechanism of aldosterone action is its binding to the mineralocorticoid receptor (MR), a member of the nuclear receptor superfamily. Over the last 40 years, numerous studies have attempted to determine the structural determinants of ligand-binding to MR. An initial set of data showed that hsp90 is bound to the receptor via specific regions and maintains it in a ligand-binding competent state. Site-directed mutagenesis and functional studies guided by a 3D model of the MR ligand-binding domain (LBD) made it possible to identify the residues responsible for the high affinity and selectivity for aldosterone, and to characterize the mechanisms of MR activation and inactivation. The recent determination of the X-ray crystal structures of the LBD of the wild-type MR and MR(S810L), which is responsible for a familial form of hypertension, has made it possible to elucidate the peculiar mechanism of activation of MR(S810L) and established a clear structure/activity relationship for steroidal and non-steroidal MR antagonists. PMID- 21820033 TI - Post-translational modification of the androgen receptor. AB - Regulation of the androgen receptor (AR) by its cognate ligand is well established, but how post-translational modification modulates AR activity is only emerging. The AR is subject to modification by phosphorylation, acetylation, methylation, SUMOylation, and ubiquitination. As several of the enzymes that modify the AR are altered in prostate cancer, defining the context and physiological effects of these modifications could provide insight into mechanisms that underpin human disease. Here, we review how post-translational modification contributes to AR function as a transcription factor with particular emphasis on phosphorylation and dephosphorylation mechanisms. PMID- 21820034 TI - Tissue-specific modulation of mineralocorticoid receptor function by 11beta hydroxysteroid dehydrogenases: an overview. AB - In the last decade significant progress has been made in the understanding of mineralocorticoid receptor (MR) function and its implications for physiology and disease. The knowledge on the essential role of MR in the regulation of electrolyte concentrations and blood pressure has been significantly extended, and the relevance of excessive MR activation in promoting inflammation, fibrosis and heart disease as well as its role in modulating neuronal cell viability and brain function is now widely recognized. Despite considerable progress, the mechanisms of MR function in various cell-types are still poorly understood. Key modulators of MR function include the glucocorticoid receptor (GR), which may affect MR function by formation of heterodimers and by differential genomic and non-genomic responses on gene expression, and 11beta-hydroxysteroid dehydrogenases (11beta-HSDs), which determine the availability of intracellular concentrations of active glucocorticoids. In this review we attempted to provide an overview of the knowledge on MR expression with regard to the presence or absence of GR, 11beta-HSD2 and 11beta-HSD1/hexose-6-phosphate dehydrogenase (H6PDH) in various tissues and cell types. The consequences of cell-specific differences in the coexpression of MR with these proteins need to be further investigated in order to understand the role of this receptor in a given tissue as well as its systemic impact. PMID- 21820035 TI - Inhibition of prolyl oligopeptidase by KYP-2047 fails to increase the extracellular neurotensin and substance P levels in rat striatum. AB - Prolyl oligopeptidase (PREP, EC 3.4.21.26) hydrolyzes neuropeptides, such as neurotensin and substance P in vitro, but its importance in the in vivo metabolism of these peptides has not been proved. This is the first report where intracerebral microdialysis combined with highly sensitive radioimmunoassay has been used to investigate the effect of PREP inhibition on the brain extracellular peptide levels in conscious rats. We show that PREP inhibition by KYP-2047 (50MUmol/kg=17mg/kg, intraperitoneally, that effectively inhibits PREP in the brain), has no effect on the neurotensin and substance P levels in the striatum extracellular space. This provides a further piece of evidence in support of the proposition that PREP is not significantly responsible for the in vivo cleavage of substance P or neurotensin, and that occasional positive cognitive effects associated with some PREP inhibitors are not mediated through elevated extracellular levels of these peptides. Direct regulation of peptide processing by PREP is not likely because the enzyme is located intracellularly and the peptide substrates are mostly extracellular. PMID- 21820036 TI - The role of adrenergic and cholinergic receptors on the antinociception of sildenafil in the spinal cord of rats. AB - The role played by spinal adrenergic and cholinergic receptors in the antinociceptive effects of intrathecal sildenafil in formalin-induced nociception was examined. Intrathecal catheters were inserted into the subarachnoid space of male Sprague-Dawley rats, and nociception was assessed using the formalin test, consisting of a subcutaneous injection of 50MUL of 5% formalin solution into the hind paw. We examined the effects of an alpha 1 adrenergic receptor antagonist (prazosin), an alpha 2 adrenergic receptor antagonist (yohimbine), a muscarinic acetylcholine receptor antagonist (atropine), and a nicotinic acetylcholine receptor antagonist (mecamylamine) on sildenafil-induced antinociception. Intrathecal sildenafil (3, 10, and 30MUg) suppressed, in a dose-dependent manner, formalin-induced flinching during phases 1 and 2 of the test. Intrathecal sildenafil (30MUg) could not show any effects against intrathecal prazosin (3MUg), yohimbine (10MUg), atropine (10MUg), and mecamylamine (10MUg) pretreatment during both phases of the formalin test. These results suggest that intrathecal sildenafil effectively attenuated the pain evoked by formalin injection. Additionally, spinal alpha 1, alpha 2, muscarinic and nicotinic receptors might play a role in sildenafil-induced antinociception. PMID- 21820037 TI - A new human dyskerin isoform with cytoplasmic localization. AB - BACKGROUND: The human DKC1 gene is causative of X-linked dyskeratosis congenita (X-DC), a syndrome characterized by mucocutaneous features, bone marrow failure, tumor susceptibility, perturbation of stem cell function, and premature aging. DKC1 is thought to produce a single protein, named dyskerin, which shows strict nucleolar localization and participates in at least two distinct nuclear functional complexes: the H/ACA small nucleolar ribonucleoproteic complex involved in RNA pseudouridylation and the active telomerase complex. METHODS: By bioinformatics and molecular analyses we identified a DKC1 splice variant able to encode a truncated form of dyskerin, confirmed its active expression in diverse human tissues by RT-PCR, and showed by immunoblotting and immunocytochemistry experiments that it actually encodes a novel protein. Stably transfected clones over-expressing the new isoform were analyzed for growth, morphology and adhesion properties. RESULTS: Our results show that DKC1 encodes a new alternatively spliced mRNA able to direct the synthesis of a variant dyskerin with unexpected cytoplasmic localization. Intriguingly, when over-expressed in HeLa cells, the new isoform promotes cell to cell and cell to substratum adhesion, increases the cell proliferation rate and leads to cytokeratin hyper-expression. CONCLUSIONS AND GENERAL SIGNIFICANCE: Our results highlight a novel degree of complexity and regulation of the human DKC1 gene and reveal that it can play a further, unpredicted role in cell adhesion. The identification of a dyskerin cytoplasmic variant reinforces the view that other mechanisms, in addition to telomere instability, can significantly contribute to the pathogenesis of the X-DC, and suggests that DKC1 nucleolar and cytoplasmic functions might cumulatively account for the plethora of manifestations displayed by this syndrome. PMID- 21820038 TI - Long-term treatment with standardized Ginkgo biloba extract (EGb 761) attenuates cognitive deficits and hippocampal neuron loss in a gerbil model of vascular dementia. AB - The standardized extract of Ginkgo biloba EGb 761 has been used to reduce cognitive dysfunction. The present study was designed to evaluate the effect of postischemic oral treatment with EGb 761 in a model of vascular dementia in gerbils. Daily oral posttreatment with EGb 761 led to a significant recovery of spatial memory assessed by the object location test, inhibited the decrease in plasma SOD activity and protected the hippocampal CA1 neurons, even when administered after the insult. These data provide further evidence for the therapeutic potential of EGb 761 in the treatment of vascular dementia. PMID- 21820039 TI - Allele frequencies of 6 autosomal STR loci in the Xibo nationality with phylogenetic structure among Chinese populations. AB - In the present study, we investigated the genetic polymorphisms of 6 autosomal STR loci Hum-CSF1PO, D13S317, D5S818, D16S539, TH01, and TPOX in the Xibo population of Liaoning, northeastern China as well as its genetic relationships with other populations in China. No significant deviations from Hardy-Weinberg equilibrium could be found for all loci. Allele frequencies in the Xibo population ranged from 0.001 to 0.507. Among all the 6 loci, D16S539 had the highest polymorphism (PIC=0.8632), whereas TPOX had the lowest (PIC=0.5179). A phylogenic tree was constructed using Poptree 2 software. In the phylogenic tree, Xibo population has a distant relationship with the other populations. PMID- 21820040 TI - Identification and expression analysis of a novel transcript of the human PRMT2 gene resulted from alternative polyadenylation in breast cancer. AB - The arginine N-methyltransferase 2 protein (PRMT2, also known as HRMT1L1) is thought to act as a coactivator of ERalpha. The present results show the occurrence of a novel transcript by alternative polyadenylation in the human PRMT2 gene. We demonstrated that the newly identified intron-retaining PRMT2L2 transcript is functionally intact, efficiently translated into protein in vivo. PRMT2 and PRMT2L2 mRNA expression profiles overlap with the distribution of ERalpha, with the strongest abundance in estrogen target tissues. Transient co transfection assays demonstrated that PRMT2L2 enhance ERalpha-mediated transactivation activity of ERE-Luc in a ligand-dependent manner. Confocal microscopy scanning revealed a distinct intra-cellular localization of their fusion proteins, suggesting that the C-terminal region absent in PRMT2L2 is critical for the localization. Statistical analysis further showed that both PRMT2 and PRMT2L2 mRNAexpressions were up-regulated in breast cancer tissues, and significantly associated with ERalpha positivity status. Thus, post transcriptional processing mechanism as alternative polyadenylation and splicing may play a crucial role in regulating human PRMT2 gene expression. PMID- 21820041 TI - Multi-drug delivery to tumor cells via micellar nanocarriers. AB - The aim of this study was to develop micellar nanocarriers for concomitant delivery of paclitaxel and 17-allylamino-17-demethoxygeldanamycin (17-AAG) for cancer therapy. Paclitaxel and 17-AAG were simultaneously loaded into polymeric micelles by a solvent evaporation method. Two candidate nanocarrier constructs, polyethylene glycol-poly(D, L-lactic acid) (PEG-PLA) micelles and PEG distearoylphosphatidylethanolamine/tocopheryl polyethylene glycol 1000 (PEG DSPE/TPGS) mixed micelles, were assessed for the release kinetics of the loaded drugs. Compared to PEG-PLA micelles, entrapment of paclitaxel and 17-AAG into PEG DSPE/TPGS mixed micelles resulted in significantly prolonged release half-lives. The simultaneous incorporation of paclitaxel and 17-AAG into PEG-DSPE/TPGS mixed micelles was confirmed by (1)H NMR analysis. Paclitaxel/17-AAG-loaded PEG DSPE/TPGS mixed micelles were as effective in blocking the proliferation of human ovarian cancer SKOV-3 cells as the combined free drugs. PEG-DSPE/TPGS mixed micelles may provide a novel and advantageous delivery approach for paclitaxel/17 AAG combination therapy. PMID- 21820042 TI - Novel acylated steroidal glycosides from Caralluma tuberculata induce caspase dependent apoptosis in cancer cells. AB - AIM OF THE STUDY: Pregnane glycosides are potent cytotoxic agents which may represent new leads in the development of anti-tumour drugs, particularly in the treatment of breast cancer, because of the structural similarity to estrogenic agonists. Caralluma species are natural sources of a wide variety of pregnane glycosides. The aim of the study was to isolate, using an activity-guided fractionation approach, novel pregnane glycosides for testing on breast cancer and other tumour lines. MATERIALS AND METHODS: The effect of crude extracts, specific organic fractions and isolated compounds from Caralluma tuberculata was tested on the growth and viability of MCF-7 estrogen-dependent, and MDA-MB-468 estrogen-independent breast cancer cells, Caco-2 human colonic cells, HUVECs and U937 cells. Neutral red uptake and MTT assays were used. Apoptosis was detected by Western blot of poly-(ADP ribose) polymerase (PARP) as were other markers of nuclear fragmentation (DNA ladder assay, staining of cells with nuclear dye DAPI). The involvement of caspases was investigated using the pan-caspase inhibitor Z-VAD-FMK. RESULTS: The ethyl acetate fraction of Caralluma tuberculata was found to be the most potent anti-proliferative fraction against all three cancer cell lines. Two novel steroidal glycosides were isolated from the active fraction after a series of chromatographic experiments. The structure of the isolated compounds was elucidated solely based on 2D-NMR (HMBC, HETCOR, DQF-COSY) and MS spectral analysis as compound 1: 12-O-benzoyl-20-O-acetyl 3beta,12beta,14beta,20beta-tetrahydroxy-pregnan-3-ylO-beta-D-glucopyranosyl-(1 >4)-beta-D-glucopyranosyl-(1 -> 4)-3-methoxy-beta-D-ribopyranoside, and as compound 2: 7-O-acetyl-12-O-benzoyl-3beta,7beta,12beta,14beta-tetrahydroxy-17beta (3-methylbutyl-O-acetyl-1-yl)-androstan-3-ylO-beta-D-glucopyranosyl-(1 -> 4)-6 deoxy-beta-D-allopyranosyl-(1 -> 4)-beta-D-cymaropyranosyl-(1 -> 4)-beta-D cymapyranosyl-(1-> 4)-beta-D-cymaropyranoside. Compound 1 (pregnane glycoside) and compound 2 (androstan glycoside) induced apoptosis at <25 MUM after 48 h as assessed by cell shrinkage, PARP cleavage, DNA fragmentation, and reversal with the caspase inhibitor. CONCLUSIONS: Two novel steroid glycosides isolated from Caralluma tuberculata possess moderate, micromolar cytotoxic activity on breast cancer and other cells in vitro, which may indicate a source of activity in vivo of interest to future drug design. PMID- 21820043 TI - Opposing effects of cortisol and dehydroepiandrosterone on the expression of the receptor for Activated C Kinase 1: implications in immunosenescence. AB - Aging is associated to a decline in immune functions that are in part related to a defective protein kinase C dependent signal transduction machinery. RACK-1 (Receptor for Activated C Kinase 1) is a scaffold protein for different kinases and membrane receptors. We have previously demonstrated, in the elderly, a defective PCKbetaII (Protein Kinase C betaII) translocation related to a decrease in RACK-1 protein expression, which is correlated to the age-associated decline in DHEA (dehydroepiandrosterone) levels. As a consequence of this signal transduction impairment, a significant decrease in immune cells functionality was observed. Furthermore, we could demonstrate that in vivo and in vitro DHEA administration restored RACK-1 level and immune functions, indicating that this hormone behaved as a positive RACK-1 regulator. We have most recently characterized the human GNB2L1 promoter region, coding for RACK-1 protein. Although no direct DHEA responsive elements were found, a glucocorticoid responsive element (GRE) was identified. The purpose of this work was to investigate, in the human pro-myelocytic cell line THP-1, whether physiological cortisol concentrations were able to modulate GNB2L1 promoter activity, RACK-1 transcription as well as cytokine production. As DHEA is endowed of anti glucocorticoid properties in several cellular systems, and as cortisol:DHEA ratio imbalance is relevant in aging, we also investigated their possible interaction at the RACK-1 expression level. We could demonstrate that cortisol acted in a dose-related manner as a GNB2L1 promoter repressor, reducing RACK-1 mRNA expression and protein level. Probably by interfering with glucocorticoid receptor binding to GRE sequence, prolonged DHEA exposure counteracted cortisol effects, restoring RACK-1 levels and cytokine production, as assessed by LPS induced TNF-alpha release. PMID- 21820044 TI - Enzymes immobilized on carbon nanotubes. AB - Enzyme immobilizations on carbon nanotubes for fabrication of biosensors and biofuel cells and for preparation of biocatalysts are rapidly emerging as new research areas. Various immobilization methods have been developed, and in particular, specific attachment of enzymes on carbon nanotubes has been an important focus of attention. The method of immobilization has an effect on the preservation of the enzyme structure and retention of the native biological function of the enzyme. In this review, we focus on recent advances in methodology for enzyme immobilization on carbon nanotubes. PMID- 21820045 TI - Measurements using 7.0 T post-mortem magnetic resonance imaging of the scalar dimensions of the fetal brain between 12 and 20 weeks gestational age. AB - In this study, scalar values for the fetal brain from 12 to 20 weeks gestational age were obtained. Fifty-two fetal specimens of 12-20 weeks gestational age with an anatomically normal and developmentally appropriate central nervous system (CNS) were scanned using a 7.0 T magnetic resonance imaging (MRI) scanner. The linear biometric measurements of the brain were then determined. All the measurements (except for the interhemispheric distance) were found to increase linearly with gestational age, although each increased at a different growth rates. The 95% confidence interval for each value was obtained. These data may be considered to be a valuable reference for the assessment of normal fetal brain development in clinical settings and as a supplement to post-mortem MRI or anatomical investigations. PMID- 21820046 TI - Oxidative stress and androgen receptor signaling in the development and progression of castration-resistant prostate cancer. AB - Aberrant androgen receptor (AR) signaling plays a critical role in androgen dependent prostate cancer (PCa), as well as in castration-resistant PCa (CRPC). Oxidative stress seems to contribute to the tumorigenesis and progression of PCa, as well as the development of CRPC, via activation of AR signaling. This notion is supported by the fact that there is an aberrant or improper regulation of the redox status in these disorders. Additionally, androgen-deprivation-induced oxidative stress seems to be involved in the pathogenesis of several disorders caused by androgen-deprivation therapy (ADT), including osteoporosis, neurodegenerative disease, and cardiovascular disease. Oxidative stress can be suppressed with antioxidants or via a reduction in reactive oxygen species production. Thus, developing new therapeutic agents that reduce oxidative stress might be useful in preventing the conversion of androgen-dependent PCa into CRPC, as well as reducing the adverse effects associated with ADT. The objective of this review is to provide an overview regarding the relationship between oxidative stress and AR signaling in the context of PCa and especially CRPC. Additionally, we discuss the potential use of antioxidant therapies in the treatment of PCa. PMID- 21820047 TI - Urinary 8-oxo-7,8-dihydro-2'-deoxyguanosine as a biomarker in type 2 diabetes. AB - The increasing prevalence of diabetes together with the associated morbidity and mortality calls for additional preventive and therapeutic strategies. New biomarkers that can be used in therapy control and risk stratification as alternatives to current methods are needed and can facilitate a more individualized and sufficient treatment of diabetes. Evidence derived from both epidemiological and mechanistic studies suggests that oxidative stress has an important role in mediating the pathologies of diabetic complications. A marker of intracellular oxidative stress that potentially could be used as a valuable biomarker in diabetes is the DNA oxidation marker 8-oxo-7,8-dihydro-2' deoxyguanosine (8-oxodG), which can be assessed noninvasively in the urine, with minimal discomfort for the patient. In this review the analytical validity of 8 oxodG is addressed by highlighting important methodological issues. The available epidemiological evidence regarding urinary 8-oxodG and type 2 diabetes is presented. A possible role for DNA oxidation in cancer development in type 2 diabetes patients is discussed, followed by an evaluation of the potential of urinary 8-oxodG as a clinical biomarker in type 2 diabetes. PMID- 21820048 TI - Role of VPO1, a newly identified heme-containing peroxidase, in ox-LDL induced endothelial cell apoptosis. AB - Myeloperoxidase (MPO) is an important enzyme involved in the genesis and development of atherosclerosis. Vascular peroxidase 1 (VPO1) is a newly discovered member of the peroxidase family that is mainly expressed in vascular endothelial cells and smooth muscle cells and has structural characteristics and biological activity similar to those of MPO. Our specific aims were to explore the effects of VPO1 on endothelial cell apoptosis induced by oxidized low-density lipoprotein (ox-LDL) and the underlying mechanisms. The results showed that ox LDL induced endothelial cell apoptosis and the expression of VPO1 in endothelial cells in a concentration- and time-dependent manner concomitant with increased intracellular reactive oxygen species (ROS) and hypochlorous acid (HOCl) generation, and up-regulated protein expression of the NADPH oxidase gp91(phox) subunit and phosphorylation of p38 MAPK. All these effects of ox-LDL were inhibited by VPO1 gene silencing and NADPH oxidase gp91(phox) subunit gene silencing or by pretreatment with the NADPH oxidase inhibitor apocynin or diphenyliodonium. The p38 MAPK inhibitor SB203580 or the caspase-3 inhibitor DEVD CHO significantly inhibited ox-LDL-induced endothelial cell apoptosis, but had no effect on intracellular ROS and HOCl generation or the expression of NADPH oxidase gp91(phox) subunit or VPO1. Collectively, these findings suggest for the first time that VPO1 plays a critical role in ox-LDL-induced endothelial cell apoptosis and that there is a positive feedback loop between VPO1/HOCl and the now-accepted dogma that the NADPH oxidase/ROS/p38 MAPK/caspase-3 pathway is involved in ox-LDL-induced endothelial cell apoptosis. PMID- 21820049 TI - Gas1 cooperates with Cdo and promotes myogenic differentiation via activation of p38MAPK. AB - Skeletal myogenesis is a multistep process that involves cell cycle exit, expression of muscle-specific genes and formation of multinucleated myotubes. Growth arrest specific gene 1 (Gas1) is a GPI-linked membrane protein and originally identified as a growth arrest-linked gene in fibroblasts. Promyogenic cell surface protein, Cdo functions as a component of multiprotein complexes that include other cell adhesion molecules, like Cadherins to mediate cell contact signaling. Here we report that Gas1 and Cdo are coexpressed in muscle cells and form a complex in differentiating myoblasts. Interestingly, Cdo(-/-) myoblasts display defects in Gas1 induction during differentiation. Overexpression or depletion of Gas1 enhances or decreases myogenic differentiation, respectively. During myoblast differentiation, Gas1 depletion causes defects in downregulation of Cdk2 and Cyclin D1 and up-regulation of miR-322, a negative regulator of Cdk2 activities. Furthermore overexpression or knockdown of Gas1 either enhances or decreases activation of p38MAPK that functions downstream of Cdo. Additionally, Gas1 overexpression in Cdo-depleted C2C12 cells restores p38MAPK activities and differentiation abilities. These data suggest that Gas1 promotes myogenic differentiation through regulation of cell cycle arrest and is critical to activate p38MAPK, most likely via association with Cdo/Cadherin multiprotein complexes. PMID- 21820050 TI - Angiotensin II stimulates in vitro branching morphogenesis of the isolated ureteric bud. AB - Mutations in the renin-angiotensin system (RAS) genes are associated with congenital anomalies of the kidney and urinary tract (CAKUT). As angiotensin (Ang) II, the principal effector peptide growth factor of the RAS, stimulates ureteric bud (UB) branching in whole intact embryonic (E) metanephroi, defects in UB morphogenesis may be causally linked to CAKUT observed under conditions of disrupted RAS. In the present study, using the isolated intact UB (iUB) assay, we tested the hypothesis that Ang II stimulates UB morphogenesis by directly acting on the UB, identified Ang II target genes in the iUB by microarray and examined the effect of Ang II on UB cell migration in vitro. We show that isolated E11.5 mouse iUBs express Ang II AT(1) and AT(2) receptor mRNA. Treatment of E11.5 iUBs grown in collagen matrix gels with Ang II (10(-5)M) increases the number of iUB tips after 48h of culture compared to control (4.8+/-0.4 vs. 2.4+/-0.2, p<0.01). A number of genes required for UB branching as well as novel genes whose role in UB development is currently unknown are targets of Ang II signaling in the iUB. In addition, Ang II increases UB cell migration (346+/-5.1 vs. 275+/-4.4, p<0.01) in vitro. In summary, Ang II stimulates UB cell migration and directly induces morphogenetic response in the iUB. We conclude that Ang II-regulated genes in the iUB may be important mediators of Ang II-induced UB branching. We hypothesize that Ang II-dependent cell movements play an important role in UB branching morphogenesis. PMID- 21820051 TI - A novel application of alpha-glucosyl hesperidin for nanoparticle formation of active pharmaceutical ingredients by dry grinding. AB - The effectiveness of alpha-glucosyl hesperidin (Hsp-G) as a novel grinding aid for the preparation of drug nanoparticles by dry grinding was investigated. Poorly water-soluble drugs and Hsp-G were mixed at a weight ratio of 1/5 and ground for 60 min by a vibrational ball mill. It was evident that all poorly water-soluble drugs used in this study formed nanoparticles after the ground mixtures were dispersed into distilled water. The dissolution profile of glibenclamide from the ground mixtures of glibenclamide/Hsp-G showed dramatic improvement from that of untreated drug crystals. Administration of the ground mixture of glibenclamide/Hsp-G to rats resulted in a significantly higher rate of decrease in blood glucose levels than that of untreated glibenclamide. The area above the time-curve of plasma-glucose concentrations using the ground mixture of glibenclamide/Hsp-G was 6-fold higher than that using untreated glibenclamide. The improved dissolution rate due to nanoparticle formation of glibenclamide, induced by co-grinding with Hsp-G, was responsible for this improvement. PMID- 21820052 TI - Nanocrystals as tool to improve piroxicam dissolution rate in novel orally disintegrating tablets. AB - In this paper, orally disintegrating tablets (ODT) were prepared using nanocrystal formulations in order to optimise dissolution properties of lipophilic, poorly soluble drug piroxicam (PRX). Different nanocrystal formulations were prepared using a high pressure homogenisation technique and poloxamer 188 as stabiliser. Characterisation of PRX nanocrystal ODT was carried out by infrared spectroscopy (FTIR), X-ray powder diffractometry (XRPD), differential scanning calorimetry and photon correlation spectroscopy. Dissolution study of PRX ODT was performed in distilled water (pH 5.5) and was compared to that of PRX coarse suspension ODT, PRX/poloxamer 188 physical mixture and bulk PRX samples. The XRPD and FTIR studies demonstrated that the homogenisation process led to a polymorphic transition from form I (bulk commercial PRX) to form III and monohydrate form of the nanocrystals. All ODT formulations prepared using PRX nanosuspensions showed a higher PRX dissolution rate compared with the ODT prepared with the coarse PRX. Since the solubility of the different PRX polymorphic forms increased only slightly from bulk PRX (form I) to monohydrate, form II and form III, we can conclude that the improvement in PRX dissolution rate is mainly caused by the increased surface-to-volume ratio due to the submicron dimension of the drug particles. PMID- 21820053 TI - The methamphetamine-sensitive circadian oscillator is dysfunctional in a transgenic mouse model of Huntington's disease. AB - A progressive disintegration of the rest-activity rhythm has been observed in the R6/2 mouse model of Huntington's disease (HD). Rest-activity rhythm is controlled by a circadian clock located in the suprachiasmatic nuclei (SCN) of the hypothalamus, although SCN-independent oscillators such as the methamphetamine (MAP)-sensitive circadian oscillator (MASCO) can also control rhythmicity, even in SCN-lesioned animals. We aimed to test whether or not the administration of MAP could restore a normal rest-activity rhythm in R6/2 mice, via the activation of the MASCO. We administered chronic low doses of MAP to wild-type (WT) and presymptomatic (7-8 weeks) R6/2 mice, in constant darkness. As expected, ~40% of the WT mice expressed a rest-activity rhythm controlled by the MASCO, with a period of around 32 h. By contrast, the MASCO was missing from almost 95% of the R6/2 mice, even at early stages of disease. Interestingly, although the MASCO was deficient, initially MAP was able to stabilize the day/night activity ratio in R6/2 mice and delay the onset of disintegration of the rest-activity rhythm driven by the SCN. Furthermore, in presymptomatic R6/2 mice treated with L-DOPA, a MASCO-like component began to emerge, although this never became established. Our data show a major dysfunction of the MASCO in presymptomatic R6/2 mice that is likely to be due to an early abnormality of the catecholaminergic systems. We suggest that the dysfunction of the MASCO in humans could be partially responsible for circadian disturbances observed in HD patients, as well as patients with other neurological diseases in which both catecholaminergic and circadian abnormalities are present, such as Parkinson's disease and schizophrenia. PMID- 21820054 TI - Pre and postsynaptic roles for Drosophila CASK. AB - CASK ('calcium/calmodulin-dependent serine protein kinase'), also known in Drosophila as 'Caki' or 'Camguk/CMG', and in C. elegans as 'Lin-2', is thought to play an important role in cell-cell junction formation and at synapses in particular. To understand the role of CASK in synapse formation and function, we functionally and morphologically analyzed Drosophila embryonic and larval glutamatergic neuromuscular junctions (NMJs) after pan-cellular and tissue specific manipulation of CASK expression. Our results show that Drosophila CASK is associated with both pre and postsynaptic membranes. Loss of presynaptic CASK led to less evoked synaptic transmission, fewer spontaneous synaptic events, and reduced synaptic vesicle cycling. These changes were accompanied by a reduction in the number of synapses but no change in overall NMJ size. Loss of postsynaptic CASK, on the other hand, caused reduced spontaneous synaptic current amplitudes and smaller glutamate-gated currents. These changes were accompanied by loss of postsynaptic glutamate receptors, but the receptor loss was subtype-specific: Only receptors containing GluRIIA subunits were lost in CASK mutants. Receptors containing GluRIIB were unaffected. PMID- 21820056 TI - Expression and purification of a biologically active Phytophthora parasitica cellulose binding elicitor lectin in Pichia pastoris. AB - The Phytophthora parasitica cellulose-binding elicitor lectin, (CBEL), is a cell wall-localized protein playing a key role in cell wall organization and adhesion of the mycelium to cellulosic substrates. CBEL is a potent elicitor of plant immune responses and this activity is linked to its ability to bind plant cell wall components. In order to scale up the production of active CBEL, we reported here the cloning and expression of a His-tagged version of CBEL in the yeast Pichia pastoris. Selection of a high-producing P. pastoris clone and optimization of the purification procedure allowed a yield of about 2mg of pure protein per liter of culture filtrate. The identity of the recombinant protein was confirmed by western-blot analysis, N-terminal protein sequencing, and by peptide mass fingerprinting. The cellulose-binding affinity and the lectin activity of the recombinant protein were identical to the native CBEL. Its elicitor activity, tested on Arabidopsis thaliana leaves, was similar to the native CBEL protein as it displays a similar biological activity on plant immune responses inducing defense gene expression and localized necroses of the infiltrated leaf tissues. The present work suggests that P. pastoris can be a suitable host for the production of compounds active on plants or for the development of new agricultural products able to stimulate plant immunity. PMID- 21820055 TI - Bimolecular Fluorescence Complementation analysis to reveal protein interactions in herpes virus infected cells. AB - Protein interactions are at the basis of all processes in living organisms. In particular, regulatory proteins do not act alone but participate in multifaceted sets of interactions that are organized into complex networks. In herpes simplex virus (HSV-1) infected cells, viral proteins interact with cellular proteins and with other viral proteins to form the protein complexes required for virus production, including transcription complexes, replication complexes and virion assembly complexes. While a number of methods have been developed to investigate protein-protein interactions such as coimmunoprecipitation, GST-binding assays and yeast 2-hybrid analyses, these approaches require removal of the proteins from the cellular environment and do not provide information on the spatial localization of the protein-protein interaction in living cells. The fluorescence based approach Bimolecular Fluorescence Complementation (BiFC) allows direct visualization of the subcellular localization of the protein complex in living cells. In BiFC, two halves of a fluorescent protein are fused to each of two interacting proteins of interest, resulting in nonfluorescent fusion proteins. Interaction of the protein partners tethers the fused fluorescent fragments in close proximity, which facilitates their association and restoration of fluorescence. Two limitations of BiFC are that there is a delay between the time that the interacting proteins associate and fluorescence complex formation and thus complex formation cannot be measured in real-time, and fluorescence complex formation is irreversible in vivo. Despite these limitations, BiFC is a powerful and sensitive approach that can be performed using standard molecular biology and cell culture protocols and a fluorescence microscope. PMID- 21820057 TI - Structural insights into the cofactor-assisted substrate recognition of yeast quinone oxidoreductase Zta1. AB - Quinone oxidoreductase (QOR EC1.6.5.5) catalyzes the reduction of quinone to hydroxyquinone using NADPH as a cofactor. Here we present the crystal structure of the zeta-crystallin-like QOR Zta1 from Saccharomycescerevisiae in apo-form at 2.00 A and complexed with NADPH at 1.59 A resolution. Zta1 forms a homodimer, with each subunit containing a catalytic and a cofactor-binding domain. Upon NADPH binding to the interdomain cleft, the two domains shift towards each other, producing a better fit for NADPH, and tightening substrate binding. Computational simulation combined with site-directed mutagenesis and enzymatic activity analysis defined a potential quinone-binding site that determines the stringent substrate specificity. Moreover, multiple-sequence alignment and kinetics assays implied that a single-residue change from Arg in lower organisms to Gly in vertebrates possibly resulted in elevation of enzymatic activity of zeta crystallin-like QORs throughout evolution. PMID- 21820058 TI - Structure and dynamics of the kinase IKK-beta--A key regulator of the NF-kappa B transcription factor. AB - The inhibitor kappaB kinase-beta (IKK-beta) phosphorylates the NF-kappaB inhibitor protein IkappaB leading to the translocation of the transcription factor NF-kappaB to the nucleus. The transcription factor NF-kappaB and consequently IKK-beta are central to signal transduction pathways of mammalian cells. The purpose of this research was to develop a 3D structural model of the IKK-beta kinase domain with its ATP cofactor and investigate its dynamics and ligand binding potential. Through a combination of comparative modelling and simulated heating/annealing molecular dynamics (SAMD) simulation in explicit water the model accuracy could be substantially improved compared to comparative modelling on its own as shown by model validation measures. The structure revealed the details of ATP/Mg(2+) binding indicating hydrophobic interactions with the adenine base and a significant contribution of Mg(2+) as a bridge between ATP phosphate groups and negatively charged side chains. The molecular dynamics trajectories of the ATP-bound and free enzyme showed two conformations in each case, which contributed to the majority of the trajectory. The ATP-free enzyme revealed a novel binding site distant from the ATP binding site that was not encountered in the ATP bound enzyme. Based on the overall structural flexibility, it is suggested that a truncated version of the kinase domain from Ala14 to Leu265 should be subjected to crystallisation trials. The 3D structure of this enzyme will enable rational design of new ligands and analysis of protein protein interactions. Furthermore, our results may provide a new impetus for wet lab based structural investigation focussing on a truncated kinase domain. PMID- 21820059 TI - Dietary administration of a Gracilaria tenuistipitata extract enhances the immune response and resistance against Vibrio alginolyticus and white spot syndrome virus in the white shrimp Litopenaeus vannamei. AB - The haemogram, phenoloxidase (PO) activity, respiratory bursts (RBs), superoxide dismutase (SOD) activity, glutathione peroxidase (GPx) activity, lysozyme activity, and the mitotic index of haematopoietic tissue (HPT) were examined after the white shrimp Litopenaeus vannamei had been fed diets containing the hot water extract of Gracilaria tenuistipitata at 0 (control), 0.5, 1.0, and 2.0 g kg(-1) for 7-35 days. Results indicated that these parameters directly increased with the amount of extract and time, but slightly decreased after 35 days. RBs, SOD activity, and GPx activity reached the highest levels after 14 days, whereas PO and lysozyme activities reached the highest levels after 28 days. In a separate experiment, white shrimp L. vannamei, which had been fed diets containing the extract for 14 days, were challenged with Vibrio alginolyticus at 2 * 10(6) cfu shrimp(-1) and white spot syndrome virus (WSSV) at 1 * 10(3) copies shrimp(-1), and then placed in seawater. The survival rate of shrimp fed the extract-containing diets was significantly higher than that of shrimp fed the control diet at 72-144 h post-challenge. We concluded that dietary administration of the G. tenuistipitata extract at <=1.0 g kg(-1) could enhance the innate immunity within 14 days as evidenced by the increases in immune parameters and mitotic index of HPT in shrimp and their enhanced resistance against V. alginolyticus and WSSV infections. Shrimp fed the extract-containing diets showed a higher and continuous increase in the humoral response indicating its persistent role in innate immunity. PMID- 21820060 TI - Inter-individual variation in blood pressure is associated with regional white matter integrity in generally healthy older adults. AB - Prior studies have documented a range of brain changes that occur as a result of healthy aging as well as neural alterations due to profound dysregulation in vascular health such as extreme hypertension, cerebrovascular disease and stroke. In contrast, little information exists about the more transitionary state between the normal and abnormal physiology that contributes to vascular disease and cognitive decline. Specifically, little information exists with regard to the influence of systemic vascular physiology on brain tissue structure in older individuals with low risk for cerebrovascular disease and with no evidence of cognitive impairment. We examined the association between resting blood pressure and diffusion tensor imaging (DTI) indices of white matter microstructure in 128 healthy older adults (43-87 years) spanning the normotensive to moderate-severe hypertensive range. Mean arterial blood pressure (MABP) was related to diffusion measures in several regions of the brain with greatest associations in the anterior corpus callosum and lateral frontal, precentral, superior frontal, lateral parietal and precuneus white matter. Associations between white matter integrity and blood pressure remained when controlling for age, when controlling for white matter lesions, and when limiting the analyses to only normotensive, pharmacologically controlled and pre-hypertensive individuals. Of the diffusion measures examined, associations were strongest between MABP and radial diffusivity which may indicate that blood pressure has an influence on myelin structure. Associations between MABP and white matter integrity followed spatial patterns resembling those often attributed to the effects of chronological age, suggesting that systemic cerebrovascular health may play a role in neural tissue degeneration classically ascribed to aging. These results demonstrate the importance of the consideration of vascular physiology in studies of cognitive and neural aging, and that this significance extends to even the normotensive and medically controlled population. These data additionally suggest that optimal management of blood pressure may require consideration of the more subtle influence of vascular health on neural health in addition to the primary goal of prevention of a major cerebrovascular event. PMID- 21820061 TI - Fast high-resolution brain imaging with balanced SSFP: Interpretation of quantitative magnetization transfer towards simple MTR. AB - Magnetization transfer (MT) reflects the exchange of magnetization between protons bound to macromolecules, such as lipids and proteins, and protons in free liquid, and thus might be an early marker for subtle and undetermined pathologic changes in tissue. Detailed analysis of the entire MT phenomenon, however, commonly requires extensive data acquisition and scanning time, and hence is only of limited clinical interest. Therefore, in practice, magnetization transfer effects are commonly confined into a simple ratio measure, the so-called magnetization transfer ratio (MTR), calculated from a MT-weighted and a non-MT weighted image. However, subtle physiologic and pathologic changes in tissue, invaluable for specific diagnostic imaging, may be lost since MTR-values depend not only on quantitative magnetization transfer (qMT) parameters but also on sequence parameters and relaxation properties. In order to evaluate and assess the diagnostic specificity of MTR versus qMT, high-resolution whole brain MT data was collected from twelve healthy volunteers using balanced steady-state free precession (bSSFP). In contrast to common MT imaging based on spoiled gradient echo (SPGR) sequences, whole brain qMT imaging can be performed with MT sensitized bSSFP within a clinically feasible acquisition time. Hence, MT sensitized bSSFP provides access to both MTR and qMT parameters within a clinical setting. The reliability and possible diagnostic value of MTR are analyzed for twelve white matter (WM) and eleven gray matter (GM) structures of the normal appearing brain. Strong correlations were found within and between longitudinal and transverse relaxation times (T1, T2) and MT parameters (ratio between macromolecular and water protons, F, and magnetization exchange rate, kf), whereas weaker correlations were observed between MTR-values and relaxation times or MT parameters. Structures with highly similar MTR-values, such as the crus cerebri and the anterior commissure in the WM, or the pallidum and the amygdala in the GM, however, were also found that showed significant differences in most quantitative parameters. This observation was confirmed from simulations revealing that the overall effect on MTR from an increase (decrease) in relaxation times may be counterbalanced with a decrease (increase) in MT parameters. These findings corroborate the expectation that qMT is superior to MTR imaging, especially for the evaluation and assessment of pathologic or physiological changes in healthy and pathologic brain tissue. PMID- 21820062 TI - DCM for complex-valued data: cross-spectra, coherence and phase-delays. AB - This note describes an extension of Bayesian model inversion procedures for the Dynamic Causal Modeling (DCM) of complex-valued data. Modeling complex data can be particularly useful in the analysis of multivariate ergodic (stationary) time series. We illustrate this with a generalization of DCM for steady-state responses that models both the real and imaginary parts of sample cross-spectra. DCM allows one to infer underlying biophysical parameters generating data (like synaptic time constants, connection strengths and conduction delays). Because transfer functions and complex cross-spectra can be generated from these parameters, one can also describe the implicit system architecture in terms of conventional (linear systems) measures; like coherence, phase-delay or cross correlation functions. Crucially, these measures can be derived in both sensor and source-space. In other words, one can examine the cross-correlation or phase delay functions between hidden neuronal sources using non-invasive data and relate these functions to synaptic parameters and neuronal conduction delays. We illustrate these points using local field potential recordings from the subthalamic nucleus and globus pallidus, with a special focus on the relationship between conduction delays and the ensuing phase relationships and cross correlation time lags between population activities. PMID- 21820063 TI - Abnormal subcortical deep-gray matter susceptibility-weighted imaging filtered phase measurements in patients with multiple sclerosis: a case-control study. AB - OBJECTIVE: To investigate abnormal phase on susceptibility-weighted imaging (SWI) filtered phase images indicative of iron content, in subcortical deep-gray matter (SDGM) of multiple sclerosis (MS) patients and healthy controls (HC), and to explore its relationship with MRI outcomes. METHODS: 169 relapsing-remitting (RR) and 64 secondary-progressive (SP) MS patients, and 126 age- and sex-matched HC were imaged on a 3T scanner. Mean phase of the abnormal phase tissue (MP-APT), normal phase tissue volume (NPTV) and normalized volume were determined for total SDGM, caudate, putamen, globus pallidus, thalamus, pulvinar nucleus of thalamus (PVN), hippocampus, amygdala, nucleus accumbens, red nucleus and substantia nigra. 63 HC were used for establishment of normal reference phase values, while additional 63 HC were used for blinded comparisons with MS patients. RESULTS: Increased MP-APT, decreased normalized volume and decreased NPTV were detected in total SDGM, caudate, putamen, globus pallidus, thalamus and PVN in MS patients compared to HC (p<.0004). MS patients also showed decreased volume in hippocampus (<.0001) and decreased NPTV in the hippocampus, amygdala and accumbens (<.0004). SPMS patients had increased MP-APT, decreased volume and decreased NPTV in total SDGM, caudate and amygdala compared to RRMS (p<.005), while individual measure differences were also detected in putamen, thalamus, hippocampus and accumbens (p<.006). RRMS patients showed a significant relationship between increased MP APT and increased lesion burden and more advanced brain atrophy (p<.004). CONCLUSIONS: Abnormal phase, indicative of higher iron content was significantly increased in MS patients compared to HC, and was related to more severe lesion burden and brain atrophy. PMID- 21820064 TI - Effects of subjective preference of colors on attention-related occipital theta oscillations. AB - Human daily behaviors are often affected by subjective preferences. Studies have shown that physical responses are affected by unconscious preferences before conscious decision making. Accordingly, attention-related neural activities could be influenced by unconscious preferences. However, few neurological data exist on the relationship between visual attention and subjective preference. To address this issue, we focused on lateralization during visual attention and investigated the effects of subjective color preferences on visual attention-related brain activities. We recorded electroencephalograph (EEG) data during a preference judgment task that required 19 participants to choose their preferred color from 2 colors simultaneously presented to the right and left hemifields. In addition, to identify oscillatory activity during visual attention, we conducted a control experiment in which the participants focused on either the right or the left color without stating their preference. The EEG results showed enhanced theta (4 6 Hz) and decreased alpha (10-12 Hz) activities in the right and left occipital electrodes when the participants focused on the color in the opposite hemifield. Occipital theta synchronizations also increased contralaterally to the hemifield to which the preferred color was presented, whereas the alpha desynchronizations showed no lateralization. The contralateral occipital theta activity lasted longer than the ipsilateral occipital theta activity. Interestingly, theta lateralization was observed even when the preferred color was presented to the unattended side in the control experiment, revealing the strength of the preference-related theta-modulation effect irrespective of visual attention. These results indicate that subjective preferences modulate visual attention related brain activities. PMID- 21820066 TI - Mitogenome rearrangement in the cold-water scleractinian coral Lophelia pertusa (Cnidaria, Anthozoa) involves a long-term evolving group I intron. AB - Group I introns are genetic insertion elements that invade host genomes in a wide range of organisms. In metazoans, however, group I introns are extremely rare, so far only identified within mitogenomes of hexacorals and some sponges. We sequenced the complete mitogenome of the cold-water scleractinian coral Lophelia pertusa, the dominating deep sea reef-building coral species in the North Atlantic Ocean. The mitogenome (16,150 bp) has the same gene content but organized in a unique gene order compared to that of other known scleractinian corals. A complex group I intron (6460 bp) inserted in the ND5 gene (position 717) was found to host seven essential mitochondrial protein genes and one ribosomal RNA gene. Phylogenetic analysis supports a vertical inheritance pattern of the ND5-717 intron among hexacoral mitogenomes with no examples of intron loss. Structural assessments of the Lophelia intron revealed an unusual organization that lacks the universally conserved omegaG at the 3' end, as well as a highly compact RNA core structure with overlapping ribozyme and protein coding capacities. Based on phylogenetic and structural analyses we reconstructed the evolutionary history of ND5-717, from its ancestral protist origin, through intron loss in some early metazoan lineages, and into a compulsory feature with functional implications in hexacorals. PMID- 21820065 TI - Registration of longitudinal brain image sequences with implicit template and spatial-temporal heuristics. AB - Accurate measurement of longitudinal changes of brain structures and functions is very important but challenging in many clinical studies. Also, across-subject comparison of longitudinal changes is critical in identifying disease-related changes. In this paper, we propose a novel method to meet these two requirements by simultaneously registering sets of longitudinal image sequences of different subjects to the common space, without assuming any explicit template. Specifically, our goal is to 1) consistently measure the longitudinal changes from a longitudinal image sequence of each subject, and 2) jointly align all image sequences of different subjects to a hidden common space. To achieve these two goals, we first introduce a set of temporal fiber bundles to explore the spatial-temporal behavior of anatomical changes in each longitudinal image sequence. Then, a probabilistic model is built upon the temporal fibers to characterize both spatial smoothness and temporal continuity. Finally, the transformation fields that connect each time-point image of each subject to the common space are simultaneously estimated by the expectation maximization (EM) approach, via the maximum a posterior (MAP) estimation of the probabilistic models. Promising results have been obtained in quantitative measurement of longitudinal brain changes, i.e., hippocampus volume changes, showing better performance than those obtained by either the pairwise or the groupwise only registration methods. PMID- 21820067 TI - Clinically applied CT arthrography to measure the sulphated glycosaminoglycan content of cartilage. AB - OBJECTIVE: Similar to delayed gadolinium enhanced MRI of cartilage, it might be possible to image cartilage quality using CT arthrography (CTa). This study assessed the potential of CTa as a clinically applicable tool to evaluate cartilage quality in terms of sulphated glycosaminoglycan content (sGAG) and structural composition of the extra-cellular matrix (ECM). METHODS: Eleven human cadaveric knee joints were scanned on a clinical CT scanner. Of each knee joint, a regular non-contrast CT (ncCT) and an ioxaglate injected CTa scan were performed. Mean X-ray attenuation of both scans was compared to identify contrast influx in seven anatomical regions of interest (ROIs). All ROIs were rescanned with contrast-enhanced MUCT, which served as the reference standard for sGAG content. Mean X-ray attenuation from both ncCT and CTa were correlated with MUCT results and analyzed with linear regression. Additionally, residual values from the linear fit between ncCT and MUCT were used as a covariate measure to identify the influence of structural composition of cartilage ECM on contrast diffusion into cartilage in CTa scans. RESULTS: CTa resulted in higher X-ray attenuation in cartilage compared to ncCT scans for all anatomical regions. Furthermore, CTa correlated excellent with reference MUCT values (sGAG) (R=0.86; R(2)=0.73; P<0.0001). When corrected for structural composition of cartilage ECM, this correlation improved substantially (R=0.95; R(2)=0.90; P<0.0001). CONCLUSIONS: Contrast diffusion into articular cartilage detected with CTa correlates with sGAG content and to a lesser extent with structural composition of cartilage ECM. CTa may be clinically applicable to quantitatively measure the quality of articular cartilage. PMID- 21820068 TI - Gene expression and cell differentiation in matrix-associated chondrocyte transplantation grafts: a comparative study. AB - OBJECTIVE: Although scaffold composition and architecture are considered to be important parameters for tissue engineering, their influence on gene expression and cell differentiation is rarely investigated in scaffolds used for matrix associated autologous chondrocyte transplantation (MACT). In this study we have therefore comparatively analyzed the gene expression of important chondrogenic markers in four clinical applied cell-graft systems with very different scaffold characteristics. METHODS: Residuals (n=165) of four different transplant types (MACI(r), Hyalograft(r)C, CaReS(r) and Novocart(r)3D) were collected during surgery and analyzed for Col1, Col2, aggrecan, versican, melanoma inhibitory activity (MIA) and IL-1beta by real-time PCR. Scaffold and cell morphology were evaluated by histology and electron microscopy. RESULTS: Despite the cultivation on 3D scaffolds, the cell differentiation on all transplant types didn't reach the levels of native cartilage. Gene expression highly differed between the transplant types. The highest differentiation of cells (Col2/Col1 ratio) was found in CaReS(r), followed by Novocart(r)3D, Hyalograft(r)C and MACI(r). IL 1beta expression also exhibited high differences between the scaffolds showing low expression levels in Novocart(r)3D and CaReS(r) and higher expression levels in MACI(r) and Hyalograft(r)C. CONCLUSIONS: Our data indicate that scaffold characteristics as well as culture conditions highly influence gene expression in cartilage transplants and that these parameters may have profound impact on the tissue regeneration after MACT. PMID- 21820069 TI - Improving subchondral bone integrity reduces progression of cartilage damage in experimental osteoarthritis preceded by osteoporosis. AB - PURPOSE: Impairment of subchondral bone density and quality aggravates cartilage damage in osteoarthritis (OA). Accordingly, we assessed whether improving microstructure and quality at subchondral bone by the bone-forming agent parathyroid hormone (PTH) [1-34] prevent cartilage damage progression in a rabbit model of OA preceded by osteoporosis (OP). METHODS: OP was induced in 20 female rabbits. At week 7, these rabbits underwent knee surgery to induce OA and, at week 12, they started either saline vehicle (n=10) or PTH (n=10) for 10 weeks. Ten healthy animals were used as controls. At week 22, microstructure was assessed by micro-computed tomography and bone remodelling by protein expression of alkaline phosphatase (ALP), metalloproteinase-9 (MMP9), osteoprotegerin (OPG) and receptor activator of nuclear factor-kappaB ligand (RANKL) at subchondral bone. Cartilage damage was evaluated using Mankin score. RESULTS: PTH reversed the decrease of bone area/tissue area, trabecular thickness, plate thickness, polar moment of inertia, ALP expression and OPG/RANKL ratio, as well as counteracted the increase of fractal dimension and MMP9 expression at subchondral bone of osteoarthritis preceded by osteoporosis (OPOA) rabbits compared to vehicle administration (P<0.05). Likewise, PTH decreased cartilage damage severity in OPOA rabbits. Good correlations were observed between subchondral bone structure or remodelling parameters, and cartilage Mankin score. CONCLUSIONS: Improvement of microstructural and remodelling parameters at subchondral bone by PTH [1-34] contributed to prevent cartilage damage progression in rabbits with early OPOA. These findings support the role of subchondral bone in OA. Further studies are warranted to establish the place of bone-forming agents as potential treatment in OA. PMID- 21820070 TI - Application of the systematic "DAmP" approach to create a partially defective C. albicans mutant. AB - An understanding of gene function often relies upon creating multiple kinds of alleles. Functional analysis in Candida albicans, a major fungal pathogen, has generally included characterization of mutant strains with insertion or deletion alleles and over-expression alleles. Here we use in C. albicans another type of allele that has been employed effectively in the model yeast Saccharomyces cerevisiae, a "Decreased Abundance by mRNA Perturbation" (DAmP) allele (Yan et al., 2008). DAmP alleles are created systematically through replacement of 30 noncoding regions with nonfunctional heterologous sequences, and thus are broadly applicable. We used a DAmP allele to probe the function of Sun41, a surface protein with roles in cell wall integrity, cell-cell adherence, hyphal formation, and biofilm formation that has been suggested as a possible therapeutic target (Firon et al., 2007; Hiller et al., 2007; Norice et al., 2007). A SUN41-DAmP allele results in approximately 10-fold reduced levels of SUN41 RNA, and yields intermediate phenotypes in most assays. We report that a sun41Delta/Delta mutant is defective in biofilm formation in vivo, and that the SUN41-DAmP allele complements that defect. This finding argues that Sun41 may not be an ideal therapeutic target for biofilm inhibition, since a 90% decrease in activity has little effect on biofilm formation in vivo. We anticipate that DAmP alleles of C. albicans genes will be informative for analysis of other prospective drug targets, including essential genes. PMID- 21820071 TI - S-Nitroso-N-acetylcysteine induces de-differentiation of activated hepatic stellate cells and promotes antifibrotic effects in vitro. AB - Nitric oxide (NO) has been shown to act as a potent antifibrogenic agent by decreasing myofibroblast differentiation. S-Nitroso-N-acetylcysteine (SNAC), a NO donor, attenuates liver fibrosis in rats, but the cellular and molecular mechanisms on liver myofibroblast-like phenotype still remain unknown. Here, we investigate the antifibrotic effects of SNAC on hepatic stellate cells, the major fibrogenic cell type in the liver. A murine GRX cell line was incubated with SNAC (100MUM) or vehicle (control group) for 72h. Cell viability was measured by MTT colorimetric assay and the conversion of myofibroblast into quiescent fat-storing cell phenotype was evaluated by Oil-Red-O staining. TGFbeta-1, TIMP-1, and MMP-13 levels were measure in the supernatant by ELISA. Profibrogenic- and fibrolytic related gene expression was quantified using real-time qPCR. SNAC induced phenotype conversion of myofibroblast-like phenotype into quiescent cells. SNAC decreased gene and protein expression of TGFbeta-1 and MMP-2 compared to control groups. Besides, SNAC down-regulated profibrogenic molecules and up-regulated MMP 13 gene expression, which plays a key role in the degradation of interstitial collagen in liver fibrosis. In conclusion, these findings demonstrate that SNAC efficiently can modulate the activation and functionality of murine hepatic stellate cells and could be considered as an antifibrotic treatment to human liver fibrosis. PMID- 21820074 TI - Humic acid enhances cigarette smoke-induced lung emphysema in mice and IL-8 release of human monocytes. AB - Tobacco smoke is the main factor in the etiology of lung emphysema. Generally prolonged, substantial exposure is required to develop the disease. Humic acid is a major component of cigarette smoke that accumulates in smokers' lungs over time and induces tissue damage. OBJECTIVES: To investigate whether humic acid pre loading potentiates the development of cigarette smoke-induced lung emphysema in mice and increases IL-8 release by human monocytes. METHODS: C57BL/6J mice received humic acid or aqueous vehicle by tracheal installation on day 0 and day 7. From day 21 to day 84, the mice were exposed to cigarette smoke or clean air for 5 days/week. Twenty-four hours after the last exposure we determined leukocytes in lung lavage, heart hypertrophy and alveolar wall destruction. Human monocytes were incubated with cigarette smoke extract (CSE), humic acid or the combination overnight. RESULTS: Humic acid nor cigarette smoke caused alveolar wall destruction within two months. Interestingly, the combination did induce lung emphysema. Humic acid, cigarette smoke or the combination did not change leukocyte types and numbers in lung lavage fluid, but the combination caused peribronchiolar and perivascular lymphocyte infiltration. Humic acid treatment resulted in a high proportion of alveolar macrophages heavily loaded with intracellular granula. Humic acid also induces the release of IL-8 from human monocytes and enhances the CSE-induced IL-8 release. CONCLUSIONS: Humic acid deposition in the lungs potentiates the development of cigarette smoke-induced interstitial inflammation and lung emphysema. Moreover, humic acid promotes IL-8 release from human monocytes. Since humic acid accumulates steadily in the lungs of smokers, this may provide an explanation for the natural history on late onset of this disease. The model described here offers a novel way to study emphysema and may direct the search for new therapeutic approaches. PMID- 21820073 TI - 17beta-Estradiol administration attenuates seawater aspiration-induced acute lung injury in rats. AB - There is very little evidence on the value of administering estrogen in cases of seawater drowning which can induce acute lung injury/acute respiratory distress syndrome (ALI/ARDS). Therefore, this study aimed to investigate whether 17beta estradiol (E2) treatment can attenuate seawater aspiration-induced ALI in rats. In the experiment, ALI was induced by endotracheal instillation of seawater (4mL/kg) and the rats were then given intraperitoneal injection of E2 (5mg/kg) 20min after seawater instillation. Finally, the changes of arterial blood gases which contained hydrogen ion concentration (pH), arterial oxygen tension (PaO(2)) and arterial carbon dioxide tension (PaCO(2)) were measured and the measurement of extravascular lung water (EVLW) was observed. The pulmonary histological changes were evaluated by hematoxylin-eosin stain. The expression of aquaporins (AQPs) 1, AQP5, and estrogen receptor-beta (ERbeta) was measured by western blotting and immunohistochemical methods. The results showed that compared with normal saline water, seawater aspiration induced more serious ALI in rats which was markedly alleviated by E2 treatment. Meanwhile, the ERbeta in lung tissues was activated after E2 administration. The seawater aspiration group also presented with severe pulmonary edema which was paralleled with over expressed AQP1 and AQP5. However, the up-regulation of AQP1 and AQP5 was suppressed by the administration of E2, resulting in an attenuation of lung edema. In conclusion, E2 treatment could effectively attenuate seawater aspiration-induced acute lung injury in rats by the down-regulation of AQP1 and AQP5. PMID- 21820075 TI - Is water uptake by reptilian eggs regulated by physiological processes of embryos or a passive hydraulic response to developmental environments? AB - Moisture availability is critical for successful embryonic development in many organisms. In most oviparous reptiles, for example, water exchange between eggs and the surrounding environment can have substantial fitness consequences, but regulation of this process is unclear. Here, we evaluate whether water uptake by eggs of the lizard Anolis sagrei is regulated by the presence of a live embryo or is a passive hydraulic response to substrate moisture conditions. Many eggs laid in our captive colony were infertile or contained embryos that died during early stages of development, yet these 'dead' eggs continued to gain mass similar to that of 'live' eggs at least during the first half of incubation. Our results suggest that water uptake by eggs is largely a passive hydraulic process during the first half of incubation, but active regulation by embryos may be necessary during latter stages. Maternal effects (e.g., deposition of salts into yolk) could influence this passive process during early incubation. PMID- 21820072 TI - The role of nitric oxide in prostaglandin biology; update. AB - The biosynthesis of nitric oxide (NO) and prostaglandin share many similarities. Two major forms of nitric oxide synthase (NOS) and cyclooxygenase (COX) have been identified: constitutive versus inducible. In general, the constitutive form functions in housekeeping and physiologic roles whereas the inducible form is up regulated by mitogenic or inflammatory stimuli and is responsible for pathophysiological responses. The cross talk between the COX and NOS pathways was initially reported in 1993 and since then, numerous studies have been undertaken to delineate the functional consequences of this interaction as well as the potential mechanism by which each pathway interacts. This review will focus in particular on recent advances in this field that extend our understanding of these two pathways under various systems. PMID- 21820076 TI - Oxygen-deficient metabolism and corneal edema. AB - Wear of low-oxygen-transmissible soft contact lenses swells the cornea significantly, even during open eye. Although oxygen-deficient corneal edema is well-documented, a self-consistent quantitative prediction based on the underlying metabolic reactions is not available. We present a biochemical description of the human cornea that quantifies hypoxic swelling through the coupled transport of water, salt, and respiratory metabolites. Aerobic and anaerobic consumption of glucose, as well as acidosis and pH buffering, are incorporated in a seven-layer corneal model (anterior chamber, endothelium, stroma, epithelium, postlens tear film, contact lens, and prelens tear film). Corneal swelling is predicted from coupled transport of water, dissolved salts, and especially metabolites, along with membrane-transport resistances at the endothelium and epithelium. At the endothelium, the Na+/K+ - ATPase electrogenic channel actively transports bicarbonate ion from the stroma into the anterior chamber. As captured by the Kedem-Katchalsky membrane-transport formalism, the active bicarbonate-ion flux provides the driving force for corneal fluid pump-out needed to match the leak-in tendency of the stroma. Increased lactate-ion production during hypoxia osmotically lowers the pump-out rate requiring the stroma to swell to higher water content. Concentration profiles are predicted for glucose, water, oxygen, carbon dioxide, and hydronium, lactate, bicarbonate, sodium, and chloride ions, along with electrostatic potential and pressure profiles. Although the active bicarbonate-ion pump at the endothelium drives bicarbonate into the aqueous humor, we find a net flux of bicarbonate ion into the cornea that safeguards against acidosis. For the first time, we predict corneal swelling upon soft-contact-lens wear from fundamental biophysico-chemical principles. We also successfully predict that hypertonic tear alleviates contact lens-induced edema. PMID- 21820077 TI - Streptozotocin-induced diabetes affects in rat liver citrate carrier gene expression by transcriptional and posttranscriptional mechanisms. AB - Citrate carrier (CiC), also known as tricarboxylate carrier, is an integral protein of the mitochondrial inner membrane. It is an essential component of the shuttle system by which mitochondrial acetyl-CoA, primer for both fatty acid and cholesterol synthesis, is transported into the cytosol, where lipogenesis occurs. Here, we report the effect of streptozotocin-induced diabetes on the activity and expression of CiC in rat liver mitochondria. A significant reduction of CiC activity and a parallel decline in the abundance of CiC mRNA were found in liver from diabetic rats. Diabetes did not influence CiC mRNA stability, whereas nuclear run-on assay revealed that the transcriptional rate of CiC mRNA decreased, when compared to control, in the nuclei from diabetic rats. The ratio of mature to precursor CiC RNA decreased in diabetic animals, indicating that the splicing of CiC RNA was also affected. The 3'-end processing rate of CiC mRNA was not altered in diabetes. These results suggest that diabetes affects CiC expression at both transcriptional and posttranscriptional levels. In addition, by in vitro transfection experiments in rat hepatocytes cultured in the absence of insulin, a reduction of CiC promoter activity was observed, and this was ascribed to a decreased expression of sterol regulatory element-binding protein-1 transcriptional factor. Furthermore, the binding of sterol regulatory element binding protein-1 to the CiC promoter was reduced in STZ-diabetic rats with respect to control ones, and it was restored to the control values after insulin treatment. PMID- 21820078 TI - Quercetin protects human-derived liver cells against mercury-induced DNA-damage and alterations of the redox status. AB - Aim of this study was to investigate the cytotoxic and genotoxic properties of inorganic and organic mercury compounds, i.e., HgCl(2) and methylmercury (MeHg). In addition, the DNA-protective and antioxidant effects of the flavonoid quercetin (QC) were studied. All experiments were conducted with human-derived liver cells (HepG2), which possess antioxidant and drug-metabolizing enzymes in an inducible form. 8-Hydroxydeoxyguanosine (8-OHdG) and comet formation were monitored as endpoints of DNA damage. The impact of the metal compounds on the redox status was also investigated, since it is assumed that their toxic effects are due to oxidative damage. A number of biochemical parameters related to oxidative stress, namely glutathione, malondialdehyde, protein carbonyl and formation of reactive oxygen species (ROS) were measured after treatment of the cells with the mercury compounds in the presence and absence of quercetin. To elucidate the mechanisms that underlie the effects of QC, three protocols (pre-, simultaneous and post-treatment) were used. Both mercury compounds (range 0.1 5.0MUM) caused induction of DNA migration and formation of 8-OHdG. In combination with the flavonoid (range 0.1-5.0MUM), DNA-protective effects of QC were observed after pre- and simultaneous treatment but not when the flavonoid was added after treatment with the metal compounds. Exposure to the metal compounds led also to substantial changes of all parameters of the redox status and co-treatment experiments with QC showed that these alterations are reversed by the flavonoid. Taken together, the results of our experiments indicate that these two mercury compounds cause DNA damage and oxidative stress in human-derived liver cells and that the flavonoid reduces these effects. Since the concentrations of the metals and of the flavonoids used in the present work reflect human exposure, our findings can be taken as an indication that QC may protect humans against the adverse effects caused by the metal. PMID- 21820079 TI - Analysis of the effectiveness of control measures against Schistosoma mekongi using an intra- and inter-village model in Champasak Province, Lao PDR. AB - Schistosomiasis mekongi is prevalent in the Khong district of Lao PDR, made up of one big island, Khong, and numerous small islands in the Mekong River. Schistosoma mekongi is spread by Neotricula aperta as the intermediate host along the Mekong River. Therefore, even if an epidemic of S. mekongi were stamped out in a certain village, infection may recur if the source of infection is a village located in the upper reaches of the Mekong River. The purpose of this study was to construct a mathematical model for the transmission of S. mekongi among villages from the upper to lower Mekong River to estimate the effect of control measures against it. The chief characteristic of the present model is competence in dealing with the spread of infection among villages through the Mekong River in consideration of the reduction in longevity of cercariae and miracidia and their diffusion in the river. The model also takes into account seasonal fluctuation in the water level of the Mekong River, which affects human behavior in terms of water contact. The results of simulations indicated that the prevalence of schistosomiasis mekongi would be suppressed to a low level for a long time in a village further downstream when universal mass treatment is performed in villages further upstream simultaneously. PMID- 21820080 TI - Cyst formation, increased anti-inflammatory cytokines and expression of chemokines support for Clonorchis sinensis infection in FVB mice. AB - To verify the hypothesis that different pathology of Clonorchis sinensis infection by mouse strains is determined by different responses of cytokines and chemokines, we compared those responses of FVB with those of BALB/c mice. All of FVB mice infected with 30 metacercariae of C. sinensis showed cystic dilatation in the liver, whereas infected BALB/c mice did not. Mature worms were recovered from 19 of 20 liver sections of FVB mice while only one of 20 sections of BALB/c mice revealed a mature worm. In both strains the proportion of CD4(+) T cells was lower in C. sinensis-infected than in the uninfected group. However, the proportion of CD8(+) T cells was elevated in C. sinensis-infected from both strains compared to uninfected mice. The Th2-associated anti-inflammatory cytokines such as IL-4, IL-5 and IL-13, IL-10 and TGF-beta, were significantly more produced by the lymphocytes of FVB than by those of BALB/c mice. Especially, the 2 anti-inflammatory cytokines, IL-10 and TGF-beta, were presumably related with susceptibility and the development of worms in the liver. C. sinensis infected FVB mice also produced more chemokines such as RANTES and MIP-1alpha in the liver lymphocytes than BALB/c mice. In conclusion, the FVB mice provide the favorable niche for C. sinensis by cyst formation in the bile duct, increased production of Th2-associated anti-inflammatory cytokines and upregulation of chemokines. PMID- 21820082 TI - Differential expression and activity of catechol-O-methyl transferase (COMT) in a generalist (Neotoma albigula) and juniper specialist (Neotoma stephensi) woodrat. AB - Mammalian herbivores, particularly dietary specialists must have an efficient means to metabolize the high doses of plant secondary compounds they consume. We found previously that Neotoma stephensi, a juniper specialist, upregulated catechol-O-methyl transferase (COMT) mRNA almost seven fold in response to an ecologically relevant diet (70% juniper). To further investigate the relevance of this enzyme with respect to juniper metabolism, we compared the protein expression, activity and kinetics of the two forms of COMT, soluble (S-COMT) and membrane bound (MB-COMT), in the blood, kidneys and liver of N. stephensi on its natural juniper diet to that of N. stephensi fed an experimental diet of 70% juniper as well as a non-toxic control diet under laboratory conditions. In addition, we compared these results to that of Neotoma albigula, a generalist species, which consumes a diet of 25% juniper in the wild. The specialist consuming juniper under both field and laboratory conditions had increased S-COMT expression and activity in their livers and kidneys, and increased S-COMT activity in their blood compared to the specialist and generalist fed the control diet. The specialist showed expression and activity of S-COMT in their kidneys that was as high as or higher than that in their livers. The generalist had an elevated V(max) for MB-COMT compared to the specialist that resulted in higher activity for MB-COMT than the specialist despite lower expression of MB-COMT in the generalist's livers and kidneys. This high activity MB-COMT may be in part responsible for differences in the behaviors of the generalist compared to the specialist. We conclude that S-COMT is important in the specialist's ability to consume high levels of juniper. PMID- 21820081 TI - Lipid particles/droplets of the yeast Saccharomyces cerevisiae revisited: lipidome meets proteome. AB - In the yeast Saccharomyces cerevisiae as in other eukaryotes non-polar lipids are a reservoir of energy and building blocks for membrane lipid synthesis. The yeast non-polar lipids, triacylglycerols (TG) and steryl esters (SE) are stored in so called lipid particles/droplets (LP) as biologically inert form of fatty acids and sterols. To understand LP structure and function in more detail we investigated the molecular equipment of this compartment making use of mass spectrometric analysis of lipids (TG, SE, phospholipids) and proteins. We addressed the question whether or not lipid and protein composition of LP influence each other and performed analyses of LP from cells grown on two different carbon sources, glucose and oleate. Growth of cells on oleate caused dramatic cellular changes including accumulation of TG at the expense of SE, enhanced the amount of glycerophospholipids and strongly increased the degree of unsaturation in all lipid classes. Most interestingly, oleate as a carbon source led to adaptation of the LP proteome resulting in the appearance of several novel LP proteins. Localization of these new LP proteins was confirmed by cell fractionation. Proteomes of LP variants from cells grown on glucose or oleate, respectively, were compared and are discussed with emphasis on the different groups of proteins detected through this analysis. In summary, we demonstrate flexibility of the yeast LP lipidome and proteome and the ability of LP to adapt to environmental changes. PMID- 21820083 TI - Identifying potential adverse effects using the web: a new approach to medical hypothesis generation. AB - Medical message boards are online resources where users with a particular condition exchange information, some of which they might not otherwise share with medical providers. Many of these boards contain a large number of posts and contain patient opinions and experiences that would be potentially useful to clinicians and researchers. We present an approach that is able to collect a corpus of medical message board posts, de-identify the corpus, and extract information on potential adverse drug effects discussed by users. Using a corpus of posts to breast cancer message boards, we identified drug event pairs using co occurrence statistics. We then compared the identified drug event pairs with adverse effects listed on the package labels of tamoxifen, anastrozole, exemestane, and letrozole. Of the pairs identified by our system, 75-80% were documented on the drug labels. Some of the undocumented pairs may represent previously unidentified adverse drug effects. PMID- 21820084 TI - Effects of a cytokine inhibitor, JTE-607, on the response to endotoxin in healthy human volunteers. AB - It is generally regarded that the excessive production of cytokines plays an important role in the pathology of autoimmune diseases and septic shock. We have investigated the ability of JTE-607, a novel inhibitor of cytokine production, to modulate the inflammatory response to endotoxin in healthy human volunteers. Three cohorts of healthy male volunteers were recruited for a randomized, placebo controlled, double-blind study. Within each cohort, 6 subjects received a single 8-hour intravenous infusion of JTE-607 (either 0.03, 0.1 or 0.3 mg/kg/h) and 3 subjects received a placebo infusion. Two hours after the start of the JTE-607 infusion, all subjects received a 30 unit/kg bolus infusion of endotoxin. JTE-607 administration resulted in the decrease in endotoxin-induced IL-10 production with mean % difference from placebo of -79.5% (P=0.040) and -86.2% (P=0.026) at 0.1 and 0.3 mg/kg/h dose, respectively. The production of endotoxin-mediated interleukin (IL)-1 receptor antagonist was significantly inhibited at 0.3 mg/kg/h dose with mean % difference from placebo of -60% (P=0.0037). Endotoxin-induced C reactive protein decreased with the increasing dose of JTE-607 with mean % difference from placebo of -32.1% (P=0.322), -82.9% (P=0.0001) and -90.3% (P<0.0001) at 0.03, 0.1 and 0.3 mg/kg/h dose, respectively. In conclusion, this study describes a cytokine modulator JTE-607, which inhibits production of IL-10, IL-1ra and C-reactive protein in a human model of endotoxemia. PMID- 21820085 TI - Stimulatory type A CpG-DNA induces a Th2-like response in human endothelial cells. AB - Unmethylated CpG-DNA motifs from pathogens are detected by the pattern recognition receptor toll-like receptor 9 (TLR9), eliciting an inflammatory immune response. These DNA sequences have been identified as potent immune modifiers and are used as adjuvants in vaccine research. Since we previously found TLR9 expression and function in human endothelial cells, we have here investigated whether endothelial cells play a role in the recognition of respective ligands and whether their response might contribute to vaccination success. We determined the effect of CpG-DNA on the inflammatory response of human endothelial cells of aortic or skin microvascular origin (HAoEC, HDMEC and HMEC-1) and compared the effects to those of two identically treated human macrophage cell lines. Using the same CpG-DNA D19(chimera) sequence in both cell types, we find the known up-regulation of pro-inflammatory cytokines in macrophages but consistent and significant inhibition of the pro-inflammatory response (IL-6, IL-8, and IFN-beta1) in endothelial cells. This inhibition is accompanied by enhanced proliferation and an increase in IL-10 gene expression. This anti-inflammatory response persists even in the presence of pro-inflammatory cytokines and low LPS concentrations, and is overruled only in the presence of relatively high concentrations of LPS. By testing different sequences, we find the strongest response with phosphorothioate bonds. Our results demonstrate an important regulatory function of endothelial cells in inflammatory responses, and the apparent Th2-like endothelial response in the human system may contribute significantly to the adjuvant activity of CpG-DNA. PMID- 21820086 TI - An anti-transferrin receptor antibody enhanced the growth inhibitory effects of chemotherapeutic drugs on human glioma cells. AB - Transferrin receptor (TfR) has been used as a target for antibody-based therapy of cancer. Anti-TfR antibody together with chemotherapeutic drugs has potential for cancer therapy. In this study, we investigated the in vitro anti-tumor effects of the anti-TfR monoclonal antibody (mAb), 7579, alone or in combination with Nimustine, a chemotherapeutic drug, on the gliomas cell lines U251 and U87MG. Our results indicated that 7579 alone dramatically down-regulated surface expression of TfR on tumor cells and induced S phase accumulation and apoptosis of tumor cells. Compared with 7579 or Nimustine used alone, the combination of 7579 with Nimustine demonstrated enhanced growth inhibitory effect on tumor cells. PI (Propidium iodide)/Annexin V staining analyzed by FCM (flow cytometry) demonstrated that 7579 enhanced the cytotoxic effects of chemotherapeutic drug on tumor cells, indicating the therapeutic effect of 7579 was mediated mainly by promoting tumor cell necrosis. Using the median-effect/combination-index isobologram method, we further evaluated the nature of 7579/chemotherapeutic drug interactions. Synergistic interaction was observed for combination of 7579 with Nimustine. Our study provides additional evidence to develop combination therapies of anti-TfR mAbs-plus chemoimmunotherapy for gliomas. PMID- 21820087 TI - Laparoscopic versus open appendicectomy in obese patients. AB - BACKGROUND: Although there appears to be no outright benefit of laparoscopic versus open surgery for acute appendicitis in the general population, it has been suggested that in obese patients a laparoscopic approach may offer more conclusive gains. The aim of this pooled analysis of comparative studies was to evaluate clinical outcome following laparoscopic and open appendicectomy in the obese population. METHODS: A systematic literature search of MEDLINE, Embase, Web of Science and the Cochrane Library databases was performed. Primary outcomes were length of operation (min) and length of hospital stay (days). Secondary outcomes were presence of post-operative complications, wound and intra-abdominal complications. Weighted mean differences were calculated to assess the size of the effect of laparoscopic appendicectomy on continuous variables and Pooled odds ratio were calculated for discrete variables. RESULTS: 2309 appendicectomies were included in this analysis, 1122 laparoscopic and 1187 open appendicectomies. Analysis of primary outcome measures revealed a shorter length of post-operative stay associated with laparoscopic appendicectomy (weighted mean difference = 1.26; 95% confidence interval = -2.36 to -0.16; p = 0.02). There was no significant difference between the groups for length of operation, post-operative complications, intra-abdominal or wound complications. CONCLUSION: The results of this pooled analysis indicate that laparoscopic appendicectomy may be beneficial in the obese population with a shorter length of hospital stay, and a similar incidence of post-operative complications. PMID- 21820088 TI - Highly efficient bioethanol production by a Saccharomyces cerevisiae strain with multiple stress tolerance to high temperature, acid and ethanol. AB - Use of super strains exhibiting tolerance to high temperature, acidity and ethanol is a promising way to make ethanol production economically feasible. We describe here the breeding and performance of such a multiple-tolerant strain of Saccharomyces cerevisiae generated by a spore-to-cell hybridization technique without recombinant DNA technology. A heterothallic strain showing a high temperature (41 degrees C) tolerant (Htg(+)) phenotype, a derivative from a strain isolated from nature, was crossed with a homothallic strain displaying high-ethanol productivity (Hep(+)), a stock culture at the Thailand Institute of Scientific and Technological Research. The resultant hybrid TJ14 displayed ability to rapidly utilize glucose, and produced ethanol (46.6g/l) from 10% glucose fermentation medium at high temperature (41 degrees C). Not only ethanol productivity at 41 degrees C but also acid tolerance (Acd(+)) was improved in TJ14 as compared with its parental strains, enabling TJ14 to grow in liquid medium even at pH 3. TJ14 maintained high ethanol productivity (46.0g/l) from 10% glucose when fermentation was done under multiple-stress conditions (41 degrees C and pH 3.5). Furthermore, when TJ14 was subjected to a repeated-batch fermentation scheme, the growth and ethanol production of TJ14 were maintained at excellent levels over ten cycles of fermentation. Thus, the multiple-stress (Htg(+) Hep(+) Acd(+)) resistant strain TJ14 should be useful for cost-effective bioethanol production under high-temperature and acidic conditions. PMID- 21820089 TI - Microbial oxidases catalyzing conversion of glycolaldehyde into glyoxal. AB - The present paper reviews oxidases catalyzing conversion of glycolaldehyde into glyoxal. The enzymatic oxidation of glycolaldehyde into glyoxal was first reported in alcohol oxidases (AODs) from methylotrophic yeasts such as Candida and Pichia, and glycerol oxidase (GLOD) from Aspergillus japonicus, although it had been reported that these enzymes are specific to short-chain linear aliphatic alcohols and glycerol, respectively. These enzymes continuously oxidized ethylene glycol into glyoxal via glycolaldehyde. The AODs produced by Aspergillus ochraceus and Penicillium purpurescens also oxidized glycolaldehyde. A new enzyme exhibiting oxidase activity for glycolaldehyde was reported from a newly isolated bacterium, Paenibacillus sp. AIU 311. The Paenibacillus enzyme exhibited high activity for aldehyde alcohols such as glycolaldehyde and glyceraldehyde, but not for methanol, ethanol, ethylene glycol or glycerol. The deduced amino acid sequence of the Paenibacillus AOD was similar to that of superoxide dismutases (SODs), but not to that of methylotrophic yeast AODs. Then, it was demonstrated that SODs had oxidase activity for aldehyde alcohols including glycolaldehyde. The present paper describes characteristics of glycolaldehyde oxidation by those enzymes produced by different microorganisms. PMID- 21820091 TI - Zoledronic acid improves bone mineral density, reduces bone turnover and improves skeletal architecture over 2 years of treatment in children with secondary osteoporosis. AB - There are limited data on the use of bisphosphonate therapy for secondary osteoporoses in childhood, and no previous reports of the use of zoledronic acid in this group. We report 20 children with a variety of underlying primary diagnoses with associated secondary osteoporosis, who were treated with 3 monthly zoledronic acid for 2 years (annualised dose 0.1mg/kg/year). There was a significant improvement in lumbar spine (by 1.88 SD+/-1.24 over first 12 months, p<0.001) and total bone mineral density as assessed by dual energy absorptiometry (DXA) scans, with a similar increase in bone mineral content for lean tissue mass (mean increase 1.34 SD in first 12 months, p<0.001). Bone turnover was reduced with a suppression of both osteocalcin and alkaline phosphatase in the first 12 months of treatment. Skeletal architecture was improved, with increased second metacarpal cortical thickness from 2.44mm to 2.72mm (p<0.001) and improved vertebral morphometry, with 7 patients who had vertebral wedging at baseline showing improved anterior (p=0.017) and middle (p=0.001) vertebral height ratios. Aside from well reported transient side effects with the first dose, there were no adverse effects reported. No adverse effects on anthropometric parameters were seen over the course of the study. Despite all patients having sustained fragility fractures prior to treatment, no fractures were reported during the study period. Further evidence is required to confirm efficacy, with long term follow up required to assess the impact of treatment on fracture risk. PMID- 21820092 TI - The transcriptional activity of osterix requires the recruitment of Sp1 to the osteocalcin proximal promoter. AB - The transcription factor osterix (Osx/Sp7) is required for osteogenic differentiation and bone formation in vivo. While Osx can act at canonical Sp1 DNA-binding sites and/or interact with NFATc1 to cooperatively regulate transcription in some osteoblast promoters, little is known about the molecular details by which Osx regulates osteocalcin (OCN) transcription. We previously identified in the OCN proximal promoter a minimal C/T-rich motif, termed OCN-CxRE (connexin-response element) that binds Sp1 and Sp3 in a gap junction-dependent manner. In the present study, we hypothesized that Osx could act via this non canonical Sp1/Sp3-binding element to regulate OCN transcription. OCN promoter luciferase reporter assays show that Osx alone is an insufficient activator that requires Sp1, but not Sp3, to synergistically stimulate OCN promoter activity. Moreover, promoter deletion analyses demonstrate that both the Sp1/Sp3-binding OCN-CxRE (-70 to -57) and the -92 to -87 region of the OCN proximal promoter are critical for Osx/Sp1 synergistic activities. Our data show that Sp1 influences Osx activity by enhancing Osx occupancy on the OCN promoter, perhaps via physical interactions between the two transcription factors. Finally, alteration of the expression of the gap junction protein connexin43 modulates the recruitment of both Sp1 and Osx to the OCN promoter. In total, our data are strongly in support of Sp1 as an essential transcription factor required for Osx recruitment and transactivation of the OCN promoter. Further, these data lend insight into a mechanism by which alteration of connexin43 impacts osteogenesis in vitro and in vivo. PMID- 21820094 TI - Deriving tissue density and elastic modulus from microCT bone scans. AB - Tissue level density and elastic modulus are intrinsic properties that can be used to quantify bone material and analyses incorporating those quantities have been used to evaluate bone on a macroscopic scale. Micro-computed tomography (microCT) technology has been used to construct tissue level finite element models to simulate macroscopic fracture strength, however, a single method for assigning voxel-specific tissue density and elastic modulus based on those data has not been universally accepted. One method prevalent in the literature utilizes an empirical relationship that derives tissue stiffness as a function of bone calcium content weight fraction. To derive calcium content weight fraction from microCT scans, a measure of tissue density is required and a constant value is traditionally used. However, experimental data suggest a non-trivial amount of tissue heterogeneity suggesting a constant tissue density may not be appropriate. A theoretical derivation for determining the relationship between voxel-specific tissue density and microCT scan data (i.e., microCT derived tissue mineral density (TMD), mgHA/cm(3)) and bone constituent properties is proposed. Constant model parameters used in the derivation include the density of water, ash, and organics (i.e., bone constituents) and the volume fraction of the organics constituent. The effect of incorporating the theoretically derived tissue density (instead of a constant value) in determining voxel-specific elastic modulus resulted in a maximum observed increase of 12GPa (5.9GPa versus 17.9GPa, for the constant value and derived tissue density formulations, respectively) for a measured TMD of 1.02gHA/cm(3). Average and bounding quantities for the four constant model parameters were defined from the literature and the influence of those values on the derived tissue density and elastic modulus relationships were also evaluated. The theoretical relationships of tissue density and elastic modulus, with the average constant model parameters applied, were consistent with previously published empirical relationships derived from experimental data. Tissue density as a function of microCT TMD was formulated as a linear relationship and the density of water and ash was shown to solely influence the proportionality (i.e., slope) between those values. The density of water and organics (i.e., collagen) and the volume fraction of the organics constituent were shown to influence the constant offset (intercept) between tissue density and TMD with no influence from ash density. Incorporating tissue density heterogeneity into the derivation of elastic modulus resulted in a significant increase in predicted modulus (for microCT TMD ranges observed for healthy tissue) as compared to when a constant tissue density was used. The presented approach provides a novel method for deriving tissue-level bone material properties and quantifies the effect of assuming tissue homogeneity when calculating elastic modulus (when using a prevalent method in the literature) from microCT scan data. PMID- 21820093 TI - Differential effects of two citrus flavanones on bone quality in senescent male rats in relation to their bioavailability and metabolism. AB - The effect of hesperidin (Hp) and naringin (Nar), two major citrus flavanones, on the regulation of bone metabolism was examined in male senescent rats. Twenty month -old gonad-intact male Wistar rats received a casein-based diet supplemented with or without either 0.5% hesperidin (Hp), 0.5% naringin (Nar) or a mix of both flavanones (Hp+Nar, 0.25% each). After 3 months, daily Hp intake significantly improved femoral bone integrity as reflected by improvements in total and regional bone mineral densities (BMD) (9.7%-12.3% improvements, p<0.05) and trabecular bone volume fraction (24.3% improvement, p<0.05) at the femur compared with control group. In contrast, naringin exerted site-specific effects on BMD (10.2% improvement at the distal metaphyseal area, p<0.05) and no further benefit to bone mass was observed with the mix of flavanones. Bone resorption (DPD) was significantly attenuated by Hp and Nar given alone (40.3% and 26.8% lower compared to control, p<0.05, respectively) but not by the mixture of the two. All treatments significantly reduced expression of inflammatory markers to a similar extent (IL-6, 81.0-87.9% reduction; NO, 34.7-39.5% reduction) compared to control. Bone formation did not appear to be strongly affected by any of the treatments (no effect on osteocalcin levels, modest modulation of tibial BMP-2 mRNA). However, as previously reported, plasma lipid-lowering effects were observed with Hp and Nar alone (34.1%-45.1% lower for total cholesterol and triglycerides compared to control, p<0.05) or together (46% lower for triglycerides, p<0.05). Surprisingly the plasma circulating level of naringin (8.15MUM) was >5-fold higher than that of hesperidin (1.44MUM) at equivalent doses (0.5%) and a linear reduction in plasma levels was observed upon co administration (0.25% each) indicating absence of competition for their intestinal absorption sites and metabolism. The higher efficacy of Hp at a lower plasma concentration than naringin, as well as the identification of the major circulating metabolite of hesperidin (hesperetin-7-O-glucuronide) underlines the importance of flavanone bioavailability and metabolism in their biological efficacy and suggests a structure-function relationship in the mechanism of action of the active metabolites. PMID- 21820095 TI - Long-term clinical outcomes of percutaneous coronary intervention for chronic total occlusions in patients with versus without diabetes mellitus. AB - There is a paucity of data on long-term outcomes after percutaneous coronary intervention (PCI) for chronic total occlusions (CTOs) in the high-risk group of patients with diabetes mellitus (DM). The aim of this study was to evaluate long term clinical outcomes after PCI of CTOs in patients with and without DM. A total of 1,742 patients with known DM status underwent PCI of CTOs at 3 tertiary care centers in the United States, South Korea, and Italy from 1998 to 2007. Five-year clinical outcomes were evaluated in patients with successful versus failed CTO PCI and the use of drug-eluting stents (DES) versus bare-metal stents (BMS) stratified according to DM status. A total of 395 patients (23%) had DM (42% of whom had insulin-dependent DM). Procedural success was similar in patients with versus without DM (69.6% vs 67.9%, p = 0.53). After successful CTO PCI, stents were implanted in 96.4% of patients with DM (BMS in 23.8%, DES in 76.2%) and in 94.0% of patients without DM (BMS in 38.6%, DES in 61.4%). Median follow-up was 3.0 years. In patients with DM, successful CTO PCI was associated with reduced long-term mortality (10.4% vs 13.0%, p <0.05) and a reduced need for coronary artery bypass grafting (2.4% vs 15.7%, p <0.01). The use of DES was associated with a reduction in target vessel revascularization in patients with DM (14.8% vs 54.1%, p <0.01) and in those without DM (17.6% vs 26.5%, p <0.01). Multivariate analysis identified insulin-dependent DM as an independent predictor of mortality in the DM cohort. In conclusion, successful CTO PCI in patients with DM was associated with a reduction in mortality and the need for coronary artery bypass grafting. Compared to non-insulin-dependent DM, patients with insulin-dependent DM had an increased risk for long-term mortality. The use of DES rather than BMS was associated with a reduction in target vessel revascularization in patients with and without DM. PMID- 21820096 TI - Recessive mutations in DOCK6, encoding the guanidine nucleotide exchange factor DOCK6, lead to abnormal actin cytoskeleton organization and Adams-Oliver syndrome. AB - Adams-Oliver syndrome (AOS) is defined by the combination of aplasia cutis congenita (ACC) and terminal transverse limb defects (TTLD). It is usually inherited as an autosomal-dominant trait, but autosomal-recessive inheritance has also been documented. In an individual with autosomal-recessive AOS, we combined autozygome analysis with exome sequencing to identify a homozygous truncating mutation in dedicator of cytokinesis 6 gene (DOCK6) which encodes an atypical guanidine exchange factor (GEF) known to activate two members of the Rho GTPase family: Cdc42 and Rac1. Another homozygous truncating mutation was identified upon targeted sequencing of DOCK6 in an unrelated individual with AOS. Consistent with the established role of Cdc42 and Rac1 in the organization of the actin cytoskeleton, we demonstrate a cellular phenotype typical of a defective actin cytoskeleton in patient cells. These findings, combined with a Dock6 expression profile that is consistent with an AOS phenotype as well as the very recent demonstration of dominant mutations of ARHGAP31 in AOS, establish Cdc42 and Rac1 as key molecules in the pathogenesis of AOS and suggest that other regulators of these Rho GTPase proteins might be good candidates in the quest to define the genetic spectrum of this genetically heterogeneous condition. PMID- 21820097 TI - A mutation in a skin-specific isoform of SMARCAD1 causes autosomal-dominant adermatoglyphia. AB - Monogenic disorders offer unique opportunities for researchers to shed light upon fundamental physiological processes in humans. We investigated a large family affected with autosomal-dominant adermatoglyphia (absence of fingerprints) also known as the "immigration delay disease." Using linkage and haplotype analyses, we mapped the disease phenotype to 4q22. One of the genes located in this interval is SMARCAD1, a member of the SNF subfamily of the helicase protein superfamily. We demonstrated the existence of a short isoform of SMARCAD1 exclusively expressed in the skin. Sequencing of all SMARCAD1 coding and noncoding exons revealed a heterozygous transversion predicted to disrupt a conserved donor splice site adjacent to the 3' end of a noncoding exon uniquely present in the skin-specific short isoform of the gene. This mutation segregated with the disease phenotype throughout the entire family. Using a minigene system, we found that this mutation causes aberrant splicing, resulting in decreased stability of the short RNA isoform as predicted by computational analysis and shown by RT-PCR. Taken together, the present findings implicate a skin-specific isoform of SMARCAD1 in the regulation of dermatoglyph development. PMID- 21820098 TI - KIF1A, an axonal transporter of synaptic vesicles, is mutated in hereditary sensory and autonomic neuropathy type 2. AB - Hereditary sensory and autonomic neuropathy type II (HSANII) is a rare autosomal recessive disorder characterized by peripheral nerve degeneration resulting in a severe distal sensory loss. Although mutations in FAM134B and the HSN2 exon of WNK1 were associated with HSANII, the etiology of a substantial number of cases remains unexplained. In addition, the functions of WNK1/HSN2 and FAM134B and their role in the peripheral nervous system remain poorly understood. Using a yeast two-hybrid screen, we found that KIF1A, an axonal transporter of synaptic vesicles, interacts with the domain encoded by the HSN2 exon. In parallel to this screen, we performed genome-wide homozygosity mapping in a consanguineous Afghan family affected by HSANII and identified a unique region of homozygosity located on chromosome 2q37.3 and spanning the KIF1A gene locus. Sequencing of KIF1A in this family revealed a truncating mutation segregating with the disease phenotype. Subsequent sequencing of KIF1A in a series of 112 unrelated patients with features belonging to the clinical spectrum of ulcero-mutilating sensory neuropathies revealed truncating mutations in three additional families, thus indicating that mutations in KIF1A are a rare cause of HSANII. Similarly to WNK1 mutations, pathogenic mutations in KIF1A were almost exclusively restricted to an alternatively spliced exon. This study provides additional insights into the molecular pathogenesis of HSANII and highlights the potential biological relevance of alternative splicing in the peripheral sensory nervous system. PMID- 21820101 TI - Acromegaly and pregnancy. AB - In women with acromegaly due to growth hormone (GH)-secreting pituitary adenomas, the occurrence of pregnancy warrants consideration of: (1) the consequences of pregnancy on the pituitary adenoma including the tumor syndrome and GH/IGF-1 secretion, (2) the consequence of GH/IGF-1 hypersecretion on the pregnant woman and the fetus, (3) the consequences of pituitary surgery and medical treatment (dopamine agonists, somatostatin analogs, GH receptor antagonist) on the pregnant woman and the developing fetus. PMID- 21820102 TI - How well do truck drivers sleep in cabin sleeper berths? AB - The aim of this study was to evaluate the sleep obtained by livestock transport truck drivers while resting in truck sleeper berths during long-haul commercial operations. Operations were carried out in the very remote regions of Australia. The sample comprised of 32 drivers who wore wrist activity monitors and reported bed-times for a two-week period. Drivers had a mean (+/-standard deviation) age of 35.41 (+/- 9.78) years and had worked as truck drivers for 13.83 (+/- 9.11) years. On average, they obtained 6.07 (+/- 1.18) hours of sleep/24-h period. The majority of sleep occurred at night, but drivers occasionally supplemented their main sleep with a daytime nap. Consistent with operational demands, drivers were most likely to sleep in cabin sleeper berths (n = 394, 77%). Only a small proportion of sleeps were sampled at home (n = 63, 12%) or at truck depots (n = 56, 11%). Mixed-model ANOVA revealed that while earlier bed-times at home yielded more sleep, there were only marginal differences in sleep quality across location. No intrinsic safety concerns associated with the use of sleeper berths were identified across consecutive days of long-haul transport operations. PMID- 21820100 TI - Exome sequencing identifies a DYNC1H1 mutation in a large pedigree with dominant axonal Charcot-Marie-Tooth disease. AB - Charcot-Marie-Tooth disease is characterized by length-dependent axonal degeneration with distal sensory loss and weakness, deep-tendon-reflex abnormalities, and skeletal deformities. It is caused by mutations in more than 40 genes. We investigated a four-generation family with 23 members affected by the axonal form (type 2), for which the common causes had been excluded by Sanger sequencing. Exome sequencing of three affected individuals separated by eight meioses identified a single shared novel heterozygous variant, c.917A>G, in DYNC1H1, which encodes the cytoplasmic dynein heavy chain 1 (here, novel refers to a variant that has not been seen in dbSNP131or the August 2010 release of the 1000 Genomes project). Testing of six additional affected family members showed cosegregation and a maximum LOD score of 3.6. The shared DYNC1H1 gene variant is a missense substitution, p.His306Arg, at a highly conserved residue within the homodimerization domain. Three mouse models with different mutations within this domain have previously been reported with age-related progressive loss of muscle bulk and locomotor ability. Cytoplasmic dynein is a large multisubunit motor protein complex and has a key role in retrograde axonal transport in neurons. Our results highlight the importance of dynein and retrograde axonal transport in neuronal function in humans. PMID- 21820099 TI - Mutations in DNAJC5, encoding cysteine-string protein alpha, cause autosomal dominant adult-onset neuronal ceroid lipofuscinosis. AB - Autosomal-dominant adult-onset neuronal ceroid lipofuscinosis (ANCL) is characterized by accumulation of autofluorescent storage material in neural tissues and neurodegeneration and has an age of onset in the third decade of life or later. The genetic and molecular basis of the disease has remained unknown for many years. We carried out linkage mapping, gene-expression analysis, exome sequencing, and candidate-gene sequencing in affected individuals from 20 families and/or individuals with simplex cases; we identified in five individuals one of two disease-causing mutations, c.346_348delCTC and c.344T>G, in DNAJC5 encoding cysteine-string protein alpha (CSPalpha). These mutations-causing a deletion, p.Leu116del, and an amino acid exchange, p.Leu115Arg, respectively-are located within the cysteine-string domain of the protein and affect both palmitoylation-dependent sorting and the amount of CSPalpha in neuronal cells. The resulting depletion of functional CSPalpha might cause in parallel the presynaptic dysfunction and the progressive neurodegeneration observed in affected individuals and lysosomal accumulation of misfolded and proteolysis resistant proteins in the form of characteristic ceroid deposits in neurons. Our work represents an important step in the genetic dissection of a genetically heterogeneous group of ANCLs. It also confirms a neuroprotective role for CSPalpha in humans and demonstrates the need for detailed investigation of CSPalpha in the neuronal ceroid lipofuscinoses and other neurodegenerative diseases presenting with neuronal protein aggregation. PMID- 21820103 TI - Clearance of albumin following ultrasound-induced blood-brain barrier opening is mediated by glial but not neuronal cells. AB - Ultrasound-mediated opening of the blood-brain barrier (BBB) in the presence of gas-filled microbubbles is a potential strategy for drug delivery across the blood-brain barrier to promote regeneration after ischemic stroke. However, related bioeffects and potential side-effects that could limit a translation into clinical application are poorly understood so far. We therefore examined the clearance of extravasated albumin following ultrasound-mediated BBB opening. Autofluorescence of albumin-bound Evans Blue dye indicated cellular albumin uptake as soon as 30min after insonation (2+/-0.72 cells/optical field). Cellular albumin uptake increased constantly over 24h (22+/-3.33 cells/optical field, p<0.05). Initially, the majority of albumin-positive cells were located in the periphery of brain capillaries. Most albumin phagocyting cells stained positive for CD163 and Iba-1, identifying them as activated microglia. Further, a small fraction of albumin-positive cells stained positive for the astroglial markers GFAP/S100B. Some perivascular cells with intracellular albumin were shown to express the endothelial marker protein EN4. Albumin uptaking cells stained negative for the neuronal TubulinIII. Thus, ultrasound-induced BBB opening leads to albumin extravasation which is phagocytized predominantly by activated microglia, astrocytes and endothelial cells. As albumin uptake into neurons has been shown to be neurotoxic, rapid albumin clearance by microglia might prevent neuronal cell death. PMID- 21820104 TI - Lipase catalysis and thiol-Michael addition: a relevant association for the synthesis of new surface-active carbohydrate esters. AB - A novel class of surface-active carbohydrate esters is prepared by a two-step strategy that takes advantage of the selectivity of enzymatic catalysis and the versatility of the thiol-Michael addition reaction. The surfactant performance of the produced aliphatic, fluorinated and silicon based sugar esters are evaluated by surface tension measurements. The novel thiolated mannose, made available in this work, appears as a powerful building block for the incorporation of unprotected sugar moieties into complex molecules. PMID- 21820105 TI - Direct conversion of cellulose to 1-(furan-2-yl)-2-hydroxyethanone in zinc chloride solution under microwave irradiation. AB - Conversion of cellulose to 1-(furan-2-yl)-2-hydroxyethanone has been demonstrated in concentrated zinc chloride solution under microwave irradiation. Compared with the conventional oil-bath heating mode, microwave irradiation significantly reduced the reaction time and increased the yield of 1-(furan-2-yl)-2 hydroxyethanone. A typical degradation reaction with cellulose produced 1-(furan 2-yl)-2-hydroxyethanone in 12.0% molar yield in ZnCl(2) solution (ZnCl(2)-H(2)O ratio=2.25:1, w/w) with microwave irradiation at 600 W for 5 minutes at 135 degrees C. PMID- 21820106 TI - Dihydroartemisinin shift the immune response towards Th1, inhibit the tumor growth in vitro and in vivo. AB - Some investigators have been found that Artemisinin and its derivates have inhibitory effect on growth of cancer cells. Among these derivatives, Dihydroartemisinin (DHA) is well known as a semi-synthetic one. In addition, T cells are proved to be essential for the destruction of cancer cells. In this research, we assessed the effects of DHA on tumor cell growth inhibition in vitro by MTT assay and in vivo by intra tumor injection of DHA against breast cancer. The results showed that the IC(50) values of DHA for RIN pancreatic tumor cell line were 30 MUM and significant decrease in the tumor size in vivo. Also we evaluate the effect of DHA on the modulation of immune response in tumor bearing animals; these include the splenocyte proliferation using the BrdU kit; measurement of cytokine profile by ELISA, and evaluate the percentage of T regulatory cells in the spleen by flowcytometry. Our results demonstrated that a significant decrease in the level of IL-4 in the animals treated with DHA and significant decreased in the level of splenic CD4(+)CD25(+) Foxp3(+) T regulatory cells. PMID- 21820107 TI - [Microbiology of surgical site infections in abdominal tract surgery patients]. AB - INTRODUCTION: Knowledge of the microbiology of surgical infections after abdominal surgery can be of use when prescribing effective empirical antibiotic treatments. METHOD: Analysis of surgical infections after abdominal surgery in patients enrolled in the Prevalence of Infections in Spanish Hospitals (EPINE) corresponding to the years 1999-2006. RESULTS: During the period of the study, 2,280 patients who were subjected to upper or lower abdominal tract surgery were diagnosed with an infection at the surgical site (SSI). Eight hundred and eighty three patients (37%) had an operation of the upper abdominal tract (gastric, hepatobiliary, and pancreatic surgery) and 1,447 patients (63%) lower abdominal tract surgery (appendectomy and colon surgery). A total of 2,617 bacterial species were isolated in the 2,280 patients included in the analysis. The most frequent microorganisms isolated were, Escherichia coli (28%), Enterococcus spp. (15%), Streptococcus spp. (8%), Pseudomonas aeruginosa (7%), and Staphylococcus aureus (5%, resistant to methicillin 2%). In the surgical infections after upper abdominal tract procedures, there were a higher proportion of isolations of staphylococci, Klebsiella pneumoniae, Enterobacter spp., Acinetobacter spp. and Candida albicans and less Escherichia coli, Bacteroides fragilis and Clostridium spp. CONCLUSION: The microbiology of SSI produced after upper abdominal tract surgery did not show any significant differences compared to those of the lower tract. However, more cases of SSI were detected due to staphylococci, Klebsiella pneumoniae, Enterobacter spp., Acinetobacter spp. and Candida albicans and less caused by Escherichia coli, Bacteroides fragilis and Clostridium spp. PMID- 21820108 TI - [Improvement in the quality of life of faecal incontinent patients after sacral root stimulation treatment]. AB - INTRODUCTION: Faecal incontinence (FI) is a highly prevalent disorder that severely affects the health related quality of life (HRQOL) of the patients who suffer from it. Neuromodulation is a minimally invasive treatment that has demonstrated its efficacy in the treatment of FI symptoms over the past 10 years. The aim of this study is to check whether there is an improvement in the quality of life, using EuroQuol (EQ-5D), in patients with faecal incontinence treated with sacral root neuromodulation. METHODOLOGY: An observational study with prospective recording of quality of life data, before and after, using the EQ-5D on a series of patients diagnosed with moderate to severe FI with a complete or repaired sphincter who had a definitive MEDTRONIC Interstim((r)) 3023 implant after a subchronic stimulation phase with a good response. RESULTS: The initial mean number of leaks was 3.1+/-1, and the final was 0.5+/-0.6. The mean number of escapes per week decreased to 2.6 escapes (CI 95%: 2.1-3.1) after the definitive implant of the sacral root stimulator (P<.001). The mean baseline health status score was 55.9+/-13, and after neuromodulation it was 63.1+/-13. Thus, the visual analogue scale score increased by 7.1 points (CI 95%: 0.37-14) after the definitive implant of the sacral root stimulator (P<.05). In the HRQOL variables studied with the EQ-5D questionnaire, we found an improvement with neuromodulation in the mobility and the presence of anxiety and/or depression variables. On the other hand we found an improvement with the neurostimulator implant, which was not significant, in personal care, performing daily activities and the presence of pain and/or discomfort. The current health was better in 11 patients (57.9%), the same in 7 (36.8%) and worse in 1 (5.3%). CONCLUSIONS: Neuromodulation is a therapy that has demonstrated a significant improvement in HRQOL measured with the EQ-5D. PMID- 21820109 TI - Factors associated with esophageal stricture formation after endoscopic mucosal resection for neoplastic Barrett's esophagus. AB - BACKGROUND: EMR for early neoplastic Barrett's esophagus is gaining favor over esophagectomy. Esophageal stricture development has been reported as a common complication of EMR, photodynamic therapy, and combination endoscopic therapy. OBJECTIVE: To determine clinical and procedural predictors of symptomatic stricture formation after EMR. DESIGN: Retrospective analysis. SETTING: Tertiary care referral university hospital. PATIENTS: Data were retrospectively reviewed on 73 patients at our institution who underwent EMR monotherapy for Barrett's esophagus with high-grade dysplasia or intramucosal cancer since January 2006. INTERVENTION: EMR. MAIN OUTCOME MEASUREMENTS: Symptomatic esophageal stricture formation. RESULTS: Symptomatic esophageal stricture formation was noted in 24.7% of patients undergoing EMR. Stricture formation on univariate analysis was associated with percentage of circumference of esophageal lumen resected, total pieces resected, number of EMR sessions, and tobacco use. A threshold effect was found at 50% of esophageal circumference resected (66.7% vs 27.2% developed strictures above and below the threshold, respectively; P = .004). A 25-pack-year or greater history of tobacco use had a threshold effect on esophageal stricture formation (77.8% vs 7.2% developed strictures above and below the threshold, respectively; P = .02). In multivariate analysis, resection of >50% of the circumference was strongly associated with stricture formation (odds ratio [OR] 4.17; 95% confidence interval [CI], 1.27-13.7). A 25-pack-year or greater history of tobacco use also trended toward stricture formation (OR 3.33; 95% CI, 0.929 12.1). LIMITATIONS: Retrospective design, sample size. CONCLUSION: Resection of at least 50% of the esophageal mucosal circumference is strongly associated with stricture formation. Patients with strong histories of tobacco use also may be more likely to develop esophageal strictures following EMR. PMID- 21820110 TI - Dysphagia caused by anterior cervical plate erosion (with videos). PMID- 21820111 TI - Endoscopic "retroperitoneal fatpexy" of a large ERCP-related jejunal perforation by using a new over-the-scope clip device in Billroth II anatomy (with video). PMID- 21820112 TI - Primary esophageal mucosa-associated lymphoid tissue lymphoma treated with endoscopic resection. PMID- 21820113 TI - A rare cause of esophageal strictures: Actinomyces. PMID- 21820114 TI - Missed injuries during the initial assessment in a cohort of 1124 level-1 trauma patients. AB - INTRODUCTION: Despite the presence of diagnostic guidelines for the initial evaluation in trauma, the reported incidence of missed injuries is considerable. The aim of this study was to assess the missed injuries in a large cohort of trauma patients originating from two European Level-1 trauma centres. METHODS: We analysed the 1124 patients included in the randomised REACT trial. Missed injuries were defined as injuries not diagnosed or suspected during initial clinical and radiological evaluation in the trauma room. We assessed the frequency, type, consequences and the phase in which the missed injuries were diagnosed and used univariate analysis to identify potential contributing factors. RESULTS: Eight hundred and three patients were male, median age was 38 years and 1079 patients sustained blunt trauma. Overall, 122 injuries were missed in 92 patients (8.2%). Most injuries concerned the extremities. Sixteen injuries had an AIS grade of >= 3. Patients with missed injuries had significantly higher injury severity scores (ISSs) (median of 15 versus 5, p<0.001). Factors associated with missed injuries were severe traumatic brain injury (GCS <= 8) and multitrauma (ISS >= 16). Seventy-two missed injuries remained undetected during tertiary survey (59%). In total, 31 operations were required for 26 initially missed injuries. CONCLUSION: Despite guidelines to avoid missed injuries, this problem is hard to prevent, especially in the severely injured. The present study showed that the rate of missed injuries was comparable with the literature and their consequences not severe. A high index of suspicion remains warranted, especially in multitrauma patients. PMID- 21820115 TI - Confronting the challenge of unsafe second-trimester abortion. AB - Unsafe abortion accounts for approximately 13% of maternal deaths worldwide roughly 47,000 deaths per year. Most deaths from unsafe abortion occur in low resource countries. Second-trimester abortion carries a higher risk of morbidity and mortality compared with first-trimester abortion and, although the former comprises the minority of abortion procedures worldwide, it is responsible for the majority of serious complications and death where unsafe abortion is prevalent. Therefore, improving access to safe second-trimester abortion must be a priority in low-income regions of the world if the majority of deaths from unsafe abortion are to be prevented. In the present paper, we consider a variety of barriers to second-trimester care, including healthcare provider training and abortion stigma, which may lead to neglect of unmet need for second-trimester services. PMID- 21820116 TI - Hematometrocolpos after failed vacuum delivery. PMID- 21820117 TI - Effectiveness of cervical cancer screening using visual inspection with acetic acid in Peru. AB - OBJECTIVE: To evaluate the effectiveness of screening using visual inspection with acetic acid (VIA). METHODS: In a low-resource area of Peru in 2005-2008, a randomly selected sample of women who had previously screened negative by VIA and Pap (intervention group), and a group of eligible women previously unscreened by VIA (comparison group) were screened by VIA. The outcome measures were histologically confirmed cervical intraepithelial neoplasia (CIN) 2-3 and invasive cervical cancer. RESULTS: There were 4252 women in the intervention group and 4392 in the comparison group. Histologically confirmed CIN 2 or worse was diagnosed in 31 (0.7%) and 115 (2.6%) women, and invasive cancer was diagnosed in 4 women (0.09%) and 43 women (1.00%), in the intervention and comparison groups, respectively. The adjusted odds ratio was 4.2 (95% confidence interval [CI], 2.7-6.4) for CIN 2 or worse, and 13.9 (95% CI, 4.9-39.6) for invasive cervical cancer in the comparison group. CONCLUSION: A lower prevalence of CIN 2-3 and invasive cervical cancer was seen in women previously screened by VIA, as compared with women not previously screened by VIA, implying that a single VIA screening can lower the population risk for cervical cancer. PMID- 21820118 TI - Lipophilicity assessment of basic drugs (log P(o/w) determination) by a chromatographic method. AB - A previously reported chromatographic method to determine the 1-octanol/water partition coefficient (log P(o/w)) of organic compounds is used to estimate the hydrophobicity of bases, mainly commercial drugs with diverse chemical nature and pK(a) values higher than 9. For that reason, mobile phases buffered at high pH to avoid the ionization of the solutes and three different columns (Phenomenex Gemini NX, Waters XTerra RP-18 and Waters XTerra MS C(18)) with appropriate alkaline-resistant stationary phases have been used. Non-ionizable substances studied in previous works were also included in the set of compounds to evaluate the consistency of the method. The results showed that all the columns provide good estimations of the log P(o/w) for most of the compounds included in this study. The Gemini NX column has been selected to calculate log P(o/w) values of the set of studied drugs, and really good correlations between the determined log P(o/w) values and those considered as reference were obtained, proving the ability of the procedure for the lipophilicity assessment of bioactive compounds with very different structures and functionalities. PMID- 21820119 TI - Microwave-assisted extractions of active ingredients from plants. AB - Microwave-assisted extraction (MAE) is widely employed in the analysis and the extraction of active compounds from plants. This review summarizes the research done during the last decade on the MAE of active ingredients from plants. Advances and modifications to improve the performance of MAE are presented and discussed in detail. Modified MAE such as vacuum microwave-assisted extraction (VMAE), nitrogen-protected microwave-assisted extraction (NPMAE), ultrasonic microwave-assisted extraction (UMAE), dynamic microwave-assisted extraction (DMAE) and other advancements in MAE are also detailed in this article. In addition, the microwave extraction procedures and the important parameters influencing its performance are also included, together with the advantages and the drawbacks of each MAE techniques. PMID- 21820120 TI - Modeling the effects of type and concentration of organic modifiers, column type and chemical structure of analytes on the retention in reversed phase liquid chromatography using a single model. AB - A previously proposed model for representing the retention factor (k) of an analyte in mixed solvent mobile phases was extended to calculate the k of different analytes with respect to the nature of analyte, organic modifier, its concentration and type of the stationary phase. The accuracy of the proposed method was evaluated by calculating mean percentage deviation (MPD) as accuracy criterion. The predicted vs. observed plots were also provided as goodness of fit criteria. The developed model prediction capability compared with a number of previous models (i.e. LSER, general LSER and Oscik equation) through MPD and fitting plots. The proposed method provided acceptable predictions with the advantage of modeling the effects of organic modifiers, mobile phase compositions, columns and analytes using a single equation. The accuracy of developed model was checked using the one column and one analyte out cross validation analyses and the results showed that the developed model was able to predict the unknown analyte retention and the analytes retentions on unknown column accurately. PMID- 21820122 TI - Molecular size fractionation of soil humic acids using preparative high performance size-exclusion chromatography. AB - High performance size-exclusion chromatography (HPSEC) is useful for the molecular size separation of soil humic acids (HAs), but there is no method available for various HAs with different chemical properties. In this paper the authors propose a new preparative HPSEC method for various soil HAs. Three soil HAs with different chemical properties were fractionated by a Shodex OHpak SB 2004 HQ column with 10mM sodium phosphate buffer (pH 7.0)/acetonitrile (3:1, v/v) as an eluent. The HAs eluted within a reasonable column range time (12-25 min) without peak tailing. Preparative HPSEC chromatograms of these HAs indicated that non-size-exclusion effects were suppressed. The separated fractions were analyzed by HPSEC to determine their apparent molecular weights. These decreased sequentially from fraction 1 to fraction 10, suggesting that the HAs had been separated by their molecular size. The size-separated fractions of the soil HA were mixed to compare them with unfractionated HA. The analytical HPSEC chromatogram of the mixed HA was almost identical to that of the unfractionated HA. It appears that the HAs do not adsorb specifically to the column during preparative HPSEC. Our preparative HPSEC method allows for rapid and reproducible separation of various soil HAs by molecular size. PMID- 21820121 TI - Highly sensitive detection of S-nitrosylated proteins by capillary gel electrophoresis with laser induced fluorescence. AB - S-nitrosylated proteins are biomarkers of oxidative damage in aging and Alzheimer's disease (AD). Here, we report a new method for detecting and quantifying nitrosylated proteins by capillary gel electrophoresis with laser induced fluorescence detection (CGE-LIF). Dylight 488 maleimide was used to specifically label thiol group (SH) after switching the S-nitrosothiol (S-NO) to SH in cysteine using the "fluorescence switch" assay. In vitro nitrosylation model-BSA subjected to S-nitrosoglutathione (GSNO) optimized the labeling reactions and characterized the response of the LIF detector. The method proves to be highly sensitive, detecting 1.3 picomolar (pM) concentration of nitrosothiols in nanograms of proteins, which is the lowest limit of detection of nitrosothiols reported to date. We further demonstrated the direct application of this method in monitoring protein nitrosylation damage in MQ mediated human colon adenocarcinoma cells. The nitrosothiol amounts in MQ treated and untreated cells are 14.8+/-0.2 and 10.4+/-0.5 pmol/mg of proteins, respectively. We also depicted nitrosylated protein electrophoretic profiles of brain cerebrum of 5-month-old AD transgenic (Tg) mice model. In Tg mice brain, 15.5+/-0.4 pmol of nitrosothiols/mg of proteins was quantified while wild type contained 11.7+/-0.3 pmol/mg proteins. The methodology is validated to quantify low levels of S-nitrosylated protein in complex protein mixtures from both physiological and pathological conditions. PMID- 21820123 TI - Mechano-chemical radical formation and polymerization initiation during wet grinding of alumina. AB - The formation of free radicals during wet grinding of alumina in a stirred media mill was studied by using the test radical 2,2-diphenyl-1-picrylhydracyl (DPPH). The kinetics of mechano-chemical radical formation follows a zeroth-order rate law. Particle breakage as well as mechanical activation of the surface of the alumina particles contributes to the radical formation. The rate constants of the radical formation due to mechanical activation of the particle surface k(A) and due to particle breakage k(B) depend on the milling process parameters. The radical formation during wet grinding of alumina was exploited to initiate mechano-chemical polymerization reactions of acrylic acid and acryl amide, respectively. In this way nanoparticles functionalized with polyacrylic acid and polyacryl amide, respectively, are obtained. The influence of the milling process parameters on the kinetics of mechano-chemical radical formation and on the grafted amount of polymer is discussed on the basis of stress energy and number of stress events in the mill. A correlation between the grafted amount of polyacryl amide on the alumina particles and the total radical formation rate was found showing that the concentration of mechano-chemically formed free radicals governs the efficacy of a chemical reaction at activated particle surfaces. PMID- 21820124 TI - Polarity of the interface in ionic liquid in oil microemulsions. AB - Ionic liquid based microemulsions were characterized by absorption solvatochromic shifts, (1)H NMR and kinetic measurements in order to investigate the properties of the ionic liquid within the restricted geometry provided by microemulsions and the interactions of the ionic liquid with the interface. Experimental results show a significant difference between the interfaces of normal water and the new ionic liquid microemulsions. Absorption solvatochromic shift experiments and kinetic studies on the aminolysis of 4-nitrophenyl laurate by n-decylamine show that the polarity at the interface of the ionic liquid in oil microemulsions (IL/O) is higher than at the interface of water in oil microemulsions (W/O) despite the fact that the polarity of [bmim][BF(4)(-)] is lower than the polarity of water. (1)H NMR experiments showed that an increase in the ionic liquid content of the microemulsion led to an increase in the interaction between [bmim][BF(4)(-)] and TX-100. The reason for the higher polarity of the microemulsions with the ionic liquid can be explained in terms of the incorporation of higher levels of the ionic liquid at the interface of the microemulsions, as compared to water in the traditional systems. PMID- 21820125 TI - Highly crosslinked poly(dimethylsiloxane) microbeads with uniformly dispersed quantum dot nanocrystals. AB - This study demonstrates how luminescent semiconductor nanocrystals (quantum dots or QDs) can be dispersed uniformly in a poly(dimethylsiloxane) (PDMS) matrix by polymerizing a mixture of the prepolymer oligomers and the nanocrystals with a relatively large concentration of crosslinking molecules. A microfluidic device is used to fabricate PDMS microbeads embedded with the QDs by using flow focusing to first form monodisperse droplets of the prepolymer/crosslinker/nanocrystal mixture in a continuous aqueous phase. The droplets are subsequently collected, and heated to polymerize them into solid microbead composites. The degree of aggregation of the nanocrystals in the matrix is studied by measuring the nonradiative resonance energy transfer (RET) between the nanocrystals. For this purpose, two quantum dots are used with maxima in their luminescence emission spectrum at 560 nm and 620 nm. When the nanocrystals are within the Forster radius (approximately 10 nm) of each other, exciton energy cascades from the QDs which emit at the shorter wavelength to the QDs which emit at the longer wavelength. This energy transfer is quantified, for two concentration ratios of the prepolmer to the crosslinker, by measuring the deviation of the microbead luminescence spectrum from a reference spectrum obtained by dispersing the QD mixture in a solvent (toluene) in which the nanocrystals do not aggregate. For a low concentration of crosslinking molecules relative to the prepolymer (5:1 by weight prepolymer to crosslinker), strong RET is observed as the emission of the 620 nm QDs is increased and the 560 nm QDs is decreased relative to the reference. In the emission spectrum for a higher concentration of crosslinkers (2:1 by weight prepolymer to crosslinker), the resonance energy transfer is less relative to the case of the low concentration of crosslinkers, and the spectrum more closely resembles the reference. This result indicates that the increase in the crosslinker concentration has reduced the nanocrystal aggregation in the cured polymer. The use of crosslinking can serve as a general paradigm for forming, from a prepolymer/nanoparticle mixture, a composite in which the particles are not aggregated. Under the usual conditions the entropic cost to a linearly growing polymer chain of surrounding nanoparticles forces them to aggregate; crosslinking kinetically entraps the particles and circumvents this aggregation driving force. The QD/polymer composite microbeads fabricated in this study find applications in bead-based platforms for high-throughput, multiplexed screening, where the emission spectrum of the QD luminescence can be used as a spectral barcode to label the beads. For microbeads in which the nanocrystals are uniformly dispersed, this barcode is undistorted by energy transfer, and is easily read. PMID- 21820126 TI - Influence of the ionic strength and solid/solution ratio on Ca(II)-for-Na+ exchange on montmorillonite. Part 2: Understanding the effect of the m/V ratio. Implications for pore water composition and element transport in natural media. AB - The aim of the present paper is to clarify previous results showing that selectivity coefficients determined for the exchange of Na(+) for Ca(2+) in montmorillonite were dependent on the solid/solution ratio. The organization of montmorillonite suspensions upon Na(+)/Ca(II) exchange was analyzed by combining optical microscopy, small-angle X-ray scattering and X-ray diffraction. All samples displayed flocculated characteristics, eliminating the possibility of contrasting accessibility of sorption sites with the solid/solution ratio. Modeling of experimental X-ray diffraction patterns was used to quantify the relative proportions of interlayer Ca(2+) and Na(+) cations along the exchange isotherm. The results further confirmed the influence of the solid/solution ratio on the degree of interlayer Ca(II)-for-Na(+) exchange, and specific selectivity coefficients for interlayer sites were determined. The effect of the solid/solution ratio was finally interpreted by the resulting local changes in the solution chemistry. We demonstrated that by accounting for the Donnan effect, the different data can be interpreted using a single selectivity coefficient. The obtained Kc constant was successfully applied to interpret existing hydrogeochemical data on a natural aquitard. This most likely represents a more constrained and valid approach for the modeling of reactive element transport in natural media than does the poorly defined Kd parameter. PMID- 21820127 TI - Facile synthesis of 3D cubic mesoporous silica microspheres with a controllable pore size and their application for improved delivery of a water-insoluble drug. AB - A facile and simplified method was developed for the synthesis of 3D cubic mesoporous SBA-16 with both a spherical morphology and controllable pore size. The addition of CTAB during the synthesis allowed not only good control over the macroscopic morphology but also a significant reduction in the synthesis time. Notably, the pore size can simultaneously be adjusted by simply controlling the heating temperature. The pharmaceutical performance of the resulting SBA-16 for the delivery of the water-insoluble drug indomethacin (IMC), a non-steroidal anti inflammatory agent used as a model drug, was systematically studied using nitrogen adsorption, powder X-ray diffraction, differential scanning calorimetry, infrared spectrometry and in vitro dissolution investigations. It was found that IMC could be effectively loaded into mesoporous SBA-16 via the solvent deposition method. An altered physical state and a marked improvement in the dissolution rate were observed for IMC after being loaded into SBA-16 microspheres. In particular, SBA-16 microspheres with the largest pore size (9.0 nm) and highly open and accessible pore networks exhibited the fastest drug release profile. We envisage that the improved drug delivery profiles obtained using SBA-16 as described in our work will offer an interesting option for the formulation of poorly water-soluble drugs. PMID- 21820128 TI - Rutile TiO2 nanowires on anatase TiO2 nanofibers: a branched heterostructured photocatalysts via interface-assisted fabrication approach. AB - A water-dichloromethane interface-assisted hydrothermal method was employed to grow rutile TiO(2) nanowires (NWs) on electrospun anatase TiO(2) nanofibers (NFs), using highly reactive TiCl(4) as precursor. The water-dichloromethane interface inhibited the formation of rutile NWs in water phase, but promoted the selective radial growth of densely packed rutile NWs on anatase NFs to form a branched heterojunction. The density and length of rutile NWs could be readily controlled by varying reaction parameters. A formation mechanism for the branched heterojunction was proposed which involved (1) the entrapment of rutile precursor nanoparticles at water-dichloromethane interface, (2) the growth of rutile NWs on anatase NFs via Ostwald ripening through the scavengering of interface-entrapped rutile nanoparticles. The heterojunction formed at anatase NF and rutile NW enhanced the charge separation of both under ultraviolet excitation, as evidenced by photoluminescence and surface photovoltage spectra. The branched TiO(2) heterostructures showed higher photocatalytic activity in degradation of rodamine B dye solution than anatase NFs, and the mixture of anatase NFs, and P25 powders, which was discussed in terms of the synergistic effect of enhanced charge separation by anatase-rutile heterojunction, high activity of rutile NWs, and increased specific area of branched heterostructures. PMID- 21820130 TI - Vitamin D supplementation and CD4 count in children infected with human immunodeficiency virus. AB - OBJECTIVE: To evaluate, in a randomized fashion, the impact of vitamin D supplementation on CD4 count and measures of vitamin D homeostasis in children infected with human immunodeficiency virus (HIV). STUDY DESIGN: Children infected with HIV (n = 54) were randomized to receive no supplementation (group 1), vitamin D 5600 IU/week (group 2), or vitamin D 11 200 IU/week (group 3) for 6 months. Viral load, CD4 percent, CD4 count, 25-hydroxyvitamin D (25[OH]D), 1,25 dihydroxyvitamin D, and other measures of vitamin D metabolism were measured at baseline and 6 months later. RESULTS: A total of 53 participants completed the study. The mean age, CD4 percent, CD4 count, and log(10) viral load at baseline were 10.3 +/- 3.9 years, 33% +/- 10%, 927 +/- 468 cells/MUL, and 1.63 (95% CI, 0.76-2.50), respectively. The mean baseline 25(OH)D level was 53.1 +/- 24.8 nmol/L; 85% of participants were vitamin D insufficient or deficient (<75 nmol/L). Serum levels of 25(OH)D increased significantly in participants who received supplementation with vitamin D (P = .0002 and P < .001 for participants receiving 800 IU/day and 1600 IU/day, respectively), but not in participants who did not receive supplementation (P = .27). Participants treated with 1600 IU/day of vitamin D achieved a higher mean increase in 25(OH)D than participants treated with 800 IU/day (P = .02). However, only 67% of the group supplemented with higher dose achieved vitamin D sufficiency. Vitamin D supplementation did not lead to an increase in CD4 percent or CD4 count. CONCLUSION: In children infected with HIV with relatively preserved immune function, vitamin D supplementation in doses as high as 1600 IU/day does not impact CD4 count. Vitamin D insufficiency is common in this population, and achieving vitamin D serum levels of >75 nmol/L may require a daily intake >=1600 IU. PMID- 21820129 TI - Assessing the role of dopamine in limb and cranial-oromotor control in a rat model of Parkinson's disease. AB - Parkinson's disease (PD) is a neurodegenerative disorder primarily characterized by sensorimotor dysfunction. The neuropathology of PD includes a loss of dopamine (DA) neurons of the nigrostriatal pathway. Classic signs of the disease include rigidity, bradykinesia, and postural instability. However, as many as 90% of patients also experience significant deficits in speech, swallowing (including mastication), and respiratory control. Oromotor deficits such as these are underappreciated, frequently emerging during the early, often hemi-Parkinson, stage of the disease. In this paper, we review tests commonly used in our labs to model early and hemi-Parkinson deficits in rodents. We have recently expanded our tests to include sensitive models of oromotor deficits. This paper discusses the most commonly used tests in our lab to model both limb and oromotor deficits, including tests of forelimb-use asymmetry, postural instability, vibrissae-evoked forelimb placing, single limb akinesia, dry pasta handling, sunflower seed shelling, and acoustic analyses of ultrasonic vocalizations and pasta biting strength. In particular, we lay new groundwork for developing methods for measuring abnormalities in the acoustic patterns during eating that indicate decreased biting strength and irregular intervals between bites in the hemi Parkinson rat. Similar to limb motor deficits, oromotor deficits, at least to some degree, appear to be modulated by nigrostriatal DA. Finally, we briefly review the literature on targeted motor rehabilitation effects in PD models. LEARNING OUTCOMES: Readers will: (a) understand how a unilateral lesion to the nigrostriatal pathway affects limb use, (b) understand how a unilateral lesion to the nigrostriatal pathway affects oromotor function, and (c) gain an understanding of how limb motor deficits and oromotor deficits appear to involve dopamine and are modulated by training. PMID- 21820131 TI - Extra-cranial venous flow in patients with multiple sclerosis. AB - INTRODUCTION: Recently, a chronic state of impaired venous drainage from the central nervous system, termed chronic cerebrospinal venous insufficiency (CCSVI) was claimed to be a pathologic condition exclusively seen in patients with multiple sclerosis (MS), suggesting that cerebral venous congestion plays a significant role in the pathogenesis of MS. This hypothesis has gained enormous attention among patients and physicians but has been questioned since. METHODS: Twenty seven patients with MS and 32 healthy controls underwent color extra cranial Doppler exam aimed to detect four parameters of abnormal venous flow: no Doppler-detected flow in the IJV or vertebral veins (VV), reflux in the internal jugular veins (IJVs), venous flow stenosis in the IJVz (cross sectional area <0.3 cm) or reverted postural control in the IJV. RESULTS: Except for one healthy patient, blood flow direction in the IJVs was normal in all subjects. When aiming to detect at least one parameter of abnormal venous flow per subject, two parameters or three parameters no significant difference was found between subjects and controls (p = 0.707, 0.62, 0.849 respectively). CONCLUSION: We found no evidence to suggest that MS patients have excess of CCSVI. In addition we failed to observe a typical venous flow pattern in MS patients. Until carefully designed controlled studies to investigate CCVSI have been completed, invasive and potentially dangerous endovascular procedures as therapy for MS should be discouraged. PMID- 21820132 TI - Circulating androgen levels are associated with subclinical atherosclerosis and arterial stiffness in healthy recently menopausal women. AB - Although increasing evidence supports an association between endogenous sex hormones and cardiovascular disease, the results still remain controversial. This study aims to examine the association between endogenous sex hormones and indices of vascular function and structure. Serum follicle-stimulating hormone, luteinizing hormone, estradiol, testosterone, sex hormone-binding globulin, dehydroepiandrosterone sulfate (DHEAS), and Delta4-androstenedione were measured in 120 healthy postmenopausal women aged 41 to 60 years. Possible associations with surrogate markers of subclinical atherosclerosis, arterial stiffness, and endothelial function were investigated. Indices of arterial structure included carotid and femoral intima-media thickness and atheromatous plaques presence. Indices of arterial function included flow-mediated dilation of the brachial artery, carotid-femoral pulse wave velocity (PWV), and augmentation index. Total testosterone and free androgen index (FAI) were the most important predictors of common carotid artery intima-media thickness (beta = 0.376 and beta = 0.236, P < .001 and P = .014, respectively). Similarly, FAI was the only significant independent predictor of PWV (beta = 0.254, P = .027) after adjusting for age, smoking, body mass index, homeostasis model assessment of insulin resistance, and blood lipids. Free estrogen index showed a positive association with PWV, independently of age, smoking, and body mass index, but not of homeostasis model assessment of insulin resistance and blood lipids. Age-adjusted levels of DHEAS exhibited a significant independent negative association with measures of augmentation index. Follicle-stimulating hormone, luteinizing hormone, estradiol, sex hormone-binding globulin, and Delta4-androstenedione were not associated with any of the vascular parameters independently of traditional cardiovascular risk factors. Higher serum testosterone and FAI are associated with subclinical atherosclerosis in healthy recently menopausal women. This association is independent of traditional cardiovascular risk factors or insulin resistance. On the contrary, serum DHEAS exhibits a negative association with arterial stiffness. PMID- 21820133 TI - Fatness, fitness, and cardiometabolic risk factors in middle-aged white men. AB - The objective was to test the hypothesis that traditional and novel cardiometabolic risk factors would be significantly different in groups of men of different fatness and fitness. Total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, glucose, insulin, high-sensitivity C-reactive protein, alanine aminotransferase, aspartate aminotransferase, gamma-glutamyltransferase, leptin, adiponectin, tumor necrosis factor-alpha, interleukin-6, interleukin-10, fibrinogen, and insulin resistance were assessed in 183 nonsmoking white men aged 35 to 53 years, including 62 who were slim and fit (waist girth <=90 cm and maximal oxygen consumption [VO(2)max] above average), 24 who were slim and unfit (waist girth <=90 cm and VO(2)max average or below), 39 who were fat and fit (waist girth >=100 cm and VO(2)max above average), and 19 who were fat and unfit (waist girth >=100 cm and VO(2)max average or below). Seventy-six percent gave blood on 2 occasions, and the average of 1 or 2 blood tests was used in statistical tests. Waist girth (centimeters) and fitness (milliliters of oxygen per kilogram of fat-free mass) were associated with high-density lipoprotein cholesterol, leptin, and insulin resistance after adjustment for age, saturated fat intake, and total energy intake. High-density lipoprotein cholesterol, triglycerides, alanine aminotransferase, and insulin resistance were significantly different in men who were fat and fit and those who were fat and unfit. These data suggest that differences in lipid and lipoprotein concentrations, liver function, and insulin resistance may explain why the risks of chronic disease are lower in men who are fat and fit than those who are fat and unfit. PMID- 21820134 TI - The association of diabetes mellitus with liver, colon, lung, and prostate cancer is independent of hypertension, hyperlipidemia, and gout in Taiwanese patients. AB - Studies have shown an association between diabetes and cancer in Western countries; but this, as well as the influence of associated metabolic factors, must be confirmed by a prospective study in other population groups. This study aimed to investigate whether the strong association of cancer and diabetes is independent from the influence of hypertension, dyslipidemia, and gout in the Taiwanese population. A total of 985,815 study subjects were identified from the National Health Insurance in 1997 and followed up from 1998 to 2009. The demographic characteristics between patients with diabetes and cancer, including age, sex, hypertension, dyslipidemia, and gout, were analyzed using the chi(2) test. Cox proportional hazard regression models were used to determine the independent effects of diabetes on the risks of cancer. A total of 104,343 diabetic patients were followed up from 1998 to 2009. After adjusting for sex, age, hypertension, dyslipidemia, and gout, the incidences of cancer at any site and in the liver, colon, lungs, and prostate in diabetic patients were independently higher, with risk ratios of 1.56 (95% confidence interval [CI], 1.43-1.71), 1.67 (95% CI, 1.39-2.01), 1.75 (95% CI, 1.49-2.06), 1.54 (95% CI, 1.26-1.88), and 1.56 (95% CI, 1.19-2.04), respectively. Only breast cancer did not show any clinical significance. There was an increased incidence of cancer at any site in the diabetic patients compared with nondiabetic subjects. The most common cancers were liver, colon, lung, breast, and prostate cancer; and except for breast cancer, their incidences increased independently of hypertension, dyslipidemia, and gout in patients with diabetes. PMID- 21820135 TI - Effects of high-fat diet and regular aerobic exercise on global gene expression in skeletal muscle of C57BL/6 mice. AB - Exercise training may decrease insulin resistance (IR) and increase glucose tolerance. However, the adaptive responses in skeletal muscle at the molecular and genetic level have not been clearly understood. Here we used oligonucleotide microarray analysis to dissect the effects of high-fat diet (HFD) and regular aerobic exercise on global gene expression in the skeletal muscle of C57BL/6 mice. C57BL/6 male mice (n = 40) were fed with normal chow (n = 20) and HFD (n = 20) for 8 weeks. The animals were then divided into 1 of 4 intervention groups: groups of mice fed with normal chow and HFD accompanied with 6-week treadmill running (60 min/d) at 75% maximum oxygen consumption (NE and HE) and their sedentary control groups (NC and HC). Oligonucleotide microarray was applied to analyze the effect of aerobic exercise and HFD at the transcriptional level, and selected genes were confirmed by real-time polymerase chain reaction. Our data showed that 6 weeks of aerobic exercise improved the plasma lipid profile and reversed the glucose intolerance induced by HFD. A set of 503 genes was differentially expressed in samples of HC mice as compared with those of the NC group. Forty of those genes were identified as involved in the process of aerobic exercise ameliorating IR by comparing the changes in expression profiles between the HE and HC groups. These changes include genes involved in metabolism, defense, and inflammation and genes of unknown function. Aerobic exercise training is able to ameliorate IR of mice maintained with HFD. The biochemical pathways involved in ameliorating IR identified in this study may represent potential targets for the treatment of IR. PMID- 21820136 TI - Influence of resting energy expenditure on blood pressure is independent of body mass and a marker of sympathetic tone. AB - Two recent examinations reported a strong association between blood pressure (BP) and resting energy expenditure (REE), independent of body mass and body composition. Both reports postulate that neurohumoral processes that contribute to variation in REE may partly mediate the body mass effect on BP. Therefore, we examined the relationship of REE and BP in 108 asymptomatic women (a) to confirm previous findings in a novel population and (b) to examine the impact of a marker of sympathetic tone on this relationship, as this was indicated as a potentially salient intermediary in previous reports. All testing was performed during a 4 day admission to the General Clinical Research Center. Resting energy expenditure was measured by indirect calorimetry, body composition was determined by dual energy x-ray absorptiometry, and 24-hour fractionated urinary norepinephrine was determined by high-performance liquid chromatography. Multiple linear regression revealed REE as a significant predictor of systolic BP (beta = 0.30, P = .04), independent of race (beta = 0. 28, P = .01), age (beta = -0.02, P = .80), height (beta = -0.38, P = .08), fat mass (beta = 0.22, P = .20), fat-free mass (beta = 0.08, P = .65), and 24-hour fractionated urinary norepinephrine (beta = 0.06, P = .57); and the same model using diastolic BP as the dependent variable approached significance (beta = 0.24, P = .09). This study affirms previous findings that REE may be a potential mediator in resting BP, independent of many well-cited factors and, additionally, a marker of sympathetic tone. PMID- 21820137 TI - The quest for the perfect biomarker of long-term glycemia: new studies, new trials and tribulations. PMID- 21820138 TI - Acute hypoglycemia causes depressive-like behaviors in mice. AB - Reports in humans advocate a link between hypoglycemia and altered mood. Such observations, however, have not been mechanistically explored. Here we examined depressive-like behaviors in mice resulting from acute hypoglycemia. Mice were fasted for 12 hours and then administered intraperitoneal insulin to induce a blood glucose nadir of 50 mg/dL at 0.75 hour after injection that by 2 hours postinjection had returned to normal. The behaviors of locomotion, forced swim, saccharin preference, and novel object recognition were subsequently examined. Mice made hypoglycemic showed depressive-like behaviors 24 hours after resolution of hypoglycemia as evidenced by increased immobility in the forced swim test (FST) and reduced saccharin preference. Movement and memory were not impacted by hypoglycemia 24 hours after its resolution. By 48 hours posthypoglycemia, depressive-like behaviors resolved. In contrast, neither peripheral insulin administration without resultant hypoglycemia nor intracerebroventricular insulin administration altered performance in the FST. The antidepressants fluoxetine and desipramine prevented hypoglycemia-induced immobility in the FST, as did the antiadrenergic agents phentolamine, metoprolol, and butoxamine. Epinephrine and norepinephrine administration caused increased immobility in the FST at 24 hours postadministration that subsequently resolved by 48 hours. These data indicate that, in mice, acute hypoglycemia through adrenergic pathways caused depressive like behaviors that exist well beyond the resolution of hypoglycemia. PMID- 21820140 TI - The relationship between adiponectin, an adiponectin gene polymorphism, and high density lipoprotein particle size: from the Mima study. AB - This study examined the association among serum adiponectin levels, a single nucleotide polymorphism (SNP) of the adiponectin gene, and the size of serum high density lipoprotein (HDL) particles in a general population. A total of 275 subjects were examined as part of the community-based Mima study. Serum adiponectin levels were measured with an enzyme-linked immunosorbent assay. Serum small-sized HDL was measured with the electrophoretic separation of lipoproteins using the Lipoprint system. Single nucleotide polymorphism G276T (rs1501299, SNP276) of the adiponectin gene was determined with a fluorescent allele-specific DNA primer assay system. Age- and sex-adjusted correlation test revealed a significant inverse relationship between small-sized HDL and adiponectin levels (r = -0.236, P < .001). More percentages of small-sized HDL were observed in the subjects with the SNP276 G/G and G/T genotypes than in those with the T/T genotype (5.5% +/- 5.0% vs 3.0% +/- 2.9%, P = .016). In a multiple regression analysis, small-sized HDL was significantly and independently correlated with triglycerides levels (beta = 0.133, P = .030), adiponectin levels (beta = -0.242, P < .001), and the SNP276 G allele (beta = -0.142, P = .014). Our findings indicated that adiponectin and SNP276 of the adiponectin gene may modify the size of HDL particles. PMID- 21820139 TI - Severity and outcome of acute stroke in women: relation to adrenal sex steroid levels. AB - Adrenal sex steroids exert diverse metabolic and neurobiological actions. Their levels have been associated with cardiovascular disease, but data concerning cerebrovascular disease are lacking. The objective of our study was to investigate the role of adrenal sex steroids in a female population suffering an acute stroke. We addressed the question of whether their levels are associated with disease severity and prognosis. A 2-year cohort study was performed in 2 tertiary hospitals, where we prospectively studied 302 consecutive postmenopausal female patients hospitalized for an acute stroke. Neurological severity on admission was assessed by the National Institutes of Health Stroke Scale; and handicap 1 month after stroke, with the modified Rankin Scale. Delta4 androstenedione levels were positively and dehydroepiandrosterone sulfate was inversely associated with stroke severity (r = 0.142, P = .014 and r = -0.153, P = .008, respectively), and both parameters remained as significant determinants even after entering other confounders in the multivariate model (r = 0.118, P = .039 and r = -0.150, P = .011, respectively). Levels of Delta4-androstenedione were significantly associated with 1-month mortality in the multivariate analysis (odds ratio with 95% confidence intervals: 1.540 [1.107-2.138)], P = .010). Delta4-androstenedione and dehydroepiandrosterone sulfate levels were associated with poor outcome in the univariate analysis, that is, combined severe handicap (modified Rankin Scale >=4) and death, 1 month poststroke, although this was not significant in the multivariate analysis. Adrenal sex steroids, and especially Delta4-androstenedione, are significantly associated with stroke severity on admission and short-term prognosis among female stroke subjects. Well-designed prospective studies will further clarify their role in cerebrovascular disease. PMID- 21820141 TI - Use of a two-stage insulin infusion study to assess the relationship between insulin suppression of lipolysis and insulin-mediated glucose uptake in overweight/obese, nondiabetic women. AB - Differences in insulin regulation of free fatty acids (FFAs) are not readily apparent at the same insulin concentrations used to differentiate relative insulin-mediated glucose disposal. Resistance to insulin-mediated glucose disposal and higher daylong FFA concentrations occur more commonly in obese individuals. However, the relationship between the ability of insulin to suppress FFA release from adipose tissue and stimulate glucose disposal in muscle has not been clearly defined in this population. The current study was initiated to test the hypothesis that these 2 facets of insulin action are related, with greater defects in insulin-mediated glucose disposal associated with less effective insulin inhibition of FFA release from adipose tissue. Subjects included 56 healthy nondiabetic overweight/moderately obese women classified as insulin resistant or insulin sensitive based on whole-body glucose disposal. All underwent a modified 240-minute 2-stage insulin infusion with basal (~15 uU/mL) and physiologically elevated (~80 uU/mL) steady-state insulin concentrations. Plasma glucose, insulin, FFA, and glycerol were measured throughout. Whereas plasma glucose differed most during physiological hyperinsulinemia in insulin resistant vs insulin-sensitive subjects, plasma FFA/glycerol differed most during basal insulin concentrations. The FFA concentrations during the basal insulin steady state correlated highly (r = 0.85, P < .001) with glucose concentrations during the hyperinsulinemic steady state. Overweight/moderately obese women exhibit dramatic differences in the ability of insulin to suppress plasma FFA, which correlate highly with differences in insulin-mediated glucose disposal. Variability in insulin regulation of FFA is most apparent at basal insulin concentrations, whereas differences in glucose disposal are most apparent during physiologic hyperinsulinemia. Both can be quantified using a simple 2-stage insulin infusion study, with first-stage FFA concentrations and second-stage glucose concentrations being most informative. PMID- 21820142 TI - Association between the severity of obstructive sleep apnea and the ratio of low density lipoprotein cholesterol to high-density lipoprotein cholesterol. AB - The positive association between the ratio of serum low-density lipoprotein cholesterol (LDL-C) to serum high-density lipoprotein cholesterol (HDL-C) and cardiovascular events has recently been receiving much attention. However, the association between the severity of obstructive sleep apnea (OSA) and this ratio has not yet been investigated. Accordingly, we sought to clarify this association and the effect of continuous positive airway pressure (CPAP) therapy on the ratio. We performed polysomnography and LDL-C/HDL-C measurements in 215 patients who were suspected of having OSA. Furthermore, LDL-C/HDL-C was again evaluated 6 months after polysomnography in 30 OSA patients for whom CPAP therapy was initiated and continued, and in 11 age- and sex-matched OSA patients for whom the therapy could not be initiated. The LDL-C/HDL-C correlated positively with apnea hypopnea index (rho = 0.28, P < .001) and negatively with the lowest arterial oxyhemoglobin saturation (rho = -0.30, P < .001). Multivariate regression analysis revealed that ln apnea-hypopnea index (or ln lowest arterial oxyhemoglobin saturation) was independently associated with LDL-C/HDL-C. The LDL C/HDL-C decreased after 6 months in the CPAP group (2.29 +/- 0.67 to 2.11 +/- 0.74, P = .02), whereas it did not change in the non-CPAP group (2.65 +/- 0.82 to 2.62 +/- 0.66, P = .81). The severity of OSA was independently associated with LDL-C/HDL-C, and LDL-C/HDL-C was significantly reduced at 6 months after CPAP therapy. These findings suggest that LDL-C/HDL-C increases in proportion to the severity of OSA, which may contribute partly to an increased risk for cardiovascular events in OSA patients. PMID- 21820143 TI - Fate of toxic cyanobacterial cells and disinfection by-products formation after chlorination. AB - Drinking water sources in many regions are subject to proliferation of toxic cyanobacteria (CB). Chlorination of source water containing toxic cyanobacterial cells for diverse treatment purposes might cause cell damage, toxin release and disinfection by-products (DBP) formation. There is limited information available on chlorination of different toxic CB cells and DBP formation potentials. This work: (1) determines the extent of lysis and toxins/taste and odor compound release in chlorinated natural water from CB cells (Anabaena circinalis, Microcystis aeruginosa, Cylindrospermopsis raciborskii, and Aphanizomenon issatsckenka) from laboratory cultures and natural blooms; (2) assesses the rates of oxidation of toxins by free chlorine under environmental conditions; (3) studies the DBP formation associated with the chlorination of CB cell suspensions. With chlorine exposure (CT) value of <4.0 mg min/L >60% cells lost viability causing toxin release. Cell membrane damage occurred faster than oxidation of released toxins. Kinetic analysis of the oxidation of toxins in natural water revealed significant differences in their susceptibility to chlorine, saxitoxins being the easiest to oxidize, followed by cylindrospermopsin and microcystin-LR. Furthermore, concentrations of trihalomethanes and haloacetic acids (<40 MUg/L) and N-nitrosodimethylamine (<10 ng/L) as chlorination by products were lower than the guideline values even at the highest CT value (220 mg min/L). However, the DBP concentrations in environmental bloom conditions with very high cell numbers were over the guideline values. PMID- 21820144 TI - An analytical solution to contaminant diffusion in semi-infinite clayey soils with piecewise linear adsorption. AB - The adsorption of contaminants onto soil particles typically is nonlinear if the contaminant concentration is sufficiently high. A simplified piecewise linear adsorption isotherm consistent with experimental results is proposed as an approximation for nonlinear adsorption behavior. This approximation allows for the use of analytical solution to model solute diffusion of contaminants that exhibit nonlinear adsorption. A moving boundary is introduced to represent significant changes in the retardation factor of clay with an increase in solute concentration. The proposed analytical solutions were validated using experimental data presented in the literature. There is negligible difference between the results obtained by the proposed analytical solution and those obtained by the linear model when C(m)/C(0) reached 0.5. The results also show that the model based on linear adsorption using the initial secant of the Freundlich isotherm leads to significantly lower estimated breakthrough time for the contaminant of interest than that obtained using the proposed model. The earlier breakthrough is due to an under-estimation of the amount of adsorption. The proposed method is relatively simple to apply and can be used for evaluating experimental results and verifying more complex numerical models. PMID- 21820145 TI - High-grade papillary urothelial carcinoma of the urinary tract: a clinicopathologic analysis of a post-World Health Organization/International Society of Urological Pathology classification cohort from a single academic center. AB - About one half of all bladder neoplasms are noninvasive, and in those, the histologic grade is a crucial prognosticator. Few single-center studies have assessed the recurrence, progression, and cancer-related mortality rates of noninvasive high-grade papillary urothelial carcinomas. With this aim, we evaluated the clinicopathologic and outcome features of 85 patients with high grade papillary urothelial carcinoma. Median age was 68 years, and 80.5% were men. Tumor size ranged from 0.3 to 13.0 cm (median, 1.6 cm). Recurrence was found in 36.5% of the patients, whereas tumor progression, defined as invasion of lamina propria or beyond, was identified in 40% of all cases. When present, lesion reappearance involved mostly 1 to 2 episodes. Metastasis appeared in 20% of the patients, and 15% died of disseminated bladder cancer. All cancer-related deaths occurred in the group of patients with progression, whereas patients with recurrence showed similar outcomes to those with no recurrence. For patients with tumor progression, clinical stage was significantly associated with outcome (P = .002). As for prognosis, tumor size was strongly associated with progression (P < .01). In conclusion, recurrence, progression, and cancer-specific mortality rates were 36.5%, 40%, and 15%, respectively. All the patients who died of cancer had a history of tumor progression. Patients with recurrences showed similar outcomes to those with no recurrence. Tumor size was strongly associated with tumor progression and cancer-specific survival, whereas clinical stage was significantly associated with outcome in the progression group. In light of the high recurrence and progression rates of high-grade papillary urothelial carcinoma, strict clinical surveillance aimed to detect early recurrent lesions, especially in patients with larger tumors, is warranted. PMID- 21820146 TI - Indeterminate cell tumor of the spleen. AB - Indeterminate cell tumor is an extremely rare neoplasm that mainly occurs in the skin. We report a case of indeterminate cell tumor arising from the spleen, a previously unreported site for indeterminate cell tumor. Histologically, the tumor showed nests, nodules, and sheets of large polygonal cells with mostly oval nuclei; open chromatin; variable nucleoli; and abundant, eosinophilic cytoplasm. Some cells possessed irregularly convoluted nuclei with nuclear grooves and granular cytoplasm, suggestive of Langerhans cells. Immunohistochemically, the tumor cells were diffusely positive for S-100 and CD1a and negative for Langerin. No Birbeck granules were found by electron microscopy. Clinical and radiologic examination showed no other organomegaly or lymphadenopathy. A diagnosis of primary indeterminate cell tumor of the spleen was rendered. To the best of our knowledge, this is the first indeterminate cell tumor reported in the spleen. Biologic insights into dendritic cells in the spleen and the pertinent literature on these entities are reviewed. PMID- 21820147 TI - Characteristics of positive surgical margins in robotic-assisted radical prostatectomy, open retropubic radical prostatectomy, and laparoscopic radical prostatectomy: a comparative histopathologic study from a single academic center. AB - Studies detailing differences in positive surgical margin among open retropubic radical prostatectomy, laparoscopic radical prostatectomy, and robotic-assisted laparoscopic radical prostatectomy are lacking. A retrospective review of all prostatectomies with positive surgical margin performed at our center in 2007 disclosed 99 cases, 6 (5%) of which were reinterpreted cases as having negative margins. Ninety-three cases were, therefore, included, corresponding to 37 retropubic radical prostatectomies, 19 laparoscopic radical prostatectomies, and 37 robotic-assisted laparoscopic radical prostatectomies. The relationship of positive surgical margin characteristics to clinicopathologic parameters and biochemical recurrence was assessed. The most commonly found positive surgical margin site was the apex/distal third in all groups (62% retropubic prostatectomies, 79% laparoscopic prostatectomies, 60% robotic-assisted prostatectomies). Total linear length of positive surgical margin sites was significantly correlated with preoperative prostate-specific antigen, preoperative prostate-specific antigen density, pT stage, and tumor volume (P <= .001). We found no significant differences among the 3 groups with respect to total linear length, number of foci, laterality, or location of positive surgical margin. The rate of biochemical recurrence was also comparable in the 3 groups. On univariate analyses, biochemical recurrence was significantly associated with preoperative prostate-specific antigen values, preoperative prostate-specific antigen density, Gleason score, number of positive surgical margins, and total linear length of positive surgical margin (P <= .02). Only preoperative prostate specific antigen density and number of positive surgical margin foci were statistically significant (P <= .03) independent predictors of biochemical recurrence. We found no significant difference in positive surgical margin characteristics or biochemical recurrence among the 3 radical prostatectomy modalities. Preoperative prostate-specific antigen density and number of positive surgical margin foci were the only independent predictors of biochemical recurrence. PMID- 21820148 TI - Vulvovaginal myofibroblastoma: expanding the morphological and immunohistochemical spectrum. A clinicopathologic study of 10 cases. AB - We analyzed the clinicopathologic features of 10 cases of vulvovaginal myofibroblastoma to widen its morphological and immunohistochemical spectrum. Most tumors (8/10 cases) were located in the vagina. The patients' age ranged from 44 to 77 years, and tumor size ranged from 0.4 to 3 cm. Histologically, 5 tumors had the characteristics of vulvovaginal myofibroblastoma. In addition, we identified 3 cases composed of spindle-shaped cells arranged in short fascicles with intervening thick collagen bands, closely reminiscent of mammary myofibroblastoma. Notably, 1 case resembled Sertoli cell tumor, sclerosing type, because of its predominant cord-like arrangement. In another case, there were highly cellular areas composed of uniform-packed, rounded cells that, at low magnification, looked like a malignant "small round blue cell tumor." A variably thick band of native connective tissue separated tumors from the overlying squamous epithelium even if, in 3 cases, tumor cells extended up to the epithelium. In 7 cases, a variable number of vessels showed perivascular hyalinization. Only rare mitotic figures were identified. All tumors were diffusely positive for vimentin, desmin, and CD99. A variable staining intensity was observed for CD34, Bcl-2, B-cell lymphoma 2 (Bcl-2) CD10, estrogen receptor, and progesterone receptor in most cases, but none expressed alpha-smooth muscle actin. We emphasize that vulvovaginal myofibroblastoma encompasses a morphological spectrum wider than previously described. The overlapping morphological and immunohistochemical features of vulvovaginal and mammary myofibroblastomas led us to speculate that these are related entities with morphological variations on a common basic theme likely dependent on anatomical location. PMID- 21820149 TI - Dysplastic lesions in inflammatory bowel disease show increased positivity for the stem cell marker aldehyde dehydrogenase. AB - The chronic inflammatory state in patients with inflammatory bowel disease places them at a substantially elevated risk for developing colorectal carcinoma. Moreover, distinguishing an inflammatory phenotype from dysplasia in inflammatory bowel disease can be difficult and has significant patient management implications. To this end, we studied the expression of the cancer stem cell marker aldehyde dehydrogenase to determine whether expression is increased in dysplastic lesions arising in inflammatory bowel disease. We studied 54 patients with inflammatory bowel disease who underwent surgical resection. Of the 54 patients, 13 exhibited high-grade dysplasia or adenocarcinoma, 19 exhibited low grade dysplasia, and 22 displayed only inflammatory atypia. Staining for aldehyde dehydrogenase was evaluated in the cytoplasm of epithelial and stromal cells. We determined the intensity of staining (0 to 3+) and the percentage of cells staining positively. Positive staining for aldehyde dehydrogenase was observed in 92% (12/13) of cases with high-grade dysplasia/adenocarcinoma and in 95% (18/19) of cases with low-grade dysplasia. Cases with inflammatory atypia showed positive staining in 45% (10/22) of cases. The sensitivity for aldehyde dehydrogenase in epithelial cells as a marker for dysplasia was 95%; specificity was 55%. For stromal cells adjacent to dysplasia, sensitivity was 44%; and specificity was 68%. Although the sensitivity of aldehyde dehydrogenase for dysplasia was excellent, specificity was less than ideal. Our findings support the hypothesis that dysplasia in inflammatory bowel disease is associated with increased aldehyde dehydrogenase positivity, which supports the cancer stem cell hypothesis. PMID- 21820150 TI - Regulatory role of p53 in cancer metabolism via SCO2 and TIGAR in human breast cancer. AB - Cancer cells show a higher rate of anaerobic respiration than normal cells. The exact mechanisms for this higher glycolysis rate in cancer cells remain to be elucidated. The results of recent studies have indicated that p53, the most commonly mutated tumor suppressor gene, may have important functions in the regulation of energy-generating metabolic pathways that switch from oxidative phosphorylation to glycolysis via the synthesis of cytochrome c oxidase 2 (SCO2), p53-transactivated TP53-induced glycolysis (TIGAR), and apoptosis regulator. We evaluated the expression of p53, SCO2, TIGAR, and COX in 113 cases of invasive breast cancer using immunohistochemistry. A high expression of p53, SCO2, TIGAR, and COX was noted in 27.5% (31 cases), 84.1% (95 cases), 74.3% (84 cases), and 73.4% (83 cases) of the breast tumors, respectively. A high p53 expression was significantly associated with low expression levels of SCO2 (P = .008), COX (P < .0001), and TIGAR (P = .007). On the survival analysis, the low SCO2-expressing breast cancer patients showed a significantly poorer prognosis than that of the high SCO2-expressing breast cancer patients (P = .0078). These results suggest that p53 can modulate the metabolic pathways via the proteins SCO2 and TIGAR in human breast cancer. PMID- 21820151 TI - Anal duct carcinoma: a report of 5 cases. AB - Anal duct carcinoma (ADC) is a rare lesion composed of glands undermining non neoplastic squamous epithelium. We describe the clinicopathologic characteristics and follow-up of 5 cases of ADC. Four definitive cases had tissue available for immunohistochemistry (IHC; CK7, CK20, prostate-specific antigen [PSA], estrogen/progesterone receptors [ER/PR], and p16) and in situ hybridization (ISH) for high-risk human papillomavirus (HR-HPV); a fifth case, with a history of ADC, had limited tissue for immunolabeling with only CK7, CK20, and p16. The mean patient age was 69.8 years. All 5 cases were CK7-positive and p16-negative. Four of 5 cases were CK20-negative. All cases with sufficient tissue (4/4) were negative for HR-HPV by ISH, PSA-negative (men), and ER/PR-negative (women). Four of 5 patients had previous malignancies, and in all 4 cases with sufficient tissue, metastasis was excluded with IHC. Of 5 patients, 3 developed metastases, whereas 2 had isolated local recurrences. ADCs are neoplasms with metastatic potential and can result in poor outcomes. PMID- 21820152 TI - Fluorescence in situ hybridization mapping of esophagectomy specimens from patients with Barrett's esophagus with high-grade dysplasia or adenocarcinoma. AB - The progression of intestinal metaplasia to esophageal adenocarcinoma in patients with Barrett's esophagus is partly driven by chromosomal alterations that activate oncogenes and inactivate tumor suppressor genes. The goal of this study was to determine how alterations of 4 frequently affected genes correlate with the range of histopathologic lesions observed in resected esophagi of patients with Barrett's esophagus. Fluorescence in situ hybridization was used to assess 83 tissue sections from 10 Barrett's esophagus esophagogastrectomy specimens for chromosomal alterations of 8q24 (MYC), 9p21 (CDKN2A; alias P16), 17q12 (ERBB2), and 20q13.2 (ZNF217). Histologic lesions assessed included gastric metaplasia (n = 8), intestinal metaplasia (n = 43), low-grade dysplasia (n = 28), high-grade dysplasia (n = 25), and adenocarcinoma (n = 16). Histologic maps showing the correlation between fluorescence in situ hybridization abnormalities and corresponding histology were created for all patients. Chromosomal abnormalities included 9p21 loss, single locus gain, and polysomy. A greater number of chromosomal alterations were detected as the severity of histologic diagnosis increased from intestinal metaplasia to adenocarcinoma. All patients had alterations involving the CDKN2A gene. CDKN2A loss was the only abnormality detected in 20 (47%) of 43 areas of intestinal metaplasia. Polysomy, the most common abnormality in dysplastic epithelium and adenocarcinoma, was observed in 16 (57%) of 28 low-grade dysplasia, 22 (88%) of 25 high-grade dysplasia, and 16 (100%) of 16 adenocarcinoma. The findings of this study improve our understanding of the role that chromosomal instability and alterations of tumor suppressor genes such as CDKN2A and oncogenes such as ERBB2 play in the progression of intestinal metaplasia to adenocarcinoma in patients with Barrett's esophagus. PMID- 21820153 TI - Pediatric adrenocortical tumors: morphological diagnostic criteria and immunohistochemical expression of matrix metalloproteinase type 2 and human leucocyte-associated antigen (HLA) class II antigens. Results from the Italian Pediatric Rare Tumor (TREP) Study project. AB - Pediatric adrenocortical tumors are neoplasms that only rarely occur in pediatric patients. Their clinical behavior is often unpredictable, and the histologic criteria of malignancy used in adults are not always useful in children. The aim of this study was to validate the prognostic value of the pathologic criteria of Wieneke et al and to evaluate the potential prognostic expression of matrix metalloproteinase 2 and human leucocyte-associated antigen (HLA) class II antigens in a series of 20 pediatric patients affected by adrenocortical tumors, who were enrolled in the Italian Pediatric Rare Tumor (TREP) Study between 2000 and 2007. The age range was 0 to 17.5 years (mean, 7.28 years) with a male-female ratio of 1:2. The mean follow-up was 64.4 months. The histologic diagnoses were reviewed, and the cases were classified using the criteria for malignancy proposed by Wieneke et al. The immunohistochemical expression of matrix metalloproteinase 2 and HLA class II antigens was scored by semiquantitative analysis and compared with the clinicopathologic parameters and outcome. Based on the scoring system of Wieneke et al, 7 tumors were classified as malignant; 12 tumors, as benign; and only 1 tumor, with "unpredictable behavior." In all cases, the clinical behavior was consistent with the pathologic criteria of Wieneke et al. Notably, areas of regressive myxoid changes, not included among the criteria of Wieneke et al, were observed in all but 1 case of malignant tumors and only in 2 cases of benign tumors. Matrix metalloproteinase 2 was focally to diffusely expressed in all malignant and in most benign tumors. HLA class II antigens immunoreactivity was absent in all benign tumors and restricted to rare isolated cells in most malignant tumors. Our findings confirm that the pathologic scoring system of Wieneke et al is a simple and reproducible diagnostic tool to predict prognosis in pediatric adrenocortical tumors. Unlike in their adult counterpart, the expression of matrix metalloproteinase 2 or the loss of HLA class II antigens does not discriminate between benign and malignant tumors in children. Although pediatric adrenocortical tumors seem to be similar histologically to their adult counterparts, it is likely that they have distinctive molecular features. PMID- 21820154 TI - Metallothionein expression in colorectal cancer: relevance of different isoforms for tumor progression and patient survival. AB - Metallothioneins are a family of small, cysteine-rich proteins with many functions. Immunohistochemical evaluation of all metallothionein 1 + 2 isoforms in colorectal tumors has demonstrated an important down-regulation compared with normal tissue, although its prognostic significance is unclear. Moreover, the contribution of individual isoforms to overall metallothionein down-regulation is not known. To address these important issues, we analyzed the messenger RNA expression levels of all functional metallothionein 1 + 2 isoforms by quantitative reverse transcription polymerase chain reaction in 22 pairs of normal and tumor-microdissected epithelia and correlated these to the overall immunohistochemical protein expression. Our results showed that 5 isoforms (MT1G, 1E, 1F, 1H, and 1M) were lost during the transition from normal mucosa to tumor, whereas MT1X and MT2A were less down-regulated, and their expression was correlated with overall protein positivity. Second, we showed that MT1G hypermethylation occurred in cell lines and in 29% of tumor samples, whereas histone deacetylase inhibitors are able to induce most isoforms. Furthermore, we analyzed by immunohistochemistry 107 normal mucosae, 25 adenomas, 81 carcinomas, and 19 lymph node metastases to evaluate metallothionein expression during different stages of cancer development and to assess its relationship to patient survival. A lower immunohistochemical expression was associated with poorer survival, although it was not an independent predictor. Overall, this study identifies for the first time the relevant metallothionein isoforms for colorectal cancer progression, supports the concept that their loss is associated with worse prognosis, and suggests 2 mechanisms for epigenetic repression of metallothionein expression in colorectal tumors. PMID- 21820155 TI - Sensitivity and specificity of finding of multinucleate trophoblastic giant cells in decidua in placentas from high-risk pregnancies. AB - This is a retrospective analysis of sensitivity and specificity of clustered placental basal plate multinucleate trophoblastic giant cells for various clinical conditions and placental lesions associated with fetal and placental hypoxia. Selected clinical and placental parameters of 375 consecutive cases of placentas with clusters of multinucleate trophoblastic giant cell (at least 3 cells with at least 3 nuclei) in the decidua (study group) were compared with all remaining 2674 placentas concurrently studied (control group) in 20-week-or-more high-risk pregnancies. Multinucleate trophoblastic giant cell was found in 12.3% of placentas. The study group had statistically significantly more cases of preeclampsia, abnormal Dopplers, induction of labor, and cesarean sections, with its placentas lighter and with more common other hypoxic lesions than in the control-group placentas. The multinucleate trophoblastic giant cell prevalence negatively correlated with gestational age (R = -0.56), peaking at the turn of the second and the third trimesters of pregnancy and declining afterward, and most strongly correlated with the excessive amount of extravillous trophoblasts in the chorionic disc (R = +0.33). The sensitivity of multinucleate trophoblastic giant cells was, on average, 3 times lower than the specificity, the latter averaging greater than 90%. In conclusion, finding of multinucleate trophoblastic giant cells is not exclusively limited to uteroplacental malperfusion of preeclampsia but is also seen in other types of high-risk pregnancy and in association with other placental hypoxic lesions and patterns. Multinucleate trophoblastic giant cells most likely reflect a premature fusion of extravillous trophoblasts because of several factors, likely including also hypoxia. Being highly specific, finding the multinucleate trophoblastic giant cells is unlikely to give a false-positive result and therefore has high value in retrospectively explaining the perinatal morbidity and mortality. PMID- 21820156 TI - The sensitivity of aquatic insects to divalent metals: a comparative analysis of laboratory and field data. AB - Laboratory studies have traditionally indicated that aquatic insects are relatively insensitive to metals while field studies have suggested them to be among the most sensitive aquatic invertebrate taxa. We reviewed and synthesized available studies in the literature to critically assess why this discrepancy exists. Despite the intense effort to study the effects of metals on aquatic biota over the past several decades, we found studies specific to insects to still be relatively limited. In general, the discrepancy between laboratory and field studies continues with few efforts having been made to elucidate the ecological and physiological mechanisms that underlie the relative sensitivity (or insensitivity) of aquatic insects to metals. However, given the limited data available, it appears that aquatic insects are indeed relatively insensitive to acute metal exposures. In contrast, we suggest that some aquatic insect taxa may be quite sensitive to chronic metal exposure and in some cases may not be protected by existing water quality criteria for metals. The discrepancy between laboratory and field studies with respect to chronic sensitivity appears to largely be driven by the relatively short exposure periods in laboratory studies as compared to field studies. It also appears that, in some cases, the sensitivity of aquatic insects in field studies may be the result of direct effects on primary producers, which lead to indirect effects via the food chain on aquatic insects. Finally, available evidence suggests that diet is an important source of metal accumulation in insects, but to date there have been no conclusive studies evaluating whether dietary metal accumulation causes toxicity. There is a clear need for developing a more mechanistic understanding of aquatic insect sensitivity to metals in long-term laboratory and field studies. PMID- 21820157 TI - The origin of lead in the organic horizon of tundra soils: atmospheric deposition, plant translocation from the mineral soil or soil mineral mixing? AB - Knowledge of the anthropogenic contribution to lead (Pb) concentrations in surface soils in high latitude ecosystems is central to our understanding of the extent of atmospheric Pb contamination. In this study, we reconstructed fallout of Pb at a remote sub-arctic region by using two ombrotrophic peat cores and assessed the extent to which this airborne Pb is able to explain the isotopic composition ((206)Pb/(207)Pb ratio) in the O-horizon of tundra soils. In the peat cores, long-range atmospheric fallout appeared to be the main source of Pb as indicated by temporal trends that followed the known European pollution history, i.e. accelerated fallout at the onset of industrialization and peak fallout around the 1960s-70s. The Pb isotopic composition of the O-horizon of podzolic tundra soil ((206)Pb/(207)Pb=1.170 +/- 0.002; mean +/- SD) overlapped with that of the peat ((206)Pb/(207)Pb=1.16 +/- 0.01) representing a proxy for atmospheric aerosols, but was clearly different from that of the parent soil material ((206)Pb/(207)Pb=1.22-1.30). This finding indicated that long-range fallout of atmospheric Pb is the main driver of Pb accumulation in podzolic tundra soil. In O-horizons of tundra soil weakly affected by cryoturbation (cryosols) however, the input of Pb from the underlying mineral soil increased as indicated by (206)Pb/(207)Pb ratios of up to 1.20, a value closer to that of local soil minerals. Nevertheless, atmospheric Pb appeared to be the dominant source in this soil compartment. We conclude that Pb concentrations in the O-horizon of studied tundra soils - despite being much lower than in boreal soils and representative for one of the least exposed sites to atmospheric Pb contaminants in Europe - are mainly controlled by atmospheric inputs from distant anthropogenic sources. PMID- 21820159 TI - Tamibarotene-induced low-grade reversible intravascular coagulation in a patient with acute promyelocytic leukemia. PMID- 21820158 TI - Circulating activated factor XI and active tissue factor as predictors of worse prognosis in patients following ischemic cerebrovascular events. AB - BACKGROUND: Elevated factor (F)XI is associated with an increased risk for ischemic stroke. Activated FXI (FXIa) and tissue factor (TF) have not been studied following stroke. The aim of the current study was to evaluate circulating FXIa and TF in patients with prior cerebrovascular events. PATIENTS/METHODS: We studied 241 patients, including 162 after ischemic stroke and 79 after transient ischemic attack (TIA), recruited 6 months to 4 years (median, 36 months) after the events. Plasma TF and FXIa activity following the index event were determined in clotting assays by measuring the response to inhibitory monoclonal antibodies. RESULTS: Active TF was detected in 25 (10.4%) of the patients, while FXIa activity (median, 37.5 [IQR 397] pM) was found in 64 (26.7%) of the patients (p<0.01). The prevalence of active TF and FXIa was higher in subjects with previous stroke compared with those with a history of TIA (13% vs 5.1%, p=0.05, and 34% vs 11.4%, p<0.0001, respectively). Patients with circulating FXIa were younger and had higher fibrinogen and interleukin-6 compared to the remainder. Patients with detectable TF or FXIa activity had higher NIHSS score, higher modified Rankin scale and lower Barthel Index than the remaining subjects (all p<0.05). CONCLUSION: Circulating active TF and FXIa can occur in patients with cerebrovascular ischemic events >=6 months after the events. The presence of these factors is associated with worse functional outcomes, which highlights the role of persistent hypercoagulable state in cerebrovascular disease. PMID- 21820160 TI - Changes in the expression of HSL and OCTN2 in the female reproductive tract of the bat, Scotophilus heathii in relation to sperm storage. AB - The aim of this study was to compare the changes in the expression of hormone sensitive lipase (HSL) and organic cation transporter 2 (OCTN2) in different regions of the female reproductive tract of bats (Scotophilus heathii) during the period of sperm storage. Western blot analysis revealed that both HSL and OCTN2 showed elevated expression in the utero-tubal junction, the site of sperm storage, compared to the vagina, cervix and uterus. An immunohistochemical study showed localization of HSL and OCTN2 in the cytoplasm of luminal epithelial cells in the utero-tubal junction of S. heathii, which suggests a role of fatty acids metabolism at the site of sperm storage. Furthermore, this study showed the presence OCTN2 immunostaining in the tail of stored sperm, which suggests a direct role of carnitine in sperm physiology. However, the role of carnitine in sperm storage needs further investigation. It is hypothesized that the utero tubal junction may be finely tuned with fat depletion to support sperm storage in the female genital tract of S. heathii. PMID- 21820162 TI - Single-port laparoscopy and extraperitoneal para-aortic lymphadenectomy: about fourteen consecutive cases. AB - OBJECTIVE: To report the feasibility and reproducibility of single port extraperitoneal para-aortic lymphadenectomy in locally advanced cervical cancer. METHODS: The same single port was used for the transperitoneal step and the extraperitoneal approach used thereafter (in the absence of peritoneal disease) for the lymphadenectomy. Para-aortic lymphadenectomy was performed via a left sided extraperitoneal approach. RESULTS: Fourteen consecutive patients with cervical cancer underwent a laparoscopic staging procedure (3 stage IB2, 10 IIB and 1 stage IVA). No patient had para-aortic FDG uptake on PET/CT. In one case lymphadenectomy was unfeasible because of vascular anomalies of the renal vessels (low insertion of 2 left renal arteries). The median operative time was 190 min (range, 135-250). The median number of lymph nodes removed was 14 [range, 2-23]. The definitive pathological analysis revealed that three patients had metastatic disease. No conversion to conventional multiport laparoscopy was necessary. CONCLUSIONS: This series reports that para-aortic lymphadenectomy technique via the extraperitoneal approach with a multichannel single port is feasible and reproducible. PMID- 21820161 TI - Phase I feasibility study of intraperitoneal cisplatin and intravenous paclitaxel followed by intraperitoneal paclitaxel in untreated ovarian, fallopian tube, and primary peritoneal carcinoma: a gynecologic oncology group study. AB - PURPOSE: Intraperitoneal chemotherapy has shown a survival advantage over intravenous chemotherapy for women with newly diagnosed optimally debulked epithelial ovarian, fallopian tube, or primary peritoneal carcinoma. However, significant toxicity has limited its acceptance. In an effort to reduce toxicity, the Gynecologic Oncology Group conducted a Phase I study to evaluate the feasibility of day 1 intravenous (IV) paclitaxel and intraperitoneal (IP) cisplatin followed by day 8 IP paclitaxel on an every 21-day cycle. METHODS: Patients with Stage IIB-IV epithelial ovarian, fallopian tube, primary peritoneal carcinomas or carcinosarcoma received paclitaxel 135mg/m(2) IV over 3h followed by cisplatin 75mg/m(2) IP on day 1 and paclitaxel 60 mg/m(2) IP on day 8 of a 21 day cycle with 6 cycles planned. Dose-limiting toxicity (DLT) was defined as febrile neutropenia or dose-delay of greater than 2 weeks due to failure to recover counts, or Grade 3-5 non-hematologic toxicity occurring within the first 4 cycles of treatment. RESULTS: Twenty of 23 patients enrolled were evaluable and nineteen (95%) completed all six cycles of therapy. Three patients experienced a DLT consisting of infection with normal absolute neutrophil count, grade 3 hyperglycemia, and grade 4 abdominal pain. CONCLUSIONS: This modified IP regimen which administers both IV paclitaxel and IP cisplatin on day one, followed by IP paclitaxel on day eight, of a twenty-one day cycle appears feasible and is an attractive alternative to the intraperitoneal treatment regimen administered in GOG-0172. PMID- 21820164 TI - Reconstitution of the mouse germ cell specification pathway in culture by pluripotent stem cells. AB - The generation of properly functioning gametes in vitro requires reconstitution of the multistepped pathway of germ cell development. We demonstrate here the generation of primordial germ cell-like cells (PGCLCs) in mice with robust capacity for spermatogenesis. PGCLCs were generated from embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) through epiblast-like cells (EpiLCs), a cellular state highly similar to pregastrulating epiblasts but distinct from epiblast stem cells (EpiSCs). Reflecting epiblast development, EpiLC induction from ESCs/iPSCs is a progressive process, and EpiLCs highly competent for the PGC fate are a transient entity. The global transcription profiles, epigenetic reprogramming, and cellular dynamics during PGCLC induction from EpiLCs meticulously capture those associated with PGC specification from the epiblasts. Furthermore, we identify Integrin-beta3 and SSEA1 as markers that allow the isolation of PGCLCs with spermatogenic capacity from tumorigenic undifferentiated cells. Our findings provide a paradigm for the first step of in vitro gametogenesis. PMID- 21820165 TI - G6PDH-activity in equine oocytes correlates with morphology, expression of candidate genes for viability, and preimplantative in vitro development. AB - Efficiencies for in vitro production of equine embryos are still low due to highly variable developmental competences of equine immature oocytes. In contrast to the equine, in vitro developmental competence of immature oocytes has been predicted successfully by the activity of glucose-6-phosphate dehydrogenase (G6PDH) indicated by brilliant cresyl blue (BCB) dye in a range of different species. Therefore, the aim of the present study was to test the association between G6PDH activity in equine oocytes with: (1) cumulus morphology and oocyte properties in terms of diameter and volume; (2) maturational competence; (3) gene expression of certain molecular markers; and (4) in vitro embryo development after intracytoplasmic sperm injection. Equine oocytes were exposed to BCB stain and were classified as BCB+ or BCB- according to their ability to convert the dye from blue to colorless. Additionally, BCB+ and BCB- oocytes were subclassified as having a compact (Cp) or expanded (Ex) cumulus complex. As a result, BCB+ oocytes had a greater proportion of expanded cumulus oocyte complexes compared with BCB- oocytes (71.2% vs. 49.5%). Moreover, we observed a significant difference in oocyte diameter and volume between BCB+ and BCB- oocytes irrespective of cumulus morphology. BCB+ oocytes reached a higher maturation rate compared with BCB- oocytes (59.0% vs. 28.7%). Regarding the analyzed candidate genes, relative transcript abundance was significantly different for nine genes. The expression of eight genes was significantly higher (P < 0.05) for BCB+ oocytes, including ATPV6E, IF-3, TFAM, DNMT1, STAT3, Aurora-A, ODC1, and CKS2 whereas BCB- oocytes showed higher in expression of COX1. These results are in line with the observed developmental competence. Cleavage rate (45.9% vs. 29.0%) and percentage of embryos that reached the blastocyst stage (9.2% vs. 1.4%) were significantly higher for embryos derived from BCB+ oocytes compared with BCB- oocytes. In conclusion, the present study provides evidence that G6PDH-activity in immature equine oocytes is a useful predictor for subsequent in vitro developmental competence. PMID- 21820163 TI - Growth of preschool children at high risk for asthma 2 years after discontinuation of fluticasone. AB - BACKGROUND: The effect on linear growth of daily long-term inhaled corticosteroid therapy in preschool-aged children with recurrent wheezing is controversial. OBJECTIVE: We sought to determine the effect of daily inhaled corticosteroid given for 2 years on linear growth in preschool children with recurrent wheezing. METHODS: Children aged 2 and 3 years with recurrent wheezing and positive modified Asthma Predictive Index scores were randomized to a 2-year treatment period of chlorofluorocarbon-delivered fluticasone propionate (176 MUg/d) or masked placebo delivered through a valved chamber with a mask and then followed for 2 years off study medication. Height growth determined by means of stadiometry was compared between treatment groups. RESULTS: In the study cohort as a whole, the fluticasone group did not have significantly less linear growth than the placebo group (change in height from baseline difference, -0.2 cm; 95% CI, -1.1 to 0.6) 2 years after discontinuation of study treatment. In post hoc analyses children 2 years old who weighed less than 15 kg at enrollment and were treated with fluticasone had less linear growth compared with those treated with placebo (change in height from baseline difference, -1.6 cm; 95% CI, -2.8 to 0.4; P = .009). CONCLUSION: Linear growth was not significantly different in high risk preschool-aged children with recurrent wheezing treated with 176 MUg/d chlorofluorocarbon-delivered fluticasone compared with placebo 2 years after fluticasone is discontinued. However, post hoc subgroup analyses revealed that children who are younger in age and of lesser weight relative to the entire study cohort had significantly less linear growth, possibly because of a higher relative fluticasone exposure. PMID- 21820167 TI - Further response to Offline about Great Ormond Street Hospital. PMID- 21820166 TI - The effect of mobile phone text-message reminders on Kenyan health workers' adherence to malaria treatment guidelines: a cluster randomised trial. AB - BACKGROUND: Health workers' malaria case-management practices often differ from national guidelines. We assessed whether text-message reminders sent to health workers' mobile phones could improve and maintain their adherence to treatment guidelines for outpatient paediatric malaria in Kenya. METHODS: From March 6, 2009, to May 31, 2010, we did a cluster-randomised controlled trial at 107 rural health facilities in 11 districts in coastal and western Kenya. With a computer generated sequence, health facilities were randomly allocated to either the intervention group, in which all health workers received text messages on their personal mobile phones on malaria case-management for 6 months, or the control group, in which health workers did not receive any text messages. Health workers were not masked to the intervention, although patients were unaware of whether they were in an intervention or control facility. The primary outcome was correct management with artemether-lumefantrine, defined as a dichotomous composite indicator of treatment, dispensing, and counselling tasks concordant with Kenyan national guidelines. The primary analysis was by intention to treat. The trial is registered with Current Controlled Trials, ISRCTN72328636. FINDINGS: 119 health workers received the intervention. Case-management practices were assessed for 2269 children who needed treatment (1157 in the intervention group and 1112 in the control group). Intention-to-treat analysis showed that correct artemether lumefantrine management improved by 23.7 percentage-points (95% CI 7.6-40.0; p=0.004) immediately after intervention and by 24.5 percentage-points (8.1-41.0; p=0.003) 6 months later. INTERPRETATION: In resource-limited settings, malaria control programmes should consider use of text messaging to improve health workers' case-management practices. FUNDING: The Wellcome Trust. PMID- 21820168 TI - Text messaging to improve adherence to malaria guidelines. PMID- 21820169 TI - The role of moderate static magnetic fields on biomineralization of osteoblasts on sulfonated polystyrene films. AB - We have investigated the effects of moderate static magnetic fields (SMFs) on murine MC3T3-E1 osteoblasts, and found that they enhance proliferations and promote differentiation. The increase in proliferation rates in response to SMFs was greater in cultures grown on partially sulfonated polytstyrene (SPS, degree of sulfonation: 33%) than in cultures grown on tissue culture plastic. We have previously shown that when the degree of sulfonation exceeded a critical value (12%) [1], spontaneous fibrillogenesis occured which allowed for direct observation of the ECM fibrillar organization under the influence of external fields. We found that the ECM produced in cultures grown on the SPS in the presence of the SMFs assembled into a lattice with larger dimensions than the ECM of the cultures grown in the absence of SMFs. During the early stages of the biomineralization process (day 7), the SMF exposed cultures also templated mineral deposition more rapidly than the control cultures. The rapid response is attributed to orientation of diamagnetic ECM proteins already present in the serum, which could then initiate further cellular signaling. SMFs also influenced late stage osteoblast differentiation as measured by the increased rate of osteocalcin secretion and gene expression beginning 15 days after SFM exposure. This correlated with a large increase in mineral deposition, and in cell modulus. GIXD and EDXS analysis confirmed early deposition of crystalline hydroxyapatite. Previous studies on the effects of moderate SMF had focused on cellular gene and protein expression, but did not consider the organization of the ECM fibers. Our ability to form these fibers has allowed us explore this additional effect and highlight its significance in the initiation of the biomineralization process. PMID- 21820170 TI - Multifunctional rare-earth self-assembled nanosystem for tri-modal upconversion luminescence /fluorescence /positron emission tomography imaging. AB - Rare-earth upconversion nanoparticles (UCNP) which can absorb low-energy photons and emit high energy photons have attracted great interest not only because of their unique application in upconversion luminescence imaging, but also because they can be used as ideal building blocks for multimodal bioimaging probes. Improving the water-solubility of UCNP and functionalizing them are as yet unresolved problems. In this present study, a general strategy was developed to achieve these two aims by converting hydrophobic upconversion nanoparticles into hydrophilic ones. This was based on the self-assembly between oleic acid, which is a capping ligand, as the guest molecule, and alpha-cyclodextrin, as the host molecule, no matter what the particle size was (10-400 nm) or what synthesis method (thermal decomposition, hydrothermal, solvothermal) was used. The synthesized hydrophilic nanoparticles can further load hydrophobic molecule, e.g. Os(II) complex. The process of self-assembly and loading was confirmed by transmission electron microscopy, X-ray powder diffraction, (1)H-nuclear magnetic resonance, Fourier transform-infrared and thermogravimetric analysis, upconversion luminescence and fluorescence spectra. Further bioapplication has also been investigated, including cell-labeling, in vivo lymphatic imaging, upconversion luminescence and positron emission tomography imaging of whole-body Kunming mice. The results indicate that this method is a potential candidate for the preparation of hydrophilic UCNP as a multimodal nanoprobe. PMID- 21820172 TI - Skeletal stem cell physiology on functionally distinct titania nanotopographies. AB - Functionalisation of the surface of orthopaedic implants with nanotopographies that could stimulate in situ osteogenic differentiation of the patient's stem or osteoprogenitor cells would have significant therapeutic potential. Mesenchymal stem cell (MSC) responses to titanium substrates patterned with nanopillar structures were investigated in this study. Focal adhesions were quantified in S phase cells, the bone-related transcription factor Runx2 was examined, osteocalcin production was noted, and Haralick computational analysis was used to assess the relatedness of the cell responses to each of the titanium substrata based on cytoskeletal textural features. Metabolomics was used as a novel means of assessing cellular responses to the biomaterial substrates by analysing the global metabolite profile of the cells on the substrata, and shows promise as a technique with high data yield for evaluating cell interactions with materials of different surface chemistry or topography. The cell response to 15 nm high nanopillars was distinct, consistent with a transition from a more quiescent phenotype on the planar substrate, to an 'active' phenotype on the pillars. These studies illustrate the potential for clinically relevant titania nanopillared substrata to modulate MSCs, with implications for orthopaedic device design and application. PMID- 21820171 TI - Changes of chondrocyte expression profiles in human MSC aggregates in the presence of PEG microspheres and TGF-beta3. AB - Biomaterial microparticles are commonly utilized as growth factor delivery vehicles to induce chondrogenic differentiation of mesenchymal stem/stromal cells (MSCs). To address whether the presence of microparticles could themselves affect differentiation of MSCs, a 3D co-aggregate system was developed containing an equal volume of human primary bone marrow-derived MSCs and non-degradable RGD conjugated poly(ethylene glycol) microspheres (PEG-MUs). Following TGF-beta3 induction, differences in cell phenotype, gene expression and protein localization patterns were found when compared to MSC aggregate cultures devoid of PEG-MUs. An outer fibrous layer always found in differentiated MSC aggregate cultures was not formed in the presence of PEG-MUs. Type II collagen protein was synthesized by cells in both culture systems, although increased levels of the long (embryonic) procollagen isoforms were found in MSC/PEG-MUs aggregates. Ubiquitous deposition of type I and type X collagen proteins was found in MSC/PEG MUs cultures while the expression patterns of these collagens was restricted to specific areas in MSC aggregates. These findings show that MSCs respond differently to TGF-beta3 when in a PEG-MUs environment due to effects of cell dilution, altered growth factor diffusion and/or cellular interactions with the microspheres. Although not all of the expression patterns pointed toward improved chondrogenic differentiation in the MSC/PEG-MUs cultures, the surprisingly large impact of the microparticles themselves should be considered when designing drug delivery/scaffold strategies. PMID- 21820173 TI - GABAergic signaling in primary lens epithelial and lentoid cells and its involvement in intracellular Ca2+ modulation. AB - Primary lens epithelial cell (LEC) cultures derived from newborn (P0) and one month-old (P30) mouse lenses were used to study GABA (gamma-aminobutyric acid) signaling expression and its effect on the intracellular Ca2+ ([Ca2+]i) level. We have found that these cultures express specific cellular markers for lens epithelial and fiber cells, all components of the functional GABA signaling pathway and GABA, thus recapitulating the developmental program of the ocular lens. Activation of both GABA-A and GABA-B receptors (GABAAR and GABABR) with the specific agonists muscimol and baclofen, respectively induces [Ca2+]i transients that could be blocked by the specific antagonists bicuculline and CGP55845 and were dependent on extracellular Ca2+. Bicuculline did not change the GABA-evoked Ca2+ responses in Ca2-containing buffers, but suppressed them significantly in Ca2+-free buffers suggesting the two receptors couple to convergent Ca2+ mobilization mechanisms with different extracellular Ca2+ sensitivity. Prolonged activation of GABABR induced wave propagation of the Ca2+ signal and persistent oscillations. The number of cells reacting to GABA or GABA+bicuculline in P30 mouse LEC cultures expressing predominantly the synaptic type GABAAR did not differ significantly from the number of reacting cells in P0 mouse LEC cultures. The GABA-induced Ca2+ transients in P30 (but not P0) mouse LEC could be entirely suppressed by co-application of bicuculline and CGP55845. The GABA-mediated Ca2+ signaling may be involved in a variety of Ca2+-dependent cellular processes during lens growth and epithelial cell differentiation. PMID- 21820174 TI - Regulation of the galanin system in the brainstem and hypothalamus by electroconvulsive stimulation in mice. AB - Induction of seizures by electroconvulsive stimulation (ECS) is amongst the most efficacious treatments for major depression. However, the working mechanism by which ECS exerts its antidepressant effects remains elusive. The galanin system is regulated by ECS in seizure-prone brain regions and has been shown to modulate depression-like behaviour. To further explore its potential role in the antidepressant effects of ECS the galanin system was investigated by in situ hybridisation and [(125)I]-galanin receptor binding during repeated ECS in the locus coeruleus, dorsal raphe and discrete nuclei of the hypothalamus. Adult mice were treated with ECS once daily for 14 consecutive days, a paradigm previously shown to exert antidepressant-like effects. Significant increases in galanin transcription were found in the locus coeruleus and dorsomedial nuclei of the hypothalamus. In addition, GalR2 mRNA levels in the ventro- and dorsomedial nuclei of the hypothalamus were upregulated whereas no GalR1 mRNA upregulation was observed. [(125)I]-galanin receptor binding was downregulated in the ventromedial nuclei of the hypothalamus and dorsal raphe. These data show that the galanin system is regulated by repeated ECS in brain regions involved in monoaminergic neurotransmission and stress modulation thus indicating a possible role of the galanin system in the therapeutic effects of ECS. PMID- 21820175 TI - Gender differences in the effects of exposure to intimate partner violence on adolescent violence and drug use. AB - OBJECTIVE: This study investigated the long-term effects of exposure to intimate partner violence in the home on adolescent violence and drug use and gender differences in these relationships. Although the general relationship between exposure to IPV and negative outcomes for youth has been demonstrated in past research, gender differences in the effects of IPV on adolescents have been rarely assessed using longitudinal data. METHODS: Longitudinal data was obtained from 1,315 adolescents and their primary caregivers participating in the Project on Human Development in Chicago Neighborhoods (PHDCN). The sample was 51% female and ethnically diverse (45% Hispanic, 37% African-American, and 14% Caucasian). Two waves of data were assessed to examine the effects of exposure to IPV, reported by caregivers when their children were aged 12 and 15, on violence and drug use, reported by adolescents 3 years later. Multivariate statistical models were employed to control for a range of child, parent, family, and neighborhood risk factors. RESULTS: Exposure to IPV did not significantly predict subsequent violence among males or females in multivariate analyses. IPV exposure was significantly related to the frequency of drug use for females but did not predict drug use among males. This gender difference was not statistically significant, however, which suggests more similarities than differences in the relationship between exposure to IPV and subsequent violence and drug use. CONCLUSIONS: This study supports prior research indicating that exposure to IPV can negatively impact adolescent development, but it suggests that these effects may be more likely to influence some outcomes (e.g., drug use) than others (e.g., interpersonal violence). The findings also emphasize the need for additional research examining the overall impact of IPV on adolescent problem behaviors and gender differences in these relationships, including longitudinal studies and investigations that control for a range of other important predictors. A better understanding of these relationships can help inform intervention efforts aimed at ensuring that adolescents living in violent households receive timely and appropriate services to help prevent the occurrence of future problem behaviors. PMID- 21820176 TI - Emotional maltreatment in Canada: prevalence, reporting and child welfare responses (CIS2). AB - OBJECTIVES: To determine the prevalence and characteristics of reports of emotional maltreatment (EMT) in Canada, as well as changes in these reports between 1998 and 2003. METHODS: This study is based on a secondary analysis of data collected in the first and second Canadian Incidence Study. Emotional maltreatment (excluding exposure to intimate partner violence) investigations were categorized into six groups: emotional abuse, emotional neglect, and other maltreatment as the only investigated form of maltreatment, and these same three groups were examined when they co-occurred with another form of maltreatment. RESULTS: Both the rate of emotional-abuse-only investigations and emotional neglect-only investigations increased almost threefold from 1998 to 2003. Substantiated emotional neglect investigations had the highest rate of transfer to ongoing services. Half of the investigations involving single forms of emotional maltreatment occurred for six months or more. Finally, emotional neglect cases (in single form and when it co-occurs with another form of maltreatment) were more likely to be associated with emotional harm and longer duration of maltreatment. CONCLUSIONS: In 2003, EMT represented a significant increasing form of maltreatment and is detected nearly twice as often in situations in which abuse or neglect are also reported. Reports of emotional abuse are two and a half times more frequent than reports of emotional neglect. Nevertheless, lack of emotional engagement may also be difficult to identify, since an omission is more difficult to detect. Reports of EMT often reveal situations of chronic victimization that have been the subject of previous reports and are associated with greater emotional impact. PMID- 21820177 TI - CIT in context: the impact of mental health resource availability and district saturation on call dispositions. AB - The goals of Crisis Intervention Team (CIT) programs include improving safety during encounters between police and persons with mental illnesses, diverting persons with mental illnesses away from the criminal justice system, and increasing referral and access to mental health services. CIT is a systemic intervention, and as such, its implementation and effectiveness are influenced by existing practices and infrastructures. However, little research has considered the context in which CIT programs are implemented. In this paper, we present research on CIT in four Chicago police districts that vary in terms of two contextual factors hypothesized to influence the impact of CIT training on how calls involving persons with mental illnesses are resolved. Using data from 112 patrol officers in four Chicago police districts, we consider the impact of mental health services availability and CIT saturation (the percentage of district personnel that are CIT certified). Findings indicate that CIT training increased direction to mental health services primarily in districts with greater availability of mental health services. In districts with low service availability, higher CIT saturation increased direction to mental services. The opposite pattern emerged for contact only or informal call resolution. No effects were found for arrest as a call outcome. PMID- 21820178 TI - Asp159 is a critical core amino acid of an IgE-binding and cross-reactive epitope of a dust mite allergen Der f 7. AB - Der f 7 and Der p 7 are important house dust mite allergens with known structure and suggested biological function recently. However, their IgE-binding determinants remain unknown. The purpose of this study is to identify the IgE reactive epitopes of Der f 7 and the determinants of IgE-mediated cross reactivity between Der f 7 and Der p 7. IgE-reactive determinants were identified by immunodot blot inhibition using synthetic overlapping peptides, allergen mutants, and a Der f 7 structural model. Our results showed that synthetic peptides with sequence (156)SILDP(160) on Der f 7 bind IgE in two of the 30 asthmatic serum samples tested. Recombinant Der f 7 I157A, L158A, or D159A mutants have reduced IgE-binding activity. Inhibition experiments confirmed Asp159 as a critical core residue for IgE-binding. Among Der p 7, Der f 7 and Der f 7 mutants with single substitution between residues 156 and 160, only the D159A mutant cannot inhibit significantly IgE-binding against Der p 7. Therefore, Asp159 contributes to IgE-mediated cross-reactivity between Der f 7 and Der p 7. The structural model constructed for Der f 7 suggests that the IgE-binding epitope forms a loop-like structure on the surface of the molecule. In conclusion, Asp 159 is a critical core residue of an IgE-binding and IgE-mediated cross-reactive epitope (156)SILDP(160) of Der f 7. Results obtained from this study provide more information on molecular and structural features related to allergenicity, underlying basis of IgE cross-reactivity between allergens, and in designing safer immunotherapy. PMID- 21820179 TI - Zebrafish immunoglobulin IgD: unusual exon usage and quantitative expression profiles with IgM and IgZ/T heavy chain isotypes. AB - The zebrafish is an emerging model for comparative immunology and biomedical research. In contrast to the five heavy chain isotype system of mice and human (IgD, IgM, IgA, IgG, IgE), zebrafish harbor gene segments for IgD, IgM, and novel heavy chain isotype called IgZ/T which appears restricted to bony fishes. The purpose of this study was to design and validate a suite of quantitative real time RT-PCR protocols to measure IgH expression in a vertebrate model which has considerable promise for modeling both pathogenic infection and chronic conditions leading to immune dysfunction. Specific primers were designed and following verification of their specificty, relative expression levels of IgD, IgM, and IgZ/T were measured in triplicate for zebrafish raised under standard laboratory conditions. During embryonic stages, low levels of each heavy chain isotype (IgH) were detected with each increasing steadily between 2 and 17 weeks post fertilization. Overall IgM>IgZ>IgD throughout zebrafish development with the copy number of IgM being several fold higher than that of IgD or IgZ/T. IgD exon usage was also characterized, as its extremely long size and presence of a stop codon in the second IgD exon in zebrafish, raised questions as to how this antibody might be expressed. Zebrafish IgD was found to be a chimeric immunoglobulin, with the third IgD exon spliced to the first IgM constant exon thereby circumventing the first and second IgD exons. Collectively, the qRT-PCR results represent the first comparative profile of IgD, IgM, IgZ/T expression over the lifespan of any fish species and the primers and assay parameters reported should prove useful in enabling researchers to rapidly quantify changes in IgH expression in zebrafish models of disease where altered IgH expression is manifested. PMID- 21820180 TI - Role of pH-regulated antigen 1 of Candida albicans in the fungal recognition and antifungal response of human neutrophils. AB - Candida albicans is an opportunistic human-pathogenic fungus, which can cause superficial but also life-threatening invasive infections. The pH-regulated antigen 1 (Pra1) of C. albicans is a surface-associated and secreted protein highly expressed in the hyphal form. Pra1 can bind to complement receptor 3 (CD11b/CD18) and can mediate adhesion to and migration of human phagocytes. Here, we investigated the role of Pra1 in the activation of human neutrophils. A C. albicans mutant strain lacking Pra1 (pra1Delta) supported neutrophil migration to a lower extent than did the parental wild-type strain. A Pra1-overexpressing C. albicans strain enhanced neutrophil migration and adherence. While inactivated hyphae of the Pra1-overexpressing mutant with surface-associated Pra1 enhanced the production and release of reactive oxygen species, myeloperoxidase, lactoferrin, and interleukin 8 by neutrophils, such responses were reduced when stimulated with inactivated hyphae of the pra1Delta strain. However, Pra1 overexpressing living hyphae, which secrete large amounts of Pra1, also caused a reduced neutrophil activation, indicating that the release of extracellular Pra1 can inhibit the activation of these innate immune cells. Similarly, soluble recombinant Pra1 inhibited the neutrophil responses elicited by cell-wall bound Pra1. Finally, fungal cells lacking Pra1 were more efficiently killed by neutrophils. In conclusion, surface-exposed Pra1 plays a role in the recognition of C. albicans, especially hyphal cells, by human neutrophils and enhances neutrophil antimicrobial responses. However, the fungus can counteract some of these defense mechanisms by releasing soluble Pra1. PMID- 21820181 TI - Prevalence and characteristics of choroidal nevi: the multi-ethnic study of atherosclerosis. AB - OBJECTIVE: To describe the prevalence of choroidal nevi in 4 racial or ethnic groups (white, black, Hispanic, and Chinese) in the United States. DESIGN: Cross sectional study. PARTICIPANTS: Participants of the second examination of the Multi-Ethnic Study of Atherosclerosis (MESA), involving 6176 persons 44 to 84 years of age without clinical cardiovascular disease at baseline selected from 6 United States communities. METHODS: Fundus images were taken using a 45 degrees digital camera through dark-adapted pupils and were graded for choroidal nevi using the modified Wisconsin Age-Related Maculopathy Grading System and the Blue Mountains Eye Study protocol. MAIN OUTCOME MEASURES: Choroidal nevi. RESULTS: The overall prevalence of choroidal nevi in the whole cohort was 2.1%, with prevalences higher in whites (4.1%) than blacks (0.7%), Hispanics (1.2%), and Chinese (0.4%; P<0.001 for any differences among groups). The lowest prevalence of choroidal nevi occurred in those 75 to 84 years of age. The nevi were subfoveal in 4% of eyes with nevi and were not associated with a decrease in visual acuity. Characteristics of the nevi (size, shape, location, color, drusen on surface) did not differ among racial or ethnic groups. With the exception of associations with higher C-reactive protein levels (odds ratio [OR] per mg/dl on the logarithmic scale, 1.23; 95% confidence interval [CI], 1.06-1.43; P = 0.01) and lower systolic blood pressure (OR per 10 mmHg, 0.90; 95% CI, 0.82-0.99; P = 0.04), choroidal nevi were not associated with other potential risk factors (e.g., gender, smoking status, alcohol consumption, lipid levels, coagulation factors, or kidney disease). CONCLUSIONS: Low prevalences of choroidal nevi were found in the 4 groups participating in the MESA cohort, with whites having higher prevalence than the other racial or ethnic groups. The higher prevalence in whites than in other groups was not explained by any of the factors studied. When choroidal nevi were present, their characteristics did not differ among racial or ethnic groups. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article. PMID- 21820182 TI - Electroretinographic assessment in major depressed patients receiving duloxetine: might differences between responders and non-responders indicate a differential biological background? AB - INTRODUCTION: Despite intense research efforts, still too little is known about the biological determinants of depression, thus soliciting diverse study approaches. Among others, the electroretinography (ERG) has been proposed even as a putative proxy (retinal) measurement of central dopaminergic activity for Major Depressive Disorder (MDD) both in drug-naive patients and subjects receiving antidepressant treatments. Nonetheless, current evidences are merely preliminary, essentially considering just older classes of antidepressants, thus requiring confirmation studies even with newer agents as duloxetine. METHOD: Twenty MDD subjects and 20 matched controls received duloxetine 60 mg/day for 12 weeks, being monitored both by standard ERG recording and by administration of the Hamilton scales for Depression and Anxiety and the Young Mania Rating Scale at baseline and week 12 (end of the study). RESULTS: ERG mean rod b-wave amplitude significantly reduced from baseline to week 12 in those depressed subjects achieving final response (p=.024), decreasing from the highest rank values to the ones, substantially unmodified, seen among non-responders and controls. LIMITATIONS: Small sample size and lack of multiple assessments. CONCLUSIONS: At least some MDD patients responding to duloxetine might exhibit a peculiar ERG pattern, hypothetically indicating a specific biological background. If confirmed by larger-sampled studies, these results might shed further light in the understanding of the biological determinants of different subtypes of depression, ideally showing alternative patterns of response upon different treatment interventions. PMID- 21820183 TI - Development and validation of a patient-report measure of fatigue associated with depression. AB - INTRODUCTION: Among researchers and clinicians who treat depression, there is growing interest in treatment of specific residual symptoms such as fatigue. However, there is no available measure that provides a detailed assessment of fatigue associated with depression. Thus, the purpose of the current study was to develop and validate a patient-reported outcome measure designed to assess depression-related fatigue and its impact. METHODS: The Fatigue Associated with Depression Questionnaire (FAsD) was developed based on literature review, clinician interviews, and focus groups and cognitive debriefing interviews with patients. Then, a draft questionnaire was administered to a sample of patients with depression. Statistical analysis first focused on item reduction and subscale identification, followed by psychometric evaluation of the FAsD. RESULTS: The per protocol sample (n = 317) was primarily female (68.1%), with a mean age of 47.0 years. Based on item performance and exploratory factor analysis, three items were dropped from the draft FAsD, yielding a final 13-item questionnaire with two subscales (experience and impact). The FAsD demonstrated good internal consistency reliability (Cronbach's alphas >= 0.88) and test-retest reliability (intraclass correlation coefficients >= 0.78). The FAsD demonstrated construct validity through strong correlations with measures assessing fatigue/energy and symptoms of depression. The FAsD also discriminated among groups of participants differentiated by clinician ratings of global severity of depression (CGI-S). LIMITATIONS: Limitations include heterogeneity of current treatments received by the sample, as well as lack of knowledge regarding the extent to which FAsD scores were influenced by patients' treatments rather than the depression itself. CONCLUSIONS: In this initial psychometric evaluation, the FAsD demonstrated good reliability, validity, and factor structure. This questionnaire may be a useful tool for evaluating treatment interventions that focus specifically on fatigue associated with depression. PMID- 21820184 TI - Cue-induced positive motivational implicit response in young adults with Internet gaming addiction. AB - This study evaluated the positive motivational implicit response to Internet gaming cues (i.e., screenshots of popular online games) to identify potential mechanisms of dyscontrolled Internet use in young adults with Internet gaming addiction (IGA). The final analysis included 64 young adults with IGA and 71 control subjects. The subjects completed the implicit association task to test their reaction to congruent pairing (Internet gaming screenshot paired with liked words) and incongruent pairing (Internet gaming screenshot paired with disliked words). The results demonstrated that, compared to the control group, the IGA group reacted faster to congruent pairing. It suggests that the IGA group had a positive motivational implicit response to screenshots of online games. Implicit cognition is an important mechanism of dyscontrolled substance use, such as alcohol dependence. This result suggests that implicit cognition might also be associated with dyscontrolled online gaming. The findings also demonstrate the important role of implicit cognition in dyscontrolled Internet use in young adults with IGA. PMID- 21820185 TI - Immunomodulation of bivalent Newcastle disease DNA vaccine induced immune response by co-delivery of chicken IFN-gamma and IL-4 genes. AB - The basic objective of this study was to enumerate whether co-administration of interferon-gamma (IFN-gamma) and/or interleukin-4 (IL-4) gene along with a bivalent Newcastle disease (ND) DNA vaccine construct could modulate the immune response to the DNA vaccine in chickens. pVIVO2 vector carrying Haemaglutinin Neuraminidase (HN) and Fusion (F) genes of Newcastle disease virus (NDV) at its two cloning sites was used as a DNA vaccine. The same vector was used to clone the chicken IFN-gamma and IL-4 genes at the multiple cloning site-1 separately. In vitro expression of IFN-gamma and IL-4 gene constructs was assessed by reverse transcriptase-polymerase chain reaction (RT-PCR) and that of HN and F genes by indirect fluorescent antibody technique (IFAT) in addition to RT-PCR. The chickens were immunized thrice intramuscularly at 21, 36 and 46 days of age with the bivalent DNA vaccine alone, or in combination with IFN-gamma/IL-4 or both cytokine gene constructs. The bivalent DNA vaccine led to increase in both NDV specific antibodies as assessed by enzyme linked immunosorbent assay (ELISA) and haemagglutination inhibition test (HI) and cell mediated immune (CMI) response as assessed by lymphocyte transformation test (LTT) employing MTT assay. Co administration of the DNA vaccine with IL-4 gene resulted in highest IgY levels while IFN-gamma produced highest CMI response. The DNA vaccine alone could afford only 10% protection against challenge infection by velogenic NDV. This protection was increased to 40% when IL-4 gene construct was co-administered with the DNA vaccine. Co-injection of IFN-gamma as well as the combination of IFN-gamma and IL 4 gene constructs with the DNA vaccine yielded 20% protection. Our study suggests that IL-4 may prove to be more appropriate as a genetic adjuvant than IFN-gamma for ND DNA vaccine. PMID- 21820186 TI - Selection of reference genes for gene expression studies in PBMC from Bama miniature pig under heat stress. AB - Heat stress decreases immune function and increases disease susceptibility in stressed animals, which are important factors for industry and public health. We investigated the molecular mechanisms underlying heat stress by profiling the expression of target genes involved in the cellular response in the blood of Bama miniature pigs (Sus scrofa domestica) over 21 days with the use of quantitative RT-PCR (qRT-PCR). Reliable standards were established for the normalization of qRT-PCR. Six potential reference genes were ranked by their stability using the geNorm and NormFinder programs. Ribosomal protein L4 (RPL4) and TATA-box-binding protein (TBP) ranked as the two most stably expressed genes, except on day 21 when beta-2-microglobulin (B2M) was the most stable. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and ribosomal RNA 18S (18SRNA) were discarded as reference genes due to their unstable expression patterns. When B2M and TBP genes were selected as standards in combination, rather than GAPDH, a significant upregulation in Toll-like receptor 2 (TLR2) expression was observed after 21 consecutive days of heat stress. These findings suggest that selection of an ideal reference gene is a key step in comparison of transcription profiles in Bama miniature pigs. PMID- 21820187 TI - Mucocele after transnasal endoscopic repair of traumatic anterior skull base fistula in children. AB - OBJECTIVES: To report the long-term sinonasal complications after endoscopic repair of anterior skull base fractures in children. This study describes mucocele formation in 6 patients treated endoscopically for posttraumatic CSF fistulae. We aim to address possible etiologic factors, specific treatments and follow-up modalities. PATIENTS AND METHODS: 12 children, mean age 5.8 years (3 10), treated endoscopically at our institution between 2004 and 2010 for an anterior cranial base fracture complicated by a CSF fistula. An iatrogenic mucocele was observed in 6 cases. A retrospective review of the files of these 6 patients was carried out demonstrating demographic characteristics, presenting signs/symptoms, site of skull base defect, repair technique, timing and onset of the mucoceles, their presentation and management. A systematic CT-scan and/or MRI was carried out at 3 months, 1 year and then annually. RESULTS: 3 patients presented after cranial trauma with persistent CSF nasal leak, and 4 with meningitis. Posttraumatic defects reached the posterior wall of the frontal sinus and the junction of ethmoid and frontal bone in 3 cases, and the cribriform plate in 3 cases. Endoscopic closure was performed in all cases, with the middle turbinate as an overlay patch. No recurrence of a CSF leak was observed. After a mean period of 16 months, a single iatrogenic mucocele was observed in 4 patients (radiological detection only), and multiple mucoceles in 2 patients. Surgical treatment was advocated in cases of proptosis, quick expansion of the mucocele leading to sinus bony wall remodelling or erosion (2 cases), and meningitis related to an erosion of the cribriform plate by the mucocele. Three mucoceles were successfully treated endoscopically, and 1 required an external approach. CONCLUSION: Mucocele incidence after endoscopic repair of skull base fractures in children is not insignificant (50% in our 12 patients series). Paediatric anatomical features, cranial trauma, and the transethmoidal approach may play a role in mucocele pathogenesis. Long-term clinical and radiological follow-up is therefore recommended. These mucoceles may be managed endoscopically with good outcomes. PMID- 21820188 TI - Velopharyngeal valving during speech, in patients with velocardiofacial syndrome and patients with non-syndromic palatal clefts after surgical and speech pathology management. AB - BACKGROUND: Velocardiofacial syndrome (VCFS) is the most common genetic syndrome associated with cleft palate. There are reports describing several anomalies associated with the palatal cleft in patients with VCFS, which can affect the characteristics of the velopharyngeal insufficiency (VPI) in these cases. OBJECTIVE: The purpose of this study is to assess velopharyngeal sphincter function during speech, using videonasopharyngoscopy (VNP) and videofluoroscopy (VF), in patients with VCFS, as compared with patients with non-syndromic palatal clefts (NSCP). MATERIAL AND METHOD: Twenty patients with VCFS corroborated by a FISH test were studied. All patients showed a palatal cleft. All patients had received previous management including speech therapy and palatal repair. These patients underwent a thorough clinical speech evaluation, including VNP and VF. Twenty patients with NSCP matched by sex, type of cleft and within the age range of the patients with VCFS were studied as controls. RESULTS: From the patients with VCFS, seventeen patients showed a submucous cleft palate. Three patients showed sub-total cleft of the secondary palate. Fourteen patients (70%) showed a coronal velopharyngeal closure pattern. Six patients (30%) showed a circular pattern. In contrast, 10 patients (50%) from the NSCP group showed a circular pattern, two of them showed a Passavant's ridge. Seven patients (35%) showed a coronal pattern and 3 patients (15%) showed a saggital pattern. Mean velum (V) and lateral pharyngeal wall (LPW) motion were significantly decreased in patients with VCFS (V=46% vs 71%; LPW=14% vs 30%; P<0.001). Size of the defect during speech was significantly increased in patients with VCFS (34.57% vs 67.37%; P<0.001). CONCLUSION: Velopharyngeal valving during speech is significantly different in patients with VCFS as compared with patients with NSCP. Several anomalies associated with the palatal cleft in patients with VCFS can explain these differences. Thus, the surgical approach for repairing a palatal cleft should consider these differences. Moreover, surgical planning should be performed according to the specific findings of the velopharyngeal sphincter in order to improve speech outcome. PMID- 21820189 TI - Potentially inappropriate prescribing (IP) for elderly medical inpatients in Taiwan: a hospital-based study. AB - Older people tend to have multiple comorbid conditions and subsequent polypharmacy, which place them at higher risk of adverse drug events, drug-drug and drug-disease interactions and IP. IP includes several patterns, such as inappropriate dose or duration, prescribing drugs having significant drug-disease or drug-drug interactions, and the omission of potentially beneficial medications. The main purpose was to evaluate the prevalence of IP among medical inpatients in a medical center, so to evaluate the associative factors of IP in Taiwan. From January to December of 2009, all patients aged 65 years and older who were discharged from the medical wards of Taipei Veterans General Hospital were randomly sampled for study (the sampling rate around 1.0%). The IP was evaluated by the STOPP and START criteria. Each medical record was carefully reviewed by physicians who had been trained. Overall, 520 records of elderly medical ward inpatients (mean age = 79.2 +/- 6.7 years, 73.8% males) were included for study. In total, 3455 items of medication were prescribed for these 520 patients (mean = 6.6 +/- 3.2 items). According to STOPP criteria, 36.2% of the study subjects had at least one potentially inappropriate medication (PIM). The most common PIMs were: (1) medications that may adversely affect those who are prone to falls, e.g., benzodiazepines, neuroleptics and first generation antihistamines (14.2%). (2) Ca-channel blockers with chronic constipation (12.3%). (3) Use of neuroleptic agents (5.6%). (4) Long-term, long-acting benzodiazepines (2.5%). (5) Prolonged use of first generation antihistamines (2.1%). Besides, 218 patients (41.9%) had at least one potentially prescribing omission (PPO). Common PPOs included: (1) statin therapy in diabetes mellitus if coexisting major cardiovascular risk factors present (19.0%). (2) Antiplatelet therapy in diabetes mellitus with co-existing major cardiovascular risk factors (12.5%). (3) Metformin with type 2 diabetes with or without metabolic syndrome (in the absence of renal impairment) (8.7%). (4) Angiotensin converting enzyme inhibitor or angiotensin II receptor blockers with chronic heart failure (7.3%). (5) Aspirin or clopidogrel with a documented history of atherosclerotic coronary, cerebral or peripheral vascular disease in patients with sinus rhythm (7.1%). Logistic regression showed that older age and number of medications were significant risk factors for PIMs. In conclusion, the prevalence of PIMs among elderly medical inpatients in a medical center in Taiwan was 36.2% and PPOs was 41.9%. Further study is needed to clarify the underlying causes of potentially IP to promote better quality of prescribing for older patients. PMID- 21820190 TI - Treatment of community-onset methicillin-resistant Staphylococcus aureus (MRSA) bacteremia: a hospital-based study. AB - S. aureus bacteremia (SAB) is a severe systemic illness, which is associated with high mortality and healthcare cost. It has been reported that older age per se is a poor prognostic factor of SAB, but little is known whether poor clinical outcomes is related to conservative attitudes of treating physicians. A retrospective cohort of 126 patients (mean age: 73.7 +/- 13.6 years, 72.2% males) with community-onset SAB during 2004-2008 in a tertiary medical center in Taiwan was obtained for study. Demographic data, clinical characteristics, primary infectious focus, metastatic lesions, access to critical care units, performance of invasive procedures, Charlson comorbidity index (CCI) and in-hospital mortality for all study subjects were collected. The overall in-hospital mortality was 32.5%, which was not significantly different between adult and elderly groups. SAB of elderly patients was more likely to be primary than that of the adult patients (20.4% vs. 3.6%, p=0.043). Deep-seated abscess, osteomyelitis and metastatic lesion with central nervous system (CNS) involvement were more common infection foci in the adult patient group. Chronic obstructive pulmonary disease and cerebrovascular accident were more common underlying conditions of the elderly group. Chances of patients admitted to intensive care unit and employment of invasive procedures were not different between groups although elderly patients were supposed to be of a greater risk of mortality. In conclusion, the overall in-hospital mortality of community-onset SAB was 32.5%, which was not different between age groups. In general, older patients were of similar chance to receive critical care and invasive procedures except arterial line and non-tunneled central venous catheters. Further prospective investigation is needed to clarify whether physicians hold different attitudes to older patients with SAB and the differences in treatment attitude resulting in poorer clinical outcomes. PMID- 21820191 TI - Morphological change of left atrium in obese individuals. PMID- 21820192 TI - Patient switching in general practice. AB - Patients switching physicians involves costs to the patients because of less continuity of care. From a theoretical model we derive that inferior physician quality as perceived by patients, implies patient shortage for the physician and more patients switching physicians. By means of a unique panel data set covering the entire population of Norwegian general practitioners (GPs) and estimation methods that adjust for potential endogeneities, we find that the occurrence of patient shortage increases the proportion of patients switching physicians by 50%. A competing hypothesis that GPs with a shortage of patients experience less switching because of superior access is rejected by data. To assist patients in making informed decisions, we suggest that the number of switches a physician experiences should be made public. PMID- 21820193 TI - Accounting for the dead in the longitudinal analysis of income-related health inequalities. AB - This paper develops an accounting framework to consider the effect of deaths on the longitudinal analysis of income-related health inequalities. Ignoring deaths or using Inverse Probability Weights (IPWs) to re-weight the sample for mortality related attrition can produce misleading results. Incorporating deaths into the longitudinal analysis of income-related health inequalities provides a more complete picture in terms of the evaluation of health changes in respect to socioeconomic status. We illustrate our work by investigating health mobility from 1999 till 2004 using the British Household Panel Survey (BHPS). We show that for Scottish males explicitly accounting for the dead rather than using IPWs to account for mortality-related attrition changes the direction of the relationship between relative health changes and initial income position, from negative to positive, while for other groups it significantly increases the strength of the positive relationship. Incorporating the dead may be vital in the longitudinal analysis of health inequalities. PMID- 21820194 TI - An investigation of stride interval stationarity while listening to music or viewing television. AB - In recent years, there has been considerable interest in the effects of auditory and visual distractions on pedestrian ambulation. A fundamental temporal characteristic of ambulation is the temporal fluctuation of the stride interval. In this paper, we investigate the stationarity of stride interval time series when people are exposed to different forms of auditory and visual distractions. An increase in nonstationary behavior may be suggestive of divided attention and more frequent central modulation of locomotion, both of which may have ramifications on pedestrian vigilance and responsiveness to environmental perturbations. One group of fifteen able-bodied (6 females) young adult participants completed a music protocol (overground walking with and without music). A second group of fifteen (7 females) did a television protocol (treadmill walking while watching TV with and without sound). Three walking trials, each 15min in duration, were performed at each participant's comfortable walking speed, with force sensitive resistors under the heel of each foot. Using the reverse arrangements test, the vast majority of time series were nonstationary, with a time-varying mean as the principal source of nonstationarity. Furthermore, the television trial with sound had the greatest number of nonstationarities followed by overground walking while listening to music. We discuss the possibility that these conditions measurably affect gait dynamics through a subconscious synchronization to external rhythms or a cyclic distraction followed by a period of increased conscious correction of gait timing. Our findings suggest that the regulation of stride timing is particularly susceptible to constant, time-evolving auditory stimuli, but that normal pacing can be restored quickly upon stimulus withdrawal. These kinds of sensory distractions should thus be carefully considered in studies of pedestrian ambulation. PMID- 21820195 TI - Translating diabetes research into global communities. PMID- 21820196 TI - Economic crisis and communicable disease control in Europe: a scoping study among national experts. AB - OBJECTIVES: The effects of the current global economic crisis on the spread and control of communicable diseases remain uncertain. This study aimed to explore experts' views about the impact of the current crisis and measures that have been undertaken by governments to mitigate an alleged adverse effect of the crisis on communicable diseases. METHODS: An online survey was conducted during November 2009-February 2010 among experts from national agencies for communicable disease control from European Union (EU) and European Free Trade Association (EFTA) countries. RESULTS: There were few specific national policies and programmes aimed at mitigating the impact of the economic crisis. Prevention services were deemed particularly susceptible to budget cuts (68%) as a result of the economic crisis compared to primary care (28%), according to survey respondents. Services targeted at vulnerable and hard-to-reach population groups were perceived to be at particular risk of deterioration (67%) in contrast to travel medicine (11%), according to respondents. CONCLUSIONS: There is a need for sustainability of financial resources, public health workforce and infrastructures to ensure that the services and programmes for the surveillance and control of the spread of communicable disease are maintained and developed. There is also a need to explore and foster better linkage in data on socioeconomic circumstances and communicable disease outcomes. PMID- 21820197 TI - Responsiveness and satisfaction with providers and carriers in a safety net insurance program: evidence from Georgia's Medical Insurance for the Poor. AB - OBJECTIVE: To evaluate provider responsiveness and beneficiary satisfaction with insurance carriers participating in the Republic of Georgia's Medical Insurance for the Poor. STUDY SETTING: A dedicated survey of approximately 3500 households in two types of regions--with different eligibility thresholds--in November and December 2008. STUDY DESIGN: Regression-based estimation of responsiveness ratings by beneficiaries and non-beneficiaries of the insurance program and estimation of mean satisfaction scores for beneficiaries. PRINCIPAL FINDINGS: In the high-threshold regions, provider responsiveness toward beneficiaries and non beneficiaries is comparable. In the low-threshold regions, beneficiary status is associated with lower responsiveness of outpatient providers. Inpatient providers may have become less responsive toward beneficiaries during the program's transition from public to private administration. While satisfaction of beneficiaries with carriers is above average, there are reports of difficulties in obtaining reimbursements and information about benefits. CONCLUSIONS: The results suggest that relying on private insurance companies to deliver public programs in middle-income settings may impact provider responsiveness and indicate the need for continuous monitoring and regulation. PMID- 21820198 TI - Circulating tumor cell detection in advanced non-small cell lung cancer patients by multi-marker QPCR analysis. AB - BACKGROUND: The aim of this study was to explore circulating tumor cell (CTC) detection in advanced non-small cell lung cancer (NSCLC). CTCs may not only serve as a prognostic marker in selected tumor types, but may also be useful as pharmacodynamic marker in drug development. METHODS: Fourty-six advanced NSCLC patients and fourty-six healthy controls were included in the study and 8.0 ml of peripheral blood was obtained from each of the participants. Immunomagnetic bead enrichment for cells expressing epithelial cell adhesion molecule (EpCAM) was performed, followed by multi-marker quantitative real-time PCR of a panel of marker genes: cytokeratin 7 (CK7), cytokeratin 19 (CK19), human epithelial glycoprotein (EGP) and fibronectin 1 (FN1). Using quadratic discriminant analysis (QDA), expression values were combined into a single score, which indicated CTC positivity or -negativity. Test characteristics were assessed using receiver operating characteristic (ROC) curve analysis. RESULTS: ROC curve analysis showed capability of discrimination between advanced NSCLC patients and healthy controls (area=0.712; 95% CI 0.606-0.819; P<0.001). A cut-off minimizing overall misclassification for QDA-positivity reached a sensitivity of 46% (95% CI 31-61) and a specificity of 93% (95% CI 82-99). CONCLUSIONS: In this exploratory study, an assay was developed for discriminating CTCs in peripheral blood samples of advanced NSCLC patients from healthy controls. The assay demonstrated an acceptable sensitivity in combination with good specificity. Further validation studies should take place in NSCLC patients and a matched control group. PMID- 21820199 TI - Gene duplication might not resolve intralocus sexual conflict. PMID- 21820201 TI - betaIII-Tubulin is required for interphase microtubule dynamics in untransformed human mammary epithelial cells. AB - Numerous works have questioned the pertinence of using betaII- and/or betaIII tubulin expression as markers of prognosis and/or prediction of breast cancer response to chemotherapy containing microtubule-targeting agents. The rationale of such studies was essentially based on microtubule dynamics analysis using purified tubulin in vitro and cancer cell lines. Nonetheless, the significance of betaII- and betaIII-tubulin expression in the control of microtubule dynamics in normal mammary epithelium has never been addressed. Here we investigate the expression and the consequences of betaII- and/or betaIII-tubulin depletion in interphase microtubule dynamics in non-tumor human mammary epithelial cells. We find that both isoforms contribute to the tubulin isotype composition in primary and immortalized human mammary epithelial cells. Moreover, while betaII-tubulin depletion has limited effects on interphase microtubule behavior, betaIII-tubulin depletion causes a strong exclusion of microtubules from lamella and a severe suppression of dynamic instability. These results demonstrate that, while betaII tubulin is dispensable, betaIII-tubulin is required for interphase microtubule dynamics in untransformed mammary epithelial cells. This strongly suggests that betaIII-tubulin is an essential regulator of interphase microtubule functions in normal breast epithelium cells. PMID- 21820202 TI - Actin: from structural plasticity to functional diversity. AB - This article addresses the multiple activities of actin. Starting out with the history of actin's discovery, purification and structure, it emphasizes the close relation between structure and function. In this context, we also point to unconventional actin conformations. Their existence in living cells is not yet well documented, however, they seem to play a special role in the supramolecular patterning that underlies some of the physiological functions of actin. Conceivably, such conformations may contribute to actin's diverse activities in the nucleus that are poorly understood so far. PMID- 21820203 TI - Systematic review of nondermatophyte mold onychomycosis: diagnosis, clinical types, epidemiology, and treatment. AB - Nondermatophyte mold (NDM) onychomycosis is difficult to diagnose given that NDMs are common contaminants of the nails and of the mycology laboratory. Diagnostic criteria and definition of cure are inconsistent between studies, which may affect the quality of published data. We identified 6 major criteria used in the literature: identification of the NDM in the nail by microscopy (using potassium hydroxide preparation), isolation in culture, repeated isolation in culture, inoculum counting, failure to isolate a dermatophyte in culture, and histology. Most studies used 3 or more of these (range = 1-5). We recommend using at least 3 of the criteria to rule out contamination; these should include potassium hydroxide preparation for direct microscopy and isolation of the organism in culture. We review geographic distribution and clinical presentations associated with different NDMs. The treatment with the greatest quantity of data and highest reported cure rates is terbinafine, for the treatment of Scopulariopsis brevicaulis and Aspergillus species infections. Topicals such as ciclopirox nail lacquer may also be effective (data originating from Scopulariopsis brevicaulis and Acremonium species infections), especially when combined with chemical or surgical avulsion of the nail. We recommend that future studies use (and clearly indicate) at least 3 of the main criteria for diagnosis, and report the clinical type of onychomycosis and the isolated organism. When evaluating different treatments, we suggest that authors clearly define their efficacy outcomes. PMID- 21820204 TI - Systemic therapy for primary hyperhidrosis: a retrospective study of 59 patients treated with glycopyrrolate or clonidine. AB - BACKGROUND: Data regarding systemic medications in the management of hyperhidrosis (HH) are limited. OBJECTIVE: The goal of this study was to provide evidence for the safety and efficacy of systemic medications for primary HH. METHODS: A retrospective chart review was conducted of patients seen at an academic dermatology department prescribed systemic medications for primary HH. RESULTS: A total of 71 patients were prescribed systemic agents. Twelve patients (17%) were lost to follow-up and were excluded from further analysis. A total of 59 patients with at least 2 months of follow-up data (mean age 28.9 +/- 12.0 years; 37 women, 22 men; mean follow-up 19.5 months) were included in the analysis. Palmoplantar and/or axillary HH was most common (42/59; 71%); followed by generalized (9/59; 15%) and craniofacial (8/59; 14%) HH. Glycopyrrolate (generally 1-2 mg once or twice daily) was prescribed to 45 patients, with response rate of 67% (30/45). Fifteen treatment failures included 6 nonresponders and 9 with adverse effects, including xerostomia and gastrointestinal disturbance. Clonidine (0.1 mg twice daily) was prescribed to 13 patients, with a response rate of 46% (6/13). Seven treatment failures included 3 nonresponders and 4 with adverse effects, all relating to decreased blood pressure. One patient responded to oxybutynin at 5 mg twice daily. There were no significant differences in efficacy (P = .21; odds ratios 0.43, 95% confidence interval 0.12 1.5) or adverse effects (P = .46; odds ratios 1.78, 95% confidence interval 0.44 7.1) in comparing glycopyrrolate versus clonidine. LIMITATIONS: This was a retrospective study from a single, university-based population. CONCLUSION: Systemic therapy with glycopyrrolate or clonidine can be effective for HH. Nearly two-thirds responded to therapy, and less than a quarter had treatment-limiting adverse effects, all of which were self-limited and nonserious. PMID- 21820205 TI - Peanut allergy: an increasingly common life-threatening disorder. AB - Allergic reactions to peanuts in children have become a significant medical and legal concern worldwide, with a rising incidence of this potentially fatal condition. Peanut allergy represents an immunoglobulin E (IgE)-mediated hypersensitivity reaction to peanut proteins and is responsible for the majority of cases of food-induced anaphylaxis. Even trace quantities of peanut in a sensitized individual can be fatal, with rapid onset of symptoms often including the cutaneous findings of urticaria, angioedema, or a diffuse nonspecific dermatitis. Peanut allergy is usually a lifelong condition, since only about 20% of affected individuals outgrow it. Some schools ban peanut butter and jelly sandwiches, once a common dietary option, as fear of medical and legal consequences is escalating. Children with peanut allergy and their families should be knowledgeable about management strategies, including carrying and properly administering self-injectable epinephrine. New immunotherapeutic options are being investigated and appear promising. PMID- 21820206 TI - Dermatology education and the Internet: traditional and cutting-edge resources. AB - BACKGROUND: The number and variety of dermatological medical resources available online has grown exponentially over the past decade. Internet-based resources allow for immediate and easy access to information for both medical education and reference purposes. Although clinicians continue to turn to the Internet for clinical information and still images, tech-savvy medical students are currently accessing a variety of exciting new resources, including discussion boards, wikis, streaming video, podcasts, journal clubs, online communities, and interactive diagnostic experiences to augment their medical education. OBJECTIVE: The objective of this study was to identify traditional and cutting-edge online dermatology resources. METHODS: We present a sampling of the top dermatology Internet resources, as assessed by a group of medical students in our university dermatology research lab. These resources were ranked by using a matrix derived from the Silberg Criteria, which assessed authorship, attribution, disclosure, currency, and content. Results indicate comparable ranking and approval of cutting-edge resources as traditional online sources. The ranked resources in each category are provided with URLs for readers' use. CONCLUSIONS: These cutting edge online dermatology resources represent excellent sources for continuing education for students and clinicians alike. Resources such as these likely represent the future of medical education, as they allow for self-directed and supplementary education as well as remote access. PMID- 21820207 TI - Hospital antibiotic consumption in Switzerland: comparison of a multicultural country with Europe. AB - The consumption of antibiotics in the inpatient setting of Switzerland was assessed to determine possible differences between linguistic regions, and to compare these results with European results. Data on antibiotic consumption were obtained from a sentinel network representing 54% of the national acute care hospitals, and from a private drug market monitoring company. Aggregated data were converted into defined daily doses (DDD). The total consumption density in Switzerland was close to the median consumption reported in European surveys. Between 2004 and 2008, the total consumption of systemic antibiotics rose from 46.1 to 54.0 DDD per 100 occupied bed-days in the entire hospitals, and from 101.6 to 114.3 DDD per 100 occupied bed-days in the intensive care units. Regional differences were observed for total consumption and among antibiotic classes. Hospitals in the Italian-speaking region showed a significantly higher consumption density, followed by the French- and German-speaking regions. Hospitals in the Italian-speaking region also had a higher consumption of fluoroquinolones, in line with the reported differences between Italy, Germany and France. Antibiotic consumption in acute care hospitals in Switzerland is close to the European median with a relatively low consumption in intensive care units. Some of the patterns of variation in consumption levels noticed among European countries are also observed among the cultural regions of Switzerland. PMID- 21820208 TI - Early prevention of pressure ulcers among elderly patients admitted through emergency departments: a cost-effectiveness analysis. AB - STUDY OBJECTIVE: Every year, approximately 6.2 million hospital admissions through emergency departments (ED) involve elderly patients who are at risk of developing pressure ulcers. We evaluated the cost-effectiveness of pressure redistribution foam mattresses on ED stretchers and beds for early prevention of pressure ulcers in elderly admitted ED patients. METHODS: Using a Markov model, we evaluated the incremental effectiveness (quality-adjusted life-days) and incremental cost (hospital and home care costs) between early prevention and current practice (with standard hospital mattresses) from a health care payer perspective during a 1-year time horizon. RESULTS: The projected incidence of ED acquired pressure ulcers was 1.90% with current practice and 1.48% with early prevention, corresponding to a number needed to treat of 238 patients. The average upgrading cost from standard to pressure-redistribution mattresses was $0.30 per patient. Compared with current practice, early prevention was more effective, with 0.0015 quality-adjusted life-days gained, and less costly, with a mean cost saving of $32 per patient. If decisionmakers are willing to pay $50,000 per quality-adjusted life-year gained, early prevention was cost-effective even for short ED stay (ie, 1 hour), low hospital-acquired pressure ulcer risk (1% prevalence), and high unit price of pressure-redistribution mattresses ($3,775). Taking input uncertainty into account, early prevention was 81% likely to be cost effective. Expected value-of-information estimates supported additional randomized controlled trials of pressure-redistribution mattresses to eliminate the remaining decision uncertainty. CONCLUSION: The economic evidence supports early prevention with pressure-redistribution foam mattresses in the ED. Early prevention is likely to improve health for elderly patients and save hospital costs. PMID- 21820209 TI - Cervical spine magnetic resonance imaging in alert, neurologically intact trauma patients with persistent midline tenderness and negative computed tomography results. AB - STUDY OBJECTIVE: We aim to determine the prevalence and factors associated with cervical discoligamentous injuries detected on magnetic resonance imaging (MRI) in acute, alert, neurologically intact trauma patients with computed tomography (CT) imaging negative for acute injury and persistent midline cervical spine tenderness. We present the cross-sectional analysis of baseline information collected as a component of a prospective observational study. METHODS: Alert, neurologically intact trauma patients presenting to a Level I trauma center with CT negative for acute injury, who underwent MRI for investigation of persistent midline cervical tenderness, were prospectively recruited. Deidentified images were assessed, and injuries were identified and graded. Outcome measures included the presence and extent of MRI-detected injury of the cervical ligaments, intervertebral discs, spinal cord and associated soft tissues. RESULTS: There were 178 patients recruited during a 2-year period to January 2009. Of these, 78 patients (44%) had acute cervical injury detected on MRI. There were 48 single column injuries, 15 two-column injuries, and 5 three-column injuries. Of the remaining 10 patients, 6 had isolated posterior muscle edema, 2 had alar ligamentous edema, 1 had epidural hematoma, and 1 had atlanto-occipital edema. The injuries to 38 patients (21%) were managed clinically; 33 patients were treated in cervical collars for 2 to 12 weeks, and 5 patients (2.8%) underwent operative management, 1 of whom had delayed instability. Ordinal logistic regression revealed that factors associated with a higher number of spinal columns injured included advanced CT-detected cervical spondylosis (odds ratio [OR] 11.6; 95% confidence interval [CI] 3.9 to 34.3), minor isolated thoracolumbar fractures (OR 5.4; 95% CI 1.5 to 19.7), and multidirectional cervical spine forces (OR 2.5; 95% CI 1.2 to 5.2). CONCLUSION: In patients with cervical midline tenderness and negative acute CT findings, we found that a subset of patients had MRI-detected cervical discoligamentous injuries and that advanced cervical spine degeneration evident on CT, minor thoracolumbar fracture, and multidirectional cervical spine forces were associated with increased injury extent. However, a larger study is required to validate which variables may reliably predict clinically important injury in such patients, thereby indicating the need for further radiographic assessment. PMID- 21820210 TI - Adolescents and young adults presenting to the emergency department intoxicated from a caffeinated alcoholic beverage: a case series. AB - We describe a case series of emergency department (ED) visits for intoxication related to the use of the caffeinated alcoholic beverage Four Loko. Medical records from the 4-month period July to November 2010 were hand searched for key words such as "intoxicated," "caffeinated," "Four Loko," "alcohol," and "EtOH." Patients were included if they were younger than 25 years. Eleven cases were included. Eight (72.7%) patients presented during October 2010. The median age was 16.4 years; 90.9% were under the legal drinking age of 21 years. Seven (63.6 %) were male patients. All arrived by emergency medical services (EMS). Four patients (36.3%) were found in high-risk settings, with altered mental status on subway tracks, in public buildings, or parks after dark. Two patients had blood alcohol concentrations greater than 200 mg/dL. Six patients (54.5%) had emesis. Two patients (18.2%) were admitted to hospital, 1 each because of seizures and persistent tachycardia. Patients intoxicated with Four Loko were younger than the legal drinking age, found in high-risk situations, and often admitted to the hospital. Many of these patients used EMS and resources in the ED for alleviation of adverse effects of Four Loko. PMID- 21820211 TI - Qualitative analysis of effective lecture strategies in emergency medicine. AB - STUDY OBJECTIVE: We empirically identify those aspects that make an effective lecture according to both quantitative and qualitative assessments of the opinions of a select group of emergency medicine educators. METHODS: The authors worked collaboratively with the Educational Meetings Committee of the American College of Emergency Physicians (ACEP) to distribute surveys to 150 participants identified as exemplary lecturers in emergency medicine. These participants had been rated in the top 10% of all lecturers by ACEP's Educational Meetings Committee, according to audience evaluations. Respondents quantitatively rated the importance of a set of strategies for the design/organization and delivery of a lecture. Additional qualitative responses were elicited from semistructured, open-ended questions that were used to identify conceptual themes and subcategories of major themes. RESULTS: One hundred fifty surveys were sent. Seventy-four (49%) of the surveys were returned, of which 67 (45%) were analyzed. Quantitative results revealed the top 3 categories of importance about design/organization (having a manageable scope of content for the allotted time, having clear objectives, and using case-based scenarios) and the top 3 categories of importance about delivery (knowledge of slides/material, having passion/enthusiasm, and interaction with the audience). Qualitative results revealed 5 thematic concepts from the analysis of 281 statements: delivery, vehicle, content, preparation, and uncontrollables, in order of descending importance according to our results. Under the category "delivery," the subcategory "engaging" was the most frequently endorsed quality. "Relevance," under the category "content," was the second most endorsed quality of all the statements obtained. CONCLUSION: Quantitative and qualitative findings indicate that a specific and directed structure, a lecturer's knowledge base, and confidence and enthusiasm for the material are key components in the development of an effective lecture. These self-reported findings help describe strategies of exemplary emergency medicine lecturers that can be considered by faculty, residents, and other presenters. PMID- 21820212 TI - TOMM40 poly-T repeat lengths, age of onset and psychosis risk in Alzheimer disease. AB - Apolipoprotein E (APOE) epsilon4 alleles increase the risk for late-onset Alzheimer disease (LOAD) and decrease the age of onset. Recently, sequencing the APOE region in a small sample of LOAD subjects identified a variable length poly T repeat sequence in the nearby gene, TOMM40, which may affect age of onset. We genotyped the TOMM40 poly-T repeat using a novel statistical approach to refine the identification of allele length in 892 LOAD subjects and evaluated its effects on age of onset. Because psychosis in LOAD is a heritable phenotype which has shown conflicting associations with APOE genotype, we also evaluated the association of poly-T repeat length with psychosis. Poly-T repeat lengths had a trimodal distribution which differed between APOE genotype groups. After accounting for APOE epsilon4 there was no association of poly-T repeat length with age of onset. Neither APOE epsilon4 nor poly-T repeat length was associated with psychosis. Our findings do not support the association of poly-T repeat length with age of onset in LOAD. The clinical implications of this repeat length polymorphism remain to be elucidated. PMID- 21820213 TI - Influence of late-life exposure to environmental enrichment or exercise on hippocampal function and CA1 senescent physiology. AB - Aged (20-22 months) male Fischer 344 rats were randomly assigned to sedentary (A SED), environmentally-enriched (A-ENR), or exercise (A-EX) conditions. After 10 12 weeks of differential experience, the 3 groups of aged rats and young sedentary controls were tested for physical and cognitive function. Spatial discrimination learning and memory consolidation, tested on the water maze, were enhanced in environmentally-enriched compared with sedentary. A-EX exhibited improved and impaired performance on the cue and spatial task, respectively. Impaired spatial learning in A-EX was likely due to a bias in response selection associated with exercise training, as object recognition memory improved for A-EX rats. An examination of senescent hippocampal physiology revealed that enrichment and exercise reversed age-related changes in long-term depression (LTD) and long term potentiation (LTP). Rats in the enrichment group exhibited an increase in cell excitability compared with the other 2 groups of aged animals. The results indicate that differential experience biased the selection of a spatial or a response strategy and factors common across the 2 conditions, such as increased hippocampal activity associated with locomotion, contribute to reversal of senescent synaptic plasticity. PMID- 21820215 TI - [Radioguided cervical lymphadenectomy in one case of recurrence of differentiated thyroid microcarcinoma]. PMID- 21820216 TI - Carbonic anhydrase inhibitors. Synthesis, molecular structures, and inhibition of the human cytosolic isozymes I and II and transmembrane isozymes IX, XII (cancer associated) and XIV with novel 3-pyridinesulfonamide derivatives. AB - A series of novel 3-pyridinesulfonamide derivatives (2-5, 9-11 and 13-15) have been synthesized and investigated as inhibitors of five isoforms of zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), that is, the cytosolic ubiquitous CA I and II, and isozymes CA IX and XII (cancer-associated), and XIV. Against the human isozyme hCA I the new compounds showed K(I)s in the range of 0.089-251 MUM, whereas toward hCA II, K(I)s = 50.5-487 nM. Isozyme hCA IX was inhibited with K(I)s in the range of 5.2-18.3 nM, while hCA XII with K(I)s = 6.0-16.4 nM, and hCA XIV with K(I)s = 76.4-152.0 nM. All of the new compounds 2-5, 9-11 and 13-15 showed excellent hCA IX inhibitory efficacy, with K(I)s = 5.2-18.3 nM, being much more effective as compared to the clinically used AAZ, MZA, EZA, DCP and IND (K(I)s = 24-50 nM). PMID- 21820214 TI - Extracellular progranulin protects cortical neurons from toxic insults by activating survival signaling. AB - To reduce damage from toxic insults such as glutamate excitotoxicity and oxidative stresses, neurons may deploy an array of neuroprotective mechanisms. Recent reports show that progranulin (PGRN) gene null or missense mutations leading to inactive protein, are linked to frontotemporal lobar degeneration (FTLD), suggesting that survival of certain neuronal populations needs full expression of functional PGRN. Here we show that extracellular PGRN stimulates phosphorylation/activation of the neuronal MEK/extracellular regulated kinase (ERK)/p90 ribosomal S6 kinase (p90RSK) and phosphatidylinositol-3 kinase (PI3K)/Akt cell survival pathways and rescues cortical neurons from cell death induced by glutamate or oxidative stress. Pharmacological inhibition of MEK/ERK/p90RSK signaling blocks the PGRN-induced phosphorylation and neuroprotection against glutamate toxicity while inhibition of either MEK/ERK/p90RSK or PI3K/Akt blocks PGRN protection against neurotoxin MPP(+). Inhibition of both pathways had synergistic effects on PGRN-dependent neuroprotection against MPP(+) toxicity suggesting both pathways contribute to the neuroprotective activities of PGRN. Extracellular PGRN is remarkably stable in neuronal cultures indicating neuroprotective activities are associated with full-length protein. Together, our data show that extracellular PGRN acts as a neuroprotective factor and support the hypothesis that in FTLD reduction of functional brain PGRN results in reduced survival signaling and decreased neuronal protection against excitotoxicity and oxidative stress leading to accelerated neuronal cell death. That extracellular PGRN has neuroprotective functions against toxic insults suggests that in vitro preparations of this protein may be used therapeutically. PMID- 21820217 TI - Synthesis and anticancer evaluation of novel 2-cyclopropylimidazo[2,1-b][1,3,4] thiadiazole derivatives. AB - A series of 2,5,6-trisubstituted imidazo[2,1-b][1,3,4]-thiadiazole derivatives 4(a-k) have been prepared by reaction of 2-amino-5-cyclopropyl-1,3,4-thiadiazole and an appropriate phenacyl bromide. Further 5-bromo 5(a-k) and 5-thiocyanato 6(a k) derivatives were synthesized in order to study the effect of these substituents on antitumor activity. Structures of these compounds were established by IR, (1)H NMR, (13)C NMR and Mass spectroscopy. Seven compounds were granted NSC code at National Cancer Institute (NCI), USA for anticancer activity at a single high dose (10(-5) M) in full NCI 60 cell panel. Among the compounds tested, 5-bromo-6-(4-chlorophenyl)-2-cyclopropylimidazo[2,1 b][1,3,4]thiadiazole 5b (NSC D-96022/1) was found to be the most active candidate of the series at five dose level screening with degree of selectivity toward Leukemic cancer cell line. PMID- 21820218 TI - Quantitative comparison of the expression of antimicrobial peptides in the oral mucosa and extraoral skin. AB - Antimicrobial peptides (AMP) defend epithelial surfaces against pathological micro-organisms. We know of no comparison of their expression between the oral mucosa and extraoral epithelium, but knowledge of differences in their quantities is of interest, possibly as a starting point for new treatments. Expression of AMP human beta-defensin (hBD)-1/-2/-3 and psoriasin in the oral mucosa and extraoral epithelium of the head and neck were measured by real-time polymerase chain reaction (RT-PCR) (n=14), immunohistochemistry (n=6), and western blot (n=8). RT-PCR showed that all the genes investigated were expressed significantly more in the oral mucosa than in the skin (hBD-1: p=0.002; hBD-2: p=0.006; hBD-3: p=0.035; psoriasin: p=0.02). Immunohistochemistry and western blot showed differential concentrations of proteins: hBD-2 (p=0.021) and hBD-3 (p=0.043) were pronounced in the oral mucosa, whereas psoriasin was raised in the extraoral skin (p=0.021). There was no difference in protein concentrations for hBD-1 (p=0.08). The observed differences in the expression of AMP may be important for new treatments such as topical application of AMP derivatives. PMID- 21820220 TI - Association between cardiac biomarkers and the development of ESRD in patients with type 2 diabetes mellitus, anemia, and CKD. AB - BACKGROUND: In patients with chronic kidney disease (CKD), as in other populations, elevations in cardiac biomarker levels predict increased risk of cardiovascular events. We examined the value of troponin T (TnT) and N-terminal pro-brain natriuretic peptide (NT-pro-BNP) in assessing the risk of developing end-stage renal disease (ESRD) in diabetic patients with CKD. STUDY DESIGN: Prospective cohort study nested within a randomized clinical trial. SETTING & PARTICIPANTS: Patients with type 2 diabetes, CKD (estimated glomerular filtration rate [eGFR], 20-60 mL/min/1.73 m(2)), and anemia enrolled in TREAT (Trial to Reduce Cardiovascular Events With Aranesp Therapy). PREDICTORS: Serum levels of the cardiac biomarkers TnT and NT-pro-BNP. OUTCOMES: Incidence of ESRD and the composite of death or ESRD. MEASUREMENTS: We measured TnT and NT-pro-BNP in baseline serum samples from the first 1,000 patients enrolled in TREAT. The relationship of these cardiac biomarker levels to the development of ESRD and death or ESRD was analyzed in multivariable regression models. RESULTS: Detectable TnT (>=0.01 ng/mL) was present in 45% of participants, and median NT pro-BNP level was elevated at 605 pg/mL. Higher levels of both cardiac biomarkers were associated independently with higher rates of ESRD, as well as death or ESRD, and remained prognostically important after adjustment for eGFR, proteinuria, and other known predictors of CKD progression. The addition of cardiac biomarkers to a multivariable model for prediction of ESRD improved discrimination of those with and without an event by 16.9% (95% CI, 6.3%-27.4%). LIMITATIONS: Observational study in a clinical trial cohort; results require validation. CONCLUSIONS: In ambulatory patients with type 2 diabetes, anemia, and CKD, TnT and NT-pro-BNP levels frequently are elevated. These cardiac-derived biomarkers enhance prediction of ESRD beyond established risk factors. Measurement of TnT and NT-pro-BNP may improve the identification of patients with CKD who are likely to require renal replacement therapy, supporting a link between cardiac injury and the development of ESRD. PMID- 21820221 TI - The role of functional status in discharge to assisted care facilities and in hospital death among dialysis patients. AB - BACKGROUND: Functional status is an important component in the assessment of hospitalized patients. We set out to determine the scope, severity, and prognostic significance of impaired functional status in acutely hospitalized dialysis patients. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: 1,286 hospitalized dialysis patients admitted and discharged from 1 of 11 area hospitals in Manitoba, Canada, from September 2003 to September 2010 with an activity of daily living (ADL) assessment within 24 hours of admission. PREDICTOR: The 12-point ADL score assesses 6 domains (bathing, toileting, dressing, incontinence, feeding, and transferring) and scores them as independent or supervision only (score, 0), partial assistance (1), and full assistance (2). Thus, higher score indicates worse functional status. Parametric and nonparametric tests were used as appropriate to determine differences in baseline characteristics. OUTCOMES: Multivariable logistic regression and Cox proportional hazards assessed the association between functional status, in-hospital death, and discharge to an assisted care facility. RESULTS: During the study period, 250 (19.4%) and 72 (5.6%) patients experienced the outcomes of in-hospital death or discharge to an assisted care facility. Abnormalities in functional status were present in >70% of the cohort. ADL score within 24 hours of admission combined with age differentiated risks of death and discharge to an assisted care facility home, ranging from 4.8%-46.6% and 0.6%-17.8%, respectively. After adjustment, ORs of death and discharge to an assisted care facility were 1.16 (95% CI, 1.11-1.22; P < 0.001; C statistic = 0.79) and 1.25 (95% CI, 1.14-1.36; P < 0.001; C statistic = 0.91) per 1-point increase in ADL score, respectively. Findings were consistent after accounting for the competing outcomes of in-hospital death or discharge to an assisted care facility versus discharge to home. LIMITATIONS: A 1 time measurement of ADLs could not differentiate temporary from long-term deterioration in functional status. CONCLUSIONS: Impaired functional status is common at the time of admission in the dialysis population. A single ADL score measurement at admission combined with age is highly predictive of poor outcomes in the hospitalized dialysis population. PMID- 21820222 TI - Wasting and sudden cardiac death in hemodialysis patients: a post hoc analysis of 4D (Die Deutsche Diabetes Dialyse Studie). AB - BACKGROUND: Wasting is common in hemodialysis patients and often is accompanied by cardiovascular disease and inflammation. The cardiovascular risk profile meaningfully changes with the progression of kidney disease, and little is known about the impact of wasting on specific clinical outcomes. This study examined the effects of wasting on the various components of cardiovascular outcome and deaths caused by infection in hemodialysis patients. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 1,255 hemodialysis patients from 178 centers participating in Die Deutsche Diabetes Dialyse Studie (4D) in 1998-2004. PREDICTOR: Moderate wasting was defined as body mass index, albumin, and creatinine values less than the median (26.7 kg/m(2), 3.8 g/dL, and 6.8 mg/dL, respectively) and C-reactive protein level less than the median (5 mg/L) at baseline. Severe wasting was defined as body mass index, albumin, and creatinine levels less than the median and C-reactive protein level greater than the median at baseline. OUTCOMES & MEASUREMENTS: Risks of sudden cardiac death (SCD), myocardial infarction (MI), stroke, combined cardiovascular events, deaths due to infection, and all-cause mortality were determined using Cox regression analyses during a median of 4 years of follow-up. RESULTS: 196 patients had wasting (severe, n = 109; and moderate, n = 87). Overall, 617 patients died (160 of SCD and 128 of infectious deaths). Furthermore, 469 patients experienced a cardiovascular event, with MI and stroke occurring in 200 and 103 patients, respectively. Compared with patients without wasting (n = 1,059), patients with severe wasting had significantly increased risks of SCD (adjusted HR, 1.8; 95% CI, 1.1-3.1), all-cause mortality (adjusted HR, 1.8; 95% CI, 1.4-2.4), and deaths due to infection (adjusted HR, 2.3; 95% CI, 1.2-4.3). In contrast, MI was not affected. The increased risk of cardiovascular events (adjusted HR, 1.5; 95% CI, 1.0-2.1) was explained mainly by the effect of wasting on SCD. LIMITATIONS: Selective patient cohort. CONCLUSIONS: Wasting was associated strongly with SCD, but not MI, in diabetic hemodialysis patients. Nonatherosclerotic cardiac disease potentially has a major role to account for the increased cardiovascular events in patients with wasting, suggesting the need for novel treatment strategies. PMID- 21820223 TI - Deservingness to state health services for South-South migrants: a preliminary study of Costa Rican providers' views. AB - Health services for undocumented migrants highlight the complex politics of the "right to health". South-South migrants, an emerging focus of migration scholarship, compose an estimated 40 percent of the world's 200 million international migrants. In Costa Rica, internationally renowned for its public health achievements, undocumented Nicaraguan migrants number between 8 and 16 percent of the population. In spite of historical, linguistic, and ethnic congruencies between peoples of the sending and receiving countries at the ends of this migratory path, access to health services is limited for migrants experiencing illegality in the global economic South. Costa Rican health providers articulated concepts of deservingness to health services for undocumented Nicaraguan migrants. This article is based on a preliminary study with a purposive sample of 22 Costa Rican health services providers. Interviewed over two field research periods (June 2005-July 2006; July, 2008), providers addressed four types of health services for undocumented migrants. Overall their views on the deservingness of health services for undocumented migrants reflected a utilitarian approach. Specifically, their talk reflected: (1) the limits to state responsibility for ensuring the health of individuals not pertaining to the nation; and (2) a concern for the threats posed to the health of Costa Rican nationals. Costa Rican providers' perceptions on health services for migrants offer partial insight for the development of future migrant health policies in receiving countries of the global economic South. PMID- 21820225 TI - Aneurysmal bone cyst: a radiolucent lesion of the mandible. Report of 3 cases. PMID- 21820224 TI - Indices of socioeconomic position across the life course as predictors of coronary calcification in black and white men and women: coronary artery risk development in young adults study. AB - Few studies have investigated the association of socioeconomic status (SES) and coronary artery calcification (CAC) and only one study has examined African Americans separately from Caucasians, despite empirical evidence suggesting that blacks have equivalent or lower CAC, relative to whites. We tested the hypotheses that lower childhood SES and lower average education, occupation, and income and change in SES (slope) in adulthood are related to risk of CAC in blacks and whites in the US CARDIA study. Parental education and occupation were measured at study entry (Year 0 in 1985-1986) and participant education, occupation, and household income were evaluated multiple times throughout a 20 year follow-up period at four sites in the United States. CAC was measured at Year 20 in 3138 (45% black) participants in CARDIA; 19% had CAC. Latent growth models and multivariate logistic regression analyses adjusted for the major risk factors for CAC. Multivariate models showed that lower paternal education in blacks and lower maternal occupational status in the full sample and in whites were related to higher risk of any CAC, independent of adult SES. Lower average adult education, occupation, and income were related to higher risk of any CAC, with the effects primarily in blacks. Our results are the first to show that SES, measured retrospectively and prospectively in multiple ways, is related to CAC, and the first to document the effects primarily in blacks. PMID- 21820226 TI - Y modification of the transconjunctival approach for management of zygomaticomaxillary complex fractures: a technical note. PMID- 21820227 TI - Closure of the radial forearm free flap donor site defect with a full-thickness skin graft from the inner arm: a preferred technique. PMID- 21820228 TI - Radiotherapy deteriorates postoperative functional outcome after partial glossectomy with free flap reconstruction. AB - PURPOSE: Most patients with tongue cancer require surgical resection of the tongue to varying degrees. As a result, quality of life, which is strongly related to speech, chewing, and swallowing, can deteriorate severely from extensive surgical treatment of tongue cancer. In addition to surgery, adjuvant therapy may affect the severity of functional impairment. Therefore, the influence of postoperative radiotherapy on functional outcome after partial glossectomy with free flap reconstruction was evaluated in patients with early oral tongue cancer. PATIENTS AND METHODS: Functional outcome was measured and charts of 31 patients with oral tongue cancer who were surgically treated at Yonsei Head and Neck Cancer Clinic from 2003 through 2008 were reviewed. Only patients who underwent partial glossectomy and reconstruction with radial forearm free flap and did not develop recurrence were included. Speech integrity was evaluated with diadochokinetic testing by a professional speech therapist. Tongue mobility was checked by measurements of upward distance, protrusion distance, and lateral deviation distance. Swallowing capacity was evaluated with the M.D. Anderson Dysphagia Inventory. RESULTS: Diadochokinetic rates of the surgery-only and postoperative radiotherapy groups were 27.8 and 23.9, respectively, which was statistically different. Swallowing capacity was significantly superior in the surgery-only group. Tongue mobility was not statistically different between the 2 groups. CONCLUSIONS: Functional outcome of speech and swallowing is negatively influenced by postoperative radiotherapy. PMID- 21820229 TI - Three-dimensional analyses of nasal forms after secondary treatment of bilateral cleft lip-nose deformity in comparison to those of healthy young adults. AB - PURPOSE: To 3-dimensionally analyze outcomes after the secondary treatment of bilateral cleft lip-nose deformity at the Department of Oral and Maxillofacial Surgery, Kagoshima University Hospital, Kagoshima, Japan. PATIENTS AND METHODS: Ten Japanese male young adults with bilateral cleft lip with or without palate (BCL+/-P) who had undergone definitive nose correction and were followed up for 1 to 4 years were enrolled in this study. Ten unaffected race- and gender-matched young adults were used as controls. All patients underwent secondary correction of the nose by open rhinoplasty through a bilateral reverse-U incision, columellar strut graft, and medial-upward advancement of the nasolabial components with vestibular expansion by use of a free mucosal graft. In 3 patients with an extremely short columella, an inferiorly based small pedicle flap from rim skin rotated into the columellar base was added for columella lengthening. Nasal forms were periodically measured by use of a 3-dimensional noncontact laser scanner. The angular and linear measurements and the curvature of the alar groove arch were compared between patients and control subjects. RESULTS: Comparison of the preoperative and postoperative nasal forms showed significant improvements in the nasal dorsum and tip angles, as well as nasal height. The size of the nasal alar grooves was also increased to the same size range as the control subjects. There were persistent differences between postoperative columellar angle and nasal width in patients and those in the control subjects. CONCLUSIONS: Our surgical procedures can provide an acceptably protruded nasal form for patients with BCL+/-P without damaging the upper lip tissue, but further improvement to prevent nasal tip overprojection may be useful. PMID- 21820230 TI - Distraction osteogenesis of maxilla and midface in postradiotherapy patients. PMID- 21820231 TI - Percutaneous dilatational tracheostomy: review of technique and evidence for its use. AB - Tracheostomy is a technique for airway management commonly used by surgeons who care for critically ill patients. Patients with traumatic facial injuries, severe odontogenic infections, and head and neck malignancies are often recipients of tracheostomies. As such, the oral and maxillofacial surgeon who frequently treats such patients should be well-trained in tracheostomy placement. For decades, the standard technique for tracheostomy was the open surgical technique. However, during the past 20 years, the use of percutaneous dilatational tracheostomy has increased. The purpose of the present report is to review the percutaneous dilatational tracheostomy technique, describe the use of intensive care units as proxies for the operating room, and review the available evidence comparing percutaneous dilatational tracheostomy to open tracheostomy. PMID- 21820232 TI - Cost differences between the anterior and posterior approaches to the iliac crest for alveolar bone grafting in patients with cleft lip/palate. AB - PURPOSE: There has been debate in the literature regarding the advantages of an anterior versus posterior approach to the iliac crest harvest for alveolar bone grafting (ABG) in patients with cleft lip and palate. The purpose of this study was to add a cost perspective to the discussion. MATERIALS AND METHODS: This was a retrospective microcost analysis for the perioperative period for 2 approaches to graft harvest for ABG in patients with cleft lip and palate. Patient charts and hospital and physician financial databases were searched for detailed cost data in the 30 days before and after ABG for 18 patients who underwent anterior or posterior iliac crest harvest at Children's Hospital Boston. In addition, short-term outcomes for these 18 patients were documented (duration of operation, need for physical therapy services, complications, and hospital length of stay) and compared with the larger study group at the same institution. RESULTS: There was a trend toward lower overall median costs for posterior compared with anterior iliac crest harvest ($18,269 vs $21,801, respectively; P = .15). The differences in cost were seen in inpatient hospital services after the operation, including ward and physical therapy costs, which were significantly lower for the posterior versus the anterior approach. This corresponded with a shorter median length of stay (1 day vs 2 days, respectively; P = .03). There was no significant difference in operating room, recovery room, or outpatient costs. More patients undergoing posterior harvest had bilateral ABG, offsetting the decreased inpatient costs with increased physician costs. CONCLUSIONS: The overall cost for ABG in patients with cleft lip and palate was not significantly different between the anterior and posterior approached to iliac crest harvest. Inpatient cost was lower in the posterior group because of a shorter length of stay. PMID- 21820233 TI - A double-blind randomized crossover study to evaluate the timing of pregabalin for third molar surgery under local anesthesia. AB - PURPOSE: This double-blind randomized crossover study compared the analgesic efficacy of pre- and postoperative administration of oral pregabalin 75 mg using a postsurgical dental pain model. MATERIALS AND METHODS: Patients requiring third molar surgery in 2 separate stages under local anesthesia were recruited. They were given pregabalin 75 mg either 1 hour before or after their first surgical extraction. They then received the same dose of pregabalin at their second surgical extraction, but those who received it before surgery received it postsurgery, and vice versa. Postoperative analgesic effects were assessed at postoperative hours 2, 4, 8, 12, 24, 48, and 72. Time to first analgesic, analgesic consumption and adverse events were also evaluated. RESULTS: Forty patients were recruited, and 34 completed the study. The area under curves for numerical rating scale pain scores 1 to 24 hours were significantly lower at rest but not during mouth opening for patients receiving postoperative pregabalin (P < .048). Pain relief was similar for the period of 24 to 72 hours. No significant difference was found in time to first analgesic, total analgesic consumption, and side effects between preoperative and postoperative groups. No difference in the incidence of adverse events was noticed in relation to the timing of pregabalin administration. CONCLUSIONS: Postoperative administration of oral pregabalin 75 mg appears to offer better analgesic efficacy than preoperative administration after third molar surgery under local anesthesia. PMID- 21820234 TI - Logistic regression models. AB - In the health sciences it is quite common to carry out studies designed to determine the influence of one or more variables upon a given response variable. When this response variable is numerical, simple or multiple regression techniques are used, depending on the case. If the response variable is a qualitative variable (dichotomic or polychotomic), as for example the presence or absence of a disease, linear regression methodology is not applicable, and simple or multinomial logistic regression is used, as applicable. PMID- 21820235 TI - An illicit economy: scavenging and recycling of medical waste. AB - This paper discusses a significant illicit economy, including black and grey aspects, associated with medical waste scavenging and recycling in a megacity, considering hazards to the specific group involved in scavenging as well as hazards to the general population of city dwellers. Data were collected in Dhaka, Bangladesh, using a variety of techniques based on formal representative sampling for fixed populations (such as recycling operatives) and adaptive sampling for roaming populations (such as scavengers). Extremely hazardous items (including date expired medicines, used syringes, knives, blades and saline bags) were scavenged, repackaged and resold to the community. Some HCE employees were also observed to sell hazardous items directly to scavengers, and both employees and scavengers were observed to supply contaminated items to an informal plastics recycling industry. This trade was made possible by the absence of segregation, secure storage and proper disposal of medical waste. Corruption, a lack of accountability and individual responsibility were also found to be contributors. In most cases the individuals involved with these activities did not understand the risks. Although motivation was often for personal gain or in support of substance abuse, participants sometimes felt that they were providing a useful service to the community. PMID- 21820236 TI - Comparing the utility of image algebra operations for characterizing landscape changes: the case of the Mediterranean coast. AB - The aim of this study is to compare various image algebra procedures for their efficiency in locating and identifying different types of landscape changes on the margin of a Mediterranean coastal plain, Cukurova, Turkey. Image differencing and ratioing were applied to the reflective bands of Landsat TM datasets acquired in 1984 and 2006. Normalized Difference Vegetation index (NDVI) and Principal Component Analysis (PCA) differencing were also applied. The resulting images were tested for their capacity to detect nine change phenomena, which were a priori defined in a three-level classification scheme. These change phenomena included agricultural encroachment, sand dune afforestation, coastline changes and removal/expansion of reed beds. The percentage overall accuracies of different algebra products for each phenomenon were calculated and compared. The results showed that some of the changes such as sand dune afforestation and reed bed expansion were detected with accuracies varying between 85 and 97% by the majority of the algebra operations, while some other changes such as logging could only be detected by mid-infrared (MIR) ratioing. For optimizing change detection in similar coastal landscapes, underlying causes of these changes were discussed and the guidelines for selecting band and algebra operations were provided. PMID- 21820238 TI - Entropy increases in kidney cancer treatment, but a bit of simplicity may emerge from chaos. PMID- 21820239 TI - Re: Todd M. Morgan, Dominic Tang, Kelly L. Stratton, et al. Preoperative nutritional status is an important predictor of survival in patients undergoing surgery for renal cell carcinoma. Eur Urol 2011;59:923-8. Re: Umberto Capitanio, Francesco Montorsi. Does preoperative nutritional status affect survival in renal cell carcinoma? The debate continues. Eur Urol 2011;59:929-30. PMID- 21820241 TI - Giant tentorial cavernous hemangioma: case report and review of literature. PMID- 21820242 TI - Non-isothermal decomposition kinetics, heat capacity and thermal safety of 37.2/44/16/2.2/0.2/0.4-GAP/CL-20/Al/N-100/PCA/auxiliaries mixture. AB - The specific heat capacity (C(p)) of 37.2/44/16/2.2/0.2/0.4-GAP/CL-20/Al/N 100/PCA/auxiliaries mixture was determined with the continuous C(p) mode of microcalorimeter. The equation of C(p) with temperature was obtained. The standard molar heat capacity of GAP/CL-20/Al/N-100/PCA/auxiliaries mixture was 1.225 J mol(-1)K(-1) at 298.15K. With the help of the peak temperature (T(p)) from the non-isothermal DTG curves of the mixture at different heating rates (beta), the apparent activation energy (E(k) and E(o)) and pre-exponential constant (A(K)) of thermal decomposition reaction obtained by Kissinger's method and Ozawa's method. Using density (rho) and thermal conductivity (lambda), the decomposition heat (Q(d), taking half-explosion heat), Zhang-Hu-Xie-Li's formula, the values (T(e0) and T(p0)) of T(e) and T(p) corresponding to beta -> 0, thermal explosion temperature (T(be) and T(bp)), adiabatic time-to-explosion (t(TIad)), 50% drop height (H(50)) of impact sensitivity, and critical temperature of hot spot initiation (T(cr,hot spot)) of thermal explosion of the mixture were calculated. The following results of evaluating the thermal safety of the mixture were obtained: T(be) = 441.64K, T(bp) = 461.66 K, t(Tlad) = 78.0 s (n = 2), t(Tlad) = 74.87 s (n = 1), t(Tlad) = 71.85 s (n = 0), H(50) = 21.33 cm. PMID- 21820243 TI - Synthesis of calcium peroxide nanoparticles as an innovative reagent for in situ chemical oxidation. AB - Chemical oxidation is one of the many different methods of site remediation that has emerged lately as an alternative method to traditional techniques. According to this research calcium peroxide is suitable choice for contaminant biodegradation in soil and ground water but speed of oxidation reaction between calcium peroxide and contaminant is slow. Synthesis of calcium peroxide in nano size by increased ratio of surface to volume can increase the speed of reaction and solve the problem. We have developed a simple surface modification technique to avoid irreversible agglomeration of calcium peroxide nanoparticles. The technique is based on hydrolysis-precipitation procedure, using CaCl(2) as a precursor. Polyethylene glycol 200 (PEG200) is used as a surface modifier. CaO(2) was identified and studied by characterization techniques, including XRD and TEM. The results indicate the ability of this method for synthesis of new reagent in nano size and improve quality of in situ chemical oxidation. Size determination by TEM image indicates the size of calcium peroxide nanoparticles approximately 15-25 nm. PMID- 21820244 TI - Randomized trial of a DVD intervention to improve readiness to self-manage joint pain. AB - A DVD (digital video disk) intervention to increase readiness to self-manage joint pain secondary to hemophilia was informed by a 2-phase, motivational volitional model of readiness to self-manage pain, and featured the personal experiences of individuals with hemophilia. The DVD was evaluated in a randomized controlled trial in which 108 men with hemophilia completed measures of readiness to self-manage pain (Pain Stages of Change Questionnaire) before and 6 months after receiving the DVD plus information booklet (n=57) or just the booklet (n=51). The effect of the DVD was assessed by comparing changes in Pain Stages of Change Questionnaire scores (precontemplation, contemplation, and action/maintenance) between groups. The impact on pain coping, pain acceptance, and health-related quality of life was tested in secondary analyses. Repeated measures analysis of variance, including all those with complete baseline and follow-up data regardless of use of the intervention, showed a significant, medium-sized, group*time effect on precontemplation, with reductions among the DVD group but not the booklet group. Significant use*time effects showed that benefits in terms of contemplation and action/maintenance were restricted to those who used the interventions at least once. The results show that low intensity interventions in DVD format can improve the motivational impact of written information, and could be used to help prepare people with chronic pain for more intensive self-management interventions. The findings are consistent with a 2-phase, motivational-volitional model of pain self-management, and provide the first insights to our knowledge of readiness to self-manage pain in hemophilia. PMID- 21820245 TI - Saturation deficit and deer density affect questing activity and local abundance of Ixodes ricinus (Acari, Ixodidae) in Italy. AB - The wood tick Ixodes ricinus, one of the most common arthropod-borne disease vectors, is of increasing relevance for human and animal health in Europe. The aim of this study was to determine the relative contribution of several abiotic and biotic factors potentially affecting questing activity and local abundance of I. ricinus in Italy, considering the scale at which these factors interact with the host-seeking ticks. Within EDEN, a large-scale EU collaborative project on eco-epidemiology of vector-borne diseases, we collected questing ticks for three consecutive years using a standard protocol at eleven sites in the Italian Alps and Apennines. A total of 25 447 I. ricinus were collected. All sites showed the same annual pattern of tick activity (bimodal for nymphs and unimodal for larvae and adults), although the abundance of nymphs was statistically different between sites and years. A Generalized Linear Mixed Model and a Linear Mixed Model fitted to data for nymphs, showed that while the principal variables affecting the local abundance of questing ticks were saturation deficit (an index combining temperature and relative humidity) and red deer density, the most important variable affecting questing nymph activity was saturation deficit. As for the timing of seasonal emergence, we confirmed that the threshold temperature at this latitude for larvae is 10 degrees C (mean maximum) while that for nymphs is 8 degrees C. PMID- 21820246 TI - Influence of toltrazuril treatment on parasitological parameters and health performance of piglets in the field--an Austrian experience. AB - Porcine coccidiosis caused by Isospora suis is one of the leading causes of neonatal diarrhea in suckling piglets. Currently the only registered drug for metaphylaxis is toltrazuril. To evaluate the effect of treatment on piglets from 7 Austrian farms without and 8 Austrian farms with toltrazuril application we examined oocyst excretion (including determination of oocysts per gram of feces; OPG), diarrhea (fecal score FS 1-4 with 3 and 4 being diarrhea), and general health (health score HS 1-4 with 3 and 4 describing poor health). Both groups included farms with different levels of hygiene. Samples from 265 litters without treatment, comprising 1588 individual samples, and 1548 samples from 258 treated litters were taken twice (around the 14th and the 21st day of life, respectively), examined by autofluorescence and, if positive, by McMaster counting. In both groups animals had less diarrhea and lower health scores during the second sampling but the treated piglets were always significantly healthier and had less diarrhea. The percentage of weaned piglets was higher in treated animals although this was not significant (p=0.052). In the first round of sampling 17.8% of the individual samples from untreated piglets were positive for oocysts (with a maximum prevalence on the 12-15th day of life) while in the treated piglets only 0.4% shed oocysts p<0.001). At the second sampling only 2.1% of the untreated animals and none of treated piglets excreted I. suis (p=0.083). Positive animals shed up to 8 * 10(3)OPG. There was an increased risk for infected piglets to develop diarrhea (odds ratio, OR 4.73) and poor health (OR 5.05) in untreated piglets, and poor hygiene without disinfection was identified as a risk factor for poor health (OR 1.90), diarrhea (OR 1.42) and oocyst excretion (OR 1.73). The risk of poor health (OR 2.89) and diarrhea (OR 1.44) was also increased for piglets under poor hygienic conditions receiving toltrazuril, so both metaphylaxis of coccidiosis and good hygiene are necessary to effectively control neonatal diarrhea. The costs of treatment are considerably lower than the estimated financial production losses. Therefore, treatment is recommended for farms where clinical coccidiosis is diagnosed. PMID- 21820248 TI - Adolescent personality profiles, neighborhood income, and young adult alcohol use: a longitudinal study. AB - Personality traits and socioeconomic factors such as neighborhood income have been identified as risk factors for future alcohol abuse, but findings have been inconsistent possibly due to interactions between risk and protective factors. The present study examined the prediction of drinking behavior using empirically derived multi-trait patterns and tested for moderation by average neighborhood income. Using latent profile analysis (LPA) in a sample of 863 Dutch adolescents, four empirical personality profiles based on 6 traits were observed: Extraverted, Dysregulated, Neurotic, and Regulated. Dysregulated and Extraverted youth drank higher quantities of alcohol more frequently in young adulthood relative to the Regulated group, above and beyond the effects of baseline adolescent drinking, age, and sex. Profile levels of neuroticism did not appear to affect drinking behavior. Average neighborhood income did not moderate adolescent personality and young adult drinking. These findings suggest that future alcohol research should consider individual trait patterns to inform prevention and intervention efforts, and theories implicating both positive and negative emotionality traits as risk factors for drinking are preferable to those emphasizing the importance of the latter. PMID- 21820247 TI - Interactive effects of estrogen and serotonin on brain activation during working memory and affective processing in menopausal women. AB - While cognitive changes and mood instability are frequent symptoms reported by menopausal women, the degree to which the decline in estrogen production is responsible is not yet clear. Several lines of evidence suggest that estrogen may produce its effects on cognition and mood through modulation of serotonergic function. To test this hypothesis, we used the tryptophan depletion (TD) paradigm to lower central serotonin levels and pharmacologically manipulated estrogen levels in healthy menopausal women. We examined the individual and combined effects of estradiol and serotonin on working memory, emotion processing and task related brain activation. Eight healthy predominantly early postmenopausal women underwent TD or sham depletion followed by functional magnetic resonance imaging (fMRI) both before and after short-term transdermal estradiol 75-150 MUg/d administration. There was an estradiol treatment by TD interaction for brain activation during performance on both the N-back Task (working memory) and Emotion Identification Task (affective processing). During the 2-back condition, TD attenuated activation prior to, but not after, estradiol treatment in the right and left dorsal lateral prefrontal and middle frontal/cingulate gyrus. During emotion identification, TD heightened activation in the orbital frontal cortex and bilateral amygdala, and this effect was attenuated by estradiol treatment. These results provide preliminary evidence that serotonergic effects directly mediate the impact of estrogen on brain activation during working memory and affective processing. PMID- 21820249 TI - Sensory quality of short- and long-term frozen stored pork products. Influence of diets varying in polyunsaturated fatty acid (PUFA) content and iodine value. AB - Predicting aspects of pork quality is becoming increasingly important from a nutritional as well as a technological point of view. Here, the influence of increasing PUFA and iodine values (IV) in feed and pigs on sensory qualities of short- and long-term frozen stored products was investigated. Entire male and female grower-finisher pigs were fed diets with iodine value products of 48 (LowIVP), 77 (MedIVP) or 99 (HighIVP) according to a restricted feeding scale. Ribs, chops and meat balls were short- (0-3 months) and long-term (6-9 months) frozen stored before sensory profiling. C18:2n-6 increased linearly in backfat with increased dietary inclusion. No negative effect on sensory quality was found in short-term stored products. After long-term storage the lean chops was the product most affected. Increasing the dietary IVP led to an increased rancid and total odour and flavour intensity, and to reduced meat and sour odour and flavour. PMID- 21820250 TI - Perineural invasion predicts increased recurrence, metastasis, and death from prostate cancer following treatment with dose-escalated radiation therapy. AB - PURPOSE: To assess the prognostic value of perineural invasion (PNI) for patients treated with dose-escalated external-beam radiation therapy for prostate cancer. METHODS AND MATERIALS: Outcomes were analyzed for 651 men treated for prostate cancer with EBRT to a minimum dose >=75 Gy. We assessed the impact of PNI as well as pretreatment and treatment-related factors on freedom from biochemical failure (FFBF), freedom from metastasis (FFM), cause-specific survival (CSS), and overall survival. RESULTS: PNI was present in 34% of specimens at biopsy and was significantly associated with higher Gleason score (GS), T stage, and prostate specific antigen level. On univariate and multivariate analysis, the presence of PNI was associated with worse FFBF (hazard ratio = 1.7, p <0.006), FFM (hazard ratio = 1.8, p <0.03), and CSS (HR = 1.4, p <0.05) compared with absence of PNI; there was no difference in overall survival. Seven-year rates of FFBF, FFM, and CCS were 64% vs. 80%, 84% vs. 92%, and 91% vs. 95% for those patients with and without PNI, respectively. On recursive partitioning analysis, PNI predicted for worse FFM and CSS in patients with GS 8-10, with FFM of 67% vs. 89% (p <0.02), and CSS of 69% vs. 91%, (p <0.04) at 7 years for those with and without PNI, respectively. CONCLUSIONS: The presence of PNI in the prostate biopsy predicts worse clinical outcome for patients treated with dose-escalated external-beam radiation therapy. Particularly in patients with GS 8-10 disease, the presence of PNI suggests an increased risk of metastasis and prostate cancer death. PMID- 21820252 TI - Alcohol consumption among HIV-positive pregnant women in KwaZulu-Natal, South Africa: prevalence and correlates. AB - BACKGROUND: HIV-positive pregnant women who drink put their children at risk of both HIV and fetal alcohol spectrum disorders. The province of KwaZulu-Natal (KZN) has the highest prevalence of HIV in South Africa, but has not before been considered an area of high alcohol consumption among women. This paper analyzes a large sample of HIV+ pregnant women in KZN to examine alcohol consumption in that population. METHODS: Data came from assessments of women enrolled in Prevention of Mother-To-Child Transmission programs at 8 clinics in KZN. Descriptive statistics and logistic regressions were used to examine the prevalence and correlates of alcohol consumption and binge drinking. RESULTS: Of 1201 women assessed, 18% reported drinking during pregnancy, and 67% of drinkers usually binged when drinking (had 3+ drinks in one sitting). Over one-third of drinkers binged twice a month or more. Women living in urban and peri-urban locations were more likely to drink, as were those with indicators of higher economic status and greater social engagement. Married women were less likely to drink, while women who had poorer mental health, used tobacco, or had a greater history of sexual risk-taking were more likely to drink. CONCLUSION: Health care workers in KZN should be aware that pregnant women who drink are likely to do so at a level that is dangerous for their babies. Some factors associated with drinking indicate social/environmental influences that need to be counteracted by greater dissemination of information about the dangers of drinking, and greater support for abstinence or moderation. PMID- 21820253 TI - Craniometric measures of microcephaly using MRI. AB - BACKGROUND: Microcephalic brains exhibit varying sizes, shapes, and dimensions when compared to normocephalic counterparts, but the extent of these differences is unresolved. AIMS: To ascertain developmental changes in brain morphology using craniometric (linear brain) measures derived from MRI in microcephalic individuals and in normocephalic controls. STUDY DESIGN: A retrospective, cross sectional cohort study. SUBJECTS: Twenty-one primary and secondary microcephalic individuals ages 2 postnatal weeks to 8.5 years with occipito-frontal circumference<2nd percentile for age; 83 age-equivalent normocephalic controls. OUTCOME MEASURES: Age, sex, weight, height, body mass index, occipito-frontal circumference, and diagnosis prompting the MRI scan. Sixteen craniometric measures to determine specific ratios and age-related changes in brain shape and size. RESULTS: Microcephalic infants and children not only have abnormally small brains but also proportionately lower weights and heights. The brain volumes of both primary and secondary microcephalics were quite variable, ranging from 266 to 723 cm(3) and 440 to 730 cm(3), respectively (p=0.34). Despite their smaller sizes, the shapes of 15/21 (71%) microcephalic brains were similar to those of age-equivalent controls. Cerebral hemispheric configurations were not consistent among the 6 misshapen brains, which included 2 primary, 3 secondary, and 1 unknown microcephalics. Older microcephalic brains could be distinguished from their normocephalic counterparts by two specific craniometric ratios (frontal cerebellar pole/sagittal cerebral length; axial temporal width/axial cerebellar width), each incorporating cerebral and cerebellar dimensions in either length or width. CONCLUSIONS: The findings should provide useful information for distinguishing the characteristics of both modern and ancient microcephalic from normocephalic brains. PMID- 21820251 TI - Correlates of amphetamine-type stimulant use and associations with HIV-related risks among young women engaged in sex work in Phnom Penh, Cambodia. AB - BACKGROUND: Amphetamine-type stimulant (ATS) use has increased in Cambodia and emerged as a significant problem among female sex workers (FSWs), potentially contributing to increased risk of HIV. We examined the prevalence of ATS use and its effect on sexual risk behaviors, and sexually transmitted infections (STI) among FSWs in Phnom Penh, Cambodia. METHODS: A one-year prospective study among young women engaged in sex work in brothels, entertainment establishments and on a freelance basis. Socio-demographics, sexual risks, and recent ATS use were assessed by self-report. Blood and urine samples were collected to detect HIV, Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (GC). Bivariate and multivariate longitudinal analyses were conducted to assess the effects of ATS use on number of sex partners, inconsistent condom use with paying partners and incident STI. RESULTS: ATS use was higher among women working freelance (35.6%) and in brothels (34.8%) compared to women working in entertainment establishments (17.7%) or in multiple venues (14.8%). ATS users reported more sex partners and days drunk in the previous month. In multivariate longitudinal analysis, ATS use was associated with having a higher number of sex partners (adjusted relative ratio 1.49; 95% CI: 1.00-2.21) and incident STI (adjusted odds ratio 5.41; 95% CI: 1.15-25.48), but not inconsistent condom use with paying partner. CONCLUSION: ATS users had more sex partners, high level of alcohol use, and were at increased risk of STI. Our findings underscore ATS use as an important emerging risk exposure that should be integrated into HIV prevention interventions targeting this population. PMID- 21820254 TI - LH and FSH concentration and follicular development in Nellore heifers submitted to fixed-time artificial insemination protocols with different progesterone concentrations. AB - Nine heifers were pre-synchronized (PGF2alpha, 12 days) and assigned into three groups with 6 repetitions each: (1) CL (~8 days old, n=13); (2) DIB+CL (n=18); (3) DIB+EB (150 MUg of PGF2alpha and 2mg estradiol benzoate, n=18). After progesterone (P4) device removal (8 days) and/or final PGF2alpha, heifers were injected with either GnRH or EB in a 3*2 factorial totalling 49 observations (5 were excluded). The blood sampling schedule: every 12 h during P4 period; for LH pulse frequency on Days 3-5, every 15 min for 6 h during P4 period; after P4 removal and EB treatment, samples were collected every 3 h for 24 h or after GnRH every 1 h for 10 h. Ovarian follicle number and diameter were evaluated by ultrasonography every 12 h until the last blood sample and then 24 h and 48 h later. After device insertion (12 h), the DIB+CL group had a lesser LH concentration than the DIB+EB group. After 36 h, all DIB+CL-treated heifers had less LH than CL-heifers, and after 60 h, the DIB+EB group had less LH than the CL group. Considering all P4 groups combined, LH peak amplitude was greater after GnRH compared to EB treatment but total area of LH peak amplitude and time to first peak was less. The CL-group had fewer follicles and a greater largest follicle diameter than DIB+CL and DIB+EB groups. When treated with EB, the DIB+CL group had a lesser ovulation rate at 24 h than the CL- and DIB+EB-groups. Fixed time artificial insemination (FTAI) protocols promoted a pre-ovulatory LH peak, independent of previous exposure to the DIB coupled with a CL or not. The progesterone excess interfered with FSH and LH secretion, follicular development and ovulation within 24 h. PMID- 21820255 TI - Molecular structure of bovine Gtl2 gene and DNA methylation status of Dlk1-Gtl2 imprinted domain in cloned bovines. AB - Somatic cell nuclear transfer (SCNT) is an inefficient process, which is due to incomplete reprogramming of the donor nucleus. DNA methylation of imprinted genes is essential to the reprogramming of the somatic cell nucleus in SCNT. Dlk1-Gtl2 imprinted domain has been widely studied in mouse and human. However, little is known in bovine, possibly because of limited appropriate sequences of bovine. In our study, we first isolated the cDNA sequence and found multiple transcript variants occurred in bovine Gtl2 gene, which was conserved among species. A probably 110-kb-long Dlk1-Gtl2 imprinted domain was detected on bovine chromosome 21. We identified the putative Gtl2 DMR and IG-DMR corresponding to the mouse and human DMRs and assessed the methylation status of the two DMRs and Dlk1 5' promoter in lungs of deceased SCNT bovines that died within 48h after birth and the normal controls. In cloned bovines, Gtl2 DMR exhibited hypermethylation, which was similar to controls. However, the methylation status of IG-DMR and Dlk1 5' promoter in clones was significantly different from controls, with severe loss of methylation in IG-DMR and hypermethylation in the Dlk1 5' promoter region. Our data suggested that abnormal methylation patterns of IG-DMR may lead to the abnormal expression of Gtl2 and Dlk1 5' hypermethylated promoter is associated with the aberrant development of lungs of cloned bovines, which consequently may contribute to the low efficiency of SCNT. PMID- 21820256 TI - A novel tool for user-friendly estimation of natural, diagnostic and professional radiation risk: Radio-Risk software. AB - BACKGROUND: Awareness of radiological risk is low among doctors and patients. An educational/decision tool that considers each patient' s cumulative lifetime radiation exposure would facilitate provider-patient communication. AIM: The purpose of this work was to develop user-friendly software for simple estimation and communication of radiological risk to patients and doctors as a part of the SUIT-Heart (Stop Useless Imaging Testing in Heart disease) Project of the Tuscany Region. METHODS: We developed a novel software program (PC-platform, Windows OS fully downloadable at http://suit-heart.ifc.cnr.it) considering reference dose estimates from American Heart Association Radiological Imaging 2009 guidelines and UK Royal College of Radiology 2007 guidelines. Cancer age and gender-weighted risk were derived from Biological Effects of Ionising Radiation VII Committee, 2006. RESULTS: With simple input functions (demographics, age, gender) the user selects from a predetermined menu variables relating to natural (e.g., airplane flights and geo-tracked background exposure), professional (e.g., cath lab workers) and medical (e.g., CT, cardiac scintigraphy, coronary stenting) sources. The program provides a simple numeric (cumulative effective dose in milliSievert, mSv, and equivalent number of chest X-rays) and graphic (cumulative temporal trends of exposure, cancer cases out of 100 exposed persons) display. CONCLUSIONS: A simple software program allows straightforward estimation of cumulative dose (in multiples of chest X-rays) and risk (in extra % lifetime cancer risk), with simple numbers quantifying lifetime extra cancer risk. Pictorial display of radiation risk may be valuable for increasing radiological awareness in cardiologists. PMID- 21820257 TI - The prevalence of bacterial contamination of standard keyboards in an urban ED. PMID- 21820258 TI - Emergency department focused bedside echocardiography in massive pulmonary embolism. AB - BACKGROUND: Massive pulmonary embolism (PE) is a common consideration in unstable patients presenting to the emergency department (ED) with chest pain, dyspnea, or cardiac arrest. It is a potentially lethal condition necessitating prompt recognition and aggressive management. Conventional diagnostic modalities in the ED, including chest computed tomography angiography and ventilation-perfusion scanning, require the unstable patient to leave the department, and raise concerns over renal injury. Several case reports document findings of massive PE on echocardiography performed in the ED; however, none was performed, interpreted, and acted upon in the form of thrombolytic therapy by an emergency physician without the additional benefit of a cardiologist's interpretation or a confirmatory imaging study. OBJECTIVE: We present a case that illustrates the utility of ED focused bedside echocardiography in suspected massive PE and briefly review direct and indirect ultrasound findings of acute PE. CASE REPORT: A case of massive PE in a 61-year-old woman is reported. In this patient with marked dyspnea, progressive hemodynamic instability, and contraindications to definitive imaging, ED focused bedside echocardiography provided valuable information that strongly suggested the diagnosis and led to alteplase administration. To our knowledge, this case represents the first report of thrombolytic therapy administration for acute massive PE based solely on clinical presentation and an emergency physician-performed bedside echocardiogram. CONCLUSION: In the hands of an experienced emergency physician ultrasonographer, ED focused bedside echocardiography provides a safe, rapid, and non-invasive diagnostic adjunct for evaluation of the patient suspected of having massive PE. PMID- 21820259 TI - Cervical ectopic pregnancy diagnosed by point-of-care emergency department ultrasound. AB - BACKGROUND: Although rare, cervical ectopic pregnancy (EP) represents a potentially lethal variation of a common first-trimester disease entity. CASE REPORT: We report a case of low abdominal pain and vaginal bleeding diagnosed as a cervical EP by point-of-care ultrasound. CONCLUSION: Familiarity with cervical EP and its sonographic appearance is essential for emergency physicians because it can be easily mistaken for an intrauterine pregnancy or other obstetric/gynecologic pathology, such as an incomplete abortion or nabothian cyst. The management of each of these differs substantially, making accurate diagnosis crucial. PMID- 21820260 TI - Ultrasound diagnosis of rectus sheath hematoma. PMID- 21820261 TI - A Patient with syncope, orthostatic hypotension, and postural-dependent focal neurological deficit. PMID- 21820262 TI - Infected urachal cyst initially misdiagnosed as an incarcerated umbilical hernia. AB - BACKGROUND: Urachal abnormalities are a rare cause of lower abdominal pain. They are often initially mistaken for more common causes of lower abdominal pain, and the diagnosis is usually made during evaluation for one of these more common conditions. CASE REPORT: We report a case of a painful periumbilical mass ultimately diagnosed as an infected urachal cyst. Although the cyst was evident sonographically, it was misidentified as an umbilical hernia, and the correct diagnosis was not made until the patient underwent computed tomography of the abdomen and pelvis before surgery. CONCLUSION: Emergency physicians should consider urachal disease in patients presenting with lower abdominal pain and should also be familiar with both the clinical and radiologic findings characteristic of this disease. PMID- 21820263 TI - Ruptured appendicitis presenting as acute scrotal swelling in a 23-month-old toddler. AB - BACKGROUND: Acute appendicitis is a common disease process in which timely diagnosis minimizes the risk of complications. OBJECTIVES: This case illustrates one example of the range of clinical presentations of young children with acute appendicitis. CASE REPORT: We describe a case in a young child presenting with an inguinal and scrotal mass that was ultimately due to perforated appendicitis with abscess formation. CONCLUSIONS: In the emergency department evaluation of these children with inguinal or scrotal complaints, we maintain that intra-abdominal processes should be included in the differential. PMID- 21820264 TI - Fournier gangrene: an unusual presentation involving the bulbous urethra and forming free gas in the urinary bladder. PMID- 21820265 TI - Malignant hypertension with papilledema. PMID- 21820267 TI - Autograft versus allograft: an economic cost comparison of anterior cruciate ligament reconstruction. AB - PURPOSE: The purpose of this study was to compare the costs associated with anterior cruciate ligament (ACL) reconstruction with either bone-patellar tendon bone (BPTB) autograft or BPTB allograft. METHODS: Surgical costs are reported, including supply costs, based on invoice costs per item used per procedure, and personnel costs calculated as cost per minute. All operations were performed at an ambulatory surgery center between March 2005 and March 2006. A total of 160 patients underwent primary ACL reconstruction with either BPTB autograft (n = 106) or BPTB allograft (n = 54). Procedure cost data were retrieved from a financial management database and divided into various categories for comparison of the 2 groups. Payment data were provided by the surgery center's billing office. RESULTS: The total mean cost per case was $4,147 +/- $943 in the allograft group compared with $3,154 +/- $704 in the autograft group; this was statistically significant (P < .001). The mean operating room time was 12 minutes greater in autograft cases (P = .006). Supply costs comprised a mean of 58.7% of total expenses in the autograft group and 72.2% in the allograft group. CONCLUSIONS: Allograft reconstruction of the ACL was significantly more expensive than autograft reconstruction. LEVEL OF EVIDENCE: Level II, economic analysis. PMID- 21820268 TI - Accidental section of the ulnar nerve in the wrist during arthroscopy. AB - Arthroscopy of the wrist is a frequently performed procedure. Its role in diagnosis and treatment is significant. The complications of arthroscopy are well known and are described in the literature. We describe a case of accidental section of the ulnar nerve during repair of the triangular fibrocartilage complex during arthroscopy. The nerve section was caused by the trocar used for drainage in the 6U portal. We propose to establish the injury mechanism and describe a safe procedure for this examination. PMID- 21820266 TI - Expression of gap junctional connexin proteins in ovine fetal ovaries: effects of maternal diet. AB - Gap junctions have been implicated in the regulation of cellular metabolism and the coordination of cellular functions during growth and differentiation of organs and tissues, and gap junctions play a major role in direct cell-cell communication. Gap junctional channels and connexin (Cx) proteins have been detected in adult ovaries in several species. Furthermore, it has been shown that several environmental factors, including maternal diet, may affect fetal organ growth and function. To determine whether maternal diet affects expression of Cx26, Cx32, Cx37, and Cx43 in fetal ovaries, sheep were fed a maintenance (M) diet with adequate (A) selenium (Se) or high (H) Se levels from 21 d before breeding to day 132 of pregnancy. From day 50 to 132 of pregnancy (tissue collection day), a portion of the ewes from the ASe and HSe groups was fed a restricted (R; 60% of M) diet. Sections of fetal ovaries were immunostained for the presence of Cxs followed by image analysis. All four Cxs were detected, but the distribution pattern differed. Cx26 was immunolocalized in the oocytes from primordial, primary, secondary, and antral follicles; in granulosa and theca layers of secondary and antral follicles; stroma; and blood vessels. Cx32 was in oocytes, granulosa, and theca cells in a portion of antral follicles; Cx37 was on the borders between oocyte and granulosa/cumulus cells of primordial to antral follicles and in endothelium; and Cx43 was on cellular borders in granulosa and theca layers and between oocyte and granulosa/cumulus cells of primordial to antral follicles. Maternal diet affected Cx26 and Cx43 expression, Cx26 in granulosa layer of antral follicles was decreased (P < 0.01) by HSe in the M and R diets, and Cx43 in granulosa layer of primary and granulosa and theca of antral follicles was increased (P < 0.05) by the M diet with HSe. Thus, Cxs may be differentially involved in regulation of fetal ovarian function in sheep. These data emphasize the importance of maternal diet in fetal growth and development. PMID- 21820269 TI - [Analysis of neuromuscular blocking drugs and sugammadex expenses, one year after its introduction into routine clinical practice]. PMID- 21820270 TI - Hip and groin pain in the professional athlete. AB - Hip and groin pain is a common condition in professional athletes and may result from an acute injury or from chronic, repetitive trauma. It is responsible for significant morbidity, which leads to time away from training and competition, and may result in a career-ending injury. The anatomic and biomechanical causes for hip and groin injuries are among the most complex and controversial in the musculoskeletal system. This makes clinical differentiation and subsequent management difficult because of the considerable overlap of symptoms and signs. This review article will evaluate several pathologic conditions of the hip and groin in athletes, divided into acute (secondary to single event) and chronic (secondary to altered biomechanical load or repetitive microtrauma) injuries, with an emphasis on imaging in the diagnosis of these injuries. Appropriate use of imaging along with clinical findings can allow accurate diagnosis and subsequent appropriate management of these patients to ultimately allow return to athletic activity. PMID- 21820271 TI - Sleep restores daytime deficits in procedural memory in children with attention deficit/hyperactivity disorder. AB - Sleep supports the consolidation of declarative and procedural memory. While prefrontal cortex (PFC) activity supports the consolidation of declarative memory during sleep, opposite effects of PFC activity are reported with respect to the consolidation of procedural memory during sleep. Patients with attention deficit/hyperactivity disorder (ADHD) are characterised by a prefrontal hypoactivity. Therefore, we hypothesised that children with ADHD benefit from sleep with respect to procedural memory more than healthy children. Sixteen children with ADHD and 16 healthy controls (aged 9-12) participated in this study. A modification of the serial-reaction-time task was conducted. In the sleep condition, learning took place in the evening and retrieval after a night of sleep, whereas in the wake condition learning took place in the morning and retrieval in the evening without sleep. Children with ADHD showed an improvement in motor skills after sleep compared to the wake condition. Sleep-associated gain in reaction times was positively correlated with the amount of sleep stage 4 and REM-density in ADHD. As expected, sleep did not benefit motor performance in the group of healthy children. These data suggest that sleep in ADHD normalizes deficits in procedural memory observed during daytime. It is discussed whether in patients with ADHD attenuated prefrontal control enables sleep-dependent gains in motor skills by reducing the competitive interference between explicit and implicit components within a motor task. PMID- 21820272 TI - Automatic intelligibility assessment of speakers after laryngeal cancer by means of acoustic modeling. AB - OBJECTIVE: One aspect of voice and speech evaluation after laryngeal cancer is acoustic analysis. Perceptual evaluation by expert raters is a standard in the clinical environment for global criteria such as overall quality or intelligibility. So far, automatic approaches evaluate acoustic properties of pathologic voices based on voiced/unvoiced distinction and fundamental frequency analysis of sustained vowels. Because of the high amount of noisy components and the increasing aperiodicity of highly pathologic voices, a fully automatic analysis of fundamental frequency is difficult. We introduce a purely data-driven system for the acoustic analysis of pathologic voices based on recordings of a standard text. METHODS: Short-time segments of the speech signal are analyzed in the spectral domain, and speaker models based on this information are built. These speaker models act as a clustered representation of the acoustic properties of a person's voice and are thus characteristic for speakers with different kinds and degrees of pathologic conditions. The system is evaluated on two different data sets with speakers reading standardized texts. One data set contains 77 speakers after laryngeal cancer treated with partial removal of the larynx. The other data set contains 54 totally laryngectomized patients, equipped with a Provox shunt valve. Each speaker was rated by five expert listeners regarding three different criteria: strain, voice quality, and speech intelligibility. RESULTS/CONCLUSION: We show correlations for each data set with r and rho>=0.8 between the automatic system and the mean value of the five raters. The interrater correlation of one rater to the mean value of the remaining raters is in the same range. We thus assume that for selected evaluation criteria, the system can serve as a validated objective support for acoustic voice and speech analysis. PMID- 21820273 TI - The effect of class imbalance on case selection for case-based classifiers: an empirical study in the context of medical decision support. AB - Case selection is a useful approach for increasing the efficiency and performance of case-based classifiers. Multiple techniques have been designed to perform case selection. This paper empirically investigates how class imbalance in the available set of training cases can impact the performance of the resulting classifier as well as properties of the selected set. In this study, the experiments are performed using a dataset for the problem of detecting breast masses in screening mammograms. The classification problem was binary and we used a k-nearest neighbor classifier. The classifier's performance was evaluated using the receiver operating characteristic (ROC) area under the curve (AUC) measure. The experimental results indicate that although class imbalance reduces the performance of the derived classifier and the effectiveness of selection at improving overall classifier performance, case selection can still be beneficial, regardless of the level of class imbalance. PMID- 21820274 TI - Regarding the temporal requirements of a hierarchical Willshaw network. AB - In a recent communication, Sacramento and Wichert (2011) proposed a hierarchical retrieval prescription for Willshaw-type associative networks. Through simulation it was shown that one could make use of low resolution descriptor patterns to decrease the total time requirements of recalling a learnt association. However, such a method introduced a dependence on a set of new parameters which define the structure of the hierarchy. In this work we compute the expected retrieval time for the random neural activity regime which maximises the capacity of the Willshaw model and we study the task of finding the optimal hierarchy parametrisation with respect to the derived temporal expectation. Still in regard to this performance measure, we investigate some asymptotic properties of the algorithm. PMID- 21820275 TI - Influence of pain associated with musculoskeletal disorders on grip force timing. AB - STUDY DESIGN: Retrospective repeated-measures design. INTRODUCTION: Pain is a common symptom associated with musculoskeletal conditions. PURPOSE: This study examined if pain resulting from a unilateral upper extremity musculoskeletal injury compromises the person's ability to rapidly initiate and release handgrip. METHODS: Delays in initiating and releasing a handgrip were determined for 28 individuals with "low pain" and 12 individuals with "high pain" in the injured upper extremity. All participants had no pain in the uninjured upper extremity. RESULTS: The high-pain group was 10% slower in initiating and releasing a grip than the low-pain group, in both injured and uninjured upper extremities, for both maximal and submaximal grips. In addition, delay in grip initiation was, on average, 8% longer for the injured than for the uninjured upper extremity. CONCLUSIONS: Unilateral musculoskeletal pain appears to delay grip initiation and relaxation bilaterally, perhaps due to a centrally mediated mechanism. LEVEL OF EVIDENCE: n/a. PMID- 21820276 TI - Scapulothoracic and scapulohumeral exercises: a narrative review of electromyographic studies. AB - STUDY DESIGN: Narrative review. INTRODUCTION: A well-constructed rehabilitation program of the shoulder complex is critical to stabilizing the scapulothoracic and scapulohumeral joints while encouraging normal scapulohumeral rhythm. Review of the literature demonstrates a variety of scapulothoracic and glenohumeral conditioning exercises. PURPOSE: To assist the occupational and physical therapist in prioritizing exercises for a shoulder conditioning program based on a narrative review of electromyographic (EMG) studies of the shoulder. METHODS: The authors performed a comprehensive literature search of approximately 250 articles describing shoulder (EMG) testing of the rotator cuff and periscapular musculature. Twenty-two articles were selected based on the author's inclusion criteria. The authors developed a flow sheet outlining each exercise, starting and ending positions, principle muscle(s), and description of exercise. Exercises were assigned to two different muscle groups: rotator cuff or periscapular depending on the principle muscles activated. RESULTS: The 22 included articles provided an evidenced-based list of exercises aimed to efficiently and maximally recruit specific rotator cuff and periscapular musculature. Based on these 22 articles, the authors were able to establish a useful series of exercises to promote glenohumeral stability and foster normal scapulohumeral rhythm. Those exercises that elicited the highest maximum voluntary isometric contraction recruitment and were cited to be critical for stability and scapulohumeral rhythm were selected for the exercise flow sheet. CONCLUSIONS: This review provides a useful evidence-based tool to establish a practical shoulder exercise program. LEVEL OF EVIDENCE: Level 5. PMID- 21820277 TI - Vena contracta width as a predictor of adverse outcomes in patients with severe isolated tricuspid regurgitation. AB - BACKGROUND: The clinical outcomes and predictors of outcomes in isolated tricuspid regurgitation (TR) are poorly defined. The aim of this study was to investigate the determinants of outcomes in severe isolated TR. METHODS: Seventy four patients (mean age, 63 +/- 12 years; 34 men) with severe isolated TR who satisfied the criteria of (1) TR jet area > 30% of right atrial area or TR jet area > 10 cm(2) and (2) a plethora of inferior vena cava or systolic flow reversal of the hepatic vein were retrospectively analyzed. The primary end points were hospitalization for worsening heart failure, tricuspid valve (TV) surgery, and cardiovascular death. RESULTS: During the median follow-up period of 53 months, 25 events occurred (three cardiovascular deaths, nine TV surgeries, and 13 hospitalizations for worsening heart failure). Univariate Cox analysis showed that younger age, female gender, larger effective regurgitant orifice, vena contracta width (VCW), and increased right atrial and right ventricular size were associated with cardiovascular events. Increased TV tethering distance and tethering area were also associated with cardiovascular events. In multivariate Cox regression analysis, larger VCW (hazard ratio, 1.72; 95% confidence interval, 1.15-2.57, P < 0.01) was an independent predictor of cardiovascular events. Compared with patients with VCW <= 7 mm, those with VCW > 7 mm had poorer long term outcomes (adjusted hazard ratio, 19.9; P < .01). Increased VCW was also an independent predictor of cardiovascular death and TV surgery (hazard ratio, 1.2; 95% confidence interval, 1.00-1.45; P = .04). CONCLUSIONS: In severe isolated TR, VCW is a powerful independent predictor of adverse outcomes. Adverse outcomes were considerable for VCW > 7 mm, which suggests that quantification of TR by Doppler echocardiography is crucial for estimating prognosis. TV surgery might be considered for patients with severe isolated TR with VCW > 7 mm. PMID- 21820278 TI - Carl Friedrich Gauss and Pravin Shah-a tribute to excellence. PMID- 21820279 TI - Atrial fibrillation and flutter outcomes and risk determination (AFFORD): design and rationale. AB - BACKGROUND: Atrial fibrillation (AF) is the most common sustained arrhythmia affecting over 700,000 individuals in Japan and 2.2 million in the USA. The proper management of patients with AF is critical due to the well-documented association with heart failure and stroke. A strategy to better define the emergency department (ED) management, admission decisions, and spectrum of risk from low to high is needed. METHODS AND SUBJECTS: The atrial fibrillation and flutter outcomes and risk determination investigation is a prospective, observational cohort study to develop a multivariable clinical prediction rule that accurately estimates risk for adverse outcomes in patients presenting to the ED with symptomatic AF. We will enroll 430 patients at 2 sites who present to the ED with symptomatic AF defined as a new or established diagnosis of AF or atrial flutter that require ED evaluation for a complaint thought related to their rhythm disturbance. The study's endpoint is to develop an accurate, objective, internally validated, reliable clinical prediction rule to risk-stratify ED patients presenting with AF exacerbations. The rule will incorporate patient history and examination findings and laboratory studies obtained upon ED presentation, as well as trends over the first 2 h of care. This investigation's primary outcome is the incidence of any AF-related adverse event at 5 days and 30 days. We expect to complete the study by the end of 2014. The study was registered at Clinicaltrials.gov NCT01138644. PMID- 21820280 TI - Recent mortality of Japanese patients with atrial fibrillation in an urban city of Tokyo. AB - BACKGROUND: In Japan, the recent status of the mortality of atrial fibrillation (AF) patients is still unclear. METHODS AND RESULTS: We used a single-hospital based cohort database in an urban city (Tokyo) in Japan, including all the new visitors from 2004 to 2009 (n=13,228). The non-adjusted death rates of AF patients for all-cause, stroke, and cardiovascular death were 1091, 97, and 727 per 100,000 patient-years, and the age-adjusted ones were 317 (95% CI, 316-318), 16 (95% CI, 16-16), and 238 (95% CI, 237-239), respectively. The age-adjusted relative risk of AF on all-cause mortality was 1.7 in the particular population. CONCLUSIONS: The present study provides the most recent data about the characteristics and the mortality of AF patients in Tokyo, thus serving as the basic information for finding problems to solve regarding Japanese AF patients. PMID- 21820281 TI - Modulation of cyanobacterial photosystem I deposition properties on alkanethiolate Au substrate by various experimental conditions. AB - We present results from atomic force microscopy (AFM) images indicating various experimental conditions, which alter the morphological characteristics of self assembled cyanobacterial PS I on hydroxyl-terminated self-assembled alkanethiolate monolayers (SAM/Au) substrates. AFM topographical images of SAM/Au substrates incubated in solutions containing different PS I concentrations solubilized with Triton X-100 as the detergent reveal large columnar aggregates (~100 nm and hence, much taller than a single PS I trimer) at high PS I concentrations. Depositions from dilute PS I suspensions reveal fewer aggregates and relatively uniform surface topography (~10 nm). Confocal fluorescence microscopy analysis of fluorescently tagged PS I deposited on to SAM/Au substrates using electric field and gravity driven techniques reveal preliminary indications of directionally aligned PS I attachments, besides corroborating a uniform monolayer formation, for the former deposition method. The complex attachment dynamics of PS I onto SAM substrates are further investigated from the AFM images of PS I/SAM/Au substrates prepared under different experimental conditions using: 1) PS I isolated as monomers and trimers 2) adsorption at elevated temperatures, and 3) different detergents with varying pH values. In each of the cases, the surface topology indicated distinct yet complex morphological and phase characteristics. These observations provide useful insight into the use of experimental parameters to alter the morphological assembly of PS I on to SAM substrates en route to successful fabrication of PS I based biohybrid photoelectrochemical devices. PMID- 21820282 TI - Antioxidant encapsulated porous poly(lactide-co-glycolide) microparticles for developing long acting inhalation system. AB - The purpose of this study was to fabricate porous poly(lactide-co-glycolide) (PLGA) microparticles for efficient pulmonary deposition and increased therapeutic duration of the antioxidant anthocyanin (ATH). These microparticles were prepared by a water-in-oil-in-water (W(1)/O/W(2)) multi-emulsion method with vaporizing ammonium bicarbonate (AB) as a porogen and starch as a viscous additive. High porosity achieved by the decomposition reaction of AB to the base of ammonia, carbon dioxide, and water vapor at 50 degrees C enabled efficient deposition of ATH throughout the entire lung in BALB/c mice. In addition, the porous microparticles incorporating starch showed sustained ATH release characteristics (up to 5 days) and protracted antioxidant activity (up to 5 days) for 2,2-diphenyl-1-pikryl-hydrazyl (DPPH) radicals, which was comparable to that of the porous microparticles without starch which completely released ATH in 2h. Furthermore, these porous microparticles incorporating starch led to longer ATH residence (up to 20 days) in in vivo lung epithelium. We believe that this system has great pharmaceutical potential as a long-acting antioxidant for continuously relieving oxidative stress in pulmonary diseases like chronic obstructive pulmonary disease (COPD). PMID- 21820283 TI - Anti-biofouling properties of an amphoteric polymer brush constructed on a glass substrate. AB - An amphoteric copolymer brush of methacrylic acid (MA) and 2-(dimethylamino)ethyl methacrylate (DMAEMA) was prepared by reversible addition-fragmentation chain transfer (RAFT) polymerization using both a free chain transfer agent (n butylsulfanylthiocarbonylsulfanyl-2-methyl propionic acid) and a radical initiator (4,4'-azobis(4-cyanopentanoic acid)) covalently fixed to a glass substrate. An aqueous solution of the copolymer, Poly(MA-r-DMAEMA), which was simultaneously obtained in liquid phase, had a sufficiently small polydispersity in its molecular weight. The copolymer brush showed effective suppression of non specific adsorption of bovine serum albumin and egg white lysozyme to the brush. In contrast, both negatively charged PolyMA and positively charged PolyDMAEMA brushes significantly adsorbed the proteins irrespective of their net charges. Upon ion beam irradiation, furthermore, a hollow space with a designed shape could be made on the glass substrate, and both HEK293 and HepG2 cells non specifically adhered to the space, forming aggregates, while no adhesion to the non-treated area on the brush was observed. These results suggest that the amphoteric polymer brushes will be useful materials for biomedical applications. PMID- 21820284 TI - [The mother-infant encounter at birth must be protected]. AB - The medical decision to separate a newborn baby from his or her mother is frequent. This medical practice must be evaluated. The scientific literature regarding humans and other mammals was reviewed in order to describe the physiology of the interactions between mother and offspring and the consequences of disrupting their interactions around birth. Mother-infant bonding is common to all mammals. Attachment is the result of three mechanisms: behavioral programing, secretion of neuroendocrine substrates, and activation of sensory cues. Breastfeeding is a fourth component that plays a crucial role. Experimental research provides evidence that early-life maternal separation can alter biological responses to stress, disturb learning behaviors, and impair social skills. Recent advances in epigenetic research may partly explain how neonatal maternal deprivation at birth can lead to biological and behavioral disorders in adulthood. Therefore, the decision to separate a newborn infant from his or her mother is not harmless and must be carefully considered. In order to better take into account these data, the organization of perinatal care in France should be revised. PMID- 21820285 TI - [Screening for developmental dysplasia of the hip: a challenge]. PMID- 21820286 TI - [Moderated form of Morquio syndrome: an unknown cause of short stature (three case reports)]. AB - Morquio disease is a rare genetic disorder characterized by the accumulation of keratan sulfate in tissues. We distinguish two forms according to the deficient enzyme: type A, with a poor prognosis, and type B. Its management is essentially symptomatic. Enzyme replacement therapy and gene therapy are still being evaluated. We report observations of three patients with Morquio disease type A in its moderate form. This article reports the latest facts in both Morquio disease diagnosis and treatment, emphasizing the minor forms usually presented by short stature that should bring out this disorder. PMID- 21820287 TI - [Acute erythroblastopenia due to Parvovirus B19 revealing hereditary spherocytosis]. AB - Acute Parvovirus B19 infection is responsible for blocking the erythroblastic line, usually with no consequences on hematopoiesis except in patients with chronic hemolytic anemia in whom it can evolve to potentially serious acute anemia. We report 2 observations of acute erythroblastopenia revealing hereditary spherocytosis in 2 children (1 boy and 1 girl) of non-consanguineous parents. PMID- 21820288 TI - [Acute vomiting in an infant]. PMID- 21820289 TI - [Potential childhood jambul toxicity and the main known pharmacologic properties]. PMID- 21820291 TI - [Severe iatrogenic airway obstruction due to lingual lymphangioma]. AB - Lymphangioma of the tongue is a rare and benign tumour involving congenital and cystic abnormalities derived from lymphatic vessels. Treatment modalities include surgery and a large number of different intralesional injections of sclerosing agents. Presently, OK-432 (Picibanil((r))) is the preferred sclerosant and when administered intralesionally will result in inflammation, sclerosis, and cicatricial contraction of the lesion. We report a case of microcystic lymphangioma of the tongue in a 5-year-old boy treated with an intralesional injection of OK-432. In the immediate postoperative period, the patient suffered severe diffuse swelling, progressive upper airway obstruction with inspiratory stridor, and respiratory distress requiring emergency fiberoptic nasotracheal intubation. Although OK-432 injections are found to be safe and effective as a first line of treatment for lymphangiomas, local swelling with potentially life threatening airway compromise should be anticipated, especially when treating lesions near the upper airway. PMID- 21820292 TI - [Aicardi syndrome associated with severe congenital ptosis]. AB - Aicardi syndrome is a rare neurodevelopmental disorder characterized by corpus callosum agenesis, chorioretinal lacunae and early-onset infantile spasms. We report a particular case of Aicardi syndrome characterized by the association of the classical triad of severe bilateral ptosis, pontocerebellar hypoplasia, and perisylvian polymicrogyria in a girl born to non-consanguineous parents, but whose mother suffered from idiopathic generalized epilepsy. PMID- 21820293 TI - Variation in volume definition between UK head and neck oncologists treating oropharyngeal carcinoma. PMID- 21820294 TI - Volumetric modulated arc therapy with simultaneous integrated boost for locally advanced rectal cancer. AB - AIMS: To report the feasibility of volumetric modulated arc therapy (VMAT) for neoadjuvant radiotherapy in locally advanced rectal cancer in a dose-escalation protocol and simultaneous integrated boost (SIB) approach. Moreover, the VMAT technique was compared with three-dimensional conformal radiotherapy (3D-CRT) and fixed-field intensity modulated radiotherapy (IMRT), in terms of target coverage and irradiation of organs at risk. MATERIALS AND METHODS: Eight patients with locally advanced rectal cancer were treated with the SIB-VMAT technique. The VMAT plans were compared with 3D-CRT and IMRT techniques in terms of several clinically dosimetric parameters. The number of monitor units and the delivery time were analysed to score the treatment efficiency. All plans were verified in a dedicated solid water phantom using a two-dimensional array of ionisation chambers. RESULTS: All techniques meet the prescription goal for planning target volume coverage, with VMAT showing the highest level of conformality. VMAT is associated with 40, 53 and 58% reduction in the percentage of volume of small bowel irradiated to 30, 40 and 50Gy, compared with 3D-CRT. No significant differences were found with respect to SIB-IMRT. VMAT plans showed a significant reduction of monitor units by nearly 20% with respect to IMRT and reduced treatment time from 14 to 5min for a single fraction. CONCLUSIONS: SIB-VMAT plans can be planned and carried out with high quality and efficiency for rectal cancer, providing similar sparing of organs at risk to SIB-IMRT and resulting in the most efficient treatment option. SIB-VMAT is currently our standard approach for radiotherapy of locally advanced rectal cancer. PMID- 21820295 TI - Biomechanics on the half shell: functional performance influences patterns of morphological variation in the emydid turtle carapace. AB - This study uses the carapace of emydid turtles to address hypothesized differences between terrestrial and aquatic species. Geometric morphometrics are used to quantify shell shape, and performance is estimated for two shell functions: shell strength and hydrodynamics. Aquatic turtle shells differ in shape from terrestrial turtle shells and are characterized by lower frontal areas and presumably lower drag. Terrestrial turtle shells are stronger than those of aquatic turtles; many-to-one mapping of morphology to function does not entirely mitigate a functional trade-off between mechanical strength and hydrodynamic performance. Furthermore, areas of morphospace characterized by exceptionally poor performance in either of the functions are not occupied by any emydid species. Though aquatic and terrestrial species show no significant differences in the rate of morphological evolution, aquatic species show a higher lineage density, indicative of a greater amount of convergence in their evolutionary history. The techniques employed in this study, including the modeling of theoretical shapes to assess performance in unoccupied areas of morphospace, suggest a framework for future studies of morphological variation. PMID- 21820296 TI - The toxicity redox mechanisms of cadmium alone or together with copper and zinc homeostasis alteration: its redox biomarkers. AB - Cadmium (Cd) is a toxic metal and can induce and/or promote diseases in humans (cancer, aging diseases, kidney and bone diseases, etc.). Its toxicity involves many mechanisms including the alteration of copper (Cu) and zinc (Zn) homeostasis leading to reactive oxygen species (ROS) production, either directly or through the inhibition of antioxidant activities. Importantly, ROS can induce oxidative damages in cells. Cadmium, Cu and Zn are also able to induce glutathione (GSH) and metallothioneins (MT) synthesis in a cell-type-dependent manner. As a consequence, the effects induced by these three metals result simultaneously from the inhibition of antioxidant activities and the induction of other factors such as GSH and MT synthesis. MT levels are regulated not only by the p53 protein in a cell-type-dependent manner, or by transcription factors such as metal-responsive transcription factor 1 (MTF-1) and cellular Zn levels but also by cellular GSH level. As described in the literature, DNA damage, GSH and MT levels are sensitive biomarkers used to identify Cd-induced toxicity alone or together with Cu and Zn homeostasis alteration. PMID- 21820297 TI - Pro- and anti-oxidant effects of polyunsaturated fatty acid supplementation in HepG2 cells. AB - PUFA are bioactive nutrients thought to be effective in the prevention of many chronic diseases. PUFA susceptibility to free radical oxidation represents the other side of the coin, and the role of PUFA as pro- or anti-oxidants is still an unanswered question. In this study we supplemented HepG2 cells with different PUFA, and observed different effects on cytotoxicity, oxidation and modulation of antioxidant defenses. These were not simply related to the length of carbon chain, or to the number and position of double bonds. ARA supply evidenced the induction of oxidative damage, while DHA supplemented cells appeared richer in antioxidant defenses. To our knowledge, our study is the first evidencing the different pro- or anti-oxidant effect of different fatty acids when supplemented to cells. Overall, this points out the importance of not generalizing dietary recommendations considering PUFA as one category, but to extend them to the individual fatty acids. PMID- 21820298 TI - The effect of airway remodelling on airway hyper-responsiveness in asthma. AB - RATIONALE: The mechanisms of airway hyper-responsiveness are only partially understood and the contribution of airway remodelling is unknown. Airway remodelling can be assessed by measuring airway distensibility, which is reduced in asthma, even when lung function is normal. We hypothesised that airway remodelling contributes to airway hyper-responsiveness in asthma, independent of steroid-responsive airway inflammation. OBJECTIVES: To determine the relationship between airway distensibility and airway responsiveness at baseline and after 12 weeks of inhaled corticosteroid therapy in a group of asthmatics with airway hyper-responsiveness. METHODS: Nineteen doctor-diagnosed asthmatics had airway distensibility measured as the slope of the relationship between conductance and lung volume by the forced oscillation technique. Lung function, exhaled nitric oxide and methacholine challenge were also measured. Subjects had inhaled corticosteroid therapy for 12 weeks after which all measurements were repeated. RESULTS: At baseline, airway distensibility (mean, 95%CI) was 0.19(0.14-0.23) cm H(2)O(-1)s(-1), exhaled nitric oxide was 13.1(10.3-16.6)ppb and airway distensibility correlated with eNO (p=0.04) and disease duration (p=0.02) but not with airway responsiveness (p=0.46), FEV(1) (p=0.09) or age (p=0.23). After treatment, exhaled nitric oxide decreased (p=0.0002), FEV(1) improved (p=0.0001), airway responsiveness improved (p=0.0002), and there was a small improvement in airway distensibility but it did not normalise (p=0.05). Airway distensibility was not correlated with either exhaled nitric oxide (p=0.49) or airway responsiveness (p=0.20). CONCLUSIONS: Uncontrolled airway inflammation causes a small decrease in the distensibility of the airways of asthmatics with airway hyper-responsiveness. The lack of association between airway responsiveness and airway distensibility, both before and after 12 weeks ICS treatment, suggests that airway remodelling does not contribute to airway hyper-responsiveness in asthma. PMID- 21820299 TI - Prevalence of thyroid disease in patients with obstructive sleep apnea. AB - OBJECTIVES: Studies have suggested that ethnicity and environment may influence thyroid disease. We aim in this study to determine the prevalence of thyroid disease among Saudi (Arab) patients with laboratory-diagnosed obstructive sleep apnea (OSA) and the characteristics and predictors of thyroid disease associated with OSA. METHODS: Serum thyroid-stimulating hormone (TSH) and free-thyroxine (FT4) levels were measured in all patients referred to the sleep disorders center for an overnight sleep study. The levels were measured within 4 weeks of the sleep study. Type I attended polysomnography (PSG) was performed for all patients. RESULTS: During the study period, 271 patients with OSA and a mean age of 48.7 +/- 14.1 yr, a body mass index (BMI) of 37.7 +/- 9.6 kg/m(2) and an AHI of 55.2 +/- 37/hr as well as 76 non-OSA patients with a mean age of 40.8 +/- 14.9 yr, a BMI of 33.7 +/- 8.9 kg/m(2) and an AHI of 3.8 +/- 3.1/hr underwent thyroid function tests. In the OSA patients, the prevalence of newly diagnosed clinical hypothyroidism was 0.4%, and the prevalence of newly diagnosed subclinical hypothyroidism was 11.1%. In the non-OSA patients, the prevalence of newly diagnosed clinical hypothyroidism was 1.4%, and the prevalence of newly diagnosed subclinical hypothyroidism was 4%. There were no cases of clinical or subclinical hyperthyroidism in the studied group. Female gender was the only predictor of clinical hypothyroidism. CONCLUSION: In the OSA patients, the prevalence of newly diagnosed clinical hypothyroidism was low; however, subclinical hypothyroidism was common among patients with OSA. PMID- 21820300 TI - 4-O-methylhonokiol inhibits colon tumor growth via p21-mediated suppression of NF kappaB activity. AB - Biphenolic components in the Magnolia family have shown several pharmacological activities such as antitumor effects. This study investigated the effects of 4-O methylhonokiol (MH), a constituent of Magnolia officinalis, on human colon cancer cell growth and its action mechanism. 4-O-methylhonokiol (0-30 MUM) decreased constitutive activated nuclear factor (NF)-kappaB DNA binding activity and inhibited growth of human colon (SW620 and HCT116) cancer cells. It also caused G0-G1 phase cell cycle arrest followed by an induction of apoptotic cell death. However, knockdown with small interfering RNA (siRNA) of p21 or transfection with cyclin D1/Cdk4 binding site-mutated p21 abrogated MH-induced cell growth inhibition, inhibition of NF-kappaB activity as well as expression of cyclin D1 and Cdk4. Conversely, inhibition of NF-kappaB with specific inhibitor or siRNA augmented MH-induced apoptotic cell death. 4-O-methylhonokiol inhibited tumor growth, NF-kappaB activity and expression of antiapoptotic proteins; however, it increased the expression of apoptotic proteins as well as p21 in xenograft nude mice bearing SW620 cancer cells. The present study reveals that MH causes p21 mediated human colon cancer cell growth inhibition through suppression of NF kappaB and indicates that this compound by itself or in combination with other anticancer agents could be useful for the treatment of cancer. PMID- 21820302 TI - Emergy analysis of the recycling options for construction and demolition waste. AB - Construction and demolition (C&D) waste is becoming a major contributor to environmental pollution. In Shanghai, China, the quantity of C&D waste is 2.11E+07 t/yr, which accounts for 45% of the total quantity of solid waste. There has been a growing promotion of recycling C&D waste as an effective way to solve this waste problem. However, the evaluation of the efficiency of recycling C&D waste as a potential source of resources is largely based on traditional economic analysis. The economic analysis emphasizes money instead of the harmony between economic benefit and environmental effects. There is a need for a new strategic approach to investigate the efficiency of recycling C&D waste to achieve the integration between economic, social and environmental effects. Emergy theory can be employed to analyze different recycling options for C&D waste. With reference to the Chinese construction industry, this paper demonstrates that the close-loop recycling option is better than the open-loop recycling option for C&D waste in terms of the integration of social, environmental and sustainable aspects. To evaluate different technology solutions for C&D waste recycling, the emergy theory and method is not limited to a cost-benefit balance but can include economic, social, environmental and sustainable effects. PMID- 21820301 TI - Enhanced autophagy plays a cardinal role in mitochondrial dysfunction in type 2 diabetic Goto-Kakizaki (GK) rats: ameliorating effects of (-)-epigallocatechin-3 gallate. AB - Oxidative stress and mitochondrial dysfunction are known to play important roles in type 2 diabetes mellitus (T2DM) and insulin resistance. However, the pathology of T2DM remains complicated; in particular, the mechanisms of mitochondrial dysfunction in skeletal muscle and other insulin-sensitive tissues are as yet unclear. In the present study, we investigated the underlying mechanisms of oxidative stress and mitochondrial dysfunction by focusing on mitochondrial dynamics, including mitochondrial biogenesis and autophagy, in skeletal muscle of a nonobese diabetic animal model--the Goto-Kakizaki (GK) rat. The results showed that GK rats exhibited impaired glucose metabolism, increased oxidative stress and decreased mitochondrial function. These dysfunctions were found to be associated with induction of LC3B, Beclin1 and DRP1 (key molecules mediating the autophagy pathway), while they appeared not to affect the mitochondrial biogenesis pathway. In addition, (-)-epigallocatechin-3-gallate (EGCG) was tested as a potential autophagy-targeting nutrient, and we found that EGCG treatment improved glucose tolerance and glucose homeostasis in GK rats, and reduced oxidative stress and mitochondrial dysfunction in skeletal muscle. Amelioration of excessive muscle autophagy in GK rats through the down-regulation of the ROS ERK/JNK-p53 pathway leads to improvement of glucose metabolism, reduction of oxidative stress and inhibition of mitochondrial loss and dysfunction. These results suggest (a) that hyperglycemia-associated oxidative stress may induce autophagy through up-regulation of the ROS-ERK/JNK-p53 pathway, which may contribute to mitochondrial loss in soleus muscle of diabetic GK rats, and (b) that EGCG may be a potential autophagy regulator useful in treatment of insulin resistance. PMID- 21820303 TI - Multiplexed SOI BioFETs. AB - Nanoscale Field Effect Transistors have emerged as a promising technology for ultrasensitive, unlabeled diagnostic applications. However, their use as quantitative sensors has been problematic because of the need for individual sensor calibration. In this work we demonstrate an internal calibration scheme for multiplexed nanoribbon field effect sensors by utilizing the initial current rates rather than end point detection. A linear response is observed consistent with initial binding kinetics. Moreover, we are able to show that top-down fabrication techniques yield reproducible device results with minimal fluctuations, enabling internal calibration. PMID- 21820304 TI - A sensitive signal-on electrochemical assay for MTase activity using AuNPs amplification. AB - A sensitive and simple signal-on electrochemical assay for detection of Dam methyltransferase (MTase) activity based on DNA-functionalized gold nanoparticles (AuNPs) amplification coupled with enzyme-linkage reactions is presented. This new assay takes advantage of the steric hindrance of AuNPs and the electrostatic repulsion between the negative-charge phosphate backbones of DNA modified on the AuNPs and redox probe [Fe(CN)(6)](3-/4-). In this method, the self-assembled ssDNA on the electrode is hybridized with its complement ssDNA modified on AuNPs to form dsDNA AuNPs bioconjugates containing specific recognition sequence of Dam MTase and methylation-sensitive restriction endonuclease Dpn I. Then, the AuNPs approach to the electrode and result in blockage of electronic transmission. It is eT OFF state. In the presence of Dam MTase and Dpn I, the specific sequence is methylated and cleavaged, which in turn release the DNA modified AuNPs from the electrode surface allowing free exchange of electrons. It generates a measurable electrochemical signal (eT ON). Differential pulse voltammetry (DPV) is employed to detect the recover current, which is related to the concentration of the Dam MTase. This method is simple, sensitive, nonradioactive and without use of gel electrophoresis, PCR or chromatographic separation. Under optimized conditions, a linear response to concentration of Dam MTase range from 0.2U/mL to 10 U/mL and a detection limit of 0.12 U/mL are obtained. Furthermore, our new assay is a promising method to detect Dam MTase in the Luria-Bertani (LB) medium, as well as to screen inhibitors or drugs for Dam MTase. PMID- 21820305 TI - A carbon nanotube-based high-sensitivity electrochemical immunosensor for rapid and portable detection of clenbuterol. AB - Carbon nanotubes have shown their unique advantages of mechanical, chemical and electronic properties in bioanalysis. We herein report a new method to efficiently and reproducibly prepare multi-walled carbon nanotubes (MWNTs) protein sensing layers for electrochemical immunosensors. This method employs centrifugation to prepare a conjugate of MWNTs and goat anti mouse-immunoglobulin G (IgG) (secondary antibody). The conjugates were then deposited on screen printed electrodes to form a nanostructured layer (MWNT-I layer). CLB monoclonal antibody was assembled through its binding to the secondary antibody. The MWNT-I layer-based electrodes were used for rapid and sensitive amperometric immunosensing detection of clenbuterol (CLB) in swine urine samples. Horseradish peroxidase-coupled CLB (CLB-HRP) competed with free CLB in the samples to bind the monoclonal antibody. It has shown significantly higher sensitivity and better reproducibility than the chemical conjugation method. This MWNT-based immunosensor is highly sensitive, leading to a limit of detection of 0.1 ng/mL within a rapid assay time of 16 min. Its sensitivity is at least 1 order of magnitude higher than that of a normal immunosensor (without MWNTs). The sensing device is portable with disposable screen-printed electrode, satisfactorily meeting the requirements for field detection of food security-related species. PMID- 21820306 TI - Pharmacodynamic synergy strictly dependent on the co-operative aggregation of enantiomers of cyclic peptides in the bacterial cell membrane. AB - The antimicrobial activity of the peptide enantiomers cyclo[D-Tle-D-Lys-D-Tle-L Ala-D-Tle-L-Ala-D-Tle-L-Ala] and cyclo[L-Tle-L-Lys-L-Tle-D-Ala-L-Tle-D-Ala-L-Tle D-Ala] against Bacillus megaterium was investigated. Both these peptides showed very low activity in both an agar diffusion assay and a broth microdilution assay. However, when both peptides were present during the experiments a potent inhibition with an IC(50) value of 2 MUM was observed. Furthermore, the peptides also showed low hemolytic activity. Neither peptide had any hemolytic activity in concentrations up to 1mM but when erythrocytes were exposed to both peptides a weak hemolytic activity could be observed with a HC(50) value of 316 MUM. PMID- 21820307 TI - Amyloidosis and exercise intolerance in ANO5 muscular dystrophy. AB - Anoctamin 5 and dysferlin mutations can result in myopathies with similar clinical phenotype. Amyloid deposits can occur in the muscle of patients with dysferlinopathy. We describe a 53-year-old woman with exercise intolerance since childhood, recurrent rhabdomyolysis and late-onset weakness. Muscle biopsy showed amyloid deposits within the blood vessel walls and around muscle fibers. Mutation analysis identified two pathogenic heterozygous mutations in anoctamin 5 and no mutations in dysferlin. To our knowledge this is the first report of muscle amyloidosis in anoctamin 5 muscular dystrophy. This finding suggests that patients with amyloid in muscle should be screened for anoctamin 5 muscular dystrophy. PMID- 21820308 TI - Speech facilitation by left inferior frontal cortex stimulation. AB - Electrophysiological studies in humans and animals suggest that noninvasive neurostimulation methods such as transcranial direct current stimulation (tDCS) can elicit long-lasting [1], polarity-dependent [2] changes in neocortical excitability. Application of tDCS can have significant and selective behavioral consequences that are associated with the cortical location of the stimulation electrodes and the task engaged during stimulation [3-8]. However, the mechanism by which tDCS affects human behavior is unclear. Recently, functional magnetic resonance imaging (fMRI) has been used to determine the spatial topography of tDCS effects [9-13], but no behavioral data were collected during stimulation. The present study is unique in this regard, in that both neural and behavioral responses were recorded using a novel combination of left frontal anodal tDCS during an overt picture-naming fMRI study. We found that tDCS had significant behavioral and regionally specific neural facilitation effects. Furthermore, faster naming responses correlated with decreased blood oxygen level-dependent (BOLD) signal in Broca's area. Our data support the importance of Broca's area within the normal naming network and as such indicate that Broca's area may be a suitable candidate site for tDCS in neurorehabilitation of anomic patients, whose brain damage spares this region. PMID- 21820309 TI - A complex of Kif18b and MCAK promotes microtubule depolymerization and is negatively regulated by Aurora kinases. AB - INTRODUCTION: Spindle assembly requires tight control of microtubule (MT) dynamics. This is dependent on a variety of MT binding proteins and their upstream regulators. The Aurora kinases have several well-described functions during cell division, but it remains unclear whether they control global spindle microtubule dynamics. RESULTS: Here, we find that simultaneous inhibition of Aurora A and B results in a dramatic decrease in spindle MT stability, and we identify the uncharacterized kinesin-8 Kif18b as a mediator of this effect. In interphase, Kif18b is nuclear, but upon nuclear envelope breakdown, Kif18b binds to astral MT plus ends through an interaction with EB1. Surprisingly, Kif18b also binds to the kinesin-13 motor MCAK, and this interaction is required for robust MT depolymerization. Furthermore, the Kif18b-MCAK interaction is negatively regulated by Aurora kinases through phosphorylation of MCAK, indicating that Aurora kinases regulate MT plus-end stability in mitosis through control of Kif18b-MCAK complex formation. CONCLUSION: Together, these results uncover a novel role for Aurora kinases in regulating spindle MT dynamics through Kif18b MCAK and suggest that the Kif18b-MCAK complex constitutes the major MT plus-end depolymerizing activity in mitotic cells. PMID- 21820311 TI - piRNA production requires heterochromatin formation in Drosophila. AB - Protecting the genome from transposable element (TE) mobilization is critical for germline development. In Drosophila, Piwi proteins and their bound small RNAs (piRNAs) provide a potent defense against TE activity. TE targeting piRNAs are processed from TE-dense heterochromatic loci termed piRNA clusters. Although piRNA biogenesis from cluster precursors is beginning to be understood, little is known about piRNA cluster transcriptional regulation. Here, we show that deposition of histone 3 lysine 9 by the methyltransferase dSETDB1 (egg) is required for piRNA cluster transcription. In the absence of dSETDB1, cluster precursor transcription collapses in germline and somatic gonadal cells and TEs are activated, resulting in germline loss and a block in germline stem cell differentiation. We propose that heterochromatin protects the germline by activating the piRNA pathway. PMID- 21820312 TI - Regulating Rap small G-proteins in time and space. AB - Signaling by the small G-protein Rap is under tight regulation by its GEFs and GAPs. These are multi-domain proteins that are themselves controlled by distinct upstream pathways, and thus couple different extra- and intracellular cues to Rap. The individual RapGEFs and RapGAPs are, in addition, targeted to specific cellular locations by numerous anchoring mechanisms and, consequently, may control different pools of Rap. Here, we review the various activating signals and targeting mechanisms of these proteins and discuss their contribution to the spatiotemporal regulation and biological functions of the Rap proteins. PMID- 21820310 TI - Nocturnin regulates circadian trafficking of dietary lipid in intestinal enterocytes. AB - BACKGROUND: Efficient metabolic function in mammals depends on the circadian clock, which drives temporal regulation of metabolic processes. Nocturnin is a clock-regulated deadenylase that controls its target mRNA expression posttranscriptionally through poly(A) tail removal. Mice lacking nocturnin (Noc( /-) mice) are resistant to diet-induced obesity and hepatic steatosis yet are not hyperactive or hypophagic. RESULTS: Here we show that nocturnin is expressed rhythmically in the small intestine and is induced by olive oil gavage and that the Noc(-/-) mice have reduced chylomicron transit into the plasma following the ingestion of dietary lipids. Genes involved in triglyceride synthesis and storage and chylomicron formation have altered expression, and large cytoplasmic lipid droplets accumulate in the apical domains of the Noc(-/-) enterocytes. The physiological significance of this deficit in absorption is clear because maintenance of Noc(-/-) mice on diets that challenge the chylomicron synthesis pathway result in significant reductions in body weight, whereas diets that bypass this pathway do not. CONCLUSIONS: Therefore, we propose that nocturnin plays an important role in the trafficking of dietary lipid in the intestinal enterocytes by optimizing efficient absorption of lipids. PMID- 21820313 TI - Phylogenomic networks. AB - Phylogenomics is aimed at studying functional and evolutionary aspects of genome biology using phylogenetic analysis of whole genomes. Current approaches to genome phylogenies are commonly founded in terms of phylogenetic trees. However, several evolutionary processes are non tree-like in nature, including recombination and lateral gene transfer (LGT). Phylogenomic networks are a special type of phylogenetic network reconstructed from fully sequenced genomes. The network model, comprising genomes connected by pairwise evolutionary relations, enables the reconstruction of both vertical and LGT events. Modeling genome evolution in the form of a network enables the use of an extensive toolbox developed for network research. The structural properties of phylogenomic networks open up fundamentally new insights into genome evolution. PMID- 21820314 TI - Five-year results of total knee arthroplasty with the Vario Knee System: a prospective analysis. AB - There have been no published reports detailing the clinical performance of the Vario Knee System (VKS) total knee arthroplasty (TKA) since its introduction in 2001. The current study was therefore undertaken to provide 5-year clinical and radiographic follow-up data for this implant. Over a 24-month period, 146 VKS TKAs were performed in 131 patients (mean age, 69 years). Prospective data and radiographs were obtained at 3 months, 1 year, and 5 years after surgery. Surgeons employed an anteromedial approach in which the cruciate was retained. The fixation method was hybrid (cemented tibia, uncemented femur) in 70% of patients, uncemented in 23%, and cemented in 7%. At 5 years, 106 patients (118 knees) were alive. Six patients (six knees) were lost to follow-up. Three knees (three patients) were revised. Five-year survival was 97.4% (95% confidence interval [CI]: 92.8-99.5) with an endpoint of revision for any reason and 99.0% (95% CI: 97.5-100) with an endpoint of revision for aseptic failure. Using the worst-case scenario, in which all six of these patients were considered as failures, survival was 91.4% (95% CI: 83.4-96.0). The mean preoperative knee and function scores improved from 37.5 and 62.1, respectively, to 90.6 and 97.4, respectively, 5 years after surgery. Radiographic loosening of either component was not observed in any of the 100 radiographs obtained. In conclusion, good clinical outcomes were observed after 5 years with the VKS TKA. Additional follow up studies will be needed to ascertain whether this performance is maintained in the long term. PMID- 21820316 TI - Regulation of photosynthesis, fluorescence, stomatal conductance and water-use efficiency of cowpea (Vigna unguiculata [L.] Walp.) under drought. AB - Drought is the major abiotic stress factor that causes extensive losses to agriculture production worldwide. The objective of this study was to evaluate the dynamics of photosynthesis and water-use efficiency parameters in 15 cowpea genotypes under well-watered and drought condition. Photosynthesis (A) and chlorophyll fluorescence (Fv'/Fm') declined linearly with decreasing soil water content whereas intrinsic water-use efficiency (WUE) increased under drought stress, suggesting stomatal regulation was a major limitation to photosynthesis. However, under increasing drought conditions, increase in ratio of intercellular CO(2) to ambient CO(2) concentrations along with reduced WUE showed the role of non-stomatal limitation of photosynthesis. The resistant nature of Fv'/Fm' and electron transport rate under drought appeared to be important mechanisms for photoinhibition protection under drought stress. Oxidative stress was apparent due to drought-induced reduction in total chlorophyll and carotenoid which was accompanied with increased leaf wax contents. The accumulation of proline appeared to be in response of drought injury rather than a drought tolerance mechanism. A clear separation based on the genotypes site of origin among the genotypes for drought tolerance could not be established when analyzed using principal component analysis. The identified genotypes and physiological traits from this study may be useful for genetic engineering and breeding programs integrating drought adaptation in cowpea. PMID- 21820317 TI - Thermal degradation of wood during photodegradation. AB - In this study, wood samples were exposed to light irradiations (direct sunlight, xenon lamp, mercury vapour lamp) and thermal treatments were carried out in dry- and in humid conditions at 90 degrees C. One part of the samples was covered by an aluminium plate during light irradiation. The samples under the aluminium plate also suffered considerable chemical changes, monitored by infrared technique and colour measurement. The sunlight produced greater colour change under the aluminium plate than the artificial light sources. During light irradiation, the carbonyl band having two maximum at 1700 and 1,746 cm(-1) increased and the peak of the aromatic skeletal vibration arising from lignin (1,510 cm(-1)) decreased together with the guaiacyl vibrations at 1,275 cm(-1). There was absorption decrease at 1,174 cm(-1) because of the ether band splitting. Under the covered surface only the ether band at 1,174 cm(-1) decreased and one carbonyl band increased with a maximum at 1,715 cm(-1). Degradation of lignin was negligible for the covered surface. Colour change generated by thermal degradation was much greater in humid condition than in dry condition. PMID- 21820315 TI - The architecture of CopA from Archeaoglobus fulgidus studied by cryo-electron microscopy and computational docking. AB - CopA uses ATP to pump Cu(+) across cell membranes. X-ray crystallography has defined atomic structures of several related P-type ATPases. We have determined a structure of CopA at 10 A resolution by cryo-electron microscopy of a new crystal form and used computational molecular docking to study the interactions between the N-terminal metal-binding domain (NMBD) and other elements of the molecule. We found that the shorter-chain lipids used to produce these crystals are associated with movements of the cytoplasmic domains, with a novel dimer interface and with disordering of the NMBD, thus offering evidence for the transience of its interaction with the other cytoplasmic domains. Docking identified a binding site that matched the location of the NMBD in our previous structure by cryo-electron microscopy, allowing a more detailed view of its binding configuration and further support for its role in autoinhibition. PMID- 21820318 TI - Effect of Toll-like receptor 2 and 4 of corneal fibroblasts on cytokine expression with co-cultured antigen presenting cells. AB - Keratocytes are the first component to contact ocular pathogens when the epithelial barrier breaks down and the emerging evidences indicated keratocytes appeared to be one of the corneal cellular immune components. Little is known about the role of Toll-like receptors (TLRs) in keratocytes, although it has been well documented that keratocytes constitutively express various TLRs including TLR2 and TLR4. In this in vitro study, the authors focused on the role of keratocytes in corneal innate immune system and cross-talk of keratocytes with resident antigen presenting cells (APCs), especially through TLR2 and TLR4. Primary cultivated keratocytes (corneal fibroblasts) from C57BL/6 mice per se actively secreted pro-inflammatory cytokines, especially interleukin (IL)-6, with a dose-dependent manner in response to Pam3CSK4 or lipopolysaccharide (LPS) challenge. With co-culture of corneal fibroblasts with APCs per se, secretion of IL-6 and tumor necrosis factor (TNF)-alpha was markedly increased and it was counterbalanced by concurrent increase in IL-10 and tumor growth factor-beta1. After Pam3CSK4 or LPS stimulation, this cytokine balance was completely broken down by overwhelming amplification of IL-6 and TNF-alpha secretion, especially in co-culture of corneal fibroblasts with macrophages, rather than with dendritic cells. Using corneal fibroblasts from TLR2 or TLR4 knockout mice, we could find the reversal of Pam3CSK4 or LPS-responsive dose-dependent increment in IL-6 and TNF-alpha. These results implied that corneal fibroblasts and their TLRs could be key components for the ocular homeostasis and pathogen-associated ocular innate immunity. PMID- 21820319 TI - Increases in body mass index during infliximab therapy in patients with Crohn's disease: an open label prospective study. AB - In the past, the impact of infliximab therapy on nutritional status in patients with Crohn's disease (CD) has not been assessed. This prospective study was to investigate the effect of infliximab on nutritional status in CD patients. Fifty consecutive patients with active CD received infliximab (5 mg/kg) at weeks 0, 2 and 6 as remission induction therapy, and then at 8 weeks intervals as maintenance therapy. Patients were followed for 60 weeks. CD activity index (CDAI) and body mass index (BMI) were monitored. A fall in CDAI by >=70 was defined as response to therapy, while CDAI<150 meant clinical remission. At week 10, 39 patients (78%) responded to infliximab induction therapy. BMI significantly increased during these 10 weeks (P<0.0001). The mean increase in BMI was significantly higher in patients who responded to infliximab vs patients who did not (P=0.03). Further, at weeks 30 and 60, 35 patients (70%) and 33 (66%) were in remission, respectively. The mean increase in BMI was significantly higher in patients who maintained remission vs patients not in remission (week 30, P=0.02; week 60, P=0.01). Patients with a low baseline BMI (<18.5) and those with small bowel involvement achieved a higher increase in BMI as compared to patients with BMI>=18.5 or patients without small bowel involvement. In this study, infliximab therapy was associated with improvement of patients' nutritional status, notably patients who responded to this biologic. Additionally, in patients with malnutrition and small bowel involvement, the nutritional impact of infliximab was higher. PMID- 21820322 TI - Air tract in the thrombus: paradoxical cerebral air embolism through a residual catheter track. AB - We report a 49-year-old woman who sustained ischemic stroke after central venous catheter removal. Brain computed tomography (CT) scan revealed air bubbles in the subarachnoid vessels. Contrast-enhanced chest CT and ultrasonography revealed a residual catheter track in the center of a jugular vein thrombus. A right-to-left shunt was confirmed by transthoracic echocardiography and transcranial Doppler with bubble contrast. The patient was ultimately diagnosed with a paradoxical cerebral air embolism through the residual catheter track in the thrombus. Rapid recognition, response, and prompt diagnosis are the most important factors in the successful treatment of such an embolism. PMID- 21820320 TI - Trends in mortality of tuberculosis patients in the United States: the long-term perspective. AB - PURPOSE: To describe long-term trends in tuberculosis (TB) mortality and to compare trends estimated from two different sources of public health surveillance data. METHODS: Trends and changes in trend were estimated by joinpoint regression. Comparisons between data sets were made by fitting a Poisson regression model. RESULTS: Since 1900, TB mortality rates estimated from death certificates have declined steeply, except for a period of no change in the 1980s. This decade had long-term consequences resulting in more TB deaths in later years than would have occurred had there been no flattening of the trend. Recent trends in TB mortality estimated from National Tuberculosis Surveillance System (NTSS) data, which record all-cause mortality, differed from trends based on death certificates. In particular, NTSS data showed TB mortality rates flattening since 2002. CONCLUSIONS: Estimates of trends in TB mortality vary by data source, and therefore interpretation of the success of control efforts will depend on the surveillance data set used. The data sets may be subject to different biases that vary with time. One data set showed a sustained improvement in the control of TB since the early 1990s whereas the other indicated that the rate of TB mortality was no longer declining. PMID- 21820323 TI - Type-based associations in grapheme-color synaesthesia revealed by response time distribution analyses. AB - Determining the nature of binding in grapheme-color synaesthesia has consequences for understanding the neural basis of synaesthesia and visual awareness in general. We evaluated type- and token-based letter-color binding using a synaesthetic version of the object-reviewing paradigm. Although mean response times failed to reveal any significant differences between synaesthetes and control participants, RT analyses with ex-Gaussian distributions revealed that the response facilitation in the synaesthesia group reflected type representations exclusively, while response facilitation in the control group, who learned letter-color associations, was dominated by token representations. Thus, letter-color associations in associator synaesthetes are type-based, and do not involve binding to object tokens, consistent with their subjective reports. Contrary to recent studies that failed to find differences between synaesthetes and non-synaesthetes with behavioral measures, response time distribution analyses indicate that color sensations in synaesthetes are not simply the extreme form of normal letter-color associations, and cannot be attributed to demand characteristics. PMID- 21820325 TI - Pregnancies in perinatally HIV-infected young women and implications for care and service programs. AB - A cohort of individuals with perinatally acquired HIV is maturing into reproductive age. This study describes pregnancy incidence and outcomes among females ages 15-25 with perinatally acquired HIV infection receiving comprehensive family-centered services in New York City. Chart reviews from 1998 2006 indicated 33 pregnancies among 96 young women. Twenty-six percent of the cohort experienced a pregnancy during the study period, with a rate of 125 per 1,000 person years in 2006. The age of first pregnancy ranged from 15-25; 24% were younger than 18. Fourteen pregnancies (42%) were terminated. Nineteen pregnancies resulted in live births, and all infants tested negative for HIV. The success of preventing vertical HIV transmission is attributed to interdisciplinary family-centered services, including reproductive health education, family planning, obstetric-gynecologic services and psychosocial support. Such approach is most likely to be effective at promoting healthy reproductive decisions and reducing morbidity in perinatally infected mothers and their children. PMID- 21820324 TI - Cystic tumor of the atrioventricular node: rare antemortem diagnosis. AB - BACKGROUND: The cystic tumor of the atrioventricular node (TAV) is a rare, congenital cardiac tumor, typically located at the base of the atrial septum. Histologically benign, this multicystic mass is a tumor of the conduction system and is considered the smallest tumor capable of causing sudden and unexpected death. TAV has shown a predilection for women with a mean age at presentation of 38 years. The majority of cases are diagnosed incidentally at autopsy, while antemortem surgical excision is rare, with ours being the fifth and sixth reported cases in the medical literature. METHODS: We present two cases, in 33- and 29-year-old women who were admitted for complaints of dyspnea, dizziness, palpitation or numbness, along with a review of the literature. One was known to have complete congenital heart block and ventricular septal defect, where an intraoperative transesophageal echocardiogram revealed a right atrial mass. The other patient had a right atrial mass visible on magnetic resonance imaging, which led to surgical resection and permanent pacemaker insertion. RESULTS: Histopathological examination revealed a tumor composed of cysts, some lined by squamous epithelium, and others by transitional epithelium. Irregular proliferation of glandular structures with squamoid nests within a fibrous stroma, with sebaceous-type differentiation, was also observed. A chronic inflammatory component with secondary lymphoid follicles was also noted. CONCLUSION: These cases are presented, along with a review of the four previously reported cases of TAV diagnosed antemortem. Awareness regarding this lesion could improve gross and microscopic characterization of TAV and increase antemortem diagnoses. PMID- 21820326 TI - Providing effective medical and case management services to HIV-infected youth preparing to transition to adult care. AB - A key aspect of maintaining health for HIV-infected adolescents is the transition from pediatric care to adult medical care. Because young people who were infected with HIV as children were initially not expected to survive until adulthood, relatively little attention has been given to issues associated with this transition to adult care. With improved life expectancies, health professionals are increasingly faced with the new challenge of working with these young people as they grapple with the unique experience of being an HIV-infected adolescent transitioning into adulthood. This article discusses the unique developmental trajectories of young people infected with HIV as children, challenges for health care professionals who work with them, and strategies for practitioners to increase the competencies needed to develop effective partnerships with these youth as they transition into adult care. PMID- 21820327 TI - Routine HIV testing in primary care clinics: a study evaluating patient and provider acceptance. PMID- 21820328 TI - A rare case of cryptococcal infection of talus with pathological fracture that healed with medical management. AB - Skeletal involvement occurs in 5% to 10% of reported cases of disseminated cryptococcal infection. We are reporting a very rare presentation of cryptococcal infection of the talus with pathological fracture, which healed with medical management. Our patient had pain and swelling around the ankle associated with fever. Radiologically, he had a lytic lesion of the talus with fracture of the talar neck. Biopsy and cultures revealed cryptococcal infection. He was treated with surgical debridement combined with antifungal therapy, and the fracture healed well by 5 months. At the end of the 1-year follow-up, he had painless ankle movement and there was no evidence of recurrence. He was able to walk without support or limp, and he could wear normal footwear. PMID- 21820329 TI - Perforator-based Pacman flap in the plantar region. AB - Numerous techniques have been used to reconstruct the plantar area to preserve the function of both recipient and donor sites and to produce satisfying results. We describe a method of plantar soft tissue reconstruction using a perforator based Pacman flap to cover the circular defects after wide excision in cases of plantar malignancy. Eight patients who underwent plantar reconstruction between September 2008 and February 2011 were reviewed in the present study. Of the 8 patients, 6 had malignant melanoma, 1 had basosquamous basal cell carcinoma, and 1 had squamous cell carcinoma. Medial (5 patients) and lateral (3 patients) plantar artery perforator-based Pacman flaps were used. All flaps provided satisfactory coverage of the soft tissue defects in the plantar region, and all patients achieved a good functional outcome after a mean follow-up of 13 (range 2 to 22) months. The median patient age was 54 (range 26 to 67) years. The median maximum diameter of the circular defects was 40 (range 20 to 70) mm, and the mean operative time was 65 (range 50 to 120) minutes from flap elevation to wound closure. We believe that good functional outcomes and minimal complications can be achieved when the perforator-based Pacman flap is used for plantar reconstruction. Furthermore, the full extent and utility of this method of plantar reconstruction remains to be determined. PMID- 21820330 TI - MicroRNA-29 regulates T-box transcription factors and interferon-gamma production in helper T cells. AB - MicroRNA (miRNA)-deficient helper T cells exhibit abnormal IFN-gamma production and decreased proliferation. However, the contributions of individual miRNAs to this phenotype remain poorly understood. We conducted a screen for miRNA function in primary T cells and identified individual miRNAs that rescue the defects associated with miRNA deficiency. Multiple members of the miR-17 and miR-92 families enhanced miRNA-deficient T cell proliferation whereas miR-29 largely corrected their aberrant interferon-gamma (IFN-gamma) expression. Repression of IFN-gamma production by miR-29 involved direct targeting of both T-bet and Eomes, two transcription factors known to induce IFN-gamma production. Although not usually expressed at functionally relevant amounts in helper T cells, Eomes was abundant in miRNA-deficient cells and was upregulated after miR-29 inhibition in wild-type cells. These results demonstrate that miR-29 regulates helper T cell differentiation by repressing multiple target genes, including at least two that are independently capable of inducing the T helper 1 (Th1) cell gene expression program. PMID- 21820331 TI - T cell receptor internalization from the immunological synapse is mediated by TC21 and RhoG GTPase-dependent phagocytosis. AB - The immunological synapse (IS) serves a dual role for sustained T cell receptor (TCR) signaling and for TCR downregulation. TC21 (Rras2) is a RRas subfamily GTPase that constitutively associates with the TCR and is implicated in tonic TCR signaling by activating phosphatidylinositol 3-kinase. In this study, we demonstrate that TC21 both cotranslocates with the TCR to the IS and is necessary for TCR internalization from the IS through a mechanism dependent on RhoG, a small GTPase previously associated with phagocytosis. Indeed, we found that the TCR triggers T cells to phagocytose 1-6 MUm beads through a TC21- and RhoG dependent pathway. We further show that TC21 and RhoG are necessary for the TCR promoted uptake of major histocompatibility complex (MHC) from antigen-presenting cells. Therefore, TC21 and RhoG dependence underlie the existence of a common phagocytic mechanism that drives TCR internalization from the IS together with its peptide-MHC ligand. PMID- 21820332 TI - Innate immune recognition of an AT-rich stem-loop DNA motif in the Plasmodium falciparum genome. AB - Although Toll-like receptor 9 (TLR9) has been implicated in cytokine and type I interferon (IFN) production during malaria in humans and mice, the high AT content of the Plasmodium falciparum genome prompted us to examine the possibility that malarial DNA triggered TLR9-independent pathways. Over 6000 ATTTTTAC ("AT-rich") motifs are present in the genome of P. falciparum, which we show here potently induce type I IFNs. Parasite DNA, parasitized erythrocytes and oligonucleotides containing the AT-rich motif induce type I IFNs via a pathway that did not involve the previously described sensors TLR9, DAI, RNA polymerase III or IFI16/p204. Rather, AT-rich DNA sensing involved an unknown receptor that coupled to the STING, TBK1 and IRF3-IRF7 signaling pathway. Mice lacking IRF3, IRF7, the kinase TBK1 or the type I IFN receptor were resistant to otherwise lethal cerebral malaria. Collectively, these observations implicate AT-rich DNA sensing via STING, TBK1 and IRF3-IRF7 in P. falciparum malaria. PMID- 21820334 TI - Polarized secretion of lysosomes at the B cell synapse couples antigen extraction to processing and presentation. AB - Engagement of the B cell receptor (BCR) by surface-tethered antigens (Ag) leads to formation of a synapse that promotes Ag uptake for presentation onto major histocompatibility complex class II (MHCII) molecules. We have highlighted the membrane trafficking events and associated molecular mechanisms involved in Ag extraction and processing at the B cell synapse. MHCII-containing lysosomes are recruited to the synapse where they locally undergo exocytosis, allowing synapse acidification and the extracellular release of hydrolases that promote the extraction of the immobilized Ag. Lysosome recruitment and secretion results from the polarization of the microtubule-organizing center (MTOC), which relies on the cell division cycle (Cdc42)-downstream effector, atypical protein kinase C (aPKCzeta). aPKCzeta is phosphorylated upon BCR engagement, associates to lysosomal vesicles, and is required for their polarized secretion at the B cell synapse. Regulation of B lymphocyte polarity therefore emerges as a central mechanism that couples Ag extraction to Ag processing and presentation. PMID- 21820335 TI - Variation in clinical practice - an impetus for change and improvement. PMID- 21820333 TI - Thymic stromal lymphopoetin-induced expression of the endogenous inhibitory enzyme SLPI mediates recovery from colonic inflammation. AB - Thymic stromal lymphopoetin (TSLP) influences numerous immune functions, including those in the colonic mucosa. Here we report that TSLP-deficient (Tslp( /-)) mice did not exhibit increased inflammation during dextran sodium sulfate (DSS)-induced colitis but failed to recover from disease, resulting in death. Increased localized neutrophil elastase (NE) activity during overt inflammation was observed in Tslp(-/-) mice and was paralleled by reduced expression of an endogenous inhibitor, secretory leukocyte peptidase inhibitor (SLPI). Pharmacological inhibition of NE or treatment with rSLPI reduced DSS-induced mortality in Tslp(-/-) mice. Signaling through TSLPR on nonhematopoietic cells was sufficient for recovery from DSS-induced colitis. Expression of the receptor occurred on intestinal epithelial cells (IEC), with stimulation inducing SLPI expression. Therefore, TSLP is critical in mediating mucosal healing after insult and functions in a nonredundant capacity that is independent of restraining T helper 1 (Th1) and Th17 cell cytokine production. PMID- 21820336 TI - Long-term follow-up of vascular reconstructions after supracondylar humerus fracture with vascular lesion in childhood. AB - INTRODUCTION: Supracondylar humerus fractures in childhood present with a pulseless but well-perfused hand in 2.6% of cases and with limb-threatening ischaemia in <1%. Conservative treatment is widely used in non-limb-threatening ischaemia, in particular if the child is very young (<2.5 years). It has been sufficiently proven that conservative treatment may retard growth. The aim of our study was to determine long-term patency rates after surgical reconstruction and growth impairment, if any, after surgical vascular reconstruction. PATIENTS AND METHODS: Between June 1990 and June 2004, 12 children (mean age 6.6 years, eight boys and four girls) with supracondylar fracture with vascular lesions underwent surgical reconstruction at the Department of Vascular Surgery at the University Hospital, Graz. Patient files were reviewed retrospectively. All patients were recalled for physical (forearm length and volume) and ultrasonographic examinations (forearm blood flow) in 2005 and for ultrasonographic examinations (reconstructed vascular area) in 2011, with a final mean follow-up time of 14.0 years (range 6.8-20.9 years). RESULTS: Twelve patients, 10 of whom had undergone growth measurements in 2005, were available for the latter examination. All were doing well, with patent vascular reconstructions. Seven reconstructed brachial arteries were enlarged, two of which with intramural calcifications, four did not show abnormalities and one presented with 45% thinning. There were no differences between affected and healthy forearms concerning volume, length and blood flow. CONCLUSIONS: Our data emphasise that surgical reconstruction is effective in terms of blood supply and growth. In cases with interposition of greater saphenous vein or venous patch plasty, we found a high risk for development of enlargements. We suggest that these patients be followed periodically, with ultrasound studies, to detect aneurysms and/or thrombotic changes as early as possible. PMID- 21820337 TI - Serum butyrylcholinesterase activity in dogs with diabetes mellitus. AB - Increased serum butyrylcholinesterase (BChE) activity is a feature of diabetes mellitus (DM) in humans and rats. The objective of this study was to evaluate serum BChE activity in diabetic dogs. The activity of the enzyme was assessed in three cohorts of animals: (1) dogs with naturally occurring DM (n=74); (2) clinically normal dogs (n=74); and (3) dogs with various other diseases (n=74). A statistically significant increase in BChE activity was found in the diabetic dogs (7.59 +/- 2.9 kUI/L) compared with the clinically normal animals (6.12 +/- 1.94 kUI/L; P<0.05), and with the dogs with other diseases (5.55 +/- 2.06 kUI/L; P<0.01). Such increased activity could be the result of the altered glucose and lipid metabolism that occurs in DM. PMID- 21820340 TI - Cross-correlations between low-gamma nuclei in solids via a common dipolar bath. AB - Correlation of chemical shifts of low-gamma nuclei (such as 15N) is an important method for assignment of resonances in uniformly-labeled biological solids. Under static experimental conditions, an efficient mixing of low-gamma nuclear spin magnetization can be achieved by a thermal contact to the common reservoir of dipole-dipole interactions in order to create 15N-15N, 13C-13C, or 15N-13C cross peaks in a 2D correlation spectrum. A thermodynamic approach can be used to understand the mechanism of magnetization mixing in various 2D correlation pulse sequences. This mechanism is suppressed under magic-angle spinning, when mixing via direct cross-polarization with protons becomes more efficient. Experimental results are presented for single-crystalline and powder samples of 15N-labeled N acetyl-L-15N-valyl-L-15N-leucine (NAVL). In addition to the thermodynamic analysis of mixing pulse sequences, two different new mixing sequences utilizing adiabatic pulses are also experimentally demonstrated. PMID- 21820341 TI - Using heat to control the sample spinning speed in MAS NMR. AB - A new approach using temperature to control the spinning speed of a sample rotor in magic-angle spinning NMR is presented. Instead of an electro-mechanical valve that regulates the flow of drive gas to control the spinning speed in traditional MAS NMR systems, we use a small heater wire located directly in the stator. The sample spinning speed is controlled very accurately with a surprisingly low heating power of 1 W. Results on a benchtop unit demonstrate the capability of the system. PMID- 21820342 TI - Molecular modeling and molecular dynamics simulation studies on pyrrolopyrimidine based alpha-helix mimetic as dual inhibitors of MDM2 and MDMX. AB - Inhibition of the interactions between the tumor suppressor protein p53 and its negative regulators, the MDM2 and MDMX oncogenic proteins, is increasingly gaining interest in cancer therapy and drug design. In this study, we carry out molecular docking, molecular dynamics (MD) simulations, and molecular mechanics Poisson-Boltzmann and generalized Born/surface area (MM-PB/GBSA) binding free energy calculations on an active compound 3a and an inactive compound NC-1, which share a common pyrrolopyrimidine-based scaffold. MD simulations and MM-PB/GBSA calculations show that the compound NC-1 may not bind to MDM2 and MDMX, in agreement with the experimental results. Detailed MM-PB/GBSA calculations on the MDM2-3a and MDMX-3a complexes unravel that the binding free energies are similar for the two complexes. Furthermore, the van der Waals energy is the largest component of the binding free energy for both complexes, which indicates that the interactions between the compound 3a and MDM2 and MDMX are dominated by shape complementarity. In addition, the analysis of individual residue contribution and protein-ligand binding mode show that the three functional groups on R1, R2, and R3 of the compound 3a can mimic the spatial orientation of the side chains of Phe19, Trp23, and Leu26 of p53, respectively. The obtained computational results suggest that the compound 3a can act as a dual inhibitor of MDM2-p53 and MDMX-p53 interactions, consistent with the experimental results. PMID- 21820343 TI - Attenuation of IGF-I receptor signaling inhibits serum-induced proliferation of prostate cancer cells. AB - OBJECTIVE: Several studies showed that high serum levels of insulin-like growth factor-I (IGF-I) correlate with an increased risk for prostate cancer, although the causal role of IGF-I remains to be established. In this study, we addressed the role of IGF-I as a serum factor on the growth of two androgen-independent cell lines (Du145 and PC3) and one androgen-dependent cell line (LNCaP). DESIGN: We investigated the effects of a blocking antibody against the IGF-I receptor (alphaIR3) on DNA synthesis in prostate cancer cells cultured in the presence of recombinant human IGF-I or normal human serum (NHS). RESULTS: We show that in all three prostate cancer cell lines, NHS exerts a markedly stronger stimulating effect on DNA synthesis than IGF-I, and that the effect of NHS can be completely abrogated by an antibody against the IGF-I receptor (alphaIR3). Using pharmacological inhibitors of the two canonical IGF-I receptor signaling pathways, we show that the phosphatidylinositol-3'-kinase (PI3K) and the Mek-Erk pathways are not required for the stimulating effect of NHS. CONCLUSION: Our observations indicate that the stimulating effect of NHS is completely dependent on IGF-I receptor signaling transduction and that IGF-I stimulates DNA synthesis in prostate cancer cells in strong synergy with other serum factors. We speculate that the role of other serum factors could explain the discrepancy between the results observed in different animal models to study the function of IGF-I in prostate cancer. PMID- 21820344 TI - Safety, efficacy and physiological actions of a lysine-free, arginine-rich formula to treat glutaryl-CoA dehydrogenase deficiency: focus on cerebral amino acid influx. AB - Striatal degeneration from glutaryl-CoA dehydrogenase deficiency (glutaric aciduria type 1, GA1) is associated with cerebral formation and entrapment of glutaryl-CoA and its derivatives that depend on cerebral lysine influx. In 2006 we designed a lysine-free study formula enriched with arginine to selectively block lysine transport across cerebral endothelia and thereby limit glutaryl-CoA production by brain. Between 2006 and present, we treated twelve consecutive children with study formula (LYSx group) while holding all other treatment practices constant. Clinical and biochemical outcomes were compared to 25 GA1 patients (PROx group) treated between 1995 and 2005 with natural protein restriction (dietary lysine/arginine ratio of 1.7+/-0.3 mg:mg). We used published kinetic parameters of the y+and LAT1 blood-brain barrier transporters to model the influx of amino acids into the brain. Arginine fortification to achieve a mean dietary lysine/arginine ratio of 0.7+/-0.2 mg:mg was neuroprotective. All 12 LYSx patients are physically and neurologically healthy after 28 aggregate patient-years of follow up (current ages 28+/-21 months) and there were no adverse events related to formula use. This represents a 36% reduction of neurological risk (95% confidence interval 14-52%, p=0.018) that we can directly attribute to altered amino acid intake. During the first year of life, 20% lower lysine intake and two-fold higher arginine intake by LYSx patients were associated with 50% lower plasma lysine, 3-fold lower plasma lysine/arginine concentration ratio, 42% lower mean calculated cerebral lysine influx, 54% higher calculated cerebral arginine influx, 15-26% higher calculated cerebral influx of several anaplerotic precursors (isoleucine, threonine, methionine, and leucine), 50% less 3-hydroxyglutarate excretion, and a 3-fold lower hospitalization rate (0.8 versus 2.3 hospitalizations per patient per year). The relationship between arginine fortification and plasma lysine indicates that transport competition exists at both cerebrovascular and gastrointestinal barriers, suggesting their co administration is key to efficacy. Monitoring the ratio between lysine and arginine in diet and plasma may prove a useful strategy for treating children with GA1. PMID- 21820345 TI - Painful diabetic neuropathy: diagnosis and management. AB - The prevalence of painful diabetic peripheral neuropathy (PDN) is about 20% in patients with type 2 diabetes and 5% in those with type 1. Patients should be systematically questioned concerning suggestive symptoms, as they are not usually volunteers. As PDN is due to small-fibre injury, the 10 g monofilament pressure test as well as the standard electrophysiological procedures may be normal. Diagnosis is based on clinical findings: type of pain (burning discomfort, electric shock-like sensation, aching coldness in the lower limbs); time of occurrence (mostly at rest and at night); and abnormal sensations (such as tingling or numbness). The DN4 questionnaire is an easy-to-use validated diagnostic tool. Three classes of drugs are of equal value in treating PDN: tricyclic antidepressants; anticonvulsants; and selective serotonin-reuptake inhibitors. These compounds may be prescribed as first-line therapy following pain assessment using a visual analogue scale. If the initial drug at its maximum tolerated dose does not lead to a decrease in pain of at least 30%, another drug class should be prescribed; if the pain is decreased by 30% but remains greater than 3/10, a drug from a different class may be given in association. PMID- 21820346 TI - [Female fertility preservation: feasibility of emergency IVF for embryo freezing]. AB - With the improvement of the anticancerous treatments, the preservation of the feminine fertility before gonadotoxic treatment tends at present to stand out as a legal obligation, with a duty of information to patients. When emergency IVF can be performed, the cryopreservation of embryos is the best mastered method which offers most chances to patients to obtain a pregnancy after cancer remission thanks to the transfer of frozen embryos. This article proposes an overview about the indications, the feasibility and the ethical and practical limitations of IVF emergency for embryo freezing before gonadotoxic anticancerous treatment. PMID- 21820347 TI - Methods for high-resolution anisotropic finite element modeling of the human head: automatic MR white matter anisotropy-adaptive mesh generation. AB - This study proposes an advanced finite element (FE) head modeling technique through which high-resolution FE meshes adaptive to the degree of tissue anisotropy can be generated. Our adaptive meshing scheme (called wMesh) uses MRI structural information and fractional anisotropy maps derived from diffusion tensors in the FE mesh generation process, optimally reflecting electrical properties of the human brain. We examined the characteristics of the wMeshes through various qualitative and quantitative comparisons to the conventional FE regular-sized meshes that are non-adaptive to the degree of white matter anisotropy. We investigated numerical differences in the FE forward solutions that include the electrical potential and current density generated by current sources in the brain. The quantitative difference was calculated by two statistical measures of relative difference measure (RDM) and magnification factor (MAG). The results show that the wMeshes are adaptive to the anisotropic density of the WM anisotropy, and they better reflect the density and directionality of tissue conductivity anisotropy. Our comparison results between various anisotropic regular mesh and wMesh models show that there are substantial differences in the EEG forward solutions in the brain (up to RDM=0.48 and MAG=0.63 in the electrical potential, and RDM=0.65 and MAG=0.52 in the current density). Our analysis results indicate that the wMeshes produce different forward solutions that are different from the conventional regular meshes. We present some results that the wMesh head modeling approach enhances the sensitivity and accuracy of the FE solutions at the interfaces or in the regions where the anisotropic conductivities change sharply or their directional changes are complex. The fully automatic wMesh generation technique should be useful for modeling an individual-specific and high-resolution anisotropic FE head model incorporating realistic anisotropic conductivity distributions towards more accurate analysis of bioelectromagnetic problems. PMID- 21820348 TI - Comments on the determination of excited state dipole moment of molecules using the method of solvatochromism. AB - The present note comments on several publications which appeared in different journals containing many inaccurate statements and lacking honest citations of basic papers dealing with the application of solvatochromism to determine excited state dipole moments. PMID- 21820349 TI - MP2, DFT and ab initio calculations on thioxanthone. AB - Density functional theory (DFT), HF and MP2 calculations have been carried out to investigate thioxanthone molecule using the standard 6-31+G(d,p) basis set. The results of MP2 calculations show a butterfly structure for thioxanthone. The calculated results show that the predicted geometry can well reproduce the structural parameters. The predicted vibrational frequencies were assigned and compared with experimental IR spectra. A good harmony between theory and experiment is found. The theoretical electronic absorption spectra have been calculated using CIS method. (13)C and (1)H NMR of the title compound have been calculated by means of B3LYP density functional method with 6-31+G(d,p) basis set. The comparison of the experimental and the theoretical results indicate that density functional B3LYP method is able to provide satisfactory results for predicting NMR properties. PMID- 21820350 TI - Application of silver nanoparticles and principal component-artificial neural network models for simultaneous determination of levodopa and benserazide hydrochloride by a kinetic spectrophotometric method. AB - A multicomponent analysis method based on principal component analysis-artificial neural network model (PC-ANN) is proposed for the simultaneous determination of levodopa (LD) and benserazide hydrochloride (BH). The method is based on the reaction of levodopa and benserazide hydrochloride with silver nitrate as an oxidizing agent in the presence of PVP and formation of silver nanoparticles. The reaction monitored at analytical wavelength 440 nm related to surface plasmon resonance band of silver nanoparticles. Differences in the kinetic behavior of the levodopa and benserazide hydrochloride were exploited by using principal component analysis, an artificial neural network (PC-ANN) to resolve concentration of analytes in their mixture. After reducing the number of kinetic data using principal component analysis, an artificial neural network consisting of three layers of nodes was trained by applying a back-propagation learning rule. The optimized ANN allows the simultaneous determination of analytes in mixtures with relative standard errors of prediction in the region of 4.5 and 6.3 for levodopa and benserazide hydrochloride respectively. The results show that this method is an efficient method for prediction of these analytes. PMID- 21820351 TI - FT-IR, FT-Raman, ab initio and DFT structural, vibrational frequency and HOMO LUMO analysis of 1-naphthaleneacetic acid methyl ester. AB - In this work, the FT-IR and FT-Raman spectra of 1-naphthaleneacetic acid methyl ester (abbreviated as 1-NAAME, C(10)H(7)CH(2)CO(2)CH(3)) have been recorded in the region 3600-10 cm(-1). The optimum molecular geometry, normal mode wavenumbers, infrared and Raman intensities, Raman scattering activities, corresponding vibrational assignments, Mullikan atomic charges and other thermo dynamical parameters were investigated with the help of HF and B3LYP (DFT) method using 6-31G(d,p), 6-311G(d,p) basis sets. Reliable vibrational assignments were made on the basis of total energy distribution (TED) calculated with scaled quantum mechanical (SQM) method. From the calculations, the molecules are predicted to exist predominantly as the C1 conformer. The correlation equations between heat capacity, entropy, enthalpy changes and temperatures were fitted by quadratic formulae. Lower value in the HOMO and LUMO energy gap explains the eventual charge transfer interactions taking place within the molecule. UV-VIS spectral analyses of 1NAAME have been researched by theoretical calculations. In order to understand electronic transitions of the compound, TD-DFT calculations on electronic absorption spectra in gas phase and solvent (DMSO and chloroform) were performed. The calculated frontier orbital energies, absorption wavelengths (lambda), oscillator strengths (f) and excitation energies (E) for gas phase and solvent (DMSO and chloroform) are also illustrated. PMID- 21820352 TI - Synthesis, spectroscopic characterization, X-ray structure and DFT studies on 4 (2-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-5-ium chloride hydrate. AB - The title molecular salt, 4-(2-hydroxyphenyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5 c]pyridin-5-ium chloride hydrate (C(12)H(14)N(3)O(+).Cl-.H(2)O), was synthesized and characterized by IR-NMR spectroscopy and single-crystal X-ray diffraction. In addition to the molecular geometry from X-ray experiment, the molecular geometry, vibrational frequencies and gauge-independent atomic orbital (GIAO) (1)H and (13)C NMR chemical shift values of the title compound in the ground state have been calculated using the density functional theory (DFT/B3LYP) method with the 6 31++G(d,p) and 6-311++G(d,p) basis sets, and compared with the experimental data. Besides, molecular electrostatic potential (MEP) distribution and non-linear optical properties of the title compound were investigated by theoretical calculations at the B3LYP/6-311++G(d,p) level. PMID- 21820353 TI - Serum antibody response to the gH/gL/pUL128-131 five-protein complex of human cytomegalovirus (HCMV) in primary and reactivated HCMV infections. AB - BACKGROUND: Recently, a new human cytomegalovirus (HCMV) glycoprotein complex has been identified and potentially proposed as a vaccine. OBJECTIVE: The aim of this study was to determine whether the HCMV gH/gL/pUL128-pUL130-pUL131 (gH/gL/pUL128 131) 5-protein (pentameric) complex (which has been recently found to be indispensable for the infection of endothelial and epithelial cells) is able to elicit a consistent antibody response in both primary and reactivated HCMV infections. STUDY DESIGN: The antibody response was determined by both indirect immunofluorescence (IFA) and ELISA, using fixed (IFA) or lysed (ELISA) epithelial (ARPE-19) cells infected with one or more adenoviral vectors, each carrying one HCMV gene and, in parallel, with a control adenovirus vector. RESULTS: The specificity of results was determined by the reactivity of human neutralizing mAbs recognizing two, three, or four proteins of the complex. In 14 cases of primary infection, an IgG antibody seroconversion to the UL128-131 gene products was consistently detected within 2-4 weeks after onset of infection, while antibodies persisted for at least 12 months. The IgG antibody response to UL128 131 gene products was generally superior to the response to gH and appeared to follow the neutralizing antibody response (as determined in epithelial cells). In reactivated infections, the antibody response showed a trend reminiscent of a booster response. IgG antibodies were detected in HCMV-seropositive healthy adult controls, but not in HCMV-seronegative individuals. CONCLUSIONS: The IgG antibody response to the pentameric complex could be a major target for the evaluation of the antibody response to a pentamer-based vaccine. PMID- 21820354 TI - Fasciculations and their F-response revisited: high-density surface EMG in ALS and benign fasciculations. AB - OBJECTIVE: To compare the prevalence of fasciculation potentials (FPs) with F responses between patients with amyotrophic lateral sclerosis (ALS) and patients with benign fasciculations. METHODS: In seven patients with ALS and seven patients with benign fasciculations, high-density surface EMG was recorded for 15 min from the gastrocnemius muscle. Template matching was used to search for pairs of FPs with a repetition within 10-110 ms. RESULTS: Interspike interval (ISI) histograms were constructed from 282 pairs of benign fasciculations and from 337 FP pairs in ALS. Peaks attributable to F-waves were found at latencies of 32 ms (benign) and 35 ms (ALS). Five patients with benign fasciculations and four patients with ALS had FPs with F-waves. CONCLUSIONS: F-waves of FPs occur in both conditions - therefore they are not diagnostically helpful. SIGNIFICANCE: F-waves confirm the distal origin of FPs for an individual axon. The occurrence of these FPs in a benign condition suggests that the generation of ectopic discharges in the distal axons is not specific to progressive neurodegeneration. PMID- 21820355 TI - Much ado about the flu: design and implementation of an e-role play for a large class of undergraduate students. AB - Role play in a face-to-face setting is becoming widely accepted as a useful pedagogy in nurse education. However, online e-role play i.e. role play which occurs using an electronic medium, is less well used, particularly with large classes. This paper will discuss the design and implementation of an online e role play for a large class (n = 414) of undergraduate Nursing and Midwifery students. It describes the rationale for the use of this method and the expected learning outcomes followed by detail about how the e-role play was designed. It also discusses challenges faced in implementing this learning activity with a large group of students and then outlines student and staff evaluation of the e role play. Finally lessons learned and implications for using this pedagogy in nurse education are considered. PMID- 21820356 TI - FGF-21 as a biomarker for muscle-manifesting mitochondrial respiratory chain deficiencies: a diagnostic study. AB - BACKGROUND: Muscle biopsy is the gold standard for diagnosis of mitochondrial disorders because of the lack of sensitive biomarkers in serum. Fibroblast growth factor 21 (FGF-21) is a growth factor with regulatory roles in lipid metabolism and the starvation response, and concentrations are raised in skeletal muscle and serum in mice with mitochondrial respiratory chain deficiencies. We investigated in a retrospective diagnostic study whether FGF-21 could be a biomarker for human mitochondrial disorders. METHODS: We assessed samples from adults and children with mitochondrial disorders or non-mitochondrial neurological disorders (disease controls) from seven study centres in Europe and the USA, and recruited healthy volunteers (healthy controls), matched for age where possible, from the same centres. We used ELISA to measure FGF-21 concentrations in serum or plasma samples (abnormal values were defined as >200 pg/mL). We compared these concentrations with values for lactate, pyruvate, lactate-to-pyruvate ratio, and creatine kinase in serum or plasma and calculated sensitivity, specificity, and positive and negative predictive values for all biomarkers. FINDINGS: We analysed serum or plasma from 67 patients (41 adults and 26 children) with mitochondrial disorders, 34 disease controls (22 adults and 12 children), and 74 healthy controls. Mean FGF-21 concentrations in serum were 820 (SD 1151) pg/mL in adult and 1983 (1550) pg/mL in child patients with respiratory chain deficiencies and 76 (58) pg/mL in healthy controls. FGF-21 concentrations were high in patients with mitochondrial disorders affecting skeletal muscle but not in disease controls, including those with dystrophies. In patients with abnormal FGF-21 concentrations in serum, the odds ratio of having a muscle-manifesting mitochondrial disease was 132.0 (95% CI 38.7-450.3). For the identification of muscle-manifesting mitochondrial disease, the sensitivity was 92.3% (95% CI 81.5 97.9%) and specificity was 91.7% (84.8-96.1%). The positive and negative predictive values for FGF-21 were 84.2% (95% CI 72.1-92.5%) and 96.1 (90.4 98.9%). The accuracy of FGF-21 to correctly identify muscle-manifesting respiratory chain disorders was better than that for all conventional biomarkers. The area under the receiver-operating-characteristic curve for FGF-21 was 0.95; by comparison, the values for other biomarkers were 0.83 lactate (p=0.037, 0.83 for pyruvate (p=0.015), 0.72 for the lactate-to-pyruvate ratio (p=0.0002), and 0.77 for creatine kinase (p=0.013). INTERPRETATION: Measurement of FGF-21 concentrations in serum identified primary muscle-manifesting respiratory chain deficiencies in adults and children and might be feasible as a first-line diagnostic test for these disorders to reduce the need for muscle biopsy. FUNDING: Sigrid Juselius Foundation, Jane and Aatos Erkko Foundation, Molecular Medicine Institute of Finland, University of Helsinki, Helsinki University Central Hospital, Academy of Finland, Novo Nordisk, Arvo and Lea Ylppo Foundation. PMID- 21820357 TI - A new biomarker for mitochondrial disease. PMID- 21820358 TI - Intermediate to long-term follow-up indicates low risk of recurrence after Double HIT endoscopic treatment for primary vesico-ureteral reflux. AB - PURPOSE: Follow-up of patients undergoing dextranomer/hyaluronic acid injection for vesico-ureteral reflux (VUR) is controversial. The purpose of our study was to test the hypothesis that patients undergoing the double hydrodistention implantation technique (Double HIT) have a higher clinical and radiographic success rate. MATERIALS AND METHODS: Patients undergoing Double HIT endoscopic injection for VUR were prospectively identified. Patients underwent an ultrasound at 6 weeks to assess the implants, and, if visible, prophylactic antibiotics were discontinued and patients were scheduled for a 1-year voiding cystourethrogram (VCUG). Radiographic success was defined as a negative VCUG and clinical success as no febrile urinary tract infections at 1 year. RESULTS: A total of 54 patients underwent endoscopic injection for VUR. Twenty-five (51%) were compliant with the 1 year follow-up; 18 non-compliant patients were contacted and their clinical status assessed. Thirty patients eventually completed the 1-year VCUG at a mean of 12.2 months (range 10-20). Among the 60% of patients with 1-year radiographic follow-up, 2 had persistent VUR for a radiologic success rate of 93%. All radiographic failures were infection-free. Of the 80% (43/54) of patients with available clinical data, 3 (7%) had afebrile UTI for a clinical success rate of 93%. CONCLUSIONS: The Double HIT leads to a 93% clinical and 93% radiographic intermediate/long-term success rate. With this technique, better outcomes were achieved with fewer recurrences than previously reported. These favorable results challenge the need for postoperative VCUG in asymptomatic patients after the Double HIT. PMID- 21820359 TI - Severe new seizures after initiation of vagus nerve stimulation therapy. AB - Vagus nerve stimulation is considered to be a safe and effective adjunctive therapy for patients with drug-resistant epilepsy. Contrary to some antiepileptic drugs, vagus nerve stimulation is not known to precipitate or aggravate new or preexisting seizures. We describe the emergence of a new type of disabling, recurrent partial seizure immediately after initiation of vagus nerve stimulation in a 51-year-old man with a known history of refractory partial epilepsy. Discontinuation of vagus nerve stimulation therapy and multiple antiepileptic drug interventions were required to abort these unexpected new seizures. We conclude that vagus nerve stimulation may induce paradoxical seizures, similarly to some antiepileptic drugs. PMID- 21820360 TI - Future directions for epidemiology in epilepsy. AB - Epidemiology continues to be an important research tool in the study of epilepsy and related disorders, providing a better understanding of the frequency, causes and natural history of the disorder. But, beyond risk factors and seizure prognosis, epidemiological studies advance knowledge of many other aspects of epilepsy. Epidemiological studies are being conducted in a new environment in which high quality neuroimaging and fast through-put genomic technologies have become routine tools in clinical diagnosis and therapeutics. Epilepsy is currently understood, not as a single, homogeneous disorder, but a multitude of different clinical syndromes and disease, each with its own cause(s), natural history, and treatment implications. That is why; the comorbidites of epilepsy represent an important area, amenable to study, as they may ultimately have a greater impact on quality of life than epilepsy itself. In this document we share our thoughts on what we think are the future directions for epidemiology in epilepsy. PMID- 21820361 TI - Trigeminal nerve stimulation in major depressive disorder: first proof of concept in an open pilot trial. AB - Modulation of brain activity via trigeminal nerve stimulation is an emerging therapy in drug-resistant epilepsy. This cranial nerve also projects to structures implicated in depression (such as the nucleus tractus solitarius and locus coeruleus). We examined the effects of external trigeminal nerve stimulation in major depressive disorder as an adjunct to pharmacotherapy. Five adults (mean age 49.6, SD 10.9, three females and two males) participated in an 8 week open-label outpatient trial; all had persistent symptoms despite adequate pharmacotherapy, with a mean score on the 28-item Hamilton Depression Rating Scale of 25.4 (SD=3.9) at entry. Nightly stimulation over the V(1) branch was well tolerated. Both the clinician-rated 28-item Hamilton Depression Rating Scale (P=0.006) and the self-rated Beck Depression Inventory (P=0.0004) detected significant symptomatic improvement. This novel neuromodulation approach may have use as an adjunct to pharmacotherapy in major depressive disorder. Additional larger trials are needed to delineate efficacy and tolerability with greater reliability. PMID- 21820363 TI - Repo-Man coordinates chromosomal reorganization with nuclear envelope reassembly during mitotic exit. AB - Repo-Man targets protein phosphatase 1 gamma (PP1gamma) to chromatin at anaphase onset and regulates chromosome structure during mitotic exit. Here, we show that a Repo-Man:PP1 complex forms in anaphase following dephosphorylation of Repo-Man. Upon activation, the complex localizes to chromosomes and causes the dephosphorylation of histone H3 (Thr3, Ser10, and Ser28). In anaphase, Repo-Man has both catalytic and structural functions that are mediated by two separate domains. A C-terminal domain localizes Repo-Man to bulk chromatin in early anaphase. There, it targets PP1 for the dephosphorylation of histone H3 and possibly other chromosomal substrates. An N-terminal domain localizes Repo-Man to the chromosome periphery later in anaphase. There, it is responsible for the recruitment of nuclear components such as Importin beta and Nup153 in a PP1 independent manner. These observations identify Repo-Man as a key factor that coordinates chromatin remodeling and early events of nuclear envelope reformation during mitotic exit. PMID- 21820362 TI - Eliminating SF-1 (NR5A1) sumoylation in vivo results in ectopic hedgehog signaling and disruption of endocrine development. AB - Sumoylation is generally considered a repressive mark for many transcription factors. However, the in vivo importance of sumoylation for any given substrate remains unclear and is questionable because the extent of sumoylation appears exceedingly low for most substrates. Here, we permanently eliminated SF-1/NR5A1 sumoylation in mice (Sf-1(K119R, K194R, or 2KR)) and found that Sf-1(2KR/2KR) mice failed to phenocopy a simple gain of SF-1 function or show elevated levels of well-established SF-1 target genes. Instead, mutant mice exhibited marked endocrine abnormalities and changes in cell fate that reflected an inappropriate activation of hedgehog signaling and other potential SUMO-sensitive targets. Furthermore, unsumoylatable SF-1 mutants activated Shh and exhibited preferential recruitment to Shh genomic elements in cells. We conclude that the sumoylation cycle greatly expands the functional capacity of transcription factors such as SF 1 and is leveraged during development to achieve cell-type-specific gene expression in multicellular organisms. PMID- 21820365 TI - Interfraction accumulation of seroma during accelerated partial breast irradiation: preliminary results of a prospective study. AB - PURPOSE: To quantify and characterize the process of seroma accumulation during accelerated partial breast irradiation using multicatheter balloon brachytherapy. MATERIALS AND METHODS: Twenty-two patients were treated using the Contura Multilumen brachytherapy catheter to a dose of 34Gy in 10 fractions over 5 treatment days. Serial aspirations of the vacuum port of the catheter were performed at the time of CT simulation and before each treatment. Volume and characteristics of fluid drawn were recorded. Univariate analysis was performed to evaluate various factors predictive of seroma formation. RESULTS: Median patient age was 59.5 years, body mass index was 31, and volume of surgical specimen was 62.4cm(3). Median time from breast conservation surgery to placement of Contura catheter was 18.5 days. Pericatheter seroma, typically scant with a median volume of 0.75mL, was noted in 91% of patients at CT simulation. A total of 203 aspirations were performed with a median-aspirated seroma volume of 4.05mL. There was no significant correlation between the volume of seroma and histology (invasive vs. in situ), quadrant of location, body mass index, reexcision or reoperation, days from breast conservation surgery to balloon placement, or the volume of specimen removed. Radiation treatment factors, including balloon volume, balloon to skin distance, and planning target volume evaluation, also did not correlate with aspirated seroma. CONCLUSIONS: Interfraction seroma accumulation has a variable pattern of development with no discernible predictors of occurrence. Routine pretreatment aspirations via vacuum port may potentially improve dosimetric reproducibility for a minority of patients. PMID- 21820364 TI - Higher percentage of positive biopsy cores and Gleason score are associated with a greater degree of prostate gland shrinkage after neoadjuvant cytoreductive therapy. AB - PURPOSE: To determine whether adverse pathologic features, including tumor grade and percent positive biopsy (PPB) cores, predict for prostate size reduction after neoadjuvant cytoreductive therapy. METHODS AND MATERIALS: Eighty-two consecutive patients who were diagnosed with prostate cancer by transperineal template-guided mapping biopsy (TTMB) received neoadjuvant cytoreductive therapy. The median number of biopsy cores was 59. Thirty patients received a leutinizing hormone-releasing hormone agonist and bicalutamide, whereas 52 patients received bicalutamide (50mg daily) and dutasteride (0.5mg daily). A transrectal ultrasound volumetric study of the prostate gland and ellipsoid volume determinations of the prostate gland and transition zone (TZ) were obtained immediately before TTMB and at 90 days (+/-7 days) after the initiation of neoadjuvant medical therapy. Univariate and multivariate regression analyses were performed to identify predictors of prostate gland and TZ volume reduction. RESULTS: At TTMB, the mean prostate volumetric and ellipsoid volumes were 55.4 cm(3) and 49.0 cm(3), respectively. After neoadjuvant medical therapy, the mean volumetric and ellipsoid prostate volumes were 30.8 cm(3) and 28.5 cm(3), respectively. On average, the prostate volume decreased by 43.9% and 41.0% on volumetric and ellipsoid measurements, respectively. The TZ volume decreased from 19.8 cm(3) to 10.1 cm(3) (mean volume reduction of 47.7%). In multivariate analysis, prostate volume cytoreduction was most closely associated with PPB (p=0.014), TTMB prostate volume (p=0.01), and drug regimen (p=0.001). CONCLUSIONS: The degree of prostate volume cytoreduction was positively associated with higher Gleason score and PPBs. Greater reductions in prostate volume may be an indicator of more aggressive cancer. PMID- 21820366 TI - A new way of solid-phase microextraction fibers preparation for selected antibiotic drug determination by HPLC-MS. AB - The polypyrrole (PPy) and polythiophene (PTh) solid phase microextraction (SPME) coatings were obtained with the use of the electropolymerisation and linear sweep voltammetry. Such fibers were modified by an ozone treatment in a gaseous phase in the concentration of 2.1 +/- 0.2 * 10(-5) mol dm(-3). Both kinds of fibers were applied in the microextraction of linezolid from standard solutions to compare the extraction efficiencies displayed by these sorption phases. In these investigations a better adsorption capacity was obtained for polypyrrole fibers and hence only these kinds of fibers were utilized in the measurements from human plasma. In all measurements the concentrations of the drugs were in the range from 1 to 20 MUg ml(-1) (standard solutions) and 1 to 15 MUg ml(-1) (human plasma). Before the measurements, an optimization of the desorption solution experiments was performed. The correlation coefficients (R) obtained in the standard solution and human plasma were in the range from 0.8399 to 0.9970. The relative standard deviations (RSDs) were in the range of 0.1-7.6%. PMID- 21820368 TI - Fat, muscles, and wages. AB - Recent studies in health economics have generated two important findings: that as a measure of fatness the body mass index (BMI) is biased; and that, when it comes to analyzing wage correlates, both fat-free mass (FFM) and body fat (BF) are better suited to the task. We validate these findings for Germany using the BIAdata Base Project and the German Socio-Economic Panel. While we find no significant correlation between BMI and wages in any of our models, simple linear regression models featuring both contemporary and time-lagged fatness measures indicate that FFM and, to a lesser extent, BF are associated with hourly wages: more specifically, the relationship between FFM/BF and hourly wages is about two to three times higher for females than for males. In contrast, fixed-effects models indicate that there is no correlation between hourly wages and both FFM and BF with one exception: a significant correlation (and one in line with expectations) is found to be the rule among job changers. PMID- 21820367 TI - Symmetry of the face in old age reflects childhood social status. AB - The association of socioeconomic status (SES) with a range of lifecourse outcomes is robust, but the causes of these associations are not well understood. Research on the developmental origins of health and disease has led to the hypothesis that early developmental disturbance might permanently affect the lifecourse, accounting for some of the burden of chronic diseases such as coronary heart disease. Here we assessed developmental disturbance using bodily and facial symmetry and examined its association with socioeconomic status (SES) in childhood, and attained status at midlife. Symmetry was measured at ages 83 (facial symmetry) and 87 (bodily symmetry) in a sample of 292 individuals from the Lothian Birth Cohort 1921 (LBC1921). Structural equation models indicated that poorer SES during early development was significantly associated with lower facial symmetry (standardized path coefficient -.25, p=.03). By contrast, midlife SES was not significantly associated with symmetry. The relationship was stronger in men (-.44, p=.03) than in women (-.12, p=.37), and the effect sizes were significantly different in magnitude (p=.004). These findings suggest that SES in early life (but not later in life) is associated with developmental disturbances. Facial symmetry appears to provide an effective record of early perturbations, whereas bodily symmetry seems relatively imperturbable. As bodily and facial symmetries were sensitive to different influences, they should not be treated as interchangeable. However, markers of childhood disturbance remain many decades later, suggesting that early development may account in part for associations between SES and health through the lifecourse. Future research should clarify which elements of the environment cause these perturbations. PMID- 21820369 TI - Direct and indirect effects of body weight on adult wages. AB - Previous estimates of the association between body weight and wages in the literature have been conditional on education and occupation. In addition to the effect of current body weight status (body mass index (BMI) or obesity) on wages, this paper examines the indirect effect of body weight status in the late-teenage years on wages operating through education and occupation choice. Using the National Longitudinal Survey of Youth 1979 data, for women, we find that a one unit increase in BMI is directly associated with 1.83% lower hourly wages whereas the indirect BMI wage penalty is not statistically significant. Neither a direct nor an indirect BMI wage penalty is found for men. However, results based on clinical weight classification reveal that the indirect wage penalty occurs to a larger extent at the upper tail of the BMI distribution for both men and women via the pathways of education and occupation outcomes. Late-teen obesity is indirectly associated with 3.5% lower hourly wages for both women and men. These results are important because they imply that the total effect of obesity on wages is significantly larger than has been estimated in previous cross-sectional studies. PMID- 21820370 TI - The modeling of energy transport for life goes on: comment on "The theory of bio energy transport in the protein molecules and its properties" by Xiao-feng Pang. PMID- 21820371 TI - The importance of the constructal framework in understanding and eventually replicating structure in tissue: comment on "The constructal law and the evolution of design in nature" by Adrian Bejan and Sylvie Lorente. PMID- 21820373 TI - [Pancreatitis in cystic fibrosis: association with genotype and pancreatic status]. AB - INTRODUCTION: Pancreatitis is an uncommon complication of cystic fibrosis (CF). Either single or recurrent acute episodes can occur and it occasionally may follow a protracted course with relentless destruction of the pancreas. Moreover mild mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) have been found in many cases of idiopathic chronic pancreatitis. We describe a group of patients with CF who had one or more episodes of pancreatitis. We have estimated its prevalence in a large population of patients with CF across Spain. METHODS: A retrospective descriptive study was conducted by collecting the demographic, clinical and laboratory data, pancreatic status and genotype of CF patients who attended the CF Units in 5 Spanish hospitals. RESULTS: The overall number of CF patients under follow-up in the five centres was 520, of which 17 cases with pancreatitis were identified. The prevalence of pancreatitis in this population was 3.3%, higher than previously reported. Noticeably eight of the 17 patients (47.06%) had pancreatic insufficiency. This appears to be, partly, in contrast with that classically found, as this complication is usually associated with patients with a certain level of pancreatic reserve. No associations with genotype, age, gender or other factors were found. CONCLUSIONS: The prevalence of pancreatitis in our CF patients was higher than that found in other CF populations, and was not limited to patients with pancreatic sufficiency. It occurred mostly in teenagers and young adults often with mild pulmonary disease. The CF genotype was variable. The course of the patients should be carefully monitored, and further information on the long-term outcome of larger cohorts of patients is needed. PMID- 21820374 TI - Compression dressing for brachioplasty. PMID- 21820372 TI - Targeting ATR and Chk1 kinases for cancer treatment: a new model for new (and old) drugs. AB - Trying to kill cancer cells by generating DNA damage is by no means a new idea. Radiotherapy and genotoxic drugs are routinely used in cancer therapy. More recent developments also explored the potential of targeting the DNA damage response (DDR) in order to increase the toxicity of radio- and chemo- therapy. Chk1 inhibitors have pioneered studies in this regard. Interestingly, early studies noted that Chk1 inhibitors were particularly toxic for p53-deficient cells. The model proposed for this observation was that this effect was due to the simultaneous abrogation of the G2 (Chk1) and G1 (p53) checkpoints. We here challenge this view, and propose a model where the toxicity of Chk1 inhibitors is rather due to the fact that these compounds generate high loads of replicative stress (RS) during S-phase, which are further boosted by the less restrictive S phase entry found in p53-deficient cells. This new model implies that the particular toxicity of Chk1 inhibitors might not be restricted to p53-deficient cells, but could be extended to other mutations that promote a promiscuous S phase entry. In addition, this rationale also implies that the same effect should also be observed for other molecules that target the RS-response (RSR), such as inhibitors of the Chk1-activating kinase ATR. PMID- 21820375 TI - The safety of autologous fat transfer in breast cancer: lessons from stem cell biology. AB - Autologous fat grafting is versatile tool in plastic surgery and is increasing used for reconstruction following breast conserving surgery for breast cancer. Part of the reconstructive qualities of the transferred fat may be due to the presence of adipose derived mesenchymal stem cells (ADMSC) playing an angiogenic and an adipogenic role. In this context it must be considered if autologously engrafted fat tissue could contribute to carcinogenesis following breast conserving surgery. In this article we review the current stem cell biology evidence on engraftment, transdifferentiation and potential carcinogenic contribution in the breast and other solid organ stem cell niches in an attempt to highlight possible areas of concern. PMID- 21820376 TI - Child abuse consultations initiated by child protective services: the role of expert opinions. AB - OBJECTIVE: To describe consultations provided by child abuse pediatricians for cases referred by child protective services (CPS); compare the opinions of the likelihood of child maltreatment of the initial physician, CPS, and the child abuse pediatrician; and examine predictors of the experts' opinions. METHODS: Cases were referred by CPS for consultations between March 1, 1998, and June 30, 2005, to 2 child abuse pediatricians at Yale-New Haven Children's Hospital. We abstracted demographic and clinical information and the opinions of the initial physician, CPS, and the child abuse expert, each coded using a 5-point scale from definite maltreatment to definite benign cause (eg, accident). RESULTS: Of 187 cases, 50.3% occurred in children younger than 1 year of age. Children's most serious injuries were fractures (50.8%), burns (16.6%), and bruises/abrasions (15.0%). The child abuse experts' opinions were 47.6% definite or probable maltreatment, 8.6% uncertain, and 43.9% definite or probable benign. Of the 119 cases with opinions from all 3 assessors, the expert agreed with the physician in 57.1% of cases (kappa = 0.34) and with CPS in 64.7% (kappa = 0.42). The best predictor of the expert's opinion that the injury was due to maltreatment was agreement between the physician and CPS that maltreatment had occurred. CONCLUSIONS: Levels of agreement were fair to poor between the child abuse expert and either the physician or CPS. Child abuse experts' opinions have important value in selected cases to confirm previous assessments by the physician and/or CPS, or to change the opinion of the case. PMID- 21820377 TI - Scapular notching in reverse shoulder arthroplasties: the influence of glenometaphyseal angle. AB - Solutions described to limit the risk of scapular notching mainly concern the glenoid. Our hypothesis is that this risk also depends upon the glenoid-humeral relationship when the arm is resting along the body. PATIENT AND METHODS: This is a retrospective study of a continuous series of 85 reverse shoulder arthroplasties; 62 of these fulfilled inclusion criteria. The following parameters were studied: body mass index (BMI), inferior overhang of the glenosphere, the angles showing the position of the glenoid (GH) and the humerus (MH) in the scapular plane as well as the glenometaphyseal angle (GM=MH-GH), during an initial postoperative follow-up, at 1 and 2 years, and at a final follow up of a mean 45 months (24-81). The parameters studied were compared in two groups with and without scapular notching. RESULTS: There were 21 instances of notching at the final follow-up. This rate was significantly correlated to the BMI, which was a mean 27.2 in patients without a notch and 22.6 in patients with a notch, while the preoperative inclination of the glenoid in these groups was respectively 92.3 degrees versus 85 degrees respectively, the inferior overhang of the glenosphere was 4mm versus 2.8mm, the GM angle was 36 degrees versus 47 degrees , the MH angle at one year of follow-up was 135 degrees versus 145 degrees and the GH angle at the final follow-up was 103 degrees versus 94 degrees respectively. The BMI was significantly correlated to the GM angle, and a low BMI was associated with high values of this angle. DISCUSSION: The relative position of the glenoid and humeral components, as shown by the GM angle, was an essential factor in the development of a scapular notching. The humeral component of the GM angle evolved in thin patients with progressive adduction of the arm, which is associated with a risk of notching. This should be taken into account when performing reverse shoulder arthroplasties. LEVEL OF EVIDENCE: Level IV retrospective study. PMID- 21820378 TI - Anterior spine surgery in recent thoracolumbar fractures: An update. AB - Surgical treatment of thoracolumbar spine fractures aims to achieve bony union and restore spinal anatomy. It may associate, as needed, decompression, reduction, graft and/or internal fixation, using a posterior, anterior or combined approach. Indications for an anterior approach weigh the pros and cons as well as the type of osteo-ligamentous lesion, degree of instability and patient's neurological status. The main interest of an anterior approach is to enable medullary decompression by corporectomy while allowing reconstruction of the anterior spine. The technique was less frequently used mainly due to its associated morbidity risk; but the development of videoscopy tools now allows less invasive surgery, compared to conventional thoracophrenolombotomy. Given also the mechanical drawbacks of posterior assembly in certain types of fracture, a video-assisted anterior approach is becoming more common. A conjunction of a staged anterior followed by a posterior approach has progressively developed, to address the needs of spinal trauma: this encompasses posterior surgical reduction internal fixation, sometimes performed in emergency, with or without laminectomy followed by corporectomy, then anterior spinal reconstruction by graft with or without osteosynthesis to improve medullary decompression and avoid secondary correction loss and non-union. Adapting vertebroplasty techniques to spinal traumatology should gradually limit indications for an anterior approach for purely mechanical purposes; this later will, however, logically remain indicated when anterior spinal cord compression is present with associated neurological deficit, whether or not persisting after posterior reduction-osteosynthesis. PMID- 21820379 TI - Occluded stent in an extraluminal plane of the right coronary artery. AB - Coronary angiography demonstrated an occluded stent outside the lumen in the right coronary artery of a patient presenting with an acute coronary syndrome. Computed tomography confirmed the extraluminal location of the occluded stent. This finding is likely due to deployment of the stent in a dissection plane. PMID- 21820380 TI - A 78-year-old woman with an acute eosinophilic gastroenteritis. AB - Eosinophil accumulation in the gastrointestinal tract is a common feature of numerous disorders including mainly parasitic infection, drug-induced allergic reactions, inflammatory bowel disease, and various connective tissue disorders. Digestive tissue eosinophilia requires thorough searching for secondary causes that may be specifically treated with antibiotics, dietary and drug elimination or immunosuppressive therapy. Frequency, prognosis and therapeutic implications must guide the diagnostic course. An acute eosinophilic gastroenteritis in a 78 year-old asthmatic woman receiving celecoxib is reported. She presented later with neurologic and cutaneous features and was finally treated by methylprednisolone and cyclophosphamide. The diagnostic approach leading to a Churg-Strauss syndrome (CSS) assertion is described. We discuss the pathogenesis, the management and the potential enhancing role of celecoxib in CSS gastrointestinal involvement. PMID- 21820381 TI - Structural and mechanistic comparisons of the metal-binding members of the vicinal oxygen chelate (VOC) superfamily. AB - The vicinal oxygen chelate family of enzymes catalyzes a highly diverse set of chemistries that derives from one common mechanistic trait: bidentate coordination to a divalent metal center by a substrate or intermediate or transition state through vicinal oxygen atoms. The array of reactions catalyzed by this family is mediated structurally by a common fold and protein-chelating residues that secure and localize a metal ion. The common fold has topological symmetry being comprised of two betaalphabetabetabeta units that form an incompletely closed barrel of beta-sheet about the metal ion. Interestingly, despite the diversity of the reactions catalyzed and the large number of metals observed to bind and promote the chemistry, this semi-symmetrical open barrel extends metal liganding side chains inward from a highly positionally conserved constellation of amino acid residues within the structure. Moreover, the core barrel fold arises from an array of possible intra/inter domain and subunit arrangements of the individual betaalphabetabetabeta units that are universally observed to stack side-by-side contacting along the first beta-strand of each. While there are examples of enzymes that use this fold and do not bind a metal ion, this review is concerned with summarizing the key structural and mechanistic correlations that can be made for the metal-dependent vicinal oxygen chelate enzyme family members. PMID- 21820382 TI - Metallothionein-like proteins turnover, Cd and Zn biokinetics in the dietary Cd exposed scallop Chlamys nobilis. AB - In this study, we tested whether metallothionein-like proteins (MTLPs) affected the biokinetics of Cd and Zn in the scallops Chlamys nobilis following dietary Cd exposure. The scallops were fed Cd-contaminated diatoms for 8 or 40 days, and then the tissue Cd concentrations, MTLP turnover and their standing stocks, Cd and Zn kinetics were monitored. After 8 days of dietary Cd exposure (at 98 or 196 MUg Cdg(-1)), their Cd levels were increased by 7.4-12.5 times, newly synthesized MLTPs by 1.7-2.1 times, and their MLTP stocks doubled. However, after 40 days of dietary Cd exposure (at 58 or 115 MUg Cdg(-1)), MTLP synthesis and MTLP stocks did not change despite the fact that Cd bioaccumulation increased by 2.7-4.2 times. MTLPs played little role in the overall Cd and Zn uptake from either food or water, since enhanced MTLP induction did not improve the sequestration of newly incoming Cd or Zn. As MTLP-metal complexes degraded, the released Cd was immediately sequestered by newly synthesized MTLPs while most Zn was depurated. This may explain why scallops eliminated Cd more slowly than Zn. Induced proteins were shown to play a minor role in the detoxification of dietary Cd in C. nobilis, but the species can modify its Cd assimilation to reduce the impact of high dietary Cd levels. MTLPs are probably unsuitable as biomarkers for environmental monitoring involving C. nobilis. PMID- 21820383 TI - Sublethal responses to ammonia exposure in the endangered delta smelt; Hypomesus transpacificus (Fam. Osmeridae). AB - The delta smelt (Hypomesus transpacificus) is an endangered pelagic fish species endemic to the Sacramento-San Joaquin Estuary in Northern California, which acts as an indicator of ecosystem health in its habitat range. Interrogative tools are required to successfully monitor effects of contaminants upon the delta smelt, and to research potential causes of population decline in this species. We used microarray technology to investigate genome-wide effects in fish exposed to ammonia; one of multiple contaminants arising from wastewater treatment plants and agricultural runoff. A 4-day exposure of 57-day old juveniles resulted in a total ammonium (NH(4)(+)-N) median lethal concentration (LC50) of 13 mg/L, and a corresponding un-ionized ammonia (NH(3)) LC50 of 147 MUg/L. Using the previously designed delta smelt microarray we assessed altered gene transcription in juveniles exposed to 10mg/L NH(4)(+)-N from this 4-day exposure. Over half of the responding genes were associated with membrane integrity and function, however, neurological and muscular function was also affected. Amongst the notable pathways affected by ammonium exposure, directly associated with cellular membranes, are energy metabolism through oxidative phosphorylation, cellular responses to environmental stimuli, highlighted through signal transduction and molecular interactions, cellular processes encompassing transport and catabolism, along with cell motility, development, communication and cell death. To assess these impacts further, key genes were selected as potential biomarkers and investigated using quantitative PCR analysis on fish exposed to 2.5, 5, 10, 20 and 40 mg/L NH(4)(+)-N. Quantitative PCR results indicate biphasic responses, pivoting around the estimated no-observed effect concentration (NOEC; 5.0mg/L NH(4)(+)-N) and below. Genes significantly affected by ammonia exposure include claudin-10, Keratin-15, Septin-3, Transmembrane protein 4, superfamily 4 (membrane), Tropomyosin, Myosin light chain, Calmodulin (muscular), Tubulin cofactor beta (neurological), Sirtuin-6 (development), and Rhesus associated type C glycoprotein 1 (gill- and skin-specific ammonium transporter). The quantitation of the ammonium transporter may highlight the capacity of delta smelt to contend with elevated levels of ammonia, the peak response of which may be indicative of short-term thresholds of tolerance. Our study supports the notion that exposure to ammonia results in cell membrane destabilization, potentially affecting membrane permeability, enhancing uptake and thus synergistic effects of multiple contaminant exposure. PMID- 21820384 TI - Brain cytochrome P450 aromatase activity in roach (Rutilus rutilus): seasonal variations and impact of environmental contaminants. AB - P450 aromatase catalyses the conversion of C19 androgens to C18 estrogens which is thought to be essential for the regulation of the reproductive function. In this study, brain aromatase activity (AA) was measured monthly over a reproductive cycle in wild roach (Rutilus rutilus) sampled in a reference site in Normandy. AA peaked during the breeding season, reaching 35 fmol mg(-1)min(-1) in both male and female fish, and was low during the rest of the year except for a significant rise in October. AA was correlated with ovary maturation (measured either as gonado-somatic index or by histological analysis of the gonads) and plasma sex-steroid levels (11-ketotestosterone in males and 17-beta-estradiol in females). Measurements of AA in polluted sites showed that activity was significantly upregulated in sites with fish showing high levels of plasma vitellogenin and large proportion of intersexuality (20-50%) thus suggesting the occurrence of estrogenic compounds and their involvement in AA modulation. PMID- 21820385 TI - Metal uptake and acute toxicity in zebrafish: common mechanisms across multiple metals. AB - Zebrafish larvae (Danio rerio) were used to examine the mechanisms of action and acute toxicities of metals. Larvae had similar physiological responses and sensitivities to waterborne metals as adults. While cadmium and zinc have previously been shown to reduce Ca(2+) uptake, copper and nickel also decreased Ca(2+) uptake, suggesting that the epithelial transport of all these metals is through Ca(2+) pathways. However, exposure to cadmium, copper or nickel for up to 48 h had little or no effect on total whole body Ca(2+) levels, indicating that the reduction of Ca(2+) uptake is not the acute toxic mechanism of these metals. Instead, mortalities were effectively related to whole body Na(+), which decreased up to 39% after 48 h exposures to different metals around their respective 96 h LC50s. Decreases in whole body K(+) were also observed, although they were not as pronounced or frequent as Na(+) losses. None of the metals tested inhibited Na(+) uptake in zebrafish (Na(+) uptake was in fact increased with exposure) and the observed losses of Na(+), K(+), Ca(2+) and Mg(2+) were proportional to the ionic gradients between the plasma and water, indicating diffusive ion loss with metal exposure. This study has shown that there is a common pathway for metal uptake and a common mechanism of acute toxicity across groups of metals in zebrafish. The disruption of ion uptake accompanying metal exposure does not appear to be responsible for the acute toxicity of metals, as has been previously suggested, but rather the toxicity is instead due to total ion loss (predominantly Na(+)). PMID- 21820386 TI - The origins of cognitive vulnerability in early childhood: mechanisms linking early attachment to later depression. AB - This paper examines the theory and research linking attachment relationships to cognitive vulnerability to depression and assesses evidence that early attachment experiences contribute to the development of these cognitive processes. Most research in this area has involved adult participants using self-report measures of both attachment and depressive vulnerabilities and thus cannot convincingly speak to the existence of such a developmental pathway. Several studies, however, have followed individuals from infancy and examined the emergence of self-esteem and responses to failure throughout childhood and adolescence. These studies suggest that early experiences in non-secure attachment relationships place an individual at-risk for developing a cognitive framework that increases their vulnerability to depression following stressful life events. The paper concludes with a discussion of how future research might best explore specific mechanisms through which distinct attachment relationships may lead to divergent developmental pathways sharing the common outcome of cognitive processes that place individuals at risk for depression. PMID- 21820387 TI - Early versus late onset obsessive-compulsive disorder: evidence for distinct subtypes. AB - The distinction between early versus late onset is important for understanding many different kinds of disorders. In an effort to identify etiologically homogeneous subtypes of obsessive-compulsive disorder (OCD), numerous studies have investigated whether early onset OCD (EO) can be reliably distinguished from a comparatively later onset form of the disorder (LO). The present article presents a systematic review and evaluation of this subtyping scheme, including meta-analyses and re-analyses of raw data. Regarding the latter, latent class analyses of nine datasets, including clinical and community samples, consistently indicated that age-of-onset is not a unimodal phenomena. Evidence suggests that there are two distinguishable groups; EO (mean onset 11 years) and LO (mean onset 23 years). Approximately three-quarters of cases of OCD (76%) were classified as EO. Meta-analyses indicated that EO, compared to LO, is (a) more likely to occur in males, (b) associated with greater OCD global severity and higher prevalence of most types of OC symptoms, (c) more likely to be comorbid with tics and possibly with other putative obsessive-compulsive spectrum disorders, and (d) associated with a greater prevalence of OCD in first-degree relatives. EO and LO were also distinguishable on other psychosocial and biological variables. Overall, results support the view that EO and LO are distinct subtypes of OCD. Comparisons with other, potentially overlapping OCD subtyping schemes are discussed, implications for DSM-V are considered, and important directions for future investigation are proposed. PMID- 21820388 TI - The role of imagery-based techniques in cognitive-behavioural therapy for adults with eating disorders. AB - Disorder-specific and transdiagnostic cognitive-behavioural models and treatments primarily target surface-level maintaining factors in order to effect symptom change. Despite this approach resulting in the most effective evidence-based approach for most eating disordered patients, a significant proportion of sufferers fail to benefit from such treatments. This conclusion suggests that deeper-level causal factors might also need to be addressed in some cases. Theoretical and empirical findings are considered in terms of the clinical applicability of imagery-based techniques and their ability to enhance cognitive behavioural treatment of the eating disorders. Imagery techniques (particularly, but not only, imagery rescripting) are proposed as a means to enhance current treatments and improve existing outcomes. Potential treatment targets include core beliefs, emotional regulation difficulties and body image disturbance. The existing literature is limited but early indications suggest that imagery rescripting is effective in modifying core beliefs in this population, and that other imagery-based methods are potentially beneficial. Areas for further clinical application and investigation are identified. PMID- 21820389 TI - Gastroesophageal reflux is not associated with dental erosion in children. AB - BACKGROUND & AIMS: Dental erosion is a complication of gastroesophageal reflux (GER) in adults; in children, it is not clear if GER has a role in dental pathologic conditions. Dietary intake, oral hygiene, high bacterial load, and decreased salivary flow might contribute independently to GER development or dental erosion, but their potential involvement in dental erosion from GER is not understood. We investigated the prevalence of dental erosion among children with and without GER symptoms, and whether salivary flow rate or bacterial load contribute to location-specific dental erosion. METHODS: We performed a cross sectional study of 59 children (ages, 9-17 y) with symptoms of GER and 20 asymptomatic children (controls); all completed a questionnaire on dietary exposure. Permanent teeth were examined for erosion into dentin, erosion locations, and affected surfaces. The dentist was not aware of GER status, and the gastroenterologist was not aware of dental status. Stimulated salivary flow was measured and salivary bacterial load was calculated for total bacteria, Streptococcus mutans, and Lactobacilli. RESULTS: Controlling for age, dietary intake, and oral hygiene, there was no association between GER symptoms and dental erosion by tooth location or affected surface. Salivary flow did not correlate with GER symptoms or erosion. Erosion location and surface were independent of total bacteria and levels of Streptococcus mutans and Lactobacilli. CONCLUSIONS: Location-specific dental erosion is not associated with GER, salivary flow, or bacterial load. Prospective studies are required to determine the pathogenesis of GER-associated dental erosion and the relationship between dental caries to GER and dental erosion. PMID- 21820390 TI - Complementary functions of the flippase ATP8B1 and the floppase ABCB4 in maintaining canalicular membrane integrity. AB - BACKGROUND & AIMS: Progressive familial intrahepatic cholestasis can be caused by mutations in ABCB4 or ATP8B1; each encodes a protein that translocates phospholipids, but in opposite directions. ABCB4 flops phosphatidylcholine from the inner to the outer leaflet, where it is extracted by bile salts. ATP8B1, in complex with the accessory protein CDC50A, flips phosphatidylserine in the reverse direction. Abcb4(-/-) mice lack biliary secretion of phosphatidylcholine, whereas Atp8b1-deficient mice have increased excretion of phosphatidylserine into bile. Each system is thought to have a role protecting the canalicular membrane from bile salts. METHODS: To investigate the relationship between the mechanisms of ABCB4 and ATP8B1, we expressed the transporters separately and together in cultured cells and studied viability and phospholipid transport. We also created mice with disruptions in ABCB4 and ATP8B1 (double knockouts) and studied bile formation and hepatic damage in mice fed bile salts. RESULTS: Overexpression of ABCB4 was toxic to HEK293T cells; the toxicity was counteracted by coexpression of the ATP8B1-CDC50A complex. In Atp8b1-deficient mice, bile salts induced extraction of phosphatidylserine and ectoenzymes from the canalicular membrane; this process was not observed in the double-knockout mice. CONCLUSIONS: ATP8B1 is required for hepatocyte function, particularly in the presence of ABCB4. This is most likely because the phosphatidylserine flippase complex of ATP8B1-CDC50A counteracts the destabilization of the membrane that occurs when ABCB4 flops phosphatidylcholine. Lipid asymmetry is therefore important for the integrity of the canalicular membrane; ABCB4 and ATP8B1 cooperate to protect hepatocytes from bile salts. PMID- 21820391 TI - Interleukin-35 mediates mucosal immune responses that protect against T-cell dependent colitis. AB - BACKGROUND & AIMS: The soluble hematopoietin receptor Epstein-Barr virus-induced protein (EBI)-3 is an immune regulator that has been associated with the pathogenesis of inflammatory bowel disease. However, the concept that EBI3 is part of an interleukin (IL)-27 heterodimer that mediates chronic inflammatory and autoimmune diseases has been challenged by the description of IL-35, a bioactive cytokine comprising EBI3 and IL-12 p35. We investigated the roles of IL-27 and IL 35 in chronic inflammation of the intestine. METHODS: We analyzed EBI3-deficient mice and IL-27p28-deficient mice with spontaneous or T-cell transfer-induced colitis and compared outcomes with wild-type mice (controls). We constructed vectors that express EBI3 covalently linked to the IL-12p35 chain (recombinant [r]IL-35). RESULTS: Intestines of EBI3-deficient mice had increased pathologic features of colitis, compared with IL-27p28-deficient or control mice; they also had shorter survival times, indicating that IL-35, rather than IL-27, protects the intestine from immune responses in mice. The mucosa of EBI3-deficient mice accumulated subsets of activated CD4+ T cells that produced T-helper (Th)1 and Th17 cytokines. Adoptive transfer of these T cells induced colitis in RAG deficient mice. The rIL-35 significantly reduced the development of several forms of experimental colitis and reduced levels of markers of Th1 and Th17 cells. CONCLUSIONS: IL-35 controls the development of T-cell-dependent colitis in mice. It might be developed as a therapeutic target for patients with chronic intestinal inflammation. PMID- 21820392 TI - Safety and immunogenicity of the tetravalent protein-conjugated meningococcal vaccine (MCV4) in recipients of related and unrelated allogeneic hematopoietic stem cell transplantation. AB - Given the high morbidity and mortality associated with meningococcal disease, in 2007 the Advisory Committee of Immunization Practices recommended immunization of all children ages 11-18 with a protein-conjugated meningococcal vaccine. There are limited data on the immunogenicity of this vaccine after allogeneic hematopoietic stem cell transplantation (allo-HCT). Since 2007, we have immunized 48 patients with the MCV4 vaccine. Two vaccinated patients who lacked follow-up titers were excluded from this analysis. Stem cells were derived from an HLA identical sibling (n = 17) or an alternative donor (n = 29). The median time to vaccination was 2.34 years after allo-HCT. Only 7 patients responded to all 4 serogroups, and 16 patients responded to none of the serogroups. The response to serogroups A, C, Y, and W-135 was 52%, 30%, 46%, and 33%, respectively. The ability to respond to 2 or more serogroups was not affected by age, diagnosis, time to vaccination, or history of graft-versus-host disease. Receipt of a T cell depleted graft was associated with a poorer response (P = .044). Eight of 16 patients who received a second MCV4 vaccination responded to all 4 serogroups. This retrospective study suggests that response to a single MCV4 vaccination is poor after allo-HCT. Administration of a 2-dose series, as currently recommended for patients with asplenia, complement deficiency, and HIV infection, should be evaluated in this patient population. PMID- 21820393 TI - Long-term complications, immunologic effects, and role of passage for outcome in mesenchymal stromal cell therapy. AB - Thirty-one patients treated with mesenchymal stromal cells (MSCs) for acute graft versus-host disease (aGVHD) or hemorrhagic cystitis between 2002 and 2007 were followed to investigate predictors of outcome, immunologic effects in vivo, and long-term survival. There was no correlation between in vitro suppression by MSCs in mixed lymphocyte cultures and outcome. Soluble IL-2 receptors were measured in blood before and after MSC infusion and declined significantly during the first week after MSC infusion (P = .03). Levels of interleukin-6 and HLA-G were unaffected. Infectious complications occurred several years after recovery from aGVHD. Cytomegalovirus viral load was high, and cytomegalovirus disease was common. Among patients recovering from aGVHD, 54% died of late infections, between 4 months and 2 years after MSC treatment. No increase in leukemia relapse or graft rejection was found. Children had a better survival rate than adults (P = .005). In GVHD patients, 1-year survival was 75% in patients who received early passage MSCs (from passages 1-2) in contrast to 21% using later passage MSCs (from passages 3-4) (P < .01). We conclude that treatment with early-passage MSCs improved survival in patients with therapy-resistant GVHD. Death from infection was common in MSC-treated patients, but there was no increase in leukemia relapse. PMID- 21820394 TI - Allogeneic stem cell transplantation in multiple myeloma relapsed after autograft: a multicenter retrospective study based on donor availability. AB - Allogeneic stem cell transplantation (allo-SCT) using reduced-intensity conditioning (RIC) is a feasible procedure in selected patients with relapsed multiple myeloma (MM), but its efficacy remains a matter of debate. The mortality and morbidity related to the procedure and the rather high relapse risk make the use of allo-SCT controversial. In addition, the availability of novel antimyeloma treatments, such as bortezomib and immunomodulatory agents, have made allo-SCT less appealing to clinicians. We investigated the role of RIC allo-SCT in patients with MM who relapsed after autologous stem cell transplantation and were then treated with a salvage therapy based on novel agents. This study was structured similarly to an intention-to-treat analysis and included only those patients who underwent HLA typing immediately after the relapse. Patients with a donor (donor group) and those without a suitable donor (no-donor group) were compared. A total of 169 consecutive patients were evaluated retrospectively in a multicenter study. Of these, 75 patients found a donor and 68 (91%) underwent RIC allo-SCT, including 24 from an HLA-identical sibling (35%) and 44 from an unrelated donor (65%). Seven patients with a donor did not undergo allo-SCT for progressive disease or concomitant severe comorbidities. The 2-year cumulative incidence of nonrelapse mortality was 22% in the donor group and 1% in the no donor group (P < .0001). The 2-year progression-free survival (PFS) was 42% in the donor group and 18% in the no-donor group (P < .0001). The 2-year overall survival (OS) was 54% in the donor group and 53% in the no-donor group (P = .329). In multivariate analysis, lack of a donor was a significant unfavorable factor for PFS, but not for OS. Lack of chemosensitivity after salvage treatment and high-risk karyotype at diagnosis significantly shortened OS. In patients who underwent allo-SCT, the development of chronic graft-versus-host disease had a significant protective effect on OS. This study provides evidence for a significant PFS benefit of salvage treatment with novel drugs followed by RIC allo-SCT in patients with relapsed MM who have a suitable donor. PMID- 21820395 TI - Management of patients with nonvariceal upper gastrointestinal bleeding. PMID- 21820396 TI - Level of alpha-fetoprotein predicts mortality among patients with hepatitis C related hepatocellular carcinoma. AB - BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) can result from hepatitis C virus (HCV)-related liver disease and is the fastest-growing cause of cancer related death in the United States. alpha-fetoprotein (AFP) has been used as a prognostic factor for HCC, but the value of AFP as a prognostic factor for HCV related HCC in the United States is unknown. We investigated whether higher levels of AFP at the time of diagnosis are associated with increased mortality of patients with HCV-related HCC. METHODS: In a retrospective study, we collected data from a cohort of HCV-infected veterans, identifying incident HCC cases from October 1, 1998, to January 1, 2007 (n = 1480 patients). The mean serum levels of AFP, obtained within 60 days before to 30 days after HCC diagnosis, were determined for 1064 patients and categorized as less than 10 ng/mL (18%), 10 to less than 100 ng/mL (30%), 100 to less than 1000 ng/mL (22%), or 1000 ng/mL or more (29%). Cox proportional hazard models were used to associate serum levels of AFP with mortality, adjusting for demographic features, clinical factors, and treatment. RESULTS: The median survival times were significantly lower among patients with higher levels of AFP: 709 days for patients with less than 10 ng/mL, 422 days for patients with 10 to less than 100 ng/mL, 208 days for patients with 100 to less than 1000 ng/mL, and 68 days for patients with 1000 ng/mL or more. In the multivariate analysis, increased levels of AFP (10 to <100, 100 to <1000, and >=1000) were associated significantly with increased mortality, compared with a serum AFP level of less than 10; hazard ratios were 1.50, 2.23, and 4.35, respectively. CONCLUSIONS: Serum AFP level at the time of diagnosis with HCV-related HCC is an independent predictor of mortality. PMID- 21820397 TI - Twenty-year transplant-free survival rate among patients with biliary atresia. AB - BACKGROUND & AIMS: Surgical treatment with Kasai portoenterostomy has improved the prognosis for patients with biliary atresia, although most patients ultimately require liver transplantation. Well-described patients with long-term, transplant-free survival are scarce; we assessed liver status and health perception among Dutch patients who survived 20 years after therapy and investigated whether the rate of transplant-free survival increases with time. METHODS: By using the Dutch national database for biliary atresia, we identified 104 patients, born between 1977 and 1988. We collected data on clinical characteristics, liver biochemistry, and ultrasonography from all transplant-free patients who were alive at age 20 years (n = 28; 27% of the patients). General health perception data (RAND-36) were collected at the last examination. RESULTS: The 20-year transplant-free survival rate increased from 20% (10 of 49) in the 1977 to 1982 cohort to 32% (18 of 55) in the 1983 to 1988 cohort (P = .03). Twenty-one percent of the long-term survivors (6 of 28) had normal liver biochemistry test results and no clinical or ultrasonographic signs of cirrhosis. The general health perception of female, but not male, patients, was lower, compared with controls (RAND-36 score, 54 +/- 14 vs 74 +/- 18; P = .005). CONCLUSIONS: More than 25% of patients with biliary atresia survive at least 20 years without liver transplantation in The Netherlands. Women with biliary atresia have a reduced perception of their health, compared with control patients. Twenty percent of long-term survivors are symptom-free, without clinical or ultrasonographic signs of cirrhosis or portal hypertension. PMID- 21820398 TI - Molecular characteristics of extended-spectrum beta-lactamases in clinical isolates of Enterobacteriaceae from the Philippines. AB - beta-Lactamases, including extended-spectrum beta-lactamases (ESBLs) and AmpC beta-lactamases, are major resistance mechanisms of Enterobacteriaceae. Emergence of plasmid-mediated quinolone resistance (PMQR) determinants in ESBL-producing isolates poses a global threat. The molecular characterisitcs of ESBL and PMQR determinants in the Philippines are not well characterized. In this study, we investigated ESBLs and AmpC beta-lactamases in clinical isolates of Enterobacteriaceae from the Philippines, and analyzed the association between ESBL and PMQR genes. A total of 91 amoxicilin non-susceptible Enterobacteriaceae were collected at the Research Institute for Tropical Medicine of the Philippines from 2006 to 2008. AmpC- or ESBL-producing isolates were screened by detecting a zone diameter for cefoxitin <= 14 mm or cefpodoxime <= 20 mm, respectively. Possible ESBL-producing strains were assessed by the ESBL confirmation test of the Clinical and Laboratory Standards Institute. PCR and sequencing were performed to detect the ESBL and PMQR genes. The number of ESBL-producers and AmpC-producers confirmed phenotypically was 17 (18.7%) and 61 (67.0%), respectively. Of 17 phenotypic ESBL-producers, 14 isolates had ESBL genes, including 6 of Escherichia coli, 3 of Enterobacter cloacae, 2 of Enterobacter aerogenes, 2 of Klebsiella pneumoniae, and 1 of Klebsiella ozaenae. Among these isolates, there were 13, 4, and 12 with bla(CTX-M), bla(SHV), and bla(TEM), respectively. Of the bla(CTX-M)-positive isolates, bla(CTX-M-15) shows the highest prevalence, followed by bla(CTX-M-3) and bla(CTX-M-14). Of 14 ESBL producers identified by PCR, 4, 6, and 7 isolates were positive for qnrB, qnrS, and aac(6')-Ib-cr, respectively. The frequency of aac(6')-Ib-cr positivity was significantly higher among CTX-M-15-producing isolates. Thus, we identified bla(CTX-M), aac(6')-Ib-cr, and qnr in ESBL-producing Enterobacteriaceae from the Philippines, and revealed a significant association between bla(CTX-M-15) and aac(6')-Ib-cr. Local epidemiological data are important for implementing appropriate antimicrobial therapy and effective infection control measures. Continuous monitoring of antimicrobial resistance genes in the Philippines will be required. PMID- 21820399 TI - The fabrication of a piezoelectric immunosensor based on DNA-antibody conjugate layer. AB - In this article, we report a method of antibody immobilization carried out by hybridizing DNA-antibody conjugates on a mixed self-assembled monolayer composed of DNA thiols and mercaptopropionic acid via sequence-specific hybridization. The proposed method was applied to fabricate an immunosensor for detecting human immunoglobulin G (IgG). Under the optimized experimental conditions, a wide linear range from 50.0 to 500 MUg/ml was reached with a detection limit of 30.13 MUg/ml. The developed immunosensor possesses advantages such as simple fabrication, wide linear range, easy regeneration, and excellent reproducibility. PMID- 21820401 TI - The complex of cytochrome c and cytochrome c peroxidase: the end of the road? AB - Cytochrome c (Cc) and cytochrome c peroxidase (CcP) form a physiological complex in the inter-membrane space of yeast mitochondria, where CcP reduces hydrogen peroxide to water using the electrons provided by ferrous Cc. The Cc-CcP system has been a popular choice of study of interprotein biological electron transfer (ET) and in understanding dynamics within a protein-protein complex. In this review we have charted seven decades of research beginning with the discovery of CcP and leading to the latest functional and structural work, which has clarified the mechanism of the intermolecular ET, addressed the putative functional role of a low-affinity binding site, and identified lowly-populated intermediates on the energy landscape of complex formation. Despite the remarkable attention bestowed on this complex, a number of outstanding issues remain to be settled on the way to a complete understanding of Cc-CcP interaction. PMID- 21820400 TI - Determination of dideoxyosone precursors of AGEs in human lens proteins. AB - Dideoxyosones (DDOs) are intermediates in the synthesis of advanced glycation endproducts (AGEs), such as pentosidine and glucosepane. Although the formation of pentosidine and glucosepane in the human lens has been firmly established, the formation of DDOs has not been demonstrated. The aim of this study was to develop a reliable method to detect DDOs in lens proteins. A specific DDO trapping agent, biotinyl-diaminobenzene (3,4-diamino-N-(3-[5-(2-oxohexahydro-1H-thieno[3,4 d]imidazol-4-yl)pentanoyl]aminopropyl)benzamide) (BDAB) was added during in vitro protein glycation or during protein extraction from human lenses. In vitro glycated human lens protein showed strong reaction in monomeric and polymeric crosslinked proteins by Western blot and ELISA. Glycation of BSA in the presence of BDAB resulted in covalent binding of BDAB to the protein and inhibited pentosidine formation. Mass spectrometric analysis of lysozyme glycated in the presence of BDAB showed the presence of quinoxalines at lysine residues at positions K1, K33, K96, and K116. The ELISA results indicated that cataractous lens proteins contain significantly higher levels of DDO than non-cataractous lenses (101.9+/-67.8 vs. 31.7+/-19.5AU/mg protein, p<0.0001). This study provides first direct evidence of DDO presence in human tissue proteins and establishes that AGE crosslink synthesis in the human lens occurs via DDO intermediates. PMID- 21820403 TI - Lipid-mediated membrane binding properties of Disabled-2. AB - Disabled-2 (Dab2) is an adaptor protein involved in several biological processes ranging from endocytosis to platelet aggregation. During endocytosis, the Dab2 phosphotyrosine-binding (PTB) domain mediates protein binding to phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P(2)) at the inner leaflet of the plasma membrane. As a result of platelet activation, Dab2 is released from alpha-granules and associates with both the alphaIIbbeta3 integrin receptor and sulfatide lipids on the platelet surface through its N-terminal region including the PTB domain (N-PTB), thus, modulating platelet aggregation. Thrombin, a strong platelet agonist, prevents Dab2 function by cleaving N-PTB within the two basic motifs required for sulfatide association, a reaction that is prevented when Dab2 is bound to these sphingolipids. We have characterized the membrane binding properties of Dab2 N-PTB using micelles enriched with Dab2 lipid ligands, sulfatides and PtdIns(4,5)P(2). Remarkably, NMR spectroscopy studies suggested differences in lipid-binding mechanisms. In addition, we experimentally demonstrated that sulfatide- and PtdIns(4,5)P(2)-binding sites overlap in Dab2 N PTB and that both lipids stabilize the protein against temperature-induced unfolding. We found that whereas sulfatides induced conformational changes and facilitated Dab2 N-PTB penetration into micelles, Dab2 N-PTB bound to PtdIns(4,5)P(2) lacked these properties. These results further support our model that platelet membrane sulfatides, but not PtdIns(4,5)P(2), protect Dab2 N-PTB from thrombin cleavage. PMID- 21820402 TI - Characteristics of the turnover of uncoupling protein 3 by the ubiquitin proteasome system in isolated mitochondria. AB - Uncoupling protein 3 (UCP3) is implicated in mild uncoupling and the regulation of mitochondrial ROS production. We previously showed that UCP3 turns over rapidly in C2C12 myoblasts, with a half-life of 0.5-4h, and that turnover can be reconstituted in vitro. We show here that rapid degradation of UCP3 in vitro in isolated brown adipose tissue mitochondria required the 26S proteasome, ubiquitin, ATP, succinate to generate a high membrane potential, and a pH of 7.4 or less. Ubiquitin containing lysine-48 was both necessary and sufficient to support UCP3 degradation, implying a requirement for polyubiquitylation at this residue. The 20S proteasome did not support degradation. UCP3 degradation was prevented by simultaneously blocking matrix ATP generation and import, showing that ATP in the mitochondrial matrix was required. Degradation did not appear to require a transmembrane pH gradient, but was very sensitive to membrane potential: degradation was halved when membrane potential decreased 10-20mV from its resting value, and was not significant below about 120mV. We propose that matrix ATP and a high membrane potential are needed for UCP3 to be polyubiquitylated through lysine-48 of ubiquitin and exported to the cytosolic 26S proteasome, where it is de-ubiquitylated and degraded. PMID- 21820404 TI - Crystal structure of the mismatch-specific thymine glycosylase domain of human methyl-CpG-binding protein MBD4. AB - Methyl-CpG (mCpG) binding domain protein 4 (MBD4) is a member of mammalian DNA glycosylase superfamily. It contains an amino-proximal methyl-CpG binding domain (MBD) and a C-terminal mismatch-specific glycosylase domain, which is an important molecule believed to be involved in maintaining of genome stability. Herein, we determined the crystal structure of C-terminal glycosylase domain of human MBD4. And the structural alignments of other helix-hairpin-helix (HhH) DNA glycosylases show that the human MBD4 glycosylase domain has the similar active site and the catalytic mechanisms as others. But the different residues in the N terminal of domain result in the change of charge distribution on the surface of the protein, which suggest the different roles that may relate some diseases. PMID- 21820405 TI - Islet-selectivity of G-protein coupled receptor ligands evaluated for PET imaging of pancreatic beta-cell mass. AB - A critical unmet need exists for methods to quantitatively measure endogenous pancreatic beta-cell mass (BCM) for the clinical evaluation of therapies to prevent or reverse loss of BCM and diabetes progression. Our objective was to identify G-protein coupled receptors (GPCRs) that are expressed with a high degree of specificity to islet beta-cells for receptor-targeted imaging of BCM. GPCRs enriched in pancreatic islets relative to pancreas acinar and hepatic tissue were identified using a database screen. Islet-specific expression was confirmed by human pancreas immunohistochemistry (IHC). In vitro selectivity assessment was determined from the binding and uptake of radiolabeled ligands to the rat insulinoma INS-1 832/13 cell line and isolated rat islets relative to the exocrine pancreas cell-type, PANC-1. Tail-vein injections of radioligands into rats were used to determine favorable image criteria of in vivo biodistribution to the pancreas relative to other internal organs (i.e., liver, spleen, stomach, and lungs). Database and IHC screening identified four candidate receptors for further in vitro and in vivo evaluation for PET imaging of BCM: prokineticin-1 receptor (PK-1R), metabotropic glutamate receptor type-5 (mGluR5), neuropeptide Y 2 receptor (NPY-2R), and glucagon-like peptide 1 receptor (GLP-1R). In vitro specificity ratios gave the following receptor rank order: PK-1R>GLP-1R>NPY 2R>mGluR5. The biodistribution rank order of selectivity to the pancreas was found to be PK-1R>VMAT2~GLP-1R>mGluR5. Favorable islet selectivity and biodistribution characteristics suggest several GPCRs as potential targets for PET imaging of pancreatic BCM. PMID- 21820406 TI - Nesprin-2 epsilon: a novel nesprin isoform expressed in human ovary and Ntera-2 cells. AB - The nuclear envelope-associated cytoskeletal protein, nesprin-2, is encoded by a large gene containing several internal promoters that produce shorter isoforms. In a study of Ntera-2 teratocarcinoma cells, a novel isoform, nesprin-2-epsilon, was found to be the major mRNA and protein product of the nesprin-2 gene. Its existence was predicted by bioinformatic analysis, but this is the first direct demonstration of both the mRNA and the 120 kDa protein which is located at the nuclear envelope. In a panel of 21 adult and foetal human tissues, the nesprin-2 epsilon mRNA was strongly expressed in ovary but was a minor isoform elsewhere. The expression pattern suggests a possible link with very early development and a likely physiological role in ovary. PMID- 21820407 TI - Inhibition of MEK5 by BIX02188 induces apoptosis in cells expressing the oncogenic mutant FLT3-ITD. AB - Fms-like tyrosine kinase-3 (FLT3) is a growth factor receptor normally expressed on hematopoietic progenitor cells. Approximately one third of all patients with AML carry an activating mutation in FLT3 that drives proliferation and survival of the leukemic cells. The most common activating mutation is the so-called internal tandem duplication (ITD), which involves an in-frame duplication of a segment of varying length in the region of the FLT3 gene that encodes the juxtamembrane domain. The pathways downstream of FLT3-ITD are partially known but further knowledge regarding the downstream signal transduction molecules is important in order to develop alternative strategies for pharmacological intervention. In this paper we have studied the role of MEK/ERK5 in FLT3-ITD mediated transformation. We have found that both wild-type FLT3 and FLT3-ITD activate MEK5 leading to the activation of ERK5. By use of the selective inhibitor of MEK5, BIX02188, we have shown that activation of AKT downstream of FLT3 is partially dependent on ERK5. Furthermore, inhibition of MEK5/ERK5 induces apoptosis of both FLT3-ITD transfected Ba/F3 cells as well as the FLT3-ITD carrying leukemic cell lines MV4-11 and MOLM-13. These results suggest that MEK5/ERK5 is important for FLT3-ITD induced hematopoietic transformation and may thus represent an alternative therapeutic target in the treatment of FLT3-ITD positive leukemia. PMID- 21820408 TI - Stearoyl-CoA desaturase is an essential enzyme for the parasitic protist Trypanosoma brucei. AB - Trypanosoma brucei, the etiologic agent of sleeping sickness, is exposed to important changes in nutrients and temperature during its life cycle. To adapt to these changes, the fluidity of its membranes plays a crucial role. This fluidity, mediated by the fatty-acid composition, is regulated by enzymes named desaturases. We have previously shown that the oleoyl desaturase is essential for Trypanosoma cruzi and T. brucei. In this work, we present experimental support for the relevance of stearoyl-CoA desaturase (SCD) for T. brucei's survival, in both its insect or procyclic-form (PCF) and bloodstream-form (BSF) stages. We evaluated this essentiality in two different ways: by generating a SCD knocked down parasite line using RNA interference, and by chemical inhibition of the enzyme with two compounds, Isoxyl and a thiastearate with the sulfur atom at position 10 (10-TS). The effective concentration for 50% growth inhibition (EC(50)) of PCF was 1.0 +/- 0.2 MUM for Isoxyl and 5 +/- 2 MUM for 10-TS, whereas BSF appeared more susceptible with EC(50) values 0.10 +/- 0.03 MUM (Isoxyl) and 1.0 +/- 0.6 MUM (10-TS). RNA interference showed to be deleterious for both stages of the parasite. In addition, T. brucei-infected mice were fed with Isoxyl, causing a reduction of the parasitemia and an increase of the rodents' survival. PMID- 21820409 TI - Protein kinase Ceta activates NF-kappaB in response to camptothecin-induced DNA damage. AB - The nuclear factor kappaB (NF-kappaB) family of transcription factors participates in the regulation of genes involved in innate- and adaptive-immune responses, cell death and inflammation. The involvement of the Protein kinase C (PKC) family in the regulation of NF-kappaB in inflammation and immune-related signaling has been extensively studied. However, not much is known on the role of PKC in NF-kappaB regulation in response to DNA damage. Here we demonstrate for the first time that PKC-eta (PKCeta) regulates NF-kappaB upstream signaling by activating the IkappaB kinase (IKK) and the degradation of IkappaB. Furthermore, PKCeta enhances the nuclear translocation and transactivation of NF-kappaB under non-stressed conditions and in response to the anticancer drug camptothecin. We and others have previously shown that PKCeta confers protection against DNA damage-induced apoptosis. Our present study suggests that PKCeta is involved in NF-kappaB signaling leading to drug resistance. PMID- 21820410 TI - Septic sera induces apoptosis and DNA fragmentation factor 40 activation in fibroblasts. AB - Sepsis, the systemic response to infection, is the leading cause of death in the intensive care units worldwide. Septic patients can succumb through the development of early refractory hypotension or late multiple organ dysfunction. Misregulation of apoptosis during sepsis may contribute to cellular dysfunction and multiple organ dysfunction. Utilizing a tissue culture model which mimics the human disease, we demonstrate that the addition of sera derived from septic patients induces apoptosis in human fibroblast cells. Addition of septic sera to 2fTGH cells induced apoptosis by activating caspase 8, caspase 3 and DNA fragmentation factor 40 (DFF 40). Interestingly, the addition of septic sera to cells which lack STAT1 (U3A cells) did not activate DFF 40. U3A cells were also shown to be resistant to septic serum induced apoptosis. These data suggest that DFF 40 mediated apoptosis plays a significant role in mediating sepsis induced cellular dysfunction. PMID- 21820412 TI - Effects of cold exposure and shear stress on endothelial nitric oxide synthase activation. AB - Endothelial nitric oxide synthase (eNOS) is the primary enzyme that produces nitric oxide (NO), which plays an important role in blood vessel relaxation. eNOS activation is stimulated by various mechanical forces, such as shear stress. Several studies have shown that local cooling of the human finger causes strong vasoconstriction, followed after several minutes by cold-induced vasodilation (CIVD). However, the role played by endothelial cells (ECs) in blood vessel regulation in respond to cold temperatures is not fully understood. In this study, we found that low temperature alone does not significantly increase or decrease eNOS activation in ECs. We further found that the combination of shear stress with temperature change leads to a significant increase in eNOS activation at 37 degrees C and 28 degrees C, and a decrease at 4 degrees C. These results show that ECs play an important role in blood vessel regulation under shear stress and low temperature. PMID- 21820411 TI - In vitro prominent bone regeneration by release zinc ion from Zn-modified implant. AB - Zinc is one of the trace elements which induce the proliferation and the differentiation of the osteoblast. In the previous study, we found that zinc ions (Zn(2+) ion)-releasing titanium implants had excellent bone fixation using a rabbit femurs model. In this study, we isolated the Zn(2+) ions (eluted Zn(2+) ion; EZ) released from the implant surface, and evaluated the effect of EZ on the osteogenesis of human bone marrow-derived mesenchymal cells (hBMCs). In the result, it was found that the EZ stimulated cell viability, osteoblast marker gene (type I collagen, osteocalcin (OC), alkaline phosphatase (ALP) and bone sialoprotein (BSP)) expressions and calcium deposition in hBMCs. PMID- 21820413 TI - Compensatory increase in lipogenic gene expression in adipose tissue of transgenic mice expressing constitutively active AMP-activated protein kinase alpha1 in liver. AB - We previously described a line of transgenic mice selectively expressing constitutively active AMPK-alpha1 under the control of liver-specific human apoE promoter with the hepatic control region sequence. In the short-term activation, the CA-AMPK-alpha1 transgenic mice at age 10-12weeks exhibited normal hepatic triglyceride content as compared to wild-type mice due to compensatory increase in mRNA expression of genes in the cholesterol and fatty acid synthesis pathways. But it was not known whether the lipogenic gene expression in white adipose tissue also changed. Here we characterized mRNA expression profile of main lipogenic genes in the cholesterol and fatty acid biosynthesis pathway in white adipose tissue. The data show that short-term chronic activation of AMPK in liver caused marked compensatory increase in lipogenic gene expression both in liver due to induction of Srebp-2 and in white adipose tissue due to upregulation of Srebp-1c. These results support the notion that in addition to its well recognized function for fat storage adipose tissue can play an adaptive role in fatty acid synthesis when fatty acid synthesis is severely reduced in liver, the main lipogenic organ in mammals. PMID- 21820414 TI - Proteomic analysis of cancer stem cells in human prostate cancer cells. AB - Results from recent studies support the hypothesis that cancer stem cells (CSCs) are responsible for tumor initiation and formation. Here, we applied a proteome profiling approach to investigate the mechanisms of CSCs and to identify potential biomarkers in the prostate cancer cell line DU145. Using MACS, the DU145 prostate cancer cell line was isolated into CD44+ or CD44- cells. In sphere culture, CD44+ cells possessed stem cell characteristics and highly expressed genes known to be important in stem cell maintenance. In addition, they showed strong tumorigenic potential in the clonogenic assay and soft agar colony formation assay. We then analyzed and identified proteins that were differentially expressed between CD44+ and CD44- using two-dimensional gel electrophoresis and LC-MS/MS. Cofilin and Annexin A5, which are associated with proliferation or metastasis in cancer, were found to be positively correlated with CD44 expression. These results provide information that will be important to the development of new cancer diagnostic tools and understanding the mechanisms of CSCs although a more detailed study is necessary to investigate the roles of Cofilin and Annexin A5 in CSCs. PMID- 21820415 TI - Dual roles of CagA protein in Helicobacterpylori-induced chronic gastritis in mice. AB - Cytotoxin-associated gene A (CagA) acts directly on gastric epithelial cells. However, the roles of CagA in host adaptive immunity against Helicobacter pylori (H. pylori) infection are not fully understood. In this study, to investigate the roles of CagA in the development of H. pylori-induced chronic gastritis, we used an adoptive-transfer model in which spleen cells from C57BL/6 mice with or without H. pylori infection were transferred into RAG2(-/-) mice, with gastric colonization of either CagA(+) H. pylori or CagA(-) H. pylori. Colonization of CagA(+) H. pylori but not CagA(-) H. pylori in the host gastric mucosa induced severe chronic gastritis in RAG2(-/-) mice transferred with spleen cells from H. pylori-uninfected mice. In addition, when CagA(+) H. pylori-primed spleen cells were transferred into RAG2(-/-) mice, CD4(+) T cell infiltration in the host gastric mucosa were observed only in RAG2(-/-) mice infected with CagA(+) H. pylori but not CagA(-) H. pylori, suggesting that colonization of CagA(+) H. pylori in the host gastric mucosa is essential for the migration of H. pylori primed CD4(+) T cells. On the other hand, transfer of CagA(-) H. pylori-primed spleen cells into CagA(+) H. pylori-infected RAG2(-/-) mice induced more severe chronic gastritis with less Foxp3(+) regulatory T-cell infiltration as compared to transfer of CagA(+) H. pylori-primed spleen cells. In conclusion, CagA in the stomach plays an important role in the migration of H. pylori-primed CD4(+) T cells in the gastric mucosa, whereas CagA-dependent T-cell priming induces regulatory T-cell differentiation, suggesting dual roles for CagA in the pathophysiology of H. pylori-induced chronic gastritis. PMID- 21820416 TI - A new experimental approach and signal processing scheme for the detection and quantitation of 31P brain neurochemicals from in vivo MRS studies using dual tuned (1H/31P) head coil. AB - Brain (31)P-neurometabolites play an important role in energy and membrane metabolism. Unambiguous identification and quantification of these neurochemicals in different brain regions would be a great aid in advancing the understanding of metabolic processes in the nervous system. Phosphomonoester (PME), consisting of phosphoethanolamine (PE) and phosphocholine (PC), is the "building block" for membranes, while phosphodiesters (PDE), consisting of glycerophosphocholine (GPC) and glycerophosphoethanolamine (GPE) metabolites are involved in the membrane breakdown process. In the clinical setting, generating well-resolved spectra for PC, PE, GPC, and GPE could be crucial phospholipids in providing information regarding membrane metabolism. We present here a new experimental approach for generating well-resolved (31)P spectra for PC and PE as well as for GPC, GPE, and other (31)P metabolites. Our results (based on uni-dimensional (1D) and multi voxel (31)P studies) indicate that an intermediate excitation pulse angle (35 degrees ) is best suited to obtain well-resolved PC/PE and GPC/GPE resonance peaks. Our novel signal processing scheme allows generating metabolite maps of different phospholipids include PC/PE and GPC/GPE using the 'time-domain frequency-domain' method as referred to in the MATLAB programming language. PMID- 21820417 TI - Inhibitor of DNA binding 1 (Id1) induces differentiation and proliferation of mouse embryonic carcinoma P19CL6 cells. AB - The inhibitor of DNA binding (Id) family of genes encodes negative regulators of basic helix-loop-helix transcription factors and has been implicated in such diverse cellular processes as differentiation, proliferation, apoptosis and migration. Id knockout mouse embryos display multiple cardiac defects but the specific role of Id1 in cardiac differentiation is unclear. In the present study, we investigated the function of Id1 in DMSO-induced P19CL6 cells, a widely accepted cell model of cardiac differentiation. We found that Id1 was upregulated during the cardiac differentiation of P19CL6 cells. The expression of cardiac specific marker genes, Gata4, alpha-MHC and ISL1, was upregulated in P19CL6 cells stably transfected with Id1 (P19CL6-Id1) during cardiac differentiation. The overexpression of Id1 reduced the number of cells in G1 phase and increased the cell population in G2, M and S phases, while knockdown of Id1 increased the number of cells in G1 phase from 48.6 +/- 2.51% to 62.2 +/- 1.52% at day 0 of cardiac induction, and from 52.5 +/- 3.41% to 63.7 +/- 1.02% at day 3 after cardiac induction, indicating that Id1 promoted proliferation of P19CL6 cells. Luciferase assays showed that the activity of TOP flash was higher in P19CL6-Id1 cells than wildtype P19CL6 cells, while Id1 expression was also upregulated in P19CL6 cells treated with Wnt3a or LiCl. This indicates that there may be positive feedback between Id1 and Wnt signaling which plays an important role in cardiac differentiation. PMID- 21820418 TI - Therapeutic potential of ghrelin treatment for unloading-induced muscle atrophy in mice. AB - Ghrelin is a growth hormone (GH) secretagogue secreted mainly from the stomach that functions in controlling muscle volume and energy homeostasis. We here studied the effects of ghrelin on unloading-induced muscle atrophy using a mouse model of hindlimb suspension (HS). Ghrelin administration during 2-week HS alleviated reductions of muscle mass in the fast-twitch fiber-rich plantaris muscle and the slow-twitch fiber-rich soleus muscle of the hindlimb. Ghrelin administration during a 5-day recovery period following 2-week HS enhanced food intake and facilitated recovery from atrophy in both muscles. Ghrelin administration normalized hypercorticosteronemia in these studies. Ghrelin's anti muscle atrophy effect was found even under pair-feeding condition, but not in mice given des-acyl ghrelin. Insulin-like growth factor (IGF)-1 mRNA expression was significantly reduced in the atrophied plantaris muscle compared with control muscles. A single ghrelin administration to HS mice acutely increased plasma GH and also amplified phosphorylation of signal transducer and activator of transcription (STAT) 5 and increased IGF-1 mRNA expression in the plantaris muscle, but not in the soleus muscle. This study demonstrated that ghrelin stimulated the GH-STAT5-IGF-1 axis in the locally atrophied plantaris muscle, and its administration alleviated muscle atrophy and facilitated recovery from muscle atrophy. Ghrelin's effects represent a novel therapeutic paradigm for the treatment of unloading-induced muscle atrophy induced by factors such as bed rest, injury, and joint immobilization. PMID- 21820419 TI - The sterile alpha-motif (SAM) domain of p63 binds in vitro monoasialoganglioside (GM1) micelles. AB - The transcription factor p63 plays pivotal roles in epidermal barrier formation and in embryonic development. The protein structures of TAp63 and DeltaNp63alpha isoforms include a C-terminal steril alpha-motif (SAM) involved in protein protein interaction. Identification of p63 SAM domain interactors could lead to the explanation of novel mechanisms of regulation of p63 activity, possibly relevant in the physiological role of p63 and in genetic disorders associated with mutations of the p63 gene. In this work, we have performed a biochemical analysis of p63 SAM domain preferences in lipid binding. We have identified the ganglioside GM1 as a high affinity interactor, capable of modulating p63 transcriptional ability exclusively on epidermal target genes. In agreement with these data we report a consistent expression profile and localization analysis of p63 and GM1 in primary keratinocytes and in human epidermal biopsies. Therefore, we propose a potential biological role of p63-GM1 interaction in regulation of p63 during epidermal differentiation. PMID- 21820420 TI - Lycium barbarum (Goji Berry) extracts and its taurine component inhibit PPAR gamma-dependent gene transcription in human retinal pigment epithelial cells: Possible implications for diabetic retinopathy treatment. AB - The peroxisome proliferator activated receptor-gamma (PPAR-gamma) is involved in the pathogenesis of diabetic retinopathy. Diabetic retinopathy is a preventable microvascular diabetic complication that damages human retinal pigment epithelial cells. Taurine is abundant in the fruit of Lycium barbarum (Goji Berry), and is reportedly beneficial for diabetic retinopathy. However, the mechanism of its action is unknown. Hence, we have investigated the mechanism of action of an extract from L. barbarum on a model of diabetic retinopathy, the retinal ARPE-19 cell line, and identified the receptor function of taurine, an active component of L. barbarum (Goji Berry) extract, which is potentially responsible for the protective effect on diabetic retinopathy. We demonstrate for the first time that L. barbarum extract and its taurine component dose-dependently enhance PPAR-gamma luciferase activity in HEK293 cell line transfected with PPAR-gamma reporter gene. This activity was significantly decreased by a selective PPAR-gamma antagonist GW9662. Moreover, L. barbarum extract and taurine dose-dependently enhanced the expression of PPAR-gamma mRNA and protein. In an inflammation model where ARPE-19 cells were exposed to high glucose L. barbarum extract and taurine down-regulated the mRNA of pro-inflammatory mediators encoding MMP-9, fibronectin and the protein expression of COX-2 and iNOS proteins. The predicted binding mode of taurine in the PPAR-gamma ligand binding site mimics key electrostatic interactions seen with known PPAR-gamma agonists. We conclude that PPAR-gamma activation by L. barbarum extract is associated with its taurine content and may explain at least in part its use in diabetic retinopathy progression. PMID- 21820421 TI - Island biogeography effects on microbial evolution may contribute to Crohn's disease. AB - Inflammatory bowel diseases (IBDs), such as Crohn's disease (CD), involve a poorly understood and complex immune response to both the biota of the human gut and the gut itself. The role of the gut biota in human health has been ill defined and attitudes toward the intestinal flora have ranged from judging them largely irrelevant to declaring them a human organ system. A better way to view the intestinal flora is as a group of evolutionarily self-interested species that form large, potentially interbreeding populations that utilize human beings as a series of semi-isolated habitats, like islands in an archipelago. Here we propose that the imposition of modern sanitation and hygiene standards has drastically attenuated the connection between the "islands" inhabited by the gut flora, and that existing work drawn from evolutionary biology studies of island ecosystems, rather than medicine, predicts that the evolution of gut flora should now be pushed toward limited-dispersion forms of intestinal microorganisms - a proposition borne out by the discovery of so-called "adherent invasive Escherichia coli." This pathogenic variant of the gut bacterium E. coli clings to and invades the intestinal epithelium and has been implicated in CD. Gut flora and diseases of the gut should arguably be studied as ecology as much as medicine, and treated within this context. PMID- 21820423 TI - Performance of glycogen phosphorylase isoenzyme BB is weak in the detection of patients with non-ST-elevation acute coronary syndrome. AB - OBJECTIVE: To examine the diagnostic performance of glycogen-phosphorylase isoenzyme-BB (GPBB) combined with cardiac troponin I (cTnI) in acute coronary syndrome (ACS). DESIGN AND METHODS: Sixty patients with chest pain were investigated; GPBB and cTnI were measured. RESULTS: ACS was confirmed in 31 patients; cTnI was >0.07 MUg/L in 15 patients and GPBB was >10 MUg/L in 6 patients. Areas under ROC curves were similar: 0.854 (cTnI+GPBB) vs. 0.843 (cTnI), p=0.728. CONCLUSION: Combination of GPBB with cTnI does not improve the detection of ACS. PMID- 21820424 TI - Clinical efficacy of propylthiouracil and its influence on prolactin in psoriatic patients. AB - OBJECTIVE: Propylthiouracil (PTU) is an effective drug for psoriasis treatment. Prolactin (PRL) is increased during psoriasis which has hyperproliferative effect on keratinocytes. Hence, the objective is to find the effect of PTU on PRL level in psoriatic patients. DESIGN AND METHODS: 25 psoriatic patients and 10 control subjects were involved in the study. Serum PRL, hematological and biochemical parameters, thyroid profile and histopathological examination were performed. RESULTS: PTU treatment for 6 weeks and 12 weeks cleared psoriatic lesions indicated by decreased PASI score (p<0.001). Patients before treatment showed significantly increased PRL levels (male p<0.01, female p<0.001) when compared to controls, which was found to decrease significantly (male p<0.01, female p<0.001) after 12 weeks. Hematological and biochemical parameters showed no significant change. Histopathology showed reduced thickening of the epidermis and acanthosis after PTU treatment. CONCLUSION: Since PRL is a growth hormone involved in hyperproliferation of keratinocytes, this study reveals the antiproliferative effect of PTU. Furthermore, no major side effects were observed following PTU treatment. PMID- 21820425 TI - Effect of chilling on sox2, sox3 and sox19a gene expression in zebrafish (Danio rerio) embryos. AB - Zebrafish embryos have not been cryopreserved due to their structural limitations. Although embryo survival rates have been used as the measured outcome for most of the cryopreservation protocols studied, there are very limited data available at the molecular level. This study focused on the effect of chilling and subsequent warming on gene expression of sox2, sox3 and sox19a which play vital roles in the development of zebrafish embryos. A quantitative RT PCR approach was used to investigate gene expression following chilling at 0 degrees C for up to 180 min. The effect on gene expression was also studied during a 180 min warming period after chilling for 30 or 60 min. There were significant decreases in sox2 (up to 4-fold) and sox3 (up to 3-fold) expressions following chilling. Significant increases in gene expressions of sox2 (up to 2 fold), sox3 (up to 33-fold) and sox19a (up to 25-fold) were observed during warming in the embryos that had been chilled for 30 min. Similarly, significant increases were observed in sox2 (up to 3-fold) and sox3 (up to 2-fold) during warming in embryos that had been chilled for 60 min. These increases may be explained by compensation for the suppression observed during chilling and/or to activate repair mechanisms or maintain homeostasis. PMID- 21820422 TI - Triptolide, histone acetyltransferase inhibitor, suppresses growth and chemosensitizes leukemic cells through inhibition of gene expression regulated by TNF-TNFR1-TRADD-TRAF2-NIK-TAK1-IKK pathway. AB - Triptolide, a diterpene triepoxide, from the Chinese herb Tripterygium wilfordii Hook.f, exerts its anti-inflammatory and immunosuppressive activities by inhibiting the transcription factor nuclear factor-kappaB (NF-kappaB) pathway, through a mechanism not yet fully understood. We found that triptolide, in nanomolar concentrations, suppressed both constitutive and inducible NF-kappaB activation, but did not directly inhibit binding of p65 to the DNA. The diterpene did block TNF-induced ubiquitination, phosphorylation, and degradation of IkappaBalpha, the inhibitor of NF-kappaB and inhibited acetylation of p65 through suppression of binding of p65 to CBP/p300. Triptolide also inhibited the IkappaBalpha kinase (IKK) that activates NF-kappaB and phosphorylation of p65 at serine 276, 536. Furthermore, the NF-kappaB reporter activity induced by TNF TNFR1-TRADD-TRAF2-NIK-TAK1-IKKbeta was abolished by the triepoxide. Triptolide also abrogated TNF-induced expression of cell survival proteins (XIAP, Bcl-x(L), Bcl-2, survivin, cIAP-1 and cIAP-2), cell proliferative proteins (cyclin D1, c myc and cyclooxygenase-2), and metastasis proteins (ICAM-1 and MMP-9). This led to enhancement of apoptosis induced by TNF, taxol, and thalidomide by the diterpene and to suppression of tumor invasion. Overall, our results demonstrate that triptolide can block the inflammatory pathway activated by TNF-TNFR1-TRADD TRAF2-NIK-TAK1-IKK, sensitizes cells to apoptosis, and inhibits invasion of tumor cells. PMID- 21820426 TI - Membrane extensions are associated with proper anterior migration of muscle cells during Caenorhabditis elegans embryogenesis. AB - C. elegans body wall muscle is formed after a series of well-orchestrated steps. With the onset of specification embryonic muscle cells accumulate under the hypodermal seam cells at the left and right sides of the embryo. Shortly thereafter they begin to migrate dorsally and ventrally resting beneath the dorsal and ventral hypodermis eventually forming the four muscle quadrants present upon hatching. In this study we describe the plasma membrane dynamics of these migrating cells and observe the extension of filopodia and lamellipodia during dorso-ventral migration but not during the earlier stages of accumulation. We also describe an anterior migration event during embryonic muscle morphogenesis, whereby the anterior-most pair of cells in each of the four muscle quadrants extends long processes to the anterior tip of the developing embryo. Anteriormost muscle cells then follow these extensions into their final positions in the developing embryo. Using RNAi and mutant analysis, we have identified laminin as being involved in mediating the dorsal-ventral muscle migrations. Finally we show that the alpha-integrin INA-1, the ephrin VAB-2 and its receptor VAB-1 and the Robo receptor SAX-3 indirectly promote the proper extension of the ventral anterior muscle processes by organizing the embryonic neurons so as to provide a clear path for muscle membrane extension. PMID- 21820427 TI - Robo1 and Robo2 have distinct roles in pioneer longitudinal axon guidance. AB - Pioneer longitudinal axons grow long distances parallel to the floor plate and precisely maintain their positions using guidance molecules released from the floor plate. Two receptors, Robo1 and Robo2, are critical for longitudinal axon guidance by the Slit family of chemorepellents. Previous studies showed that Robo1(-/-);2(-/-) double mutant mouse embryos have disruptions in both ventral and dorsal longitudinal tracts. However, the role of each Robo isoform remained unclear, because Robo1 or 2 single mutants have mild or no errors. Here we utilized a more sensitive genetic strategy to reduce Robo levels for determining any separate functions of the Robo1 and 2 isoforms. We found that Robo1 is the predominant receptor for guiding axons in ventral tracts and prevents midline crossing. In contrast, Robo2 is the main receptor for directing axons within dorsal tracts. Robo2 also has a distinct function in repelling neuron cell bodies from the floor plate. Therefore, while Robo1 and 2 have some genetic overlap to cooperate in guiding longitudinal axons, each isoform has distinct functions in specific longitudinal axon populations. PMID- 21820428 TI - The role of innate immunity in the pathogenesis of preneoplasia in drug-induced chronic hepatitis based on a mouse model. AB - Innate immunity factors such as conversion of the 26S proteasome to form the immunoproteasome and the Toll-like receptor signaling pathways are activated in chronic hepatitis induced by the carcinogenic drug DDC. Over time, preneoplastic hepatocyte phenotypes appear in the liver parenchyma. These changed hepatocytes expand in number because they have a growth advantage over normal hepatocytes when responding to chronic liver injury. The changed hepatocytes can be identified using immunofluorescent antibodies to preneoplastic cells e.g. FAT10/UbD, A2 macroglobulin, glutathione transpeptidase, alpha fetoprotein, glycipan 3, FAS, and gamma glutamyl transpeptidase. The formation of the preneoplastic cells occurs concomitant with activation of the Toll-like receptor signaling pathways and the transformation of the 26S proteasome to form the immunoproteasome. This transformation is in response to interferon stimulating response element on the promoter of the FAT10/UbD gene. NFkappaB, Erk, p38 and Jnk are also up regulated. Specific inhibitors block these responses in vitro in a mouse tumor cell line exposed to interferon gamma. Mallory-Denk bodies form in these preneoplastic cells, because of the depletion of the 26S proteasome due to formation of the immunoproteasome. Thus, MDB forming cells are also markers of the preneoplastic hepatocytes. The UbD positive preneoplastic cells regress when the liver injury induced chronic hepatitis subsides. When the drug DDC is refed to mice and chronic hepatitis is activated, the preneoplastic cell population expands and Mallory-Denk bodies rapidly reform. This response is remembered by the preneoplastic cells for at least four months indicating that an epigenetic cellular memory has formed in the preneoplastic cells. This proliferative response is prevented by feeding methyl donors such as S-adenosylmethionine or betaine. Drug feeding reduces the methylation of H(3) K4, 9, and 27 and this response is prevented by feeding the methyl donors. After 8 to 15months of drug withdrawal in mice the preneoplastic liver cells persist as single or small clusters of cells in the liver lobules. Multiple liver tumors form, some of which are hepatocellular carcinomas. The tumors immunostain positively for the same preneoplastic markers as the preneoplastic cells. Similar cells are identified in human cirrhosis and hepatocellular carcinoma indicating the relevance of the drug model described here to the preneoplastic changes associated with human chronic hepatitis and hepatocellular carcinoma. PMID- 21820429 TI - Accumulation of Ku70 at DNA double-strand breaks in living epithelial cells. AB - Ku70 and Ku80 play an essential role in the DNA double-strand break (DSB) repair pathway, i.e., nonhomologous DNA-end-joining (NHEJ). No accumulation mechanisms of Ku70 at DSBs have been clarified in detail, although the accumulation mechanism of Ku70 at DSBs plays key roles in regulating the NHEJ activity. Here, we show the essential domains for the accumulation and function of Ku70 at DSBs in living lung epithelial cells. Our results showed that EGFP-Ku70 accumulation at DSBs began immediately after irradiation. Our findings demonstrate that three domains of Ku70, i.e., the alpha/beta, DNA-binding, and Ku80-binding domains, but not the SAP domain, are necessary for the accumulation at or recognition of DSBs in the early stage after irradiation. Moreover, our findings demonstrate that the leucine at amino acid 385 of Ku70 in the Ku80-binding domain, but not the three target amino acids for acetylation in the DNA-binding domain, is involved in the localization and accumulation of Ku70 at DSBs. Furthermore, accumulations of XRCC4 and XLF, but not that of Artemis, at DSBs are dependent on the presence of Ku70. These findings suggest that Artemis can work in not only the Ku-dependent repair process, but also the Ku-independent process at DSBs in living epithelial cells. PMID- 21820430 TI - The intracellular domain of Jagged-1 interacts with Notch1 intracellular domain and promotes its degradation through Fbw7 E3 ligase. AB - Notch signaling involves the proteolytic cleavage of the transmembrane Notch receptor after binding to its transmembrane ligands. Jagged-1 also undergoes proteolytic cleavage by gamma-secretase and releases an intracellular fragment. In this study, we have demonstrated that the Jagged-1 intracellular domain (JICD) inhibits Notch1 signaling via a reduction in the protein stability of the Notch1 intracellular domain (Notch1-IC). The formation of the Notch1-IC-RBP-Jk Mastermind complex is prevented in the presence of JICD, via a physical interaction. Furthermore, JICD accelerates the protein degradation of Notch1-IC via Fbw7-dependent proteasomal pathway. These results indicate that JICD functions as a negative regulator in Notch1 signaling via the promotion of Notch1 IC degradation. PMID- 21820431 TI - Control of cell adhesion and compartmentalization in the intestinal epithelium. AB - Continuous cell renewal in the intestinal mucosa occurs without disrupting the integrity of the epithelial layer. Despite the restrictions imposed by strong cell-to-cell adhesions, epithelial intestinal cells migrate constantly between tissue compartments. Alterations in cell adhesion and compartmentalization play key roles in diseases of the intestine. In particular, decreased E-cadherin mediated adhesion during inflammatory bowel disease and loss of EphB/ephrin-B mediated compartmentalization in colorectal cancer have recently emerged as key players of these prevalent pathologies. Here we will review our current knowledge on how cell-to-cell adhesion, migration and cell positioning are coordinated in the intestinal epithelium. We will highlight what the in vivo genetic analysis of intestinal epithelium has taught us about the complex regulation of cell adhesion and migration in homeostasis and disease. PMID- 21820432 TI - Relationship between sensorimotor gating deficits and dopaminergic neuroanatomy in Nurr1-deficient mice. AB - Nurr1 (NR4A2) is an orphan nuclear receptor highly essential for the development and maintenance of dopaminergic neurons. Reduced expression of Nurr1 has been linked to the etiopathogenesis of Parkinson's disease and other dopamine-related disorders such as schizophrenia. Recent experimental work in mice with a heterozygous constitutive deletion of Nurr1 has revealed that this genetic manipulation leads to the presence of sensorimotor gating dysfunctions in the form of reduced prepulse inhibition of the acoustic startle reflex. However, the neuronal substances for this behavioral manifestation remain essentially unknown. Since converging evidence supports a key role of the central dopamine system in the regulation of prepulse inhibition, we hypothesized that the emergence of prepulse inhibition deficits in adult Nurr1-deficient mice may be linked to dopaminergic neuroanatomical changes. To test this hypothesis, we followed a within-subject approach in which sensorimotor gating performance was correlated with post-mortem expression of several dopaminergic markers in relevant striatal and midbrain regions. We found that prepulse inhibition deficits in Nurr1 deficient mice were paralleled by reduced numbers of substantia nigra dopamine cells expressing tyrosine hydroxylase, and by decreased tyrosine hydroxylase and dopamine transporter immunoreactivity in ventral parts of the striatum. Most interestingly, we also revealed a striking negative correlation between prepulse inhibition levels and tyrosine hydroxylase immunoreactivity in Nurr1-deficient mice in dorsal striatal regions (caudate putamen) and ventral striatal regions (nucleus accumbens core and shell). Our findings thus suggest that the emergence of prepulse inhibition deficits induced by heterozygous constitutive deletion of Nurr1 is, at least in part, related to alterations in presynaptic components of the striatal dopamine system. The constellation of neuroanatomical and behavioral alterations in Nurr1-deficient mice observed here confirms previous impressions that the consequences of Nurr1 down-regulation capture neuronal and behavioral pathologies relevant especially for (but not limited to) Parkinson's disease. PMID- 21820433 TI - Effects of age and cortical infarction on EEG dynamic changes associated with spike wave discharges in F344 rats. AB - Rodent models of absence seizures are used to investigate the network properties and regulatory mechanisms of the seizure's generalized spike and wave discharge (SWD). As rats age, SWDs occur more frequently, suggesting aging-related changes in the regulation of the corticothalamic mechanisms generating the SWD. We hypothesized that brain resetting mechanisms - how the brain "resets" itself to a more normal functional state following a transient period of abnormal function, e.g., a SWD - are impaired in aged animals and that brain infarction would further affect these resetting mechanisms. The main objective of this study was to determine the effects of aging, infarction, and their potential interaction on the resetting of EEG dynamics assessed by quantitative EEG (qEEG) measures of linear (signal energy measured by amplitude variation; signal frequency measured by mean zero-crossings) and nonlinear (signal complexity measured by the pattern match regularity statistic and the short-term maximum Lyapunov exponent) brain EEG dynamics in 4- and 20-month-old F344 rats with and without brain infarction. The main findings of the study were: 1) dynamic resetting of both linear and nonlinear EEG characteristics occurred following SWDs; 2) animal age significantly affected the degree of dynamic resetting in all four qEEG measures: SWDs in older rats exhibited a lower degree of dynamic resetting; 3) infarction significantly affected the degree of dynamic resetting only in terms of EEG signal complexity: SWDs in infarcted rats exhibited a lower degree of dynamic resetting; and 4) in all four qEEG measures, there was no significant interaction effect between age and infarction on dynamic resetting. We conclude that recovery of the brain to its interictal state following SWDs was better in young adult animals compared with aged animals, and to a lesser degree, in age-matched controls compared with infarction-injured animal groups, suggesting possible effects of brain resetting mechanisms and/or the disruption of the epileptogenic network that triggers SWDs. PMID- 21820434 TI - Influence of Echinostoma paraensei (Lie and Basch, 1967) infection on the calcium content in Biomphalaria glabrata (Say, 1818). AB - The calcium content in the hemolymph and shell of Biomphalaria glabrata (Say, 1818) was determined after exposure to different parasite burdens (5 and 50 miracidia) of Echinostoma paraensei (Lie and Basch, 1967). The snails were dissected 1, 2, 3, and 4 weeks after infection to collect the hemolymph and shell. An increase in calcemia was observed in snails infected with both miracidial doses. A significant decrease in the calcium ions in the shell was observed, coinciding with the calcemia peak in the hemolymph. This indicates greater mobilization of calcium between the shell and hemolymph to regulate the calcium content in the body when the snail is exposed to stress conditions, as has also been observed in some other infected snail species. The results obtained indicate that in this model, the calcium metabolism depends on the miracidial dose used. PMID- 21820435 TI - Identification of a novel Arabidopsis thaliana nitric oxide-binding molecule with guanylate cyclase activity in vitro. AB - While there is evidence of nitric oxide (NO)-dependent signalling via the second messenger cyclic guanosine 3',5'-monophosphate (cGMP) in plants, guanylate cyclases (GCs), enzymes that catalyse the formation of cGMP from guanosine 5' triphosphate (GTP) have until recently remained elusive and none of the candidates identified to-date are NO-dependent. Using both a GC and heme-binding domain specific (H-NOX) search motif, we have identified an Arabidopsis flavin monooxygenase (At1g62580) and shown electrochemically that it binds NO, has a higher affinity for NO than for O(2) and that this molecule can generate cGMP from GTP in vitro in an NO-dependent manner. PMID- 21820436 TI - Vasopressin, ATP and catecholamines differentially control potassium secretion in inner ear cell line. AB - A strict control of endolymph composition (high potassium, low sodium fluid) and volume is instrumental for a proper functioning of the inner ear. Alteration of endolymph homeostasis is proposed in the pathogenesis of Meniere's disease. However, the mechanisms controlling endolymph secretion remain elusive. By using the vestibular EC5v cells, we provide evidence for the presence of vasopressin, catecholamine and purinergic signaling pathways, coupled to adenylate cyclase, phosphoinositidase C and Ca(2+) activation. We demonstrate that vasopressin and catecholamines stimulate while ATP inhibits apical potassium secretion by EC5v cells. These results open new interesting perspectives for the management of inner ear diseases. PMID- 21820437 TI - Somatostatin receptor 5 is palmitoylated by the interacting ZDHHC5 palmitoyltransferase. AB - Many G-protein coupled receptors are palmitoylated in their C-terminal, intracellular regions. So far no enzymes responsible for this modification have been described. We identified an interaction of the membrane proximal helix 8 of somatostatin receptor 5 (SSTR5) with the N-terminal region of the putative palmitoyltransferase ZDHHC5 using the Ras recruitment interaction screening system. ZDHHC5 and SSTR5 are colocalized at the plasma membrane and can be efficiently coimmunoprecipitated from transfected cells. Coexpression of ZDHHC5 in HEK293 cells increased palmitoylation of SSTR5 whereas knock-down of endogenous ZDHHC5 by siRNAs decreased it. Our data identify the first palmitoyltransferase for a G-protein coupled receptor. PMID- 21820438 TI - BH3-only protein Bim inhibits activity of antiapoptotic members of Bcl-2 family when expressed in yeast. AB - Proteins of the Bcl-2 family regulate programmed cell death in mammals by promoting the release of cytochrome c from mitochondria in response to various proapoptotic stimuli. The mechanism by which BH3-only members of the family activate multidomain proapoptotic proteins Bax and Bak to form a pore in mitochondrial membranes remains under dispute. We report that cell death promoting activity of BH3-only protein Bim can be reconstituted in yeast when both Bax and antiapoptotic protein Bcl-X(L) are present, suggesting that Bim likely activates Bax indirectly by inhibiting antiapoptotic proteins. PMID- 21820439 TI - Intra-striatal estradiol in female rats impairs response learning within two hours of treatment. AB - Estradiol treatment administered systemically or directly to the dorsolateral striatum across two days impairs performance on a response task in which rats learn to make a specific body turn to locate food on a maze. Estradiol can act through both slow and rapid signaling pathways to regulate learning impairments, however it is impossible to dissociate the slow from the rapid contributions of estradiol following long exposures. To assess the rapid effects of estradiol on striatum-sensitive learning, we trained rats on a response learning task after either relatively short or long treatments of estradiol infused directly into the striatum. Three-month-old female rats were ovariectomized 21 days before training and received guide cannulae implanted bilaterally into the dorsolateral striatum. For short duration treatments, rats were given bilateral infusions (0.5 MUl) of 17beta-estradiol-sulfate (0, 5, 50, or 500 nM in aCSF-vehicle) either 2h or 15 min prior to training. For long duration treatments, rats received a series of estradiol infusions (500 nM) at 48, 24, and 2h prior to training. Replicating previous findings (Zurkovsky et al., 2007), intra-striatal estradiol treatments given for two days prior to training impaired response learning. Estradiol induced impairments in performance were also demonstrated 2h, but not 15 min, after single infusions. Thus, estradiol acts within hours of exposure in the striatum, a structure lacking classical estrogen receptors, to impair response learning. PMID- 21820440 TI - Corticosterone microinjected into nucleus pontis oralis increases tonic immobility in rats. AB - Tonic immobility (TI) is also known as "immobility response", "immobility reflex", "animal hypnosis", etc. It is an innate antipredatory behavior characterized by an absence of movement, varying degrees of muscular activity, and a relative unresponsiveness to external stimuli. Experimentally, TI is commonly produced by manually forcing an animal into an inverted position and restraining it in that position until the animal becomes immobile. Part of the neural mechanism(s) of TI involves the medullo-pontine reticular formation, with influence from other components of the brain, notably the limbic system. It has been observed that TI is more prolonged in stressed animals, and systemic injection of corticosterone (CORT) also potentiates this behavior. At present, the anatomical brain regions involved in the CORT modulation of TI are unknown. Thus, our study was made to determine if some pontine areas could be targets for the modulation of TI by CORT. A unilateral nucleus pontis oralis (PnO) microinjection of 1 MUL of CORT (0.05 MUg/1 MUL) in rats resulted in clear behavioral responses. The animals had an increased duration of TI caused by clamping the neck (in this induction, besides of body inversion and restraint, there is also clamping the neck), with an enhancement in open-field motor activity, which were prevented by pretreatment injection into PnO with 1 MUL of the mineralocorticoid-receptor antagonist spironolactone (0.5 MUg/1 MUL) or 1 MUL of the glucocorticoid-receptor antagonist mifepristone (0.5 MUg/1 MUL). In contrast, these behavioral changes were not seen when CORT (0.05 MUg/1 MUL) was microinjected into medial lemniscus area or paramedian raphe. Our data support the idea that, in stressful situations, glucocorticoids released from adrenals of the prey reach the PnO to produce a hyper arousal state, which in turn can prolong the duration of TI. PMID- 21820441 TI - Serotonin 5-HT2A receptor-mediated hypertrophy is negatively regulated by caveolin-3 in cardiomyoblasts and neonatal cardiomyocytes. AB - The serotonin 5-HT(2A) receptor belongs to the G-protein-coupled receptors (GPCRs) superfamily and mediates the hypertrophic response to serotonin (5-HT) in cardiac myocytes. At present the regulatory mechanisms of 5-HT(2A) receptor induced myocyte hypertrophy are not fully understood. The localization and the compartmentation of GPCRs within specialized membrane microdomains are known to modulate their signalling pathway. Therefore, we hypothesized that caveolae microdomains and caveolin-3, the predominant isoform of cardiac caveolae, might be regulators of 5-HT(2A) receptor signalling. We demonstrate that 5-HT(2A) receptors interact with caveolin-3 upon 5-HT stimulation and traffic into caveolae membrane microdomains. We provide evidence that caveolin-3 knockdown abolishes the redistribution of 5-HT(2A) receptors into caveolae and enhances 5 HT(2A) receptor-induced myocyte hypertrophic markers such as cell size, protein synthesis and ANF gene expression. Importantly, we demonstrate that caveolin-3 and caveolae structures are negative regulators of 5-HT(2A) receptor-induced nuclear factor of activated T cells (NFAT) transcriptional activation. Taken together, our data demonstrate that caveolin-3 and caveolae microdomains are important regulators of the hypertrophic response induced by 5-HT(2A) receptors. These findings thus open new insights to target heart hypertrophy under the enhanced serotonin system. This article is part of a Special Issue entitled "Local Signaling in Myocytes". PMID- 21820442 TI - HIV Tat protein inhibits hERG K+ channels: a potential mechanism of HIV infection induced LQTs. AB - HIV-infected patients have a high prevalence of long QT syndrome (LQTs). hERG K(+) channel encoded by human ether-a-go-go related gene contributes to IKr K(+) currents responsible for the repolarization of cardiomyocytes. Inhibition of hERG K(+) channels leads to LQTs. HIV Tat protein, the virus transactivator protein, plays a pivotal role in AIDS. The aim of the present study is to examine the effects of HIV Tat protein on hERG K(+) channels stably expressed in HEK293 cells. The hERG K(+) currents were recorded by whole-cell patch-clamp technique and the hERG channel expression was measured by real-time PCR and Western blot techniques. HIV Tat protein at 200 ng/ml concentration showed no acute effect on hERG currents, but HIV Tat protein (200 ng/ml) incubation for 24 h significantly inhibited hERG currents. In HIV Tat incubated cells, the inactivation and the recovery time from inactivation of hERG channels were significantly changed. HIV Tat protein incubation (200 ng/ml) for 24h had no effect on the hERG mRNA expression, but dose-dependently inhibited hERG protein expression. The MTT assay showed that HIV Tat protein at 50 ng/ml and 200 ng/ml had no effect on the cell viability. HIV Tat protein increased reactive oxygen species (ROS) generation and the inhibition of hERG channel protein expression by HIV Tat protein was prevented by antioxidant tempol. HIV Tat protein in vivo treatment reduced IKr currents and prolonged action potential duration of guinea pig cardiomyocytes. We conclude that HIV Tat protein inhibits hERG K(+) currents through the inhibition of hERG protein expression, which might be the potential mechanism of HIV infection induced LQTs. PMID- 21820443 TI - Crystal structure of the archaeal asparagine synthetase: interrelation with aspartyl-tRNA and asparaginyl-tRNA synthetases. AB - Asparagine synthetase A (AsnA) catalyzes asparagine synthesis using aspartate, ATP, and ammonia as substrates. Asparagine is formed in two steps: the beta carboxylate group of aspartate is first activated by ATP to form an aminoacyl-AMP before its amidation by a nucleophilic attack with an ammonium ion. Interestingly, this mechanism of amino acid activation resembles that used by aminoacyl-tRNA synthetases, which first activate the alpha-carboxylate group of the amino acid to form also an aminoacyl-AMP before they transfer the activated amino acid onto the cognate tRNA. In a previous investigation, we have shown that the open reading frame of Pyrococcus abyssi annotated as asparaginyl-tRNA synthetase (AsnRS) 2 is, in fact, an archaeal asparagine synthetase A (AS-AR) that evolved from an ancestral aspartyl-tRNA synthetase (AspRS). We present here the crystal structure of this AS-AR. The fold of this protein is similar to that of bacterial AsnA and resembles the catalytic cores of AspRS and AsnRS. The high resolution structures of AS-AR associated with its substrates and end-products help to understand the reaction mechanism of asparagine formation and release. A comparison of the catalytic core of AS-AR with those of archaeal AspRS and AsnRS and with that of bacterial AsnA reveals a strong conservation. This study uncovers how the active site of the ancestral AspRS rearranged throughout evolution to transform an enzyme activating the alpha-carboxylate group into an enzyme that is able to activate the beta-carboxylate group of aspartate, which can react with ammonia instead of tRNA. PMID- 21820445 TI - Model combining hydrodynamics and fractal theory for analysis of in vivo peripheral pulmonary and systemic resistance of shunt cardiac defects. AB - The fractal state of the arterial vascular tree is considered to have a universal dimension related to the principle of minimum work rate, but can demonstrate the capacity to adapt to other dimensions in disease states such as congenital high flow pulmonary hypertension (PH) by a process that is incompletely understood. To document and interpret fractal adaptation in patients with different degrees of PH, pulmonary and systemic vascular resistance was analyzed by a model that evaluated the fractal dimension, x, of the Poiseuille resistance contribution of the arterial vessel radius between 10 and 100MUm, via the proportionality Q?(R(peri)/BL)(-x/4), with Q, R(peri), and BL clinically observed variables representing total pulmonary or systemic blood flow, its peripheral arterial resistance, and body length, respectively. Identification of x in the pulmonary (P) and systemic (S) beds was evaluated from hemodynamic data of 213 patients, categorized into 7 groups by PH grade. In controls without PH, x(P)=2.2 while the dimension increased to 3.0, with the systemic dimension constant at x(S)=3.1. Our model predicts that severe grades of PH are associated with: a more elongated and hindered vessel in the periphery, and reductions in vessel numbers, as unit pulmonary resistive arterial trees (N(1)) and their component intra-acinar arteries (N(W)). These model network changes suggest a complex adaptive process of arterial network reorganization in the pulmonary circulation to minimize the work rate of high-flow congenital heart defects. PMID- 21820446 TI - Oscillatory dynamics in the coevolution of cooperation and mobility. AB - Although cooperation is a fundamental aspect of our society, it has been a longstanding puzzle in biological and social sciences because cooperation is often costly to those who practice it while others benefit. Recent studies have shown that natural selection favors cooperation when cooperators are more likely to interact with each other than with defectors, an effect called positive assortment. It might be that, in the real world, mobility makes positive assortment possible. However, to our knowledge, the coevolutionary dynamics of cooperation and mobility remains poorly understood. In this study, using an individual-based model where both cooperativeness and mobility are evolved under natural selection, we demonstrate that the coevolutionary dynamics results in the oscillation of the frequency of cooperation as long as the benefit-to-cost ratio of cooperation is large. This finding suggests that natural selection favors or fine-tunes a mobility rate by which cooperation can be maintained dynamically in the form of an oscillation without any other high cognitive abilities such as individual identification or memory of the past actions of other individuals. PMID- 21820444 TI - Polymerase chaperoning and multiple ATPase sites enable the E. coli DNA polymerase III holoenzyme to rapidly form initiation complexes. AB - Cellular replicases include three subassemblies: a DNA polymerase, a sliding clamp processivity factor, and a clamp loader complex. The Escherichia coli clamp loader is the DnaX complex (DnaX(3)deltadelta'chipsi), where DnaX occurs either as tau or as the shorter gamma that arises by translational frameshifting. Complexes composed of either form of DnaX are fully active clamp loaders, but tau confers important replicase functions including chaperoning the polymerase to the newly loaded clamp to form an initiation complex for processive replication. The kinetics of initiation complex formation were explored for DnaX complexes reconstituted with varying tau and gamma stoichiometries, revealing that tau mediated polymerase chaperoning accelerates initiation complex formation by 100 fold. Analyzing DnaX complexes containing one or more K51E variant DnaX subunits demonstrated that only one active ATP binding site is required to form initiation complexes, but the two additional sites increase the rate by ca 1000-fold. For tau-containing complexes, the ATP analogue ATPgammaS was found to support initiation complex formation at 1/1000th the rate with ATP. In contrast to previous models that proposed ATPgammaS drives hydrolysis-independent initiation complex formation by tau-containing complexes, the rate and stoichiometry of ATPgammaS hydrolysis coincide with those for initiation complex formation. These results show that although one ATPase site is sufficient for initiation complex formation, the combination of polymerase chaperoning and the binding and hydrolysis of three ATPs dramatically accelerates initiation complex formation to a rate constant (25-50 s(-1)) compatible with double-stranded DNA replication. PMID- 21820447 TI - Hamilton's rule in multi-level selection models. AB - Hamilton's rule is regarded as a useful tool in the understanding of social evolution, but it relies on restrictive, overly simple assumptions. Here we model more realistic situations, in which the traditional Hamilton's rule generally fails to predict the direction of selection. We offer modifications that allow accurate predictions, but also show that these Hamilton's rule type inequalities do not predict long-term outcomes. To illustrate these issues we propose a two level selection model for the evolution of cooperation. The model describes the dynamics of a population of groups of cooperators and defectors of various sizes and compositions and contains birth-death processes at both the individual level and the group level. We derive Hamilton-like inequalities that accurately predict short-term evolutionary change, but do not reliably predict long-term evolutionary dynamics. Over evolutionary time, cooperators and defectors can repeatedly change roles as the favored type, because the amount of assortment between cooperators changes in complicated ways due to both individual-level and group-level processes. The equation that governs the dynamics of cooperator/defector assortment is a certain partial differential equation, which can be solved numerically, but whose behaviour cannot be predicted by Hamilton's rules, because Hamilton's rules only contain first-derivative information. In addition, Hamilton's rules are sensitive to demographic fitness effects such as local crowding, and hence models that assume constant group sizes are not equivalent to models like ours that relax that assumption. In the long-run, the group distribution typically reaches an equilibrium, in which case Hamilton's rules necessarily become equalities. PMID- 21820449 TI - Mas receptors in modulating relaxation induced by perivascular adipose tissue. AB - AIMS: Perivascular adipose tissue (PVAT) is known to secrete vascular relaxation factors, and angiotensin 1-7 [Ang-(1-7)] acting on the endothelium is one of the endothelium-dependent relaxation factors. Mas protein is the receptor for Ang-(1 7). Using aorta from Mas-knockout (K/O) and wild type (FVB) mice, we wished to establish the essential role of Mas receptors in mediating the endothelium dependent relaxation response induced by relaxation factors from PVAT. MAIN METHODS: Thoracic aortic rings from K/O and FVB mice were prepared with or without PVAT (PVAT+ and PVAT-) and/or intact endothelium (E+) or with the endothelium removed (E-) for functional studies. The contraction and relaxation responses of these vessels to agonist in the presence of different receptor antagonists were studied. KEY FINDINGS: PVAT attenuated the contraction induced by phenylephrine (PHE) in the presence of endothelium only in vessels from FVB mice. Mas receptor antagonists D-Ala-Ang-(1-7) (A779) or D-Pro(7)-Ang-(1-7) enhanced the contraction induced by PHE only in vessels from FVB mice. Ang-(1-7) caused a relaxation response only in E+vessels from FVB mice. Transfer of donor solution from PVAT+ vessels to PVAT- recipient vessels caused a relaxation response among FVB vessels and not among vessels from K/O mice. SIGNIFICANCE: Mas receptors are essential in mediating the endothelium-dependent relaxation response induced by PVAT, therefore highlighting the important role of Ang-(1-7) in the control of vascular functions through PVAT. PMID- 21820448 TI - C-type natriuretic peptide does not attenuate the development of pulmonary hypertension caused by hypoxia and VEGF receptor blockade. AB - AIMS: C-type natriuretic peptide (CNP) is a local regulator of vascular tone and remodeling in many vascular beds. However, the role of CNP in modulating pulmonary arterial hypertensive and vascular remodeling responses is unclear. The purpose of this study was to determine if CNP is capable of preventing the development of pulmonary hypertension (PH). MAIN METHODS: We used animal models of PH caused by chronic hypoxia alone or in combination with the vascular endothelial growth factor (VEGF) receptor blocker SU5416. We measured pulmonary hemodynamics, right ventricular hypertrophy and vascular remodeling effects in response to a continuous infusion of low dose or high dose CNP or vehicle placebo. KEY FINDINGS: Right ventricular hypertrophy and a marked elevation in right ventricular systolic pressure (RVSP) were seen in both models of PH. Rats treated with the combination of SU5416 and chronic hypoxia also developed pulmonary endothelial hyperproliferative lesions. Continuous intravenous infusion of CNP at either dose did not attenuate the development of PH, right ventricular hypertrophy or vascular remodeling in either of the models of PH despite a three fold increase in serum CNP levels. SIGNIFICANCE: CNP does not prevent the development of PH in the chronic hypoxia or SU5416 plus hypoxia models of pulmonary hypertension suggesting that CNP may not play an important modulatory role in human PH. PMID- 21820450 TI - Modulation of endothelial cell network formation in vitro by molecular signaling of head and neck squamous cell carcinoma (HNSCC) exposed to cetuximab. AB - Overexpression of EGFR plays a key-role in head and neck squamous cell carcinoma (HNSCC) and justifies the extensive use of cetuximab, a monoclonal anti-EGFR antibody, as well as EGFR-tyrosine kinase inhibitors (EGFR-TKI), which have been reported to inhibit tumor cell growth and the secretion of pro-angiogenic factors by tumor cells, such as VEGF and IL-8. Moreover, vessel normalization in tumors, suggesting a more complex mediation of endothelial cell growth control has also been observed in vivo. The present study was designed to investigate the angiogenic consequences of exposure of HNSCC tumor cell lines to cetuximab and intercellular signaling between tumor and endothelial cells by secretion of pro- and anti-angiogenic mediators in the conditioned media (CM). The results achieved showed that cetuximab decreased the secretion of VEGF by HNSCC cells and that exposure of human umbilical vein endothelial cells (HUVEC) to CM from HNSCC cells exposed to cetuximab induced an increase in endothelial cell network formation. Angiogenesis proteome profiling showed that cetuximab induced a complex alteration of the secretion of pro- and anti-angiogenic factors by HNSCC cells without enabling to identify a unique molecular marker. Expression of endothelial membrane receptors (VEGFR-2, EGFR, PECAM-1 and Notch-4) was investigated and only EGFR expression was found influenced when HUVEC were exposed to CM from cetuximab exposed HNSCC cells. These results showed that the decrease in the secretion of pro-angiogenic agents like VEGF by HNSCC cells exposed to cetuximab could not be sufficient to justify its anti-angiogenic activity in vitro. PMID- 21820451 TI - Competitive binding at a nicotinic receptor transmembrane site of two alpha7 selective positive allosteric modulators with differing effects on agonist-evoked desensitization. AB - Positive allosteric modulators (PAMs) of nicotinic acetylcholine receptors (nAChRs) have attracted considerable interest as a novel area of therapeutic drug discovery. Two types of alpha7-selective PAMs have been identified (type I and type II). Whilst both potentiate peak agonist-induced responses, they have different effects on the rate of agonist-induced receptor desensitization. Type I PAMs have little or no effect on the rapid rate of desensitization that is characteristic of alpha7 nAChRs, whereas type II PAMs cause dramatic slowing of receptor desensitization. Previously, we have obtained evidence indicating that PNU-120596, a type II PAM, causes potentiation by interacting with an allosteric transmembrane site. In contrast, other studies have demonstrated the importance of the 'M2-M3 segment' in modulating the effects of the type I PAM NS1738 and have led to the proposal that NS1738 may interact with the extracellular N terminal domain. Here, our aim has been to compare the mechanism of allosteric potentiation of alpha7 nAChRs by NS1738 and PNU-120596. Functional characterization of a series of mutated alpha7 nAChRs indicates that mutation of amino acids within a proposed intrasubunit transmembrane cavity have a broadly similar effect on these two PAMs. In addition, we have employed a functional assay designed to examine the ability of ligands to act competitively at either the orthosteric or allosteric binding site of alpha7 nAChRs. These data, together with computer docking simulations, lead us to conclude that both the type I PAM NS1738 and the type II PAM PNU-120596 bind competitively at a mutually exclusive intrasubunit transmembrane site. PMID- 21820452 TI - Susceptibility to the long-term anxiogenic effects of an acute stressor is mediated by the activation of the glucocorticoid receptors. AB - The specificity of the response of an organism is an important variable influencing stress-related parameters and psychopathological states. We have shown that trait anxiety in C57BL/6 mice, determined by their emergence latencies in the free choice open field test, positively correlates with the long-term behavioral and neuroendocrinological changes induced by a stressor. Here, we show that this interindividual variability is caused by a different reactivity of the hypothalamus-pituitary-adrenal (HPA) axis upon exposure to a stressor. Mice with high trait anxiety (long emergence latency, LEL) display a more pronounced stress induced activation of the HPA axis than mice with low trait anxiety (short emergence latency, SEL). Moreover, stress-induced activation of tyrosine hydroxylase and corticotropin-releasing hormone occurred in LEL but not SEL mice. In search of the molecular mechanisms underlying these differences, we found that under non-stressed conditions mRNA and protein levels of the glucocorticoid receptor in the hippocampus were higher in LEL mice compared to SEL mice. Also, systemic injection of the glucocorticoid receptor antagonist RU486 decreased the stress-induced activation of the HPA axis and the long-term anxiogenic effects of stress observed in LEL mice. Finally, the rewarding properties of cocaine were enhanced in LEL mice compared to SEL mice, suggesting a causal link between trait anxiety, stress activity and the behavioral responses to drugs of addiction. PMID- 21820453 TI - Acetylcholinesterase inhibitors rapidly activate Trk neurotrophin receptors in the mouse hippocampus. AB - Acetylcholinesterase inhibitors are first-line therapies for Alzheimer's disease. These drugs increase cholinergic tone in the target areas of the cholinergic neurons of the basal forebrain. Basal forebrain cholinergic neurons are dependent upon trophic support by nerve growth factor (NGF) through its neurotrophin receptor, TrkA. In the present study, we investigated whether the acetylcholinesterase inhibitors donepezil and galantamine could influence neurotrophin receptor signaling in the brain. Acute administration of donepezil (3 mg/kg, i.p.) led to the rapid autophosphorylation of TrkA and TrkB neurotrophin receptors in the adult mouse hippocampus. Similarly, galantamine dose-dependently (3, 9 mg/kg, i.p.) increased TrkA and TrkB phosphorylation in the mouse hippocampus. Both treatments also increased the phosphorylation of transcription factor CREB and tended to increase the phosphorylation of AKT kinase but did not alter the activity of MAPK42/44. Chronic treatment with galantamine (3 mg/kg, i.p., 14 days), did not induce changes in hippocampal NGF and BDNF synthesis or protein levels. Our findings show that acetylcholinesterase inhibitors are capable of rapidly activating hippocampal neurotrophin signaling and thus suggest that therapies targeting Trk signaling may already be in clinical use in the treatment of AD. PMID- 21820454 TI - Hippocampal AMPA autoreceptors positively coupled to NMDA autoreceptors traffic in a constitutive manner and undergo adaptative changes following enriched environment training. AB - alpha-Amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) autoreceptors exist on glutamate hippocampal terminals. Aimed at investigating whether these autoreceptors traffic constitutively, (S)AMPA-evoked [(3)H]D-ASP release from synaptosomes enriched with peptides that impede the interaction of GluA2 subunits with cytosolic proteins involved in receptor movements [namely Glutamate Receptor Interacting Protein (GRIP), Protein Interacting with C kinase 1 (PICK1), N-ethyl maleimide-Sensitive Fusion protein NSF proteins] was monitored. (S)AMPA alone had no effect on the spontaneous release of [(3)H]D-ASP from control synaptosomes, but became efficacious in the presence of cyclothiazide or when preventing GluA2/GRIP/PICK1, but not GluA2/NSF, interaction. Hippocampal glutamatergic terminals also possess NMDA autoreceptors. 10 MUM NMDA/1 MUM glycine-induced [(3)H]D-ASP release was concentration-dependently increased by (S)AMPA. Cyclothiazide potentiated the 10 MUM NMDA/1 MUM glycine/50 MUM (S)AMPA-induced [(3)H]D-ASP overflow, while NBQX halved and MK-801 abolished it, suggesting NMDA AMPA autoreceptor cross-talk. Western Blot analysis of sub-synaptic fractions confirmed presynaptic GluN2B-GluA2/3 co-localization. Impeding GluA2/GRIP/PICK1 interaction facilitated the NMDA/glycine/(S)AMPA-induced release of [(3)H]D-ASP, while competing for GluA2/NSF interaction reduced it, indicating that NMDA receptor favours AMPA receptor insertion in synaptosomal plasmamembranes. Finally, rearing mice in enriched environment unveiled the (S)AMPA-induced release of [(3)H]D-ASP, but leaved unmodified that caused by NMDA/glycine. The NBQX-sensitive, 50 MUM (S)AMPA-evoked release of [(3)H]D-ASP was insensitive to cyclothiazide and to peptide interfering with GluA2/GRIP/PICK1 interaction but was addictive to that caused by NMDA/glycine. Presynaptic GluA2/3 immunoreactivity in EE hippocampal terminals was increased, while GluN2B was unchanged. We conclude that hippocampal AMPA autoreceptors positively coupled to NMDA autoreceptors traffic in a constitutive manner and undergo functional up regulation in EE animals. PMID- 21820455 TI - Tracking problem solving by multivariate pattern analysis and Hidden Markov Model algorithms. AB - Multivariate pattern analysis can be combined with Hidden Markov Model algorithms to track the second-by-second thinking as people solve complex problems. Two applications of this methodology are illustrated with a data set taken from children as they interacted with an intelligent tutoring system for algebra. The first "mind reading" application involves using fMRI activity to track what students are doing as they solve a sequence of algebra problems. The methodology achieves considerable accuracy at determining both what problem-solving step the students are taking and whether they are performing that step correctly. The second "model discovery" application involves using statistical model evaluation to determine how many substates are involved in performing a step of algebraic problem solving. This research indicates that different steps involve different numbers of substates and these substates are associated with different fluency in algebra problem solving. PMID- 21820456 TI - The display of paced mating behavior in a rat model of endometriosis. AB - Endometriosis is a disorder associated with chronic pelvic pain and ill effects on women's sexual health. The present study examined the effects of pelvic endometriotic implants on the display of paced mating behavior in female rats. Approximately 2 months after the surgical induction of endometriosis, rats were tested for paced mating behavior during proestrus (Experiment 1) or after bilateral ovariectomy and hormone replacement (Experiment 2). Although endometriotic implants were confirmed at autopsy, rats with surgical endometriosis in both experiments exhibited normal patterns of paced mating behavior. The positive relationship between implant material and contact-return latency following ejaculation in Experiment 2 suggests that the sensitivity to vigorous mating stimulation may be influenced by endometriosis. PMID- 21820457 TI - Cytotoxic and haemolytic steroidal glycosides from the Caribbean sponge Pandaros acanthifolium. AB - Six new steroidal saponins, pandarosides K-M (1-3) and their methyl esters (4-6), were isolated as minor components, after a careful chemical reinvestigation of the Caribbean sponge Pandaros acanthifolium. Their structures were established on the basis of spectroscopic analyses and comparison with the data obtained from previous metabolites of this family. All new compounds showed moderate to weak activity against four parasitic protozoa. Additionally, these compounds and previously reported pandarosides and acanthifoliosides were tested on three human tumour cell lines, and their haemolytic and liposome permeabilizing activity were assessed. Two pandarosides exhibited moderate to strong cytotoxic effect, while three acanthifoliosides showed strong haemolytic activity. PMID- 21820458 TI - Regioselective oxidation of cholic acid and its 7beta epimer by using o iodoxybenzoic acid. AB - Rational exploration directed by DFT (density functional theory) based atomic Fukui indices, lead to development of regioselective oxidation of cholic acid and its 7beta epimer by o-iodoxybenzoic acid. In case of cholic acid only, 7alpha hydroxyl underwent oxidation, where as in its 7beta epimer the selectivity was towards 12alpha-hydroxy group. Since these oxidations are the key steps in synthesis of ursodeoxycholic acid starting from cholic acid these findings may be useful in devising a protection free synthetic route. PMID- 21820460 TI - Distribution of bisphenol A into tissues of adult, neonatal, and fetal Sprague Dawley rats. AB - Bisphenol A (BPA) is an important industrial chemical used in the manufacture of polycarbonate plastic products and epoxy resin-based food can liners. The presence of BPA metabolites in urine of >90% of Americans aged 6-60 suggests ubiquitous and frequent exposure in the range of 0.02-0.2MUg/kgbw/d (25th-95th percentiles). The current study used LC/MS/MS to measure placental transfer and concentrations of aglycone (receptor-active) and conjugated (inactive) BPA in tissues from Sprague-Dawley rats administered deuterated BPA (100MUg/kg bw) by oral and IV routes. In adult female rat tissues, the tissue/serum concentration ratios for aglycone BPA ranged from 0.7 in liver to 5 in adipose tissue, reflecting differences in tissue perfusion, composition, and metabolic capacity. Following IV administration to dams, placental transfer was observed for aglycone BPA into fetuses at several gestational days (GD), with fetal/maternal serum ratios of 2.7 at GD 12, 1.2 at GD 16, and 0.4 at GD 20; the corresponding ratios for conjugated BPA were 0.43, 0.65, and 3.7. These ratios were within the ranges observed in adult tissues and were not indicative of preferential accumulation of aglycone BPA or hydrolysis of conjugates in fetal tissue in vivo. Concentrations of aglycone BPA in GD 20 fetal brain were higher than in liver or serum. Oral administration of the same dose did not produce measurable levels of aglycone BPA in fetal tissues. Amniotic fluid consistently contained levels of BPA at or below those in maternal serum. Concentrations of aglycone BPA in tissues of neonatal rats decreased with age in a manner consistent with the corresponding circulating levels. Phase II metabolism of BPA increased with fetal age such that near-term fetus was similar to early post-natal rats. These results show that concentrations of aglycone BPA in fetal tissues are similar to those in other maternal and neonatal tissues and that maternal Phase II metabolism, especially following oral administration, and fetal age are critical in reducing exposures to the fetus. PMID- 21820459 TI - Arsenic transformation predisposes human skin keratinocytes to UV-induced DNA damage yet enhances their survival apparently by diminishing oxidant response. AB - Inorganic arsenic and UV, both human skin carcinogens, may act together as skin co-carcinogens. We find human skin keratinocytes (HaCaT cells) are malignantly transformed by low-level arsenite (100nM, 30weeks; termed As-TM cells) and with transformation concurrently undergo full adaptation to arsenic toxicity involving reduced apoptosis and oxidative stress response to high arsenite concentrations. Oxidative DNA damage (ODD) is a possible mechanism in arsenic carcinogenesis and a hallmark of UV-induced skin cancer. In the current work, inorganic arsenite exposure (100nM) did not induce ODD during the 30weeks required for malignant transformation. Although acute UV-treatment (UVA, 25J/cm(2)) increased ODD in passage-matched control cells, once transformed by arsenic to As-TM cells, acute UV actually further increased ODD (>50%). Despite enhanced ODD, As-TM cells were resistant to UV-induced apoptosis. The response of apoptotic factors and oxidative stress genes was strongly mitigated in As-TM cells after UV exposure including increased Bcl2/Bax ratio and reduced Caspase-3, Nrf2, and Keap1 expression. Several Nrf2-related genes (HO-1, GCLs, SOD) showed diminished responses in As-TM cells after UV exposure consistent with reduced oxidant stress response. UV-exposed As-TM cells showed increased expression of cyclin D1 (proliferation gene) and decreased p16 (tumor suppressor). UV exposure enhanced the malignant phenotype of As-TM cells. Thus, the co-carcinogenicity between UV and arsenic in skin cancer might involve adaptation to chronic arsenic exposure generally mitigating the oxidative stress response, allowing apoptotic by-pass after UV and enhanced cell survival even in the face of increased UV-induced oxidative stress and increased ODD. PMID- 21820461 TI - Properties and cDNA cloning of a hyaluronidase from the stonefish Synanceia verrucosa venom. AB - The venoms of two classes of fish, freshwater stingray (members of the genus Potamotrygon) and stonefish (members of the genus Synanceia), contain not only proteinaceous toxins but also hyaluronidases, which are considered as spreading factors that facilitate the tissue diffusion of toxins by degrading hyaluronan. So far, the freshwater stingray Potamotrygon motoro hyaluronidase and the stonefish Synanceia horrida hyaluronidase (SFHYA1) have been purified and characterized, although their spreading activity is still unclear. In this study, a 59 kDa hyaluronidase was partially purified from the stonefish Synanceia verrucosa and shown to be optimally active at pH 6.6, 37 degrees C and 0.15 M NaCl. Importantly, the S. verrucosa hyaluronidase enhanced the capillary permeability-increasing activity of the S. verrucosa toxin (neoverrucotoxin), providing evidence for its spreading activity. Furthermore, the primary structure of the S. verrucosa hyaluronidase was elucidated by cDNA cloning. The S. verrucosa hyaluronidase (463 amino acid residues) shares as high as 92% sequence identity with SFHYA1 but less than 50% with other hyaluronidases. Nevertheless, one catalytic residue and four substrate positioning residues, which constitute the active site of human hyaluronidases, are conserved in the S. verrucosa hyaluronidase. PMID- 21820462 TI - Aging, longevity and health. AB - The IARU Congress on Aging, Longevity and Health, held on 5-7 October 2010 in Copenhagen, Denmark, was hosted by Rector Ralf Hemmingsen, University of Copenhagen and Dean Ulla Wewer, Faculty of Health Sciences, University of Copenhagen and was organized by Center for Healthy Aging (CEHA) under the leadership of CEHA Managing Director Lene Juel Rasmussen and Prof. Vilhelm Bohr, National Institute on Aging, NIH, Baltimore, USA (associated to CEHA). The Congress was attended by approximately 125 researchers interested in and/or conducting research on aging and aging-related topics. The opening Congress Session included speeches by Ralf Hemmingsen, Ulla Wewer, and Lene Juel Rasmussen and Keynote Addresses by four world renowned aging researchers: Povl Riis (The Age Forum), Bernard Jeune (University of Southern Denmark), George Martin (University of Washington, USA) and Jan Vijg (Albert Einstein School of Medicine, USA) as well as a lecture discussing the art-science interface by Thomas Soderqvist (Director, Medical Museion, University of Copenhagen). The topics of the first six Sessions of the Congress were: Neuroscience and DNA damage, Aging and Stress, Life Course, Environmental Factors and Neuroscience, Muscle and Life Span and Life Span and Mechanisms. Two additional Sessions highlighted ongoing research in the recently established Center for Healthy Aging at the University of Copenhagen. This report highlights outcomes of recent research on aging related topics, as described at the IARU Congress on Aging, Longevity and Health. PMID- 21820463 TI - Insulin-like growth factor binding protein-6 delays replicative senescence of human fibroblasts. AB - Cellular senescence can be induced by a variety of mechanisms, and recent data suggest a key role for cytokine networks to maintain the senescent state. Here, we have used a proteomic LC-MS/MS approach to identify new extracellular regulators of senescence in human fibroblasts. We identified 26 extracellular proteins with significantly different abundance in conditioned media from young and senescent fibroblasts. Among these was insulin-like growth factor binding protein-6 (IGFBP-6), which was chosen for further analysis. When IGFBP-6 gene expression was downregulated, cell proliferation was inhibited and apoptotic cell death was increased. Furthermore, downregulation of IGFBP-6 led to premature entry into cellular senescence. Since IGFBP-6 overexpression increased cellular lifespan, the data suggest that IGFBP-6, in contrast to other IGF binding proteins, is a negative regulator of cellular senescence in human fibroblasts. PMID- 21820464 TI - Effects of sensitization on the detection of an instrumental contingency. AB - While prior exposure to drugs of abuse permanently changes many behaviors, the underlying psychological mechanisms are relatively obscure. Here, the effects of sensitization on the detection of an action-outcome relationship were assessed, using a particularly stringent contingency degradation procedure. Rats were trained to leverpress until the probability of reinforcement for a response on one lever, or alternative reinforcement for a response on a second lever was reduced to 0.05 per second. Sensitization was then carried out (1mg/kg d amphetamine/day for 7 days). Then, one reinforcer was also made available for a lack of response on either lever (p=0.05/s), maintaining its contiguity with the original response but eliminating its contingent relationship. Sensitized animals were more active, particularly early in the contingency degradation phase, but reduced responding directed at the degraded action-outcome contingency at a similar rate as controls. However, controls also reduced responding directed at the nondegraded contingency until very late in training, while sensitized animals maintained nondegraded responding at baseline levels. It was suggested that the relatively specific response shown by sensitized animals may reflect either improved action-outcome utilization or discrimination of relevant task features. PMID- 21820465 TI - Breast cancer screening for women ages 50 to 69 years a systematic review of observational evidence. AB - OBJECTIVE: To systematically review the observational evidence concerning the effect of screening on breast cancer mortality in actual populations of women ages 50-69 years. METHODS: We searched MEDLINE and multiple reference lists for relevant cohort and ecologic studies. At least 2 authors reviewed abstracts and full texts of studies meeting eligibility criteria. We rated each accepted study on standard quality criteria and developed a Summary Evidence Table. RESULTS: Seventeen studies met eligibility criteria. Five studies found no to small effect of screening (0-12% relative risk reduction [RRR] in breast cancer mortality), 4 found a large effect (greater than 33% RRR), and 8 found a moderate effect (13% to 33% reduction). The authors found concerns about quality in all studies. There was insufficient evidence to determine whether the effectiveness of screening is decreasing over time. CONCLUSIONS: Current observational evidence shows that breast cancer screening in actual populations of women ages 50 to 69 reduces breast cancer mortality; the magnitude of the effect is probably smaller than predicted in the randomized controlled trials. Because the magnitude may change (either increase or decrease) in the future, further ecologic studies are needed. The methodology and infrastructure for these studies should be improved. PMID- 21820466 TI - Associations of objectively-assessed physical activity and sedentary time with depression: NHANES (2005-2006). AB - BACKGROUND: Studies provide conflicting evidence for the protective effects of moderate-to-vigorous-intensity physical activity on depression. Recent evidence suggests that sedentary behaviors may also be associated with depression. PURPOSE: To examine the associations of accelerometer-derived moderate-to vigorous-intensity physical activity and sedentary time with depression among a population-based sample. METHODS: Cross-sectional study using 2,862 adults from the 2005-2006 US National Health and Nutrition Examination Survey. ActiGraph accelerometers were used to derive both moderate-to-vigorous-intensity physical activity and sedentary time. RESULTS: Depression occurred in 6.8% of the sample. For moderate-to-vigorous-intensity physical activity, compared with those in quartile 1 (least active), significantly lower odds of depression were observed for those participants in quartiles 2 (OR=0.55, 95% CI, 0.34 to 0.89), 3 (OR=0.49, 95% CI, 0.26 to 0.93), and 4 (most active) (OR=0.37, 95% CI, 0.20 to 0.70) (p for trend p<0.01). In overweight/obese participants only, those in quartile 4 (most sedentary) had significantly higher odds for depression than those in quartile 1 (least sedentary) [quartile 3 vs 1 (OR=1.94, 95% CI, 1.01 to 3.68) and 4 vs 1 (OR=3.09, 95% CI, 1.25 to 7.68)]. CONCLUSION: The current study identified lower odds of depression were associated with increasing moderate-to vigorous-intensity physical activity and decreasing sedentary time, at least within overweight/obese adults. PMID- 21820467 TI - 4-(Ethoxycarbonyl) phenyl-1-amino-oxobutanoic acid-chitosan complex as a new matrix for silver nanocomposite film: preparation, characterization and antibacterial activity. AB - The present work describes the preparation of new chitosan complex with 4 (ethoxycarbonyl) phenyl-1-amino-oxobutanoic acid (ETHA), as a matrix for silver nanoparticles to obtain a nanocomposite film by solution casing method. The characterization of the prepared nanocomposite film was made by Fourier transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD), differential scanning calorimetry (DSC), thermogravimetry (TG) and scanning electron microscopy (SEM). The optical property of nanocomposite film was analyzed by UV-Visible and photo luminescence (PL) spectroscopy. The nanocomposite film was screen for antibacterial activity with Staphylococcus aureus (gram positive), Pseudomonas aurigionasa (gram negative) and Escherichia coli (gram negative) bacteria by adopting the disk diffusion method. The result of antibacterial study revealed that the prepared nanocomposite film may be a promising candidate for wide range of bio-medical applications. PMID- 21820468 TI - Detection of oseltamivir sensitive/resistant strains of pandemic influenza A virus (H1N1) from patients admitted to hospitals in Thailand. AB - Oseltamivir has been used widely for prophylaxis or treatment during outbreaks of the pandemic influenza virus (H1N1) in several countries. The aim of this study was to develop a real-time RT-PCR (reverse transcription-polymerase chain reaction) to be applied for detection and monitoring of the oseltamivir resistant strains of this virus during three outbreaks (May 2009 to October 2010) in Thailand. The real-time RT-PCR assay for detecting H275Y proved highly specific for the pandemic influenza virus (H1N1) as no cross-amplification was detected with other respiratory viruses or human total RNA. The assay was also highly sensitive with a detection limit as low as 100 copies/MUL for both wild-type and resistant strains. The performance of the assay was evaluated in terms of amplification efficiency (100%). The results obtained by real-time RT-PCR were in complete agreement with direct nucleotide sequencing. However, real-time RT-PCR provided more detail on the relative quantities of ratios between resistant and sensitive strains in each individual. The results revealed that four of 1288 (0.31%) patients were infected with the oseltamivir resistant strain. The number of patients infected by resistant strains was higher during the third (0.61%) and second (0.24%) waves than during the first (0%) outbreak. In conclusion, the real time RT-PCR assay for H275Y detection is advantageous because it is specific, sensitive, and provides quantitative data. And it would be useful for large-scale testing and monitoring of oseltamivir resistant strains of the pandemic influenza A virus (H1N1). PMID- 21820470 TI - A DNA vaccine encoding foot-and-mouth disease virus B and T-cell epitopes targeted to class II swine leukocyte antigens protects pigs against viral challenge. AB - Development of efficient and safer vaccines against foot-and-mouth disease virus (FMDV) is a must. Previous results obtained in our laboratory have demonstrated that DNA vaccines encoding B and T cell epitopes from type C FMDV, efficiently controlled virus replication in mice, while they did not protect against FMDV challenge in pigs, one of the FMDV natural hosts. The main finding of this work is the ability to improve the protection afforded in swine using a new DNA vaccine prototype (pCMV-APCH1BTT), encoding FMDV B and T-cell epitopes fused to the single-chain variable fragment of the 1F12 mouse monoclonal antibody that recognizes Class-II Swine Leukocyte antigens. Half of the DNA-immunized pigs were fully protected upon viral challenge, while the remaining animals were partially protected, showing a delayed, shorter and milder disease than control pigs. Full protection in a given vaccinated-pig correlated with the induction of specific IFNgamma-secreting T-cells, detectable prior to FMDV-challenge, together with a rapid development of neutralizing antibodies after viral challenge, pointing towards the relevance that both arms of the immune response can play in protection. Our results open new avenues for developing future FMDV subunit vaccines. PMID- 21820472 TI - Cardiotonic steroids trigger non-classical testosterone signaling in Sertoli cells via the alpha4 isoform of the sodium pump. AB - The alpha4 isoform of the Na(+),K(+)-ATPase (sodium pump) is known to be expressed in spermatozoa and to be critical for their motility. In the investigation presented here, we find that the rat-derived Sertoli cell line 93RS2 also expresses considerable amounts of the alpha4 isoform in addition to the alpha1 isoform. Since Sertoli cells are not motile, one can assume that the function of the alpha4 isoform in these cells must differ from that in spermatozoa. Thus, we assessed a potential involvement of this isoform in signaling pathways that are activated by the cardiotonic steroid (CTS) ouabain, a highly specific sodium pump ligand. Treatment of 93RS2 cells with ouabain leads to activation of the c-Src/c-Raf/Erk1/2 signaling cascade. Furthermore, we show for the first time that the activation of this cascade by ouabain results in phosphorylation and activation of the transcription factor CREB. This signaling cascade is induced at low nanomolar concentrations of ouabain, consistent with the involvement of the alpha4 isoform. This is further supported by experiments involving siRNA: silencing of alpha4 expression entirely blocks ouabain-induced activation of Erk1/2 whereas silencing of alpha1 has no effect. The findings of this study unveil new aspects in CTS/sodium pump interactions by demonstrating for the first time ouabain-induced signaling through the alpha4 isoform. The c Src/c-Raf/Erk1/2/CREB cascade activated by ouabain is identical to the so-called non-classical signaling cascade that is normally triggered in Sertoli cells by testosterone. Taking into consideration that CTS are produced endogenously, our results may help to gain new insights into the physiological mechanisms associated with male fertility and reproduction. PMID- 21820471 TI - Inhibitors of SARS-CoV entry--identification using an internally-controlled dual envelope pseudovirion assay. AB - Severe acute respiratory syndrome-associated coronavirus (SARS-CoV) emerged as the causal agent of an endemic atypical pneumonia, infecting thousands of people worldwide. Although a number of promising potential vaccines and therapeutic agents for SARS-CoV have been described, no effective antiviral drug against SARS CoV is currently available. The intricate, sequential nature of the viral entry process provides multiple valid targets for drug development. Here, we describe a rapid and safe cell-based high-throughput screening system, dual envelope pseudovirion (DEP) assay, for specifically screening inhibitors of viral entry. The assay system employs a novel dual envelope strategy, using lentiviral pseudovirions as targets whose entry is driven by the SARS-CoV Spike glycoprotein. A second, unrelated viral envelope is used as an internal control to reduce the number of false positives. As an example of the power of this assay a class of inhibitors is reported with the potential to inhibit SARS-CoV at two steps of the replication cycle, viral entry and particle assembly. This assay system can be easily adapted to screen entry inhibitors against other viruses with the careful selection of matching partner virus envelopes. PMID- 21820473 TI - Ghrelin inhibited serotonin release from hippocampal slices. AB - Ghrelin (Ghr) is a peptide produced peripherally and centrally. It participates in the modulation of different biological processes. In our laboratory we have shown that (a) Ghr administration, either intracerebroventricular or directly into the hippocampus enhanced memory consolidation in a step down test in rats (b) the effect of Ghr upon memory decreases in animals pretreated with a serotonin (5-HT) reuptake inhibitor, Fluoxetine, suggesting that Ghr effects in the hippocampus could be related to the availability of 5-HT. It has been demonstrated that Ghr inhibits 5-HT release from rat hypothalamic synaptosomes. Taking in mint these evidences, we studied the release of radioactive 5-HT to the superfusion medium from hippocampal slices treated with two doses of Ghr (0.3 and 3 nm/MUl). Ghr inhibited significantly the 5-HT release in relation to those superfused with artificial cerebrospinal fluid (ACSF) (H = 9.48, df = 2, p <= 0.05). In another set of experiments, Ghr was infused into the CA1 area of hippocampus of the rats immediately after training in the step down test and the 5-HT release from slices was studied 24h after Ghr injection showing that in this condition also the 5-HT release was inhibited (H = 11.72, df = 1, p <= 0.05). In conclusion, results provide additional evidence about the neurobiological bases of Ghr action in hippocampus. PMID- 21820469 TI - Lymphocytic choriomeningitis virus (LCMV) infection of macaques: a model for Lassa fever. AB - Arenaviruses such as Lassa fever virus (LASV) and lymphocytic choriomeningitis virus (LCMV) are benign in their natural reservoir hosts, and can occasionally cause severe viral hemorrhagic fever (VHF) in non-human primates and in human beings. LCMV is considerably more benign for human beings than Lassa virus, however certain strains, like the LCMV-WE strain, can cause severe disease when the virus is delivered as a high-dose inoculum. Here we describe a rhesus macaque model for Lassa fever that employs a virulent strain of LCMV. Since LASV must be studied within Biosafety Level-4 (BSL-4) facilities, the LCMV-infected macaque model has the advantage that it can be used at BSL-3. LCMV-induced disease is rarely as severe as other VHF, but it is similar in cases where vascular leakage leads to lethal systemic failure. The LCMV-infected macaque has been valuable for describing the course of disease with differing viral strains, doses and routes of infection. By monitoring system-wide changes in physiology and gene expression in a controlled experimental setting, it is possible to identify events that are pathognomonic for developing VHF and potential treatment targets. PMID- 21820474 TI - Registration of influenza vaccines for children in Europe. AB - Current trivalent inactivated influenza vaccines (TIV) for seasonal use have all been licensed in the EU based on serological data only. European Medicines Agency (EMA) guidelines for development of influenza vaccines and acceptance criteria are in place for adults but not for children. The Paediatric Committee initiated a review of the literature on influenza vaccines for children, which led to the conclusion that for new influenza vaccines the Paediatric Investigation Plan (PIP) will need to include an efficacy trial. A review of the serological assays raised questions on the relevance of the current assays for children and on the methodological differences in the performance of the neutralisation test. The basis for the current correlate for immune protection is been discussed and the role of antibodies to the neuraminidase for protection against disease has increasingly been recognised. These considerations, together with the experiences gathered during the pandemic, resulted in an ongoing revision of the EMA guidelines for influenza vaccines to be replaced by a single guideline with the aim of having better characterised influenza vaccines that will also address the needs of children. PMID- 21820475 TI - A polyvalent hybrid protein elicits antibodies against the diverse allelic types of block 2 in Plasmodium falciparum merozoite surface protein 1. AB - Merozoite surface protein 1 (MSP1) of Plasmodium falciparum has been implicated as an important target of acquired immunity, and candidate components for a vaccine include polymorphic epitopes in the N-terminal polymorphic block 2 region. We designed a polyvalent hybrid recombinant protein incorporating sequences of the three major allelic types of block 2 together with a composite repeat sequence of one of the types and N-terminal flanking T cell epitopes, and compared this with a series of recombinant proteins containing modular sub components and similarly expressed in Escherichia coli. Immunogenicity of the full polyvalent hybrid protein was tested in both mice and rabbits, and comparative immunogenicity studies of the sub-component modules were performed in mice. The full hybrid protein induced high titre antibodies against each of the major block 2 allelic types expressed as separate recombinant proteins and against a wide range of allelic types naturally expressed by a panel of diverse P. falciparum isolates, while the sub-component modules had partial antigenic coverage as expected. This encourages further development and evaluation of the full MSP1 block 2 polyvalent hybrid protein as a candidate blood-stage component of a malaria vaccine. PMID- 21820476 TI - Seasonal influenza: the burden of disease in children. AB - During the past decade, accumulating data on the impact of influenza virus related disease in children have become available. In this review, we summarize and discuss these data. We conclude that mortality due to influenza in children is relatively limited. But, in contrast, influenza-related hospitalizations occur frequently. The bulk of the influenza-related disease burden is experienced in the outpatient setting. This results in sometimes very high consultation rates, frequent complications, and substantial parental work absenteeism. PMID- 21820477 TI - Cost-effectiveness and socio-economic aspects of childhood influenza vaccination. AB - Children have high rates of healthcare utilization due to influenza. In addition, children also transmit influenza to others in their households and the community. The costs of influenza in children include the direct medical care costs from increased outpatient visits and hospitalizations, and also indirect costs due to productivity losses especially for their parents and due to transmission of the virus to others. A variety of studies using different methods and assumptions have assessed the cost-effectiveness of influenza vaccination of children, and many find that vaccination is either cost saving or cost effective. PMID- 21820478 TI - Different influenza vaccine formulations and adjuvants for childhood influenza vaccination. AB - Pediatric influenza is a very common disease: attack rates range from 23% to 48% during interpandemic years and are significantly higher during pandemics. Influenza-related complications seem to be more common in children at risk because of an underlying chronic severe disease, but recently collected data clearly demonstrate that otherwise healthy children can also suffer from severe influenza and that the annual number of deaths is no different between the two groups. The aim of this review is to discuss the characteristics of all influenza vaccines in order to evaluate the real likelihood of prevention, as well as the safety and tolerability of the different formulations and adjuvants. The data indicate that further studies collecting efficacy and effectiveness data and evaluating the immunogenicity and safety of the different formulations and adjuvants should lead to the identification of more ideal influenza vaccines that could be used with significant advantage in the entire pediatric population. PMID- 21820479 TI - Vaccination strategies to protect children against seasonal and pandemic influenza. AB - To protect children against infection with seasonal influenza viruses, this age group is vaccinated annually in some countries. However, currently used inactivated seasonal influenza vaccines do not protect well against antigenically distinct pandemic influenza virus strains. Furthermore, annual vaccination may prevent infection with seasonal influenza viruses and subsequently the induction of heterosubtypic immunity. Therefore, the development of influenza vaccines that induce broad protective immunity should be considered a priority. In the absence of such vaccines children that are vaccinated annually against seasonal influenza should in a pandemic scenario also receive pandemic vaccines as soon as these become available. In order to protect young infant under six months of age for which no vaccines are registered at present, vaccination of pregnant women should be considered. This would afford protection through maternally derived antibodies. In addition, vaccination of close family members of young infants is recommended, to prevent transmission within the household. PMID- 21820480 TI - Vaccination during pregnancy to protect infants against influenza: why and why not? AB - Influenza is a significant cause of morbidity and mortality for pregnant women and infants worldwide. Influenza vaccination during pregnancy has been shown to be safe and highly effective and should be recommended for all pregnant women before the influenza season. Despite existing recommendations, the vaccine is underused in most countries. Obstacles to immunization include insufficient awareness of the disease burden and of the importance and safety of immunization, fear of liability and the wish to minimize interventions during pregnancy. Therefore, educational interventions for the public and health care workers are necessary to increase protection of pregnant women and young infants from influenza related complications. PMID- 21820481 TI - Effectiveness and safety of influenza vaccination in children: European perspective. AB - Accumulating evidence for the substantial burden of influenza in children has increased interest in the vaccination of young children against influenza. So far, however, few European countries have issued official recommendations to vaccinate healthy children, which is largely due to the popular belief that inactivated influenza vaccines are ineffective in young children. Virologically confirmed studies performed during different seasons have yielded widely varying estimates for vaccine effectiveness and suggested that the match between the vaccine and the circulating strains of influenza viruses is one of the key drivers of the effectiveness of the vaccine. In seasons with good antigenic match, inactivated influenza vaccines are clearly effective also in children younger than 2 years of age. The live attenuated influenza vaccine provides even greater effectiveness in children, but the overall potential of this vaccine is limited by its licensure for only children older than 2 years of age. The safety record of seasonal inactivated influenza vaccines is excellent even in the youngest children. PMID- 21820482 TI - A follow-up MRI study of the fusiform gyrus and middle and inferior temporal gyri in schizophrenia spectrum. AB - While longitudinal magnetic resonance imaging (MRI) studies have demonstrated progressive gray matter reduction of the superior temporal gyrus (STG) during the early phases of schizophrenia, it remains largely unknown whether other temporal lobe structures also exhibit similar progressive changes and whether these changes, if present, are specific to schizophrenia among the spectrum disorders. In this longitudinal MRI study, the gray matter volumes of the fusiform, middle temporal, and inferior temporal gyri were measured at baseline and follow-up scans (mean inter-scan interval=2.7 years) in 18 patients with first-episode schizophrenia, 13 patients with schizotypal disorder, and 20 healthy controls. Both schizophrenia and schizotypal patients had a smaller fusiform gyrus than controls bilaterally at both time points, whereas no group difference was found in the middle and inferior temporal gyri. In the longitudinal comparison, the schizophrenia patients showed significant fusiform gyrus reduction (left, 2.6%/year; right, -2.3%/year) compared with schizotypal patients (left: 0.4%/year; right: -0.2%/year) and controls (left: 0.1%/year; right: 0.0%/year). However, the middle and inferior temporal gyri did not exhibit significant progressive gray matter change in all diagnostic groups. In the schizophrenia patients, a higher cumulative dose of antipsychotics during follow-up was significantly correlated with less severe gray matter reduction in the left fusiform gyrus. The annual gray matter loss of the fusiform gyrus did not correlate with that of the STG previously reported in the same subjects. Our findings suggest regional specificity of the progressive gray matter reduction in the temporal lobe structures, which might be specific to overt schizophrenia within the schizophrenia spectrum. PMID- 21820483 TI - A qualitative and quantitative investigation into the effect of fluoride formulations on enamel erosion and erosion-abrasion in vitro. AB - OBJECTIVES: To investigate the effect of a single application of highly concentrated SnF(2) and NaF solutions and a NaF/CaF(2) varnish on human enamel subjected to hydrochloric acid erosion and tooth brush abrasion. METHODS: Forty enamel samples were prepared from human third molars and NaF (9500ppm, pH 8.0), SnF(2) (9500ppm, pH 2.6) solutions; Bifluorid10((r)) varnish (42,500ppm, NaF 5%, CaF(2) 5%) and deionized water (control) was applied to the enamel. Following this three, six and nine cycles of erosion [1 cycle=erosion (0.01M HCl, pH 2.2, 2min)+artificial saliva (1h, pH 7.0)] and erosion-abrasion [1 cycle=erosion (0.01M HCl, pH 2.2, 2min)+artificial saliva (1h, pH 7.0)+abrasion (120 linear strokes in artificial saliva from Tepe medium soft brushes 200g loading)] were carried out. The fluoride treated enamel was analysed using Knoop microhardness, scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDS). RESULTS: For erosion alone, there was significantly less microhardness reduction in the Bifluorid10((r)) group after three and six cycles of erosion (P<0.05), however no other groups showed statistically different hardness (P>0.05). The EDS analysis showed that only the Bifluorid10((r)) group had any detectable fluorine following erosion and erosion-abrasion (0.1wt.% and 0.2wt.% fluorine respectively). The surface fluorine was found to have been removed after erosion and erosion-abrasion for all other surface treatments. Although precipitates were observed after application of the surface treatments, following erosion-abrasion, no visible surface effects from any fluoride preparation remained. CONCLUSIONS: Enamel surface precipitates from application NaF, SnF(2) solutions appear to not be able to provide protection against gastric erosion and tooth brush abrasion. The NaF/CaF(2) varnish provided limited protection against erosion but the role for such varnishes in gastric erosion and tooth brush abrasion remains uncertain. PMID- 21820484 TI - Origin and evolution of the long non-coding genes in the X-inactivation center. AB - Random X chromosome inactivation (XCI), the eutherian mechanism of X-linked gene dosage compensation, is controlled by a cis-acting locus termed the X inactivation center (Xic). One of the striking features that characterize the Xic landscape is the abundance of loci transcribing non-coding RNAs (ncRNAs), including Xist, the master regulator of the inactivation process. Recent comparative genomic analyses have depicted the evolutionary scenario behind the origin of the X-inactivation center, revealing that this locus evolved from a region harboring protein-coding genes. During mammalian radiation, this ancestral protein-coding region was disrupted in the marsupial group, whilst it provided in eutherian lineage the starting material for the non-translated RNAs of the X inactivation center. The emergence of non-coding genes occurred by a dual mechanism involving loss of protein-coding function of the pre-existing genes and integration of different classes of mobile elements, some of which modeled the structure and sequence of the non-coding genes in a species-specific manner. The rising genes started to produce transcripts that acquired function in regulating the epigenetic status of the X chromosome, as shown for Xist, its antisense Tsix, Jpx, and recently suggested for Ftx. Thus, the appearance of the Xic, which occurred after the divergence between eutherians and marsupials, was the basis for the evolution of random X inactivation as a strategy to achieve dosage compensation. PMID- 21820485 TI - Mineralocorticoid receptors in the pathophysiology of chronic kidney diseases and the metabolic syndrome. AB - Recent studies indicate that aldosterone/mineralocorticoid receptor (MR) is a major contributor of chronic kidney disease (CKD) progression. Aldosterone/MR induces glomerular podocyte injury, causing the disruption of the glomerular filtration barrier and proteinuria. Conversely, MR antagonists substantially reduce proteinuria, which can be partly attributable to the protective effects on podocytes. Aldosterone excess, caused by adipocyte-derived aldosterone-releasing factors and other mechanisms, can be pathologically important in the renal complication of metabolic syndrome. A rat model of metabolic syndrome exhibits podocyte injury and proteinuria with serum aldosterone elevation, and the renal damage is prevented by MR blockade. Accumulating data also indicate that MR inhibition can confer renoprotection in a subgroup with low or normal aldosterone levels. We have recently identified the cross-talk between MR and small GTPase Rac1, providing one theoretical basis for the renoprotective effects of MR antagonists in non-high-aldosterone subjects. MR blockade can be a promising strategy for preventing CKD progression, and future clinical trials will conclusively determine the efficacy and tolerability of selective MR inhibition in CKD and metabolic syndrome. PMID- 21820486 TI - The endocrine and paracrine control of menstruation. AB - During the reproductive life, the human endometrium undergoes cycles of substantial remodeling including, at menstruation, a massive but delimited tissue breakdown immediately followed by scarless repair. The present review aims at summarizing the current knowledge on the endocrine and paracrine control of menstruation in the light of recent observations that undermine obsolete dogmas. Menstruation can be globally considered as a response to falling progesterone concentration. However, tissue breakdown is heterogeneous and tightly controlled in space and time by a complex network of regulators and effectors, including cytokines, chemokines, proteases and various components of an inflammatory response. Moreover, menstruation must be regarded as part of a complex and integrated mechanism of tissue remodeling including features that precede and follow tissue lysis, i.e. decidualization and immediate post-menstrual regeneration. The understanding of the regulation of menstruation is of major basic and clinical interest. Indeed, these mechanisms largely overlap with those controlling other histopathological occurrences of tissue remodeling, such as development and cancer, and inappropriate control of menstrual features is a major potential cause of two frequent endometrial pathologies (i.e. abnormal uterine bleeding and endometriosis). PMID- 21820487 TI - Circulating levels of GDNF in bipolar disorder. AB - Neurotrophic factors regulate the survival and growth of neurons, and influence synaptic efficiency and plasticity. Several studies suggest the existence of a relationship between changes in neurotrophic levels and bipolar disorder (BD). The glial cell-line derived neurotrophic factor (GDNF) influences monoaminergic neurons and glial cells, but its role in BD patients is controversial. In order to elucidate it we evaluated plasma levels of GDNF in a sample of 70 BD patients (35 in mania and 35 in euthymia) and compared with 50 healthy controls matched for age, gender and educational levels. GDNF plasma levels were measured by enzyme-linked immunosorbent assay (ELISA). Patients were assessed by a Mini International Neuropsychiatric Interview (MINI-plus), Young Mania and Hamilton Depression Rating Scales. Plasma GDNF levels were significantly increased in BD patients in euthymia compared with BD patients in mania and healthy controls (p<0.05). GDNF plasma levels were correlated with age (rho=0.30, p<0.05) and negatively correlated with manic symptoms in BD patients (rho=-0.54, p<0.05). Our results provide evidence that peripheral levels of GDNF are related with different mood states in BD, reinforcing the involvement of neurotrophic factors in its physiopathology. PMID- 21820488 TI - Hyperthermia impaired pre-attentive processing: an auditory MMN study. AB - This study investigated the effect of hyperthermia on pre-attentive processing by recording the mismatch negativity (MMN) component of ERPs. 36 right-handed young male undergraduates were divided into two groups, a control group with 1h of exposure at 25 degrees C and a heat group with 1h of exposure at 50 degrees C. MMNs were recorded before and after heat exposure. It was found that, although there was no group difference before heat exposure, MMN declined significantly in the heat group compared to the control group after heat exposure for 1h, indicating that passive heat exposure could damage pre-attentive processing. The MMN component could be a good index to assess cognitive functioning in a hot environment. PMID- 21820489 TI - Developmental expression of oxytocin receptors in the neonatal medulla oblongata and pons. AB - The distribution of oxytocin receptors (OTRs) in the postnatal brain stem of rats was examined by immunohistochemistry. Fibrous or rounded shaped OTR immunoreactive structures were distributed densely in sensory nuclei, such as the gracile nucleus, the solitary nucleus, and the spinal trigeminal nucleus, evenly in the reticular formation of the medulla oblongata and pons, and moderately in the locus coeruleus during the neonatal period, but disappeared by postnatal day 10. Few OTR-immunoreactive structures were distributed in motor nuclei. Many rounded OTR-immunoreactive structures were discovered layered and partially overlapping with GM-130-immunoreacivity in the neuronal Golgi apparatus, which was confirmed by electron microscopy. The present study suggests that a transient type of OTR may be functioning in neuronal development during the neonatal period. PMID- 21820490 TI - GABA(B) restrains release from singly-evoked GABA terminals. AB - Neurotransmitter release regulation is highly heterogeneous across the brain. The fundamental units of release, individual boutons, are difficult to access and poorly understood. Here we directly activated single boutons on mechanically isolated nucleus tractus solitarius (NTS) neurons to record unitary synaptic events under voltage clamp. By scanning the cell surface with a stimulating pipette, we located unique sites that generated evoked excitatory postsynaptic currents (eEPSCs) or evoked inhibitory postsynaptic currents (eIPSCs) events. Stimulus-response relations had abrupt thresholds for all-or-none synaptic events consistent with unitary responses. Thus, irrespective of shock intensity, focal stimulation selectively evoked either eEPSCs or eIPSCs from single retained synaptic boutons and never recruited other synapses. Evoked EPSCs were rarely encountered. Our studies, thus, focused primarily on the more common GABA release. At most locations, shocks often failed to release GABA even at low frequencies (0.075 Hz), and eIPSCs succeeded only on average 2.7+/-0.7 successful IPSCs per 10 shocks. Activation of eIPSCs decreased spontaneous IPSCs in the same neurons. The GABA(A) receptor antagonist gabazine (3 MUM) reversibly blocked eIPSCs as did tetrodotoxin (TTX) (300 nM). The initial low rate of successful eIPSCs decreased further in a use-dependent manner at 0.5 Hz stimulation depressing 70% in 2 min. The selective GABA(B) receptor antagonist 3-[[(3,4 Dichlorophenyl)methyl]amino]propyl] diethoxymethyl)phosphinic acid (CGP 52432) (5 MUM) had three actions: tripling the initial release rate, slowing the use dependent decline without changing amplitudes, and blocking the shock-related decrease in spontaneous IPSCs. The results suggest strong, surprisingly long lasting, negative feedback by GABA(B) receptors within single GABA terminals that determine release probability even in isolated terminals. PMID- 21820492 TI - Effects of treadmill exercise on the expression of netrin-1 and its receptors in rat brain after cerebral ischemia. AB - Recent evidence suggests that exercise improves functional outcome in animal models of cerebral ischemia. Since netrin-1 and its receptors, deleted in colorectal cancer (DCC) and uncoordinated gene 5B (Unc5B), act as important regulators in neural and vascular activities, we sought to determine whether netrin-1 and DCC and Unc5B are involved in the neuroprotective effects of exercise on rats with induced cerebral ischemia. A total of 108 rats were randomly distributed into three groups: sham-operated group (n = 12), middle cerebral artery occlusion (MCAO) group (n = 48), MCAO+treadmill exercise group (n = 48). Behavioral testing indicated that treadmill exercise could significantly improve neurologic deficits of rats with cerebral ischemia at day 14 and 28 after MCAO (n = 12, P<0.05 and P<0.01), but there was no significant difference at day 4 and 7. Quantitative reverse transcription polymerase chain reaction (qPCR) and Western blot analysis revealed that treadmill exercise enhanced netrin-1 and DCC expression, while it suppressed Unc5B expression in rat peri-ischemic brain area, especially at day 14 and 28 after MCAO (n = 4, P<0.05 or P<0.01). Immunofluorescence analysis showed that in the peri-ischemic area, netrin-1 was expressed in neuronal perikarya, DCC, however, was expressed in neural processes and peri-vascular astrocytes, while Unc5B was expressed mostly in neuronal perikarya and some processes. These results suggest that netrin-1 and its receptors DCC and Unc5B may engage in exercise-induced neural circuit remodeling in the peri-ischemic area, and exercise may promote survival of neurons in this area by regulating netrin-1-Unc5B signaling. Additionally, netrin-1 may also play a role in brain-blood barrier via DCC-immunoreactive peri-vascular astrocytes. In conclusion, we demonstrate that treadmill exercise has beneficial effects that may be attributed, at least in part, to the involvement of netrin-1 and its receptors DCC and Unc5B in the neuronal and vascular activities in brain-ischemic rats. PMID- 21820491 TI - Phosphodiesterase-5 is a therapeutic target for peripheral neuropathy in diabetic mice. AB - Peripheral neuropathy is a common and major complication of diabetes, the underlying mechanisms of which are not fully understood. Using a mouse model of type II diabetes, the present study investigated the role of phosphodiesterase-5 (PDE5) in peripheral neuropathy. BKS.Cg-m+/+Leprdb/J (db/db) mice were treated with sildenafil, a specific inhibitor of PDE5, at doses of 2 and 10 mg/kg or saline. Levels of PDE5 and morphometric parameters in sciatic nerve tissue as well as the motor and sensory function were measured in these mice. In diabetic mice, PDE5 expression in sciatic nerve tissue was significantly upregulated, whereas the myelin sheath thickness, myelin basic protein (MBP), and subcutaneous nerve fibers were significantly reduced. Treatment with sildenafil significantly improved neurological function, assayed by motor and sensory conducting velocities and thermal and mechanical noxious stimuli, concomitantly with increases in myelin sheath thickness, MBP levels, and subcutaneous nerve fibers. In vitro, hyperglycemia upregulated PDE5 in Schwann cells and reduced Schwann cell proliferation, migration, and expression of brain-derived neurotrophic factor (BDNF). Blockage of PDE5 with sildenafil increased cyclic guanosine monophosphate (cGMP) and completely abolished the effect of hyperglycemia on Schwann cells. Sildenafil upregulated cGMP-dependent protein kinase G I (PKGI), whereas inhibition of PKGI with a PKG inhibitor, KT5823, suppressed the inhibitory effect of sildenafil on Schwann cells. These data indicate that hyperglycemia substantially upregulates PDE5 expression and that the cGMP/PKG signaling pathway activated by sildenafil mediates the beneficial effects of sildenafil on diabetic peripheral neuropathy. PMID- 21820493 TI - Individual auditory thalamic reticular neurons have large and cross-modal sources of cortical and thalamic inputs. AB - In the present study, the sources of thalamic and cortical inputs of thalamic reticular nucleus (TRN) neurons were examined by investigating the responses of the TRN neurons to electrical stimulation of different sites in the thalamus and the cortex of the rat. The recurrent excitation of the corticothalamic system that is triggered by electrical stimulation was eliminated by ablating the auditory cortex and by temporarily inactivating the medial geniculate body (MGB), when studying the sources of thalamic and cortical inputs, respectively. Single TRN neurons responded to electrical stimulation of 50-100 MUA of the thalamus over a large area (dorsoventrally 1.2-2.4 mm and mediolaterally 1.0-2.3 mm, n=9). Four of 16 auditory TRN neurons responded to electrical stimulation of the lateral geniculate nucleus. The TRN neurons responded to cortical stimulation over a rostrocaudal distance of 2.6+/-0.5 mm (range: 1.5-3.5 mm, n=24) of the auditory cortex. Visual or auditory TRN neurons also responded to electrical stimulation in the auditory or visual cortices, respectively. The present study revealed that each TRN neuron received a wide range of inputs from both ascending thalamic and descending cortical projections. The projection could be cross modal. Having a strong and lasting inhibition on the thalamus, the TRN neurons are likely to be involved in adjusting global states relating to awareness and attention in the thalamocortical system. PMID- 21820494 TI - Protective effect of 2,2'-dithienyl diselenide on kainic acid-induced neurotoxicity in rat hippocampus. AB - In this study, we investigated the effects of 2,2'-dithienyl diselenide (DTDS), an organoselenium compound, against seizures induced by kainic acid (KA) in rats. Rats were pretreated with DTDS (50 or 100 mg/kg) by oral route 1 h before KA injection (10 mg/kg, intraperitoneal). Our results showed that DTDS (100 mg/kg) was effective in increasing latency for the onset of the first clonic seizure episode induced by KA, as well as in decreasing the appearance of seizures and the Racine's score. DTDS also caused a decrease in the excitatory electroencephalographic (EEG) changes, resulting from KA exposure in hippocampus and cerebral cortex of rats. Besides, elevated reactive species (RS) and carbonyl protein levels and Na(+), K(+)-ATPase activity in hippocampus of rats treated with KA were ameliorated by DTDS (50 and 100 mg/kg). Lastly, as evidenced by Cresyl-Violet stain, DTDS (100 mg/kg) elicited a protective effect against KA induced neurodegeneration in rat hippocampus 7 days after KA injection. In conclusion, the present study showed that DTDS attenuated KA-induced status epilepticus in rats and the subsequent hippocampal damage. PMID- 21820495 TI - A new belamcandaquinone from the seeds of Iris bungei Maxim. AB - A novel dimeric 1,4-benzoquinone and resorcinol derivative, Belamcandaquinone N (1), and two known compounds, 3-hydroxyirisquinone (2) and 5-[(Z)-10 heptadecenyl] resorcinol (3), were isolated from the seeds of Iris bungei Maxim. Their structures were elucidated by spectroscopic methods and comparing with literature data of known compounds. These compounds showed remarkable cytotoxic activity against RM-1 cell lines. PMID- 21820496 TI - Genetic polymorphism of CYP4A11 and CYP4A22 genes and in silico insights from comparative 3D modelling in a French population. AB - The CYP4A subfamily is known to omega-hydroxylate the endogenous arachidonic acid into 20-hydroxyeicosatetranoic acid, which has renovascular and tubular functions. The aim of this work was to report a comprehensive investigation of the CYP4A11 and CYP4A22 genetic polymorphisms in a French population. Using PCR SSCP and sequencing strategies, a total of 26 sequence variations were identified comprising 3 missense mutations for CYP4A11 (Ser404Phe, Phe434Ser and Arg505His) and 7 missense mutations for CYP4A22 (Arg126Trp, Gly130Ser, Asn152Tyr, Val185Phe, Cys231Arg, Leu428Pro and Leu509Phe). In comparison with SNPs reported in the database (dbSNP) of the National Center for Biotechnology information (NCBI), 6 and 3 novel polymorphisms were identified in CYP4A11 and CYP4A22, respectively. The potential impact of the amino acid substitutions on the structure and/or catalytic activity of the enzymes has been estimated by the construction and validation of the CYP4A 3D models. These results could be helpful for further investigations of the potential role of CYP4A variants in the genetic susceptibility to cardiovascular diseases in humans such as arterial hypertension. PMID- 21820497 TI - 3,3'-Diindolylmethane induces immunotoxicity via splenocyte apoptosis in neonatal mice. AB - 3,3'-Diindolylmethane (DIM), a major product of indole-3-carbinol derived from vegetables of the genus Brassica, exhibits chemotherapeutic activity and various immune modulatory effects in animal models and in vitro studies. Although extensive studies have only focused on DIM's beneficial effects, the toxic effects of DIM on the immune systems have not been clearly elucidated. The aim of this study was to explore the immunotoxic effects of DIM in a neonatal mouse and to further evaluate whether DIM administration affects rotavirus (RV)-induced gastroenteritis. Interestingly, multiple immunotoxic effects were observed in the DIM treated group, including decreases in various immune cells (F4/80(+), CD11c(+), CD19(+), and CD3(+) cells) in the spleen, induction of splenic white pulp atrophy, an increase in immune cell apoptosis, and decreased expression of various toll-like receptors (TLRs) in the spleen and small intestine. Apoptosis was notably promoted by up-regulating caspase-3 activity and by the change in the ratio of Bcl-2/Bax activities. Finally, oral administration of DIM led to deterioration of RV-induced intestinal disease and delayed viral clearance in the intestine and MLNs. Our results indicate that oral administration of DIM in neonatal mice induces immunotoxicity and hampers efficient RV clearance in the intestine. This new information about the immunotoxic roles of DIM in a newborn mouse model may provide valuable clues for the development of a safe supplement, especially one designed for human infants. PMID- 21820498 TI - Clioquinol is sulfated by human jejunum cytosol and SULT1A3, a human-specific dopamine sulfotransferase. AB - Clioquinol, originally marketed as an oral intestinal amebicide, was widely used for multiple intestinal disorders. Its use as an oral agent was, however, discontinued because of its possible association with subacute myelo-optico neuropathy or SMON. Meanwhile, its use for neurodegenerative diseases has recently been suggested. The metabolic fate of clioquinol, however, is poorly described. Since clioquinol is excreted as a sulfate in animals and humans, we have sought to identify a human sulfotransferase (SULT) responsible for the sulfation. We found that sulfating activities of human jejunal cytosols to clioquinol were well correlated with those to dopamine, a typical SULT1A3 substrate. Consistently, recombinant SULT1A3 showed the highest activity to clioquinol in vitro among the human SULTs examined. The S(50) value for the clioquinol sulfation by SULT1A3 was similar to the K(m) value for that by cytosols from human jejunum, where SULT1A3 is abundantly expressed. Moreover, clioquinol inhibited both human jejunal cytosol- and SULT1A3-mediated sulfations of dopamine in a dose-dependent manner, showing similar IC(50) values. These results suggest that SULT1A3, which is highly expressed in intestine but not in liver, is responsible for the clioquinol sulfation in humans, raising a possibility that orally administered clioquinol might inhibit dopamine sulfation in human intestines. PMID- 21820499 TI - In vivo imaging of drug delivery systems in the gastrointestinal tract. AB - An essential basis for the understanding of the complex interplay between oral drug delivery systems and gastrointestinal physiology is the ability to relate deposition of the dosage form to the plasma concentration time profile. The pharmaceutical scientist requires an array of methods that provide information on formulation disposition without influencing the physiological process, commonly termed "non-invasive" imaging modalities. In this paper, a short historical view on the suitability of different imaging modalities for the investigation of the fate of drug delivery systems in the GI tract is given. The focus of the review is the presentation of currently mostly used methodologies scintigraphy, magnetic tracking techniques like magnetic marker monitoring (MMM), magnetic moment imaging (MMI), AC biosusceptometry (ACB) and magnetic resonance imaging and the discussion of their strengths and weaknesses. PMID- 21820500 TI - Physicochemical properties of macrogol ointment and emulsion ointment blend developed for regulation of water absorption. AB - Pressure ulcers can form with excess pressure and shearing stress on skin tissue. Because pressure ulcer is often accompanies by exudates, selection of appropriate topical emulsion ointment is difficult. Blended ointments consisting of emulsion base and water-soluble base are clinically used for adjustment of wound moist environment. Because regulating the amount of wound exudates can enhance treatment efficacy, two new blended ointments were developed. LY-SL blended ointment consisted of lysozyme hydrochloride water-in-oil (w/o) emulsion (LY cream) and sulfadiazine macrogol (polyethylene glycol) ointment (SL-pasta). TR-SL blended ointment consisted of tretinoin tocoferil oil-in-water (o/w) emulsion (TR cream) and SL-pasta (TR-SL). LY-SL and TR-SL were applied to Franz diffusion cell with cellulose membranes for the evaluation of water absorption characteristics at 32 degrees C. Water absorption rate constants (mg/cm(2)/min(0.5)) were 12.5, 16.3 and 34.6 for LY-cream, TR-cream and SL-pasta, respectively. Water absorption rate constants for LY-SL and TR-SL (SL-pasta 70%) exhibited intermediate values of 21.2 and 27.2, as compared to each ointment alone, respectively. Because amount of water absorbed was linearly related to square root of time, it was suggested that water-absorbable macrogol was surrounded by oily ingredients forming matrix structure. This diffusion-limited structure may regulate water absorption capacity. This is the first report of physicochemical properties of macrogol ointment and emulsion ointment blend developed for regulation of water absorption. The blended ointment can properly regulate amount of exudates in wounds and may be useful for treatment of pressure ulcers. PMID- 21820501 TI - Narrow noise band detection in a complex masker: masking level difference due to harmonicity. AB - Three experiments investigated listeners' ability to detect a narrow band of noise, centered on one partial of a random-phase complex tone, as a function of inharmonicity. Inharmonicity was generated by randomly mistuning the partial frequencies from a 100-Hz fundamental frequency (F0). In experiment 1, masked detection thresholds were lower when the masker was harmonic than when it was inharmonic for target bands in the range 0.5-2.5 kHz. The presence of this masking level difference due to harmonicity (HMLD) in regions of resolved partials and the reduction of the HMLD with increasing center frequency did not support the idea that HMLD was primarily caused by the envelope modulations produced by the beating of unresolved partials within an auditory filter. In experiment 2, masker mistunings ranging beyond 12% of the F0 disrupted the HMLD while smaller mistunings gave thresholds similar to a harmonic masker. In experiment 3, all partials contributed to some extent to the HMLD, but the harmonicity of partials neighboring the target had a greater influence than distant partials. The observed HMLDs can best be accounted for by a mechanism of harmonic cancellation. PMID- 21820502 TI - Inonotus obliquus extracts suppress antigen-specific IgE production through the modulation of Th1/Th2 cytokines in ovalbumin-sensitized mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Chaga mushroom (Inonotus obliquus, IO) has been used as a folk remedy for cancer, digestive system diseases, and other illnesses in Russia and Eastern Europe. AIM OF THE STUDY: In the present study, we investigated the immunomodulating effects of IO through in vivo and ex vivo studies. MATERIALS AND METHODS: Serum immunoglobulins (IgE, IgG(1), and IgG(2a)) and cytokines (interleukin (IL)-4, interferon (IFN)-gamma, and IL-2) were measured in concanavalin A (ConA)-stimulated splenocytes and CD4(+) T cells. The nitric oxide (NO) secretion of lipopolysaccharide (LPS)-stimulated peritoneal macrophages was also measured after oral administration of 50, 100, or 200 mg kg( 1) d(-1) IO hot water extract (IOE) to ovalbumin (OVA)-sensitized BALB/c mice. RESULTS: We found that the OVA-induced increase in serum IgE and IgG(2a) was significantly suppressed when IOE was orally administered after the second immunization with OVA. ConA stimulation in spleen cells isolated from OVA sensitized mice treated with 100 mg kg(-1) IOE resulted in a 25.2% decrease in IL 4 production and a 102.4% increase in IFN-gamma, compared to the controls. Moreover, IL-4, IFN-gamma, and IL-2 were significantly reduced after ConA stimulation in isolated CD4(+)T cells. We also determined that IOE inhibits the secretion of NO from LPS-stimulated peritoneal macrophages ex vivo. CONCLUSIONS: We suggest that IO modulates immune responses through secretion of Th1/Th2 cytokines in immune cells and regulates antigen-specific antibody production. PMID- 21820503 TI - Role of age and uncoupling protein-2 in oxidative stress, RAGE/AGE interaction and inflammatory liver injury. AB - The objective of this study is to clarify whether age-related oxidative stress enhances hepatic vulnerability via increased interaction of advanced glycation endproducts (AGE) with their receptor RAGE. To further address the role of uncoupling of mitochondrial respiration, mitochondrial uncoupling protein-2 wild type (UCP2+/+) and knock out (UCP2-/-) mice were used and studied at an age of 8 (young), 38 (adult) and 76 weeks (senescent). First, we could show that UCP2 protein expression increased with age in UCP2+/+ mice. Second, in both mouse strains oxidative stress, as measured by malondialdehyde concentrations and the ratio of glutathione to glutathione disulfide, as well as hepatic RAGE expression and highly modified AGE accumulation significantly increased with age. This, however, was far more pronounced in UCP2-/- mice, in particular at the young age of 8 wk. In addition, the hepatic activity of the AGE precursor detoxifying enzyme glyoxalase-I was significantly decreased in 8 wk old UCP2-/- animals and concomitantly caused 2-fold higher levels of methylglyoxal-modified AGE in these animals. We further showed that the numbers of hepatic cells expressing sRAGE which acts as a decoy for RAGE ligands decreased with age and were markedly lower in the UCP2-/- than the UCP2+/+ mice. As a consequence, young 8 wk old UCP2-/- mice benefited from treatment with recombinant mouse RAGE to block the RAGE/AGE interaction, when challenged with galactosamine/lipopolysaccharide for the induction of acute liver injury. They showed less pronounced tissue damage and slightly lower mortality rate, while older UCP2+/+ and UCP2-/- mice revealed comparably high mortality rates and extent of liver injury, irrespective of their treatment with rRAGE. Taken together, the present study underlines the role of UCP2 in the age-related increase of oxidative stress and the oxidative stress related RAGE/AGE interaction. In young animals, blockade of the RAGE/AGE interaction is of benefit, while in older animals, this protective effect is lost, supposedly due to the fact that with age other factors than enhanced hepatic glycation products predominantly determine liver injury and injury related mortality rate. PMID- 21820504 TI - Validation of the REA bioassay to detect estrogenic activity in the water cycle. AB - Endocrine disrupting compounds (EDCs) with estrogenic potency contaminate water and might eventually cause adverse effects to the aquatic environment. Many estrogenic compounds are not completely removed by wastewater treatment systems and, together with the run-off from agricultural areas, they enter surface waters. Chemical analytical methods to determine these compounds are usually expensive and laborious. Therefore, screening bioassays which are able to detect compounds based on their effects offer a solution for prior selection of samples that need to be chemically analyzed. In this study, the REA (RIKILT yeast Estrogen bioAssay), which has been developed to detect estrogenic compounds in calf urine and animal feed at RIKILT, is validated at the Water Board Laboratory of Waterproef for water samples. According to EC Decision 2002/657, detection capability CCbeta, specificity and stability have to be determined for the internal validation of a qualitative screening test. In addition, surface water and effluent samples were analyzed to further demonstrate the applicability of the validated test procedure. Results demonstrate that the REA assay is reproducible and specific for estrogenic compounds in water and meets the criteria as prescribed in EC Decision 2002/657. The assay was sensitive enough to detect estrogenic activity of pollutants in water with a limit of quantification (LOQ) below 1 ng EEQ/L. This means that samples can be compared with preliminary threshold levels for drinking water and surface waters (7 and 1 ng EEQ/L, respectively). The stability of estrogenic activity in water samples is at least 4 weeks, when stored at 4 degrees C. PMID- 21820505 TI - Prolactin, neurogenesis, and maternal behaviors. AB - Elevated prolactin during pregnancy increases neurogenesis in the subventricular zone of the lateral ventricle (SVZ) of the maternal brain. Evidence from our laboratory has shown that low prolactin in early pregnancy, and the consequent suppression of neurogenesis in the SVZ in the adult brain, is associated with increased postpartum anxiety and markedly impaired maternal behavior. Daughters of low prolactin mothers also display increased anxiety and a significant delay in the onset of puberty, which is associated with epigenetic changes in neuronal development (see Fig. 1). This suggests that, in rodents, low prolactin in early pregnancy exerts long-term effects that influence maternal mood postpartum, and offspring development. This mini-review aims to summarize the evidence showing that the prolactin-induced increase in SVZ neurogenesis during pregnancy underlies normal postpartum maternal interactions with pups. PMID- 21820506 TI - In cardiac myoblasts, cellular redox regulates FosB and Fra-1 through multiple cis-regulatory modules. AB - Depending on the dose, norepineprine (NE) can induce hypertrophy or apoptosis in cardiac myocytes. Reactive oxygen species (ROS) play a key role in mediating both responses, but the mechanisms are not understood as yet. Earlier we demonstrated that the two pathways are marked by the differential induction of FosB and Fra-1, two members of the AP-1 family of transcription factors. We now demonstrate that NE induces both fosB and fra-1 at the transcriptional level. Catalase and MnTMPyP (a superoxide dismutase mimetic) suppress their activation by NE. In contrast, in cells without NE treatment, MnTMPyP upregulates their expression, whereas catalase inhibits it. Thus, regulation of fosB and fra-1 by ROS is context specific. To delineate the mechanisms, the 1493- and 2689-bp upstream regions of the fosB and fra-1 genes were cloned into the luciferase vector and assayed for transient expression. Catalase and MnTMPyP regulated both promoters the same as their endogenous counterparts in NE-treated and untreated cells. Deletion, mutation, and ChIP analyses suggested that multiple cis-elements including SP-1, CEBP, and AP-1 in the fosB promoter make discrete contributions to mediating the redox response. A gel mobility-shift-based oxidation-reduction assay suggested that, whereas SP-1 is a direct sensor of cellular redox state, CEBP is not. This study suggests that multiple redox signals generate gene-specific modules affecting their expression. PMID- 21820507 TI - Impact of bile salt adaptation of Lactobacillus delbrueckii subsp. lactis 200 on its interaction capacity with the gut. AB - In a previous work, bile-salt-resistant derivatives were obtained from non intestinal lactobacilli. The aim of this work was to investigate the impact of bile adaptation of Lactobacillus delbrueckii subsp. lactis 200 on morphology, surface properties, in vivo interaction capacity with the gut and ability to activate the gut immune response. Electron microscopy studies, growth kinetics in the presence of bovine and porcine bile, the capacity to deconjugate bile acids, hydrophobicity, autoaggregation and co-aggregation capacities were studied for the parental strain and its bile-resistant derivative in vitro. Additionally, survival in intestinal fluid, the interaction with the gut and the immunomodulating capacities were studied in mice. Bile salt adaptation conferred upon the adapted strain a higher capacity to withstand physiological concentrations of bile salts and greater survival capacity in intestinal fluid. However, bile salt exposure reduced cell hydrophobicity, autoaggregation and adhesion capacities, resulting in reduced persistence in the intestinal lumen and delayed capacity to activate the gut immune response. Insight into the effects of bile salts upon the interaction and immunomodulating capacity of lactobacilli with the gut is provided, relating in vitro and in vivo results. PMID- 21820508 TI - Natural phenylalanine hydroxylase variants that confer a mild phenotype affect the enzyme's conformational stability and oligomerization equilibrium. AB - Hyperphenylalaninemias are genetic diseases prevalently caused by mutations in the phenylalanine hydroxylase (PAH) gene. The wild-type PAH enzyme is a homotetramer regulated by its substrate, cofactor and phosphorylation. We reproduced a full-length wild-type protein and seven natural full-length PAH variants, p.I65M, p.N223Y, p.R297L, p.F382L, p.K398N, p.A403V, and p.Q419R, and analyzed their biochemical and biophysical behavior. All mutants exhibited reduced enzymatic activity, namely from 38% to 69% of wild-type activity. Biophysical characterization was performed by size-exclusion chromatography, light scattering and circular dichroism. In the purified wild-type PAH, we identified the monomer in equilibrium with the dimer and tetramer. In most mutants, the equilibrium shifted toward the dimer and most tended to form aggregates. All PAH variants displayed different biophysical behaviors due to loss of secondary structure and thermal destabilization. Specifically, p.F382L was highly unstable at physiological temperature. Moreover, using confocal microscopy with the number and brightness technique, we studied the effect of BH4 addition directly in living human cells expressing wild-type PAH or p.A403V, a mild mutant associated with BH4 responsiveness in vivo. Our results demonstrate that BH4 addition promotes re-establishment of the oligomerization equilibrium, thus indicating that the dimer-to-tetramer shift in pA403V plays a key role in BH4 responsiveness. In conclusion, we show that the oligomerization process and conformational stability are altered by mutations that could affect the physiological behavior of the enzyme. This endorses the hypothesis that oligomerization and folding defects of PAH variants are the most common causes of HPAs, particularly as regards mild human phenotypes. PMID- 21820509 TI - Encapsulation of Abeta(1-15) in PLGA microparticles enhances serum antibody response in mice immunized by subcutaneous and intranasal routes. AB - The aim of the present work was to develop an easy, safe and effective vaccine in Balb/c mice using the Abeta(1-15) peptide as immunogen entrapped in PLGA microparticles to reduce the risk of an adverse T cell-mediated response. Abeta(1 15,) which contains the N-terminal antibody epitope of the full Abeta(1-42) peptide was encapsulated in PLGA by a modified solvent evaporation/extraction technique using a double emulsion system. Microparticles were characterized in terms of size distribution (1.22+/-0.28 MUm), encapsulation efficiency (75.05+/ 4.17%), surface associated peptide (59.81+/-0.96%) and "in vitro" release profile. Balb/c mice were immunized by subcutaneous and intranasal routes with three 30 MUg doses of the peptide microencapsulated in PLGA. A solution of the peptide alone and an emulsion in the Freund's adjuvant were administered subcutaneously as control groups. Antibody levels elicited against the toxic Abeta(1-40) fraction in the serum of PLGA microparticles treated groups were higher than that of the peptide alone groups. Our initial results indicate that immunotherapy with Abeta(1-15) loaded PLGA microparticles could be a promising approach for the future development of a safe vaccine against Alzheimer's disease. PMID- 21820510 TI - Polyglutamic acid-based nanocomposites as efficient non-viral gene carriers in vitro and in vivo. AB - A series of polyethylenimine (PEI) and gamma-polyglutamic acid (PGA) nanocomposites (PPGA) was prepared and evaluated in terms of their cell viability and transfection efficiency in vitro and in vivo. On complexion with pDNA, the positively charged PPGA/DNA nanocomposites resulted in a higher level of in vitro reporter gene transfection (2.7-7.9-fold) as compared to native PEI, and selected commercial reagents and >95% cell viability in HEK293, HeLa and HepG2 cell lines. Further, PPGA-5 nanocomposite (the best working system in terms of transfection efficiency among the series) was found to efficiently transfect primary mouse keratinocytes up to 22% above the control level. PPGA-5, when tested for in vivo cytotoxicity in Drosophila, did not induce any stress in the exposed larvae in comparison with control. In vivo gene expression using PPGA-5 showed the highest transfection efficiency in spleen of mouse closely followed by heart tissues after intravenous injection through tail vein. Besides, these nanocomposites also delivered siRNA efficiently into mammalian cells, resulting in ~ 80% suppression of EGFP expression. These results together demonstrated the potential of the projected nanocomposites for in vivo gene delivery. PMID- 21820511 TI - Solutions as solutions--synthesis and use of a liquid polyester excipient to dissolve lipophilic drugs and formulate sustained-release parenterals. AB - Solid poly(lactides) and poly(lactide-co-glycolides) are widely used polymers for sustained-release parenterals. However, they have some unfavorable properties regarding manufacturing of the formulations and administration to the patient due to their solid aggregate state. In contrast, hexyl-substituted poly(lactic acid) (hexPLA, poly(2-hydroxyoctanoic acid)) is a viscous degradable polyester. To date, a two-step ring-opening polymerization was used for its synthesis. Here, we investigated a novel one-pot one-step melt polycondensation method to prepare hexPLA for biomedical applications by a simple green chemistry process. No catalyst or solely pharmaceutically acceptable catalysts and environmentally friendly purification methods without organic solvents were used. The resulting hexPLA polymers are stable under dry heat sterilization conditions. Low molecular weight hexPLAs with less than 5000 g/mol are less viscous than high molecular weight polymers. HexPLA can dissolve lipophilic active substances, with generally high incorporation capacities in low molecular weight polymers. The incorporation of solid compounds increases the viscosity and glass transition temperature, whereas the addition of small amounts of plasticizers or sparse warming significantly decreases the viscosity. Loratadine is soluble in hexPLA up to 28%. This highly concentrated Loratadine-hexPLA formulation released the active compound entirely over 14 days without initial burst in a zero order kinetic, matching the clinical requirements for such a sustained-release formulation. This demonstrates the potential of hexPLA as an excipient for injectable sustained release formulations. PMID- 21820512 TI - Effects of immunosuppressive therapy after experimental small bowel transplantation in rats. AB - Significant improvements of graft and patient survival have been achieved over the past 20 years in the field of intestinal transplantation. Tacrolimus monotherapy with corticosteroids, or in combination with sirolimus is the most commonly used immunosuppressive regimen. Early (24h) after experimental allogenic small bowel transplantation in rats, sirolimus reduces the cellular and molecular inflammatory response with subsequent graft dysmotility more efficiently than tacrolimus, with contrary effects at 7 days after transplantation. This study evaluates three immunosuppressive strategies in the post-acute phase after intestinal transplantation - tacrolimus or sirolimus monotherapy and the combination therapy of tacrolimus with infliximab. After orthotopic intestinal transplantation between Brown Norway and Lewis rats, animals received 14 days of immunosuppressive treatment. Histology, infiltration of neutrophils, monocytes and macrophages, cytokine and mediator mRNA expression (real time RT-PCR) and smooth muscle function in a standard organ bath were assessed at 14 days after transplantation in all treatment groups and isogenic controls. Allogenic transplanted rats without immunosuppressive therapy and non-transplanted animals served as further control. Tacrolimus prevented acute rejection and graft dysmotility more effectively (p >= 0.05) than sirolimus. Reduced mRNA expression levels of CD4, IFN-gamma, IL-6, IL-10, iNOS, NFkappaB, TNF-alpha and MCP-1 (p <= 0.05) were observed in tacrolimus treated animals compared to sirolimus. Additional infliximab application did not influence the cellular and molecular inflammatory response in the post-acute phase after transplantation. In conclusion, the severe cellular and molecular inflammatory response in allogenic transplanted grafts without immunosuppressive therapy is ameliorated by all three immunosuppressive regimens, but tacrolimus was found to be more efficient than sirolimus at 14 days after transplantation. Our findings do not rule out the usage of sirolimus as single immunosuppressive therapy, but indicate and confirm the potency and effectivity of tacrolimus as basis immunosuppressant in the field of intestinal transplantation. PMID- 21820514 TI - What have we learned from gene expression profiles in Huntington's disease? AB - The availability of many high-quality genome-wide expression datasets has provided an exciting and unique opportunity to better understand the molecular etiology of Huntington's disease. Combining this knowledge with other aspects of huntingtin biology and disease modification screens is yielding important new insights into disease-mitigating therapeutic strategies. Having followed this line of inquiry for some time, we note that there have been a number of surprises regarding the subsequently confirmed relationships between gene expression and disease etiology. Moreover, the complexity and sheer number of proposed mechanisms by which huntingtin can perturb gene expression continues to expand. Nonetheless, ongoing efforts to enthusiastically and critically evaluate the relationships between HD pathobiology and gene expression promise to deliver accurate predictions as to which therapeutic strategies will be most effective. An exciting new arm of this research also demonstrates the power of pharmacogenomics to detect (and rule out) important neuroprotective gene expression effects. PMID- 21820513 TI - Diapocynin and apocynin administration fails to significantly extend survival in G93A SOD1 ALS mice. AB - NADPH oxidase has recently been identified as a promising new therapeutic target in ALS. Genetic deletion of NADPH oxidase (Nox2) in the transgenic SOD1(G93A) mutant mouse model of ALS was reported to increase survival remarkably by 97 days. Furthermore, apocynin, a widely used inhibitor of NADPH oxidase, was observed to dramatically extend the survival of the SOD1(G93A) ALS mice even longer to 113 days (Harraz et al. J Clin Invest 118: 474, 2008). Diapocynin, the covalent dimer of apocynin, has been reported to be a more potent inhibitor of NADPH oxidase. We compared the protection of diapocynin to apocynin in primary cultures of SOD1(G93A)-expressing motor neurons against nitric oxide-mediated death. Diapocynin, 10 MUM, provided significantly greater protection compared to apocynin, 200 MUM, at the lowest statistically significant concentrations. However, administration of diapocynin starting at 21 days of age in the SOD1(G93A)-ALS mouse model did not extend lifespan. Repeated parallel experiments with apocynin failed to yield protection greater than a 5-day life extension in multiple trials conducted at two separate institutions. The maximum protection observed was an 8-day extension in survival when diapocynin was administered at 100 days of age at disease onset. HPLC with selective ion monitoring by mass spectrometry revealed that both apocynin and diapocynin accumulated in the brain and spinal cord tissue to low micromolar concentrations. Diapocynin was also detected in the CNS of apocynin-treated mice. The failure to achieve significant protection with either apocynin or diapocynin raises questions about the utility for treating ALS patients. PMID- 21820515 TI - The survival promoting peptide Y-P30 promotes cellular migration. AB - Y-P30, the 30 amino acid N-terminal peptide of the dermcidin gene, has been found to promote neuronal survival and differentiation. Its early presence in development and import to the fetal brain led to the hypothesis that Y-P30 has an influence on proliferation, differentiation and migration. Neurospheres derived from neural stem cells isolated from E13 mouse cortex and striatal ganglionic eminences were treated with Y-P30, however, the proportion of progenitors, neurons and astrocytes generated in differentiation assays was not altered. A short Y-P30 treatment of undifferentiated striatal and cortical neurospheres failed to alter the proportion of BrdU-positive cells. A longer treatment reduced the percentage of BrdU-positive cells and GABA-immunoreactive neurons only in striatal spheres. The presence of Y-P30 enhanced migration of T24 human bladder carcinoma cells in a wound-healing assay in vitro. Further, Y-P30 enhanced migration of T24 cells, rat primary cortical astrocytes and PC12 cells in chemotactic Boyden chamber assays. Together, these findings suggest that a major function of Y-P30 is to promote migration of neural and non-neural cell types. PMID- 21820517 TI - Dietary arginine and repeated handling increase disease resistance and modulate innate immune mechanisms of Senegalese sole (Solea senegalensis Kaup, 1858). AB - Stress is known to impair immune function and disease resistance in fish. In the present study, repeated handling was employed as a chronic stressor in order to verify whether its attributed immunosuppressive effects could be minimized by dietary arginine supplementation. Therefore, Senegalese sole (Solea senegalensis) were air exposed daily for 3 min during 14 days (handling) or left undisturbed (control). In addition, both control and handled specimens were fed 3 diets with graded levels of arginine (Arg 4.4, Arg 5.7 and Arg 6.9 g 16 g(-1) N). Following the 14 days stress challenge and feeding on those diets, fish were infected with Photobacterium damselae subsp. piscicida (strain PC566.1; LD(50) 5 * 10(3) cfu mL(-1)) and fed the same experimental diets. Respiratory burst activity and nitric oxide production of head-kidney leucocytes increased parallel to dietary arginine supplementation. HIF-1, HAMP-1, MIP1-alpha and gLYS expression values and some humoral parameters augmented in control specimens fed the Arg 5.7 and Arg 6.9 diets. Interestingly, repeated acute stress increased both disease resistance and some innate immune mechanisms in handled fish. The role of dietary arginine and repeated handling on Senegalese sole innate immunity and disease resistance are discussed. PMID- 21820516 TI - Solution structure and dynamics of ADF from Toxoplasma gondii. AB - Toxoplasma gondii ADF (TgADF) belongs to a functional subtype characterized by strong G-actin sequestering activity and low F-actin severing activity. Among the characterized ADF/cofilin proteins, TgADF has the shortest length and is missing a C-terminal helix implicated in F-actin binding. In order to understand its characteristic properties, we have determined the solution structure of TgADF and studied its backbone dynamics from 15N-relaxation measurements. TgADF has conserved ADF/cofilin fold consisting of a central mixed beta-sheet comprised of six beta-strands that are partially surrounded by three alpha-helices and a C terminal helical turn. The high G-actin sequestering activity of TgADF relies on highly structurally and dynamically optimized interactions between G-actin and G actin binding surface of TgADF. The equilibrium dissociation constant for TgADF and rabbit muscle G-actin was 23.81 nM, as measured by ITC, which reflects very strong affinity of TgADF and G-actin interactions. The F-actin binding site of TgADF is partially formed, with a shortened F-loop that does not project out of the ellipsoid structure and a C-terminal helical turn in place of the C-terminal helix alpha4. Yet, it is more rigid than the F-actin binding site of Leishmania donovani cofilin. Experimental observations and structural features do not support the interaction of PIP2 with TgADF, and PIP2 does not affect the interaction of TgADF with G-actin. Overall, this study suggests that conformational flexibility of G-actin binding sites enhances the affinity of TgADF for G-actin, while conformational rigidity of F-actin binding sites of conventional ADF/cofilins is necessary for stable binding to F-actin. PMID- 21820518 TI - Network modulation during complex syntactic processing. AB - Complex sentence processing is supported by a left-lateralized neural network including inferior frontal cortex and posterior superior temporal cortex. This study investigates the pattern of connectivity and information flow within this network. We used fMRI BOLD data derived from 12 healthy participants reported in an earlier study (Thompson, C. K., Den Ouden, D. B., Bonakdarpour, B., Garibaldi, K., & Parrish, T. B. (2010b). Neural plasticity and treatment-induced recovery of sentence processing in agrammatism. Neuropsychologia, 48(11), 3211-3227) to identify activation peaks associated with object-cleft over syntactically less complex subject-cleft processing. Directed Partial Correlation Analysis was conducted on time series extracted from participant-specific activation peaks and showed evidence of functional connectivity between four regions, linearly between premotor cortex, inferior frontal gyrus, posterior superior temporal sulcus and anterior middle temporal gyrus. This pattern served as the basis for Dynamic Causal Modeling of networks with a driving input to posterior superior temporal cortex, which likely supports thematic role assignment, and networks with a driving input to inferior frontal cortex, a core region associated with syntactic computation. The optimal model was determined through both frequentist and Bayesian Model Selection and turned out to reflect a network with a primary drive from inferior frontal cortex and modulation of the connection between inferior frontal cortex and posterior superior temporal cortex by complex sentence processing. The winning model also showed a substantive role for a feedback mechanism from posterior superior temporal cortex back to inferior frontal cortex. We suggest that complex syntactic processing is driven by word-order analysis, supported by inferior frontal cortex, in an interactive relation with posterior superior temporal cortex, which supports verb argument structure processing. PMID- 21820519 TI - Monophyly and phylogenetic relationships of the catfish genus Glyptothorax (Teleostei: Sisoridae) inferred from nuclear and mitochondrial gene sequences. AB - Glyptothorax Blyth (1860) is the most species-diverse and widely-distributed genus in the Sisoridae, but few studies have examined monophyly of the genus and phylogenetic relations within it. We used the nuclear RAG2 gene and mitochondrial COI and Cyt b genes from 50 of the approximately 70 species to examine monophyly of Glyptothorax and phylogenetic relationships within the genus. Molecular phylogenetic trees were constructed using maximum parsimony, maximum likelihood and Bayesian inference methods. All methods strongly supported monophyly of Glyptothorax, with Bagarius as its sister group. Both analyses of two- and three gene datasets recovered nine major subclades of Glyptothorax, but some internal nodes remained poorly resolved. The phylogenetic relationships within the genus and existing taxonomic problems are discussed. PMID- 21820520 TI - In vivo laboratory practicals in research-led teaching: an example using glucose tolerance tests in lean and obese mice. AB - The use of animal models is an essential part of medical research and drug development. The essential skills required to be able to do such research includes experimental design, statistical analysis and the actual handling and treating of the animals (in vivo skills). The number of students in the U.K. receiving training in handling and experimenting on animals has declined rapidly in the last few decades which has led to initiatives to increase numbers of students with these skills to meet demand. Within the Department of Pharmacology and Therapeutics at King's College London, we run a course for 2nd year undergraduates entitled "Animal models of disease and injury". This course not only covers the theoretical and ethical aspects of using animals in research, but also contains practical laboratory classes in which students get hands-on experience using animals. One of the laboratory classes we run is a glucose tolerance test in obese and lean mice. This is an example of research-led teaching which aims to develop research skills through engaging students in research like activities. In this paper, we outline the methodology of the glucose tolerance practical and highlight some of the skills we and the students think they gain by research-led teaching such as this. PMID- 21820521 TI - Safety and efficacy of retreatment with a bioengineered hyaluronate for painful osteoarthritis of the knee: results of the open-label Extension Study of the FLEXX Trial. AB - OBJECTIVE: To evaluate the safety of repeated intra-articular (IA) injections of Euflexxa(r) (1% sodium hyaluronate; IA--BioHA) for painful knee osteoarthritis (OA). DESIGN: Participants who completed the randomized, double-blind, 26-week FLEXX Trial comparing IA-BioHA to IA saline (IA-SA) for knee OA(1) received three weekly IA-BioHA injections in a 26-week Extension Study. Adverse events (AEs) were recorded and the effect of treatment on knee pain was measured immediately following a 50-foot walk test using a 100 mm visual analog scale (VAS). Responder rate, Medical Outcomes Study Short Form 36 scores, Patient's Global Assessment, and intake of rescue medication were also evaluated. RESULTS: The Extension Study included 433 subjects, 219 who received IA-BioHA and 214 who received IA-SA during the FLEXX Trial. Safety results from the Extension Study indicated that 43.4% (188/433) of subjects had AEs, of which 4.8% (21/433) were deemed treatment related AEs. Two AEs in the Extension Study led to discontinuation, and no joint effusion was reported. Patients who continued with IA-BioHA in the Extension Study maintained their improvement from baseline, with an average reduction in pain in the VAS score of -3.5 mm. Patients initially treated with IA-SA in the FLEXX Trial also had a reduction in VAS score of -9.0 mm. Secondary efficacy variables also improved during the Extension Study. CONCLUSIONS: Repeat injections of IA-BioHA were effective, safe, well tolerated, and not associated with an increase in AEs, such as synovial effusions. Additional symptom improvements were noted for subjects who received either IA-BioHA or IA-SA in the FLEXX Trial. CLINICAL TRIAL REGISTRATION NUMBER: NCT00379236. PMID- 21820522 TI - MicroRNAs of rat articular cartilage at different developmental stages identified by Solexa sequencing. AB - BACKGROUND: Expression profiles of microRNAs (miRNAs) can shape the repertoire of proteins expressed in development, differentiation and diseases. This study aimed to identify miRNA profile of articular cartilage at different developmental stages in rats. METHODS: Three small RNA libraries were constructed from the femoral head cartilage of Sprague-Dawley (SD) rats at postnatal day 0, day 21 and day 42 and sequenced by a deep sequencing approach. Then a bioinformatics approach was employed to distinguish genuine miRNAs from small RNAs represented in the mass sequencing data. The expression of indicated miRNAs was determined by stem-loop RT-qPCR to valuate the consistency with Solexa sequencing. RESULTS: Two hundred and fifty-eight of 310 known miRNA and miRNA* genes were organized into 91 compact clusters. Two hundred and forty-six miRNAs were detected in all three small RNA libraries of rat articular cartilage. Forty-six, fifty-two and fifty six miRNA* genes were identified from three small RNA libraries, respectively, and 86 novel miRNA candidate genes were found simultaneously. In addition, 23 known miRNAs were up-regulated (fold change >= 4); six were down-regulated (fold change <= -4) during articular cartilage development. The predicted targets of differentially expressed miRNAs were locally secreted factors and transcription factors that regulate proliferation and differentiation of chondrocytes. The same expression tendency of indicated miRNAs during articular cartilage development stages was observed by using Solexa sequencing and stem-loop RT-qPCR. CONCLUSION: Our study provided a unique opportunity to decipher how the elaboration of the miRNA repertoire contributes to the development process of articular cartilage. PMID- 21820523 TI - Current and future models for understanding airway diseases. PMID- 21820524 TI - Effect of environmental temperature on growth- and reproduction-related hormones gene expression in the female blue gourami (Trichogaster trichopterus). AB - Fish are ectothermic vertebrates, and their gonadal development and spawning are affected by changes in environmental temperature. Recent global temperature changes have increased the importance of studying the effect of temperature on reproduction. The aim of this paper was to study the effect of temperature on oogenesis and hormone gene expression related to reproduction and growth in the blue gourami female maintained under non-reproductive and reproductive conditions. In females under non-reproductive conditions, vitellogenic oocytes, gonadotropin-releasing hormone 3 (GnRH3), beta luteinizing hormone (betaLH) and growth hormone (GH) mRNA levels were affected by temperature changes. In females maintained under reproductive conditions with non-reproductively active males, a percentage of females in the final oocyte maturation (FOM) stage, pituitary adenylyl cyclase activating polypeptide (PACAP and PRP-PACAP), gonadotropins and GH mRNA levels were affected due to temperature changes. In females maintained under reproductive conditions with reproductively active males, also GnRH3 and insulin-like growth factor 1 (IGF-1) were affected by temperature changes. In conclusion, in blue gourami females, changes in environmental temperature affect oogenesis through changes in brain and pituitary hormone mRNA levels. PMID- 21820525 TI - Digestive enzyme activity of two stonefly species (Insecta, Plecoptera) and their feeding habits. AB - The digestive enzymes of two stoneflies species, Hemimelaena flaviventris and Isoperla morenica, were studied for the first time. These species are temporary water inhabitants and exhibit great feeding plasticity. Although they are traditionally referred to as predators, a previous study revealed that H. flaviventris incorporates some diatoms into its diet in addition to feeding usually on several prey, and I. morenica (in that study under the name of I. curtata) only feeds on animals occasionally. The enzymatic activities of digestive amylase, lipase, protease, trypsin and chymotrypsin were determined for each species at the same developmental stage. The results show that H. flaviventris has a greater digestive enzymatic pool and higher relative and absolute protease, lipase and trypsin activities than I. morenica. The latter has a relative higher amylase activity. As higher amylase activity is typical of phytophagous species and higher protease activity typical of carnivorous species; these results reveal that H. flaviventris is a more efficient zoophagous species than I. morenica. The ecological implications of these findings, including the higher secondary production of H. flaviventris in its habitat, are discussed. PMID- 21820527 TI - Drug development in the light of translational science: shine or shade? AB - Approximately a decade ago, translational medicine was invented both as a catchword and as a novel approach to improve success in drug development and ameliorate the low-output syndrome from collapsing pipelines. However, no major breakthroughs regarding rates of expensive late attrition or market approvals have been detected, and drug industry condensation continues to accelerate. Here, I discuss what went wrong: namely the fact that the concept does not exist apart from general claims and attributes, and no robust structures, such as toolboxes, algorithms, reproducible standards and procedures, and assessment tools have been developed and/or implemented. Translational medicine might be a clue to the survival of biomedical research, but it needs to be filled with scientific and operational substance. PMID- 21820526 TI - The candidate tumor suppressor SASH1 interacts with the actin cytoskeleton and stimulates cell-matrix adhesion. AB - SASH1, a member of the SLY-family of signal adapter proteins, is a candidate tumor suppressor in breast and colon cancer. Reduced expression of SASH1 is correlated with aggressive tumor growth, metastasis formation, and inferior prognosis. However, the biological role of SASH1 remains largely unknown. To unravel the function of SASH1, we have analyzed the intracellular localization of endogenous SASH1, and have generated structural SASH1 mutants. SASH1 localized to the nucleus as well as to the cytoplasm in epithelial cells. In addition, SASH1 was enriched in lamellipodia and membrane ruffles, where it co-distributed with the actin cytoskeleton. Moreover, we demonstrate a novel interaction of SASH1 with the oncoprotein cortactin, a known regulator of actin polymerization in lamellipodia. Enhanced SASH1 expression significantly increased the content of filamentous actin, leading to the formation of cell protrusions and elongated cell shape. This activity was mapped to the central, evolutionarily conserved domain of SASH1. Furthermore, expression of SASH1 inhibited cell migration and lead to increased cell adhesion to fibronectin and laminin, whereas knock-down of endogenous SASH1 resulted in significantly reduced cell-matrix adhesion. Taken together, our findings unravel for the first time a mechanistic role for SASH1 in tumor formation by regulating the adhesive and migratory behaviour of cancer cells. PMID- 21820528 TI - Acid suppressants and hip fracture: duplicate publication bias? PMID- 21820529 TI - Are different biological mechanisms involved in the transmission of maternal versus paternal stress-induced vulnerability to offspring? PMID- 21820530 TI - Sensitization in relation to posttraumatic stress disorder. PMID- 21820531 TI - Who is resilient to depression? Multimodal imaging of the hippocampus in preclinical chronic mild stress model may provide clues. PMID- 21820533 TI - Multidisciplinary practical guidelines for gastrointestinal access for enteral nutrition and decompression from the Society of Interventional Radiology and American Gastroenterological Association (AGA) Institute, with endorsement by Canadian Interventional Radiological Association (CIRA) and Cardiovascular and Interventional Radiological Society of Europe (CIRSE). PMID- 21820534 TI - Clinical trial registration. PMID- 21820535 TI - Normal walking speed: a descriptive meta-analysis. AB - BACKGROUND: Walking speed has implications for community functioning and is predictive of important outcomes. Determining whether an individual's walking speed is limited requires normal values for comparison. OBJECTIVES: To use meta analysis to describe normal gait speed for healthy individuals within age and gender strata. DATA SOURCES: PubMed, the Cumulative Index of Nursing and Allied Health (CINAHL), Scopus, Science Citation Index and articles identified by hand searches. STUDY SELECTION CRITERIA: Inclusion required that the gait speed of apparently healthy adults was documented as they walked at a normal pace over a course of 3 to 30 m. Summary data were excluded unless obtained from at least 10 participants within a gender and decade stratum. STUDY APPRAISAL AND SYNTHESIS METHODS: The two authors independently reviewed articles and extracted data. Accuracy was confirmed by the other author. Data were grouped within gender and decade strata. A meta-analysis macro was used to consolidate data by strata and to determine homogeneity. RESULTS: Forty-one articles contributed data to the analysis. Combined, they provided data from 23111 subjects. The gait speed was homogeneous within strata and ranged from a mean of 143.4 cm/second for men aged 40 to 49 years to a mean of 94.3 cm/second for women aged 80 to 99 years. LIMITATIONS: The data presented herein may not be useful as a standard of normal if gait is measured over short distances from the command 'go' or if a turn is involved. CONCLUSIONS AND IMPLICATIONS: The consolidation of data from multiple studies reported in this meta-analysis provides normative data that can serve as a standard against which individuals can be compared. Doing so will aid the interpretation of their performance. PMID- 21820536 TI - Is pelvic floor muscle training effective when taught in a general fitness class in pregnancy? A randomised controlled trial. AB - OBJECTIVES: Pelvic floor muscle training (PFMT) following vaginal assessment of correct contraction can prevent and treat urinary incontinence in the peripartum period. The aim of this study was to evaluate the effectiveness of PFMT instructed in a general fitness class for pregnant women. DESIGN: Single-blind randomised controlled trial. SETTING: University-conducted primary care study. PARTICIPANTS: One hundred and five sedentary primiparous women randomised to a general fitness class including PFMT (n=52) or a control group (n=53). Ten and 11 women were lost to follow-up in the exercise and control groups, respectively. INTERVENTION: Twelve weeks of training comprising twice-weekly 1-hour fitness classes including three sets of eight to 12 maximal pelvic floor muscle contractions. The control group received usual care. OUTCOME MEASURE: Number of women reporting urinary, flatus or anal incontinence. RESULTS: No significant differences were found in the number of women reporting urinary, flatus or anal incontinence between the exercise group and the control group during pregnancy or at 6 weeks post partum. CONCLUSIONS: No effect of PFMT was found when the exercises were taught in a general fitness class for pregnant women without individual instruction of correct PFM contraction. Low adherence and the small sample size may have contributed to the negative results. Further studies are warranted to assess the effect of population-based PFMT in the prevention of urinary and fecal incontinence. PMID- 21820537 TI - The sensitivity, specificity and reliability of the GALS (gait, arms, legs and spine) examination when used by physiotherapists and physiotherapy students to detect rheumatoid arthritis. AB - OBJECTIVE: To evaluate the sensitivity, specificity and reliability of the gait, arms, legs and spine (GALS) examination to detect signs and symptoms of rheumatoid arthritis when used by physiotherapy students and physiotherapists. METHODS: Two physiotherapy students and two physiotherapists were trained to perform the GALS examination by viewing an instructional DVD and attending a workshop. Two rheumatologists familiar with the GALS examination also participated in the workshop. All healthcare professionals performed the GALS examination on 25 participants with rheumatoid arthritis recruited through a rheumatology practice and 23 participants without any arthritides recruited from a primary care centre. Each participant was assessed by one rheumatologist, one physiotherapist and one physiotherapy student. Abnormalities of gait, arms, legs and spine, including their location and description, were recorded, along with whether or not a diagnosis of rheumatoid arthritis was suspected. Healthcare professionals understood the study's objective to be their agreement on GALS findings and were unaware that half of the participants had rheumatoid arthritis. Sensitivity, specificity and likelihood ratios were calculated to determine the ability of the GALS examination to screen for rheumatoid arthritis. RESULTS: Using rheumatologists' findings on the study day as the standard for comparison, sensitivity and specificity were 71 to 86% and 69 to 93%, respectively. Positive likelihood ratios ranged from 2.74 to 10.18, while negative likelihood ratios ranged from 0.21 to 0.38. CONCLUSIONS: The GALS examination may be a useful tool for physiotherapists to rule out rheumatoid arthritis in a direct access setting. Differences in duration and type of experience of each healthcare professional may contribute to the variation in results. The merits of introducing the GALS examination into physiotherapy curricula and practice should be explored. PMID- 21820538 TI - Exploring the use of the 'Adapted Miracle Question' in the assessment of low back pain. AB - BACKGROUND: Low back pain is a complex condition, often recurring or chronic, which has proved difficult to characterise. To explore an alternative approach to assessing low back pain, an expert panel adapted the 'Miracle Question' from Solution-Focused Brief Therapy. This asks about a forward scenario of waking without the problems that the client had presented with. The question was adapted to: What would you do if you did not have back pain? OBJECTIVES: To explore the use of the Adapted Miracle Question (AMQ) within an interview study of patients with low back pain. DESIGN, SETTING AND PARTICIPANTS: The AMQ was used in an interview study of 34 participants recruited from the UK Back Skills Training (BeST) trial, assessing the effectiveness of a cognitive behavioural approach intervention for the management of low back pain. Responses to the AMQ were analysed thematically and then case by case. RESULTS: Interviewees talked about details of their activities and ability to function that would be different, and about change to their quality of life. Some talked about work. Five interviewees said that it would make no difference to them. When considered overall, the responses could be categorised as: no change; some change in activity/function; a return to their pre-back pain state; and life would be transformed. CONCLUSION: The AMQ was straightforward to ask and prompted a breadth of responses which may be useful in tailoring treatment. This question warrants further evaluation in the clinical setting. PMID- 21820539 TI - Musculoskeletal techniques for clinically stable adults with cystic fibrosis: a preliminary randomised controlled trial. AB - AIMS: To assess the sensitivity of selected outcome measures to any change resulting from treatment of adults with cystic fibrosis with physiotherapy musculoskeletal techniques, use the data for sample size calculations for future studies and assess the acceptability of the methods to potential participants. DESIGN: Preliminary, prospective, single-blind, randomised controlled trial. SETTING: Specialist cystic fibrosis centre. PARTICIPANTS: Adults recruited from a cystic fibrosis outpatient clinic. INTERVENTIONS: The control group received normal optimal physiotherapy care and the intervention group received weekly musculoskeletal treatment for 6 weeks in addition to normal optimal physiotherapy care. OUTCOME MEASURES: Recorded at baseline, 3, 6 and 12 weeks. The outcome measures were posture (thoracic index), chest wall excursion, forced expiratory volume in 1 second (FEV1), visual analogue scale for pain, modified shuttle test and Cystic Fibrosis Quality of Life Questionnaire--Section One (physical functioning). STATISTICAL ANALYSIS: Descriptive statistics [using medians and interquartile ranges (IQRs)] and linear regression mixed model. RESULTS: From a total of 20 subjects, 10 were randomised to each group. Fifty percent of subjects were male, with a median age of 27 years (IQR 25 to 34), median FEV(1) of 1.75 l (IQR 1.4 to 2.4) and median body mass index of 20.8 (IQR 20.0 to 23.5). Baseline differences between groups in thoracic index and modified shuttle test made any differences difficult to interpret, but the results for thoracic index and chest wall excursion at the third rib in the treatment group showed a trend towards improvement. The usefulness of FEV1, the visual analogue scale for pain and the Cystic Fibrosis Quality of Life Questionnaire as measures is unclear. CONCLUSION: Further musculoskeletal studies in people with cystic fibrosis should consider using thoracic index and a measure of lung function in addition to FEV1. The musculoskeletal techniques appear to be acceptable to people with cystic fibrosis, and do not seem to have associated adverse effects. PMID- 21820540 TI - Master's level study: learning transitions towards clinical expertise in physiotherapy. AB - BACKGROUND: Evidence suggests that practitioners who successfully complete a UK Master's level course, accredited by the Manipulation Association of Chartered Physiotherapists (MACP), enhance their clinical practice and demonstrate attributes of clinical expertise. What remains unclear is the process by which practitioners change and enhance their practice. Greater understanding of the learning process would help to inform programme design and delivery, and enhance the quality of the educational experience and impact for practitioners. OBJECTIVE: To explain the learning process experienced by physiotherapists on completion of an MACP-approved Master of Science (MSc) course. DESIGN: A naturalistic inquiry was conducted using a single theory-seeking case study. Dimensional analysis was used to develop a substantive theory of the learning transition. PARTICIPANTS: Twenty-six semi-structured interviews were carried out with 11 alumni from one MACP-approved MSc programme. RESULTS: The learning transition was from uncritical practice knowledge with routine, therapist-centred clinical practice to critical understanding of practice knowledge that enabled patient-centred practice and the capability to learn in, and from, practice. This development towards clinical expertise was primarily facilitated by critical evaluation of practice knowledge, particularly through mentorship in clinical practice. This highly challenging experience was helped by high levels of support from the mentor. The learning transition varied between participants and depended on a host of moderating factors. CONCLUSION: This is the first documented theoretical explanation of how physiotherapists enhance their clinical practice and develop attributes of clinical expertise within an MACP-approved MSc course. This explanatory theory may be of value for educational programmes that seek to facilitate practitioners' development towards clinical expertise. This study also offers a novel model of learning transition that may be applicable to other educational settings. PMID- 21820541 TI - User experiences, preferences and choices relating to functional electrical stimulation and ankle foot orthoses for foot-drop after stroke. AB - OBJECTIVES: To explore experiences, preferences and choices relating to the use of ankle foot orthoses (AFOs) and functional electrical stimulation (FES) for foot-drop by people who have suffered a stroke and their carers, with the aim of informing clinical decision-making. DESIGN: Semi-structured interviews explored individual experiences through a phenomenological approach. The Interpretative Phenomenological Analysis framework was used to enable organisation and interpretation of qualitative interview data. SETTING: Participants who had used both transcutaneous FES and one of several types of AFO were recruited from a single FES clinic. PARTICIPANTS: Nine people who had suffered a stroke and four carers were recruited purposively, including people between 2 and 9 years post stroke, with different degrees of difficulty in walking. RESULTS: Participants described experiences, preferences and choices relating to AFO and FES use. All but one person expressed a preference for FES use and related this to being able to move the ankle more freely; walk more normally, safely and independently; and greater comfort. Several people also used AFOs when the FES equipment failed, when travelling and near water. One person rationed their use of FES on a daily basis due to allergic reactions. CONCLUSIONS: The consensus in this sample demonstrated positive and negative experiences of both FES and AFO use. Participants weighed up the pros and cons, and despite predominant preferences for FES, many also used AFOs due to some drawbacks of FES. Further research and development are required to reduce drawbacks and further explore users' experiences. PMID- 21820542 TI - Postmastectomy lymphoedema: different patterns of fluid distribution visualised by ultrasound imaging compared with magnetic resonance imaging. AB - OBJECTIVES: Postmastectomy lymphoedema remains a disabling complication caused by treatment for breast cancer. The increased thickness of the dermal layer and the increased volume of the subcutis represent the most important contributions to the total swelling of the arm. Ultrasound imaging of the subcutaneous layer results in different patterns of reflected ultrasound waves depending on the morphological alternations that occurred due to impaired lymphatic drainage. The aim of this study was to compare these echographic images with those obtained using magnetic resonance imaging to explain the nature of the morphological changes. DESIGN: Observational study. SETTING: Patients were recruited from the Breast Clinic at the University Hospital Brussels. PARTICIPANTS: Seven women (mean age 60 years) with unilateral breast cancer who subsequently developed lymphoedema. MAIN OUTCOME MEASURES: The water displacement technique was applied to determine arm volumes, and echographic and magnetic resonance images were used to evaluate changes in tissue structures. RESULTS: Volumetric measurements of the arm (mean affected arm 3241 ml vs unaffected arm 2538 ml) showed a significant increase in total arm volume of 703 ml (95% confidence interval 324 to 1084 ml). Using echography, the thickness of the dermal and subcutaneous layers showed an average increase of 0.2 to 0.8mm and 3.9 to 7.2mm, respectively. The differences between the affected arm and the unaffected arm for all upper and lower arm measurements (i.e. volumetry, dermal and subcutaneous thickness) were significant, but no significant differences were registered for hand measurements. On echography, the dermis showed uniform changes, with a homogenous hypo-echogenic appearance compared with the contralateral side due to water influx. Different patterns of structural changes could be visualised within the subcutis: (1) uniformly hypo-echogenic due to the diffuse spread of water through the subcutis; (2) hyperechogenic areas surrounded by hypo-echogenic streaks visualised on magnetic resonance imaging as adipose tissue surrounded by fluid embedded in fibrous tissue; and (3) homogenously hyperechogenic due to the overgrowth of adipose tissue with a minimal amount of water. CONCLUSIONS: Echographic images can help to determine the likelihood that complex physical therapy will reduce lymphoedema, and evaluate treatment results by measuring tissue thickness and evaluating tissue consistency. PMID- 21820543 TI - A plantar flexion device exercise programme for patients with peripheral arterial disease: a randomised prospective feasibility study. AB - OBJECTIVES: To determine if the use of a plantar flexion device (Step It pedal) in a newly developed exercise programme is of benefit to patients with peripheral arterial disease. DESIGN: Prospective feasibility trial with patients randomised to either standard care or the Step It exercise programme plus standard care. SETTING: Physiotherapy Department at Cumberland Infirmary, Carlisle, UK. PARTICIPANTS: Patients were identified from the vascular team's referral list. In total, 42 patients agreed to take part; 18 in the control group and 24 in the intervention group. INTERVENTIONS: Eligible participants were randomised and received either standard care or took part in a plantar flexion resistance exercise programme, involving the Step It pedal, for a period of 12 weeks. MAIN OUTCOME MEASURES: Maximum walking distance, claudication distance and ankle brachial pressure index. RESULTS: Eighty-three percent of patients completed the study. Improvements in median distance to claudication symptoms and maximum walking distance were observed in the intervention group but not in the control group. Nine out of 15 (60%) participants in the control group and 14 out of 20 (70%) participants in the intervention group improved their walking distance. Ankle brachial pressure index remained virtually unchanged in both groups. CONCLUSIONS: Due to the variability of patients' fitness in the sample, it cannot be concluded whether use of the Step It pedal has additional benefits to patients over standard care. However, the study completion rate implies that patients with peripheral arterial disease are receptive to undertaking exercise programmes. PMID- 21820544 TI - Effect of motion control running shoes compared with neutral shoes on tibial rotation during running. AB - OBJECTIVE: To determine whether a motion control running shoe reduces tibial rotation in the transverse plane during treadmill running. DESIGN: An experimental study measuring tibial rotation in volunteer participants using a repeated measures design. SETTING: Human Movement Laboratory, School of Health Professions, University of Brighton. PARTICIPANTS: Twenty-four healthy participants were tested. The group comprised males and females with size 6, 7, 9 and 11 feet. The age range for participants was 19 to 31 years. MAIN OUTCOME MEASURES: The total range of proximal tibial rotation was measured using the Codamotion 3-D Movement Analysis System. RESULTS: A one-tailed paired t-test indicated a statistically significant decrease in the total range of proximal tibial rotation when a motion control shoe was worn (mean difference 1.38 degrees , 95% confidence interval 0.03 to 2.73, P=0.04). CONCLUSIONS: There is a difference in tibial rotation in the transverse plane between a motion control running shoe and a neutral running shoe. The results from this study have implications for the use of supportive running shoes as a form of injury prevention. PMID- 21820545 TI - Should physiotherapists use acupuncture for treating patients with cancer-induced bone pain? A discussion paper. AB - BACKGROUND: Patients suffering from pain due to bony metastases in cancer represent a challenge to the physiotherapist as part of the multidisciplinary team. Adequate pain relief improves quality of life and functional status, yet conventional analgesia often has undesirable side-effects and non-pharmacological treatments (e.g. some electrotherapies) may be contraindicated in cancer. Acupuncture is a potential treatment for cancer-induced bone pain (CIBP) as it has few side effects and is relatively easy to administer. There is a dearth of research on the use of acupuncture in treating CIBP and some practitioners express fears about treating cancer patients with acupuncture. OBJECTIVES: To discuss the use of acupuncture for CIBP by reviewing the physiological rationale for using acupuncture to treat CIBP and the risks and benefits of using acupuncture in clinical practice. DATA SOURCES: Evidence was identified by searching seven major databases: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, PsycINFO, AMED and SPORTDiscus. Evidence was synthesised by the authors to raise issues and discussion points within a narrative review framework. FINDINGS: Available physiological evidence supports potentially efficacious effects of acupuncture for reduction of CIBP. Clinical literature suggests that acupuncture may be effective as an adjunctive treatment for CIBP and that risks are manageable. However, there is a need for well designed randomised controlled trials to investigate efficacy and effectiveness in patients. CONCLUSIONS: Acupuncture has the potential to provide sustained background analgesia and/or rapid onset analgesia for breakthrough pain if the appropriate points and techniques are used. PMID- 21820546 TI - Preservation of lower limb strength after a short course of pulmonary rehabilitation with no maintenance: a 6-month follow-up study. PMID- 21820547 TI - Repeated application of self-adhesive transcutaneous electrical nerve stimulation electrodes: an assessment of skin microflora. PMID- 21820548 TI - Cutting-edge methodologies applied to the challenges of Chagas disease. PMID- 21820549 TI - Epidemiology of American trypanosomiasis (Chagas disease). AB - Trypanosoma cruzi, the cause of American trypanosomiasis, or Chagas disease, is a protozoan parasite that is enzootic and endemic in much of the Americas, where it infects a wide variety of wild and domestic mammals as well as many species of triatomine vectors, in addition to humans. Historically, vector-borne transmission of T. cruzi has been the most important mechanism through which humans have become infected with the parasite, but transmission by blood transfusion and congenital transmission also have been important. In many of the endemic countries transmission of T. cruzi has improved markedly in recent years as vector control and donor screening programs have been implemented on a widespread basis. In the United States autochthonous transmission of T. cruzi appears to be extremely rare. Five persons are known to have become infected with T. cruzi through organ transplants here, and prior to the implementation of blood donor screening in 2007 five instances of transmission by transfusion had been reported. Current estimates put the total number of T. cruzi-infected persons living in the United States at 300,000, essentially all of whom are immigrants from the endemic countries. The obstacles that stand in the way of the total elimination of T. cruzi transmission throughout the endemic range are economic and political, and no major technological advances are needed to accomplish this goal. PMID- 21820550 TI - Acute and congenital Chagas disease. AB - The acute phase of Chagas disease lasts 4-8 weeks and is characterized by microscopically detectable parasitaemia. Symptoms are usually mild with severe acute disease occurring in less than 1% of patients. Orally transmitted Trypanosoma cruzi outbreaks can have more severe acute morbidity and higher mortality than vector-borne infection. Congenital T. cruzi infection occurs in 1 10% of infants of infected mothers. Most congenital infections are asymptomatic or cause non-specific signs, requiring laboratory screening for detection. A small proportion of congenital infections cause severe morbidity with hepatosplenomegaly, anaemia, meningoencephalitis and/or respiratory insufficiency, with an associated high mortality. Infected infants are presumed to carry the same 20-30% lifetime risk of cardiac or gastrointestinal disease as other infected individuals. Most control programs in Latin America employ prenatal serological screening followed by microscopic examination of cord blood from infants of seropositive mothers. Recent data confirm that polymerase chain reaction (PCR) is more sensitive and detects congenital infections earlier than conventional techniques. For infants not diagnosed at birth, conventional serology is recommended at at 6 to 9 months of age. In programs that have been evaluated, less than 20% of at risk infants completed all steps of the screening algorithm. A sensitive, specific and practical screening test for newborns is needed to enable Chagas disease to be added to newborn screening programs. PMID- 21820551 TI - Cell-based therapy in Chagas disease. AB - Chagas disease was first described one century ago, yet the mechanisms underlying chagasic cardiomyopathy remain elusive. Disease progression often leads to heart failure and patients with this infectious cardiomyopathy have a poor prognosis. Treatment options for heart failure due to Chagas disease are not different from standard therapy. Over the past decade, cell-based therapies have emerged as a new alternative in the treatment of this disease, not only because of the possibility of replacing lost vessels and cardiomyocytes but also because these cells could potentially influence the microenvironmental changes that perpetuate the disease. In this chapter, we will review current knowledge on cell-based therapies for the treatment of Chagas disease. PMID- 21820553 TI - Experimental chemotherapy and approaches to drug discovery for Trypanosoma cruzi infection. AB - In the 100 years since the discovery of Chagas disease, only two drugs have been developed and introduced into clinical practice, and these drugs were introduced over 40 years ago. The tools of drug discovery have improved dramatically in the interim; however, this has not translated into new drugs for Chagas disease. This has been largely because the main practitioners of drug discovery are pharmaceutical companies who are not financially motivated to invest in Chagas disease and other "orphan" diseases. As a result, it has largely been up to academic groups to bring drug candidates through the discovery pipeline and to clinical trials. The difficulty with drug discovery in academia has been the challenge of bringing together the diverse expertise in biology, chemistry, and pharmacology in concerted efforts towards a common goal of developing therapeutics. Funding is often inadequate, but lack of coordination amongst academic investigators with different expertise has also contributed to the slow progress. The purpose of this chapter is to provide an overview of approaches that can be accomplished in academic settings for preclinical drug discovery for Chagas disease. The chapter addresses methods of drug screening against Trypanosoma cruzi cultures and in animal models and includes general topics on compound selection, testing for drug-like properties (including oral bioavailability), investigating the pharmacokinetics and toxicity of compounds, and finally providing parameters to help with triaging compounds. PMID- 21820552 TI - Targeting Trypanosoma cruzi sterol 14alpha-demethylase (CYP51). AB - There are at least two obvious features that must be considered upon targeting specific metabolic pathways/enzymes for drug development: the pathway must be essential and the enzyme must allow the design of pharmacologically useful inhibitors. Here, we describe Trypanosoma cruzi sterol 14alpha-demethylase as a promising target for anti-Chagasic chemotherapy. The use of anti-fungal azoles, which block sterol biosynthesis and therefore membrane formation in fungi, against the protozoan parasite has turned out to be highly successful: a broad spectrum anti-fungal drug, the triazole compound posaconazole, is now entering phase II clinical trials for treatment of Chagas disease. This review summarizes comparative information on anti-fungal azoles and novel inhibitory scaffolds selective for Trypanosomatidae sterol 14alpha-demethylase through the lens of recent structure/functional characterization of the target enzyme. We believe our studies open wide opportunities for rational design of novel, pathogen-specific and therefore more potent and efficient anti-trypanosomal drugs. PMID- 21820554 TI - Vaccine development against Trypanosoma cruzi and Chagas disease. AB - The pathology of Chagas disease presents a complicated and diverse picture in humans. The major complications and destructive evolutionary outcomes of chronic infection by Trypanosoma cruzi in humans include ventricular fibrillation, thromboembolism and congestive heart failure. Studies in animal models and human patients have revealed the pathogenic mechanisms during disease progression, pathology of disease and features of protective immunity. Accordingly, several antigens, antigen-delivery vehicles and adjuvants have been tested to elicit immune protection to T. cruzi in experimental animals. This review summarizes the research efforts in vaccine development against Chagas disease during the past decade. PMID- 21820555 TI - Genetic epidemiology of Chagas disease. AB - Genetic epidemiological approaches hold great promise for improving the understanding of the determinants of susceptibility to infection with Trypanosoma cruzi and the causes of differential disease outcome in T. cruzi-infected individuals. To date, a variety of approaches have been used to understand the role of genetic factors in Chagas disease. Quantitative genetic techniques have been used to estimate the heritabilities for seropositivity for T. cruzi infection and traits that are associated with disease progression in chronic T. cruzi infection. These studies have demonstrated that a significant proportion of the variation in seropositivity and a number of traits related to Chagas disease progression is attributable to genetic factors. Candidate gene studies have provided intriguing evidence for the roles of numerous individual genes in determining cardiac outcomes in chronically infected individuals. Recent results from a long-term study of Chagas disease in a rural area of Brazil have documented that over 60% of the variation in seropositivity status is attributable to genetic factors in that population. Additionally, there are significant genetic effects on a number of electrocardiographic measures and other Chagas disease-related traits. The application of genome-wide approaches will yield new evidence for the roles of specific genes in Chagas disease. PMID- 21820556 TI - Kissing bugs. The vectors of Chagas. AB - A complete picture of Chagas disease requires an appreciation of the many species of kissing bugs and their role in transmitting this disease to humans and other mammals. This chapter provides an overview of the taxonomy of the major species of kissing bugs and their evolution. Knowledge of systematics and biological kinship of these insects may contribute to novel and useful measures to control the bugs. The biology of kissing bugs, their life cycle, method of feeding and other behaviours contributing to the transmission of Trypanosoma cruzi are explained. We close with a discussion of vector control measures and the allergic complications of kissing bug bites, a feature of particular importance in the United States. PMID- 21820557 TI - Advances in imaging of animal models of Chagas disease. AB - Since serial studies of patients are limited, researchers interested in Chagas disease have relied on animal models of Trypanosoma cruzi infection to explore many aspects of this important human disease. These studies have been important for evaluation of the immunology, pathology, physiology and other aspects of pathogenesis. While larger animals have been employed, mice have remained the most favoured animal model, as they recapitulate many aspects of the human disease, are easy to manipulate genetically and are amenable to study by small animal imaging technologies. Further, developments in non-invasive imaging technologies have permitted the study of the same animal over an extended period of time by multiple imaging modalities, thus permitting the study of the transition from acute infection through the chronic stage and during therapeutic regimens. PMID- 21820558 TI - The genome and its implications. AB - Trypanosoma cruzi has a heterogeneous population composed of a pool of strains that circulate in the domestic and sylvatic cycles. Genome sequencing of the clone CL Brener revealed a highly repetitive genome of about 110Mb containing an estimated 22,570 genes. Because of its hybrid nature, sequences representing the two haplotypes have been generated. In addition, a repeat content close to 50% made the assembly of the estimated 41 pairs of chromosomes quite challenging. Similar to other trypanosomatids, the organization of T. cruzi chromosomes was found to be very peculiar, with protein-coding genes organized in long polycistronic transcription units encoding 20 or more proteins in one strand separated by strand switch regions. Another remarkable feature of the T. cruzi genome is the massive expansion of surface protein gene families. Because of the high genetic diversity of the T. cruzi population, sequencing of additional strains and comparative genomic and transcriptome analyses are in progress. Five years after its publication, the genome data have proven to be an essential tool for the study of T. cruzi and increasing efforts to translate this knowledge into the development of new modes of intervention to control Chagas disease are underway. PMID- 21820559 TI - Genetic techniques in Trypanosoma cruzi. AB - It is almost 20 years since genetic manipulation of Trypanosoma cruzi was first reported. In this time, there have been steady improvements in the available vector systems, and the applications of the technology have been extended into new areas. Episomal vectors have been modified to enhance the level of expression of transfected genes and to facilitate the sub-cellular location of their products. Integrative vectors have been adapted to allow the development of inducible expression systems and the construction of vectors which enable genome modification through telomere-associated chromosome fragmentation. The uses of reverse genetic approaches to dissect peroxide metabolism and the mechanisms of drug activity and resistance in T. cruzi are illustrated in this chapter as examples of how the technology has been used to investigate biological function. Although there remains scope to improve the flexibility of these systems, they have made valuable contributions towards exploiting the genome sequence data and providing a greater understanding of parasite biology and the mechanisms of infection. PMID- 21820560 TI - Nuclear structure of Trypanosoma cruzi. AB - The presence of nucleus in living organisms characterizes the Eukaryote domain. The nucleus compartmentalizes the genetic material surrounded by a double membrane called nuclear envelope. The nucleus has been observed since the advent of the light microscope, and sub-compartments such as nucleoli, diverse nuclear bodies and condensed chromosomes have been later recognized, being part of highly organized and dynamic structure. The significance and function of such organization has increased with the understanding of transcription, replication, DNA repair, recombination processes. It is now recognized as consequence of adding complexity and regulation in more complex eukaryotic cells. Here we provide a description of the actual stage of knowledge of the nuclear structure of Trypanosoma cruzi. As an early divergent eukaryote, it presents unique and/or reduced events of DNA replication, transcription and repair as well as RNA processing and transport to the cytosol. Nevertheless, it shows peculiar structure changes accordingly to the cell cycle and stage of differentiation. T. cruzi proliferates only as epimastigote and amastigote stages, and when these forms differentiate in trypomastigote forms, their cell cycle is arrested. This arrested stage is capable of invading mammalian cells and of surviving harsh conditions, such as the gut of the insect vector and mammalian macrophages. Transcription and replication decrease during transformation in trypomastigotes implicating large alterations in the nuclear structure. Recent evidences also suggest that T. cruzi nucleus respond to oxidative and nutritional stresses. Due to the phylogenetic proximity with other well-known trypanosomes, such as Trypanosoma brucei and Leishmania major, they are expected to have similar nuclear organization, although differences are noticed due to distinct life cycles, cellular organizations and the specific adaptations for surviving in different host environments. Therefore, the general features of T. cruzi nuclear structure regarding unique characteristics of this protozoan parasite will be described. PMID- 21820561 TI - Aspects of Trypanosoma cruzi stage differentiation. AB - Trypanosoma cruzi alternates between different morphological and functional types during its life cycle. Since the discovery of this parasite at the beginning of the twentieth century, efforts have been made to determine the basis of its pathogenesis in the course of Chagas disease and its biochemical constituents. There has also been work to develop tools and strategies for prophylaxis of the important disease caused by these parasites which affects millions of people in Latin America. The identification of axenic conditions allowing T. cruzi growth and differentiation has led to the identification and characterization of stage specific antigens as well as a better characterization of the biological properties and biochemical particularities of each individual developmental stage. The recent availability of genomic data should pave the way to new progress in our knowledge of the biology and pathogenesis of T. cruzi. This review addresses the differentiation and major stage-specific antigens of T. cruzi and attempts to describe the complexity of the parasite and of the disease it causes. PMID- 21820563 TI - Signal transduction in Trypanosoma cruzi. AB - Signal transduction plays a key role in regulating important functions in both multicellular and unicellular organisms and largely controls the manner in which cells respond to stimuli. Signal transduction pathways coordinate the functions in different type of cells in animals and control the growth and differentiation in unicellular organisms. Intracellular signal transduction pathways are largely activated by second messenger molecules. Trypanosoma cruzi has a complex life cycle involving four morphogenetic stages with various second messenger systems able to regulate its growth and differentiation. Signal transduction often alters the status of phosphorylation in target proteins and thus alters the activities of these proteins. In this review, two major signal transduction pathways, cyclic AMP-dependent pathway and mitogen-activated protein kinase pathway, are discussed. Protein phosphatases are also discussed due to their importance in dephosphorylating target proteins and terminating signal transduction. Understanding of the unique pathways in this pathogen may lead to the development of novel therapeutic agents. PMID- 21820562 TI - The role of acidocalcisomes in the stress response of Trypanosoma cruzi. AB - Acidocalcisomes of Trypanosoma cruzi are acidic calcium-containing organelles rich in phosphorus in the form of pyrophosphate (PP(i)) and polyphosphate (poly P). Acidification of the organelles is driven by vacuolar proton pumps, one of which, the vacuolar-type proton pyrophosphatase, is absent in mammalian cells. A calcium ATPase is involved in calcium uptake, and an aquaporin is important for water transport. Enzymes involved in the synthesis and degradation of PPi and poly P are present within the organelle. Acidocalcisomes function as storage sites for cations and phosphorus, participate in PP(i) and poly P metabolism and volume regulation and are essential for virulence. A signalling pathway involving cyclic AMP generation is important for fusion of acidocalcisomes to the contractile vacuole complex, transference of aquaporin and volume regulation. This pathway is an excellent target for chemotherapy as shown by the effects of phosphodiesterase C inhibitors on parasite survival. PMID- 21820564 TI - Editorial comment. PMID- 21820566 TI - Editorial comment. PMID- 21820568 TI - Editorial comment. PMID- 21820570 TI - Editorial comment. PMID- 21820571 TI - Comparative efficacy of commercially available and emerging antimicrobial urinary catheters against bacteriuria caused by E. coli in vitro. AB - OBJECTIVES: To compare the efficacy of both commercially available and emerging urinary catheter technologies in relation to their effects on bacteriuria caused by Escherichia coli in vitro. Antiseptic urinary catheters have recently become commercially available and others are in the developmental stage. METHODS: Silver alloy-coated catheters, antibiotic Nitrofurazone (NF)-coated catheters, and nitric oxide (NO)-coated catheters were tested against a noncoated control for their antiseptic ability. Inhibition of bacterial growth, biofilm formation, and the number of live bacteria within the biofilm, using up to 10(3) bacterial load were evaluated. Experiments were performed either in E. coli containing Luria broth media or in urine infected with E. coli. RESULTS: NF- and NO-coated catheters had equivalent antimicrobial activity and eradicated all bacteria in planktonic and biofilm states. Silver-coated catheters had no effect on E. coli growth or biofilm formation compared with the control, although silver-coated catheters did inhibit bacterial levels within the biofilm by 50%. CONCLUSIONS: NF and NO-coated catheters are highly effective in preventing planktonic growth and biofilm formation. Silver-coated catheters were not found to be effective in this study. PMID- 21820573 TI - Editorial comment. PMID- 21820574 TI - Editorial comment. PMID- 21820576 TI - BioGlue iceball stabilization to minimize the risk of hemorrhage during laparoscopic renal cryoablation. AB - OBJECTIVE: To evaluate the application of a BioGlue adhesive shell to minimize iceball fracture. Iceball fracture and hemorrhage is common with laparoscopic cryoablation (LCA) of larger (>4 cm) renal tumors. METHODS: Twenty large iceballs were created in porcine kidneys using 3 cryoablation probes in a nonsurvival study. Each kidney underwent an upper and lower pole ablation. One pole in each kidney was covered with 5 mL of BioGlue and the opposite pole served as a control. A double freeze-thaw cycle was performed (10 minutes freeze and 5 minutes active thaw) in both renal poles simultaneously. The probes were removed and the sites were monitored for 20 minutes under direct vision. Fracture length (mm), severity of fracture depth, severity of bleeding (absent, mild, moderate, severe), and estimated blood loss (EBL) (mL) were recorded. RESULTS: In the control group, the mean fracture length was 1.9 mm (range, 0-3 mm). Blood loss was absent in 10%, mild in 60%, and moderate in 30% of ablations. The mean EBL was 20.5 mL (range, 0-50 mL). For the BioGlue ablations, there were no parenchymal fractures. Blood loss was mild in 30% and absent in 70% of sites with an average EBL of 5 mL (range, 0-20). Two bleeding sites occurred as a result of subcapsular hematomas caused by initial probe placement. CONCLUSIONS: BioGlue application minimized the frequency and magnitude of renal fracture. EBL was lower with BioGlue application and most sites demonstrated no postablation bleeding. Further clinical study of the BioGlue shell should be performed to confirm these results. PMID- 21820577 TI - Editorial comment. PMID- 21820579 TI - Editorial comment. PMID- 21820580 TI - Prostate cancer gene 3 score predicts prostate biopsy outcome in men receiving dutasteride for prevention of prostate cancer: results from the REDUCE trial. AB - OBJECTIVES: To examine the ability of the urinary prostate cancer gene 3 (PCA3) assay to predict biopsy-detected cancers in men receiving dutasteride in the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) study cohort. METHODS: Urine and serum samples from 930 men in the active arm were acquired at years 2 and 4 of the biopsy visits. In addition to univariate logistic regression and receiver operating characteristic analysis, multivariate analysis for association with biopsy outcome was performed for PCA3 score in the presence of serum prostate-specific antigen (PSA), age, prostate volume, and family history of prostate cancer. RESULTS: At year 2, the univariate PCA3 score area under the receiver operating characteristic curve (AUC) was 0.668 versus 0.603 for PSA. At year 4, the PCA3 assay significantly predicted the biopsy outcome (AUC 0.628, 95% confidence interval 0.556-0.700), and the PSA level was not predictive (AUC 0.556, 95% confidence interval 0.469-0.642). The year 2 multivariate model yielded an AUC of 0.712. Removing the PCA3 score decreased the AUC to 0.660 (P = .0166 vs the full model). The median PCA3 scores in the dutasteride arm were not different from those in the 1072 men in the placebo arm (16.2 and 17.2 at year 2, P = .1755; and 18.8 and 18.1 at year 4, P = .2340, respectively). However, the PSA values were reduced >50% in the dutasteride arm at both visits (both P < .0001 vs placebo). At a PCA3 score cutoff of 35, the sensitivity and specificity were equivalent between the 2 arms. CONCLUSIONS: In the present study, the PCA3 assay outperformed PSA for cancer detection in men undergoing dutasteride treatment and improved the diagnostic accuracy when combined with the PSA level and other clinical variables. In addition, no adjustment in PCA3 score was needed to yield equivalent clinical performance between the dutasteride and placebo arms. These findings are particularly important in light of the potential role of dutasteride for prostate cancer chemoprevention. PMID- 21820581 TI - Editorial comment. PMID- 21820583 TI - Editorial comment. PMID- 21820584 TI - Editorial comment. PMID- 21820585 TI - First percutaneous computed tomography-guided radiofrequency ablation of renal tumor in horseshoe kidney. AB - OBJECTIVE: To report the first case of percutaneous radiofrequency ablation of a tumor in a horseshoe kidney. MATERIALS AND METHODS: A 75-year-old man presented with a 3-cm solid mass on the isthmus of a horseshoe kidney. The tumor was discovered incidentally on a routine computed tomography scan performed during follow-up of a colon carcinoma treated with open hemicolectomy. The patient presented a high anesthetic risk (American Society of Anesthesiologists score of 3) because of a comorbid cardiovascular condition. Biopsy of the mass revealed type I papillary carcinoma. We performed percutaneous radiofrequency ablation using a posterior approach. RESULTS: No complications occurred, and postoperative computed tomography 3 months after the procedure showed no significant contrast enhancement in the treated area. CONCLUSIONS: To our knowledge, this is the first case of a tumor in a horseshoe kidney satisfactorily treated with percutaneous radiofrequency ablation. The technique could represent an alternative to traditional surgery in selected cases. PMID- 21820586 TI - miR-21 modulates cell apoptosis by targeting multiple genes in renal cell carcinoma. AB - OBJECTIVES: To explore the mechanism of miR-21 involved in the development of renal cell carcinoma. METHODS: Cell proliferation and apoptosis were measured after repression of miR-21 expression by antisense oligonucleotides. miR-21 targets were scanned using target prediction programs. After reduction of miR-21, Fas ligand and metalloproteinase inhibitor 3 (TIMP3) expression and luciferase activity were detected by Western blot and luciferase reporter assay. The effect of TIMP3 on miR-21-induced cell survival was determined by transfection with TIMP3 lacking 3' untranslated region and miR-21. RESULTS: The reduction of miR-21 by antisense oligonucleotides inhibited cell proliferation and induced cell apoptosis by activation of caspase pathway in renal cell carcinoma cells. Moreover, bioinformatics analysis revealed that miR-21 has the potential to regulate multiple apoptosis-related genes. The reduction of miR-21 inhibited Fas ligand and TIMP3 expression by targeting the binding site within the 3' untranslated region. Finally, the introduction of TIMP3 cDNA without 3' untranslated region abrogated miR-21-induced cell survival. CONCLUSIONS: Together, these findings indicate that miR-21 plays a key role in regulating cell apoptosis by targeting multiple genes in renal cell carcinoma. PMID- 21820587 TI - Therapeutic effects of connexin inhibitors on detrusor overactivity induced by bladder outlet obstruction in rats. AB - OBJECTIVES: To investigate the alterations in Connexin 43 (Cx43) and connexin 26 (Cx26) levels in the bladder outlet obstruction (BOO)-induced detrusor overactivity and examine the effect of connexin inhibitors on this condition. METHODS: Fifty Sprague-Dawley rats were divided into 4 groups: sham-operated control group (n = 10), BOO group (n = 10), and 2 groups that were administered connexin inhibitors. The first of these 2 groups was administered 18beta glycyrrhetinic acid (BOO-18beta-GA group, n = 15) and the second group was given oleamide (BOO-oleamide group, n = 15). Cystometrogram was performed in all groups after 2 weeks of obstruction. The expression levels of Cx26 and Cx43 were analyzed using immunohistochemical staining and Western blot. RESULTS: The intercontraction interval was markedly shorter in the BOO group compared with the control group (P <.05). Intercontraction intervals in the BOO-18beta-GA and BOO oleamide groups at 2 weeks were significantly longer than that observed for the BOO group (P <.05). The expression of Cx43 and Cx26 were increased in the BOO group. After administration of connexin inhibitors, downregulation of Cx43 and Cx26 was noted. CONCLUSIONS: These results suggest that upregulation of Cx43 and Cx26 induce detrusor overactivity after BOO, and connexin inhibitors may have some role in relieving BOO-induced detrusor overactivity in rats. PMID- 21820588 TI - Re: Grases et al.: Origin and types of calcium oxalate monohydrate papillary renal calculi (Urology 2010;76:1339-1345). PMID- 21820589 TI - Sometimes too much of a good thing may not be that good. PMID- 21820591 TI - Re: Lock et al.: Early experience with contrast-enhanced ultrasound in the diagnosis of testicular masses: a feasibility study (Urology 2011;77:1049-1053). PMID- 21820592 TI - Re: Geng et al.: XRCC1 genetic polymorphism Arg399Gln and prostate cancer risk: a meta-analysis (Urology 2009;74:648-653). PMID- 21820594 TI - Re: Mancini et al.: Antegrade subinguinal sclerotization with temporary clamping of the spermatic cord: a new surgical technique for varicocele (Urology 2011;77:223-226). PMID- 21820595 TI - Re: Khairy-Salem et al.: Semirigid ureteroscopy in management of large proximal ureteral calculi: is there still a role in developing countries? (Urology 2011;77:1064-1068). PMID- 21820597 TI - Re: Saber et al.: New minimal access hydrocelectomy (Urology 2011;77:487-490). PMID- 21820599 TI - Re: Goel et al.: Mechanical suction: an effective and safe method to remove large and tenacious clots from the urinary bladder (Urology 2011;77:494-496). PMID- 21820600 TI - Re: Liberman et al.: Perioperative mortality is significantly greater in septuagenarian and octogenarian patients treated with radical cystectomy for urothelial carcinoma of the bladder (Urology 2011;77:660-663). PMID- 21820603 TI - Effects of a 900-MHz electromagnetic field on oxidative stress parameters in rat lymphoid organs, polymorphonuclear leukocytes and plasma. AB - BACKGROUND AND AIMS: The present study investigated the effects of a 900-MHz electromagnetic field (EMF) for 2 h/day for 45 days on lymphoid organs (spleen, thymus, bone marrow), polymorphonuclear leukocytes (PMNs) and plasma of rats, focusing on changes in the enzymatic and nonenzymatic antioxidant system. We determined whether there is any difference between immature and mature rats in terms of oxidative damage caused by EMF and tested recovery groups to determine whether EMF-induced damage is reversible in immature and mature rats. METHODS: Twenty four immature and 24 mature rats were divided randomly and equally into six groups as follows: two control groups, immature (2 weeks old) and mature (10 weeks old); two groups were exposed to 900 MHz (28.2 +/- 2.1 V/m) EMF for 2 h/day for 45 days. Two recovery groups were kept for 15 days after EMF exposure. RESULTS: Substantial, deleterious biochemical changes were observed in oxidative stress metabolism after EMF exposure. Antioxidant enzyme activity, glutathione levels in lymphoid organs and the antioxidant capacity of the plasma decreased, but lipid peroxidation and nitric oxide levels in PMNs and plasma and also myeloperoxidase activity in PMNs increased. Oxidative damage was tissue specific and improvements seen after the recovery period were limited, especially in immature rats. CONCLUSIONS: In the present study, much higher levels of irreversible oxidative damage were observed in the major lymphoid organs of immature rats than in mature rats. PMID- 21820604 TI - A moderate-intensity static magnetic field enhances repair of cartilage damage in rabbits. AB - BACKGROUND AND AIMS: Electromagnetic fields have been proposed to enhance healing of cartilage defects by stimulation of chondrocyte proliferation, proteoglycan synthesis as well as decreasing pain and improving motion in osteoarthritic patients. However, the effects of a moderate-intensity static magnetic field on cartilage repair have not been investigated. This study tries to determine the effects of a moderate-intensity permanent magnetic field of 40 mT on cartilage repair. METHODS: Defects of 3 mm in diameter and 6 mm in depth were made on the weight bearing surface of the right medial femoral condyle of 30 rabbits. The animals were divided randomly into three equal groups (magnet, sham and control). In the magnet group, cylindrical permanent magnets were implanted subcutaneously medial to the medial femoral condyle, while in the sham group the cylindrical ceramic were not magnetized, and nothing was implanted in controls. After 12 weeks of observation, Mankin's microscopic scoring was done on all specimens, and irregularity of surface characteristics, cell colonization, hypocellularity, cartilage matrix formation, and presence of empty lacunae were investigated. RESULTS: Each of these characteristics showed significant differences in magnet group relative to control and sham groups (p <0.05). Mankin's score was 1.6 +/- 0.6 in magnet group, 7.2 +/- 1.6 in sham group and 7.7 +/- 1 in control group (p <0.001). CONCLUSIONS: [corrected] In this animal study, microscopic Mankin's scoring depicted histological improvement in cartilage of magnet group. PMID- 21820605 TI - Body weight loss after myocardial infarction in rats as a marker of early heart failure development. AB - BACKGROUND AND AIMS: We evaluated the use of body weight (BW) loss soon after acute myocardial infarction (MI) in rats as a marker of acute heart failure (HF). METHODS: Female Wistar rats (200-240 g) were submitted either to sham operation or to coronary artery occlusion. In individual cages, daily BW and food and water intake were measured. Seven days later, cardiac function was evaluated by left ventricular catheterization. HF was defined by a left ventricular end-diastolic pressure greater than the upper limit of the 95% confidence interval. MI group was then divided into those that developed HF (n = 27; MI-HF) and those that did not (n = 47; MI). RESULTS: The MI-HF group experienced increased BW loss (sham: 4.2 +/- 0.6% MI: 0.4 +/- 0.8%, MI-HF: -4.9 +/- 1.2%; p <0.05) and reduced water and food intake compared with other groups. HF animals showed greater lung weight (sham: 1.460 +/- 0.076 g, MI: 1.748 +/- 0.086 g, MI-HF: 2.033 +/- 0.13 g; p <0.05). Infarct area was significantly different between the groups (MI: 35.9 +/- 0.9%, MI-HF: 39.7 +/- 1.3%; p <0.05). ROC curve showed that BW loss over 7 days has 100% sensitivity and 72.3% specificity for identifying acute HF. Moreover, excluding the effect of infarct area on these results, a sample of animals with the same infarct area displayed similar morphometric and hemodynamic patterns as the entire sample. Multivariate linear regression analysis confirmed that BW loss is a HF marker independent of infarct area. CONCLUSIONS: BW is an easy and reliable noninvasive method to detect HF early after MI in rats. PMID- 21820606 TI - MicroRNA-21 modulates chemosensitivity of breast cancer cells to doxorubicin by targeting PTEN. AB - BACKGROUND AND AIMS: Ovexpression of microRNA-21 (miR-21) is found in various human cancers. Our aim is to investigate the association of miR-21 expression with the sensitivity of breast cancer cells to doxorubicin (ADR). METHODS: The half maximal inhibitory concentration (IC(50)) value of ADR in resistant MCF 7/ADR or parental MCF-7 cells was determined by MTT assay. TaqMan RT-PCR or Western blot assay was performed to detect the expression of mature miR-21 and tumor suppressor gene (PTEN) protein. MCF-7 or MCF-7/ADR cell line was transfected with miR-21mimic or inhibitor. The IC(50) value of ADR was determined. Flow cytometry and TUNEL assays were performed to analyze apoptosis. The activity of caspase-3 was analyzed. RESULTS: The IC(50) of ADR in MCF-7 and MCF-7/ADR cells was 0.21 +/- 0.05 and 16.5 +/- 0.08 MUmol/L, respectively. We showed that upregulation of miR-21 in MCF-7/ADR cells was concurrent with downregulation of PTEN protein. MiR-21 mimic or inhibitor could obviously affect the sensitivity of breast cancer cells to ADR. Moreover, miR-21 inhibitor could enhance caspase-3-dependent apoptosis in MCF-7/ADR cells. Overexpression of PTEN could mimic the same effects of miR-21 inhibitor in MCF-7/ADR cells and PTEN siRNA could increase the resistance of MCF-7 cells to ADR. MiR-21 inhibitor could increase PTEN protein expression and the luciferase activity of a PTEN 3' untranslated region-based reporter construct in MCF-7/ADR cells. PTEN-siRNA could partially reverse the increased chemosensitivity of MCF-7/ADR cells induced by miR-21 inhibitor. CONCLUSIONS: Dysregulation of miR-21 plays critical roles in the ADR resistance of breast cancer, at least in part via targeting PTEN. PMID- 21820607 TI - Potential of human decidua stem cells for angiogenesis and neurogenesis. AB - BACKGROUND AND AIMS: Placenta as a fetomaternal organ is a potential source of fetal as well as maternal stem cells. This present study describes novel properties of the cells isolated from the maternal part of term placenta membrane, the decidua basalis. METHODS: Colony-forming unit-fibroblast (CFU-F) frequency and immunophenotype of human decidua-derived stem cells (hDSC) was carried out using flow cytometry. Quantitative polymerase chain reaction was performed to reveal the stemness, angiogenic- and endothelial cell-associated genes expression in serial-passage hDSC. Adipogenic and osteogenic differentiation potential of passage 5 (P5) cells were determined. We also performed immunostaining of common angiogenic/endogenic (CD31 and vWF) and neurogenic markers (GFAP, NF, NSE, vimentin and nestin) on hDSC at P5. RESULTS: HDSC contains high clonogenic precursor with 1:25 CFU-F frequency. Mesenchymal stem cell-associated markers CD90, CD9, CD44, CD73 and HLA ABC were highly expressed in P0 and P5 hDSC. The specific lineage markers CD117, CD45, CD34, CD31 and HLA DR DP DQ were scarcely expressed. HDSC expressed all the stem cell associated genes and the expression was maintained until P5. Also, the cells are capable of differentiating into adipogenic and osteogenic lineage. Positive expressions of angiogenic/endogenic markers (CD31, vWF) and neurogenic markers (GFAP, NF, NSE, vimentin and nestin) were demonstrated by hDSC. CONCLUSIONS: Human decidua contains stem cells with great proliferation capacity and mesenchymal properties. Expressions of angiogenic/endogenic and neurogenic markers support the conclusion that hDSC is a promising stem cell source for neurogenesis as well as angiogenesis. PMID- 21820608 TI - Genetic susceptibility to juvenile idiopathic arthritis in Iranian children. AB - BACKGROUND AND AIMS: This study was comprised of Iranian children with oligoarthritis and rheumatoid factor negative (RF) polyarthritis subtypes of juvenile idiopathic arthritis (JIA) to determine the association of HLA-DRB1 alleles in Iran. METHODS: HLA-DRB1 alleles were investigated in 33 Iranian children with oligoarthritis and RF negative polyarthritis JIA and compared with 45 healthy controls. HLA typing was performed by PCR with sequence specific primers in either of the two groups and followed by direct detection of HLA polymorphism by sequence analysis in patient group. RESULTS: HLA-DRB1*11 was found to be the most frequent allele associated with oligoarthritis and RF negative polyarthritis JIA in Iran followed by HLA-DRB1*8. The frequencies of HLA DRB1*04 and *13 were not significantly different in both groups. CONCLUSIONS: We concluded that there was a significant difference in allele frequencies between patients and control group that may help in predicting the susceptibility to oligoarthritis and rheumatic factor negative polyarthritis JIA. PMID- 21820609 TI - Relation of HLA-A, -B, -DRB1 alleles and haplotypes in patients with acute leukemia: a case control study. AB - BACKGROUND AND AIMS: A relationship between acute leukemia and HLA alleles has been demonstrated in several studies. However, the frequencies of HLA class I (A, B) and class II (DRB1) alleles and haplotypes has not already been determined in Turkish patients with acute leukemia. METHODS: We investigated the relation of the HLA alleles and haplotypes in 237 adult acute leukemia patients [103 acute lymphoblastic leukemia (ALL), 134 acute myeloid leukemia, (AML)] and 360 unrelated normal subjects by PCR-SSOP method using Luminex technology. RESULTS: Allele frequencies of HLA-A*03, and B*51 were higher in patients with AML compared with the controls (p = 0.019, and p = 0.001; respectively). Furthermore, HLA-A*11 and DRB1*01 allele frequencies were determined to be higher in patients with ALL (p = 0.01, p = 0.001; respectively), whereas DRB1*13 allele frequencies lower than controls (p = 0.003). The most observed haplotypes A*03 B*51 DRB1*11 (3.73 vs. 0%) in patients with AML; A*02 B*35 DRB1*01 (2.91 vs. 0%) and A*02 B*51 DRB1*11 (2.91 vs. 1.96%) in patients with ALL were determined. On the contrary, the most observed haplotype was A*02 B*35 DRB1*13 (2.19%) in the controls. We found A*02 B*39 DRB1*16 haplotype negatively associated with AML, whereas A*02 B*35 DRB1*13 was in ALL (p = 0.015, and p = 0.017; respectively). CONCLUSIONS: These results suggest that HLA-A*03 and B*51 alleles may play a presumptive predisposing factor in AML. In addition, HLA-A*11 and DRB*01 alleles have been found to be associated with ALL, whereas DRB1*13 allele was determined to be negatively associated. PMID- 21820610 TI - Association of NAT2 polymorphisms with type 2 diabetes in a population from Bosnia and Herzegovina. AB - BACKGROUND AND AIMS: N-acetyltransferase 2 (NAT2) is a drug-metabolizing enzyme, which is genetically variable in human populations. Polymorphisms in the NAT2 gene have been associated with drug efficacy and toxicity as well as disease susceptibility. Recently, an association of NAT2 gene variation with risk of type 2 diabetes mellitus (T2DM) has been suggested. This is the first study performed in a population from Bosnia and Herzegovina (BH) in which the frequency of two common NAT2 polymorphisms, 341T>C (NAT2*5) and 590G>A (NAT2*6) was determined in diabetic patients. METHODS: The frequency of the NAT2*5 (341T>C) and NAT2*6 (590G>A) polymorphisms was analyzed by employing TaqMan SNP Genotyping Assays (Applied Biosystems) in a group of 63 patients with T2DM and 79 nondiabetic subjects. RESULTS: Our data demonstrated that the frequencies of NAT2*5 (341T>C) and NAT2*6 (590G>A) polymorphisms in BH population were in line with the Caucasians genotype data. The NAT2*5 and NAT2*6 alleles were in high linkage disequilibrium (D' = 0.969). Strinkingly, there was a significant difference in genotype frequencies for NAT2*5 (p <0.05) and NAT2*6 (p <0.001) polymorphisms between diabetic and nondiabetic subjects. NAT2*5 polymorphism was associated with 2.4-fold increased risk for developing T2DM (adjusted OR = 2.40, 95% CI = 1.10-5.25, p = 0.028). On the contrary, NAT2*6 variant significantly decreased by 5-fold susceptibility to the disease (adjusted OR = 0.20, 95% CI = 0.09-0.43, p <0.001). CONCLUSIONS: Our data demonstrated that NAT2 genetic variation appeared to be an important risk factor in development of T2DM. PMID- 21820611 TI - Relationship between circulating adipokines and insulin resistance during pregnancy and postpartum in women with gestational diabetes. AB - BACKGROUND AND AIMS: We undertook this study to assess the relationship between circulating adipokines and insulin resistance during pregnancy and postpartum in women with gestational diabetes mellitus (GDM). METHODS: This was a prospective study including 60 women with GDM and 60 subjects with normal gestation who were evaluated at gestational week 30, 6 weeks and 6 months postpartum. Circulating adipokines that were evaluated during the study were leptin, adiponectin, retinol binding protein-4 (RBP4), and tumor necrosis factor-alpha (TNF-alpha). RESULTS: Women with GDM showed higher insulin resistance measured by HOMA-IR than subjects with normal gestation (2.3 +/- 2.3 vs. 1.3 +/- 0.95). There was no difference between groups in adipokines; however, in women with a healthy pregnancy, RBP4 was associated with insulin resistance (r = 0.47, p <0.05). At 6 weeks and 6 months postpartum, women with previous GDM exhibited persistent elevated leptin and insulin resistance. RBP4 was associated with insulin resistance only in women with a previous healthy pregnancy (r = 0.51, p <0.05). In addition, progressively impaired glucose tolerance was observed after delivery in women with previous GDM. CONCLUSIONS: It was demonstrated that GDM is associated with greater insulin resistance than observed in normal pregnancy; however, adipokines are similar in both groups. RBP4 levels are significantly associated with insulin resistance in healthy women during pregnancy and postpartum. After a pregnancy complicated by GDM, leptin and insulin resistance remain elevated and glucose tolerance worsens. PMID- 21820612 TI - Association of L55M and Q192R polymorphisms of paraoxonase-1 gene with preeclampsia. AB - BACKGROUND AND AIMS: Although preeclampsia is one of the most common complications of pregnancy, the exact etiology of preeclampsia is unknown. Paraoxonase-1 (PON1) is a high-density lipoprotein-associated enzyme, which exhibits antioxidative and antiatherogenic activities. This study was aimed to determine the possible association between L55M and Q192R polymorphisms of paraoxonase-1 gene as well as serum PON1 and arylesterase (ARE) activities in preeclampsia. METHODS: This case-control study was performed on 105 preeclampsia patients and 84 normal healthy pregnant women. The polymorphisms of PON1 were determined using tetra ARMS-PCR method and serum paroxonase (PON1) and arylesterase (ARE) activities were measured spectrophotometrically. RESULTS: Results showed that 192 QR genotype of PON1 was higher among preeclampsia patients (43.8%) than control subjects (31.0%) (crude OR = 1.92, 95% CI, 1.03 3.57; adjusted OR = 2.07, 95% CI, 1.04-4.16,). The R allele is a risk factor for preeclampsia (OR = 1.64, 95% CI, 1.03-2.60, p = 0.038). There were no significant differences regarding L55M genotypes or alleles frequencies of PON1 among groups (p >0.05). We found that serum paraoxonase and aryesterase activities were significantly higher in preeclampsia than controls (p <0.05). CONCLUSIONS: PON1 allele 192R is a risk factor for preeclampsia. The clinical significance of an increase of serum PON1 and ARE activities in preeclampsia remains to be elucidated. More studies in larger samples with different ethnic groups are required to validate our findings. PMID- 21820613 TI - Carbon dioxide-enriched water inhalation in patients with allergic rhinitis and its relationship with nasal fluid cytokine/chemokine release. AB - BACKGROUND AND AIMS: Allergic rhinitis is characterized by eosinophil infiltration and accumulation in the nasal mucosa mainly due to IL-3, IL-5, and eotaxin activities. We undertook this study to investigate a possible in vivo effect of carbon dioxide-enriched water inhalation in patients with allergic rhinitis. METHODS: Twenty five consecutive patients inhaled carbon dioxide enriched water at Fonti di Rabbi Spa Centre (Trento, Italy). Symptom scores for nasal obstruction, itching and sneezing were obtained before and after treatment. Nasal lavage was collected, and IL-3, IL-5, and eotaxin levels were assessed using the quantitative sandwich enzyme immunoassay technique. Cytometric analysis was performed on samples to measure total cell count, CD45+ cells, and percentages of polymorphonucleates and lymphocytes. RESULTS: There were statistically significant differences in chemokine levels and in cell populations between patients and healthy controls before treatment. After carbon dioxide enriched water inhalation, we observed statistically significant improvements in symptom scores, chemokine levels, and percentages of cell populations. CONCLUSIONS: Our results seem to confirm the role of IL-3, IL-5, and eotaxin in the pathophysiology of allergy and the beneficial effect of carbon dioxide enriched water inhalation in patients affected by allergic rhinitis. PMID- 21820614 TI - Osteopontin levels in patients with hepatitis C virus-related hepatocellular carcinoma. PMID- 21820616 TI - Brown algae. PMID- 21820617 TI - Acquisition of an animal gene by microsporidian intracellular parasites. PMID- 21820618 TI - Anhydrobiosis: the model worm as a model? AB - New work now shows that the dauer larvae of Caenorhabditis elegans can survive anhydrobiotically. The genetic tractability of this model organism may be useful in studying how organisms survive when losing most or all of their water. PMID- 21820619 TI - Associative memory: without a trace. AB - Some transient sensory stimuli can cause prolonged activity in the brain. Trace conditioning experiments can reveal the time over which these lasting representations can be utilized and where they reside. PMID- 21820620 TI - Adaptive introgression: the seeds of resistance. AB - Populations of the European house mouse have acquired resistance to anticoagulant pesticides from a closely related species. This discovery improves our understanding of the circumstances in which interspecific genetic exchange is likely to facilitate adaptation. PMID- 21820621 TI - Cognitive neuroscience: swapping bodies in the brain. AB - A recent study has found that activity in multisensory brain areas, namely the premotor cortex, intraparietal cortex and the putamen, mirrors the vividness of ownership over a mannequin, induced by the body-swap illusion. PMID- 21820622 TI - Tissue remodeling: making way for cellular invaders. AB - Cellular invasion through protein matrices is a critical process during epithelial-mesenchymal transitions. A recent study of Caenorhabditis elegans vulval development reports a novel invasive mechanism in which cells coordinate spatially restricted degradation and sliding of a basement membrane during cellular ingression and tissue formation. PMID- 21820623 TI - Microbial genomics: E. coli relatives out of doors and out of body. AB - Genome comparisons have shown that several clades of Escherichia isolated primarily from non-host habitats are adapted to life outside of hosts, and that these very close relatives of E. coli have historically not shared environments with gut-associated E. coli. PMID- 21820624 TI - Parahippocampal cortex: translating vision into space. AB - Two recent imaging studies have shed new light on information representation in human parahippocampal cortex. Despite their different approaches, the two studies both support the view that this brain region represents space at an elementary level. PMID- 21820625 TI - Evolution of development: diversified dorsoventral patterning. AB - Patterning of the dorsoventral axis by graded BMP signaling is conserved in the evolution of animals. However, this system has also proven to be highly adaptable, as is now highlighted by its short-range function in the leech Helobdella. PMID- 21820626 TI - Centrosome size: scaling without measuring. AB - Centrosome size is controlled by a limiting component mechanism in which a fixed quantity of precursor protein is divided up among however many centrosomes are present. This simple scheme explains size control and scaling of centrosomes relative to cell volume. PMID- 21820627 TI - Cell migration: PKA and RhoA set the pace. AB - A new study shows that protein kinase A (PKA) activity establishes a signaling loop that governs protrusion-retraction cycles in migrating cells. PKA activity near the leading edge of protrusions phosphorylates RhoA and inhibits its activity via increased association with RhoGDI. PMID- 21820628 TI - Cell division orientation in animals. AB - Cell division orientation during animal development can serve to correctly organize and shape tissues, create cellular diversity or both. The underlying cellular mechanism is regulated spindle orientation. Depending on the developmental context, extrinsic signals or intrinsic cues control the correct orientation of the mitotic spindle. Cell geometry has been known to be another determinant of spindle orientation and recent results have shed new light on the link between cellular shape and cell division orientation. The importance of controlling spindle orientation is manifested in neurodevelopmental defects such as microcephaly, tumor initiation as well as defects in tissue architecture and cell fate misspecification. Here, we summarize the role of oriented cell division during animal development and also outline the cellular and molecular mechanisms in selected invertebrate and vertebrate systems. PMID- 21820629 TI - In-hospital use of automated external defibrillators does not improve survival. AB - The use of automated external defibrillators (AEDs) following a cardiac arrest in the out-of-hospital setting has demonstrated increased survival rates, likely because up to 71% of out-of-hospital cardiac arrests are associated with rhythm disturbances that are able to be treated with defibrillation. It is less clear whether the use of AEDs in the hospital setting would be effective because fewer patients (approximately 25%) have initial cardiac rhythms that respond to defibrillation and because survival may be compromised if the use of AEDs contributes to interruptions in the delivery of chest compressions. METHODS: The authors of this study used data from the National Registry of Cardiopulmonary Resuscitation (NRCPR) to evaluate the association between survival after an in hospital cardiac arrest and use of an AED. Data was drawn from patients 18 years of age or older, who had an index pulseless, in-hospital cardiac arrest in clinical area where an AED was available for patient treatment. The sample comprised 11,695 patients from 204 hospitals. The primary outcome measure was survival to hospital discharge. The authors also reported secondary outcomes such as return of spontaneous circulation (ROSC) for at least 20 min during the acute resuscitation; survival at 24h; and neurological status among those patients surviving to hospital discharge. RESULTS: Of the 11,695 patients with cardiac arrests, the majority (82.2%; n=9616) were in a nonshockable rhythm, such as asystole or pulseless electrical activity (PEA). Only 17.8% (n=2079) of patients in the study were in a shockable rhythm (ventricular fibrillation and pulseless ventricular tachycardia). AEDs were used on 4515 patients (38.6%). An overall survival to discharge rate of 18.1% (n=2117) was reported. The use of an AED was associated with lower survival rates (16.3% vs 19.3%; adjusted rate ratio [RR], 0.85; 95% confidence interval [CI], 0.78-0.92; P<0.001). AED use in those patients with asystole or PEA (unshockable rhythms) was associated with lower survival (10.4% vs 15.4%; adjusted RR, 0.74; 95% CI, 0.65-0.83; P<0.001). Where shockable rhythms, such as ventricular tachycardia or ventricular fibrillation, were present, AED use did not increase survival (38.4% vs 39.8%; adjusted RR, 1.00; 95% CI, 0.88-1.13; P=0.99). These trends were consistent for AED use in both monitored and nonmonitored hospital units (p>.10). For cardiac arrest due to asystole or PEA the use (or not) of an AED did not influence the rates of ROSC. For cardiac arrests due to ventricular fibrillation or pulseless ventricular tachycardia the rates of ROSC and survival at 24 h did not differ by AED use. AED use did not shorten the time to defibrillation and for those patients with ROSC, and was not associated with shorter CPR times or fewer administered defibrillations. Overall the authors concluded that the use of AEDs in hospitalised patients following cardiac arrest was not associated with improved survival. PMID- 21820630 TI - Estimating the number of serious road injuries in the Netherlands. AB - PURPOSE: This paper describes a new estimation method of the number of road injuries in The Netherlands. METHODS: The bases for this method are the hospital inpatient registry and the police crash record database. Both databases contain errors and omissions. The police database in particular suffers from serious underreporting, and is also inaccurate in indicating injury severity. The hospital database is inaccurate in indicating that a patient was involved in a road crash. Nonetheless, in principle it contains all serious road injuries. After linking both databases an estimating method, inspired by capture-recapture, was used to estimate the number of road injuries. The differences in registration for transport mode, injury severity, and region of crash have been taken into account. RESULTS: This leads to an estimation of the number of serious road injuries in the Netherlands in 1993-2008. CONCLUSIONS: We found that 85% of the road injuries are recognizable as such in the hospital registry. The registration rate of the police registry is different for road injuries in crashes involving motorized vehicles (58% in 2008) and for road injuries in crashes not involving motorized vehicles (4% in 2008). PMID- 21820631 TI - Mesothelioma from chrysotile asbestos: update. AB - PURPOSE: There are different mineral classes of asbestos, including serpentines and amphiboles. Chrysotile is the main type of serpentine and by far the most frequently used type of asbestos (about 95% of world production and use). There has been continuing controversy over the capability of chrysotile asbestos to cause pleural and peritoneal mesothelioma. This review is to help clarify the issue by detailing cases and epidemiology studies worldwide where chrysotile is the exclusive or overwhelming fiber exposure. METHODS: A worldwide literature review was conducted of asbestos and associated mesothelioma including case series, case-control and cohort epidemiology studies searching for well documented chrysotile asbestos associated mesothelioma cases. RESULTS: Chrysotile asbestos exposures have occurred in many countries around the world from mining, manufacturing and community exposures. There have been many documented cases of mesothelioma from those exposures. CONCLUSIONS: Chrysotile asbestos, along with all other types of asbestos, has caused mesothelioma and a world-wide ban of all asbestos is warranted to stop an epidemic of mesothelioma. PMID- 21820633 TI - Making sense of the evidence using comparative effectiveness to guide clinical decision making, policy and coverage. PMID- 21820632 TI - Adolescent marijuana use from 2002 to 2008: higher in states with medical marijuana laws, cause still unclear. AB - PURPOSE: Since 1996, 16 states have legalized marijuana use for medical purposes. The current study provides a scientific assessment of the association of medical marijuana laws (MML) and adolescent marijuana use using national data. METHOD: State representative survey data on approximately 23,000 12-17 year olds were collected by the National Survey on Drug Use and Health annually from 2002-2008. Yearly state-specific estimates of prevalence of past-month marijuana use and perception of its riskiness were statistically tested for differences between states with and without MML by year and across years. RESULTS: States with MML had higher average adolescent marijuana use, 8.68% (95% CI: 7.95-9.42) and lower perception of riskiness, during the period 2002-2008 compared to states without MML, 6.94% (95% CI: 6.60-7.28%). In the eight states that passed MML since 2004, in the years prior to MML passage, there was already a higher prevalence of use and lower perceptions of risk in those states compared to states that have not passed MML. CONCLUSIONS: While the most likely of several possible explanations for higher adolescent marijuana use and lower perceptions of risk in MML states cannot be determined from the current study, results clearly suggest the need for more empirically-based research on this topic. PMID- 21820634 TI - MR spectroscopy using normalized and non-normalized metabolite ratios for differentiating recurrent brain tumor from radiation injury. AB - RATIONALE AND OBJECTIVES: To compare the ability of normalized versus non normalized metabolite ratios to differentiate recurrent brain tumor from radiation injury using magnetic resonance spectroscopy (MRS) in previously treated patients. MATERIALS AND METHODS: Twenty-five patients with previous diagnosis of primary intracranial neoplasm confirmed with biopsy/resection, previously treated with radiation therapy (range, 54-70 Gy) with or without chemotherapy and new contrast enhancing lesion on a 1.5 T magnetic resonance imaging at the site of the primary neoplasm participated in this retrospective study. After MRS, clinical, radiological, and histopathology data were used to classify new contrast-enhancing lesions as either recurrent neoplasm or radiation injury. Volume of interest included both the lesion and normal-appearing brain on the contralateral side. Non-normalized metabolic ratios were calculated from choline (Cho), creatine (Cr), and N-acetylaspartate (NAA) spectroscopic values obtained within the contrast-enhancing lesion: Cho/Cr, NAA/Cr, and Cho/NAA. Normalized ratios were calculated using the metabolic values from the contralateral normal side: Cho/normal creatinine (nCr), Cho/normal N acetylaspartate (nNAA), Cho/normal choline, NAA/nNAA, NAA/nCr, and Cr/nCr. Results were correlated with the final diagnosis by Wilcoxon rank-sum analysis. RESULTS: Two of three non-normalized ratios, Cho/NAA (sensitivity 86%, specificity 90%) and NAA/Cr (sensitivity 93%, specificity 70%) significantly associated with tumor recurrence even after correcting for multiple comparisons. Of the six normalized ratios, only Cho/nNAA significantly correlated with tumor recurrence (sensitivity 73%, specificity 40%), but did not remain significant after correcting for multiple comparisons. CONCLUSION: Cho/NAA and NAA/Cr were the two ratios with the best discriminating ability and both had better discriminating ability than their corresponding normalized ratios (Area under the curve = 0.92 versus 0.77, AUC= 0.85 vs. 0.66), respectively. PMID- 21820635 TI - Assessing the role of magnetic resonance imaging in the management of gravid patients at risk for placenta accreta. AB - RATIONALE AND OBJECTIVES: The role of magnetic resonance imaging (MRI) in the diagnosis of placenta accreta remains uncertain. The purpose of this study was to evaluate the incremental benefit of MRI after ultrasound (US) for a large cohort of gravid patients at risk for a placenta accreta. MATERIALS AND METHODS: A retrospective review of outcomes in women with risk factors for a placenta accreta between November 1995 and February 2008 was performed. Inclusion criteria were high-risk women with abnormal placenta implantation on US or operative diagnosis of placenta accreta, with or without a prenatal MRI. Delivery mode, diagnosis, and transfusion requirements were compared. RESULTS: Ranging in age from 19 to 43 years, with zero to five prior cesarean sections, 139 women met inclusion criteria. The MRI was performed in 28.7% (40/139). US, MRI, and operative diagnoses were highly correlated (P < .001). Women who underwent both US and MRI were more likely to deliver by cesarean hysterectomy (P < .001). When the cohort is stratified by outcome diagnosis (normal, previa, accreta), no difference in delivery mode is found; regardless of whether subjects were imaged by US alone or US and MRI. Transfusion requirements were highest in the US and MRI group (mean of 3.9 units vs. 0.9 units in the US only group, P < .001). CONCLUSION: This study fails to demonstrate that the incremental use of MRI for placenta accreta changes delivery mode in stratified analysis. Patients who underwent both US and MRI were most likely to have a cesarean hysterectomy delivery, and required more blood products, suggesting that undergoing tests may be indicative of an abnormal and at risk patient population. PMID- 21820636 TI - 235 minus 55 equals 180. PMID- 21820637 TI - [National Congress XXXVII SEEIUC, Bilbao 2011]. PMID- 21820638 TI - [Central auditory processes evaluated with psychoacoustic tests in normal children]. AB - OBJECTIVE: To identify the natural tendencies of hits and calculate the cutoff for a test group of central auditory processes (CAP): binaural fusion, filtered words, dichotic digits, frequency patterns and duration patterns and ambient sounds in normal 5-, 7-, 9- and 11-year-old children. MATERIAL AND METHODS: We studied 369 children (738 ears) who attend public schools in Puebla City, administering 6 CAP tests (two binaural and four monaural); we used an audiometer at 50dB SL re-threshold at 1 kHz, from a CD recorded at the CCECADET-UNAM-INR (Centre for Applied Science and Technological Development at the National Autonomous University of Mexico and the National Institute for Rehabilitation). RESULTS: We determined the cutoff points for the six tests. CONCLUSION: This information represents an advance in the normative standards in the field of psychoacoustic tests for CAP in Spanish and in the socio-educational context prevalent in Mexico. It is important to evaluate these results against CAP disorders. PMID- 21820639 TI - Deep neck infection. Review of 286 cases. AB - INTRODUCTION: Deep neck infections (DNI) are potentially lethal processes and are susceptible to severe complications. This study shows an increment of the incidence and investigated the cause. More than 30% of cases are idiopathic, but they are commonly related to a dental or oropharyngeal infection. MATERIAL AND METHODS: We present 286 consecutive cases in a retrospective 11-year study. We analysed the clinical picture, antecedents and concurrent diseases, and diagnostic and therapeutic approaches that could be related to developing a DNI. RESULTS: A mayor increase in DNI incidence in our setting was seen in the last few years. The mayor complications were mediastinitis, septic shock with disseminated intravascular coagulation syndrome, necrotising fasciitis and acute respiratory failure. A lower cranial nerve palsy that develops into dysphagia and leukoencephalopathy are the most frequent sequela. We found 10% of aspiration pneumonia. Mortality in adults was 5.9% and in children, 6.2%. CONCLUSIONS: Deep neck infections constitute a medical and surgical emergency. Severe complications may arise in a short time. We must be vigilant to alarm symptoms such as dyspnea, stridor, pain in the floor of the mouth, sialohrrea, trismus, etc. Improvements in antibiotic therapy, diagnostic imaging and critical patient support modalities have decreased mortality and there is a better prognosis, with complications being identified and treated earlier. PMID- 21820640 TI - [Electrophysiological characterisation of envelope-following responses]. AB - INTRODUCTION: The auditory ability to discriminate rapid changes in the envelope of language sounds is essential for speech comprehension. This ability is deteriorated in some neurological diseases such as multiple sclerosis, auditory neuropathy, sensorineural hearing loss, presbycusis and primary developmental language disorder. Envelope-following responses (EFRs) in humans are useful in objective measurement of temporal processing in the auditory nervous system. OBJECTIVES: To evaluate EFRs in healthy younger subjects and to investigate the effects of subject states on the EFRs recorded. METHODS: Eleven young subjects were included; six of them were awake and five were asleep. EFRs were evoked by white noise carrier stimuli with a sweep of modulation frequencies from 20 to 200Hz presented at 50dB HL. RESULTS: The EFRs we recorded were similar in all subjects. There were two principal components. During both subject sleep and wakefulness, the first component (located between 30-50Hz) was significantly larger than the second component (located between 80-110Hz). There was also a significant effect of sleep on the EFR amplitude for the modulation frequencies between 88-110, 155-165 and 190-200Hz. However, there were no significant effects of sleep on the principal EFR components. CONCLUSIONS: These results corroborate the usefulness of the EFR technique for objective measurement of human auditory temporal processing. PMID- 21820641 TI - [Head and neck sarcomas. Our experience]. AB - INTRODUCTION: Head and neck sarcomas are a heterogeneous group of malignant tumours that vary greatly in clinical presentation, with different histopathological and biological characteristics. MATERIAL AND METHODS: This was a retrospective study of patients with sarcoma located in the head and neck treated in our centre over a period of 25 years. RESULTS: During the study period, a total of 25 patients were diagnosed with sarcomas in the head and neck, accounting for 0.5% of all malignancies at this level. The most common treatments included surgical resection of the tumour, often supplemented with radiotherapy and/or adjuvant chemotherapy. The final local control, including the salvage, was 52%, with an adjusted survival of 51% at 5 years and 32% at 12 years. CONCLUSIONS: Surgical treatment of patients with head and neck sarcomas achieves acceptable results of local control and survival. PMID- 21820643 TI - The model Lysozyme-PSSNa system for electrostatic complexation: Similarities and differences with complex coacervation. AB - We review, based on structural information, the mechanisms involved when putting in contact two nano-objects of opposite electrical charge, in the case of one negatively charged polyion, and a compact charged one. The central case is mixtures of PSS, a strong flexible polyanion (the salt of a strong acid, and with high linear charge density), and Lysozyme, a globular protein with a global positive charge. A wide accurate and consistent set of information in different situations is available on the structure at local scales (5-1000A), due to the possibility of matching, the reproducibility of the system, its well-defined electrostatics features, and the well-defined structures obtained. We have related these structures to the observations at macroscopic scale of the phase behavior, and to the expected mechanisms of coacervation. On the one hand, PSS/Lysozyme mixtures show accurately many of what is expected in PEL/protein complexation, and phase separation, as reviewed by de Kruif: under certain conditions some well-defined complexes are formed before any phase separation, they are close to neutral; even in excess of one species, complexes are only modestly charged (surface charges in PEL excess). Neutral cores are attracting each other, to form larger objects responsible for large turbidity. They should lead the system to phase separation; this is observed in the more dilute samples, while in more concentrated ones the lack of separation in turbid samples is explained by locking effects between fractal aggregates. On the other hand, although some of the features just listed are the same required for coacervation, this phase transition is not really obtained. The phase separation has all the macroscopic aspects of a fluid (undifferentiated liquid/gas phase) - solid transition, not of a fluid-fluid (liquid-liquid) one, which would correspond to real coacervation). The origin of this can be found in the interaction potential between primary complexes formed (globules), which agrees qualitatively with a potential shape of the type repulsive long range attractive very short range. Finally we have considered two other systems with accurate structural information, to see whether other situations can be found. For Pectin, the same situation as PSS can be found, as well as other states, without solid precipitation, but possibly with incomplete coacervation, corresponding to differences in the globular structure. It is understandable that these systems show smoother interaction potential between the complexes (globules) likely to produce liquid-liquid transition. Finally, we briefly recall new results on Hyaluronan/Lysozyme, which present clear signs of coacervation in two liquid phases, and at the same time the existence of non-globular complexes, of specific geometry (thin rods) before any phase separation. These mixtures fulfill many of the requirements for complex coacervation, while other theories should also be checked like the one of Shklovskii et al. PMID- 21820642 TI - [Treatment-resistant adult atopic dermatitis]. PMID- 21820644 TI - Left circumflex occlusion in acute myocardial infarction (from the National Cardiovascular Data Registry). AB - Compared to occlusions of other major coronary arteries, patients presenting with acute left circumflex (LCx) occlusion usually have ST-segment elevation on the electrocardiogram <50% of the time, potentially delaying treatment and resulting in worse outcomes. In contemporary practice, little is known about the clinical outcomes of patients with LCx territory occlusion without ST-segment elevation myocardial infarction (STEMI). We identified patients with myocardial infarction from April 2004 to June 2009 in the CathPCI Registry treated with percutaneous coronary intervention for culprit LCx territory occlusion, excluding those with previous coronary artery bypass grafting. Logistic generalized estimating equation modeling was used to compare the outcomes, including in-hospital mortality between patients with STEMI and non-STEMI (NSTEMI) adjusting for differences in the baseline characteristics. Of the 27,711 patients with myocardial infarction and acute LCx territory occlusion, 18,548 (67%) presented with STEMI and 9,163 (33%) with NSTEMI. With the exception of a greater proportion of cardiac risk factors and cardiac history in the NSTEMI group, the demographic and baseline characteristics were clinically similar between the 2 groups, despite the statistical significance resulting from the large population. The patients with STEMI were more likely to have a proximal LCx culprit lesion (63% vs 27%, p <0.0001) and had greater risk-adjusted in-hospital mortality (odds ratio 1.36, 95% confidence interval 1.12 to 1.65, p = 0.002) compared to patients with NSTEMI. In conclusion, acute LCx territory occlusion often presents as NSTEMI, but patients with NSTEMI and occlusion have a lower mortality risk than those with STEMI, possibly because of factors such as the amount of myocardium involved, the lesion location along the vessel, and/or a dual blood supply. PMID- 21820645 TI - What is the residual anastomosis rate? PMID- 21820646 TI - Depressive symptoms predict inflexibly high levels of experiential avoidance in response to daily negative affect: a daily diary study. AB - Experiential avoidance (EA) is an emotion-regulation strategy used to control or avoid unpleasant internal experiences. Despite the important role of avoidance in depressive disorders, there is relatively little research directly examining the role of EA in the development and maintenance of depression, and most of this research relies on measurement of EA as a global and stable personality trait. In this study we sought to extend the research on EA and depression by using a daily diary design and multilevel analysis to examine how the daily relationship between EA and negative affect (NA) varies as a function of baseline depressive symptoms. In order to achieve this goal we created a new state measure of EA assessing several avoidant behaviors. The findings revealed that participants with more depressive symptoms used more daily EA overall. Additionally, the difference in daily EA between those with higher versus lower depressive symptoms was greater on days when participants experienced less NA. This moderation effect was found only concurrently whereas one-day lagged analysis failed to reveal this effect. These findings provide preliminary support for the hypothesis that depression is associated with an inflexibly high level of avoidant emotion regulation. PMID- 21820648 TI - Maternal cannabis use alters ventral striatal dopamine D2 gene regulation in the offspring. AB - BACKGROUND: Prenatal cannabis exposure has been linked to addiction vulnerability, but the neurobiology underlying this risk is unknown. METHODS: Striatal dopamine and opioid-related genes were studied in human fetal subjects exposed to cannabis (as well as cigarettes and alcohol). Cannabis-related gene disturbances observed in the human fetus were subsequently characterized with an animal model of prenatal Delta-9-tetrahydrocannabinol (THC) (.15 mg/kg) exposure. RESULTS: Prenatal cannabis exposure decreased dopamine receptor D2 (DRD2) messenger RNA expression in the human ventral striatum (nucleus accumbens [NAc]), a key brain reward region. No significant alterations were observed for the other genes in cannabis-exposed subjects. Maternal cigarette use was associated with reduced NAc prodynorphin messenger RNA expression, and alcohol exposure induced broad alterations primarily in the dorsal striatum of most genes. To explore the mechanisms underlying the cannabis-associated disturbances, we exposed pregnant rats to THC and examined the epigenetic regulation of the NAc Drd2 gene in their offspring at postnatal day 2, comparable to the human fetal period studied, and in adulthood. Chromatin immunoprecipitation of the adult NAc revealed increased 2meH3K9 repressive mark and decreased 3meH3K4 and RNA polymerase II at the Drd2 gene locus in the THC-exposed offspring. Decreased Drd2 expression was accompanied by reduced dopamine D2 receptor (D(2)R) binding sites and increased sensitivity to opiate reward in adulthood. CONCLUSIONS: These data suggest that maternal cannabis use alters developmental regulation of mesolimbic D(2)R in offspring through epigenetic mechanisms that regulate histone lysine methylation, and the ensuing reduction of D(2)R might contribute to addiction vulnerability later in life. PMID- 21820649 TI - Ibuprofen and lipoic acid codrug 1 control Alzheimer's disease progression by down-regulating protein kinase C epsilon-mediated metalloproteinase 2 and 9 levels in beta-amyloid infused Alzheimer's disease rat model. AB - Alzheimer's disease (AD) commonly begins with loss of recent memory and is associated to pathological and histological hallmarks such as beta amyloid plaques, neural tangles (NFT), cholinergic deficit, extensive neuronal loss and synaptic changes in the cerebral cortex and hippocampus. The amyloid cascade hypothesis implies the activity of beta, gamma secretases which mediate the cleavage of APP (Amyloid Precursor Protein), the formation of amyloidogenic Abeta fragment (1-42), which compacts into amyloid plaques, while the cleavage by alpha secretase of APP, within the Abeta segment (non-amyloidogenic processing) forms sAPP and prevents the formation of Abeta. Among the proteases which have Abeta degrading activity, Metalloproteinase (MMP) 2, disclosing beta secretase-like activity, is included, while MMP9 seems to contribute to neuronal death. In addition, since intracellular signaling protein kinase C (PKC) can control either directly alpha secretase or indirectly through regulation of ERK1/2, preventing the formation of beta amyloid, created by beta and gamma secretase, and prolonging the life span of Alzheimer's disease mutant mice, here we show the effects exerted by new codrug 1 on PKC epsilon-mediated MMP2 and MMP9 levels regulation in Abeta (1-40) infused rat cerebral cortex. Interestingly codrug 1, lowering metalloproteinases expression via PKC epsilon down-modulation, seems to control Alzheimer's disease induced cerebral amyloid deposits, neuronal death and, lastly, behavioral deterioration. PMID- 21820647 TI - Abnormal hypothalamic response to light in seasonal affective disorder. AB - BACKGROUND: Vulnerability to the reduction in natural light associated with fall/winter is generally accepted as the main trigger of seasonal affective disorder (SAD), whereas light therapy is a treatment of choice of the disorder. However, the relationship between exposure to light and mood regulation remains unclear. As compared with green light, blue light was shown to acutely modulate emotion brain processing in healthy individuals. Here, we investigated the impact of light on emotion brain processing in patients with SAD and healthy control subjects and its relationship with retinal light sensitivity. METHODS: Fourteen symptomatic untreated patients with SAD (34.5 +/- 8.2 years; 9 women) and 16 healthy control subjects (32.3 +/- 7.7 years; 11 women) performed an auditory emotional task in functional magnetic resonance imaging during the fall/winter season, while being exposed to alternating blue and green monochromatic light. Scotopic and photopic retinal light sensitivities were then evaluated with electroretinography. RESULTS: Blue light enhanced responses to auditory emotional stimuli in the posterior hypothalamus in patients with SAD, whereas green light decreased these responses. These effects of blue and green light were not observed in healthy control subjects, despite similar retinal sensitivity in SAD and control subjects. CONCLUSIONS: These results point to the posterior hypothalamus as the neurobiological substrate involved in specific aspects of SAD, including a distinctive response to light and altered emotional responses. PMID- 21820650 TI - Amelioration of behavioral aberrations and oxidative markers by green tea extract in valproate induced autism in animals. AB - Exposure to toxicants prenatally and postnatally could have deleterious consequences on the offspring. Postnatal exposure to valproate in mice pups is capable of inducing experimental autism resulting in neurobehavioral aberrations. Consumption of green tea has been associated with neuronal protection against the impact of toxicants. We investigated the role of green tea extract in reversing cardinal behavioral changes and aberrations in oxidative stress induced by valproate exposure. Young mice of both genders received a single dose of valproate (400mg/kg subcutaneously) on postnatal day 14 followed by a daily dose of green tea extract (75 and 300mg/kg) orally up to postnatal day 40. Mice pups were subjected to behavioral testing to assess motor co-ordination, nociceptive response, locomotion, anxiety, exploratory activity and cognition on various postnatal days up to postnatal day 40. At the end of behavioral testing, blood was withdrawn from the retro orbital plexus for the estimation of lipid peroxides. Animals were sacrificed on postnatal day 41 and whole brain was subjected to histopathological examination. Our studies revealed a significant improvement in behavioral assessments particularly with 300mg/kg of green tea extract. Formation of markers of oxidative stress was reduced at both dose levels. Histological findings confirm the neuroprotective effect of green tea at a dose of 300mg/kg. In conclusion it can be stated that green tea exerts neuronal cytoprotective action possibly due to anti-oxidant action and could be efficacious in the management of autism. PMID- 21820651 TI - Telephone versus face-to-face administration of the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, for diagnosis of psychotic disorders. AB - OBJECTIVE: The current study aims to compare telephone vs face-to-face administration of the version of Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, (SCID) for diagnosis of "any psychotic disorder" in a clinical population in Iran. METHOD: The sample consisted of 72 subjects from 2 psychiatric outpatient services in Tehran, Iran. The subjects were interviewed using face-to-face SCID for the purpose of diagnosing psychotic disorders. A second independent telephone SCID was administered to the entire sample within 5 to 10 days, and the lifetime and 12 month diagnoses were compared. RESULTS: The positive likelihood ratio of telephone-administered SCID for diagnosis of "any lifetime psychotic disorder" was 5.1 when compared with the face-to-face SCID. The value for the primary psychotic disorders in the past 12 months was lower (2.3). CONCLUSIONS: The data indicate that telephone administration of the SCID is an acceptable method to differentiate between subjects with lifetime psychotic disorders and those who have had no psychotic disorders and provides a less resource-demanding alternative to face-to-face assessments. PMID- 21820652 TI - Impact of human papillomavirus infection on the neovaginal and vulval tissues of women who underwent surgical treatment for Mayer-Rokitansky-Kuster-Hauser syndrome. AB - OBJECTIVE: To evaluate the impact of human papillomavirus (HPV) infections on the neovaginal and vulval tissues of women who underwent surgical treatment for Mayer Rokitansky-Kuster-Hauser (MRKH) syndrome. DESIGN: Multicenter observational study. SETTING: University and community hospitals. PATIENT(S): Thirty-three women who had previously undergone neovagina reconstruction due to MRKH and who were referred to our centers for the evaluation and treatment of HPV neovaginal/vulval-related lesions. INTERVENTION(S): HPV infections were confirmed by polymerase chain reaction analysis or hybrid capture 2 tests; the patients underwent vaginoscopy, pap smear, and biopsy of the lesion and were treated by laser vaporization. Follow-up was conducted for 5 years. MAIN OUTCOME MEASURE(S): HPV-related neovaginal/vulval lesions, HPV testing, follow-up, recurrence rate. RESULT(S): Seventeen patients showed vulval lesions, and 16 patients neovaginal lesions. HPV testing results were positive for low-risk HPVs in 27 patients and high-risk HPVs in six patients. All the vulval lesions were condylomata, whereas 10 neovaginal lesions were condylomata, three were vaginal intraepithelial neoplasia (VAIN) degree 1, two were VAIN degree 2, and one was an adenocarcinoma. Eight patients were lost to follow-up. Twenty patients tested positive for an HPV infection, and seven patients (28%) had a recurrence of the lesion in the follow up time. CONCLUSION(S): Patients who underwent neovagina reconstruction have sexual relationships and are HPV exposed. These patients should be evaluated after surgery for HPV infections to prevent HPV-related diseases and cancers. PMID- 21820653 TI - Polycystic ovary-like syndrome in adolescent competitive swimmers. AB - OBJECTIVE: To investigate the potential effects of intensive swimming on clinical and hormonal pubertal development in adolescent girls and to determine whether hyperandrogenism contributes to menstrual disorders. DESIGN: Cross-sectional study. SETTING: Endocrinology and gynecology pediatric units of academic hospitals. PATIENT(S): Eighteen competitive swimmers and 18 age-matched control subjects with breast stages IV or V. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Clinical, biologic, and ultrasonographic investigations. RESULT(S): A high number of cases of hyperandrogenism was seen in swimmers compared with control subjects (n = 11 vs. n = 5 with T level >0.5 ng/mL), as well as a higher LH/FSH ratio (1.5 vs. 0.9) and SHBG level (58.4 vs. 39.5 nmol/L) and more oligomenorrhea (n = 9 vs. n = 4). Half of the swimmers with hyperandrogenism presented pauci- or multifollicular ovaries determined by pelvic ultrasound. Free T was not significantly different between the two groups. CONCLUSION(S): Hyperandrogenism and oligomenorrhea may be part of the spectrum of polycystic ovary syndrome in elite swimmers. Our findings suggest that hyperandrogenism may have preceded the intensive training of these swimmers and may have predisposed the choice of sport for these girls. Intensive swimming may in turn have attenuated the clinical expression of their hyperandrogenism. Follow-up after the cessation of intensive activity would be helpful to evaluate the endocrine and metabolic profiles of these swimmers. PMID- 21820654 TI - Fetal reduction for hyperreactio luteinalis. AB - OBJECTIVE: To present an unusual case of hyperreactio luteinalis and a comprehensive review of the recent literature. Hyperreactio luteinalis is a benign ovarian condition of pregnancy that at times becomes life threatening. The medical literature provides only case reports. DESIGN: Case report and systematic review of the literature. SETTING: University Center. PATIENT(S): A multiparous woman with polycystic ovary syndrome who underwent ovarian stimulation with oral and injectable medications and conceived triplets. She presented at 10 weeks of pregnancy with hyperreactio luteinalis. INTERVENTION(S): Fetal reduction to singleton. MAIN OUTCOME MEASURE(S): Resolution of condition. RESULT(S): The condition resolved 6 weeks after fetal reduction. The patient delivered at term without further complications. CONCLUSION(S): Our review showed that many unnecessary surgeries are performed to treat hyperreactio luteinalis. When feasible, fetal reduction may improve outcome and represents an effective approach that does not compromise maternal well-being or future fertility. PMID- 21820656 TI - Small-scale, homelike facilities in dementia care: a process evaluation into the experiences of family caregivers and nursing staff. AB - BACKGROUND: Current developments in institutional dementia care aim at the downsizing of facilities and increasing their homelike appearance. Small-scale living facilities are an example of this movement, in which a small group of residents (usually six to eight) live together in a homelike environment. Residents are encouraged to participate in normal daily activities and nursing staff is part of the household with integrated tasks. Despite the increase of these facilities, little is known about experiences of family caregivers of residents and nursing staff. OBJECTIVE: To gain an in-depth insight into the experiences of family caregivers and nursing staff with small-scale living facilities. DESIGN: A process evaluation was conducted alongside the final measurement of an effectiveness study, using a cross-sectional, descriptive design. SETTINGS: Two types of institutional dementia care in the Netherlands: small-scale living facilities and regular wards in nursing homes. PARTICIPANTS: In total, 130 family caregivers and 309 nursing staff workers in both care settings participated in a survey questionnaire. Additional in-depth interviews were conducted with a random selection of 24 participants in small-scale living facilities: 13 family caregivers and 11 nursing staff workers. METHODS: Survey questions for family caregivers focused on care service delivery; questions for nursing staff were related to skills. The interviews especially related to positive and negative aspects of small-scale living facilities and skills for nursing staff. RESULTS: Both family caregivers and staff mainly reported positive experiences with small-scale living facilities, especially the personal attention that nursing staff provides to residents, their involvement with residents and the emphasis on autonomy in daily life. Barriers mainly related to nursing staff working alone during a large part of the day. Family caregivers in small-scale living facilities were more satisfied with the care facility and nursing staff than those in regular wards. CONCLUSION: The findings of the study revealed several positive aspects of small-scale living facilities related to physical, social and organizational aspects that could be used as tools to implement changes in institutional dementia care settings. PMID- 21820655 TI - Epidemiology and pattern of paediatric and adolescent trauma deaths in a level 1 trauma centre in Benin city, Nigeria. AB - BACKGROUND: Trauma is a common cause of death amongst children/adolescents, and data on its epidemiology and pattern are crucial for policy formulation. The aim of this study was to determine the epidemiology and pattern of paediatric/adolescent trauma death in a Nigerian referral trauma centre. METHODS: The clinical and autopsy data of all paediatric/adolescent trauma death at the University of Benin Teaching Hospital between 1999 and 2010 were analysed in a retrospective study. RESULTS: Of 905 trauma-related deaths, 78 (9%) involved children/adolescents who comprised 49 males and 29 females, with a male/female ratio 1.7:1 and a mean age of 9.2 +/- 5 years (range <1-18 years). The Injury Arrival time varied from 1h to 4 days (mean 18 h). Thirteen (17%) cases were dead on arrival (DOA), and majority of the deaths occurred within the first week on admission. Road traffic accident (RTA), accounting for 61 (78%) cases, was the leading cause of trauma death. Other causes included burns, eight (10%); gunshot injury, five (6%); and stab and sport injuries, two (3%) cases each. Head injury which occurred in 44 (56%) cases was the commonest cause of death, followed by haemorrhagic shock in 25 (32%), hypovolaemic shock in five (6%), septic shock in three (4%) and spinal cord injury in one (1%). CONCLUSION: Head injury following RTA was the major cause of paediatric/adolescent trauma deaths. Increased road safety campaign, appropriate injury control policies, legislations, enforcement, development of high-quality trauma system, and emergency medical services are advocated. PMID- 21820657 TI - Leoligin, the major lignan from Edelweiss, activates cholesteryl ester transfer protein. AB - OBJECTIVE: Cholesteryl ester transfer protein (CETP) plays a central role in the metabolism of high-density lipoprotein particles. Therefore, we searched for new drugs that bind to CETP and modulate its activity. METHODS: A preliminary pharmacophore-based parallel screening approach indicated that leoligin, a major lignan of Edelweiss (Leontopodium alpinum Cass.), might bind to CETP. Therefore we incubated leoligin ex vivo at different concentrations with human (n=20) and rabbit plasma (n=3), and quantified the CETP activity by fluorimeter. Probucol served as positive control. Furthermore, we dosed CETP transgenic mice with leoligin and vehicle control by oral gavage for 7 days and measured subsequently the in vivo modulation of CETP activity (n=5 for each treatment group). RESULTS: In vitro, leoligin significantly activated CETP in human plasma at 100 pM (p=0.023) and 1 nM (p=0.042), respectively, whereas leoligin concentrations of 1 mM inhibited CETP activity (p=0.012). The observed CETP activation was not species specific, as it was similar in magnitude for rabbit CETP. In vivo, there was also a higher CETP activity after oral dosage of CETP transgenic mice with leoligin (p=0.015). There was no short-term toxicity apparent in mice treated with leoligin. CONCLUSION: CETP agonism by leoligin appears to be safe and effective, and may prove to be a useful modality to alter high-density lipoprotein metabolism. PMID- 21820658 TI - Induction of macrophage scavenger receptor type BI expression by tamoxifen and 4 hydroxytamoxifen. AB - OBJECTIVE: Scavenger receptor type BI (SR-BI) is an HDL receptor that is expressed by macrophages. SR-BI expression is tightly linked to the development of atherosclerosis. Tamoxifen has been shown to be atheroprotective. However, the involved mechanisms have not been fully elucidated. METHODS AND RESULTS: In this study, we investigated the effect of tamoxifen and 4-hydroxytamoxifen on macrophage SR-BI expression. Macrophage cell lines and peritoneal macrophages isolated from wild-type mice were used to determine changes in SR-BI mRNA and protein expression in response to tamoxifen and 4-hydroxytamoxifen. We observed that tamoxifen and 4-hydroxytamoxifen increased SR-BI protein expression in a macrophage cell line derived from female mice (J774 cells) but not in a line derived from male mice (RAW cells). Similar observations were obtained in primary macrophages isolated from wild-type male and female mice. Thus, the induction of macrophage SR-BI expression by tamoxifen and 4-hydroxytamoxifen is sex-dependent. Furthermore, we observed that SR-BI expression was induced by activating the oestrogen receptor (ER, specifically ERalpha) but was inhibited by inactivating the ER. However, the increased macrophage SR-BI protein expression was independent of transcription because SR-BI mRNA expression and promoter activity were not influenced by tamoxifen and 4-hydroxytamoxifen. Instead, tamoxifen increased the stability of macrophage SR-BI protein. Tamoxifen administration to mice had no effect on hepatic SR-BI protein expression but improved the serum lipid profile. CONCLUSION: Our study demonstrates that tamoxifen and 4 hydroxytamoxifen induce macrophage SR-BI protein expression via a post transcriptional mechanism. PMID- 21820659 TI - miR-21, miR-210, miR-34a, and miR-146a/b are up-regulated in human atherosclerotic plaques in the Tampere Vascular Study. AB - OBJECTIVE: MicroRNAs are small non-coding RNAs that inversely regulate their target gene expression. The whole miRNA profile of human atherosclerotic plaques has not been studied previously. The aim of this study was to investigate the miRNA expression profile in human atherosclerotic plaques as compared to non atherosclerotic left internal thoracic arteries (LITA), and to connect this expression to the processes in atherosclerosis. METHODS: The miRNA expression profiles of six LITAs and 12 atherosclerotic plaques obtained from aortic, carotid, and femoral atherosclerotic arteries from Tampere Vascular Study were analyzed. The analyses were performed with Agilent's miRNA Microarray. The expression levels of over 4-fold up-regulated miRNAs were verified with qRT-PCR from a larger population (n=50). Messenger RNA levels were analyzed with Illumina's Expression BeadChip to study miRNA target expression. RESULTS: Ten miRNAs were found to be differently expressed in atherosclerotic plaques when compared to controls (p<0.05). The expression of miR-21, -34a, -146a, -146b-5p, and -210 was verified and found to be significantly up-regulated in atherosclerotic arteries versus LITAs (p<0.001, fold changes 4.61, 2.55, 2.87, 2.82, and 3.92, respectively). Several predicted targets of these miRNAs were down-regulated, and gene set enrichment analysis showed several pathways which could be differently expressed due to this miRNA profile. CONCLUSIONS: The microRNA expression profile differs significantly between atherosclerotic plaques and control arteries. The most up-regulated miRNAs are involved in processes known to be connected to atherosclerosis. Interfering with the miRNA expression in the artery wall is a potential way to affect atherosclerotic plaque and cardiovascular disease development. PMID- 21820660 TI - Probing softness of the parietal pleural surface at the micron scale. AB - The pleural surfaces of the chest wall and lung slide against each other, lubricated by pleural fluid. During sliding motion of soft tissues, shear induced hydrodynamic pressure deforms the surfaces, promoting uniformity of the fluid layer thickness, thereby reducing friction. To assess pleural deformability at length scales comparable to pleural fluid thickness, we measured the modulus of the parietal pleura of rat chest wall using atomic force microscopy (AFM) to indent the pleural surface with spheres (radius 2.5 and 5 MUm). The pleura exhibited two distinct indentation responses depending on location, reflecting either homogeneous or significantly heterogeneous tissue properties. We found an elastic modulus of 0.38-0.95 kPa, lower than the values measured using flat-ended cylinders >100 MUm radii (Gouldstone et al., 2003, Journal of Applied Physiology 95, 2345-2349). Interestingly, the pleura exhibited a three-fold higher modulus when probed using 2.5 vs. 5 MUm spherical tips at the same normalized depth, confirming depth dependent inhomogeneous elastic properties. The observed softness of the pleura supports the hypothesis that unevenness of the pleural surface on this scale is smoothed by local hydrodynamic pressure. PMID- 21820662 TI - Dispersive liquid-liquid microextraction using non-chlorinated, lighter than water solvents for gas chromatography-mass spectrometry determination of fungicides in wine. AB - A novel and low solvent consumption method for the sensitive determination of fungicide residues in wine samples is proposed. Analytes were extracted by dispersive liquid-liquid microextraction (DLLME) and further determined by gas chromatography-mass spectrometry (GC-MS). Under optimized conditions, a binary mixture of acetone and 1-undecanol (0.5 and 0.05 mL, respectively) was used to extract target compounds from diluted (1:1) wine samples. After centrifugation, the floating phase of 1-undecanol was solidified and separated from the liquid hydro-alcoholic matrix. Thereafter, it was allowed to melt at room temperature and injected in the GC-MS system. The method showed relative standard deviations (RSDs, %) below 13%, limits of quantification (LOQs) between 0.2 and 3.2 ng mL( 1) and linear responses for concentrations up to 300 ng mL(-1). The efficiency of the liquid-phase microextraction process was scarcely affected by the characteristics of wine samples, consequently pseudo-external standard calibration (using matrix matched standards of red and white wine) sufficed to achieve acceptable accuracy values: relative recoveries from 81 to 120%. The applicability of the method was demonstrated with commercial wine samples. PMID- 21820661 TI - Overcoming matrix effects using the dilution approach in multiresidue methods for fruits and vegetables. AB - During recent years matrix effects in liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) have quickly become a major concern in food analysis. The phenomenon of ion suppression can lead to errors in the quantification of the analytes of interest, as well as can affect detection capability, precision, and accuracy of the method. Sample dilution is an easy and effective method to reduce interfering compounds, and so, to diminish matrix effects. In this work, matrix effects of 53 pesticides in three different matrices (orange, tomato and leek) were evaluated. Several dilutions of the matrix were tested in order to study the evolution of signal suppression. Dilution of the extracts led to a reduction of the signal suppression in most of the cases. A dilution factor of 15 demonstrated to be enough to eliminate most of the matrix effects, opening the possibility to perform quantification with solvent based standards in the majority of the cases. In those cases where signal suppression could not be reduced, a possible solution would be to use stable isotope-labelled internal standards for quantification of the problematic pesticides. PMID- 21820663 TI - Simultaneous analysis of select pharmaceuticals and personal care products in fish tissue using pressurized liquid extraction combined with silica gel cleanup. AB - Analytical improvements were developed and validated for measuring select personal care products (PCPs) and two pharmaceuticals in fish tissue. The method was validated using fortified fillet tissue for twelve PCPs including fragrance materials, alkylphenols, photo initiators, and triclosan as well as two pharmaceuticals including carbamazepine (anti-seizure) and diazepam (anti convulsant). The analytical method utilized pressurized liquid extraction (PLE) combined with silica gel cleanup, gel permeation chromatography, and gas chromatography ion-trap tandem mass spectrometry. Silica gel cleanup was combined with the PLE to produce one automated extraction/cleanup technique. This analytical improvement served to reduce the incurred cost, time, and loss of potential target analytes associated with independent cleanup steps. The combined extraction/cleanup technique resulted in an average increase of 10% in analyte recoveries. Average triplicate recoveries and relative standard deviations for the entire method, using 2.5 g of fish fillet tissue, were 92 +/- 9% (recoveries ranged from 64 to 131%). The sensitivity of the analytical methods was improved by optimizing the resonant collision induced dissociation energy to the hundredths place (0.01 V). Improvements in ion production range from 24 to 122% for six of the 12 PCPs. Statistically derived method detection limits (MDLs) were also lowered on average by a factor of 8 and ranged from 1.2 to 38 ng/g wet weight. MDLs for carbamazepine and diazepam were 18 and 3.7 ng/g wet weight, respectively. Galaxolide and tonalide were measured in an environmental sample at concentrations of 81 and 5.5 ng/g wet weight, respectively. PMID- 21820664 TI - Cork-based activated carbons as supported adsorbent materials for trace level analysis of ibuprofen and clofibric acid in environmental and biological matrices. AB - In this contribution, powdered activated carbons (ACs) from cork waste were supported for bar adsorptive micro-extraction (BAMUE), as novel adsorbent phases for the analysis of polar compounds. By combining this approach with liquid desorption followed by high performance liquid chromatography with diode array detection (BAMUE(AC)-LD/HPLC-DAD), good analytical performance was achieved using clofibric acid (CLOF) and ibuprofen (IBU) model compounds in environmental and biological matrices. Assays performed on 30 mL water samples spiked at the 25.0 MUg L(-1) level yielded recoveries around 80% for CLOF and 95% for IBU, under optimized experimental conditions. The ACs textural and surface chemistry properties were correlated with the results obtained. The analytical performance showed good precision (<15%), suitable detection limits (0.24 and 0.78 MUg L(-1) for CLOF and IBU, respectively) and good linear dynamic ranges (r(2)>0.9922) from 1.0 to 600.0 MUg L(-1). By using the standard addition methodology, the application of the present approach to environmental water and urine matrices allowed remarkable performance at the trace level. The proposed methodology proved to be a viable alternative for acidic pharmaceuticals analysis, showing to be easy to implement, reliable, sensitive and requiring low sample volume to monitor these priority compounds in environmental and biological matrices. PMID- 21820665 TI - Extraction of pesticides, dioxin-like PCBs and PAHs in water based commodities using liquid-liquid microextraction and analysis by gas chromatography-mass spectrometry. AB - Water based samples such as flavored drinks, juices and drinking water may contain contaminants at ultra trace level belonging to different chemical classes. A novel, simple, low-cost and fast method was developed and validated for trace residue extraction of pesticides, dioxin-like PCBs and PAHs from water and water based samples followed by analysis through gas chromatography (GC) coupled with time-of-flight mass spectrometry (ToFMS). The extraction solvent type, volume; sample volume and other extraction conditions were optimized. This was achieved by extracting 10 mL sample with 250 MUL chloroform by vortexing (1 min, standing time of 2 min) followed by centrifugation (6000 rpm, 5 min). The bottom organic layer (200 MUL) was pipetted out, evaporated to near dryness and reconstituted in 20 MUL of ethyl acetate+cyclohexane (1:9) mixture resulting in an enrichment factor of 400. The recoveries of all compounds were within 76-120% (+/-10%) with the method detection limit (MDL) ranging from 1 to 250 ng/L depending on the analyte response. The MDLs were 400 times lower than the instrument quantification limits that ranged from 0.4 to 100 ng/mL. The method was further validated in water based drinks (e.g. apple, lemon, pineapple, orange, grape and pomegranate juice). For the juices with suspended pulp, the extraction was carried out with 400 MUL chloroform. The extract was analyzed by GC-ToFMS at both 1D and GC*GC modes to chromatographically separate closely eluting interfering compounds the effect of which could not be minimized otherwise. The resulting peak table was filtered to identify a range of compounds belonging to specific classes viz. polycyclic aromatic hydrocarbons, chlorinated, brominated, and nitro compounds. User developed scripts were employed on the basis of identification of the molecular ion and isotope clusters or other spectral characteristics. The method performed satisfactorily in analyzing both incurred as well as market samples. PMID- 21820666 TI - In situ aqueous derivatization and determination of non-steroidal anti inflammatory drugs by salting-out-assisted liquid-liquid extraction and gas chromatography-mass spectrometry. AB - A new analytical method for the determination of trace levels of five non steroidal anti-inflammatory drugs (NSAIDs: clofibric acid, ibuprofen, naproxen, diclofenac and ketoprofen) in water samples is described. The analytical procedure involves in situ aqueous derivatization with N-(3-dimethylaminopropyl) N'-ethylcarbodiimide hydrochloride (EDC) and 2,2,2-trifluoroethylamine hydrochloride (TFEA) and salting-out liquid-liquid extraction (SALLE), followed by gas chromatography-programmed temperature vaporizer-mass spectrometry (GC-PTV MS). The influence of several parameters on the efficiency of the derivatization (stirring time, reaction time, reagent concentration and pH), and the extraction (solvent, volume, salts and stirring time) and injection steps (liner, injection volume, liner temperature, injection time, venting time and venting flow) was investigated. The detection limits of the method in water varied from 0.042 MUg/L for ibuprofen to 1.2 MUg/L for ketoprofen. The relative standard deviations (RSD) values were found to be relatively low (<10% for all compounds). The methodology developed was applied to the determination of NSAIDs in several environmental matrices including tap, river, sea and influent and effluent waste water samples. The results obtained show the presence of ibuprofen and naproxen in the influent waste water sample. PMID- 21820667 TI - Alterations of the surface and morphology of tetraalkyl-ammonium modified montmorillonites upon acid treatment. AB - The effect of short alkyl chain cations on the modification of the structure, surface and textural properties of organo-montmorillonites upon their acid treatment was investigated. Samples prepared from Ca-SAz montmorillonite and tetramethylammonium (Me(4)N(+)-), tetraethylammonium (Et(4)N(+)-), tetrapropylammonium (Pr(4)N(+)-) and tetrabutylammonium (Bu(4)N(+)-) salts were treated in 6 M HCl at 80 degrees C for 2-8 h and analyzed by different methods. Acid treatment of organo-montmorillonites caused gradual release of Al and Mg from the octahedral sheets and destruction of their layered structure. The extent of the changes depended significantly on the size of organo-cation. While large plate-like particles of Ca-SAz and Me(4)N-SAz were disintegrated during acid treatment and smaller fine grains were created, the morphology of Bu(4)N-SAz was modified only slightly. Pore size analysis showed generation of pore network upon organo-montmorillonites dissolution. After longer acid attack, pore volume increased and pore size distribution curves were shifted to pores with diameter above 25 A. The surface area of acid-treated samples increased due to destruction of the montmorillonite layers and formation of the SiO(2)-rich reaction product. The highest value 475 m(2)/g was observed for Me(4)N-SAz treated 4 h. Surface area of Et(4)N-SAz, Pr(4)-SAz and Bu(4)N-SAz was 441, 419 and 293 m(2)/g, respectively, after 8 h treatment. Similar decomposition level was observed for Ca-SAz and Me(4)N-SAz, and less destruction was found for Et(4)N-SAz, Pr(4)-SAz and very low for Bu(4)N-SAz. Though Bu(4)N(+) is short alkyl chain cation, its size is large enough to cover the inner and outer surfaces of montmorillonite and thus to protect the clay layers from acid attack. PMID- 21820668 TI - Effect of particle surface selectivity on composite nanostructures in nanoparticle/diblock copolymer mixture dilute solution. AB - In this study the phase behavior of nanoparticle/diblock copolymer composites in dilute solution has been investigated by the hybrid particle-field (HPF) method. We focus on the influence of particle surface selectivity (i.e. hydrophobic and hydrophilic) on the distribution of nanoparticles in the micelles formed by the diblock copolymers. These two types of particle surface selectivity are simulated systematically. The different competition between the energy from enthalpy and the energy from entropy has been observed in the two kinds of composite systems. Our simulation results show that the particle surface selectivity is a crucial factor for determining the thermodynamic properties in the complex dilute solution, and the morphologies of micelles are controlled by the volume fraction of the nanoparticles. The change of particle distribution in various micelles enriches the composite microstructures that can be formed by nanoparticle and diblock copolymer. PMID- 21820669 TI - Complex mammary adenoma with sebaceous differentiation in a dog. AB - Sebaceous metaplasia arising within a complex adenoma of the left fourth mammary gland is described in a 9-year-old miniature pinscher bitch. Microscopically, the tumour was composed of tubular and ductular structures admixed with clusters of spindle-shaped, myoepithelial-like cells and units formed of well-differentiated sebocytes surrounded by basaloid cells. Abundant lipid droplets were identified within the latter population by Sudan III staining. Immunohistochemical expression of cytokeratin AE1/AE3 was detected in epithelial cells and in the cells with sebaceous differentiation. PMID- 21820670 TI - DNA hypomethylation of MB-COMT promoter in the DNA derived from saliva in schizophrenia and bipolar disorder. AB - The failure in the discovery of etiology of psychiatric diseases, despite extensive genetic studies, has directed the attention of neuroscientists to the contribution of epigenetic modulations, which play important roles in fine-tuning of gene expression in response to environmental factors. Previously, we analyzed 115 human post-mortem brain samples from the frontal lobe and reported DNA hypo methylation of the membrane-bound catechol-O-methyltransferase (MB-COMT) gene promoter, associated with an increased gene expression, as a risk factor for schizophrenia (SCZ) and bipolar disorder (BD). Since most epigenetic modifications are tissue specific and the availability of brain tissue to identify epigenetic aberrations in living subjects is limited, detection of epigenetic abnormalities in other tissues that represent the brain epigenetic marks is one of the critical steps to develop diagnostic and therapeutic biomarkers for mental diseases. Here, hypothesizing that; those factors that lead to the brain MB-COMT promoter DNA hypo-methylation may also cause concurrent epigenetic aberrations in peripheral tissues, we analyzed MB-COMT promoter methylation in DNA derived from the saliva in SCZ, BD and their first-degree relatives (20 cases each) as well as 25 control subjects. Using bisulfite DNA sequencing and quantitative methylation specific PCR (qMSP), we found that similar to the brain, MB-COMT promoter was hypo-methylated (~50%) in DNA derived from the saliva in SCZ and BD compared to the control subjects (p = 0.02 and 0.037, respectively). These studies suggest that DNA methylation analysis of MB COMT promoter in saliva can potentially be used as an available epigenetic biomarker for disease state in SCZ and BD. PMID- 21820671 TI - Cigarette smoking in community-dwelling patients with schizophrenia in China. AB - This study examined the prevalence of cigarette smoking and its socio-demographic and clinical characteristics in Chinese schizophrenia patients. A sample of 540 community-dwelling patients (female/male: 50.4% vs. 49.6%) with schizophrenia was interviewed using standardized assessment instruments. The patients' basic socio demographic and clinical data including smoking were collected. The prevalence of cigarette smoking was 28.5% in the whole sample, and 53.6% and 4.0% for men and women, respectively. In univariate analyses, male sex, use of first generation antipsychotics (FGAs) and alcohol consumption were significantly associated with smoking. In multiple logistic regression analysis, male sex, alcohol consumption, older age and lower level of education were independently associated with smoking. The prevalence of smoking in Chinese schizophrenia patients is considerably lower than most figures reported from Western settings. The dramatic differences between males and females underscore the influence of cultural norms on smoking. PMID- 21820673 TI - Historical perspectives of The American Association for Thoracic Surgery: Fred A. Crawford, Jr. PMID- 21820672 TI - Meta-analysis of randomized controlled trials to assess the effectiveness and safety of Free and Easy Wanderer Plus, a polyherbal preparation for depressive disorders. AB - Free and Easy Wanderer Plus (FEWP) is a polyherbal preparation which therapeutic benefits have been extensively evaluated in patients with various depressive disorders. The purpose of this meta-analysis was to assess the overall effectiveness and safety of FEWP. Following systematic review, a total of 14 high quality randomized controlled trials (RCTs) were identified and included in the meta-analysis. Statistically greater treatment effects were found in FEWP monotherapy compared to placebo and in FEWP combined with conventional anti depressants (CADs) compared to CADs alone. Patients taking FEWP alone and combined with CADs experienced fewer adverse events of dizziness, headache, dry mouth, nausea, and constipation compared to CADs alone. These data suggest that FEWP may be an effective herbal agent in treating depressive symptoms. The addition of FEWP also enhances antidepressant effects of CADs. FEWP may have a higher safety profile compared to CADs. PMID- 21820674 TI - Historical perspectives of The American Association for Thoracic Surgery: Mortimer J. Buckley (1932-2007). PMID- 21820675 TI - Historical perspectives of The American Association for Thoracic Surgery: Paul C. Samson (1905-1982). PMID- 21820676 TI - Historical perspectives of The American Association for Thoracic Surgery: Lyman A. Brewer III (1907-1988). PMID- 21820677 TI - Historical perspectives of The American Association for Thoracic Surgery: Evarts A. Graham (1883-1957). PMID- 21820678 TI - Historical perspectives of The American Association for Thoracic Surgery: Brian B. Blades (1906-1977). PMID- 21820679 TI - Historical perspectives of the American Association for Thoracic Surgery: Edward D. Churchill (1895-1972). PMID- 21820680 TI - Bearing the burden of boat harbours: heavy contaminant and fouling loads in a native habitat-forming alga. AB - Boat harbours are an increasingly common form of artificial habitat. This paper presents a comparative study of contaminants and foulers of a habitat-forming native kelp (Saccharina latissima) in four marinas and four reference locations along the south-west coast of the UK. Fouling of algal laminae was light (<2% cover) in reference locations, while epibiota cover ranged from 25% to 80% of laminae in marinas. Metals associated with antifouling paints were up to six times more concentrated in algal tissues from marinas than from the reference locations. Marinas also carried the greatest cover and diversity of non indigenous epibiota on the kelp laminae. This indicates not only a potential stress to kelps in these environments, but also the possibility that detached laminae will act as vectors for the dispersal of non-indigenous species. The development of boat harbours creates habitats that are high risk source localities for pollution-tolerant fouling organisms. PMID- 21820681 TI - Baseline of organotin pollution in fishes, clams, shrimps, squids and crabs collected from the west coast of India. AB - Organotins, especially tributyltins (TBT) are highly toxic to many marine organisms. These compounds are introduced in marine waters by ship trafficking, ship scrapping activities, as antifouling compounds and sewage disposal. Marine fishes, crustaceans and molluscans are easily prone to organotins contamination. In view of this, a baseline monitoring study was conducted in order to establish the levels of organotins in edible marine fishes, bivalves, shrimps, squids and crabs collected from Mumbai, Goa and Karwar on the west coast of India. At these locations average organotin concentration found in fishes, clams, shrimps, squids and crabs was 108, 852, 179, 70 and 89 ng Sn g(-1)dw, respectively. In all the samples butyltins dominated over phenyltins. The levels of organotins suggest that all the organisms were contaminated with organotins and their consumption may pose health problems to humans. PMID- 21820682 TI - Can pharmaceuticals interfere with the synthesis of active androgens in male fish? An in vitro study. AB - The in vitro interference of fibrate (gemfibrozil, clofibrate, clofibric acid), anti-inflammatory (ibuprofen, diclofenac), and anti-depressive (fluoxetine, fluvoxamine) drugs with key enzymatic activities-C17,20-lyase and CYP11beta involved in the synthesis of active androgens in gonads of male carp have been investigated. Among the tested compounds, fluvoxamine and fluoxetine were the strongest inhibitors of C17,20-lyase and CYP11beta enzymes, with IC50s in the range of 321-335 MUM and 244-550 MUM, respectively. To our knowledge this is the first report on the interaction of pharmaceutical compounds with enzymatic systems involved in the synthesis of oxy-androgens. As oxy-androgens are known to influence spermatogenesis and stimulate reproductive behavior and secondary sexual characteristics in male fish, this work highlights the need for further investigating these endpoints when designing specific in vivo studies to assess the endocrine disruptive effect of pharmaceuticals in fish. PMID- 21820683 TI - P/Ca in coral skeleton as a geochemical proxy for seawater phosphorus variation in Daya Bay, northern South China Sea. AB - The P/Ca ratio in coral skeletons is considered to be a direct proxy for the nutrient P in seawater. We examined the reliability of this proxy by analyzing P/Ca in a Porites coral collected from a eutrophic area in the northern South China Sea. P concentrations were significantly higher compared to previously reported values from pristine and open seas, corresponding to the elevated nutrients from the study site. We compared coral P/Ca against recent in-situ records of seawater P concentrations. Our results show that P/Ca was primarily a function of TP sw rather than PO(4)sw, and that the signal of skeletal P included not only phosphate, but also organic phosphorus. Besides the form of skeletal P, sub-sampling and analytical procedures and the distinctive nutrient regime were the most reasonable explanations for our results. We suggest that total P in coral skeletons may be an efficient proxy for seawater P variations and associated phytoplankton dynamics in eutrophic environments. PMID- 21820685 TI - Prophylactic treatment with telmisartan induces tissue-specific gene modulation favoring normal glucose homeostasis in Cohen-Rosenthal diabetic hypertensive rats. AB - The objectives were to assess the potential of long-term prophylactic administration of telmisartan, an angiotensin II receptor antagonist and a partial peroxisome proliferator activator receptor (PPAR)gamma agonist, in preventing the development of hypertension and hyperglycemia and to demonstrate the alteration in gene expression associated with the development of hyperglycemia and insulin resistance in Cohen-Rosenthal diabetic hypertensive rat, a unique model of hypertension and type 2 diabetes mellitus comorbidity. Cohen-Rosenthal diabetic hypertensive rats were continuously treated with telmisartan (3 mg/[kg d]) starting at age 6 to 8 weeks before developing hypertension or diabetes. Weight changes, blood pressure, blood insulin, adiponectin, glucose tolerance, and insulin sensitivity were monitored. Fat, liver, and muscle messenger RNAs were examined for the expression of genes potentially involved in the onset of insulin resistance. In addition to the expected antihypertensive effect of prophylactic telmisartan, diabetes was blunted, evidenced at the end of the study by a significantly lower glucose level. This was accompanied by improved glucose tolerance, increased sensitivity to insulin, reduction in fasting insulin levels and homeostasis model assessment index, as well as an increase in serum adiponectin. Telmisartan also prevented the increase in serum triglycerides and the associated appearance of lipid droplets in the liver. Diabetes induced tissue-specific changes in messenger RNAs expression of the following selected genes, which were restored by telmisartan treatment: PPARgamma, PPARdelta, PPARgamma coactivator 1alpha, adiponectin, adiponectin receptor 1, adiponectin receptor 2, phosphotyrosine binding domain and a pleckstrin homology domain-containing adaptor protein, adenosine monophosphate kinase, and glucose translocator 4. Telmisartan blunted the development of hypertension, insulin resistance, and diabetes in prediabetic Cohen-Rosenthal diabetic hypertensive rats through pleiotropic activity, involving specific gene regulation of target organs. PMID- 21820684 TI - Postprandial changes in plasma acylcarnitine concentrations as markers of fatty acid flux in overweight and obesity. AB - This study determined whether reductions in postprandial plasma nonesterified fatty acid (FFA) flux would lead to reductions in plasma acylcarnitine (AC) concentrations. Plasma AC was measured by liquid chromatography with tandem mass spectrometry in the fasting state and over 6 hours after a high-fat (50% energy) meal was fed to 16 overweight and obese subjects with a wide range of insulin sensitivities. Body composition was measured by dual-energy x-ray absorptiometry; insulin sensitivity by insulin-modified, frequently sampled intravenous glucose tolerance test; substrate oxidation by indirect calorimetry; blood metabolite and hormone concentrations biochemically; and fatty acid flux by using stable isotope tracers. Lean body mass and fasting fat oxidation correlated positively (r > 0.522, P < .05), whereas glucose oxidation correlated negatively (r < -0.551, P < .04), with fasting AC. Postprandially, plasma glucose, insulin, and triglyceride concentrations increased; and FFA concentrations decreased significantly. The responses of plasma AC species depended on chain length and saturation, with C14:0, C16:0, and C18:0 remaining unchanged, and unsaturated species (eg, C14:1, C14:2) falling significantly (21%-46%, P < .03). Postmeal nadir AC concentrations were positively associated with lean body mass, postprandial fatty acid flux, and FFA concentrations (r > 0.515, P < .05). By contrast, nadir AC correlated negatively with insulin sensitivity and spillover of meal-derived fatty acids (r < -0.528, P < .04). Conditions that impact fatty acid flux contribute to the control of postprandial plasma AC concentrations. These data underscore the need for a better understanding of postprandial fatty acid oxidation and dietary fat delivery in the setting of adipose insulin resistance to determine how postprandial lipemia contributes to chronic disease risk. PMID- 21820686 TI - PAF increases phagocytic capacity and superoxide anion production in equine alveolar macrophages and blood neutrophils. AB - Phagocytosis exerted by alveolar macrophages and neutrophils is crucial in the clearance of exogenous particles deposited in the airways. Therefore, substances that activate these phagocytes in the airways can exert important effects on the particle clearance rate. PAF, particularly, was proved to be a potent activator of several immune cells and was shown to be present in the equine lower airways in specific conditions, such as after exercise. The present study aimed to investigate if PAF is able to increase the phagocytic capacity and the production of superoxide anion in equine alveolar macrophage and blood neutrophils. The results show that PAF increased these parameters in both phagocytes even in concentrations as low as 0.1 and 1.0 nM. On that ground, the present work suggests that PAF is involved in the process of particle clearance in equine lower airways. PMID- 21820687 TI - Measurement of thrombopoietic activity through the quantification of megakaryocytes in bone marrow cytology and reticulated platelets. AB - Reticulated platelets are considered as marker for bone marrow thrombopoiesis. The aim of the study was evaluate the role of reticulated platelets as markers of thrombopoiesis in dogs. Reticulated platelets analysis by flow cytometry and megakaryocyte quantification by bone marrow cytology were determined in 29 healthy adult dogs (control group), 14 dogs with thrombocytopenia without megakaryocytic hypoplasia (group A) and 14 dogs with thrombocytopenia which presented megakaryocytic hypoplasia (group B), detected by bone marrow aspiration cytology. Blood samples were collected and the platelet rich plasma was obtained for reticulated platelets quantification in flow cytometry. Megakaryocytes were quantified in aspiration cytology by two techniques in marrow particles, and correlated to reticulated platelets counts. There are no differences between megakaryocyte quantification. Although there is no correlation between reticulated platelet values and megakaryocyte in bone marrow cytology, the interpretation of reticulated platelet values can be based both on absolute or relative corrected values. PMID- 21820688 TI - [Tissue engineering of hard tissues in stomatology and maxillo-facial surgery, a global challenge]. PMID- 21820689 TI - [Engineering a bone free flap for maxillofacial reconstruction: technical restrictions]. AB - Vascularisation is a key for success in bone tissue engineering. Creating a functional vascular network is an important concern so as to ensure vitality in regenerated tissues. Many strategies were developed to achieve this goal. One of these is cellular growth technique by perfusion bioreactor chamber. These new technical requirements came along with improved media and chamber receptacles: bioreactors (chapter 2). Some bone tissue engineering processes already have clinical applications but for volumes limited by the lack of vascularisation. Resorbable or non-resorbable membranes are an example. They are used separately or in association with bone grafts and they protect the graft during the revascularization process. Potentiated osseous regeneration uses molecular or cellular adjuvants (BMPs and autologous stem cells) to improve osseous healing. Significant improvements were made: integration of specific sequences, which may guide and enhance cells differentiation in scaffold; nano- or micro-patterned cell containing scaffolds. Finally, some authors consider the patient body as an ideal bioreactor to induce vascularisation in large volumes of grafted tissues. "Endocultivation", i.e., cellular culture inside the human body was proven to be feasible and safe. The properties of regenerated bone in the long run remain to be assessed. The objective to reach remains the engineering of an "in vitro" osseous free flap without morbidity. PMID- 21820690 TI - [Contribution of low-intensity pulsed ultrasounds to bone regeneration]. AB - A maxillo-facial surgeon manages patients with bone defects due to trauma, malformations or of iatrogenic origin. The surgical management has potentially deleterious effects and its cost for society is increasing. Hence, it is crucial to develop techniques stimulating bone growth, stimulating the regeneration of a fracture or filling bone deficit. Ultrasounds (US), vibrations of the same nature as sound but with frequencies above the highest audible frequency for men (above 20 kHz), are used in many fields, particularly in medicine, usually at frequencies of around 0.5 to 5 MHz (million cycles per second). Their biological effects are not fully understood yet, but it is well known that US have effects on organic tissues when their mechanical energy is converted into thermic energy. These effects induce vasodilation and modification of membrane permeability. Several publications present the benefit of US for the stimulation of bone regeneration after a fracture. We present an overview of current knowledge on the effect of pulsed ultrasound on craniofacial bone regeneration, with study results conducted within Inserm unit U1032 in Lyon, the current reference lab on this issue. PMID- 21820691 TI - Currency as a potential environmental vehicle for transmitting parasites among food-related workers in Alexandria, Egypt. AB - Transmission of parasites may occur indirectly via inanimate objects in the surrounding environment. One of the objects most handled and exchanged by people are currency coins and banknotes, which could be one of the most potential vehicles to transmit parasites, even between countries. However, study of the potential contamination of currency in circulation with intestinal parasites has not been given the interest it deserves and the present study is the first pilot study in Alexandria, Egypt. It was revealed that 60.2% of 103 banknotes and 56.6% of 99 coins obtained from food-related workers had been contaminated with one or more parasitic species. Protozoa were the predominant parasites, with microsporidia and Cryptosporidium spp. being the most prevalent. There was no statistically significant difference between currency types regarding parasitological contamination, but there was a significant (P<0.001) association between the physical condition of currency and its contamination. Moreover, the source of the currency was not statistically associated with parasitological contamination. The denomination of coins was not statistically associated with parasitological contamination, whilst that of banknotes was with the lower denominations being more contaminated. PMID- 21820692 TI - KATP channels in mesenchymal stromal stem cells: strong up-regulation of Kir6.2 subunits upon osteogenic differentiation. AB - The promising use of mesenchymal stromal cells (MSC) in regenerative technologies accounts for necessity of detailed study of their physiology. Proliferation and differentiation of multipotent cells often involve changes in their metabolic state. In the present study, we analyzed the expression of ATP-sensitive potassium (K(ATP)) channels in MSC and upon in vitro differentiation. K(ATP) channels are present in many cells and regulate a variety of cellular functions by coupling cell metabolism with membrane potential. Kir6.1, Kir6.2 and SUR2A were expressed in undifferentiated MSC, whereas SUR2B and SUR1 were not detected on cDNA and protein level. Upon adipogenic differentiation Kir6.1 and SUR2A showed a significant reduction of the amount of mRNA by 84% and 95%, respectively, whereas Kir6.2 expression was unchanged. Osteogenic differentiation strongly up-regulated Kir6.2 mRNA (28-fold) whereas Kir6.1 and SUR2A showed no significant change in expression. Quantitative Western blot analysis and immunofluorescence staining confirmed the elevated expression of Kir6.2 upon osteogenic differentiation. Taken together, expression changes of K(ATP) channels may contribute to in vitro differentiation of MSC and represent changes in the metabolic state of the developing tissue. PMID- 21820693 TI - Ultrasound therapy modulates osteocalcin expression during bone repair in rats. AB - The aim of this study was to measure the temporal pattern of the protein expression of RUNX2, RANKL, OPG, and osteocalcin after ultrasound therapy during the process of bone healing by immunohistochemistry. The animals were randomly distributed into two groups: control or ultrasound-treated group. A non-critical size bone defects were surgically created at the upper third of the tibia. The treatments started 24h post-surgery, and they are performed for 3, 6, and 12 sessions, with an interval of 48h. A low-intensity pulsed ultrasound (1.5MHz, 1:4 duty cycle, intensity SATA 30mW/cm(2), 20min/session, stationary mode application) was used. On days 7, 13, and 25 post-injury, rats were killed individually by carbon dioxide asphyxia. The tibias were removed for analysis. The histopathological analysis pointed out no remarkable differences between groups for all periods evaluated. However, immunohistochemical data revealed that ultrasound therapy produced an up-regulation of osteocalcin at day 7th and 13th post-surgery. Taken together, our results indicate that ultrasound therapy modulates osteocalcin expression during bone repair in rats as depicted by differential immunopression at the initial and intermediate stages of recovery. PMID- 21820694 TI - A new approach to data evaluation in the non-target screening of organic trace substances in water analysis. AB - Non-target screening via high performance liquid chromatography-mass spectrometry (HPLC-MS) has gained increasingly in importance for monitoring organic trace substances in water resources targeted for the production of drinking water. In this article a new approach for evaluating the data from non-target HPLC-MS screening in water is introduced and its advantages are demonstrated using the supply of drinking water as an example. The crucial difference between this and other approaches is the comparison of samples based on compounds (features) determined by their full scan data. In so doing, we take advantage of the temporal, spatial, or process-based relationships among the samples by applying the set operators, UNION, INTERSECT, and COMPLEMENT to the features of each sample. This approach regards all compounds, detectable by the used analytical method. That is the fundamental meaning of non-target screening, which includes all analytical information from the applied technique for further data evaluation. In the given example, in just one step, all detected features (1729) of a landfill leachate sample could be examined for their relevant influences on water purification respectively drinking water. This study shows that 1721 out of 1729 features were not relevant for the water purification. Only eight features could be determined in the untreated water and three of them were found in the final drinking water after ozonation. In so doing, it was possible to identify 1 adamantylamine as contamination of the landfill in the drinking water at a concentration in the range of 20 ng L(-1). To support the identification of relevant compounds and their transformation products, the DAIOS database (Database-Assisted Identification of Organic Substances) was used. This database concept includes some functions such as product ion search to increase the efficiency of the database query after the screening. To identify related transformation products the database function "transformation tree" was used. PMID- 21820695 TI - Formation of nitrogenous disinfection by-products from pre-chloramination. AB - A sampling survey investigated the formation of nitrogenous disinfection by products (N-DBPs) and carbonaceous DBPs (C-DBPs) from pre-chloramination, an increasingly common treatment strategy in China for regulated C-DBP control, followed by subsequent conventional water treatment processes, i.e., coagulation, sedimentation, and filtration. Dihalogenated N-DBPs typically peaked in the summer and early autumn with a relatively higher temperature, with the maximum levels of dichloroacetamide (DCAcAm), dichloroacetonitrile (DCAN), bromochloroacetonitrile, dibromoacetonitrile and dichloroacetone at 1.8, 6.3, 6.0, 2.6 and 1.8MUgL(-1) in the finished water, respectively. Also, the levels of all the dichlorinated N-DBPs were correlated with the ratio of dissolved organic nitrogen (DON) to dissolved organic carbon, implying autochthonous DON played an essential role in the formation of these DBPs. In contrast, the yields of trihalogenated DBPs [chloroform (CF), trichloronitromethane (TCNM) and trichloroacetone (TCAce)] appeared not to be significantly affected by seasons. CF and DCAN were the dominant species in trihalomethanes (THMs) and dihaloacetonitriles (DHANs), respectively. Bromine was more readily incorporated into DHANs to form brominated DBPs than THMs during pre-chloramination. Although pre-chloramination can ensure the finished water to meet with the current Chinese THM regulatory limits, the increased levels of TCNM and TCAce may be a new water quality concern. PMID- 21820696 TI - The role of phytoplankton in the modulation of dissolved and oyster cadmium concentrations in Deep Bay, British Columbia, Canada. AB - We previously identified dissolved cadmium (Cd(diss)) as the main source of this metal in cultured Pacific oysters, Crassostrea gigas, in Deep Bay, British Columbia, Canada (Lekhi et al., 2008). Total suspended particulate Cd (Cd(part)) was not found to be a significant source of oyster Cd (Cd(oys)), with Cd(part) >20 MUm negatively correlated with Cd(oys) concentration. High phytoplankton abundance in spring and summer was hypothesized to reduce Cd(oys) indirectly by drawing down Cd(diss) and increasing oyster growth. In the present study we expanded on these results by examining specifically how the phytoplankton community composition modulates both Cd(diss) and Cd(oys) concentrations in Deep Bay. Based on calculations of nutrients and Cd(diss) drawdown, phytoplankton accounted for approximately 90% of the overall summer reduction in Cd(diss) in the bay. Diatoms were the dominant phytoplankton group, being correlated negatively with Cd(oys) and positively with Cd(part). This suggests that diatom growth mediates the transfer of Cd from the dissolved to the particulate phase, resulting in lower Cd(oys). Spring blooms and sporadic harmful algal blooms may mediate a large flux of Cd(part) to the sediments. Thus, phytoplankton act as a sink, rather than a source, of Cd to oysters in Deep Bay and have a crucial role in the seasonality of Cd(oys) by reducing the concentration of Cd(diss) during the summer. Based on environmental variables, two descriptive models for annual Cd(oys) concentrations were developed using multiple linear regression. The first model (R(2)=0.870) was created to explain the maximum variability in Cd(oys) concentrations throughout the year, while the second (R(2)=0.806) was based on parameters that could be measured easily under farm conditions. Oyster age heavily affected both models, with the first model being secondarily affected by temperature and the second one being more sensitive to changes in salinity. PMID- 21820697 TI - Increased expression of TF in BMP-7-treated human mononuclear cells depends on activation of select MAPK signaling pathways. AB - Bone morphogenetic protein (BMP)-7 regulates atherosclerotic plaque calcification, and it contributes to increased thrombogenicity of lipid-rich lesions by enhancement of TF expression in monocytes/macrophages by unknown mechanism. Since Erk1/2, JNK and p38 mitogen activated protein kinases (MAPKs) regulate TF expression, we studied involvement of MAPK pathways in BMP-7-induced activation of TF in human mononuclear cells (MNCs). Whole blood from healthy volunteers was treated with BMP-7, MNCs were isolated, and TF expression was assessed by western blot (WB) and In-Cell Western assay. Phosphorylation and nuclear translocation of Smad1/5/8 in response to BMP-7 stimulation of MNCs was evaluated by WB and confocal microscopy. Activation of MAPKs was judged by measuring the levels of phoshorylated Erk1/2, JNK, and p38 in the lysates of MNCs. The impact of Erk1/2 and p38 activation was studied by use of PD98059 and SB203580 inhibitors, respectively. Stimulation of whole blood with BMP-7 increased the levels of TF in the lysates of MNCs by 7-fold as compared to 12 fold after LPS stimulation. It was followed by elevation in TF fuctional activity. It was accompanied by elevated levels of phosphorylated Smad 1/5/8 and nuclear translocation of Smad1/5/8 proteins. Treatment of whole blood with BMP-7 led to a phosphorylation of Erk1/2, JNK and p38 MAPKs. BMP-7-induced TF expression was partially inhibited by Erk1/2 inhibitor, whereas TF expression was completely abolished by p38 inhibitor. BMP-7-dependent activation of TF in human MNCs by BMP-7 is accompanied by activation of canonic Smad1/5/8 signaling pathway and depends on activation of Erk1/2 and p38. PMID- 21820698 TI - Factor IX propeptide mutation and life threatening bleeding. PMID- 21820699 TI - Bladder leiomyoma in a 6-year-old boy. AB - The present report describes a 6-year-old boy with leiomyoma of the bladder and the imaging characteristics of the lesion, including images from ultrasonography, computed tomography, and the histopathologic examination. Leiomyoma of bladder is extremely rare in children. The present case, to our knowledge, represents the second reported case of bladder leiomyoma in pediatric patients since 1966. Although preoperative imaging can be useful to assess the disease extent, the final diagnosis depends on the histopathologic examination findings. Surgical excision is the ideal option to confirm the diagnosis and to treat the disorder. The prognosis is good after complete resection. PMID- 21820700 TI - Anatomical variation between the prone, supine, and supine oblique positions on computed tomography: implications for percutaneous nephrolithotomy access. AB - OBJECTIVE: To determine anatomical variations between the prone, supine, and supine oblique positions that are likely to affect percutaneous renal access. MATERIAL AND METHODS: Twenty patients underwent computed tomography urograms in the supine and prone positions. Twenty patients underwent supine oblique and prone scans. Mean nephrostomy tract length, maximum access angle, and anterior posterior renal position were calculated. RESULTS: Mean nephrostomy tract length was shorter in the prone position (82.6 mm right kidney, 85.4 mm left kidney) compared with the supine position (108.3 mm right kidney, P<.001; 103.7 mm left kidney, P<.001). Prone tract length was also shorter than supine oblique tract length (86.1 mm vs 96.5 mm; P=.048). Mean maximum access angle was significantly greater (P=.018 right kidney; P=.007 left kidney) in the prone position (right kidney 99.7 degrees , left kidney 104.0 degrees ) compared with the supine position (right kidney 87.7 degrees , left kidney 89.4 degrees ). The same was true for the prone compared with the supine oblique position (75.8 degrees vs 58.7 degrees ; P=.004). No difference was noted in anterior-posterior renal position between the supine and prone positions (20.3 mm vs 26.7 mm; P=.094) or supine oblique and prone positions (22.8 mm vs 15.6 mm; P=.45). CONCLUSIONS: The prone position is associated with a significantly shorter nephrostomy tract length and more potential access sites, which may improve ease and safety of percutaneous renal access. PMID- 21820701 TI - Squamous cell carcinoma of the enlarged prostatic utricle in an adult. AB - A 39-year-old man with gross terminal hematuria and urethral discharge for 5 months was found to have a partial cystic and partial solid mass above the normal site of prostate, which was confirmed by magnetic resonance imaging (MRI) and transrectal ultrasonagraphy. A radical resection of the tumor was performed, and classical squamous cell carcinoma was confirmed by pathologic assay. PMID- 21820702 TI - Sperm organelle morphologic abnormalities: contributing factors and effects on intracytoplasmic sperm injection cycles outcomes. AB - OBJECTIVE: To (1) analyze possible relationships between motile sperm organelle morphology examination (MSOME) and sperm chromatin status, aneuploidy incidence, and patient's age; (2) determine the effects of sperm morphologic abnormalities on intracytoplasmic sperm injection (ICSI) outcomes; and (3) identify the benefits of intracytoplasmic morphologically selected sperm injection (IMSI) in patients with high DNA fragmentation rate. METHODS: The study was performed in 50 patients undergoing ICSI cycles. The MSOME, sperm DNA fragmentation, and sperm aneuploidy incidence were performed in 200 sperm cells of each patient. Regression models were used to assess the relationships among sperm morphology and sperm aneuploidy, sperm DNA fragmentation, patient's age, and ICSI outcomes. In cycles with patients showing a high incidence of DNA fragmentation, oocytes were split into 2 groups according to the sperm selection method: Standard-ICSI (n = 82) and IMSI (n = 79). Fertilization and high-quality embryo rates were compared between the groups. RESULTS: A close relationship between sperm DNA fragmentation and the presence of vacuoles in the MSOME was noted. The patient's age was correlated to the presence of vacuoles. No correlation between sperm aneuploidy and IMSI was observed. Vacuolated cells were negatively correlated with fertilization, pregnancy, and implantation. In patients with a high incidence of sperm DNA fragmentation, fertilization and high-quality embryo rates were similar when comparing IMSI and Standard-ICSI. CONCLUSIONS: Our data demonstrate a correlation between paternal age and the incidence of nuclear vacuoles, as well as an effect of large and small vacuoles on late embryo development. PMID- 21820703 TI - Postoperative adhesions after application of topical hemostatic agents: outcomes in a rat partial nephrectomy model. AB - OBJECTIVE: To compare 3 kinds of topical hemostatic agents in terms of adhesive strength, control of hemorrhage, and postoperative intra-abdominal adhesions in an experimental partial nephrectomy (PN) model. METHODS: A total of 27 Wistar rats were divided into 5 groups. PN was performed in 6 rats (control group) with the conventional technique, in which the lower pole of the kidney was excised and sutured after hilar control. In 5 rats, oxidized cellulose was placed over the excised part of the kidney following conventional technique. In 6 rats, the hemostatic plant extract was used without hilar control. In 5 rats, the hemostatic agent chitosan was used without hilar control. As a sham group, 5 rats underwent a laparotomy and handling of the renal pedicle without the removal of renal pole. On the tenth day after the operation, the degree of adhesions to the operated kidney were evaluated. Histopathological evaluation was also performed by a blinded pathologist. RESULTS: Mean warm ischemia times for control and oxidized cellulose groups were 4.85 +/- 0.75 and 4.28 +/- 1.28 minutes, respectively (P = .662). Wound healing was excellent in all groups except in 1 rat in the chitosan group. Chitosan was associated with significantly higher intestinal and peritoneal adhesion scores, although histopathologically comparable scores were revealed. CONCLUSION: In our rat model, chitosan and the hemostatic plant extract were as effective as conventional suturing in achieving hemostasis even without hilar control. Warm ischemia was eliminated and PN time was significantly decreased. The use of oxidized cellulose was not associated with higher scores of adhesion, suppuration, or hematoma. PMID- 21820704 TI - Hemiscrotal agenesis: new variation in a rare anomaly. AB - Scrotal agenesis is a rarely encountered developmental anomaly of the scrotum, with only 6 cases of complete agenesis reported in published studies. We report, to our knowledge, the first case of hemiscrotal agenesis. The specific embryologic basis of scrotal agenesis is unknown but is likely multifactorial, involving localized androgen insensitivity, localized 5alpha-reductase deficiency, and/or failure of labioscrotal fold formation. PMID- 21820705 TI - Long-term results of the tension-free vaginal tape procedure in an unselected group: a 7-year follow-up study. AB - OBJECTIVES: To evaluate long-term effectiveness and late complications after treatment of female stress urinary incontinence with tension-free vaginal tape (TVT). METHODS: We performed a prospective observational study. Follow-up examinations included a standardized questionnaire, medical history, voiding diary, gynecologic examination with cough test, and introital ultrasound. RESULTS: One-hundred-eight women (68.8%) from the initial cohort of 157 patients and 79.6% of those alive and able to cooperate were assessed. The median follow up time was 102 months (range 85-124). The objective cure rate was 89.8%. The subjective cure rate was 82.4%, 13% had improved, 2.8% regarded the continence situation as unchanged, and 1.8% had an impaired stress urinary incontinence. No late-onset adverse effects of the surgery were found. Urge incontinence was the main reason for dissatisfaction with the surgery (in 90% of discontent patients). CONCLUSIONS: Our data showed good results more than 7 years after TVT, demonstrating a high level of long-lasting efficacy for this minimally invasive incontinence procedure. PMID- 21820707 TI - Functional outcomes after management of end-stage neurological bladder dysfunction with ileal conduit in a multiple sclerosis population: a monocentric experience. AB - OBJECTIVE: To assess the outcome of cutaneous noncontinent urinary diversion (CNCUD) for neurogenic bladder management in multiple sclerosis (MS) patients. METHODS: We retrospectively reviewed the charts of our MS patients who underwent surgery for CNCUD between 1994 and 2009. To assess the impact of urinary problems on health-related quality of life (HRQOL), a Qualiveen questionnaire was completed by the patients (scale 0 = no impact of urinary problems and 4 = high adverse impact). RESULTS: Overall, 53 patients with a median age of 51 years were included in the study. The mean Expanded Disability Status Scale score before surgery was 7.48 +/-1.02 (range 6.5-9). The mean duration of follow-up was 73 months (range 6-168). The complication rate was 55%. Minor postoperative complications (Clavien grades I-II) occurred in 23 cases, and major complications (Clavien grades III-IV) occurred in 6 cases. The mean creatinine levels before surgery and at the last follow-up were 0.63 +/- 0.2 mg/dL and 0.73 +/- 0.53 mg/dL, respectively. The mean overall HRQOL scores before surgery and at last follow-up, and which assess the impact of the urinary problems on the patient, were 2.1 +/- 1.18 and 1.16 +/- 0.63 (P = .02), respectively. CONCLUSION: Cystectomy and CNCUD are indicated in MS-impaired patients who are refractory to medical treatment and they can result in disappearance of neurological bladder symptoms. CNCUD appears to be the procedure of choice to improve the quality of life of selected patients, despite the fact that it is associated with high perioperative morbidity. PMID- 21820706 TI - Prostate cancer risk alleles and their associations with other malignancies. AB - OBJECTIVE: To determine whether certain risk alleles are responsible for the relationship between prostate cancer (CaP) and other malignancies. CaP has been associated with other common malignancies. Recently, numerous single nucleotide polymorphisms (SNPs) have been associated with CaP susceptibility. METHODS: We genotyped 1121 patients with CaP for 36 risk alleles known to be significantly associated with CaP susceptibility and determined their relationships to other malignancies in CaP probands and their first-degree relatives. RESULTS: The most common other malignancies in the CaP probands were nonmelanoma skin cancer (13.6%), leukemia (7.3%), melanoma (3.9%), non-Hodgkin's lymphoma (0.7%), colorectal cancer (0.6%), and multiple myeloma (0.3%). Among the probands, a significantly increased frequency of leukemia was found in the carriers of SNP rs2736098 (5p15, P = .03) and melanoma in the carriers of either SNP rs1512268 (8p21, P = .006) or SNP rs5759167 (22q13, P = .02). Multiple myeloma was more common in carriers of SNP rs9364554 (6q25, P = .02). The probands who were carriers of SNP rs16901979 (8q24) were significantly more likely to report a family history of melanoma (P = .03), and the probands with a family history of multiple myeloma and non-Hodgkin's disease were significantly more likely to be carriers of SNP rs12621278 (2q31, P = .04) and rs6465657 (7q21, P = .02), respectively. CONCLUSION: Certain alleles associated with CaP susceptibility might be associated with an increased or a decreased risk of other malignancies in CaP probands and their first-degree relatives. Additional studies are warranted to examine the underlying mechanisms of these SNPs in CaP and other malignancies. PMID- 21820708 TI - Radical hysterectomy with adjuvant radiotherapy versus definitive radiotherapy alone for FIGO stage IIB cervical cancer. AB - OBJECTIVES: The aim of this study was to compare the treatment outcomes and adverse effects of radical hysterectomy followed by adjuvant radiotherapy with definitive radiotherapy alone in patients with FIGO stage IIB cervical cancer. METHODS: We retrospectively reviewed the medical records of FIGO stage IIB cervical cancer patients who were treated between April 1996 and December 2009. During the study period, 95 patients were treated with radical hysterectomy, all of which received adjuvant radiotherapy (surgery-based group). In addition, 94 patients received definitive radiotherapy alone (RT-based group). The recurrence rate, progression-free survival (PFS), overall survival (OS), and treatment related complications were compared between the two groups. RESULTS: Radical hysterectomy followed by adjuvant radiotherapy resulted in comparable recurrence (44.2% versus 41.5%, p=0.77), PFS (log-rank, p=0.57), and OS rates (log-rank, p=0.41) to definitive radiotherapy alone. The frequencies of acute grade 3-4 toxicities were similar between the two groups (24.2% versus 24.5%, p=1.0), whereas the frequencies of grade 3-4 late toxicities were significantly higher in the surgery-based group than in the RT-based group (24.1% versus 10.6%, p=0.048). Cox multivariate analyses demonstrated that treatment with surgery followed by adjuvant radiotherapy was associated with an increased risk of grade 3-4 late toxicities, although the statistical significance of the difference was marginal (odds ratio 2.41, 95%CI 0.97-5.99, p=0.059). CONCLUSIONS: Definitive radiotherapy was found to be a safer approach than radical hysterectomy followed by postoperative radiotherapy with less treatment-related complications and comparable survival outcomes in patients with FIGO stage IIB cervical cancer. PMID- 21820709 TI - Recurrence patterns and surveillance for patients with early stage endometrial cancer. AB - INTRODUCTION: To evaluate the recurrence patterns and the clinical and economic role of surveillance with vaginal cytology in women with low risk endometrial cancer. METHODS: Patients undergoing primary surgery with final pathology consistent with a grade 1 endometrial cancer confined to the endometrium (FIGO 1988 stage IA) between 9/1997-12/2007 were retrospectively identified. Follow-up data for at least 2 years was also collected, including diagnosis of a recurrence, symptomatology at that time, and method of detection. Costs for vaginal cytology were estimated using Medicare charge-to-cost ratios adjusted to 2010 costs. RESULTS: One hundred fifty-four patients met study inclusion criteria. The mean age was 54.4 years and the mean follow-up was 46.9 months. Four recurrences were detected, occurring 16-73 months after the initial diagnosis. During a scheduled visit, one patient was found to have an asymptomatic vaginal cuff recurrence, detected on physical examination. The remaining three cases were diagnosed at an unscheduled visit after the presence of symptoms (vaginal bleeding, abdominal pain, shortness of breath) prompted further evaluation. In all, cytology detected no cases of recurrence and the estimated cost associated with cytology alone for all patients over the study time frame was approximately $7,760 per year. CONCLUSIONS: Patients with grade 1 endometrial cancer confined to the endometrium have a low risk of recurrence (2.6%) and were detected on clinical findings alone. Emphasis should be placed on counseling patients on symptoms of recurrence and performing a thorough physical examination. The elimination of vaginal cytology for this select group of patients may be appropriate and result in a significant reduction in health care costs. PMID- 21820710 TI - The case of a viable pregnancy post vaginal radical trachelectomy followed by combined chemo-radiation therapy. PMID- 21820711 TI - The association of obesity and asthma severity and control in children. AB - BACKGROUND: The association between obesity and asthma severity and control in children is not well understood. OBJECTIVE: The objective of this study was to examine the association of childhood body mass index (BMI) percentile for age of 85% or greater with the number of beta-agonist canisters dispensed, corticosteroid courses, emergency department visits, and hospitalizations for asthma. METHODS: A retrospective cohort of 32,321 children aged 5 to 17 years and given a diagnosis of asthma who received at least 1 asthma (controller or rescue) medication and were enrolled in Kaiser Permanente from 2004-2008 was identified. Outcomes from electronic medical records included beta-agonist canister and nebulizer units dispensed per year, hospitalizations and emergency department visits for asthma exacerbations, and oral corticosteroid courses. Potential confounding factors known to influence asthma outcomes were also collected: demographics, parental education level, asthma controller use, gastroesophageal reflux disease diagnosis, and diabetes mellitus diagnosis. Multiple logistic regression models were used to measure the independent association of BMI status with outcomes. RESULTS: Even after adjusting for demographics, parental education level, asthma controller use, and gastroesophageal reflux disease and diabetes mellitus diagnoses, overweight (BMI percentile for age, 85% to 94%) and obese (BMI percentile for age, >= 95%) children were more likely to have increased beta agonists dispensed (odds ratio of 1.15 [95% CI, 1.02-1.27] and odds ratio of 1.17 [95% CI, 1.06-1.29], respectively) and increased risk for oral corticosteroids dispensed (odds ratio of 1.21 [95% CI, 1.13-1.29] and odds ratio of 1.28 [95% CI, 1.21-1.36], respectively) compared with normal-weight (BMI percentile for age, 16% to 84%) children. CONCLUSIONS: Our findings suggest that childhood obesity is associated with an increased risk of worse asthma control and exacerbations. PMID- 21820712 TI - Immunization with modified vaccinia virus Ankara prevents eczema vaccinatum in a murine model of atopic dermatitis. PMID- 21820713 TI - Short ragweed pollen triggers allergic inflammation through Toll-like receptor 4 dependent thymic stromal lymphopoietin/OX40 ligand/OX40 signaling pathways. AB - BACKGROUND: Allergic diseases affect a large population. Pollen, an ubiquitous allergen, is the trigger of seasonal rhinitis, conjunctivitis, and asthma, as well as an exacerbating factor of atopic dermatitis. However, the underlying mechanism by which pollen induces thymic stromal lymphopoietin (TSLP)-triggered allergic inflammation through epithelial innate immunity is largely unknown. OBJECTIVE: We sought to explore whether short ragweed (SRW) pollen induces TSLP/OX40 ligand (OX40L)/OX40 signaling through Toll-like receptor (TLR) 4 dependent pathways in patients with allergic disease. METHODS: Three models were used for this study, a well-characterized murine model of allergic conjunctivitis induced by SRW pollen, a topical challenge model on the murine ocular surface, and a culture model of primary human corneal epithelium exposed to aqueous extract of defatted SRW pollen (SRWe). RESULTS: The topical challenges with SRW pollen generated typical allergic conjunctivitis in BALB/c mice. Clinical signs, stimulated TSLP/OX40L/OX40 signaling, and T(H)2 cytokine levels in the ocular mucosa and draining cervical lymph nodes were significantly reduced or eliminated in TLR4-deficient (Tlr4-d) or myeloid differentiation primary response gene 88 (MyD88) knockout (MyD88(-/-)) mice compared with those seen in their wild-type littermates. SRWe stimulated TSLP production by ocular epithelia in wild-type but not Tlr4-d or MyD88(-/-) mice. SRWe-stimulated TSLP was blocked by TLR4 antibody and nuclear factor kappaB inhibitor in murine and human corneal epithelia. CONCLUSION: For the first time, we have shown that SRW pollen, acting as a functional TLR4 agonist, initiates TLR4-dependent TSLP/OX40L/OX40 signaling, which triggers T(H)2-dominant allergic inflammation. These findings shed light on the understanding of mucosal epithelial innate immunity and create new therapeutic targets to cure allergic diseases. PMID- 21820714 TI - Effect of prenatal indoor pet exposure on the trajectory of total IgE levels in early childhood. AB - BACKGROUND: The presence of pets in a home during the prenatal period and during early infancy has been associated with a lower prevalence of allergic sensitization and total IgE levels in middle childhood. No studies have examined the effect of pet exposure in a population-based cohort by using multiple early life measures of serum total IgE. OBJECTIVE: We sought to examine within individual longitudinal trends in total IgE levels during early childhood and assess the effect of indoor prenatal pet exposure on those trends. Also, we sought to use a statistical method that was flexible enough to allow and account for unequally spaced study contacts and missing data. METHODS: Using the population-based Wayne County Health, Environment, Allergy and Asthma Longitudinal Study birth cohort (62% African American), we analyzed 1187 infants with 1 to 4 measurements of total IgE collected from birth to 2 years of age. Effects of pet exposure on the shape and trajectory of IgE levels were assessed by using a multilevel longitudinal model, accommodating repeated measures, missing data, and the precise time points of data collection. RESULTS: The best fit shape to the trajectory of IgE levels was nonlinear, with an accelerated increase before 6 months. Total IgE levels were lower across the entire early life period when there was prenatal indoor pet exposure (P < .001). This effect was statistically significantly stronger in children delivered by means of cesarean section versus those delivered vaginally (P < .001 and P < .06, respectively) and in those born to non-African American (P < .001) versus African American (P < .3) mothers. CONCLUSION: Pet exposure and delivery mode might be markers of infant exposure to distinct microbiomes. The effect of exposures might vary by race, suggesting a differential effect by ancestry. PMID- 21820715 TI - Baseline differences explain the apparent benefits of combining oxymetazoline with intranasal corticosteroids. PMID- 21820717 TI - House dust mite sensitization in toddlers predicts current wheeze at age 12 years. AB - BACKGROUND: Identification of children at risk of developing asthma provides a window of opportunity for risk-reducing interventions. Allergen sensitization might identify high-risk children. OBJECTIVE: We sought to determine whether skin prick tests (SPTs) to individual allergens up to age 2 years predict wheeze at age 12 years. METHODS: In a birth cohort of 620 children oversampled for familial allergy, sensitization was assessed by using SPTs (monosensitized, polysensitized, or either) to 6 allergens at ages 6, 12, and 24 months. Wheeze and eczema were recorded 18 times during the first 2 years. Current wheeze was recorded at age 12 years. Adjusted associations were evaluated by multiple logistic regression. RESULTS: A positive SPT to house dust mite (HDM) at age 1 or 2 years predicted wheeze at age 12 years (adjusted odds ratio: 1 year, 3.31 [95% CI 1.59-6.91]; 2 years, 6.37 [95% CI, 3.48-11.66]). Among wheezy 1-year-olds, those who were HDM sensitized had a 75% (95% CI, 51% to 91%) probability of wheeze at age 12 years compared with a 36% (95% CI, 23% to 50%) probability among those not sensitized. Among eczematous 1-year-olds, those who were HDM sensitized had a 67% (95% CI, 45% to 84%) probability of wheeze at age 12 years compared with a 35% (95% CI, 25% to 45%) probability among those not sensitized. Among 1 year-old children with both eczema and wheeze, the probability of wheeze at age 12 years was 64% (95% CI, 35% to 87%) if HDM sensitized and 50% (95% CI, 26% to 74%) if not. CONCLUSION: HDM sensitization at age 1 or 2 years in wheezing and eczematous children at increased familial allergy risk predicts asthma and may inform management of these high-risk groups. PMID- 21820718 TI - Relationships between fetal biometry, maternal factors and birth weight of purebred domestic cat kittens. AB - The goal of this study was to evaluate the relation between kittens' birth weights and biometrical factors from the kittens and the mother during pregnancy. Knowing fetal birth weight could help in detecting abnormalities before parturition. A Caesarean-section or a postnatal management plan could be scheduled. Consequently, the neonatal mortality rate should be decreased. We used ultrasonographic measurements of femur length (FL) or fetal biparietal diameter (BPD), pregnancies, and maternal factors to obtain a model of prediction. For this purpose, linear mixed-effects models were used because of random effects (several fetuses for one queen and a few paired measurements) and fixed effects (litter size, pregnancy rank, weight, wither height, and age of the queen). This study was performed in 24 purebred queens with normal pregnancies and normal body conditions. Queens were scanned in the second half of pregnancy, using a micro convex probe. They gave birth to 140 healthy kittens whose mean birth weight was 104 g (ranged 65 to 165 g). No correlation between the birth weight and the age of the queen, as a maternal factor alone, was observed. But the birth weight was found to be inversely proportional to the pregnancy rank and the litter size. Moreover, birth weight increased when the weight and wither height of queen increased. BPD and FL increased linearly during pregnancy so a model was used to estimate mean birth weight. Using this model, we found a correlation between mean birth weights and an association of parameters: maternal factors (wither height and age), and litter size. PMID- 21820720 TI - Cleavage pattern and survivin expression in porcine embryos by somatic cell nuclear transfer. AB - Mammalian embryos produced in vitro show a high rate of early developmental failure. Numerous somatic cell nuclear transfer (SCNT) embryos undergo arrest and show abnormal gene expression in the early developmental stages. The purpose of this study was to analyze porcine SCNT embryo development and investigate the cause of porcine SCNT embryo arrest. The temporal cleavage pattern of porcine SCNT embryos was analyzed first, and the blastocyst origin at early developmental stage was identified. To investigate markers of arrest in the cleavage patterns of preimplantation SCNT embryos, the expression of survivin-the smallest member of the inhibitor of apoptosis (IAP) gene family, which suppresses apoptosis and regulates cell division-was compared between embryos showing normal cleavage and arrested embryos. A total of 511 SCNT embryos were used for cleavage pattern analysis. Twenty-four hours post activation (hpa), embryos were classified into five groups based on the cleavage stage as follows; 1-cell, 2-cell, 4-cell, 8 cell and fragmentation (frag). In addition, 48 hpa embryos were more strictly classified into 15 groups based on the cleavage stage of 24 hpa; 1-1 cell (24 hpa 48 hpa), 1-2 cell, 1-4 cell, 1-8 cell, 1 cell-frag, 2-2 cell, 2-4 cell, 2-8 cell, 2 cell-frag, 4-4 cell, 4-8 cell, 4 cell-frag, 8-8 cell, 8 cell-frag, and frag frag. These groups were cultured until 7 d post activation, and were evaluated for blastocyst formation. At 24 hpa, the proportion of 2-cell stage was significantly higher (44.5%) than those in the other cleavage stages (1-cell: 13.4%; 4-cell: 17.9%; 8-cell: 10.3%; and frag: 13.9%). At 48 hpa, the proportion of embryos in the 2-4 cell stage was significantly higher (32.4%) than those in the other cleavage stages (2-8 cell: 8.2%; 4-8 cell: 12.1%; and frag-frag: 13.9%). Some embryos arrested at 48 hpa (1-1 cell: 5.8%; 2-2 cell: 2.8%; 4-4 cell: 3.8%; 8-8 cell: 6.5%; and total arrested embryos: 18.9%). Blastocyst formation rates were higher in 2-4 cell cleavage group (20.2%) than in other groups. SCNT embryos in 2-4 cell stage showed stable developmental competence. In addition, we investigated survivin expression in porcine SCNT embryos during the early developmental stages. The levels of survivin mRNA in 2-cell, 4-cell stage SCNT embryos were significantly higher than those of arrested embryos. Survivin protein expression showed a similar pattern to that of survivin mRNA. Normally cleaving embryos showed higher survivin protein expression levels than arrested embryos. These observations suggested that 2-4 cell cleaving embryos at 48 hpa have high developmental competence, and that embryonic arrest, which may be influenced by survivin expression in porcine SCNT embryos. PMID- 21820719 TI - Effect of energy source during culture on in vitro embryo development, resistance to cryopreservation and sex ratio. AB - The aim of this work was to evaluate whether minimizing the glucose concentration during culture or replacing the hexose with other energy substrates and/or embryotrophic compounds would affect the in vitro development, the resistance to cryopreservation and the sex ratio of bovine embryos. In vitro matured and fertilized oocytes were randomly assigned to 4 groups for in vitro culture, that differed in the energy substrates included: group A) 1.5 mM glucose, as in standard SOF; group B) 0.15 mM glucose; group C) 0.125 mM G3P, in the presence of 0.15 mM glucose and group D) 0.34 mM citrate, in combination with 2.77 mM myo inositol. Blastocysts were evaluated on day 7, then vitrified by cryotop in 16.5% DMSO, 16.5% EG and 0.5 M sucrose and warmed in decreasing concentration of sucrose (0.25 to 0.15 M sucrose). The survival rates were assessed after 24 h in vitro culture. Finally, the blastocysts produced were sexed by PCR. An increased blastocyst rate was recorded in groups B, C and D, i.e., when glucose concentration was reduced, compared to group A (28.2, 41.0, 35.7 and 35.8, respectively in groups A, B, C and D; P < 0.01). However, the embryos cultured in group D showed the slowest developmental speed, indicated by the lowest percentage of advanced stage-embryos (expanded and hatched blastocysts) out of the total blastocysts (56.1, 45.8, 56.9 and 31.8 %, respectively in groups A, B, C and D; P < 0.01). Furthermore, survival rates after 24 h culture of vitrified warmed blastocysts also decreased in group D (73.3, 73.1, 71.4 and 58.4%, respectively in groups A, B, C and D; P < 0.01). Interestingly, in group D a higher percentage of female embryos was obtained compared to group A, with intermediate values in groups B and C (45.6, 53.4, 50.0 and 61.5%, respectively in groups A, B, C and D; P < 0.05). In conclusion, it was demonstrated that the energy substrate during in vitro culture affects both the production and the viability of blastocysts. Furthermore, manipulating the metabolic profile of embryos during in vitro culture may have an impact on sex ratio. PMID- 21820721 TI - Successful pregnancy following transfer of feline embryos derived from vitrified immature cat oocytes using 'stepwise' cryoprotectant exposure technique. AB - Oocyte cryopreservation is the desired tool for the 'long-term' storage of female genetic potential especially for endangered/valuable species. This study aims at examining the ability of different cryoprotectant (CPA) and CPA exposure techniques to protect immature feline oocytes against cryoinjury during vitrification. Immature oocytes were submitted to different CPA exposure techniques: 1) 2-step DMSO, 2) 4-step DMSO, 3) 2-step EG, 4) 4-step EG, 5) 2-step EG plus DMSO and 6) 4-step EG plus DMSO. Non-CPA treated, non-vitrified oocytes served as controls. The oocytes were then submitted either to in vitro maturation (Experiment 1, n = 334) or to vitrification/warming (Experiment 2, n = 440). The stage of nuclear maturation was subsequently determined. In Experiment 3, the vitrified immature oocytes (n = 254) were matured and fertilized in vitro, and their developmental competence was assessed. A total of 424 embryos derived from vitrified immature oocytes were transferred into the oviduct of 6 recipient queens (Experiment 4). Vitrification reduced significantly the meiotic and developmental competence of immature cat oocytes compared with the non-vitrified controls. The EG alone or a combination of EG and DMSO yielded higher maturation rates than DMSO, irrespective of the CPA equilibration techniques used. The 4 step EG vitrification resulted in the highest maturation rate (37.6%) but cleavage and blastocyst rates were significantly lower than the non-vitrified controls (24.8% and 30.2% vs 62.5% and 49.3%, respectively). Pregnancy was established in recipients receiving embryos derived from non-vitrified and vitrified/warmed immature oocytes. It is concluded that the stepwise CPA exposure technique can be successfully applied for vitrification of immature cat oocytes, in terms of in vitro development but it is likely to affect in utero development. PMID- 21820722 TI - The effect of seminal plasma on alpaca sperm function. AB - In order to advance the development of assisted reproductive technologies in alpacas and other Camelids, the objective of this study was to explore the role of seminal plasma concentration on motility and functional integrity of alpaca sperm. Sixteen male alpacas > 3 y of age were used. In Experiment 1, epididymal sperm were incubated for 0 to 6 h in 0, 10, 25, 50, or 100% seminal plasma and motility was assessed. In Experiment 2, epididymal sperm were incubated in 0, 10, or 100% seminal plasma for 3 h and motility, acrosome integrity and DNA integrity were assessed. In Experiment 3, ejaculated sperm were incubated in 10, 25, 50, or 100% seminal plasma for 0 to 6 h and motility assessed. In Experiment 4, ejaculated sperm were incubated in 10 or 100% seminal plasma for 3 h and motility, acrosome integrity, DNA integrity, and viability were assessed. Epididymal and ejaculated sperm maintained motility longer when incubated in the presence of 10% seminal plasma compared to 0, 25, 50, or 100% seminal plasma (P < 0.001). The mean +/- SEM percentage of epididymal sperm with intact acrosomes was less (P < 0.001) in samples incubated in 0% seminal plasma (39.4 +/- 3.73) compared to 10% (75.3 +/- 1.20) or 100% (77.4 +/- 0.90) within 1 h after incubation. However, DNA integrity of ejaculated and epididymal sperm was not significantly affected by seminal plasma concentration. The mean viability of ejaculated sperm was reduced in the presence of 100 (12.7 +/- 2.33) compared to 10% (36.2 +/- 4.68) seminal plasma (P < 0.001) within 1 h of incubation. We concluded that alpaca semen should be diluted to a final concentration of 10% seminal plasma to prolong motility, preserve acrosome integrity, and maintain viability of sperm. PMID- 21820723 TI - Mitochondrial distribution, ATP-GSH contents, calcium [Ca2+] oscillation during in vitro maturation of dromedary camel oocytes. AB - Dromedary camel oocytes have the ability to spontaneous parthenogenetic activation and development in vivo and in vitro. The present study was conducted to investigate changes in mitochondrial distribution, adenosine triphosphate (ATP), and glutathione (GSH) contents and [Ca(2+)] oscillation during in vitro maturation and spontaneous parthenogentic activation of dromedary camel oocytes. Dromedary camel cumulus-oocyte complexes (COCs) were matured in TCM199 medium supplemented with 10% FCS + 10 MUg/mL FSH + 10 IU hCG + 10 IU eCG + 10 ng/mL EGF and 50 MUg/mL gentamycine. Maturation was performed at 38.5 degrees C under 5% CO(2) in humidified air for 40 h. After maturation and removal of cumulus cells, oocytes were classified into: immature cultured (Group 1); metaphase II (M II, Group 2); and spontaneously parthenogenetically activated (with 2 polar bodies, Group 3); cleaved embryos (Group 4); and immature oocytes served as a control (Group 5). Cytoplasmic mitochondrial distribution, ATP-GSH contents, calcium [Ca(2+)] oscillation were determined. Results indicated that M II and spontaneously parthenogenetically activated oocytes represent 37.53% and 32.67% of the cultured oocytes, respectively, and 3.3% cleaved and developed to 2-16 cell stage embryos. Mitochondrial distribution, ATP-GSH contents and [Ca(2+)] oscillation were significantly (P < 0.01) differ between immature and matured dromedary camel oocytes. Mitochondrial distribution showed clustering form in matured oocytes without polar body. High polarized mitochondrial distribution (HPM) was detected in M II and spontaneously parthenogenetically activated oocytes, and the intensity of MitoTracker Red was higher in spontaneously parthenogenetically activated than M II. ATP-GSH contents and the duration of [Ca(2+)] oscillation were significantly (P < 0.01) higher in spontaneously parthenogenetically activated than M II oocytes or that matured without polar body. In conclusion, the higher incidence of spontaneously parthenogenetically activated in vitro matured dromedary camel oocytes could be attributed to the high polarized mitochondrial distribution associated with significantly higher ATP-GSH contents and duration of [Ca(2+)] oscillation. PMID- 21820724 TI - Liposomes for cryopreservation of bovine sperm. AB - In this study, the effect of various unilamellar liposomes on cryopreservation of bovine spermatozoa has been investigated. Liposomes were composed of saturated lipids with various acyl chain lengths: DSPC (18:0), DPPC (16:0), DMPC (14:0), or DLPC (12:0). Alternatively, liposomes were prepared using unsaturated egg phosphatidylcholine (EPC) or DOPC (18:1, neutral), alone or in combination with lipids with various head groups: DOPS (negatively charged), DOPG (negatively charged), and DOPE (neutral). Fourier transform infrared spectroscopy studies showed that bovine sperm membranes display a gradual phase transition from 10 to 24 (o)C. Phase transition temperatures of the liposomes varied from -20 to +53 (o)C. Sperm was incubated in the presence of liposomes for either 6 or 24 h at 4 degrees C prior to freezing. Postfreeze survival rates were determined based on the percentage of progressively motile cells as well as the percentage of acrosome- and plasma membrane-intact cells. With DOPC liposomes a postthaw progressive motility of 43% was obtained compared with 59% using standard egg yolk freezing extender. Postthaw progressive motility increased up to 52% using DOPC:DOPG (9:1) liposomes, whereas DOPC:DOPS or DOPC:DOPE liposomes did not increase survival compared with DOPC liposomes. Among the saturated lipids, only DMPC was found to increase cryosurvival, up to 44% based on progressive motility. DLPC liposomes caused a complete loss in cell viability, already prior to freezing, whereas DPPC and DSPC liposomes neither positively nor negatively affected cryosurvival. Taken together, the higher postthaw survival obtained with DOPC:DOPG liposomes as compared with DOPC liposomes can likely be attributed to increased liposome-sperm interactions between the charged phosphatidylglycerol groups and charged regions in the sperm membranes. Interestingly, the lipid phase state of the liposomes during preincubation is not the decisive factor for their cryoprotective action. PMID- 21820725 TI - Earthquake disaster response in christchurch, New Zealand. PMID- 21820726 TI - Load-bearing capacity and failure types of anterior zirconia crowns veneered with overpressing and layering techniques. AB - OBJECTIVES: The aim of this study was to test whether the load bearing capacity of anterior zirconia crowns veneered with overpressed or layered, is similar and to evaluate the failure types. METHODS: Standardized zirconia frameworks were fabricated and randomly divided into 8 groups (N=120, n=15 per test group). Four groups were veneered with one of the layered veneering porcelains: Zirox, GC Initial ZR, VITA VM9 or IPS e.max Ceram and the other four groups were veneered with overpressed veneering porcelains: PressX Zr, GC Initial LF, VITA PM9 or IPS e.max ZirPress. The crowns were cemented on their corresponding CoCr abutment and the specimens were loaded at an angle of 45 degrees in a Universal Testing Machine to determine the fracture load. Data were analyzed using one-way and two way ANOVA, followed by a post hoc Scheffe test, t-test and Weibull analysis (alpha=0.05). RESULTS: Within three manufacturers of veneering porcelain, fracture load values were not statistically significant between overpressed and layered porcelain systems. Within one manufacturer of veneering porcelain, the overpressed crowns (IPS e.max ZirPress: 1519 +/- 334 N) demonstrated significantly higher (p<0.05) fracture load than that of the layered one (IPS e.max Ceram: 894 +/- 160 N). Except with IPS e.max ZirPress, where exclusively only chipping of the veneering porcelain was observed, all other porcelain systems showed predominantly framework fractures together with fracture of the veneering porcelain. CONCLUSION: Overpressed veneering porcelains for zirconia frameworks exhibited similar or better fracture load compared with layered ones. PMID- 21820727 TI - The influence of laser-textured dentinal surface on bond strength. AB - OBJECTIVE: To assess the influence of laser-textured surfaces on the adhesion of composite to dentin after being rotary prepared. METHODS: Thirty healthy teeth were kept in 0.1% thymol solution prior to being ground down to dentin to create a 4 * 4 mm2 flat surface. Teeth were divided into 3 groups (n=10). Groups 1 and 2 utilized the prototype Erbium doped, Yttrium-Aluminum-Garnet Er:YAG laser by Dental Photonics, Inc. A single pulse was delivered to each spot to create an equally spaced square 4 * 4 mm2 matrix of micro craters. All craters had 100 MUm diameter/45 MUm depth; two different spacing patterns were prepared in Groups 1 and 2. In Group 1, distance between crater centers was 50 MUm; Group 2 had 100 MUm. In Group 3 (control), 10 samples were prepared without laser texturing. G bond (GC America) was applied to testing area of all samples in all groups according to manufacturer's instructions. Bonding resin was applied and shear bond strength tests were employed using an Instron machine to measure adhesive strength. RESULTS: One-way analysis of variance (ANOVA) was used to compare the 3 groups. Pair wise t-tests implementing the Bonferroni correction for multiple comparisons found a statistically significant difference between Group 3 and Group 2 (p=0.019) but no statistically significant difference between Group 3 and Group 1 (p=0.263) or Group 1 and Group 2 (p=0.743). SIGNIFICANCE: The bond strengths between bonded composite to laser-textured dentinal surfaces with larger spacing patterns are greater than that of non-textured surfaces. PMID- 21820728 TI - Retentive strength and sealing ability of new self-adhesive resin cements in fiber post luting. AB - OBJECTIVE: To assess by means of "thin-slice" push-out test, light and scanning electron microscopy, the interfacial strength and sealing ability of new self adhesive resin cements when used to lute fiber posts into endodontically treated teeth. METHODS: RelyX Unicem 2 Automix (3M ESPE, RUA), Maxcem Elite (Kerr, ME) and seT (SDI, S) were utilized in combination with RelyX Fiber Posts (3M ESPE). In each group 5 posted roots were used for push-out testing and 5 were processed for observations of interfacial morphology and nanoleakage under light microscope and scanning electron microscope. Five to six slices were obtained from each posted root. The statistical significance of the influence on post push-out strength of luting agent, dowel space level, and between-factor interaction was assessed using Two-Way Analysis of Variance (ANOVA) and Tukey test as needed. Differences in nanoleakage scores were also statistically evaluated (Kruskal Wallis ANOVA) (p<0.05). RESULTS: Luting agent was a significant factor for post push-out strength. The interfacial strength achieved by RUA (9.3+/-2.6MPa) was significantly higher than that of ME (6.7+/-2.7MPa) and that of S (5.4+/-3.1MPa), which were comparable to each other. Dowel space level and between factor interaction were not statistically significant. Statistically comparable interfacial nanoleakage was observed in all the groups. SIGNIFICANCE: The three new self-adhesive resin cements exhibited similar sealing properties, although the post retentive ability was superior with RUA. PMID- 21820729 TI - Evaluation of resin composite polymerization by three dimensional micro-CT imaging and nanoindentation. AB - OBJECTIVES: Light-cured composites undergo shrinkage during polymerization. The aim of this study was to evaluate regional shrinkage within a light-cured composite during polymerization by microcomputed tomography and mechanical properties by nanoindentation in bonded or non-bonded class-I cavity. METHODS: Zirconium oxide spherical fillers (30 MUm diameter) were added as markers to a composite resin, filled into a box-shaped class I cavity with or without a bonding agent. The marker fillers were traced in 3D scans obtained by micro-CT before and after polymerization using a software (TRI/3D-BON). The average hardness of the resin composites determined by nanoindentation at each 250 MUm depth was plotted against depth. RESULTS: In the bonded cavity, the filler particles at the top region moved toward the bottom of cavity, but at deeper depths, the direction of vertical movement changed toward the top of cavity (irradiated surface). A significant linear regression was found between filler displacement and composite depth (R(2)=0.9761). In the unbounded cavity, all the fillers moved toward the light curing source, and a significant power-law regression was found between filler displacement and composite depth (R(2)=0.849). In both groups, the data scattering increased at regions deeper than 3.5 mm, where the hardness, representing degree of conversion of composite, significantly decreased compared to the surface region. SIGNIFICANCE: The magnitude and direction of regional polymerization shrinkage depends on boundary conditions, depth and conversion degree. Polymerization shrinkage effect is most significant at the deepest part of the cavity. The application of micro-CT combined with sophisticated image analysis is a novel approach to investigate shrinkage mechanisms of dental composites. PMID- 21820730 TI - Brief report: understanding intention to be physically active and physical activity behaviour in adolescents from a low socio-economic status background: an application of the Theory of Planned Behaviour. AB - The aim of this brief report is to report on the utility of the Theory of Planned Behaviour (TPB) for predicting the physical activity intentions and behaviour of British adolescents from lower-than-average socio-economic backgrounds. A prospective questionnaire design was employed with 197, 13-14 year olds (76 males, 121 females). At time 1 participant completed standard measures of TPB variables. One week later (Time 2), participants completed the Physical Activity Questionnaire for Adolescents (PAQ-A) as a measure of physical activity behaviour. Hierarchical regression analyses showed that attitude and perceived behavioural control jointly accounted for 25% of the variance in intention (p = 0.0001). Perceived behavioural control emerged as the only significant predictor of physical activity behaviour and explained 3.7% of the variance (p = 0.001). Therefore, attitude and PBC successfully predicts intention towards physical activity and PBC predicts physical activity behaviour in British adolescents from lower-than-average socio-economic backgrounds. PMID- 21820731 TI - Screening with pulse oximetry for congenital heart disease. PMID- 21820732 TI - Pulse oximetry screening for congenital heart defects in newborn infants (PulseOx): a test accuracy study. AB - BACKGROUND: Screening for congenital heart defects relies on antenatal ultrasonography and postnatal clinical examination; however, life-threatening defects often are not detected. We prospectively assessed the accuracy of pulse oximetry as a screening test for congenital heart defects. METHODS: In six maternity units in the UK, asymptomatic newborn babies (gestation >34 weeks) were screened with pulse oximetry before discharge. Infants who did not achieve predetermined oxygen saturation thresholds underwent echocardiography. All other infants were followed up to 12 months of age by use of regional and national registries and clinical follow-up. The main outcome was the sensitivity and specificity of pulse oximetry for detection of critical congenital heart defects (causing death or requiring invasive intervention before 28 days) or major congenital heart disease (causing death or requiring invasive intervention within 12 months of age). FINDINGS: 20,055 newborn babies were screened and 53 had major congenital heart disease (24 critical), a prevalence of 2.6 per 1000 livebirths. Analyses were done on all babies for whom a pulse oximetry reading was obtained. Sensitivity of pulse oximetry was 75.00% (95% CI 53.29-90.23) for critical cases and 49.06% (35.06-63.16) for all major congenital heart defects. In 35 cases, congenital heart defects were already suspected after antenatal ultrasonography, and exclusion of these reduced the sensitivity to 58.33% (27.67-84.83) for critical cases and 28.57% (14.64-46.30) for all cases of major congenital heart defects. False-positive results were noted for 169 (0.8%) babies (specificity 99.16%, 99.02-99.28), of which six cases were significant, but not major, congenital heart defects, and 40 were other illnesses that required urgent medical intervention. INTERPRETATION: Pulse oximetry is a safe, feasible test that adds value to existing screening. It identifies cases of critical congenital heart defects that go undetected with antenatal ultrasonography. The early detection of other diseases is an additional advantage. FUNDING: National Institute for Health Research Health Technology Assessment programme. PMID- 21820733 TI - Establishment of a model academic health system in Qatar. PMID- 21820734 TI - The assembly of cell-encapsulating microscale hydrogels using acoustic waves. AB - Microscale hydrogels find widespread applications in medicine and biology, e.g., as building blocks for tissue engineering and regenerative medicine. In these applications, these microgels are assembled to fabricate large complex 3D constructs. The success of this approach requires non-destructive and high throughput assembly of the microgels. Although various assembly methods have been developed based on modifying interfaces, and using microfluidics, so far, none of the available assembly technologies have shown the ability to assemble microgels using non-invasive fields rapidly within seconds in an efficient way. Acoustics has been widely used in biomedical arena to manipulate droplets, cells and biomolecules. In this study, we developed a simple, non-invasive acoustic assembler for cell-encapsulating microgels with maintained cell viability (>93%). We assessed the assembler for both microbeads (with diameter of 50 MUm and 100 MUm) and microgels of different sizes and shapes (e.g., cubes, lock-and-key shapes, tetris, saw) in microdroplets (with volume of 10 MUL, 20 MUL, 40 MUL, 80 MUL). The microgels were assembled in seconds in a non-invasive manner. These results indicate that the developed acoustic approach could become an enabling biotechnology tool for tissue engineering, regenerative medicine, pharmacology studies and high throughput screening applications. PMID- 21820735 TI - Influence of chondroitin sulfate and hyaluronic acid on structure, mechanical properties, and glioma invasion of collagen I gels. AB - To mimic the extracellular matrix surrounding high grade gliomas, composite matrices composed of either acid-solubilized (AS) or pepsin-treated (PT) collagen and the glycosaminoglycans chondroitin sulfate (CS) and hyaluronic acid (HA) are prepared and characterized. The structure and mechanical properties of collagen/CS and collagen/HA gels are studied via confocal reflectance microscopy (CRM) and rheology. CRM reveals that CS induces fibril bundling and increased mesh size in AS collagen but not PT collagen networks. The presence of CS also induces more substantial changes in the storage and loss moduli of AS gels than of PT gels, in accordance with expectation based on network structural parameters. The presence of HA significantly reduces mesh size in AS collagen but has a smaller effect on PT collagen networks. However, both AS and PT collagen network viscoelasticity is strongly affected by the presence of HA. The effects of CS and HA on glioma invasion is then studied in collagen/GAG matrices with network structure both similar to (PT collagen-based gels) and disparate from (AS collagen-based gels) those of the corresponding pure collagen matrices. It is shown that CS inhibits and HA has no significant effect on glioma invasion in 1.0 mg/ml collagen matrices over 3 days. The inhibitory effect of CS on glioma invasion is more apparent in AS than in PT collagen gels, suggesting invasive behavior in these environments is affected by both biochemical and network morphological changes induced by GAGs. This study is among the few efforts to differentiate structural, mechanical and biochemical effects of changes to matrix composition on cell motility in 3D. PMID- 21820736 TI - Bioprinting of growth factors onto aligned sub-micron fibrous scaffolds for simultaneous control of cell differentiation and alignment. AB - The capability to spatially control stem cell orientation and differentiation simultaneously using a combination of geometric cues that mimic structural aspects of native extracellular matrix (ECM) and biochemical cues such as ECM bound growth factors (GFs) is important for understanding the organization and function of musculoskeletal tissues. Herein, oriented sub-micron fibers, which are morphologically similar to musculoskeletal ECM, were spatially patterned with GFs using an inkjet-based bioprinter to create geometric and biochemical cues that direct musculoskeletal cell alignment and differentiation in vitro in registration with fiber orientation and printed patterns, respectively. Sub micron polystyrene fibers (diameter ~ 655 nm) were fabricated using a Spinneret based Tunable Engineered Parameters (STEP) technique and coated with serum or fibrin. The fibers were subsequently patterned with tendon-promoting fibroblast growth factor-2 (FGF-2) or bone-promoting bone morphogenetic protein-2 (BMP-2) prior to seeding with mouse C2C12 myoblasts or C3H10T1/2 mesenchymal fibroblasts. Unprinted regions of STEP fibers showed myocyte differentiation while printed FGF 2 and BMP-2 patterns promoted tenocyte and osteoblast fates, respectively, and inhibited myocyte differentiation. Additionally, cells aligned along the fiber length. Functionalizing oriented sub-micron fibers with printed GFs provides instructive cues to spatially control cell fate and alignment to mimic native tissue organization and may have applications in regenerative medicine. PMID- 21820738 TI - Effects of nerve growth factor (NGF), fluoxetine, and amitriptyline on gene expression profiles in rat brain. AB - Evidence suggests that nerve growth factor (NGF) may have antidepressant properties but the pharmacological mechanisms remain unknown. Previously, we found that NGF improved performance in the forced swim test in Flinders Sensitive Line rats, but did not appear to have similar biochemical actions with the antidepressant fluoxetine. Gene expression profiles for neurotransmitter receptors and regulator-related genes in the amygdala/hippocampus were determined in rats treated for 14days with NGF, fluoxetine, amitriptyline, or saline. Gene expression was measured using an RT(2) profiler PCR Array System to determine the basis for this effect. Compared with saline, there were numerous genes with significantly altered mRNA levels in the amygdala/hippocampal region. Overlap was found between the mRNA levels of genes altered by NGF and the two antidepressant medications including genes related to the cholinergic and dopaminergic systems. However, decreased mRNA levels of Drd5, Sstr3, Htr3a, and Cckar genes in the amygdala/hippocampus were uniquely regulated by NGF. The results of this study are consistent with a previous conclusion that the antidepressant effects of NGF are mediated through non-traditional receptors for traditionally considered neurotransmitters and may suggest a particular utility of NGF in treating comorbid depression and addiction. PMID- 21820739 TI - Assessment of heavy metal tolerance in native plant species from soils contaminated with electroplating effluent. AB - Heavy metals concentrations of (Cr, Zn, Fe, Cu and Ni) were determined in plants and soils contaminated with electroplating industrial effluent. The ranges of total soil Cr, Zn, Fe, Cu and Ni concentrations were found to be 1443-3240, 1376 3112, 683-2228, 263-374 and 234-335 mg kg-1, respectively. Metal accumulation, along with hyperaccumulative characteristics of the screened plants was investigated. Present study highlighted that metal accumulation in different plants varied with species, tissues and metals. Only one plant (Amaranthus viridis) accumulated Fe concentrations over 1000 mg kg-1. On the basis of TF, eight plant species for Zn and Fe, three plant species for Cu and two plant species for Ni, could be used in phytoextraction technology. Although BAF of all plant species was lesser than one, these species exhibited high metal adaptability and could be considered as potential hyperaccumulators. Phytoremediation potential of these plants can be used to remediate metal contaminated soils, though further investigation is still needed. PMID- 21820737 TI - Elucidating the mechanobiology of malignant brain tumors using a brain matrix mimetic hyaluronic acid hydrogel platform. AB - Glioblastoma multiforme (GBM) is a malignant brain tumor characterized by diffuse infiltration of single cells into the brain parenchyma, which is a process that relies in part on aberrant biochemical and biophysical interactions between tumor cells and the brain extracellular matrix (ECM). A major obstacle to understanding ECM regulation of GBM invasion is the absence of model matrix systems that recapitulate the distinct composition and physical structure of brain ECM while allowing independent control of adhesive ligand density, mechanics, and microstructure. To address this need, we synthesized brain-mimetic ECMs based on hyaluronic acid (HA) with a range of stiffnesses that encompasses normal and tumorigenic brain tissue and functionalized these materials with short Arg-Gly Asp (RGD) peptides to facilitate cell adhesion. Scanning electron micrographs of the hydrogels revealed a dense, sheet-like microstructure with apparent nanoscale porosity similar to brain extracellular space. On flat hydrogel substrates, glioma cell spreading area and actin stress fiber assembly increased strongly with increasing density of RGD peptide. Increasing HA stiffness under constant RGD density produced similar trends and increased the speed of random motility. In a three-dimensional (3D) spheroid paradigm, glioma cells invaded HA hydrogels with morphological patterns distinct from those observed on flat surfaces or in 3D collagen-based ECMs but highly reminiscent of those seen in brain slices. This material system represents a brain-mimetic model ECM with tunable ligand density and stiffness amenable to investigations of the mechanobiological regulation of brain tumor progression. PMID- 21820740 TI - Levels of selected persistent organic pollutants in blood from delivering women in seven selected areas of Sao Paulo State, Brazil. AB - Persistent organic pollutants (POPs) present in the living environment are thought to have detrimental health effects on the population, with pregnant women and the developing foetus being at highest risk. We report on the levels of selected POPs in maternal blood of 155 delivering women residing in seven regions within the Sao Paulo State, Brazil. The following selected POPs were measured in the maternal whole blood: 12 polychlorinated biphenyls (PCBs) congeners (IUPAC Nos. 99, 101, 118, 138, 153, 156, 163, 170, 180, 183, 187, 194); dichlordiphenyltrichloroethane p,p'-DDT, diphenyldichloroethylene p,p'-DDE and other pesticides such as hexachlorocyclohexanes (alpha-HCH, beta-HCH, gamma-HCH), hexachlorobenzene (HCB), chlordane derivatives cis-chlordane, trans-chlordane, oxy-chlordane, cis-nonachlor and trans-nonachlor. Statistical comparisons between regions were performed only on compounds having concentrations above LOD in 70% of the samples. PCB118 congener was found to be highest in the industrial site (mean 4.97 ng/g lipids); PCB138 congener concentration was highest in the Urban 3 site (mean 4.27 ng/g lipids) and congener PCB153 was highest in the industrial and Urban 3 sites with mean concentration of 7.2 ng/g lipids and 5.89ng/g lipids respectively. Large differences in levels of p,p'-DDE between regions were observed with the Urban 3 and industrial sites having the highest concentrations of 645 ng/g lipids and 417 ng/g lipids, respectively; beta-HCH was found to be highest in the Rural 1 site; the gamma-HCH in Rural 1 and industrial; the HCB in the Rural 1 and industrial sites and oxy-chlordane and t-NC in the Rural 2 sites. An association between levels of some contaminants and maternal age and parity was also found. PMID- 21820741 TI - Myopia-related optic disc and retinal changes in adolescent children from singapore. AB - PURPOSE: To examine early myopia-related optic disc and retinal changes in a Singapore Chinese adolescent sample without confounding ocular or systemic disease. DESIGN: Population-based cross-sectional study. PARTICIPANTS: Children aged 12 to 16 years at a follow-up visit for Singapore Cohort Study of Risk Factors for Myopia. METHODS: Detailed eye examinations, including cycloplegic autorefraction and contact biometry, were performed. Retinal photographs were acquired using nonmydriatic retinal photography among children who attended follow-up examinations in 2006, and were graded for myopia-related optic disc signs and macular changes by a single experienced grader. Optic nerve head parameters were measured adjusting for camera and ocular magnification with appropriate formulae. MAIN OUTCOME MEASURES: Optic disc changes (tilt, beta peripapillary atrophy [beta-PPA], and optic nerve parameters) and macular changes (staphyloma, lacquer cracks, Fuchs' spot, and chorioretinal atrophy). RESULTS: Retinal photography data were available for 1227 children (median age, 14 years; range 12-16). Tilted optic discs were found in 454 subjects (37%), and were associated with myopic spherical equivalent refractions (-3.6 diopters [D] vs 1.3 D; P<0.0001), higher cylindrical error (0.9 vs 0.7 D; P = 0.0001) and longer axial length (24.93 vs 23.96 mm; P<0.0001). The pattern of distribution of the axes of the tilted discs and corneal curvature were similar (P = 0.4). All linear optic nerve parameters, except vertical disc diameter (P = 0.15), were significantly smaller in eyes with than without tilted discs (P <0.001) after adjusting for confounders. Apart from 20 cases, all eyes with tilted optic discs had associated beta-PPA. We identified only 1 case each (0.1% prevalence) of staphyloma and lacquer cracks in this sample. CONCLUSIONS: In this Asian adolescent population, tilted optic discs were highly prevalent, in contrast with the lower prevalence reported in Caucasian populations. Eyes with tilted discs tended to have smaller optic cups with smaller cup-to-disc ratios, and were associated with myopic refraction, higher astigmatism, and longer axial length. There were similar patterns of distribution between the axis of disc tilt and the axis of corneal curvature, which could have embryologic origins. In contrast with optic disc changes, myopic macular changes were rare in this age group, suggesting that these changes may develop later in life. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any of the materials discussed in this article. PMID- 21820742 TI - Analyzing temporal patterns of infant sleep and negative affective behavior: a comparison between different statistical models. AB - OBJECTIVE: Variability in infant sleep and negative affective behavior (NAB) is a developmental phenomenon that has long been of interest to researchers and clinicians. However, analyses and delineation of such temporal patterns were often limited to basic statistical approaches, which may prevent adequate identification of meaningful variation within these patterns. Modern statistical procedures such as additive models may detect specific patterns of temporal variation in infant behavior more effectively. METHOD: Hundred and twenty-one mothers were asked to record different behaviors of their 4-44 weeks old healthy infants by diaries for three days consecutively. Circadian patterns as well as individual trajectories and day-to-day variability of infant sleep and NAB were modeled with generalized linear models (GLMs) including a linear and quadratic polynomial for time, a GLM with a polynomial of the 8th order, a GLM with a harmonic function, a generalized linear mixed model (GLMM) with a polynomial of the 8th order, a generalized additive model, and a generalized additive mixed model (GAMM). RESULTS: The semi-parametric model GAMM was found to fit the data of infant sleep better than any other parametric model used. GLMM with a polynomial of the 8th order and GAMM modeled temporal patterns of infant NAB equally well, although the GLMM exhibited a slightly better model fit while GAMM was easier to interpret. Besides the well-known evening clustering in infant NAB we found a significant second peak in NAB around midday that was not affected by the constant decline in the amounts of NAB across the 3-day study period. CONCLUSION: Using advanced statistical procedures (GAMM and GLMM) even small variations and phenomena in infant behavior can be reliably detected. Future studies investigating variability and temporal patterns in infant variables may benefit from these statistical approaches. PMID- 21820743 TI - Creativity and affective temperaments in non-clinical professional artists: an empirical psychometric investigation. AB - OBJECTIVE: Manic-depression/bipolar disorder was linked to creativity, with affective temperaments allegedly favoring creative expression and achievement, but a few studies only empirically tested the link. METHODS: 152 undergraduate students attending preparatory courses for creative artistic professions and 152 students in areas expected to lead to a profession mostly requiring the application of the learned rules were invited to fill in the TEMPS-A (Temperament Evaluation of the Memphis, Pisa, Paris and San Diego - Autoquestionnaire), the General Health Questionnaire (GHQ) and the Creative Achievement Questionnaire (CAQ). Latent class analysis (LCA) was used to investigate the links between creativity scores and measures of psychopathology. RESULTS: Creative participants and controls did not differ in terms of sex (males=47%), age (24.5 years, SD=3.8), or socioeconomic status. Creative people scored higher than controls on the CAQ and on the cyclothymic, hyperthymic and irritable subscales of the TEMPS A, but not on the GHQ. Greater involvement in creative activities rather than being a creative achiever best differentiated those into the "risk for bipolar spectrum" class from the other two classes extracted by the LCA from the TEMPS-A. LIMITATIONS: The use of self-report measures to evaluate both creative involvement and the risk of psychopathology, and the exclusive focus on artistic creativity limit the generalizability of the findings. CONCLUSIONS: This study confirms that the cyclothymic dimension of the bipolar spectrum is linked to creativity, and this link is likely to result from increased involvement into pleasurable activities, including creative ones. PMID- 21820745 TI - Cardiovascular parameters of computed tomographic pulmonary angiography to assess pulmonary vascular resistance in patients with chronic thromboembolic pulmonary hypertension. AB - OBJECTIVES: The purpose is to identify the role of cardiovascular parameters of computed tomographic pulmonary angiography (CTPA) to assess pulmonary vascular resistance (PVR) in patients with chronic thromboembolic pulmonary hypertension (CTEPH). BACKGROUND: The assessment of PVR is of great importance in the management of patients with CTEPH. The role of CPTA in assessment of PVR of CTEPH remains to be explored. METHODS: Clinical and radiological data of 90 patients (55 men, age 17-84 years) with CTEPH were retrospectively reviewed in this study. All patients received CTPA before right-heart catheterization. Cardiovascular parameters and Pulmonary Artery Obstruction Indices including Qanadli Index and Mastora Index were evaluated on CTPA. Hemodynamic PVR was calculated with the standard formula according to data from right-heart catheterization. The correlation of cardiovascular parameters of CTPA and PVR was analyzed. RESULTS: In Cardiovascular parameters, neither Qanadli Index(r=0.134, p=0.208) nor Mastora Index (r=0.149, p=0.90) did correlate with PVR. Cobb angle(r=0.613, p=0.000), the ratio of right to left ventricular area(r=0.422, p=0.000)and the ratio of right to left ventricular transverse diameter (r=0.410, p=0.000) respectively correlated with PVR. By receiver operating characteristic curve analysis, a Cobb angle cutoff value of 67.55 degrees had a sensitivity of 72.5% and a specificity of 84.0% to determine PVR >=1000 (dyn.sec/cm(5)) and its Area Under Curve is (0.800 +/- 0.048). By stepwise linear regression analysis, Cobb angle was only one variable (R=0.601) shown to be independently associated with PVR, leading to the following equation: PVR=25.796 * Cobb angle-585.935(F=37.929, p=0.000). CONCLUSION: The analysis of CTPA-derived cardiovascular parameters, especially the Cobb angle, is a reliable tool for estimating PVR in patients with CTEPH, but Pulmonary Artery Obstruction Indices do not correlate with PVR. PMID- 21820746 TI - A cross sectional study of the prevalence and risk factors for owner misperception of canine body shape in first opinion practice in Glasgow. AB - The objectives of the study were to investigate whether owners were able to assign the correct body shape to their dog and to assess the dog and owner level factors associated with incorrect owner assessment of dog body shape. Six hundred and eighty questionnaires were administered to dog owners in 5 first opinion practices around Glasgow during July 2007. At the same time, the interviewer and owner assessed the body shape of each dog. The interviewer assessment of body shape was taken as the gold standard. Incorrect owner assessment of dog body shape (misperception) was divided into two groups: underestimation and overestimation. Multinomial logistic regression and classification and regression trees (CART) were used to assess risk factors associated with each type of misperception. Misperception of dog body shape was present in 44.1% of owners with underestimation (i.e. the owner considered the animal to have a leaner body shape from the gold standard assessment) being the most common form of misperception. Risk factors identified by both multinomial logistic regression and CART were gender of owner, age of the dog and dog body shape. The classification tree appeared to have improved predictive ability when compared to the multinomial model. PMID- 21820747 TI - The incidence of the healthcare costs of smoking. AB - Smokers earn less than non-smokers, but much is still unknown about the source(s) of the smoker's wage gap. We build on the work of Bhattacharya and Bundorf (2009), who provide evidence that obese workers receive lower wages on account of their higher expected healthcare costs. Similarly, we find that smokers who hold employer-sponsored health insurance (ESI) receive significantly lower wages than their non-smoking peers, while smokers who are not insured through their employer endure no such wage penalty. Our results have two implications: first, the incidence of smokers' elevated medical costs appears to be borne by smokers themselves in the form of lower wages. Second, differences in healthcare costs between smokers and non-smokers are a significant source of the smoker's wage gap. PMID- 21820748 TI - Golf players exhibit changes to grip speed parameters during club release in response to changes in club stiffness. AB - The influence of golf club stiffness on driving performance is currently unclear, and it is possible that this ambiguity is due in part to golfer adaptation to equipment. The purpose of the current study was to elucidate mechanisms of adaptation to club stiffness, during the golf swing, by employing tendon vibration to distort proprioceptive feedback. Vibration (~50 Hz, ~1 mm amplitude) was applied to the upper extremities of 24 golfers using DC motors with eccentric weights. Golfers hit golf balls in a laboratory setting using three clubs of varying shaft stiffness, and club kinematics were recorded using high speed (180 Hz) digital cameras. The results demonstrated significant slowing of the club grip during club release for a high-stiffness shaft with vibration. This suggests that, when proprioceptive feedback is available, players adapt to changes in club stiffness by modifying the release dynamics of the club late in the downswing. PMID- 21820749 TI - Genetic diversity of emetic toxin producing Bacillus cereus Korean strains. AB - Bacillus cereus is divided into emetic and enterotoxin producing strains. Emetic B. cereus showed the low level of genetic diversity and single evolutionary lineage but no specific study of the genotypic characterization of emetic B. cereus Korean strains has been conducted. The objective of this study was to investigate the genotypic diversity of emetic B. cereus Korean strains. A total 39 strains (35 clinical and 4 food isolates) was analyzed for the genotypic characterization. A total of 17 distinct patterns were obtained from the random amplified polymorphic DNA (RAPD) banding patterns and the majority of clusters belong to group 3. The pulsed-field gel electrophoresis (PFGE) banding patterns were divided into 17 distinct pulsotypes, and groups B and C were dominated. Emetic B. cereus Korean strains showed diverse pulsotypes in contrast with previous studies. All strains were resistant to beta-lactam antibiotics such as penicillin and ampicillin. Combining biochemical properties, PFGE types, RAPD types and antibiotic resistance types, a total of 7 composite clusters were found. The majority of composite clusters were consisted with cluster 5 and 6. Enterotoxin producing reference strains belong to composite cluster 7. However, JNHE 6 (Jeollabuk-do Research Institute of Health & Environment; cluster 1) and JNHE 36 (cluster 2) which possessed the ability of starch hydrolysis and saline fermentation showed different composite clusters comparing with most emetic B. cereus. JNHE 7 and JNHE 53 formed composite cluster 3 and 4. Emetic B. cereus Korean strains showed genotypic diversity comparing with the previous studies. PMID- 21820744 TI - Inflammation in the early stages of neurodegenerative pathology. AB - Inflammation is secondary to protein accumulation in neurodegenerative diseases, including Alzheimer's, Parkinson's and Amyotrophic Lateral Sclerosis. Emerging evidence indicate sustained inflammatory responses, involving microglia and astrocytes in animal models of neurodegeneration. It is unknown whether inflammation is beneficial or detrimental to disease progression and how inflammatory responses are induced within the CNS. Persistence of an inflammatory stimulus or failure to resolve sustained inflammation can result in pathology, thus, mechanisms that counteract inflammation are indispensable. Here we review studies on inflammation mediated by innate and adaptive immunity in the early stages of neurodegeneration and highlight important areas for future investigation. PMID- 21820750 TI - Shelf life of reduced pork back-fat content sausages as affected by antimicrobial compounds and modified atmosphere packaging. AB - The combined use of antimicrobial compounds and modified atmosphere packaging (MAP) on shelf life of reduced pork back-fat content sausages was investigated in this study. First, a pre-screening of different antimicrobial compounds and MAP was addressed. In particular, the consumer test was used as a tool to select the most pleasant antimicrobial compounds, whereas both sausage color and cell load of main spoilage microorganisms were used to choose optimal MAP. Afterwards, antimicrobial compounds (lemon alkott and thymol) and MAP (MAP1: 20% CO(2), 5% O(2), 75% N(2)) that had shown the best performance were used to run the shelf life tests. In order to assess the influence of the variables described beforehand on the shelf life of investigated sausages, the sensorial and microbiological (mesophilic and psychrotrophic bacteria, Enterobacteriaceae, Pseudomonas spp., lactic acid bacteria and coccus-shaped lactic acid bacteria) quality was monitored during storage. Results recorded in this study suggested that Pseudomonas spp. were responsible for sausage unacceptability in all samples, except for thymol and thymol-MAP samples. For these samples, the sensorial quality was the limiting factor while the microbial growth did not limit the shelf life. In particular, for thymol and thymol-MAP samples a shelf life value of more than 5 days with respect to the other samples (2 days) was obtained. PMID- 21820751 TI - Glycated haemoglobin (HbA1c) for the diagnosis of diabetes mellitus--practical implications. PMID- 21820752 TI - Independent complexity patterns in single neuron activity induced by static magnetic field. AB - We applied a combination of fractal analysis and Independent Component Analysis (ICA) method to detect the sources of fractal complexity in snail Br neuron activity induced by static magnetic field of 2.7 mT. The fractal complexity of Br neuron activity was analyzed before (Control), during (MF), and after (AMF) exposure to the static magnetic field in six experimental animals. We estimated the fractal dimension (FD) of electrophysiological signals using Higuchi's algorithm, and empirical FD distributions. By using the Principal Component Analysis (PCA) and FastICA algorithm we determined the number of components, and defined the statistically independent components (ICs) in the fractal complexity of signal waveforms. We have isolated two independent components of the empirical FD distributions for each of three groups of data by using FastICA algorithm. ICs represent the sources of fractal waveforms complexity of Br neuron activity in particular experimental conditions. Our main results have shown that there could be two opposite intrinsic mechanisms in single snail Br neuron response to static magnetic field stimulation. We named identified ICs that correspond to those mechanisms - the component of plasticity and the component of elasticity. We have shown that combination of fractal analysis with ICA method could be very useful for the decomposition and identification of the sources of fractal complexity of bursting neuronal activity waveforms. PMID- 21820753 TI - Lung cancer associated venous thromboembolic disease: a comprehensive review. AB - The association of cancer and thrombotic events was first described by Trousseau in 1865. The spectrum of these episodes vary in severity, and these can present during or even prior to the diagnosis of cancer. Multiple factors in patients with lung cancer are associated with a higher risk of thrombosis. Patient related, cancer-related and treatment-related factors contribute to the development of a thrombotic event. The incidence of thrombotic events in patients with lung cancer is one of the highest among all cancers. Certain particular conditions in lung cancer may be responsible to elevate this risk. Tissue factor (TF) over-expression is considered to be the most important element in cancer related thrombosis. Several oncogenes and tumor suppressor genes have been implicated with this over-expression. The development of thrombosis in a cancer patient adversely influences prognosis. The use of prophylactic anticoagulation in lung cancer patients has been investigated but no consensus has been obtained regarding which patients are more likely to benefit. Models exist that can help predict this risk, but validation is required. Treatment guidelines of anticoagulation in patients who develop a thrombotic event are also discussed, but lung cancer patients have distinct characteristics that have to be taken in consideration. It is of great importance to identify the elements that will predict the risk of developing cancer-associated thrombosis because it will consequently influence the management and prognosis of the patient. PMID- 21820755 TI - Role of beta1-adrenoceptor autoantibodies in the pathogenesis of dilated cardiomyopathy. AB - Dilated cardiomyopathy (DCM) is a common cause of heart failure. After the identification of several immune regulatory abnormalities in DCM increasing attention has been focused on autoimmune mechanisms as potential key elements in the pathogenesis of the disease. DCM has appeared to be often related to elevated levels of autoantibodies against cardiac structural or functional proteins. Among several autoantibodies (AABs) which react against cardiac cellular proteins that have been detected in sera from DCM patients, those against beta1-adrenoreceptors (beta1-ARs) appeared particularly relevant from a pathophysiological point of view. The available experimental and clinical data suggest that in beta1-AAB positive patients with DCM the cardiomyopathy might be a beta1-AR-targeted autoimmune disease. This review summarizes the present knowledge about beta1 AABs, their role in DCM etiopathogenesis and the therapeutic benefits of beta1 AAB removal. Special attention is focused on the possible origin of beta1-AABs, their interaction with the beta1-ARs, the prevalence of beta1-AABs in patients with DCM and the potential pathophysiologic impact of these AABs in the development and progression of the disease. Attention is also given to the amelioration of beta1-AAB cardiotoxicity by beta1-AR antagonists and especially to immunoadsorption (IA) therapy. Responsiveness to IA therapy and its long-term efficiency, as well as post-IA reappearance of beta1-AABs and its impact on patients' outcome are also discussed in detail. Finally the important question of whether the therapeutic results of IA are indeed related to beta1-AAB removal is analyzed on the basis of available data. Overall the review aims to provide an exhaustive overview of the available experimental and clinical data on beta1-AABs in DCM and also a theoretical and practical basis for clinicians who are or intend in future to be engaged in this field. PMID- 21820756 TI - Tracking viral movement in plants by means of chlorophyll fluorescence imaging. AB - Many techniques have been applied to understand viral cell-to-cell movement in host plants, but little progress has been made in understanding viral vascular transport mechanisms. We propose the use of chlorophyll fluorescence imaging techniques, not only to diagnose the viral infection, but also to follow the movement of the virus through the vascular system and its subsequent spread into the leaves. In Nicotiana benthamiana plants, imaging of chlorophyll fluorescence parameters such as F(PSII) and NPQ proved useful to follow infections with Pepper mild mottle virus. The results demonstrate a correlation between changes in the chlorophyll fluorescence parameters and the viral distribution analyzed by tissue printing. PMID- 21820754 TI - Macrophage diversity in cardiac inflammation: a review. AB - Cardiac inflammatory disease represents a significant public health burden, and interesting questions of immunopathologic science and clinical inquiry. Novel insights into the diverse programming and functions within the macrophage lineages in recent years have yielded a view of these cells as dynamic effectors and regulators of immunity, host defense, and inflammatory disease. In this review, we examine and discuss recent investigations into the complex participation of mononuclear phagocytic cells in the pathology of animal models of myocarditis. PMID- 21820757 TI - Correlation of leaf senescence and gene expression/activities of chlorophyll degradation enzymes in harvested Chinese flowering cabbage (Brassica rapa var. parachinensis). AB - Chinese flowering cabbage is one of the main leafy vegetables produced in China. They have a rapid leaf yellowing due to chlorophyll degradation after harvest that limits their marketing. In the present study, leaf senescence of the cabbages was manipulated by ethylene and 6-benzyl aminopurine (6-BA) treatment to investigate the correlation of leaf senescence and chlorophyll degradation related to gene expression/activities in the darkness. The patterns of several senescence associated markers, including a typical marker, the expression of senescence-associated gene SAG(12), demonstrated that ethylene accelerated leaf senescence of the cabbages, while 6-BA retarded this progress. Similar to the trends of BrSAG(12) gene expression, strong activation in the expression of three chlorophyll degradation related genes, pheophytinase (BrPPH), pheophorbide a oxygenase (BrPAO) and red chlorophyll catabolite reductase (BrRCCR), was detected in ethylene treated and control leaves during the incubation, while no evident increase was recorded in 6-BA treated leaves. The overall dynamics of Mg dechelatase activities in all treatments displayed increasing trends during the senescence process, and a delayed increase in the activities was observed for 6 BA treated leaves. However, chlorophyllase activity as well as the expression of BrChlase1 and BrChlase2 decreased with the incubation in all treatments. Taken together, the expression of BrPPH, BrPAO and BrRCCR, and the activity of Mg dechelatase was closely associated with the chlorophyll degradation during the leaf senescence process in harvested Chinese flowering cabbages under dark conditions. PMID- 21820758 TI - Sequential outbreaks of multidrug-resistant Acinetobacter baumannii in intensive care units of a tertiary referral hospital in Italy: combined molecular approach for epidemiological investigation. AB - A laboratory-based surveillance study was conducted from January 2007 to May 2010 in San Martino Tertiary Referral Hospital in Genoa, Italy in which the molecular epidemiology of multidrug-resistant Acinetobacter baumannii was investigated in the five intensive care units (ICUs). A total of 53 A. baumannii strains were isolated from patients admitted to ICUs (69.8%) and to other epidemiologically linked hospital wards (30.2%) and were genotyped by repetitive extragenic palindromic polymerase chain reaction (REP-PCR), multilocus sequence typing (MLST) and adeB sequence typing. REP-PCR fingerprinting analysis, MLST and adeB typing results were well correlated and allowed us to classify strains causing epidemic events into three major epidemic clones: A (REP-I/ST4, adeB-STII genotype) isolated for the first time in May 2007, B (REP-IV/ST95, adeB-STI genotype) from November 2007 to May 2009 and C (REP-VII/ST118, adeB-STII genotype) from July 2008 to May 2010. MLST results demonstrated that epidemic clones A and C were related as they were members of the widespread clonal complex CC92. The genetic determinants of carbapenem resistance were investigated and resistance associated with the presence of the bla(OxA-58-like) gene with ISAba2 and ISAba3 elements flanking it in clone A, and with the bla(OxA-23-like) gene flanked by ISAba1 in clones B and C. A molecular approach allowed the prompt introduction of infection control measures and the evaluation of data in a global epidemiological context. PMID- 21820759 TI - Nosocomial transmission of measles: do we need extra precautions to avoid it? PMID- 21820760 TI - Efficacy of an infection control programme in reducing nosocomial bloodstream infections in a Senegalese neonatal unit. AB - Neonatal nosocomial infections are public health threats in the developing world, and successful interventions are rarely reported. A before-and-after study was conducted in the neonatal unit of the Hopital Principal de Dakar, Senegal to assess the efficacy of a multi-faceted hospital infection control programme implemented from March to May 2005. The interventions included clustering of nursing care, a simple algorithm for empirical therapy of suspected early-onset sepsis, minimal invasive care and promotion of early discharge of neonates. Data on nosocomial bloodstream infections, mortality, bacterial resistance and antibiotic use were collected before and after implementation of the infection control programme. One hundred and twenty-five infants were admitted immediately before the programme (Period 1, January-February 2005) and 148 infants were admitted immediately after the programme (Period 2, June-July 2005). The two groups of infants were comparable in terms of reason for admission and birth weight. After implementation of the infection control programme, the overall rate of nosocomial bloodstream infections decreased from 8.8% to 2.0% (P=0.01), and the rate of nosocomial bloodstream infections/patient-day decreased from 10.9 to 2.9/1000 patient-days (P=0.03). Overall mortality rates did not differ significantly. The proportion of neonates who received antimicrobial therapy for suspected early-onset sepsis decreased significantly from 100% to 51% of at-risk infants (P<0.001). The incidence of drug-resistant bacteria was significantly lower after implementation of the programme (79% vs 12%; P<0.001), and remained low one year later. In this neonatal unit, simple, low-cost and sustainable interventions led to the control of a high incidence of bacterial nosocomial bloodstream infections, and the efficacy of these interventions was long-lasting. Such interventions could be extended to other low-income countries. PMID- 21820761 TI - Does buffered lidocaine decrease the pain of local infiltration? PMID- 21820762 TI - Use of audit and feedback with fluorescent targeting to achieve rapid improvements in room cleaning in the intensive care unit and ward settings. AB - Environmental contamination of high-touch surfaces in patient rooms can lead to the transmission of clinically significant pathogens; thus, such surfaces should be cleaned routinely and thoroughly. Fluorescent targeting can be used to provide feedback to frontline cleaning staff on the thoroughness of room cleaning, which can result in substantial improvements in performance. We demonstrate that auditing with fluorescent targeting can be implemented in both the ward and intensive care unit settings using only modest resources, resulting in rapid improvements in cleaning thoroughness. PMID- 21820764 TI - [Young men who have sex with men: a group at high risk for HIV infection?]. AB - OBJECTIVES: To compare variables associated with the risk of HIV among men <= 25 years old who have sex with men (YMSM) and those >25 years old, and to determine the variables associated with unprotected anal intercourse (UAI) in YMSM with casual sexual partners. METHOD: For 1 month, 485 participants <= 25 years old and 1,470 aged >25 years old completed a pen-and-paper survey carried out in gay venues (GV) or via the Internet in Madrid, Barcelona, Bilbao and San Sebastian (Spain). The survey investigated sexual behaviors in the past 3 months according to whether the men met sexual partners in GV (SPGV) or on the Internet (SPI). RESULTS: No significant differences were found between YMSM and those >25 years old with respect to UAI with SPGV (23% vs. 30%, p>0.05) and SPI (29% vs. 30%, p>0.05), condom use in the last anal intercourse and having had a sexually transmitted infection (STI) in the last year (19% vs. 23%, p>0.05). However, respondents>25 years old had a higher average number of SPGV (9.2 vs. 7, p<0.05) and SPI (8.9 vs. 6.4, p<0.05), were more likely to have used drugs while having UAI (68% vs. 55%, p<0.05, with SPI, and 73% vs. 55%, p<0.05, with SPGV) and had a higher prevalence of HIV (11% vs. 4%, p<0.05). When exploring other variables, we found that YMSM more frequently had receptive UAI with SPI (73% vs. 57%, p<0.05), had less time to be in a stable relationship, and their sexual partner more frequently convinced them to have UAI (8% vs. 0%, p<0.05). In multivariate analysis, UAI in YMSM with casual sexual partners was not associated with any of the variables. CONCLUSIONS: YMSM do not constitute a group at increased risk of HIV/STI infection compared with respondents >25 years old. However, there are some variables could contribute to vulnerability in this group. PMID- 21820765 TI - [Impact of divorce on quality of life in children aged 8-12 years in the province of Alicante (Spain)]. AB - OBJECTIVES: To examine differences in quality of life according to family structure in Spanish children for the first time, and to determine whether the quality of life of children with divorced parents differs according to perceived interparental conflict. METHOD: A cross-sectional, descriptive study was carried out in 1,025 children aged between 8 and 12 years old, recruited from seven randomly-selected schools in the province of Alicante. Of the total sample, 861 children had married parents and 164 had divorced parents. The children completed the Child Health and Illness Profile-Child Edition and those with divorced parents also provided information on the current relationship between their parents. RESULTS: Quality of life was higher in children with married parents than in those with divorced parents, with higher scores in all dimensions. Children who reported conflict between their parents after the divorce had worse quality of life. CONCLUSIONS: These results confirm significant differences in quality of life according to family structure and revealed the relationship between children's self-perceived health and interparental conflict after divorce. We emphasize the importance of health professionals in providing guidance to divorced parents on preventing their children's health problems and facilitating adaptation to the new family situation. PMID- 21820766 TI - [Requirements for and expectations of health technology assessment in Galicia (Spain). A qualitative study from the perspective of decision-makers and clinicians]. AB - OBJECTIVE: To explore perceptions of the use of health technology assessment (HTA) in the Galician public health system, identify opinions on the usefulness of the products and services developed by the Galician Health Technology Assessment Agency (avalia-t), and determine the barriers and facilitators to the transfer of results to clinical practice. METHOD: We performed a qualitative study based on in-depth semi-structured interviews of 20 intentionally selected experts (10 health care professionals and 10 hospital decision makers). The interviews were tape recorded and transcribed for inductive thematic analysis. RESULTS: Interest in HTA activities was high, but most informants considered these activities to be underused as a tool to aid decision making in clinical practice. A series of key factors was identified to guarantee HTA use: greater dissemination of HTA activities and availability of the results, increased involvement and communication among health care professionals in the selection and prioritization of relevant research, contextualization and adaptation of results to the local context, increased organizational support and greater financial resources. CONCLUSIONS: The present study allows end-users opinions on the utility of the various products/services offered by HTA agencies to be contrasted in order to adapt HTA activity to their needs and requirements. The involvement of health care professionals in all HTA fields is perceived as one of the main lines of action for HTA agencies. Such involvement could be achieved by reinforcing personal contact and increasing feedback to collaborators. PMID- 21820763 TI - [The Cohort of the Spanish HIV Research Network (CoRIS) and its associated biobank; organizational issues, main findings and losses to follow-up]. AB - INTRODUCTION: This article describes the development of the Cohort of the Spanish Research Network (CoRIS), its methodological and organizational aspects, the demographic and clinical characteristics of the subjects enrolled and quantifies the losses to follow-up and associated factors. METHODS: Multicentre cohort of HIV-positive naive subjects recruited in 28 sites of Spain from 2004-onwards. Missing and inconsistent data were submitted to internal quality controls and the datasets were externally audited. Multiple logistic regression models were used. RESULTS: As of October 2009, 5,514 subjects had been recruited, representing 11,708 person-years with a median follow-up time of 1.81 years. Most are men (78.8%), infected by sexual transmission (46.1% men who have sex with men and 35.2% heterosexual persons) and Spanish (69.7%). During follow-up 64.5% have started Antiretroviral Therapy (ART) and 201 deaths have occurred. New HIV diagnoses accounted for 80.7% of the sample. Some 52% of subjects had at least one baseline sample in the BioBank while naive to ART. Losses to follow-up (18.9%) were more frequent in younger people, in injecting drug users, in persons of non-Spanish origin, in persons with primary or lower educational level, and in those with a CD4 count over 350 cells/mm(3) at time of recruitment. CONCLUSIONS: The implementation of CoRIS has been successful; the cohort has wide representation at national level, is actively recruiting new members and blood samples, and has excellent data quality. Losses to follow-up are of similar magnitude to other cohort studies, as are the factors associated with them. PMID- 21820767 TI - [Factors explaining the application of the law of patient autonomy by surgical staff]. AB - OBJECTIVE: To examine which contextual factors explain the implementation of the Patient Autonomy Law (LAP) by professionals involved in the surgical process. METHODS: A descriptive cross sectional study survey. It was conducted at the Hospital Virgen Macarena in Seville with the surgical staff. Dependent variable: the application of LAP. INDEPENDENT VARIABLES: the perception of socio-structural organizational characteristics according to Kanter's model (organizational culture, sociopolitical support, access to information, and access to resources), the perception of interprofessional collaboration, and knowledge of the LAP. We performed exploratory analysis, bivariate with parametric and nonparametric tests depending on the nature of the distributions; simple regression to determine the weight of each explanatory variable on the application of the LAP and, multiples introducing in the models those variables that had obtained significant regression coefficients. The analysis performed with a confidence level of 95%. RESULTS: PARTICIPANTS: 170 professionals (response rate: 60.28%). Behaviour according to the LAP is present in a medium-high level among physicians and nurses. Significant differences were observed in the application of the LAP according to the different sociolaboral variables and considering medical staff, the working environment and the specialty. Multiple regression analyses revealed the relationship between the application of the LAP and interprofessional collaboration, in physicians. CONCLUSIONS: Kanter's model and the scale of interprofessional collaboration, may contribute to the explanation of the influence of the hospital context in the implementation of the LAP and the results may guide us when designing strategies to implement the law. It would be necessary to overcome the traditional structures and create decentralized and flexible conditions that encourage teamwork and shared decision making. PMID- 21820768 TI - Quinonoid and phenazine compounds: synthesis and evaluation against H37Rv, rifampicin and isoniazid-resistance strains of Mycobacterium tuberculosis. AB - Several quinonoid and phenazine compounds were synthesized in moderate to high yields and showed activity against H(37)Rv, rifampicin and isoniazid-resistance strains of Mycobacterium tuberculosis. The cytotoxity of the compounds were evaluated against human peripheral blood mononuclear cells (PBMC) and these substances emerge as promising antitubercular prototypes. PMID- 21820770 TI - Perioperative nutrition in malnourished surgical cancer patients - a prospective, randomized, controlled clinical trial. AB - BACKGROUND & AIMS: Malnourished surgical patients are supposed to benefit from perioperative nutrition. It is unclear, however, whether enteral intervention really surpasses the parenteral one, and whether the modification of standard formula matters. The aim of the study was to evaluate the clinical value of the route and type of perioperative nutritional support. METHODS: A group of 167 malnourished patients (91 M, 76 F, mean age 61.4 years) operated between June 2001 and December 2008 was randomly assigned during postoperative period to four groups according to nutritional intervention: enteral and parenteral, standard or immunomodulating. All patients received parenteral nutrition before surgery for 14 days, which provided homogenous groups for the postoperative evaluation. The trial was designed to test the hypothesis that enteral nutrition and/or immunonutrition can reduce the incidence of postoperative complications. RESULTS: The incidence of individual complications was comparable among all four groups (p > 0.05). Infectious complications occurred in 23 of 84 patients with standard diets and in 20 of 83 patients receiving immunomodulatory formula (odds ratio 0.84; 95% CI 0.42 to 1.69). There were no significant differences in infectious complications' ratio in patients receiving enteral (24/84 patients) and parenteral formulas (19/83 patients). Neither immunomodulating formulas nor enteral feeding significantly affected the length of hospitalization, overall morbidity and mortality rates. CONCLUSIONS: Results demonstrated that postoperative nutritional intervention generates comparable results regardless of the route and formula used and that preoperative intervention is of the utmost importance. The study was registered in the Clinical Trials Database - number: NCT 00558155. PMID- 21820769 TI - Biphenyl-3-yl alkylcarbamates as fatty acid amide hydrolase (FAAH) inhibitors: steric effects of N-alkyl chain on rat plasma and liver stability. AB - Secondary alkylcarbamic acid biphenyl-3-yl esters are a class of Fatty Acid Amide Hydrolase (FAAH) inhibitors, which include the reference compounds URB597 and URB694. Given the intrinsic reactivity of the carbamate group, the in vivo potency of these molecules in rats is strongly affected by their hydrolysis in plasma or hepatic metabolism. In the present study, in vitro chemical and metabolic stability assays (rat plasma and rat liver S(9) fraction) were used to investigate the structure-property relationships (SPRs) for a focused series of title compounds, where lipophilicity and steric hindrance of the carbamate N substituent had been modulated. The resulting degradation rates indicate that a secondary or tertiary alkyl group at the carbamate nitrogen atom increases hydrolytic stability towards rat plasma esterases. The calculated solvent accessible surface area (SASA) of the carbamate fragment was employed to describe the differences observed in rate constants of hydrolysis in rat plasma (log k(plasma)), suggesting that stability in plasma increases if the substituent exerts a shielding effect on the carbamate carbonyl. Stability in rat liver S(9) fraction is increased when a tertiary carbon is bound to the carbamate nitrogen atom, while other steric effects showed complex relationships with degradation rates. The SPRs here described may be applied at the pharmacokinetic optimization of other classes of carbamate FAAH inhibitors. PMID- 21820771 TI - Inventory and vertical migration of 90Sr fallout and 137Cs/90Sr ratio in Spanish mainland soils. AB - In this paper the inventory of (90)Sr in 34 points distributed along the Spanish peninsular territory is presented. Obtained values range between 173 Bq/m(2) and 2047 Bq/m(2). From these data set and those (137)Cs data obtained in a previous work the (137)Cs/(90)Sr activity ratio has been established, laying this value between 0.9 and 3.6. Also the migration depth of both radionuclides has been analysed obtaining for (137)Cs an average value 57% lower than that obtained for (90)Sr. Additionally, this paper presents the results obtained in 11 sampling points in which the activity vertical profile has been measured. These profiles have been analysed to state the behaviour of strontium in soils and after, by using a convective-diffusive model, the parameters of the model which governs the vertical migration of (90)Sr in the soil, v (apparent convection velocity) and D (apparent diffusion coefficient) have been evaluated. Mean values obtained are 0.20 cm/year and 3.67 cm(2)/year, respectively. PMID- 21820772 TI - Effect of polyglycolic acid sheets with fibrin glue (MCFP technique) on the healing of wounds after partial resection of the border of the tongue in rabbits: a preliminary study. AB - The aim of this study was to examine the effectiveness of covering wounds to the tongue with a polyglycolic acid (PGA) sheet and fibrin glue. Eighteen mature male Japanese white rabbits had a unilateral glossectomy involving an area 10mm*10mm*2mm. After glossectomy the tongues were covered with PGA sheets 8mm*8mm in size and fibrin glue (mucosal defect covered with fibrin glue and polyglycolic acid sheet=MCFP) 1 week after the operation (n=3), after 2 weeks (n=3), and after 4 weeks (n=3). In control groups, after 1, 2, and 4 weeks (n=3 in each group), the partially resected tongues were closed with absorbable sutures (polyglactin 910). One week (experimental and control groups 1), 2 weeks (experimental and control groups 2) and 4 weeks (experimental and control groups 3) after operation the tongues were harvested and stained for microscopic examination. Histological examination showed that the covered wound surface had not epithelialised and the basal layer had yet to form in experimental group 1, but had formed in experimental group 2. However, in control group 1, epithelialisation of the sutured wound had begun. Immunohistochemical examination showed that, in experimental group 1, the non-uniform epithelial layer of the covered wound surface expressed cytokeratin AE1/AE3, and the epithelial and connective tissue layers stained strongly for FGF-2. Similar results were obtained in experimental group 2, whereas in experimental group 3, FGF-2 was expressed only in the connective tissue layer, and epithelialisation was complete. However, in control group 1, AE1/AE3 was expressed in the epithelial layer, and FGF was expressed in the connective tissue layer beneath the basal layer. In control groups 2 and 3, AE1/AE3 and FGF-2 were expressed in patterns similar to those in experimental groups 2 and 3. We suggest that this method is useful and the operation is simple. However, further testing of the method is needed and it should be widely used clinically before it is recommended. PMID- 21820773 TI - The use of a CCTV link in head and neck oncology diagnostic clinics. PMID- 21820774 TI - Swedish midwives' rating of risks during labour progress and their attitudes toward performing intrapartum interventions: a web-based survey. AB - OBJECTIVE: to study how Swedish midwives working in low-risk labour ward units rate intrapartum risks compared to their midwifery colleagues working in standard care labour wards. A second aim was to describe midwives' attitudes toward performing different types of interventions during a normal labour. DESIGN: an explorative study was carried out in 2009, using a web-based questionnaire containing 31 questions on midwives' risk ratings and attitudes to interventions during labour, as well as personal comments. SETTING: four labour ward units in Stockholm, Sweden. Two labour ward units with expected normal deliveries ('low risk') and two standard care units with all types of deliveries. PARTICIPANTS: seventy-seven registered clinically practicing midwives. FINDINGS: midwives in all units stated that factors to be considered for risk estimation were: previous delivery outcome, result of cardiotocography test (CTG) on admission to labour ward and quality of amniotic fluid. Midwives working at the low-risk units preferred to be more expectant during normal birth than their colleagues working at the standard care units. Examples of this were regarding second vaginal examination during labour (p=0.001) and/or amniotomy (p=0.012). Furthermore, midwives working at the low-risk units more often considered that first-time mothers could give birth without epidural analgesia during labour (p=0.019) and that the labouring woman should be encouraged to push according to her own spontaneous urge (p=0.040). Midwives at low-risk units were more reluctant to use an intravenous vein catheter than their colleagues at standard care units (p=0.001) and also to use oxytocin in order to augment contractions (p=0.013). Further, the open-ended question showed that attitudes to different types of interventions differed between midwives working at low-risk units or the standard care units working with all types of deliveries. CONCLUSION: the Swedish midwives estimated risks similarly regardless of whether they worked in low-risk or in standard care units, but midwives working at low-risk units reported that they perform less routine interventions and have a more expectant attitude towards performing interventions. PMID- 21820775 TI - 'It's more than just having a baby' women's experiences of a maternity service for Australian Aboriginal and Torres Strait Islander families. AB - OBJECTIVE: the Malabar Community Midwifery Link Service was developed to meet the needs of women from Aboriginal and Torres Strait Islander communities in suburban Sydney, Australia. This paper reports the evaluation from the perspective of the Aboriginal and Torres Strait Islander women who accessed the service. METHODS: a descriptive study using quantitative and qualitative approaches was undertaken for the first two years of the service. Clinical outcomes for women who gave birth in 2007 and 2008 were collected prospectively. A focus group with Aboriginal and Torres Strait Islander women was conducted, then tape recorded, transcribed verbatim and analysed qualitatively. FINDINGS: 353 women gave birth through the Malabar service during 2007 and 2008. Over 40% of the babies born were identified as Aboriginal and Torres Strait Islander. Almost all the women had their first antenatal visit before 20 weeks of pregnancy. The service was successful in reducing the number of women smoking cigarettes during pregnancy. Women felt the service provided ease of access, continuity of care and caregiver, trust and trusting relationships. CONCLUSIONS: the Malabar service is an excellent example of a primary health care model of care that is meeting the needs of the community. Improving maternal and neonatal outcomes takes considerable time as the underlying causes of the disparities are complex. IMPLICATIONS: further research into ways to ensure that services like Malabar can address issues like smoking in pregnancy and the range of social and emotional issues faced by Australian Aboriginal and Torres Strait Islander women and families needs to be undertaken. More community-based appropriate services should be developed for these families. PMID- 21820776 TI - Feelings of women regarding end-of-life decision making after ultrasound diagnosis of a lethal fetal malformation. AB - OBJECTIVE: this study investigated the feelings of women regarding end-of-life decision making after ultrasound diagnosis of a lethal fetal malformation. The aim of this study was to present the decision making process of women that chose for pregnancy termination and to present selected speeches of women about their feelings. DESIGN: open psychological interviews conducted by a psychologist immediately after the diagnosis of fetal malformation by ultrasound. Analysis of the results was performed through a content analysis technique. SETTING: the study was carried out at a public university hospital in Brazil. PARTICIPANTS: 249 pregnant women who had received the diagnosis of a severe lethal fetal malformation. FINDINGS: fetal anencephaly was the most frequent anomaly detected in 135 cases (54.3%). Termination of pregnancy was decided by 172 (69.1%) patients and legally authorised by the judiciary (66%). The reason for asking for termination was to reduce suffering in all of them. In the 77 women who chose not to terminate pregnancy (30.9%), the reasons were related to feelings of guilt (74%). KEY CONCLUSIONS: the results support the importance of psychological counselling for couples when lethal fetal malformation is diagnosed. The act of reviewing moral and cultural values and elements of the unconscious provides assurance in the decision-making process and mitigates the risk of emotional trauma and guilt that can continue long after the pregnancy is terminated. PMID- 21820777 TI - Appraisal of life events scale in a sample of Greek infertile women undergoing fertility treatment: a confirmatory factor analysis. AB - OBJECTIVE: to examine the construct validity of the Greek version of the Appraisal of Life Events (ALE) scale, originally developed by Ferguson et al. (1999), in a sample of infertile women. As there are no data concerning the validity of the ALE scale in infertile populations, a special focus was placed on construct validity through confirmatory factor analysis (CFA). SETTING: public hospital in Athens, Greece. DESIGN: cross-sectional study. PARTICIPANTS: 160 women undergoing fertility treatment with in-vitro fertilisation. METHODS: the ALE scale was 'forward-backward' translated from English to Greek. The translated instrument was then administered to a set of infertile women for pilot testing. CFA was used to test the construct validity of the ALE scale. FINDINGS: CFA supported the superiority of a model with three correlated first-order factors (challenge, threat and loss) and one second-order factor (stress appraisal) that underlay the first-order factors of threat and loss. CONCLUSION: the ALE scale was found to have a multidimensional structure. IMPLICATIONS FOR PRACTICE: the assessment of infertility appraisal during in-vitro fertilisation through a valid instrument may lead to the identification of women who are at greater risk of experiencing high stress, not only during fertility treatment but also during pregnancy and postnatal period in case of a successful IVF treatment. PMID- 21820778 TI - Not-patient and not-visitor: a metasynthesis fathers' encounters with pregnancy, birth and maternity care. AB - INTRODUCTION: the active engagement of fathers in maternity care is associated with long-term health and social benefits for the mother, baby and family. The maternity care expectations and experiences of expectant and new fathers have received little attention to date. AIM: to identify and synthesise good quality qualitative research that explores the views and experiences of fathers who have encountered maternity care in high resource settings. METHODS: based on a pre determined search strategy, relevant databases were searched for papers published between January 1999 and January 2010. Backchaining of the reference lists in included papers was undertaken. INCLUSION CRITERIA: good quality qualitative research studies exploring fathers' involvement in maternity care through pregnancy, birth, and up to 6 months postnatally, that were undertaken in high resource countries. No language restrictions were imposed. ANALYTIC STRATEGY: the analysis was based on the metaethnographic techniques of Noblit and Hare (1988) as amended by Downe et al. (2007). FINDINGS: from 856 hits 23 papers were included. The emerging themes were as follows: risk and uncertainty, exclusion, fear and frustration, the ideal and the reality, issues of support and experiencing transition. SYNTHESIS: fathers feel themselves to be 'partner and parent' but their experience of maternity care services is as 'not-patient and not-visitor'. This situates them in an interstitial and undefined space (both emotionally and physically) with the consequence that many feel excluded and fearful. CONCLUSIONS: fathers cannot support their partner effectively in achieving the ideal of transition to a successful pregnancy, joyful birth and positive parenthood experience unless they are themselves supported, included, and prepared for the reality of risk and uncertainty in pregnancy, labour and parenthood and for their role in this context. PMID- 21820779 TI - Obstetric conditions and risk of first ever mental health contact during infancy, childhood and adolescence. AB - OBJECTIVE: the main aim of this study was to investigate whether risk of first ever occasion of outpatient or inpatient service for a mental disorder among male children and adolescents may be associated with obstetric conditions. DESIGN, SETTING AND PARTICIPANTS: this study was a population-based birth-cohort study of males born between 1980 and 1984 in Western Australia (WA). Males were identified using birth registry records and followed-up over a 19 year period using linked health data available through the Western Australian Data Linkage System. MEASUREMENTS: multivariate logistic regression was employed to estimate the risk of first ever mental health contact at different stages of mental development in childhood and adolescence. MAIN FINDINGS: vacuum and forceps assisted delivery and emergency caesarean were associated with an increased risk of first ever mental health contact. The risk of first ever mental health contact was similar for spontaneous vaginal delivery and elective caesarean. Although outcomes varied by age group, children with stillborn siblings were at increased risk of first ever mental health contact as were babies with 7-9 Apgar score at 5 mins and those born to mothers with several previous live births. CONCLUSIONS AND IMPLICATIONS: vacuum and forceps assisted delivery and/or the pathophysiological causes that lead to these clinical procedures, as well as other obstetric conditions, which may be associated with (asymptomatic) brain injury at birth, which may increase the risk of mental disorders. PMID- 21820780 TI - Relationship of knee shear force and extensor moment on knee translations in females performing drop landings: a biplane fluoroscopy study. AB - BACKGROUND: Research has linked knee extensor moment and knee shear force to the non-contact anterior cruciate ligament injury during the landing motion. However, how these biomechanical performance factors relate to knee translations in vivo is not known as knee translations cannot be obtained with traditional motion capture techniques. The purpose of this study was to combine traditional motion capture with high-speed, biplane fluoroscopy imaging to determine relationships between knee extensor moment and knee shear force profiles with anterior and lateral tibial translations occurring during drop landing in female athletes. METHODS: 15 females performed drop landings from a height of 40 cm while being recorded using a high speed, biplane fluoroscopy system and simultaneously being recorded using surface marker motion capture techniques to estimate knee joint angle, reaction force and moment profiles. FINDINGS: No significant statistical relationships were observed between peak anterior or posterior knee shear force and peak anterior and lateral tibial translations; or, between peak knee extensor moment and peak anterior and lateral tibial translations. Although differences were noted in peak shear force (P=0.02) and peak knee extensor moment (P<0.001) after stratification into low and high shear force and moment cohorts, no differences were noted in anterior and lateral tibial translations (all P >= 0.18). INTERPRETATION: Females exhibiting high knee extensor moment and knee shear force during drop landings do not yield correspondingly high anterior and lateral tibial translations. PMID- 21820782 TI - Institutional policy learning and public consultation: the Canadian xenotransplantation experience. AB - Attempts to evaluate public consultations, participatory technology assessment, and deliberative democracy have typically considered impacts on either policy or participants. The determination of impacts on policy institutions has been limited due to the challenges of tracing effects through the policy process, or penetrating bureaucratic walls. This paper presents findings from a retrospective study exploring the institutional lessons learned from a 2001 Canadian national public consultation on xenotransplantation. The consultation was conducted through an arm's-length process and involved the use of citizen juries in six regional sites. We conducted in-depth interviews of regulatory and policy actors who were engaged in early policy discussions and the consultation process. We reviewed evaluations of this process, both internal and external, which gave us richer insights into what institutional actors saw as the impacts of this consultative experience on their policy environment. Participants in our research identified a broader shift toward openness in policy culture which they linked specifically to the innovative consultation process employed for xenotransplantation. We argue that beyond input into policy decisions, a consultation may have an impact in terms of its contribution to overall shifts in institutional culture (related to institutional learning), such as an "opening" of technological decision processes to a broader range of actors, knowledge, and values. PMID- 21820781 TI - Childhood socio-economic status and the onset, persistence, and severity of DSM IV mental disorders in a US national sample. AB - Although significant associations between childhood socio-economic status (SES) and adult mental disorders have been widely documented, SES has been defined using several different indicators often considered alone. Little research has examined the relative importance of these different indicators in accounting for the overall associations of childhood SES with adult outcomes. Nor has previous research distinguished associations of childhood SES with first onsets of mental disorders in childhood, adolescence, and adulthood from those with persistence of these disorders into adulthood in accounting for the overall associations between childhood SES and adult mental disorders. Disaggregated data of this sort are presented here for the associations of childhood SES with a wide range of adult DSM-IV mental disorders in the US National Comorbidity Survey Replication (NCS R), a nationally-representative sample of 5692 adults. Childhood SES was assessed retrospectively with information about parental education and occupation and childhood family financial adversity. Associations of these indicators with first onset of 20 DSM-IV disorders that included anxiety, mood, behavioral, and substance disorders at different life-course stages (childhood, adolescence, early adulthood, and mid-later adulthood) and the persistence/severity of these disorders were examined using discrete-time survival analysis. Lifetime disorders and their ages-of-onset were assessed retrospectively with the WHO Composite International Diagnostic Interview. Different aspects of childhood SES predicted onset, persistence, and severity of mental disorders. Childhood financial hardship predicted onset of all classes of disorders at every life-course stage with odds-ratios (ORs) of 1.7-2.3. Childhood financial hardship was unrelated, in comparison, to disorder persistence or severity. Low parental education, although unrelated to disorder onset, significantly predicted disorder persistence and severity, whereas parental occupation was unrelated to onset, persistence, or severity. Some, but not all, of these associations were explained by other co occurring childhood adversities. These specifications have important implications for mental health interventions targeting low-SES children. PMID- 21820783 TI - Analysis of stress distribution on fixation of bilateral sagittal split ramus osteotomy with resorbable plates and screws using the finite-element method. AB - PURPOSE: To determine the most appropriate stress distribution in fixation with resorbable screws and plates after bilateral sagittal split ramus osteotomy using the finite-element method. MATERIALS AND METHODS: This experimental study was performed on simulated human mandibles using computer software. The osteotomy line was applied to the simulated model and experimental loads of 75, 135, and 600 N were exerted on the model in accordance with the vector of occlusal force. The distribution pattern of stress was assessed and compared in 8 fixation methods: 1 resorbable screw, 2 resorbable screws in a vertical pattern, 2 resorbable screws in a horizontal pattern, 3 resorbable screws in an L pattern, 3 resorbable screws in a backward-L pattern, 1 miniplate with 2 screws, 1 miniplate with 4 screws, and 2 parallel miniplates with 4 screws each. RESULTS: Among the simulated fixations, 2 parallel miniplates showed the greatest primary stability and the single screw and the 2-hole miniplate showed the least tolerance to posterior forces. CONCLUSIONS: This study showed the 2-miniplate/4-hole plate pattern was the strongest and the single-screw and 2-hole plate patterns were the weakest of fixations in this bilateral sagittal split ramus osteotomy model. The finite-element method showed that polymer-based resorbable screws and plates (polyglycolic acid and d,l-polylactide acid) provide satisfactory primary stability in this model. PMID- 21820784 TI - Review of 43 osteomas of the craniomaxillofacial region. AB - PURPOSE: To present and discuss the demographic and clinical aspects and the management of 44 cases of osteomas of the craniomaxillofacial region. MATERIALS AND METHODS: A retrospective chart review was performed of all cases of osteoma diagnosed from 2000 through 2010. The data collected included age at diagnosis, gender, lesion location, presenting symptoms, type of osteoma, treatment, and outcomes. RESULTS: Forty-two patients with 43 osteomas were diagnosed during the study period. Their mean age was 48 years. The male-to-female ratio was 0.4:1. Twenty-one patients were asymptomatic, whereas 10 patients complained about headache and neuralgia, and 11 patients presented with facial asymmetry. Only 21 symptomatic osteomas were surgically removed after histologic diagnosis, whereas for the asymptomatic lesions a careful follow-up was maintained. CONCLUSIONS: The slow growth of osteomas allows a conservative attitude toward asymptomatic lesions. Thus, when surgery is performed, it is extremely important to plan a surgical approach that minimizes any damage to the adjacent structures. PMID- 21820785 TI - Dental student perceptions of oral and maxillofacial surgery as a specialty. AB - PURPOSE: The specialty of oral and maxillofacial surgery (OMS) encompasses the diagnosis and surgical management of a variety of pathologic, functional, and esthetic conditions of the oral and maxillofacial region. Despite the specialty's prominent role in the field of dentistry, a lack of complete understanding still remains among dental and medical health professionals as to the exact scope and expertise of the oral and maxillofacial surgeon. The present study aimed to analyze a population of dental students' perceptions of OMS as a specialty with respect to treatment rendered, referral patterns, and a general opinion of the specialty as a whole. MATERIALS AND METHODS: A survey consisting of 10 multiple choice questions was compiled and distributed to dental students through an on line polling service (SurveyMonkey). A total of 5 dental student classes at a single dental school were polled using school-based electronic mail, including the graduating seniors. All answers were kept confidential, and no individual students were identified. The students were not able to retake the survey once completed. The final tallies of the survey results were compiled and submitted for statistical analysis. RESULTS: Statistically significant associations between the year of dental education and student perceptions of OMS were determined. As dental students progress through their undergraduate studies, their perceptions change with regard to the referral of dental implants. Periodontists were found to have statistically significantly greater rates of referral than oral and maxillofacial surgeons from dental students in the fourth year and recent graduates compared with younger dental students from the first, second, and third years for placement of dental implants. Statistically insignificant in terms of a changing dental student perception was the finding that third molar removal was within the domain of the oral and maxillofacial surgeon, as well as the management of cleft lip and palate deformities and mandibular fracture repair. Almost all the dental classes believed that the specialty of OMS was both medical and dental in nature and that it is a very important dental specialty. CONCLUSIONS: Dental student perceptions of OMS change throughout their undergraduate training. The reasons for such a change are multivariate and might include factors such as the amount of didactic training and clinical exposure. It is vital to both recognize and address this change at an undergraduate level of training in an effort to increase educated referrals to a surgeon who might provide the best treatment options for the patient. A stronger understanding of the dental students' perception of OMS provides an opportunity for the oral and maxillofacial academic faculty to better educate students and, ultimately, strengthen our specialty. PMID- 21820786 TI - Cervical necrotizing fasciitis with descending mediastinitis: literature review and case report. AB - Cervical necrotizing fasciitis (CNF) can develop from odontogenic infections that spread to the deep fascial planes of the neck. This polymicrobial infection is rapidly progressive, destructive, and often fatal. Prompt diagnosis, recognition of acuity, aggressive, repeated surgical treatment, and medical management contribute to improved survival. Nevertheless, the progression of the disease to descending mediastinitis and septic shock leads to a poor prognosis and decreased survival. A comprehensive review of the current data regarding CNF was conducted using MEDLINE, PubMed, Scopus, and Google Scholar. The diagnostic elements, comorbid conditions, treatment modalities, complications, and survival rates were analyzed. CNF has a reported mortality rate of 7% to 20%, depending on the extent of neck involvement. When the disease progresses into the thorax, such as in the subset of patients with CNF complicated by descending necrotizing mediastinitis (DNM) of odontogenic origin, the mortality rate increases to 41%. This is greater than the reported mortality rate of 22% for DNM in cardiothoracic studies. When DNM is present, the risk of developing septic shock appears to be much greater, 22% versus 7%. In the presence of CNF, DNM, and sepsis, the mortality rate increases to 64%. Those who survive CNF complicated by DNM and sepsis have truly beaten the odds. CNF is an uncommon, but potentially fatal, condition that oral and maxillofacial surgeons might be called on to manage emergently. Treatment includes surgery and medical intensive care. Surgeons offer the best odds of patient survival by following these basic principles: airway security, early aggressive incision and drainage plus debridement with thoracotomy, as needed, close surveillance with computed tomography, and a low threshold for retreatment. In immunocompromised patients, even greater vigilance is required. Antibiotic therapy should be adjusted as cultures and sensitivities become available. Advances in interventional radiology might lead to improved survival by allowing guided minimally invasive drainage in critically ill patients who cannot tolerate additional surgical insult. Despite the technologic advances in diagnosis and treatment, CNF complicated by DNM mediastinitis and sepsis still results in astoundingly high mortality. PMID- 21820787 TI - Mandibular mucormycosis in immunocompromised patients: report of 2 cases and review of the literature. AB - Mucormycosis, also known as zygomycosis, is an opportunistic fungal infection caused by a series of fungi in the Mucorales family in people with immune disorders. It is harmless to a healthy person, but when it has invaded the internal organs, it is frequently fatal in immunocompromised patients. It is known for having a very poor prognosis; however, with aggressive medical and surgical management, survival rates are currently thought to exceed 80%. It has 7 predominant clinical forms: rhinocerebral, pulmonary, cutaneous, gastrointestinal, central nervous system, disseminated, and, rarely, miscellaneous (ie, bone, kidney, cardiac, mediastinum, oral). Although oral involvement of this condition has been reported relatively frequently in the literature, mandibular involvement is a rarer condition than oral involvement. The purpose of this article is to report the treatment of isolated cases of mandibular mucormycosis and a review of the literature. PMID- 21820789 TI - The very elderly selected for invasive strategy: a "Younger" subgroup with non-ST elevation acute coronary syndromes? PMID- 21820788 TI - P3 event-related potentials and childhood maltreatment in successful and unsuccessful psychopaths. AB - Although P3 event-related potential abnormalities have been found in psychopathic individuals, it is unknown whether successful (uncaught) psychopaths and unsuccessful (caught) psychopaths show similar deficits. In this study, P3 amplitude and latency were assessed from a community sample of 121 male adults using an auditory three-stimulus oddball task. Psychopathy was assessed using the Psychopathy Checklist-Revised (Hare, 2003) while childhood physical maltreatment was assessed using the Conflict Tactic Scale (Straus, 1979). Results revealed that compared to normal controls, unsuccessful psychopaths showed reduced parietal P3 amplitudes to target stimuli and reported experienced more physical abuse in childhood. In contrast, successful psychopaths exhibited larger parietal P3 amplitude and shorter frontal P3 latency to irrelevant nontarget stimuli than unsuccessful psychopaths. This is the first report of electrophysiological processing differences between successful and unsuccessful psychopaths, possibly indicating neurocognitive and psychosocial distinctions between these two subtypes of psychopathy. PMID- 21820790 TI - [Malnutrition and heart failure]. PMID- 21820792 TI - [Noninvasive remote telemonitoring for ambulatory patients with heart failure and emergency department services]. PMID- 21820793 TI - [Mitochondrial dynamics: a potential new therapeutic target for heart failure]. AB - Mitochondria are dynamic organelles able to vary their morphology between elongated interconnected mitochondrial networks and fragmented disconnected arrays, through events of mitochondrial fusion and fission, respectively. These events allow the transmission of signaling messengers and exchange of metabolites within the cell. They have also been implicated in a variety of biological processes including embryonic development, metabolism, apoptosis, and autophagy. Although the majority of these studies have been confined to noncardiac cells, emerging evidence suggests that changes in mitochondrial morphology could participate in cardiac development, the response to ischemia-reperfusion injury, heart failure, and diabetes mellitus. In this article, we review how the mitochondrial dynamics are altered in different cardiac pathologies, with special emphasis on heart failure, and how this knowledge may provide new therapeutic targets for treating cardiovascular diseases. PMID- 21820794 TI - What is the learning curve for single-port access laparoscopic-assisted vaginal hysterectomy? AB - OBJECTIVE: Single-port access (SPA) surgery is a rapidly advancing technique in laparoscopic surgery. Currently, there is limited evidence on the learning curve and complications of performing SPA laparoscopic-assisted vaginal hysterectomies (LAVHs). STUDY DESIGN: One hundred patients who initially planned to undergo a SPA-LAVH for benign indications between May 2008 and October 2009 were enrolled. All operative data were prospectively collected. Patients were arranged in order based on the date of surgery and the outcomes were compared between quartiles (cases 1-25, 26-50, 51-75, and 76-100). Proficiency was defined as the point at which the slope of the curve becomes less steep for operative time. Plateau was defined as the point at which the slope is zero. A comparison of the data on a quartile was performed. Locally weighted regression generated smoothed lines that represent operative time over the sequence of the operations. RESULTS: Most SPA LAVHs were successful, but additional ports were needed in 5 patients because of pelvic adhesions (n=3) and large uterine size (n=2). There were 3 cases with post operative complications (hemorrhage, 1; vesicovaginal fistula, 1; and cuff abscess, 1), who were managed without sequelae. Without increased operative morbidities, the operative time decreased from a median of 133.0 min (interquartile range, 107.5-162.5 min) in the first quartile to a median of 100.0 min (interquartile range, 85.0-117.5 min) for the last quartile (p=0.011). The proficiency and plateau were determined after approximately 25 and 75 cases, respectively. CONCLUSIONS: The SPA-LAVH was safe, effective, and reproducible after training, and with the current technique, had a low rate of complications. PMID- 21820795 TI - A choice experiment analysis for solid waste disposal option: a case study in Malaysia. AB - In Malaysia, most municipal wastes currently are disposed into poorly managed 'controlled tipping' systems with little or no pollution protection measures. This study was undertaken to assist the relevant governmental bodies and service providers to identify an improved waste disposal management strategy. The study applied the choice experiment technique to estimate the nonmarket values for a number of waste disposal technologies. Implicit prices for environmental attributes such as psychological fear, land use, air pollution, and river water quality were estimated. Compensating surplus estimates incorporating distance from the residences of the respondents to the proposed disposal facility were calculated for a number of generic and technology-specific choice sets. The resulting estimates were higher for technology-specific options, and the distance factor was a significant determinant in setting an equitable solid waste management fee. PMID- 21820796 TI - Phytoplankton as bioindicator for waste stabilization ponds. AB - Waste stabilization ponds are an appropriate technology for domestic onsite wastewater treatment. It is a low-cost technology, requires low maintenance, is highly efficient, mostly natural and remarkably sustainable. In facultative ponds, the existence of an algal population is very important for the stability of the symbiotic relation with aerobic bacteria. The aim of this work is to determine the pattern of microalgae in the facultative and maturation ponds to obtain information for the operation and maintenance work. The important parameters for phytoplankton measured in this study are the organic load, temperature, light penetration, dissolved oxygen and nutrients. Methodology consists in: analysis of main water quality parameters, plankton taxonomic determination and abundance calculation related with the maintenance operations. Results show that cyanobacteria are present in under-loaded conditions and chlorophyceae are present when the pond is overloaded. Using this methodology over time we can obtain a year round pattern to use the phytoplankton as a bioindicator of the pond's conditions. Our conclusion is that the phytoplankton determination and density can be used to know the pond's performance and help the operation and maintenance tasks. PMID- 21820797 TI - The optimal rebiopsy prostatic scheme depends on patient clinical characteristics: results of a recursive partitioning analysis based on a 24-core systematic scheme. AB - BACKGROUND: The most beneficial number and the location of prostate biopsies remain matters of debate, especially after an initial negative biopsy. OBJECTIVE: To identify the optimal combination of sampling sites (number and location) to detect prostate cancer (PCa) in patients previously submitted to an initial negative prostatic biopsy. DESIGN, SETTING, AND PARTICIPANTS: A transrectal ultrasound-guided systematic 24-core prostate biopsy (24PBx) was performed prospectively in 340 consecutive patients after a first negative biopsy (at least 12 cores). MEASUREMENTS: We relied on a classification and regression tree analysis to identify three clinically different subgroups of patients at dissimilar risk of harboring PCa at second biopsy. Subsequently, we set the cancer-positive rate of the 24PBx at 100% and calculated PCa detection rates for 255 possible combinations of sampling sites. We selected the optimal biopsy scheme (defined as the combination of sampling sites that detected 95% of all the cancers with the minimal number of biopsy cores) for each patient subgroup. RESULTS AND LIMITATIONS: After an initial negative biopsy, cancer was detected at rebiopsy in 95 men (27.9%). At a given number of cores, the cancer detection rates varied significantly according to the different combination of sites considered. Three different PCa risk groups were identified: (1) previous report of atypical small acinar proliferation of the prostate (ASAP), (2) no previous ASAP and ratio of free prostate-specific antigen (fPSA) to total PSA (%fPSA) <=10%, and (3) no previous ASAP and %fPSA >10%. For patients with previous ASAP or patients with no previous ASAP and %fPSA <=10%, two schemes with different combinations of 14 cores were most favorable. The optimal sampling in patients with no previous ASAP and %fPSA >10% was a scheme with a combination of 20 cores. CONCLUSIONS: Both the number and the location of biopsy cores taken affect cancer detection rates in a repeated biopsy setting. We developed an internally validated flowchart to identify the most advantageous set of sampling sites according to patient characteristics. PMID- 21820798 TI - Detection of TFPI2 methylation in the serum of colorectal cancer patients. AB - We examined whether TFPI2 methylation can be used as a molecular marker for colorectal cancers by detecting TFPI2 methylation in colorectal cancer patients' sera by using quantitative methylation-specific polymerase chain reaction (qMSP). The qMSP analysis showed that 39 of 215 (18%) patients exhibited TFPI2 methylation in their serum DNA, suggesting that TFPI2 methylation frequently existed in colorectal cancer patients' sera. After completion of qMSP analysis, clinicopathological data were correlated with molecular data. TFPI2 methylation was significant in the sera of patients with large (p = 0.0022), poorly differentiated carcinoma (p = 0.0164), deep invasion (p = 0.0002), lymph node metastasis (p = 0.0147), or distant metastasis (p < 0.0001). Moreover, TFPI2 methylation was observed more frequently according to the progression of TNM stage, suggesting that serum TFPI2 methylation could be detected more easily in patients with advanced colorectal cancer. We also examined whether serum TFPI2 methylation would be useful in the detection of colorectal cancer, compared to the conventional tumor markers. Detection rates of colorectal cancer using the tumor markers TFPI2 methylation, CEA and CA19-9, in the serum were 18%, 33%, and 17%, respectively. In cases where we combined all three markers, the detection rate was 42%. High sensitivity of qMSP enables detection of smaller amounts of serum tumor DNA. In principle, the methylation status of a primary tumor is not required in advance to detect circulating tumor DNA, suggesting the potential of qMSP as a cancer screening method. PMID- 21820799 TI - A simplified approach to evaluate human and aquatic exposure to a chemical spilled in a river. AB - This study presents an approach and a model to evaluate the potential exposure from an episodic chemical spill into a river. The River Dilution Model (RDM) was developed to predict chemical concentrations in a river as a function of the downstream distance and the time after an instantaneous release. RDM is one dimensional dilution model in an Excel spreadsheet which allows for a quick screening appraisal. RDM predictions showed reasonably good agreement with measured values of peak concentration and arrival time at distances of 3.1-7.7 km downstream of the dye release point. RDM significantly over predicted peak concentrations at greater distances because it did not consider chemical removal processes occurring in the long travel time. This paper describes how to use the predicted chemical concentrations to assess the potential human and aquatic hazards. Several sources of information were identified to define model input and toxicity information. RDM and the approach were applied in a case study to demonstrate how to evaluate the potential hazard for a spill of hydraulic fluid. The approach will enable facilities to assess potential impacts with readily available tools, and then decide which engineering or administrative controls are needed to prevent or manage a chemical spill. PMID- 21820800 TI - Teratogenic effects of triphenyltin on embryos of amphibian (Xenopus tropicalis): a phenotypic comparison with the retinoid X and retinoic acid receptor ligands. AB - Triphenyltin (TPT) has high binding affinity with the retinoid X receptor (RXR) in animals. The natural ligand of RXR, 9-cis-retinoic acid (RA), is known to induce featured malformations in vertebrate embryos by disrupting RA signal. Limited information is available on the TPT effects on amphibians. We exposed embryos of amphibian (Xenopus tropicalis) to TPT, 9-cis-RA, all-trans-RA (ligand of retinoic acid receptor, RAR), and LGD1069 (a selective ligand of RXR). The 72h LC50 of TPT was 5.25 MUg Sn/L, and 72h EC50 was 0.96 MUg Sn/L. TPT induced multiple malformations including enlarged proctodaeum and narrow fins. TPT at 5 MUg Sn/L inhibited the differentiation of skins and muscles. The reduced brain, loss of external eyes and bent axis were observed in RXR and RAR ligands treatments. TPT and tributyltin (TBT) inhibited the mRNA expression of RXRalpha and increased that of TRbeta. The phenotypes of malformations induced by TPT were similar to those by TBT and were much different from those by the RXR and RAR ligands. These results indicated that TPT was acute toxic and had high teratogenicity to amphibian embryos, and that TPT induced phenotypes of malformations. TPT and TBT might have a similar teratogenic mechanism, which seems not to be mainly mediated through RA signal. PMID- 21820801 TI - Determination of potassium permanganate demand variation with depth for oxidation remediation of soils from a PAHs-contaminated coking plant. AB - Bench-scale experiments were conducted to investigate the potassium permanganate demand, a key parameter for in situ chemical oxidation (ISCO) system design, and its variation with depth in PAHs-contaminated site of a coking plant. The concentrations of permanganate decreased rapidly during the first 8 d of the reaction process. The reaction follows first order kinetics, with rate constant ranging from 0.01 to 0.3/h. The total oxidant demand (TOD) is significantly higher for clayey silt fill than for soils of other lithology. The typical TOD is about 50 g MnO(4)(-)/kg soil for clayey silt fill, 20-40 g MnO(4)(-)/kg soil for silt, silty clay and 1-7 g MnO(4)(-)/kg soil for fine sand. Statistical analysis revealed that TOD was positively correlated with total organic carbon (TOC) content, clay content and PAHs concentrations, besides sand content, meanwhile TOC was the parameter with the strongest influence on oxidant demand. After 32 d duration of oxidation, PAHs in all tested soils were effectively removed, with total removal percent ranging from 78% to 99%, and small molecular weight PAHs were removed to a greater extent than high molecular weight PAHs. Parameters obtained in this study, combined with soil bulk density, soil porosity and soil moisture, can be used for full-scale ISCO system design and application in coking contaminated site. PMID- 21820802 TI - Influence of floc size and structure on membrane fouling in coagulation ultrafiltration hybrid process--the role of Al13 species. AB - Coagulation application prior to ultrafiltration process was carried out to increase humic acid (HA) removal and membrane permeability. The [Al(13)O(4)(OH)(24)(H(2)O)(12)](7+) polycation (Al(13) species) was used in the coagulant process and polyaluminum chloride (PACl) was also used for comparison. Characteristics of aggregates pre-coagulated by Al(13) species and PACl were investigated using a laser diffraction particle sizing device. Additionally, membrane fouling was investigated under different coagulation conditions. The various resistances caused by Al(13) and PACl treatment effluents were determined using the membrane fouling index equation. The results indicated that at dose of 1 and 3mg/L, Al(13) produced larger flocs than PACl; while when dosage further increased, the PACl-HA flocs were much larger. The flocs formed by Al(13) were strong and compact, and those formed by PACl were weak and loosely structured with the exception of the flocs generated at 1mg/L. The investigation of membrane fouling demonstrated that Al(13) contributed to the best effluent permeating at 5mg/L and the corresponding dose for PACl was 7 mg/L. The adsorption resistance of effluent pre-treated by Al(13) accounted for a smaller percentage of the total resistances compared with that by PACl. PMID- 21820804 TI - Simple method for reliable predicting flash points of unsaturated hydrocarbons. AB - This work introduces a simple method for prediction of the flash point of different classes of unsaturated hydrocarbons including alkenes, alkynes and aromatics. Elemental composition is used as a core function that can be revised for some compounds by a correcting function. The predicted flash points for a data set of 173 unsaturated hydrocarbons are in good agreement with the measured values such that the root mean square (rms) error is 9 K. The estimated flash points for 76 furthers compounds have been compared with two new group additivity methods, where these methods can be applied, that the new method gives a lower rms value. It is shown that the new model can easily be used for any unsaturated hydrocarbons with complex molecular structures. PMID- 21820803 TI - Significant enhancement of the NO2 sensing capability in networked SnO2 nanowires by Au nanoparticles synthesized via gamma-ray radiolysis. AB - gamma-Ray radiolysis was applied to the synthesis of Au nanoparticles. The growth behavior of Au nanoparticles was systematically investigated as a function of the processing parameters under gamma-ray radiolysis. The surface of the networked SnO(2) nanowires fabricated through the vapor-phase selective growth process was uniformly functionalized with the Au nanoparticles by the gamma-ray radiolysis process. Au nanoparticle-functionalized SnO(2) nanowires were compared to bare SnO(2) nanowires in terms of the NO(2) sensing characteristics. Au functionalization sharply improved the sensitivity and response time of SnO(2) nanowire-based gas sensors, most likely due to the spillover and the catalytic effects of Au nanoparticles. The methodology used in this work can be easily extended to synthesize various combinations of metal nanoparticles and oxide nanowires, which may be useful materials for use in detecting hazardous substances. PMID- 21820805 TI - Elecrokinetic separation of sulphate and lead from sludge of spent lead acid battery. AB - A novel electrokinetic (EK) technique is applied to separate lead and sulphate from the sludge of used/spent lead acid battery. XRD reveals that the sludge is a mixture of (PbO)(4) [Pb(SO(4))], Pb(2)O(3), PbSO(4), Pb(S(2)O(3)) and Pb(2)(SO(4)) which upon DC voltage application in a EK cell employing either titanium electrodes or titanium substrate insoluble anode as electrodes caused migration of sulphates and lead ions respectively into anode and cathode compartments, and accumulation of insoluble lead oxides at the central compartment. The insoluble lead oxides accumulated at the central compartment in the ratio 1:3, respectively for the high oxygen over-voltage Ti-anode (Ti-EK cell) and low oxygen over-voltage TSIA-anode (TSIA-EK cell) shows the superiority of Ti anode over TSIA anode. Also thermal investigation reveals Pb deposited at Ti-cathode is superior to that from TSIA cathode. This process does not release air/soil pollutants which are usually associated with high temperature pyrotechnic process. PMID- 21820806 TI - In situ incorporation of nickel nanoparticles into the mesopores of MCM-41 by manipulation of solvent-solute interaction and its activity toward adsorptive desulfurization of gas oil. AB - In this contribution, different amounts of nickel were incorporated into the mesopores of MCM-41 via an in situ approach. A hydrophobic nickel precursor was incorporated into the nanochannels of mesoporous silica by manipulation of solvent-solute interaction. The synthesized material was characterized using X ray diffraction, nitrogen physisorption, temperature programmed reduction, and transmission electron microscopy. The results implicate the formation of MCM-41 with well-ordered hexagonal structure and establish also the presence of nickel nanoparticles inside the nanochannels of mesoporous silica. Adsorptive desulfurization of gas oil was conducted using the nickel-incorporated MCM-41 samples. The effects of nickel concentration, temperature of process and feed flow rate on the desulfurization process were examined. The MCM-41 containing 6 wt.% of nickel had both the highest breakthrough sulfur adsorption capacity and total sulfur adsorption capacity, which were 0.69 and 1.67 mg sulfur/g adsorbent, respectively. The breakthrough sulfur adsorption capacity was almost regained after reductive regeneration of spent adsorbent. The obtained results suggest that the method applied for the synthesis of Niy/MCM resulted in formation of well-dispersed, accessible and small nickel nanoparticles incorporated into the pores of MCM-41 which might be an advantage for adsorption of refractory sulfur compounds from low sulfur gas oil. PMID- 21820807 TI - Anthelmintic activity of Cymbopogon martinii, Cymbopogon schoenanthus and Mentha piperita essential oils evaluated in four different in vitro tests. AB - Anthelmintic resistance is a worldwide concern in small ruminant industry and new plant-derived compounds are being studied for their potential use against gastrointestinal nematodes. Mentha piperita, Cymbopogon martinii and Cymbopogon schoenanthus essential oils were evaluated against developmental stages of trichostrongylids from sheep naturally infected (95% Haemonchus contortus and 5% Trichostrogylus spp.) through the egg hatch assay (EHA), larval development assay (LDA), larval feeding inhibition assay (LFIA), and the larval exsheathment assay (LEA). The major constituent of the essential oils, quantified by gas chromatography for M. piperita oil was menthol (42.5%), while for C. martinii and C. schoenanthus the main component was geraniol (81.4% and 62.5%, respectively). In all in vitro tests C. schoenanthus essential oil had the best activity against ovine trichostrongylids followed by C. martini, while M. piperita presented the least activity. Cymbopogon schoenanthus essential oil had LC(50) value of 0.045 mg/ml in EHA, 0.063 mg/ml in LDA, 0.009 mg/ml in LFIA, and 24.66 mg/ml in LEA. The anthelmintic activity of essential oils followed the same pattern in all in vitro tests, suggesting C. schoenanthus essential oil could be an interesting candidate for nematode control, although in vivo studies are necessary to validate the anthelmintic properties of this oil. PMID- 21820808 TI - PCR assay for the cell-free copro-DNA detection of Angiostrongylus cantonensis in rat faeces. AB - To facilitate improved detection of the first stage larvae (L1) of Angiostrongylus cantonensis from rat faeces, a TaqMan((r)) probe real-time PCR method for the detection in situ was developed targeting the second internal transcribed region of the ribosomal DNA (ITS2) of A. cantonensis. The assay was capable of detecting a single L1 in a grain of fresh faeces (weight 320 +/- 125 mg) from the experimental infected Sprague-Dawley rats, and the method can also detect cell-free copro-DNA from positive faeces placed for up to 12 months at ambient environment. The present study exhibited a high level of specificity for A. cantonensis, with no fluorescence signals were observed in reference control consisting of four parasite species commonly found in the intestine of rat. This approach can overcome the limitations of DNA-based identification that faecal materials should be stored in 70% ethanol or kept as frozen samples for further tests, and thus it might be suitable and feasible for the detection of target DNA in faecal materials preserved at ambient temperature, but the detecting efficiency will depend on the amount of DNA in the samples and the time placed for the samples due to DNA degradation. PMID- 21820809 TI - Effects of testosterone on attention and memory for emotional stimuli in male rhesus monkeys. AB - Increasing evidence in humans and other animals suggests that testosterone (T) plays an important role in modulating emotion. We previously reported that T treatment in rhesus monkeys undergoing chemically induced hypogonadism results in increased watching time of videos depicting fights between unfamiliar conspecifics (Lacreuse et al., 2010). In the current study, we aimed to further investigate the effect of T manipulations on attention and memory for emotional stimuli in male rhesus monkeys. Six males (7 years old) were administered Depot Lupron to suppress endogenous T levels and treated with either testosterone enanthate (TE, 5 mg/kg) or oil, before crossing over to the alternate treatment. Animals were tested for 16 weeks on two computerized touchscreen tasks with both social and nonsocial emotional and neutral stimuli. The Dot-Probe task was used to measure attention, and the Delayed-Non-Matching-to-Sample task with a 1s delay (DNMS) was used to measure recognition memory for these stimuli. Performance on the two tasks was examined during each of four month-long phases: Baseline, Lupron alone, Lupron+TE and Lupron+oil. It was predicted that T administration would lead to increased attention to negative social stimuli (i.e., negative facial expressions of unfamiliar conspecifics) and would improve memory for such stimuli. We found no evidence to support these predictions. In the Dot-Probe task, an attentional bias towards negative social stimuli was observed at baseline, but T treatment did not enhance this bias. Instead, monkeys had faster response times when treated with T compared to oil, independently of the emotional valence or social relevance of stimuli, perhaps reflecting an enhancing effect of T on reward sensitivity or general arousal. In the DNMS, animals had better memory for nonsocial compared to social stimuli and showed the poorest performance in the recognition of positive facial expressions. However, T did not affect performance on the task. Thus, even though monkeys were sensitive to the social relevance and emotional valence of the stimuli in the two tasks, T manipulations had no effect on attention or memory for these stimuli. Because habituation to the stimuli may have mitigated the effect of treatment in the attentional task, we suggest that T may increase attentional biases to negative social stimuli only during early exposure to the stimuli with acute treatment or when stimuli are highly arousing (i.e., dynamically presented) with chronic treatment. In addition, the data suggest that T does not enhance working memory for emotional stimuli in young male macaques. PMID- 21820811 TI - Effects of mood and urgency on activation of general and specific alcohol expectancies. AB - We tested the interaction of a mood manipulation with positive and negative urgency on activation of general and specific alcohol expectancies. In Study 1, high negative urgency was associated with increased positive-alcohol IAT scores following a negative mood induction, F(1, 93)=5.71, p<.01. In Study 2, high positive and negative urgency were associated with faster ETASK reaction times for global positive and tension reduction expectancies. These associations did not differ across mood conditions or expectancy subtypes. Our results suggest that positive and negative urgency are associated with increased activation of general, positive alcohol cognitions, rather than mood-specific subtypes. PMID- 21820810 TI - Patterns of use, sequence of onsets and correlates of tobacco and cannabis. AB - BACKGROUND: While most individuals initiate their use of tobacco prior to onset of cannabis use, recent reports have identified a smaller subset of youth who report onset of cannabis use prior to tobacco use. In this study, we characterize patterns of cannabis and tobacco use (tobacco but not cannabis, cannabis but not tobacco or both) and compare the factors associated with onset of tobacco before cannabis and cannabis before tobacco. METHODS: Data on 1812 offspring aged 12-32 years, drawn from two related offspring of Vietnam Era twin studies, were used. Individuals were divided into tobacco but not cannabis (T), cannabis but not tobacco (C) and users of both substances (CT). Those who used both could be further classified by the timing of onset of tobacco and cannabis use. Multinomial logistic regression was used to characterize the groups using socio demographic and psychiatric covariates. Furthermore, data on parental smoking and drug use was used to identify whether certain groups represented greater genetic or environmental vulnerability. RESULTS: 22% (N=398) reported T, 3% (N=55) reported C and 44% reported CT (N=801). Of the 801 CT individuals, 72.8% (N=583), 9.9% (N=77) and 17.3% (N=139) reported onset of tobacco before cannabis, cannabis before tobacco and onsets at the same age. C users were as likely as CT users to report peer drug use and psychopathology, such as conduct problems while CT was associated with increased tobacco use relative to T. Onset of tobacco prior to cannabis, when compared onset of cannabis before tobacco or reporting initiation at the same age was associated with greater cigarettes smoked per day, however no distinct factors distinguished the group with onset of cannabis before tobacco from those with initiation at the same age. CONCLUSION: A small subset of individuals report cannabis without tobacco use. Of those who use both cannabis and tobacco, a small group report cannabis use prior to tobacco use. Follow-up analyses that chart the trajectories of these individuals will be required to delineate their course of substance involvement. PMID- 21820812 TI - Error in noninvasive spectrophotometric measurement of blood hemoglobin concentration under conditions of blood loss. AB - This paper discusses a current misinterpretation between different parameters of hemoglobin concentration measurement and its amplification under conditions of blood loss. The paper details the distinction between microcirculatory hematocrit and the hematocrit of the macrocirculation to analyze clinical use of real-time patient hemoglobin concentration measurement by noninvasive point-of-care devices such as the Rainbow Pulse CO-OximetryTM (Masimo Corp., Irvine, CA). The hemoglobin concentration or hematocrit values have clinical significance such as for diagnosing anemia or as indicators to when a blood transfusion is needed. The device infers hemoglobin concentration from spectrophotometry of the fingertip and therefore the measured absorption is due to hemoglobin present in capillaries as well as in larger vessels, and the device accordingly reports the hemoglobin concentration as 'total hemoglobin' in a proprietary SpHb parameter. SpHb and macro hemoglobin concentration are different parameters. However, the numerical resemblance of SpHb values to values of macro hemoglobin concentrations, combined with the widely used unspecified term "Hb" in the medical setting, suggests that SpHb values are often interpreted by the clinician as macro hematocrit values. The claim of this paper is that under conditions of blood loss the portion of the SpHb total hemoglobin measure that is contributed from microcirculation increases, due to the decrease of macro hematocrit while microcirculatory hematocrit remains constant when above a critical value. The device is calibrated from phlembotomy drawn blood (from a vein in the arm), which is the gold standard in blood collection, and hence this changing contribution of microcirculatory hemoglobin to the SpHb value would distort the gap between macro hemoglobin and total hemoglobin, SpHb. The hypothesis is that if clinicians indeed interpret the SpHb values as macro hemoglobin values then there is an unreported discrepancy between SpHb to macro hemoglobin concentrations during blood loss due to the increasing effect of microcirculatory hemoglobin measurement on the mixed parameter, SpHb. PMID- 21820813 TI - The role of mast cells and angiogenesis in benign and malignant neoplasms of the uterus. AB - In this study, we looked for a relationship between the extent of angiogenesis and mast cell density (MCD) in human leiomyomas and endometrial carcinomas (EC), and investigated the clinicopathological relevance of mast cells (MCs) in EC. Specimens of 15 control, 20 leiomyoma, and 23 EC patients were investigated immunohistochemically using anti-CD31 and anti-tryptase antibodies. In EC, both stromal and myometrial expressions of CD31 were significantly higher than in the controls (p<0.01 and p=0.013; respectively). Stromal tryptase expression was not significantly lower than that of leiomyoma. In addition, in the leiomyoma group, CD31 and tryptase expressions were not much different compared to the controls. Moreover, a correlation was detected between cancer histological grade and both stromal and myometrial expressions of CD31 (p=0.017 and p=0.005; respectively). The findings show that high grade EC has a higher degree of vascularization than EC of lower grade, but MCD does not increase in parallel with the histological grade. This study has demonstrated that MCD does not correlate with angiogenesis and progression of grade in EC. Moreover, MCD in EC was found to be lower than in benign lesions of the uterus. In conclusion, MCs may not account for the angiogenic process which facilitates tumor growth. PMID- 21820814 TI - Curcumin protects the dorsal root ganglion and sciatic nerve after crush in rat. AB - The goal of this study was to quantify the histological changes in the dorsal root ganglion (DRG) and the sciatic nerve in rats subjected to sciatic nerve crush (SNC) following curcumin treatment. The rats were divided into four groups, each including five animals, and underwent the following intervention: group I: control animals which received olive oil; group II: sham-operated animals whose skin of the posterior thigh was opened, sutured, and received the vehicle; group III: SNC animals which received the vehicle; and group IV: SNC plus curcumin (100 mg/kg/day) solved in the vehicle. On the 28th day, the fifth lumbar DRG and sciatic nerve were removed. Volume of the ganglion, mean cell volume, total volume of DRG cells (A- and B-cells), and total surface of DRG cells, total number, diameter, and area of the myelinated nerve fibers were estimated using stereological methods. Except for the volume of the ganglion, all other parameters were decreased after nerve crush. In curcumin-treated rats, these parameters decreased, but to a lesser extent, and the values were significantly higher than in the non-treated SNC group (p<0.04). It can be concluded that in rats after crush, curcumin has a protective effect on the DRG and sciatic nerve. PMID- 21820815 TI - Increased tissue immunoexpression of YKL-40 protein in high grade serous ovarian cancers. AB - YKL-40 is a glycoprotein secreted by numerous human cells, such as cartilage, synovial, and endothelial cells. The biological role of YKL-40 has not yet been fully unveiled, however, its participation is perceived in angiogenesis, growth, proliferation, differentiation, and remodeling processes. The primary goal of our study was to evaluate possible differences in tissue immunoexpression of YKL-40, assumed between high grade and low-grade ovarian cancers and between the above mentioned cancer types and benign lesions. Another purpose was to find out whether immunoexpression of the studied protein could correlate with the tumor proliferation process, evaluated by Ki-67 immunoexpression. The analysis comprised 45 women, diagnosed and treated for epithelial ovarian tumors at the Medical University of Lodz between 1997 and 2002. YKL-40 protein immunoexpression was semiquantitatively assessed, whereas immunoexpression of Ki-67 was evaluated using a computer image analysis system. Significantly higher immunoexpression values of both examined proteins were observed in high-grade serous ovarian cancers vs. low-grade and benign tumors. Moreover, a significant positive correlation was identified between the immunoexpressions of YKL-40 and Ki-67 proteins in the studied groups of tumors. In conclusion, the obtained data suggest an overt prominence of TKL-40 tissue immunoexpression of YKL-40 in high grade serous ovarian tumors, which could then be approached as a helpful, additional marker to identify more aggressive ovarian cancers. PMID- 21820816 TI - Southern California Society for Surgery of the Hand (SCSSH) selection for the Journal of Hand Surgery 2010 article of the year. PMID- 21820817 TI - Role of elective hand surgery and tourniquet use in patients with prior breast cancer treatment. PMID- 21820818 TI - A percutaneous technique to treat unstable dorsal fracture-dislocations of the proximal interphalangeal joint. AB - PURPOSE: Unstable dorsal fracture-dislocations of the proximal interphalangeal (PIP) joint are complex injuries that are difficult to treat and usually require operative fixation. There are a number of surgical techniques for treating these injuries but none has emerged as superior. The purposes of this study were to describe a simple percutaneous technique to treat unstable dorsal fracture dislocations of the PIP joint and to report short-term postoperative results. METHODS: We treated 6 patients with unstable dorsal fracture-dislocations of the PIP joint with the technique of closed reduction, percutaneous fracture reduction, and pinning via a volar approach and also with dorsal block pinning. We collected information on postoperative stability, range of motion at the PIP and distal interphalangeal joints, and radiographic outcomes. We also administered the Disabilities of the Arm, Shoulder, and Hand and visual analog pain scale questionnaires. RESULTS: At a mean follow-up of 18 months (range, 6-57 mo), there were no subluxation or dislocation events. The mean range of motion was from 4 degrees of extension to 93 degrees of flexion at the PIP joint and from 1 degrees of extension to 73 degrees of flexion at the distal interphalangeal joint. Radiographic analysis revealed a concentric reduction and union in all cases. The mean Disabilities of the Arm, Shoulder, and Hand score was 8 and the mean visual analog pain score was 1.4 out of 10. There were no minor or major complications. CONCLUSIONS: This percutaneous technique reliably restored stability to the PIP joint, allowed for concentric reduction of the joint, and produced excellent radiographic and clinical outcomes. The postoperative management course with this technique is critical to the outcome. PMID- 21820819 TI - Reinstatement of methamphetamine seeking in male and female rats treated with modafinil and allopregnanolone. AB - BACKGROUND: Sex differences in methamphetamine (METH) use (females>males) have been demonstrated in clinical and preclinical studies. This experiment investigated the effect of sex on the reinstatement of METH-seeking behavior in rats and determined whether pharmacological interventions for METH-seeking vary by sex. Treatment drugs were modafinil (MOD), an analeptic, and allopregnanolone (ALLO), a neuroactive steroid and progesterone metabolite. METHOD: Male and female rats were trained to self-administer i.v. infusions of METH (0.05 mg/kg/infusion). Next, rats self-administered METH for a 10-day maintenance period. METH was then replaced with saline, and rats extinguished lever-pressing behavior over 18 days. A multi-component reinstatement procedure followed whereby priming injections of METH (1mg/kg) were administered at the start of each daily session, preceded 30 min by MOD (128 mg/kg, i.p.), ALLO (15 mg/kg, s.c.), or vehicle treatment. MOD was also administered at the onset of the session to determine if it would induce the reinstatement of METH-seeking behavior. RESULTS: Female rats had greater METH-induced reinstatement responding compared to male rats following control treatment injections. MOD (compared to the DMSO control) attenuated METH-seeking behavior in male and female rats; however, ALLO only reduced METH-primed responding in females. MOD alone did not induce the reinstatement of METH-seeking behavior. CONCLUSIONS: These results support previous findings that females are more susceptible to stimulant abuse compared to males, and ALLO effectively reduced METH-primed reinstatement in females. Further, results illustrate the utility of MOD as a potential agent for prevention of relapse to METH use in both males and females. PMID- 21820820 TI - Detection of florfenicol resistance genes in Riemerella anatipestifer isolated from ducks and geese. AB - The cat gene, coding for chloramphenicol acetyltransferase has been reported for conferring the chloramphenicol resistance for Riemerella anatipestifer. Chloramphenicol acetyltransferases, however, are unable to inactivate florfenicol. In this study, 66 R. anatipestifer isolates were investigated for their susceptibility to chloramphenicol and florfenicol and the presence of floR gene. Results showed nine florfenicol intermediate or resistant R. anatipestifer isolates were all floR positive. The expression of floR gene in E. coli and inhibition studies with PAbetaN indicated that the floR gene was as an efflux pump conferring resistance to both chloramphenicol and florfenicol. Southern hybridization revealed the floR was located in the plasmid DNA of five isolates and in the chromosomal DNA of four isolates. Furthermore, two novel floR-carrying plasmids designated pRA0726 and pRA0846 were sequenced completely. pRA0726 was 11,704 bp in size with 10 putative open reading frames which included the floR, catB and bla(OXA-209) resistance genes. The most differences between sequences of pRA0846 and pRA0726 were the absence of a bla(OXA-209) gene and the deletion of 321 nucleotides of orf1 in pRA0846. Plasmid curing tests demonstrated that pRA0726 carried functional coding proteins for resistance to phenicol and beta lactam antimicrobials. To the best of our knowledge, this is the first report of presence of the floR and bla(OXA-209) resistance genes in R. anatipestifer. PMID- 21820821 TI - Faecal shedding of CTX-M-producing Escherichia coli in horses receiving broad spectrum antimicrobial prophylaxis after hospital admission. AB - The objective of this longitudinal study was to investigate the occurrence and genetic background of faecal Escherichia coli resistant to cefotaxime (CTX) in horses receiving broad-spectrum antimicrobial prophylaxis after admission to a veterinary teaching hospital. The ten horses enrolled in the study were treated with cefquinome either alone (n=4) or in combination with metronidazole (n=3) or other antimicrobial agents (n=3). CTX-resistant coliforms in faeces collected before, during and after treatment were quantified on selective MacConkey agar supplemented with CTX, and a colony isolated randomly from each positive sample was characterized by pulsed-field gel electrophoresis, and by PCR detection and sequencing of bla(TEM), bla(SHV), bla(CTX-M) and bla(CMY). All horses were negative for CTX-resistant coliforms at admission but became positive within the first three days of treatment. The average faecal densities of CTX-resistant coliforms increased significantly following antimicrobial prophylaxis (P<0.001). Genetic characterization of 29 faecal isolates revealed that this effect was due to proliferation of E. coli producing either CTX-M-1 (n=28) or CTX-M-14 (n=1). Five CTX-M-1 isolates produced additional beta-lactamases (TEM-1, CMY-34 and the novel variant CMY-53). Shedding of CTX-M-producing E. coli appeared intermittent in four horses and persisted two weeks after antimicrobial treatments in five of six patients tested after discharge from hospital. Nosocomial transmission was suggested by finding five identical CTX-M-1-producing E. coli pulsotypes in multiple horses. The originality of the study lies in the unanticipated high frequency and genetic diversity of CTX-M-producing E. coli observed in the faecal flora of hospitalized patients receiving broad-spectrum antimicrobial prophylaxis. PMID- 21820822 TI - Fetal behavior in normal dichorionic twin pregnancy. AB - OBJECTIVES: A prospective study was performed to compare fetal behavioral development in healthy dichorionic twins and singletons, and identify twin intra pair associations (synchrony) of fetal movements and rest-activity cycles using different criteria to define synchrony. SUBJECTS AND METHODS: Twenty pregnant women carrying dichorionic twins participated. Serial simultaneous 1-hr recordings of fetal movements were made on twins between 11 and 40 weeks' gestation (wGA) using two ultrasound machines. All twins were born healthy after 36 wGA and of appropriate weight for gestation. The incidences of fetal generalized body movements (GM) and breathing movements in twins were compared with institutional reference values for singletons. A comprehensive smoothing procedure on the raw movement data was performed to evaluate previously reported variation in twin intra-pair synchrony. RESULTS: Twin fetuses were less active (GM) than singletons throughout pregnancy, but their breathing activity was higher in the third trimester. The incidences of fetal GM, quiescence, and breathing were fairly correlated within twin pairs. However, the temporal association or simultaneous occurrence of these activities was poor, especially after 30 weeks' gestation, coinciding with emerging rest-activity cycles. There was no evidence of a consistently more active ('dominant') twin half. Potential confounders had no effect on behavioral development in fetal twins. CONCLUSIONS: The results show differential behavioral development between normal dichorionic fetal twins and singletons. Within fetal twin-pairs, we found poor synchrony of movements and independent occurrence of rest-activity cycles. Previous research on fetal twin behavior appears to have overestimated the degree of intra-pair movement synchrony. PMID- 21820823 TI - The effect of treatment with flunixin meglumine at different times relative to hCG administration on ovulation failure and luteal function in mares. AB - Flunixin meglumine (FM), a prostaglandin synthetase inhibitor, causes ovulatory failure in the mare. However, the effect of the FM treatment relative to the time of hCG administration on the ovulation failure has not been determined nor has its effect on the luteal function of treated mares. Estrous mares with a follicle >=32 mm (range of 32-38 mm) were treated with 1.7 mg/kg b.w. of FM iv at zero, 12, 24 and 36 h (n=6), at 24 and 36 h (n=6), at 28 and 36 h (n=6), at 24h (n=6) or at 30 h (n=6) after treatment with 1500 IU hCG. One group received no FM (control, n=6). Progesterone concentrations were determined using RIA. Mares treated with FM 0-36 h and 24-36 h had higher (P<0.05) incidence of ovulatory failure (83 and 80%, respectively) than mares treated twice at 28 and 36 h, or once at 24 or at 30 h after hCG (16.7, 0 and 0%, respectively). The anovulatory follicles of FM treated mares luteinized and produced progesterone (>2 ng/ml). The progesterone concentration was lower in mares treated with FM at zero to 36 h and at 24-36 h after hCG than in the other groups. In conclusion, the FM administration was effective in blocking ovulation only when the treatment began <=24 h after hCG and was continued every 12 h until >=36 h. In addition, the FM induced anovulatory follicles underwent luteinization of follicular cells with active production of progesterone. PMID- 21820824 TI - Identification of sperm subpopulations in canine ejaculates: effects of cold storage and egg yolk concentration. AB - The aim of this study was to evaluate the effects of cold storage and egg yolk concentration on the distribution of spermatozoa within the different subpopulations. Twenty ejaculates from 4 dogs were collected, diluted in either TRIS buffer containing 20% (TEY20) or 10% centrifuged egg yolk (TEY10) and cooled following a conventional protocol. The kinematic parameters of individual spermatozoa were evaluated in fresh ejaculates and after 24 and 72 h of preservation at 5 degrees C. A multivariate clustering procedure separated 54,261 motile spermatozoa into four subpopulations: Subpopulation 1 consisting of poorly active and non-progressive spermatozoa (19.80%), Subpopulation 2 consisting of slow and low-linear spermatozoa (25.21%), Subpopulation 3 consisting of high speed and progressive spermatozoa (23.88%), and Subpopulation 4 consisting of highly active but non-progressive spermatozoa (31.11%). Although, cold storage had a significant (P<0.05) effect on both the frequency distribution of spermatozoa within subpopulations and the motion characteristics of each subpopulation, the sperm subpopulation structure was perfectly maintained after cold storage. Subpopulations 1 and 2 significantly (P<0.001) decreased during cold storage (Subpopulation 1: 26.6, 16.9 and 18.4%; and Subpopulation 2: 33.6, 21.3 and 24.0%, respectively, for fresh, 24 and 72 h post-cooled), whereas Subpopulations 3 and 4 significantly (P<0.05) increased (Subpopulation 3: 16.7, 27.6 and 24.3%, and Subpopulation 4: 23.1, 34.1 and 33.4%, respectively, for fresh, 24 and 72 h post-cooled). Regarding the relative percentage of spermatozoa within each extender, Subpopulation 3 was more frequently observed in TEY20 after both 24 and 72 h of cold storage. Significant correlations (P<0.05) were found between the proportions of spermatozoa assigned to Subpopulation 3 in the fresh ejaculates and those in stored samples after 24 h (r=0.48498). In conclusion, cold storage significantly modified both the specific parameters and the distribution of spermatozoa within subpopulations. These changes did not affect the general motile sperm structure present in dog, which is conserved during cold storage. The analysis of the changes observed in structures of subpopulations also suggests that the TEY20 provide more effective preservation of dog semen during cold storage. PMID- 21820825 TI - Influence of cryoprotectants glycerol and amides, combined with antioxidants on quality of frozen-thawed boar sperm. AB - The present study was undertaken to examine whether the cooling and freezing extenders containing a mixture of antioxidants (AOs) catalase, Na-pyruvate and mercaptoethanol and one of three types of cryoprotectants (CPs) would be able to improve the quality of frozen-thawed boar sperm. The collected semen, only the sperm-rich fraction, was diluted 1:1 with Androhep plusTM extender, stored at 15 degrees C for 2 h and centrifuged. The centrifuged sperm pellet was re-suspended in lactose-egg yolk extender and divided into four groups for mixing with freezing extenders containing different kinds of CPs at 5 degrees C: (I) glycerol (GLY) as control; (II) GLY with AOs; (III) dimethyl formamide (DMF) with AOs and (IV) dimethyl acetamide (DMA) with AOs. Processed sperm were packaged in 0.25-mL straws and frozen using a controlled rate freezer. After thawing, the diluted thawed sperm were incubated at 38 degrees C for 10 min and was assessed for motility by CASA, membrane/acrosome integrity by FITC-PNA/PI and DNA integrity (DFI) by SCSA. All sperm parameters evaluated, except DFI, were negatively affected (P<0.001) when using DMF (III) or DMA (IV) as CPs instead of GLY (I and II). Total sperm motility was lower (P<0.001) in the samples supplemented with AOs (32.4 +/- 1.2, 23.9 +/- 1.5, 6.9 +/- 0.7, and 10.3 +/- 0.9%, for treatments I, II, III and IV, respectively). The quality of sperm frozen in DMF was not different from DMA (P>0.05). There was no difference in DFI among the studied groups (P>0.05). In conclusion, based on the present results, addition of AOs to cooling and freezing extenders and/or replacement of GLY with DMF or DMA could not improve quality of frozen-thawed boar sperm. PMID- 21820826 TI - Pig oocyte vitrification by cryotop method: effects on viability, spindle and chromosome configuration and in vitro fertilization. AB - Three experiments were designed to evaluate the effects of vitrification using Cryotop method on MII porcine oocyte viability, chromosomes configuration, meiotic spindle morphology and in vitro fertilization; to do this, in vitro matured oocytes were subjected to the cryoprotectant treatment excluding the plunging into liquid nitrogen, the whole vitrification/warming/rehydration procedure or no treatment (control). In experiment 1 viable oocytes were not reduced by either cryoprotectants or vitrification when they were evaluated immediately after warming and cryoprotectant dilution. However, after a 2 h incubation, the survival rate significantly decreased (P<0.05). In experiment 2 cryoprotectant exposure significantly (P<0.05) influenced spindle morphology even if chromosome organization did not vary, while vitrification significantly (P<0.05) increased oocytes with damaged spindles and chromosomes displaced from the metaphase plate. No significant improvements in these parameters were observed after 2 h of incubation but, on the contrary, the rate of oocytes with normal chromosome configuration was reduced. In experiment 3 significant differences among the three groups in the fertilization rate but not in the percentages of monospermy fertilization were recorded; in addition, exposure to cryoprotectants and vitrification significantly (P<0.05) increased degenerated oocyte rate. Overall, these findings confirm that porcine oocytes at MII stage are very sensitive to vitrification, which reduces the rate of viable oocytes and alters microtubule organization, thus impairing fertilization; in addition, incubation of oocytes for 2 h after devitrification seems to be detrimental rather than ameliorative. Further improvements of the current protocol will be necessary in order to optimize the Cryotop method for vitrifying pig matured oocytes. PMID- 21820827 TI - Diet and social disadvantage: the 'Medical Home' improves nutrition in childhood and diminishes likelihood of disease in adult life. AB - It is well appreciated that malnutrition in early life has an adverse impact on the overall health of adults. In this review, we address the impact of malnutrition, social disadvantages, and poverty on the lives of children. An integrated response to these difficulties associated in the lives of children, families and the communities in which they live - the "Medical Home" - is suggested as a means to promote health for all ages. The four types of malnutrition delineated by the World Health Organization are discussed, as are differences between "socioeconomic status" and "social gradient." The latter construct is more meaningful from a health care standpoint as differences within each of the socioeconomic groupings are greater than differences between them. Poverty affects food choices with a profound impact on nutritional status. This review suggests how providing a "Medical Home" can improve dietary habits, improve overall nutrition and prevent disease. PMID- 21820828 TI - Decontamination of blood soaked electronic devices using ultrasonic technology. AB - With advancements in technology allowing for the miniaturization of consumer electronics, criminal investigations of all types frequently involve the forensic examination of electronic devices, such as cellular telephones, smartphones, and portable flash memory; in some extreme, violent cases, these devices are found covered in blood. Due to the complexity of such devices, standard operating procedures for the complete removal of blood had not previously been established by the Royal Canadian Mounted Police prior to this study. The electronics industry has adopted the use of the ultrasonic cleaner for sanitizing printed circuit boards (PCBs) by removing residues and contaminants. High frequency sound waves created by the machine penetrate and remove dirt and residues; however, early research during the 1950s recorded these sound waves breaking the internal bonds of integrated circuit chips. Experimentation with modern ultrasonic technology was used to determine if internal components were damaged, as well as if ultrasonic cleaning was the most suitable method for the removal of dried and liquid blood from a PCB. Several disinfectant solutions were compared against the 0.5% Triton((r)) X-100 detergent solution in the ultrasonic cleaner, including: 10% sodium hypochlorite bleach, 85% isopropyl alcohol, and Conflikt((r)) disinfectant spray. The results not only demonstrated that the ultrasonic cleaner did not damage the vital memory chip on the PCB, but also, with the assistance of Conflikt((r)), was able to remove all traces of blood as indicated by Hemastix((r)) reagent strips. Of five methods experimented with, two cycles of ultrasonic cleaning followed by sanitization with Conflikt((r)) proved to be the only procedure capable of removing all traces of blood, as confirmed with both Hemastix((r)) reagent strips and the hemochromogen test. PMID- 21820829 TI - Dose modulated retrospective ECG-gated versus non-gated 64-row CT angiography of the aorta at the same radiation dose: comparison of motion artifacts, diagnostic confidence and signal-to-noise-ratios. AB - PURPOSE: To compare ECG-gated and non-gated CT angiography of the aorta at the same radiation dose, with regard to motion artifacts (MA), diagnostic confidence (DC) and signal-to-noise-ratios (SNRs). MATERIALS AND METHODS: Sixty consecutive patients prospectively randomized into two groups underwent 64-row CT angiography, with or without dose-modulated ECG-gating, of the entire aorta, due to several pathologies of the ascending aorta. MA and DC were both assessed using a four-point scale. SNRs were calculated by dividing the mean enhancement by the standard deviation. The dose-length-product (DLP) of each examination was recorded and the effective dose was estimated. RESULTS: Dose-modulated ECG-gating showed statistically significant advantages over non-gated CT angiography, with regard to MA (p<0.001) and DC (p<0.001), at the aortic valve, at the origin of the coronary arteries, and at the dissection membrane, with a significant correlation (p<0.001) between MA and DC. At the aortic wall, however, ECG-gated CT angiography showed statistically significant fewer MA (p<0.001), but not a statistically significant higher DC (p=0.137) compared to non-gated CT angiography. At the supra-aortic vessels and the descending aorta, the ECG triggering showed no statistically significant differences with regard to MA (p=0.861 and 0.526, respectively) and DC (p=1.88 and 0.728, respectively). The effective dose of ECG-gated CT angiography (23.24mSv; range, 18.43-25.94mSv) did not differ significantly (p=0.051) from that of non-gated CT angiography (24.28mSv; range, 19.37-29.27mSv). CONCLUSION: ECG-gated CT angiography of the entire aorta reduces MA and results in a higher DC with the same SNR, compared to non-gated CT angiography at the same radiation dose. PMID- 21820830 TI - Astrocytic energy metabolism and glutamate formation--relevance for 13C-NMR spectroscopy and importance of cytosolic/mitochondrial trafficking. AB - Glutamate plays a double role in (13)C-nuclear magnetic resonance (NMR) spectroscopic determination of glucose metabolism in the brain. Bidirectional exchange between initially unlabeled glutamate and labeled alpha-ketoglutarate, formed from pyruvate via pyruvate dehydrogenase (PDH), indicates the rate of energy metabolism in the tricarboxylic acid (V(TCA)) cycle in neurons (V(PDH, n)) and, with additional computation, also in astrocytes (V(PDH, g)), as confirmed using the astrocyte-specific substrate [(13)C]acetate. Formation of new molecules of glutamate during increased glutamatergic activity occurs only in astrocytes by combined pyruvate carboxylase (V(PC)) and astrocytic PDH activity. V(PDH, g) accounts for ~15% of total pyruvate metabolism in the brain cortex, and V(PC) accounts for another ~10%. Since both PDH-generated and PC-generated pyruvates are needed for glutamate synthesis, ~20/25 (80%) of astrocytic pyruvate metabolism proceed via glutamate formation. Net transmitter glutamate [gamma aminobutyric acid (GABA)] formation requires transfer of newly synthesized alpha ketoglutarate to the astrocytic cytosol, alpha-ketoglutarate transamination to glutamate, amidation to glutamine, glutamine transfer to neurons, its hydrolysis to glutamate and glutamate release (or GABA formation). Glutamate-glutamine cycling, measured as glutamine synthesis rate (V(cycle)), also transfers previously released glutamate/GABA to neurons after an initial astrocytic accumulation and measures predominantly glutamate signaling. An empirically established ~1/1 ratio between glucose metabolism and V(cycle) may reflect glucose utilization associated with oxidation/reduction processes during glutamate production, which together with associated transamination processes are balanced by subsequent glutamate oxidation after cessation of increased signaling activity. Astrocytic glutamate formation and subsequent oxidative metabolism provide large amounts of adenosine triphosphate used for accumulation from extracellular clefts of neuronally released K(+) and glutamate and for cytosolic Ca(2+) homeostasis. PMID- 21820831 TI - Quantification of fumaric acid in liver, spleen and urine by high-performance liquid chromatography coupled to photodiode-array detection. AB - Quantification of fumaric acid, an endogenous dicarboxylic acid with interesting biomedical applications either through its own biological activity or as a linker constitutive of the porous iron(III) fumarate metal organic framework (MOF) MIL 88A based drug nanocarrier (MIL stands for Material from Institut Lavoisier), has been developed in different rat biological complex media (liver, spleen and urine). After a liquid-liquid extraction procedure, fumaric acid concentration was determined by a simple and accurate high-performance liquid chromatography (HPLC) method coupled to a photodiode-array detector (PDA) using aminosalicylic acid as internal standard (IS) and a gradient elution. The recovery of fumaric acid reaches 89% and 92% for urine (for concentrations of 0.05 and 1MUgml(-1), respectively) and 90% for liver and spleen tissues, exceeding 89% in all instances in comparison with the IS. Linearity has been kept from 0.05 to 1MUgml( 1) and from 0.5 to 10MUgg(-1) of fumaric acid in urine and tissues, respectively. The limit of detection of the method was 0.01MUg per injection. This method has finally allowed the quantification of fumaric acid in rat urine and tissue samples after the intravenous administration of MIL-88A nanoparticles. PMID- 21820832 TI - The left common iliac artery also compresses the left common iliac vein. AB - BACKGROUND: The higher prevalence of venous disorders in the left lower limb is currently ascribed to compression of the left common iliac vein (LCIV) by the right common iliac artery (RCIA). This study evaluated the occurrence of LCIV compression by the left common iliac artery (LCIA). METHODS: The anatomy of iliac vessels was evaluated by computed tomography (CT) in 100 asymptomatic individuals. Traditional axial projections, multiple planar, and curved planar reconstructions were used to investigate LCIV morphology. RESULTS: Compression of the LCIV by the LCIA was found in 20% of participants, whereas compression by the RCIA occurred in 25% and by both iliac arteries in 21%. Axial projections demonstrated a mean reduction in caliber of the LCIV at LCIA crossing of 22.25% (range 0%-90%). Caliber reduction of >20%, 50%, and 70% was observed in 41, 21, and 6 individuals, respectively. The mean LCIV reduction in caliber at RCIA crossing calculated in the axial CT was 24.49% (range, 0%-95%). Caliber reduction of >20%, 50%, and 70%, was observed in 46, 22, and 5 subjects, respectively. Multiple planar reconstructions demonstrated that in contrast to the RCIA, the compressive LCIA determines an eccentric deformation of the vein along its major axis, thus inducing a marked distortion of the lumen that varies from 22 to 37 mm. CONCLUSIONS: LCIV compression by the LCIA occurs in a relevant number of asymptomatic individuals and compression by the RCIA coexists in about one-half. The patterns of compression by LCIA correlate well with venographic and anatomic findings, which demonstrated damage of the LCIV unrelated to the RCIA crossing. Further investigations are needed to evaluate the hemodynamic and pathophysiologic implications of such compressive relationships. In fact, even if not necessarily associated with chronic venous disorders, LCIV compression by the overlying arteries must be considered a condition "permissive" of future development of chronic congestion or iliofemoral thrombosis. PMID- 21820833 TI - Completion duplex ultrasound predicts early graft thrombosis after crural bypass in patients with critical limb ischemia. AB - OBJECTIVE: To determine if intraoperative distal graft end-diastolic velocity (EDV) using completion duplex ultrasound (CDU) predicts patency of crural bypass in patients with critical limb ischemia (CLI). METHODS: Records of 116 non consecutive patients who underwent crural revascularization with vein conduit and CDU between 1998 and 2008 were reviewed. Bypass grafts were performed for rest pain (34%) or tissue loss (66%), while 56% of the reported cases were categorized as "disadvantaged" because of compromised vein quality or diseased arterial outflow. A 10-MHz low-profile transducer was used to image the entire bypass at case completion. Technical adequacy of the grafts was verified by absence of retained valves, arteriovenous fistulas, or localized velocity increases and presence of bypass-dependent distal pulses. Modified Rutherford scores were calculated as surrogate markers of runoff resistance and compared to distal graft EDV. The primary study end point was graft patency during a 1-year posttreatment period. Patency rates were determined using Kaplan-Meier life table methodology and compared using the log-rank test. Predictors of graft patency were determined by Cox proportional hazards. RESULTS: Primary, primary-assisted, and secondary patency for all crural bypasses were 62%, 66%, and 70% at 1 year, respectively. When stratified by tertiles of distal graft EDV (0 - <5 cm/s, 5-15 cm/s, >15 cm/s), 1-year primary patency rates were 32%, 64%, and 84% (P = .001). Low (0 - < 5 cm/s) distal graft EDV (hazard ratio [HR], 3.3 confidence interval [CI], 1.74 6.41; P < .001), poor-quality conduit (HR, 2.5; CI, 1.19-5.21; P = .016), age <70 (HR, 2.08; CI, 1.06-4.00; P = .031), and lack of statin use (HR, 2.04; CI, 1.04 4.00; P = .038) were independent predictors of graft failure. While the modified Rutherford score correlated with distal graft EDV (P = .05), it was not an independent predictor of patency (P = .58). Predictors of low EDV (<5 cm/s) included single-vessel runoff (odds ratio [OR], 3.33; CI, 1.14-9.71; P = .027), poor conduit (OR, 2.94; CI, 1.16-7.41; P = 0.024), and diabetes (OR, 2.86; CI, 1.14-7.21; P = .025). CONCLUSIONS: Distal graft EDV predicts crural vein graft patency in patients with CLI. Grafts with EDV <5 cm/s remain at high risk for early failure. The impacts on patency of statins, age, and poor-quality conduit are, again, confirmed. These results highlight the value of EDV using intraoperative CDU for anticipating and, possibly, improving results of open crural revascularization. PMID- 21820834 TI - Intracranial collateralization determines hemodynamic forces for carotid plaque disruption. AB - INTRODUCTION: Percent diameter reduction provides an imperfect assessment of the risk for stroke from carotid atheroembolism. Stroke associated with atherosclerotic carotid stenosis commonly results from plaque disruption brought about by hemodynamic shear stress and Bernoulli forces. The aim of the present study was to predict the effect of incomplete intracranial collateralization through the circle of Willis (COW) on disruptive hemodynamic forces acting on carotid plaques. METHODS: A simple circuit model of the major pathways and collaterals that form and supply the COW was developed. We modeled the intra- and extracranial arterial circuits from standard anatomic references, and the pressure-flow relationships within these conduits from standard fluid mechanics. The pressure drop caused by (laminar and turbulent) flow along the internal carotid artery path was then computed. Carotid circulation to the brain was classified as being with or without collateral connections through the COW, and the extracranial carotid circuit as being with or without severe stenosis. The pressure drop was computed for each scenario. Finally, a linear circuit model was used to compute brain blood flow in the presence/absence of a disconnected COW. RESULTS: Pressure drop across a carotid artery stenosis increased as the flow rate within the carotid conduit increased. Poststenotic turbulence from a sudden expansion distal to the stenosis resulted in an additional pressure drop. Despite the stenosis, mean brain blood flow was sustained at 4.15 mL/s bilaterally. In the presence of an intact (collateralized) COW, this was achieved by enhanced flow in the contralateral (normal) carotid artery. However, in a disconnected COW, this was achieved by sustained systolic and enhanced diastolic flow through the stenosed artery. For a similar degree of stenosis, flow and velocity across the plaque was much higher when the COW was disconnected compared with an intact COW. Furthermore, the pressure drop across a similar stenosis was significantly higher with a disconnected COW compared with an intact COW. CONCLUSIONS: Incomplete intracranial collateralization through the COW results in increased flow rates and velocities, and therefore large pressure drops across a carotid artery stenosis. This exerts large disruptive shear stress on the plaque compared with patients with an intact COW. Percent diameter reduction provides an inaccurate assessment of risk for atheroembolic stroke. An assessment of carotid flow rates, flow velocities, and the intracranial collateral circulation may add independent information to refine the estimation of stroke risk in patients with asymptomatic carotid atherosclerosis. PMID- 21820835 TI - Outcomes of acute intraoperative surgical conversion during endovascular aortic aneurysm repair. AB - PURPOSE: Outcomes and predictors of acute surgical conversion during endovascular aortic aneurysm repair (EVAR) were examined using the American College of Surgeons-National Safety and Quality Improvement Project (ACS-NSQIP) Database (2005 to 2008). METHODS: Acute intraoperative surgical conversions occurring during elective EVAR were identified using Current Procedural Terminology codes. Nonemergent EVAR and primary open surgical repairs of infrarenal aneurysms were examined for comparison. Perioperative morbidity was categorized as wound, pulmonary, venous thromboembolic, genitourinary, cardiovascular, operative, and septic. Mortality, overall morbidity, and length of stay (LOS) were examined. RESULTS: We identified 72 acute conversions, 2414 open repairs, and 6332 EVAR without acute conversion. Demographics and comorbidities were generally similar among operative groups. Mean operative time was 274 minutes for acute conversion vs 226 minutes for primary open repair and 162 minutes for EVAR (conversion vs EVAR and open repair vs EVAR P < .0001 for each; conversion vs open repair P = .0014; analysis on rank operative time). Blood transfusion was required in 69% of acute conversions (mean volume, 6.0 units) vs 73% of open repairs (mean volume, 3.3 units) and 12% of EVARs (mean volume, 2.6 units; P < .0001 for each pair-wise comparison; analysis on rank number of units among those transfused). Major morbidity was 28% for acute conversions, 28% for open repairs, and 12% for EVARs. Mortality was 4.2% for acute conversions, 3.2% for open repairs, and 1.3% for EVARs. Median (quartile 1, quartile 3) LOS was 7 (5, 9) days for acute conversion and open repair, and 2 (1, 3) days for EVAR. Morbidity and mortality were significantly higher for acute conversion and open repair vs EVAR. The OR (95% confidence interval) for morbidity was 2.9 (1.7-4.8) after conversion and 2.8 (2.5-3.2) after open repair (P < .0001 for both) and for mortality was 3.4 (1.0 10.9; P = .0437) for conversion and 2.5 (1.9-3.5; P < .0001) for open repair. Morbidity and mortality were similar between acute conversion and open repair. A similar pattern among repair groups was demonstrated for LOS, with similar LOS for acute conversions and open repair, which were significantly longer than those observed for EVAR. No significant demographic or medical risk factor predictors of acute conversion during EVAR were identified. CONCLUSION: Acute surgical conversion was a rare complication affecting 1.1% of EVAR cases, with no broadly identifiable at-risk population. When conversion did occur, morbidity and mortality rates paralleled those observed for elective open repair. PMID- 21820837 TI - An economic evaluation of an abdominal aortic aneurysm screening program in Italy. AB - OBJECTIVES: Abdominal aortic aneurysm (AAA) is defined as a localized dilatation of an aortic vessel. Though predominantly asymptomatic, it is a chronic degenerative condition associated with life-threatening risk of rupture. The early diagnosis of AAA, ie, before it ruptures, is therefore important; a simple, effective diagnostic method is ultrasound examination. To assess the benefit of screening in Italy, we developed a cost-effective Markov model comparing screening vs nonscreening scenarios. METHODS: A 13-health-states Markov model was developed to compare two cohorts of 65- to 75-year-old men: the first group undergoing screening for AAA by means of ultrasound (US), the second following the current practice of incidental detection. The following health states were distinguished: no AAA, unknown small AAA (3-3.9 cm), followed-up small AAA (1 year), unknown medium-sized AAA (4-4.9 cm), followed-up medium-sized AAA (6 months), unknown large AAA (>5 cm), elective repair, emergency repair, postelective-repair AAA, postemergency-repair AAA, rejected large AAA, and death. Transitions between health states were simulated by using 6-month cycles. Transition probabilities were derived from a literature review of relevant randomized controlled trial and from a screening program that is currently ongoing at San Martino Hospital in Genoa, Italy. The Italian National Health Service (NHS) perspective was adopted and incremental cost per life-year saved was calculated with a lifetime horizon; costs and health benefits were discounted at an annual rate of 3% from year 2 onward. Uncertainty surrounding the model inputs was tested by means of univariate, multivariate, and probabilistic sensitivity analyses. RESULTS: Considering an attendance rate of 62%, the individual cost per invited subject was ?60 (US $83.2); 0.011 additional quality adjusted life years (QALY) were gained per patient in the screened cohort, corresponding to an incremental cost-effectiveness ratio (ICER) of ?5673/QALY (US $7870/QALY). The results were sensitive to some parameter variations but consistent with the base case scenario. They suggest that on the basis of a willingness-to-pay threshold of ?50,000/QALY, screening for AAA is cost effective, with a probability approaching 100%. CONCLUSIONS: As in economic evaluations developed in other countries, such as the UK, Canada, and The Netherlands, setting up a screening program for AAA can be considered cost effective from the Italian NHS perspective. PMID- 21820838 TI - Abdominal aortic aneurysm and abdominal wall hernia as manifestations of a connective tissue disorder. AB - BACKGROUND: Abdominal aortic aneurysms (AAAs) and abdominal wall hernias represent chronic degenerative conditions. Both aortic aneurysms and inguinal hernias share common epidemiologic features, and several investigators have found an increased propensity for hernia development in patients treated for aortic aneurysms. Chronic inflammation and dysregulation in connective tissue metabolism constitute underlying biological processes, whereas genetic influences appear to be independently associated with both disease states. A literature review was conducted to identify all published evidence correlating aneurysms and hernias to a common pathology. METHODS: PubMed/Medline was searched for studies investigating the clinical, biochemical, and genetic associations of AAAs and abdominal wall hernias. The literature was searched using the MeSH terms "aortic aneurysm, abdominal," "hernia, inguinal," "hernia, ventral," "collagen," "connective tissue," "matrix metalloproteinases," and "genetics" in all possible combinations. An evaluation, analysis, and critical overview of current clinical data and pathogenic mechanisms suggesting an association between aneurysms and hernias were undertaken. RESULTS: Ample evidence lending support to the clinical correlation between AAAs and abdominal wall hernias exists. Pooled analysis demonstrated that patients undergoing aortic aneurysm repair through a midline abdominal incision have a 2.9-fold increased risk of developing a postoperative incisional hernia compared with patients treated for aortoiliac occlusive disease (odds ratio, 2.86; 95% confidence interval, 1.97-4.16; P < .00001), whereas the risk of inguinal hernia was 2.3 (odds ratio, 2.30; 95% confidence interval, 1.52 3.48; P < .0001). Emerging evidence has identified inguinal hernia as an independent risk factor for aneurysm development. Although mechanisms of extracellular matrix remodeling and the imbalance between connective tissue degrading enzymes and their inhibitors instigating inflammatory responses have separately been described for both disease states, comparative studies investigating these biological processes in aneurysm and hernia populations are scarce. A genetic predisposition has been documented in familial and observational segregation studies; however, the pertinent literature lacks sufficient supporting evidence for a common genetic basis for aneurysm and hernia. CONCLUSIONS: Insufficient data are currently available to support a systemic connective tissue defect affecting the structural integrity of the aortic and abdominal wall. Future investigations may elucidate obscure aspects of aneurysm and hernia pathophysiology and create novel targets for pharmaceutical and gene strategies for disease prevention and treatment. PMID- 21820839 TI - Contiguous bilateral head and neck paragangliomas in a carrier of the SDHB germline mutation. AB - Paragangliomas are extremely rare neoplasms with multicentric presentation usually linked to familial tumor syndromes. This patient presented with the uncommon combination of concurrent bilateral carotid body tumors and a unilateral glomus jugulare mass that demonstrated vascular continuity. During treatment, the patient was found to be heterozygous for the SDHB germline mutation, an autosomal dominant genotype of the familial paraganglioma syndromes associated with increased malignancy. The unique profile of the SDHB patient as regards primary evaluation, surgical considerations, and extended surveillance was explored and has led to a proposed treatment algorithm for these patients. PMID- 21820840 TI - Endovascular retrieval of a TrapEase permanent inferior vena cava filter from the aorta. AB - Intra-aortic inferior vena cava filter placement is a rare event. We describe a case in which a permanent vena caval filter was retrieved from the aorta with endovascular techniques. Knowledge of filter design, catheters, and available wires is important to perform this procedure safely. PMID- 21820841 TI - Improving retrieval rates of temporary inferior vena cava filters. AB - PURPOSE: Most studies have shown that the rate of inferior vena cava filter (IVCF) retrieval rarely exceeds 30%. A review of practices in our own institution revealed similar results (18%). Within the last year, few centers have demonstrated improved retrieval rates. Our hypothesis was that developing a dedicated program would improve IVCF retrieval. We report the results of an ongoing study following the development of this program. METHODS: This is a cohort of nontrauma consecutive patients who had an IVCF placed by the vascular service over a 12-month period (January 2010-January 2011) and were followed prospectively. A dedicated nurse practitioner was responsible in developing a database, maintaining contact with all the patients, and ensuring that arrangements were made for retrieval when indications for IVCF protection were no longer present. Demographics, indication for filter placement, timing to filter retrieval, and complications during placement and retrieval were prospectively collected. Retrieval rate was compared to the baseline institution data. RESULTS: During the study period, 42 patients had an IVCF placed. There were 27 men and 15 women with a mean age of 58 (25 to 88 years old). Two patients were excluded (one due to mortality and one had multiple filters) leaving 40 patients in the study. Indications for IVCF placement were absolute in 23 of 40 patients (58%), relative in 10 of 40 patients (25%), while seven patients (17%) had an IVCF placed for prophylaxis as they were considered high risk for pulmonary embolism (PE) and could not receive any chemical regimen. During follow-up, five filters were converted to permanent. Therefore, retrieval was successful in 19 of 22 patients with an 86% success rate and no complications. Median time to retrieval was 21 days ranging from 4 to 140 days. Retrieval rate for IVCFs designated as temporary at the time of placement was 70% (19 of 27), which was significantly higher compared to our baseline data of 18% (P < .001). CONCLUSION: Initial data show that a dedicated program that closely monitors patients with temporary IVCFs for ongoing need of filter prophylaxis can result in high retrieval rates. The endurance and long-term success of such a program needs to be further validated. PMID- 21820842 TI - Arthroscopic remplissage with Bankart repair for the treatment of glenohumeral instability with Hill-Sachs defects. AB - PURPOSE: To determine whether arthroscopic remplissage with Bankart repair is an effective treatment strategy for patients with Bankart lesions and large Hill Sachs defects. METHODS: Between 2006 and 2008, 20 patients underwent arthroscopic Bankart repair with remplissage for the treatment of recurrent anterior glenohumeral instability and large Hill-Sachs defects. Preoperative imaging in all patients identified avulsion of the anterior inferior glenohumeral ligament with an associated Hill-Sachs defect that involved greater than 25% of the humeral head. Patients were followed up postoperatively with the Western Ontario Shoulder Instability score, the American Shoulder and Elbow Surgeons score, and the Penn Shoulder Score. Recurrent subluxation or dislocation was documented. RESULTS: There were 15 male patients and 5 female patients. The mean age of the patients was 27.3 years. The mean length of follow-up in this series was 29.2 months (range, 24.3 to 37.7 months). At final follow-up, 3 patients reported recurrence of instability, which spontaneously reduced in all cases. The mean American Shoulder and Elbow Surgeons score was 92.5 (pain, 47.3; function, 45.3). The mean Penn score was 90 of 100 (pain, 27.3 of 30; satisfaction, 8.5 of 10; function, 54.3 of 60). The mean total Western Ontario Shoulder Instability score was 72.74% (mean physical symptom score, 77.10%; mean sports and recreation score, 70.25%; mean lifestyle score, 75%; mean emotions score, 58.50%). CONCLUSIONS: Using an all-arthroscopic remplissage technique with Bankart repair, we were able to restore function, diminish pain, and yield satisfaction in 85% of the patients in this study. Our results compare favorably with historic controls with similar pathology at early- to intermediate-term follow-up in terms of recurrence. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 21820843 TI - Meniscal repair versus partial meniscectomy: a systematic review comparing reoperation rates and clinical outcomes. AB - PURPOSE: The aim of this investigation was to compare reoperation rates and clinical outcomes after meniscal repair and partial meniscectomy. METHODS: A systematic literature review was performed to identify outcome studies of arthroscopic meniscal repair (inside-out, outside-in, and all-inside techniques) or partial meniscectomy in patients with traumatic meniscal tears. The studies included patients with no previous injuries or operations. RESULTS: At short- and long-term follow-up, partial meniscectomy had a lower reoperation rate (1.4% [2 of 143] and 3.9% [52 of 1,319], respectively) than isolated meniscal repair (16.5% [47 of 284] and 20.7% [30 of 145], respectively). There was a slightly higher reoperation rate after partial lateral meniscectomy compared with partial medial meniscectomy. Repairs of the medial meniscus resulted in higher reoperation rates than repairs of the lateral meniscus. Meniscal repairs at the time of anterior cruciate ligament reconstruction had a lower failure rate than isolated repairs. In the limited number of studies with long-term clinical outcome scores, meniscal repair was associated with higher Lysholm scores and less radiologic degeneration than partial meniscectomy. CONCLUSIONS: Whereas meniscal repairs have a higher reoperation rate than partial meniscectomies, they are associated with better long-term outcomes. LEVEL OF EVIDENCE: Level IV, systematic review of Level I-IV studies. PMID- 21820844 TI - [Surgery and invasive procedures in patients on long-term treatment with oral direct thrombin or factor Xa inhibitors]. AB - Direct oral anticoagulants (DOAs), inhibitors of factor IIa or Xa, are expected to replace vitamin K antagonists in most of their indications. It is likely that patients on long-term treatment with DOAs will be exposed to elective or emergency surgery or invasive procedures. Due to the present lack of experience in such conditions, we cannot make recommendations, but only propose perioperative management for optimal safety as regards the risk of bleeding and thrombosis. DOAs may increase surgical bleeding, they have no validated antagonists, they cannot be monitored by simple, standardised laboratory assays, and their pharmacokinetics vary significantly from patient to patient. Although DOAs differ in many respects, the proposals in the perioperative setting need not be specific to each. For procedures with low risk of haemorrhage, a therapeutic window of 48 h (last administration 24h before surgery, restart 24h after) is proposed. For procedures with medium or high haemorrhagic risk, we suggest stopping DOAs 5 days before surgery to ensure complete elimination of the drug in all patients. The treatment should be resumed only when the risk of bleeding has been controlled. In patients with a high risk of thrombosis (e.g. those in atrial fibrillation with an antecedent of stroke), bridging with heparin (low molecular weight, or unfractionated if the former is contraindicated) is proposed. In emergency, the procedure should be postponed for as long as possible (minimum 1-2 half-lives) and non-specific anti-haemorrhagic agents, such as recombinant human activated factor VIIa, or prothrombin concentrates, should not be given for prophylactic reversal, due to their uncertain benefit-risk. PMID- 21820845 TI - [Cardiac complications following hip fracture surgery]. AB - Hip fracture is a major health burden due to both its frequency and its deep impact on patient's outcome. The key issue of this poor outcome seems to be cardiac complications. The onset of these cardiac complications seems to appear early in the clinical course in the form of perioperative myocardial ischemia that are both preventable and treatable. Their clinical and electrocardiographic pattern is very poor and they can be thoroughly detected by only either a systematic electrocardiographic 12 lead monitoring or troponin dosage. PMID- 21820846 TI - [Unusual cause of primary pyomyositis in a diabetic patient: streptococcus pneumoniae]. PMID- 21820847 TI - Fibromatosis colli. PMID- 21820848 TI - Cerebral fat embolism syndrome after simultaneous bilateral total knee arthroplasty: a case series. AB - Total knee arthroplasty (TKA), particularly when performed as a simultaneous bilateral procedure, theoretically increases the risk for entry of fat globules into the blood stream. The frequency of cerebral fat embolism syndrome (CFES) was retrospectively investigated among 2345 simultaneous bilateral TKA procedures performed from August 2006 to May 2010. During that period, 9 patients presented with neurologic deficits after surgery and underwent brain magnetic resonance imaging. For identification of CFES among them, we used both magnetic resonance imaging findings and clinical criteria modified from the original one of Gurd and Wilson (J Bone Joint Surg Br 1974; 56B:408). Four patients fulfilled the modified criteria. The overall incidence of CFES occurring after simultaneous bilateral TKA was 0.17%. Cerebral fat embolism syndrome should be ruled out, although rare, in patients who present with neurologic impairment after TKA. PMID- 21820849 TI - Magnitude of limb lengthening after primary total knee arthroplasty. AB - Patients will often perceive a change in lower limb length after total knee arthroplasty (TKA). From this observed finding, we asked how frequently does a change in limb length occur after TKA. Preoperative and postoperative full-length standing radiographs were obtained for 102 knees in 98 patients who underwent TKA. Digital radiography software was used to measure the mechanical axis and limb length of the operative and nonoperative legs. Overall, 83% of the knees measured showed an increase in limb length after TKA. Preoperative varus alignment was associated with an average lengthening of 5.2 mm. Preoperative valgus alignment was associated with an average lengthening of 8.4 mm. Patients with a valgus deformity greater than 10 degrees demonstrated the greatest average lengthening. It is the conclusion of this study that limb lengthening occurs frequently after TKA, back to a length similar to the nonoperative limb. PMID- 21820850 TI - Use of methadone as a coanalgesic. PMID- 21820851 TI - Preliminary assessment of a neuropathic pain treatment and referral algorithm for patients with cancer. AB - CONTEXT: The purpose of this case series study was to pilot test an evidence based neuropathic pain (NP) treatment and referral algorithm for use by oncology nurses when managing cancer-related NP. OBJECTIVES: The primary study objective was to assess patient-reported outcomes (pain severity, changes in activities of daily living, and satisfaction) resulting from algorithm use. METHODS: Outpatients (n=20) with cancer-related NP scores >=4 on a 0-10 numeric rating scale participated in the study. NP assessment, treatment, and referral to ancillary providers were guided by an evidence-based NP algorithm that was implemented by oncology nurse practitioners. Based on efficacy evidenced through randomized clinical trials published at the time of study implementation, the following drugs were included in the algorithm: lidocaine patch, gabapentin, oxycodone, tramadol, morphine, methadone, duloxetine, pregabalin, and nortriptyline. Recommendations for starting dose, dose escalation, drug combinations, treatment duration, and contraindications were included for first tier drugs. Patient-reported outcomes (pain severity, functional capacity, and satisfaction) were assessed monthly over 12 weeks. RESULTS: Average NP severity (P=0.001), general activity (P<0.001), mood (P=0.002), walking ability (P=0.01), ability to perform normal work (P=0.002), relationships (P=0.002), sleep (P=0.01), life enjoyment (P<0.001), and patient satisfaction (P=0.003) all improved by 12 weeks. CONCLUSION: Evidence from this pilot study suggests that NP evidence-based treatment may result in improved symptoms, function, and patient satisfaction. A randomized controlled trial is needed to further assess algorithm efficacy. PMID- 21820852 TI - Decreasing rate of capsule complications in cataract surgery: eight-year study of incidence, risk factors, and data validity by the Swedish National Cataract Register. AB - PURPOSE: To define the incidence of capsule complication and its risk factors in Sweden over an 8-year period. SETTING: Fifty-two ophthalmic surgery units in Sweden. DESIGN: Database study. METHODS: Data were collected prospectively in the Swedish National Cataract Register (NCR) from 2002 through 2009. The NCR contains 97.3% of the total number of cataract extractions in Sweden over the 8-year study period. One mandatory variable in the register is capsule complications during surgery. As a means to validate the accuracy of register data on capsule complications, a randomly selected sample of 2400 registrations was compared with corresponding medical records. RESULTS: The analyses were based on 602,553 cataract extractions reported to the NCR. A capsule complication was reported in 12,574 cataract extractions, corresponding to a frequency of 2.09%. The incidence of this complication consistently decreased each year from 2002 to 2006, after which it stabilized. Poor corrected distance visual acuity in the surgical eye (<= 0.1), the occurrence of glaucoma, diabetic retinopathy, and age were among the parameters significantly related to a capsule complication. Some of these parameters also decreased over time. However, even after adjusting for this, there was an obvious decrease in capsule complications over time. The validity test showed a certain underreporting of capsule complications to the registry, but it was not significant and did not change over time. CONCLUSION: The incidence of capsule complications decreased over time. This may be partly the result of fewer risk factors and of better surgical quality. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 21820853 TI - Emotional processing in obsessive-compulsive disorder. AB - The aim of the present study was to investigate whether there are differences in emotional processing among people with obsessive-compulsive disorder, using Lang's dimensional model of emotions. A total of 22 individuals with obsessive compulsive disorder participated in the study and were compared to a control group (n=25). All participants assessed a set of photographs with emotional content (pleasant, neutral, unpleasant, and with obsessive-compulsive content) using the Self-Assessment Manikin pictorial scales for rating emotional valence (pleasant/unpleasant), arousal (calm/aroused) and dominance (controlling/controlled). The results show significant differences in the processing of emotional images among individuals with obsessive-compulsive disorder and the high predictive value of dominance for diagnosis. PMID- 21820854 TI - Understanding the relationship of perceived social support to post-trauma cognitions and posttraumatic stress disorder. AB - Poor social support in the aftermath of a traumatic event is a well-established risk factor for posttraumatic stress disorder (PTSD) among adult trauma survivors. Yet, a great deal about the relationship between social support and PTSD remains poorly understood. In this study, we analyzed data from 102 survivors of a serious motor vehicle accident (MVA) at 4 weeks (Time 1) and 16 weeks (Time 2) post-MVA. We assessed the role of perceived dyadic social support, positive dyadic interaction, and negative dyadic interaction in the development and maintenance of PTSD. In addition, we examined how these social support constructs work together with negative post-trauma cognitions to affect the maintenance of PTSD. Neither perceived social support nor the quality of social interaction (i.e., positive or negative) was associated with PTSD symptom severity at Time 1. However, among those with elevated PTSD symptom severity at Time 1, greater social support and positive social interaction and lower negative social interaction were each associated with reductions in PTSD symptom severity from Time 1 to Time 2. For social support and negative social interaction, this association ceased to be significant when jointly assessed with negative post trauma cognitions, suggesting that perceived social support and negative dyadic interaction were associated with maintenance of PTSD symptom severity because of their association with negative post-trauma cognitions. These results provide support to models and treatments of PTSD that emphasize the role of negative post trauma cognitions in maintenance of PTSD. PMID- 21820855 TI - Progress in the removal of di-[2-ethylhexyl]-phthalate as plasticizer in blood bags. AB - Polyvinylchloride (PVC) is used in blood component containers as well as in many other medical devices because it shows optimal inertness, durability, and resistance to heat and chemicals. However, the polymer itself does not provide good handling characteristics or the necessary properties for red blood cell (RBC) survival. PVC thus needs to be plasticized, and di-(2-ethylhexyl)phthalate (DEHP) has been the most common plasticizer to produce the required flexibility to PVC. However, DEHP has been found to leach out from the containers, causing toxic effects, as demonstrated mainly in rodents. It is considered to be a possible carcinogen and suspected to also produce endocrine effects especially in young males. Although controversial, it is commonly accepted that in vulnerable patients such as newborns, trauma patients, or pregnant women, high exposure to DEHP should be avoided. The replacement of the common PVC + DEHP blood bags poses technical challenges due to the positive influence of the DEHP molecules on the red blood cell (RBC) membrane, and thus it has been shown to affect RBC storage and survival after transfusion. Different approaches are thus being taken to find a suitable alternative to DEHP for blood components bags. Environmentalists even favor the substitution of the PVC to avoid not only the plasticizers but even the other residues contained in the polymer material. Consequently, whereas the simplest solution is the substitution of the DEHP by other plasticizers, alternative plasticizer-free materials are becoming explored. Even modifications of existing materials are being presented by some research groups, ranging from covering of the DEHP-containing materials to alloys or special additive solutions. Different strategies as well as the most promising approaches are presented in this review. In any case, the degree of stabilization of RBCs undergoing prolonged storage will dictate the final acceptance for such alternatives. PMID- 21820856 TI - Indication for surgery, the revised cardiac risk index, and 1-year mortality. AB - BACKGROUND: Patients who undergo vascular surgery are at increased risk of perioperative cardiovascular morbidity and mortality. The Revised Cardiac Risk Index (RCRI) is a validated and widely used bedside tool for estimating the risk of a perioperative major adverse myocardial event. We hypothesized that inclusion of the indication for surgery would add independent and prognostic information to the RCRI in predicting all-cause 30-day and 1-year mortality in open infrainguinal vascular surgical procedures. METHODS: This was a retrospective study of 603 patients who underwent open infrainguinal bypass vascular surgery between January 2002 and January 2008 at a tertiary care medical center. RCRI and indication for surgery were determined. The primary outcomes of interest were all cause 30-day mortality (which included all in-hospital mortality, regardless of time) and all-cause 1-year mortality. RESULTS: Overall 30-day mortality was 32 (5.3%). Independent risk factors for early death were RCRI score, being of age >=80 years, American Society of Anesthesiologists Physical Status classification = 4, and emergency surgery. Overall 1-year mortality, including early deaths, was 114 (18.9%). Indication for surgery, RCRI score, age, American Society of Anesthesiologists Physical Status classification = 4, female sex, and emergency surgery were all independent predictors of 1-year mortality. CONCLUSIONS: The RCRI score was associated with both 30-day and 1-year mortality in patients undergoing lower extremity bypass surgery. Indication for surgery was predictive of 1-year mortality but not of 30-day mortality. PMID- 21820857 TI - Reprise of article: the CREST results: another piece to an unfinished puzzle. PMID- 21820858 TI - Advancing imitation and requesting skills in toddlers with Down syndrome. AB - Drawing upon information about the Down syndrome behavioral phenotype and empirically based intervention strategies, we examined intervention addressing early communication impairments in young children with Down syndrome. Intervention involved multiple opportunities, shaping, prompting, and reinforcement to address both verbal imitation and requesting. Intervention also incorporated the relative strengths in social development characteristic of the Down syndrome behavioral phenotype by focusing on a more social request prior to addressing the more impaired instrumental request, as well as incorporating social consequences. Three of the four toddlers with Down syndrome were taught verbal imitation skills, two of whom generalized to novel sounds. All four toddlers with Down syndrome acquired requesting skills in the form of gaze shifting and vocalizing; three were also taught verbal approximations of requesting words (e.g., "mm" for "more") using imitative prompts. These results contribute to the small, but growing, literature demonstrating behavior analytic interventions informed by an understanding of the Down syndrome behavioral phenotype. PMID- 21820859 TI - A neurocognitive perspective on developmental disregard in children with hemiplegic cerebral palsy. AB - A common problem in children with hemiplegic cerebral palsy (CP) is the asymmetrical development of arm and hand capacity caused by the lack of use of the affected upper limb, or developmental disregard. In this paper, we provide a neuropsychological model that relates developmental disregard to attentional processes and motor learning. From this model, we hypothesize that high attentional demands associated with the use of the affected upper limb might hinder its use in daily life, and therefore may be a factor in developmental disregard. This can be assessed with a dual-task paradigm. However, until now, this has not been applied to children with CP. We provide recommendations for using a dual-task paradigm in children with CP based on empirical studies in typically developing children and children with developmental coordination disorder. Ultimately, these dual-task studies may be used to improve interventions aimed at reducing developmental disregard. PMID- 21820860 TI - Urinary fluoride concentration in children with disabilities following long-term fluoride tablet ingestion. AB - Urine is the most commonly utilized biomarker for fluoride excretion in public health and epidemiological studies. Approximately 30-50% of fluoride is excreted from urine in children. Urinary fluoride excretion reflects the total fluoride intake from multiple sources. After administering fluoride tablets to children with disabilities, urinary fluctuation patterns should be investigated. The purpose of this study was to monitor the short and long term fluctuating patterns of urinary fluoride concentration after fluoride tablets were ingested by children with disabilities. Children with disabilities aged 6-12 years old were selected randomly and were divided into three groups: Group A, 1.0mg fluoride tablet, Group B, 0.5mg fluoride tablet, and Group C, control group. The urine samples were collected in the morning (MU) and 2h after fluoride tablets were ingested (AU). Urine was collected on the day prior to fluoride intake (baseline), the first, the third, the fifth and the eighth day of fluoride ingestion for a short term, and once every 6 months for a total of 18 months for long-term observation. The AU sample showed statistically significantly higher concentrations of urine fluoride than those of the MU samples, and no statistically significant difference was noticed in the MU samples among the three groups. Group A showed the highest urinary fluoride concentration (UFC) among the three groups. UFC increased as ingested fluoride tablet dosage increased, and it returned to the baseline level on the following day and persisted throughout the study period. PMID- 21820861 TI - A combined training intervention programme increases lean mass in youths with Down syndrome. AB - AIM: The present study aimed to determine whether youths with Down syndrome (DS) are able to increase lean mass and decrease fat mass, after 21 weeks of conditioning combined with a plyometric jumps training program. METHODS: Twenty six participants with DS (15 males) aged 10-19 years joined the study. Participants were divided into two comparable groups, exercise (EG; n = 13) and control (CG). Total and regional (trunk, upper and lower limbs) lean and fat masses were assessed by dual energy X-ray absorptiometry (DXA), at baseline and after the intervention. ANCOVA tests were used to evaluate differences between groups in pre- and post-training moments. Repeated measures of ANOVA adjusted by the increments in height and Tanner were applied to test the differences between pre and post-training moments. Adjusted percentages of change were calculated and differences between groups evaluated with Student's t test. RESULTS: After the training period, EG showed an increase in total and lower limbs lean mass, while no changes in adiposity depots were observed. CG did not change neither the lean mass nor the fat mass except for decreased upper limbs fat mass (all p < 0.05) during the same period of time. As a result, time by exercise interactions were found for whole body and lower limbs lean mass (both p < 0.05). No differences in the percentage of fat were observed between groups at baseline or post-training. Overall, 21 weeks of conditioning combined with plyometric jumps training was an effective method for increasing lean mass in youths with DS; however, no changes in fat mass were observed. PMID- 21820862 TI - Improving subspace learning for facial expression recognition using person dependent and geometrically enriched training sets. AB - In this paper, the robustness of appearance-based subspace learning techniques in geometrical transformations of the images is explored. A number of such techniques are presented and tested using four facial expression databases. A strong correlation between the recognition accuracy and the image registration error has been observed. Although it is common-knowledge that appearance-based methods are sensitive to image registration errors, there is no systematic experiment reported in the literature. As a result of these experiments, the training set enrichment with translated, scaled and rotated images is proposed for confronting the low robustness of these techniques in facial expression recognition. Moreover, person dependent training is proven to be much more accurate for facial expression recognition than generic learning. PMID- 21820863 TI - Grip force control in individuals with hand osteoarthritis. AB - Individuals with hand osteoarthritis (OA) experience pain and stiffness that could result in significant limitations in the performance of everyday activities involving upper extremities. The purpose of the study was to evaluate grip force control in individuals with hand OA during the lifting of an object. The study design used was a case-control study. Ten females with hand OA and a group of age matched females performed two functional tasks: lifting an instrumented object vertically while the load was suddenly changed and lifting and placing the object on a shelf. Load Force Peak, Grip force at liftoff, Grip Force Peak, Time Lag, and Latency were measured and analyzed. Individuals with hand OA were able to modulate the magnitude and temporal parameters of grip force; however, they applied higher grip forces (at liftoff [p=0.002]; Grip Force Peak [p=0.039]) and demonstrated a longer Latency (p=0.015) to manipulate the instrumented object when compared with the control subjects. The Load Force Peak and Time Lag were not significantly different between the two groups. Detailed information about how individuals with hand OA perform prehension activities of daily living will help to better understand the limitations of grip force control in these individuals. PMID- 21820864 TI - Validity, reliability, and responsiveness of a digital version of the visual analog scale. AB - The design used in this study was a prospective cohort. Pain intensity levels recorded by the digital version of the visual analog scale (VAS-D) are easy to both score and share with other health care professionals. The purpose of the study was to examine the test-retest reliability, concurrent validity, and responsiveness of the VAS-D. Thirty-three people with upper extremity injuries reported pain intensity levels before and after performing four maximal grip contractions (pre- and postgripping). Our version of the VAS-D had high test retest reliability (r=0.96) and good concurrent validity (r=0.84-0.97) with both the paper version of the VAS (VAS-P) and the verbal numerical rating scale (NRS V). Responsiveness of the VAS-D was indicated by a significant increase in pain levels from pre- to postgripping. Similar responsiveness to that of the VAS-P and NRS-V was indicated by similar effect size coefficients and analysis of variance of pain change scores. In conclusion, the VAS-D is a reliable, valid, and responsive measure of pain intensity for people with upper extremity injuries. However, differences in accuracy (resolution) among the VAS-D, VAS-P, or NRS-V may render the three pain scales not fully compatible. LEVEL OF EVIDENCE: Not applicable. PMID- 21820865 TI - Comprehensive assessment of changes in left atrial volumes and function after ST segment elevation acute myocardial infarction: role of two-dimensional speckle tracking strain imaging. AB - BACKGROUND: Left atrial (LA) size has been associated with adverse outcome in patients after acute myocardial infarction. However, data about the occurrence of late LA enlargement and changes in LA function during follow-up are scarce. The purpose of the current study was to evaluate changes in LA size and function during 1-year follow-up. METHODS: The study population comprised 407 patients with acute myocardial infarction who were treated with primary percutaneous coronary intervention. At baseline and 12 months, two-dimensional echocardiography was performed to assess LA volumes and function using speckle tracking strain and strain rate. RESULTS: The mean age was 60 +/- 11 years, and most patients were men (78%). LA maximal volume increased from 25 +/- 8 to 28 +/- 8 mL/m(2) (P < .001) from baseline to 1 year. Echocardiographic assessment at 1 year follow-up showed that 92 patients (25%) had developed LA remodeling (defined as an increase of >=8 mL/m(2) in LA maximal volume). On multivariate analysis, only LA maximal volume at baseline (odds ratio, 0.95; 95% confidence interval, 0.91-0.98; P = .003) and LA strain at baseline (odds ratio, 0.94; 95% confidence interval, 0.92-0.97; P < .001) were independent predictors of LA remodeling during follow-up. Interestingly in patients without LA remodeling, no changes were observed in LA function during follow-up. However, in patients with LA remodeling, LA function significantly worsened during follow-up. In line, LA strain and strain rate were significantly lower at 12 months compared with baseline (24 +/- 7% vs 27 +/- 6%, P < .001, and 1.8 +/- 0.5 vs 2.4 +/- 0.7 sec( 1), P < .001, respectively). CONCLUSIONS: LA remodeling occurred in 22% of patients after acute myocardial infarction. In patients without LA remodeling, no changes in LA function were observed, but in patients with LA remodeling, LA function deteriorated significantly. PMID- 21820866 TI - A novel bilayer approach to ventricular septal deformation analysis by speckle tracking imaging in children with right ventricular overload. AB - BACKGROUND: The aim of this study was to evaluate functional differences between the left and right sides of the ventricular septum in children with right ventricular overload. METHODS: Radial, longitudinal, and circumferential strain on both sides of the ventricular septum were compared using speckle-tracking echocardiography in patients with preoperative atrial septal defects (n = 22), postoperative tetralogy of Fallot (n = 23) and age-matched normal controls (n = 44). The duration between peak strain of the left and right ventricular septum (TLt-Rt) was also evaluated. RESULTS: Radial and circumferential strain in the control group were significantly higher on the left than the right ventricular septum (41.3 +/- 12.8% vs 22.6 +/- 6.8% and -28.0 +/- 5.4% vs -22.5 +/- 4.8%, respectively; P < .0001 for both), whereas longitudinal strain did not significantly differ (-22.0 +/- 4.9% and -20.7 +/- 5.2%, respectively). TLt-Rt was 52.9 +/- 35.6, 33.4 +/- 29.0, and 38.7 +/- 31.0 msec for radial, longitudinal, and circumferential strain, respectively. Longitudinal and circumferential strain on both sides were significantly increased in patients with atrial septal defects compared with controls (P < .05), although radial strain was similar on both sides. Radial strain on the right side was significantly increased in patients with tetralogy of Fallot compared with controls (P < .05), whereas that on the left side was significantly reduced (P < .001). Longitudinal strain on both sides was significantly decreased (P < .01 and P < .001 for the left and right sides, respectively). In addition, TLt-Rt in patients with tetralogy of Fallot was significantly increased with radial and circumferential deformation (P < .05 for both). CONCLUSIONS: Deformation of both sides of the ventricular septum functionally differed. Bilayer analysis of the ventricular septum can help in the evaluation of right ventricular performance under volume and pressure overload. PMID- 21820867 TI - Morphological studies of the murine heart based on probabilistic and statistical atlases. AB - This study directly compares morphological features of the mouse heart in its end relaxed state based on constructed morphometric maps and atlases using principal component analysis in C57BL/6J (n=8) and DBA (n=5) mice. In probabilistic atlases, a gradient probability exists for both strains in longitudinal locations from base to apex. Based on the statistical atlases, differences in size (49.8%), apical direction (15.6%), basal ventricular blood pool size (13.2%), and papillary muscle shape and position (17.2%) account for the most significant modes of shape variability for the left ventricle of the C57BL/6J mice. For DBA mice, differences in left ventricular size and direction (67.4%), basal size (15.7%), and position of papillary muscles (16.8%) account for significant variability. PMID- 21820868 TI - Antiproliferation of melanoma cells by polysaccharide isolated from Zizyphus jujuba. AB - OBJECTIVE: Zizyphus jujuba, a traditional Chinese herb rich in functional components such as polysaccharide, has been widely consumed in Asian countries. The objective of this study was to determine the antiproliferation effect of melanoma cells as affected by deproteinized polysaccharide (DPP) isolated from Z. jujuba. METHODS: Deproteinized polysaccharide was obtained through boiling water extraction, ethanol precipitation, deproteinization, and dialysis, and the molecular weight of DPP was determined by high-performance gel-filtration chromatography. Melanoma cell viability was assessed by the 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, the cell cycle was analyzed by flow cytometry, the formation of apoptotic bodies was observed under a fluorescence microscope at 450 nm, and caspase-3 and caspase-9 were measured by an assay kit. RESULTS: Deproteinized polysaccharide was composed of two fractions with average molecular weights of 143 108 and 67 633 Da. The 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test showed that the antiproliferation effect of DPP on melanoma cells followed a dose- and time dependent course. The 50% inhibitory concentration of DPP in inhibiting melanoma cell growth was 3.99 +/- 0.10 mg/mL after 24-h treatment but decreased significantly to 3.36 +/- 0.14 mg/mL after 48 h. The cell cycle assay revealed melanoma cells to be arrested in G2/M phase. Moreover, with DPP treatment, the apoptotic bodies were generated, accompanied by an increase in caspase-3 and caspase-9 activity. CONCLUSIONS: This outcome suggested that DPP may be used as a potential anti-skin cancer agent for further in vivo and clinical trial experiments. PMID- 21820869 TI - Radical scavenging activity of flavonoids from Trollius chinensis Bunge. AB - OBJECTIVE: Flos trollii is considered as functional tea, as well as a traditional medicinal herb, in China. In this study, total phenolic and flavonoid contents of Flos trollii were determined by a colorimetric method. The antioxidative potential of the hydroalcoholic extract of Flos trollii (FTE, extracted by alcohol:water, 80:20) was also evaluated by various antioxidant assays. METHODS: Chemiluminescence technique was used to determine the radical scavenging activities of FTE toward different reactive oxygen species, including superoxide anion (O(-2).), hydroxyl radical (OH.), lipid-derived radicals (R.), and singlet oxygen ((1)O(2)). RESULTS: FTE could effectively scavenge O(-2)., OH., R., and (1)O(2) at an efficient concentration (EC(50)) of 46, 5.64, 5.19, and 3.97 mg/mL, respectively. Moreover, the radical scavenging activities of FTE were higher than those of ascorbic acid. Further, FTE had higher 1,1 diphenyl-2-picrylhydrazyl radical (DPPH) radical-scavenging activity with EC(50) 44 mg/mL, compared with butylated hydroxytoluenesynthetic antioxidant with EC(50) 52 mg/mL. CONCLUSION: All results indicated that FTE is a powerful antioxidant, deserving of better utilization of the extracted Flos trollii as antioxidants. PMID- 21820870 TI - Baseline insulin/glucose ratio as a marker for the clinical course of hyperglycemic critically ill children treated with insulin. AB - OBJECTIVE: The objective of this study was to investigate the relations of baseline insulin/glucose ratio to the clinical course of critically ill children. Such information will provide insight into the pathophysiologic mechanisms leading to hyperglycemia and will optimize preventive and therapeutic measures for hyperglycemia in critically ill children. METHODS: Sixty-four consecutively admitted critically ill children with hyperglycemia, defined as a blood glucose level higher than 8 mmol/L (>145 mg/dL) and treated with insulin according to a glucose-control protocol, were included. Demographic data and clinical and laboratory parameters were collected. Insulin sensitivity was investigated by calculating the ratio of insulin to the blood glucose level just before the start of insulin administration. Results are expressed as median (range). RESULTS: Sixty-four children (24 girls) 7.0 y of age (0.3-16.9 y) with various diagnoses were included. A hyperinsulinemic response, indicated by an increased insulin/glucose ratio (>18 pmol/mmol), was seen in 55% of children. The durations of insulin therapy, mechanical ventilation, and pediatric intensive care unit length of stay in children with a hyperinsulinemic response were longer than in children with a hypoinsulinemic response. CONCLUSION: Hyper- and hypoinsulinemic responses play a role in the occurrence of hyperglycemia in critically ill children. Each is associated with a particular clinical course after the initiation of insulin therapy. It would be worthwhile to further investigate if the insulinemic response to hyperglycemia, determined by the insulin/glucose ratio in combination with the type of organ dysfunction, could be used in clinical practice to determine the need for insulin therapy. PMID- 21820872 TI - Destined for greater obesity. PMID- 21820871 TI - Dietary intervention induces flow of changes within biomarkers of lipids, inflammation, liver enzymes, and glycemic control. AB - OBJECTIVE: To determine how changes in lipids, liver enzymes, and inflammatory and glycemia markers intercorrelate during prolonged dietary intervention in obese participants with or without type 2 diabetes (T2D). METHODS: We examined the dynamics and intercorrelations among changes in biomarkers during the 2-y Dietary Intervention Randomized Controlled Trial (DIRECT) in 322 participants (including 46 with T2D; 52 y of age, body mass index 31 kg/m(2)) throughout rapid weight loss (0-6 mo) and weight-maintenance/regain (7-24 mo) phases. RESULTS: The 2-y increase of high-density lipoprotein cholesterol was greater in participants with T2D (+9.41 versus+6.57 mg/dL, P < 0.05), although they tended to have smaller waist circumferences (-2.1 versus -4.0 cm, P = 0.08). In models adjusted for age, sex, and weight loss, the 2-year decrease of triacylglycerols was associated with increases of low-density and high-density lipoprotein cholesterol. An increase of apolipoprotein A1 was associated with a decrease in high-sensitive C-reactive protein (P < 0.05 for all comparisons). Exclusively in participants with T2D, the 2-year decrease in triacylglycerols was further correlated with decreases in apolipoprotein B100 and liver enzymes, and a decrease in fasting glucose correlated with decreases in low-density lipoprotein cholesterol, apolipoprotein B100, and alanine aminotransferase (P < 0.05 for all comparisons). In the entire group, multivariate models adjusted for age, sex, intervention group, and 6-mo weight loss identified decreased high-sensitive C reactive protein at 6 mo as an exclusive predictor of a greater decrease in triacylglycerols (beta = 0.154, P = 0.008) and a greater increase in high-density lipoprotein cholesterol (beta = -0.452, P = 0.005) during the subsequent 18 mo. CONCLUSIONS: Long-term dietary intervention induces a flow of changes within biomarkers and the cross-talk is likely to be stronger in T2D. A decrease in systemic inflammation during the weight-loss phase may predict greater long-term improvement in lipids (www.ClinicalTrials.gov, identifier NCT00160108). PMID- 21820873 TI - A meta-analysis of polycystic ovary syndrome in women taking valproate for epilepsy. AB - PURPOSE: To conduct a meta-analysis to quantify whether valproate (VPA) is associated with an increased risk of polycystic ovary syndrome (PCOS) in women with epilepsy. METHODS: A comprehensive literature search for all published studies of MEDLINE and EMBASE was performed for English language studies published from 1st January 1990 to 4th February 2011. The studies included should be prospective and controlled. We then performed a meta-analysis to identify polycystic ovary syndrome in women with epilepsy treated with VPA. RESULTS: The meta-analysis included 11 studies that met inclusion/exclusion criteria, involving 556 women with epilepsy treated with VPA, 593 women treated with other antiepileptic drugs (AEDs), 120 women with untreated epilepsy and 329 healthy controls. The calculated incidence of PCOS in women treated with VPA was higher than that in women treated without VPA (10 studies included, P<0.05, OR 3.04, 95% CI 2.09-4.43). According to different definitions or diagnostic criteria of PCOS, the results were different. VPA's treatment was associated with higher incidence of PCOS in the criteria of hyperandrogenism and/or hyperandrogenemia, oligoovulation (4 studies included, P<0.05, OR 3.22, 95% CI 1.79-5.80), and in the criteria of two of the three following fulfilled: appearance of polycystic ovary (PCO) on the ultrasonogram, elevated serum testosterone levels and irregular (oligo-/amenorrhea) menstrual cycles (1 post hoc reanalysis study included, P<0.05, OR 5.01, 95% CI 2.40-10.49. Another prospective and crosssectional included, P<0.05, OR 3.50, 95% CI 1.30-9.40). However, in the criteria of PCO with ovulatory dysfunction (polymenorrhea, amenorrhea, or oligomenorrhea), clinical and/or biochemical evidence of hyperandrogenism according to National Institutes of Child Health and Human Development (NICHHD) and The National Institutes of Health (NIH) Consensus Conference, VPA did not increase the PCOS incidence compared with other AEDs (4 studies included, P>0.05, OR 1.37, 95% CI 0.59-3.19). Data on PCOS's components were pooled. PCO was higher in women treated with VPA than in those without VPA (6 studies included, P<0.05, OR 1.94, 95% CI 1.28-2.95) or in healthy controls (4 studies included, P<0.05, OR 4.99, 95% CI 2.97-8.37). VPA treated women were more subject to hyperandrogenism than non-VPA treated women (5 studies included, P<0.05, OR 2.35, 95% CI 1.57 3.53). There is significant difference of menstrual disorders between VPA treated women and non-VPA treated women (7 studies included, P<0.05, OR 1.64, 95% CI 1.19 2.25). CONCLUSIONS: Results of this meta-analysis suggest that the raw incidence of PCOS in VPA treated women with epilepsy is approximately 1.95 folds that in other AEDs treated women. PCOS and its components may be associated with VPA treated women with epilepsy. We recommend monitoring PCOS and its components in women with VPA mono-/polytherapy. In light of limitations and heterogenicity, there is surely the need for more prospective studies to identify VPA and PCOS. PMID- 21820874 TI - Imputation techniques for the detection of microstructural changes in schizophrenia, with an application to magnetization transfer imaging. AB - Neuroimaging techniques such as magnetization transfer imaging allow the detection of microstructural alterations of tissue, and for this reason have been applied to the study of disorders such as schizophrenia. However, they are also sensitive to partial volume effects arising from mixed compartments, such as those comprising cerebral spinal fluid, which makes separate evaluation of volumetric and structural alterations difficult. Ensuing regional differences in the distribution of data and signal-to-noise ratio add further potential bias to their assessment. In the present study we simultaneously applied tissue segmentation, statistical imputation, and nonparametric inference to address these issues and improve the validity of statistical inference. In a case study of N=32 schizophrenic patients matched to the same number of controls, we compared a standard voxel-based analysis with one supplemented by the imputation technique. We were able to replicate significant results in the imputed analysis and even extend them in the areas not excluded by excessive partial volume effects. Application of segmentation algorithms in this dataset also suggested that partial volume effects from spinal fluid potentially affect inference in most cortical gray matter, unless remedial steps are undertaken. Refined imputation methods may be particularly attractive in future research settings characterized by large samples and the availability of adequate computational resources. PMID- 21820875 TI - Are we addressing the 'right stuff' to enhance adherence in schizophrenia? Understanding the role of insight and attitudes towards medication. AB - BACKGROUND: Despite the fact that medication adherence is among the most important health related behaviors in relapse prevention and recovery in schizophrenia, it is often not sufficiently endorsed by patients. Poor insight and negative attitudes towards medication are risk factors for non-adherence. Their relationship and the influence of more general attitudes towards pharmacotherapy besides attitudes towards antipsychotics have not been fully understood. The present study investigated whether these factors independently influence adherence or whether they mediate one another. METHODS: A cross sectional sample of 150 outpatients completed the Beliefs about Medication Questionnaire. It assesses patients' beliefs about antipsychotic medication in terms of necessity and concerns and more general beliefs about pharmacotherapy in terms of distrust. Additionally, the patients' global awareness of illness (Scale to assess Unawareness of Mental Disorder), and medication adherence (Brief Adherence Rating Scale, Service Engagement Scale) were assessed. RESULTS: Using structural equation modeling, the study found evidence for a mediational model. Awareness of illness contributed to medication adherence via patients' perceived necessity of antipsychotics. The model further revealed a direct negative relationship between concerns regarding antipsychotics and adherence and an indirect negative effect of a general distrust regarding pharmacotherapy and adherence via antipsychotic specific attitudes. CONCLUSION: Interventions to enhance medication adherence may be more effective if they focus on treatment related attitudes rather than on global insight into illness. Clinicians may not only enhance the patients' perceived necessity of antipsychotic treatment but also explore and address concerns and the patients' distrust in pharmacotherapy in a more personalized way. PMID- 21820876 TI - Pre-clinical studies of a new quinolone (UB-8902) against Acinetobacter baumannii resistant to ciprofloxacin. AB - The in vitro activity and in vivo efficacy of a new ciprofloxacin derivative (UB 8902) were evaluated. In vitro time-kill curves were performed for ciprofloxacin (CIP), moxifloxacin (MXF) and UB-8902 against CIP-susceptible (Ab58) and CIP resistant (Ab661 and Ab33) Acinetobacter baumannii strains. UB-8902 showed similar bactericidal activity to CIP and MXF against these strains. In the in vivo experiments in mice, the toxicity of UB-8902, its 50% protective dose (PD(50)) (peritoneal sepsis model), its pharmacokinetic/pharmacodynamic (PK/PD) parameters and its efficacy in a pneumonia model were studied. The maximum tolerated dose of UB-8902 was 512 mg/kg. PD(50) values were 16, 128 and 32 mg/kg for Ab58, Ab661 and Ab33, respectively. Pharmacokinetic parameters of UB-8902 were similar to MXF and were lower than those for CIP, whilst pharmacodynamic parameters were better than CIP. In the pneumonia model, UB-8902 decreased the bacterial lung concentration [4.62 colony-forming units (CFU)/g and 4.15log(10)CFU/g] and positive blood cultures (60% and 62.5%) for Ab58 and Ab33, respectively, compared with the control. In conclusion, UB-8902 presents bactericidal activity against A. baumannii strains resistant to CIP. Moreover, it is effective at reducing mortality in a model of peritoneal sepsis with a dose lower than the toxic one, and it is efficacious in a murine pneumonia model. PMID- 21820877 TI - Activity of ACHN-490 against meticillin-resistant Staphylococcus aureus (MRSA) isolates from patients in US hospitals. AB - The activity of ACHN-490 was evaluated against 493 meticillin-resistant Staphylococcus aureus (MRSA) isolates collected in 2009-2010 from 23 US hospitals. The MIC(50) and MIC(90) values (minimal inhibitory concentrations for 50% and 90% of the organisms, respectively) for ACHN-490 were 1 and 2 MUg/mL compared with 8 and 32 MUg/mL for amikacin, 0.5 and 1 MUg/mL for gentamicin and 2 and >16 MUg/mL for tobramycin. The gene encoding the aminoglycoside-modifying enzyme APH(2")-Ia/AAC(6')-Ie was present in 12% of the subset of 84 isolates examined by polymerase chain reaction (PCR), whilst the gene encoding ANT(4')-Ia was present in 89% of isolates. ACHN-490 activity was not affected by either enzyme. PMID- 21820878 TI - Common and distinct neural correlates of emotional processing in Bipolar Disorder and Major Depressive Disorder: a voxel-based meta-analysis of functional magnetic resonance imaging studies. AB - Neuroimaging studies have consistently shown functional brain abnormalities in patients with Bipolar Disorder (BD) and Major Depressive Disorder (MDD). However, the extent to which these two disorders are associated with similar or distinct neural changes remains unclear. We conducted a systematic review of functional magnetic resonance imaging studies comparing BD and MDD patients to healthy participants using facial affect processing paradigms. Relevant spatial coordinates from twenty original studies were subjected to quantitative Activation Likelihood Estimation meta-analyses based on 168 BD and 189 MDD patients and 344 healthy controls. We identified common and distinct patterns of neural engagement for BD and MDD within the facial affect processing network. Both disorders were associated with increased engagement of limbic regions. Diagnosis-specific differences were observed in cortical, thalamic and striatal regions. Decreased ventrolateral prefrontal cortical engagement was associated with BD while relative hypoactivation of the sensorimotor cortices was seen in MDD. Increased responsiveness in the thalamus and basal ganglia were associated with BD. These findings were modulated by stimulus valence. These data suggest that whereas limbic overactivation is reported consistently in patients with mood disorders, future research should consider the relevance of a wider network of regions in formulating conceptual models of BD and MDD. PMID- 21820879 TI - Duloxetine's modest short-term influences in subcortical structures of first episode drug-naive patients with major depressive disorder and panic disorder. AB - We developed this study to follow up the hanges in subcortical structures after 6 weeks' treatment with therapy of duloxetine in first episode drug-naive patients with major depressive disorder and panic disorder. Fifteen patients received duloxetine 60mg/d therapy for 6 weeks and achieved remission. They all underwent structural magnetic resonance imaging (MRI) of the brain at baseline and week 6. Fifteen healthy controls were also scanned twice at baseline and week 6 to exclude possible biases. Structural MRI data were preprocessed with FMRIB's Integrated Registration and Segmentation Tool function (FIRST version 1.2) of FSL (FMRIB Software Library; version 4.1.1) to perform subcortical segmentations of the brain using a shape and appearance model. Nonparametric corrections of these structural volumes in an F-test between pre- and post-treatment were used to identify the changes after duloxetine therapy. A false discovery correction of the F-test by FIRST was also performed. A paired t-test using SPSS was applied to confirm the changes in these structures. The patients had consistent changes of volumes in bilateral nucleus accumbens, left putamen, left hippocampus and brainstem after 6 weeks of treatment with duloxetine. There were no consistent changes in other subcortical structures. There were modest increases of the volumes of the above areas, which were not significant after false discovery correction by FIRST F-test comparisons. The volumetric increases were correlated with responses of clinical symptoms. The results suggested that duloxetine possibly contributed to modest increases in several subcortical areas of these patients with remission. PMID- 21820880 TI - Total internal reflection imaging of microorganism adhesion using an oil immersion objective. AB - In this paper, we report the results of total internal reflection microscopy investigations of the interaction of two types of microorganisms: Saccharomyces cerevisiae and Escherichia coli with substrates. It is shown that with this method qualitative and quantitative information about cells-substrate interaction can be obtained. One can easily make a difference between attached and non attached as well as between dead and alive cells, and more generally can follow the dynamics of the process of cells' attachment to substrates. Quantitative information about the cell size and cell-substrate distance is obtained by using a model in which yeast cells and bacteria are approximated by ellipsoids, and multiple reflections of the evanescent waves between the cells and the substrate are neglected. PMID- 21820881 TI - The synergistic chaperoning operation in a Bi-chaperone system consisting of alpha-crystallin and beta-casein: bovine pancreatic insulin as the target protein. AB - While chaperone activity of alpha-crystallin (alpha-Crs) is important in maintaining lens transparency that of beta-casein (beta-CN) is vital to prevent the development of corpora amylacea (accumulation of amyloid deposits in mammary glands). These two chaperone proteins are amphiphilic, each contains distinct polar and non-polar regions in the structure. While polar domain of alpha-Crs is highly electropositive, the counterpart domain in beta-CN is strongly electronegative. In this study a Bi-chaperone system consisting of alpha-Crs and beta-CN with different molar ratios were used to prevent the chemical-induced insulin aggregation spectroscopically. As shown, alpha-Crs and beta-CN in the Bi chaperone system exhibit synergistic chaperoning operation which strongly depends to the specific ratio of the chaperone components. The results of both fluorescence study and native gel electrophoresis confirmed the non-covalent interactions between alpha-Crs and beta-CN. Consequently the synergistic activity can be explained with the possible electrostatic interactions between their polar/charged domains which bring them in close proximity, allowing their synergistic chaperoning operation in the Bi-chaperone system. PMID- 21820882 TI - Eurasian wild asses in time and space: morphological versus genetic diversity. AB - The Equidae have a long evolutionary history that has interested palaeontologists for a long time. Their morphology-based taxonomy, however, is a matter of controversy. Since most equid species are now extinct, the phylogenetic tree based on genetic data can be established only imperfectly via deduction of present day genomes and little is known about the past genetic diversity of these species. Recent studies of ancient DNA preserved in fossil bones have led to a simplification of the phylogenetic tree and the classification system. The situation is still particularly unclear for the wild asses whose geographical distribution in the Pleistocene and the early Holocene stretched from Northern Africa to Eurasia before they became endangered or extinct. Therefore, we performed a phylogeographic study of bone remains of wild asses covering their former geographic range over the past 100,000 years based on the analysis of ancient mitochondrial DNA. Here, we will not show but rather discuss our results calling the morphology-based classification into question and indicating that morphological criteria alone can be an unreliable index in inferring various equid species. Indeed, the diversity of mitochondrial lineages in populations with similar morphology along with genetic signatures shared between morphologically distinct animals reveal a significant morphological plasticity among Equus species. The classification of palaeontological species based on morphological and genetic criteria will be discussed. PMID- 21820883 TI - Recycling of WEEE: characterization of spent printed circuit boards from mobile phones and computers. AB - This paper presents a comparison between printed circuit boards from computers and mobile phones. Since printed circuits boards are becoming more complex and smaller, the amount of materials is constantly changing. The main objective of this work was to characterize spent printed circuit boards from computers and mobile phones applying mineral processing technique to separate the metal, ceramic, and polymer fractions. The processing was performed by comminution in a hammer mill, followed by particle size analysis, and by magnetic and electrostatic separation. Aqua regia leaching, loss-on-ignition and chemical analysis (inductively coupled plasma atomic emission spectroscopy - ICP-OES) were carried out to determine the composition of printed circuit boards and the metal rich fraction. The composition of the studied mobile phones printed circuit boards (PCB-MP) was 63 wt.% metals; 24 wt.% ceramics and 13 wt.% polymers; and of the printed circuit boards from studied personal computers (PCB-PC) was 45 wt.% metals; 27 wt.% polymers and ceramics 28 wt.% ceramics. The chemical analysis showed that copper concentration in printed circuit boards from personal computers was 20 wt.% and in printed circuit boards from mobile phones was 34.5 wt.%. According to the characteristics of each type of printed circuit board, the recovery of precious metals may be the main goal of the recycling process of printed circuit boards from personal computers and the recovery of copper should be the main goal of the recycling process of printed circuit boards from mobile phones. Hence, these printed circuit boards would not be mixed prior treatment. The results of this paper show that copper concentration is increasing in mobile phones and remaining constant in personal computers. PMID- 21820884 TI - Self-referencing SPR-biosensors based on penetration difference of evanescent waves. AB - SPR based biosensors register binding of analytes to the surface with immobilized receptors by measuring changes of the refractive index near this surface. An important task in the improvement of this measurement technology is a separation of signals, corresponding to the changes in the chemosensitive layer, from undesired contributions of bulk phase, for example, due to fluctuations of temperature, concentrations of solutes, pressure. The wavelength of the incident light influences strongly the penetration depth of the corresponding evanescent wave. This dependence was exploited here for compensation of the contribution of the bulk refractive index. It was performed using differential SPR measurements at two wavelengths with differing penetration depths. Theoretical analysis and numerical optimization of the suggested approach, named a Penetration Difference Self-Referencing SPR (PDSR-SPR), were performed. Experimental test was performed using 658 and 980 nm laser diodes. Over 20 times suppression of variations of bulk refractive index with magnitude up to 1000 MURIU was observed. Finally, PDSR SPR approach was applied for monitoring of antibodies binding to the immobilized antigens. PMID- 21820885 TI - A label-free electrochemical DNA sensor based on exonuclease III-aided target recycling strategy for sequence-specific detection of femtomolar DNA. AB - The present work demonstrates a rapid, single-step and ultrasensitive label-free and signal-off electrochemical sensor for specific DNA detection with excellent discrimination ability for single-nucleotide polymorphisms, taking advantage of Exonuclease III (Exo III)-aided target recycling strategy to achieve signal amplification. Exo III has a specifical exo-deoxyribonuclease activity for duplex DNAs in the direction from 3' to 5' terminus, however its activity on the duplex DNAs with 3'-overhang and single-strand DNA is limited. In response to the specific features of Exo III, the proposed E-DNA sensor is designed such that, in the presence of target DNA, the electrode self-assembled signaling probe hybridizes with the target DNA to form a duplex in the form of a 3'-blunt end at signaling probe and a 3'-overhang end at target DNA. In this way, Exo III specifically recognizes this structure and selectively digests the signaling probe. As a result, the target DNA dissociates from the duplex and recycles to hybridize with a new signaling probe, leading to the digestion of a large amount of signaling probes gradually. A redox mediator, Ru(NH(3))(6)(3+) (RuHex) is employed to electrostatically adsorbed onto signaling probes, which is directly related to the amount and the length of the signaling probes remaining in the electrode, and provides a quantitative measure of sequence-specific DNA with the experimentally measured (not extrapolated) detection limit as low as 20 fM. Moreover, this E-DNA sensor has an excellent differentiation ability for single mismatches with fairly good stability. PMID- 21820886 TI - Separation and simultaneous detection of anticancer drugs in a microfluidic device with an amperometric biosensor. AB - A simple and highly sensitive method for simultaneous detection of anticancer drugs is developed by integrating the preconcentration and separation steps in a microfluidic device with an amperometric biosensor. An amperometric detection with dsDNA and cardiolipin modified screen printed electrodes are used for the detection of anticancer drugs at the end of separation channel. The preconcentration capacity is enhanced thoroughly using field amplified sample stacking and field amplified sample injection techniques. The experimental parameters affecting the analytical performances, such as pH, temperature, buffer concentration, water plug length, and detection potential are optimized. A reproducible response is observed during multiple injections of samples with a RSD <5%. The calibration plots are linear with the correlation coefficient between 0.9913 and 0.9982 over the range of 2-60 pM. The detection limits of four drugs are determined to be between 1.2 (+/- 0.05) and 5.5 (+/- 0.3) fM. The applicability of the device to the direct analysis of anticancer drugs is successfully demonstrated in a real spiked urine sample. Device was also examined for interference effect of common chemicals present in real samples. PMID- 21820887 TI - Novel 3-dimensional dendrimer platform for glycolipid microarray. AB - Glycolipids are important biological molecules that modulate cellular recognitions and pathogen adhesions. In this paper, we report a sensitive glycolipid microarray for non-covalently immobilizing glycolipids on a microarray substrate and we perform a set of immunoassays to explore glycolipid-protein interactions. This substrate utilizes a three-dimensional hydrazide functionalized dendrimer monolayer attached onto a microscopic glass surface, which possesses the characteristics to adsorb glycoliplids non-covalently and facilitates multivalent attributes on the substrate surface. In the proof-of concept experiments, gangliosides such as GM1, FucGM1, GM3, GD1b, GT1b, and GQ1b, and a lipoarabinomannan were tested on the substrate and interrogated with toxins and antibodies. The resulting glycolipid microarrays exhibited hypersensitivity and specificity for detection of glycolipid-protein interactions. In particular, a robust and specific binding of a pentameric cholera toxin B subunit to the GM1 glycolipid spotted on the array has demonstrated its superiority in sensitivity and specificity. In addition, this glycolipid microarray substrate was used to detect lipoarabinomannan in buffer within a limit-of-detection of 125 ng/mL. Furthermore, Mycobacterium tuberculosis (Mtb) Lipoarabinomannan was tested in human urine specimens on this platform, which can effectively identify urine samples either infected or not infected with Mtb. The results of this work suggest the possibility of using this glycolipid microarray platform to fabricate glycoconjugate microarrays, which includes free glycans and glycolipids and potential application in detection of pathogen and toxin. PMID- 21820888 TI - Color changing block copolymer films for chemical sensing of simple sugars. AB - We investigated the use of functionalized photonic block copolymer films for the detection of glucose. Polystyrene-b-poly(2-vinyl pyridine) (PS-b-P2VP) block copolymers were chemically functionalized with 2-(bromomethyl)phenylboronic acid and cast into films that reflect a visible color when exposed to aqueous media. The 2-(bromomethyl)phenylboronic acid functionality can reversibly bind to glucose. When exposed to high concentrations of glucose the polymer responded with a red shift in color. Low concentration exposure of glucose caused the polymer films to blue shift in color. The BCP films also exhibited a selective response to fructose, mannose or galactose, giving a different response depending on which sugar is present. The color of the polymer was tuned to blue, green, yellow or orange by varying the film's crosslink density. The color change can be visually observed without the use of equipment such as a spectrometer. PMID- 21820889 TI - Power production enhancement with a polyaniline modified anode in microbial fuel cells. AB - In this paper, an approach of improving power generation of microbial fuel cells (MFCs) by using a HSO(4)(-) doped polyaniline modified carbon cloth anode was reported. The modification of carbon cloth anode was accomplished by electrochemical polymerization of aniline in 5% H(2)SO(4) solution. A dual chamber MFC reactor with the modified anode achieved a maximum power density of 5.16 Wm(-3), an internal resistance of 90 Omega, and a start-up time of 4 days, which was respectively 2.66 times higher, 65.5% lower, and 33.3% shorter than the corresponding values of the MFC with unmodified anode. Evidence from X-ray photoelectron spectroscopy and scanning electron microscopy results proved that the formation of biofilm on the anode surface could prevent the HSO(4)(-) doped polyaniline to be de-doped, and the results from electrochemical tests confirmed that the electrochemical activity of the modified anode was enhanced significantly after inoculation. Charge transfer was facilitated by polyaniline modification. All the results indicated that the polyaniline modification on the anode was an efficient approach of improving the performance of MFCs. PMID- 21820890 TI - Simultaneous detection of dual proteins using quantum dots coated silica nanoparticles as labels. AB - Simultaneous detection of multianalytes associated with a particular cancer is beneficial for disease diagnosis. Here, a facile immunosensing strategy was designed to allow simultaneous electrochemical detection of dual proteins, in a single run. CdSe and PbS water-soluble quantum dots (QDs) were prepared and coated on monodisperse silica nanoparticles as labels for proteins detection. Rabbit immunoglobulin G antigen (IgG) and carcinoembryonic antigen (CEA) were chosen as model proteins for analysis. After a typical sandwich immunoassay, CdSe and PbS QDs labels were introduced onto the Au substrates' surface, which were then dissolved and could be simultaneously monitored by square-wave-voltammetric (SWV) stripping measurements. Under selected conditions, IgG and CEA could be assayed in the ranges of 0.05-40 ng mL(-1) and 0.05-25 ng mL(-1), respectively. The proposed method possessed high sensitivity, good precision, and satisfactory reproducibility and regeneration. PMID- 21820891 TI - Apoptosis of lung carcinoma cells induced by a flexible optical fiber-based cold microplasma. AB - Atmospheric pressure plasmas have been used as a therapy for cancer. However, the fairly large size and rigidity of present plasma-delivery systems obstructs the precise treatment of tumors in harder-to-reach internal organs such as the lungs, pancreas, and duodenum. In order to improve the targeted delivery of plasmas a highly flexible microplasma jet device is fabricated using a hollow-core optical fiber with an inner diameter of either 15 MUm, 55 MUm, or 200 MUm. Described herein, based on this device, are results on lung carcinoma therapy using a microplasma cancer endoscope. Despite the small inner diameter and the low gas flow rate, the generated plasma jets are shown to be sufficiently effective to induce apoptosis, but not necrosis, in both cultured mouse lung carcinoma and fibroblast cells. Further, the lung carcinoma cells were found to be more sensitive to plasma treatment than the fibroblast cells based on the overall plasma dose conditions. This work enables directed cancer therapies using on highly flexible and precise hollow optical fiber-based plasma device and offers enhancements to microplasma cancer endoscopy using an improved method of plasma targeting and delivery. PMID- 21820892 TI - Label-free electrochemical measurement of protein tyrosine kinase activity and inhibition based on electro-catalyzed tyrosine signaling. AB - A novel label-free electrochemical method for measuring the activity of protein tyrosine kinases (PTK) has been developed. Epidermal growth factor receptor (EGFR), a typical PTK associated with a large percentage of all solid tumors, was used as the model kinase. Poly(glu, tyr) (4:1) peptide, as a substrate of EGFR, was covalently immobilized on the surface of indium tin oxide (ITO) electrode by silane chemistry. The tyrosine (Tyr) residue in the polypeptide served as an electrochemical signal reporter. Its voltammetric current was catalyzed by a dissolved electron mediator Os(bpy)(3)(2+) (bpy=2,2'-bipyridine) for increased sensitivity. Phosphorylation of the Tyr led to a loss of its electrochemical current, thus providing a sensing mechanism for PTK activity. Experimental conditions for the silanization of ITO surface and immobilization of polypeptide were investigated in details to facilitate the generation of Tyr electrochemical signal. The proposed biosensor exhibited high sensitivity and excellent stability. The limit of detection for EGFR was 1 UmL(-1). Furthermore, this biosensor can also be used for quantitative analysis of kinase inhibition. On the basis of the inhibitor concentration dependent electrochemical signal, the half maximal inhibition value IC(50) of three EGFR inhibitors, PD-153035, OSI-774 and ZD-1839, and their corresponding inhibition constants K(i) were estimated, which were in agreement with those obtained from the conventional kinase assay. This electrochemical biosensor can be implemented in an array format for the high throughput assay of in vitro PTK activity and PTK inhibitors screening for practical diagnostic application and drug discovery. PMID- 21820893 TI - Regenerative Surface Plasmon Resonance (SPR) biosensor: real-time measurement of fibrinogen in undiluted human serum using the competitive adsorption of proteins. AB - Epidemiological studies suggest that elevated plasma fibrinogen levels are associated with an increased risk of cardiovascular disorders. Normal fibrinogen level is in the range of 1.5-4.5mg/mL, depending upon both genetic (intrinsic) and environmental (extrinsic) factors. An increase of 0.25mg/mL from the normal level can often be correlated with a high risk of cardiovascular disease. Thus, it is useful to monitor fibrinogen level in serum of a patient for clinical diagnosis. We report a regenerative biosensor that measures real-time fibrinogen levels in undiluted serum. The biosensor uses Surface Plasmon Resonance (SPR), highly sensitive optical technique. The biosensor does not use bio-receptors (i.e., antibodies, enzymes, DNA, etc.) unlike conventional biosensors, and deploys the nature of competitive adsorption of proteins to achieve selective detection of fibrinogen. We measured fibrinogen-spiked serum samples with a concentration of 1.5-4.5 mg/mL, and repeated six measurement trials to obtain statistical distribution of the measurements using the regeneration method of the sensing surface. The SPR biosensor has a sensitivity of 42 mDeg/(mg/mL) for a fibrinogen concentration in the range of 0.5-2.5 mg/mL, whereas it was hard to correlate the measurements to the spiked-fibrinogen samples of above 2.5 mg/mL. PMID- 21820894 TI - Predictive factors for flatfoot: The role of age and footwear in children in urban and rural communities in South West Nigeria. AB - BACKGROUND: Flatfoot is common in children and its prevalence influenced by several factors. This study investigated the role of age and type of foot wear as predictors of flatfoot in school age children in urban and rural areas in south western Nigeria. METHODS: 560 children between 6 and 12 years, divided into two groups; rural and urban were studied. Each subject's static footprint was taken on a white duplicating paper after which the instep was measured for classification into high arch, normal, flat or severe flat. The BMI of each subject was calculated from the anthropometric data. The type of footwear with which the subjects were shod was also recorded. Data analysis was by Epi Info statistical package version 3.5.1 (2008). RESULTS: Chi-square showed a significant (p<0.05) association between the presence of flatfoot, age and type of footwear. Comparison of the prevalence of flatfoot by age group indicated a significant difference at age 10 years. Simple logistic regressions, however, showed that age was a significant (p<0.05) predictor for flat foot while the type of footwear was not. CONCLUSION: In this study, age is the primary predictor for flatfoot while the type of footwear is not. PMID- 21820896 TI - Experimental study of the anaerobic urban wastewater treatment in a submerged hollow-fibre membrane bioreactor at pilot scale. AB - The aim of this study was to assess the effect of several operational variables on both biological and separation process performance in a submerged anaerobic membrane bioreactor pilot plant that treats urban wastewater. The pilot plant is equipped with two industrial hollow-fibre ultrafiltration membrane modules (PURON(r) Koch Membrane Systems, 30 m2 of filtration surface each). It was operated under mesophilic conditions (at 33 degrees C), 70 days of SRT, and variable HRT ranging from 20 to 6h. The effects of the influent COD/SO4-S ratio (ranging from 2 to 12) and the MLTS concentration (ranging from 6 to 22 g L-1) were also analysed. The main performance results were about 87% of COD removal, effluent VFA below 20 mg L-1 and biogas methane concentrations over 55% v/v. Methane yield was strongly affected by the influent COD/SO4-S ratio. No irreversible fouling problems were detected, even for MLTS concentrations above 22 g L-1. PMID- 21820895 TI - Models of place and grid cell firing and theta rhythmicity. AB - Neuronal firing in the hippocampal formation (HF) of freely moving rodents shows striking examples of spatialorganization in the form of place, directional, boundary vector and grid cells. The firing of place and grid cells shows an intriguing form of temporal organization known as 'theta phase precession'. We review the mechanisms underlying theta phase precession of place cell firing, ranging from membrane potential oscillations to recurrent connectivity, and the relevant intra-cellular and extra-cellular data. We then consider the use of these models to explain the spatial structure of grid cell firing, and review the relevant intra-cellular and extra-cellular data. Finally, we consider the likely interaction between place cells, grid cells and boundary vector cells in estimating self-location as a compromise between path-integration and environmental information. PMID- 21820897 TI - Steam reforming of bio-oil from rice husks fast pyrolysis for hydrogen production. AB - Steam reforming of two kinds of bio-oil from rice husks fast pyrolysis was conducted for hydrogen production at three temperatures (650, 750 and 850 degrees C) with Ni-based catalyst in a fixed-bed reactor. The gas composition and organic compounds in liquid condensate were detected by gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS), respectively. In addition, the carbon deposition was also investigated. The results showed that the mole fraction range of hydrogen was within 55.8-61.3% at all temperatures and more hydrogen was produced at the higher temperature. The highest H2 efficiency of bio oil steam reforming was 45.33% when extra water was added. The bio-oil with lower content of chemical compounds has a higher H2 efficiency, but its hydrogen volume was less. Analysis of the liquid condensate showed that most of the organic compounds were circularity compounds. The carbon deposition can decrease the bio oil conversion, and it was easier to form at the temperature of 750 degrees C. PMID- 21820898 TI - The natural product CCR5 antagonist anibamine and its analogs as anti-prostate cancer agents. AB - Prostate cancer is a leading cause of death among males in the United States. As the chemokine receptor CCR5 is over-expressed in more aggressive forms of prostate cancer, and is also a critical receptor in inflammation, chemokine receptor CCR5 antagonists could potentially act as anti-prostate cancer agents. Anibamine, a natural product CCR5 antagonist, provides a unique molecular scaffold for the generation of novel analogs with possible anti-prostate cancer activity. A series of analogs of anibamine were designed, synthesized and tested against several prostate cancer cell lines. The analogs all acted as CCR5 antagonists at micromolar range affinity to the receptor while their anti proliferative activity varied depending on the cell line type and their chemical structural properties. Further basal cytotoxicity characterization on these compounds indicated some of them may be suitable for in vivo studies. PMID- 21820899 TI - Structure of human caspase-6 in complex with Z-VAD-FMK: New peptide binding mode observed for the non-canonical caspase conformation. AB - Caspase-6 is a cysteine protease implicated in neuronal survival and apoptosis. Deregulation of caspase-6 activity was linked to several neurodegenerative disorders including Alzheimer's and Huntington's Diseases. Several recent studies on the structure of caspase-6 feature the caspase-6 zymogen, mature apo-caspase-6 as well as the Ac-VEID-CHO peptide complex. All structures share the same typical dimeric caspase conformation. However, mature apo-caspase-6 crystallized at low pH revealed a novel, non-canonical inactive caspase conformation speculated to represent a latent state of the enzyme suitable for the design of allosteric inhibitors. In this treatise we present the structure of caspase-6 in the non canonical inactive enzyme conformation bound to the irreversible inhibitor Z-VAD FMK. The complex features a unique peptide binding mode not observed previously. PMID- 21820900 TI - Coffee and muscle cramps. PMID- 21820901 TI - Current research on SMN protein and treatment strategies for spinal muscular atrophy. PMID- 21820902 TI - Ground reaction forces during gait in pregnant fallers and non-fallers. AB - Pregnant women are at a high risk of experiencing a fall. To our knowledge, ground reaction forces (GRFs) in pregnant fallers and non-fallers have not been reported. PURPOSE: The purpose of this study was to examine the effects of pregnancy and fall history on GRFs during walking. METHODS: Forty one pregnant subjects in the mid 2nd and 3rd trimesters (pregnant fallers: n=15, pregnant non fallers: n=14), and 40 control women walked at a freely chosen walking speed along an 8m walkway. A force plate, hidden in the walkway, was used to collect GRFs (1080Hz). Kinematic data (120Hz) were collected from a marker placed on the lumbar spine to estimate walking velocity. GRF variables included mediolateral Center of Pressure (COP) excursion, and GRFs normalized to body mass. A two factor ANOVA (trimester x fall group) was used to compare subject demographics, and walking velocity (alpha=0.05). A two factor ANCOVA (trimester*fall group, covariate: velocity) was performed to examine other GRF variables (Bonferroni corrected alpha=0.006) and the mediolateral COP excursion (alpha=0.05). RESULTS: Walking velocity was greater in the control group (p<0.05). No differences were seen in the GRFs or COP movement between trimesters or between pregnant fallers and non-fallers. CONCLUSIONS: When walking velocity was considered in the statistical model, ground reaction forces are essentially unchanged by pregnancy. PMID- 21820903 TI - CH/pi hydrogen bonds play a role in ligand recognition and equilibrium between active and inactive states of the beta2 adrenergic receptor: an ab initio fragment molecular orbital (FMO) study. AB - We examined CH/pi hydrogen bonds using an ab initio fragment molecular orbital (FMO) method, combined with the CHPI program, to evaluate complexes of active (bound with agonist 1) and inactive (bound with inverse agonist 2) beta2 adrenergic receptor (beta(2)AR) states. In both states, we found that CH/pi hydrogen bonds were present. Subtle changes in the binding pocket between the active and inactive states of beta(2)AR were observed. Comparison of the CH/pi networks in both states suggests that the networks differ at the beta(2)AR core. Recombination of the CH/pi hydrogen bonds occurred during conversion between the two states. We suggest that CH/pi hydrogen bonds play a key role in ligand recognition and conversion between the active and inactive states. PMID- 21820904 TI - Development of a 99Mo/99mTc generator using alumina microspheres for industrial radiotracer applications. AB - A chromatographic (99)Mo/(99m)Tc generator for industrial applications has been developed using alumina microspheres synthesized through sol-gel process to obtain (99m)Tc in both aqueous and non-aqueous media. The sorbent was mesoporous, mechanically strong and possessed high surface area. (99m)Tc could be eluted from generator system using either acetone or 0.9% NaCl solution with appreciably high yields and high radiochemical as well as radionuclidic purity. The facile, versatile generator provides an efficient way to access (99m)Tc at industrial sites for radiotracer applications. PMID- 21820905 TI - Mercury methylation and reduction potentials in marine water: An improved methodology using 197Hg radiotracer. AB - A highly sensitive laboratory methodology for simultaneous determination of methylation and reduction of spiked inorganic mercury (Hg(2+)) in marine water labelled with high specific activity radiotracer ((197)Hg prepared from enriched (196)Hg stable isotope) was developed. A conventional extraction protocol for methylmercury (CH(3)Hg(+)) was modified in order to significantly reduce the partitioning of interfering labelled Hg(2+) into the final extract, thus allowing the detection of as little as 0.1% of the Hg(2+) spike transformed to labelled CH(3)Hg(+). The efficiency of the modified CH(3)Hg(+) extraction procedure was assessed by radiolabelled CH(3)Hg(+) spikes corresponding to concentrations of methylmercury between 0.05 and 4ngL(-1). The recoveries were 73.0+/-6.0% and 77.5+/-3.9% for marine and MilliQ water, respectively. The reduction potential was assessed by purging and trapping the radiolabelled elemental Hg in a permanganate solution. The method allows detection of the reduction of as little as 0.001% of labelled Hg(2+) spiked to natural waters. To our knowledge, the optimised methodology is among the most sensitive available to study the Hg methylation and reduction potential, therefore allowing experiments to be done at spikes close to natural levels (1-10ngL(-1)). PMID- 21820906 TI - Comparative studies of different concretes on the basis of some photon interaction parameters. AB - Different photon interaction parameters viz. linear attenuation coefficient, mass attenuation coefficient, penetration depth, equivalent atomic number, exposure buildup factor have been computed for seven different concretes (ordinary, hematite-serpentine, ilmenite-limonite, basalt-magnetite, ilmenite, steel-scrap and steel magnetite) in the energy region of 0.015-15.0MeV. The computed parameters were studied as a function of incident photon energy, chemical composition and penetration depth of the selected concretes. It has been observed that among the selected concretes, steel magnetite offers maximum value for linear attenuation coefficient, mass attenuation coefficient, equivalent atomic number and least values in terms of penetration depth equivalent to mean free path and exposure buildup factors. Hence, it is concluded that it offers better shielding among the selected concretes. It is expected that in case of any nuclear accident, the presented buildup factor data may be helpful in estimating the effective dose given to people living in buildings constructed from one of the selected concretes. PMID- 21820907 TI - Lessons from a mathematical hypothesis: modification of the endoventricular circular patch plasty. PMID- 21820908 TI - Tricuspid regurgitation in left ventricular assist device patients. PMID- 21820909 TI - Is total debranching a safe procedure for extensive aortic-arch disease? A single experience of 27 cases. AB - OBJECTIVE: Thoracic, arch, and proximal descending thoracic aorta diseases are still considered an enormous challenge. The hybrid approach developed in recent years (supra-aortic trunks debranching and thoracic endovascular repair aortic repair; TEVAR) may improve the morbidity and mortality of the population at risk. The aim of this study was to analyze retrospectively our experience in the hybrid treatment of aortic-arch aneurysms and dissections. METHOD: We carried out a retrospective review of 27 patients who required a surgical debranching of the supra-aortic trunks and a TEVAR in the management of the aortic arch and proximal descending thoracic aortic disease. The aortic lesions included 18 degenerative arch-aortic aneurysms, four complicated aortic dissections, two subclavian artery aneurysms, and three penetrating atherosclerotic ulcers. Technical success was achieved in all patients. RESULTS: The 30-day mortality rate was 11.1% (3/27). Mean follow-up was 16.7 months (range, 1-56), and the survival rate was 77.8%. The endoleaks' rate was 3.7% (1/27), due to a stent-graft migration. CONCLUSION: Hybrid approaches may represent an alternative option in the treatment of complex aortic lesions involving the arch and the proximal descending thoracic aorta in high-risk patients and emergency cases. However, the promising early results need to be confirmed by longer follow-up and larger comparative series. PMID- 21820910 TI - Risk factors of depressive and anxiety symptoms 8 years after coronary artery bypass grafting. AB - OBJECTIVE: The aim was to assess the severity and course of self-reported depressive and anxiety symptoms 8 years after coronary artery bypass grafting (CABG). METHODS: Out of 53 CABG patients, 37 were examined 8 years later (68% men), mean age - 58.2 (SD 9.3) years. They completed the Spielberger State-Trait Anxiety Questionnaire and the Beck Depression Inventory (BDI). Out of the remaining 16 patients, seven died and nine did not respond. RESULTS: The response group had the mean BDI scores of 13.3 (SD 8.0) before CABG and 11.5 (SD 9.5) at follow-up (p = 0.38). Over 37.8% remained depressed. Non-depressed patients before CABG remained free from depressive symptoms further on, whereas depressed patients continued suffering, even 8 years after the operation. Before the operation, the mean anxiety state score was 44.3 (SD 12.0). After CABG (3 months and 8 years), the significant reduction of anxiety symptoms was observed (respectively: p = 0.02, p = 0.01). Postoperative complications, lower physical and mental well-being, somatic symptoms and negative life attitude were related to bad prognosis several years after surgery. CONCLUSIONS: Depressive and anxiety symptoms occurred in many cardiosurgical patients before and after CABG. Good results of the surgical procedure did not cause reduction of depressive symptoms. Anxiety symptoms were much more common perioperatively than depressive ones and decreased significantly after surgery. Preoperative assessment of depressive and anxiety symptoms can indicate the risk group and suggest care proceedings during the rehabilitation period to improve the effectiveness of surgical coronary revascularization. PMID- 21820911 TI - Radial artery patency. PMID- 21820912 TI - Evaluation of coronary allograft vasculopathy using multi-detector row computed tomography: a systematic review. AB - Coronary allograft vasculopathy (CAV) is a significant cause of morbidity and mortality after cardiac transplantation and requires frequent surveillance with catheter-based coronary angiography (CCA). Multi-detector row computed tomography (MDCT) has been shown to be effective in assessing atherosclerosis in native coronary arteries. This article systematically reviews the literature to determine the accuracy of MDCT in CAV assessment. An English-language literature search was performed using EMBASE, OVID, PubMed, and Cochrane Library databases. Studies that directly compared MDCT with CCA and/or IVUS for the detection of coronary artery stenosis or significant intimal thickening in cardiac transplant patients were analyzed. Data were pooled to obtain weighted sensitivities, specificities, and diagnostic accuracies. Negative and positive predictive values (NPV/PPV) were calculated. A total of seven studies with a sum of 272 patients were included in this review. There were three studies examining 16-slice MDCT and four studies looking at 64-slice MDCT in CAV. Using per-segment analysis, MDCT assessed between 91% and 96% of all coronary segments when evaluating for stenosis. Pooled estimates for sensitivity and specificity for MDCT ranged from 82% to 89% and 89% to 99%, respectively, while NPV was 99%. Per-patient analysis revealed a sensitivity of 87-100% and NPV of 96-100%. PPV was less than 50% for 64-slice MDCT in both per-segment and per-patient analysis. When compared with IVUS, MDCT had a sensitivity of 74-96% and specificity of 88-92% in assessment of intimal thickening. NPV and PPV were 80-81% and 84-98%, respectively. The high sensitivity and NPV of MDCT suggest that it may be a useful, noninvasive screening tool to rule out CAV. PMID- 21820913 TI - The elusive link between aortic wall histology and echocardiographic anatomy in bicuspid aortic valve: implications for prophylactic surgery. AB - OBJECTIVE: Prediction of aortic dissection or rupture is extremely difficult in patients with bicuspid aortic valve. We aimed to identify clinical and echocardiography predictors of histological abnormalities of the aortic wall in patients with bicuspid aortic valve undergoing aortic surgery. METHODS: We assessed the histology of the aortic wall and clinical and echocardiography variables in a cohort of patients with bicuspid aortic valve (n = 127) and a wide spectrum of valvar disease who underwent replacement of the ascending aorta (with or without aortic valve surgery). Histology was classified using a 5-grade system developed by Larson and Edward. RESULTS: Histological alterations of the aortic wall were absent/mild (grade 0-1) in 77 patients (61%) and moderate/severe (grade 2-3) in 50 (39%). Patients with moderate/severe histological alterations were younger (47 +/- 17 vs 53 +/- 16; p = 0.042). Eighteen patients out of 48 (38%) with an ascending aorta diameter <= 4.5 cm had grade 2-3 aortic wall disease as did 8 out of 18 (44%) with a diameter <= 4 cm. Nineteen out of 46 (41%) patients with a maximal ascending aortic area/height ratio < 10 cm(2) m(-1) had moderate/severe histological alterations. Multivariate logistic regression analysis showed that the indexed diameter of the aortic annulus was significantly associated with grade 2-3 aortic wall disease (odds ratio (OR): 12.22, 95% confidence interval (CI): 1.65-90.38, p = 0.014). CONCLUSIONS: A high proportion of patients with bicuspid aortic valve and mild to moderate aortic dilatation have severe histological abnormalities of the aortic wall that are not predictable by clinical and echocardiographic findings. These observations suggest that risk stratification for aortic dissection or rupture in patients with bicuspid aortic valve is so far quite suboptimal and future investigations are warranted. PMID- 21820914 TI - Valve surgery in a mucopolysaccharidosis type I patient: early prosthetic valve endocarditis. AB - Mucopolysaccharidosis (MPS) are rare genetic disorders, caused by enzymatic defects that lead to abnormal glycosaminoglycan metabolism and its accumulation. Hurler-Scheie syndrome (MPS I) is associated with a deficiency of the lysosomal enzyme alpha-L-iduronidase. Enzymatic replacement with intravenous laronidase is a frequently utilized therapeutic option. In patients with MPS I, progressive glycosaminoglycan storage in the heart can lead to valvular abnormalities; however, few surgical heart valve interventions have been reported in MPS I patients. We present an unusual case of a double-valve replacement in an MPS I patient, complicated by early infective endocarditis requiring surgical reintervention. We also present a comprehensive literature review of valve surgery in patients with MPS I and a brief summary of the most relevant surgical considerations, including valve selection and infection prevention. PMID- 21820915 TI - Analysis of CCR5 and CX3CR1 gene polymorphisms in association with unexplained recurrent miscarriages among north Indian women. AB - CONTEXT: Recurrent miscarriage (RM), defined as three or more consecutive losses before the 20th week of gestation, affects 0.5-2% of pregnant women. In over 80% of cases, RM remains unexplained after investigations, suggesting the involvement of genetic factors. OBJECTIVES: The present study investigates the common polymorphisms of chemokine receptors CCR5 (NG_012637.1:g.5303A>G) and CX3CR1 (NG_016362.1:g.21065C>T, Thr280Met and NG_016362.1:g.20971G>A, Val249Ile) and their association with recurrent miscarriages (RM) among north Indian women. PARTICIPANTS AND METHODS: In a retrospective case-control study 200 well characterized patients with unexplained RM and 300 controls were genotyped for three polymorphic markers of CCR5 and CX3CR1 by restriction digestion of PCR amplified fragments. RESULTS: Alleles and genotypes of CX3CR1 Val249Ile revealed statistically significant associations with RM cases when compared with the controls. The homozygous variant genotype Ile/Ile was found to be significantly higher among patients (p=0.0002) when compared with the homozygous wild type Val/Val genotype. The haplotype of CX3CR1 that carried major alleles of Thr280Met and Val249Ile (T-V) showed statistically significant protective association (p<0.0001, OR=0.41, 95% CI=0.31-0.54). The haplotype A-T-V (all wild type alleles) revealed a statistically significant protective association (p<0.0001, OR=0.41, 95% CI=0.34-0.62), whereas the haplotypes G-T-I, A-T-I and A-M-V modified the risk of RM 1.9-fold, 5.5-fold and 5.1-fold respectively. CONCLUSIONS: A common polymorphism of CX3CR1 gene, Val240Ile is associated with the risk of RM in north Indian women. Risk of RM may also be modified by the presence of haplotypes T-I, M-V, G-T-I, A-T-I and A-M-V. PMID- 21820916 TI - Chemokines plasma levels in preterm newborns of preeclamptic mothers. AB - Information on leukocyte activation in newborn infants of preeclamptic mothers is scarce. IL-8 and GRO-alpha are the main pro-inflammatory cytokines involved in leukocyte activation. The objective was to evaluate IL-8 and GRO-alpha plasma levels in preterm newborns infants of preeclamptic mothers. Newborns with gestational age<36 weeks and birth weight<2000 g were included and divided: non preeclamptic (n=64) and preeclamptic groups (n=55). Exclusion criteria were major congenital malformations, inborn errors of metabolism or chromosomal anomalies, congenital infections, death in delivery room, and maternal chronic hypertension without preeclampsia. IL-8 and GRO-alpha were measured by enzyme immunoassay in the first 48 h. Groups were similar in birth weight, gestational age, Apgar scores at 5 min, sepsis, RDS, mechanical ventilation, TPN, NEC, intraventricular hemorrhage and death. The preeclamptic group had more neutropenia, SGA, cesarean section, and less rupture of membranes>18 h. IL-8 was higher in the non preeclamptic [157.1 pg/mL (86.4-261.3) and 26.54 pg/mL (3.6-87.2) p<0.001]. GRO alpha levels were similar in both groups [229.5 pg/mL (116.6-321.3) and 185.5 pg/mL (63.9-306.7) p=0.236]. After multiple regression analysis only absence of preeclampsia was associated with high IL-8 levels. Our data suggest that leukocyte activation may be impaired in infants of preeclamptic mothers. PMID- 21820917 TI - Clinical perspectives for regulatory T cells in transplantation tolerance. AB - Three main types of CD4+ regulatory T cells can be distinguished based upon whether they express Foxp3 and differentiate naturally in the thymus (natural Tregs) or are induced in the periphery (inducible Tregs); or whether they are FoxP3 negative but secrete IL-10 in response to antigen (Tregulatory type 1, Tr1 cells). Adoptive transfer of each cell type has proven highly effective in mouse models at preventing graft vs. host disease (GVHD) and autoimmunity. Although clinical application was initially hampered by low Treg frequency and unfavorable ex vivo expansion properties, several phase I trials are now being conducted to assess their effect on GVHD following hematopoietic stem cell transplantation (HSCT) and in type I diabetes. Human Treg trials for HSCT recipients have preceded other indications because GVHD onset is precisely known, the time period needed for prevention relatively short, initial efficacy is likely to provide life-long protection, and complications of GVHD can be lethal. This review will summarize the clinical trials conducted to date that have employed Tregs to prevent GVHD following HSCT and discuss recent advances in Treg cellular therapy. PMID- 21820918 TI - Ulcerated carotid plaques with ultrasonic echolucency are causatively associated with thromboembolic cerebrovascular events. AB - The presence of ulcerated carotid plaques is a risk factor for ischemic stroke, which is associated with thromboembolism. We evaluated the relationship between ulcerated carotid plaques and cerebrovascular events in patients with acute ischemic stroke or transient ischemic attack. We extracted 48 consecutive patients with ulcerated carotid plaques from a cohort of 1111 patients with acute ischemic stroke or transient ischemic attack. All patients were evaluated by carotid ultrasonography and diffusion-weighted magnetic resonance imaging. We defined thromboembolic events by excluding potential cardiac sources of embolism, stroke in posterior circulation, contralateral lesions, and single and small (<1.5 cm) subcortical lesions, and we considered the remaining patients with cortical lesions or multiple or large subcortical lesions as having experienced a thromboembolic cerebrovascular event. We compared ultrasonographic findings in the patients with and those without a thromboembolic cerebrovascular event. A relationship with thromboembolic events was suspected in 10 patients (21%) with ulcerated carotid plaques. The proportion of smokers was significantly higher in the group of patients with a thromboembolic event (90% vs 53%; P = .03). Logistic regression demonstrated a significant association between thromboembolic events and the presence of echolucent ulcerated plaques (odds ratio, 9.34, 95% confidence interval, 1.65-53.0), even though maximum intima-media thickness and other variables of ulcerated plaques (eg, depth of ulcers, thickness of the plaque, or the degree of stenosis) did not differ significantly between the 2 groups. Our findings indicate that although cerebrovascular events are closely associated with echolucent ulcerated carotid plaques, the prevalence of thromboembolism was not very high (~20%) in our cohort of Japanese patients with ulcerated carotid plaques. PMID- 21820919 TI - Hospital prenotification of stroke patients by emergency medical services improves stroke time targets. AB - BACKGROUND: Prenotification to hospitals by emergency medical services of patients with suspected stroke is recommended to reduce delays in time-dependent therapies. We hypothesized that hospital prenotification would reduce recommended stroke time targets. METHODS: We used the Robert Wood Johnson University Hospital (RWJUH) Brain Attack Database, which includes demographic and clinical data on all emergency department (ED) patients alerted as a Brain Attack between January 1, 2009 and June 30, 2010. Outcome variables included the time from door to stroke team arrival, computed tomographic (CT) scan completion, CT scan interpretation, electrocardiogram, laboratory results, treatment decision, and intravenous (IV) tissue plasminogen activator (tPA) administration. The primary independent variable was brain attack activation before arrival to the emergency department (ED; prenotification) versus on or after ED arrival (no prenotification). Analysis of covariance was used with patient predictors as covariates in addition to the one of interest (prenotification vs no prenotification). P <= .05 was considered statistically significant. RESULTS: There were 229 patients (114 prenotification and 115 no prenotification) alerted as having a brain attack within the study period. Patients with prehospital notification were older (69.5 years vs 61.5 years; P = .0002), had more severe strokes (National Institutes of Health Stroke Scale score of 11.1 vs 6.9; P < .0001), and received IV tPA twice as often (27% vs 15%; P = .024). Prenotification resulted in a significant reduction in all stroke time targets except door to treatment decision and tPA administration. CONCLUSIONS: Prehospital notification of suspected stroke patients reduces time to stroke team arrival, CT scan completion, and CT scan interpretation. IV thrombolysis occurred twice as often in the prenotification group. PMID- 21820920 TI - Remifentanil in cardiac surgery: a meta-analysis of randomized controlled trials. AB - OBJECTIVE: The authors conducted a review of randomized controlled trials to identify advantages in clinically relevant outcomes in patients undergoing cardiac surgery with remifentanil. DESIGN: Meta-analysis. SETTING: Hospitals. PARTICIPANTS: A total of 1,473 patients from 16 randomized trials. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULT: PubMed, BioMedCentral, and conference proceedings were searched (updated May 2010) for randomized trials that compared remifentanil with fentanyl or sufentanil in cardiac anesthesia. Four independent reviewers performed data extraction, with divergences resolved by consensus. Overall analysis showed that the use of remifentanil was associated with a significant reduction in postoperative mechanical ventilation (WMD = -139 min [ 244, -32], p for effect = 0.01, p for heterogeneity < 0.001, I(2) = 89%); length of hospital stay (WMD = -1.08 days [-1.60, -0.57], p for effect < 0.0001, p for heterogeneity = 0.004, I(2) = 71%); and cardiac troponin-I release (WMD = -2.08 ng/mL [-3.93, -0.24], p for effect = 0.03, p for heterogeneity < 0.02, I(2) = 74%). No difference was noted in mortality (3/344 [0.87%] in the remifentanil group vs [1.06%] the control group, OR 0.76 [0.17-3.38], p for effect = 0.72, p for heterogeneity = 0.35, I(2) = 5%). CONCLUSIONS: Remifentanil reduces cardiac troponin release, time of mechanical ventilation, and length of hospital stay in patients undergoing cardiac surgery. PMID- 21820921 TI - Tomosynthesis-based imaging of the breast. PMID- 21820922 TI - Elective endovascular vs. open repair for abdominal aortic aneurysm in patients aged 80 years and older: systematic review and meta-analysis. AB - OBJECTIVES: Endovascular treatment (EVAR) of abdominal aortic aneurysm (AAA) is thought to be of benefit, particularly in patients aged >=80 years. This issue was investigated in the present meta-analysis. DESIGN: The study design involved a systematic review of the literature and meta-analysis. METHODS: Systematic review of the literature and meta-analysis of data on elective EVAR vs. open repair of AAA in patients aged >=80 years were performed. RESULTS: Six observational studies reporting on 13,419 patients were included in the present analysis. Pooled analysis showed higher immediate postoperative mortality after open repair compared with EVAR (risk ratio 3.87, 95% confidence interval (CI) 3.19-4.68; risk difference, 6.2%, 95%CI 5.4-7.0%). The pooled immediate mortality rate after open repair was 8.6%, whereas it was 2.3% after EVAR. Open repair was associated with a significantly higher risk of postoperative cardiac, pulmonary and renal complications. Pooled analysis of three studies showed similar overall survival at 3 years after EVAR and open repair (risk ratio 1.10, 95%CI 0.77 1.57). CONCLUSIONS: The results of this meta-analysis suggest that elective EVAR in patients aged >=80 years is associated with significantly lower immediate postoperative mortality and morbidity than open repair and should be considered the treatment of choice in these fragile patients. These results indicate also that, when EVAR is not feasible, open repair can be performed with acceptable immediate and late survival in patients at high risk of aneurysm rupture. PMID- 21820923 TI - Origins and function of 3-ribosylurate in bovid erythrocytes. AB - 3-Ribosylurate is a dominant feature on high performance liquid chromatography (HPLC) profiles of acid extracts of erythrocytes from cows and buffalo, but is HPLC-undetectable in acid extracts of erythrocytes from all other species examined to date. Various aspects of this unique low molecular weight substance remain unexplored since it was first identified. In this study, the mutation(s) responsible for the appearance of ribosylurate in these cells is shown to be specific to members of both tribes of the Bovinae subfamily (Bovidae family), being detectable in the erythrocytes of both the cow and the buffalo (Bovini tribe) as well as in the kudu (Strepsicerotini tribe), but not in representative species from the other subfamilies of the Bovidae family. More specifically, expression of the mutation(s) seems to be restricted to the erythrocyte lineage of these species, ribosylurate being undetectable in cow white blood cells and primary cultures of fibroblasts. Novel evidence is presented that ribosylurate has antioxidant activity. Accumulation of high levels specifically within the haemoglobin-rich milieu of circulating erythrocytes may serve to protect perfused tissues by removing pathophysiological levels of hydrogen peroxide from plasma. Maintenance of ribosylurate levels may be important in conditions associated with oxidative stress in Bovinae. PMID- 21820924 TI - Evaluation of the association between GHR exon 3 polymorphism and polycystic ovary syndrome among Han Chinese women. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) and type 2 diabetes (T2D) are two common metabolic disorders in reproductive-aged women, and both are associated with insulin resistance. Evidence has indicated that the growth hormone receptor (GHR) exon 3 polymorphism is associated with T2D and the GHRd3 allele may have the preventive effect on the disease. However, the genetic effect of this polymorphism on PCOS is unknown. The present study thus aims to evaluate the association between the GHR exon 3 polymorphism and PCOS. DESIGN: A total of 432 patients with PCOS and 441 healthy control subjects were included. All of them were Han Chinese women and well characterized. Genotyping experiments of GHR exon 3 polymorphism were performed with a standard protocol of PCR and gel electrophoresis. RESULTS: GHRd3 allele frequency in PCOS patients was significantly higher compared to the control subjects (19.1% vs. 14.3%; P=0.007, OR=1.416; 95% CI=1.099-1.825). Further analyses indicated that the GHRd3 allele was associated with increased waist and hip circumstance in healthy women (P=0.016; 0.003), and also with 1-h, 2-h and area under the curve (AUC) plasma glucose levels among PCOS patients (all P<0.05). But, no association of GHR exon 3 polymorphism with insulin resistance in the patients was observed. CONCLUSIONS: The present study provides the first evidence that GHR exon 3 polymorphism is associated with PCOS in Han Chinese women. The GHRd3 allele may contribute to an impact of glucose metabolism but not insulin resistance. PMID- 21820925 TI - Safety and palatability of polyethylene glycol 3350 as an oral laxative in cats. AB - Recurrent constipation is a common problem in cats. Laxatives often are the cornerstone for management of recurrent constipation; however, there is a paucity of published research on laxative use in cats. This study investigated the safety and palatability of polyethylene glycol (PEG3350) in normal cats. All cats consumed the PEG3350 laxative for 4 weeks without changes in weight or food intake. In all cats soft stools were achieved. Effective doses varied widely in experimental cats, so individualized dosing is important. Mild, non-clinical hyperkalemia was noted although the cause is unknown. PMID- 21820926 TI - Concurrent infection with Cryptococcus neoformans/gattii species complex and Mycobacterium avium affecting the subcutis and bone of a pelvic limb in a cat. AB - This paper describes a cat with severe localised infections with Cryptococcus neoformans/gattii species complex and Mycobacterium avium affecting the subcutis and underlying fascia and bone of the right pelvic limb. The simultaneous isolation of both pathogens in this patient was unexpected and posed unique issues concerning both diagnosis and clinical management. The aetiopathogenesis of this infection is discussed in relation to aspects of diagnosis and therapy. PMID- 21820927 TI - Avulsion of the lateral head of the gastrocnemius muscle in a cat. AB - A 7-year-old male, castrated, domestic shorthair cat was presented with a plantigrade stance of the left pelvic limb. An avulsion of the lateral head of the gastrocnemius muscle was diagnosed based on clinical examination and radiographic assessment. Surgical reduction and fixation were achieved with modified locking loop sutures through bone tunnels in the supracondylar tuberosity of the distal femur. Additionally, a temporary calcaneotibial positional screw was placed in order to neutralise forces on the gastrocnemius muscle. No postoperative complications were encountered and the cat made a full recovery. PMID- 21820928 TI - Modelling the influence of thermal effects induced by radio frequency electric field on the dynamics of the ATPase nano-biomolecular motors. AB - We model the dynamics of the F(0) component of the F(0)F(1)-ATPase mitochondrion based nano-motor operating in a stochastically-fluctuating medium that represents the intracellular environment. The stochastic dynamics are modeled via Langevin equation of motion wherein fluctuations are treated as white noise. We have investigated the influence of an applied alternating electric field on the rotary motion of the F(0) rotor in such an environment. The exposure to the field induces a temperature rise in the mitochondrion's membrane, within which the F(0) is embedded. The external field also induces an electric potential that promotes a change in the mitochondrion's transmembrane potential (TMP). Both the induced temperature and the change in TMP contribute to a change in the dynamics of the F(0). We have found that for external fields in the radio frequency (RF) range, normally present in the environment and encountered by biological systems, the contribution of the induced thermal effects, relative to that of the induced TMP, to the dynamics of the F(0) is more significant. The changes in the dynamics of the F(0) part affect the frequency of the rotary motion of the F(0)F(1)-ATPase protein motor which, in turn, affects the production rate of the ATP molecules. PMID- 21820929 TI - [Specific considerations on the prescription and therapeutic interchange of statins]. AB - OBJECTIVE: The pharmaceutical industry currently offers six different statins in Spain and there is one more soon to be available. Choosing the most appropriate drug and dose is determined by the therapeutic target (reduction in LDL-C levels). Statin doses that decrease LDL-C at the same percentage are considered equivalent. Evaluating the pharmacokinetic characteristics of each statin can be useful when setting selection criteria, helping to determine which statin may be more appropriate for a patient based on their individual characteristics and on the other co-administered drugs. METHODS: We reviewed the pharmacokinetics properties of each statin and its possible involvement in drug interactions. RESULTS: CYP3A4 was responsible for the metabolism of lovastatin, simvastatin and atorvastatin; fluvastatin depends on CYP2C9; P-glycoprotein is responsible for decreased atorvastatin, pravastatin, simvastatin and lovastatin concentrations. The OATPA1B1 transporter involved in all statins' access to the hepatocyte, except for fluvastatin, is essential for rosuvastatin and pravastatin. These circumstances cause those drugs inhibiting or inducing isoenzymes or transporters' activity not to have the same effect on the different statins. CONCLUSION: The pharmacokinetics is important when choosing the best statin and could be a limitation in the use of interchange therapeutic programmes when other drugs are present. PMID- 21820930 TI - [Discontinuation and long-term adherence to beta interferon therapy in patients with multiple sclerosis]. AB - OBJECTIVE: To determine discontinuation rate and degree of adherence to first line treatment with interferon-beta (INFbeta) in patients with multiple sclerosis (MS), identifying causes and associated factors. MATERIAL AND METHOD: A retrospective observational study that included patients with MS treated with INFbeta during 2001. The patients were followed-up from the beginning of treatment until the end of 2006. The data sources used were a computer database compiled in the outpatients' area, medical records and application protocols for beginning and monitoring treatment for MS. Patient characteristics at baseline, treatment and continuity were included in the information collected. RESULTS: The study included 131 patients. Mean follow-up was 74 +/- 26 years. 641% of the patients were treated with only one drug during the study. At 2 years follow-up 99% of patients had discontinued INFbeta therapy and at 5 years 412% had done so. Men, patients with relapsing-remitting MS and those treated with INFbeta1a i.m. continued treatment for a longer period, but this was statistically significant only in patients with 10 years or less of disease progression at the beginning of therapy. Main causes of discontinuation were lack of efficacy (388%) and adverse effects (328%). Compliant patients presented lower discontinuation rates (558% vs. 75%). CONCLUSIONS: treatment of MS patients with IFNbeta is discontinued mainly due to lack of efficacy and adverse effects. Greater understanding of patients' views can help to identify those at greatest risk of lack of adherence, thereby helping to improve treatment. PMID- 21820931 TI - [Postoperative radiotherapy in non-small cell lung cancer]. AB - Postoperative radiotherapy remains controversial in non-small cell lung cancer. The conclusions of several meta-analysis are still questioned, partly because of flaws in the randomized trials taken into account. The technological improvements of modern radiotherapy and several clinical observations have led to the launch of a new phase III trial. PMID- 21820932 TI - [The future of breast cancer radiotherapy: From one size fits all to taylor-made treatment]. AB - Various subgroups of breast tumours have been identified during the last 10 years according to the risk of local relapse. Prognostic factors for local relapse are age, surgical margins, tumour size, Her2 expression and hormonal receptors status. For tumours with a high risk of local relapse, an increased in boost dose or the addition of new drugs (trastuzumab, antiangiogenics, PARP inhibitors) could be considered. For low risk tumours, hypofractionated, accelerated partial breast and intraoperative radiotherapy are being evaluated. The classical schedule (45-50 Gy to the whole gland followed by a boost dose of 16 Gy) is no longer the universal rule. Treatment individualization, according to clinical and biological characteristics of the tumour and - possibly - to the radiobiological profile of the patient, is likely to be the future of breast cancer radiotherapy. PMID- 21820933 TI - [Management of inflammatory breast cancer after neo-adjuvant chemotherapy]. AB - PURPOSE: To assess the benefit of breast surgery for inflammatory breast cancer. PATIENTS AND METHODS: This retrospective series was based on 232 patients treated for inflammatory breast cancer. All patients received primary chemotherapy followed by either exclusive radiotherapy (118 patients, 51%) or surgery with or without radiotherapy (114 patients, 49%). The median follow-up was 11 years. RESULTS: The two groups were comparable apart from fewer tumors smaller than 70 mm (43% vs 33%, P=0.003), a higher rate of clinical stage N2 (15% vs 5%, P=0.04) and fewer histopathological grade 3 tumors (46% vs 61%, P<0.05) in the no-surgery group. The addition of surgery was associated with a significant improvement in locoregional disease control (P=0.04) but with no significant difference in overall survival rates or disease-free intervals. Late toxicities were not significantly different between the two treatment groups except for a higher rate of fibrosis in the no-surgery group (P<0.0001), and more lymphedema in the surgery group (P=0.002). CONCLUSION: Our data suggest an improvement in locoregional control in patients treated by surgery, in conjunction with chemotherapy and radiotherapy, for inflammatory breast cancer. PMID- 21820934 TI - Associations of vitamin D receptor gene polymorphisms FokI and BsmI with susceptibility to rheumatoid arthritis and Behcet's disease in Tunisians. AB - OBJECTIVES: Reports of immunomodulating effects of vitamin D suggest a need for examining allele and genotype frequencies of the vitamin D nuclear receptor gene (VDR) in patients with autoimmune diseases. T-helper-1 (Th1) counts in peripheral blood are increased in both rheumatoid arthritis (RA) and Behcet's disease (BD). We studied VDR polymorphisms in patients with these two diseases in Tunisia. METHODS: In 108 patients with RA, 131 patients with BD, and 152 controls, we studied FokI and BsmI VDR polymorphisms, using the restriction fragment length polymorphism technique. RESULTS: The FokI polymorphism alleles and genotype were significantly more common in the RA group than in the controls (P=0.001 and P=0.005, respectively). The FokI F allele and F/F genotype were significantly associated with BD (P=0.0003 and P=0.002, respectively). Furthermore, in the group with BD, the FokI polymorphism was significantly associated with the presence of vascular manifestations (P=0.006). In patients with RA, the FokI polymorphism was significantly associated with female gender (P=0.003). No significant associations were found between the Bsm1 polymorphism and RA or BD. CONCLUSION: The VDR F allele is associated with RA and BD in Tunisians. PMID- 21820935 TI - [Intramedullary pinning of the radius in acute Galeazzi's fractures in adults: 23 case reports]. AB - OBJECTIFS: Consensual treatment of the Galeazzi's fracture is a plate osteosynthesis of the radius more or less associated to the confection of a plaster cast in distal radio-ulnar joint (DRUJ) dislocation. The authors are reporting in this study the clinical and functionnal results of the intra medullary pinning of the radius in this type of fracture in adult. METHODS: During a prospective study from January 2003 to December 2006, 23 patients (20 men and three women), average-aged of 32 years (16-70 years) presenting with a Galeazzi's fracture were treated by an intra-medullary pinning of the radius. The DRUJ dislocations were locked 17 times by a brachio-ante-brachio-palmar plaster cast in the supination position, and six times by an ulno-radial pinning. Only the 16 over-aged patients presenting with closed recent fractures were included in this study. The DRUJ dislocation was ranked according to Mansat, the radial fracture according to Muller (AO). The assessment of the treatment results used Mestdagh's criteria. In this study, each pseudarthrosis of the radius was considered as a failure. RESULTS: The DRUJ dislocation was reparted into six sprains, eight subdislocations, and three Galeazzi's fracture equivalents. The radius fractures were simple (n=20) or wedge fractures (n=3). These fractures were located at the proximal third (n=13), middle third (n=7) and distal third (n=3). The average consolidation delay was 10 weeks (8 to16 weeks). Two pseudarthrosis have been observed and then treated by a plate osteosynthesis. At the mean follow up of 37 months (18 to 41 months), the mean score according to Mestdagh was 7.8 points, with 20 satisfying results. Nineteen patients were satisfied by their treatment; the reasons were: the esthetic care of their scar, and the good functionnal resumption, as well as before the fracture. CONCLUSION: The intra-medullary pinning of radius in Galeazzi's fractures, in contrary to the previous studies, give good results compared to a plate osteosynthesis treatment. The systematic complementary lock by brachio-ante-brachio-palmar plaster cast during 3 to 4 weeks has balanced the stability defect that Mikic was reproaching to it. Moreover, it confers the benefits of elastic closed osteosynthesis. That less simple and less expensive method represents an alternative to a plate osteosynthesis in Galeazzi's fractures in adult, if it is well standardized. PMID- 21820936 TI - [External validation of simple ultrasound rules of Timmerman on 122 ovarian tumors]. AB - OBJECTIVE: To study the correlation between the nature of the ovarian tumors presumed according to the ultrasound criteria of Timmerman and the final histological diagnosis. PATIENTS AND METHODS: We made a prospective study during a period of 4 years, concerning consecutive patients having an ovarian tumor, investigated by pelvic ultrasonography using Timmerman's rules estimating their benign or malignant characteristics in order to determine the efficiency of this score. The diagnostic reference was histology. Sensitivity and specificity of these criteria were calculated with their 95% confidence intervals. RESULTS: One hundred and twenty-two patients having adnexal masse were included between January 2002 and December 2005. Among these tumors, 88.5% (108/122) were benign, and 11.5% (14/122) were malignant or borderline. The ultrasound-based rules of classification were applicable for 89.3% (109/122) of them. The sensitivity of these rules was 73% (95% CI [45-100]) and the specificity was 97% (IC 95% CI [94 100]). DISCUSSION AND CONCLUSION: Most adnexal masses can be classified according to the ultrasound simple rules of the score of Timmerman with a good specificity to eliminate their malignant or borderline characteristics. Tumors which cannot be classified according to these rules must be referred to an expert ultrasonographist. PMID- 21820937 TI - [Should a laparoscopy be necessary in case of infertility with normal tubes at hysterosalpingography?]. AB - The aetiological assessment of an infertile couple includes several complementary biological and morphological examinations. Initial exploration of the female genital tract requires the performance of pelvic ultrasound and hysterosalpingography. The value of systematic laparoscopy in infertility assessment is still subject to debate. The aim of the present review is to evaluate arguments against the systematic use of laparoscopy and to define the place of the other tests as Chlamydia Trachomatis serology, hysterosalpingosonography and MR-IRM. In our opinion, laparoscopy is of course indicated in infertility assessments not only when anomalies are revealed by hysterosalpingography but also in the following circumstances: past history of infection (especially a positive Chlamydia antibody blood test) and/or pelvic surgery (a significant risk of adhesions), unexplained secondary infertility, unexplained infertility after the age of 38 (when choosing between artificial insemination and direct enrolment in an IVF programme) and failure of 3 cycles of good-quality intra-uterine inseminations (with ovarian stimulation and a sufficient number of spermatozoids). PMID- 21820938 TI - Global parameter of ultrasound exploitation (GPUE) in the reactors for wastewater treatment by sono-Fenton oxidation. AB - Modeling of the sonochemical reactors presents a great challenge due to issues related to the experimental investigation and description of the primary effects of the ultrasound. The main idea proposed in this work was to establish an algorithm consisting of the viable laboratory analyses and basic elements of chemical reaction engineering. In this paper, a novel modeling approach is presented. Proposed approach is characterized by the following; ultrasound was investigated as an auxiliary source of energy and the kinetic constants determined for the basic oxidation reactions, i.e. Fenton type oxidation were treated as independent of the ultrasound. Sonochemical effectiveness factor is expressed as a global parameter of the ultrasound exploitation (GPUE) that was introduced in the kinetic model as the e(US) factor. Factor e(US) is modeled as a function of employed frequency, actual power of the transducer, portion of the cavitationally active zone, i.e. dimensionless active volume and the average temperature in the reactor. Lumped system has been assumed. In order to obtain all the necessary data, the experimental study included different sets of experiments. The kinetics of the sonochemical processes, e.g. US/Fe(2+)/H(2)O(2), US/Fe(2+)/S(2)O(8)(2-), US/Fe(2+)/HSO(5)(-) was investigated in the term of mineralization of model wastewaters containing different types of organic pollutants. The Weissler dosimetry and peroxodisulfate decomposition upon sonication, were used to facilitate the determination of e(US). They follow zero order kinetics, thus can be used as a model reaction to reflect all the primary effects of ultrasound and to establish the empirical correlation for e(US) calculation. Finally, GPUE has been introduced in the adequate kinetic models and the overall model was validated. PMID- 21820939 TI - A standardized objective method for continuously measuring the kinematics of cultures covering a mechanically damaged site. AB - The kinematics of cell migration is frequently being studied in the context of wound healing. Scratch wound assays in vitro are particularly popular, being a cost-effective method for characterizing the kinematic parameters of cultures. However, currently there are no objective and standardized measures of these kinematic parameters. We addressed these issues by developing an automatic and quantitative method for determining time-dependent damage areas in "wound healing" monolayer culture experiments by means of image processing. "Wound" area over time data are then fitted to a Richards function (non-symmetric sigmoid) from which we determine the migration rate, time for onset of mass cell migration and time for end of mass cell migration. We demonstrate the utility of our present method by conducting "wound healing" experiments in 8 cultures of NIH3T3 fibroblast cells which were monitored by time-lapse microscopy. The measures derived from Richards function fits to the area-time curves (normalized root mean squared errors <=3.8%) are calculated based on the entire time course of the data. Accordingly this method is substantially more reliable than the common practice where migration rates are determined based on two time points (start and end stages of migration). PMID- 21820941 TI - Uncovering the genetic underpinnings of cognition. PMID- 21820940 TI - Which measures of physical function and motor impairment best predict quality of life in Parkinson's disease? AB - INTRODUCTION: Our objective was to compare the relative value of elements of the motor system in predicting the physical mobility domain of health related quality of life in patients with Parkinson's disease in order to specify targets for intervention. METHODS: In this cross-sectional study, the Parkinson's disease questionnaire-39 was administered to 263 subjects with Parkinson's disease to assess health related quality of life. Demographics, motor impairments and physical function were assessed using the Unified Parkinson disease rating scale, 10-m walk test, 6-min walk test, Freezing of gait questionnaire, Timed up & go, functional gait assessment, Berg balance test, functional reach and 9-hole peg test. RESULTS: The results revealed that demographic factors accounted for 19.7% of the variance in Parkinson disease questionnaire-39 mobility score. When motor impairments were added to the model, the bradykinesia composite score contributed a significant portion of the variance (R(2) change = 0.12, p < 0.001). The tremor and rigidity composite scores did not contribute significantly. The Freezing of gait questionnaire was the strongest predictor (R(2) change = 0.23, p < 0.001) of the physical function tests followed by Functional gait assessment (R(2) change = 0.06, p < 0.001) and 6-min walk test (R(2) change = 0.01, p = 0.01). Collectively, 61% of the variance in Parkinson disease questionnaire-39 mobility score and 41.5% of the Parkinson disease questionnaire-39(total) score was accounted for. DISCUSSION: These results suggest greater value of physical function tests, and not tests of motor impairments, in predicting health related quality of life. PMID- 21820942 TI - Plasmodesmata - membrane tunnels with attitude. AB - Plasmodesmata are doors in the rigid cell wall. In multicellular tissues, they allow the passage of molecules needed to create physiological gradients and, by closure, symplastic boundaries, which are necessary for the fundamental processes of plant growth, development and defence. Despite this central role in plant growth our knowledge of their contribution has been hindered by difficulties in biochemical and molecular characterisation. Recent advances in proteomic, biochemical, cell biological and genetic analysis of their structure and function is showing that plasmodesmata are plastic yet highly regulated structures. They require the perception of small molecule signals (such as reactive oxygen species) to activate local changes in the cell wall that place physical constraints on the channel. This article reviews recent evidence that highlights the roles of the membrane subcomponents both as structural elements and as environments for resident signalling molecules. PMID- 21820944 TI - Analysis of binding interaction between (-)-epigallocatechin (EGC) and beta lactoglobulin by multi-spectroscopic method. AB - The binding interaction between (-)-epigallocatechin (EGC) with bovine beta lactoglobulin (betaLG) was investigated by fluorescence, circular dichroism (CD) and Fourier transform infrared (FTIR) spectroscopy methods. The binding parameters were determined by Stern-Volmer equation and the thermodynamic parameters were calculated according to the van't Hoff equation. The results suggested that betaLG was bound by EGC, which resulted in change of native conformation of betaLG. van der Waals interactions and hydrogen bonding probably played major roles in the binding process. Our study is helpful for further elucidation of binding interactions between catechins with milk proteins, which would contribute to the development of novel milk products. PMID- 21820943 TI - Long-distance transport, vacuolar sequestration, tolerance, and transcriptional responses induced by cadmium and arsenic. AB - Iron, zinc, copper and manganese are essential metals for cellular enzyme functions while cadmium, mercury and the metalloid arsenic lack any biological function. Both, essential metals, at high concentrations, and non-essential metals and metalloids are extremely reactive and toxic. Therefore, plants have acquired specialized mechanisms to sense, transport and maintain essential metals within physiological concentrations and to detoxify non-essential metals and metalloids. This review focuses on the recent identification of transporters that sequester cadmium and arsenic in vacuoles and the mechanisms mediating the partitioning of these metal(loid)s between roots and shoots. We further discuss recent models of phloem-mediated long-distance transport, seed accumulation of Cd and As and recent data demonstrating that plants posses a defined transcriptional response that allow plants to preserve metal homeostasis. This research is instrumental for future engineering of reduced toxic metal(loid) accumulation in edible crop tissues as well as for improved phytoremediation technologies. PMID- 21820945 TI - Synthesis and interaction studies of benzimidazole derivative with human serum albumin. AB - A benzimidazole derivative, 1-(2-picolyl)-3-(2-picolyl) benzimidazole iodide (PPB), was synthesized. Fourier transform infrared spectroscopy (FT-IR), UV visible, three-dimensional (3D) fluorescence, synchronous fluorescence (SF) and fluorescence spectroscopic methods were used to determine the PPB binding mode and the effects of PPB on protein stability and secondary structure. Fluorescence results revealed the presence of static type of quenching mechanism in the binding of PPB to human serum albumin (HSA). The binding constants between PPB and HSA were obtained according to Scatchard equation. The number of binding sites, the binding constants and the thermodynamic parameters were measured. The results showed a spontaneous binding of PPB to HSA through hydrogen bonds and van der Waals forces. In addition, the distance between PPB and the Trp 214 was estimated via employing the Forster's non-radiative energy transfer theory, and was found to be 3.49 nm, which indicated that PPB can bind to HSA with high probability. Site marker competitive experiments indicated that the binding of PPB to HSA primarily took place in subdomain IIA. PMID- 21820946 TI - Growth and characterization of thiosemicarbazide hydrochloride: a semiorganic NLO material. AB - Thiosemicarbazide hydrochloride (TSCHCL) was synthesized by mixing thiosemicarbazide and hydrochloride in 1:1 molar ratio in double distilled water. Single crystals of TSCHCL were grown by slow evaporation at room temperature and were characterized by single crystal X-ray diffraction study to determine the molecular structure and by FT-IR, (1)H and (13)C NMR spectral analyses to confirm the synthesized compound. Thermogravimetric and differential thermal analyses reveal the thermal stability of the crystal. The transmission spectrum of TSCHCL showed that the crystal is transparent in the wavelength range 380-1100 nm. High resolution X-ray diffractometry (HRXRD) was employed to evaluate the perfection of the grown crystal. Mechanical properties of the grown crystal were studied using Vickers microhardness test. Second harmonic generation efficiency of the powdered TSCHCL was tested using Nd:YAG laser and is ~1.5 times that of potassium dihydrogen orthophosphate. PMID- 21820947 TI - Synthesis and vibrational spectroscopic analysis of some Hofmann type clathrates. AB - New Hofmann type clathrates in the form of M(pp)(2)Ni(CN)(4).2G (where pp = 1 phenylpiperazine, G = 1,4-dioxane and M = Ni, Co or Cd) have been prepared in powder form and their FT-IR and FT-Raman spectra are reported. The results suggest that the present compounds are similar in structure to the Hofmann type clathrates and their structures consist of conjugated polymeric layers of |M Ni(CN)(4)|(infinity) with the pp bound to the metal (M) atom. PMID- 21820948 TI - Electronic and vibrational spectra of novel Lanreotide peptide capped gold nanoparticles. AB - Lanreotide, a somatostatin analogue peptide used for peptide receptor mediated therapy in metastatic neuroendocrine tumors, was used as capping agent of gold nanoparticles (GNPs) obtained by citrate reduction method. The displacement of the citrate groups from the GNPs surface by Lanreotide (LAN) molecules was evidenced by infrared and Raman spectra. The nanoparticles system, Au@LAN, was also characterized from HRTEM (High-Resolution Transmission Electron Microscopy) and Z-contrast images, UV-vis and EDS spectra. The stability on aging in water solution of the composite is discussed from the UV-vis spectra. The affinity constant of Au@LAN conjugate, calculated from Capillary Zone Electrophoresis data, was found to be 0.52. All the experimental evidence supports that the gold nanoparticles are effectively capped by the Lanreotide molecules through relatively strong covalent interactions. This result opens the possibility of combining the optical properties of gold nanoparticles and of Lanreotide molecule to form a bifunctional system for potential biomedical applications. PMID- 21820949 TI - Investigation on the pH-dependent binding of benzocaine and lysozyme by fluorescence and absorbance. AB - The interaction mechanism between benzocaine (BZC) and lysozyme (Lys) has been investigated by fluorescence, synchronous fluorescence, ultraviolet-vis (UV) absorption spectra, and three-dimensional fluorescence (3-D) in various pH medium. The observations of fluorescence spectra were mainly rationalized in terms of a static quenching process at lower concentration of BZC (C(BZC)/C(Lys)<9) and a combined quenching process at higher concentration of BZC (C(BZC)/C(Lys)>9) at pH 7.4 and 8.4. However, the fluorescence quenching was mainly arisen from static quenching by complex formation in all studied drug concentrations at pH 3.5. The structural characteristics of BZC and Lys were probed, and their binding affinities were determined under different pH conditions (pH 3.5, 7.4, and 8.4). The results indicated that the binding abilities of BZC to Lys decreased at the pH below and above the simulative physiological condition (pH 7.4) due to the alterations of the protein secondary and tertiary structures or the structural change of BZC. The effect of BZC on the conformation of Lys was analyzed using UV, synchronous fluorescence and three dimensional fluorescence under different pH conditions. These results indicate that the binding of BZC to Lys causes apparent change in the secondary and tertiary structures of Lys. The effect of Zn(2+) on the binding constant of BZC with Lys under various pH conditions (pH 3.5, 7.4, and 8.4) was also studied. PMID- 21820950 TI - Effect of solvent on absorption and fluorescence spectra of a typical fluorinated azo dye for its acidic and basic structures. AB - The effect of 15 polar solvents on absorption and fluorescence energies of a typical fluorinated azo dye, 4-(2,3,5,6-tetrafluoro-pyridin-4-yl azo)-phenol, was reported for its acidic, MH, and basic, M, structures. For MH, the absorption energy is described on the basis of multi-linear equation with Taft's pi* (solvent polarity) and beta (hydrogen bond acceptor) parameters while the fluorescence energy varies rectilinearly with free energy of transferring the proton to the surrounding solvent, DeltaG(t) degrees . For M, the hydrogen bonding donor ability of protic solvent, alpha, is a predominant factor which affects the absorption energy while in aprotic solvents, the absorption energy correlates linearly with Kirkwood function. As the ability of the solvent for hydrogen bonding increases, the absorption band width will increase in parallel with the transition energy. PMID- 21820951 TI - A promising phosphorescent iridium complex with fluorine substituents: synthesis, crystal structure, photo- and electro-luminescence performance. AB - In this paper, we report a phosphorescent Ir(III) emitter of Ir(acac-F6)(F BT)(2), where acac-F6 = 1,1,1,5,5,5-hexafluoropentane-2,4-dione and F-BT = 2-(2 fluorophenyl)benzo[d]thiazole, including its crystal structure, electronic nature, photophysical characteristics, thermal and electrochemical properties. Data suggest that Ir(acac-F6)(F-BT)(2) is a promising emitter with high quantum yield of 0.19 and good thermal stability, along with its proper energy levels for charge carrier transportation. Electroluminescence (EL) devices using Ir(acac F6)(F-BT)(2) as emitter are also fabricated, and their electroluminescence performances are investigated in detail. The optimal EL device shows a maximum luminance of 27,000 cd/cm(2) and a peak current efficiency of 8.7 cd/A. PMID- 21820952 TI - Study on the interaction of amino phosphine ester derivatives with DNA by spectroscopy, modeling and calorimetry. AB - The binding properties of amino phosphate ester derivatives, compound 1 and 2 with calf thymus DNA (CT-DNA) were investigated by UV spectra, fluorescence spectra, molecular modeling and isothermal titration calorimetry (ITC). The intrinsic binding constants K(b) of compound 1 and 2 with CT-DNA were determined by fluorescence spectroscopy and ITC, respectively. The results indicated that the two compounds bind to CT-DNA with different binding affinity, which is in the order of compound 1>compound 2. At the same time, fluorescence spectra suggested that the mechanism of the binding of the two compounds to CT-DNA is a static enhancing type. According to the ethidium bromide displacement experiments, UV spectra, molecular modeling and ITC studies, it can be concluded that compound 1 and 2 are intercalators that can slide into the G-C rich region of CT-DNA. Furthermore, ITC data showed that compound/DNA binding is enthalpy controlled. PMID- 21820953 TI - A comparative study on the ionic liquid [bmim][BF4] and its solution with transient absorption spectroscopy. AB - A detailed study was explored to compare the transient absorption spectra of the neat 1-butyl-3-methylimidazolium tetrafluoroborate ([bmim][BF(4)]) with its solution in water or acetonitrile. It was concluded that the excited triplet state (3)[bmim](+*) was produced after 266 nm laser irradiation, and then the neutral radical [bmim] and the cation radical [bmim] (2+) were formed through two possible paths. The transient absorption spectra of the neat [bmim][BF(4)] and its solution were similar but the reaction kinetics were different due to their different local structures such as dimeric or cluster. The energy transfer between excited [bmim][BF(4)] and beta-carotene further affirmed the existence of (3)[bmim](+*). And the reaction that the hydrated electron captured by [bmim](+) to produce [bmim] in solution was observed. PMID- 21820954 TI - Intrauterine transmission and clinical outcome of 248 pregnancies with primary cytomegalovirus infection in relation to gestational age. AB - BACKGROUND: The risk of intrauterine cytomegalovirus (CMV) infection and disease in the fetus or newborn largely depends on time of primary maternal infection during pregnancy. OBJECTIVES: Prospective cohort study of pregnancy outcome in relation to gestational age at primary maternal CMV infection. STUDY DESIGN: In a total of 248 pregnancies with primary infection the onset of infection was determined by IgG seroconversion, IgG avidity and/or onset of clinical symptoms. Congenital infection was diagnosed by CMV detection in amniotic fluid, fetal tissue or urine of the neonate in the first 2 weeks of life. Clinical symptoms were retrieved from ultrasound and medical records. RESULTS: The intrauterine transmission rates following primary CMV infection in the pre- and periconceptional period were 16.7% (4/24) and 34.5% (10/29), respectively. For the first, second and third trimester of pregnancy transmission rates were 30.1% (25/83), 38.2% (29/76) and 72.2% (26/36), respectively. The rate of symptomatically infected fetuses or newborns at birth was 22.8% for any symptoms and 10.3% for severe manifestations. No symptoms were observed in infected newborns of mothers with primary infection in the preconceptional period and in the third trimester. CONCLUSIONS: The risk of intrauterine transmission following primary maternal infection in the third trimester is high, but the risk of neonatal disease is low. The highest risk of severe symptoms in the fetus and newborn exists around conception and in the first trimester of pregnancy. PMID- 21820955 TI - Strategy for the extraction of yeast DNA from artisan agave must for quantitative PCR analysis. AB - An efficient method for the direct extraction of yeast genomic DNA from agave must was developed. The optimized protocol, which was based on silica-adsorption of DNA on microcolumns, included an enzymatic cell wall degradation step followed by prolonged lysis with hot detergent. The resulting extracts were suitable templates for subsequent qPCR assays that quantified mixed yeast populations in artisan Mexican mezcal fermentations. PMID- 21820956 TI - Analysis of expressed sequence tags from the marine microalga Pseudochattonella farcimen (Dictyochophyceae). AB - Pseudochattonella farcimen (Eikrem, Edvardsen, et Throndsen) is a unicellular alga belonging to the Dictyochophyceae (Heterokonta). It forms recurring blooms in Scandinavian coastal waters, and has been associated to fish mortality. Here we report the sequencing and analysis of 10,368 expressed sequence tags (ESTs) corresponding to 8,149 unique gene models from this species. Compared to EST libraries from other heterokonts, P. farcimen contains a high number of genes with functions related to cell communication and signaling. We found several genes encoding proteins related to fatty acid metabolism, including eight fatty acid desaturases and two phospholipase A2 genes. Three desaturases are highly similar to Delta4-desaturases from haptophytes. P. farcimen also possesses three putative polyketide synthases (PKSs), belonging to two different families. Some of these genes may have been acquired via horizontal gene transfer by a common ancestor of brown algae and dictyochophytes, together with genes involved in mannitol metabolism, which are also present in P. farcimen. Our findings may explain the unusual fatty acid profile previously observed in P. farcimen, and are discussed from an evolutionary perspective and in relation to the ichthyotoxicity of this alga. PMID- 21820957 TI - Update of the reference and HBM values derived by the German Human Biomonitoring Commission. AB - In 2007, we reviewed the working principles and working procedures of the German Human Biomonitoring Commission together with the reference values and human biomonitoring (HBM) values derived up to that time. Since then, the Commission has decided to derive additionally HBM I values on the basis of tolerable daily intakes and has used and evaluated this new approach on the metabolites of (2 ethylhexyl) phthalate (DEHP) in urine. Furthermore, the Commission has derived a HBM I value for thallium in urine, has recinded the HBM values for lead in blood, and has updated the HBM values for cadmium in urine. Based on the representative data of the German Environmental Survey on Children from 2003 to 2006 (GerES IV), the Commission has updated the reference values for a large number of environmental pollutants in urine and blood of children in Germany. Since 2007, the Commission has derived new and updated reference values for PFOS and PFOA in human plasma, for thallium in urine, for aromatic amines in urine, for a comprehensive number of phthalate metabolites in urine, and for organochlorine pesticides in human breast milk. Furthermore, the Commission has evaluated background exposure levels for two naphthalene metabolites and acrylamide (using acrylamide-haemoglobin adduct) for the general population. This paper reports the new values, including those already published, in order to provide an updated overview. PMID- 21820958 TI - Surveillance on chronic arsenic exposure in the Mekong River basin of Cambodia using different biomarkers. AB - Thousands of Cambodia populations are currently at high risks of both toxic and carcinogenic effects through drinking arsenic-rich groundwater. In order to determine and assess the use of arsenic contents in different biological samples as biomarkers of chronic arsenic exposure from drinking arsenic-rich groundwater in Cambodia, individual scalp hair, fingernail and toenail were collected from three different provinces in the Mekong River basin of Cambodia. After washing and acid-digestion, digestate was analyzed for total arsenic by an inductively coupled plasma mass spectrometry. Chemical analysis of the acid-digested hair revealed that among 270 hair samples cut from Kandal, 78.1% had arsenic content in scalp hair (As(h)) greater than the typical As(h) (1.00 MUg g(-1)), indicating possible arsenic toxicity. Concurrently, 1.2% and 0.6% were found elevated in Kratie (n=84) and Kampong Cham (n=173), respectively. Similarly, the upper end of the ranges for arsenic contents in fingernail (As(fn)) and toenail (As(tn)) clipped from Kandal (fingernail n=241; toenail n=187) were higher than the normal arsenic content in nail (0.43-1.08 MUg g(-1)), however, none was observed elevated in both Kratie (fingernail n=76, toenail n=42) and Kampong Cham (fingernail n=83; toenail n=52). Significant positive intercorrelations between groundwater arsenic concentration (As(w)), average daily dose (ADD) of arsenic, As(h), As(fn) and As(tn) suggest that As(h), As(fn) and As(tn) can be used as biomarkers of chronic arsenic exposure from drinking arsenic-rich groundwater, in which As(h) is more favorable than As(fn) and As(tn) due to the ease of sample processing and analytical measurements, respectively. PMID- 21820959 TI - Physical demands of professional rugby league training and competition using microtechnology. AB - OBJECTIVES: To investigate the physical demands of professional rugby league match-play using microtechnology, and to compare these demands with typical training activities used to prepare players for competition. DESIGN: Prospective cohort study. METHODS: Thirty elite rugby league players participated in this study. Seven hundred and eighty-six. training data sets and 104 data sets from National Rugby League matches were collected over one playing season. Movement was recorded using a commercially available microtechnology unit (minimaxX, Catapult Innovations), which provided information on speeds, distances, accelerations, physical collisions and repeated high-intensity efforts. RESULTS: Mean distances covered during match-play by the hit-up forwards, wide-running forwards, adjustables, and outside backs were 3,569 m, 5,561 m, 6,411 m, and 6,819 m, respectively. Hit-up forwards and wide-running forwards were engaged in a greater number of moderate and heavy collisions than the adjustables and outside backs, and more repeated high-intensity effort bouts per minute of play (1 bout every 4.8-6.3 min). The physical demands of traditional conditioning, repeated high-intensity effort exercise, and skill training activities were all lower than the physical demands of competition. CONCLUSIONS: These results demonstrate that absolute distances covered during professional rugby league matches are greater for outside backs, while the collision and repeated high intensity effort demands are higher for hit-up forwards and wide-running forwards. The specific physical demands of competitive play, especially those demands associated with collisions and repeated high-intensity efforts, were not well matched by those observed in traditional conditioning, repeated high intensity effort exercise, and skills training activities. Further research is required to investigate whether modifications need to be made to these training activities to better prepare players for the demands of National Rugby League competition. PMID- 21820960 TI - Distinguishing psychological characteristics of expert cricket batsmen. AB - OBJECTIVES: This paper sought to determine the psychological characteristics and skills that are fundamental to batting success in the sport of cricket. DESIGN AND METHOD: Following on from the findings of an earlier qualitative investigation which suggested that a favourable mix of psychological attributes and skills are critical to high performance in batting (Weissensteiner et al.(10)), adult-aged batsmen of two different skill levels (highly skilled n=11; lesser skilled n=10) completed a battery of psychological tests that included measures of mental toughness (Mental Toughness Inventory), perfectionism (Multidimensional Perfectionism Scale), coping ability (Athletic Coping Skills Inventory-28), and optimism (Attributional Styles Questionnaire). RESULTS: Contrary to the research hypothesis, it was found that the highly skilled batsmen were only distinguishable from batsmen of lesser skill by their higher degree of global mental toughness. The skilled batsmen scored significantly higher on mental toughness dimensions relating to motivation (Personal Bests, Task Value and Commitment), coping skill (Perseverance) and self-belief (Potential). CONCLUSIONS: If mental toughness can be reliably predicted at an earlier age, it may be an attribute worthy of inclusion in future talent identification and development programs. PMID- 21820961 TI - Reliability of the 8-repetition maximum test in men and women. AB - OBJECTIVE: The 8-repetition maximum test has been recommended as a method of prescribing an intensity for resistance training in healthy adults, athletes, and patients with health conditions. Yet, limited research related to the reliability of 8-repetition maximum testing has been conducted. The purpose of this study was to determine the reliability of the 8-repetition maximum test in men and women. DESIGN: Test-retest reliability study. METHODS: Twenty-eight people (14 males, 14 females, mean age=23.0 years [standard deviation=1.3]) with no exercise contraindications participated in this study. After familiarization, each participant underwent 8-repetition maximum testing using 4 different exercises. For all participants, the 8-repetition maximum test was performed during 2 sessions with 2-3 days between sessions. The intraclass correlation coefficient (ICC([1,2])), typical error as the coefficient of variation (TE(CV)), and the Bland-Altman plot were used to assess reliability. Unpaired t-test was used to determine the influence of gender on differences between initial test and retest values. RESULTS: Excellent reliability of the 8-repetition maximum test was found for all exercises (ICC([1,2])>0.9). The range of TE(CV) values was 3.4-10.4%. The Bland-Altman plot illustrated that 27 out of 28 data points for total 8 repetition maximum scores were within the 95% limits of agreement. Unpaired t test indicated no significant difference between men and women in variations between initial test and retest 8-repetition maximum scores. CONCLUSION: The findings of this study suggest that an 8-repetition maximum test protocol that includes familiarization is reliable in men and women. PMID- 21820963 TI - Collaborative learning among undergraduate students in community health nursing. AB - Teamwork can benefit students, enhancing their ability to think critically, solve problems creatively, and collaborate effectively. We piloted a collaborative learning project with undergraduate community health nursing students (N = 83) that entailed working in teams to explore epidemiologic data, synthesize the literature, and develop an evidence-based plan for nursing intervention and evaluation pertaining to a public health issue. Project evaluation consisted of pre- and post-project surveys by students, peer evaluation, and formative and summative evaluation by faculty. Having students work in teams, while challenging both for faculty and students, may be a viable strategy for preparing the next generation of nurses for inter- and intraprofessional collaboration. Our experience suggests that instituting a collaborative learning experience as part of an undergraduate course in community health nursing can be an effective way to expose students to constructive approaches to teamwork and prepare them for evidence-based nursing practice in the future. PMID- 21820964 TI - The correlation between bladder volume wall index and the pattern of uroflowmetry/external sphincter electromyography in children with lower urinary tract malfunction. AB - OBJECTIVE: To evaluate the relationship between bladder volume wall index (BVWI) and the pattern of uroflowmetry in children with lower urinary tract malfunction. PATIENTS & METHODS: 91 children aged 4-15 years with history of bladder dysfunction and 59 age/sex-matched healthy children with negative urine culture in previous month were enrolled. Uroflowmetry and kidney and bladder sonography were performed in all children. BVWI was measured by dividing maximum bladder volume index by mean bladder thickness. It was expressed as percentage by dividing calculated BVWI by expected BVWI, and values between 70% and 130% were presumed normal. Urodynamic study was done in symptomatic cases. RESULTS: The bladder was thick (<70%) in 39 (28 cases, 11 controls) and thin (>130%) in 35 (18 cases, 17 controls) (P > 0.05). Uroflowmetry was abnormal in 82 (61 cases, 21 controls) (P < 0.05). Severe sphincter dyssynergia was detected in 47% of cases compared with 20% of controls (P < 0.05).There was no relationship between BVWI and uroflowmetry in cases or in controls (P > 0.05). The median post-void residual urine was not statistically different between the groups (20 vs 12.3 ml) (P > 0.05). When both bladder sonography and uroflowmetry were abnormal, they had an association with abnormal urodynamics (P < 0.05). CONCLUSION: Among children with lower urinary tract dysfunction, the pattern of uroflowmetry could not be predicted from the BVWI, but in cases with combined abnormal bladder sonography and uroflowmetry results, there was a significant association with an abnormal urodynamic study. PMID- 21820962 TI - Interferon-lambda and therapy for chronic hepatitis C virus infection. AB - Interferon (IFN)-alpha, a type-I IFN, is widely used to treat chronic hepatitis C virus infection, but the broad expression of IFN-alpha receptors often leads to adverse reactions in many organs. Here, we examine IFN-lambda, a type-III IFN, as a therapeutic alternative to IFN-alpha. Like IFN-alpha, IFN-lambda also induces antiviral activity in hepatocytes, but might induce fewer adverse reactions because its receptor is largely restricted to cells of epithelial origin. We also discuss the recent discovery of single nucleotide polymorphisms (SNPs) near the human IFN-lambda3 gene, IL28B, that correlate strongly with the ability to achieve a sustained virological response to therapy with pegylated IFN-alpha plus ribavirin in patients with chronic hepatitis C. PMID- 21820965 TI - Endometrial stromal sarcoma of uterus. AB - Endometrial stromal sarcomas are the second most common uterine sarcomas. Currently, they are classified into low-grade endometrial stromal sarcomas and undifferentiated endometrial sarcoma. Low-grade endometrial stromal sarcomas are biologically low-grade uterine sarcomas, and typically composed of uniform cells intimately associated with prominent arterioles, resembling the endometrial stroma in proliferative phase. There is usually little cytological atypia or pleomorphism, and mitoses are scanty. In contrast, undifferentiated endometrial sarcomas are frankly malignant, lack specific differentiation and any features of normal endometrial stroma. It is a highly aggressive neoplasm, often exhibiting myometrial invasion, haemorrhage and necrosis, as well as marked nuclear pleomorphism and high mitotic activity. The diagnosis of undifferentiated endometrial sarcoma is reached after excluding other uterine tumours with a sarcomatous component, such as adenosarcoma and malignant mixed Mullerian tumour. Histological variants of endometrial stromal sarcomas, including the so called 'high-grade endometrial stroma sarcomas' are addressed. The problems with histologic diagnosis and application of immunohistochemical studies and molecular pathology are highlighted. PMID- 21820966 TI - Acetylcholine-mediated neurotransmission within the nucleus raphe magnus exerts a key role in the organization of both interictal and postictal antinociception. AB - The role of the acetylcholine-mediated system in the organization of postictal antinociception was investigated. For this purpose, nicotinic and muscarinic cholinergic receptor antagonists were microinjected into the nucleus raphe magnus (NRM), a key structure of the endogenous pain inhibitory system. After the tail flick test baseline recording, male Wistar rats (N=8 per group) were submitted to stereotaxic surgery for the introduction of a guide cannula aiming at the NRM. Five days after surgery, atropine or mecamylamine (1 ug/0.2 uL, 3 ug/0.2 uL, or 5 ug/0.2 uL) was microinjected into the NRM. The tail-flick withdrawal latency was recorded immediately after peripheral treatment with pentylenetetrazole (PTZ) (64 mg/kg), in two different interictal time windows, and for 130 minutes after the last seizure evoked by intraperitoneal injection of PTZ. The blockade of GABA mediated Cl(-) influx caused tonic-clonic convulsions in all animals followed by sustained postictal antinociception lasting 110 minutes after seizures; the nociceptive threshold was also found to be high in interictal periods. Pretreatment of the NRM with either atropine or mecamylamine antagonized both interictal and postictal antinociception, suggesting the involvement of cholinergic mechanisms recruiting muscarinic and nicotinic cholinergic receptors of the NRM in the organization of tonic-clonic seizure-induced antinociception. PMID- 21820967 TI - Behavioral and EEG effects of GABAergic manipulation of the nigrotectal pathway in the Wistar audiogenic rat strain. AB - The superior colliculus (SC), substantia nigra pars reticulata (SNPr), and striatum have been characterized as important structures involved in the modulation of seizure activity. In the current study, bicuculline (GABA(A) antagonist) and muscimol (GABA(A) agonist) were microinjected into the deep layers of either the anterior SC (aSC) or posterior SC (pSC) of genetically developed Wistar audiogenic rats. Behavior and EEG activity were studied simultaneously. Only muscimol microinjected into the pSC had behavioral and EEG anticonvulsant effects in Wistar audiogenic rats, eliciting EEG oscillation changes in both SNPr and pSC, primarily during tonic seizures. The SC of Wistar audiogenic rats thus comprises two functionally different subregions, pSC and aSC, defined by distinct behavioral and EEG features. The pSC has proconvulsant audiogenic seizure activity in Wistar audiogenic rats. Our data suggest that this phenomenon may be a consequence of the genetic selection of the Wistar audiogenic rat strain. PMID- 21820969 TI - Pain acceptance, hope, and optimism: relationships to pain and adjustment in patients with chronic musculoskeletal pain. AB - There is growing interest in the role that positive aspects of psychological adjustment, such as pain acceptance, hope, and optimism, may play in explaining adjustment in persons suffering from persistent pain. This study conducted in obese patients with persistent musculoskeletal pain (N = 89) examined the degree to which pain acceptance and hope explained pain intensity, pain unpleasantness, psychological distress, and pain-related disability, after controlling for the effects of optimism. In correlational analyses, pain acceptance and optimism were associated with psychological distress and pain disability with hope being related to only psychological distress. Pain acceptance, optimism, and hope were not significantly associated with pain. Hierarchical linear regression (HLR) analyses found that pain acceptance remained a significant predictor of psychological distress and pain disability after controlling for optimism, demographic, and medical variables. HLR analyses found that hope was not a significant predictor of psychological distress after controlling for optimism, pain acceptance, and demographic and medical variables. The results of this study are important because they indicate that pain acceptance, hope, and optimism are all related to pain adjustment. They also highlight the importance of controlling for optimism when examining the effects of pain acceptance and hope on pain adjustment. PERSPECTIVE: In a sample of obese patients with persistent musculoskeletal pain, pain acceptance was a significant predictor of psychological distress and pain disability even after controlling for optimism, demographic, and medical variables. These results add to the growing literature on the importance of pain acceptance in understanding adjustment to persistent pain. PMID- 21820970 TI - "He says, she says": a comparison of fathers' and mothers' verbal behavior during child cold pressor pain. AB - Mothers' behavior has a powerful impact on child pain. Maternal attending talk (talk focused on child pain) is associated with increased child pain whereas maternal non-attending talk (talk not focused on child pain) is associated with decreased child pain. The present study compared mothers' and fathers' verbal behavior during child pain. Forty healthy 8- to 12-year-old children completed the cold pressor task (CPT)-once with their mothers present and once with their fathers present in a counterbalanced order. Parent verbalizations were coded as Attending Talk or Non-Attending Talk. Results indicated that child symptom complaints were positively correlated with parent Attending Talk and negatively correlated with parent Non-Attending Talk. Furthermore, child pain tolerance was negatively correlated with parent Attending Talk and positively correlated with parent Non-Attending Talk. Mothers and fathers did not use different proportions of Attending or Non-Attending Talk. Exploratory analyses of parent verbalization subcodes indicated that mothers used more nonsymptom-focused verbalizations whereas fathers used more criticism (a low-frequency occurence). The findings indicate that for both mothers and fathers, verbal attention is associated with higher child pain and verbal non-attention is associated with lower child pain. The results also suggest that mothers' and fathers' verbal behavior during child pain generally does not differ. PERSPECTIVE: To date, studies of the effects of parental behavior on child pain have focused almost exclusively on mothers. The present study compared mothers' and fathers' verbal behavior during child pain. The results can be used to inform clinical recommendations for mothers and fathers to help their children cope with pain. PMID- 21820971 TI - Recommendation to revise the AJCC/UICC breast cancer staging system for inclusion of proven prognostic factors: ER/PR receptor status and HER2 neu. PMID- 21820972 TI - Second primary ipsilateral breast cancer with contralateral axillary involvement: a case report and literature review. AB - After breast-conserving surgery for an initial breast cancer, the incidence of lymphatic drainage to sites other than the ipsilateral axilla, such as the contralateral axilla, increases significantly at the time of a second primary ipsilateral breast cancer. Given the likelihood of altered lymphatic drainage, and in the absence of distant metastatic sites, consideration should be given to treating patients with a second primary ipsilateral breast cancer and contralateral axillary lymph node involvement with curative intent. This clinical issue may become more common as the incidence of second primary ipsilateral breast cancer would be expected to increase due to widespread adoption of breast conserving surgery, improved prognosis for patients with an initial early-stage breast cancer, and highly sensitive screening modalities such as magnetic resonance imaging. PMID- 21820973 TI - A decade of advances in cytotoxic chemotherapy for metastatic colorectal cancer. AB - Over the past decade treatment for metastatic colorectal cancer (mCRC) has advanced beyond single-agent fluoropyrimidine use to include various cytotoxic combination regimens and novel targeted therapies. Despite the targeted therapy era, traditional cytotoxic agents remain the mainstay of therapy. Improvements in survival in mCRC can be attributed mostly to combination therapy, with enhanced efficacy due to optimization of fluoropyrimidine dosing and the addition of irinotecan and/or oxaliplatin. Despite the enormous progress, few patients with metastatic disease are cured. To realize that ambitious goal we need a better understanding of predictive molecular markers of response, mechanisms of drug toxicity, innate and acquired drug resistance as well as how to optimize cytotoxic agents in combination with newer targeted therapies. PMID- 21820974 TI - Treatment advances in liver-limited metastatic colorectal cancer. AB - Over the last several decades advances in the management and treatment of patients with liver metastases from colorectal cancer (CRC) has changed a disease with a dismal prognosis to one with a potential for cure in some patients. Advances have been made through coordinated management of patients by surgeons, medical oncologists, radiologists, and other health care professionals coupled with advances in treatment options. Although these advances have clearly impacted patient outcomes, it is clear that the benefit of traditional surgical approaches and the use of cytoxic chemotherapy are reaching a plateau. Continued research to develop new and more active therapies, including targeted or biologic agents, is needed. This review discusses the advances made in management of patients with liver-limited metastatic disease. PMID- 21820975 TI - Reirradiation of prostate cancer with rectum preservation: eradicative high-dose rate brachytherapy with natural type hyaluronate injection. AB - INTRODUCTION: Reirradiation of locally recurrent prostate cancer after radiotherapy is limited because of its toxicity to the rectum that is closely adjacent to the prostate. To solve geometric anatomic constraints, including rectal size and distance from the prostate, we developed a technique that modifies the geometry by noninvasive direct intervention. METHODS AND MATERIALS: In a patient with local recurrence of prostate cancer at 18 months after initial radiotherapy of 61.8 GyE(LQ2,3) (gray equivalent in 2 Gy/fraction at alpha/beta=3 calculated with linear quadratic [LQ] model) to the prostate, we prescribed 16 Gy (60.8 GyE(LQ2,3) or 78.2 GyE(LQ2,1.6)) of reirradiation by high-dose-rate brachytherapy, using a bolus injection of native-type hyaluronate to create and maintain a distance between the prostate and the rectum and decrease rectal size during treatment. RESULTS: The procedure was achieved in 10min, without complications. Rectal D(2cc) of the reirradiation was 5.58 Gy (9.58 GyE(LQ2,3)). Compared with the initial radiation, the gel injection resulted in an improved therapeutic ratio. The patient was regularly followed up at our clinic; at over 3.5 years after reirradiation, there was no evidence of recurrence or radiation related toxicities greater than Grade 2, maintaining a nadir prostate-specific antigen level of 0.03 ng/mL without hormonal therapy. CONCLUSION: We consider that this technique is useful for achieving safe and curative reirradiation of prostate cancer. PMID- 21820976 TI - Simultaneous determination of ascorbic acid, aminothiols, and methionine in biological matrices using ion-pairing RP-HPLC coupled with electrochemical detector. AB - A novel highly sensitive ion-pairing reversed-phase high performance liquid chromatography/electrochemical detection method for simultaneous determination of l-ascorbic acid, aminothiols, and methionine in biological matrices was developed, optimized, and validated. Reduced forms of the analytes were extracted from the sample matrices with 10% meta-phosphoric acid solution((aqueous)). To determine the total vitamin C, the total aminothiols, and the total methionine, samples were treated with tris(2-carboxyethyl)phosphine solution in 0.05% trifluoroacetic acid solution((aqueous)) subsequent to deproteination to reduce the oxidized forms of these compounds. Various analytes were separated on a C(18) (250 * 4.6 mm, 5 MUm) analytical column using methanol-0.05% trifluoroacetic acid solution((aqueous)) (05/95, v/v), containing 0.1mM 1-octane sulphonic acid as the ion-pairing agent) as the isocratic mobile phase pumped at a flow rate of 1.5 mL min(-1) at room temperature. The column eluents were monitored at a voltage of 0.85 V. These analytes were efficiently resolved in less than 20 min using n acetyl cysteine as the internal standard. The present method was specific for the analysis of these analytes and demonstrated acceptable values for linearity (r(2)>0.999 in the range of 0.2-10,000 ng mL(-1) for all the analytes), recovery (>96%), precision (%RSD <= 2.0), and sensitivity (on column limit of detection: 250-400 fg and limit of quantification: 0.8-1.25 pg), indicating that the proposed method could be efficiently used for determination of these analytes in the context of clinical research. PMID- 21820977 TI - Self-assembly molecularly imprinted polymers of 17beta-estradiol on the surface of magnetic nanoparticles for selective separation and detection of estrogenic hormones in feeds. AB - This paper reports a surface molecular self-assembly strategy for molecular imprinting on magnetic nanoparticles for selective separation and detection of estrogens in feeds. First, gamma-methacryloxypropyltrimethoxysilane (MEMO) was successfully assembled at the surface magnetic nanoparticles through simple free radical polymerization, and subsequently, the copolymerization was further assembled between methacrylic acid (MAA) and ethylene glycol dimethacrylate (EGDMA) in the presence of templates 17beta-estradiol (E2). The synthesized magnetic molecularly imprinted polymers for E2 (E2-MMIPs) showed quick separation, large adsorption capacity, high selectivity and fast binding kinetics for E2. Meanwhile, a dispersive solid-phase extraction (DSPE) based on E2-MMIPs has been established for efficient separation and fast enrichment of estrogens from the feeds. The assay exhibited a linear range of 0.1-4 MUM for E2 and estriol (E3) with the correlation coefficient above 0.9996 and 0.9994, respectively. Recoveries of E2 from three kinds of feeds spiked at different concentration levels ranged from 92.7% to 97.0% with RSD<4.7%, and recoveries of E3 ranged from 71.9% to 83.1% with RSD<4.9%, respectively. The method is simple and sensitive, and can be used as an alternative tool to effectively separate and enrich the trace of estrogens in agricultural products by HPLC-UV. PMID- 21820978 TI - Validation of a method for the determination of the anticancer agent Combretastatin A1 phosphate (CA1P, OXi4503) in human plasma by HPLC with post column photolysis and fluorescence detection. AB - A validated method for the determination of Combretastatin A1 phosphate (CA1P, OXi4503), a bisphosphate prodrug of the vascular disrupting agent Combretastatin A1 in human plasma has been developed using fluorescence detection after post column photolysis. The separation used the ion-pairing agent tetrabutylammonium hydrogen sulphate, and this agent was also required to give consistently high recovery from plasma. Initially, the range was shown to be linear (r(2)>0.995) from the LOQ of 0.025 MUM to 5 MUM, but as the trial progressed to much higher doses, using a lower injection volume, the assay was subsequently subject to limited revalidation to cover the range from 0.05 to 50 MUM. Intra-assay precision and accuracy ranged from 2.2 to 11.8% and 1.8 to 13% respectively, and for inter-assay from 4.4 to 14.9% and 1.7 to 6.5%. Mean recovery of OXi4503 from plasma was 80.2%. PMID- 21820979 TI - Comparative study of the LC-MS/MS and UPLC-MS/MS for the multi-residue analysis of quinolones, penicillins and cephalosporins in cow milk, and validation according to the regulation 2002/657/EC. AB - The aim of this study was to develop and validate an analytical method to simultaneously determine European Union-regulated beta-lactams (penicillins and cephalosporins) and quinolones in cow milk. The procedure involves a new solid phase extraction (SPE) to clean-up and pre-concentrate the three series of antibiotics before analysis by liquid chromatography-tandem mass spectrometry (LC MS/MS) and ultra-high-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). LC-MS/MS and UPLC-MS/MS techniques were also compared. The method was validated according to the Directive 2002/657/EC and subsequently applied to 56 samples of raw cow milk supplied by the Laboratori Interprofessional Lleter de Catalunya (ALLIC) (Laboratori Interprofessional Lleter de Catalunya, Control Laboratory Interprofessional of Milk of Catalunya). PMID- 21820980 TI - Determining the pharmacokinetics of psilocin in rat plasma using ultra performance liquid chromatography coupled with a photodiode array detector after orally administering an extract of Gymnopilus spectabilis. AB - This study established ultra-performance liquid chromatography coupled with a photodiode array detector for determining psilocin and its pharmacokinetics in rat plasma after orally administering an extract of Gymnopilus spectabilis. The extract was separated on an ODS C18 column (2.3 MUm, 100 mm * 2.1 mm I.D.) by gradient elution with (A) water containing 50mM AcONH(4) and (B) acetonitrile. The wavelength was set at 265 nm and the injection volume was 10 MUL. Under these conditions, the calibration curve was linear over the concentration range 0.2-20 MUg/mL with a correlation coefficient of r(2)=0.9992. The inter- and intraday precision levels were less than 7% and the accuracies (%) were within the range 92.0-102.5%. The method was sufficiently valid to be applied to a pharmacokinetics study of psilocin in rat plasma. The pharmacokinetic parameters of psilocin in rat plasma after the oral administration of a G. spectabilis extract were as follows: C(max), 0.43 +/- 0.12 MUg/mL; T(max), 90 +/- 2.1 min; AUC(0->t), 1238.3 +/- 96.4 (MUg/mL) min; and T(1/2), 117.3 +/- 40.3 min. PMID- 21820981 TI - Physical insights to the bio-energy transport in the protein molecules: comment on "The theory of bio-energy transport in the protein molecules and its properties" by Pang Xiao-feng. PMID- 21820982 TI - [Assessment of iodine nutritional status and thyroxine levels in pregnant women from different geographic areas of the Castile and Leon]. AB - BACKGROUND AND OBJECTIVES: Iodine nutritional status in pregnant women is important for neuronal development of the fetus, and may vary depending on the geographic area. Thyroid function and urinary iodine excretion were therefore assessed in pregnant women from three different provinces of a large Spanish autonomous community. PATIENTS AND METHODS: A descriptive study was conducted in the three healthcare areas of Burgos, Avila, and Ponferrada on 1,200 women in the first trimester of pregnancy The study consisted of a survey and thyroid hormone and urinary iodine measurements. RESULTS: Use of iodized salt and iodine containing pharmacological compounds was reported by 40% and 17% of pregnant women respectively. Median urinary iodine excretion in the total group was 121 mcg/L, with lower values in Burgos (117 mcg/L) and Ponferrada (118 mcg/L) and higher levels in Avila (130 mcg/L). Urinary iodine excretion was less than 100 mcg/L in 34% of women and was undetectable in 3.3%. Excretion levels lower than 150 mcg/L were found in 69.8% of women. Low thyroxine levels were detected in 1.1%, and thyrotropin levels were increased in 4.7%. CONCLUSIONS: Iodine deficiency currently exists in pregnant women from different areas of our large autonomous community. Consumption of iodized salt and iodine-containing pharmacological compounds is not widely established. It would be of great interest to conduct studies in other geographic areas and to advise an increased iodine intake in women who plan to become pregnant and in pregnant women from the very start of pregnancy. PMID- 21820983 TI - Institution-based prospective inception cohort studies in neonatal rare disease research. AB - In rare diseases, wherein the conduct of randomized controlled clinical trials (RCTs) is challenging, cohort studies can offer important, and, in certain instances, high quality (e.g. the prospective inception cohort study) evidence on relationships among risk factors, treatments, and outcomes. The objective of this perspective article is to provide an overview of salient issues in the design and application of institution-based prospective inception cohort studies in neonatal rare disease research, with emphasis on quality assurance measures. Rigorous implementation of the prospective inception cohort study is challenging, and application to neonates renders it even more difficult. However, when performed collaboratively among institutions employing uniform methods and quality assurance mechanisms, institution-based prospective inception cohort studies can provide optimal observational evidence to inform the design and execution of RCTs in this special pediatric population. PMID- 21820984 TI - Surgical management of adrenal tumors. AB - Laparoscopic adrenalectomy has become the preferred method for removal of almost all adrenal tumors. An important component in selecting patients for this operation is a thorough understanding of the clinical presentation (mainly hypertension) and diagnostic workup for the full variety of functioning and nonfunctioning adrenal tumors including genetic evaluation when necessary (MEN2, VonHippel-Landau [VHL], type 1 neurofibromatosis [NF1], succinate dehydrogenase mutations [SDH], and MEN1). The indications and contraindications for a laparoscopic approach are discussed with regard to each tumor type. Relevant literature about partial and bilateral adrenalectomy is also summarized. Main areas of controversy are discussed including the size threshold to avoid risk of adrenal capsular effraction and the appropriateness of laparoscopic resection for suspected and known malignancy. This article presents recent data to help the surgeon make well-informed decisions and to optimize the operative approach for a wide variety of adrenal pathologies (secreting vs. non-secreting, benign vs. malignant tumors). PMID- 21820985 TI - Influence of two masticating conditions on assessment of movement path stability. AB - PURPOSE: The purpose of this study was to clarify whether differences in masticating conditions affected masticatory path stabilities of healthy subjects and TMD patients. METHODS: Twenty healthy female subjects as the healthy group, and 20 female Temporomandibular Disorders (TMD) patients as the TMD group, were selected. Incisal point movement of during mastication of both masticating condition 1 (mc1; crispy bread chewed until swallowing on the free side) and masticating condition 2 (mc2; softened chewing-gum chewed for 20s on the habitual side) were recorded by MKG. As for mc1, out of all cycles during mastication only those cycles on the habitual chewing side were analyzed. As for mc2, the ten cycles from the fifth cycle were analyzed. For these analyzed sections, the indicators representing movement path stability were calculated and compared between the two groups. RESULTS: As for mc1, though the values of the indicators representing path stability were larger for the TMD group, there were cases where no significant differences were found between the two groups. As for mc2, the values were significantly larger for the TMD group (SDs; P<0.05, SD/ODs; P<0.01). CONCLUSIONS: From these results, it was suggested that the differences in masticating conditions affected the assessment of masticatory path stabilities of healthy subjects and TMD patients and the conditions should be considered for analyzing masticatory movement. PMID- 21820986 TI - Infrequent presentations of mucormycosis in patients with myelodysplastic syndrome and acute leukemia: case series and review of literature. PMID- 21820987 TI - Colic lesions induced by Colokit preparation. PMID- 21820988 TI - Mercury as a cause of fulminant hepatic failure in a child: case report and literature review. AB - Fulminant hepatic failure (FHF) in children is devastating unless urgent liver transplantation is undergone. Intoxication or drug-related FHF is a well-known group of causes leading to FHF. Mercury intoxication is described in the literature to cause hepatitis but not described to cause DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome and FHF in the same patient. We describe a child with mercury intoxication and FHF with clinical features fulfilling DRESS syndrome criteria. To our best knowledge, this is the first case report of fatal acute liver failure secondary to mercury intoxication in the English literature. Mercury intoxication should receive a worldwide attention to its consequences in order to minimize the morbidities and mortalities that arise from its intoxication. PMID- 21820989 TI - Nickel-quinolones interaction. Part 5-Biological evaluation of nickel(II) complexes with first-, second- and third-generation quinolones. AB - The nickel(II) complexes with the quinolone antibacterial agents oxolinic acid, flumequine, enrofloxacin and sparfloxacin in the presence of the N,N'-donor heterocyclic ligand 2,2'-bipyridylamine have been synthesized and characterized. The quinolones act as bidentate ligands coordinated to Ni(II) ion through the pyridone oxygen and a carboxylato oxygen. The crystal structure of [(2,2' bipyridylamine)bis(sparfloxacinato)nickel(II)] has been determined by X-ray crystallography. UV study of the interaction of the complexes with calf-thymus DNA (CT DNA) has shown that they bind to CT DNA with [(2,2' bipyridylamine)bis(flumequinato)nickel(II)] exhibiting the highest binding constant to CT DNA. The cyclic voltammograms of the complexes have shown that in the presence of CT DNA the complexes can bind to CT DNA by the intercalative binding mode which has also been verified by DNA solution viscosity measurements. Competitive study with ethidium bromide (EB) has shown that the complexes can displace the DNA-bound EB indicating that they bind to DNA in strong competition with EB. The complexes exhibit good binding propensity to human or bovine serum albumin protein having relatively high binding constant values. The biological properties of the [Ni(quinolonato)(2)(2,2'-bipyridylamine)] complexes have been evaluated in comparison to the previously reported Ni(II) quinolone complexes [Ni(quinolonato)(2)(H(2)O)(2)], [Ni(quinolonato)(2)(2,2'-bipyridine)] and [Ni(quinolonato)(2)(1,10-phenanthroline)]. The quinolones and their Ni(II) complexes have been tested for their antioxidant and free radical scavenging activity. They have been also tested in vitro for their inhibitory activity against soybean lipoxygenase. PMID- 21820990 TI - Assessing clinical trials of Internet addiction treatment: a systematic review and CONSORT evaluation. AB - Although there is ongoing debate concerning the clinical status of Internet addiction, and the quality of the extant literature in this emerging field is not optimal, several clinical trials of both pharmacological and psychological treatments for Internet addiction have been published in recent years. A systematic review investigating the reporting quality of eight treatment studies is presented. Reporting quality was defined according to the 2010 Consolidating Standards of Reporting Trials (CONSORT) statement. An evaluation of the reviewed studies highlighted several key limitations, including (a) inconsistencies in the definition and diagnosis of Internet addiction, (b) a lack of randomization and blinding techniques, (c) a lack of adequate controls or other comparison groups, and (d) insufficient information concerning recruitment dates, sample characteristics, and treatment effect sizes. It is concluded that improvements in future studies' design and reporting would be of significant benefit to both researchers and clinicians, and to the overall positioning of Internet addiction in the behavioral addiction field. PMID- 21820991 TI - Prevalence and clinical course of depression: a review. AB - Depression is one of the leading causes of disease worldwide. Historically conceived as either a disease of the mind or of the brain, treatment options followed this aetiology. Current diagnostic assessment of depression is based on descriptions of symptoms, their presence and magnitude over time. Epidemiological studies demonstrate that depressive disorders are highly prevalent: displaying high rates of lifetime incidence, early age onset, high chronicity, and role impairment. These studies have deepened our understanding of the course of depression; remission, recovery, relapse and recurrence. An illustration of recovery rates has begun to demonstrate the complexity of the nature and course of depression. The majority recovers; however, recovery may not be permanent and future episodes carry the threat of chronicity. A key variable influencing rates of recovery, relapse, and recurrence is the presence of medical or psychiatric comorbid illnesses. The review considers the literature on Major Depression beginning with a brief historical overview, its classification, and a synthesis of the current knowledge regarding prevalence and course. PMID- 21820992 TI - Global and deep molecular analysis of microbiota signatures in fecal samples from patients with irritable bowel syndrome. AB - BACKGROUND & AIMS: Irritable bowel syndrome (IBS) has been associated with disruptions to the intestinal microbiota, but studies have had limited power, coverage, and depth of analysis. We aimed to define microbial populations that can be used discriminate the fecal microbiota of patients with IBS from that of healthy subjects and correlate these with IBS intestinal symptom scores. METHODS: The microbiota composition was assessed by global and deep molecular analysis of fecal samples from 62 patients with IBS patients and 46 healthy individuals (controls). We used a comprehensive and highly reproducible phylogenetic microarray in combination with quantitative polymerase chain reaction. RESULTS: The intestinal microbiota of IBS patients differed significantly (P = .0005) from that of controls. The microbiota of patients, compared with controls, had a 2 fold increased ratio of the Firmicutes to Bacteroidetes (P = .0002). This resulted from an approximately 1.5-fold increase in numbers of Dorea, Ruminococcus, and Clostridium spp (P < .005); a 2-fold decrease in the number of Bacteroidetes (P < .0001); a 1.5-fold decrease in numbers of Bifidobacterium and Faecalibacterium spp (P < .05); and, when present, a 4-fold lower average number of methanogens (3.50 * 10(7) vs 8.74 * 10(6) cells/g feces; P = .003). Correlation analysis of the microbial groups and IBS symptom scores indicated the involvement of several groups of Firmicutes and Proteobacteria in the pathogenesis of IBS. CONCLUSIONS: Global and deep molecular analysis of fecal samples indicates that patients with IBS have a different composition of microbiota. This information might be used to develop better diagnostics and ultimately treatments for IBS. PMID- 21820993 TI - Catheter ablation of ventricular tachycardia after left ventricular reconstructive surgery for ischemic cardiomyopathy. AB - BACKGROUND: After surgical ventricular restoration (SVR) for ischemic cardiomyopathy, ventricular tachycardias (VTs) are an important reason for postoperative morbidity and mortality. OBJECTIVE: The purpose of this study was to elucidate the VT substrate, VT characteristics, and outcome of radiofrequency catheter ablation (RFCA) in patients with VT after SVR. METHODS: Twelve (3%) of 416 patients referred for RFCA for VT after myocardial infarction in three centers had undergone SVR. After induction of VT, left ventricular (LV) electroanatomical mapping was performed. Ablation target sites were identified by entrainment, substrate, and/or pace mapping. RESULTS: Four (33%) patients presented within the perioperative period with incessant VT, and eight (67%) presented with incessant or recurrent VT late after SVR (VT cycle length 453 +/- 102 ms). The region of surgical scar was identified by electroanatomical mapping in 11 patients. Twenty-eight VTs (cycle length 384 +/- 95 ms) were induced. The VT exit was bordering the surgical scar in 20 (71%) VTs, of which 15 were at the septal side. All VTs were abolished in five patients: in four only the clinical VTs were abolished, and in one reinducibility was not tested. In two patients, ablation failed after which surgical ablation was performed successfully. During follow-up, three (25%) patients died (nonarrhythmic deaths); all had presented early after SVR. Two (17%) experienced recurrent VT. CONCLUSION: VT after LV SVR seems to have a bimodal presentation; one-third presented with incessant VT in the acute postoperative phase and had a high mortality. Two-thirds presented late after SVR; in these patients RFCA is usually effective. Successful ablation sites are frequently located at the border of surgical scars and patch material. PMID- 21820994 TI - Amyloidogenicity and clinical phenotype associated with five novel mutations in apolipoprotein A-I. AB - The phenotype of hereditary apolipoprotein A-I amyloidosis is heterogeneous with some patients developing extensive visceral amyloid deposits and end-stage renal failure as young adults and others having only laryngeal and/or skin amyloid, which may be of little clinical consequence. Clinical management and prognosis of patients with systemic amyloidosis depend entirely on correct identification of the fibril protein, such that light chain amyloidosis (AL, previously referred to as "primary"), the most frequently diagnosed type, is treated with chemotherapy, which has absolutely no role in hereditary apolipoprotein A-I amyloidosis. We report five novel apolipoprotein A-I variants, four of which were amyloidogenic and one of which was incidental in a patient with systemic AL amyloidosis. Interestingly, only one of four patients with apolipoprotein A-I amyloidosis had a family history of similar disease. Laser microdissection and tandem mass spectrometry-based proteomics were used to confirm the amyloid fibril protein and, for the first time in apolipoprotein A-I amyloidosis, demonstrated that only mutated protein as opposed to wild-type apolipoprotein A-I was deposited as amyloid. The clinical spectrum and outcome of hereditary apolipoprotein A-I amyloidosis are reviewed in detail and support the need for sequencing of the apolipoprotein A-I gene among patients with apparent localized amyloidosis in whom IHC is nondiagnostic of the fibril protein, even in the absence of a family history of disease. PMID- 21820995 TI - Interferon-gamma influences the composition of leukocytic infiltrates in murine lyme carditis. AB - Interferon (IFN)-gamma is present in lesions of patients with Lyme disease and positively correlates with the severity of manifestations. To investigate the role of IFNgamma in the development of Lyme carditis, wild-type and IFNgamma deficient C57BL/6 mice were infected with the causative bacterium, Borrelia burgdorferi. Histological analysis revealed no change in the severity of carditis between wild-type and IFNgamma-deficient mice at 14, 21, 25, and 28 days after infection. However, a distinct shift in the types of leukocytes within the hearts of IFNgamma-deficient mice was observed at 25 days. In the absence of IFNgamma, the number of neutrophils in the heart was increased, whereas the number of T lymphocytes was decreased. Bacterial loads within hearts were the same as in wild type mice. Macrophages secrete chemokines that recruit immune cells, which could contribute to the accumulation of leukocytes in murine Lyme carditis. The ability of IFNgamma and B. burgdorferi to activate murine macrophages was examined, and the two stimuli synergistically induced chemoattractants for mononuclear cells (ie, CXCL9, CXCL10, CXCL11, CXCL16, and CCL12) and decreased those for neutrophils (ie, CXCL1, CXCL2, and CXCL3). IFNgamma and B. burgdorferi also synergistically enhanced secretion of CXCL9 and CXCL10 by murine cardiac endothelial cells. These results indicate that IFNgamma influences the composition of inflammatory infiltrates in Lyme carditis by promoting the accumulation of leukocytes associated with chronic inflammation and suppressing that of cells that typify acute inflammation. PMID- 21820996 TI - Flow cytometry: an alternative method for direct quantification of antigens adsorbed to aluminum hydroxide adjuvant. AB - Flow cytometry (FC) has been widely used in biological research; however, its use for vaccine characterization has been very limited. Here we describe the development of an FC method for the direct quantification of two Neisseria meningitidis vaccine antigens, in mono- and multivalent formulations, while still adsorbed on aluminum hydroxide (AH) suspension. The antibody-based method is specific and sensitive. Because FC allows microscopic particle examination, the entire aluminum suspension carrying adsorbed antigen(s) can be analyzed directly. In addition to determining antigen concentration and identity, the assay is able to determine the distribution of the antigens on AH. High correlation coefficients (r(2)) were routinely achieved for a broad range of antigen doses from 0 to 150 MUg/dose. Traditional assays for quantitative and qualitative antigen characterization on AH particles involve either complete aluminum dissolution or antigen desorption from the adjuvant. Because our direct method uses the whole AH suspension, the cumbersome steps used by traditional methods are not required. Those steps are often inefficient in desorbing the antigens and in some cases can lead to protein denaturation. We believe that this novel FC based assay could circumvent some of the complex and tedious antigen-adjuvant desorption methods. PMID- 21820997 TI - Detection of vaccinia virus DNA by quartz crystal microbalance. AB - In this study, we describe a detection system for the indirect detection of vaccinia virus by DNA analysis. The system uses quartz crystal microbalance (QCM) as the detection technique and polymerase chain reaction (PCR) for amplification. Different immobilization strategies for the capture probe on the quartz chip are studied. For the QCM detection of hybridisation, the influence of the structure and length of target DNA is analyzed. For the detection of DNA from an amplification product, an efficient denaturation procedure is developed. On the basis of these investigations, vaccinia virus DNA is detected with only a low number of amplification rounds and a short analysis time. Specificity can be clearly shown. To enhance the signal strength and to have a further proof of specificity, a gold nanoparticle-tagged enhancer sequence can be used. PMID- 21820998 TI - Isolation of functional mitochondria from rat kidney and skeletal muscle without manual homogenization. AB - Isolation of functional and intact mitochondria from solid tissue is crucial for studies that focus on the elucidation of normal mitochondrial physiology and/or mitochondrial dysfunction in conditions such as aging, diabetes, and cancer. There is growing recognition of the importance of mitochondria both as targets for drug development and as off-target mediators of drug side effects. Unfortunately, mitochondrial isolation from tissue is generally carried out using homogenizer-based methods that require extensive operator experience to obtain reproducible high-quality preparations. These methods limit dissemination, impede scale-up, and contribute to difficulties in reproducing experimental results over time and across laboratories. Here we describe semiautomated methods to disrupt tissue using kidney and muscle mitochondria preparations as exemplars. These methods use the Barocycler, the PCT Shredder, or both. The PCT Shredder is a mechanical grinder that quickly breaks up tissue without significant risk of overhomogenization. Mitochondria isolated using the PCT Shredder are shown to be comparable to controls. The Barocycler generates controlled pressure pulses that can be adjusted to lyse cells and release organelles. The mitochondria subjected to pressure cycling-mediated tissue disruption are shown to retain functionality, enabling combinations of the PCT Shredder and the Barocycler to be used to purify mitochondrial preparations. PMID- 21820999 TI - Utility of solid-phase spectrophotometry to determine trace amounts of zinc in environmental and biological samples. AB - A solid-phase spectrophotometric analysis has been proposed for preconcentration and determination of Zn(II) in real samples. The procedure is based on sorption of zinc(II) as 5-(2-benzothiazolylazo)-8-hydroxyquinoline (BTAHQ) complex on dextran-type anion-exchange gel (Sephadex DEAE A-25). The influences of the analytical parameters, including pH of the aqueous solution, amounts of BTAHQ, and sample volume, were investigated. The absorbance of the gel at 675 and 750 nm, packed in a 1.0-mm cell, was measured directly. The molar absorptivities were found to be 2.50*10(7) and 9.55*10(7)L mol(-1) cm(-1) for 500 and 1000 ml, respectively. Calibration was linear over the range of 0.05-1.10 MUg L(-1) with a relative standard deviation of less than 1.60% (n=10). The detection and quantification limits of the 500-ml sample method were 12 and 40 ng L(-1) on using 50 mg. For the 1000-ml sample, the detection and quantification limits were 7.5 and 25 ng L(-1) using a 50-mg exchanger. Increasing the sample volume can enhance sensitivity. No considerable interferences were observed from other investigated anions and cations on the Zn(II) determination. The proposed method was applied to determine zinc in environmental samples, including natural water, food, certified reference materials, meat, and biological samples, comparing the results simultaneously with those obtained using a flame atomic absorption spectrophotometer, whereby the validity of the method was tested. PMID- 21821000 TI - Suppression of HPV E6 and E7 expression by BAF53 depletion in cervical cancer cells. AB - Deregulation of the expression of human papillomavirus (HPV) oncogenes E6 and E7 plays a pivotal role in cervical carcinogenesis because the E6 and E7 proteins neutralize p53 and Rb tumor suppressor pathways, respectively. In approximately 90% of all cervical carcinomas, HPVs are found to be integrated into the host genome. Following integration, the core-enhancer element and P105 promoter that control expression of E6 and E7 adopt a chromatin structure that is different from that of episomal HPV, and this has been proposed to contribute to activation of E6 and E7 expression. However, the molecular basis underlying this chromatin structural change remains unknown. Previously, BAF53 has been shown to be essential for the integrity of higher-order chromatin structure and interchromosomal interactions. Here, we examined whether BAF53 is required for activated expression of E6 and E7 genes. We found that BAF53 knockdown led to suppression of expression of E6 and E7 genes from HPV integrants in cervical carcinoma cell lines HeLa and SiHa. Conversely, expression of transiently transfected HPV18-LCR-Luciferase was not suppressed by BAF53 knockdown. The level of the active histone marks H3K9Ac and H4K12Ac on the P105 promoter of integrated HPV 18 was decreased in BAF53 knockdown cells. BAF53 knockdown restored the p53 dependent signaling pathway in HeLa and SiHa cells. These results suggest that activated expression of the E6 and E7 genes of integrated HPV is dependent on BAF53-dependent higher-order chromatin structure or nuclear motor activity. PMID- 21821001 TI - Increased galectin-3 facilitates leukemia cell survival from apoptotic stimuli. AB - Galectin-3 is regulated for cancer cell survival and apoptosis depending upon the cell type and stimulus. We investigated a glycogen synthase kinase (GSK) 3beta/galectin-3-regulated mechanism used by leukemia cells to escape from apoptotic stimuli. Galectin-3 expression was time- and transcription-dependently deregulated in K562 chronic myeloid leukemia cells stimulated for apoptosis by cisplatin (a platinum-based chemotherapy drug), sphingolipid ceramide analog C(2) ceramide, and LY294002 (a phosphatidylinositol 3-kinase inhibitor). Notably, galectin-3 was upregulated in survival cells. Forced galectin-3 expression caused resistance to apoptosis, whereas knockdown galectin-3 expression increased susceptibility to apoptosis. Sub-cellular distribution of inducible galectin-3 was mitochondria-specific. Apoptotic stimuli decreased pro-survival Bcl-2 family protein expression (especially Mcl-1), whereas galectin-3 overexpression reversed but it was enhanced by a galectin-3 expression knockdown. Under apoptotic stimulation, GSK-3beta was activated after Akt was inactivated and GSK-3beta was inhibited-either pharmacologically or using short hairpin RNA to abolish galectin 3, increase apoptosis, and inhibit colony formation-which suggests a pro-survival role for GSK-3beta. We found that GSK-3beta upregulated galectin-3 and stabilized anti-apoptotic Bcl-2 family proteins, which is important for the escape of leukemia cells from apoptotic stimuli. PMID- 21821002 TI - The defective protein level of myosin light chain phosphatase (MLCP) in the isolated saphenous vein, as a vascular conduit in coronary artery bypass grafting (CABG), harvested from patients with diabetes mellitus (DM). AB - We examined the contractile reactivity to 5-hydroxytryptamine (5-HT) in isolated human saphenous vein (SV), as a vascular conduit in coronary artery bypass grafting (CABG), harvested from patients with diabetes mellitus (DM) and non-DM (NDM). Vascular rings of endothelium-denuded SV were used for functional and biochemical experiments. The vasoconstrictions caused by 5-HT were significantly greater (hyperreactivity) in the DM group than in the NDM group. RhoA/ROCK pathway is activated by various G-protein-coupled receptor agonists and consequently induces phosphorylation of myosin phosphatase target subunit 1 (MYPT1), a subunit of myosin light chain phosphatase (MLCP), which inhibits MLCP activity. In the resting state of the vessels, total tissue protein levels of 5 HT(2A) receptor, 5-HT(1B) receptor, RhoA, ROCK1, and ROCK2 did not differ between NDM and DM groups. However, the total protein level of MYPT1 was significantly lower in the DM group than in the NDM group. Furthermore, the ratio of P(Thr(696))-MYPT1 to total MYPT1 was significantly higher in the DM group than in the NDM group. These results suggest that the hyperreactivity to 5-HT in the SV smooth muscle of patients with DM is due to not only enhanced phosphorylation of MLCP but also defective protein level of MLCP. Thus, we reveal for the first time that the defective protein level of MLCP in the DM group can partially explain the poor patency of SV graft harvested from patients with DM. PMID- 21821003 TI - Epidermal growth factor receptors destined for the nucleus are internalized via a clathrin-dependent pathway. AB - The epidermal growth factor (EGF) transduces its actions via the EGF receptor (EGFR), which can traffic from the plasma membrane to either the cytoplasm or the nucleus. However, the mechanism by which EGFR reaches the nucleus is unclear. To investigate these questions, liver cells were analyzed by immunoblot of cell fractions, confocal immunofluorescence and real time confocal imaging. Cell fractionation studies showed that EGFR was detectable in the nucleus after EGF stimulation with a peak in nuclear receptor after 10 min. Movement of EGFR to the nucleus was confirmed by confocal immunofluorescence and labeled EGF moved with the receptor to the nucleus. Small interference RNA (siRNA) was used to knockdown clathrin in order to assess the first endocytic steps of EGFR nuclear translocation in liver cells. A mutant dynamin (dynamin K44A) was also used to determine the pathways for this traffic. Movement of labeled EGF or EGFR to the nucleus depended upon dynamin and clathrin. This identifies the pathway that mediates the first steps for EGFR nuclear translocation in liver cells. PMID- 21821004 TI - ATF3 represses PDX-1 expression in pancreatic beta-cells. AB - The downregulation of PDX-1 expression plays an important role in development of type 2 diabetes. However, the negative regulator of PDX-1 expression is not well known. In this study, we analyzed the mouse PDX-1 promoter to characterize the effects of ATF3 on PDX-1 expression in pancreatic beta-cells. Both thapsigargin treatment, an inducer of ER stress, and ATF3 expression decreased PDX-1 expression in pancreatic beta-cells, MIN6N8. Furthermore, they also repressed the activity of -4.5 Kb promoter of mouse PDX-1 gene. Transfection studies with 5' deleted-reporters showed that ATF3 repressed the activity of 0.9Kb PDX-1 promoter, whereas it did not affect the activity of 0.7 Kb PDX-1 promoter, suggesting that ATF3 responsive element is located between the -903 and -702. An electrophoretic mobility shift assay and chromatin immunoprecipitation assay demonstrated that ATF3 binds directly to the promoter region spanning from -759 to -738. Moreover, mutation of the putative ATF/CRE site between -752 and -745 abrogated ATF3-mediated transrepression of the PDX-1 promoter. PDX-1 was decreased in MIN6N8 cells treated with high glucose or high palmitate, whereas ATF3 was increased, indicating that ATF3 plays a role in hyperglycemia or hyperlipidemia-mediated downregulation of PDX-1 expression. Collectively, these results demonstrate that ATF3 represses PDX-1 expression via binding to an ATF3 responsive element in its promoter, which plays an important role in suppression of pancreatic beta-cells function. PMID- 21821005 TI - The trafficking proteins Vacuolar Protein Sorting 35 and Neurobeachin interact with the glycine receptor beta-subunit. AB - Inhibitory glycine receptors (GlyRs) are densely packed in the postsynaptic membrane due to a high-affinity interaction of their beta-subunits with the scaffolding protein gephyrin. Here, we used an affinity-based proteomic approach to identify the trafficking proteins Vacuolar Protein Sorting 35 (Vps35) and Neurobeachin (Nbea) as novel GlyR beta-subunit (GlyRbeta) interacting proteins in rat brain. Recombinant Vps35 and a central fragment of Nbea bound to the large intracellular loop of GlyRbeta in glutathione-S-transferase pull-downs; in addition, Vps35 displayed binding to gephyrin. Immunocytochemical staining of spinal cord sections revealed Nbea immunoreactivity apposed to and colocalizing with marker proteins of inhibitory synapses. Our data are consistent with roles of Vps35 and Nbea in the retrieval and post-Golgi trafficking of synaptic GlyRs and possibly other neurotransmitter receptors. PMID- 21821006 TI - Genistein promotes DNA demethylation of the steroidogenic factor 1 (SF-1) promoter in endometrial stromal cells. AB - It has recently been demonstrated that genistein (GEN), a phytoestrogen in soy products, is an epigenetic modulator in various types of cells; but its effect on endometrium has not yet been determined. We investigated the effects of GEN on mouse uterine cells, in vivo and in vitro. Oral administration of GEN for 1 week induced mild proliferation of the endometrium in ovariectomized (OVX) mice, which was accompanied by the induction of steroidogenic factor 1 (SF-1) gene expression. GEN administration induced demethylation of multiple CpG sites in the SF-1 promoter; these sites are extensively methylated and thus silenced in normal endometrium. The GEN-mediated promoter demethylation occurred predominantly on the luminal side, as opposed to myometrium side, indicating that the epigenetic change was mainly shown in regenerated cells. Primary cultures of endometrial stromal cell colonies were screened for GEN-mediated alterations of DNA methylation by a high-resolution melting (HRM) method. One out of 20 colony forming cell clones showed GEN-induced demethylation of SF-1. This clone exhibited a high proliferation capacity with continuous colony formation activity through multiple serial clonings. We propose that only a portion of endometrial cells are capable of receiving epigenetic modulation by GEN. PMID- 21821007 TI - Induction of diabetes with signs of autoimmunity in primates by the injection of multiple-low-dose streptozotocin. AB - AIM: To develop a preclinical large animal model of autoimmune diabetes to facilitate the translational research of autoimmune diabetes in human. MATERIALS AND METHODS: Nine young rhesus monkeys received multiple-low-dose (MLD) intravenous injections of streptozotocin for five consecutive days, followed by two additional boosting injections of STZ given 1 week apart. The induction of autoimmune diabetes was evaluated by regular metabolic testing, serological assessment of islet-reactive autoantibodies and histological examination of pancreatic tissues. RESULTS: Seven of nine treated animals became diabetic with moderate hyperglycemia initially and more severe hyperglycemia thereafter. All diabetic animals exhibited severely impaired glucose tolerance, limited islet function, and required insulin therapy to maintain relatively normal glucose metabolism and healthy status. Serological tests showed that all diabetic monkeys developed autoantibodies specifically against insulin and islet antigens. Furthermore, histological examination of the pancreata from diabetic animals revealed evidence of specific destruction of islet beta cells and islets infiltrated with T lymphocytes. Overt and persistent diabetes can be induced in young rhesus monkeys by the injection of MLD-STZ, and autoimmune responses to pancreatic islet cells seem to be involved in the development of glucose intolerance and diabetes. CONCLUSION: These data indicate for the first time that autoimmune diabetes can be induced in primates; this may serve as a valuable preclinical model for studying the pathogenesis of and potential therapies for autoimmune diabetes in humans. PMID- 21821008 TI - Specific expression of the human voltage-gated proton channel Hv1 in highly metastatic breast cancer cells, promotes tumor progression and metastasis. AB - The newly discovered human voltage-gated proton channel Hv1 is essential for proton transfer, which contains a voltage sensor domain (VSD) without a pore domain. We report here for the first time that Hv1 is specifically expressed in the highly metastatic human breast tumor tissues, but not in poorly metastatic breast cancer tissues, detected by immunohistochemistry. Meanwhile, real-time RT PCR and immunocytochemistry showed that the expression levels of Hv1 have significant differences among breast cancer cell lines, MCF-7, MDA-MB-231, MDA-MB 468, MDA-MB-453, T-47D and SK-BR-3, in which Hv1 is expressed at a high level in highly metastatic human breast cancer cell line MDA-MB-231, but at a very low level in poorly metastatic human breast cancer cell line MCF-7. Inhibition of Hv1 expression in the highly metastatic MDA-MB-231 cells by small interfering RNA (siRNA) significantly decreases the invasion and migration of the cells. The intracellular pH of MDA-MB-231 cells down-regulated Hv1 expression by siRNA is obviously decreased compared with MDA-MB-231 with the scrambled siRNA. The expression of matrix metalloproteinase-2 and gelatinase activity in MDA-MB-231 cells suppressed Hv1 by siRNA were reduced. Our results strongly suggest that Hv1 regulates breast cancer intracellular pH and exacerbates the migratory ability of metastatic cells. PMID- 21821009 TI - Persistent expression of Nqo1 by p62-mediated Nrf2 activation facilitates p53 dependent mitotic catastrophe. AB - Prolonged mitosis due to aberrant chromosome segregation permits cells to enter the G1 phase without cytokinesis and subsequently triggers the p53-dependent cell death program, known as mitotic catastrophe. Cells which fail to go through mitotic catastrophe create aneuploidy, posing a risk of oncogenesis. In the present report, we show that p62-mediated non-canonical activation of Nrf2 leads to the persistent expression of Nqo1, which plays a critical role for p53 stabilization during mitotic catastrophe. With prolonged exposure to nocodazole, a microtubule-depolymerizing agent, p62-deficient HCT116 cells exhibited an accumulation of a polyploid population with a limited appearance of apoptotic cells, which was attributable to the attenuated stabilization of p53. Combinatorial gene manipulation analysis verified that the regulatory cascade with a hierarchy of p62-Keap1-Nrf2-Nqo1 is required for p53 stabilization for mitotic catastrophe. This is consistent with the role of Nqo1 as a gatekeeper for proteasomal degradation of p53. Thus, we demonstrate for the first time the functional connection between the non-canonical Nrf2 pathway and p53-dependent cell death program upon prolonged mitosis. PMID- 21821010 TI - Glutathione increases the binding affinity of a bovine B12 trafficking chaperone bCblC for vitamin B12. AB - Intracellular B(12) metabolism involves a B(12) trafficking chaperone CblC that is well conserved in mammals including human. The protein CblC is known to bind cyanocobalamin (CNCbl, vitamin B(12)) inducing the base-off transition and convert it into an intermediate that can be used in enzyme cofactor synthesis. The binding affinity of human CblC for CNCbl was determined to be K(d)=~6-16 MUM, which is relatively low considering sub-micromolar B(12) concentrations (0.03-0.7 MUM) in normal cells. In the current study, we discovered that the base-off transition of CNCbl upon binding to bCblC, a bovine homolog of human CblC, is facilitated in the presence of reduced form of glutathione (GSH). In addition, GSH dramatically increases the binding affinity for CNCbl lowering the K(d) from 27.1 +/- 0.2-0.24 +/- 0.09 MUM. The effect of GSH is due to conformational change of bCblC upon binding with GSH, which was indicated by limited proteolysis and urea-induced equilibrium denaturation of the protein. The results of this study suggest that GSH positively modulates bCblC by increasing the binding affinity for CNCbl, which would enhance functional efficiency of the protein. PMID- 21821011 TI - The NCI-N87 cell line as a gastric epithelial barrier model for drug permeability assay. AB - The objective of this study was to evaluate the human NCI-N87 cell line as a model for gastric permeability drug studies under pH conditions of the stomach. The optimal conditions that led NCI-N87 cells to form a typical differentiated gastric epithelial barrier were a seeding density of 2.5 * 105 cells/cm2 on porous inserts and growth in serum-complemented RPMI-1640 medium until 18-27 days post-confluency. The resulting cell monolayers showed moderately high transepithelial electrical resistance (TEER) values of about 500 Omega cm2, cells of polygonal morphology expressing E-cadherin and ZO-1 proteins at their contact surfaces, and production of mucus clusters. The monolayers withstood apical pH of 7.4 down to 3.0 with the basal pH fixed at 7.4. The apparent permeability coefficients (P(app)) of model compounds were evaluated in the apical-to basolateral and basolateral-to-apical directions under different pH gradients. The monolayers were impermeable to the integrity marker Lucifer Yellow (low P(app) of 0.3-1.1 * 10-6 cm/s). The furosemide P(app) (0.4-1.5 * 10-5 cm/s) were slightly dependent on pH but remained moderate. The caffeine P(app) (4.2-5.0 * 10 5 cm/s) were higher and insensitive to pH changes. The NCI-N87 cell line provides a useful in vitro tool to assess gastric drug permeability and absorption under physiologic conditions prevailing in the human stomach. PMID- 21821012 TI - PARP1 inhibitors attenuate AKT phosphorylation via the upregulation of PHLPP1. AB - Poly(ADP-ribose) polymerase-1 (PARP1) inhibitors are emerging as an important class of drugs for treating BRCA-deficient cancers. Recent discoveries have shown that PARP1 inhibitors may treat other cancer patients in addition to the relatively small proportion of patients carrying BRCA mutations. However, the additional targets by which PARP1 inhibitor-mediated tumor suppression remain poorly understood. In this study, we show that two PARP1 inhibitors, PJ-34 and 3 AB, attenuate AKT phosphorylation at serine 473 (S473) independent of DNA repair impairment. These inhibitors decrease the AKT-associated phosphorylation of FOXO3A, enhance the nuclear retention of FOXO3A, and activate its transcriptional activity. We further demonstrate that treatment with PJ-34 or 3-AB dramatically increases the level of PHLPP1. Overexpression of PHLPP1 enhances the PARP1 inhibitor-induced downregulation of AKT phosphorylation and increases tumor cell death. In contrast, knockdown of PHLPP1 abrogates the PARP1 inhibitor-mediated AKT inhibition and desensitizes cells to its treatment. Therefore, our findings not only show the robust role of PARP1 inhibitors in AKT inhibition but also develop a novel strategy to increase the effectiveness of cancer treatment via PARP1 inhibitor-induced PHLPP1 upregulation. PMID- 21821013 TI - Augmentation of hepatic and renal oxidative stress and disrupted glucose homeostasis by monocrotophos in streptozotocin-induced diabetic rats. AB - Several recent studies have demonstrated that organophosphorus insecticides (OPI) possess the potential to disrupt glucose homeostasis leading to hyperglycemia in experimental animals. The propensity of OPI to induce hyperglycemia along with oxidative stress may have far-reaching consequences on diabetic outcomes and associated complications. The primary objective of this study was to assess the potential of monocrotophos (MCP), an extensively used OPI, on hepatic and renal oxidative stress markers and dysregulation of hepatic glucose homeostasis in experimentally induced diabetic rats. Rats rendered diabetic by a single dose of streptozotocin (60mg/kg b.w) were orally administered MCP (0.9mg/kg b.w/d for 5d). Monocrotophos per se caused only a marginal increase in blood glucose levels but significantly elevated the blood glucose levels and also disrupted glucose homeostasis by depleting liver glycogen content and increasing the gluconeogenetic enzyme activities in diabetic rats. Experimentally induced diabetes was also associated with alterations in antioxidant enzymes in liver and kidney. MCP markedly enhanced lipid peroxidation in kidney and altered the enzymatic antioxidant defense mechanisms in both liver and kidney of diabetic rats. Collectively our data provides evidence that MCP has the propensity to augment the oxidative stress and further disrupt glucose homeostasis in diabetic rats. PMID- 21821014 TI - Red cell distribution width, C-reactive protein, the complete blood count, and mortality in patients with coronary disease and a normal comparison population. AB - BACKGROUND: Red cell distribution width (RDW) is associated with morbidity and mortality in coronary artery disease (CAD), but the connection of RDW with chronic inflammation is equivocal. METHODS: In 1,489 patients with CAD and 8.4 15.2 years of follow-up all-cause mortality and RDW were studied using Cox regression. RDW and its associations with inflammation, liver function, renal function, and body mass were assessed. A population of 449 normal (No-CAD) patients also was evaluated. RESULTS: RDW predicted all-cause mortality in a step wise manner (HR=1.37 per quintile; 95% CI=1.29, 1.46; p-trend<0.001). A significant but meaningless correlation between RDW and high-sensitivity C reactive protein (hsCRP) was identified (r=0.181; p<0.001). With full adjustment, RDW remained significant (p-trend<0.001) and the strongest predictor of mortality among all factors included in the model. RDW also strongly predicted all-cause mortality in the normal control population (HR=1.33 per quintile, CI=1.15, 1.55; p-trend<0.001), but hsCRP did not predict mortality among normal controls. CONCLUSIONS: RDW was associated with mortality in patients with CAD and may provide clinically useful prognostication. Although RDW was correlated with hsCRP, they were independent predictors of mortality. RDW has been incorporated into risk prediction tool using data from basic chemistries available at: http://intermountainhealthcare.org/IMRS. PMID- 21821015 TI - Correlation of misfolded transthyretin in abnormal vitreous and high myopia related ocular pathologies. AB - BACKGROUND: High myopia is usually defined as eyes with -6 dioptres (D) of myopia, or >26.0 mm in axial length. Progressive and excessive elongation of the eyeball leads to secondary ocular diseases such as macular detachment (MD) and macular hole (MH). Higher transthyretin (TTR) levels had been detected in abnormal serums, but the situation in vitreous humor and the mechanism are still unclear. METHOD: Transthyretin concentrations in vitreous of 80 high myopia patients and 20 healthy controls were determined by ELISA. After affinity purification, SDS-PAGE, Western-blot, and circular dichroism (CD) spectroscopy were employed for the secondary structure research. RESULTS: Vitreous transthyretin concentration of MD patients was ~1.1 times higher than that of MH patients, and 4.1 times higher than that of healthy controls. TTR in MD patients' vitreous showed a much more stable tetrameric structure. In neutral condition, compared with the secondary structure of healthy TTR, purified TTR in MD and MH vitreous samples showed lower beta-sheets content; ~50% of beta-sheets of the TTR in MD vitreous samples were lost. CONCLUSIONS: The results suggested that MD and MH patients had higher vitreous TTR concentrations; TTR in MD vitreous had an abnormally stable tetrameric structure, possibly due to misfolding. PMID- 21821016 TI - Worsening of the clinical-hematological picture in a patient with a rare PK-LR compound heterozygosis after mitral replacement. AB - We report a case of a patient affected by compound heterozygosis for two PK-LR gene mutations: p.R486W (c.1456C>T) and p.M403I (c.1209G>A). Our patient suffered from an initial moderate hemolytic anemia which subsequently evolved into a severe form after mitral prosthetic valve replacement for valve regurgitation. Thereafter, the clinical features evolved into a worsening of anemia, heart failure and pulmonary hypertension, in the absence of valve dysfunction. This clinical picture improved only after an intensive transfusion regimen. This case highlights aspects concerning the intricate balance between the risks and benefits of a mechanical prosthetic valve implant in PK-deficient patients. PMID- 21821018 TI - Potentiation of the antitumor effect of 11-keto-beta-boswellic acid by its 3 alpha-hexanoyloxy derivative. AB - We recently discovered that a propionyloxy derivative of 11-keto-beta-boswellic acid (PKBA) showed better anticancer potential than other boswellic acids including AKBA, encompassing the importance of acyl group at the 3-alpha-hydroxy position of KBA. In continuation of our previous work, other higher derivatives (with increasing alkoxy chain length at 3-alpha-hydroxy position) including butyryloxy (BKBA) and hexanoyloxy (HKBA) derivatives of KBA were synthesized. The respective IC(50) values of BKBA and HKBA in HL-60 cells were found to be 7.7 and 4.5 MUg/ml. IC(50) value of HKBA was comparatively lower than that of BKBA, and further lower than that of the previously reported derivative (PKBA, IC(50) 8.7 MUg/ml). In order to compare the anticancer potential of HKBA with PKBA, detailed in vitro pro-apoptotic and in vivo anticancer studies were carried out. The induction of apoptosis by HKBA was measured using various parameters including fluorescence and scanning electron microscopy, DNA fragmentation and Annexin V FITC binding. The extent of DNA damage was measured using neutral comet assay. HKBA was further evaluated for its effect on DNA cell cycle and mitochondria where it was found to arrest cells in G(2)/M phase and also induced loss of mitochondrial membrane potential. These events were associated with increased expression of cytosolic cytochrome c and cleavage of PARP. Target based studies showed that HKBA inhibited the enzymatic activity of topoisomerases I and II at low doses than that of PKBA. In vivo studies also revealed a low dose inhibitory effect of HKBA on ascitic and solid murine tumor models. PMID- 21821017 TI - Molecular dissection of cis-regulatory modules at the Drosophila bithorax complex reveals critical transcription factor signature motifs. AB - At the Drosophila melanogaster bithorax complex (BX-C) over 330kb of intergenic DNA is responsible for directing the transcription of just three homeotic (Hox) genes during embryonic development. A number of distinct enhancer cis-regulatory modules (CRMs) are responsible for controlling the specific expression patterns of the Hox genes in the BX-C. While it has proven possible to identify orthologs of known BX-C CRMs in different Drosophila species using overall sequence conservation, this approach has not proven sufficiently effective for identifying novel CRMs or defining the key functional sequences within enhancer CRMs. Here we demonstrate that the specific spatial clustering of transcription factor (TF) binding sites is important for BX-C enhancer activity. A bioinformatic search for combinations of putative TF binding sites in the BX-C suggests that simple clustering of binding sites is frequently not indicative of enhancer activity. However, through molecular dissection and evolutionary comparison across the Drosophila genus we discovered that specific TF binding site clustering patterns are an important feature of three known BX-C enhancers. Sub-regions of the defined IAB5 and IAB7b enhancers were both found to contain an evolutionarily conserved signature motif of clustered TF binding sites which is critical for the functional activity of the enhancers. Together, these results indicate that the spatial organization of specific activator and repressor binding sites within BX C enhancers is of greater importance than overall sequence conservation and is indicative of enhancer functional activity. PMID- 21821019 TI - Electrophysiological effects of ivabradine in dog and human cardiac preparations: potential antiarrhythmic actions. AB - Ivabradine is a novel antianginal agent which inhibits the pacemaker current. The effects of ivabradine on maximum rate of depolarization (V(max)), repolarization and spontaneous depolarization have not yet been reported in human isolated cardiac preparations. The same applies to large animals close to human in heart size and spontaneous frequency. Using microelectrode technique action potential characteristics and by applying patch-clamp technique ionic currents were studied. Ivabradine exerted concentration-dependent (0.1-10 MUM) decrease in the amplitude of spontaneous diastolic depolarization and reduction in spontaneous rate of firing of action potentials and produced a concentration- and frequency dependent V(max) block in dog Purkinje fibers while action potential duration measured at 50% of repolarization was shortened. In the presence of ivabradine, at 400 ms cycle length, V(max) block developed with an onset kinetic rate constant of 13.9 +/- 3.2 beat(-1) in dog ventricular muscle. In addition to a fast recovery of V(max) from inactivation (tau=41-46 ms) observed in control, a second slow component for recovery of V(max) was expressed (offset kinetics of V(max) block) having a time constant of 8.76 +/- 1.34 s. In dog after attenuation of the repolarization reserve ivabradine moderately but significantly lengthened the repolarization. In human, significant prolongation of repolarization was only observed at 10 MUM ivabradine. Ivabradine in addition to the Class V antiarrhythmic effect also has Class I/C and Class III antiarrhythmic properties, which can be advantageous in the treatment of patients with ischemic heart disease liable to disturbances of cardiac rhythm. PMID- 21821020 TI - Liver mitochondrial function and redox status in an experimental model of non alcoholic fatty liver disease induced by monosodium L-glutamate in rats. AB - The purpose of this work was to determine if mitochondrial dysfunction is involved in the development of non-alcoholic fatty liver disease (NAFLD). Using a model of obesity induced by the neonatal treatment of rats with monosodium L glutamate (MSG), several parameters of liver mitochondrial function and their impact on liver redox status were evaluated. Specifically, fatty acid beta oxidation, oxidative phosphorylation and Ca(2+)-induced mitochondrial permeability transition were assessed in isolated liver mitochondria, and reduced glutathione (GSH), linked thiol contents and the activities of several enzymes involved in the control of redox status were measured in the liver homogenate. Our results demonstrate that liver mitochondria from MSG-obese rats exhibit a higher beta-oxidation capacity and an increased capacity for oxidising succinate, without loss in the efficiency of oxidative phosphorylation. Also, liver mitochondria from obese rats were less susceptible to the permeability transition pore (PTP) opening induced by 1.0 MUM CaCl(2). Cellular levels of GSH were unaffected in the livers from the MSG-obese rats, whereas reduced linked thiol contents were increased. The activities of glucose-6-phosphate dehydrogenase, glutathione reductase and glutathione peroxidase were increased, while catalase activity was unaffected and superoxide dismutase activity was reduced in the livers from the MSG-obese rats. In this model of obesity, liver fat accumulation is not a consequence of mitochondrial dysfunction. The enhanced glucose-6 phosphate dehydrogenase activity observed in the livers of MSG-obese rats could be associated with liver fat accumulation and likely plays a central role in the mitochondrial defence against oxidative stress. PMID- 21821021 TI - Plectin regulates invasiveness of SW480 colon carcinoma cells and is targeted to podosome-like adhesions in an isoform-specific manner. AB - Co-ordination of cytoskeletal networks and their dynamics is an essential feature of cell migration and cancer cell invasion. Plectin is a large cytolinker protein that influences tissue integrity, organisation of actin and intermediate filaments, and cell migration. Alternatively spliced plectin isoforms are targeted to different subcellular locations. Here, we show that plectin ablation by siRNA impaired migration, invasion and adhesion of SW480 colon carcinoma cells. A previously less well characterised plectin isoform, plectin-1k, co localised with epithelial integrins, N-WASP, cortactin, and dynamin in podosome like adhesions in invasive SW480 colon carcinoma cells. Transfection of alternative plectin N-terminal constructs demonstrated that the first exons of isoforms 1k, 1 and 1d can target the actin-binding domain of plectin to podosome like adhesions. Finally, Plectin-1k N-terminus rescued adhesion site formation in plectin knock-down cells. Thus, plectin participates in actin assembly and invasiveness in carcinoma cells in an isoform-specific manner. PMID- 21821022 TI - The unfolded protein response and its role in intestinal homeostasis and inflammation. AB - The unfolded protein response (UPR) is a signaling pathway from the endoplasmic reticulum (ER) to the nucleus that protects cells from the stress caused by misfolded or unfolded proteins [1, 2]. As such, ER stress is an ongoing challenge for all cells given the central biologic importance of secretion as part of normal physiologic functions. This is especially the case for cells that are highly dependent upon secretory function as part of their major duties. Within mucosal tissues, the intestinal epithelium is especially dependent upon an intact UPR for its normal activities [3]. This review will discuss the UPR and the special role that it provides in the functioning of the intestinal epithelium and, when dysfunctional, its implications for understanding mucosal homeostasis and intestinal inflammation, as occurs in inflammatory bowel disease (IBD). PMID- 21821024 TI - Lecithin retinol acyltransferase and its S175R mutant have a similar secondary structure content and maximum insertion pressure but different enzyme activities. AB - Recent work on Lecithin:retinol acyltransferase (LRAT) allowed to gather a large amount of information on its secondary structure, enzymatic properties and membrane binding. A truncated form of LRAT (tLRAT) as well as its S175R mutant leading to retinis pigmentosa, a severe form of retinal dystrophy, were studied to understand the role of this mutation on the dysfunction of this protein. Consistently with previous reports, the S175R-tLRAT mutant was shown to lack enzyme activity. However, very similar secondary structures probed by circular dichroism have been obtained with the S175R-tLRAT mutant and tLRAT. Moreover, similar values of maximum insertion pressure of the S175R-tLRAT mutant and tLRAT have been obtained using Langmuir monolayers, thus suggesting that the S175R mutation has no effect on the membrane binding properties of tLRAT. These findings leave open the possibility that the loss of enzymatic activity associated with the S175R mutant is related to loss of an essential nucleophile near the active site, or alternatively, to steric obstruction of the active site that impedes substrate binding. PMID- 21821023 TI - Decreasing dietary linoleic acid promotes long chain omega-3 fatty acid incorporation into rat retina and modifies gene expression. AB - Age-related macular degeneration (AMD) may be partially prevented by dietary habits privileging the consumption of omega3 long chain polyunsaturated fatty acids (omega3s) while lowering linoleic acid (LA) intake. The present study aimed to document whether following these epidemiological guidelines would enrich the neurosensory retina and RPE with omega3s and modulate gene expression in the neurosensory retina. Rat progenitors and pups were fed with diets containing low or high LA, and low or high omega3s. After scotopic single flash and 8-Hz-Flicker electroretinography, rat pups were euthanized at adulthood. The fatty acid profile of the neurosensory retina, RPE, liver, adipose tissue and plasma was analyzed using gas chromatography. Gene expression was analyzed with real-time PCR in the neurosensory retina. Diets rich in omega3s efficiently improved the incorporation of omega3s into the organs and tissues. This raising effect was magnified by lowering LA intake. Compared to a diet with high LA and low omega3s, low LA diets significantly upregulated LDL-receptor gene expression. Similar but not significant upregulation of CD36, ABCA1, ALOX5 and ALOX12 gene expression was observed in rats fed with low LA. No effect was observed on retinal function. Increasing the intake in omega3s and lowering LA improved the enrichment with omega3s of the tissues, including the neurosensory retina and RPE, and upregulated genes involved in lipid trafficking in the neurosensory retina. Those results consistently reinforced the beneficial role of omega3s in the prevention of AMD, especially when the diet contained low levels of LA, as suggested from epidemiological data. PMID- 21821025 TI - Effect of globus pallidus internus stimulation on neuronal activity in the pedunculopontine tegmental nucleus in the primate model of Parkinson's disease. AB - The pedunculopontine tegmental nucleus (PPN) is being explored as a site for deep brain stimulation (DBS) for the treatment of patients with medically refractory gait and postural abnormalities (MRGPA) associated with Parkinson's disease (PD). The PPN is involved in initiation and modulation of gait and other stereotyped motor behaviors and is inter-connected with the pallido-thalamo-cortical circuit. Internal segment of the globus pallidus (GPi) DBS is effective at treating the motor signs associated with PD, however its impact on MRGPA is limited and its effect on PPN neuronal activity is unknown. The current work characterizes the effect of therapeutically-effective GPi DBS on PPN neuronal activity in a single rhesus monkey made parkinsonian using 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP). A scaled-down, quadripolar DBS lead was implanted into sensorimotor GPi under electrophysiological and stereotactic guidance. Single neuron activity was recorded from PPN before, during and after DBS. GPi DBS reduced the mean discharge rate of PPN neurons from 16.8 Hz to 12.8 Hz, with 30 (66.7%) neurons showing a decreased mean rate, 3 (6.7%) increased and 12 (26.7%) unchanged. Consistent with known GABAergic projections from GPi to PPN, and with previous observations that stimulation increases output from the stimulated structure, GPi DBS suppressed activity in the PPN. The present observations, together with previous reports of improvement in MRGPA during low frequency stimulation in PPN, suggest that activation of PPN output may be required to improve MRGPA and may account for the lack of improvement in MRGPA typically observed with GPi or subthalamic nucleus (STN) DBS. PMID- 21821026 TI - New insights into non-coding RNA networks in Huntington's disease. PMID- 21821027 TI - Early suppression of intracranial EEG signals predicts ischemic outcome in adult mice following hypoxia-ischemia. AB - The objective of this study is to determine whether early alterations in intracranial EEG activity predict overall outcome in non-anesthetized adult mice following hypoxia-ischemia (HI). Adult C57BL/6 mice received surgical implantation of bilateral intracranial EEG electrodes in the hippocampus and cerebral cortex. Animals were subjected to a hypoxic-ischemic (HI) episode consisting of permanent occlusion of the right common carotid artery and subsequent systemic hypoxia (8% O(2) for 30 min). EEG activities were sorted based on the observance of motor seizures, poor physical outcome, brain injury, and mortality. EEG signals were quantified as amplitude, variance, and root mean square, and early alterations in these parameters were compared. Animals with poor-HI outcome exhibited longer and more profound suppression of EEG signals in the hippocampus ipsilateral to the carotid artery occlusion during HI. Of the parameters chosen to quantify EEG activity, root mean square demonstrated the greatest sensitivity in predicting subsequent outcome. Thus, ipsilateral hippocampal EEG signals are a reliable early marker for assessing HI outcome in adult mice, and further characterization of ischemic EEG signals may aid in the development of novel quantitative variables for use in animal models of experimental cerebral ischemia. PMID- 21821028 TI - Characterization of the threonine-phosphatase of mouse eyes absent 3. AB - Eyes absent (EYA) has tyrosine- and threonine-phosphatase activities in their C terminal and N-terminal regions, respectively. Using various mutants of mouse EYA3, we showed that the 68-amino acid domain between positions 53 and 120 was necessary and sufficient for its threonine-phosphatase activity. Point mutations were then introduced, and residues Cys-56, Tyr-77, His-79, and Tyr-90 were essential for the EYA3s threonine-phosphatase. The 68-amino acid domain is not well conserved among the four mouse EYA members, but is evolutionally highly conserved in the orthologous EYA members of different species, suggesting that the threonine-phosphatase of EYA3 has a function distinct from that of the other EYAs. PMID- 21821029 TI - Aurora-A phosphorylates hnRNPK and disrupts its interaction with p53. AB - Amplification of Aurora-A, encoding a cell cycle-regulating kinase, has been reported in human cancers. Although Aurora-A is known to directly phosphorylate and down-regulate p53, the detailed mechanism remains unclear. Here we show that Aurora-A phosphorylates hnRNPK, a transcriptional coactivator of p53, on serine 379. This phosphorylation does not affect the post-transcriptional activity or cellular localization of hnRNPK, but disrupts its interaction with p53. Inverse correlation between Aurora-A activity and hnRNPK-p53 interaction was further demonstrated in DNA-damaged cells. Our results provide an alternative mechanism, whereby via phosphorylating hnRNPK Aurora-A participates in regulating p53 activity during DNA damage. PMID- 21821030 TI - Asymmetric dimethylarginine confers the communication between endothelial and smooth muscle cells and leads to VSMC migration through p38 and ERK1/2 signaling cascade. AB - Communication between endothelial and smooth muscle cells (SMCs) contributes to atherosclerosis induced by atherogenic factors, such as oxide LDL. Asymmetric dimethylarginine (ADMA), a newly found cardiovascular risk factor, accumulates in the culture medium of oxide LDL (oxLDL)-treated endothelial cells and positively correlates with atherosclerosis. This study demonstrates that ADMA mediates the communication between endothelial cells and SMCs induced by oxLDL leading to SMC migration. In addition, the present study suggests exogenous ADMA directly induces SMC migration via p38 and ERK1/2 MAPK signaling transduction way. Investigations to identify the factors regulating VSMC migration may provide novel insights into atherosclerosis and its complications. PMID- 21821031 TI - Loss of DeltaNp63alpha promotes mitotic exit in epithelial cells. AB - Protein p63 is a key regulator in cell proliferation and cell differentiation in stratified squamous epithelium. DeltaNp63alpha is the most commonly expressed p63 isoform, which is often overexpressed in human tumor. In the present work we report the potential involvement of DeltaNp63alpha in cell cycle regulation. DeltaNp63alpha accumulated in mitotic cells but its expression decreased during mitotic exit. Moreover, DeltaNp63alpha knockdown promoted mitotic exit. DeltaNp63alpha shares a conserved destruction box (D-box) motif with other potential targets of the Anaphase-Promoting Complex/Cyclosome (APC/C). Overexpression of APC/C coactivator Cdh1 destabilized DeltaNp63alpha. Our results suggest that DeltaNp63alpha level is cell cycle-regulated and may play a role in the regulation of mitotic exit. PMID- 21821032 TI - Luciferase activity of the intracellular microcrystal of the firefly squid, Watasenia scintillans. AB - The arm light organ of the firefly squid, Watasenia scintillans, emits extremely bright flashes of light, which are caused by a luciferin-luciferase reaction involving ATP, Mg(2+) and molecular oxygen. The molecular mechanism underlying the bioluminescence reaction has remained unresolved, because the luciferase could not be identified or isolated. The arm light organ contains numerous rod like bodies that are 2-6 MUm long and 1-2 MUm thick. This paper addresses the characterization of the extracted rod-like body. We found that the rod-like bodies emit the light in vitro by the luciferin-luciferase reaction. Furthermore, by using the X-ray powder diffraction method, we confirmed that the rod-like bodies are well-ordered microcrystals. PMID- 21821033 TI - Cytochrome bd oxidase and nitric oxide: from reaction mechanisms to bacterial physiology. AB - Experimental evidence suggests that the prokaryotic respiratory cytochrome bd quinol oxidase is responsible for both bioenergetic functions and bacterial adaptation to different stress conditions. The enzyme, phylogenetically unrelated to the extensively studied heme-copper terminal oxidases, is found in many commensal and pathogenic bacteria. Here, we review current knowledge on the catalytic intermediates of cytochrome bd and their reactivity towards nitric oxide (NO). Available information is discussed in the light of the hypothesis that, owing to its high NO dissociation rate, cytochrome bd confers resistance to NO-stress, thereby providing a strategy for bacterial pathogens to evade the NO mediated host immune attack. PMID- 21821034 TI - Ultrastructural analysis, zinc transporters, glucose transporters and hormones expression in New world primate (Callithrix jacchus) and human pancreatic islets. AB - The New world primates (NWP) Callithrix jacchus separated from man approximately 50 million years ago and is a potential alternative small non-human primate model for diabetes research. Ultrastructure, and gene expression of pancreatic islets and the recently described diabetes auto antigenic zinc transporters families in human, NWP and pig pancreas were studied. Morphologically NWP islets were larger than pig islets and similar in size to human islets. NWP islets alpha cells had high dense core surrounded by a limiting membrane, beta cells by the mixed morphology of the granule core, and delta cells by moderate opaque core. Antibody staining for insulin, glucagon, somatostatin and Glucagon-like peptide-1 (GLP-1) showed that the distribution pattern of the different cell types within islets was comparable to pig and human islets. In all three species protein expression of zinc transporter ZnT8 was detected in most of the insulin producing beta cells whereas Zip14 expression was widely expressed in alpha and beta cells. In both human and NWP little or no expression of Glut2 was observed compared to Glut1 and glucokinase at the protein level, however the messenger RNA level of Glut2 was greater than Glut1 and glucokinase. In contrast all three glucose transporters were expressed in pig islets at the protein level. The expression of Zip14 in islets is reported for the first time. In conclusion NWP pancreatic islets express comparable islet cell types and distribution to humans and pigs. Importantly, marmosets have a similar glucose transporter profile to humans, making this non-endangered primate species a useful animal model for pancreatic biology. PMID- 21821035 TI - Lack of sexual experience does not reduce the responses of LH, estrus or fertility in anestrous goats exposed to sexually active males. AB - We investigated whether LH secretion, estrous behavior and fertility would differ between sexually inexperienced and experienced anestrous goats exposed to the males. Male goats were rendered sexually active during the reproductive rest season by exposure to 2.5 months of artificial long days. Two groups of anovulatory sexually inexperienced and sexually experienced does were exposed to males during 15 days (n = 20 per group). LH pulsatility was determined every 15 min from 4h before to 8h after introducing males (Day 0). Estrous behavior was recorded twice daily. Pregnancy rates were determined on Day 50. Fertility was determined at parturition. Male sexual behavior was registered on days 1 and 2 during 1h. Before introducing the males, the number of LH pulses did not differ between groups. After introduction of the males, all females increased their LH pulsatility, but the number of pulses did not differ between sexually inexperienced and experienced goats. The proportion of females displaying estrous behavior with a high pregnancy rate and fertility did not differ between inexperienced and experienced goats. The sexual behavior of the males did not differ significantly between those interacting with sexually inexperienced or experienced goats. We conclude that goats can show substantial endocrine and reproductive responses to males, even in the absence of previous sexual experience, when sexually active bucks are used. PMID- 21821036 TI - Single molecule measurements of tumor necrosis factor alpha and interleukin-6 in the plasma of patients with Crohn's disease. AB - The quantitative measurement of inflammatory cytokines in blood has been limited by insufficient sensitivity of conventional immunoassays. This limitation has prevented the widespread clinical monitoring of cytokine concentrations in chronic inflammatory diseases. We applied a sensitive, single molecule detection technology to measure TNF-alpha and IL-6 in the plasma of patients with Crohn's disease (CD), before and after treatment with anti-TNF-alpha therapy. Plasma from 17 patients with CD was collected prior to initiation of anti-TNF-alpha therapy, and the Crohn's disease activity index (CDAI) was determined for each patient. A sub-set of these patients returned for follow up 12 weeks after treatment started. Plasma from age- and gender-matched controls was also collected. Digital ELISAs were developed for TNF-alpha and IL-6, and the plasma concentrations of these cytokines were determined using digital ELISA. The limits of detection of the TNF-alpha and IL-6 digital ELISAs were 0.008 pg/mL and 0.006 pg/mL, respectively. Both cytokines were detected in all samples using digital ELISA and the concentrations of TNF-alpha and IL-6 in the plasma of patients with CD were (3.6+/-0.9) pg/mL and (10.9+/-11.2) pg/mL, respectively. TNF-alpha levels in patients and healthy controls were not significantly different, but the IL-6 levels in plasma were significantly elevated in patients compared to controls. After therapy, the mean reduction of the concentrations of free TNF-alpha and IL 6 were 46% and 58%, respectively. Digital ELISA provided the first quantitative measurements of TNF-alpha and IL-6 concentrations in the plasma of all patients in a population with CD. The changes in cytokine concentrations after therapy- which could be quantified because of the high sensitivity of digital ELISA--could be used for monitoring therapeutic efficacy. PMID- 21821037 TI - One-step homogeneous C-reactive protein assay for saliva. AB - BACKGROUND: Cardiovascular disease is the leading cause of death in the world. Human C-reactive protein (CRP) has been used in the risk assessment of coronary events. Human saliva mirrors the body's health and well-being and is non invasive, easy to collect and ideal for third world countries as well as for large patient screening. The aim was to establish a saliva CRP reference range and to demonstrate the clinical utility of salivary CRP levels in assessing the coronary events in a primary health care setting. METHODS: We have used a homogeneous bead based assay to detect CRP levels in human saliva. We have developed a rapid 15 min (vs 90 min), sequential, one-step assay to detect CRP in saliva. Saliva was collected from healthy volunteers (n=55, ages 20-70 years) as well as from cardiac patients (n=28, ages 43-86 years). RESULTS: The assay incubation time was optimised from 90 min to 15 min and generated a positive correlation (n=29, range 10-2189 pg/mL, r2=0.94; Passing Bablok slope 0.885, Intercept 0, p>0.10), meaning we could decrease the incubation time and produce equivalent results with confidence. The mean CRP level in the saliva of healthy human volunteers was 285 pg/mL and in cardiac patients was 1680 pg/mL (p<0.01). Analysis of CRP concentrations in paired serum and saliva samples from cardiac patients gave a positive correlation (r2=0.84, p<0.001) and the salivary CRP concentration capable of distinguishing healthy from diseased patients. CONCLUSIONS: The results suggest that this minimally invasive, rapid and sensitive assay will be useful in large patient screening studies for risk assessment of coronary events. PMID- 21821038 TI - Effects of diet and water supply on energy intake and water loss in a mygalomorph spider in a fluctuating environment of the central Andes. AB - The metabolic and water evaporation strategies in spiders may be part of a set of physiological adaptations to tolerate low or unpredictable food availability, buffering spiders against environmental fluctuations such as those of the high mountains of the central Andes. The aim of this study is to analyze experimentally the variations in metabolic rate and the rate of evaporative water with food and/or water restriction in a high mountain mygalomorph spider population (Paraphysa sp.). We found that the low metabolism of this spider was not affected by water restriction, but its metabolism was depressed after 3 weeks of food deprivation. The spider did not show seasonal metabolic changes but it presented seasonal changes in the rate of evaporative water loss at high temperatures. Females with egg sacs reduced their metabolic rate and evaporative water at high temperatures. These findings constitute a set of possible adaptations to a highly fluctuating Mediterranean environment, which is completely covered with snow for many months and then progresses rapidly to a very dry climate with high temperatures. PMID- 21821039 TI - A PCR-based tool for cultivation-independent detection and quantification of Metarhizium clade 1. AB - The entomopathogenic fungus Metarhizium anisopliae and sister species are some of the most widely used biological control agents for insects. Availability of specific monitoring and quantification tools are essential for the investigation of environmental factors influencing their environmental distribution. Naturally occurring as well as released Metarhizium strains in the environment traditionally are monitored with cultivation-dependent techniques. However, specific detection and quantification may be limited due to the lack of a defined and reliable detection range of such methods. Cultivation-independent PCR-based detection and quantification tools offer high throughput analyses of target taxa in various environments. In this study a cultivation-independent PCR-based method was developed, which allows for specific detection and quantification of the defined Metarhizium clade 1, which is formed by the species Metarhizium majus, Metarhizium guizhouense, Metarhizium pingshaense, Metarhizium anisopliae, Metarhizium robertsii and Metarhiziumbrunneum, formerly included in the M. anisopliae cryptic species complex. This method is based on the use of clade specific primers, i.e. Ma 1763 and Ma 2097, that are positioned within the internal transcribed spacer regions 1 and 2 of the nuclear ribosomal RNA gene cluster, respectively. BLAST similarity searches and empirical specificity tests performed on target and non-target species, as well as on bulk soil DNA samples, demonstrated specificity of this diagnostic tool for the targeted Metarhizium clade 1. Testing of the primer pair in qPCR assays validated the diagnostic method for specific quantification of Metarhizium clade 1 in complex bulk soil DNA samples that significantly correlated with cultivation-dependent quantification. The new tool will allow for highly specific and rapid detection and quantification of the targeted Metarhizium clade 1 in the environment. Habitat with high Metarhizium clade 1 densities can then be analyzed for habitat preferences in greater detail using cultivation-dependent techniques and genetic typing of isolates. PMID- 21821040 TI - Engineering GST M2-2 for high activity with indene 1,2-oxide and indication of an H-site residue sustaining catalytic promiscuity. AB - The substrate-binding H-site of human glutathione transferase (GST) M2-2 was subjected to iterative saturation mutagenesis in order to obtain an efficient enzyme with the novel epoxide substrate indene 1,2-oxide. Residues 10, 116, and 210 were targeted, and the activities with the alternative substrates, benzyl isothiocyanate and the prodrug azathioprine, undergoing divergent chemical reactions were monitored for comparison. In general, increased activities were found when the smaller residues Gly, Ser, and Ala replaced the original Thr210. The most active mutant T210G was further mutated at position 116, but no mutant showed enhanced catalytic activity. However, saturation mutagenesis of position 10 identified one double mutant T210G/I10C with 100-fold higher specific activity with indene 1,2-oxide than wild-type GST M2-2. This enhanced epoxide activity of 50 MUmol min(-1) mg(-1) resulted primarily from an increased k(cat) value (70 s( 1)). The specific activity is 24-fold higher than that of wild-type GST M1-1, which is otherwise the most proficient GST enzyme with epoxide substrates. A second double mutant T210G/I10W displayed 30-fold increased activity with azathioprine, 0.56 MUmol min(-1) mg(-1). In both double mutants, the replacement of Ile10 led to narrowed acceptance of alternative substrates. Ile10 is evolutionarily conserved in related class Mu GSTs. Conservation usually indicates preservation of a particular function, and in the Mu class, it would appear that the conserved Ile10 is not necessary to maintain catalytic functions but to prevent loss of broad substrate acceptance. In summary, our data underscore the facile transition between alternative substrate selectivity profiles in GSTs by a few mutations. PMID- 21821041 TI - The TbetaR-I pre-helix extension is structurally ordered in the unbound form and its flanking prolines are essential for binding. AB - Transforming growth factor beta isoforms (TGF-beta) are among the most recently evolved members of a signaling superfamily with more than 30 members. TGF-beta play vital roles in regulating cellular growth and differentiation, and they signal through a highly restricted subset of receptors known as TGF-beta type I receptor (TbetaR-I) and TGF-beta type II receptor (TbetaR-II). TGF-beta's specificity for TbetaR-I has been proposed to arise from its pre-helix extension, a five-residue loop that binds in the cleft between TGF-beta and TbetaR-II. The structure and backbone dynamics of the unbound form of the TbetaR-I extracellular domain were determined using NMR to investigate the extension's role in binding. This showed that the unbound form is highly similar to the bound form in terms of both the beta-strand framework that defines the three-finger toxin fold and the extension and its characteristic cis-Ile54-Pro55 peptide bond. The NMR data further showed that the extension and two flanking 3(10) helices are rigid on the nanosecond-to-picosecond timescale. The functional significance of several residues within the extension was investigated by binding studies and reporter gene assays in cultured epithelial cells. These demonstrated that the pre-helix extension is essential for binding, with Pro55 and Pro59 each playing a major role. These findings suggest that the pre-helix extension and its flanking prolines evolved to endow the TGF-beta signaling complex with its unique specificity, departing from the ancestral promiscuity of the bone morphogenetic protein subfamily, where the binding interface of the type I receptor is highly flexible. PMID- 21821043 TI - The bacteriophage lambda gpNu3 scaffolding protein is an intrinsically disordered and biologically functional procapsid assembly catalyst. AB - Procapsid assembly is a process whereby hundreds of copies of a major capsid protein assemble into an icosahedral protein shell into which the viral genome is packaged. The essential features of procapsid assembly are conserved in both eukaryotic and prokaryotic complex double-stranded DNA viruses. Typically, a portal protein nucleates the co-polymerization of an internal scaffolding protein and the major capsid protein into an icosahedral capsid shell. The scaffolding proteins are essential to procapsid assembly. Here, we describe the solution based biophysical and functional characterization of the bacteriophage lambda (lambda) scaffolding protein gpNu3. The purified protein possesses significant alpha-helical structure and appears to be partially disordered. Thermally induced denaturation studies indicate that secondary structures are lost in a cooperative, apparent two-state transition (T(m)=40.6+/-0.3 degrees C) and that unfolding is, at least in part, reversible. Analysis of the purified protein by size-exclusion chromatography suggests that gpNu3 is highly asymmetric, which contributes to an abnormally large Stokes radius. The size-exclusion chromatography data further indicate that the protein self-associates in a concentration-dependent manner. This was confirmed by analytical ultracentrifugation studies, which reveal a monomer-dimer equilibrium (K(d,app)~50 MUM) and an asymmetric protein structure at biologically relevant concentrations. Purified gpNu3 promotes the polymerization of gpE, the lambda major capsid protein, into virus-like particles that possess a native-like procapsid morphology. The relevance of this work with respect to procapsid assembly in the complex double-stranded DNA viruses is discussed. PMID- 21821042 TI - The Staphylococcus aureus pathogenicity island 1 protein gp6 functions as an internal scaffold during capsid size determination. AB - Staphylococcus aureus pathogenicity island 1 (SaPI1) is a mobile genetic element that carries genes for several superantigen toxins. SaPI1 is normally stably integrated into the host genome but can become mobilized by "helper" bacteriophage 80alpha, leading to the packaging of SaPI1 genomes into phage-like transducing particles that are composed of structural proteins supplied by the helper phage but having smaller capsids. We show that the SaPI1-encoded protein gp6 is necessary for efficient formation of small capsids. The NMR structure of gp6 reveals a dimeric protein with a helix-loop-helix motif similar to that of bacteriophage scaffolding proteins. The gp6 dimer matches internal densities that bridge capsid subunits in cryo-electron microscopy reconstructions of SaPI1 procapsids, suggesting that gp6 acts as an internal scaffolding protein in capsid size determination. PMID- 21821044 TI - Structural constraints in collaborative competition of transcription factors against the nucleosome. AB - Cooperativity in transcription factor (TF) binding is essential in eukaryotic gene regulation and arises through diverse mechanisms. Here, we focus on one mechanism, collaborative competition, which is of interest because it arises both automatically (with no requirement for TF coevolution) and spontaneously (with no requirement for ATP-dependent nucleosome remodeling factors). Previous experimental studies of collaborative competition analyzed cases in which target sites for pairs of cooperating TFs were contained within the same side of the nucleosome. Here, we utilize new assays to measure cooperativity in protein binding to pairs of nucleosomal DNA target sites. We focus on the cases that are of greatest in vivo relevance, in which one binding site is located close to the end of a nucleosome and the other binding site is located at diverse positions throughout the nucleosome. Our results reveal energetically significant positive (favorable) cooperativity for pairs of sites on the same side of the nucleosome but, for the cases examined, energetically insignificant cooperativity between sites on opposite sides of the nucleosome. These findings imply a special significance for TF binding sites that are spaced within one-half nucleosome length (74 bp) or less along the genome and may prove useful for prediction of cooperatively acting TFs genome wide. PMID- 21821045 TI - Aggregation kinetics of interrupted polyglutamine peptides. AB - Abnormally expanded polyglutamine domains are associated with at least nine neurodegenerative diseases, including Huntington's disease. Expansion of the glutamine region facilitates aggregation of the impacted protein, and aggregation has been linked to neurotoxicity. Studies of synthetic peptides have contributed substantially to our understanding of the mechanism of aggregation because the underlying biophysics of polyglutamine-mediated association can be probed independent of their context within a larger protein. In this report, interrupting residues were inserted into polyglutamine peptides (Q20), and the impact on conformational and aggregation properties was examined. A peptide with two alanine residues formed laterally aligned fibrillar aggregates that were similar to the uninterrupted Q20 peptide. Insertion of two proline residues resulted in soluble, nonfibrillar aggregates, which did not mature into insoluble aggregates. In contrast, insertion of a beta-turn template (D)PG rapidly accelerated aggregation and resulted in a fibrillar aggregate morphology with little lateral alignment between fibrils. These results are interpreted to indicate that (a) long-range nonspecific interactions lead to the formation of soluble oligomers, while maturation of oligomers into fibrils requires conformational conversion and (b) that soluble oligomers dynamically interact with each other, while insoluble aggregates are relatively inert. Kinetic analysis revealed that the increase in aggregation caused by the (D)PG insert is inconsistent with the nucleation-elongation mechanism of aggregation featuring a monomeric beta-sheet nucleus. Rather, the data support a mechanism of polyglutamine aggregation by which monomers associate into soluble oligomers, which then undergo slow structural rearrangement to form sedimentable aggregates. PMID- 21821046 TI - Stepwise unfolding of a beta barrel protein by the AAA+ ClpXP protease. AB - In the AAA+ ClpXP protease, ClpX uses the energy of ATP binding and hydrolysis to unfold proteins before translocating them into ClpP for degradation. For proteins with C-terminal ssrA tags, ClpXP pulls on the tag to initiate unfolding and subsequent degradation. Here, we demonstrate that an initial step in ClpXP unfolding of the 11-stranded beta barrel of superfolder GFP-ssrA involves extraction of the C-terminal beta strand. The resulting 10-stranded intermediate is populated at low ATP concentrations, which stall ClpXP unfolding, and at high ATP concentrations, which support robust degradation. To determine if stable unfolding intermediates cause low-ATP stalling, we designed and characterized circularly permuted GFP variants. Notably, stalling was observed for a variant that formed a stable 10-stranded intermediate but not for one in which this intermediate was unstable. A stepwise degradation model in which the rates of terminal-strand extraction, strand refolding or recapture, and unfolding of the 10-stranded intermediate all depend on the rate of ATP hydrolysis by ClpXP accounts for the observed changes in degradation kinetics over a broad range of ATP concentrations. Our results suggest that the presence or absence of unfolding intermediates will play important roles in determining whether forced enzymatic unfolding requires a minimum rate of ATP hydrolysis. PMID- 21821047 TI - HIV-1 reverse transcriptase dissociates during strand transfer. AB - Steps in the replication of human immunodeficiency virus type 1 (HIV-1) occurring in the virus but not in the host are preferred targets of antiretroviral therapy. Strand transfer is unique; the DNA strand being made by viral reverse transcriptase (RT) is moved from one RNA template position to another. Understanding the mechanism requires knowing whether the RT directly mediates the template exchange or dissociates during the exchange, so that it occurs by polymer dynamics. Earlier work in vitro showed that the presence of an RT trapping polymer would allow synthesis on the original or donor template but completely block transfer and subsequent synthesis on the second or acceptor template. One interpretation is that the RT must dissociate during transfer, but an alternative is that sequestration of non-polymerizing RTs prevents polymerization-independent ribonuclease H (RNase H) cleavages of the donor template necessary for strand exchange. To resolve this ambiguity, we designed a primer-template system that allows strand transfer without RNase H activity. Using an RNase H negative mutant RT, we showed that a polymer trap still prevented strand transfer. This confirms that RT dissociates during strand transfer. The presence of HIV-1 nucleocapsid protein, which promotes strand exchange, had little effect on this outcome. Additional assays showed that both the wild-type RT and a multiple nucleoside RT inhibitor-resistant HIV-1 RT containing an extended fingers domain, which is characterized by its enhanced primer-template binding affinity, were unable to transfer with the trapping polymer. This implies that common sequence variations among RTs are unlikely to alter dissociation feature. PMID- 21821048 TI - Drosophila BTB/POZ domains of "ttk group" can form multimers and selectively interact with each other. AB - The BTB (bric-a-brac, tramtrack and broad complex)/POZ (poxvirus and zinc finger) domain is a conserved protein-protein interaction motif contained in a variety of transcription factors involved in development, chromatin remodeling, insulator activity, and carcinogenesis. All well-studied mammalian BTB domains form obligate homodimers and, rarely, tetramers. Only the BTB domain of the Drosophila GAGA factor (GAF) has been shown to exist as higher-order multimers. The BTB domain of GAF belongs to the "ttk group" that contains several highly conserved sequences not found in other BTB domains. Here, we have shown by size-exclusion chromatography, chemical cross-linking, and nondenaturing PAGE that four additional BTB domains of the ttk group-Batman, Mod(mdg4), Pipsqueak, and Tramtrack-can form multimers, like GAF. Interestingly, the BTB domains of GAF and Batman have formed a wide range of complexes and interacted in the yeast two hybrid assay with other BTB domains tested. In contrast, the BTB domains of Mod(mdg4), Pipsqueak, and Tramtrack have formed stable high-order multimer complexes and failed to interact with each other. The BTB domain of Drosophila CP190 protein does not belong to the ttk group. This BTB domain has formed stable dimers and has not interacted with domains of the ttk group. Previously, it was suggested that GAF oligomerization into higher-order complexes facilitates long range activation by providing a protein bridge between an enhancer and a promoter. Unexpectedly, experiments in the Drosophila model system have not supported the role of GAF in organization of long-distance interaction between the yeast GAL4 activator and the white promoter. PMID- 21821051 TI - Green-beard effect predicts the evolution of traitorousness in the two-tag Prisoner's dilemma. AB - Cooperation, a costly interaction in which individuals benefit one another, plays a crucial role in many of the major transitions of evolution. Yet, as illustrated by the Prisoner's dilemma, cooperative systems are fragile because cooperators can be exploited by defectors who reap the benefits of cooperation but do not reciprocate. This barrier to cooperation may be overcome if cooperators have a recognisable phenotypic tag that allows them to adopt the conditional strategy of cooperating with fellow tag-mates while defecting against others, a mechanism known as the 'green-beard effect'. The resulting intra-tag cooperator strategy is particularly effective in structured populations where local clumps of cooperative tag-mates can find refuge. While intra-tag cooperation is robust against unconditional defectors in the spatial Prisoner's dilemma (at least when the cost of cooperation is low), the role of extra-tag cooperators - individuals who cooperate only with those bearing a different tag - has received little attention, despite the fact that these traitors form mixed-tag aggregations whose heterogeneous makeup potentially allows the exploitation of multiple other strategies. Using a spatial model of the two-tag Prisoner's dilemma, I show that extra-tag cooperation readily evolves under low to intermediate cost-benefit ratios of mutual cooperation (r). Specifically, at low r, mixed-tag aggregations of extra-tag cooperators take over the population, while at intermediate r, such aggregations coexist with intra-tag cooperators and unconditional defectors with whom they engage in non-transitive spatial invasibility. In systems with more than two tags, however, the dilution of extra-tag cooperators within mixed-tag aggregations prevents the strategy from being effective. Thus, the same beard chromodynamics that promotes within-group cooperation also predicts the evolution of traitorous between-group cooperation, but only when the number of beard colours is low. PMID- 21821049 TI - Slow formation of stable complexes during coincubation of minimal rRNA and ribosomal protein S4. AB - Ribosomal protein S4 binds and stabilizes a five-helix junction or five-way junction (5WJ) in the 5' domain of 16S ribosomal RNA (rRNA) and is one of two proteins responsible for nucleating 30S ribosome assembly. Upon binding, both protein S4 and 5WJ reorganize their structures. We show that labile S4 complexes rearrange into stable complexes within a few minutes at 42 degrees C, with longer coincubation leading to an increased population of stable complexes. In contrast, prefolding the rRNA has a smaller effect on stable S4 binding. Experiments with minimal rRNA fragments show that this structural change depends only on 16S residues within the S4 binding site. SHAPE (selective 2'-hydroxyl acylation analyzed by primer extension) chemical probing experiments showed that S4 strongly stabilizes 5WJ and the helix (H) 18 pseudoknot, which become tightly folded within the first minute of S4 binding. However, a kink in H16 that makes specific contacts with the S4 N-terminal extension, as well as a right-angle motif between H3, H4, and H18, requires a minute or more to become fully structured. Surprisingly, S4 structurally reorganizes the 530-loop and increases the flexibility of H3, which is proposed to undergo a conformational switch during 30S assembly. These elements of the S4 binding site may require other 30S proteins to reach a stable conformation. PMID- 21821050 TI - The N-terminal domains of myosin binding protein C can bind polymorphically to F actin. AB - The regulation of vertebrate striated muscle contraction involves a number of different molecules, including the thin-filament accessory proteins tropomyosin and troponin that provide Ca(2+)-dependent regulation by controlling access to myosin binding sites on actin. Cardiac myosin binding protein C (cMyBP-C) appears to modulate this Ca(2+)-dependent regulation and has attracted increasing interest due to links with inherited cardiac diseases. A number of single amino acid mutations linked to clinical diseases occur in the N-terminal region of cMyBP-C, including domains C0 and C1, which previously have been shown to bind to F-actin. This N-terminal region also has been shown to both inhibit and activate actomyosin interactions in vitro. Using electron microscopy and three-dimensional reconstruction, we show that C0 and C1 can each bind to the same two distinctly different positions on F-actin. One position aligns well with the previously reported binding site that clashes with the binding of myosin to actin, but would force tropomyosin into an "on" position that exposes myosin binding sites along the filament. The second position identified here would not interfere with either myosin binding or tropomyosin positioning. It thus appears that the ability to bind to at least two distinctly different positions on F-actin, as observed for tropomyosin, may be more common than previously considered for other actin binding proteins. These observations help to explain many of the seemingly contradictory results obtained with cMyBP-C and show how cMyBP-C can provide an additional layer of regulation to actin-myosin interactions. They also suggest a redundancy of C0 and C1 that may explain the absence of C0 in skeletal muscle. PMID- 21821052 TI - Hierarchical cooperativity mediated by chromatin remodeling; the model of the MMTV transcription regulation. AB - Chromatin remodeling machineries are abundant and diverse in eukaryotic cells but their importance in gene expression remains unclear. Although the influence of nucleosome position on the regulation of gene expression is generally envisioned under the equilibrium perspective, it is proposed that given the ATP-dependence of chromatin remodeling enzymes, certain mechanisms necessitate non-equilibrium treatments. In particular, examination of the celebrated chromatin remodeling system of the mouse mammary tumor virus, in which the binding of transcription factors opens the way to other ones, reveals that breaking equilibrium offers a subtle mode of transcription factor cooperativity, avoids molecular trapping phenomena and allows to reconcile previously conflicting experimental data. The mechanism proposed here provides a control lever of promoter sensitivity and responsiveness, increasing the discernment of gene expression. PMID- 21821053 TI - On parameters of the human genome. AB - There are mathematical constants that describe universal relationship between variables, and physical/chemical constants that are invariant measurements of physical quantities. In a similar spirit, we have collected a set of parameters that characterize the human genome. Some parameters have a constant value for everybody's genome, others vary within a limited range. The following nine human genome parameters are discussed here, number of bases (genome size), number of chromosomes (karyotype), number of protein-coding gene loci, number of transcription factors, guanine-cytosine (GC) content, number of GC-rich gene-rich isochores, density of polymorphic sites, number of newly generated deleterious mutations in one generation, and number of meiotic crossovers. Comparative genomics and theoretical predictions of some parameters are discussed and reviewed. This collection only represents a beginning of compiling a more comprehensive list of human genome parameters, and knowing these parameter values is an important part in understanding human evolution. PMID- 21821055 TI - Dimethyl sulphoxide and dimethyl sulphone are potent inhibitors of IL-6 and IL-8 expression in the human chondrocyte cell line C-28/I2. AB - AIMS: Reactive oxygen species (ROS) are highly diffusable and reactive molecules which modulate gene transcription, particularly of pro-inflammatory cytokines which play a crucial role in the nascency and progression of chronic inflammatory diseases such as rheumatoid arthritis (RA) and osteoarthritis (OA). Since thiols could be potent inhibitors of the production of cytokines, the effects of dimethyl sulphoxide (DMSO) and dimethyl sulphone (DMS) on constitutive and IL 1beta-induced IL-6 and IL-8 expression in the human chondrocyte cell line C-28/I2 were evaluated. MAIN METHODS: C-28/I2 cells were incubated for 12h with different concentrations of DMSO or DMS. The secretion of IL-6 and IL-8 was quantified by enzyme-linked immunosorbent assays (ELISAs). The impact of DMSO and DMS on the regulation of p38 and ERK1/2 mitogen-activated protein kinases (MAPKs) was confirmed by Western blot experiments. Furthermore, C-28/I2 cells were stimulated with IL-1beta in the absence or presence of DMSO and DMS and IL-6 and IL-8 expression was quantified by ELISAs and quantitative real-time polymerase chain reaction (qRT-PCR). KEY FINDINGS: C-28/I2 cells constitutively expressed large quantities of IL-6 and IL-8. Long-term exposure of cells to DMSO (1%) or DMS (100mM) led to a dramatic downregulation of IL-6 and IL-8 expression which was accompanied by the deactivation of ERK1/2. Both substances also blocked IL-1beta induced IL-6 and IL-8 expression. SIGNIFICANCE: In this study, we demonstrate that both DMSO and DMS represent strong anti-inflammatory properties by blocking constitutive as well as IL-1beta-induced IL-6 and IL-8 expression in the human chondrocyte cell line C-28/I2. PMID- 21821056 TI - Maternal inflammation, growth retardation, and preterm birth: insights into adult cardiovascular disease. AB - The "fetal origin of adult disease Hypothesis" originally described by Barker et al. identified the relationship between impaired in utero growth and adult cardiovascular disease risk and death. Since then, numerous clinical and experimental studies have confirmed that early developmental influences can lead to cardiovascular, pulmonary, metabolic, and psychological diseases during adulthood with and without alterations in birth weight. This so called "fetal programming" includes developmental disruption, immediate adaptation, or predictive adaptation and can lead to epigenetic changes affecting a specific organ or overall health. The intrauterine environment is dramatically impacted by the overall maternal health. Both premature birth or low birth weight can result from a variety of maternal conditions including undernutrition or dysnutrition, metabolic diseases, chronic maternal stresses induced by infections and inflammation, as well as hypercholesterolemia and smoking. Numerous animal studies have supported the importance of both maternal health and maternal environment on the long term outcomes of the offspring. With increasing rates of obesity and diabetes and survival of preterm infants born at early gestational ages, the need to elucidate mechanisms responsible for programming of adult cardiovascular disease is essential for the treatment of upcoming generations. PMID- 21821057 TI - Electrophysiological correlates of non-symbolic numerical magnitude processing in children: joining the dots. AB - Whether and in what way enumeration processes differ for small and large sets of objects is still a matter of debate. In order to shed light on this issue, EEG data were obtained from 60 normally developing elementary school children. Adopting a standard non-symbolic numerical comparison paradigm allowed us to manipulate numerical distance between stimulus arrays for different quantity ranges, i.e. the subitizing, counting and estimation ranges. In line with the existing literature, the amplitudes of parietal positive going ERP components showed systematic effects of numerical distance, which did not depend on set size. In contrast to the similarities in surface distribution of electrophysiological activity across all number ranges, applying source localization we found distance related current density effects in inferior parietal processing systems to be similar for all numerical ranges, there was, however, considerable variation in the involvement of medial parietal and lateral occipital regions. The precuneus, which is known to be involved in visual imagery, showed distance effects exclusively for numerical comparisons on large set sizes. In contrast, the processing of small quantities and stimulus arrays arranged into canonical patterns relied on lateral occipital areas that are linked to higher-level shape recognition. These findings suggest, on the one hand, that for explicit numerical decisions an involvement of domain-specific resources does not depend on quantity features of the visual input. On the other hand, it seems that the recruitment of mediating perceptual systems differs between the apprehension of small quantities and the enumeration of large sets of objects. PMID- 21821058 TI - Depressive symptoms and sub-clinical atherosclerosis in Africans: role of metabolic syndrome, inflammation and sympathoadrenal function. AB - Depressive symptoms have been consistently associated with sub-clinical atherosclerosis and future risk of coronary heart disease events. However, the pathways linking depression and coronary atherosclerosis are poorly understood. These types of data are particularly sparse in sub-Saharan Africa, which is presently experiencing an exponential rise in CVD. We examined the association between depressive symptoms and mean carotid intima media thickness (mCIMT), and the extent to which this association could be explained by sympathoadrenal function, inflammatory, and metabolic pathways. A sample of 186 black (aged 44.0+/-8.0years) and 203 Caucasians (aged 44.8+/-10.8years) were recruited as part of the Sympathetic Activity and Ambulatory Blood Pressure in Africans (SABPA) study - presently the only study in sub-Saharan Africa focusing on the contribution of the psychosocial risk factors to cardiovascular health. Depressive symptoms were assessed using the self administered 9-item Patient Health Questionnaire. After adjusting for age, sex, ethnicity, and anti hypertensive drugs use, participants with severe depressive symptoms had higher mCIMT in comparison to participants with no symptoms (beta=0.038mm, 95% CI, 0.001 to 0.074mm). Metabolic syndrome was the only significant mediator of the association between depressive symptoms and mCIMT, and accounted for approximately 21% of the effect. In summary, depressive symptoms were associated with an excess burden of sub-clinical vascular disease. Treatment of metabolic syndrome in patients with depression may partly reduce the risk of sub-clinical vascular disease development. PMID- 21821059 TI - Altered cardiovascular reactivity and osmoregulation during hyperosmotic stress in adult rats developmentally exposed to polybrominated diphenyl ethers (PBDEs). AB - Polybrominated diphenyl ethers (PBDEs) and the structurally similar chemicals polychlorinated biphenyls (PCBs) disrupt the function of multiple endocrine systems. PCBs and PBDEs disrupt the secretion of vasopressin (VP) from the hypothalamus during osmotic activation. Since the peripheral and central vasopressinergic axes are critical for osmotic and cardiovascular regulation, we examined whether perinatal PBDE exposure could impact these functions during physiological activation. Rats were perinatally dosed with a commercial PBDE mixture, DE-71. Dams were given 0 (corn oil control), 1.7 (low dose) or 30.6 mg/kg/day (high dose) in corn oil from gestational day (GD) 6 through postnatal day (PND) 21 by oral gavage. In the male offspring exposed to high dose PBDE plasma thyroxine and triiodothyronine levels were reduced at PND 21 and recovered to control levels by PND 60 when thyroid stimulating hormone levels were elevated. At 14-18 months of age, cardiovascular responses were measured in four groups of rats: Normal (Oil, normosmotic condition), Hyper (Oil, hyperosmotic stress), Hyper PBDE low (1.7 mg/kg/day DE-71 perinatally, hyperosmotic stress), and Hyper PBDE high (30.6 mg/kg/day DE-71 perinatally, hyperosmotic stress). Systolic blood pressure (BP), diastolic BP, and heart rate (HR) were determined using tail cuff sphygmomanometry and normalized to pretreatment values (baseline) measured under basal conditions. Hyperosmotic treatment yielded significant changes in systolic BP in PBDE exposed rats only. Hyper PBDE low and high dose rats showed 36.1 and 64.7% greater systolic BP responses at 3h post hyperosmotic injection relative to pretreatment baseline, respectively. No treatment effects were measured for diastolic BP and HR. Hyper and Hyper PBDE rats showed increased mean plasma osmolality values by 45 min after injection relative to normosmotic controls. In contrast to Hyper rats, Hyper PBDE (high) rats showed a further increase in mean plasma osmolality at 3h (358.3+/-12.4mOsm/L) relative to 45 min post hyperosmotic injection (325.1+/-11.4mOsm/L). Impaired osmoregulation in PBDE treated animals could not be attributed to decreased levels of plasma vasopressin. Our findings suggest that developmental exposure to PBDEs may disrupt cardiovascular reactivity and osmoregulatory responses to physiological activation in late adulthood. PMID- 21821060 TI - B1-induced caspase-independent apoptosis in MCF-7 cells is mediated by down regulation of Bcl-2 via p53 binding to P2 promoter TATA box. AB - The Bcl-2 family contains a panel of proteins which are conserved regulators of apoptosis in mammalian cells, like the anti-apoptotic protein Bcl-2. According to its significant role in altering susceptibility to apoptosis, the deciphering of the mechanism of Bcl-2 expression modulation may be crucial for identifying therapeutics strategies for cancer. Treatment with naphthalimide-based DNA intercalators, including M2-A and R16, generally leads to a decrease in Bcl-2 intracellular amounts. Whereas the interest for these chemotherapeutics is accompanied by advances in the fundamental understanding of their anticancer properties, the molecular mechanism underlying changes in Bcl-2 expression remains poorly understood. We report here that p53 contributes to Bcl-2 down regulation induced by B1, a novel naphthalimide-based DNA intercalating agent. Indeed, the decrease in Bcl-2 protein levels observed during B1-induced apoptosis was correlated to the decrease in mRNA levels, as a result of the inhibition of Bcl-2 transcription and promoter activity. In this context, we evaluated p53 contribution in the Bcl-2 transcriptional down-regulation. We found a significant increase of p53 binding to P(2) promoter TATA box in MCF7 cells by chromatin immunoprecipitation. These data suggest that B1-induced caspase-independent apoptosis in MCF-7 cells is associated with the activation of p53 and the down regulation of Bcl-2. Our study strengthens the links between p53 and Bcl-2 at a transcriptional level, upon naphthalimide-based DNA intercalator treatment. PMID- 21821061 TI - Toxicological interactions between the mycotoxins beauvericin, deoxynivalenol and T-2 toxin in CHO-K1 cells in vitro. AB - Beauvericin (BEA), deoxynivalenol (DON) and T-2 toxin (T-2) are important food borne mycotoxins that have been implicated in human health. In this study, the acute toxicity of individual and combined mycotoxins (BEA, DON and T-2) were tested in immortalized hamster ovarian cells (CHO-K1) at 24, 48 and 72 h of exposure, by the tetrazolium salt (MTT) and neutral red (NR) assays. The IC(50) values obtained for all mycotoxins by the MTT and NR assays ranged from 0.017 to 12.08 MUM and from 0.042 to 17.22 MUM, respectively. Both, individual and combined mycotoxins demonstrated a significant cytotoxic effect in CHO-K1 cells in a dose-dependent manner. When mycotoxins were assayed individually, T-2 showed the strongest IC(50) values (from 0.017 to 0.052 MUM), by both endpoints tested, followed by DON (0.53-2.30 MUM) and BEA, showing this last one, the weakest IC(50) values (from 2.77 to 17.22 MUM). On the other hand, cytotoxicity interactions were evaluated by the isobologram method. In acute binary tests, DON+BEA (CI=1.60-25.07) and DON+T-2 (CI=1.74-7.71) showed antagonism at 24, 48 and 72 h of exposure. By contrast, the binary BEA+T-2 combination (CI=0.35-0.78) showed synergism at all time of exposure tested. The tertiary BEA+DON+T-2 combination demonstrated synergism effect (CI=0.47-0.86) after 24 and 48 h of exposure; however moderate antagonistic effect (CI=1.14-1.60) was presented after 72 h of exposure at the lower doses. These results provide quantitative evidence regarding potentially important interactions between BEA, DON and T-2 depending of the time of exposure. The combination index-isobologram equation method can serve as a useful tool in food risk assessment. Due to the potent toxic effects of BEA, DON and T-2, its combined exposure might be an important trigger for development of several diseases in humans, from the mycotoxicological point of view, especially after long period of exposure time. PMID- 21821062 TI - Prevention of thermal aggregation of an allosteric protein by small molecules: some mechanistic insights. AB - Detailed knowledge of conformation and dynamics of native, intermediate and unfolded states of a protein is essential in searching for effective small molecules to prevent its aggregation. In a recent study we have demonstrated how allosteric effectors may influence protein-protein interactions at high temperatures using glutamate dehydrogenase (GDH) as a model allosteric protein. In the present study, thermal aggregation of this well-characterized enzyme was investigated in the presence of a number of amino acids (including Gly, Glu, Trp, Pro, Lys, Arg), polyamines (putrescine and spermidine) and chaperone-like molecules (cyclodextrins and caseins) as non-specific effectors. It was shown that some amino acids and polyamines may suppress aggregation via interaction with native species and may preserve the activity of the enzyme while cyclodextrins and caseins may exert their anti-aggregation potential via binding to aggregation-prone intermediates, without having any capacity to protect its native structure from unfolding. Observations describing the similarities and differences between the specific ligands and non-specific small molecules related to their interaction with native and aggregation-prone states of GDH are presented and discussed. It is argued that the type of studies described in the present communication is useful for the development of effective strategies for prevention of aggregation by small molecules. PMID- 21821063 TI - Inhibitory effect of carboxymethylpachymaran on cyclophosphamide-induced oxidative stress in mice. AB - The aim of the present study was to investigate the immunomodulatory effect and antioxidant activity of carboxymethylpachymaran on cyclophosphamide-induced immunosuppression in mice in vivo. The results showed that carboxymethylpachymaran could be used to overcome the cyclophosphamide-induced immunosuppression in mice. Moreover, it significantly increased the thymus and spleen indices, lysozyme, catalase and superoxidase dismutase activities, and total antioxidant capacity. In contrast, it decreased xanthine oxidase activity and malondialdehyde levels. The results indicated that carboxymethylpachymaran might play an important role in the prevention of oxidative damage in the immunological system. PMID- 21821064 TI - Estrous cycle stage influences on neuronal responsiveness to repeated anxiogenic stress in female rats. AB - Experiments were carried out to investigate (i) whether estrous cycle stage influences nociceptive responsiveness to anxiogenic stress and (ii) whether prior experience of the stressor modifies the response. Exposure to mild anxiogenic vibration stress evoked hyperalgesia, reflected by a decrease in tail flick latency, only in animals in the late diestrus phase. Stress evoked hyperalgesia in late diestrus regardless of whether the rat was experiencing the stress for the first time or had been exposed to the stress previously, when in another cycle stage. Whilst the behavioral response to stress appeared to be determined exclusively by estrous cycle stage, the stress-evoked pattern of Fos expression in the periaqueductal grey matter (PAG) depended not only on cycle stage but also on whether the rat had previous experience of the stress. First exposure to stress in late diestrus evoked a 50% decrease in Fos expression compared to non stressed controls, particularly in the lateral and dorsolateral sectors of the rostral PAG. In contrast, in experienced rats in late diestrus the pattern of Fos expression increased up to 4-fold, particularly in the ventral half of the caudal PAG but also in the lateral and dorsolateral parts. At other cycle stages Fos expression was not changed except for an increase in rats in proestrus. The results suggest that in females, changes in gonadal hormone levels during the estrous cycle impact significantly on the processing of fear-inducing stimuli by the PAG. These hormonal influences may also influence how the PAG responds to a subsequent anxiogenic challenge. PMID- 21821065 TI - Early-life stress mediated modulation of adult neurogenesis and behavior. AB - Early life is a period of unique sensitivity during which experience can confer enduring effects on brain structure and function. During early perinatal life the quality of the surrounding environment and experiences, in particular the parent child relationship, is associated with emotional and cognitive development later in life. For instance, adverse early-life experience is correlated with an increased vulnerability to develop psychopathologies and aging-related cognitive decline. These are thought to be mediated by acute and long-lasting effects on the, at that time still developing, stress-neuroendocrine and cognitive systems. Adult hippocampal neurogenesis is involved in learning and memory while both regulation of the stress response as well as early-life stress is known to permanently reduce neurogenesis, and to be implicated in these functional deficits. In order to increase our understanding of the influence of the perinatal environment on the long-lasting programming of neurogenesis, we here discuss immediate and lasting effects of various adverse early-life experiences on hippocampal neurogenesis and the associated behavioral alterations. Considering the persistence of these effects, the underlying molecular mechanisms, with focus on the potential epigenetic mechanisms will be discussed as well. Finally, special attention will be paid to the prominent sex differences in early-life stress-induced alterations in neurogenesis. PMID- 21821066 TI - Molecular characterization of Plasmodium falciparum putative polynucleotide kinase/phosphatase. AB - Polynucleotide kinase/phosphatase (PNKP) is a bifunctional enzyme that can phosphorylate the 5'-OH termini and dephosphorylate the 3'-phosphate termini of DNA. It is a DNA repair enzyme involved in the processing of strand break termini, which permits subsequent repair proteins to replace missing nucleotides and rejoin broken strands. Little is known about DNA repair in Plasmodium falciparum, including the roles of PNKP in repairing parasite DNA. We identified a P. falciparum gene encoding a protein with 24% homology to human PNKP and thus suggestive of a putative PNKP. In this study, the PNKP gene of P. falciparum strain K1 (PfPNKP) was successfully cloned and expressed in E. coli as a GST PfPNKP recombinant protein. MALDI-TOF/TOF analysis of the protein confirmed the identity of PfPNKP. Assays for enzymatic activity were carried out with a variety of single- and double-stranded substrates. Although 3'-phosphatase activity was detected, PfPNKP was observed to dephosphorylate single-stranded substrates or double-stranded substrates with a short 3'-single-stranded overhang, but not double-stranded substrates that mimicked single-strand breaks. We hypothesize that unlike human PNKP, PfPNKP may not be involved in single-strand break repair, since alternative terminal processing mechanisms can substitute for PfPNKP, and that PfPNKP DNA repair actions may be confined to overhanging termini of double strand breaks. PMID- 21821067 TI - Development of a small-scale bioreactor method to monitor the molecular diversity and environmental impacts of bacterial biofilm communities from an acid mine drainage impacted creek. AB - Shamokin Creek is a tributary of the Susquehanna River in central Pennsylvania that is heavily impacted by the acid mine drainage (AMD) caused by the oxidation of pyrite from the region's extensive anthracite coal mining industry. Recent studies have begun to characterize the microbial communities present in this and other AMD-impacted waters, but varying environmental conditions have complicated attempts to determine the ecological impacts of individual bacterial species within these communities. This study developed a small-scale biofilm reactor protocol that allowed us to simultaneously monitor the development of bacterial biofilm communities in AMD-impacted creek collected water using terminal restriction fragment length polymorphism (T-RFLP) analysis of 16S rRNA genes, while assessing the impacts that the developing biofilms were having on water quality. Our analysis confirmed that the diversity and composition of these small in situ biofilm communities could be monitored using molecular methods, and indicated the possible presence of many taxa frequently found in AMD environments, including Sulfobacillus, Nitrospira, Desulfovibrio, Geobacter, and Leptothrix species. A significant increase in the total sulfate was observed in the bioreactor, and as most likely due to the accumulation of sulfur-oxidizing bacteria such as Sulfobacillus in the biofilms. This system will allow us to study the microbial ecology of Shamokin Creek through controlled experiments that will ultimately integrate microscopic, molecular, physiological and chemical analyses, and that can be utilized to develop more effective and cost-efficient environmental remediation techniques for AMD-impacted areas. PMID- 21821068 TI - Effect of PCR amplicon length on suppressing signals from membrane-compromised cells by propidium monoazide treatment. AB - Treatment of microbiological samples with viability dyes prior to extraction of DNA and PCR amplification for downstream analysis has evolved into a commonly applied method. The addition of this easy-to-perform step to the sample analysis procedure inhibits the amplification of DNA from dead cells with compromised cell membranes. The method is currently used both in combination with quantitative PCR (qPCR), end-point PCR, and isothermal amplification. We present here a detailed study of the effect of amplicon size on amplification signals from unstressed and heat-exposed cells after treatment with propidium monoazide (PMA). PMA treatment was shown to be more efficient in excluding dead cells from the analysis both in combination with qPCR (PMA-qPCR) and denaturing gradient gel electrophoresis (PMA DGGE), when longer amplicons were used. When applied to pure cultures of the fish pathogens Vibrio anguillarum and Flavobacterium psychrophilum exposed to a heat gradient ranging from mild to lethal, qPCR product lengths did not influence PMA qPCR results at low temperatures, whereas an increasingly strong impact was seen at higher temperatures. Membrane permeability as a result of heat exposure might however have to be considered a conservative parameter for cell death for these pathogens as culturability and redox activity were lost at lower stress intensities than membrane integrity. When applying PMA-DGGE to an environmental water sample which was either left untreated or was exposed to heat, differences to non-PMA treated samples tended to slightly increase when amplified fragments in the first round of the nested PCR were longer, whereas the impact of 1st-round cycle numbers remains unclear. PMID- 21821069 TI - Purine P2Y receptors in ATP-mediated regulation of non-quantal acetylcholine release from motor nerve endings of rat diaphragm. AB - We established the effect of ATP, which is released together with acetylcholine (ACh), on the non-quantal ACh release (NQR) in rat diaphragm endplates and checked what kind of purine receptors are involved. NQR was estimated by the amplitude of endplate hyperpolarization (the H-effect) following the blockade of postsynaptic nicotinic receptors and cholinesterase. 100 MUM ATP reduced the H effect to 66% of the control. The action of ATP remained unchanged after the inhibition of ionotropic P2X receptors by Evans blue and PPADS, but disappeared after the application of the broad spectrum P2 receptor antagonist suramin, metabotropic P2Y receptor blocker reactive blue 2 and U73122, an inhibitor of phospholipase C. P2Y-mediated regulation is not coupled to presynaptic voltage dependent Ca(2+) channels. During the simultaneous application of ATP and glutamate (which is another ACh cotransmitter reducing non-quantal release), the additive depressant effect led to a disappearance of the H-effect. This can be explained by the independence of the action of ATP and glutamate. Unlike the effects of purines on the spontaneous quantal secretion of ACh, its non-quantal release is regulated via P2Y receptors coupled to G(q/11) and PLC. ATP thus regulates the neuromuscular synapse by two different pathways. PMID- 21821070 TI - Subcortical vascular dementia. AB - Subcortical vascular dementia (SVD) is a small vessel disease with dementia that exhibits relatively uniform clinical and pathological features and constitutes approximately half of vascular dementia (VaD) cases. This subtype is further classified into Binswanger's disease and multiple lacunar infarctions. The former is characterized by diffuse white matter lesions, and the latter is characterized by lacunar infarctions. Both of these entities are related to hypertensive small vessel changes. Subcortical vascular dementia may exhibit slowly progressive vascular Parkinsonism and dementia but can be differentiated from Alzheimer's disease because it is associated with more extensive white matter lesions, less severe hippocampal atrophy and the absence of cerebral amyloid angiopathy (CAA), which may be indicated radiologically by lobar microbleeds, cortical subarachnoid hemorrhage (SAH) and cortical microinfarctions. Cerebral amyloid angiopathy may manifest as dementia and constitute the cortical type counterpart of SVD in small vessel disease with dementia. This paper provides an overview of the clinical features, pathogenesis and treatment for SVD, as well as its relationship to CAA and Alzheimer's disease. PMID- 21821071 TI - Evaluation of tongue sensory disturbance by somatosensory evoked magnetic fields following tongue stimulation. AB - Quantitative measurement is required in clinical situation for sensory disturbance of the tongue due to lingual nerve injury. To assess disabled sensory function of the tongue, somatosensory evoked magnetic fields (SEFs) were measured following electric tongue stimulation in 13 patients with sensory disturbance by unilateral lingual nerve injury and in 10 age-matched healthy volunteers. Affected- and healthy-sides of the tongue were stimulated separately with the same intensity. Although the healthy-side stimulation induced clear responses over the contralateral hemisphere of all participants, the affected-side stimulation evoked hardly traceable responses in 6 patients and no activity in the remaining 7 patients. We evaluated the cortical activity via activated root mean-square (aRMS), which is the time-averaged activity between 10 and 150 ms from the 18-channel RMS over the contralateral hemisphere. The laterality index of aRMS, expressed as [(left-right)/(left+right)], was out of the pre-defined normal range (-0.287 to 0.337) in 12 patients, and within the range in all healthy volunteers. The test sensitivity and specificity of the procedure were 92.3% and 100%, respectively. Tongue SEFs are reproducible and objective method to evaluate sensory disturbance of the tongue. PMID- 21821072 TI - Influence of carbohydrates and proteins concentration on fermentative hydrogen production using canteen based waste under acidophilic microenvironment. AB - Functional role of biomolecules viz., carbohydrates and proteins on acidogenic biohydrogen (H(2)) production was studied through the treatment of canteen based composite food waste. The performance was evaluated in an anaerobic sequencing batch reactor (AnSBR) at pH 6 with five variable organic loading conditions (OLR1, 0.854; OLR2, 1.69; OLR3, 3.38; OLR4, 6.54 and OLR5, 9.85kgCOD/m(3)-day). Experimental data depicted the feasibility of H(2) production from the stabilization of food waste and was found to depend on the substrate load. Among the five loading conditions studied, OLR4 documented maximum H(2) production (69.95mmol), while higher substrate degradation (3.99kgCOD/m(3)-day) was observed with OLR5. Specific hydrogen yield (SHY) vary with the removal of different biomolecules and was found to decrease with increase in the OLR. Maximum SHY was observed with hexose removal at OLR1 (139.24mol/kg Hexose(R) at 24h), followed by pentoses (OLR1, 108.26mol/kg Pentose(R) at 48h), proteins (OLR1, 109.71mol/kg Protein(R) at 48h) and total carbohydrates (OLR1, 58.31mol/kg CHO(R) at 24h). Proteins present in wastewater helped to maintain the buffering capacity but also enhanced the H(2) production by supplying readily available organic nitrogen to the consortia. Along with carbohydrates and proteins, total solids also registered good removal. PMID- 21821073 TI - The initial metabolic conversion of levulinic acid in Cupriavidus necator. AB - Levulinic acid or 4-ketovaleric acid is a potential renewable substrate for production of polyhydroxyalkanoates. In this work, the initial reactions of LA metabolism by Cupriavidus necator were examined in vitro. The organic acid was converted by membrane-bound crude enzymes obtained from the cells pre-grown on LA, while no LA activity was detected from cells pre-grown on acetic acid. Acetyl CoA and propionyl-CoA were two major intermediates in the initial reactions of LA conversion. A mass balance on propionyl-CoA accounts for 84 mol% of LA added in vitro. It explains an interesting phenomenon that 3-hydroxbutyrate and 3 hydroxyvalerate are two major monomers of the biopolyester formed from LA, instead of 4-hydroxvalerate that has the similar chemical structure of LA as the precursor. A Monod model was used to describe the kinetics of LA utilization as a sole carbon source or a co-substrate of glucose and fructose. The MU(max) and K(m) of LA alone were 0.26 h-1 and 0.01 g/L, respectively. The content and composition of PHA are also dependent on the culture conditions such as carbon to nitrogen ratio. The in vitro observation is supported by the high utilization rate of LA and the high molar percentage of 3HB and 3HV in the PHA derived from LA. PMID- 21821074 TI - In vitro and in vivo efficacy of edelfosine-loaded lipid nanoparticles against glioma. AB - Edelfosine is the prototype molecule of a family of anticancer drugs collectively known as synthetic alkyl-lysophospholipids. This drug holds promise as a selective antitumor agent, and a number of preclinical assays are in progress. In this study, we observe the accumulation of edelfosine in brain tissue after its oral administration in Compritol(r) and Precirol(r) lipid nanoparticles (LN). The high accumulation of edelfosine in brain was due to the inhibition of P glycoprotein by Tween(r) 80, as verified using a P-glycoprotein drug interaction assay. Moreover, these LN were tested in vitro against the C6 glioma cell line, which was later employed to establish an in vivo xenograft mouse model of glioma. In vitro studies revealed that edelfosine-loaded LN induced an antiproliferative effect in C6 glioma cell line. In addition, in vivo oral administration of drug loaded LN in NMRI nude mice bearing a C6 glioma xenograft tumor induced a highly significant reduction in tumor growth (p<0.01) 14days after the beginning of the treatment. Our results showed that Tween(r) 80 coated Compritol(r) and Precirol(r) LN can effectively inhibit the growth of C6 glioma cells in vitro and suggest that edelfosine-loaded LN represent an attractive option for the enhancement of antitumor activity on brain tumors in vivo. PMID- 21821075 TI - VEGF-C as a decision-making biomarker for selected patients with invasive bladder cancer who underwent bladder-preserving radical surgery. AB - BACKGROUND AND AIMS: We proved the feasibility of radical transurethral resection in selected patients with muscle-invasive bladder cancer with a minimum follow-up of >5 years. A follow-up schedule was developed based on progression and recurrence during this period. METHODS: The study included 93 patients with invasive bladder cancer treated by radical transurethral resection. Student t test was used for continuous variables to establish clinical progression predictive factors. VEGF-C protein expressions were tested by immunohistochemistry postsurgery. RESULTS: The overall survival and disease specific survival rates for all 93 patients were 59.1% and 65.2%, respectively. The clinical stage of the tumor influenced overall survival (p = 0.024) and disease-specific survival (p = 0.047). A significantly higher overall survival and disease-specific survival rate for patients with low levels of VEGF-C was 69.6% and 75.0%, respectively, than for those with high levels of VEGF-C (45.9 and 54.1%, respectively, p <0.05).The presence of bladder Tis reduced the survival rate (41.2 vs. 65.3%) and disease-specific survival (45.4 vs. 72.1%). Sensitivity, specificity and accuracy of VEGF-C in the evaluation of disease progression were 76.7, 77.8, 77.4%, respectively. CONCLUSIONS: Patients with T2 stage, low level of VEGF-C and absence of bladder Tis were associated with high overall survival and disease-specific survival rate. VEGF-C level can evaluate disease progression and assist in choosing the appropriate treatment. PMID- 21821077 TI - Refers to: J.-P. Rasigade, N. Sicot, F. Laurent, G. Lina, F. Vandenesch, J. Etienne, A history of Panton-Valentine leukocidin (PVL)-associated infection protects against death in PVL-associated pneumonia, Vaccine 29 (25) (2011) 4185 4186. PMID- 21821078 TI - A mixture of three prebiotics does not affect vaccine specific antibody responses in healthy term infants in the first year of life. AB - BACKGROUND: Previous studies have shown, that prebiotics can modulate the immune response in infants at risk for allergy, leading to a lower incidence of atopic dermatitis. Few studies have evaluated the effect of prebiotic carbohydrates alone on the vaccine-specific antibody response as a marker for the development of the immune system in healthy infants not at risk for allergy. AIM: This study evaluates the effect of adding a specific prebiotic mixture of short chain galacto-oligosaccharides (scGOS)/long chain fructo-oligosaccharides (lcFOS) ratio 9:1 and pectin-derived acidic oligosaccharides (pAOS) to formula feeding on the specific immunoglobulin responses to Haemophilus influenza type b (Hib) and tetanus immunization in healthy non-atopic infants during the first year of life. METHODS: This substudy has been embedded in a multinational multicenter RCT (n=1130 children) to evaluate the effect of study prebiotics on the incidence of fever episodes during the first year of life. The study prebiotics were administered throughout the first year of life. This is a substudy on the vaccine specific immunoglobulin responses to Hib and tetanus immunizations. Only data of the Dutch children, 80 in the prebiotics group and 84 in the control group, were used for this substudy. They all followed the national vaccination schedule leading to a homogeneous group. Blood was sampled at 6 and 12 months of age. RESULTS: Hib immunizations: median values did not differ between groups at the age of 6 and 12 months. At the age of 12 months, 34 out of 37 (91.9%) infants in the prebiotics group and 31 out of 34 infants (91.2%) in the control group had Hib antibody levels >1.0 MUg/ml. Tetanus immunizations: median values did not differ between groups at the age of 6 and 12 months and were above the cut-off value of 0.1 IU/ml in all infants in both the prebiotics and the control group. CONCLUSION: No effect of prebiotics supplementation on vaccination specific antibody levels was found in children up to the age of 12 months; the vaccine specific antibody levels in infants fed the study prebiotics or a control diet were similar during the first year of life. We hypothesize that this specific prebiotic mixture, which resembles the composition of oligosaccharides in human milk, mainly promotes Th1 and Treg dependent immune responses and induces a down regulation of IgE-mediated allergic responses, while the desired vaccine-specific serum antibody responses remain intact. PMID- 21821079 TI - Parental acceptance of human papillomavirus (HPV) vaccination in Indonesia: a cross-sectional study. AB - BACKGROUND: Cervical cancer ranks the second most frequent cancer in Indonesian women. In Indonesia, human papillomavirus (HPV) vaccine acceptance has not been studied before. OBJECTIVE: To determine parental HPV vaccine acceptance in Indonesia, and factors that influence their decision. Factors include sociodemographic factors, knowledge of HPV, HPV vaccination and cervical cancer, health beliefs about cervical cancer, and attitudes towards vaccination in general. METHODS: 746 parents, with at least 1 daughter aged 0-14, were interviewed using questionnaires based on published and adjusted interviews. Interviews were done in sub district public health centers, general governmental hospitals, and via house-visits, in 5 Indonesian provinces. RESULTS: Parental HPV vaccine acceptance was 96.1%. Logistic regression revealed that age, beliefs regarding cervical cancer, and attitudes towards vaccination in general were significantly associated with HPV vaccine acceptance. Of the participants, 66.0%, 16.6%, and 15.8% had heard about cervical cancer, HPV, and HPV vaccination respectively. The mean total knowledge score was 1.91(Standard Deviation 2.31) on a 0-8 scale. Health beliefs about cervical cancer and attitudes towards vaccination in general were positive. Participants named the high cost of the vaccine, fear for side-effects, and chosen vaccination locations as possible barriers towards HPV vaccine implementation. DISCUSSION: Parental HPV vaccine acceptance is high, but knowledge about HPV and cervical cancer is low. During HPV vaccination programs, focus should not only be on providing information, but also on existing beliefs and attitudes towards cervical cancer and vaccination in general. If HPV vaccination programs were to be implemented in Indonesia, the indicated barriers should be taken into account. PMID- 21821080 TI - Comparing pneumococcal conjugate vaccine schedules based on 3 and 2 primary doses: systematic review and meta-analysis. AB - BACKGROUND: Pneumococcal conjugate vaccines (PCV) were first licensed for use with 3 primary doses in infancy and a booster dose. The evidence for the effects of different schedules was examined in this systematic review and meta-analysis. METHODS: We searched 12 databases and trial registers up to March 2010. We selected randomised controlled trials (RCTs), cohort and case-control studies making direct comparisons between PCV schedules with (2p) or (3p) primary doses, with (+1) or without (+0) a booster dose. We extracted data on clinical, nasopharyngeal carriage and immunological outcomes and used meta-analysis to combine results where appropriate. RESULTS: Seropositivity levels (antibody concentration >=0.35 MUg/ml) following 3p and 2p PCV schedules were high for most serotypes (5 RCTs). Differences between schedules were generally small and tended to favour 3p schedules, particularly for serotypes 6B and 23F; between-study heterogeneity was high. Seropositivity levels following 3p+1 and 2p+1 schedules were similar but small differences favouring 3p+1 schedules were seen for serotypes 6B and 23F. We did not identify any RCTs reporting clinical outcomes for these comparisons. In 2 RCTs there was weak evidence of a reduction in carriage of S. pneumoniae serotypes included in the vaccine when 3p+0 schedules were compared to 2p+0 at 6 months of age. CONCLUSIONS: Most data about the relative effects of different PCV schedules relate to immunological outcomes. Both 3p and 2p schedules result in high levels of seropositivity. The clinical relevance of differences in immunological outcomes between schedules is not known. There is an absence of clinical outcome data from RCTs with direct comparisons of any 2p with any 3p PCV schedule. PMID- 21821081 TI - Echographic measurement of skin thickness in sites suitable for intradermal vaccine injection in infants and children. AB - Whereas the knowledge of skin thickness is essential to determine microneedle length and ensure proper administration of and better responses to intradermal vaccines, very few figures are available, especially in infants and children. Using ultrasound echography, we investigated skin thickness in 384 children aged 4-7, 12-18, and 54-66 months at potential body sites for intradermal vaccine delivery: deltoid, suprascapular, upper back, and lumbar area. The mean epidermis plus dermis thickness was significantly higher at the suprascapular than at the deltoid site (1.29mm vs. 1.22mm) and remained relatively unchanged whatever the BMI, age, sex, and skin phototype. In the 43 children aged 54-66 months, the mean skin thickness was significantly higher in the upper than in the lumbar area (1.39mm vs. 1.31mm). In this study setting, the heterogeneity in skin thickness cannot be considered sufficient to indicate various microneedle lengths for various ages or injection sites. PMID- 21821082 TI - Prevention of influenza virus shedding and protection from lethal H1N1 challenge using a consensus 2009 H1N1 HA and NA adenovirus vector vaccine. AB - Vaccines against emerging pathogens such as the 2009 H1N1 pandemic virus can benefit from current technologies such as rapid genomic sequencing to construct the most biologically relevant vaccine. A novel platform (Ad5 [E1-, E2b-]) has been utilized to induce immune responses to various antigenic targets. We employed this vector platform to express hemagglutinin (HA) and neuraminidase (NA) genes from 2009 H1N1 pandemic viruses. Inserts were consensuses sequences designed from viral isolate sequences and the vaccine was rapidly constructed and produced. Vaccination induced H1N1 immune responses in mice, which afforded protection from lethal virus challenge. In ferrets, vaccination protected from disease development and significantly reduced viral titers in nasal washes. H1N1 cell mediated immunity as well as antibody induction correlated with the prevention of disease symptoms and reduction of virus replication. The Ad5 [E1-, E2b-] should be evaluated for the rapid development of effective vaccines against infectious diseases. PMID- 21821084 TI - Efficacy of dual vaccination of pandemic H1N1 2009 influenza and seasonal influenza on institutionalized elderly: a one-year prospective cohort study. AB - BACKGROUND: The influenza A (H1N1) 2009 pandemic was declared by the WHO in April 2009. In Hong Kong, the vaccination program began in December 2009 in addition to the annual seasonal trivalent influenza vaccination program. The clinical efficacy of dual vaccination was unknown. METHOD: From December 2009 to November 2010, a prospective 12-month cohort study on institutionalized elderly of nine nursing homes was conducted. Elderly persons who were followed up by the Hong Kong West Community Geriatric Assessment Team and had been vaccinated by the Department of Health were included. Outcome measures included all cause mortality, all cause hospitalization, hospitalization for fever on admission and hospitalization for pneumonia based on ICD-9-CM. RESULTS: 711 elderly persons were included. 274 received both seasonal influenza vaccine and (H1N1) 2009 vaccine (H1N1-TIV), 368 received seasonal influenza vaccine only (TIV alone) and 69 received no vaccination (unvaccinated). Baseline characteristics were well matched between the groups, except there were fewer females in the TIV alone. The 12-month mortality rates of the H1N1-TIV, TIV alone and unvaccinated were 10.6%, 19.8% and 29%, respectively. Multivariate analysis demonstrated that dual vaccination in the institutionalized elderly significantly reduced all cause mortality by 54% (Hazard Ratio [HR] 0.46; 95% confidence interval [CI] 0.29-0.72; p<0.001) and 74% (HR 0.26; CI 0.13-0.49; p<0.001), compared with vaccination of seasonal vaccination alone and no vaccination, respectively. Dual vaccination also reduced all cause hospitalization, hospitalization for fever on admission and hospitalization for pneumonia compared with seasonal vaccination alone and the unvaccinated group. CONCLUSION: Dual vaccination with both H1N1 and seasonal vaccinations provided additional protection to institutionalized elderly in reducing mortality and hospitalization. PMID- 21821083 TI - Conceptual framework for behavioral and social science in HIV vaccine clinical research. AB - HIV vaccine clinical research occurs within a context where biomedical science and social issues are interlinked. Previous HIV vaccine research has considered behavioral and social issues, but often treated them as independent of clinical research processes. Systematic attention to the intersection of behavioral and social issues within a defined clinical research framework is needed to address gaps, such as those related to participation in trials, completion of trials, and the overall research experience. Rigorous attention to these issues at project inception can inform trial design and conduct by matching research approaches to the context in which trials are to be conducted. Conducting behavioral and social sciences research concurrent with vaccine clinical research is important because it can help identify potential barriers to trial implementation, as well as ultimate acceptance and dissemination of trial results. We therefore propose a conceptual framework for behavioral and social science in HIV vaccine clinical research and use examples from the behavioral and social science literature to demonstrate how the model can facilitate identification of significant areas meriting additional exploration. Standardized use of the conceptual framework could improve HIV vaccine clinical research efficiency and relevance. PMID- 21821085 TI - Cost-effectiveness of universal rotavirus vaccination in reducing rotavirus gastroenteritis in Ireland. AB - We evaluated the cost-effectiveness of universal infant rotavirus (RV) vaccination compared to current standard of care of "no vaccination". Two RV vaccines are currently licensed in Ireland: Rotarix and RotaTeq. A cohort model used in several European countries was adapted using Irish epidemiological, resource utilisation and cost data. The base case model considers the impact of Rotarix vaccination on health-related quality of life of children under five years old from a healthcare payer perspective. Other scenarios explored the use of RotaTeq, impact on one caregiver, on societal costs and on cases that do not seek medical attention. Cost was varied between the vaccine list price (?100/course) in the base case and an assumed tender price (?70/course). One-way and probabilistic sensitivity analyses were conducted. Implementing universal RV vaccination may prevent around 1970 GP visits, 3280 A&E attendances and 2490 hospitalisations. A vaccination programme was estimated to cost approximately ?6.54 million per year but ?4.65 million of this would be offset by reducing healthcare resource use. The baseline ICER was ?112,048/QALY and ?72,736/QALY from the healthcare payer and societal perspective, respectively, falling to ?68,896 and ?43,916/QALY, respectively, if the impact on one caregiver was considered. If the price fell to ?70 per course, universal RV vaccination would be cost saving under all scenarios. Results were sensitive to vaccination costs, incidence of RV infection and direct medical costs. Universal RV vaccination would not be cost-effective under base case assumptions. However, it could be cost-effective at a lower vaccine price or from a wider societal perspective. PMID- 21821086 TI - Safety of pandemic H1N1 vaccines in children and adolescents. AB - During the 2009 influenza A (H1N1) pandemic several pandemic H1N1 vaccines were licensed using fast track procedures, with relatively limited data on the safety in children and adolescents. Different extensive safety monitoring efforts were put in place to ensure timely detection of adverse events following immunization. These combined efforts have generated large amounts of data on the safety of the different pandemic H1N1 vaccines, also in children and adolescents. In this overview we shortly summarize the safety experience with seasonal influenza vaccines as a background and focus on the clinical and post marketing safety data of the pandemic H1N1 vaccines in children. We identified 25 different clinical studies including 10,505 children and adolescents, both healthy and with underlying medical conditions, between the ages of 6 months and 23 years. In addition, large monitoring efforts have resulted in large amounts of data, with almost 13,000 individual case reports in children and adolescents to the WHO. However, the diversity in methods and data presentation in clinical study publications and publications of spontaneous reports hampered the analysis of safety of the different vaccines. As a result, relatively little has been learned on the comparative safety of these pandemic H1N1 vaccines - particularly in children. It should be a collective effort to give added value to the enormous work going into the individual studies by adhering to available guidelines for the collection, analysis, and presentation of vaccine safety data in clinical studies and to guidance for the clinical investigation of medicinal products in the pediatric population. Importantly the pandemic has brought us the beginning of an infrastructure for collaborative vaccine safety studies in the EU, USA and globally. PMID- 21821087 TI - The incidence and direct medical cost of hospitalization due to rotavirus gastroenteritis in Kyoto, Japan, as estimated from a retrospective hospital study. AB - Anticipating imminent licensure of rotavirus vaccine for use in Japan, we estimated the incidence of rotavirus hospitalization and calculated the direct medical cost associated with rotavirus hospitalization in a hospital that provided virtually exclusive pediatric beds to the local community adjacent to the northern outskirts of metropolitan Kyoto, Japan. For a 2 year period between September, 2008 and August, 2010, there were 103 hospitalizations due to acute gastroenteritis among children less than 5 years of age. Stool specimens from 77 (75%) of the 103 hospitalized patients were tested for rotavirus antigen, and 46 (60%) were positive. The proportion of rotavirus positives was 65% in the peak season months (January-June) and 17% in the off-season months (July-December). By extrapolating the test results to those patients with acute gastroenteritis who were not tested, 13 additional cases were estimated to be rotavirus positive. Assuming that all patients with rotavirus gastroenteritis less than 5 years of age in the catchment (5532 according to the 2005 census) were admitted to this hospital, the annual incidence of rotavirus hospitalization was estimated to be 4.1 (testing-unadjusted)-5.3 (adjusted) per 1000 child-years. Thus, it was estimated that one child in 48 or one child in 37 born in this area would be hospitalized due to rotavirus gastroenteritis by the age of 5 years. The incidence of rotavirus hospitalization was similar to the rate in Ise city (4.9 per 1000 child-years), also in central Japan, and lower than the rate in Honjo city in northern Japan (13 per 1000 child-years). Nevertheless, the burden of rotavirus hospitalization was substantial, and the total direct medical cost was estimated to be 6.6 billion Japanese Yen (US$ 57 million). While economic analysis and comparisons with alternative preventive procedures may be necessary, this study provides the policymakers and pediatricians with further evidence that is necessary to decide whether to introduce rotavirus vaccines into the routine childhood immunization schedule in Japan. PMID- 21821088 TI - In vitro and in vivo assessment of the genotoxic activity of aloesin. AB - Aloesin is a chromone that is a component of Aloe spp. It may have potential as a functional food ingredient as it has been shown to likely have beneficial effects in persons in a pre-diabetic state or who have metabolic syndrome. In this study the safety of aloesin has been evaluated using a series of in vitro and in vivo genotoxicity assays including, bacterial mutation, mammalian cell cytogenetic, and mouse micronucleus tests. Aloesin did not induce reverse mutations in Salmonella typhimurium and Escherichia coli at any of the tested dose levels up to 10,000 MUg/plate. Similarly, aloesin did not increase the incidence of chromosome aberrations when incubated with Chinese hamster lung cells at any of the tested concentrations up to 10,000 MUg/mL. In vivo, there was no effect of aloesin on the incidence of micronucleated erythrocytes following oral administration on two consecutive days at doses up to 5000 mg/kg body weight. There was no evidence of toxicity to bone marrow. The results of these studies demonstrate that aloesin is without genotoxic potential. PMID- 21821089 TI - Frequency and outcomes of accidental ingestion of tobacco products in young children. AB - This review assesses published literature related to frequency and outcomes associated with accidental ingestion of tobacco and pharmaceutical nicotine products among young children. Twenty-seven years of annual reports by American Association of Poison Control Centers (AAPCC) were analyzed for occurrence and outcomes associated with accidental ingestion events involving tobacco and pharmaceutical nicotine products among young children. Over a 27-year period, and of >50 million contacts for all categories combined, 217,340 contacts involving ingestion of tobacco products were reported. Approximately 89% involved children <6 years old. One fatality was reported, however the co-ingestion of both cigarettes and diazepam complicates an assessment of a contributory role of tobacco. The rate of major, non-fatal, outcomes was <0.1%. Data from AAPCC reports and other sources indicate the frequency of accidental poisoning events is relatively low for tobacco products compared with other products such as drugs, dietary supplements, cleaning products, and personal care products. These findings, along with those for pharmaceutical nicotine products, are consistent with published case reports and reviews, indicating that the frequency and severity of outcomes associated with accidental ingestion of tobacco products by young children appear to be relatively low. However, adults should keep tobacco products out of the reach of children. PMID- 21821090 TI - Evaluation of the genotoxic potential of single-wall carbon nanotubes by using a battery of in vitro and in vivo genotoxicity assays. AB - The genotoxic potential of a high purity sample of single-wall carbon nanotubes (SWCNTs) was evaluated using a battery of in vitro and in vivo genotoxicity assays. These comprised a bacterial reverse mutation test (Ames test), an in vitro chromosomal aberration test, and an in vivo mouse bone marrow micronucleus test. The SWCNTs exerted no genotoxicity in Salmonella typhimurium TA97, TA98, TA100, and TA1535, or in Escherichia coli WP2 uvrA/pKM101, whether in the absence or presence of metabolic activation and at concentrations of 12.5-500 MUg/plate. In the chromosomal aberration test, at 300-1000 MUg/mL, the SWCNTs did not increase the number of structural or numerical chromosomal aberrations, whether the test was conducted with or without metabolic activation. In the in vivo bone marrow micronucleus test, doses of 60 mg/kg and 200mg/kg SWCNTs did not affect the proportions of immature and total erythrocytes, nor did it increase the number of micronuclei in the immature erythrocytes of mice. The results of these studies show that the high purity and well-dispersed sample of SWCNTs are not genotoxic under the conditions of the in vitro bacterial reverse mutation assay, chromosomal aberration assay, or in vivo bone marrow micronucleus test, and thus appear not to pose a genotoxic risk to human health in vivo. PMID- 21821091 TI - Mutagenic, cytotoxic, and genotoxic properties of tobacco smoke produced by cigarillos available on the Canadian market. AB - Cigarillos (aka little cigars) have been increasing in popularity unlike cigarettes; but relatively little is known about the toxicology of the mainstream smoke (MSS) from such products. Therefore, the objective of this work was to compare the toxicological properties of the MSS (Health Canada Intensive smoking conditions) from a range of cigarillo products with the toxicological properties of MSS of cigarettes. Three in vitro assays were used to evaluate the toxicities of the MSS total particulate matter (TPM): (1) mutagenicity using Ames assay with Salmonella strains TA98 and TA100 with S9 metabolic activation (+S9); (2) cytotoxicity using the Neutral Red Uptake (NRU) assay with CHO (Chinese Hamster Ovary) cells; and (3) genotoxicity using the micronucleus assay with CHO cells and short-term exposures (3-h +/- S9). The Ames assay (TA100+S9) and the NRU assay were also applied to the gas/vapour phase of the MSS that passed through the Cambridge pad. On a per-milligram-nicotine basis, the preferred way of comparing toxicities of different types of tobacco products, the MSS from cigarillos was not less toxic, and in some cases more toxic (TPM fraction TA98+S9, NRU), than the MSS from cigarettes. Thus, our findings support our prior work on smoke mutagenicity that showed MSS from cigarillos was not less toxic than MSS from cigarettes. PMID- 21821092 TI - Profiles of DARPP-32 in the insular cortex with schizophrenia: a postmortem brain study. AB - In patients with schizophrenia, various physical disorders are sometimes discovered only when they have reached a later and more severe stage. This phenomenon is believed to be caused, at least in part, by an increase in pain threshold. The gamma-aminobutyric acid (GABA)-ergic and glutamatergic systems in the rostral agranular insular cortex (RAIC) are thought to be involved in the regulation of pain threshold. However, no postmortem studies of the cerebral cortex have previously been published. Dopamine and cAMP-regulated phosphoprotein 32 kD (DARPP-32), which is involved in the GABAergic and glutamatergic systems, is considered to be crucial for elucidating the pathogenesis of schizophrenia. Using specific antibodies, we conducted immunohistochemical examinations of the RAIC in 10 subjects from a healthy control group, and 11 subjects from a schizophrenia group. The sex, age, and postmortem interval (PMI) of the schizophrenia group were matched to those of the healthy control group. We revealed that the density of DARPP-32-immunoreactive (IR) neurons in the II and III layers of the RAIC was significantly decreased (p<0.05) in the schizophrenia group compared with the healthy control group. Our findings could partially explain the molecular basis of the pain threshold abnormalities found in patients with schizophrenia. PMID- 21821093 TI - Three-year clinical outcome of single implant-retained mandibular overdentures- results of preliminary prospective study. AB - OBJECTIVES: The aim of this preliminary prospective study was to evaluate the clinical outcome, the oral health-related quality of life (OHRQoL), and the subjective chewing ability of patients with mandibular complete dentures retained by a single implant placed in the mandible midline. METHODS: Patients wearing complete dentures were treated with a single implant in the mandible, followed by relining of the dentures and incorporation of ball attachments for implant retention. Implant outcome, prosthodontic maintenance, subjective chewing ability, and the oral health impact profile of the patients were assessed at baseline and at four weeks after connecting the denture and implant. RESULTS: Eleven patients were enrolled in this investigation, and the mean observation period was 43.4 months (minimum period: 35, maximum period: 52 months). No implants were lost during observation period, but four dentures needed repair because of the fracture of the denture base in the midline area. A significant improvement was observed in the OHRQoL of the patients after the attachment of the mandibular dentures with a single midline implant. Furthermore, the subjective chewing ability of the patients was significantly improved after implant connection. CONCLUSIONS: Within the limitations of this preliminary prospective clinical study, single implant-supported mandibular overdentures were a successful treatment option for older edentulous patients who showed improvements in their OHRQoL and chewing ability. PMID- 21821094 TI - Neurodegenerative disease biomarkers: guideposts for disease prevention through early diagnosis and intervention. PMID- 21821096 TI - Changes in ovarian protein expression during primordial follicle formation in the hamster. AB - Although many proteins have been shown to affect the transition of primordial follicles to the primary stage, factors regulating the formation of primordial follicles remains sketchy at best. Differentiation of somatic cells into early granulosa cells during ovarian morphogenesis is the hallmark of primordial follicle formation; hence, critical changes are expected in protein expression. We wanted to identify proteins, the expression of which would correlate with the formation of primordial follicles as a first step to determine their biological function in folliculogenesis. Proteins were extracted from embryonic (E15) and 8 day-old (P8) hamster ovaries and fractionated by two-dimensional gel electrophoresis. Gels were stained with Proteosilver, and images of protein profiles corresponding to E15 and P8 ovaries were overlayed to identify protein spots showing altered expression. Some of the protein spots were extracted from SyproRuby-stained preparative gels, digested with trypsin, and analyzed by mass spectrometry. Both E15 and P8 ovaries had high molecular weight proteins at acidic, basic, and neutral ranges; however, we focused on small molecular weight proteins at 4-7 pH range. Many of those spots might represent post-translational modification. Mass spectrometric analysis revealed the identity of these proteins. The formation of primordial follicles on P8 correlated with many differentially and newly expressed proteins. Whereas Ebp1 expression was downregulated in ovarian somatic cells, Sfrs3 expression was specifically upregulated in newly formed granulosa cells of primordial follicles on P8. The results show for the first time that the morphogenesis of primordial follicles in the hamster coincides with altered and novel expression of proteins involved in cell proliferation, transcriptional regulation, and metabolism. Therefore, formation of primordial follicles is an active process requiring differentiation of somatic cells into early granulosa cells and their interaction with the oocytes. PMID- 21821095 TI - The regulation of embryo implantation and endometrial decidualization by progesterone receptor signaling. AB - During the early stages of pregnancy, fertilized embryos must attach to the uterine epithelium, invade into the underlying uterine stroma, and the stroma must then differentiate in a process termed decidualization in order for a successful pregnancy to be initiated. The steroid hormone progesterone (P4) is an integral mediator of these early pregnancy events, exerting its effects via the progesterone receptor (PR). Insights gained from the use of mouse models and genomic profiling has identified many of the key molecules enlisted by PR to execute the paradigm of early pregnancy. This review describes several of the molecules through which the PR exerts its pleiotropic effects including ligands, receptors, chaperones, signaling proteins and transcription factors. Understanding these molecules and their concatenation is of vital importance to our ability to clinically treat reproductive health problems like infertility and endometriosis. PMID- 21821097 TI - Amphetamine sensitization in reproductively experienced female rats. AB - Recent studies have supported the hypothesis that pregnancy and parturition are associated with altered sensitivity of brain dopamine systems. An increased behavioral sensitivity to a direct-acting D1/D2 receptor agonist (apomorphine) has also been observed several weeks after lactation, suggesting that these adaptations are long-lasting. To further characterize this phenomenon, the effects of reproductive experience on behavioral sensitization to an indirect acting dopamine agonist (amphetamine) in female rats were studied. In two separate experiments, nulliparous and primiparous (12-16 weeks post-weaning) female rats were pretreated with amphetamine (1.0 or 5.0mg/kg) or vehicle (saline) once daily for 5 consecutive days. After 10 days of withdrawal, all animals were challenged with a low dose of amphetamine (25% of pretreatment dose). Locomotor activity was measured following each drug or vehicle administration. Locomotor sensitization to amphetamine challenge was observed in all animals pretreated with 1mg/kg, regardless of reproductive experience. In contrast, primiparous animals pretreated with 5mg/kg amphetamine displayed a significantly larger locomotor response to the challenge compared to nulliparous controls. The findings indicate enhanced behavioral sensitization to amphetamine in reproductively experienced rats, and confirm previous reports of lasting adaptations of dopamine systems following pregnancy and lactation. PMID- 21821098 TI - The endocannabinoid 2-arachidonoylglycerol mediates D1 and D2 receptor cooperative enhancement of rat nucleus accumbens core neuron firing. AB - Many motivated and addiction-related behaviors are sustained by activity of both dopamine D1- and D2-type receptors (D1Rs and D2Rs) as well as CB1 receptors (CB1Rs) in the nucleus accumbens (NAc). Here, we use in vitro whole-cell patch clamp electrophysiology to describe an endocannabinoid (eCB)-dopamine receptor interaction in adult rat NAc core neurons. D1R and D2R agonists in combination enhanced firing, with no effect of a D1R or D2R agonist alone. This D1R+D2R mediated firing increase required CB1Rs, since it was prevented by the CB1R antagonists AM251 and Rimonabant. The D1R+D2R firing increase also required phospholipase C (PLC), the major synthesis pathway for the eCB 2 arachidonoylglycerol (2-AG) and one of several pathways for anandamide. Further, inhibition of 2-AG hydrolysis with the monoglyceride lipase (MGL) inhibitor JZL184 allowed subthreshold levels of D1R+D2R receptor agonists to enhance firing, while inhibition of anandamide hydrolysis with the fatty acid amide hydrolase (FAAH) inhibitors URB597 or AM3506 did not. Filling the postsynaptic neuron with 2-AG enabled subthreshold D1R+D2R agonists to increase firing, and the 2AG+D1R+D2R increase in firing was prevented by a CB1R antagonist. Also, the metabotropic glutamate receptor 5 (mGluR5) blocker MPEP prevented the ability of JZL184 to promote subthreshold D1R+D2R enhancement of firing, while the 2 AG+D1R+D2R increase in firing was not prevented by the mGluR5 blocker, suggesting that mGluR5s acted upstream of 2-AG production. Thus, our results taken together are consistent with the hypothesis that NAc core eCBs mediate dopamine receptor (DAR) enhancement of firing, perhaps providing a cellular mechanism underlying the central role of NAc core D1Rs, D2Rs, CB1Rs, and mGluR5s during many drug seeking behaviors. PMID- 21821101 TI - Functional properties of the basal ganglia's re-entrant loop architecture: selection and reinforcement. AB - Multifunctional agents with limited motor resources must decide what actions will best ensure their survival. Moreover, given that in an unpredictable world things don't always work out, considerable advantage is to be gained by learning from experience - instrumental behaviour that maximises reward and minimises punishment. In this review we will argue that the re-entrant looped architecture of the basal ganglia represents biological solutions to these fundamental behavioural problems of selection and reinforcement. A potential solution to the selection problem is provided for by selective disinhibition within the parallel loop architecture that connects the basal ganglia with external neural structures. The relay points within these loops permit the signals of a particular channel to be modified by external influences. In part, these influences have the capacity to modify overall selections so that the probability of re-selecting reinforced behaviours in the future is altered. This is the basic process of instrumental learning, which we suggest decomposes into two sub problems for the agent: (i) learning which external events it causes to happen and learning precisely what it is doing that is causal; and (ii) having determined agency and discovered novel action-outcome routines, how best to exploit this knowledge to maximise future reward acquisitions. Considerations of connectional architecture and signal timing suggest that the short-latency, sensory-evoked dopamine response, which can modulate the re-entrant loop structure within the basal ganglia, is ideally suited to reinforce the determination of agency and the discovery of novel actions. Alternatively, recent studies showing that presence or absence of reward can selectively modulate the magnitude of signals in structures providing input signals to the basal ganglia, offer an alternative mechanism for biasing selection within the re-entrant loop architecture. We suggest that this mechanism may be better suited to ensure the prioritisation of inputs associated with reward. PMID- 21821100 TI - Relationship between noise-induced hearing-loss, persistent tinnitus and growth associated protein-43 expression in the rat cochlear nucleus: does synaptic plasticity in ventral cochlear nucleus suppress tinnitus? AB - Aberrant, lesion-induced neuroplastic changes in the auditory pathway are believed to give rise to the phantom sound of tinnitus. Noise-induced cochlear damage can induce extensive fiber growth and synaptogenesis in the cochlear nucleus, but it is currently unclear if these changes are linked to tinnitus. To address this issue, we unilaterally exposed nine rats to narrow-band noise centered at 12 kHz at 126 dB sound pressure level (SPL) for 2 h and sacrificed them 10 weeks later for evaluation of synaptic plasticity (growth-associated protein 43 [GAP-43] expression) in the cochlear nucleus. Noise-exposed rats along with three age-matched controls were screened for tinnitus-like behavior with gap prepulse inhibition of the acoustic startle (GPIAS) before, 1-10 days after, and 8-10 weeks after the noise exposure. All nine noise-exposed rats showed similar patterns of severe hair cell loss at high- and mid-frequency regions in the exposed ear. Eight of the nine showed strong up-regulation of GAP-43 in auditory nerve fibers and pronounced shrinkage of the ventral cochlear nucleus (VCN) on the noise-exposed side, and strong up-regulation of GAP-43 in the medial ventral VCN, but not in the lateral VCN or the dorsal cochlear nucleus. GAP-43 up regulation in VCN was significantly greater in Noise-No-Tinnitus rats than in Noise-Tinnitus rats. One Noise-No-Tinnitus rat showed no up-regulation of GAP-43 in auditory nerve fibers and only little VCN shrinkage, suggesting that auditory nerve degeneration plays a role in tinnitus generation. Our results suggest that noise-induced tinnitus is suppressed by strong up-regulation of GAP-43 in the medial VCN. GAP-43 up-regulation most likely originates from medial olivocochlear neurons. Their increased excitatory input on inhibitory neurons in VCN may possibly reduce central hyperactivity and tinnitus. PMID- 21821099 TI - Avoiding mouse traps in schizophrenia genetics: lessons and promises from current and emerging mouse models. AB - Schizophrenia is one of the most common psychiatric disorders, but despite progress in identifying the genetic factors implicated in its development, the mechanisms underlying its etiology and pathogenesis remain poorly understood. Development of mouse models is critical for expanding our understanding of the causes of schizophrenia. However, translation of disease pathology into mouse models has proven to be challenging, primarily due to the complex genetic architecture of schizophrenia and the difficulties in the re-creation of susceptibility alleles in the mouse genome. In this review we highlight current research on models of major susceptibility loci and the information accrued from their analysis. We describe and compare the different approaches that are necessitated by diverse susceptibility alleles, and discuss their advantages and drawbacks. Finally, we discuss emerging mouse models, such as second-generation pathophysiology models based on innovative approaches that are facilitated by the information gathered from the current genetic mouse models. PMID- 21821102 TI - Galanin and the orexin 2 receptor as possible regulators of enkephalin in the paraventricular nucleus of the hypothalamus: relation to dietary fat. AB - Recent studies show that the non-opioid peptides, galanin (GAL) and orexin (OX), are similar to the opioid enkephalin (ENK) in being stimulated by dietary fat and also in enhancing the consumption of a high-fat diet (HFD). This suggests that, when an HFD is provided, these non-opioids may stimulate the opioid system to promote excess consumption of this diet. Using single- and double-labeling immunohistochemistry, the present study sought to identify possible neuroanatomical substrates for this close relationship. Focusing on the hypothalamic paraventricular nucleus (PVN), and particularly its anterior (aPVN), middle (mPVN) and posterior (pPVN) parts, the experiments examined whether GAL itself or the receptors for GAL and OX are stimulated by an HFD in the same areas and possibly the same neurons as ENK. Compared to animals fed a standard chow diet, rats consuming an HFD exhibited an increased density of medial parvocellular neurons immunoreactive (IR) for GAL in the mPVN and aPVN and for ENK in the mPVN and pPVN, distinguishing the mPVN as an area where both peptides were affected. While showing little evidence for GAL and ENK colocalization with a chow diet, double-labeling studies in HFD-fed rats revealed significant colocalization specifically in medial parvocellular neurons of the mPVN. Immediately posterior to this site, further analyses revealed a similar relationship between the OX 2 receptor (OX(2)R) and ENK in HFD-treated animals. While increasing the density of neurons immunoreactive for OX(2)R as well as for the GAL 1 receptor but not OX 1 receptor, HFD consumption increased the colocalization only of OX(2)R and ENK, specifically in the medial parvocellular neurons of the pPVN. These changes in HFD-fed rats, showing GAL and OX(2)R to colocalize with ENK exclusively in neurons of the medial parvocellular mPVN and pPVN, respectively, suggest possible neural substrates through which the non opioid peptides may functionally interact with ENK when exposed to an HFD. PMID- 21821104 TI - Identification and characterization of alternative splice variants of the mouse Trek2/Kcnk10 gene. AB - Two-pore domain K(+) (K(2P)) channels underlie leak or background potassium conductances in many cells. The Trek subfamily of K(2P) channels, which includes Trek1/Kcnk2 and Trek2/Kcnk10 and has been implicated in depression, nociception, and cognition, exhibits complex regulation and can modulate cell excitability in response to a wide array of stimuli. While alternative translation initiation and alternative splicing contribute to the structural and functional diversity of Trek1, the impact of post-transcriptional modifications on the expression and function of Trek2 is unclear. Here, we characterized two novel splice isoforms of the mouse Trek2 gene. One variant is a truncated form of Trek2 that possesses two transmembrane segments and one pore domain (Trek2-1p), while the other (Trek2b) differs from two known mouse Trek2 isoforms (Trek2a and Trek2c) at the extreme amino terminus. Both Trek2-1p and Trek2b, and Trek2a and Trek2c, showed prominent expression in the mouse CNS. Expression patterns of the Trek2 variants within the CNS were largely overlapping, though some isoform-specific differences were noted. Heterologous expression of Trek2-1p yielded no novel whole-cell currents in transfected human embryonic kidney (HEK) 293 cells. In contrast, expression of Trek2b correlated with robust K(+) currents that were ~fivefold larger than currents measured in cells expressing Trek2a or Trek2c, a difference mirrored by significantly higher levels of Trek2b found at the plasma membrane. This study provides new insights into the molecular diversity of Trek channels and suggests a potential role for the Trek2 amino terminus in channel trafficking and/or stability. PMID- 21821105 TI - Epigallocatechin gallate ameliorates behavioral and biochemical deficits in rat model of load-induced chronic fatigue syndrome. AB - Chronic fatigue syndrome is a heterogeneous disorder with unknown pathogenesis and etiology, characterized by tiredness, difficulty in concentration and memory, and concomitant skeletal and muscular pain, thus affecting both mental and physical domains. The pathogenesis of chronic fatigue syndrome is multifactorial and involves increased oxido-nitrosative stress along with generation of pro inflammatory cytokines such as TNF-alpha. In the present study chronic fatigue was produced in rats by plunging a load of 10 +/- 2% body weight and subjecting them to forced swim inside a rectangular jar daily for 28 days. Endurance capacity and post-swim fatigue were assessed on 1st, 7th, 14th, 21st and 28th days. EGCG was administered daily by oral gavage 30 min before forced swim session. On the 29th day, after assessment of various behavioral parameters, blood was collected through tail vein, and animals were sacrificed to harvest the brains, spleens and thymus. Chronic fatigue group exhibited significant behavioral alterations along with enhanced oxido-nitrosative stress and serum TNF alpha level as compared to naive group. Chronic treatment with EGCG restored all the behavioral and biochemical alterations associated with chronic fatigue syndrome. The present study signifies the therapeutic potential of EGCG for the treatment of chronic fatigue syndrome. PMID- 21821103 TI - Activating transcription factor 4, a mediator of the integrated stress response, is increased in the dorsal root ganglia following painful facet joint distraction. AB - Chronic neck pain is one of the most common musculoskeletal disorders in the US. Although biomechanical and clinical studies have implicated the facet joint as a primary source of neck pain, specific cellular mechanisms still remain speculative. The purpose of this study was to investigate whether a mediator (activating transcription factor; 4ATF4) of the integrated stress response (ISR) is involved in facet-mediated pain. Holtzman rats underwent C6/C7 facet joint loading that produces either painful (n=16) or nonpainful (n=8) responses. A sham group (n=9) was also included as surgical controls. Behavioral sensitivity was measured and the C6 dorsal root ganglia (DRGs) were harvested on day 7 to evaluate the total and neuronal ATF4 expression. In separate groups, an intra articular ketorolac injection was administered either immediately (D0 ketorolac) or 1 day (D1 ketorolac) after painful facet joint loading. Allodynia was measured at days 1 and 7 after injury to assess the effects on behavioral responses. ATF4 and BiP (an indicator of ISR activation) were separately quantified at day 7. Facet joint loading sufficient to elicit behavioral hypersensitivity produced a threefold increase in total and neuronal ATF4 expression in the DRG. After ketorolac treatment at the time of injury, ATF4 expression was significantly (P<0.01) reduced despite not producing any attenuation of behavioral responses. Interestingly, ketorolac treatment at day 1 significantly (P<0.001) alleviated behavioral sensitivity at day 7, but did not modify ATF4 expression. BiP expression was unchanged after either intervention time. Results suggest that ATF4-dependent activation of the ISR does not directly contribute to persistent pain, but it may sensitize neurons responsible for pain initiation. These behavioral and immunohistochemical findings imply that facet-mediated pain may be sustained through other pathways of the ISR. PMID- 21821106 TI - Acoustic assessment of mean grain size in pharmaceutical compacts. AB - An ultrasonic non-destructive technique for the microstructure length-scale characterization of solid dosage pharmaceutical tablets is presented. The technique is based on the relationship between the attenuation of longitudinal ultrasonic elastic waves and the size of micro-structural features in the tablet material. In the reported experiments, the ultrasonic attenuation in microcrystalline cellulose (MCC)-lactose monohydrate (LMH) blended pharmaceutical compacts is measured by means of two pitch-catch experiments. The frequency dependent attenuation coefficient for the MCC-LMH compacts is then related to the mean grain diameter for each compact. For verification purposes, the mean grain diameter of the compacts was also established using micro-scale X-ray computerized tomography (MicroXCT). The mean grain diameters established by both routines agree well, and support the efficacy of the ultrasonic attenuation technique. The microstructure of a pharmaceutical compact (i.e., grain sizes and micro-feature size distribution) has been shown to have a profound effect on its mechanical properties, namely hardness, porosity, and mass density distribution, and in turn, can critically impact the dissolution profile and structural integrity of a compact. The ultrasonic technique presented provides a non destructive and rapid method for determining the mean grain diameter size for powder compacts, thus providing a more timely and cost-effective method, compared to traditional techniques, of characterizing a compact's internal microstructure. PMID- 21821107 TI - Characterization and evaluation of chitosan nanoparticles for dopamine brain delivery. AB - The aim of this study was to characterize nanoparticles (NPs) composed of chitosan (CS) and evaluate their potential for brain delivery of the neurotransmitter Dopamine (DA). For this purpose, CS based NPs were incubated with DA at two different concentrations giving rise to nanocarriers denoted as DA/CSNPs (1) and DA/CSNPs (5), respectively. X-ray Photoelectron Spectroscopy (XPS) analysis confirmed that DA was adsorbed onto the external surface of such NPs. The cytotoxic effect of the CSNPs and DA/CSNPs was assessed using the MTT test and it was found that the nanovectors are less cytotoxic than the neurotransmitter DA after 3 h of incubation time. Transport studies across MDCKII MDR1 cell line showed that DA/CSNPs (5) give rise to a significant transport enhancing effect compared with the control and greater than the corresponding DA/CSNPs (1). Measurement of reactive oxygen species (ROS) suggested a low DA/CSNPs neurotoxicity after 3 h. In vivo brain microdialysis experiments in rat showed that intraperitoneal acute administration of DA/CSNPs (5) (6-12 mg/kg) induced a dose-dependent increase in striatal DA output. Thus, these CS nanoparticles represent an interesting technological platform for DA brain delivery and, hence, may be useful for Parkinson's disease treatment. PMID- 21821108 TI - Anti-inflammatory activity of ethanol extract derived from Phaseolus angularis beans. AB - ETHNOPHARMACOLOGICAL SIGNIFICANCE: Phaseolus angularis Wight (adzuki bean) is an ethnopharmacologically well-known folk medicine that is prescribed for infection, edema, and inflammation of the joints, appendix, kidney and bladder in Korea, China and Japan. AIM OF STUDY: The anti-inflammatory effect of this plant and its associated molecular mechanisms will be investigated. MATERIALS AND METHODS: The immunomodulatory activity of Phaseolus angularis ethanol extract (Pa-EE) in toll like receptor (TLR)-activated macrophages induced by ligands such as lipopolysaccharide (LPS), Poly (I:C), and pam3CSK was investigated by assessing nitric oxide (NO) and prostaglandin (PG)E(2) levels. To identify which transcription factors such as nuclear factor (NF)-kappaB and their signaling enzymes can be targeted to Pa-EE, biochemical approaches including reporter gene assays, immunoprecipitation, kinase assays, and immunoblot analyses were also employed. Finally, whether Pa-EE was orally available, ethanol (EtOH)/hydrochloric acid (HCl)-induced gastritis model in mice was used. RESULTS: Pa-EE dose-dependently suppressed the release of PGE(2) and NO in LPS-, Poly(I:C) , and pam3CSK-activated macrophages. Pa-EE strongly down-regulated LPS-induced mRNA expression of inducible NO synthase (iNOS) and cyclooxygenase (COX)-2. Interestingly, Pa-EE markedly inhibited NF-kappaB, activator protein (AP)-1, and cAMP response element binding protein (CREB) activation; further, according to direct kinase assays and immunoblot analyses, Pa-EE blocked the activation of the upstream signaling molecules spleen tyrosine kinase (Syk), p38, and transforming growth factor beta-activated kinase 1 (TAK1). Finally, orally administered Pa-EE clearly ameliorated EtOH/HCl-induced gastritis in mice. CONCLUSION: Our results suggest that Pa-EE can be further developed as a promising anti-inflammatory remedy because it targets multiple inflammatory signaling enzymes and transcription factors. PMID- 21821109 TI - Anti-diabetic activity of Chiliadenus iphionoides. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Chiliadenus iphionoides (Boiss. & Blanche) Brullo (Asteraceae), a small aromatic shrub found throughout Israel, is used traditionally in the treatment of diabetes mellitus. In this study, Chiliadenus iphionoides anti-diabetic activity was characterized using cellular and animal models. MATERIALS AND METHODS: Pancreatic beta cells, adipocytes, and skeletal myotubes were treated with an ethanolic extract of Chiliadenus iphionoides to study the extract's effects on insulin secretion and glucose uptake. The sand rat (Psammomys obesus) was used to study Chiliadenus iphionoides acute and long term effects in vivo. An oral starch tolerance test was performed as well as a 30 day feeding study. RESULTS: Chiliadenus iphionoides extract increased insulin secretion in beta cells as well as glucose uptake in adipocytes and skeletal myotubes. The extract also displayed hypoglycemic activity in the diabetic sand rat. CONCLUSIONS: Chiliadenus iphionoides exhibits considerable anti-diabetic activity, although the mechanism of action remains to be determined. PMID- 21821110 TI - Antinociceptive and hypnotic properties of Celastrus orbiculatus. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Celastrus orbiculatus, a woody vine of the Celastraceae family, has been widely used as a traditional medicine for the treatment of many diseases, including rheumatoid arthritis and odontalgia. In this study, we assessed the sedative and antinociceptive activities of the methanolic extract of Celastrus orbiculatus (MCO). MATERIALS AND METHODS: The antinociceptive effect of MCO was evaluated using several experimental pain models, including thermal nociception methods, such as the tail immersion and the hotplate tests, as well as chemical nociception induced by intraperitoneal acetic acid and subplantar formalin administration in mice. To verify the possible connection of the opioid receptor to the antinociceptive activity of MCO, we performed a combination test with naloxone, a nonselective opioid receptor antagonist. The sedative effect of MCO was studied using the pentobarbital induced sleeping model. RESULTS: MCO demonstrated strong and dose-dependent antinociceptive activity compared to tramadol and indomethacin in various experimental pain models. The combination test using naloxone revealed that the antinociceptive activity of MCO is associated with activation of the opioid receptor. MCO also caused decreased sleep latency and increased sleeping time in the pentobarbital-induced sleeping model; however, MCO alone did not induce sleep. CONCLUSIONS: In the present study, MCO showed potent antinociceptive and sedative activities. Based on these results, MCO may be considered a valuable anti-nociceptive and hypnotic agent for the treatment of various diseases. PMID- 21821111 TI - Blunting of adaptive responses to resistance exercise training in women over 75y. AB - BACKGROUND: It is unclear how aging affects adaptive responses to resistance exercise training (RET), especially in women. We hypothesized that (i) increases in muscle mass and function after RET would be blunted in older women, and (ii) reduced 'pro-anabolic' changes in gene expression after a single bout of RE may underlie the blunting. METHODS: Muscle biopsies were obtained from 9 older (76 82y) and 16 younger (19-30y) women at rest and 2.5h after RE (6*20 quadriceps maximal voluntary contractions (MVCs)) for measurement of select anabolic (e.g. IGFs, MyoD) and catabolic (e.g. MAFBx, MuRF-1) transcripts by RT-PCR. Thereafter participants undertook a supervised program of RET (4*15 MVCs 3* wk/12wk). We measured knee extensor muscle volume, fatty infiltration, and mechanical muscle quality before and after RET. RESULTS: Before RET, older women were ~30% weaker (MVC 208 vs. 297N) and had ~40% less quadriceps muscle (0.97 vs. 1.54L) with greater fatty infiltration (14% vs. 10%). The most notable difference in mRNA expression after RE was for regulated in development and DNA damage response 1 (REDD1) (an endogenous suppressor of mammalian target of rapamycin (mTOR) signaling), which was depressed (-80%), but only in young women. Moreover, adaptive responses to RET were blunted in older women with respect to increases in muscle volume (+2.5% (old) vs. +6.2% (young)) and strength (+16% (old) vs. +27% (young)). CONCLUSIONS: Adaptations to RET are markedly blunted in older women, perhaps in-part due to the inability to downregulate REDD1 and thus upregulate mTOR signaling after RE. PMID- 21821112 TI - Calorie restriction (CR) reduces age-dependent decline of non-homologous end joining (NHEJ) activity in rat tissues. AB - Even though CR has shown to enhance base excision repair (BER) and nucleotide excision repair (NER) capacities, it has not been reported whether CR can enhance non-homologous end joining (NHEJ) activity. To examine the effect of CR on NHEJ activity, ad libitum (AL)- and calorie restricted (CR)-dieted rats were used. Age dependent decline of NHEJ activity was apparent in the lung, liver, and kidney and appeared to be slightly decreased in spleen. CR reduced age-dependent decline of NHEJ activity in all tissues, even though the extent of recovery was variable among tissues. Moreover, CR appeared to reduce age-dependent decline of XRCC4 protein level. These results suggest that CR could reduce age-dependent decline of NHEJ activity in various tissues of rats possibly through up-regulation of XRCC4. PMID- 21821113 TI - Modulation of cell adhesion, proliferation and differentiation on materials designed for body implants. AB - The interaction of cells and tissues with artificial materials designed for applications in biotechnologies and in medicine is governed by the physical and chemical properties of the material surface. There is optimal cell adhesion to moderately hydrophilic and positively charged substrates, due to the adsorption of cell adhesion-mediating molecules (e.g. vitronectin, fibronectin) in an advantageous geometrical conformation, which makes specific sites on these molecules (e.g. specific amino acid sequences) accessible to cell adhesion receptors (e.g. integrins). Highly hydrophilic surfaces prevent the adsorption of proteins, or these molecules are bound very weakly. On highly hydrophobic materials, however, proteins are adsorbed in rigid and denatured forms, hampering cell adhesion. The wettability of the material surface, particularly in synthetic polymers, can be effectively regulated by physical treatments, e.g. by irradiation with ions, plasma or UV light. The irradiation-activated material surface can be functionalized by various biomolecules and nanoparticles, and this further enhances its attractiveness for cells and its effectiveness in regulating cell functions. Another important factor for cell-material interaction is surface roughness and surface topography. Nanostructured substrates (i.e. substrates with irregularities smaller than 100nm), are generally considered to be beneficial for cell adhesion and growth, while microstructured substrates behave more controversially (e.g. they can hamper cell spreading and proliferation but they enhance cell differentiation, particularly in osteogenic cells). A factor which has been relatively less investigated, but which is essential for cell-material interaction, is material deformability. Highly soft and deformable substrates cannot resist the tractional forces generated by cells during cell adhesion, and cells are not able to attach, spread and survive on such materials. Local variation in the physical and chemical properties of the material surface can be advantageously used for constructing patterned surfaces. Micropatterned surfaces enable regionally selective cell adhesion and directed growth, which can be utilized in tissue engineering, in constructing microarrays and in biosensorics. Nanopatterned surfaces are an effective tool for manipulating the type, number, spacing and distribution of ligands for cell adhesion receptors on the material surface. As a consequence, these surfaces are able to control the size, shape, distribution and maturity of focal adhesion plaques on cells, and thus cell adhesion, proliferation, differentiation and other cell functions. PMID- 21821114 TI - Cell growth and cell cycle in Saccharomyces cerevisiae: basic regulatory design and protein-protein interaction network. AB - In this review we summarize the major connections between cell growth and cell cycle in the model eukaryote Saccharomyces cerevisiae. In S. cerevisiae regulation of cell cycle progression is achieved predominantly during a narrow interval in the late G1 phase known as START (Pringle and Hartwell, 1981). At START a yeast cell integrates environmental and internal signals (such as nutrient availability, presence of pheromone, attainment of a critical size, status of the metabolic machinery) and decides whether to enter a new cell cycle or to undertake an alternative developmental program. Several signaling pathways, that act to connect the nutritional status to cellular actions, are briefly outlined. A Growth & Cycle interaction network has been manually curated. More than one fifth of the edges within the Growth & Cycle network connect Growth and Cycle proteins, indicating a strong interconnection between the processes of cell growth and cell cycle. The backbone of the Growth & Cycle network is composed of middle-degree nodes suggesting that it shares some properties with HOT networks. The development of multi-scale modeling and simulation analysis will help to elucidate relevant central features of growth and cycle as well as to identify their system-level properties. Confident collaborative efforts involving different expertises will allow to construct consensus, integrated models effectively linking the processes of cell growth and cell cycle, ultimately contributing to shed more light also on diseases in which an altered proliferation ability is observed, such as cancer. PMID- 21821115 TI - Genome-wide profiling of DNA methylation in human cancer cells. AB - Global changes in DNA methylation correlate with altered gene expression and genomic instability in cancer. We have developed a methylation-specific digital sequencing (MSDS) method that can assess DNA methylation on a genomic scale. MSDS is a simple, low-cost method that combines the use of methylation-sensitive restriction enzymes with second generation sequencing technology. DNA methylation in two colon cancer cell lines, HT29 and HCT116, was measured using MSDS. When methylation levels were compared between the two cell lines, many differentially methylated regions (DMRs) were identified in CpG island shore regions (located within 2kb of a CpG island), gene body regions and intergenic regions. The number of DMRs in the vicinity of gene transcription start sites correlated with the level of expression of TACC1, CLDN1, and PLEKHC1 (FERMT2) genes, which have been linked to carcinogenesis. The MSDS method has the potential to provide novel insight into the functional complexity of the human genome. PMID- 21821118 TI - Distribution of PDE8A in the nervous system of the Sprague-Dawley rat. AB - Phosphodiesterases (PDEs) are essential regulators of cyclic nucleotide signaling. Little is known of the distribution and function of the cyclic adenosine monophosphate (cAMP) hydrolyzing PDE8A family. Employing immunohistochemistry and Western blots this study maps the distribution of PDE8A in the brain of adult male Sprague-Dawley rats and in the trigeminal ganglion. PDE8A was confined to neuronal perikaryal cytoplasm and to processes extending from those perikarya. The neurons exhibiting PDE8A-immunoreactivity were widely distributed in the forebrain, brain stem, and cerebellum. Strongly immunoreactive neurons were located in the olfactory bulb, the septal area, zona incerta, and reticular nucleus of the thalamus. Less immunoreactivity was seen in the hippocampus and cerebral cortex. Intense staining was detected in both the substantia nigra and the sensory trigeminal nucleus. In cerebellum PDE8A immunoreactivity was located not only in the Purkinje cells, but also in the granular cells as well as the parallel fibres in the molecular layer. PDE8A immunoreactivity was represented in the epithelial lining of the choroids plexus, the dura mater, and the neurons of the trigeminal ganglion. The localization of the cAMP degrading PDE8A may indicate a role for PDE8A in cAMP signaling related to pain transmission, motor function, cognition and olfaction. PMID- 21821116 TI - Influenza virus pathophysiology and brain invasion in mice with functional and dysfunctional Mx1 genes. AB - Mice with a dysfunctional myxovirus resistance-1 (dMx1) gene transport intranasally-instilled PR8 influenza virus to the olfactory bulb (OB) within 4 h post-infection. To determine if the presence of a functional Mx1 (fMx1) gene would influence this brain viral localization and/or disease, we infected mature C57BL/6 dMx1 and fMx1 mice under the same conditions and observed sickness behaviors, viral nucleoprotein (NP) RNA expression and innate immune mediator (IIM) mRNA expression in selected tissues at 15 and 96 h post-infection. Virus invaded the OB and lungs comparably in both sub-strains at 15 and 96 h as determined by nested PCR. In contrast, virus was present in blood and somatosensory cortex of dMx1, but not fMx1 mice at 96 h. At 15 h, sickness behaviors were comparable in both sub-strains. By 96 h dMx1, but not fMx1, were moribund. In both 15 and 96 h lungs, viral NP was significantly elevated in the dMx1 mice compared to the fMx1 mice, as determined by quantitative PCR. OB expression of most IIM mRNAs was similar at both time periods in both sub strains. In contrast, lung IIM mRNAs were elevated in fMx1 at 15 h, but by 96 h were consistently reduced compared to dMx1 mice. In conclusion, functional Mx1 did not alter OB invasion by virus but attenuated illness compared to dMx1 mice. Inflammation was similar in OBs and lungs of both strains at 15 h but by 96 h it was suppressed in lungs, but not in OBs, of fMx1 mice. PMID- 21821119 TI - Characterization of the peroxide sensitivity of COX-deficient yeast strains reveals unexpected relationships between COX assembly proteins. AB - A number of distinct cuproproteins of the mitochondrial inner membrane are required for the assembly of cytochrome oxidase (COX), thought to function in a "bucket brigade" fashion to provide copper to the Cu(A) and Cu(B) sites. In yeast, the loss of two these proteins, Sco1p and Cox11p, leads to respiratory deficiency and a specific inability to survive exposure to hydrogen peroxide (H(2)O(2)). Using a quantitative assay, we have identified subtle differences in the peroxide-sensitive phenotypes between sco1 and cox11 mutant strains. Interestingly, the peroxide sensitivity of the sco1 null strain can be suppressed by overexpressing either SCO2 or COX11, although overexpression of neither SCO1 nor SCO2 can rescue the cox11 null strain. We also find that overexpression of either CTT1, encoding the cytosolic catalase T, or CTA1, encoding the mitochondrial matrix catalase, suppresses the peroxide sensitivity in both the sco1 and the cox11 null mutants. Direct measurement of peroxide metabolism shows that sco1 and cox11 null strains fail to degrade a significant amount of exogenously provided H(2)O(2). Taken together, our data demonstrate that although Cox11p and Sco1p play distinct roles in COX assembly, they seem to play overlapping or related roles in peroxide metabolism that require further investigation. PMID- 21821122 TI - Psychoanalysis and social cognitive neuroscience: a new framework for a dialogue. AB - The fields of psychoanalysis and neuroscience use different methods of description, analysis and comprehension of reality, and because each is based on a different methodology, each approach constructs a different representation of reality. Thus, psychoanalysis could contribute to a general psychology involving neuroscience to the extent that a "psychoanalytical psychology" (the theory of mental functioning that is extrapolated from psychoanalytical practice) defines natural objects of study (mind functions) for a multidisciplinary approach. However, the so called "naturalisation" of psychoanalytical concepts (metapsychology) does not imply the reduction of these concepts to biology; rather, it suggests a search for compatibility between psychoanalytical concepts and neuroscientific description. Such compatibility would mean the search for common objects that could be described from either a psychoanalytic or a neuroscientific point of view. We suggest that inter-subjectivity, empathy or "co thinking" processes, from early development to the psychoanalytic relationship or the interaction between the patient and the analyst, could be such a common object for cognitive social neuroscience and psychoanalysis. Together, neuroscience and psychoanalysis could then contribute to a multidisciplinary approach of psychic inter- or co-activity. PMID- 21821121 TI - Conjugated linoleic acid-induced apoptosis in mouse mammary tumor cells is mediated by both G protein coupled receptor-dependent activation of the AMP activated protein kinase pathway and by oxidative stress. AB - Conjugated linoleic acid (CLA) has shown chemopreventive activity in several tumorigenesis models, in part through induction of apoptosis. We previously demonstrated that the t10,c12 isomer of CLA induced apoptosis of TM4t mouse mammary tumor cells through both mitochondrial and endoplasmic reticulum (ER) stress pathways, and that the AMP-activated protein kinase (AMPK) played a critical role in the apoptotic effect. In the current study, we focused on the upstream pathways by which AMPK was activated, and additionally evaluated the contributing role of oxidative stress to apoptosis. CLA-induced activation of AMPK and/or induction of apoptosis were inhibited by infection of TM4t cells with an adenovirus expressing a peptide which blocks the interaction between the G protein coupled receptor (GPCR) and Galpha(q), by the phospholipase C (PLC) inhibitor U73122, by the inositol trisphosphate (IP(3)) receptor inhibitor 2-APB, by the calcium/calmodulin-dependent protein kinase kinase alpha (CaMKK) inhibitor STO-609 and by the intracellular Ca(2+) chelator BAPTA-AM. This suggests that t10,c12-CLA may exert its apoptotic effect by stimulating GPCR through Galpha(q) signaling, activation of phosphatidylinositol-PLC, followed by binding of the PLC generated IP(3) to its receptor on the ER, triggering Ca(2+) release from the ER and finally stimulating the CaMKK-AMPK pathway. t10,c12-CLA also increased oxidative stress and lipid peroxidation, and antioxidants blocked its apoptotic effect, as well as the CLA-induced activation of p38 MAPK, a downstream effector of AMPK. Together these data elucidate two major pathways by which t10,c12-CLA induces apoptosis, and suggest a point of intersection of the two pathways both upstream and downstream of AMPK. PMID- 21821123 TI - Protective behavior of tamoxifen against Hg2+-induced toxicity on kidney mitochondria: in vitro and in vivo experiments. AB - Heavy metals are known to induce functional alterations in kidney mitochondria, this damage plays a central role in the mercury-induced acute renal failure. In fact, mercury causes rapid and dramatic changes in the membrane's ionic permeability in such a way that a supra load of mitochondrial Ca(2+) occurs. As a consequence, the phenomenon of permeability transition takes place. In this work we studied in vitro and in vivo the protective effect of the selective estrogen receptor modulator tamoxifen on the deleterious action of mercury-induced nonselective permeability in kidney mitochondria. Added in vitro tamoxifen inhibited membrane nonspecific pore opening, brought about by Hg(2+), as well as the oxidative damage of the enzyme cis-aconitase. In vivo the administration of tamoxifen prevented Hg(2+)-induced poisoning on mitochondrial energy-dependent functions. Permeability transition was analyzed by measuring matrix Ca(2+) retention, mitochondrial swelling, and the build up and maintenance of a transmembrane electric gradient. The pharmacologic action of tamoxifen on mercury poisoning could be ascribed to its cyclosporin-like action. PMID- 21821120 TI - Recent progress toward understanding the molecular mechanisms that regulate skeletal muscle mass. AB - The maintenance of muscle mass is critical for health and issues associated with the quality of life. Over the last decade, extensive progress has been made with regard to our understanding of the molecules that regulate skeletal muscle mass. Not surprisingly, many of these molecules are intimately involved in the regulation of protein synthesis and protein degradation [e.g. the mammalian target of rapamycin (mTOR), eukaryotic initiation factor 2B (eIF2B), eukaryotic initiation factor 3f (eIF3f) and the forkhead box O (FoxO) transcription factors]. It is also becoming apparent that molecules which sense, or control, the energetic status of the cell play a key role in the regulation of muscle mass [e.g. AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC1alpha)]. In this review we will attempt to summarize the current knowledge of how these molecules regulate skeletal muscle mass. PMID- 21821124 TI - Gene expression levels assessed by CA1 pyramidal neuron and regional hippocampal dissections in Alzheimer's disease. AB - To evaluate molecular signatures of an individual cell type in comparison to the associated region relevant towards understanding the pathogenesis of Alzheimer's disease (AD), CA1 pyramidal neurons and the surrounding hippocampal formation were microaspirated via laser capture microdissection (LCM) from neuropathologically confirmed AD and age-matched control (CTR) subjects as well as from wild type mouse brain using single population RNA amplification methodology coupled with custom-designed microarray analysis with real-time quantitative polymerase-chain reaction (qPCR) validation. CA1 pyramidal neurons predominantly displayed downregulation of classes of transcripts related to synaptic transmission in AD versus CTR. Regional hippocampal dissections displayed downregulation of several overlapping genes found in the CA1 neuronal population related to neuronal expression, as well as upregulation of select transcripts indicative of admixed cell types including glial-associated markers and immediate-early and cell death genes. Gene level distributions observed in CA1 neurons and regional hippocampal dissections in wild type mice paralleled expression mosaics seen in postmortem human tissue. Microarray analysis was validated in qPCR studies using human postmortem brain tissue and CA1 sector and regional hippocampal dissections obtained from a mouse model of AD/Down syndrome (Ts65Dn mice) and normal disomic (2N) littermates. Classes of transcripts that have a greater percentage of the overall hybridization signal intensity within single neurons tended to be genes related to neuronal communication. The converse was also found, as classes of transcripts such as glial-associated markers were under represented in CA1 pyramidal neuron expression profiles relative to regional hippocampal dissections. These observations highlight a dilution effect that is likely to occur in conventional regional microarray and qPCR studies. Thus, single population studies of specific neurons and intrinsic circuits will likely yield informative gene expression profile data that may be subthreshold and/or underrepresented in regional studies with an admixture of cell types. PMID- 21821125 TI - A canine BCAN microdeletion associated with episodic falling syndrome. AB - Episodic falling syndrome (EFS) is a canine paroxysmal hypertonicity disorder found in Cavalier King Charles spaniels. Episodes are triggered by exercise, stress or excitement and characterized by progressive hypertonicity throughout the thoracic and pelvic limbs, resulting in a characteristic 'deer-stalking' position and/or collapse. We used a genome-wide association strategy to map the EFS locus to a 3.48 Mb critical interval on canine chromosome 7. By prioritizing candidate genes on the basis of biological plausibility, we found that a 15.7 kb deletion in BCAN, encoding the brain-specific extracellular matrix proteoglycan brevican, is associated with EFS. This represents a compelling causal mutation for EFS, since brevican has an essential role in the formation of perineuronal nets governing synapse stability and nerve conduction velocity. Mapping of the deletion breakpoint enabled the development of Multiplex PCR and Multiplex Ligation-dependent Probe Amplification (MLPA) genotyping tests that can accurately distinguish normal, carrier and affected animals. Wider testing of a larger population of CKCS dogs without a history of EFS from the USA revealed that carriers are extremely common (12.9%). The development of molecular genetic tests for the EFS microdeletion will allow the implementation of directed breeding programs aimed at minimizing the number of animals with EFS and enable confirmatory diagnosis and pharmacotherapy of affected dogs. PMID- 21821126 TI - The Phenix software for automated determination of macromolecular structures. AB - X-ray crystallography is a critical tool in the study of biological systems. It is able to provide information that has been a prerequisite to understanding the fundamentals of life. It is also a method that is central to the development of new therapeutics for human disease. Significant time and effort are required to determine and optimize many macromolecular structures because of the need for manual interpretation of complex numerical data, often using many different software packages, and the repeated use of interactive three-dimensional graphics. The Phenix software package has been developed to provide a comprehensive system for macromolecular crystallographic structure solution with an emphasis on automation. This has required the development of new algorithms that minimize or eliminate subjective input in favor of built-in expert-systems knowledge, the automation of procedures that are traditionally performed by hand, and the development of a computational framework that allows a tight integration between the algorithms. The application of automated methods is particularly appropriate in the field of structural proteomics, where high throughput is desired. Features in Phenix for the automation of experimental phasing with subsequent model building, molecular replacement, structure refinement and validation are described and examples given of running Phenix from both the command line and graphical user interface. PMID- 21821127 TI - Expression, purification and structural characterization of functionally replete thrombospondin-1 type 1 repeats in a bacterial expression system. AB - The matrix glycoprotein thrombospondin-1 (TSP-1) is a prominent regulator of endothelial cells and angiogenesis. The anti-angiogenic and anti-tumorigenic properties of TSP-1 are in part mediated by the TSP-1 type 1 repeat domains 2 and 3, TSR(2,3). Here, we describe the expression and purification of human TSR(2,3) in milligram quantities from an Escherichia coli expression system. Microvascular endothelial cell migration assays and binding assays with a canonical TSP-1 ligand, histidine-rich glycoprotein (HRGP), indicate that recombinant TSR(2,3) exhibits anti-chemotactic and ligand binding properties similar to full length TSP-1. Furthermore, we determined the structure of E. coli expressed TSR(2,3) by X-ray crystallography at 2.4A and found the structure to be identical to the existing TSR(2,3) crystal structure determined from a Drosophila expression system. The TSR(2,3) expression and purification protocol developed in this study allows for facile expression of TSR(2,3) for biochemical and biophysical studies, and will aid in the elucidation of the molecular mechanisms of TSP-1 anti angiogenic and anti-tumorigenic activities. PMID- 21821128 TI - Purification and immunogenicity study of human papillomavirus 58 virus-like particles expressed in Pichia pastoris. AB - Two human papillomavirus (HPV) prophylactic vaccines are currently available in the market: Gardasil and Cervarix. These two vaccines work against tumor high risk subtypes HPV 16 and HPV 18. However, they do not include other high-risk subtypes such as HPV 58. Epidemiological research in China shows that HPV 58 is a prevalent high-risk subtype, second only to HPV 16 and HPV 18. Thus, for cervical cancer prevention in China, developing a vaccine against HPV 58 is necessary. In this study, HPV 58 virus-like particles (VLPs) were expressed in the Pichia pastoris, and subsequently purified through pretreatment and a three-step purification process consisting of strong cation exchange chromatography, size exclusion chromatography, and hydroxyapatite chromatography. The highly purified HPV 58 VLPs were confirmed by sodium dodecyl sulfate polyacrylamide gel electrophoresis, electron microscopy, dynamic laser scattering, and ultracentrifugation. The purified VLPs were used to immunize mice to test their ability to induce humoral immunity. Enzyme-linked immunosorbent assays were performed on the sera of the immunized mice and significantly high anti-HPV 58 VLP antibody titers were observed. The immunogenicity study demonstrates that the purified HPV 58 VLPs are HPV vaccine candidates. PMID- 21821129 TI - Heterologous expression and purification of the soybean 7S globulin alpha' subunit extension region: in vitro evidence of its involvement in cell cholesterol homeostasis. AB - In a previous paper, the biological activity of a 216-amino acid recombinant truncated form of the soybean 7S globulin alpha' subunit, known to control cholesterol and triglyceride homeostasis, was described. In this work, a shorter version of the polypeptide chain, spanning 142 amino acid residues from the N terminus and thus exclusively including the so-called extension region, was cloned and overexpressed in Pichia pastoris. The yield of the recombinant polypeptide, which was termed alpha'E, was 8-fold greater than the previous truncated version. The alpha'E polypeptide was purified by simple conventional biochemical techniques to make it available for biological assays. Human hepatoma cell lines (Hep G2) were used to monitor the uptake and degradation of labeled low-density lipoproteins (LDL), according to an established procedure. The LDL uptake (+86%) and degradation (+94%) by cells tested at the highest alpha'E dose (2 MUM) were similar to those found in cells incubated with 1 MUM simvastatin, a potent inhibitor of cholesterol biosynthesis. Additionally, the cell response to alpha'E was found to be dose-dependent. The present findings strongly suggest that this recombinant polypeptide, or a fragment thereof, is the molecular determinant for cholesterol homeostasis and open new prospects for understanding the mechanism involved in this biological response, as a gateway to its utilization in lipid-lowering therapies. PMID- 21821130 TI - plusTipTracker: Quantitative image analysis software for the measurement of microtubule dynamics. AB - Here we introduce plusTipTracker, a Matlab-based open source software package that combines automated tracking, data analysis, and visualization tools for movies of fluorescently-labeled microtubule (MT) plus end binding proteins (+TIPs). Although +TIPs mark only phases of MT growth, the plusTipTracker software allows inference of additional MT dynamics, including phases of pause and shrinkage, by linking collinear, sequential growth tracks. The algorithm underlying the reconstruction of full MT trajectories relies on the spatially and temporally global tracking framework described in Jaqaman et al. (2008). Post processing of track populations yields a wealth of quantitative phenotypic information about MT network architecture that can be explored using several visualization modalities and bioinformatics tools included in plusTipTracker. Graphical user interfaces enable novice Matlab users to track thousands of MTs in minutes. In this paper, we describe the algorithms used by plusTipTracker and show how the package can be used to study regional differences in the relative proportion of MT subpopulations within a single cell. The strategy of grouping +TIP growth tracks for the analysis of MT dynamics has been introduced before (Matov et al., 2010). The numerical methods and analytical functionality incorporated in plusTipTracker substantially advance this previous work in terms of flexibility and robustness. To illustrate the enhanced performance of the new software we thus compare computer-assembled +TIP-marked trajectories to manually traced MT trajectories from the same movie used in Matov et al. (2010). PMID- 21821131 TI - The mechanical properties of tail tendon fascicles from lubricin knockout, wild type and heterozygous mice. AB - The purpose of this study was to analyze the effects of lubricin on tendon stiffness and viscoelasticity. A total of 36 mice were tested with 12 mice in each of the following groups: lubricin knock-out -/-, heterozygous +/- and wild type +/+. A ramp test was used to determine the elastic modulus by pulling the fascicles to 2.5% strain amplitude at a rate of 0.05 mm/s. Then, followed by a relaxation test that pulled the fascicles to 5% strain amplitude at a rate of 2 mm/s. The fascicles were allowed to relax for 2 min at the maximum strain and a single-cycle relaxation ratio was used to characterize viscoelastic properties. There was no significant difference in the Young's modulus between the three groups (p > 0.05), but the knockout mice had a significantly (p < 0.05) lower relaxation ratio than the wild type mice. Based on these data, we concluded that lubricin expression has an effect on the viscoelastic properties of tendon fascicles. The clinical significance of this finding, if any, remains to be demonstrated. PMID- 21821132 TI - Near tubule and intertubular bovine dentin mapped at the 250 nm level. AB - In this study, simultaneous diffraction and fluorescence mapping with a (250nm)(2), 10.1keV synchrotron X-ray beam investigated the spatial distribution of carbonated apatite (cAp) mineral and elemental Ca (and other cations including Zn) around dentin tubules. In 1MUm thick sections of near-pulp root dentin, where peritubular dentin (PTD) is newly forming, high concentrations of Zn, relative to those in intertubular dentin (ITD), were observed adjacent to and surrounding the tubule lumens. Some but not all tubules exhibited hypercalcified collars (high Ca signal relative to the surrounding ITD), and, when present, the zone of high Ca did not extend around the tubule. Diffraction rings from cAp 00.2 and 11.2+21.1+30.0 reflections were observed, and cAp was the only crystal phase detected. Profiles of Ca, Zn and cAp diffracted intensities showed the same transitions from solid to tubule lumen, indicating the same cAp content and organization in ITD far from the tubules and adjacent to them. Further, the matching Ca and diffraction profiles demonstrated that all of the Ca is in cAp or that any noncrystalline Ca was uniformly distributed throughout the dentin. Variation of 00.2 and 11.2+21.1+30.0 diffracted intensity was consistent with the expected biaxial crystallographic texture. Extension of X-ray mapping from near 1MUm resolution to the 250nm level, performed here for dentin and its tubules, will provide new understanding of other mineralized tissues. PMID- 21821133 TI - Transcriptional regulation of selenium-dependent glutathione peroxidase from Venerupis philippinarum in response to pathogen and contaminants challenge. AB - Glutathione peroxidases (GPx) are key enzymes in the antioxidant systems of living organisms by catalyzing the reduction of peroxides to non-reactive products. In the present study, the full-length cDNA encoding a selenium dependent GPx was identified from Venerupis philippinarum (designated as VpSe GPx), and the spatial and temporal expression patterns post-Vibrio anguillarum, heavy metals and benzo[a]pyrene (B[a]P) challenge were also investigated. VpSe GPx possessed all the conserved features critical for the fundamental structure and function of glutathione peroxidase. The VpSe-GPx mRNA was found to be most abundantly expressed in hepatopancreas. Vibrio challenge could significantly up regulate the mRNA expression of VpSe-GPx, and the highest expression level was detected at 24 h post-infection with 6.5-fold increase compared with that in the control group. For heavy metals exposure, the expression of VpSe-GPx was significantly induced by 20, 40 MUg L(-1) Cd and 10, 20 MUg L(-1) Cu but depressed by 10 MUg L(-1) Cd and 40 MUg L(-1) Cu. With regards to B[a]P exposure, the expression of VpSe-GPx mRNA was significantly induced at 48 and 96 h post challenge. All these results suggested that VpSe-GPx was potentially involved in mediating the immune response and antioxidant defense in V. Philippinarum. PMID- 21821134 TI - Identification of CD3epsilon, CD4, CD8beta splice variants of Atlantic salmon. AB - In vertebrates, CD3 complex and CD4 and CD8 co-receptors are essential for signal transduction during T cell activation. In the present study, we report the mRNA spliced variants of the Atlantic salmon CD3epsilon, CD4 and CD8beta and the effect of pathogen encounter on the expression of these variants. CD3epsilon is alternatively spliced in thymus, head kidney, spleen and gills to give rise to the complete mRNA sequence and to an alternative product that lacks the transmembrane exon. CD4 is also alternatively spliced in the thymus, head kidney, spleen and gills to form two variants, although the alternative product is barely detectable. The alternative product lacks the exon 1B encoding the D1 domain, which is essential for binding to MHC class II proteins. Two amplicons were also found for the CD8beta gene; sequencing analysis revealed that the main PCR product corresponds to the previously reported CD8beta sequence, whereas the variant sequence encodes a potential protein that lacks the Ig-like domain. The expression of CD3, CD4, CD8beta genes also analyzed in head kidney of LPS-treated and IPNV infected salmon and different patterns of expression were observed. The presence and balance of the different variants of T cell co-receptors could be related to the ability of fish to induce a particular type of immune response, as well as, the ability of the pathogen to modify the fish immune response. PMID- 21821135 TI - Genetic variation in nicotinic receptors affects brain networks involved in reorienting attention. AB - Prior evidence suggests that a genetic variation in nicotinic receptors modulates visuospatial attention in humans. Brain areas contributing to this modulation are largely unknown. Here we investigate the influence of the nicotinic receptor gene CHRNA4 (rs 1044396) on brain networks involved in detecting unattended events. Subjects were genotyped and studied with functional magnetic resonance imaging while performing a cued target detection task with valid, neutral and invalid trials. Two brain areas within a core region of the attention network, the right temporoparietal junction, showed a genotype dependent modulation. CHRNA4 C/C homozygotes showed differentially higher neural activity in the right middle temporal gyrus when reorienting attention was required in invalid trials. In contrast, T/T homozygotes had stronger activations within the right superior temporal gyrus. An analysis of functional connectivity further revealed that these temporoparietal regions have a distinct connectivity pattern. The superior temporal gyrus recruited by T/T homozygotes shows stronger connections to temporal and parietal brain regions, which are primarily involved in shifting attention, independent of stimulus frequency. In contrast, the middle temporal gyrus exhibits stronger connections to the caudate nucleus, which is involved in detecting violations of expectations. These findings suggest that, depending on genotype, detection of stimuli outside the focus of attention is more driven by reorienting or by expectation signals. PMID- 21821136 TI - When the brain is prepared to learn: enhancing human learning using real-time fMRI. AB - The rate of learning or memory formation varies over time for any individual, partly due to moment-to-moment fluctuation of brain state. Functional neuroimaging has revealed the neural correlates of learning and memory, but here we asked if neuroimaging can causally enhance human learning by detection of brain states that reveal when a person is prepared or not prepared to learn. The parahippocampal cortex (PHC) is essential for memory formation for scenes. Here, activation in PHC was monitored in real-time, and scene presentations were triggered when participants entered "good" or "bad" brain states for learning of novel scenes. Subsequent recognition memory was more accurate for scenes presented in "good" than "bad" brain states. These findings show that neuroimaging can identify in real-time brain states that enhance or depress learning and memory formation, and knowledge about such brain states may be useful for accelerating education and training. Further, the use of functional neuroimaging as a causal, rather than correlative, tool to study the human brain may open new insights into the neural basis of human cognition. PMID- 21821137 TI - Additional gene data and increased sampling give new insights into the phylogenetic relationships of Neogastropoda, within the caenogastropod phylogenetic framework. AB - Neogastropoda, a highly diversified group of predatory marine snails, has often been contradicted in molecular phylogenetic studies. This is partly the consequence of limited neogastropod taxa or outgroups analyzed or insufficient gene sequences employed. This paper reports the most extensive molecular study of the group published to date with increased neogastropod taxa, multiple representatives of caenogastropod outgroups, and additional gene sequences. Data were collected from the entire 18S rRNA, histone H3, and three partial mitochondrial genes. Maximum parsimony, maximum likelihood and Bayesian analyses were conducted. In the caenogastropod phylogenetic framework, Hypsogastropoda was contradicted owing to the inclusion of Cerithioidea. Contrary to previous molecular studies, all the results recovered Neogastropoda as a monophyletic group, which confirms the monophyly of Neogastropoda and the validity of morphological synapomorphies that usually define Neogastropoda as monophyletic. Tonnoidea was shown to be paraphyletic with respect to Ficidae, and together this group formed a monophyletic clade as the sister group to Neogastropoda, which supported the "high mesogastropod" hypothesis of the origin of Neogastropoda. All neogastropod families were strongly supported except Buccinidae, Turridae and Cancellariidae. Our results shed light on the status of Neogastropoda, a controversial group, within Caenogastropoda. PMID- 21821138 TI - Target organ identification of jellyfish envenomation using systemic and integrative analyses in anesthetized dogs. AB - Proper treatment of jellyfish envenomed patients can be successfully achieved only from an understanding of the overall functional changes and alterations in physiological parameters under its envenomation. The majority of previous investigations on jellyfish venoms have covered only a couple of parameters at a time. Unlike most other fragmentary jellyfish studies, we employed an integrative toxicological approach, including hemodynamics, clinical chemistry and hematology analyses, using N. nomurai jellyfish venom (NnV) in dogs. After the baseline measurements for mean arterial pressure (MAP), cardiac output (CO) and heart rate (HR), NnV was intravenously administered to the dogs at doses of 0.1 or 0.3mg/kg body weight. The dogs showed significant decreases in MAP (-27.4+/-3.7 and 48.1+/-9.9 mmHg), CO (-1.1+/-0.1 L/min and -1.0+/-0.2 L/min), and HR (-4.5+/-0.3 and -9.9+/-3.1 beats/min) comparing with the respective baseline controls. The onset of systemic hypotension and bradycardia occurred within 1 min of NnV injection and they lasted for 1-35 min, depending on the NnV doses. Interestingly, serum biochemical analyses of envenomed dogs exhibited dramatic increases of alkaline phosphatase (ALP), creatine phosphokinase (CPK), alanine aminotransferase (ALT) and aspartate aminotransferase (AST), indicating its possible target organs. In conclusion, we have demonstrated simultaneously, for the first time, the multiple organ toxicities (cardiotoxic, myotoxic and hepatotoxic) of a scyphozoan jellyfish venom. Based on these results, an integrative toxinological approach using dogs appears to be effective in predicting jellyfish venom toxicities and designing their therapeutic strategies. We expect this method can be applied to other jellyfish venom research as well. PMID- 21821139 TI - Moving in the right direction: how eukaryotic cells migrate along chemical gradients. AB - Many cells have the ability to grow or migrate towards chemical cues. Oriented growth and movement require detection of the external chemical gradient, transduction of signals, and reorganization of the cytoskeleton. Recent studies in Dictyostelium discoideum and mammalian neutrophils have revealed a complex signaling network that enables cells to migrate in chemical gradients. PMID- 21821141 TI - RAD51 paralogs: roles in DNA damage signalling, recombinational repair and tumorigenesis. AB - Chromosomal double-strand breaks (DSBs) have the potential to permanently arrest cell cycle progression and endanger cell survival. They must therefore be efficiently repaired to preserve genome integrity and functionality. Homologous recombination (HR) provides an important error-free mechanism for DSB repair in mammalian cells. In addition to RAD51, the central recombinase activity in mammalian cells, a family of proteins known as the RAD51 paralogs and consisting of five proteins (RAD51B, RAD51C, RAD51D, XRCC2 and XRCC3), play an essential role in the DNA repair reactions through HR. The RAD51 paralogs act to transduce the DNA damage signal to effector kinases and to promote break repair. However, their precise cellular functions are not fully elucidated. Here we discuss recent advances in our understanding of how these factors mediate checkpoint responses and act in the HR repair process. In addition, we highlight potential functional similarities with the BRCA2 tumour suppressor, through the recently reported links between RAD51 paralog deficiencies and tumorigenesis triggered by genome instability. PMID- 21821142 TI - Metabolic engineering of cellular transport for overproduction of the platform chemical 1,5-diaminopentane in Corynebacterium glutamicum. AB - The present work describes the development of a superior strain of Corynebacterium glutamicum for diaminopentane (cadaverine) production via metabolic engineering of cellular transport processes. In C. glutamicum DAP-3c, a tailor-made producer, the diaminopentane forming enzyme, lysine decarboxylase, was inhibited in vivo by its end-product, suggesting a potential bottleneck at the level of the export. The previously proposed lysine exporter lysE was shown not to be involved in diaminopentane export. Its deletion did not reduce diaminopentane secretion and could therefore be exploited to completely eliminate the export of lysine, an undesired by-product. Genome-wide transcription profiling revealed the up-regulation of 35 candidate genes as response to diaminopentane overproduction, including several transporters. The highest expression increase (2.6-fold) was observed for a permease, encoded by cg2893. Targeted gene deletion in the producer resulted in a 90% reduced diaminopentane secretion. Genome-based overexpression of the exporter, however, revealed a 20% increased yield, a 75% reduced formation of the undesired by-product N-acetyl diaminopentane and a substantially higher viability, reflected by increased specific rates for growth, glucose uptake and product formation. Similarly, deletion of cg2894, TetR type repressor neighboring the permease gene, resulted in improved production properties. The discovery and amplification of the permease, as presented here, displays a key contribution towards superior C. glutamicum strains for production of the platform chemical diaminopentane. The exact function of the permease remained unclear. Its genetic modification had pronounced effects on various intracellular pools of the biosynthetic pathway, which did not allow a final conclusion on its physiological role, although a direct contribution to diaminopentane export appears possible. PMID- 21821143 TI - Metabolic flux analysis of CHO cells at growth and non-growth phases using isotopic tracers and mass spectrometry. AB - Chinese hamster ovary (CHO) cells are the main platform for production of biotherapeutics in the biopharmaceutical industry. However, relatively little is known about the metabolism of CHO cells in cell culture. In this work, metabolism of CHO cells was studied at the growth phase and early stationary phase using isotopic tracers and mass spectrometry. CHO cells were grown in fed-batch culture over a period of six days. On days 2 and 4, [1,2-(13)C] glucose was introduced and the labeling of intracellular metabolites was measured by gas chromatography mass spectrometry (GC-MS) at 6, 12 and 24h following the introduction of tracer. Intracellular metabolic fluxes were quantified from measured extracellular rates and (13)C-labeling dynamics of intracellular metabolites using non-stationary (13)C-metabolic flux analysis ((13)C-MFA). The flux results revealed significant rewiring of intracellular metabolic fluxes in the transition from growth to non growth, including changes in energy metabolism, redox metabolism, oxidative pentose phosphate pathway and anaplerosis. At the exponential phase, CHO cell metabolism was characterized by a high flux of glycolysis from glucose to lactate, anaplerosis from pyruvate to oxaloacetate and from glutamate to alpha ketoglutarate, and cataplerosis though malic enzyme. At the stationary phase, the flux map was characterized by a reduced flux of glycolysis, net lactate uptake, oxidative pentose phosphate pathway flux, and reduced rate of anaplerosis. The fluxes of pyruvate dehydrogenase and TCA cycle were similar at the exponential and stationary phase. The results presented here provide a solid foundation for future studies of CHO cell metabolism for applications such as cell line development and medium optimization for high-titer production of recombinant proteins. PMID- 21821140 TI - Origins and activity of the Mediator complex. AB - The Mediator is a large, multisubunit RNA polymerase II transcriptional regulator that was first identified in Saccharomyces cerevisiae as a factor required for responsiveness of Pol II and the general initiation factors to DNA binding transactivators. Since its discovery in yeast, Mediator has been shown to be an integral and highly evolutionarily conserved component of the Pol II transcriptional machinery with critical roles in multiple stages of transcription, from regulation of assembly of the Pol II initiation complex to regulation of Pol II elongation. Here we provide a brief overview of the evolutionary origins of Mediator, its subunit composition, and its remarkably diverse collection of activities in Pol II transcription. PMID- 21821144 TI - Hematopoietic prostaglandin D synthase (HPGDS): a high stability, Val187Ile isoenzyme common among African Americans and its relationship to risk for colorectal cancer. AB - Intestinal tumors in Apc(Min/+) mice are suppressed by over-production of HPGDS, which is a glutathione transferase that forms prostaglandin D(2) (PGD(2)). We characterized naturally occurring HPGDS isoenzymes, to see if HPGDS variation is associated with human colorectal cancer risk. We used DNA heteroduplex analysis and sequencing to identify HPGDS variants among healthy individuals. HPGDS isoenzymes were produced in bacteria, and their catalytic activities were tested. To determine in vivo effects, we conducted pooled case-control analyses to assess whether there is an association of the isoenzyme with colorectal cancer. Roughly 8% of African Americans and 2% of Caucasians had a highly stable Val187lle isoenzyme (with isoleucine instead of valine at position 187). At 37 degrees C, the wild-type enzyme lost 15% of its activity in 1h, whereas the Val187Ile form remained >95% active. At 50 degrees C, the half life of native HPGDS was 9min, compared to 42 min for Val187Ile. The odds ratio for colorectal cancer among African Americans with Val187Ile was 1.10 (95% CI, 0.75-1.62; 533 cases, 795 controls). Thus, the Val187Ile HPGDS isoenzyme common among African Americans is not associated with colorectal cancer risk. Other approaches will be needed to establish a role for HPGDS in occurrence of human intestinal tumors, as indicated by a mouse model. PMID- 21821146 TI - Inhibition of epoxy-eicosanoid degradation improves the tocolytic effects of indomethacin in the uterus from pregnant women. AB - The incidence of preterm birth is an increasing problem. Indomethacin, a non specific cyclooxygenase inhibitor, has been largely used as tocolytic in the treatment of preterm labor. The aim of the present study was to assess a putative synergistic tocolytic effect between the inhibition of the production of prostanoids and stabilization of epoxides fatty acids, particularly arachidonate on spontaneous uterine contractile activity. The experimental work was performed on uterine biopsies from consenting women undergoing elective cesarean delivery at term. Isometric tension measurements were performed on fresh human myometrial strips. Contractile activities have been monitored upon individual and combined treatments of indomethacin, DDMS, an inhibitor of hydroxy-eicosanoids production and AUDA, an inhibitor of epoxy-eicosanoids degradation. Interestingly, a significant and consistent synergic effect was observed when indomethacin and AUDA were simultaneously added, raising the possibility of a combined clinical use of cyclooxygenase and sEH inhibitors in attempt to treat preterm labor. PMID- 21821145 TI - Crosstalk between EET and HO-1 downregulates Bach1 and adipogenic marker expression in mesenchymal stem cell derived adipocytes. AB - Epoxygenase activity and synthesis of epoxyeicosatrienoic acids (EETs) have emerged as important modulators of obesity and diabetes. We examined the effect of the EET-agonist 12-(3-hexylureido)dodec-8(2) enoic acid on mesenchymal stem cell (MSC) derived adipocytes proliferation and differentiation. MSCs expressed substantial levels of EETs and inhibition of soluble epoxide hydrolase (sEH) increased the level of EETs and decreased adipogenesis. EET agonist treatment increased HO-1 expression by inhibiting a negative regulator of HO-1 expression, Bach-1. EET treatment also increased betacatenin and pACC levels while decreasing PPARgamma C/EBPalpha and fatty acid synthase levels. These changes were manifested by a decrease in the number of large inflammatory adipocytes, TNFalpha, IFNgamma and IL-1alpha, but an increase in small adipocytes and in adiponectin levels. In summary, EET agonist treatment inhibits adipogenesis and decreases the levels of inflammatory cytokines suggesting the potential action of EETs as intracellular lipid signaling modulators of adipogenesis and adiponectin. PMID- 21821147 TI - The systematics and population genetics of Opisthorchis viverrini sensu lato: implications in parasite epidemiology and bile duct cancer. AB - Together with host and environmental factors, the systematics and population genetic variation of Opisthorchis viverrini may contribute to recorded local and regional differences in epidemiology and host morbidity in opisthorchiasis and cholangiocarcinoma (CCA). In this review, we address recent findings that O. viverrini comprises a species complex with varying degrees of population genetic variation which are associated with specific river wetland systems within Thailand as well as the Lao PDR. Having an accurate understanding of systematics is a prerequisite for a meaningful assessment of the population structure of each species within the O. viverrini complex in nature, as well as a better understanding of the magnitude of genetic variation that occurs within different species of hosts in its life cycle. Whether specific genotypes are related to habitat type(s) and/or specific intermediate host species are discussed based on current available data. Most importantly, we focus on whether there is a correlation between incidence of CCA and genotype(s) of O. viverrini. This will provide a solid basis for further comprehensive investigations of the role of genetic variation within each species of O. viverrini sensu lato in human epidemiology and genotype related morbidity as well as co-evolution of parasites with primary and secondary intermediate species of host. PMID- 21821148 TI - The ecology of the Bithynia first intermediate hosts of Opisthorchis viverrini. AB - Opisthorchiasis, together with its associated cholangiocarcinoma, is one of the most important human parasitic diseases on continental Southeast Asia. A great deal of epidemiological data from humans is available on this disease, particularly from the northeast of Thailand, however, only limited information is available on those aspects of the life cycle relating to its Bithynia (Gastropoda) and cyprinid fish intermediate hosts. Here we review the information which is available on the Bithynia hosts of Opisthorchis viverrini. Only one major ecological study has been carried out at one site on a single species of Bithynia. We show not only that detailed ecological studies are required to clarify the epidemiology of opisthorchiasis, but also that the taxonomic status of the Bithynia species transmitting O. viverrini requires clarification. PMID- 21821149 TI - Identification of an amino acid residue in ATP-binding cassette transport G1 critical for mediating cholesterol efflux. AB - The ATP-binding cassette transporter G1 (ABCG1) mediates free cholesterol efflux onto lipidated apolipoprotein A-I (apoA-I) and plays an important role in macrophage reverse cholesterol transport thereby reducing atherosclerosis. However, how ABCG1 mediates the efflux of cholesterol onto lipidated apoA-I is unclear. Since the crystal structure of ABCG family is not available, other approaches such as site-directed mutagenesis have been widely used to identify amino acid residues important for protein functions. We noticed that ABCG1 contains a single cysteine residue in its putative transmembrane domains. This cysteine residue locates at position 514 (Cys(514)) within the third putative transmembrane domain and is highly conserved. Replacement of Cys(514) with Ala (C514A) essentially abolished ABCG1-mediated cholesterol efflux onto lipidated apoA-I. Substitution of Cys(514) with more conserved amino acid residues, Ser or Thr, also significantly decreased cholesterol efflux. However, mutation C514A had no detectable effect on protein stability and trafficking. Mutation C514A also did not affect the dimerization of ABCG1. Our findings demonstrated that the sulfhydryl group of Cys residue located at position 514 plays a critical role in ABCG1-mediated cholesterol efflux. This article is part of a Special Issue entitled Advances in High Density Lipoprotein Formation and Metabolism: A Tribute to John F. Oram (1945-2010). PMID- 21821150 TI - Research-IQ: development and evaluation of an ontology-anchored integrative query tool. AB - Investigators in the translational research and systems medicine domains require highly usable, efficient and integrative tools and methods that allow for the navigation of and reasoning over emerging large-scale data sets. Such resources must cover a spectrum of granularity from bio-molecules to population phenotypes. Given such information needs, we report upon the initial design and evaluation of an ontology-anchored integrative query tool, Research-IQ, which employs a combination of conceptual knowledge engineering and information retrieval techniques to enable the intuitive and rapid construction of queries, in terms of semi-structured textual propositions, that can subsequently be applied to integrative data sets. Our initial results, based upon both quantitative and qualitative evaluations of the efficacy and usability of Research-IQ, demonstrate its potential to increase clinical and translational research throughput. PMID- 21821151 TI - Temporal pattern of the posterior expression of Wingless in Drosophila blastoderm. AB - In most animals, the antero-posterior (A-P) axis requires a gradient of Wnt signaling. Wnts are expressed posteriorly in many vertebrate and invertebrate embryos, forming a gradient of canonical Wnt/beta-Catenin activity that is highest in the posterior and lowest in the anterior. One notable exception to this evolutionary conservation is in the Drosophila embryo, in which the A-P axis is established by early transcription factors of maternal origin. Despite this initial axial establishment, Drosophila still expresses Wingless (Wg), the main Drosophila Wnt homologue, in a strong posterior band early in embryogenesis. Since its discovery 30 years ago this posterior band of Wg has been largely ignored. In this study, we re-examined the onset of expression of the Wg posterior band in relation to the expression of Wg in other segments, and compared the timing of its expression to that of axial regulators such as gap and pair-rule genes. It was found that the posterior band of Wg is first detected in blastoderm at mid nuclear cycle 14, before the segment-polarity stripes of Wg are formed in other segments. The onset of the posterior band of Wg expression was preceded by that of the gap gene products Hunchback (hb) and Kruppel (Kr), and the pair-rule protein Even-skipped (Eve). Although the function of the posterior band of Wg was not analyzed in this study, we note that in temperature-sensitive Wg mutants, in which Wg is not properly secreted, the posterior band of Wg expression is diminished in strength, indicating a positive feedback loop required for Wg robust expression at the cellular blastoderm stage. We propose that this early posterior expression could play a role in the refinement of A-P patterning. PMID- 21821152 TI - Expression of inflammatory and apoptosis factors following coronary stent implantation in coronary heart disease patients. AB - We investigated the changes in characteristics of neutrophil CD11b, monocyte CD11b, platelet CD62P, endothelin (ET), and neutrophil CD178 in patients with coronary heart disease (CHD) before and after primary coronary stenting. A total of 41 patients with CHD who underwent coronary stenting and 40 control subjects were enrolled in the study. In CHD patients, peripheral blood samples were taken 24 h before and 30 min, 24 h, and 72 h after successful coronary stenting. All markers were significantly elevated in patients with CHD compared with controls (P<0.05). Time-course studies revealed that the expressions of neutrophil CD11b, monocyte CD11b, platelet CD62P, and ET were lower at 30 min post-operation (PO) compared with that at 24 h before operation (BO) (P<0.05). All levels significantly increased from 30 min PO to 24 h PO (P<0.05) and decreased thereafter until 72 h PO (P>0.05). Time course changes in neutrophil CD11b levels after coronary stenting were significantly higher in patients with unstable angina pectoris than in patients with stable angina pectoris (P<0.05). CD11b levels were related to CD62P in patients with CHD (P<0.05). Neutrophil CD11b and monocyte CD11b levels were significantly increased in patients with CHD who underwent coronary stenting compared with controls (P<0.05). Results show that CD11b levels increased, meanwhile, the levels of CD62P and ET increased in CHD patients after coronary stenting. In addition, neutrophil CD178 levels of apoptosis factor in patients, which is important for regression of inflammation, remained high for a period of time after coronary stenting. PMID- 21821153 TI - Treatment with rituximab in patients with mixed cryoglobulinemia syndrome: results of multicenter cohort study and review of the literature. AB - OBJECTIVE: Mixed cryoglobulinemia syndrome (MCs) is a systemic vasculitis characterized by multiple organ involvement due to the vascular deposition of immune-complexes, mainly the cryoglobulins. B-lymphocyte expansion represents the underlying pathological alteration frequently triggered by hepatitis C virus (HCV) infection. The treatment of MCs syndrome is generally based on antiviral drugs and/or immunosuppressors, among which rituximab, an anti-CD20 monoclonal antibody, has been usefully employed for both cutaneous and visceral MCs organ involvement. This multicenter study retrospectively evaluated the effects of rituximab in a large series of patients with active MCs. The observed results were compared to those emerging from the updated review of the literature on this topic. METHODS: The study included 87 patients (male/female 19/68, mean age 62.3+/-11.4SD years, mean disease duration 9+/-6.2SD years, HCV infection in 92% of cases) with active cryoglobulinemic vasculitis evaluated before rituximab monotherapy and after 6-month follow-up by means of main clinico-serological parameters. A PubMed search up to May 31, 2011, was done to find published clinical studies, including case reports of MCs treated with rituximab. RESULTS: A significant clinical improvement was observed in a relevant percentage of cases, regardless the presence/absence of associated HCV infection; namely, complete/partial remission of pre-treatment active manifestations was observed in 74% of skin purpuric lesions, up to 87% of non-healing vasculitic leg ulcers, and 44% of the peripheral neuropathy, mainly paresthesias (patient's visual analogical scale from 62+/-25 to 37+/-27; p<=.0001). Moreover, cryoglobulinemic nephropathy, observed in 38 patients, significantly improved in 95% of cases (serum creatinine from 1.8+/-1.1SD to 1.4+/-0.8SD mg/dl, p<=.0001; 24-hour proteinuria from 2.2+/-2.1SD to 0.9+/-1.7SD g/24h, p<=.0001), with complete remission in the 50%. Among 6 patients with complicating non-Hodgkin's B-cell lymphoma a complete or partial remission was observed in 5/6. A complete remission of abdominal vasculitis was also observed in one patient. These beneficial effects were mirrored by the improvement of cryoglobulinemic serological hallmarks, namely cryocrit and low complement C4, in half cases. The safety of rituximab was confirmed by the small number of side effects recorded during the 6-month follow-up. On the whole, the results of the present study are in keeping with those reported in 39 papers present in world literature, including a total of 279 MCs patients. CONCLUSIONS: Rituximab may be regarded as useful and safe pathogenetic treatment of cryoglobulinemic vasculitis. The actual role of this drug should be definitely confirmed by randomized controlled trials, as well as its position in the therapeutical strategy, mainly with respect to antiviral treatment in HCV-associated MCs. PMID- 21821154 TI - Caudal-related homeodomain proteins CDX1/2 bind to DNA replication-related element binding factor. AB - In the intestinal epithelium, the CDX1 and CDX2 homeodomain genes play proliferative and tumor suppressor roles, respectively. The transcription factor DNA replication-related element binding factor (DREF), is an 80kDa polypeptide homodimer that plays an important role in regulating cell proliferation-related genes. Homeodomain genes encode DNA-binding proteins that play crucial roles during development by defining the body plan and determining cell fate. However, until now, the regulation of DREF function by caudal-related homeodomain proteins is poorly understood. In this study, recombinant CDX1/2 homeodomains (CDX1, amino acids [aa] 152-216 and CDX2, aa 184-248) and the DNA-binding domain of Drosophila DREF (dDREF; aa 1-125) were isolated in order to investigate the regulatory mechanism of their interaction. The expression and purification of the truncated CDX1/2 and DREF proteins were successfully performed in Escherichia coli. Models of the CDX1/2 homeodomain and dDREF were constructed using SWISS-MODEL software, a program for relative protein structure modeling. The binding of CDX1/2 and DREF proteins was detected by fluorescence measurement, size-exclusion column (SEC) chromatography, His-tagged pull-down assay, and surface plasmon resonance spectroscopy (BIAcore). In addition, we identified that four different mutants of CDX1 (S185A, N190A, T194A, and V212A) were bound to dDREF with different degrees of interaction. Our results indicate that CDX1/2 homeodomains interact with the DNA-binding domain of dDREF, thereby regulating its transcription activity. PMID- 21821155 TI - MicroRNA in HCV infection and liver cancer. AB - In the more than two-decades since hepatitis C virus (HCV) was identified, there has been considerable improvement in our understanding of virus life cycle due largely to the development of in vitro culture systems for virus replication. Still challenges remain: HCV infection is a major risk factor for chronic hepatitis, liver cirrhosis and hepatocellular carcinoma worldwide; yet mechanistic details of HCV infection-associated hepatocarcinogenesis remain incompletely understood. A protective vaccine is not yet available, and current therapeutic options result in sustained virus clearance only in a subset of patients. Recent interest has focused on small non-protein coding RNAs, microRNAs (miRNAs), the dependence of virus replication on miRNAs, and miRNA-regulated genes in liver cancer. Functional analysis of the miRNA-targeted genes in liver cancer has advanced our understanding of the "oncomiRs" and their role in hepatocarcinogenesis. This review focuses on the dependence of HCV replication on miRNA and role of miRNA-targeted tumor suppressor genes as molecular markers of and possible targets for developing oncomiR-targeted therapy of chronic hepatitis and HCC. This article is part of a Special Issue entitled: MicroRNAs in viral gene regulation. PMID- 21821158 TI - The tyrosine kinase inhibitor nilotinib inhibits proliferation and osteoblast differentiation of human mesenchymal stromal cells. PMID- 21821156 TI - Autologous bone marrow cell implantation in the treatment of non-traumatic osteonecrosis of the femoral head: Five year follow-up of a prospective controlled study. AB - OBJECTIVE: To determine the efficacy of bone marrow cell implantation into the necrotic lesion of the femoral head on clinical symptoms and the progression of osteonecrosis of the femoral head in comparison with core decompression. METHODS: We studied nineteen patients and twenty four hips with early stage osteonecrosis of the femoral head. The hips were allocated to either core decompression only or core decompression and implantation of bone marrow cells. Both patients and assessors were blind with respect to treatment group assignment. The primary outcomes were clinical symptoms and disease progression. RESULTS: Bone marrow implantation afforded a significant reduction in pain and in joint symptoms and reduced the incidence of fractural stages. At 60 months, eight of the eleven hips in the control group had deteriorated to the fractural stage whereas only three of the thirteen hips in the bone marrow graft group had progressed to that stage. Survival analysis showed a significant difference in the time to failure between the two groups at 60 months. Patients had only minor side-effects after the treatments. CONCLUSIONS: This long term follow-up study confirmed that implantation of autologous bone marrow cells in the necrotic lesion might be an effective treatment for patients with early stages of osteonecrosis of the femoral head. PMID- 21821159 TI - Single visit fabrication of a porcelain laminate veneer with CAD/CAM technology: a clinical report. AB - Computer-assisted design and computer-assisted milling (CAD/CAM) technology has been shown to be an effective dental treatment adjunct. This article demonstrates its use in the fabrication of an in-office, one visit, porcelain laminate veneer. PMID- 21821160 TI - Hallermann-Streiff syndrome patient treated with removable prosthesis: a clinical report. AB - Hallermann-Streiff syndrome is a rare congenital disorder characterized by bird like facies and dental anomalies. A description of a 21-year-old Hispanic woman with Hallermann-Streiff syndrome, whose anterior open occlusal relationship and smile were improved with overdentures is presented. The treatment was satisfactory in terms of both esthetics and phonetics, excluding the need for aggressive surgical treatment. PMID- 21821161 TI - Freedom of rotation of selected overdenture attachments: an in vitro study. AB - STATEMENT OF PROBLEM: Attachments for mandibular overdentures may not allow for adequate freedom of rotation. PURPOSE: The purpose of this study was to subject 3 commonly used stud types of resilient attachments to rotation and to measure and compare the degree of rotation that occurs before the attachments bind. MATERIAL AND METHODS: Three stud attachments (ERA, Locator Extended Range, O-Ring System) with their corresponding metal housings were evaluated, first for a single implant system and secondly for a 2-attachment parallel implant system for the mandibular arch. Both the manufacturers' most and least retentive components were tested in each system. In the Locator system, the medium retention (3 lbs) for the standard is the most retentive of the extended range. A total of 60 test specimens, 5 per group, were fabricated. The attachments were connected to a 115 mm rod and attached to a testing device composed of a base, implant analogs, and a vertical plate holding graph paper. A free-sliding plastic block, which supported the metal rod parallel to the base, was removed to release the rod. The distance the rod fell was photographed and input into a computer with software designed to measure linear movement. Three-way ANOVA with heteroscedasticity consistent standard errors was used for data analyses (alpha=.05). RESULTS: Significant differences found among the most retentive components showed that the Locator had a greater freedom of rotation than the ERA (P=.001). The most retentive components in all systems showed that 1 attachment had a greater freedom of rotation than 2 (P=.005). When testing the least retentive components, all systems were significantly different (P<.003), with the freedom of rotation ranking being O-Ring System > Locator Extended Range > ERA. For all 3 systems, the least retentive components showed the most freedom (P<=.008). CONCLUSIONS: The least retentive components offer greater rotation than the most retentive components for all attachment systems tested and for both single and double attachments. Using the most retentive components, the Locator Extended Range attachment allows greater rotation than does the ERA for both single and double attachments. Using the least retentive components, the ORS attachment allows the most rotation and ERA the least for both single and double attachments. Using the most retentive components, one attachment allows greater rotation than does 2 attachments for the attachment systems evaluated. PMID- 21821162 TI - Analysis of the periimplant tissue of craniofacial implants by sulcus fluid flow rate (SFFR). AB - STATEMENT OF PROBLEM: The tissue surrounding craniofacial implants is prone to inflammation; however, no adequate instrument is currently available to measure this objectively. PURPOSE: The purpose of this study was to describe the parameters influencing the sulcus fluid flow rate in the extraoral periimplant tissue environment. MATERIAL AND METHODS: Thirty-four patients with 112 craniofacial implants participated. The sulcus fluid flow rate (SFFR) was measured with standardized paper strips. The influence of cleansing liquids, implant location, presence of purulent exudates, smoking habits, depth of crevice, and previous irradiation on the sulcus fluid flow rate were evaluated with covariate adjusted finite mixture models. RESULTS: Two latent subgroups of SFFR were identified based on a mixed model. The majority (95.5%) had a mean value of 1.44 mm, and the smaller subgroup (4.5%) had a mean value of 10.4 mm. The SFFR values were increased when purulent exudates were present (regression coefficient 1.41), 95% CI (0.67, 2.16). The depth of the crevice influenced the SFFR per unit depth (regression coefficient 0.37), 95% CI (0.22, 0.53). Additional covariates, such as the implant location, history of smoking, and prior irradiation, had no statistical effect on SFFR. CONCLUSIONS: SFFR can be measured objectively in the extraoral periimplant tissue. PMID- 21821163 TI - Gender differences in the form of maxillary central incisors analyzed using AutoCAD software. AB - STATEMENT OF PROBLEM: Female teeth are considered more rounded and male teeth more quadrangular. Although lacking in scientific support, this theory helps in selecting the mold of artificial teeth for dentures. Parameters that are more reliable are sought to determine gender differences in tooth form. PURPOSE: The purpose of this study was to assess possible differences between genders in terms of tooth form: oval, triangular, or quadrangular. MATERIAL AND METHODS: The sample comprised 433 subjects with a mean age of 15 years selected from a population of Brazilian high school students. The maxillary right central incisor (MCI) of each subject was photographed. The images were adjusted to standardize the long axis of the tooth in the vertical position. The AutoCAD computer program was used to analyze graphically the geometric form of the tooth. According to analysis results, form was classified as oval, triangular, or quadrangular. Intraexaminer consistency was analyzed by using linear correlation coefficient and Bland Altman analysis. The relationship between gender and tooth form was analyzed by chi-square and linear regression (alpha=.05). RESULTS: In women, the form was 57.73% (n=127) oval, 23.54% (n=52) triangular, and 18.64% (n=41) quadrangular; while in men, the form was 54.93% (n=117) oval, 36.15% (n=77) triangular, and 8.92% (n=19) quadrangular (P<.001). CONCLUSIONS: The oval form was the most prevalent in both genders. However, the triangular form was more common in men than in women, and the quadrangular form more frequent in women than in men. PMID- 21821164 TI - Choosing the esthetic angle of the face: experiments with laypersons and prosthodontists. AB - STATEMENT OF PROBLEM: Most faces are not symmetrical, and this complicates the task of aligning the anterior segment of the teeth for the restorative dentist, orthodontist, or oral and maxillofacial surgeon. The dental literature provides conflicting advice regarding guidelines for aligning the anterior teeth. PURPOSE: The purpose of this study was to determine the sensitivity of laypersons to variations in the alignment of the anterior segment within a symmetrical face, and to investigate which guidelines were preferred by laypersons and prosthodontists when aligning this segment. MATERIAL AND METHODS: Lay participants (21) were shown a series of 25 modified images of faces on a computer screen and asked to indicate 'noticeability' of tilt and, with another series of 19 images, preference for angulation of the anterior segment. Prosthodontists (14) were shown a further set of 7 images and asked to use a Clinometer to select an appropriate angle. Statistical comparisons were performed with multinomial goodness-of-fit tests and repeated measures ANOVA, followed by Sidak multiple comparisons tests (alpha=.05). RESULTS: The average angle at which the tilt of the anterior segment within a symmetrical face became noticeable to the laypersons was approximately 1 degree. No significant correlation (P=.15) was found between the laypersons' choice of angle for the anterior segment and the angle of the eyes, lips, or horizon, but an angle of 0 degrees was chosen significantly more often than the other angles offered (P<.001). The prosthodontists generally chose an angle close to zero. CONCLUSIONS: The results suggest that the threshold tilt within a symmetrical face, for noticeability by laypersons, is about 1 degree, and that for both laypersons and prosthodontists, the most important guideline is not any individual facial feature or the horizon but the face as a whole. PMID- 21821165 TI - Comparative radiopacity of ceramics and metals with human and bovine dental tissues. AB - STATEMENT OF PROBLEM: Ceramics should be radiopaque enough to be seen on radiographs and to be distinguishable from tooth structures. Information on the radiopacity of different ceramics used in restorative dentistry is limited. PURPOSE: The purpose of this study was to investigate the radiopacity of ceramics in comparison with human and bovine dental hard tissues and metals. MATERIAL AND METHODS: A total of 128 disk-shaped specimens, 6 * 1 mm (n=8), were prepared from dental ceramic materials and metals. The optical densities of each material, along with 2 tooth sections (canine and molar teeth), bovine dentin and enamel specimens, and 2 different aluminum step wedges, were measured from radiographic images using a transmission densitometer. The optical densities of the specimens were used to determine the equivalent aluminum thicknesses. The data were analyzed by nonparametric 1-way ANOVA (Kruskal-Wallis) and Student-Newman-Keuls multiple range tests for post hoc comparison (alpha=.05). RESULTS: Among ceramic materials, Cercon Zirconia had the highest and the Cergo Pressable Ceramic had the lowest radiopacity values. Cergo Pressable Ceramic, Noritake Super Porcelain EX3 dentin, IPS Empress e.max Press, Cercon Kiss dentin, IPS Empress 2, Cercon Ceram dentin, bovine dentin, human canine, and molar tooth dentin radiopacity measurements were not significantly different. The radiopacity measurements of In Ceram Alumina, In-Ceram Spinell, Celay Alumina, Titanium alloy (Ti-6Al-4V), Celay Zirconia, In-Ceram Zirconia, NiCr alloy, Wieland Zirconia, Cercon Zirconia, and 22-carat gold were significantly higher than that of bovine enamel (P<.05). CONCLUSIONS: Significant differences in radiopacity were found among ceramic materials, when compared to metals, bovine enamel and human and bovine dentin. Cercon and Wieland Zirconia had high radiopacity values, which were similar to metals. PMID- 21821167 TI - Dimensional stability of irreversible hydrocolloid impression materials as a function of pouring time: a systematic review. AB - STATEMENT OF PROBLEM: Pouring time of irreversible hydrocolloid impressions differs depending on the brand and intended use, either of which may result in variable dimensional stability. PURPOSE: The purpose of this study was to investigate the available literature on dimensional stability of irreversible hydrocolloid impression materials as a function of pouring time and disinfectant solutions used. MATERIAL AND METHODS: Three electronic database searches (Medline, PubMed, and EMBASE) were conducted to identify in vitro peer-reviewed studies published in English between the early 1970s and October 2010. Selection criteria included in vitro studies, irreversible hydrocolloid as impression material, and storage time. Heterogeneity in the methodology of the selected studies precluded a meta-analysis. RESULTS: Of 62 initially selected studies only 18 were included. Traditional irreversible hydrocolloids were generally stable when poured immediately. However, stability decreased as time elapsed. New irreversible hydrocolloid substitutes appear to allow delay in pouring time and repouring of impressions without significant side effects. CONCLUSIONS: Shorter storage time of irreversible hydrocolloid impressions before pouring is desirable, although this may not be necessary for the extended-pour types. The lack of a standardized technique for studying the effect of storage condition, with or without the use of disinfectants, makes it difficult to make clear recommendations. PMID- 21821166 TI - Relative fracture toughness of bis-acryl interim resin materials. AB - STATEMENT OF PROBLEM: Fracture of the interim partial denture may cause patient discomfort and result in unplanned appointments and expense. At present, limited information is available concerning the fracture toughness of bis-acryl interim resins, especially immediately following fabrication. PURPOSE: The purpose of this investigation was to evaluate the relative fracture toughness and Weibull parameters of 4 commercial chemically polymerized (Protemp Garant 3, Perfectemp II, Integrity, Temphase) and 1 dual polymerizing (Luxatemp Solar) bis-acryl interim resin materials with various filler loading after 1 hour and 24 hours. MATERIAL AND METHODS: Disk-shaped, mini-compact test specimens (8.20 * 1.85 mm thick, n=18) with introduced pre-cracks were prepared in a pre-heated split-mold and maintained at 37 degrees C for 5 minutes during polymerization to simulate clinical conditions. Polymerization temperature was measured using an infrared digital thermometer. Specimens were stored in distilled water at 37 degrees C after which the peak load to fracture was recorded at 1 and 24 hours and the fracture toughness (K(1c)) was calculated. An overall Weibull analysis of the fracture toughness was performed incorporating the fracture toughness data with factors polymerization method, time of testing and filler load of the resin. Weibull analysis was performed at (alpha =.05). Fracture surfaces of representative specimens were examined using scanning electron microscopy. RESULTS: The overall Weibull analysis results showed significant differences (P<.001) in fracture toughness between the times of testing (1 and 24 hours), polymerization method, and as a function of filler loading. The results of the individual Weibull survival analyses showed a significant increase in Weibull Characteristic Strength (sigmao) values between 1 and 24 hours for all materials. The Weibull moduli (m) for the interim resins ranged between 5.8 and 10.3. SEM analysis of fractured surfaces revealed that crack propagation occurred primarily through the resin matrix between filler particles. CONCLUSIONS: Post-gelation polymerization has an important role in determining the fracture properties of both chemical and dual-polymerized bis-acryl interim materials within the first 24 hours. For the materials tested, the higher the filler load, the lower the fracture toughness. PMID- 21821168 TI - A technique for retrieval of cement-retained implant-supported prostheses. AB - Predictable retrievability of cement-retained prostheses has been a clinical concern. This article presents a technique that describes an implant restoration design which will allow predictable removal of cement-retained implant-supported prostheses. PMID- 21821169 TI - What does cost have to do with it? PMID- 21821170 TI - China's major health challenge: control of chronic diseases. PMID- 21821171 TI - Blowing the whistle on intimidation of NHS whistleblowers. PMID- 21821172 TI - Health care for young offenders. PMID- 21821173 TI - What is the future of epidemiology? PMID- 21821175 TI - Nora Volkow--challenging the myths about drug addiction. PMID- 21821176 TI - Xpert MTB/RIF test for tuberculosis. PMID- 21821177 TI - Xpert MTB/RIF test for tuberculosis. PMID- 21821179 TI - Xpert MTB/RIF test for tuberculosis. PMID- 21821181 TI - Sharing information on adverse events. PMID- 21821180 TI - Blood-cell banking for workers at the Fukushima Daiichi nuclear power plant. PMID- 21821183 TI - Blood-cell banking for workers at the Fukushima Daiichi nuclear power plant. PMID- 21821184 TI - Need for close watch on children's health after Fukushima disaster. PMID- 21821185 TI - Development of drugs against chemical, biological, radiological, or nuclear agents. PMID- 21821186 TI - Multiple endocrine abnormalities. PMID- 21821188 TI - Myocardial revascularization by coronary arterial bypass graft: past, present, and future. AB - The history of coronary artery bypass graft surgery is an amazing story that evolved from a basic understanding of the etiology of coronary artery disease to highly sophisticated methods of restoring blood flow to the myocardium. Adjunctive techniques of anticoagulation, coronary artery imaging, and cardiopulmonary bypass contributed greatly to our ability to provide surgical revascularization. Today, coronary artery bypass graft surgery is the treatment of choice for many patients with complex coronary artery disease. The future will certainly bring improved results with better graft patency with less operative insult and morbidity as the final chapter in the story remains untold. PMID- 21821189 TI - [Ultrastructural changes in the trabecular meshwork and increased IOP. Which came first, the chicken or the egg?]. PMID- 21821190 TI - [Dacryocystorhinostomy in adolescents and young adults]. AB - OBJECTIVE: To study the relative frequency, causes, anatomical and functional outcomes and complications of dacryocystorhinostomy (DCR) in patients between the second and fifth decade of life. METHOD: A retrospective, nonrandomized, interventional study of a clinical series of 12 patients who underwent DCR from March 2007 to March 2009, performed by a single surgeon, with an age range between 10 and 48 years. Recorded data included age at surgery, date of surgery, gender, affected side, cause of obstruction, surgical technique, outcome and complications. The relative frequency of such cases over the total was calculated. RESULTS: DCR in patients between 13-48 years old represented 14.11% of the total (12:85). In this group 88.8% were females and in 75% surgery was on the right side. The most frequent cause of obstruction was low idiopathic obstruction (58.33%) whereas 41.66% were secondary. An external DCR was performed on 66.67% of patients and the rest were endonasal DCR. Anatomical success was achieved with resolution of symptoms in 91.6% of patients. One case had a hypertrophic scar. CONCLUSION: Adolescents and young adults represent a significant percentage of cases undergoing DCR surgery. Both the external and endoscopic approach is shown to be a valid alternative for treating these patients, with good results and low incidence of complications. PMID- 21821191 TI - [Ultrasound diagnosis in vasoproliferative tumours of the ocular fundus]. AB - OBJECTIVE: The aim of this work is to describe the ultrasound features in vasoproliferative tumours of the ocular fundus (VPTOF). METHODS: The medical records corresponding to eight patients were retrospectively studied. Clinical data from the complete ophthalmologic examination and ultrasonographic findings were analysed. RESULTS: Nodular masses affecting either the retina or both the retina and the choroid were found. The surface contour of the tumour was regular in 5, and irregular in 3 cases. In terms of dimensions (mm/ SD), the average major base was 7.14/2.56; the minor base 6.74/2.48 and the height 2.38/1.26. Internal structure was always solid and irregular and reflectivity was mostly medium to high in 6 eyes. Angle kappa was not present in any case. No vascularity signs were detected. CONCLUSION: According to the results it is suggested that when a differential diagnosis of VPTOF is carried out, not only should ophthalmoscopic signs be studied, but an ultrasound examination should also be done. PMID- 21821192 TI - [Treatment of wet age-related macular degeneration with ranibizumab in clinical practice: results and prognostic factors]. AB - OBJECTIVES: To evaluate the efficacy of ranibizumab in wet age-related macular degeneration (ARMD), and to identify prognostic factors. METHODS: A retrospective longitudinal study of 79 eyes treated with intravitreal Ranibizumab in our hospital due to wet ARMD, with an initial regimen of three consecutive monthly injections, followed by injections on demand based on the exploratory findings. We conducted a descriptive study of the baseline examination (n=79), and 3 (n=79), 6 (n=67) and 12 months (n=49) after starting treatment. The characteristics of the baseline examination and annual examination results were compared using univariate and multivariate analysis. RESULTS: After the three initial injections, the 93.67% of patients lost fewer than 15 letters, and 19% gained 15 points or more. This result remained similar at 1 year (83.67% and 20.40%, respectively). After 1 year of treatment 40.82% had a VA >= 0.3 and 22'45% had a VA <= 0.1. We used a median of 5 injections per year. The increased AV at the beginning and the persistence of large intraretinal cysts at 3 months (P=.0013), as well as the development of fibrosis during evolution (P=.0005), are associated with visual deterioration. CONCLUSIONS: The guidelines used here stabilised or improved visual acuity in most patients. The most favourable cases are those with initially lower VA or large intraretinal cysts resolved after the loading phase. The appearance of fibrosis implies a poor long-term visual prognosis. PMID- 21821193 TI - [Repair of a leaking bleb filtration with conjunctival and amniotic membrane transplantation]. AB - CLINICAL CASE: A 71-year-old woman presented with a leaking bleb after a combined phacotrabeculectomy performed 13 years ago. To construct a new filtering bleb, the necrotic area was fully excised. The amniotic membrane was inserted over the scleral flap underneath healthy conjunctiva edges. A conjunctiva-Tenon autograft from the contralateral eye was sutured and was sealed with fibrin adhesive. DISCUSSION: We propose a new surgical technique to repair late leak failures after trabeculectomy with mitomycin C in blebs with a large avascular area. Transplantation of amniotic membrane and conjunctival autograft may be used to repair late leak failures with inadequate conjunctiva to advance. PMID- 21821195 TI - [I Afro-Asian Congress of Ophthalmology. Cairo, 1958]. PMID- 21821194 TI - [Sterile non-traumatic corneal perforation treated with Tachosil(r)]. AB - CASE REPORT: An 83 year-old male reported to the emergency room with red eye and ocular pain. The slit-lamp examination showed a central corneal perforation of 1mm in diameter, with no associated infection or inflammatory process. The patient had no history of trauma. It was decided to apply a patch of Tachosil((r)) at the site of corneal perforation. After 36 hours of occlusion, a layer of fibrin covered the perforation, closing the defect. Successful healing of the corneal perforation was observed in the follow-up, with no recurrences of the process. CONCLUSIONS: Tachosil((r)) is collagen sponge with human fibrin and human thrombin used in cardiological and neurosurgical surgery for haemostasis and the occlusion of vessels and meninges. We present the first indication in ophthalmology of Tachosil((r)) as an effective alternative in the treatment of sterile non-traumatic corneal perforations less than 1.5 mm in size. PMID- 21821196 TI - [The tears of Istanbul]. PMID- 21821197 TI - Commentary: Exercise and spinal manipulative therapy for chronic low back pain: time to call for a moratorium on future randomized trials? PMID- 21821198 TI - Commentary: Toward a unified model for investigating health service use in degenerative spinal disorders. PMID- 21821199 TI - Commentary: Predictors of outcome from operative management of lumbar spinal stenosis: a plea for better design and reporting practices. PMID- 21821200 TI - Commentary: Predictive factors influencing clinical outcome with operative management of lumbar spinal stenosis. PMID- 21821201 TI - Commentary: Managing patients with back pain: putting money where our mouths are not. PMID- 21821202 TI - Details on the association between heavy lifting and low back pain. PMID- 21821205 TI - Global teens and tobacco: a review of the globalization of the tobacco epidemic. AB - Worldwide, the burden of suffering to children caused by tobacco does not just originate from exposure to tobacco smoke or smoking, but includes exposure to tobacco-friendly media, poverty associated with money spent on tobacco, increased incidence of tobacco-related fires, and the harms related to child labor in tobacco cultivation. Despite global efforts through human rights acts, the Framework Convention on Tobacco Control, and the MPOWER report, tobacco use continues to accelerate in most countries. While the efforts that have been taken, such as smoking bans in public, are worthy actions, not enough is being done to protect children and teens. More can be done at the policy level, by individuals, and by health care providers. PMID- 21821206 TI - Dawn of a new era for the American journal of geriatric pharmacotherapy. PMID- 21821208 TI - It is just so sad. PMID- 21821209 TI - Assessing the surgical skills of urology residents after preurology general surgery training: the surgical skills learning needs of new urology residents. AB - OBJECTIVE: Resident work-hour restrictions and a reduction in general surgery training have impacted urologic training. We sought to assess the educational needs of urology residents after preurology training in general surgery to compare self-reported outcomes to those of supervising faculty and to determine which aspects of preurology training have an impact on those needs. DESIGN: A survey was distributed electronically to urology residents and faculty of Accreditation Council for Graduate Medical Education (ACGME) residency programs. Residents evaluated 11 surgical skills with regard to their importance to subsequent urology training and their self-assessed proficiency with those skills. Faculty members evaluated the same skills with regard to their importance and their residents' proficiency with those skills. All individuals evaluated 11 general surgery rotations with regard to their importance to later urology training. The responses were analyzed using the paired Wilcoxon test, and faculty responses were compared with resident responses using the Fisher exact test and the chi(2)-test. SETTING: Urologic surgery residency programs in the United States. PARTICIPANTS: There were 305 resident responses and 58 faculty responses. RESULTS: For each surgical skill, residents perceived skills as being more important than their self-assessed proficiency with those skills (p < 0.001). Resident and faculty assessments of surgical skills and of general surgery rotations were similar. More time spent in general surgery training was associated with increased self-assessed proficiency. No difference was found between resident and faculty assessment of global surgical skills (p = 0.76) or general surgery rotation importance (p = 0.87). CONCLUSIONS: A discrepancy was determined between urology residents' perceptions of the importance of surgical skills and their proficiency with those skills. The duration of general surgery training might have an impact on self-assessed skills proficiency. Concordance was demonstrated between resident and faculty perceptions of residents' surgical skills and of general surgery rotations. PMID- 21821210 TI - Development of an industry relations policy by the association of program directors in surgery: a report from the finance committee. PMID- 21821211 TI - Do strong resident teachers help medical students on objective examinations of knowledge? AB - BACKGROUND: Despite a lack of formal training, surgical residents at our institution have an integral role instructing medical students on their general surgery clerkship. It is unknown how the instruction provided by surgical residents affects the students' testable knowledge base and performance on standardized surgical examinations. The purpose of this survey study was to evaluate the impact of surgical resident teachers on medical student performance on the National Board of Medical Examiners surgery shelf examination. STUDY DESIGN: Surveys were provided to all third-year medical students completing an 8 week clerkship in general surgery. Students were asked to rate the quality and quantity of instruction received from surgical residents. Resident instruction was evaluated in several categories using a 5-point Likert scale. Analyses were conducted to evaluate the impact of survey responses on student percentile scores on the surgery shelf examination. RESULTS: Seventy-five of 110 (67.3%) students completed the surveys over a period of 22 months. Forty-two individual residents were evaluated in several categories, and an overall teaching evaluation was completed. The mean shelf percentile score by the medical students was 48.1 +/- 31.4 (range, 1st to 98th percentile). Using univariate analyses, no individual resident factors or overall factors had a significant effect on student performance. A regression analysis revealed that overall quality of instruction had a significantly positive impact on student performance (p = 0.038). Individual residents and increasing PGY level had a significantly negative impact on the students' shelf performance (p < 0.001). The model R(2) showed our model to predict only 13.8% of the student's examination score variability. CONCLUSIONS: A statistically significant relationship exists between student performance on the shelf examination and their perception of the overall quality of instruction that they receive from surgical residents. However, this seems to account only for a small portion of the variability in student percentile scores. PMID- 21821212 TI - Ductal carcinoma in situ in the Department of Defense. AB - OBJECTIVE: Our objective is to investigate some of the trends and variables within the ductal carcinoma in situ (DCIS) diagnosed population and to compare them with the greater civilian populations to identify any possible areas of deficiency or superiority in comparison with civilian institutions. DESIGN: A retrospective analysis of 5023 patients. SETTING: 81st Medical Group Clinical Research Laboratory at Keesler AFB, Mississippi. PARTICIPANTS: All patients treated for ductal carcinoma in situ entered into the Automated Central Tumor Registry (ACTUR) between January 1988 and December 2009. RESULTS: Overall, the rate of finding invasive components after surgery for suspected DCIS was 8.6% (95% confidence interval [CI] = 7.79-9.33). Compared with other published rates, the military has a statistically significant lower rate (p < 0.001). From age 25 until age 65, there is a significant negative correlation of finding invasive cancer after treatment for DCIS (Spearman Rank Correlation = -0.051, p = 0.001). No statistically significant correlations were found between tumor size or grade and finding an invasive component. CONCLUSIONS: The military medical system has provided a reduced probability of finding invasive cancer after treatment for DCIS compared to civilian institutions. Reduced physician workload, patient proactiveness, and public health involvement are among the likely factors. PMID- 21821213 TI - Improving satisfaction ratings of surgical patients from referral to follow-up in the faculty medical center clinic. AB - OBJECTIVE: The objective of this study was to evaluate patient satisfaction in an outpatient community-based surgical clinic to seek opportunities for improvement. METHODS: A paper survey was distributed to patients at the Faculty Medical Center Clinic over a 12-week period. The survey allowed patients to rate their experience on a 5-point scale from "very dissatisfied" to "very satisfied." The survey addressed referral to the clinic, appointment scheduling, visit experience, wait times, laboratory testing, and satisfaction with surgery. Separate from the surveys, data were collected regarding wait time in clinic prior to being placed in an examining room, time spent waiting for the physician, time spent with the physician, overall time spent in clinic, and appointment time to surgery. RESULTS: During the 12-week time period, 87 surveys were returned from patients in the surgery clinic for a 69% response rate. Most patients were referred to the surgery clinic from the emergency department or their primary care physicians at 44% and 43%, respectively. Just over half of the patients responded that they were "very satisfied" with their overall experience. Of those surveyed, 40% of patients were "very satisfied" with their wait time for the first visit to the clinic, 52% with time in waiting room, 43% with time in examining room, and 47% with time spent with physician. Only 16.4% of patients were "very dissatisfied" or "mostly dissatisfied" with time waiting for appointment, 17.9% with time available for appointment, 14.3% with time in waiting room, 18.2% in time waiting in examination room for the physician, and 20.9% of time wait to schedule surgery. Data were also collected on 203 surgical clinic patients during this time. Of the 203 patients, 55% were new patients, 31% were postoperative patients, and 14% were in the clinic for another type of visit. CONCLUSIONS: Overall patient satisfaction was good for the clinic, yet there were areas to improve. Efficiency of scheduling patients, improving wait time for waiting room, examining room, and time prior to scheduling surgery are areas that need improvement. Modification of the current practice at the surgery clinic could result in improvement of patient satisfaction in future evaluation. PMID- 21821214 TI - Interest in and perceived barriers to flexible-track residencies in general surgery: a national survey of residents and program directors. AB - OBJECTIVE: The American Board of Surgery now permits general surgery residents to complete their clinical training over a 6-year period. Despite this new policy, the level of interest in flexible scheduling remains undefined. We sought to determine why residents and program directors (PDs) are interested in flexible tracks and to understand implementation barriers. DESIGN: National survey. SETTING: All United States general surgery residency programs that participate in the Association of Program Directors in Surgery listserv. PARTICIPANTS: PDs and categorical general surgery residents in the United States. MAIN OUTCOME MEASURES: Attitudes about flexible tracks in surgery training. A flexible track was defined as a schedule that allows residents to pursue nonclinical time during residency with resulting delay in residency completion. RESULTS: Of the 748 residents and 81 PDs who responded, 505 residents and 45 PDs were supportive of flexible tracks (68% vs 56%, p = 0.03). Residents and PDs both were interested in flexible tracks to pursue research (86% vs 82%, p = 0.47) and child bearing (69% vs 58%, p = 0.13), but residents were more interested in pursuing international work (74% vs 53%, p = 0.004) and child rearing (63% vs 44%, p = 0.02). Although 71% of residents believe that flexible-track residents would not be respected as the equal of other residents, only 17% of PDs indicated they would not respect flexible-track residents (p < 0.001). CONCLUSION: Most residents and PDs support flexible tracks, although they differ in their motivation and perceived barriers. This finding lends support to the new policy of the American Board of Surgery. PMID- 21821215 TI - Observation of clinical teaching: interest in a faculty development program for surgeons. AB - OBJECTIVES: Observation of clinical teaching is a powerful tool to develop faculty teaching skills. However, the process of being observed can be intimidating for any educator. Our aim is to assess interest in an Observation of Teaching Program within an academic surgical department. DESIGN: An electronic survey asking faculty to indicate interest in participation in a faculty development program that consists of a peer, expert, and/or cross-disciplinary physician observation of teaching was used. Faculty members were also asked whether they would like to observe other faculty as part of a peer-review track. The results were compiled for descriptive statistical analysis. SETTING: Electronic survey. PARTICIPANTS: In all, 46 faculty, all of whom have assigned medical student and resident teaching responsibilities, were introduced to the Observation of Teaching Program and surveyed on their interest in participating. RESULTS: A total of 87% (40/46) of faculty responded after 2 e-mails and 75% (30/40) indicated interest in the Observation of Teaching Program. All faculty who responded positively indicated interest in expert review (30/30), 90% (27/30) in peer review, 87% (26/30) in surgeon review, and 83% (25/30) in cross disciplinary physician review. A total of 48% (19/40) indicated interest in observing others. Of those who were not interested in the Observation of Teaching Program, restrictions on time (4/10), not enough clinical care responsibilities (2/10), not wanting to be watched (2/10), and program did not seem effective (1/10) were cited as reasons for not participating. CONCLUSIONS: Surgical faculty are interested in being observed and receiving feedback about their clinical teaching by experts, peers, colleagues, and cross-disciplinary physicians. Professional development programs for surgeons should consider observation as a teaching methodology. PMID- 21821216 TI - Perceptions of operating room learning experiences during the obstetrics and gynecology clerkship. AB - BACKGROUND: There is little published describing curriculum development for the medical student in the operating room (OR). PURPOSE: Explore student and faculty perceptions of learning experiences in the OR during the Obstetrics and Gynecology (Ob/Gyn) clerkship as a prelude to defining OR-specific learning objectives and curriculum. METHODS: Fourth year students and Obstetrics and Gynecology faculty participated in structured, audiotaped focus groups aimed at defining OR educational objectives and curriculum content. Review of audiotapes identified emergent themes used to categorize perceived learning experiences. RESULTS: Two focus groups including 13 students and 1 focus group including 5 faculty were conducted. Four dominant categories of OR learning were identified: (1) development of a foundation of clinical knowledge; (2) surgical technique and skill acquisition; (3) personal insight into career choice; and (4) surgical culture and OR functioning. CONCLUSIONS: Students and faculty were aligned regarding general categories of key OR learning experiences, building an experiential framework for developing OR-specific learning objectives and curricular components. PMID- 21821217 TI - Simulation speak. AB - The concept of using simulation to gain and improve practical skills in a safe and low-risk environment has been employed extensively in the airline industry to train pilots for many years now. The use of simulation techniques to train surgeons, however, is a new but rapidly expanding and developing area of surgical education. The introduction of simulation to surgical training curricula has inevitably led to a plethora of simulation technology entering the commercial market, as well as the introduction of new terminology used to describe both the equipment itself, and the methods used to test and validate it for use in the training of surgeons. The terminology has its basis mostly in statistical methodology, and the terms are used throughout the surgical literature, often interchangeably and with multiple meanings. In our experience, this terminology is where most confusion arises. Interpreting the literature is difficult for those not directly involved in the field. This article aims to define the statistical terms used to describe the many forms of validity testing and types of surgical simulator, and consequently to act as a reference guide for those unfamiliar with this rapidly evolving field of technology and surgical training. PMID- 21821218 TI - Strategies to accommodate resident work-hour restrictions: impact on surgical education. AB - BACKGROUND: The introduction of duty-hour restrictions has impacted surgical training. Several strategies were introduced by training programs in response to these restrictions. The purpose of this study was to assess the various strategies employed by residency programs to comply with work-hour restrictions with respect to the impact on the quality of surgical education. METHODS: A national survey was developed and distributed to resident members of the Resident and Associate Society of the American College of Surgeons in all accredited residency programs across North America. Questions in the survey addressed 10 separate accommodation strategies used by training programs to adhere to resident work-hour restrictions. Resident respondents completed a 5-point Likert scale rating each strategy according to its impact on surgical education (detrimental, not very helpful, neutral, somewhat helpful, and very helpful). RESULTS: A total of 599 (9.7%) responses were received from 6186 members of the Resident Associate Society. The use of health information technology (IT), nurse practitioners, and physician assistants were most highly rated. Hiring clinical fellows, establishing nonteaching services, and shift-work scheduling were the three most poorly rated accommodations to work-hour restrictions with respect to resident education. CONCLUSIONS: Hospital IT and nonphysician care providers were rated by residents to optimize surgical education in the current work-hour limitation environment. We infer that strategies which lead to increased efficiency and redistribution of resident workload allow surgical trainees to spend more time on activities perceived to have higher educational value. PMID- 21821219 TI - Teaching emergency and essential surgical care in Sierra Leone: a model for low income countries. AB - BACKGROUND: Surgeons OverSeas (SOS), a New York-based organization with a mission to save lives in developing countries, conducted a surgical needs assessment in Sierra Leone in 2008 which identified a large gap in surgical knowledge. We hypothesized that knowledge transfer could be improved by conducting workshops with significant local faculty participation. DESIGN: Description of emergency and essential surgical care workshops (EESC) workshops and follow-up. SETTING: Freetown and Bo, Sierra Leone. PARTICIPANTS: International and local health providers in Sierra Leone. METHODS: SOS organized EESC workshops in collaboration with significant local surgeons' support. Data on subsequent workshops were recorded. RESULTS: Fifteen instructors were identified and assisted with teaching. Nine of the instructors were specialists from Sierra Leone. Each workshop lasted 3 days. Feedback was gathered after these workshops Subsequent to the SOS workshops, 8 other workshops were undertaken by local surgeons in Sierra Leone, 5 of which were organized and taught solely by local surgeons working for the Sierra Leone Ministry of Health and Sanitation. Three other workshops were organized with external support. CONCLUSIONS: EESC workshops organized with significant local input are useful for knowledge transfer and empower local surgeons to conduct subsequent workshops on their own. PMID- 21821220 TI - Teaching subcuticular suturing to medical students: video versus expert instructor feedback. AB - OBJECTIVE: Given limitations in surgical educational resources, more efficient teaching methods are needed. We sought to evaluate 3 strategies for improving skills in subcuticular suturing-practice with an instructional video, practice with expert instructor supervision, and independent practice. DESIGN: Fifty-eight medical students volunteered for this research. Students viewed a video on subcuticular suturing then completed a pretest requiring closure of an incision in a plastic model. Students were randomized among 3 groups: practice with an instructional video (group A), practice with supervision by an expert instructor (group B), and independent practice (group C). After instruction, students completed a posttest, then a retention test 1 week later. Their performances were video recorded and evaluated using a validated scoring instrument composed of global and task-specific subscales. RESULTS: Performances measured using both subscales improved significantly from pretest to post-test only for group B. However, when comparing student performances between pretest and retention posttest, significant improvements on both subscales were seen only in group A. CONCLUSION: These results suggest that practice with an instructional video is an effective method for acquiring skill in subcuticular suturing. PMID- 21821221 TI - The effectiveness of a cognitive task analysis informed curriculum to increase self-efficacy and improve performance for an open cricothyrotomy. AB - OBJECTIVE: This study explored the effects of a cognitive task analysis (CTA) informed curriculum to increase surgical skills performance and self-efficacy beliefs for medical students and postgraduate surgical residents learning how to perform an open cricothyrotomy. METHODS: Third-year medical students and postgraduate year 2 and 3 surgery residents were assigned randomly to either the CTA group (n = 12) or the control group (n = 14). The CTA group learned the open cricothyrotomy procedure using the CTA curriculum. The control group received the traditional curriculum. RESULTS: The CTA group outperformed the control group significantly based on a 19-point checklist score (CTA mean score: 17.75, standard deviation [SD] = 2.34; control mean score: 15.14, SD = 2.48; p = 0.006). The CTA group also reported significantly higher self-efficacy scores based on a 140-point self-appraisal inventory (CTA mean score: 126.10, SD = 16.90; control: 110.67, SD = 16.8; p = 0.029). CONCLUSIONS: The CTA curriculum was effective in increasing the performance and self-efficacy scores for postgraduate surgical residents and medical students performing an open cricothyrotomy. PMID- 21821222 TI - Using elements from an acute abdominal pain Objective Structured Clinical Examination (OSCE) leads to more standardized grading in the surgical clerkship for third-year medical students. AB - BACKGROUND: There is poor reliability in the Likert-based assessments of patient interaction and general knowledge base for medical students in the surgical clerkship. The Objective Structured Clinical Examination (OSCE) can be used to assess these competencies. OBJECTIVE: We hypothesize that using OSCE performance to replace the current Likert-based patient interaction and general knowledge base assessments will not affect the pass/fail rate for third-year medical students in the surgical clerkship. METHODS: In this retrospective study, third year medical student clerkship data from a three-station acute abdominal pain OSCE were collected from the 2009-2010 academic year. New patient interaction and general knowledge base assessments were derived from the performance data and substituted for original assessments to generate new clerkship scores and ordinal grades. Two-sided nonparametric statistics were used for comparative analyses, using an alpha = 0.05. RESULTS: Seventy third-year medical students (50.0% female) were evaluated. A sign test showed a difference in the original (4.45/5) and the new (4.20/5) median patient interaction scores (p < 0.01). A sign test did not show a difference in the original (4.00/5) and the new (4.11/5) median general knowledge base scores (p = 0.28). Nine clerkship grades changed between these different grading schemes (p = 0.045), with an overall agreement of 87.1% and a kappa statistic of 0.81. There were no differences in the pass/fail rate (p > 0.99). CONCLUSIONS: We conclude that there are no differences in pass/fail rate, but there is a more standardized distribution of patient interaction assessments and utilization of the full spectrum of possible passing grades. We recommend that the current patient interaction assessment for third-year medical students in the surgical clerkship be replaced with that found through trained standardized patients in this three-station acute abdominal pain OSCE. PMID- 21821223 TI - Video gaming enhances psychomotor skills but not visuospatial and perceptual abilities in surgical trainees. AB - INTRODUCTION: There is considerable interest in the identification and assessment of underlying aptitudes or innate abilities that could potentially predict excellence in the technical aspects of operating. However, before the assessment of innate abilities is introduced for high-stakes assessment (such as competitive selection into surgical training programs), it is essential to determine that these abilities are stable and unchanging and are not influenced by other factors, such as the use of video games. The aim of this study was to investigate whether experience playing video games will predict psychomotor performance on a laparoscopic simulator or scores on tests of visuospatial and perceptual abilities, and to examine the correlation, if any, between these innate abilities. METHODS: Institutional ethical approval was obtained. Thirty-eight undergraduate medical students with no previous surgical experience were recruited. All participants completed a self-reported questionnaire that asked them to detail their video game experience. They then underwent assessment of their psychomotor, visuospatial, and perceptual abilities using previously validated tests. The results were analyzed using independent samples t tests to compare means and linear regression curves for subsequent analysis. RESULTS: Students who played video games for at least 7 hours per week demonstrated significantly better psychomotor skills than students who did not play video games regularly. However, there was no difference on measures of visuospatial and perceptual abilities. There was no correlation between psychomotor tests and visuospatial or perceptual tests. CONCLUSIONS: Regular video gaming correlates positively with psychomotor ability, but it does not seem to influence visuospatial or perceptual ability. This study suggests that video game experience might be beneficial to a future career in surgery. It also suggests that relevant surgical skills may be gained usefully outside the operating room in activities that are not related to surgery. PMID- 21821224 TI - Sim one, do one, teach one: considerations in designing training curricula for surgical simulation. AB - Although there is considerable interest in the use of simulation for the acquisition of fundamental surgical skills through goal-directed practice in a safe environment, there is little evidence guiding educators on how best to implement simulation within surgical skills curricula. This article reviews the application of the expert performance model in surgery and the role of simulation in surgical skills acquisition. The focus is on implementation of deliberate practice, highlighting the principles of part-task training, proficiency-based training and overtraining. With resident and educator time at a premium, the identification of an optimally effective and efficient training strategy has significant implications for how surgical skills training is incorporated into residency programs, which is critical in today's environment. PMID- 21821225 TI - Powell's pearls: eponyms in medical and surgical history. Sister Joseph's Nodule; Sister Mary Joseph (1856-1939). PMID- 21821226 TI - Clinical and prognostic implications of the initial response to aspirin in patients with acute coronary syndrome. AB - Increased platelet reactivity and decreased response to antiplatelet drugs may result in recurrent ischemic events after acute coronary syndrome (ACS). We evaluated laboratory response to aspirin in patients with ACS before and after percutaneous coronary intervention (PCI) and assessed its effect on major adverse clinical events. Sixty-three consecutive patients with ACS were tested for response to aspirin by light transmittance aggregometry (LTA) and the IMPACT-R test (with arachidonic acid) before and 2 to 4 days after PCI and clopidogrel loading. Patients were followed for clinical events up to 15 months from PCI. Response to aspirin improved significantly after PCI and clopidogrel treatment (mean arachidonic acid-induced LTA decreased from 34.9 +/- 3.35% before PCI to 15.2 +/- 2.2% and surface coverage increased from 2.2 +/- 0.27% to 6.2 +/- 0.6%, p <0.0001 for the 2 methods). Improved response to aspirin after PCI correlated with response to clopidogrel (LTA and IMPACT-R, p <0.01). Patients with good laboratory response to aspirin before but not after PCI had a significantly lower major cardiovascular event rate during 15-month follow-up in multivariate analysis. In conclusion, laboratory response to aspirin is highly dynamic in patients with ACS. Improved response to aspirin after PCI may result from stabilization of coronary artery disease and/or clopidogrel treatment. Laboratory response to aspirin before PCI and clopidogrel loading is a sensitive marker for platelet reactivity that correlates with clinical outcome in patients with ACS. PMID- 21821227 TI - Effect of cardiac resynchronization therapy-defibrillator implantation on health status in patients with mild versus moderate symptoms of heart failure. AB - Indications for cardiac resynchronization therapy (CRT) have expanded to include patients with mild congestive heart failure (CHF) symptoms (New York Heart Association [NYHA] functional class II) because of a demonstrated morbidity reduction in this subset of patients. However, little is known about postimplantation changes in their self-reported health status compared to patients with more severe CHF. The aim of this study was to examine the influence of baseline NYHA functional class on health status changes in the first 12 months after implantation of a CRT with defibrillator (CRT-D). Patients with first-time CRT-D (n = 169, 75% men, mean age 62.1 +/- 10.7 years) were recruited from 3 Dutch hospitals. All patients completed the SF-36 Health Survey at the time of implantation and at 12 months after implantation. Mildly (NYHA functional class II; n = 54) and moderately (NYHA functional class III; n = 115) symptomatic CHF patients showed improved health status in several SF-36 domains at 12 months after CRT-D. When adjusting for baseline health status, the groups did not differ with respect to their health status improvement over time, but after adjustment for demographic and clinical factors, the mildly symptomatic patients reported relatively more improvement in general health (B = 10.15, SE = 3.31, p = 0.003) and social functioning (B = 10.64, SE = 3.74, p = 0.005). In conclusion, NYHA functional class II patients reported equal, and in some domains even more, improvement in health status compared to NYHA functional class III patients at 12 months after CRT-D. Hence, CRT not only prevents clinical adverse events in patients with mild CHF symptoms but also improves health status. PMID- 21821228 TI - A video study of drop instillation in both glaucoma and retina patients with visual impairment. AB - PURPOSE: To compare self-administration of drops in both visually impaired glaucoma subjects and retina subjects. DESIGN: Prospective, observational study. METHODS: SETTING: Distinct glaucoma and retina practices. STUDY POPULATION: Subjects with glaucoma or retinal diseases with visual acuity of 20/60 or worse in 1 eye, significant field loss, or both. OBSERVATION PROCEDURES: Subjects were video recorded self-instilling a drop onto the worse eye. MAIN OUTCOME MEASURE: Proper instillation of eye drop onto ocular surface. RESULTS: We included 409 subjects (205 glaucoma, 204 retina). Differences between the groups included the following: glaucoma subjects included fewer females (P = .05), included fewer white persons (P < .005), had worse visual acuity (P < .005), had less self reported arthritis (P < .05), were younger (P < .005), and had more previous exposure to drop use (P < .005). Glaucoma subjects had more bilateral impairment (60% vs 42%; P < .0005). Retina subjects instilled more drops (1.7 vs 1.4; P = .02) and more frequently touched the bottle to the eye (47% vs 33%; P = .003). Of subjects claiming not to miss the eye, nearly one third from each group (P = .32) actually missed. Approximately one third of each group could not get a drop onto the eye (30% retina vs 29% glaucoma; P = .91). Among subjects placing 1 drop onto the eye without touching the adnexae, there was a trend for glaucoma patients to perform better, although both groups did poorly (success, 39% glaucoma vs 31% retina; P = .09). CONCLUSIONS: Among visually impaired subjects, regardless of cause, drop administration was a problem. Both groups wasted drops, contaminated bottles, and had inaccurate perception of their abilities. This has implications for future therapeutic delivery systems. PMID- 21821229 TI - Histology of the parapapillary region in high myopia. AB - PURPOSE: To examine histomorphometrically the parapapillary region in highly myopic eyes. DESIGN: Retrospective laboratory investigation. METHODS: We examined a highly myopic glaucomatous group (36 human globes; axial length >26.5 mm) and a non-highly myopic group (28 globes with secondary angle-closure glaucoma; 17 eyes with malignant choroidal melanoma). Using light microscopy, pupil-optic nerve sections were assessed. RESULTS: The length of the scleral flange (sclera between optic nerve border and optic nerve dura mater) increased with axial length (P < .001; correlation coefficient r = 0.70) and decreased with its thickness (P < .001; r = 0.75). In all highly myopic eyes (n = 15) with a distance of >0.5 mm between optic nerve border and beginning of Bruch membrane, the parapapillary region consisted of an elongated parapapillary scleral flange associated with a scleral flange thinning and a retrobulbar cerebrospinal fluid space extended into the retroparapapillary region. The parapapillary retina was composed of retinal nerve fiber layer (or its remnants) only, without elements of any other retinal layer, without underlying Bruch membrane or choroid. These histologic features were not detected in any of the non-highly myopic eyes. CONCLUSIONS: Since parapapillary scleral thickness influences the lamina cribrosa biomechanics, the findings may partially explain the increased glaucoma susceptibility in highly myopic eyes. The implications of an absence of Bruch membrane and choroid in the highly myopic parapapillary region, and the implications of the retrobulbar parapapillary extension of the cerebrospinal spinal fluid space for the pathophysiology of the optic nerve head, have to be elucidated. PMID- 21821230 TI - Inhibitory effects of IL-12 on experimental tooth movement and root resorption in mice. AB - OBJECTIVE: Interleukin (IL)-12 is an important cytokine for innate and adaptive immunity. We previously reported that IL-12 inhibits tumour necrosis factor (TNF) alpha-mediated osteoclast formation by inducing apoptosis. We also reported that TNF-alpha plays an important role in mechanical loading-induced osteoclast formation and bone resorption during orthodontic tooth movement. In this study, we investigated the effects of IL-12 on mechanical tooth movement in mice. DESIGN: A Ni-Ti closed coil spring was inserted between the upper incisors and the upper left first molar in mice. IL-12 was injected locally adjacent to the first molar every other day during the experimental period, at doses varying from 0 to 1.5MUg/day. After 12 days, the animals were killed and their jaws were processed for histological evaluation using tartrate-resistant acid phosphatase (TRAP) and TdT-mediated dUTP-biotin nick end-labelling (TUNEL) staining, and measurements of the root resorption area. RESULTS: In the IL-12-treated mice, tooth movement and root resorption appeared to be reduced. In TUNEL-stained sections, many apoptotic cells were recognized on the pressure side in the IL-12 treated mice. CONCLUSIONS: Our findings suggest that IL-12 inhibits not only mechanical tooth movement, but also root resorption during orthodontic tooth movement. These findings may arise through apoptosis induced by IL-12. PMID- 21821231 TI - Impact of anticipatory processing versus distraction on multiple indices of anxiety in socially anxious individuals. AB - In models of social phobia, anticipatory processing before a social-evaluative event is a key maintaining factor for the disorder. This study investigated the impact of anticipatory processing versus distraction before a social-evaluative task on affective (self-reported anxiety), psychophysiological (skin conductance), cognitive (self-reported maladaptive self-beliefs) and behavioural (in-situation performance) responses of participants. High and low socially anxious undergraduates were randomly allocated to either an anticipatory processing or distraction condition, and then completed an impromptu speech task. Relative to distraction, anticipatory processing increased self-reported anxiety in all participants, and increased skin conductance and the strength of conditional and high standard beliefs in the high (but not low) socially anxious participants. Unconditional beliefs were not affected. For high socially anxious individuals, anticipatory processing was also indirectly associated with poorer speech performance by increasing self-reported anxiety. Anticipatory processing appears to have multiple adverse effects in socially anxious individuals. PMID- 21821232 TI - New triterpene oligoglycosides from the Caribbean sponge Erylus formosus. AB - Seven new triterpene glycosides, erylosides R(1) (1), T(1) (3), T(2) (4), T(3) (5), T(4) (6), T(5) (7), and T(6) (8) along with the known formoside (2) were isolated from the sponge Erylus formosus collected along the Caribbean coast of Mexico. Glycoside 1 was determined as a trisaccharide, glycoside 2 as a tetrasaccharide while glycosides 3-8 were hexasaccharide. Their carbohydrate chains were unprecedented and have never been found in oligosaccharides from other biological sources, except Erylus spp. Three carbohydrate chains in the glycosides 3 and 6, 4 and 7, 5 and 8 correspondingly are new. The glycosides 1-5 have penasterol as aglycone while glycosides 6-8 proved to be glycoconjugates of 24-methylene-14-carboxy-lanost-8(9)-en-3beta-ol. PMID- 21821233 TI - Human immunodeficiency virus type 1 Tat induces B7-H1 expression via ERK/MAPK signaling pathway. AB - In HIV-infected subjects, B7-H1 synthesis and expression are up-regulated, and the degree of dysregulation correlates with the severity of disease. HIV-1 Tat protein, the viral transactivating factor, represents a key target for the host immune response. However, the relationship between B7-H1 and Tat protein has not been addressed. Here, we chose human endothelial cells which provide costimulatory signals sufficiently to influence T cells. We used recombinant pcDNA3.1(+)-Tat plasmid to transfect human endothelial cells ECV304 to establish stable Tat-expressed cell strain, and found that HIV-1 Tat was able to induce B7 H1 expression in ECV304 cells by Real-time PCR and flow cytometry analysis, and inhibited lymphocyte proliferation in co-culture system. Moreover, by using pharmacological inhibitor of ERK pathway, HIV-1 Tat induces B7-H1 expression via ERK/MAPK signaling pathway was corroborated. In summary, our results indicate that HIV-1 Tat could induce B7-H1 synthesis in ECV304 cells through ERK/MAPK signaling pathway. PMID- 21821234 TI - Imagery of errors in typing. AB - Using a typing task we investigated whether insufficient imagination of errors and error corrections is related to duration differences between execution and imagination. In Experiment 1 spontaneous error imagination was investigated, whereas in Experiment 2 participants were specifically instructed to imagine errors. Further, in Experiment 2 we manipulated correction instructions (whether or not to correct errors) and controlled for visual feedback in executed typing (letters appearing on the screen or not). Participants executed and imagined typing proverbs of different lengths. Errors and error corrections explained a significant amount of variance of execution minus imagination differences in Experiment 1, and in Experiment 2 when participants were instructed to correct errors, but not when participants were instructed not to correct errors. In Experiment 2 participants corrected and reported more errors with than without visual feedback. However, the relation between execution-imagination duration differences and errors and error corrections was unaffected by visual feedback. The types of errors reported less often in imagination than in execution were related to processes in typing execution. We conclude that errors and error corrections are not spontaneously imagined during motor imagery, and that even when attention is drawn to their occurrence only some are imagined. This may be due to forward models not predicting all aspects of an action, imprecise forward models, or a neglect of monitoring error signals during motor imagery. PMID- 21821235 TI - Personality disorders and autism spectrum disorders: what are the connections? AB - BACKGROUND: The relationship between autism spectrum disorders/pervasive developmental disorders and personality disorders is not completely clear, although both concepts imply lifelong impairment. The purpose of the present study was to investigate the presence of possible personality disorders in a group of young adults with Asperger syndrome. METHOD: Fifty-four young adults with a clinical diagnosis of Asperger syndrome were assessed with Structured Clinical Interview for DSM-IV Axis II disorders to evaluate the presence of a concomitant personality disorder and completed the Autism Spectrum Quotient to measure level of autistic features. Autism spectrum diagnosis was confirmed by Diagnostic Interview for Social and Communication Disorders with a collateral informant. RESULTS: Approximately half of the study group fulfilled criteria for a personality disorder, all belonging to cluster A or C. There was a significant difference across sex: men with Asperger syndrome meeting personality disorder criteria much more often than women with Asperger syndrome (65% vs 32%). Participants fulfilling criteria for a personality disorder showed more marked autistic features according to the Autism Spectrum Quotient. CONCLUSIONS: There is a considerable overlap in symptoms between Asperger syndrome and certain personality disorders. Similarities and differences of the two concepts are discussed in the framework of the Diagnostic and Statistical Manual of Mental Disorders classification system. PMID- 21821236 TI - Insight in schizophrenia and risk of suicide: a systematic update. AB - BACKGROUND: Suicide has been shown to represent the major single cause of premature death among patients with schizophrenia spectrum disorders. Insight has been proposed to increase such risk. However, this subject has not been sufficiently investigated, and inconclusive results have been reported. OBJECTIVE: The objective of this study is to systematically examine the role of insight in the risk of suicide attempts and completed suicide among patients with schizophrenia and related disorders. METHOD: Articles assessing insight and suicidality in patients with schizophrenia spectrum disorders published between 1977 and 2010 were reviewed. A MEDLINE search strategy was used to identify studies using keywords. Application of meta-analytic techniques to selected studies was not possible because of important methodological differences between them. RESULTS: Fifteen studies met predetermined selection criteria. Ten failed to demonstrate a positive association between insight and risk for suicide. DISCUSSION: There is little evidence to support the suggestion that insight may represent a risk factor for suicide in patients with schizophrenia. If there is an association between such risk and insight, it appears to be mediated by other variables such as depression and, above all, hopelessness. Further studies with larger samples and longer follow-up periods in naturalistic conditions, in which insight should be evaluated from a multidimensional approach, are required to analyze this issue in depth, given the crucial implications that it may have on the development of a model for suicide prevention in schizophrenia. PMID- 21821237 TI - Prevalence of diabetes in patients with major depressive disorder: a population based study. AB - OBJECTIVE: We conducted this population-based study to detect the prevalence and associated factors of diabetes in patients with major depressive disorder (MDD) in Taiwan. METHODS: The National Health Research Institute provided a database of 1,000,000 random subjects for health service study. We obtained a random sample of 766,427 subjects 18 years or older, in 2005. Study subjects who had at least one service claim during 2005 for either outpatient or inpatient care, with a primary diagnosis of MDD or with a primary or secondary diagnosis of diabetes, were identified. RESULTS: The 1-year prevalence of diabetes in patients with MDD was higher than that in the general population (11.65% vs 6.53%; odds ratio, 1.53; 95% confidence interval, 1.39-1.69) in 2005. Compared with the general population, patients with MDD had a higher prevalence of diabetes in all age groups, except age 18 to 29 years; among men and women; among all insurance amount groups; among those living in the northern and southern regions; and among residents living in urban, suburban, and rural areas. A higher prevalence of diabetes in patients with MDD was associated with increased age, use of antipsychotic agents, use of mood stabilizers, and residence in suburban areas. CONCLUSIONS: Patients with MDD had a much higher prevalence of diabetes in young adult age group and in men than in the general population. Consequently, we must emphasize prevention, early detection, and adequate treatment of diabetes in patients with MDD. PMID- 21821238 TI - Working memory deficit in premenstrual dysphoric disorder and its associations with difficulty in concentrating and irritability. AB - OBJECTIVE: This study evaluates working memory deficit among women with premenstrual dysphoric disorder (PMDD) and whether such a deficit and its premenstrual aggravation is associated with difficulty in concentrating, irritability, and impaired daily function or not. METHOD: Sixty women with PMDD (PMDD group) and 60 women without PMDD (control group) completed the assessment. Severity of irritability, difficulty concentrating, total symptoms, and functional impairment of PMDD were evaluated by the Premenstrual Symptoms Screening Tool. All participants performed N2 and N3 back tasks to assess working memory in both luteal and follicular phases. RESULTS: The PMDD group had significantly poorer performance on N2 and N3 back tasks than the control group did in the luteal phase but not in the follicular phase. Compared to the control group, the PMDD group also exhibited more deterioration in performance of N3 back task in the luteal phase. Performance of N2 and N3 back tasks in luteal phase was significantly associated with irritability, symptom severity, and functional impairment by PMDD. CONCLUSIONS: Working memory deficit is aggravated in the luteal phase among women with PMDD. Appropriate interventions are needed to prevent negative consequences of working memory deficit. PMID- 21821239 TI - Reliability of a shortened version of the Zagazig Depression Scale and prevalence of depression in an Egyptian university student sample. AB - BACKGROUND: There is some evidence that university students are at higher risk of depression; but rates have been found to vary widely across different countries, and there have been few surveys in representative samples. This study was carried out to assess the reliability of the Arabic-language Zagazig Depression Scale (ZDS) in a sample of Egyptian university students and to use the ZDS to assess the prevalence of depression. METHODS: The study was a cross-sectional survey of a representative sample of 988 undergraduate students from Assiut University, Egypt (response rate, 82.3%). Prevalence of depressive symptoms was assessed using the ZDS, a self-report Arabic-language version of the Hamilton Rating Scale, modeled on the Carroll Rating Scale for Depression. RESULTS: Participants had a mean ZDS score of 17.8 (+/- 9.0) out of a possible maximum score of 46. Using the recommended cutoffs for the ZDS, 37.6% of the students were found to have at least moderate depression, with 71% exceeding the cutoff for mild depression. The internal consistency of the ZDS was excellent (Cronbach alpha = 0.904), as was the split-half correlation coefficient. CONCLUSION: This survey revealed a worryingly high rate of depressive symptoms in a representative sample of Egyptian university students. The ZDS is a reliable and acceptable tool for assessing mental health in a university population. PMID- 21821240 TI - Personality disorders among patients accessing alcohol detoxification treatment: prevalence and gender differences. AB - BACKGROUND: Alcohol abuse and dependence are frequently associated with psychiatric disorders and personality disorders (PDs) with differences among gender. However, only few studies investigated gender differences in PDs among alcoholics. The aim of this study was to investigate PDs in a sample of patients accessing inpatient alcohol detoxification treatment and to describe gender differences in prevalence and comorbidity of PDs. METHODS: The study population consisted of 206 patients entering alcohol detoxification treatment in a specialized clinic in Italy. At enrollment, patients filled in the Millon Clinical Multiaxial Inventory-III for the assessment of PDs. RESULTS: The sample consisted of 150 males and 56 females. Twenty-five percent of males vs 12.5% of females had 1 PD; 16% vs 23%, 2 PDs; and 46% vs 48%, more than 3 PDs. A statistically significant higher proportion of females got high scores on avoidant (21.4% vs 9.3%), self-defeating (50.0% vs 24.0%), and borderline scales (42.9% vs 25.3%). Depressive, self-defeating, and borderline PDs were frequently associated both to other PDs and among each other, particularly among females. CONCLUSIONS: Borderline PD is confirmed to be more frequent among females than among males accessing alcohol detoxification treatment. More studies are needed to clarify prevalence and associations of PDs, prognosis, and gender differences in alcoholics patients. PMID- 21821241 TI - Effects of sunshine on suicide rates. AB - OBJECTIVES: Seasonal spring peaks of suicide are well described in epidemiological studies, but their origin is poorly understood. More recent evidence suggests that this peak may be associated with the increase in the duration of sunshine in spring. We investigated the effect of number of sunshine hours per month on suicide rates in Austria between 1996 and 2006. METHODS: Suicide data, differentiated by month of suicide, sex, and method of suicide (violent vs nonviolent methods), were provided by Statistics Austria. Data on the average number of sunshine hours per month were calculated from 39 representative meteorological stations (provided by the Austrian Central Institute for Meteorology and Geodynamics). For statistical analysis, analysis of variance tests, Kruskal-Wallis tests, and Pearson correlation tests were used. RESULTS: A total of 16,673 suicides with a median of 126 +/- 19.8 suicides per month occurred in the examined period. A clear seasonal pattern was observed, with suicide frequencies being highest between March and May and lowest between November and January (df = 11, F = 5.2, P < .0001) for men (df = 11, F = 4.9, P < .0001) and women (df = 11, F = 2.4, P = .008). The average number of sunshine hours per month was significantly correlated with the number of suicides among both sexes (r = .43, P < .0001), violent methods (r = .48, P < .0001) but not with nonviolent methods (r = .03, P = .707). CONCLUSIONS: This study shows that seasonal changes in sunshine account for variations in the number of suicides and especially violent suicides. We propose that sunshine, via interactions with serotonin neurotransmission, may trigger increased impulsivity and promote suicidal acts. However, because of the hypothesis-generating design of this study, more research is needed to further clarify the role of sunshine in triggering neurobiologic changes, which might contribute to suicidal behavior. PMID- 21821242 TI - Severe social anxiety in early psychosis is associated with poor premorbid functioning, depression, and reduced quality of life. AB - OBJECTIVE: The main aim of the present study was to examine whether patients with first-episode psychosis (FEP) with severe social anxiety show poorer premorbid and current functioning, higher level of current clinical symptoms, and better "insight into illness." Furthermore, we wanted to explore whether social anxiety is associated with reduced quality of life (QoL). METHOD: A sample of 144 individuals with an FEP was divided into 3 groups depending on current level of social anxiety symptoms measured by the Liebowitz Social Anxiety Scale. Analysis of variance was performed including measures of demographic and clinical characteristics. A hierarchical regression analysis was performed to explore possible predictors of QoL. RESULTS: The most severe social anxiety group revealed poorer premorbid adjustment, lower social functioning, and higher levels of depression. Furthermore, this group revealed a higher awareness of illness and experienced reduced QoL. Overall, social anxiety was associated with reduced QoL even after adjusting for psychotic symptoms and depression. CONCLUSION: Severe social anxiety in FEP is associated with poor premorbid functioning and distinct clinical characteristics, besides being a possible predictor of QoL. PMID- 21821243 TI - Hyperthyroidism advances luteolysis in the pregnant rat through changes in prostaglandin balance. AB - OBJECTIVE: To investigate the underlying mechanisms implicated in the premature luteolysis induced by hyperthyroidism in pregnant rats. DESIGN: Experimental basic study. SETTING: Research institute. ANIMAL(S): Groups of 6-8 adult female Wistar rats were injected SC daily with T(4) (0.25 mg/kg) or vehicle, starting 8 days before mating, and killed by decapitation on days 19 (G19), 20 (G20), and 21 (G21) of pregnancy. INTERVENTION(S): Corpora lutea and truncal blood of control and hyperthyroid rats were obtained. MAIN OUTCOME MEASURE(S): Circulating and intraluteal hormones were determined by using RIA and luteal messenger RNA (mRNA) expression of enzymes and factors involved in P synthesis and metabolism by reverse transcriptase-polymerase chain reaction. 20alpha-Hydroxysteroid dehydrogenase (20alphaHSD) mRNA and protein expression was also determined by quantitative reverse transcriptase-polymerase chain reaction and Western blot. RESULT(S): Hyperthyroidism advanced luteolysis and 20alphaHSD expression induction by one day without changes in enzymes involved in P synthesis, decreased circulating E(2) and luteal estrogen receptor beta, and increased luteal prostaglandin F(2alpha) on G19 and G20 and prostaglandin E(2) on G19, while decreasing it on G20. Thus, decreased estrogenic influence and high prostaglandin F(2alpha)/prostaglandin E(2) ratio favors premature induction of 20alphaHSD on hyperthyroid rats. CONCLUSION: Hyperthyroidism affects luteolysis in pregnant rats through alterations in luteal prostaglandin balance and decreased luteotrophic factors favoring the luteolytic action of prostaglandin F(2alpha) that induces premature 20alphaHSD expression that in turn advances circulating P fall and delivery. PMID- 21821244 TI - The effect of increasing obesity on the response to and outcome of assisted reproductive technology: a national study. AB - OBJECTIVE: To evaluate the effect of increasing female obesity on response to and outcome of assisted reproductive technology (ART) treatment. DESIGN: Historical cohort study. SETTING: Clinic-based data. PATIENT(S): A total of 152,500 ART cycle starts from the Society for Assisted Reproductive Technology Clinical Outcomes Reporting System for 2007-2008, limited to women with documented height and grouped by body mass index (BMI, [weight/height(2)]). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Cycle cancellation overall, cycle cancellation due to low response, treatment failure (not pregnant vs. pregnant), and pregnancy failure (fetal loss or stillbirth vs. live birth), as adjusted odds ratios and 95% confidence intervals, with cycles among normal-weight women as the reference group. RESULT(S): Cycle cancellation overall and cancellation due to low response using autologous oocytes significantly paralleled increasing BMI. The odds of treatment failure rose significantly with autologous-fresh cycles, from 1.03 for cycles among overweight women (BMI 25.0-29.9) to 1.53 for cycles among women with BMIs >= 50.0 kg/m(2). Likewise, the odds of pregnancy failure were most significant with increasing BMI among women with autologous-fresh cycles, increasing from 1.10 for cycles to overweight women to 2.29 for cycles to women with BMI >= 50.0 kg/m(2). CONCLUSION(S): These results indicate significantly higher odds of cycle cancellation. In addition, treatment and pregnancy failures with increasing obesity significantly increased starting with overweight women. PMID- 21821245 TI - Different effects of epidermal growth factor on smooth muscle cells derived from human myometrium and from leiomyoma. AB - OBJECTIVE: To determine different effects of epidermal growth factor (EGF) on cultured smooth muscle cells (SMCs) derived from human myometrium and leiomyoma. DESIGN: EGF effects on DNA synthesis and intracellular signal transduction were studied in cultured SMCs from leiomyoma and its matched myometrium. SETTING: Research laboratories. PATIENT(S): Patients 35-50 years old with uterine leiomyomas. INTERVENTION(S): Hysterectomy. MAIN OUTCOME MEASURE(S): Signal transduction from EGF receptor. RESULT(S): As analyzed by laser scanning cytometry (LSC), EGF treatment stimulated DNA synthesis and induced polyploidization of leiomyomal, but not myometrial, SMCs. EGF stimulation was inhibited by AG1478, an EGF receptor (EGFR) inhibitor and PD98059, a mitogen activated protein kinase (MAPK) kinase (MEK) inhibitor. Both leiomyomal and myometrial SMCs had similar expression levels of EGFR, but EGF treatment induced transient phosphorylation activation of EGFR and Akt in leiomyomal SMCs. Consequently, EGF triggered transient phosphorylation activation of p44/42 MAPK in leiomyomal SMCs, followed by down-regulation of p27. In myometrial SMCs, however, EGF induced sustained activation of EGFR, Akt, and p44/42 MAPK with up regulation of p27. CONCLUSION(S): EGF stimulates DNA synthesis and polyploidization in leiomyomal SMCs through transient activation of the EGFR-MAPK pathway. Given that polyploidization plays a role in tumorigenesis, our results shed new light on the pathogenesis of human uterine leiomyoma. PMID- 21821246 TI - Green tea epigallocatechin-3-gallate inhibits angiogenesis and suppresses vascular endothelial growth factor C/vascular endothelial growth factor receptor 2 expression and signaling in experimental endometriosis in vivo. AB - OBJECTIVE: To investigate the antiangiogenesis mechanism of epigallocatechin-3 gallate (EGCG) in an endometriosis model in vivo. DESIGN: Animal studies. SETTING: University laboratory. ANIMAL(S): Human endometrium from women with endometriosis (n = 10) was transplanted into immunocompromised mice. INTERVENTION(S): Mice (n = 30) were randomly treated with EGCG, vitamin E (antioxidant control), or vehicle (negative control) for microvessel imaging. MAIN OUTCOME MEASURE(S): Endometriotic implants were collected for angiogenesis microarray and pathway analysis. Differentially expressed angiogenesis molecules were confirmed by quantitative polymerase chain reaction, Western blot, and immunohistochemistry. Effects of EGCG on angiogenesis signal transduction were further characterized in a human endothelial cell line. Microvessel parameters and the angiogenesis signaling pathway in endometriotic implants and endothelial cells were studied. RESULT(S): EGCG, but not vitamin E, inhibited microvessels in endometriotic implants. EGCG selectively suppressed vascular endothelial growth factor C (VEGFC) and tyrosine kinase receptor VEGF receptor 2 (VEGFR2) expression. EGCG down-regulated VEGFC/VEGFR2 signaling through c-JUN, interferon gamma, matrix metalloproteinase 9, and chemokine (C-X-C motif) ligand 3 pathways for endothelial proliferation, inflammatory response, and mobility. EGCG also suppressed VEGFC expression and reduced VEGFR2 and ERK activation in endothelial cells. VEGFC supplementation attenuated the inhibitory effects by EGCG. CONCLUSION(S): EGCG inhibited angiogenesis and suppressed VEGFC/VEGFR2 expression and signaling pathway in experimental endometriosis in vivo and endothelial cells in vitro. PMID- 21821248 TI - Mating by proxy: a novel perspective to donor conception. AB - How single, partnered lesbian, and partnered heterosexual women undertaking donor insemination rate the importance of donor characteristics is explored in the context of Trivers's parental investment theory. Consistent with this theory, single women placed higher value on biographical traits reflective of the donor's level of potential resources (occupation, hobbies, age) and good character compared with either partnered lesbian or heterosexual women. PMID- 21821247 TI - Adenomyosis does not affect implantation, but is associated with miscarriage in patients undergoing oocyte donation. AB - OBJECTIVE: To evaluate the effect of adenomyosis on endometrial gene expression and its correlation with clinical outcome. DESIGN: Transcriptomic analysis of the endometrium of women with adenomyosis during the window of implantation. Retrospective matched cohort study of the impact of adenomyosis on oocyte donation (OD) outcome. SETTING: University-affiliated infertility clinic (2005 2009). PATIENT(S): Endometrial samples were analyzed using microarrays in women with adenomyosis and healthy controls. The clinical study included three groups: adenomyosis, endometriosis, and control. INTERVENTION(S): Endometrial biopsies in natural cycles 7 days after the LH peak; controlled ovarian stimulation in donors; ET in recipients after replacement therapy. MAIN OUTCOME MEASURE(S): Differentially expressed genes; implantation, pregnancy, miscarriage, and term pregnancy rates in OD. RESULT(S): There is a similar endometrial gene expression pattern in both the adenomyosis group and controls, and nonparametric tests revealed 34 dysregulated genes in adenomyosis patients but none belonged to the group of window of implantation genes. Implantation in OD did not differ among the three groups. However, miscarriage was significantly higher in the adenomyosis group vs. the adenomyosis + endometriosis and control groups. Term pregnancy rate was also significantly lower in the adenomyosis group compared with others. CONCLUSION(S): Clinical and molecular data show that implantation is not affected by adenomyosis, but the higher miscarriage rates associated with this condition lead to lower term pregnancy rates, indicating a clear negative effect on the final outcome of OD. PMID- 21821249 TI - Use of cyanoacrylate glue as a rescue therapy of a duodenal diverticular rebleeding. PMID- 21821250 TI - Flexible endoscopic septoplasty for bilobed Zenker's diverticulum. PMID- 21821251 TI - Esophageal perforation by fish bone ingestion. PMID- 21821252 TI - Breaking the barrier: using extractable fully covered metal stents to treat benign biliary hilar strictures. AB - BACKGROUND: Most benign biliary strictures nowadays are managed endoscopically with plastic stents or with a insertion of a fully covered self-expandable metal stent (fcSEMS). The paradigm for the treatment of benign hilar strictures precludes the use of an fcSEMS because it obstructs the intrahepatic bile ducts, in particular, the contralateral hepatic duct. It is unknown whether use of a plastic stent in the opposite hepatic duct after deployment of an fcSEMS across the liver hilum provides an adequate solution for this problem. OBJECTIVE: To evaluate the use of an fcSEMS in combination with a contralateral plastic stent in the treatment of benign hilar strictures. DESIGN: Case series. SETTING: Tertiary referral hospital. PATIENTS: Two consecutive patients with benign hilar strictures. INTERVENTIONS: Placement of an intrahepatically deployed fcSEMS in conjunction with a contralateral 10F plastic stent for 4 to 5 months followed by stent removal and cholangiogram. MAIN OUTCOME MEASUREMENTS: Clinical and laboratory follow-up of at least 9 months. RESULTS: In both patients, the indwelling period of the stents was uneventful as was stent removal. Both strictures resolved, and there were no clinical or biochemical signs of a recurrent stricture. LIMITATIONS: Small number of patients. CONCLUSIONS: Treatment of benign hilar strictures with an fcSEMS deployed across the liver hilum in conjunction with a contralateral plastic stent placement is feasible without ensuing cholangitis caused by bile duct occlusion. PMID- 21821253 TI - Endoscopic management of postesophagectomy hemorrhagic radiation gastritis with radiofrequency ablation and argon plasma coagulation. PMID- 21821254 TI - Revisiting the impact of job satisfaction and organizational commitment on nurse turnover intention: an individual differences analysis. AB - BACKGROUND: Nurse turnover is an important contributing factor to the worldwide nursing shortage. Many studies have examined the antecedents of nurse turnover to gain a better understanding of the problem and help hospitals reduce their turnover rates. However, an important shortcoming of this research stream is its exclusive focus on explaining turnover behavior of the "average nurse", thereby disregarding individual differences between nurses and groups of nurses. OBJECTIVES: To examine individual differences in the relationships between two crucial turnover antecedents - job satisfaction and organizational commitment - and nurse turnover intention. PARTICIPANTS: A sample of 287 nurses working for a variety of Belgian hospitals participated in the study. METHODS: A survey method was used to collect quantitative data, which were analyzed through standard multiple linear regression, mixture regression models and t-tests. RESULTS: In the total sample of hospital nurses, both job satisfaction and organizational commitment significantly predicted nurse turnover intention. However, subsequent individual differences analyses revealed the existence of two subgroups of nurses. In the satisfaction focused group, only job satisfaction was found to predict nurse turnover intention, whereas in the satisfaction and commitment focused group both job satisfaction and organizational commitment were related to turnover intention. Furthermore, nurses in the latter group displayed stronger turnover intention, were significantly younger and had less job tenure and organizational tenure than nurses in the satisfaction focused group. CONCLUSIONS: The debate on the antecedents of nurse turnover still continues, as the existing models fail to fully grasp nurse turnover. The present study identifies individual differences in nurse turnover antecedents among groups of nurses as a possible reason for the absence of one comprehensive turnover model that holds for the general nursing population. Further studies are needed in order to capture the total impact of the underlying individual differences in nurse turnover antecedents. PMID- 21821255 TI - Nano-structured polyaniline-ionic liquid composite film coated steel wire for headspace solid-phase microextraction of organochlorine pesticides in water. AB - A novel nano-structured polyaniline-ionic liquid (i.e. 1-butyl-3 methylimidazolium hexafluorophosphate, BMIPF(6)) composite (BPAN) film coated steel wire was prepared by electrochemical deposition. Scanning electron microscopy images showed that the obtained porous BPAN coating consisted of nanofibers, whose diameter ranged from 50 to 80 nm. Furthermore, the novel nano structured composite coating was very stable at relatively high temperatures (up to 350 degrees C) and it could be used for more 250 times without obvious decrease of the extraction efficiency. The novel BPAN coating was used for the headspace solid-phase microextraction (HS-SPME) of organochlorine pesticides (i.e. hexachlorocyolohexane, dichlorodiphenyldichloroethylene, dichlorodiphenyldichloroethane, dichlorodiphenyltrichloroethane), coupled with gas chromatography-electron capture detection (GC-ECD). The BPAN coating showed better analytical capability on the whole compared with common polyaniline (PANI) and polydimethylsiloxane (PDMS) coatings. The key parameters influencing extraction efficiency were investigated and optimized, including desorption time, stirring speed, extraction temperature, extraction time and ionic strength. The relative standard deviations (RSDs) for single fiber repeatability ranged from 2.3 to 8.7% (n=6) and the RSDs for fiber-to-fiber reproducibility (n=6) were 4.2 12.1%, respectively. The linear ranges exceeded three magnitudes with correlation coefficients above 0.99. The detection limits were 0.12-0.31 ng L(-1). The proposed method was successfully applied for the determination of organochlorine pesticides in lake water, waste water and sewage treatment plant effluent with good recoveries from 88.9 to 112.9%. PMID- 21821256 TI - Numerical modeling of the elution peak profiles of retained solutes in supercritical fluid chromatography. AB - In supercritical fluid chromatography (SFC), the significant expansion of the mobile phase along the column causes the formation of axial and radial gradients of temperature. Due to these gradients, the mobile phase density, its viscosity, its velocity, its diffusion coefficients, etc. are not constant throughout the column. This results in a nonuniform flow velocity distribution, itself causing a loss of column efficiency in certain cases, even at low flow rates, as they do in HPLC. At high flow rates, an important deformation of the elution profiles of the sample components may occur. The model previously used to account satisfactorily for the retention of an unsorbed solute in SFC is applied to the modeling of the elution peak profiles of retained compounds. The numerical solution of the combined heat and mass balance equations provides the temperature and the pressure profiles inside the column and values of the retention time and the band profiles of retained compounds that are in excellent agreement with independent experimental data for large value of mobile phase reduced density. At low reduced densities, the band profiles can strongly depend on the column axial distribution of porosity. PMID- 21821257 TI - Enhancement of beta-crystalline phase of poly(vinylidene fluoride) in the presence of hyperbranched copolymer wrapped multiwalled carbon nanotubes. AB - Many efforts have been performed on the poly(vinylidene fluoride), PVDF, due to its piezoelectric, pyroelectric and ferroelectric potentials. In this regard, how to fabricate the PVDF with high content of beta-phase, which is also the direct contribution to PVDF's prominent property, becomes a critical issue. In this study, starting with the alpha-phase dominated sample, the PVDF with extremely high content of beta-crystalline phase was obtained by the incorporation of multiwalled carbon nanotubes (MWCNTs) modified by hyperbranched copolymers (HBCs). We proved that, via XRD, DSC as well as the structural characterizations from the polarized optical microscopy and transmission electron microscopy (TEM), the success of this strategy was ascribed to the enhanced dispersibility and stability of MWCNTs endowed by the HBCs, which significantly favors the formation of the beta-crystalline phase of PVDF. PMID- 21821258 TI - Adsorption of fluoride from aqueous solution by graphene. AB - A batch adsorption system was applied to investigate the adsorption of fluoride from aqueous solution by graphene. The adsorption capacities and rates of fluoride onto graphene at different initial pH, contact time, and temperature were evaluated. The experimental results showed that graphene is an excellent fluoride adsorbent with an adsorption capacity of up to 17.65 mg/g at initial fluoride concentration of 25 mg/L and temperature of 298 K. The isotherm analysis indicated that the adsorption data can be well described by Langmuir isotherm model. Thermodynamic studies revealed that the adsorption reaction was a spontaneous and endothermic process. PMID- 21821259 TI - Preparation and cell response of bio-mineralized Fe3O4 nanoparticles. AB - Silk fibroin (SF)-coated Fe(3)O(4) nanoparticles (NPs) with good superparamagnetism were successfully prepared via a bio-mineralization process at room temperature. Two cell tests revealed that mineralized SF-coated Fe(3)O(4) NPs presented good cytocompatibility for L929 and osteoblast cells and higher cell density after 5 d with high concentrations of SF-coated Fe(3)O(4) NPs (up to 0.5 mg/mL). These resulted from SF surface coating on NPs, nano-surface morphology and iron ion release of Fe(3)O(4) NPs. The mineralized SF-coated Fe(3)O(4) NPs could be envisioned for various bone orthopedic and therapeutic applications, in which SF-coated NPs location is controlled through an external magnetic field to promoted bone growth. PMID- 21821260 TI - Wettability of polymeric solids by ternary mixtures composed of hydrocarbon and fluorocarbon nonionic surfactants. AB - Contact angle (theta) measurements on poly(tetrafluoroethylene) (PTFE) and polymethyl methacrylate (PMMA) surface were carried out for the systems containing ternary mixtures of surfactants composed of: p-(1,1,3,3 tetramethylbutyl)phenoxypoly(ethylene glycols), Triton X-100 (TX100), Triton X 165 (TX165) and Triton X-114 (TX114), and fluorocarbon surfactants, Zonyl FSN100 (FSN100) and Zonyl FSO100 (FSO100). The aqueous solutions of ternary surfactant mixtures were prepared by adding TX114, FSN100 or FSO100 to binary mixtures of TX100+TX165, where the synergistic effect in the reduction of the surface tension of water (gamma(LV)) was determined. From the obtained contact angle values, the relationships between costheta, the adhesion tension and surface tension of solutions, costheta and the reciprocal of the surface tension were determined. On the basis of these relationships, the correlation between the critical surface tension of PTFE and PMMA wetting and the surface tension of these polymers as well as the work of adhesion of aqueous solutions of ternary surfactant mixtures to PTFE and PMMA surface were discussed. The critical surface tension of PTFE and PMMA wetting, gamma(C), determined from the contact angle measurements of aqueous solutions of surfactants including FSN100 or FSO100 was also discussed in the light of the surface tension changes of PTFE and PMMA under the influence of film formation by fluorocarbon surfactants on the surface of these polymers. The gamma(C) values of the studied polymeric solids were found to be different for the mixtures composed of hydrocarbon surfactants in comparison with those of hydrocarbon and fluorocarbon surfactants. In the solutions containing fluorocarbon surfactants, the gamma(C) values were different taking into account the contact angle in the range of FSN100 and FSO100 concentration corresponding to their unsaturated monolayer at water-air interface or to that saturated. PMID- 21821261 TI - From the 2-dimensional unstable polyelectrolyte multilayer to the 3-dimensional stable dry polyelectrolyte capsules. AB - Polystyrene-poly(acrylic acid)/poly(allylamine hydrochloride) polyelectrolyte multilayer was found to be instable and apt to reconstruct in the pure water. By depositing polystyrene-poly(acrylic acid)/poly(allylamine hydrochloride) multilayer on the polystyrene-poly(acrylic acid) hybrid CaCO(3) templates, novel polyelectrolyte capsules could be prepared after the removal of the templates. The resultant capsules could keep their three-dimensional (3D) spherical shape after being dried at room temperature, dramatically different from the conventional polyelectrolyte capsules based on nonhybrid templates by layer-by layer procedure. The instable polyelectrolyte multilayer, hybrid templates, and assembly cycles were demonstrated to be three indispensable factors responsible for the formation of this type of 3D stable capsules. The formation mechanism was also discussed in this study. PMID- 21821262 TI - Novel water-soluble and pH-responsive anticancer drug nanocarriers: doxorubicin PAMAM dendrimer conjugates attached to superparamagnetic iron oxide nanoparticles (IONPs). AB - PH-responsive drug release system based on the conjugates of PAMAM dendrimers doxorubicin (PAMAM-DOX) and superparamagnetic iron oxide (Fe(3)O(4)) nanoparticles (IONPs) has been constructed and characterized. The IONPs were stabilized by mPEG-G2.5 PAMAM dendrimers. The anticancer drug DOX was conjugated to the dendrimer segments of amino-stabilized IONPs using hydrazine as the linker via hydrazone bonds, which is acid cleavable and can be used as an ideal pH responsive drug release system. The drug release profiles of DOX-PAMAM dendrimer conjugates were studied at pH 5.0 and 7.4. The results showed that the hydrolytic release profile can be obtained only at the condition of lysosomal pH (pH=5.0), and IONPs participated in carrying DOX to the tumor by the Enhanced Permeability and Retention (EPR) effect. These novel DOX-conjugated IONPs have the potential to enhance the effect of MRI contrast and cancer therapy in the course of delivering anticancer drugs to their target sites. Although the dendrimer-DOX coated IONPs do not have any targeting ligands attached on their surface, they are potentially useful for cancer diagnosis in vivo. PMID- 21821263 TI - Diffusion tensor imaging and cognitive speed in children with multiple sclerosis. AB - OBJECTIVES: To compare white matter (WM) integrity in children with MS and healthy children using diffusion tensor imaging (DTI), and correlate DTI findings with disease activity, lesion burden, and cognitive processing speed. METHODS: Fractional anisotropy (FA) and mean diffusivity (MD) in normal-appearing white matter (NAWM) were measured in four corpus callosum (CC), eight hemispheric regions, and the normal-appearing thalamus of 33 children and adolescents with MS and 30 age-matched healthy controls. Images were acquired on a GE LX 1.5T scanner. DTI parameters used were 25 directions, b = 1000 s/mm(2), and 5mm slice thickness. MS patients had T2 lesion volumes and Expanded Disability Status Scale (EDSS) scores were measured; all participants underwent two speeded cognitive tasks (Visual Matching and Symbol Digit Modalities Test (SDMT)). RESULTS: MS participants displayed lower FA values in the genu (p<0.005), splenium (p<0.001) and in NAWM of bilateral parietal, temporal, and occipital lobes (p<0.001) versus controls. FA and MD in the thalamus did not differ between groups. Higher lesion volumes correlated with reduced FA in CC and hemispheric NAWM. DTI metrics did not correlate with EDSS. FA values in CC regions correlated with Visual Matching (p<0.001) and SDMT (p<0.005) in MS participants only. INTERPRETATION: DTI analyses indicate widespread NAWM disruption in children with MS-with the degree of abnormality correlating with impaired cognitive processing speed. These findings support an early onset tissue pathology in MS and illustrate its functional consequence. PMID- 21821264 TI - Pulse pressure is associated with walking impairment in multiple sclerosis. AB - Persons with multiple sclerosis (MS) have reduced gait performance and this is associated with disability and disease progression. The current study sought to test the hypothesis that higher central (aortic and carotid) and peripheral (brachial) pulse pressure (PP), manifestations of ventricular-vascular uncoupling related to increased arterial stiffness and pressure from wave reflections, would be associated with reduced gait performance in persons with MS. Participants consisted of 33 individuals with MS and 33 age/sex matched controls. Central blood pressure (BP) was assessed via applanation tonometry. Brachial BP was measured using an automated oscillometric cuff. PP was defined as systolic BP- diastolic BP. Gait performance was measured as 6-minute walk (6 MW) distance. Within the sample with MS, the 6 MW distance was significantly associated with brachial (r = -.49, p<.005), aortic (r = -.52, p<.001), and carotid (r = -.57, p<.001) pulse pressure. There was no association between any PP measure and 6 MW distance in controls (p>0.05 for all). In conclusion, PP is a predictor of gait performance in persons with MS. These findings suggest that vascular senescence and altered ventricular-vascular coupling may contribute, in part, to the deterioration of physical function in persons with MS. PMID- 21821265 TI - Baseline and longitudinal patterns of hippocampal connectivity in mild cognitive impairment: evidence from resting state fMRI. AB - The hippocampus is believed to have close relationship with many cerebral cortexes and constitute memory network to modulate and facilitate communication, which makes it especially interesting and meaningful in the study of functional connectivity in mild cognitive impairment (MCI). However, functional connectivity between the hippocampus and other brain regions remains unclear in MCI. Furthermore, the longitudinal changes of the hippocampal connectivity have not been reported. In the study, resting state functional MRI (fMRI) was used to examine changes in hippocampal connectivity comparing 14 patients and 14 healthy age-matched controls. We found that functional connectivity between the hippocampus and a set of regions was disrupted in MCI, these regions are: the right frontal lobe, the bilateral temporal lobe and the right insular. While, the left posterior cingulate cortex, precuneus, hippocampus, caudate and right occipital gyrus showed increased connectivity to the hippocampus in MCI. Additionally, we traced the seven MCI patients and compared the hippocampal connectivity in initial stage and 3 years later stage. Several regions presented decreased connectivity to the hippocampus after 3 years. Finally, the hippocampal connectivity with some regions showed significant correlation with the cognitive performance of patients. Based on these findings, the decreased hippocampal connectivity might indicate reduced integrity of hippocampal cortical memory network in MCI. In addition, the increased hippocampal connectivity suggested compensation for the loss of memory function. With the development of the disease, the hippocampal connectivity may lose some compensation and add some more disruption due to the pathological changes. PMID- 21821266 TI - Fifteen-year experience with minimally invasive approach for reoperations involving the mitral valve. AB - OBJECTIVE: Reoperative sternotomy to address mitral valve pathology carries substantial risk, especially with patent bypass grafts or an aortic valve prosthesis. We previously reported our early experience with minimally invasive right thoracotomy and peripheral cannulation as an alternative strategy, and we recently reviewed our cumulative 15-year hospital outcomes with this approach. METHODS: Between June 1996 and April 2010, we performed right minithoracotomy for reoperations involving the mitral valve on 167 patients, 85 (51%) of these since 2006. Seventy-one percent had undergone previous coronary artery bypass grafting and 38% a previous valve procedure. Fibrillatory arrest was used in 77% and aortic clamping and root cardioplegia in 23%. Nineteen procedures were performed with robotic assistance. RESULTS: Mitral repair frequency increased during each 5 year interval of our experience (1996-2000, 43%; 2001-2005, 53%; 2006-2010, 72%; P = .019), including 80% of native mitral valves without stenosis. Concomitant procedure frequency, most commonly atrial fibrillation ablation, also increased during each 5-year interval (0%, 21%, 48%; P < .0001). Thirty-day mortality was 3.0% (5/167), 0% since 2005. There were no conversions to sternotomy or aortic dissections. Stroke, in 2.4% (4/167), was statistically unrelated to fibrillatory arrest. Increased New York Heart Association functional class (odds ratio, 5.6; 95% confidence interval 1.1-27.8; P = .037) was the only independent predictor of mortality in multivariable analysis. CONCLUSIONS: Our updated experience confirmed the effectiveness of minimally invasive right thoracotomy to treat mitral pathology while avoiding reoperative sternotomy risk. We found fibrillatory and cardioplegic arrest methods to be safe myocardial preservation strategies with this approach. PMID- 21821268 TI - Relative risk assessment of cruise ships biosolids disposal alternatives. AB - A relative risk assessment of biosolids disposal alternatives for cruise ships is presented in this paper. The area of study encompasses islands and marine waters of the Caribbean Sea. The objective was to evaluate relative human health and ecological risks of (a) dewatering/incineration, (b) landing the solids for disposal, considering that in some countries land-disposed solids might be discharged in the near-shore environment untreated, and (c) deep ocean disposal. Input to the Bayesian assessment consisted of professional judgment based on available literature and modeling information, data on constituent concentrations in cruise ship biosolids, and simulations of constituent concentrations in Caribbean waters assuming ocean disposal. Results indicate that human health and ecological risks associated with land disposal and shallow ocean disposal are higher than those of the deep ocean disposal and incineration. For incineration, predicted ecological impacts were lower relative to deep ocean disposal before considering potential impacts of carbon emissions. PMID- 21821267 TI - Decrease in inflammatory response does not prevent placental dysfunction after fetal cardiac bypass in goats. AB - OBJECTIVE: One of the most significant responses to fetal cardiac bypass is severe placental dysfunction characterized by increased vascular resistance. We tested the hypothesis that fetal cardiac bypass triggers the activation of nuclear factor kappa-B (NF-KB), a major regulator of inflammatory response, and that pharmacologic inhibition of NF-KB activation by pyrrolidine dithiocarbamate alleviates fetal cardiac bypass-induced placental dysfunction. METHODS: Fifteen pregnant goats at 120 to 140 days' gestation were equally divided into the control group with a sham procedure of fetal sternotomy and cannulation (CG), the fetal bypass group (FB), and the fetal bypass group with 300 mg pyrrolidine dithiocarbamate before sternotomy (FP). Fetal cardiac bypass was performed for 30 minutes. Umbilical arterial flow rate was measured by ultrasonic flowmeter and placental vascular resistance was calculated. Fetal plasma levels of nitric oxide (NO), endothlin-1 (ET-1), 6-keto-prostaglandin F1alpha (6-K), thromboxane B(2) (TXB2), interleukin 6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) were assayed. IL-6 and TNF-alpha mRNA were analyzed by real-time polymerase chain reaction. NF-KB activation was evaluated by electrophoretic mobility shift assay. RESULTS: Placental vascular resistance significantly increased in the FB and FP groups compared with the CG group. Increases in plasma levels of NO were observed in all 3 groups. Plasma levels of ET-1 rose significantly in the FB and FP groups without noticeable difference between them. Plasma levels of 6-K, TXB(2), IL-6, and TNF-alpha increased significantly in the FB group compared with the CG and FP groups. The transcription levels of IL-6 and TNF-alpha mRNA in the placental tissues of the FB group were significantly higher than in the FP and CG groups. The amount of activated NF-KB in the placental tissues of the FB group was also significantly higher than that in the FP and CG groups. CONCLUSIONS: Fetal cardiac bypass-induced inflammatory response possibly mediated by NF-KB caused placental dysfunction. Pharmacologic inhibition of NF-KB activation and decrease in the inflammatory response did not alleviate the placental dysfunction. PMID- 21821269 TI - Intraoperative contrast echocardiography to verify the surgical occlusion of a single extrahepatic portosystemic shunt in a dog. AB - This report details a bubble echocardiographic study carried out during the surgical treatment of a congenital single extrahepatic portosystemic shunt (PSS) in a Labrador Retriever. After celiotomy, agitated saline was injected through a jejunal vein and microbubbles appeared rapidly in the right cardiac chambers. The test confirmed the presence of a PSS, helping the surgeon to identify the vessel concerned and to rule out a second shunt. Successively, portography confirmed what the exploratory celiotomy had revealed before with the aid of the bubble study: a single shunt was located between the portal vein and the right renal vein. It was completely ligated, as all the criteria for this solution were met. Intraoperative contrast echocardiography (ICE) was easy to perform, helpful and undemanding. It is proposed here as an intraoperative ancillary test to diagnose all PSS and to confirm successful treatment when complete shunt closure is possible. PMID- 21821270 TI - Reverberation-ray matrix analysis for wave propagation in multiferroic plates with imperfect interfacial bonding. AB - The dispersion behavior of waves in multiferroic plates with imperfect interfacial bonding has been investigated via the method of reverberation-ray matrix, which is directly established from the three-dimensional equations of magneto-electro-elasticity in the form of state space formalism. A generalized spring-layer model is employed to characterize the interfacial imperfection. By introducing a dual system of local coordinates for each single layer, the numerical instability usually encountered in the state space method can be avoided. Based on the proposed method, a typical sandwich plate made of piezoelectric and piezomagnetic phases is considered in numerical examples to calculate the dispersion curves and mode shapes. It is demonstrated that the results obtained by the present method is unconditionally stable as compared to the traditional state space method. The influence of different interfacial bonding conditions on the dispersion characteristics and corresponding mode shapes is investigated. PMID- 21821271 TI - Evaluating sludge minimization caused by predation and viral infection based on the extended activated sludge model No. 2d. AB - The Activated Sludge Model No. 2d (ASM2d) was extended to incorporate the processes of both predation and viral infection. The extended model was used to evaluate the contributions of predation and viral infection to sludge minimization in a sequencing batch reactor (SBR) system enriching polyphosphate accumulating organisms (PAOs). Three individual decay processes formulated according to the general model rules were used in the extended model. The model was firstly calibrated and validated by different experimental results. It was used to evaluate the potential extent of predation and viral infection on sludge minimization. Simulations indicate that predation contributes roughly two times more to sludge minimization than viral infection in the SBR system enriching PAOs. The sensitivity analyses of the selected key parameters reveal that there are thresholds on both predation and viral infection rates, if they are too large a minimal sludge retention time is obtained and the effluent quality is deteriorating. Due to the thresholds, the contributions of predation and viral infection to sludge minimization are limited to a maximal extent of about 21% and 9%, respectively. However, it should be noted that the parameters concerning predation and viral infection were not calibrated separately by independent experiment in our study due to the lack of an effective method, especially for the parameters regarding viral infection. Therefore, it is essential to better evaluate these parameters in the future. PMID- 21821272 TI - Partitioning of metals in a degraded acid sulfate soil landscape: influence of tidal re-inundation. AB - The oxidation and acidification of sulfidic soil materials results in the re partitioning of metals, generally to more mobile forms. In this study, we examine the partitioning of Fe, Cr, Cu, Mn, Ni and Zn in the acidified surface soil (0 0.1 m) and the unoxidised sub-soil materials (1.3-1.5 m) of an acid sulfate soil landscape. Metal partitioning at this acidic site was then compared to an adjacent site that was previously acidified, but has since been remediated by tidal re-inundation. Differences in metal partitioning were determined using an optimised six-step sequential extraction procedure which targets the "labile", "acid-soluble", "organic", "crystalline oxide", "pyritic" and "residual" fractions. The surficial soil materials of the acidic site had experienced considerable losses of Cr, Cu, Mn and Ni compared to the underlying parent material due to oxidation and acidification, yet only minor losses of Fe and Zn. In general, the metals most depleted from the acidified surface soil materials exhibited the greatest sequestration in the surface soil materials of the tidally remediated site. An exception to this was iron, which accumulated to highly elevated concentrations in the surficial soil materials of the tidally remediated site. The "acid-soluble", "organic" and "pyritic" fractions displayed the greatest increase in metals following tidal remediation. This study demonstrates that prolonged tidal re-inundation of severely acidified acid sulfate soil landscapes leads to the immobilisation of trace metals through the surficial accumulation of iron oxides, organic material and pyrite. PMID- 21821273 TI - Trichloroethylene decomposition and in-situ dry sorption of Cl-products by calcium oxides prepared from hydrated limes. AB - A comparison of CaOs produced by calcining two types of hydrated lime and calcium carbonate was made for decomposition of trichloroethylene and in-situ dry sorption of the decomposed Cl-products using a lab-scale gas flow type tubular packed bed reactor. About 20 mg of CaO sample was mixed with about 2 g of Al2O3 particles and packed in the reactor and allowed to react with a flowing standard gas containing 500 ppm of C2HCl3 (N2 balance) at 673 and 873 K, under the condition that the reaction of CaO with C2HCl3 might be completed within a few hours. It was found that no thermal decomposition of C2HCl3 at or below 673 K was observed in a reactor packed only with Al2O3 particles. However, a considerable amount of decomposition of C2HCl3 was obtained in a reactor packed with CaO and Al2O3, even at 673 K. For 1 mol of CaO prepared by calcining highly reactive Ca(OH)2 at 673 K, decomposition of 0.42 mol of C2HCl3 and in-situ absorption product of 0.53 mol of CaCl2 were obtained. At 873 K, about 46% of C2HCl3 was thermally decomposed. The total amount of C2HCl3 decomposed in CaO-Al2O3 particle bed at 873 K became nearly twice larger than that at 673 K. For 1 mol of CaO prepared by calcining highly reactive Ca(OH)2 at 873 K, decomposition of 0.59 mol of C2HCl3 and in-situ absorption product of 0.67 mol of CaCl2 were obtained. Small amounts of C2Cl2, C2Cl4, CCl4, etc. were detected during decomposition of C2HCl3 at 673 and 873 K. It was recognized that the data on decomposition of C2HCl3 as well as in-situ dry sorption of Cl-products in CaO particle bed were correlated with specific surface area of the CaO employed. PMID- 21821274 TI - Preparation of glass-ceramics from molten steel slag using liquid-liquid mixing method. AB - A novel approach to prepare glass-ceramics from molten steel slag (MSS) was proposed. In laboratory, the water-quenched steel slag was melted at 1350 degrees C to simulate the MSS. A mixture of additive powders in wt.% (55 quartz powder, 5 Na2O, 16 emery powder, 15 CaO, 8 MgO, 1 TiO2) were melted into liquid at 1350 degrees C separately. Then the MSS and the molten additives were mixed homogeneously in order to obtain parent glass melt. The proportion of MSS in the melt was 50 wt.%. The melt was subsequently cast, annealed, heat-treated and transformed into glass-ceramics. Their microstructure and crystallization behavior were analyzed. The samples exhibited excellent properties and displayed bulk crystallization. The major crystallized phase was diopside ((Fe0.35Al0.20Mg0.44)Ca0.96(Fe0.08Si0.70Al0.20)2O6.12), which was uniformly distributed in the microstructure. The novel approach may help iron and steel industry achieve zero disposal of steel slag with utilization of the heat energy of the MSS. PMID- 21821275 TI - Determining C/N ratios for typical organic wastes using biodegradable fractions. AB - It is well established that an optimal aerobic and anaerobic microbial metabolism is achieved with a C/N ratio between 20 and 30. Most studies are currently based on chemically-measured carbon and nitrogen contents. However, some organic wastes can be composed of recalcitrant carbon fractions that are not bioavailable. To know the biodegradable C/N ratio, two different methods to determine the aerobic and anaerobic biodegradable organic carbon (BOCAE and BOCAN) are proposed and used to analyze a wide variety of different organic samples. In general, raw wastes and digested products have more amount of BOCAE. On the contrast, the samples collected after an aerobic treatment have higher content of BOCAN. In any case, all the BOC fractions are lower than the total organic carbon (TOC). Therefore, the C/N ratios based on BOC are always lower than the total C/N ratio based on the TOC measure. The knowledge of the real bioavailable C/N ratio is crucial for the biological treatments of organic materials. To reduce the test time necessary for BOC determination, the values of BOC for all the samples obtained at different times were compared and correlated with the final BOC. A method that allows for the determination of BOCAE in 4 d is proposed. In relation to the anaerobic assay, the biogas potential calculated after 21 and 50 d was positively correlated with the final potential defined after 100 d of assay. PMID- 21821276 TI - Aquaculture effects on environmental and public welfare - the case of Mediterranean mariculture. AB - Aquatic farming has been considered, during the last decades, as the fastest growing food production industry powered by governmental and technological impulsion. Compensation for fisheries decline, creation of new jobs and source of financial windfall are the most important benefits. However, similar to most of the human food-production activities, aquaculture raised several issues related to the environmental welfare and consumer safety. An effort to record the aquaculture-environment and -human safety interactions with regard to the Mediterranean mariculture, is attempted herein. We focused on this geographical area due to its individualities in both the hydrological and physicochemical characteristics and the forms of aquaculture activities. The cage farming of euryhaline marine fish species and more recently of bluefin tuna and mollusk farming are the dominating aquaculture activities. The impacts of these activities to the environment, through wastes offloads, introduction of alien species, genetic interactions, disease transfer, release of chemicals, use of wild recourses, alterations of coastal habitats and disturbance of wildlife, are analytically considered. Also the consumer safety issues related to the farming are assessed, including generation of antibiotic-resistant microorganisms, contaminants transferred to humans though food chain and other hazards from consumption of aquacultured items. Within these, the major literature findings are critically examined and suggestions for scientific areas that need further development are made. The major tasks for future aquaculture development in this region are: (i) to ensure sustainability and (ii) to balance the risks to public or environmental health with the substantial economical benefits. In regard with monitoring, tools must be created or adapted to predict the environmental costs and estimate consumer impact. At a canonistic and legal basis, the establishment of appropriate legal guidelines and common policies from all countries involved should be mandatory. PMID- 21821277 TI - Graft reconstruction of inferior vena cava for renal cell carcinoma stage pT3b or greater. AB - OBJECTIVES: To review the methods and outcomes for simultaneous radical nephrectomy and inferior vena cava (IVC) graft reconstruction at our institution. Renal cell carcinoma has the potential to propagate and invade the IVC, requiring resection and/or reconstruction of the IVC concurrently with radical nephrectomy. METHODS: A prospective database of patients undergoing simultaneous radical nephrectomy with IVC reconstruction for renal cell carcinoma was queried. The data were collected and analyzed for patients who had undergone IVC graft reconstruction. RESULTS: A total of 17 patients were identified from 1999 to 2010, with a median age of 61 years (range 36-77). The tumor was right sided in 14 patients. The median tumor size was 12 cm (range 7.5-23), 15 tumors had clear cell histologic findings, and 16 were high grade. Seven patients had clinical metastasis found on imaging preoperatively, with another 4 having lymph node metastasis on pathologic examination. Of the 17 patients, 11 underwent patch grafting (3 expanded polytetrafluoroethylene and 8 bovine pericardium) and 6 underwent IVC interposition (3 Dacron and 3 expanded polytetrafluoroethylene). Also, 5 and 3 patients underwent cardiopulmonary and venovenous bypass, respectively. The mean estimated blood loss was 4 L, and the mean hospitalization was 7 days (range 5-16). Six patients experienced perioperative complications, with 1 perioperative mortality. Two patients overall developed graft thrombosis. Of the 6 patients initially without metastasis, the recurrence-free and overall survival rate was 50% and 83%, respectively, at a mean of 55 months. Of the 11 patients initially with metastasis, the recurrence-free and overall survival rate was 18% and 45%, respectively, at a mean of 13 months. CONCLUSIONS: For selected patients with advanced renal cell carcinoma and extensive IVC thrombus, resection with patch or interposition grafting of the IVC yields acceptable patency rates, minimal complications related to the graft, and reasonable oncologic results in a high-risk patient population. PMID- 21821278 TI - Evaluating the significance of location of lymph node metastasis and extranodal disease in women with stage IIIC endometrial cancer. AB - OBJECTIVE: To determine the prognostic significance of location of lymph node metastasis and extranodal disease for women with stage IIIC endometrial cancer. METHODS: Data were extracted from the Surveillance, Epidemiology, and End Results database between 1988 and 2005. Statistical analysis used Chi-square test, Kaplan Meier method, and Cox proportional hazards model. RESULTS: A total of 2559 women were identified; 1453 stage IIIC1, and with 906 stage IIIC2 tumors. Compared to stage IIIC1; more stage IIIC2 patients demonstrated high-risk factors such as grade III disease (p<0.001), unfavorable histologic types (p=0.01), concurrent disease at other extrauterine sites (p<0.001), and greater than two positive lymph nodes (p<0.001). While the 5-year disease specific survival was comparable (p>0.05) among node positive patients found to have positive peritoneal cytology (44.0%), adnexal/serosal metastasis (42.9%), and vaginal/parametrial involvement (41.8%); it differed individually in all three categories from those with nodal metastasis alone (67.0%, p<0.001). Among women with extranodal disease, the location of nodal metastasis had no effect on survival (HR=0.92; 95% CI, 0.74 1.14). For women with node only stage IIIC tumors, those patients with positive para-aortic nodes were more likely to die from their tumors (HR=1.40; 95% CI, 1.12-1.75). CONCLUSION(S): Location of lymph node metastasis is prognostic in patients with nodal disease alone, and not in those with extranodal disease. Extranodal disease is associated with a poor prognosis and should be regarded in conjunction with location of lymph node metastasis for risk-stratification in stage IIIC endometrial cancer. PMID- 21821279 TI - Assessment of lysosomal membrane stability and peroxisome proliferation in the head kidney of Atlantic cod (Gadus morhua) following long-term exposure to produced water components. AB - There is a need for sensitive biological effect methods by which to detect impacts of chronic exposure to low concentrations of contaminants. Two methods shown to be potentially useful for monitoring purposes in fish include lysosomal membrane stability and peroxisome proliferation. These biological endpoints were assessed in Atlantic cod (Gadus morhua) head kidney following exposure to a mixture of produced water components including polycyclic aromatic hydrocarbons, phenol, and alkylphenols. Lysosomal damage of head kidney cells occurred within the first two weeks and did not recover during the entire exposure period (32 weeks). Lysosomal membrane stability was not affected by gender and was responsive at low concentrations of contamination, indicating that lysosomal membrane stability measured in the head kidney could be a useful biomarker for effects of offshore pollution. Peroxisome proliferation, measured as acyl-CoA oxidase activity in the head kidney, appeared to be a potential biomarker in male cod exposed less than 16 weeks. PMID- 21821280 TI - Scaffold vascularization in vivo driven by primary human osteoblasts in concert with host inflammatory cells. AB - Successful cell-based tissue engineering requires a rapid and thorough vascularization in order to ensure long-term implant survival and tissue integration. The vascularization of a scaffold is a complex process, and is modulated by the presence of transplanted cells, exogenous and endogenous signaling proteins, and the host tissue reaction, among other influencing factors. This paper presents evidence for the significance of pre-seeded osteoblasts for the in vivo vascularization of a biodegradable scaffold. Human osteoblasts, cultured on silk fibroin micronets in vitro, migrated throughout the interconnected pores of the scaffold and produced extensive bone matrix. When these constructs were implanted in SCID mice, a rapid and thorough vascularization of the scaffold by the host blood capillaries occurred. This profound response was not seen for the silk fibroin scaffold alone. Moreover, when the pre-cultivation time of human osteoblasts was reduced from 14 days to only 24 h, the significant effect these cells exerted on vascularization rate in vivo was still detectable. From these studies, we conclude that matrix and soluble factors produced by osteoblasts can serve to instruct host endothelial cells to migrate, proliferate, and initiate the process of scaffold vascularization. This finding represents a potential paradigm shift for the field of tissue engineering, especially in bone, as traditional strategies to enhance scaffold vascularization have focused on endovascular cells and regarded osteoblasts primarily as cell targets for mineralization. In addition, the migration of host macrophages and multinucleated giant cells into the scaffold was also found to influence the vascularization of the biomaterial. Therefore, the robust effect on scaffold vascularization seen by pre-culturing with osteoblasts appears to occur in concert with the pro-angiogenic stimuli arising from host immune cells. PMID- 21821281 TI - Photo-cured hyaluronic acid-based hydrogels containing simvastatin as a bone tissue regeneration scaffold. AB - We describe in this study the positive influences on in vitro and in vivo osteogenesis of photo-cured hyaluronic acid (HA) hydrogels loaded with simvastatin (SIM). Prior to loading SIM, we first characterized the HA hydrogels for their mechanical properties and swelling ratios. The results from this testing indicated that these two factors improved as the substitution degree of 2 aminoethyl methacrylate (AEMA) increased. MTT and live/dead assays showed that the HA hydrogels have good biocompatibility for use as scaffolds for bone tissue regeneration. Moreover, another MTT assay showed that the photo-cured HA hydrogels III fabricated with 30% AEMA (300 mg) conjugated HA (HA-AEMA iii) loaded with between 0.1 and 1 mg of SIM had a similar cytotoxicity as compared to the HA hydrogel III itself. The sustained release of SIM was observed to occur in the HA hydrogel III loaded with 1 mg of SIM. In vitro and in vivo experiments showed that the HA hydrogel III loaded with 1 mg of SIM had a significant influence on osteogenesis. PMID- 21821282 TI - Regeneration of uterine horns in rats by collagen scaffolds loaded with collagen binding human basic fibroblast growth factor. AB - Severe damages of uterine endometrium which prevent embryos from implantation and placentation finally often result in infertility or pregnant complications. There is lack of effective treatments due to the limitation of native materials available and complexity of the function and internal environment of uterus. In the present study, a collagen targeting basic fibroblast growth factor (bFGF) delivery system was constructed by a collagen membrane loaded with bFGF fused a collagen-binding domain (CBD) to the N-terminal which limits the diffusion of bFGF from collagen. We tested the bFGF delivery system in rats under the severe uterine damage model (partial rat uterine horn excision/reconstruction), and found this delivery system improved regeneration abilities of uterine endometrium and muscular cells, improved vascularization, as well as better pregnancy outcomes in rats. Therefore, this targeting delivery system may be an effective strategy for uterine tissue regeneration. PMID- 21821283 TI - Multiobjective design optimisation of coronary stents. AB - We present here a multi-objective and multi-disciplinary coronary stent design optimization paradigm. Coronary stents are tubular, often mesh-like, structures which are deployed in diseased (stenosed) artery segments to provide a scaffolding feature that compresses atheromatus plaque, hence restoring luminal area and maintaining vessel patency. A three variable geometry parameterisation of a CYPHER (Cordis Corporation, Johnson & Johnson co.) type stent is proposed to explore the functionality of a sequence of circumferential rings connected by 'n' shaped links. The performance of each design is measured by six figures of merit (objectives/metrics) representing (i) acute recoil, (ii) tissue stresses, (iii) haemodynamic disturbance, (iv) drug delivery, (v) uniformity of drug distribution, and (vi) flexibility. These metrics are obtained from computational simulations of (i) structural deformation through balloon inflated expansion of a stent into contact with a stenosed vessel, (ii) pulsatile flow over the deformed stent embedded in the vessel wall, (iii) steady-state drug distribution into the tissue, and (iv) flexibility of a stent in response to an applied moment. Design improvement is obtained by a multi-objective surrogate modelling approach using a non-dominated sorting genetic algorithm (NSGA-II) to search for an optimal family of designs. A number of trade-offs between the different objectives are identified. In particular a conflict between pairs of the following objectives are shown -- (a) volume average stress vs. recoil, (b) volume average drug vs. volume average stress, (c) flexibility vs. volume average stress, (d) flexibility vs. haemodynamic disturbance, (e) volume average drug vs. haemodynamic disturbance, and (f) uniformity of drug vs. volume average stress. Different paradigms to choose the optimal designs from the obtained Pareto fronts are presented and under each such paradigm, the optimal designs and there relative positions with respect to a representative CYPHER stent are shown. The methodology and the results of this work could potentially be useful in further optimisation studies and development of a family of stents with increased resistance to in-stent restenosis and thrombosis. PMID- 21821285 TI - Passage of 4-nonylphenol across the human placenta. AB - 4-nonylphenol (4-NP) is an estrogenic endocrine active chemical that is present in detergents and is known to contaminate food and drinking water. The aim of the present study was to evaluate whether 4-NP crosses the human placenta and if so, to what extent. Human placentae obtained from healthy term singleton pregnancies were utilized in a dual ex-vivo re-circulating model of placental perfusion. Six placentae were perfused for 180 min following addition of 4-NP (30 ng/mL) to the maternal perfusate. Antipyrine and FITC dextran were used as positive and negative controls respectively to validate the integrity of the circuits. 4-NP was measured by High Performance Liquid Chromatography coupled with Fluorescence Detection (HPLC-FD). After 180 min of perfusion the transfer percentages for antipyrine and 4-NP were 25.6 +/- 1.4% (mean +/- s.e.m, n = 6) and 22.75 +/- 3.76% respectively and the transfer index for 4-NP was 0.8. We conclude that the intact form of 4-NP at environmentally relevant concentrations can transfer across the human placenta albeit at a slow rate. PMID- 21821284 TI - A synthetic substrate to support early mesodermal differentiation of human embryonic stem cells. AB - Our ability to guide differentiation of human pluripotent stem cells (hPSCs) toward desired lineages efficiently and reproducibly in xeno-free conditions is the key to advancing hPSC technology from the laboratory to clinical use. Here we report an engineered biomimetic substrate functionalized with both peptide ligands for alpha5beta1 and alpha6beta1 integrins to support efficient early mesodermal differentiation of human embryonic stem cells (hESCs) when cultured in a differentiation medium containing BMP4. In contrast, mesodermal differentiation is not induced on substrates functionalized with either ligand alone even though the culture medium is identical. Mesodermal differentiation was characterized by immunofluorescent staining, flow cytometric analysis, and RT-PCR analysis of early mesodermal markers Brachyury, Mixl1, and Wnt3. The early mesodermal progenitors derived on the substrate functionalized with both integrin ligands have the normal developmental potential to further differentiate along the hemato endothelial and cardiac lineages. Immobilized ligands for alpha5beta1 and alpha6beta1 integrins both are permissive, necessary, and sufficient insoluble ligands in this engineered system to support early mesodermal differentiation of hESCs. This synthetic substrate, in conjunction with defined soluble factors, constructs a well-controlled and xeno-free early mesodermal differentiation niche that offers advantages over the previously reported niche constructed with the Matrigel-coated substrate. PMID- 21821286 TI - The arcuate NPY, POMC, and CART expressions responding to food deprivation are exaggerated in young female rats that experienced neonatal maternal separation. AB - This study was conducted to examine the effect of neonatal maternal separation on the hypothalamic feeding peptides expression in young female offspring. Sprague Dawley pups were separated from dam for 3h daily during PND 1-14 (MS), or left undisturbed except routine cage cleaning (NH). Weanling female pups were housed in group and the arcuate mRNA levels of neuropeptide Y (NPY), proopiomelanocortin (POMC), and cocaine-amphetamine regulated transcript (CART) were examined at two months of age with or without food deprivation. The basal arcuate expression levels of these peptides did not differ between NH and MS group. However, a 48 h of food deprivation significantly increased NPY mRNA level, and decreased POMC and CART, in the arcuate nucleus of MS females, but not in NH females. Fasting induced elevation of the plasma corticosterone tended to be greater in MS group than in NH, but the basal levels did not differ between the groups. Plasma leptin levels were decreased in MS females compared with NH, and food deprivation significantly suppressed the leptin levels both in NH and MS groups. Results suggest that MS experience may increase stress vulnerability in female rats and exaggerate the feeding peptides expression in the arcuate nucleus responding to metabolic stress food deprivation. PMID- 21821287 TI - A novel gene LRP5 on 11q13.2 is rearranged in two patients with acute myeloid leukemia. PMID- 21821288 TI - Effect of acid blue 80, an anthracenedione dye, on rainbow trout liver, gill and gut cells in vitro. AB - Acid Blue 80 (AB80) is a dark blue colorant that like other synthetic dyes can get into the environment. Cultures of rainbow trout cell lines were dosed with AB80 either directly, which involved mixing AB80 stock solution into the medium over cells, or indirectly, which involved replacing the medium in cultures with medium that had AB80. A dose-dependent decline in cell viability was found in cultures with or without fetal bovine serum (FBS) after direct dosing. However, for FBS cultures, indirect dosing caused no loss of viability over 24h and in the long term was detrimental to RTgill-W1 but not RTL-W1 cultures. After 6 days at 50mg/L cytotoxicity was evident and by 9 days RTgill-W1 cell number had declined. Yet AB at 1mg/L elicited no changes over 9 days in any cell line. AB80 appears to have the potential to be toxic at only very high concentrations. PMID- 21821289 TI - Influence of divalent metal ions on E2-induced ER pathway in goldfish (Carassius auratus) hepatocytes. AB - Metal ions existing in the environment could influence the estrogen pathway in aquatic animal, but the detailed mechanism is still delusive. We here showed that in male Carassius auratus hepatocytes, copper (Cu) or cadmium (Cd), did not directly induce vitellogenin (VTG) expression. Interestingly, co-exposure with Cd2+ (or Cu2+) and 17-beta-estradiol (E2) greatly increased the VTG level, comparing with single treatment of E2. Meanwhile, Cd2+ or Cu2+ (but not E2) triggers HSP70 expression. But, mixture of Cd2+ or Cu2+ with E2 did not obviously raise HSP70 level. E2 also had no obvious effect on reactive oxygen species. Co treatment of Cd2+ and E2 showed no obvious increase compared to single treatment with Cd2+. We further assume that Cd2+-involved oxidative stress generates misfolded proteins, resulting in the competition of HSP70 proteins from a heterocomplex (with estrogen receptor). Thus, dissociation of the heterocomplex actives the receptor-ligand binding activity and promotes the E2-induced VTG expression. PMID- 21821290 TI - [Discoscanner: indications, technique, tips and tricks, interpretation]. AB - Discography test associated with the scanner (discoscanner) is an exam that has been a renewed interest in recent few years. Thanks to the emergence of new interventions such as disc prosthesis, the procedures require confirmation of the disc level to deal with and the origin of discogenic symptoms. The aim of this paper is to describe the techniques, challenges and tips as well as the interpretation of functional and morphological examination. PMID- 21821291 TI - Brain cancer associated with environmental lead exposure: evidence from implementation of a National Petrol-Lead Phase-Out Program (PLPOP) in Taiwan between 1979 and 2007. AB - BACKGROUND AND OBJECTIVE: In 1981, a Petrol-Lead Phase-Out Program (PLPOP) was launched in Taiwan for the abatement of environmental lead emissions. The present study was intended to examine whether the high Petrol-Lead Emission Areas (PLEA) would result in an increase in the incidence rate of brain cancer based on a national data bank. METHODS: The national brain cancer incidence data was obtained from the Taiwan National Cancer Registry. Age standardized incidence rates were calculated based on the 2000 WHO world standard population, and gasoline consumption data was obtained from the Bureau of Energy. The differences in the trend tests for age-standardized incidence rates of brain cancer between high, median, low, and small PLEA were analyzed. RESULTS: A significant increase was found from small to high PLEA in age-standardized incidence rates of brain cancer. By taking six possible confounders into account, the age-standardized incidence rates for brain cancer were highly correlated with the median and high PLEA by reference to the small PLEA. CONCLUSION: After being adjusted for a number of relevant confounders, it could be concluded that high PLEA might result in an increase in the incidence rate of brain cancer resulting from high lead exposures. PMID- 21821292 TI - Dietary intake of 17alpha-ethinylestradiol promotes leukocytes infiltration in the gonad of the hermaphrodite gilthead seabream. AB - A wide variety of chemicals discharged from industrial and municipal sources have been reported to disrupt the endocrine system of animals, which may be exposed via the food chain and contaminated water. 17alpha-Ethinylestradiol (EE(2)), a drug used in oral contraceptives and hormone replacement therapy, has a widespread presence in the aquatic environment. Current knowledge on the sensitivity of marine fish to estrogenic environmental chemicals is limited. We report here the effects of dietary intake of EE(2) on gilthead seabream, a marine hermaphrodite teleost, focusing on the immune events that take place in the gonad. When seabream males were fed with 5, 50, 125 and 200MUg EE(2)/g food for 7, 14, 21 and 28days an infiltration of acidophilic granulocytes and B lymphocytes occurred in the testis as the same time that spermatogenesis is disrupted. Moreover, the dietary intake of EE(2) promoted a dose-dependent up regulation of the expression of genes coding for cytokines, chemokines and adhesion molecules correlated with a leukocyte infiltration. PMID- 21821293 TI - Complement mediated apoptosis leads to the loss of retinal ganglion cells in animal model of glaucoma. AB - This study investigated the role of complement in the protection of retinal ganglion cells (RGCs) in chronic ocular hypertension model of glaucoma. Intraocular pressure (IOP) was elevated in the right eye of Lewis rats by laser photocoagulation (two treatments, 7days apart) of episcleral and limbal veins. Left eye did not receive laser treatment and served as control. Animals were injected with cobra venom factor every fifth day starting day 7 after first laser, to deplete the complement system. Animals were sacrificed at 6-week post laser. Levels of C3 split products and membrane attack complex (MAC) were elevated in the retina of eyes with increased IOP and complement depletion reduced the loss of Brn3a(+) RGCs accompanied by decreased expression of GFAP and reduced MAC deposition. In complement depleted rats with increased IOP, reduced TUNEL(+) cells in ganglion cell layer, and decreased levels of active caspase-8 and active caspase-9 was observed compared to PBS treated complement sufficient rats with increased IOP. Interestingly, complement depletion also resulted in reduction of calcium influx and levels of BAD in the retinal cells of the eyes with increased IOP. Together, our results provide evidence that complement mediated apoptosis plays a pivotal role in the loss of RGCs in chronic ocular hypertension model of glaucoma. PMID- 21821294 TI - Examining the relationship between lifetime stressful life events and the onset of major depression in Chinese women. AB - BACKGROUND: In European and US studies, patients with major depressive disorder (MDD) report more stressful life events (SLEs) than controls, but this relationship has rarely been studied in Chinese populations. METHODS: Sixteen lifetime SLEs were assessed at interview in two groups of Han Chinese women: 1970 clinically ascertained with recurrent MDD and 2597 matched controls. Diagnostic and other risk factor information was assessed at personal interview. Odds ratios (ORs) were calculated by logistic regression. RESULTS: 60% of controls and 72% of cases reported at least one lifetime SLE. Fourteen of the sixteen SLEs occurred significantly more frequently in those with MDD (median odds ratio of 1.6). The three SLEs most strongly associated with risk for MDD (OR>3.0) preceded the onset of MDD the majority of the time: rape (82%), physical abuse (100%) and serious neglect (99%). LIMITATIONS: Our results may apply to females only. SLEs were rated retrospectively and are subject to biases in recollection. We did not assess contextual information for each life event. CONCLUSIONS: More severe SLEs are more strongly associated with MDD. These results support the involvement of psychosocial adversity in the etiology of MDD in China. PMID- 21821295 TI - Subjective recognition of adverse events with antidepressant in people with depression: a prospective study. AB - BACKGROUND: While it has been reported that physicians may under-recognize adverse effects of antidepressants thoroughly in clinical settings, subjective bias in recognition of adverse effects (AEs) with antidepressants has not been specifically investigated. METHODS: Four-hundred ninety-three participants with depressive disorders (ICD-10) were assessed for the severity of 20 common AEs and their inferred causal relationship with antidepressants, together with the Quick Inventory for Depressive Symptoms (QIDS). These assessments occurred twice at the 1st visit (when they were antidepressant free) and 2nd visit (10 days after the initiation of antidepressants). 'Possible AEs' and 'under-recognized AEs' were defined as 'events with exacerbation in the severity' and 'events with negative causal attribution to antidepressants' at the time of the 2nd visit, respectively. RESULTS: Three-hundred sixty-three participants (73.6%) experienced >= 1 under-recognized AEs. Flu like symptoms (96.5% of participants who experienced possible AEs), sexual dysfunction (94.2%), blurred vision (93.4%), anxiety/tension (91.1%) and sweating (89.2%) were found to be prevalent as under recognized AEs. Participants with under-recognized AEs had less improvement in the QIDS than those without (27.1% vs. 11.1% decrease, p<0.001). LIMITATIONS: It is intrinsically challenging to exactly differentiate between antidepressant AEs and symptoms of depression. And the severity of depression, that of AEs and causal relationship between AEs and antidepressants were assessed not by objective but subjective scales. CONCLUSIONS: An overall trend to under-recognize AEs of antidepressants was found and people with a lesser degree of early improvement tend to understate the causality, which has an implication in interpreting voluntarily expression of AEs. PMID- 21821296 TI - Leisure activity, mobility limitation and stress as modifiable risk factors for depressive symptoms in the elderly: results of a national longitudinal study. AB - Few national longitudinal studies have investigated the modifiable risk factors for depression in the elderly. This study investigated the risk factors and health-related behaviors associated with depressive symptoms using a national survey of Taiwanese elderly with a 4-year follow-up period. In this prospective cohort study, 1481 non-demented population-based elderly were interviewed at baseline in 2003 and at follow-up in 2007. The independent variables included demographics, chronic medical diseases and health-related behaviors assessed at baseline. The dependent variable was depressive symptoms assessed at follow-up. Reduced rank regression was applied to characterize independent factors related to depressive symptoms. The prevalence of depressive symptoms at follow-up was 21.1%. The results of multivariate analyses revealed three independent risk factors for depressive symptoms: fewer leisure activities (odds ratio, OR=0.56, 95% confidence interval, CI=0.38-0.83, p=0.0034), more mobility limitations (OR=1.93, 95% CI=1.30-2.86, p=0.0011) and higher stress levels (OR=2.43, 95% CI=1.68-3.50, p<0.0001). The leisure activities least associated with depression were reading newspapers/books and doing outdoor building projects; the two mobility limitations most associated with depression were difficulty in lifting things and in climbing stairs. The two stresses most associated with depression were perceived health stress and financial stress. These results indicated that interventions to prevent or reduce depression in older adults should include practical strategies aimed at these modifiable risk factors. PMID- 21821297 TI - Erythropoietin resistance contributes to anaemia in chronic heart failure and relates to aberrant JAK-STAT signal transduction. AB - BACKGROUND: Chronic heart failure (CHF) patients are frequently anaemic despite elevated endogenous erythropoietin (Epo) levels. We tested the hypothesis that this might be due to Epo resistance and investigated whether any defects apparent were due to Epo receptor (EpoR) downregulation and/or impaired Epo-induced signal transduction. METHODS: We studied 28 CHF patients (age 64 +/- 10 yrs, LVEF 29 +/- 9%, 89% male) and 12 healthy controls (65 +/- 11 yrs, 75% male). Circulating erythroid progenitors (BFU-E) were cultured with 0, 1, 3 and 9 U/mL Epo. Circulating erythroblast surface EpoR and intracellular phosphorylated Signal Transducer and Activator of Transcription (phosphoSTAT)-5 expression were determined by flow cytometry. RESULTS: Whilst BFU-E from control and non-anaemic subjects required only 3 U/mL Epo to significantly increase their numbers from baseline (1 U/mL), those from anaemic patients required 9 U/mL Epo. Lower Epo sensitivities related to higher interleukin-6 (r=-0.41, P=0.01) and soluble tumour necrosis factor receptor 2 (r=-0.38, P=0.02) levels. EpoR-positive cells were more abundant in anaemic patients (P<0.001). Although erythroblasts from anaemic patients exhibited higher baseline EpoR and phosphoSTAT5 expression (all P<0.05), Epo stimulation triggered significant increases in phosphoSTAT5 levels only in erythroblasts from control subjects and not in those from anaemic patients. CONCLUSION: The responsiveness of erythroid cells to Epo is diminished in anaemic CHF patients. This is not due to EpoR downregulation but relates to a profound blunting of Epo-induced JAK-STAT signalling. Whilst residual Epo sensitivity can be exploited clinically with erythropoietic agents, targeting the mechanisms underlying Epo resistance in CHF may provide greater efficacy. PMID- 21821298 TI - Questionnaire-based survey on the clinical management of canine leishmaniosis in the Madrid region (central Spain). AB - This paper describes a questionnaire designed to gain information on how veterinarians clinically manage canine leishmaniosis (CanL) in the Madrid region (central Spain). The present survey is one of the several similar questionnaire based surveys conducted within the framework of the project EDEN (Emerging Diseases in a changing European eNvironment). The questionnaire sought to obtain data regarding the main clinical manifestations observed, the diagnostic methods used and the preventive measures recommended. Its Spanish version was sent by post to veterinary practitioners within the study area in two lots, one sent out in December 2006 and the other in March 2007. Only 174 of the 760 questionnaires sent were completed and returned (reply rate of 23%). Among the completed questionnaires, clinics differed widely in terms of features such as the habitats of the dogs (urban, peri-urban or rural) and patient volumes. Clinics attending dogs from peri-urban/rural habitats reported more suspected (p<0.001), confirmed (p=0.001) and newly diagnosed (p=0.001) cases/year than clinics providing service to a city clientele alone. According to the veterinary practitioners, skin lesions, lymphadenomegaly and weight loss were commonly observed, although these signs are not specific to CanL. Signs described to be of high diagnostic value were epistaxis and kidney disease. All the veterinarians polled reported that a suspicion of Leishmania infantum infection was confirmed by at least a serological method; the immunofluorescence antibody test (IFAT) being the technique most used. To prevent the disease, most vets recommended topical synthetic pyrethroids applied as impregnated collars or spot-ons. It is observed that despite considerable progress is being made in clinical management and controlling the disease, in Madrid Region its incidence continues to increase. PMID- 21821300 TI - Advancing radiation oncology through scientific publication--100 volumes of Radiotherapy and Oncology. PMID- 21821299 TI - Molecular aptamers for drug delivery. AB - The active targeting of drugs in a cell-, tissue- or disease-specific manner represents a potentially powerful technology with widespread applications in medicine, including the treatment of cancers. Aptamers have properties such as high affinity and specificity for targets, easy chemical synthesis and modification, and rapid tissue penetration. They have become attractive molecules in diagnostics and therapeutics rivaling and, in some cases, surpassing other molecular probes, such as antibodies. In this review, we highlight the recent progress in aptamer-mediated delivery for therapeutics and disease-targeting based on aptamer integration with a variety of nanomaterials, such as gold nanorods, DNA micelles, DNA hydrogels and carbon nanotubes. PMID- 21821301 TI - Acquisition of MV-scatter-free kilovoltage CBCT images during RapidArcTM or VMAT. AB - PURPOSE: To perform kilovoltage (kV) cone beam computed tomography (CBCT) imaging concomitant with the delivery of megavoltage (MV) RapidArc treatment, and demonstrate the feasibility of obtaining MV-scatter-free kV CBCT images. METHODS AND MATERIALS: RapidArc/CBCT treatment and imaging plans are designed, and delivered on the Varian TrueBeam, using its Developer Mode. The plan contains 250 control points for MV-radiation delivery, each over an arc of 0.4-0.7(o). Interlaced between successive MV delivery control points are imaging control points, each over an arc of 0.7-1.1(o). During the 360(o) gantry rotation for the RapidArc delivery, CBCT projections of a phantom are acquired at 11 frames per second. The kV projections with minimal MV-scatter are selected, based on gantry angle, and the CBCT(s) image reconstructed. For comparison, a reference CBCT(r) image is acquired in the normal way. In addition, to examine the effect of MV scatter we acquire CBCT(c) using the same treatment plan without the imaging control points, i.e. with continuous MV delivery during the 360(o) rotation. Quantitative evaluation of image qualities is performed based on the concepts of CNR (contrast-to-noise ratio) and NSTD (normalized standard deviation). RESULTS: The different types of CBCT images were reconstructed, evaluated, and compared. Visual comparison indicates that the image quality of CBCT(s) is similar to that of the reference CBCT(r), and that the quality of CBCT(c) is significantly degraded by the MV-scatter. Quantitative evaluation of the image quality indicates that MV-scatter significantly decreases the CNR of CBCT (from ~7 to ~3.5 in one comparison). Similarly, MV-scatter significantly increases the inhomogeneity of image intensity, e.g. from ~0.03 to ~0.06 in one comparison. CONCLUSION: We have developed a method to acquire MV-scatter-free kV CBCT images concomitant with the delivery of RapidArc treatment. Engineering development is necessary to improve the process, e.g. by synchronization of the MV and kV beams. PMID- 21821302 TI - Residual DNA double strand breaks in perfused but not in unperfused areas determine different radiosensitivity of tumours. AB - PURPOSE: Micromilieu-dependent quantification of gammaH2AX after irradiation in vivo and correlation with local tumour control. MATERIALS AND METHODS: Local tumour control was evaluated after irradiation of FaDu and SKX xenografts with ambient single doses. gammaH2AX foci were quantified in perfused and unperfused regions after different irradiation doses and at different time points. RESULTS: The TCD(50) of FaDu was 2-times higher compared to SKX (28.0Gy [95% C.I. 24.6; 31.3Gy] for FaDu; 14.9Gy [10.9; 18.9] for SKX, p<0.001). The induction of foci did not differ between the tumour models. Residual foci were twice higher in perfused SKX regions compared to FaDu, no difference was observed in the non perfused region between both tumour models. The number of residual foci increased with a 2-times higher slope in perfused SKX-regions compared to FaDu, while no difference was detected in unperfused regions. Already within the perfused regions, this slope decreased with distance from perfused vessels. CONCLUSION: The dose-response of residual gammaH2AX foci is highly dependent on tumour cell oxygenation in well perfused areas. This dependence decreases further away from tumour vessels. Only gammaH2AX evaluation in perfused tumour areas can distinguish between the different radiocurability of the two tumour models. PMID- 21821303 TI - Gefitinib plus cisplatin and radiotherapy in previously untreated head and neck squamous cell carcinoma: a phase II, randomized, double-blind, placebo-controlled study. AB - BACKGROUND AND PURPOSE: To assess the efficacy and safety of gefitinib given concomitantly and/or as maintenance therapy to standard cisplatin/radiotherapy for previously untreated, unresected, stage III/IV non-metastatic SCCHN. MATERIALS AND METHODS: In this phase II, double-blind, study, 226 patients were randomized to gefitinib 250mg/day, 500mg/day or placebo in two phases: a concomitant phase (gefitinib or placebo with chemoradiotherapy), followed by a maintenance phase (gefitinib or placebo alone). Primary endpoint was local disease control rate (LDCR) at 2years; secondary endpoints were LDCR at 1year, objective response rate, progression-free survival, overall survival, and safety and tolerability. RESULTS: Gefitinib (250 and 500mg/day) did not improve 2-year LDCR compared with placebo either when given concomitantly with chemoradiotherapy (32.7% vs. 33.6%, respectively; OR 0.921, 95% CI 0.508, 1.670 [1-sided p=0.607]) or as maintenance therapy (28.8% vs. 37.4%, respectively; OR 0.684, 95% CI 0.377, 1.241 [1-sided p=0.894]). Secondary efficacy outcomes were broadly consistent with the 2-year LDCR results. In both doses, gefitinib was well-tolerated and did not adversely affect the safety and tolerability of concomitant chemoradiotherapy. CONCLUSION: Gefitinib was well-tolerated, but did not improve efficacy compared with placebo when given concomitantly with chemoradiotherapy, or as maintenance therapy alone. PMID- 21821304 TI - Nomogram to predict ipsilateral breast relapse based on pathology review from the EORTC 22881-10882 boost versus no boost trial. AB - BACKGROUND AND PURPOSE: The EORTC 22881-10882 trial showed that for patients treated with breast conserving therapy (BCT), a 16Gy boost dose significantly improved local control, but increased the risk of breast fibrosis. A model to estimate the risk of ipsilateral breast relapse (IBR) already exists, but now a model has been developed which takes boost treatment into account and is based on centrally reviewed pathology. MATERIALS AND METHODS: A Cox model was developed based on central pathology review data and clinical data of 1603 patients from the EORTC 22881-10882 trial with a median follow-up of 11.5years. From a predefined set of variables, predictors with a maximal effect on 10-year IBR rate >4% were retained in the model. Bootstrap re-sampling was used to assess model calibration and discrimination. The results are presented in the form of a nomogram. RESULTS: Apart from young age and no boost, presence of DCIS adjacent to the invasive tumor was associated with increased risk of IBR (HR 1.96, p=0.001). Patients with high grade invasive tumors were younger than patients with low/intermediate grade (p<0.0001). The nomogram includes histologic grade, DCIS, tumor diameter, age, tamoxifen, chemotherapy, and boost with a concordance probability estimate of 0.68. CONCLUSIONS: The nomogram for predicting IBR 10years after BCT includes seven factors, with young age, presence of DCIS and boost treatment as the most dominant factors. The nomogram estimates IBR and confirms the importance of a boost dose. Combined with a model to predict fibrosis published previously, the nomogram presented here may assist in decision making for individual patients. PMID- 21821305 TI - Clinical outcome of protocol based image (MRI) guided adaptive brachytherapy combined with 3D conformal radiotherapy with or without chemotherapy in patients with locally advanced cervical cancer. AB - BACKGROUND: To analyse the overall clinical outcome and benefits by applying protocol based image guided adaptive brachytherapy combined with 3D conformal external beam radiotherapy (EBRT)+/-chemotherapy (ChT). METHODS: Treatment schedule was EBRT with 45-50.4Gy+/-concomitant cisplatin chemotherapy plus 4*7Gy High Dose Rate (HDR) brachytherapy. Patients were treated in the "protocol period" (2001-2008) with the prospective application of the High Risk CTV concept (D90) and dose volume constraints for organs at risk including biological modelling. Dose volume adaptation was performed with the aim of dose escalation in large tumours (prescribed D90>85Gy), often with inserting additional interstitial needles. Dose volume constraints (D(2cc)) were 70-75Gy for rectum and sigmoid and 90Gy for bladder. Late morbidity was prospectively scored, using LENT/SOMA Score. Disease outcome and treatment related late morbidity were evaluated and compared using actuarial analysis. FINDINGS: One hundred and fifty six consecutive patients (median age 58years) with cervix cancer FIGO stages IB IVA were treated with definitive radiotherapy in curative intent. Histology was squamous cell cancer in 134 patients (86%), tumour size was >5cm in 103 patients (66%), lymph node involvement in 75 patients (48%). Median follow-up was 42months for all patients. Interstitial techniques were used in addition to intracavitary brachytherapy in 69/156 (44%) patients. Total prescribed mean dose (D90) was 93+/ 13Gy, D(2cc) 86+/-17Gy for bladder, 65+/-9Gy for rectum and 64+/-9Gy for sigmoid. Complete remission was achieved in 151/156 patients (97%). Overall local control at 3years was 95%; 98% for tumours 2-5cm, and 92% for tumours >5cm (p=0.04), 100% for IB, 96% for IIB, 86% for IIIB. Cancer specific survival at 3years was overall 74%, 83% for tumours 2-5cm, 70% for tumours >5cm, 83% for IB, 84% for IIB, 52% for IIIB. Overall survival at 3years was in total 68%, 72% for tumours 2-5cm, 65% for tumours >5cm, 74% for IB, 78% for IIB, 45% for IIIB. In regard to late morbidity in total 188 grade 1+2 and 11 grade 3+4 late events were observed in 143 patients. G1+2/G3+4 events for bladder were n=32/3, for rectum n=14/5, for bowel (including sigmoid) n=3/0, for vagina n=128/2, respectively. INTERPRETATION: 3D conformal radiotherapy+/-chemotherapy plus image (MRI) guided adaptive intracavitary brachytherapy including needle insertion in advanced disease results in local control rates of 95-100% at 3years in limited/favourable (IB/IIB) and 85-90% in large/poor response (IIB/III/IV) cervix cancer patients associated with a moderate rate of treatment related morbidity. Compared to the historical Vienna series there is relative reduction in pelvic recurrence by 65 70% and reduction in major morbidity. The local control improvement seems to have impact on CSS and OS. Prospective clinical multi-centre studies are mandatory to evaluate these challenging mono-institutional findings. PMID- 21821306 TI - Prediction of the prognosis and surgical indications for pulmonary metastectomy from colorectal carcinoma in patients with combined hepatic metastases. AB - BACKGROUND: The value of surgical treatment for patients with pulmonary and hepatic metastases from colorectal carcinoma is controversial. The purpose of this study was to analyze our initial experience with this aggressive strategy, and to define the prognosis and the surgical indications. METHODS: The records of 35 patients who underwent surgical treatments for both hepatic and pulmonary metastases from colorectal carcinoma, from January 1997 to December 2008, were retrospectively analyzed. RESULTS: There were 18 females and 17 males with a median age was 62.0 years. The primary colorectal neoplasm was located at the colon in 23 patients (65.7%) and in the rectum in 12 patients (34.3%). The overall 5-year and 10-year survival rates were 65.3% and 31.5% from the date of primary colorectal resection, respectively. For patients who underwent metachronous hepatic and pulmonary surgical treatment, the 10-year survival rate was 40.9%, which was significantly better than that of those undergoing synchronous hepatic and pulmonary surgical treatment (p=0.0265). Patients who have pulmonary less than ten of metastasis thus seemed to have a better prognosis than those with more than ten, but the difference was quite significant (p=0.0719). In a multivariate Cox proportional hazards model, synchronous hepatic and pulmonary metastases was identified as an independent predictor of adverse survival (p=0.0073). CONCLUSIONS: The results of our study suggest that hepatic and pulmonary surgical treatment can provide a better prognosis for patients with metachronous hepatic and pulmonary metastases from colorectal carcinoma. We believe that aggressive metastasectomy can be an option for selected patients, even if a patient has been previously treated for hepatic and pulmonary metastases from colorectal carcinoma. PMID- 21821307 TI - Ipilimumab (Yervoy) and the TGN1412 catastrophe. AB - The development of the anti-CTLA-4 antibody (ipilimumab; marketed as Yervoy) immune regulatory therapy was based on the premise that "Abrogation of the function of CTLA-4 would permit CD28 to function unopposed and might swing the balance in favor of immune stimulation, tolerance breakdown and tumor eradication..." (Weber, 2009). By now, the vast majority of data collected from more than 4000 patients proves that this prediction was entirely correct. Paradoxically, the successful blockade of immune checkpoints raises the question whether an anti-CTLA-4 antibody could ever become an important therapy against cancer. T cells lost their ability to discriminate between self and non-self. Thus, tolerance to self tissues was broken in ~70% of the patients. In the recent industry-sponsored phase III clinical trial of ipilimumab, 147 (38.7%) of the patients experienced severe adverse events and 6.8% suffered dose-limiting events (8.4%, in the ipilimumab-alone group). There were 14 deaths related to the study drugs and 7 of these were associated with immune-related adverse events. In contrast, the complete response rate was only 0.2%, in one patient out of 403 who received ipilimumab plus a peptide vaccine. Promoters of ipilimumab appear to be unmindful of the clinical trial catastrophe in London. Then, a humanized "superagonist" anti-CD28 monoclonal antibody, TGN1412, which "preferentially" activated regulatory T cells, at a higher dose, also activated all CD28 positive T cells. This precipitated a "cytokine storm" leading to life-threatening multiple organ failure in the six healthy human volunteers. Neither anti-CD28 nor anti-CTLA-4 therapies rely on antigen-specificity. Both release free antibody into the body against common molecular targets that are expressed on the targeted as well as on the non-targeted T cells. At lower antibody doses specific T cells are preferentially activated. With increasing antibody dose, however, the kinetics of the interaction is pushed in favor of widespread non-specific T cell expansion. Using the law of mass action we calculated that the vast majority of the CTLA-4 receptors on all activated T cells (including melanoma specific T cells) in the phase III clinical trial of ipilimumab will have been saturated. This would explain the runaway immune response observed. The conclusions drawn by the authors of the ipilimumab trial paper could bear an independent inspection and reassessment concerning the validation of the blockade of immune checkpoints as an important therapeutic strategy against cancer. PMID- 21821308 TI - Lenalidomide therapy in treatment-refractory cutaneous lupus erythematosus: histologic and circulating leukocyte profile and potential risk of a systemic lupus flare. AB - BACKGROUND: Lenalidomide is a thalidomide analogue that may serve as an adjunctive therapy for treatment-refractory cutaneous lupus erythematosus (CLE). OBJECTIVES: We evaluate the use of lenalidomide in CLE and describe the skin and circulating leukocyte profile of treatment-refractory patients before and after treatment. METHODS: Five subjects were treated with lenalidomide in an unblinded open-label study. Immunohistochemistry of skin was performed for T-cell markers, glycosaminoglycans, and CXCL10, an interferon-inducible chemokine, before and after treatment. Immunophenotyping and measurement of interferon-inducible genes from peripheral blood mononuclear cells was also performed before and after treatment. RESULTS: Four subjects demonstrated clinical improvement of their skin, however one of these responders subsequently developed symptoms of systemic lupus erythematosus. Small changes in rare circulating leukocyte subsets, plasmacytoid dendritic cells, and regulatory T cells were observed with treatment and may correlate with clinical response. Treatment was associated with increased circulating HLA-DR expression and decreased markers of interferon-mediated pathways, regardless of clinical response. LIMITATIONS: Our results are limited by small sample size and the measurement of rare populations of circulating cell subsets. CONCLUSIONS: Lenalidomide may have usefulness as therapy for severe, treatment-refractory CLE. However, our preliminary data suggest that lenalidomide may activate T cells and trigger systemic disease in some patients with CLE. We also saw a different histologic and circulating leukocyte phenotype in the nonresponding subject. Further characterization of the skin and circulating leukocyte profile of treatment-refractory patients will improve our understanding of CLE. PMID- 21821309 TI - Calciphylaxis: a systematic review of existing and emerging therapies. AB - Calciphylaxis, also known as calcific uremic arteriolopathy, is a cutaneous ischemic small vessel vasculopathy seen in 1 to 4% of patients with chronic kidney disease on hemodialysis. It is associated with extreme pain and a 60 to 80% mortality rate in the setting of few and frequently ineffective therapeutic options, although this may be changing based on reports of success with newer therapies. PMID- 21821310 TI - Use of topical antibiotics as prophylaxis in clean dermatologic procedures. AB - BACKGROUND: Topical antibiotics are not indicated for routine postoperative care in clean dermatologic procedures, but may be widely used. OBJECTIVE: We sought to describe topical antibiotic use in clean dermatologic surgical procedures in the United States. METHODS: The 1993 to 2007 National Ambulatory Medical Care Survey database was queried for visits in which clean dermatologic surgery was performed. We analyzed provider specialty, use of topical antibiotics, and associated diagnoses. Use of topical antibiotic over time was analyzed by linear regression. RESULTS: An estimated 212 million clean dermatologic procedures were performed between 1993 and 2007; topical antibiotics were reported in approximately 10.6 million (5.0%) procedures. Dermatologists were responsible for 63.3% of dermatologic surgery procedures and reported use of topical antibiotic prophylaxis in 8.0 million (6.0%). Dermatologists were more likely to use topical antibiotic prophylaxis than nondermatologists (6.0% vs 3.5%). Use of topical antibiotic prophylaxis decreased over time. LIMITATIONS: Data were limited to outpatient procedures. The assumption was made that when topical antibiotics were documented at procedure visits they were being used as prophylaxis. CONCLUSIONS: Topical antibiotics continue to be used as prophylaxis in clean dermatologic procedures, despite being ineffective for this purpose and posing a risk to patients. Although topical antibiotic use is decreasing, prophylactic use should be eliminated. PMID- 21821311 TI - Hobnail hemangioma reclassified as superficial lymphatic malformation: a study of 52 cases. AB - BACKGROUND: Hobnail hemangioma (HH) is currently classified as a benign vascular tumor, although it is not well understood whether this lesion differentiates toward blood or lymphatic endothelial cells. Immunostaining with the endothelial marker Wilms tumor 1 (WT1) helps distinguish between vascular neoplasms and malformations, being positive in the former and negative in the latter. OBJECTIVE: We sought to investigate WT1, human herpesvirus 8 latent nuclear antigen, D2-40, and Ki-67 immunoprofile in HH, to gain further insight into its histogenesis. METHODS: We evaluated 52 HHs collected in Dermatohistopathologische Gemeinschaftslabor, Friedrichshafen, Germany. Immunohistochemical expression of WT1 was performed in all cases. Ten of 52 lesions were also studied for D2-40 and Ki-67 staining and 12 lesions were stained for human herpesvirus 8 latent nuclear antigen. RESULTS: All 52 HHs were completely negative for WT1 immunostaining. Immunohistochemistry performed in 10 HHs showed diffuse and strong positive staining for D2-40 in 8 lesions and focal positivity in two. All cases tested showed negative staining for Ki-67 and human herpesvirus 8 latent nuclear antigen. LIMITATIONS: There are no limitations. CONCLUSIONS: Although the exact histogenesis of HH is unknown, most of the performed immunohistochemical studies support a lymphatic line of differentiation. However, on the basis of the WT1 negativity, we believe that HH is better considered as a lymphatic malformation rather than a lymphatic neoplasm. PMID- 21821312 TI - Current status of the sunscreen regulation in the United States: 2011 Food and Drug Administration's final rule on labeling and effectiveness testing. PMID- 21821313 TI - Risk factors for prosthetic hip and knee infections according to arthroplasty site. AB - Prosthetic joint infection is a devastating complication of arthroplasty. Previous epidemiological studies have assessed factors associated with arthroplasty infections but have not assessed the impact of comorbidity on infection at different arthroplasty locations. We used a case-control design to investigate risk factors for prosthetic joint infection with reference to the anatomical site. During an eight-year period at a single hospital, 63 patients developed a prosthetic joint infection (36 hips, 27 knees). Cases of prosthetic hip or knee joint infection were matched 1:2 to controls. The results suggest that factors associated with arthroplasty infections differ with anatomical location. Following knee arthroplasty, wound discharge was associated with an increased risk of prosthetic joint infection whereas the presence of a drain tube reduced the risk. By contrast, increased body mass index, increased drain tube loss and superficial incisional surgical site infections (SSIs) were associated with prosthetic hip infection. When analysed as a combined cohort, systemic steroid use, increased SSI drain tube losses, wound discharge, and superficial incisional SSIs were predictors of infection. PMID- 21821314 TI - Response to Anderson RE, Young V, Stewart M, Robertson C, Dancer SJ, 'Cleanliness audit of clinical surfaces and equipment: who cleans what?'. PMID- 21821315 TI - Targeting NR2A-containing NMDA receptors reduces L-DOPA-induced dyskinesias. AB - Levodopa (L-DOPA)-induced dyskinesias represent the main side effect of the therapeutic strategy clinically used in Parkinson's disease (PD) treatment. The first beneficial "honeymoon" phase of L-DOPA therapy is followed by a phase of deterioration in which L-DOPA administration causes motor fluctuations in the drug efficacy ("on-off" state) and dyskinesias. Alterations of the composition and function of N-methyl-D-aspartate (NMDA) receptor represent one of the main causes for the striatal synaptic changes described in experimental model of dyskinesias. In the present study, the modulation of the composition of synaptic NMDA receptor by using a cell-permeable peptide targeting NR2A subunit during the development of dyskinesias led to a reduction of the percentage of parkinsonian rats developing dyskinetic movements. PMID- 21821317 TI - [Diagnosis and treatment of urethral recurrence after radical cystectomy in the male]. AB - CONTEXT: From 4%-6% of males subjected to radical cystectomy due to urothelial carcinoma will have urethral recurrence (UR) during the follow-up. OBJECTIVE: To analyze the diagnosis, treatment and course of the patients with UR following a cystectomy. ACQUIRING OF EVIDENCE: Analysis of original articles and reviews related with the diagnosis, treatment and course of patients subjected to radical cystectomy and who develop UR. The articles were obtained from a search in PubMed. SYNTHESIS OF EVIDENCE: Most of the UR appear during the first 3 years of the cystectomy. Approximately 50% of the URs of contemporary series were diagnosed through urethral cytology, the patient being asymptomatic. The urethrectomy is the treatment of choice in patients with UR and cutaneous diversion. In patients with orthotopic bladder replacement (OBR): 1) the treatment of the intraurethral BCG can be useful in patients with carcinoma in situ (CIS), 2) papillary type conservative treatment in UR has contradictory results, 3) when the uretrectomy is necessary, the ileal duct or conversion of the OBR in a continent urinary derivation can be used. CONCLUSIONS: Urethral cytology is a test having high sensitivity and can contribute to the diagnosis of UR in the earliest stages. In patients with OBR, the diagnosis of a UR is a therapeutic challenge. The bladder tumor, urethral recurrence and presence of an upper urinary tract tumor in 25% of the cases may be a cause of death in these patients. PMID- 21821316 TI - Blood pressure is associated with higher brain amyloid burden and lower glucose metabolism in healthy late middle-age persons. AB - Epidemiological studies suggest that elevated blood pressure (BP) in midlife is associated with increased risk of Alzheimer's disease (AD) in late life. In this preliminary study, we investigated the extent to which BP measurements are related to positron emission tomography (PET) measurements of fibrillar amyloid beta burden using Pittsburgh Compound-B (PiB) and fluorodeoxyglucose (FDG) PET measures of cerebral metabolic rate for glucose metabolism (CMRgl) in cognitively normal, late middle-aged to older adult apolipoprotein E (APOE) epsilon4 homozygotes, heterozygotes and noncarriers. PiB PET results revealed that systolic BP (SBP) and pulse pressure (PP) were each positively correlated with cerebral-to-cerebellar PiB distribution volume ratio (DVR) in frontal, temporal, and posterior-cingulate/precuneus regions, whereas no significant positive correlations were found between PiB distribution volume ratios and diastolic BP (DBP). FDG PET results revealed significant inverse correlations between each of the BP measures and lower glucose metabolism in frontal and temporal brain regions. These preliminary findings provide additional evidence that higher BP, likely a reflection of arterial stiffness, during late midlife may be associated with increased risk of presymptomatic AD. PMID- 21821318 TI - [Successful treatment of post circumcision glanular ischemia-necrosis with hyperbaric oxygen and intravenous pentoxifylline]. PMID- 21821319 TI - [Hexavalent chromium and bladder cancer risk]. PMID- 21821320 TI - [Epidemiology of nasopharyngeal carriage of Streptococcus pneumoniae in children < 6 years old in Seville]. AB - INTRODUCTION: The aim of this investigation was to study the epidemiology of nasopharyngeal (NP) colonization with Streptococcus pneumoniae after the introduction of the heptavalent pneumococcal conjugate vaccine (PCV7). METHODS: NP swabs were obtained from 848 children aged 6 months to six years seen in four primary care centres (healthy children) and in two emergency depeartments (sick children) from Seville. The study was conducted between February 2005 and June 2008. RESULTS: A total of 278 (33%) children carried S. pneumoniae. Pneumococcal colonization was independently predicted by school attendance or child care participation (OR 2.21; 95% CI 1.54- 3.15; P=.0001) and younger age. Recent antibiotic use was protective (OR 0.68; 95% CI 0.48-0.94; P=.02). PCV7 uptake was 41%. Risk of carriage of PCV7- type pneumococci was lower among children who had received >=1 dose of PCV7 (7% vs 29%; [OR 0.21; 95% CI 0.09-0.49; P=.0001]). The proportion of pneumococcal isolates with oral penicillin non-susceptibility and amoxicillin resistance were 33% and 3%, respectively. Amoxicillin resistance in colonized children was associated with prior antibiotic usage (OR 4.29; 95% CI 1.09-20.02). CONCLUSIONS: NP colonization rates with PCV7- type pneumococci were low compared to those found in studies prior to PCV7 introduction, both in vaccinated and unvaccinated subjects. Factors related to age and overcrowding increased the prevalence of pneumococcal carriage. Use of antibiotics reduced the overall carriage of pneumococci, but was a risk factor for colonization with amoxicillin resistant pneumococci. PMID- 21821321 TI - Synthesis of 4beta-triazole-podophyllotoxin derivatives by azide-alkyne cycloaddition and biological evaluation as potential antitumor agents. AB - A representative synthetic process of derivatizing the natural product podophyllotoxin utilizing the copper-catalyzed azide-alkyne cycloaddition (CuAAC) is described including molecular design, reaction optimization and X-ray structure confirmation. Evaluation of cytotoxicity against human cancer cell lines (Hela, K562 and K562/A02) using MTT assay proves that these triazole derivatives have good antitumor activities. High activities toward the drug resistant K562/A02 cell line reveal promising future for these derivatives. The rarely prepared 1,5-disubstituted triazole isomers, which would be omitted by the "click chemistry", were found to have superior cytotoxicities to that of the 1,4 disubstituted isomers. PMID- 21821322 TI - [Pyoderma gangrenosum, subcorneal pustular dermatosis and aseptic spleen abscess: "a neutrophilic disease"]. AB - Neutrophilic diseases may have various clinical presentations but share common histopathological manifestations with an aseptic infiltrate of polymorphonuclears neutrophils. The association with various diseases is frequent and must be systematically discussed. We report a patient who presented three different synchronous clinical manifestations of neutrophilic disease: pyoderma gangrenosum, subcorneal pustular dermatosis and aseptic spleen abscesses. PMID- 21821323 TI - Moving to Opportunity: does long-term exposure to 'low-poverty' neighborhoods make a difference for adolescents? AB - This study re-analyzed data on adolescent health outcomes (N = 1780; M age = 15.15, SD = 2.30) from a 5-year evaluation of the Moving to Opportunity (MTO) Program. The MTO program is a randomized experiment conducted in five cities in the United States (Baltimore, Boston, Chicago, Los Angeles and New York) in which low-income families living in public housing in 'high-poverty' neighborhoods were offered vouchers and assistance to move to 'low-poverty' neighborhoods. The objective was to reexamine program effects as a function of exposure to 'low poverty' neighborhoods to determine whether beneficial effects reported for girls' mental health and behavior generalized to other outcomes for girls and to boys. As found in previous evaluations, girls in the MTO program group, whose families remained in 'low-poverty' neighborhoods for comparatively long periods (approximately 5 years), had better mental health and engaged in fewer risky behaviors than a matched control sample of girls, whose families stayed in 'high poverty' neighborhoods. Further, additional benefits for girls were seen in the education domain. Adverse program effects on boys' behavior problems, reported in other MTO research using different methods, were not evident in our analysis. Findings suggest that programs relocating low-income families to 'low-poverty' neighborhoods should provide supports to families and to receiving communities to promote residential stability and social integration. PMID- 21821324 TI - How is health-related "deservingness" reckoned? Perspectives from unauthorized im/migrants in Tel Aviv. AB - Do unauthorized im/migrants have a right to health? Do they deserve health care, or health protection, or access to the social determinants of good health? Are they party to prevailing social contracts, or does their exclusion from mainstream systems of health promotion, prevention, and care "make sense"? Questions like these, which generate considerable attention in multiple spheres of scholarship, policy, and public debate, revolve around an issue that merits substantially greater consideration among social scientists of health: health related "deservingness." In addition to putting the issue of health-related deservingness squarely on the map as an object of analysis, this article further argues that we cannot focus solely on those with power, influence, and public voice. Rather, we also must investigate how deservingness is reckoned in relation to--and, furthermore, from the perspectives of-- unauthorized im/migrants and members of other groups commonly constructed in public and policy discourse as undeserving. Additionally, we must consider the complicated relationship between universalizing juridical arguments about formal entitlement to health rights, on one hand, and situationally specific, vernacular moral arguments about deservingness, on the other. The paper analyzes findings from a 29-month mixed methods study conducted in Tel Aviv, Israel, that approached unauthorized im/migrants as subjects, rather than simply objects, of ethical deliberation. Participants' conceptions of health-related deservingness are investigated using two sources of data: (1) quantitative findings from a self-administered, closed ended survey conducted with 170 im/migrant patients at an NGO-run Open Clinic (2002-2003), and (2) qualitative findings from the larger ethnographic study of which the survey was part (2000-2010). The study findings both (1) contradict commonly circulating assumptions that unauthorized im/migrants are "freeloaders," and (2) highlight the need for rigorous investigation of how unauthorized im/migrants, among other marginalized and vulnerable groups, conceptualize their own relative deservingness of health-related concern and investment. PMID- 21821325 TI - Unusual and rare complications of orthognathic surgery: a literature review. PMID- 21821326 TI - Comprehensive epigenetic analysis using oral rinse samples: a pilot study. AB - PURPOSE: To prove that chromatin immunoprecipitation assay can be performed with oral rinse samples and to develop a protocol for comprehensive analysis of functional interactions among DNA methylation, histone modification, and gene expression using such samples. MATERIALS AND METHODS: Eleven cancer cell lines and oral rinse samples from 10 patients with oral squamous cell carcinoma and 3 healthy subjects were examined. The expression of CDKN2A, a tumor suppressor gene, was determined by reverse transcription/polymerase chain reaction and immunohistochemistry. Promoter DNA methylation was assessed by methylation specific polymerase chain reaction. Chromatin modifications were analyzed by a chromatin immunoprecipitation assay using antibodies for dimethylation and acetylation of lysine 9 of histone H3. RESULTS: Epigenetic control of CDK2NA was observed in vitro in 11 cancer cell lines. Using the present protocol, comprehensive epigenetic analysis could be successfully performed with oral rinse samples. All patients were comfortable using the prescribed amount (16 mL) of normal saline to rinse their mouths. Nine patients (90%) and 1 healthy subject (33%) showed dimethylation of lysine 9 of histone H3. Moreover, 8 patients (80%) showed hypoacetylation of lysine 9 of histone H3, which was not observed in healthy subjects. CONCLUSIONS: The present study showed for the first time that chromatin modifications can be analyzed using oral rinse samples by chromatin immunoprecipitation analysis. To evaluate the contribution of histone modifications for carcinogenesis of oral squamous cell carcinoma, studies including a larger number of subjects should be conducted in the future. PMID- 21821328 TI - Evaluation of a navigation system for dental implantation as a tool to train novice dental practitioners. AB - PURPOSE: This study evaluated the benefits of a virtual reality navigation system for teaching the surgical stage of dental implantation to final-year dental students. The study aimed to assess the students' performance in dental implantation assignments by comparing freehand protocols with virtual reality navigation. MATERIALS AND METHODS: Forty final-year dentistry students without previous experience in dental implantation surgery were given an implantation assignment comprising 3 tasks. Marking, drilling, and widening of implant holes were executed by a freehand protocol on the 2 mandibular sides by 1 group and by virtual reality navigation on 1 side and contralaterally with the freehand protocol by the other group. Subjective and objective assessments of the students' performance were graded. RESULTS: Marking with the navigation system was more accurate than with the standard protocol. The 2 groups performed similarly in the 2-mm drilling on the 2 mandibular sides. Widening of the 2 mesial holes to 3 mm was significantly better with the second execution in the standard protocol group, but not in the navigation group. The navigation group's second-site freehand drilling of the molar was significantly worse than the first. The execution of all assignments was significantly faster in the freehand group than in the navigation group (60.75 vs 77.25 minutes, P = .02). Self assessment only partly matched the objective measurements and was more realistic in the standard protocol group. CONCLUSIONS: Despite the improved performance with the navigation system, the added value of training in dental implantation surgery with virtual reality navigation was minimal. PMID- 21821329 TI - Osteochondroma after mandibular dislocation. PMID- 21821327 TI - Human masseter muscle fiber type properties, skeletal malocclusions, and muscle growth factor expression. AB - PURPOSE: We identified masseter muscle fiber type property differences in subjects with dentofacial deformities. PATIENTS AND METHODS: Samples of masseter muscle were collected from 139 young adults during mandibular osteotomy procedures to assess mean fiber areas and percent tissue occupancies for the 4 fiber types that comprise the muscle. Subjects were classified into 1 of 6 malocclusion groups based on the presence of a skeletal Class II or III sagittal dimension malocclusion and either a skeletal open, deep, or normal bite vertical dimension malocclusion. In a subpopulation, relative quantities of the muscle growth factors IGF-I and GDF-8 gene expression were quantified by real-time polymerase chain reaction. RESULTS: Fiber properties were not different in the sagittal malocclusion groups, but were very different in the vertical malocclusion groups (P <= .0004). There were significant mean fiber area differences for type II (P <= .0004) and type neonatal-atrial (P = .001) fiber types and for fiber percent occupancy differences for both type I-II hybrid fibers and type II fibers (P <= .0004). Growth factor expression differed by gender for IGF-I (P = .02) and GDF-8 (P < .01). The ratio of IGF-I:GDF-8 expression associates with type I and II mean fiber areas. CONCLUSION: Fiber type properties are very closely associated with variations in vertical growth of the face, with statistical significance for overall comparisons at P <= .0004. An increase in masseter muscle type II fiber mean fiber areas and percent tissue occupancies is inversely related to increases in vertical facial dimension. PMID- 21821330 TI - Factor VII deficiency resulting in acute hemorrhage in orthognathic surgery: a case report. PMID- 21821332 TI - Aggression and peer victimization: genetic, neurophysiological, and neuroendocrine considerations. PMID- 21821331 TI - Aerosol deposition of hydroxyapatite and 4-hexylresorcinol coatings on titanium alloys for dental implants. AB - PURPOSE: Aerosol deposition is a newly developed technique, and it can deliver the drug from a hydroxyapatite (HA)-coated surface. 4-Hexylresorcinol (4-HR) is a well-known antiseptic. The influence of the 4-HR component of HA coatings on titanium surfaces was studied in vitro and in vivo. MATERIALS AND METHODS: X-ray diffraction and Fourier transform infrared techniques were used for the evaluation of the coating. The cellular response of the coating was evaluated by scanning electron microscopic study, MTT assay, alkaline phosphatase assay, and osteocalcin assay. In addition, the dental implant was coated with HA or HA + 4 HR. The implant was installed into the tibia of a rabbit after contamination by Aggregatibacter actinomycetemcomitans. The torque test and histologic analysis were then performed at 8 weeks after the operation. RESULTS: By use of an aerosol deposition technique, the combination of HA and 4-HR was successfully coated onto a titanium surface, which was confirmed by x-ray diffraction and Fourier transform infrared techniques. MG63 cells attached more rapidly to the HA + 4-HR coating than to the HA-only coating. The HA + 4-HR coating had significantly increased osteocalcin expression and alkaline phosphatase activity compared with the HA-only coating (P < .05). The dental implant coated with HA + 4-HR had a significantly higher removal torque value than that coated with HA alone at 8 weeks after surgery (P < .05). On histologic analysis, both the bone formation value and the bone-to-implant contact value were significantly higher in the HA + 4-HR group than in the HA-only group at 8 weeks after surgery (P < .05). CONCLUSIONS: Collectively, the HA + 4-HR-coated dental implant had clear advantages over the HA-coated dental implant. Therefore HA + 4-HR coatings can be considered for patients who need immediate implant installation after tooth extraction or who have poor-quality bone. PMID- 21821333 TI - Technical requirements of spirometers in the strategy for guaranteeing the access to quality spirometry. AB - Access to quality spirometry is an essential objective in order to be able to minimize the underdiagnosis of respiratory diseases, especially in those that are most frequent, such as COPD and asthma. This objective can be reached in the short term, but it requires the simultaneous integration of different strategies: training of the health-care professionals who perform spirometry, definition of standards for the transmission of the information, technical requirements for acquiring apparatuses and the correct interpretation of the results. This present study shows the use of standards for the electronic exchange of clinical information. In order to normalize the treatment of the data related with spirometry and to enable the exchange of information, we have used the standard CDA R2 (Clinical Document Architecture, Release 2) of HL7 (Health Level Seven), version 3. HL7 is a product by HL7 International, a non-profit organization that deals in the production of standards in the health-care setting in order to facilitate interoperability. Furthermore, defining these standards is essential for ensuring that they are adopted by spirometer manufacturers. Be means of this process, the base is set for facilitating access to spirometry at the health-care level, while at the same time it is a fundamental technical element for designing quality control programs of the explorations. PMID- 21821334 TI - [Efficacy of mycophenolate associated with methotrexate as a maintenance treatment for systemic sclerosis-associated interstitial lung disease]. PMID- 21821335 TI - High value of combined serum C-reactive protein and BODE score for mortality prediction in patients with stable COPD. AB - INTRODUCTION: Both BODE score (body mass index, degree of airflow obstruction, functional dyspnea, and exercise capacity) and serum C-reactive protein (CRP) are validated predictors of mortality in patients with chronic obstructive pulmonary disease (COPD). The aim of this study is to investigate the predictive value of combined serum CRP and BODE score for mortality in COPD patients. PATIENTS AND METHODS: A cohort of 114 clinically stable COPD patients was assessed for predictors of longitudinal mortality. Variables included age, gender, current smoking status, pack-years, maximal inspiratory/expiratory pressure, BODE score (body mass index, degree of airflow obstruction, functional dyspnea, and exercise capacity), serum CRP, and fibrinogen. Predictors were assessed by Cox proportional hazards regression model. Survival was estimated by Kaplan-Meier method and log-rank test. RESULTS: Serum CRP (P=0.005; HR=1.042; 95% CI=1.019 1.066) and BODE score (P=0.032; HR=1.333; 95% CI=1.025-1.734) were independent predictors of survival in the multivariate analysis. The cumulative survival rates of COPD patients were sorted from the worst to the best as following: serum CRP >3mg/L & quartile 3-4; serum CRP >3mg/L & quartile 1-2; serum CRP <=3mg/L & quartile 3-4; serum CRP <=3mg/L & quartile 1-2 (P<0.001). CONCLUSIONS: Serum CRP and BODE score are independent predictors of survival in stable COPD patients. Combination of serum CRP and BODE score has higher predictive value in clinical practice. PMID- 21821336 TI - Severe respiratory failure secondary to a ventriculo-pleural shunt. PMID- 21821337 TI - Diffuse pulmonary lymphangiomatosis with mediastinal affectation. PMID- 21821338 TI - Risk factors for asthma onset between the ages of 12 and 40. Results of the FENASMA study. AB - OBJECTIVES: To describe the clinical profile of patients with asthma and to identify possible risk factors for its development in subjects over the age of 12. PATIENTS AND METHODS: A multicenter study of cases and controls. Recruited for inclusion were case subjects between the ages of 12 and 40 diagnosed with asthma, with an onset of symptoms after the age of 12. Control subjects were selected, with ages between 12 and 40, who did not have childhood asthma and did not present symptoms of asthma at the time of the study. RESULTS: We evaluated 923 subjects: 247 cases and 671 controls. 54.9% were women. Mean age of the cases was 28.3 +/- 8.2; mean age of controls was 30.8 +/- 7.1 (p<0.001). In the logistic regression analysis, it was observed that the determining factors for the of the presence of asthma were hypersensitivity to animals or other allergens, presence of rhinitis, family history of asthma, occupational risk/exposure to irritants and the hypersensitivity/intolerance to NSAIDs. In said analysis, it was also demonstrated that age was a protection factor, as well as level of education. CONCLUSIONS: The risk factors for the development of asthma at an adult age are hypersensitivity to animals or other allergens, rhinitis, family history of asthma, occupational risk/exposure to irritants and the hypersensitivity/intolerance to NSAIDs, while age and level of education are protection factors. PMID- 21821341 TI - Minimally invasive approach to cases of lost intra-uterine device: a 7-year experience. AB - OBJECTIVES: To evaluate the effectiveness of hysteroscopy and laparoscopy for diagnosis and treatment in women with lost intra-uterine devices (IUDs), and to elucidate the most common extra-uterine locations of lost IUDs. STUDY DESIGN: Retrospective clinical study at Ataturk University Hospital, Erzurum, Turkey. Women with lost IUDs presenting in the last 7 years were referred to the obstetrics and gynaecology clinics. Women whose lost IUDs were removed using a Novak curette were excluded from the study. RESULTS: Of the 55 cases studied, 29 (52.7%) lost IUDs were located inside the uterine cavity, 23 (41.8%) were located outside the uterine cavity, and three (5.5%) were embedded in the myometrium. The most common extra-uterine location of lost IUDs was around the uterosacral ligaments (n=8, 34.7%). Considerable association was found between the position of the uterus and the extra-uterine location of lost IUDs. In all eight cases where the lost IUD was located around the uterosacral ligaments, the uterine position was anteverted and perforation was found on the posterior side of the uterus. IUD removal was performed successfully in 46 women (83.6%) by either hysteroscopy or laparoscopy. CONCLUSIONS: Lost IUDs inside or outside the uterine cavity can be managed by minimally invasive approaches. If an anteverted uterus is seen on laparoscopy, the initial exploration for the lost IUD should be made around the uterosacral ligaments. PMID- 21821340 TI - [Rationale and methods of the study on nutrition and cardiovascular risk in Spain (ENRICA)]. AB - INTRODUCTION AND OBJECTIVES: The ENRICA study aims to assess the frequency and distribution of the main components of the natural history of cardiovascular disease in Spain, including food consumption and other behavioral risk factors, biological risk factors, early damage of target organs, and diagnosed morbidity. METHODS: A cross-sectional survey of 11,991 individuals representative of the non institutionalized population aged 18 years and older in Spain was conducted from June 2008 to October 2010. Data collection comprised 3 sequential stages: a) computer-assisted telephone interview to obtain information on lifestyle, knowledge and attitudes about cardiovascular disease risk factors, and the signs and symptoms of heart attack and stroke, subjective health, and morbidity; b) first home visit, to collect blood and urine samples for analysis by a central laboratory, and c) second home visit, to measure anthropometric variables and blood pressure and to administer a computer-assisted dietary history; data on functional limitations are also collected from participants aged 65 years and older. DISCUSSION: The ENRICA study has shown the feasibility of a large home based health interview and examination survey in Spain. It will provide valuable information to support and evaluate national strategies against cardiovascular disease and other chronic diseases in Spain. Moreover, a 3-year prospective follow-up of the study participants, including a new physical exam, is planned to start in the second semester of 2011 and will update lifestyle information and biological variables. (ClinicalTrials.gov number, NCT01133093). PMID- 21821343 TI - Simulation and source identification of X-ray contrast media in the water cycle of Berlin. AB - This article describes the development of a model to simulate the fate of iodinated X-ray contrast media (XRC) in the water cycle of the German capital, Berlin. It also handles data uncertainties concerning the different amounts and sources of input for XRC via source densities in single districts for the XRC usage by inhabitants, hospitals, and radiologists. As well, different degradation rates for the behavior of the adsorbable organic iodine (AOI) were investigated in single water compartments. The introduced model consists of mass balances and includes, in addition to naturally branched bodies of water, the water distribution network between waterways and wastewater treatment plants, which are coupled to natural surface waters at numerous points. Scenarios were calculated according to the data uncertainties that were statistically evaluated to identify the scenario with the highest agreement among the provided measurement data. The simulation of X-ray contrast media in the water cycle of Berlin showed that medical institutions have to be considered as point sources for congested urban areas due to their high levels of X-ray contrast media emission. The calculations identified hospitals, represented by their capacity (number of hospital beds), as the most relevant point sources, while the inhabitants served as important diffusive sources. Deployed for almost inert substances like contrast media, the model can be used for qualitative statements and, therefore, as a decision support tool. PMID- 21821342 TI - Body mass index, recreational physical activity and female urinary incontinence in Gansu, China. AB - OBJECTIVE: To elucidate the influence of recreational physical activity, body mass index (BMI), and waist circumference on the risk of specific types of urinary incontinence. STUDY DESIGN: We conducted a population-based cross sectional survey in Gansu, China among 2603 women aged 20 years or older. RESULTS: The study found that BMI was positively associated with urinary incontinence (P for trend=0.008) and the association was mainly observed for stress urinary incontinence (OR=1.4, 95% CI: 1.1, 1.9 for BMI=24.0-27.9 kg/m2; OR=2.3, 95% CI: 1.5, 3.6 for BMI >= 28.0 kg/m2; P for trend=0.0005). A positive association between stress incontinence (OR=1.7, 95% CI: 1.2, 2.5) and waist circumference was observed for women who had waist circumference between 70 cm and 75 cm compared to waist circumference less than 70 cm. Recreational physical activity was inversely associated with overall and mixed urinary incontinence (P for trend <0.0001 for both). A significant interaction between physical activity and waist circumference was found for overall (P=0.0007) and stress incontinence (P=0.001). CONCLUSIONS: The findings that physical activity inversely associated with urinary incontinence and its interaction with waist circumference warrant further investigation, particularly in prospective studies. PMID- 21821344 TI - Research on environmental impacts of tourism in China: progress and prospect. AB - With the rapid development of tourism industry in China since 1980, the country has experienced an increasing use of its natural and cultural environment for tourism, resulting in tourism resources being adversely impacted in many tourism destinations. This paper described the research progress in tourism impacts on the environment in the context of China through a review of the growing literature in this field. Specifically, research on tourism impacts on the biophysical and socio-cultural environments, tourism carrying capacity, environmental quality assessment, and measures for the protection and management of tourism resources was reviewed. The review found that the majority of research was qualitative and descriptive in nature, and there was a lack of case studies and theoretical development. Future research should focus on the evaluation of environmental impacts, particularly those gradual cumulative impacts on the tourism environment; examination of the quantitative relationship between the impact and the level of tourism use for different activities; development of methods to estimate the carrying capacity; and understanding of positive impacts of tourism. PMID- 21821345 TI - Effects of ultrasound on osteotomy healing in a rabbit fracture model. AB - This study investigated the effects of ultrasound (US) at different frequencies on fracture healing over a three-week period in a rabbit fibular fracture model. Forty-five adult New Zealand White rabbits were divided into five groups: a control group and four groups treated with US frequencies of 0.5, 1.0, 1.5 and 2.0 MHz (0.5 W/cm(2), 200-MUs burst, pulsed 1:4). After anesthesia, transverse osteotomy was performed on the fibula bone. This was followed by intravital staining and fluorescence microscopic examination of new bone formation and biomechanical tests of torsional stiffness at the osteotomy site. Results showed that total new bone formation and torsional stiffness of the fibula were greater in all US-treated groups than in the control group. No significant difference was found between any of the four US-treated groups. The US treatment also enhanced bone growth of the sham-treated contralateral fracture site. These results suggest that US treatment at 0.5, 1.0, 1.5 or 2.0 MHz can enhance fracture healing in a rabbit model. Furthermore, the effects of US on fracture healing at present parameters might not be confined locally. PMID- 21821346 TI - Automatic adaptive parameterization in local phase feature-based bone segmentation in ultrasound. AB - Intensity-invariant local phase features based on Log-Gabor filters have been recently shown to produce highly accurate localizations of bone surfaces from three-dimensional (3-D) ultrasound. A key challenge, however, remains in the proper selection of filter parameters, whose values have so far been chosen empirically and kept fixed for a given image. Since Log-Gabor filter responses widely change when varying the filter parameters, actual parameter selection can significantly affect the quality of extracted features. This article presents a novel method for contextual parameter selection that autonomously adapts to image content. Our technique automatically selects the scale, bandwidth and orientation parameters of Log-Gabor filters for optimizing local phase symmetry. The proposed approach incorporates principle curvature computed from the Hessian matrix and directional filter banks in a phase scale-space framework. Evaluations performed on carefully designed in vitro experiments demonstrate 35% improvement in accuracy of bone surface localization compared with empirically-set parameterization results. Results from a pilot in vivo study on human subjects, scanned in the operating room, show similar improvements. PMID- 21821347 TI - Ultrasonographic assessment of growth and estimation of birthweight in late gestation fetal sheep. AB - Our aim was to identify which ultrasound parameters can be most accurately measured and best predict ovine fetal weight in late gestation. Singleton pregnancies were established using embryo transfer in 32 adolescent ewes, which were subsequently overnourished to produce fetuses of variable size (1720-6260 g). Ultrasound measurements at 126-133 days gestation were compared with fetal weight/biometry at late-gestation necropsy (n = 19) or term delivery (n = 13). Abdominal circumference (AC) and renal volume (RV) correlated best with physical measurements (r = 0.78-0.83) and necropsy/birth weight (r = 0.79-0.84). Combination of AC + RV produced an estimated fetal weight equation [Log EFW = 2.115 + 0.003 AC + 0.12 RV - 0.005 RV(2)] with highest adjusted R(2) (0.72) and lowest mean absolute/percentage prediction error (396-550 g/11.1%-13.2%). In conclusion, AC and RV are parameters of choice for assessment of late-gestation ovine fetal growth and can be used to estimate fetal weight with similar accuracy to human fetuses. PMID- 21821348 TI - Variance of speed of sound and correlation with acoustic impedance in canine corneas. AB - The clinical standard for measuring corneal thickness is ultrasound pachymetry that assumes a constant speed of sound. The purpose of this study was to examine the variance of speed of sound and its relationship with acoustic impedance in healthy eyes of canines with a large age span. Corneal speed of sound and acoustic impedance were measured in 34 canine eyes at room temperature (21 +/- 1 degrees C). The mean speed of sound was 1577 +/- 10 m/s ranging from 1553 to 1594 m/s. There was a strong correlation between speed of sound and acoustic impedance (R = 0.84, p < 0.001). Corneal speed of sound had a small variance in healthy canines over 1-year-old, but was significantly lower in younger canines suggesting an age effect. The strong correlation between corneal speed of sound and acoustic impedance may offer a potential means to noninvasively detect abnormal speed of sound for more accurate corneal thickness estimation. PMID- 21821349 TI - Treatment of rabbit liver cancer in vivo using miniaturized image-ablate ultrasound arrays. AB - In the preclinical studies reported here, VX2 cancer within rabbit liver has been treated by bulk ultrasound ablation employing miniaturized image-ablate arrays. Array probes were constructed with 32 elements in a 2.3 * 20 mm(2) aperture, packaged within a 3.1 mm stainless steel tube with a cooling and coupling balloon for in vivo use. The probes were measured capable of 50% fractional bandwidth for pulse-echo imaging (center frequency 4.4 MHz) with >110 W/cm(2) surface intensity available at sonication frequencies 3.5 and 4.8 MHz. B-scan imaging performance of the arrays was measured to be comparable to larger diagnostic linear arrays, although nearfield image quality was reduced by ringdown artifacts. A series of in vivo ablation procedures was performed using an unfocused 32-element aperture firing at 4.8 MHz with exposure durations 20-70.5 s and in situ spatial average, temporal average intensities 22.4-38.5 W/cm(2). Ablation of a complete tumor cross-section was confirmed by vital staining in seven of 12 exposures, with four exposures ablating an additional margin >1 mm beyond the tumor in all directions. Analysis suggests a threshold ablation effect, with complete ablation of tumor cross-sections for exposures with delivery of >838 J acoustic energy. The results show feasibility for in vivo liver cancer ablation using miniaturized image ablate arrays suitable for interstitial deployment. PMID- 21821350 TI - Simultaneous ultrasound assessment of brachial artery shear stimulus and flow mediated dilation during reactive hyperemia. AB - In flow-mediated dilation (FMD) studies, brachial artery diameter changes due to reactive hyperaemia are typically measured through manual or automatic analysis of high resolution B-mode images while the stimulus of diameter change, i.e., the flow change, is qualitatively estimated by measuring the mean velocity in the vessel and assuming a parabolic velocity profile. This article describes an experimental approach to simultaneously measure the wall shear rate (WSR) and the diameter variations, through multigate spectral Doppler and B-mode image processing, respectively. By using an ultrasound advanced open platform (ULA-OP), experimental results from the brachial arteries of 15 presumed healthy volunteers have been obtained. The mean increments during reflow against baseline were 105% +/- 22% for the peak WSR and 8% +/- 3% for the FMD. The mean time interval between the WSR peak and the beginning of plateau of diameter waveform was 38 +/- 8 s. The results confirm that in young healthy subjects the postischemic vasodilation of brachial artery is largely correlated to the WSR increase. PMID- 21821351 TI - The lognormal perfusion model for disruption replenishment measurements of blood flow: in vivo validation. AB - Dynamic contrast enhanced ultrasound (DCE-US) is evolving as a promising tool to noninvasively quantify relative tissue perfusion in organs and solid tumours. Quantification using the method of disruption replenishment is best performed using a model that accurately describes the replenishment of microbubble contrast agents through the ultrasound imaging plane. In this study, the lognormal perfusion model was validated using an exposed in vivo rabbit kidney model. Compared against an implanted transit time flow meter, longitudinal relative flow measurement was (*3) less variable and correlated better when quantification was performed with the lognormal perfusion model (Spearman r = 0.90, 95% confidence interval [CI] = 0.05) vs. the prevailing mono-exponential model (Spearman r = 0.54, 95% CI = 0.18). Disruption-replenishment measurements using the lognormal perfusion model were reproducible in vivo to within 12%. PMID- 21821352 TI - Targeted long-term venous occlusion using pulsed high-intensity focused ultrasound combined with a pro-inflammatory agent. AB - Esophageal and gastric varices are associated with significant morbidity and mortality for cirrhotic patients. The current modalities available for treating bleeding esophageal and gastric varices, namely endoscopic band ligation and sclerotherapy, require frequent sessions to obtain effective thrombosis and are associated with significant adverse effects. A more effective therapy that results in long-term vascular occlusion has the potential to improve patient outcomes. In this study, we investigated a new potential method for inducing long term vascular occlusion by targeting segments of a rabbit's auricular vein in vivo with low-duty-cycle, high-peak-rarefaction pressure (9 MPa), pulsed high intensity focused ultrasound in the presence of intravenously administered ultrasound microbubbles followed by local injection of fibrinogen and a pro inflammatory agent (ethanol, cyanoacrylate or morrhuate sodium). The novel method introduced in this study resulted in acute and long-term complete vascular occlusions when injecting a pro-inflammatory agent with fibrinogen. Future investigation and translational studies are needed to assess its clinical applicability. PMID- 21821353 TI - Diagnostic accuracy of ultrasonography vs. electromyography in carpal tunnel syndrome: a systematic review of literature. AB - A plethora of research investigates sonography vs. electrodiagnostic testing (EDX) for diagnosis of carpal tunnel syndrome (CTS). Through database searches, hand searches and communication with authors, 582 abstracts published from 1999 to 2009 were identified. A comprehensive systematic review process resulted in inclusion of 23 studies. Significant methodologic discrepancies among the studies limited the ability to complete a meta-analysis to identify specific diagnostic thresholds. Instead, the data were reviewed to provide implications for clinical utility of sonography as a screening tool as a compliment to EDX and to suggest continued and future research. The largest cross-sectional area of the median nerve within the carpal tunnel region has high potential for clinical screening, especially in individuals with severe CTS. Identifying swelling of the nerve through comparative measurements, qualitative analysis and Doppler techniques all require further investigation. Screening protocols may be enhanced through exploration of sonography in patients with mild CTS and false-negative EDX. PMID- 21821354 TI - Transcranial Doppler studies on cerebral autoregulation suggest prolonged cerebral vasoconstriction in a subgroup of patients with orthostatic intolerance. AB - We studied the cerebral autoregulation in a subgroup of patients with orthostatic intolerance, who exhibited excessively decreased middle cerebral artery flow velocity (MCAFV) on transcranial Doppler sonography (TCD) during head-up tilt (HUT) test but without orthostatic hypotension or postural tachycardia. Twenty patients and 20 age- and sex-matched controls underwent Valsalva maneuver (VM) and HUT test with simultaneous monitoring of MCAFV by TCD and blood pressure, heart rate recordings. The pulsatility index (PI), cerebrovascular resistance (CVR) and autoregulatory indices were calculated. During HUT, patients had marked MCAFV reduction (-29.0 +/- 5.25% vs. -8.01 +/- 4.37%), paradoxically decreased PI (0.68 +/- 0.17 vs. 0.96 +/- 0.28) but increased CVR (45.7 +/- 16.7% vs. 14.3 +/- 12.6%). The MCAFV decreased similarly during early phase II of VM in both groups but did not recover to baseline in patients during late phase II, phase III and less overshoot in phase IV (-11 +/- 16.7% vs. +2.2 +/- 17.9 %; -15.4 +/- 16.5% vs. -2.4 +/- 17.8% and 16.7 +/- 22.9% vs. 38.7 +/- 26.5%, respectively). We concluded that in these patients, cerebrovascular vasoconstriction in response to physiologic stimulation was normal but relaxation during and after stimulation were impaired, indicating prolonged cerebral vasoconstriction. PMID- 21821355 TI - Assessing the viscoelastic properties of thrombus using a solid-sphere-based instantaneous force approach. AB - The viscoelastic properties of thrombus play a significant role when the clot closes a leak in a vessel of the blood circulation. The common method used to measure the viscoelastic properties of a clot employs a rheometer but this might be unsuitable due to the clot fiber network being broken up by excessive deformation. This study assessed the feasibility of using a novel acoustic method to assess the viscoelastic properties of blood clots. This method is based on monitoring the motion of a solid sphere in a blood clot induced by an applied instantaneous force. Experiments were performed in which a solid sphere was displaced by a 1 MHz single-element focused transducer, with a 20 MHz single element focused transducer used to track this displacement. The spatiotemporal behavior of the sphere displacement was used to determine the viscoelastic properties of the clot. The experimental system was calibrated by measuring the viscoelastic modulus of gelatin using different types of solid spheres embedded in the phantoms and, then, the shear modulus and viscosity of porcine blood clots with hematocrits of 0% (plasma), 20% and 40% were assessed. The viscoelastic modulus of each clot sample was also measured directly by a rheometer for comparison. The results showed that the shear modulus increased from 173 +/- 52 (mean +/- SD) Pa for 40%-hematocrit blood clots to 619.5 +/- 80.5 Pa for plasma blood clots, while the viscosity decreased from 0.32 +/- 0.07 Pa?s to 0.16 +/- 0.06 Pa?s, respectively, which indicated that the concentration of red blood cells and the amount of fibrinogen are the main determinants of the clot viscoelastic properties. PMID- 21821357 TI - Hepatic oval cell lines generate hepatocellular carcinoma following transfection with HBx gene and treatment with aflatoxin B1 in vivo. AB - Hepatic oval cells (HOC) are considered to be the stem cells of the liver and have been linked to the development of hepatic malignancies. Studies have demonstrated that chronic hepatitis B virus (HBV) infection and dietary aflatoxin B1 (AFB1) exposure are among the most important risk factors for the development of hepatocellular carcinoma (HCC). However, little research has been done to evaluate the role of oval cells in these two environmental factors on hepatocarcinogenesis. In this study, partial transformation of rat HOC (LE/6) were accomplished by transfected HBV x gene (HBx), and then transfected cells were implanted both intra-hepatically and subcutaneously into nude mice treated with AFB1 in vivo. We found the oval cells produced tumors (4/24 of the animals) in liver following transfection with HBx gene and treatment with AFB1. These intrahepatic tumors included HCC cells (immunopositive for HepParl, ALB, CK8 and AFP) and mesenchymal cells (immunopositive for Vimentin and SMA). Whereas mesenchymal tumors were observed at the subcutaneous tissue with a similar rate in all controls treated with cell lines (10/24 in HBx-oval cells/AFB1 group, 8/20 in HBx-oval cells/non-AFB1 group, 10/20 in non-HBx/AFB1 group; 9/20 in non HBx/non-AFB1 group). Conversely, none of the controls developed intrahepatic tumors. These results provide an evidence that oval cells have the capacity to generate HCC through the combined effects of the HBx and AFB1 in the liver microenvironment. PMID- 21821358 TI - Cooperia punctata: effect on cattle productivity? AB - Cooperia spp. have become the most prevalent parasites in United States cow/calf operations as observed in the USDA NAHMS (National Animal Health Monitoring System) Beef Cow/Calf survey in 2008. This is at least in part due to the widespread use of macrocyclic lactones that have recently been shown to have a reduced activity against these parasites. The effects of Cooperia spp. on cattle productivity are largely unknown. This study was conducted to assess their effect upon cattle housed under conditions found in American feedlots. Two hundred yearling calves (average weight 460 lb/209 kg) were acquired from northwestern Arkansas and northeastern Oklahoma and were vaccinated and dewormed upon arrival at the feedlot. Animals were comingled and preconditioned for approximately one month, and were fed a standard growing ration throughout the study. Calves were randomly divided into two groups (n=80, infected and control) and each group was further divided into two replicate pens (n=40). Calves from the two infected pens were orally inoculated with a gavage of 1 * 10(5) and 0.825 * 10(5) infective larvae of a recent isolate of Cooperia punctata on day 0 and 14, respectively, with the two control pens receiving a similar volume of tap water. Data collected included biweekly fecal egg counts, daily individual feed consumption and weight gain over the 60-day test period. The presence of C. punctata (>99% of recovered worms) was confirmed by necropsy and recovery from the small intestine on days 35 and 60 post infection (PI) in a subset of animals. Egg counts were positive by day 14 PI and remained at numbers similar to values seen in field studies. The control group gained weight 7.5% more rapidly (p=0.02) than infected animals (3.24 lb/1.47 kg per day vs. 3.0 lb/1.36 kg per day, respectively). The Cooperia infected calves also consumed 1.5 lb (0.68 kg) less dry feed per day than the control animals (p=0.02). These data suggest that C. punctata has a deleterious effect on both appetite and nutrient uptake or utilization. At necropsy (days 35 and 60), the draining mesenteric lymph nodes of infected animals were increased in size and the small intestinal mucosa was thickened and covered with a thick layer of mucus in the infected animals. The most prominent histological changes in the Cooperia- infected animals included a moderate increase in the number of intraepithelial lymphocytes and globule leukocytes, as well as aggregates of eosinophils within the lower lamina propria. The only significant difference was an increase in the goblet cell density at day 60. Anthelmintic sensitivity/resistance of the Cooperia isolate used was determined by treatment of one pen of infected calves with a macrocyclic lactone and the other pen with a benzimidazole at the completion of the study. The macrocyclic lactone treatment (n=40) did not remove the parasites (FECRT=8.8%), while treatment with a benzimidazole was very effective (FECRT=98.1%). This study demonstrated that C. punctata has a significant effect on cattle productivity, both reduced weight gain and decreased feed intake compared to controls. PMID- 21821359 TI - Development of an egg hatch assay for the diagnosis of triclabendazole resistance in Fasciola hepatica: proof of concept. AB - The aim of this study was to develop an Egg Hatch Assay (EHA) test for the detection of triclabendazole (TCBZ) resistance in Fasciola hepatica. A number of fluke isolates were used, of differing sensitivity to TCBZ. Eggs were exposed to solutions of triclabendazole sulphoxide (TCBZ.SO) for 14 days, then triggered to hatch. Egg development was divided into 6 distinct and easily identifiable stages: dead, empty, unembryonated, cell division, eye spot and hatched. The number of eggs reaching those stages was recorded. Initially, the discriminating dose (1% hatch) was determined for the Cullompton isolate, used as TCBZ susceptible (TCBZ-S) standard. Once this concentration had been resolved, the response of different isolates to this concentration was examined. The hatch rate of the Fairhurst isolate was not significantly different from that of the Cullompton isolate, confirming its TCBZ-S status. The Patagonia isolate has not been exposed to TCBZ in the field and should be TCBZ-S: the results of the EHA supported this. The egg hatch response of the Oberon and Dutch isolates differed significantly from that of the Cullompton isolate; the former isolates are regarded as TCBZ-resistant (TCBZ-R) and the results confirmed this. Another isolate, the Leon isolate, was originally described as being TCBZ-R, but has since been shown to be TCBZ-S. There was no difference in its response to TCBZ.SO in the EHA from the Cullompton (and Fairhurst and Patagonia) isolate(s), further indicating its TCBZ-S status. The impact of TCBZ.SO treatment on the component stages of egg development was determined and revealed differences between the isolates. In conclusion, the results of the study have shown that it is possible to discriminate between TCBZ-S and TCBZ-R isolates of F. hepatica on the basis of the response of their eggs to an EHA and the test could be used to evaluate the TCBZ sensitivity of unknown field isolates. PMID- 21821360 TI - Prevalence of adrenal haemorrhage in non-surviving patients with burns. AB - PURPOSE: The purpose of this study was to investigate the prevalence of adrenal haemorrhage (AH) in non-surviving patients with severe burns by combining the clinical notes and autopsy data. METHODS: A retrospective review of all adult (age >18 years) burn patients who died in the Helsinki Burn Centre, Helsinki, Finland during 1.1.1995 to 31.12.2005 was conducted. Patients diagnosed with AH either in the clinical charts or in the autopsy reports were sorted out. Special attention was paid to the course of events preceding death and autopsy findings. RESULTS: We identified four patients, creating a prevalence of 5.6%. None of the patients was diagnosed with AH alive. Three patients we diagnosed with bilateral AH, all young men. Cause of death was multiple organ failure (MOF) in all three cases. On the autopsy, they were diagnosed with 5+/-1 organ failures. One case of unilateral AH was established, an elderly male with hot air sauna burns. Clinical charts and autopsy data suggest idiopathic AH. CONCLUSIONS: The prevalence of AH is higher than previously estimated in non-surviving patients with burns. Bilateral AH occurred later then 1 week after the burn trauma. Bilateral AH always presented with sepsis, multiple organ failure and acute renal failure. PMID- 21821361 TI - Concerns about stability and accuracy of a burn model. PMID- 21821362 TI - Effects of an alcohol intervention on drinking among female college students with and without a recent history of sexual violence. AB - OBJECTIVE: Alcohol misuse among college students is a significant public health problem that can have negative long-term implications. One important correlate of problem drinking among college female populations is sexual violence. The current study investigated: (1) past year sexual violence and its association with alcohol consumption and related psychosocial variables (stress, coping, and mental health); and (2) whether the impact of an alcohol intervention was different for college women with a history of sexual violence compared to those without such a history. METHODS: Female undergraduate students (N=351) who participated in the Brief Alcohol Screen in College Students (BASICS) completed web-based surveys measuring alcohol and drug use, psychosocial factors, and sexual violence at baseline and six-month follow-up. RESULTS: At baseline, women who experienced sexual violence reported less use of protective alcohol strategies, more positive coping skills, and more mental health symptoms. Following the intervention, alcohol consumption decreased significantly among the entire sample; however no significant differences in consumption were identified based on a history of sexual violence. Yet, compared to women not reporting sexual violence, women who reported recent sexual violence showed greater improvements in mental health outcomes (p<0.05). CONCLUSIONS: Findings suggest that brief alcohol interventions may have a differential impact on alcohol related outcomes based on whether or not women have experienced recent sexual violence. PMID- 21821363 TI - Examining correlates of different cigarette access behaviours among Canadian youth: data from the Canadian Youth Smoking Survey (2006). AB - Understanding factors associated with youth cigarette access behaviours can provide insight into the development of more effective means of preventing youth from accessing cigarettes. This cross-sectional study used self-reported data collected from 41,886 students in grades 9 to 12 who participated in the 2006-07 Youth Smoking Survey to examine the student- and school-level characteristics that differentiate youth smokers who usually access cigarettes from a social source versus buying their own from retailers. Multi-level regression analyses revealed significant between-school variability in the odds of a smoking student reporting that they usually buy their own cigarettes. Important student-level characteristics associated with how youth usually access their cigarettes included binge drinking and being asked for age or photo identification when purchasing cigarettes from a retailer. Future studies should further explore the school- and student-level characteristics associated with youth cigarette access behaviour. PMID- 21821364 TI - Screening instruments for detecting illicit drug use/abuse that could be useful in general hospital wards: a systematic review. AB - AIM: To identify and describe screening instruments for detecting illicit drug use/abuse that are appropriate for use in general hospital wards and review evidence for reliability, validity, feasibility and acceptability. METHODS: Instruments were identified from a number of screening instrument databases/libraries and Google Scholar. They were independently assessed for eligibility by two reviewers. MEDLINE, EMBASE, PSYCINFO, and Cochrane Library were searched for articles published up to February 2010. Two reviewers independently assessed the identified articles for eligibility and extracted data from the eligible studies. RESULTS: 13 instruments, ASSIST, CAGE-AID, DAST, DHQ/PDHQ, DUDIT, DUS, NMASSIST, SIP-AD, SDS, SMAST-AID, SSI-SA, TICS and UNCOPE were included in the review. They had 2 to 28 items and took less than 10 min to administer and score. Evidence on validity, reliability, acceptability and feasibility of instruments in adult patients not known to have a substance abuse problem was scarce. Of the 21 studies included in the review, only one included participants from general hospital wards. Reported sensitivity, specificity and predictive values varied widely both between studies of the same instrument and also between different instruments. No study was identified comparing two or more of the included instruments. CONCLUSION: The review identified and described 13 instruments that could be useful in general hospital wards. There is however lack of evaluation of illicit drug use screening instruments in general hospital wards. Currently clinicians or researchers searching for a simple, reliable, general screening instrument for current drug use to guide practice or research in general hospital wards do not have enough comparative evidence to choose between the available measures. PMID- 21821365 TI - Self-regulation as a buffer of the relationship between parental alcohol misuse and alcohol-related outcomes in first-year college students. AB - Alcohol misuse among college students is a large public health concern, thus, it is imperative to identify factors that reduce this risk. One risk factor associated with developing alcohol-related problems is meeting criteria for being an adult child of an alcoholic (ACOA). Conversely, self-regulation has been identified as a protective factor that is inversely associated with drinking related outcomes. The purpose of the present study was to examine whether self regulation buffers the risk associated with ACOA status on alcohol use and alcohol-related consequences. In a sample of 195 first-year college students, we found that ACOA status had a unique effect on both alcohol consumption and alcohol-related consequences. Self-regulation was unrelated to alcohol use but inversely associated with alcohol-related consequences. Notably, self-regulation moderated the effect of ACOA status on alcohol-related problems (but not alcohol consumption) such that self-regulation was most strongly related to alcohol related problems among ACOAs. Our results suggest that self-regulation helps explain the resilience of many ACOAs. PMID- 21821366 TI - Infrapatellar fat pad may be with tendon repairing ability and closely related with the developing process of patella Baja. AB - Patella Baja, as a common complication of knee trauma or knee surgery, was very difficult to deal with, and scarring and shortening of the patellar tendon were looked on as the most important reason for it. Infrapatellar fat pad, also known as Hoffa's fat pad was traditionally regarded as with only buffering and lubricating functions in knee joints, which can limit the knee's excessive activities, absorb shocks from the anterior knee and reduces friction between the patellar tendon and the tibia, it should be with direct protection function and avoid the damage of patella tendon. Recently, a large number of studies had shown that adipose tissue was an accessible and abundant source of mesenchymal stem cells for tissue engineering. Adipose derived stem cells (ADSCs) can be induced to differentiate into adipocytes, osteoblasts, nerve cells, tendon cells and so on. In addition, interestingly, infrapatellar fat pad were just located behind the patellar tendon, and SDF-1 (stromal cell-derived factor-1), as a powerful cytokine that regulates inflammatory cell recruitment and stem cell homing, was unregulated after ligament injury, so there may be a certain correlation between ADSCs from infrapatellar fat pad and injured tendons, maybe ADSCs from infrapatellar fat pad can biologically repair injured tendons when patella tendon was damaged. We hypothesized injured patella tendon repairing should include not only the self-repairing of the tendon, but also the biological repairing from ADSCs in infrapatellar fat pad. When both of the repairing failed to repair the damage of the tendon, patellar tendon may begin to shrink and scar, which will result in patella Baja. In our opinion, healthy infrapatellar fat pad was with direct protection function of patella tendon and full of rich ADSCs, which may play an important part in patella tendon repairing and the developing process of patella Baja. PMID- 21821367 TI - Near-infrared hyperspectral imaging for grading and classification of pork. AB - In this study, a hyperspectral imaging technique was developed to achieve fast, accurate, and objective determination of pork quality grades. Hyperspectral images were acquired in the near-infrared (NIR) range from 900 to 1700 nm for 75 pork cuts of longissimus dorsi muscle from three quality grades (PSE, RFN and DFD). Spectral information was extracted from each sample and six significant wavelengths that explain most of the variation among pork classes were identified from 2nd derivative spectra. There were obvious reflectance differences among the three quality grades mainly at wavelengths 960, 1074, 1124, 1147, 1207 and 1341 nm. Principal component analysis (PCA) was carried out using these particular wavelengths and the results indicated that pork classes could be precisely discriminated with overall accuracy of 96%. Algorithm was developed to produce classification maps of the tested samples based on score images resulting from PCA and the results were compared with the ordinary classification method. Investigation of the misclassified samples was performed and showed that hyperspectral based classification can aid in class determination by showing spatial location of classes within the samples. PMID- 21821368 TI - Arthroscopic treatment of rotator cuff disease. AB - The goal of this article is to summarize the current concepts on rotator cuff disease with an emphasis on arthroscopic treatment. Most rotator cuff tears are the result of an ongoing attritional process. Once present, a tear is likely to gradually increase in size. Partial-thickness and subscapularis tears can both be successfully treated arthroscopically if conservative management fails. Partial tears involving greater than 50% of tendon thickness should be repaired. Articular-sided partial tears involving less than 50% of the rotator cuff can reliably be treated with debridement. A more aggressive approach should be considered for low-grade tears (<50%) if they occur on the bursal side. Biomechanical and anatomic studies have shown clear superiority with dual-row fixation compared with single-row techniques. However, current studies have yet to show clear clinical advantage with dual-row over single-row repairs. Biceps tenotomy or tenodesis can reliably provide symptomatic improvement in patients with irreparable massive tears. True pseudoparalysis of the shoulder is a contraindication to this procedure alone and other alternatives should be considered. PMID- 21821369 TI - Changes in the plasma proteome follows chronic opiate administration in simian immunodeficiency virus infected rhesus macaques. AB - BACKGROUND: Substantive plasma proteomic changes follow lentiviral infection and disease pathobiology. We posit that such protein alterations are modified during drug abuse, further serving to affect the disease. To this end, we investigated the effect of opiate administration on the plasma proteome of Indian-strain rhesus monkeys infected with simian immunodeficiency virus (SIV) strain smm9. METHODS: Whole blood was collected at 7 weeks prior to and 1.4 and 49 weeks after viral infection. Viral load, CD4(+) T cell subsets, and plasma protein content were measured from monkeys that did or did not receive continuous opiate administrations. The plasma proteome was identified and quantified by isobaric tags for relative and absolute quantitation labeling (iTRAQ) and mass spectrometry. RESULTS: While substantive changes in plasma proteins were seen during SIV infection, the addition of opiates led to suppression of these changes as well as increased variance of the proteome. These changes demonstrate that opiates induce broad but variant immune suppression in SIV-infected monkeys. CONCLUSION: The broad suppressive changes seen in plasma of SIV-infected monkeys likely reflect reduced multisystem immune homeostatic responses induced by opiates. Such occur as a consequence of complex cell-to-cell interactions operative between the virus and the host. We conclude that such changes in plasma proteomic profiling may be underappreciated and as such supports the need for improved clinical definitions. PMID- 21821370 TI - Maternal active smoking and newborn body composition. AB - OBJECTIVE: Maternal smoking during pregnancy is associated with a reduction in birth size but very few studies have collated changes in neonatal anthropometry. Our aims were both to assess body composition differences by anthropometry between new-borns from smoking mothers and those from non-smoking mothers, and to show whether these differences affect proportional body mass distribution. METHODS: Caucasian mothers and their full term singleton new-borns (N=1216) were selected during 2009. A structured questionnaire was completed regarding obstetric and demographic data, as well as tobacco consumption. Women were categorized, according to their smoking habits, into a non-smoking group (never smoked or stopped smoking prior to pregnancy) and a smoking group (smoked throughout pregnancy). RESULTS: 22.1% of mothers smoked during pregnancy (median: 6 cigarettes/day, range: l-40). Smoking mothers were significantly younger than non-smoking mothers but there were no differences regarding other aspects which could affect infant weight. Infants from non-smoking mothers were heavier, longer, and body circumferences were all larger than those from smoking mothers (p<0.001), but the Ponderal Index showed no statistical differences. Skinfold thicknesses were significantly lower in new-borns from smoking mothers but these differences were less evident than those from body size. Subcutaneous fat distribution did not show statistical differences between the two groups. After gestational age, to smoke during gestation is the second main determinant of birth weight. CONCLUSIONS: Smoking during pregnancy involves a generalized reduction of most axiological parameters as a result of proportionate fetal growth impairment. In those infants born from mothers who smoked during gestation, neonatal lean body mass appears to be more affected than body fat, and distribution of subcutaneous fat is not different. PMID- 21821371 TI - Freezing stallion semen with the new Caceres extender improves post thaw sperm quality and diminishes stallion-to-stallion variability. AB - Ejaculates from 7 stallions were split and simultaneously frozen in three different extenders, INRA 96 egg yolk glycerol, Ghent and the newly developed extender Caceres. After thawing, samples were evaluated for motility (CASA system) sperm membrane integrity and early membrane changes (YoPro-1/Eth staining), acrosome integrity (FICT-PNA), and mitochondrial membrane potential (JC-1) (flow cytometry). Samples frozen in Caceres extender consistently showed the best results in post-thaw motility (increases ranging from 11 to 17%, p<0.05) and velocity (p<0.05), membrane integrity (increases ranging from 11 to 14%, p<0.05) and mitochondrial membrane potential (p<0.05). It is concluded that this new extender should be included in a freezeability test to determine the best extender for each individual. PMID- 21821372 TI - The association of serum C-reactive protein, uric acid and magnesium with insulin resistance in Chinese postmenopausal women with prediabetes or early untreated diabetes. AB - OBJECTIVES: This study aimed to evaluate the association of serum inflammatory markers (C-reactive protein (CRP) and uric acid (UA)), magnesium and other CVD risk factors with insulin resistance (IR) among Chinese postmenopausal women with prediabetes. STUDY DESIGN AND MAIN OUTCOMES MEASURES: This is a cross-sectional analysis of baseline data among 180 postmenopausal women with prediabetes or early untreated diabetes. Major anthropometric and biochemical measures included body mass index (BMI), waist to hip ratio (WHR), fasting and postload glucose and insulin, serum CRP, UA, lipids profile, and magnesium. IR was estimated using fasting glucose and insulin by homeostasis model assessment (HOMA). RESULTS: Multivariate linear regression analyses indicated that Lg CRP, WHR, serum triglycerides (TGs) and magnesium were the major predictors of HOMA-IR. A multivariate logistic analyses showed that a CRP level above 3.0 mg/l was significantly associated with a 2.8-fold risk of having higher HOMA-IR (>2.52). BMI plays a key role in mediating the relationship of CRP and IR. Elevated serum TG (>1.71 mmol/l), WHR (>0.88), UA (>357 mmol/l) and lower serum magnesium (<0.78 mg/l) were associated with 5.26 (95%CI: 2.52-10.98, P<0.05), 3.02 (95%CI: 1.64 5.55, P<0.05), 1.97 (95%CI: 1.02-3.83, P=0.05) and 0.51 (95%CI: 0.28-0.81) folds risk of higher HOMA-IR, respectively in the unadjusted model. Serum magnesium, but not UA was an independent risk factor of HOMA-IR. CONCLUSION: The present study in prediabetic or early untreated diabetic Chinese postmenopausal women indicated that IR is significantly associated with increased inflammation (CRP and UA), serum TG, WHR and lower serum magnesium. PMID- 21821373 TI - Age estimation by pulp/tooth ratio in lower premolars by orthopantomography. AB - Accurate age estimation has always been a problem for forensic scientists, and apposition of secondary dentine is often used as an indicator of age. Since 2004, in order to examine patterns of secondary dentine apposition, Cameriere et al. have been extensively studying the pulp/tooth area ratio of the canines by panoramic and peri-apical X-ray images. The main aim of this paper is to examine the relationship between age and age-related changes in the pulp/tooth area ratio in monoradicular teeth, with the exception of canines, by orthopantomography. A total of 606 orthopantomograms of Spanish white Caucasian patients (289 women and 317 men), aged between 18 and 75 years and coming from Bilbao and Granada (Spain), was analysed. Regression analysis of age of monoradicular teeth indicated that the lower premolars were the most closely correlated with age. An ANCOVA did not show significant differences between men and women. Multiple regression analysis, with age as dependent variable and pulp/tooth area ratio as predictor, yielded several formulae. R(2) ranged from 0.69 to 0.75 for a single lower premolar tooth and from 0.79 to 0.86 for multiple lower premolar teeth. Depending on the available number of premolar teeth, the mean of the absolute values of residual standard error, at 95% confidence interval, ranged between 4.34 and 6.02 years, showing that the pulp/tooth area ratio is a useful variable for assessing age with reasonable accuracy. PMID- 21821374 TI - Simultaneous quantitative determination of 9 active components in traditional Chinese medicinal preparation ShuangDan oral liquid by RP-HPLC coupled with photodiode array detection. AB - A simple, accurate and reliable method for the simultaneous separation and determination of 9 active components (danshensu, protocatechuic acid, protocatechuic aldehyde, caffeic acid, rosmarinic acid, salvianolic acid B, paeonol, paeoniflorin and gallic acid) in traditional Chinese medicinal preparation ShuangDan (SD) oral liquid was developed using reverse phase high performance liquid chromatography (RP-HPLC) coupled with photodiode array (PDA) detection. The chromatographic separation was performed on a SinoChrom ODS-BP C(18) column with gradient elution using methanol (A) and 3% glacial acetic acid aqueous solution (B) at a flow rate of 1.0mLmin(-1), and with a PDA detection. Good linear behaviors over the investigated concentration ranges were observed with the values of r(2) higher than 0.9992 for all the analytes. The recoveries and relative standard deviation (RSD), measured at three concentration levels, varied from 98.21% to 101.82% and 0.07% to 1.37%, respectively. The proposed method enables the simultaneous identification and determination of 9 active components in a single run for the quality control of ShuangDan oral liquid. PMID- 21821376 TI - What I learned one night in the red light district. PMID- 21821375 TI - Identification of novel sildenafil-analogues in an adulterated herbal food supplement. AB - A new herbal product advertised as potency pill was sent for analysis by the local authority. The product was tested for the presence of potential derivatives of PDE-5 inhibitors, such as sildenafil, vardenafil, and tadalafil. Sildenafil analogues were identified, in which the piperazine ring and the sulfonyl group were replaced by a piperazinone and a hydroxyethyl structure, respectively. The chemical structures were established by LC-MS in ESI negative mode, UV and NMR spectroscopy (including DEPT, HSQC, HMBC, H,H-COSY, H,H-TOCSY and H,H-NOESY experiments). This is the first report of piperazinonafil and isopiperazinonafil as adulterant in an herbal food supplement. PMID- 21821377 TI - The skill of summary in clinician-patient communication: a case study. AB - OBJECTIVE: To investigate the use and impact of the micro-skill of summary in clinical encounters, a core skill that has little empirical investigation of its use and outcomes. METHODS: This exploratory study used a mixed method design. Video recordings of ten consultations between simulated patients and medical students were analysed to identify types of summary used. Two contrasting cases were then micro-analysed and follow up interviews held with the 2 students and simulated patients, involved in the consultations, using the video recording as a trigger. RESULTS: Ninety-nine summaries were identified and grouped into six types: reflective, screening, clarifying, paraphrasing, interim and full. Summary appeared to aid accuracy. However, summaries about the patient's perspective were summarised less frequently than the biomedical perspective. When summaries were repeatedly incorrect they made the simulated patient feel they were not being listened to. CONCLUSIONS: The use and effect of summary appears more complex than the medical literature suggests and may have both positive and negative attributes. Further research is needed to investigate whether these preliminary findings are replicated within doctor-patient consultations. PRACTICE IMPLICATIONS: When teaching use of summary we need to address: type, purpose, accuracy, effect on patient and flexible use to suit the patient. PMID- 21821378 TI - Patterns in admission delays to outpatient methadone treatment in the United States. AB - Waiting lists for methadone treatment have existed in many U.S. communities, but little is known nationally about what patient and service system factors are related to admission delays that stem from program capacity shortfalls. Using a combination of national data sources, this study examined patterns in capacity related admission delays to outpatient methadone treatment in 40 U.S. metropolitan areas (N = 28,920). Patient characteristics associated with admission delays included racial/ethnic minority status, lower education, criminal justice referral, prior treatment experience, secondary cocaine or alcohol use, and co-occurring psychiatric problems. Injection drug users experienced fewer delays, as did self-pay patients and referrals from health care and addiction treatment providers. Higher community-level utilization of methadone treatment was associated with delay, whereas delays were less common in communities with higher utilization of alternative modalities. These findings highlight potential disparities in timely admission to outpatient methadone treatment. Implications for improving treatment access and service system monitoring are discussed. PMID- 21821379 TI - A multi-level analysis of counselor attitudes toward the use of buprenorphine in substance abuse treatment. AB - Despite evidence that buprenorphine is effective and safe and offers greater access as compared with methadone, implementation for treatment of opiate dependence continues to be weak. Research indicates that legal and regulatory factors, state policies, and organizational and provider variables affect adoption of buprenorphine. This study uses hierarchical linear modeling to examine National Treatment Center Study data to identify counselor characteristics (attitudes, training, and beliefs) and organizational factors (accreditation, caseload, access to buprenorphine, and other evidence-based practices) that influence implementation of buprenorphine for treatment of opiate dependence. Analyses showed that provider training about buprenorphine, higher prevalence of opiate-dependent clients, and less treatment program emphasis on a 12-step model predicted greater counselor acceptance and perceived effectiveness of buprenorphine. Results also indicate that program use of buprenorphine for any treatment purpose (detoxification, maintenance, and/or pain management) and time (calendar year in data collection) was associated with increased diffusion of knowledge about buprenorphine among counselors and with more favorable counselor attitudes toward buprenorphine. PMID- 21821381 TI - [Post-surgery cognitive disorders: prevention, diagnosis and treatment strategies]. AB - Hip fracture is an important step in the autonomy evolution in elderly. As gait is particularly jeopardised after such a traumatism, cognition may also be acutely impaired. Elderly post-surgery delirium is frequent, but chronic progression of cognitive impairment and dementia may occur. The concept of cognitive reserve is crucial for understanding risk factors of post-surgery delirium in elderly. The more the cognitive reserve is decreased before such a traumatism, the higher the delirium and dementia progression risk is. A neurodegenerative disease such as Alzheimer's disease may be clinically silent prior the traumatic event, and may decompensate soon after as the cognitive reserve is not sufficient anymore. Dementia may then lead to progressive autonomy loss. A systematic interdisciplinary approach is needed to prevent frail patients from delirium, and to early cure it to decrease the risk of long-term autonomy loss. PMID- 21821382 TI - [Why a special issue on haemorrhoidal disease?]. PMID- 21821380 TI - Diastolic function predicts survival after renal revascularization. AB - PURPOSE: The purpose of this study was to define the relationship between left ventricular diastolic function and survival after renal revascularization. METHODS: Seventy-six adult patients (49 women, 27 men; mean age: 63 +/- 13 years) with preoperative echocardiography who underwent renal revascularization for atherosclerotic disease were identified. Diastolic function was estimated from the early diastolic transmitral flow velocity (E), the atrial transmitral flow velocity (A), and the mitral annular tissue doppler velocity (e'). Patients were divided into two groups of diastolic dysfunction as either none/mild (E/A <= 0.75, E/e' <10) or moderate/severe (E/A >0.75, E/e' >= 10). Perioperative and follow-up mortality were determined from a prospective vascular database and the National Death Index. Descriptive statistics were calculated and postoperative survival was estimated by product-limit methods. Associations between preoperative factors, perioperative factors, and follow-up survival were examined using proportional hazards regression models. A forward stepwise variable selection procedure was used to select a "best" model to predict follow-up survival. RESULTS: Seventy-six patients were followed for an average of 41.9 months after renal revascularization. Within this group, 47 of 76 patients (61.8%) were identified as having moderate or severe diastolic dysfunction. Diastolic dysfunction had no apparent association with abnormal systolic function. The mean ejection fraction for those with moderate/severe diastolic dysfunction was 57.7% +/- 11.5%. When comparing the moderate/severe and none/mild groupings of diastolic dysfunction, there was a significant difference in left ventricular mass index (151.9 +/- 48.9 vs 125.3 +/- 31.7; P = .0087). There were five deaths in the perioperative period and 20 deaths on follow-up. Among perioperative survivors, hypertension was cured or improved in 82% of the none/mild group and 53% of the moderate/severe group (P = .012). In multivariable analysis, none/mild diastolic dysfunction was significantly and independently associated with an improvement in blood pressure after revascularization (odds ratio [OR], 6.2; 95% confidence interval [CI], 1.4-28.6; P = .018). Ejection fraction was not associated with survival. After forward variable selection, moderate/severe diastolic dysfunction (hazard ratio [HR], 5.8; 95% CI 1.4-25; P = .018) was the only variable to demonstrate a significant and independent association with follow-up survival. CONCLUSION: Diastolic dysfunction, but not systolic dysfunction, was frequent in patients with renovascular disease. Blood pressure response and follow-up survival after renal revascularization demonstrated significant and independent associations with diastolic function. Consideration of diastolic function should be included in the management of patients with atherosclerotic renovascular disease. PMID- 21821384 TI - [Surgical treatment of haemorrhoidal disease]. AB - Haemorrhoidal disease is always benign. Are only operated on patients who are handicapped in their every day life, and for whom more conservative techniques failed or are at great chance for failure. Among numerous surgical procedures, only two have been extensively evaluated: pedicular haemorrhoidectomy, and Longo's procedure. The former is more efficient at long term, but exposes to more painful and prolonged postoperative course. The latter exposes to more recurrences, and its indications are more elective. Patient must be informed of potential risks associated with surgery, because they interfere with therapeutic proposal. PMID- 21821383 TI - [Genital piercings: epidemiology, sociocultural aspects, sexuality and complications]. AB - Body piercing has gained tremendous popularity since the mid nineties. Genital piercings constitute a peculiar variant of piercing due to its sensitive localization. Health care providers are often very little informed about those piercings. Besides, negative stereotypes are often attributed to the bearers of such piercings. This review focuses not only on the medical aspects of genital piercings but also on the social, cultural and psychological background that surround those piercings. PMID- 21821385 TI - [Management of haemorrhoidal disease]. AB - Except for complications, therapeutic strategy for hemorrhoidal disease depends on patient complaint and data from clinical examination. Management is mostly progressive and first aims at releasing symptoms rather than achieving anatomic resilience. In patients with haemorrhoids responsible for insignificant symptoms and with no alteration of quality of life, no treatment is mandatory. Patient complaint, either related to bleeding or prolapse, must prone active management. Medical treatment must be offered as a primary approach in the majority of patients with non-complicated hemorrhoidal disease, followed if necessary by office-based procedure. Surgical treatment is indicated when office-based procedures proved ineffective or immediately after medical treatment failed in patients with Grade IV haemorrhoids. In case of local or general complication, or associated proctologic disease, surgical management is most often required. PMID- 21821386 TI - [Haemorrhoidal disease: from pathophysiology to clinical presentation]. AB - Hemorrhoidal disease is the first cause of proctological consultation although epidemiology is poorly documented. Pathophysiology is complex and involves a fragmentation of supporting tissues as well as vascular changes with hypervascularization and/or impaired venous return. The only complication of external hemorrhoids is thrombosis, which is responsible for acute anal pain irrespective of bowel movements. Internal hemorrhoids most frequently cause prolapse and/or bleeding which is easily recognizable. Physical examination always confirms the diagnosis and a colonoscopy is required after 40 or 45 in order to rule out colorectal cancer. PMID- 21821387 TI - [A brief history of treatment of haemorrhoids: from ancient Egypt to modern times...]. PMID- 21821388 TI - [An osteoma of the maxilla?]. PMID- 21821389 TI - How to write a scientific paper--writing the methods section. PMID- 21821390 TI - Acute limb ischemia in cancer patients: should we surgically intervene? AB - BACKGROUND: Cancer patients have an increased risk of venous thromboembolic events. Certain chemotherapeutic agents have also been associated with the development of thrombosis. Reported cases of acute arterial ischemic episodes in cancer patients are rare. METHODS: Patients who underwent surgery for acute limb ischemia associated with malignancy in a university teaching hospital over a 10 year period were identified. Patient demographics, cancer type, chemotherapy use, site of thromboembolism, treatment and outcome were recorded. RESULTS: Four hundred nineteen patients underwent surgical intervention for acute arterial ischemia, 16 of these patients (3.8%) had associated cancer. Commonest cancer sites were the urogenital tract (n = 5) and the lungs (n = 5). Eight patients (50%) had been recently diagnosed with cancer, and four (25%) of these cancers were incidental findings after presentation with acute limb ischemia. Four patients (25%) developed acute ischemia during chemotherapy. The superficial femoral artery was the most frequent site of occlusion (50%), followed by the brachial (18%) and popliteal (12%) arteries. All patients underwent thromboembolectomy, but two (12%) patients subsequently required a bypass procedure. Six patients (37%) had limb loss, and in-patient mortality was 12%. Histology revealed that all occlusions were due to thromboembolism, with no tumor cells identified. At follow-up, 44% of patients were found to be alive after 1 year. CONCLUSION: Cancer and chemotherapy can predispose patients to acute arterial ischemia. Unlike other reports that view this finding as a preterminal event most appropriately treated by palliative measures, in this series, early diagnosis and surgical intervention enabled limb salvage and patient survival. PMID- 21821391 TI - The screen for social interaction (SSI): a screening measure for autism spectrum disorders in preschoolers. AB - We report on the preliminary validity and utility of the Ghuman-Folstein Screen for Social Interaction (SSI), a measure of social interaction that can serve to screen for autism spectrum disorders (ASDs) in clinical samples of young high risk children. Caregivers of 350 children (176 younger participants, ages 24-42 months, mean age = 34.1 months; and 174 older participants, ages 43 to 61 months, mean age = 52.4 months) with ASDs, non-ASD developmental and/or psychiatric disorders, or without developmental concerns completed the SSI. A series of analyses resulted in shortened versions of the SSI: a 26-item SSI-Younger (SSI-Y) and a 21-item SSI-Older (SSI-O) version. The SSI-Y and SSI-O showed moderate convergence with ASD diagnostic measures and significantly differentiated ASD and non-ASD clinical groups. Sensitivity and specificity values for discriminating ASD and non-ASD clinical participants were 0.87 and 0.71, respectively for the SSI-Y and 0.81 and 0.70, respectively for the SSI-O. Scoring recommendations were made based on the ROC results. PMID- 21821392 TI - Effect of upper limb deformities on gross motor and upper limb functions in children with spastic cerebral palsy. AB - The aims of this study were to investigate the nature and extent of upper limb deformities via the use of various classifications, and to analyze the relationship between upper limb deformities and gross motor or upper limb functionality levels. Upper extremity data were collected from 234 children with spastic cerebral palsy (CP) who were admitted to the university hospital for intensive rehabilitation. Upper limb deformities were classified according to the Zancolli classification for finger and wrist extension ability, the Gshwind and Tonkin classification for supination ability, and the House classification for thumb-in-palm deformity. Digital deformity was also classified. Upper limb function was assessed using the Upper Extremity Rating Scale (UERS) and the Upper Limb Physician's Rating Scale (ULPRS). Gross motor function was assessed using the Gross Motor Functional Classification System (GMFCS). Among the 234 children observed, 70.5% had a limitation in forearm supination, and 62.8% had problems with wrist and finger extension in at least one limb. Thumb-in-palm deformity of at least one hand was found in 47.0% of patients. Swan neck deformity was the most common finger deformity. Upper limb functional measures, the ULPRS and the UERS, significantly correlated with the degree of upper limb deformity, as assessed by the Gschwind and Tonkin, Zancolli, and House classifications. Further, the degree of upper limb deformity was significantly related to the GMFCS level in children with bilateral CP, but not in children with unilateral CP. Limitation of forearm supination was the most common upper limb deformity in children with spastic CP. The degree of upper limb deformity significantly affected upper limb function in these children. PMID- 21821393 TI - Correspondence between traditional models of functional analysis and a functional analysis of manding behavior. AB - Functional analysis procedures have been effectively used to determine the maintaining variables for challenging behavior and subsequently develop effective interventions. However, fear of evoking dangerous topographies of maladaptive behavior and concerns for reinforcing infrequent maladaptive behavior present challenges for people working in applied settings. The present investigation sought to evaluate the utility of an adjunctive functional analysis model that involved the reinforcement of mands rather than problem behavior and compared the results to traditional functional analyses. The results from the manding analysis yielded results similar to the traditional FA in 3 of 4 cases. These findings suggest that manding analyses may represent a useful assessment tool for difficult to assess problem behavior or for individuals in settings where consultative support is limited. PMID- 21821394 TI - An efficient method for nonnegatively constrained Total Variation-based denoising of medical images corrupted by Poisson noise. AB - Medical images obtained with emission processes are corrupted by noise of Poisson type. In the paper the denoising problem is modeled in a Bayesian statistical setting by a nonnegatively constrained minimization problem, where the objective function is constituted by a data fitting term, the Kullback-Leibler divergence, plus a regularization term, the Total Variation function, weighted by a regularization parameter. Aim of the paper is to propose an efficient numerical method for the solution of the constrained problem. The method is a Newton projection method, where the inner system is solved by the Conjugate Gradient method, preconditioned and implemented in an efficient way for this specific application. The numerical results on simulated and real medical images prove the effectiveness of the method, both for the accuracy and the computational cost. PMID- 21821395 TI - Metaphor interpretation and use: a window into semantics in schizophrenia. AB - The nature of putative semantic anomalies in schizophrenia is controversial. Metaphor interpretation and use provide a useful methodology with which to probe semantics since metaphors are critical in reasoning processes and in how conceptual knowledge is organized. The first study examined free speech for figurative language. The second study explored whether emotional versus non emotional metaphorical language interpretation elicits differences in the tendencies to produce idiosyncratic (bizarre) or literal interpretations or use of other metaphors to describe the meaning of a metaphor. The third study examined the interpretation of time metaphors. We expected the time perspective in ambiguous sentences to be differentially influenced by previously presented unambiguous sentences of a specific perspective, either events moving relative to a stationary observer (moving-time) or an observer moving relative to a stationary event (moving-ego). First, we found that patients used a similar amount of figurative language as control participants. Second, we did not find any difference between the groups in terms of idiosyncratic interpretations, although patients did interpret more metaphors literally and controls utilized more figurative language. Third, we did not find evidence of a difference between the groups in terms of time perspectives influencing ambiguous target sentences differentially. As operationalized here, the interpretation and use of metaphors is similar in patients with schizophrenia to that of healthy control participants. To the extent that metaphors recruit semantic processes this area of cognition is generally intact in schizophrenia. PMID- 21821396 TI - Characteristics of homicide offenders with Schizophrenia from the Russian Federation. AB - BACKGROUND: It has been suggested that the characteristics of homicides committed by people with schizophrenia from regions with a high total homicide rate differ from the characteristics of homicides by people with schizophrenia from regions with low rates of homicide. METHODS: Homicide offenders in the Chuvash Republic of the Russian Federation have been systematically examined for over 30 years. This study reports on a review of the documents from pre-trial psychiatric assessments and legal proceedings of all people charged with homicide offenses between 1981 and 2010 who were found to have schizophrenia. FINDINGS: There were 133 people (120 men, 13 women) with an ICD-10 diagnosis of schizophrenia who committed a homicide offense in the 30 years of the study, including 15 repeat homicide offenders and 9 homicides with multiple victims. The odds ratio (OR) for homicide associated with schizophrenia was 13.5, 95% confidence interval (CI) (11.4-16.0). The mean age of the offenders was 34.8 (SD 9.6) and most had the paranoid subtype of schizophrenia (78%). The majority of victims were family members (51%) or acquaintances (43%). Delusions of persecution, auditory hallucinations and other positive symptoms were present in 58% of offenders at the time of the homicide. The remaining 42% exhibited negative symptoms such as emotional deficits, had antisocial attitudes or were regarded as having impaired self-control. Alcohol intoxication was reported at the time of 45% of homicides. Stabbing was the most common method and few of the homicides involved firearms. CONCLUSION: The characteristics of homicide offenders with schizophrenia from Chuvashia do not appear to differ greatly from those of homicide offenders with schizophrenia from regions with far lower rates of homicide. PMID- 21821397 TI - Molecular characterisation of multidrug-resistant Salmonella enterica serotype Infantis from humans, animals and the environment in Italy. AB - During 2005-2006, Salmonella enterica serotype Infantis strains isolated from human and non-human sources and resistant to ampicillin (A), chloramphenicol (C), streptomycin (S), sulphonamide (Su), tetracycline (T), kanamycin (K) and trimethoprim/sulfamethoxazole (Sxt) emerged in Italy. The aim of this study was to analyse the molecular basis of antibiotic resistance and to evaluate the clonal origin of multiresistant S. Infantis strains isolated from different sources. Seventy S. Infantis strains, susceptible or resistant to antimicrobial drugs, were chosen for this study. Polymerase chain reaction (PCR) and conjugation experiments were performed to identify and localise the resistance genes in multidrug-resistant strains. PCR-based replicon typing was carried out for characterisation of conjugative plasmids. All strains were tested by pulsed field gel electrophoresis (PFGE) according to the PulseNet protocol, and cluster analysis was performed using BioNumerics software. Strains with resistance (R) type ACSSuTKSxt harboured bla(TEM-1), strA-B, sul2, tet(B), catA1 and aphA-1 resistance genes as well as a 2.2-kb class 1 integron containing folA, catB3, aadA4 and sul1 gene cassettes. A unique plasmid, belonging to the HI1 incompatibility group, harboured all the resistance genes. Cluster analysis showed that all ACSSuTKSxt-resistant strains belonged to a large cluster (A) with >90% genetic similarity. The presence of a plasmid harbouring all the resistance gene cassettes as well as molecular typing by PFGE demonstrated the circulation of a cluster of S. Infantis R-type ACSSuTKSxt during 2005-2006 in Italy. The presence of a plasmid conferring multidrug resistance could have facilitated the spread of a group of similar isolates through a variety of sources. PMID- 21821398 TI - Small-molecular virulence inhibitors show divergent and immunomodulatory effects in infection models of Salmonella enterica serovar Typhimurium. AB - The virulence-associated Salmonella pathogenicity island 2 (SPI2) type III secretion system supports intracellular replication of Salmonella enterica serovar Typhimurium in macrophage-like RAW264.7 cells. In contrast, the salicylidene acylhydrazide INP0010 and the benzimidazole omeprazole prevent virulence factor-mediated replication of S. Typhimurium in these cells. Here we show that INP0010 enhances expression of inducible nitric oxide synthase (iNOS), nitric oxide (NO) production, the oxidative burst and tumour necrosis factor alpha (TNFalpha) release in infected RAW264.7 cells. INP0010 also inhibited SPI2 activity in RAW264.7 cells. The ability of INP0010 to suppress bacterial intracellular replication correlated with NO production. The iNOS inhibitor N monomethyl-l-arginine restored SPI2 activity and antagonised the bacteriostatic effect of INP0010. Omeprazole, which inhibited iNOS expression in RAW264.7 cells, likewise antagonised INP0010. In infected epithelioid MDCK cells that did not express NO upon infection, INP0010 enhanced bacterial intracellular replication. In Caenorhabditis elegans, INP0010 significantly attenuated the virulence of S. Typhimurium. In this infection model, the attenuating effect of INP0010 was further enhanced by omeprazole. These results demonstrate that chemically unrelated virulence inhibitors may act in an antagonistic or additive manner, that their effect depends on the infection model applied, and that the attenuating effects of INP0010 in part relate to its ability to promote the SPI2 antagonist NO. PMID- 21821399 TI - Antimicrobial polyethyleneimine-silver nanoparticles in a stable colloidal dispersion. AB - Excellent colloidal stability and antimicrobial activity are important parameters for silver nanoparticles (AgNPs) in a range of biomedical applications. In this study, polyethyleneimine (PEI)-capped silver nanoparticles (PEI-AgNPs) were synthesized in the presence of sodium borohydride (NaBH(4)) and PEI at room temperature. The PEI-AgNPs had a positive zeta potential of approximately +49 mV, and formed a stable nanocolloid against agglomeration due to electrostatic repulsion. The particle size and hydrodynamic cluster size showed significant correlations with the amount of PEI and NaBH(4). PEI-AgNPs and even PEI showed excellent antimicrobial activity against Staphylococus aureus and Klebsiella pneumoniae. The cytotoxic effects of PEI and PEI-AgNPs were confirmed by an evaluation of the cell viability. The results suggest that the amount of PEI should be minimized to the level that maintains the stability of PEI-AgNPs in a colloidal dispersion. PMID- 21821400 TI - Design and characterization of bi-soft segmented polyurethane microparticles for biomedical application. AB - Bi-soft segmented poly(ester urethane urea) microparticles were prepared and characterized aiming a biomedical application. Two different formulations were developed, using poly(propylene glycol), tolylene 2,4-diisocyanate terminated pre polymer (TDI) and poly(propylene oxide)-based tri-isocyanated terminated pre polymer (TI). A second soft segment was included due to poly(E-caprolactone) diol (PCL). Infrared spectroscopy, used to study the polymeric structure, namely its H bonding properties, revealed a slightly higher degree of phase separation in TDI microparticles. TI-microparticles presented slower rate of hydrolytic degradation, and, accordingly, fairly low toxic effect against macrophages. These new formulations are good candidates as non-biodegradable biomedical systems. PMID- 21821401 TI - Support vector methods for survival analysis: a comparison between ranking and regression approaches. AB - OBJECTIVE: To compare and evaluate ranking, regression and combined machine learning approaches for the analysis of survival data. METHODS: The literature describes two approaches based on support vector machines to deal with censored observations. In the first approach the key idea is to rephrase the task as a ranking problem via the concordance index, a problem which can be solved efficiently in a context of structural risk minimization and convex optimization techniques. In a second approach, one uses a regression approach, dealing with censoring by means of inequality constraints. The goal of this paper is then twofold: (i) introducing a new model combining the ranking and regression strategy, which retains the link with existing survival models such as the proportional hazards model via transformation models; and (ii) comparison of the three techniques on 6 clinical and 3 high-dimensional datasets and discussing the relevance of these techniques over classical approaches fur survival data. RESULTS: We compare svm-based survival models based on ranking constraints, based on regression constraints and models based on both ranking and regression constraints. The performance of the models is compared by means of three different measures: (i) the concordance index, measuring the model's discriminating ability; (ii) the logrank test statistic, indicating whether patients with a prognostic index lower than the median prognostic index have a significant different survival than patients with a prognostic index higher than the median; and (iii) the hazard ratio after normalization to restrict the prognostic index between 0 and 1. Our results indicate a significantly better performance for models including regression constraints above models only based on ranking constraints. CONCLUSIONS: This work gives empirical evidence that svm based models using regression constraints perform significantly better than svm based models based on ranking constraints. Our experiments show a comparable performance for methods including only regression or both regression and ranking constraints on clinical data. On high dimensional data, the former model performs better. However, this approach does not have a theoretical link with standard statistical models for survival data. This link can be made by means of transformation models when ranking constraints are included. PMID- 21821402 TI - New developments in ESCOP. PMID- 21821403 TI - Rebuttal to comment from Demonty et al. (2011). PMID- 21821404 TI - Brain natriuretic peptide measurement in pulmonary medicine. AB - Serum levels of natriuretic peptides are well established as important biomarkers in patients with cardiac disease. Less attention has been placed on the role of natriuretic peptides in patients with pulmonary conditions. In several well defined groups of patients with pulmonary disease natriuretic peptides provide the clinician with clinically valuable information. A limitation of the interpretation of natriuretic peptides in pulmonary disease is the confounding effect of concurrent conditions such as heart failure, hypoxia, sepsis and renal failure. The present paper reviews the role of natriuretic peptides for diagnosis, risk stratification and prognosis of several pulmonary disorders. PMID- 21821405 TI - Low CURB-65 is of limited value in deciding discharge of patients with community acquired pneumonia. AB - BACKGROUND: The relationship between clinical judgment and indications of the CURB-65 score in deciding the site-of-care for patients with community-acquired pneumonia (CAP) has not been fully investigated. The aim of this study was to evaluate reasons for hospitalization of CAP patients with CURB-65 score of 0 and 1. METHODS: An observational, retrospective study of consecutive CAP patients was performed at the Fondazione Ca Granda, Milan, Italy, between January 2005 and December 2006. The medical records of hospitalized patients with CAP having a CURB-65 score of 0 and 1 were identified and reviewed to determine whether there existed a clinical basis to justify hospitalization. RESULTS: Among the 580 patients included in the study, 218 were classified with a CURB-65 score of 0 or 1. Among those, 127 were hospitalized, and reasons that justified hospitalization were found in 104 (83%) patients. Main reasons for hospitalization included the presence of hypoxemia on admission (35%), failure of outpatient therapy (14%) and the presence of cardiovascular events on admission (9.7%). Used as the sole indicator for inappropriate hospitalization, the CURB-65 score had a poor positive predictive value of 52%. CONCLUSIONS: Although the CURB-65 has been proposed as a tool to guide the site of care decision by international guidelines, this score is not ideal by itself, and should not be regarded as providing decision support information if a score of 0 and 1 is present. In CAP patients with CURB-65 scores of 0 or 1, further evaluations should be performed and completed by clinical judgment. PMID- 21821406 TI - Waste collection multi objective model with real time traceability data. AB - Waste collection is a highly visible municipal service that involves large expenditures and difficult operational problems, plus it is expensive to operate in terms of investment costs (i.e. vehicles fleet), operational costs (i.e. fuel, maintenances) and environmental costs (i.e. emissions, noise and traffic congestions). Modern traceability devices, like volumetric sensors, identification RFID (Radio Frequency Identification) systems, GPRS (General Packet Radio Service) and GPS (Global Positioning System) technology, permit to obtain data in real time, which is fundamental to implement an efficient and innovative waste collection routing model. The basic idea is that knowing the real time data of each vehicle and the real time replenishment level at each bin makes it possible to decide, in function of the waste generation pattern, what bin should be emptied and what should not, optimizing different aspects like the total covered distance, the necessary number of vehicles and the environmental impact. This paper describes a framework about the traceability technology available in the optimization of solid waste collection, and introduces an innovative vehicle routing model integrated with the real time traceability data, starting the application in an Italian city of about 100,000 inhabitants. The model is tested and validated using simulation and an economical feasibility study is reported at the end of the paper. PMID- 21821407 TI - Select chemical and engineering properties of wastewater biosolids. AB - The select chemical and engineering characteristics of biosolids produced at a wastewater treatment plant in Eastern Australia were investigated to assess its suitability as structural fill material in road embankments. Results of comprehensive set of geotechnical experimentation including compaction, consolidation, creep, hydraulic conductivity and shear strength tests implied that biosolids demonstrate behavior similar to highly organic clays with a higher potential for consolidation and settlement. Results of chemical study including heavy metals, dichloro diphenyl trichloroethane (and derivatives) and organochlorine pesticides, indicate that biosolids samples are within the acceptable limits which allows their usage under certain guidelines. Results of tests on pathogens (bacteria, viruses or parasites) also indicated that biosolids were within the safe acceptable limits. Technical and management suggestions have been provided to minimize the possible environmental risks of using biosolids in road embankment fills. PMID- 21821408 TI - Ultrasensitive electrochemical detection of Bacillus thuringiensis transgenic sequence based on in situ Ag nanoparticles aggregates induced by biotin streptavidin system. AB - A novel electrochemical biosensor was developed for detecting short DNA oligonucleotide of Bacillus thuringiensis (Bt) transgenic sequence based on Ag nanoparticle aggregates. To fabricate this DNA biosensor, the thiol-modified capture DNA (cDNA) was first anchored on gold (Au) electrode, and then the target DNA (tDNA) was hybridized with the immobilized cDNA. Subsequently, the probe DNA (pDNA) functionalized by biotinylated Ag nanoparticle was associated with the fixed tDNA, and the single Ag nanoparticle label was obtained (cited as SAg label). Finally, dissociative biotinylated Ag nanoparticle was bound to the resultant biotinylated SAg label assembled on Au electrode by virtue of bridge molecule streptavidin (SA) through biotin-SA specific interaction, which could lead to in situ aggregate of Ag nanoparticles on Au electrode and induce a novel tag including multiple Ag nanoparticles (cited as MAg tag). The novel tag exhibited excellent electroactive property in the solid-state Ag/AgCl process and was successfully applied to Bt transgenic sequence assay. A detection limit of 10 fM was achieved, which was improved by three orders of magnitude as compared to the SAg label. Furthermore, this novel DNA biosensor demonstrated a good selectivity towards tDNA. PMID- 21821409 TI - A transformer of molecular beacon for sensitive and real-time detection of phosphatases with effective inhibition of the false positive signals. AB - Molecular beacons (MBs) have shown great potential in measurement of enzyme activities. However, currently available methods for monitoring of phosphatases only use MBs as a signal reporter. Extra substrates for the phosphatases are needed to hybridize to the MB either as a primer or as a template. Moreover, few MB-based methods have been used to detect enzyme activities in real biological samples due to insufficient sensitivity or false positive interference signals caused by nonspecific nucleases. In this work, a novel type of fluorescent probe was designed and synthesized for monitoring of phosphatases by integrating the DNA substrate and the signaling structures into a single molecule. Such a new design not only significantly simplified the probing system and greatly enhanced the sensitivity, but also offered a practical way to guard against the false positive signal problems in the application to real samples. The unique design of the assay format should be widely applicable to many other enzymatic assays using oligonucleotide fluorescent probes. PMID- 21821410 TI - Biomaterials meet microfluidics: building the next generation of artificial niches. AB - Biomaterials are increasingly being developed as in vitro microenvironments mimicking in vivo stem cell niches. However, current macroscale methodologies to produce these niche models fail to recapitulate the spatial and temporal characteristics of the complex native stem cell regulatory systems. Microfluidic technology offers unprecedented control over the spatial and temporal display of biological signals and therefore promises new avenues for stem cell niche engineering. Here we discuss how the two approaches can be combined to generate more physiological models of stem cell niches that could facilitate the identification of new mechanisms of stem cell regulation, profoundly impacting drug discovery and ultimately therapeutic applications of stem cells. PMID- 21821411 TI - Trigger features and excitation in the retina. AB - This review focuses on recent advances in our understanding of how neural divergence and convergence give rise to complex encoding properties of retinal ganglion cells. We describe the apparent mismatch between the number of cone bipolar cell types, and the diversity of excitatory input to retinal ganglion cells, and outline two possible solutions. One proposal is for diversity in the excitatory pathways to be generated within axon terminals of cone bipolar cells, and the second invokes narrow-field glycinergic amacrine cells that can apparently act like bipolar cells by providing excitatory drive to ganglion cells. Finally we highlight two advances in technique that promise to provide future insights; automation of electron microscope data collection and analysis, and the use of the ideal observer to quantitatively compare neural performance at all levels. PMID- 21821412 TI - Continuous flowing membraneless microbial fuel cells with separated electrode chambers. AB - Microbial fuel cell (MFC) is an emerging technology in the energy and environment field. Its application is limited due to its high cost caused by the utilization of membranes and noble metal catalysts. In this paper, a membraneless MFC, with separated electrode chambers, was designed. The two separated chambers are connected via a channel and the continuous electrolyte flow from anode to cathode drives proton transfer. The proton mass transfer coefficiency in this MFC is 0.9086 cm/s, which is higher than reported MFCs with membranes, such as J-cloth and glass fiber. The maximum output voltage is 160.7 mV, with 1000 Omega resistor. Its peak power density is 24.33 mW/m3. SCOD removal efficiency can reach 90.45% via this MFC. If the connection between the two electrode chambers is blocked, the performance of MFC will decrease severely. All the above results prove the feasibility and advantages of this special MFC model. PMID- 21821413 TI - Synthesis of rhodamine B-benzenesulfonamide conjugates and their inhibitory activity against human alpha- and bacterial/fungal beta-carbonic anhydrases. AB - A series of fluorescent sulfonamide carbonic anhydrase (CA, EC 4.2.1.1) inhibitors were obtained by attaching rhodamine B moieties to the scaffold of benzenesulfonamides. The new compounds have been investigated for the inhibition of 12 human alpha-CA isoforms (hCA I-hCA XIV), three bacterial and one fungal beta-class enzymes from the pathogens Mycobacterium tuberculosis and Candida albicans. All types of inhibitory activities have been detected, with several compounds showing low nanomolar inhibition against the transmembrane isoforms hCA IX, XII (cancer-associated) and XIV. The beta-CAs were inhibited in the micromolar range by these compounds which may have applications for the imaging of hypoxic tumors or bacteria due to their fluorescent moieties. PMID- 21821414 TI - Synthesis and antioxygenic activities of seabuckthorn flavone-3-ols and analogs. AB - A practical synthesis of polyhydroxy- and regiospecifically methylated flavone-3 ols which are components of commercial 'seabuckthorn flavone' has been achieved by modified Algar-Flynn-Oyamada method. Antioxidant activities of seabuckthorn extracts, isolated products and a number of flavone-3-ols have been determined. Structure-activity relationships have been discussed. Amongst the compounds tested, gallic acid, which is also present in seabuckthorn, was found to be the most effective antioxidant and radioprotectant. PMID- 21821415 TI - The impact of fatty acids on the antibacterial properties of N-thiolated beta lactams. AB - Bacterial fatty acid synthesis (FAS) is a potentially important, albeit controversial, target for antimicrobial therapy. Recent studies have suggested that the addition of exogenous fatty acids (FAs) to growth media can circumvent the effects of FAS-targeting compounds on bacterial growth. Consequently, such agents may have limited in vivo applicability for the treatment of human disease, as free FAs are abundant within the body. Our group has previously developed N thiolated beta-lactams and found they function by interfering with FAS in select pathogenic bacteria, including MRSA. To determine if the FAS targeting activity of N-thiolated beta-lactams can be abrogated by exogenous fatty acids, we performed MIC determinations for MRSA strains cultured with the fatty acids oleic acid and Tween 80. We find that, whilst the activity of the known FAS inhibitor triclosan is severely compromised by the addition of both oleic acid and Tween 80, exogenous FAs do not mitigate the antibacterial activity of N-thiolated beta lactams towards MRSA. Consequently, we propose that N-thiolated beta-lactams are unique amongst FAS-inhibiting antimicrobials, as their effects are unimpeded by exogenous FAs. PMID- 21821416 TI - Inhibition of the helicase activity of the HCV NS3 protein by symmetrical dimeric bis-benzimidazoles. AB - Dimeric bis-benzimidazoles (DBn) are the compounds specifically binding to A-T enriched sequences in the DNA minor groove. Due to this property they can inhibit DNA-dependent enzymes. We show that inhibition of the helicase activity of HCV NS3 protein by DBn was due to a novel mechanism, which involved direct binding of the ligands to the enzyme. The binding potency and inhibition efficacy depended on the length of the linker between the benzimidazole fragments. The most effective inhibitor DB11 partially prevented activation of NTPase activity of NS3 by poly(U) and increased affinity of the enzyme to the helicase substrate DNA. PMID- 21821417 TI - A novel indium-111-labeled gonadotropin-releasing hormone peptide for human prostate cancer imaging. AB - The purpose of this study was to evaluate the tumor targeting and imaging properties of a novel (111)In-labeled gonadotropin-releasing hormone (GnRH) peptide {1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-Ahx-(D Lys(6)-GnRH1)} for human prostate cancer. The biodistribution and tumor imaging properties of (111)In-DOTA-Ahx-(D-Lys(6)-GnRH1) were determined in DU145 human prostate cancer-xenografted nude mice. (111)In-DOTA-Ahx-(d-Lys(6)-GnRH1) exhibited rapid tumor uptake (1.27 +/- 0.40% ID/g at 0.5h post-injection) coupled with fast whole-body clearance through the urinary system. The DU145 human prostate cancer-xenografted tumor lesions were clearly visualized by single photon emission computed tomography (SPECT)/CT at 0.5h post-injection of (111)In DOTA-Ahx-(D-Lys(6)-GnRH1). The successful imaging of DU145 human prostate cancer xenografted tumor lesions using (111)In-DOTA-Ahx-(d-Lys(6)-GnRH1) highlighted its potential as a novel imaging probe for human prostate cancer imaging. PMID- 21821418 TI - Visualizing changes in lower body coordination with different types of foot orthoses using self-organizing maps (SOM). AB - Human movement involves the coordination of individual segments controlled by the central nervous system and powered by the muscles. However, visualization of this high-dimensional coordination between kinematic and kinetic parameters is challenging. The purposes of this study were (a) to identify differences in lower extremity coordination between different types of foot orthoses using Kohonen self-organizing maps (SOM) and (b) to demonstrate the SOM visualization of high dimensional coordination in gait. This study used gait data for twenty subjects while running in four different orthotic conditions (control, posted, molded, and posted-molded) from a previous study. Data for one exemplar participant was used to demonstrate the visualization technique. In this visualization, areas on an output map represent certain characteristics of the gait cycle. By comparing trials of gait in different orthotic conditions a visual analysis of high dimensional coordination is possible. Posting orthoses were shown to reduce and molded orthoses were shown to increase ankle mobility, respectively. However, when posting and molding were combined, the effects of the molded orthoses over rode those of the posted orthoses. In fact, trials using posted-molded orthoses enhanced the effects of molded orthoses. SOMs may contribute to a better understanding of changes in the coordination of kinematic and kinetic variables at certain phases of the gait cycle under different conditions. PMID- 21821419 TI - Symptomatic calcification of the anterior cruciate ligament: A case report. AB - We report a rare case of symptomatic calcification of the ACL. A 31-year-old man complained of severe knee pain with restriction of knee motion from 30 degrees to 130 degrees for a week. Plain radiographs and multi-planar CT revealed calcification within the intercondylar notch with no osteoarthritic changes. MRI revealed a low signal intensity mass near the intact ACL. The ACL appeared bulged by arthroscopy and white and creamy fluid exuded from the partially excised synovial membrane. Pain subsided immediately postoperatively. Histologically, the calcific deposit near the ACL showed negligible degenerative changes and resembled calcifying tendinitis of the rotator cuff. Although calcific deposits rarely affect the knee joint, calcification of the ACL should be included in differential diagnoses for acute knee pain and restricted range of motion such as mechanical locking. This case illustrates that arthroscopic removal of the deposits can be effective. PMID- 21821420 TI - Synthesis and in vivo evaluation of [O-methyl-11C] N-[3,5-dichloro-2 (methoxy)phenyl]-4-(methoxy)-3-(1-piperazinyl)benzenesulfonamide as an imaging probe for 5-HT6 receptors. AB - The serotonin receptor 6 (5-HT(6)) is implicated in the pathophysiology of cognitive diseases, schizophrenia, anxiety and obesity and in vivo studies of this receptor would be of value for studying the pathophysiology of these disorders. Therefore, N-[3,5-dichloro-2-(methoxy)phenyl]-4-(methoxy)-3-(1 piperazinyl)benzenesulfonamide (SB399885), a selective and high affinity (pK(i)=9.11) 5-HT(6) antagonist, has been radiolabeled with carbon-11 by O methylation of the corresponding desmethyl analogue with [(11)C]MeOTf in order to determine the suitability of [(11)C]SB399885 to quantify 5-HT(6)R in living brain using PET. Desmethyl-SB399885 was prepared, starting from 1-(2-methoxyphenyl) piperazine hydrochloride, in excellent yield. The yield obtained for radiolabeling of [(11)C]SB399885 was 30+/-5% (EOS) and the total synthesis time was 30min at EOB. PET studies with [(11)C]SB399885 in baboon showed fast uptake followed by rapid clearance in the brain. Highest uptake of radioactivity of [(11)C]SB399885 in baboon brain were found in temporal cortex, parahippocampal gyrus, pareital cortex, amygdala, and hippocampus. Poor brain entry and inconsistent brain uptake of [(11)C]SB399885 compared to known 5-HT(6)R distribution limits its usefulness for the in vivo quantification of 5-HT(6)R with PET. PMID- 21821421 TI - Halogen-substituted (C-beta-D-glucopyranosyl)-hydroquinone regioisomers: synthesis, enzymatic evaluation and their binding to glycogen phosphorylase. AB - Electrophilic halogenation of C-(2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl) 1,4-dimethoxybenzene (1) afforded regioselectively products halogenated at the para position to the D-glucosyl moiety (8, 9) that were deacetylated to 3 (chloride) and 16 (bromide). For preparing meta regioisomers, 1 was efficiently oxidized with CAN to afford C-(2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl) 1,4 benzoquinone 2 which, in either MeOH or H(2)O-THF containing few equivalents of AcCl, added hydrochloric acid to produce predominantly meta (with respect to the sugar moiety) chlorinated hydroquinone derivatives 5 and 18, this latter being deacetylated to 4. The deacetylated meta (4, 5) or para (3, 16) halohydroquinones were evaluated as inhibitors of glycogen phosphorylase (GP, a molecular target for inhibition of hepatic glycogenolysis under high glucose concentrations) by kinetics and X-ray crystallography. These compounds are competitive inhibitors of GPb with respect to alpha-D-glucose-1-phosphate. The measured IC(50) values (MUM) [169.9+/-10.0 (3), 95 (4), 39.8+/-0.3 (5) 136.4+/-4.9 (16)] showed that the meta halogenated inhibitors (4, 5) are more potent than their para analogs (3, 16). The crystal structures of GPb in complex with these compounds at high resolution (1.97-2.05 A) revealed that the inhibitors are accommodated at the catalytic site and stabilize the T conformation of the enzyme. The differences in their inhibitory potency can be interpreted in terms of variations in the interactions with protein residues of the different substituents on the aromatic part of the inhibitors. PMID- 21821422 TI - Microscopic characterization of peptide nanostructures. AB - Peptide-based nanomaterials have been utilized for various applications from regenerative medicine to electronics since they provide several advantages including easy synthesis methods, numerous routes for functionalization and biomimicry of secondary structures of proteins which leads to design of self assembling peptide molecules to form nanostructures. Microscopic characterization at nanoscale is critical to understand processes directing peptide molecules to self-assemble and identify structure-function relationship of the nanostructures. Here, fundamental studies in microscopic characterization of peptide nanostructures are discussed to provide insights in widely used microscopy tools. In this review, we will encompass characterization studies of peptide nanostructures with modern microscopes, such as TEM, SEM, AFM, and advanced optical microscopy techniques. We will also mention specimen preparation methods and describe interpretation of the images. PMID- 21821423 TI - Production of the phytoalexins trans-resveratrol and delta-viniferin in two economy-relevant grape cultivars upon infection with Botrytis cinerea in field conditions. AB - Leaves, shoots and flowers from two different economy-relevant grape cultivars, Merlot and Cabernet Sauvignon, were examined to assess the distribution of phytoalexins upon inoculation with Botrytis cinerea at pre-bloom, bloom, and post bloom stages. Mass spectrometric analysis evidenced considerable levels of trans resveratrol (3,5,4'-trihydroxystilbene), albeit higher in Cabernet Sauvignon, in leaves from both grape cultivars following fungal infection at all the examined stages of development. Although both these cultivars are reported to be sensitive against fungal infections, in Cabernet Sauvignon leaves and flowers, we were also able to measure relevant quantities of the resveratrol dehydrodimer delta viniferin. While infection by B. cinerea occurs at bloom stage, high-sensitivity of the HPLC-mass spectrometric analytic method allowed detecting measurable levels of viniferins even in early pre-bloom stages in Cabernet Sauvignon flowers and to evidence even slight resveratrol differences between the cultivars. Concordingly, Cabernet Sauvignon better responded to fungal infection. This analysis allowed us to conclude that, even when analyzing fungal infection sensitive cultivars, the HPLC-MS method holds the sensitivity to highlight the slightest differences in the concentrations of the two phytoalexins and correlate them to different anti-fungal response potential. PMID- 21821424 TI - Enzyme kinetics, inhibitors, mutagenesis and electron paramagnetic resonance analysis of dual-affinity nitrate reductase in unicellular N(2)-fixing cyanobacterium Cyanothece sp. PCC 8801. AB - The assimilatory nitrate reductase (NarB) of N(2)-fixing cyanobacterium Cyanothece sp. PCC 8801 is a monomeric enzyme with dual affinity for substrate nitrate. We purified the recombinant NarB of Cyanothece sp. PCC 8801 and further investigated it by enzyme kinetics analysis, site-directed mutagenesis, inhibitor kinetics analysis, and electron paramagnetic resonance (EPR) spectroscopy. The NarB showed 2 kinetic regimes at pH 10.5 or 8 and electron-donor conditions methyl viologen or ferredoxin (Fd). Fd-dependent NR assay revealed NarB with very high affinity for nitrate (K(m)1, ~1MUM; K(m)2, ~270MUM). Metal analysis and EPR results showed that NarB contains a Mo cofactor and a [4Fe-4S] cluster. In addition, the R352A mutation on the proposed nitrate-binding site of NarB greatly altered both high- and low-affinity kinetic components. Furthermore, the effect of azide on the NarB of Cyanothece sp. PCC 8801 was more complex than that on the NarB of Synechococcus sp. PCC 7942 with its single kinetic regime. With 1mM azide, the kinetics of the wild-type NarB was transformed from 2 kinetic regimes to hyperbolic kinetics, and its activity was enhanced significantly under medium nitrate concentrations. Moreover, EPR results also suggested a structural difference between the two NarBs. Taken together, our results show that the NarB of Cyanothece sp. PCC 8801 contains only a single Mo-catalytic center, and we rule out that the enzyme has 2 independent, distinct catalytic sites. In addition, the NarB of Cyanothece sp. PCC 8801 may have a regulatory nitrate binding site. PMID- 21821426 TI - Characterization of the sulfurtransferase family from Oryza sativa L. AB - Sulfurtransferases (Str) comprise a group of enzymes widely distributed in archaea, eubacteria, and eukaryota which catalyze the transfer of a sulfur atom from suitable sulfur donors to nucleophilic sulfur acceptors. Neither the in vivo sulfur donors nor the acceptors of Str could be clearly identified in any of the organisms investigated so far. In Oryza sativa L. 24 Str (OsStr) encoding genes have been identified and subdivided into six groups according to their sequence homology. To half of the Oryza Str a direct homolog and to 40% at least a similar protein in Arabidopsis thaliana (L.) Heynh. could be allocated. Only the group comprising two-domain Str contains more Oryza Str than Arabidopsis Str. According to EST abundance analysis most of the OsStr mRNAs accumulate in several plant tissues. OsStr22, the homolog to the best characterized Str1 from Arabidopsis (AtStr1), shows the highest expression in middle-aged plants whereas AtStr1 shows the highest expression in senescent plants. Heterologously expressed and purified OsStr22 shows very low enzyme activity in comparison to the Arabidopsis and the Brassica napus L. Str. The data obtained so far constitute the basis to analyze differences among the Str family from monocotyledonous and dicotyledonous plants. PMID- 21821425 TI - Antioxidant response of tobacco (Nicotiana tabacum) hairy roots after phenol treatment. AB - Phenol is released to the environment from a wide variety of industrial effluents and it causes severe problems to human health and ecosystem. In the present study, we determined that Nicotiana tabacum hairy roots (HRs) double transgenic (DT) for two peroxidase genes (tpx1 and tpx2) showed higher phenol removal efficiency than wild type (WT) HRs after 120 h of phenol treatment at the expense of endogenous H(2)O(2). Besides, to determine whether phenol could induce oxidative stress on tobacco HRs, we analyzed the antioxidant response, superoxide anion (O(2)(-)) localization and malondialdehyde (MDA) levels. Both HRs treated with phenol, showed significant increases in peroxidase (PX) activity mainly at the end of the assay (120 h) being PX activity from transgenic HRs 40% higher than that of WT HRs. Superoxide dismutase (SOD) and ascorbate peroxidase (APX) activities showed significant increases from 24 to 120 h of phenol treatment. PX, SOD and APX isoforms were also analyzed and slight changes were observed only in PX patterns. Both HRs showed significant differences in total glutathione (TGSH) content during treatment, being higher in DT HRs than in WT HRs. At the end of the assay, a greater accumulation of O(2)(-) in different root zones was observed in WT and DT HRs. Moreover, phenol was able to increase the MDA levels in WT HRs from 48 to 120 h of the treatment, but no significant changes were observed in DT HRs. Results suggest that under these experimental conditions, DT HRs would be more tolerant to phenol than WT HRs. PMID- 21821427 TI - Open loop fascial sling for severe congenital blepharoptosis. AB - PURPOSE: Severe congenital eyelid ptosis present as a functional and aesthetic problem. The choices of procedures depend mainly on providing an additional elevator force to the upper lid to elevate it, and maintain a reasonable eye opening and vision. We describe a simple open loop fascia lata suspension sling to the frontalis muscle to treat patients with severe eyelid ptosis and poor levator function. METHODS: Sixty nine lids in 51 patients, were enrolled in this study, all had severe eyelid ptosis and had autogenous fascial sling used for the correction of the ptosis. RESULTS: The final lid level and contour was evaluated after the follow-up period and showed that the results were satisfactory in 77% of the patients. The unsatisfactory results were due to under correction in 10%, poor lid crease in 6%, lid notch in 4%, and entropion in 3% of the operated lids. CONCLUSIONS: The accurate evaluation and implementation of this technique can correct the problem of ptosis provided that the patients exercises the frontalis muscle in order to accomplish the desired lid level. PMID- 21821428 TI - Virtual angioscopy finds the intimal tear of an acute thoracic aortic dissection. PMID- 21821430 TI - Coordination of respiratory muscles assessed by means of nonlinear forecasting of demodulated myographic signals. AB - Pulmonary diseases such as obstructive sleep apnea syndrome (OSAS) affect function of respiratory muscles. Individuals with OSAS suffer intermittent collapse of the upper airways during sleep due to unbalanced forces generated by the contraction of the diaphragm and upper airway dilator muscles. Respiratory rhythm and pattern generation can be described via nonlinear or coupled oscillators; therefore, the resulting activation of different respiratory muscles may be related to complex nonlinear interactions. The aims of this work were: to evaluate locally linear models for fitting and prediction of demodulated myographic signals from respiratory muscles; and to analyze quantitatively the influence of a pulmonary disease on this nonlinear forecasting related to low and moderate levels of respiratory effort. Electromyographic and mechanomyographic signals from three respiratory muscles (genioglossus, sternomastoid and diaphragm) were recorded in OSAS patients and controls while awake during an increased respiratory effort. Variables related to auto and cross prediction between muscles were calculated from the r(2) coefficient and the estimation of residuals, as functions of prediction horizon. In general, prediction improved linearly with higher levels of effort. A better prediction between muscle activities was obtained in OSAS patients when using genioglossus as the predictor signal. The prediction was significant for more than two respiratory cycles in OSAS patients compared to only a half cycle in controls. It could be concluded that nonlinear forecasting applied to genioglossus coupling with other muscles provides a promising assessment to monitor pulmonary diseases. PMID- 21821429 TI - Blood protein concentrations in the first two postnatal weeks associated with early postnatal blood gas derangements among infants born before the 28th week of gestation. The ELGAN Study. AB - AIM: To explore the relationships between blood gas derangements and blood concentrations of inflammation-related proteins shortly after preterm birth. DESIGN: Observational cohort. SETTING: Fourteen neonatal intensive care units. SUBJECTS: Seven hundred and forty five infants born before the 28th week of gestation who were classified by their blood gas derangements during the first three postnatal days and by the concentrations of 25 proteins in their blood on days 1, 7, and 14. We classified these newborns by whether or not they had a highest or lowest PaO2, PCO2, and lowest pH in the most extreme quartile, and by whether or not they had a protein concentration in the highest quartile. RESULTS: Blood gas derangements on two days were much more likely to be accompanied or followed by sustained or recurrent systemic inflammation than a derangement on only one day. This was most evident for acidemia, and slightly less so for hypercapnia. CONCLUSIONS: Our finding that protein concentration patterns indicative of systemic inflammation are associated with several blood gas derangements raises the possibility that organ damage attributed to these derangements might be accompanied by or involve an inflammatory response. PMID- 21821432 TI - Racial-ethnic differences in lacunar infarction in a multiethnic stroke population. AB - A higher incidence of lacunar infarction (LI) has been reported in nonwhite stroke populations. This study examined racial-ethnic differences in the clinical presentation and imaging findings of a racially-ethnically diverse population with acute LIs. Patients with acute LIs were identified over a 3-year period. Baseline clinical characteristics, vascular risk factors, and magnetic resonance imaging findings were analyzed. Comparisons were made between African Americans, Caribbean blacks, Caribbean Hispanics, and non-Hispanic whites. During the study period, 1036 patients with ischemic stroke were admitted, 194 of whom (25%) had a LI. The proportion of LI was the highest in Caribbean blacks (40%) and lowest in non-Hispanic whites (7%), with African Americans (25%) and Caribbean Hispanics (22%) showing a similar frequency. The mean patient age was 62 +/- 12 years, and the study group was 55% male. Hypertension (92%) and dyslipidemia (74%) were the most frequent risk factors. The prevalence of hypertension was highest in African Americans and Caribbean blacks, whereas Caribbean Hispanics were more likely to smoke and have dyslipidemia. Despite similar vascular risk factors and a shared genealogy, the proportion of LI differed in African Americans and Caribbean blacks. Conversely, no difference in the prevalence of LI was seen in African Americans and Caribbean Hispanics, even though the 2 groups had differences in vascular risk factors. Our findings suggest that other determinants besides traditional vascular risk factors influence the risk of LI. PMID- 21821431 TI - Sclerotherapy of abdominal lymphatic malformations with doxycycline. AB - PURPOSE: To assess the safety and efficacy of percutaneous image-guided sclerotherapy with doxycycline as primary treatment of intraabdominal lymphatic malformations (LMs). MATERIALS AND METHODS: Retrospective review was performed of all cases of abdominal, mesenteric, or retroperitoneal LMs referred to a single center that were subsequently treated with image-guided percutaneous sclerotherapy. RESULTS: Ten patients were included, of whom six were male. The mean age was 13 years (range, 2-28 y). Preprocedural cross-sectional imaging demonstrated a macrocystic malformation in nine patients and a mixed macrocystic/microcystic malformation in one. The malformation was accessed under sonographic guidance, followed by injection of opacified sclerosant agent under fluoroscopic guidance. A drainage catheter was placed in eight cases, in which sclerotherapy was repeated through the catheter for another 1 day (n = 2) or 2 days (n = 6). Doxycycline was reconstituted at 10 mg/mL, with a mean per-session dose of 608 mg (range, 80-1,000 mg) and a mean total dose of 1,230 mg (range, 80 3,000 mg). Peritoneal spill was identified in one case, but the patient remained asymptomatic. No other complications were encountered. Follow-up imaging was available in eight patients: complete resolution was seen in seven, with partial resolution in one. There was no recurrence of clinical symptoms in the follow-up period. CONCLUSIONS: Initial results indicate that percutaneous image-guided sclerotherapy of macrocystic intraabdominal LMs with doxycycline is a safe and effective procedure. PMID- 21821433 TI - Survival benefit of lung transplantation in individuals with severe alpha1-anti trypsin deficiency (PiZZ) and emphysema. AB - BACKGROUND: The objective of lung transplantation (LTx) is to prolong life, but the survival benefit for patients with severe alpha(1)-anti-trypsin deficiency (PiZZ) and emphysema is still unclear. The aim of this study was to assess whether PiZZ patients who have undergone lung transplantation (the lung transplant group, TxG) do better than patients who have continued on the usual medical therapy (the non-transplant group, NTxG). METHODS: Between 1990, when the first patient received a lung transplant in Sweden, until June 2010, a total of 83 PiZZ patients with severe emphysema underwent transplantation. Seventy appropriate controls were identified from the Swedish National AAT Deficiency Registry. Each control was matched with a patient who had received a lung transplant, for age, gender, smoking history (number of pack-years) and lung function at the time of transplantation. RESULTS: Both controls and lung transplant patients had low spirometric values with a mean FEV(1) of 23 +/- 6% and 22 +/- 9% of predicted value, respectively (not a statistically significant difference). Of the 83 transplant patients, 62 (75%) underwent single-lung transplantation (SLTx). During follow-up, 37 (45%) deaths occurred in the TxG and 45 (64%) in the NTxG. In the TxG, the estimated median survival time was 11 years (95% confidence interval [CI] 9 to 14 years), compared with 5 years (95% CI 4 to 6 years) for the NTxG (p = 0.006). The most common cause of death was pulmonary infection among the transplant patients (38%) and respiratory failure (60%) among the controls. CONCLUSION: Lung transplantation significantly improves long-term survival of patients with severe alpha(1)-anti-trypsin deficiency (PiZZ) and emphysema. PMID- 21821434 TI - Donor quality of life in living-donor lobar lung transplantation. AB - BACKGROUND: Living-donor lobar lung transplantation has been established as a life-saving option for end-stage pulmonary diseases. However, factors associated with quality of life (QOL) of living lung donors have not been fully investigated. METHODS: A cross-sectional study was performed at Okayama University using the version 2 questionnaire of the 36-item Short Form (SF-36) Health Survey. Linear regression analysis was used to estimate the relationship of donor factors and recipient outcomes using the SF-36 component summary scores. RESULTS: Of 65 donors, 42 (65%) agreed to participate in this study; the mean age was 42 +/- 1 (range 25 to 59) years. Mean time from the operation to questionnaire was 39 +/- 4 (range 1 to 78) months. Donor-recipient relationships were as follows: sibling (18 cases); spouse (9 cases); parent (11 cases); and child (4 cases). Thirty-four of 42 donors were paired with those who donated their organ to the same recipient. Both physical and mental health scores in donors were higher than those in the general Japanese population. Lower mental health scores were seen in those who donated to their child or parent. There was a significant correlation in mental health scores between the paired donors. In the univariate analysis, donor age (r = -0.35, p = 0.02), donor-recipient relationship (r = 0.38, p = 0.01) and recipient death (r = -0.42, p = 0.006) were factors significantly associated with donor mental health scores. CONCLUSIONS: The average QOL in the living lung donors was better than that of the general population. However, a fatal outcome in the recipient significantly impacted donor mental health QOL. Ensuring that donor candidates consider both the risks/benefits of donation, and the potential recipient outcomes may be critical in the informed consent process. PMID- 21821435 TI - Allosensitization and outcomes in pediatric heart transplantation. AB - BACKGROUND: Allosensitization among children being considered for heart transplantation remains a great challenge. Controversy exists as to the best approach for those with elevated panel-reactive antibody (PRA) titers. We sought to define the association between elevated PRA and outcomes using data from the multi-institutional Pediatric Heart Transplant Study Group. METHODS: Between January 1993 and December 2008, 3,016 patients (>1 month of age) were listed for heart transplantation. PRA data at listing were available for 2,500 (83%) patients, and 2,237 underwent transplantation with PRA data being available for 1,904 (85%). Because various PRA assays were employed (e.g., cell-based and solid phase) we entered the highest value regardless of methodology. RESULTS: Among the factors associated with high PRA at transplant were Status 1 at listing, previous sternotomy and prior Norwood procedure. An elevated PRA at listing was associated with higher risk of death while waiting. Of subjects with PRA >= 50% only 57% were transplanted by 1 year on the waitlist, as compared with 76% of those with PRA <10%. Waitlist mortality for the highly allosensitized subjects (>= PRA 50%) was 19% by 12 months. Survival at 1 year after transplantation was significantly lower in those with PRA >= 50% versus those with PRA <10% (73% vs 90%, respectively, p < 0.0001). Those with elevated PRA who had a negative prospective crossmatch had no difference in survival compared with those without allosensitization. There was no significant association between PRA levels and time to first rejection or development of coronary allograft vasculopathy. CONCLUSIONS: Significant allosensitization is associated with more than a 2-fold increased risk of death within the first transplant year. Although prospective crossmatching abrogates the risk of post-transplant mortality, it may contribute to higher pre-transplant attrition due to longer waitlist times. There is a critical need for strategies to minimize the impact of allosensitization and antibody-mediated rejection immediately after transplantation. PMID- 21821436 TI - Commentary on Dan Lloyd: "Neural correlates of temporality". PMID- 21821437 TI - Predictors of refractory epilepsy in north India: a case-control study. AB - The study was done to identify the predictors of refractory epilepsy in the North Indian population attending a tertiary care centre. This case-control study from August 2006 to December 2008 enrolled 200 consecutive patients of intractable epilepsy and 200 age matched controls with well controlled epilepsy. The factors which were significant in univariate analysis were age of onset before fourteen years (OR 7.92), partial seizures (OR 6.27), presence of neurological deficits (OR 19.68), perinatal insult (OR 11.00), delayed milestones (OR 13.93), history of CNS infection (OR 7.45), febrile seizures (4.33), high initial seizure frequency of more than one per month (OR 14.26), non response to first Anti Epileptic Drug (AED) (OR 6.71) and abnormal brain imaging (OR 20.47). On multivariate analysis significant predictors were radiological evidence of structural cerebral abnormality (OR 20.47), non response to first AED (OR 19.21), delayed mile stones (OR 9.09), high initial seizure frequency of more than one per month (OR 6.71), partial seizure type (OR 6.27), febrile seizures (OR 5.66) and age of onset before fourteen years (OR 3.09). It is thus possible to identify a certain profile of patients with epilepsy who are likely to be refractory to medical therapy. These observations would be useful in selecting patients early for evaluation in Northern India where a high surgical treatment gap exists. PMID- 21821438 TI - Analysis of insurance claims after vascular surgery: a tool for quality improvement? PMID- 21821439 TI - Selective serotonin reuptake inhibitors and oral bleeding complications after invasive dental treatment. AB - OBJECTIVE: The purpose of this study was to examine the frequency of oral bleeding complications after invasive dental procedures in patients taking selective serotonin reuptake inhibitor (SSRI) medications. STUDY DESIGN: In this retrospective cohort study, we included dental patients who had invasive dental treatment and were taking an SSRI medication. Data collected included demographics, medical history, dental visits and procedures, and use of adjunctive measures to control bleeding. Primary outcomes included documentation of return visits or phone calls to the dental clinic or emergency department (ED) for oral bleeding, and oral bleeding or use of blood products for inpatients. RESULTS: There were 92 patients taking SSRIs who had 145 invasive procedure visits, consisting of extractions, implant surgery, alveoloplasty, periodontal surgery, subgingival scaling and root planning, and biopsy. There were 110 extraction visits yielding a total of 167 extractions. Among all patients, there was 1 return visit to the clinic and 1 telephone call with a chief complaint of oral bleeding. CONCLUSIONS: The frequency of oral bleeding complications after invasive dental treatment is low to negligible in patients on SSRI medications. PMID- 21821440 TI - Minimum-intensity projection for in-depth morphology study of mesiobuccal root. AB - OBJECTIVE: This micro-computed tomography (MCT) study investigated the utility of thin-slab minimum-intensity projection (TS-MinIP) technique as an adjunct to 3 dimensional (3D) modeling for in-depth morphology study. STUDY DESIGN: One hundred one extracted maxillary first molars were scanned for microtomographic analysis (SkyScan). Two-dimensional TS-MinIP and 3D images of mesiobuccal (MB) roots were produced and analyzed to record the number and configurations of the canals, the incidence and location of accessory canals, loop, and intercanal connections, and number of foramina. RESULTS: Multiple-canal MB roots were present in 76.2%, and all of the roots had intercanal communications. Weine type III configuration was the most common in the multiple-canal roots. Accessory canals were found in 78.2% of the roots. Configurations that were nonclassifiable were found in 10.9% of the MB roots. CONCLUSIONS: MB root canal anatomy was complex, and MinIP may serve as an adjunct to 3D modeling for in-depth morphology study. PMID- 21821441 TI - Dental specialists need to lead the way to becoming superordinate oral physicians. PMID- 21821442 TI - Burning mouth syndrome: mast cell connection. PMID- 21821444 TI - A model for the pathogenesis of bisphosphonate-associated osteonecrosis of the jaw and teriparatide's potential role in its resolution. AB - OBJECTIVE: The objective of this study was to present a comprehensive model for the pathogenesis of bisphosphonate-associated osteonecrosis of the jaw (BON). STUDY DESIGN: Review of PubMed literature relevant to BON, bisphosphonates (BPs), and bone remodeling. RESULTS: Six case reports of spontaneous resolution of BON lesions following administration of teriparatide (Forteo; Eli Lilly and Co., Indianapolis, IN) were identified. These reports suggest that osteoanabolic therapies may hold promise in BON management. Here we propose that BON pathogenesis is multifactorial and is the combined result of attenuated osteoblastic activity (owing to the patient's underlying disease, e.g., osteoporosis or multiple myeloma), BP-mediated osteoclast toxicity, and the resultant compromised osteoblast-osteoclast interactions during bone remodeling. Consequently, a vicious cycle of ineffective local remodeling results in the persistence of defective bone, compromised tissue perfusion, and if unresolved, ultimately leads to necrosis. CONCLUSIONS: Our model for BON pathogenesis advocates for earlier therapeutic intervention in BON. The biological rationale for teriparatide's efficacy in BON justifies further investigation. PMID- 21821445 TI - Immunohistochemical expression of nuclear factor kappaB, matrix metalloproteinase 9, and endoglin (CD105) in odontogenic keratocysts, dentigerous cysts, and radicular cysts. AB - OBJECTIVE: The aim of this study was to compare the immunohistochemical expression of nuclear factor kappaB (NF-kappaB), matrix metalloproteinase 9 (MMP 9), and CD105 in odontogenic keratocysts (OKCs), dentigerous cysts (DCs), and radicular cysts (RCs). STUDY DESIGN: Twenty cases of OKCs, 20 DCs, and 20 RCs were analyzed. A labeling index (LI), which expresses the percentage of NF-kappaB stained nuclei, was calculated for the analysis of NF-kappaB expression. Expression of MMP-9 in the epithelium and in the capsule of each lesion was scored as 0 (<10% stained cells), 1 (10%-50% stained cells), or 2 (>50% stained cells). In addition, MMP-9 immunostaining was analyzed in endothelial cells of vessels with a conspicuous lumen. The angiogenic index was determined based on the number of anti-CD105 antibody-stained microvessels. RESULTS: In the epithelial component, the NF-kappaB LI was higher in OKCs than in DCs and RCs (P < .001). Analysis of MMP-9 expression in the epithelial component showed a predominance of score 2 in OKCs (90%), DCs (70%), and RCs (65%; P = .159). Evaluation of the NF-kappaB LI according to the expression of MMP-9 in the epithelial lining revealed no significant difference between lesions (P = .282). In the fibrous capsule, the highest percentage of MMP-9-stained cells (score 2) was observed in OKCs (P = .100). Analysis of the expression of MMP-9 in the vessels of odontogenic cysts showed a predominance of score 2 in OKCs (80%) and RCs (50%) and of score 1 in DCs (75%; P = .002). Mean microvessel count was high in RCs (16.9), followed by DCs (12.1) and OKCs (10.0; P = .163). No significant difference in microvessel count according to the expression of MMP-9 was observed between groups (P = .689). CONCLUSIONS: The results suggest that the more aggressive biologic behavior of OKCs is related to the higher expression of MMP-9 and NF-kappaB in those lesions. The differences in the biologic behavior of the lesions studied do not seem to be associated with the angiogenic index. PMID- 21821446 TI - Effect of sodium hypochlorite on human pulp cells: an in vitro study. AB - BACKGROUND: The purpose of this study was to determine the effect of sodium hypochlorite (NaOCl) on human pulp cells to provide an aid in determining its optimum concentration in maintaining the viability of remaining pulp cells in the revascularization of immature permanent teeth with apical periodontitis. STUDY DESIGN: Human pulp tissue cells taken from extracted third molars were plated, incubated, and subjected to various concentrations of NaOCl (0.33%, 0.16%, 0.08%, and 0.04%) for 5-, 10-, and 15-minute time intervals to simulate possible contact times in vivo. The Cell Titer-Glo Luminescent Cell Viability Assay was used to determine the number of viable cells present in culture following treatment. RESULTS: The results showed an increase in cell viability with the lowering of NaOCl concentration. The use of 0.04% NaOCl was similar to the control, indicating nearly complete preservation of cell viability at all time intervals tested. As sodium hypochlorite concentration increased from 0.04% to 0.33%, cell viability decreased correspondingly. CONCLUSIONS: The results indicate that the lowest concentration of NaOCl tested did not affect the viability of cells. This may prove beneficial in developing a new treatment protocol to help preserve existing vital pulp cells in revascularization cases. PMID- 21821447 TI - Surgical endodontic management of an invasive cervical resorption class 4 with mineral trioxide aggregate: a 6-year follow-up. AB - Invasive cervical resorption is a type of external resorption rarely seen as an adverse effect after a guided tissue regeneration procedure for a periodontal condition. This case report summarizes the surgical endodontic management of an invasive cervical resorption class 4 (Heithersay) with mineral trioxide aggregate, in a mandibular incisor of a 67-year-old man. A 6-year clinical follow up with radiovisiography and cone-beam computerized tomography revealed complete healing. A surgical endodontic management could promote healing and survival of a tooth with advanced root resorption due to a periodontal condition. PMID- 21821448 TI - Are matrix and vascular changes involved in the pathogenesis of deep digital flexor tendon injury in the horse? AB - It was hypothesised that there is increased blood vessel frequency and proteoglycan staining intensity within the distal aspect of the deep digital flexor tendon (DDFT) in horses with chronic foot pain. Samples of the DDFT from three standardised sites from 10 age-matched mature horses, with chronic foot pain (Group L) or with no history of forelimb lameness (Group N), were collected for this study. A histological analysis of haematoxylin and eosin-stained sections focussed on the frequency and location of blood vessels, while safranin 0 fast green staining was used for semi-quantitative assessment of matrix proteoglycan. The frequency and immunoreactivity of endothelial cell-labelled blood vessels were determined using factor VIII immunolocalisation. There was increased frequency of blood vessels (P=0.048) and increased proteoglycan staining intensity (P=0.028) in Group L, compared with Group N. Qualitative micro anatomical differences in the matrix and tenocytes were noted between Groups N and L. There was reduced factor VIII staining within the vasculature of horses from Group L, compared with Group N. The results suggested that chronic foot pain may be associated with altered DDFT matrix composition, which could be a potential indicator of degenerative change. The increased vascularity may represent a reparative response to a degenerative tendonopathy. PMID- 21821449 TI - MECP2 triplication in 3 brothers - a rarely described cause of familial neurological regression in boys. AB - Male patients with large duplications of the methyl CpG-binding protein 2 (MECP2) gene have been identified with a characteristic phenotype consisting of infantile hypotonia replaced by spasticity, developmental delay, severe mental retardation and recurrent respiratory infections. Only one patient with MECP2 triplication, with a more severe phenotype has been reported so far. We report three brothers of unrelated parents with MECP2 triplication. Their phenotypic features include macrocephaly with large ears, infantile hypotonia, developmental delay, significant constipation, recurrent severe respiratory tract infections from early childhood, and seizures followed by neurological regression in late childhood. Our cases indicate that MECP2 triplication is similar to or more severe than that of MECP2 duplication syndrome. PMID- 21821450 TI - Correlation of SMN2, NAIP, p44, H4F5 and Occludin genes copy number with spinal muscular atrophy phenotype in Tunisian patients. AB - OBJECTIVES: Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder which is characterized by a high clinical variability with severe, intermediate, mild and adult forms. These forms are caused, in 95% of cases, by a homozygous deletion of exon 7 of SMN1 gene. Our purpose was the determination of a possible genotype-phenotype correlation between the copy number of SMN2, NAIP, p44, H4F5 and occludin genes localized in the same SMN1 region (5q13) and the severity of the disease in SMA Tunisian patients. PATIENTS AND METHODS: Twenty six patients affected by SMA were enrolled in our study. MLPA and QMPSF were used to measure copy numbers of these genes. RESULTS: We found that 31.3% of type I patients carried one copy of SMN2, while all patients of other forms had at least 2 copies. NAIP was absent in 87.5% of type I patients. Furthermore, all SMA type I patients had one copy of H4F5. No correlation was found for p44 and occludin genes. CONCLUSION: There is a close relationship between SMN2, NAIP and H4F5 gene copy number and SMA disease severity, which is compatible with the previous reports. PMID- 21821452 TI - Neurological complications and behavioral problems in patients with phenylketonuria in a follow-up unit. AB - OBJECTIVE: To investigate the relationship between neurological complications, neuroradiological findings, and behavioral problems, age at diagnosis and dietary control along the follow-up of the PKU patients in our metabolic unit. DESIGN: Retrospective study of the PKU patients diagnosed and controlled in our unit from 1985 to 2010. METHODS: Registry of patients in a database with 50 items filled in by review of the clinical histories. Statistical study of the data (SPSS, 19.0 version). RESULTS: 121 patients were included (median age: 16.0, range 1 month-46 years). 76% of them were diagnosed through neonatal screening. 12.4% had mild PKU, 19% moderate-PKU and 68.6% classic-PKU. 88.4% of patients were treated with a protein-restricted diet, and 11.6% with BH4. 97.7% of the early diagnosed patients had normal IQ, while 46.3% of late diagnosed patients had mental retardation, 28.5% were borderline and 25% had normal IQ. In early diagnosed patients, there was a significantly negative correlation between IQ [mean (SD) 100 (11.1)] and the index of dietary control during the first six years of life [median (range) 310 (105-992)] and that of the immediately past year [348 (106 1127)] (p < 0.0001). The proportion of patients with late diagnosis and neurological and behavioral problems was significantly higher than that of the early diagnosed ones (p < 0.001). The proportion of early diagnosed patients with neurological and behavioral problems who had good, intermediate or poor dietary control during the first 6 years of life and the immediately past year was significantly different (p < 0.001). CONCLUSIONS: The results show the impact of early diagnosis and good dietary treatment on the IQ and on the percentage of neurological complications and behavioral problems in PKU patients. PMID- 21821453 TI - Parotid salivary duct sialocele associated with glandular duct stenosis in a cat. AB - Feline parotid salivary duct sialocele is an uncommon disorder that has been previously reported in association with traumatic rupture of the duct in only two cats. Both cases were successfully treated by proximal duct ligation. We describe the successful surgical treatment of a parotid duct sialocele, secondary to spontaneous salivary duct stenosis, in an adult domestic shorthair cat. The cat was referred for assessment of a recurrent fluid-filled swelling on the left side of the face. Cytology of the aspirated fluid was consistent with serous saliva. The anatomical localisation of the lesion and the nature of the fluid were indicative of parotid gland/duct involvement. Retrograde sialography by parotid duct cannulation was unsuccessful because the left parotid duct opening was stenosed and obstructed by scar tissue. Surgical exploration revealed a parotid salivary duct sialocele, which was completely removed along with the parotid gland without complications. PMID- 21821454 TI - [Acute carpometacarpal joint dislocation of the long fingers: study of 100 cases]. AB - OBJECTIVES: The authors report clinical and radiological results of carpometacarpal dislocations treated in emergency over a period of 7 years (2002 2009). Mechanisms of injury and diagnosis pitfalls are specified, and treatment options are discussed. METHODS: A retrospective study of 100 carpometacarpal dislocations was performed. Most commonly trauma was a punch (56%). In half the cases, lesions were located only within the fifth ray. Carpal or metacarpal fractures were associated in a majority of cases (88%). Surgical treatment was carried out in all cases either by closed reduction and percutaneous pinning (60%), or by open reduction and internal fixation (40%). The mean follow-up was 5 months. Anatomic reduction of dislocation, consolidation and reduction of associated fractures were analysed on the last follow-up x-rays. Evaluation tools were pain score, range of motion and grip strength. RESULTS: Radiological criteria were satisfactory in 68% of cases. Non-satisfactory X ray criteria were mainly associated with closed reduction and percutaneous pinning. At final follow up, 81% of the patients were pain-free and had recovered complete range of motion. In 16% of patients pain was only found during grip strength test. CONCLUSIONS: Carpometacarpal luxations are not as rare as suggested by literature. Early diagnosis and treatment are essential for the prognosis. Increasing indications of a scan enable better analysis by identifying all injuries. Open reduction by which allows the treatment of all associated injuries must be promoted. PMID- 21821455 TI - [Is there a real place for robotics in proximal tubal surgery?]. AB - Tubal surgery requires a fine gesture. Its complexity, the difficulty of learning, the low recognition at the time of T2A and the success of Assisted Reproductive Technology (ART) could have announced the obituary of this surgery. However, in well-trained hands, tubal surgery avoids unnecessary ARTs and even allows pregnancies when medical technology fails. In this context, it is legitimate to ask whether the contribution of new technologies in the operating theatre, such as robotic surgery, can lead to an easy realization of microsurgery on a particularly complex portion of Fallopian tubes: the proximal segment. PMID- 21821456 TI - Applicability of an on-site test for its use in post-mortem blood. AB - The number of deaths related to drugs of abuse makes necessary the use of an on site test for those cases in which a rapid detection of the consumed drug is required. Cozart(r) DDS test provides a simple, fast and reliable tool for the qualitative on-site analysis in post-mortem blood. Owing that this test is prepared for oral fluid samples, a validation becomes essential in order to use it for a different matrix than the established one. According to that, results obtained by Cozart(r) DDS test used in post-mortem blood samples have been compared with a qualitative gas chromatography-mass spectrometry (GC/MS/MS). Positive results for cocaine family compounds (COC-F) were 43.75%, for opiates family compounds (OPI-F) 25.78%, and for cannabis family compounds (THC-F) 2.34%. Negative results were 28.13%. No amphetamines (AMP) or methamphetamines (MA) were found. Sensitivity and specificity was available for cocaine and opiates but not for cannabis because only five cases were detected. Sensitivity, specificity, predictive positive value and predictive negative value for cocaine were 98%, 91%, 88% and 99%, respectively. Sensivilty, specificity, predictive positive value (PPV) and predictive negative value (NPV) for opiates were 93%, 92%, 76% and 98%, respectively. Likelihood positive ratios for cocaine and opiates have been 10.92 and 11.69, respectively, while likelihood negative ratios have been 0.02 and 0.08, respectively. Results show the suitability of Cozart(r) DDS test for the qualitative detection of cocaine and opiates in post-mortem blood. PMID- 21821457 TI - Deletion mapping and paternal origin of a Mexican AMELY negative male. AB - The amelogenin represents the gender marker most widely used for human identification and biomedical purposes. However, some failures in sex-typing have been observed globally. In this study, we could approximate the population frequency of AMELY negative males in 1230 individuals from five states of Mexico (0.081%). For the sole AMELY negative male detected, we constructed a deletion map by means of 10 markers (7 STS and 3 Y-STRs). This allowed classifying the case into the most common category (Class I deletion), according to the nomenclature proposed by Jobling et al. (2007). Interestingly, the Mexican sample was R1a1(*), a Y-chromosome haplogroup non-previously reported for AMELY negative cases. The geographic distribution of R1a1(*), and the Y-STR haplotype similarity with a reported case from Slovenia, suggests an Eastern-Europe paternal origin for this case from Mexico. To our knowledge, this is the first report in Latin America that implies a low population frequency and European paternal origin of AMELY negative cases. PMID- 21821458 TI - Massive hemoperitoneum due to ruptured ectopic gestation: postmortem CT findings in a deeply frozen deceased person. AB - A deceased 23 year old female was repatriated from a 3rd world country in a deeply frozen state as no conventional mortuary refrigeration was available. Prior to her death the deceased had complained of abdominal pain, nausea and vomiting followed by collapse. She was unable to be resuscitated. Postmortem CT scanning on arrival at our mortuary (105 h after death) revealed a large volume hemoperitoneum in two distinct forms. In the pelvis, uniform hyperdense material with a mean Hounsfield unit (HU) density of 74, encircled the uterus and Fallopian tubes. In the upper abdomen there was a highly unusual appearance of multiple, thin, parallel and intersecting linear structures having a mean HU density of -10 to 10 within more dense, dependent material (mean HU density of 50) around the spleen and liver. CT also revealed a sac in the uterine cavity and a complex cystic mass of 4*2.5 cm in diameter in the right adnexum. No other cause for bleeding was detected. Findings were interpreted by the forensic radiologist as a ruptured right adnexal ectopic gestation with frozen clotted blood in the pelvis (so-called "sentinel clot") and crystallization of serum in frozen liquid blood filling the upper abdominal cavity. Urgent postmortem serum (beta)hCG was elevated (7714 International Units/L), consistent with early pregnancy. Once time had elapsed to allow the body to fully thaw, an autopsy limited to the abdomen confirmed all CT findings albeit without the icicles. This case exemplifies the value of the clinical CT "sentinel clot" sign in localizing the source of abdominal hemorrhage on postmortem imaging and highlights the value of postmortem CT scanning in determining cause of death even in a deeply frozen individual. PMID- 21821459 TI - Diagnosis of fulminant type 1 diabetes mellitus in an autopsy case with postmortem changes. AB - A Japanese female in her thirties was found dead in her apartment; the postmortem interval was estimated to be approximately 3 days. Several postmortem changes were evident. Acute gastroenteritis had been diagnosed 3 days earlier. On autopsy, no specific findings other than fatty liver were observed. On hematoxylin eosin staining, mild fibrosis, and invasion of neutrophils in the pancreatic parenchyma, severe fatty liver, and extensive vacuolation of renal tubular cells were observed. Biochemical analyses revealed extremely high beta hydroxybutyrate concentrations in body fluids with moderate elevation of hemoglobin A1c. Toxicological analyses of organ and urine samples were negative. We concluded that severe ketoacidosis had occurred in the deceased. Subsequently, selective destruction of pancreatic beta-cells was demonstrated. Considered together, results indicated that the cause of death was fulminant type 1 diabetes mellitus. This report illustrates the fact that a combination of biochemical and immunohistochemical investigations can be useful for diagnosing this condition in cases with evident postmortem changes. PMID- 21821460 TI - Homicidal hanging. AB - Homicide by hanging is an extremely rare incident [1]. Very few cases have been reported in which a person is rendered senseless and then hanged to simulate suicidal death; though there are a lot of cases in wherein a homicide victim has been hung later. We report a case of homicidal hanging of a young Sikh individual found hanging in a well. It became evident from the results of forensic autopsy that the victim had first been given alcohol mixed with pesticides and then hanged by his turban from a well. The rare combination of lynching (homicidal hanging) and use of organo-phosporous pesticide poisoning as a means of homicide are discussed in this paper. PMID- 21821461 TI - Long-term improvement under deferiprone in a case of neurodegeneration with brain iron accumulation. PMID- 21821462 TI - TRB3 overexpression due to endoplasmic reticulum stress inhibits AKT kinase activation of tongue squamous cell carcinoma. AB - Our investigation aims to evaluate the significance of TRB3, an endoplasmic reticulum stress (ERS)-inducible gene, and explore its relationship with AKT in oral tongue squamous cell carcinoma (OTSCC). Expression of TRB3 and phosphorylated AKT (p-AKT) in OTSCC tissues and adjacent normal tissues were assessed by RT-PCR, Western blot and immunohistochemistry assay. Correlation of TRB3 and AKT was validated by TRB3 adenovirus plasmid (Ad-TRB3) transfection and short hairpin RNA (shRNA) inhibition. The mRNA expression of TRB3 was significantly higher than adjacent noncancerous tissues by RT-PCR in 15 of 18 specimens of OTSCC (83.3%, P<0.01). Both of TRB3 and AKT were highly expressed in 13 of 18 (72.2%) specimens of OTSCC comparing with adjacent noncancerous tissues by Western blot assay (P<0.05). TRB3 was significantly elevated in 49.2% (63/128) of pathologically confirmed specimens and 13.3% (4/30) of adjacent noncancerous specimens by immunohistochemical analysis (P<0.01). TRB3 overexpression was closely correlated with tumor pathological T stage, lymph node metastasis and tumor recurrence. In addition, both mRNA and protein expression of TRB3 was increased under thapsigargin (TG) or tunicmycin (TU)-induced ERS in Tca8113 and CAL-27 cells. Moreover, expression of p-AKT protein decreased when Ad-TRB3 was transected with OTSCC Tca8113 cells. However, expression of p-AKT protein increased when TRB3 was inhibited by TRB3 shRNA inhibition. TRB3 expression was closely correlated with OTSCC prognosis. Under ERS, TRB3 was up-regulated, resulting in inhibiting the activation of AKT in OTSCC. PMID- 21821463 TI - Ameloblastomas have already been treated successfully with intralesional chemotherapy in dogs, why not in humans? PMID- 21821464 TI - Plant endosomal trafficking pathways. AB - Endosomes regulate both the recycling and degradation of plasma membrane (PM) proteins, thereby modulating many cellular responses triggered at the cell surface. Endosomes also play a role in the biosynthetic pathway by taking proteins to the vacuole and recycling vacuolar cargo receptors. In plants, the trans-Golgi network (TGN) acts as an early/recycling endosome whereas prevacuolar compartments/multivesicular bodies (MVBs) take PM proteins to the vacuole for degradation. Recent studies have demonstrated that some of the molecular complexes that mediate endosomal trafficking, such as the retromer, the ADP ribosylation factor (ARF) machinery, and the Endosomal Sorting Complexes Required for Transport (ESCRTs) have both conserved and specialized functions in plants. Whereas there is disagreement on the subcellular localization of the plant retromer, its function in recycling vacuolar sorting receptors (VSRs) and modulating the trafficking of PM proteins has been well established. Studies on Arabidopsis ESCRT components highlight the essential role of this complex in cytokinesis, plant development, and vacuolar organization. In addition, post translational modifications of plant PM proteins, such as phosphorylation and ubiquitination, have been demonstrated to act as sorting signals for endosomal trafficking. PMID- 21821465 TI - Advances in understanding archaea-virus interactions in controlled and natural environments. AB - Our understanding of host-virus interactions in archaeal systems generally lags behind our knowledge of host-virus interactions in bacterial and eukaryotic systems. This is due to the limited number of archaeal host-virus systems available for study under laboratory conditions, as well as the absence of diseases known to be caused by archaea. However, in recent years there has been a rapid expansion of our understanding of archaeal host-virus interactions combining traditional genetic and biochemical approaches with 'omics' based approaches in both laboratory and natural environmental studies. We highlight here the emerging features of host-virus interactions in archaea with a particular emphasis on host-virus interactions gathered from the study of archaeal viruses from high temperature acidic thermal environments. PMID- 21821466 TI - New tuberculosis drugs on the horizon. AB - Tuberculosis (TB) remains a major global health concern whose control has been exacerbated by HIV and the emergence of multidrug-resistant (MDR-TB) and extensively drug-resistant (XDR-TB) strains of Mycobacterium tuberculosis. The demand for new and faster acting TB drugs is thus greater than ever. In the past decade intensive efforts have been made to discover new leads for TB drug development using both target-based and cell-based approaches. Here, we describe the most promising anti-tubercular drug candidates that are in clinical development and introduce some nitro-aromatic compounds that inhibit a new target, DprE1, an essential enzyme involved in a crucial step in mycobacterial cell wall biosynthesis. PMID- 21821467 TI - Spectroscopic studies on the lanthanide sensitized luminescence and chemiluminescence properties of fluoroquinolone with different structure. AB - Lanthanide sensitized luminescence and chemiluminescence (CL) are of great importance because of the unique spectral properties, such as long lifetime, large Stokes shifts, and narrow emission bands characteristic to lanthanide ions (Ln(3+)). With the fluoroquinolone (FQ) compounds including enoxacin (ENX), norfloxacin (NFLX), lomefloxacin (LMFX), fleroxacin (FLRX), ofloxacin (OFLX), rufloxacin (RFX), gatifloxacin (GFLX) and sparfloxacin (SPFX), the luminescence and CL properties of Tb(3+)-FQ and Eu(3+)-FQ complexes have been investigated in this contribution. Ce(4+)-SO(3)(2-) in acidic conditions was taken as the CL system and sensitized CL intensities of Tb(3+)-FQ and Eu(3+)-FQ complexes were determined by flow-injection analysis. The luminescence and CL spectra of Tb(3+) FQ complexes show characteristic peaks of Tb(3+) at 490 nm, 545 nm, 585 nm and 620 nm. Complexes of Tb(3+)-ENX, Tb(3+)-NFLX, Tb(3+)-LMFX and Tb(3+)-FLRX display relatively strong emission intensity compared with Tb(3+)-OFLX, Tb(3+)-RFX, Tb(3+)-GFLX and Tb(3+)-SPFX. Quite weak peaks with unique characters of Eu(3+) at 590 nm and 617 nm appear in the luminescence and CL spectra of Eu(3+)-ENX, but no notable sensitized luminescence and CL of Eu(3+) could be observed when Eu(3+) is added into other FQ. The distinct differences on emission intensity of Tb(3+)-FQ and Eu(3+)-FQ might originate from the different energy gap between the triplet levels of FQ and the excited levels of the Ln(3+). The different sensitized luminescence and CL signals among Tb(3+)-FQ complexes could be attributed to different optical properties and substituents of these FQ compounds. The detailed mechanism involved in the luminescence and CL properties of Tb(3+)-FQ and Eu(3+) FQ complexes has been investigated by analyzing the luminescence and CL spectra, quantum yields, and theoretical calculation results. PMID- 21821468 TI - Spectroscopic studies on the influence of 10 mol% of glycine on nonlinear optical crystal L-valinium picrate. AB - Nonlinear optics is a fascinating field, which plays a vital role in the emerging field of photonics and optoelectronics. A new nonlinear optical crystal of glycine mixed L-valine picrate (GVP) have been grown from saturated aqueous solution by slow evaporation method at a temperature of 36 degrees C using a constant temperature bath of accuracy of +/-0.01 degrees C. The synthesized organic optical material has been purified by repeated recrystallization. Single crystal X-ray diffraction analysis has been made to determine the cell parameters and it confirms the crystal lattice to be orthorhombic. UV-vis-NIR spectrum have recorded for GVP crystals in the range from 190 nm to 1100 nm and it is found that the crystal has cut-off at 450 nm. Fourier transform infrared transmission has confirmed the presence of the functional group present in the title compound. The spectrum has been recorded by KBr pellet technique. The (1)H and (13)C NMR spectra have been recorded to elucidate the molecular structure of GVP crystals. The second harmonic generation (SHG) of the grown crystal have been confirmed by Kurtz-Perry method using Nd:YAG laser as source. PMID- 21821469 TI - Auditory evoked potentials remain abnormal after CPAP treatment in patients with severe obstructive sleep apnoea. AB - OBJECTIVE: To assess the effects of 3 months of optimal CPAP treatment on auditory event related potentials (AERP) in patients with severe obstructive sleep apnoea (OSA) compared with healthy controls. METHODS: Auditory odd-ball related N1, P2, N2 and P3 AERP components were assessed in 9 severe OSA subjects and 9 healthy controls at baseline evaluation and at ~3 months follow-up in both groups, with OSA subjects treated with continuous positive air-way pressure (CPAP) during this period. RESULTS: Severe OSA subjects showed significantly delayed, P2, N2 and P3 latencies, and significantly different P2 and P3 amplitudes compared to controls at baseline (group effect, all p<0.05). At follow up evaluation P3 latency shortened in treated OSA patients but remained prolonged compared to controls (group by treatment interaction, p<0.05) despite high CPAP compliance (6h/night). The earlier AERP (P2 and N2) components did not change in either controls or OSA patients at follow-up and remained different in patients versus controls. CONCLUSIONS: This study demonstrates that in severe OSA patients AERP responses show minimal or no improvement and remain abnormal following 3 months of optimal CPAP treatment. SIGNIFICANCE: Persistent cortical sensory processing abnormalities despite treatment in severe OSA may have implications for daytime neurobehavioral performance and safety in OSA patients. AERP responses may help identify residual performance deficits and risks. PMID- 21821470 TI - Development of a novel aptamer-based sensing system using atomic force microscopy. AB - Atomic force microscopy (AFM) can dynamically detect the adhesion or affinity force between a sample surface and a cantilever. This feature is useful as a detection method using aptamers--single-strand DNA that recognizes its target with very high affinity. The present study proposes a novel DNA aptamer-based sensing system using AFM. In this study, thrombin was chosen as the target molecule, and a DNA aptamer-based AFM sensing system based on competition was developed. The affinity force between the gold chip and the cantilever decreased as the concentration of thrombin increased. Moreover, a low detection limit of 0.2 nM was achieved. Therefore, the AFM sensing system used would be appropriate for the measurement of various chemical compounds. PMID- 21821471 TI - Comparison of real-time reverse-transcription loop-mediated isothermal amplification and real-time reverse-transcription polymerase chain reaction for detection of noroviruses in municipal wastewater. AB - The monitoring of NVs in municipal wastewater by both real-time RT-LAMP and real time RT-PCR, and the comparison of these two methods with respect to NV detection were carried out. The change in NVs detected by real-time RT-LAMP agreed well with that detected by real-time RT-PCR. In contrast, the correlation between the copy number determined by real-time RT-PCR and the threshold time (Tt) determined by real-time RT-LAMP obtained during monitoring was not significant (0.1100/100,000) in Asia, and central and south Africa. The incidence of oesophageal cancer in Spain has been approximately 8/100,000 among men and 1/100,000 among women. Oesophageal cancers are histologically classifi ed as squamous cell carcinoma (SCC) or adenocarcinoma, both with different associated risk factors. While SCCs have become increasingly less common, the incidence of adenocarcinoma has risen steeply. In the SEOM Clinical Guidelines for Oesophageal Cancer we propose rules for adequate initial diagnosis and staging as well as treatment recommendations from early to advanced disease. PMID- 21821485 TI - SEOM clinical guidelines for the treatment of anal cancer. AB - Anal carcinoma is an uncommon disorder accounting for less than 2% of large bowel malignancies and 1-6% of anorectal tumours. Its incidence ranges between 0.5 and 1% per 100,000. Local staging should be done with MR imaging using an external pelvic phased-array coil. Treatment strategy should be optimally discussed in a multidisciplinary team. HIV-positive patients seem to achieve similar response rate and overall survival to HIV-negative patients but with increased toxicity and higher local recurrences. Combined modality treatment with irradiation and chemotherapy has resulted in complete response over 90% and local control over 85%. This guide gives recommendations for diagnosis, staging and treatment. PMID- 21821486 TI - SEOM clinical guidelines for the treatment of pancreatic cancer. AB - Pancreatic cancer (PC) is one of the main causes of cancer-related death in the United States and Europe. Due to its poor long-term survival, all patients with PC should undergo a comprehensive evaluation by a Multidisciplinary Tumor Committee to establish the best therapeutic strategy. Pathologic PC diagnosis should be made according to the latest WHO classification of malignant tumours and an accurate staging is crucial to assess resectability, determine the extension and, in some cases, reestablish biliary flow. For patients with localised resectable disease the standard treatment option is radical pancreatic resection. The aim of resection is to obtain microscopically negative margins (R0) and also to resect the drainage lymph nodes. In those cases diagnosed with locally advanced unresectable or metastatic PC, palliative bypass of intestinal or biliary obstruction followed by chemotherapy or chemoradiation remains the main palliative treatment option. Since 1997, gemcitabine monotherapy has been considered the standard of care for advanced PC. In recent years new chemotherapy combinations and targeted agents have demonstrated significant antitumoral activity, increasing the armamentarium that can be used against this lethal disease. PMID- 21821487 TI - Hepatocellular and biliary tract carcinomas: SEOM clinical guidelines. AB - While hepatocellular carcinoma (HCC) is a relatively common tumour with an annual incidence in the EU of 8 cases/100,000 inhabitants, bile tract carcinoma (BTC) is much less common, with an incidence of 4 cases per 100,000 inhabitants per year. In both cases, when planning treatment it is essential to perform accurate staging, evaluate hepatic functional reserve and performance status, and obtain the opinion of the patient. The only curative treatment is surgery. However, several interventional radiological techniques can help to achieve local disease control and the alleviation of symptoms. In addition, sorafenib (HCC) and chemotherapy (BTC) may contribute to prolong survival in patients with disseminated disease. Therefore, the therapeutic strategy should always be discussed and planned within a multidisciplinary tumour board. PMID- 21821488 TI - SEOM clinical guidelines for the diagnosis and treatment of gastroenteropancreatic neuroendocrine tumours (GEP NETS). AB - Gastroenteropancreatic neuroendocrine tumours (GEP NETs) represent a heterogenous family of tumours with growing incidence and challenging clinical management. Unlike other solid tumours, they have the ability to secrete different peptides and neuramines that cause distinct clinical syndromes. However, many are clinically silent until advanced disease. This guideline aims to provide practical recommendations for the diagnosis and treatment of GEP NETs. Most recent histological and staging classifications, as well as available therapeutic approaches, such as surgery, locoregional therapy, peptide receptor radionuclide therapy (PRRT) and hormonal or systemic therapy, are discussed in this manuscript, including some recent relevant achievements with novel targeted agents. Clinical presentation (with or without hormonal syndrome), histological tumour features (including proliferation index (Ki-67) and the presence or not of somatostatin receptors), tumour stage, and location of primary tumour and distant metastasis are all key issues that shall be taken into consideration to properly design and integrate the most adequate therapeutic strategy. PMID- 21821489 TI - SEOM clinical guidelines for the treatment of invasive bladder cancer. AB - The purpose of this article is to provide updated recommendations for the diagnosis and treatment of muscle- invasive and metastatic bladder cancer. The diagnosis of muscle-invasive bladder cancer is made by transurethral resection and following histopathologic evaluation. Invasive bladder cancer should be staged according to the UICC system. Patients with confirmed muscle-invasive bladder cancer should be staged by computed tomography scans of the chest, abdomen and pelvis. Radical cystectomy is the treatment of choice for both sexes and lymph node dissection should be an integral part of cystectomy. In muscle- invasive bladder cancer (cT2-4aN0M0) patients with good performance status (PS 0 1) and correct renal function, neoadjuvant chemotherapy should be recommended. Adjuvant chemotherapy is widely used in high-risk patients with pathologic stage T3 or T4 and/or positive nodes and within clinical trials. Multimodality bladder preserving treatment in localised disease is currently regarded only as an alternative in selected, well informed and compliant patients for whom cystectomy is not considered for clinical or personal reasons. In metastatic disease, the first-line treatment for patients is cisplatin-containing combination chemotherapy. Recently, vinflunine has been approved in Europe for second-line treatment and is an option for second-line therapy in patients progressing to first-line platinum-based chemotherapy. PMID- 21821490 TI - SEOM clinical guidelines for diagnosis and treatment of testicular seminoma (2010). AB - Testicular cancer represents the most common malignancy in males aged 15-34 years. Nearly 40% of cases correspond to seminomas and three quarters of them are diagnosed with stage I disease. After orchiectomy, clinical staging should include serial tumour marker assays (alphafetoprotein must be negative), abdominal CT scan and chest X-ray films. Patients with stage I disease can be followedup (active surveillance) or receive adjuvant carboplatin chemotherapy (those with rete testis invasion or non-compliant with follow-up). More advanced disease (stage II and III) and patients with extragonadal seminomas should receive chemotherapy (3-4 courses of BEP) according to IGCCCG risk classification. Residual lesions must be managed by surveillance if they are smaller than 3 cm, while those larger than 3 cm should be evaluated by means of PET. Surgery is only recommended in PET-positive lesions. PMID- 21821491 TI - SEOM guidelines: non-seminomatous germ cell cancer (NSGCC). AB - Non-seminomatous germ cell cancer (NSGCC) is a curable disease; its treatment has not essentially changed since the 1980s. BEP (bleomycin, etoposide, cisplatin) chemotherapy remains the standard of care. NSGCC's management can be summarised by three trees of decision, which contemplate staging, treatment with chemotherapy and management of postchemotherapy residual disease. The role of high-dose chemotherapy remains to be established. TIP (paclitaxel, iposfamide, cisplatin) chemotherapy is still the standard salvage treatment for patients progressing after BEP chemotherapy. Surgical removal of any residual disease is mandatory. For patients with poor prognosis, consultation with a centre of expertise is strongly recommended. PMID- 21821492 TI - SEOM guidelines for the treatment of malignant pleural mesothelioma. AB - Mesothelioma is a rare malignant tumour. Asbestos is the principal aetiological agent of malignant pleural mesothelioma (MPM) (~80% of cases). The incidence of MPM is still increasing and will peak within the next 10 years. There are three main histological types of MPM: epithelial (~60%), sarcomatous and mixed. There is no standard approach for patients with MPM. Surgery (radical extra-pleural pneumonectomy or pleurectomy/decortication) may be part of the initial treatment for carefully selected patients, generally combined with neoadjuvant or adjuvant chemotherapy and/or adjuvant radiotherapy, and should only be performed by experienced thoracic surgeons as part of a multidisciplinary team. Radiotherapy could be used as prophylaxis to reduce the incidence of recurrence at sites of diagnoses or therapeutic instrument insertion, in a multimodal treatment to improve locoregional control and to palliate symptoms. Based on the better compliance of neoadjuvant chemotherapy, lower rate of surgical morbidity and the possibility to select the optimal patients to be submitted to surgery, a neoadjuvant strategy is a better option than adjuvant chemotherapy, although there is no standard optimal sequence and types of treatment for multimodal therapy. In patients with no resectable disease, chemotherapy is the best option with platinum and pemetrexed or raltitrexed. At this time there is no widely approved salvage therapy. PMID- 21821493 TI - SEOM clinical guidelines for the treatment of thyroid cancer. AB - Although thyroid cancer represents less than 1% of malignant tumours, its increased incidence detected in recent years and the appearance and development of new drugs targeting specific molecular targets has attracted the attention of the doctors involved in this pathology, especially medical oncologists. For this reason it is important at this critical point, when treatment may be substantially changed, to establish and agree updated guidelines. These guidelines should incorporate the newly developed strategies that, although still preliminary in evidence level, will surely have an important role, especially in relapsed and refractory tumours, which are unsuitable for surgical or radio iodine treatment. Particular histological and molecular features of these tumours must be taken into account in order to optimise therapeutic approaches. PMID- 21821494 TI - SEOM clinical guidelines for hereditary cancer. AB - Research in genetics has facilitated the identification of highly penetrant genes responsible for a large number of diseases. In the oncology field, genetic counselling and gene testing are focused on the two most common syndromes in familial cancer: hereditary breast and ovarian cancer syndrome (HBOC) and hereditary non-polyposis colorectal cancer or Lynch syndrome (LS). The objective of this guideline in hereditary cancer is to summarise the current state of knowledge and make recommendations in the areas of diagnosis, prevention and treatment of hereditary cancer. PMID- 21821496 TI - SEOM guidelines on thrombosis in cancer patients. AB - The association between cancer and thrombosis is well established. Venous thromboembolism (VTE) is considered a main cause of mortality and morbidity in cancer patients and is commonly underestimated by oncologists. In recent years the incidence rates of VTE have notably increased. Several studies have clearly shown that cancer patients who are diagnosed with VTE present a poorer prognosis. The Spanish Society of Medical Oncology (SEOM) presents the guidelines for thrombosis and cancer in order to improve the prevention and management of VTE. PMID- 21821495 TI - SEOM clinical guidelines for using molecular markers in clinical practice. AB - Nowadays, treatment selection for most types of cancers is based on anatomical, histological and clinical criteria, which are defi ned by the selection criteria used in registration phase III trials. However, different cancers present distinct molecular features, so the current approach results in a lack of specificity of cancer therapy, which is associated with decreased efficacy and unnecessary toxicities and costs. Molecular diagnostics has proved able to predict the efficacy of selected targeted therapies. This allows the selection of specific treatments for different types of cancer, increasing their efficiency. Even though the number of treatments for solid tumours that can be selected based on molecular diagnostic tools is limited, much effort is being put into the identification of new biomarkers. This guideline reviews molecular diagnostic biomarkers that allow selection of specific therapies that have obtained regulatory approval as treatment of solid tumours. PMID- 21821497 TI - [Cardiovascular risk assessment and risk stratification- guided therapy: predict, prevent and individualize]. AB - Modern concept in primary prevention of cardiovascular diseases (CVD) entails assessing the person's global risk and making the right management in accordance with these results. Correspondingly, 3 steps recommended for the prevention of CVD under risk guidance are: (a) risk assessment via a proper system like Framingham Risk Score, SCORE, QRISK, PROCAM; (b) decision-making in the proper management in terms of informing the patient about lifestyle changes that he or she can cope and drug selection; and (c) evaluation of treatment decision in terms of cost effectiveness. Although, a significant decline is observed in CVD morbidity and mortality, particularly in the western countries, we still are trying to approach to competent quality measures about management under CV risk guidance. This review summarizes the main challenges regarding risk stratification-guided management strategy in primary prevention of CVD. PMID- 21821498 TI - Clinical outcomes of mitral valve repair in mitral regurgitation: a prospective analysis of 100 consecutive patients. AB - OBJECTIVE: Mitral valve repair has become the procedure of choice for almost every type of mitral regurgitation (MR) in the current surgical era. We assessed clinical outcomes of mitral valve repair in severe MR. METHODS: In this prospective cohort study, 103 patients (61 male, 42 female, mean age 53.2+/-14.8 years), who were planned to undergo valve repair were included. Mitral valve pathology was regurgitant in 86% and mixed in 14% of patients. The intention to perform mitral repair was successful in 100 (97.1%) of patients. Concomitant procedures were performed in 57 (57%) patients including 31 coronary artery bypass grafting and 13 tricuspid valve repairs. After surgery, early (<30 days) and late (>30 days) complications were recorded. Postoperative echocardiography was performed in all patients at discharge and during clinical follow-up. Late survival and freedom from adverse events including thromboembolism, endocarditis, reoperation, and residual severe MR were estimated by using the Kaplan-Meier survival analysis. RESULTS: There was no early mortality. Echocardiographic assessment of patients at discharge revealed no/trivial regurgitation in 89% and mild (1+) MR in 11% of all patients. Late mortality occurred in only one patient at 14 months because of renal failure. The mean follow-up period of patients was 21.2+/-10.3 months. Echocardiographic examination during follow-up revealed that mitral insufficiency was none or mild in 96% of patients. Three (3%) patients had moderate (2+) MR and were treated medically. Mitral insufficiency recurrence with severe (3+) regurgitation occurred in one (1%) patient undergoing coronary artery revascularization and concomitant left ventricular aneurysmectomy. Re-operation was needed in only one (1%) case because of infective endocarditis that was treated with mechanical valve replacement. Kaplan-Meier estimates were 99+/-2.7% for late survival and 98+/-2.2%, 99+/-2.7%, 99+/-2.7% and 99+/-0.9% for freedom from thromboembolism, endocarditis, reoperation, and residual severe MR, respectively. CONCLUSION: This study showed that mitral valve repair provides excellent surgical outcomes. Repair procedures are safe, and highly effective, but operations require a considerable surgical experience. PMID- 21821499 TI - Clinical significance of intestinal type fatty acid binding protein in patients undergoing coronary artery bypass surgery. AB - OBJECTIVE: The aim of this study was to determine whether serum levels of intestinal type fatty acid binding protein (I-FABP) are related to intestinal ischemia in patients undergoing coronary bypass surgery. METHODS: The study was planned as prospective, observational. Elective coronary artery bypass candidate patients between ages of 50 and 70 were consecutively included in the study. Thirty-five patients scheduled for cardiopulmonary bypass (CPB) were identified as the CPB group and 16 patients not scheduled for CPB were identified as the off pump coronary artery bypass surgery (OPCAB) group. The variables between and within the groups were analyzed with Student's t, Mann-Whitney U, Friedman and Wilcoxon tests respectively. RESULTS: In both CPB and OPCAB groups, I-FABP level at the end of the operation was significantly higher than that noted at the beginning of the operation (p<0.005). In the CPB group, there was a significant drop in I-FABP from the end of the operation to each of the postoperative time points (12(th) hour and 24(th) hour) (respectively p<0.001, p<0.001). In the OPCAB group, the I-FABP levels at both postoperative time points were lower than that at the end of the operation (p<0.001), and the level at 24-hour post-surgery was significantly lower than at both the end-of-operation I-FABP value (p<0.001) and the 12-hour post-surgery I-FABP value. CONCLUSION: Since we have not observed any intestinal ischemia through our research, slight changes of I-FABP measurements make us believe that I-FABP would be a valuable way to monitor for intestinal ischemia in patients who undergo cardiac surgery. PMID- 21821500 TI - The effect of streptokinase therapy in STEMI and conventional therapy in NSTEMI patients on TIMI risk index, B-type natriuretic peptide and high-sensitive C reactive protein. AB - OBJECTIVE: In this study, it was aimed to investigate the effect of streptokinase therapy in ST elevation myocardial infarction (STEMI) and conventional therapy in non-ST elevation myocardial infarction (NSTEMI) patients on the thrombolysis in myocardial infarction (TIMI) risk index (TRI), B-type natriuretic peptide (BNP), and high-sensitive C-reactive protein (hs-CRP) levels. METHODS: Eighty-six STEMI (male/female ratio: 65/21, mean age 57.52+/-9.87 years) and eighty NSTEMI patients (male/female ratio: 50/30, mean age 57.6+/-1.7 years) were included in this prospective observational study. Hs-CRP and BNP were measured and TIMI risk index was calculated in all patients. Coronary angiography was performed in all patients for principally determining TIMI flow rate. Chi-square test, paired t test or Wilcoxon signed rank test, ANOVA and Spearman correlation analysis were used for statistical analysis where appropriate. RESULTS: STEMI patients had higher systolic blood pressure, heart rate, BNP and hs-CRP values than NSTEMI patients at admission (p=0.04, p=0.01, p=0.001 and p=0.01, respectively). Thrombolytic therapy in STEMI patients resulted in statistically significant higher levels of BNP, hs-CRP and TRI values compared to baseline levels (p=0.001, p=0.001 and p=0.042, respectively). For NSTEMI patients conventional therapy yielded statistically significant decrease in systolic blood pressure levels and increase in TRI (p=0.001 and p=0.047, respectively). We found significantly lower BNP, hs-CRP in patients with higher TIMI flow rate (p=0.001 and p=0.001 respectively). CONCLUSION: Thrombolytic therapy with streptokinase failed to decrease BNP, hs-CRP and TRI values in STEMI patients. Conventional therapy in NSTEMI patients also resulted in higher TRI values than baseline values. We reached TIMI 3 flow in only 10.5% of the study patients, which may be responsible for our findings. PMID- 21821501 TI - Value of IGF-I levels in the evaluation of response to treatment with levosimendan in patients with severe heart failure. AB - OBJECTIVE: Levosimendan treatment has inotropic, anti-stunning, and cardioprotective effects in the setting of acute decompensated heart failure (HF). Among studies conducted on the treatment of heart failure, those based on the growth hormone axis are of particular interest. The aim of this study was to determine the value of baseline insulin-like growth factor 1 (IGF-I) measurements in predicting response to levosimendan treatment. METHODS: The study population included patients on standard heart failure treatment who presented with functional capacity NYHA class 3-4 and left ventricular (LV) ejection fraction less than 35% were enrolled in this prospective, cohort study. Pre- and post treatment symptoms of patients (72 hours after the completion of levosimendan infusion) and echocardiographic parameters were evaluated and blood samples were collected. Mann-Whitney U, Pearson Chi-square and Wilcoxon Sign Rank tests were used for statistical analysis. Correlations were determined using Spearman correlation analysis. RESULTS: Thirty patients were enrolled in this study, 83.3% of whom were male and 16.7% were female, with a mean age of 62.6 +/-10.1 years. Mean baseline IGF-I level was 106.9+/-47.0 ug/L. Statistically significant improvements were observed in NYHA class, mean brain natriuretic peptide (BNP) levels, LV ejection fraction and LV end-systolic volume values following treatment with levosimendan (respective pre-treatment and post-treatment values: 3.5+/-0.5 vs. 2.5+/-0.7, p<0.001; 1209.8+/-398.6 pg/ml vs. 704.1+/-344.6 pg/ml, p<0.001, and 25.7+/-6.6% vs. 29.0+/-6.8%, p=0.021, and 164.1+/-45.7 ml vs. 152.8+/-50.6 ml, p=0.012). Fourteen patients (46.7%) had low IGF-I levels, taking into consideration variations due to age and gender. Patients with normal baseline IGF-I values showed more significant decreases in BNP levels in response to treatment compared to those with low baseline IGF-I levels (650.5+/-367.2 pg/ml vs. 340.1+/-269.0 pg/ml, p=0.014). CONCLUSION: Baseline IGF-I levels may be used to predict response to levosimendan treatment in patients hospitalized for decompensated HF. PMID- 21821502 TI - Acute and long-term follow-up results of percutaneous mitral balloon valvuloplasty: a single-center study. AB - OBJECTIVE: Percutaneous mitral balloon valvuloplasty (PMBV) is the method of choice in treatment of patients with hemodynamically significant mitral stenosis. We aimed to analyze acute and long-term clinical and echocardiographic consequences of PMBV. METHODS: In this retrospective cohort study; 311 patients who underwent PMBV in our Cardiology Clinic at Turkiye Yuksek Ihtisas Education and Research Hospital between January 2000 and March 2004 were evaluated for acute procedural outcomes and primary endpoints (death, rePMBV, mitral valve replacement (MVR)). All 311 patients were contacted by phone call or letter at least five years after the procedure. Of the 311 patients, 87 who defined NYHA class II-IV symptoms were invited for a control visit and detailed echocardiographic evaluation. Sixty-three patients out of 87 who completed follow up were enrolled for long-term consequences. Those 63 patients were subclassified into two groups as those without any negative event (n=26) (Group 1) and those with mitral valve area (MVA) (<1.5 cm(2)), rePMBV or referral to MVR (n=37) (Group 2) on follow up to 6.4+/-1.6 years. RESULTS: In the analysis of 311 patients, acute post procedural success, which was defined as mitral valve area (MVA) >=1.5 cm(2) without severe mitral regurgitation, was 94% and was only associated with preprocedural MVA (p=0.008). In the logistic regression analysis, preprocedural MVA was the only independent parameter, associated with acute procedural success (Expbeta=0.004, 95%CI 0.0001-0.234, p=0.008). In the long-term follow up of 63 patients, the patients with uneventful course (Group 1) had significantly higher MVA (p<0.001), lower mean (p=0.001) and peak (p<0.001) transmitral gradients immediately after the procedure when we compared to the patients in Group 2. It was also noticed that patients with at least 60% improvement in MVA experienced composite end point much less frequently compared to those with less than 60% improvement in MVA (5% vs. 30.4%, p=0.009). Kaplan Meier analysis yielded significantly diverging cumulative survival curves for those with and without at least 60% improvement in MVA (p=0.003). CONCLUSION: Concerning long-term follow up data of patients undergoing PMBV in a single center, it seems only acute postprocedural MVA was significantly associated with long-term consequences. PMID- 21821503 TI - A systematic review of the impact of adherence on the effectiveness of e therapies. AB - BACKGROUND: As the popularity of e-therapies grows, so too has the body of literature supporting their effectiveness. However, these interventions are often plagued by high attrition rates and varying levels of user adherence. Understanding the role of adherence may be crucial to understanding how program usage influences the effectiveness of e-therapy interventions. OBJECTIVE: The aim of this study was to systematically review the e-therapy literature to (1) describe the methods used to assess adherence and (2) evaluate the association of adherence with outcome of these interventions. METHODS: A systematic review of e therapy interventions was conducted across disease states and behavioral targets. Data were collected on adherence measures, outcomes, and analyses exploring the relationship between adherence measures and outcomes. RESULTS: Of 69 studies that reported an adherence measure, only 33 (48%) examined the relationship between adherence and outcomes. The number of logins was the most commonly reported measure of adherence, followed by the number of modules completed. The heterogeneity of adherence and outcome measures limited analysis. However, logins appeared to be the measure of adherence most consistently related to outcomes in physical health interventions, while module completion was found to be most related to outcomes in psychological health interventions. CONCLUSIONS: There is large variation in the reporting of adherence and the association of adherence with outcomes. A lack of agreement about how best to measure adherence is likely to contribute to the variation in findings. Physical and psychological outcomes seem influenced by different types of adherence. A composite measure encompassing time online, activity completion, and active engagements with the intervention may be the best measure of adherence. Further research is required to establish a consensus for measuring adherence and to understand the role of adherence in influencing outcomes. PMID- 21821505 TI - The case of the missing data. PMID- 21821504 TI - A virtual clinic for diabetes self-management: pilot study. AB - BACKGROUND: Internet-based interventions to assist in diabetes management have the potential to provide patients with the information and support they need to become effective self-managers. OBJECTIVE: To assess the feasibility, acceptability, and effectiveness of an Internet-based virtual clinic designed to facilitate self-management in patients who used insulin pumps to manage their diabetes. METHODS: For a period of 6 months, 17 patients joined the virtual clinic. The system allowed patients to communicate with health professionals, interact with peers and access information. HbA1c, quality of life, and self efficacy were monitored at baseline and after 6 months. Questionnaires and qualitative interviews examined patient experiences. RESULTS: Participants found the virtual clinic easy to use and positively rated its design. Peer support was the most valued aspect and the discussion boards the most used component. All participants highly rated the virtual clinic in terms of improving communication with peers, but few agreed it had improved communication with health care professionals. No significant improvements in physiological and psychological measurements were found. Regarding HbA1c measurements, there was no significant difference found between the pre- and post-test results (P = .53). Mean ADDQoL scores at baseline were -2.1 (SD 1.1, range -3.4 to -0.5) compared to -2.0 (SD 1.2, range, -4.6 to -0.4) post-test (n = 12), (P = .62). Surprisingly, patients' confidence in their ability to perform self-care tasks was found to be significantly reduced from baseline to follow up (P = .045). CONCLUSIONS: An Internet-based system to aid the management of diabetes appears feasible and well accepted by patients. The pilot study did not identify evidence of an impact on improving quality of life or self-efficacy in patients who used insulin pump therapy. PMID- 21821506 TI - Local infiltration analgesia versus intrathecal morphine for postoperative pain management after total knee arthroplasty: a randomized controlled trial. AB - BACKGROUND: Local infiltration analgesia (LIA)--using a combination of local anesthetics, nonsteroidal anti-inflammatory drugs, and epinephrine, injected periarticularly during surgery-has become popular in postoperative pain management after total knee arthroplasty (TKA). We compared intrathecal morphine with LIA after TKA. METHODS: In this double-blind study, 50 patients scheduled to undergo TKA under spinal anesthesia were randomized into 2 groups: group M, 0.1 mg morphine was injected intrathecally together with the spinal anesthetic and in group L, LIA using ropivacaine, ketorolac, and epinephrine was infiltrated in the knee during the operation, and 2 bolus injections of the same mixture were given via an intraarticular catheter postoperatively. Postoperative pain, rescue analgesic requirements, mobilization, and home readiness were recorded. Patient assessed health quality was recorded using the Oxford Knee Score and EQ-5D during 3 months follow-up. The primary endpoint was IV morphine consumption the first 48 postoperative hours. RESULTS: Mean morphine consumption was significantly lower in group L than in group M during the first 48 postoperative hours: 26 +/- 15 vs 54 +/- 29 mg, i.e., a mean difference for each 24-hour period of 14.2 (95% confidence interval [CI] 7.6 to 20.9) mg. Pain scores at rest and on movement were lower during the first 48 hours in group L than in group M (P < 0.001). Pain score was also lower when walking in group L than in group M at 24 hours and 48 hours postoperatively (P < 0.001). In group L, more patients were able to climb stairs at 24 hours: 50% (11 of 22) versus 4% (1 of 23), i.e., a difference of 46% (95% CI 23.5 to 68.5) and at 48 hours: 70% (16 of 23) versus 22% (5 of 23), i.e., a difference of 48% (95% CI 23 to 73). Median (range) time to fulfillment of discharge criteria was shorter in group L than in group M, 51 (24-166) hours versus 72 (51-170) hours. The difference was 23 (95% CI 18 to 42) hours (P = 0.001). Length of hospital stay was also shorter in group L than in group M: median (range) 3 (2-17) versus 4 (2-14) days (P = 0.029). Patient satisfaction was greater in group L than in group M (P = 0.001), but no differences were found in knee function, side effects, or in patient-related outcomes, Oxford Knee score, or EQ-5D. CONCLUSIONS: LIA technique provided better postoperative analgesia and earlier mobilization, resulting in shorter hospital stay, than did intrathecal morphine after TKA. PMID- 21821507 TI - Review article: Dexmedetomidine in children: current knowledge and future applications. AB - More than 200 studies and reports have been published regarding the use of dexmedetomidine in infants and children. We reviewed the English literature to summarize the current state of knowledge of this drug in children for the practicing anesthesiologist. Dexmedetomidine is an effective sedative for infants and children that only minimally depresses the respiratory system while maintaining a patent airway. However, dexmedetomidine does depress the cardiovascular system. Specifically, bradycardia, hypotension, and hypertension occur to varying degrees depending on the age of the child. Hypertension is more prevalent when larger doses of dexmedetomidine are given to infants. Consistent with its 2-hour elimination half-life, recovery after dexmedetomidine may be protracted in comparison with other sedatives. Dexmedetomidine provides and augments analgesia and diminishes shivering as well as agitation postoperatively. The safety record of dexmedetomidine suggests that it can be used effectively and safely in children, with appropriate monitoring and interventions to manage cardiovascular sequelae. PMID- 21821508 TI - Perioperative exacerbation of valproic acid-associated hyperammonemia: a clinical and genetic analysis. AB - We present a case of significant deterioration of chronic hyperammonemia after general anesthesia for neurosurgery despite aggressive treatment. Preoperative evaluation demonstrated that hyperammonemia was most likely related to valproic acid treatment. Genomic analysis revealed that the patient was heterozygotic for a missense polymorphism in the carbamoyl phosphate synthase 1 gene (4217C>A, rs1047891). This mutation was previously suggested to be associated with chronic hyperammonemia. Replacement of threonine with asparagine decreases the activity of carbamoyl phosphate synthase in the urea cycle. Genetic screening can potentially identify a population at risk before initiation of antiepileptic therapy. PMID- 21821509 TI - An echocardiographic evaluation of valvular function and ventricular patch repair during surgical exclusion of left ventricular pseudoaneurysm. PMID- 21821510 TI - Statistical grand rounds: Importance of appropriately modeling procedure and duration in logistic regression studies of perioperative morbidity and mortality. AB - Multiple logistic regression studies frequently are performed with duration (e.g., operative time) included as an independent variable. We use narrative review of the statistical literature to highlight that when the association between duration and outcome is presumptively significant, the procedure itself (e.g., video-assisted thoracoscopic lobectomy or thoracotomy lobectomy) needs to be tested for inclusion in the logistic regression. If the procedure is a true covariate but excluded in lieu of category of procedure (e.g., lung resection), estimates of the odds ratios for other independent variables are biased. In addition, actual durations are sometimes used as the independent variable, rather than scheduled (forecasted) durations. Only the scheduled duration is known when a patient would be randomized in a trial of preoperative or intraoperative intervention and/or meets with the surgeon and anesthesiologist preoperatively. By reviewing the literature about logistic regression and about predicting case duration, we show that the use of actual instead of scheduled duration can result in biased logistic regression results. PMID- 21821511 TI - Continuous peripheral nerve blocks: a review of the published evidence. AB - A continuous peripheral nerve block, also termed "perineural local anesthetic infusion," involves the percutaneous insertion of a catheter adjacent to a peripheral nerve, followed by local anesthetic administration via the catheter, providing anesthesia/analgesia for multiple days or even months. Continuous peripheral nerve blocks may be provided in the hospital setting, but the use of lightweight, portable pumps permits ambulatory infusion as well. This technique's most common application is providing analgesia after surgical procedures. However, additional indications include treating intractable hiccups; inducing a sympathectomy and vasodilation to increase blood flow after a vascular accident, digit transfer/replantation, or limb salvage; alleviating vasospasm of Raynaud disease; and treating peripheral embolism and chronic pain such as complex regional pain syndrome, phantom limb pain, trigeminal neuralgia, and cancer induced pain. After trauma, perineural infusion can provide analgesia during transportation to a distant treatment center, or while simply awaiting surgical repair. Catheter insertion may be accomplished using many possible modalities, including nerve stimulation, ultrasound guidance, paresthesia induction, fluoroscopic imaging, and simple tactile perceptions ("facial click"). Either a nonstimulating epidural-type catheter may be used, or a "stimulating catheter" that delivers electrical current to its tip. Administered infusate generally includes exclusively long-acting, dilute, local anesthetic delivered as a bolus only, basal only, or basal-bolus combination. Documented benefits appear to be dependent on successfully improving analgesia, and include decreasing baseline/breakthrough/dynamic pain, supplemental analgesic requirements, opioid related side effects, and sleep disturbances. In some cases, patient satisfaction and ambulation/functioning may be improved; an accelerated resumption of passive joint range-of-motion realized; and the time until discharge readiness as well as actual discharge from the hospital or rehabilitation center achieved. Lastly, postoperative joint inflammation and inflammatory markers may be decreased. Nearly all benefits occur during the infusion itself, but several randomized controlled trials suggest that in some situations there are prolonged benefits after catheter removal as well. Easily rectified minor complications occur somewhat frequently, but major risks including clinically relevant infection and nerve injury are relatively rare. This article is an evidence-based review of the published literature involving continuous peripheral nerve blocks. PMID- 21821512 TI - A prospective survey of patient-controlled epidural analgesia with bupivacaine and clonidine after total hip replacement: a pre- and postchange comparison with bupivacaine and hydromorphone in 1,000 patients. AB - BACKGROUND AND OBJECTIVES: Patient-controlled epidural analgesia (PCEA) with bupivacaine and hydromorphone provides high quality analgesia after orthopedic surgery but is associated with a frequent incidence of opioid-related side effects (15%-30%). Epidural clonidine has a different side effect profile, but there are no large surveys documenting its use. We performed this prospective survey to evaluate analgesia and the side effect profile in total hip replacement patients before and after a systematic change from PCEA with bupivacaine/hydromorphone to bupivacaine/clonidine. METHODS: Five hundred consecutive patients received PCEA with 0.06% bupivacaine and hydromorphone (10 mcg/mL) as a previously described prechange control group. The standard analgesic regimen was then systematically changed to 0.06% bupivacaine and clonidine (1 mcg/mL) without changing the PCEA settings or other aspects of perioperative care, and 500 consecutive patients were included as a postchange group. All data were prospectively entered and then abstracted from the electronic medical record. Data collection included daily verbal pain scores (VPS), pruritus, nausea, hypotension, need for IV fluid boluses, sedation, and respiratory depression. An online survey to measure staff satisfaction with the changeover was sent to all participating surgeons, anesthesiologists, physical therapists, and physician's assistants. RESULTS: Patient characteristics were similar between groups. Most patients received central neuraxial anesthesia (99%). The clonidine group had lower VPS at rest (2.3 vs 3.7, P<0.001 with 95% confidence interval [CI] of difference of 1.4 [1.1, 1.7]) on POD0. The incidence of nausea was 10% 11% for clonidine and 13%-15% for hydromorphone. The incidence of pruritus was less with clonidine (1 vs 10%, P<0.01 with 95% CI of difference of 9% [6, 12]). However, the incidence of hypotension (20 vs 11%, P<0.001 with 95% CI of differences 9% [5, 14]) and IV fluid boluses was more frequent with clonidine (36 vs 19%, P<0.001 with 95% CI of differences of 16 [11, 12]). Sixty-five percent of staff completed the online survey, and 70% considered clonidine worse than hydromorphone. CONCLUSION: The systematic changeover from epidural hydromorphone to clonidine produced mixed results without obvious superiority. The VPS at rest was reduced only on postoperative day 0; pruritus was reduced, but hypotension was increased. On the basis of medical staff preference, we discontinued the systematic change and returned to our previous standard solution of bupivacaine and hydromorphone for PCEA after total hip replacement. PMID- 21821513 TI - A randomized comparison of intraoperative PerfecTemp and forced-air warming during open abdominal surgery. AB - BACKGROUND: The PerfecTemp is an underbody resistive warming system that combines servocontrolled underbody warming with viscoelastic foam pressure relief. Clinical efficacy of the system has yet to be formally evaluated. We therefore tested the hypothesis that intraoperative distal esophageal (core) temperatures with the PerfecTemp (underbody resistive) warming system are noninferior to upper body forced-air warming in patients undergoing major open abdominal surgery under general anesthesia. METHODS: Adults scheduled for elective major open abdominal surgery (liver, pancreas, gynecological, and colorectal surgery) under general anesthesia were enrolled at 2 centers. Patients were randomly assigned to underbody resistive or forced-air warming. Resistive heating started when patients were transferred to the operating room table; forced-air warming started after patients were draped. The primary outcome was noninferiority of intraoperative time-weighted average core temperature, adjusted for baseline characteristics and using a buffer of 0.5 degrees C. RESULTS: Thirty-six patients were randomly assigned to underbody resistive heating and 34 to forced-air warming. Baseline and surgical characteristics were generally similar. We had sufficient evidence (P=0.018) to conclude that underbody resistive warming is not worse than (i.e., noninferior to) upper-body forced-air warming in the time weighted average intraoperative temperature, with a mean difference of -0.12 degrees C [95% confidence interval (CI) -0.37 to 0.14]. Core temperatures at the end of surgery averaged 36.3 degrees C [95% CI 36 to 36.5] in the resistive warming patients and 36.6 degrees C [95% CI 36.4 to 36.8] in those assigned to forced-air warming for a mean difference of -0.34 degrees C [95% CI -0.69 to 0.01]. CONCLUSIONS: Mean intraoperative time-weighted average core temperatures were no different, and significantly noninferior, with underbody resistive heating in comparison with upper-body forced-air warming. Underbody resistive heating may be an alternative to forced-air warming. PMID- 21821514 TI - The limitations of near-infrared spectroscopy to assess cerebrovascular reactivity: the role of slow frequency oscillations. AB - BACKGROUND: A total hemoglobin reactivity index (THx) derived from near-infrared spectroscopy (NIRS) has recently been introduced to assess cerebrovascular reactivity noninvasively. Analogously to the pressure reactivity index (PRx), THx is calculated as correlation coefficient with arterial blood pressure (ABP). However, the reliability of THx in the injured brain is uncertain. Although slow oscillations have been described in NIRS signals, their significance for assessment of autoregulation remains unclear. In the current study, we investigated the role of slow oscillations of total hemoglobin for NIRS-based cerebrovascular reactivity monitoring. METHODS: This study was based on a retrospective analysis of data that were consecutively recorded for a different project published previously. Thirty-seven patients with traumatic brain injury and admitted to Addenbrooke's Neurosciences Critical Care Unit between June 2008 and June 2009 were included. After artifact removal, we performed spectral analysis of the tissue hemoglobin index (THI, a measure of oxy- and deoxygenated hemoglobin) and intracranial pressure (ICP) signal. PRx and THx were calculated as moving correlations between ICP and ABP, and THI and ABP, respectively. The agreement between PRx and THx as a function of normalized power of slow oscillations (0.015-0.055 Hz) contained in the input signals was assessed performing between-subject and within-subject correlation analyses. Furthermore, the correlation between the THx values derived from the right and left sides was analyzed. RESULTS: The agreement between PRx and THx depended on the power of slow oscillations in the input signals. Between-subject comparisons revealed a significant correlation between THx and PRx (r = 0.80, 95% confidence interval 0.53-0.92, P < 0.01) for patients with normalized slow wave activity >0.4 in the THI signal, compared with r = 0.07 (95% confidence interval -0.40 to 0.51, P = 0.79) in the remaining files. Furthermore, within-subject comparisons suggested that THx may be used as a substitute for PRx only when there is an at least moderate agreement (r = 0.36) between the THx values derived from the right and left sides. CONCLUSIONS: Our results suggest that the NIRS-based cerebrovascular reactivity index THx can be used as a noninvasive substitute for PRx, but only during phases with sufficient slow wave power in the input signal. Furthermore, a good agreement between the THx measures on both sides seems to be a prerequisite for comparison of a global (PRx) versus the more local (THx) index. Nevertheless, noninvasive assessment of cerebrovascular reactivity may be desirable in patients without ICP monitoring and help to guide ABP management in these patients. PMID- 21821515 TI - Barriers to adverse event and error reporting in anesthesia. AB - BACKGROUND: Although anesthesiologists are leaders in patient safety, there has been little research on factors affecting their reporting of adverse events and errors. First, we explored the attitudinal/emotional factors influencing reporting of an unspecified adverse event caused by error. Second, we used a between-groups study design to ask whether there are different perceived barriers to reporting a case of anaphylaxis caused by an error compared with anaphylaxis not caused by error. Finally, we examined strategies that anesthesiologists believe would facilitate reporting. Where possible, we contrasted our results with published findings from other physician groups. METHODS: An anonymous, self administered, mailed survey was conducted of 629 consultant anesthesiologists and 263 anesthesiology residents on the mailing list of the Australian and New Zealand College of Anaesthetists in Victoria, Australia. Participants were randomized into "Error" versus "No Error" groups for the specified anaphylaxis adverse event section of the survey. Data were analyzed using nonparametric descriptive and inferential tests. RESULTS: There were 433 usable returned surveys, a usable response rate of 49%. First, there was only 1 of 13 statements on attitudinal/emotional factors that influenced reporting of an unspecified adverse event caused by error with which more anesthesiologists agreed/strongly agreed than disagreed/strongly disagreed: "Doctors who make errors are blamed by their colleagues." Second, when an error rather than no error had caused anaphylaxis, participants were more likely to agree/strongly agree that 6 statements about litigation, getting into trouble, disciplinary action, being blamed, unsupportive colleagues, and not wanting the case discussed in meetings, were perceived as reporting barriers. Finally, the most favored assistive strategies for reporting were generalized deidentified feedback about adverse event and error reports, role models such as senior colleagues who openly encourage reporting, and legislated protection of reports from legal discoverability. CONCLUSION: The majority of anesthesiologists in our study did not agree that the attitudinal/emotional barriers surveyed would influence reporting of an unspecified adverse event caused by error, with the exception of the barrier of being concerned about blame by colleagues. The probable influence of 6 perceived barriers to reporting a specified adverse event of anaphylaxis differed with the presence or absence of error. Anesthesiologists in our study supported assistive reporting strategies. There seem to be some differences between our results and previously published research for other physician groups. PMID- 21821516 TI - The impact of phenylephrine, ephedrine, and increased preload on third-generation Vigileo-FloTrac and esophageal doppler cardiac output measurements. AB - BACKGROUND: Cardiac output (CO) monitoring based on pulse contour analysis (Vigileo-FloTrac) has the potential to be used for goal-directed fluid therapy in the perioperative setting. However, factors such as vasopressor usage may impact Vigileo-FloTrac's reliability in tracking CO changes. We tested third-generation Vigileo-FloTrac system's ability to accurately measure the changes in CO induced by vasopressor administration and increased preload in comparison with esophageal Doppler measurements. METHODS: In 33 anesthetized patients, CO was monitored simultaneously by the third-generation Vigileo-FloTrac and esophageal Doppler. Hemodynamic challenges included phenylephrine (to increase vasomotor tone), ephedrine (to increase myocardial contractility and heart rate), and whole-body tilting (to increase preload). Measurements were performed before and after each intervention. RESULTS: Overall, 176 pairs of CO measurements were obtained. The difference between paired pulse contour and Doppler measurements of CO was 0.14 +/- 2.13 L/min (mean +/- SD), and the percentage error (2 SD of the difference divided by the mean CO of the reference method) was 66%. The trending ability of pulse contour versus Doppler was 23% (concordance, the percentage of the total number of data points that are in 1 of the 2 quadrants of agreement) after phenylephrine treatment, 69% (concordance) after ephedrine treatment, and 96% (concordance) after whole-body tilting. CONCLUSIONS: The pulse contour method of measuring CO, as implemented in the third-generation Vigileo-FloTrac device, accurately tracks changes in CO when preload changes. However, the pulse contour method does not accurately track changes in CO induced with phenylephrine and ephedrine. PMID- 21821517 TI - The minimum effective anesthetic volume of 0.75% ropivacaine in ultrasound-guided interscalene brachial plexus block. AB - BACKGROUND: The use of ultrasound to monitor needle placement and spread of local anesthetics (LA) has allowed reductions in the volume of LA required to anesthetize peripheral nerves. In the current study we investigated the minimal volume necessary to accomplish surgical anesthesia with interscalene brachial plexus block. METHODS: Twenty ASA physical status I-III patients, ages 18 to 75 years and scheduled for shoulder surgery under interscalene brachial plexus block, were enrolled. Using a previously validated step-up/step-down method, we determined the injection volume of 0.75% ropivacaine used for consecutive patients by the outcome of the preceding block. The starting volume was 15 mL (3 injections of 5 mL per each trunk); in the case of block failure, the volume was increased by 1 mL, whereas after successful block, the volume was reduced by 1 mL. The study was stopped upon achieving the secondary stopping rule of 10 consecutive successful interscalane blocks using 5 mL of ropivacaine 0.75%. Successful surgical anesthesia with the brachial plexus block was defined as presence of adequate motor block (motor score of <=2 on 0 to 4 scale), absent sensation to cold and pinprick sensation within 30 minutes of injection, and absence of the need for general anesthesia for completion of surgery. Duration of sensory blockade was assessed by asking the patient to record the time of first pain sensation. RESULTS: Under our study conditions, successful surgical anesthesia for arthroscopic shoulder surgery can be achieved with 5 mL of 0.75% ropivacaine, or approximately 1.7 mL per each of the 3 trunks of the brachial plexus (superior, middle, and inferior). The study was stopped after 10 consecutive successful blocks with 5 mL of LA (100%, 95% confidence interval [CI]: 74.1%-100%). For the group as a whole, the median (range) sensory block onset time was 5 (5-20) minutes, the median (range) motor block for the biceps was 7.5 (5-15) minutes, and for abduction 10 (5-15) minutes. The median (range) block duration was 9.9 (5-19) hours, and the mean (SD) block performance time was 8.0 +/- 3.2 minutes. Mean duration of analgesia was 9.9 +/- 3.7 hours. Duration of analgesia was not associated with volume of LA (r = 0.05, P = 0.83). CONCLUSIONS: All patients in our study had successful surgical blocks with 5 mL of LA. However, the lower limit of the CI (calculated on the assumption of a single failure) does include the possibility of a 25% failure rate; thus studies using similar stopping rules for doses higher than 5 mL are nonetheless warranted. PMID- 21821518 TI - Preoperative pulse pressure and major perioperative adverse cardiovascular outcomes after lower extremity vascular bypass surgery. AB - BACKGROUND: Preoperative increased pulse pressure (PP) has been found to be a predictor of major adverse cardiovascular events (MACEs) after coronary artery bypass graft surgery. In this study, we evaluated the predictive ability of increased preoperative PP to identify MACEs in patients with peripheral vascular disease undergoing lower extremity vascular bypass surgery. METHODS: We used the prospectively collected vascular surgery database at our institution to identify 412 consecutive patients who had lower extremity bypass surgery between January 2003 and December 2004. Preoperative demographics including comorbidities, medications, intraoperative characteristics, and postoperative MACE outcomes (myocardial infarction, congestive heart failure, stroke, and in-hospital mortality) were recorded. PP data as a continuous and categorical variable (PP <80 or >=80 mm Hg) were tested for the ability to predict postoperative MACEs. A final parsimonious logistic regression was built to evaluate the predictive ability of PP. RESULTS: MACEs occurred in 5.7% of patients in the PP <80 mm Hg group compared with 8.8% in the PP >=80 mm Hg group (P = 0.229). Patients with MACEs were older (76 +/- 10 years vs 68 +/- 12 years; P = 0.001), had a history of myocardial infarction (9% vs 4%; P = 0.049), and had a preoperative PP of 75 +/- 19 mm Hg vs 71 +/- 21 mm Hg (P = 0.306). In the final logistic regression model, only age in years was a predictor of MACEs (odds ratio, 1.062; 95% confidence interval, 1.02-1.10; P = 0.02). There was no relationship between PP >=80 mm Hg and risk for MACEs (odds ratio, 1.36; 95% confidence interval, 0.62 2.90; P = 0.44). CONCLUSIONS: Preoperative increase in PP is not a predictor of adverse cardiovascular outcomes in patients having lower extremity revascularization surgery. PMID- 21821519 TI - Introduction to proceedings of the NHLBI workshop: New Horizons in cardioprotection--a focused issue of journal of cardiovascular pharmacology and therapeutics. PMID- 21821520 TI - State of the science of cardioprotection: Challenges and opportunities- proceedings of the 2010 NHLBI Workshop on Cardioprotection. AB - The National Heart, Lung, and Blood Institute convened a Workshop on September 20 21, 2010, "New Horizons in Cardioprotection," to identify future research directions for cardioprotection against ischemia and reperfusion injury. Since the early 1970s, there has been evidence that the size of a myocardial infarction could be altered by various interventions. Early coronary artery reperfusion has been an intervention that consistently reduces myocardial infarct size in animal models as well as humans. Most cardiologists agree that the best way to treat acute ST-segment elevation myocardial infarction is to reperfuse the infarct artery as soon as possible and to keep the infarct artery patent. In general, stenting is superior to angioplasty, which is superior to thrombolysis. There is no accepted adjunctive therapy to acutely limit myocardial infarct size along with reperfusion that is routinely used in clinical practice. In the Kloner experimental laboratory, some adjunctive therapies have reproducibly limited infarct size (regional hypothermia, preconditioning, cariporide, combinations of the above, remote preconditioning, certain adenosine agonists, and late sodium current blockade). In clinical trials, a host of pharmacologic adjunctive therapies have failed to either reduce infarct size or improve clinical outcome. Potential reasons for the failure of these trials are discussed. However, some adjunctive therapies have shown promise in data subanalyses or subpopulations of clinical trials (adenosine, therapeutic hypothermia, and hyperoxemic reperfusion) or in small clinical trials (atrial natriuretic peptide, ischemic postconditioning, and cyclosporine, the mitochondrial permeability transition pore inhibitor). A recent clinical trial with remote conditioning induced by repetitive inflation of a brachial artery cuff begun prior to hospitalization showed promise in improving myocardial salvage and there are several reports in the cardiothoracic literature, suggesting that remote preconditioning protects hearts during surgery. Thus, in 2011, there is hope that applying some of the body's own conditioning mechanisms may provide protection against ischemic damage. PMID- 21821521 TI - Cell death pathways in acute ischemia/reperfusion injury. AB - The consequence of myocardial ischemia is energetic stress, while reperfusion is accompanied by abrupt ionic shifts and considerable oxidative stress. Cells die by apoptotic and necrotic pathways. After the acute injury, the healing myocardium is subject to biomechanical stress and inflammation, which can trigger a smaller but more sustained wave of cell death, as well as changes in the metabolic and functional characteristics of surviving cells. The goal of cardioprotection is to prevent cell death during the acute injury as well as to modulate the detrimental processes that ensue during remodeling. This review will focus on acute injury, and the central premise is that mitochondria are the key determinant of cardiomyocyte fate. PMID- 21821522 TI - How and when do myocytes die during ischemia and reperfusion: the late phase. AB - While the majority of the cardiac myocyte death that makes up the final infarct occurs during ischemia and the first few minutes of reperfusion, cell death does not stop there. In fact necrosis and apoptosis, and potentially autophagy, can continue in the previously ischemic area for up to 3 days post-reperfusion. Several mechanisms can potentially contribute to this death continuum: (1) myocytes that have already passed the point of no return despite reperfusion; (2) continued dysfunction of the coronary microvasculature; and (3) infiltration of inflammatory cells. The latter in particular leads to elevated myocardial concentrations of reactive oxygen species (ROS), inflammatory cytokines, activation of toll-like receptors, secretion of toxic enzymes, and activation of the complement cascade--all of which can lead to myocyte death. However, there is a considerable lack of studies that comprehensively examine the time course, nature, and mechanisms of post-reperfusion myocyte death. Moreover, cell death types (apoptosis, necrosis, and autophagy) are inextricably linked to one another. Therefore, we do not know whether specific blockade of necrosis during the acute phase of myocyte death will instead enhance apoptosis during the late phase, that is, will we be simply delaying the inevitable? Consequently, the purpose of this article is to briefly review what we do, and more importantly what we do not, know about cardiac cell death in the reperfused heart and what is needed to advance our understanding of this phenomenon. PMID- 21821523 TI - No-reflow phenomenon: maintaining vascular integrity. AB - The no-reflow phenomenon relates to the inability to reperfuse regions of the myocardium after ischemia, despite removal of the large epicardial coronary artery occlusion. The mechanism involves microvascular obstruction. In experimental studies, using markers for flow (thioflavin S, carbon black, microspheres), perfusion defects associated with no-reflow demonstrated ultrastructural evidence of localized endothelial swelling and blebs that appeared to obstruct flow. In humans no-reflow is more complicated due to the microemboli of atherosclerotic debris and thrombi generated by percutaneous coronary intervention. The no-reflow zone expands during the first few hours of reperfusion suggesting an element of reperfusion injury. In animal models, extensive no-reflow was associated with worse infarct expansion. The phenomenon of no-reflow following reperfusion therapy for myocardial infarction in humans has been demonstrated by magnetic resonance imaging, echo contrast agents, thallium, technecium-99m-labeled albumin microspheres, Thrombolysis In Myocardial Infarction (TIMI) scores, and myocardial blush grade. Patients exhibiting no reflow following reperfusion therapy for myocardial infarction have greater left ventricular dilation and remodeling, more congestive heart failure, shock, and reduced survival. Certain vasodilators (adenosine, nitroprusside, nicorandil, and calcium blockers) are used acutely in the catheterization laboratory and appear to improve no-reflow, but systematic studies on therapy for no-reflow are needed. There is now clinical evidence that no-reflow is a strong predictor of long-term mortality that is independent of and beyond that provided by infarct size. Identifying and treating no-reflow may have important benefits including enhancing delivery of nutrients and cells required for healing and reducing infarct expansion and ventricular remodeling, which ultimately may reduce congestive heart failure and mortality. PMID- 21821524 TI - Clinically useful cardioprotection: ischemic preconditioning then and now. AB - Ischemic preconditioning (IP) is the most effective, reproducible form of protection against myocardial cell death yet described. The mechanism of classic IP has not been identified, but recent investigations have focused on the mitochondrial permeability transition pore (mPTP). Similarly, the mechanism of the "second window of protection" (SWOP) is not known but thought to involve increased expression of important gene products. Currently, IP in the clinical arena is limited to cardiac surgery, planned angioplasty, and organ preservation protocols. To move preconditioning into a broader clinical arena will require resolution of important fundamental yet stubborn problems involving both basic and clinical science. Important unresolved issues include the mechanisms involved in the transition from reversible to irreversible injury, the amount of potential salvageable myocardium present at the onset of reperfusion, the identity and signaling of the mPTP, the optimization of protocols, the identity of end effectors (SWOP), and the identification of the best experimental model systems. From a clinical standpoint, important issues include the influence of comorbidities on cardioprotection, identification of appropriate animal models, the lack of a biologic marker of the cardioprotective state, the influence of coexistent therapeutic drugs, potential toxicity of pharmacologic mimics, and the window of opportunity for significant protection. Ischemic preconditioning has yielded promising results in other organs including the brain as well as tissue preservation for certain surgical procedures that will require definition of the underlying mechanism(s) to be fully exploited clinically. Over the past 25 years, the scientific community has learned much regarding the biology and potential mechanisms of IP and the concept has been expanded to many other organ systems in many other clinically relevant scenarios. To realize the full clinical potential will require continued investigation into the mechanism. PMID- 21821525 TI - Remote ischemic preconditioning: current knowledge, unresolved questions, and future priorities. AB - Remote ischemic preconditioning (RIPC) is the phenomenon whereby brief episodes of ischemia-reperfusion applied in distant tissues or organs render the myocardium resistant to a subsequent sustained episode of ischemia. Reduction of infarct size with RIPC has been documented in response to (i) brief antecedent ischemia in a remote coronary vascular bed (intra-cardiac protection); (ii) collection and transfer of coronary effluent from perconditioning "donor" hearts to naive "receptor" hearts (inter-cardiac protection); (iii) brief ischemia applied in skeletal muscle, mesentery, and other organs (interorgan protection); and (iv) remote nociception ("remote PC of trauma"). Moreover, the paradigm has expanded to encompass temporal modifications in the application of the remote stimulus (remote perconditioning and remote postconditioning). Progress has also been made in translating the concept of RIPC to patients undergoing planned ischemic events: evidence for attenuation of cardiac enzyme release with RIPC has been reported after elective abdominal aortic aneurysm repair, angioplasty, and coronary artery bypass graft surgery. However, despite these advances in characterization and clinical application, the mechanisms of RIPC--most notably, the means by which the protective stimulus is communicated to the heart--remain poorly defined and, in all likelihood, are model dependent. PMID- 21821526 TI - Perconditioning and postconditioning: current knowledge, knowledge gaps, barriers to adoption, and future directions. AB - The broad definition of "conditioning" is the application of a series of alternating intervals of brief ischemia (hypoxia) and reperfusion (reoxygenation) applied in the setting of prolonged ischemia causing myocardial infarction. While the conditioning stimulus is applied before the major (index) ischemic event in ischemic preconditioning, it is applied during the event in perconditioning, and applied after the event (reperfusion) in postconditioning. Studies on perconditioning have only recently demonstrated a reduction in infarct size by remote ischemia applied during transport of heart attack victims to the hospital before percutaneous coronary interventions (PCIs). The "conditioning" paradigm has been extended to include remote perconditioning and remote postconditioning. However, the biology of perconditioning is virtually unknown. Postconditioning has enjoyed enthusiastic attention from scientists that have done much to demonstrate that the model of triggers, mediators, and effectors used in preconditioning may also apply to postconditioning, with the addition and important contribution of physiological mechanisms resulting in cardioprotection, including gradual normalization of tissue pH, reduction in generation of reactive oxygen species, and avoidance of hypercontracture. This same schema has not been confirmed in perconditioning. However, the unknowns in both conditioning paradigms far outweigh the knowns. Why postconditioning does not exert cardioprotection in experimental models of comorbidities and aging, yet reduces postischemic injury and contractile dysfunction in older patients with multiple comorbidities is a conundrum for which no answers are forthcoming. The optimal algorithm is unknown, as is the interrelationship between the many molecular, cellular, and physiological pathways that purportedly "mediate" or "trigger" the conditioning responses. Whether there are common pathways engaged in all 3 forms of conditioning, and what nuances separate one form of conditioning from another are unanswered questions. Yet, the translational potential of per- and postconditioning will drive further experimental work and clinical trials, which will ask unprecedented cooperation and information sharing between basic and clinician scientists, and creative developments from industry. PMID- 21821528 TI - Is it time to translate ischemic preconditioning's mechanism of cardioprotection into clinical practice? AB - After three decades of intense research on cardioprotection, we still do not have an approved intervention for limiting infarct size in the patient with acute myocardial infarction (AMI) aside from reperfusion therapy. Yet approximately 25% of patients with AMI that are reperfused are still at risk for heart failure because of excessive muscle necrosis. This article will try to make the case that ischemic preconditioning (IPC), still the most potent anti-infarct intervention ever described, is ready for serious clinical testing now. Over the past 25 years, IPC's mechanism has been largely elucidated and targets a reperfusion injury. Ischemic preconditioning was never considered an intervention for AMI because of its need for pretreatment. However, knowledge of IPC's mechanism has revealed a large number of drugs and interventions that will activate IPC's signaling pathway at the time of reperfusion. Several small clinical trials suggest that they can be quite effective, but so far industry seems to have little interest in developing them. So, while basic scientists are in a continuous cycle of discovery and publication for new and novel cardioprotectants, there has been little effort devoted to translating these interventions into clinical practice. We believe that there are suitable IPC based interventions that are ready for clinical testing today and the time has come for large-scale clinical trials. PMID- 21821529 TI - Cardioprotection by ivabradine through heart rate reduction and beyond. AB - The present review summarizes the experimental and clinical evidence for the anti ischemic action of the selective bradycardic agent ivabradine. Improvements in myocardial blood flow and contractile function during experimental myocardial ischemia and the clinical anti-anginal effect are largely mediated by heart rate reduction. However, a significant reduction in infarct size by ivabradine persists in the absence of heart rate reduction, and such protection can also be recruited when ivabradine is given only during early reperfusion. The mechanisms for such pleiotropic action of ivabradine remain to be resolved. PMID- 21821527 TI - The role of comorbidities in cardioprotection. AB - Cardioprotective strategies such as pre- and postconditioning result in a robust reduction in infarct size in young, healthy male animals. However, there are data suggesting that the protection is diminished in animals with comorbidities such as hypertension, hypercholesterolemia, and diabetes. It is important to understand at a mechanistic level the reasons for these differences. The effects of sex and diseases need to be considered in design of cardioprotective interventions in animal studies and clinical trials. PMID- 21821530 TI - New frontiers in myocardial protection: a systems biology approach. AB - Myocardial ischemic injury and cardioprotection are characterized by a cascade of molecular changes, which includes gene expression, protein expression, protein localization, interactions, and posttranslational modifications (PTMs). A systems biology approach allows the study of these genes and proteins on a large scale; the omics technologies have led to new discoveries that further enhance our understanding of these molecular events. The complexity of the prosurvival signaling networks in cardiac cells is increasingly recognized; they afford beneficial effects on the integrity and functionality of a common effector, the mitochondrion. Mitochondrial proteome undergoes dynamic modifications in the course of ischemic injury; depending on the degree of injury, a variety of functional clusters are being affected including the changes in their protein properties (eg, PTMs), which consequently impact their function. The mitochondrial proteome appears to have inherent molecular machinery that initiates a versatile prosurvival mode, resisting environmental challenges. The molecular features in these mitochondrial pathways enabling adaptations involve distinct phosphorylation sites, S-nitrosylation cysteine residues, and other important amino acid domains subjected to PTMs. They become critical players in the determination of cell death and survival. Cardioprotective protein kinases, such as protein kinase C?, can activate these PTMs, and provide a unique therapeutic platform for the use of small peptide regulators. Combining genomics and metabolomics discovery with that of proteomics information allows biological insights into cardioprotection at an integrated systems level. The current review discusses the systems biology concepts of myocardial ischemic injury and cardioprotection, as well as outlines the interrelationships of proteomics, genomics, and metabolomics in the quest to comprehend the prosurvival cell signaling networks. PMID- 21821531 TI - Myocardial protection in heart surgery. AB - One of the unmet clinical needs in heart surgery is the prevention of myocardial stunning and necrosis that occurs as a result of ischemia-reperfusion. Myocardial stunning, a frequent consequence after heart surgery, is characterized by a requirement for postoperative inotropic support despite a technically satisfactory heart operation. In high-risk patients with marginal cardiac reserve, stunning is a major cause of prolonged critical care and may be associated with as much as a 5-fold increase in mortality. In contrast, the frequency of myocardial necrosis (myocardial infarction [MI]) after cardiac surgery is less appreciated and its consequences are much more subtle. The consequences may not be apparent for months to years. While we now have a much better understanding of the molecular mechanisms underlying myocardial stunning and MI, we still have no effective way to prevent these complications, nor a consistently effective means to engage the well-studied endogenous mechanisms of cardioprotection. The failure to develop clinically effective interventions is multifactorial and can be attributed to reliance on findings obtained from subcellular and cellular studies, to drawing conclusions from preclinical large animal studies that have been conducted in a disease-free state, and to accepting less than robust surrogate markers of injury in phase II clinical trials. These factors also explain the disappointing failure to identify effective adjuvant therapy in the setting of percutaneous coronary revascularization for acute MI (AMI) and reperfusion injury. These issues have contributed to the disappointing outcomes of large and costly phase III trials, resulting in a lack of enthusiasm on the part of the pharmaceutical industry to engage in further drug development for this indication. The purpose of this review is to (1) define the scope of the clinical problem; (2) summarize the outcomes of selected phases II and III clinical trials; and (3) identify the gap that needs to be closed in order to address the unmet clinical need. PMID- 21821532 TI - Infarct size reduction in patients with STEMI: why we can do it! AB - Major progress has been made over the last three decades for the treatment of patients with ST elevation myocardial infarction (STEMI). The major objective of this treatment is to reduce infarct size, which is the major prognostic factor in this population. Most of the efforts have been focused on improving reperfusion therapy in order to open as quickly as possible, and to prevent reocclusion, of the culprit coronary artery. During the past years, preclinical research has allowed researchers to well-characterize animal models of acute MI and precisely describe the major determinants of infarct size, that is area at risk, collateral flow, duration of ischemia, and timing of the protective intervention with respect to reflow. Recent reports have clearly demonstrated that lethal reperfusion injury exists, that it is of significant importance, and that it can be prevented by protective interventions applied immediately before reflow. Time has come to, on top of reperfusion therapy, better protect the muscle against lethal reperfusion injury. Although many past infarct size reduction studies have been negative, recent proof-of-concept studies have shown that infarct size reduction is possible in patients with STEMI, at least in part because the major determinants of infarct size have been taken into account. Accumulated knowledge from animal models together with encouraging results obtained in phase II infarct size reduction clinical trials should help us improve the design of future studies aimed at reducing infarct size in patients with STEMI. PMID- 21821533 TI - Remote ischemic conditioning: a clinical trial's update. AB - Coronary artery disease (CAD) is the leading cause of death and disability worldwide, and early and successful restoration of myocardial reperfusion following an ischemic event is the most effective strategy to reduce final infarct size and improve clinical outcome. This process can, however, induce further myocardial damage, namely acute myocardial ischemia-reperfusion injury (IRI) and worsen clinical outcome. Therefore, novel therapeutic strategies are required to protect the myocardium against IRI in patients with CAD. In this regard, the endogenous cardioprotective phenomenon of "ischemic conditioning," in which the heart is put into a protected state by subjecting it to one or more brief nonlethal episodes of ischemia and reperfusion, has the potential to attenuate myocardial injury during acute IRI. Intriguingly, the heart can be protected in this manner by applying the "ischemic conditioning" stimulus to an organ or tissue remote from the heart (termed remote ischemic conditioning or RIC). Furthermore, the discovery that RIC can be noninvasively applied using a blood pressure cuff on the upper arm to induce brief episodes of nonlethal ischemia and reperfusion in the forearm has greatly facilitated the translation of RIC into the clinical arena. Several recently published proof-of-concept clinical studies have reported encouraging results with RIC, and large multicenter randomized clinical trials are now underway to investigate whether this simple noninvasive and virtually cost-free intervention has the potential to improve clinical outcomes in patients with CAD. In this review article, we provide an update of recently published and ongoing clinical trials in the field of RIC. PMID- 21821534 TI - Magnetic resonance imaging for area at risk, myocardial infarction, and myocardial salvage. AB - Almost all published preclinical studies of cardioprotective agents include a measurement of area at risk, infarct size, and thus allow determination of myocardial salvage as an indicator of therapeutic benefit. Until recently, single photon emission tomography (SPECT) imaging with injection of sestamibi prior to intervention was the only clinical method suitable for making similar assessments in patients. Over the past 5 years, a large number of articles have documented that magnetic resonance imaging (MRI) can noninvasively determine area at risk, infarct size, and myocardial salvage. While T2-weighted imaging has been the method used most commonly, precontrast T1-weighted images and early gadolinium enhancement (EGE) images can also determine the size of the area at risk. All 3 of these MRI methods detect the area at risk based on myocardial edema resulting from ischemia. Late gadolinium enhancement (LGE) images provide a well-accepted reference standard for infarct size in all of those methods. Finally, LGE images can also provide a single modality measure of myocardial salvage based on the "wave front" of myocardial injury associated with the progressively more severe damage associated with acute myocardial infarction (MI). Essentially, the LGE images can provide an endocardial-based snap shot of infarct size and salvaged myocardium is estimated as the viable myocardium within the circumferential extent of the infarct. Thus, the purpose of this review is to provide an overview of how MRI can determine the area at risk, infarct size, and thus measure myocardial salvage. PMID- 21821535 TI - Tc-99m SPECT sestamibi for the measurement of infarct size. AB - There are a variety of approaches to assess the efficacy of reperfusion therapy, and myocardial protection, in acute myocardial infarction. This review summarizes the available evidence validating the use of technetium-99m sestamibi single photon emission computed tomography (SPECT) for this purpose. Multiple lines of evidence have validated its clinical utility. SPECT sestamibi infarct size has been used as an endpoint in multiple randomized clinical trials. A smaller number of clinical trials have used both early and later imaging with SPECT sestamibi to assess myocardium at risk and myocardial salvage. SPECT sestamibi has a number of limitations which must be recognized. Nevertheless, SPECT sestamibi infarct size is a well-validated measurement with a long track record of performance as an endpoint in multicenter, randomized clinical trials. PMID- 21821536 TI - Development of an NIH consortium for preclinicAl AssESsment of CARdioprotective therapies (CAESAR): a paradigm shift in studies of infarct size limitation. AB - An estimated 935,000 Americans suffer a myocardial infarction every year; because their prognosis is determined by the size of the infarct, reducing infarct size is of paramount importance to alleviate morbidity and mortality. For 40 years, the National Heart, Lung, and Blood Institute (NHLBI) has invested enormous resources (at least several hundred million dollars) in preclinical studies aimed at developing infarct-sparing therapies, and several hundred (if not thousands) therapies have been claimed to limit infarct size in preclinical models. Unfortunately, due largely to methodological problems, this enormous investment has not produced any notable clinical application, and no cardioprotective therapy is currently available for clinical use. Clearly, after 40 years of futile efforts, a new approach is needed to overcome the problems that have impeded the translation of cardioprotective therapies. The time has come to apply to preclinical research on cardioprotection, the same standards of scientific rigor that are applied to clinical trials. In compliance with the recommendations of an National Heart, Lung, and Blood Institute (NHLBI)-sponsored workshop held in June 2003 and using the clinical trial networks established by the NHLBI as a model for developing a collaborative infrastructure for research sharing, a preclinical consortium has been organized that will operate in a manner analogous to a clinical trial network. This infrastructure has been named CAESAR (Consortium for preclinicAl assESsment of cARdioprotective therapies). Under the direction of Roberto Bolli, 4 Institutions (University of Louisville, Johns Hopkins, Emory University, and Medical College of Virginia) will work together to conduct blinded, randomized, and adequately powered studies using a rigorous design, dose-response analyses, optimal statistical methods, independent data analysis Cores, an independent statistical Core, verification of tetrazolium data with histology and plasma biomarkers, and relevant animal models (including conscious animals and models of comorbidities). Therapies will be tested in 3 species (anesthetized mouse, conscious rabbit, and conscious pig). A major goal is to ensure reproducibility; to this end, each study in each species will be performed in 2 centers using identical protocols. The structure of CAESAR will ensure that the consortium will be a true public resource available to all interested investigators and that all proposed studies will be evaluated in an equitable fashion. Proposals for studying cardioprotective therapies will be solicited from the entire scientific community. The consortium will be available at no cost to all National Institutes of Health (NIH)-funded investigators. This unique infrastructure will enable rigorous preclinical evaluation of promising cardioprotective therapies and will serve the entire scientific community (both in the academia and in the biomedical industry), thereby constituting a public resource. Consortium for preclinicAl assESsment of cARdioprotective therapies will be a major paradigm shift in cardioprotection. By screening promising therapies and identifying those that are truly effective in relevant experimental models and, thus, most likely to be effective in patients, CAESAR will dramatically advance our ability to rationally translate basic findings into clinical use. This article will summarize the rationale, structure, and operation of the NHLBI CAESAR Consortium. PMID- 21821537 TI - Commentary on selected aspects of cardioprotection. AB - Three aspects of cardioprotection are discussed in this article. The first is myocyte death as a function of the duration and severity of ischemia in experimental acute myocardial infarction in the dog heart. The short period of time during which reperfusion with arterial blood will salvage myocytes is demonstrated along with data showing that this period diminishes significantly if collateral flow is very low or absent. The second topic is a discussion of potential mechanisms underlying postconditioning. It begins with a review of the changes that lead to irreversible injury during acute ischemia in the dog heart along with a discussion of the genesis of contraction band necrosis and no reflow when myocardium is salvaged by unrestricted reperfusion with arterial blood in order to provide a basis to discuss the potential mechanisms underlying postconditioning, a situation in which reflow is intermittent and restricted. Postconditioning is reported to achieve greater myocyte salvage than unrestricted reflow. Potential explanations for this beneficial effect include: first, sufficient sarcolemmal repair occurring during the intermittent reflow (reoxygenation) to prevent cell death by explosive cell swelling, and second, prevention of the opening of the mitochondrial permeability transition pore, thereby preventing mitochondrial failure and cell death in the reperfused tissue. Since there is no way available to identify and specifically study the myocytes that would have died if not protected by postconditioning, direct demonstration of mechanisms is difficult or impossible. Finally, the third topic in this commentary is an analysis of the obstacles faced by investigators using small rodent hearts to establish cardioprotective mechanisms. Such studies provide valid data but the relationship of the changes and the proposed mechanisms underlying these changes are not necessarily directly transferable to ischemic large animal hearts including the heart of man. PMID- 21821538 TI - Clinical efforts to reduce myocardial infarct size--the next step. AB - Prompt myocardial reperfusion reduces infarct size in patients experiencing coronary occlusion. However, its clinical value is limited because reperfusion also causes ischemic myocardial reperfusion injury (IMRI). Considerable research to reduce IMRI has been conducted. Three interventions appear to be promising: 1) myocardial conditioning, which consists of repetitive occlusions of coronary or other arteries prior to or at the time of myocardial reperfusion; 2) the administration of cyclosporine A; and 3) the administration of adenosine. A plan for the testing of these interventions in patients with acute myocardial infarction is described. PMID- 21821539 TI - Relation of prenatal smoking exposure and use of psychotropic medication up to young adulthood. AB - The study objective was to determine the relation of prenatal smoking exposure to the use of psychotropic medication up to young adulthood by using population based longitudinal register data consisting of all singletons born in Finland from 1987 to 1989 (n = 175,869). Information on maternal smoking was assessed during antenatal care and received from the Finnish Medical Birth Register. Information on the children's psychotropic medication (1994-2007) was received from the Drug Prescription Register, and the children's psychiatric diagnoses related to outpatient (1998-2007) and inpatient (1987-2007) care were derived from the Finnish Hospital Discharge Register. A total of 15.3% (n = 26,083) of the children were exposed to prenatal smoking. The incidence of psychotropic medication use was 8.3% in unexposed children, 11.3% in children exposed to <10 cigarettes per day (adjusted odds ratio = 1.36, 95% confidence interval: 1.29, 1.43), and 13.6% in children exposed to >10 cigarettes per day (odds ratio = 1.63, 95% confidence interval: 1.53, 1.74). The exposure was significantly associated with the risk for all medication use and for both single- and multiple drug consumption even after adjustment (e.g., mothers' severe psychiatric illnesses). These findings show that exposure to smoking during pregnancy is linked to both mild and severe psychiatric morbidity. PMID- 21821540 TI - Use of surveillance, epidemiology, and end results-medicare data to conduct case control studies of cancer among the US elderly. AB - Cancer is an important cause of morbidity in the elderly, and many medical conditions and treatments influence cancer risk. The Surveillance, Epidemiology, and End Results (SEER)-Medicare database can be used to conduct population-based case-control studies that elucidate the etiology of cancer among the US elderly. SEER-Medicare links data on malignancies ascertained through SEER cancer registries to claims from Medicare, the US government insurance program for people over age 65 years. Under one approach described herein, elderly cancer cases are ascertained from SEER data (1987-2005). Matched controls are selected from a 5% random sample of Medicare beneficiaries. Risk factors of interest, including medical conditions and procedures, are identified by using linked Medicare claims. Strengths of this design include the ready availability of data, representative sampling from the US elderly population, and large sample size (e.g., under one scenario: 1,176,950 cases, including 221,389 prostate cancers, 185,853 lung cancers, 138,041 breast cancers, and 124,442 colorectal cancers; and 100,000 control subjects). Limitations reflect challenges in exposure assessment related to Medicare claims: restricted range of evaluable risk factors, short time before diagnosis/selection for ascertainment, and inaccuracies in claims. With awareness of limitations, investigators have in SEER-Medicare data a valuable resource for epidemiologic research on cancer etiology. PMID- 21821541 TI - Psychosocial risk factors and heart failure hospitalization: a prospective cohort study. AB - Prospective studies on the role of psychosocial factors in heart failure development are virtually nonexistent. The authors aimed to address the effect of psychosocial factors on the risk of heart failure hospitalization in men and women free of cardiovascular disease. In 1991-1993, the 8,670 participants of the Copenhagen City Heart Study (Denmark) were asked comprehensive questions on major life events, work-related stress, social network, vital exhaustion, and sleep medication and were followed in nationwide registries until 2007, with less than 0.2% loss to follow-up. Almost one-fourth of the population reported some degree of vital exhaustion. The vital exhaustion score was associated with a higher risk of heart failure in a dose-response manner (P < 0.002), with high vital exhaustion being associated with a 2-fold higher risk of heart failure in both men (hazard ratio = 1.93, 95% confidence interval: 1.20, 3.10) and women (hazard ratio = 2.56, 95% confidence interval: 1.80, 3.65). Contrary to expectation, major life events, social network, and sleeping medication did not play an individual role for heart failure hospitalization. Because of the high prevalence of vital exhaustion in the population, even a modestly higher risk of heart failure associated with vital exhaustion may be of importance in the planning of future preventive strategies for heart failure. PMID- 21821542 TI - Intake of probiotic food and risk of preeclampsia in primiparous women: the Norwegian Mother and Child Cohort Study. AB - Probiotics have been suggested to modify placental trophoblast inflammation, systemic inflammation, and blood pressure, all potentially interesting aspects of preeclampsia. The authors examined the association between consumption of milk based probiotic products in pregnancy and development of preeclampsia and its subtypes. The study was performed in the Norwegian Mother and Child Cohort Study by using a prospective design in 33,399 primiparous women in the years 2002-2008. The intake of milk-based products containing probiotic lactobacilli was estimated from a self-reported food frequency questionnaire. Preeclampsia diagnoses were obtained from the Norwegian Medical Birth Registry. Intake of probiotic milk products was associated with reduced risk of preeclampsia. The association was most prominent in severe preeclampsia (adjusted odds ratio (OR) = 0.79, 95% confidence interval (CI): 0.66, 0.96). With probiotic intakes divided into categories representing no, monthly, weekly, or daily intake, a lower risk for preeclampsia (all subtypes) was observed for daily probiotic intake (OR = 0.80, 95% CI: 0.66, 0.96). Lower risks for severe preeclampsia were observed for weekly (OR = 0.75, 95% CI: 0.57, 0.98) and daily (OR = 0.61, 95% CI: 0.43, 0.89) intakes. These results suggest that regular consumption of milk-based probiotics could be associated with lower risk of preeclampsia in primiparous women. PMID- 21821543 TI - Association between housing affordability and mental health: a longitudinal analysis of a nationally representative household survey in Australia. AB - Evidence about the mental health consequences of unaffordable housing is limited. The authors investigated whether people whose housing costs were more than 30% of their household income experienced a deterioration in their mental health (using the Short Form 36 Mental Component Summary), over and above other forms of financial stress. They hypothesized that associations would be limited to lower income households as high housing costs would reduce their capacity to purchase other essential nonhousing needs (e.g., food). Using fixed-effects longitudinal regression, the authors analyzed 38,610 responses of 10,047 individuals aged 25 64 years who participated in the Household, Income, and Labour Dynamics in Australia (HILDA) Survey (2001-2007). Respondents included those who remained in affordable housing over 2 consecutive waves (reference group) or had moved from affordable to unaffordable housing over 2 waves (comparison group). For individuals living in low-to-moderate income households, entering unaffordable housing was associated with a small decrease in their mental health score independent of changes in equivalized household income or having moved house (mean change = -1.19, 95% confidence interval: -1.97, -0.41). The authors did not find evidence to support an association for higher income households. They found that entering unaffordable housing is detrimental to the mental health of individuals residing in low-to-moderate income households. PMID- 21821544 TI - Power and limits of modern cancer diagnostics: cancer of unknown primary. AB - BACKGROUND: Cancer of unknown primary (CUP) is diagnosed at a metastatic stage but no diagnostic effort is spared to find the primary cancers because these will guide the treatment. Consequently, the diagnostic work-up for CUP is more comprehensive than for any other cancer, resulting in detection of second cancers unrelated to CUP. We want to use the detection rate of second cancers as a measure of efficacy of the diagnostic modalities in finding tumors, assuming that the detection rates have increased with modern technologies. PATIENTS AND METHODS: The number of CUP patients identified in the nation-wide Swedish Database was 28,574 and relative risks (RRs) for second cancers were recorded in three periods from 1980 through 2008. The first 5 months after CUP were considered critical for second cancers to be diagnosed during the intense work-up for CUP. RESULTS: Among second cancers, diagnosable by computed tomography or magnetic resonance imaging, there was a large 6.80-fold increase in RR immediately following CUP diagnosis from the period 1980-1989 to 2000-2008. Over the same periods, the increase in in situ tumors was 7.16-fold. CONCLUSION: These data suggest that improvements in the resolution and availability of powerful imaging techniques result in increasingly sensitive detection of tumors. PMID- 21821545 TI - A phase II pilot trial incorporating bevacizumab into dose-dense doxorubicin and cyclophosphamide followed by paclitaxel in patients with lymph node positive breast cancer: a trial coordinated by the Eastern Cooperative Oncology Group. AB - BACKGROUND: E2104 was designed to evaluate the safety of two different strategies incorporating bevacizumab into anthracycline-containing adjuvant therapy as a precursor to a definitive randomized phase III trial. PATIENTS AND METHODS: Patients were sequentially assigned to one of two treatment arms. In addition to dose-dense doxorubicin and cyclophosphamide followed by paclitaxel (Taxol) (ddAC >T), all patients received bevacizumab (10 mg/kg every 2 weeks * 26) initiated either concurrently with AC (Arm A: ddBAC->BT->B) or with paclitaxel (Arm B: ddAC >BT->B). The primary end point was incidence of clinically apparent cardiac dysfunction (CHF). RESULTS: Patients enrolled were 226 in number (Arm A 104, Arm B 122). Grade 3 hypertension, thrombosis, proteinuria and hemorrhage were reported for 12, 2, 2 and <1% of patients, respectively. Two patients developed grade 3 or more cerebrovascular ischemia. Three patients in each arm developed CHF. There was no significant difference between arms in the proportion of patients with an absolute decrease in left ventricular ejection fraction of >15% or >10% to below the lower limit of normal post AC or post bevacizumab. CONCLUSIONS: Incorporation of bevacizumab into anthracycline-containing adjuvant therapy does not result in prohibitive cardiac toxicity. The definitive phase III trial (E5103) was activated with systematic and extensive cardiac monitoring to define the true impact of bevacizumab on cardiac function. PMID- 21821546 TI - A metabolic phenotyping approach to understanding relationships between metabolic syndrome and breast tumour responses to chemotherapy. AB - PURPOSE: Breast cancer is associated with adverse outcomes in patients with the metabolic syndrome phenotype. To study this further, we examined the relationship between serum metabolite levels and the components of metabolic syndrome with treatment outcomes in breast cancer. METHODS: A total of 88 women with measurable breast cancer were studied; their serum metabolites as assessed by (1)H nuclear magnetic resonance spectroscopy, blood pressure, lipids, glucose, body mass index and waist circumference were recorded and correlated with treatment response. RESULTS: We identified metabolic syndrome in approximately half of our cohort (42 patients) and observed a significant trend (P = 0.03) of increased incidence of metabolic syndrome in partial response (33.3%), stable disease (42.9%) and progressive disease groups (66.1%). High blood sugar predicted a poor response (P < 0.001). Logistic regression of metabonomic data demonstrated that high lactate (P = 0.03) and low alanine (P = 0.01) combined with high glucose (P = 0.01) were associated with disease progression. CONCLUSIONS: Metabolic syndrome is commonly observed in metastatic breast cancer and these patients have poorer outcomes. These data, which support our previous findings, suggest that high blood glucose as part of metabolic syndrome is associated with a poor response in breast cancer. They also validate new therapeutic approaches that focus on metabolism. PMID- 21821547 TI - Recurrence risk score based on the specific activity of CDK1 and CDK2 predicts response to neoadjuvant paclitaxel followed by 5-fluorouracil, epirubicin and cyclophosphamide in breast cancers. AB - BACKGROUND: We established the cell cycle profiling (C2P) assay for specific activity (SA; activity/expression) of cyclin-dependent kinases (CDKs). C2P risk score (C2P-RS) based on CDK1 and CDK2 SAs was significantly associated with relapse in breast cancer (BC). This study was conducted to investigate the predictive value of C2P-RS for neoadjuvant chemotherapy (NAC). PATIENTS AND METHODS: Among 124 eligible patients, 122 were treated with weekly paclitaxel followed by 5-fluorouracil, epirubicin and cyclophosphamide (P-FEC) and 2 were treated with paclitaxel monotherapy. C2P-RS was determined via C2P using frozen biopsy samples before NAC. RESULTS: Negative estrogen receptor (ER), negative progesterone receptor (PR), positive human epidermal growth factor receptor 2 (HER2), high Ki-67 expression and intermediate + high C2P-RS were significantly associated with high pathological complete response (pCR) rates compared with positive ER (30% versus 9%), positive PR (25% versus 6%), negative HER2 (34% versus 11%), low Ki-67 expression (24% versus 7%) or low C2P-RS (24% versus 9%), respectively. The combination of C2P-RS and Ki-67 had a stronger impact on pCR than each parameter alone, and a multivariate analysis showed that the combination was an independent predictor of pCR (odds ratio 3.3, 95% confidence interval 1.1-9.5). CONCLUSIONS: C2P-RS was significantly associated with pCR after P-FEC and may be a useful predictor for chemotherapy in BCs. PMID- 21821549 TI - Adjuvant capecitabine chemotherapy using a tailored-dose strategy in elderly patients with colon cancer. AB - BACKGROUND: This study was conducted to analyze the feasibility of adjuvant capecitabine therapy using a tailored-dose escalation strategy in elderly patients with colon cancer (CC). METHODS: CC patients (>= 70 years of age) who received adjuvant capecitabine were enrolled. The starting dosage of capecitabine was 2000 mg/m(2)/day (days 1-14, every 3 weeks). On the second cycle, the dosage was escalated to 2500 mg/m(2)/day if the patient tolerated the first cycle. Dose intensity (DI), toxicity, and the change in quality of life (QoL) were evaluated. RESULTS: Of 82 patients enrolled, 67 completed eight cycles. Dose escalation to 2500 mg/m(2)/day was possible in 56 patients, and this dosage was maintained in 24 patients until the completion of chemotherapy (eight cycles). Forty-one patients completed therapy with a DI >= 1333 mg/m(2)/day [relative dose intensity (RDI) >= 80%]. Toxic effects were tolerable and the QoL was not compromised during treatment. Creatinine clearance < 50 ml/min and Charlson-Age comorbidity index >= 8 were related to a reduced capecitabine dosage (RDI < 80%). CONCLUSIONS: A tailored-dose escalation strategy was feasible in elderly CC patients receiving adjuvant capecitabine chemotherapy. Decreased renal function and an increased number of comorbidities were independently predictive of reduced administration of the capecitabine dose. PMID- 21821548 TI - A phase II study evaluating the safety and efficacy of an adenovirus-DeltaLMP1 LMP2 transduced dendritic cell vaccine in patients with advanced metastatic nasopharyngeal carcinoma. AB - BACKGROUND: Individuals with metastatic Epstein-Barr virus (EBV)-positive nasopharyngeal carcinoma (NPC) continue to have poor outcomes. To evaluate the ability of a dendritic cell (DC) vaccine to target subdominant EBV antigens LMP1 and LMP2 expressed by NPC cells, we vaccinated patients using autologous DCs transduced with an adenovirus encoding a truncated LMP1 (DeltaLMP1) and full length LMP2 (Ad-DeltaLMP1-LMP2). MATERIALS AND METHODS: Sixteen subjects with metastatic NPC received Ad-DeltaLMP1-LMP2 DC vaccines i.d. biweekly for up to five doses. Toxicity, immune responses and clinical responses were determined. RESULTS: Most patients had extensive disease, with a median of three visceral sites of involvement (range 1-7). No significant toxicity was observed. Ad DeltaLMP1-LMP2 DCs induced delayed type hypersensitivity responses in 9 out of 12 patients, but although these DCs activated LMP1/2-specific T cells in vitro, no such increase in the frequency of peripheral LMP1/2-specific T cells was detected. Three patients had clinical responses including one with partial response (for 71/2 months) and two with stable disease (for 61/2 and 71/2 months). CONCLUSIONS: Ad-DeltaLMP1-LMP2 transduced DCs can be successfully generated and safely administered to patients with advanced NPC. Since efficacy was limited, future studies should focus on DC vaccines with greater potency administered to subjects with less tumor burden. PMID- 21821550 TI - Histology and outcomes of newly detected lung lesions in melanoma patients. AB - BACKGROUND: Melanoma frequently metastasizes to the lung. Improved radiologic techniques may decrease the need for biopsy of such lesions. The aim of this study was to examine factors predictive of a positive biopsy of melanoma. METHODS: Using the Memorial Sloan-Kettering Cancer Center melanoma database, all patients with melanoma who had undergone biopsy of a suspicious new lung lesion from 1996 to 2009 were identified. Age, date of diagnosis, histology, and stage were obtained. Chart review was carried out to obtain medical history, smoking status, radiological appearance, and histology of lung lesions biopsied. RESULTS: Two hundred and twenty-nine patients were identified; median age was 63 years; 48% were never smokers; 27% had a prior nonmelanoma cancer; 88% of lung nodules were malignant: 69% melanoma, 19% other cancers. Among 113 patients undergoing positron emission tomography (PET), proportions of benign, melanoma, and nonmelanoma 2-[fluorine-18]fluoro-2-deoxy-D-glucose-avid nodules did not differ (P = 0.53). On multivariable analysis, >stage I melanoma, negative smoking history, multiple lung nodules, and no prior nonmelanoma cancer were significantly associated with a melanoma biopsy result rather than other cancer. CONCLUSIONS: In this study, 31% of lung lesions were not melanoma. In the subset undergoing PET, this did not differentiate between benign and malignant lesions. Biopsy is mandated in melanoma patients with new lung nodules. PMID- 21821551 TI - Role of the multidisciplinary team in breast cancer management: results from a large international survey involving 39 countries. AB - BACKGROUND: The optimal management of patients with breast cancer (BC) requires the expertise of specialists from different disciplines. This has led to the evolution of multidisciplinary teams (MDTs), allowing all key professionals to jointly discuss individual patients and to contribute independently to clinical decisions. Data regarding BC MDTs in different regions and countries are scarce. METHODS: The investigators of a large global phase III adjuvant BC trial being conducted by the Breast International Group were invited to respond to a questionnaire about the extent, structure, and function of BC MDTs. RESULTS: One hundred and fifty-two responses from 39 countries were received, and remarkable differences were noted in different geographic regions. Sixty-five percent of the respondents from eastern Europe, 63% from western Europe, 35% from Asia, and 25% from South America declared that MDT was a mandatory part of BC care in their country. Ninety percent of the respondents from Europe stated their MDTs met weekly, compared with only half of the respondents from Asia. CONCLUSION: This survey is perhaps the first large-scale effort to collect information regarding BC MDTs from different parts of the world and provides objective information of frequency, composition, function, and working mechanism of BC MDTs. PMID- 21821552 TI - Alcohol, drugs, sexual behavior, and HIV in Trinidad and Tobago--the way forward. AB - The HIV epidemic in Trinidad and Tobago is primarily heterosexual, fueled by a high level of risky sex, gender inequality, and alcohol and drug use; however, the influence of alcohol and drugs has been neglected in the literature. Research shows that current HIV prevention approaches have failed to substantially impact sexual behavior change. This may be so because they do not incorporate a comprehensive understanding of the sociocultural factors underlying sexual behavior. There is an urgent need to understand how socially accepted patterns of alcohol and drug use contribute to sexual behaviors and HIV risk in Trinidad and Tobago. Moreover, specialized, evidence-based interventions are needed for HIV infected substance abusers. Using an adaptation of the cognitive behavioral stress management (CBSM) protocol, this intervention project aimed to assess effectiveness in reducing relapse and risky behaviors among recovering HIV infected substance abusers in Trinidad and Tobago. PMID- 21821553 TI - Use of chlorhexidine mouthwash in children receiving chemotherapy: a review of literature. AB - The aim of this literature review was to evaluate the effectiveness of chlorhexidine mouthwash as an intervention in children receiving chemotherapy, with a focus on randomized clinical trials. A literature search was performed between 1980 and 2010. The control groups consisted of placebo, no intervention, or another intervention group. Oral mucositis was scored by either the World Health Organization scale or modified Oral Assessment Guide. The review of literature included 5 studies fulfilling the inclusion criteria, in which chlorhexidine was evaluated and 4 studies showed a significant preventive effect on the development or severity of oral mucositis; the remaining study showed no benefit of using chlorhexidine mouthwash when compared with the placebo group. Ultimately, it can be suggested from the data presented here that chlorhexidine may play a part in reducing oral mucosal damage during chemotherapy for children with cancer, possibly due to a reduction in oral microflora and plaque. PMID- 21821555 TI - Substance abuse and other substantive matters. PMID- 21821556 TI - Remaking England's National Health Service? Not so fast. PMID- 21821557 TI - The looming expansion and transformation of public substance abuse treatment under the Affordable Care Act. AB - Public substance abuse treatment services have largely operated as an independent part of the overall health care system, with unique methods of administration, funding, and service delivery. The Affordable Care Act of 2010 and other recent health care reforms, coupled with declines in state general revenue spending, will change this. Overall funding for these substance abuse services should increase, and they should be better integrated into the mainstream of general health care. Reform provisions are also likely to expand the variety of substance abuse treatment providers and shift services away from residential and stand alone programs toward outpatient programs and more integrated programs or care systems. As a result, patients should have better access to care that is more medically based and person-centered. PMID- 21821558 TI - The urgency of providing comprehensive and integrated treatment for substance abusers with HIV. AB - Substance abuse is linked to many new cases of HIV infection. Barriers such as the myth that drug users cannot adhere to HIV/AIDS treatment block progress in curbing the spread of HIV in that population. In this article we explain the need to aggressively seek out high-risk, hard-to-reach substance abusers and to offer them HIV testing, access to treatment, and the necessary support to remain in treatment--both for HIV and for substance abuse. We summarize evidence showing that injection drug users can successfully undergo HIV treatment; that many substance abusers adhere to antiretroviral therapy as well as do people who don't inject drugs; and that injection drug users who undergo substance abuse treatment are more likely to obtain and stay in treatment for their HIV infection. This evidence makes a strong case for integrating substance abuse treatment with HIV treatment programs and providing substance abusers with universal access to HIV treatment. But an integrated strategy will require changes in the health care system to overcome lingering obstacles that inhibit the merging of substance abuse treatment with HIV programs. PMID- 21821559 TI - Group Health's initiative to avert opioid misuse and overdose among patients with chronic noncancer pain. AB - Increased opioid prescribing for chronic pain that is not due to cancer has been accompanied by large increases in abuse and overdose of prescription opioids. This paper describes how Group Health, a Seattle-based nonprofit health care system, implemented a major initiative to make opioid prescribing safer. In the initiative's first nine months, clinicians developed documented care plans for almost 6,000 patients receiving long-term opioid therapy for chronic pain. Evaluation of the initiative's effects on care processes and trends in adverse events is under way. PMID- 21821560 TI - The evidence doesn't justify steps by state Medicaid programs to restrict opioid addiction treatment with buprenorphine. AB - Many state Medicaid programs restrict access to buprenorphine, a prescription medication that relieves withdrawal symptoms for people addicted to heroin or other opiates. The reason is that officials fear that the drug is costlier or less safe than other therapies such as methadone. To find out if this is true, we compared spending, the use of services related to drug-use relapses, and mortality for 33,923 Massachusetts Medicaid beneficiaries receiving either buprenorphine, methadone, drug-free treatment, or no treatment during the period 2003-07. Buprenorphine appears to have significantly expanded access to treatment because the drug can be prescribed by a physician and taken at home compared with methadone, which by law must be administered at an approved clinic. Buprenorphine was associated with more relapse-related services but $1,330 lower mean annual spending than methadone when used for maintenance treatment. Mortality rates were similar for buprenorphine and methadone. By contrast, mortality rates were 75 percent higher among those receiving drug-free treatment, and more than twice as high among those receiving no treatment, compared to those receiving buprenorphine. The evidence does not support rationing buprenorphine to save money or ensure safety. PMID- 21821561 TI - Proportion of antidepressants prescribed without a psychiatric diagnosis is growing. AB - Over the past two decades, the use of antidepressant medications has grown to the point that they are now the third most commonly prescribed class of medications in the United States. Much of this growth has been driven by a substantial increase in antidepressant prescriptions by nonpsychiatrist providers without an accompanying psychiatric diagnosis. Our analysis found that between 1996 and 2007, the proportion of visits at which antidepressants were prescribed but no psychiatric diagnoses were noted increased from 59.5 percent to 72.7 percent. These results do not clearly indicate a rise in inappropriate antidepressant use, but they highlight the need to gain a deeper understanding of the factors driving this national trend and to develop effective policy responses. To the extent that antidepressants are being prescribed for uses not supported by clinical evidence, there may be a need to improve providers' prescribing practices, revamp drug formularies, or vigorously pursue implementation of broad reforms of the health care system that will increase communication between primary care providers and mental health specialists. PMID- 21821562 TI - Massachusetts' health care reform increased access to care for Hispanics, but disparities remain. AB - Hispanics are more likely than any other racial or ethnic group in the United States to lack health insurance. This paper draws on quantitative and qualitative research to evaluate the extent to which health reforms in Massachusetts, a model for the Affordable Care Act of 2010, have reduced disparities in insurance coverage and access to health care. We found that rates of coverage and the likelihood of having a usual provider increased dramatically for Massachusetts Hispanics after the state's reforms, but disparities remained. The increase in insurance coverage among Hispanics was more than double that experienced by non Hispanic whites. Even so, in 2009, 78.9 percent of Hispanics had coverage, versus 96 percent of non-Hispanic whites. Language and other cultural factors remained significant barriers: Only 66.6 percent of Hispanics with limited proficiency in English were insured. One-third of Spanish-speaking Hispanics still did not have a personal provider in 2009, and 26.8 percent reported not seeing a doctor because of cost, up from 18.9 percent in 2005. We suggest ways to reduce such disparities through national health care reform, including simplified enrollment and reenrollment processes and assistance in finding a provider and navigating an unfamiliar care system. PMID- 21821563 TI - Florida doctors seeing Medicaid patients show broad interest in federal incentives for adopting electronic health records. AB - The Health Information Technology for Economic and Clinical Health (HITECH) Act of 2009 aims to expand the use of electronic health records by offering financial incentives to physicians to fully adopt and implement them. We surveyed Florida physicians who deliver care to Medicaid participants to identify their interest in participating in the incentive program. More than 60 percent of all respondents expressed interest in applying for the incentives; of those already using electronic health record systems, 86 percent intend to apply for funding. This relatively high proportion of physicians creates the potential to reach the overall policy goals of the law. Among those not planning to seek incentives, common barriers--especially among nonusers of electronic health records--were "costs involved" (69 percent), "need more information about incentive program" (42 percent), and uncertainty about what system to purchase (42 percent). We suggest that these findings hold implications for the Regional Extension Centers working to help physicians achieve the federal meaningful-use criteria that are a condition of receiving the incentives. In particular, the centers should focus on providing physicians with information about costs of electronic health record systems. PMID- 21821564 TI - Survey in sub-Saharan Africa shows substantial support for government efforts to improve health services. AB - Public opinion can play an important role in shaping health policy alternatives and outcomes. However, little is known about how citizens in developing countries evaluate government performance in the health sector. Through a survey conducted in 2008 in twenty sub-Saharan African countries, we examined public priorities and perceptions of government efforts to improve health services. In sixteen of these countries, health was one of the top five priorities the public thought the government should address. A staggering proportion of citizens in most of the sampled countries reported having gone without medicines or medical treatment in the previous year, and going without health care was most strongly correlated with views on health services. By contrast, greater access to health care was associated with more positive impressions of government efforts to improve health services. Population health indicators, such as life expectancy and childhood mortality, were not correlated with citizens' evaluation of government efforts. Results suggest that improving access to health care will be a key factor in improving perceptions of government performance. PMID- 21821566 TI - Public-private integrated partnerships demonstrate the potential to improve health care access, quality, and efficiency. AB - Around the world, publicly owned and run health services face challenges. In poor countries in particular, health services are characterized by such problems as inadequate infrastructure and equipment, frequent shortages of medicines and supplies, and low quality of care. Increasingly, both developed- and developing country governments are embracing public-private partnerships to harness private financing and expertise to achieve public policy goals. An innovative form of these partnerships is the public-private integrated partnership, which goes a step further than more common hospital building and maintenance arrangements, by combining infrastructure renewal with delivery of clinical services. We describe the benefits and risks inherent in such integrated partnerships and present three case studies that demonstrate innovative design. We conclude that these partnerships have the potential to improve access, quality, and efficiency in health care. More such partnerships should be launched and rigorously evaluated, and their lessons should be widely shared to guide policy makers in the effective use of this model. PMID- 21821565 TI - Local residents trained as 'influence agents' most effective in persuading African couples on HIV counseling and testing. AB - Couples in sub-Saharan Africa are the largest group in the world at risk for HIV infection. Couples counseling and testing programs have been shown to reduce HIV transmission, but such programs remain rare in Africa. Before couples counseling and testing can become the norm, it is essential to increase demand for the services. We evaluated the effectiveness of several promotional strategies during a two-year program in Kitwe and Ndola, Zambia. The program attracted more than 7,600 couples through the use of radio broadcasts, billboards, and other strategies. The most effective recruiting technique was the use of local residents trained as "influence agents" to reach out to friends, neighbors, and others in their sphere of influence. PMID- 21821567 TI - Economic perspectives on the advance market commitment for pneumococcal vaccines. AB - Pharmaceutical companies have long been reluctant to invest in producing new vaccines for the developing world because they have little prospect of earning an attractive return. One way to stimulate such investment is the use of an advance market commitment, an innovative financing program that guarantees manufacturers a long-term market. Under this arrangement, international donors pay a premium for initial doses sold to developing countries. In exchange, companies agree to continue supplying the vaccine over the longer term at more sustainable prices. This article provides a preliminary economic analysis of a pilot advance market commitment program for pneumococcal vaccines, explaining the principles behind the program's design and assessing its early performance. Spurred by the advance market commitment--and other contemporaneous initiatives that also increased resources to vaccine suppliers--new, second-generation pneumococcal vaccines have experienced a much more rapid rollout in developing countries than older first generation vaccines. PMID- 21821568 TI - Performance-based financing experiment improved health care in the Democratic Republic of Congo. AB - In some low-income countries such as Cambodia and Rwanda, experimental performance-based payment systems have led to rapid improvements in access to health care and the quality of that care. Under this type of payment scheme, funders--including foreign governments and international aid programs--subsidize local health care providers for achieving certain benchmarks. The benchmarks can include such measures as child immunizations or childbirth in a health facility. In this article we report the results of a performance-based payment experiment conducted in the Democratic Republic of Congo, which is one of the poorest countries in the world and has an extremely high level of child and maternal mortality. We found that providing performance-based subsidies resulted in lower direct payments to health facilities for patients, who received comparable or better services and quality of care than those provided at a control group of facilities that were not financed in this way. The disparity occurred despite the fact that the districts receiving performance-based subsidies received external foreign assistance of approximately $2 per capita per year, compared to the $9 $12 in external assistance received by the control districts. The experiment also revealed that performance-based financing mechanisms can be effective even in a troubled nation such as the Democratic Republic of Congo. PMID- 21821570 TI - Setting cost-effectiveness thresholds as a means to achieve appropriate drug prices in rich and poor countries. AB - Finding better mechanisms to enable differential pricing that reflects different degrees of willingness to pay across countries with different income levels is an important challenge for drug manufacturers and policy makers. Drug prices must be high enough to meet manufacturers' needs--covering costs and ensuring adequate investment in research and development, as well as producing a profit--but low enough to allow consumers access to medicines that they need. Examining drug pricing, we found that in rich countries, insurance coverage can make consumers insensitive to price, which means that manufacturers' prices are largely unrestrained unless payers intervene. In middle- and low-income countries, where most consumers pay for drugs out of pocket, we found that the poorest countries face the highest prices, relative to their mean per capita income. We recommend that countries and payers set their own cost-effectiveness thresholds to reflect how much they are willing to pay for "health gain"--in other words, for a measured improvement in the health of a person or a population. Adopting this approach broadly should lead to appropriate price differences across and within countries, benefiting consumers and manufacturers alike. PMID- 21821571 TI - Pharmaceutical companies' variation of drug prices within and among countries can improve long-term social well-being. AB - Drug prices vary considerably across and within countries. On average, pharmaceutical companies charge lower prices in low-income countries than in industrialized nations. Manufacturers' ability to price products differently for different markets--a practice known as price discrimination--increases their profits overall. But it is also likely to result in greater investment in research and development, and therefore in more new drugs on the market. Although reducing price discrimination in order to cut costs might benefit consumers in the short run, it would harm them in the long run by reducing the number of new drugs developed. PMID- 21821572 TI - The level of income appears to have no consistent bearing on pharmaceutical prices across countries. AB - A generally accepted view is that it is more efficient and ethical if global pharmaceutical prices vary according to countries' relative income. To understand manufacturers' pricing strategies, we compared average pharmaceutical prices in fourteen middle-income countries to those in three high-income countries and a low-income region in western Africa from 1999 through 2008. We found that some middle-income countries pay more for pharmaceuticals than high-income countries- for example, prices in several middle-income countries exceeded those in the United Kingdom for some years of the study period. Other middle-income countries paid less than low-income countries--for example, average prices in India were consistently below prices in western Africa. These variations suggest that we need new policies on pharmaceutical pricing to improve access to pharmaceuticals around the world. PMID- 21821573 TI - Prices of pharmaceuticals in poor countries are much lower than in wealthy countries. AB - Keeping pharmaceuticals affordable in poor countries is important for public health. Economic models suggest that manufacturers should be able to charge substantially lower prices in those markets than in industrialized countries without drastically reducing their profits. We report the results of a study of thirty drugs in twenty-nine countries, showing that many prices are already substantially discounted in middle-income and developing countries, compared to prices in the United States and other industrialized countries, and do not exceed long-run marginal costs. We also argue that the so-called peak load pricing model offers an economic foundation for fair drug pricing in the case of developing countries, and is a better solution than other pricing models to the problem of how to reduce drug prices in these countries to the level of manufacturers' marginal costs. PMID- 21821574 TI - Hospice and the 'end game'. PMID- 21821577 TI - The perverse incentives of global reimbursement. PMID- 21821579 TI - We need more supply-side regulation. PMID- 21821581 TI - Isolation, characterization, and cross-species amplification of polymorphic microsatellite markers for Pilosocereus machrisii (Cactaceae). AB - PREMISE OF THE STUDY: Microsatellite primers were developed in Pilosocereus machrisii, a columnar cactus with a patchy distribution in eastern tropical South America, to assess its genetic diversity and population structure. METHODS AND RESULTS: Eleven microsatellite markers were developed, of which one was monomorphic among 51 individuals from two populations. The number of alleles per polymorphic locus ranged from two to eight, and the total number of alleles was 57. From the 11 isolated loci, nine were successfully amplified in the other four Pilosocereus species. CONCLUSIONS: The results showed that these markers will be useful for studies of genetic diversity, patterns of gene flow, and population genetic structure in P. machrisii, as well as across other congeneric species. PMID- 21821582 TI - Development and characterization of polymorphic microsatellite markers in Dysosma pleiantha (Berberidaceae). AB - PREMISE OF THE STUDY: The development of compound microsatellite markers was conducted in Dysosma pleiantha to investigate genetic diversity and population genetic structure of this threatened medicinal plant. METHODS AND RESULTS: Using the compound microsatellite marker technique, 14 microsatellite markers that were successfully amplified showed polymorphism when tested on 38 individuals from three populations in eastern China. Overall, the number of alleles per locus ranged from 2 to 14, with an average of 7.71 alleles per locus. CONCLUSIONS: These results indicate that these microsatellite markers are adequate for detecting and characterizing population genetic structure and genetic diversity in Dysosma pleiantha. PMID- 21821583 TI - Genomic and EST microsatellite markers for Aquilegia flabellata and cross amplification in A. oxysepala (Ranunculaceae). AB - PREMISE OF THE STUDY: The goal of this study was to identify genomic and expressed sequence tag (EST)-derived microsatellite markers from the species Aquilegia flabellata and assess their transferability in A. oxysepala. METHODS AND RESULTS: Eleven genomic and nine EST-derived microsatellite loci were characterized in A. flabellata. These microsatellite primers amplified 66 alleles in all 20 loci. The observed heterozygosity (H(O)) for each population ranged from 0.00 to 0.94. CONCLUSIONS: All of the 20 loci were successfully amplified in A. oxysepala. These genomic and EST-derived microsatellite markers will be useful in further genetic structure, speciation, and adaptive evolution studies. PMID- 21821584 TI - Development and characterization of microsatellite markers for Panax notoginseng (Araliaceae), a Chinese traditional herb. AB - PREMISE OF THE STUDY: Microsatellite primers were developed for a Chinese traditional herb, Panax notoginseng, to investigate its genetic diversity and cultivar breeding. METHODS AND RESULTS: Twelve polymorphic microsatellite loci were isolated from the microsatellite-enriched genomic library of Panax notoginseng. The polymorphisms were assessed in two populations and an assemblage containing individuals from the entire distribution area. The number of alleles per locus ranged from 3 to 12, with a mean of 5.8; the observed and expected heterozygosity values ranged from 0.0411 to 0.8472 and from 0.0804 to 0.7653, respectively. CONCLUSIONS: These new microsatellite markers will be useful for investigating the genetic diversity of this cultivated Panax notoginseng as well as assist in cultivar breeding. PMID- 21821585 TI - Development and characterization of polymorphic microsatellite primers in Reaumuria soongorica (Tamaricaceae). AB - PREMISE OF THE STUDY: Polymorphic microsatellite markers were developed in Reaumuria soongorica, a desert shrub occurring widely in western China, to investigate its genetic diversity and population genetic structure. METHODS AND RESULTS: Using the combined biotin capture technique, 10 novel polymorphic microsatellite loci primer sets were isolated and characterized in 90 individuals from six populations of R. soongorica. Five to 14 alleles per locus were identified for these microsatellites. Observed and expected heterozygosities ranged from 0.132 to 0.593, and 0.217 to 0.803, respectively. CONCLUSIONS: These microsatellite markers provide a useful tool to assess the genetic variation and population structure of R. soongorica. PMID- 21821586 TI - Development of polymorphic microsatellite markers for Incarvillea sinensis (Bignoniaceae). AB - PREMISE OF THE STUDY: Microsatellite markers were developed for Incarvillea sinensis var. sinensis (Bignoniaceae), an annual herb endemic to Inner Mongolia, to study the degree to which delayed self-fertilization is favored. METHODS AND RESULTS: Eight polymorphic primer sets were isolated and characterized in two Inner Mongolia populations of I. sinensis var. sinensis with a relatively simple and fast subcloning method. Numbers of alleles per locus ranged from 2 to 7, with observed and expected heterozygosities ranging from 0 to 0.261 and from 0 to 0.778, respectively. CONCLUSIONS: These markers will be useful for future studies of self-fertilization adaptability in I. sinensis var. sinensis. PMID- 21821587 TI - Microsatellite marker development in tung trees (Vernicia montanaand V. fordii, Euphorbiaceae). AB - PREMISE OF THE STUDY: The tung tree is valuable for tung oil, which is derived from the oilseeds of the tree. Microsatellite markers were developed in tung trees (Vernicia montanaand V. fordii) for use in population genetic studies and, particularly, analyses of genetic relationships among germplasms. METHODS AND RESULTS: A total of 20 microsatellite markers were developed and characterized in V. montanaand tested for cross-amplification in V. fordii, using the Fast Isolation by AFLP of Sequences COntaining Repeats protocol. These markers showed rich polymorphism when assessed in 120 samples of V. montanaand six samples of V. fordii. CONCLUSIONS: The developed microsatellite markers will be of great use for investigating genetic diversity of germplasms, analyzing population structure, and facilitating molecular breeding in tung trees. PMID- 21821588 TI - Development of microsatellite loci for Cephalotaxus oliveri (Cephalotaxaceae) and cross-amplification in Cephalotaxus. AB - PREMISE OF THE STUDY: Microsatellite loci were developed for Cephalotaxus oliveri, an endemic and endangered conifer in China, which will allow assessment of the levels of genetic diversity and a means to understand the genetic consequences of habitat fragmentation. METHODS AND RESULTS: Using the Fast Isolation by AFLP of Sequences COntaining (FIASCO) Repeats protocol, 19 microsatellite loci were identified in C. oliveri, 13 of which were polymorphic within a sample of 52 individuals representing five natural populations. The actual number of alleles per locus ranged from one to five. Twelve polymorphic loci were also successfully amplified in C. fortunei. CONCLUSIONS: These microsatellite loci will provide a useful tool for further investigating genetic variation in natural populations of C. oliveri, which will inform future conservation and management strategies. Additionally, cross-amplification in C. fortunei suggested the potential utility of these loci in this and other congeneric species. PMID- 21821589 TI - Development of microsatellite markers for Euryale ferox (Nymphaeaceae), an endangered aquatic plant species in Japan. AB - PREMISE OF THE STUDY: Microsatellite markers were developed to investigate genetic diversity and genetic structure of Euryale ferox, a vulnerable aquatic plant. METHODS AND RESULTS: Ten microsatellite loci were isolated and characterized for this species. Eight loci showed polymorphisms with two or three alleles per locus. As for the polymorphic markers, the expected and observed heterozygosities ranged from 0.00 to 0.08 and 0.17 to 0.64, respectively. CONCLUSIONS: The 10 microsatellite markers described here will be useful for investigating genetic diversity, genetic structure, and gene flow between populations of E. ferox. PMID- 21821590 TI - Frequent pseudogenization and loss of the plastid-encoded sulfate-transport gene cysA throughout the evolution of liverworts. AB - PREMISE OF THE STUDY: The presence or absence of a functional copy of a plastid gene may reflect relaxed selection, and may be phylogenetically significant, reflecting shared ancestry. In some liverworts, the plastid gene cysA is a pseudogene (inferred to be nonfunctional). We surveyed 63 liverworts from all major clades to determine whether the loss of cysA is phylogenetically significant, whether intact copies of cysA are under selective constraints, and whether rates of nucleotide substitution differ in other plastid genes from taxa with and without a functional copy of cysA. METHODS: Primers annealing to flanking and internal regions were used to amplify and sequence cysA from 61 liverworts. Two additional cysA sequences were downloaded from NCBI. The ancestral states of cysA were reconstructed on a phylogenetic hypothesis inferred from seven markers. Rates of nucleotide substitution were estimated for three plastid loci to reflect the intrinsic mutation rate in the plastid genome. The ratio of nonsynonymous to synonymous substitutions was estimated for intact copies of cysA to infer selective constraints. KEY RESULTS: Throughout liverworts, cysA has been lost up to 29 times, yet intact copies of cysA are evolving under selective constraints. Gene loss is more frequent in groups with an increased substitution rate in the plastid genome. CONCLUSIONS: The number of inferred losses of cysA in liverworts exceeds any other reported plastid gene. Despite frequent losses, cysA is evolving under purifying selection in liverworts that retain the gene. It appears that cysA is lost more frequently in lineages characterized by a higher rate of nucleotide substitutions in the plastid. PMID- 21821591 TI - Differential response of the homoploid hybrid species Iris nelsonii (Iridaceae) and its progenitors to abiotic habitat conditions. AB - PREMISE OF THE STUDY: Homoploid hybrid speciation involves the evolution of reproductive isolation between a hybrid lineage and its progenitors without a change in chromosome number. Ecological divergence presumably plays a large role in the stabilization of hybrid lineages, as all homoploid hybrid species described to date are reported to be ecologically divergent from their progenitors. However, the described ecological divergence in most systems is anecdotal and has not been empirically tested. METHODS: We assessed the vegetative response of Iris nelsonii, a homoploid hybrid species, and its three progenitor species, I. brevicaulis, I. fulva, and I. hexagona, to different abiotic conditions (i.e., varied sunlight availability and flooding conditions) that largely characterize the habitats of these four species in their natural habitats in Louisiana, USA. KEY RESULTS: The species differed in their responses to the water-level treatment for many of the response variables, including rhizome weight, ramet growth, plant height, and two principal components used to characterize the data. The species differed in their response to the light-level treatment for root allocation and the principal component used to characterize plant size. Iris nelsonii significantly differed from its progenitors, including its most closely related progenitor species, in response to many of the treatments. CONCLUSIONS: The differential response to abiotic habitat conditions of I. nelsonii suggests that this species is ecologically divergent from its progenitor species. PMID- 21821592 TI - Context-dependent recruitment of Guettarda viburnoides in a Neotropical forest savanna mosaic. AB - PREMISE OF THE STUDY: Seed dispersal is a key process for plant regeneration in tropical areas. Differences in disperser behavior result in a nonrandom distribution of seeds among habitats. Patterns of seed dispersal may cascade through the entire recruitment phase or uncoupling between developmental stages may occur such that patterns of seed dispersal are discordant with patterns of recruitment. Here, we analyzed how habitat and interannual variability affect the recruitment dynamics of a bird-dispersed tree, Guettarda viburnoides (RUB.). METHODS: Over 3 years, we determined the habitats where seeds of G. viburnoides are dispersed, and we experimentally quantified postdispersal seed predation, seedling emergence, and survival in four habitats of a forest-savanna mosaic in Bolivia. KEY RESULTS: Habitat affected seed dispersal, seed predation, and seedling emergence. The strength of postdispersal processes, however, varied between years and no consistent within-habitat pattern emerged. Uncoupling among different life-stages was observed across habitats, and spatial concordance was found between seed rain and sapling recruitment patterns. CONCLUSIONS: Habitat can affect seed dispersal, postdispersal processes and the recruitment dynamics of a Neotropical tree in a heterogeneous landscape. Additionally, our results show interannual variability in the strength of postdispersal processes, which leads to shifts in habitat suitability between years. Therefore, to better understand the role of site suitability for recruitment, we need to explicitly consider not only variation in habitat-specificity for dispersal and postdispersal processes, but also how this variation can shift under different environmental conditions-that is, the context dependence of suitability. PMID- 21821593 TI - Low genetic diversity, moderate local adaptation, and phylogeographic insights in Cornus nuttallii (Cornaceae). AB - PREMISE OF THE STUDY: Genetic knowledge is completely lacking for Pacific dogwood (Cornus nuttallii), a western North American temperate tree that is pollinated and dispersed by biological vectors. We investigated how history, geography, and climate have affected population genetic structure, local adaptation, and the phylogeography of this species. METHODS: We examined patterns and levels of diversity in nuclear microsatellites (SSRs) and cpDNA haplotypes in populations from across the species range. We compared these results to population differentiation and genetic clines in phenotypic traits in a common garden. KEY RESULTS: Genetic diversity was low for both nuclear SSRs and cpDNA. There was a lack of population structure (F(ST) = 0.090) in the coastal portion of the species range, with estimates of population genetic diversity in microsatellite markers decreasing with latitude from California to British Columbia. A disjunct interior population in Idaho 450 km from the coastal range had the lowest diversity but the highest divergence of all populations studied. Only a single nucleotide polymorphism was discovered after sequencing 5547 base pairs in seven noncoding regions of cpDNA. Both cpDNA haplotypes were widely distributed throughout the species range. Quantitative variation among populations was moderate (0.11 <= Q(ST) <= 0.63), and weak but significant adaptive clines were found between quantitative traits and population climatic variables (0.09 <= R(2) <= 0.34). CONCLUSIONS: Cornus nuttallii likely faced a population bottleneck in a single southern refugium during the Last Glacial Maximum. Despite low genetic diversity, it is weakly to moderately locally adapted. PMID- 21821594 TI - Paleocene Malvaceae from northern South America and their biogeographical implications. AB - PREMISE OF THE STUDY: The clade Bombacoideae + Malvoideae ('Malvatheca group' sensu Baum et al.) in Malvaceae comprises a mostly tropical lineage with derived taxa that now thrive in higher latitudes. The sparse fossil record, especially for Malvoideae, obscures interpretations of past distributions. We describe fossil leaves of Malvoideae from the middle-late Paleocene Cerrejon Formation in Colombia, which contains evidence for the earliest known neotropical rainforest. METHODS: Fifty-six leaf compressions belonging to Malvaceae were collected from the Cerrejon Formation in northern Colombia. Leaf architectural characters were scored and optimized for 81 genera of Malvaceae. Synapomorphic characters and unique character combinations support natural affinities for the fossil leaves. Fossil pollen from the same formation was also assessed. KEY RESULTS: Despite convergence of overall leaf architecture among many Malvaceae, Malvaciphyllum macondicus sp. nov. can be assigned to the clade Eumalvoideae because of distal and proximal bifurcations of the costal secondary and agrophic veins, a synapomorphy for this clade. CONCLUSIONS: The leaf compressions, the oldest fossils for Eumalvoideae, indicate a minimum divergence time of 58-60 Ma, older than existing estimates from molecular analyses of living species. The abundance of eumalvoid leaves and of bombacoid pollen in the midlate Paleocene of Colombia suggests that the Malvatheca group (Malvoideae + Bombacoideae) was already a common element in neotropical forests and does not support an Australasian origin for Eumalvoideae. PMID- 21821595 TI - A morphological and molecular study in the Deschampsia cespitosa complex (Poaceae; Poeae; Airinae) in northern North America. AB - PREMISE OF THE STUDY: In the North American Arctic, the existence of one or several taxa closely related to Deschampsia cespitosa var. cespitosa has remained a puzzle for many years. Extreme morphological variation, lack of clear limits between alleged forms, and an extended geographic range often render identification keys incomplete, and raise the question of how many species this taxon represents. METHODS: Morphological and molecular analysis, including multivariate statistics, ITS and the cpDNA marker trnK-rps16, was conducted on D. cespitosa var. cespitosa and related taxa using 201 herbarium specimens from northern North America (Alaska, Canada, and Greenland). Fifty-three morphological centeracters were recorded from all specimens, while sequences were retrieved from 167 specimens. KEY RESULTS: Results show that Deschampsia cespitosa (L.) P. Beauv. var. cespitosa, D. cespitosa subsp. alpina (L.) Tzvelev, D. cespitosa subsp. beringensis (Hulten) W. E. Lawr., D. brevifolia R. Br., D. cespitosa (L.) P. Beauv. subsp. glauca (Hartm.) C. Hartm., D. mackenzieana Raup, D. cespitosa subsp. orientalis Hulten, and D. pumila (Griseb.) Ostenf. differed significantly in a few morphological variables, but molecularly are a closely related group with several sequences and haplotypes that are nearly identical. CONCLUSIONS: Overall, the evidence points to the existence of a single species, Deschampsia cespitosa. The occurrence of slightly different morphological types related to specific geographical distributions allows recognition of three additional taxa at the infraspecific level, D. cespitosa subsp. alpina, D. cespitosa subsp. beringensis, and D. brevifolia. All studied taxa showed morphological variation in a gradient, suggesting the existence of phenotypic plasticity. PMID- 21821596 TI - Differences in the scaling of area and mass of Ginkgo biloba (Ginkgoaceae) leaves and their relevance to the study of specific leaf area. AB - PREMISE OF THE STUDY: The manner in which the area of the leaf lamina (A) scales with respect to the dry mass of the lamina (M) is an important functional trait that is correlated with whole-plant growth rates and habitat preferences across diverse species. However, the extent to which the scaling between these two variables differs among leaves collected from different types of shoots within the canopy of a tree is poorly understood. Should they exist, significant differences in the A vs. M scaling relationship within canopies would raise a number of important questions, in particular what constitutes an adequate sampling procedure to determine the whole-canopy A vs. M relationship. METHODS: To address this issue, we used a large data set representing 13 biologically distinct categories of leaves sampled from mega- and microsporangiate trees of the dioecious gymnosperm Ginkgo biloba. KEY RESULTS: Analyses of the data for these 13 categories of leaves identify seven statistically significantly different modes of A vs. M scaling that result in significant differences in how specific leaf area (SLA) changes as M varies within the canopies of Ginkgo. CONCLUSIONS: These results indicate that the protocols used to sample leaves for the analysis of foliar functional traits such as specific leaf area need to acknowledge and cope with the effects of leaf and shoot polymorphisms on the quantification of functional traits (and on the construction and testing of hypotheses about these traits). PMID- 21821597 TI - The lower bound to the evolution of mutation rates. AB - Despite substantial attention from theoreticians, the evolutionary mechanisms that drive intra- and interspecific variation in the mutation rate remain unclear. It has often been argued that mutation rates associated with the major replicative polymerases have been driven down to their physiological limits, defined as the point at which further enhancement in replication fidelity incurs a cost in terms of reproductive output, but no evidence in support of this argument has emerged for cellular organisms. Here, it is suggested that the lower barrier to mutation rate evolution may ultimately be defined not by molecular limitations but by the power of random genetic drift. As the mutation rate is reduced to a very low level, a point will eventually be reached at which the small advantage of any further reduction is overwhelmed by the power of drift. This hypothesis is consistent with a number of observations, including the inverse relationship between the per-site mutation rate and genome size in microbes, the negative scaling between the per-site mutation rate and effective population size in eukaryotes, and the elevated error rates associated with less frequently deployed polymerases and repair pathways. PMID- 21821600 TI - Characterization of hollow hydroxyapatite/copper microspheres prepared from the reduction of copper-modified hydroxyapatite by glucose. AB - This study employed a co-precipitation method to synthesize copper-modified hydroxyapatite (HA) powders, where Cu(2+) ions had entered the structure of HA and occupied Ca(1) sites in the columns parallel to the c-axis. Through a hydrothermal treatment, hollow HA/copper (Cu(2)O and/or Cu) microspheres with core-shell structures were prepared in solutions containing glucose, sodium carbonate and sodium citrate. When prolonging the reduction time, Cu(2+) ions dissolved from copper-modified HA were reduced by glucose initially to Cu(+) ions and then to Cu atoms, which would precipitate as copper on the surface of HA. The formation of microspheres with hollow structures was explained by the Kirkendall effect which states that diffusion behaviors of ions were different for HA and copper precipitations. Hybrid HA/copper powders might find their applications in gas sensors, catalysts, electrodes and so on. PMID- 21821598 TI - Global gene expression analysis of transgenic, mannitol-producing, and salt tolerant Arabidopsis thaliana indicates widespread changes in abiotic and biotic stress-related genes. AB - Mannitol is a putative osmoprotectant contributing to salt tolerance in several species. Arabidopsis plants transformed with the mannose-6-phosphate reductase (M6PR) gene from celery were dramatically more salt tolerant (at 100 mM NaCl) as exhibited by reduced salt injury, less inhibition of vegetative growth, and increased seed production relative to the wild type (WT). When treated with 200 mM NaCl, transformants produced no seeds, but did bolt, and exhibited less chlorosis/necrosis and greater survival and dry weights than the WT. Without salt there were no M6PR effects on growth or phenotype, but expression levels of 2272 genes were altered. Many fewer differences (1039) were observed between M6PR and WT plants in the presence of salt, suggesting that M6PR pre-conditioned the plants to stress. Previous work suggested that mannitol is an osmoprotectant, but mannitol levels are invariably quite low, perhaps inadequate for osmoprotectant effects. In this study, transcriptome analysis reveals that the M6PR transgene activated the downstream abscisic acid (ABA) pathway by up-regulation of ABA receptor genes (PYL4, PYL5, and PYL6) and down-regulation of protein phosphatase 2C genes (ABI1 and ABI2). In the M6PR transgenic lines there were also increases in transcripts related to redox and cell wall-strengthening pathways. These data indicate that mannitol-enhanced stress tolerance is due at least in part to increased expression of a variety of stress-inducible genes. PMID- 21821602 TI - Predictive accuracy of dynamic risk factors for aboriginal and non-aboriginal sex offenders: an exploratory comparison using STABLE-2007. AB - Although Aboriginal offenders are overrepresented in Canadian prisons, there is limited research examining the extent to which commonly used risk factors and risk scales are applicable to Aboriginals. Aboriginal (n = 88) and non-Aboriginal (n = 509) sex offenders on community supervision were compared on the dynamic risk factors of STABLE-2007. Data on sexual, violent, any crime, and any recidivism (including breaches) were collected with an average follow-up of 3.4 years. Aboriginal offenders scored significantly higher than non-Aboriginal offenders on STABLE-2007 total scores and on several items measuring general criminality. STABLE-2007 did not significantly predict recidivism with Aboriginal offenders (although it did for non-Aboriginals). The general antisociality items were generally significantly less predictive for Aboriginals than non Aboriginals, whereas items assessing sexual self-regulation and relationship stability predicted similarly for both groups. These exploratory results suggest that Aboriginal sex offenders are a higher-needs group but that some STABLE-2007 items are not predictive with this population. PMID- 21821601 TI - Updated longitudinal data on acute exacerbation of chronic hepatitis B in patients with breast cancer receiving anthracycline-based adjuvant chemotherapy: therapeutic vs. pre-emptive use of lamivudine. AB - OBJECTIVE: Following our previous report on acute exacerbation of chronic hepatitis B in breast cancer patients receiving anthracyline-based adjuvant chemotherapy, updated longitudinal data were analyzed focusing on therapeutic and pre-emptive use of lamivudine. METHODS: Records of 3259 patients at Asan Medical Center between August 2001 and November 2009 were reviewed. The alanine aminotransferase level was graded by Common Terminology Criteria for Adverse Events version 3.0. Hepatitis B virus reactivation was defined as a >=10-fold increase in hepatitis B virus DNA level compared with baseline or an absolute increase of >10(5) copies/ml. Acute exacerbation or hepatitis flare-up was defined as an increase of serum alanine aminotransferase level to three or more times the upper limit of normal. RESULTS: In 169 patients showing positive hepatitis B surface antigen, preemptive lamivudine prophylaxis was administered to 41 patients. Overall, 18 (14.1%) of 128 patients without prophylaxis and 2 (4.9%) of 41 patients with prophylaxis showed acute exacerbation during adjuvant chemotherapy (P= 0.164). Toxic or unknown origin hepatitis occurred in 18 (14.1%) of 128 patients without prophylaxis and 1 (2.4%) of 41 patients with prophylaxis (P= 0.046). Treatment interruption occurred in 26 (19.6%) patients without prophylaxis and in 2 (4.8%) patients with prophylaxis (P= 0.062). Age (>=55) was the associated factor for acute exacerbation of chronic hepatitis B (P= 0.040), and the ultrasonographic findings showed the association in subgroup analysis (P= 0.032). CONCLUSIONS: Pre-emptive use of lamivudine seems to reduce the degree of alanine aminotransferase abnormality and the incidence of hepatitis flare-up. Age (>=55) at initiation of adjuvant chemotherapy was an independently associated factor. PMID- 21821604 TI - Effect of acupuncture for gastrointestinal activity differs depending on the pathophysiological condition. PMID- 21821603 TI - Impact of the ventilator bundle on ventilator-associated pneumonia in intensive care unit. AB - OBJECTIVE: The ventilator bundle is being promoted to prevent adverse events in ventilated patients including ventilator-associated pneumonia (VAP). We aimed to: (i) examine adoption of the ventilator bundle elements; (ii) determine effectiveness of individual elements and setting characteristics in reducing VAP; (iii) determine effectiveness of two infection-specific elements on reducing VAP; and, (iv) assess crossover effects of complying with VAP elements on central line associated bloodstream infections. DESIGN: Cross-sectional survey. SETTING: Four hundred and fifteen ICUs from 250 US hospitals. PARTICIPANTS: Managers/directors of infection prevention and control departments. INTERVENTIONS: Adoption and compliance with ventilator bundle elements. MAIN OUTCOME MEASURES: VAP rates. RESULTS: The mean VAP rate was 2.7/1000 ventilator days. Two-thirds (n = 284) reported presence of the full ventilator bundle policy. However, only 66% (n = 188/284) monitored implementation; of those, 39% (n = 73/188) reported high compliance. Only when an intensive care unit (ICU) had a policy, monitored compliance and achieved high compliance were VAP rates lower. Compliance with individual elements or just one of two infection-related element had no impact on VAP (beta = -0.79, P= 0.15). There was an association between complying with two infection elements and lower rates (beta = -1.81, P< 0.01). There were no crossover effects. Presence of a full-time hospital epidemiologist (HE) was significantly associated with lower VAP rates (beta = -3.62, P< 0.01). CONCLUSIONS: The ventilator bundle was frequently present but not well implemented. Individual elements did not appear effective; strict compliance with infection elements was needed. Efforts to prevent VAP may be successful in settings of high levels of compliance with all infection-specific elements and in settings with full-time HEs. PMID- 21821605 TI - Racial/ethnic disparities in patterns and determinants of criminal justice involvement among youth in substance abuse treatment programs. AB - Adolescent substance abuse is a criminal behavior; however, not all criminal behaviors result in criminal justice involvement. This study examined disparities among adolescents aged 12 to 17 admitted to substance abuse treatment nationwide. Findings indicate significant disparities in patterns and determinants of criminal justice involvement between White and minority adolescents. Minorities were significantly more likely to be involved with the criminal justice system, even after controlling for criminal behaviors, substance abuse, mental health problems, and socioenvironmental risk. Findings reveal that connections to the educational system may be especially important for minority groups. The importance of developing systems of treatment for adolescents in the community and correctional system that are part of the same continuum of care is highlighted. PMID- 21821606 TI - Predicting left ventricular dysfunction after valve repair for mitral regurgitation due to leaflet prolapse: additive value of left ventricular end systolic dimension to ejection fraction. AB - AIMS: Left ventricular (LV) dysfunction is the first cause of late mortality after mitral valve surgery. In this retrospective analysis, we studied the association between preoperative echocardiographic LV measures and occurrence of LV dysfunction after mitral valve repair (MVR). METHODS AND RESULTS: Between 1991 and 2009, 335 consecutive patients underwent MVR for severe mitral regurgitation due to leaflet prolapse in our institution. Echocardiography was performed preoperatively and at 10.8 (9.1-12.0) months after surgery in 303 patients who represented the study population. Cardiac events were recorded during follow-up. LV ejection fraction (EF) decreased from 68 +/- 9% before surgery to 59 +/- 9% post-operatively (P < 0.001). Preoperative EF <64% and LV end-systolic diameter (ESD) >= 37 mm were the best cut-off values for the prediction of post-operative LV dysfunction (EF < 50%). On the basis of a combined analysis, the occurrence of post-operative LV dysfunction was 9% when EF was >= 64% and LVESD < 37 mm, 21% with EF < 64% or LVESD >= 37 mm, and 33% with EF < 64% and LVESD >= 37 mm (P for trend < 0.001). The combined variable EF < 64% and LVESD >= 37 mm added incremental prognostic value to the multivariable regression model (P = 0.001). CONCLUSION: Simple preoperative echocardiography measures allow the prediction of LV dysfunction after MVR in patients with leaflet prolapse. Patients with preoperative EF >= 64% and LVESD < 37 mm incur relatively low risk of post operative LV dysfunction. PMID- 21821607 TI - Sublingual isosorbide dinitrate for the detection of obstruction in hypertrophic cardiomyopathy. AB - AIMS: Hypertrophic cardiomyopathy (HCM) is predominantly associated with left ventricular outflow tract (LVOT) obstruction. The assessment of the obstruction with a provoking test should be a routine part of HCM evaluation. The aim of the study was to determine the utility of a sublingual spray application of isosorbide dinitrate (ISDN) for detection of an obstruction. METHODS AND RESULTS: We have prospectively analysed 77 consecutive HCM patients, measuring the LVOT gradient at rest, using the sublingual spray application of ISDN (2.5 mg; after 2, 5, and 10 min), and with exercise echocardiography. An obstruction was defined as a gradient >= 30 mmHg. An obstruction was present in 15 patients (19%) at rest, in 42 patients (55%) after ISDN, and in 55 patients (71%) after exercise. The ISDN test had a sensitivity of 76% and the specificity of 100% relative to exercise echocardiography, while at-rest measurements had a sensitivity of 27% and a specificity of 100%. The chronological difference in the prevalence of obstructions during the ISDN test was statistically significant (P < 0.05); at ISDN plus 2 min, obstructions were seen in only 29 patients (38%, gradient 28.8 +/- 25.0 mmHg), however, at ISDN plus 5 and 10 min, obstructions were found in 42 patients (55%, gradient 44.5 +/- 39.6 mmHg). CONCLUSION: The ISDN test is a reliable screening method for the detection of an HCM obstruction, however, the measurement should be delayed 5-10 min after the application of ISDN. Patients with negative ISDN tests should undergo exercise echocardiography. PMID- 21821608 TI - Anomalous origin of the right coronary artery from the pulmonary artery coexisting with aortopulmonary window and partial abnormal drainage of the pulmonary vein. PMID- 21821609 TI - Echocardiographic evaluation of systolic and mean pulmonary artery pressure in the follow-up of patients with pulmonary hypertension. AB - AIMS: To identify a correction of the modified Bernoulli formula used to estimate systolic and mean pulmonary artery pressure [sPAP and mPAP; respectively: sPAP = 4 * TRv (tricuspid regurgitation velocity)(2)+ RAP (right atrial pressure); and mPAP = 0.61sPAP + 2], applicable in the follow-up of pulmonary hypertension (PH) patients. METHODS AND RESULTS: From January 1979 to December 2009, 60 patients with precapillary (class I and IV) and 'out of proportion' PH were consecutively enrolled in the PH Registry of Trieste. All patients underwent both echocardiographic and right heart catheter evaluation. We used a simple-linear regression method in order to compare sPAP and mPAP Doppler-estimated values with the respective right-heart catheterization invasive variables. The comparison of the estimated with the traditional modified Bernoulli formula echo-Doppler data and the effective invasive values confirmed a significant association between them (for sPAP P< 0.001; for mPAP P= 0.006). Simple-linear-regression-derived formulas were sPAP = 1.07 * (4TRv(2)+ RAP) + 7.4 (1) and mPAP = 1.1 * (0.61sPAP + 2) + 2.5 (2). These regression-corrected formulas were validated in an external population of PH patients. CONCLUSION: Our data suggest that formulas (1) and (2) could be more reliable with respect to the traditional modified Bernoulli equation, when estimating echocardiographically sPAP and mPAP in patients with PH confirmed by right-heart catheterization. PMID- 21821610 TI - Triple left ventricular outflow tract obstruction. AB - A 59-year-old man had, over a period of 5 years, three different clinical scenarios which led to dynamic left ventricular outflow tract obstruction (LVOTO). Initially, this man who suffered from hypertrophic cardiomyopathy presented with asymmetric septal hypertrophy and systolic anterior motion (SAM) of the anterior mitral leaflet, along with mitral regurgitation. He was treated by septal myectomy and mitral valve repair with insertion of an artificial mitral ring. Several years later, he presented with severe LVOTO, this time related to the anteriorly displaced mitral coaptation site and the prosthetic ring. The ring and the anterior mitral leaflet were resected and a prosthetic mitral valve implanted. Several years later, the patient presented with LVOTO for a third time. It was now SAM of the remaining posterior leaflet that was responsible for the LVOTO. PMID- 21821611 TI - Diagnostic influence of cardiovascular screening by pocket-size ultrasound in a cardiac unit. AB - AIMS: We aimed to study the diagnostic influence of adding a routine cardiovascular ultrasound screening of the cardiac anatomy and function, the pericardium, the pleura and the abdominal great vessels by the new pocket-size ultrasound device (pUS) with grey scale and colour Doppler imaging. METHODS AND RESULTS: In 119 randomly selected patients admitted to a cardiac unit at a non university hospital, routinely adding a cardiovascular ultrasonography of only 4.4 min with a pocket-size device corrected the primary diagnosis in 16% of patients. In addition, 29% had the primary diagnosis verified and in 10% an additional important diagnosis was made. Higher age predicted any diagnostic influence of pUS screening with an increase of 61% (P=0.003) per 10 years of higher age. Overall, the pUS screening had a sensitivity and specificity with respect to detecting at least moderate pathology of 97 and 93%. Positive and negative predictive values were 93 and 87%, respectively. In the sub-group of subjects with a change in the primary diagnosis following pUS there was no false negative or false-positive findings. CONCLUSION: Screening by pUS assessed vascular and cardiac anatomy and function accurately and enabled correction of the diagnosis in 16% of patients admitted to a cardiac unit. In 55% of the participants, the cardiovascular ultrasound screening had important diagnostic influence. We suggest that it would be appropriate to implement strategies and systems for routinely adding an ultrasound cardiovascular examination to patients in cardiac units. PMID- 21821612 TI - It's time for change with the management of non-specific chronic low back pain. PMID- 21821613 TI - Allometric scaling of peak power output accurately predicts time trial performance and maximal oxygen consumption in trained cyclists. AB - OBJECTIVE: The purpose of this study was to determine if peak power output (PPO) adjusted for body mass(0.32) is able to accurately predict 40-km time trial (40 km TT) performance. METHODS: 45 trained male cyclists completed after familiarisation, a PPO test including respiratory gas analysis, and a 40-km TT. PPO, maximal oxygen consumption (VO(2max)) and 40-km TT time were measured. Relationships between 40-km TT performance and (I) absolute PPO (W) and VO(2max) (l/min), (II) relative PPO (W/kg) and VO(2max) (ml/min/kg) and (III) PPO and VO(2max) adjusted for body mass (W/kg(0.32) and ml/min/kg(0.32), respectively) were studied. RESULTS: The continuous ramp protocol resulted in a similar relationship between PPO and VO(2max) (r=0.96, p<0.0001) compared with a stepwise testing protocol but was associated with a lower standard error of the estimated when predicting VO(2max). PPO adjusted for body mass (W/kg(0.32)) had the strongest relationship with 40-km TT performance (s) (r=-0.96, p<0.0001). Although significant relationships were also found between absolute (W) and/or relative PPO (W/kg) and 40-km TT performance (s), these relationships were significantly weaker than the relationship between 40-km TT performance and PPO adjusted for body mass (W/kg(0.32)) (p<0.0001). CONCLUSIONS: VO(2max) can be accurately predicted from PPO when using a continuous ramp protocol, possibly even more accurately than when using a stepwise testing protocol. 40-km TT performance (s) in trained cyclists can be predicted most accurately by PPO adjusted for body mass (W/kg(0.32)). As both VO(2max) and 40-km TT performance can be accurately predicted from a PPO test, this suggests that (well)-trained cyclists can possibly be monitored more frequently and with fewer tests. PMID- 21821614 TI - Comparison of full field digital (FFD) and computed radiography (CR) mammography systems in Greece. AB - The purpose of this study is to evaluate and compare the performance of 52 full field digital (FFD) and computed radiography (CR) mammography systems checked by the Greek Atomic Energy Commission with respect to dose and image quality. Entrance surface air kerma (ESAK) was measured and average glandular dose (AGD) was calculated according to the European protocol on dosimetry in mammography. The exposures were performed using the clinical protocol of each laboratory. The image quality was assessed by the total score of resolved phantom structures incorporated in an American College of Radiology accreditation phantom. The mean ESAK values for FFD and CR systems were 4.59 +/- 1.93 and 5.0 +/- 1.78 mGy, respectively, whereas the AGD yielded a mean value of 1.06 +/- 0.36 mGy for the FFD and 1.04 +/- 0.35 mGy for the CR systems. Considering image quality, FFD systems indicated a mean total score of 13.04 +/- 0.89, whereas CR systems a mean total score of 11.54 +/- 1.06. PMID- 21821615 TI - Spanish experience in education and training in radiation protection in medicine. AB - In most of its publications, the International Commission on Radiological Protection has highlighted the importance of education and training in radiation protection (RP) for medical exposures. Spain, like other Member States of the European Union, has implemented the Directive and the Guidelines in the medical area. The purpose of this paper is to present the Spanish experience in RP education and training in medicine, the different objectives established according to professional levels, existing regulations and feedback obtained from various RP actions. PMID- 21821616 TI - Current issues in radiation protection in medicine. PMID- 21821617 TI - Assessment of personnel absorbed dose at production of medical radioisotopes by a cyclotron. AB - The medical radioisotope (201)Tl is produced by a cyclotron through the (203)Tl(p, 3n)(201)Pb reaction in the nuclear medicine research group of Agricultural, Medical and Industrial Research Schools in Iran. The produced (201)Pb decays to (201)Tl by electron capture. One of the most important problems that may occur is malfunction of a part of target or beam line, so that it needs the bombardment to be stopped and the problem fixed. In this work, induced radioactivity of the target, aluminium case of target, beam line and concrete walls of the thallium target room were calculated by Monte Carlo method. Then by using the results of the Monte Carlo simulation, the whole body absorbed dose to cyclotron personnel during repair and after stopping the bombardment, were assessed at different places of target room. PMID- 21821619 TI - Results and challenges for the endovascular repair of aortic arch aneurysms. AB - Endovascular aortic arch reconstruction provides an attractive alternative to treat aortic arch disease in high-risk patients who would otherwise be unsuitable for open repair. Success with multibranched stent grafts in the thoracoabdominal aorta along with recent advances in design such as the precurved inner nitinol cannula have simplified the endovascular reconstruction of aortic arch aneurysms with multibranched stent grafts. These devices allow for greater flexibility in conforming to difficult anatomy and preserving important side branches. During the first surgical stage, a left carotid -subclavian bypass or left subclavian artery transposition is performed. The second stage is the endovascular procedure. The device is inserted through a transfemoral approach, and crossing of the aortic valve with the device is necessary. The stent graft is deployed during brief periods of rapid pacing. Bridging from the branches to the innominate and left common carotid arteries requires a suitable covered stent. In the case of a large-diameter innominate artery, a custom-made bridging limb has to be used to ensure that adequate length and size are available. Direct flow to the innominate and left common carotid arteries do not cease for any significant time during the procedure. Initial experience with mean follow up more than 6 months is encouraging. The method is not suitable for patients with extensive atheromatous involvement of the aortic arch. Careful preoperative planning (preoperative imaging, device construction, and access issues), high endovascular skills, and appropriate imaging equipment are imperative for a successful result. Long-term follow-up is necessary to evaluate the efficacy and safety of these new devices. PMID- 21821618 TI - Concomitant forms of abuse and help-seeking behavior among white, African American, and Latina women who experience intimate partner violence. AB - This study uses National Violence against Women Survey data to investigate the differential impact of concomitant forms of violence (sexual abuse, stalking, and psychological abuse) and ethnicity on help-seeking behaviors of women physically abused by an intimate partner (n = 1,756). Controlling for severity of the physical abuse, women who experienced concomitant sexual abuse are less likely to seek help, women who experienced concomitant stalking are more likely to seek help, whereas concomitant psychological abuse is not associated with help seeking. Ethnic differences are found in help seeking from friends, mental health professionals, police, and orders of protection. Implications for service outreach are discussed. PMID- 21821620 TI - ANCA-associated vasculitis is linked to carriage of the Z allele of alpha1 antitrypsin and its polymers. AB - BACKGROUND: Small studies have linked alpha1 antitrypsin (alpha1AT) deficiency to patients with antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV). OBJECTIVE: To test the validity and the mechanism of this association between alpha1AT and AAV. METHODS: The distribution of alpha1AT deficiency alleles Z and S was compared between 856 White Europeans with AAV and 1505 geographic and ethnically matched healthy controls. Genotyping was performed by allelic discrimination assay. RESULTS: were compared between cases and controls using chi(2) tests. The serum and renal biopsies for alpha1AT polymers were compared using the polymer-specific 2C1 antibody. The role of alpha1AT polymers in promoting inflammation was investigated by examining their ability to prime neutrophils for ANCA activation as assessed by CD62L shedding, superoxide production and myeloperoxidase degranulation. Results The Z but not the S allele was over-represented in the patients compared with controls (HR=2.25, 95% CI 1.60 to 3.19). Higher concentrations of polymers of alpha1AT were detected in serum from patients carrying the Z allele than in those not carrying the Z allele (median (IQR) 1.40 (0.91-3.32) mg/dl vs 0.17 (0.06-0.28) mg/dl, p<0.001); polymers of alpha1AT were also seen in the renal biopsy of a patient with vasculitic glomerulonephritis. Polymers of alpha1AT primed neutrophils with CD62L shedding and increased superoxide production following ANCA activation. Carriage of the Z allele was not associated with disease severity, survival or relapse. CONCLUSIONS: The Z but not the S deficiency allele is associated with AAV. Polymers of alpha1AT are present in the serum and glomeruli of at least some patients with the Z allele, which may promote inflammation through priming of neutrophils. PMID- 21821622 TI - Weight loss as treatment for knee osteoarthritis symptoms in obese patients: 1 year results from a randomised controlled trial. AB - OBJECTIVE: To evaluate 1-year symptomatic improvement in obese patients with knee osteoarthritis (OA) on an intensive low-energy diet (LED) maintained by frequent consultations with a dietician compared to minimal attention. METHODS: The LED programme consisted of group therapy with dietary consultations and two periods of a low-calorie diet of 810 kcal/day during weeks 0-8 and weeks 32-36. The control group only received dietary instruction and attention for 2 h at baseline, and at weeks 8, 32, 36 and 52. The primary end point (total Western Ontario and McMaster Universities (WOMAC) index) was assessed as the mean group difference during and after 1 year. RESULTS: The study population consisted of 89 patients, 89% women, average age 63 years. After 1 year, mean weight loss in the LED group was -10.9 kg (11%) versus -3.6 kg (4%) in the control group (p<0.0001). There was no difference between the groups in total WOMAC index (p=0.11), although both groups improved. However, the LED intervention resulted in less WOMAC pain (7.7 mm), with a group mean difference of 7.2 mm (95% CI 1.0 to 13.4, p=0.022). After one year 14 (32.8%) responded to LED versus 7 (15.6%) to control, with an absolute benefit of 16.3% (-1.1& to 33.6%, p=0.066). CONCLUSION: Continuous reinforcement of a weight loss programme can be successful over a year in obese knee OA patients. Weight loss was statistically reflected only by a reduction in pain. However, the overall clinical benefits of the intervention on health should lead to a strong recommendation of weight loss in this group of patients. PMID- 21821621 TI - Identifying patients with axial spondyloarthritis in primary care: how useful are items indicative of inflammatory back pain? AB - BACKGROUND: The value of clinical items defining inflammatory back pain to identify patients with axial spondyloarthritis (SpA) in primary care is unclear. OBJECTIVE: To identify predictive clinical parameters for a diagnosis of axial SpA in patients with chronic back pain presenting in primary care. METHODS: Consecutive patients aged < 45 years (n=950) with back pain for > 2 months who presented to orthopaedic surgeons (n=143) were randomised based on four key questions for referral to rheumatologists (n=36) for diagnosis. RESULTS: The rheumatologists saw 322 representative patients (mean age 36 years, 50% female, median duration of back pain 30 months). 113 patients (35%) were diagnosed as axial SpA (62% HLA B27+), 47 (15%) as ankylosing spondylitis (AS) and 66 (21%) as axial non-radiographic SpA (nrSpA). Age at onset <= 35 years, improvement by exercise, improvement with non-steroidal anti-inflammatory drugs, waking up in the second half of the night and alternating buttock pain were identified as most relevant for diagnosing axial SpA by multiple regression analysis. Differences between AS and nrSpA were detected. No single item was predictive, but >= 3 items proved useful for good sensitivity and specificity by receiver operating characteristic modelling. CONCLUSION: This study shows that a preselection in primary care of patients with back pain based on a combination of clinical items is useful to facilitate the diagnosis of axial SpA. PMID- 21821623 TI - Flower power: its association with bee power and floral functional morphology in papilionate legumes. AB - BACKGROUND AND AIMS: A test was made of the hypothesis that papilionate legume flowers filter pollinators according to their ability to exert strength to open flowers to access rewards. In addition, interactions with pollen vectors were expected to explain the structural complexity of the architecture of these flowers since operative flower strength may be determined by a combination of morphological traits which form part of an intrafloral functional module. METHODS: Six papilionate species were studied: Collaea argentina, Desmodium uncinatum, Galactia latisiliqua, Lathyrus odoratus, Spartium junceum and Tipuana tipu. Measurements were made of the strength needed to open keels and the strength that pollinators were capable of exerting. Morphological traits of all petals were also measured to determine which of them could be either mutually correlated or correlated with operative strength and moment of strength and participated in a functional module. KEY RESULTS: It was observed that pollinators were capable in all cases of exerting forces higher and often several times higher than that needed to access floral rewards, and no association could be detected between floral operative strength and strength exerted by the corresponding pollinators. On the other hand, strong and significant correlations were found among morphometric traits and, of these, with operative strength and moment. This was particularly evident among traits of the keel and the wings, presumably involved in the functioning of the floral moveable mechanism. CONCLUSIONS: Though visitors are often many times stronger than the operative strength of the flowers they pollinate, exceptionally weak bees such as Apis mellifera cannot open the strongest flowers. On the other hand, strong correlations among certain petal morphometric traits (particularly between the keel and wings) give support to the idea that an intrafloral module is associated with the functioning of the mechanism of these legume flowers. In addition, the highly significant correlations found across petals support the view of functional phenotypic integration transcending the ontogenetic organization of flower structure. PMID- 21821624 TI - Modelling seagrass growth and development to evaluate transplanting strategies for restoration. AB - BACKGROUND AND AIMS: Seagrasses are important marine plants that are under threat globally. Restoration by transplanting vegetative fragments or seedlings into areas where seagrasses have been lost is possible, but long-term trial data are limited. The goal of this study is to use available short-term data to predict long-term outcomes of transplanting seagrass. METHODS: A functional-structural plant model of seagrass growth that integrates data collected from short-term trials and experiments is presented. The model was parameterized for the species Posidonia australis, a limited validation of the model against independent data and a sensitivity analysis were conducted and the model was used to conduct a preliminary evaluation of different transplanting strategies. KEY RESULTS: The limited validation was successful, and reasonable long-term outcomes could be predicted, based only on short-term data. CONCLUSIONS: This approach for modelling seagrass growth and development enables long-term predictions of the outcomes to be made from different strategies for transplanting seagrass, even when empirical long-term data are difficult or impossible to collect. More validation is required to improve confidence in the model's predictions, and inclusion of more mechanism will extend the model's usefulness. Marine restoration represents a novel application of functional-structural plant modelling. PMID- 21821625 TI - Simulating the grazing of a white clover 3-D virtual sward canopy and the balance between bite mass and light capture by the residual sward. AB - BACKGROUND AND AIMS: The productivity and stability of grazed grassland rely on dynamic interactions between the sward and the animal. The descriptions of the sward canopies by standard 2-D representations in studies of animal-sward interactions at the bite scale need to be improved to account for the effect of local canopy heterogeneity on bite size and regrowth ability. The aim of this study was to assess a methodology of 3-D digitized canopies in order to understand the balance between bite mass and light interception by the residual sward. METHODS: 3-D canopy structures of four white clover swards were recorded using a POLHEMUS electromagnetic digitizer and adapted software (POL95). Plant components were removed after digitizing to determine aerial dry matter. Virtual canopies were synthesized and then used to derive canopy geometrical parameters, to compute directional interception and to calculate bite mass. The bit masses of cattle and sheep were simulated according to their form, depth and placement on the patch, taking account of explicit sward architecture. The resulting light interception efficiency (LIE) of each organ was then calculated using a projective method applied to the virtual residual sward. This process enabled an evaluation of light interception based on Beer's law at the bite scale. KEY RESULTS: The patterns of the vertical profiles of LAI appeared as bimodal, triangular or skewed parabolic functions. For a single bite of similar area and depth, the lowest mass was observed with half-spherical form and the highest for the cylindrical form, whatever the initial sward structure. The differences between the actual LIE and that calculated by Beer's law were marked for residual swards shorter than 8 cm. Bite mass and LIE values after grazing were more strongly affected by the initial structure of the sward than by bite form and placement. CONCLUSIONS: 3-D digitizing techniques enabled a definition of the geometry of each component in sward canopies and an accurate description of their vertical and horizontal heterogeneities. The discrepancy between Beer's law results and actual light interception was reduced when the sward regrew rapidly and if the rest period was long. Studies on the biting process would greatly benefit from this method as a framework to formulate and test hypotheses in a quantitative manner. PMID- 21821626 TI - Floral development and floral phyllotaxis in Anaxagorea (Annonaceae). AB - Background and Aims Anaxagorea is the phylogenetically basalmost genus in the large tropical Annonaceae (custard apple family) of Magnoliales, but its floral structure is unknown in many respects. The aim of this study is to analyse evolutionarily interesting floral features in comparison with other genera of the Annonaceae and the sister family Eupomatiaceae. Methods Live flowers of Anaxagorea crassipetala were examined in the field with vital staining, liquid fixed material was studied with scanning electron microscopy, and microtome section series were studied with light microscopy. In addition, herbarium material of two other Anaxagorea species was cursorily studied with the dissecting microscope. Key Results Floral phyllotaxis in Anaxagorea is regularly whorled (with complex whorls) as in all other Annonaceae with a low or medium number of floral organs studied so far (in those with numerous stamens and carpels, phyllotaxis becoming irregular in the androecium and gynoecium). The carpels are completely plicate as in almost all other Annonaceae. In these features Anaxagorea differs sharply from the sister family Eupomatiaceae, which has spiral floral phyllotaxis and ascidiate carpels. Flat stamens and the presence of inner staminodes differ from most other Annonaceae and may be plesiomorphic in Anaxagorea. However, the inner staminodes appear to be non secretory in most Anaxagorea species, which differs from inner staminodes in other families of Magnoliales (Eupomatiaceae, Degeneriacae, Himantandraceae), which are secretory. Conclusions Floral phyllotaxis in Anaxagorea shows that there is no signature of a basal spiral pattern in Annonaceae and that complex whorls are an apomorphy not just for a part of the family but for the family in its entirety, and irregular phyllotaxis is derived. This and the presence of completely plicate carpels in Anaxagorea makes the family homogeneous and distinguishes it from the closest relatives in Magnoliales. PMID- 21821627 TI - Efficacy and safety of a switch to unboosted atazanavir in combination with nucleoside analogues in HIV-1-infected patients with virological suppression under antiretroviral therapy. AB - BACKGROUND: Limited data are available on the use of unboosted atazanavir in combination with nucleoside reverse transcriptase inhibitors (NRTIs) in treatment experienced HIV-infected patients. METHODS: We conducted a multicentre, retrospective study among patients with plasma HIV-1 RNA levels <50 copies/mL under antiretroviral therapy who switched to unboosted atazanavir + NRTIs between January 2002 and December 2008. Virological failure during follow-up was defined as a confirmed plasma HIV-1 RNA level >50 copies/mL. Baseline risk factors for virological failure were identified using Cox proportional hazards models. RESULTS: A total of 886 patients were analysed. At baseline, median age was 44 years, 71.5% were males and median CD4 cell count was 490 cells/mm(3). NRTIs used in combination with atazanavir were tenofovir, abacavir and emtricitabine/lamivudine in 36.9%, 44.1% and 94.4% of patients, respectively. Median follow-up was 21 months. The 3 year probability of virological failure was 20.1%. Only a history of virological failure under NRTIs [hazard ratio (HR) 1.63, P = 0.049] and under protease inhibitors (HR 2.04, P = 0.006) were significantly associated with the risk of virological failure. Among the 431 patients without a prior history of virological failure, the 3 year probability of virological failure was 11.3%, and only hepatitis C virus co-infection (HR 2.25, P = 0.026) and abacavir use (HR 0.43, P = 0.04) were associated with the risk of virological failure. Safety of the switch was satisfactory, with improvement of the lipid profile. CONCLUSIONS: In patients with virological suppression and no prior history of virological failure, a switch to unboosted atazanavir in combination with NRTIs is associated with a low probability of virological failure and a good safety profile. PMID- 21821628 TI - Stem cell therapy for articular cartilage defects. AB - BACKGROUND: Stem cells are easily accessible and have great potential for healing articular cartilage defects. These features make stem cell therapy an appealing approach for treating severely impaired joint function. SOURCES OF DATA: Clinical and basic research articles and literature reviews. AREAS OF AGREEMENT: Stem cells possess the potential to build articular cartilage. Malalignment and instability corrections and proper rehabilitation are crucial prerequisites for surgical procedures involving stem cell therapy. Smoking reduces the result. AREAS OF CONTROVERSY: Ethical concerns remain unresolved. No standards are established for inducing stem cell potential, optimizing culturing media or harvesting. The risk of failure has not been determined. GROWING POINTS: Surgical scaffolds can improve results. Care givers should focus on re-educating patients. Improved funding is needed for developing the therapy. AREAS TIMELY FOR DEVELOPING RESEARCH: Define guidelines for stem cell therapy and demonstrate effectiveness. PMID- 21821629 TI - Role of organisational structure in implementation of sedation protocols: a comparison of Canadian and French ICUs. AB - PURPOSE: Use of sedation protocols is associated with fewer mechanical ventilation days in critically ill patients. Canadian intensive care units (ICUs) often have a higher nurse-patient ratio and more specialised training of ICU nurses than French ICUs. Considering these differences, the purpose of this study was to compare implementation of sedation protocols as indicated by frequency of sedation assessment and response to levels of sedation between a Canadian and a French ICU. METHODS: This was a retrospective observational study of 30 patients who were mechanically ventilated for at least 24 h in each of two tertiary care ICUs in Vancouver, Canada and Montpellier, France. The authors tabulated all Richmond Agitation-Sedation Scale scores, frequency of score measurement, target scores, frequency and magnitude of scores that were out of target range, and the response to these scores within 1 h of measurement. Practices between the two hospitals were compared using regression modelling, adjusting for patient age, sex, and Acute Physiology and Chronic Health Evaluation (APACHE) II score. RESULTS: Although sedation scores were measured more frequently in the Canadian ICU, there were fewer appropriate adjustments in medications in response to scores that were outside the target range in this ICU than in the French ICU, which had a lower nurse-patient ratio and no specialised training of nurses (OR 0.26 (95% CI 0.13 to 0.50) for scores that were higher than target, and OR 0.14 (95% CI 0.07 to 0.28) for scores that were lower than target). CONCLUSION: Differences in sedation management between these ICUs are likely related to factors other than nurse-patient ratio or specialised training of ICU nurses. PMID- 21821631 TI - Modifications of bone material properties in postmenopausal osteoporotic women long-term treated with alendronate. AB - OBJECTIVE: Given recent concern about long-term safety of bisphosphonate (BP) therapy, the effects of long-term alendronate (ALN) therapy on intrinsic bone properties were studied among postmenopausal osteoporotic (PMOP) women. DESIGN AND METHODS: Transiliac bone biopsies were obtained from 32 outpatient clinic PMOP women treated with oral ALN for 6.4 +/- 2.0 years. Variables reflecting bone mineralization were measured both at tissue level using quantitative microradiography and at crystal level by Fourier transform infrared microspectroscopy. Bone microhardness was investigated by Vickers indentation tests. RESULTS: were compared with those from 22 age-matched untreated PMOP women. Results Long-term treatment with ALN was associated with a 84% (P<0.001) lower remodeling activity compared with untreated PMOP women, leading to an increased degree of mineralization in both cortical and trabecular bone (+9 and +6%, respectively, P<0.05). Despite a more mature and more mineralized bone matrix, after treatment, cortical and trabecular microhardness and crystallinity were lower than that measured in untreated patients. None of the variables reflecting material properties were significantly correlated to the duration of the treatment. CONCLUSION: Increased degree of mineralization associated with lower crystallinity and microhardness in ALN long-term-treated PMOP women suggests that ALN could alter the quality of bone matrix. The study also suggested that after 3 years of treatment, the changes in material properties are not dependent on the duration of the treatment. Further studies are requested to assess the short-term (<3 years) effects of BPs on bone intrinsic properties. PMID- 21821632 TI - Prevalence and associated risk factors for postpartum depression in women attending a tertiary hospital, Delhi, India. AB - BACKGROUND: Maternal mental health is a largely ignored issue in the Indian population. Considering the high prevalence of postpartum depression, mental health assessment and screening of high-risk cases should be a part of routine antenatal care. AIM: To study the prevalence of women at risk for peripartum depression using Edinburgh Postnatal Depression Scale (EPDS) score in a tertiary teaching hospital in New Delhi, and to study the associated risk factors in the Indian population. METHOD: Five hundred and six (506) peripartum women were interviewed using a structured questionnaire, which included sociodemographic details like socioeconomic status, family structure, relationship with husband and mother-in-law, past obstetric history and gender of children, any history of previous psychiatric illness and outcome of current pregnancy in terms of mode of delivery, gender of newborn and neonatal complications. EPDS scoring was done using a Hindi translated version. Data were analysed using Epi Info version 3.32. RESULTS: Thirty one (6%) out of 506 women scored >= 10 on the EPDS. Birth of female child, nuclear family structure and poor marital relationship were found to have a statistically significant correlation with peripartum depression. CONCLUSION: The 6% prevalence of women at risk of peripartum depression in our study, which is similar to other such studies, is significant and hence maternal mental health assessment should be made a part of routine antenatal and postnatal care. PMID- 21821633 TI - Positive body image: inter-ethnic and rural-urban differences among an indigenous sample from Malaysian Borneo. AB - BACKGROUND: Previous studies examining body image from a cross-cultural perspective have tended to neglect samples from different ethnic groups or along a rural-urban continuum. To overcome this limitation, the present study examined positive body image among rural and urban women from three major indigenous ethnic groups in Sabah, Malaysia. METHOD: A total of 202 women completed the Body Appreciation Scale, as well as measures of media exposure and financial security, and provided their demographic details. RESULTS: RESULT: s showed that there were significant rural-urban differences in body appreciation, with rural participants having significantly higher body appreciation than urban participants. A comparison with a previous data set of West Malaysian women (Swami & Chamorro-Premuzic, 2008) showed that the current urban sample had significantly lower body appreciation and that the rural group had significantly higher body appreciation. Further results showed that research site (urban vs rural) explained 11.0% of the variance in body appreciation. Participant body mass index and exposure to western forms of media explained an additional 2.0% of the variance. CONCLUSION: These results suggest that there are differences in body image between rural and urban women. Results are discussed in relation to the promotion of positive body image, particularly in developing societies where health care resources may be limited. PMID- 21821634 TI - Antiplatelet therapy in percutaneous coronary intervention: is variability of response clinically relevant? PMID- 21821635 TI - Imaging of atrial septal defects: echocardiography and CT correlation. PMID- 21821636 TI - Percutaneous coronary intervention after transcatheter aortic valve implantation. PMID- 21821637 TI - Use of a superficial femoral artery autograft as a femoral vein replacement during en bloc sarcoma resection. AB - INTRODUCTION: Soft tissue malignancy encasing axial vessels presents a surgical challenge when the goal is limb-preserving radical excision. REPORT: We describe a case where limb-preserving resection of a myxoid liposarcoma involving the femoral vessels was successfully performed in the absence of autologous superficial vein for vascular reconstruction. The proximal ipsilateral superficial femoral artery was harvested as an autograft for venous reconstruction, with the arterial defect bridged using a polytetrafluoroethylene interposition graft. DISCUSSION: This technique may be selectively extended to other indications where limb viability is dependent upon availability of a high quality graft, and conventional conduits are either unavailable or unreliable. PMID- 21821638 TI - Effect of acetylcholine on mitogen response of peripheral lymphocytes isolated from rats exposed to chronic stress. AB - The purpose of this study was to clarify the effects of acetylcholine (Ach) on lymphocyte function in rats under chronic stress. The authors isolated peripheral lymphocytes from rats 5 weeks after stress treatment and then measured interleukin-2 (IL-2) production after stimulation with concanavalin A or phytohemagglutinin-L. Although mitogen-induced IL-2 production of the stress group was lower than that of the control group, the addition of Ach significantly increased mitogen-induced IL-2 production in both groups. This effect of Ach was inhibited by atropine in the control group only. The changes (increasing rates) in mitogen-induced IL-2 production from basal condition showed a negative correlation with serum corticosterone concentrations. The authors observed no correlation between the effects of Ach (changes in mitogen-induced IL-2 production with Ach compared to those without Ach) and serum corticosterone concentration. These findings suggest that stimulation of the parasympathetic nervous system improves lymphocyte function during chronic stress. PMID- 21821639 TI - A rodent model to advance the field treatment of crush muscle injury during earthquakes and other natural disasters. AB - Approximately 170 earthquakes of 6.0 or higher magnitude occur annually worldwide. Victims often suffer crush muscle injuries involving impaired blood flow to the affected muscle and damage to the muscle fiber membrane. Current rescue efforts are directed toward preventing acute kidney injury (AKI), which develops upon extrication and muscle reperfusion. But field-usable, muscle specific interventions may promote muscle regeneration and prevent or minimize the pathologic changes of reperfusion. Although current rodent crush injury models involve reperfusion upon removal of the crush stimulus, an analysis of their methodological aspects is needed to ensure adequate simulation of the earthquake-related crush injury. The objectives of this systematic review are to (a) describe rodent crush muscle injury models, (b) discuss the benefits and limitations of these models, and (c) offer a recommendation for animal models that would increase our understanding of muscle recovery processes after an earthquake-induced crush muscle injury. The most commonly used rodent model uses a clamping or pressing crush stimulus directly applied to murine hindlimb muscle. This model has increased our understanding of muscle regeneration but its open approach does not adequately represent the earthquake-related crush injury. The model we recommend for developing field-usable, muscle-specific interventions is a closed approach that involves a nonclamping crush stimulus. Findings from studies employing this recommended model may have greater relevance for developing interventions that lessen the earthquake's devastating impact on individual and community health and quality of life, especially in developing countries. PMID- 21821640 TI - Methodological issues for studying the rest-activity cycle and sleep disturbances: a chronobiological approach using actigraphy data. AB - Shift work schedules, intensive physical exercise late in the day, psychological stress, or a busy lifestyle might induce disorders of the circadian structure, which can affect health on both the physiological and neurobehavioral levels. Rest-activity rhythm is strongly connected with an organism's circadian structure, and irregular sleep-wake patterns can lead to a disruption of entrainment, resulting in physiological and neurobehavioral dysfunction. Shift nurses are often subject to disturbances in the quality and duration of their sleep, raising the possibility of negative impacts on their health and their patients' safety. Researchers have used actigraphy in a number of studies to assess sleep patterns. Because of the close connection between sleep and circadian structure, it may be useful to extend the evaluation of actigraphy data to the analysis of the rest-activity rhythm with rhythmometric procedures to provide a better understanding of possible sleep disorders in relation to entrainment. Actigraphy is an easy and reliable way to study these rhythms and identify possible circadian-rhythm disorders. In this article, the authors discuss methodological issues concerning the evaluation of the rest-activity rhythm, with a focus on actigraphy. PMID- 21821642 TI - Immediate effects of reiki on heart rate variability, cortisol levels, and body temperature in health care professionals with burnout. AB - Burnout is a work-related mental health impairment comprising three dimensions: emotional exhaustion, depersonalization, and reduced personal accomplishment. Reiki aims to help replenish and rebalance the body's energetic system, thus stimulating the healing process. The objective of this placebo-controlled, repeated measures, crossover, single-blind, randomized trial was to analyze the immediate effects of Reiki on heart rate variability (HRV), body temperature, and salivary flow rate and cortisol level in health care professionals with burnout syndrome (BS). Participants included 21 health care professionals with BS, who were asked to complete two visits to the laboratory with a 1-week interval between sessions. They were randomly assigned the order in which they would receive a Reiki session applied by an experienced therapist and a placebo treatment applied by a therapist with no knowledge of Reiki, who mimicked the Reiki treatment. Temperature, Holter ECG recordings (standard deviation of the normal-to-normal interval [SDNN], square root of mean squared differences of successive NN intervals [RMSSD], HRV index, low frequency component [LF], and high frequency component [HF]), salivary flow rate and cortisol levels were measured at baseline and postintervention by an assessor blinded to allocation group. SDNN and body temperature were significantly higher after the Reiki treatment than after the placebo. LF was significantly lower after the Reiki treatment. The decrease in the LF domain was associated with the increase in body temperature. These results suggest that Reiki has an effect on the parasympathetic nervous system when applied to health care professionals with BS. PMID- 21821641 TI - Interleukin-10 predicts preterm birth in acculturated Hispanics. AB - OBJECTIVE: Among Hispanics living in the United States, acculturation is associated with an increased risk for preterm birth. Inflammatory pathways are also associated with preterm birth. As such, the current study sought to investigate the potential relationships among preterm birth, acculturation of Hispanic women, and inflammatory markers. STUDY DESIGN: The authors performed an observational study on pregnant Hispanic women in Texas at 22-24 weeks' gestation (n = 470). The authors obtained demographic data prenatally as well as birth outcome data from the medical chart after delivery. The authors obtained venous blood and used plasma to assay interleukin-1 receptor antagonist (IL-1RA), interleukin-6 (IL-6), and interleukin-10 (IL-10). The authors used logistic regression to understand whether the presence or the absence of IL-10 levels was related to acculturation and the risk of preterm birth. RESULTS: The authors observed interactions between undetectable IL-10 levels and years in the United States and undetectable IL-10 levels and being born in the United States in models predicting preterm birth. Follow-up probes of these interactions suggested that when IL-10 was undetectable, preterm birth became more likely as time living in the United States increased, chi(2) = 5.15 (1, 416), p = .020, odds ratio (OR) = 3.17, and was more likely in participants born in the United States than in those born elsewhere, chi(2) = 5.35 (1, 462), p = .020, OR = 16.78. The authors observed no interactions among acculturation, preterm birth, and IL-1RA and IL-6 levels. CONCLUSION: Acculturated Hispanics who lack the protective effects of IL 10 experience a markedly higher risk of preterm birth than nonacculturated Hispanics. PMID- 21821644 TI - Head of Israel Medical Association ends hunger strike after government concessions on extra jobs. PMID- 21821645 TI - Don't risk patient care to cut costs, regulator warns foundation trusts. PMID- 21821646 TI - Radiotherapy audit shows less regional variation than feared. PMID- 21821647 TI - Management of stable angina: summary of NICE guidance. PMID- 21821648 TI - A man with dilated veins on his upper chest. PMID- 21821649 TI - Unplanned and assisted conception pregnancies. PMID- 21821650 TI - US rate of HIV infection rises sharply among young black gay men. PMID- 21821651 TI - Scotland invests in early detection of cancer. PMID- 21821652 TI - Medicinal plants as antiemetics in the treatment of cancer: a review. AB - Chemotherapy- and radiotherapy-induced nausea and vomiting are the most common, intractable and unpleasant side effects in patients undergoing treatment for cancer. 5-Hydroxytryptamine-3 (5-HT3) receptor antagonists plus dexamethasone have significantly improved the control of acute nausea and vomiting, but delayed nausea and vomiting remains a significant clinical problem. Combined neurokinin-1 receptor antagonists with 5-HT3 antagonists and steroids are observed to be better in the control of both acute and delayed emesis. However, the use of these antiemetics is observed to possess inherent side effects. The medicinal plants such as Scutellaria baicalensis, Korean red ginseng, American ginseng berry, Ganoderma lucidum, Zingiber officinale, grape seed extract, and the oil of Mentha spicata are reported to be effective in the treatment of nausea and vomiting mostly in preclinical studies. Of these, ginger has also been evaluated for its efficacy in humans and the results have been contradictory. The current review for the first time summarizes the results related to these properties. An attempt is also made to address the lacunae in these published studies and to emphasize aspects that need further investigations for these plants to be of use in clinics in the future. PMID- 21821653 TI - Prevalence and correlates of vitamin and supplement usage among men with a family history of prostate cancer. AB - HYPOTHESES: Men who have a brother with prostate cancer have a 2-fold increased risk of being diagnosed with prostate cancer. Strategies employed by these men to reduce prostate cancer risk are not well understood. Preliminary studies have shown that men with a family history of prostate cancer have a high rate of vitamin and supplement usage aimed at the prevention of prostate cancer. STUDY DESIGN: The authors analyzed data from a cross-sectional study of men with familial and hereditary prostate cancer and their unaffected brothers. A total of 542 unaffected men who had at least one brother who had been diagnosed with prostate cancer regarding their use of vitamins and supplements, as well as the motivation for use, were interviewed. METHODS: The associations between subject characteristics and vitamin and supplement use were evaluated using an unconditional logistic regression modeling approach. RESULTS: Overall, 59.2% and 36.5% of men reported ever using and currently using, respectively, one or more vitamins or supplements (including multivitamins). One third of men took a vitamin or supplement that has been targeted for prostate health or cancer prevention, including green tea, magnesium, male hormones, saw palmetto, selenium, soy, vitamins A, C, E, and zinc. Increasing age at time of survey was associated with vitamin/supplement use (odds ratio [OR] = 1.03; 95% confidence interval [CI] = 1.01-1.05). After adjusting for age at time of survey, being younger than an affected brother was associated with vitamin and supplement use (OR = 1.51; 95% CI = 1.01-2.25). A total of 25% of men reported obtaining information from books or articles as the most common source of information. CONCLUSIONS: The findings indicate that men at an increased risk for prostate cancer report a high rate of vitamin and supplement use, including supplements targeted for prostate cancer prevention. Men with a family history of prostate cancer represent a target population for future chemopreventative agents. PMID- 21821654 TI - Chronic kidney disease prevalence and secular trends in a UK population: the impact of MDRD and CKD-EPI formulae. AB - INTRODUCTION: Most UK laboratories use the MDRD4 formula to estimate glomerular filtration rate (eGFR), but this may exaggerate chronic kidney disease (CKD) prevalence. In a large adult population, we examined the impact of the more accurate CKD-EPI formulae on prevalence estimates, and on secular trends in prevalence. METHODS: We extracted all serum creatinine (SCr) results for adults, processed in our laboratory during two 1-year periods (2004, 2009-10). To minimize the effect of acute illness, a patient's lowest SCr was used for each period. eGFR (traceable to isotope dilution mass spectrometry value) was calculated using the MDRD4 and CKD-EPI formulae. Prevalence estimates were compared, with sub-group analysis by age and sex. RESULTS: In 2004, 102 322 patients had SCr tested (35.4% of the adult population), rising to 123 121 (42.3%) in 2009-10. The proportion tested rose with age to 86% of 85- to 89-year olds. The prevalence of CKD stages 3-5 was lower with the CKD-EPI formulae than the MDRD4 formula. The CKD-EPI formulae reclassified 17 014 patients (5.8%) to milder stages of CKD, most commonly from eGFR 60-89 ml/min/1.73m(2) and CKD stage 3A, in women, and in those <70 years old. 5172 patients (1.8%), mostly elderly women, were reclassified to more severe stages of CKD. Between the two time periods, the prevalence of CKD stages 3-5 rose from 5.44% to 5.63% of the population using MDRD4, but was static at 4.94% with CKD-EPI. CONCLUSION: The CKD EPI formulae, which are more accurate than the MDRD4 formula at higher GFR, reduced the estimated prevalence of CKD stages 3-5 by 0.5% in 2004 and 0.7% in 2009-10. The greatest reclassification was seen in CKD 3A, particularly amongst middle-aged females. The minor rise in CKD prevalence between 2004 and 2009-10 seen with the MDRD4 formula was not confirmed with the CKD-EPI formulae. The CKD EPI formulae may reduce overdiagnosis of CKD, but further assessment in the elderly is required before widespread implementation. PMID- 21821655 TI - Reporter mRNAs cleaved by Rnt1p are exported and degraded in the cytoplasm. AB - For most protein coding genes, termination of transcription by RNA polymerase II is preceded by an endonucleolytic cleavage of the nascent transcript. The 3' product of this cleavage is rapidly degraded via the 5' exoribonuclease Rat1p which is thought to destabilize the RNA polymerase II complex. It is not clear whether RNA cleavage is sufficient to trigger nuclear RNA degradation and transcription termination or whether the fate of the RNA depends on additional elements. For most mRNAs, this cleavage is mediated by the cleavage and polyadenylation machinery, but it can also be mediated by Rnt1p. We show that Rnt1p cleavage of an mRNA is not sufficient to trigger nuclear degradation or transcription termination. Insertion of an Rnt1p target site into a reporter mRNA did not block transcription downstream of the cleavage site, but instead produced two unstable cleavage products, neither of which were stabilized by inactivation of Rat1p. In contrast, the 3' and 5' cleavage products were stabilized by the deletion of the cytoplasmic 5' exoribonuclease (Xrn1p) or by inactivation of the cytoplasmic RNA exosome. These data indicate that transcription termination and nuclear degradation is not the default fate of cleaved RNAs and that specific promoter and/or sequence elements are required to determine the fate of the cleavage products. PMID- 21821656 TI - Identifying transcriptional start sites of human microRNAs based on high throughput sequencing data. AB - MicroRNAs (miRNAs) are critical small non-coding RNAs that regulate gene expression by hybridizing to the 3'-untranslated regions (3'-UTR) of target mRNAs, subsequently controlling diverse biological processes at post transcriptional level. How miRNA genes are regulated receives considerable attention because it directly affects miRNA-mediated gene regulatory networks. Although numerous prediction models were developed for identifying miRNA promoters or transcriptional start sites (TSSs), most of them lack experimental validation and are inadequate to elucidate relationships between miRNA genes and transcription factors (TFs). Here, we integrate three experimental datasets, including cap analysis of gene expression (CAGE) tags, TSS Seq libraries and H3K4me3 chromatin signature derived from high-throughput sequencing analysis of gene initiation, to provide direct evidence of miRNA TSSs, thus establishing an experimental-based resource of human miRNA TSSs, named miRStart. Moreover, a machine-learning-based Support Vector Machine (SVM) model is developed to systematically identify representative TSSs for each miRNA gene. Finally, to demonstrate the effectiveness of the proposed resource, an important human intergenic miRNA, hsa-miR-122, is selected to experimentally validate putative TSS owing to its high expression in a normal liver. In conclusion, this work successfully identified 847 human miRNA TSSs (292 of them are clustered to 70 TSSs of miRNA clusters) based on the utilization of high-throughput sequencing data from TSS-relevant experiments, and establish a valuable resource for biologists in advanced research in miRNA-mediated regulatory networks. PMID- 21821657 TI - Sequential binding and sensing of Zn(II) by Bacillus subtilis Zur. AB - Bacillus subtilis Zur (BsZur) represses high-affinity zinc-uptake systems and alternative ribosomal proteins in response to zinc replete conditions. Sequence alignments and structural studies of related Fur family proteins suggest that BsZur may contain three zinc-binding sites (sites 1-3). Mutational analyses confirm the essential structural role of site 1, while mutants affected in sites 2 and 3 retain partial repressor function. Purified BsZur binds a maximum of two Zn(II) per monomer at site 1 and site 2. Site 3 residues are important for dimerization, but do not directly bind Zn(II). Analyses of metal-binding affinities reveals negative cooperativity between the two site 2 binding events in each dimer. DNA-binding studies indicate that BsZur is sequentially activated from an inactive dimer (Zur(2):Zn(2)) to a partially active asymmetric dimer (Zur(2):Zn(3)), and finally to the fully zinc-loaded active form (Zur(2):Zn(4)). BsZur with a C84S mutation in site 2 forms a Zur(2):Zn(3) form with normal metal- and DNA-binding affinities but is impaired in formation of the Zur(2):Zn(4) high affinity DNA-binding state. This mutant retains partial repressor activity in vivo, thereby supporting a model in which stepwise activation by zinc serves to broaden the physiological response to a wider range of metal concentrations. PMID- 21821658 TI - Thermococcus kodakarensis encodes three MCM homologs but only one is essential. AB - The minichromosome maintenance (MCM) complex is thought to function as the replicative helicase in archaea and eukaryotes. In eukaryotes, this complex is an assembly of six different but related polypeptides (MCM2-7) but, in most archaea, one MCM protein assembles to form a homohexameric complex. Atypically, the Thermococcus kodakarensis genome encodes three archaeal MCM homologs, here designated MCM1-3, although MCM1 and MCM2 are unusual in having long and unique N terminal extensions. The results reported establish that MCM2 and MCM3 assemble into homohexamers and exhibit DNA binding, helicase and ATPase activities in vitro typical of archaeal MCMs. In contrast, MCM1 does not form homohexamers and although MCM1 binds DNA and has ATPase activity, it has only minimal helicase activity in vitro. Removal of the N-terminal extension had no detectable effects on MCM1 but increased the helicase activity of MCM2. A T. kodakarensis strain with the genes TK0096 (MCM1) and TK1361 (MCM2) deleted has been constructed that exhibits no detectable defects in growth or viability, but all attempts to delete TK1620 (MCM3) have been unsuccessful arguing that that MCM3 is essential and is likely the replicative helicase in T. kodakarensis. The origins and possible function(s) of the three MCM proteins are discussed. PMID- 21821659 TI - Improved accuracy of supervised CRM discovery with interpolated Markov models and cross-species comparison. AB - Despite recent advances in experimental approaches for identifying transcriptional cis-regulatory modules (CRMs, 'enhancers'), direct empirical discovery of CRMs for all genes in all cell types and environmental conditions is likely to remain an elusive goal. Effective methods for computational CRM discovery are thus a critically needed complement to empirical approaches. However, existing computational methods that search for clusters of putative binding sites are ineffective if the relevant TFs and/or their binding specificities are unknown. Here, we provide a significantly improved method for 'motif-blind' CRM discovery that does not depend on knowledge or accurate prediction of TF-binding motifs and is effective when limited knowledge of functional CRMs is available to 'supervise' the search. We propose a new statistical method, based on 'Interpolated Markov Models', for motif-blind, genome-wide CRM discovery. It captures the statistical profile of variable length words in known CRMs of a regulatory network and finds candidate CRMs that match this profile. The method also uses orthologs of the known CRMs from closely related genomes. We perform in silico evaluation of predicted CRMs by assessing whether their neighboring genes are enriched for the expected expression patterns. This assessment uses a novel statistical test that extends the widely used Hypergeometric test of gene set enrichment to account for variability in intergenic lengths. We find that the new CRM prediction method is superior to existing methods. Finally, we experimentally validate 12 new CRM predictions by examining their regulatory activity in vivo in Drosophila; 10 of the tested CRMs were found to be functional, while 6 of the top 7 predictions showed the expected activity patterns. We make our program available as downloadable source code, and as a plugin for a genome browser installed on our servers. PMID- 21821661 TI - Emerging infectious diseases as a global health threat. Introduction. PMID- 21821662 TI - Endovascular treatment of two aortoduodenal fistulae. AB - We report the endovascular treatment of two patients presenting with aortoduodenal fistulae. The first patient was a 66-year-old man admitted with hematemesis. He was on clopidogrel and had received a cryopreserved aortic graft for a mycotic abdominal aortic aneurysm five years earlier. Computed tomography (CT) showed aortic pseudoaneurysms in close contact with the duodenum. Endovascular repair was carried out. Twenty-seven months after the procedure the patient remains asymptomatic. The second patient was a 78-year-old man admitted with abdominal pain and nausea. CT revealed an abdominal aortic pseudoaneurysm and aortoduodenal fistula. He suffered from severe chronic obstructive pulmonary disease that greatly increased his surgical morbidity and mortality. An endovascular repair was performed under epidural anesthesia. The patient died of a postoperative pneumonia 38 days after surgery. These two cases illustrate the importance of endovascular aortic repair especially when an open surgical procedure is either difficult or impossible. PMID- 21821663 TI - Patient-reported symptoms are independent of disease severity in patients with primary varicose veins. AB - The objective of this paper is to explore patterns of incompetence and disease distribution in patients with chronic venous disorders and to correlate this with CEAP (Clinical, Etiologic, Anatomic and Pathologic) classification and presenting symptoms to determine which features of chronic venous disorder (CVD) could be used to guide a patient pathway for referral and treatment. Consecutive patients attending a one-stop venous clinic at a university teaching hospital were recruited over a 12-month period. Patients were clinically assessed, assigned CEAP scores, duplex-scanned and categorized. Data were analyzed to identify associations between symptomatology and disease. Four hundred twenty-four limbs were divided into groups A (C2-3) (339) and B (C4-6) (85). The number of men, mean patient age, varicose vein diameter and quality-of-life score (Aberdeen Varicose Vein Questionnaire - AVVS) were significantly higher in group B (P < 0.01). Ache occurred more commonly in group A and in women (P < 0.01). Ache and pain were seen more frequently with saphenofemoral junction reflux (P < 0.05). Group A women were more likely to be offered surgical intervention while men were managed conservatively (P < 0.05). In conclusion, CVD symptoms are independent of disease severity assessed by CEAP score. Advanced disease is associated with larger venous diameters, older age and corresponds to a poorer quality of life. Objective markers such as CEAP, Venous Clinical Severity Score and AVVS should be used in determining a patient pathway for referral and treatment of CVD. PMID- 21821664 TI - Automatic extraction of angiogenesis bioprocess from text. AB - MOTIVATION: Understanding key biological processes (bioprocesses) and their relationships with constituent biological entities and pharmaceutical agents is crucial for drug design and discovery. One way to harvest such information is searching the literature. However, bioprocesses are difficult to capture because they may occur in text in a variety of textual expressions. Moreover, a bioprocess is often composed of a series of bioevents, where a bioevent denotes changes to one or a group of cells involved in the bioprocess. Such bioevents are often used to refer to bioprocesses in text, which current techniques, relying solely on specialized lexicons, struggle to find. RESULTS: This article presents a range of methods for finding bioprocess terms and events. To facilitate the study, we built a gold standard corpus in which terms and events related to angiogenesis, a key biological process of the growth of new blood vessels, were annotated. Statistics of the annotated corpus revealed that over 36% of the text expressions that referred to angiogenesis appeared as events. The proposed methods respectively employed domain-specific vocabularies, a manually annotated corpus and unstructured domain-specific documents. Evaluation results showed that, while a supervised machine-learning model yielded the best precision, recall and F1 scores, the other methods achieved reasonable performance and less cost to develop. AVAILABILITY: The angiogenesis vocabularies, gold standard corpus, annotation guidelines and software described in this article are available at http://text0.mib.man.ac.uk/~mbassxw2/angiogenesis/ CONTACT: xinglong.wang@gmail.com. PMID- 21821665 TI - Tree-structured algorithm for long weak motif discovery. AB - MOTIVATION: Motifs in DNA sequences often appear in degenerate form, so there has been an increased interest in computational algorithms for weak motif discovery. Probabilistic algorithms are unable to detect weak motifs while exact methods have been able to detect only short weak motifs. This article proposes an exact tree-based motif detection (TreeMotif) algorithm capable of discovering longer and weaker motifs than by the existing methods. RESULTS: TreeMotif converts the graphical representation of motifs into a tree-structured representation in which a tree that branches with nodes from every sequence represents motif instances. The method of tree construction is novel to motif discovery based on graphical representation. TreeMotif is more efficient and scalable in handling longer and weaker motifs than the existing algorithms in terms of accuracy and execution time. The performances of TreeMotif were demonstrated on synthetic data as well as on real biological data. AVAILABILITY: https://sites.google.com/site/shqssw/treemotif CONTACT: sunh0013@e.ntu.edu.sg SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 21821667 TI - Understanding pathways for scaling up health services through the lens of complex adaptive systems. AB - Despite increased prominence and funding of global health initiatives, efforts to scale up health services in developing countries are falling short of the expectations of the Millennium Development Goals. Arguing that the dominant assumptions for scaling up are inadequate, we propose that interpreting change in health systems through the lens of complex adaptive systems (CAS) provides better models of pathways for scaling up. Based on an understanding of CAS behaviours, we describe how phenomena such as path dependence, feedback loops, scale-free networks, emergent behaviour and phase transitions can uncover relevant lessons for the design and implementation of health policy and programmes in the context of scaling up health services. The implications include paying more attention to local context, incentives and institutions, as well as anticipating certain types of unintended consequences that can undermine scaling up efforts, and developing and implementing programmes that engage key actors through transparent use of data for ongoing problem-solving and adaptation. We propose that future efforts to scale up should adapt and apply the models and methodologies which have been used in other fields that study CAS, yet are underused in public health. This can help policy makers, planners, implementers and researchers to explore different and innovative approaches for reaching populations in need with effective, equitable and efficient health services. The old assumptions have led to disappointed expectations about how to scale up health services, and offer little insight on how to scale up effective interventions in the future. The alternative perspectives offered by CAS may better reflect the complex and changing nature of health systems, and create new opportunities for understanding and scaling up health services. PMID- 21821666 TI - NeuroPedia: neuropeptide database and spectral library. AB - SUMMARY: Neuropeptides are essential for cell-cell communication in neurological and endocrine physiological processes in health and disease. While many neuropeptides have been identified in previous studies, the resulting data has not been structured to facilitate further analysis by tandem mass spectrometry (MS/MS), the main technology for high-throughput neuropeptide identification. Many neuropeptides are difficult to identify when searching MS/MS spectra against large protein databases because of their atypical lengths (e.g. shorter/longer than common tryptic peptides) and lack of tryptic residues to facilitate peptide ionization/fragmentation. NeuroPedia is a neuropeptide encyclopedia of peptide sequences (including genomic and taxonomic information) and spectral libraries of identified MS/MS spectra of homolog neuropeptides from multiple species. Searching neuropeptide MS/MS data against known NeuroPedia sequences will improve the sensitivity of database search tools. Moreover, the availability of neuropeptide spectral libraries will also enable the utilization of spectral library search tools, which are known to further improve the sensitivity of peptide identification. These will also reinforce the confidence in peptide identifications by enabling visual comparisons between new and previously identified neuropeptide MS/MS spectra. AVAILABILITY: http://proteomics.ucsd.edu/Software/NeuroPedia.html CONTACT: bandeira@ucsd.edu SUPPLEMENTARY INFORMATION: Supplementary materials are available at Bioinformatics online. PMID- 21821668 TI - Mapping of NRF binding motifs of NF-kappaB p65 subunit. AB - NF-kappaB repressing factor (NRF) is a nuclear transcription factor that binds to a specific DNA sequence in NF-kappaB target promoters. Previous reports suggested that NRF interferes with the transcriptional activity of NF-kappaB binding sites through a direct interaction with NF-kappaB subunits. The aim of this study was to map specific NRF binding domains in the NF-kappaB proteins, p65 and p50. Our data demonstrate that NRF is able to interact with the p65 subunit and inhibit its transcription enhancing activity in reporter gene experiments. Using tandem affinity purifications (TAP), we show that NRF protein significantly binds to the endogenous p65, subunit but not to the p50 subunit. The selective binding activity of the NRF protein is consistently mediated by the N-terminal domain of NRF (Amino acids 1-380). Moreover, the Rel homology domain (RHD) of p65 is sufficient for binding to the N-terminal domain of NRF. Using detailed peptide mapping studies, we finally identify three peptide motifs in p65 RHD showing distinctive binding specificities for the NRF protein. According to the predicted structure of p65, all three peptide motifs align within an exposed region of p65 and might hint at promising targets for inhibitors. PMID- 21821669 TI - Noggin null allele mice exhibit a microform of holoprosencephaly. AB - Holoprosencephaly (HPE) is a heterogeneous craniofacial and neural developmental anomaly characterized in its most severe form by the failure of the forebrain to divide. In humans, HPE is associated with disruption of Sonic hedgehog and Nodal signaling pathways, but the role of other signaling pathways has not yet been determined. In this study, we analyzed mice which, due to the lack of the Bmp antagonist Noggin, exhibit elevated Bmp signaling. Noggin(-/-) mice exhibited a solitary median maxillary incisor that developed from a single dental placode, early midfacial narrowing as well as abnormalities in the developing hyoid bone, pituitary gland and vomeronasal organ. In Noggin(-/-) mice, the expression domains of Shh, as well as the Shh target genes Ptch1 and Gli1, were reduced in the frontonasal region at key stages of early facial development. Using E10.5 facial cultures, we show that excessive BMP4 results in reduced Fgf8 and Ptch1 expression. These data suggest that increased Bmp signaling in Noggin(-/-) mice results in downregulation of the hedgehog pathway at a critical stage when the midline craniofacial structures are developing, which leads to a phenotype consistent with a microform of HPE. PMID- 21821670 TI - Specific correction of a splice defect in brain by nutritional supplementation. AB - Recent studies emphasize the importance of mRNA splicing in human genetic disease, as 20-30% of all disease-causing mutations are predicted to result in mRNA splicing defects. The plasticity of the mRNA splicing reaction has made these mutations attractive candidates for the development of therapeutics. Familial dysautonomia (FD) is a severe neurodegenerative disorder, and all patients have an intronic IVS20+6T>C splice site mutation in the IKBKAP gene, which results in tissue-specific skipping of exon 20 and a corresponding reduction in ikappaB kinase complex associated protein (IKAP) levels. We created transgenic mouse lines using a human IKBKAP bacterial artificial chromosome (BAC) into which we inserted the IKBKAP splice mutation (FD BAC) and have shown that the transgenic mice exhibit the same tissue-specific aberrant splicing patterns as seen in FD patients. We have previously demonstrated that the plant cytokinin kinetin can significantly improve the production of wild-type IKBKAP transcripts in FD lymphoblast cell lines by improving exon inclusion. In this study, we tested the ability of kinetin to alter IKBKAP splicing in the transgenic mice carrying the FD BAC and show that it corrects IKBKAP splicing in all major tissues assayed, including the brain. The amount of wild-type IKBKAP mRNA and IKAP protein was significantly higher in the kinetin-treated mice. These exciting results prove that treatment of FD, as well as other mechanistically related splicing disorders, with kinetin holds great promise as a potential therapeutic aimed at increasing normal protein levels, which may, in turn, slow disease progression. PMID- 21821671 TI - Pyrimethamine inhibits adult polycystic kidney disease by modulating STAT signaling pathways. AB - Autosomal dominant polycystic kidney disease (ADPKD) is a commonly inherited disorder mostly caused by mutations in PKD1, encoding polycystin-1 (PC1). The disease is characterized by development and growth of epithelium-lined cyst in both kidneys, often leading to renal failure. There is no specific treatment for this disease. Here, we report a sustained activation of the transcription factor signal transducer and activator of transcription 3 (STAT3) in ischemic injured and uninjured Pkd1 knockout polycystic kidneys and in human ADPKD kidneys. Through a chemical library screen, we identified the anti-parasitic compound pyrimethamine as an inhibitor of STAT3 function. Treatment with pyrimethamine decreases cell proliferation in human ADPKD cells and blocks renal cyst formation in an adult and a neonatal PKD mouse model. Moreover, we demonstrated that a specific STAT3 inhibitor, S3I-201, reduces cyst formation and growth in a neonatal PKD mouse model. Our results suggest that PC1 acts as a negative regulator of STAT3 and that blocking STAT3 signaling with pyrimethamine or similar drugs may be an attractive therapy for human ADPKD. PMID- 21821672 TI - A variant OSR1 allele which disturbs OSR1 mRNA expression in renal progenitor cells is associated with reduction of newborn kidney size and function. AB - Human nephrons are formed during fetal life through an interaction between the branching ureteric bud and progenitor cells. The wide variation in final nephron number has been attributed to allelic variants of genes regulating ureteric bud arborization. Here, we hypothesize that dysfunctional variants of the Odd-Skipped Related 1 (OSR1) gene which compromise the renal progenitor cell pool might also limit newborn kidney size and function. We show that OSR1 is expressed in human mesenchymal stem cells, the blastemal component of Wilms tumors and CD24+/CD133+ progenitor cells isolated from the mature kidney. We identified an OSR1(rs12329305(T)) allele in 6% of normal Caucasians which alters an exon2 splice enhancer. This variant is predicted to reduce spliceosome-binding affinity and stability of the OSR1 mRNA. In cultured cells, the OSR1(rs12329305)(T) allele produced no identifiable transcript. Normal Caucasian newborns from Montreal with the OSR1(rs12329305)(T) allele had kidney volume 11.8% smaller (P= 0.006) and cord blood cystatin C levels 12.6% higher (P = 0.005) than those with wild-type genotype. Effects of the OSR1(rs12329305)(T) allele are additive with genes that alter ureteric bud branching. Kidney volume was reduced more in newborns bearing both RET(rs1800860)(A) and OSR1(rs12329305)(T) alleles (22%, P= 0.0008) and cystatin C was increased by 17% (P= 0.006) versus newborns with wild-type alleles. Although only two subjects had PAX2(rs11599825)(A) and OSR1(rs12329305)(T) alleles, kidney size was reduced by 27% and cystatin C was increased by 14% versus wild-types (P= NS). PMID- 21821673 TI - Myotonic dystrophy, when simple repeats reveal complex pathogenic entities: new findings and future challenges. AB - Expanded, non-coding RNAs can exhibit a deleterious gain-of-function causing human disease through abnormal interactions with RNA-binding proteins. Myotonic dystrophy (DM), the prototypical example of an RNA-dominant disorder, is mediated by trinucleotide repeat-containing transcripts that deregulate alternative splicing. Spliceopathy has therefore been a major focus of DM research. However, changes in gene expression, protein translation and micro-RNA metabolism may also contribute to disease pathology. The exciting finding of bidirectional transcription and non-conventional RNA translation of trinucleotide repeat sequences points to a new scenario, in which DM is not mediated by one single expanded RNA transcript, but involves multiple pathogenic elements and pathways. The study of the growing number of human diseases associated with toxic repeat containing transcripts provides important insight into the understanding of the complex pathways of RNA toxicity. This review describes some of the recent advances in the understanding of the molecular mechanisms behind DM and other RNA dominant disorders. PMID- 21821675 TI - Thyroid hormone is a MAPK-dependent growth factor for human myeloma cells acting via alphavbeta3 integrin. AB - Experimental and clinical observations suggest that thyroid hormone [l-thyroxine (T(4)) and 3,5,3'-triiodo-l-thyronine (T(3))] can support cancer cell proliferation. T(3) and T(4) promote both tumor cell division and angiogenesis by activating mitogen-activated protein kinase (MAPK) via binding to a hormone receptor on the alphavbeta3 integrin, overexpressed on many cancer cells. We have studied the responsiveness of several MM cell lines to T(3) and T(4) and characterized hormonal effects on cell survival, proliferation, and MAPK activation. Overnight T(3) (1-100 nmol/L) and T(4) (100 nmol/L) incubation enhanced, up to 50% (P < 0.002), MM cell viability (WST-1 assay) and increased cell proliferation by 30% to 60% (P < 0.01). Short exposure (10 minutes) to T(3) and T(4) increased MAPK activity by 2.5- to 3.5-fold (P < 0.03). Pharmacologic MAPK inhibition blocked the proliferative action of T(3) and T(4). Antibodies to the integrin alphavbeta3 dimer and alphav and beta3 monomers (but not beta1) inhibited MAPK activation and subsequent cell proliferation in response to thyroid hormone, indicating dependence upon this integrin. Moreover, tetraiodothyroacetic acid (tetrac), a non-agonist T(4) analogue previously shown to selectively block T(3)/T(4) binding to alphavbeta3 receptor site, blocked induction of MAPK by the hormones in a dose-dependent manner. This demonstration of the role of thyroid hormones as growth factors for MM cells may offer novel therapeutic approaches. PMID- 21821674 TI - Lrig1 is an estrogen-regulated growth suppressor and correlates with longer relapse-free survival in ERalpha-positive breast cancer. AB - Lrig1 is the founding member of the Lrig family and has been implicated in the negative regulation of several oncogenic receptor tyrosine kinases including ErbB2. Lrig1 is expressed at low levels in several cancer types but is overexpressed in some prostate and colorectal tumors. Given this heterogeneity, whether Lrig1 functions to suppress or promote tumor growth remains a critical question. Previously, we found that Lrig1 was poorly expressed in ErbB2-positive breast cancer, suggesting that Lrig1 has a growth-inhibitory role in this tumor type. However, breast cancer is a complex disease, with ErbB2-positive tumors accounting for just 25% of all breast cancers. To gain a better understanding of the role of Lrig1 in breast cancer, we examined its expression in estrogen receptor alpha (ERalpha)-positive disease which accounts for the majority of breast cancers. We find that Lrig1 is expressed at significantly higher levels in ERalpha-positive disease than in ERalpha-negative disease. Our study provides a molecular rationale for Lrig1 enrichment in ERalpha-positive disease by showing that Lrig1 is a target of ERalpha. Estrogen stimulates Lrig1 accumulation and disruption of this induction enhances estrogen-dependent tumor cell growth, suggesting that Lrig1 functions as an estrogen-regulated growth suppressor. In addition, we find that Lrig1 expression correlates with prolonged relapse-free survival in ERalpha-positive breast cancer, identifying Lrig1 as a new prognostic marker in this setting. Finally, we show that ErbB2 activation antagonizes ERalpha-driven Lrig1 expression, providing a mechanistic explanation for Lrig1 loss in ErbB2-positive breast cancer. This work provides strong evidence for a growth-inhibitory role for Lrig1 in breast cancer. PMID- 21821677 TI - Call for a proactive approach to supporting the dairy sector. PMID- 21821676 TI - IKKbeta overexpression leads to pathologic lesions in stratified epithelia and exocrine glands and to tumoral transformation of oral epithelia. AB - Alterations in nuclear factor kappaB (NFkappaB) signaling have been related with several diseases and importantly also with cancer. Different animal models with increased or diminished NFkappaB signaling have shown that NFkappaB subunits and their regulators are relevant to the pathophysiology of different organs and tissues. In particular, both the deletion of the regulatory subunit beta of the kinase of the inhibitor of NFkappaB (IKKbeta) and its overexpression in epidermis lead to the development of skin inflammatory diseases not associated with tumoral lesions. In this work, we have studied the consequences of IKKbeta overexpression in other organs and tissues. We found that elevated IKKbeta levels led to altered development and functionality of exocrine glands (i.e., mammary glands) in transgenic female mice. In oral epithelia, increased IKKbeta expression produced lichenoid inflammation with abundant granulocytes, macrophages, and B cells, among other inflammatory cells. This inflammatory phenotype was associated with high incidence of tumoral lesions in oral epithelia, contrary to what was found in skin. Moreover, IKKbeta also increased the malignant progression of both spontaneous and experimentally induced oral tumors. These results highlight the importance of IKKbeta in epithelial and glandular homeostasis as well as in oral tumorigenesis and open the possibility that IKKbeta activity might be implicated in the development of oral cancer in humans. PMID- 21821678 TI - Consortium to head up teaching and research initiative in China. PMID- 21821679 TI - Bluetongue virus 'assembly kit' offers hope for improved vaccines. PMID- 21821681 TI - Impact of economics on animal welfare. PMID- 21821682 TI - Stunning before slaughter--not just an issue for livestock. PMID- 21821683 TI - Continuing concern about OV tendering. PMID- 21821686 TI - A/H1N1/pdm09 virus: dynamics of infection in pigs and people. PMID- 21821687 TI - British Veterinary Zoological Society's 50th anniversary. PMID- 21821688 TI - Tendering for TB testing. PMID- 21821689 TI - Veterinary certification for exporting pig meat to China. PMID- 21821690 TI - Where have all the young vets gone? PMID- 21821691 TI - Rotavirus in a wild English red squirrel (Sciurus vulgaris) identified by electron microscopy. PMID- 21821695 TI - ATP analog enhances the actions of a heat shock protein 90 inhibitor in multiple myeloma cells. AB - Heat shock protein (HSP) 90 regulates client oncoprotein maturation. The chaperone function of HSP90 is blocked by 17-N-allylamino-17 demethoxygeldanamycin (17-AAG), although it results in transcription and translation of antiapoptotic HSP proteins. Using three myeloma cell lines, we tested whether inhibition of transcription/translation of HSP or client proteins will enhance 17-AAG-mediated cytotoxicity. 8-Chloro-adenosine (8-Cl-Ado), currently in clinical trials, inhibits bioenergy production, mRNA transcription, and protein translation and was combined with 17-AAG. 17-AAG treatment resulted in HSP transcript and protein level elevation. In the combination, 8-Cl-Ado did not abrogate HSP mRNA and protein induction. HSP90 requires ATP to stabilize client proteins; hence, expression of signal transducer and activator of transcription 3 (STAT3), Raf-1, and Akt was analyzed. 17-AAG alone resulted in <10% change in STAT3, Raf-1, and Akt protein levels, whereas no change was observed for 4E-BP1. In contrast, the combination treatment resulted in a >50% decrease in client protein levels and marked hypophosphorylation of 4E-BP1. 8-Cl Ado alone resulted in a <30% decrease of client proteins and 4E-BP1 hypophosphorylation. 8-Cl-Ado combined with 17-AAG resulted in more than additive cytotoxicity. In conclusion, 8-Cl-Ado, which targets transcription, translation, and cellular bioenergy, enhanced 17-AAG-mediated cytotoxicity in myeloma cells. PMID- 21821697 TI - Pharmacological characterization of 2-methyl-N-((2'-(pyrrolidin-1 ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine (PF-04455242), a high-affinity antagonist selective for kappa-opioid receptors. AB - 2-Methyl-N-((2'-(pyrrolidin-1-ylsulfonyl)biphenyl-4-yl)methyl)propan-1-amine (PF 04455242) is a novel kappa-opioid receptor (KOR) antagonist with high affinity for human (3 nM), rat (21 nM), and mouse (22 nM) KOR, a ~ 20-fold reduced affinity for human MU-opioid receptors (MORs; K(i) = 64 nM), and negligible affinity for delta-opioid receptors (K(i) > 4 MUM). PF-04455242 also showed selectivity for KORs in vivo. In rats, PF-04455242 blocked KOR and MOR agonist induced analgesia with ID(50) values of 1.5 and 9.8 mg/kg, respectively, and inhibited ex vivo [(3)H](2-(benzofuran-4-yl)-N-methyl-N-((5S,7R,8R)-7-(pyrrolidin 1-yl)-1-oxaspiro[4.5]decan-8-yl)acetamide ([(3)H]CI977) and [(3)H](2S)-2-[[2 [[(2R)-2-[[(2S)-2-amino-3-(4-hydroxyphenyl) propanoyl]amino]propanoyl]amino]acetyl]-methylamino]-N-(2-hydroxyethyl)-3 phenylpropanamide ([(3)H]DAMGO) binding to KOR and MOR receptors with ID(50) values of 2.0 and 8.6 mg/kg, respectively. An in vivo binding assay was developed using (-)-4-[(3)H]methoxycarbonyl-2-[(1-pyrrolidinylmethyl]-1-[(3,4 dichlorophenyl)acetyl]-piperidine ([(3)H]PF-04767135), a tritiated version of the KOR positron emission tomography ligand (-)-4-[(11)C]methoxycarbonyl-2-[(1 pyrrolidinylmethyl]-1-[(3,4-dichlorophenyl)acetyl]-piperidine ([(11)C]GR103545) in which PF-04455242 had an ID(50) of 5.2 mg/kg. PF-04455242 demonstrated antidepressant-like efficacy (mouse forced-swim test), attenuated the behavioral effects of stress (mouse social defeat stress assay), and showed therapeutic potential in treating reinstatement of extinguished cocaine-seeking behavior (mouse conditioned place preference). KOR agonist-induced plasma prolactin was investigated as a translatable mechanism biomarker. Spiradoline (0.32 mg/kg) significantly increased rat plasma prolactin levels from 1.9 +/- 0.4 to 41.9 +/- 4.9 ng/ml. PF-04455242 dose-dependently reduced the elevation of spiradoline induced plasma prolactin with an ID(50) of 2.3 +/- 0.1 mg/kg, which aligned well with the ED(50) values obtained from the rat in vivo binding and efficacy assays. These data provide further evidence that KOR antagonists have potential for the treatment of depression and addiction disorders. PMID- 21821696 TI - Activated G protein alpha s subunits increase the ethanol sensitivity of human glycine receptors. AB - It is well known that ethanol modulates the function of the Cys loop ligand-gated ion channels, which include the inhibitory glycine receptors (GlyRs). Previous studies have consistently shown that transmembrane and extracellular sites are essential for ethanol actions in GlyRs. In addition, recent evidence has shown that the ethanol modulation of GlyRs is also affected by G protein activation through Gbetagamma subunits. However, more specific roles of G protein alpha subunits on ethanol actions are unknown. Here, we show that the allosteric effect of ethanol on the human alpha(1) GlyR is selectively enhanced by the expression of Galpha(s) Q-L. For example, constitutively active Galpha(s), but not Galpha(q) or Galpha(i), was able to displace the alcohol sensitivity of GlyRs toward low millimolar concentrations (17 +/- 4 versus 48 +/- 5% at 100 mM). Experiments under conditions that increased cAMP and protein kinase A (PKA)-mediated signaling, on the contrary, did not produce the same enhancement in sensitivity, suggesting that the Galpha(s) Q-L effect was not dependent on cAMP/PKA-dependent signaling. On the other hand, the effect of Galpha(s) Q-L was blocked by a Gbetagamma scavenger (9 +/- 3% of control). Furthermore, two mutant receptors previously shown to have impaired interactions with Gbetagamma were not affected by Galpha(s) Q-L, suggesting that Gbetagamma is needed for enhancing ethanol sensitivity. These results support the conclusion that activated Galpha(s) can facilitate the Gbetagamma interaction with GlyRs in presence of ethanol, independent of increases in cAMP signaling. Thus, these data indicate that the activated form of Galpha(s) is able to positively influence the effect of ethanol on a type of inhibitory receptor important for motor control, pain, and respiration. PMID- 21821698 TI - ABT-737 induces apoptosis in mantle cell lymphoma cells with a Bcl-2high/Mcl-1low profile and synergizes with other antineoplastic agents. AB - PURPOSE: Mantle cell lymphoma (MCL) is considered to be incurable. ABT-737 is a BH3 mimetic that targets Bcl-2, which is overexpressed in MCL and implicated in drug resistance. The present work investigated the antitumor effect of ABT-737. EXPERIMENTAL DESIGN: Six MCL cell lines and primary MCL cells (n = 13) were used. Sensitivity to ABT-737 was assessed, and expression levels of Bcl-2 and Mcl-1 were analyzed. Finally, ABT-737 was combined with other cytotoxic agents to promote tailored therapy. RESULTS: MINO and GRANTA-519 cell lines were highly sensitive to ABT-737 [the median lethal dose (LD50) = 20 and 80 nmol/L, respectively], whereas other cell lines were resistant. In primary MCL cells, 46% of patients' samples were sensitive to ABT-737. The analysis of protein expression levels revealed that both sensitive cell lines and primary MCL cells could be characterized by a Bcl-2(high)/Mcl-1(low) profile, whereas resistant MCL cells contained high levels of Mcl-1. ABT-737 induced a rapid disruption of both Bcl-2/Bax and Bcl-2/Bik complexes. In addition, silencing of Mcl-1 by siRNA sensitized MCL cell lines to ABT-737. Similarly, flavopiridol, which induces Mcl 1 downregulation, in combination with ABT-737 led to a synergistic anti-MCL effect in ABT-737-resistant cell lines. This synergy was also observed when ABT 737 was combined with either bortezomib or cytarabine. CONCLUSIONS: The present work shows that ABT-737 induces strong apoptosis in MCL cells expressing a Bcl 2(high)/Mcl-1(low) profile. In ABT-737-resistant MCL cells, downregulation of Mcl 1 overcomes Mcl-1-induced resistance and synergizes ABT-737 effects. Our results strongly support the use of ABT-737 according to the Bcl-2/Mcl-1 tumor cell profiles in the treatment of MCL. PMID- 21821699 TI - Combining EGFR and mTOR blockade for the treatment of epithelioid sarcoma. AB - PURPOSE: Molecular deregulations underlying epithelioid sarcoma (ES) progression are poorly understood yet critically needed to develop new therapies. Epidermal growth factor receptor (EGFR) is overexpressed in ES; using preclinical models, we examined the ES EGFR role and assessed anti-ES EGFR blockade effects, alone and with mTOR inhibition. EXPERIMENTAL DESIGN: EGFR and mTOR expression/activation was examined via tissue microarray (n = 27 human ES specimens; immunohistochemistry) and in human ES cell lines (Western blot and quantitative reverse transcriptase PCR). Cell proliferation, survival, migration, and invasion effects of EGFR and mTOR activation treated with erlotinib (anti EGFR small-molecule inhibitor) alone and combined with rapamycin were assessed in cell culture assays. In vivo growth effects of erlotinib alone or with rapamycin were evaluated using severe combined immunodeficient mouse ES xenograft models. RESULTS: EGFR was expressed and activated in ES specimens and cell lines. EGFR activation increased ES cell proliferation, motility, and invasion and induced cyclin D1, matrix metalloproteinase (MMP) 2, and MMP9 expression. EGFR blockade inhibited these processes and caused significant cytostatic ES growth inhibition in vivo. mTOR pathway activation at varying levels was identified in all tissue microarray-evaluable ES tissues; 88% of samples had no or reduced PTEN expression. Similarly, both ES cell lines showed enhanced mTOR activity; VAESBJ cells exhibited constitutive mTOR activation uncoupled from EGFR signaling. Most importantly, combined erlotinib/rapamycin resulted in synergistic anti-ES effects in vitro and induced superior tumor growth inhibition in vivo versus single agent administration. CONCLUSIONS: EGFR and mTOR signaling pathways are deregulated in ES. Preclinical ES model-derived insights suggest that combined inhibition of these targets might be beneficial, supporting evaluations in clinical trials. PMID- 21821700 TI - Curcumin treatment suppresses IKKbeta kinase activity of salivary cells of patients with head and neck cancer: a pilot study. AB - PURPOSE: To determine whether curcumin would inhibit IkappaB kinase beta (IKKbeta) kinase activity and suppress expression of proinflammatory cytokines in head and neck squamous cell carcinoma cancer (HNSCC) patients. EXPERIMENTAL DESIGN: Saliva was collected before and after subjects chewed curcumin tablets. Protein was extracted and IKKbeta kinase activity measured. Interleukin (IL)-6 and IL-8 levels in the salivary supernatants were measured by ELISA. IL-6, IL-8, and other interleukin were also measured independently with ELISA to confirm the inhibitory effect of curcumin on expression and secretion of salivary cytokines. RESULTS: Curcumin treatment led to a reduction in IKKbeta kinase activity in the salivary cells of HNSCC patients (P < 0.05). Treatment of UM-SCC1 cells with curcumin as well as with post-curcumin salivary supernatant showed a reduction of IKKbeta kinase activity. Significant reduction of IL-8 levels (P < 0.05) was seen in post-curcumin samples from patients with dental caries. Although there was reduced IL-8 expression in 8 of 21 post-curcumin samples of HNSCC patients, the data did not reach statistical significance. Saliva samples from HNSCC patients were also analyzed in a blinded fashion for expression of cytokines. IL-10, IFN gamma, IL-12p70, and IL-2 clustered together, and granulocyte macrophage colony stimulating factor and TNF-alpha clustered together. Log10 ratio analysis showed decrease in expression of all nine cytokines in both the salivary supernatant and salivary cells of curcumin-treated samples. CONCLUSIONS: Curcumin inhibited IKKbeta kinase activity in the saliva of HNSCC patients, and this inhibition correlated with reduced expression of a number of cytokines. IKKbeta kinase could be a useful biomarker for detecting the effect of curcumin in head and neck cancer. PMID- 21821701 TI - SHP-1 expression accounts for resistance to imatinib treatment in Philadelphia chromosome-positive cells derived from patients with chronic myeloid leukemia. AB - We prove that the SH2-containing tyrosine phosphatase 1 (SHP-1) plays a prominent role as resistance determinant of imatinib (IMA) treatment response in chronic myelogenous leukemia cell lines (sensitive/KCL22-S and resistant/KCL22-R). Indeed, SHP-1 expression is significantly lower in resistant than in sensitive cell line, in which coimmunoprecipitation analysis shows the interaction between SHP-1 and a second tyrosine phosphatase SHP-2, a positive regulator of RAS/MAPK pathway. In KCL22-R SHP-1 ectopic expression restores both SHP-1/SHP-2 interaction and IMA responsiveness; it also decreases SHP-2 activity after IMA treatment. Consistently, SHP-2 knocking-down in KCL22-R reduces either STAT3 activation or cell viability after IMA exposure. Therefore, our data suggest that SHP-1 plays an important role in BCR-ABL-independent IMA resistance modulating the activation signals that SHP-2 receives from both BCR/ABL and membrane receptor tyrosine kinases. The role of SHP-1 as a determinant of IMA sensitivity has been further confirmed in 60 consecutive untreated patients with chronic myelogenous leukemia, whose SHP-1 mRNA levels were significantly lower in case of IMA treatment failure (P < .0001). In conclusion, we suggest that SHP-1 could be a new biologic indicator at baseline of IMA sensitivity in patients with chronic myelogenous leukemia. PMID- 21821703 TI - Dual-functional capability of CD3+CD56+ CIK cells, a T-cell subset that acquires NK function and retains TCR-mediated specific cytotoxicity. AB - CD3(+)CD56(+) cytokine-induced killer (CIK) cells display a potent cytolytic activity. The adhesion molecule lymphocyte function-associated antigen-1 plays a crucial role in binding as well as in cytolytic activity of CIK cells against tumor target cells expressing the corresponding ligands. CIK cells express activating natural killer (NK) receptors, including NKG2D, DNAX accessory molecule-1 (DNAM-1), and low levels of NKp30. Cell signaling not only through TCR/CD3 but also through NKG2D, DNAM-1, and NKp30 leads to CIK cell activation resulting in granule exocytosis, cytokine secretion, and cytotoxicity. Antibody blocking experiments showed that DNAM-1, NKG2D, and NKp30 are involved in the TCR independent tumor cell recognition and killing. Anti-CMV-specific CIK cells could be expanded in standard CIK cultures and mediate both specific, MHC-restricted recognition and TCR-independent NK-like cytolytic activity against leukemic cell lines or fresh leukemic blasts. Antibody blocking of lymphocyte function associated antigen-1 and DNAM-1 led to significant reduction of both CTL and NK cell functions, whereas blocking of NKG2D and NKp30 only inhibited NK-like cytotoxicity. Their dual-effector function suggests that CIK cells, when used in a clinical setting, may control both neoplastic relapses and viral infections, 2 frequently associated complications in patients who received a transplant. PMID- 21821702 TI - Development of thymic NK cells from double negative 1 thymocyte precursors. AB - The differentiation of natural killer (NK) cells and a subpopulation of NK cells which requires an intact thymus, that is, thymic NK cells, is poorly understood. Previous in vitro studies indicate that double negative (CD4-CD8-, DN) thymocytes can develop into cells with NK cell markers, but these cells have not been well characterized. Herein, we generated and characterized NK cells differentiating from thymic DN precursors. Sorted DN1 (CD44+CD25-) CD122-NK1.1- thymocytes from Rag1(-/-) mice were adoptively transferred into Rag1(-/-)Ly5.1 congenic mice. After intrathymic injection, donor-derived cells phenotypically resembling thymic NK cells were found. To further study their differentiation, we seeded sorted DN1 CD122-)NK1.1- thymocytes on irradiated OP9 bone marrow stromal cells with IL-15, IL-7, Flt3L, and stem cell factor. NK1.1+ cells emerged after 7 days. In vitro differentiated NK cells acquired markers associated with immature bone marrow derived NK cells, but also expressed CD127, which is typically found on thymic NK cells. Furthermore, we found that in vitro cells generated from thymic precursors secreted cytokines when stimulated and degranulated on target exposure. Together, these data indicate that functional thymic NK cells can develop from a DN1 progenitor cell population. PMID- 21821706 TI - In vivo imaging of the molecular distribution of the VEGF receptor during angiogenesis in a mouse model of ischemia. AB - Vascular endothelial growth factor (VEGF) plays a critical role in angiogenesis and has been applied to medical therapy. However, because vascular imaging at the molecular level is impossible, the detailed in vivo dynamics of VEGF and its receptor (VEGFR) remain unknown. In this study, to understand the molecular distribution of VEGF and the VEGFR, we prepared ischemic mice with a new surgical method and induced angiogenesis in the gastrocnemius muscle. Then, we made a VEGF conjugated fluorescence nanoparticle and performed staining of VEGFR-expressing cells with the fluorescent probe, demonstrating the high affinity of the probe for VEGFR. To observe the physiologic molecular distribution of VEGFR, we performed in vivo single-particle imaging of gastrocnemius in the ischemic leg with the fluorescent probe. The results suggested that only a 3-fold difference of VEGFR distribution is involved in the formation of branched vasculature in angiogenesis, although previous ex vivo data showed a 13-fold difference in its distribution, indicating that a method inducing a several-fold local increase of VEGFR concentration may be effective in generating site-specific angiogenesis in ischemic disease. This new in vivo imaging of ischemic mice could make useful contributions to understanding the mechanisms of angiogenesis and to developing a VEGFR-related drug. PMID- 21821705 TI - Selective depletion of plasma prekallikrein or coagulation factor XII inhibits thrombosis in mice without increased risk of bleeding. AB - Recent studies indicate that the plasma contact system plays an important role in thrombosis, despite being dispensable for hemostasis. For example, mice deficient in coagulation factor XII (fXII) are protected from arterial thrombosis and cerebral ischemia-reperfusion injury. We demonstrate that selective reduction of prekallikrein (PKK), another member of the contact system, using antisense oligonucleotide (ASO) technology results in an antithrombotic phenotype in mice. The effects of PKK deficiency were compared with those of fXII deficiency produced by specific ASO-mediated reduction of fXII. Mice with reduced PKK had ~ 3-fold higher plasma levels of fXII, and reduced levels of fXIIa-serpin complexes, consistent with fXII being a substrate for activated PKK in vivo. PKK or fXII deficiency reduced thrombus formation in both arterial and venous thrombosis models, without an apparent effect on hemostasis. The amount of reduction of PKK and fXII required to produce an antithrombotic effect differed between venous and arterial models, suggesting that these factors may regulate thrombus formation by distinct mechanisms. Our results support the concept that fXII and PKK play important and perhaps nonredundant roles in pathogenic thrombus propagation, and highlight a novel, specific and safe pharmaceutical approach to target these contact system proteases. PMID- 21821704 TI - Follicular lymphoma tumor-infiltrating T-helper (T(H)) cells have the same polyfunctional potential as normal nodal T(H) cells despite skewed differentiation. AB - The follicular lymphoma (FL) T-cell microenvironment plays a critical role in the biology of this disease. We therefore determined the lineage, differentiation state, and functional potential of FL-infiltrating CD4(+) T-helper cells (T(H)) compared with reactive and normal lymph node (NLN) T(H) cells. Relative to NLNs, FL cells have decreased proportions of naive and central memory but increased proportions of effector memory T(H) cells. We further show differences in the distribution and anatomical localization of CXCR5(+) T(H) populations that, on the basis of transcription factor analysis, include both regulatory and follicular helper T cells. On Staphylococcus enterotoxin-B stimulation, which stimulates T cells through the T-cell receptor, requires no processing by APCs, and can overcome regulator T cell-mediated suppression, the proportion of uncommitted primed precursor cells, as well as T(H)2 and T(H)17 cells is higher in FL cells than in reactive lymph nodes or NLNs. However, the proportion of T(H)1 and polyfunctional T(H) cells (producing multiple cytokines simultaneously) is similar in FL cells and NLNs. These data suggest that, although T(H)-cell differentiation in FL is skewed compared with NLNs, FL T(H) cells should have the same intrinsic ability to elicit antitumor effector responses as NLN T(H) cells when tumor suppressive mechanisms are attenuated. PMID- 21821707 TI - Bcr-abl signals to desensitize chronic myeloid leukemia cells to IFNalpha via accelerating the degradation of its receptor. AB - Constitutive activity of Bcr-abl fusion protein kinase causes chronic myeloid leukemia (CML). Inhibitors of Bcr-abl such as imatinib mesylate have replaced the cytokine IFNalpha as the primary treatment for the management of patients with this malignancy. We found that pretreatment of CML cells with imatinib mesylate augments the antigrowth effects of IFNalpha. Furthermore, introduction of Bcr-abl into non-CML cells inhibits the cellular responses to IFNalpha. This inhibition is mediated via a mechanism that involves activation of protein kinase D2. The latter promotes an accelerated phosphorylation-dependent degradation of the interferon-alpha/beta receptor 1 chain of the type I interferon receptor, leading to attenuation of IFNalpha signaling. We discuss the relationship between Bcr-abl activity and IFNalpha signaling as a molecular basis of the combination of inhibitors of Bcr-abl and IFNalpha for CML treatment. PMID- 21821708 TI - Siglec-9 is a novel leukocyte ligand for vascular adhesion protein-1 and can be used in PET imaging of inflammation and cancer. AB - Leukocyte migration to sites of inflammation is regulated by several endothelial adhesion molecules. Vascular adhesion protein-1 (VAP-1) is unique among the homing-associated molecules as it is both an enzyme that oxidizes primary amines and an adhesin. Although granulocytes can bind to endothelium via a VAP-1 dependent manner, the counter-receptor(s) on this leukocyte population is(are) not known. Here we used a phage display approach and identified Siglec-9 as a candidate ligand on granulocytes. The binding between Siglec-9 and VAP-1 was confirmed by in vitro and ex vivo adhesion assays. The interaction sites between VAP-1 and Siglec-9 were identified by molecular modeling and confirmed by further binding assays with mutated proteins. Although the binding takes place in the enzymatic groove of VAP-1, it is only partially dependent on the enzymatic activity of VAP-1. In positron emission tomography, the 68Gallium-labeled peptide of Siglec-9 specifically detected VAP-1 in vasculature at sites of inflammation and cancer. Thus, the peptide binding to the enzymatic groove of VAP-1 can be used for imaging conditions, such as inflammation and cancer. PMID- 21821709 TI - IGF binding protein 2 supports the survival and cycling of hematopoietic stem cells. AB - The role of IGF binding protein 2 (IGFBP2) in cell growth is intriguing and largely undefined. Previously we identified IGFBP2 as an extrinsic factor that supports ex vivo expansion of hematopoietic stem cells (HSCs). Here we showed that IGFBP2-null mice have fewer HSCs than wild-type mice. While IGFBP2 has little cell-autonomous effect on HSC function, we found decreased in vivo repopulation of HSCs in primary and secondary transplanted IGFBP2-null recipients. Importantly, bone marrow stromal cells that are deficient for IGFBP2 have significantly decreased ability to support the expansion of repopulating HSCs. To investigate the mechanism by which IGFBP2 supports HSC activity, we demonstrated that HSCs in IGFBP2-null mice had decreased survival and cycling, down-regulated expression of antiapoptotic factor Bcl-2, and up-regulated expression of cell cycle inhibitors p21, p16, p19, p57, and PTEN. Moreover, we found that the C-terminus, but not the RGD domain, of extrinsic IGFBP2 was essential for support of HSC activity. Defective signaling of the IGF type I receptor did not rescue the decreased repopulation of HSCs in IGFBP2-null recipients, suggesting that the environmental effect of IGFBP2 on HSCs is independent of IGF-IR mediated signaling. Therefore, as an environmental factor, IGFBP2 supports the survival and cycling of HSCs. PMID- 21821711 TI - KLF1 gene mutations cause borderline HbA(2). AB - Increased hemoglobin A(2) (HbA(2); ie, levels > 3.9%) is the most important feature of beta-thalassemia carriers. However, it is not uncommon to find persons with borderline HbA(2) (levels, 3.3%-3.8%), who pose a relevant screening problem. Several genotypes have been associated with borderline HbA(2), but sometimes the reasons for this unusual phenotype are unknown. In this paper, we report, for the first time, that mutations of KLF1 result in HbA(2) levels in the borderline range. Six different KLF1 mutations were identified in 52 of 145 subjects with borderline HbA(2) and normal mean corpuscular volume and mean corpuscular hemoglobin. Two mutations (T327S and T280_H283del) are here reported for the first time. The prevalent mutation in Sardinians is S270X, which accounts for 80.8% of the total. The frequent discovery of KLF1 mutations in these atypical carriers may contribute significantly to the thalassemia screening programs aimed at identification of at risk couples. PMID- 21821710 TI - FERM domain mutations induce gain of function in JAK3 in adult T-cell leukemia/lymphoma. AB - Adult T-cell leukemia/lymphoma (ATLL) is an incurable disease where most patients succumb within the first year of diagnosis. Both standard chemotherapy regimens and mAbs directed against ATLL tumor markers do not alter this aggressive clinical course. Therapeutic development would be facilitated by the discovery of genes and pathways that drive or initiate ATLL, but so far amenable drug targets have not been forthcoming. Because the IL-2 signaling pathway plays a prominent role in ATLL pathogenesis, mutational analysis of pathway components should yield interesting results. In this study, we focused on JAK3, the nonreceptor tyrosine kinase that signals from the IL-2R, where activating mutations have been found in diverse neoplasms. We screened 36 ATLL patients and 24 ethnically matched controls and found 4 patients with mutations in JAK3. These somatic, missense mutations occurred in the N-terminal FERM (founding members: band 4.1, ezrin, radixin, and moesin) domain and induced gain of function in JAK3. Importantly, we show that these mutant JAK3s are inhibited with a specific kinase inhibitor already in human clinical testing. Our findings underscore the importance of this pathway in ATLL development and offer a therapeutic handle for this incurable cancer. PMID- 21821712 TI - Phase 2 study of cladribine followed by rituximab in patients with hairy cell leukemia. AB - We conducted this study to determine the feasibility and safety of cladribine followed by rituximab in patients with hairy cell leukemia including the vari-ant form (HCLv). Cladribine 5.6 mg/m2 given IV over 2 hours daily for 5 days was followed ~ 1 month later with rituximab 375 mg/m2 IV weekly for 8 weeks. Responses were recorded and BM minimal residual disease (MRD) was evaluated after the completion of rituximab. Thirty-six patients have been treated including 5 with HCLv. Median age was 57 years (range, 37-89). All patients (100%) have achieved complete response (CR), defined as presence of no hairy cells in BM and blood with normalization of counts (absolute neutrophil count [ANC]> 1.5 * 109/L, hemoglobin [Hgb] > 12.0 g/dL, platelets [PLT] > 100 * 109/L), as well as resolution of splenomegaly. There were no grade 3 or 4 nonhematologic adverse events directly related to the treatment. Only 1 patient (with HCLv) has relapsed; median CR duration has not been reached (range,1+-63+ months). Three patients with HCLv died including 1 with relapsed disease and 2 from unrelated malignancies. Median survival duration has not been reached (range, 2+-64+ months). Treatment with cladribine followed by rituximab is effective tk;4and may increase CR rate. This study was registered at www.clinicaltrials.gov as NCT00412594. PMID- 21821713 TI - An important role for Akt3 in platelet activation and thrombosis. AB - The Akt family of serine/threonine kinases includes Akt1, Akt2, and Akt3 isoforms. Prior studies have reported that Akt1 and Akt2, but not Akt3, are expressed in platelets. Here, we show that Akt3 is expressed in substantial amounts in platelets. Akt3(-/-) mouse platelets selectively exhibit impaired platelet aggregation and secretion in response to low concentrations of thrombin receptor agonists and thromboxane A2 (TXA2), but not collagen or VWF. In contrast, platelets from Akt1(-/-) or Akt2(-/-) mice are defective in platelet activation induced by thrombin, TXA2, and VWF, but only Akt1(-/-) platelets show significant defects in response to collagen, indicating differences among Akt isoforms. Akt3(-/-) platelets exhibit a significant reduction in thrombin-induced phosphorylation of glycogen synthase kinase 3beta (GSK-3beta) at Ser9, which is known to inhibit GSK-3beta function. Thus, Akt3 is important in inhibiting GSK 3beta. Accordingly, treatment of Akt3(-/-) platelets with a GSK-3beta inhibitor rescued the defect of Akt3(-/-) platelets in thrombin-induced aggregation, suggesting that negatively regulating GSK-3beta may be a mechanism by which Akt3 promotes platelet activation. Importantly, Akt3(-/-) mice showed retardation in FeCl3-induced carotid artery thrombosis in vivo. Thus, Akt3 plays an important and distinct role in platelet activation and in thrombosis. PMID- 21821714 TI - Adverse psychological outcomes in long-term survivors of hematopoietic cell transplantation: a report from the Bone Marrow Transplant Survivor Study (BMTSS). AB - Little information exists regarding long-term psychological health of hematopoietic cell transplantation (HCT) survivors. Using resources offered by the Bone Marrow Transplant Survivor Study (BMTSS), we evaluated adverse psychological outcomes in 1065 long-term HCT survivors and a healthy comparison group composed of siblings. Psychological health status was evaluated using the Brief Symptom Inventory-18. Twenty-two percent of the HCT survivors reported adverse psychological outcomes, compared with 8% of the siblings. Exposure to prednisone was associated with psychological distress across all domains (anxiety, depression, and somatic distress). Fifteen percent of the HCT survivors reported somatic distress, representing an almost 3-fold higher risk comparing to siblings. Among survivors, in addition to low annual household income and self reported poor health, having severe/life-threatening conditions and presence of active chronic GVHD were associated with a 2-fold increased risk for somatic distress. Seven percent of the HCT survivors expressed suicidal ideation; patients with higher scores on depression subscale were most vulnerable. This study demonstrates that somatic distress is the biggest challenge faced by survivors long after HCT. These results identify vulnerable subpopulations and provide patients, families, and healthcare providers with necessary information to plan for post-HCT needs many years after HCT. PMID- 21821715 TI - A novel two-promoter-one-gene system of the chorionic gonadotropin beta gene enables tissue-specific expression. AB - The New World monkey (NWM), Callithrix jacchus, a preferred model in medical research, displays an interesting endocrine regulation of reproduction: LH, the heterodimeric glycoprotein hormone, is functionally replaced by the chorionic gonadotropin (CG), a hormone indispensable for establishment of pregnancy in humans and normally expressed in the placenta. In the marmoset pituitary, the expression of the beta-subunit (CGB) gene is regulated similar to human LH beta subunit, but its placental regulation is unknown. This study intended to decipher the underlying mechanism of tissue-specific expression of CGB in the marmoset placenta. We identified a new placental transcriptional start site, described a new, previously undiscovered exon, and define a novel placental core promoter in the marmoset CGB gene. This promoter contains a TATA box and binding sites for activating protein 2 and selective promoter factor 1, the latter acting synergistically by forming a regulation cassette. Differential first exon usage directed the tissue-specific expression. Methylation analyses revealed a tissue specific pattern in the placental promoter indicating additional epigenetic regulation of gene expression. Our findings point toward a hitherto unknown evolutionary plasticity in the LH/CG hormonal system in NWM, which could be used as a model to study human CGB regulation in clinical pathologies. PMID- 21821716 TI - Binding of activating transcription factor 6 to the A5/Core of the rat insulin II gene promoter does not mediate its transcriptional repression. AB - Pancreatic beta-cells have a well-developed endoplasmic reticulum due to their highly specialized secretory function to produce insulin in response to glucose and nutrients. It has been previously reported that overexpression of activating transcription factor 6 (ATF6) reduces insulin gene expression in part via upregulation of small heterodimer partner. In this study, we investigated whether ATF6 directly binds to the insulin gene promoter, and whether its direct binding represses insulin gene promoter activity. A bioinformatics analysis identified a putative ATF6 binding site in the A5/Core region of the rat insulin II gene promoter. Direct binding of ATF6 was confirmed using several approaches. Electrophoretic mobility shift assays in nuclear extracts from MCF7 cells, isolated rat islets and insulin-secreting HIT-T15 cells showed ATF6 binding to the native A5/Core of the rat insulin II gene promoter. Antibody-mediated supershift analyses revealed the presence of both ATF6 isoforms, ATF6alpha and ATF6beta, in the complex. Chromatin immunoprecipitation assays confirmed the binding of ATF6alpha and ATF6beta to a region encompassing the A5/Core of the rat insulin II gene promoter in isolated rat islets. Overexpression of the active (cleaved) fragment of ATF6alpha, but not ATF6beta, inhibited the activity of an insulin promoter-reporter by 50%. However, the inhibitory effect of ATF6alpha was insensitive to mutational inactivation or deletion of the A5/Core. Therefore, although ATF6 binds directly to the A5/Core of the rat insulin II gene promoter, this direct binding does not appear to contribute to its repressive activity. PMID- 21821717 TI - Two proteins with different functions are derived from the KlHEM13 gene. AB - Two proteins that differ at the N terminus (l-KlCpo and s-KlCpo) are derived from KlHEM13, a single-copy-number gene in the haploid genome of Kluyveromyces lactis. Two transcriptional start site (tss) pools are detectable using primer extension, and their selection is heme dependent. One of these tss pools is located 5' of the first translation initiation codon (TIC) in the open reading frame of KlHEM13, while the other is located between the first and second TICs. In terms of functional significance, only s-KlCpo complements the heme deficiency caused by the Deltahem13 deletion in K. lactis. Data obtained from immune detection in subcellular fractions, directed mutagenesis, chromatin immunoprecipitation (ChIP) assays, and the functional relevance of DeltaKlhem13 deletion for KlHEM13 promoter activity suggest that l-KlCpo regulates KlHEM13 transcription. A hypothetical model of the evolutionary origins and coexistence of these two proteins in K. lactis is discussed. PMID- 21821719 TI - Molecular analysis of the membrane insertion domain of proteinase 3, the Wegener's autoantigen, in RBL cells: implication for its pathogenic activity. AB - PR3, also called myeloblastin, is a neutrophil serine protease that promotes myeloid cell proliferation by cleaving the cyclin-dependent kinase inhibitor p21(cip1/waf1). In addition, it is the target of ANCA in GPA, a necrotizing vasculitis. Anti-PR3 ANCA binding to membrane-expressed PR3 triggers neutrophil activation, potentiating vascular inflammation. This study performed in RBL cells identifies the structural motifs of PR3 membrane anchorage and examines its impact on PR3 proinflammatory and proliferative functions. With the use of MD simulations and mutagenesis, we demonstrate that the mutations of four hydrophobic (F180, F181, L228, F229) or four basic (R193, R194, K195, R227) amino acids abrogated PR3 membrane anchorage. The hydrophobic patch-deficient PR3 mutant (PR34H4A) was still able to cleave the synthetic substrate Boc-Ala-Pro-Val in cell lysates. However, in contrast to WT PR3, PR34H4A was not expressed at the plasma membrane after degranulation and failed to cleave extracellular fibronectin, was not externalized after apoptosis and did not impair macrophage phagocytosis of apoptotic cells, did not promote myeloid cell proliferation and failed to cleave p21/waf1. PR3 membrane insertion appears to be pivotal for its proinflammatory activities, such as extracellular proteolysis and impairment of apoptotic cell clearance, but also for myeloid cell proliferation. Targeting membrane-associated PR3 might constitute a novel, anti-inflammatory therapeutic strategy in inflammatory disease especially in vasculitis, but this approach has to be validated in mature neutrophils. PMID- 21821718 TI - Cryptococcal titan cell formation is regulated by G-protein signaling in response to multiple stimuli. AB - The titan cell is a recently described morphological form of the pathogenic fungus Cryptococcus neoformans. Occurring during the earliest stages of lung infection, titan cells are 5 to 10 times larger than the normal yeast-like cells, thereby resisting engulfment by lung phagocytes and favoring the persistence of infection. These enlarged cells exhibit an altered capsule structure, a thickened cell wall, increased ploidy, and resistance to nitrosative and oxidative stresses. We demonstrate that two G-protein-coupled receptors are important for induction of the titan cell phenotype: the Ste3a pheromone receptor (in mating type a cells) and the Gpr5 protein. Both receptors control titan cell formation through elements of the cyclic AMP (cAMP)/protein kinase A (PKA) pathway. This conserved signaling pathway, in turn, mediates its effect on titan cells through the PKA-regulated Rim101 transcription factor. Additional downstream effectors required for titan cell formation include the G(1) cyclin Pcl103, the Rho104 GTPase, and two GTPase-activating proteins, Gap1 and Cnc1560. These observations support developing models in which the PKA signaling pathway coordinately regulates many virulence-associated phenotypes in diverse human pathogens. PMID- 21821720 TI - Granulosal and thecal expression of bone morphogenetic protein- and activin binding protein mRNA transcripts during bovine follicle development and factors modulating their expression in vitro. AB - Evidence supports local roles for transforming growth factor beta superfamily members including activins and bone morphogenetic proteins (BMP) in follicle development. Access of these ligands to signalling receptors is likely modulated by extracellular binding proteins (BP). In this study, we compared ex vivo expression of four BPs (chordin, gremlin, noggin and follistatin) in granulosal (GC) and theca interna (TC) compartments of developing bovine antral follicles (1 18 mm). Effects of FSH and IGF on BMP and BP expression by cultured GC, and effects of LH and BMPs on BP expression by cultured TC were also examined. Follicular expression of all four BP transcripts was higher in GC than TC compartments (P < 0.001) a finding confirmed by immunohistochemistry. Follicle category affected (P < 0.01) gremlin and follistatin mRNA abundance, with a significant cell-type * follicle category interaction for chordin, follistatin and noggin. Noggin transcript abundance was lower (P < 0.05) in GC of large 'E active' than 'E-inactive' follicles while follistatin mRNA level was higher (P < 0.01). FSH enhanced CYP19, FSHR, INHBA and follistatin by GC without affecting BMP or BMP-BP expression. IGF increased CYP19 and follistatin, reduced BMP4, noggin and gremlin but did not affect chordin or FSHR mRNA levels. LH increased TC androgen secretion but had no effect on BMP or BP expression. BMPs uniformly suppressed TC androgen production whilst increasing chordin, noggin and gremlin mRNA levels up to 20-fold (P < 0.01). These findings support the hypothesis that extracellular BP, mostly from GC, contribute to the regulation of intrafollicular BMP/activin signalling. Enhancement of thecal BP expression by BMP implies an autoregulatory feedback role to prevent excessive signalling. PMID- 21821721 TI - An observational study for venous thromboembolism risk assessment among hospitalized patients in general surgery clinics across Turkey. AB - OBJECTIVE: Venous thromboembolism (VTE) still remains a significant public health problem due to gaps between recommendations and clinical practice in VTE prophylaxis. This is the first clinical study designed to evaluate the applicability of a standard 'VTE prophylaxis and risk factor assessment form (VTE PRAF)' and prescription of VTE prophylaxis among hospitalized patients in the daily practice of general surgeons in Turkey. METHOD: A total of 1472 patients (mean age: 52.4 +/- 16.9 years; 50.6% were men) were included in cross-sectional (n = 537), first longitudinal (n = 452) or the second longitudinal (n = 483) phases. Data on demographics, hospitalization, surgical intervention and prophylaxis were collected during the cross-sectional phase, whereas utilization of form was evaluated during longitudinal phases. RESULTS: While 62.1% of patients were identified to be at 'high+ highest' risk, prophylaxis was evident only for 65.9%. Utilization of the form was higher in the second longitudinal phase (P < 0.001) but there was no relation between implementation of the form and prophylaxis use. VTE-PRAF was completed for 70.6% and 84.8% of patient who received prophylaxis while it was completed for 50.8% and 50.4% of patients with no prophylaxis, in the first and second longitudinal phases, respectively. Prophylaxis was administered in 58.6% and 62.6% of patients with completed VTE PRAF in the first and second longitudinal phases, respectively. 'Suggested' and 'used' prophylaxis regimens were significantly more consistent for the cases evaluated with VTE-PRAF (P < 0.001). CONCLUSION: Based on the use of prophylaxis only for 65.9% of general surgery inpatients at high risk for VTE, low use of prophylaxis is assumed to remain a significant threat to public health across Turkey. Inclusion of a standard VTE-PRAF in the hospital protocol seems to raise clinical awareness of VTE risk assessment and appropriate management in VTE which otherwise well-known to be associated with significant mortality and morbidity. Impact of e-VTE-PRAF is worth investigating. PMID- 21821722 TI - The deep venous system of the lower extremity: new nomenclature. AB - The correct and precise nomenclature of the veins of the lower extremity is a necessary tool for communication. Three important changes have been done over the last 13 years. Terminologia Anatomica, the latest version of the Latin anatomical nomenclature, was published in 1998, extended in the area of the lower extremity veins with two consensus documents, in 2001, during the 14th World Congress of the International Union of Phlebology and in 2004 during the 21st World Congress of the International Union of Angiology. This article is a free continuation of two previous articles, reviewing the detailed anatomy and correct nomenclature of the superficial veins of the lower extremities and veins of pelvis. Now, it is concentrated on the deep venous system, in which 15 new terms have been added in both Latin and English languages. PMID- 21821723 TI - Lectin-like oxidized LDL receptor 1 is involved in CRP-mediated complement activation. AB - BACKGROUND: C-reactive protein (CRP) is purported to be a risk factor that acts independently of LDL cholesterol in predicting all-cause mortality in patients with ischemic heart disease. Lectin-like oxidized LDL receptor 1 (LOX-1) impairs endothelial function and exacerbates myocardial injury. We recently demonstrated that CRP increased vascular permeability through direct binding to LOX-1. Here we examined, using a hypertensive rat model, whether LOX-1 is involved in CRP induced complement activation. METHODS AND RESULTS: In the cultured LOX-1 expressing cell line hLOX-1-CHO, CRP increased complement activation, but did not do so in native CHO cells. Depleting C1q from serum abolished CRP-induced complement activation. Incubation of CRP with serum on immobilized recombinant LOX-1 similarly showed that CRP activated C1q-requiring classical complement pathway in a LOX-1-dependent manner. Interestingly, the interaction between CRP and LOX-1 was dependent on Ca2+ ion and competed with phosphocholine, suggesting that LOX-1 bound to the B-face of CRP with a phosphocholine-binding domain. This was in contrast to Fcgamma receptors, to which CRP bound in A-face with complement-binding domain. In vivo, intradermal injection of CRP to hypertensive SHRSP rats induced complement activation detected by C3d deposition and leukocyte infiltration around the injected area. Anti-LOX-1 antibody reduced the extent of complement activation and leukocyte infiltration. CONCLUSIONS: LOX-1 appears to be involved in CRP-induced complement activation, and thus may serve to locate the site of CRP-induced complement activation and inflammation. PMID- 21821724 TI - An about-face for C-reactive protein? PMID- 21821725 TI - Pilot test results of an HIV prevention intervention for high-risk women. AB - Minority women, incarcerated women, and women using drugs or engaged in survival sex are most vulnerable to HIV. This pilot study was designed to estimate efficacy of an intervention, Women First!, to help these women correctly and consistently use male condoms. Women (N = 74) were recruited from jails, substance-abuse treatment centers, and public health clinics, and enrolled in a randomized controlled trial with an attention-only comparison group. The intervention, based on social cognitive theory and the theory of gender and power and awakening, was delivered over 6 weeks; unprotected vaginal intercourse and correct condom use were measured before and after the intervention. Changes on the dependent variables did not rise to statistical significance due to low power, but descriptive statistics and the multivariate partial eta(2) effect size estimate of 0.27 suggest that Women First! is a promising intervention. Future research will require improvements in recruitment, retention, and measurement. PMID- 21821726 TI - Methodological challenges in physical activity research with older adults. AB - The aging adult population is growing, as well as the incidence of chronic illness among older adults. Physical activity (PA) has been demonstrated in the literature to be a beneficial component of self-management for chronic illnesses commonly found in the older adult population. Health sciences research seeks to develop new knowledge, practices, and policies that may benefit older adults' management of chronic illness and quality of life. However, research with the older adult population, though beneficial, includes potential methodological challenges specific to this age group. This article discusses common methodological issues in research among older adults, with a focus on PA intervention studies. Awareness and understanding of these issues may facilitate future development of research studies devoted to the aging adult population, through appropriate modification and tailoring of sampling techniques, intervention development, and data measures and collection. PMID- 21821727 TI - Increased hyaluronan fragmentation during pulmonary ischemia. AB - Hyaluronan (HA), a glycosaminoglycan critical to the lung extracellular matrix, has been shown to dissociate into low-molecular-weight (LMW) HA fragments following exposure to injurious stimuli. In the present study we questioned whether lung HA changed during ischemia and whether changes had an effect on subsequent angiogenesis. After left pulmonary artery ligation (LPAL) in mice, we analyzed left lung homogenates immediately after the onset of ischemia (0 h) and intermittently for 14 days. The relative expression of HA synthase (HAS)1, HAS2, and HAS3 was determined by real-time RT-PCR, total HA in the lung was measured by an ELISA-like assay, gel electrophoresis was performed to determine changes in HA size distribution, and the activity of hyaluronidases was determined by zymography. A 50% increase in total HA was measured 16 h after the onset of ischemia and remained elevated for up to 7 days. Furthermore, a fourfold increase in LMW HA fragments (495-30 kDa) was observed by 4 h after LPAL. Both HAS1 and HAS2 showed increased expression 4-16 h after LPAL, yet no changes were seen in hyaluronidase activity. These results suggest that both HA fragmentation and activation of HA synthesis contribute to increased HA levels during lung ischemia. Delivery of LMW HA fragments in an in vitro tube formation assay or directly to the ischemic mouse lung in vivo both resulted in increased angiogenesis. We conclude that ischemic injury results in matrix fragmentation, which leads to stimulation of neovascularization. PMID- 21821728 TI - Lysophosphatidic acid receptor 1 modulates lipopolysaccharide-induced inflammation in alveolar epithelial cells and murine lungs. AB - Lysophosphatidic acid (LPA), a bioactive phospholipid, plays an important role in lung inflammation by inducing the release of chemokines and lipid mediators. Our previous studies have shown that LPA induces the secretion of interleukin-8 and prostaglandin E(2) in lung epithelial cells. Here, we demonstrate that LPA receptors contribute to lipopolysaccharide (LPS)-induced inflammation. Pretreatment with LPA receptor antagonist Ki16425 or downregulation of LPA receptor 1 (LPA(1)) by small-interfering RNA (siRNA) attenuated LPS-induced phosphorylation of p38 MAPK, I-kappaB kinase, and I-kappaB in MLE12 epithelial cells. In addition, the blocking of LPA(1) also suppressed LPS-induced IL-6 production. Furthermore, LPS treatment promoted interaction between LPA(1) and CD14, a LPS coreceptor, in a time- and dose-dependent manner. Disruption of lipid rafts attenuated the interaction between LPA(1) and CD14. Mice challenged with LPS increased plasma LPA levels and enhanced expression of LPA receptors in lung tissues. To further investigate the role of LPA receptors in LPS-induced inflammation, wild-type, or LPA(1)-deficient mice, or wild-type mice pretreated with Ki16425 were intratracheally challenged with LPS for 24 h. Knock down or inhibition of LPA(1) decreased LPS-induced IL-6 release in bronchoalveolar lavage (BAL) fluids and infiltration of cells into alveolar space compared with wild type mice. However, no significant differences in total protein concentration in BAL fluids were observed. These results showed that knock down or inhibition of LPA(1) offered significant protection against LPS-induced lung inflammation but not against pulmonary leak as observed in the murine model for lung injury. PMID- 21821729 TI - Curcumin augments lung maturation, preventing neonatal lung injury by inhibiting TGF-beta signaling. AB - There is no effective intervention to prevent or treat bronchopulmonary dysplasia (BPD). Curcumin has potent antioxidant and anti-inflammatory properties, and it modulates signaling of peroxisome proliferator-activated receptor-gamma (PPARgamma), an important molecule in the pathobiology of BPD. However, its role in the prevention of BPD is not known. We determined 1) if curcumin enhances neonatal lung maturation, 2) if curcumin protects against hyperoxia-induced neonatal lung injury, and 3) if this protection is mediated by blocking TGF-beta. Embryonic day 19 fetal rat lung fibroblasts were exposed to 21% or 95% O(2) for 24 h following 1 h of treatment with curcumin. Curcumin dose dependently accelerated e19 fibroblast differentiation [increased parathyroid hormone-related protein (PTHrP) receptor, PPARgamma, and adipocyte differentiation-related protein (ADRP) levels and triolein uptake] and proliferation (increased thymidine incorporation). Pretreatment with curcumin blocked the hyperoxia-induced decrease (PPARgamma and ADRP) and increase (alpha-smooth muscle actin and fibronectin) in markers of lung injury/repair, as well as the activation of TGF-beta signaling. In a separate set of experiments, neonatal Sprague-Dawley rat pups were exposed to 21% or 95% O(2) for 7 days with or without intraperitoneal administration of curcumin. Analysis for markers of lung injury/repair [PTHrP receptor, PPARgamma, ADRP, fibronectin, TGF-beta receptor (activin receptor-like kinase 5), and Smad3] and lung morphology (radial alveolar count) demonstrated that curcumin effectively blocks TGF-beta activation and hyperoxia-induced lung injury. Therefore, curcumin accelerates lung maturation by stimulating key alveolar epithelial-mesenchymal interactions and prevents hyperoxia-induced neonatal lung injury, possibly by blocking TGF-beta activation, suggesting that it is a potential intervention against BPD. PMID- 21821730 TI - Improved bioavailability of epoxyeicosatrienoic acids reduces TP-receptor agonist induced tension in human bronchi. AB - Epoxyeicosatrienoic acid (EET) and thromboxane A(2) are arachidonic acid derivatives. The former has initially been defined as an epithelium-derived hyperpolarizing factor displaying broncho-relaxing and anti-inflammatory properties, as recently demonstrated, whereas thromboxane A(2) induces vaso- and bronchoconstriction upon binding to thromboxane-prostanoid (TP)-receptor. EETs, however, are quickly degraded by the soluble epoxide hydrolase (sEH) into inactive diol compounds. The aim of this study was to investigate the effects of 14,15-EET on TP-receptor activation in human bronchi. Tension measurements performed on native bronchi from various species, acutely treated with increasing 14,15-EET concentrations, revealed specific and concentration-dependent relationships as well as a decrease in the tension induced by 30 nM U-46619, used as a synthetic TP-receptor agonist. Interestingly, acute treatments with 3 MUM N (methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide, an epoxygenase inhibitor, which minimizes endogenous production of EET, resulted in an increased reactivity to U-46619. Furthermore, we demonstrated that chronic treatments with trans-4-[4 (3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB), a sEH inhibitor, reduced human bronchi reactivity to U-46619. During our tension measurements, we also observed that human bronchi generated small-amplitude contractions; these spontaneous activities were reduced upon acute 14,15-EET treatments in the presence of t-AUCB. Altogether, these data demonstrate that endogenous and exogenous 14,15-EET could interfere with the activation of TP-receptors as well as with spontaneous oscillations in human airway smooth muscle tissues. PMID- 21821731 TI - Chronic intermittent hypoxia-induced vascular enlargement and VEGF upregulation in the rat carotid body is not prevented by antioxidant treatment. AB - Chronic intermittent hypoxia (CIH), a characteristic of sleep obstructive apnea, enhances carotid body (CB) chemosensory responses to hypoxia, but its consequences on CB vascular area and VEGF expression are unknown. Accordingly, we studied the effect of CIH on CB volume, glomus cell numbers, blood vessel diameter and number, and VEGF immunoreactivity (VEGF-ir) in male Sprague-Dawley rats exposed to 5% O(2), 12 times/h for 8 h or sham condition for 21 days. We found that CIH did not modify the CB volume or the number of glomus cells but increased VEGF-ir and enlarged the vascular area by increasing the size of the blood vessels, whereas the number of the vessels was unchanged. Because oxidative stress plays an essential role in the CIH-induced carotid chemosensory potentiation, we tested whether antioxidant treatment with ascorbic acid may impede the vascular enlargement and the VEGF upregulation. Ascorbic acid, which prevents the CB chemosensory potentiation, failed to impede the vascular enlargement and the increased VEGF-ir. Thus present results suggest that the CB vascular enlargement induced by CIH is a direct effect of intermittent hypoxia and not secondary to the oxidative stress. Accordingly, the subsequent capillary changes may be secondary to the mechanisms involved in the neural chemosensory plasticity induced by intermittent hypoxia. PMID- 21821732 TI - Attitudes of physicians regarding anticoagulation for atrial fibrillation: a systematic review. AB - BACKGROUND: the efficacy of warfarin for prevention of stroke in patients with atrial fibrillation (AF) is well established, but many people with AF who would benefit from warfarin are not receiving it. This systematic review aims to determine physicians' attitudes to the prescription of warfarin for AF, and identify reasons for its underuse. METHODS: an electronic search of MEDLINE (1950 present), EMBASE (1980-present), CINAHL (1994-present), PsycINFO (1987-present) and Web of Knowledge (1970-present) was performed in November 2010 to identify all studies which addressed, via survey, physicians' attitudes regarding anticoagulation for patients with AF. RESULTS: a total of 1,375 citations were identified. Of these citations, 44 full text studies were obtained for scrutinisation; 14 of these studies were rejected leaving 30 studies which were included in the review. All included studies were cross-sectional surveys and addressed physicians' opinions of anticoagulation in AF as a primary or secondary aim. Increasing age, increased bleeding risk, previous bleeds, falls risk, co morbidities and ability to comply with treatment influenced whether physicians would prescribe anticoagulation for AF. CONCLUSION: physicians are reticent to recommend warfarin for elderly patients in AF, despite evidence of increased benefit in these patients compared with younger patients. Risk of falls and previous bleeding were also shown to be disproportionate barriers to warfarin prescription. Further studies are required to determine how best to overcome these perceived barriers to appropriate anticoagulation. PMID- 21821733 TI - The safety and regulation of natural products used as foods and food ingredients. AB - The use of botanicals and dietary supplements derived from natural substances as an adjunct to an improved quality of life or for their purported medical benefits has become increasingly common in the United States. This review addresses the safety assessment and regulation of food products containing these substances by the U.S. Food and Drug Administration (FDA). The issue of safety is particularly critical given how little information is available on the toxicity of some of these products. The first section uses case studies for stevia and green tea extracts as examples of how FDA evaluates the safety of botanical and herbal products submitted for consideration as Generally Recognized as Safe under the Federal Food, Drug, and Cosmetics Act. The 1994 Dietary Supplement Health Education Act (DSHEA) created a regulatory framework for dietary supplements. The article also discusses the regulation of this class of dietary supplements under DSHEA and addresses the FDA experience in analyzing the safety of natural ingredients described in pre-market safety submissions. Lastly, we discuss an ongoing interagency collaboration to conduct safety testing of nominated dietary supplements. PMID- 21821735 TI - Cannabidiol, a major phytocannabinoid, as a potent atypical inhibitor for CYP2D6. AB - Delta(9)-Tetrahydrocannabinol, cannabidiol (CBD), and cannabinol are the three major cannabinoids contained in marijuana, which are devoid of nitrogen atoms in their structures. In this study, we investigated the inhibitory effects of the major phytocannabinoids on the catalytic activity of human CYP2D6. These major cannabinoids inhibited the 3-[2-(N,N-diethyl-N-methylammonium)ethyl]-7-methoxy-4 methylcoumarin (AMMC) and dextromethorphan O-demethylase activities of recombinant CYP2D6 and pooled human liver microsomes in a concentration-dependent manner (IC(50) = 4.01-24.9 MUM), indicating the strongest inhibitory potency of CBD. However, these cannabinoids showed no or weak metabolism-dependent inhibition. CBD competitively inhibited the CYP2D6 activities with the apparent K(i) values of 1.16 to 2.69 MUM. To clarify the structural requirement for CBD mediated CYP2D6 inhibition, effects of CBD-related compounds on the AMMC O demethylase activity of recombinant CYP2D6 were examined. Olivetol (IC(50) = 7.21 MUM) inhibited CYP2D6 activity as potently as CBD did (IC(50) = 6.52 MUM), whereas d-limonene did not show any inhibitory effect. Pentylbenzene failed to inhibit CYP2D6 activity. Furthermore, neither monomethyl nor dimethyl ethers of CBD inhibited the activity. Cannabidivarin having a propyl side chain inhibited CYP2D6 activity; its inhibitory effect (IC(50) = 10.2 MUM) was less potent than that of CBD. On the other hand, orcinol and resorcinol showed lack of inhibition. The inhibitory effect of CBD on CYP2D6 activity was more potent than those of 16 compounds without nitrogen atoms tested, such as progesterone. These results indicated that CBD caused potent direct CYP2D6 inhibition, in which two phenolic hydroxyl groups and the pentyl side chain of CBD may play important roles. PMID- 21821734 TI - TTA-P2 is a potent and selective blocker of T-type calcium channels in rat sensory neurons and a novel antinociceptive agent. AB - Several agents that are preferential T-type calcium (T-channel) blockers have shown promise as being effective in alleviating acute and chronic pain, suggesting an urgent need to identify even more selective and potent T-channel antagonists. We used small, acutely dissociated dorsal root ganglion (DRG) cells of adult rats to study the in vitro effects of 3,5-dichloro-N-[1-(2,2-dimethyl tetrahydro-pyran-4-ylmethyl)-4-fluoro-piperidin-4-ylmethyl]-benzamide (TTA-P2), a derivative of 4-aminomethyl-4-fluoropiperdine, on T currents, as well as other currents known to modulate pain transmission. We found that TTA-P2 potently and reversibly blocked DRG T currents with an IC(50) of 100 nM and stabilized channel in the inactive state, whereas high-voltage-activated calcium and sodium currents were 100- to 1000-fold less sensitive to channel blocking effects. In in vivo studies, we found that intraperitoneal injections of 5 or 7.5 mg/kg TTA-P2 reduced pain responses in mice in phases 1 and 2 of the formalin test. Furthermore, TTA-P2, at 10 mg/kg i.p., selectively and completely reversed thermal hyperalgesia in diabetic rats treated with streptozocin but had no effect on the nociceptive response of healthy animals. The antihyperalgesic effects of TTA-P2 in diabetic rats were completely abolished by administration of oligonucleotide antisense for Ca(V)3.2 isoform of T channels. Thus, TTA-P2 is not only the most potent and selective blocker of T channels in sensory neurons yet described, but it also demonstrates the potential for the pharmacological effectiveness of this approach in addressing altered nociceptive responses in animal models of both inflammatory and neuropathic pain. PMID- 21821736 TI - Q172H replacement overcomes effects on the metabolism of cyclophosphamide and efavirenz caused by CYP2B6 variant with Arg262. AB - There are a number of reports indicating that CYP2B6*6 (c.516G>T and c.785A>G) is responsible for decreased clearance of efavirenz (EFV), although increased disposition of cyclophosphamide (CPA) in individuals with this polymorphism was observed. Thus, we hypothesized that the effects of the two single nucleotide polymorphisms (SNPs) of CYP2B6*6 on the metabolism of drugs might be considerably different between these two agents. To clarify this possibility, we expressed two major variants of this enzyme, CYP2B6.6 (Q172H and K262R) and CYP2B6.4 (K262R), and investigated metabolic activities of these variants toward EFV and CPA. Kinetic analyses clearly indicated that CYP2B6.4 possessed enhanced metabolic activity toward EFV compared with that of the wild-type enzyme (CYP2B6.1), whereas CPA was metabolized less efficiently by CYP2B6.4 than by CYP2B6.1. On the other hand, CYP2B6.6 showed a completely opposite character, suggesting that Q172H gives inverse effects on metabolic activities of CYP2B6 affected by K262R. Although it is recognized that effects of amino acid change in cytochrome P450 on the metabolic activity depend on substrates, this study revealed SNPs giving an opposite effect on the metabolism of two clinically important drugs currently used. Furthermore, this study provides the first evidence that Q172H can reverse the direction of the effect caused by K262R in CYP2B6 on the metabolism of certain drugs. PMID- 21821737 TI - Increased thermal and osmotic stress resistance in Listeria monocytogenes 568 grown in the presence of trehalose due to inactivation of the phosphotrehalase encoding gene treA. AB - The food-borne pathogen Listeria monocytogenes is a problem for food processors and consumers alike, as the organism is resistant to harsh environmental conditions and inimical barriers implemented to prevent the survival and/or growth of harmful bacteria. One mechanism by which listeriae mediate survival is through the accumulation of compatible solutes, such as proline, betaine and carnitine. In other bacteria, including Escherichia coli, the synthesis and accumulation of another compatible solute, trehalose, are known to aid in the survival of stressed cells. The objective of this research was to investigate trehalose metabolism in L. monocytogenes, where the sugar is thought to be transferred across the cytoplasmic membrane via a specific phosphoenolpyruvate phosphotransferase system and phosphorylation to trehalose-6-phosphate (T6P). The latter is subsequently broken down into glucose and glucose-6-phosphate by alpha,alpha-(1,1) phosphotrehalase, the putative product of the treA gene. Here we report on an isogenic treA mutant of L. monocytogenes 568 (568:DeltaTreA) which, relative to the wild-type strain, displays increased tolerances to multiple stressors, including heat, high osmolarity, and desiccation. This is the first study to examine the putative trehalose operon in L. monocytogenes, and we demonstrate that lmo1254 (treA) in L. monocytogenes 568 indeed encodes a phosphotrehalase required for the hydrolysis of T6P. Disruption of the treA gene results in the accumulation of T6P which is subsequently dephosphorylated to trehalose in the cytosol, thereby contributing to the stress hardiness observed in the treA mutant. This study highlights the importance of compatible solutes for microbial survival in adverse environments. PMID- 21821738 TI - Cloning, expression, and characterization of a new beta-agarase from Vibrio sp. strain CN41. AB - A new agarase, AgaA(CN41), cloned from Vibrio sp. strain CN41, consists of 990 amino acids, with only 49% amino acid sequence identity with known beta-agarases. AgaA(CN41) belongs to the GH50 (glycoside hydrolase 50) family but yields neoagarotetraose as the end product. AgaA(CN41) was expressed and characterized. PMID- 21821739 TI - Transmission of intestinal Bifidobacterium longum subsp. longum strains from mother to infant, determined by multilocus sequencing typing and amplified fragment length polymorphism. AB - The gastrointestinal tracts of neonates are colonized by bacteria immediately after birth. It has been discussed that the intestinal microbiota of neonates includes strains transferred from the mothers. Although some studies have indicated possible bacterial transfer from the mother to the newborn, this is the first report confirming the transfer of bifidobacteria at the strain level. Here, we investigated the mother-to-infant transmission of Bifidobacterium longum subsp. longum by genotyping bacterial isolates from the feces of mothers before delivery and of their infants after delivery. Two hundred seven isolates from 8 pairs of mothers and infants were discriminated by multilocus sequencing typing (MLST) and amplified fragment length polymorphism (AFLP) analysis. By both methods, 11 strains of B. longum subsp. longum were found to be monophyletic for the feces of the mother and her infant. This finding confirms that these strains were transferred from the intestine of the mother to that of the infant. These strains were found in the first feces (meconium) of the infant and in the feces at days 3, 7, 30, and 90 after birth, indicating that they stably colonize the infant's intestine immediately after birth. The strains isolated from each family did not belong to clusters derived from any of the other families, suggesting that each mother-infant pair might have unique family-specific strains. PMID- 21821740 TI - Oxidoreductive cellulose depolymerization by the enzymes cellobiose dehydrogenase and glycoside hydrolase 61. AB - Several members of the glycoside hydrolase 61 (GH61) family of proteins have recently been shown to dramatically increase the breakdown of lignocellulosic biomass by microbial hydrolytic cellulases. However, purified GH61 proteins have neither demonstrable direct hydrolase activity on various polysaccharide or lignacious components of biomass nor an apparent hydrolase active site. Cellobiose dehydrogenase (CDH) is a secreted flavocytochrome produced by many cellulose-degrading fungi with no well-understood biological function. Here we demonstrate that the binary combination of Thermoascus aurantiacus GH61A (TaGH61A) and Humicola insolens CDH (HiCDH) cleaves cellulose into soluble, oxidized oligosaccharides. TaGH61A-HiCDH activity on cellulose is shown to be nonredundant with the activities of canonical endocellulase and exocellulase enzymes in microcrystalline cellulose cleavage, and while the combination of TaGH61A and HiCDH cleaves highly crystalline bacterial cellulose, it does not cleave soluble cellodextrins. GH61 and CDH proteins are coexpressed and secreted by the thermophilic ascomycete Thielavia terrestris in response to environmental cellulose, and the combined activities of T. terrestris GH61 and T. terrestris CDH are shown to synergize with T. terrestris cellulose hydrolases in the breakdown of cellulose. The action of GH61 and CDH on cellulose may constitute an important, but overlooked, biological oxidoreductive system that functions in microbial lignocellulose degradation and has applications in industrial biomass utilization. PMID- 21821741 TI - Salicylate functions as an efflux pump inducer and promotes the emergence of fluoroquinolone-resistant Campylobacter jejuni mutants. AB - Salicylate, a nonsteroidal anti-inflammatory compound, has been shown to increase the resistance of Campylobacter to antimicrobials. However, the molecular mechanism underlying salicylate-induced resistance has not yet been established. In this study, we determined how salicylate increases antibiotic resistance and evaluated its impact on the development of fluoroquinolone-resistant Campylobacter mutants. Transcriptional fusion assays, real-time quantitative reverse transcription-PCR (RT-PCR), and immunoblotting assays consistently demonstrated the induction of the CmeABC multidrug efflux pump by salicylate. Electrophoretic mobility shift assays further showed that salicylate inhibits the binding of CmeR (a transcriptional repressor of the TetR family) to the promoter DNA of cmeABC, suggesting that salicylate inhibits the function of CmeR. The presence of salicylate in the culture medium not only decreased the susceptibility of Campylobacter to ciprofloxacin but also resulted in an approximately 70-fold increase in the observed frequency of emergence of fluoroquinolone-resistant mutants under selection with ciprofloxacin. Together, these results indicate that in Campylobacter, salicylate inhibits the binding of CmeR to the promoter DNA and induces expression of cmeABC, resulting in decreased susceptibility to antibiotics and in increased emergence of fluoroquinolone resistant mutants under selection pressure. PMID- 21821742 TI - Comparison of surface sampling methods for virus recovery from fomites. AB - The role of fomites in infectious disease transmission relative to other exposure routes is difficult to discern due, in part, to the lack of information on the level and distribution of virus contamination on surfaces. Comparisons of studies intending to fill this gap are difficult because multiple different sampling methods are employed and authors rarely report their method's lower limit of detection. In the present study, we compare a subset of sampling methods identified from a literature review to demonstrate that sampling method significantly influences study outcomes. We then compare a subset of methods identified from the review to determine the most efficient methods for recovering virus from surfaces in a laboratory trial using MS2 bacteriophage as a model virus. Recoveries of infective MS2 and MS2 RNA are determined using both a plaque assay and quantitative reverse transcription-PCR, respectively. We conclude that the method that most effectively recovers virus from nonporous fomites uses polyester-tipped swabs prewetted in either one-quarter-strength Ringer's solution or saline solution. This method recovers a median fraction for infective MS2 of 0.40 and for MS2 RNA of 0.07. Use of the proposed method for virus recovery in future fomite sampling studies would provide opportunities to compare findings across multiple studies. PMID- 21821743 TI - Characterization of Bacillus thuringiensis L-isoleucine dioxygenase for production of useful amino acids. AB - We determined the enzymatic characteristics of an industrially important biocatalyst, alpha-ketoglutarate-dependent l-isoleucine dioxygenase (IDO), which was found to be the enzyme responsible for the generation of (2S,3R,4S)-4 hydroxyisoleucine in Bacillus thuringiensis 2e2. Depending on the amino acid used as the substrate, IDO catalyzed three different types of oxidation reactions: hydroxylation, dehydrogenation, and sulfoxidation. IDO stereoselectively hydroxylated several hydrophobic aliphatic l-amino acids, as well as l isoleucine, and produced (S)-3-hydroxy-l-allo-isoleucine, 4-hydroxy-l-leucine, (S)-4-hydroxy-l-norvaline, 4-hydroxy-l-norleucine, and 5-hydroxy-l-norleucine. The IDO reaction product of l-isoleucine, (2S,3R,4S)-4-hydroxyisoleucine, was again reacted with IDO and dehydrogenated into (2S,3R)-2-amino-3-methyl-4 ketopentanoate, which is also a metabolite found in B. thuringiensis 2e2. Interestingly, IDO catalyzed the sulfoxidation of some sulfur-containing l-amino acids and generated l-methionine sulfoxide and l-ethionine sulfoxide. Consequently, the effective production of various modified amino acids would be possible using IDO as the biocatalyst. PMID- 21821744 TI - Cell surface attachment structures contribute to biofilm formation and xylem colonization by Erwinia amylovora. AB - Biofilm formation plays a critical role in the pathogenesis of Erwinia amylovora and the systemic invasion of plant hosts. The functional role of the exopolysaccharides amylovoran and levan in pathogenesis and biofilm formation has been evaluated. However, the role of biofilm formation, independent of exopolysaccharide production, in pathogenesis and movement within plants has not been studied previously. Evaluation of the role of attachment in E. amylovora biofilm formation and virulence was examined through the analysis of deletion mutants lacking genes encoding structures postulated to function in attachment to surfaces or in cellular aggregation. The genes and gene clusters studied were selected based on in silico analyses. Microscopic analyses and quantitative assays demonstrated that attachment structures such as fimbriae and pili are involved in the attachment of E. amylovora to surfaces and are necessary for the production of mature biofilms. A time course assay indicated that type I fimbriae function earlier in attachment, while type IV pilus structures appear to function later in attachment. Our results indicate that multiple attachment structures are needed for mature biofilm formation and full virulence and that biofilm formation facilitates entry and is necessary for the buildup of large populations of E. amylovora cells in xylem tissue. PMID- 21821745 TI - Unique regulatory mechanism for D-galactose utilization in Aspergillus nidulans. AB - This study describes two novel regulators, GalX and GalR, that control d galactose utilization in Aspergillus nidulans. This system is unique for A. nidulans since no GalR homologs were found in other ascomycetes. GalR shares significant sequence identity with the arabinanolytic and xylanolytic regulators AraR and XlnR, but GalX is more distantly related. PMID- 21821746 TI - Influence of pore structure on the effectiveness of a biogenic carbonate surface treatment for limestone conservation. AB - A ureolytic biodeposition treatment was applied to five types of limestone in order to investigate the effect of pore structure on the protective performance of a biogenic carbonate surface treatment. Protective performance was assessed by means of transport and degradation processes, and the penetration depth of the treatment was visualized by microtomography. Pore size governs bacterial adsorption and hence the location and amount of carbonate precipitated. This study indicated that in macroporous stone, biogenic carbonate formation occurred to a larger extent and at greater depths than in microporous stone. As a consequence, the biodeposition treatment exhibited the greatest protective performance on macroporous stone. While precipitation was limited to the outer surface of microporous stone, biogenic carbonate formation occurred at depths of greater than 2 mm for Savonnieres and Euville. For Savonnieres, the presence of biogenic carbonate resulted in a 20-fold decreased rate of water absorption, which resulted in increased resistance to sodium sulfate attack and to freezing and thawing. While untreated samples were completely degraded after 15 cycles of salt attack, no damage was observed in biodeposition-treated Savonnieres. From this study, it is clear that biodeposition is very effective and more feasible for macroporous stones than for microporous stones. PMID- 21821747 TI - Matrix-assisted laser desorption ionization (MALDI)-time of flight mass spectrometry- and MALDI biotyper-based identification of cultured biphenyl metabolizing bacteria from contaminated horseradish rhizosphere soil. AB - Bacteria that are able to utilize biphenyl as a sole source of carbon were extracted and isolated from polychlorinated biphenyl (PCB)-contaminated soil vegetated by horseradish. Isolates were identified using matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS). The usage of MALDI Biotyper for the classification of isolates was evaluated and compared to 16S rRNA gene sequence analysis. A wide spectrum of bacteria was isolated, with Arthrobacter, Serratia, Rhodococcus, and Rhizobium being predominant. Arthrobacter isolates also represented the most diverse group. The use of MALDI Biotyper in many cases permitted the identification at the level of species, which was not achieved by 16S rRNA gene sequence analyses. However, some isolates had to be identified by 16S rRNA gene analyses if MALDI Biotyper-based identification was at the level of probable or not reliable identification, usually due to a lack of reference spectra included in the database. Overall, this study shows the possibility of using MALDI-TOF MS and MALDI Biotyper for the fast and relatively nonlaborious identification/classification of soil isolates. At the same time, it demonstrates the dominant role of employing 16S rRNA gene analyses for the identification of recently isolated strains that can later fill the gaps in the protein-based identification databases. PMID- 21821748 TI - Acquired antibiotic resistance: are we born with it? AB - The rapid emergence of antibiotic resistance (AR) is a major public health concern. Recent findings on the prevalence of food-borne antibiotic-resistant (ART) commensal bacteria in ready-to-consume food products suggested that daily food consumption likely serves as a major avenue for dissemination of ART bacteria from the food chain to human hosts. To properly assess the impact of various factors, including the food chain, on AR development in hosts, it is important to determine the baseline of ART bacteria in the human gastrointestinal (GI) tract. We thus examined the gut microbiota of 16 infant subjects, from the newborn stage to 1 year of age, who fed on breast milk and/or infant formula during the early stages of development and had no prior exposure to antibiotics. Predominant bacterial populations resistant to several antibiotics and multiple resistance genes were found in the infant GI tracts within the first week of age. Several ART population transitions were also observed in the absence of antibiotic exposure and dietary changes. Representative AR gene pools including tet(M), ermB, sul2, and bla(TEM) were detected in infant subjects. Enterococcus spp., Staphylococcus spp., Klebsiella spp., Streptococcus spp., and Escherichia coli/Shigella spp. were among the identified AR gene carriers. ART bacteria were not detected in the infant formula and infant foods examined, but small numbers of skin-associated ART bacteria were found in certain breast milk samples. The data suggest that the early development of AR in the human gut microbiota is independent of infants' exposure to antibiotics but is likely impacted by exposure to maternal and environmental microbes during and after delivery and that the ART population is significantly amplified within the host even in the absence of antibiotic selective pressure. PMID- 21821749 TI - Inhibition of Escherichia coli CFT073 fliC expression and motility by cranberry materials. AB - In humans, uropathogenic Escherichia coli (UPEC) is the most common etiological agent of uncomplicated urinary tract infections (UTIs). Cranberry extracts have been linked to the prevention of UTIs for over a century; however, a mechanistic understanding of the way in which cranberry derivatives prevent bacterial infection is still lacking. In this study, we used a fliC-lux reporter as well as quantitative reverse transcription-PCR to demonstrate that when UPEC strain CFT073 was grown or exposed to dehydrated, crushed cranberries or to purified cranberry-derived proanthocyanidins (cPACs), expression of the flagellin gene (fliC) was inhibited. In agreement with these results, transmission electron microscopy imaging of bacteria grown in the presence of cranberry materials revealed fewer flagella than those in bacteria grown under control conditions. Furthermore, we showed that swimming and swarming motilities were hindered when bacteria were grown in the presence of the cranberry compounds. Because flagellum mediated motility has been suggested to enable UPEC to disseminate to the upper urinary tract, we propose that inhibition of flagellum-mediated motility might be a key mechanism by which cPACs prevent UTIs. This is the first report to show that cranberry compounds inhibit UPEC motility via downregulation of the fliC gene. Further studies are required to establish whether these inhibitors play a role in vivo. PMID- 21821750 TI - Chlortetracycline-resistant intestinal bacteria in organically raised and feral Swine. AB - Organically raised swine had high fecal populations of chlortetracycline (CTC) resistant (growing at 64 MUg CTC/ml) Escherichia coli, Megasphaera elsdenii, and anaerobic bacteria. By comparison, CTC-resistant bacteria in feral swine feces were over 1,000-fold fewer and exhibited lower taxonomic diversity. PMID- 21821751 TI - Maturation of released spores is necessary for acquisition of full spore heat resistance during Bacillus subtilis sporulation. AB - The first ~10% of spores released from sporangia (early spores) during Bacillus subtilis sporulation were isolated, and their properties were compared to those of the total spores produced from the same culture. The early spores had significantly lower resistance to wet heat and hypochlorite than the total spores but identical resistance to dry heat and UV radiation. Early and total spores also had the same levels of core water, dipicolinic acid, and Ca and germinated similarly with several nutrient germinants. The wet heat resistance of the early spores could be increased to that of total spores if early spores were incubated in conditioned sporulation medium for ~24 h at 37 degrees C (maturation), and some hypochlorite resistance was also restored. The maturation of early spores took place in pH 8 buffer with Ca(2+) but was blocked by EDTA; maturation was also seen with early spores of strains lacking the CotE protein or the coat associated transglutaminase, both of which are needed for normal coat structure. Nonetheless, it appears to be most likely that it is changes in coat structure that are responsible for the increased resistance to wet heat and hypochlorite upon early spore maturation. PMID- 21821752 TI - Enteral tube feeding alters the oral indigenous microbiota in elderly adults. AB - Enteral tube feeding is widely used to maintain nutrition for elderly adults with eating difficulties, but its long-term use alters the environment of the oral ecosystem. This study characterized the tongue microbiota of tube-fed elderly adults by analyzing the 16S rRNA gene. The terminal restriction fragment length polymorphism (T-RFLP) profiles of 44 tube-fed subjects were compared with those of 54 subjects fed orally (average age, 86.4 +/- 6.9 years). Bar-coded pyrosequencing data were also obtained for a subset of the subjects from each group (15 tube-fed subjects and 16 subjects fed orally). The T-RFLP profiles demonstrated that the microbiota of the tube-fed subjects was distinct from that of the subjects fed orally (permutational multivariate analysis of variance [perMANOVA], P < 0.001). The pyrosequencing data revealed that 22 bacterial genera, including Corynebacterium, Peptostreptococcus, and Fusobacterium, were significantly more predominant in tube-fed subjects, whereas the dominant genera in the subjects fed orally, such as Streptococcus and Veillonella, were present in much lower proportions. Opportunistic pathogens rarely detected in the normal oral microbiota, such as Corynebacterium striatum and Streptococcus agalactiae, were often found in high proportions in tube-fed subjects. The oral indigenous microbiota is disrupted by the use of enteral feeding, allowing health threatening bacteria to thrive. PMID- 21821753 TI - Relevance of Bifidobacterium animalis subsp. lactis plasminogen binding activity in the human gastrointestinal microenvironment. AB - Human plasmin(ogen) is regarded as a component of the molecular cross talk between the probiotic species Bifidobacterium animalis subsp. lactis and the human host. However, up to now, only in vitro studies have been reported. Here, we demonstrate that the probiotic strain B. animalis subsp. lactis BI07 is capable of recruiting plasmin(ogen) present at physiological concentrations in crude extracts from human feces. Our results provide evidence that supports the significance of the B. lactis-plasmin(ogen) interaction in the human gastrointestinal tract. PMID- 21821754 TI - Overcoming fluctuation and leakage problems in the quantification of intracellular 2-oxoglutarate levels in Escherichia coli. AB - 2-Oxoglutarate is located at the junction between central carbon and nitrogen metabolism, serving as an intermediate for both. In nitrogen metabolism, 2 oxoglutarate acts as both a carbon skeletal carrier and an effector molecule. There have been only sporadic reports of its internal concentrations. Here we describe a sensitive and accurate method for determination of the 2-oxoglutarate pool concentration in Escherichia coli. The detection was based on fluorescence derivatization followed by reversed-phase high-pressure liquid chromatography separation. Two alternative cell sampling strategies, both of which were based on a fast filtration protocol, were sequentially developed to overcome both its fast metabolism and contamination from 2-oxoglutarate that leaks into the medium. We observed rapid changes in the 2-oxoglutarate pool concentration upon sudden depletion of nutrients: decreasing upon carbon depletion and increasing upon nitrogen depletion. The latter was studied in mutants lacking either of the two enzymes using 2-oxoglutarate as the carbon substrate for glutamate biosynthesis. The results suggest that flux restriction on either reaction greatly influences the internal 2-oxoglutarate level. Additional study indicates that KgtP, a 2 oxoglutarate proton symporter, functions to recover the leakage loss of 2 oxoglutarate. This recovery mechanism benefits the measurement of cellular 2 oxoglutarate level in practice by limiting contamination from 2-oxoglutarate leakage. PMID- 21821755 TI - Macroscopic biofilms in fracture-dominated sediment that anaerobically oxidize methane. AB - Methane release from seafloor sediments is moderated, in part, by the anaerobic oxidation of methane (AOM) performed by consortia of archaea and bacteria. These consortia occur as isolated cells and aggregates within the sulfate-methane transition (SMT) of diffusion and seep-dominant environments. Here we report on a new SMT setting where the AOM consortium occurs as macroscopic pink to orange biofilms within subseafloor fractures. Biofilm samples recovered from the Indian and northeast Pacific Oceans had a cellular abundance of 10(7) to 10(8) cells cm( 3). This cell density is 2 to 3 orders of magnitude greater than that in the surrounding sediments. Sequencing of bacterial 16S rRNA genes indicated that the bacterial component is dominated by Deltaproteobacteria, candidate division WS3, and Chloroflexi, representing 46%, 15%, and 10% of clones, respectively. In addition, major archaeal taxa found in the biofilm were related to the ANME-1 clade, Thermoplasmatales, and Desulfurococcales, representing 73%, 11%, and 10% of archaeal clones, respectively. The sequences of all major taxa were similar to sequences previously reported from cold seep environments. PhyloChip microarray analysis detected all bacterial phyla identified by the clone library plus an additional 44 phyla. However, sequencing detected more archaea than the PhyloChip within the phyla of Methanosarcinales and Desulfurococcales. The stable carbon isotope composition of the biofilm from the SMT (-35 to -430/00) suggests that the production of the biofilm is associated with AOM. These biofilms are a novel, but apparently widespread, aggregation of cells represented by the ANME-1 clade that occur in methane-rich marine sediments. PMID- 21821756 TI - Association of antibiotic resistance in agricultural Escherichia coli isolates with attachment to quartz. AB - Surface water can be contaminated by bacteria from various sources, including manure from agricultural facilities. Attachment of these bacteria to soil and organic particles contributes to their transport through the environment, though the mechanism of attachment is unknown. As bacterial attachment to human tissues is known to be correlated with antibiotic resistance, we have investigated here the relationship between bacterial attachment to environmental particles and antibiotic resistance in agricultural isolates. We evaluated 203 Escherichia coli isolates collected from swine facilities for attachment to quartz, resistance to 13 antibiotics, and the presence of genes encoding 13 attachment factors. The genes encoding type I, EcpA, P pili, and Ag43 were detected, though none was significantly related to attachment. Quartz attachment was positively and significantly (P < 0.0038) related to combined resistance to amoxicillin/streptomycin/tetracycline/sulfamethazine/tylosin/chlortetracycline and negatively and significantly (P < 0.0038) related to combined resistance to nalidixic acid/kanamycin/neomycin. These results provide clear evidence for a link between antibiotic resistance and attachment to quartz in agricultural isolates. We propose that this may be due to encoding by the responsible genes on a mobile genetic element. Further exploration of the relationship between antibiotic resistance and attachment to environmental particles will improve the understanding and modeling of environmental transport processes, with the goal of preventing human exposure to antibiotic-resistant or virulent microorganisms. PMID- 21821757 TI - Persistence of antibiotic resistance: evaluation of a probiotic approach using antibiotic-sensitive Megasphaera elsdenii strains to prevent colonization of swine by antibiotic-resistant strains. AB - Megasphaera elsdenii is a lactate-fermenting, obligately anaerobic bacterium commonly present in the gastrointestinal tracts of mammals, including humans. Swine M. elsdenii strains were previously shown to have high levels of tetracycline resistance (MIC=64 to >256 MUg/ml) and to carry mosaic (recombinant) tetracycline resistance genes. Baby pigs inherit intestinal microbiota from the mother sow. In these investigations we addressed two questions. When do M. elsdenii strains from the sow colonize baby pigs? Can five antibiotic-sensitive M. elsdenii strains administered intragastrically to newborn pigs affect natural colonization of the piglets by antibiotic-resistant (AR) M. elsdenii strains from the mother? M. elsdenii natural colonization of newborn pigs was undetectable (<10(4) CFU/g [wet weight] of feces) prior to weaning (20 days after birth). After weaning, all pigs became colonized (4 * 10(5) to 2 * 10(8) CFU/g feces). In a separate study, 61% (76/125) of M. elsdenii isolates from a gravid sow never exposed to antibiotics were resistant to chlortetracycline, ampicillin, or tylosin. The inoculation of the sow's offspring with mixtures of M. elsdenii antibiotic-sensitive strains prevented colonization of the offspring by maternal AR strains until at least 11 days postweaning. At 25 and 53 days postweaning, however, AR strains predominated. Antibiotic susceptibility phenotypes and single nucleotide polymorphism (SNP)-based identities of M. elsdenii isolated from sow and offspring were unexpectedly diverse. These results suggest that dosing newborn piglets with M. elsdenii antibiotic-sensitive strains delays but does not prevent colonization by maternal resistant strains. M. elsdenii subspecies diversity offers an explanation for the persistence of resistant strains in the absence of antibiotic selection. PMID- 21821758 TI - Modification of the technical properties of Lactobacillus johnsonii NCC 533 by supplementing the growth medium with unsaturated fatty acids. AB - The aim of this study was to investigate the influence of supplementing growth medium with unsaturated fatty acids on the technical properties of the probiotic strain Lactobacillus johnsonii NCC 533, such as heat and acid tolerance, and inhibition of Salmonella enterica serovar Typhimurium infection. Our results showed that the membrane composition and morphology of L. johnsonii NCC 533 were significantly changed by supplementing a minimal Lactobacillus medium with oleic, linoleic, and linolenic acids. The ratio of saturated to unsaturated plus cyclic fatty acids in the bacterial membrane decreased by almost 2-fold when minimal medium was supplemented with unsaturated fatty acids (10 MUg/ml). The subsequent acid and heat tolerance of L. johnsonii decreased by 6- and 20-fold when the strain was grown in the presence of linoleic and linolenic acids, respectively, compared with growth in oleic acid (all at 10 MUg/ml). Following acid exposure, significantly higher (P < 0.05) oleic acid content was detected in the membrane when growth medium was supplemented with linoleic or linolenic acid, indicating that saturation of the membrane fatty acids occurred during acid stress. Cell integrity was determined in real time during stressed conditions using a fluorescent viability kit in combination with flow cytometric analysis. Following heat shock (at 62.5 degrees C for 5 min), L. johnsonii was unable to form colonies; however, 60% of the bacteria showed no cell integrity loss, which could indicate that the elevated heat inactivated vital processes within the cell, rendering it incapable of replication. Furthermore, L. johnsonii grown in fatty acid-enriched minimal medium had different adhesion properties and caused a 2 fold decrease in S. enterica serovar Typhimurium UK1-lux invasion of HT-29 epithelial cells compared with bacteria grown in minimal medium alone. This could be related to changes in the hydrophobicity and fluidity of the membrane. Our study shows that technical properties underlying probiotic survivability can be affected by nutrient composition of the growth medium. PMID- 21821759 TI - Bacterial display and screening of posttranslationally thioether-stabilized peptides. AB - A major hurdle in the application of therapeutic peptides is their rapid degradation by peptidases. Thioether bridges effectively protect therapeutic peptides against breakdown, thereby strongly increasing bioavailability, enabling oral and pulmonary delivery and potentially significantly optimizing the receptor interaction of selected variants. To efficiently select optimal variants, a library of DNA-coupled thioether-bridged peptides is highly desirable. Here, we present a unique cell surface display system of thioether-bridged peptides and successfully demonstrate highly selective screening. Peptides are posttranslationally modified by thioether bridge-installing enzymes in Lactococcus lactis, followed by export and sortase-mediated covalent coupling to the lactococcal cell wall. This allows the combinatorial optimization and selection of medically and economically highly important therapeutic peptides with strongly enhanced therapeutic potential. PMID- 21821760 TI - Abundance and distribution of Synechococcus spp. and cyanophages in the Chesapeake Bay. AB - Despite the increasing knowledge of Synechococcus spp. and their co-occurring cyanophages in oceanic and coastal water, little is known about their abundance, distribution, and interactions in the Chesapeake Bay estuarine ecosystem. A 5 year interannual survey shows that Synechococcus spp. and their phages are persistent and abundant members of Chesapeake Bay microbial communities. Synechococcus blooms (106 cells ml-1) were often observed in summer throughout the Bay, contributing 20 to 40% of total phytoplankton chlorophyll a. The distribution of phycoerythrin-containing (PE-rich) Synechococcus cells appeared to mostly correlate with the salinity gradient, with higher abundances at higher salinities. Cyanophages infectious to Synechococcus were also abundant (up to 6 * 105 viruses ml-1 by the most probable number assay) during summer months in the Bay. The covariation in abundance of Synechococcus spp. and cyanophages was evident, although the latitude of observed positive correlation varied in different years, mirroring the changing environmental conditions and therefore the host-virus interactions. The impacts of cyanophages on host Synechococcus populations also varied spatially and temporally. Higher phage-related Synechococcus mortality was observed in drought years. Virus-mediated host mortality and subsequent liberation of dissolved organic matter (DOM) may substantially influence oceanic biogeochemical processing through the microbial loop as well as the microbial carbon pump. These observations emphasize the influence of environmental gradients on natural Synechococcus spp. and their phage population dynamics in the estuarine ecosystem. PMID- 21821761 TI - High-throughput typing method to identify a non-outbreak-involved Legionella pneumophila strain colonizing the entire water supply system in the town of Rennes, France. AB - Two legionellosis outbreaks occurred in the city of Rennes, France, during the past decade, requiring in-depth monitoring of Legionella pneumophila in the water network and the cooling towers in the city. In order to characterize the resulting large collection of isolates, an automated low-cost typing method was developed. The multiplex capillary-based variable-number tandem repeat (VNTR) (multiple-locus VNTR analysis [MLVA]) assay requiring only one PCR amplification per isolate ensures a high level of discrimination and reduces hands-on and time requirements. In less than 2 days and using one 4-capillary apparatus, 217 environmental isolates collected between 2000 and 2009 and 5 clinical isolates obtained during outbreaks in 2000 and 2006 in Rennes were analyzed, and 15 different genotypes were identified. A large cluster of isolates with closely related genotypes and representing 77% of the population was composed exclusively of environmental isolates extracted from hot water supply systems. It was not responsible for the known Rennes epidemic cases, although strains showing a similar MLVA profile have regularly been involved in European outbreaks. The clinical isolates in Rennes had the same genotype as isolates contaminating a mall's cooling tower. This study further demonstrates that unknown environmental or genetic factors contribute to the pathogenicity of some strains. This work illustrates the potential of the high-throughput MLVA typing method to investigate the origin of legionellosis cases by allowing the systematic typing of any new isolate and inclusion of data in shared databases. PMID- 21821762 TI - Initiation of polyene macrolide biosynthesis: interplay between polyketide synthase domains and modules as revealed via domain swapping, mutagenesis, and heterologous complementation. AB - Polyene macrolides are important antibiotics used to treat fungal infections in humans. In this work, acyltransferase (AT) domain swaps, mutagenesis, and cross complementation with heterologous polyketide synthase domain (PKS) loading modules were performed in order to facilitate production of new analogues of the polyene macrolide nystatin. Replacement of AT(0) in the nystatin PKS loading module NysA with the propionate-specific AT(1) from the nystatin PKS NysB, construction of hybrids between NysA and the loading module of rimocidin PKS RimA, and stepwise exchange of specific amino acids in the AT(0) domain by site directed mutagenesis were accomplished. However, none of the NysA mutants constructed was able to initiate production of new nystatin analogues. Nevertheless, many NysA mutants and hybrids were functional, providing for different levels of nystatin biosynthesis. An interplay between certain residues in AT(0) and an active site residue in the ketosynthase (KS)-like domain of NysA in initiation of nystatin biosynthesis was revealed. Some hybrids between the NysA and RimA loading modules carrying the NysA AT(0) domain were able to prime rimocidin PKS with both acetate and butyrate units upon complementation of a rimA deficient mutant of the rimocidin/CE-108 producer Streptomyces diastaticus. Expression of the PimS0 loading module from the pimaricin producer in the same host, however, resulted in production of CE-108 only. Taken together, these data indicate relaxed substrate specificity of NysA AT(0) domain, which is counteracted by a strict specificity of the first extender module KS domain in the nystatin PKS of Streptomyces noursei. PMID- 21821763 TI - Identification of a transcriptional repressor involved in benzoate metabolism in Geobacter bemidjiensis. AB - Subsurface environments contaminated with aromatic compounds can be remediated in situ by Geobacter species. A transcription factor that represses expression of bamA, a benzoate-inducible gene, in Geobacter bemidjiensis during growth with acetate was identified. It is likely that this repressor also regulates other genes involved in aromatic compound metabolism. PMID- 21821764 TI - Microbial dynamics during aerobic exposure of corn silage stored under oxygen barrier or polyethylene films. AB - The aims of this study were to compare the effects of sealing forage corn with a new oxygen barrier film with those obtained by using a conventional polyethylene film. This comparison was made during both ensilage and subsequent exposure of silage to air and included chemical, microbiological, and molecular (DNA and RNA) assessments. The forage was inoculated with a mixture of Lactobacillus buchneri, Lactobacillus plantarum, and Enterococcus faecium and ensiled in polyethylene (PE) and oxygen barrier (OB) plastic bags. The oxygen permeability of the PE and OB films was 1,480 and 70 cm3 m-2 per 24 h at 23 degrees C, respectively. The silages were sampled after 110 days of ensilage and after 2, 5, 7, 9, and 14 days of air exposure and analyzed for fermentation characteristics, conventional microbial enumeration, and bacterial and fungal community fingerprinting via PCR denaturing gradient gel electrophoresis (DGGE) and reverse transcription (RT)-PCR DGGE. The yeast counts in the PE and OB silages were 3.12 and 1.17 log10 CFU g-1, respectively, with corresponding aerobic stabilities of 65 and 152 h. Acetobacter pasteurianus was present at both the DNA and RNA levels in the PE silage samples after 2 days of air exposure, whereas it was found only after 7 days in the OB silages. RT-PCR-DGGE revealed the activity of Aspergillus fumigatus in the PE samples from the day 7 of air exposure, whereas it appeared only after 14 days in the OB silages. It has been shown that the use of an oxygen barrier film can ensure a longer shelf life of silage after aerobic exposure. PMID- 21821765 TI - Chemoenzymatic synthesis of N-acetyl-D-neuraminic acid from N-acetyl-D glucosamine by using the spore surface-displayed N-acetyl-D-neuraminic acid aldolase. AB - Chemoenzymatic synthesis of N-acetyl-d-neuraminic acid from N-acetyl-d glucosamine using the spore surface-displayed N-acetyl-d-neuraminic acid aldolase at a high concentration (53.9 g liter(-1)) was achieved in this study. Thus, displaying a target enzyme on the surface of spores might be an alternative for integration of biocatalytic conversion into chemical synthesis. PMID- 21821766 TI - Whole-genome sequencing and phenotypic analysis of Bacillus subtilis mutants following evolution under conditions of relaxed selection for sporulation. AB - Little is known about how genetic variation at the nucleotide level contributes to competitive fitness within species. During a 6,000-generation study of Bacillus subtilis evolved under relaxed selection for sporulation, a new strain, designated WN716, emerged with significantly different colony and cell morphologies; loss of sporulation, competence, acetoin production, and motility; multiple auxotrophies; and increased competitive fitness (H. Maughan and W. L. Nicholson, Appl. Environ. Microbiol. 77:4105-4118, 2011). The genome of WN716 was analyzed by OpGen optical mapping, whole-genome 454 pyrosequencing, and the CLC Genomics Workbench. No large chromosomal rearrangements were found; however, 34 single-nucleotide polymorphisms (SNPs) and +1 frameshifts were identified in WN716 that resulted in amino acid changes in coding sequences of annotated genes, and 11 SNPs were located in intergenic regions. Several classes of genes were affected, including biosynthetic pathways, sporulation, competence, and DNA repair. In several cases, attempts were made to link observed phenotypes of WN716 with the discovered mutations, with various degrees of success. For example, a +1 frameshift was identified at codon 13 of sigW, the product of which (SigW) controls a regulon of genes involved in resistance to bacteriocins and membrane damaging antibiotics. Consistent with this finding, WN716 exhibited sensitivity to fosfomycin and to a bacteriocin produced by B. subtilis subsp. spizizenii and exhibited downregulation of SigW-dependent genes on a transcriptional microarray, consistent with WN716 carrying a knockout of sigW. The results suggest that propagation of B. subtilis for less than 2,000 generations in a nutrient-rich environment where sporulation is suppressed led to rapid initiation of genomic erosion. PMID- 21821767 TI - Lytic myophage Abp53 encodes several proteins similar to those encoded by host Acinetobacter baumannii and phage phiKO2. AB - Acinetobacter baumannii is an important Gram-negative opportunistic pathogen causing nosocomial infections. The emergence of multiple-drug-resistant A. baumannii isolates has increased in recent years. Directed toward phage therapy, a lytic phage of A. baumannii, designated Abp53, was isolated from a sputum sample in this study. Abp53 has an isometric head and a contractile tail with tail fibers (belonging to Myoviridae), a latent period of about 10 min, and a burst size of approximately 150 PFU per infected cell. Abp53 could completely lyse 27% of the A. baumannii isolates tested, which were all multiple drug resistant, but not other bacteria. Mg(2+) enhanced the adsorption and productivity of, and host lysis by, Abp53. Twenty Abp53 virion proteins were visualized in SDS-polyacrylamide gel electrophoresis, with a 47-kDa protein being the predicted major capsid protein. Abp53 has a double-stranded DNA genome of 95 kb. Sequence analyses of a 10-kb region revealed 8 open reading frames. Five of the encoded proteins, including 3 tail components and 2 hypothetical proteins, were similar to proteins encoded by A. baumannii strain ACICU. ORF1176 (one of the tail components, 1,176 amino acids [aa]), which is also similar to tail protein gp21 of Klebsiella phage phiKO2, contained repeated domains similar to those within the ACICU_02717 protein of A. baumannii ACICU and gp21. These findings suggest a common ancestry and horizontal gene transfer during evolution. As phages can expand the host range by domain duplication in tail fiber proteins, repeated domains in ORF1176 might have a similar significance in Abp53. PMID- 21821768 TI - Frequent mutations within the genomic magnetosome island of Magnetospirillum gryphiswaldense are mediated by RecA. AB - Genes for magnetosome formation in magnetotactic bacteria are clustered in large genomic magnetosome islands (MAI). Spontaneous deletions and rearrangements were frequently observed within these regions upon metabolic stress. This instability was speculated to be due to RecA-dependent homologous recombination between the numerous sequence repeats present within the MAI. Here we show that a RecA deficient strain of Magnetospirillum gryphiswaldense (IK-1) no longer exhibits genetic instability of magnetosome formation. Strain IK-1 displayed higher sensitivity to oxygen and UV irradiation. Furthermore, the lack of RecA abolished allelic exchange in the mutant. Cells of strain IK-1 displayed a slightly altered (i.e., more elongated) morphology, whereas the absence of RecA did not affect the ability to synthesize wild-type-like magnetosomes. Our data provide evidence that the observed genetic instability of magnetosome formation in the wild type is due predominantly to RecA-mediated recombination. In addition, increased genetic stability could make strain IK-1 a useful tool for the expression of genes and further genetic engineering, as well as for biotechnological production of bacterial magnetosomes. PMID- 21821769 TI - Identification and characterization of two adenosine phosphorylase activities in Mycobacterium smegmatis. AB - Purine nucleoside phosphorylase (PNP) is an important enzyme in purine metabolism and cleaves purine nucleosides to their respective bases. Mycobacterial PNP is specific for 6-oxopurines and cannot account for the adenosine (Ado) cleavage activity that has been detected in M. tuberculosis and M. smegmatis cultures. In the current work, two Ado cleavage activities were identified from M. smegmatis cell extracts. The first activity was biochemically determined to be a phosphorylase that could reversibly catalyze adenosine + phosphate <-> adenine + alpha-D-ribose-1-phosphate. Our purification scheme led to a 30-fold purification of this activity, with the removal of more than 99.9% of total protein. While Ado was the preferred substrate, inosine and guanosine were also cleaved, with 43% and 32% of the Ado activity, respectively. Our data suggest that M. smegmatis expresses two PNPs: a previously described trimeric PNP that can cleave inosine and guanosine only and a second, novel PNP (Ado-PNP) that can cleave Ado, inosine, and guanosine. Ado-PNP had an apparent K(m) (K(m) ( app)) of 98 +/- 6 MUM (with Ado) and a native molecular mass of 125 +/- 7 kDa. The second Ado cleavage activity was identified as 5'-methylthioadenosine phosphorylase (MTAP) based on its biochemical properties and mass spectrometry analysis. Our study marks the first report of the existence of MTAP in any bacterium. Since human cells do not readily convert Ado to Ade, an understanding of the substrate preferences of these enzymes could lead to the identification of Ado analogs that could be selectively activated to toxic products in mycobacteria. PMID- 21821770 TI - Localization and assembly of the novel exosporium protein BetA of Bacillus anthracis. AB - The exosporium of Bacillus anthracis is comprised of two distinct layers: a basal layer and a hair-like nap that covers the basal layer. The hair-like nap contains the glycoproteins BclA and, most likely, BclB. BclA and BclB are directed to assemble into the exosporium by motifs in their N-terminal domains. Here, we identify a previously uncharacterized putative gene encoding this motif, which we have named betA (Bacillus exosporium-targeted protein of B. anthracis). Like bclA, betA encodes a putative collagenlike repeat region. betA is present in several genomes of exosporium-producing Bacillus species but, so far, not in any others. Using fluorescence microscopic localization of a BetA-enhanced green fluorescent protein (eGFP) fusion protein and immunofluorescence microscopy with anti-BetA antibodies, we showed that BetA resides in the exosporium basal layer, likely underneath BclA. BetA assembles at the spore surface at around hour 5 of sporulation and under the control of BxpB, similar to the control of deposition of BclA. We suggest a model in which BclA and BetA are incorporated into the exosporium by a mechanism that depends on their similar N termini. These data suggest that BetA is a member of a growing family of exosporium proteins that assemble under the control of targeting sequences in their N termini. PMID- 21821771 TI - Role of phase variation in the resistance of Myxococcus xanthus fruiting bodies to Caenorhabditis elegans predation. AB - The phenomenon of phase variation between yellow and tan forms of Myxococcus xanthus has been recognized for several decades, but it is not known what role this variation may play in the ecology of myxobacteria. We confirm an earlier report that tan variants are disproportionately more numerous in the resulting spore population of a M. xanthus fruiting body than the tan vegetative cells that contributed to fruiting body formation. However, we found that tan cells may not require yellow cells for fruiting body formation or starvation-induced sporulation of tan cells. Here we report three differences between the yellow and tan variants that may play important roles in the soil ecology of M. xanthus. Specifically, the yellow variant is more capable of forming biofilms, is more sensitive to lysozyme, and is more resistant to ingestion by bacteriophagous nematodes. We also show that the myxobacterial fruiting body is more resistant to predation by worms than are dispersed M. xanthus cells. PMID- 21821772 TI - Processing is required for a fully functional protein P30 in Mycoplasma pneumoniae gliding and cytadherence. AB - The cell wall-less prokaryote Mycoplasma pneumoniae causes bronchitis and atypical pneumonia in humans. Mycoplasma attachment to the host respiratory epithelium is required for colonization and mediated largely by a differentiated terminal organelle. P30 is an integral membrane protein located at the distal end of the terminal organelle. The P30 null mutant II-3 is unable to attach to host cells and nonmotile and has a branched cellular morphology compared to the wild type, indicating an important role for P30 in M. pneumoniae biology. P30 is predicted to have an N-terminal signal sequence, but the presence of such a motif has not been confirmed experimentally. In the current study we analyzed P30 derivatives having epitope tags engineered at various locations to demonstrate that posttranslational processing occurred in P30. Several potential cleavage sites predicted in silico were examined, and a processing-defective mutant was created to explore P30 maturation further. Our results suggested that signal peptide cleavage occurs between residues 52 and 53 to yield mature P30. The processing-defective mutant exhibited reduced gliding velocity and cytadherence, indicating that processing is required for fully functional maturation of P30. We speculate that P30 processing may trigger a conformational change in the extracellular domain or expose a binding site on the cytoplasmic domain to allow interaction with a binding partner as a part of functional maturation. PMID- 21821773 TI - The N-terminal region of the medium subunit (PduD) packages adenosylcobalamin dependent diol dehydratase (PduCDE) into the Pdu microcompartment. AB - Salmonella enterica produces a proteinaceous microcompartment for B(12)-dependent 1,2-propanediol utilization (Pdu MCP). The Pdu MCP consists of catabolic enzymes encased within a protein shell, and its function is to sequester propionaldehyde, a toxic intermediate of 1,2-propanediol degradation. We report here that a short N-terminal region of the medium subunit (PduD) is required for packaging the coenzyme B(12)-dependent diol dehydratase (PduCDE) into the lumen of the Pdu MCP. Analysis of soluble cell extracts and purified MCPs by Western blotting showed that the PduD subunit mediated packaging of itself and other subunits of diol dehydratase (PduC and PduE) into the Pdu MCP. Deletion of 35 amino acids from the N terminus of PduD significantly impaired the packaging of PduCDE with minimal effects on its enzyme activity. Western blotting showed that fusing the 18 N terminal amino acids of PduD to green fluorescent protein or glutathione S transferase resulted in the association of these fusion proteins with the MCP. Immunoprecipitation tests indicated that the fusion proteins were encapsulated inside the MCP shell. PMID- 21821774 TI - Components of the Rv0081-Rv0088 locus, which encodes a predicted formate hydrogenlyase complex, are coregulated by Rv0081, MprA, and DosR in Mycobacterium tuberculosis. AB - Mycobacterium tuberculosis, the etiological agent of tuberculosis, remains a significant cause of morbidity and mortality throughout the world despite a vaccine and cost-effective antibiotics. The success of this organism can be attributed, in part, to its ability to adapt to potentially harmful stress within the host and establish, maintain, and reactivate from long-term persistent infection within granulomatous structures. The DosRS-DosT/DevRS-Rv2027c, and MprAB two-component signal transduction systems have previously been implicated in aspects of persistent infection by M. tuberculosis and are known to be responsive to conditions likely to be found within the granuloma. Here, we describe initial characterization of a locus (Rv0081-Rv0088) encoding components of a predicted formate hydrogenylase enzyme complex that is directly regulated by DosR/DevR and MprA, and the product of the first gene in this operon, Rv0081. In particular, we demonstrate that Rv0081 negatively regulates its own expression and that of downstream genes by binding an inverted repeat element in its upstream region. In contrast, DosR/DevR and MprA positively regulate Rv0081 expression by binding to recognition sequences that either partially or completely overlap that recognized by Rv0081, respectively. Expression of Rv0081 initiates from two promoter elements; one promoter located downstream of the DosR/DevR binding site but overlapping the sequence recognized by both Rv0081 and MprA and another promoter downstream of the DosR/DevR, Rv0081, and MprA binding sites. Interestingly, Rv0081 represses Rv0081 and downstream determinants following activation of DosRS-DosT/DevRS-Rv2027c by nitric oxide, suggesting that expression of this locus is complex and subject to multiple levels of regulation. Based on this and other published information, a model is proposed detailing Rv0081-Rv0088 expression by these transcription factors within particular growth environments. PMID- 21821775 TI - Evolutionary history and functional characterization of three large genes involved in sporulation in Bacillus cereus group bacteria. AB - The Bacillus cereus group of bacteria is a group of closely related species that are of medical and economic relevance, including B. anthracis, B. cereus, and B. thuringiensis. Bacteria from the Bacillus cereus group encode three large, highly conserved genes of unknown function (named crdA, crdB, and crdC) that are composed of 16 to 35 copies of a repeated domain of 132 amino acids at the protein level. Bioinformatic analysis revealed that there is a phylogenetic bias in the genomic distribution of these genes and that strains harboring all three large genes mainly belong to cluster III of the B. cereus group phylogenetic tree. The evolutionary history of the three large genes implicates gain, loss, duplication, internal deletion, and lateral transfer. Furthermore, we show that the transcription of previously identified antisense open reading frames in crdB is simultaneously regulated with its host gene throughout the life cycle in vitro, with the highest expression being at the onset of sporulation. In B. anthracis, different combinations of double- and triple-knockout mutants of the three large genes displayed slower and less efficient sporulation processes than the parental strain. Altogether, the functional studies suggest an involvement of these three large genes in the sporulation process. PMID- 21821776 TI - Medicago truncatula CYP716A12 is a multifunctional oxidase involved in the biosynthesis of hemolytic saponins. AB - Saponins, a group of glycosidic compounds present in several plant species, have aglycone moieties that are formed using triterpenoid or steroidal skeletons. In spite of their importance as antimicrobial compounds and their possible benefits for human health, knowledge of the genetic control of saponin biosynthesis is still poorly understood. In the Medicago genus, the hemolytic activity of saponins is related to the nature of their aglycone moieties. We have identified a cytochrome P450 gene (CYP716A12) involved in saponin synthesis in Medicago truncatula using a combined genetic and biochemical approach. Genetic loss-of function analysis and complementation studies showed that CYP716A12 is responsible for an early step in the saponin biosynthetic pathway. Mutants in CYP716A12 were unable to produce hemolytic saponins and only synthetized soyasaponins, and were thus named lacking hemolytic activity (lha). In vitro enzymatic activity assays indicate that CYP716A12 catalyzes the oxidation of beta amyrin and erythrodiol at the C-28 position, yielding oleanolic acid. Transcriptome changes in the lha mutant showed a modulation in the main steps of triterpenic saponin biosynthetic pathway: squalene cyclization, beta-amyrin oxidation, and glycosylation. The analysis of CYP716A12 expression in planta is reported together with the sapogenin content in different tissues and stages. This article provides evidence for CYP716A12 being a key gene in hemolytic saponin biosynthesis. PMID- 21821777 TI - Do TRPC-like currents and G protein-coupled receptors interact to facilitate myogenic tone development? AB - The objective of this study was to determine whether G(q/11)-coupled receptor activation can enhance the mechanosensitivity of a canonical transient receptor potential (TRPC)-like current and consequently the myogenic responsiveness of rat anterior cerebral arteries. Initial patch-clamp experiments revealed the presence of a basal cation current in isolated smooth muscle cells that displayed evidence of double rectification, which was blocked by trivalent cations (Gd(3+) and La(3+)). PCR analysis identified the expression of TRPC1, 3, 6 and 7 mRNA and, characteristic of TRPC-like current, the whole-cell conductance was insensitive to a Na(+)-dependent transport (amiloride), TRP vanilloid (ruthenium red), and chloride channel (DIDS, niflumic acid, and flufenamate) inhibitors. One notable exception was tamoxifen, which elicited a dual effect, blocking or activating the TRPC-like current at 1 and 10 MUM, respectively. This TRPC-like current was augmented by constrictor agonists (uridine 5'-triphosphate and U46619) or hyposmotic challenge (303 to 223 mOsm/l), a mechanical stimulus. Although each stimulus was effective alone, smooth muscle cells pretreated with agonist did not augment the whole-cell response to hyposmotic challenge. Consistent with these electrophysiological recordings, functional experiments revealed that neither UTP nor U46619 enhanced the sensitivity of intact cerebral arteries to hyposmotic challenge or elevated intravascular pressure. In summary, this study found no evidence that G(q/11)-coupled receptor activation augments the mechanosensitivity of a TRPC-like current and consequently the myogenic responsiveness of anterior cerebral arteries. PMID- 21821778 TI - Mechanisms of atrial-selective block of Na+ channels by ranolazine: I. Experimental analysis of the use-dependent block. AB - Atrial-selective inhibition of cardiac Na(+) channel current (I(Na)) and I(Na) dependent parameters has been shown to contribute to the safe and effective management of atrial fibrillation. The present study examined the basis for the atrial-selective actions of ranolazine. Whole cell I(Na) was recorded at 15 degrees C in canine atrial and ventricular myocytes and in human embryonic kidney (HEK)-293 cells expressing SCN5A. Tonic block was negligible at holding potentials from -140 to -100 mV, suggesting minimal drug interactions with the closed state. Trains of 40 pulses were elicited over a range of holding potentials to determine use-dependent block. Guarded receptor formalism was used to analyze the development of block during pulse trains. Use-dependent block by ranolazine increased at more depolarized holding potentials, consistent with an interaction of the drug with either preopen or inactivated states, but was unaffected by longer pulse durations between 5 and 200 ms, suggesting a weak interaction with the inactivated state. Block was significantly increased at shorter diastolic intervals between 20 and 200 ms. Responses in atrial and ventricular myocytes and in HEK-293 cells displayed a similar pattern. Ranolazine is an open state blocker that unbinds from closed Na(+) channels unusually fast but is trapped in the inactivated state. Kinetic rates of ranolazine interactions with different states of atrial and ventricular Na(+) channels were similar. Our data suggest that the atrial selectivity of ranolazine is due to a more negative steady-state inactivation curve, less negative resting membrane potential, and shorter diastolic intervals in atrial cells compared with ventricular cells at rapid rates. PMID- 21821779 TI - SDF-1/CXCR4 mediates acute protection of cardiac function through myocardial STAT3 signaling following global ischemia/reperfusion injury. AB - Stromal cell-derived factor-1alpha (SDF-1) has been reported to mediate cardioprotection through the mobilization of stem cells into injured tissue and an increase in local angiogenesis after myocardial infarction. However, little is known regarding whether SDF-1 induces acute protection following global myocardial ischemia/reperfusion (I/R) injury and if so, by what molecular mechanism. SDF-1 binding to its cognate receptor CXCR4 has been shown to activate STAT3 in a variety of cells. STAT3 is a cardioprotective factor and may mediate SDF-1/CXCR4-induced acute protection. We hypothesized that SDF-1 would improve myocardial function through CXCR4-increased STAT3 activation following acute I/R. Isolated mouse hearts were subjected to 25-min global ischemia/40-min reperfusion and divided into groups of 1) vehicle; 2) SDF-1; 3) AMD3100, a CXCR4 inhibitor; 4) SDF-1 + AMD3100; 5) Stattic, a STAT3 inhibitor; 6) SDF-1 + Stattic; 7) cardiomyocyte-restricted ablation of STAT3 (STAT3KO); 8) STAT3KO + SDF-1; 9) Ly294002, an inhibitor of the Akt pathway; and 10) SDF-1 + Ly294002. Reagents were infused into hearts within 5 min before ischemia. SDF-1 administration significantly improved postischemic myocardial functional recovery in a dose dependent manner. Additionally, pretreatment with SDF-1 reduced cardiac apoptotic signaling and increased myocardial STAT3 activation following acute I/R. Inhibition of the SDF-1 receptor CXCR4 neutralized these protective effects by SDF-1 in hearts subjected to I/R. Notably, inhibition of the STAT3 pathway or use of STAT3KO hearts abolished SDF-1-induced acute protection following myocardial I/R. Our results represent the first evidence that the SDF-1/CXCR4 axis upregualtes myocardial STAT3 activation and, thereby, mediates acute cardioprotection in response to global I/R. PMID- 21821780 TI - Mechanisms of atrial-selective block of Na+ channels by ranolazine: II. Insights from a mathematical model. AB - Block of Na(+) channel conductance by ranolazine displays marked atrial selectivity that is an order of magnitude higher that of other class I antiarrhythmic drugs. Here, we present a Markovian model of the Na(+) channel gating, which includes activation-inactivation coupling, aimed at elucidating the mechanisms underlying this potent atrial selectivity of ranolazine. The model incorporates experimentally observed differences between atrial and ventricular Na(+) channel gating, including a more negative position of the steady-state inactivation curve in atrial versus ventricular cells. The model assumes that ranolazine requires a hydrophilic access pathway to the channel binding site, which is modulated by both activation and inactivation gates of the channel. Kinetic rate constants were obtained using guarded receptor analysis of the use dependent block of the fast Na(+) current (I(Na)). The model successfully reproduces all experimentally observed phenomena, including the shift of channel availability, the sensitivity of block to holding or diastolic potential, and the preferential block of slow versus fast I(Na.) Using atrial and ventricular action potential-shaped voltage pulses, the model confirms significantly greater use dependent block of peak I(Na) in atrial versus ventricular cells. The model highlights the importance of action potential prolongation and of a steeper voltage dependence of the time constant of unbinding of ranolazine from the atrial Na(+) channel in the development of use-dependent I(Na) block. Our model predictions indicate that differences in channel gating properties as well as action potential morphology between atrial and ventricular cells contribute equally to the atrial selectivity of ranolazine. The model indicates that the steep voltage dependence of ranolazine interaction with the Na(+) channel at negative potentials underlies the mechanism of the predominant block of I(Na) in atrial cells by ranolazine. PMID- 21821782 TI - 19,20-EpDPE, a bioactive CYP450 metabolite of DHA monoacyglyceride, decreases Ca2+ sensitivity in human pulmonary arteries. AB - The aim of this study was to investigate the effect of docosahexaenoic acid monoacylglyceride (MAG-DHA) on human pulmonary arterial tone. Tension measurements on pulmonary arterial tissues demonstrated that MAG-DHA reduced U 46619-induced tone, which is highly sensitive to the H-1152 inhibitor. Results also showed that MAG-DHA treatments decreased RhoA activity levels, which in turn inactivated the Rho-kinase pathway, leading to a reduction in U-46619-induced Ca(2+) sensitivity of permeabilized pulmonary artery smooth muscle cells. According to the mechanical responses assessing U-46619-induced Ca(2+) sensitivity in the absence or presence of 3 MUM MAG-DHA, MAG-DHA plus 1 MUM N methylsulfonyl-6-(2-propargyloxyphenyl) hexanamide (MS-PPOH, a cytochrome P-450 epoxygenase inhibitor) and 300 nM 19,20-epoxydocosapentaenoic acid (a cytochrome P-450 epoxygenase-dependent DHA metabolite), our data suggest that the MAG-DHA is metabolized in a bioactive epoxymetabolite. This epoxyeicosanoid in turn decreases active tone and Ca(2+) sensitivity of smooth muscles cells through an inhibition of the Rho-kinase pathway. Together, these data provide primary evidence regarding the mode of action of MAG-DHA in human pulmonary arteries and suggest that this compound may be of pharmacological interest in patients with pulmonary hypertension to generate intracellular bioactive metabolites. PMID- 21821781 TI - Sex differences in baroreflex sensitivity, heart rate variability, and end organ damage in the TGR(mRen2)27 rat. AB - The aim of this investigation was to evaluate sex differences in baroreflex and heart rate variability (HRV) dysfunction and indexes of end-organ damage in the TG(mRen2)27 (Ren2) rat, a model of renin overexpression and tissue renin angiotensin-aldosterone system overactivation. Blood pressure (via telemetric monitoring), blood pressure variability [BPV; SD of systolic blood pressure (SBP)], spontaneous baroreflex sensitivity, HRV [HRV Triangular Index (HRV-TI), standard deviation of the average NN interval (SDNN), low and high frequency power (LF and HF, respectively), and Poincare plot analysis (SD1, SD2)], and cardiovascular function (pressure-volume loop analysis and proteinuria) were evaluated in male and female 10-wk-old Ren2 and Sprague Dawley rats. The severity of hypertension was greater in Ren2 males (R2-M) than in Ren2 females (R2-F). Increased BPV, suppression of baroreflex gain, decreased HRV, and associated end organ damage manifested as cardiac dysfunction, myocardial remodeling, elevated proteinuria, and tissue oxidative stress were more pronounced in R2-M compared with R2-F. During the dark cycle, HRV-TI and SDNN were negatively correlated with SBP within R2-M and positively correlated within R2-F; within R2-M, these indexes were also negatively correlated with end-organ damage [left ventricular hypertrophy (LVH)]. Furthermore, within R2-M only, LVH was strongly correlated with indexes of HRV representing predominantly vagal (HF, SD1), but not sympathetic (LF, SD2), variability. These data demonstrated relative protection in females from autonomic dysfunction and end-organ damage associated with elevated blood pressure in the Ren2 model of hypertension. PMID- 21821783 TI - Chewing reduces sympathetic nervous response to stress and prevents poststress arrhythmias in rats. AB - Reducing stress is important in preventing sudden death in patients with cardiovascular disease, as stressful events may cause autonomic imbalance and trigger fatal arrhythmias. Since chewing has been shown to inhibit stress-induced neuronal responses in the hypothalamus, we hypothesized that chewing could ameliorate stress-induced autonomic imbalance and prevent arrhythmias. To test this hypothesis, we analyzed changes in radiotelemetered electrocardiograms in rats that were allowed to chew a wooden stick during a 1-h period of immobilization stress. Chewing significantly reduced the occurrence of ventricular premature beats (VPBs) and complex ventricular ectopy after immobilization and prevented stress-induced prolongation of the QT interval of VPBs throughout the 10-h experimental period. It also prevented prolongation of the QRS complex and fluctuations in the QT interval in normal sinus rhythm beats preceding VPBs during both immobilization and in the poststress period. Fast Fourier transform-based spectral analysis of heart-rate variability further showed that chewing significantly inhibited the stress-induced increase in the power ratio of low-to-high frequency activity (LF/HF: a marker of sympathetic activity) during immobilization and in addition was associated with blunting of the stress-induced increase in plasma noradrenaline observed at the termination of immobilization. Similar suppressive effects on the occurrence of VPBs and the LF/HF were observed in rats that were administered the beta-adrenergic blocker propranolol before immobilization. These results indicate that chewing can ameliorate sympathetic hyperactivity during stress and prevent poststress arrhythmias and suggest that chewing may provide a nonpharmacological and cost effective treatment option for patients with a high risk of stress-induced fatal arrhythmia. PMID- 21821784 TI - Intermittent hypobaric hypoxia improves postischemic recovery of myocardial contractile function via redox signaling during early reperfusion. AB - Intermittent hypobaric hypoxia (IHH) protects hearts against ischemia-reperfusion (I/R) injury, but the underlying mechanisms are far from clear. ROS are paradoxically regarded as a major cause of myocardial I/R injury and a trigger of cardioprotection. In the present study, we investigated whether the ROS generated during early reperfusion contribute to IHH-induced cardioprotection. Using isolated perfused rat hearts, we found that IHH significantly improved the postischemic recovery of left ventricular (LV) contractile function with a concurrent reduction of lactate dehydrogenase release and myocardial infarct size (20.5 +/- 5.3% in IHH vs. 42.1 +/- 3.8% in the normoxic control, P < 0.01) after I/R. Meanwhile, IHH enhanced the production of protein carbonyls and malondialdehyde, respective products of protein oxidation and lipid peroxidation, in the reperfused myocardium and ROS generation in reperfused cardiomyocytes. Such effects were blocked by the mitochondrial ATP-sensitive K(+) channel inhibitor 5-hydroxydecanoate. Moreover, the IHH-improved postischemic LV performance, enhanced phosphorylation of PKB (Akt), PKC-epsilon, and glycogen synthase kinase-3beta, as well as translocation of PKC-epsilon were not affected by applying H(2)O(2) (20 MUmol/l) during early reperfusion but were abolished by the ROS scavengers N-(2-mercaptopropionyl)glycine (MPG) and manganese (III) tetrakis (1-methyl-4-pyridyl)porphyrin. Furthermore, IHH-reduced lactate dehydrogenase release and infarct size were reversed by MPG. Consistently, inhibition of Akt with wortmannin and PKC-epsilon with epsilonV1-2 abrogated the IHH-improved postischemic LV performance. These findings suggest that IHH-induced cardioprotection depends on elevated ROS production during early reperfusion. PMID- 21821785 TI - Scintillation proximity assay of arginine methylation. AB - Methylation of arginine residues, catalyzed by protein arginine methyltransferases (PRMTs), is one important protein posttranslational modification involved in epigenetic regulation of gene expression. A fast and effective assay for PRMT can provide valuable information for dissecting the biological functions of PRMTs, as well as for screening small-molecule inhibitors of arginine methylation. Currently, among the methods used for PRMT activity measurement, many contain laborious separation procedures, which restrict the applications of these assays for high-throughput screening (HTS) in drug discovery. The authors report here a mix-and-measure method to measure PRMT activity based on the principle of scintillation proximity assay (SPA). In this assay, (3)H-AdoMet was used as methyl donor, and biotin-modified histone H4 peptide served as a methylation substrate. Following the methylation reaction catalyzed by PRMTs, streptavidin-coated SPA beads were added to the reaction solution, and SPA signals were detected by a MicroBeta scintillation counter. No separation step is needed, which simplifies the assay procedure and greatly enhances the assay speed. Particularly, the miniaturization and robustness suggest that this method is suited for HTS of PRMT inhibitors. PMID- 21821786 TI - Benzotriazoles and indazoles are scaffolds with biological activity against Entamoeba histolytica. AB - Parasitic infections caused by Entamoeba histolytica are still major threats against public health, especially in developing countries. Although current therapies exist, the problems associated with parasite resistance and negative side effects make it imperative to search for new therapeutic agents. A systematic scaffold analysis reported herein of a public database containing 474 antiamoebic compounds reveals that benzimidazole is the most active scaffold reported thus far. To gain insights into the antiamoebic activity of novel compounds, the authors report herein the biological activity of 12 compounds, including benzotriazole and indazole derivatives, scaffolds not previously tested against E. histolytica. Compounds with the benzotriazole and indazole scaffolds showed low micromolar activity (IC(50) = 0.304 and 0.339 uM) and are more active than metronidazole, which is the drug of choice used for the treatment of amebiosis. The novel compounds have similar properties to approved drugs. Compounds with novel scaffolds represent promising starting points of an optimization program against E. histolytica. PMID- 21821787 TI - In silico-based structural analysis of arylthiophene derivatives for FTase inhibitory activity, hERG, and other toxic effects. AB - In the present investigation, the authors have performed an in silico-based analysis on a series of arylthiophene derivatives for the determination of their structural features responsible for farnesyltransferase (FTase) inhibitory activity, hERG blocking activity, and toxicity by quantitative structure-activity relationship and pharmacophore analysis techniques. The statistically significant models derived through multiple linear regression analysis were validated by different validation methods. The applicability of the descriptors contributed in the selected models show that the polar and polarizable properties on the van der Waals (vdW) surface area of the molecules are important for the FTase inhibitory and hERG blocking activities, while being detrimental for the toxicity of the molecules. It is interesting to note that the topological properties, molecular flexibility, and connectivity of the molecules are positively correlated to all the activities (FTase inhibition, hERG blocking, and toxicity). This implies that the flexibility of the molecules is the common feature for interaction in all targets, whereas the presence of polar groups on the molecular surface (vdW) is a determinant for the favorable (FTase inhibition) or unwanted effect (hERG blocking and toxicity) of the molecules. The pharmacophore analysis of the molecules demonstrated that the aromatic/hydrophobicity and polarizability features are important pharmacophore contours favorable for these activities. PMID- 21821788 TI - Robust statistics show no evidence for a relationship between fiber density and memory performance. PMID- 21821790 TI - Retraction for Lipardi and Paterson, "Identification of an RNA-dependent RNA polymerase in Drosophila involved in RNAi and transposon suppression". PMID- 21821789 TI - Retrotransposons that maintain chromosome ends. AB - Reverse transcriptases have shaped genomes in many ways. A remarkable example of this shaping is found on telomeres of the genus Drosophila, where retrotransposons have a vital role in chromosome structure. Drosophila lacks telomerase; instead, three telomere-specific retrotransposons maintain chromosome ends. Repeated transpositions to chromosome ends produce long head to tail arrays of these elements. In both form and function, these arrays are analogous to the arrays of repeats added by telomerase to chromosomes in other organisms. Distantly related Drosophila exhibit this variant mechanism of telomere maintenance, which was established before the separation of extant Drosophila species. Nevertheless, the telomere-specific elements still have the hallmarks that characterize non-long terminal repeat (non-LTR) retrotransposons; they have also acquired characteristics associated with their roles at telomeres. These telomeric retrotransposons have shaped the Drosophila genome, but they have also been shaped by the genome. Here, we discuss ways in which these three telomere specific retrotransposons have been modified for their roles in Drosophila chromosomes. PMID- 21821792 TI - Selection of HSV capsids for envelopment involves interaction between capsid surface components pUL31, pUL17, and pUL25. AB - During egress from the nucleus, HSV capsids that contain DNA (termed C capsids) are preferentially enveloped at the inner nuclear membrane over capsid types lacking DNA. Using coimmunoprecipitation and biochemical analyses of wild-type and mutant capsids, we identify an interaction between a complex of pU(L)17/pU(L)25, termed the C capsid-specific complex (CCSC), and pU(L)31, a component of the nuclear egress complex (NEC). We also show that the interactions between these components are dependent on expression of all three proteins but occur independently of the pU(L)31 interacting protein and NEC component pU(L)34, as well as a kinase encoded by U(S)3 that phosphorylates both pU(L)31 and pU(L)34. The interaction between the CCSC and pU(L)31 in the NEC suggests a mechanism to conserve viral resources by promoting assembly of only those viral particles with the potential to become infectious. PMID- 21821793 TI - Efficient generation of transgene-free human induced pluripotent stem cells (iPSCs) by temperature-sensitive Sendai virus vectors. AB - After the first report of induced pluripotent stem cells (iPSCs), considerable efforts have been made to develop more efficient methods for generating iPSCs without foreign gene insertions. Here we show that Sendai virus vector, an RNA virus vector that carries no risk of integrating into the host genome, is a practical solution for the efficient generation of safer iPSCs. We improved the Sendai virus vectors by introducing temperature-sensitive mutations so that the vectors could be easily removed at nonpermissive temperatures. Using these vectors enabled the efficient production of viral/factor-free iPSCs from both human fibroblasts and CD34(+) cord blood cells. Temperature-shift treatment was more effective in eliminating remaining viral vector-related genes. The resulting iPSCs expressed human embryonic stem cell markers and exhibited pluripotency. We suggest that generation of transgene-free iPSCs from cord blood cells should be an important step in providing allogeneic iPSC-derived therapy in the future. PMID- 21821794 TI - Phosphatidylinositol monophosphate-binding interface in the oomycete RXLR effector AVR3a is required for its stability in host cells to modulate plant immunity. AB - The oomycete pathogen Phytophthora infestans causes potato late blight, one of the most economically damaging plant diseases worldwide. P. infestans produces AVR3a, an essential modular virulence effector with an N-terminal RXLR domain that is required for host-cell entry. In host cells, AVR3a stabilizes and inhibits the function of the E3 ubiquitin ligase CMPG1, a key factor in host immune responses including cell death triggered by the pathogen-derived elicitor protein INF1 elicitin. To elucidate the molecular basis of AVR3a effector function, we determined the structure of Phytophthora capsici AVR3a4, a close homolog of P. infestans AVR3a. Our structural and functional analyses reveal that the effector domain of AVR3a contains a conserved, positively charged patch and that this region, rather than the RXLR domain, is required for binding to phosphatidylinositol monophosphates (PIPs) in vitro. Mutations affecting PIP binding do not abolish AVR3a recognition by the resistance protein R3a but reduce its ability to suppress INF1-triggered cell death in planta. Similarly, stabilization of CMPG1 in planta is diminished by these mutations. The steady state levels of non-PIP-binding mutant proteins in planta are reduced greatly, although these proteins are stable in vitro. Furthermore, overexpression of a phosphatidylinositol phosphate 5-kinase results in reduction of AVR3a levels in planta. Our results suggest that the PIP-binding ability of the AVR3a effector domain is essential for its accumulation inside host cells to suppress CMPG1 dependent immunity. PMID- 21821797 TI - P2X(7) is a scavenger receptor for apoptotic cells in the absence of its ligand, extracellular ATP. AB - Phagocytosis of apoptotic cells is essential during development and tissue remodeling. Our previous study has shown that the P2X(7) receptor regulates phagocytosis of nonopsonized particles and bacteria. In this study, we demonstrate that P2X(7) also mediates phagocytosis of apoptotic lymphocytes and neuronal cells by human monocyte-derived macrophages under serum-free conditions. ATP inhibited this process to a similar extent as observed with cytochalasin D. P2X(7)-transfected HEK-293 cells acquired the ability to phagocytose apoptotic lymphocytes. Injection of apoptotic thymocytes into the peritoneal cavity of wild type mice resulted in their phagocytosis by macrophages, but injection of ATP prior to thymocytes markedly decreased this uptake. In contrast, ATP failed to inhibit phagocytosis of apoptotic thymocytes in vivo by P2X(7)-deficient peritoneal macrophages. The surface expression of P2X(7) on phagocytes increased significantly during phagocytosis of either beads or apoptotic cells. A peptide screen library containing 24 biotin-conjugated peptides mimicking the extracellular domain of P2X(7) was used to evaluate the binding profile to beads, bacteria, and apoptotic cells. One peptide showed binding to all particles and cell membrane lipids. Three other cysteine-containing peptides uniquely bound the surface of apoptotic cells but not viable cells, whereas substitution of alanine for cysteine abolished peptide binding. Several thiol-reactive compounds including N-acetyl-L-cysteine abolished phagocytosis of apoptotic SH-SY5Y cells by macrophages. These data suggest that the P2X(7) receptor in its unactivated state acts like a scavenger receptor, and its extracellular disulphide bonds play an important role in direct recognition and engulfment of apoptotic cells. PMID- 21821796 TI - Tolerance induced by apoptotic antigen-coupled leukocytes is induced by PD-L1+ and IL-10-producing splenic macrophages and maintained by T regulatory cells. AB - Ag-specific tolerance is a highly desired therapy for immune-mediated diseases. Intravenous infusion of protein/peptide Ags linked to syngeneic splenic leukocytes with ethylene carbodiimide (Ag-coupled splenocytes [Ag-SP]) has been demonstrated to be a highly efficient method for inducing peripheral, Ag-specific T cell tolerance for treatment of autoimmune disease. However, little is understood about the mechanisms underlying this therapy. In this study, we show that apoptotic Ag-SP accumulate in the splenic marginal zone, where their uptake by F4/80(+) macrophages induces production of IL-10, which upregulates the expression of the immunomodulatory costimulatory molecule PD-L1 that is essential for Ag-SP tolerance induction. Ag-SP infusion also induces T regulatory cells that are dispensable for tolerance induction but required for long-term tolerance maintenance. Collectively, these results indicate that Ag-SP tolerance recapitulates how tolerance is normally maintained in the hematopoietic compartment and highlight the interplay between the innate and adaptive immune systems in the induction of Ag-SP tolerance. To our knowledge, we show for the first time that tolerance results from the synergistic effects of two distinct mechanisms, PD-L1-dependent T cell-intrinsic unresponsiveness and the activation of T regulatory cells. These findings are particularly relevant as this tolerance protocol is currently being tested in a Phase I/IIa clinical trial in new-onset relapsing-remitting multiple sclerosis. PMID- 21821799 TI - Allogeneic HLA-A*02-restricted WT1-specific T cells from mismatched donors are highly reactive but show off-target promiscuity. AB - T cells recognizing tumor-associated Ags such as Wilms tumor protein (WT1) are thought to exert potent antitumor reactivity. However, no consistent high-avidity T cell responses have been demonstrated in vaccination studies with WT1 as target in cancer immunotherapy. The aim of this study was to investigate the possible role of negative thymic selection on the avidity and specificity of T cells directed against self-antigens. T cell clones directed against the HLA-A*0201 binding WT1(126-134) peptide were generated from both HLA-A*02-positive (self-HLA restricted) and HLA-A*02-negative [nonself (allogeneic) HLA [allo-HLA] restricted] individuals by direct ex vivo isolation using tetramers or after in vitro priming and selection. The functional avidity and specificity of these T cell clones was analyzed in-depth. Self-HLA-restricted WT1-specific clones only recognized WT1(126-134) with low avidities. In contrast, allo-HLA-restricted WT1 clones exhibited profound functional reactivity against a multitude of HLA-A*02 positive targets, even in the absence of exogenously loaded WT1 peptide, indicative of Ag-binding promiscuity. To characterize this potential promiscuity, reactivity of the T cell clones against 400 randomly selected HLA-A*0201-binding peptides was investigated. The self-HLA-restricted WT1-specific T cell clones only recognized the WT1 peptide. In contrast, the allo-HLA-restricted WT1 reactive clones recognized besides WT1 various other HLA-A*0201-binding peptides. In conclusion, allogeneic HLA-A*02-restricted WT1-specific T cells isolated from mismatched donors may be more tumor-reactive than their autologous counterparts but can show specific off-target promiscuity of potential clinical importance. As a result of this, administration of WT1-specific T cells generated from HLA mismatched donors should be performed with appropriate precautions against potential off-target effects. PMID- 21821798 TI - Translation of HLA-HIV associations to the cellular level: HIV adapts to inflate CD8 T cell responses against Nef and HLA-adapted variant epitopes. AB - Strong statistical associations between polymorphisms in HIV-1 population sequences and carriage of HLA class I alleles have been widely used to identify possible sites of CD8 T cell immune selection in vivo. However, there have been few attempts to prospectively and systematically test these genetic hypotheses arising from population-based studies at a cellular, functional level. We assayed CD8 T cell epitope-specific IFN-gamma responses in 290 individuals from the same cohort, which gave rise to 874 HLA-HIV associations in genetic analyses, taking into account autologous viral sequences and individual HLA genotypes. We found immunological evidence for 58% of 374 associations tested as sites of primary immune selection and identified up to 50 novel HIV-1 epitopes using this reverse genomics approach. Many HLA-adapted epitopes elicited equivalent or higher magnitude IFN-gamma responses than did the nonadapted epitopes, particularly in Nef. At a population level, inclusion of all of the immunoreactive variant CD8 T cell epitopes in Gag, Pol, Nef, and Env suggested that HIV adaptation leads to an inflation of Nef-directed immune responses relative to other proteins. We concluded that HLA-HIV associations mark viral epitopes subject to CD8 T cell selection. These results can be used to guide functional studies of specific epitopes and escape mutations, as well as to test, train, and evaluate analytical models of viral escape and fitness. The inflation of Nef and HLA-adapted variant responses may have negative effects on natural and vaccine immunity against HIV and, therefore, has implications for diversity coverage approaches in HIV vaccine design. PMID- 21821800 TI - Lack of Th17 cell generation in patients with severe burn injuries. AB - Immunodeficient patients with severe burn injuries are extremely susceptible to infection with Candida albicans. In addition to Th1 cells, IL-17-producing CD4(+) T cells (Th17 cells) have recently been described as an important effector cell in host anti-Candida resistance. In this study, therefore, we tried to induce Th17 cells in cultures of severely burned patient PBMC by stimulation with the C. albicans Ag (CAg). In the results, the biomarkers for Th17 cells (IL-17 production and intracellular expression of IL-17 and retinoic acid receptor related orphan receptor gammat) were not displayed by burn patient PBMC stimulated with CAg, whereas these biomarkers of Th17 cells were detected in cultures of healthy donor PBMC stimulated with CAg. Burn patient sera were shown to be inhibitory on CAg-stimulated Th17 cell generation in healthy donor PBMC cultures; however, Th17 cells were induced by CAg in healthy donor PBMC cultures supplemented with burn patient sera that were previously treated with anti-IL-10 mAb. Also, the biomarkers of Th17 cells were not induced by CAg in healthy donor PBMC cultures supplemented with rIL-10. IL-10 was detected in serum specimens derived from severely burned patients. These results indicate that Th17 cells are not generated in burn patient PBMC cultures supplemented with CAg. IL-10, produced in response to burn injuries, is shown to be inhibitory on Th17 cell generation. The high susceptibility of severely burned patients to C. albicans infection might be influenced if burn-associated IL-10 production is intervened. PMID- 21821801 TI - Pulmonary collectins play distinct roles in host defense against Mycobacterium avium. AB - Pulmonary collectins, surfactant protein A (SP-A) and surfactant protein D (SP D), play important roles in the innate immunity of the lung. Mycobacterium avium is one of the well-known opportunistic pathogens that can replicate within macrophages. We examined the effects of pulmonary collectins in host defense against M. avium infection achieved via direct interaction between bacteria and collectins. Although both pulmonary collectins bound to M. avium in a Ca(2+) dependent manner, these collectins revealed distinct ligand-binding specificity and biological activities. SP-A and SP-D bound to a methoxy group containing lipid and lipoarabinomannan, respectively. Binding of SP-D but not SP-A resulted in agglutination of M. avium. A chimeric protein with the carbohydrate recognition domain of SP-D, which chimera revealed a bouquet-like arrangement similar to SP-A, also agglutinated M. avium. The ligand specificity of the carbohydrate recognition domain of SP-D seems to be necessary for agglutination activity. The binding of SP-A strongly inhibited the growth of M. avium in culture media. Although pulmonary collectins did not increase membrane permeability of M. avium, they attenuated the metabolic rate of the bacteria. Observations under a scanning electron microscope revealed that SP-A almost completely covers bacterial surfaces, whereas SP-D binds to certain areas like scattered dots. These observations suggest that a distinct binding pattern of collectins correlates with the difference of their biological activities. Furthermore, the number of bacteria phagocytosed by macrophages was significantly increased in the presence of SP-D. These data indicate that pulmonary collectins play critical roles in host defense against M. avium. PMID- 21821803 TI - Use of visible and near-infrared spectroscopy to predict pork longissimus lean color stability. AB - This study evaluated the use of visible and near-infrared (VISNIR) spectroscopy to predict lean color stability in pork loin chops. Spectra were collected immediately after and approximately 1 h after rib removal on 1,208 loins. Loins were aged for 14 d before a 2.54-cm chop was placed in simulated retail display. Spectra were collected on aged loins immediately after removal from the vacuum package and on chops 10 min after cutting. Instrumental color measurements [L*, a*, b*, hue angle, chroma, and E (overall color change)] were determined on d 0, 1, 7, 11, and 14 of display. Principal components analysis of display d 0 and 14 values of these traits identified a factor (first principal component; PC1) explaining 67% of the variance that was related to color change. Partial least squares regression was used to develop 3 models to predict PC1 values by using VISNIR spectra collected in the plant, on aged loins, and on chops. Loins with predicted PC1 values less than 0 were classified as having a stable color, whereas values greater than 0 were classified as having a labile lean color. Loins classified as stable by the in-plant model had smaller (P < 0.05) L* values than those classified as labile. Hue angle and DeltaE values were less (P < 0.05) and a* and chroma values were greater (P < 0.05) after d 7 of display in loins predicted to have a stable color than in loins predicted to have a labile lean color. Similarly, chops from loins classified as stable using the aged loin model had smaller (P < 0.05) L* values than those from loins classified as labile. Furthermore, loins predicted to be stable had smaller (P < 0.05) hue angle and DeltaE values and greater (P < 0.05) a* and chroma values after d 7 of display than did loins predicted to be labile. Results for the chop model were similar to those from the 2 loin models. Chops predicted to have a stable lean color had smaller (P < 0.05) L* values than did those predicted to have a labile lean color. Chops classified as stable had smaller (P < 0.05) hue angle and DeltaE values and greater (P < 0.05) a* and chroma values after d 7 of display compared with chops classified as labile. All 3 models effectively segregated chops based on color stability, particularly with regard to redness. Regardless of the model being used, d 14 display values for a*, hue angle, and DeltaE in loins classified as stable were similar to the d 7 values of loins classified as labile. Thus, these results suggest that VISNIR spectroscopy would be an effective technology for sorting pork loins with regard to lean color stability. PMID- 21821804 TI - Technical note: Determination of cell-specific gene expression in bovine skeletal muscle tissue using laser microdissection and reverse-transcription quantitative polymerase chain reaction. AB - Skeletal muscle is a very heterogeneous tissue consisting of diverse cell types with specific transcription profiles. Therefore, the measured mRNA abundance of a certain cell type marker is influenced by the transcriptional activity as well as by the usually unknown number of contributing cells in the sample. In studies on the transcriptional activity of adipogenic genes, as indicators for the development of intramuscular adipocytes, an altered number of adipocytes or respective progenitor cells can mask changes in transcriptional activity. To overcome this problem, we started to use laser microdissection to isolate RNA of adipocytes and muscle fibers separately for downstream analysis. Even muscle fiber types can be collected and analyzed separately. Laser microdissection in combination with biopsy techniques enables gene expression studies of particular cell types during the life cycle of an animal. First experiences using laser microdissection for adipogenic gene expression studies in bovine skeletal muscle are described, and the influence of sample preparation and future challenges are discussed. PMID- 21821805 TI - Reducing concentrated animal feeding operations permitting requirements. AB - Many owners and operators of concentrated animal feeding operations (CAFO) need to secure National Pollutant Discharge Elimination System permits from the federal or state permitting authority. Because of the expense and inconvenience of permit applications, farm groups have challenged revisions to the federal CAFO Rule as well as state regulations claiming selected provisions exceeded the authority of the permitting agency. In 2011, 2 courts responded with decisions that clarify federal and state permitting regulations. Another goal of agricultural groups is to change the regulatory authority of the state from an environmental agency to a department of agriculture. These developments suggest that by altering the permitting authority, CAFO owners and operators may alleviate some of the burdens of the permitting process. PMID- 21821806 TI - Technical note: Modifying Atlantic salmon (Salmo salar) jumping behavior to facilitate innovation of parasitic sea lice control techniques. AB - Industrial salmon farms are reservoirs of parasitic sea lice (Lepeophtheirus salmonis and Caligus spp.), which causes both production inefficiencies and contributes to population-level declines of wild salmon and trout. Current control methods vary in effect and stimulate controversy by the discharge of chemicals into the environment. An alternate control method uses a thin, chemical infused oil layer on the sea surface. As farmed salmon jump through the surface, the treatment makes contact with the lipophilic carapace of sea lice and kills them. To enhance the effectiveness of this method, we tested whether the natural jumping behavior of salmon could be increased and directed. In a 2,000-m(3) experimental sea-cage, we removed the ability of groups of salmon to access the surface for different periods (0 to 48 h) and measured their surface behaviors after the surface became accessible again. Surface removal for 24 and 48 h induced 93% of salmon to jump in the 2 h after surface access was reinstated, a result that differed (P < 0.001) from the shorter duration (0 to 12 h) treatments. Salmon without surface access for 24 and 48 h jumped 2 to 3 times more often (P < 0.001), and made their first jump 2 to 3 times sooner (P = 0.003) on average after surface access became available than salmon in the shorter duration treatments. Our results indicate that removal of surface access for short periods may lead to loss of air from the physostomous swim bladder and cause negative buoyancy. This creates a behavioral drive for salmon to jump, swallow air and fill their swim bladders once surface access is reinstated. By combining the increased jumping behavior induced by this technique with a floating, oil-infused treatment, efficiency of sea lice treatments may be improved and treatment chemicals can be re-collected, thus decreasing environmental pollution. PMID- 21821807 TI - Intake and digestion of whole-crop barley and wheat silages by dairy heifers. AB - The effect of maturity at harvest on the digestibility and intake of large bale silage made from whole-crop barley and wheat when fed to growing heifers was evaluated. Two crops of spring barley (Hordeum distichum cv. Filippa and Kinnan) and 1 of winter wheat (Triticum aestivum cv. Olevin) were harvested at the heading, milk, and dough stages of maturity. The silage was fed to 36 dairy heifers in a balanced crossover experiment with 3 periods and 9 treatments (diets based on 3 crops and 3 stages of maturity), organized into 6 pairs of 3 * 3 Latin squares. No clear relationship was observed between intake and stage of maturity of whole-crop cereal silage, but intake was positively correlated to silage DM content (P < 0.001, r = 0.46) and negatively correlated to NDF content (P < 0.001, r = -0.42). Organic matter digestibility decreased between the heading and milk stages of maturity in all crops (P < 0.001), did not differ between the milk and the dough stages in the 2 barley crops, but increased in the wheat silage (P = 0.034). The NDF digestibility decreased between the heading and milk stages in all crops (P < 0.001), whereas it decreased in 1 barley crop (P < 0.001), increased in the other barley (P = 0.025), and was unchanged in the wheat between the milk and dough stages of maturity. Starch digestibility was less in the 2 barley crops compared with the wheat at the dough stage of maturity (P < 0.001). The feeding value of the whole-crop barley and wheat declined between the heading and milk stages of maturity, but thereafter the effect of maturity on the feeding value was minor. PMID- 21821808 TI - Analysis of the effect of the bovine adenosine triphosphate-binding cassette transporter G2 single nucleotide polymorphism Y581S on transcellular transport of veterinary drugs using new cell culture models. AB - In commercial dairy production, the risk of drug residues and environmental pollutants in milk from ruminants has become an outstanding problem. One of the main determinants of active drug secretion into milk is the ATP-binding cassette transporter G2/breast cancer resistance protein (ABCG2/BCRP). It is located in several organs associated with drug absorption, metabolism, and excretion, and its expression is highly induced during lactation in the mammary gland of ruminants, mice, and humans. As a consequence, potential contamination of milk could expose suckling infants to xenotoxins. In cows, a SNP for this protein affecting quality and quantity of milk production has been described previously (Y581S). In this study, our main purpose was to determine whether this polymorphism has an effect on transcellular transport of veterinary drugs because this could alter substrate pharmacokinetics and milk residues. We stably expressed the wild-type bovine ABCG2 and the Y581S variant in Madin-Darby canine kidney epithelial cells (MDCKII) and MEF3.8 cell lines generating cell models in which the functionality of the bovine transporter could be addressed. Functional studies confirmed the greater functional activity in mitoxantrone accumulation assays for the Y581S variant with a greater relative V(MAX) value (P = 0.040) and showed for the first time that the Y581S variant presents greater transcellular transport of the model ABCG2 substrate nitrofurantoin (P = 0.024) and of 3 veterinary antibiotics, the fluoroquinolone agents enrofloxacin (P = 0.035), danofloxacin (P = 0.001), and difloxacin (P = 0.008), identified as new substrates of the bovine ABCG2. In addition, the inhibitory effect of the macrocyclic lactone ivermectin on the activity of wild-type bovine ABCG2 and the Y581S variant was also confirmed, showing a greater inhibitory potency on the wild-type protein at all the concentrations tested (5 MUM, P = 0.017; 10 MUM, P = 0.001; 25 MUM, P = 0.008; and 50 MUM, P = 0.003). Differential transport activity depending on the genotype together with the differential inhibition pattern might have clinical consequences, including changes in substrate pharmacokinetics (and subsequently pharmacodynamics) and more specifically, changes in secretion of ABCG2 substrates into milk, potentially implying important consequences to veterinary therapeutics. PMID- 21821809 TI - Digestibility of amino acids in corn, corn coproducts, and bakery meal fed to growing pigs. AB - The objectives of this experiment were to determine the apparent ileal digestibility and the standardized ileal digestibility (SID) of CP and AA in bakery meal, corn gluten meal, corn gluten feed, corn germ meal, and hominy feed and to compare these values with the apparent ileal digestibility and SID of CP and AA in corn and distillers dried grains with solubles (DDGS). Eight growing barrows (initial BW: 82.5 +/- 5.5 kg) were randomly allotted to an 8 * 8 Latin square design with 8 diets and 8 periods. Diets contained corn, DDGS, bakery meal, corn gluten meal, corn gluten feed, corn germ meal, or hominy feed as the sole source of protein and AA. An N-free diet was used to measure basal endogenous losses of AA and protein. Pigs were fed experimental diets for eight 7 d periods, with ileal digesta being collected on d 6 and 7 of each period. Results indicated that the SID of Lys in corn gluten meal (78.7%) was greater (P < 0.01) than in DDGS, bakery meal, corn germ meal, and hominy feed (46.0, 48.4, 68.4, and 58.8%, respectively). The SID of all indispensable AA except Arg, Leu, and Met in bakery meal were not different from those in DDGS. The SID of Arg, His, Leu, and Met in corn gluten feed were less (P < 0.01) than in corn, but the SID of all other indispensable AA in corn gluten feed were not different from those in corn. However, for most indispensable AA, the SID in corn gluten feed was not different from the SID in DDGS. The SID of all indispensable AA in corn germ meal, except Arg, His, Leu, and Met, were not different from the SID in corn. Likewise, the SID of all indispensable AA in corn germ meal, except Arg and Leu, were not different from those in DDGS. The SID of Ile, Met, Phe, and Val in hominy feed were less (P < 0.01) than in corn, but the SID of the remaining indispensable AA in hominy feed were not different from the SID of indispensable AA in corn. All indispensable AA in hominy feed also had SID values that were not different from the SID values of AA in DDGS, except for Arg and Lys, which had greater (P < 0.01) SID than in DDGS. In conclusion, bakery meal had SID values of most AA that were less than in corn, but corn gluten meal had SID values for most AA that were greater than the SID of AA in corn, bakery meal, and corn coproducts. PMID- 21821810 TI - Effects of exogenous enzymes in corn-based and Canadian pearl millet-based diets with reduced soybean meal on growth performance, intestinal nutrient digestibility, villus development, and selected microbial populations in broiler chickens. AB - An experiment was conducted to compare a commercial corn-soybean meal diet with a pearl millet diet containing less soybean meal (-27%), alone or in combination with exogenous enzymes, on growth performance, jejunal villus development, ileal CP, and AA digestibility, and cecal microbial populations in broilers. One hundred sixty 1-d-old male Ross 508 broilers (5/cage) were randomly allocated to one of the following dietary treatments: 1) a standard corn-soybean meal control diet (CTL); 2) a pearl millet-soybean meal diet (PM); 3) CTL + exogenous enzymes (CE); and 4) PM + exogenous enzymes (PE) with 8 replicate cages/treatment. The PM and PE diets contained less soybean meal because of greater CP and AA contents of pearl millet. All diets were isonitrogenous and isocaloric. Body weight and feed intake were recorded weekly over 35 d. At d 21 and 35, 8 broilers per treatment were euthanized for sample collection and analyses. Gain-to-feed was greater (P < 0.01) for pearl millet- than corn-based diets. Apparent ileal digestibility (AID) of CP and most AA was similar between corn-based and pearl millet-based diets, and enzyme supplementation improved AID of CP (P < 0.01) and most AA at both d 21 and 35. However, for AID of some AA at d 21, the response to enzyme supplementation was less pronounced in broilers fed pearl millet-based diets than those fed corn-based diets (grain * enzyme, P <= 0.05). The villus was longer (P < 0.01) in broilers fed PM and PE than CTL and CE at d 35. Similarly, at d 35, lactobacilli loads were greater (P < 0.01) in broilers fed PM and PE than CTL and CE. It is concluded that, in comparison with corn, broiler diets formulated with pearl millet require less soybean meal and can be used to improve growth performance traits, intestinal lactobacilli populations, and villus development, whereas enzyme supplementation increases AID of CP and AA. PMID- 21821811 TI - Technical note: Effect of determining baseline plasma urea nitrogen concentrations on subsequent posttreatment plasma urea nitrogen concentrations in 20- to 50-kilogram pigs. AB - Plasma urea N (PUN) has been used as an indicator of AA requirements and efficiency of AA utilization in swine. However, PUN concentrations vary among a population of pigs, even a population with a close range of BW and fed the same diet. Thus, pretreatment or baseline PUN concentrations are used as a covariate to reduce variation of posttreatment PUN. However, this procedure increases experimental costs and stress to the pigs. Data from 14 experiments (26 to 28 d in duration) conducted using PUN as a response variable were compiled into 1 data set. Each experiment had 4 to 6 treatments. The purpose of this technical report was to summarize the effect of determining pretreatment baseline PUN concentrations on subsequent posttreatment PUN concentrations in 20- to 50-kg pigs. In all experiments, pigs were fed corn- and soybean meal-based diets and low-CP diets with various AA additions; pigs were assigned to dietary treatments in a randomized complete block design with a minimum of 4 replicates of 3 to 5 pigs each. Before the start of each experiment, all pigs were fed a common diet for a minimum of 3 d. Blood samples were collected from each pig before allotment to dietary treatments (d 0) and at the end of each experiment. The baseline (d 0) PUN was analyzed as a covariate for posttreatment PUN. Data from each experiment were analyzed without and with baseline PUN in the statistical model. In all experiments combined, there were 768 possible treatment comparisons. The covariate baseline PUN was statistically significant (P < 0.10) in 9 of 14 experiments. However, only 8 treatment differences changed statistical significance as a result of analyzing the data with baseline PUN as a covariate. These 8 treatment differences were in 3 experiments. These results indicate that it is not always necessary to determine baseline PUN concentrations when feeding diets with large differences in AA content. PMID- 21821812 TI - First-pass splanchnic metabolism of dietary cysteine in weanling pigs. AB - Cysteine is a semi-indispensable AA in neonates and is synthesized from the indispensable AA, methionine, by transsulfuration. We previously showed that the gastrointestinal tract (GIT) is a metabolically important site of methionine transsulfuration to cysteine, yet the metabolic fate of dietary cysteine in the GIT has not been established. Cysteine use by gut epithelial cells may play an important role for maintenance of glutathione synthesis and cellular redox function. Our aim was to quantify the extent of gastrointestinal first-pass cysteine metabolism in young pigs. Four-week-old weanling pigs (n = 10) were fed a liquid milk-replacer diet and given an intragastric and intravenous [1 (13)C]cysteine infusion on 2 separate days in a crossover design. Arterial and portal blood samples were collected for cysteine isotopic enrichment by gas chromatography-mass spectrometry and for (13)CO(2) enrichment by isotope ratio mass spectrometry. Our results indicated that dietary cysteine is metabolized during its first-pass splanchnic metabolism, accounting for about 40% of dietary cysteine intake. We also showed that intestinal absorption was the major metabolic fate of dietary cysteine, representing about 75% of intake, indicating that the GIT utilizes 25% of the dietary cysteine intake. Thus, utilization by the GIT represents about one-half (approximately 53%) of the first-pass, splanchnic uptake of dietary cysteine. Moreover, a substantial proportion of dietary splanchnic cysteine metabolism was consumed by the GIT via nonoxidative pathways. We conclude that the gut utilizes 25% of the dietary cysteine intake and that synthesis of mucosal epithelial proteins, such as glutathione and mucin, are a major nonoxidative metabolic fate for cysteine. PMID- 21821813 TI - Use of soybean hulls as a replacement for dry rolled corn in beef cattle feedlot receiving diets. AB - Consecutive receiving studies were used to evaluate the replacement of starch (dry rolled corn; DRC) with a nonforage fiber source (soybean hulls; SBH) on performance, mineral, and blood metabolite status of newly arrived feedlot steer calves. Steers in yr 1 (Y1; 9 pens/diet, 8 to 10 animals/pen) and yr 2 (Y2; 6 pens/diet, 9 to 10 animals/pen) were blocked by weaning management, and then stratified by BW and randomly assigned to pens. Pens were randomly assigned to an oat silage-based diet containing starch (HS) from DRC or digestible fiber (HF) from SBH. Diets were formulated for 12% CP (DM basis) and to meet or exceed NRC (1996) nutrient requirements for Ca, P, and vitamins A and E. Mineral status was assessed in Y1 only via liver biopsies and serum samples collected on d 3 and 28. Mineral concentrations on d 28 were compared using d 3 concentrations as a covariate. Glucose, NEFA, and plasma urea N status were assessed in Y2 only via blood collections on d 0, 3, 7, 14, 28, and 59. Morbidity (<10%) and mortality rates were not different (P > 0.10) between treatments across years. Daily BW gain was similar (P > 0.10) between treatments both during the receiving period and cumulatively across years. Overall, feed intake was greater (P = 0.007) for steers fed HF compared with steers fed HS in Y1, but was not different in Y2 (P = 0.13). Steers consuming the HS diet tended (P = 0.07) to have better BW gain efficiency in Y1 only. Across years, BW gain efficiency and ADG were similar between treatments (P > 0.10), although DMI was greater for steers fed HF (P = 0.003). Based on 2 yr of performance, the calculated ME content of SBH was estimated at 92.5% of the ME value of DRC (2.74 vs. 2.96 Mcal/kg, respectively). Mineral concentrations on d 28 were similar (P > 0.10) for most minerals assayed. There was a steeper (P = 0.005) decline in hepatic Cu concentrations early in the feeding period for steers fed HF, resulting in decreased (P = 0.001) d 28 hepatic concentrations. Hepatic Mn was greater (P = 0.003) in steers fed HF on d 28 as a result of greater (P = 0.006) Mn accumulation during the initial 28 d on feed. Blood metabolites in Y2 (using d 0 values as a covariate) were similar (P > 0.10) across treatments, except for reduced (P = 0.025) plasma urea N concentrations on d 7 and greater (P = 0.050) NEFA concentrations on d 28 for steers fed HS. These studies indicate that the use of SBH in receiving diets can support BW gain similar to the use of DRC. PMID- 21821814 TI - Meta-analysis to predict sweating and respiration rates for Bos indicus, Bos taurus, and their crossbreds. AB - The overall objective of this work was to develop empirical equations from a meta analysis study to be used to implement initial values in a mechanistic heat balance model. The meta-analysis was conducted to 1) develop prediction equations for sweating and respiration rate (SR, g.m(-2).h(-1) and RR, breaths.min(-1), respectively) based on skin and body temperature (T(s) and T(b), degrees C, respectively) for different breed types: Bos indicus, Bos taurus, and their crossbreds, and 2) evaluate the fit of existing SR equations and the SR and RR equations (from objective 1) against independent data sets. Fourteen studies were collected for the SR analysis, 12 for fitting and 2 for evaluation. The fitted SR equations (Thompson model) for the 3 breeds types were B. indicus, SR = 0.085e(0.22.T(s)); B. taurus, SR = 0.75e(0.15.T(s)); and crossbreds, SR = 0.015e(0.25.T(s)). Twenty-three studies were collected for the RR analysis, 20 for fitting and 3 for evaluation. The fitted RR equations for the 3 breed types were B. indicus, RR = -1,660 + 43.8.T(b); B. taurus, RR = -1,385 + 37.T(b); and crossbreds, RR = -2,226 + 59.T(b). Three SR equations (Maia, McArthur, and Gatenby models) from the literature were evaluated against the Thompson model using the 14 studies. The McArthur model predicted SR within the correct range, but with an increased slope bias because the equation was linear and not the correct shape. The Maia model overpredicted SR for all breed types with the greatest overprediction being for crossbreds. The Gatenby model overpredicted SR for B. taurus (root mean square error of prediction = 506 g.m(-2).h(-1)), but was the best predictor for B. indicus. The Thompson model overpredicted SR for B. indicus (root mean square error of prediction ranged from 134 to 265 g.m(-2).h( 1)), but was the best predictor for B. taurus and crossbreds. The Thompson model was a good predictor for RR across all breed types. The meta-analysis showed that the Thompson model outperformed previous models for both RR and SR with the exception of the SR of B. indicus, which was best predicted by the Gatenby model. PMID- 21821815 TI - Identification and characterization of hierarchical structures in dog breeding schemes, a novel method applied to the Norfolk Terrier. AB - Popular sires, a limited population size, and the founder event are widely considered the main reasons for the low genetic diversity observed in many dog breeds. However, these factors have had only a small role in the historic decrease in diversity observed in the Norfolk Terrier breed. We show that the decrease in this breed has been mainly due to large, popular kennels. Dogs from these kennels have, on average, larger genetic contributions to subsequent generations than others. A test for the presence of a popular kennel effect is proposed and applied (P < 0.001). These kennels were found to be the same as nuclei of selection existing in other livestock species. This result revealed a hierarchical structure of dog breeding schemes, with an asymmetric gene flow predominantly from the nuclei toward the main population. Possible reasons for this structure and implications for future population management are discussed. The main reason is probably that the breed type was established by large, popular kennels and that small kennel breeders used their stud dogs to benefit from the achievements of the popular kennels. Many kennels, however, were unable to make their own substantial genetic contributions to the breed. PMID- 21821816 TI - Transcript abundance of hormone receptors, mammalian target of rapamycin pathway related kinases, insulin-like growth factor I, and milk proteins in porcine mammary tissue. AB - Prolactin, glucocorticoids, and insulin are commonly used to induce milk protein synthesis in bovine mammary cell cultures. In addition, administration of GH increases milk yield in dairy cows, likely via the mammalian target of rapamycin (mTOR) pathway and IGF-I synthesis. As such, the hypothesis of this study was that mRNA abundance of hormone receptors, mammalian target of mTOR pathway related kinases, IGF-I, and milk protein-encoding genes increases in the porcine mammary gland in response to greater lactation demand. Selected genes included those encoding for receptors of GH (GHR), insulin (INSR), glucocorticoid (NR3C1), prolactin (PRLR), IGF-I (IGF-I), mTOR (FRAP1), and p70S6 kinases (RPS6KB1), and the milk proteins alpha-lactalbumin (LALBA) and beta-casein (CSN2). Mammary tissue was biopsied from 4 sows on d 110 of gestation (prepartum), d 5 and 17 of lactation, and d 5 after weaning (postweaning), and gene expression was quantified by reverse-transcription quantitative PCR. Compared with prepartum, d 5 of lactation increased (P < 0.001) NR3C1, tended to increase (P = 0.06) GHR, and decreased (P < 0.001) PRLR mRNA abundance. Compared with d 5 of lactation, d 17 of lactation increased PRLR (P < 0.001) and decreased GHR (P < 0.01). Expression of INR and FRAP1 did not differ when comparing either prepartum or d 17 of lactation with d 5 of lactation. Compared with d 17 of lactation, postweaning decreased (P < 0.001) PRLR, did not affect INSR, and increased both IGF-I and GHR (P < 0.05) mRNA abundance. From prepartum to d 17 of lactation, NR3C1 mRNA abundance was positively correlated with CSN2 (r = 0.85; P < 0.001) and LALBA mRNA abundance (r = 0.79; P = 0.002), whereas mRNA abundance of GHR tended to be positively correlated with that of IGF-I (r = 0.46; P = 0.06). In conclusion, expression of the genes NR3C1, PRLR, GHR, and IGF-I changed in the porcine mammary gland during the prepartum to postweaning periods, but only NR3C1 mRNA abundance was positively correlated with expression of CSN2 and LALBA. PMID- 21821817 TI - Chemical composition of growing pigs and its relationship with body tissue composition assessed by X-ray-computed tomography. AB - Ninety hybrid (mainly Large White * Landrace) pigs from 2 experimental replicates were used to study the potential use of computed tomography (CT) as a nondestructive technology for estimating the chemical body composition of growing pigs. Body tissue components (lean, fat, and bone) of 6 live pigs from each sex (boars, gilts, and barrows) were assessed by CT imaging before slaughter at approximately 30, 60, 90, 120, and 150 kg of BW. After slaughter, the empty body components were ground and frozen until analyzed for protein, lipid, ash, and moisture content. Several growth functions were evaluated and the allometric function (Y = aBW(b)), which was evaluated as log(10)chemical component weight = b(0) + b(1)log(10)BW, provided the best fit to the data. For each sex, the allometric coefficient (b(1)) for protein (0.92 to 0.99) was close to but less than 1; for ash (1.03 to 1.12), it was close to but greater than 1; for moisture (0.82 to 0.86), it was less than 1, and for lipid (1.61 to 1.71), it was greater than 1. Deposition rates (change in component weight per unit change in BW) for each chemical component were predicted using derivatives of the function. The mean deposition rates for protein and lipid were 0.141 and 0.286 kg/kg of BW gain, respectively. The deposition rate for protein was generally stable across different BW, whereas that for lipid increased as BW increased. In addition, linear, quadratic, exponential, and logistic functions were fitted to the data to study the relationship between the CT data and chemical components. The linear function was assessed to be the best equation, based on the Bayesian information criterion. The prediction equation for protein (kg) = -1.64 + 0.28 * CT lean (kg), and for lipid (kg) = -0.69 + 1.09 * CT fat (kg), had R(2) values of 0.924 and 0.987, respectively. Sex had no effect (P > 0.05) on the prediction of protein and lipid. The effect of BW was not significant (P > 0.05) for the prediction of lipid, but it was significant (P > 0 0.05) for the prediction of protein. However, the addition of BW to the base prediction equation for protein resulted in an increase of only 0.013 in the R(2) value. It was concluded from this study that CT scanning has great potential as a nondestructive technology for estimating the physical and chemical body composition of pigs. Additional research is required to validate the utility and accuracy of the prediction equations. PMID- 21821818 TI - Camelina meal and crude glycerin as feed supplements for developing replacement beef heifers. AB - Angus * Gelbvieh rotationally crossbred yearling heifers (n = 99, yr 1; n = 105, yr 2) were used in a 2-yr randomized complete block design experiment with repeated measures to determine the effect of feeding camelina biodiesel coproducts (meal and crude glycerin) on serum concentrations of triiodothyronine, thyroxine, insulin, beta-hydroxybutyrate, and glucose, as well as on growth and reproductive performance. Heifers were assigned to 1 of 15 pens, and pens were assigned initially to receive 7.03 k.*heifer(-1).d(-1) of bromegrass hay plus 0.95 kg.heifer(-1).d(-1) of 1 of 3 supplements for 60 d before breeding: 1) control (50% ground corn and 50% soybean meal, as-fed basis); 2) mechanically extracted camelina meal; or 3) crude glycerin (50% soybean meal, 33% ground corn, 15% crude glycerin, 2% corn gluten meal; as-fed basis). Preprandial blood samples were collected via the jugular vein on d 0, 30, and 60 of the feeding period. A 2 injection PGF(2alpha) protocol (d 60 and 70 of the study) was used to synchronize estrus. Heifers were artificially inseminated 12 h after estrus was first detected. Heifers not detected in estrus within 66 h received a GnRH injection and were artificially inseminated. Dietary treatment * sampling period interactions were not detected (P = 0.17 to 0.87). Dietary treatment did not affect BW (P = 0.44 to 0.59) or serum concentrations of thyroxine (P = 0.96), beta-hydroxybutyrate (P = 0.46), glucose (P = 0.59), or insulin (P = 0.44). Serum concentrations of triiodothyronine were greater (P = 0.05) in heifers fed camelina meal. Additionally, dietary treatment did not affect the percentage of heifers detected in estrus before timed AI (P = 0.83), first-service pregnancy rates of those heifers detected in estrus (P = 0.97), or overall first-service pregnancy rates (P = 0.58). Heifers fed camelina meal, however, had greater (P = 0.05) first-service pregnancy rates to timed AI than did heifers fed the control and crude glycerin supplements. The cost per pregnancy was similar for heifers fed the crude glycerin or the control supplement, whereas the cost per pregnancy was the least for heifers fed camelina meal. We conclude that camelina coproducts can replace conventional corn-soybean meal supplements in the diets of developing replacement beef heifers. PMID- 21821819 TI - Opportunities and risks of the proposed FCTC protocol on illicit trade. AB - Illicit trade in tobacco products presents a threat to public health because it undermines the use of tax and price policies, which are among the most effective mechanisms for reducing tobacco consumption. Parties to the WHO Framework Convention on Tobacco Control (FCTC) are in the final stages of negotiating a protocol aimed at strengthening international cooperation in the fight against illicit tobacco trade. While an effective multilateral response to illicit tobacco trade would make a significant contribution to global tobacco control, achieving this through the FCTC forum is challenging. First, while illicit tobacco trade is a health problem, the expertise, experience and capacity needed to combat illicit trade are not traditionally found in health agencies. The development of links with other agencies, both domestic and international, is critical to ensure both an effective response and an efficient use of limited governmental and non-governmental resources. Second, in many parts of the world, the tobacco industry cooperates closely with governments in the combating of illicit trade. This cooperation poses risks for tobacco control, particularly if relationships and norms of cooperation spill over into other areas of FCTC implementation. An examination of the industry's positioning suggests that it sees an opportunity to portray itself as 'legitimate' and 'responsible', a friend of governments, and a way to integrate itself into FCTC processes. This paper makes suggestions for moving forward in this challenging area towards ensuring that the approach taken actually reduces illicit tobacco trade, strengthens tobacco tax policies and does not operate to undermine the FCTC. PMID- 21821820 TI - Motor racing, tobacco company sponsorship, barcodes and alibi marketing. AB - BACKGROUND: Sponsorship of Formula One (F1) motor racing, which has been used as an indirect medium of tobacco advertising for several decades, was prohibited by the 2005 European Union Tobacco Advertising Directive. Most F1 tobacco sponsorship of motor racing in the EU has since ceased, with the exception of the Scuderia Ferrari team, which continues to be funded by Philip Morris. In 2007, the Marlboro logo on Ferrari cars and other race regalia was replaced by an evolving 'barcode' design, which Ferrari later claimed was part of the livery of the car, and not a Marlboro advertisement. OBJECTIVE: To determine whether the 'barcode' graphics used by Ferrari represent 'alibi' Marlboro advertising. METHODS: Academic and grey literature, and online tobacco industry document archives, were searched using terms relevant to tobacco marketing and motorsport. RESULTS: Tobacco sponsorship of F1 motor racing began in 1968, and Philip Morris has sponsored F1 teams since 1972. Phillip Morris first used a 'barcode' design, comprising red vertical parallel lines below the word Marlboro on the British Racing Motors F1 car in 1972. Vertical or horizontal 'barcode' designs have been used in this way, latterly without the word Marlboro, ever since. The modern 'barcode' logos occupied the same position on cars and drivers' clothing as conventional Marlboro logos in the past. The shared use of red colour by Marlboro and Ferrari is also recognised by Philip Morris as a means of promoting brand association between Marlboro and Ferrari. CONCLUSION: The Ferrari 'barcode' designs are alibi Marlboro logos and hence constitute advertising prohibited by the 2005 EU Tobacco Advertising Directive. PMID- 21821822 TI - Language in the cerebellum. AB - PURPOSE: To explore increasingly compelling evidence that the adult human cerebellum is involved in nonmotor affective and cognitive activity, including language-functions that have in the past been associated largely with the limbic system and the cerebral cortex. METHOD: We review clinical studies of patients with cerebellar lesions, nonclinical neuroimaging studies of individuals engaged in completing selected tasks, and neuroanatomical as well as neuroimaging studies of brain interconnections. In the course of this review, we also report on a variety of hypotheses regarding the nature of the cerebellum's work in affective processing and language/cognition. RESULTS: This review suggests that the cerebellum has considerable influence in language processing and other related higher level affective/cognitive activities. CONCLUSION: We conclude with a preliminary list of important clinical implications of these results. PMID- 21821821 TI - Risk for poor performance on a language screening measure for bilingual preschoolers and kindergarteners. AB - PURPOSE: This study documents the risk for language impairment in Latino children who had different levels of exposure to English and Spanish. METHOD: A total of 1,029 preschool- and kindergarten-age children were screened in the domains of semantics and morphosyntax in both Spanish and English. Parent report was used to document current exposure to and use of Spanish and English, as well as year of first exposure to English. Risk for language impairment was compared for language group, year of first English exposure, age, and mother's education. RESULTS: While bilingual children's scores on each subtest were significantly lower compared to their functional monolingual peers, they were no more likely to fall in the at-risk range based on a combination of all 4 subtests. Maternal education and year of first English exposure were weakly associated with risk for language impairment but not with language group (via 5 levels of first and second language exposure). CONCLUSIONS: Prevalence of risk for language impairment when both languages are tested is not related to language group. PMID- 21821823 TI - Money and mimicry: when being mimicked makes people feel threatened. PMID- 21821824 TI - Introduction for National Cholesterol Month. PMID- 21821826 TI - Exposure to acute intermittent hypoxia augments somatic motor function in humans with incomplete spinal cord injury. AB - BACKGROUND: Neural plasticity may contribute to motor recovery following spinal cord injury (SCI). In rat models of SCI with respiratory impairment, acute intermittent hypoxia (AIH) strengthens synaptic inputs to phrenic motor neurons, thereby improving respiratory function by a mechanism known as respiratory long term facilitation. Similar intermittent hypoxia-induced facilitation may be feasible in somatic motor pathways in humans. OBJECTIVE: Using a randomized crossover design, the authors tested the hypothesis that AIH increases ankle strength in people with incomplete SCI. METHODS: Ankle strength was measured in 13 individuals with chronic, incomplete SCI before and after AIH. Voluntary ankle strength was estimated using changes in maximum isometric ankle plantar flexion torque generation and plantar flexor electromyogram activity following 15 low oxygen exposures (Fio(2) = 0.09, 1-minute intervals). Results were compared with trials where subjects received sham exposure to room air. RESULTS: AIH increased plantar flexion torque by 82 +/- 33% (P < .003) immediately following AIH and was sustained above baseline for more than 90 minutes (P < .007). Increased ankle plantar flexor electromyogram activity (P = .01) correlated with increased torque (r(2) = .5; P < .001). No differences in plantar flexion strength or electromyogram activity were observed in sham experiments. CONCLUSIONS: AIH elicits sustained increases in volitional somatic motor output in persons with chronic SCI. Thus, AIH has promise as a therapeutic tool to induce plasticity and enhance motor function in SCI patients. PMID- 21821827 TI - Discovery of novel P2Y14 agonist and antagonist using conventional and nonconventional methods. AB - P2Y14 is a member of the pyrimidinergic GPCR family. UDP-Glc has been previously shown to activate human P2Y14, whereas UDP was unable to activate the receptor. In this study, the authors used conventional and nonconventional methods to further characterize P2Y14 and its ligands. Conventional calcium mobilization and nonconventional cellular impedance functional assays revealed that UMP and UDP selectively activated HEK cells coexpressing P2Y14 and Galpha(qi5). In the impedance assays, the presence of exogenous Galpha(qi5) resulted in agonist induced Gq signaling, whereas in the absence of exogenous Galpha(qi5), the signal was indicative of Gi. The authors established the first P2Y14 membrane filtration binding assay using a novel optimized expression vector and [(3)H]UDP as radioligand. UDP-Glc, UMP, and UDP dose dependently inhibited [(3)H]UDP binding in the binding assay, and saturation analysis revealed that UDP bound P2Y14 with a K(D) = 10 nM and a B(max) = 110 pmol/mg. The authors screened a phosphonate library and identified compound A, which inhibited UDP-Glc-mediated calcium signaling in the fluorometric imaging plate reader assay (IC(50) = 2.3 uM) and competed for [(3)H]UDP binding in the novel binding assay with a K(i) = 1280 nM. PMID- 21821825 TI - Relationship of IgG and IgM autoantibodies and immune complexes to oxidized LDL with markers of oxidation and inflammation and cardiovascular events: results from the EPIC-Norfolk Study. AB - Levels of IgG and IgM autoantibodies (AA) to malondialdehyde (MDA)-LDL and apoB immune complexes (ICs) were measured in 748 cases and 1,723 controls in the EPIC Norfolk cohort and their association to coronary artery disease (CAD) events determined. We evaluated whether AA and IC modify CAD risk associated with secretory phospholipase A(2) (sPLA(2)) type IIA mass and activity, lipoprotein associated PLA(2) activity, lipoprotein (a) [Lp(a)], oxidized phospholipids on apoB-100 (OxPL/apoB), myeloperoxidase, and high sensitivity C-reactive protein. IgG ICs were higher in cases versus controls (P = 0.02). Elevated levels of IgM AA and IC were inversely associated with Framingham Risk Score and number of metabolic syndrome criteria (p range 0.02-0.001). In regression analyses adjusted for age, smoking, diabetes, LDL-cholesterol, HDL-cholesterol, and systolic blood pressure, the highest tertiles of IgG and IgM AA and IC were not associated with higher risk of CAD events compared with the lowest tertiles. However, elevated levels of IgM IC reduced the risk of Lp(a) (P = 0.006) and elevated IgG MDA-LDL potentiated the risk of sPLA(2) mass (P = 0.018). This epidemiological cohort of initially healthy subjects shows that IgG and IgM AA and IC are not independent predictors of CAD events but may modify CAD risk associated with elevated levels of oxidative biomarkers. PMID- 21821828 TI - Introducing George L. Spaeth, the 2010 recipient of the Weisenfeld Award. PMID- 21821829 TI - Valid relevance in medical practice: the inadequacy of the linear model of health and disease: the Weisenfeld lecture. PMID- 21821830 TI - Sunitinib in combination with docetaxel and prednisone in chemotherapy-naive patients with metastatic, castration-resistant prostate cancer: a phase 1/2 clinical trial. AB - BACKGROUND: This phase 1/2 study assessed sunitinib combined with docetaxel (Taxotere) and prednisone in chemotherapy-naive metastatic, castration-resistant prostate cancer (mCRPC) patients. PATIENTS AND METHODS: To determine the recommended phase 2 dose (RP2D), 25 patients in four dose escalation cohorts received 3-week cycles of sunitinib (2 weeks on, 1 week off), docetaxel and prednisone, preceded by a 4-week sunitinib 50 mg/day lead in. RP2D was evaluated in 55 additional patients. The primary end point was prostate-specific antigen (PSA) response rate. RESULTS: One phase 1 dose-limiting toxicity occurred (grade 3 hyponatremia). The RP2D was sunitinib 37.5 mg/day, docetaxel 75 mg/m(2) and prednisone 5 mg b.i.d. During phase 2, confirmed PSA responses occurred in 31 patients [56.4% (95% confidence interval 42.3-69.7)]. Median time to PSA progression was 9.8 months. Forty-one patients (75%) were treated >3 months, 12 (22%) completed the study (16 cycles) and 43 (78%) discontinued (36% for disease progression and 27% adverse events). The most frequent treatment-related grade 3/4 adverse events were neutropenia (53%; 15% febrile) and fatigue/asthenia (16%). Among 33 assessable patients, 14 (42.4%) had confirmed partial response. Median progression-free and overall survivals were 12.6 and 21.7 months, respectively. CONCLUSION: This combination was moderately well tolerated, with promising response rate and survival benefit, justifying further investigation in mCRPC. PMID- 21821831 TI - Seeds of Brassicaceae weeds have an inherent or inducible response to the germination stimulant karrikinolide. AB - BACKGROUND AND AIMS: Karrikinolide (KAR(1)) is a smoke-derived chemical that can trigger seeds to germinate. A potential application for KAR(1) is for synchronizing the germination of weed seeds, thereby enhancing the efficiency of weed control efforts. Yet not all species germinate readily with KAR(1), and it is not known whether seemingly non-responsive species can be induced to respond. Here a major agronomic weed family, the Brassicaceae, is used to test the hypothesis that a stimulatory response to KAR(1) may be present in physiologically dormant seeds but may not be expressed under all circumstances. METHODS: Seeds of eight Brassicaceae weed species (Brassica tournefortii, Raphanus raphanistrum, Sisymbrium orientale, S. erysimoides, Rapistrum rugosum, Lepidium africanum, Heliophila pusilla and Carrichtera annua) were tested for their response to 1 um KAR(1) when freshly collected and following simulated and natural dormancy alleviation, which included wet-dry cycling, dry after-ripening, cold and warm stratification and a 2 year seed burial trial. KEY RESULTS: Seven of the eight Brassicaceae species tested were stimulated to germinate with KAR(1) when the seeds were fresh, and the remaining species became responsive to KAR(1) following wet-dry cycling and dry after-ripening. Light influenced the germination response of seeds to KAR(1), with the majority of species germinating better in darkness. Germination with and without KAR(1) fluctuated seasonally throughout the seed burial trial. CONCLUSIONS: KAR(1) responses are more complex than simply stating whether a species is responsive or non-responsive; light and temperature conditions, dormancy state and seed lot all influence the sensitivity of seeds to KAR(1), and a response to KAR(1) can be induced. Three response types for generalizing KAR(1) responses are proposed, namely inherent, inducible and undetected. Given that responses to KAR(1) were either inherent or inducible in all 15 seed lots included in this study, the Brassicaceae may be an ideal target for future application of KAR(1) in weed management. PMID- 21821833 TI - Estimated glomerular filtration rate and its association with the retinol-binding protein 4 (RBP4) locus on human chromosome 10q23. AB - BACKGROUND: We tested for associations between estimated glomerular filtration rate (eGFR) and retinol-binding protein 4 (RBP4) haplotypes found on human chromosome 10q23. This locus had been linked to eGFR in a previous linkage scan in patients with Type 2 diabetes mellitus. METHODS: We analysed 469 patients with Type 2 diabetes and 174 normoalbuminuric controls for associations between RBP4 haplotypes and eGFR. For comparison with controls, 295 cases with proteinuria/end stage renal disease were tested for associations with advanced diabetic nephropathy. Genotyping was performed using high-resolution DNA melting assays. Data analysis was performed using the haplo.stats package. RESULTS: Genetic variations in RBP4 were not associated with advanced diabetic nephropathy. Compared with the common A/G/G/C haplotype, C/A/A/C carriers among the normoalbuminuric controls had higher eGFR values among younger patients but lower eGFRs among the older patients (effect size=2.2, P=3.3*10(-7)). Furthermore, while eGFR values were fairly consistent over the range of systolic blood pressure (SBP) values for the common haplotype, eGFR in C/A/A/C carriers increased with SBP (effect size=3.6, P=1.5*10(-2)). There was a significant interaction between the C/A/A/C haplotype and HbA1c as they affect eGFR compared to the common haplotype (effect size=2.1, P=2.1*10(-3)). Power calculations demonstrated that our study had >90% power to detect the observed interactions even while performing multiple hypotheses testing. The interaction between SBP and the C/A/A/C haplotype remained significant (P=2.8*10(-2)) even when these three haplotype-environment interactions were simultaneously estimated. CONCLUSION: RBP4 haplotypes may be important in genetically modulating renal function in response to environmental challenges among patients with Type 2 diabetes. PMID- 21821832 TI - Sporophytic self-incompatibility genes and mating system variation in Arabis alpina. AB - BACKGROUND AND AIMS: Sporophytic self-incompatibility (SI) prevents inbreeding in many members of the Brassicaceae, and has been well documented in a variety of high-profile species. Arabis alpina is currently being developed as a model system for studying the ecological genetics of arctic-alpine environments, and is the focus of numerous studies on population structure and alpine phylogeography. Although it is highly inbreeding throughout most of its range, populations in central Italy have been identified that show inbreeding coefficients (F(IS)) more typical of self-incompatible relatives. The purpose of this study was to establish whether this variation is due to a functioning SI system. METHODS: Outcrossing rate estimates were calculated based on 16 allozyme loci and self compatibility assessed based on controlled pollinations for six Italian populations that have previously been shown to vary in F(IS) values. Putative SRK alleles (the gene controlling the female component of SI in other Brassicaceae) amplified from A. alpina were compared with those published for other species. Linkage of putative SRK alleles and SI phenotypes was assessed using a diallel cross. KEY RESULTS: Functional avoidance of inbreeding is demonstrated in three populations of A. alpina, corresponding with previous F(IS) values. The presence is described of 15 putative SRK-like alleles, which show high sequence identity to known alleles from Brassica and Arabidopsis and the high levels of synonymous and nonsynonymous variation typical of genes under balancing selection. Also, orthologues of two other members of the S-receptor kinase gene family, Aly8 (ARK3) and Aly9 (AtS1) are identified. Further to this, co-segregation between some of the putative S-alleles and compatibility phenotypes was demonstrated using a full-sibling cross design. CONCLUSIONS: The results strongly suggest that, as with other species in the Brassicaceae, A. alpina has a sporophytic SI system but shows variation in the strength of SI within and between populations. PMID- 21821834 TI - Post-transplantation encapsulating peritoneal sclerosis in a young child. AB - Encapsulating peritoneal sclerosis (EPS) is a very rare condition in children. Nevertheless, EPS should be considered when a child with a history of peritoneal dialysis (PD) presents with signs of bowel obstruction. We describe a child with post-transplantation EPS and discuss risk factors, diagnosis and treatment options. CT scan should be performed promptly to confirm the diagnosis. Treatment consists of cessation of the PD, if applicable, and adequate nutrition, either parenteral or enteral. Further medical therapy remains controversial but may involve steroids and/or interruption of calcineurin inhibitors. PMID- 21821835 TI - Long-term risk of ESRD in IgAN; validation of Japanese prognostic model in a Norwegian cohort. AB - BACKGROUND: Recently, a Japanese model used to predict 10-year risk of end-stage renal disease (ESRD) in IgA nephropathy (IgAN) patients was published. We tested the applicability of the Japanese model in predicting 10- to 20-year risk of ESRD and all-cause mortality in a cohort of Norwegian IgAN patients. METHODS: A cohort of IgAN patients (1988-2004) were identified in the Norwegian Kidney Biopsy Registry (NKBR) and ESRD or death during follow-up through 2008 was identified through record linkage with the Norwegian Renal Registry (ESRD) and the Norwegian Population Registry (deaths). Data from the NKBR were used to classify patients into nine different prognostic groups (0-1, 1-5, 5-10, 10-20, 20-30, 30-50, 50 70, 70-90 and >90% risk of ESRD) according to the Japanese prognostic model. The predicted risk was compared to the measured risk of ESRD in the different prognostic groups. RESULTS: In eight of the nine risk groups, representing 597/633 (94%) of the patients in our cohort, the observed 10-year risk was within or close to the expected 10-year risk of ESRD. ESRD occurring after >10 years of observation was most frequent in the groups with 5-30% expected risk at 10 years of follow-up. A close association between risk of ESRD and risk of death prior to ESRD was observed. CONCLUSIONS: The Japanese prognostic model is applicable to predict 10-year risk of ESRD in Norwegian IgAN patients. A new finding in the present study is that the model can also be used to predict which patients have the highest risk of developing ESRD after 10-20 years of follow-up as well as all cause mortality risk. PMID- 21821836 TI - Accelerated atherosclerosis in haemodialysis patients; correlation of endothelial function with oxidative DNA damage. AB - BACKGROUND: Accelerated atherosclerosis is the major cause of mortality in patients on chronic haemodialysis (HD). The aim of this study was to evaluate the relationship between oxidative DNA damage [8-hydroxy-2' deoxyguanosine/deoxyguanosine ratio (8-OHdG/dG ratio)], oxidative stress biomarkers and endothelial function in HD patients as an indicator of atherosclerosis. METHODS: Forty-four chronic HD patients without known atherosclerotic disease and 55 age- and sex-matched healthy individuals were included in the study. Plasma malondialdehyde (MDA) levels and 8-OHdG/dG ratio were determined as oxidative stress markers. Superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities were measured as antioxidants. Endothelial function was assessed by ultrasonography. RESULTS: 8-OHdG/dG ratio and MDA levels were higher in HD patients than controls while SOD and GPx activities were lower in HD patients compared to controls. Flow-mediated dilatation FMD% in HD patients were lower than the control group (7.28 +/- 0.79 versus 11.18 +/- 0.82, P < 0.001). There was a significant negative correlation between FMD% and 8-OHdG/dG ratio (r = -0.678, P < 0.01) and MDA levels (r = 0.517, P < 0.01), while there was a significant positive correlation between FMD% and SOD (r = 0.538, P < 0.01) and GPx levels (r = 0.720, P < 0.01). CONCLUSIONS: Our data have demonstrated that HD patients exhibit increased oxidative DNA damage and decreased antioxidant activity. We propose that endothelial function is negatively correlated with 8-OHdG/dG ratio and positively correlated with antioxidant enzymes. To our knowledge, this is the first study to demonstrate the inverse relationship between endothelial function and plasma oxidative DNA damage in HD patients. PMID- 21821837 TI - DNA methylation rebalances gene dosage after mammalian gene duplications. AB - Although gene duplication plays a major role in organismal evolution, it may also lead to gene dosage imbalance, thereby having an immediate adverse effect on an organism's fitness. Investigating the evolution of the expression patterns of genes that duplicated after the divergence of rodents and primates, we confirm that adaptive evolution has been involved in dosage rebalance after gene duplication. To understand mechanisms underlying this process, we examined 1) microRNA (miRNA)-mediated gene regulation, 2) cis-regulatory sequence modifications, and 3) DNA methylation. Neither miRNA-mediated regulation nor cis regulatory changes was found to be associated with expression reduction of duplicate genes. By contrast, duplicate genes, especially lowly expressed copies, were heavily methylated in the upstream region. However, for duplicate genes encoding proteins that are members of macromolecular complexes, heavy methylation in the genic region was not consistently observed. This result held after controlling potential confounding factors, such as enrichment in functional categories. Our results suggest that during mammalian evolution, DNA methylation plays a dominant role in dosage rebalance after gene duplication by inhibiting transcription initiation of duplicate genes. PMID- 21821838 TI - Changes in depressive symptoms in the context of disablement processes: role of demographic characteristics, cognitive function, health, and social support. AB - OBJECTIVES: Gerontological research suggests that depressive symptoms show antecedent and consequent relations with late-life disability. Less is known, however, about how depressive symptoms change with the progression of disability related processes and what factors moderate such changes. METHODS: We applied multiphase growth models to longitudinal data pooled across 4 Swedish studies of very old age (N = 779, M age = 86 years at disability onset, 64% women) to describe change in depressive symptoms prior to disability onset, at or around disability onset (the measurement wave at which assistance in personal activities of daily living was first recorded), and postdisability onset. RESULTS: Results indicate that, on average, depressive symptoms slightly increase with approaching disability, increase at onset, and decline in the postdisability phase. Age, study membership, being a woman, and multimorbidity were related to depressive symptoms, but social support emerged as the most powerful predictor of level and change in depressive symptoms. DISCUSSION: Our findings are consistent with conceptual notions implicating disability-related factors as key contributors to late-life change and suggest that contextual and psychosocial factors play a pivotal role for how well people adapt to late-life challenges. PMID- 21821839 TI - Age, criterion flexibility, and associative recognition. AB - OBJECTIVE: The goal of this study was to compare the extent to which young and older adults exhibit flexibility in adjusting decision criteria in response to changes in recognition task difficulty. METHODS: Forty-eight young and 48 older adults studied a list of word pairs and then took 2 successive tests of associative recognition, an easy test consisting of intact study pairs and new lure pairs and a hard test pitting intact study pairs against rearranged lures. The order of the 2 tests was manipulated, with half of the participants in each age group receiving the easy test first and half receiving the hard test first. RESULTS: When the easy test preceded the hard test, participants in both age groups adopted a more stringent response criterion on the harder test. When the hard test preceded the easy test, no criterion shift was seen in either age group. DISCUSSION: These results suggest that older adults have preserved metacognitive abilities with regard to assessing the consequences for accuracy of maintaining a lenient criterion when discrimination between experienced and new information becomes more difficult and further suggests that they can take appropriate action to control error rates under these conditions. PMID- 21821840 TI - Molecular cytogenetic evaluation of the aneugenic effects of teniposide in somatic and germinal cells of male mice. AB - The ability of topoisomerase II inhibitor, teniposide, to induce aneuploidy and meiotic delay in somatic and germinal cells of male mice was investigated by fluorescence in situ hybridisation (FISH) assay using labelled DNA probes and 5 bromo-2'-deoxyuridine (BrdU) incorporation assay, respectively. Colchicine and mitomycin C were used as a positive control aneugen and clastogen, respectively, and these compounds produced the expected responses. Using FISH assay with centromeric and telomeric DNA probes for erythrocyte, micronuclei (MN) showed that teniposide is not only clastogenic but also aneugenic in somatic cells in vivo. The assay also showed that chromosomes can be enclosed in the MN before and after centromere separation. By using the BrdU incorporation assay, it could be shown that the meiotic delay caused by teniposide in germ cells was ~48 h. Disomic and diploid sperms were shown in epididymal sperm hybridised with DNA probes specific for chromosomes 8, X and Y after teniposide treatment. The prevalence of autodiploid (XX88 and YY88) sperm and disomic XX8 or YY8 sperm indicates that the second meiotic division was more sensitive to teniposide than the first meiotic division. The results also suggest that earlier prophase stages contribute relatively less to teniposide-induced aneuploidy. Both the clastogenic and the aneugenic potential of teniposide can give rise to the development of secondary tumours and abnormal reproductive outcomes in cured cancer patients and medical personnel exposing to drug regimens that include teniposide. Thus, genetic counselling of these patients should take place before the start of chemotherapy and should take the present results into consideration. PMID- 21821841 TI - Systemic policies towards a healthier and more responsible food system. PMID- 21821842 TI - Cardiac hybrid imaging in a patient with a single coronary artery originating from the right sinus of Valsalva. PMID- 21821843 TI - Heart-rate reduction by If-channel inhibition with ivabradine restores collateral artery growth in hypercholesterolemic atherosclerosis. AB - AIMS: Collateral arteries protect tissue from ischaemia. Heart rate correlates with vascular events in patients with arterial obstructive disease. Here, we tested the effect of heart-rate reduction (HRR) on collateral artery growth. METHODS AND RESULTS: The I(f)-channel inhibitor ivabradine reduced heart rate by 11% in wild-type and 15% in apolipoprotein E (ApoE)(-/-) mice and restored endothelium-dependent relaxation in aortic rings of ApoE(-/-) mice. Microsphere perfusion and angiographies demonstrated that ivabradine did not change hindlimb perfusion in wild-type mice but improved perfusion in ApoE(-/-) mice from 40.5 +/ 15.8-60.2 +/- 18.5% ligated/unligated hindlimb. Heart rate reduction (13%) with metoprolol failed to improve endothelial function and perfusion. Protein expression of endothelial nitric oxide synthase (eNOS), phosphorylated eNOS, and eNOS activity were increased in collateral tissue following ivabradine treatment of ApoE(-/-) mice. Co-treatment with nitric oxide-inhibitor N (G)-nitro-L arginine methyl ester abolished the effects of ivabradine on arteriogenesis. Following ivabradine, classical inflammatory cytokine expression was lowered in ApoE(-/-) circulating mononuclear cells and in plasma, but unaltered in collateral-containing hindlimb tissue, where numbers of perivascular macrophages also remained unchanged. However, ivabradine reduced expression of anti arteriogenic cytokines CXCL10and CXCL11 and of smooth muscle cell markers smoothelin and desmin in ApoE(-/-) hindlimb tissue. Endothelial nitric oxide synthase and inflammatory cytokine expression were unchanged in wild-type mice. Ivabradine did not affect cytokine production in HUVECs and THP1 mononuclear cells and had no effect on the membrane potential of HUVECs in patch-clamp experiments. CONCLUSION: Ivabradine-induced HRR stimulates adaptive collateral artery growth. Important contributing mechanisms include improved endothelial function, eNOS activity, and modulation of inflammatory cytokine gene expression. PMID- 21821844 TI - Determinants of magnetic resonance imaging detected carotid plaque components: the Rotterdam Study. AB - AIMS: Components of carotid atherosclerotic plaque such as intraplaque haemorrhage and lipid core are important determinants of plaque progression and destabilization. The association between plaque components and risk factors for cardiovascular disease is not well studied. METHODS AND RESULTS: Participants from the population-based Rotterdam Study with carotid wall thickening on ultrasound (n = 1006) underwent high-resolution magnetic resonance imaging for carotid plaque characterization. Maximum wall thickening, the degree of stenosis, and the presence of intraplaque haemorrhage, lipid core, and calcification were assessed in both carotid arteries and their associations with cardiovascular risk factors were investigated. Intraplaque haemorrhage and lipid core were present in almost 25% of plaques, respectively, and occurred simultaneously in 9% of plaques. In men, intraplaque haemorrhage and lipid core were more prevalent compared with women (28.8 vs. 18.3 and 28.9 vs. 21.7%, respectively). Intraplaque haemorrhage occurred more frequently at older age [odds ratio (OR) per 10 years 1.8, 95% confidence interval 1.6-2.1], in men (OR 2.2, 1.7-2.9), in persons with hypertension (multivariate adjusted OR 1.4, 1.1-1.8), and in current smokers (multivariate adjusted OR 1.6, 1.2-2.3). Men (OR 1.5, 1.2-1.9) and subjects with hypercholesterolaemia (multivariate adjusted OR 1.4, 1.1-1.7) more often exhibited a lipid core. CONCLUSION: In subjects from the general population with carotid wall thickening, intraplaque haemorrhage and lipid core-both considered indicators of unstable plaque-are highly frequent and more prevalent in men compared with women. Furthermore, different risk factors are associated with these plaque components: hypertension and current smoking were risk factors for the presence of intraplaque haemorrhage, and hypercholesterolaemia was the only risk factor for lipid core presence. PMID- 21821845 TI - Blood pressure tracking during pregnancy and the risk of gestational hypertensive disorders: the Generation R Study. AB - AIMS: Blood pressure tracking can be used to examine the predictability of future values by early measurements. In a population-based prospective cohort study, among 8482 pregnant women, we examined whether blood pressure in early pregnancy tracks to third trimester and whether this tracking is influenced by maternal characteristics and is associated with the risk of gestational hypertensive disorders. METHODS AND RESULTS: Blood pressure was measured in each trimester of pregnancy. Information about doctor-diagnosed pregnancy-induced hypertension and preeclampsia was obtained from medical records. Correlation coefficients between first and third trimester for systolic and diastolic blood pressure were 0.47 and 0.46, respectively. The odds ratio for staying in the highest tertile from first to third trimester for systolic blood pressure was 3.09 [95% confidence interval (CI): 2.73, 3.50] and for diastolic blood pressure 3.28 (95% CI: 2.90, 3.69). Blood pressure tracking coefficients were lower in younger, shorter, and non European women and in women with higher gestational weight gain. Systolic and diastolic blood pressure changes from second to third trimester, but not from first to second trimester, were positively associated with the risks of pregnancy induced hypertension and preeclampsia. CONCLUSION: Blood pressure tracks moderately during pregnancy and is influenced by maternal characteristics. Second to third trimester increases in systolic and diastolic blood pressure are associated with an increased risk of gestational hypertensive disorders. PMID- 21821846 TI - Mitochondrial haplogroups associated with end-stage heart failure and coronary allograft vasculopathy in heart transplant patients. AB - AIMS: Mitochondrial haplogroups are known to influence individual predisposition to a wide spectrum of metabolic and degenerative diseases, including ischaemic cardiovascular diseases. We have examined the influence of the mitochondrial DNA (mtDNA) background on the development of human end-stage heart failure (HF) in patients undergoing heart transplantation. The influence of mtDNA haplogroups on the incidence of transplant-related complications, mainly cardiac allograft vasculopathy (CAV), and on post-transplant survival was also studied. METHODS AND RESULTS: The most common mitochondrial haplogroups in European populations were genotyped in 450 heart transplant recipients, 248 heart transplant donors, and 206 healthy controls. Mitochondrial haplogroups were determined by PCR amplification of short mtDNA fragments, followed by restriction fragment length polymorphism analysis. After adjustment for age and sex the frequency of haplogroup H was significantly higher in heart transplant recipients than in controls [OR: 1.86 (95% confidence intervals, CI: 1.27-2.74), P= 0.014], and in heart donors [OR: 1.47 (95% CI: 0.99-2.19), P= 0.032]. Likewise, haplogroup Uk was found significantly more frequently among CAV patients than in non-CAV heart allograft recipients [OR: 4.1 (95% CI: 1.51-11.42), P= 0.042]. Finally, heart donor haplogroups had no influence on the morbidity or mortality after heart transplantation. CONCLUSIONS: Mitochondrial haplogroups behave like risk factors for the progress to end-stage HF in a Spanish cardiac transplant population. Mitochondrial DNA variants may have some influence on the appearance of cardiac transplant complications. PMID- 21821847 TI - Seeking new heights in acute heart failure syndromes: lessons from ASCEND and EVEREST. PMID- 21821848 TI - Early calcific degeneration of a CoreValve transcatheter aortic bioprosthesis. PMID- 21821850 TI - Dilemma: how to make use of a CARISMA-tic profile? PMID- 21821849 TI - The survival of patients with heart failure with preserved or reduced left ventricular ejection fraction: an individual patient data meta-analysis. AB - AIMS: A substantial proportion of patients with heart failure have preserved left ventricular ejection fraction (HF-PEF). Previous studies have reported mixed results whether survival is similar to those patients with heart failure and reduced EF (HF-REF). METHODS AND RESULTS: We compared survival in patients with HF-PEF with that in patients with HF-REF in a meta-analysis using individual patient data. Preserved EF was defined as an EF >= 50%. The 31 studies included 41 972 patients: 10 347 with HF-PEF and 31 625 with HF-REF. Compared with patients with HF-REF, those with HF-PEF were older (mean age 71 vs. 66 years), were more often women (50 vs. 28%), and have a history of hypertension (51 vs. 41%). Ischaemic aetiology was less common (43 vs. 59%) in patients with HF-PEF. There were 121 [95% confidence interval (CI): 117, 126] deaths per 1000 patient years in those with HF-PEF and 141 (95% CI: 138, 144) deaths per 1000 patient years in those with HF-REF. Patients with HF-PEF had lower mortality than those with HF-REF (adjusted for age, gender, aetiology, and history of hypertension, diabetes, and atrial fibrillation); hazard ratio 0.68 (95% CI: 0.64, 0.71). The risk of death did not increase notably until EF fell below 40%. CONCLUSION: Patients with HF-PEF have a lower risk of death than patients with HF-REF, and this difference is seen regardless of age, gender, and aetiology of HF. However, absolute mortality is still high in patients with HF-PEF highlighting the need for a treatment to improve prognosis. PMID- 21821852 TI - Cost effectiveness of cardiac resynchronization therapy in Greece: an analysis based on the CArdiac REsychronization in Heart Failure trial. AB - AIMS: Health economic considerations have become increasingly important in healthcare. The aim of this study was to investigate the incremental cost effectiveness of cardiac resynchronization therapy (CRT) plus medical therapy compared with medical therapy alone in the Greek health-care system. METHODS AND RESULTS: The health economic analysis was based on the CARE-HF trial, a randomized clinical trial estimating the efficacy of adding CRT (n = 409) to optimal pharmacological treatment (n = 404) in patients with moderate-to-severe heart failure with markers of cardiac dyssynchrony. Health care resource use from CArdiac REsychronization in Heart Failure was combined with costs for CRT implantation and hospitalization from publicly available sources. The analysis was based on a lifetime perspective, with the life expectancy estimated from the clinical trial data. Shorter time horizons were explored in the sensitivity analysis. The cost per quality-adjusted life year (QALY) gained with CRT was ?6,045 in Greece, with a 95% confidence interval for the cost-effectiveness ratio of ?4,292-9,411 per QALY gained. CONCLUSIONS: The results of the economic evaluation of CRT in Greek health-care setting indicate that it is a cost effective treatment compared with traditional pharmacological therapy. Cardiac resynchronization therapy can therefore be recommended for routine use in patients with moderate-to-severe heart failure and markers of dyssynchrony. PMID- 21821853 TI - Dorsal spinal cord injury as a cause of recurrent asystole requiring permanent cardiac pacing. AB - Numerous unusual causes of atrioventricular block (AVB) with cardiac pacemaker implantation have been documented including cough, deglutition, or other vagally mediated mechanism. In spinal cord lesions, only high cervical spinal cord lesion has been reported as a cause of severe bradycardia. We report a case with not cervical but dorsal vertebral trauma and persistent paroxysmal AVB requiring cardiac pacemaker implantation. PMID- 21821851 TI - Post-operative atrial fibrillation: a maze of mechanisms. AB - Post-operative atrial fibrillation (POAF) is one of the most frequent complications of cardiac surgery and an important predictor of patient morbidity as well as of prolonged hospitalization. It significantly increases costs for hospitalization. Insights into the pathophysiological factors causing POAF have been provided by both experimental and clinical investigations and show that POAF is 'multi-factorial'. Facilitating factors in the mechanism of the arrhythmia can be classified as acute factors caused by the surgical intervention and chronic factors related to structural heart disease and ageing of the heart. Furthermore, some proarrhythmic mechanisms specifically occur in the setting of POAF. For example, inflammation and beta-adrenergic activation have been shown to play a prominent role in POAF, while these mechanisms are less important in non-surgical AF. More recently, it has been shown that atrial fibrosis and the presence of an electrophysiological substrate capable of maintaining AF also promote the arrhythmia, indicating that POAF has some proarrhythmic mechanisms in common with other forms of AF. The clinical setting of POAF offers numerous opportunities to study its mechanisms. During cardiac surgery, biopsies can be taken and detailed electrophysiological measurements can be performed. Furthermore, the specific time course of POAF, with the delayed onset and the transient character of the arrhythmia, also provides important insight into its mechanisms. This review discusses the mechanistic interaction between predisposing factors and the electrophysiological mechanisms resulting in POAF and their therapeutic implications. PMID- 21821854 TI - Gender disparities in anxiety and quality of life in patients with an implantable cardioverter-defibrillator. AB - AIMS: A paucity of studies in implantable cardioverter-defibrillator (ICD) patients has examined gender disparities in patient-reported outcomes, such as anxiety and quality of life (QoL). We investigated (i) gender disparities in anxiety and QoL and (ii) the magnitude of the effect of gender vs. New York Heart Association (NYHA) functional class (III/IV), ICD shock, and Type D personality on these outcomes. METHODS AND RESULTS: Implantable cardioverter-defibrillator patients (n = 718; 81% men) completed the State-Trait Anxiety Inventory (STAI) and the Short-Form Health Survey 36 (SF-36) at baseline and 12 months post implantation. The magnitude of the effect was indicated using Cohen's effect size index. Multivariate analysis of covariance for repeated measures showed no differences between men and women on mean scores of anxiety (F((1,696)) = 2.67, P = 0.10). Differences in QoL were observed for only two of the eight subscales of the SF-36, with women reporting poorer physical functioning (F((1,696)) = 7.14, P = 0.008) and vitality (F((1,696)) = 4.88, P = 0.028) than men. With respect to anxiety, effect sizes at baseline and 12 months for gender, NYHA class, and ICD shocks were small. A large effect size for Type D personality was found at both time points. For QoL, at baseline and 12 months, the effect sizes for gender were small, while the influence of NYHA class and Type D personality was moderate to large. CONCLUSIONS: Men and women did not differ on mean anxiety or QoL scores, except for women reporting poorer QoL on two domains. The relative influence of gender on anxiety and QoL was less than that of NYHA functional class and Type D personality. PMID- 21821855 TI - Predictors of mortality in patients with chronic kidney disease and an implantable defibrillator: an EPGEN substudy. AB - AIMS: Chronic kidney disease (CKD) is increasingly prevalent, and is an independent risk factor for cardiovascular mortality. Clinical trials of the implantable cardioverter-defibrillator (ICD) have demonstrated a survival benefit over medical therapy for the prevention of sudden cardiac death, but its benefit in patients with concomitant CKD is unclear. METHODS AND RESULTS: We studied 199 subjects with CKD, defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m(2), who underwent ICD implantation in the Duke Electrophysiology Genetic and Genomic Studies (EPGEN) biorepository. The mean age of the cohort was 67.8 +/- 9.3 years, and the mean eGFR was 41.1 +/- 13.2 mL/min/1.73 m(2). There were 63 deaths over a mean follow-up of 31.1 +/- 18.8 months, corresponding to an annual mortality rate of 12.2%. Additionally, there was a 7% annual rate of appropriate ICD therapy. Using Cox regression analysis, older age, lower ejection fraction, and lower eGFR were found to be significant predictors of mortality. There was a gradient of risk associated with lower renal function: a 10 mL/min reduction in eGFR conferred a 48% increase in the risk of death (P < 0.001). Further adjustment for appropriate ICD therapy did not modify these associations. CONCLUSION: In patients with CKD treated with a defibrillator, more advanced renal dysfunction is associated with reduced survival despite appropriate defibrillator therapy. This may be due to competing mortality risks in this population that attenuate the benefit of the ICD in reducing arrhythmic death. Age, ejection fraction, and kidney disease severity can be used to risk stratify patients before device implantation. PMID- 21821856 TI - Characteristics and long-term outcome of echocardiographic super-responders to cardiac resynchronisation therapy: 'real world' experience from a single tertiary care centre. AB - BACKGROUND: The individual benefit from cardiac resynchronisation therapy (CRT) varies largely among patients. AIMS: To compare different definitions of echocardiographic super-response to CRT regarding their ability to predict the incidence of adverse events. METHODS: Three definitions of super-response to CRT were evaluated in 110 consecutive patients with CRT implantation: (1) an absolute increase in ejection fraction of >= 10%; (2) a decrease in left ventricular end systolic volume of >= 30%; and (3) a decrease in left ventricular end-diastolic volume of >= 20%. The primary endpoint was a combination of time to death, heart transplantation, ventricular assist device implantation and hospitalisation for heart failure. Secondary endpoints included time to first appropriate implantable cardioverter defibrillator (ICD) discharge during follow-up. RESULTS: All three definitions of super-response were highly predictive of a reduced risk for reaching the primary combined endpoint (3-year estimators: 64% +/- 7% vs 82% +/- 7% for ejection fraction >= 10%; 63% +/- 8% vs 92% +/- 5% for end-systolic volume >= 30%; and 62% +/- 8% vs 94% +/- 4% for end-diastolic volume >= 20%; all p<0.001). In all three analyses, super-responders had a significantly shorter time from diagnosis of heart failure until the time point of CRT implantation. However, even super-responders, independent of the definition, did experience appropriate ICD discharges during follow-up. CONCLUSIONS: All three definitions of super-response are highly predictive for a favourable outcome after CRT. However, even patients with pronounced reverse left ventricular remodelling experience appropriate ICD discharges during follow-up. PMID- 21821857 TI - Variant ECG pattern associated with acute proximal left anterior descending occlusion. PMID- 21821858 TI - An early percutaneous catheter-mounted valve. PMID- 21821859 TI - Are lower survival rates among men who have had an out-of-hospital cardiac arrest in the home primarily due to female-witnessed arrest and poorer bystander cardiopulmonary resuscitation quality? PMID- 21821860 TI - Epigenomic profiling in polycythaemia vera and essential thrombocythaemia shows low levels of aberrant DNA methylation. AB - AIMS: The purpose of this study was to compare the DNA-methylation signature in classic chronic Philadelphia negative myeloproliferative neoplasms (MPN), polycythaemia vera (PV) and essential thrombocythaemia (ET), in order to obtain a global insight into DNA-methylation changes associated with these malignancies. METHODS: Thirty-five MPN samples from 11 ET JAK2 V617F, 12 ET JAK2 wild type (WT) and 12 PV JAK2 V617F patients as well as 12 from healthy donors were analysed. DNA samples extracted from whole peripheral blood were hybridised to the 'HumanMethylation27 DNA Analysis BeadChip.' RESULTS: All groups showed a very homogeneous methylation pattern. Only the ZNF577 gene showed a differential methylation profile between PV JAK2 V617F positive and controls. This aberrant methylation was correlated with a differential gene expression of ZNF577. No aberrant hypermethylation was found in the SOCS-1 and SOCS-3 genes. CONCLUSIONS: According to our results, an aberrant methylation pattern does not seem to play a crucial role in MPN pathogenesis; nor does it justify phenotypical differences between PV and ET. PMID- 21821861 TI - The prognostic benefits of routine staining with elastica to increase detection of venous invasion in colorectal cancer specimens. PMID- 21821862 TI - Lymph node distribution and pattern of metastases in the mesorectum following total mesorectal excision using the modified fat clearing technique. AB - AIM: To define the distribution, size, location and metastasis of lymph nodes (LNs) within the mesorectum from rectal cancer specimens following total mesorectal excision (TME) surgery without neoadjuvant therapy. METHODS: Specimens from 60 patients who underwent TME were treated with modified fat clearing solution to retrieve LNs. The mesorectum was divided into right lateral, anterior, posterior and left lateral sides, which were further subdivided into three levels (upper, middle and lower). RESULTS: 1436 LNs were harvested, including 985 small LNs (<5 mm in size). The number of LNs from the anterior, posterior and bilateral mesorectum was 125 (8.7%), 696 (48.5%) and 615 (42.8%), respectively. In the longitudinal axis, the difference in distribution at the three levels was not significant. 200 LN metastases (mLNs) were detected in 33 patients. 48% (96/200) of these were small LNs. More mLNs, especially small LNs, were shown in the more advanced T stage patients. The mLN metastasis rate was not influenced by tumour level. CONCLUSION: Small LN detection increased the accuracy of N staging by 20% in this study. The incidence of metastasis was the same among the anterior, bilateral and posterior areas of the mesorectum. An increased incidence of mLN metastasis in small LNs was associated with more advanced T staging. mLN metastasis rates in both middle and low rectal cancer were higher in the distal mesorectum than that in the proximal mesorectum. LN number and density were not consistent with spread of the primary tumour. Distal mLNs were found in 35% of cases of both middle and distal rectal cancer, implying a need for TME in both. PMID- 21821863 TI - A simple automated device for children's renal biopsy: advantage in obtaining more tissue. AB - Sufficient tissue yield is essential for renal biopsy. We have developed a simple automated renal biopsy device (Chen device) that constantly obtains more tissue. Since the Bard device is extensively used around the world, we compared our device with the Bard device. Pediatric patients were biopsied with either the Chen (n=247) or Bard (n=200) devices. No major complications were encountered and the incidence of minor complications was comparable between two devices. However, the average length of tissue obtained by the Chen device per biopsy (1.78+/-0.73 cm) was significantly longer than that obtained by the Bard device (1.23+/-0.45 cm). Accordingly, 61.94% of biopsies with the Chen device had 20 or more glomeruli, whereas only 18% of biopsies with the Bard device had this number (p<0.001). Thus, the Chen device has the advantage of obtaining more renal tissue per biopsy while being equally efficient and safe as the Bard device. PMID- 21821864 TI - High-dose statin before percutaneous coronary intervention lowers risk of periprocedural myocardial infarction and 30-day major cardiac adverse events. PMID- 21821865 TI - Sustained disease remission and inhibition of radiographic progression in methotrexate-naive patients with rheumatoid arthritis and poor prognostic factors treated with abatacept: 2-year outcomes. AB - OBJECTIVE: To assess the efficacy and safety of abatacept plus methotrexate versus methotrexate alone in early erosive rheumatoid arthritis (RA). METHODS: The AGREE was a 2-year phase IIIb multinational study in early (<= 2 years) RA. During the double-blind period (year 1), patients were randomly assigned 1:1 to receive abatacept+methotrexate or methotrexate alone; all patients received open label abatacept+methotrexate during year 2. Clinical outcomes assessed included 28-joint disease activity score (DAS28) defined remission, low disease activity score (LDAS), American College of Rheumatology (ACR) responses and physical function. Radiographic outcomes were assessed using the Genant-modified Sharp total score (TS). Safety was monitored throughout. RESULTS: Of the 459 patients completing year 1, 433 patients (94.3%) completed year 2. DAS28-defined remission, LDAS, ACR and physical function were sustained through year 2 in the original abatacept+methotrexate group, with 55.2% in remission at 2 years. Upon introduction of abatacept in the methotrexate-alone group, additional patients achieved DAS28-defined remission (44.5% vs 26.9%), LDAS (60.4% vs 43.2%) and improved ACR 70 (49.8% vs 31.7%) for year 2 versus year 1. Less radiographic progression was observed at 2 years in the original abatacept+methotrexate group than the methotrexate-alone group (change in TS 0.84 vs 1.75, p<0.001). No new safety issues were seen. Similar rates of serious adverse events, serious infections and autoimmune events were observed in years 1 and 2. CONCLUSIONS: The AGREE trial was the first to examine the impact of T-cell co-stimulation modulation with abatacept in patients with early erosive RA. Early treatment with abatacept+methotrexate resulted in greater sustainable clinical, functional and radiographic benefits than methotrexate alone, with acceptable safety and tolerability. TRIAL REGISTRATION: NCT00122382. PMID- 21821866 TI - Bone marrow-derived mesenchymal stem cells from early diffuse systemic sclerosis exhibit a paracrine machinery and stimulate angiogenesis in vitro. AB - OBJECTIVE: To characterise bone marrow-derived mesenchymal stem cells (MSCs) from patients with systemic sclerosis (SSc) for the expression of factors implicated in MSC recruitment at sites of injury, angiogenesis and fibrosis. The study also analysed whether the production/release of bioactive mediators by MSCs were affected by stimulation with cytokines found upregulated in SSc serum and tissues, and whether MSCs could modulate dermal microvascular endothelial cell (MVEC) angiogenesis. METHODS: MSCs obtained from five patients with early severe diffuse SSc (SSc-MSCs) and five healthy donors (H-MSCs) were stimulated with vascular endothelial growth factor (VEGF), transforming growth factor beta (TGFbeta) or stromal cell-derived factor-1 (SDF-1). Transcript and protein levels of SDF-1 and its receptor CXCR4, VEGF, TGFbeta(1) and receptors TbetaRI and TbetaRII were evaluated by quantitative real-time PCR, western blotting and confocal microscopy. VEGF, SDF-1 and TGFbeta(1) secretion in culture supernatant was measured by ELISA. MVEC capillary morphogenesis was performed on Matrigel with the addition of MSC-conditioned medium. RESULTS: In SSc-MSCs the basal expression of proangiogenic SDF-1/CXCR4 and VEGF was significantly increased compared with H-MSCs. SSc-MSCs constitutively released higher levels of SDF-1 and VEGF. SDF-1/CXCR4 were upregulated after VEGF stimulation and CXCR4 redistributed from the cytoplasm to the cell surface. VEGF was increased by SDF-1 challenge. VEGF, TGFbeta and SDF-1 stimulation upregulated TGFbeta(1), TbetaRI and TbetaRII in SSc-MSCs. TbetaRII redistributed from the cytoplasm to focal adhesion contacts. SSc-MSC-conditioned medium showed a greater proangiogenic effect on MVECs than H-MSCs. Experiments with blocking antibodies showed that MSC-derived cytokines were responsible for this potent proangiogenic effect. CONCLUSION: SSc MSCs constitutively overexpress and release bioactive mediators/proangiogenic factors and potentiate dermal MVEC angiogenesis. PMID- 21821867 TI - Delays in assessment of patients with rheumatoid arthritis: variations across Europe. AB - OBJECTIVE: The first 3 months after symptom onset represent an important therapeutic window for rheumatoid arthritis (RA). This study investigates the extent and causes of delay in assessment of patients with RA in eight European countries. METHOD: Data on the following levels of delay were collected from 10 centres (Berlin, Birmingham, Heraklion, Lund, Prague, Stockholm, Umea, Vienna, Warsaw and Zurich): (1) from onset of RA symptoms to request to see healthcare professional (HCP); (2) from request to see HCP to assessment by that HCP; (3) from initial assessment by HCP to referral to rheumatologist; and (4) from referral to rheumatologist to assessment by that rheumatologist. RESULTS: Data were collected from 482 patients with RA. The median delay across the 10 centres from symptom onset to assessment by the rheumatologist was 24 weeks, with the percentage of patients seen within 12 weeks of symptom onset ranging from 8% to 42%. There were important differences in the levels underlying the total delays at individual centres. CONCLUSIONS: This research highlights the contribution of patients, professionals and health systems to treatment delay for patients with RA in Europe. Although some centres have strengths in minimising certain types of delay, interventions are required in all centres to ensure timely treatment for patients. PMID- 21821868 TI - The impact of knee and hip chondrocalcinosis on disability in older people: the ProVA Study from northeastern Italy. AB - OBJECTIVES: Chondrocalcinosis is frequently associated with osteoarthritis. The role of osteoarthritis in the onset and progression of disability is well known. The impact of chondrocalcinosis on disability has never been investigated in epidemiological studies. METHODS: Progetto Veneto Anziani is a survey of 3099 older Italians, focusing on chronic diseases and disability. Assessment was by questionnaires, physical performance tests and clinical evaluations. Chondrocalcinosis was determined by x-ray readings of 1629 consecutive subjects. Knee and hip osteoarthritis severity was evaluated by summing the radiographic features score (RFS) assigned during x-ray reading. RESULTS: SUBJECTS: with chondrocalcinosis were older and more frequently women (age-adjusted p<0.0001). The gender association disappeared following adjustment for osteoarthritis severity. However, at the knee, the prevalence of osteoarthritis was higher in chondrocalcinosis patients independently of age and sex (age-adjusted p<0.0001). No difference was found between chondrocalcinosis and controls in sociodemographic variables and comorbidity. Knee chondrocalcinosis was strongly associated with clinical features of knee osteoarthritis and with disability assessment parameters in the bivariate analysis. Most associations remained after adjusting for age. After further adjustment for RFS, a significant association remained for knee deformity and pain, the need for a cane, difficulty walking 500 m, using a toilet, shopping and repeatedly rising from a chair. CONCLUSIONS: Pain and physical function are the outcome measures of choice for assessing disability in osteoarthritis patients. The presence of chondrocalcinosis contributes to both, independently of age and osteoarthritis severity, thus compromising the quality of life and worsening comorbidity. PMID- 21821869 TI - Ovulation induction with clomifene: a primary care perspective. AB - Infertility affects one in seven couples during their lifetime. Approximately one quarter of these will have an ovulatory disorder contributing to their inability to conceive. Ovulatory disorders represent the simplest form of infertility to treat, and where this is not a result of ovarian failure or poor ovarian reserve most women require ovulation induction with clomifene citrate (CC). This review aims to examine the role of CC in a general practice setting. CC is a simple, relatively safe, easily administered and well-tolerated efficacious drug. There is, however, a 10% risk of multiple births associated with its use. CC has been used in general practice for many years and continues to be used. Currently, guidelines do not describe its use in the general practice setting and the evidence for monitoring its use with mid-luteal progesterone estimation or ultrasound scanning is conflicting. PMID- 21821870 TI - Health benefits of traffic-related air pollution reduction in different socioeconomic groups: the effect of low-emission zoning in Rome. AB - OBJECTIVES: Few studies have assessed the effects of policies aimed to reduce traffic-related air pollution. The aims of this study were to evaluate the impact, in terms of air quality and health effects, of two low-emission zones established in Rome in the period 2001-2005 and to assess the impact by socioeconomic position (SEP) of the population. METHODS: We evaluated the effects of the intervention on various stages in the full-chain model, that is, pressure (number and age distribution of cars), emissions, PM(10) and NO(2) concentrations, population exposure and years of life gained (YLG). The impact was evaluated according to a small-area indicator of SEP. RESULTS: During the period 2001-2005, there was a decrease in the total number of cars (-3.8%), NO(2) and PM(10) emissions and concentrations (from 22.9 to 17.4 MUg/m(3) for NO(2) and from 7.8 to 6.2 MUg/m(3) for PM(10)), and in the residents' exposure. In the two low-emission zones, there was an additional decrease in air pollution concentrations (NO(2): -4.13 and -2.99 MUg/m(3); PM(10): -0.70 and -0.47 MUg/m(3)). As a result of the policy, 264 522 residents living along busy roads gained 3.4 days per person (921 YLG per 100,000) for NO(2) reduction. The gain was larger for people in the highest SEP group (1387 YLG per 100,000) than for residents in the lowest SEP group (340 YLG per 100,000). CONCLUSION: The traffic policy in Rome was effective in reducing traffic-related air pollution, but most of the health gains were found in well-off residents. PMID- 21821872 TI - Realizing the full nanofiller enhancement in melt-spun fibers of poly(vinylidene fluoride)/carbon nanotube composites. AB - Strong interfacial interaction is extremely important for achieving efficient mechanical reinforcement in polymer/inorganic nanoparticle composites. In this study, it was demonstrated for the first time that largely improved interfacial interaction could be obtained in continuously melt-spun fibers of poly(vinylidene fluoride) (PVDF)/multi-walled carbon nanotube (MWCNTs) composites, just by an increasing of the deformation extent (draw ratio). The superior interaction is attributed to high deformation inducing a formation of charge-transfer-type F-C bonding between all-trans conformation PVDF chains and extended MWCNTs. As a result, a large mechanical enhancement has been achieved. For the fibers prepared at the highest draw ratio of 200, the tensile strength and modulus are improved for 235% and 109%, respectively, after adding only 0.5 wt% MWCNTs to PVDF. More importantly, a mechanical model fitting, based on the rule of mixtures, indicates that in the case of the highest draw ratio the theoretical strength of MWCNTs is comparable to its real failure strength measured directly between two opposing AFM cantilever tips (Yu et al 2000 Science 287 637). Our present study suggests a great deal of promise for achieving highly efficient CNT enhancement via the non covalent interaction arising from simple physical fabrication like melt-spinning. PMID- 21821871 TI - The importance of studying history: lessons learnt from a trial of tacrolimus in myasthenia gravis. PMID- 21821873 TI - Force modulation for enhanced nanoscale electrical sensing. AB - Scanning probe microscopy employing conductive probes is a powerful tool for the investigation and modification of electrical properties at the nanoscale. Application areas include semiconductor metrology, probe-based data storage and materials research. Conductive probes can also be used to emulate nanoscale electrical contacts. However, unreliable electrical contact and tip wear have severely hampered the widespread usage of conductive probes for these applications. In this paper we introduce a force modulation technique for enhanced nanoscale electrical sensing using conductive probes. This technique results in lower friction, reduced tip wear and enhanced electrical contact quality. Experimental results using phase-change material stacks and platinum silicide conductive probes clearly demonstrate the efficacy of the proposed technique. Furthermore, conductive-mode imaging experiments on specially prepared platinum/carbon samples are presented to demonstrate the widespread applicability of this technique. PMID- 21821874 TI - Mapping nanoscale elasticity and dissipation using dual frequency contact resonance AFM. AB - We report on a technique that simultaneously quantifies the contact stiffness and dissipation of an AFM cantilever in contact with a surface, which can ultimately be used for quantitative nanomechanical characterization of surfaces. The method is based on measuring the contact resonance frequency using dual AC resonance tracking (DART), where the amplitude and phase of the cantilever response are monitored at two frequencies on either side of the contact resonance. By modelling the tip-sample contact as a driven damped harmonic oscillator, the four measured quantities (two amplitudes and two phases) allow the four model parameters, namely, drive amplitude, drive phase, resonance frequency and quality factor, to be calculated. These mechanical parameters can in turn be used to make quantitative statements about localized sample properties. We apply the method to study the electromechanical coupling coefficients in ferroelectric materials and the storage and loss moduli in viscoelastic materials. PMID- 21821875 TI - The radical scavenger IAC (bis(1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl) decantionate) decreases mortality, enhances cognitive functions in water maze and reduces amyloid plaque burden in hAbetaPP transgenic mice. AB - The purpose of this study was to evaluate the efficacy of the radical scavenger IAC (bis(1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl) decantionate) in alleviating behavioral deficits and reducing amyloid-beta (Abeta) accumulation in an Alzheimer's disease (AD) transgenic Tg2576 mouse model. Daily treatment with IAC (3-30 mg/kg, i.p.) was started at the age of 6 months and continued until the mice were 13 months old. At the age of 9 months and again at 12 months, the mice were tested in open field and water maze tests. At the age of 13 months, the mice were sacrificed and the brains processed for immunohistochemistry. Mortality was significantly reduced in all IAC-treated groups. In addition, IAC treatment improved the water maze hidden platform training performance but had no effect on motor activity in the open field or water maze swim speed in transgenic mice. Lastly, IAC treatment (10 mg/kg) significantly reduced the cortical Abeta plaque burden. In vitro, IAC is able to increase the number of neurites and neurite branches in cultured cortical primary neurons. In conclusion, IAC slowed down the development of the AD-like phenotype in Tg2576 mice and accelerated neurite growth in cultured neurons. PMID- 21821878 TI - The host-binding domain of the P2 phage tail spike reveals a trimeric iron binding structure. AB - The adsorption and infection of bacteriophage P2 is mediated by tail fibres and tail spikes. The tail spikes on the tail baseplate are used to irreversibly adsorb to the host cells. Recently, a P2 phage tail-spike protein, gpV, was purified and it was shown that a C-terminal domain, Ser87-Leu211, is sufficient for the binding of gpV to host Escherichia coli membranes [Kageyama et al. (2009), Biochemistry, 48, 10129-10135]. In this paper, the crystal structure of the C-terminal domain of P2 gpV is reported. The structure is a triangular pyramid and looks like a spearhead composed of an intertwined beta-sheet, a triple beta-helix and a metal-binding region containing iron, calcium and chloride ions. PMID- 21821879 TI - In silico identification and crystal structure validation of caspase-3 inhibitors without a P1 aspartic acid moiety. AB - Using a fragment-based docking procedure, several small-molecule inhibitors of caspase-3 were identified and tested and the crystal structures of three inhibitor complexes were determined. The crystal structures revealed that one inhibitor (NSC 18508) occupies only the S1 subsite, while two other inhibitors (NSC 89167 and NSC 251810) bind only to the prime part of the substrate-binding site. One of the major conformational changes observed in all three caspase-3 inhibitor complexes is a rotation of the Tyr204 side chain, which blocks the S2 subsite. In addition, the structural variability of the residues shaping the S1 S4 as well as the S1' subsites supports an induced-fit mechanism for the binding of the inhibitors in the active site. The high-resolution crystal structures reported here provide novel insights into the architecture of the substrate binding site, which might be useful for the design of more potent caspase inhibitors. PMID- 21821880 TI - Structure of the RuBisCO chaperone RbcX from the thermophilic cyanobacterium Thermosynechococcus elongatus. AB - The crystal structure of TeRbcX, a RuBisCO assembly chaperone from the cyanobacterium Thermosynechococcus elongatus, a thermophilic organism, has been determined at 1.7 A resolution. TeRbcX has an unusual cysteine residue at position 103 that is not found in RbcX proteins from mesophilic organisms. Unlike wild-type TeRbcX, a mutant protein with Cys103 replaced by Ala (TeRbcX-C103A) could be readily crystallized. The structure revealed that the overall fold of the TeRbcX homodimer is similar to those of previously crystallized RbcX proteins. Normal-mode analysis suggested that TeRbcX might adopt an open or closed conformation through a hinge movement pivoted on a kink in two long alpha4 helices. This type of conformational transition is presumably connected to RbcL (the large RuBisCO subunit) binding during the chaperone function of the RuBisCO assembly. PMID- 21821881 TI - Conservation of a crystallographic interface suggests a role for beta-sheet augmentation in influenza virus NS1 multifunctionality. AB - The effector domain (ED) of the influenza virus virulence factor NS1 is capable of interaction with a variety of cellular and viral targets, although regulation of these events is poorly understood. Introduction of a W187A mutation into the ED abolishes dimer formation; however, strand-strand interactions between mutant NS1 ED monomers have been observed in two previous crystal forms. A new condition for crystallization of this protein [0.1 M Bis-Tris pH 6.0, 0.2 M NaCl, 22%(w/v) PEG 3350, 20 mM xylitol] was discovered using the hanging-drop vapour-diffusion method. Diffraction data extending to 1.8 A resolution were collected from a crystal grown in the presence of 40 mM thieno[2,3-b]pyridin-2-ylmethanol. It was observed that there is conservation of the strand-strand interface in crystals of this monomeric NS1 ED in three different space groups. This observation, coupled with conformational changes in the interface region, suggests a potential role for beta-sheet augmentation in NS1 function. PMID- 21821882 TI - Structure of saxthrombin, a thrombin-like enzyme from Gloydius saxatilis. AB - Snake-venom thrombin-like enzymes (SVTLEs) are serine proteases that are widely distributed in snakes from the Crotalinae subfamily of the Viperidae. In contrast to other snake-venom serine proteases, they have a biochemical activity similar to that of thrombin and play an important role in the process of blood coagulation. However, SVTLEs cannot activate factor VIII, which is essential in blood-clot stabilization. Consequently, blood clots produced by SVTLEs are not stable and are cleared rapidly. This characteristic makes SVTLEs attractive as potential candidates for antithrombotic therapy. Saxthrombin, an SVTLE from Gloydius saxatilis, was purified and crystallized to obtain a high-quality crystal, from which data were acquired to 1.43 A resolution. Preliminary X-ray diffraction analysis showed that the crystal belonged to space group C2, with unit-cell parameters a = 94.2, b = 52.2, c = 50.1 A, beta = 96.7 degrees . The crystal structure was determined by molecular replacement and the final R factor was 18.69%; the R(free) was 20.01%. This is the first report of a crystal structure of an SVTLE. Saxthrombin belongs to the typical alpha/beta-hydrolase fold of serine proteases. Its structure was compared with those of thrombin and other snake-venom serine proteases. The observed differences in the amino-acid composition of the loops surrounding the active site appear to contribute to different surface-charge distributions and thus alter the shape of the active site cleft, which may explain the differences in substrate affinity. PMID- 21821883 TI - Structure of the Mycobacterium tuberculosis soluble inorganic pyrophosphatase Rv3628 at pH 7.0. AB - The 1.5 A resolution crystal structure of the Mycobacterium tuberculosis soluble inorganic pyrophosphatase Rv3628 at pH 7.0 is reported. The M. tuberculosis and M. leprae genomes include genes for the only two family I inorganic pyrophosphatases known to contain two histidines in the active site. The role of these two residues in catalysis is not fully understood. Mutational and functional studies of the M. tuberculosis enzyme showed that His21 and His86 are not essential for pyrophosphate hydrolysis, but are responsible for a shift in the optimal pH for the reaction compared with the Escherichia coli enzyme. Comparison with the structure previously reported at pH 5.0 provides further insight into the role of the two histidines. Two potassium-binding sites are found as a result of the high potassium concentration in the mother liquor. PMID- 21821884 TI - Structure of filamin A immunoglobulin-like repeat 10 from Homo sapiens. AB - Filamin A (FlnA) plays a critical role in cytoskeletal organization, cell motility and cellular signaling. FlnA utilizes different binding sites on a series of 24 immunoglobulin-like domains (Ig repeats) to interact with diverse cytosolic proteins and with cytoplasmic portions of membrane proteins. Mutations in a specific domain, Ig10 (FlnA-Ig10), are correlated with two severe forms of the otopalatodigital syndrome spectrum disorders Melnick-Needles syndrome and frontometaphyseal dysplasia. The crystal structure of FlnA-Ig10 determined at 2.44 A resolution provides insight into the perturbations caused by these mutations. PMID- 21821885 TI - Conformational bias imposed by source microseeds results in structural ambiguity. AB - The p38 MAP kinase pathway is an essential component of numerous cellular signalling networks which are usually activated in response to extracellular environmental stress conditions. In addition to the canonical activation, several alternative activation pathways have been identified for p38; one of these, in which p38 is initially phosphorylated on Tyr323 and consequently autoactivated, is exclusive to T cells and is induced by TCR activation. Intrinsically active and inactive mutants at position 323 have been developed in order to evaluate the structural changes that occur upon TCR-induced activation. In order to promote crystal growth, cross streak-seeding techniques were utilized. This technique has gained popularity in promoting crystal growth when spontaneous nucleation induces critical defects or is being entirely hindered. The crystal characteristics of some mutants were highly similar to those of the wild-type source seeds (form A). In contrast, other mutants crystallized spontaneously with a different space group and molecular packing (form B). One of the active mutants (Y323T) crystallized in both crystal forms, displaying different packing characteristics and significant differences in molecular conformation that were clearly dictated by the source seeds. This implies that the source seeds used in cross streak seeding could, in some cases, impose bias on the structural outcome of the studied molecule. Such incidents could occur when the conformational freedom permits crystal packing while not reflecting the authentic structure. PMID- 21821886 TI - Preliminary X-ray crystallographic studies of UDP-glucose-4-epimerase from Aspergillus nidulans. AB - UDP-glucose-4-epimerase (GALE) from Aspergillus nidulans was overexpressed in Escherichia coli, purified via His-tag affinity chromatography and cocrystallized with UDP-galactose using the microbatch method. The crystals diffracted to 2.4 A resolution using synchrotron radiation on the Canadian Light Source 08ID-1 beamline. Examination of the data with d*TREK revealed nonmerohedral twinning, from which a single lattice was ultimately extracted for processing. The final space group was found to be C2, with unit-cell parameters a = 66.13, b = 119.15, c = 161.42 A, beta = 98.48 degrees . An initial structure solution has been obtained via molecular replacement employing human GALE (PDB entry 1hzj) as a template model. PMID- 21821887 TI - Crystallization and preliminary X-ray crystallographic studies of swine CD8alpha. AB - CD8alphaalpha homodimers or CD8alphabeta heterodimers form on the T-cell surface, where they are essential as co-receptors for MHC class I molecules in activation of the CTL response. To date, swine have been found to show the highest percentage of lymphocytes with surface expression of CD8alpha. Crystallographic analysis of swine CD8alpha (sCD8alpha) to 1.8 A resolution revealed that the crystals belonged to space group P3(2)21, with unit-cell parameters a = 80.97, b = 80.97, c = 95.19 A. The Matthews coefficient and the solvent content were calculated to be 3.23 A(3) Da(-1) and 61.89%, respectively. These results may aid further structural and functional analyses of sCD8alpha. PMID- 21821888 TI - Crystallization and X-ray diffraction analysis of nylon-oligomer hydrolase (NylC) from Agromyces sp. KY5R. AB - 6-Aminohexanoate-oligomer hydrolase (NylC) from Agromyces sp. KY5R was expressed in Escherichia coli JM109 and purified by ammonium sulfate fractionation, anion exchange column chromatography and gel-filtration chromatography. NylC was crystallized by the sitting-drop vapour-diffusion method with sodium citrate as a precipitant in 0.1 M HEPES buffer pH 7.5 containing 0.2 M NaCl. Diffraction data were collected from native and K(2)PtCl(4)-derivative crystals to resolutions of 2.00 and 2.20 A, respectively. The obtained crystal was plate-shaped, with an I centred orthorhombic space group and unit-cell parameters a = 155.86, b = 214.45, c = 478.80 A. The anomalous difference Patterson map of the K(2)PtCl(4) derivative crystal suggested that the space group was I222 rather than I2(1)2(1)2(1). PMID- 21821889 TI - Purification and crystallization of yeast glycosylphosphatidylinositol transamidase subunit PIG-S (PIG-S(71-467)). AB - The transfer of glycosylphosphatidylinositol (GPI) anchors onto eukaryotic proteins is catalyzed by the transamidase complex, which is composed of at least five subunits (PIG-K, PIG-S, PIG-T, PIG-U and GPAA1). Here, the recombinant protein PIG-S(71-467) from Saccharomyces cerevisiae, including residues 71-467 of the entire 534-residue protein, was cloned, expressed and purified to homogeneity. The monodisperse protein was crystallized by the vapour-diffusion method. A diffraction data set was collected to 3.2 A resolution with 91.6% completeness. The crystals belonged to space group C2, with unit-cell parameters a = 106.72, b = 59.33, c = 124.3 A, beta = 114.19 degrees , and contained two molecules in the asymmetric unit. PMID- 21821890 TI - Crystallization and preliminary X-ray diffraction studies of BmooPLA2-I, a platelet-aggregation inhibitor and hypotensive phospholipase A2 from Bothrops moojeni venom. AB - Phospholipases A(2) (PLA(2)s) are enzymes that cause the liberation of fatty acids and lysophospholipids by the hydrolysis of membrane phospholipids. In addition to their catalytic action, a wide variety of pharmacological activities have been described for snake-venom PLA(2)s. BmooPLA(2)-I is an acidic, nontoxic and catalytic PLA(2) isolated from Bothrops moojeni snake venom which exhibits an inhibitory effect on platelet aggregation, an immediate decrease in blood pressure, inducing oedema at a low concentration, and an effective bactericidal effect. BmooPLA(2)-I has been crystallized and X-ray diffraction data have been collected to 1.6 A resolution using a synchrotron-radiation source. The crystals belonged to space group C222(1), with unit-cell parameters a = 39.7, b = 53.2, c = 89.2 A. The molecular-replacement solution of BmooPLA(2)-I indicated a monomeric conformation, which is in agreement with nondenaturing electrophoresis and dynamic light-scattering experiments. A comparative study of this enzyme with the acidic PLA(2) from B. jararacussu (BthA-I) and other toxic and nontoxic PLA(2)s may provide important insights into the functional aspects of this class of proteins. PMID- 21821891 TI - Cloning, expression, purification, crystallization and preliminary X-ray diffraction studies of a 12R-LOX-chaperone complex. AB - Lipoxygenases are a family of nonheme iron-containing dioxygenases. An Escherichia coli expression system producing the bacterial chaperones GroES and GroEL was engineered and successfully used to produce large quantities of recombinant human 12R-LOX (LOXR; MW 80.34 kDa; 701 amino-acid residues). The co overproduction of the two chaperones with 12R-LOX resulted in increased solubility of 12R-LOX and allowed the purification of milligram amounts of active enzyme for structural studies by X-ray diffraction. The lipoxygenase protein was purified on an affinity column and a gel-filtration column with chaperone protein (MW 57.16 kDa). The LOXR-chaperone complex was crystallized with ligand by the hanging-drop vapor-diffusion method using 1.5 M ammonium hydrogen phosphate as precipitant. The crystals belonged to the monoclinic system, space group P2(1), with unit-cell parameters a = 138.97, b = 266.11, c = 152.26 A, beta = 101.07 degrees . Based on the calculated Matthews coefficient (3.1 A(3) Da(-1)), it is estimated that one molecule of LOXR complexed with two molecules of chaperone is present in the asymmetric unit of the crystal lattice. X-ray diffraction data were collected to 4 A resolution using synchrotron radiation. PMID- 21821892 TI - Crystallization and preliminary crystallographic analysis of a PHD domain of human JARID1B. AB - Histone lysine methylation can be removed by proteins containing JmjC domains in a sequence- and methylation state-specific manner. JARID1B, a protein containing PHD and JmjC domains, is a histone demethylase specific for H3K4me2 and H3K4me3 which requires Fe(II) and alpha-ketoglutarate (alpha-KG) as cofactors to remove the methyl group. JARID1B has also been shown to play a critical role in the development of breast cancer. JARID1B contains JmjN, Arid and JmjC domains, a C5HC2 zinc-finger domain and three PHD domains. The first PHD domain (PHD1(JARID1B); residues 306-360) is located at the N-terminus and is important for both histone demethylase activity and histone-tail recognition of JARID1B. Here, the expression, purification and crystallization of PHD1(JARID1B) is reported. A PHD1(JARID1B) crystal was grown by the hanging-drop vapour-diffusion method in reservoir solution consisting of 0.1 M HEPES pH 7.0, 2.2 M ammonium sulfate at 277 K. A zinc SAD data set was collected from a PHD1(JARID1B) crystal. The diffraction pattern of the PHD1(JARID1B) crystal extended to 1.65 A resolution using synchrotron radiation. The crystal belonged to space group P4(3), with unit-cell parameters a = 51.7, b = 51.7, c = 36.2 A. PMID- 21821893 TI - Crystallization and preliminary X-ray analysis of a cold-active beta galactosidase from the psychrotrophic and halotolerant Planococcus sp. L4. AB - beta-Galactosidases catalyze the hydrolysis of a galactosyl moiety from the nonreducing termini of oligosaccharides or from glycosides. A novel GH family 42 cold-active beta-galactosidase identified from the psychrotrophic and halotolerant Planococcus sp. L4 (BgaP) was crystallized and a complete data set was collected from a single frozen crystal on an in-house X-ray source. The crystal diffracted to 2.8 A resolution and belonged to space group P1, with unit cell parameters a = 104.29, b = 118.12, c = 121.12 A, alpha = 62.66, beta = 69.48, gamma = 70.74 degrees . A likely Matthews coefficient of 2.58 A(3) Da(-1) and solvent content of 52.32% suggested the presence of six protein subunits in the asymmetric unit. PMID- 21821894 TI - Purification, crystallization and preliminary X-ray analysis of glucokinase from Streptomyces griseus in complex with glucose. AB - Glucokinase catalyzes the phosphorylation of glucose using ATP to yield glucose 6 phosphate. SgGlkA is a bacterial group III glucokinase from Streptomyces griseus that seems to play a regulatory role in carbon catabolite repression in this organism. SgGlkA was expressed in Escherichia coli, purified and crystallized using the sitting-drop vapour-diffusion method at 293 K. A crystal of SgGlkA in complex with glucose was obtained using a reservoir solution consisting of 0.9 M sodium/potassium tartrate, 0.2 M NaCl and 0.1 M imidazole pH 8.1 and diffracted X rays to 1.84 A resolution. The crystal of SgGlkA in complex with glucose belonged to space group P6(2)22 or P6(4)22, with unit-cell parameters a = b = 109.19, c = 141.18 A. The crystal contained one molecule in the asymmetric unit. PMID- 21821895 TI - Crystallization and diffraction analysis of thioredoxin reductase from Streptomyces coelicolor. AB - Thioredoxin reductases are homodimeric flavoenzymes that catalyze the transfer of electrons from NADPH to oxidized thioredoxin substrate. Bacterial thioredoxin reductases represent a promising target for the development of new antibiotics. Recombinant thioredoxin reductase TrxB from Streptomyces coelicolor was crystallized using the hanging-drop vapour-diffusion method. X-ray diffraction data were collected from cryocooled crystals to 2.4 A resolution using a synchrotron-radiation source. The crystals belonged to the primitive monoclinic space group P2(1), with unit-cell parameters a = 82.9, b = 60.6, c = 135.4 A, alpha = gamma = 90.0, beta = 96.5 degrees . PMID- 21821896 TI - Preliminary crystallographic analysis of a possible transcription factor encoded by the mimivirus L544 gene. AB - Mimivirus is the prototype of a new family (the Mimiviridae) of nucleocytoplasmic large DNA viruses (NCLDVs), which already include the Poxviridae, Iridoviridae, Phycodnaviridae and Asfarviridae. Mimivirus specifically replicates in cells from the genus Acanthamoeba. Proteomic analysis of purified mimivirus particles revealed the presence of many subunits of the DNA-directed RNA polymerase II complex. A fully functional pre-transcriptional complex appears to be loaded in the virions, allowing mimivirus to initiate transcription within the host cytoplasm immediately upon infection independently of the host nuclear apparatus. To fully understand this process, a systematic study of mimivirus proteins that are predicted (by bioinformatics) or suspected (by proteomic analysis) to be involved in transcription was initiated by cloning and expressing them in Escherichia coli in order to determine their three-dimensional structures. Here, preliminary crystallographic analysis of the recombinant L544 protein is reported. The crystals belonged to the orthorhombic space group C222(1) with one monomer per asymmetric unit. A MAD data set was used for preliminary phasing using the selenium signal present in a selenomethionine-substituted protein crystal. PMID- 21821897 TI - Purification, crystallization and preliminary X-ray structure analysis of the laccase from Ganoderma lucidum. AB - The ligninolytic enzymes of the basidiomycetes play a key role in the global carbon cycle. A characteristic property of these enzymes is their broad substrate specificity, which has led to their use in various biotechnologies, thus stimulating research into the three-dimensional structures of ligninolytic enzymes. This paper presents the purification, crystallization and preliminary X ray analysis of the laccase from the ligninolytic basidiomycete Ganoderma lucidum. PMID- 21821898 TI - Overexpression, crystallization and preliminary X-ray crystallographic analysis of Pyrococcus furiosus PF2050, a member of the DUF2666 protein family. AB - Pyrococcus furiosus PF2050, a putative uncharacterized protein, was overexpressed in Escherichia coli, purified and crystallized at 298 K using 2-methyl-2,4 pentanediol as the precipitant. X-ray diffraction data were collected to a resolution of 1.56 A at 100 K using synchrotron X-rays. The crystal was found to belong to space group P2(1), with unit-cell parameters a = 41.76, b = 66.43, c = 46.38 A, beta = 96.62 degrees . The asymmetric unit contained one subunit of PF2050, with a crystal volume per protein weight (V(M)) of 2.21 A(3) Da(-1) and a solvent content of 44.41%. PMID- 21821899 TI - Expression, purification and preliminary crystallographic analysis of Rv3002c, the regulatory subunit of acetolactate synthase (IlvH) from Mycobacterium tuberculosis. AB - Branched amino-acid biosynthesis is important to bacterial pathogens such as Mycobacterium tuberculosis (Mtb), a microorganism that presently causes more deaths in humans than any other prokaryotic pathogen (http://www.who.int/tb). In this study, the molecular cloning, expression, purification, crystallization and preliminary crystallographic analysis of recombinant IlvH, the small regulatory subunit of acetohydroxylic acid synthase (AHAS) in Mtb, are reported. AHAS carries out the first common reaction in the biosynthesis of valine, leucine and isoleucine. AHAS is an essential enzyme in Mtb and its inactivation leads to a lethal phenotype [Sassetti et al. (2001), Proc. Natl Acad. Sci. USA, 98, 12712 12717]. Thus, inhibitors of AHAS could potentially be developed into novel anti Mtb therapies. PMID- 21821900 TI - Purification, crystallization and preliminary X-ray crystallographic analysis of the receiver and stalk domains (PA3346RS) of the response regulator PA3346 from Pseudomonas aeruginosa PAO1. AB - The regulatory domain (PA3346RS), comprising the receiver and stalk domains, of the response regulator PA3346 requires phosphorylation for activation with magnesium ions as cofactors in order to modulate the downstream protein phosphatase activity for the regulation of swarming motility in Pseudomonas aeruginosa PAO1. Fusion-tagged recombinant PA3346RS of total molecular mass 25.3 kDa has been overexpressed in Escherichia coli, purified using Ni(2+)-NTA and Q Sepharose ion-exchange columns and crystallized using the hanging-drop vapour diffusion method. X-ray diffraction data were collected from PA3346RS crystals to 2.0 A resolution. The crystal belonged to space group P4(1) or P4(3), with unit cell parameters a = 82.38, c = 73.34 A. Preliminary analysis indicated the presence of a dimer of PA3346RS in the asymmetric unit, with a solvent content of 48.6%. PMID- 21821901 TI - Expression, purification and preliminary crystallographic analysis of human thyroid hormone responsive protein. AB - Thyroid hormone responsive protein (Thrsp, also known as Spot 14 and S14) is a carbohydrate-inducible and thyroid-hormone-inducible nuclear protein specific to liver, adipose and lactating mammary tissues. Thrsp functions to activate genes encoding fatty-acid synthesis enzymes. Recent studies have shown that in some cancers human Thrsp (hS14) localizes to the nucleus and is amplified, suggesting that it plays a role in the regulation of lipogenic enzymes during tumourigenesis. Thrsp, a member of the Spot 14 superfamily, is an acidic homodimeric protein with no sequence similarity to other mammalian gene products and its biochemical function is elusive. To shed light on the structure-function relationship of this protein, human Thrsp was crystallized. Recombinant human Thrsp (hThrsp), the N-terminally truncated human Thrsp(10-146) (hThrsp9) and their selenomethionyl (SeMet) derivatives were expressed in Escherichia coli, purified and crystallized using the hanging-drop vapour-diffusion method. Diffraction-quality crystals were grown at 293 K using Li(2)SO(4) as a precipitant. Using synchrotron radiation, data for the hThrsp SeMet derivative, hThrsp9 and its SeMet derivative were collected to 4.0, 3.0 and 3.6 A resolution, respectively, at 100 K. The crystals of full-length hThrsp and its SeMet derivative belonged to space group P4(1)2(1)2, with approximate unit-cell parameters a = b = 123.9, c = 242.1 A, alpha = beta = gamma = 90.0 degrees . In contrast, the crystals of the truncated hThrsp9 and its SeMet derivative belonged to space group P2(1)2(1)2(1), with approximate unit-cell parameters a = 91.6, b = 100.8, c = 193.7 A, alpha = beta = gamma = 90.0 degrees . A molecular-replacement solution calculated using a murine Spot 14 structure as a search model indicated the presence of six molecules per asymmetric unit, comprising three hThrsp homodimers. PMID- 21821902 TI - Purification, crystallization and preliminary X-ray diffraction analysis of the human mismatch repair protein MutSbeta. AB - MutSbeta is a eukaryotic mismatch repair protein that preferentially targets extrahelical unpaired nucleotides and shares partial functional redundancy with MutSalpha (MSH2-MSH6). Although mismatch recognition by MutSalpha has been shown to involve a conserved Phe-X-Glu motif, little is known about the lesion-binding mechanism of MutSbeta. Combined MSH3/MSH6 deficiency triggers a strong predisposition to cancer in mice and defects in msh2 and msh6 account for roughly half of hereditary nonpolyposis colorectal cancer mutations. These three MutS homologs are also believed to play a role in trinucleotide repeat instability, which is a hallmark of many neurodegenerative disorders. The baculovirus overexpression and purification of recombinant human MutSbeta and three truncation mutants are presented here. Binding assays with heteroduplex DNA were carried out for biochemical characterization. Crystallization and preliminary X ray diffraction analysis of the protein bound to a heteroduplex DNA substrate are also reported. PMID- 21821903 TI - Crystallization and preliminary X-ray analysis of the yeast tRNA-thiouridine modification protein 1 (Tum1p). AB - Yeast tRNA-thiouridine modification protein 1 (Tum1p), a crucial component of the Urm1 system, is believed to play important roles in protein urmylation and tRNA thiouridine modification. Previous studies have demonstrated that the conserved residue Cys259 in the C-terminal rhodanese-like domain of Tum1p is essential for these sulfur-transfer activities. Here, recombinant Tum1p protein has been cloned and overexpressed in Escherichia coli strain BL21 (DE3). After purification, crystals of Tum1p were obtained by the hanging-drop vapour-diffusion method and diffracted to 1.9 A resolution. The preliminary X-ray data showed that the tetragonal Tum1p crystal belonged to space group I4(1), with unit-cell parameters a = b = 120.94, c = 48.35 A. The asymmetric unit of the crystal was assumed to contain one protein molecule, giving a Matthews coefficient of 2.41 A(3) Da(-1) and a solvent content of 49.0%. PMID- 21821904 TI - Purification, crystallization and preliminary crystallographic analysis of recombinant Lac15 from a marine microbial metagenome. AB - Laccases are members of the blue multi-copper oxidase family that can oxidize a wide range of aromatic compounds. A new bacterial laccase (Lac15) has recently been obtained from a marine microbial metagenome from the South China Sea and characterized. In this work, recombinant Lac15 was overexpressed in Escherichia coli, purified and crystallized using the hanging-drop vapour-diffusion method. An X-ray diffraction data set was collected to 2.2 A resolution. The crystal belonged to space group C121, with unit-cell parameters a = 123.41, b = 91.36, c = 86.157 A, beta = 112.10 degrees . PMID- 21821905 TI - Expression, purification and preliminary crystallographic analysis of O acetylhomoserine sulfhydrylase from Mycobacterium tuberculosis. AB - The gene product of the open reading frame Rv3340 from Mycobacterium tuberculosis is annotated as encoding a probable O-acetylhomoserine (OAH) sulfhydrylase (MetC), an enzyme that catalyzes the last step in the biosynthesis of methionine, which is an essential amino acid in bacteria and plants. Following overexpression in Escherichia coli, the M. tuberculosis MetC enzyme was purified and crystallized using the hanging-drop vapor-diffusion method. Native diffraction data were collected from crystals belonging to space group P2(1) and were processed to a resolution of 2.1 A. PMID- 21821906 TI - Crystallization and preliminary X-ray analysis of CYP153C1 from Novosphingobium aromaticivorans DSM12444. AB - Cytochrome P450 (CYP) enzymes constitute a large family of haemoproteins that catalyze the monooxygenation of a great variety of endogenous and exogenous organic compounds. In common with other members of the CYP153 family of alkane hydroxylases, CYP153C1 from the oligotrophic bacterium Novosphingobium aromaticivorans DSM 12444 can bind linear alkanes such as heptane, octane and nonane. Here, the production, purification and crystallization of CYP153C1 and the collection of high-resolution diffraction data to 1.77 A resolution are reported. The crystals belonged to space group P2(1)2(1)2(1), with unit-cell parameters a = 61.0, b = 96.3, c = 149.8 A, alpha = beta = gamma = 90.0 degrees . Preliminary X-ray diffraction data analysis revealed that the asymmetric unit is most likely to contain two protein molecules. PMID- 21821907 TI - Expression, purification, crystallization and preliminary crystallographic analysis of Cg1458: a novel oxaloacetate decarboxylase from Corynebacterium glutamicum. AB - Oxaloacetate decarboxylase catalyses the decarboxylation of oxaloacetate to pyruvate and CO(2). Recently, the Corynebacterium glutamicum gene product Cg1458 was determined to be a soluble oxaloacetate decarboxylase. To elucidate the mechanism of oxaloacetate decarboxylation by Cg1458, recombinant Cg1458 was purified and crystallized. The best crystal was grown from 0.2 M MgCl(2), 0.1 M Bis-Tris pH 6.0, 25%(w/v) polyethylene glycol 3350 using the hanging-drop method. The crystals belonged to space group P4(3)2(1)2, with unit-cell parameters a = b = 124.1, c = 73.6 A. The crystals are most likely to contain a dimer in the asymmetric unit, with a V(M) value of 2.27 A(3) Da(-1). A full data set was collected at 1.9 A resolution using synchrotron radiation on beamline BL17U of SSRF, Shanghai, China. Structure-solution attempts by molecular replacement were successful with PDB entries 3qdf or 2dfu as the template. PMID- 21821908 TI - From screen to structure with a harvestable microfluidic device. AB - Advances in automation have facilitated the widespread adoption of high throughput vapour-diffusion methods for initial crystallization screening. However, for many proteins, screening thousands of crystallization conditions fails to yield crystals of sufficient quality for structural characterization. Here, the rates of crystal identification for thaumatin, catalase and myoglobin using microfluidic Crystal Former devices and sitting-drop vapour-diffusion plates are compared. It is shown that the Crystal Former results in a greater number of identified initial crystallization conditions compared with vapour diffusion. Furthermore, crystals of thaumatin and lysozyme obtained in the Crystal Former were used directly for structure determination both in situ and upon harvesting and cryocooling. On the basis of these results, a crystallization strategy is proposed that uses multiple methods with distinct kinetic trajectories through the protein phase diagram to increase the output of crystallization pipelines. PMID- 21821911 TI - Regulatory B cells are identified by expression of TIM-1 and can be induced through TIM-1 ligation to promote tolerance in mice. AB - T cell Ig domain and mucin domain protein 1 (TIM-1) is a costimulatory molecule that regulates immune responses by modulating CD4+ T cell effector differentiation. However, the function of TIM-1 on other immune cell populations is unknown. Here, we show that in vivo in mice, TIM-1 is predominantly expressed on B rather than T cells. Importantly, TIM-1 was expressed by a large majority of IL-10-expressing regulatory B cells in all major B cell subpopulations, including transitional, marginal zone, and follicular B cells, as well as the B cell population characterized as CD1d(hi)CD5+. A low-affinity TIM-1-specific antibody that normally promotes tolerance in mice, actually accelerated (T cell-mediated) immune responsiveness in the absence of B cells. TIM-1+ B cells were highly enriched for IL-4 and IL-10 expression, promoted Th2 responses, and could directly transfer allograft tolerance. Both cytokine expression and number of TIM 1+ regulatory B cells (Bregs) were induced by TIM-1-specific antibody, and this was dependent on IL-4 signaling. Thus, TIM-1 is an inclusive marker for IL-10+ Bregs that can be induced by TIM-1 ligation. These findings suggest that TIM-1 may be a novel therapeutic target for modulating the immune response and provide insight into the signals involved in the generation and induction of Bregs. PMID- 21821912 TI - Preclinical assessment of CNS drug action using eye movements in mice. AB - The drug development process for CNS indications is hampered by a paucity of preclinical tests that accurately predict drug efficacy in humans. Here, we show that a wide variety of CNS-active drugs induce characteristic alterations in visual stimulus-induced and/or spontaneous eye movements in mice. Active compounds included sedatives and antipsychotic, antidepressant, and antiseizure drugs as well as drugs of abuse, such as cocaine, morphine, and phencyclidine. The use of quantitative eye-movement analysis was demonstrated by comparing it with the commonly used rotarod test of motor coordination and by using eye movements to monitor pharmacokinetics, blood-brain barrier penetration, drug receptor interactions, heavy metal toxicity, pharmacologic treatment in a model of schizophrenia, and degenerative CNS disease. We conclude that eye-movement analysis could complement existing animal tests to improve preclinical drug development. PMID- 21821913 TI - IgE stimulates human and mouse arterial cell apoptosis and cytokine expression and promotes atherogenesis in Apoe-/- mice. AB - IgE has a key role in the pathogenesis of allergic responses through its ability to activate mast cells via the receptor FcepsilonR1. In addition to mast cells, many cell types implicated in atherogenesis express FcepsilonR1, but whether IgE has a role in this disease has not been determined. Here, we demonstrate that serum IgE levels are elevated in patients with myocardial infarction or unstable angina pectoris. We found that IgE and the FcepsilonR1 subunit FcepsilonR1alpha were present in human atherosclerotic lesions and that they localized particularly to macrophage-rich areas. In mice, absence of FcepsilonR1alpha reduced inflammation and apoptosis in atherosclerotic plaques and reduced the burden of disease. In cultured macrophages, the presence of TLR4 was required for FcepsilonR1 activity. IgE stimulated the interaction between FcepsilonR1 and TLR4, thereby inducing macrophage signal transduction, inflammatory molecule expression, and apoptosis. These IgE activities were reduced in the absence of FcepsilonR1 or TLR4. Furthermore, IgE activated macrophages by enhancing Na+/H+ exchanger 1 (NHE1) activity. Inactivation of NHE1 blocked IgE-induced macrophage production of inflammatory molecules and apoptosis. Cultured human aortic SMCs (HuSMCs) and ECs also exhibited IgE-induced signal transduction, cytokine expression, and apoptosis. In human atherosclerotic lesions, SMCs and ECs colocalized with IgE and TUNEL staining. This study reveals what we believe to be several previously unrecognized IgE activities that affect arterial cell biology and likely other IgE-associated pathologies in human diseases. PMID- 21821914 TI - Desmoglein 3-specific CD4+ T cells induce pemphigus vulgaris and interface dermatitis in mice. AB - Pemphigus vulgaris (PV) is a severe autoimmune disease involving blistering of the skin and mucous membranes. It is caused by autoantibodies against desmoglein 3 (Dsg3), an adhesion molecule critical for maintaining epithelial integrity in the skin, oral mucosa, and esophagus. Knowing the antigen targeted by the autoantibodies renders PV a valuable model of autoimmunity. Recently, a role for Dsg3-specific CD4+ T helper cells in autoantibody production was demonstrated in a mouse model of PV, but whether these cells exert cytotoxicity in the tissues is unclear. Here, we analyzed 3 Dsg3-specific TCRs using transgenic mice and retrovirus induction. Dsg3-specific transgenic (Dsg3H1) T cells underwent deletion in the presence of Dsg3 in vivo. Dsg3H1 T cells that developed in the absence of Dsg3 elicited a severe pemphigus-like phenotype when cotransferred into immunodeficient mice with B cells from Dsg3-/- mice. Strikingly, in addition to humoral responses, T cell infiltration of Dsg3-expressing tissues led to interface dermatitis, a distinct form of T cell-mediated autoimmunity that causes keratinocyte apoptosis and is seen in various inflammatory/autoimmune skin diseases, including paraneoplastic pemphigus. The use of retrovirally generated Dsg3-specific T cells revealed that interface dermatitis occurred in an IFN-gamma and TCR avidity-dependent manner. This model of autoimmunity demonstrates that T cells specific for a physiological skin-associated autoantigen are capable of inducing interface dermatitis and should provide a valuable tool for further exploring the immunopathophysiology of T cell-mediated skin diseases. PMID- 21821915 TI - Renal collecting duct epithelial cells regulate inflammation in tubulointerstitial damage in mice. AB - Renal tubulointerstitial damage is the final common pathway leading from chronic kidney disease to end-stage renal disease. Inflammation is clearly involved in tubulointerstitial injury, but it remains unclear how the inflammatory processes are initiated and regulated. Here, we have shown that in the mouse kidney, the transcription factor Kruppel-like factor-5 (KLF5) is mainly expressed in collecting duct epithelial cells and that Klf5 haploinsufficient mice (Klf5+/- mice) exhibit ameliorated renal injury in the unilateral ureteral obstruction (UUO) model of tubulointerstitial disease. Additionally, Klf5 haploinsufficiency reduced accumulation of CD11b+ F4/80(lo) cells, which expressed proinflammatory cytokines and induced apoptosis among renal epithelial cells, phenotypes indicative of M1-type macrophages. By contrast, it increased accumulation of CD11b+ F4/80(hi) macrophages, which expressed CD206 and CD301 and contributed to fibrosis, in part via TGF-beta production--phenotypes indicative of M2-type macrophages. Interestingly, KLF5, in concert with C/EBPalpha, was found to induce expression of the chemotactic proteins S100A8 and S100A9, which recruited inflammatory monocytes to the kidneys and promoted their activation into M1-type macrophages. Finally, assessing the effects of bone marrow-specific Klf5 haploinsufficiency or collecting duct- or myeloid cell-specific Klf5 deletion confirmed that collecting duct expression of Klf5 is essential for inflammatory responses to UUO. Taken together, our results demonstrate that the renal collecting duct plays a pivotal role in the initiation and progression of tubulointerstitial inflammation. PMID- 21821916 TI - Glycogen synthase kinase-3 is essential for beta-arrestin-2 complex formation and lithium-sensitive behaviors in mice. AB - Lithium is the first-line therapy for bipolar disorder. However, its therapeutic target remains controversial. Candidates include inositol monophosphatases, glycogen synthase kinase-3 (GSK-3), and a beta-arrestin-2/AKT/protein phosphatase 2A (beta-arrestin-2/AKT/PP2A) complex that is known to be required for lithium sensitive behaviors. Defining the direct target(s) is critical for the development of new therapies and for elucidating the molecular pathogenesis of this major psychiatric disorder. Here, we show what we believe to be a new link between GSK-3 and the beta-arrestin-2 complex in mice and propose an integrated mechanism that accounts for the effects of lithium on multiple behaviors. GSK 3beta (Gsk3b) overexpression reversed behavioral defects observed in lithium treated mice and similar behaviors observed in Gsk3b+/- mice. Furthermore, immunoprecipitation of striatial tissue from WT mice revealed that lithium disrupted the beta-arrestin-2/Akt/PP2A complex by directly inhibiting GSK-3. GSK 3 inhibitors or loss of one copy of the Gsk3b gene reduced beta-arrestin 2/Akt/PP2A complex formation in mice, while overexpression of Gsk3b restored complex formation in lithium-treated mice. Thus, GSK-3 regulates the stability of the beta-arrestin-2/Akt/PP2A complex, and lithium disrupts the complex through direct inhibition of GSK-3. We believe these findings reveal a new role for GSK-3 within the beta-arrestin complex and demonstrate that GSK-3 is a critical target of lithium in mammalian behaviors. PMID- 21821917 TI - Disruption of PPARgamma/beta-catenin-mediated regulation of apelin impairs BMP induced mouse and human pulmonary arterial EC survival. AB - Reduced bone morphogenetic protein receptor 2 (BMPR2) expression in patients with pulmonary arterial hypertension (PAH) can impair pulmonary arterial EC (PAEC) function. This can adversely affect EC survival and promote SMC proliferation. We hypothesized that interventions to normalize expression of genes that are targets of BMPR2 signaling could restore PAEC function and prevent or reverse PAH. Here we have characterized, in human PAECs, a BMPR2-mediated transcriptional complex between PPARgamma and beta-catenin and shown that disruption of this complex impaired BMP-mediated PAEC survival. Using whole genome-wide ChIP-Chip promoter analysis and gene expression microarrays, we delineated PPARgamma/beta-catenin dependent transcription of target genes including APLN, which encodes apelin. We documented reduced PAEC expression of apelin in PAH patients versus controls. In cell culture experiments, we showed that apelin-deficient PAECs were prone to apoptosis and promoted pulmonary arterial SMC (PASMC) proliferation. Conversely, we established that apelin, like BMPR2 ligands, suppressed proliferation and induced apoptosis of PASMCs. Consistent with these functions, administration of apelin reversed PAH in mice with reduced production of apelin resulting from deletion of PPARgamma in ECs. Taken together, our findings suggest that apelin could be effective in treating PAH by rescuing BMPR2 and PAEC dysfunction. PMID- 21821919 TI - Polyphenols in alcoholic beverages activating constitutive androstane receptor CAR. AB - The constitutive androstane receptor CAR is a xenosensing nuclear receptor that can be activated by natural polyphenols such as flavonoids and catechins. We examined alcoholic beverage phytochemicals for their ability to activate CAR. HepG2 cells were transfected with CAR expression vector and its reporter gene, and then treated with trans-resveratrol, ellagic acid, beta-caryophyllene, myrcene, and xanthohumol. A luciferase assay revealed that ellagic acid and trans resveratrol activated both human and mouse CAR. Since CAR regulates many genes involved in energy metabolism, the possibility exists that these polyphenols would reduce the risk of certain alcohol-induced metabolic disorders with the help of CAR. PMID- 21821918 TI - Reduction of ER stress via a chemical chaperone prevents disease phenotypes in a mouse model of primary open angle glaucoma. AB - Mutations in myocilin (MYOC) are the most common genetic cause of primary open angle glaucoma (POAG), but the mechanisms underlying MYOC-associated glaucoma are not fully understood. Here, we report the development of a transgenic mouse model of POAG caused by the Y437H MYOC mutation; the mice are referred to herein as Tg MYOC(Y437H) mice. Analysis of adult Tg-MYOC(Y437H) mice, which we showed express human MYOC containing the Y437H mutation within relevant eye tissues, revealed that they display glaucoma phenotypes (i.e., elevated intraocular pressure [IOP], retinal ganglion cell death, and axonal degeneration) closely resembling those seen in patients with POAG caused by the Y437H MYOC mutation. Mutant myocilin was not secreted into the aqueous humor but accumulated in the ER of the trabecular meshwork (TM), thereby inducing ER stress in the TM of Tg-MYOC(Y437H) mice. Furthermore, chronic and persistent ER stress was found to be associated with TM cell death and elevation of IOP in Tg-MYOC(Y437H) mice. Reduction of ER stress with a chemical chaperone, phenylbutyric acid (PBA), prevented glaucoma phenotypes in Tg-MYOC(Y437H) mice by promoting the secretion of mutant myocilin in the aqueous humor and by decreasing intracellular accumulation of myocilin in the ER, thus preventing TM cell death. These results demonstrate that ER stress is linked to the pathogenesis of POAG and may be a target for treatment in human patients. PMID- 21821920 TI - Comparison of the thermal stabilities of the alphabeta heterodimer and the alpha subunit of avian myeloblastosis virus reverse transcriptase. AB - Avian myeloblastosis virus reverse transcriptase (AMV RT) is a heterodimer consisting of a 63-kDa alpha subunit and a 95-kDa beta subunit. In this study, we explored the role of the interaction between the alpha and beta subunits on AMV RT stability. The recombinant AMV RT alpha subunit was expressed in insect cells and purified. It exhibited lower thermal stability than the native AMV RT alphabeta heterodimer. Unlike the alphabeta heterodimer, the alpha subunit was not stabilized by template-primer. These results suggest that interaction between the alpha and beta subunits is important for AMV RT stability. PMID- 21821921 TI - Melanin biosynthesis inhibitors from Tarragon Artemisia dracunculus. AB - The EtOH extract of tarragon Artemisia dracunculus, a perennial herb in the family Asteraceae, was found to potently inhibit alpha-melanocyte-stimulating hormone (alpha-MSH) induced melanin production in B16 mouse melanoma cells. Bioassay-guided fractionation led to the isolation of two alkamide compounds, isobutyl (1) and piperidiyl (2) amides of undeca-2E,4E-dien-8,10-dynoic acid. The respective EC(50) values for melanin biosynthesis inhibition were 1.8 and 2.3 ug/mL for 1 and 2. PMID- 21821922 TI - Comparative and stability analyses of 9- and 13-Oxo-octadecadienoic acids in various species of tomato. AB - Peroxisome proliferator-activated receptor-alpha (PPARalpha) regulates lipid metabolism. We have reported that tomato fruit contains 9-Oxo-(10E,12E) octadecadienoic acid (9-Oxo-(10E,12E)-ODA), a PPARalpha agonist. In this study, we found that various tomato samples contained 9-Oxo-(10E,12Z)-ODA and its 13-Oxo ODA isomers. Furthermore, several isomers showed structural stability under hot and acidic conditions. PMID- 21821923 TI - Functional-food constituents in the fruiting bodies of Stropharia rugosoannulata. AB - Nine compounds (1-9) were isolated from the fruiting bodies of Stropharia rugosoannulata. Compounds 1-5, 8, and 9 suppressed the formation of osteoclast. Compounds 2 and 5 showed anti-fungal activity, and their MIC were 250 uM and 500 uM respectively. Compounds 2-6 showed inhibitory effects on thapsigargin toxicity. PMID- 21821924 TI - Polyhydroxyalkanoate (PHA) synthesis by class IV PHA synthases employing Ralstonia eutropha PHB(-)4 as host strain. AB - Class IV polyhydroxyalkanoate (PHA) synthase from Bacillus cereus YB-4 (PhaRC(YB4)) or B. megaterium NBRC15308(T) (PhaRC(Bm)) was expressed in Ralstonia eutropha PHB(-)4 to compare the ability to produce PHA and the substrate specificity of PhaRCs. PhaRC(YB4) produced significant amounts of PHA and had broader substrate specificity than PhaRC(Bm). PMID- 21821925 TI - Calreticulin inhibits prion protein PrP-(23-98) aggregation in vitro. AB - Because prion protein PrP-(23-98) was recently found to polymerize into amyloid like and proteinase K-resistant spherical aggregates in the presence of NADPH plus copper ions, we tested to determine whether calreticulin (CRT) inhibits PrP (23-98) aggregation in vitro. The results indicated that CRT suppressed PrP-(23 98) aggregation, and that CRT-mediated solubilization occurred in the aggregates. PMID- 21821926 TI - Drosophila GTPase nucleostemin 2 changes cellular distribution during larval development and the GTP-binding motif is essential to nucleoplasmic localization. AB - Nucleostemin (NS), a nucleolar guanosine triphosphate (GTP)-binding protein, plays significant roles in cell cycle progression and ribosomal biogenesis. Drosophila Nucleostemin 2 (NS2), a member of the Drosophila NS family, regulates early eye development and is essential to cell survival in vivo, but the underlying mechanisms have yet to be clarified. Biochemical analysis using the recombinant NS2 protein indicated that NS2 has GTPase activity. Immunohistochemistry revealed that NS2 changes in subcellular locus from the nucleolus to the nucleoplasm during larval development, and that a mutation in the ATP/GTP-binding site motif A (p-loop) prevents nuclear localization of NS2 and results in cytoplasmic distribution. Furthermore, downregulation of NS2 altered the rRNA proportions between the nucleus and the cytoplasm. These results suggest that NS2 at least requires GTP to import into the nucleoplasm. PMID- 21821927 TI - Increases in gene-targeting frequencies due to disruption of kueA as a ku80 homolog in citric acid-producing Aspergillus niger. AB - Low efficiencies of gene targeting hamper functional genomics in industrially important strains of Aspergillus niger. To generate strains showing high gene targeting frequencies in A. niger WU-2223L producing citric acid, disruption of kueA encoding Ku80 homolog was performed. Disruption of kueA increased gene targeting frequencies to 70%, and had no effect on citric acid production. PMID- 21821928 TI - A non-NadB type L-aspartate dehydrogenase from Ralstonia eutropha strain JMP134: molecular characterization and physiological functions. AB - We report the molecular characterization and physiological function of a novel L aspartate dehydrogenase (AspDH). The purified enzyme was a 28-kDa dimeric protein, exhibiting high catalytic activity for L-aspartate (L-Asp) oxidation using NAD and/or NADP as cofactors. Quantitative real-time PCR analysis indicated that the genes involved in the AspDH gene cluster, poly-3-hydroxyalkanoate (PHA) biosynthesis, and the TCA cycle were substantially induced by L-Asp in wild-type cells. In contrast, expression of the aspartase and aspartate aminotransferase genes was substantially induced in the AspDH gene knockout mutant (DeltaB3576) but not in the wild type. GC-MS analyses revealed that the wild-type strain synthesized poly-3-hydroxybutyrate from fructose or L-Asp, whereas the DeltaB3576 mutant did not synthesize PHA from L-Asp. AspDH gene cluster products might be involved in the biosynthesis of the PHA precursor, revealing that AspDH was a non NadB type enzyme, and thus entirely different from the previously reported NadB type enzymes working in NAD biosynthesis. PMID- 21821929 TI - Calcium ion-dependent increase in thermostability of dextran glucosidase from Streptococcus mutans. AB - Dextran glucosidase from Streptococcus mutans (SmDG), which belongs to glycoside hydrolase family 13 (GH13), hydrolyzes the non-reducing terminal glucosidic linkage of isomaltooligosaccharides and dextran. Thermal deactivation of SmDG did not follow the single exponential decay but rather the two-step irreversible deactivation model, which involves an active intermediate having 39% specific activity. The presence of a low concentration of CaCl2 increased the thermostability of SmDG, mainly due to a marked reduction in the rate constant of deactivation of the intermediate. The addition of MgCl2 also enhanced thermostability, while KCl and NaCl were not effective. Therefore, divalent cations, particularly Ca2+, were considered to stabilize SmDG. On the other hand, CaCl2 had no significant effect on catalytic reaction. The enhanced stability by Ca2+ was probably related to calcium binding in the beta->alpha loop 1 of the (beta/alpha)(8) barrel of SmDG. Because similar structures and sequences are widespread in GH13, these GH13 enzymes might have been stabilized by calcium ions. PMID- 21821930 TI - Construction of multidrug-sensitive yeast with high sporulation efficiency. AB - Budding yeast is often used in chemical genetics for screening, target identification, and compound verification, but its high-level drug resistance has made the analysis of compounds difficult. Here we report the construction of 12geneDelta0HSR, a strain that lacks eight efflux pumps located on the plasma membrane and four transcription factors involved in expression of efflux pumps, and contains the RME1(ins-308A) mutation. This strain retained sufficient transformation, mating, and sporulation efficiency for genetic analysis in addition to hypersensitivity against several compounds. 12geneDelta0HSR is a useful tool for chemical biology, not only in chemical screening but in target identification and verification of bioactive compounds. PMID- 21821931 TI - SNX-2112, a novel Hsp90 inhibitor, induces G2/M cell cycle arrest and apoptosis in MCF-7 cells. AB - SNX-2112 is a heat shock protein 90 (Hsp90) inhibitor with anticancer properties currently in clinical trials. This study investigated the effects of SNX-2112 on inhibition of cell growth, the cell cycle, and apoptosis in MCF-7 human breast cancer cells, in addition to the various molecular mechanisms. The results of 3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and flow cytometric analysis suggest that SNX-2112 inhibits cell growth in a time- and dose-dependent manner more potently than 17-(allylamino)-17-demethoxygeldanmycin (17-AAG), a traditional Hsp90 inhibitor, probably as a result of cell-cycle arrest at the G2/M phase and the induction of apoptosis. Downregulation of Bcl-2 and Bcl-xL, upregulation of Bax, cleavage of caspase-9 and poly (ADP-ribose) polymerase (PARP), and degradation of the breast cancer-related Hsp90 client proteins human epidermal growth factor receptor-2 (HER2), Akt, Raf-1, and nuclear factor kappa-B kinase (IKK) were observed in SNX-2112 treated cells by Western blot assay. These findings suggest that the molecular mechanisms of cell-growth inhibition by SNX-2112 involve activation of the mitochondrial apoptotic pathway and the degradation of breast cancer-related proteins. PMID- 21821932 TI - Synthesis of stable isotope-labeled precursors for the biosyntheses of capsaicinoids, capsinoids, and capsiconinoids. AB - Stable isotope-labeled precursors were synthesized for an analysis by liquid chromatography-tandem mass spectrometry (LC-MS/MS) to elucidate the biosynthetic flow of capsaicinoids, capsinoids, and capsiconinoids. [1'-(13)C][5-(2)H] Vanillin was prepared by the condensation of guaiacol with [(13)C]-chloroform and a D(2)O treatment. Labeled vanillylamine, vanillyl alcohol, ferulic acid, and coniferyl alcohol were prepared from the labeled vanillin. The labeled vanillylamine was converted to labeled capsaicinoid in a crude enzyme solution extracted from pungent Capsicum fruits. PMID- 21821933 TI - Analysis of the mechanism of inhibition of human matrix metalloproteinase 7 (MMP 7) activity by green tea catechins. AB - Green tea catechins inhibit human matrix metalloproteinase 7 (MMP-7) activity non competitively, and the galloyl group is essential for potent inhibition (Oneda et al., J. Biochem., 133, 571-576 (2003)). In this study, we analyzed the mechanism of this inhibition. In the hydrolysis of (7-methoxycoumarin-4-yl)acetyl-L-Pro-L Leu-Gly-L-Leu-[N(3)-(2,4-dinitrophenyl)-L-2,3-diaminopropionyl]-L-Ala-L-Arg NH(2), the inhibitory effects of (-)-epigallocatechin-3-gallate (EGCG), (-) gallocatechin-3-gallate (GCG), (-)-epicatechin-3-gallate (ECG), and (-)-catechin 3-gallate (CG) increased with increasing pH levels from 7.0 to 8.5. The inhibitory effects of EGCG and GCG were more potent than those of ECG and CG, and increased with increasing CaCl(2) concentrations from 10 to 50 mM. The fluorescence of EGCG and GCG decreased with increasing CaCl(2) concentrations and with the addition of MMP-7, while those of ECG and CG did not. Our results suggest that these differences result from that in the B ring, EGCG and GCG have phenol hydroxyl groups at the 3', 4', and 5' positions, while ECG and CG have them at the 3' and 4' positions. PMID- 21821934 TI - B-transferase with a Pro234Ser substitution acquires AB-transferase activity. AB - A/B-Transferase is a glycosyltransferase that transfers a sugar substrate onto H antigen, which is responsible for the synthesis of glycoprotein- and glycolipid conjugates termed A/B-antigens. One polymorphism that causes the Pro234Ser substitution in B-transferase was recently found in a genotyping study, and might be cis-AB. In the present study, we analyzed the phenotypes arising from the enzymatic specificity of B-transferase with the Pro234Ser mutation. To evaluate the effect of the P234S mutation on enzymatic specificity, we generated an expression plasmid for B-transferase with Pro234Ser as well as A-transferase with Leu266Met, which is frequently found in cis-ABs. Transfection of B transferase/P234S or A-transferase/L266M cDNA into HeLa cells, an O-blood group cell line, resulted in an AB-phenotype by absorption-elution testing and immunostaining, whereas A- and B-transferase-expressing HeLa cells exhibited only their own activity. Molecular simulation indicated that the P234S mutation causes a conformational change in the substrate pocket making it suitable for N acetylgalactosamine. PMID- 21821935 TI - Orally administered glucosylceramide improves the skin barrier function by upregulating genes associated with the tight junction and cornified envelope formation. AB - Dietary glucosylceramide improves the skin barrier function. We used a microarray system to analyze the mRNA expression in SDS-treated dorsal skin of the hairless mouse to elucidate the molecular mechanisms involved. The transepidermal water loss of mouse skin was increased by the SDS treatment, this increase being significantly reduced by a prior oral administration of glucosylceramides. The microarray-evaluated mRNA expression ratio showed a statistically significant increase in the expression of genes related to the cornified envelope and tight junction formation when compared with all genes in the glucosylceramide-fed/SDS treated mouse skin. We then examined the contribution of glucosylceramide metabolites to the tight junction formation of cultured keratinocytes. The SDS treatment of cultured keratinocytes significantly decreased the transepidermal electrical resistance, this decrease being significantly ameliorated in the presence of sphingosine or phytosphingosine, the major metabolites of glucosylceramide. These results suggest that an oral administration of glucosylceramide improved the skin barrier function by up-regulating genes associated with both the cornified envelope and tight junction formation. PMID- 21821936 TI - Intracellular ATP levels affect secondary metabolite production in Streptomyces spp. AB - The addition of extracellular ATP (exATP) to four Streptomyces strains had similar effects: low exATP levels stimulated antibiotic production and high levels reduced it. Compared with antibiotic production, the concentrations of intracellular ATP (inATP) in the tested strains were opposite, which suggests a role of inATP in regulating secondary metabolite production. Under inactivation of the polyphosphate kinase gene (ppk) in Streptomyces lividans, we observed the same results: when the inATP level in the mutant strain was lower than in the parent strain, more antibiotic was produced. Combining all the results, a strong inverse relationship between [inATP] and the secondary metabolite production is suggested by this study. PMID- 21821937 TI - ROS production and apoptosis induction by formation of Gts1p-mediated protein aggregates. AB - GTS1 of Saccharomyces cerevisiae is a pleiotropic gene. Its induction leads to a variety of biological phenomena represented by cell aggregation. The C-terminal polyglutamine sequence in Gts1p is indispensable for its pleiotropy and nuclear localization. This sequence is often observed in polyglutamine diseases, such as Huntington disease, and is believed to induce protein aggregation, leading to cell death. In this study, protein aggregates were formed in a polyglutamine dependent manner in cells inducing GTS1, and heat-shock protein family, translation elongation factor, and mitochondrial proteins were trapped in Gts1p mediated protein aggregates. Moreover, the polyglutamine sequence of Gts1p was indispensable to the induction of reactive oxygen species (ROS) production and apoptosis. Deletion of the genes encoding Por1p and Yhb1p altered the profiles of ROS production and apoptosis caused by GTS1 induction, suggesting that the trapping of these proteins in Gts1p-mediated protein aggregates inhibits the intrinsic functions of these proteins. PMID- 21821938 TI - Variation in biomass properties among rice diverse cultivars. AB - Biomass properties of rice straws were compared among eight cultivars that formed a mini diverse set. The ethanol productivity from rice straws was evaluated employing a laboratory-scale method based on dilute acid-hydrolysis pretreatment. The results indicated significant variation in biomass properties among the cultivars. PMID- 21821939 TI - Production of Glycolipid Biosurfactants, cellobiose lipids, by Cryptococcus humicola JCM 1461 and their interfacial properties. AB - Cryptococcus humicola JCM 1461 efficiently produced cellobiose lipids (CLs), bolaform biosurfactants. The main product was identified as 16-O-(2",3",4",6' tetra-O-acetyl-beta-cellobiosyl)-2-hydroxyhexadecanoic acid. The production yield of CLs reached 13.1 g/L under the intermittent feeding of glucose. The critical micelle concentrations (CMC) of the main product at pH 4.0 and 7.0 were 3.3*10( 5) M and 4.1*10(-4) M respectively. PMID- 21821940 TI - Non-acidic compounds induce the intense sweet taste of neoculin, a taste modifying protein. AB - Neoculin, a sweet protein found in the fruit of Curculigo latifolia, has the ability to change sourness into sweetness. Neoculin turns drinking water sweet, indicating that non-acidic compounds may induce the sweetness. We report that ammonium chloride and certain amino acids elicit the intense sweetness of neoculin. Neoculin can thus sweeten amino acid-enriched foods. PMID- 21821941 TI - An in vitro analysis system using a fluorescence protein reporter for evaluating anti-inflammatory effects in macrophages. AB - Monitoring of inflammation in adipose tissues, which causes insulin resistance, is valuable in evaluating insulin resistance. We developed an in vitro analysis system using a fluorescence protein (FP) as a reporter gene driven by pro inflammatory cytokine promoters such as monocyte chemoattractant protein-1 (MCP 1) and tumor necrosis factor-alpha (TNFalpha). In the reporter-transfected RAW264 cells, the protein expression levels of green fluorescence protein (GFP) were increased by inflammatory stimulations such as lipopolysaccharide (LPS), conditioned medium prepared using hypertrophied 3T3-L1 adipocytes, and a co culture system. The changes in fluorescence intensity were equivalent to those of the mRNA and protein expression levels for each cytokine. Moreover, the effects of 15-deoxy-12,14Delta-prostaglandine J(2), a natural anti-inflammatory compound, were detectable in this system. These data indicate that the FP system developed here is an analysis system of low cost with simple procedures for evaluating inflammation, suggesting usability in the large-scale screening of anti inflammatory compounds. PMID- 21821942 TI - Functional characterization of HY5 homolog genes involved in early light signaling in Physcomitrella patens. AB - The developmental programs of Physcomitrella patens, a basal lineage of land plants, are regulated by phytohormones and light-signaling responses. In this study, our attention was focused on the HY5-family of transcription factors, which are known to play important roles immediately downstream of photoreceptors during the early photomorphogenesis of Arabidopsis thaliana. We retrieved two HY5 homologs, named PpHY5a and PpHY5b, from the whole genome sequence database of P. patens. Arabidopsis transgenic plants overproducing the basic leucine zipper (bZIP) domain of PpHY5a exhibited a phenotype of short hypocotyls, suggesting a functional relationship between PpHY5 and Arabidopsis HY5. A loss-of-function Deltahy5a Deltahy5b double mutant was defective in the vigorous protrusion of caulonema cells from the protonema networks of P. patens under light and dark conditions. These results suggest that the function of HY5-homologs in P. patens is evolutionarily conserved, and is implicated in a process of caulonema development. PMID- 21821943 TI - Achillinin A, a cytotoxic guaianolide from the flower of Yarrow, Achillea millefolium. AB - Achillinin A (2beta,3beta-epoxy-1alpha,4beta,10alpha-trihydroxyguai-11(13)-en 12,6alpha-olide, 1), a new guaianolide isolated from the flower of Achillea millefolium, exhibited potential antiproliferative activity to A549, RERF-LC-kj and QG-90 cells with 50% inhibitory concentration (IC(50)) values of 5.8, 10 and 0.31 uM, respectively. PMID- 21821944 TI - A new glycosylated dihydrophaseic acid from cacao germs (Theobroma cacao L.). AB - Cacao beans are composed of cacao nibs and germs. Although numerous chemical and physiological studies on cacao nib compounds have been reported, there is little information on cacao germ compounds. We therefore analyzed an extract from the cacao germ, and found two compounds that were specific to the germ. One of these two compounds was identified as the new glycosylated abscisic acid metabolite, dihydrophaseic acid-4'-O-6"-(beta-ribofuranosyl)-beta-glucopyranoside, and the other as the known compound, dihydrophaseic acid-4'-O-beta-D-glucopyranoside. PMID- 21821945 TI - Tissue distribution of hesperetin in rats after a dietary intake. AB - Hesperetin, the aglycone of hesperidin present in citrus fruits, possesses various biological activities. We assessed the tissue distribution of hesperetin in rats fed with a 0.2% hesperetin diet for 4 weeks. Its highest concentration was found in the liver, and the second highest was in the aorta. The aorta is assumed to be one of the main target tissues of hesperetin for exerting its functions. PMID- 21821946 TI - Simultaneous enrichment of deglycosylated ginsenosides and monacolin K in red ginseng by fermentation with Monascus pilosus. AB - To improve its bioavailability and pharmacological effects in humans, red ginseng was fermented with a newly isolated fungus, Monascus pilosus KMU103. Most of the ginsenosides were converted to deglycosylated ginsenocides, such as Rh(1), Rh(2), and Rg(3). The total amount of ginsenosides Rh(1), Rh(2), and Rg(3) was 838.7 mg/kg in the red ginseng, and increased to 4,117 mg/kg after 50 L fermentation in 13% red ginseng and 2% glucose. In addition, the Monascus-fermented red ginseng contained 3,089 mg/kg of monacolin K, one of the metabolites produced by Monascus known to reduce cholesterol in the blood. This newly developed Monascus-fermented red ginseng should result in improved health effects, not only by biotransforming gisenosides to deglycosylated ones but also by creating additional bioactive compounds. PMID- 21821947 TI - Possible evidence of contamination by catechins in deconjugation enzymes from Helix pomatia and Abalone entrails. AB - beta-Glucuronidase and sulfatase are the major deconjugating enzymes used in the cleavage of the glucuronate and sulfate moieties, respectively, from certain conjugated food factors including polyphenols. In the present study, we found that compounds having the same molecular weights as catechins were present in Helix pomatia- and/or Abalone entrails-derived beta-glucuronidase and sulfatase by liquid chromatography tandem mass spectrometry (LC-MS/MS) with multiple reaction monitoring methods. On the other hand, the same molecular weights as catechins were undetectable in Escherichia coli-derived beta-glucuronidase and Aerobacter aerogenes-derived sulfatase. By high performance liquid chromatography, enzyme-derived catechins were not detected because of approximately 1,000-fold lower sensitivity as compared to LC-MS/MS. These results suggest that the catechins in these enzymes might be attributed to the diets of the organisms as the enzyme sources. PMID- 21821948 TI - Identification of novel short peptide inhibitors of soluble 37/48 kDa oligomers of amyloid beta42. AB - Since the soluble oligomers of 42-residue amyloid beta (Abeta42) might be neurotoxins at an early stage of Alzheimer's disease (AD), inhibition of soluble Abeta42 oligomerization should be effective in the treatment of AD. We have found by phage display that a 7-residue peptide, SRPGLRR, exhibited inhibitory activity against soluble 37/48 kDa oligomers of Abeta42. In the present study, we newly prepared 3- and 4-residue random peptides libraries and performed pannings of them against soluble Abeta42 to search for important factors in the inhibition of Abeta42 oligomerization. After the fifth round, arginine-containing peptides were enriched in both libraries. SDS-PAGE and size-exclusion chromatography indicated that the inhibitory activities of 4-residue peptides against the soluble 37/48 kDa oligomers of Abeta42 were higher than those of the 3-residue peptides, and RFRK exhibited strong inhibitory activity as well as SRPGLRR. These short peptides should be useful for the suppression of soluble Abeta42 oligomer formation. PMID- 21821949 TI - Asymmetric synthesis and sensory evaluation of sedanenolide. AB - The synthesis and sensory evaluation of enantiomeric sets of sedanenolide (1) and 3-butylphthalide (3) are described. The asymmetric synthesis was achieved via the intramolecular Diels-Alder reaction of chiral propargylester (5) which was prepared from optically active propargyl alcohol (4) and 2,4-pentadienoic acid. The sensory evaluation of these enantiomers revealed that there were distinct differences between their aroma character and odor threshold. PMID- 21821950 TI - A method for the simultaneous determination of 3T3-L1 adipocyte metabolites by liquid chromatography/mass spectrometry using [(13)C]-stable isotopes. AB - A useful method employing liquid chromatography mass spectrometry (LC/MS) and a stable isotope was developed for simultaneous examination of major metabolism in adipocytes, de novo fatty acid synthesis, glycerol output, and glucose uptake with high sensitivity. The addition of thiazolidinediones, potent agonists of peroxisome proliferator-activated receptors-gamma, for 10 d increased glucose uptake in a dose-dependent manner. Fatty acid (FA) synthesis increased at low concentrations of thiazolidinediones (TZDs) and decreased at high concentrations. It is important to assess adipocytes from various examples of metabolism, because each example of adipocyte metabolism is directly related to obesity or metabolic syndrome in various ways. The technique makes metabolic examination easier than conventional methods by means of radioisotopes and makes it possible to identify metabolites and to apply them in biomarker screening. PMID- 21821951 TI - Remarkable expression in the colon adenocarcinoma of Hmat-Xa, a human mannosyltransferase-like gene, that is homologous to drosophila gene GC15914. AB - We cloned a novel human mannosyltransferase-like gene, designated Hmat-Xa, as a gene homologous to the Drosophila GC15914 gene encoding the 9QVXN0 protein: see "Project Report for FY2002 on the 'Construction of Libraries of Human Genes Participating in Glycosylation' project" 43-45 (2003), New Energy and Industrial Technology Development Organization (NEDO), NEDO and Research Association for Biotechnology, Tokyo, Japan (in Japanese). After that, the GTDC1 gene, as reported by Zhao et al., DNA Cell Biol., 23, 183-187 (2004), was found to be the same as the Hmat-Xa gene. Domain EXFGI/L/VX(2)L/VE in the Hmat-Xa protein, also present in both human mannosyltransferase II/III and mannosyltransferase IV/V, which are involved in the synthesis of lipid-linked oligosaccharides, and some bacterial mannosyltransferases. A real-time PCR study of Hmat-Xa mRNA expression in human normal and tumor multiple tissue cDNA identified its tissue-specific expression and its remarkable expression in colon adenocarcinoma as compared to the normal counterpart. Thus the elevated expression of Hmat-Xa might serve as a candidate marker for colon adenocarcinoma. PMID- 21821952 TI - Isolation and anti-fatty liver activity of a novel cerebroside from the sea cucumber Acaudina molpadioides. AB - Cerebrosides are a kind of important bioactive substance in sea cucumber. A novel cerebroside, AMC-2, was purified from the less-polar lipid fraction of the sea cucumber Acaudina molpadioides by repeated column chromatography. The major structure of AMC-2 was analyzed by gas chromatography-mass spectra. The amide linked fatty acid unit was confirmed to be four saturated and monounsaturated alpha-hydroxy fatty acids, the long-chain base was dihydroxy sphingoid base with one double bond, and the glycosyl group was glucose. We also investigated the anti-fatty liver activity of AMC-2 in rats with fatty liver induced by orotic acid. AMC-2 significantly reduced hepatic triglyceride (TG) and total cholesterol (TC) levels at a diet supplement of 0.03% and 0.006%. The indexes of stearoyl-CoA desaturase (SCD) activity and mRNA expression were significantly decreased by AMC 2. This indicates that AMC-2 ameliorated nonalcoholic fatty liver disease (NAFLD) through suppression of SCD activity and impaired the biosynthesis of monounsaturated fatty acids in the livers of the rats. PMID- 21821953 TI - Immunohistochemical localization of endogenous D-Aspartate in the marine brown Alga Sargassum fusiforme. AB - Immunohistochemical localization (cellular localization) of endogenous D aspartate in the marine brown alga Sargassum fusiforme was investigated by the use of a specific polyclonal antibody raised against D-aspartate. D-Aspartate immunoreactivity was evident in the medullary layer in the blade of the alga, and weak staining was found in the cortical layer, whereas epidermal cells were found to lack D-aspartate. Within the cells of the layers, immunoreactivity was confirmed only in the cytosol and not in the cell wall, chloroplast, or vacuole. These results suggest that D-aspartate is present in S. fusiforme cells, and excludes the possibility that it is derived from attached or symbiotic organisms such as marine bacteria. This is the first report describing the localization of free D-aspartate in plant cells. PMID- 21821954 TI - Protein tyrosine phosphatase 1B and alpha-glucosidase inhibitory Phlorotannins from edible brown algae, Ecklonia stolonifera and Eisenia bicyclis. AB - The present work investigates protein tyrosine phosphatase 1B (PTP1B) and the alpha-glucosidase inhibitory activities of two edible brown algae, Ecklonia stolonifera and Eisenia bicyclis, as well as in their isolated phlorotannins. Since the individual extracts and fractions showed significant inhibitory activities, column chromatography was performed to isolate six phlorotannins, phloroglucinol (1), dioxinodehydroeckol (2), eckol (3), phlorofurofucoeckol-A (4), dieckol (5), and 7-phloroeckol (6). Phlorotannins 3-6 were potent and noncompetitive PTP1B inhibitors with IC(50) values ranging from 0.56 to 2.64 uM; 4-6 exhibited the most potent alpha-glucosidase inhibition with IC(50) values ranging from 1.37 to 6.13 uM. Interestingly, 4 and 6 were noncompetitive, while 5 exhibited competitive inhibition in an alpha-glucosidase assay. E. stolonifera and E. bicyclis as well as their isolated phlorotannins therefore possessed marked PTP1B and alpha-glucosidase inhibitory activities; this could lead to opportunities in the development of therapeutic agents to control the postprandial blood glucose level and thereby prevent diabetic complications. PMID- 21821955 TI - The importance of inter-species cell-cell co-aggregation between Lactobacillus plantarum ML11-11 and Saccharomyces cerevisiae BY4741 in mixed-species biofilm formation. AB - Cells of Lactobacillus plantarum ML11-11, an isolate from Fukuyama pot vinegar, and the yeast Saccharomyces cerevisiae formed significant mixed-species biofilms with concurrent inter-species co-aggregation. The co-aggregation did not occur with heated or proteinase K-treated ML11-11 cells, or in the presence of D mannose, suggesting that surface proteins of ML11-11 and mannose-containing surface substance(s) of yeast were the predominant contributing factors. Sugar fatty acid ester inhibited mixed-species biofilm formation, but did not inhibit co-aggregation, suggesting that the cell-cell adhesion and cell-polystylene adhesion are controlled by different mechanisms. Microscopic observation and microflora analysis revealed that inter-species co-aggregation plays an important role in the formation of the mixed-species biofilm. PMID- 21821956 TI - Fritillaria ussuriensis extract inhibits the production of inflammatory cytokine and MAPKs in mast cells. AB - Fritillaria ussuriensis (FU, derived from the bulbs of various species of the genus Fritillaria, including Fritillaria thunbergii Miq.) is used in herbal medicine to treat conditions such as eczema, skin burns, and frostbite. In this study, we investigated the mechanism of the anti-allergy effect of FU. FU extract (80 mg/kg), orally administered to Sprague-Dawley (SD) rats, significantly inhibited the passive cutaneous anaphylaxis (PCA) reaction. It inhibited the compound 48/80-induced release of histamine from rat peritoneal mast cells in a concentration-dependent manner. Significant inhibitory effects of the FU extract on IL-6, IL-8, and TNF-alpha (1, 10, and 100 ug/mL) were observed in HMC-1 cells. Treatment with FU attenuated PMA plus A23187-induced phosphorylation of all three MAPKs, especially at concentrations of 10 and 100 ug/mL. Further, it (80 mg/kg) led to significant inhibition of mast-cell accumulation in ear tissue at the chronic phase. These results indicate that it inhibits allergic reactions. PMID- 21821957 TI - Post-translational isoprenylation of tryptophan. AB - Bacillus subtilis and related bacilli produce a post-translationally modified oligopeptide, ComX pheromone, that stimulates natural genetic competence controlled by quorum sensing. The ComX pheromones are formed by geranylation or farnesylation on a tryptophan residue at the 3 position of its indole ring. This results in the formation of a tricyclic structure including, a newly formed five membered ring, similar to proline. Isoprenylation of ComX to form ComX pheromones is essential for pheromonal activity, and is functionally more crucial than its amino acid sequence. The ComX pheromone is the first example of isoprenoidal modifiations of tryptophan residues in living organisms and post-translational isoprenylation of any amino acid in prokaryotes. Because the presence of geranylated compounds is unusual in primary and secondary metabolites outside the plant kingdom, post-translational geranylation in bacilli is unprecedented in nature. PMID- 21821958 TI - Synthesis of microbial signaling molecules and their stereochemistry-activity relationships. AB - Microbial signaling molecules such as autoinducers and microbial hormones play important roles in intercellular communication in microorganisms. Information transfer between the individual cells of a microorganism is one of the most important biological events among them. Researchers often suffer from extremely low levels of microbial signaling molecule contents, which prevent them from understanding chemistry and biology of intercellular communication in microorganisms. Chemical synthesis is a powerful tool to obtain sufficient amounts of sample and to clarify the structure of a molecule. This review focuses on the synthesis and stereochemistry-bioactivity relationships of five microbial signaling molecules, Vibrio cholerae autoinducer-1 (CAI-1), AI-2 precursor (DPD), an acylhomoserine lactone from Rhizobium leguminosarum (small bacteriocin), a diffusible extracellular factor of Xanthomondas campestris pv. campestris, and Phytophthora mating hormone alpha1. PMID- 21821959 TI - Antihypertensive and vasorelaxant effects of water-soluble proanthocyanidins from persimmon leaf tea in spontaneously hypertensive rats. AB - The antihypertensive and vasorelaxant effects of water-soluble proanthocyanidins, extracted in persimmon leaf tea, were investigated in spontaneously hypertensive rats, rat aortas, and human umbilical vein endothelial cells. Oral administration of proanthocyanidins significantly decreased the systolic blood pressure of the rats after 4 h, as compared with distilled water controls. A vasorelaxant effect on rat aortas was induced by proanthocyanidins, and it was abolished by removal of the endothelium and inhibition of endothelial nitric oxide synthase and soluble guanylyl cyclase activity. The phosphorylation levels of endothelial nitric oxide synthase (Ser-1177) and the upstream kinase Akt (Ser-473) in umbilical cells also increased in a time-dependent manner after the addition of a proanthocyanidin-rich fraction. These results suggest that the antihypertensive effect of proanthocyanidins in persimmon leaf tea is due to vasorelaxation via an endothelium-dependent nitric oxide/cGMP pathway, and that proanthocyanidins might be useful in dietary lowering of blood pressure. PMID- 21821960 TI - Kinetic behaviour of free lipase and mica-based immobilized lipase catalyzing the synthesis of sugar esters. AB - The utilization of natural mica as a biocatalyst support in kinetic investigations is first described in this study. The formation of lactose caprate from lactose sugar and capric acid, using free lipase (free-CRL) and lipase immobilized on nanoporous mica (NER-CRL) as a biocatalyst, was evaluated through a kinetic study. The apparent kinetic parameters, K(m) and V(max), were determined by means of the Michaelis-Menten kinetic model. The Ping-Pong Bi-Bi mechanism with single substrate inhibition was adopted as it best explains the experimental findings. The kinetic results show lower K(m) values with NER-CRL than with free-CRL, indicating the higher affinity of NER-CRL towards both substrates at the maximum reaction velocity (V(max,app)>V(max)). The kinetic parameters deduced from this model were used to simulate reaction rate data which were in close agreement with the experimental values. PMID- 21821961 TI - Prognostic impact of myocardial interstitial fibrosis in non-ischemic heart failure. -Comparison between preserved and reduced ejection fraction heart failure.-. AB - BACKGROUND: Although myocardial fibrosis plays an important role in the progression of heart failure (HF), its prognostic impact still remains to be clarified. METHODS AND RESULTS: A total of 172 consecutive patients with chronic HF, who underwent cardiac catheterization and endomyocardial biopsy between January 2001 and September 2008, were examined. They were divided into 2 groups: HF with preserved ejection fraction (HFPEF; left ventricular ejection fraction [LVEF] >= 50%, n=81); and HF with reduced LVEF (HFREF; LVEF < 50%, n=91). The collagen volume fraction (CVF) in biopsy samples was calculated and its prognostic impact examined. Mean follow-up in the HFPEF and the HFREF groups was 41 +/- 33 months and 41 +/- 26 months, respectively. Although CVF was similar between the 2 groups (1.83 +/- 1.54% vs. 2.07 +/- 2.35%), CVF was significantly correlated with LV end-diastolic pressure in the HFREF group but not in the HFPEF group. When HF stage was adjusted, the long-term prognosis was comparable between the 2 groups. When the patients were divided into 2 groups according to median CVF, however, severe fibrosis was a significant predictor for all-cause death (P=0.014) and cardiac events (P=0.02) in the HFREF, but not in the HFPEF group. CONCLUSIONS: Myocardial fibrosis evaluated on biopsy samples is a useful indicator for long-term survival, suggesting that it may be an important therapeutic target as well. PMID- 21821962 TI - Effectiveness of paclitaxel-eluting stents in complex clinical patients. Insights from the TAXUS Japan Postmarket surveillance study.-. AB - BACKGROUND: The TAXUS Japan Postmarket Surveillance Study (TAXUS-PMS) enrolled patients receiving percutaneous coronary intervention in real-world clinical practice. This analysis focuses on outcomes in the overall patient population and in a subgroup of diabetic patients. METHODS AND RESULTS: Between July 2007 and December 2008, 2,132 patients (with 2,504 lesions) were consecutively enrolled at 56 sites in Japan. One-year outcomes were analyzed. The prevalence of patients with diabetes was 44% (21% of diabetics were insulin-treated) and 5.5% of patients were receiving ongoing hemodialysis. The majority of patients received paclitaxel-eluting stents (PES) for 'off-label' indications (68.2%). The rate of major adverse cardiovascular events (cardiac death, myocardial infarction, and target vessel revascularization (TVR)) at 1 year was 8.2%, driven mainly by TVR (6.9%). No differences in TVR, late loss or restenosis rates were found between diabetic and non-diabetic patients; outcomes in insulin- compared with oral hypoglycemic-treated diabetic patients, were similar. Multiple stent implantation and ostial lesion location were independent predictors for both major adverse cardiac events (MACE) and target lesion revascularization (TLR). Hemodialysis was an independent predictor for MACE but not TLR whereas in-stent restenosis was an independent predictor for TLR. CONCLUSIONS: TAXUS-PMS demonstrated a consistent, positive effect of PES in complex clinical cases. PES diminished the increased risk of clinical restenosis in diabetic patients, leading to a similar low risk of cardiac events in diabetic and non-diabetic patients. PMID- 21821963 TI - Intensive lipid-lowering therapy with rosuvastatin stabilizes lipid-rich coronary plaques. -Evaluation using dual-source computed tomography.-. AB - BACKGROUND: Clinical studies using invasive modalities have reported that statin therapy stabilizes coronary plaque vulnerability. The serial changes of lipid rich coronary plaques (LRCPs) during rosuvastatin treatment were evaluated non invasively in patients with acute coronary syndrome (ACS) using dual-source computed tomography (DSCT). METHODS AND RESULTS: A total of 11 consecutive ACS patients, and 13 LRCPs were serially evaluated on DSCT before and 24 weeks after rosuvastatin treatment. Compared with the baseline, there was no change in post treatment minimal lumen diameter, lumen volume, or longitudinal length of LRCPs. By contrast, the ratio of lipid core volume to plaque volume significantly decreased from 48.0 +/- 9.9% to 43.7 +/- 10.6% (P=0.04), and plaque volume decreased from 144.5 +/- 85.5 mm3 to 119.8 +/- 78.0 mm3 (P=0.07). The remodeling index of target LRCPs significantly decreased from 1.16 +/- 0.10 to 1.06 +/- 0.12 (P=0.02). Percent reduction of plaque volume was significantly greater in patients with a lower ratio of low-density lipoprotein to high-density lipoprotein (L/H ratio <= 1.5) at follow-up than patients with higher L/H ratio (>1.5; median -31.7% vs. -6.8%, P=0.03). CONCLUSIONS: Rosuvastatin therapy reduced the volume of lipid cores and LRCPs and increased the CT attenuation value of LRCPs. DSCT is an effective modality for the non-invasive evaluation of LRCPs in patients with ACS. ). PMID- 21821964 TI - Association of the leptin to high-molecular-weight adiponectin ratio with metabolic syndrome. AB - Recent studies have reported that leptin and adiponectin are associated with metabolic syndrome. The leptin/adiponectin ratio has been suggested as an atherosclerotic index. The objective of this study was to compare the degree of association of metabolic syndrome with adiponectin levels, leptin levels, leptin/adiponectin ratio, and leptin/high-molecular-weight (HMW) adiponectin ratio. The study population included 3272 Koreans (men: 1915, women: 1357; age, 30-84 years), who had visited the Health Examination Center. Adipokines were divided into quartiles, and metabolic syndrome was defined by the National Cholesterol Education Program Adult Treatment Panel-III (NCEP ATP III). A logistic regression model was fitted to establish the association between adipokines and metabolic syndrome. Adipokines, such as adiponectin, HMW adiponectin, and leptin, were found to be statistically related to metabolic syndrome. Compared to the lowest quartile, the leptin/HMW adiponectin ratio in the highest quartile was associated with a 5-fold increase in the probability of prevalent metabolic syndrome, which was independent of age, smoking status, exercise, low-density lipoprotein (LDL) cholesterol, and body mass index. There was a linear increase in the leptin/HMW adiponectin ratio as the number of metabolic syndrome components increased. The leptin/HMW adiponectin ratio had the highest odds ratio in women. In addition, compared to adiponectin or leptin alone, the AUC of the leptin/adiponectin ratio and leptin/HMW adiponectin ratio was higher for metabolic syndrome. We may suggest that the leptin/HMW adiponectin ratio is not superior to other adipokine markers, but is as effective as the leptin/total adiponectin ratio. PMID- 21821967 TI - Perceptions and practices of Japanese nurses regarding tobacco intervention for cancer patients. AB - BACKGROUND: We investigated the perceptions and practices regarding tobacco intervention among nurses, as improvement of such practices is important for the management of patients who smoke. METHODS: Self-administered questionnaires were delivered by hospital administrative sections for nursing staff to 2676 nurses who were working in 3 cancer hospitals and 3 general hospitals. Of these, 2215 (82.8%) responded. RESULTS: Most nurses strongly agreed that cancer patients who had preoperative or early-clinical-stage cancer but continued to smoke should be offered a tobacco use intervention. In contrast, they felt less need to provide tobacco use intervention to patients with incurable cancer who smoked. Most nurses felt that although they assessed and documented the tobacco status of cancer patients, they were not successful in providing cessation advice, assessing patient readiness to quit, and providing individualized information on the harmful effects of tobacco use. In multivariate analysis, nurses who received instruction on smoking cessation programs during nursing school were more likely to give cessation advice (odds ratio, 1.61; 95% confidence interval, 1.15-2.26), assess readiness to quit (1.73, 1.09-2.75), and offer individualized explanations of the harmful effects of tobacco (1.94, 1.39-2.69), as compared with nurses who had not received such instruction. CONCLUSIONS: The perceptions of Japanese nurses regarding tobacco intervention for cancer patients differed greatly by patient treatment status and prognosis. The findings highlight the importance of offering appropriate instruction on smoking cessation to students in nursing schools in Japan. PMID- 21821968 TI - Pharmacological study on Alzheimer's drugs targeting calcium/calmodulin-dependent protein kinase II. AB - In the brain of Alzheimer's disease patients, down-regulation of both cholinergic and glutamatergic systems have been found and is thought to play an important role in impairment of cognition, learning, and memory. Nefiracetam is a pyrrolidine-related nootropic drug exhibiting various pharmacological actions such as a cognitive-enhancing effect. The present study was undertaken to elucidate mechanisms underlying the action of nefiracetam on glutamatergic receptors and intracellular protein kinases. N-Methyl-D-aspartate (NMDA)-evoked currents were recorded from rat cortical neurons in long-term cultured primary neurons using the whole-cell patch-clamp technique. NMDA-evoked currents were greatly and reversibly potentiated by bath application of nefiracetam, resulting in a bell-shaped dose-response curve. The maximum potentiation of 170% relative to the control was produced at 10 nM. Treatment with an inhibitor of the glycine binding site of the NMDA receptor, 7-chlorokynurenic acid, at 1 uM prevented augmentation of NMDA-evoked currents by nefiracetam. In rat hippocampal CA1 slices, field excitatory postsynaptic potentials were recorded by stimulation of Schaffer collateral/commissural pathways. Nefiracetam treatment significantly enhanced long-term potentiation (LTP) with the same bell-shaped dose-response curve. Furthermore, nefiracetam-induced LTP enhancement was closely associated with calcium/calmodulin-dependent protein kinase II (CaMKII) activation with concomitant increase in phosphorylation of AMPA-type glutamate receptor subunit 1 (GluA1) (Ser-831) as a postsynaptic CaMKII substrate. In conclusion, nefiracetam enhances NMDA-receptor function through stimulation of its glycine binding site and nefiracetam-induced CaMKII activation likely contributes to improvement of cognition, learning, and memory. PMID- 21821969 TI - Roles of heterotrimeric GTP-binding proteins in the progression of heart failure. AB - Heart failure is a major cause of death in developed countries, and the development of an epoch-making cure is desired from the viewpoint for improving the quality of life and reducing the medical cost of the patient. The importance of neurohumoral factors, such as angiotensin (Ang) II and catecholamine, for the progression of heart failure has been supported by a variety of evidence. These agonists stimulate seven transmembrane-spanning receptors that are coupled to heterotrimeric GTP-binding proteins (G proteins). Using specific pharmacological tools to assess the involvement of G protein signaling pathways, we have revealed that alpha subunit of G(q) (Galpha(q)) activates Ca(2+)-dependent hypertrophic signaling through diacylglycerol-activated transient receptor potential canonical (TRPC) channels (TRPC3 and TRPC6: TRPC3/6). In contrast, activation of Galpha(12) family proteins in cardiomyocytes confers pressure overload-induced cardiac fibrosis via stimulation of purinergic P2Y(6) receptors induced by extracellular nucleotides released from cardiomyocytes. In fact, direct or indirect inhibition of TRPC3/6 or P2Y(6) receptors attenuates pressure overload-induced cardiac dysfunction. These findings will provide a new insight into the molecular mechanisms underlying pathogenesis of heart failure. PMID- 21821970 TI - Abrupt cessation of one-year clopidogrel treatment is not associated with thrombotic events. AB - We aimed to examine the rate of thrombotic events after discontinuation of one year clopidogrel therapy in patients with implanted coronary stent, and to determine platelet aggregability by multiple electrode analyzer after cessation of clopidogrel. This prospective, multicenter study enrolled 200 patients subjected to coronary stent implantation and treated with aspirin + clopidogrel one year after the stent placement. Platelet aggregation was measured using 3 agonists [adenosine diphosphate with PGE(1) (ADPHS), arachidonic-acid (ASPI), and thrombin receptor activating peptide (TRAP)] on the day of cessation of clopidogrel and at 10, 45, and 90 days after clopidogrel was stopped. Two thrombotic events were registered during the 6-months follow up (one ischemic stroke and one myocardial infarction; incidence of 1%). The mean values of ADP + PGE(1)- and ASPI-induced aggregation 10 - 90 days after the cessation of clopidogrel were significantly higher than values obtained before the termination of the drug (P < 0.001, all). Cessation of clopidogrel did not influence the TRAP induced aggregation, which reached the plateau in all measurements. In conclusion, the incidence of thrombotic events after the cessation of one-year clopidogrel treatment might be lower than expected in patients with implanted coronary stent. PMID- 21821971 TI - Comparison of the effects of omeprazole and rabeprazole on ticlopidine metabolism in vitro. AB - The thienopyridine derivative ticlopidine (TCL) is an inhibitor of adenosine diphosphate-induced platelet aggregation. Combination therapy with a thienopyridine derivative and aspirin is standard after coronary stenting, although more hemorrhagic complications occur with the combination therapy than with aspirin alone. A proton pump inhibitor (PPI) is required for prevention or treatment of upper gastrointestinal bleeding in such cases. We examined the effects of PPIs [omeprazole (OPZ) and rabeprazole (RPZ)] on TCL metabolism using pooled human liver microsomes prepared from various human liver blocks and 12 individual human liver microsomes. We calculated the K(i) values of each PPI for TCL metabolic activity and compared the inhibitory effect of each PPI on TCL metabolism. The K(i) values of OPZ and RPZ were 1.4 and 12.7 uM, respectively. The inhibitory effect of OPZ (78.6 +/- 0.05%) was significantly greater than that of RPZ (24.2 +/- 0.05%) (P < 0.001). Interestingly, a negative correlation existed between the inhibitory effect of OPZ and CYP2C19 activity (r = -0.909, P < 0.001). These results suggest that the inhibitory effect of OPZ is more potent than that of RPZ in vitro. In conclusion, RPZ appears preferable when administering TCL, aspirin, and a PPI in combination. PMID- 21821973 TI - [Feature articles: current status and future direction of the treatment of hematological disorders with molecular-targeting agents (1)]. PMID- 21821972 TI - Involvement of dopaminergic receptor signaling in the effects of glutamatergic receptor antagonists on conditioned place aversion induced by naloxone in single dose morphine-treated rats. AB - A better understanding of the neurochemical mechanisms mediating the aversive consequences of drug withdrawal is important for understanding drug addiction. We previously demonstrated that the inhibitory effect of glutamate receptor antagonists on the conditioned place aversion (CPA) induced by naloxone precipitated withdrawal after a single morphine exposure could be blocked by dopamine receptor antagonists. Thus, a glutamatergic-dopaminergic interaction may participate in this phenomenon. The current study was undertaken to further characterize this interaction by employing both D(1) (SCH 23390) and D(2) (raclopride and eticlopride) dopamine receptor antagonists. The influence of these antagonists on the attenuation of CPA by MK-801 (NMDA receptor antagonist), GYKI 52466 (AMPA receptor antagonist), and MCPG (metabotropic glutamate receptor antagonist) was determined in rats receiving a single dose of morphine. The dopamine antagonists showed either a significant reversal or a tendency to reverse the effects of MK-801 on CPA. The effect of GYKI 52466 was also attenuated by the blockade of either D(1) or D(2) receptors. The effect of MCPG, however, was only blocked by D(2) antagonists and not by the D(1) antagonist SCH 23390. These results add evidence to the hypothesis that a glutamatergic dopaminergic interaction may be involved in the CPA induced by naloxone precipitated withdrawal following a single morphine exposure and suggest that both D(1) and D(2) dopamine receptor signaling mechanisms play a role in mediating the aversive aspects of acute dependence. PMID- 21821974 TI - [Epigenetic therapy in myelodysplastic syndromes]. PMID- 21821975 TI - [Molecular mechanisms of lenalidomide for the treatment of myelodysplastic syndromes]. PMID- 21821976 TI - [TKI therapy for CML]. PMID- 21821977 TI - [Application of novel tyrosine-kinase inhibitors for the treatment of leukemia and Ph-negative myeloproliferative neoplasms]. PMID- 21821978 TI - [All-trans retinoic acid and arsenic trioxide: their molecular mechanisms of action and updated clinical progress in APL therapy]. PMID- 21821979 TI - [Development of novel therapies targeting leukemia stem cells]. PMID- 21821980 TI - [Structure and function of MYST family histone acetyltransferases]. PMID- 21821981 TI - [Therapy for malignancies and inflammatory disorders by modulating human dendritic cell functions]. PMID- 21821982 TI - [Harnessing myeloid dendritic cell subsets in novel cancer immunotherapy]. PMID- 21821983 TI - [Control of immune responses by regulatory dendritic cells]. PMID- 21821984 TI - [Plasmacytoid dendritic cells as therapeutic targets in novel therapeutics for autoimmune diseases]. PMID- 21821985 TI - [Specific surface markers of AML-leukemic stem cells]. PMID- 21821986 TI - [Exacerbation of autoimmune neutropenia to agranulocytosis in association with severe autoimmune thrombocytopenia and hemolytic anemia in a patient with Sjogren's syndrome]. AB - A 73-year-old woman with Sjogren's syndrome and autoimmune neutropenia (AIN) associated with large granular lymphocytosis of the polyclonal T cell type, demonstrated autoimmune thrombocytopenia (AIT) at diagnosis of sigmoid colon cancer. Ten months later, both AIN and AIT had exacerbated to agranulocytosis and severe thrombocytopenia below 10*10(9)/L, respectively. There were no dysplastic features of bone marrow hematopoietic cells. Furthermore, an in vitro assay of hematopoietic progenitors showed normal granuloid and erythroid colony formation. Although we serially treated her with prednisolone (oral), filgrastim, intravenous high-dose immunoglobulin infusion, cyclophosphamide (oral), danazol, cyclosporine A (oral), and rituximab, number of neutrophils and platelets elevated only temporarily. During the course of agranulocytosis and severe thrombocytopenia, the patient also developed autoimmune hemolytic anemia (AIHA). She died of pneumonia 5 months after the onset of agranulocytosis. This case is very unique and novel in terms of autoimmune phenomena simultaneously directed to granulocytes, platelets, and red blood cells under the background of Sjogren's syndrome. PMID- 21821987 TI - [Two cases of discordant lymphomas consisting of MALT lymphoma and follicular lymphoma]. AB - We report here rare cases of discordant lymphoma consisting of MALT lymphoma and follicular lymphoma. Case 1: A 53-year-old woman was diagnosed with MALT lymphoma of the left parotid gland and follicular lymphoma of the duodenum and small intestine. Case 2: A 38-year-old woman was diagnosed with MALT lymphoma of the intestine and follicular lymphoma of the duodenum and bone marrow. Recently, it has been suggested that duodenal follicular lymphoma has intermediate characteristics of nodal follicular lymphoma and MALT lymphoma. It is interesting that both of these cases demonstrated duodenal follicular lymphoma. These cases suggest that MALT lymphoma and duodenal follicular lymphoma share some common pathological condition. PMID- 21821988 TI - [Successful treatment with low-dose dasatinib in a patient with chronic eosinophilic leukemia intolerant to imatinib]. AB - A 77-year-old man with cough and dyspnea was admitted to hospital. Chest X-ray demonstrated reticulated shadows in the bilateral inferior lung fields and marked eosinophilia was detected in peripheral blood. Although he received steroid pulse therapy, eosinophilia became more serious and he was referred to our hospital. Bone marrow examination demonstrated a hypercellular marrow that consisted predominantly of dysplastic eosinophils with differentiation. FISH analysis of bone marrow cells demonstrated 4q12 deletion and RT-PCR analysis detected FIP1L1 PDGFRA fusion gene, leading to the diagnosis of chronic eosinophilic leukemia (CEL). Treatment with low-dose imatinib was immediately initiated; however, drug induced systemic edema was progressive and became intolerable. Therefore, we changed imatinib to low-dose dasatinib (20 mg/day), resulting in complete molecular response of CEL after 3 months without any severe adverse effects. This is the first report on the efficacy of low-dose dasatinib for the treatment of CEL. The peak level (Cmax) of dasatinib in this patient was 55.3 nM, which exceeded the concentration of dasatinib required to inhibit cells with FIP1L1 PDGFRA by 50%. Thus, low-dose dasatinib with therapeutic drug monitoring can be a useful therapy for imatinib-intolerant CEL even in elderly patients. PMID- 21821989 TI - [Extranodal NK/T-cell lymphoma, nasal type, developed in a patient with rheumatoid arthritis]. AB - It is well known that patients with rheumatoid arthritis (RA) have a higher risk of developing malignant lymphoma (ML) than the general population. Most of these lymphomas occur in patients receiving immunosuppressive (IS) agents such as methotrexate (MTX). Spontaneous regression of tumors is often observed after the discontinuation of IS drugs, especially in patients with Epstein-Barr virus positive lymphoma. Here we encountered an RA patient who developed extranodal NK/T-cell lymphoma, nasal type during treatment of RA with MTX and etanercept. Despite the discontinuation of MTX and etanercept, the tumor did not show any regression. Complete response was achieved after treatment with concurrent chemoradiotherapy. ML of NK-cell origin is extremely rare, while the majority of ML cases associated with RA are of B-cell origin. This report describes extranodal NK/T-cell lymphoma, nasal type case associated with RA. Such cases should be accumulated to evaluate the mechanism of onset and clinical characteristics of NK/T-cell lymphoma associated with RA. PMID- 21821990 TI - [Membranous nephropathy with nephrotic syndrome developed after allogeneic hematopoietic stem cell transplantation for acute lymphoblastic leukemia]. AB - A 38-year-old man was diagnosed with acute lymphoblastic leukemia. We performed myeloablative bone marrow transplantation from an unrelated donor during the patient's first complete remission. After engraftment, he developed acute graft versus-host disease involving the gastrointestinal tract on day 32. Steroids and mycophenolate mofetil were initiated from day 39. His symptoms improved and the dose of immunosuppressants was tapered and then discontinued on day 421. On day 491, he developed nephrotic syndrome (NS). Based on renal biopsy, membranous nephropathy was diagnosed. There were no apparent symptoms or abnormal laboratory data suggestive of chronic graft-versus-host disease (cGVHD). Steroid therapy was initiated from day 518 and proteinuria improved significantly. NS is very rare following allogeneic hematopoietic stem cell transplantation (allo-HSCT). When there is no concomitant cGVHD, as in this case, allo-HSCT-associated NS is difficult to distinguish from idiopathic NS. PMID- 21821991 TI - [Angioimmunoblastic T-cell lymphoma with marked polyclonal plasmacytosis in peripheral blood and bone marrow mimicking plasma cell leukemia]. AB - A 70-year-old man was admitted to our hospital with fever, generalized lymphadenopathy and hypoxia in October 2009. Blood examination demonstrated leukocytosis, anemia, thrombocytopenia and hyper gamma-globulinemia. Peripheral blood and bone marrow smear showed marked plasma cell proliferation mimicking plasma cell leukemia. However, flow cytometric analysis showed that plasma cells were of polyclonal origin and M-protein was not detected by immunofixation of serum protein. Elevations of soluble interleukin 2 receptor and serum IL-6 were observed. A heavy Epstein-Barr viral load was detected in serum by real-time PCR. Biopsy was obtained from the right inguinal lymph node. The pathological diagnosis was angioimmunoblastic T-cell lymphoma (AITL) and rearrangement of the T-cell receptor Cbeta1 gene was detected. The patient was treated with CHOP therapy, and all clinical manifestations, including fever, lymphadenopathy, anemia, thrombocytopenia, hyper gamma-globulinemia, plasmacytosis and hypoxia, were improved. Only a few reported cases have demonstrated AITL with marked polyclonal plasmacytosis. Although pathological mechanisms of plasmacytosis in AITL patients have not been fully elucidated, it is suggested that IL-6 and IL-10 were involved in its pathogenesis in the present case. PMID- 21821992 TI - Foreign gene transfer to cardiomyocyte using a replication-defective recombinant coxsackievirus B3 without cytotoxicity. AB - BACKGROUND: Replication-competent coxsackievirus B3 (CVB3) has been used as a gene transfer vector for cultured cardiomyocytes and hearts in vivo. However, CVB3 induces cell lysis when it replicates in infected cells. In this study, we investigated whether a replication-defective rCVB3 vector could be generated and used as a noncytotoxic gene transfer vector for cardiomyocytes. METHODS: We generated a replication-defective luciferase-expressing CVB3 plasmid. This recombinant cDNA and pCMV-P1 plasmids were amplified and cotransfected into Hek293 cells using transfection reagents. Replication-defective rLuCVB3 virus was recovered from the cells and cell culture supernatants for 3 days after transfection. The generated rLuCVB3 viruses were concentrated on a 30% sucrose cushion and semiquantified using a luciferase assay. In addition, foreign gene delivery by the rLuCVB3 was tested in cultured cardiomyocytes and intact mouse hearts after rLuCVB3 infection. RESULTS: Luciferase was expressed in Hek293, HeLa cells and cardiomyocytes after rLuCVB3 infection. In addition, these cells did not show a significant cytopathic effect after 72 h. Luciferase protein expression or activity were detected for 3 days in the myocardium of rLuCVB3 infected mouse hearts without producing cytotoxicity or inflammation. CONCLUSION: As a proof-of-concept, these data indicate that a replication-defective rCVB3 vector can be generated and used as a novel gene transfer system to transfect exogenous genes into cardiomyocytes without generating cytotoxicity. PMID- 21821993 TI - Unusual case of 'trapped fourth ventricle' in a child with posthemorrhagic hydrocephalus--lessons learnt. AB - In most of the children with posthemorrhagic hydrocephalus (PHH), multidisciplinary follow-up is performed, with the focus on consequences of prematurity, cerebral palsy (CP) and hydrocephalus. A large fourth ventricle is common in these children but imaging performed in order to document ventricles and tissue damage is not oriented to exclude coexisting rare pathologies. We report a 3-year-old child with spastic CP, secondary to prematurity and PHH. A ventriculoperitoneal shunt was inserted at the age of 2 months. On follow-up imaging the child demonstrated well-drained supratentorial ventricles with a persistent large fourth ventricle. Because of a neurological change in spasticity and new-onset torticollis, a repeat MRI was performed, suggesting a cystic, nonenhancing lesion of the fourth ventricle. The surgical exploration revealed a large dermoid of the fourth ventricle. We analyze the differential diagnosis of a clinically significant large fourth ventricle in a shunted child with PHH and CP. This includes conditions without pressure in the posterior fossa such as tissue loss due to cerebellar atrophy, or pathologies causing a true increase in pressure of the fourth ventricle (isolated fourth ventricle, cystic lesions and neoplasms of the fourth ventricle). Neurologically compromised children pose additional challenges in reaching a definitive diagnosis and hence require a careful regular assessment of their clinical status with additional well-timed imaging with appropriate protocols to allow appropriate treatment when indicated and to avoid morbidity due to delayed diagnosis. We present a rare coexistence of a dermoid tumor within the fourth ventricle in a CP child with PHH and express the dilemmas associated with its management. PMID- 21821994 TI - A cheap minimally painful and widely usable alternative for retrieving ureteral stents. AB - OBJECTIVE: To describe a cheap, minimally painful and widely usable method for retrieving ureteral stents by using an ureteroscope. SUBJECTS AND METHODS: Sixty seven patients with ureteral stents were enrolled in this study. The patients were randomized into a cystoscopic (35 patients) and a ureteroscopic (32 patients) group. All stents were retrieved by a flexible cystoscope in the first group and by a ureteroscope in the second group under local anesthesia. Patients in each group were assessed for stented time, stent side, cause of stent placement, operative time, peroperative pain, postoperative pain, irritative voiding symptoms and hematuria. Also costs of instruments were calculated. RESULTS: Stents were successfully retrieved in 67 patients. There were no statistical differences in the two groups regarding patient gender and age or stent side, operative time, stented time, mean operative pain score, irritative voiding symptom scores and hematuria. Total selling price was USD 20.399 for flexible instruments and USD 10.516 for rigid ones. Total maintenance price was higher in flexible instruments than in the rigid ones (USD 197.8 and 51.7 per use, respectively). CONCLUSION: Ureteroscopic stent retrieval is a minimally painful, safe and highly tolerable method under local anesthesia as well as flexible cystoscopic retrieval. Also, it is a cheap and widely usable method. PMID- 21821995 TI - Recombination in the nonstructural gene region in type 2 dengue viruses. AB - In view of the rising prevalence of dengue virus and mixing of host and vector populations, complete full-length sequence determination of dengue strains isolated from different epidemic areas is important for the study of virus evolution, pathogenicity, vaccine efficiency and diagnosis. Based on the genomic analysis of 51 complete dengue virus sequences, all of which cocirculated in Thailand between 1974 and 2001, we report here the occurrence of homologous recombination in the NS5 nonstructural gene region of dengue virus type 2 (DENV 2) strains. In order to analyze those 51 virus sequences at one time, we chose to use a highly sensitive recombination detection program called RDP. When RDP detects a possible recombination event, further bootscanning and phylogenetic tree analyses are applied to these candidate sequences to identify this recombination event. We found that within the DENV-2 subfamily, the strain ThNH63/93 is the evolutionary product of a recombination event between ThNH62/93 and ThD2_0284_90 strains. The strain ThNH62/93 was identified as the major parent, while the strain ThD2_0284_90 was the minor parent. The recombination site was determined to localize between positions 7967 (+/- 36 nt) and 8283 (+/- 36 nt) with a significance level of p < 0.001. Our results showed, for the first time, that an intraserotype recombination event occurred between DENV-2 strains in the nonstructural gene region; by contrast, an interserotype recombination between different serotypes of dengue strains was not identified. This study thus supports the theory that homologous recombination plays a key role in dengue virus evolution. PMID- 21821996 TI - Ethical principles: an essential part of the process in disorders of sex development care. PMID- 21821997 TI - Cerebral gas embolism from bronchoscopic argon plasma coagulation: a case report. AB - Argon plasma coagulation (APC) is a common and safe bronchoscopic technique used in the management of obstructing lesions and hemorrhage in the central airways. Complications of bronchoscopic APC are uncommon and include hemorrhage, perforation and fire in the airways. While bronchoscopic APC has been reported to cause systemic gas embolization and associated cardiovascular collapse, we report a case of cerebral gas embolization that occurred during bronchoscopic APC and highlight underappreciated potential risk factors for its occurrence. PMID- 21821998 TI - Fertility preservation in heterotopic cervical pregnancy: what is the best procedure? AB - We describe a patient who underwent assisted reproduction techniques and was diagnosed with heterotopic cervical pregnancy, and then discuss the management of this entity, which is rare and has no standard protocols. Treatment consisted of intra-arterial methotrexate (50 mg/m(2) body surface area) and simultaneous selective embolization of uterine arteries. The literature is also reviewed to identify other approaches and outcomes. PMID- 21821999 TI - Characterization of pulmonary venous hypertension patients with reactive pulmonary hypertension as compared to proportional pulmonary hypertension. AB - BACKGROUND: Patients with pulmonary venous hypertension (PVH) secondary to left heart disease can be further classified according to their hemodynamic profile: pulmonary hypertension (PH) in proportion to the pulmonary capillary wedge pressure (PCWP) and PH out of proportion to the PCWP or reactive PH. Currently, there are no measures that enable prediction of the development of reactive PH in patients with left heart disease. OBJECTIVES: In this study, we aim to characterize PVH patients with reactive PH as compared to proportional PH in an attempt to create a distinct profile for patients with left heart disease carrying a high risk for the development of reactive PH. METHODS: Thirty-three PVH patients with reactive PH and 29 PVH patients with proportional PH were analyzed retrospectively over a 6-year period. Clinical, laboratory, echocardiographic and hemodynamic parameters were noted and compared between subgroups. RESULTS: There was no significant difference between PVH patients with reactive and proportional PH with regard to gender, age (65.91 +/- 11.9 vs. 66.69 +/- 10.5 years) and body surface area (1.89 +/- 0.24 vs. 1.9 +/- 0.23 m(2)). Prevalence of the metabolic syndrome components was similar in both groups. Interestingly, PCWP was similar in both groups, as were the structural and functional parameters of the left heart. CONCLUSIONS: PVH patients with reactive PH have a similar profile as patients with proportional PH; consequently, the evolution of reactive PH is unpredictable. Therefore, it is imperative that physicians maintain a high index of suspicion for the development of reactive PH even in the early stage of heart disease. PMID- 21822000 TI - Age-related macular degeneration and risk factors for the development of choroidal neovascularisation in the fellow eye: a 3-year follow-up study. AB - INTRODUCTION: The presence of large-sized drusen (>=125 MUm), soft indistinct drusen, pigmentary changes, a large area of drusen and a choroidal neovascular membrane in one eye have been found to be predictive risk factors of late exudative age-related macular degeneration (AMD). Multimodal imaging potentially increases the possibility of indentifying further potential risk factors of developing wet AMD. PURPOSE: To identify morphological and/or functional baseline risk factors for the development of choroidal neovascularization (CNV) in a multimodal set of images from fellow eyes of patients with exudative AMD. METHODS: Single-center, prospective, observational, longitudinal 2-year plus 1 year extension study of 62 patients with neovascular AMD in one eye (the nonstudy eye) and early age-related maculopathy (ARM) in the fellow eye (study eye). Best corrected ETDRS visual acuity, fluorescein angiography (FA) and indocyanine green angiography (ICG), fundus photography, retinal leakage analysis, fundus autofluorescence imaging and optical coherence tomography (OCT Stratus 4.0.2, Carl Zeiss Meditech Inc.) were performed at baseline and every 6 months in order to identify both conversion to CNV as well as possible predictive features present before conversion. A semiautomated computer-assisted grading system was used for classifying fundus color images. Only eyes with 3 years of follow-up were considered for statistical analysis. RESULTS: Fifty-two patients completed the 3-year study follow-up: 26 men and 26 women aged from 56 to 92 years (mean +/ SD: 76 +/- 6 years). CNV confirmed with FA developed in 46% of the 52 study eyes during the 3-year follow-up (24 converted eyes: 7 in the first year, 11 in the second and 6 in the third). A significantly higher risk for conversion to wet AMD was found only for leakage on a retinal leakage analyzer (odds ratio, OR = 5.0; 95% confidence interval, CI = 1.5-16.4; p = 0.006) detected at least in one visit before the onset of exudative lesions, for baseline ICG hot spots (OR = 7.2; 95% CI = 2.0-25.7; p = 0.002), baseline late ICG hot spots (OR = 4.7; 95% CI = 1.4 15.4; p = 0.009) and baseline early ICG hypofluorescent spots (OR = 3.7; 95% CI = 1.2-12.1; p = 0.025). The total area of drusen, the area of drusen in subfield 1, inner circle or outer circle, the total number of drusen and the number of drusen >=125 MUm, fundus autofluorescence patterns, OCT findings and the severity of ARM at baseline did not show any correlation with an increased risk of conversion to wet AMD. CONCLUSION: At 3 years, progression from early to late exudative AMD was superior to the expected rate (44%). ICG early and late hyperfluorescent spots or areas, ICG early hypofluorescent spots or areas and early leakage detected with the retinal leakage analyzer, but not pigmentary changes, large drusen, number and area of drusen at any location or a greater severity of ARM at baseline, showed to be a predictive parameter of conversion to wet AMD. PMID- 21822001 TI - The effect of N(G)-nitro-L-arginine methyl ester, a nitric oxide synthase inhibitor, on respiratory mechanics in rats. AB - BACKGROUND: Data describing the inhibitory effects of nitric oxide synthase (NOS) on respiratory mechanics are conflicting, and no data are available concerning possible effects on the viscoelasticity of the respiratory system, on the inspiratory work of breathing (WOB) or on respiratory system hysteresis. OBJECTIVES: The aim of this study was to measure the effects of NOS inhibition by N(G)-nitro-L-arginine methyl ester (L-NAME) on respiratory mechanics in normal anesthetized rats. METHODS: Using the end-inflation occlusion method, it was possible to quantify the ohmic and viscoelastic airway resistance and elastance of the respiratory system. Ohmic resistance is the normalized-to-flow pressure dissipation due to viscous forces opposing the airflow in the airways, as predicted by the Poiseuille law. Viscoelastic resistance is the normalized-to flow pressure dissipation due to the resistance of respiratory system tissue to deformation during inflation, which is recovered after the arrest of the inspiratory flow (stress relaxation). The inspiratory WOB, its elastic and resistive components, and hysteresis were also calculated. RESULTS: L-NAME induced an increment in the ohmic airway resistance and in the resistive ohmic inspiratory WOB. The viscoelastic resistance due to stress relaxation and the elastic properties of the respiratory system were not modified, and no effect was detected on the related components of the inspiratory WOB and on hysteresis. CONCLUSIONS: NO acts in normal rats to reduce the ohmic component of airway resistance, decreasing the ohmic inspiratory WOB. The elastic and viscoelastic components are unaltered. Hysteresis is also unaltered, suggesting that NO has negligible effects on alveolar surfactant activity. PMID- 21822002 TI - CSF shunt complications in infants--an experience from Pakistan. AB - AIMS AND OBJECTIVE: The main aim of the study was to find out the postoperative complications and long-term outcome of cerebrospinal fluid-shunted patients in an infantile age group with a poor socioeconomic background. MATERIAL AND METHODS: A prospective study of 100 cases of infantile hydrocephalus was conducted at Pakistan Institute of Medical Sciences, Islamabad, Pakistan. All selected patients suffering from congenital and post-meningitic hydrocephalus were operated on for ventriculoperitoneal shunt. However, cases of hydrocephalus secondary to myelomeningocele were not included. Patients were followed postoperatively for 2 years. Prior consent for surgery was taken from all parents and the study was approved by the hospital's academic and ethical council. RESULTS: The majority of patients were brought quite late to the medical facilities because of social taboos and socioeconomic conditions. Early signs and symptoms of hydrocephalus were either ignored or misunderstood. Shunt infection and shunt failure rates remained at 14 and 10%, respectively. 50% of shunt blocks occurred in the first postoperative year and another 50% within 2 years. The highest percentage (40-45%) of death occurred in patients suffering from congenital hydrocephalus, in the first postoperative year. CONCLUSIONS: This study concluded that the outcome and prognosis of shunted infantile hydrocephalus in developing countries is suboptimal due to different socioeconomic conditions. However, under such circumstances, careful selection of patients, timely intervention and adherence to meticulous aseptic surgical techniques can alter the prognosis of cerebrospinal fluid-shunted infants. PMID- 21822003 TI - Cerebrospinal fluid hydrothorax without ventriculoperitoneal shunt migration in an infant. AB - Cerebrospinal fluid (CSF) hydrothorax is a rare complication of a ventriculoperitoneal shunt (VPS), and even rarer in the absence of shunt migration into the thoracic compartment. Because of the limited volume within the thoracic cavity, hydrothorax in infants can rapidly cause severe respiratory distress. The case of an infant with recurrent CSF hydrothorax despite a well positioned VPS is presented. A ventriculoatrial shunt was successfully performed as the definitive treatment. The absence of ascites or predisposing factors for decreased peritoneal absorption and a false-negative beta(2)-transferrin CSF marker are some of the factors that can add to the diagnostic challenge in these patients. This is a potentially life-threatening condition in infants, which should be closely considered in patients with VPS who develop hydrothorax, although diagnosis is not always straight forward. The etiology and pathophysiology of this very rare disease continue to be elusive, and treatment with ventriculoatrial shunt provides good results. PMID- 21822004 TI - Sturge-Weber syndrome. PMID- 21822005 TI - Ureteric avulsion caused by lumbar exostosis. AB - A 72-year-old woman sustained a ureteric avulsion following circulatory collapse at home. Urosonographic imaging revealed hydronephrosis at the left kidney, and abdominal emergency computed tomography showed some fluid around it. Left retrograde pyelography proved ureteral disruption at the level of the ureteropelvic junction (UPJ). Immediate open surgery was performed to restore ureteropelvic continuity. Correct and early diagnosis of UPJ transsection is difficult under emergency service conditions and lack of symptoms. With the rapid increase in the aging population, the presence of degenerative exostoses will increase, and its exclusive pathomechanism and pattern of injury might be seen more frequently in emergency care. Trauma specialists should be aware of this pathology. PMID- 21822006 TI - P450c17 deficiency caused by compound heterozygosity for two novel mutations presenting as hypotension in early infancy. AB - BACKGROUND/AIMS: P450c17 deficiency is an uncommon steroidogenic disorder that typically presents as a sexually infantile adolescent phenotypic female with hypertension and hypokalemia. Although cortisol synthesis is impaired, elevated corticosterone and deoxycorticosterone ordinarily prevent adrenal insufficiency. Thus, diagnosis prior to puberty is rare. We report novel clinical features of an infant with complete P450c17 deficiency due to two novel mutations in CYP17A1. METHODS: A 10-week-old, 46,XY phenotypic female presented with hypotension, developed hypokalemic hypertension post-resuscitation, then hyperkalemic hyponatremia upon weaning salt supplements. All CYP17A1 exons of the proband and parents were PCR-amplified and sequenced. Cosyntropin, GnRH agonist, and hCG tests were performed. RESULTS: Sequencing demonstrated compound heterozygosity for two novel CYP17A1 mutations, C327dupT and C362G>A (W121X), both generating premature stop codons in exon 2 and predicting non-functional enzymes. Plasma corticosterone was very elevated, deoxycorticosterone normal, cortisol detectable, and aldosterone low-normal at baseline. Responses to cosyntropin of corticosterone and progesterone were elevated, deoxycorticosterone and aldosterone normal, cortisol subnormal, and 17alpha-hydroxycorticosteroid intermediates undetectable. GnRH agonist/hCG testing showed no androgenic response. CONCLUSION: This is the first report of P450c17 deficiency presenting in a 46,XY female infant with hypotensive shock, a state exacerbated by the atypical absence of deoxycorticosterone elevation. PMID- 21822007 TI - White matter protection with insulin-like growth factor 1 and hypothermia is not additive after severe reversible cerebral ischemia in term fetal sheep. AB - Moderate cerebral hypothermia significantly improves survival without disability from perinatal hypoxia-ischemia. However, protection is partial. Insulin-like growth factor 1 (IGF-1) plays a key role in oligodendrocyte survival and myelination. The purpose of this study was to test the hypothesis that the combination of IGF-1 plus hypothermia could reduce postischemic white matter damage compared with hypothermia alone. Unanesthetized near-term fetal sheep received 30 min of cerebral ischemia, followed by either an infusion of 3 MUg of IGF-1 intracerebroventricularly from 4.5 to 5.5 h plus cooling from 5.5 to 72 h (IGF-1 + hypothermia; n = 8), vehicle infusion plus cooling from 5.5 to 72 h (vehicle + hypothermia; n = 12), sham cooling plus sham infusion (ischemia control; n = 12) or sham ischemia (n = 5). The fetal extradural temperature was reduced from 39.4 +/- 0.1 degrees C to between 30 and 33 degrees C. White matter was assessed after 5 days. Ischemia was associated with severe loss of CNPase positive oligodendrocytes in white matter compared with sham ischemia (380 +/- 138 vs. 1,180 +/- 152 cells/field; mean +/- SD; p < 0.001). Delayed hypothermia reduced cell loss (847 +/- 297 cells/field, p < 0.01, vs. ischemia control), but there was no significant difference between vehicle + hypothermia and IGF-1 + hypothermia (1,015 +/- 211 cells/field; NS). Ischemia was associated with increased caspase 3 expression in white matter (216 +/- 41 vs. 19 +/- 18 cells/field; p < 0.001). Hypothermia reduced numbers of activated caspase 3 positive cells (116 +/- 81 cells/field; p < 0.05), with no significant difference between vehicle + hypothermia and IGF-1 + hypothermia (91 +/- 27 cells/field; NS). In conclusion, delayed cotreatment with IGF-1 plus hypothermia after ischemia was associated with an improvement in white matter damage similar to that achieved by hypothermia alone. PMID- 21822008 TI - Effect of intravitreal bevacizumab based on optical coherence tomography patterns of diabetic macular edema. AB - AIM: To compare the effects of intravitreal bevacizumab on different morphologic patterns of diabetic macular edema (DME) classified using optical coherence tomography (OCT). MATERIALS AND METHODS: Medical records for 65 eyes of 48 patients were retrospectively reviewed, and each subject was classified as one of three DME types according to the OCT features: diffuse retinal thickening (DRT), cystoid macular edema (CME), serous retinal detachment (SRD). Subjects were given three monthly intravitreal injections of bevacizumab (1.25 mg/0.05 ml). The clinical course of best-corrected visual acuity (BCVA) with a logarithm of the minimum angle of resolution chart and central foveal thickness (CFT) using OCT was monitored for 12 months after the injections. On follow-up, injections were repeated if DME remained or was aggravated. RESULTS: Of the 65 eyes with DME, 29 eyes were of the DRT type, 21 of the CME type, and 15 of the SRD type. Before the injection, CFT and BCVA were, respectively, 377.1 +/- 145.9 MUm and 0.54 +/- 0.36 in the DRT type, 427.7 +/- 143.1 MUm and 0.59 +/- 0.42 in the CME type, and 485.1 +/- 187.1 MUm and 0.65 +/- 0.27 in the SRD type; there was no significant difference in CFT and BCVA between DME types (p > 0.05). At 6 months, the changes in BCVA and CFT differed significantly between OCT types (p < 0.05). At 12 months, changes in CFT and BCVA from baseline were not significantly different between groups (p > 0.05). The DRT type was associated with a greater reduction in the CFT and greater BCVA improvement than the CME or SRD types. CONCLUSIONS: Three monthly injections of intravitreal bevacizumab seem to be effective treatment in the first 6 months, but the therapeutic effect is temporary and repeated injections of bevacizumab should be considered to maintain the therapeutic effect after 6 months. In addition, intravitreal injection of bevacizumab was more effective in the DRT type than in the CME or SRD types of DME. PMID- 21822010 TI - Glomerular expression of kidney injury molecule-1 and podocytopenia in diabetic glomerulopathy. AB - BACKGROUND/AIMS: Studies have shown that kidney injury molecule-1 (KIM-1) is upregulated in damaged renal proximal tubules. In this study, we examined KIM-1 expression in glomerular epithelial cells in diabetic glomerulopathy. METHODS: Renal histology, immunostaining and Western blot for protein level, and real-time PCR for mRNA expression of KIM-1 and podocyte markers were evaluated in untreated or losartan-treated Zucker lean (Fa/+) and Zucker diabetic fatty (Fa/Fa) rats. RESULTS: The diabetic rats showed an increased glomerular expression of KIM-1. KIM-1 staining was localized primarily in the hyperplastic parietal epithelium of Bowman's capsule in the early stages of diabetes with subsequent increase in KIM 1-positive cells in the glomerular tuft in the more advanced stages. The increase in glomerular KIM-1 was associated with a decrease in podocytes in Fa/Fa rats. Antiproteinuric treatment with losartan attenuated podocytopenia and decreased renal expression of KIM-1 in treated diabetic rats. In an in vitro study, albumin overload increased KIM-1 protein in the primary cultures of rat glomerular epithelial cells. CONCLUSION: These results show that glomerular KIM-1 expression was increased, in proportion to the extent of proteinuria and podocytopenia in the diabetic animals, supporting that KIM-1 could be used as a potential biomarker for glomerular injury in proteinuric kidney disease. PMID- 21822009 TI - Molecular and cellular evidence for the alternative lengthening of telomeres (ALT) mechanism in chicken. AB - Telomere maintenance is an important genetic mechanism controlling cellular proliferation. Normally, telomeres are maintained by telomerase which is downregulated upon cellular differentiation in most somatic cell lineages. Telomerase activity is upregulated in immortalized cells and cancers to support an infinite lifespan and uncontrolled cell growth; however, some immortalized and transformed cells lack telomerase activity. Telomerase-negative tumors and immortalized cells utilize an alternative mechanism for maintaining telomeres termed alternative lengthening of telomeres (ALT). This research explored evidence for the ALT pathway in chicken cell lines by studying nontransformed immortalized cell lines (DF-1 and OU2) and comparing them to a normal (mortal) cell line and a transformed cell line (DT40). The research consisted of molecular and cellular analyses including profiling of telomeric DNA (array sizing and total content), telomerase activity, and expression of genes involved in the telomerase, recombination, and ALT pathways. In addition, an immunofluorescence analysis for an ALT marker, i.e. ALT-associated promyelocytic leukemia bodies (APBs), was conducted. Evidence for ALT was observed in the telomerase-negative immortalized cell lines. Additionally, the APB marker was also found in the other cell systems. The attributes of the chicken provide an additional vertebrate model for investigation of the ALT pathway. PMID- 21822011 TI - Outcome of intravenous thrombolysis in stroke patients weighing over 100 kg. AB - BACKGROUND: Intravenous thrombolysis with alteplase for ischemic stroke is fixed at a maximal dose of 90 mg for safety reasons. Little is known about the clinical outcomes of stroke patients weighing >100 kg, who may benefit less from thrombolysis due to this dose limitation. METHODS: Prospective data on 1,479 consecutive stroke patients treated with intravenous alteplase in six Swiss stroke units were analyzed. Presenting characteristics and the frequency of favorable outcomes, defined as a modified Rankin scale (mRS) score of 0 or 1, a good outcome (mRS score 0-2), mortality and symptomatic intracranial hemorrhage (SICH) were compared between patients weighing >100 kg and those weighing <=100 kg. RESULTS: Compared to their counterparts (n = 1,384, mean body weight 73 kg), patients weighing >100 kg (n = 95, mean body weight 108 kg) were younger (61 vs. 67 years, p < 0.001), were more frequently males (83 vs. 60%, p < 0.001) and more frequently suffered from diabetes mellitus (30 vs. 13%, p < 0.001). As compared with patients weighing <=100 kg, patients weighing >100 kg had similar rates of favorable outcomes (45 vs. 48%, p = 0.656), good outcomes (58 vs. 64%, p = 0.270) and mortality (17 vs. 12%, p = 0.196), and SICH risk (1 vs. 5%, p = 0.182). After multivariable adjustment, body weight >100 kg was strongly associated with mortality (p = 0.007) and poor outcome (p = 0.007). CONCLUSION: Our data do not suggest a reduced likehood of favorable outcomes in patients weighing >100 kg treated with the current dose regimen. The association of body weight >100 kg with mortality and poor outcome, however, demands further large-scale studies to replicate our findings and to explore the underlying mechanisms. PMID- 21822012 TI - Local head and neck cooling leads to hypothermia in healthy volunteers. AB - BACKGROUND: Prehospital cooling of acute stroke patients would be ideal when associated with minor or no side effects. Therefore, we evaluated a cooling cap for the surface of head and cervical regions in awake volunteers. METHODS: 10 healthy volunteers were treated by external cooling for 190 min using a gel-based cooling device. Vital signs, rectal temperature, tympanic temperature, the extent of shivering and individual perception of frostiness and discomfort were measured. RESULTS: All participants (median age 35 years) successfully completed the treatment and experienced only mild to moderate discomfort. No serious adverse events and no shivering were noticed. There was a significant drop in the tympanic temperature to 34.68 degrees C (difference from baseline: 1.7 degrees C, 95% CI: 0.61-2.7 degrees C, p = 0.001), in the rectal temperature to 36.65 degrees C (difference from baseline: 0.65 degrees C, 95% CI: 0.06-1.2 degrees C, p = 0.019) and in the heart rate (difference from baseline: 15 beats/min, 95% CI: 0.63-30 beats/min, p = 0.035). CONCLUSION: Treatment with the cooling device was well tolerated by all participants. The technique had measurable effects on core body temperature (rectal) and tympanic temperature (may reflect temperature at the external ear and skin rather than intracranial). It can be considered as a simple therapeutic approach to patients with suspected stroke in the prehospital setting. PMID- 21822013 TI - Accelerated coronary atherosclerosis revealed by arrhythmogenic coronary spasm. AB - Coronary artery spasm is sometimes associated with life-threatening ventricular arrhythmias. Based on intravascular ultrasound findings, it appears that coronary artery spasm promotes negative arterial remodeling, suggesting that patients with coronary artery spasm might be at higher risk of accelerated coronary atherosclerosis. We report the cases of 3 patients with ventricular arrhythmia secondary to coronary artery spasm complicated by accelerated coronary atherosclerosis. Consequently, coronary disease progression should be considered in the case of angina pectoris recurrence in patients with coronary artery spasm, especially in those with coronary artery spasm complicated by ventricular arrhythmia. PMID- 21822014 TI - Familial evaluation for diagnosis of arrhythmogenic right ventricular dysplasia. AB - Most sudden cardiac deaths in young athletes are caused by previously undetected inherited cardiac diseases. Here, we report a case of a young male athlete in whom a presumptive diagnosis of hypertrophic cardiomyopathy (HCM) was made following a near sudden cardiac death. Although his imaging studies initially suggested HCM, a detailed clinical and genetic evaluation of the patient and his asymptomatic father led to the diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVD) in both. DNA sequencing revealed that each individual was heterozygous for two rare variants in the PKP2 and DSC2 genes, both of which were previously shown to be associated with ARVD and to encode desmosomal proteins, i.e. the previously reported splicing variant c2489 + 1A > G in the PKP2 gene and the novel p.I109M variant in the DSC2 gene. Imaging and electrophysiologic studies further supported a diagnosis of ARVD in the father. This case highlights the importance of detailed clinical evaluation and genetic testing of family members when dealing with sudden cardiac death or unexplained cardiomyopathies in the young. PMID- 21822015 TI - Oral health-related quality of life in Hong Kong preschool children. AB - OBJECTIVES: To assess the impact of early childhood caries (ECC) on the quality of life in a population of preschool children and their families in Hong Kong. METHODS: A random sample of 1,296 Chinese preschool children participated in the survey and were subjected to an oral examination for their ECC status by 2 trained examiners. The parents were asked to respond to the Early Childhood Oral Health Impact Scale (ECOHIS) and an extra set of questions concerning their sociodemographic background. RESULTS: The final data analysis included 1,261 children with a mean (+/-SD) age of 3.9 +/- 0.66 years. The prevalence figures for ECC and severe ECC were 19.9 and 15.2%, respectively. Decayed teeth were found in 34.3% of the children while only 5.2% had filled teeth. The mean (+/-SD) dmft in this group of children was 1.5 +/- 2.98. Higher ECOHIS scores were found in parents with lower education or income level, or with children who were born in mainland China (p < 0.05), or with children who had decayed, missing, or filled teeth (p < 0.001). In multiple regression analyses, decayed teeth and filled teeth in primary dentition were the better predictors (p < 0.001) of the ECOHIS score among the various parent and child characteristics collected in this survey. CONCLUSIONS: The findings of this study showed that parents of young children with dental caries experience perceived that both the children and other family members had poorer quality of life. PMID- 21822017 TI - Cariogenic microorganisms and oral conditions in asthmatic children. AB - This study evaluated the caries risk of asthmatic patients on the basis of mutans streptococci (MS) and lactobacilli levels in saliva samples as well as the index of oral hygiene and dental caries (DMFT index). The study population was composed of 80 asthmatic children, aged 3-15 years, who use specific medication, and 80 matched, healthy control children. The parents were interviewed about oral health related factors. The World Health Organization criteria were used for dental examinations. The Kohler and Bratthal methodology was used to detect salivary MS levels and dilutions of saliva were done for lactobacilli counting. No differences between asthma and control groups were observed for caries prevalence in children aged 3-6 and 7-10 years, except in severe cases in the younger group. However, higher caries prevalence for permanent dentition was observed in 11- to 15-year-old asthmatic children. An increased dental biofilm was observed in the asthma group, as well as salivary levels of MS. No differences were observed in levels of lactobacilli. No statistical correlations were found between medication, frequency of treatment, method of consumption and caries experience, dental biofilm and salivary levels of MS or lactobacilli. However, there was a correlation between MS levels and treatment duration. The logistic regression revealed that MS level is an important risk factor for increased caries experience. Asthma should be evaluated as a risk factor for caries experience because it can increase the levels of MS and the dental biofilm. PMID- 21822016 TI - Immunological and microbiologic changes during caries development in young children. AB - We explored the association between caries development, colonization with caries associated microflora, and immunity as children begin the transition to mixed dentition. Forty children received dental examinations at 3-4 years of age, repeated a year later. Children were grouped into caries-free (n = 23; CF) and caries-active (n = 17; CA >=3 new lesions on follow-up). Salivary IgA and IgA antibody to Streptococcus mutans virulence epitopes were measured by Luminex assay. Mutans streptococci (MS), lactobacilli and total microorganisms were enumerated on selective media from plaque samples. There was no significant difference in baseline levels of MS or lactobacilli between CF and CA groups. However, both MS and lactobacilli levels were higher at follow-up in the CA group. Furthermore, children with detectable lactobacilli at baseline had significantly higher caries risk. Salivary IgA concentrations increased significantly in both groups during the study. Both CF and CA groups also displayed significant increases in salivary IgA antibody levels to glucosyltransferase, glucan-binding protein (Gbp) and antigen I/II salivary binding region. CF antibody levels to seven peptides associated with domains of biological importance increased at follow-up, in contrast to increases to only three peptides in CA saliva samples. Multivariate modeling showed that a lower baseline level of salivary IgA anti-GbpB was associated with higher caries risk. These data indicate that MS and lactobacilli are associated with caries in this population, that the secretory immune system is undergoing significant maturation during this period, and that the breadth of mucosal IgA response to epitopes of S. mutans virulence components may influence the degree to which these cariogenic microorganisms can cause disease. PMID- 21822018 TI - Effect of a sugar-free chewing gum containing magnolia bark extract on different variables related to caries and gingivitis: a randomized controlled intervention trial. AB - The effect of magnolia bark extract (MBE) on different variables related to caries and gingivitis administered daily through a sugar-free chewing gum was evaluated. The study was performed with healthy adult volunteers at high risk for caries as a randomized double-blind interventional study. 120 subjects with a salivary mutans streptococci (MS) concentration >=10(5) CFU/ml and presence of bleeding on probing >25% were enrolled and divided into three groups: magnolia, xylitol and control. The study design included examinations at baseline, after 7 days, after 30 days of gum use and 7 days after the end of gum use. Plaque pH was assessed using the strip method following a sucrose challenge. Area under the curve (AUC(5.7) and AUC(6.2)) was recorded. Whole saliva was collected and the number of salivary MS (CFU/ml) was counted. Bleeding on probing was recorded as a proxy of dental plaque. Data were analyzed using ANOVA repeated measures. Magnolia gum significantly reduced plaque acidogenicity, MS salivary concentration and gingival bleeding compared to xylitol and control gums. Subjects from the magnolia and xylitol groups showed both MS concentration (p = 0.01 and 0.06, respectively) and AUC(5.7) (p = 0.01 and 0.04, respectively) to be significantly lower compared to baseline. Thirty-day use of a chewing gum containing MBE showed beneficial effects on oral health, including reduction of salivary MS, plaque acidogenicity and bleeding on probing. PMID- 21822019 TI - Decision-making in frontotemporal dementia: clinical, theoretical and legal implications. AB - BACKGROUND: The behavioral variant of frontotemporal dementia (bvFTD) is characterized by progressive changes in personality and social interaction, loss of empathy, disinhibition and impulsivity, most of which generally precede the onset of cognitive deficits. In this study, we investigated decision-making cognition in a group of patients with an early bvFTD diagnosis whose standard neuropsychological performance was within normal range for all variables. METHODS: The Iowa Gambling Task was administered to this group of early bvFTD patients, to a group of early bvFTD patients who had shown impaired performance on the classical neuropsychological battery and to healthy controls. RESULTS: Decision-making was impaired in both bvFTD patient groups, whether they had shown impaired or normal performance in the classical neuropsychological evaluation. CONCLUSIONS: Patients with early bvFTD may perform normally on standard cognitive tests, and yet develop severe deficits in judgment and decision-making. In many current legal systems, early bvFTD patients showing preserved cognitive functioning who commit unlawful acts run the risk of not being able to plead insane or not guilty on the grounds of diminished responsibility beyond reasonable doubt. This represents a unique legal and ethical dilemma. Our findings have important implications for medicolegal decisions relating to capacity and culpability, and regarding the philosophical concept of 'free will'. PMID- 21822020 TI - A review of transcranial magnetic stimulation in the in vivo functional evaluation of central cholinergic circuits in dementia. AB - Central cholinergic circuits of human brain can be tested non-invasively by coupling electrical peripheral stimulation with transcranial magnetic stimulation (TMS) of the motor cortex. The short-latency afferent inhibition (SAI) is reduced in cholinergic forms of dementia, such as Alzheimer disease (AD) and dementia with Lewy bodies, while it is normal in non-cholinergic forms of dementia, such as frontotemporal dementia. This finding suggests that this method can be used as a non-invasive additional tool for discriminating between cholinergic and non cholinergic forms of dementia. Interestingly, SAI was also found to be significantly smaller in early AD patients. Identification of SAI abnormalities that occur early in the course of AD will allow earlier diagnosis and treatment with cholinergic drugs. In patients with vascular dementia, SAI responses varied widely; the number of patients with abnormal SAI conceivably reflects the percentage of subjects with a significant cholinergic dysfunction. It has recently been demonstrated that brain microbleeds have an impact on SAI that is independent of the extent of associated white matter changes and ischemic stroke. Since SAI can be increased by acetylcholinesterase inhibitors, TMS may help in identifying the patients who would be suitable for long-term treatment with cholinergic agents. PMID- 21822021 TI - Comparing aye-aye (Daubentonia madagascariensis) presence and distribution between degraded and non-degraded forest within Ranomafana National Park, Madagascar. AB - The aye-aye is considered the most widely distributed lemur in Madagascar; however, the effect of forest quality on aye-aye abundance is unknown. We compared aye-aye presence across degraded and non-degraded forest at Ranomafana National Park, Madagascar. We used secondary signs (feeding sites, high activity sites) as indirect cues of aye-aye presence and Canarium trees as an indicator of resource availability. All 3 measured variables indicated higher aye-aye abundance within non-degraded forest; however, the differences across forest type were not significant. Both degraded and non-degraded forests showed a positive correlation between feeding sites and high activity sites. We found that Canarium, an important aye-aye food source, was rare and had limited dispersal, particularly across degraded forest. This preliminary study provides baseline data for aye-aye activity and resource utilization across degraded and non degraded forests. PMID- 21822022 TI - Unifying ideas for non-parametric linkage analysis. AB - OBJECTIVES: Non-parametric linkage analysis (NPL) exploits marker allele sharing among affected relatives to map genes influencing complex traits. Computational barriers force approximate analysis on large pedigrees and the adoption of a questionable perfect data assumption (PDA) in assigning p values. To improve NPL significance testing on large pedigrees, we examine the adverse consequences of missing data and PDA. We also introduce a novel statistic, Q-NPL, appropriate for NPL analysis of quantitative traits. METHODS: Using simulated and real data sets with qualitative traits, we compare NPL analysis results for four testing procedures and various degrees of missing data. The simulated data sets vary from all nuclear families, to all large pedigrees, to a mix of pedigrees of different sizes. We implemented the Kong and Cox linear adjustment of p values in the software packages Mendel and SimWalk. We perform similar analysis with Q-NPL on quantitative traits of various heritabilities. RESULTS: The Kong and Cox extension for significance testing is robust to realistic missing data patterns, greatly improves p values in approximate analyses, and works equally well for qualitative and quantitative traits and small and large pedigrees. The Q-NPL statistic is robust to missing data and shows good power to detect linkage for quantitative traits with a wide spectrum of heritabilities. CONCLUSIONS: The Kong and Cox extension should be a standard tool for calculating NPL p values. It allows the combination of exact and estimated analyses into a single significance score. Q-NPL should be a standard statistic for NPL analysis of quantitative traits. The new statistics are implemented in Mendel and SimWalk. PMID- 21822023 TI - Serum S100A12 (EN-RAGE) levels in patients with decreased renal function and subclinical chronic inflammatory disease. AB - BACKGROUND: The calcium-binding protein S100A12 (EN-RAGE) causes inflammation through interaction with the multiligand receptor for advanced glycation end products (RAGE). The aim of the study was to determine S100A12 levels and describe their relationship to inflammatory markers in patients with decreased renal function. METHODS: The studied group consisted of 46 patients with various degrees of chronic renal insufficiency (CHRI), 31 long-term hemodialysis (HD) patients and 24 healthy controls. S100A12 and soluble RAGE were assessed immunochemically (ELISA), and routine biochemical parameters were measured. RESULTS: S100A12 levels were not different in CHRI (166 +/- 140 ng/ml) and HD patients (127 +/- 101 ng/ml) compared to controls (126 +/- 106 ng/ml; p = 0.20, n.s.). In CHRI patients, S100A12 correlated with C-reactive protein (CRP) levels, orosomucoid, and inversely with alpha(2)-macroglobulin. In HD patients, S100A12 correlated with age, CRP, orosomucoid, fibrinogen and leukocyte levels. In multivariate regression analysis after adjustment for age, S100A12 levels remained correlated with: orosomucoid in CHRI patients; CRP, leukocytes, fibrinogen and negatively with sRAGE in HD patients; and leukocytes in controls. CONCLUSIONS: Although S100A12 levels were not elevated in patients with decreased kidney function, a relation to markers of inflammation was found. Further studies are required to demonstrate the significance of S100A12 in patients with decreased renal function. PMID- 21822024 TI - Racial and geographic differences in prevalence, awareness, treatment and control of dyslipidemia: the reasons for geographic and racial differences in stroke (REGARDS) study. AB - BACKGROUND/AIMS: There are racial and geographic disparities in stroke mortality, with higher rates among African Americans (AAs) and those living in the southeastern US ('stroke belt'). Racial and geographic differences in dyslipidemia prevalence, awareness, treatment and control may, in part, account for the observed disparities in stroke mortality. METHODS: Reasons for Geographic and Racial Differences in Stroke (REGARDS) is a national observational study of community-dwelling black and white participants aged 45 and older, with oversampling from the stroke belt. As of January 15, 2007, 26,122 participants were enrolled and a fasting lipid panel was available of 21,068. Awareness, treatment and control of dyslipidemia were estimated overall and compared across race-sex-region strata. RESULTS: There were 55% of the participants with dyslipidemia and no racial differences in prevalence. Adjusting for demographic and established stroke risk factors, AAs had a lower prevalence (OR 0.74; 95% CI: 0.66, 0.77) and were less likely to be aware (0.69; 0.61, 0.78), treated (0.77; 0.67, 0.89) and controlled (0.67; 0.58, 0.77) than whites. There was lower control outside of the stroke belt (0.87; 0.76, 0.99). CONCLUSION: Racial, but not geographic, differences in dyslipidemia management may play a role in the excess stroke burden in the Southeast. PMID- 21822025 TI - Socioeconomic and cardiovascular variables explaining regional variations in stroke mortality in Chile: an ecological study. AB - BACKGROUND: Regional differences in stroke mortality rates have been described in Chile. These could be related to the distribution of cardiovascular risk factors, the quality of medical care or socioeconomic status influencing incidence or case fatality rates. Our objective was to investigate variables explaining the variability in stroke mortality rates in the different regions of Chile. METHODS: Adjusted stroke mortality rates in different regions were calculated for the year 2003. Variables were added from three sources: the National Death Certificate Database, the National Socioeconomic Characterization Survey and the National Health Survey. A logistic regression model was used to investigate regions, demographic variables and socioeconomic variables associated with the risk of death from stroke. A linear regression model was used to study the association of socioeconomic variables and cardiovascular risk factors with the standardized mortality rate by region and the contribution of these to the variability. RESULTS: A twofold increase was found in adjusted stroke mortality rates among regions. Greater risk was associated with older age, female gender and residence in regions V, VII, VIII and IX. Sixty-two percent of the regional variability rate was explained by the combined prevalence of poverty (34%), diabetes (17%), sedentarism (8%) and overweight (3%). CONCLUSION: The risk of death from stroke in Chile is associated with age, sex and living in four specific regions of the country. The majority of the increased risk in these regions is explained by the prevalence of poverty, diabetes, a sedentary lifestyle and overweight. PMID- 21822026 TI - Sun exposure, vitamin D intake and progression to disability among veterans with progressive multiple sclerosis. AB - BACKGROUND: Early life events have been suggested to influence multiple sclerosis (MS) susceptibility, and to potentially modulate its clinical course. We assessed vitamin D-related exposures from childhood to disease onset and their associations with MS progression. METHODS: Among veterans in the Multiple Sclerosis Surveillance Registry, 219 reported having the progressive form and met the inclusion criteria. Participants reported their past sun exposure, vitamin D related intake and age at disability milestones using the Patient-Determined Disease Steps (PDDS). The Cox proportional hazards model was used to examine the association between vitamin D-related exposures and time (years) to disability. RESULTS: Low average sun exposure in the fall/winter before disease onset was associated with an increased risk of progressing to a PDDS score of 8 (hazard ratio, HR: 2.13, 95% confidence interval, CI: 1.20-3.78), whereas use of cod liver oil during childhood and adolescence was associated with a reduced risk (HR: 0.44, 95% CI: 0.20-0.96). CONCLUSIONS: These results suggest that exposure to vitamin D before MS onset might slow disease-related neurodegeneration and thus delay progression to disability among patients with the progressive subtype. PMID- 21822027 TI - Occurrence of hepatocellular carcinoma was not a rare event during and immediately after antiviral treatment in Japanese HCV-positive patients. AB - Advanced chronic hepatitis C patients with sustained virolological response by antivirals remain at risk for hepatocellular carcinoma (HCC). We investigated the incidence of HCC during and immediately after peginterferon-alfa-2a and ribavirin (RBV) treatment in patients with chronic hepatitis C in Japan. HCC was detected in 8 of 238 patients during and after these treatments (mean follow-up period: 572 +/- 252 days). In conclusion, occurrence of HCC is not a rare event during and immediately after peginterferon-alfa-2a plus RBV treatment. In cases with cirrhosis, higher alpha-fetoprotein levels, old age, or a previous history of HCC treatment, clinicians should be especially alert for the possible development of HCC during and immediately after peginterferon-alfa-2a and RBV treatment. Clinicians should regularly check for the possible development of HCC even in chronic hepatitis C patients under treatment. PMID- 21822028 TI - I-CLIP: improved stratification of advanced hepatocellular carcinoma patients by integrating plasma IGF-1 into CLIP score. AB - OBJECTIVE: Improving the prognostic stratification of unresectable hepatocellular carcinoma (HCC) patients is critically needed. Since patients' survival is closely linked to the severity of the underlying liver disease, and insulin-like growth factor-1 (IGF-1) is produced predominantly in the liver, we hypothesized that IGF-1 may correlate with patients' survival and hence improve the prognostic ability of the Cancer of the Liver Italian Program (CLIP) score. METHODS: Baseline plasma IGF-1 and clinicopathologic parameters were available from 288 patients. Multivariate Cox regression models, Kaplan-Meier curves, and the log rank test were applied. Recursive partitioning was used to determine the optimal cut point for IGF-1 using training/validation samples. Prognostic ability of the I-CLIP (I = IGF) was compared to CLIP using C-index. RESULTS: IGF-1 significantly correlated with the clinicopathologic features. With an optimal IGF-1 cut point of 26 ng/ml, the overall survival of patients with IGF-1 >26 was 17.7 months (95% CI 13.6-22.8), and with IGF-1 <=26 was 5.8 months (95% CI 4.0-12.5), p < 0.0001. The concordance probabilities for CLIP and I-CLIP were 0.7037 and 0.7096, respectively (p < 0.0001). CONCLUSIONS: Our preliminary results indicate that I CLIP significantly improved prognostic stratification of patients with advanced HCC. However, independent validation of our study is warranted. PMID- 21822029 TI - Audiometric records analysis in a clinical population in China. AB - OBJECTIVE: The objective of this study was to characterize the typical hearing loss presenting at a clinical audiology center. METHODS: Audiometric records for 8,032 cases were obtained from the database at Beijing Tongren Hospital, Capital Medical University. Based on this information, age distribution, audiometric configuration, type, degree and asymmetry of hearing loss were characterized. RESULTS: Results showed that 48.4% of all cases of hearing loss occurred from 31 to 60 years of age, sloping hearing loss was the most common audiometric configuration, and sensorineural hearing loss dominated the type of hearing loss for both males and females. Mean pure-tone hearing thresholds revealed significant differences between genders, that is, thresholds for females were poorer than those for males from 250 to 1,000 Hz, whereas thresholds for males were poorer than those for females from 2,000 to 8,000 Hz. Analysis showed that 57.3% of audiograms showed some degree of asymmetry. No significant difference was found between genders for the average asymmetric thresholds. CONCLUSION: This study provides the characteristics of age distribution, audiometric configuration, type, degree and asymmetry of hearing loss from a representative clinical audiology center. These data are useful for public policy efforts involving hearing loss prevention and rehabilitative program development. PMID- 21822030 TI - Laryngeal fracture due to blunt trauma presenting with pneumothorax and pneumomediastinum. AB - AIM: Injuries due to traffic accidents are frequent in childhood, and they have high mortality and morbidity. Laryngeal injury due to a traffic accident is a rare pathology and might be missed if not suspected. Here we present a laryngeal fracture in a child after a blunt chest trauma during a traffic accident that presented with pneumomediastinum and pneumothorax. CASE: A 14-year-old girl was referred for pneumomediastinum. Her physical examination was normal except subcutaneous emphysema, edema and tenderness in the cervical area, hoarseness, facial and extremity abrasions and ecchymoses. Chest tomography revealed pneumothorax and pneumomediastinum, and cranial tomography revealed maxillofacial fractures. Upper airway damage was suspected, flexible endoscopy revealed right vocal cord paralysis and cervical tomography revealed thyroid cartilage fracture. The fracture was repaired and tracheotomy was performed. She was discharged on postoperative day 6. Facial fractures were repaired in another center. Tracheotomy was removed on postoperative day 20. Her hoarseness, although decreased, still persists. CONCLUSION: Pneumomediastinum is a rare result of a laryngeal fracture and if not suspected, the fracture can easily be missed. It should be kept in mind after blunt cervical trauma with pneumomediastinum and/or pneumothorax. Direct endoscopy and cervical tomography may be necessary for the differential diagnosis. PMID- 21822031 TI - Comparison of scores of application methods of the Epworth Sleepiness Scale: self administered or nurse administered. AB - PURPOSE OF THE STUDY: The aim of this study was to investigate the impact of two different application methods (self or nurse administered) on Epworth Sleepiness Scale (ESS) scores and compare the scores according to their correlations between polysomnographic findings. PROCEDURES: 114 patients agreed to participate by completing the Turkish version of the ESS with 2 different methods of application, but the complete results of polysomnography (PSG) were available for 101 patients. RESULTS: The scores of the nurse-administered ESS were clinically significantly correlated with the apnea-hypoapnea index. Scores of the self administered ESS were not correlated with any of the demographic and PSG parameters. In the reliability analysis, the scores of the self-administered and the nurse-administered ESS were quite consistent. CONCLUSION AND MESSAGE: We considered that to complete the ESS with the method of nurse administration could change the reliability and sensitivity. In conclusion, the ESS may be a more reliable tool for measuring the severity of excessive daytime sleepiness or obstructive sleep apnea by a change in the administration method. PMID- 21822032 TI - Stabilization of reactive nitroxides using invasomes to allow prolonged electron paramagnetic resonance measurements. AB - The detection of the antioxidative capacity of the skin is of great practical relevance since free radicals are involved in many skin damaging processes, including aging and inflammation. The nitroxide TEMPO (2,2,6,6-tetramethyl-1 piperidinyloxyl) in combination with electron paramagnetic resonance spectroscopy was found suitable for measuring the antioxidative capacity since its reaction with reducing agents is considerably fast. Yet, in order to achieve longer measurement times, e.g. in inflammatory skin diseases, the stabilizing effect of an invasome (ultraflexible vesicle/liposome) suspension with TEMPO was investigated ex vivo on porcine skin and in vivo on human skin. Invasomes increased the measurement time ex vivo 2-fold and the reduction was significantly slowed down in vivo, which is due to membrane-associated and therefore protected TEMPO. Furthermore, TEMPO accumulation in the membrane phase as well as the decreasing polarity of the ultimate surroundings of TEMPO during skin penetration explains the stabilizing effect. Thus, an invasome suspension with TEMPO exhibits stabilizing effects ex vivo and in vivo. PMID- 21822033 TI - Epidermal barrier treatments based on vernix caseosa. AB - BACKGROUND/AIMS: Premature infants lack the vernix caseosa, have an incompetent stratum corneum (SC) barrier and are predisposed to infection. Use of topical agents to improve barrier function has had mixed outcomes. The aim was to determine the effect of vernix versus common barrier creams on the rate and quality of the epidermal barrier repair following controlled wounding. METHODS: Minor wounds were created with (1) laser ablation in the minipig and (2) tape stripping of mother's volar skin as a model for premature skin. Native vernix was applied to the mother's tape-stripped skin. Treatments were no occlusion (NO), vernix and a petrolatum-based cream (PBC) in the pig, and NO, vernix, PBC, an oil in-water cream (OWC), a semipermeable film (SP) and full occlusion (FO) in adults. RESULTS: Outcomes for both trials were barrier recovery and skin hydration (moisture accumulation rate, MAT), initial hydration, erythema and dryness in adults. Vernix and PBC produced greater barrier repair than NO in the pig. SP produced greater recovery than NO and FO in adults. Vernix yielded greater recovery than FO and was similar to PBC, OWC and NO. Vernix had a directionally higher MAT than OWC and directionally higher initial hydration than NO. CONCLUSIONS: The findings suggest that vernix-based topical creams would be effective for the treatment of epidermal wounds and show promise to augment SC repair and maturation in infants. PMID- 21822034 TI - An encapsulated fruit and vegetable juice concentrate increases skin microcirculation in healthy women. AB - BACKGROUND/AIM: Microcirculation in the dermis of the skin is important for nutrient delivery to this tissue. In this study, the effects of a micronutrient concentrate (Juice Plus+(r); 'active group'), composed primarily of fruit and vegetable juice powder, on skin microcirculation and structure were compared to placebo. STUDY DESIGN/METHODS: This 12-week study had a monocentric, double-blind placebo and randomized controlled design with two treatment groups consisting of 26 healthy middle-aged women each. The 'oxygen to see' device was used to evaluate microcirculation. Skin density and thickness were measured using ultrasound. Measurements for skin hydration (Corneometer(r)), transepidermal water loss and serum analysis for carotenoids and alpha-tocopherol were also performed. RESULTS: By 12 weeks, microcirculation of the superficial plexus increased by 39%. Furthermore, skin hydration increased by 9% while skin thickness increased by 6% and skin density by 16% in the active group. In the placebo group, microcirculation decreased, and a slight increase in skin density was observed. CONCLUSION: Ingestion of a fruit- and vegetable-based concentrate increases microcirculation of the skin at 12 weeks of intervention and positively affects skin hydration, density and thickness. PMID- 21822035 TI - Antibiotic resistance mechanisms of clinically important bacteria. AB - Bacterial resistance to antimicrobial drugs is an increasing health and economic problem. Bacteria may be innate resistant or acquire resistance to one or few classes of antimicrobial agents. Acquired resistance arises from: (i) mutations in cell genes (chromosomal mutation) leading to cross-resistance, (ii) gene transfer from one microorganism to other by plasmids (conjugation or transformation), transposons (conjugation), integrons and bacteriophages (transduction). After a bacterium gains resistance genes to protect itself from various antimicrobial agents, bacteria can use several biochemical types of resistance mechanisms: antibiotic inactivation (interference with cell wall synthesis, e.g., beta-lactams and glycopeptide), target modification (inhibition of protein synthesis, e.g., macrolides and tetracyclines; interference with nucleic acid synthesis, e.g., fluoroquinolones and rifampin), altered permeability (changes in outer membrane, e.g., aminoglycosides; new membrane transporters, e.g., chloramphenicol), and "bypass" metabolic pathway (inhibition of metabolic pathway, e.g., trimethoprim-sulfamethoxazole). PMID- 21822036 TI - Frequent methylation of RASSF1 and RARB in urine sediments from patients with early stage prostate cancer. AB - BACKGROUND. Prostate cancer (PCa) is the second most prevalent malignancy among males, characterized by high mortality rates. Aberrant DNA methylation in promoters of tumor suppressor genes is an early and frequent event during prostate carcinogenesis. Modern techniques allow a sensitive detection of DNA methylation biomarkers in bodily fluids from cancer patients offering a noninvasive tool for PCa monitoring. Our study aimed at the analysis of DNA methylation in urine sediments from PCa patients for the selection of most informative noninvasive biomarkers. MATERIAL AND METHODS. Real-time methylation specific polymerase chain reaction was used for the detection of methylated RASSF1, RARB, and GSTP1 genes in catheterized urine specimens from 34 patients with biopsy-proven early or medium stage PCa. RESULTS. At least one gene was methylated in urine sediments from 28 cases with PCa, with a sensitivity of the test reaching 82%. RASSF1 was methylated in 71% (24 of 34), RARB in 44% (15 of 34), and GSTP1 in 3% (1 of 34) of the specimens. High level of methylation (>=50%) in RARB and RASSF1 genes was detected in 40% and 20% of cases, respectively. A significant association was observed between high level of RARB methylation and Gleason score (P=0.01), while methylation of at least one gene occurred more frequently in urine DNA of older patients (P=0.02). CONCLUSIONS. Results of our study show a high sensitivity of DNA methylation biomarkers, especially RASSF1 and RARB, for the early and noninvasive detection of PCa. PMID- 21822037 TI - Differential diagnosis between chronic pancreatitis and pancreatic cancer: a prospective study of 156 patients. AB - The aim of this study was to evaluate prospectively the efficacy of different imaging methods in differentiating between chronic pancreatitis and cancer in focal pancreatic lesions and staging of adenocarcinoma. MATERIAL AND METHODS. Between June 2005 and October 2007, 156 consecutive patients were enrolled into the prospective clinical trial. The patients were randomized into two groups. Ultrasonoscopy and endoscopic ultrasound were performed in both the groups. Group A patients were additionally examined by computed tomography and tumor marker assay, while in the group B, intraoperative ultrasonoscopy with biopsy and urgent histological examination were done. Results of each imaging technique regarding differential diagnosis and cancer stage were compared with the findings of surgical and histological examination. RESULTS. Chronic pancreatitis and adenocarcinoma were documented in 58 (37.2%) and 78 (50%) patients, respectively. The size of the lesions and clinical presentation were similar in both the groups, but cancer patients were older than patients with pancreatitis (P<0.001). Preoperatively endosonoscopy had the highest accuracy in assessing differential diagnosis (92.1%) and adenocarcinoma (91.8%), whereas computed tomography had the highest accuracy in assessing tumor size (84.5%) and transabdominal ultrasonography in assessing lymph node involvement (78.9%) and distant metastases (88.6%). Intraoperative ultrasound was the most accurate imaging technique in the assessment of differential diagnosis (100%), adenocarcinoma (98.5%), extent of primary tumor (84.8%), lymph node involvement (87.9%), and distant metastases (100%). CONCLUSIONS. In the differential diagnosis between chronic pancreatitis and adenocarcinoma, preoperative ultrasonography and intraoperative ultrasound are the best imaging methods. When ultrasonography is nondiagnostic, computed tomography and endoscopic ultrasound are alternative techniques. PMID- 21822038 TI - Factors affecting self-eruption of displaced permanent maxillary canines. AB - The aim of this study was to examine the possibility of the spontaneous eruption of displaced unerupted maxillary canines after the extraction of the deciduous canine and dental arch expansion and to determine the impact of initial canine position on treatment success rate. Materials and METHODS. The study sample included 50 patients (mean age, 13.5 years [SD, 2.2]) with unilaterally displaced unerupted maxillary canines. Deciduous canines were extracted, and the space for displaced canine was created at the beginning of the study. The follow-up period for the spontaneous eruption was 12 months. The initial vertical, horizontal, labio-palatal position and angle of inclination to the midline of the displaced canine were assessed on panoramic radiographs. RESULTS. Only 42% of displaced canines erupted spontaneously within one-year period (52.9% of labially displaced canines and 36.4% of palatally displaced canines). A significant difference of inclination was determined between spontaneously erupted and unerupted teeth in the labially displaced canine group (P<0.01), with no difference in the palatally displaced canine group. The receiver operating characteristic curve analysis showed that the critical angle of inclination for the spontaneous eruption of the retained canine was 20o (sensitivity 0.759; specificity 0.571; P<0.05). The majority of unerupted canines (75.9%) were inclined more than 20o. The initial height of canine was crucial for spontaneous eruption (sensitivity 0.966; specificity 0.81; P<0.001). This was true for both palatal and labial cases. CONCLUSIONS. The initial vertical position of the labially and palatally displaced canines and the inclination of the labially displaced canines were the most important predictors for spontaneous eruption of the cuspid. PMID- 21822039 TI - Concomitant autologous chondrocyte implantation with osteochondral grafting for treatment of a massive osteochondral defect in the bilateral knees of a child. AB - We report the case of a 15-year-old patient who underwent concomitant autologous chondrocyte implantation and osteochondral grafting for the treatment of a massive osteochondritis dissecans defect in the left knee and autologous chondrocyte implantation in the right knee joint. Magnetic resonance imaging showed large osteochondral defects in both the knee joints measuring 8-9 cm(2). Both defects were located in the weight-bearing areas of the medial femoral condyles. Therefore, simultaneous autologous chondrocyte implantation (ACI) and osteochondral autograft transplantation (OAT) for the left knee defect and ACI for the right knee joint were performed. Osteochondral plugs were harvested from the patellofemoral joint of the same left knee and grafted into the most dorsal regions of the large osteochondral defect of the left knee. The remaining osteochondral defect was covered with ACI using collagen type I and III membrane and chondrocyte cells. The membrane was implanted into more proximal part of the osteochondral defect of the left knee. Time interval between operations of the left and right knee joints was 6 months. Magnetic resonance imaging at 6 months after each knee surgery showed good preservation of the OAT and ACI grafts. The most recent follow-up examination, performed 12 months after surgeries, has shown excellent results with an International Knee Documentation Committee score of 95.59+/-4.64 and 96.88+/-4.69 for the right and left knee joints, respectively, and full range of knee motions with no symptoms. In this clinical case, the combination of ACI and OAT methods in a one-step procedure produced a good reconstruction of the joint surface with excellent clinical outcomes in the both knee joints of the same patient. Autologous osteochondral grafting and autologous chondrocyte implantation can be combined for the treatment of large osteochondral defects of the knee. PMID- 21822040 TI - Investigation of the antimicrobial activity of Rhaponticum (Rhaponticum carthamoides D.C. Iljin) and shrubby cinquefoil (Potentilla fruticosa L.). AB - The aim of the study was to determine antimicrobial activity of rhaponticum and shrubby cinquefoil extracts. MATERIAL AND METHODS. Ethanol extract from the leaves of rhaponticum (Rhaponticum carthamoides D.C. Iljin) and shrubby cinquefoil (Potentilla fruticosa L.) was produced at the Department of Food Technology, Kaunas University of Technology. The antimicrobial activity of the viscous extract or rhaponticum and shrubby cinquefoil was evaluated using standard microorganism cultures (bacteria Staphylococcus aureus ATCC 25923, Enterococcus faecalis ATCC 29212, Escherichia coli ATCC 25922, Klebsiella pneumoniae ATCC 33499, Pseudomonas aeruginosa ATCC 27853, Proteus mirabilis ATCC 12459, Bacillus subtilis ATCC 6633, Bacillus cereus ATCC 8035 and fungi Candida albicans ATCC 60193). The minimum inhibitory concentration (MIC) of the examined preparations was determined. RESULTS. Both studied preparations - rhaponticum (Rhaponticum carthamoides D.C. Iljin) and shrubby cinquefoil (Potentilla fruticosa L.) - demonstrated similar antimicrobial activity. The highest sensitivity to the studied preparations was observed in microbes with eukaryotic cell structure: Candida albicans, which is a fungus, and a spore-forming prokaryotic bacterium, Bacillus cereus. The highest resistance was observed in Escherichia coli and Klebsiella pneumoniae. CONCLUSIONS. The studied preparations - viscous extracts of rhaponticum and shrubby cinquefoil - are substances with antimicrobial activity against gram-positive (Staphylococcus aureus and Enterococcus faecalis) and gram-negative (Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Proteus mirabilis) bacteria, spore forming bacteria (Bacillus subtilis and Bacillus cereus), and fungi (Candida albicans). PMID- 21822041 TI - Factors related to gender differences in toothbrushing among Lithuanian middle aged university employees. AB - BACKGROUND AND OBJECTIVES. Many previous studies showed clear gender differences in the percentages of adults reporting toothbrushing more than once a day. This study evaluated the factors determining gender differences in toothbrushing among Lithuanian middle-aged university employees. MATERIAL AND METHODS. A questionnaire survey was anonymously conducted among 35- to 44-year-old employees (n=862) of four universities in Lithuania in 2005. The response rate was 64% (n=553). Data covered toothbrushing frequency, habitual dental attendance, dental health attitudes and knowledge, and subject's background information. RESULTS. Of all respondents, 68% reported brushing their teeth more than once a day (73% of women and 49% of men, P<0.001) and 51% indicated checkup-based habitual dental attendance (54% of women and 41% of men, P=0.012). The majority reported good dental status as being important to them and poor oral health as injurious to general health. Of all respondents, 44% indicated that "Lack of time is the main reason for incomplete oral self-care" (61% of men and 40% of women, P<0.001). Logistic regression models showed that the strongest factor affecting toothbrushing frequency was the importance of good dental health to them (OR, 1.6; 95% CI, 1.1-2.4; P=0.02) among women and statement that "Poor oral health can be injurious to general health" (OR, 2.6; 95% CI, 1.2-5.5; P=0.01) and checkup-based habitual dental attendance (OR, 2.4; 95% CI, 1.0-5.9; P=0.06) among men. CONCLUSIONS. Due to different determinants affecting toothbrushing frequency among men and women, different oral health motivation programs by gender should be developed. PMID- 21822042 TI - [Recommendations for the prevention and management of tuberculosis in patients treated with tumor necrosis factor alpha inhibitors: a consensus of lithuanian pulmonologists and rheumatologists]. AB - Patients receiving tumor necrosis factor alpha inhibitors for the treatment of rheumatic diseases (rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis) are at high risk of developing tuberculosis during treatment. This article gives the recommendations for the prevention and management of tuberculosis in patients with rheumatic diseases before initiating therapy with tumor necrosis factor alpha inhibitors. They are adapted considering the high prevalence of tuberculosis, high drug resistance of Mycobacterium tuberculosis, and extensive bacille Calmette-Guerin vaccination against tuberculosis in Lithuania. In order to reduce the risk of tuberculosis, the screening should be done before starting antitumor necrosis factor alpha therapy. This includes complete medical history and posterior-anterior, lateral chest radiography. Tuberculin skin test using the Mantoux method with 5 tuberculin units and interferon-gamma release assay should be performed in patients without posttuberculous radiological lesions. If Ghon's complex or untreated posttuberculous lesions are present, or if the results the Mantoux test or interferon-gamma release assay are positive, the patient should be treated for latent tuberculosis. For the treatment of latent tuberculosis, isoniazid and rifampicin are given for 3 months, and the introduction of antitumor necrosis factor alpha therapy is delayed at least for one month. In cases of suspected active Mycobacterium tuberculosis infection, tuberculosis should be confirmed microbiologically or morphologically, and adequate antituberculosis treatment should be initiated. PMID- 21822043 TI - Proliferative potential in benign mixed salivary gland tumors and its value in primary and recurrent neoplasms. AB - OBJECTIVE. Mixed salivary gland tumors are characterized by a marked diversity in the cell proliferation. It course in the stromal component, and, especially in recurrent neoplasms, is not completely understood. This study evaluated cell proliferative potential, its value and the clinical course of primary and recurrent salivary gland pleomorphic adenomas (PA). MATERIALS AND METHODS. 322 benign salivary gland tumors were used in this study. The cell proliferation was estimated by Ki-67 expression levels. RESULTS. Ki-67 immunoreactivity showed a wide range of spectra; in the epithelial and stromal type of PA the cell proliferation had the value from 0.07+/-0.03 (95% CI 0.01-0.14) to 4.81+/-0.60 (95% CI 3.61-6.02) and from 0 to 0.79+/-0.11 (95% CI 0.57-1.00), respectively. The Ki-67 value was higher in recurrent tumors compared with primary, and the mean number of Ki-67-positive cells per visual microscopic field constituted 2.14+/-1.60 (95% CI 1.47-2.47) comparing with 1.43 (95% CI 0.97-1.55) revealed in primary tumors. CONCLUSION. Cell proliferation values correlate with a recurrence of neoplasm, and elevation of proliferation potential in the stromal component of recurrent PA is indicative of clinical course change for the worse. PMID- 21822044 TI - Relationship between radiographic changes in the temporomandibular joint and bone mineral density: a population based study. AB - OBJECTIVE. The aim of this population based study was to compare radiographic changes in the temporomandibular joint (TMJ) with the lumbar spine and femoral neck BMD. To find whether there is any relationship between TMJ radiographic changes, vitamin D (25(OH)D) and bone markers levels and the number of missing teeth. MATERIAL AND METHODS. The study included 95 randomly selected participants. Bilateral TMJ images were obtained using an orthopantomograph (OPTG) and were evaluated for presence of radiographic signs. BMD was measured by dual energy X-ray absorptiometry (DXA). BMD of the lumbar spine (LT score) and femur (FT score) was detected by DXA. The level of type I collagen telopeptide fragments (P1NP), of C-telopeptide crosslaps of type I collagen (CTX-1) and of 25(OH)D were also measured. RESULTS. Subjects with a lower LT score had significantly fewer occluding pairs of teeth (p=0.018) and were more frequent users of removable prostheses (p=0.008). Radiographic changes were negatively correlated with P1NP (p=0.041). CTX-1 correlated positively with P1NP (p<0.001) and negatively with 25(OH)D (p=0.042). Occluding pairs of teeth were positively correlated with the LT score (p=0.012) and FT score (p<0.001). Radiography showed changes in the TMJ of 57% of participants. Out of 95 participants, 60% demonstrated an abnormally low LT value. CONCLUSIONS. This population based study indicates that TMJ radiographic changes and teeth loss seems to be related to the low level of BMD and 25(OH)D level. PMID- 21822045 TI - Prognostic factors and epidemiological characteristics of cutaneous and mucosal head and neck melanoma. AB - OBJECTIVE. To describe the prognostic factors and epidemiological characteristics of cutaneous and mucosal head and neck melanoma and to identify the variables associated with mortality from this disease. MATERIAL AND METHODS. Patients treated for head and neck melanoma in the Oncology Centre of Latvia, Riga during a 10-year period were identified. Records from 124 cases were analyzed in a descriptive, retrospective study. For each patient, information regarding age, sex, tumor anatomic site, as well as ulceration, histological tumor subtypes, Breslow thickness and Clark invasion level was viewed. Disease specific survival rates were calculated. The frequencies of all study variables and their 95% confidence intervals were determined. Kaplan-Meier survival curves were produced to illustrate the survival differences for each variable. RESULTS. The patients' mean age was 67.36 years. The study included 81 females (65.32%) and 43 males (34.67%). The prevalent anatomical site for cutaneous head and neck melanoma was the cheek - 49% (n=55) and the intraocular site for mucosal melanoma (61.5%). A high percentage of thick cutaneous melanoma was detected. In 53 cases (47.3%) out of 112 cutaneous melanoma the tumor ulceration was found. Nodular melanoma subtype was predominating (38%). The incidence of cutaneous melanoma has increased unequally whereas mucosal melanoma of the head and neck is an uncommon cancer and the incidence rates in Latvia during a ten year period are decreasing. CONCLUSION. Female sex, advanced age, facial skin, tumor thickness, nodular subtype and ulceration carried a relevant risk of poor prognosis. PMID- 21822046 TI - Comparative analysis of CRT Buffer, GC saliva check buffer tests and laboratory titration to evaluate saliva buffering capacity. AB - OBJECTIVE. The purpose of this study is to evaluate the ability of two commercial strip tests and laboratory titration to detect saliva buffer capacity. MATERIALS AND METHODS. Sixty-four patients were examined. Stimulated saliva was collected and buffer capacity was determined with two different chair-side strip tests in addition to immediate transportation to the laboratory to check the buffering ability by titrating with 0.005 M HCl and measuring pH by digital pH/Ion meter, used as a gold standart. The correlation were analyzed using the Spearman Rank Correlation Test, Cohen's Kappa coefficient and Pearson's Correlation test, p < 0.01. Sensitivity and specificity were used to measure precision of these tests. RESULTS. The response rate was 80%. High buffer capacity was found in 23.4% of cases, medium in 62.5%, and low in 14.1%. The Spearman Rank Correlation coefficient between the titration method and CRT Buffer test was 0.685 and the GC Saliva Check Buffer was 0.837. The Kappa coefficient for the CRT Buffer test was 0.508, while the coefficient for the GC Saliva Check Buffer was 0.752. The Pearson Correlation for the GC Saliva Check was 0.675. The difference is found in the buffer capacity at initial pH and at pH value 3. CONCLUSIONS. Both colorimetric tests correlate with the acid titration method in laboratory and are usable for saliva buffer capacity detection in dental offices. Buffer capacity detected in laboratory at different pH values can provide more information regarding caries risk. PMID- 21822047 TI - The relation between oral hygiene skills and the prevalence of dental caries among 4 - 6-year-old children. AB - AIM OF THE STUDY. To evaluate the tooth brushing skills and the prevalence of dental caries as well as its intensity in relation to oral hygiene skills among 4 - 6-year-old children. MATERIAL AND METHODS. The cross-sectional study was performed from November 16, 2009 to January 12, 2010. 235 children (4 - 6-year old) were randomly selected from kindergartens in Plunge and Jonava in Lithuania. The results of study were registered in the special forms prepared in accordance with the recommendations of WHO. Parents of the children were asked to fill in the questionnaires. RESULTS. The results of the study show that 91% (Plunge) and 90% (Jonava) of 4 - 6-year-old children have caries in their primary teeth. The prevalence of caries is different in relation to age: 78.7% of 4-year-old children, 97.3% of 5-year-old children, and 95.3% of 6-year-old children. The intensity of caries is as follows: 4.9 (SN=+/-4.9), 7.5 (SN=+/-4.5), and 8.2 (SN=+/-4.7). CONCLUSIONS. There is the high prevalence of caries, particularly of not treated forms, among 4 - 6-year-old children. The oral hygiene index is just satisfactory. PMID- 21822048 TI - Evaluation of oral health status of retirement-age population in Latvia. AB - INTRODUCTION. Latvian government Health care financing regulations do not envisage free dental care in nursing homes. Consequently, in this situation arises need to carry out comparative evaluation of oral health status and quantity indicators of dental prosthodontics among retirement-age population in Latvia. The aim of the study was to estimate oral health and dental prosthodontics indicators among retirement-age population in Latvia. PATIENTS AND METHODS. We examinated 465 retirement-age inhabitants in Latvia. We assessed dental status, quantity and quality of the existing complete dental prostheses. We also evaluated the DMF-T index. RESULTS. Oral health indicators among Latvian retirement-age population are better than those for nursing homes residents in the same age group. Complete dental prostheses used by nursing homes residents do not meet denture's quality criteria. Retirement-age patients have oral hygiene problems. CONCLUSIONS. DMF-T index among Latvian retirement-age population is lower than among residents of nursing homes. The major component of DMF-T index is the number of lost teeth. The assessment of dental prostheses among residents of nursing homes showed unsatisfactory results. Retirement-age population in Latvia needs treatment of oral mucosal diseases, improvement of oral hygienic measures and increase of amount of dental prosthodontics. PMID- 21822049 TI - Preclinical studies for pharmacokinetics and biodistribution of Ad-stTRAIL, an adenovirus delivering secretable trimeric TRAIL for gene therapy. AB - Malignant glioma is the most frequent type in brain tumors. The prognosis of this tumor has not been significantly improved for the past decades and the average survival of patients is less than one year. Thus, an effective novel therapy is urgently needed. TNF-related apoptosis inducing ligand (TRAIL), known to have tumor cell-specific killing activity, has been investigated as a novel therapeutic for cancers. We have developed Ad-stTRAIL, an adenovirus delivering secretable trimeric TRAIL for gene therapy and demonstrated the potential to treat malignant gliomas. Currently, this Ad-stTRAIL gene therapy is under phase I clinical trial for malignant gliomas. Here, we report preclinical studies for Ad stTRAIL carried out using rats. We delivered Ad-stTRAIL intracranially and determined its pharmacokinetics and biodistribution. Most Ad-stTRAIL remained in the delivered site and the relatively low number of viral genomes was detected in the opposite site of brain and cerebrospinal fluid. Similarly, only small portion of the viral particles injected was found in the blood plasma and major organs and tissues, probably due to the brain-blood barrier. Multiple administrations did not lead to accumulation of Ad-stTRAIL at the injection site and organs. Repeated delivery of Ad-stTRAIL did not show any serious side effects. Our data indicate that intracranially delivered Ad-stTRAIL is a safe approach, demonstrating the potential as a novel therapy for treating gliomas. PMID- 21822051 TI - The tumor suppressor Lats2 is pivotal in Aurora A and Aurora B signaling during mitosis. AB - Accurate coordination between chromosome segregation and cytokinesis by various mitotic kinases, such as Aurora, prevent tetraploidization and subsequent tumorigensis. The tumor suppressors Lats1 and Lats2 are serine/threonine kinases that localize to the centrosome and regulate cell cycle progression and apoptosis. In the present study, Aurora A was demonstrated to phosphorylate Lats2 on serine 380 (S380) during mitosis. Immunocytochemical observations revealed that the subcellular localization of Lats2 was distinct during the cell cycle and depended on which site was phosphorylated. Interestingly, the S380-phosphorylated Lats2 protein (pS380) colocalized at the central spindle with Aurora B. Physical interactions were observed between Aurora A, Lats2, Lats1 and Aurora B. The Lats1 kinase was shown to phosphorylate Aurora B. Cells expressing a nonphosphorylated mutant (S380A) of Lats2 caused chromosome missegregation and cytokinesis failure, similar to cells with aberrantly expressed Aurora B. Together, the results suggest that the Aurora A-Lats1/2-Aurora B axis might be a novel pathway that regulates accurate mitotic progression by ensuring the proper mitotic localization of Lats2. PMID- 21822050 TI - Bridging the gap: facilities and technologies for development of early stage therapeutic mAb candidates. AB - Therapeutic monoclonal antibodies (mAbs) currently dominate the biologics marketplace. Development of a new therapeutic mAb candidate is a complex, multistep process and early stages of development typically begin in an academic research environment. Recently, a number of facilities and initiatives have been launched to aid researchers along this difficult path and facilitate progression of the next mAb blockbuster. Complementing this, there has been a renewed interest from the pharmaceutical industry to reconnect with academia in order to boost dwindling pipelines and encourage innovation. In this review, we examine the steps required to take a therapeutic mAb from discovery through early stage preclinical development and toward becoming a feasible clinical candidate. Discussion of the technologies used for mAb discovery, production in mammalian cells and innovations in single-use bioprocessing is included. We also examine regulatory requirements for product quality and characterization that should be considered at the earliest stages of mAb development. We provide details on the facilities available to help researchers and small-biotech build value into early stage product development, and include examples from within our own facility of how technologies are utilized and an analysis of our client base. PMID- 21822052 TI - Mcl-1 and YY1 inhibition and induction of DR5 by the BH3-mimetic Obatoclax (GX15 070) contribute in the sensitization of B-NHL cells to TRAIL apoptosis. AB - The pan Bcl-2 family antagonist Obatoclax (GX15-070), currently in clinical trials, was shown to sensitize TRAIL-resistant tumors to TRAIL-mediated apoptosis via the release of Bak and Bim from Mcl-1 or Bcl-2/Bcl-XL complexes or by the activation of Bax, though other mechanisms were not examined. Herein, we hypothesize that Obatoclax-mediated sensitization to TRAIL apoptosis may also result from alterations of the apoptotic pathways. The TRAIL-resistant B-cell line Ramos was used as a model for investigation. Treatment of Ramos cells with Obatoclax significantly inhibited the expression of several members of the Bcl-2 family, dissociated Bak from Mcl-1 and inhibited the NFkappaB activity. Cells treated with Mcl-1 siRNA were sensitized to TRAIL apoptosis. We examined whether the sensitization of Ramos to TRAIL by Obatoclax resulted from signaling of the DR4 and/or DR5. Transfection with DR5 siRNA, but not with DR4 siRNA, sensitized the cells to apoptosis following treatment with Obatoclax and TRAIL. The signaling via DR5 correlated with Obatoclax-induced inhibition of the DR5 repressor Yin Yang 1 (YY1). Transfection with YY1 siRNA sensitized the cells to TRAIL apoptosis following treatment with Obatoclax and TRAIL. Overall, the present findings reveal a new mechanism of Obatoclax-induced sensitization to TRAIL apoptosis and the involvement of the inhibition of NFkappaB activity and downstream Mcl-1 and YY1 expressions and activities. PMID- 21822053 TI - Characterization of the cell of origin for small cell lung cancer. AB - Small cell lung carcinoma (SCLC) is a neuroendocrine subtype of lung cancer that affects more than 200,000 people worldwide every year with a very high mortality rate. Here, we used a mouse genetics approach to characterize the cell of origin for SCLC; in this mouse model, tumors are initiated by the deletion of the Rb and p53 tumor suppressor genes in the lung epithelium of adult mice. We found that mouse SCLCs often arise in the lung epithelium, where neuroendocrine cells are located, and that the majority of early lesions were composed of proliferating neuroendocrine cells. In addition, mice in which Rb and p53 are deleted in a variety of non-neuroendocrine lung epithelial cells did not develop SCLC. These data indicate that SCLC likely arises from neuroendocrine cells in the lung. PMID- 21822054 TI - tRNA genes protect a reporter gene from epigenetic silencing in mouse cells. AB - It is a well-established fact that the tRNA genes in yeast can function as chromatin barrier elements. However, so far there is no experimental evidence that tRNA and other Pol III-transcribed genes exhibit barrier activity in mammals. This study utilizes a recently developed reporter gene assay to test a set of Pol III-transcribed genes and gene clusters with variable promoter and intergenic regions for their ability to prevent heterochromatin-mediated reporter gene silencing in mouse cells. The results show that functional copies of mouse tRNA genes are effective barrier elements. The number of tRNA genes as well as their orientation influence barrier function. Furthermore, the DNA sequence composition of intervening and flanking regions affects barrier activity of tRNA genes. Barrier activity was maintained for much longer time when the intervening and flanking regions of tRNA genes were replaced by AT-rich sequences, suggesting a negative role of DNA methylation in the establishment of a functional barrier. Thus, our results suggest that tRNA genes are essential elements in establishment and maintenance of chromatin domain architecture in mammalian cells. PMID- 21822056 TI - Infections associated with monoclonal antibody and fusion protein therapy in humans. AB - Monoclonal antibodies (mAbs), especially those that interact with immune or hematologic leukocyte membrane targets, have changed the outcome of numerous diseases. However, mAbs can block or reduce immune cells and cytokines, and can lead to increased risk of infection. Some of these risks are predictable and can be explained by their mechanisms of action. Others have been observed only after the mAbs were licensed and used extensively in patients. In this review, we focus on infectious complications that occur upon treatment with mAbs or Fc-containing fusion proteins targeting leukocyte membrane proteins, including CD52, CD20, tumor necrosis factor, VLA4, CD11a and CTLA4. We report their known infectious risks and the recommendations for their use. Although most of these drugs are clinically safe when the indications are respected, we emphasize the need for regular updating of pharmacovigilance data. PMID- 21822057 TI - On the chromatin structure of eukaryotic telomeres. AB - Telomeres prevent chromosome fusions and degradation by exonucleases and are implicated in DNA repair, homologous recombination, chromosome pairing and segregation. All these functions of telomeres require the integrity of their chromatin structure, which has been traditionally considered as heterochromatic. In agreement with this idea, different studies have reported that telomeres associate with heterochromatic marks. However, these studies addressed simultaneously the chromatin structures of telomeres and subtelomeric regions or the chromatin structure of telomeres and Interstitial Telomeric Sequences (ITSs). The independent analysis of Arabidopsis telomeres, subtelomeric regions and ITSs has allowed the discovery of euchromatic telomeres. In Arabidopsis, whereas subtelomeric regions and ITSs associate with heterochromatic marks, telomeres exhibit euchromatic features. We think that this scenario could be found in other model systems if the chromatin organizations of telomeres, subtelomeric regions and ITSs are independently analyzed. PMID- 21822055 TI - Cohesin and related coiled-coil domain-containing complexes physically and functionally connect the dots across the genome. AB - Interactions between genetic regions located across the genome maintain its three dimensional organization and function. Recent studies point to key roles for a set of coiled-coil domain-containing complexes (cohibin, cohesin, condensin and monopolin) and related factors in the regulation of DNA-DNA connections across the genome. These connections are critical to replication, recombination, gene expression as well as chromosome segregation. PMID- 21822058 TI - Methylation patterns in sentinel genes in peripheral blood cells of heavy smokers: Influence of cruciferous vegetables in an intervention study. AB - Changes in DNA methylation patterns are a hallmark of tobacco-induced carcinogenesis. We have conducted a randomized 4-week intervention trial to investigate the effects of three dietary regimens to modify DNA methylation patterns in peripheral white blood cells of heavy smokers. A group of 88 smokers were randomly assigned to and distributed among three diets, including (1) normal isocaloric diet (balanced in fruits and vegetables), according to international guidelines; (2) a diet enriched in flavonoids and isothiocyanates (particularly cruciferous vegetables); (3) a regimen consisting of diet 1 supplemented with flavonoids (green tea and soy products). Methylation patterns were analyzed by pyrosequencing in LINE1 (Long Interspersed DNA Elements), RASSF1A, ARF and CDKN2a (tumor suppressor genes), MLH1 (mismatch DNA repair) and MTHFR (folate metabolism). Three distinct patterns of methylation were observed. In LINE1, methylation showed a small but reproducible increase with all three regimens. MTHFR was constitutively methylated with no significant modulation by diets. The four other loci showed low basal levels of methylation with no substantial change after intervention. These data suggest that the isocaloric diet may stabilize global epigenetic (LINE1 DNA methylation) patterns in peripheral white blood cells but does not provide evidence for methylation changes in specific genes associated with this short-term dietary intervention. PMID- 21822059 TI - TCP1 positively regulates the expression of DWF4 in Arabidopsis thaliana. AB - Brassinosteroids (BRs) are a group of major phytohormones playing critical roles in plant growth and development. Within the last two decades, key events of BR biosynthesis and signal transduction have been gradually elucidated. The detailed molecular mechanisms controlling bioactive levels of BRs, however, are not fully understood. TCP1 is a member of class II TCP proteins in Arabidopsis thaliana. The role of TCP1 in BR biosynthesis was discovered by an activation tagging analysis aiming to screen for genetic suppressors of an intermediate allele named bri1-5 of the BR receptor gene BRI1. Overexpression of TCP1 partially suppresses the defective phenotypes of bri1-5 via direct up-regulation of DWF4, one of the target genes of TCP1. PMID- 21822060 TI - Suppression of late-flowering and semi-dwarf phenotypes in the Arabidopsis clock mutant lhy-12;cca1-101 by phyB under continuous light. AB - Photoperiodic flowering in Arabidopsis is controlled not only by floral activators such as GI, CO, and FT, but also by repressors such as SVP and FLC. Double mutations in LHY and CCA1 (lhy;cca1) accelerated flowering under short days, mainly by the GI-CO dependent pathway. In contrast, lhy;cca1 showed delayed flowering under continuous light (LL), probably due to the GI-CO independent pathway. This late-flowering phenotype was suppressed by svp, flc, and elf3. However, how SVP, FLC, and ELF3 mediate LHY/CCA1 and flowering time is not fully understood. We found that lhy;cca1 exhibited short hypocotyls and petioles under LL, but the molecular mechanism for these effects has not been elucidated. To address these questions, we performed a screen for mutations that suppress either or both of the lhy;cca1 phenotypes under LL, using two different approaches. We identified two novel mutations, a dominant (del1) and a recessive (phyB-2511) allele of phyB. The flowering times of single mutants of three phyB alleles, hy3 1, del1, and phyB-2511, are almost the same and earlier than those of wild-type plants. A similar level of acceleration of flowering time was observed in all three phyB mutants tested when combined with the late-flowering mutations co-2 and SVPox. However, the effect of phyB-2511 on lhy;cca1 was different from those by hy3-1 or del1. svp-3 did not strongly enhance the early-flowering phenotypes of phyB-2511 or del1. These results suggest that light signaling via PhyB may affect factors downstream of the clock proteins, controlling flowering time and organ elongation. phyB mutations with different levels of effects on lhy;cca1 dependent late flowering would be useful to determine a specific role for PHYB in the flowering pathway controlled by lhy;cca1 under LL. PMID- 21822061 TI - Golgi-localized UDP-glucose transporter is required for cell wall integrity in rice. AB - Cell wall-related nucleotide sugar transporters (NSTs) theoretically supply the cytosolic nucleotide sugars for glycosyltransferases (GTs) to carry out ploysaccharide synthesis and modification in the Golgi apparatus. However, the regulation of cell wall synthesis by NSTs remains undescribed. Recently, we have reported the functional characterization of Oryza sativa nucleotide sugar transport (Osnst1) mutant and its corresponding gene. OsNST1/BC14 is localized in the Golgi apparatus and transports UDP-glucose. This mutant provides us with a unique opportunity for evaluation of its abroad impacts on cell wall structure and components. We previously examined cell wall composition of bc14 and wild type plants. Here, the spatial distribution of these cell wall alterations was analyzed by immunolabeling approach. Analysis of the sugar yield in different cell wall fractions indicated that this mutation improves the extractability of cell wall components. Field emission scanning electron microscopy further showed that the orientation of microfibrils in bc14 is irregular when compared to that in wild type. Therefore, this UDP-glucose transporter, making substrates available for polysaccharide biosynthesis, plays a critical role in maintaining cell wall integrity. PMID- 21822062 TI - Auxin binding-protein1 (ABP1), a receptor to regulate auxin transport and early auxin genes in an interlocking system with PIN proteins and the receptor TIR1. AB - Compared to the past 10 years, a flurry of publications, reviews, and experimental papers on ABP1 appeared in the last couple of years. Certainly, the reason is that new methods and conceptual approaches appeared to tackle the questions posed by this enigmatic auxin-binding protein. Part of the enigma is the obvious central importance of ABP1, documented by the embryo-lethal property of the homozygous T-DNA insertion into this gene1. At the same time, this very property hindered progress in studying ABP1. Another delaying influence on ABP1 research was the fact that regulation of early auxin genes was fully explained by the mechanism provided by TRI1, the second auxin receptor2-4. PMID- 21822063 TI - Regulation of shoot meristem integrity during Arabidopsis vegetative development. AB - Shoot growth and development is mediated by the activity of the shoot meristem, which initiates leaves and axillary meristems. Meristem maintenance is achieved by a poorly understood process that functions to sustain the balance of stem cell perpetuation in the central zone (CZ) and organogenesis in the peripheral zone (PZ). A recent study showed that two related homeodomain transcription factors, pennywise (PNY) and pound-foolish (PNF), regulate meristem maintenance by controlling the integrity of the CZ. The non-flower producing phenotype displayed by pny pnf plants can be rescued by genetically increasing the size of the shoot meristem. In this addendum, we show that augmenting the size of the central region of pny pnf shoot meristems partially rescues the meristem termination phenotype that occurs during early stages of vegetative development. Thus, regulation of CZ integrity by PNY and PNF is crucial for vegetative and reproductive development. PMID- 21822064 TI - A cry for help from leaf to root: above ground insect feeding leads to the recruitment of rhizosphere microbes for plant self-protection against subsequent diverse attacks. AB - Plants have evolved general and specific defense mechanisms to protect themselves from diverse enemies, including herbivores and pathogens. To maintain fitness in the presence of enemies, plant defense mechanisms are aimed at inducing systemic resistance: in response to the attack of pathogens or herbivores, plants initiate extensive changes in gene expression to activate "systemic acquired resistance" against pathogens and "indirect defense" against herbivores. Recent work revealed that leaf infestation by whiteflies, stimulated systemic defenses against both an airborne pathogen and a soil-borne pathogen, which was confirmed by the detection of the systemic expression of pathogenesis-related genes in response to salicylic acid and jasmonic acid-signaling pathway activation. Further investigation revealed that plants use self protection mechanisms against subsequent herbivore attacks by recruiting beneficial microorganisms called plant growth-promoting rhizobacteria/fungi, which are capable of reducing whitefly populations. Our results provide new evidence that plant-mediated aboveground to belowground communication and vice versa are more common than expected. PMID- 21822065 TI - Light as both an input and an output of wound-induced reactive oxygen formation in Arabidopsis leaves. AB - The wound response of plants is characterised by rapid changes in gene expression, biochemistry and physiology, and is important both in its own right and as a model for studying events elicited by herbivory. We have recently identified links between light and the wound response in Arabidopsis leaves. This includes an influence of the external light environment on the molecular and biochemical response to wounding, and the observation that endogenous bioluminescence (light emission) is a consequence of tissue damage. Here, we show that this link extends to the production of reactive oxygen species. We show that wounding causes rapid, light-dependent production of superoxide and hydrogen peroxide in chloroplasts via disruption of photosynthesis, and that wound-induced bioluminescence is a consequence of the generation of singlet oxygen. PMID- 21822066 TI - Cocreating a communicative space to develop a mindfulness meditation manual for women in recovery from substance abuse disorders. AB - Mindfulness-Based Stress Reduction (MBSR) programs are becoming more integrated into the treatment of persons with substance use disorders (SUDs). A focus of MBSR is to increase awareness of sensations in the body and accept them in the moment without judgment. Little is known about the readiness of women, with posttraumatic stress disorder (PTSD), and their level of comfort to participate in MBSR programs. Habermas' ideal speech situation guided a cooperative inquiry with 45 women at 3 treatment centers. Women engaged in activities of MBSR and shared opinions on how to develop a manual that would address the readiness of women with SUDs-PTSD to participate in MBSR. PMID- 21822067 TI - Factors related to posttraumatic stress symptoms in women experiencing police involved intimate partner violence. AB - Relationships among intimate partner violence (IPV), Post Traumatic Stress Disorder (PTSD) symptoms, health, and danger, using M.A. Dutton's Empowerment framework, were examined among 423 ethnically diverse women in contact with police due to IPV. Significant predictors of PTSD symptoms in multivariate analysis included Danger Assessment score, poor overall health, abuse leading to pain, victim expectations of future injury victimization, feeling unsafe, and shame. Results provide further evidence supporting routine assessment for violent trauma and PTSD as well as the need for research testing holistic interventions for women traumatized by violence. PMID- 21822069 TI - From the editor. PMID- 21822068 TI - Theories of intimate partner violence: from blaming the victim to acting against injustice: intersectionality as an analytic framework. AB - Intimate partner violence (IPV) has garnered increasing public and academic attention in the past several decades. Theories about the causes, prevention, and intervention for IPV have developed in complexity. This article provides an overview of the historical roots of IPV, as well as a description and critique of historical and contemporary theories of IPV causes and women's responses to IPV. This is followed by a discussion of the most current theoretical developments and application of critical theories to the problem of IPV. The article concludes with theoretically based implications for nursing practice and research with women who are experiencing IPV. PMID- 21822070 TI - A lifelong journey of moving beyond wartime trauma for survivors from Hiroshima and Pearl Harbor. AB - This study examines 51 stories of health, shared by people who survived the wartime trauma of Hiroshima and Pearl Harbor, seeking to identify turning points that moved participants along over their lifetime. The central turning point for Hiroshima survivors was "becoming Hibabusha (A-bomb survivor)" and for Pearl Harbor survivors was "honoring the memory and setting it aside." Wartime trauma was permanently integrated into survivors' histories, surfacing steadily over decades for Hiroshima survivors and intermittently over decades for Pearl Harbor survivors. Regardless of experience or nationality, participants moved through wartime trauma by connecting with others, pursuing personal and global peace. PMID- 21822071 TI - Balancing in moments of vulnerability while dancing the dialectic. AB - Questions about the existence of horizontal violence and the forms it takes dominate the literature. To move the dialogue forward, this article proffers the thesis that it is through a deeper understanding of moments of vulnerability and adult epistemological development that we may best alter the occurrence and continuance of horizontal violence in the nursing profession. The constructive development tradition has laid important groundwork for considering moments of vulnerability wherein which horizontal violence may begin and be perpetuated and explains how it has become so pervasive in the nursing field. New solutions are proposed and directions for further inquiry suggested. PMID- 21822073 TI - The search for safety, control, and voice for mothers living with the legacy of childhood violence experiences: a critical feminist narrative inquiry. AB - We explored the experiences of 12 women who mothered their children while they encountered challenges stemming from the legacy of childhood violence experiences. We examined the participants' narratives through critical, feminist, and symbolic interaction lenses to locate the forces and conditions facilitating and constraining women's mothering choices and decisions. Women's stories revealed their agency in the face of enduring distrust experiences. Women were determined to "change the story." They met pervasive self-doubt with a "search for anchors" and "constant comparisons." Persistent distrust of others meant women relied on "hypervigilance" and "gatekeeping." Implications for knowledge development, research, and practice are discussed. PMID- 21822072 TI - Unwanted unprotected sex: condom coercion by male partners and self-silencing of condom negotiation among adolescent girls. AB - This exploratory study used the theory of reasoned action and the theory of gender and power to guide elicitation of partner-related impediments to condom use among 64 adolescent girls living in poor urban areas with high rates of HIV and partner abuse. About 53% indicated that they had experienced unwanted, unprotected vaginal sex and 25% indicated that they were unable to discuss condom use with a partner. Novel qualitative findings related to condom coercion, condom sabotage, and self-silencing of condom negotiation are discussed in the context of connecting partner abuse to interpersonal control over condom use. Implications for intervention design are discussed. PMID- 21822074 TI - Minding the gaps: moving handover research forward. PMID- 21822075 TI - Is anaesthetic cardioprotection clinically relevant? Another futile search for a magic bullet? PMID- 21822076 TI - The European Consensus Statement on intraoperative fluid therapy in children: a step in the right direction. PMID- 21822077 TI - Effects of hydroxyzine-midazolam premedication on sevoflurane-induced paediatric emergence agitation: a prospective randomised clinical trial. AB - BACKGROUND AND AIM: Anaesthesia with sevoflurane leads to a high prevalence of emergence agitation in paediatric patients. This study investigates the effects of combining hydroxyzine and midazolam on sevoflurane-induced emergence agitation in paediatric patients undergoing infraumbilical surgery with a caudal block. PATIENTS AND METHODS: Eighty-four children 1-7 years of age undergoing general anaesthesia with sevoflurane and caudal block were assigned to two groups. Children in group M (n = 42) were premedicated with 0.5 mg kg oral midazolam and children in group MH (n = 42) were premedicated with 0.5 mg kg oral midazolam and 1 mg kg hydroxyzine given 30 min before anaesthesia induction. A caudal epidural block was performed following anaesthesia induction. Induction quality, parental separation scores and emergence agitation were evaluated. Emergence agitation was evaluated with the PAED score (Paediatric Anesthesia Emergence Delirium) every 5 min during the first 30 min after admission to recovery room. Induction quality and parental separation were assessed with 4-point scores. Postoperative pain was evaluated with the 10-point Children's and Infants' Postoperative Pain Scale. RESULTS: Median parental separation (3 vs. 2; P = 0.01), induction quality (2 vs. 2; P = 0.03) and sedation scores (3 vs. 2; P = 0.003) were significantly better in the MH group compared to the M group. Median PAED score of group M (15) was higher than that of group MH (11; P < 0.001) and the number of children with PAED scores more than 16 was also higher in group M (n = 16) compared to group MH (n = 2; P < 0.001). None of the children had a pain score more than 3 throughout the study period. CONCLUSION: The incidence of sevoflurane-induced emergence agitation was significantly lower in children premedicated with a midazolam and hydroxyzine combination compared to those premedicated with midazolam only. Furthermore, the midazolam and hydroxyzine combination provided better premedication quality than midazolam alone. PMID- 21822083 TI - Gastric volvulus manifesting as infantile wheezing: a puzzling presentation. AB - Gastric volvulus is a rare disease in the pediatric population. Its clinical presentation is exceedingly variable, and without a high index of suspicion, delayed or missed diagnosis is not uncommon as illustrated by this report of a 13 month-old boy with a puzzling presentation of chronic wheezing and cough for 1 year. There were no gastrointestinal symptoms. The symptoms were attributed to bronchiolitis, pneumonia, laryngomalacia, or reactive airway disease by several practicing physicians. A detailed history revealed that the wheezing got worse after large meals. This information prompted an upper gastrointestinal contrast study, which led to the identification of organoaxial gastric volvulus and coexisting gastroesophageal reflux. The respiratory symptoms resolved dramatically after antireflux medications and lifestyle modification for gastroesophageal reflux. This report highlights chronic gastric volvulus in the differential diagnosis of infantile wheezing, particularly when the wheezing is present very early in life and associated with feeding. PMID- 21822084 TI - Pyogenic flexor tenosynovitis in children. AB - Pyogenic flexor tenosynovitis is an uncommon, emergent hand infection. The literature lacks any description of the disease and the variability of its manifestations in young children. We describe 3 cases. Two cases were diagnosed and treated promptly, and the third presented late, with atypical clinical signs, causing a delay in his diagnosis and treatment and stressing the caution to be taken with the evaluation of these children with signs of hand infection. PMID- 21822085 TI - Pulmonary hemorrhage: a rare complication of opioid overdose. AB - Children and adolescents with pulmonary hemorrhage are infrequently encountered in the emergency department (ED). We describe a case of a 16 year-old boy who presented to a pediatric ED with pulmonary hemorrhage and respiratory distress. The patient's unusual initial presentation resulted in the consideration of a broad differential diagnosis for his symptoms, including traumatic, neurological, respiratory, and toxicological causes. After resuscitation in the ED, a prolonged admission, and extensive testing, no cause could be found other than severe opioid toxicity. This case illustrates a rare, life-threatening presentation of opiod toxicity in a healthy adolescent and underlines the potentially serious nature of such exposures. PMID- 21822086 TI - Contact dermatitis with severe scalp swelling and upper airway compromise due to black henna hair dye. AB - Temporary tattooing with black henna is known to cause contact dermatitis; however, this adverse effect is not considered to be life threatening. We report a female adolescent who used black henna as a hair dye and developed severe contact dermatitis with scalp, facial, and neck swelling causing hoarseness and stridor. A flexible bronchoscopy showed a normal epiglottis, and the patient was intubated, ventilated, and eventually recovered. We conclude that the use of black henna hair dye in sensitized patients can be life threatening. PMID- 21822087 TI - Diagnosis of a craniopharyngioma after acute brainstem herniation in an emergency department. AB - A 9-year-old previously healthy girl presented with 3 weeks of intermittent emesis and headache to a community emergency department, where she had rapid decompensation due to increased intracranial pressure. Head computed tomography revealed a calcified suprasellar mass consistent with a craniopharyngioma. Despite medical and surgical intervention, the patient had progression of herniation with global cerebral infarction, and care was withdrawn. Although craniopharyngiomas are typically thought to be benign, slow-growing intracranial tumors, this case emphasizes the need for an expeditious diagnostic evaluation when symptoms that may be referable to intracranial hypertension are evident. Craniopharyngiomas and emergency management of intracranial hypertension are reviewed. PMID- 21822088 TI - Pneumococcal pneumonia complicating purulent pericarditis in a previously healthy girl: a rare yet possible fatal complication in the antibiotic era. AB - Purulent pericarditis is an extremely rare complication of invasive Streptococcus pneumoniae infection among children in the antibiotic era, and its mortality remains high if left untreated. This report involves a 41/2-year-old girl who presented to our emergency department with productive cough, shortness of breath, and left-sided chest pain with a diagnosis of pneumococcal pneumonia. She subsequently developed life-threatening conditions including bilateral empyema with respiratory failure, purulent pericarditis, and multiple organ failure leading to death. The case highlights that purulent pericarditis is a rare yet possible disorder complicating pneumococcal disease in the antibiotic era. The increase in strains resistant to penicillin should alert emergency physicians to the potential for reemergence of pneumococcal pericarditis in children. PMID- 21822089 TI - Panayiotopoulos syndrome presenting with status epilepticus and cardiorespiratory arrest: a case report. AB - Panayiotopoulos syndrome is early-onset benign childhood epilepsy, now classified as an electroclinical syndrome. The original description in 1989 focused on the triad of nocturnal seizures, tonic eye deviation, and vomiting. With available data from the long-term studies, a wide variety of manifestations have been described, with recognition of autonomic features as being the most prominent aspect of this epilepsy. The presenting symptoms are usually focal seizures comprising autonomic symptoms and/or behavioral changes. Majority of these seizures are in sleep, with half of the seizures progressing to become secondarily generalized. Occasionally, these seizures can present with prominent autonomic features such as ictal vomiting, pallor, flushing/cyanosis, and tachycardia with prolonged thermoregulatory changes lasting for hours, constituting autonomic status epilepticus. Recovery from this autonomic status epilepticus is within hours and is always complete. Autonomic status epilepticus has been previously reported in this epilepsy syndrome, but ictal cardiorespiratory arrest is extremely rare, with only 4 cases being reported in literature. All 4 cases reported in literature recovered spontaneously and did not require resuscitation. Here we present a 31/2-year-old male child with Panayiotopoulos syndrome who presented with status epilepticus and ictal cardiorespiratory arrest requiring cardiopulmonary resuscitation for revival. PMID- 21822090 TI - Little boy black and blue. AB - Tooth decay is common in US children, especially for children in low-income families. More than half of second-grade children have cavities. Therefore, root canal procedures are becoming more common in children. We report a case of a 2 year-old boy with a rare complication of a root canal procedure secondary to sodium hypochlorite toxicity. Sodium hypochlorite, a commonly used root canal irrigant, and its toxicity are reviewed. PMID- 21822091 TI - Influenza vaccination, diagnosis, and treatment in children. AB - Between 2009 and 2010, the influenza H1N1 pandemic swept across the globe, disproportionately affecting the pediatric population. This pandemic strain is expected to circulate again with other seasonal influenza strains during the 2010 2011 season. This article reviews the new 2010 to 2011 Centers for Disease Control and Prevention and American Academy of Pediatrics recommendations for vaccination against the influenza virus for pediatric patients. It reviews the various testing modalities and the benefits and disadvantage of each test and offers an approach to diagnostic testing. Lastly, it reviews the indications and recommendations for treatment of children with presumed or confirmed influenza infection. PMID- 21822093 TI - Pain assessment for children: overcoming challenges and optimizing care. AB - There is growing evidence that children have short- and long-term physical, physiological, and psychological effects due to untreated acute pain. Because the majority of children who seek care in an emergency department present with pain or experience pain during the evaluation and treatment in the emergency department, optimal assessment and treatment of pain are paramount for this population. This review will highlight the many complexities of the assessment of pain for the pediatric patient. In addition, a variety of factors that affect the self-report of pain in children will be identified. Optimizing the utility of a pain assessment remains a challenge for the health care provider in the emergency setting. The common goal of a decreased experience of pain for children through improved analgesic administration remains. PMID- 21822094 TI - ECGs in the ED. PMID- 21822095 TI - Pediatric emergency medicine: legal briefs. PMID- 21822096 TI - The "lymphangioma": an incorrect and outdated term. PMID- 21822097 TI - Outbreak of hemolytic-uremic syndrome linked to Shiga toxin-producing enteroaggregative Escherichia coli O104:H4. PMID- 21822098 TI - Society for Pediatric Research 2010 Presidential Address: Academic pediatrics and the narrative of discovery. PMID- 21822099 TI - Clinical and biological aspects of rotator cuff pathology. PMID- 21822100 TI - Animal models for translational research on shoulder pathologies: from bench to bedside. AB - Several animal models have been used for in vivo and in vitro shoulder research. In vitro models, consisting of cadaveric specimens, are useful in providing basic understanding of the functioning of the shoulder and for biomechanical experiments. In vivo models provide the means to model living phenomena, such as tendon healing process, tendinopathy, instability, and adaptive responses to surgery. However, intrinsic differences among different species make translation to human shoulder pathologies difficult. Most of the animals used in experimental settings are quadrupeds, using the forelimbs for weight-bearing during locomotion, with no or minimal overhead activity. The various animal models already used to study shoulder pathologies are presented in this article. However, there is a lack of validation for these animal models, which provides challenge to the further research in this field. PMID- 21822102 TI - Biomechanical factors in rotator cuff pathology. AB - The rotator cuff provides dynamic stability and is critical to normal shoulder function. Forces generated by the rotator cuff facilitate the motions involved in activities of daily living and the more demanding movements of athletics and manual labor. Injury and pathology of the rotator cuff are common and the unique anatomical and biomechanical characteristics of the cuff contribute to the etiology of its injury. This review provides a biomechanical and anatomic context to understanding normal rotator cuff function and summarizes recent work describing biomechanical implications of cuff pathology. PMID- 21822101 TI - Biological factors in the pathogenesis of rotator cuff tears. AB - Rotator cuff tears are common, and lead to shoulder pain and functional impairment. Despite their frequency and related disability, etiology and pathogenesis are still debated. Multiple factors contribute to tears of the rotator cuff. Extrinsic factors are anatomic variables, such as acromial morphologic characteristics, os acromiale, and acromial spurs that compress the rotator cuff by bony impingement or direct pressure from the surrounding soft tissue. Intrinsic factors arise from the tendon itself, because of tensile overload, aging, microvascular supply, traumatisms, or degeneration. Little information is available from a cellular and molecular point of view. We reviewed the biological factors involved in the pathogenesis of rotator cuff tears. Understanding the mechanism of rotator cuff pathology would facilitate the rationale for therapeutic interventions, by guiding the design, selection, and implementation of treatment strategies such as biologic modulation and preventive measures. PMID- 21822103 TI - Role of metalloproteinases in rotator cuff tear. AB - The role of matrix metalloproteinases (MMPs) and their inhibitors (TIMPS) in the pathophysiology of rotator cuff tears has not been established yet. Recent advances empathize about the role of MMPs and TIMPS in extracellular matrix (ECM) remodeling and degradation in rotator cuff tears pathogenesis and healing after surgical repair. An increase in MMPs synthesis and the resulting MMPs mediated alterations in the ECM of tendons have been implicated in the etiopathogenesis of tendinopathy, and there is an increase in the expression of MMPs and a decrease in TIMP messenger ribonucleic acid expression in tenocytes from degenerative or ruptured tendons. Importantly, MMPs are amenable to inhibition by cheap, safe, and widely available drugs such as the tetracycline antibiotics and bisphosphonates. A better understanding of relationship and activity of these molecules could provide better strategies to optimize outcomes of rotator cuff therapy. PMID- 21822104 TI - Inflammation in overuse tendon injuries. AB - Overuse tendon injuries present with pain and swelling of the affected tendon with associated decrease in exercise tolerance and function of the limb. After early inflammatory and degenerative hypotheses, the term "tendinopathy" is now deemed a more appropriate reflection of the mixed histopathological picture seen in operative biopsies from affected patients. The condition presents histopathological evidence of "failed healing response," but its etiology remains unclear. The incidence of tendinopathy is increased in individuals with obesity and decreased insulin sensitivity (as seen in type 1 and type 2 diabetes mellitus). These groups of patients also exhibit an increased risk of developing a state of chronic low-grade, systemic inflammation. This paper considers the theoretical bases to discuss whether these conditions may predispose to the development of tendinopathy and the implication that such a relationship may have on its management. PMID- 21822105 TI - Role of growth factors in rotator cuff healing. AB - The histologic lesion underlying overuse rotator cuff tendinopathy is a failed healing response, with haphazard proliferation of tenocytes, disruption of tendon cells and collagen fibers, and increased noncollagenous extracellular matrix. Recent attention has focused on the biological pathways by which tendons heal, leading to the identification of several growth factors (GFs) involved in this process. No studies have been published on the time course of the various GFs during rotator cuff healing process in vivo, in humans. We review what is known about these GFs and their role in rotator cuff healing. PMID- 21822106 TI - Histopathology of rotator cuff tears. AB - The pathogenesis of rotator cuff tears is multifactorial. Tendon abnormalities of the rotator cuff include alteration of collagen fiber structure, tenocytes, cellularity, and vascularity. Ruptured tendons show marked collagen degeneration and disordered arrangement of collagen fibers. Fibroblast population decreases as the size of the tear in the rotator cuff increases. The larger fibroblast population seen in the smaller tears is also actively proliferating and is part of an active reparative process. Inflammatory cell infiltrate correlates inversely to rotator cuff tear size in the torn supraspinatus tendon samples, with larger tears showing a marked reduction in all cell types. As tear size increase, there is also a progressive decrease in the number of blood vessels. Whether rotator cuff tear heals spontaneously is an important pathologic and clinical question. Histologic changes indicative of repair and inflammation lead to consider biological options in addition to biomechanical treatment of the rotator cuff tears. PMID- 21822107 TI - Calcific tendinopathy of the rotator cuff tendons. AB - Calcific tendinopathy (CT) of the tendons of the rotator cuff is common in white populations, with a reported prevalence varying from 2.7% to 22%, mostly affecting women between 30 and 50 years. Although CT shows a strong tendency toward self-healing by spontaneous resorption of the deposits, it does not always follow this typical pattern. The etiopathogenesis of CT is still unknown. Many pathogenetic theories have been proposed, and clinical associations between CT and diabetes and thyroid disorders have been reported. The choice of therapeutic approach should depend on the evolution of the condition. PMID- 21822108 TI - The role of platelet-rich plasma in rotator cuff repair. AB - The shoulder is a common source of disability resulting from traumatic and degenerate tears of the rotator cuff, subacromial impingement, and osteoarthritis. Nonoperative management has focused on treatment of the predisposing factors, the use of analgesics and anti-inflammatory medication usually in association with local anesthetic and steroid injections. Surgical intervention allows debridement of the degenerate cuff and partial thickness cuff tears, subacromial bursitis, impinging bone spurs and osteophytes together with rotator cuff repairs. Repairs of degenerate and torn tissue are often prone to failure due to many intrinsic and extrinsic factors. It is assumed that some biological therapies might improve clinical, mechanical, and histologic outcomes. Injections of platelet-rich plasma (PRP) have led to reduced pain and improved recovery in other degenerate pathologies areas together with the restoration of function. This study reviews the current literature on PRP and in particular discusses its relevance in the treatment of rotator cuff tears. PMID- 21822109 TI - Arthroscopic knots and strength sutures for rotator cuff repair. AB - Most arthroscopic rotator cuff reconstruction techniques require a method of securing the tendon to the bone to obtain a stable construct. The available options include knotless technology and suture welding, but the most common method uses suture anchors and knots. Tissue quality, surgical technique, repair material, and tension overload influence the stability of tissue repair. Arthroscopic knots are technically demanding because they are tied through cannulas with long-handled knot pushers. The strength of the repair is also influenced by the suture material used. In this study, we review the state-of-the art of arthroscopic knots and suture materials being used for arthroscopic rotator cuff repair. PMID- 21822110 TI - Clinical tests for the diagnosis of rotator cuff disease. AB - Several tests have been described to examine the shoulder. However, there is a lack of consensus on clinical assessment of patients with shoulder pain and suspected rotator cuff pathology. This review reports the diagnostic accuracy of clinical tests for rotator cuff pathology. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 21 clinical tests for rotator cuff pathology are reported from the available literature. Twenty studies investigated supraspinatus pathology, 12 infraspinatus pathology, and 9 subscapularis pathology. Most tests for rotator cuff pathology are inaccurate, and the recent literature shows that there is insufficient evidence to recommend 1 clinical test over another for diagnosis of rotator cuff pathology. Poor diagnostic accuracy of clinical tests for rotator cuff pathology may be related to the close relationships of structures in the shoulder, to a lack of understanding of anatomical basis of the tests, or to their lack of reproducibility. PMID- 21822111 TI - Imaging of the rotator cuff. AB - The imaging evaluation of the rotator cuff augments the clinical evaluation. Radiography, computed tomography, and magnetic resonance imaging all have various roles in the assessment of the rotator cuff, which can be combined with arthrography for added detail. Furthermore, ultrasound is a very useful technique that provides functional information that is not offered by simple anatomic imaging. PMID- 21822112 TI - Current imaging of the rotator cuff. AB - Rotator cuff pathology is a common cause of shoulder pain, and imaging plays a major role in the management of shoulder problems. General radiography may be useful as an initial screening test particularly in trauma and arthritis. Musculoskeletal ultrasound and magnetic resonance imaging are the most suitable modalities for the investigation of the rotator cuff, having high sensitivities and specificities for full-thickness tears. Musculoskeletal ultrasound and magnetic resonance imaging are less accurate in the detection of partial thickness tears with greater observer variability. This article reviews the normal and pathologic imaging features of the rotator cuff and highlights the potential usefulness and limitations of various imaging modalities in the assessment of the tendon and the potential impact of imaging findings on clinical patient care. PMID- 21822113 TI - Scoring systems for the functional assessment of patients with rotator cuff pathology. AB - Ideally, an outcome instrument measures phenomena that are directly relevant to the patient and provides a comprehensive assessment of the impact of a condition on the patient's daily life. During the past decades, several rating scales have been developed to assess the functional status of patients with shoulder pain. Several scoring systems are currently available for the evaluation of patients with rotator cuff pathology. Each of them evaluates shoulder function using specific variables. The main features of these scoring systems are presented in this review. Although many scoring systems are commonly used to evaluate shoulder function, we are still far from a single outcome evaluation system, which is reliable, valid, and sensitive to clinically relevant changes, takes into account both patient's and physician's perspective, and is short and practical to use. PMID- 21822114 TI - Cost effectiveness of drug-eluting stents as compared with bare metal stents in patients with coronary artery disease. AB - The aim of this study was to estimate the incremental cost effectiveness of replacing bare metal stents (BMS) by drug-eluting stents (DES) when using trial data and registry data. We developed a Markov model (model of cost effectiveness of coronary artery disease) in which 60-year-old patients started by undergoing percutaneous coronary intervention for acute or subacute coronary artery disease. The patients are followed until death or 100 years of age. Data on the occurrence of events (revascularization, acute myocardial infarction, and death) were based on Scandinavian registry data. Separate analyses were conducted with data on effectiveness based on randomized controlled trials and patient registries. On using trial data, it was found that sirolimus-eluting stents (SES) yield 0.003 greater life expectancy and $3300 lower costs than do BMS (dominant strategy). Paclitaxel-eluting stents (PES) yield 0.148 more life years than do SES at additional lifetime costs of $2800 ($21,400 per life year gained). On using registry data, the cost per life year gained was found to be $4900 when replacing BMS with DES. Probabilistic sensitivity analyses, on the other hand, indicate that PES only has a 50%-75% probability of being cost effective, regardless of the type of effectiveness data. DESs are cost effective with current willingness to pay for life year gains. Whether PES or SES is the most effective DES remains uncertain. PMID- 21822115 TI - Local therapy in metastatic breast cancer is associated with improved survival. AB - Patients presenting with stage-IV breast cancer are usually offered systemic chemotherapy to control metastatic tumor burden and palliative radiation therapy to manage the symptomatic primary tumor. The aim of this study was to assess the result of local therapy on the overall outcome of patients with metastatic breast cancer. We reviewed medical records of all patients with metastatic breast cancer that presented to our institution between 2000 and 2009. Based on the treatment received, the patients were grouped as follows: group 1 included patients who underwent surgery and also received radiotherapy and chemotherapy/hormonal therapy, group 2 included patients who received radiotherapy and chemotherapy/hormonal therapy only, and group 3 included patients who received chemotherapy/hormonal therapy alone. Of the 37 patients included in the study, 10 patients were placed in group 1, 17 patients in group 2, and 10 patients in group 3. About 38% had high to anaplastic tumor grade, and 48% had >=2 metastatic sites in the body. Overall, the average survival time was 3.13 years (range: 0-17 years). A significant difference in survival estimates was noted between groups 1, 2, and 3 with mean survival times of 8.83, 4.9, and 2.26 years, respectively (log rank chi = 10.44, P = 0.005). In age-adjusted multivariate Cox regression model (chi = 21.729, P= 0.001), high/anaplastic tumor grade (P = 0.036), African American race (P = 0.009), central nervous system metastasis (P = 0.003), group 2 (P = 0.006), and group 3 (P = 0.002) were associated with poor survival. Survival was not associated with estrogen and progesterone receptor and visceral or bone metastases. We conclude that aggressive local control of primary tumor in patients presenting with stage-IV breast cancer is associated with improved survival. PMID- 21822116 TI - A novel immunogen to modulate cytokine production and promote immune system reconstitution in HIV-AIDS. AB - This 'proof of concept' study was implemented in anticipation of identifying and testing a novel antigen of human origin as a potential immunogen in a paradigm that emphasizes immunomodulation and immune system reconstitution as requisites to the development of an effective human immunodeficiency virus (HIV)-acquired immune deficiency syndrome vaccine. Fifteen HIV-infected, highly active antiretroviral therapy (HAART) naive, otherwise healthy male seropositive patients were stratified by [CD4+] into 3 groups of 5 patients: group 1 >500/mm; group 2 > 250/mm but <500/mm; and group 3 < 250/mm. Five healthy male subjects were used as controls. Replicate peripheral blood mononuclear cell (PBMC) [H]thymidine uptake phytohemaglutinin-stimulated proliferation studies, and serum cytokine assays were carried out in the presence or absence of Kveim antigen at dilutions ranging from 0.001 to 100 MUg/mL. Serum cytokines [interleukin-2 (IL 2), IL-4, IL-6, interferon gamma, and tumor necrosis factor alpha] were assayed using standardized methodology. Nonparametric statistical analyses and linear regression analysis were used to test for statistical significance and strength of associations. PBMCs harvested from HIV-infected patients and incubated, ex vivo, demonstrated reproducible, antigen concentration-dependent changes in cytokine production over a range of antigen concentrations (0.001-100 MUg/mL) in contrast to antigen-naive PBMCs and controls. Significant correlations were demonstrated between antigen concentration and the amount of cytokines secreted. The magnitude of the cytokine response and the patterns of cytokine secretion were HIV group-specific and could be used to identify and distinguish between the 3 groups of HIV-infected subjects. A shift toward the production of type 1-like (Th1) cytokines characteristically seen in systemic sarcoidosis and associated with effective HAART was seen when patterns of cytokine secretion were compared between antigen exposed and antigen-naive PBMCs. PBMCs harvested from seropositive HIV-infected patients and exposed to the Kveim antigen have the following properties: (1) They demonstrate proliferation and exhibit an antigen concentration-dependent secretion of cytokines. The magnitude of the cytokine response can be used to identify and distinguish between groups of seropositive patients stratified by [CD4+]. (2) These PBMCs secrete cytokines in patterns suggestive of a shift to a type 1-like (Th1) response characteristic of HAART and sarcoidosis as opposed to the type 2-like (Th2) cytokine profile characteristic of HIV-acquired immune deficiency syndrome. PMID- 21822117 TI - Age old dapsone in the treatment of idiopathic thrombocytopenic purpura--a case report with review. AB - Idiopathic thrombocytopenic purpura (ITP) is characterized by premature platelet destruction in the reticuloendothelial system due to the presence of autoantibodies against the platelet membrane proteins. Patients who are resistant to the traditional treatment options that include the administration of steroids, IV immunoglobulin, and antirhesus D immunoglobulin and the performance of a splenectomy are diagnosed to have refractory chronic ITP. Management options in these patients are not well defined. Long-term steroids, rituximab, danazol, azathioprine, and cyclophosphamide have variable efficacy and at the same time carry significant side effects. We present the case of a patient treated effectively with dapsone, a drug that is much safer than other drugs and which can be used before resorting to splenectomy; we also include a review of the literature establishing its role in the management of ITP. PMID- 21822118 TI - Altered mental status in a young, healthy female. AB - A young previously healthy patient presented with fever and altered mental status. Her evaluation would eventually reveal a profound hyponatremia in the setting of a viral meningoencephalitis. This case report reviews the evaluation of hyponatremia and treatment options for syndrome of inappropriate antidiuretic hormone hypersecretion, her ultimate diagnosis. PMID- 21822119 TI - HDAC inhibition delays cell cycle progression of human bladder cancer cells in vitro. AB - Our aim was to analyze the impact of the histone deacetylase (HDAC)-inhibitor valproic acid (VPA) on bladder cancer cell growth in vitro. RT-4, TCCSUP, UMUC-3, and RT-112 bladder cancer cells were treated with VPA (0.125-1 mmol/l) without and with preincubation periods of 3 and 5 days. Controls remained untreated. Tumor cell growth, cell cycle progression, and cell cycle-regulating proteins were investigated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, flow cytometry, and western blotting, respectively. Effects of VPA on histone H3 and H4 acetylation and HDAC3 and HDAC4 were also determined. Without preincubation, no tumor cell growth reduction was observed with 0.125 and 0.25 mmol/l VPA in TCCSUP, UMUC-3, and RT-112 cells, whereas 0.5 and 1 mmol/l VPA diminished the cell number significantly. VPA (0.25 mmol/l) did exert tumor growth-blocking effects after a 3-day preincubation. To achieve antitumor effects with VPA (0.125 mmol/l), a 5-day preincubation was necessary. A 3-day or 5-day preincubation was also necessary to distinctly delay cell cycle progression, with maximum effects at VPA (1 mmol/l). After the 5-day preincubation, the cell cycle regulating proteins cdk1, cdk2, cdk4, and cyclins B, D1, and E were reduced, whereas p27 was enhanced. Diminished HDAC3 and 4 expression induced by VPA was accompanied by elevated acetylation of H3 and H4. VPA exerted growth-blocking properties on a panel of bladder cancer cell lines, commensurate with dose and exposure time. Long-term application induced much stronger effects than did shorter application and should be considered when designing therapeutic strategies for treating bladder carcinoma. PMID- 21822120 TI - Complete pathologic response with combination oxaliplatin and 5-fluorouracil chemotherapy in an older patient with advanced gastric cancer. AB - Management of gastric cancer in older adults is challenging. Perioperative treatment with epirubicin, cisplatin, and 5-fluorouracil combination chemotherapy and surgery is considered the standard treatment of locally advanced gastric adenocarcinoma. However, this chemotherapy regimen is not well tolerated in older adults. Here, we report a case of an older patient with locally advanced gastric cancer who was treated with modified FOLFOX-6 (oxaliplatin, leucovorin, and 5 fluorouracil) regimen and achieved a complete pathological response. PMID- 21822121 TI - BI 2536-mediated PLK1 inhibition suppresses HOS and MG-63 osteosarcoma cell line growth and clonogenicity. AB - Osteosarcoma is the most common primary malignant tumor of bone, which frequently occurs in the second decade of life. Despite the improvements in neoadjuvant chemotherapy, the outcome of patients with chemoresistant or metastatic tumors is still poor. Therefore, there is a need for the development of more efficient therapeutic agents. BI 2536, an innovative selective inhibitor of Polo-like kinase 1, has shown anticancer potential promoting mitotic arrest and apoptosis in a variety of tumor cells, including osteosarcoma. Here, we present more evidence of the antiproliferative effects of BI 2536 on HOS and MG-63 osteosarcoma cell lines. Our results showed that nanomolar concentrations (10, 50, and 100 nmol/l) of the drug significantly decreased cell proliferation and clonogenic capacity, inducing mitotic arrest and aneuploidy. Interestingly, although BI 2536 mediated a moderate increase of apoptosis after 48 h in HOS cells, no increased caspase-3 activity was detected for MG-63 cells. In contrast to previous studies, we show that perturbation of normal mitotic progression by BI 2536 in these osteosarcoma cell lines results in caspase-independent mitotic catastrophe followed by necrosis. Our findings reinforce the likelihood of directing against Polo-like kinase 1 as a therapeutic option in the treatment of osteosarcoma. PMID- 21822122 TI - Mechanism of EGER-related cancer drug resistance. AB - Drug resistance in cancer arises from a complex range of biochemical and molecular events, which ultimately result in tumor cell survival. Identifying key genes and signal pathways involved in the molecular mechanisms of drug resistance is essential for establishment of new drug targets for preventing further resistance development and spreading. Epidermal growth factor receptor (EGFR) was the first growth factor receptor proposed as a target for cancer therapy. Significant progress in studying EGFR gene expression and mutation has been made in understanding the molecular events involved in EGFR-targeted agents. Recently, some individual chromosomal features such as EGFR copy number variation were demonstrated as new aspects related to drug sensitivity. Identifying these functional regulators of drug resistance will benefit therapeutic decision making. In this study, we describe an extensive investigation of the published literature on mutation, amplification, and expression of EGFR and its downstream signaling that directly contribute to EGFR inhibitor resistance, including the gene status of KRAS, BRAF, PIK3CA, PTEN, MEK, and AKT on response to therapy. Analysis of these gene signatures identified reveals general modes of action of multicomponent therapies and the mechanisms of specific drug combinations, highlights the potential value of molecular interaction profiles in the discovery of novel therapies, and provides more information for personalized cancer medicine. PMID- 21822123 TI - Identification of a checkpoint modulator with synthetic lethality to p53 mutants. AB - The G(2) checkpoint is an indispensable pathway for cancers lacking p53 function, for delaying cell cycle progression, and for completing DNA repair. Therefore, disruption of this pathway is expected to offer selective therapy for these highly prevalent cancers. The aim of this study was to identify an inhibitor of the G(2) checkpoint including the ataxia-telangiectasia-mutated and Rad3-related checkpoint kinase 1 pathway that selectively suppresses the growth of p53 deficient cells. To obtain molecules with a novel mechanism of action, we constructed a high-throughput screening system that detected abrogation of the G(2) checkpoint in X-irradiated HT-29 cells. The screening resulted in identification of a guanidine analog, CBP-93872 that dose dependently inhibited the G(2) checkpoint induced by DNA damage. Interestingly, CBP-93872 directly suppressed the growth of p53-mutated cancer cell lines with wild-type CDKN2A by eliciting G(1) arrest, but not CDKN2A-deleted and/or wild-type p53 lines. CBP 93872 decreased phospho-cdc2 Y15 by inhibiting phosphorylation of Chk1, but did not suppress phospho-Chk2 or the kinase activities of either Chk1 or Chk2 in cellular or cell-free assays. These results suggest that a checkpoint modulator through suppression of Chk1 phosphorylation provides synthetic lethality to p53 deficient cells. PMID- 21822124 TI - Hemolysis during cardiac extracorporeal membrane oxygenation: a case-control comparison of roller pumps and centrifugal pumps in a pediatric population. AB - Extracorporeal membrane oxygenation (ECMO) is a lifesaving therapy, which has been used for the support of children with a broad range of diseases. Two pumps of differing mechanisms have been used to generate the extracorporeal flow: roller-head pumps and centrifugal pumps. Seven patients supported during ECMO with Levitronix Centrimag (Centrimag group [CG]) were matched to 14 patients supported with Stockert-Shiley SIII (Stockert-Shiley group [SSG]) at a single institution from July 2007 to July 2009. We hypothesized that hemolysis as measured by plasma-free hemoglobin (PFH) is elevated in the SSG versus the CG during cardiac ECMO. Categorical data were analyzed using Fisher's exact test. Plasma-free hemoglobin differences between groups were analyzed using both Wilcoxon rank sum and beta regression. Overall, SSG patients had two times the odds of having a higher PFH than CG patients adjusting for repeated measures (odds ratio [OR] = 1.96, 95% confidence interval [CI]: [1.15-3.34], p < 0.014). Differences between circuit failure in the first 168 hours did not reach statistical significance (1/7 CG vs. 7/14 SSG; p = 0.174). In this population of cardiac patients requiring ECMO support, more hemolysis occurred in the SSG, a roller-head pump supported group, when compared with the CG, a centrifugal pump supported group. Differences in circuit life did not reach statistical significance. This pilot study contrasts with past studies, which have demonstrated more hemolysis occurring with centrifugal pumps when compared with roller-head pumps. PMID- 21822125 TI - Intrarater and interrater variability of point of care coagulation testing using the ROTEM delta. AB - This study aimed to assess intrarater and interrater variability of coagulation point-of-care testing (POCT) using ROTEM delta operated by trained staff. Arterial blood samples were taken from 43 anesthetized piglets aged up to 6 weeks and weighing 4-6 kg. The following clotting measurements were recorded: clotting time, clot formation time (CFT), maximum clot firmness (MCF) and alpha angle using ROTEM delta assays ExTEM, InTEM, FibTEM and ApTEM. Intrarater variability was assessed when a single operator performed the same assay simultaneously in all four channels of the ROTEM device. Interrater variability was assessed by two different operators simultaneously performing the same assay. Variance components of the data were analyzed using linear mixed modeling. Three hundred and forty three tests from 86 samples were loaded and analyzed. The intraclass correlation coefficient (ICC) was more than 0.7 for clotting measurements except for CFT and alpha in InTEM. For intrarater and interrater assessment, different relative variability for the ROTEM measurements were found with consistently higher variability for clotting time and CFT and lower variability of MCF and alpha angle. Interrater variability was not statistically significant as supported using Akaike's information criterion. Piglet coagulation testing using ROTEM delta showed a high ICC. Variability was significantly lower in MCF and angle alpha compared with clotting time and CFT. No further variability was added by a second user. Based on these data, ROTEM delta appears to be suitable as POCT. PMID- 21822126 TI - Redox-based thrombelastographic method to detect carboxyhemefibrinogen-mediated hypercoagulability. AB - Cigarette smoking is associated with plasmatic hypercoagulability, and carbon monoxide has been demonstrated to enhance coagulation by binding to a fibrinogen bound heme. Our objective was to design and test a redox-based method to detect carboxyhemefibrinogen. Normal, pooled, citrated plasma was exposed to 0-100 MUmol/l carbon monoxide releasing molecule-2 (tricarbonyldichlororuthenium (II) dimer; CORM-2) before or after exposure to the organic reductant phenylhydroxylamine (PHA, 0-30 mmol/l), a compound that rapidly converts Fe(+2) to Fe(+3) in heme. Addition of calcium and tissue factor activation in disposable thrombelastographic cups was performed, followed by data collection at 37 degrees C for 15 min. Elastic modulus (G, dynes/cm(2)) was the primary endpoint. CORM-2 significantly increased G values by 67.8% compared to unexposed plasma; pretreatment with 10 mmol/l PHA significantly decreased G values in CORM-2 exposed plasma by 77.1%, whereas 30 mmol/l PHA was required to significantly decrease G values by 64.0% in plasma following CORM-2 pre-exposure. G values were not significantly different between unexposed plasma and plasma exposed to CORM-2 followed by 30 mmol/l PHA addition. Conversion of fibrinogen-bound to the metheme state alone decreased G by 34.3-38.9% following exposure to 10-30 mmol/l PHA. Conversion of fibrinogen-bound heme Fe(+2) to Fe(+3) with PHA abrogated carbon monoxide-mediated increases in clot strength. Clinical trials are planned to investigate smoking individuals to mechanistically link carboxyhemefibrinogen formation with in-vitro hypercoagulability. PMID- 21822128 TI - Peripheral ulcerative keratitis after cataract surgery in a patient with ocular cicatricial pemphigoid. AB - PURPOSE: To describe a case of peripheral ulcerative keratitis (PUK) that developed in the immediate postoperative period after uncomplicated cataract surgery in a patient with ocular cicatricial pemphigoid. METHODS: Single interventional case report. An elderly white woman with stable ocular cicatricial pemphigoid underwent an uncomplicated clear corneal phacoemulsification procedure in the left eye. In the immediate postoperative period, PUK developed adjacent to the corneal wound in the left eye. RESULTS: The PUK was successfully treated with a bandage contact lens to the left eye, optimizing the ocular surface with punctal plugs and topical and systemic steroid therapy. After a 7-week course of tapering topical and systemic steroids, the PUK completely resolved. There was no further flare-up over a 12-month period. CONCLUSIONS: PUK can develop after clear corneal cataract surgery in patients with stable ocular cicatricial pemphigoid. Perioperative immunosuppression should be considered to minimize the chance of PUK developing in such cases. PMID- 21822127 TI - Platelet-mediated thrombolysis in patients with delta-storage pool deficiency: a thrombelastographic analysis. AB - We present the first thrombelastographic descriptions of three patients with delta-storage pool deficiency, a platelet disorder that involves a deficiency of dense granules and moderate bleeding. The patients demonstrated a 49-54% loss of platelet-mediated clot strength over a 1-2-h period after normal thrombus formation. This pattern persisted, with some attenuation of loss of strength following administration of epsilon aminocaproic acid, desmopressin and platelets for tonsillectomy. Assessment of platelet function in patients with platelet granule disorders can be accomplished with thrombelastographic methods in ambulatory and perioperative settings; however, the effects of therapy for this disorder cannot be monitored with thrombelastography without obtaining a blood sample prior to prophylactic hemostatic intervention. PMID- 21822129 TI - Comorbidities between nose and skin allergy. AB - PURPOSE OF REVIEW: This review focuses on comorbidities between nose and skin allergies. For this purpose, allergic rhinitis and chronic rhinosinusitis (CRS) were selected as examples of nasal disorders and atopic dermatitis and urticaria as examples of allergic skin disorders and the individual entities of both localizations were evaluated and compared in relation to their prevalence and coincidence, underlying pathophysiological mechanisms, genetic data and shared therapy options. RECENT FINDINGS: The inter-relationships between atopic dermatitis and allergic rhinitis are the best studied, but even for the other comorbidities it was possible to demonstrate comparable pathomechanisms in addition to a high prevalence and coincidence, particularly in the case of atopically assisted forms. In this context, the interactions of IgE, mast cells and eosinophils play a special role, but genetic issues, the significance of epithelial barrier defects and colonization with Staphylococcus aureus are also important sharing issues. SUMMARY: Allergic skin disorders such as atopic dermatitis and urticaria are frequently associated with comorbidities of the nose as well as allergic rhinitis and CRS. By contrast, different manifestations of these diseases involve the nose and the skin. These are not separate diseases but are linked by complex and currently unclear/insufficiently defined inter relationships. PMID- 21822130 TI - Ocular allergy. AB - PURPOSE OF REVIEW: Ocular allergy is often encountered by allergists, ophthalmologists, pediatricians, and primary care physicians. An understanding of the immunologic mechanisms, the differential diagnosis, the clinical features, and the treatment of ocular allergy will be useful to all physicians who encounter these patients. RECENT FINDINGS: Basic and clinical research has provided a better understanding of the cells, mediators, and immunologic events which occur in ocular allergy. New pharmacological agents, including more potent mast cell stabilizers, and low-dose corticosteroids, have improved the efficacy and safety of ocular allergy treatment. SUMMARY: Physicians who currently treat ocular allergy have a greater familiarity with the signs and symptoms of allergic disease, a better understanding of the mechanisms and clinical features of allergic conjunctivitis, and improved therapeutic tools to deliver satisfactory outcomes in the management of ocular allergy. PMID- 21822131 TI - Ocular surface damage by ophthalmic compounds. AB - PURPOSE OF REVIEW: To describe the changes of the ocular surface following chronic use of eye drop therapies. The possible pathogenetic mechanisms responsible for specific signs and symptoms are described and discussed. RECENT FINDINGS: Topical treatments for ocular diseases may trigger an inflammatory response in predisposed patients, with local activation of immune cells and ocular surface damage. The resulting clinical picture may vary substantially, from mild to severe, sharing a red eye as a hallmark presentation. Recent in vitro, in-vivo, and clinical data suggest that these detrimental effects are not solely related to eye drop preservatives and may be caused by the medication itself, especially for patients with preexisting ocular diseases. However, no specific tests are currently available to make a clear cut diagnosis between what is caused by the disease and what is the effect of its therapy. Patients' history and clinical features remain essential to hypothesize the underlying pathogenetic mechanism. SUMMARY: Topical therapies may induce ocular surface allergic reactions, dry eye-like reactions, and epithelial damage. Patients in need of chronic therapies are at higher risk of facing these detrimental effects of eye drop therapies and should be treated with unpreserved compounds. PMID- 21822132 TI - Relevance and implication of genetic determinants to asthma pathophysiology. AB - PURPOSE OF REVIEW: The number of single nucleotide polymorphisms (SNPs) found to be associated with asthma and related phenotypes outnumbers those with functional impacts. In this review we briefly described some of the approaches used to investigate functionality of SNPs, and summarized recent findings related to the characterization of functional SNPs in asthma. RECENT FINDINGS: For disease associated SNPs residing in the promoter or 3' untranslated regions, differential protein binding affinity between the major and minor alleles is often the first logical area of investigation. In this review, we described SNPs associated with asthma or related phenotypes in five genes which in the past 12 months have new data implicating potential mechanisms in asthma development. SUMMARY: Variability in treatment responses poses a great challenge in asthma management. It is established that the genetic makeup of individuals plays a role in asthma development, yet the mechanisms remain unclear. Investigations on the functional impacts of disease-associated SNPs will help us gain insights into potential disease mechanisms, and ultimately lead to effective therapies for those who suffer from asthma. PMID- 21822133 TI - Allergic complications with laser-assisted in-situ keratomileusis. AB - PURPOSE OF REVIEW: This article reviews the complications of laser-assisted in situ keratomileusis (LASIK) associated with ocular allergy. This review will provide guidance and heighten the need for a more comprehensive allergic evaluation before recommending LASIK procedure to patients. The material provided allows enhanced awareness of the potential postsurgical effects on allergic responses of the ocular surface and management thereof. RECENT FINDINGS: Ocular allergy is often underdiagnosed and has been previously reported only in a handful of peer-reviewed journals as the cause for ocular irritation and visual morbidity in post-LASIK dry eye disease. Diffuse lamellar keratitis is one complication of LASIK that has been linked to atopic individuals. LASIK causes significant inflammation in normal eyes, which is only exacerbated in atopic patients. Atopy may be a contributing factor in patients with patients with post LASIK dry eye symptoms. Further investigation is required to better understand the complications of LASIK in allergic patients. SUMMARY: LASIK surgery has been associated with increased anterior surface inflammatory processes that include dry eye syndromes and ocular allergy. In addition, poorer outcomes of LASIK procedures have been reported in patients with moderate to severe ocular allergies and chronic forms of allergic conjunctivitis, which is an absolute contraindication to the LASIK procedure. We propose preoperative and postoperative management algorithms for allergic LASIK candidates. PMID- 21822134 TI - Ultrasonography of the lumbar spine for neuraxial and lumbar plexus blocks. AB - PURPOSE OF REVIEW: Ultrasonography of the spine has evolved into a well described technique that can be applied to facilitate neuraxial and lumbar plexus blockade. RECENT FINDINGS: There is increasing evidence for the clinical benefits of ultrasound imaging prior to administration of neuraxial blockade. Recent randomized controlled trials have shown that efficacy of epidural analgesia is improved, and the technical difficulty of spinal and epidural anaesthesia is reduced. Ultrasound imaging may also permit more accurate prediction of the depth to epidural and intrathecal spaces and more accurate identification of intervertebral levels. The use of ultrasound in lumbar plexus blockade has been described in the context of both preprocedural imaging and real-time needle guidance; however, its clinical benefit in this setting has not yet been clearly established. SUMMARY: Preprocedural ultrasound imaging of the spine may reduce the technical difficulty of neuraxial blockade and also improve clinical efficacy. Similar benefits are expected in the setting of lumbar plexus blockade although there is currently no evidence to confirm this. Real-time ultrasound guided neuraxial and lumbar plexus blockade are challenging techniques that need further validation. PMID- 21822135 TI - Infectious complications of regional anesthesia. AB - PURPOSE OF REVIEW: Regional anesthesia is commonly used to provide intraoperative anesthesia and postoperative analgesia. Potential complications of both neuraxial and peripheral regional techniques include infectious sequelae. This review examines important components of practice that are known to minimize the risk of infection associated with regional anesthesia. RECENT FINDINGS: Healthcare associated infections increase morbidity and mortality, patient pain and suffering, direct medical costs, and hospital length-of-stay. Recently published national guidelines from subspecialty societies and government agencies emphasize the importance of strict aseptic technique in the prevention of infectious complications associated with regional anesthesia. Proper hand hygiene, the use of surgical masks, appropriate antiseptic selection and application, and proper preparation of local anesthetic infusate solutions are all considered essential components of asepsis. Anesthesia providers need to adhere to strict aseptic guidelines to minimize the risk of potentially devastating infectious complications. SUMMARY: Infectious complications associated with regional anesthesia are exceedingly rare events. Adherence to strict aseptic guidelines as published by the American Society of Regional Anesthesia and Pain Medicine, American Society of Anesthesiologists, and the Royal College of Anaesthetists may reduce the risk of infectious complications. PMID- 21822136 TI - Functional and structural imaging of pain-induced neuroplasticity. AB - PURPOSE OF REVIEW: The understanding of the mechanisms underlying chronic pain is of major scientific and clinical interest. This review focuses on neuroimaging studies of pain-induced neuroplastic changes in the human brain and discusses five major categories of pain-induced neuroplastic changes. RECENT FINDINGS: First, peripheral or central sensitization may result in increased nociceptive input to the brain and also changes the processing of nociceptive information within the brain. Second, chronic nociceptive input from the periphery or from lesions within the central nervous system may result in cortical reorganization and maladaptive neuroplasticity within somatosensory and motor systems. Thirdly, there is evidence for pain-induced changes in large-scale neuronal network connectivity. Fourth, in patients with chronic pain, structural brain changes may occur. Finally, there is discussion that in chronic pain patients the endogenous pain-modulatory system may function aberrantly. SUMMARY: Recent work has substantially broadened our insights into neuroplastic changes that are involved in pain chronification. Future research will focus on the question of whether neuroimaging techniques can be used in the individual chronic pain patient as a biomarker that would allow for an objective diagnosis of different pain conditions and for the prediction of individual responses to specific therapies. PMID- 21822137 TI - Management of carotid disease in patients undergoing coronary artery bypass surgery: is it time to change our approach? AB - PURPOSE OF REVIEW: The management of concurrent severe carotid and coronary disease is a subject of ongoing debate in the absence of randomized clinical trials. Amidst the growing controversy, the clinician has to carefully tailor the best strategy for a given patient based on neurologic and cardiac symptoms. This review aims to compile current evidence in this area to help plan strategies for the optimal management of coexisting severe carotid and coronary disease. RECENT FINDINGS: Carotid revascularization with carotid endarterectomy (CEA) or stenting (CAS) is frequently performed in conjunction with coronary artery bypass surgery (CABG) in the United States for asymptomatic carotid disease. The risk of perioperative stroke with unilateral asymptomatic 70-99% carotid stenosis is likely small based on several observational data. Moreover, the risk associated with both staged and combined CEA-CABG procedures in the asymptomatic population may outweigh any benefit. Carotid artery stenting is an alternative option in patients with severe coronary disease who are considered 'high risk' for CEA. Neurologically symptomatic patients require carotid revascularization prior to or in conjunction with CABG surgery. Ultimately, the choice of carotid revascularization or conservative management will depend on clinical characteristics, anatomy, and local expertise. SUMMARY: Severe carotid disease in the CABG population is often unilateral and asymptomatic. Based on the available data, conservative carotid therapy in the low-risk asymptomatic individuals is likely the best treatment option. Carotid revascularization may be justified in symptomatic or high-risk patients such as those with contralateral carotid occlusion or bilateral severe stenosis. PMID- 21822138 TI - Acute type B aortic dissection: current management strategies. AB - PURPOSE OF REVIEW: Endovascular techniques are increasingly employed to treat patients with acute and chronic diseases of the thoracic aorta. This review focuses on current indication and results of thoracic endovascular stent-graft repair in patients with acute type B aortic dissection. RECENT FINDINGS: In patients with type B acute dissections, endovascular treatment should be considered in the presence of complications such as impending rupture, malperfusion, aneurysmal expansion, and uncontrolled pain or blood pressure. No data exist showing improved outcomes after prophylactic endovascular repair of uncomplicated acute dissections. Thus, primary treatment of asymptomatic patients remains medical. SUMMARY: Endovascular stent-graft repair of complicated type B acute dissection is associated with favorable short-term and mid-term results. Longer-term follow-up is warranted to assess its durability and potential progression of the disease at the downstream aorta. PMID- 21822139 TI - Total cardiovascular disease risk assessment: a review. AB - PURPOSE OF REVIEW: The high risk strategy for the prevention of cardiovascular disease (CVD) requires an assessment of an individual's total CVD risk so that the most intensive risk factor management can be directed towards those at highest risk. Here we review developments in the assessment and estimation of total CVD risk. RECENT FINDINGS: Recent advances have focused on newer approaches to expressing risk, including lifetime risk and risk age; these are particularly useful in communicating risk to younger individuals. Additionally, increased emphasis has been placed on the role of body weight and abdominal obesity in CVD risk. Several recent large studies have clarified a number of issues relevant to the management of CVD risk, a matter of growing global concern. SUMMARY: Simple risk estimation systems utilizing only easily measured variables have a role in improving the accessibility and cost effectiveness of risk estimation. The addition of newer variables to risk estimation systems may be particularly useful for those at intermediate risk, in order to more correctly reclassify such individuals into appropriate risk categories. PMID- 21822140 TI - Bronchobiliary fistula: a rare cause of acute dyspnea in emergency department. PMID- 21822141 TI - Hemoperitoneum caused by a ruptured corpus luteum in adults with immune thrombocytopenic purpura. PMID- 21822142 TI - The effect of a chest imaging lecture on emergency department doctors' ability to interpret chest CT images: a randomized study. AB - OBJECTIVE: To assess the chest computed tomography (CT) imaging interpreting skills of emergency department (ED) doctors and to study the effect of a CT chest imaging interpretation lecture on these skills. PARTICIPANTS AND METHODS: Sixty doctors in two EDs were randomized, using computerized randomization, to either attend a chest CT interpretation lecture or not to attend this lecture. Within 2 weeks of the lecture, the participants completed a questionnaire on demographic variables, anatomical knowledge, and diagnostic interpretation of 10 chest CT studies. Outcome measures included anatomical knowledge score, diagnosis score, and the combined overall score, all expressed as a percentage of correctly answered questions (0-100). RESULTS: Data on 58 doctors were analyzed, of which 27 were randomized to attend the lecture. The CT interpretation lecture did not have an effect on anatomy knowledge scores (72.9 vs. 70.2%), diagnosis scores (71.2 vs. 69.2%), or overall scores (71.4 vs. 69.5%). Twenty-nine percent of doctors stated that they had a systematic approach to chest CT interpretation. Overall self-perceived competency for interpreting CT imaging (brain, chest, abdomen) was low (between 3.2 and 5.2 on a 10-point Visual Analogue Scale). CONCLUSION: A single chest CT interpretation lecture did not improve chest CT interpretation by ED doctors. Less than one-third of doctors had a systematic approach to chest CT interpretation. A standardized systematic approach may improve interpretation skills. PMID- 21822143 TI - Investigating the effect of antioxidant treatment on the protective effect of preconditioning in anesthetized rabbits. AB - Reactive oxygen and nitrogen species are critical in preconditioning (PC). We sought to determine the effect of N-2-mercaptopropionyl glycine (MPG) on infarct size and on the oxidative status. Rabbits were exposed to 30-minute regional ischemia of the heart, which was followed by 3-hour reperfusion: (1) a control group without further intervention, (2) a PC1 group that was subjected to one cycle of PC, (3) a PC4 group that was subjected to 4 cycles of PC, (4) an MPG group that was treated with MPG for 60 minutes, starting 10 minutes before reperfusion, (5) MPG-PC1, and (6) the MPG-PC4 groups that were treated with the same dose of MPG and with 1 or 4 cycles of PC, respectively. Blood samples were drawn and collected for metabonomic analysis. In another series of experiments, 6 groups respective to the described ones were subjected to 30-minute regional ischemia of the heart and 20 minutes of reperfusion, after which pieces of heart tissue were quickly excised for malondialdehyde, nitrotyrosine, and glutathione content assessment. All PC and MPG groups developed smaller infarct size compared with control (16.5% +/- 3.9%, 13.7% +/- 3.1%, 18.6% +/- 5.0%, 9.7% +/- 2.0%, 15.0% +/- 2.8% vs. 48.05% +/- 7.2%; P < 0.05). MPG did not prevent lipid peroxidation and nitrotyrosine formation but enhanced the glutathione content. PC and MPG induced similar nuclear magnetic resonance changes. Long MPG infusion reduces the infarct size without abolishing the effect of PC, providing novel insights into the activity of MPG in PC. PMID- 21822144 TI - Effect of multiple doses of omeprazole on the pharmacokinetics, pharmacodynamics, and safety of a single dose of rivaroxaban. AB - Many patients with acute coronary syndrome receive chronic dual antiplatelet therapy (acetylsalicylic acid and clopidogrel) for secondary event prophylaxis, and new oral anticoagulants are being investigated as adjunctive therapy in this indication. Gastrointestinal side effects such as bleeding are commonly associated with antiplatelet use; accordingly, many patients receive proton pump inhibitors (PPIs) to mitigate this. PPIs can reduce the antiplatelet activity of clopidogrel through cytochrome P450 2C19 inhibition, and pantoprazole reduces the bioavailability of dabigatran, a direct thrombin inhibitor that acts via cytochrome P450 2C19-independent mechanisms. These observations support the investigation of potential pharmacokinetic and pharmacodynamic interactions between PPIs and anticoagulants. We evaluated the influence of administering once daily omeprazole 40 mg for 5 days on the pharmacokinetics and pharmacodynamics of a single 20-mg dose of the oral direct factor Xa inhibitor, rivaroxaban, in a randomized, open-label, 2-way, crossover, drug-drug interaction study in healthy subjects. No clinically meaningful interactions were observed; geometric mean ratios were 101%, 101%, and 93.5% for rivaroxaban area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration (AUClast), or until infinity (AUCinfinity), and maximum plasma concentration (Cmax), respectively. Prothrombin time increased similarly in both treatment groups, with maximal values observed approximately 4 hours post rivaroxaban administration. A single 20-mg rivaroxaban dose appears well tolerated when administered alone or after 5 days of once-daily omeprazole 40 mg administration. PMID- 21822145 TI - Modulation of vasoactivity and platelet aggregation by selective 5-HT receptor antagonism in humans. AB - BACKGROUND: Distinct serotonin [5-hydroxytryptamine (5-HT)] receptors are involved in platelet aggregation and vasoconstriction. Compounds that simultaneously and selectively inhibit the pertaining 5-HT receptors may therefore represent a therapeutic strategy for arterial thrombosis, observed frequently after atherosclerotic plaque rupture. The vasoactive and antiplatelet effects of the combined 5-HT1B and 5-HT2A receptor blocker SL65.0472-00 were investigated in humans to elucidate the functional involvement of these receptors. METHODS: Twenty-four volunteers, divided into 2 groups of 12, received an oral dose of 20 mg of SL65.0472-00 or placebo in a randomized, double-blind, crossover study. Pre dose and at 2, 4, and 6 hours after dosing, intra-arterial infusions of 5-HT1B agonist sumatriptan (n = 12) or 5-HT (n = 12) were administered. Forearm blood flow (FBF) was measured using plethysmography, and platelet aggregation was measured using whole blood aggregometry induced by a combination of a threshold collagen concentration and an excess of 5-HT. Treatments were compared using analysis of variance. RESULTS: After placebo treatment, infusion of 1 ng.kg.min 5-HT induced vasodilatation (FBF +80% change from baseline), whereas infusion of 30 and 80 ng.kg.min 5-HT resulted in vasoconstriction (FBF -25% and -50%). After SL65.0472-00 treatment, all 5-HT doses induced vasodilatation (FBF +25%-60%). Sumatriptan dose dependently decreased FBF (maximally -35%), but this effect was not altered by SL65.0472-00 treatment. 5-HT-induced platelet aggregation was effectively inhibited by 90% after SL65.0472-00 treatment for at least 6 hours. CONCLUSIONS: SL65.0472-00 has potent antagonistic effect on 5-HT-induced vasoconstriction and platelet aggregation but not on sumatriptan-induced vasoconstriction. This suggests that in humans, SL65.0472-00 is a 5-HT2A blocker without clear 5-HT1B antagonistic activity. PMID- 21822146 TI - Direct vasoactive properties of thienopyridine-derived nitrosothiols. AB - Thienopyridines (ticlopidine, clopidogrel, and prasugrel) require in vivo metabolism to exhibit a critical thiol group in the active form that binds to the P2Y12 platelet receptor to inhibit platelet activation. We hypothesized that formation of thienopyridine-derived nitrosothiols (ticlopidine-SNO, clopidogrel SNO, and prasugrel-SNO) occurs directly from the respective parent drug. Pharmaceutical-grade thienopyridine (ticlopidine, clopidogrel chloride, clopidogrel sulfate, clopidogrel besylate, or prasugrel) was added to nitrite in aqueous solution to form the respective thienopyridine-SNO (Th-SNO). An isolated aortic ring preparation was used to test vasoactivity of the Th-SNO derivatives. Increasing nitrite availability resulted in increased Th-SNO formation for all drugs (other than ticlopidine). Th-SNO induced significant endothelium independent relaxation of preconstricted aortic rings. Clopidogrel-chloride-SNO displayed rapid-release kinetics in a chemical environment, which was reflected by immediate and transient vasorelaxation when compared with the SNO derivatives of the other thienopyridines. Accounting for differences in yield, clopidogrel chloride-SNO exhibited the greatest propensity to immediately relax vascular tissue. Th-SNO derivatives exhibit nitrovasodilator properties by supplying NO that can directly activate vascular soluble guanylate cyclase to induce vasorelaxation. Differences in SNO yield and vasoactivity exist between thienopyridine preparations that might be important to our understanding of the direct pharmacological effectiveness of thienopyridines on vascular and platelet function. PMID- 21822148 TI - Brain AT1 receptor activates the sympathetic nervous system through toll-like receptor 4 in mice with heart failure. AB - The activation of angiotensin II type 1 receptor (AT1R) in the brain plays a pivotal role in enhanced sympathetic drive in heart failure (HF). Activation of the AT1R in the brain produces oxidative stress and inflammation. Toll-like receptor 4 (TLR4) signaling in the brain induces the inflammatory cascade. We hypothesized that sympathoexcitation is mediated by the AT1R-activated TLR4 in the brainstem in HF. As a model of HF, the left coronary artery was ligated to induce a large myocardial infarction and subsequent chronic heart failure (CHF) in Institute of Cancer Research mice. On day 10 after the surgery, we started intracerebroventricular infusion of losartan (CHF-Los) or vehicle (CHF-Veh) via osmotic minipumps for 14 days. Expression level of the TLR4 in the brainstem was significantly higher in HF mice than in sham mice and significantly lower in CHF Los mice than in CHF-Veh mice. Urinary norepinephrine excretion was significantly higher in HF mice than in sham mice and was significantly lower in CHF-Los than in CHF-Veh. Chronic intracerebroventricular infusion of angiotensin II increased the expression level of the second messenger of the TLR4. These results suggest that activation of the TLR4 via AT1R in the brainstem contributes to the sympathoexcitation probably due to the inflammation in the brain of the myocardial infarction-induced HF. PMID- 21822149 TI - Psychosocial functioning and health-related quality of life in paediatric inflammatory bowel disease. AB - OBJECTIVES: The present systematic review examined the literature focusing on psychosocial functioning and health-related quality of life (HRQOL) in young people with inflammatory bowel disease (IBD). It aimed to critique the methodological quality of the identified studies, discuss the implications of their findings, and make recommendations for future research. PATIENTS AND METHODS: Relevant articles (January 1990-December 2009) were subject to strict inclusion and exclusion criteria. Identified papers were rated for methodological quality using SIGN 50 and Critical Appraisal Skills Programme guidelines before data extraction. RESULTS: Of 2141 articles initially identified, 278 were screened in detail, leaving 12 articles for inclusion in the review: 3 having "acceptable" and 9 having "good" quality rating scores. These 12 studies yielded a combined total of 5330 participants including 790 with IBD and 4540 controls (ages 4-18 years). Five main outcomes--self--esteem, HRQOL, anxiety and depression, social competence, and behavioural functioning-were examined. Three of the 4 controlled studies addressing self-reported HRQOL found it to be significantly lower in the participants with IBD. The evidence for lowered self esteem, self-reported symptoms of depression and anxiety, impaired social competence, and behavioural problems were conflicting. Methodological heterogeneity was noted in terms of areas of functioning addressed, measures used, sample size, and use of control groups. CONCLUSIONS: HRQOL is lower in patients with IBD, but conflicting results and methodological flaws limit conclusions on other aspects of psychosocial functioning. Future research should present data on effect sizes, avoid confounding findings by not combining across age groups or disease severity indices, and consider investigating body image disturbance. PMID- 21822150 TI - Nasobiliary drainage in an episode of intrahepatic cholestasis in a child with mild ABCB11 disease. PMID- 21822151 TI - Comparative study of kyphoplasty for chronic painful osteoporotic vertebral compression fractures via unipedicular versus bipedicular approach. AB - STUDY DESIGN: A comparative study of chronic painful osteoporotic vertebral compression fractures (OVCFs), which underwent kyphoplasty via unipedicular versus bipedicular approach. OBJECTIVE: To assess the clinical and radiographical outcomes in treating chronic painful OVCFs compared by unipedicular and bipedicular kyphoplasty (KP). SUMMARY OF BACKGROUND DATA: OVCFs commonly occur in aged people and as many as one-third of them progress to chronic pain. Our previous research has proved that unipedicular and bipedicular KP can achieve comparable radiographical and clinical results in early stage. To give a medium term and long-term assessment, we completed the comparison of outcomes 6 months and 2 years after surgery. METHODS: Fifty patients with a total of 56 chronic painful OVCFs completed the follow-ups of 2 weeks, 6 months, and 2 years after surgery. Group I (n=27) were treated with unipedicular KP and group II (n=23) with bipedicular KP. Preoperative and postoperative visual analog scale and Oswestry disability index scores were compared within each group and between groups. The radiographic outcomes were evaluated by the restoration rate and vertebral height lost rate in the most compressed point of the vertebral bodies. RESULTS: Significant improvement on the visual analog scale and Oswestry disability index scores were noted in each group (P<0.001), and there was no significant difference between the 2 groups. Although the restoration rate in group II was higher than in group I (P=0.005) in early stage, the height lost ratio showed no significant differences 6 months or 2 years later (P=0.746, 0.627). CONCLUSIONS: Chronic painful OVCFs should be candidates for KP, and there was no difference in pain relief when treated with either unipedicular or bipedicular KP.Although the bipedicular KP is more efficacious in vertebral height restoration in early stage, the unipedicular KP can maintain the same degree of the restored vertebral height in the long run. PMID- 21822152 TI - Postdischarge monitoring using interactive voice response system reduces 30-day readmission rates in a case-managed Medicare population. AB - BACKGROUND: Automated home monitoring systems have been used to coordinate care to improve patient outcomes and reduce rehospitalizations, but with little formal study of efficacy. The Geisinger Monitoring Program (GMP) interactive voice response protocol is a post-hospital discharge telemonitoring system used as an adjunct to existing case management in a primary care Medicare population to reduce emergency department visits and hospital readmissions. OBJECTIVES: To determine if use of GMP reduced 30-day hospital readmission rates among case managed patients. RESEARCH DESIGN: A pre-post parallel quasi-experimental study. METHODS: A total of 875 Medicare patients who were enrolled in the combined case management and GMP program were compared with 2420 matched control patients who were only case managed. Claims data were used to document an acute care admission followed by a readmission within 30 days in the preintervention and postintervention periods (ie, before and during 2009). Regression modeling was used to estimate the within-patient effect of the intervention on readmission rates. RESULTS: The use of GMP with case management was associated with a 44% reduction in 30-day readmissions in the study cohort (95% confidence interval, 23%-60%, P=0.0004), when using the control group to control for secular trends. Similar estimates were obtained when using different propensity score adjustment methods or different approaches to handling dropout observations. CONCLUSIONS: Investing in automated monitoring systems may reduce hospital readmission rates among primary care case-managed patients. Evidence from this quasi-experimental study demonstrates that the combination of telemonitoring and case management, as compared with case management alone, may significantly reduce readmissions in a Medicare Advantage population. PMID- 21822153 TI - O-6-methylguanine-DNA methyltransferase (MGMT) immunohistochemical expression in pituitary corticotroph adenomas. AB - BACKGROUND: O-6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme that counteracts chemotherapeutic cytotoxicity of alkylating agents such as temozolomide. Low levels of MGMT expression have been shown to correlate with longer survival in glioma patients treated with temozolomide. The same is true in pituitary adenomas. OBJECTIVE: We investigated the immunohistochemical expression of MGMT in a variety of corticotroph adenoma subtypes to determine the potential utility of temozolomide as a therapeutic agent. METHODS: The tumors consisted of 40 cases of adrenocorticotropin-secreting pituitary tumors in Cushing disease, 12 Crooke cell adenomas, and 7 subtype I silent corticotroph adenomas. Staining for MGMT was assessed by light microscopy; nuclear reactivity was estimated semiquantitatively as present in < 10%, 10% to 25%, 25% to 50%, 50% to 75%, and > 75% of cells. RESULTS: Immunoexpression showed no correlation with patient age, sex, tumor size, invasiveness, or recurrence in patients with Cushing disease. Among adrenocorticotropin-secreting adenomas associated with Cushing disease, most invasive (60%) and recurrent (86%) tumors showed low MGMT immunopositivity, defined as < 25%. Most (75%) Crooke cell adenomas exhibited an MGMT immunoreactivity of <= 50%. All subtype I silent corticotroph adenomas showed < 10% MGMT staining. CONCLUSION: Our descriptive findings of low MGMT expression in adrenocorticotropin-producing pituitary adenomas, particularly aggressive tumors, suggest that they may be suitable candidates for temozolomide therapy. PMID- 21822154 TI - Therapeutic effects of intra-arterial delivery of bone marrow stromal cells in traumatic brain injury of rats--in vivo cell tracking study by near-infrared fluorescence imaging. AB - BACKGROUND: A noninvasive and effective route of cell delivery should be established to yield maximal therapeutic effects for central nervous system (CNS) disorders. OBJECTIVE: To elucidate whether intra-arterial delivery of bone marrow stromal cells (BMSCs) significantly promotes functional recovery in traumatic brain injury (TBI) in rats. METHODS: Rat BMSCs were transplanted through the ipsilateral internal carotid artery 7 days after the onset of cortical freezing injury. The BMSCs were labeled with fluorescent dye, and in vivo optical imaging was employed to monitor the behaviors of cells for 4 weeks after transplantation. Motor function was assessed for 4 weeks, and the transplanted BMSCs were examined using immunohistochemistry. RESULTS: In vivo optical imaging and histologic analysis clearly demonstrated that the intra-arterially injected BMSCs were engrafted during the first pass without systemic circulation, and the transplanted BMSCs started to migrate from the cerebral capillary bed to the injured CNS tissue within 3 hours. Intra-arterial BMSC transplantation significantly promoted functional recovery after cortical freezing injury. A subgroup of BMSCs expressed the phenotypes of neurons, astrocytes, and endothelial cells around the injured neocortex 4 weeks after transplantation. CONCLUSION: Intra-arterial transplantation may be a valuable option for prompt, noninvasive delivery of BMSCs to the injured CNS tissue, enhancing functional recovery after TBI. In vivo optical imaging may provide important information on the intracerebral behaviors of donor cells by noninvasive, serial visualization. PMID- 21822155 TI - Ventral "spinal epidural meningeal cysts"--not epidural and not cysts? Case series and review of the literature. AB - BACKGROUND: Ventral spinal epidural meningeal cysts are rare entities for which the pathogenesis is poorly understood. OBJECTIVE: We present the clinical, radiographic, surgical, and pathologic findings of 4 patients with extensive ventral spinal epidural meningeal cysts and review the relevant literature. In addition, we discuss a suspected mechanism for pathogenesis. METHODS: Four patients with anterior spinal epidural meningeal cysts are retrospectively reviewed. RESULTS: Ventral spinal epidural meningeal cysts are often large, extending on average from C2 to L1 in our series. Patients typically present with a prolonged course of symptoms and signs, including segmental muscle weakness and atrophy, subtle myelopathy, mild to moderate spinal pain, and headache. Histopathologic analysis of the cyst wall demonstrates collagenous tissue consistent with dura but without arachnoid features. Dynamic computed tomographic myelography is the study of choice for localization of the primary dural defect. Patient symptoms and neurological deficits routinely improve after appropriate surgical intervention. CONCLUSION: Diverse signs and symptoms herald the presentation of ventral spinal meningoceles. Intraoperative, radiographic, and pathological findings are all suggestive of an intradural dissection as the etiology. Hence, they may be more appropriately named "ventral spinal intradural dissecting meningoceles." Definitive treatment involves identification and obliteration of the dural defect. PMID- 21822156 TI - The natural history of cranial dural arteriovenous fistulae with cortical venous reflux--the significance of venous ectasia. AB - BACKGROUND: The quoted risk of hemorrhage from dural arteriovenous fistulae with cortical venous reflux varies widely, and the influence of angiographic grade on clinical course has not previously been reported. OBJECTIVE: To assess the risk of hemorrhage and the influence of angiographic grade on this risk, compared with known predictors of hemorrhage such as presentation. METHODS: Seventy-five fistulae with cortical venous reflux identified in our arteriovenous malformations clinic between 1992 and 2007 were followed up clinically, and their angiograms were reviewed. RESULTS: There were 8 hemorrhages in 90 years of follow up. The annual incidence of hemorrhage before any treatment was 13%, and 4.7% after partial treatment, giving an overall incidence of 8.9% before definitive treatment. Borden and Cognard grades were poor discriminators of risk for lesions with the exception of Cognard type IV lesions. These lesions, characterized by venous ectasia, had a 7-fold increase in the incidence of hemorrhage (3.5% no ectasia vs 27% with ectasia). Patients presenting with hemorrhage (20%) or nonhemorrhagic neurological deficit (22%) had a higher incidence of hemorrhage than those with a benign presentation (4.3%), but this may be directly linked to the presence of venous ectasia. CONCLUSION: In this series untreated dural arteriovenous fistulae with cortical venous reflux had a 13% annual incidence of hemorrhage after diagnosis. There was a significant difference between those with and without venous ectasia. This should be confirmed by further studies, but probably defines a high-risk subgroup of patients that requires rapid intervention. PMID- 21822157 TI - The use of intraoperative navigation for percutaneous procedures at the skull base including a difficult-to-access foramen ovale. AB - BACKGROUND: We describe the use of an intraoperative CT scan obtained using the Medtronic O-arm (Littleton, Massachusetts) for image-guided cannulation of the foramen ovale not previously accessible with the use of fluoroscopy alone. Unlike previously described procedures, this technique does not require placement of an invasive head clamp and may be used with an awake patient. OBJECTIVE: To describe the use of intraoperative neuronavigation for accessing skull base foramina and, specifically, cannulating of the foramen ovale during percutaneous rhizotomy procedures using an intraoperative image guidance CT scanner (Medtronic O-arm, Littleton, Massachusetts). METHODS: A noninvasive Landmark Fess Strap attached to a spine reference frame was applied to the heads of 4 patients who harbored a difficult-to-access foramen ovale. An intraoperative HD3D skull base scan using a Medtronic O-arm was obtained, and Synergy Spine software was used to create 3D reconstructions of the skull base. Using image guidance, we navigated the needle to percutaneously access the foramen ovale by the use of a single tract for successful completion of balloon compression of the trigeminal nerve. RESULTS: All 4 patients (3 females and 1 male; ages 65-75) underwent the procedure with no complications. CONCLUSION: Based on our experience, neuronavigation with the use of intraoperative O-arm CT imaging is useful during these cases. PMID- 21822158 TI - Onyx embolization of extradural spinal arteriovenous malformations with intradural venous drainage. AB - BACKGROUND: Extradural arteriovenous malformations (AVMs) are uncommon vascular malformations of the spine. They are characterized by an arteriovenous communication (localized in the paraspinal soft tissues and the epidural venous plexus) that may have retrograde intradural venous drainage. Surgical treatment of extradural AVMs can be challenging because of the common location ventral to the dural sac and the presence of arterialized venous lakes. OBJECTIVE: To assess the effectiveness of embolization with a liquid embolic material (Onyx; ev3 Inc, Irvine, California) in 7 consecutive patients with extradural spinal AVMs and intradural venous drainage. METHODS: We retrospectively collected information regarding patient characteristics, clinical presentation, symptom duration, diagnostic imaging, treatment, complications, and clinical and radiological follow-up. RESULTS: Patients were 5 men and 2 women (mean age, 66 years; range, 45-76 years). Symptom duration varied from 2 months to 6 years. Six patients underwent embolization of the AVM as the primary treatment; 1 patient was treated after attempted surgery. Complete obliteration was demonstrated in each patient on completion angiography and was confirmed during follow-up in 6. Three patients had resolution of their preembolization symptoms. Three patients had improvement but not complete resolution of their motor deficits. In 1 patient, the AVM was an incidental finding during an investigation for chronic low-back pain; symptoms were not thought to be related to the AVM, and symptoms were not ameliorated by successful embolization. CONCLUSION: Our early experience with these uncommon lesions suggests that Onyx embolization is a valuable and effective strategy for extradural spinal AVMs and intradural venous drainage. PMID- 21822159 TI - Comparing the Nidek MP-1 and Humphrey field analyzer in normal subjects. AB - PURPOSE: To compare visual fields on the Nidek MP-1 to those obtained on the Humphrey field analyzer (HFA) in healthy volunteers and assess the effects of differences in stimulus parameters and testing strategies that may influence the interpretation of results in patients. A secondary aim was to establish MP-1 normative data to calculate the total deviation analyses and global indices analogous to those used by the HFA. METHODS: Fifty healthy volunteers (age 43.5 +/- 13.9 years, range, 18 to 68 years) underwent repeat MP-1 and HFA visual field testing, using the 10-2 pattern. MP-1 data were converted to HFA equivalent dB units. Between instrument comparisons of HFA and MP-1 sensitivities, regression of sensitivity with age and examination duration were assessed. Test-retest variability was examined between visits. RESULTS: MP-1 (mean = 32.82 dB, SD = 1.92 dB) and HFA sensitivities (mean = 32.84 dB, SD = 1.83 dB) were not significantly different (p = 0.759). SD values for the HFA (range, 1.11 to 3.30 dB) were similar to the MP-1 (range, 0.14 to 2.75 dB). However, asymmetry comparisons between instruments showed significantly decreased superior rather than inferior retinal values for the MP-1. There was a small but significant difference (p = 0.004) in mean test duration between the MP-1 (mean = 6:11 min, SD = 1:49 min) and the HFA (mean = 5:14 min, SD = 0:42 min). There was also a difference in the decline of mean sensitivity with age, a decline of 0.1 and 0.4 dB per decade was noted in MP-1 and HFA sensitivity, respectively. Test-retest variability was similar between instruments. A small but non-significant increase in mean sensitivity at the second visit for both the MP-1 (p = 0.060) and HFA (p = 0.570) was found. CONCLUSIONS: Both instruments showed similar variability and test-retest variability when results were compared using equivalent units. However, there are important differences in sensitivity values, stimulus parameters, and testing strategies that have to be taken into account when comparisons are made. PMID- 21822160 TI - Abandonment of low-vision devices in an outpatient population. AB - PURPOSE: To investigate abandonment rate of prescribed low-vision devices for near tasks and factors associated with abandonment in a U.S. outpatient population. METHODS: A telephone survey was administered to 88 patients with low vision from four clinical sites about 1 year after examination and prescription of devices. Patients were surveyed on timing and frequency of use and reasons for abandonment of devices. The main outcome measure (abandonment) was defined as patient report of no use of prescribed device in the previous 3 months. Multivariate logistic regression was used to investigate significant vision and demographic factors related to abandonment. RESULTS: Of 119 prescribed devices, 19% (95% CI, 12 to 26) had not been used within the previous 3 months. Mean (+/ SD) better eye visual acuity at examination was 0.61 +/- 0.29 logMAR, and mean age was 77 +/- 17 years. Mean time between device prescription and survey was 11 +/- 3 months. Device abandonment was not associated with age (p = 0.863), time since prescription (p = 0.125), visual acuity (p = 0.804), or category of magnification device (spectacle, handheld, stand, or video) (p = 0.412). There was a significant association between documented non-central visual field loss and abandonment of magnification device (p = 0.046). Repeat administration of the survey resulted in the same abandonment classification in 15 of 15 patients (100%). CONCLUSIONS: Abandonment rate was similar for this outpatient population to those previously reported in the U.S. veteran inpatient population and in other countries. Patients with visual field loss may be more likely to abandon prescribed devices. PMID- 21822161 TI - Secondary pseudomyopia induced by amisulpride. AB - PURPOSE: To report a case of pseudomyopia induced by antipsychotic drug administration. METHODS: A 30-year-old woman was referred to our ophthalmology department complaining of blurred vision, especially at distance, in both eyes. The patient had been prescribed antipsychotic drugs (haloperidol and biperiden) as treatment for her schizophrenic symptoms and had recently undergone a change of treatment to amisulpride. She had a manifest refraction of -4.00/-1.00 * 180 in the OD and -3.75/-1.25 * 175 in the OS whereas her cycloplegic refraction was 1.75/-1.00 * 180 in the OD and -1.00/-1.25 * 175 in the OS, respectively. RESULTS: A diagnosis of likely drug-induced pseudomyopia was made. Therefore, the patient was advised to visit her psychiatrist, who added an extra 2 mg of biperiden, an anticholinergic agent, to the pre-existing amisulpride treatment, achieving a cessation of the visual symptoms a few days later. CONCLUSIONS: Pseudomyopia can be induced by the antipsychotic drug amisulpride. Additional treatment with anticholinergic agents can be used to eliminate this side effect. PMID- 21822162 TI - Randomized clinical trial France DMLA2: effect of trimetazidine on exudative and nonexudative age-relatedmacular degeneration. AB - PURPOSE: To evaluate the effect of trimetazidine (TMZ) in a randomized, double blind, placebo-controlled clinical trial on the occurrence of choroidal neovascularization or geographic atrophy in age-related macular degeneration. METHODS: A total of 1,086 patients from France, Belgium, and Spain with soft drusen and/or retinal pigment epithelium abnormalities in the study eye and choroidal neovascularization in the contralateral eye were randomly assigned to receive orally placebo or TMZ 70 mg daily (35 mg * 2) and followed-up for 3 years to 5 years. RESULTS: Treatment duration ranged between 0.4 months and 67.8 months with a mean +/- SD of 38 +/- 16 months. Three hundred and fifty-eight patients developed choroidal neovascularization (incidence per 100 patient-years: TMZ 10.86; placebo 11.13). Trimetazidine did not prevent the choroidal neovascularization (hazard ratio = 0.97; 95% confidence interval, 0.77-1.20; P = 0.781). However, there was a trend favoring TMZ for retinal atrophy, a secondary endpoint (HR = 0.76; 95% confidence interval, 0.56-1.02; P = 0.069). Overall, the difference in atrophy incidence between TMZ and placebo was not statistically different. Differences within some prespecified subgroups of patients showed superiority of TMZ in men (HR = 0.50; 95% confidence interval, 0.28-0.89; p = 0.016), in patients aged <=75 years (HR = 0.58; 95% confidence interval, 0.38 0.88; p = 0.010), or in patients presenting with isolated pigmentary changes (HR = 0.19; 95% confidence interval, 0.05-0.70; p = 0.005). CONCLUSION: Trimetazidine failed to prevent choroidal neovascularization. Subgroup analyses suggest that this drug could be tested as preventive therapy for geographic atrophy, although the overall comparison showed no statistically significant differences in the progression of geographic atrophy. PMID- 21822163 TI - Elevation of angiogenic factor Cysteine-rich 61 levels in vitreous of patients with proliferative diabetic retinopathy. AB - PURPOSE: Cysteine-rich 61 (Cyr61) is one of the angiogenic factors involved in proliferative diabetic retinopathy (PDR). To further investigate its role, we measure and compare the vitreous levels of Cyr61 and vascular endothelial growth factor in patients with PDR and to localize Cyr61 expression in associated proliferative epiretinal membranes. METHODS: Vitreous obtained from 56 patients with active PDR, 16 patients with active PDR pretreated with bevacizumab, 19 patients with quiescent PDR, 15 non-PDR patients with diabetic macular edema, and 25 patients with non-diabetic-related eye diseases were subjected to enzyme linked immunosorbent assay for Cyr61 and vascular endothelial growth factor levels. Epiretinal membranes from 18 patients were stained immunohistochemically for Cyr61. RESULTS: Vitreous Cyr61 levels were significantly higher in active PDR patients, quiescent PDR patients, and diabetic macular edema patients compared with non-diabetic control patients (P < 0.01). Pretreatment of bevacizumab significantly suppressed vitreous vascular endothelial growth factor levels; however, it did not inhibit vitreous Cyr61 levels in active PDR patients. Cysteine-rich 61 was strongly detected in endothelial cells and myofibroblasts within active PDR membranes but not in idiopathic epiretinal membrane. CONCLUSION: Vitreous Cyr61 levels were related to different states of PDR and correlated with vascular endothelial growth factor levels in PDR patients. Pretreatment of bevacizumab did not inhibit vitreous Cyr61 levels in active PDR patients. Cysteine-rich 61 might mediate angiogenesis and post-angiogenic fibrosis in PDR. PMID- 21822165 TI - Disagreement with some statements from Lai et al. PMID- 21822168 TI - Toll-like receptor 4 polymorphisms and the risk of gram-negative bacterial infections after liver transplantation. AB - BACKGROUND: Toll-like receptor 4 (TLR4) is the main immune molecule that recognizes lipopolysaccharide from gram-negative bacteria. Single-nucleotide polymorphisms (SNPs) in the TLR4 gene that impair lipopolysaccharide recognition may influence gram-negative bacterial infections after liver transplantation. METHODS: TLR4 D299G and T399I SNPs were assessed in a cohort of 706 liver transplant recipients and were associated with the clinical characteristics and outcome of gram-negative bacterial infections. Cox proportional hazard model was performed to determine covariates associated with outcomes after gram-negative bacterial infections. RESULTS: Of 706 patients, there were 108 with microbiologically confirmed gram-negative bacterial infections, 135 with clinically suspected but not confirmed infections, and 463 patients without gram negative bacterial infections. The proportions of TLR4 D299G (5/108 [4.6%] vs. 32/463 [6.9%]; P=0.39) and T399I SNPs (19/108 [17.6%] vs. 68/463 [14.7%]; P=0.45) did not differ between those with or without microbiologically confirmed gram negative bacterial infections. Female gender (odds ratio 2.30, 95% confidence interval [CI]1.50-3.53; P<0.001) and ulcerative colitis (odds ratio 2.18, 95% CI 1.08-4.38; P=0.03) were associated with gram-negative bacterial infections. Among 108 patients with gram-negative bacterial infections, alcoholic liver disease (relative risk [RR] 4.87, 95% CI 1.54-15.44; P=0.007), initial septic shock (RR 10.19, 95% CI 2.70-38.37; P=0.001), and nosocomially-acquired infection (RR 4.61, 95% CI 1.51-14.14; P=0.007) were significantly associated with 90-day mortality after gram-negative bacterial infections. In contrast, TLR4 D299G and T399I SNPs were not significantly associated with mortality after gram-negative bacterial infections. CONCLUSION: In this cohort of liver transplant recipients with long term follow-up, no significant association was observed between TLR4 D299G and T399I SNPs and the risk and outcome of gram-negative bacterial infections. PMID- 21822169 TI - Impact of adjuvant immunotherapy using liver allograft-derived lymphocytes on bacteremia in living-donor liver transplantation. AB - BACKGROUND: Bacteremia is one of the leading causes of mortality in living-donor liver transplant (LDLT) recipients. Lymphocytes, including natural killer cells, are believed to play a role in the first line of defense against invading infectious microbes. METHODS: From January 2004 to December 2009, 114 consecutive LDLT recipients were studied for postoperative bacteremia. The impact of adjuvant immunotherapy using activated liver allograft-derived lymphocytes on bacteremia was retrospectively evaluated by a one-to-one match using propensity score to overcome bias due to the different distribution of covariates for the two groups. RESULTS: After one-to-one matching, 21 patients who did not receive adjuvant immunotherapy and 21 who did not receive adjuvant immunotherapy had the same preoperative and operative characteristics. Six (28.6%) of the 21 patients who did not receive adjuvant immunotherapy had bacteremia, whereas only one (4.8%) of the 21 patients who received adjuvant immunotherapy had bacteremia; thus, the incidence of bacteremia in patients who had received adjuvant immunotherapy was significantly lower than that in patients who had not received adjuvant immunotherapy (P=0.038). CONCLUSIONS: Adjuvant immunotherapy using liver allograft-derived lymphocytes may be a promising modality for reducing the postoperative bacteremia after LDLT. PMID- 21822170 TI - Kidney-pancreas transplantation is associated with near-normal sexual function in uremic type 1 diabetic patients. AB - BACKGROUND: Sexual function is altered in patients with type 1 diabetes (T1D) and end-stage renal disease (ESRD), thus affecting quality of life. The present study aimed to analyze sexual function in patients with T1D and ESRD (T1D+ESRD) who received a simultaneous kidney-pancreas (KP) or kidney-alone (KD) transplantation. METHODS: Ten KP, 10 KD, 9 T1D+ESRD patients and 11 healthy control subjects were evaluated according to the following parameters: (1) medical/sexual history and physical examination; (2) International Index of Erectile Function; (3) Beck's inventory for depression; (4) assessment of hormonal profile; (5) quantitative sensory testing of both hand and penile sensory thresholds; and (6) hemodynamic penile assessment. RESULTS: Controls and KP patients showed a higher rate of self-reported satisfactory erectile function as compared with KD and T1D+ESRD patients. Circulating androgens level resulted lower in both groups of transplanted patients and in patients with T1D+ESRD compared with healthy controls, albeit a relatively better profile was observed in KP. Both transplanted and T1D+ESRD patients showed peripheral hyposensitivity; however, healthy controls and KP showed better penile hemodynamic parameters compared with KD and T1D+ESRD. CONCLUSIONS: Our study demonstrates that sexual function, circulating sex steroids milieu, penile sensitivity, and hemodynamics are near-normalized for the most part in KP transplantation. Further studies are needed to assess the beneficial role and the overall impact of KP transplantation on sexual function in a long-term setting and a larger cohort of patients. PMID- 21822171 TI - First experience with the use of a recombinant CD3 immunotoxin as induction therapy in pig-to-primate xenotransplantation: the effect of T-cell depletion on outcome. AB - BACKGROUND: We have previously reported life-supporting kidney xenograft-survival greater than 80 days using a steroid-free antithymocyte globulin (ATG)-based induction regimen (ATG regimen) in a GalT-KO pig-to-baboon thymokidney (TK) model. We evaluated two induction regimens, a newly developed anti-monkey CD3 recombinant immunotoxin (anti-CD3 rIT) and an anti-human CD2 antibody (LoCD2), by assessing T-cell depletion (TCD) and graft survival. METHODS: Four baboons received anti-CD3 rIT; the time course of TCD was studied in two animals and the other two received GalT-KO TK transplants. Two additional baboons underwent GalT KO TK transplantation after treatment with LoCD2. All other treatments were identical to previous TCD studies with ATG. TCD was assessed by flow-cytometry; renal function was evaluated by serum creatinine and histology. RESULTS: Baboons that received the anti-CD3 rIT died from pneumonia or cardiac failure on days 15 and 23. Both animals in the rIT group died with functioning grafts. Thymokidney grafts from baboons treated with the LoCD2 regimen were rejected by day 14. TCD levels in baboons receiving the anti-CD3 rIT regimen were 150 to 250 cells/MUL for at least 14 days, whereas baboons receiving the LoCD2 recovered to more than 300 cells/MUL by day 7. CONCLUSIONS: The newly developed anti-CD3 rIT could be a useful TCD agent in baboons. However, optimal dosage, treatment duration, and bioactivity must be studied to avoid side effects. A LoCD2-based regimen was not effective for preventing xenogeneic rejection. Optimal TCD levels less than 250/MUL during the induction period seem to be important for success of xeno thymokidney transplantation. PMID- 21822172 TI - Signal joint T-cell receptor excision circle assay in miniature swine. AB - OBJECTIVE: Assays for T cell receptor excision circles (TREC) have been utilized in human, primate, and mouse models as a measure of thymic activity, but no comparable assay has been described in artiodactyls. We describe the development of the porcine signal joint (sj) TREC assay, and provide a likely reason for previous difficulties in its identification in artiodactyls. DESIGN AND METHODS: Utilizing the homology between the known genomic sequences in sjTREC in human and mouse, polymerase chain reaction (PCR) primers were derived for the putative porcine sjTREC. Primers from the psiJalpha side of the sjTREC were derived from the known porcine sequence. RESULTS: The sjTREC in two artiodactyls, swine and sheep, was identified using forward primers from the psiJalpha region, and reverse primers from the putative delta-rec region. Unlike in the detection of primate TRECs, initially the use of similar primers close to the delta-rec failed to yield the sjTREC product. Marching about 800 basepairs into delta-rec, primers derived from a homology region between human and mouse led to the detection of sjTREC. Comparing sjTREC amongst the species revealed highest homology between the two artiodactyls. A quantitative PCR (QPCR) assay of porcine sjTREC was also developed. CONCLUSION: Identification and analysis of the sjTREC sequences in two artiodactyls suggested why previous attempts at cloning the pig TREC using known sjTREC sequences were unsuccessful. The development of the porcine signal joint TREC assay should enable a more direct quantification of thymic activity in porcine models of transplant biology. PMID- 21822174 TI - Magnetic resonance elastography and biomarkers to assess fibrosis from recurrent hepatitis C in liver transplant recipients. AB - BACKGROUND: Imaging techniques evaluating liver stiffness (magnetic resonance elastography [MRE]) and biomarkers may be useful indicators of fibrosis stage in hepatitis C virus (HCV)+patients. Our aim was to compare the accuracy of MRE and biomarkers in staging fibrosis because of recurrent HCV in liver transplant (LT) recipients with hepatocellular carcinoma. METHODS: Liver magnetic resonance imaging and MRE, FIBROSpectII, aspartate aminotransferase-to-platelet ratio index (aspartate aminotransferase [AST]: platelet index), AST:alanine aminotransferase ratio, and magnetic resonance imaging/MRE-guided biopsies targeting the stiffest regions (right and left lobes) were performed in HCV+LT recipients. Sensitivity, specificity, positive predictive value (PPV)/negative predictive value (NPV), and likelihood ratios were calculated for the best cutoff by receiver operating characteristic analysis. RESULTS: Thirty-two recipients were included: 28 men, age 60 (+/-6.4) years, and time since LT 3.25 (+/-1.68) years. Both MRE (P=0.0001) and FIBROSpectII (P=0.009) were significantly different between no fibrosis and more than or equal to stage 1 groups, whereas aspartate aminotransferase-to-platelet ratio index and AST:alanine aminotransferase ratio were not different. Areas under the receiver operating characteristic curve were 0.87 for MRE and 0.84 for FIBROSpectII. MRE cutoff of 3.81 kPa had 87.5% sensitivity, 79.2% specificity, 58.3% PPV, and 95.0% NPV; FIBROSpectII cutoff of 42 had 87.5% sensitivity, 70.0% specificity, 53.8% PPV, and 93.3% NPV for detection of more than or equal to stage 1 fibrosis. Two patients had high MRE values because of unexpected acute rejection and portal vein thrombosis. CONCLUSIONS: MRE and FIBROSpectII are highly sensitive in detecting fibrosis due to recurrent HCV. Both are limited by the low specificity/PPV and confounding because of other graft complications. Values below the MRE and FIBROSpectII cutoffs, however, strongly suggest the absence of fibrosis and may avert the need for protocol biopsy staging. PMID- 21822173 TI - Sensitized recipients exhibit accelerated but not hyperacute rejection of vascularized composite tissue allografts. AB - BACKGROUND: Currently, the donor-recipient matching process for vascularized composite tissue allotransplantation (VCTA) closely follows the standard practices for solid organ transplantation. Sensitization is considered a contraindication to VCTA. However, the role of sensitization in VCTA rejection is largely unstudied. METHODS: Major histocompatibility-mismatched ACI (RT1) donors and Wistar Furth (WF) (RT1) recipients were used to determine whether sensitization would lead to hyperacute rejection in VCTA as in other organs, such as kidneys. WF rats were presensitized to ACI antigens by skin transplantation and received heterotopic osteomyocutaneous VCTA flaps. Kidney transplants served as controls. RESULTS: Production of anti-donor antibody was detected in WF recipients after rejection of the ACI skin grafts. Sensitized WF rats rejected VCTA grafts from ACI rats significantly faster (P<0.05) than unsensitized recipients, but not hyperacutely. Rejection in the sensitized recipients was not prevented by immunosuppression with FK506 and mycophenolate mofetil. In contrast, kidney allografts from ACI rats were hyperacutely rejected within 30 min by sensitized recipients. To confirm the role of antibody-mediated rejection in the sensitized recipients, serum from presensitized rats was adoptively transferred into naive WF rats. Hyperacute rejection occurred only in transplanted kidneys but not VCTA. Histologic examination of tissues from acceleratedly rejected VCTA showed dense lymphocytic infiltrates, and no antibody deposition. CONCLUSIONS: VCTA are rejected in an accelerated fashion but not hyperacutely in the presence of allosensitization and preformed anti-donor antibody. The rejection of VCTA in sensitized recipients is mainly cell mediated and differs mechanistically from that for renal transplants. PMID- 21822175 TI - On rare and "super-rare" diseases: an insight from the Republic of Macedonia. AB - Rare diseases (RD) are becoming increasingly important as possible targets of new forms of treatment, as a valuable source of a novel insight in fundamental lows of biology, and in the specific mechanisms of many diseases. Molecular methods have created a better diagnosis and oftentimes treatment. RDs pose significant problem for the patients, since their problems are often not recognized by the medical community and shunned by the health insurance. The cumulative costs of diagnosis and treatment of RDs is significant for any society, oftentimes bearably acceptable for developing countries. PMID- 21822176 TI - Urine proteomics in clinical applications: technologies, principal considerations and clinical implementation. AB - The technology platforms for proteome analysis have advanced considerably over the last few years. Due to these improvements the number of studies on the analysis of the proteome/peptidome with the aim of defining biomarkers has escalated. In this review, we will summarise the technical aspects that relate to the proteomics field targeting the discovery of biomarkers for disease diagnosis. We will describe the course from biomarker discovery or 'potential' biomarkers to those that are clinically important. We also present several examples of successful proteomic studies that have defined 'biomarker patterns' for clinical applications, focussed on urine as a material source and capillary electrophoresis coupled mass spectrometry as a technology. Finally, current challenges and considerations for future studies will be discussed. PMID- 21822177 TI - The role of epigenetics in kidney diseases. AB - Epigenetics is the study of changes in gene expression that occur without changes in DNA sequence. These reversible modifications include DNA methylation, histone acetylation and RNA interference. Epigenetic changes are fundamental for the regulatory physiological processes that regulate gene activity; therefore, these changes are altered in response to environmental factors or disease states, but, in many circumstances, they are also believed to contribute to disease occurrence and progression. So far, studies of the epigenome have been scarce in nephrology. However, there is evidence that in the uremic milieu, several features such as inflammation, dyslipidaemia, hyperhomocysteinaema, oxidative stress as well as vitamin and nutritional deficiencies may affect the epigenome, and impact patient outcome. The present review describes the current knowledge on epigenetic alterations in the course of various kidney disease states. Although the science of epigenetics is still in its infancy, it seems that it may help elucidate the pathogenic mechanisms in uraemia, and allow novel treatment strategies to be developed. PMID- 21822178 TI - Rare diseases with renal involvement in the Republic of Macedonia. AB - Rare diseases (RDs) pose a significant set of problems for patients, since their disease and general social and health situation are often not recognized by the medical community and shunned by health insurance. The sheer number of RDs (5000 8000) and the number of patients (6-8% of the population) are challenging for every society. We wanted to get a better understanding of the rare diseases affecting the kidneys and urinary tract (RDAKUT) in the Republic of Macedonia and we investigated principally the PubMed Central articles of Macedonian medical professionals dealing with RDAKUT, but we also used information on RDAKUT from local sources. A significant number of RDs have been published, demonstrating the awareness and skill of Macedonian medical professionals despite pretty limited diagnostic facilities. We still feel that RDAKUT are underdiagnosed (e.g. Fabry's disease has not yet been reported), and that many patients with RDs have a long way to go before an accurate diagnosis. Increased awareness and ameliorated education are needed by the physicians; while health insurance must include RDAKUT covering their diagnosis and treatment costs. Neonatal screening for ~30 diseases (instead of just hypothyroidism) is also required. Patients' organizations exist and they are active in promoting their interests before of the health authorities. PMID- 21822179 TI - Renal histopathology and clinical course in patients with Wegener's granulomatosis--single centre experience from the Republic of Macedonia. AB - The aim of this study was to evaluate the clinical course of patients with Wegener's granulomatosis (WG) with renal involvement, to examine histopatological form seen in renal biopsies and present follow-up of the patients. A retrospective analysis was carried out of 18 patients presenting with WG and active renal disease at the University Nephrology Department, Ss. Cyril and Methodius University, Skopje, R. Macedonia. All patients were ANCA positive and had a percutaneous renal biopsy taken on their admission. 12 patients were male, 6 female, aged 48.61+/-13.77 (M+/-SD). All had extrarenal symptoms prior to admission. Oligoanuria was present in 7/18 (38.9%) of the patients, serum urea levels of the whole group were 40.67+/-18.13 mmol/l (M+/-SD) and for serum creatinine 691.06+/-384.93 umol/l (M+/-SD). Necrotizing glomerulonephritis with crescents was present in 11/18 (61.11%) of the patients, the others presented diffuse proliferative extracapillary glomerulonephritis. All patients were treated with steroids and cyclophosphamide, and plasmapheresis was performed in 7/18 (38.9%) of the patients. Probability rate for surviving after one month was 0.6111 and after three months 0.3889 (Kaplan-Meier). The current treatment of WG in our study did not prevent serious complications and development of ESRD in a large number of our patients. This systemic disorder is still a serious problem and early diagnosis and alternative strategies for the management of the disease will be an important objective for further studies. PMID- 21822180 TI - Effects of ozone on nasal mucosa (endothelial cells). AB - After exposure to ozone, humans develop neutrophil infiltration of the nasal mucosa. To investigate the events contributing to inflammatory cell recruitment in the nasal mucosa we exposed 10 healthy nonsmoking volunteers to 400 ppb ozone or filtered air for 2h at rest on two separate occasions. Nasal biopsies were performed 6h after ozone/filtered air exposure. The nasal biopsies were embedded in glycol mathacrylate and immunostained for inflammatory cells, including neutrophils, mast cells, total T-cells (CD3), T-cell subsets CD8 and CD4, macrophages, eosinophils adhesion molecules (P-selectin, E-selectin, ICAM-1, VCAM 1), cytokines (TNF-alpha, IL-1beta, GM-CSF, IL-6), chemokines (IL-8 and RANTES), and nuclear factor NF-kappaB. No significant changes were seen in the number of T cells, and T-cell subsets, eosinophils, macrophages, or percentages of vessels expressing P-selectin, VCAM-1, GM-CSF, IL-6 and RANTES in the biopsies. The number of neutrophils and mast cells in the submucosa was significantly higher after ozone exposure (p=0.009 and p=0.005 respectively). The percentage of vessels expressing E-selectin (p=0.01), ICAM-1 (p=0.005), IL-8 (p=0.02), TNF alpha (p=0.02), IL-1beta (p=0.009), and NF-kappaB (p=0.05) increased significantly after ozone exposure as compared to filtered air exposure. Exposure of normal subjects to ozone increases the expression of proinflammatory cytokines resulting in upregulation of IL-8 and adhesion molecules via activation of NF kappaB, leading to neutrophil inflitration in the nasal mucosa. PMID- 21822181 TI - Role of interleukin-8 in differentiation of uncomplicated from complicated parapneumonic effusion. AB - The aim of this study was to investigate the value and significance of interleukin-8 in differentiation of uncomplicated parapneumonic effusion (UCPPE) from complicated parapneumonic effusion (CPPE). Using an IMMULITE 1000 Analyzer, with chemiluminescent immunometric assay, levels of interleukin-8 (IL-8) were measured in the pleural fluid of patients with UCPPE (n=30), and CPPE (n=30), and three classical parameters (pH, glucose, and LDH) in these two groups. Receiver operating curves were to assess the sensitivity and specifity of interleukin-8 for differentiating between the two patient groups. IL-8 levels were statistically higher in the CPPE group. A positive significant correlation, was found between levels of IL-8 and and lactate dehydrogenase (LDH) (r=0.68, p<0.05). There was also a positive significant correlation between IL-8 and protein level in pleural effusion (r=0.306, r<0.01). There was a significant negative correlation between levels of IL-8 and pH (r=-0.83, p<0.05), and of IL-8 and glucose in pleural fluid (r=-0.61, p<0.05). A cut-off value of 1805.81 pg/ml, differentiated CPPE from UPPE with a sensitivity of 100% and a specifity of 98%. IL-8 may be used as an alternative marker for the complication of parapneumonic effusion. PMID- 21822183 TI - Socio-demographic predictors and reasons for vitamin and/or mineral food supplement use in a group of outpatients in Skopje. AB - BACKGROUND: Vitamins and/or mineral food supplements (VMS) are mono- or multi component products prepared in different pharmaceutical forms and categorized as food supplements. Numerous researchers have investigated the epidemiological predictors of use of VMS in population. Data of this kind in our setting are limited. AIMS: This survey aimed to gain information on the prevalence of use, certain sociodemographic predictors and reasons for VMS use in a group of 256 outpatients in Skopje. MATERIALS AND METHODS: This study was designed as an open ended, cross-sectional survey. Data on VMS use were collected by survey method with a specially designed questionnaire as an instrument for this research. Appropriate statistical tests were used to analyse the data. RESULTS: Data from 256 outpatients from Skopje were analysed. Of them, one hundred and five (41.02%) reported using VMS. Female outpatients (p<0.01) and participants of Macedonian ethnicity (p<0.01), with a higher educational level (p<0.01) and those having their own income (p<0.05) reported significantly higher consumption of VMS. We found a statistically significant difference between the group of users and non users of VMS regarding smoking status (p<0.05), alcohol consumption (p<0.05) and presence of a chronic disease (p<0.01). Physicians, magazines and friends were the most common source of information on VMS while maintaining good health and prevention of disease was the most common reasons for the use of these products. Only 63% of the users had disclosed the information on taking VMS to their physicians. CONCLUSION: This research provided an insight into VMS in our setting. Predictors on the use of VMS are of interest since these products contribute to total intake of vitamins and minerals in the population and they represent a source of valuable information when planning public health activities. PMID- 21822182 TI - Cross-reactive epitopes present in campylobacter jejuni serotypes isolated from enteritis patients. AB - Campylobacter jejuni (C. jejuni) infection frequently triggers autoimmune mediated neuropathies, especially the Guillain-Barre syndrome (GBS). The molecular mimicry between the core oligosaccharides of bacterial lipopolysaccharides (LPSs) and the human gangliosides presumably results in the production of anti-neural cross-reactive antibodies which are likely to be a contributory factor in the induction and pathogenesis of GBS. The aim of our study was to determine the presence of cross-reactive epitopes in C. jejuni LPSs isolated from enteritis patients and to determine their antigen reactivity. For that purpose we collected stool specimens from 21 patients with enteritis and without neurological symptoms. Seven different serotypes of C. jejuni (0:27; 0:6/0:7; 0:38; 0:3; 0:1/0:44; 0:19; 0:37) were detected using the Penner system. Unexpectedly, one serotype from this group was detected as 0:19, a serotype rarely isolated from enteritis patient and in close association with GBS. Binding studies using cholera toxin-B subunit and peanut agglutinin, showed the presence of ganglioside-like epitopes in C. jejuni strains 0:37, 0:19 and 0:27. Reactivity with sera from patient with GBS, with confirmed previous exposure to C. jejuni and with high a titre of anti-ganglioside antibodies, showed that the same three LPSs from C. jejuni serotypes 0:37, 0:19 and 0:27 bear cross-reactive epitopes in their LPSs structures. Our results confirm the results from previous studies that LPSs from certain C. jejuni serotypes bear cross-reactive ganglioside-like epitopes which might be involved in the induction of GBS after C. jejuni infection. PMID- 21822184 TI - Reproductive outcome after hysteroscopic metroplasty in patients with infertility and recurrent pregnancy loss. AB - INTRODUCTION: Patients with uterine malformations have decreased reproductive potential and an unfavourable reproductive outcome starting even from the first pregnancy. Patients with untreated uterine malformations have a term delivery rate of 40%-65%. Hysteroscopic metroplasty is a standard, safe and minimally invasive method for treatment of uterine malformations, which provides a normal uterine cavity in patients with hysteroscopically correctible types of uterine malformations. The aim of the study was to analyse the variables associated with reproductive outcome before and after hysteroscopic metroplasty. MATERIAL AND METHODS: We analysed the variables determining reproductive outcome after 216 interventions with hysteroscopic metroplasty in 202 patients which were done at the University Obstetrics and Gynecology Clinic in Skopje during a three-year period, from 01.01.2006 to 31.12.2008. Patients were divided into three groups: patients with recurrent pregnancy loss, patients with secondary infertility and foetal loss and patients with primary infertility. The follow-up period lasted for two years (24 months). Statistical analysis was performed using the Chi square test and p<0.05 was considered to be statistically significant. RESULTS: During the follow-up period of two years after hysteroscopic metroplasty there were a total of 113 pregnancies, of which 46 belonged to the group of primary infertility. Analysis of the reproductive outcome of those patients (compared before and after hysteroscopic metroplasty) showed a significant (p<0.05) decrease in the abortion rate from 89.6% to 12.4%, as well as an increase of term delivery rate from 1.4% to 74.4%. In the group of preterm deliveries there was a rise from 9% to 13.2%, which was not significant. The group of primary infertility had a pregnancy rate of 36%. CONCLUSION: Hysteroscopic metroplasty significantly improves the reproductive outcome in patients with surgically correctible uterine malformation. PMID- 21822185 TI - Impact of body mass index (BMI) and age on the outcome of the IVF process. AB - BACKGROUND: The goal of this study was to examine the impact of body mass index (BMI) and age on the outcome of the IVF process. MATERIALS AND METHODS: This was a retrospective case-control study, of all patients undergoing IVF from 2008-2010 in the Re-Medika IVF Centre. A total of 1238 fresh, non-donor IVF cycles were analyzed, but to minimize the bias, only the first cycle for each patient in that period was analysed (N-920). The patients underwent standard protocols for COH and embryology treatment. In all retrieved oocytes, or in 100% of the cases, the process of fertilization was realized with the method of intracytoplasmic sperm insemination (ICSI). The primary end-point assessed was clinical pregnancy rate. Patients were initially grouped into four BMI categories. The data are presented as frequencies (qualitative data) and as mean+/-SD (quantitative data). Preliminary comparisons between groups with different BMI were made by the Chi square and one-way ANOVA test. Because fertility declines with age, there is a Pearson-correlation coefficient to see if BMI depends on age, and the resulting value r=0.15 (p<0.05) showed that BMI is age-dependent, the relationship between them showed multicollinearity. However, the calculated error tolerance of 0.9 indicates stability of the model. Furthermore, to adjust the known fertility decline with age, every response or outcome is analysed by the method of multiple linear (continuous data) or logistic (qualitative data) regression, where the independent variables are taken: BMI, age and BMI interaction*age. RESULTS: Increased BMI significantly reduces the chance of clinical pregnancy (normal weight vs. overweight: clinical pregnancy rate: 49.2%, vs. 34.3%). Age, analysed as a single factor, significantly reduces clinical pregnancy rate. Interaction of BMI and age significantly affects clinical pregnancy rate. (BMI vs. BMI*Age vs. Age-p 0,01 vs. 0,001 vs. <0,0001). CONCLUSION: Increased body mass of patients entering IVF has a negative impact on the final outcome and certainly reduces the success of the process resulting in reduced clinical pregnancy. Interaction of BMI and age showed a strong significant impact on the outcome of IVF seen through the achievement of clinical pregnancy. PMID- 21822186 TI - Morphological characteristics of the first part of the vertebral artery. AB - Because of their anatomical localization, vertebral arteries were neglected in research for a long period of time. Vertebral arteries are responsible for about 30% of the brain blood supply. The aim of this study was to examine the vertebral artery's course in the first segment, and to define the anatomic variations and percentage of their appearance in the adult population using CT angiography. The data derived from this study may find useful application in a wide range of medical fields, such as anatomy, radiology and surgery. For that purpose during a 6-month period we examined 30 patients with CT angiography. The origin of the vertebral artery in all 30 patients was from the subclavian artery. The diameter of the left vertebral artery was from 1.6-5.20 mm., average 3.35 mm. The diameter of the right vertebral artery was from 1.64-5.40 mm., average 3.19 mm. Hypoplasia of the vessel was found in four patients. We found no aplasia of the vessel in this series. A contorted course was found in 12 (40%) patients. In all 30 (100%) patients the vertebral artery entered the foramen transversum at the level of the sixth cervical vertebra. Although the incidence of anatomical variations is rare, their presence is significant in the diagnostic and surgical procedures in the head and neck region. Insufficient knowledge can lead to serious iatrogenic injures. PMID- 21822187 TI - The role of clinical diagnosis in meniscal lesions of the knee. AB - The aim of the present paper is to evaluate the importance of clinical examination in the process of diagnosing meniscal lesions, as well as to establish the accuracy of clinical examination in comparison to the arthroscopic diagnosis. In the last 5 years, in the Orthopedic Surgery Clinic in Skopje, the authors have diagnosed and treated 205 patients suffering from meniscal lesions. The method of anamnestic testing, and of clinical examination and the statistical method have been applied. All the patients were subjected to the following tests: well taken anamnesis of the knee injury mechanism, standard orthopedic examination (Stainman I and II, McMurray and Appley test), standard radiographic images of the knee, additional examination with MRI for some of the patients and arthroscopic examination. The results obtained with clinically established diagnosis were compared to the results obtained with arthroscopic diagnosis. Comparing the results of the clinical and arthroscopic diagnoses, an insufficiency of the clinical diagnosis of almost 20% was established. The results are close to those given in the professional literature which refers to the standardized approach in taking the anamnestic data and the realization of the physical signs and tests examination technique. It means that the physical signs and tests, as well as the well-taken anamnesis, are the foundation for establishing a diagnosis of meniscal lesions. Arthroscopy is truly the only golden standard for the diagnosis of all entities of the knee joint, including meniscal lesions. PMID- 21822188 TI - Clinical and radiographic analysis of the operative procedure results according to the method of Mitchell and Keller used for correction of hallux valgus deformities. AB - The aim of this study is to make a correlation of the clinical and radiographic results after performing two different surgical procedures for correction of hallux valgus deformity. MATERIAL AND METHODS: The study included 70 patients having hallux valgus deformity of the foot, and they were divided into two groups. The first group (Group 1) was composed of 35 patients who were treated by osteotomy of the I-st metatarsal bone according to Mitchell, while the second group (Group 2) was also composed of 35 patients who were treated by resectional arthroplasty according to Keller. Clinical (pain and metatarsalgia, as well as most dominant symptoms) and radiographic examinations (I metatarsophalangeal angle and I intermetatarsal angle) were analysed comparatively during the evaluation. The analysis of the clinical and radiographic results was performed pre-operatively and post-operatively for the two groups. RESULTS: According to their sex, the patients were 5 men and 65 women. Using the method of Mitchell, pain as a clinical symptom post-operatively was found in only 3 patients out of the 35 with operated feet, while in the other group of patients treated by the method of Keller, there was no presence of pain in any of the patients. Comparatively, this does not present a statistically significant difference (p>0.05). Nor do, the differences in the distribution of metatrsalgia incidence show a statistical significance between the two groups (p>0.05). There is no significant difference (p>0.05) in the patients of the two groups concerning the pre-operative mean dimension values of the I metatarsophalangeal angle and I intermetatarsal angle. However, the radiographic analysis of the same angles in both groups, one year post-operatively, showed a high statistically significant difference (p<0.001). SUMMARY: Mitchell's operative technique could be recommended as an effective procedure for the correction of hallux valgus and metatarsus primus varus in young and middle-aged patients, while the resection arthroplasty according to the method of Keller is recommended for older patients with arthrotic changes. PMID- 21822189 TI - Estimation of time since death through electric and chemical excitability of muscles. AB - Electric and chemical excitability of muscles present a supravital reaction which is of major importance in achieving a more precise estimating of the time since death in the early post-mortem period. The purpose of this paper is to examine the electric and chemical excitability of the muscles in cases with a known time of death, in order to determine their importance in the estimation of time since death. Electric excitability and chemical stimulation have been analysed in 50 cases with a known time of death, taken for autopsy at the Institute of Forensic Medicine and Criminology in Skopje in the course of the year 2005. Testing of electric excitability of the muscles was done with a device for electric stimulation, providing a direct current of 50 mA intensity and 50 Hz frequency. Testing of chemical excitability of the eye pupils was done by injecting miotic Carbahol into the front eye chamber of the right eye and mydriatic Adrenalin HCl into the front eye chamber of the left eye. By analysis and processing of the obtained results, it was determined that the electric excitability of the muscles is of a major importance in determining the time since death within a post-mortem period of up to 10 hours and chemical excitability for a post-mortem period of up to 12 hours. PMID- 21822190 TI - Family history in patients with schizophrenia and depressive symptoms. AB - BACKGROUND: Depressive symptoms are common in schizophrenia and they can occur during any phase of the disorder. Some authors report an association between depression in schizophrenic patients and a positive family history of depression. AIM: The aim of this study was to evaluate depressive symptoms in schizophrenic patients and to compare their family history with that in patients with depressive disorder. MATERIAL AND METHODS: The examined group consisted of 50 patients with schizophrenic disorder, both inpatients and outpatients treated at the University Psychiatry Clinic who had prominent depressive symptoms (total score>7 on 17-item Hamilton Depression Rating Scale). The control group consisted of 50 patients with depressive disorder. Differential diagnosis was established on the basis of ICD-10 diagnostic criteria. Patients were evaluated with PANSS, 17-item Hamilton Depression Rating Scale (HAMD) and a questionnaire for demographic and clinical data. RESULTS: The clinical depression seen in patients with schizophrenia differed significantly from that in patients with depressive disorder. Depressive symptomatology was significantly more frequently reported in a family history of schizophrenic patients with depressive symptoms than in patients with depressive disorder. CONCLUSION: Schizophrenic patients with prominent depressive symptoms have significantly more frequently a positive family history of depression compared to patients with depressive disorder. PMID- 21822191 TI - Alpha asymmetry in QEEG recordings in young patients with anxiety. AB - Anxiety is defined as a subjective sense of worry, apprehension, fear and distress. When severe, it can affect a child's thinking, decision-making ability, perceptions of the environment, learning and concentration. Basal instability in cortical arousal, as reflected in measures of quantitative electroencephalography (qEEG), is common in most of the anxiety disorders. SUBJECTS AND METHODS: The sample was composed of 26 children and teenagers aged 11.73+/-4.03 years, F:M=1:2. The group was diagnosed as having Generalized Anxiety Disorder (GAD). EEG was recorded with Quantitative EEG equipment--Mitsar-amplifier[with 19 electrodes with 250 Hz sampling rate in the 0.3-70 Hz frequency range in the following conditions: eyes opened and eyes closed, at least 5 minutes each. RESULTS AND CONCLUSIONS: A statistically significant difference of spectra power in alpha band between left and right hemisphere was obtained. The right frontal asymmetry is specific to the right-handed. In eyes-open condition the percentage of children manifesting right asymmetry is up to 92.31% and in the eyes-closed condition it is 88.46%. Left frontal asymmetry was typical of left-handed children. We did not confirm the posterior right asymmetry suggested by other authors. The correlations between asymmetry and hand preference of children was very strong (r=0.68-0.85) and statistically significant (p<0.05) only for frontal regions of the brain. For parietal regions this was weak and statistically not significant. PMID- 21822192 TI - Are there any gender differences in the QEEG power spectrum in patients with schizophrenia? AB - The aim of the study was to investigate the gender differences in patients with schizophrenia in age of onset, other demographic and clinical characteristics and their relationship with QEEG power spectrum measures. MATERIAL AND METHODS: Thirty patients with schizophrenia were enrolled in the study, 17 female and 13 male, mean age 34 years. Comprehensive assessment of the symptoms of schizophrenia was performed using PANSS (Positive and Negative Syndrome Scale), BPRS (Brief Psychiatric Rating Scale) and CGI (Clinical Global Impression) scale. The age of onset of schizophrenia and the duration of psychosis was assessed using the medical history and parts of the IRAOS (Interview for Retrospective Assessment of Onset of Schizophrenia). RESULTS: Female patients had more severe psychopathology with statistically significant differences in PANSS and BPRS scores (larger total scores) and on the positive subscale of PANSS. QEEG power spectrum showed statistical significant difference only for the beta band in female patients. Women were less employed and had longer duration of illness and previous treatment. There were no differences in the mean age of onset of the disease (26 years in male and 25 years in female patients) and in the familiar occurrence. CONCLUSION: Fast basic activity in beta bands was associated with female patients with schizophrenia who presented more severe psychopathology and had longer duration of the disease and previous treatment. Considering the relatively small sample the current results must be replicated with a larger group of subjects to confirm the findings. PMID- 21822193 TI - Cut-off value of mantoux induration in tuberculous children in R. Macedonia and their nutritional status. AB - INTRODUCTION: The interpretation of the Mantoux test, as well as knowledge of factors that affect the test's induration size, is significant for the early diagnosis of tuberculosis in children. AIMS: To determine the Mantoux test induration cut-off size which distinguishes between positive and negative results in Macedonian children suffering from tuberculosis. To find whether there is any correlation between the nutritional status (malnutrition) and the Mantoux induration size. MATERIALS AND METHODS: A retrospective and descriptive study was carried out in 270 patients up to 14 years old with diagnosed tuberculosis, treated during the period of 2003-2007 in the Pediatric Tuberculosis Department at the Kozle Institute for Respiratory Diseases in Children, Skopje, Macedonia. The cut-off value of the Mantoux test induration size was determined by analysis of the test results distribution. The nutritional status was calculated as the weight for age standard (z-score). Correlation between the TST results and the nutritional status was calculated with Pearson's coefficient of correlation. RESULTS: Two hundred and seventy (270) children with tuberculosis were included in the study. The lung form of tuberculosis was present in 87.8% of the children. 53.7% of the patients were male, and 46.3% were female. The age group of 1-2 years was the most numerous (15.2%), followed by the group aged 7-8 years (10.4%). 33 children (12.2%) were undernourished (z-score<-2). The Mantoux test induration size was in the range of 0 to 32 mm, with an average of 13.4 mm. The distribution of the frequencies of the indurations had a bimodal form, with the primary mode at 0 mm, the secondary mode at 15-19 mm, and antimode at 5-9 mm. The Mantoux test had a sensitivity of 82.5%, specificity of 62%, positive predictive value of 68.46% and negative predictive value of 78.61%. Pearson's coefficient of correlation (r) of 0.175 showed a weak positive correlation between the results of TST (induration size) and the nutriational status. CONCLUSIONS: The cut-off value of the induration which distinguishes negative from positive Mantoux reaction was 5 mm. The interpretation of the test is recommended to be carried out depending on the risk factors for TB development, which surround the children. The Mantoux test in malnourished children should be interpreted with caution. PMID- 21822194 TI - Presence of caries with different levels of oral hygiene. AB - The objective of this abstract is to examine the presence of caries in the adult population with different levels of oral hygiene; to examine the concentration of Streptococcus Mutans in saliva of patients with different levels of oral hygiene; to examine the correlation among Streptococcus Mutans, caries and level of oral hygiene. This examination was made on 50 (fifty) patients, both male and female, at the age of 20 to 65. The examinees were split into 5 groups. The examinations and sampling were done randomly at the Department of Cariology and Endodontics at the Faculty of Dental Medicine in Skopje. The microbiological researches were made at the Institute of Microbiology and parasitology at the Faculty of Medicine in Skopje. The examination of all patients was made according to a unique methodology. The results obtained indicate that the Plaque index level and the number of Streptococcus Mutans in saliva (CFU) are correlated to the number of carious teeth in all age groups except for Group V (61-65) where the Plaque index level and the level of Streptococcus Mutans in saliva were much higher compared to the number of carious teeth (51-99 and >100 CFU), particularly for examinees with prosthesis. Initial enamel caries was dominant in patients up to the age of 50, and for those older than 50 surface root caries was dominant. Initial caries was present in 28.62% of Group I and was 5.66% in Group V, unlike the root surface caries in Group 1, with 1.14%, and Group 5 with 28.30%. PMID- 21822195 TI - Clinical performance of fluoride-releasing dental restoratives. AB - OBJECTIVES: The purpose of the this study was to evaluate the performance of several different fluoride-releasing restoratives placed on deciduous and immature permanent teeth in respect of time; and additionally to compare the effect of conditioning prior to their placement. MATERIAL AND METHODS: A total of 270 restorations--restored with one conventional glass-ionomer cement, one resin modified glass-ionomer cement, one compomer and one fluoride-releasing glass ionomer cement (135 placed on deciduous and 135 on permanent immature teeth)- were evaluated. The fillings were analysed after 1 month, 6, 12 and 18 months, by the criteria for evaluation of the dental clinical materials given by Ryge. RESULTS: Restorations mostly gave excellent results, especially those placed on permanent immature teeth. Actually, Dyract AP and Unifil Flow were marked (A) after 18 months in 93.3% of the cases. Fuji IX restorations had the lowest retention rate, especially on deciduous teeth, due mostly to bad oral hygiene habits. Dissatisfaction with the tested criteria was, above all, because of the bad marginal adaptation and the colour dismatch of the restorations. Conditioning prior to the application of the restoratives was beneficial. CONCLUSIONS: Fluoride-releasing materials are a revolution in the treatment of tooth decay, especially in children. This is mostly due to their ability to reduce seconddary and recurrent caries levels and the simplified application. PMID- 21822197 TI - Early-onset ocular ochronosis in a girl with alkaptonuria (AKU) and a novel mutation in homogentisate 1,2-dioxygenase (HGD). AB - Alkaptonuria (AKU) is a disorder of phenylalanine/tyrosine metabolism due to a defect in the enzyme homogentisate 1,2-dioxygenase (HGD). This recessive disease is caused by mutations in the HGD gene. We report a 14-year-old girl who was referred after presenting black urine. Careful examination revealed ochronosis of the conjunctiva. There was no affection of the cardiac valves. Elevated excretion of homogentisic acid in urine was found. Sequence analysis of the HGD gene from genomic DNA revealed that the patient is a compound heterozygote with a previously described mutation (c.473C>T, p.Pro158Leu), and a novel one (c.821C>T, p.Pro274Leu). Her mother is heterozygous for the novel mutation, while the brother is heterozygous for the previously described mutation. In summary, we describe an alkaptonuric patient with ocular ochronosis and a novel HGD mutation, c.821C>T, p.Pro274Leu. PMID- 21822196 TI - Iron overload in patients with transfusion dependent myelodisplastic syndrome. AB - The myelodisplastic syndrome is a heterogeneous group of diseases, characterised by ineffective and dysplastic haematopoesis and pancytopenia in the peripheral blood, followed by progressive disturbance of differentiation of the haematopoetic stem cell, resulting in evolution of the disease towards acute leukaemia. According to the latest WHO classification, the term myelodisplastic syndrome includes diseases with an indolent course, as well as diseases with a fast evolution towards acute leukaemia. Because of this diversity, haematologists base their therapeutic decisions on prognostic scoring systems which incorporate all the significant factors with an influence on survival in this group of patients with myelodisplastic syndrome. Bearing in mind that anaemia is the most frequent form of cytopenia in patients with myelodisplastic syndrome, it is common that at some point of the disease almost every patient with myelodisplastic syndrome is transfusion-dependent. Frequently applied transfusions secure the correction of anaemia in these patients, giving them a good quality of life, but at the same time endangering them with the potential threat of iron overload, when the physiological mechanisms of iron excretion from the organism become insufficient. There is a clear correlation between transfusion dependence and the overall survival in patients with myelodisplastic syndrome. Chelators secure the lowering of the iron surfeit and are indicated in transfusion-dependant patients with myelodisplastic syndrome ( need for two blood units monthly, during one year ), when the ferritin level increases over 1000, in patients who are candidates for transplantation as well as in patients from good prognostic groups with median survival over one year. The therapy with chelators lasts as long as the patient is transfusion-dependant. PMID- 21822198 TI - Immunosupressive treatment with cyclosporin-A for a patient with hypoplastic myelodisplastic syndrome: a case report. AB - BACKGRAOUND: Imunosupressive therapy with antithymocyte globulin (ATG), cyclosporine (CsA) or both has been shown to induce haematological responses in a subset of patients with myelodysplastic syndromes (MDS), in particular in the hypocellular form of MDS. CASE REPORT: We report our first case with hypocellular MDS treated with CsA. A 54-year-old female referred to our Department due to weakness and severe pancytopenia. Hypocellular form of MDS was diagnosed after bone marrow biopsy. Treatment with CsA was started one year after diagnosis. Treatment with CsA resulted in clinical improvement, a very good partial haematological response, resolution of transfusion requirement and an increase in bone marrow cellularity. CONCLUSIONS: In our experience, immunosuppressive treatment with CsA and/or ATG could be an alternative for patients with hypoplastic MDS for whom there is no possibility of allogenic bone marrow transplantation as only curative therapy. PMID- 21822199 TI - Giant retroperitoneal liposarcoma: a case report. AB - BACKGROUND: Liposarcoma is a neoplasm of mesodermic origin derived from adipose tissue and represents the most frequent histopathological variety of the retroperitoneum. Retroperitoneal liposarcoma may grow to a large size without symptoms. Approximately 20% of the tumours are >10 cm at the time of diagnosis and may reach extremely giant dimensions. CASE PRESENTATION: We present the case of a 58-year-old woman with a giant retroperitoneal liposarcoma. The patient presented at our clinic with diffuse abdominal pain and enormous abdominal distension. She had swellings and redness of the right leg. CT scan revealed a 50*25 cm sized enhancing soft mass. Ultrasound guided biopsy was negative for the presence of malignant cells. A double "J" ureteral stent was placed in the right ureter. We performed surgery with complete resection of the tumorous mass without multiorgan resection and with macroscopic free margins. A well differentiated, lipoma-like subtype of retroperitoneal liposarcoma, weighing 13.4 kg, was diagnosed in the histopathological report. At 6 months after surgery a new CT scan was done and there was no evidence of recurrence. Currently, after 12 months of follow-up, the patient is asymptomatic and disease free. CONCLUSION: Surgery is the gold standard for treatment of retroperitoneal liposarcomas, well differentiated retroperitoneal liposarcomas, that have a minimal metastatic potential. It is preferable to place a ureteral stent before surgery for minimizing the risk of intraoperative lesions of ureters. Symptoms in lower extremities, such as swelling, redness and others, that are due to compression in the retroperitoneum by giant tumours, can disappear after their surgical removal. PMID- 21822200 TI - Association between lipoprotein(a) and oxygen reactive metabolite in asymptomatic subjects. AB - INTRODUCTION: Lipoprotein(a) [Lp(a)] is generally considered a risk factor for cardiovascular disease (CVD). The coexistence of Lp(a) and oxidative status may be associated with the pathophysiology of the Lp(a)-CVD linkage. OBJECTIVES: The aim of the present study was to investigate the correlation between Lp(a) and oxidative status using the diacron Reactive Oxygen Metabolite (d-ROM) test as an oxidative stress-related marker in asymptomatic subjects. PATIENTS AND METHODS: The serum levels of Lp(a) and d-ROM were measured in 322 subjects (male/female 138/184; mean age 58.5 years) in addition to body mass index, blood pressure, glycemia, and lipid profile. RESULTS: The median levels of Lp(a) were 14.6 mg/dl (interquartile range 6.7-30.3) and the mean levels of d-ROM were 332 +/- 67 U. Carr. A simple linear regression analysis showed that the d-ROM level was significantly and positively correlated with Lp(a) (correlation coefficient = 0.22, P <0.01). Multivariate-adjusted analyses confirmed this weak but significant correlation, independent of confounding variables. This correlation appeared to be relatively stronger in men than in women. CONCLUSIONS: A positive correlation between Lp(a) and oxidative status, as assessed by d-ROM, in this population may be partially associated with the Lp(a)-CVD relationship. PMID- 21822201 TI - Tumor-infiltrating neutrophils in pancreatic neoplasia. AB - The interaction between tumor cells and inflammatory cells has an important role in cancer initiation and progression; however, this interaction has not been systematically investigated in pancreatic neoplasia. In this study, the presence of tumor-infiltrating neutrophils within and/or adjacent to neoplastic cells was investigated in pancreatic neoplasms. Areas with >10 tumor-infiltrating neutrophils/100 epithelial cells were arbitrarily classified as positive. Those with 11-15 tumor-infiltrating neutrophils were considered 'borderline' while those with >15 tumor-infiltrating neutrophils were considered 'significant'. Among 363 invasive ductal carcinomas, 15 showed significant tumor-infiltrating neutrophils (8 were micropapillary carcinomas and 7 were undifferentiated carcinomas). Of 19 mucinous cystic neoplasms with a carcinomatous high-grade papillary component, 11 showed significant tumor-infiltrating neutrophils (mean, 25; range, 14-63 tumor-infiltrating neutrophils). Among intraductal papillary mucinous neoplasms, significant tumor-infiltrating neutrophils were identified in 4/16 pancreatobiliary type, but were uncommon in other types (1/11 oncocytic and 1/23 intestinal types had borderline tumor-infiltrating neutrophils, and 0/10 gastric type had tumor-infiltrating neutrophils). Non-carcinomatous (low-grade and non-papillary) components of these neoplasms did not have tumor-infiltrating neutrophils. Tumor-infiltrating neutrophils were not striking in neuroendocrine tumors (40), serous cystadenomas (18), acinar cell carcinomas (9) or solid pseudopapillary neoplasms (8). In conclusion, significant tumor-infiltrating neutrophils are uncommon in pancreatic ductal adenocarcinoma, and when they occur it is typically in the micropapillary and undifferentiated types with a known poor prognosis. Among pre-invasive neoplasia, tumor-infiltrating neutrophils show a predilection for papillary in-situ carcinomas of mucinous cystic neoplasms, or less commonly, pancreatobiliary-type intraductal papillary mucinous neoplasms (both of which express cell surface-associated mucin 1 (MUC1)). MUC1 expression by these tumors may have biologic implications, considering its recently established relationship with inflammatory cells in carcinogenesis, and the differential expression of mucins in pancreatic neoplasia. Larger studies are needed to investigate the association between tumor-infiltrating neutrophils and pancreatic neoplasms and their role in their clinical behavior. PMID- 21822202 TI - Retrograde venous invasion in renal cell carcinoma: a complication of sinus vein and main renal vein invasion. AB - Renal cell carcinoma, especially clear cell, gains access to the venous system as the initial route of extrarenal spread. Intravenous growth can involve extrarenal veins or renal veins in other portions of the kidney, referred to herein as retrograde venous invasion. This study investigates the incidence and defines the pathological features of retrograde venous invasion. Retrograde venous invasion is defined as rounded nodules of tumor separated from the primary tumor and in a location that conforms to the venous outflow. Nine cases of retrograde venous invasion were identified in a series of 115 renal cell carcinomas (8%). Two blocks from each case were stained with elastic van Gieson, Masson trichrome, CD31 and desmin to evaluate intravenous involvement. All cases were staged using the 2010 TNM staging schema. The tumors ranged in size from 4.2 to 17 cm. All cases showed sinus vein and main renal vein invasion (pT3a); three cases involved the vena cava (pT3b). Direct continuity between the primary tumor and tumor in the main renal vein was grossly evident in every case. Involved sinus veins could be followed retrograde to the cortex between renal pyramids with tumor nodules arrayed along the pyramid-cortex interface. Histologically, the involved parenchymal veins lacked a smooth muscle media and elastica. CD31 demonstrated an endothelial cell lining around many nodules. As intravenous nodules enlarged endothelium was lost, extra-venous invasion occurred and nodules coalesced and merged with the primary tumor. In conclusion, retrograde venous invasion occurred only with main renal vein involvement. Gross evaluation allowed detection in every case. Histological confirmation of intravenous nature is challenging due to the absence of smooth muscle in parenchymal veins. As retrograde growth becomes extensive nodules coalesce and merge with the primary tumor and may be included in measurement of primary tumor size if this process is unrecognized. PMID- 21822203 TI - Clinicopathological features of senile systemic amyloidosis: an ante- and post mortem study. AB - Senile systemic amyloidosis is a common age-related amyloidosis that involves accumulation of wild-type transthyretin, with cardiac dysfunction being a predominant result. The importance of obtaining an accurate diagnosis of senile systemic amyloidosis has been increasingly recognized, so that novel treatments are being developed. However, the clinicopathological features of senile systemic amyloidosis remain to be completely understood. Here, we evaluated cardiac specimens from 181 consecutive post-mortem cases older than 40 years, including 6 cases of senile systemic amyloidosis, and 5 cases of familial amyloidotic polyneuropathy, which is a hereditary systemic amyloidosis caused by mutant forms of transthyretin. Furthermore, we studied ante-mortem clinicopathological findings of 11 senile systemic amyloidosis cases, in which 9 cases underwent gastrointestinal tract biopsy and/or subcutaneous tissue biopsy, at Kumamoto University Hospital. Of the autopsied cases of elderly Japanese (older than 80 years), 12% had senile systemic amyloidosis, with the percentage increasing with age. The occurrence of senile systemic amyloidosis in elderly Japanese patients was lower than that in previous reports, which suggests that a genetic background and/or environmental factor(s) may have important roles in the occurrence of senile systemic amyloidosis. Transthyretin amyloid deposits in familial amyloidotic polyneuropathy cases developed mainly in the pericardium and the surrounding muscle fascicles, whereas in cases with senile systemic amyloidosis the transthyretin amyloid deposits had a patchy plaque-like shape and developed mainly inside the ventricular wall. Biopsies from senile systemic amyloidosis patients evidenced amyloid deposits in 44% (4/9) of gastrointestinal tract and subcutaneous tissue samples combined. As myocardial biopsy may be dangerous for elderly people, the use of a combination of gastrointestinal tract and subcutaneous tissue biopsies may make diagnosis of senile systemic amyloidosis easier. PMID- 21822204 TI - Pediatric B-lymphoblastic leukemia with RUNX1 amplification: clinicopathologic study of eight cases. AB - B-lymphoblastic leukemia (a.k.a. precursor B-cell acute lymphoblastic leukemia) is a heterogeneous disease at the clinical, morphologic, immunophenotypic and genetic levels. Recurrent genetic abnormalities in B-lymphoblastic leukemia with prognostic significance are well known and specifically delineated in the WHO 2008 classification (eg hyperdiploidy, t(9;22)(q34;q11.2); BCR-ABL1, t(12;21)(p13;q22); ETV6-RUNX1). In recent years, a subgroup of B-lymphoblastic leukemia with the recurring genetic alteration of RUNX1 amplification has emerged. This subgroup has a low incidence (2%) and an increased risk of relapse and overall worse outcome. Given these apparently distinctive clinicopathologic features, we evaluated eight cases of pediatric B-lymphoblastic leukemia with RUNX1 amplification treated on Children's Oncology Group protocols from 2000 2009. Compared with 25 consecutive B-lymphoblastic leukemia cases without RUNX1 amplification, we identified a trend toward male predominance (P-value=0.082) and low white blood cell count at presentation (P-value=0.081) in B-lymphoblastic leukemia with RUNX1 amplification. Older age at presentation was significant (median age 9.5 years, P-value=0.006). There was no significant difference in the presence of central nervous system disease, CD20 or myeloid antigen positivity on the blasts or percent circulating blasts in B-lymphoblastic leukemia with RUNX1 amplification versus other B-lymphoblastic leukemia types. Seven of eight patients (88%) are alive and free of disease at the time of last checkup (mean 50 months, range 14-116 months). Although we see a relatively good outcome in our small cohort of patients, recent findings from the Children's Oncology Group on a large set of patients suggests otherwise that these patients may have an inferior outcome compared with patients with B-lymphoblastic leukemia without RUNX1 amplification. Long-term follow-up in larger cohorts including minimal residual disease correlation is required. PMID- 21822205 TI - Pleuroparenchymal fibroelastosis in patients with pulmonary disease secondary to bone marrow transplantation. AB - This study presents four patients who underwent bone marrow transplantation and subsequently developed pleuroparenchymal fibroelastosis, hitherto reported as an idiopathic condition. All presented clinically with pneumothorax and subpleural fibrosis on high-resolution computed tomography. In addition to the expected obliterative bronchiolitis, histopathology showed coexistent subpleural changes, and the relationship of pathology in multiple anatomic compartments in post bone marrow transplantation pulmonary disease is discussed. PMID- 21822206 TI - Angiomatoid fibrous histiocytoma: unusual sites and unusual morphology. AB - Angiomatoid fibrous histiocytoma is a soft tissue neoplasm of low malignant potential, typically occurring in the superficial soft tissues of the extremities in children and young adults. Occurrence outside somatic soft tissues is most uncommon. This report describes eight such cases, involving the lung (three cases), mediastinum (one case), vulva (two cases), retroperitoneum (one case) and ovary (one case), with the latter three locations being hitherto unreported sites of occurrence. Patients had a median age of 48 years, and presented with symptoms related to the mass lesion (five cases) or were incidentally found to harbor a tumor (three cases). Besides the typical histological features such as an outer shell of lymphoid tissue, multinodular aggregates of dendritic-like tumor cells, blood-filled spaces and abundant admixed plasma cells, unusual features were found focally in some cases, including clear cells, rhabdomyoblast-like cells, pulmonary edema-like pattern and tumor cell cords lying in a myxoid stroma. Immunoreactivity for the epithelial membrane antigen, desmin, smooth-muscle actin, CD68 and CD99 was found in 100, 63, 43, 100 and 100% of cases, respectively. Molecular studies provided support for the diagnosis in all seven tested cases-EWS gene translocation in six cases (partner gene being CREB1 in three and ATF1 in two in which information was available) and FUS gene translocation in one case. Comparison of the reported cases of extrasomatic angiomatoid fibrous histiocytoma with their somatic soft tissue counterparts showed a number of differences: higher mean age, slight male predominance (particularly for bone lesions), larger tumors, higher frequency of systemic symptoms, higher recurrence rate, myxoid change being more common and a much higher frequency of EWS/ATF1 gene fusion. PMID- 21822207 TI - Gray zone lymphoma: chromosomal aberrations with immunophenotypic and clinical correlations. AB - The term gray zone lymphoma has been applied to tumors that demonstrate transitional morphologic and immunophenotypic features between classical Hodgkin's lymphoma and diffuse large B-cell lymphoma, especially primary mediastinal large B-cell lymphoma. Histopathological and genetic data are limited for these unusual cases. We analyzed cases of gray zone lymphoma (n=27), mediastinal composite lymphoma (n=3) and mediastinal synchronous/metachronous lymphoma (n=3) by morphology, immunophenotyping and fluorescence in situ hybridization. Mediastinal involvement was assured in 24/33 patients (73%). The patient cohort showed a male predominance (M:F ratio; 20:13) and a median age of 32 years (range, 16-91 years). Patients with mediastinal disease were significantly younger (median age: 29.5 years) than patients presenting without evident mediastinal disease (median age: 55 years). Gains including amplifications in 2p16.1 (REL/BCL11A locus) were observed in 33% of all patients, whereas alterations affecting the JAK2/PDL2 locus in 9p24.1 were present in 55%. Further studies revealed rearrangement of the CIITA locus at 16p13.13 in 8/30 cases (27%) and 7/26 cases (27%) demonstrated gains of 8q24 (MYC). Genetic aberrations involving 2p16.1, 9p24.1 and 8q24 showed a higher incidence in cases with evident mediastinal involvement. However, this was not statistically significant when compared with cases without known mediastinal involvement. Twelve of the 27 cases of gray zone lymphoma were morphologically more reminiscent of classical Hodgkin's lymphoma, whereas the other gray zone lymphomas presented with morphological features more closely resembling large B cell lymphoma. Both morphological groups of gray zone lymphoma were similarly positive for Cyclin E (75 and 93%) and p63 (50 and 53%, respectively) expression. These findings further support a close relationship between gray zone lymphoma, classical Hodgkin's lymphoma and primary mediastinal large B-cell lymphoma, and suggest that some cases of gray zone lymphoma without mediastinal disease may share similar genetic alterations. PMID- 21822208 TI - Morphoproteomics demonstrates activation of mammalian target of rapamycin pathway in papillary thyroid carcinomas with nuclear translocation of MTOR in aggressive histological variants. AB - We used morphoproteomics to investigate mammalian target of rapamycin (MTOR) signaling pathway in papillary thyroid carcinomas and correlated the results with clinicopathological parameters. Archival paraffin-embedded tissue of papillary thyroid carcinomas was obtained from 30 patients, including 15 classical type and 8 follicular, 4 tall-cell, 1 columnar-cell, 1 diffuse sclerosing and 1 cribriform variants. Immunohistochemical stains were performed for three phosphorylated (p) protein analytes: p-MTOR (Ser2448), p-Akt (Ser473) and p-p70S6K (Thr389). Chromogenic signals and subcellular compartmentalization (nuclear, cytoplasmic and plasmalemmal) were evaluated. Clinicopathological parameters were reviewed. Immunoreactivities for p-MTOR, p-Akt and p-p70S6K were observed in all papillary thyroid carcinomas. In addition to an expression of p-MTOR in cytoplasmic location, nuclear translocation of p-MTOR with variable loss of plasmalemmal expression, and with concomitant nuclear expression of p-Akt, was also identified in all tall-cell, columnar-cell and diffuse sclerosing variants of papillary thyroid carcinoma. There were no significant differences in the clinicopathological parameters, including tumor size, extrathyroidal extension, angioinvasion and nodal metastases between the groups with and without nuclear expression of p-MTOR (P>0.05). The expressions of p-MTOR in cytoplasmic and/or plasmalemmal locations with the concomitant immunoreactivity for p-p70S6K in all papillary thyroid carcinomas indicate the activation of MTOR complex 1 pathway. The nuclear translocation of p-MTOR evidences the activation of MTOR complex 2 and is identified only in the known aggressive histological variants of papillary thyroid carcinoma, including tall-cell, columnar-cell and diffuse sclerosing variants. Thus, these results suggest the constitutive activation of MTOR signaling pathway in papillary thyroid carcinomas and provide a new insight of biogenetic basis for the aggressive histological variants of papillary thyroid carcinoma. The pattern of expression of p-MTOR in papillary thyroid carcinomas may serve as a diagnostic/prognostic marker and a potential therapeutic target. PMID- 21822209 TI - Therapy: selective oxycution? PMID- 21822210 TI - Metastasis: opposing forces in invasion. PMID- 21822211 TI - Chromosomal instability: a lack of new origins drives fragility. PMID- 21822213 TI - FBF represses the Cip/Kip cell-cycle inhibitor CKI-2 to promote self-renewal of germline stem cells in C. elegans. AB - Although the decision between stem cell self-renewal and differentiation has been linked to cell-cycle modifications, our understanding of cell-cycle regulation in stem cells is very limited. Here, we report that FBF/Pumilio, a conserved RNA binding protein, promotes self-renewal of germline stem cells by repressing CKI 2(Cip/Kip), a Cyclin E/Cdk2 inhibitor. We have previously shown that repression of CYE-1 (Cyclin E) by another RNA-binding protein, GLD-1/Quaking, promotes germ cell differentiation. Together, these findings suggest that a post transcriptional regulatory circuit involving FBF and GLD-1 controls the self renewal versus differentiation decision in the germline by promoting high CYE 1/CDK-2 activity in stem cells, and inhibiting CYE-1/CDK-2 activity in differentiating cells. PMID- 21822212 TI - MicroRNA regulation by RNA-binding proteins and its implications for cancer. AB - Non-protein-coding transcripts have been conserved throughout evolution, indicating that crucial functions exist for these RNAs. For example, microRNAs (miRNAs) have been found to modulate most cellular processes. The protein classes of RNA-binding proteins include essential regulators of miRNA biogenesis, turnover and activity. RNA-RNA and protein-RNA interactions are essential for post-transcriptional regulation in normal development and may be deregulated in disease. In reviewing emerging concepts of the interplay between miRNAs and RNA binding proteins, we highlight the implications of these complex layers of regulation in cancer initiation and progression. PMID- 21822214 TI - The B-cell antigen receptor signals through a preformed transducer module of SLP65 and CIN85. AB - Spleen tyrosine kinase Syk and its substrate SLP65 (also called BLNK) are proximal signal transducer elements of the B-cell antigen receptor (BCR). Yet, our understanding of signal initiation and processing is limited owing to the incomplete list of SLP65 interaction partners and our ignorance of their association kinetics. We have now determined and quantified the in vivo interactomes of SLP65 in resting and stimulated B cells by mass spectrometry. SLP65 orchestrated a complex signal network of about 30 proteins that was predominantly based on dynamic interactions. However, a stimulation-independent and constant association of SLP65 with the Cbl-interacting protein of 85 kDa (CIN85) was requisite for SLP65 phosphorylation and its inducible plasma membrane translocation. In the absence of a steady SLP65/CIN85 complex, BCR-induced Ca(2+) and NF-kappaB responses were abrogated. Finally, live cell imaging and co immunoprecipitation experiments further confirmed that both SLP65 and CIN85 are key components of the BCR-associated primary transducer module required for the onset and progression phases of BCR signal transduction. PMID- 21822215 TI - The tumour antigen PRAME is a subunit of a Cul2 ubiquitin ligase and associates with active NFY promoters. AB - The human tumour antigen PRAME (preferentially expressed antigen of melanoma) is frequently overexpressed in tumours. High PRAME levels correlate with poor clinical outcome of several cancers, but the mechanisms by which PRAME could be involved in tumourigenesis remain largely elusive. We applied protein-complex purification strategies and identified PRAME as a substrate recognition subunit of a Cullin2-based E3 ubiquitin ligase. PRAME can be recruited to DNA in vitro, and genome-wide chromatin immunoprecipitation experiments revealed that PRAME is specifically enriched at transcriptionally active promoters that are also bound by NFY and at enhancers. Our results are consistent with a role for the PRAME ubiquitin ligase complex in NFY-mediated transcriptional regulation. PMID- 21822216 TI - Nucleophosmin deposition during mRNA 3' end processing influences poly(A) tail length. AB - During polyadenylation, the multi-functional protein nucleophosmin (NPM1) is deposited onto all cellular mRNAs analysed to date. Premature termination of poly(A) tail synthesis in the presence of cordycepin abrogates deposition of the protein onto the mRNA, indicating natural termination of poly(A) addition is required for NPM1 binding. NPM1 appears to be a bona fide member of the complex involved in 3' end processing as it is associated with the AAUAAA-binding CPSF factor and can be co-immunoprecipitated with other polyadenylation factors. Furthermore, reduction in the levels of NPM1 results in hyperadenylation of mRNAs, consistent with alterations in poly(A) tail chain termination. Finally, knockdown of NPM1 results in retention of poly(A)(+) RNAs in the cell nucleus, indicating that NPM1 influences mRNA export. Collectively, these data suggest that NPM1 has an important role in poly(A) tail length determination and may help network 3' end processing with other aspects of nuclear mRNA maturation. PMID- 21822220 TI - Pushing the envelope. PMID- 21822217 TI - Ribosome biogenesis factors bind a nuclear envelope SUN domain protein to cluster yeast telomeres. AB - Two interacting ribosome biogenesis factors, Ebp2 and Rrs1, associate with Mps3, an essential inner nuclear membrane protein. Both are found in foci along the nuclear periphery, like Mps3, as well as in the nucleolus. Temperature-sensitive ebp2 and rrs1 mutations that compromise ribosome biogenesis displace the mutant proteins from the nuclear rim and lead to a distorted nuclear shape. Mps3 is known to contribute to the S-phase anchoring of telomeres through its interaction with the silent information regulator Sir4 and yKu. Intriguingly, we find that both Ebp2 and Rrs1 interact with the C-terminal domain of Sir4, and that conditional inactivation of either ebp2 or rrs1 interferes with both the clustering and silencing of yeast telomeres, while telomere tethering to the nuclear periphery remains intact. Importantly, expression of an Ebp2-Mps3 fusion protein in the ebp2 mutant suppresses the defect in telomere clustering, but not its defects in growth or ribosome biogenesis. Our results suggest that the ribosome biogenesis factors Ebp2 and Rrs1 cooperate with Mps3 to mediate telomere clustering, but not telomere tethering, by binding Sir4. PMID- 21822218 TI - The pore structure and gating mechanism of K2P channels. AB - Two-pore domain (K2P) potassium channels are important regulators of cellular electrical excitability. However, the structure of these channels and their gating mechanism, in particular the role of the bundle-crossing gate, are not well understood. Here, we report that quaternary ammonium (QA) ions bind with high-affinity deep within the pore of TREK-1 and have free access to their binding site before channel activation by intracellular pH or pressure. This demonstrates that, unlike most other K(+) channels, the bundle-crossing gate in this K2P channel is constitutively open. Furthermore, we used QA ions to probe the pore structure of TREK-1 by systematic scanning mutagenesis and comparison of these results with different possible structural models. This revealed that the TREK-1 pore most closely resembles the open-state structure of KvAP. We also found that mutations close to the selectivity filter and the nature of the permeant ion profoundly influence TREK-1 channel gating. These results demonstrate that the primary activation mechanisms in TREK-1 reside close to, or within the selectivity filter and do not involve gating at the cytoplasmic bundle crossing. PMID- 21822221 TI - E. coli crisis opens door for Alexion drug trial. PMID- 21822224 TI - US court bolsters biotech patent protection. PMID- 21822225 TI - FDA approves first cell therapy for wrinkle-free visage. PMID- 21822226 TI - FDA panel votes to pull Avastin in breast cancer, again. PMID- 21822231 TI - Novel schemes skirt NICE barrier. PMID- 21822232 TI - Supreme Court ruling prompts universities to tighten employee contracts. PMID- 21822233 TI - Newsmaker: Lycera. PMID- 21822235 TI - Move over ZFNs. PMID- 21822236 TI - IMI moves forward. PMID- 21822237 TI - Biosimilars-why terminology matters. PMID- 21822239 TI - Synergies between synthetic biology and metabolic engineering. PMID- 21822240 TI - Knockout rats generated by embryo microinjection of TALENs. PMID- 21822242 TI - Heritable gene targeting in zebrafish using customized TALENs. PMID- 21822241 TI - Targeted gene disruption in somatic zebrafish cells using engineered TALENs. PMID- 21822243 TI - Finding the niche for human somatic cell nuclear transfer. PMID- 21822244 TI - Transgenic salmon: a final leap to the grocery shelf? PMID- 21822246 TI - Recent patent applications in microbial diagnostics. PMID- 21822245 TI - Human DNA patent renewals on the decline. PMID- 21822247 TI - An infrared fluorescent protein for deeper imaging. PMID- 21822248 TI - Linkage illuminates a complex genome. PMID- 21822249 TI - First CHO genome. PMID- 21822252 TI - Ferri-liposomes as an MRI-visible drug-delivery system for targeting tumours and their microenvironment. AB - The tumour microenvironment regulates tumour progression and the spread of cancer in the body. Targeting the stromal cells that surround cancer cells could, therefore, improve the effectiveness of existing cancer treatments. Here, we show that magnetic nanoparticle clusters encapsulated inside a liposome can, under the influence of an external magnet, target both the tumour and its microenvironment. We use the outstanding T2 contrast properties (r2=573-1,286 s(-1) mM(-1)) of these ferri-liposomes, which are ~95 nm in diameter, to non-invasively monitor drug delivery in vivo. We also visualize the targeting of the tumour microenvironment by the drug-loaded ferri-liposomes and the uptake of a model probe by cells. Furthermore, we used the ferri-liposomes to deliver a cathepsin protease inhibitor to a mammary tumour and its microenvironment in a mouse, which substantially reduced the size of the tumour compared with systemic delivery of the same drug. PMID- 21822253 TI - Tunable metallic-like conductivity in microbial nanowire networks. AB - Electronic nanostructures made from natural amino acids are attractive because of their relatively low cost, facile processing and absence of toxicity. However, most materials derived from natural amino acids are electronically insulating. Here, we report metallic-like conductivity in films of the bacterium Geobacter sulfurreducens and also in pilin nanofilaments (known as microbial nanowires) extracted from these bacteria. These materials have electronic conductivities of ~5 mS cm(-1), which are comparable to those of synthetic metallic nanostructures. They can also conduct over distances on the centimetre scale, which is thousands of times the size of a bacterium. Moreover, the conductivity of the biofilm can be tuned by regulating gene expression, and also by varying the gate voltage in a transistor configuration. The conductivity of the nanofilaments has a temperature dependence similar to that of a disordered metal, and the conductivity could be increased by processing. PMID- 21822254 TI - A resource of vectors and ES cells for targeted deletion of microRNAs in mice. AB - The 21-23 nucleotide, single-stranded RNAs classified as microRNAs (miRNA) perform fundamental roles in diverse cellular and developmental processes. In contrast to the situation for protein-coding genes, no public resource of miRNA mouse mutant alleles exists. Here we describe a collection of 428 miRNA targeting vectors covering 476 of the miRNA genes annotated in the miRBase registry. Using these vectors, we generated a library of highly germline-transmissible C57BL/6N mouse embryonic stem (ES) cell clones harboring targeted deletions for 392 miRNA genes. For most of these targeted clones, chimerism and germline transmission can be scored through a coat color marker. The targeted alleles have been designed to be adaptable research tools that can be efficiently altered by recombinase mediated cassette exchange to create reporter, conditional and other allelic variants. This miRNA knockout (mirKO) resource can be searched electronically and is available from ES cell repositories for distribution to the scientific community. PMID- 21822255 TI - An unbiased genome-wide analysis of zinc-finger nuclease specificity. AB - Zinc-finger nucleases (ZFNs) allow gene editing in live cells by inducing a targeted DNA double-strand break (DSB) at a specific genomic locus. However, strategies for characterizing the genome-wide specificity of ZFNs remain limited. We show that nonhomologous end-joining captures integrase-defective lentiviral vectors at DSBs, tagging these transient events. Genome-wide integration site analysis mapped the actual in vivo cleavage activity of four ZFN pairs targeting CCR5 or IL2RG. Ranking loci with repeatedly detectable nuclease activity by deep sequencing allowed us to monitor the degree of ZFN specificity in vivo at these positions. Cleavage required binding of ZFNs in specific spatial arrangements on DNA bearing high homology to the intended target site and only tolerated mismatches at individual positions of the ZFN binding sites. Whereas the consensus binding sequence derived in vivo closely matched that obtained in biochemical experiments, the ranking of in vivo cleavage sites could not be predicted in silico. Comprehensive mapping of ZFN activity in vivo will facilitate the broad application of these reagents in translational research. PMID- 21822256 TI - Quantitative fluorescence imaging of protein diffusion and interaction in living cells. AB - Diffusion processes and local dynamic equilibria inside cells lead to nonuniform spatial distributions of molecules, which are essential for processes such as nuclear organization and signaling in cell division, differentiation and migration. To understand these mechanisms, spatially resolved quantitative measurements of protein abundance, mobilities and interactions are needed, but current methods have limited capabilities to study dynamic parameters. Here we describe a microscope based on light-sheet illumination that allows massively parallel fluorescence correlation spectroscopy (FCS) measurements and use it to visualize the diffusion and interactions of proteins in mammalian cells and in isolated fly tissue. Imaging the mobility of heterochromatin protein HP1alpha (ref. 4) in cell nuclei we could provide high-resolution diffusion maps that reveal euchromatin areas with heterochromatin-like HP1alpha-chromatin interactions. We expect that FCS imaging will become a useful method for the precise characterization of cellular reaction-diffusion processes. PMID- 21822257 TI - The inducible kinase IKKi is required for IL-17-dependent signaling associated with neutrophilia and pulmonary inflammation. AB - Interleukin 17 (IL-17) is critical in the pathogenesis of inflammatory and autoimmune diseases. Here we report that Act1, the key adaptor for the IL-17 receptor (IL-7R), formed a complex with the inducible kinase IKKi after stimulation with IL-17. Through the use of IKKi-deficient mice, we found that IKKi was required for IL-17-induced expression of genes encoding inflammatory molecules in primary airway epithelial cells, neutrophilia and pulmonary inflammation. IKKi deficiency abolished IL-17-induced formation of the complex of Act1 and the adaptors TRAF2 and TRAF5, activation of mitogen-activated protein kinases (MAPKs) and mRNA stability, whereas the Act1-TRAF6-transcription factor NF-kappaB axis was retained. IKKi was required for IL-17-induced phosphorylation of Act1 on Ser311, adjacent to a putative TRAF-binding motif. Substitution of the serine at position 311 with alanine impaired the IL-17-mediated Act1-TRAF2-TRAF5 interaction and gene expression. Thus, IKKi is a kinase newly identified as modulating IL-17 signaling through its effect on Act1 phosphorylation and consequent function. PMID- 21822258 TI - Treatment with IL-17 prolongs the half-life of chemokine CXCL1 mRNA via the adaptor TRAF5 and the splicing-regulatory factor SF2 (ASF). AB - Interleukin 17 (IL-17) promotes the expression of chemokines and cytokines via the induction of gene transcription and post-transcriptional stabilization of mRNA. We show here that IL-17 enhanced the stability of chemokine CXCL1 mRNA and other mRNAs through a pathway that involved the adaptor Act1, the adaptors TRAF2 or TRAF5 and the splicing factor SF2 (also known as alternative splicing factor (ASF)). TRAF2 and TRAF5 were necessary for IL-17 to signal the stabilization of CXCL1 mRNA. Furthermore, IL-17 promoted the formation of complexes of TRAF5 TRAF2, Act1 and SF2 (ASF). Overexpression of SF2 (ASF) shortened the half-life of CXCL1 mRNA, whereas depletion of SF2 (ASF) prolonged it. SF2 (ASF) bound chemokine mRNA in unstimulated cells, whereas the SF2 (ASF)-mRNA interaction was much lower after stimulation with IL-17. Our findings define an IL-17-induced signaling pathway that links to the stabilization of selected mRNA species through Act1, TRAF2-TRAF5 and the RNA-binding protein SF2 (ASF). PMID- 21822259 TI - Self-assembly of a sulphur-terminated graphene nanoribbon within a single-walled carbon nanotube. AB - The ability to tune the properties of graphene nanoribbons (GNRs) through modification of the nanoribbon's width and edge structure widens the potential applications of graphene in electronic devices. Although assembly of GNRs has been recently possible, current methods suffer from limited control of their atomic structure, or require the careful organization of precursors on atomically flat surfaces under ultra-high vacuum conditions. Here we demonstrate that a GNR can self-assemble from a random mixture of molecular precursors within a single walled carbon nanotube, which ensures propagation of the nanoribbon in one dimension and determines its width. The sulphur-terminated dangling bonds of the GNR make these otherwise unstable nanoribbons thermodynamically viable over other forms of carbon. Electron microscopy reveals elliptical distortion of the nanotube, as well as helical twist and screw-like motion of the nanoribbon. These effects suggest novel ways of controlling the properties of these nanomaterials, such as the electronic band gap and the concentration of charge carriers. PMID- 21822260 TI - Magnetic manipulation of self-assembled colloidal asters. AB - Self-assembled materials must actively consume energy and remain out of equilibrium to support structural complexity and functional diversity. Here we show that a magnetic colloidal suspension confined at the interface between two immiscible liquids and energized by an alternating magnetic field dynamically self-assembles into localized asters and arrays of asters, which exhibit locomotion and shape change. By controlling a small external magnetic field applied parallel to the interface, we show that asters can capture, transport, and position target microparticles. The ability to manipulate colloidal structures is crucial for the further development of self-assembled microrobots. PMID- 21822261 TI - Programming magnetic anisotropy in polymeric microactuators. AB - Polymeric microcomponents are widely used in microelectromechanical systems (MEMS) and lab-on-a-chip devices, but they suffer from the lack of complex motion, effective addressability and precise shape control. To address these needs, we fabricated polymeric nanocomposite microactuators driven by programmable heterogeneous magnetic anisotropy. Spatially modulated photopatterning was applied in a shape-independent manner to microactuator components by successive confinement of self-assembled magnetic nanoparticles in a fixed polymer matrix. By freely programming the rotational axis of each component, we demonstrate that the polymeric microactuators can undergo predesigned, complex two- and three-dimensional motion. PMID- 21822262 TI - Highly monodisperse core-shell particles created by solid-state reactions. AB - The size distribution of particles, which is essential for many properties of nanomaterials, is equally important for the mechanical behaviour of the class of alloys whose strength derives from a dispersion of nanoscale precipitates. However, particle size distributions formed by solid-state precipitation are generally not well controlled. Here we demonstrate, through the example of core shell precipitates in Al-Sc-Li alloys, an approach to forming highly monodisperse particle size distributions by simple solid-state reactions. The approach involves the use of a two-step heat treatment, whereby the core formed at high temperature provides a template for growth of the shell at lower temperature. If the core is allowed to grow to a sufficient size, the shell develops in a 'size focusing' regime, where smaller particles grow faster than larger ones. These results suggest strategies for manipulating precipitate size distributions in similar systems through simple variations in thermal treatments. PMID- 21822263 TI - Co3O4 nanocrystals on graphene as a synergistic catalyst for oxygen reduction reaction. AB - Catalysts for oxygen reduction and evolution reactions are at the heart of key renewable-energy technologies including fuel cells and water splitting. Despite tremendous efforts, developing oxygen electrode catalysts with high activity at low cost remains a great challenge. Here, we report a hybrid material consisting of Co3O4 nanocrystals grown on reduced graphene oxide as a high-performance bi functional catalyst for the oxygen reduction reaction (ORR) and oxygen evolution reaction (OER). Although Co3O4 or graphene oxide alone has little catalytic activity, their hybrid exhibits an unexpected, surprisingly high ORR activity that is further enhanced by nitrogen doping of graphene. The Co3O4/N-doped graphene hybrid exhibits similar catalytic activity but superior stability to Pt in alkaline solutions. The same hybrid is also highly active for OER, making it a high-performance non-precious metal-based bi-catalyst for both ORR and OER. The unusual catalytic activity arises from synergetic chemical coupling effects between Co3O4 and graphene. PMID- 21822264 TI - Inactivating mutations of the chromatin remodeling gene ARID2 in hepatocellular carcinoma. AB - Through exomic sequencing of ten hepatitis C virus (HCV)-associated hepatocellular carcinomas (HCC) and subsequent evaluation of additional affected individuals, we discovered novel inactivating mutations of ARID2 in four major subtypes of HCC (HCV-associated HCC, hepatitis B virus (HBV)-associated HCC, alcohol-associated HCC and HCC with no known etiology). Notably, 18.2% of individuals with HCV-associated HCC in the United States and Europe harbored ARID2 inactivation mutations, suggesting that ARID2 is a tumor suppressor gene that is relatively commonly mutated in this tumor subtype. PMID- 21822265 TI - The genome of the extremophile crucifer Thellungiella parvula. AB - Thellungiella parvula is related to Arabidopsis thaliana and is endemic to saline, resource-poor habitats, making it a model for the evolution of plant adaptation to extreme environments. Here we present the draft genome for this extremophile species. Exclusively by next generation sequencing, we obtained the de novo assembled genome in 1,496 gap-free contigs, closely approximating the estimated genome size of 140 Mb. We anchored these contigs to seven pseudo chromosomes without the use of maps. We show that short reads can be assembled to a near-complete chromosome level for a eukaryotic species lacking prior genetic information. The sequence identifies a number of tandem duplications that, by the nature of the duplicated genes, suggest a possible basis for T. parvula's extremophile lifestyle. Our results provide essential background for developing genomically influenced testable hypotheses for the evolution of environmental stress tolerance. PMID- 21822266 TI - Exome sequencing supports a de novo mutational paradigm for schizophrenia. AB - Despite its high heritability, a large fraction of individuals with schizophrenia do not have a family history of the disease (sporadic cases). Here we examined the possibility that rare de novo protein-altering mutations contribute to the genetic component of schizophrenia by sequencing the exomes of 53 sporadic cases, 22 unaffected controls and their parents. We identified 40 de novo mutations in 27 cases affecting 40 genes, including a potentially disruptive mutation in DGCR2, a gene located in the schizophrenia-predisposing 22q11.2 microdeletion region. A comparison to rare inherited variants indicated that the identified de novo mutations show a large excess of non-synonymous changes in schizophrenia cases, as well as a greater potential to affect protein structure and function. Our analyses suggest a major role for de novo mutations in schizophrenia as well as a large mutational target, which together provide a plausible explanation for the high global incidence and persistence of the disease. PMID- 21822269 TI - Harmonin inhibits presynaptic Cav1.3 Ca2+ channels in mouse inner hair cells. AB - Harmonin is a scaffolding protein that is required for normal mechanosensory function in hair cells. We found a presynaptic association of harmonin and Ca(v)1.3 Ca(2+) channels at the mouse inner hair cell synapse, which limits channel availability through a ubiquitin-dependent pathway. PMID- 21822268 TI - Frequent mutations of chromatin remodeling genes in transitional cell carcinoma of the bladder. AB - Transitional cell carcinoma (TCC) is the most common type of bladder cancer. Here we sequenced the exomes of nine individuals with TCC and screened all the somatically mutated genes in a prevalence set of 88 additional individuals with TCC with different tumor stages and grades. In our study, we discovered a variety of genes previously unknown to be mutated in TCC. Notably, we identified genetic aberrations of the chromatin remodeling genes (UTX, MLL-MLL3, CREBBP-EP300, NCOR1, ARID1A and CHD6) in 59% of our 97 subjects with TCC. Of these genes, we showed UTX to be altered substantially more frequently in tumors of low stages and grades, highlighting its potential role in the classification and diagnosis of bladder cancer. Our results provide an overview of the genetic basis of TCC and suggest that aberration of chromatin regulation might be a hallmark of bladder cancer. PMID- 21822271 TI - Anisotropic encoding of three-dimensional space by place cells and grid cells. AB - The subjective sense of space may result in part from the combined activity of place cells in the hippocampus and grid cells in posterior cortical regions such as the entorhinal cortex and pre- and parasubiculum. In horizontal planar environments, place cells provide focal positional information, whereas grid cells supply odometric (distance measuring) information. How these cells operate in three dimensions is unknown, even though the real world is three-dimensional. We investigated this issue in rats exploring two different kinds of apparatus: a climbing wall (the 'pegboard') and a helix. Place and grid cell firing fields had normal horizontal characteristics but were elongated vertically, with grid fields forming stripes. It seems that grid cell odometry (and by implication path integration) is impaired or absent in the vertical domain, at least when the rat itself remains horizontal. These findings suggest that the mammalian encoding of three-dimensional space is anisotropic. PMID- 21822270 TI - Hippocampal CA1 pyramidal cells form functionally distinct sublayers. AB - Hippocampal CA1 pyramidal neurons have frequently been regarded as a homogeneous cell population in biophysical, pharmacological and modeling studies. We found robust differences between pyramidal neurons residing in the deep and superficial CA1 sublayers in rats. Compared with their superficial peers, deep pyramidal cells fired at higher rates, burst more frequently, were more likely to have place fields and were more strongly modulated by slow oscillations of sleep. Both deep and superficial pyramidal cells fired preferentially at the trough of theta oscillations during maze exploration, whereas deep pyramidal cells shifted their preferred phase of firing to the peak of theta during rapid eye movement (REM) sleep. Furthermore, although the majority of REM theta phase-shifting cells fired at the ascending phase of gamma oscillations during waking, nonshifting cells preferred the trough. Thus, CA1 pyramidal cells in adjacent sublayers can address their targets jointly or differentially, depending on brain states. PMID- 21822267 TI - Germline mutations in RAD51D confer susceptibility to ovarian cancer. AB - Recently, RAD51C mutations were identified in families with breast and ovarian cancer. This observation prompted us to investigate the role of RAD51D in cancer susceptibility. We identified eight inactivating RAD51D mutations in unrelated individuals from 911 breast-ovarian cancer families compared with one inactivating mutation identified in 1,060 controls (P = 0.01). The association found here was principally with ovarian cancer, with three mutations identified in the 59 pedigrees with three or more individuals with ovarian cancer (P = 0.0005). The relative risk of ovarian cancer for RAD51D mutation carriers was estimated to be 6.30 (95% CI 2.86-13.85, P = 4.8 * 10(-6)). By contrast, we estimated the relative risk of breast cancer to be 1.32 (95% CI 0.59-2.96, P = 0.50). These data indicate that RAD51D mutation testing may have clinical utility in individuals with ovarian cancer and their families. Moreover, we show that cells deficient in RAD51D are sensitive to treatment with a PARP inhibitor, suggesting a possible therapeutic approach for cancers arising in RAD51D mutation carriers. PMID- 21822272 TI - TopFIND, a knowledgebase linking protein termini with function. PMID- 21822273 TI - Revealing off-target cleavage specificities of zinc-finger nucleases by in vitro selection. AB - Engineered zinc-finger nucleases (ZFNs) are promising tools for genome manipulation, and determining off-target cleavage sites of these enzymes is of great interest. We developed an in vitro selection method that interrogates 10(11) DNA sequences for cleavage by active, dimeric ZFNs. The method revealed hundreds of thousands of DNA sequences, some present in the human genome, that can be cleaved in vitro by two ZFNs: CCR5-224 and VF2468, which target the endogenous human CCR5 and VEGFA genes, respectively. Analysis of identified sites in one cultured human cell line revealed CCR5-224-induced changes at nine off target loci, though this remains to be tested in other relevant cell types. Similarly, we observed 31 off-target sites cleaved by VF2468 in cultured human cells. Our findings establish an energy compensation model of ZFN specificity in which excess binding energy contributes to off-target ZFN cleavage and suggest strategies for the improvement of future ZFN design. PMID- 21822274 TI - Natural products reveal cancer cell dependence on oxysterol-binding proteins. AB - Cephalostatin 1, OSW-1, ritterazine B and schweinfurthin A are natural products that potently, and in some cases selectively, inhibit the growth of cultured human cancer cell lines. The cellular targets of these small molecules have yet to be identified. We have discovered that these molecules target oxysterol binding protein (OSBP) and its closest paralog, OSBP-related protein 4L (ORP4L)- proteins not known to be involved in cancer cell survival. OSBP and the ORPs constitute an evolutionarily conserved protein superfamily, members of which have been implicated in signal transduction, lipid transport and lipid metabolism. The functions of OSBP and the ORPs, however, remain largely enigmatic. Based on our findings, we have named the aforementioned natural products ORPphilins. Here we used ORPphilins to reveal new cellular activities of OSBP. The ORPphilins are powerful probes of OSBP and ORP4L that will be useful in uncovering their cellular functions and their roles in human diseases. PMID- 21822275 TI - Mechanistic evidence for a front-side, SNi-type reaction in a retaining glycosyltransferase. AB - A previously determined crystal structure of the ternary complex of trehalose-6 phosphate synthase identified a putative transition state-like arrangement based on validoxylamine A 6'-O-phosphate and uridine diphosphate in the active site. Here linear free energy relationships confirm that these inhibitors are synergistic transition state mimics, supporting front-face nucleophilic attack involving hydrogen bonding between leaving group and nucleophile. Kinetic isotope effects indicate a highly dissociative oxocarbenium ion-like transition state. Leaving group (18)O effects identified isotopically sensitive bond cleavages and support the existence of a hydrogen bond between the nucleophile and departing group. Bronsted analysis of nucleophiles and Taft analysis highlight participation of the nucleophile in the transition state, also consistent with a front-face mechanism. Together, these comprehensive, quantitative data substantiate this unusual enzymatic reaction mechanism. Its discovery should prompt useful reassessment of many biocatalysts and their substrates and inhibitors. PMID- 21822276 TI - MAP4 and CLASP1 operate as a safety mechanism to maintain a stable spindle position in mitosis. AB - Correct positioning of the mitotic spindle is critical to establish the correct cell-division plane. Spindle positioning involves capture of astral microtubules and generation of pushing/pulling forces at the cell cortex. Here we show that the tau-related protein MAP4 and the microtubule rescue factor CLASP1 are essential for maintaining spindle position and the correct cell-division axis in human cells. We propose that CLASP1 is required to correctly capture astral microtubules, whereas MAP4 prevents engagement of excess dynein motors, thereby protecting the system from force imbalance. Consistent with this, MAP4 physically interacts with dynein-dynactin in vivo and inhibits dynein-mediated microtubule sliding in vitro. Depletion of MAP4, but not CLASP1, causes spindle misorientation in the vertical plane, demonstrating that force generators are under spatial control. These findings have wide biological importance, because spindle positioning is essential during embryogenesis and stem-cell homeostasis. PMID- 21822277 TI - RALA and RALBP1 regulate mitochondrial fission at mitosis. AB - Mitochondria exist as dynamic interconnected networks that are maintained through a balance of fusion and fission. Equal distribution of mitochondria to daughter cells during mitosis requires fission. Mitotic mitochondrial fission depends on both the relocalization of the large GTPase DRP1 to the outer mitochondrial membrane and phosphorylation of Ser 616 on DRP1 by the mitotic kinase cyclin B CDK1 (ref. 2). We now report that these processes are mediated by the small Ras like GTPase RALA and its effector RALBP1 (also known as RLIP76, RLIP1 or RIP1; refs 3, 4). Specifically, the mitotic kinase Aurora A phosphorylates Ser 194 of RALA, relocalizing it to the mitochondria, where it concentrates RALBP1 and DRP1. Furthermore, RALBP1 is associated with cyclin B-CDK1 kinase activity that leads to phosphorylation of DRP1 on Ser 616. Disrupting either RALA or RALBP1 leads to a loss of mitochondrial fission at mitosis, improper segregation of mitochondria during cytokinesis and a decrease in ATP levels and cell number. Thus, the two mitotic kinases Aurora A and cyclin B-CDK1 converge on RALA and RALBP1 to promote mitochondrial fission, the appropriate distribution of mitochondria to daughter cells and ultimately proper mitochondrial function. PMID- 21822278 TI - Endolysosomal sorting of ubiquitylated caveolin-1 is regulated by VCP and UBXD1 and impaired by VCP disease mutations. AB - The AAA-ATPase VCP (also known as p97) cooperates with distinct cofactors to process ubiquitylated proteins in different cellular pathways. VCP missense mutations cause a systemic degenerative disease in humans, but the molecular pathogenesis is unclear. We used an unbiased mass spectrometry approach and identified a VCP complex with the UBXD1 cofactor, which binds to the plasma membrane protein caveolin-1 (CAV1) and whose formation is specifically disrupted by disease-associated mutations. We show that VCP-UBXD1 targets mono ubiquitylated CAV1 in SDS-resistant high-molecular-weight complexes on endosomes, which are en route to degradation in endolysosomes. Expression of VCP mutant proteins, chemical inhibition of VCP, or siRNA-mediated depletion of UBXD1 leads to a block of CAV1 transport at the limiting membrane of enlarged endosomes in cultured cells. In patient muscle, muscle-specific caveolin-3 accumulates in sarcoplasmic pools and specifically delocalizes from the sarcolemma. These results extend the cellular functions of VCP to mediating sorting of ubiquitylated cargo in the endocytic pathway and indicate that impaired trafficking of caveolin may contribute to pathogenesis in individuals with VCP mutations. PMID- 21822279 TI - The T-box transcription factor Eomesodermin acts upstream of Mesp1 to specify cardiac mesoderm during mouse gastrulation. AB - Instructive programmes guiding cell-fate decisions in the developing mouse embryo are controlled by a few so-termed master regulators. Genetic studies demonstrate that the T-box transcription factor Eomesodermin (Eomes) is essential for epithelial-to-mesenchymal transition, mesoderm migration and specification of definitive endoderm during gastrulation. Here we report that Eomes expression within the primitive streak marks the earliest cardiac mesoderm and promotes formation of cardiovascular progenitors by directly activating the bHLH (basic helix-loop-helix) transcription factor gene Mesp1 upstream of the core cardiac transcriptional machinery. In marked contrast to Eomes/Nodal signalling interactions that cooperatively regulate anterior-posterior axis patterning and allocation of the definitive endoderm cell lineage, formation of cardiac progenitors requires only low levels of Nodal activity accomplished through a Foxh1/Smad4-independent mechanism. Collectively, our experiments demonstrate that Eomes governs discrete context-dependent transcriptional programmes that sequentially specify cardiac and definitive endoderm progenitors during gastrulation. PMID- 21822280 TI - Simultaneous visualization of the extracellular and cytoplasmic domains of the epidermal growth factor receptor. AB - To our knowledge, no structural study to date has characterized, in an intact receptor, the coupling of conformational change in extracellular domains through a single-pass transmembrane domain to conformational change in cytoplasmic domains. Here we examine such coupling, and its unexpected complexity, using nearly full-length epidermal growth factor receptor (EGFR) and negative-stain EM. The liganded, dimeric EGFR ectodomain can couple both to putatively active, asymmetrically associated kinase dimers and to putatively inactive, symmetrically associated kinase dimers and monomers. Inhibitors that stabilize the active or inactive conformation of the kinase active site, as well as mutations in the kinase dimer interface and a juxtamembrane phosphorylation site, shift the equilibrium among the three kinase association states. This coupling of one conformation of an activated receptor ectodomain to multiple kinase-domain arrangements reveals previously unanticipated complexity in transmembrane signaling and facilitates regulation of receptor function in the juxtamembrane and cytoplasmic environments. PMID- 21822281 TI - Biogenic mechanisms and utilization of small RNAs derived from human protein coding genes. AB - Efforts to catalog eukaryotic transcripts have uncovered many small RNAs (sRNAs) derived from gene termini and splice sites. Their biogenesis pathways are largely unknown, but a mechanism based on backtracking of RNA polymerase II (RNAPII) has been suggested. By sequencing transcripts 12-100 nucleotides in length from cells depleted of major RNA degradation enzymes and RNAs associated with Argonaute (AGO1/2) effector proteins, we provide mechanistic models for sRNA production. We suggest that neither splice site-associated (SSa) nor transcription start site associated (TSSa) RNAs arise from RNAPII backtracking. Instead, SSa RNAs are largely degradation products of splicing intermediates, whereas TSSa RNAs probably derive from nascent RNAs protected by stalled RNAPII against nucleolysis. We also reveal new AGO1/2-associated RNAs derived from 3' ends of introns and from mRNA 3' UTRs that appear to draw from noncanonical microRNA biogenesis pathways. PMID- 21822282 TI - An autoinhibitory helix in the C-terminal region of phospholipase C-beta mediates Galphaq activation. AB - The enzyme phospholipase C-beta (PLCbeta) is a crucial regulator of intracellular calcium levels whose activity is controlled by heptahelical receptors that couple to members of the Gq family of heterotrimeric G proteins. We have determined atomic structures of two invertebrate homologs of PLCbeta (PLC21) from cephalopod retina and identified a helix from the C-terminal regulatory region that interacts with a conserved surface of the catalytic core of the enzyme. Mutations designed to disrupt the analogous interaction in human PLCbeta3 considerably increase basal activity and diminish stimulation by Galphaq. Galphaq binding requires displacement of the autoinhibitory helix from the catalytic core, thus providing an allosteric mechanism for activation of PLCbeta. PMID- 21822283 TI - Structure-function studies of nucleocytoplasmic transport of retroviral genomic RNA by mRNA export factor TAP. AB - mRNA export is mediated by the TAP-p15 heterodimer, which belongs to the family of NTF2-like export receptors. TAP-p15 heterodimers also bind to the constitutive transport element (CTE) present in simian type D retroviral RNAs, and they mediate the export of viral unspliced RNAs to the host cytoplasm. We have solved the crystal structure of the RNA recognition and leucine-rich repeat motifs of TAP bound to one symmetrical half of the CTE RNA. L-shaped conformations of protein and RNA are involved in a mutual molecular embrace on complex formation. We have monitored the impact of structure-guided mutations on binding affinities in vitro and transport assays in vivo. Our studies define the principles by which CTE RNA subverts the mRNA export receptor TAP, thereby facilitating the nuclear export of viral genomic RNAs, and, more generally, provide insights on cargo RNA recognition by mRNA export receptors. PMID- 21822284 TI - Trimeric structure and flexibility of the L1ORF1 protein in human L1 retrotransposition. AB - The LINE-1 (L1) retrotransposon emerges as a major source of human interindividual genetic variation, with important implications for evolution and disease. L1 retrotransposition is poorly understood at the molecular level, and the mechanistic details and evolutionary origin of the L1-encoded L1ORF1 protein (L1ORF1p) are particularly obscure. Here three crystal structures of trimeric L1ORF1p and NMR solution structures of individual domains reveal a sophisticated and highly structured, yet remarkably flexible, RNA-packaging protein. It trimerizes via an N-terminal, ion-containing coiled coil that serves as scaffold for the flexible attachment of the central RRM and the C-terminal CTD domains. The structures explain the specificity for single-stranded RNA substrates, and a mutational analysis indicates that the precise control of domain flexibility is critical for retrotransposition. Although the evolutionary origin of L1ORF1p remains unclear, our data reveal previously undetected structural and functional parallels to viral proteins. PMID- 21822285 TI - Postpartum mammary gland involution drives progression of ductal carcinoma in situ through collagen and COX-2. AB - The prognosis of breast cancer in young women is influenced by reproductive history. Women diagnosed within 5 years postpartum have worse prognosis than nulliparous women or women diagnosed during pregnancy. Here we describe a mouse model of postpartum breast cancer that identifies mammary gland involution as a driving force of tumor progression. In this model, human breast cancer cells exposed to the involuting mammary microenvironment form large tumors that are characterized by abundant fibrillar collagen, high cyclooxygenase-2 (COX-2) expression and an invasive phenotype. In culture, tumor cells are invasive in a fibrillar collagen and COX-2-dependent manner. In the involuting mammary gland, inhibition of COX-2 reduces the collagen fibrillogenesis associated with involution, as well as tumor growth and tumor cell infiltration to the lung. These data support further research to determine whether women at high risk for postpartum breast cancer would benefit from treatment with nonsteroidal anti inflammatory drugs (NSAIDs) during postpartum involution. PMID- 21822286 TI - Direct targeting of Sec23a by miR-200s influences cancer cell secretome and promotes metastatic colonization. AB - Although the role of miR-200s in regulating E-cadherin expression and epithelial to-mesenchymal transition is well established, their influence on metastatic colonization remains controversial. Here we have used clinical and experimental models of breast cancer metastasis to discover a pro-metastatic role of miR-200s that goes beyond their regulation of E-cadherin and epithelial phenotype. Overexpression of miR-200s is associated with increased risk of metastasis in breast cancer and promotes metastatic colonization in mouse models, phenotypes that cannot be recapitulated by E-cadherin expression alone. Genomic and proteomic analyses revealed global shifts in gene expression upon miR-200 overexpression toward that of highly metastatic cells. miR-200s promote metastatic colonization partly through direct targeting of Sec23a, which mediates secretion of metastasis-suppressive proteins, including Igfbp4 and Tinagl1, as validated by functional and clinical correlation studies. Overall, these findings suggest a pleiotropic role of miR-200s in promoting metastatic colonization by influencing E-cadherin-dependent epithelial traits and Sec23a-mediated tumor cell secretome. PMID- 21822287 TI - Oncogenic PIK3CA-driven mammary tumors frequently recur via PI3K pathway dependent and PI3K pathway-independent mechanisms. AB - PIK3CA gain-of-function mutations are a common oncogenic event in human malignancy, making phosphatidylinositol 3-kinase (PI3K) a target for cancer therapy. Despite the promise of targeted therapy, resistance often develops, leading to treatment failure. To elucidate mechanisms of resistance to PI3K targeted therapy, we constructed a mouse model of breast cancer conditionally expressing human PIK3CA(H1047R). Notably, most PIK3CA(H1047R)-driven mammary tumors recurred after PIK3CA(H1047R) inactivation. Genomic analyses of recurrent tumors revealed multiple lesions, including focal amplification of Met or Myc (also known as c-Met and c-Myc, respectively). Whereas Met amplification led to tumor survival dependent on activation of endogenous PI3K, tumors with Myc amplification became independent of the PI3K pathway. Functional analyses showed that Myc contributed to oncogene independence and resistance to PI3K inhibition. Notably, PIK3CA mutations and c-MYC elevation co-occur in a substantial fraction of human breast tumors. Together, these data suggest that c-MYC elevation represents a potential mechanism by which tumors develop resistance to current PI3K-targeted therapies. PMID- 21822288 TI - Structure of the membrane domain of respiratory complex I. AB - Complex I is the first and largest enzyme of the respiratory chain, coupling electron transfer between NADH and ubiquinone to the translocation of four protons across the membrane. It has a central role in cellular energy production and has been implicated in many human neurodegenerative diseases. The L-shaped enzyme consists of hydrophilic and membrane domains. Previously, we determined the structure of the hydrophilic domain. Here we report the crystal structure of the Esherichia coli complex I membrane domain at 3.0 A resolution. It includes six subunits, NuoL, NuoM, NuoN, NuoA, NuoJ and NuoK, with 55 transmembrane helices. The fold of the homologous antiporter-like subunits L, M and N is novel, with two inverted structural repeats of five transmembrane helices arranged, unusually, face-to-back. Each repeat includes a discontinuous transmembrane helix and forms half of a channel across the membrane. A network of conserved polar residues connects the two half-channels, completing the proton translocation pathway. Unexpectedly, lysines rather than carboxylate residues act as the main elements of the proton pump in these subunits. The fourth probable proton translocation channel is at the interface of subunits N, K, J and A. The structure indicates that proton translocation in complex I, uniquely, involves coordinated conformational changes in six symmetrical structural elements. PMID- 21822289 TI - Polar actomyosin contractility destabilizes the position of the cytokinetic furrow. AB - Cytokinesis, the physical separation of daughter cells at the end of mitosis, requires precise regulation of the mechanical properties of the cell periphery. Although studies of cytokinetic mechanics mostly focus on the equatorial constriction ring, a contractile actomyosin cortex is also present at the poles of dividing cells. Whether polar forces influence cytokinetic cell shape and furrow positioning remains an open question. Here we demonstrate that the polar cortex makes cytokinesis inherently unstable. We show that limited asymmetric polar contractions occur during cytokinesis, and that perturbing the polar cortex leads to cell shape oscillations, resulting in furrow displacement and aneuploidy. A theoretical model based on a competition between cortex turnover and contraction dynamics accurately accounts for the oscillations. We further propose that membrane blebs, which commonly form at the poles of dividing cells and whose role in cytokinesis has long been enigmatic, stabilize cell shape by acting as valves releasing cortical contractility. Our findings reveal an inherent instability in the shape of the dividing cell and unveil a novel, spindle-independent mechanism ensuring the stability of cleavage furrow positioning. PMID- 21822290 TI - Modulation of Rab GTPase function by a protein phosphocholine transferase. AB - The intracellular pathogen Legionella pneumophila modulates the activity of host GTPases to direct the transport and assembly of the membrane-bound compartment in which it resides. In vitro studies have indicated that the Legionella protein DrrA post-translationally modifies the GTPase Rab1 by a process called AMPylation. Here we used mass spectrometry to investigate post-translational modifications to Rab1 that occur during infection of host cells by Legionella. Consistent with in vitro studies, DrrA-mediated AMPylation of a conserved tyrosine residue in the switch II region of Rab1 was detected during infection. In addition, a modification to an adjacent serine residue in Rab1 was discovered, which was independent of DrrA. The Legionella effector protein AnkX was required for this modification. Biochemical studies determined that AnkX directly mediates the covalent attachment of a phosphocholine moiety to Rab1. This phosphocholine transferase activity used CDP-choline as a substrate and required a conserved histidine residue located in the FIC domain of the AnkX protein. During infection, AnkX modified both Rab1 and Rab35, which explains how this protein modulates membrane transport through both the endocytic and exocytic pathways of the host cell. Thus, phosphocholination of Rab GTPases represents a mechanism by which bacterial FIC-domain-containing proteins can alter host-cell functions. PMID- 21822291 TI - Protection of repetitive DNA borders from self-induced meiotic instability. AB - DNA double strand breaks (DSBs) in repetitive sequences are a potent source of genomic instability, owing to the possibility of non-allelic homologous recombination (NAHR). Repetitive sequences are especially at risk during meiosis, when numerous programmed DSBs are introduced into the genome to initiate meiotic recombination. In the repetitive ribosomal DNA (rDNA) array of the budding yeast Saccharomyces cerevisiae, meiotic DSB formation is prevented in part through Sir2 dependent heterochromatin formation. Here we show that the edges of the rDNA array are exceptionally susceptible to meiotic DSBs, revealing an inherent heterogeneity in the rDNA array. We find that this localized DSB susceptibility necessitates a border-specific protection system consisting of the meiotic ATPase Pch2 and the origin recognition complex subunit Orc1. Upon disruption of these factors, DSB formation and recombination increased specifically in the outermost rDNA repeats, leading to NAHR and rDNA instability. Notably, the Sir2-dependent heterochromatin of the rDNA itself was responsible for the induction of DSBs at the rDNA borders in pch2Delta cells. Thus, although the activity of Sir2 globally prevents meiotic DSBs in the rDNA, it creates a highly permissive environment for DSB formation at the junctions between heterochromatin and euchromatin. Heterochromatinized repetitive DNA arrays are abundant in most eukaryotic genomes. Our data define the borders of such chromatin domains as distinct high risk regions for meiotic NAHR, the protection of which may be a universal requirement to prevent meiotic genome rearrangements that are associated with genomic diseases and birth defects. PMID- 21822292 TI - Streptolysin S-like virulence factors: the continuing sagA. AB - Streptolysin S (SLS) is a potent cytolytic toxin and virulence factor that is produced by nearly all Streptococcus pyogenes strains. Despite a 100-year history of research on this toxin, it has only recently been established that SLS is just one of an extended family of post-translationally modified virulence factors (the SLS-like peptides) that are produced by some streptococci and other Gram-positive pathogens, such as Listeria monocytogenes and Clostridium botulinum. In this Review, we describe the identification, genetics, biochemistry and various functions of SLS. We also discuss the shared features of the virulence-associated SLS-like peptides, as well as their place within the rapidly expanding family of thiazole/oxazole-modified microcins (TOMMs). PMID- 21822293 TI - Imaging mass spectrometry in microbiology. AB - Imaging mass spectrometry tools allow the two-dimensional visualization of the distribution of trace metals, metabolites, surface lipids, peptides and proteins directly from biological samples without the need for chemical tagging or antibodies, and are becoming increasingly useful for microbiology applications. These tools, comprising different imaging mass spectrometry techniques, are ushering in an exciting new era of discovery by enabling the generation of chemical hypotheses based on the spatial mapping of atoms and molecules that can correlate to or transcend observed phenotypes. In this Innovation article, we explore the wide range of imaging mass spectrometry techniques that is available to microbiologists and describe the unique applications of these tools to microbiology with respect to the types of samples to be investigated. PMID- 21822294 TI - Function, structure and mechanism of bacterial photosensory LOV proteins. AB - LOV (light, oxygen or voltage) domains are protein photosensors that are conserved in bacteria, archaea, plants and fungi, and detect blue light via a flavin cofactor. LOV domains are present in both chemotrophic and phototrophic bacterial species, in which they are found amino-terminally of signalling and regulatory domains such as sensor histidine kinases, diguanylate cyclases phosphodiesterases, DNA-binding domains and regulators of RNA polymerase sigma factors. In this Review, we describe the current state of knowledge about the function of bacterial LOV proteins, the structural basis of LOV domain-mediated signal transduction, and the use of LOV domains as genetically encoded photoswitches in synthetic biology. PMID- 21822295 TI - Autophagic deficiency is related to steroidogenic decline in aged rat Leydig cells. AB - Late-onset hypogonadism (LOH) is closely related to secondary androgen deficiency in aged males, but the mechanism remains unclear. In this study, we found that reduced testosterone production in aged rat Leydig cells is associated with decreased autophagic activity. Primary rat Leydig cells and the TM3 mouse Leydig cell line were used to study the effect of autophagic deficiency on Leydig cell testosterone production. In Leydig cells from young and aged rats, treatment with wortmannin, an autophagy inhibitor, inhibited luteinising hormone (LH)-stimulated steroidogenic acute regulatory (StAR) protein expression and decreased testosterone production. In contrast, treatment with rapamycin, an autophagy activator, enhanced LH-stimulated steroidogenesis in Leydig cells from aged, but not young, rats. Intracellular reactive oxygen species (ROS) levels were increased in both young and aged Leydig cells treated with wortmannin but decreased only in aged Leydig cells treated with rapamycin. Furthermore, an increased level of ROS, induced by H(2)O(2), resulted in LH-stimulated steroidogenic inhibition. Finally, knockdown of Beclin 1 decreased LH-stimulated StAR expression and testosterone production in TM3 mouse Leydig cells, which were associated with increased intracellular ROS level. These results suggested that autophagic deficiency is related to steroidogenic decline in aged rat Leydig cells, which might be influenced by intracellular ROS levels. PMID- 21822297 TI - Optimal culture conditions for the generation of natural killer cell-induced dendritic cells for cancer immunotherapy. AB - Dendritic cell (DC)-based vaccines continue to be considered an attractive tool for cancer immunotherapy. DCs require an additional signal from the environment or other immune cells to polarize the development of immune responses toward T helper 1 (Th1) or Th2 responses. DCs play a role in natural killer (NK) cell activation, and NK cells are also able to activate and induce the maturation of DCs. We investigated the types of NK cells that can induce the maturation and enhanced function of DCs and the conditions under which these interactions occur. DCs that were activated by resting NK cells in the presence of inflammatory cytokines exhibited increased expression of several costimulatory molecules and an enhanced ability to produce IL-12p70. NK cell-stimulated DCs potently induced Th1 polarization and exhibited the ability to generate tumor antigen-specific cytotoxic T lymphocyte responses. Our data demonstrate that functional DCs can be generated by coculturing immature DCs with freshly isolated resting NK cells in the presence of Toll-like receptor agonists and proinflammatory cytokines and that the resulting DCs effectively present antigens to induce tumor-specific T cell responses, which suggests that these cells may be useful for cancer immunotherapy. PMID- 21822298 TI - MicroRNAs are key regulators controlling iNKT and regulatory T-cell development and function. AB - MicroRNAs (miRNAs) are an abundant class of evolutionarily conserved, small, non coding RNAs that post-transcriptionally regulate expression of their target genes. Emerging evidence indicates that miRNAs are important regulators that control the development, differentiation and function of different immune cells. Both CD4(+)CD25(+)Foxp3(+) regulatory T (Treg) cells and invariant natural killer T (iNKT) cells are critical for immune homeostasis and play a pivotal role in the maintenance of self-tolerance and immunity. Here, we review the important roles of miRNAs in the development and function of iNKT and Treg cells. PMID- 21822299 TI - An ErbB-3 antibody, MP-RM-1, inhibits tumor growth by blocking ligand-dependent and independent activation of ErbB-3/Akt signaling. AB - The ErbB receptors, such as ErbB-1 and ErbB-2, have been intensely pursued as targets for cancer therapeutics. Although initially efficacious in a subset of patients, drugs targeting these receptors led invariably to resistance, which is often associated with reactivation of the ErbB-3-PI3K-Akt signaling. This may be overcome by an ErbB-3 ligand that abrogates receptor-mediated signaling. Toward this end, we have generated a mouse monoclonal antibody, MP-RM-1, against the extracellular domain (ECD) of ErbB-3 receptor. Assessment of human tumor cell lines, as well as early passage tumor cells revealed that MP-RM-1 effectively inhibited both NRG-1beta-dependent and -independent ErbB-3 activation. The antagonizing effect of MP-RM-1 was of non-competitive type, as binding of [(125)I]-labeled NRG-1beta to ErbB-3 was not influenced by the antibody. MP-RM-1 treatment led, in most instances, to decreased ErbB-3 expression. In addition, MP RM-1 was able to inhibit the colony formation ability of tumor cells and tumor growth in two human tumor xenograft nude mouse models. Treatment with the antibody was associated with a decreased ErbB-3 and Akt phosphorylation and ErbB 3 expression in the excised tumor tissue. Collectively, these results indicate that MP-RM-1 has the potential to interfere with signaling by ErbB-3 and reinforce the notion that ErbB-3 could be a key target in cancer-drug design. PMID- 21822296 TI - MicroRNA in TLR signaling and endotoxin tolerance. AB - Toll-like receptors (TLRs) in innate immune cells are the prime cellular sensors for microbial components. TLR activation leads to the production of proinflammatory mediators and thus TLR signaling must be properly regulated by various mechanisms to maintain homeostasis. TLR4-ligand lipopolysaccharide (LPS) induced tolerance or cross-tolerance is one such mechanism, and it plays an important role in innate immunity. Tolerance is established and sustained by the activity of the microRNA miR-146a, which is known to target key elements of the myeloid differentiation factor 88 (MyD88) signaling pathway, including IL-1 receptor-associated kinase (IRAK1), IRAK2 and tumor-necrosis factor (TNF) receptor-associated factor 6 (TRAF6). In this review, we comprehensively examine the TLR signaling involved in innate immunity, with special focus on LPS-induced tolerance. The function of TLR ligand-induced microRNAs, including miR-146a, miR 155 and miR-132, in regulating inflammatory mediators, and their impact on the immune system and human diseases, are discussed. Modulation of these microRNAs may affect TLR pathway activation and help to develop therapeutics against inflammatory diseases. PMID- 21822300 TI - PP2A-B56alpha controls oncogene-induced senescence in normal and tumor human melanocytic cells. AB - Oncoprotein C-MYC is overexpressed in human metastatic melanomas and melanoma derived cells where it is required for the suppression of oncogene-induced senescence (OIS). The genetic events that maintain high levels of C-MYC in melanoma cells and their role in OIS are unknown. Here we report that C-MYC in cells from several randomly chosen melanoma lines was upregulated at the protein level, and largely because of the increased protein stability. Of all known regulators of C-MYC stability, levels of B56alpha subunit of the PP2A tumor suppressor complex were substantially suppressed in all human melanoma cells compared with normal melanocytes. Accordingly, immunohistochemical analysis revealed that the lowest and the highest amounts of PP2A-B56alpha were predominantly detected in metastatic melanoma tissues and in primary melanomas from patients with good clinical outcome, respectively. Importantly, PP2A B56alpha overexpression suppressed C-MYC in melanoma cells and induced OIS, whereas depletion of PP2A-B56alpha in normal human melanocytes upregulated C-MYC protein levels and suppressed BRAF(V600E)- and, less efficiently, NRAS(Q61R) induced senescence. Our data reveal a mechanism of C-MYC overexpression in melanoma cells and identify a functional role for PP2A-B56alpha in OIS of melanocytic cells. PMID- 21822301 TI - MicroRNA-335 acts as a metastasis suppressor in gastric cancer by targeting Bcl-w and specificity protein 1. AB - Aberrant expression of miR-335 has been frequently reported in cancer studies, suggesting that there is a close correlation between miR-335 and cancer during its development, progression, metastasis and prognosis. The expression of miR-335 in gastric cancer and its effects are not known. Relative expression of miR-335 in 4 gastric cancer cell lines and in 70 gastric cancer tissues was confirmed by real-time quantitative reverse transcriptase-PCR compared with controls. Transwell cell migration and Matrigel invasion assay in vitro and metastasis formation assay in vivo were used to examine the effects of miR-335 expression on gastric cancer cell invasion and metastasis. The effect of miR-335 expression on gastric cancer cell proliferation was estimated by the 3-(4,5-dimethylthiazol-2 yl)-2, 5-diphenyltetrazolium bromide assay. Luciferase reporter assay and western blot were used to examine the potential target genes and related pathways. Gene silencing with small-interfering RNA was used to examine the effects of target genes on gastric cancer cell invasion. miR-335 was dramatically downregulated in gastric cancer cell lines than in the normal gastric cell line GES-1. Low expression of miR-335 was significantly associated with lymph-node metastasis, poor pT stage, poor pN stage and invasion of lymphatic vessels. Overexpression of miR-335 suppressed gastric cancer cell invasion and metastasis in vitro and in vivo, but has no significant effects on cell proliferation. Furthermore, miR-335 might suppress gastric cancer invasion and metastasis by targeting Bcl-w and specificity protein 1 (SP1). Taken together, our results provide evidence that miR-335 might function as a metastasis suppressor in gastric cancer by targeting SP1 directly and indirectly through the Bcl-w-induced phosphoinositide 3-kinase Akt-Sp1 pathway. miR-335 showing altered expression at different stages of gastric cancer could be a target for gastric cancer therapies and could be further developed as a potential prognostic factor. PMID- 21822302 TI - Overexpression of ribosomal RNA in prostate cancer is common but not linked to rDNA promoter hypomethylation. AB - Alterations in nucleoli, including increased numbers, increased size, altered architecture and increased function are hallmarks of prostate cancer cells. The mechanisms that result in increased nucleolar size, number and function in prostate cancer have not been fully elucidated. The nucleolus is formed around repeats of a transcriptional unit encoding a 45S ribosomal RNA (rRNA) precursor that is then processed to yield the mature 18S, 5.8S and 28S RNA species. Although it has been generally accepted that tumor cells overexpress rRNA species, this has not been examined in clinical prostate cancer. We find that indeed levels of the 45S rRNA, 28S, 18S and 5.8S are overexpressed in the majority of human primary prostate cancer specimens as compared with matched benign tissues. One mechanism that can alter nucleolar function and structure in cancer cells is hypomethylation of CpG dinucleotides of the upstream rDNA promoter region. However, this mechanism has not been examined in prostate cancer. To determine whether rRNA overexpression could be explained by hypomethylation of these CpG sites, we also evaluated the DNA methylation status of the rDNA promoter in prostate cancer cell lines and the clinical specimens. Bisulfite sequencing of genomic DNA revealed two roughly equal populations of loci in cell lines consisting of those that contained densely methylated deoxycytidine residues within CpGs and those that were largely unmethylated. All clinical specimens also contained two populations with no marked changes in methylation of this region in cancer as compared with normal. We recently reported that MYC can regulate rRNA levels in human prostate cancer; here we show that MYC mRNA levels are correlated with 45S, 18S and 5.8S rRNA levels. Further, as a surrogate for nucleolar size and number, we examined the expression of fibrillarin, which did not correlate with rRNA levels. We conclude that rRNA levels are increased in human prostate cancer, but that hypomethylation of the rDNA promoter does not explain this increase, nor does hypomethylation explain alterations in nucleolar number and structure in prostate cancer cells. Rather, rRNA levels and nucleolar size and number relate more closely to MYC overexpression. PMID- 21822303 TI - Sox2 expression in breast tumours and activation in breast cancer stem cells. AB - The cancer stem cell (CSC) model does not imply that tumours are generated from transformed tissue stem cells. The target of transformation could be a tissue stem cell, a progenitor cell, or a differentiated cell that acquires self-renewal ability. The observation that induced pluripotency reprogramming and cancer are related has lead to the speculation that CSCs may arise through a reprogramming like mechanism. Expression of pluripotency genes (Oct4, Nanog and Sox2) was tested in breast tumours by immunohistochemistry and it was found that Sox2 is expressed in early stage breast tumours. However, expression of Oct4 or Nanog was not found. Mammosphere formation in culture was used to reveal stem cell properties, where expression of Sox2, but not Oct4 or Nanog, was induced. Over expression of Sox2 increased mammosphere formation, effect dependent on continuous Sox2 expression; furthermore, Sox2 knockdown prevented mammosphere formation and delayed tumour formation in xenograft tumour initiation models. Induction of Sox2 expression was achieved through activation of the distal enhancer of Sox2 promoter upon sphere formation, the same element that controls Sox2 transcription in pluripotent stem cells. These findings suggest that reactivation of Sox2 represents an early step in breast tumour initiation, explaining tumour heterogeneity by placing the tumour-initiating event in any cell along the axis of mammary differentiation. PMID- 21822305 TI - Deficiency of the macrophage growth factor CSF-1 disrupts pancreatic neuroendocrine tumor development. AB - Tumor-associated macrophages have recently emerged as a key regulatory cell type during cancer progression, and have been found to promote tumor malignancy in the majority of studies performed to date. We show in this study that CD68(+) macrophages positively correlate with tumor grade and liver metastasis in human pancreatic neuroendocrine tumors (PNETs). To investigate the potential mechanisms whereby macrophages can promote PNET progression, we crossed the RIP1-Tag2 (RT2) mouse model of pancreatic islet cancer to colony-stimulating factor-1 (CSF-1) deficient Csf1(op/op) mice, which have reduced numbers of tissue macrophages. Csf1(op/op) RT2 mice had a substantial reduction in cumulative tumor burden, which interestingly resulted from a significant decrease in angiogenic switching and tumor number, rather than an evident effect on tumor growth. In the tumors that did develop in CSF-1-deficient animals, however, there were no significant differences in tumor cell proliferation, apoptosis, angiogenesis or invasion. CSF 1 deficiency decreased macrophage infiltration by approximately 50% during all stages of RT2 tumor progression. Interestingly, several cytokines were upregulated in CSF-1-deficient RT2 tumors, and neutrophil infiltration was increased. These results show that macrophages are important for promoting PNET development and suggest that additional factors contribute to the recruitment and survival of myeloid cells in RT2 tumors in the absence of CSF-1. PMID- 21822304 TI - MDM2 regulates MYCN mRNA stabilization and translation in human neuroblastoma cells. AB - The MYCN gene has a critical role in determining the clinical behavior of neuroblastoma. Although it is known that genomic amplification occurs in high risk subsets, it remains unclear how MYCN expression is regulated in the pathogenesis of neuroblastomas. Here, we report that MYCN expression was regulated by the oncoprotein MDM2 at the post-transcriptional level and was associated with neuroblastoma cell growth. Increasing MDM2 by ectopic overexpression in the cytoplasm enhanced both mRNA and protein expression of MYCN. Mechanistic studies found that the C-terminal RING domain of the MDM2 protein bound to the MYCN mRNA's AREs within the 3'UTR and increased MYCN 3'UTR mediated mRNA stability and translation. Conversely, MDM2 silencing by specific siRNA rendered the MYCN mRNA unstable and reduced the abundance of the MYCN protein in MYCN-amplified neuroblastoma cell lines. Importantly, this MDM2 silencing resulted in a remarkable inhibition of neuroblastoma cell growth and induction of cell death through a p53-independent pathway. Our results indicate that MDM2 has a p53-independent role in the regulation of both MYCN mRNA stabilization and its translation, suggesting that MDM2-mediated MYCN expression is one mechanism associated with growth of MYCN-associated neuroblastoma and disease progression. PMID- 21822306 TI - Identification of a novel pro-apoptotic role of NF-kappaB in the regulation of TRAIL- and CD95-mediated apoptosis of glioblastoma cells. AB - We recently reported that nuclear factor-kappa B (NF-kappaB) promotes DNA damage triggered apoptosis in glioblastoma, the most common brain tumor. In the present study, we investigated the role of NF-kappaB in death receptor-mediated apoptosis. Here, we identify a novel pro-apopotic function of NF-kappaB in TRAIL- and CD95-induced apoptosis. Inhibition of NF-kappaB by overexpression of the dominant-negative IkappaBalpha-superrepressor (IkappaBalpha-SR) significantly decreases tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)- or CD95-induced apoptosis. Vice versa, activation of NF-kappaB via overexpression of constitutively active IkappaB kinase complex (IKK)beta (IKK-EE) significantly increases TRAIL-mediated apoptosis. Intriguingly, NF-kappaB inhibition reduces the recruitment of Fas-associated death domain and caspase-8 and formation of the death-inducing signaling complex (DISC) upon stimulation of TRAIL receptors or CD95. This results in reduced TRAIL-mediated activation of caspases, loss of mitochondrial potential and cytochrome c release in IkappaBalpha-SR-expressing cells. In comparison, NF-kappaB inhibition strongly enhances TNF-alpha-mediated apoptosis. Comparative studies revealed that TNF-alpha rapidly stimulates transcriptional activation and upregulation of anti-apoptotic proteins, whereas TRAIL causes apoptosis before transcriptional activation. Thus, this study demonstrates for the first time that NF-kappaB exerts a pro-apoptotic role in TRAIL- and CD95-induced apoptosis in glioblastoma cells by facilitating DISC formation. PMID- 21822307 TI - A common single-nucleotide polymorphism in cyclooxygenase-2 disrupts microRNA mediated regulation. AB - Elevated expression of the prostaglandin synthase cyclooxygenase-2 (COX-2) is commonly observed in many chronic inflammatory diseases and cancer. However, the mechanisms allowing for pathogenic COX-2 overexpression are largely unknown. The gene for COX-2 (PTGS2) carries a common single-nucleotide polymorphism (SNP) at position 8473 (T8473C), in exon 10 that is associated with diseases in which COX 2 overexpression is a contributing factor. We demonstrate that the T8473C SNP resides within a region that targets COX-2 mRNA for degradation through microRNA mediated regulation. miR-542-3p was identified to bind transcripts derived from the 8473T allele and promote mRNA decay. By contrast, the presence of the variant 8473C allele interfered with miR-542-3p binding, allowing for mRNA stabilization, and this effect was rescued using a mutated miR-542-3p at the respective 8473 site. Colon cancer cells and tissue displayed COX-2 mRNA levels that were dependent on T8473C allele dosage, and allele-specific expression of COX-2 was observed to be a contributing factor promoting COX-2 overexpression. These findings provide a novel molecular explanation underlying disease susceptibility associated with COX-2 T8473C SNP, and identify it as a potential marker for identifying cancer patients best served through selective COX-2 inhibition. PMID- 21822309 TI - Fra-1 controls motility of bladder cancer cells via transcriptional upregulation of the receptor tyrosine kinase AXL. AB - Fos-related antigen 1 (Fra-1) is a Fos family member overexpressed in several types of human cancers. Here, we report that Fra-1 is highly expressed in the muscle-invasive form of the carcinoma of the bladder (80%) and to a lesser extent in superficial bladder cancer (42%). We demonstrate that in this type of cancer Fra-1 is regulated via a C-terminal instability signal and C-terminal phosphorylation. We show that manipulation of Fra-1 expression levels in bladder cancer cell lines affects cell morphology, motility and proliferation. The gene coding for AXL tyrosine kinase is directly upregulated by Fra-1 in bladder cancer and in other cell lines. Importantly, our data demonstrate that AXL mediates the effect of Fra-1 on tumour cell motility but not on cell proliferation. We suggest that AXL may represent an attractive therapeutic target in cancers expressing high Fra-1 levels. PMID- 21822308 TI - Functional interactions between Choline kinase alpha, epidermal growth factor receptor and c-Src in breast cancer cell proliferation. AB - Epidermal growth factor receptor (EGFR) family members and c-Src are co overexpressed in many cancers. The synergistic effect of EGFR and c-Src has been shown in the tumorigenesis of breast and other cancers. Reported mechanisms of synergy include transcriptional regulation by STAT5b and the regulation of cellular ATP production by mitochondrial protein COX II. Here, we report a new mechanism of EGFR-c-Src synergy through choline kinase alpha (CHKA). The first enzyme of the phosphatidyl choline production pathway, CHKA, is overexpressed in many cancers, and the product of the enzyme, phosphocholine, is also increased in tumor cells. In this report, we find that CHKA forms a complex with EGFR in a c Src-dependent manner. Endogenous CHKA and EGFR co-immunoprecipitated from a variety of breast cancer cell lines and immortalized mammary epithelial cells. CHKA interacted with the EGFR kinase domain upon c-Src co-overexpression and was phosphorylated in a c-Src-dependent manner on Y197 and Y333. Overexpression of EGFR and c-Src increased total cellular activity and protein levels of CHKA. Mutation of CHKA Y197 and Y333 reduced complex formation, EGFR-dependent activation of CHKA enzyme activity and epidermal growth factor (EGF)-dependent DNA synthesis. Furthermore, small interfering RNA-mediated knockdown of CHKA in MCF-7 and MCF-10A cells reduced EGF-dependent cell proliferation. Together, these results strongly implicate a new c-Src-dependent link between CHKA and EGFR, which contributes to the regulation of cell proliferation and tumorigenesis. PMID- 21822311 TI - A Rac1/PAK1 cascade controls beta-catenin activation in colon cancer cells. AB - P21-activated kinase 1 (PAK1) is associated with colon cancer progression and metastasis, whereas the molecular mechanism remains elusive. Here, we show that downregulation of PAK1 in colon cancer cells reduces total beta-catenin level, as well as cell proliferation. Mechanistically, PAK1 directly phosphorylates beta catenin proteins at Ser675 site and this leads to more stable and transcriptional active beta-catenin. Corroborating these results, PAK1 is required for full Wnt signaling, and superactivation of beta-catenin is achieved by simultaneous knockdown of adenomatous polyposis coli protein and activation of PAK1. Moreover, we show that Rac1 functions upstream of PAK1 in colon cancer cells and contributes to beta-catenin phosphorylation and accumulation. We conclude that a Rac1/PAK1 cascade controls beta-catenin S675 phosphorylation and full activation in colon cancer cells. Supporting this conclusion, overexpression of PAK1 is observed in 70% of colon cancer samples and is correlated with massive beta catenin accumulation. PMID- 21822310 TI - 1q gain and CDT2 overexpression underlie an aggressive and highly proliferative form of Ewing sarcoma. AB - Despite extensive characterization of the role of the EWS-ETS fusions, little is known about secondary genetic alterations and their clinical contribution to Ewing sarcoma (ES). It has been demonstrated that the molecular structure of EWS ETS lacks prognostic value. Moreover, CDKN2A deletion and TP53 mutation, despite carrying a poor prognosis, are infrequent. In this scenario identifying secondary genetic alterations with a significant prevalence could contribute to understand the molecular mechanisms underlying the most aggressive forms of ES.We screened a 67 ES tumor set for copy number alterations by array comparative genomic hybridization. 1q gain (1qG), detected in 31% of tumor samples, was found markedly associated with relapse and poor overall and disease-free survival and demonstrated a prognostic value independent of classical clinical parameters. Reanalysis of an expression dataset belonging to an independent tumor set (n=37) not only validated this finding but also led us to identify a transcriptomic profile of severe cell cycle deregulation in 1qG ES tumors. Consistently, a higher proliferation rate was detected in this tumor subset by Ki-67 immunohistochemistry. CDT2, a 1q-located candidate gene encoding a protein involved in ubiquitin ligase activity and significantly overexpressed in 1qG ES tumors, was validated in vitro and in vivo proving its major contribution to this molecular and clinical phenotype. This integrative genomic study of 105 ES tumors in overall renders the potential value of 1qG and CDT2 overexpression as prognostic biomarkers and also affords a rationale for the application of already available new therapeutic compounds selectively targeting the protein-ubiquitin machinery. PMID- 21822312 TI - Loss of EBP50 stimulates EGFR activity to induce EMT phenotypic features in biliary cancer cells. AB - Scaffold proteins form multiprotein complexes that are central to the regulation of intracellular signaling. The scaffold protein ezrin-radixin-moesin-binding phosphoprotein 50 (EBP50) is highly expressed at the plasma membrane of normal biliary epithelial cells and binds epidermal growth factor receptor (EGFR), a tyrosine kinase receptor with oncogenic properties. This study investigated EBP50 EGFR interplay in biliary cancer. We report that in a collection of 106 cholangiocarcinomas, EBP50 was delocalized to the cytoplasm of tumor cells in 66% of the cases. Ectopic expression of EBP50 was correlated with the presence of satellite nodules and with the expression of EGFR, which was at the plasma membrane, implying a loss of interaction with EBP50 in these cases. In vitro, loss of interaction between EBP50 and EGFR was mimicked by EBP50 depletion using a small interfering RNA approach in human biliary carcinoma cells co-expressing the two proteins at their plasma membrane, and in which interaction between EBP50 and EGFR was validated. EBP50 depletion caused an increase in EGFR expression at their surface, and a sustained activation of the receptor and of its downstream effectors (extracellular signal-regulated kinase 1/2, signal transducer and activator of transcription 3) in both basal and EGF-stimulated conditions. Cells lacking EBP50 showed epithelial-to-mesenchymal transition-associated features, including reduction in E-cadherin and cytokeratin-19 expression, induction of S100A4 and of the E-cadherin transcriptional repressor, Slug, and loss of cell polarity. Accordingly, depletion of EBP50 induced the disruption of adherens junctional complexes, the development of lamellipodia structures and the subsequent acquisition of motility properties. All these phenotypic changes were prevented upon inhibition of EGFR tyrosine kinase by gefitinib. These findings indicate that loss of EBP50 at the plasma membrane in tumor cells may contribute to biliary carcinogenesis through EGFR activation. PMID- 21822313 TI - CAPC negatively regulates NF-kappaB activation and suppresses tumor growth and metastasis. AB - CAPC, also known as LRRC26, is expressed in normal prostate and salivary gland. We developed a mAb to CAPC and used it to characterize the protein and study its function. CAPC protein was detected in normal prostate and salivary gland, in several human breast cancer cell lines and in the prostate cancer cell line LNCaP. Knockdown of CAPC by siRNA in LNCaP cells enhanced anchorage-independent growth in soft agar. Conversely, overexpression of CAPC in MDA-231 breast cancer cells and A431 epidermoid cancer cells inhibited growth in soft agar and tumorigenesis in nude mice, and suppressed the metastasis of MDA-231 cells to the lung. Overexpression of CAPC downregulated NF-kappaB activity and its target genes, including GM-CSF (CSF2), CXCL1, IL8 and LTB1. It also suppressed genes encoding the serine protease mesotrypsin (PRSS3) and cystatin SN (CST1). CAPC expressing tumors showed a decrease in the number of proliferating cells and a large increase in ECM. The role of CAPC in the suppression of tumor growth and metastasis may be through its alteration of the tumor microenvironment. PMID- 21822314 TI - ECIL 3-2009 update guidelines for antifungal management. PMID- 21822315 TI - Non-myeloablative allogenic BMT for myelodysplastic syndrome successfully controlled accompanying relapsing polychondritis. PMID- 21822316 TI - Hematopoietic stem-cell transplantation following solid-organ transplantation in children. AB - Reports of hematopoietic stem-cell transplantation (HSCT) following solid-organ transplantation have been described in adults mainly as case reports. These reports demonstrate feasibility but likely do not reflect true outcomes due to a positive reporting bias. We report herein the outcomes of all our pediatric recipients of allogeneic HSCT following previous solid-organ transplantation between 2000 and 2009. Four children were identified. Two patients underwent heart transplantation followed by cord-blood allogeneic HSCT for T-cell lymphoma/post transplant lymphoproliferative disease (PTLD) and two patients underwent liver transplantation followed by living-donor allogeneic HSCT for severe aplastic anemia (SAA). The mean time between transplants was 4.2 years (range 1.5-6 years). All patients engrafted; however, all patients died from 37 days to 1 year after HSCT. Causes of death included infections (n=2), multi-organ failure (n=1) and solid-organ graft rejection (n=1). Though three patients survived beyond day+100, multiple complications were observed including EBV re activation followed by EBV-positive PTLD (n=1) and five episodes of severe infections. The patients transplanted for lymphoma did not have evidence of recurrence at last follow-up. Although feasibilty has been shown with this cohort, we conclude that allogeneic HSCT in immunosuppressed patients following solid-organ transplantation remains a very high risk procedure that results in severe morbidity and mortality in children. PMID- 21822317 TI - A rapid e-volution. PMID- 21822318 TI - Aristolochic acids. PMID- 21822319 TI - Captafol. PMID- 21822320 TI - Cobalt-tungsten carbide: powders and hard metals. PMID- 21822321 TI - o-Nitrotoluene. PMID- 21822322 TI - Riddelliine. PMID- 21822323 TI - Styrene. PMID- 21822324 TI - NTP 12th Report on Carcinogens. AB - The Report on Carcinogens (RoC) is a scientific public health document on cancer hazards to which people in the U.S. may be exposed. Published biennially, each edition of the report is cumulative and consists of substances newly reviewed in addition to those listed in previous editions. The Twelfth RoC contains 240 substance profiles, some of which (e.g., Estrogens, Steroidal) consist of a class of structurally related chemicals or agents. These include 54 profiles for substances listed as known to be human carcinogens and 186 profiles for substances listed as reasonably anticipated to be human carcinogens. Each profile contains: (1) the listing status, (2) a brief description of each substance, which can be chemicals, substances, mixtures, or exposure circumstances, with a summary of the evidence for its ability to cause cancer including cancer studies in humans and in experimental animals, and studies on mechanisms of carcinogenesis, which may include metabolism and genotoxicity (ability to damage genes) studies, (3) relevant information on properties, use, production, and exposure, (4) a summary of the regulations and guidelines that are likely to decrease exposure to the substance, and (5) references to scientific literature used to support the listings. The substances listed in the RoC do not include all human carcinogens. KEYWORDS: http://ntp.niehs.nih.gov/go/19914. PMID- 21822325 TI - Experimental Validation of a Fundamental Model for PCR Efficiency. AB - Recently a theoretical analysis of PCR efficiency has been published by Booth et al., (2010). The PCR yield is the product of three efficiencies: (i) the annealing efficiency is the fraction of templates that form binary complexes with primers during annealing, (ii)the polymerase binding efficiency is the fraction of binary complexes that bind to polymerase to form ternary complexes and (iii)the elongation efficiency is the fraction of ternary complexes that extend fully. Yield is controlled by the smallest of the three efficiencies and control could shift from one type of efficiency to another over the course of a PCR experiment. Experiments have been designed that are specifically controlled by each one of the efficiencies and the results are consistent with the mathematical model. The experimental data has also been used to quantify six key parameters of the theoretical model. An important application of the fully characterized model is to calculate initial template concentration from real-time PCR data. Given the PCR protocol, the midpoint cycle number (where the template concentration is half that of the final concentration) can be theoretically determined and graphed for a variety of initial DNA concentrations. Real-time results can be used to calculate the midpoint cycle number and consequently the initial DNA concentration, using this graph. The application becomes particularly simple if a conservative PCR protocol is followed where only the annealing efficiency is controlling. PMID- 21822326 TI - noloco: An efficient implementation of van der Waals density functionals based on a Monte-Carlo integration technique. AB - The treatment of van der Waals interactions in density functional theory is an important field of ongoing research. Among different approaches developed recently to capture these non-local interactions, the van der Waals density functional (vdW-DF) developed in the groups of Langreth and Lundqvist is becoming increasingly popular. It does not rely on empirical parameters, and has been successfully applied to molecules, surface systems, and weakly-bound solids. As the vdW-DF requires the evaluation of a six-dimensional integral, it scales, however, unfavorably with system size. In this work, we present a numerically efficient implementation based on the Monte-Carlo technique for multi-dimensional integration. It can handle different versions of vdW-DF. Applications range from simple dimers to complex structures such as molecular crystals and organic molecules physisorbed on metal surfaces. PMID- 21822327 TI - Parallel Discrete Molecular Dynamics Simulation With Speculation and In-Order Commitment. AB - Discrete molecular dynamics simulation (DMD) uses simplified and discretized models enabling simulations to advance by event rather than by timestep. DMD is an instance of discrete event simulation and so is difficult to scale: even in this multi-core era, all reported DMD codes are serial. In this paper we discuss the inherent difficulties of scaling DMD and present our method of parallelizing DMD through event-based decomposition. Our method is microarchitecture inspired: speculative processing of events exposes parallelism, while in-order commitment ensures correctness. We analyze the potential of this parallelization method for shared-memory multiprocessors. Achieving scalability required extensive experimentation with scheduling and synchronization methods to mitigate serialization. The speed-up achieved for a variety of system sizes and complexities is nearly 6* on an 8-core and over 9* on a 12-core processor. We present and verify analytical models that account for the achieved performance as a function of available concurrency and architectural limitations. PMID- 21822328 TI - Enhancing Interpersonal Psychotherapy for Mothers and Expectant Mothers on Low Incomes: Adaptations and Additions. AB - Intervening with depressed women during their childbearing years, especially with those on low incomes, is critically important. Not only do mothers and expectant mothers suffer unnecessarily, but their untreated depression has critical negative consequences for their families. Despite this, these women have proven especially difficult to engage in psychotherapy. In this paper we describe several adaptations and additions we have made to a brief form of Interpersonal Psychotherapy (IPT) to meet the needs of mothers and expectant mothers living on low incomes in the community who suffer from depression, but face significant practical, psychological, and cultural barriers to engaging in and staying in treatment. In addition, we present some preliminary data on the extent to which our enhanced, brief IPT approach promotes improvements in treatment engagement and retention relative to usual care for expectant mothers on low incomes. PMID- 21822329 TI - When values matter: Expressing values in behavioral intentions for the near vs. distant future. AB - It was predicted that because of their abstract nature, values will have greater impact on how individuals plan their distant future than their near future. Experiments 1 and 2 found that values better predict behavioral intentions for distant future situations than near future situations. Experiment 3 found that whereas high-level values predict behavioral intentions for more distant future situations, low-level feasibility considerations predict behavioral intentions for more proximate situation. Finally, Experiment 4 found that the temporal changes in the relationship between values and behavioral intentions depended on how the behavior was construed. Higher correspondence is found when behaviors are construed on a higher level and when behavior is planned for the more distant future than when the same behavior is construed on a lower level or is planned for the more proximal future. The implications of these findings for self consistency and value conflicts are discussed. PMID- 21822330 TI - Cognitive consequences of affirming the self: The relationship between self affirmation and object construal. AB - Previous research suggests that affirming one's important values is a powerful way of protecting one's general self integrity, allowing non-defensive processing of self-relevant information. In a series of four studies linking self affirmation with construal level, we find that in addition to any self buffering effect, thinking about one's values and why they are important more generally shifts cognitive processing towards superordinate and structured thinking. Self affirmation leads participants to perceive a greater degree of structure within their selves (Study 1), to increasingly identify actions in terms of their endstates (Study 2), to more strongly distinguish between primary and secondary object features (Study 3) and to perform better on tasks requiring abstract, structured thinking than those requiring detail-oriented, concrete thinking. Together, these findings suggest that thinking about important values helps individuals to structure information and focus on the big picture. PMID- 21822331 TI - Spontaneous trait inference and construal level theory: Psychological distance increases nonconscious trait thinking. AB - Can psychological distance affect how much perceivers form spontaneous trait inferences (STI) from others' behaviors? On the basis of construal level theory (CLT) which posits that distant (vs. near) entities are represented more in terms of their abstract, global, and decontextualized features, we predicted that perceived distance would increase the tendency for perceivers to draw spontaneous trait inferences from behavioral information about actors. In two experiments, participants learned about people who were perceived as being distant or proximal to the self, and STI formation was subsequently assessed. We found that perceivers were more likely to form STIs about distant vs. near actors from the same behavioral information. These findings generalized across two distance dimensions: space and time. In addition, we found that priming individuals to adopt a high-level (vs. low-level) construal mindset also resulted in increased STI (Experiment 3). In sum, psychological distance facilitates STI formation, and this occurs via high-level construal of actors and their behaviors. PMID- 21822332 TI - The Relationship Context: Its Effects on Low-Income Women's Desire for a Baby. AB - Little is known about the influence of relationship characteristics on a woman's desire for a baby with her partner. This study addresses that gap, using data from a study of 1,114 low-income women in the southeast who were in a relationship. Controlling for sociodemographic factors, women who were in more established relationships, who had not had a previous child with their partner, or who had higher expectations of their partner were generally more likely to want a baby with him. In investigating women's childbearing desires, it is important to consider not only individual characteristics but also women's relationship characteristics. PMID- 21822333 TI - An Extension of SIC Predictions to the Wiener Coactive Model. AB - The survivor interaction contrasts (SIC) is a powerful measure for distinguishing among candidate models of human information processing. One class of models to which SIC analysis can apply are the coactive, or channel summation, models of human information processing. In general, parametric forms of coactive models assume that responses are made based on the first passage time across a fixed threshold of a sum of stochastic processes. Previous work has shown that that the SIC for a coactive model based on the sum of Poisson processes has a distinctive down-up-down form, with an early negative region that is smaller than the later positive region. In this note, we demonstrate that a coactive process based on the sum of two Wiener processes has the same SIC form. PMID- 21822334 TI - Context of Acceptability of Topical Microbicides: Sexual Relationships. AB - Domains central to the effects of sexual relationships on the acceptability of a vaginal protection method were explored in 14 focus groups and 38 in-depth interviews with women and men recruited from a health department's sexually transmitted infections (STI) and family planning clinics. Findings indicate that acceptability depended on a couple's relationship type, classified as serious, casual, or "new." Potential barriers to communication about product use may be overcome through direct or indirect covert use, depending on relationship type. More men than women thought women should always tell their partners if they use microbicides, regardless of relationship type. Results indicate the importance of the relationship context in understanding the likely acceptability of using microbicides, and perhaps any method of STI/HIV protection. PMID- 21822335 TI - Fathers' Involvement with Their Nonresident Children and Material Hardship. AB - Children in single-parent families, particularly children born to unmarried parents, are at high risk for experiencing material hardship. Previous research based on cross-sectional data suggests that father involvement, especially visitation, diminishes hardship. This article uses longitudinal data to examine the associations between nonresident fathers' involvement with their children and material hardship in the children's households. Results suggest that fathers' formal and informal child support payments and contact with their children independently reduce the number of hardships in the mothers' households; however, only the impact of fathers' contact with children is robust in models that include lagged dependent variables or individual fixed effects. Furthermore, cross-lagged models suggest that material hardship decreases future father involvement, but future hardship is not diminished by father involvement (except in-kind contributions). These results point to the complexity of these associations and to the need for future research to focus on heterogeneity of effects within the population. PMID- 21822336 TI - Confronting the Material Convoy in Later Life. AB - We adapt a metaphor from life course studies to designate the whole of one's possessions, across time, as a convoy of material support. This dynamic collection of things supports daily life and the self, but it can also present difficulty in later life. To alleviate the purported burdens of the material convoy, a discourse has arisen that urges elders and their family members to reduce the volume of possessions. An analysis of 11 such possession management texts shows authors addressing two distinct audiences about elders' need to downsize: family members and elders themselves. Authors who speak to family members do so with an urgent, unsentimental tone that echoes mainstream clutter control advice about disorderly, overfull households. In texts for elders, the standard critique about consumption and unruly lives is gentler, more sensitive to the meaning of things, and underplays the emotions of divestment. There is stress on the responsibility to spare the next generation and control one's legacy. These latter texts seem to respect that downsizing in later life symbolizes a narrowing of the life world. PMID- 21822337 TI - Practical asymmetric synthesis of beta-hydroxy gamma-amino acids via complimentary aldol reactions. AB - Orthogonally protected chiral beta-hydroxy-gamma-amino acids can be accessed in >100 g quantities from readily available starting materials and reagents in 3-4 steps. These chiral synthons contain two adjacent stereocenters along with suitably protected functional groups (O-TBS, N-Boc) for downstream reactivity. Implementation of two existing aldol technologies allows rapid access to all possible stereoisomers of 1. The guiding principles during reaction optimization were reaction scalability and operational efficiency. Conversion of the amino acids to a variety of chiral building blocks in 1-2 steps demonstrates their synthetic utility. PMID- 21822338 TI - Synthesis of the dysiherbaine tetrahydropyran core utilizing improved tethered aminohydroxylation conditions. AB - A concise stereoselective route to the dysiherbaine tetrahydropyran core was achieved in 9 steps and 39% overall yield. Donohoe's improved tethered aminohydroxylation conditions were employed to concurrently install the amino and alcohol groups and construct the tetrahydropyran ring, which features four contiguous cis-stereocenters. PMID- 21822339 TI - "HOW ASIAN AM I?" ASIAN AMERICAN YOUTH CULTURES, DRUG USE, AND ETHNIC IDENTITY CONSTRUCTION. AB - This article analyzes the construction of ethnic identity in the narratives of 100 young Asian Americans in a dance club/rave scene. We examine how illicit drug use and other consuming practices shape their understanding of Asian American identities, finding three distinct patterns. The first presents a disjuncture between Asian American ethnicity and drug use, seeing their own consumption as exceptional. The second argues their drug consumption is a natural outgrowth of their Asian American identity, allowing them to navigate the liminal space they occupy in American society. The final group presents Asian American drug use as normalized and constructs identity through taste and lifestyle boundary markers within social contexts of the dance scenes. These three narratives share a sense of ethnicity as dynamic, provisional, and constructed, allowing us to go beyond the static, essentialist models of ethnic identity that underlie much previous research on ethnicity, immigration, and substance use. PMID- 21822340 TI - Exploring the role of exposure frequency in recognizing pronunciation variants. AB - Words can be pronounced in multiple ways in casual speech. Corpus analyses of the frequency with which these pronunciation variants occur (e.g., Patterson & Connine, 2001) show that typically, one pronunciation variant tends to predominate; this raises the question of whether variant recognition is aligned with exposure frequency. We explored this issue in words containing one of four phonological contexts, each of which favors one of four surface realizations of word-medial /t/: [t], [?], [r], or a deleted variant. The frequencies of the four realizations in all four contexts were estimated for a set of words in a production experiment. Recognition of all pronunciation variants was then measured in a lexical decision experiment. Overall, the data suggest that listeners are sensitive to variant frequency: Word classification rates closely paralleled production frequency. The exceptions to this were [t] realizations (i.e., canonical pronunciations of the words), a finding which confirms other results in the literature and indicates that factors other than exposure frequency affect word recognition. PMID- 21822341 TI - Modelling the distribution of domestic ducks in Monsoon Asia. AB - Domestic ducks are considered to be an important reservoir of highly pathogenic avian influenza (HPAI), as shown by a number of geospatial studies in which they have been identified as a significant risk factor associated with disease presence. Despite their importance in HPAI epidemiology, their large-scale distribution in monsoon Asia is poorly understood. In this study, we created a spatial database of domestic duck census data in Asia and used it to train statistical distribution models for domestic duck distributions at a spatial resolution of 1 km. The method was based on a modelling framework used by the Food and Agriculture Organisation to produce the Gridded Livestock of the World (GLW) database, and relies on stratified regression models between domestic duck densities and a set of agro-ecological explanatory variables. We evaluated different ways of stratifying the analysis and of combining the prediction to optimize the goodness of fit of the predictions. We found that domestic duck density could be predicted with reasonable accuracy (mean RMSE and correlation coefficient between log-transformed observed and predicted densities being 0.58 and 0.80, respectively), using a stratification based on livestock production systems. We tested the use of artificially degraded data on duck distributions in Thailand and Vietnam as training data, and compared the modelled outputs with the original high-resolution data. This showed, for these two countries at least, that these approaches could be used to accurately disaggregate provincial level (administrative level 1) statistical data to provide high resolution model distributions. PMID- 21822342 TI - Modular high frame rate detector for synchrotron applications. AB - The development of detectors often lags the development in X-ray sources. However, advanced detectors are critical for fully utilizing and exploiting the capabilities of the new bright sources. We report on the development of a modular high frame rate detector for synchrotron applications such as small angle X-ray scattering (SAXS) and wide angle X-ray scattering (WAXS). The detector consists of four modules, each providing an imaging area of 5*5 cm(2) and capable of frame rates of 200 frames per second (fps) with full resolution, and 650 fps with smaller region of interest (ROI). Details of the detector design and experiments at synchrotron beamlines are discussed in the paper. PMID- 21822343 TI - Control system for the 2nd generation Berkeley AutoMounters (BAM2) at GM/CA CAT macromolecular crystallography beamlines. AB - GM/CA CAT at Sector 23 of the Advanced Photon Source (APS) is an NIH funded facility for crystallographic structure determination of biological macromolecules by X-ray diffraction.A second generation Berkeley automounter is being integrated into the beamline control system at the 23-BM experimental station. This new device replaces the previous all-pneumatic gripper motions with a combination of pneumatics and XYZ motorized linear stages. The latter adds a higher degree of flexibility to the robot including auto-alignment capability, accommodation of a larger capacity sample Dewar of arbitrary shape, and support for advanced operations such as crystal washing, while preserving the overall simplicity and efficiency of the Berkeley automounter design. PMID- 21822344 TI - Diamond X-ray Photodiode for White and Monochromatic SR beams. AB - High purity, single crystal CVD diamond plates are screened for quality and instrumented into a sensor assembly for quantitative characterization of flux and position sensitivity. Initial investigations have yielded encouraging results and have led to further development. Several limiting complications are observed and discussed, as well as mitigations thereof. For example, diamond quality requirements for x-ray diodes include low nitrogen impurity and crystallographic defectivity. Thin electrode windows and electronic readout performance are ultimately also critical to device performance. Promising features observed so far from prototype devices include calculable responsivity, flux linearity, position sensitivity and timing performance. Recent results from testing in high flux and high speed applications are described. PMID- 21822345 TI - A new beamstop for microfocus X-ray capillary beams. AB - In order to accurately measure the photon flux and to assist in aligning the beam, we have designed a modified beam stop device based on a photo diode integrated with the beam stop. The beam stop contains a small CdWO(4) crystal that completely stops the X-rays and at the same time produces photoluminescence proportional to the X-ray flux. The light is then guided to a photosensitive diode, using a flexible light pipe, to monitor the flux. With this device we achieve the goal of stopping the primary X-ray beam and simultaneously monitoring the X-ray intensity, thus eliminating the need for integrating ion-chambers into the capillary or collimator mount. PMID- 21822346 TI - Optics Concept for a Pair of Undulator Beamlines for MX. AB - We describe a concept for x-ray optics to feed a pair of macromolecular crystallography (MX) beamlines which view canted undulator radiation sources in the same storage ring straight section. It can be deployed at NSLS-II and at other low-emittance third-generation synchrotron radiation sources where canted undulators are permitted, and makes the most of these sources and beamline floor space, even when the horizontal angle between the two canted undulator emissions is as little as 1-2 mrad. The concept adopts the beam-separation principles employed at the 23-ID (GM/CA-CAT) beamlines at the Advanced Photon Source (APS), wherein tandem horizontally-deflecting mirrors separate one undulator beam from the other, following monochromatization by a double-crystal monochromator. The scheme described here would, in contrast, deliver the two tunable monochromatic undulator beams to separate endstations that address rather different and somewhat complementary purposes, with further beam conditioning imposed as required. A downstream microfocusing beamline would employ dual-stage focusing for work at the micron scale and, unique to this design, switch to single stage focusing for larger beams. On the other hand, the upstream, more highly automated beamline would only employ single stage focusing. PMID- 21822347 TI - Comparing Vacuum and Extreme Ultraviolet Radiation for Postionization of Laser Desorbed Neutrals from Bacterial Biofilms and Organic Fullerenes. AB - Vacuum and extreme ultraviolet radiation from 8 - 24 eV generated at a synchrotron was used to postionize laser desorbed neutrals of antibiotic-treated biofilms and a modified fullerene using laser desorption postionization mass spectrometry (LDPI-MS). Results show detection of the parent ion, various fragments, and extracellular material from biofilms using LDPI-MS with both vacuum and extreme ultraviolet photons. Parent ions were observed for both cases, but extreme ultraviolet photons (16 - 24 eV) induced more fragmentation than vacuum ultraviolet (8 - 14 eV) photons. PMID- 21822348 TI - Developing a measure of interpretation bias for depressed mood: An ambiguous scenarios test. AB - The tendency to interpret ambiguous everyday situations in a relatively negative manner (negative interpretation bias) is central to cognitive models of depression. Limited tools are available to measure this bias, either experimentally or in the clinic. This study aimed to develop a pragmatic interpretation bias measure using an ambiguous scenarios test relevant to depressed mood (the AST-D). In Study 1, after a pilot phase (N = 53), the AST-D was presented via a web-based survey (N = 208). Participants imagined and rated each AST-D ambiguous scenario. As predicted, higher dysphoric mood was associated with lower pleasantness ratings (more negative bias), independent of mental imagery measures. In Study 2, self-report ratings were compared with objective ratings of participants' imagined outcomes of the ambiguous scenarios (N = 41). Data were collected in the experimental context of a functional Magnetic Resonance Imaging scanner. Consistent with subjective bias scores, independent judges rated more sentences as negatively valenced for the high versus low dysphoric group. Overall, results suggest the potential utility of the AST-D in assessing interpretation bias associated with depressed mood. PMID- 21822349 TI - Calculating tissue shear modulus and pressure by 2D Log-Elastographic methods. AB - Shear modulus imaging, often called elastography, enables detection and characterization of tissue abnormalities. In this paper the data is two displacement components obtained from successive MR or ultrasound data sets acquired while the tissue is excited mechanically. A 2D plane strain elastic model is assumed to govern the 2D displacement, u. The shear modulus, MU, is unknown and whether or not the first Lame parameter, lambda, is known the pressure p = lambda? . u which is present in the plane strain model cannot be measured and is unreliably computed from measured data and can be shown to be an order one quantity in the units kPa. So here we present a 2D Log-Elastographic inverse algorithm that: (1) simultaneously reconstructs the shear modulus, MU, and p, which together satisfy a first order partial differential equation system, with the goal of imaging MU; (2) controls potential exponential growth in the numerical error; and (3) reliably reconstructs the quantity p in the inverse algorithm as compared to the same quantity computed with a forward algorithm. This work generalizes the Log-Elastographic algorithm in [20] which uses one displacement component, is derived assuming the component satisfies the wave equation, and is tested on synthetic data computed with the wave equation model. The 2D Log-Elastographic algorithm is tested on 2D synthetic data and 2Din-vivo data from Mayo Clinic. We also exhibit examples to show that the 2D Log Elastographic algorithm improves the quality of the recovered images as compared to the Log-Elastographic and Direct Inversion algorithms. PMID- 21822350 TI - A Query Expansion Framework in Image Retrieval Domain Based on Local and Global Analysis. AB - We present an image retrieval framework based on automatic query expansion in a concept feature space by generalizing the vector space model of information retrieval. In this framework, images are represented by vectors of weighted concepts similar to the keyword-based representation used in text retrieval. To generate the concept vocabularies, a statistical model is built by utilizing Support Vector Machine (SVM)-based classification techniques. The images are represented as "bag of concepts" that comprise perceptually and/or semantically distinguishable color and texture patches from local image regions in a multi dimensional feature space. To explore the correlation between the concepts and overcome the assumption of feature independence in this model, we propose query expansion techniques in the image domain from a new perspective based on both local and global analysis. For the local analysis, the correlations between the concepts based on the co-occurrence pattern, and the metrical constraints based on the neighborhood proximity between the concepts in encoded images, are analyzed by considering local feedback information. We also analyze the concept similarities in the collection as a whole in the form of a similarity thesaurus and propose an efficient query expansion based on the global analysis. The experimental results on a photographic collection of natural scenes and a biomedical database of different imaging modalities demonstrate the effectiveness of the proposed framework in terms of precision and recall. PMID- 21822351 TI - First observation of two hyperfine transitions in antiprotonic He. AB - We report on the first experimental results for microwave spectroscopy of the hyperfine structure of p-3He+. Due to the helium nuclear spin, p-3He+ has a more complex hyperfine structure than p-4He+, which has already been studied before. Thus a comparison between theoretical calculations and the experimental results will provide a more stringent test of the three-body quantum electrodynamics (QED) theory. Two out of four super-super-hyperfine (SSHF) transition lines of the (n,L)=(36,34) state were observed. The measured frequencies of the individual transitions are 11.12559(14) GHz and 11.15839(18) GHz, less than 1 MHz higher than the current theoretical values, but still within their estimated errors. Although the experimental uncertainty for the difference of these frequencies is still very large as compared to that of theory, its measured value agrees with theoretical calculations. This difference is crucial to be determined because it is proportional to the magnetic moment of the antiproton. PMID- 21822353 TI - Novel Taxoid-Based Tumor-Targeting Drug Conjugates. AB - A long standing problem of conventional cancer chemotherapy is the lack of tumor specificity. Tumor-targeting drug delivery systems have been explored to overcome this problem. These systems combine a powerful cytotoxic anticancer agent with a tumor-targeting molecule via a suitable linker to form highly efficacious drug conjugates. These conjugates can deliver potent cytotoxic drugs specifically to tumors and cancer cells with minimal systemic toxicity. This article describes the design, development and application of novel taxoid-based tumor-targeting drug-conjugates, which possess excellent specificity and efficacy in vitro and in vivo. PMID- 21822352 TI - Treatment of Pediatric Bipolar Disorder: A Review. AB - AIM: To review the diagnosis and the pharmacologic and psychosocial interventions for pediatric bipolar disorder (PBD). METHODS: A comprehensive literature review of studies discussing the diagnosis and treatment of PBD was conducted. RESULTS: A context for understanding controversies and difficulties in the diagnosis of PBD is provided. An evidence-based assessment protocol for PBD is reviewed. The evidence for the following three categories of pharmacologic interventions are reviewed: Lithium, antiepileptics, and second generation antipsychotics. Algorithms for medication decisions are briefly reviewed. Existing psychosocial treatments and the evidence for those treatments are also reviewed. CONCLUSION: Despite recent developments in understanding the phenomenology of PBD and in identifying pharmacologic and psychosocial interventions, critical gaps remain. PMID- 21822354 TI - Semiparametric Bayesian inference for repeated fractional measurement data. AB - We discuss inference for repeated fractional data, with outcomes between 0 to 1, including positive probability masses on 0 and 1. The point masses at the boundaries prevent the routine use of logit and other commonly used transformations of (0, 1) data. We introduce a model augmentation with latent variables that allow for the desired positive probability at 0 and 1 in the model. A linear mixed effect model is imposed on the latent variables. We propose a Bayesian semiparametric model for the random effects distribution. Specifically, we use a Polya tree prior for the unknown random effects distribution. The proposed model can capture possible multimodality and skewness of random effect distribution. We discuss implementation of posterior inference by Markov chain Monte Carlo simulation. The proposed model is illustrated by a simulation study and a cancer study in dogs. PMID- 21822355 TI - Optimization of a Microfluidic Mixing Process for Gene Expression-Based Bio dosimetry. AB - In recent decades advances in radiation imaging and radiation therapy have led to a dramatic increase in the number of people exposed to radiation. Consequently, there is a clear need for personalized biodosimetry diagnostics in order to monitor the dose of radiation received and adapt it to each patient depending on their sensitivity to radiation exposure (Hall E.J. and Brenner D. J., 2008). Similarly, after a large-scale radiological event such as a dirty bomb attack, there will be a major need to assess, within a few days the radiation doses received by tens of thousands of individuals. Current high throughput devices can handle only a few hundred individuals per day. Hence there is a great need for a very fast self-contained non-invasive biodosimetric device based on a rapid blood test.This paper presents a case study where regression methods and designed experiments are used to arrive at the optimal settings for various factors that impact the kinetics in a biodosimetric device. We use ridge regression to initially identify a set of potentially important variables in the mixing process which is one of the critical sub systems of the device. This was followed by a series of designed experiments to arrive at the optimal setting of the significant microfluidic cartridge and piezoelectric disk (PZT) (D. Sadler, F. Zenhausern, U.S. Patent 6,986,601; Lee, S. Y., Ko, B., Yang, W., 2005) related factors. This statistical approach has been utilized to study the microfluidic mixing to mix water and dye mixtures of 70 MUl volume. The outcome of the statistical design, experimentation and analysis was then exploited for optimizing the design, fabrication and assembly of the microfluidic devices. As a result of the experiments that were performed, the system was fine tuned and the mixing time was reduced from 5.5 minutes to 2 minutes. PMID- 21822356 TI - Reduced Sensory Oscillatory Activity during Rapid Auditory Processing as a Correlate of Language-Learning Impairment. AB - Successful language acquisition has been hypothesized to involve the ability to integrate rapidly presented, brief acoustic cues in sensory cortex. A body of work has suggested that this ability is compromised in language-learning impairment (LLI). The present research aimed to examine sensory integration during rapid auditory processing by means of electrophysiological measures of oscillatory brain activity using data from a larger longitudinal study. Twenty nine children with LLI and control participants with typical language development (n=18) listened to tone doublets presented at a temporal interval that is essential for accurate speech processing (70-ms interstimulus interval). The children performed a deviant (pitch change of second tone) detection task, or listened passively. The electroencephalogram was recorded from 64 electrodes. Data were source-projected to the auditory cortices and submitted to wavelet analysis, resulting in time-frequency representations of electrocortical activity. Results show significantly reduced amplitude and phase-locking of early (45-75 ms) oscillations in the gamma-band range (29-52 Hz), specifically in the LLI group, for the second stimulus of the tone doublet. This suggests altered temporal organization of sensory oscillatory activity in LLI when processing rapid sequences. PMID- 21822357 TI - HPV16E6-dependent c-fos expression contributes to AP-1 complex formation in SiHa cells. AB - To date, the major role of HPV16E6 in cancer has been considered to be its ability to inhibit the p53 tumor-suppressor protein, thereby thwarting p53 mediated cytotoxic responses to cellular stress signals. Here, we show that HPV16E6-dependent c-fos oncogenic protein expression contributes to AP-1 complex formation under oxidative stress in SiHa cells (HPV16-positive squamous cell carcinoma of the cervix). In addition, we examined the role of HPV16E6 in TGF alpha-induced c-fos expression and found that the c-fos protein expression induced by TGF-alpha is HPV16E6 dependent. Thus, our results provide the first evidence that HPV16E6 contributes to AP-1 complex formation after both ligand dependent and independent EGFR activation, suggesting a new therapeutic approach to the treatment of HPV-associated tumors. PMID- 21822358 TI - Effects of dietary protein and fat contents on renal function and inflammatory cytokines in rats with adriamycin-induced nephrotic syndrome. AB - The effects of dietary protein and fat on renal function-related blood and urine parameters, such as albumin, urinary protein,and inflammatory cytokines were investigated in adriamycin- (ADR) induced nephrotic syndrome rats. ADR (2 mg/kg BW) was injected i.p. weekly for six weeks to develop nephrotic syndrome; thereafter rats were fed low-protein/high-fat (LPHF) or high-protein/low-fat (HPLF) diets for five weeks. Renal function-related blood and urine parameters were measured before and after dietary intervention. Serum levels of albumin, TG, and creatinine were significantly higher in the LPHF group than in the HPLF group. Serum levels of albumin were low and urinary protein excretion protein was high in HPLF group. BUN and UUN levels were higher in the HPLF group than in the LPHF. Urinary excretion of creatinine was significantly higher in the HPLF group than in the LPHF group. Serum inflammatory cytokine levels did not differ between the two groups, however the levels of IL-6, TNF-alpha, and IL-13 in splenocyte supernatants were significantly higher in the LPHF group than in the HPLF group. We confirmed that protein and fat contents in diet affect renal function-related blood and urine parameters and splenocyte inflammatory cytokine levels in ADR induced nephrotic syndrome rats. PMID- 21822359 TI - Simulation of Drug Uptake in a Two Compartmental Fractional Model for a Biological System. AB - This paper presents a very effective numerical method for the solution of the two compartmental pharmacokinetic model for oral drug administration. This model consists of a set of two fractional order differential equations which connect the two compartments. The first compartment represents the gut while the second compartment corresponds to the drug concentration in the target tissue. For ease of computation, the numerical solution is also created as a Matlab function. PMID- 21822360 TI - N-6 Substituted Deoxygenated Derivatives of L-like 5'-Noraristeromycin. AB - Several N-6 substituted derivatives (4-11) of (+)-4'-deoxy-5'-noraristeromycin (2) and its unsaturated counterpart (3) have been prepared. The derivatives are designed to systematically vary the hydrophobic/hydrophilic balance of the lead compounds. These compounds were evaluated against a large number of viruses but, no significant antiviral activity was observed. Also, no cytotoxicity to host cells was found. PMID- 21822361 TI - Hybrid photodetector for single-molecule spectroscopy and microscopy. AB - We report benchmark tests of a new single-photon counting detector based on a GaAsP photocathode and an electron-bombarded avalanche photodiode developed by Hamamatsu Photonics. We compare its performance with those of standard Geiger mode avalanche photodiodes. We show its advantages for FCS due to the absence of after-pulsing and for fluorescence lifetime measurements due to its excellent time resolution. Its large sensitive area also greatly simplifies setup alignment. Its spectral sensitivity being similar to that of recently introduced CMOS SPADs, this new detector could become a valuable tool for single-molecule fluorescence measurements, as well as for many other applications. PMID- 21822362 TI - De-N-acetylated sialic acid is immunogenic and elicits antibodies that are protective against Neisseria meningitidis. AB - Recently, we showed that monoclonal antibodies (mAbs) that are reactive with derivatives of polysialic acid containing de-N-acetylated neuraminic acid (Neu) residues are protective against N. meningitidis group B strains (Moe et al. 2005, Infect Immun73: 2123; Flitter et al., in preparation). In addition, we found that fully de-N-acetylated PSA (i.e. poly alpha 2,8 Neu) conjugated to tetanus toxoid (DeNAc) elicits IgM and IgG antibodies of all subclasses in mice that bind to group B strains, activate human complement deposition, are protective in an infant rat model of meningococcal bacteremia and are bactericidal against group C strains (Moe et al, in press). We show here that anti-DeNAc mAbs, DA1 and DA2 (both IgM), are reactive with polysaccharides containing Neu, bind to group B, C, W135 and Y but not X strains grown in chemically defined media (CDM). However, when the group X strain is grown in CDM supplemented with human plasma, DA2 binds. Also both mAbs mediate bactericidal activity against B, C, W135, and X strains with human complement. The results suggests that N. meningitidis express and/or acquire zwitterionic de-N-acetyl sialic acid antigens that can be the target of protective antibodies. PMID- 21822363 TI - Numerical Estimation in Deaf and Hearing Adults. AB - Deaf students often lag behind hearing peers in numerical and mathematical abilities. Studies of hearing children with mathematical difficulties highlight the importance of estimation skills as the foundation for formal mathematical abilities, but research with adults is limited. Deaf and hearing college students were assessed on the Number-to-Position task as a measure of estimation, and completed standardised assessments of arithmetical and mathematical reasoning. Deaf students performed significantly more poorly on all measures, including making less accurate number-line estimates. For deaf students, there was also a strong relationship showing that those more accurate in making number-line estimates achieved higher scores on the math achievement tests. No such relationship was apparent for hearing students. Further insights into the estimation abilities of deaf individuals should be made, including tasks that require symbolic and non-symbolic estimation and which address the quality of estimation strategies being used. PMID- 21822364 TI - Modeling and Measuring the Effects of Mutual Impedance on Multi-Cell CMUT Configurations. AB - This paper presents a numerical method for calculating the frequency response of a CMUT with a large number of cells. In a multi-cell configuration, commonly found in CMUTs, each cell is affected by the acoustic loading from neighboring cells. Thus, for an accurate model of a multi-cell CMUT element it is better to consider the mutual acoustic impedance instead of the acoustic impedance of a single cell only. We calculate the velocity of every cell (plate movement) simultaneously, with the mutual impedance effects taken into account. The model predicts that the cells exhibit different frequency responses, based on their locations in the element. We used a laser interferometer to validate the model by measuring the displacement response of a CMUT immersed in vegetable oil. The device has 169 circular cells (single crystal silicon plates, 500 nm thick, 21 MUm radii) placed in a hexagonal cell arrangement. The measurement results agree well with the numerical results. The computation time of our method is significantly shorter than finite element based calculations. Our model can be used for finding optimized cell configurations for CMUTs utilized in various applications such as medical imaging and therapeutic treatment. PMID- 21822365 TI - Design Optimization for a 2-D Sparse Transducer Array for 3-D Ultrasound Imaging. AB - In 3-D ultrasound imaging where 2-D transducer arrays with more than hundreds of elements are used, sparse arrays can be used to reduce the number of active ultrasound channels. Under a restriction of desired number of active channels, we can maximize the image quality by optimally choosing the positions of active elements. Here we use the method of simulated annealing to find the optimal configuration of a 2-D sparse array. This algorithm tries to minimize the value of an objective function defined as the energy ratio between the nonfocal and focal regions in the point spread function (PSF). Optimal configurations were found for the cases of choosing 16, 20, 24, 28, and 32 transmit and receive elements from a 16*16-element rectangular transducer array. With only 32 transmit and 32 receive elements, we could achieve an energy ratio of 16%, compared to 6% of the full array, which is the gold standard utilizing all the 256 elements for both transmit and receive. Using Field II, we simulated imaging with the optimal sparse arrays, for off-axis targets as well as on-axis targets, and the resulting images were compared with those from some other configurations, such as full transmit full-receive, full-transmit x-receive, x-transmit boundary-receive, and so on. PMID- 21822366 TI - Construal Levels and Psychological Distance: Effects on Representation, Prediction, Evaluation, and Behavior. AB - Construal level theory (CLT) is an account of how psychological distance influences individuals' thoughts and behavior. CLT assumes that people mentally construe objects that are psychologically near in terms of low-level, detailed, and contextualized features, whereas at a distance they construe the same objects or events in terms of high-level, abstract, and stable characteristics. Research has shown that different dimensions of psychological distance (time, space, social distance, and hypotheticality) affect mental construal and that these construals, in turn, guide prediction, evaluation, and behavior. The present paper reviews this research and its implications for consumer psychology. PMID- 21822367 TI - A practical approach to the diagnosis of pelvic inflammatory disease. AB - The diagnosis of acute pelvic inflammatory disease (PID) is usually based on clinical criteria and can be challenging for even the most astute clinicians. Although diagnostic accuracy is advocated, antibiotic treatment should be instituted if there is a diagnosis of cervicitis or suspicion of acute PID. Currently, no single test or combination of diagnostic indicators have been found to reliably predict PID, and laparoscopy cannot be recommended as a first line tool for PID diagnosis. For this reason, the clinician is left with maintaining a high index of suspicion for the diagnosis as he/she evaluates the lower genital tract for inflammation and the pelvic organs for tenderness in women with genital tract symptoms and a risk for sexually transmitted infection. This approach should minimize treating women without PID with antibiotics and optimize the diagnosis in a practical and cost-effective way. PMID- 21822368 TI - Biliary complications postlaparoscopic cholecystectomy: mechanism, preventive measures, and approach to management: a review. AB - Laparoscopic cholecystectomy has emerged as a gold standard therapeutic option for the management of symptomatic cholelithiasis. However, adaptation of LC is associated with increased risk of complications, particularly bile duct injury ranging from 0.3 to 0.6%. Occurrence of BDI results in difficult reconstruction, prolonged hospitalization, and high risk of long-term complications. Therefore, more emphasis is placed on preventing these complications. In addition to adequate training, several techniques have been proposed to prevent bile duct injury including use of 30 degrees scope, adequate delineation of structures in Calot's triangle (critical view), avoidance of diathermy close to common hepatic duct, and intraoperative cholangiogram, and to maintain a low threshold to conversion to open approach when uncertain. Management of Bile duct injury depends on the nature of injury, time of detection, and the expertise available, and would range from simple subhepatic drainage to Roux-en-Y hepaticojejunostomy particularly performed at specialised centers. This article based on the literature review aims to review the biliary complications following laparoscopic cholecystectomy with reference to its mechanism , preventive measures to be taken, and the management approach. PMID- 21822369 TI - Sensitivity Analysis and Bounding of Causal Effects With Alternative Identifying Assumptions. AB - When identification of causal effects relies on untestable assumptions regarding nonidentified parameters, sensitivity of causal effect estimates is often questioned. For proper interpretation of causal effect estimates in this situation, deriving bounds on causal parameters or exploring the sensitivity of estimates to scientifically plausible alternative assumptions can be critical. In this paper, we propose a practical way of bounding and sensitivity analysis, where multiple identifying assumptions are combined to construct tighter common bounds. In particular, we focus on the use of competing identifying assumptions that impose different restrictions on the same non-identified parameter. Since these assumptions are connected through the same parameter, direct translation across them is possible. Based on this cross-translatability, various information in the data, carried by alternative assumptions, can be effectively combined to construct tighter bounds on causal effects. Flexibility of the suggested approach is demonstrated focusing on the estimation of the complier average causal effect (CACE) in a randomized job search intervention trial that suffers from noncompliance and subsequent missing outcomes. PMID- 21822370 TI - Music and Cochlear Implants: Not in Perfect Harmony. PMID- 21822371 TI - Efficient synthesis and reactions of 1,2-dipyrrolylethynes. AB - Various dipyrroles possess important motifs for construction of pyrrole containing pigments. A series of 1,2-dipyrrolylethynes (4a-d) has been efficiently synthesized using an improved one-pot double Sonagashira coupling from trimethylsilylethyne and various 2-iodopyrroles. The resulting 1,2 dipyrrolylethynes were further transformed into novel indolyl-, ethenyl- and carboranyl-dipyrroles (5-7) using the Larock indole synthesis, stereoselective catalytic hydrogenation, or B(10)H(14). Indolyl-dipyrroles were found to selectively bind fluoride ions using one pyrrolic and the indolyl NHs, whereas the carboranyl- and ethenyl-dipyrroles are potentially valuable precursors for the synthesis of porphyrin isomers and expanded pigments. PMID- 21822372 TI - Mesenchymal stem cells: angels or demons? AB - Mesenchymal stem cells (MSCs) have been used in cell-based therapy in various disease conditions such as graft-versus-host and heart diseases, osteogenesis imperfecta, and spinal cord injuries, and the results have been encouraging. However, as MSC therapy gains popularity among practitioners and researchers, there have been reports on the adverse effects of MSCs especially in the context of tumour modulation and malignant transformation. These cells have been found to enhance tumour growth and metastasis in some studies and have been related to anticancer-drug resistance in other instances. In addition, various studies have also reported spontaneous malignant transformation of MSCs. The mechanism of the modulatory behaviour and the tumorigenic potential of MSCs, warrant urgent exploration, and the use of MSCs in patients with cancer awaits further evaluation. However, if MSCs truly play a role in tumour modulation, they can also be potential targets of cancer treatment. PMID- 21822373 TI - Successful aging and the epidemiology of HIV. AB - By 2015, it is estimated that nearly half of those living with HIV in the US will be 50 years of age and older. This dramatic change in the demographics of this clinical population represents unique challenges for patients, health care providers, and society-at-large. Fortunately, because of highly active antiretroviral therapy (HAART) and healthy lifestyle choices, it is now possible for many infected with HIV to age successfully with this disease; however, this depends upon one's definition of successful aging. It is proposed that successful aging is composed of eight factors: length of life, biological health, cognitive efficiency, mental health, social competence, productivity, personal control, and life satisfaction. Unfortunately, HIV and medication side effects can compromise these factors, thus diminishing one's capacity to age successfully with this disease. This article explores how HIV, medication side effects from HAART, and lifestyle choices can compromise the factors necessary to age successfully. Implications for practice and research are posited. PMID- 21822374 TI - Medical treatment and long-term outcome of chronic atrial fibrillation in the aged with chest distress: a retrospective analysis versus sinus rhythm. AB - Although "chest distress" is the most frequent complication in the aged with chronic atrial frbrillation (AF) in clinical practice, there are few data on the association between chronic AF and coronary artery disease (CAD) in the aged in terms of medical treatment and long-term outcome. We assessed coronary artery lesions in such patients and evaluated the efficacy of medical treatment in long term follow-ups. Of 315 elderly patients (mean age: 77.39 +/- 6.33 years) who had undergone coronary angiography for chest distress, 297 exhibited sinus rhythm (SR), whereas 18 patients exhibited chronic AF. Patients with AF were followed for 4.22 +/- 2.21 years. Average diastolic blood pressure (DBP) of AF patients was observed to be markedly less than that of patients with SR (57.33 +/- 6.87 mmHg vs 71.08 +/- 10.54 mmHg, t-test: P < 0.01). Compared with SR patients, severe stenosis of the coronary artery in AF patients was reduced (73.06% vs 44.44%, Chi-square test: P < 0.01). AF patients with chest distress had high CHADS2 score (3.72 +/- 1.27), but only 33.3% patients received oral anticoagulants, and such patients had a significantly lower rate of revascularization (21.43% vs 55.63%, Chi-square test: P < 0.01), and higher rate of all-cause death (22.22% vs 4.38%, Chi-square test: P < 0.01) and thromboembolism (16.67% vs 1.68%, Chi-square test: P < 0.01) in the long-term follow-ups compared with SR patients. Chest distress in the aged with AF was related to insufficient coronary blood supply that was primarily due to a reduced DBP rather than to occult CAD. Adequate and safe medical therapy was difficult to achieve in these patients. Such patients typically have a poor prognosis, and optimal therapeutic strategies to treat them are urgently needed. PMID- 21822375 TI - Adverse drug reaction suggested by a clinical vignette. PMID- 21822376 TI - Comparison of two treatments for coxarthrosis: local hyperthermia versus radio electric asymmetrical brain stimulation. AB - BACKGROUND: It is well known that psychological components are very important in the aging process and may also manifest in psychogenic movement disorders, such as coxarthrosis. This study analyzed the medical records of two similar groups of patients with coxarthrosis (n = 15 in each) who were treated in two different clinics for rehabilitation therapy. METHODS: Patients in Group A were treated with a course of traditional physiotherapy, including sessions of local hyperthermia. Group B patients were treated with only a course of radioelectric asymmetrical brain stimulation (REAC) to improve their motor behavior. RESULTS: Group A showed a significant decrease in symptoms of pain and stiffness, and an insignificant improvement in range of motion and muscle bulk. A single patient in this group developed worsened symptoms, and pain did not resolve completely in any patient. The patients in Group B had significantly decreased levels of pain and stiffness, and a significant improvement in range of motion and muscle bulk. No patients worsened in Group B, and the pain resolved completely in one patient. CONCLUSION: Both treatments were shown to be tolerable and safe. Patients who underwent REAC treatment appeared to have slightly better outcomes, with an appreciable improvement in both their physical and mental states. These aspects are particularly important in the elderly, in whom functional limitation is often associated with or exacerbated by a psychogenic component. PMID- 21822377 TI - Radio electric asymmetric brain stimulation in the treatment of behavioral and psychiatric symptoms in Alzheimer disease. AB - PURPOSE: Behavioral and psychiatric symptoms of dementia (BPSD) are common in Alzheimer's disease (AD) and disrupt the effective management of AD patients. The present study explores the use of radio electric asymmetric brain stimulation (REAC) in patients who have had a poor response to pharmacological treatment. PATIENTS AND METHODS: Eight patients (five females and three males; mean [+/ standard deviation] age at study baseline: 69.9 +/- 3.0 years) diagnosed with AD according to the DSM-IV-TR criteria (mean onset age of AD: 65.4 +/- 3.5 years) were cognitively and psychometrically assessed with the Mini-Mental State Examination (MMSE), the Activity of Daily Living (ADL), the Instrumental Activity of Daily Living (IADL), and the Neuropsychiatric Inventory (NPI), prior to and after each of 2 REAC treatment cycles. RESULTS: Scores on the MMSE and all subscales of the NPI (frequency, severity, and distress), the ADL, and the IADL were significantly improved following the initial REAC treatment. There was further significant improvement in all measurements (with a tendency for improvement in the IADL) after the second REAC treatment cycle. CONCLUSION: The improvement of cognitive and behavioral/psychiatric functioning following REAC treatment suggests that this innovative approach may be an effective, safe, and tolerable alternative to pharmacological treatment of AD patients, especially in the area of BPSD. Elderly patients suffering from other types of dementia may also benefit from REAC treatment. PMID- 21822378 TI - Preparation and evaluation of lidocaine hydrochloride in cyclodextrin inclusion complexes for development of stable gel in association with chlorhexidine gluconate for urogenital use. AB - Inclusions of lidocaine hydrochloride in cyclodextrins were prepared to obtain stable complexes compatible for association with chlorhexidine in a new gel formulation for use in urogenital applications. Two cyclodextrins, beta cyclodextrin and methyl-beta-cyclodextrin, were used for encapsulating lidocaine hydrochloride through solubilization and kneading techniques. The lidocaine cyclodextrin complexes were characterized by ultraviolet spectroscopy, Fourier transform infrared spectroscopy, differential scanning calorimetry, and X-ray diffraction. The results revealed that the techniques generated good yields of inclusion products that maintained the functional properties of lidocaine. In addition, the inclusion products obtained improved the compatibility of lidocaine hydrochloride with chlorhexidine in solution and a gel formulation. The gel formulation displayed desirable rheological and physicochemical properties. The results presented here are the first description of the inclusion of lidocaine with cyclodextrins, which improves compatibility with chlorhexidine in formulations for simultaneous delivery. PMID- 21822380 TI - Effect of interaction of magnetic nanoparticles of Fe3O4 and artesunate on apoptosis of K562 cells. AB - The present study evaluated whether the magnetic nanoparticles of Fe(3)O(4) (MNPs Fe(3)O(4)) could enhance the activity of artesunate (ART), and to explore its potential mechanisms. Cytotoxicity of the copolymer of ART with MNPs-Fe(3)O(4) on K562 cells was detected by MTT assay and the apoptosis rate of K562 cells was measured by flow cytometry. Protein expression levels of bcl-2, bax, bcl-rambo, caspase-3, and survivin in K562 cells were measured by Western blot. After being incubated with the copolymer of ART with MNPs-Fe(3)O(4) for 48 hours, the growth inhibition rate of K562 cells was significantly increased compared with that of K562 cells treated with ART alone (P < 0.05), and the apoptosis rate of K562 cells was increased significantly compared with that of K562 cells treated with ART alone, suggesting that MNPs-Fe(3)O(4) can enhance the activity of ART. Interestingly, the copolymer-induced cell death was attenuated by caspase inhibitor Z-VAD-FMK. Our results also showed that treatment with the copolymer of MNPs-Fe(3)O(4) and ART increased the expression of bcl-2, bax, bcl-rambo, and caspase-3 proteins, and decreased the expression of survivin protein in K562 cells compared with ART treatment alone. These results suggest that MNPs Fe(3)O(4) can enhance ART-induced apoptosis, which may be related to the upregulation of bcl-rambo and downregulation of survivin. PMID- 21822379 TI - Liposomes containing glycocholate as potential oral insulin delivery systems: preparation, in vitro characterization, and improved protection against enzymatic degradation. AB - BACKGROUND: Oral delivery of insulin is challenging and must overcome the barriers of gastric and enzymatic degradation as well as low permeation across the intestinal epithelium. The present study aimed to develop a liposomal delivery system containing glycocholate as an enzyme inhibitor and permeation enhancer for oral insulin delivery. METHODS: Liposomes containing sodium glycocholate were prepared by a reversed-phase evaporation method followed by homogenization. The particle size and entrapment efficiency of recombinant human insulin (rhINS)-loaded sodium glycocholate liposomes can be easily adjusted by tuning the homogenization parameters, phospholipid:sodium glycocholate ratio, insulin:phospholipid ratio, water:ether volume ratio, interior water phase pH, and the hydration buffer pH. RESULTS: The optimal formulation showed an insulin entrapment efficiency of 30% +/- 2% and a particle size of 154 +/- 18 nm. A conformational study by circular dichroism spectroscopy and a bioactivity study confirmed the preserved integrity of rhINS against preparative stress. Transmission electron micrographs revealed a nearly spherical and deformed structure with discernable lamella for sodium glycocholate liposomes. Sodium glycocholate liposomes showed better protection of insulin against enzymatic degradation by pepsin, trypsin, and alpha-chymotrypsin than liposomes containing the bile salt counterparts of sodium taurocholate and sodium deoxycholate. CONCLUSION: Sodium glycocholate liposomes showed promising in vitro characteristics and have the potential to be able to deliver insulin orally. PMID- 21822381 TI - Reversible exposure of hydrophobic residues on albumin as a novel strategy for formulation of nanodelivery vehicles for taxanes. AB - BACKGROUND: We report herein a novel strategy for the preparation of protein based nanodelivery vehicles for hydrophobic active pharmaceutical ingredients. METHODS: The procedure consisted of three steps, ie, exposure of hydrophobic residues of a protein to a pH-induced partial unfolding: interaction between hydrophobic residues on the protein and the hydrophobic active pharmaceutical ingredient, and a final step where the structure of the protein was reversed to a native-like state by returning to neutral pH. As proof of concept, the interaction of paclitaxel with partially unfolded states of human serum albumin was evaluated as a potential method for the preparation of water-soluble complexes of the taxane with albumin. RESULTS: We found that paclitaxel readily binds to pH-induced partially unfolded albumin, leading to the formation of optically clear water-soluble complexes. The complexes thus formed were more stable in solution when the albumin native state was at least partially restored by neutralization of the solution to a pH around 7. It was also observed that the hydrodynamic radius of human serum albumin was only slightly increased after the cycle of pH changes, remaining in a monomeric state with a size according to paclitaxel binding. Furthermore, paclitaxel binding did not affect the overall exposure of charged groups of human serum albumin, as evaluated by its interaction with an ionic exchange resin. CONCLUSION: The in vitro biological activity of the complexes formed was qualitatively equivalent to that of a Cremophor((r))-based formulation. PMID- 21822382 TI - A novel nanostructured biosensor for the detection of the dust mite antigen Der p2. AB - The group 2 allergen, Der p2, has been reported to activate innate toll-like receptors (TLRs) on respiratory epithelial cells and thus aggravate respiratory diseases. In this study, a highly sensitive nanostructured biosensor based on a 3D sensing element with uniformly deposited gold nanoparticles is proposed for the detection of the dust mite antigen Der p2. The barrier layer comprises an anodic aluminum oxide (AAO) film which is used as the template in this highly sensitive nanostructured biosensor. Simple electrochemical deposition without reducing agent and stabilizer was enough to uniformly synthesize gold nanoparticles on the surface of the barrier layer. The size and the distribution density of the nanoparticles can be well controlled by the applied potential during electrochemical deposition. Following this procedure, the dust mite monoclonal antibodies (IgG) were then immobilized through the 11-MUA (11 mercaptoundecanoic acid), (1-ethyl-3-(3-dimethyl-aminopropyl)-carbodiimide)/(N hydroxysuccinimide) self-assembled monolayer approach for the dust mite antigen Der p2 detection. The detection limit of the proposed 3D gold nanoparticle-based nanostructured biosensor was examined using electrochemical impedance spectroscopy analysis and found to be 1 pg/mL. The dynamic range was found to be 5 MUg/mL. The proposed nanostructured biosensor would be useful for fast detection of rare molecules in a solution. PMID- 21822383 TI - Proposal for Alzheimer's diagnosis using molecular buffer and bus network. AB - A novel design of an optical trapping tool for tangle protein (tau tangles, beta amyloid plaques) and molecular motor storage and delivery using a PANDA ring resonator is proposed. The optical vortices can be generated and controlled to form the trapping tools in the same way as the optical tweezers. In theory, the trapping force is formed by the combination between the gradient field and scattering photons, and is reviewed. By using the intense optical vortices generated within the PANDA ring resonator, the required molecular volumes can be trapped and moved dynamically within the molecular buffer and bus network. The tangle protein and molecular motor can transport and connect to the required destinations, enabling availability for Alzheimer's diagnosis. PMID- 21822384 TI - Cost-effectiveness analysis of memantine for moderate-to-severe Alzheimer's disease in the Netherlands. AB - OBJECTIVE: The purpose of this study was to estimate the cost-effectiveness of memantine relative to standard care in patients with moderate-to-severe Alzheimer's disease in the Netherlands. METHODS: A country-adapted five-year Markov model simulated disease progression through a series of states, defined by dependency and disease severity. Transition probabilities were derived from trials, with utility and epidemiological data obtained from a longitudinal Dutch cohort. Cost-effectiveness was described in terms of quality-adjusted life years and time spent in a nondependent state or in a moderate severity state. RESULTS: Memantine monotherapy versus standard care led to 0.058 quality-adjusted life years gained (1.207 versus 1.265), longer time in a nondependent state (from 1.602 to 1.751 years) and in a moderate state (from 2.051 to 2.141 years), and no additional costs (?113,927 versus ?110,097). Robustness of results was confirmed through sensitivity analyses. CONCLUSION: Memantine is dominant compared with standard care in the Netherlands. Results are consistent with similar economic evaluations in other countries. PMID- 21822385 TI - Update on treatment options for Lambert-Eaton myasthenic syndrome: focus on use of amifampridine. AB - In Lambert-Eaton myasthenic syndrome (LEMS), antibodies against presynaptic voltage-gated calcium channels reduce the quantal release of acetylcholine, causing muscle weakness and autonomic dysfunction. More than half of the affected patients have associated small cell lung cancer, and thorough screening for an underlying malignancy is crucial. The mainstay of treatment for LEMS is symptomatic but immunotherapy is needed in more severely affected patients. Symptomatic therapies aim at increasing the concentration of acetylcholine at the muscle endplate. While acetylcholinesterase inhibitors were the first drugs to be used for the amelioration of symptoms, 3,4-diaminopyridine (3,4-DAP, amifampridine) has been shown to be more effective. 3,4-DAP blocks presynaptic potassium channels, thereby prolonging the action potential and increasing presynaptic calcium concentrations. This then results in increased quantal release of acetylcholine. The efficacy of 3,4-DAP for increasing muscle strength and resting compound muscle action potentials has been demonstrated by four placebo-controlled trials. Side effects are usually mild, and the most frequently reported are paresthesias. The most common serious adverse events are epileptic seizures. 3,4-DAP is currently the treatment of choice in patients with Lambert Eaton myasthenic syndrome. PMID- 21822386 TI - Investigation of insulin resistance in narcoleptic patients: dependent or independent of body mass index? AB - BACKGROUND: Narcolepsy is a severe sleep-wake cycle disorder resulting in most cases from a lack of orexin, the energy balance-regulating hormone. Narcoleptic patients have been reported to suffer from an excess morbidity of Type 2 diabetes, even after correction for their often elevated body mass index. METHODS: To explore whether narcolepsy is specifically associated with a propensity to develop insulin resistance, we measured fasting glucose, insulin, and intact proinsulin levels in 43 narcoleptic patients and 47 controls matched for body mass index and age. The proinsulin-to-insulin ratio was calculated. Insulin resistance was determined using the homeostatic model assessment method. RESULTS: Narcoleptic patients did not show elevated insulin resistance parameters. CONCLUSION: In contrast with earlier reports, we found no evidence that narcolepsy specifically elevates the risk of insulin resistance (and consequently of type 2 diabetes) independently of body mass index. PMID- 21822387 TI - Remembering and forgetting: directed forgetting effect in obsessive-compulsive disorder. AB - It has been reported that episodic memory seems to be impaired in patients with obsessive-compulsive disorder (OCD) because the patients repeat a specific checking behavior, but it is still unknown if OCD patients show memory impairments associated with their unique symptoms or not. To study episodic memory in OCD patients, we examined the directed forgetting effect. Patients with OCD and healthy control participants were given a list of 24 emotionally neutral everyday words (12 remember [R]-cued words and 12 forget [F]-cued words) under two conditions: List and Item. The results of our study showed that OCD patients recalled a number of F-cued words similar to that for controls and relatively fewer R-cued words than controls under both List and Item conditions. Consequently, the directed forgetting effect was smaller in OCD patients than controls. Our results demonstrated that both selective encoding and retrieval inhibition processes are impaired in OCD, and we suggest that recall of unfavorable items to be forgotten intruded into necessary items to be remembered. This impairment in episodic memory may partially account for some of the unique clinical symptoms of OCD. PMID- 21822388 TI - Long-term treatment of bipolar disorder with a radioelectric asymmetric conveyor. AB - BACKGROUND: The bipolar spectrum disorders are considered an important and frequent psychiatric problem. The clinical complexity of these illnesses due to the coexistence of depressive and excitative phases is correlated with the global difficulty of adequate treatment; consequently, the prognosis is not optimal. For this reason, in recent years, novel nonpharmacologic physical approaches have been tested for bipolar disorders, with encouraging results. The aim of this study was to evaluate the long-term effectiveness of a radioelectric asymmetric brain stimulation device associated with lithium (REAC-lithium) versus previous treatments in subjects with bipolar disorder I or II, evaluated as the number of recurrences compared with the period of illness preceding treatment with REAC lithium. METHODS: The charts of 56 bipolar patients attending our institute were retrospectively evaluated. Treatment with REAC-lithium was administered following the standard Rinaldi-Fontani Institute protocol. Add-on treatments were allowed in the event of manic or depressive recurrence. Eight patients (Group 1) were followed for 30.2 +/- 3.0 months, 14 patients (Group 2) were followed for 25.3 +/ 3.3 months, 25 patients (Group 3) were followed for 20.3 +/- 1.6 months, and nine patients (Group 4) were followed for 16.2 +/- 0.5 months. RESULTS: After REAC-lithium treatment, the number of manic and depressive episodes in Group 1 decreased from 2.1 +/- 0.6 and 3.0 +/- 0.7 to 0.12 +/- 0.0 and 0.8 +/- 0.4, respectively. In Group 2, the number of manic and depressive episodes decreased from 2.4 +/- 0.6 and 3.9 +/- 0.7 to 0.14 +/- 0.2 and 0.0 +/- 0.0, respectively. In Group 3, the number of manic and depressive episodes decreased from 2.6 +/- 0.8 and 3.6 +/- 0.9 to 0.04 +/- 0.0 and 0.0 +/- 0.0, respectively. In Group 4, the number of manic and depressive episodes decreased from 2.6 +/- 1.1 and 3.7 +/ 1.0 to 0.1 +/- 0.0 and 0.0 +/- 0.0, respectively. All results were statistically significant. CONCLUSION: REAC showed good efficacy in treating both the manic and depressive phases of bipolar disorder, and in the prevention of recurrences/relapses. PMID- 21822389 TI - Choking risk among psychiatric inpatients. PMID- 21822390 TI - Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy in an Israeli family. AB - Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic form of hereditary cerebral microangiopathy, and is caused by over 170 different mutations in the NOTCH3 gene at locus 19p13.1-13.26. We report the first study of familial CADASIL in a 39-year-old Jewish woman and her mother who had died previously. The patient's investigations revealed a normal hemogram with no vascular risk factors or chronic disease. Lumbar puncture was normal. Cranial computed tomography scan revealed bilateral diffuse hypodensities in the subcortical white matter. Cranial magnetic resonance imaging showed hyperintense lesions in the cerebral white matter on T2-weighted images. On electron microscopy, a characteristic granular osmiophilic material was seen in the basement membrane surrounding the pericytes and smooth muscle cells in small-sized and medium-sized vessels. Molecular analysis of the NOTCH3 gene was performed with automatic sequencing of exon 3 and 4 (and intron-exon boundaries) showing a nucleotide c.268C > T substitution, leading to a pathogenic amino acid substitution of p.Arg90Cys, confirming a diagnosis of CADASIL. This mutation was also found in the patient's mother. Although the exact prevalence of CADASIL is not known, this disorder has been reported worldwide, and now including Jews, with a genotype and clinical phenotype similar to that in other ethnic groups. PMID- 21822391 TI - Long-acting injectable risperidone in partially adherent and nonadherent patients with schizophrenia. AB - BACKGROUND: Long-acting injectable antipsychotics may improve medication adherence, thereby improving overall treatment effectiveness. This study aimed to evaluate the effectiveness, safety, and tolerability of risperidone long-acting injection in schizophrenic patients switched from oral antipsychotic medication. METHODS: In a 12-month, multicenter, open-label, noncomparative study, symptomatically stable patients on oral antipsychotic medication with poor treatment adherence during the previous 12 months received intramuscular injections of risperidone long-acting injection (25 mg starting dose) every 2 weeks. The primary endpoint was the change in Positive and Negative Syndrome Scale (PANSS) total score. RESULTS: Of the 60 patients who were screened, 53 received at least one injection (safety population), and 51 provided at least one postbaseline assessment. Mean PANSS total scores improved significantly throughout the study and at endpoint. Significant improvements were also observed in Clinical Global Impression of Severity, Personal and Social Performance, and Drug Attitude Inventory scales. Risperidone long-acting injection was safe and well-tolerated. Severity of movement disorders on the Extrapyramidal Symptom Rating Scale was reduced significantly. The most frequently reported adverse events were insomnia (22.6%), increased prolactin (17.0%), and weight gain (13.2%). CONCLUSION: Risperidone long-acting injection was associated with significant symptomatic improvements in stable patients with schizophrenia following a switch from previous antipsychotic medications. PMID- 21822393 TI - Therapeutic potential of rivaroxaban in the prevention of venous thromboembolism following hip and knee replacement surgery: a review of clinical trial data. AB - Rivaroxaban (Bayer AG, Leverkusen, Germany) is a highly selective direct inhibitor of factor Xa. It has completed Phase III clinical trials evaluating its efficacy and safety against enoxaparin in the prophylaxis against venous thromboembolism (VTE) in orthopedic patients following primary total hip and total knee arthroplasty. Rivaroxaban has been extensively studied worldwide in 12,729 patients in the Regulation of Coagulation in Major Orthopedic Surgery Reducing the Risk of DVT and PE (RECORD) program. Pivotal clinical trials have demonstrated the superior efficacy in reducing total VTE in comparison with both the North American and European regimens of enoxaparin. Safety of the drug was found to be excellent, with no demonstrable cardiovascular or hepatic effects and no statistically significant increase in major bleeding. A pooled analysis of data collected on the patients from the four RECORD trials revealed rivaroxaban to be the first antithrombotic agent to demonstrate superiority over another antithrombotic (enoxaparin) in reducing symptomatic VTE and all-cause mortality. While there was a significant difference in the composite safety endpoint of major and clinically relevant nonmajor bleeding in the pooled analysis with the use of rivaroxaban compared with enoxaparin, there was no significant difference in major bleeding or in any other bleeding. PMID- 21822392 TI - Oral antiplatelet therapy in diabetes mellitus and the role of prasugrel: an overview. AB - Diabetics have a prothrombotic state that includes increased platelet reactivity. This contributes to the less favorable clinical outcomes observed in diabetics experiencing acute coronary syndromes as well as stable coronary artery disease. Many diabetics are relatively resistant to or have insufficient response to several antithrombotic agents. In the setting of percutaneous coronary intervention, hyporesponsiveness to clopidogrel is particularly common among diabetics. Several strategies have been examined to further enhance the benefits of oral antiplatelet therapy in diabetics. These include increasing the dose of clopidogrel, triple antiplatelet therapy with cilostazol, and new agents such as prasugrel. The large TRITON TIMI 38 randomized trial compared clopidogrel to prasugrel in the setting of percutaneous coronary intervention for acute coronary syndromes. The diabetic subgroup (n = 3146) experienced considerable incremental benefit with a 4.8% reduction in cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke at 15-month follow-up with prasugrel treatment. Among diabetics on insulin this combined endpoint was reduced by 7.9% at 15 months. Major bleeding was not increased in the diabetic subgroup. This confirms the general hypothesis that more potent oral antiplatelet therapy can partially overcome the prothrombotic milieu and safely improve important clinical outcomes in diabetics. PMID- 21822394 TI - Pre-eclampsia: pathophysiology, diagnosis, and management. AB - The incidence of pre-eclampsia ranges from 3% to 7% for nulliparas and 1% to 3% for multiparas. Pre-eclampsia is a major cause of maternal mortality and morbidity, preterm birth, perinatal death, and intrauterine growth restriction. Unfortunately, the pathophysiology of this multisystem disorder, characterized by abnormal vascular response to placentation, is still unclear. Despite great polymorphism of the disease, the criteria for pre-eclampsia have not changed over the past decade (systolic blood pressure > 140 mmHg or diastolic blood pressure >= 90 mmHg and 24-hour proteinuria >= 0.3 g). Clinical features and laboratory abnormalities define and determine the severity of pre-eclampsia. Delivery is the only curative treatment for pre-eclampsia. Multidisciplinary management, involving an obstetrician, anesthetist, and pediatrician, is carried out with consideration of the maternal risks due to continued pregnancy and the fetal risks associated with induced preterm delivery. Screening women at high risk and preventing recurrences are key issues in the management of pre-eclampsia. PMID- 21822397 TI - Mobile Care (Moca) for Remote Diagnosis and Screening. AB - Moca is a cell phone-facilitated clinical information system to improve diagnostic, screening and therapeutic capabilities in remote resource-poor settings. The software allows transmission of any medical file, whether a photo, x-ray, audio or video file, through a cell phone to (1) a central server for archiving and incorporation into an electronic medical record (to facilitate longitudinal care, quality control, and data mining), and (2) a remote specialist for real-time decision support (to leverage expertise). The open source software is designed as an end-to-end clinical information system that seamlessly connects health care workers to medical professionals. It is integrated with OpenMRS, an existing open source medical records system commonly used in developing countries. PMID- 21822395 TI - Increased reactive oxygen metabolites is associated with cardiovascular risk factors and vascular endothelial damage in middle-aged Japanese subjects. AB - BACKGROUND: Vascular endothelium, a provider of nitric oxide, is essential for the maintenance of homeostasis in healthy vascular systems. Increased oxidative stress promotes vascular inflammation and is a common pathway involved in endothelial damage. The present study sought to investigate the usefulness of derivative reactive oxygen metabolites (d-ROM) as an oxidative stress marker for detecting endothelial damage in the clinical setting in subjects with early-stage atherosclerosis. METHODS: Study 1 investigated the relationship between serum d ROM levels and cardiovascular risk factors in apparently healthy middle-aged subjects (n = 1992, 49 +/- 8 years) who participated in our health checkup program. Study 2 analyzed the association between d-ROM levels and endothelial function assessed by flow-mediated dilation and that between d-ROM levels and high-sensitivity C reactive protein (hs-CRP) levels in middle-aged outpatients with mild-to-moderate cardiovascular risk (n = 43, 40 +/- 5 years). RESULTS: In study 1, the d-ROM level was independently correlated with age, systolic blood pressure, fasting plasma glucose, low-density lipoprotein cholesterol, and brain natriuretic peptide in univariate and multivariate regression analysis. In study 2, the d-ROM level was correlated positively with the hs-CRP level and inversely with the flow-mediated dilation value. Patients in the highest tertile of d-ROM had significantly lower flow-mediated dilation values compared with patients in the other tertiles. Moreover, after subdivision of patients into four groups according to d-ROM and hs-CRP levels, patients with high levels of both d-ROM and hs-CRP showed significantly reduced flow-mediated dilation as compared with those with low levels of both indices. CONCLUSION: The close relationship of d-ROM with cardiovascular risk factors, brain natriuretic peptide, inflammatory markers (hs CRP), and endothelial function (flow-mediated dilation) suggest that d-ROM is a useful oxidative stress marker for detection of endothelial damage in the clinical setting. Assessment of d-ROM, especially combined with hs-CRP, may be a possible predictor of cardiovascular disease. PMID- 21822396 TI - Incident prediabetes/diabetes and blood pressure in urban and rural communities in the Democratic Republic of Congo. AB - BACKGROUND: The Democratic Republic of Congo (DRC) faces increased morbidity and mortality due to treatable and preventable noncommunicable diseases. However, it continues to struggle with political and economic instability, which impedes much needed health infrastructure improvements. The present study was designed as a low-cost determination of the prevalence of incident prediabetes/diabetes in the DRC. METHOD: Fasting blood glucose, body mass index, blood pressure, and age were assessed in adult participants in health screenings conducted throughout urban and rural DRC. Communities were divided into three categories, based on physical activity (means of transport) and diet, ie, traditional (nonmotorized transport and vegetable/starch-based diets); transitional (incorporating traditional practices with motorized transport) and modern (motorized transport and protein/ processed foods). Fasting blood glucose and blood pressure were established using finger prick blood samples and monitors approved by the US Food and Drug Administration. RESULTS: The prevalence of incident prediabetes/diabetes was over 47% for the traditional population, 88.6% for the transitional population, and 91.4% for the modern communities. Fasting blood glucose levels analyzed through an analysis of covariance, with age and body mass index as covariates, demonstrated that fasting blood glucose levels of male and female subgroups in the traditional community (101.8 +/- 29.3 mg/dL and 95.4 +/- 27.8 mg/dL, respectively), were significantly reduced compared with the transitional (122.1 +/- 19.4 mg/dL and 122.8 +/- 23.9 mg/dL), and modern (118.8 +/- 15.9 mg/dL and 114.1 +/- 17.1 mg/dL) populations. Additionally, for the male and female subgroups, logistic regression analysis confirmed a significant association between incident prediabetes/diabetes, fasting blood glucose, diet, and level of physical activity. CONCLUSION: There is a higher than expected prevalence of incident prediabetes/diabetes in the DRC adult population, without a clear association with risk factors pertaining to diet, level of physical activity, body mass index, and blood pressure. The substantial morbidity and mortality associated with diabetes highlights the critical need for further and more precise diabetic diagnostic testing throughout the DRC. PMID- 21822398 TI - Improving drug abuse treatment delivery through adoption of harmonized electronic health record systems. AB - A great divide currently exists between mainstream health care and specialty substance use disorders (SUD) treatment, concerning the coordination of care and sharing of medical information. Improving the coordination of SUD treatment with other disciplines of medicine will benefit SUD patients. The development and use of harmonized electronic health record systems (EHR) containing standardized person-level information will enable improved coordination of healthcare services. We attempt here to illuminate the urgent public health need to develop and implement at the national level harmonized EHR including data fields containing standardized vocabulary/terminologies relevant to SUD treatment. The many advantages and barriers to harmonized EHR implementation in SUD treatment service groups, and pathways to their successful implementation, are also discussed. As the US Federal Government incentivizes Medicare and Medicaid Service providers nationwide for "meaningful use" of health information technology (HIT) systems, relevant stakeholders may face relatively large and time-consuming processes to conform their local practices to meet the federal government's "meaningful use" criteria unless they proactively implement data standards and elements consistent with those criteria. Incorporating consensus based common data elements and standards relevant to SUD screening, diagnosis, and treatment into the federal government's "meaningful use" criteria is an essential first step to develop necessary infrastructure for effective coordination of HIT systems among SUD treatment and other healthcare service providers to promote collaborative-care implementation of cost-effective, evidence-based treatments and to support program evaluations. PMID- 21822400 TI - Field Deployable Method for Arsenic Speciation in Water. AB - Contamination of drinking water supplies by arsenic is a world-wide problem. Total arsenic measurements are commonly used to investigate and regulate arsenic in water, but it is well understood that arsenic occurs in several chemical forms, and these exhibit different toxicities. It is problematic to use laboratory-based speciation techniques to assess exposure as it has been suggested that the distribution of species is not stable during transport in some types of samples. A method was developed in this study for the on-site speciation of the most toxic dissolved arsenic species: As (III), As (V), monomethylarsonic acid (MMA) and dimethylarsenic acid (DMA). Development criteria included ease of use under field conditions, applicable at levels of concern for drinking water, and analytical performance.The approach is based on selective retention of arsenic species on specific ion-exchange chromatography cartridges followed by selective elution and quantification using graphite furnace atomic absorption spectroscopy. Water samples can be delivered to a set of three cartridges using either syringes or peristaltic pumps. Species distribution is stable at this point, and the cartridges can be transported to the laboratory for elution and quantitative analysis. A set of ten replicate spiked samples of each compound, having concentrations between 1 and 60 ug/L, were analyzed. Arsenic recoveries ranged from 78-112 % and relative standard deviations were generally below 10%. Resolution between species was shown to be outstanding, with the only limitation being that the capacity for As (V) was limited to approximately 50 ug/L. This could be easily remedied by changes in either cartridge design, or the extraction procedure. Recoveries were similar for two spiked hard groundwater samples indicating that dissolved minerals are not likely to be problematic. These results suggest that this methodology can be use for analysis of the four primary arsenic species of concern in drinking water supplies. PMID- 21822399 TI - Formation of C-C Bonds via Iridium-Catalyzed Hydrogenation and Transfer Hydrogenation. AB - The formation of C-C bonds via catalytic hydrogenation and transfer hydrogenation enables carbonyl and imine addition in the absence of stoichiometric organometallic reagents. In this review, iridium-catalyzed C-C bond-forming hydrogenations and transfer hydrogenations are surveyed. These processes encompass selective, atom-economic methods for the vinylation and allylation of carbonyl compounds and imines. Notably, under transfer hydrogenation conditions, alcohol dehydrogenation drives reductive generation of organoiridium nucleophiles, enabling carbonyl addition from the aldehyde or alcohol oxidation level. In the latter case, hydrogen exchange between alcohols and pi-unsaturated reactants generates electrophile-nucleophile pairs en route to products of hydro hydroxyalkylation, representing a direct method for the functionalization of carbinol C-H bonds. PMID- 21822401 TI - Presence and Quality of Kindergarten Children's Friendships: Concurrent and Longitudinal Associations with Child Adjustment in the Early School Years. AB - The presence and quality of friendships are posited to have developmental significance, yet little is known about the extent to which children without friends versus low-quality friendships compare on socioemotional adjustment. The current study utilized data from a subsample of 567 children (289 boys) participating in the NICHD Study of Early Child Care and Youth Development. Based on maternal reports at kindergarten, four friendship groups were formed: no friends, low quality, average quality, and high quality, and these groups were used to predict teacher-reported behavior problems and social skills concurrently (in kindergarten) and longitudinally (in first and third grade). Concurrently, low-quality friendships were associated with greater externalizing behavior, whereas high-quality friendships were associated with greater social skills. Longitudinally, having no friends in kindergarten was associated with higher levels of externalizing behavior for boys, but lower levels for girls. Children without friends also showed more internalizing problems at first grade. Lastly, having a high-quality friendship in kindergarten was associated with greater social skills in first and third grades, but only for boys. Results underscore high-quality friendship as a context for the development of social skills and indicate different trajectories of problem behavior for kindergarten children with no friends versus low-quality friendships. PMID- 21822402 TI - Attributions and Attitudes of Mothers and Fathers in the United States. AB - OBJECTIVE.: The present study examined mean level similarities and differences as well as correlations between U.S. mothers' and fathers' attributions regarding successes and failures in caregiving situations and progressive versus authoritarian attitudes. DESIGN.: Interviews were conducted with both mothers and fathers in 139 European American, Latin American, and African American families. RESULTS.: Interactions between parent gender and ethnicity emerged for adult-controlled failure and perceived control over failure. Fathers reported higher adult-controlled failure and child-controlled failure attributions than did mothers, whereas mothers reported attitudes that were more progressive and modern than did fathers; these differences remained significant after controlling for parents' age, education, and possible social desirability bias. Ethnic differences emerged for five of the seven attributions and attitudes examined; four remained significant after controlling for parents' age, education, and possible social desirability bias. Medium effect sizes were found for concordance between parents in the same family for attributions regarding uncontrollable success, child-controlled failure, progressive attitudes, authoritarian attitudes, and modernity of attitudes after controlling for parents' age, education, and possible social desirability bias. CONCLUSIONS.: This work elucidates ways that parent gender and ethnicity relate to attributions regarding U.S. parents' successes and failures in caregiving situations and to their progressive versus authoritarian parenting attitudes. PMID- 21822403 TI - Differential Protein Expression in Sugarcane during Sugarcane-Sporisorium scitamineum Interaction Revealed by 2-DE and MALDI-TOF-TOF/MS. AB - To understand the molecular basis of a specific plant-pathogen interaction, it is important to identify plant proteins that respond to the pathogen attack. Two sugarcane varieties, NCo376 and Ya71-374, were used in this study. By applying 2 dimensional electrophoresis (2-DE), the protein expression profile of sugarcane after inoculating with Sporisorium scitamineum was analyzed. In total, 23 differentially expressed proteins were identified by MALDI-TOF-TOF/MS. Bioinformatics analysis revealed that the functions of these 20 differential proteins were associated with such functions as photosynthesis, signal transduction, and disease resistance, while the function of the remaining three proteins was not determined. From above, we can assume that the protein regulatory network during the interaction between sugarcane and S. scitamineum is complicated. This represents the first proteomic investigation focused on highlighting the alterations of the protein expression profile in sugarcane exposed to S. scitamineum, and it provides reference information on sugarcane response to S. scitamineum stress at the protein level. PMID- 21822404 TI - Use of an exogenous plasmid standard and quantitative PCR to monitor spatial and temporal distribution of Enterococcus spp. in beach sands. AB - Studies using culture dependent methods have indicated that enterococci, the fecal indicator used to monitor marine waters for the potential of enteric disease risk to swimmers, can be abundant in beach sands and may contribute to water column indicator exceedances. A quantitative PCR (qPCR) method for the Enterococcus genus was tested and applied to more rapidly determine the amount of enterococci in beach sands and study their distribution over space and time. The qPCR method amplified a 23S rDNA sequence specific to Enterococcus (Ludwig and Schliefer, 2000), and was used to examine subsamples and composite samples of wet and dry beach sand from Avalon Bay, CA. The differences in efficiency of DNA recovery and inhibition in qPCR reactions were accounted for by spiking pairs of duplicate subsamples with a known amount of pGEM plasmid before or after extraction, respectively (Coyne et al. 2005). This study revealed levels of environmental inhibition that were similar in wet and dry sands, and efficiency of DNA recovery that was observably lower for wet beach sands and varied between years. Using the correction factors generated by this method to estimate the abundance of Enterococcus, we show that wet and dry beach sands both have Enterococcus spp. populations that can vary dramatically from day to day, and often are potentially higher than the equivalent health standards mandated for recreational waters. PMID- 21822405 TI - NEAR-INFRARED DYES: Probe Development and Applications in Optical Molecular Imaging. AB - The recent emergence of optical imaging has brought forth a unique challenge for chemists: development of new biocompatible dyes that fluoresce in the near infrared (NIR) region for optimal use in biomedical applications. This review describes the synthesis of NIR dyes and the design of probes capable of noninvasively imaging molecular events in small animal models. PMID- 21822407 TI - Electrochemical Oscillations of Nickel Electrodissolution in an Epoxy-Based Microchip Flow Cell. AB - We investigate the nonlinear dynamics of transpassive electrodissolution of nickel in sulfuric acid in an epoxy-based microchip flow cell. We observed bistability, smooth, relaxation, and period-2 waveform current oscillations with external resistance attached to the electrode in the microfabricated electrochemical cell with 0.05 mm diameter Ni wire under potentiostatic control. Experiments with 1mm * 0.1 mm Ni electrode show spontaneous oscillations without attached external resistance; similar surface area electrode in macrocell does not exhibit spontaneous oscillations. Combined experimental and numerical studies show that spontaneous oscillation with the on-chip fabricated electrochemical cell occurs because of the unusually large ohmic potential drop due to the constrained current in the narrow flow channel. This large IR potential drop is expected to have an important role in destabilizing negative differential resistance electrochemical (e.g., metal dissolution and electrocatalytic) systems in on-chip integrated microfludic flow cells. The proposed experimental setup can be extendend to multi-electrode configurations; the epoxy-based substrate procedure thus holds promise in electroanalytical applications that require collector-generator multi-electrodes wires with various electrode sizes, compositions, and spacings as well as controlled flow conditions. PMID- 21822406 TI - Radiolabeled oligonucleotides for antisense imaging. AB - Oligonucleotides radiolabeled with isotopes emitting gamma-rays (for SPECT imaging) or positrons (for PET imaging) can be useful for targeting messenger RNA (mRNA) thereby serving as non-invasive imaging tools for detection of gene expression in vivo (antisense imaging). Radiolabeled oligonucleotides may also be used for monitoring their in vivo fate, thereby helping us better understand the barriers to its delivery for antisense targeting. These developments have led to a new area of molecular imaging and targeting, utilizing radiolabeled antisense oligonucleotides. However, the success of antisense imaging relies heavily on overcoming the barriers for its targeted delivery in vivo. Furthermore, the low ability of the radiolabeled antisense oligonucleotide to subsequently internalize into the cell and hybridize with its target mRNA poses additional challenges in realizing its potentials. This review covers the advances in the antisense imaging probe development for PET and SPECT, with an emphasis on radiolabeling strategies, stability, delivery and in vivo targeting. PMID- 21822408 TI - Marine carotenoids and cardiovascular risk markers. AB - Marine carotenoids are important bioactive compounds with physiological activities related to prevention of degenerative diseases found principally in plants, with potential antioxidant biological properties deriving from their chemical structure and interaction with biological membranes. They are substances with very special and remarkable properties that no other groups of substances possess and that form the basis of their many, varied functions and actions in all kinds of living organisms. The potential beneficial effects of marine carotenoids have been studied particularly in astaxanthin and fucoxanthin as they are the major marine carotenoids. Both these two carotenoids show strong antioxidant activity attributed to quenching singlet oxygen and scavenging free radicals. The potential role of these carotenoids as dietary anti-oxidants has been suggested to be one of the main mechanisms for their preventive effects against cancer and inflammatory diseases. The aim of this short review is to examine the published studies concerning the use of the two marine carotenoids, astaxanthin and fucoxanthin, in the prevention of cardiovascular diseases. PMID- 21822409 TI - Thermal transition properties of hoki (Macruronus novaezelandiae) and ling (Genypterus blacodes) skin collagens: implications for processing. AB - Hoki (Macruronus novaezelandiae) and ling (Genypterus blacodes) are cold-water fish caught in New Zealand waters. Their skins are a major component of the post processing waste stream. Valuable products could be developed from the skins, as they are primarily composed of collagen, which has many commercial applications. We prepared acid soluble collagens (ASC) from hoki and ling skins, and analyzed their thermal denaturation properties using a Rapid ViscoTM Analyzer. At slower heating rates the denaturation temperature (TD) of hoki and ling collagens decreased. This result is consistent with the model of irreversible rate kinetics for the denaturation of collagen. We determined the effects of solvents that disrupt hydrogen bonding on ASC stability. Increasing concentrations of urea from 0.1 M to 1.0 M and acetic acid from 0.1 M to 0.5 M decreased TD. This resulted from the effects of these reagents on the hydrogen bonds that stabilize the collagen triple helix. PMID- 21822410 TI - Antiviral activities of sulfated polysaccharides isolated from Sphaerococcus coronopifolius (Rhodophytha, Gigartinales) and Boergeseniella thuyoides (Rhodophyta, Ceramiales). AB - Water-soluble sulfated polysaccharides isolated from two red algae Sphaerococcus coronopifolius (Gigartinales, Sphaerococcaceae) and Boergeseniella thuyoides (Ceramiales, Rhodomelaceae) collected on the coast of Morocco inhibited in vitro replication of the Human Immunodeficiency Virus (HIV) at 12.5 MUg/mL. In addition, polysaccharides were capable of inhibiting the in vitro replication of Herpes simplex virus type 1 (HSV-1) on Vero cells values of EC50 of 4.1 and 17.2 MUg/mL, respectively. The adsorption step of HSV-1 to the host cell seems to be the specific target for polysaccharide action. While for HIV-1, these results suggest a direct inhibitory effect on HIV-1 replication by controlling the appearance of the new generations of virus and potential virucidal effect. The polysaccharides from S. coronopifolius (PSC) and B. thuyoides (PBT) were composed of galactose, 3,6-anhydrogalactose, uronics acids, sulfate in ratios of 33.1, 11.0, 7.7 and 24.0% (w/w) and 25.4, 16.0, 3.2, 7.6% (w/w), respectively. PMID- 21822411 TI - A new hydroxylated nonaprenylhydroquinone from the Mediterranean marine sponge Sarcotragus spinosulus. AB - Chemical investigation of the Mediterranean sponge Sarcotragus spinosulus led to the isolation of a new hydroxylated nonaprenylhydroquinone, along with two known metabolites, hepta- and octaprenylhydroquinones. The structure of the new metabolite was assigned by extensive 1D and 2D NMR analyses and MS studies. The antileukemic effect of the three compounds towards the chronic myelogenous leukemia (CML) cells line K562 was also evaluated. PMID- 21822412 TI - Digestive enzymes of the crustaceans Munida and their application in cheese manufacturing: a review. AB - Crustaceans Munida (fam. Galatheideae, ord. Decapodi) were fished in the Southern Adriatic Sea and their proteolytic activities were characterized and tested for potential application in cheese manufacturing. Enzymes extracted from whole crustaceans, mainly serine proteases, showed high caseinolytic and moderate clotting activities. Analysis by 2D zymography of the digestive enzymes extracted from Munida hepatopancreas, showed the presence of several isotrypsin- and isochymotrypsin-like enzymes in the range of 20-34 kDa and 4.1-5.8 pI. Moreover, specific enzymatic assays showed the presence of aminopeptidases and carboxypeptidases A and B. Overall, optimum activity was achieved at pH 7.5 and 40-45 degrees C. Caseinolytic activity, determined both spectrophotometrically and by SDS gel electrophoresis, indicated higher activity on beta-casein than on alpha-casein. Miniature cheddar-type cheeses and Pecorino-type cheeses were manufactured by adding starter, rennet and Munida extracts to milk. Reverse-phase HPLC and MALDI-ToF mass spectrometry showed a more complex pattern of proteolytic products in cheeses made using Munida instead of chymosin. Munida extracts were found to degrade the chymosin-derived beta-casein fragment f193-209, one of the peptides associated with bitterness in cheese. In conclusion, Munida digestive enzymes represent a promising tool for development of new cheese products and shorten cheese ripening when used either alone or in addition to calf rennet. PMID- 21822413 TI - Assessment of bioflocculant production by Bacillus sp. Gilbert, a marine bacterium isolated from the bottom sediment of Algoa Bay. AB - The bioflocculant-producing potentials of a marine bacteria isolated from the bottom sediment of Algoa Bay was investigated using standard methods. The 16S rDNA sequence analysis revealed 98% similarity to that of Bacillus sp. HXG-C1 and the nucleotide sequence was deposited in GenBank as Bacillus sp. Gilbert with accession number HQ537128. Bioflocculant was optimally produced when sucrose (72% flocculating activity) and ammonium chloride (91% flocculating activity) were used as sole sources of carbon and nitrogen, respectively; an initial pH 6.2 of the production medium; and Mg2+ as cation. Chemical analysis of the purified bioflocculant revealed the compound to be a polysaccharide. PMID- 21822414 TI - Cembranoids with 3,14-ether linkage and a secocembrane with bistetrahydrofuran from the Dongsha Atoll soft coral Lobophytum sp. AB - Four new cembranoids, lobophylins A-D (1-4), and one novel secocembrane, lobophylin E (5) were isolated from a soft coral Lobophytum sp. The structures of new metabolites were elucidated on the basis of extensive spectroscopic methods. Among these metabolites, 1-4 are rarely found cembranoids possessing a tetrahydrofuran moiety with a 3,14-ether linkage. In addition, 5 is the first secocembrane possessing two tetrahydrofuran moieties with 3,14- and 4,7-ether linkages. PMID- 21822415 TI - Proteomic analysis of anti-tumor effects of 11-dehydrosinulariolide on CAL-27 cells. AB - The anti-tumor effects of 11-dehydrosinulariolide, an active ingredient isolated from soft coral Sinularia leptoclados, on CAL-27 cells were investigated in this study. In the MTT assay for cell proliferation, increasing concentrations of 11 dehydrosinulariolide decreased CAL-27 cell viability. When a concentration of 1.5 MUg/mL of 11-dehydrosinulariolide was applied, the CAL-27 cells viability was reduced to a level of 70% of the control sample. The wound healing function decreased as the concentration of 11-dehydrosinulariolide increased. The results in this study indicated that treatment with 11-dehydrosinulariolide for 6 h significantly induced both early and late apoptosis of CAL-27 cells, observed by flow cytometric measurement and microscopic fluorescent observation. A comparative proteomic analysis was conducted to investigate the effects of 11 dehydrosinulariolide on CAL-27 cells at the molecular level by comparison between the protein profiling (revealed on a 2-DE map) of CAL-27 cells treated with 11 dehydrosinulariolide and that of CAL-27 cells without the treatment. A total of 28 differential proteins (12 up-regulated and 16 down-regulated) in CAL-27 cells treated with 11-dehydrosinulariolide have been identified by LC-MS/MS analysis. Some of the differential proteins are associated with cell proliferation, apoptosis, protein synthesis, protein folding, and energy metabolism. The results of this study provided clues for the investigation of biochemical mechanisms of the anti-tumor effects of 11-dehydrosinulariolide on CAL-27 cells and could be valuable information for drug development and progression monitoring of oral squamous cell carcinoma (OSCC). PMID- 21822416 TI - Bromophenols in marine algae and their bioactivities. AB - Marine algae contain various bromophenols that have been shown to possess a variety of biological activities, including antioxidant, antimicrobial, anticancer, anti-diabetic, and anti-thrombotic effects. Here, we briefly review the recent progress of these marine algal biomaterials, with respect to structure, bioactivities, and their potential application as pharmaceuticals. PMID- 21822417 TI - In vivo and in vitro anti-inflammatory activity of neorogioltriol, a new diterpene extracted from the red algae Laurencia glandulifera. AB - Neorogioltriol is a tricyclic brominated diterpenoid isolated from the organic extract of the red algae Laurencia glandulifera. In the present study, the anti inflammatory effects of neorogioltriol were evaluated both in vivo using carrageenan-induced paw edema and in vitro on lipopolysaccharide (LPS)-treated Raw264.7 macrophages. The in vivo study demonstrated that the administration of 1 mg/kg of neorogioltriol resulted in the significant reduction of carregeenan induced rat edema. In vitro, our results show that neorogioltriol treatment decreased the luciferase activity in LPS-stimulated Raw264.7 cells, stably transfected with the NF-kappaB-dependent luciferase reporter. This effect on NF kappaB activation is not mediated through MAPK pathways. The inhibition of NF kappaB activity correlates with decreased levels of LPS-induced tumor necrosis factor-alpha (TNFalpha) present in neorogioltriol treated supernatant cell culture. Further analyses indicated that this product also significantly inhibited the release of nitric oxide and the expression of cyclooxygenase-2 (COX 2) in LPS-stimulated Raw264.7 cells. These latter effects could only be observed for neorogioltriol concentrations below 62.5 MUM. To our knowledge, this is the first report describing a molecule derived from Laurencia glandulifera with anti inflammatory activity both in vivo and in vitro. The effect demonstrated in vitro may be explained by the inhibition of the LPS-induced NF-kappaB activation and TNFalpha production. NO release and COX-2 expression may reinforce this effect. PMID- 21822418 TI - Abnormalities of thymic stroma may contribute to immune dysregulation in murine models of leaky severe combined immunodeficiency. AB - Lymphostromal cross-talk in the thymus is essential to allow generation of a diversified repertoire of T lymphocytes and to prevent autoimmunity by self reactive T cells. Hypomorphic mutations in genes that control T cell development have been associated with immunodeficiency and immune dysregulation both in humans and in mice. We have studied T cell development and thymic stroma architecture and maturation in two mouse models of leaky severe combined immune deficiency, carrying hypomorphic mutations in rag1 and lig4 genes. Defective T cell development was associated with abnormalities of thymic architecture that predominantly affect the thymic medulla, with reduction of the pool of mature medullary thymic epithelial cells (mTECs). While the ability of mTECs to express autoimmune regulator (Aire) is preserved in mutant mice, the frequency of mature mTECs expressing Aire and tissue-specific antigens is severely reduced. Similarly, the ability of CD4(+) T cells to differentiate into Foxp3(+) natural regulatory T cells is preserved in rag1 and lig4 mutant mice, but their number is greatly reduced. These data indicate that hypomorphic defects in T cell development may cause defective lymphostromal cross-talk and impinge on thymic stromal cells maturation, and thus favor immune dysregulation. PMID- 21822419 TI - The plant Mediator and its role in noncoding RNA production. AB - Mediator, a conserved multiprotein complex in animals, plants, and fungi, is a cofactor of RNA Polymerase II (Pol II). It is known to promote basal Pol II mediated transcription as well as bridge sequence-specific transcriptional regulators and Pol II to integrate regulatory information. Pol II transcribes not only protein-coding genes but also intergenic regions to generate noncoding RNAs such as small RNAs (microRNAs and small interfering RNAs) and long noncoding RNAs. Intriguingly, two plant-specific polymerases, Pol IV and Pol V, have evolved from Pol II and play a role in the production of small interfering RNAs and long noncoding RNAs at heterochromatic regions to maintain genome stability through transcriptional gene silencing (TGS). Recent studies have defined the composition of the plant Mediator and evaluated its role in noncoding RNA production in relationship to Pol II, Pol IV and Pol V. Here, we review the functions of Mediator and that of noncoding RNAs generated by Pol II, Pol IV and Pol V in plants, and discuss a role of Mediator in epigenetic regulation via noncoding RNA production. PMID- 21822420 TI - Changes in the 24 h Rhythmicity of Liver PPARs and Peroxisomal Markers When Feeding Is Restricted to Two Daytime Hours. AB - Restricted feeding (RF) during daytime is associated with anticipatory activity before feeding, marked hyperphagia after mealtime, adjustments in hepatic metabolism, and the expression of a food-entrained oscillator (FEO). 24 h rhythmicity of liver PPARalpha, beta, and gamma, peroxisomal markers (PMP70, AOX, and catalase), and free fatty acids (FFAs) during RF was evaluated. The effect of fasting-refeeding was also studied. Results showed (1) higher levels of FFA before feeding, (2) a shift of PPARalpha and PPARgamma before and of PPARbeta peaks after feeding, (3) an increase in peroxisomal markers, (4) a shift of PMP70 and AOX peaks before feeding, and of maximal catalase activity in the dark period, (5) changes in the fasting-refeeding response, and (6) high correlations (>0.9) of serum corticosterone with PPARalpha and PPARgamma and of PMP70 with PPARbeta. In conclusion, 24 h rhythmicity of FFA, liver PPARs, and peroxisomal markers are biochemical adaptations associated with daytime RF and FEO expression. PMID- 21822421 TI - Exocrine pancreatic insufficiency in diabetes mellitus: a complication of diabetic neuropathy or a different type of diabetes? AB - Pancreatic exocrine insufficiency is a frequently observed phenomenon in type 1 and type 2 diabetes mellitus. Alterations of exocrine pancreatic morphology can also be found frequently in diabetic patients. Several hypotheses try to explain these findings, including lack of insulin as a trophic factor for exocrine tissue, changes in secretion and/or action of other islet hormones, and autoimmunity against common endocrine and exocrine antigens. Another explanation might be that diabetes mellitus could also be a consequence of underlying pancreatic diseases (e.g., chronic pancreatitis). Another pathophysiological concept proposes the functional and morphological alterations as a consequence of diabetic neuropathy. This paper discusses the currently available studies on this subject and tries to provide an overview of the current concepts of exocrine pancreatic insufficiency in diabetes mellitus. PMID- 21822423 TI - Blood sugar lowering effect of Coccinia grandis (L.) J. Voigt: path for a new drug for diabetes mellitus. AB - BACKGROUND: Role of herbs in the management and control of diabetes has emerged fast over the years. We assessed the efficacy of Coccinia grandis (locally known as Ken, Kovakka) leaves as a hypoglycemic agent. METHODS: Double-blind phase I clinical trial was conducted at the general hospital and a private hospital in Matara in August 2009. All the participants were given a common meal for dinner, and they maintained a 10-hour fasting period. Sixty-one healthy volunteers were given a meal containing 20 g of leaves of Coccinia grandis which was mixed with a measured amount of scraped coconut and table salt for breakfast, and other 61 were given the placebo meal which also contained scraped coconut and salt. Glucose tolerance test was performed blindly for the two groups. Mixed factorial design analysis of variance and student's t-test were applied. RESULTS: Overall blood sugar levels of the experimental group were also significantly lower than those of the control group (F(1,117) 5.56, P < 0.05). Increase in the blood sugar levels from fasting to one hour (F(1,117) 6.77, P < 0.05) and two hours (F(1,117) 5.28, P < 0.05) postprandially was statistically significant for participants who were in the control group than those of in the experimental group. The mean difference of postprandial blood sugar levels (mg/dL) after one hour (20.2, 95% confidence interval, 4.81 to 35.5) and two hours (11.46, 95% confidence interval; 1.03 to 21.9) was statistically significant between the two groups. CONCLUSIONS: Coccinia grandis has a blood sugar lowering effect. However further studies are needed to validate our findings. PMID- 21822422 TI - Treatment of streptozotocin-induced diabetic rats with alogliptin: effect on vascular and neural complications. AB - We sought to determine the effect of dipeptidyl peptidase IV (DPP-IV) inhibition on streptozotocin diabetes-induced vascular and neural dysfunction. After 4 weeks of untreated diabetes, rats were treated for 12 weeks with Alogliptin (DPP-IV inhibitor). Diabetes caused a slowing of motor and sensory nerve conduction velocity, thermal hypoalgesia, reduction in intraepidermal nerve fiber density in the hindpaw, and impairment in vascular relaxation to acetylcholine and calcitonin gene-related peptide in epineurial arterioles. Treatment significantly improved motor nerve conduction velocity and thermal response latency. Sensory nerve conduction velocity was marginally improved with treatment of diabetic rats, and treatment did not improve the decrease in intraepidermal nerve fiber density. Vascular relaxation by epineurial arterioles to calcitonin gene-related peptide but not acetylcholine was significantly improved with treatment. These studies suggest that some but not all vascular and neural complications associated with type 1 diabetes can be improved with the inhibition of DPP-IV activity. PMID- 21822424 TI - Diabetic inhibition of preconditioning- and postconditioning-mediated myocardial protection against ischemia/reperfusion injury. AB - Ischemic preconditioning (IPC) or postconditioning (Ipost) is proved to efficiently prevent ischemia/reperfusion injuries. Mortality of diabetic patients with acute myocardial infarction was found to be 2-6 folds higher than that of non-diabetic patients with same myocardial infarction, which may be in part due to diabetic inhibition of IPC- and Ipost-mediated protective mechanisms. Both IPC and Ipost-mediated myocardial protection is predominantly mediated by stimulating PI3K/Akt and associated GSK-3beta pathway while diabetes-mediated pathogenic effects are found to be mediated by inhibiting PI3K/Akt and associated GSK-3beta pathway. Therefore, this review briefly introduced the general features of IPC- and Ipost-mediated myocardial protection and the general pathogenic effects of diabetes on the myocardium. We have collected experimental evidence that indicates the diabetic inhibition of IPC- and Ipost-mediated myocardial protection. Increasing evidence implies that diabetic inhibition of IPC- and Ipost-mediated myocardial protection may be mediated by inhibiting PI3K/Akt and associated GSK-3beta pathway. Therefore any strategy to activate PI3K/Akt and associated GSK-3beta pathway to release the diabetic inhibition of both IPC and Ipost-mediated myocardial protection may provide the protective effect against ischemia/reperfusion injuries. PMID- 21822426 TI - Academic software applications for electromagnetic brain mapping using MEG and EEG. PMID- 21822425 TI - Cell-based therapies for diabetic complications. AB - In recent years, accumulating experimental evidence supports the notion that diabetic patients may greatly benefit from cell-based therapies, which include the use of adult stem and/or progenitor cells. In particular, mesenchymal stem cells and the circulating pool of endothelial progenitor cells have so far been the most studied populations of cells proposed for the treatment of vascular complications affecting diabetic patients. We review the evidence supporting their use in this setting, the therapeutic benefits that these cells have shown so far as well as the challenges that cell-based therapies in diabetic complications put out. PMID- 21822427 TI - A Double-Blind, Randomized Clinical Trial of Niacinamide 4% versus Hydroquinone 4% in the Treatment of Melasma. AB - Background. Multiple modalities have been used in the treatment of melasma with variable success. Niacinamide has anti-inflammatory properties and is able to decrease the transfer of melanosomes. Objective. To evaluate the therapeutic effect of topical niacinamide versus hydroquinone (HQ) in melasma patients. Patients and Methods. Twenty-seven melasma patients were randomized to receive for eight weeks 4% niacinamide cream on one side of the face, and 4% HQ cream on the other. Sunscreen was applied along the observation period. They were assessed by noninvasive techniques for the evaluation of skin color, as well as subjective scales and histological sections initially and after the treatment with niacinamide. Results. All patients showed pigment improvement with both treatments. Colorimetric measures did not show statistical differences between both sides. However, good to excellent improvement was observed with niacinamide in 44% of patients, compared to 55% with HQ. Niacinamide reduced importantly the mast cell infiltrate and showed improvement of solar elastosis in melasma skin. Side effects were present in 18% with niacinamide versus 29% with HQ. Conclusion. Niacinamide induces a decrease in pigmentation, inflammatory infiltrate, and solar elastosis. Niacinamide is a safe and effective therapeutic agent for this condition. PMID- 21822428 TI - The histological and immunohistochemical aspects of bile reflux in patients with gastroesophageal reflux disease. AB - Introduction. The pathogenesis of GERD is strongly related with mixed acid and bile reflux. Benign and malignant esophageal and gastric lesions have been associated with synergetic activity between those parameters. Bile reflux causes reactive gastropathy evaluated with Bile Reflux Index (BRI). The aim was to investigate if the sequence: bile reflux-intestinal metaplasia-GERD-esophagitis, is associated with apoptotic/oncogenetic disturbances. Materials/Methods. Fifteen asymptomatic subjects and 53 GERD patients underwent gastroscopy with biopsies. The specimens examined histologically and immunohistochemically for p53, Ki-67, Bax, and Bcl-2. Results. Elevated BRI score detected in 47% (25/53) of patients with GERD and in 13% (2/15) of controls (P = 0.02). Severe esophageal lesions were significantly more common in BRI (+) patients (14/25) compared to BRI (-) ones (P = 0.0049). Immunohistochemical analysis did not show associations between BRI score and biomarker expression. Conclusions. Bile reflux gastropathy is associated with GERD severity, but not with oncogene expression or apoptotic discrepancies of the upper GI mucosa. PMID- 21822429 TI - The Role of C-Choline-PET/CT-Guided Secondary Lymphadenectomy in Patients with PSA Failure after Radical Prostatectomy: Lessons Learned from Eight Cases. AB - Introduction. (11)C-choline-PET/CT is a promising technique for detection/restaging of patients with biochemical failure (BF) after curative therapy for prostate cancer (PCA). The aim of this paper was to evaluate the PSA response in patients with BF after radical prostatectomy (RP) who underwent secondary lymphadenectomy (LAD) due to (11)C-choline-PET/CT findings. Material and Methods. Eight patients with BF and positive lymph nodes in (11)C-choline PET/CT after RP were retrospectively included in the study. Extended LAD until the common iliac arteries was performed in all patients. Results. Six of 8 patients had histologically proven lymph node metastases. Four patients showed an initial PSA reduction after LAD, and in 4 patients the PSA increased. Two of the latter had no histological lymph node metastases. Conclusions. Because 50% of our patients showed an initial PSA response, our data suggest that positive (11)C choline-PET/CT after RP and BF could help to select patients that could benefit from secondary LAD. PMID- 21822430 TI - Internet-based support for cardiovascular disease management. AB - With significant declines in cardiovascular disease (CVD) mortality, attention has shifted to patient management. Programs designed to manage CVD require the involvement of health professionals for comanagement and patients' self management. However, these programs are commonly limited to large urban centers, resulting in limited access for rural patients. The use of telehealth potentially overcomes geographical barriers and can improve access to care for patients. The current research explores how an Internet-based platform might facilitate collaboration among healthcare providers comanaging patients and enhance behavioural change in patients. Forty-eight participants were interviewed including: (a) patients (n = 12), (b) physicians (n = 11), (c) nurses (n = 13), and (d) allied health professionals (n = 10). The results were organized and analyzed in three central themes: (1) role of technology for CVD management, (2) challenges to technology adoption, and (3) incentives for technology adoption. Health care providers and patients supported future implementation of Internet based technology support for CVD management. PMID- 21822431 TI - Subcutaneous single injection digital block with epinephrine. AB - The aim of this study was to investigate the anesthetic effect and risk of epinephrine for subcutaneous single injection digital block. Either 3.0 mL 1.0% Lidocaine or a 3.0 mL 1.0% Lidocaine with (1 : 100,000) epinephrine was injected into the subcutaneous space at the middle point of the palmar digital crease of the 18 middle fingers of 9 healthy volunteers. The SpO(2) of the fingers decreased to a maximum of 97. No subjects showed any symptoms of ischemic injury. The time to anesthesia for the fingers was significantly shorter (P < 0.05), and the duration of anesthesia was significantly longer (P < 0.01) for the fingers in the epinephrine group. In conclusion, a subcutaneous single injection digital blocks with 3.0 mL of 1.0% Lidocaine and (1 : 100,000) epinephrine were safe, reducing the time to the onset of anesthesia, while also markedly prolonging the anesthesia. PMID- 21822432 TI - Identification of a novel mutation in a pseudohypoparathyroidism family. AB - Pseudohypoparathyroidism type Ia (PHP Ia) is defined as a series of disorders characterized by multihormone resistance in end-organs and Albright hereditary osteodystrophy (AHO) phenotype. PHP Ia is caused by heterozygous inactivating mutations in GNAS, which encodes the stimulatory G-protein alpha subunit (Gsa). A patient with typical clinical manifestations of pseudohypoparathyroidism (PHP) (round face, short stature, centripetal obesity, brachydactyly, and multi-hormone resistance: parathyroid hormone (PTH), thyroid-stimulating hormone (TSH), and gonadotropins) presented at our center. The sequence of the GNAS gene from the patient and her families revealed a novel missense mutation (Y318H) in the proband and her mother. An in vitro Gsa functional study showed that Gsa function was significantly impaired. These results stress the importance of GNAS gene investigation. PMID- 21822433 TI - A new in vivo model system to assess the toxicity of semiconductor nanocrystals. AB - In the emerging area of nanotechnology, a key issue is related to the potential impacts of the novel nanomaterials on the environment and human health, so that this technology can be used with minimal risk. Specifically designed to combine on a single structure multipurpose tags and properties, smart nanomaterials need a comprehensive characterization of both chemicophysical properties and adequate toxicological evaluation, which is a challenging endeavour; the in vitro toxicity assays that are often employed for nanotoxicity assessments do not accurately predict in vivo response. To overcome these limitations and to evaluate toxicity characteristics of cadmium telluride quantum dots in relation to surface coatings, we have employed the freshwater polyp Hydra vulgaris as a model system. We assessed in vivo acute and sublethal toxicity by scoring for alteration of morphological traits, population growth rates, and influence on the regenerative capabilities providing new investigation clues for nanotoxicology purposes. PMID- 21822435 TI - Populations of select cultured and uncultured bacteria in the rumen of sheep and the effect of diets and ruminal fractions. AB - The objective of this study was to assess the importance of select cultured and uncultured bacteria in the rumen by quantifying their populations and the effect of diets and ruminal fractions. Full-length 16S rRNA gene (rrs) sequences were recovered from rumen samples using specific primers designed from partial sequences recovered previously. Five uncultured bacterial operational taxonomic units (OTUs) were quantified using specific quantitative PCR (qPCR) in fractionated ruminal samples from sheep fed either hay alone or hay plus corn. Species Fibrobacter succinogenes, Ruminococcus albus, R. flavefaciens, Ruminobacter amylophilus, Selenomonas ruminantium, and Mitsuokella multacida and genera Butyrivibrio and Prevotella were also quantified as comparison. The full length rrs sequence improved taxonomic assignments of partial rrs sequences. Genus Prevotella had the greatest abundance. Of the three major cultured cellulolytic species, R. flavefaciens was most abundant, followed by R. albus and F. succinogenes. The five uncultured bacterial OTUs, classified to genus Acetivibrio, genus Allobaculum, family Ruminococcaceae, order Clostridiales, or class Clostridia, had abundance comparable to that of the above species of genera except Prevotella. Corn supplementation and fractions affected distribution of the rumen bacteria, but to a limited extent. When compared to the qPCR data, sequence frequencies in the rrs clone libraries tended to overestimate the abundance of the bacteria represented. This study showed that abundance and population dynamics of uncultured bacteria can be quantified by specific qPCR, which complements the results of rrs clone libraries. This study also revealed that some uncultured bacteria might be as important as some of the well characterized bacteria in the rumen. The approach used should be applicable to assess the abundance and potential importance of uncultured bacteria in other environments. PMID- 21822434 TI - The Role of mTOR Inhibitors for the Treatment of B-Cell Lymphomas. AB - Despite the fact that the majority of lymphomas initially respond to treatment, many patients relapse and die from disease that is refractory to current regimens. The need for new treatment strategies in lymphomas has led to the investigation and evaluation of novel agents that target cellular pathways. The mammalian target of rapamycin (mTOR) is a representative pathway that may be implicated in lymphomagenesis. Rapamycin and especially its derivatives (temsirolimus, everolimus, and deforolimus) represent the first described mTOR inhibitors. These agents have shown promising results in the treatment of lymphoid malignancies. On the other hand, new ATP-competitive mTOR inhibitors that provoke a broader inhibition of mTOR activity are in early stages of clinical development. The purpose of this paper is to summarize the existing knowledge about mTOR inhibitors and their use in the treatment of B-cell lymphomas. Relevant issues regarding mTOR biology in general as well as in B-cell lymphoid neoplasms are also discussed in short. PMID- 21822436 TI - Management of obstetric perineal tears: do obstetrics and gynaecology residents receive adequate training? Results of an anonymous survey. AB - Background/Aim. To evaluate the obstetrics and gynaecology residents' perspective of their training and experience in the management of perineal tears that occur during assisted vaginal delivery. We hypothesised that residents would perceive room for improvement in their knowledge of pelvic floor anatomy and the training received in tears repair. Design. Descriptive cross-sectional study. Population/Setting. Seventy-two major residents from all teaching hospitals in Catalonia. Methods. A questionnaire was designed to evaluate experience, perception of the training and supervision provided. Results. The questionnaire was sent to all residents (n = 72), receiving 46 responses (64%). The participants represented 15 out of the 16 teaching hospitals included in the study (94% of the hospitals represented). Approximately, 52% of residents were in their third year while 48% were in their fourth. The majority of them thought that their knowledge of pelvic floor anatomy was poor (62%), although 98% felt confident that they would know when an episiotomy was correctly indicated. The survey found that they lacked experience in the repair of major degree tears (70% had repaired fewer than ten), and most did not carry out followup procedures. Conclusion. The majority of them indicated that more training in this specific area is necessary (98%). PMID- 21822437 TI - Prolonged QT Syndrome and Seizure Secondary to Alkaline Earth Metal Deficiency: A Case Report. AB - Introduction. Alkaline earth metal deficiency is recognized as a cause of both seizure and long QT syndrome. Their deficiency can have significant repercussions on the function of cells, tissues, and organs of the body. An understanding of the role of electrolytes allows an appreciation of the significance of depleted levels on cell function. Case Report. A 65-year-old lady was admitted with symptoms of chest discomfort, vomiting, increased stoma output, and dizziness. Two days following admission she suffered a tonic-clonic seizure. ECG review demonstrated a prolonged QTc interval, raising the possibility of an underlying Torsades de Pointes as the precipitant. This was attributed to electrolyte disturbance arising as a result of multiple aetiologies. Discussion. This paper highlights the multisystem effects of electrolyte disturbance, with emphasis upon its role in precipitating cardiac arrhythmia and neurological symptoms. PMID- 21822438 TI - Effectiveness of a smoking cessation intervention for methadone-maintained women: a comparison of pregnant and parenting women. AB - Women in substance abuse programs have high rates of smoking. Pregnancy represents a unique opportunity for intervention, but few data exist to guide tailoring of effective interventions. In this study, 44 pregnant and 47 nonpregnant opioid-dependent women enrolled in comprehensive substance abuse treatment received a 6-week smoking cessation intervention based on the 5A's counseling model. The number of daily cigarettes decreased by 49% for pregnant patients and 32% for nonpregnant patients at the 3-month followup. Length of time in substance abuse treatment did not correlate with smoking cessation or reduction for either group. Factors predicting reduction of cigarette smoking differed for pregnant versus nonpregnant patients. For pregnant patients, lower levels of nicotine use prior to intervention and self-reported cigarette cravings predicted successful reduction in smoking. For nonpregnant patients, lower affiliative attachment to cigarettes, reliance on cigarettes for cognitive enhancement, and greater sense of control predicted more successful outcomes. PMID- 21822439 TI - Modeling the QSAR of ACE-Inhibitory Peptides with ANN and Its Applied Illustration. AB - A quantitative structure-activity relationship (QSAR) model of angiotensin converting enzyme- (ACE-) inhibitory peptides was built with an artificial neural network (ANN) approach based on structural or activity data of 58 dipeptides (including peptide activity, hydrophilic amino acids content, three-dimensional shape, size, and electrical parameters), the overall correlation coefficient of the predicted versus actual data points is R = 0.928, and the model was applied in ACE-inhibitory peptides preparation from defatted wheat germ protein (DWGP). According to the QSAR model, the C-terminal of the peptide was found to have principal importance on ACE-inhibitory activity, that is, if the C-terminal is hydrophobic amino acid, the peptide's ACE-inhibitory activity will be high, and proteins which contain abundant hydrophobic amino acids are suitable to produce ACE-inhibitory peptides. According to the model, DWGP is a good protein material to produce ACE-inhibitory peptides because it contains 42.84% of hydrophobic amino acids, and structural information analysis from the QSAR model showed that proteases of Alcalase and Neutrase were suitable candidates for ACE-inhibitory peptides preparation from DWGP. Considering higher DH and similar ACE-inhibitory activity of hydrolysate compared with Neutrase, Alcalase was finally selected through experimental study. PMID- 21822440 TI - Traditional Herbal Medicine, Rikkunshito, Induces HSP60 and Enhances Cytoprotection of Small Intestinal Mucosal Cells as a Nontoxic Chaperone Inducer. AB - Increasing incidence of small intestinal ulcers associated with nonsteroidal anti inflammatory drugs (NSAIDs) has become a topic with recent advances of endoscopic technology. However, the pathogenesis and therapy are not fully understood. The aim of this study is to examine the effect of Rikkunshito (TJ-43), a traditional herbal medicine, on expression of HSP60 and cytoprotective ability in small intestinal cell line (IEC-6). Effect of TJ-43 on HSP60 expression in IEC-6 cells was evaluated by immunoblot analysis. The effect of TJ-43 on cytoprotective abilities of IEC-6 cells against hydrogen peroxide or indomethacin was studied by MTT assay, LDH-release assay, caspase-8 activity, and TUNEL. HSP60 was significantly induced by TJ-43. Cell necrosis and apoptosis were significantly suppressed in IEC-6 cells pretreated by TJ-43 with overexpression of HSP60. Our results suggested that HSP60 induced by TJ-43 might play an important role in protecting small intestinal epithelial cells from apoptosis and necrosis in vitro. PMID- 21822441 TI - Complementary and Alternative Drugs Use among Preoperative Patients: A Cross Sectional Study in Italy. AB - Complementary and alternative drugs (CADs) are widely used in preoperative patients and may lead to potential interactions and adverse reactions. The aim of our study is to evaluate the prevalence and the predictors of CADs use among preoperative patients using data from an Italian survey. This cross-sectional study, which enrolled 478 patients (response rate: 83.5%), was carried out in three Tuscany hospitals (Italy). The prevalence of CADs use was 49.8%: 233 out of 238 participants used herbal products and/or dietary supplements. Valeriana officinalis was the most reported product (19.4%). According to univariate analysis, users were commonly identified among middle-aged or older patients; unadjusted ORs were 2.1 (95% CI: 1.3-3.3) for patients aged 48-69 years, and 3.0 (95% CI: 1.9-4.7) for those of 70-95 years, when compared with individuals aged 18-47 years. Except for education and gender, adjusted estimates showed consistent results with univariate analyses: direct association was observed with higher education, and-although not significantly-with female gender. The high prevalence of CAD use in preoperative period could be suggestive of a certain risk of adverse effects due to CADs interactions. A careful medical history of CADs consumption should be ascertained before surgery. PMID- 21822442 TI - A study on the reliability of sasang constitutional body trunk measurement. AB - Objective. Body trunk measurement for human plays an important diagnostic role not only in conventional medicine but also in Sasang constitutional medicine (SCM). The Sasang constitutional body trunk measurement (SCBTM) consists of the 5 widths and the 8-circumferences which are standard locations currently employed in the SCM society. This study suggests to what extent a comprehensive training can improve the reliability of the SCBTM. Methods. We recruited 10 male subjects and 5 male observers with no experience of anthropometric measurement. We conducted measurements twice before and after a comprehensive training. Relative technical error of measurement (%TEMs) was produced to assess intra and inter observer reliabilities. Results. Post-training intra-observer %TEMs of the SCBTM were 0.27% to 1.85% reduced from 0.27% to 6.26% in pre-training, respectively. Post-training inter-observer %TEMs of those were 0.56% to 1.66% reduced from 1.00% to 9.60% in pre-training, respectively. Post-training % total TEMs which represent the whole reliability were 0.68% to 2.18% reduced from maximum value of 10.18%. Conclusion. A comprehensive training makes the SCBTM more reliable, hence giving a sufficiently confident diagnostic tool. It is strongly recommended to give a comprehensive training in advance to take the SCBTM. PMID- 21822443 TI - Oviposition and Embryotoxicity of Indigofera suffruticosa on Early Development of Aedes aegypti (Diptera: Culicidae). AB - Aqueous extract of Indigofera suffruticosa leaves obtained by infusion was used to evaluate the oviposition, its effect on development of eggs and larvae, and morphological changes in larvae of Aedes aegypti. The bioassays were carried out with aqueous extract in different concentrations on eggs, larvae, and female mosquitoes, and the morphological changes were observed in midgut of larvae. The extract showed repellent activity on A. aegypti mosquitoes, reducing significantly the egg laying by females with control substrate (343 (185-406)) compared with the treated substrate (88 (13-210)). No eclosion of A. aegypti eggs at different concentrations studied was observed. The controleclodedin 35%. At concentration of 250 MUg/mL, 93.3% of larvae remained in the second instar of development and at concentrations of 500, 750, and 1000 MUg/mL the inhibitory effect was lower with percentages of 20%, 53.3%, and 46.6%, respectively. Morphological changes like disruption on the peritrophic envelope (PE), discontinued underlying epithelium, increased gut lumen, and segments with hypertrophic aspects were observed in anterior region of medium midgut of larvae of A. aegypti. The results showed repellent activity, specific embryotoxicity, and general growth retardation in A. aegypti by medium containing aqueous extract of I. suffruticosa leaves. PMID- 21822444 TI - The tibetan uterotonic zhi byed 11: mechanisms of action, efficacy, and historical use for postpartum hemorrhage. AB - Objective. To explore evidence for the traditional Tibetan medicine, Zhi Byed 11 (ZB11), for use as a uterotonic. Methods. The eleven ingredients in ZB11 were chemically analyzed by mass spectroscopy. A review was conducted of Western allopathic literature for scientific studies on ZB11's individual components. Literature from Tibetan and other traditional paradigms were reviewed. Results. Potential mechanisms of action for ZB11 as a uterotonic include laxative effects, a dose-dependant increase in smooth muscle tissue peristalsis that may also affect the uterus smooth muscle, and chemical components that are prostaglandin precursors and/or increase prostaglandin synthesis. A recent RCT demonstrated comparable efficacy to misoprostol in reducing severe postpartum hemorrhage (PPH) (>1000 mL) and greater effect than placebo. Historical and anecdotal evidence for ZB11 and its ingredients for childbirth provide further support. Discussion. ZB11 and its ingredients are candidates for potentially effective uterotonics, especially in low-resource settings. Further research is warranted to understand the mechanisms of action and synergy between ingredients. PMID- 21822445 TI - Activation of Latent TGF-beta1 by Thrombospondin-1 is a Major Component of Wound Repair. AB - PURPOSE: Thrombospondin 1 (TSP1) is a matrix glycoprotein that regulates cell adhesion, migration, and proliferation, and is a natural inhibitor of angiogenesis. Recent evidence suggests that TSP1 is a major physiologic activator of latent transforming growth factor-beta1 (TGF-beta1), and that TGF-beta1 is important for wound healing. The purpose of this study was to examine whether excisional wound healing in TSP1-deficient mice is compromised as a result of deficient TGF-beta1 activation. MATERIALS AND METHODS: Punch wounds were made on the dorsum of TSP1 deficient and wild-type mice and the area of granulation tissue, number of microvessels, and inflammatory cell infiltration was evaluated over a period of 28 days. RESULTS: TSP1 deficient mice showed impaired wound healing with persistent granulation tissue, decreased collagen content over time, and delayed arrival of macrophages compared to wild-type littermates. The number of microvessels in wounds of TSP1-deficient mice was approximately two-fold greater than in wild-type littermates 10 days after injury. Topical application of TSP1, or KRFK (a peptide derived from TSP1 that activates latent TGF-beta1), to wounds of TSP1-deficient mice rescued wild-type patterns of wound repair and partially recovered local levels of TGF-beta1 expression. Topical application of anti-TGF-beta neutralizing antibody impaired the ability of KRFK to rescue normal patterns of wound neovascularization in TSP1-deficient mice. CONCLUSIONS: These results demonstrate that TSP1 plays a key role in the orchestration of wound healing, and that TSP1-mediated activation of local TGF-beta1 is an important step in this process. PMID- 21822446 TI - Asymptotic identity in min-plus algebra: a report on CPNS. AB - Network calculus is a theory initiated primarily in computer communication networks, especially in the aspect of real-time communications, where min-plus algebra plays a role. Cyber-physical networking systems (CPNSs) are recently developing fast and models in data flows as well as systems in CPNS are, accordingly, greatly desired. Though min-plus algebra may be a promising tool to linearize any node in CPNS as can be seen from its applications to the Internet computing, there are tough problems remaining unsolved in this regard. The identity in min-plus algebra is one problem we shall address. We shall point out the confusions about the conventional identity in the min-plus algebra and present an analytical expression of the asymptotic identity that may not cause confusions. PMID- 21822448 TI - Extravascular lipid deposit (xanthelasma) induced by a plant sterol-enriched margarine. AB - Plant sterol-enriched margarine consumption is known to significantly reduce concentrations of plasma low density lipoprotein (LDL) cholesterol. However, there is no evidence that such margarines may reduce cardiovascular events. This is the first report of a significant increase in the plasma concentration of phytosterols due to plant sterol-enriched margarine consumption leading to extravascular lipid deposits (xanthelasma), in a woman with hypercholesterolaemia. Because increased plasma levels of phytosterols may promote atherosclerosis, the present observation raises concern about potential cardiovascular risk after long-term consumption of these margarines. PMID- 21822449 TI - Recurrent small bowel infarction in a young man: polycythaemia or vasculitis? AB - A 29-year-old man presented with a 3 day history of right lower quadrant pain, nausea and vomiting. There was tenderness in the right lower quadrant. At surgery the appendix was normal but an infarcted terminal ileum segment was found and resected. Histopathological examination was suggestive of vasculitis. The patient was discharged in good condition and follow-up for the first year was unremarkable. Unfortunately he developed another episode of bowel ischaemia in the second year and underwent resection of a short segment of proximal ileum. An autoimmune profile was negative. However, subsequent blood tests confirmed polycythaemia. Small bowel infarction due to polycythaemia in a young patient is rare and may be difficult to diagnose on clinical grounds. PMID- 21822450 TI - Thrombotic thrombocytopenic purpura in a patient with HIV from Zimbabwe. AB - A woman in her 40s originally from Zimbabwe presented to our accident department in the UK with a 4 day history of menorrhagia and exertional chest pain. Her clinical examination was unremarkable. Routine blood tests revealed a haemoglobin value of 6.8 g/dl and a platelet count of 15*10(9)/l, with normal renal function and coagulation profile. Blood film showed microangiopathic haemolytic anaemia and thrombocytopenia. On direct questioning, she admitted to being HIV positive, and receiving antiviral therapy at another hospital. A diagnosis of HIV associated thrombotic thrombocytopenic purpura (TTP) was made. The patient was transferred to a tertiary centre for urgent plasma exchange. She required 8 days of 1.5 litre exchanges with solvent detergent fresh frozen plasma (FFP) and high dose steroids. She responded within 24 h with increasing haemoglobin and platelet counts, and at discharge her haemoglobin was 10.7 g/dl and platelet count 253*10(9)/l. PMID- 21822451 TI - Heterogeneously Catalyzed Continuous-Flow Hydrogenation Using Segmented Flow in Capillary Columns. PMID- 21822447 TI - Acid peptic diseases: pharmacological approach to treatment. AB - Acid peptic disorders are the result of distinctive, but overlapping pathogenic mechanisms leading to either excessive acid secretion or diminished mucosal defense. They are common entities present in daily clinical practice that, owing to their chronicity, represent a significant cost to healthcare. Key elements in the success of controlling these entities have been the development of potent and safe drugs based on physiological targets. The histamine-2 receptor antagonists revolutionized the treatment of acid peptic disorders owing to their safety and efficacy profile. The proton-pump inhibitors (PPIs) represent a further therapeutic advance due to more potent inhibition of acid secretion. Ample data from clinical trials and observational experience have confirmed the utility of these agents in the treatment of acid peptic diseases, with differential efficacy and safety characteristics between and within drug classes. Paradigms in their speed and duration of action have underscored the need for new chemical entities that, from a single dose, would provide reliable duration of acid control, particularly at night. Moreover, PPIs reduce, but do not eliminate, the risk of ulcers in patients taking NSAIDs, reflecting untargeted physiopathologic pathways and a breach in the ability to sustain an intragastric pH of more than 4. This review provides an assessment of the current understanding of the physiology of acid production, a discussion of medications targeting gastric acid production and a review of efficacy in specific acid peptic diseases, as well as current challenges and future directions in the treatment of acid-mediated diseases. PMID- 21822452 TI - Structural rearrangement of SULT2A1: effects on dehydroepiandrosterone and raloxifene sulfation. AB - BACKGROUND: Human cytosoloic sulfotransferase (SULT) 2A1 is a major hepatic isoform and sulfates hydroxyl groups in structurally diverse sterols and xenobiotics. SULT2A1 crystal structures resolved in the presence and absence of 3',5'-diphosphoadenosine (PAP) or dehydropeiandrosterone (DHEA) suggest a significant rearrangement of the peptide that forms the surface of the active site in the presence of PAP. MATERIALS AND METHODS: Molecular modeling was used to examine the effects of the rearrangement in SULT2A1 associated with 3' phosphoadenosine 5'-phosphosulfate (PAPS) binding on the binding of DHEA and raloxifene. The kinetics of DHEA and raloxifene sulfation was analyzed to investigate the effects of the rearrangement on SULT2A1 activity. RESULTS: Molecular models indicate that DHEA is able to bind to SULT2A1 in both conformations (open, without PAP; closed, with PAP) in a catalytic configuration, whereas raloxifene bound in a catalytic conformation only in the open structure. Raloxifene did not bind in the smaller, closed substrate binding pocket. Kinetic analysis of DHEA sulfation was consistent with a random Bi-Bi reaction mechanism, whereas raloxifene sulfation was more indicative of an ordered reaction mechanism with raloxifene binding first. Initial burst kinetics with DHEA yielded similar results after preincubation of SULT2A1 with DHEA or PAPS. Preincubation of SULT2A1 with raloxifene showed a burst of raloxifene sulfate formation with the addition of PAPS. In contrast, little raloxifene sulfate was formed if SULT2A1 was preincubated with PAPS and the reaction initiated with raloxifene. CONCLUSIONS: The structural rearrangements in SULT2A1 caused by PAPS binding can alter the sulfation mechanism and kinetics of different substrates. PMID- 21822453 TI - Lack of substrate inhibition in a monomeric form of human cytosolic SULT2A1. AB - Mammalian cytosolic sulfotransferases (SULTs) frequently show substrate inhibition during the sulfation of increasing concentrations of substrates. SULT2A1, a major human liver isoform responsible for the conjugation of hydroxysteroids, bile acids and aliphatic hydroxyl groups in drugs and xenobiotics, is a homodimer and displays substrate inhibition during the conjugation of dehydroepiandrosterone (DHEA). Maltose binding protein (MBP) SULT2A1 fusion protein, produced as an intermediate step in the purification of the SULT2A1 homodimer, elutes during size exclusion chromatography as a monomer. The initial-rate parameters (K(m) and V(max)) of the monomer (MBP-SULT2A1) and native SULT2A1 dimer for DHEA sulfation are extremely similar; however, the monomer is not inhibited by DHEA. Intrinsic fluorescence studies show that two DHEA molecules bind each SULT2A1 subunit, one in the catalytic site and one in an apparent allosteric site. Lack of dimerization in the MBP-SULT2A1 fusion protein decreased the K(d) for binding of DHEA at the allosteric site. These results suggest that formation of the homodimer is associated with structural rearrangements leading to increased DHEA binding at an allosteric site that is associated with substrate inhibition. PMID- 21822454 TI - Quantitative Models for Causal Analysis in the Era of Genome Wide Association Studies. PMID- 21822456 TI - Masculorum concubitores: views on homosexuality among Catholics in Recife, Brazil. AB - This study focuses on Catholics' views towards homosexuality. The discussion is based on an ethnographic survey involving interviews with priests and lay leaders as well as participant observation of daily life in a working-class neighborhood in Recife, Pernambuco State, Brazil. The analysis points to persistent prejudice against homosexuality in the neighborhood and among Catholic clergy and lay leaders interviewed in the study. The priests base their assertions on the dialectics between desire/practice and chastity/reproduction. This interplay allows them to distinguish between "homosexuality," condition of desire, and "homosexualism," a sin of the flesh. Based on this understanding, they produce an attitude of tolerance towards homosexuals. Laypeople prove to be more intolerant and focus their assertions on the difference between the sexes as the condition for good, natural, and sanctified sexual interaction. This attitude appears to be consistent with the way the sex/gender system operates in the neighborhood, where homosexuality is evaluated in terms masculinity and femininity. In this setting, it is interesting to observe how the discourses of homosexual movements challenge lay people and destabilize their religious certainties. PMID- 21822455 TI - Designing the optimal vaccine: the importance of cytokines and dendritic cells. AB - Many vaccines existing today provide strong protection against a wide variety of infectious organisms, and these consist of either live attenuated or inactivated microorganisms. Most of these vaccines were developed empirically and there has not been a clear understanding of the immunological principles that contribute to this success. Recent advances in systems biology are being applied to the study of vaccines in order to determine which immunological parameters are the best predictors of success. New approaches to vaccine development include the identification of peptide epitopes and the manipulation of the immune response to generate the most appropriate response. Vaccines are being developed to prevent and/or treat such conditions as cancer and autoimmunity in addition to infectious diseases. Vaccines targeting this diverse group of diseases may need to elicit very different types of immune responses. Recent advances in our understanding of the functions of dendritic cells (DC) and cytokines in orchestrating qualitatively different immune responses has allowed the design of vaccines that can elicit immune responses appropriate for cancer, autoimmunity or infectious organisms. This review will focus on recent advances in the ways DC and cytokines can be used to develop the most appropriate and effective vaccines. PMID- 21822457 TI - N-(4-Hydroxyphenyl) Retinamide Potentiated Anti-tumor Efficacy of Genistein in Human Ewing's Sarcoma Xenografts. AB - BACKGROUND: Ewing's sarcoma is a pediatric tumor that mainly occurs in soft tissues and bones. New therapeutic strategies are urgently needed for treatment of Ewing's sarcoma. We examined for the first time the efficacy of N-(4 hydroxyphenyl) retinamide (4-HPR) and genistein (GST) alone and also in combination for controlling growth of human Ewing's sarcoma SK-N-MC and RD-ES xenografts. METHODS: Efficacy of combination therapy was evaluated using histopathological parameters. Molecular mechanisms of combination therapy were detected using Western blotting and immunofluorescence microscopy. RESULTS: Histopathological examination of tumor sections showed that control group maintained characteristic growth of tumors, 4-HPR alone caused differentiation of tumor cells, GST alone induced apoptosis to some extent, and combination of 4-HPR and GST significantly induced apoptosis in both Ewing's sarcoma xenografts. Time dependent reductions in body weight, tumor volume, and tumor weight were also found. Combination therapy increased Bax:Bcl-2 ratio to trigger mitochondrial release of Smac/Diablo into the cytosol to down regulate the baculovirus inhibitor-of-apoptosis repeat containing (BIRC) proteins such as BIRC-2 and BIRC 3 and thereby promote apoptosis. Activation of caspase-3 and mitochondrial release of apoptosis-inducing factor (AIF) occurred in course of apoptosis. Down regulation of the survival factor NF-kappaB and the angiogenic factors VEGF and FGF2 and increase in caspase-3 activity controlled tumor growth. In situ immunofluorescent labelings showed overexpression of calpain, caspase-12, and caspase-3, and AIF in xenografts, indicating induction of cysteine proteases and AIF for apoptosis. CONCLUSIONS: Results revealed that combination of 4-HPR and GST could be highly effective treatment for inhibiting Ewing's sarcomas in vivo. PMID- 21822458 TI - Developing a program to promote stress resilience and self-care in first-year medical students. AB - BACKGROUND: Facilitating stress resilience in future physicians is an important role of medical educators and administrators. We developed an extracurricular program and pilot tested the program on first year medical students. METHODS: Presentations on topics related to mental health, help-seeking, and stress resilience were presented (one topic per session). Attendance was voluntary. Attendees were requested to complete anonymous evaluations following each presentation. Primary outcome variables were rates of agreement that the presentation (1) was interesting, (2) provided valuable information, and (3) provided information relevant for the student's future practice as a physician. RESULTS: Each of the seven topics was attended on average by approximately half of the student body. Evaluations were very positive that presentations were interesting and provided information useful to maintaining balance during medical school (all had >=85% rates of agreement). Evaluations by students were variable (41%-88% rates of agreement) on whether each presented information relevant for future practice. CONCLUSIONS: The results support that first-year medical students value explicit guidance on ways to bolster stress resilience and self care during medical school. It is important to clarify with each presentation how the information is relevant to their future practice as a physician. PMID- 21822459 TI - Evaluating Mediated Perception of Narrative Health Messages: The Perception of Narrative Performance Scale. AB - Narrative media health messages have proven effective in preventing adolescents' substance use but as yet few measures exist to assess perceptions of them. Without such a measure it is difficult to evaluate the role these messages play in health promotion or to differentiate them from other message forms. In response to this need, a study was conducted to evaluate the Perception of Narrative Performance Scale that assesses perceptions of narrative health messages. A sample of 1185 fifth graders in public schools at Phoenix, Arizona completed a questionnaire rating of two videos presenting narrative substance use prevention messages. Confirmatory factor analyses were computed to identify the factor structure of the scale. Consistent with prior studies, results suggest a 3 factor structure for the Perception of Narrative Performance Scale: interest, realism, and identification (with characters). In addition, a path analysis was performed to test the predictive power of the scale. The analysis shows that the scale proves useful in predicting intent to use substances. Finally, practical implications and limitations are discussed. PMID- 21822461 TI - Biopanning Phage-Display Libraries on Small Tissue Sections Captured by Laser Capture Microdissection. AB - Phage-display technology has been widely used for developing tumor-targeting agents. Laser capture microdissection (LCM) has proven to be an accurate method to select specific cells from histological sections. Our goal was to develop a method to combine phage-display with LCM to obtain phage-displayed ligands that bind to selected cells in human solid tumors. Two panning strategies were evaluated and optimized. The first strategy was to pan on patient tissue mounted to LCM slides before LCM occurred. The poor panning output showed that phage did not tolerate the drying conditions during LCM. The second strategy was to pan on tumor cells from the patient tumor tissue that were isolated by LCM. The catapulted tumor cells were transferred to a filter unit which retained cells but allowed rinsing of unbound phage. Six commercially available filter units were evaluated and the one with the lowest nonspecific binding to phage was selected for the panning steps. The smallest number of cells (500) in which panning could be successfully accomplished was also determined. A micropipette system was developed to further decrease background by removing catapulted cells from the filter unit after panning was complete. This left behind nearly all background binding phage in the filter unit. This strategy led to the selection of individual phage antibody clones (5 out of 79 tested) specific for tumor cells of the patient's cancer tissue. Immunofluorescence staining on tumor tissues from the same patient showed that these clones have selective signals on tumor island cells, while the scFv library only showed low nonspecific signals on tumor tissues. We established a method of panning on a small number of LCM-captured solid tumor specimens. The quick identification of specific phage-displayed antibodies in the cancer tissue of human patients will greatly enhance the therapy and diagnosis of cancer. PMID- 21822462 TI - The Landscape for Pharmaceutical Innovation: Drivers of Cost-Effective Clinical Research. PMID- 21822463 TI - EXTRACTION AND ANALYSIS OF ACTIN NETWORKS BASED ON OPEN ACTIVE CONTOUR MODELS. AB - Network structures formed by actin filaments are present in many kinds of fluorescence microscopy images. In order to quantify the conformations and dynamics of such actin filaments, we propose a fully automated method to extract actin networks from images and analyze network topology. The method handles well intersecting filaments and, to some extent, overlapping filaments. First we automatically initialize a large number of Stretching Open Active Contours (SOACs) from ridge points detected by searching for plus-to-minus sign changes in the gradient map of the image. These initial SOACs then elongate simultaneously along the bright center-lines of filaments by minimizing an energy function. During their evolution, they may merge or stop growing, thus forming a network that represents the topology of the filament ensemble. We further detect junction points in the network and break the SOACs at junctions to obtain "SOAC segments". These segments are then re-grouped using a graph-cut spectral clustering method to represent the configuration of actin filaments. The proposed approach is generally applicable to extracting intersecting curvilinear structures in noisy images. We demonstrate its potential using two kinds of data: (1) actin filaments imaged by Total Internal Reflection Fluorescence Microscopy (TIRFM) in vitro; (2) actin cytoskeleton networks in fission yeast imaged by spinning disk confocal microscopy. PMID- 21822464 TI - Determination of the Pharmacokinetics and Oral Bioavailability of Salicylamine, a Potent gamma-Ketoaldehyde Scavenger, by LC/MS/MS. AB - Levels of reactive gamma-ketoaldehydes derived from arachidonate increase in diseases associated with inflammation and oxidative injury. To assess the biological importance of these gamma-ketoaldehydes, we previously identified salicylamine as an effective gamma-ketoaldehyde scavenger in vitro and in cells. To determine if salicylamine could be administered in vivo, we developed an LC/MS/MS assay to measure salicylamine in plasma and tissues. In mice, half-life (t(1/2)) was 62 minutes. Drinking water supplementation (1-10 g/L) generated tissue concentrations (10-500 MUM) within the range previously shown to inhibit gamma-ketoaldehydes in cells. Therefore, oral administration of salicylamine can be used to assess the contribution of gamma-ketoaldehydes in animal models of disease. PMID- 21822465 TI - Clinical Application of Image-Based CFD for Cerebral Aneurysms. AB - During the last decade, the convergence of medical imaging and computational modeling technologies has enabled tremendous progress in the development and application of image-based computational fluid dynamics modeling of patient specific blood flows. These techniques have been used for studying the basic mechanisms involved in the initiation and progression of vascular diseases, for studying possible ways to improve the diagnosis and evaluation of patients by incorporating hemodynamics information to the anatomical data typically available, and for the development of computational tools that can be used to improve surgical and endovascular treatment planning. However, before these technologies can have a significant impact on the routine clinical practice, it is still necessary to demonstrate the connection between the extra information provided by the models and the natural progression of vascular diseases and the outcome of interventions. This paper summarizes some of our contributions in this direction, focusing in particular on cerebral aneurysms. PMID- 21822466 TI - Effect of Brucella infection on reproduction conditions of female breeding cattle and its public health significance in Western tigray, northern ethiopia. AB - The most common clinical manifestations of brucellosis in livestock are associated with reproduction. This paper reports the result of a cross-sectional study conducted between October, 2007 and April, 2008 in Western Tigray, North Ethiopia, with the objectives of assessing the effect of Brucella infection on reproduction conditions of female breeding bovine and to explore the presence of Brucella seroreactors in vulnerable humans. A total of 1,354 and 246 sera were collected from female cattle and humans, respectively. The sera were screened using Rose Bengal plate test (RBPT), and positive samples were confirmed by complement fixation test (CFT). Reproductive conditions for female cattle and risk to human brucellosis seropositivity were tested by using logistic regression analysis. The result indicated that the overall prevalence in female cattle was 6.1%. The study showed 1.2% prevalence among human risk groups, all of which were herdsmen. Logistic regression identified parity status, calving interval, abortion history, and abortion period were significantly associated with seropositivity. The association was not significant with reproductive status and parity number. Proper hygienic practices and team work between veterinary and health personnel should improve the efforts to combat disease transmission. PMID- 21822467 TI - Monitoring Temperature and Heart Rate during Surgical Field Implantation of PTT 100 Satellite Transmitters in Greenland Sea Birds. AB - Information on cloacae temperature (CT), heart rate (HR), Isoflurane use, and oxygen flow was collected during field implantation of Platform Terminal Transmitters (PTT-) 100 satellite transmitters in Greenland sea birds. Information was obtained from 14 intracoelomic and 5 subcutaneous implantations in thick-billed murres (Uria lomvia) and 9 intracoelomic implantations in common eiders (Somateria mollissima). CT decreased in the order subcutaneous murres > intracoelomic eiders > intracoelomic murres due to the explorative exposure to the surroundings and increased heat loss (murres smaller than eiders) and were preheated to 35 degrees C. During all implantations, heat loss was prevented using electric heat and rescue blankets. Regarding HR, the fluctuations were most pronounced during the intracoelomic murre implantations as a result of lower PTT temperature and lower body size leading to more pronounced digital manipulations and stimulation of the pelvic nerve plexus. Based on these results, we therefore suggest that HR and CT are carefully monitored in order to adjust anaesthesia and recommend the use of an electric heat blanket and preheating of PTTs to body temperature in order to prevent unnecessary heat loss causing physiological stress to the birds. PMID- 21822468 TI - Genetics of atrial fibrillation and possible implications for ischemic stroke. AB - Atrial fibrillation is the most common cardiac arrhythmia mainly caused by valvular, ischemic, hypertensive, and myopathic heart disease. Atrial fibrillation can occur in families suggesting a genetic background especially in younger subjects. Additionally recent studies have identified common genetic variants to be associated with atrial fibrillation in the general population. This cardiac arrhythmia has important public health implications because of its main complications: congestive heart failure and ischemic stroke. Since atrial fibrillation can result in ischemic stroke, one might assume that genetic determinants of this cardiac arrhythmia are also implicated in cerebrovascular disease. Ischemic stroke is a multifactorial, complex disease where multiple environmental and genetic factors interact. Whether genetic variants associated with a risk factor for ischemic stroke also increase the risk of a particular vascular endpoint still needs to be confirmed in many cases. Here we review the current knowledge on the genetic background of atrial fibrillation and the consequences for cerebrovascular disease. PMID- 21822470 TI - A comparison of cooling techniques to treat cardiac arrest patients with hypothermia. AB - Introduction. We sought to compare the performance of endovascular cooling to conventional surface cooling after cardiac arrest. Methods. Patients in coma following cardiopulmonary resuscitation were cooled with an endovascular cooling catheter or with ice bags and cold-water-circulating cooling blankets to a target temperature of 32.0-34.0 degrees C for 24 hours. Performance of cooling techniques was compared by (1) number of hourly recordings in target temperature range, (2) time elapsed from the written order to initiate cooling and target temperature, and (3) adverse events during the first week. Results. Median time in target temperature range was 19 hours (interquartile range (IQR), 16-20) in the endovascular group versus. 10 hours (IQR, 7-15) in the surface group (P = .001). Median time to target temperature was 4 (IQR, 2.8-6.2) and 4.5 (IQR, 3 6.5) hours, respectively (P = .67). Adverse events were similar. Conclusion. Endovascular cooling maintains target temperatures better than conventional surface cooling. PMID- 21822471 TI - Therapeutic hypothermia after cardiac arrest: experience at an academically affiliated community-based veterans affairs medical center. AB - At laboratory and clinical levels, therapeutic hypothermia has been shown to improve neurologic outcomes and mortality following cardiac arrest. We reviewed each cardiac arrest in our community-based Veterans Affairs Medical Center over a three-year period. The majority of cases were in-hospital arrests associated with initial pulseless electrical activity or asystole. Of a total of 100 patients suffering 118 cardiac arrests, 29 arrests involved comatose survivors, with eight patients completing therapeutic cooling. Cerebral performance category scores at discharge and six months were significantly better in the cooled cohort versus the noncooled cohort, and, in every case except for one, cooling was offered for appropriate reasons. Mean time to initiation of cooling protocol was 3.7 hours and mean time to goal temperature of 33 degrees C was 8.8 hours, and few complications clearly related to cooling were noted in our case series. While in patient hospital mortality of cardiac arrest was high at 65% mortality during hospital admission, therapeutic hypothermia was safe and feasible at our center. Our cooling times and incidence of favorable outcomes are comparable to previously published reports. This study demonstrates the feasibility of implementing, a cooling protocol a community setting, and the role of neurologists in ensuring effective hospital-wide implementation. PMID- 21822472 TI - A review of social and relational aspects of deep brain stimulation in Parkinson's disease informed by healthcare provider experiences. AB - Background. Although the clinical effectiveness of deep brain stimulation (DBS) in Parkinson's disease is established, there has been less examination of its social aspects. Methods and Results. Building on qualitative comments provided by healthcare providers, we present four different social and relational issues (need for social support, changes in relationships (with self and partner) and challenges with regards to occupation and the social system). We review the literature from multiple disciplines on each issue. We comment on their ethical implications and conclude by establishing the future prospects for research with the possible expansion of DBS for psychiatric indications. Conclusions. Our review demonstrates that there are varied social issues involved in DBS. These issues may have significant impacts on the perceived outcome of DBS by patients. Moreover, the fact that the social impact of DBS is still not well understood in emerging psychiatric indications presents an important area for future examination. PMID- 21822469 TI - Antithrombotic medication for cardioembolic stroke prevention. AB - Embolism of cardiac origin accounts for about 20% of ischemic strokes. Nonvalvular atrial fibrillation is the most frequent cause of cardioembolic stroke. Approximately 1% of population is affected by atrial fibrillation, and its prevalence is growing with ageing in the modern world. Strokes due to cardioembolism are in general severe and prone to early recurrence and have a higher long-term risk of recurrence and mortality. Despite its enormous preventive potential, continuous oral anticoagulation is prescribed for less than half of patients with atrial fibrillation who have risk factors for cardioembolism and no contraindications for anticoagulation. Available evidence does not support routine immediate anticoagulation of acute cardioembolic stroke. Anticoagulation therapy's associated risk of hemorrhage and monitoring requirements have encouraged the investigation of alternative therapies for individuals with atrial fibrillation. New anticoagulants being tested for prevention of stroke are low-molecular-weight heparins (LMWH), unfractionated heparin, factor Xa inhibitors, or direct thrombin inhibitors like dabigatran etexilate and rivaroxaban. The later exhibit stable pharmacokinetics obviating the need for coagulation monitoring or dose titration, and they lack clinically significant food or drug interaction. Moreover, they offer another potential that includes fixed dosing, oral administration, and rapid onset of action. There are several concerns regarding potential harm, including an increased risk for hepatotoxicity, clinically significant bleeding, and acute coronary events. Therefore, additional trials and postmarketing surveillance will be needed. PMID- 21822473 TI - Anxiety and cardiovascular risk: Review of Epidemiological and Clinical Evidence. AB - An increasing body of evidence suggests that anxiety is an independent predictor of adverse cardiovascular (CV) events. Individuals with high levels of anxiety are at increased risk of coronary heart disease, congestive heart failure, stroke, fatal ventricular arrhythmias, and sudden cardiac death. Anxiety following a major cardiac event can impede recovery, and is associated with a higher morbidity and mortality. This linkage between anxiety and CV disease is further corroborated by evidence suggesting that treatment of anxiety may improve cardiac symptoms. However, the mechanisms underlying the observed associations are not entirely delineated. Several intermediary mechanisms have been suggested, including sympathetic activation, impaired vagal control, reduced heart rate variability, stimulation of the hypothalamic-pituitary axis, hyperventilation induced coronary spasm, oxidative stress, increased inflammatory mediators, and unhealthy lifestyle. There is a need for several clinical trials to explicate the complex associations between anxiety and CV disease, which may be compounded by the involvement of other psychosocial factors. In this review, we examine the epidemiological evidence for the association between anxiety and CV disease, and discuss the proposed mechanisms that may be responsible for this association. PMID- 21822474 TI - Prospective Changes in Health-Related Quality of Life and Emotional Outcomes in Kidney Transplantation over 6 Years. AB - Little is known on long-term outcomes in kidney transplantation. This study evaluated changes and predictors of generic and transplantation-specific health related quality of life (HQoL) over six years in N = 102 kidney transplant survivors using the Short-form Health Survey-36 and the Transplant Effects questionnaire. Mixed models analysis was used to determine long-term outcomes. Emotional HQoL improved over time: Mental Component score, Mental Health, Energy (Ps = .000). Physical HQoL deteriorated: Physical Component Score (P = .001), Pain (P = .002). LRD transplant recipients had greater decline in physical functioning (P = .003) and PCS (P = .000) compared to cadaver recipients. Worry about the transplant (P = .036) and feelings of responsibility (P = .008) increased significantly over time. Worry about the transplant and perceived ability to work predicted 12.7% and 31.1% in variance in MCS and PCS, respectively. Efforts should be made to maintain HQoL and emotional outcomes with ongoing monitoring and support programs throughout the course of posttransplant care. PMID- 21822475 TI - Use of nucleic Acid analogs for the study of nucleic Acid interactions. AB - Unnatural nucleosides have been explored to expand the properties and the applications of oligonucleotides. This paper briefly summarizes nucleic acid analogs in which the base is modified or replaced by an unnatural stacking group for the study of nucleic acid interactions. We also describe the nucleoside analogs of a base pair-mimic structure that we have examined. Although the base pair-mimic nucleosides possess a simplified stacking moiety of a phenyl or naphthyl group, they can be used as a structural analog of Watson-Crick base pairs. Remarkably, they can adopt two different conformations responding to their interaction energies, and one of them is the stacking conformation of the nonpolar aromatic group causing the site-selective flipping of the opposite base in a DNA double helix. The base pair-mimic nucleosides can be used to study the mechanism responsible for the base stacking and the flipping of bases out of a nucleic acid duplex. PMID- 21822477 TI - Difficult-to-Treat or Resistant Hypertension: Etiology, Pathophysiology, and Innovative Therapies. AB - Despite the many therapeutic options available today for the treatment of hypertension, a sizable number of patients still remain resistant to treatment. The prevalence of resistant hypertension in the general population under optimal conditions is about 3-5%. Although several factors and conditions can be identified and corrected a percentage of hypertensive patients remain with unacceptably high blood pressure levels. The high prevalence of hypertension in the general population renders this small percentage significant, in terms of actual patient numbers. This special issue of the journal expoars a whole spectrum of topics related to resistant hypertension: several articles address pathophysiolog and secondary causes of resistant hypertension and modern approaches to therapy. Of interest is the referance to the newer interventional approaches, that is, Baroreceptor stimulation therapy and catheter based sympathetic renal denervation. PMID- 21822476 TI - Modulation of tyrosine hydroxylase, neuropeptide y, glutamate, and substance p in Ganglia and brain areas involved in cardiovascular control after chronic exposure to nicotine. AB - Considering that nicotine instantly interacts with central and peripheral nervous systems promoting cardiovascular effects after tobacco smoking, we evaluated the modulation of glutamate, tyrosine hydroxylase (TH), neuropeptide Y (NPY), and substance P (SP) in nodose/petrosal and superior cervical ganglia, as well as TH and NPY in nucleus tractus solitarii (NTS) and hypothalamic paraventricular nucleus (PVN) of normotensive Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR) after 8 weeks of nicotine exposure. Immunohistochemical and in situ hybridization data demonstrated increased expression of TH in brain and ganglia related to blood pressure control, preferentially in SHR, after nicotine exposure. The alkaloid also increased NPY immunoreactivity in ganglia, NTS, and PVN of SHR, in spite of decreasing its receptor (NPY1R) binding in NTS of both strains. Nicotine increased SP and glutamate in ganglia. In summary, nicotine positively modulated the studied variables in ganglia while its central effects were mainly constrained to SHR. PMID- 21822478 TI - Carotid baroreceptor stimulation for the treatment of resistant hypertension. AB - Interventional activation of the carotid baroreflex has been an appealing idea for the management of resistant hypertension for several decades, yet its clinical application remained elusive and a goal for the future. It is only recently that the profound understanding of the complex anatomy and pathophysiology of the circuit, combined with the accumulation of relevant experimental and clinical data both in animals and in humans, has allowed the development of a more effective and well-promising approach. Indeed, current data support a sustained over a transient reduction of blood pressure through the resetting of baroreceptors, and technical deficits have been minimized with a subsequent recession of adverse events. In addition, clinical outcomes from the application of a new implantable device (Rheos) that induces carotid baroreceptor stimulation point towards a safe and effective blood pressure reduction, but longer experience is needed before its integration in the everyday clinical practice. While accumulating evidence indicates that carotid baroreceptor stimulation exerts its benefits beyond blood pressure reduction, further research is necessary to assess the spectrum of beneficial effects and evaluate potential hazards, before the extraction of secure conclusions. PMID- 21822479 TI - Keratinase Production by Three Bacillus spp. Using Feather Meal and Whole Feather as Substrate in a Submerged Fermentation. AB - Three Bacillus species (B. subtilis LFB-FIOCRUZ 1270, B. subtilis LFB-FIOCRUZ 1273, and B. licheniformis LFB-FIOCRUZ 1274), isolated from the poultry industry, were evaluated for keratinase production using feathers or feather meal as the sole carbon and nitrogen sources in a submerged fermentation. The three Bacillus spp. produced extracellular keratinases and peptidases after 7 days. Feather meal was the best substrate for keratinase and peptidase production in B. subtilis 1273, with 412 U/mL and 463 U/ml. The three strains were able to degrade feather meal (62-75%) and feather (40-95%) producing 3.9-4.4 mg/ml of soluble protein in feather meal medium and 1.9-3.3 mg/ml when feather medium was used. The three strains produced serine peptidases with keratinase and gelatinase activity. B. subtilis 1273 was the strain which exhibited the highest enzymatic activity. PMID- 21822480 TI - Computational approach to identify enzymes that are potential therapeutic candidates for psoriasis. AB - Psoriasis is well known as a chronic inflammatory dermatosis. The disease affects persons of all ages and is a burden worldwide. Psoriasis is associated with various diseases such as arthritis. The disease is characterized by well demarcated lesions on the skin of the elbows and knees. Various genetic and environmental factors are related to the pathogenesis of psoriasis. In order to identify enzymes that are potential therapeutic targets for psoriasis, we utilized a computational approach, combining microarray analysis and protein interaction prediction. We found 6,437 genes (3,264 upregulated and 3,173 downregulated) that have significant differences in expression between regions with and without lesions in psoriasis patients. We identified potential candidates through protein-protein interaction predictions made using various protein interaction resources. By analyzing the hub protein of the networks with metrics such as degree and centrality, we detected 32 potential therapeutic candidates. After filtering these candidates through the ENZYME nomenclature database, we selected 5 enzymes: DNA helicase (RUVBL2), proteasome endopeptidase complex (PSMA2), nonspecific protein-tyrosine kinase (ZAP70), I-kappa-B kinase (IKBKE), and receptor protein-tyrosine kinase (EGFR). We adopted a computational approach to detect potential therapeutic targets; this approach may become an effective strategy for the discovery of new drug targets for psoriasis. PMID- 21822481 TI - Headache associated with myasthenia gravis: the impact of mild ocular symptoms. AB - Myasthenia gravis (MG) patients visiting outpatient clinics frequently complain of headache. However, there have been few reports on the relation between chronic headache and myasthenia gravis (MG). We aimed to investigate whether MG symptoms affect the development or worsening of chronic headache. Among the 184 MG patients who were followed at the MG clinics, tension-type headache was observed in 71 (38.6%) patients and 9 (4.9%) complained of migraine. Twenty-five (13.6%) complained that headache appeared or was exacerbated after the MG onset. The investigation into differences in the clinical characteristics of the MG patients showed that women tended to suffer from MG-associated headache more often than men. Logistic regression analyses revealed that female gender and mild ocular symptoms were independently predictive of headache associated with MG. Our results suggest that treatment of chronic headache should be required to improve the quality of life in MG patients. PMID- 21822482 TI - Mating and Parental Care in Lake Tanganyika's Cichlids. AB - Cichlid fishes of Lake Tanganyika display a variety of mating and parental care behaviors, including polygamous and monogamous mouthbrooding and substrate breeding, cooperative breeding, as well as various alternative reproductive tactics such as sneaking and piracy. Moreover, reproductive behaviors sometimes vary within species both in space and in time. Here, I survey reports on mating and parenting behaviors of Lake Tanganyika cichlid species and address the evolution of mating and parental care patterns and sexual dimorphism. Notes on measures of sexual selection intensity and the difficulties of defining mating systems and estimating selection intensities at species level conclude the essay. PMID- 21822483 TI - Current trends in implantable left ventricular assist devices. AB - The shortage of appropriate donor organs and the expanding pool of patients waiting for heart transplantation have led to growing interest in alternative strategies, particularly in mechanical circulatory support. Improved results and the increased applicability and durability with left ventricular assist devices (LVADs) have enhanced this treatment option available for end-stage heart failure patients. Moreover, outcome with newer pumps have evolved to destination therapy for such patients. Currently, results using nonpulsatile continuous flow pumps document the evolution in outcomes following destination therapy achieved subsequent to the landmark Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure Trial (REMATCH), as well as the outcome of pulsatile designed second-generation LVADs. This review describes the currently available types of LVADs, their clinical use and outcomes, and focuses on the patient selection process. PMID- 21822484 TI - Comparison of predictive equations for resting energy expenditure in overweight and obese adults. AB - Objective. To compare values from predictive equations of resting energy expenditure (REE) with indirect calorimetry (IC) in overweight and obese adults. Methods. Eighty-two participants aged 30 to 60 years old were retrospectively analyzed. The persons had a body mass index >=25 kg/m(2). REE was estimated by IC and other five equations of the literature (Harris and Benedict, WHO1, WHO2, Owen, Mifflin). Results. All equations had different values when compared to those of IC. The best values were found by Harris and Benedict, WHO1, and WHO2, with high values of intraclass correlation coefficient and low values of mean difference. Furthermore, WHO1 and WHO2 showed lower systematic error and random. Conclusion. No predictive equations had the same values of REE as compared to those of indirect calorimetry, and those which least underestimated REE were the equations of WHO1, WHO2, and Harris and Benedict. The next step would be to validate the new equation proposed. PMID- 21822486 TI - Adiponectinemia is associated with uricemia but not with proinflammatory status in women with metabolic syndrome. AB - Metabolic syndrome (MS) is a cluster of glucose intolerance, hypertension, and dyslipidemia with visceral fat accumulation. This study was undertaken to assess which components of metabolic syndrome (MS), including uric acid and proinflammatory markers, are related to adiponectin levels in overweight and obese women with MS. Ninety-one women (60 with MS and 31 controls) were assessed in relation to classical and inflammatory parameters of MS. In comparison to controls, patients with MS showed significant differences in parameters that are typically associated with MS and in inflammatory markers. Fibrinogen, CRP, and C3 were positively, whereas albumin was inversely correlated with abdominal adiposity and insulin resistance. Adiponectin was inversely correlated with waist circumference and uric acid levels. Activities of adiponectin and proinflammatory markers are not correlated in overweight and obese women with MS. In addition to abdominal adiposity, uric acid may be implicated in a decrease of adiponectin in MS patients. PMID- 21822485 TI - A review of weight control strategies and their effects on the regulation of hormonal balance. AB - The estimated prevalence of obesity in the USA is 72.5 million adults with costs attributed to obesity more than 147 billion dollars per year. Though caloric restriction has been used extensively in weight control studies, short-term success has been difficult to achieve, with long-term success of weight control being even more elusive. Therefore, novel approaches are needed to control the rates of obesity that are occurring globally. The purpose of this paper is to provide a synopsis of how exercise, sleep, psychological stress, and meal frequency and composition affect levels of ghrelin, cortisol, insulin GLP-1, and leptin and weight control. We will provide information regarding how hormones respond to various lifestyle factors which may affect appetite control, hunger, satiety, and weight control. PMID- 21822487 TI - Can Better Mother-Daughter Relations Reduce the Chance of a Suicide Attempt among Latinas? AB - National surveys and other research on adolescent Latinas show that adolescent females have higher rates of suicidal ideation, planning, and attempts than other ethnic and racial minority youth. Internalizing behaviors and family conflicts are commonly associated with suicidality in research on adolescents. In the case of Latinas, we explore the connection between adolescent Hispanic cultural involvement, mother-adolescent mutuality, internalizing behaviors, and suicidality. This paper presents data from a study of 232 Latinas, some with a recent history of suicide attempts (n = 122). The results show that higher adolescent Hispanic cultural involvement was associated with greater mother daughter mutuality and thus led to reduction in the likelihood of suicide attempts. The relationship between mother-daughter mutuality and suicide attempts among Latinas is mediated by specific internalizing behaviors (withdrawn depressive). Our findings highlight the positive effect that Latino cultural values have in the relationship between Latina adolescent and their mothers and confirm the importance that internalizing behaviors and the mother-daughter relationship have for suicide attempters. PMID- 21822488 TI - Psychopathology and Suicide among Quebec Physicians: A Nested Case Control Study. AB - Objective. To describe a psychiatric profile and characteristics of physicians who killed themselves in Quebec between 1992 and 2009. Method. The cases of 36 physicians (7 females and 29 males) and 36 nonphysicians who committed suicide were matched for age and gender and examined in a nested case control design. All subjects were judged as definite suicide by the Quebec Coroner Head Office. Consensus regarding DSM-IV diagnoses was established by two forensic psychiatrists. Results. Rates of all Axis I diagnoses were 83% for physicians and 91% for nonphysicians at the time of suicide. Major depressive disorders were the most frequently observed pathology in both groups (61% and 56%, resp.). Conclusions. Physicians and nonphysicians who committed suicide in Quebec suffered from the same type of psychiatric disorder at the time of killing themselves. The findings advocate strongly for more efficient suicide prevention measures including early detection and treatment of mood disorders for the physicians. PMID- 21822489 TI - Utility of Quantitative Tc-MAA SPECT/CT for yttrium-Labelled Microsphere Treatment Planning: Calculating Vascularized Hepatic Volume and Dosimetric Approach. AB - Objectives. The aim of this study was to assess the effectiveness of SPECT/CT for volume measurements and to report a case illustrating the major impact of SPECT/CT in calculating the vascularized liver volume and dosimetry prior to injecting radiolabelled yttrium-90 microspheres (Therasphere). Materials and Methods. This was a phantom study, involving volume measurements carried out by two operators using SPECT and SPECT/CT images. The percentage of error for each method was calculated, and interobserver reproducibility was evaluated. A treatment using Therasphere was planned in a patient with three hepatic arteries, and the quantitative analysis of SPECT/CT for this patient is provided. Results. SPECT/CT volume measurements proved to be accurate (mean error <6% for volumes >=16 cm(3)) and reproductive (interobserver agreement = 0.9). In the case report, (99m)Tc-MAA SPECT/CT identified a large liver volume, not previously identified with angiography, which was shown to be vascularized after selective MAA injection into an arterial branch, resulting in a large modification in the activity of Therasphere used. Conclusions. MAA SPECT/CT is accurate for vascularized liver volume measurements, providing a valuable contribution to the therapeutic planning of patients with complex hepatic vascularization. PMID- 21822490 TI - Anti-MuSK-Positive Myasthenia Gravis in a Patient with Parkinsonism and Cognitive Impairment. AB - Muscle-specific tyrosine kinase- (MuSK-) antibodies-positive Myasthenia Gravis accounts for about one third of Seronegative Myasthenia Gravis and is clinically characterized by early onset of prominent bulbar, neck, shoulder girdle, and respiratory weakness. The response to medical therapy is generally poor. Here we report a case of late-onset MuSK-antibodies-positive Myasthenia Gravis presenting with signs of cognitive impairment and parkinsonism in addition to bulbar involvement and external ophthalmoplegia. The pattern of involvement of both peripheral and central nervous system dysfunction might suggest a common pathogenic mechanism, involving impaired cholinergic transmission. PMID- 21822491 TI - Quality of Life in Prodromal HD: Qualitative Analyses of Discourse from Participants and Companions. AB - Persons who are at risk for Huntington's Disease (HD) can be tested for the HD gene expansion before symptom onset. People with the gene expansion, but no clinical diagnosis, are in the prodromal phase of HD. This study explored quality of life (QOL) in prodromal HD. Interviews about QOL, conducted with 9 prodromal HD participants and 6 companions, were transcribed. Discourse was coded for emotional valence, content (e.g., coping, spirituality, interpersonal relationships, HD in others, and employment), and time frame (e.g., current, past, and future). Respondents were more positive than negative about the present, which was their major focus. The most common statements were about positive attitudes. Positive statements were made about spirituality, and negative statements were made about HD in other people. Relationships, employment, and coping with HD reflected both positivity and negativity. Participants and companions spoke of the future with different concerns. Applicability of findings to the clinical management of HD are discussed. PMID- 21822492 TI - Memory for emotional pictures in patients with Alzheimer's dementia: comparing picture-location binding and subsequent recognition. AB - Emotional content typically facilitates subsequent memory, known as the emotional enhancement effect. We investigated whether emotional content facilitates spatial and item memory in patients with Alzheimer's dementia (AD). Twenty-three AD patients, twenty-three healthy elderly, and twenty-three young adults performed a picture relocation task and a delayed recognition task with positive, negative, and neutral stimuli. AD patients showed a benefit in immediate spatial memory for positive pictures, while healthy young and older participants did not benefit from emotional content. No emotional enhancement effects on delayed item recognition were seen. We conclude that AD patients may have a memory bias for positive information in spatial memory. Discrepancies between our findings and earlier studies are discussed. PMID- 21822493 TI - Attention-deficit/hyperactivity disorder in childhood is associated with cognitive test profiles in the geriatric population but not with mild cognitive impairment or Alzheimer's disease. AB - The frequency of ADHD in the aging population and its relationship to late-life cognitive decline has not been studied previously. To address this gap in our understanding, the Wender-Utah ADHD Rating scale (WURS) was administered to 310 geriatric subjects with cognitive status ranging from normal cognition to mild cognitive impairment to overt dementia. The frequency of WURS-positive ADHD in this sample was 4.4%. WURS scores were not related to cognitive diagnoses, but did show nonlinear associations with tasks requiring sustained attention. The frequency of ADHD appears stable across generations and does not appear to be associated with MCI or dementia diagnoses. The association of attentional processing deficits and WURS scores in geriatric subjects could suggest that such traits remain stable throughout life. Caution should be considered when interpreting cognitive test profiles in the aging population that exhibit signs and symptoms of ADHD, as attentional deficits may not necessarily imply the existence of an underlying neurodegenerative disease state. PMID- 21822494 TI - Chemical assistance in refolding of bacterial inclusion bodies. AB - Escherichia coli is one of the most widely used hosts for the production of recombinant proteins but insoluble expression of heterologous proteins is a major bottleneck in production of recombinant proteins in E. coli. In vitro refolding of inclusion body into proteins with native conformations is a solution for this problem but there is a need for optimization of condition for each protein specifically. Several approaches have been described for in vitro refolding; most of them involve the use of additives for assisting correct folding. Cosolutes play a major role in refolding process and can be classified according to their function as aggregation suppressors and folding enhancers. This paper presents a review of additives that are used in refolding process of insoluble recombinant proteins in small scale and industrial processes. PMID- 21822495 TI - Treatment of locally advanced melanoma by isolated limb infusion with cytotoxic drugs. AB - Since its introduction in the late 1950s, isolated limb perfusion (ILP) has been the preferred treatment option for locally advanced melanoma and sarcoma confined to a limb. This treatment results in high response rates with a satisfying duration of response in both tumor types. A drawback of ILP, however, is the invasive and complex character of the procedure. Isolated limb infusion (ILI) has been designed in the early 1990s as a minimally invasive alternative to ILP. Results of this simple procedure, reported by various centers around the world, show comparable response rates for melanoma and sarcoma when compared to ILP. Due to its minimally invasive character, ILI may replace ILP in the future as the preferred treatment for these locally advanced limb tumors. PMID- 21822497 TI - Incidence of Obstetric and Foetal Complications during Labor and Delivery at a Community Health Centre, Midwives Obstetric Unit of Durban, South Africa. AB - The objectives of this retrospective cohort study were to estimate the incidence of obstetric complications during labor and delivery and their demographic predictors. A total of 2706 pregnant women were consecutively admitted to a midwife obstetric unit with labor pain between January and December 2007 constituted the sample. Among them 16% were diagnosed with obstetrical and foetal complications. The most frequently observed foetal and obstetric complications were foetal distress (35.5/1000) and poor progress of labor (28.3/1000), respectively. Primigravid and grandmultiparity women were 12 (OR = 11.89) and 5 (OR = 4.575) times, respectively, more likely to have complications during labor and delivery. Women without antenatal care had doubled (OR = 1.815, 95% CI, 1.310; 2.515) the chance of having complications. Mothers age <20 years was protective (OR = 0.579, 95% CI, 0.348; 0.963) of complications during delivery compared to women who were >=35 years. National and local policies and intervention programmes must address the need of the risk groups of pregnant women during labor and delivery. PMID- 21822496 TI - Lipids, lipoproteins, and age-related macular degeneration. AB - Age-related macular degeneration (AMD) is the leading cause of blindness among the elderly. While excellent treatment has emerged for neovascular disease, treatment for early AMD is lacking due to an incomplete understanding of the early molecular events. A prominent age-related change is the accumulation of neutral lipid in normal Bruch's membrane (BrM) throughout adulthood and also disease-related BrM accumulations called basal deposits and drusen. AMD lesion formation has thus been conceptualized as sharing mechanisms with atherosclerotic plaque formation, where low-density lipoprotein (LDL) retention within the arterial wall initiates a cascade of pathologic events. However, we do not yet understand how lipoproteins contribute to AMD. This paper explores how systemic and local production of lipoproteins might contribute to the pathogenesis of AMD. PMID- 21822498 TI - Molecular Diagnosis of Sexually Transmitted Chlamydia trachomatis in the United States. AB - Chlamydia, with its Chlamydia trachomatis etiology, is the most common bacterial sexually transmitted infection in the United States and is often transmitted via asymptomatic individuals. This review summarizes traditional and molecular-based diagnostic modalities specific to C. trachomatis. Several commercially available, FDA-approved molecular methods to diagnose urogenital C. trachomatis infection include nucleic acid hybridization, signal amplification, polymerase chain reaction, strand displacement amplification, and transcription-mediated amplification. Molecular-based methods are rapid and reliable genital specimen screening measures, especially when applied to areas of high disease prevalence. However, clinical and analytical sensitivity for some commercial systems decreases dramatically when testing urine samples. In vitro experiments and clinical data suggest that transcription-mediated amplification has greater analytical sensitivity than the other molecular-based methods currently available. This difference may be further exhibited in testing of extragenital specimens from at-risk patient demographics. The development of future molecular testing could address conundrums associated with confirmatory testing, medicolegal testing, and test of cure. PMID- 21822499 TI - Direct evidence for lineage-dependent effects of bone marrow stromal cells on tumor progression. AB - We sought to characterize the function of bone marrow stromal cell (BMSC) populations in tumor progression. Because this function may depend on the cell lineage and mouse strain heterogeneity, we first characterized ex vivo the BMSCs harvested from C57BL/6 versus FVB mice and established their in vivo function in tumor growth and metastasis experiments. All plastic-adherent BMSCs expressed platelet-derived growth factor receptor beta (PDGFRbeta) and stem cell antigen 1 (Sca1), consistent with a mesenchymal precursor phenotype, as well as CD80. Moreover, these BMSCs were capable of differentiation along mesenchymal lineage into adipocytes, osteoblasts, chondrocytes or myofibroblasts. However, further phenotypic analysis detected a distinct populations of myeloid (CD11b(+)) precursor cells amongst the ex vivo expanded BMSCs -with specific surface marker phenotypes and gene expression pattern. When co-implanted with metastatic cancer cells, all the BMSCs persisted and integrated into tumor stroma, but only myeloid BMSCs significantly promoted tumor growth and metastasis. These data demonstrate the differential effect of BMSCs sub-populations on tumor progression. These results may have important implications for anti-tumor therapy and for the use of mesenchymal BMSCs as cell-based therapies. PMID- 21822500 TI - Nucleotide Analogues as Probes for DNA and RNA Polymerases. AB - Nucleotide analogues represent a major class of anti-cancer and anti-viral drugs, and provide an extremely powerful tool for dissecting the mechanisms of DNA and RNA polymerases. While the basic assays themselves are relatively straight forward, a key issue is to appropriately design the studies to answer the mechanistic question of interest. This article addresses the major issues involved in designing these studies, and some of the potential difficulties that arise in interpreting the data. Examples are given both of the type of analogues typically used, the experimental approaches with different polymerases, and issues with data interpretation. PMID- 21822501 TI - Prospective Memory, Personality, and Working Memory: A Formal Modeling Approach. AB - Prospective memory (PM) involves remembering to perform an action in the future. The current study applies a multinomial model to investigate the contribution of individual differences in personality, as well as individual differences in working memory span, to performance in an event-based PM task. The model includes a parameter P that measures the prospective component, or remembering that something is to be done. The model also includes a parameter M that measures the ability to discriminate between target and non-target events, part of the retrospective component of PM tasks. The model has been applied to investigate the effects of working memory variability in just one prior study, but has not been used in previous investigations of personality and PM. Working memory span and the personality dimension of conscientiousness showed differences between the higher and lower groups in PM performance. Modeling results showed that individuals higher in conscientiousness had higher estimated of M relative to individuals lower on the conscientiousness dimension. Conscientiousness did not affect the P parameter. In contrast, individuals with higher working memory span scores had higher estimates of P relative to individuals with lower span scores, but the two working memory groups did not differ in terms of parameter M. PMID- 21822502 TI - Constitutive Modeling of Anisotropic Finite-Deformation Hyperelastic Behaviors of Soft Materials Reinforced by Tortuous Fibers. AB - Many biological materials are composites composed of a soft matrix reinforced with stiffer fibers. These stiffer fibers may have a tortuous shape and wind through the soft matrix. At small material deformation, these fibers deform in a bending mode and contribute little to the material stiffness; at large material deformation, these fibers deform in a stretching mode and induce a stiffening effect in the material behavior. The transition from bending mode deformation to stretching mode deformation yields a characteristic J-shape stress-strain curve. In addition, the spatial distribution of these fibers may render the composite an anisotropic behavior. In this paper, we present an anisotropic finite-deformation hyperelastic constitutive model for such materials. Here, the matrix is modeled as an isotropic neo-Hookean material. "The behaviors of single tortuous fiber are represented by a crimped fiber model". The anisotropic behavior is introduced by a structure tensor representing the effective orientation distribution of crimped fibers. Parametric studies show the effect of fiber tortuosity and fiber orientation distribution on the overall stress-strain behaviors of the materials. PMID- 21822503 TI - From amine to ruthenaziridine to azaallyl: unusual transformation of di-(2 pyridylmethyl)amine on ruthenium. AB - The complexation of di-(2-pyridylmethyl)amine to RuHCl(PPh(3))(3) affords the salt [RuH{kappa(3)N-fac-1,3-di-(2-pyridylmethyl)amine}(PPh(3))(2)]Cl. Reaction with potassium tert-butoxide at room temperature yields the unusual ruthenaziridine complex RuH{kappa(3)C(alk)NN(py)-1,3-di-(2 pyridylmethyl)amine}(PPh(3))(2), where the central nitrogen atom, adjacent alkyl carbon, and pyridine arm coordinate to the metal, leaving the second pyridine arm uncoordinated. Surprisingly, heating of this ruthenaziridine complex with concomitant H(2) formation affords the ruthenium azaallyl complex RuH(kappa(3)N 1,3-di-(2-pyridyl)-2-azaallyl)(PPh(3))(2). This is a rare example of a 4d metal complex containing the azaallyl ligand. X-Ray crystal structures and NMR characterization of all three compounds are presented herein. PMID- 21822504 TI - Intrinsic disorder in the androgen receptor: identification, characterisation and drugability. AB - The androgen receptor (AR) regulates networks of genes in response to the steroid hormones testosterone and dihydrotestosterone. The receptor protein is made up of both stably folded globular domains, involved in hormone and DNA binding, and regions of intrinsic disorder, including the N-terminal domain (NTD). The AR-NTD has a modular activation function (termed AF1) and is important for gene regulation, participating in multiple protein-protein interactions. Biophysical studies have revealed that AR-NTD/AF1 has limited stable secondary structure and conforms to a 'collapsed disordered' conformation. The AR-NTD/AF1 has the propensity to adopt an alpha-helical conformation in response to a natural osmolyte or a co-regulatory binding partner. The AR is a key drug target in the management of advanced prostate cancer and recently a small molecule inhibitor was identified that interacts with the NTD/AF1 and impairs protein-protein interactions and recruitment of the receptor to target genes. In this review the role of intrinsic disorder in AR function is discussed along with the potential to develop new drugs that will target the structurally plastic NTD. PMID- 21822505 TI - Microporous carbon adsorbents with high CO2 capacities for industrial applications. AB - In this study we attempt to investigate the potential use of two zeolite template carbon (ZTC), EMT-ZTC and FAU-ZTC, to capture CO(2) at room temperature. We report their high pressure CO(2) adsorption isotherms (273 K) that show for FAU ZTC the highest carbon capture capacity among published carbonaceous materials and competitive data with the best organic and inorganic adsorbing frameworks ever-known (zeolites and mesoporous silicas, COFs and MOFs). The importance of these results is discussed in light of mitigation of CO(2) emissions. In addition to these new experimental CO(2) adsorption data, we also present new insight into the adsorption process of the two structures by Monte Carlo simulations: we propose that two separate effects are responsible for the apparent similarity of the adsorption behaviour of the two structures: (i) pore blocking occurring on EMT-ZTC, and (ii) the change of the carbon polarizability due to the extreme curvature of FAU-ZTC. PMID- 21822506 TI - Electronic structure of aqueous borohydride: a potential hydrogen storage medium. AB - Borohydride salts have been considered as good prospects for transportable hydrogen storage materials, with molecular hydrogen released via hydrolysis. We examine details of the hydration of sodium borohydride by the combination of X ray absorption spectroscopy and first principles' theory. Compared to solid sodium borohydride, the aqueous sample exhibits an uncharacteristically narrow absorption feature that is shifted to lower energy, and ascribed to the formation of dihydrogen bonds between borohydride and water that weaken the boron-hydrogen covalent bonds. Water also acts to localize the highly excited molecular orbitals of borohydride, causing transitions to excited states with p character to become more intense and a sharp feature, uncharacteristic of tetrahedral molecules, to emerge. The simulations indicate that water preferentially associates with borohydride on the tetrahedral corners and edges. PMID- 21822507 TI - Synthesis, structure and photophysical properties of binuclear methylplatinum complexes containing cyclometalating 2-phenylpyridine or benzo{h}quinoline ligands: a comparison of intramolecular Pt-Pt and pi-pi interactions. AB - The binuclear cyclometalated complexes [Pt(2)Me(2)(ppy)(2)(MU-dppm)], 1a, and [Pt(2)Me(2)(bhq)(2)(MU-dppm)], 1b, in which ppy = 2-phenylpyridyl, bhq = benzo{h}quinoline and dppm = bis(diphenylphosphino)methane, were synthesized by the reaction of [PtMe(SMe(2))(ppy)] or [PtMe(SMe(2))(bhq)] with 1/2 equiv of dppm at room temperature, respectively. Complexes 1a and 1b were fully characterized by multinuclear ((1)H, (31)P, (13)C, and (195)Pt) NMR spectroscopy and were further identified by single crystal X-ray structure determination. A comparison of the intramolecular Pt-Pt and pi-pi interactions in complexes 1a and 1b has been made on the basis of data on crystal structures and wave functions analysis. The binuclear complexes 1a and 1b are luminescent in the solid state, and showing relatively intense orange-red emissions stemming from (3)MMLCT excited states. The reaction of complex 1b with excess MeI gave the binuclear cyclometalated Pt(IV)-Pt(IV) complex [Pt(2)Me(4)(bhq)(2)(MU-I)(2)], 2. Crystal structure of complex 2 shows intermolecular C-H...I and C-H...pi interactions in solid state. PMID- 21822508 TI - Can azulene-like molecules function as substitution-free molecular rectifiers? AB - The feasibility of employing azulene-like molecules as a new type of high performance substitution-free molecular rectifier has been explored using NEGF DFT calculation. The electronic transport behaviors of metal-molecule-metal junctions consisting of various azulene-like dithiol molecules are investigated, which reveals that the azulene-like molecules exhibit high conductance and bias dependent rectification effects. Among all the substitution-free azulene-like structures, cyclohepta[b]cyclopenta[g]naphthalene exhibits the highest rectification ratio, revealing that the all fused aromatic ring structure and an appropriate separation between the pentagon and heptagon rings are essential for achieving both high conductance and high rectification ratio. The rectification ratio can be increased by substituting the pentagon ring with electron withdrawing group and/or the heptagon ring with electron donating groups. Further increase of the rectification ratio may also be obtained by lithium adsorption on the pentagon ring. This work reveals that azulene-like molecules may be used as a new class of highly conductive unimolecular rectifiers. PMID- 21822509 TI - Novel self-assembling system based on resorcinarene and cationic surfactant. AB - Mixed association of calix[4]resorcinarene with ethyl sulfonate groups on the lower rim and dimethylaminomethyl groups on the upper rim (CR) and cationic surfactant 4-aza-1-hexadecyl-azoniabicyclo[2.2.2]octane bromide (DABCO-16) is studied by methods of tensiometry, conductometry, potentiometry and NMR spectroscopy at fixed CR concentration and varied surfactant concentration. Beyond ca. 0.4 mM of DABCO-16, mixed aggregates enriched by CR are proved to be formed due to electrostatic forces, while beyond ca. 5 mM, aggregates enriched by surfactant occur due to the hydrophobic effect. Spectrophotometry monitoring of the solubilization of a hydrophobic dye, Orange OT, demonstrated that only the second type of mixed aggregate enriched by DABCO-16 is capable of binding the organic probe, while the mixed system where the surfactant is a minor component shows no binding capacity towards Orange OT. This finding can be used for the design of nanocontainers with controllable binding/release properties. PMID- 21822510 TI - Photoassociation spectroscopy of ultracold metastable 3He dimers. AB - The bound states of the fermionic (3)He(2 (3)S(1)) + (3)He(2 (3)P(j)) system, where j = 0, 1, 2, are investigated using the recently available ab initio short range (1,3,5)Sigma(+)(g,u) and (1,3,5)Pi(g,u) potentials computed by Deguilhem et al. (J. Phys. B: At., Mol. Opt. Phys., 2009, 42, 015102). Single-channel and multichannel calculations have been undertaken in order to investigate the effects of Coriolis and non-adiabatic couplings. The possible experimental observability of the theoretical levels is assessed using criteria based upon the short-range character of each level and their coupling to metastable ground states. Purely long-range levels have been identified and 30 short-range levels near five asymptotes are suggested for experimental investigation. PMID- 21822511 TI - Stereoselective approaches to 2,3,6-trisubstituted piperidines. An enantiospecific synthesis of quinolizidine (-)-217A. AB - The enantiospecific and diastereocontrolled total synthesis of alkaloid (-)-217A is described that employs a stepwise [3+3] annelation strategy and a piperidine 2,3-cyclopropanation-ring opening reaction as the key steps. PMID- 21822512 TI - Complexes comprised of a dendrimer and a vesicle: role of vesicle size and the surface tension of the vesicle membrane. AB - Mesoscale simulations are performed to study the complexes between a dendrimer and a vesicle of amphiphilic molecules. In particular, the assembled structures and dynamics of these complexes are investigated by tuning vesicle size and the surface tension of vesicle membrane. Our simulations demonstrate that a dendrimer based bulge containing amphiphilic molecules forms in the vesicle membrane when a dendrimer adheres to a vesicle. We find that vesicle size and the surface tension of the vesicle membrane permit effective accesses to control the shape change of the bulge structure with respect to various hydrophobic interactions in the complexes. The analysis for the energy of the vesicle reveals that the change of elastic energy induced by various densities of amphiphilic molecules in the membrane plays an important role in this bulge-shape control. Because both charged dendrimers and vesicles are effective nanodevices for targeted drug delivery, our findings shed light on the effective means of developing multitasking nanocarriers as targeted drug delivery platforms. PMID- 21822513 TI - New nickel(II) and iron(II) helicates and tetrahedra derived from expanded quaterpyridines. AB - As an extension of prior studies involving the linear quaterpyridine ligand, 5,5'''-dimethyl-2,2':5',5'':2'',2'''-quaterpyridine 1, the synthesis of the related expanded quaterpyridine derivatives 2 and 3 incorporating dimethoxy substituted 1,4-phenylene and tetramethoxy-substituted 4,4'-biphenylene bridges between pairs of 2,2'-bipyridyl groups has been carried out via double-Suzuki coupling reactions between 5-bromo-5'-methyl-2'-bipyridine and the appropriate di pinacol-diboronic esters using microwave heating. Reaction of 2 and 3 with selected Fe(II) or Ni(II) salts yields a mixture of both [M(2)L(3)](4+) triple helicates and [M(4)L(6)](8+) tetrahedra, in particular cases the ratio of the products formed was shown to be dependent on the reaction conditions; the respective products are all sufficiently inert to allow their chromatographic separation and isolation. Longer reaction times and higher concentrations were found to favour tetrahedron formation. The X-ray structures of solvated [Ni(2)(2)(3)](PF(6))(4), [(PF(6)) ? Fe(4)(2)(6)](PF(6))(7), [Fe(4)(3)(6)](PF(6))(8) and [Ni(4)(3)(6)](PF(6))(8) have been determined, while the structure of the parent Fe(II) cage in the series, [(PF(6)) ? Fe(4)(1)(6)](PF(6))(7), was reported previously. The internal volumes of the Fe(II) tetrahedral cages have been calculated and increase from 102 A(3) for [Fe(4)(1)(6)](8+) to 227 A(3) for [Fe(4)(2)(6)](8+) to 417 A(3) for [Fe(4)(3)(6)](8+) and to an impressive 839 A(3) for [Ni(4)(3)(6)](8+). The corresponding void volume in the triple helicate [Ni(2)(2)(3)](4+) is 29 A(3). PMID- 21822514 TI - Ba5Ga4Se10: a new selenidogallate containing the novel [Ga4Se10](10-) anionic cluster with Ga in a mixed-valence state. AB - The new compound Ba(5)Ga(4)Se(10) has been synthesized for the first time. It crystallizes in the tetragonal space group I4/mcm with a = 8.752(2) A, c = 13.971(9) A, and Z = 2. The structure contains discrete [Ga(4)Se(10)](10-) anions and charge-compensating Ba(2+) cations. The novel highly anionic [Ga(4)Se(10)](10 ) cluster is composed of two Ga(Se)(4) tetrahedra and two Ga(Ga)(Se)(3) tetrahedra with Ga in the 2+/3+ valence states. It also exhibits an unusually long Ga-Se distance of 2.705(2) A, which has only been observed under high pressure conditions before. A band gap of 2.20(2) eV was deduced from the UV/vis diffuse reflectance spectrum. PMID- 21822515 TI - Direct synthesis of enaminone functionalized biaryl ethers by CuI-catalyzed O arylation of enaminone functionalized phenols. AB - The O-arylation of o-enaminone functionalized phenols, namely, (E)-3 (dimethylamino)-1-(2-hydroxyphenyl)prop-2-en-1-ones, has been achieved via a self promoted process in the presence of CuI, which provided a class of new biaryl ethers bearing a reactive enaminone fragment. The reactions were performed under mild conditions and the functionalized biaryl ether products have been found as useful building blocks for the assembly of heterocyclic compounds. PMID- 21822516 TI - Behaviour of different lichen species as biomonitors of air pollution by PAHs in natural ecosystems. AB - Six different species of lichens (Parmelia sulcata Tayl., Evernia prunastri (L.) Ach., Ramalina farinacea, Pseudevernia furfuracea (L.) Zopf., Usnea sp. and Lobaria pulmonaria (Schreb.) Hoffm.) were collected in two mountain valleys in Central Pyrenees: the Aspe and Aragon valleys. Two multivariate techniques have been applied with different purposes, ANOVA and Discriminant Analysis (DA), to evaluate the data. The PAHs spatial distribution was studied in the three more abundant and widespread species in the area: P. sulcata, E. prunastri (L.) Ach. and R. farinacea in terms of total PAHs, PAHs related to the combustion processes and toxicity. Different behaviour of each lichen species to trap PAHs was found, being P. sulcata the best one to monitor the most persistent PAHs of pyrogenic origin and E. prunastri the most appropriate to provide information about pyrogenic and petrogenic PAHs. Traffic was the most relevant influence in PAHs bioaccumulation in lichen species. PMID- 21822517 TI - Facile approach to graphene oxide and poly(N-vinylcarbazole) electro-patterned films. AB - A facile approach of making scalable nanocomposite and electro-patterned films using graphene oxide (GO) and poly(N-vinylcarbazole) (PVK) is reported. The method involves the layering of polystyrene colloidal templates, electrodeposition of the composite film on template array, and finally removal of the sacrificial templates to reveal the patterned GO-PVK arrays. PMID- 21822518 TI - Franck-Condon factors and radiative lifetime of the A2Pi(1/2)-X2Sigma+ transition of ytterbium monofluoride, YbF. AB - The fluorescence spectrum resulting from laser excitation of the A(2)Pi(1/2)< X(2)Sigma(+) (0,0) band of ytterbium monofluoride, YbF, has been recorded and analyzed to determine the Franck-Condon factors. The measured values are compared with those predicted from Rydberg-Klein-Rees (RKR) potential energy curves. From the fluorescence decay curve the radiative lifetime of the A(2)Pi(1/2) state is measured to be 28 +/- 2 ns, and the corresponding transition dipole moment is 4.39 +/- 0.16 D. The implications for laser cooling YbF are discussed. PMID- 21822519 TI - Luminescent infinite coordination polymer materials from metal-terpyridine ligation. AB - A new class of infinite coordination polymers (CP) was synthesized using a tetrahedral tetrakis[4-(4'-phenyl-2,2':6',2''-terpyridine)phenyl]methane ligand as an organic node to direct the three-dimensional growth of the network and M(II) (M = Zn, Fe, Ni, and Ru) ions as inorganic linkers, an approach that is the opposite of the metal-as-a-node strategy used in the construction of metal organic frameworks (MOFs). The unusual rod-like morphology of the resulting microporous materials can be tuned via solvents and reaction conditions. The covalent entrapment of a [Ru(tpy)(2)](2+) moiety in the skeleton of the 3D network enables the Ru-CP to exhibit room-temperature luminescence. PMID- 21822520 TI - A 3D chiral porous In(III) coordination polymer with PtS topological net. AB - The solvothermal reaction of In(III) and 1,2,4,5-benzeneteracarboxylic acid with the presence of piperazine leads to the generation of a novel 3D chiral porous coordination polymer with PtS topological net. Interestingly, the resulting crystals were not a racemic mixture but enantiomeric excess, which was confirmed by the measurement of optical rotation of bulk samples using solid vibrational circular dichroism (VCD) spectra and the solid circular dichroism (CD) spectra based on large crystals from one crystallization. High-pressure CO(2) and CH(4) adsorption measurement at 298 K reveals that activated 1 can absorb 45.8 cm(3) (STP)/g CO(2) at 22 atm and 22.5 cm(3) (STP)/g CH(4) at 25 atm. PMID- 21822521 TI - A magnetite/oxidized carbon nanotube composite used as an adsorbent and a matrix of MALDI-TOF-MS for the determination of benzo[a]pyrene. AB - A magnetite/oxidized carbon nanotube composite, Fe(3)O(4)@SiO(2)/OCNT, was fabricated in a simple way, and it was successfully used as a magnetic solid phase extraction sorbent and a significant matrix of the matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) for the detection of benzo[a]pyrene (BaP). PMID- 21822522 TI - C-branched chiral (racemic) macrocyclic amino acids: structure of their Ni(II), Zn(II) and Cu(II) complexes. AB - A new procedure for the synthesis of macrocyclic embedded bis-alpha-amino acids and their use as cation-ligands is described. These compounds are able to form stable Cu(II), Zn(II) and Ni(II) complexes as long as they have a flexible tether between the two nitrogen atoms. For a given macrocycle, the X-ray diffraction studies revealed diastereomerically pure complexes having different geometries depending on the metal ion. PMID- 21822523 TI - Model and experimental studies for contact angles of surfactant solutions on rough and smooth hydrophobic surfaces. AB - Despite the practical need, no models exist to predict contact angles or wetting mode of surfactant solutions on rough hydrophobic or superhydrophobic surfaces. Using Gibbs' adsorption equation and a literature isotherm, a new model is constructed based on the Wenzel and Cassie equations. Experimental data for aqueous solutions of sodium dodecyl sulfate (SDS) contact angles on smooth Teflon surfaces are fit to estimate values for the adsorption coefficients in the model. Using these coefficients, model predictions for contact angles as a function of topological f (Cassie) and r (Wenzel) factors and SDS concentration are made for different intrinsic contact angles. The model is also used to design/tune surface responses. It is found that: (1) predictions compare favorably to data for SDS solutions on five superhydrophobic surfaces. Further, the model predictions can determine which wetting mode (Wenzel or Cassie) occurred in each experiment. The unpenetrated or partially penetrated Cassie mode was the most common, suggesting that surfactants inhibit the penetration of liquids into rough hydrophobic surfaces. (2) The Wenzel roughness factor, r, amplifies the effect of surfactant adsorption, leading to larger changes in contact angles and promoting total wetting. (3) The Cassie solid area fraction, f, attenuates the lowering of contact angles on rough surfaces. (4) The amplification/attenuation is understood to be due to increased/decreased solid-liquid contact-area. PMID- 21822524 TI - From VO2 (B) to VO2 (A) nanobelts: first hydrothermal transformation, spectroscopic study and first principles calculation. AB - The phase transition process from VO(2) (B) to VO(2) (A) was first observed through a mild hydrothermal approach, using hybrid density functional theory (DFT) calculations and crystallographic VO(2) topology analysis. All theoretical analyses reveal that VO(2) (A) is a thermodynamically stable phase and has a lower formation energy compared with the metastable VO(2) (B). For the first time, X-ray absorption spectroscopy (XAS) of the V L-edge and O K-edge was performed on different VO(2) phases, and the differences in the electronic structure of the two polymorphic forms provide further experimental evidence of the more stable VO(2) (A). Consequently, transformation from VO(2) (B) to VO(2) (A) is much easier to be realized from a dynamical point of view. Notably, the transformation of VO(2) (B) into VO(2) (A) show the sequence VO(2) (B)-high temperature VO(2) (A(H)) phase-low-temperature VO(2) (A) phase, which was achieved by hydrothermal treatment, respectively. Also, an alternative synthesis route was proposed based on the above hydrothermal transformation, and VO(2) (A) was successfully prepared via the simple one-step hydrothermal method by hydrolysis of VO(acac)(2) (acac = acetylacetonate). Therefore, VO(2) nanostructures with controlled phase compositions can be obtained in high yields. Through elucidating the structural evolution in the crystallographic shear mechanism, we can easily guide the design of other metal oxide nanostructures with controllable phases. PMID- 21822525 TI - Treatment and secondary prevention of venous thromboembolism in cancer patients. Current strategies and new therapeutic options. AB - Cancer is a major and independent risk factor of venous thromboembolism (VTE). In clinical practice, a high number of VTE events occurs in patients with cancer, and treatment of cancer-associated VTE differs in several aspects from treatment of VTE in the general population. However, treatment in cancer patients remains a major challenge, as the risk of recurrence of VTE as well as the risk of major bleeding during anticoagulation is substantially higher in patients with cancer than in those without cancer. In several clinical trials, different anticoagulants and regimens have been investigated for treatment of acute VTE and secondary prophylaxis in cancer patients to prevent recurrence. Based on the results of these trials, anticoagulant therapy with low-molecular-weight heparins (LMWH) has become the treatment of choice in cancer patients with acute VTE in the initial period and for extended and long-term anticoagulation for 3-6 months. New oral anticoagulants directly inhibiting thrombin or factor Xa, have been developed in the past decade and studied in large phase III clinical trials. Results from currently completed trials are promising and indicate their potential use for treatment of VTE also in cancer patients. However, the role of the new oral thrombin and factor Xa inhibitors for VTE treatment in cancer patients still has to be clarified in further studies specifically focusing on cancer-associated VTE. This brief review will summarize the current strategies of initial and long-term VTE treatment in patients with cancer and discuss the potential use of the new oral anticoagulants. PMID- 21822526 TI - Risk of venous thromboembolism and primary prophylaxis in cancer. Should all patients receive thromboprophylaxis? AB - Venous thromboembolism (VTE) is a common complication in patients with cancer that causes significant morbidity and mortality. Several patient-, tumour- and treatment-related risk factors for VTE in cancer patients have been identified. An effective and safe thromboprophylaxis in cancer patients at high risk of VTE is desirable. Recently, the identification of potential biomarkers and the development of risk scoring models for prediction of cancer-associated VTE have been published. Whether primary VTE prophylaxis based on risk assessment through these biomarkers and risk prediction models might be useful, is currently not yet known. However, thromboprophylaxis is clearly indicated in high-risk situations. While VTE prophylaxis is recommended in cancer patients undergoing surgery and in hospitalised patients with acute disease, studies in ambulatory cancer patients are still rare and evidence for primary VTE prophylaxis is currently limited. In this review, risk factors associated with VTE in cancer patients and current approaches of thromboprophylaxis in different settings, specifically in ambulatory cancer patients are subjected to a critical evaluation. PMID- 21822527 TI - Radiographic evaluation of osteotomized ulnar segments following arthroscopic treatment for canine medial coronoid disease. AB - OBJECTIVE: To assess movement of ulnar segments radiographically, following proximal and midshaft ulnar osteotomy or ostectomy after arthroscopic treatment for dogs diagnosed with medial coronoid disease. METHODS: Fragmentation and cartilage wear were treated arthroscopically and the presence of incongruity confirmed. Osteotomies were performed at the mid-point or proximal third of the length of the ulna. The distance of separation between the ulnar segments and the adjacent radius were measured and followed by serial radiographs postoperatively until healing had occurred. RESULTS: Proximal oblique osteotomies located at one third the length of the ulna were associated with the most movement of the ulnar segments, most notably of the proximal segment. Osteotomies or ostectomies performed in the middle demonstrated less segmental movement and on average, slightly longer time to heal. Movement of the ulnar segments in both groups occurred immediately, and then peaked at two to four weeks postoperatively, tending to plateau thereafter. CLINICAL SIGNIFICANCE: Radioulnar incongruity is considered a facet of the aetiopathogenesis of canine medial coronoid disease. This creates abnormal loads and focal wear along the medial coronoid process. Performing an oblique osteotomy at a location measured at the proximal third of the length of the ulna allows increased movement of the proximal segment, which may result in unloading of the medial compartment. Performing an osteotomy or ostectomy distally dampens segmental movement due to constraint of the interosseous ligament. These findings suggest that a proximal oblique osteotomy at this location creates immediate favourable movement with low morbidity. PMID- 21822528 TI - The double-arch modified type-1b external skeletal fixator. Technique description and functional outcome for surgical management of canine antebrachial limb deformities. AB - OBJECTIVES: To describe acute correction of antebrachial angular and rotational limb deformities (ARLD) using a new external skeletal fixator (ESF). METHODS: Dogs that were presented with lameness caused by ARLD were treated by radial and ulnar osteotomies and acute realignment. A modified type-1b ESF incorporating double arches (DA-ESF) and a novel connecting configuration facilitated alignment with six degrees of freedom. Bilateral deformities were corrected surgically in the same session. Aseptic preparation of both antebrachii allowed comparison of limb alignment. Radiographic evaluation was performed using centre of rotation of angulation (CORA) methodology. RESULTS: Thirty-five antebrachii (22 dogs) underwent surgery. Postoperative limb function was graded as good (n = 31), fair (n = 2), or poor (n = 2). Persistent medial carpal instability was associated with a suboptimal outcome. Postoperative radiographic images of the frontal and sagittal plane joint angles and elbow-to-carpus translation were compared with values that were reported in previous studies, and were within published reference ranges in most cases. Complications included delayed radial osteotomy union (n = 5), delayed ulnar osteotomy union (n = 2) and implant-associated morbidity (n = 3). CLINICAL RELEVANCE: A practical technique for acute correction of complex antebrachial ARLD is suggested, incorporating a new configuration of ESF. Putative limitations of radiographic planning using CORA may be compensated by careful attention to intra-operative visual and palpatory assessment. PMID- 21822529 TI - Skin movement during the kinematic analysis of the canine pelvic limb. AB - OBJECTIVES: To determine whether the canine pelvic limb can be considered a linkage of rigid bodies during kinematic analysis. METHODS: The lengths of the femur and tibia based on skin markers were examined throughout gait cycles in six dogs trotting on a treadmill at 2 m/sec. The angular kinematics of the hip, stifle and tarsal joints were calculated based on a conventional stifle marker (CSM) and computed virtual stifle positions (VSP). Based on the CSM and VSP, the kinematic data from the joints were compared and the agreement among them determined. The difference between the CSM and VSP coordinates were illustrated. RESULT: The femoral and tibial lengths based on skin markers were not constant throughout a gait cycle and the lengths changed in repeatable patterns in each dog. There was close agreement between the joint angles based on the CSM and VSP in the tarsal joint but not in the hip and stifle joints, where the kinematics based on the CSM tended to calculate smaller angular excursion than the kinematics based on VSP. The pattern of displacement of the CSM was repeatable through a gait cycle. CLINICAL RELEVANCE: There was skin movement which causes considerable artifact during kinematic analysis of the canine pelvic limb. The skin movement has to be accounted for during canine kinematic analysis. PMID- 21822530 TI - Partial scapulectomy for treatment of an articular fracture of the scapula in a cat. AB - A seven-month-old cat was referred, after having been missing for one week, for evaluation and treatment of a right forelimb injury and facial fractures. On physical examination, a moderate partial weight-bearing lameness of the right forelimb was present, with palpable crepitus in the glenohumeral joint. Dental radiographs revealed a midline palatal fracture and rostral fractures of the left maxillary canine alveolar bone. Radiographs of the right shoulder revealed a Type III or intra- articular fracture of the scapula with moderate displacement of the fracture at the articular surface. Early fibrous healing of the fracture was observed and the caudal aspect of the medial glenohumeral ligament was ruptured. Due to the chronicity, reduction and stabilization was not attempted. Instead, the caudal aspect of the medial glenohumeral ligament was incised along its origin and approximately 30% of the glenoid was removed. The caudal glenohumeral ligament was attached to the subscapularis muscle. Three years after surgery, the owner reported that the cat continued to experience no visible lameness and led an active lifestyle. This case report demonstrates that a partial caudal scapulectomy can result in full return of function of the forelimbs in cats with scapular fractures, especially when joint involvement is severe and the articular cartilage is affected. To the authors' knowledge, this is the first report of a partial scapulectomy, utilized for fracture management, in the veterinary literature. PMID- 21822531 TI - Massive osteolysis in a dog resembling Gorham's disease in humans. AB - An eight-month-old mixed-breed dog was presented with a history of sudden onset pelvic limb lameness. Radiographic and computed tomographic examinations demonstrated an osteolytic process involving the lumbar spine and pelvis. A comprehensive work-up including serial radiographic skeletal survey, biopsy, routine laboratory investigation and evaluation of parathyroid hormone (PTH) and 25-hydroxy-vitamin D levels failed to reveal any underlying cause for the osteolysis. Conservative treatment using the bisphosphonate drug alendronate and oral analgesic medications resulted in a return to nearly normal long-term function, despite massive lumbar and pelvic osteolysis. The clinical, radiological and histopathological features in this dog are reported, and similarities with the human condition known as Gorham's disease are discussed. PMID- 21822532 TI - Cytoprotective effect of gamma-tocopherol against tumor necrosis factor alpha induced cell dysfunction in L929 cells. AB - The antioxidant vitamin gamma-tocopherol exerts protective and anti-inflammatory effects in various models of critical illness. The combination of actinomycin D and tumor necrosis factor alpha (TNFalpha) in the immortalized fibroblast cell line L929 is a well-established method to model pro-inflammatory cytotoxicity in cultured cells in vitro. The present study had two aims. First, we wished to characterize the contribution of reactive oxygen species (ROS) to the cell dysfunction and this commonly used model system of cell death. Second, we wished to investigate the effects of gamma-tocopherol on this response. Cells were exposed to actinomycin D (0.5 ug/ml) + TNFalpha (100 pg/ml) in the absence or presence of 1 h of gamma-tocopherol pre-treatment. The earliest change that was detected in our system in response to TNFalpha was an increase in mitochondrial oxidant production, already apparent at 45 min. Changes in glycolysis and oxidative phosphorylation parameters were already apparent at 2 h, as detected by the Seahorse Biosciences XF24 Flux Analyzer. By 6 h, a slight decrease in Cell Index was detected by impedance-based analysis, employing an electronic sensor array system (XCelligence). At the same time, a slight decrease in cell viability was detected by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) method, along with a significant increase in lactate dehydrogenase (LDH) release into the culture medium, and a detectable degree of mitochondrial membrane depolarization. Between 12 and 24 h, the cell viability (already at a low level) further declined, which coincided with a secondary, marked decline in the mitochondrial membrane potential. Pre-treatment of the cells with gamma tocopherol (10-300 uM) provided a significant protection against all of the functional alterations induced by actinomycin D and TNFalpha. The current study provides direct evidence that reactive oxidant formation plays an important role in the current experimental model of cell dysfunction, and demonstrates the protective effects of the potent endogenous antioxidant vitamin, gamma tocopherol. The mechanisms described in the current study may, in part, contribute to the protective effects of gamma-tocopherol in various models of critical illness. PMID- 21822533 TI - Fibronectin regulates proteoglycan production balance in transforming growth factor-beta1-induced chondrogenesis. AB - Transforming growth factor (TGF)-beta and bone morphogenetic protein (BMP) induce a cartilage-specific extracellular matrix (ECM) gene, aggrecan, in a chondrogenic cell line, ATDC5. The results of our recent study show that TGF-beta1, but not BMP-4, strongly induces an ECM gene, fibronectin, during chondrogenesis. However, the role of fibronectin in chondrogenesis is unclear. In the current study, our results showed that TGF-beta1, but not BMP-4, led to versican-dominant proteoglycan production during chondrogenesis of ATDC5 cells. siRNA-mediated reduction of fibronectin and interference in the liaison between fibronectin and integrins by the Arg-Gly-Asp-Ser (RGDS) peptide increased aggrecan expression, and decreased versican expression by TGF-beta1 stimulation. These data suggest that fibronectin is a critical mediator for TGF-beta-specific production balance of 2 major proteoglycans, aggrecan and versican, during chondrogenesis. PMID- 21822534 TI - Pen-2 overexpression induces Abeta-42 production, memory defect, motor activity enhancement and feeding behavior dysfunction in NSE/Pen-2 transgenic mice. AB - Pen-2 is a key regulator of the gamma-secretase complex, which is involved in the production of the amyloid beta (Abeta)-42 peptides, which ultimately lead to Alzheimer's disease (AD). While Pen-2 has been studied in vitro, Pen-2 function in vivo in the brains of transgenic (Tg) mice overexpressing human Pen-2 (hPen-2) protein has not been studied. This study aimed to determine whether Pen-2 overexpression could regulate the AD-like phenotypes in Tg mice. NSE/hPen-2 Tg mice were produced by the microinjection of the NSE/hPen-2 gene into the pronucleus of fertilized eggs. The expression of the hPen-2 gene under the control of the NSE promoter was successfully detected only in the brain and kidney tissue of NSE/hPen-2 Tg mice. Also, 12-month-old NSE/hPen-2 Tg mice displayed behavioral dysfunction in the water maze test, motor activity and feeding behavior dysfunction in food intake/water intake/motor activity monitoring system. In addition, tissue samples displayed dense staining with antibody to the Abeta-42 peptide. Furthermore, NSE/hPen-2 Tg mice exhibiting feeding behavior dysfunction were significantly more apt to display symptoms related to diabetes and obesity. These results suggest that Pen-2 overexpression in NSE/hPen-2 Tg mice may induce all the AD-like phenotypes, including behavioral deficits, motor activity and feeding behavior dysfunction, Abeta-42 peptide deposition and chronic disease induction. PMID- 21822535 TI - Sodium valproate blocks the transforming growth factor (TGF)-beta1 autocrine loop and attenuates the TGF-beta1-induced collagen synthesis in a human hepatic stellate cell line. AB - Histone acetylation and deacetylation have been thought to be related to gene expression, and there are many reports indicating that histone deacetylase inhibitors (HDACis) exert antifibrogenic effects in several organs. In injured livers, hepatic stellate cells (HSCs) are activated in response to profibrogenic mediators and produce large amounts of extracellular matrix. In particular, transforming growth factor-beta1 (TGF-beta1) is considered as a key factor in accelerating hepatic fibrosis because it is released from activated HSCs and further stimulates them. The present study aimed to clarify whether sodium valproate (VPA) has suppressive effects on cultured human HSCs (LI90). We showed that treatment with VPA had no significantly suppressive effect on cell proliferation at a concentration of 1 mM, which corresponded approximately to the serum concentration obtained by the administration of a clinical dose. However, VPA prevented the morphological changes characteristic for activation and inhibited the expression of collagen type 1 alpha1 (COL1A1) and TGF-beta1 in activated LI90 cells at the mRNA and protein levels. Our results support the hypothesis that VPA exerts antifibrogenic activity with little cytotoxicity at 1 mM, and HDACis are expected to be used in clinical practice for the treatment of fibrotic diseases. PMID- 21822537 TI - Evidence for cardiac atrophic remodeling in cancer-induced cachexia in mice. AB - Cachexia is a common complication in cancer patients, which dramatically reduces quality of life and survival. In contrast to the well-studied feature of skeletal muscle loss, alterations in cardiac muscle are unclear. Recently, we reported that heart contractile function was significantly impaired in mice with colon-26 (C26) tumors, a widely used rodent model of cancer cachexia. In the present study, we investigated the potential underlying mechanisms for decreased heart function, specifically related to cardiac remodeling and atrophy. In cachectic mice bearing C26 tumors compared to mice without tumors, there was a gene expression pattern for cardiac remodeling, including increased BNP and c-fos, decreased PPARalpha and its responsive gene CPT1beta, and a switch from 'adult' isoforms (MHCalpha, GLUT4) to 'fetal' isoforms (MHCbeta and GLUT1). Echocardiography identified a decreased cardiac wall thickness. RT-PCR and Western blotting revealed a decreased amount of cardiac myofibrillar proteins MHC and troponin I, induced expression of E-3 ligases (MuRF-1 and Atrogin-1) and increased protein ubiquitination, providing evidence for cardiac atrophy in mice with cancer cachexia. Regulatory signaling pathways mediating these changes may include p44/42 MAPK. Together, these data provide evidence that pathways leading to cardiac remodeling and atrophy occur in mice with C26 cachexia. PMID- 21822536 TI - Tobacco-specific carcinogen nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1 butanone induces AKT activation in head and neck epithelia. AB - Exposure to tobacco carcinogens is causally associated with head and neck squamous cell carcinoma (HNSCC), but the underlying molecular mechanisms remain unclear. Here, we reported that AKT is activated at a higher frequency in both HNSCC tumors and the adjacent mucosa from HNSCC patients who are smokers than those from HNSCC patients who are non-smokers. Adding physiologically relevant concentrations of 4-(methylnitrosamino)-1-(3-pyridyl)-1-1butanone (NNK), a major tobacco carcinogen, to normal head and neck epithelial cells and HNSCC cell lines, rapidly and constitutively activated AKT through phosphorylation in a dose and time-dependent manner. AKT phosphorylation was associated with activation of downstream signaling mediators BAD, MDM2, GSK-3beta, mTOR. These alterations correlated with increased proliferation and decreased etoposide-induced apoptosis in NNK-exposed cells. Finally, NNK exposure to mouse head and neck epithelia resulted in epithelial hyperproliferation and reduced apoptosis, which is correlated with AKT activation. Our results suggest that AKT activation is an early event and plays a pivotal role in mediating tobacco-induced HNSCC carcinogenesis. PMID- 21822538 TI - p53 siRNA inhibits apoptosis of U2OS cells treated with azurin. AB - The bacterial redox protein azurin selectively induces apoptosis in human osteosarcoma U2OS cells. We constructed a p53 siRNA to test the role that p53 plays in the apoptosis-inducing role of azurin in U2OS cells. Cells treated with p53 siRNA and azurin showed more viable cells, a lower apoptosis rate, lower caspase-3 activity, and up-regulation of bcl-2, downregulation of bax compared to cells treated with negative siRNA and azurin. Cells treated with negative siRNA and azurin yielded positive TUNEL dying, whereas cells treated with p53 siRNA and azurin yielded few positive cells. These results suggested that p53 siRNA was capable of inhibi-ting the apoptosis induced by azurin 2 days after treatment with p53 siRNA and azurin. Azurin may induce apoptosis through combination with p53. The decrease in p53 protein levels did not inhibit cell apoptosis rates, but rather increased these rates in U2OS osteosarcoma cells 3 days after treatment with p53 siRNA. Since U2OS cells are p53 wild-type cancer cells, p53 potentially acts as an oncogene in U2OS osteosarcoma cells. Treatment with azurin may transform the function of p53 from inhibiting to inducing apoptosis. PMID- 21822539 TI - Colon cancer-derived factors activate NF-kappaB in myeloid cells via TLR2 to link inflammation and tumorigenesis. AB - The exact mechanism for the contribution of NF-kappaB activation during colon carcinogenesis is unclear. The present study aimed to determine the manner in which colon cancer cells induce inflammatory responses in order to link tumor growth. Macrophages were stimulated with cultured medium from the supernatants of several colon cancer cell lines. Macrophage accumulation and NF-kappaB activation were observed in samples that were stimulated with supernatant from tumor cells that showed constitutive NF-kappaB activity. NF-kappaB activation in the stimulated macrophages was dependent on TLR2 and IKKbeta, but not TLR4. Various cytokines, such as IL-6, were induced in a TLR2-dependent manner. Tumor cells that were cultured with the supernatant of macrophages originally stimulated with the tumor cell cultured media grew more rapidly than those stimulated with the supernatant of unstimulated macrophages. Taken together, colon cancer-derived factors induce the accumulation of macrophages and activate NF-kappaB through a TLR2-dependent mechanism, suggesting an important link between inflammation and tumor growth. PMID- 21822540 TI - Association of APOE polymorphisms and insulin resistance with TCM syndromes in type 2 diabetes patients with macroangiopathy. AB - To investigate the association between apolipo-protein E (APOE) polymorphisms and insulin resistance and Traditional Chinese Medicine (TCM) syndromes in type 2 diabetes mellitus (T2DM) with macroangiopathy, 60 patients with T2DM macroangiopathy were enrolled and divided into three groups: dryness-heat due to deficiency of yin, Qi-Yin deficiency, and Yin-Yang deficiency, according to the TCM syndromes, with a control group of 20 healthy individuals. APOE genotype analysis was performed with polymerase chain reaction amplification and restriction fragment length polymorphism, and the results showed that the proportion of the epsilon4/4 and epsilon3/4 genotypes and frequencies of the epsilon4 and epsilon3 alleles were higher in the Qi-Yin deficiency group (P<0.05). Among the T2DM macroangiopathy patients, the E4 group had the largest number of cases, as well as a significantly longer disease course compared to the E2 group (P<0.05). The insulin resistance index (IRI), insulin action index and body mass index (BMI) of patients in the Yin-Yang deficiency group were significantly different from those of patients with dryness-heat due to deficiency of yin and Qi-Yin deficiency. Furthermore, correlation analysis of the BMI and IRI of patients in the Yin-Yang deficiency group revealed a correlation coefficient r=0.696 (P<0.01) and a typical correlation between them. In conclusion, the Qi-Yin deficiency in T2DM patients with macroangiopathy is associated with the APOE E4 and E3 genotypes. Thus, the APOE gene polymorphism can, to some degree, reflect the TCM syndrome types of T2DM patients with macroangiopathy. Insulin resistance plays an important role in the occurrence of T2DM macroangiopathy and is closely associated with the Yin-Yang deficiency according to the TCM differentiating types. PMID- 21822541 TI - Role of GOLPH3 and GOLPH3L in the proliferation of human rhabdomyosarcoma. AB - GOLPH3 was originally identified by proteomic analyses of Golgi proteins localized in the trans-Golgi network. Recently, it was reported that GOLPH3 is up regulated in various types of malignancies, including melanoma, colon cancer and lung cancer. However, the mechanism through which GOLPH3 is involved in the pathogenesis of rhabdomyosarcoma remains unidentified. In order to explore the function of GOLPH3 and its isoform, GOLPH3L, in the pathogenesis of rhabdomyosarcoma, we investigated the expression and knockdown effects of GOLPH3 and GOLPH3L in human rhabdomyosarcoma. Western blot analysis and real-time PCR revealed that human rhabdomyosarcoma cell lines and biopsy specimens exhibited an increased expression of GOLPH3 and GOLPH3L. GOLPH3 and GOLPH3L knockdown by siRNA prevented the proliferation of human rhabdomyosarcoma cell lines. In addition, double-knockdown of GOLPH3 and GOLPH3L also prevented the proliferation of rhabdomyosarcoma cell lines. Our findings improve the understanding of rhabdomyosarcoma pathogenesis and suggest that the knockdown of GOLPH3 or GOLPH3L may be an effective treatment for rhabdomyosarcoma. PMID- 21822542 TI - Modified Yi Guan Jian, a Chinese herbal formula, induces anoikis in Bel-7402 human hepatocarcinoma cells in vitro. AB - Liver cancer is the fifth most common malignancy worldwide. Liver YIN deficiency is a common clinical syndrome of traditional Chinese medicine in liver cancer. Yi Guan Jian is an ancient classic liver YIN tonifying herbal formula used for the treatment of liver disease with liver YIN deficiency, which is also currently used for liver cancer treatment. However, as an ancient formula, Yi Guan Jian (YGJ) is not entirely suitable for liver cancer treatment. In the present study, we optimized the prescription of YGJ according to the current principles of Chinese herbal medication, and evaluated the anticancer effects of modified Yi Guan Jian (MYGJ) in Bel-7402 human hepatocarcinoma cells. The results show that MYGJ inhibited the growth of Bel-7402 cells in adherent or in suspension cultures, and was more effective in Bel-7402 cells in suspension. MYGJ also inhibited anchorage-independent growth of Bel-7402 cells in soft agar. MYGJ induced anoikis in Bel-7402 cells accompanied by caspase-3, -8 and -9 activation, which was blocked by the pan-caspase inhibitor, Z-VAD-FMK. Furthermore, MYGJ inhibited the expression and phosphorylation of p38 MAPK in Bel-7402 cells. These findings suggest that MYGJ is sufficient to induce caspase-mediated anoikis in Bel-7402 cells in vitro, and may be associated with down-regulation of p38 MAPK. The present study also provides insight into the application of ancient Chinese herbal formulas. PMID- 21822543 TI - Protein kinase Cdelta in tumorigenesis of human malignant fibrous histiocytoma. AB - Protein kinase Cdelta (PKCdelta), an isoform of PKC, has been shown to act as a critical mediator of tumor progression and apoptosis; however, its role in musculoskeletal tumors is still unknown. In the current study, we examined the expression of PKCdelta in human musculoskeletal tumor tissue samples, and investigated the effects of siRNA downregulation of PKCdelta on human malignant fibrous histiocytoma (MFH) cell proliferation, migration, and apoptosis, to elucidate its functional roles in musculoskeletal tumorigenesis. Of note, real time PCR analysis revealed that mRNA expression of PKCdelta in high-grade musculoskeletal MFH tumors was significantly lower than that in benign schwannomas. siRNA downregulation of PKCdelta significantly increased human MFH cell proliferation and migration, and markedly suppressed apoptosis. These findings suggest that PKCdelta has a negative effect on tumorigenesis and/or acts as a pro-apoptotic kinase in human MFH cells. The data presented here could be applied in the development of new therapeutic avenues, with the elevation of PKCdelta expression being one potential strategy to prevent MFH progression. Thus, PKCdelta may be a potent therapeutic target for human MFH. PMID- 21822544 TI - Hypoxia induces hemorrhagic transformation in pituitary adenomas via the HIF 1alpha signaling pathway. AB - The hypoxia inducible factor 1 alpha (HIF-1alpha) activity has been associated with various hemorrhagic events. The biological role of HIF-1alpha in the hemorrhagic transformation of pituitary adenomas remains unknown. We hypothesized that fast growing tumor cells tend to predispose themselves to sublethal hypoxia and activate the HIF-1alpha signaling pathway, leading to hemorrhagic transformation in pituitary adenomas. Here, we used apoplectic and non-apoplectic pituitary adenomas to determine the involvement of HIF-1alpha signaling in intratumoral hemorrhage. We employed HIF-1alpha overexpression/knockdown strategies to examine the association between HIF-1alpha signaling and hemorrhagic presentation in vitro and in vivo. In support of our hypothesis, compared with non-hemorrhagic pituitary adenomas, higher cellular proliferation was observed in hemorrhagic ones and it correlated with increased HIF-1alpha signaling. HIF-1alpha overexpression activated its downstream genes, vascular endothelial growth factor and the proapoptotic BNIP3, in MMQ pituitary adenoma cells and this up-regulation was attenuated by HIF-1 siRNA. In vivo studies using MMQ cell xenografts in nude mice showed that HIF-1alpha overexpression significantly promoted hemorrhagic transformation. Our study indicates that tumor hypoxia, following rapid tumor growth, may promote hemorrhagic transformation in pituitary adenomas via the HIF-1alpha signaling pathway. PMID- 21822545 TI - Cerebellar zones: history, development, and function. AB - The longitudinal and transverse zonal arrangement of axonal projections to and from the cerebellum, even more than the well-known laminar cytoarchitecture, is the hallmark of cerebellar anatomy. No model of cerebellar function, whether in motor control, cognition, or emotion, will be complete without understanding the development and function of zones. To this end, a special issue of this journal is dedicated to zones, and the purpose of this article is to summarize the research and review articles that are contained within. The special issue begins by considering some of the very first studies in the 1960s and 1970s that led to our modern understanding of this unique and defining anatomical substructure. Then, it considers the molecular analogs of longitudinal zones in the form of stripes in the cerebellar cortex and related sub-areas in the deep cerebellar nuclei, and it includes studies on the genetic underpinnings of stripes and zones. Several articles address the evolution of both embryonic clusters and adult zones across vertebrate species, and others discuss the functional and clinical relevance of zones. While we do not yet fully understand the role of zones with respect to motor behavior in all of its complexities, cerebellar function is clearly modular, and combinatorial models of complex motor movements based on multi-purpose modules are beginning to emerge. This special issue, by refocusing attention on this fundamental organization of the cerebellum, sets the stage for future studies that will more fully reveal the cellular, developmental, behavioral, and clinical relevance of zones. PMID- 21822546 TI - Crossing zones in the vestibulocerebellum: a commentary. AB - The contention of this commentary, focused on the vestibulocerebellum (particularly the flocculus), is that the great importance for our understanding of cerebellar organization in terms of climbing fiber zones, begun years ago by Voogd [1969, 2011] and Oscarsson [1969], needs to be matched by coming more to grips with the other fundamental geometrical organization of the cerebellum, the parallel fibers. The central issue is the selection of those parallel fiber signals to be transformed into Purkinje cell activity in the different zones. At present, in comparison to our knowledge of vestibulocerebellar climbing fiber inputs, the deficiencies in our knowledge of the zonal anatomy and physiology of vestibulocerebellar mossy fibers and granule cells are glaring. The recent emphasis on molecularly oriented investigations points to the need to reinvigorate pursuit of unanswered questions about cerebellar anatomy, the handmaiden of physiology. PMID- 21822547 TI - Orthostatic hypotension is differentially associated with the cerebellar versus the parkinsonian variant of multiple system atrophy: a comparative study. AB - Orthostatic hypotension (OH) is a cardinal feature of autonomic failure in multiple system atrophy (MSA); however, there are few comparative data on OH in the motor subtypes of MSA. In the present retrospective study, postural blood pressure drop after 3 min of standing was determined in 16 patients with the cerebellar variant of MSA (MSA-C) and in 17 patients with the Parkinson variant (MSA-P). Twenty idiopathic Parkinson's disease (IPD) patients matched for age, sex, disease duration and dopaminergic therapy served as control group. OH frequency and severity were more pronounced in MSA-C followed by MSA-P and IPD. Differences in brainstem pathology are likely to account for the tight association of MSA-C and OH. A simple standing test should be obligatory in the work-up of patients with sporadic late-onset ataxias. PMID- 21822548 TI - Multiple alleles for resistance and susceptibility modulate the defense response in the interaction of tetraploid potato (Solanum tuberosum) with Synchytrium endobioticum pathotypes 1, 2, 6 and 18. AB - The obligate biotrophic, soil-borne fungus Synchytrium endobioticum causes wart disease of potato (Solanum tuberosum), which is a serious problem for crop production in countries with moderate climates. S. endobioticum induces hypertrophic cell divisions in plant host tissues leading to the formation of tumor-like structures. Potato wart is a quarantine disease and chemical control is not possible. From 38 S. endobioticum pathotypes occurring in Europe, pathotypes 1, 2, 6 and 18 are the most relevant. Genetic resistance to wart is available but only few current potato varieties are resistant to all four pathotypes. The phenotypic evaluation of wart resistance is laborious, time consuming and sometimes ambiguous, which makes breeding for resistance difficult. Molecular markers diagnostic for genes for resistance to S. endobioticum pathotypes 1, 2, 6 and 18 would greatly facilitate the selection of new, resistant cultivars. Two tetraploid half-sib families (266 individuals) segregating for resistance to S. endobioticum pathotypes 1, 2, 6 and 18 were produced by crossing a resistant genotype with two different susceptible ones. The families were scored for five different wart resistance phenotypes. The distribution of mean resistance scores was quantitative in both families. Resistance to pathotypes 2, 6 and 18 was correlated and independent from resistance to pathotype 1. DNA pools were constructed from the most resistant and most susceptible individuals and screened with genome wide simple sequence repeat (SSR), inverted simple sequence region (ISSR) and randomly amplified polymorphic DNA (RAPD) markers. Bulked segregant analysis identified three SSR markers that were linked to wart resistance loci (Sen). Sen1-XI on chromosome XI conferred partial resistance to pathotype 1, Sen18-IX on chromosome IX to pathotype 18 and Sen2/6/18-I on chromosome I to pathotypes 2,6 and 18. Additional genotyping with 191 single nucleotide polymorphism (SNP) markers confirmed the localization of the Sen loci. Thirty-three SNP markers linked to the Sen loci permitted the dissection of Sen alleles that increased or decreased resistance to wart. The alleles were inherited from both the resistant and susceptible parents. PMID- 21822549 TI - Clinicopathological features and prognostic factors of adenocarcinoma of the esophagogastric junction according to Siewert classification: experiences at a single institution in Japan. AB - BACKGROUND: Treatment strategy for adenocarcinoma of the esophagogastric junction (AEG) remains controversial. The aims of this study are to evaluate results of surgery for AEG, to clarify clinicopathological differences according to the Siewert classification, and to define prognostic factors. METHODS: We retrospectively analyzed 179 consecutive patients with Siewert type I, II, and III AEG who underwent curative (R0) resection at the National Cancer Center Hospital East between January 1993 and December 2008. RESULTS: Patients with AEG were divided according to tumor: 10 type I (5.6%), 107 type II (59.8%), and 62 type III (34.6%). Larger, deeper tumors and nodal metastasis were more common in type III than type II tumors. No significant differences were seen in 5-year survival rates among the three types: type I (51.4%), type II (51.8%), and type III (62.6%). Multivariate analysis showed that depth of tumor and mediastinal lymph node metastasis were independent prognostic indicators. The recurrence rate for patients with mediastinal lymph node metastasis was 87.5%. The risk factors for mediastinal lymph node metastasis were length of esophageal invasion and histopathological grade. CONCLUSIONS: Mediastinal lymph node metastasis and tumor depth were significant and independent factors for poor prognosis after R0 resection for AEG. Esophageal invasion and histopathological grade were significant and independent factors for mediastinal lymph node metastasis. PMID- 21822550 TI - Validation of statistical predictive models meant to select melanoma patients for sentinel lymph node biopsy. AB - INTRODUCTION: To identify melanoma patients at sufficiently low risk of nodal metastases who could avoid sentinel lymph node biopsy (SLNB), several statistical models have been proposed based upon patient/tumor characteristics, including logistic regression, classification trees, random forests, and support vector machines. We sought to validate recently published models meant to predict sentinel node status. METHODS: We queried our comprehensive, prospectively collected melanoma database for consecutive melanoma patients undergoing SLNB. Prediction values were estimated based upon four published models, calculating the same reported metrics: negative predictive value (NPV), rate of negative predictions (RNP), and false-negative rate (FNR). RESULTS: Logistic regression performed comparably with our data when considering NPV (89.4 versus 93.6%); however, the model's specificity was not high enough to significantly reduce the rate of biopsies (SLN reduction rate of 2.9%). When applied to our data, the classification tree produced NPV and reduction in biopsy rates that were lower (87.7 versus 94.1 and 29.8 versus 14.3, respectively). Two published models could not be applied to our data due to model complexity and the use of proprietary software. CONCLUSIONS: Published models meant to reduce the SLNB rate among patients with melanoma either underperformed when applied to our larger dataset, or could not be validated. Differences in selection criteria and histopathologic interpretation likely resulted in underperformance. Statistical predictive models must be developed in a clinically applicable manner to allow for both validation and ultimately clinical utility. PMID- 21822551 TI - Sarcopenia as a prognostic factor among patients with stage III melanoma. AB - BACKGROUND: Several hypotheses proposed to explain the worse prognosis for older melanoma patients include different tumor biology and diminished host response. If the latter were true, then biologic frailty, and not age, should be an independent prognostic factor in melanoma. METHODS: Our prospective institutional review board (IRB)-approved database was queried for stage III patients with computed tomography (CT) scans at time of lymph node dissection (LND). Psoas area (PA) and density (PD) were determined in semi-automated fashion. Kaplan-Meier (K M) survival estimates and Cox proportional-hazard models were used to determine PA and PD impact on survival and surgical complications. RESULTS: Among 101 stage III patients, PD was significantly associated with both disease-free survival (DFS) (P = 0.04) and distant disease-free survival (DDFS) (P = 0.0002). Cox multivariate modeling incorporating thickness, age, ulceration, and N stage showed highly significant association with PD and both DFS and DDFS. DDFS was significantly associated with Breslow thickness (P = 0.04), number of positive nodes (P = 0.001), ulceration (P = 0.04), and decreasing muscle density (P = 0.01), with hazard ratio of 0.55 [95% confidence interval (CI) 0.35-0.87]. PD also correlated with surgical complications, with odds ratio (OR) of 1.081 [95% CI 1.016-1.150, P = 0.01]. CONCLUSIONS: Decreased psoas muscle density on CT, an objective measure of frailty, was as important a predictor of outcome as tumor factors in a cohort of stage III melanoma patients. On multivariate analysis, frailty, not age, was associated with decreased disease-free survival and distant disease-free survival, and higher rate of surgical complications. PMID- 21822552 TI - The association of protease activated receptor 1 gene -506 I/D polymorphism with disease-free survival in breast cancer patients. AB - BACKGROUND: Recent data have shown that tumor development and dissemination may be regulated by procoagulant/anticoagulant axis. The aim of the present study was to search for an association of the protease activated receptor (PAR)1 gene -506 insertion/deletion (I/D), factor V Leiden (FVL), prothrombin (PT) G20210A, and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphisms with disease-free survival (DFS) in breast cancer. METHODS: Genotyping of -506 I/D in the promoter region of PAR1 gene was performed by single-strand conformation polymorphism analysis and sequencing. FVL, PT G20210A, and MTHFR C677T were also determined by the method of polymerase chain reaction-based DNA analysis. Data regarding patient's age, menopausal status, tumor size, lymph node status, disease stage, tumor grade, estrogen and progesterone receptor, c-erb B2 expression, PAR1 -506 I/D, MTHFR C677T, FVL, and PT G20210A polymorphisms were examined by the univariate and multivariate analyses. RESULTS: Recurrent disease occurred in 29 patients (19.6 %) within a median of 20 months. It was found that tumor size, lymph node status, tumor stage, tumor grade, c-erbB2 expression, and PAR1 -506 I/D polymorphism were associated with DFS when Kaplan-Meier method was applied (P<.05). By Cox proportional hazards model, the presence of allele D at -506 locus (P=.0249) and small tumor size (P=.0001) were significant favorable prognostic factor, but c-erbB2 expression was an adverse prognostic factor (P=.0049). CONCLUSION: Our study suggested the protective effect of the allele D at -506 locus of PAR1 gene on the recurrence of breast cancer. PMID- 21822554 TI - Molecular predictors of prognosis in lung cancer. AB - Lung carcinoma is the leading cause of cancer mortality worldwide. Currently, cancer staging and prognosis are determined using histopathology and clinical factors such as lymph node status. However, even the earliest stage of non-small cell lung carcinoma has a widely varying prognosis. In this review, the evolution and refinement of molecular predictors of prognosis in lung carcinoma are described. PMID- 21822553 TI - High expression of delta-like ligand 4 predicts poor prognosis after curative resection for pancreatic cancer. AB - BACKGROUND: Delta-like ligand 4 (DLL4)-Notch signaling plays a key role in tumor angiogenesis, but its prognostic value in patients with pancreatic ductal adenocarcinoma (PDAC) remains unclear. Our aim was to determine whether high DLL4 expression is correlated with poor prognosis after curative resection for PDAC. METHODS: Surgical specimens obtained from 89 patients with PDAC were immunohistochemically assessed for DLL4 and vascular endothelial growth factor receptor 2 (VEGFR-2) expression. Prognostic significance of DLL4 expression was evaluated by Kaplan-Meier method and Cox regression. The correlations of DLL4 expression with VEGFR-2 expression, tumor stage, and lymph node metastasis were examined by chi-square test and multivariate logistic regression. RESULTS: There were 38 (42.7%) and 51 patients who showed high and low DLL4 expression, respectively. Survival curves showed that patients with low DLL4 expression had a significantly better survival than those with high DLL4 expression (P < .001). Multivariate survival analysis demonstrated that high DLL4 expression was independently associated with both reduced overall survival (hazard ratio [HR] 2.24; 95% confidence interval [95% CI] 1.14-4.38) and reduced progression-free survival (HR 2.37; 95% CI 1.22-4.60). Multivariate logistic regression analyses showed that high DLL4 expression was independently associated with both advanced tumor stage (odds ratio [OR] 6.84; 95% CI 2.42-9.36) and lymph node metastasis (OR 3.27; 95% CI 1.04-10.34). We also found a positive correlation between DLL4 and VEGFR-2 expression (P < .001). CONCLUSIONS: High DLL4 expression is significantly associated with poor prognosis for surgically resected PDAC, advanced tumor stage, and lymph node metastasis. Application of adjuvant therapy targeting DLL4-Notch signaling may improve prognosis. PMID- 21822555 TI - Laparoscopic left nephrectomy with "en bloc" distal splenopancreatectomy. AB - BACKGROUND: Multiorgan resection for cancer is considered a demanding laparoscopic procedure. We report a laparoscopic radical nephrectomy and distal splenopancreatectomy for a locally advanced kidney tumor. METHODS: A 67-year-old woman presented with left flank pain and hematuria. CT scan showed a left kidney upper pole large mass with direct extension to spleen and pancreatic tail, but not metastases. With the patient on the right flank, three 10-mm trocars were placed forming an isosceles triangle in the left subcostal arch. Entering the lesser sac, splenic vessels were separately divided between clips. The pancreatic tail was dissected free and divided with Ultracision. The left renal vein was dissected free, and the aorta was exposed to perform the lymphadenectomy. Superior mesenteric artery and left renal vein and artery were isolated, and renal vessels were separately divided with a vascular stapler. The left kidney was mobilized. The specimen was inserted in a bag and retrieved transvaginally through a posterior colpotomy. RESULTS: Total operation time was 210 minutes. Estimated blood loss was 250 mL. The patient was discharged after 7 days. Final stage of disease was pT4N0M0 G2 R0 renal cell carcinoma. The patient came back 6 years later presenting a ductal adenocarcinoma of pancreatic head. At the second look laparoscopy, very few adhesions were found in right upper quadrant, and the posterior colpotomy scar was very small. The patient died 1 year after Whipple operation. CONCLUSIONS: Oncologic rules of an "en bloc" resection can be respected also with a laparoscopic approach. PMID- 21822556 TI - Robotic coloanal anastomosis with or without intersphincteric resection for low rectal cancer: starting with the perianal approach followed by robotic procedure. AB - BACKGROUND: Coloanal anastomosis (CAA)/intersphincteric resection (ISR) is a promising method of sphincter-preserving surgery for very low rectal cancer. Recently, a robotic system has been attempted in CAA/ISR. By means of a robotic system, an excellent stereoscopic view may be obtained with high illumination, and adequate traction and countertraction can be easily performed in a narrow pelvis using the Endowrist function. During robotic CAA/ISR, although the robotic system is necessary to perform pelvic dissection that comes before the perianal approach, the huge robotic arms located in the low abdominal region could interfere with comfortable perianal dissection for the surgeon. Therefore, the robotic system has to be withdrawn and then set up again above the patient's abdomen, which is time-consuming. Moreover, this process also makes it difficult to maintain the aseptic circumstance of the robotic system. To address this problem, it is necessary to change the sequence of the procedure. METHODS: Patients with low rectal adenocarcinoma located within 6 cm above the anal verge were recruited and underwent robotic CAA/ISR. We performed the perianal approach first before docking the robotic system. In the transanal approach, manual dissection started at the level of the dentate line (for cases of CAA) or intersphincteric groove (for cases of ISR). The mucosa was stripped from the starting point to just above the levators. Robotic dissection was followed while maintaining pneumoperitoneum via packed gauzes in the anus. The surgical principles included high ligation of inferior mesenteric vessels and total mesorectal excision. Splenic flexure mobilization was selectively performed when the end of the remaining sigmoid colon could not reach the anal canal after the routine mobilization of the left colon side. After completion of total mesorectal excision, further dissection continued to the pelvic floor (Fig. 1). The puborectalis muscle sling was laterally exposed, and the anococcygeal ligament was noted on the posterior side of the anal canal. Intersphincteric dissection through the puborectalis ended at the intra-anal canal. Finally, the dissection plane could meet the perianal dissection plane. At this point, we could identify the gauze, which was packed via the perianal approach before beginning robotic dissection. The muscular rectal wall was divided by a cautery at the level of the puborectalis muscle by robotic arms. While performing the CAA/ISR, secure and meticulous dissection through the pelvic floor is important for oncological safety, which could be easily performed with the aid of robotic ergonomic Endowrist function and a magnified three-dimensional view even in a narrow pelvic cavity. Specimen extraction was done through the anus or additional minilaparotomy skin incision. In some cases, a planned ileostomy site was used as the minilaparotomy incision. For patients with bulky and heavy mesorectum, it is difficult and even dangerous to extract the specimen via the anus, which could induce traction injuries to the marginal vessels. Hand-sewn coloanal anastomosis was performed after removing the robotic cart from the operation field. The entire operative procedure is shown in the video. Early surgical outcomes, morbidity, and short-term follow-up data were extracted from a prospectively collected database. RESULTS: Robotic CAA/ISR for low rectal cancer was performed on 47 patients between August 2007 and December 2010. Forty-one patients underwent robotic CAA, and six patients underwent robotic ISR. There were 28 male and 19 female patients. The median age was 58 (range 32-86) years. The median body mass index was 23.3 (range 14.6-28.0) kg/m(2). Five patients (10.6%) had a history of abdominal surgery. According to American Society of Anesthesiology disease classification, 35 patients (74.5%) were class I, and 12 (25.5%) patients class II. The median distance between adenocarcinoma and the anal verge was 4 (range 1-6) cm. Preoperative chemoradiotherapy was provided to 19 patients (40.4%). There was no conversion to laparoscopic or open procedure. Operation time for robotic CAA/ISR was 360.9 +/- 128.5 (mean +/- standard deviation) min. For specimen retrieval, transanal extraction was performed in 23 cases (49%) and minilaparotomy was created for 24 cases (51%), including three cases of planned ileostomy site. Protective ileostomy was performed for 37 patients (78.7%). Blood loss was 158.0 +/- 236.5 ml. The disease stage of the patients was as follows: stage 0, n = 1; stage I, n = 20; stage II, n = 5; stage III, n = 12; and pathologic complete response, n = 9. Tumor size was 2.7 +/- 1.5 cm. The distal resection margin was 1.0 +/- 1.2 cm. The circumferential resection margins were positive in 3 patients (6.4%). The number of retrieved lymph nodes was 9.8 +/- 5.8. The first postoperative bowel movement was observed on day 2 (range, days 1 5). The median diet consumption began on day 3 (range, days 2-21). The median hospital stay was 9 (range 5-30) days. There were 10 complications in the early postoperative period (21.3%): 3 anastomotic leakages (6.4%), 1 wound infection (2.1%), 5 pelvic abscesses (10.6%), and 1 postoperative ileus (2.1%). During the short-term follow-up periods (median 21.3 months, range 3.5-40.7 months), one local recurrence, three distal metastases, and one combined recurrence were observed. Two-year disease-free survival rate was 83.7%. CONCLUSIONS: Robotic CAA/ISR can be performed with good technical efficiency and acceptable morbidity. Further randomized, controlled studies assessing long-term survival, pelvic autonomic nerve function, and bowel function are needed before robotic CAA/ISR becomes widely accepted. Changing the sequence of the procedure, and thus performing the perianal approach before robotic dissection, may be a feasible method to avoid interference of the robotic system in the surgeon's moves using nonrobotic instruments while performing robotic CAA/ISR. PMID- 21822558 TI - Recurrence and poor prognosis following resection of small hepatitis B-related hepatocellular carcinoma lesions are associated with aberrant tumor expression profiles of glypican 3 and osteopontin. AB - BACKGROUND: Early detection and following appropriate treatments of hepatocellular carcinoma (HCC) is still the gold standard for favored outcome of HCC patients; nevertheless, a small portion of hepatitis B virus (HBV)-related small HCC (<5 cm) patients got poor prognosis. Furthermore, the study for small HBV-HCC was limited. Therefore, the aim of this study was to explore the potential genetic signature for HBV-related small HCC as novel prognostic factors. METHODS: We examined expression profiles of HBV-related small HCC using an Affymetrix U133A GeneChip, evaluated differential gene expression by quantitative real-time polymerase chain reaction (qRT-PCR), and finally validated these expression patterns by immunohistochemistry (IHC). RESULTS: A total of 57 genes were differentially expressed between tumor and normal parts (n = 20 pairs) using Affymetrix U133A chip, and 16 genes were further evaluated by qRT-PCR. The result was compatible with the finding of oligonucleotide microarray (Pearson's correlation, r = 0.87). Furthermore, the expression pattern in HCC tissue by IHC in another group of small HBV-HCC (n = 100) showed overexpression of either osteopontin (OPN) or glypican 3 (GPC3) is an independent prognostic factor for disease-free survival (DFS) in HBV-positive small HCC (P < 0.01 and 0.03, respectively). Long-term DFS and overall survival (OS) for small HBV-HCC patients with high risk (both elevated GPC3(+)/OPN(+)) were DFS 0%, OS 0%, respectively; on the other hand, DFS and OS in patients with moderate (only 1 gene elevated) or low (OPN(-)/GPC3(-)) risk were 35.0 and 46.5%, respectively. CONCLUSIONS: Elevation of both OPN and GPC3 may act as an adverse indicator for HBV-related small HCC patients after curative resection. PMID- 21822557 TI - Prognostic value of resection of primary tumor in patients with stage IV colorectal cancer: retrospective analysis of two randomized studies and a review of the literature. AB - BACKGROUND: In patients with metastatic colorectal cancer (mCRC) with an asymptomatic primary tumor, there is no consensus on the indication for resection of the primary tumor. METHODS: A retrospective analysis was performed on the outcome of stage IV colorectal cancer (CRC) patients with or without resection of the primary tumor treated in the phase III CAIRO and CAIRO2 studies. A review of the literature was performed. RESULTS: In the CAIRO and CAIRO2 studies, 258 and 289 patients had undergone a primary tumor resection and 141 and 159 patients had not, respectively. In the CAIRO study, a significantly better median overall survival and progression-free survival was observed for the resection compared to the nonresection group, with 16.7 vs. 11.4 months [P<0.0001, hazard ratio (HR) 0.61], and 6.7 vs. 5.9 months (P=0.004; HR 0.74), respectively. In the CAIRO2 study, median overall survival and progression-free survival were also significantly better for the resection compared to the nonresection group, with 20.7 vs. 13.4 months (P<0.0001; HR 0.65) and 10.5 vs. 7.8 months (P=0.014; HR 0.78), respectively. These differences remained significant in multivariate analyses. Our review identified 22 nonrandomized studies, most of which showed improved survival for mCRC patients who underwent resection of the primary tumor. CONCLUSIONS: Our results as well as data from literature indicate that resection of the primary tumor is a prognostic factor for survival in stage IV CRC patients. The potential bias of these results warrants prospective studies on the value of resection of primary tumor in this setting; such studies are currently being planned. PMID- 21822559 TI - Laparoscopic right hepatectomy with intrahepatic transection of the right bile duct. AB - BACKGROUND: Although our earlier videos demonstrated extrahepatic control of the hepatic arterial, portal venous, and biliary system, we have begun transecting the biliary system intraparenchymally for lesions distant from hilar plate and the confluence of the right and left hepatic ducts.1 (-) 3 METHODS: The patient was a 50-year old gentleman with synchronous colorectal hepatic metastasis, who underwent 6 cycles of neoadjuvant chemotherapy with a Folfox-based regimen followed by laparoscopic right hepatectomy plus wedge resection of segment 4 and microwave ablation for a lesion in segment 2. This was followed 1 month later by laparoscopic proctocolectomy. Of note, the patient was also treated with Avastin for 1 month, which was stopped 2 months prior to his liver surgery. Pneumoperitoneum was obtained with the Veress needed; alternatively, the open technique may need to be used in patients who have undergone previous surgery. A 12-mm blunt tip balloon trocar was placed approximately 1 hand-breadth below the right costal margin. Two 12-mm working trocars were placed to the left and right of this optic trocar, and trocars were then placed in the left sub xiphoid region and in the right flank for the assistants. The right hepatic artery was triply clipped proximally and twice distally prior to being sharply transected. The right hepatic portal vein was then transected using a laparoscopic vascular GIA stapler device (TriStapler, Covidien, Norwalk, CT). The anterior surface of the liver was examined, and there was a clear line of demarcation along Cantlie's line. Using the ultrasonic shears (Harmonic Scalpel, Ethicon, Cincinnati, OH), the liver parenchyma was then transected. In the area of the right hepatic duct, the liver parenchyma was transected with a single firing of the laparoscopic GIA vascular stapler device. The right hepatic vein was then identified and similarly transected with a single firing of the laparoscopic vascular GIA stapler device. Hemostasis along the hepatic parenchyma was reinforced with the laparoscopic bipolar device. The two trocars on the right of the patient are connected into 1 incision, and a gel port is placed to facilitate removal of the specimen; alternatively, an old incision can be used. For patients who will need a laparoscopic or open colectomy, a lower midline incision is made. RESULTS: From Jan 2009 to Oct 2010, 13 patients underwent right hepatectomy. The average age was 63.5 years (range, 46-87 years). The indication for surgery were all for cancer including 11 colorectal metastasis, 1 anal cancer metastasis, and 1 cholangiocarcinoma. In these 13 patients, 1 patient (7.7%) required conversion to an open approach because of bleeding, 1 additional patient required laparoscopic hand assistance, and the remaining patients were completed laparoscopically. There were no surgical mortalities at 30 or 90 days. Complications occurred in 2 (15%) patients, and included 1 patient who was converted to an open procedure because of hemorrhage and was complicated by a bile leak; the second patient with complication also developed a 1-bile leak, both of which responded to percutaneous treatments. The mean hospital stay was 7.7 days (range, 5-17 days). The mean operative time was 401 min (range, 220-600 min). The mean estimated blood loss was 878 cm(3) (range, 100-3,000 cm(3)). All patients underwent an R0 resection. DISCUSSION: Laparoscopic major hepatectomy is feasible. As in open hepatectomies, intrahepatic transection of the right bile duct may be safer because there is a decreased risk of injury to the left hepatic duct.4 (,) 5 Larger series with longer-term follow-up are necessary. PMID- 21822560 TI - The immunological impact of neoadjuvant chemotherapy on the tumor microenvironment of esophageal squamous cell carcinoma. AB - BACKGROUND: Esophageal cancer is an aggressive cancer with poor prognosis. However, little is known about the immune response in the tumor microenvironment after neoadjuvant chemotherapy. PURPOSE: To investigate the immunological impact of neoadjuvant chemotherapy in the tumor microenvironment of esophageal squamous cell carcinoma. METHODS: Eighteen patients with esophageal squamous cell carcinoma with and without neoadjuvant chemotherapy were analyzed using immunohistochemical methods for human leukocyte antigen (HLA) class I heavy chain, CD4-, CD8-, and Foxp3-positive cell infiltration. RESULTS: The number of CD4 T cells in the stroma and within the cancer nest was significantly higher in the neoadjuvant chemotherapy group. The number of CD8 T cells in the stroma was significantly higher in the neoadjuvant chemotherapy group. HLA class I expression was more downregulated in the control group compared with the neoadjuvant chemotherapy group. CONCLUSION: Neoadjuvant chemotherapy utilizing 5 fluorouracil and cisplatin in esophageal squamous cell carcinoma is useful to induce CD4 and CD8 T lymphocytes in the tumor microenvironment and to maintain HLA class I expression levels in combination with its direct cytotoxic effects. PMID- 21822561 TI - Electrochemotherapy in the treatment of Kaposi sarcoma cutaneous lesions: a two center prospective phase II trial. AB - BACKGROUND: Electrochemotherapy (ECT) is an emerging treatment for cutaneous lesions of different tumor types. The combination of chemotherapy and electroporation enhances drug uptake into tumoral cells. However, its role in the treatment of Kaposi sarcoma (KS) has not yet been well defined, and to date, literature reports are scarce. We prospectively evaluated clinical activity and safety of ECT in KS patients. METHODS: Twenty-three patients with histologically confirmed unresectable KS, not treatable by radiotherapy or intralesional vincristine therapy, were enrolled onto the study according to the European Standard Operating Procedures of Electrochemotherapy (ESOPE) guidelines and treated with a pulse generator. RESULTS: A response to the first ECT session was obtained in all patients, with a complete response (CR) in 14 (60.9%) of 23 patients. A second ECT was performed in 5 (21.7%) and a third in 2, with a median interval between two sessions of 5.1 (range 2.5-25.5) months. Overall, a total of 15 patients (65%) experienced a CR. After a median follow-up of 1.5 years (range 2 months to 4.2 years), 16 patients maintained the response, 4 after repeated courses. Sustained local control of treated lesions was present in 20 of 23 patients. The overall survival rate was 74.4% at 2 years. CONCLUSIONS: ECT represents an additional therapeutic tool for the management of KS cutaneous lesions, characterized by a definite clinical activity and long-lasting remissions. The absence of systemic side effects and the low impact on the immune system also make this treatment suitable for elderly people, even with repeated courses. PMID- 21822562 TI - Be alert to tuberculosis-mediated glomerulonephritis: a retrospective study. AB - Mycobacterium tuberculosis infection causing glomerulonephritis is a rare disorder. This retrospective study analyzed the clinical characteristics of patients diagnosed with tuberculosis-mediated glomerulonephritis (TB-GN) between 2002 and 2009, as well as the diagnostic tools used. These findings were then compared with those of patients with primary glomerulonephritis (P-GN). The records of all patients were reviewed. The diagnosis of TB-GN was based on renal hematuria and/or proteinuria and cure after antituberculosis therapy alone plus urine culture positive for M. tuberculosis, demonstration of typical tubercle granulomas on renal biopsy specimens, or the detection of M. tuberculosis DNA by polymerase chain reaction (PCR) on renal specimens. Forty-six patients with TB-GN and 49 patients with P-GN were included. Compared with patients in the P-GN group, most (76%) patients with TB-GN had a history of TB. Systemic symptoms were much more frequent in patients with TB-GN than local genitourinary symptoms. Serological testing showed a statistical difference between the two groups. Immunoglobulin A nephropathy was found in the majority (72%) of patients with TB GN. M. tuberculosis DNA detection was positive in 39 (84.8%) patients, a much higher positive rate of diagnosis than that with urine culture for M. tuberculosis. The manifestation of TB-GN is atypical and nonspecific. It warrants a high index of suspicion when patients with renal hematuria and proteinuria fail to respond to standard treatments for P-GN. Clinicians should pay close attention to the medical history and results of special laboratory tests. M. tuberculosis DNA detection on renal biopsy specimens should be considered in order to confirm the diagnosis of TB-GN. PMID- 21822563 TI - Pneumococcal antigen testing of blood culture broth to enhance the detection of Streptococcus pneumoniae bacteremia. AB - The purpose of this investigation was to enhance the detection of pneumococcal bacteremia cases using the Binax NOW(r) immunochromatographic test (ICT) on blood culture broth as part of surveillance in two rural Thailand provinces. Blood cultures were collected as clinically indicated from hospitalized patients. ICT was performed on broth from culture bottles flagged as positive by BactT/ALERT(r) (alarm-positive) but which failed to grow organisms on subculture. During the period May 2005-June 2007, ICT was positive on 43 (24%) of 182 alarm-positive blood cultures with no growth on subculture. Compared to pneumococcal bacteremia cases confirmed by culture, cases detected only by ICT had a longer median time from culture collection to incubation and a longer median time from alarm positivity to subculture, and were more likely to be from patients pretreated with antibiotics. In a subsequent surveillance period (July 2007-December 2009), ICT continued to detect additional pneumococcal cases, but in a lower proportion of samples (7 of 221, 3.2%). Recently, as part of a separate study, ICT applied to uninoculated blood culture broth produced weak-positive results, mandating caution if testing broth from patient blood cultures. The antigen testing of blood culture broth appears to enhance the detection of pneumococcal bacteremia, but a controlled evaluation is needed. PMID- 21822564 TI - Biofilm formation and virulence of uropathogenic Escherichia coli in urine after consumption of cranberry-lingonberry juice. AB - Cranberry-lingonberry juice (CLJ) was effective in preventing urinary tract infections (UTIs) in our earlier randomized clinical trial. We aimed to test whether consumption of CLJ at a similar dose to earlier reduces the biofilm formation and virulence of uropathogenic Escherichia coli in urine. Twenty healthy women drank 100 ml of CLJ daily for two weeks. Urine samples were obtained 2-4 hours after the last dose. Control samples were taken after a one week period without berry consumption. Biofilm formation of 20 E. coli strains was measured at 72 hours by the polystyrene microtitre plate method. Quantitative real-time PCR analyses were performed for selected genes. Four of the 20 clinical strains produced more biofilm in urine after CLJ consumption (P < 0.05) and one produced less. Expression levels of the pga, cpxA, fimA and papF genes did not differ between bacteria grown in control urine and urine obtained after CLJ consumption, except for pga gene expression, which was reduced in one strain after CLJ (P = 0.04). It appears that the effect of CLJ in preventing UTIs is not explained by mechanisms that reduce biofilm formation or the expression of selected virulence genes of Escherichia coli in urine. PMID- 21822565 TI - High prevalence of mec complex C and ccrC is independent of SCCmec type V in Staphylococcus haemolyticus. AB - Staphylococcus haemolyticus is one of the most clinically relevant coagulase negative staphylococci (CoNS), particularly in immunocompromised patients; however, little is known regarding its molecular epidemiology. In this work, we characterized the genetic background and the SCCmec region of 36 methicillin resistant S. haemolyticus (MRSHae) and 10 methicillin-susceptible S. haemolyticus (MSSHae) collected from neutropenic patients in Tunisia between 2002 and 2004. The molecular characterization of MRSHae by pulsed-field gel electrophoresis (PFGE) showed that the great majority of the isolates (77.8%) belonged to only four types. SCCmec typing by polymerase chain reaction (PCR) and Southern hybridization showed that isolates belonging to each PFGE type could carry either one or two SCCmec types. SCCmec V was the most common, but mec complex C was frequently associated to ccr allotypes other than ccrC. The mec complex class C was predominant in MRSHae (47%) and ccrC was predominant among both methicillin resistant and -susceptible isolates (31 and 50%, respectively). Interestingly, one half (50%) of the MRSHae isolates analyzed lacked the known ccr complexes (ccrAB and ccrC), although they carried the mecA. Conversely, all MSSHae carrying a ccrC complex were multidrug-resistant, although they lack the mecA. The results suggest that ccrC and mec complex C are frequent and may exist autonomously and independently of SCCmec type V in S. haemolyticus. Moreover, the data obtained suggest that small chromosomal rearrangements promoting the loss or structural variation of mec and ccr complex appear to occur frequently, which probably provide S. haemolyticus with a specialized means for SCCmec trapping and/or diversification. PMID- 21822566 TI - Evidence affects hypothesis judgments more if accumulated gradually than if presented instantaneously. AB - In a hypothesis comparison task involving quantifiable evidence, we investigated whether judgments of relative probability were affected by gradual evidence accumulation and by making a series of revised ratings, rather than a single final one. Each trial of our task required participants to rate the probability that a focal hypothesis, rather than its alternative, was correct. We manipulated (1) the strength of evidence supporting the focal hypothesis, (2) the strength of evidence supporting its alternative, and (3) whether that evidence was presented in three sequential portions (gradually accumulated evidence condition) or, instead, was all presented instantaneously (control condition). In a second experiment, we also manipulated (4) the number of successive ratings made within a trial with gradually accumulated evidence. Regardless of how many ratings were made per trial, gradual evidence accumulation increased the effects of evidence strength on ratings of relative probability. PMID- 21822567 TI - Can surgeons predict what makes a good TKA? Intraoperative surgeon impression of TKA quality does not correlate with Knee Society scores. AB - BACKGROUND: Surgeons generally agree on what they want to achieve when performing TKA. However, we do not know which technical quality goals are correct, important, or irrelevant to achieve adequate function or durability. QUESTIONS/PURPOSES: We asked whether a surgeon can predict postoperative Knee Society scores (KSSs) of TKAs at the time of surgery based on perceived technical quality of surgery. PATIENTS AND METHODS: We reviewed all 1050 patients undergoing 1193 primary TKAs performed by a single surgeon between 2000 and 2004. The surgeon intraoperatively recorded his impression of the technical quality of surgery based on 15 factors (on a 1-10 scale, with 10 being highest quality) and degree of difficulty (on a 1-10 scale, with 10 being most difficult). We correlated these impressions to KSSs. One hundred thirty-nine of the 1050 patients had technical quality scores of less than 8, including 15 knees with major technical downgrades with clear deficiencies we presumed would affect outcomes. Minimum followup was 24 months (mean, 48 months; range, 24-60 months). RESULTS: We found no difference in mean KSSs between the 1054 TKAs with technical quality scores of more than 8 and the 124 knees with technical quality scores of less than 8. However, mean KSSs were lower in the 15 knees with technical quality scores of less than 6.5 than in the 124 knees with technical quality scores of less than 8, but these 15 knees also had a higher degree of difficulty than the 124 knees. CONCLUSIONS: The surgeon's subjective view of technical quality of surgery did not predict KSSs unless the technical quality score was extremely low. More than one technical problem was associated with lower scores. It is unclear whether this is a question of the subjective ratings or our inability to define quality. PMID- 21822568 TI - Can stress radiography of the knee help characterize posterolateral corner injury? AB - BACKGROUND: Conventional MRI is limited for characterizing the posterolateral corner of the knee due to the region's anatomic variability and complexity; further, MRI is a static study and cannot demonstrate pathologic laxity. Stress radiography may provide additional information about instability. QUESTIONS/PURPOSES: We therefore (1) correlated varus stress radiography with MRI findings, (2) compared opening in patients who underwent surgical posterolateral corner stabilization versus those who did not, and (3) determined whether stress radiography findings could supplement MRI for making treatment decisions. PATIENTS AND METHODS: We retrospectively studied 26 patients (27 knee injuries) and correlated lateral compartment opening on varus stress radiography with severity of posterolateral corner injury on MRI. We compared radiographic findings in 18 patients with complete injuries who underwent posterolateral corner stabilization with five who did not. RESULTS: A complete posterolateral corner injury on MRI was associated with an average of 18.6 mm (10.0-36.5 mm) of varus opening versus 12.8 mm (7.5-17.0 mm) in partial injuries. Opening in operative cases that underwent stabilization was 16.5 mm (11.0-36.5 mm) versus 11.0 mm (7.5-13.5 mm) for those that did not. Ten of 15 partial injuries underwent stabilization, for which the varus opening was 13.6 mm (11.0-17.0 mm). Average varus opening in partial injuries that did not undergo stabilization was 11.0 mm (7.5-13.5 mm). CONCLUSIONS: Varus stress radiography correlated to MRI findings for posterolateral corner injury. The injuries we treated with reconstruction were associated with increased varus opening. In patients with partial posterolateral corner injury on MRI, we used degree of opening on varus stress radiography to aid the decision for stabilization. LEVEL OF EVIDENCE: Level IV, diagnostic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 21822569 TI - A more reliable method to assess acetabular component position. AB - BACKGROUND: Acetabular component position is associated with joint function and bearing wear. Current techniques for determining acetabular component version on standard radiographs lack reliability. Other, more consistent techniques are time consuming and require additional equipment or software. QUESTIONS/PURPOSES: We compared three methods of acetabular component position assessment: (1) Einzel Bild-Roentgen-Analyse (EBRA), (2) Woo and Morrey, and (3) the new ischiolateral method. PATIENTS AND METHODS: We assessed axial component position for 52 hips, with at least three radiographic series, using EBRA, and on true lateral radiographs using the Woo and Morrey method and a new method that uses the ischium as a skeletal landmark, the ischiolateral method. RESULTS: The mean SDs of the ischiolateral (2.15 degrees ) and EBRA (2.06 degrees ) methods were lower than that of the Woo and Morrey method (3.65 degrees ) but were not different from one another. We observed a SD of greater than 4 degrees in 19 (36.5%) hip series using the Woo and Morrey method, compared to six series (11.5%) for both the ischiolateral and EBRA methods. Twenty-four (12.6%) Woo and Morrey measurements were greater than 4 degrees from the mean for the hip series, compared to seven (3.8%) for ischiolateral and nine (4.7%) for EBRA. The intraclass correlation coefficients for intra- and interobserver reliability for the ischiolateral method and EBRA were the same (0.9). CONCLUSIONS: Referencing the ischium standardizes pelvic position on each lateral radiograph and provides a simple and reliable means to assess axial component position, which is a surrogate for the planar anteversion measured by EBRA. PMID- 21822570 TI - Lateral unicompartmental knee arthroplasty through a lateral parapatellar approach has high early survivorship. AB - BACKGROUND: The literature suggests lateral unicompartmental knee arthroplasties are associated with low revision rates. However, there are fewer reports describing techniques for lateral unicompartmental arthroplasty and whether technique influences ROM and function compared to reports for medial unicompartmental arthroplasty. QUESTIONS/PURPOSES: We report our indications for lateral unicompartmental arthroplasty, how we perform this procedure, and the subsequent Knee Society scores, ROM, and revision and reoperation rates. PATIENTS AND METHODS: From a retrospective review of electronic records from 2004 through 2008, we identified 93 patients who had 100 lateral unicompartmental arthroplasties. Indications were complete lateral bone-on-bone arthrosis with a correctible deformity and maintenance of the medial joint space on varus stress radiographs or isolated lateral disease by diagnostic arthroscopy. Average age was 68 years. Seventy percent of patients were women. At followup, we obtained Knee Society scores and ROM. Minimum followup was 24 months (average, 39 months; range, 24-81 months). RESULTS: At followup, Knee Society scores averaged 46 for pain, 94 for clinical, and 89 for function, and ROM averaged 124 degrees . Three patients had reoperations: one an open reduction and internal fixation for fracture at 2 years postoperatively, one an arthroscopy for a medial meniscal tear, and one a revision for pain. CONCLUSIONS: Based on our observations, we believe complete cartilage loss laterally and correctible deformity with maintenance of the medial joint on varus stress radiographs are reasonable indications for lateral unicompartmental arthroplasty. We recommend a lateral parapatellar approach can be utilized. The early reoperation and revision rates were low. PMID- 21822571 TI - Stem and osteotomy length are critical for success of the transfemoral approach and cementless stem revision. AB - BACKGROUND: The transfemoral approach is an extensile surgical approach that is performed routinely to facilitate cement and implant removal and improve exposure for revision stem implantation. Previous studies have looked at clinical results of small patient groups. The factors associated with fixation failure of cementless revision stems when using this approach have not been examined. QUESTIONS/PURPOSES: We determined (1) the clinical results and (2) complications of the transfemoral approach and (3) factors associated with fixation failure of revision stems when using the transfemoral approach. PATIENTS AND METHODS: We retrospectively examined all our patients in whom femoral stem revision was performed through a transfemoral approach between December 1998 and April 2004 and for whom a minimal followup of 2 years was available. One hundred patients were available for this study. The mean (+/- SD) postoperative followup was 5 years (+/- 1.64 years). RESULTS: The average Harris hip score improved from 45.2 (+/- 14.02) preoperatively to 83.4 (+/- 11.86) at final followup. Complete radiographic bony consolidation of the osteotomy site was observed in 95% of patients. Dislocations occurred in 9% of patients. Four revision stem fixation failures were observed, all occurring in patients with primary three-point fixation. Three-point fixation was associated with short osteotomy flaps and long revision stems. CONCLUSIONS: The transfemoral approach is associated with a high rate of osteotomy flap bony healing and good clinical results. When using the transfemoral approach, a long osteotomy flap should be performed and the shortest possible revision stem should be implanted. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 21822572 TI - Orthopaedic case of the month: Painful lower-leg mass in a 76-year-old man. PMID- 21822573 TI - Risk factors for peroneal nerve injury and recovery in knee dislocation. AB - BACKGROUND: Acute knee dislocation is rare but has a high rate of associated neurovascular injuries and potentially limb-threatening complications. These include the substantial morbidity associated with peroneal nerve injury: neuropathic pain, decreased mobility, and considerably reduced function, which not only impairs patient function but complicates treatment. QUESTIONS/PURPOSES: We therefore identified and quantified the risks associated with specific factors for peroneal nerve injury and recovery in patients with knee dislocations. PATIENTS AND METHODS: We retrospectively reviewed the charts of 26 patients, from among a cohort of all 91 knee dislocations, with a peroneal nerve palsy over a 5 year period. We then used univariable and multivariable statistics to identify risk factors predicting peroneal nerve injury and recovery. RESULTS: Gender (odds ratio, 5.47), body mass index (odds ratio, 1.14), and fibular head fracture (odds ratio, 4.77) were associated with peroneal nerve injury. Only younger age was associated with peroneal nerve recovery. CONCLUSIONS: Knowledge of the risk factors for peroneal nerve injury and the predictors of recovery in knee dislocation allows the treating surgeon to have a better understanding of the nature of the neurologic injury and modify management based on the anticipated return of nerve function. LEVEL OF EVIDENCE: Level II, prognostic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 21822575 TI - Determination of 16 polycyclic aromatic hydrocarbons in water using fluorinated polyaniline-based solid-phase microextraction coupled with gas chromatography. AB - The study on the performance of a fluorinated polyaniline (PANI) as a fiber coating for solid-phase microextraction (SPME) had been reported and 16 polycyclic aromatic hydrocarbons (PAHs) were selected to evaluate the performance of this fiber. Various parameters including sample volume, extraction temperature, time of desorption and extraction, pH and ionic strength were investigated intensively. A direct comparison between PANI-SPME fiber and commercial fiber was conducted. The results showed that the PANI-SPME coating had high affinity towards target compounds and the proposed method was successfully applied for the detection of real samples: rainfall and Taihu Lake water collected from Southern China. The whole PANI-SPME-GC method offers acceptable accuracy, precision and sensitivity and low detection limits, which is applicable to monitor trace levels of PAHs in real water bodies. PMID- 21822574 TI - Early and adequate antibiotic therapy in the treatment of severe sepsis and septic shock. AB - Severe sepsis and septic shock are conditions that pose difficult challenges to physicians and the health care system. In the past 10 years, a number of retrospective and prospective observational studies have shed light on the importance of a rapid and systematic approach to treatment of these conditions. A key component is early and appropriate use of antibiotics. Delay of even 6 h can dramatically increase hospital mortality. In addition, multivariate analyses have demonstrated that inappropriate initial antibiotics lead to worse outcomes. The treating physician can rapidly identify risk factors for initial inappropriate antibiotics at the bedside, such as recent antibiotic therapy or recent hospitalization. Organized antibiotic order sets have been shown to significantly improve timely appropriate antibiotic administration in septic patients. Finally, emerging laboratory data suggest that early in the course of septic shock, the pharmacokinetics of common broad spectrum antibiotics may be significantly altered due to increased volumes of distribution having dosing implications for antibiotics in septic shock. PMID- 21822576 TI - Accumulation of mercury and other heavy metals in edible fishes of Cochin backwaters, Southwest India. AB - Mercury, a global pollutant, has become a real threat to the developing countries like India and China, where high usage of mercury is reported. Mercury and other heavy metals deposited in to the aquatic system can cause health risk to the biota. The common edible fishes such as Mugil cephalus, Arius arius, Lutjanus ehrenbergii, Etroplus suratensis were collected from Cochin backwaters, Southwest India and analysed for mercury and other heavy metals (zinc, cadmium, lead and copper) in various body parts. Kidney and liver showed highest concentration of metals in most fishes. The omnivore and bottom feeder (E. suratensis) showed high concentration of mercury (14.71 mg/kg dry weight) and other metals (1.74 mg/g total metal concentration). The average mercury concentration obtained in muscle was 1.6 mg/kg dry weight (0.352 mg/kg wet weight), which is higher than the prescribed limits (0.3 mg/kg wet weight). The concentration of other heavy metals in the muscles of fishes were found in a decreasing order Zn>Cu>Cd>Pb and are well below WHO permissible limits that were safe for human consumption. Metal selectivity index (MSI) obtained for all the metals except mercury showed that both carnivores and omnivores have almost same kind of affinity towards the metals especially Zn and Cd, irrespective of their feeding habit. The MSI values also indicate that the fishes have the potential to accumulate metals. High tissue selectivity index (TSI) values were reported for kidney, muscle and brain for all metals suggests that the metal concentration in these tissues can serve as an indication of metal polluted environment. Even if the daily intakes of Zn, Cd, Pb and Cu from these fishes are within the provisional maximum daily intake recommended by WHO/FAO, the quality is questionable due to the high hazard index obtained for mercury (>1). Fishes like E. suratensis being a favourite food of people in this region, the high consumption of it can lead to chronic disorders as this fish has high concentration of metals. PMID- 21822577 TI - Volatile hydrocarbon emissions from vehicles and vertical ventilations in the Hsuehshan traffic tunnel, Taiwan. AB - The concentrations of 56 volatile organic hydrocarbons (VOCs) were measured simultaneously in the southbound bore, the northbound bore and the exhaust air shafts of the Hsuehshan tunnel near Yilan, Taiwan during 2007 and 2008. A total of 60 integrated air samples were collected using stainless steel canisters and analyzed using GC/FID and GC/MS. The highest temperature and lowest relative humidity were observed at the exit of the tunnel owing to the accumulation in the tunnel of waste heat that was exhausted from vehicles. The five most abundant species in all samples were ethylene, acetylene, isopentane, propylene, and toluene. The exit/entrance ratios of total non-methane hydrocarbon (NMHC) concentration were 7.8 and 4.8 for the southbound and northbound bores, respectively. Furthermore, the most abundant species of emission rate (ER) is toluene (21.93-42.89 mg s(-1)), followed by isopentane, ethylene, propylene and 1 butene, with ER ranging from 2.50 to 9.31 mg s(-1) for the three shafts. The ozone formation potential (OFP)/total NMHC ratios in three exhaust air shafts show that the reactivities of these emissions are similar to those of vehicle emissions. PMID- 21822578 TI - Assessment of the impact of petroleum and petrochemical industries to the surrounding areas in Malaysia using mosses as bioindicator supported by multivariate analysis. AB - Biomonitoring of multi-element atmospheric deposition using terrestrial moss is a well-established technique in Europe. Although the technique is widely known, there were very limited records of using this technique to study atmospheric air pollution in Malaysia. In this present study, the deposition of 11 trace metals surrounding the main petroleum refinery plant in Kerteh Terengganu (eastern part of peninsular Malaysia) has been evaluated using two local moss species, namely Hypnum plumaeforme and Taxithelium instratum as bioindicators. The study was also done by means of observing whether these metals are attributed to work related to oil exploration in this area. The moss samples have been collected at 30 sampling stations in the vicinity of the petrochemical industrial area covering up to 15 km to the south, north, and west in radius. The contents of heavy metal in moss samples were analyzed by energy dispersive x-ray fluorescence technique. Distribution of heavy metal content in all mosses is portrayed using Surfer software. Areas of the highest level of contaminations are highlighted. The results obtained using the principal components analysis revealed that the elements can be grouped into three different components that indirectly reflected three different sources namely anthropogenic factor, vegetation factor, and natural sources (soil dust or substrate) factor. Heavy metals deposited mostly in the distance after 9 km onward to the western part (the average direction of wind blow). V, Cr, Cu, and Hg are believed to have originated from local petrochemical based industries operated around petroleum industrial area. PMID- 21822579 TI - Fluorescence study on the structure of ionic liquid aggregates in aqueous solutions. AB - Although ionic liquids are a relatively novel class of materials, it is well documented that they form micelles through aggregation of cation aliphatic tails. However, anion self-assembly has not yet been reported. In this study, we analyzed the intrinsic fluorescence of p-toluenesulfonate groups (tosylate) as part of the ionic liquid 1-ethyl-3-methylimidazolium tosylate ([emim][TOS]) and p toluenesulfonic acid (pTSA), in aqueous solution. pTSA was found to have overlapping monomer and excimer emissions for chromophore concentrations from 10( 3) to 1 M, whereas [emim][TOS], in the same conditions, showed monomer emission slightly broadened by much weaker excimer emission. These different photophysical behaviors of the same chromophore in the two compounds are explained by the formation of ion pairs by [emim][TOS], which can also be inferred from the loss of vibrational structure of the absorption spectra with respect to pTSA. Despite this different behavior regarding ion pairing, anion aggregation was observed in the excitation spectra of both pTSA and [emim][TOS]. While the absorption spectra corresponded to single chromophores, the excitation spectra changed from those characteristic of a single chromophore (below 10(-3) M) to red-shifted narrow bands (above 0.1 M) typical of J aggregates. Between those concentrations, the excitation spectra split into blue- and red-shifted bands with relative intensities that changed with concentration as the chromophores rearranged in their clusters from head-to-head to head-to-tail aggregates. Differences between the absorption and excitation spectra were ascribed to aggregation-induced fluorescence enhancement. PMID- 21822580 TI - Determination of tetracaine hydrochloride by fluorescence quenching method with some aromatic amino acids as probes. AB - A novel fluorescence quenching method for the determination of tetracaine hydrochloride (TA.HCl) concentration with some aromatic amino acids as fluorescence probe has been developed. In pH 6.3 acidic medium, tryptophane (Trp), tyrosine (Tyr) or phenylalanine (Phe) can react with tetracaine hydrochloride to form an ion-association complex by electrostatic attraction, aromatic stacking interaction and Van der Waals' force, which lead to fluorescence quenching of above amino acids. The maximum fluorescence excitation and emission wavelengths of them are located at 278, 274, 258 nm and 354, 306, 285 nm, respectively. The relative fluorescence intensity (F (0)/F) is proportional to the TA.HCl concentration in certain range. The linear ranges and detection limits are 1.2-5.0 MUg/mL and 0.37 MUg/mL for Tyr-TA.HCl system, 1.3 6.0 MUg/mL and 0.38 MUg/mL for Trp-TA.HCl system, and 1.4-6.0 MUg/mL and 0.41 MUg/mL for Phe-TA.HCl system. The optimum reaction conditions, influencing factors and the effect of coexisting substances are investigated. And the results show the method has a good selectivity. Judging from the effect of temperature, the Stern-Volmer plots and fluorescence lifetime determination, the quenching of fluorescence of amino acids by TA.HCl is a static quenching process. PMID- 21822581 TI - Detection of DNA via the fluorescence quenching of Mn-doped ZnSe D dots/doxorubicin/DNA ternary complexes system. AB - This manuscript reports a method for the detection of double-stranded DNA, based on Mn:ZnSe d-dots and intercalating agent doxorubicin (DOX). DOX can quench the photoluminescence (PL) of Mn:ZnSe d-dots through photoinduced electron transfer process, after binding with Mn:ZnSe d-dots. The addition of DNA can result in the formation of the Mn:ZnSe d-dots-DOX-DNA ternary complexes, the fluorescence of the Mn:ZnSe d-dots-DOX complexes would be further quenched by the addition of DNA, thus allowing the detection of DNA. The formation mechanism of the Mn:ZnSe d dots-DOX-DNA ternary complexes was studied in detail in this paper. Under optimal conditions, the quenched fluorescence intensity of Mn:ZnSe d-dots-DOX system are perfectly described by Stern-Volmer equation with the concentration of hsDNA ranging from 0.006 MUg mL(-1) to 6.4 MUg mL(-1). The detection limit (S/N = 3) for hsDNA is 0.5 ng mL(-1). The proposed method was successfully applied to the detection of DNA in synthetic samples and the results were satisfactory. PMID- 21822582 TI - Proliferative potential and phenotypic analysis of long-term cultivated human granulosa cells initiated by addition of follicular fluid. AB - PURPOSE: The aim of this study was to develop and optimize a strategy for long term cultivation of luteinizing human granulosa cells (GCs). METHODS: GCs were cultivated in DMEM/F12 medium supplemented with 2% fetal calf serum. In vitro proliferation of GCs was supported by follicular fluid as well as FSH and growth factors. RESULTS: The cultured GCs were maintained for 45 days with a doubling time of 159 +/- 24 h. GCs initiated by the addition of follicular fluid and cultivated under low serum conditions reached 10 +/- 0.7 population doublings. GCs maintain the typical phenotypic expression and the telomere length according to specific culture conditions. CONCLUSION: Our present study has demonstrated that GCs can be maintained in vitro for at least 45 days and this cell model can be beneficial when studying hormonal regulation associated with follicular maturation and preparation of oocytes for fertilization. PMID- 21822583 TI - Maturitas ex vivo: the case for oocyte in vitro maturation in human ARTs. PMID- 21822584 TI - NOBOX does right for the follicle reserve: insights into premature ovarian failure. PMID- 21822585 TI - Bone mass of Spanish school children: impact of anthropometric, dietary and body composition factors. AB - The purpose of this study was to: (a) determine the relationship between quantitative ultrasound (QUS) results and anthropometric, dietary and body composition factors and establish reference ranges for amplitude-dependent speed of sound (Ad-SoS) in the phalanges and broadband ultrasound attenuation (BUA) in the calcaneus of children from Extremadura, Spain, and (b) to present reference curves for this population. Healthy children (n = 245), aged 4-16 years, were included (124 girls and 121 boys). Phalangeal and calcaneal QUS measurements were performed using DBM Sonic Bone Profiler and McCue CUBA Clinical ultrasound devices, respectively. Weight, height and body mass index (BMI) were evaluated by anthropometric methods. Fat percentage, fat mass, lean mass (FFM) and total body water (TBWater) were evaluated by bioelectrical impedance measurements using a Holtain body composition analyzer. Food intake was evaluated by a 7-day food record. A gender analysis revealed that Ad-SoS and BUA parameters increased significantly with age and that both positively correlated with age, weight, height, BMI, FFM and TBWater. For both genders, Ad-SoS showed significant and positive correlations with age, weight, height, BMI, FFM, BUA and TBWater. PMID- 21822586 TI - Fibroblast growth factor 23 as a phosphotropic hormone and beyond. AB - Fibroblast growth factor 23 (FGF23) is produced by bone and reduces serum phosphate by inhibiting proximal tubular phosphate reabsorption and intestinal phosphate absorption. Excess actions of FGF23 cause several kinds of hypophosphatemic rickets/osteomalacia while deficient actions of FGF23 result in hyperphosphatemic tumoral calcinosis. In addition, FGF23 has been shown to prevent the development of hyperphosphatemia during the progression of chronic kidney disease-mineral and bone disorder. Epidemiological studies have indicated that high FGF23 levels are associated with unfavorable events including higher mortality, cardiovascular events, progression of CKD and fracture; however, these associations are not observed unequivocally and it is not evident why they are present. While FGF23 has been shown to be a hormone that regulates phosphate metabolism, it remains to be established whether FGF23 has roles other than regulating mineral homeostasis. PMID- 21822587 TI - Epitope mapping of human VWF A3 recognized by monoclonal antibody SZ-123 and SZ 125 using MALDI mass spectrometry. AB - von Willebrand factor (VWF) serves as a molecular bridge between the constituents of the subendothelium, such as collagen, and receptors of the platelet membrane, primarily GPIb. We have previously reported two monoclonal antibodies (mAbs), SZ 123 and SZ-125, which specifically bind the VWF A3 domain and block the interaction of VWF with collagen type III and ristocetin- or botrocetin-induced platelet aggregation. Here, we identified the epitopes recognized by SZ-123 and SZ-125 using matrix-assisted laser desorption ionization mass spectrometry in combination with proteolysis protection assays. Our results demonstrated that SZ 123 recognizes a discontinuous epitope, involving the residues (989)AHLLSLVDVMQR(1000) and (1017)YLTSEMHGARPGASK(1031) of VWF. SZ-125 recognizes a linear epitope, encompassing the sequence (1001)EGGPSQIGDALGFAVR(1016). Immunoassays further indicated that the synthetic peptide, NH2-EGGPSQIGDALGFAVR COOH, is sufficient for the binding to SZ-125. These results provide insight into the mechanistic basis for the inhibition of VWF binding to collagen by SZ-123/SZ 125. PMID- 21822588 TI - Mechanisms of dendritic cell trafficking across the blood-brain barrier. AB - Although the central nervous system (CNS) is considered to be an immunoprivileged site, it is susceptible to a host of autoimmune as well as neuroinflammatory disorders owing to recruitment of immune cells across the blood-brain barrier into perivascular and parenchymal spaces. Dendritic cells (DCs), which are involved in both primary and secondary immune responses, are the most potent immune cells in terms of antigen uptake and processing as well as presentation to T cells. In light of the emerging importance of DC traficking into the CNS, these cells represent good candidates for targeted immunotherapy against various neuroinflammatory diseases. This review focuses on potential physiological events and receptor interactions between DCs and the microvascular endothelial cells of the brain as they transmigrate into the CNS during degeneration and injury. A clear understanding of the underlying mechanisms involved in DC migration may advance the development of new therapies that manipulate these mechanistic properties via pharmacologic intervention. Furthermore, therapeutic validation should be in concurrence with the molecular imaging techniques that can detect migration of these cells in vivo. Since the use of noninvasive methods to image migration of DCs into CNS has barely been explored, we highlighted potential molecular imaging techniques to achieve this goal. Overall, information provided will bring this important leukocyte population to the forefront as key players in the immune cascade in the light of the emerging contribution of DCs to CNS health and disease. PMID- 21822590 TI - Subretinal pigment epithelial infiltrates in primary vitreoretinal lymphoma. PMID- 21822589 TI - A lifespan approach to neuroinflammatory and cognitive disorders: a critical role for glia. AB - Cognitive decline is a common problem of aging. Whereas multiple neural and glial mechanisms may account for these declines, microglial sensitization and/or dystrophy has emerged as a leading culprit in brain aging and dysfunction. However, glial activation is consistently observed in normal brain aging as well, independent of frank neuroinflammation or functional impairment. Such variability suggests the existence of additional vulnerability factors that can impact neuronal-glial interactions and thus overall brain and cognitive health. The goal of this review is to elucidate our working hypothesis that an individual's risk or resilience to neuroinflammatory disorders and poor cognitive aging may critically depend on their early life experience, which can change immune reactivity within the brain for the remainder of the lifespan. For instance, early-life infection in rats can profoundly disrupt memory function in young adulthood, as well as accelerate age-related cognitive decline, both of which are linked to enduring changes in glial function that occur in response to the initial infection. We discuss these findings within the context of the growing literature on the role of immune molecules and neuroimmune crosstalk in normal brain development. We highlight the intrinsic factors (e.g., chemokines, hormones) that regulate microglial development and their colonization of the embryonic and postnatal brain, and the capacity for disruption or "re programming" of this crucial process by external events (e.g., stress, infection). An impact on glia, which in turn alters neural development, has the capacity to profoundly impact cognitive and mental health function at all stages of life. PMID- 21822591 TI - Reduction of liver stiffness by antiviral therapy in chronic hepatitis B. AB - BACKGROUND: Liver stiffness (LS) has been reported to correlate with fibrosis stage (F). The correlation between LS and fibrosis stage and the reduction of LS by antiviral therapy were examined in patients with hepatitis B infection. METHODS: LS was measured by FibroScan in 212 patients infected with hepatitis B virus. Liver biopsies were done in 51 patients. Changes of LS were assessed in 29 patients treated with nucleotide or nucleoside analogs and 52 patients without antiviral therapy. RESULTS: LS was significantly correlated with fibrosis stage (rho = 0.686, P < 0.0001). The optimal cut-off values of LS were 7.1 kPa for F >= 2, 10.7 kPa for F >= 3, and 16.0 kPa for F4. LS was significantly reduced by antiviral therapy, from 12.9 (range 6.2-17.9) kPa to 6.6 (4.4-10.3) kPa measured at an interval of 512 (range 366-728) days (P < 0.0001). Eleven of 19 (58%) patients with baseline fibrosis stages of F3-4 deduced from LS had 2-point or greater reductions of deduced stage at the last LS measurement. The change ratio of hyaluronic acid (P = 0.0390) was associated with a 2-point or greater reduction of deduced fibrosis stage. Without antiviral therapy, LS tended to increase, increasing from 6.1 (range 3.9-8.5) kPa to 6.3 (range 4.4-9.7) kPa at an interval of 422 (range 358-709) days (P = 0.0682). CONCLUSIONS: LS was significantly correlated with fibrosis stage in patients with chronic hepatitis B. The reduction of LS by antiviral therapy was significantly correlated with the reduction of hyaluronic acid. Thus, we conclude that LS can be useful to assess the progression and regression of liver fibrosis stage noninvasively. PMID- 21822592 TI - Renal complications of Castleman's disease: report of two cases and analysis of 75 cases. AB - Biopsy-proven renal complications of Castleman's disease (CD) are rare and current knowledge is largely based on sporadic case reports. We reported two more cases, both of which were multicentric CD with hyaline-vascular pathological pattern and presented with chronic renal failure. Case 1 was multicentric CD with renal mesangial proliferative glomerulonephritis complications, and case 2 was multicentric CD with membranoproliferative glomerulonephritis-like complications. Although both were eventually administered corticosteroids combined with cytotoxic drugs, both behaved in an aggressive and relapsing manner. We then made an analysis of 75 cases of biopsy-proven renal complications of CD (including our two cases) which were reported in 51 English literatures from January 1954 to March 2011. We found that the clinical and histological findings of renal complications of CD were heterogeneous. Death was observed in 17% patients after a median follow-up time of 22 months (0-204 months) since histological diagnosis of renal complications. The estimated 5-year cumulative survival rate was 75%. Better understanding and therapeutic interventions are required in further investigations. PMID- 21822594 TI - Interactions between P-limitation and different C conditions on the fatty acid composition of an extremophile microalga. AB - The extremophilic microalga Chlamydomonas acidophila inhabits very acidic waters (pH 2-3.5), where its growth is often limited by phosphorus (P) or colimited by P and inorganic carbon (CO(2)). Because this alga is a major food source for predators in acidic habitats, we studied its fatty acid content, which reflects their quality as food, grown under a combination of P-limited and different carbon conditions (either mixotrophically with light + glucose or at high or low CO(2), both without glucose). The fatty acid composition largely depended on the cellular P content: stringent P-limited cells had a higher total fatty acid concentration and had a lower percentage of polyunsaturated fatty acids. An additional limitation for CO(2) inhibited this decrease, especially reflected in enhanced concentrations of 18:3(9,12,15) and 16:4(3,7,10,13), resulting in cells relatively rich in polyunsaturated fatty acids under colimiting growth conditions. The percentage of polyunsaturated to total fatty acid content was positively related with maximum photosynthesis under all conditions applied. The two factors, P and CO(2), thus interact in their effect on the fatty acid composition in C. acidophila, and colimited cells P-limited algae can be considered a superior food source for herbivores because of the high total fatty acid content and relative richness in polyunsaturated fatty acids. PMID- 21822593 TI - Involvement of the endocannabinoid system in reward processing in the human brain. AB - RATIONALE: Disturbed reward processing in humans has been associated with a number of disorders, such as depression, addiction, and attention-deficit hyperactivity disorder. The endocannabinoid (eCB) system has been implicated in reward processing in animals, but in humans, the relation between eCB functioning and reward is less clear. OBJECTIVES: The current study uses functional magnetic resonance imaging (fMRI) to investigate the role of the eCB system in reward processing in humans by examining the effect of the eCB agonist Delta(9) tetrahydrocannabinol (THC) on reward-related brain activity. METHODS: Eleven healthy males participated in a randomized placebo-controlled pharmacological fMRI study with administration of THC to challenge the eCB system. We compared anticipatory and feedback-related brain activity after placebo and THC, using a monetary incentive delay task. In this task, subjects are notified before each trial whether a correct response is rewarded ("reward trial") or not ("neutral trial"). RESULTS: Subjects showed faster reaction times during reward trials compared to neutral trials, and this effect was not altered by THC. THC induced a widespread attenuation of the brain response to feedback in reward trials but not in neutral trials. Anticipatory brain activity was not affected. CONCLUSIONS: These results suggest a role for the eCB system in the appreciation of rewards. The involvement of the eCB system in feedback processing may be relevant for disorders in which appreciation of natural rewards may be affected such as addiction. PMID- 21822595 TI - Botulinum toxin and anal fissure: efficacy and safety systematic review. AB - PURPOSE: The main purpose of this study was to investigate the efficacy and safety of botulinum toxin in the treatment of anal fissure. An answer was attempted to the following research questions: (i) what is the efficacy of botulinum toxin in healing of anal fissure compared to placebo, (ii) what is the efficacy of botulinum toxin in healing of anal fissure compared to other means of chemical sphincterotomy, (iii) what is the efficacy of botulinum toxin in healing of anal fissure compared to surgical sphincterotomy, (iv) what is the short term safety of botulinum toxin injections and (v) what is the long term safety of botulinum toxin injections. METHODS: Clinical trials investigating the effect of botulinum toxin in the treatment of anal fissure met inclusion criteria. Case reports and case series were also included for the estimation of safety. Meta analysis was not performed due to clinical heterogeneity. RESULTS: The comparator could be placebo, nitroglycerin ointment, or lateral internal sphincterotomy, with dosage ranging from 20 IU to 50 IU of botulinum toxin. Fissure healing was the most commonly reported primary endpoint but the time period from botulinum toxin injection to fissure healing ranged from 2 weeks to 4 months. Accordingly, outcome data were also heterogenous. CONCLUSIONS: Botulinum toxin injections should be considered a minimally invasive therapeutic option for the treatment of chronic anal fissure. However, well designed randomized trials are needed for the valid estimation of the efficacy and safety of botulinum toxin in this therapeutic indication. PMID- 21822596 TI - Laparoscopic versus conventional open surgery for immune function in patients with colorectal cancer. AB - OBJECTIVE: To systematically evaluate the immune function in patients with colorectal cancer after laparoscopic surgery (LS) and conventional open surgery (OS). METHODS: PUBMED, EMBASE, and the Cochrane library were searched and randomized controlled trials (RCTs) comparing the immunological difference between LS and OS were included. Two authors extracted data and assessed trial quality. RESULTS: Eleven studies including 695 patients were analysed. Immune competent cells demonstrated no significant differences between LS and OS in six trials. Eight trials assessed various perioperative plasma cytokine concentrations with no significant differences in interleukin-6 (IL-6) and C reactive protein (CRP) levels between LS and OS. However, meta-analysis showed higher T suppressor lymphocytes (CD8+) counts on postoperative days (POD) 1-3 and lower plasma levels of CRP on POD 0-1 in LS group compared with OS group. CONCLUSION: Although LS groups displayed higher T suppressor lymphocyte (CD8+) counts on postoperative days (POD) 1-3 and lower plasma levels of CRP on POD 0-1, there is no sufficient evidence to support superior preservation of global immune function with LS compared to OS. PMID- 21822597 TI - Diverse roles for auxiliary subunits in phosphorylation-dependent regulation of mammalian brain voltage-gated potassium channels. AB - Voltage-gated ion channels are a diverse family of signaling proteins that mediate rapid electrical signaling events. Among these, voltage-gated potassium or Kv channels are the most diverse partly due to the large number of principal (or alpha) subunits and auxiliary subunits that can assemble in different combinations to generate Kv channel complexes with distinct structures and functions. The diversity of Kv channels underlies much of the variability in the active properties between different mammalian central neurons and the dynamic changes that lead to experience-dependent plasticity in intrinsic excitability. Recent studies have revealed that Kv channel alpha subunits and auxiliary subunits are extensively phosphorylated, contributing to additional structural and functional diversity. Here, we highlight recent studies that show that auxiliary subunits exert some of their profound effects on dendritic Kv4 and axonal Kv1 channels through phosphorylation-dependent mechanisms, either due to phosphorylation on the auxiliary subunit itself or by influencing the extent and/or impact of alpha subunit phosphorylation. The complex effects of auxiliary subunits and phosphorylation provide a potent mechanism to generate additional diversity in the structure and function of Kv4 and Kv1 channels, as well as allowing for dynamic reversible regulation of these important ion channels. PMID- 21822598 TI - The secretory KCa1.1 channel localises to crypts of distal mouse colon: functional and molecular evidence. AB - The colonic epithelium absorbs and secretes electrolytes and water. Ion and water absorption occurs primarily in surface cells, whereas crypt cells perform secretion. Ion transport in distal colon is regulated by aldosterone, which stimulates both Na(+) absorption and K(+) secretion. The electrogenic Na(+) absorption is mediated by epithelial Na(+) channel (ENaC) in surface cells. Previously, we identified the large conductance Ca(2+)-activated K(+) channel, K(Ca)1.1 or big potassium (BK) channel, as the only relevant K(+) secretory pathway in mouse distal colon. The exact localisation of K(Ca)1.1 channels along the crypt axis is, however, still controversial. The aim of this project was to further define the localisation of the K(Ca)1.1 channel in mouse distal colonic epithelium. Through quantification of mRNA extracted from micro-dissected surface and crypt cells, we confirmed that Na(+)/K(+)/2Cl(-) (NKCC1) is expressed primarily in the crypts and gamma-ENaC primarily in the surface cells. The K(Ca)1.1 alpha-subunit mRNA was like NKCC1, mainly expressed in the crypts. The crypt to surface expression pattern of the channels and transporters was not altered when plasma aldosterone was elevated. The mRNA levels for NKCC1, gamma ENaC and K(Ca)1.1 alpha-subunit were, however, under these circumstances substantially augmented (K(Ca)1.1 alpha-subunit, twofold; NKCC1, twofold and ENaC, tenfold). Functionally, we show that ENaC-mediated Na(+) absorption and BK channel-mediated K(+) secretion are two independent processes. These findings show that K(Ca)1.1-mediated K(+) secretion mainly occurs in the crypts of the murine distal colon. This is in agreement with the general model of ion secretion being preferentially located to the crypt and not surface enterocytes. PMID- 21822599 TI - Usefulness of postoperative nadir prostate-specific antigen value by ultrasensitive assay as a predictor of prostate-specific antigen relapse for pathological T3 or positive surgical margins after radical prostatectomy for prostate cancer. AB - PURPOSE: Our aim was to identify prognostic factors and examine the usefulness of postoperative nadir prostate-specific antigen (PSA) value obtained by ultrasensitive assay for prediction of PSA relapse in prostate cancer patients with pathological T3 (pT3) or positive surgical margins. METHODS: We analyzed 102 patients who were pathological T2 with positive surgical margins or pT3 without pathological lymph node metastasis or neoadjuvant hormonal therapy. Patients were classified into three groups according to postoperative nadir PSA value: <0.01 ng/ml, >=0.01 ng/ml but <0.02 ng/ml, and >=0.02 but <0.10 ng/ml. PSA relapse-free rate was compared according to postoperative nadir PSA. Univariate and multivariate analyses with the Cox proportional hazards regression model identified prognostic factors for PSA relapse. RESULTS: Of the 102 patients, 22 (21.6%) developed PSA relapse within a median follow-up time of 31.3 months. PSA relapse-free rate at 30 months was 81.2%. Univariate and multivariate analyses revealed that postoperative nadir PSA was the only statistically significant risk factor: postoperative nadir PSA >=0.01 ng/ml but <0.02 ng/ml (P = 0.009, HR: 4.502, 95% CI: 1.457-13.916); >=0.02 ng/ml but <0.10 ng/ml (P < 0.001, HR: 15.126, 95% CI: 4.738-48.292). PSA relapse-free rates at 30 months in patients with postoperative nadir PSA <0.01 ng/ml, >=0.01 ng/ml but <0.02 ng/ml, and >=0.02 ng/ml but <0.10 ng/ml were 91.9, 57.1, and 20.0%, respectively. CONCLUSIONS: Postoperative nadir PSA value obtained by ultrasensitive assay was useful as a predictor of PSA relapse among patients with adverse pathological features. Patients with postoperative nadir PSA of <0.01 ng/ml may have low risk of PSA relapse. PMID- 21822600 TI - True duplication of the vas deferens: a case report and review of literature. AB - BACKGROUND: Duplication of the vas deferens is the identification of a second vas deferens within the spermatic cord; it is a rarely reported congenital anomaly. Duplicate vas deferens should not be confused with double vas deferens that describes ipsilateral renal agenesis with a blind ureter ending in the ejaculatory system. DATA SOURCES: We present a case of duplicated vas deferens, and a PubMed Medline (National Library of Medicine) search was performed using the terms "[duplicated OR double]" and "vas deferens". Nineteen papers for a total of twenty-two cases (including ours) were identified. CONCLUSIONS: Duplication of vas deferens is a rare finding; it is likely under-reported and underrecognized. Failure to recognize this variation can result in injury to the vas deferens or an ineffective vasectomy. Following identification of a suspected duplicated vas deferens, the structure should be tracked from the internal ring down to the epididymis and intra-operative Doppler should be performed. Post operatively, renal and bladder imaging can be considered though there have been no reported cases of non-testicular genito-urinary anomalies associated with duplicated vas deferens. PMID- 21822601 TI - A novel SOX10 mutation in a patient with PCWH who developed hypoxic-ischemic encephalopathy after E. coli sepsis. AB - We describe a male infant with a novel SOX10 mutation and a severe course of PCWH -a special phenotype of Shah-Waardenburg syndrome involving peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung's disease. The patient had severe hypoplastic hypoganglionosis of the small and total colonic intestine together with peripheral and central dysmyelination. The patient was completely dependent on parenteral nutrition. We identified a novel frameshift mutation, p.Asp293GlyfsX10, in the SOX10 gene of this patient. The mutation would encode a protein that lacked the transactivation domain and resulted in the largest duplication described to date. At the age of 20 months, the boy presented with a severe complication with a translocation of Escherichia coli and developed sepsis leading to severe hypoxic-ischemic encephalopathy with persistent vegetative state (PVS). The boy died at the age of 24 months. CONCLUSION: Septic encephalopathy with hypoxic-ischemic encephalopathy can be a serious complication in severe sepsis. It is unknown to what extent the mutant SOX10 protein influenced the degree of brain injury--for example central nervous system susceptibility to hypoxia-during sepsis, which may explain the severe encephalopathy with clinical signs of PVS the boy developed. PMID- 21822602 TI - A single major QTL controls expression of larval Cry1F resistance trait in Ostrinia nubilalis (Lepidoptera: Crambidae) and is independent of midgut receptor genes. AB - The European corn borer, Ostrinia nubilalis (Lepidoptera: Crambidae), is an introduced crop pest in North America that causes major damage to corn and reduces yield of food, feed, and biofuel materials. The Cry1F toxin from Bacillus thuringiensis (Bt) expressed in transgenic hybrid corn is highly toxic to O. nubilalis larvae and effective in minimizing feeding damage. A laboratory colony of O. nubilalis was selected for high levels of Cry1F resistance (>12,000-fold compared to susceptible larvae) and is capable of survival on transgenic hybrid corn. Genetic linkage maps with segregating AFLP markers show that the Cry1F resistance trait is controlled by a single quantitative trait locus (QTL) on linkage group 12. The map position of single nucleotide polymorphism (SNP) markers indicated that midgut Bt toxin-receptor genes, alkaline phosphatase, aminopeptidase N, and cadherin, are not linked with the Cry1F QTL. Evidence suggests that genes within this genome interval may give rise to a novel Bt toxin resistance trait for Lepidoptera that appears independent of known receptor-based mechanisms of resistance. PMID- 21822603 TI - Early outcome of an implant system with a resorbable adhesive calcium-phosphate coating--a prospective clinical study in partially dentate patients. AB - This study aims to investigate the early outcome of a dental implant with bioactive calcium-phosphate (CaP) coating in the first year of usage in different clinical indications in partially edentulous patients, after early and delayed prosthetic loading. Therefore, in a prospective follow-up study, the cumulative survival and success rate of a conical, self-drilling and self-tapping implant system after 6 months and 1 year post-insertion was evaluated. A total of 311 CaP coated implants were placed in 124 patients. Seventy-two implants in clinical high-quality bone situation were loaded after 2 weeks post-insertion with the definite restoration; the rest after 6 months. The indication for implant placement was treatment of partial dentate mandible and maxilla. One hundred sixty-three implants were placed in the posterior mandible, 117 in the posterior maxilla. In the frontal maxilla, 25 implants and in the frontal mandible, eight implants were used. In 126 cases (36%), bone augmentation procedures (guided bone regeneration and sinus lift) were performed concomitant with implant placement. The difference between primary and secondary stability (implant stability quotient (ISQ), Periotest, insertion torque), peri-implant clinical parameter as well as survival and success criteria were evaluated. In total, ISQ mean values after 6 months were higher than after implant placement. Periotest values increased in the period of the first 6 months and remained constant afterwards. After 6 months of insertion, the mean bone loss was 0.051 mm. After 12 months, a bone gain with a mean of +0.016 mm was observed; implants in the posterior maxilla showed significant less bone resorption than implants in the posterior mandible (p < 0.0001). In the most of the implants (74%), clinical normal gingival tissue could be observed. In 24%, a mild inflammation was analysed. In 35 implants, a provocation of peri-implant bleeding was possible. In the early loading group, no implant failure was seen. Altogether, one implant in D4 bone has been lost. The cumulative survival rate summed up to 99.7%. In general, implant success assessment analysis according to Albrektsson and Buser displayed success in 99.7% of the implants. With respect to the patient selection including 124 implants with minor and major augmentations as well as early loading prosthetic function, the 1-year clinical use of the studied implant system with CaP coating showed good results, comparable to that of conventional implants without a specific coating. After 1 year, neither special disadvantages nor benefits of CaP-coated implants could be evaluated. Long-term results are further needed. PMID- 21822605 TI - Antitrypanosomal activities of acetylated bruceines A and C; a structure-activity relationship study. AB - The crude extract of Brucea javanica showed strong in vitro inhibitory activity against Trypanosoma evansi. Among the isolated quassinoids, bruceines A, C, and bruceantinol were found to be the most potent compounds against T. evansi. To gain a deeper understanding of the relationship between the free hydroxyl groups and the activity, several O-acetylated derivatives of bruceines A and C were synthesized and their in vitro antitrypanosomal activities against trypomastigotes of T. evansi were examined and compared with those of the original compounds. The following structure-activity relationships were observed: (1) the free hydroxyl groups at positions C-3, C-11, and C-12 are essential for antitrypanosomal activity; (2) the C-11 and C-12 hydroxyl groups are more important for the activity than the enolic hydroxyl group at C-3, and; (3) the free hydroxyl group at C-4' of bruceine C does not have any significant effect on the activity. PMID- 21822604 TI - Cardio-renal syndrome: an entity cardiologists and nephrologists should be dealing with collegially. AB - Heart failure may lead to acute kidney injury and vice versa. Chronic kidney disease may affect the clinical outcome in terms of cardiovascular morbidity and mortality while chronic heart failure may cause CKD. All these disorders contribute to the composite definition of cardio-renal syndromes. Renal impairment in HF patients has been increasingly recognized as an independent risk factor for morbidity and mortality; however, the most important clinical trials in HF tend to exclude patients with significant renal dysfunction. The mechanisms whereby renal insufficiency worsens the outcome in HF are not known, and several pathways could contribute to the "vicious heart/kidney circle." Traditionally, renal impairment has been attributed to the renal hypoperfusion due to reduced cardiac output and decreased systemic pressure. The hypovolemia leads to sympathetic activity, increased renin-angiotensin-aldosterone pathways and arginine-vasopressin release. All these mechanisms cause fluid and sodium retention, peripheral vasoconstriction and an increased congestion as well as cardiac workload. Therapy addressed to improve renal dysfunction, reduce neurohormonal activation and ameliorate renal blood flow could lead to a reduction in mortality and hospitalization in patients with cardio-renal syndrome. PMID- 21822607 TI - A new iridoid glycoside and NO production inhibitory activity of compounds isolated from Russelia equisetiformis. AB - From the 1-BuOH-soluble fraction of a MeOH extract of the leaves of Russelia equisetiformis, one new iridoid glucoside was isolated along with 24 known compounds, comprising iridoids and iridoid glucosides, phenyl propane glucosides, phenyl ethanoids, lignan glucosides, and flavonoid glucosides. The structure of the new compound was elucidated to be 10-O-cinnamoyl sinuatol. Of the 25 compounds isolated, rehmaglutin B exhibited moderate inhibitory activity toward NO production, which was not associated with cytotoxicity. PMID- 21822606 TI - Inhibitory activities of Puerariae Flos against testosterone 5alpha-reductase and its hair growth promotion activities. AB - Crude drugs expected to have an estrogenic effect were screened for their inhibitory activity on testosterone 5alpha-reductase. Testosterone 5alpha reductase is an enzyme catalyzing the conversion of testosterone to dihydrotestosterone, which possesses high affinity for the androgen receptor. Among the crude drugs tested, we focused on Puerariae Flos (the flowers of Pueraria thomsonii) due to its potent inhibitory activity and suitability for commercial use. The 50% ethanolic extract of Puerariae Flos (PF-ext) showed inhibitory activity of 60.2% at 500 MUg/ml against testosterone 5alpha-reductase. Interestingly, it was more potent than that of Puerariae Radix (roots of Pueraria lobata). PF-ext also showed in vivo anti-androgenic activity using a hair growth assay in testosterone-sensitive male C57Black/6NCrSlc strain mice. We demonstrated saponins, including soyasaponin I and kaikasaponin III, to be active components in PF-ext. In addition, hair growth promotion activity in C3H/He mice at 2 mg/mouse/day of the topical administration of PF-ext was demonstrated. Thus, Puerariae Flos is a promising crude drug for treating androgenic alopecia. PMID- 21822608 TI - Comparative analysis on the diagnosis and treatments of multisegment intramedullary spinal cord tumors between the different age groups. AB - Multisegment intramedullary spinal cord tumors (MSICT) are a special type of spinal cord tumor. Up to now, no comparative clinical study of MSICT has been performed according to different age groups. Seventy-seven patients underwent microsurgery for MSICT. As grouped with two different methods, the parametric and nonparametric data of MSICT and patients were comparatively analyzed using statistically correlative methods. Forty-eight patients were males and 29 were females, ranging in age from 4 to 64 years (mean, 32.9 years). Among the six groups, being divided with intervals of 10 years, the whole difference in the initial symptoms of patients (Z = 17.4, P = 0.004) and in the histological classification of tumors (Z = 12.5, P = 0.03) was statistically significant, respectively. Neurodevelopmental tumor and benign glioma predominated in adolescents and decreased in frequency into adulthood where ependymoma became more predominant. In the 25 years old grouping method, there were 27 adolescent and 50 adult patients. The difference in initial symptoms of patients (Z = -2.08, P = 0.04) was statistically significant between the two groups. Pain with motor weakness and gait deterioration predominated in adolescents and decreased in frequency into adulthood where sensory disturbances became more predominant. PMID- 21822609 TI - The ACCOMPLISH Trial: will first-line hypertension therapy change? PMID- 21822611 TI - Broca and the biology of language. PMID- 21822610 TI - Utilizing risk scores in determining the optimal revascularization strategy for complex coronary artery disease. AB - Percutaneous coronary intervention (PCI) of multivessel and/or left main stem disease have been shown to be potentially legitimate revascularization alternatives in appropriately selected patients. Risk stratification is an important component in guiding patients to identify the most appropriate revascularization modality (PCI or coronary artery bypass grafting [CABG]) in conjunction with the Heart Team. The aim of this paper is to give the clinician a concise overview of the important established and evolving contemporary risk models in aiding this decision-making process. Risk models, based on clinical and anatomical variables alone, the novel concept of functional anatomical risk scores, and risk models combining aspects from both clinical and anatomical scores, are all discussed. The emerging concepts of the patient-empowered risk/benefit tradeoff between PCI and CABG to help personalize the choice of revascularization modality are also explored. PMID- 21822612 TI - The efficiency of CAPE on retardation of hepatic fibrosis in biliary obstructed rats. AB - The aim of this study was to evaluate the possible protective effects of caffeic acid phenethyl ester (CAPE) against cholestatic oxidative stress and liver damage in the common bile duct ligated rats. A total of 18 male Sprague-Dawley rats were divided into three groups: control, bile duct ligation (BDL) and BDL + received CAPE; each group contain 6 animals. The rats in CAPE treated groups were given CAPE (10 MUmol/kg) once a day intraperitoneally (i.p) for 2 weeks starting just after BDL operation. The changes demonstrating the bile duct proliferation and fibrosis in expanded portal tracts include the extension of proliferated bile ducts into lobules, inflammatory cell infiltration into the widened portal areas were observed in BDL group. Treatment of BDL with CAPE attenuated alterations in liver histology. The proliferating cell nuclear antigen and the activity of TUNEL in the BDL were observed to be reduced with the QE treatment. The application of BDL clearly increased the tissue hydroxyproline (HP) content, malondialdehyde (MDA) levels and decreased the antioxidant enzyme (superoxide dismutase (SOD), glutathione peroxidase (GPx)) activities. CAPE treatment significantly decreased the elevated tissue HP content, and MDA levels and raised the reduced of SOD, and GPx enzymes in the tissues. The data indicate that CAPE attenuates BDL-induced cholestatic liver injury, bile duct proliferation, and fibrosis. The hepatoprotective effect of CAPE is associated with antioxidative potential. PMID- 21822613 TI - Unusual retinal layer organization in HPC-1/syntaxin 1A knockout mice. AB - HPC-1/syntaxin 1A (STX1A) is abundantly expressed in neurons. STX1A is believed to regulate exocytosis in synaptic vesicles. In our recent studies, STX1A knockout (KO) mice showed normal development, and basal synaptic transmission in cultured hippocampal neurons appeared to be normal. However, behavioral abnormalities were observed in STX1A KO mice. In the normal rodent retina, the STX1A protein is expressed in two synaptic layers (plexiform layers). Here, to evaluate the effects of the loss of STX1A on retinal structure, we examined the retinal layer structure in STX1A KO mice using hematoxylin staining and immunostaining. We found that the general layer structures in the retina were preserved in all genotypes. However, the outer plexiform layer (OPL) was significantly thicker in KO and heterozygous mutant (HT) mice compared with that in wild-type (WT) mice. No significant differences were observed in the thicknesses of the other layers. Immunostaining for protein kinase C alpha showed that the alignment of rod bipolar cell bodies in the inner nuclear layer (INL) was slightly disrupted in HT and KO retinas. Furthermore, the dendrites of these cells in the OPL of KO mice were sparse, compared to those in WT mice. Our results show that STX1A KO mice have increased thickness of the OPL and changes in the morphology of the INL that may contribute to the change in OPL thickness. We suggest that STX1A may play a role in the structural formation of the INL and OPL in the retina. PMID- 21822614 TI - A probable relationship between characteristic accumulation of doxorubicin and P glycoprotein transporter in rat liver. AB - Correlations between the distribution of anthracycline antibiotics doxorubicin (DX) and daunorubicin (DR) in the liver of rats injected with a single i.v. injection of each drug and the reported distribution of P-glycoprotein transporter for the drug was histochemically examined. Immunocytochemical studies for DX or DR using monoclonal antibody that equally detects both drugs, as well as conventional electron microscopy were employed. DX persisted for more than 5 days in the cytoplasm and nuclei of the hepatocytes in a characteristic granular morphology on the bile capillaries. Meanwhile, DR distributed in almost the same pattern, but more rapidly decreased to a level that almost no granular morphology in the hepatocytes was visible 24 h after the injection. Also, unknown large cells that strongly reacted with the antibody appeared in the hepatic sinusoids near the interlobular triads rather than the central vein. The accumulation sites of DX or DR on the bile capillaries seems to correspond to specific sites where the ATP-binding cassette transport protein P-glycoprotein for the anthracycline occurs, suggesting a possibility that DX or DR is actually and actively excreted at these sites, possibly through P-glycoprotein. This is supported by conventional electron microscopic studies, since no specific subcellular organelles such as lysosomes assemble in the vicinity of the bile capillaries of the hepatocytes. PMID- 21822615 TI - Phenotype of single hepatocytes expressing an activated version of beta-catenin in liver of transgenic mice. AB - The gene CTNNB1 encoding beta-catenin is mutated in about 30% of hepatocellular carcinoma, generally often combined with other genetic alterations. In transgenic mice, it has been shown that activation of beta-catenin in more than 70% of all hepatocytes causes immediate proliferation leading to hepatomegaly. In this study we established a novel mouse model where beta-catenin is activated only in individual, dispersed hepatocytes. Hepatocyte-specific expression of activated point-mutated beta-catenin (human beta-catenin(S33Y)) was established using the Cre/loxP system. Expression of several downstream targets of beta-catenin signaling such as glutamine synthetase and several cytochrome P450 isoforms was confirmed by immunostaining. Only a minor portion of hepatocytes expressed the beta-catenin(S33Y) transgene, which were mainly positioned as dispersed individual cells within the normal liver parenchyma. The hepatocytes with activated beta-catenin did not show increased proliferation and the mice did not develop hepatomegaly. In conclusion, activated beta-catenin in single hepatocytes induces a gene expression pattern in hepatocytes which is similar to that of Ctnnb1-mutated mouse liver tumors, but is apparently not sufficient to induce increased cell proliferation. Therefore, onset of proliferation seems to require concomitant activation of beta-catenin in clusters of hepatocytes, suggesting a role of cell-cell communication in this process. PMID- 21822616 TI - Scube2 expression extends beyond the central nervous system during mouse development. AB - The Scube (Signal peptide CUB EGF-like domain-containing protein) family consists of three independent members evolutionarily conserved from zebrafish to humans. Scube2 transcripts have been identified primarily in forebrain and trunk neuroepithelium and the anterior hindbrain of the mouse embryo, becoming progressively localized to the dorsal forebrain, hindbrain and neural tube. Zebrafish You-class mutants lack a functional C-terminal domain within the Scube2 protein and present with altered myotomal morphology, curled tail and weak cyclopia. These defects are characteristic of disrupted Hedgehog signaling, which is consistent with the downregulation of Hedgehog targets such as Ptc1, MyoD and Eng observed in these mutants. Indeed, human SCUBE2 can form a complex with Sonic hedgehog and its receptor PTC1, acting to promote SHH-induced signaling. Here we have characterized Scube2 expression in detail within the developing mouse embryo using wholemount and section in situ hybridisation and demonstrate the presence of transcripts within a more extensive range than previously reported. In addition to neuroectoderm of the early embryo, expression was also found in the developing face, heart, vasculature and multiple regions of the endochondral skeleton. These findings suggest that Scube2 may play an important role during development of multiple regions in the embryo. PMID- 21822617 TI - Retrospective analysis of primary gastric diffuse large B cell lymphoma in the rituximab era: a multicenter study of 95 patients in Japan. AB - Primary gastric diffuse large B cell lymphoma (PG-DLBCL) is common subtype of extranodal non-Hodgkin lymphoma. The optimal treatment strategy for PG-DLBCL in the rituximab era still remains unknown. To evaluate clinical outcomes of PG DLBCL in the rituximab era, we conducted a retrospective, multicenter analysis of 95 patients with PG-DLBCL. In 58 patients with localized disease, 3-year progression-free survival (PFS) and overall survival (OS) were 91% and 91% for patients with six cycles of rituximab plus CHOP (R-CHOP) and 92% and 95% for patients with three to four cycles of R-CHOP plus radiotherapy (Log-rank test, P = 0.595 and P = 0.278, respectively). In 37 patients with advanced disease, 3 year PFS and 3-year OS were 43% and 64% for patients with R-CHOP chemotherapy with or without radiotherapy. On multivariate analysis, advanced stage and elevated serum LDH levels were independent predictors of survival in patients with PG-DLBCL. One patient with localized disease relapsed in lymph node, and eight patients with advanced disease relapsed in lymph node (n = 3), stomach (n = 2), central nervous system (CNS; n = 2), and duodenum (n = 1). Intriguingly, CNS relapse developed within 6 months after initial series of treatment (4.9 and 5.8 months, respectively), and stomach relapse developed in later phase (27.2 and 32.9 months, respectively). Clinical outcomes of PG-DLBCL were extremely favorable for localized-stage patients in the rituximab era, although these might be poor for advanced-stage patients even in the rituximab era. Further prospective analyses are warranted. PMID- 21822618 TI - In vitro vessel-forming capacity of endothelial progenitor cells in high glucose conditions. AB - In type 2 diabetes, the impairment of vascular repair processes and angiogenesis are due to endothelial progenitor cell (EPC) dysfunction. In this study, we established a quantitative methodology to assess EPC function by using an in vitro 5-(6)-carboxyfluorescein diacetate succinimidyl ester-labeling vessel formation assay. The EPCs were cultured in three different glucose concentrations (100, 189.5, and 295.5 mg/dl of D: -glucose) representing normal control and diabetes with either good or poor glycemic control, respectively. We found that the in vitro vessel-forming capacity was impaired in EPCs cultured in high glucose concentrations compared to normal control (43.4 +/- 0.8% and 34.7 +/- 0.7% vs. 50.8 +/- 2.1%). We further studied expression of various genes involved in vessel formation. There was a lower level of angiopoietin 1 gene expression in EPCs cultured in high glucose concentrations. The addition of recombinant angiopoietin 1 significantly increased the vessel-forming capacity of EPCs cultured in high glucose concentration (35.3 +/- 2.0% to 48.8 +/- 2.7%), whereas the addition of angiopoietin 2 (a competitive inhibitor of angiopoietin 1) impaired the vessel-forming capacity of EPCs cultured in normal glucose concentration (51.8 +/- 1.3% to 41.3 +/- 0.6%). We conclude that the in vitro vessel-forming capacity of EPCs cultured in high glucose concentration is impaired due to low levels of angiopoietin 1. PMID- 21822620 TI - Chipping away at the surface of the endothelial progenitor cell (EPC) mystery. PMID- 21822619 TI - A novel role of andrographolide, an NF-kappa B inhibitor, on inhibition of platelet activation: the pivotal mechanisms of endothelial nitric oxide synthase/cyclic GMP. AB - Andrographolide is a novel NF-kappaB inhibitor from the leaves of Andrographis paniculata. Platelet activation is relevant to a variety of thrombotic diseases. However, no data are available concerning the effects of andrographolide in platelet activation. The aim of this study was to examine the mechanisms of andrographolide in preventing platelet activation. Andrographolide (25-75 MUMU) exhibited a more potent activity of inhibiting platelet aggregation stimulated by collagen. Andrographolide inhibited collagen-stimulated platelet activation accompanied by relative Ca(2+) mobilization; thromboxane A(2) formation; and phospholipase C (PLC)gamma2, protein kinase C (PKC), mitogen-activated protein kinase (MAPK), and Akt phosphorylation. Andrographolide markedly increased cyclic GMP, but not cyclic AMP levels. Andrographolide also stimulated endothelial nitric oxide synthase (eNOS) expression, NO release, and vasodilator-stimulated phosphoprotein (VASP) phosphorylation. ODQ, an inhibitor of guanylate cyclase, markedly reversed the andrographolide-mediated inhibitory effects on platelet aggregation, p38 MAPK and Akt phosphorylation, and the andrographolide-mediated stimulatory effect on VASP phosphorylation. Furthermore, a PI3 kinase inhibitor (LY294002) but not a PKC inhibitor (Ro318220) significantly diminished p38 MAPK phosphorylation; nevertheless, a p38 MAPK inhibitor (SB203580) and LY294002 diminished PKC activity stimulated by collagen. Andrographolide also reduced collagen-triggered hydroxyl radical (OH([Symbol: see text])) formation. In vivo studies revealed that andrographolide (22 and 55 MUg/kg) is effective in reducing the mortality of ADP-induced acute pulmonary thromboembolism and significantly prolonged platelet plug formation in mice. This study demonstrates for the first time that andrographolide possesses a novel role of antiplatelet activity, which may involve the activation of the eNOS-NO/cyclic GMP pathway, resulting in the inhibition of the PI3 kinase/Akt-p38 MAPK and PLCgamma2-PKC cascades, thereby leading to inhibition of platelet aggregation. PMID- 21822622 TI - Braking self-cannibalism in cancer. PMID- 21822621 TI - epsilon/zeta systems: their role in resistance, virulence, and their potential for antibiotic development. AB - Cell death in bacteria can be triggered by activation of self-inflicted molecular mechanisms. Pathogenic bacteria often make use of suicide mechanisms in which the death of individual cells benefits survival of the population. Important elements for programmed cell death in bacteria are proteinaceous toxin-antitoxin systems. While the toxin generally resides dormant in the bacterial cytosol in complex with its antitoxin, conditions such as impaired de novo synthesis of the antitoxin or nutritional stress lead to antitoxin degradation and toxin activation. A widespread toxin-antitoxin family consists of the epsilon/zeta systems, which are distributed over plasmids and chromosomes of various pathogenic bacteria. In its inactive state, the bacteriotoxic zeta toxin protein is inhibited by its cognate antitoxin epsilon. Upon degradation of epsilon, the zeta toxin is released allowing this enzyme to poison bacterial cell wall synthesis, which eventually triggers autolysis. epsilon/zeta systems ensure stable plasmid inheritance by inducing death in plasmid-deprived offspring cells. In contrast, chromosomally encoded epsilon/zeta systems were reported to contribute to virulence of pathogenic bacteria, possibly by inducing autolysis in individual cells under stressful conditions. The capability of toxin-antitoxin systems to kill bacteria has made them potential targets for new therapeutic compounds. Toxin activation could be hijacked to induce suicide of bacteria. Likewise, the unique mechanism of zeta toxins could serve as template for new drugs. Contrarily, inhibition of virulence-associated zeta toxins might attenuate infections. Here we provide an overview of epsilon/zeta toxin-antitoxin family and its potential role in the development of new therapeutic approaches in microbial defense. PMID- 21822623 TI - An aneurysmal bone cyst within the proximal fibula causing common peroneal nerve palsy. AB - The case of a 15-year-old patient presenting with pain as well as paraesthesia over the lateral aspect of the leg is reported. Clinical and radiological investigations showed an aneurysmal bone cyst arising from the proximal fibula and pressing on the common peroneal nerve. Surgical decompression of the nerve and curettage of the cyst was performed resulting in complete resolution of his symptoms. Our aim is to alert surgeons that this problem may occur and that the entire nerve needs to be exposed when dealing with the cyst. PMID- 21822624 TI - Contralateral metastasis of parotid gland in advanced breast cancer with peripheral facial paralysis. AB - PURPOSE: Malignant tumors of the parotid gland are very rare. Until now there have only been a few reported cases of patients with distant metastasis of breast cancer in the parotid gland. This case shows the rarity of the disease. METHODS: This case is about a 74-year-old woman with an invasive lobular carcinoma of the left breast. The initial diagnosis was made four years ago. The operation which was done was a quadrantectomy and axillary lymph node dissection. It was followed by radiotherapy of the breast. The recommended chemotherapy was declined by the patient. RESULTS: Three years after the initial diagnosis of lobular invasive breast cancer a nodular change in the cicatrice of the mastectomy occurred. The patient also had a contralateral peripheral facial paralysis, caused by a distant metastasis in the right parotid gland. CONCLUSIONS: When there is a tumor in the parotid gland and a histological classified adenocarcinoma is found, the differential diagnosis of breast cancer metastasis should be considered. PMID- 21822625 TI - A global perspective on complementary and alternative medicine use among people living with HIV/AIDS in the era of antiretroviral treatment. AB - Complementary and alternative medicine (CAM) is a popular adjunct to conventional medicine across medical populations, and is particularly relevant in the global HIV epidemic. Use of antiretroviral therapy (ART) to treat HIV is ubiquitous in high-resource areas and efforts to increase coverage in low-resource areas are underway. To better understand the role of CAM in HIV treatment and the implications of CAM use for ART uptake and adherence, we review international research published between 2007 and 2011. Findings confirm that CAM is commonly used as an adjunct to ART; however, in countries where ART is less accessible, many HIV-positive individuals take a pluralistic approach to health care, incorporating both traditional and, when available, conventional medicine. The reviewed studies provide no consensus on whether the use of CAM interferes with ART uptake or adherence; instead, research suggests that illness-related behaviors are driven by multiple factors and determined, at least in part, by the availability and accessibility of ART. PMID- 21822626 TI - Mental health: a focus on stress, coping, and mental illness as it relates to treatment retention, adherence, and other health outcomes. AB - Mental health problems are prevalent among HIV-infected individuals, with some estimates that 50% likely meet criteria for one or more psychiatric disorders. The mental health of HIV-infected individuals is important not only for quality of-life concerns, but also in regard to HAART adherence and biological disease progression. The current review focuses on research published between 2009 and April of 2011, exploring mental health, coping, and stress in relation to HIV care behaviors including HAART adherence, quality of life, treatment retention, health care utilization, and disease progression amongst HIV-infected individuals. Specifically, we reviewed the most prevalent and interfering concerns among HIV-infected individuals-depression, post-traumatic stress disorder, interpersonal violence, stigma and shame, and body image concerns. Despite advances over the last 2 years documenting the deleterious effects of mental health on important HIV self-care behaviors, there is continued need for developing and disseminating evidence-based psychosocial interventions that integrate treating mental health problems with improving self-care behaviors for those living with HIV. PMID- 21822627 TI - No "magic bullet": exploring community mobilization strategies used in a multi site community based randomized controlled trial: Project Accept (HPTN 043). AB - As community-level interventions become more common in HIV prevention, processes such as community mobilization (CM) are increasingly utilized in public health programs and research. Project Accept, a multi-site community randomized controlled trial, is testing the hypothesis that CM coupled with community-based mobile voluntary counseling and testing and post-test support services will alter community norms and reduce the incidence of HIV. By using a multiple-case study approach, this qualitative study identifies seven major community mobilization strategies used in Project Accept, including stakeholder buy-in, formation of community coalitions, community engagement, community participation, raising community awareness, involvement of leaders, and partnership building, and describes three key elements of mobilization success. PMID- 21822628 TI - Using people to cope with the hunger: social networks and food transfers amongst HIV/AIDS afflicted households in KwaZulu-Natal, South Africa. AB - Household afflicted by HIV/AIDS are particularly prone to food insecurity. This article explores the role of community networks in meeting household food deficits. One hundred households exhibiting a range (0-5) of HIV/AIDS proxies related to orphan fostering, prime adult chronic illness and mortality were visited at quarterly intervals for a year. At each assessment, donated food types consumed in the past 48 h were recorded, and household food security was monitored through an experiential measure. Factors determining access to donated foods were explored qualitatively by means of participant observation and semi structured interviews. Poor households with prime adult chronic illness were prone to food insecurity, and used the most donated foods. However, not all households perceived to be afflicted with HIV/AIDS were able to access donated foods due to stigma and social exclusion. Concerted action must be taken by government, non-government and community agents if social food transfer networks are to be transformed into coordinated community action. PMID- 21822629 TI - Prospective comparison of echocardiography versus cardiac magnetic resonance imaging in patients with Ebstein's anomaly. AB - Ebstein's anomaly (EA) is primarily diagnosed by echocardiography. The purpose of this study was to compare echocardiography and magnetic resonance imaging (MRI) in EA. Data from cardiac MRI and echocardiography were prospectively collected from 16 patients with EA. Imaging data also were compared with intraoperative findings. Information provided by MRI and echocardiography were comparable for left ventricular size and function, tricuspid valve repairability, qualitative assessment of right-sided cavities, and visibility of septal and anterior tricuspid valve leaflets. The posterior tricuspid valve leaflet and tricuspid valve fenestrations were better visualized with MRI; associated heart defects were equally recognized, apart from small shunts that tended to be more readily diagnosed with echocardiography. Quantification of right-cavity size and right ventricular ejection fraction was possible only with cardiac MRI. The degree of tricuspid valve regurgitation was underestimated by echocardiography (2 patients) and by MRI (4 patients) when compared with intraoperative assessment. When evaluating EA, echocardiography and MRI provide complementary data. For visualization of the posterior tricuspid valve leaflet and quantitative assessment of right ventricular size and function, MRI is preferable. For appropriate risk stratification in EA, both MRI and echocardiography should be performed before cardiac surgery. PMID- 21822630 TI - Effects of the KiVa anti-bullying program on adolescents' depression, anxiety, and perception of peers. AB - The present study investigated the effects of the KiVa antibullying program on students' anxiety, depression, and perception of peers in Grades 4-6. Furthermore, it was investigated whether reductions in peer-reported victimization predicted changes in these outcome variables. The study participants included 7,741 students from 78 schools who were randomly assigned to either intervention or control condition, and the program effects were tested with structural equation modeling. A cross-lagged panel model suggested that the KiVa program is effective for reducing students' internalizing problems and improving their peer-group perceptions. Finally, changes in anxiety, depression, and positive peer perceptions were found to be predicted by reductions in victimization. Implications of the findings and future directions for research are discussed. PMID- 21822631 TI - Pneumatic robotic systems for upper limb rehabilitation. AB - The aim of rehabilitation robotic area is to research on the application of robotic devices to therapeutic procedures. The goal is to achieve the best possible motor, cognitive and functional recovery for people with impairments following various diseases. Pneumatic actuators are attractive for robotic rehabilitation applications because they are lightweight, powerful, and compliant, but their control has historically been difficult, limiting their use. This article first reviews the current state-of-art in rehabilitation robotic devices with pneumatic actuation systems reporting main features and control issues of each therapeutic device. Then, a new pneumatic rehabilitation robot for proprioceptive neuromuscular facilitation therapies and for relearning daily living skills: like taking a glass, drinking, and placing object on shelves is described as a case study and compared with the current pneumatic rehabilitation devices. PMID- 21822633 TI - Ethics in the discipline(s) of bioethics. AB - The development of a code of ethics for a profession can be an indicator of the coherence and stability of a discipline as a unique and singular entity. Since "bioethics", as a discipline, is not one profession but many, practiced by persons with not one but many varying responsibilities and training, it has been argued that no code of ethics is possible for the discipline(s) of bioethics. I argue that a code of ethics is possible for bioethics by looking at the nature of the various disciplines and noting necessary overlap between them, and deriving the ethics from the nature of the discipline(s) themselves. I show how this can be done by arguing that strict rules about funding and conflict of interest are necessary for bioethicists. PMID- 21822632 TI - Protein C anticoagulant system--anti-inflammatory effects. AB - Activated protein C (APC) plays active roles in preventing progression of a number of disease processes. These include thrombosis due to its direct anticoagulant activity which is likely augmented by its cytoprotective activity, thereby limiting exposure of procoagulant cellular membrane surfaces on cells. Beyond that, the pathway signals the cells to prevent apoptosis, to dampen inflammation, to increase endothelial barrier function, and to selectively downregulate some genes implicated in disease progression. Most of these functions are manifested to APC binding to endothelial protein C receptor (EPCR) allowing PAR1 activation, but activation of other PARS is also implicated in some cases. In addition to EPCR orchestrating these changes, CD11b is also capable of supporting APC signaling. Selective control of these pathways offers potential in new therapeutic approaches to disease. PMID- 21822634 TI - Inclusive consultation: a hermeneutical approach to ethical deliberation in the clinical setting. AB - The problem of ethical consultations in the clinical setting should be reasonable, but it cannot be reduced to reason and philosophical theory alone. I will argue that emotions are constitutively and discursively relevant features of the evaluative experience of persons. Ethical consultations should include emotions. Emotions like shame and guilt are complex and learned reactions of persons, which form one basis of ethical reflection. I argue that ethical consultation can rely neither on a strict theory or method nor on a philosophical theory that is external to the situational triggers of consultations in the clinical setting. Emotions are one essential trigger of the need for ethical consultations. I will show that methodologically consultation depends on understanding the evaluative experiences of persons who cooperate in the clinical setting. Moreover, such evaluative experiences includes emotive reactions as well as reason. My conclusion is that ethical consultation in the clinical setting needs a conceptual understanding of epistemic, justificatory and methodological inclusiveness. This circumstance can be summarized: ethical consultations need the ongoing development of a moral hermeneutics of clinical consultation. PMID- 21822635 TI - Emotions and ethical considerations of women undergoing IVF-treatments. AB - Women who suffer from fertility issues often use in vitro fertilization (IVF) to realize their wish to have children. However, IVF has its own set of strict administration rules that leave the women physically and emotionally exhausted. Feeling alienated and frustrated, many IVF users turn to internet IVF-centered forums to share their stories and to find information and support. Based on the observation of Dutch and Greek IVF forums and a selection of 109 questionnaires from Dutch and Greek IVF forum users, we investigate the reasons why users of IVF participate in online communities centered on IVF, their need for emotional expression and support, and how they experience and use the information and support they receive through their participation in the online community. We argue that the emotional concerns expressed in such forums should be taken into account by health care ethics committees for IVF-related matters in order to promote more patient-oriented care and support for women going through IVF. PMID- 21822636 TI - Psychotropic medication during endocrine treatment for breast cancer. AB - PURPOSE: Psychological problems are frequently mentioned in women treated for breast cancer in whom depression is mentioned as the most common disorder. The aim was to study the prescription of psychotropic medication in women with endocrine treatment for breast cancer in women in our prospective and consecutive pharmacy database. METHODS: Women (n = 2,172) with at least one prescription of tamoxifen, fulvestrant, anastrazole, letrozole or exemestane were considered as breast cancer patients treated with endocrine therapy. This group was compared with an age- and family physician-matched group of women without cancer (n = 8,129), and the incidence risk ratio (IRR) and the 95% confidence intervals (95% CI) were calculated. In addition, the prevalence of these psychotropic medication prescriptions and the 95% CI were calculated. RESULTS: There was an increased prescription of psychotropic medication in the female breast cancer patients on endocrine therapy: anxiolytics (IRR 2.07, 95% CI 1.87-2.29), hypnotics and sedatives (IRR 2.59, 95% CI 2.34-2.87) and anti-depressants (IRR 1.46, 95% CI 1.28-1.65). The prevalences of anxiolytics, hypnotics and sedatives were also increased in this group, indicating an increased use over time of these drugs. The prevalence of anti-depressant prescription was not increased, indicating short-term use only. CONCLUSIONS: This study indicated increased psychological distress due to breast cancer diagnosis and/or treatment in women on endocrine therapy. Anti-depressants were only prescribed for a short time. These data can contribute to an improved awareness of the impact of breast cancer (treatment) and therefore potentially to the optimizing of support for these patients. PMID- 21822637 TI - Behavioral risk factors and their relationship to tumor characteristics in Hispanic and non-Hispanic white long-term breast cancer survivors. AB - Hispanics are more likely to be diagnosed with breast cancer at a younger age, with more advanced stage at diagnosis, hormone receptor-negative tumors, and worse prognosis than non-Hispanic whites (NHW). Little is known regarding the association between behavioral risk factors and breast tumor characteristics and whether these associations vary by race/ethnicity. We evaluated the association between several behavioral risk factors and tumor phenotype in a population-based study of Hispanics and NHWs. Participants are cases (846 Hispanic and 1,625 NHW women) diagnosed with breast cancer between 1999 and 2004 in Arizona, Colorado, New Mexico, or Utah. The association between breast cancer characteristics and obesity, physical activity, smoking, alcohol intake, and reproductive factors was examined. Logistic regression was used to compute the ethnic-specific odds ratios for the association between these risk factors and estrogen receptor (ER) status, tumor size, and histologic grade. Hispanics had more ER-negative tumors (28 vs. 20%), tumors >2 cm (39 vs. 27%), and poorly differentiated tumors (84 vs. 77%) than NHW. Among premenopausal women, obesity was associated with more ER-negative cancers among NHW [OR = 2.47 (95% CI: 1.08, 5.67)] but less ER-negative cancers among Hispanics [OR = 0.29 (0.13, 0.66)]. Obesity was associated with larger tumors among NHW [OR = 1.58 (1.09, 2.29)], but not among Hispanics. Never using mammography was associated with larger tumors in both ethnic groups. Moderate alcohol drinking and moderate and vigorous physical activity were weakly associated with smaller tumors in both ethnic groups. Our findings suggest that the association of obesity and other behavioral risk factors with breast cancer characteristics differ by ethnicity. We observed a divergent pattern between Hispanic and NHW cases in the association between obesity and ER status and tumor size. These observations suggest that a complex set of metabolic and hormonal factors related to estrogen and insulin pathways influence tumor characteristics. PMID- 21822638 TI - Immunohistochemically defined subtypes and outcome in occult breast carcinoma with axillary presentation. AB - The aim of this study is to evaluate the outcome of occult breast cancer (OBC) in patients with axillary presentation overall and according to the immunohistochemically defined tumour subtypes. We reviewed information on 15,490 consecutive primary breast cancer patients, who underwent surgery at the European institute of oncology between September 1997 and December 2008. Patients with OBC were compared with an equal number of patients with small invasive breast carcinomas (pT1) observed at the same institution during the same period, matched for year of surgery, age, nodal status and biological features. Eighty patients with OBC (study group) and 80 patients with early breast cancer (control group) were identified. There was no significant difference in the disease-free survival (5 years DFS 66 vs. 68% P = 0.91) and the overall survival (5 years OS 80 and 86% P = 0.99) between the OBC and control groups. A statistically significant worse outcome was observed within the group of OBC for patients with more than four involved lymph nodes and with triple negative tumours. The outcome of OBC patients is comparable with that of matched patients with small sized breast cancer. High risk of relapse and death was observed in OBC patients with triple negative tumours and extensive nodal involvement. PMID- 21822639 TI - Excised and irradiated volumes in relation to the tumor size in breast-conserving therapy. AB - In early-stage breast cancer and DCIS patients, breast-conserving therapy is today's standard of care. The purpose of this study was to evaluate the relation between the microscopic tumor diameter (mTD), the excised specimen (ES) volume, and the irradiated postoperative complex (POC) volume, in patients treated with breast-conserving therapy. In 186 patients with pTis-2N0 breast cancer, the mTDs, ES, and POC volumes (as delineated on the radiotherapy-planning CT scan), were retrospectively determined. Linear regression analysis was performed to study the association between the mTD, and the ES and POC volumes. The explained variance (r (2)) was calculated to establish the proportion of variation in the outcome variable that could be explained by the determinant (P <= 0.05). Moreover, the influence of tumor characteristics, age, surgical procedures, and breast size was studied. Median mTD was 1.2 cm (range 0.1-3.6 cm), median ES volume was 60 cm(3) (range 6-230 cm(3)) and median POC volume was 15 cm(3) (range 0.5-374 cm(3)). The POC was not clearly visible on the majority of the CT scans, based on a median assigned cavity visualization score of 3 (range 1-5). The explained variance for the mTD on the ES volume was low (r(2) = 0.08, P < 0.001). A slightly stronger association was observed in palpable tumors (r(2) = 0.23, P < 0.001) and invasive lobular carcinomas (r(2) = 0.39, P = 0.01). Furthermore, weak associations were observed between POC volume and mTD (r(2) = 0.04, P = 0.01), and POC and ES volume (r(2) = 0.23, P < 0.001). A weak association was observed between breast volume and ES volume (r(2) = 0.27, P < 0.001). In conclusion, both the excised and the irradiated POC volumes did not show a clinically relevant association with the mTD in women with early-stage breast cancer treated with breast conserving therapy. Future studies should focus on improvement of surgical localization, development of image-guided, minimally invasive operation techniques, and more accurate image-guided target volume delineation in radiotherapy. PMID- 21822641 TI - Influence of medium components on the expression of recombinant lipoproteins in Escherichia coli. AB - Bacterial lipoproteins are crucial antigens for protective immunity against bacterial pathogens. Expression of exogenous lipoproteins in Escherichia coli at high levels is thought to be an extremely difficult endeavor because it frequently results in incomplete or absent lipid modification. Previously, we identified a fusion sequence (D1) from a Neisseria meningitidis lipoprotein that induced a non-lipidated protein, E3 (the domain III of the dengue virus envelope protein), to become lipidated. However, without optimizing the growth conditions, some of the D1-fusion proteins were not lipidated. Here, we report the influence of medium components on the expression of recombinant lipoproteins in E. coli. For high-level expression of mature lipoproteins in the C43 (DE3) strain, M9 medium was better than M63 and the rich medium. Furthermore, we analyzed the influence of other media factors (including nitrogen and carbon sources, phosphate, ferrous ions, calcium, magnesium, and pH) on the levels of lipoprotein expression. The results showed that excess nitrogen sources and phosphate in M9 medium could increase the amount of immature lipoproteins, and glucose was a better carbon source than glycerol for expressing mature lipoproteins. We also found that lipoproteins tended to be completely processed in the alkaline environment, even in the nutrient-rich medium. Additional constructs expressing different immunogens or lipid signal peptides as targets were also utilized, demonstrating that these targets could be expressed as completely mature lipoproteins in the M9 medium but not in the rich medium. Our results provide the useful information for expressing mature exogenous lipoproteins in E. coli. PMID- 21822640 TI - Evaluation of antiurolithic effect and the possible mechanisms of Desmodium styracifolium and Pyrrosiae petiolosa in rats. AB - Chinese herbs Desmodium styracifolium (Ds) and Pyrrosiae petiolosa (Pp) have been widely used to treat urolithiasis with few side effects in traditional Chinese medicine (TCM). In vitro crystallization study has confirmed their prophylaxis of Calcium oxalate (CaO( x )) stones formation. However, little is known on their possible mechanisms in vivo. In the present study, we proposed to systematically evaluate their antilithic effects and clarify the underlying mechanism of Ds and Pp using a rat nephrolithiasis model and administering the aqueous extracts. Adult male Wistar rats were fed with 5% ammonium oxalate (AmO( x )) forage to induce nephrolithiasis. After 1 week, the rats were randomly divided into eight groups, and given low, medium, and high dose of each herb treatments (275, 550 and 1,100 mg/kg for Ds and 150, 300 and 600 mg/kg for Pp) by gavage for 3 weeks. In contrast to urolithic rats, urinary oxalate significantly reduced, and urinary calcium increased in medium and high dose Ds groups. Few depositions were observed in kidney with slight dilation of tubules and inflammatory infiltration. Osteopontin (OPN), nitric oxide (NO), and malondialdehyde (MDA) levels significantly decreased, but Superoxide dismutase (SOD) activities were enhanced in kidneys. In high dose Pp group, crystals were found in the dilation of tubules with slight inflammatory infiltration. Partial serum and urinary variables returned to the normal range. In conclusion, medium and high dose Ds has beneficial effect in preventing CaO( x ) stone formation by rising urinary Citrate excretion, decreasing urinary calcium, diuresis, and antioxidative effects. Although high dose Pp has relatively weak prophylaxis, it indicates significant anti-inflammatory and antioxidant effects. PMID- 21822642 TI - UDP-N-acetylglucosamine enolpyruvyl transferase as a potential target for antibacterial chemotherapy: recent developments. AB - The emergence of antibiotic resistance in bacterial pathogens has foxed the health organizations which are actively scrambling for solutions. The available data indicate an increased morbidity in infections often leading to mortality among patients where drug-resistant pathogens have negated the effect of the medicines. In the context of developing "novel bacterial inhibitors" for killing or arresting the growth of drug-resistant pathogens, UDP-N-acetylglucosamine enolpyruvyl transferase (MurA) is an enzyme that provides hope for the future. This enzyme catalyzes the first committed step in the biosynthesis of peptidoglycan, an integral and essential component of the bacterial cell wall. MurA enzyme is neither present nor required by mammals and shows poor homology with human proteins. Therefore, it is an ideal target for antibacterial chemotherapy. Till date, 18 structures of MurA (in native and ligand-bound forms) from different bacterial pathogens have been solved. In the last 2 years, eight structures of bacterial MurA have been submitted to the Protein Data Bank and many inhibitors discovered. The present review discusses the structural and functional features of MurA of bacterial pathogens along with the development of MurA-targeted inhibitors. PMID- 21822643 TI - A carrier fusion significantly induces unfolded protein response in heterologous protein production by Aspergillus oryzae. AB - In heterologous protein production by filamentous fungi, target proteins are expressed as fusions with homologous secretory proteins, called carriers, for higher production yields. Although carrier fusion is thought to overcome the bottleneck in transcriptional and (post)translational processes during heterologous protein production, there is limited knowledge of its physiological effects on the host strain. In this study, we performed DNA microarray analysis by comparing gene expression patterns of two Aspergillus oryzae strains expressing either carrier- or non-carrier-fused bovine chymosin (CHY). When CHY was expressed as a fusion with alpha-amylase (AmyB), the production level increased by approximately 2-fold as compared with the non-carrier-fused CHY. DNA microarray analysis revealed that the carrier fusion significantly up-regulated many genes involved in endoplasmic reticulum (ER) protein-folding and secretion. Consistently, hacA transcripts were efficiently spliced in the strain expressing the carrier-fused CHY, indicating an unfolded protein response (UPR). The carrier fused CHY was detected intracellularly without processing at the Kex2 cleavage site, which is likely recognized in the Golgi, and the carrier fusion delayed extracellular CHY production in the early growth phase as compared with the non carrier-fused expression. Taken together, our data suggest a proposal that the carrier fusion temporarily accumulates the carrier-fused CHY in the ER and significantly induces UPR. PMID- 21822644 TI - MICALs in control of the cytoskeleton, exocytosis, and cell death. AB - MICALs form an evolutionary conserved family of multidomain signal transduction proteins characterized by a flavoprotein monooxygenase domain. MICALs are being implicated in the regulation of an increasing number of molecular and cellular processes including cytoskeletal dynamics and intracellular trafficking. Intriguingly, some of these effects are dependent on the MICAL monooxygenase enzyme and redox signaling, while other functions rely on other parts of the MICAL protein. Recent breakthroughs in our understanding of MICAL signaling identify the ability of MICALs to bind and directly modify the actin cytoskeleton, link MICALs to the docking and fusion of exocytotic vesicles, and uncover MICALs as anti-apoptotic proteins. These discoveries could lead to therapeutic advances in neural regeneration, cancer, and other diseases. PMID- 21822645 TI - The regulatory function of SPARC in vascular biology. AB - SPARC is a matricellular protein, able to modulate cell/ECM interactions and influence cell responses to growth factors, and therefore is particularly attuned to contribute to physiological processes involving changes in ECM and cell mobilization. Indeed, the list of biological processes affected by SPARC includes wound healing, tumor progression, bone formation, fibrosis, and angiogenesis. The process of angiogenesis is complex and involves a number of cellular processes such as endothelial cell proliferation, migration, ECM degradation, and synthesis, as well as pericyte recruitment to stabilize nascent vessels. In this review, we will summarize current results that explore the function of SPARC in the regulation of angiogenic events with a particular emphasis on the modulation of growth factor activity by SPARC in the context of blood vessel formation. The primary function of SPARC in angiogenesis remains unclear, as SPARC activity in some circumstances promotes angiogenesis and in others is more consistent with an anti-angiogenic activity. Undoubtedly, the mercurial nature of SPARC belies a redundancy of functional proteins in angiogenesis as well as cell-type-specific activities that alter signal transduction events in response to unique cellular milieus. Nonetheless, the investigation of cellular mechanisms that define functional activities of SPARC continue to contribute novel and exciting paradigms to vascular biology. PMID- 21822646 TI - [Prosthetic iris devices]. AB - Aniridia or iris deficiencies can severely affect visual function in mostly younger patients and should therefore be corrected. Currently various technical options for the treatment of iris deficiencies are available. The present review considers the main causes of aniridia and the incidence and summarizes the negative effects on visual function. A brief historical overview of the development of prosthetic iris devices is given. Currently available prosthetic iris devices, mainly iris diaphragm lenses and segmental prosthetic iris devices, are presented along with the specific advantages and disadvantages. The management of patients with iris deficiencies is often challenging due to the great heterogeneity and complexity of the underlying ocular problems. Thus an individual approach considering the often difficult pathological situation is mandatory. However, some universally valid recommendations for the implantation of prosthetic iris devices can be given. The literature from 2000 onward is reviewed and all articles on implantation of prosthetic iris devices are evaluated. The results are discussed and also summarized in a table. PMID- 21822647 TI - [Artificial iris]. AB - The flexible iris prosthesis according to Koch with a customized iris design serves for anterior segment reconstruction in patients with partial or complete aniridia. It is designed for implantation in the ciliary sulcus and is recommended only for pseudophakic or aphakic eyes. The multilayered implant consists of a core of a silicone matrix with incorporated color pigment coated with another layer of medical grade silicone. As a design variant the implant is available with or without an additionally embedded tissue layer. Without tissue the implant is more flexible, can be easily folded and perfectly adapts to the anatomical course of the sulcus. In contrast, implants with tissue show a greater rigidity and provide a better grip for sutures. This article describes various techniques for implantation of partial and full prostheses and gives instructions for calculating the implant size. Full prostheses can be combined with other reconstructive measures, such as sutured intraocular lenses and are particularly helpful in silicone oil surgery by avoiding endothelial contact. With careful consideration of the indications and application the flexible iris prosthesis is a valuable extension of the spectrum of reconstructive anterior segment surgery. PMID- 21822648 TI - [An outpatient education program for patients and partners after implantation of implantable cardioverter defibrillators (ICD)]. AB - BACKGROUND: The implantation of an implantable cardioverter defibrillator (ICD) is commonly followed by a physical and psychological process of adaptation to the new situation. Psychological support is often not provided and patients are left alone with questions and their needs. Because of the emerging sense of support group programs have proven to be apt for clearing up questions and addressing personal concerns. In the present study a psychoeducational program is presented and evaluated in detail. MATERIAL AND METHODS: A total of 308 patients with ICDs as well as their partners participated in a 2 day psychoeducational program. Of the patients 100 as well as their partners were asked to complete questionnaires concerning anxiety and depression (HADS) as well as their satisfaction with the program. The program consists of five modules: a warm up and getting to know each other; medical and technical information concerning the ICD, psychoeducation concerning the topics anxiety and avoidance, relaxation and an experience report of a patient who has had an ICD for many years. RESULTS: The evaluation results of 72 participants are present. All patients would definitively recommend participation in the program to other patients with an ICD without restrictions. The satisfaction with the five different modules of the intervention was very high. The depression as well as the anxious symptomatology in the HADS decreased significantly in the 1 year follow-up but did not exceed the cut-off point of 8. The anxiety and depression symptoms of the partners decreased significantly and exceeded the cut-off point of 8 in the follow-up. PMID- 21822649 TI - [Was that something?]. AB - My defi has now saved my life several times in the past. On the other hand it has also often given me a shock in situations which from a medical point of view were not absolutely necessary. In particular it is the coping with this shock which brings me to contradict the standard phrase"Don't be afraid you are protected by the defibrillator!". But I am afraid because my quality of life is substantially impaired not only by the high number of shocks suffered. Each new defi shock triggers in me a series of recurring reaction patterns. There is a tendency to observe by me that with every new shock the restoration of a rudimentary emotional equilibrium always takes longer. However, I want to be able to appear in public again without being accompanied every step of the way by the notion of collapsing in public or to twitch like an electric eel. I can't get used to the idea of an existence as a ticking time bomb. PMID- 21822650 TI - [Psychocardiological practice guidelines for ICD implantation and long-term care]. AB - In the literature there are only very few reports on systematic education or information for patients after implantation. Research in this field has only just begun so that there are no sufficiently evaluated models which could serve as the foundations for recommendations. Approximately 80% of affected patients, relatives and partners show a good cognitive acceptance and are capable of coping with the situation. However, in the first 12 months following ICD implantation some 20% of patients are in a state of anxiety and depression. These patients must be recognized and if necessary treated and given support. For this reason it is important in the consultation and routine appointments to give patients the chance to express their views on this if necessary. Only then can cardiologists recognize whether a patient is under substantial mental stress. It is recommended that immediately after the implantation and before being discharged from hospital, a screening procedure for anxiety and depression should be carried out using, e.g. the Hospital Anxiety and Depression Scale (HADS) and to distribute a questionnaire on desired information and unanswered questions. This would not only give a lead in for a targeted consultation during the follow-up appointment in the first year but also allow the opportunity to offer such patients an education course in order to specifically approach the problem being experienced. Patients who have experienced more than 5 shocks in 12 months or more than 3 shocks in 1 episode should attend a psychocardiological consultation in order to check whether there are post-traumatic disorders. It is imperative that these be treated because they do not in general resolve spontaneously. PMID- 21822651 TI - Osteolipoma: radiological, pathological, and cytogenetic analysis of three cases. AB - Osteolipoma is a rare variant of lipoma consisting of mature adipose tissue and mature lamellar bone. The presence of non-fatty elements may lead to a wide differential diagnosis on radiology including benign and malignant lipomatous and nonlipomatous entities. The pathological diagnosis is also confounded by the presence of heterologous differentiation. Fortunately, most lipomas harbor classic cytogenetic aberrations, and the finding of translocations involving 12q13-15 may aid in the correct diagnosis. We report three cases of osteolipoma with radiological, histological, and cytogenetic correlation. PMID- 21822652 TI - Osteogenesis imperfecta type V. PMID- 21822654 TI - A 33-year-old male with a strenuous occupation and gradual inability to lift, pull, and push heavy weights during working: diagnosis and discussion. PMID- 21822655 TI - No association between the SNPs (rs56134796; rs3824934; rs41302375) in the TRPC6 gene promoter and infantile hypertrophic pyloric stenosis in Chinese people. AB - PURPOSE: Our aim is to verify the association of three Single nucleotide polymorphisms (SNPs) (-218A/G, -254C/G, -361A/T) in the promoter of TRPC6 in 168 sporadic cases with infantile hypertrophic pyloric stenosis (IHPS) and 164 controls in Chinese people. METHODS: All participants were genotyped using polymerase chain reaction and direct sequencing. And the chi(2) value was calculated. A value of P less than 0.05 was considered statistically significant. We also got the P value of Hardy-Weinberg equilibrium test, and the value of P greater than 0.05 was assumed to be at Hardy-Weinberg equilibrium in this population. RESULTS: The results tell us that there are no significant differences in the allele and genotype frequencies of all these three SNPs between the case and the control groups (P > 0.05). CONCLUSION: These three TRPC6 SNPs have no association with the IHPS in Chinese people. However, we cannot deny that TRPC6 would be a susceptible gene with IHPS in Chinese people. May be other SNPs in TRPC6 would have some association with the IHPS in Chinese people. But in this study our results may be due to the fact that these SNPs are not the functional SNPs for the development of IHPS in Chinese people. PMID- 21822656 TI - Extended lower trapezius myocutaneous flap in burn scar reconstruction of the face and neck of children. AB - BACKGROUND: We aimed to present the use of extended lower trapezius myocutaneous flaps in children with scaring and contractures of the face and neck due to burns. METHODS: We retrospectively reviewed the use of 12 extended trapezius myocutaneous flaps in 7 males and 4 females ranging in age from 1.5 to 7 years. An expander was embedded under the deep layer of the lower trapezius in order to ensure the integrity of the vascular network between the lower trapezius muscle and the skin. Dissection was performed at the deep layer of the supraspinous muscle where the descending branch of the transverse cervical artery passes between the deep layer of the trapezius muscle and the superficial layer of the supraspinous muscle. RESULTS: All surgeries were performed successfully with no intraoperative complications. The flaps ranged in size from 30 * 18 cm to 38 * 22 cm. There were no postoperative complications, except for mild tip necrosis in one case. There were no donor site complications. All patients had good functional and cosmetic outcomes. CONCLUSIONS: The extended lower trapezius myocutaneous flap is valuable in the management of burn reconstruction in the pediatric population. PMID- 21822657 TI - Highly regioselective synthesis of 3'-O-acyl-trifluridines catalyzed by Pseudomonas cepacia lipase. AB - 3'-O-Acyl-trifluridines were prepared successfully through an enzymatic approach for the first time. Among the ten commercially available lipases tested, Pseudomonas cepacia lipase displayed the highest regioselectivity towards the acylation of 3'-hydroxyl of trifluridine. Furthermore, the effects of some crucial factors on the enzymatic myristoylation of trifluridine were examined. The optimal reaction medium, molar ratio of trifluridine to vinyl myristate and reaction temperature were found to be anhydrous THF, 1:7 and 50 degrees C, under which the reaction rate, substrate conversion, and 3'-regioselectivity were 63.9 mM/h, >99.0%, and 99%, respectively. Additionally, the enzyme recognition of the chain length of the acyl donors was investigated. The results showed that 3' regioselectivity of the enzyme maintained 99% with the increment of acyl chain length (C6, C10, and C14). The reason might derive from the strong hydrophobic interaction between 5-CF(3) group of the base moiety and Leu 287 located in the medium-sized pocket of the active site. PMID- 21822658 TI - Enzymatic synthesizing of phytosterol oleic esters. AB - A method of synthesizing the phytosterol esters from oleic acid and sterols was studied, using immobilized lipase Candida sp. 99-125 as catalyst. Molar ratio (oleic acid/phytosterols), temperature, reaction period, organic solvents, catalyst, and silica-gel drier were optimized, and the result showed that 93.4% of the sterols had been esterified under the optimal synthetic condition: the molar ratio of oleic acid/phytosterol is 1:1 in 10 mL iso-octane, immobilized lipase (w, 140% of the sterols), incubated in an orbital shaker (200 rpm) at a temperature of 45 degrees C for 24 h. The immobilized lipase could be reused for at least 13 times with limited loss of esterification activity. The conversion still maintained up to 86.6%. Hence, this developed process for synthesizing phytosterol esters could be considered as simple and low-energy consumption compared to existing chemical processes. PMID- 21822660 TI - Access to care and optimal treatment of chronic hepatitis B in Asian Americans: an evolving agenda. PMID- 21822659 TI - Impact of patient and disease characteristics on therapeutic success during adalimumab treatment of patients with rheumatoid arthritis: data from a German noninterventional observational study. AB - The objective of this study was to use data from a noninterventional study to evaluate the effectiveness of adalimumab in rheumatoid arthritis (RA) patients during routine clinical practice and to explore the potential impact of patient and disease characteristics in response to adalimumab therapy. A total of 2,625 RA patients with specified data at baseline (prior to initiating adalimumab treatment) and 12 months entered this study between April 2003 and March 2009. We evaluated response to adalimumab therapy and conducted stepwise regression and subgroup analyses of factors influencing therapeutic response. During the 1-year adalimumab treatment period, disease activity decreased from a baseline mean disease activity score-28 joints (DAS28) of 5.9-3.9, while functional capacity improved from 59.0 to 68.4 Funktionsfragebogen Hannover (FFbH) percentage points. In multivariate regression models, high baseline DAS28 was the strongest positive predictor for decrease in disease activity, and high baseline functional capacity was associated with reduced gains in functional capacity. Male gender was a positive predictor of therapeutic response for both disease activity and functional capacity, while older age and multiple previous biologics were associated with a reduced therapeutic response. Subset analyses provided further support for the impact of baseline DAS28, FFbH, and prior biologic therapy on therapeutic response during treatment. We conclude that treatment with adalimumab leads to decreased disease activity and improved function during routine clinical practice. Patients with high disease activity and low functional capacity are particularly benefitted by adalimumab therapy. PMID- 21822661 TI - Uneven distribution of ceramides, sphingomyelins and glycerophospholipids between heads and tails of rat spermatozoa. AB - Previous work showed that rat germ cells and spermatozoa contain ceramides and sphingomyelins with high proportions of nonhydroxy and 2-hydroxy (2-OH) polyunsaturated fatty acids (PUFA) with very long chains (VLCPUFA). The aim of this study was to assess how these lipids are distributed between the heads and tails of mature spermatozoa in comparison with other membrane lipid classes. In addition to quantitative differences due to the fact that these gametes have a long, voluminous tail and a minute head, several compositional dissimilarities emerged between these two regions. The total cholesterol/total phospholipid ratio, the choline/ethanolamine glycerophospholipid (ChoGpl/EtnGpl) ratio, and the proportion of plasmalogens within these two classes, were much larger in the head than in the tail. Whereas EtnGpl was rich in 22:5n-6 in both regions, ChoGpl had plenty of 22:4n-9, especially in the heads. An important proportion of the head EtnGpl- 22:5n-6 and ChoGpl 22:4n-9 was in plasmenyl- (rather than in phosphatidyl-) subclasses. The heads concentrated all of the sphingomyelin species with nonhydroxy- and 2-OH VLCPUFA, and the tails most of the saturated fatty acids that are present in total sperm sphingomyelin. Unexpectedly, virtually all of the abundant spermatozoal ceramides, predominantly made up by species with 2-OH VLCPUFA, was located in the tail. The fact that intact rat spermatozoa constitutively have much more VLCPUFA-containing ceramide than sphingomyelin is explained by the present findings, since the former are mostly lipids of the large tail while the latter mostly collect in the small head. PMID- 21822662 TI - MRI findings are more common in selected patients with acute low back pain than controls? AB - PURPOSE: The purpose of this study is to investigate if lumbar disc pathology identified on MRI scans is more common in patients with acute, likely discogenic, low back pain than matched controls. METHODS: We compared rates of MRI findings between 30 cases with low back pain and 30 pain-free controls. Cases were patients presenting for care with likely discogenic low back pain (demonstrated centralisation with repeated movement testing), of moderate intensity and with minimal past history of back pain. Controls were matched for age, gender and past history of back pain. Cases and controls underwent MRI scanning which was read for the presence of a range of MRI findings by two blinded assessors. RESULTS: The presence of disc degeneration, modic changes and disc herniation significantly altered the odds of a participant being a case or control. For example subjects were 5.2 times more likely to be a case than a control when disc degeneration grade of >=3 was present, and 6.0 times more likely with modic changes. The presence of a high-intensity zone or annular tear was found to significantly alter odds for one assessor but not the other assessor. CONCLUSION: MRI findings including disc degeneration, modic changes and herniation are more common in selected people with current acute (likely discogenic) low back pain than in controls without current low back pain. Further investigation of the value of MRI findings as prognostic factors and as treatment effect modifiers is required to assess the potential clinical importance of these findings. PMID- 21822663 TI - Paraplegia after posterior only correction of congenital kyphosis. PMID- 21822665 TI - The painful knee after TKA: a diagnostic algorithm for failure analysis. AB - Pain after total knee arthroplasty (TKA) represents a common observation in about 20% of the patients after surgery. Some of these painful knees require early revision surgery within 5 years. Obvious causes of failure might be identified with clinical examinations and standard radiographs only, whereas the unexplained painful TKA still remains a challenge for the surgeon. It is generally accepted that a clear understanding of the failure mechanism in each case is required prior considering revision surgery. A practical 10-step diagnostic algorithm is described for failure analysis in more detail. The evaluation of a painful TKA includes an extended history, analysis of the type of pain, psychological exploration, thorough clinical examination including spine, hip and ankle, laboratory tests, joint aspiration and test infiltration, radiographic analysis and special imaging techniques. It is also important to enquire about the length and type of conservative therapy. Using this diagnostic algorithm, a sufficient failure analysis is possible in almost all patients with painful TKA. PMID- 21822666 TI - Mechanical properties and in vivo performance of a novel sliding-lock bioabsorbable poly-p-dioxanone stent. AB - A bioabsorbable poly-p-dioxanone (PPDO) stent with a novel sliding-lock structure was fabricated to treat stenotic peripheral vessels. The sliding-lock PPDO stents have greater radial strength (107 kPa) than PPDO stents with conventional net tube structure (32 kPa). The sliding-lock PPDO stents were implanted into the iliac arteries of pigs, and implantation success rate was 90% indicating the feasibility of this design. Additionally, we found that sliding-lock PPDO stents kept vessels patent, although by 3 and 6 months post implantation, luminal diameter decreased slightly due to intimal hyperplasia. At 1 month post implantation, the stents were sparsely covered with endothelial cells, and by 6 months, the stents were mostly absorbed and inflammatory reaction gradually decreased as the stents were absorbed. This study shows favorable mechanical strength, degradability and efficacy for the sliding-lock PPDO stents, and supports further research and development of this unique design of polymer stents for applications in vascular devices. PMID- 21822667 TI - MTHFR 677TT genotype and toxicity of methotrexate: controversial results. PMID- 21822668 TI - Nucleoside transporters are widely expressed in ovarian carcinoma effusions. AB - OBJECTIVE: Equilibrative and concentrative nucleoside transporters (ENTs and CNTs) mediate the cellular uptake of anticancer nucleosides and sensitivity to such compounds. We studied the expression of ENTs and CNTs in ovarian carcinoma effusions. METHODS: ENT1, ENT2, ENT4 and CNT3 expression was analyzed in 66 ovarian carcinoma effusions (61 peritoneal, 5 pleural) from 64 ovarian carcinoma patients by flow cytometry. The majority of patients received platinum-based chemotherapy. Results were analyzed for association with clinicopathologic parameters and survival. RESULTS: With the exception of one ENT2-negative effusion, ENT1, ENT2, ENT4 and CNT3 protein was detected on carcinoma cells in all effusions, with expression observed in 1-95% of tumor cells. Nucleoside transporter expression was comparable between peritoneal and pleural effusions and was unrelated to age, tumor grade, International Federation of Gynecology and Obstetrics (FIGO) stage, residual tumor volume after surgery, previous exposure to chemotherapy and response to chemotherapy at diagnosis (P > 0.05). No correlation was found between ENT or CNT expression and overall survival or progression-free survival, although higher ENT2 expression was associated with a trend for longer overall (45 vs. 23 months; P = 0.055) and progression-free (17 vs. 5 months; P = 0.087) survival. CONCLUSION: Nucleoside transporters are frequently expressed in ovarian carcinoma effusions, but their expression generally appears to be unrelated to chemoresponse in this cancer in a cohort of patients treated by platinum-based chemotherapy. The role of ENT2 as a prognostic marker in this disease, as well as the role of these molecules in determining chemoresponse in patients treated by nucleoside analogs, merits further research. PMID- 21822669 TI - Dietary selenium (Se) and vitamin E (V(E)) supplementation modulated methylmercury-mediated changes in markers of cardiovascular diseases in rats. AB - Epidemiological studies demonstrated that human exposure to methylmercury (MeHg) may contribute to the development and progression of metabolic and cardiovascular disorders. However, the mechanisms involved and the role of selenium (Se) and vitamin E (V(E)) supplementation in modulating MeHg cardiovascular toxicities remain unclear. This study examined the effects of Se and V(E) supplementation on MeHg-mediated systemic oxidative stress, antioxidant defense, inflammation, and endothelial dysfunction in an animal model. Male Sprague-Dawley rats were fed a starch-based casein diet or the same diet supplemented with 1 or 3 mg Se/kg diet and with or without 250 or 750 mg V(E)/kg diet. After 28 days of dietary treatment, rats were gavaged with 0 or 3 mg MeHg/kg BW for 14 consecutive days. Results suggested that exposure to MeHg may increase the risk of cardiovascular disease by decreasing circulating paraoxonase-1 activities, increasing serum oxidized low density lipoprotein levels, and associated systemic inflammation and endothelial dysfunction as reflected by increased leukocyte counts and serum levels of intercellular adhesion molecule-1 and monocyte chemotactic protein-1. Se and V(E) supplementation may either alleviate or augment the effects of MeHg, depending on their doses and combinations. PMID- 21822670 TI - The hOGG1 gene 5'-UTR variant c.-53G>C contributes to the risk of gastric cancer but not colorectal cancer in the Chinese population: the functional variation of hOGG1 for gastric cancer risk. AB - PURPOSE: The incidence and mortality of gastric and colorectal cancers are among the highest malignant tumors in China. The aim of this study is to investigate whether variations of the human oxoguanine glycosylase 1 (hOGG1) gene are related to the risk of gastric and colorectal cancers in the Chinese population. METHODS: There were 622 gastric cancer patients, 383 colorectal cancer patients, and 932 healthy controls recruited to screen for variations in the 5'untranslated region (UTR) and to screen for the missense mutation (p.Ser326Cys) in exon7 of the hOGG1 gene using high-resolution melting curve analysis (HRM) and subsequent sequencing. The promoter luciferase activity assay was applied to assess the potential influence of the detected variants on gene function. RESULTS: Four variations, c.-53G>C, c.-45G>A, c.-23A>G, and c.-18G>T, were detected in the 5' UTR of the hOGG1 gene. The case-control study indicated that the c.-53G/C heterozygous genotype was markedly associated with gastric cancer (P = 0.008, OR = 2.304, 95% CI, 1.258-4.221), but not with colorectal cancer. The clinicopathological association analysis showed that the variant of c.-53G>C in the hOGG1 gene was prevalent in low-differentiation patients (P = 0.012, OR = 3.174, 95% CI: 1.352-7.448). This variant decreased the gene promoter activity by approximately 17.8% (P = 0.041) and exhibited a synergistic effect with the missense mutation p.Ser326Cys of hOGG1 by enhancing susceptibility to gastric cancers. CONCLUSIONS: The variant c.-53G>C in the 5'-UTR of the hOGG1 gene is a risk factor for gastric cancer and is potentially associated with low differentiation degree, but not with colorectal cancer, in the Chinese population. PMID- 21822671 TI - Genetic detection and analysis of porcine bocavirus type 1 (PoBoV1) in European wild boar (Sus scrofa). AB - Novel porcine parvoviruses showing the genetic characteristics of bocaviruses have recently been identified. The first such porcine bocavirus (PoBoV1), described as boca-like virus (PBo-likeV), was discovered in PMWS affected pigs in Sweden. Later, several other bocaviruses with divergent genomes were reported under various names in domestic pigs. This is the first report of the presence of bocaviruses in European wild boars. 842 wild boar samples originating from the Western region of Romania (Transylvania) were collected during the 2006/2007 and the 2010/2011 hunting seasons and tested for the presence of PoBoV1 by polymerase chain reaction and sequencing. The results showed 12.94% (109/842) overall positivity, with an increasing prevalence from the 2006/2007 (9.14%, 43/470) to the 2010/2011 (17.74%, 66/372) season (P < 0.01). Differences between the prevalence of the virus in 6-12-month-old-animal (77.06%, 84/109) and 12-36-month old-animal (22.94%, 25/109) (P < 0.01) indicated that the infection occurred mainly in younger pigs. Comparative sequence analysis of partial VP1/2 genes from wild boars and those available in the GenBank showed only minor differences, indicating that PoBoV1 circulating within the wild boar populations and domestic pigs from different geographic regions were highly similar. PMID- 21822672 TI - Strategy for a generic resistance to geminiviruses infecting tomato and papaya through in silico siRNA search. AB - Use of siRNA is a powerful methodology to particularly knockdown the targeted genes in a sequence specific manner. The potential of siRNA can be harnessed for silencing specific geminiviral genes in papaya and tomato plant hosts, thus making them resistant to the respective viruses. The challenge is in designing exogenous siRNA which can trigger silencing of viral genes irrespective of the genetic variability in different viral isolates and at the same time the selected siRNA does not target any plant gene (off target silencing). In this study, we have designed siRNA from the most conserved regions of viral coat protein (AV1) and replicase (AC1) genes retrieved from different isolates of geminiviruses infecting papaya (PLCV), and tomato (TLCV & TLCV, Northern India), so as to give a broad spectrum resistance and efficient silencing as it is highly homology dependent strategy. Software siRNA finder (Ambion) was used on the selected conserved sequences in order to select only those putative siRNA oligonucleotides which fulfill all the basic criteria required as per the algorithm. Finally, a cross search using BLAST was performed to confirm that the designed siRNAs do not have any homology to plant genome sequences. The putative siRNA sequences thus designed to target essential genes of geminiviruses and introduced into the plants may facilitate developing papaya and tomato crops with generic resistance to geminiviruses. PMID- 21822673 TI - Coordination of lapachol to bismuth(III) improves its anti-inflammatory and anti angiogenic activities. AB - Complex [Bi(Lp)(2)]Cl was obtained with 4-hydroxy-3-(3-methylbut-2 enyl)naphthalene-1,2-dione, "lapachol" (HLp). Lapachol, [Bi(Lp)(2)]Cl and BiCl(3) were evaluated in a murine model of inflammatory angiogenesis induced by subcutaneous implantation of polyether polyurethane sponge discs. Intraperitoneal (i.p.) administration of lapachol or [Bi(Lp)(2)]Cl reduced the hemoglobin content in the implants suggesting that reduction of neo-vascularization was caused by lapachol. In the per os treatment only [Bi(Lp)(2)]Cl decreased the hemoglobin content in the implants. Likewise, N-acetylglucosaminidase (NAG) activity decreased in the implants of the groups i.p. treated with lapachol and [Bi(Lp)(2)]Cl while in the per os treatment inhibition was observed only for [Bi(Lp)(2)]Cl. Histological analysis showed that the components of the fibro vascular tissue (vascularization and inflammatory cell population) were decreased in lapachol- and complex-treated groups. Our results suggest that both lapachol and [Bi(Lp)(2)]Cl exhibit anti-angiogenic and anti-inflammatory activities which have been attributed to the presence of the lapachol ligand. However, coordination to bismuth(III) could be an interesting strategy for improvement of lapachol's therapeutic properties. PMID- 21822674 TI - Task relevance predicts gaze in videos of real moving scenes. AB - Low-level stimulus salience and task relevance together determine the human fixation priority assigned to scene locations (Fecteau and Munoz in Trends Cogn Sci 10(8):382-390, 2006). However, surprisingly little is known about the contribution of task relevance to eye movements during real-world visual search where stimuli are in constant motion and where the 'target' for the visual search is abstract and semantic in nature. Here, we investigate this issue when participants continuously search an array of four closed-circuit television (CCTV) screens for suspicious events. We recorded eye movements whilst participants watched real CCTV footage and moved a joystick to continuously indicate perceived suspiciousness. We find that when multiple areas of a display compete for attention, gaze is allocated according to relative levels of reported suspiciousness. Furthermore, this measure of task relevance accounted for twice the amount of variance in gaze likelihood as the amount of low-level visual changes over time in the video stimuli. PMID- 21822675 TI - Directional binary wavelet patterns for biomedical image indexing and retrieval. AB - A new algorithm for medical image retrieval is presented in the paper. An 8-bit grayscale image is divided into eight binary bit-planes, and then binary wavelet transform (BWT) which is similar to the lifting scheme in real wavelet transform (RWT) is performed on each bitplane to extract the multi-resolution binary images. The local binary pattern (LBP) features are extracted from the resultant BWT sub-bands. Three experiments have been carried out for proving the effectiveness of the proposed algorithm. Out of which two are meant for medical image retrieval and one for face retrieval. It is further mentioned that the database considered for three experiments are OASIS magnetic resonance imaging (MRI) database, NEMA computer tomography (CT) database and PolyU-NIRFD face database. The results after investigation shows a significant improvement in terms of their evaluation measures as compared to LBP and LBP with Gabor transform. PMID- 21822676 TI - [Correlation of cervical cytology and histology]. AB - A lack of correlation of cytological diagnoses with subsequent histological tissue diagnoses in cervical pathology is caused by either sampling or by interpretation errors. The term sampling error refers to both obtaining cytological material by a cervical smear as well as obtaining tissue samples by surgical procedures such as biopsy or conization. The term interpretation error refers to a lack of correlation as a consequence of the subjective variability in the diagnostic evaluation of cytological, histological or colposcopic findings. This so-called interobserver variability is well known and of considerable significance. Cytological-histological correlation is an important and mandatory method of quality assurance in the cytology laboratory. Lack of correlation can be crucial for the patient because of possible over treatment or under treatment. It can also undermine the relationship between cytopathologists and clinicians. It is therefore crucial to recognize the sources of error presented in this review and to make an effort to resolve discordances by communication and second review. PMID- 21822677 TI - When is it necessary to perform nuclear renogram in patients with a unilateral neonatal hydronephrosis? AB - PURPOSE: To examine whether anteroposterior(AP) pelvic diameter on postnatal renal ultrasound scan (US) can predict both initial differential renal function (DRF) and deterioration in DRF in patients with prenatally diagnosed hydronephrosis. METHODS: One hundred and thirty-three patients diagnosed with a unilateral prenatal hydronephrosis, confirmed postnatally, were evaluated. We tried to find the cutoff values for initial AP diameter and change in AP diameter based on initial DRF and renal outcome. Reduction of 5% or more was considered as deterioration in function. All patients had an initial US scan at a mean age of 1.62 weeks (1-4) and nuclear renogram at 13.24 weeks (7-21). All patients had a second US at a mean age of 10.58 weeks (6-19). 119 patients had a second renogram. RESULTS: Initial mean pelvic diameter was 20.86 (11-49) mm. When AP pelvic diameter was less than 20 mm, 98.6% of all renal units had a function of >=40%. The cutoff point for AP pelvic diameter was 19.05 when DRF was >=45% (P < 0.001). When the reduction in hydronephrosis in pelvic diameter was analyzed to predict the initial renal function, a cutoff point of 1.3 mm decrease was found when initial renal function was >=40% (P < 0.001). The reduction in AP pelvic diameter was 2.1 mm when initial DRF was >=45% (P = 0.009). For all patients except 3 individuals, if there was a reduction in AP diameter or the AP diameter was stable, then no reduction in function was observed. CONCLUSION: When the AP pelvic diameter is less than 20 mm at presentation, DRF is normal. If the AP diameter is stable or decreases, there is unlikely to be a significant deterioration in renal function. Consequently, in selected patients, congenital unilateral hydronephrosis can be followed with serial ultrasounds. PMID- 21822678 TI - Effect of daily mixed nutritional supplementation on immune indices in soldiers undertaking an 8-week arduous training programme. AB - The aim was to investigate the influence of a daily mixed nutritional supplement during an 8-week arduous training programme on immune indices and mediators including circulating leucocyte counts; bacterially stimulated neutrophil degranulation; interleukin-6 (IL-6), cortisol and saliva secretory immunoglobulin A (SIgA). Thirty men (mean (SD): age 25 (3) years; body mass, 80.9 (7.7) kg) received a habitual diet (CON, n = 15) or received a habitual diet plus an additional food supplement (SUP, n = 15). From weeks 0-6, CON received 14.0 MJ day(-1) and SUP received 19.7 MJ day(-1), and during a final 2-week field exercise in weeks 7 and 8, CON received 17.7 MJ day(-1) and SUP received 21.3 MJ day(-1). Blood and saliva were taken at rest after an overnight fast at weeks 0, 6 and 8. Body mass loss over the 8 weeks was greater in CON (CON, 5.0 (2.3); SUP, 1.6 (1.5) kg: P < 0.001). Training-induced decreases in circulating total leucocytes (CON: weeks 0, 8.0 (2.1); weeks 8, 6.5 (1.6) 10(9) l(-1), P < 0.01), lymphocytes (21%, P < 0.01) and monocytes (20%, P < 0.01) were prevented by the nutritional supplement. Saliva SIgA secretion rate increased approximately twofold by week 8 in SUP (P < 0.01) and was greater at week 8 compared with CON (P < 0.01). Circulating neutrophils, bacterially stimulated neutrophil degranulation, IL-6 and cortisol were similar in CON and SUP at week 8. In conclusion, a daily mixed nutritional supplement prevented the decrease in circulating total leucocytes, lymphocytes and monocytes and increased saliva SIgA output during an 8-week arduous training programme. The increase in saliva SIgA with nutritional supplementation during training may reduce susceptibility to upper respiratory infection. PMID- 21822679 TI - Mycorrhizal networks affect ectomycorrhizal fungal community similarity between conspecific trees and seedlings. AB - Ectomycorrhizal (EM) networks (MN) are thought to be an important mode of EM fungal colonization of coniferous seedlings. How MNs affect EM communities on seedlings, and how this varies with biotic and abiotic factors, is integral to understanding their importance in seedling establishment. We examined EM fungal community similarity between mature trees and conspecific interior Douglas-fir (Pseudotsuga menziesii var. glauca) seedlings in two experiments where seed and nursery-grown seedlings originating from different locations were planted at various distances from trees along a climatic gradient. At harvest, trees shared 60% of their fungal taxa in common with outplanted seedlings and 77% with germinants, indicating potential for seedlings to join the network of residual trees. In both experiments, community similarity between trees and seedlings increased with drought. However, community similarity was lower among nursery seedlings growing at 2.5 m from trees when they were able to form an MN, suggesting MNs reduced seedling EM fungal richness. For field germinants, MNs resulted in lower community similarity in the driest climates. Distance from trees affected community similarity of nursery seedlings to trees, but there was no interaction of provenance with MNs in their effect on similarity in either nursery seedlings or field germinants as hypothesized. We conclude that MNs of trees influence EM colonization patterns of seedlings, and the strength of these effects increases with climatic drought. PMID- 21822680 TI - Liver response of rabbits to Eimeria coecicola infections. AB - Intestinal coccidiosis of rabbits induced by E. coecicola causes enormous economic losses in rabbit farms. Here, we investigate the effect of E. coecicola on the liver of the rabbit Oryctolagus cuniculus. On day 7 p.i., fecal expulsion of E. coecicola oocysts is maximal and rabbits have lost approximately 25% of their weight. The liver, though not targeted by parasites, exhibits several signs of moderate inflammations, i.e., inflammatory cellular infiltrations around the central vein, dilatated blood sinusoids, increase in vacuolated hepatocytes, hypertrophic Kupffer cells, and lipid peroxidation as well as decreases in catalase and superoxide dismutase activities. Liver injuries are also indicated by an increase in blood plasma, by an increase in liver enzymes such as alanine transaminase, aspartate transaminase, alkaline phosphatase, and gamma glutamyl transferase, and a decrease in total protein and albumin. Circulating neutrophils have increased from 61% on day 0 p.i. to 71.3% on day 7 p.i., while lymphocytes are decreased from 37% to 26%. Agilent two-color oligo microarray technology, in combination with quantitative PCR, reveals that the expressions of 56 genes are upregulated and that of 22 genes are downregulated in the liver. The genes are largely involved in metabolism, calcium homeostasis, transport, and diverse signaling processes in the liver. In addition, numerous genes encoding for different regions of T-cell receptor as well as IgM, IgG, and IgA antibodies are both up- and downregulated in the liver by E. coecicola infections. The latter data suggest that the liver is not only 'passively' inflamed by intestinal infections with E. coecicola but rather is actively involved in the host defense against the intestinal Eimeria parasites. PMID- 21822681 TI - Effects of clonal variation on growth, metabolism, and productivity in response to trophic factor stimulation: a study of Chinese hamster ovary cells producing a recombinant monoclonal antibody. AB - The growth, metabolism, and productivity of five Chinese hamster ovary (CHO) clones were explored in response to stimulation with insulin (5 mg/L) and LONG((r))R(3)IGF-I (20 MUg/L or 100 MUg/L). All five clones were derived from the same parental CHO cell line (DG44) and produced the same recombinant monoclonal antibody, with varying specific productivities. There was no uniform response among the clones to stimulation with the different trophic factors. One of the high productivity clones (clone D) exhibited significantly better growth in response to LONG((r))R(3)IGF-I; whereas the other clones showed equivalent or slightly better growth in the presence of insulin. Three out of the five clones had higher specific productivities in the presence of insulin (although not statistically significant); one was invariant, and the final clone exhibited slightly higher specific productivity in the presence of LONG((r))R(3)IGF-I. Total product titers exhibited moderate variation between culture conditions, again with neither trophic factor being clearly superior. Overall product titers were affected by variations in both integrated viable cell density and specific productivity. Nutrient uptake and metabolite generation patterns varied strongly between clones and much less with culture conditions. These results point to the need for careful clonal analysis when selecting clones, particularly for platform processes where media and culture conditions are predetermined. PMID- 21822682 TI - A fully autologous co-culture system utilising non-irradiated autologous fibroblasts to support the expansion of human keratinocytes for clinical use. AB - Autologous keratinocytes can be used to augment cutaneous repair, such as in the treatment of severe burns and recalcitrant ulcers. Such cells can be delivered to the wound bed either as a confluent sheet of cells or in single-cell suspension. The standard method for expanding primary human keratinocytes in culture uses lethally irradiated mouse 3T3 fibroblasts as feeder cells to support keratinocyte attachment and growth. In an effort to eliminate xenobiotic cells from clinical culture protocols where keratinocytes are applied to patients, we investigated whether human autologous primary fibroblasts could be used to expand keratinocytes in culture. At a defined ratio of a 6:1 excess of keratinocytes to fibroblasts, this co-culture method displayed a population doubling rate comparable to culture with lethally irradiated 3T3 cells. Furthermore, morphological and molecular analysis showed that human keratinocytes expanded in co-culture with autologous human fibroblasts were positive for proliferation markers and negative for differentiation markers. Keratinocytes expanded by this method thus retain their proliferative phenotype, an important feature in enhancing rapid wound closure. We suggest that this novel co-culture method is therefore suitable for clinical use as it dispenses with the need for lethally irradiated 3T3 cells in the rapid expansion of autologous human keratinocytes. PMID- 21822683 TI - Apoptotic effects of hydrogen peroxide and vitamin C on chicken embryonic fibroblasts: redox state and programmed cell death. AB - The pro-apoptotic effects of hydrogen peroxide and the purported anti-apoptotic effects of Vitamin C on chicken embryonic fibroblasts were investigated. Hydrogen peroxide induced morphological changes in a dose dependent manner, and a myriad of autophagosomes were observed using transmission electron microscopy. Doxorubicin elicited alterations were not inhibited by co-incubation with Vitamin C except that mitochondrial structure was slightly improved. TUNEL assay, cytotoxicity analysis and flow cytometry revealed that the cytotoxicity, DNA fragmentation and apoptotic rates were dose dependent upon treatment with hydrogen peroxide. Calcium homeostasis was disrupted in a dose dependent manner, and cell cycle was blocked at G(2)/M checkpoint at low concentration and S/G(2) checkpoint at high concentration respectively upon treatment with hydrogen peroxide. The administration of Vitamin C only has a modest effect against doxorubicin induced apoptosis, calcium homeostasis disruption and cell cycle arrest. This research demonstrated that the elevation of reactive oxygen species is sufficient to induce the apoptosis of chicken embryonic fibroblasts, whereas the administration of Vitamin C does not necessarily have certain anti-apoptotic effects, especially when the stimulus is not directly linked with redox state. PMID- 21822684 TI - Investigation of the force associated with the formation of lacerations and skull fractures. AB - Post-mortem examination is often relied upon in order to determine whether a suspicious death was natural, accidental, suicidal or homicidal. However, in many cases the mechanism by which a single injury has been inflicted cannot be determined with certainty based on pathological examination alone. Furthermore the current method of assessing applied force relating to injury is restricted to an arbitrary and subjective scale (mild, moderate, considerable, or severe). This study investigates the pathophysiological nature of head injuries caused by blunt force trauma, specifically in relation to the incidence and formation of a laceration. An experimental model was devised to assess the force required to cause damage to the scalp and underlying skull of porcine specimens following a single fronto-parietal impact. This was achieved using a drop tower equipped with adapted instrumentation for data acquisition. The applied force and implement used could be correlated with resultant injuries and as such aid pathological investigation in the differentiation between falls and blows. Experimentation revealed prevalent patterns of injury specific to the reconstructed mechanism involved. It was found that the minimum force for the occurrence of a laceration was 4,000 N. PMID- 21822685 TI - Genetic variants of fibroblast growth factor receptor 2 (FGFR2) are associated with breast cancer risk in Chinese women of the Han nationality. AB - Fibroblast growth factor receptor 2 (FGFR2), a recently described risk factor for breast cancer, plays important roles in cell growth, invasiveness, motility, and angiogenesis. In attempt to investigate whether FGFR2 polymorphisms are associated with a risk of breast cancer in Chinese women of the Han nationality, we genotyped single-nucleotide polymorphisms (SNPs) of seven FGFR2 sites (rs2981582, rs17102287, rs17542768, rs10510097, rs11200012, rs3750817, rs2981578) in 816 women including 388 breast cancer patients and 428 healthy controls via the polymerase chain reaction single-strand conformation polymorphism procedure as well as sequence detection. Our results suggest that the A allele and AA genotype of SNP rs2981578 appear to be protective factors associated with breast cancer, while the CT genotype of SNP rs3750817 is a putative risk factor. PMID- 21822686 TI - Bi-linear dose--response relationship in general populations with low-level cadmium exposures in non-polluted areas in Japan. AB - BACKGROUND AND OBJECTIVES: Previous findings suggest that the dose (e.g., cadmium in urine)-response (e.g., tubular dysfunction markers in urine) relationship after environmental exposure to cadmium (Cd) may be in a shape of a hockey stick with a steep slope when Cd exposure exceeds a certain level, i.e., the point of flexion. However, less attention has been paid to the relation below the flexion point whether it is linear or not. The present study was initiated to examine through epidemiological analyses whether the assumption of linearity holds true when Cd exposure is low. METHODS: Data were cited from previous publications of this research group on Cd, alpha(1)-microglobulin (alpha(1)-MG), beta(2) microglobulin (beta(2)-MG), N-acetyl-beta-D: -glucosaminidase (NAG), and creatinine (CR) in urine from more than 17,000 adult Japanese women. The cases were selected for age (50-59 years), urine specific gravity (1.010-1.030) and CR (0.3-3.0 g/l), and 5,306 cases were available after selection (the group selected in terms of age and urine density, or the AD-selected group). RESULTS: Statistical analyses of the AD-selected group revealed that the relation was not linear. In case of beta(2)-MG, the slope of the regression line between Cd as an independent variable and beta(2)-MG a dependent variable was steeper at lower Cd level (i.e., <2.5 MUg/l) and shallower when Cd was higher, showing a clear trend of leveling off. The same was also the case for alpha(1)-MG and NAG. When Cd was 2.0-2.1 MUg/l or higher, alpha(1)-MG, beta(2)-MG, and NAG were in excess of the 95%-tile values for the markers in more than 5% of the population. The significance of the observation was discussed in reference to existing criteria for Cd such as 2.5 or 5.2 MUg/g cr or for beta(2)-MG of 300 MUg/g cr. CONCLUSIONS: When the present observation of bilinear relation at low Cd exposure levels was combined with the previous observation of very sharp increase in responses among heavily exposed cases, it appeared likely that the overall relationship is tri-phasic in Cd dose-response relationship in humans. A substantial fraction (>5%) of the populations had the marker levels in excess of the 95%-tile values when Cd was >=2 MUg/l. Comparison with findings in reported literature suggests that the presence of such cases by itself may not necessarily mean a risk of tubular dysfunction and that other factors including Cd levels in urine should be considered together. PMID- 21822687 TI - Evaluation of bone markers in hypophosphatemic rickets/osteomalacia. AB - N-terminal propeptide of type I procollagen (PINP) is a marker of newly formed type I collagen. However, its role in hypophosphatemic rickets/osteomalacia has not yet been established. Metabolic bone markers were examined in patients with oncogenic osteomalacia (OOM) and X-linked hypophosphatemic rickets (XLH), and in healthy controls. OOM and XLH patients were found to have hypophosphatemia secondary to elevated levels of serum fibroblast growth factor 23 (FGF-23). OOM patients had reduced levels of 1,25-dihydroxy vitamin D (1,25D) compared with XLH patients and healthy controls, despite attenuation of the reduction in these levels in the XLH patients secondary to active vitamin D supplementation. In contrast to patients with XLH, OOM patients showed a significant increase in serum PINP, which is suggestive of accelerated bone matrix formation. Bone alkaline phosphatase (BAP) and the BAP/PINP ratio were also increased in OOM but not in XLH patients, suggesting the presence of a disturbance in bone mineralization in OOM. Long-term supplementation of active form vitamin D and inorganic phosphate (IP) may have attenuated the defect in bone mineralization in the XLH patients, resulting in the normalization of PINP, BAP, and the BAP/PINP ratio. The present results suggest that, as with BAP, PINP is an appropriate metabolic bone marker in the assessment of hypophosphatemic rickets/osteomalacia. PMID- 21822688 TI - Strain-dependent effects of acute, chronic, and withdrawal from chronic nicotine on fear conditioning. AB - The effects of nicotine on cognitive processes such as learning and memory may play an important role in the addictive liability of tobacco. However, it remains unknown whether genetic variability modulates the effects of nicotine on learning and memory. The present study characterized the effects of acute, chronic, and withdrawal from chronic nicotine administration on fear conditioning, somatic signs, and the elevated plus maze in 8 strains of inbred mice. Strain-dependent effects of acute nicotine and nicotine withdrawal on contextual fear conditioning, somatic signs, and the elevated plus maze were observed, but no association between the effects of acute nicotine and nicotine withdrawal on contextual fear conditioning were observed, suggesting that different genetic substrates may mediate these effects. The identification of genetic factors that may alter the effects of nicotine on cognition may lead to more efficacious treatments for nicotine addiction. PMID- 21822689 TI - Comparative proteomic and radiobiological analyses in human lung adenocarcinoma cells. AB - In clinic, many non-small cell lung cancer (NSCLC) patients receive radiation therapy after chemotherapy failure. However, whether the multidrug resistance (MDR) can elevate the radioresistance (RDR) remains unclear. To evaluate the MDR's effect on the RDR, screen MDR- and RDR-related proteins in human lung adenocarcinoma (HLA) cells and tissues A549, and A549/DDP cells after irradiation were analyzed by colony-forming assay and flow cytometry. Two-dimensional electrophoresis (2-DE) and matrix-assisted laser desorption/ionization time-of flight mass spectrometry (MALDI-TOF-MS) were utilized to identify differentially expressed proteins (DEPs) between them. The value of D0, Dq, and SF2 increased, the mean percentage in G2 phase and apoptosis rate significantly decreased in A549/DDP cells compared with A549 cells. 40 DEP points were found, and among them 27 were identified through proteomics. Four up-regulated proteins (HSPB1, Vimentin, Cofilin-1, and Annexin A4) in MDR cells compared with non-MDR cells, were confirmed by Western blot. Immuno-histochemistry showed that they were also over-expressed in MDR tissues compared with non-MDR counterparts of HLA. These results proved that the MDR in HLA cells and tissues increased the RDR. HSPB1, Vimentin, Cofilin-1, and Annexin A4 are potential biomarkers for predicting HLA response to MDR and RDR, and novel treatment targets of HLA. PMID- 21822690 TI - Role of JNK-1 regulation in the protection of contact-inhibited fibroblasts from oxidative stress. AB - The molecular signaling events leading to protection from oxidative stress induced apoptosis upon contact inhibition have not been fully investigated. Previous research has indicated a role for mitogen-activated protein kinases (MAPKs) in the regulation of contact inhibition, and these proteins have also been associated with cell cycle regulation and stress-induced apoptosis. The potential role of the MAPK JNK-1 in the stress-response of actively proliferating and contact-inhibited cells was investigated. Actively proliferating normal fibroblasts (BJ) and fibrosarcoma cells (HT-1080) were stressed with H2O2, and levels of activated JNK-1 and cleaved PARP were ascertained. Similarly, these results were compared with levels of activated JNK-1 and cleaved PARP detected in H2O2-stressed confluent fibrosarcoma or contact-inhibited fibroblast cells. Contact-inhibited fibroblasts were protected from apoptosis in comparison to subconfluent fibroblasts, concurrent with decreased JNK-1 activation. Increased culture density of fibrosarcoma cells was not protective against apoptosis, and these cells did not demonstrate density-dependent alterations in the JNK-1 stress response. This decreased activation of JNK-1 in stressed, contact-inhibited cells did not appear to be dependent upon increased expression of MKP-1; however, over expression of MKP-1 was sufficient to result in a slight decrease in H2O2 stimulated PARP cleavage. Increasing the antioxidant capacity of fibroblasts through NAC-treatment not only lessened H2O2-stimulated JNK-1 activation, but also did not influence the expression of MKP-1. Taken together, these results suggest that regulation of negative regulation of JNK-1 upon contact inhibition is protective against apoptosis, and that this regulation is independent of MKP 1. PMID- 21822691 TI - Inherited and somatic mitochondrial DNA mutations in Guam amyotrophic lateral sclerosis and parkinsonism-dementia. AB - There is increasing evidence for mitochondrial dysfunction in neurodegenerative disorders, although the exact role of mitochondrial DNA (mtDNA) mutations in this process is unresolved. We investigated inherited and somatic mtDNA substitutions and deletions in Guam amyotrophic lateral sclerosis (ALS) and parkinsonism dementia (PD). Hypervariable segment 1 sequences of Chamorro mtDNA revealed that the odds ratio of a PD or ALS diagnosis was increased for individuals in the E1 haplogroup while individuals in the E2 haplogroup had decreased odds of an ALS or PD diagnosis. Once the disorders were examined separately, it became evident that PD was responsible for these results. When the entire mitochondrial genome was sequenced for a subset of individuals, the nonsynonymous mutation at nucleotide position 9080, shared by all E2 individuals, resulted in a significantly low odds ratio for a diagnosis of ALS or PD. Private polymorphisms found in transfer and ribosomal RNA regions were found only in ALS and PD patients in the E1 haplogroup. Somatic mtDNA deletions in the entire mtDNA genome were not associated with either ALS or PD. We conclude that mtDNA haplogroup effects may result in mitochondrial dysfunction in Guam PD and reflect Guam population history. Thus it is reasonable to consider Guam ALS and PD as complex disorders with both environmental prerequisites and small genetic effects. PMID- 21822692 TI - Marburg's disease: a diagnostic dilemma. AB - This report describes the clinical, radiological and autopsy findings of a young male suffering from acute, monophasic demyelinating disease presenting with acute onset of altered sensorium and a short past history of progressive multiple neurological deficits. The radiological findings revealed acute infarcts in the territory of anterior cerebral artery. The antemortem diagnosis centred on an infective (tubercular) aetiology leading to demyelination based on presence of tubercle bacilli in bronchoalveolar lavage (BAL) fluid. The autopsy revealed multiple subacute and acute plaques showing demyelination, giant astrocytes, numerous macrophages and little perivascular inflammation, thereby confirming the diagnosis of Marburg's type of multiple sclerosis. Marburg's type is a fulminant demyelinating disorder characterised by a severe, rapidly evolving clinical course. Death occurs due to brain stem involvement or severe widespread cerebral lesions. PMID- 21822693 TI - Hypothalamic dysfunction in a patient with primary lymphoma of the central nervous system. AB - A 60-year-old woman with no previous history of chronic disease or malignancy presented with intense back and left leg pain and sleep disturbances. The patient had been treated unsuccessfully for the past 6 months with analgetics. Magnetic resonance imaging showed a soft tissue tumor in the L5-S1 region that involved the spinal canal, and a pathohistological analysis of the tumor specimen confirmed the presence of non-Hodgkin, diffuse large B cell lymphoma. After the diagnosis was confirmed, malaise, nausea, and vomiting developed. Multislice computed tomography of the endocranium showed focal infiltration of the hypothalamus and lateral ventricle; dissemination of a systemic lymphoma was excluded. Therapy was initiated as per the De Angelis protocol. After intravenous and intrathecal administration of metotrexate, the patient developed signs of central diabetes insipidus, which responded to therapy with an antidiuretic hormone analog. Despite the obvious infiltration of the hypothalamus, we cannot exclude an idiosyncratic effect of methotrexate on the central diabetes insipidus. PMID- 21822694 TI - POEMS syndrome with a giant pancreas cyst. PMID- 21822695 TI - CSF hydrothorax after ventriculoperitoneal shunt without catheter migration: a case report. AB - Ventriculoperitoneal (VP) shunting is the most common procedure performed for the management of hydrocephalus. VP shunt related complications remain a persistent problem in current clinical practice. Five-year-old female patient was admitted to our hospital with persistent dyspnea complaint. The patient was operated at the age of 3 months and a VP shunt established in a different clinic due to hydrocephalus associated with Dandy-Walker malformation. The patient's chest X ray revealed right sided pleural effusion. Thorasentesis was performed and the effusion was drained with a chest tube. The discharged liquid was consistent with CSF. Scintigraphic radionuclide shunt analyses were performed and CSF passage from abdomen to chest and lower mediastinal region was determined in the late static images. The patient was operated and the incorporated ventriculoperitoneal shunt was removed. Hydrothorax was completely resolved after early postoperative stage. CSF hydrothorax especially without catheter migration is an unusual but potentially serious-clinical complication. PMID- 21822696 TI - Diagnostic difficulties with central nervous system actinomycosis. AB - When faced with expanding brain lesions of unknown origin showing a ring-shaped enhancement on post-contrast imaging, we use definite criteria to direct further investigation and distinguish among a number of possible diagnostic hypotheses. However, a correct diagnosis may be difficult in some cases, especially when dealing with less frequent conditions. This is the case of actinomycosis, a highly treatable but insidious infection for which nowadays there may be a low level of attention. Brain localization is associated with a significant morbidity and may represent a true diagnostic pitfall. Here we report the difficulties encountered with a case of central nervous system actinomycosis. PMID- 21822698 TI - Delayed subdural hematoma and cerebral venous thrombosis in a patient with spontaneous intracranial hypotension. PMID- 21822697 TI - Negative predictors of clinical response to triptans in patients with migraine. AB - Moderate to severe migraine attacks are treated with triptans. However, about 25% of migraineurs fail to respond to triptans. We investigated the involvement of gene polymorphisms, personality traits and characteristics of headache, and made a scoring system for prediction of clinical response to triptans in patients with migraine. Gene polymorphisms including serotonin (5-HT)(1B) receptor G861C and dopamine receptor 2 (DRD2) C939T, personality traits and characteristics of headache were investigated in 46 consistent responders and 14 inconsistent responders to triptans. The multivariate stepwise logistic regression analysis revealed that age, periorbital/deep orbital pain and C/C genotype carrier at DRD2 C939T were significant factors that contributed independently to the negative response to triptans in patients with migraine. Their odds ratios were 6.329 (40 69 vs. 20-39 years, 95% CI 1.441-27.778), 6.772 (no vs. yes, periorbital/deep orbital pain, 95% CI 1.159-39.580) and 14.085 (non-C/C vs. C/C genotype at DRD2 C939T, 95% CI 1.253-166.667), respectively. The predictive index (PI) of clinical response to triptans in patients with migraine was calculated using these three factors. The score in inconsistent responders (1.6 +/- 0.6) was significantly higher than that in consistent responders (0.8 +/- 0.7, P < 0.001). Sensibility of low-score (RI = 0) group was 100%, and specificity of high-score (PI >= 2) group was 87%. The proposed scoring system should in the future be the object of larger studies to confirm its validity. PMID- 21822699 TI - Atypical presentation of a novel Presenilin 1 R377W mutation: sporadic, late onset Alzheimer disease with epilepsy and frontotemporal atrophy. AB - Mutations within Presenilin 1 (PSEN1) represent the most common cause of monogenic Alzheimer Disease (AD). The clinical phenotype is highly variable, even if early onset disease with an autosomal dominant pattern of inheritance and presenting memory deficits usually occur. In the present work, we described the case of a late-onset AD patient, without any positive family history for dementia, and associated with seizures and behavioural symptoms. Structural and functional neuroimaging showed frontotemporal changes without posterior biparietal brain abnormalities. Cerebrospinal analysis was consistent with AD pattern, with decreased Abeta42 and increased Tau and phospho-Tau. A novel pathogenetic mutation within PSEN1 gene was detected within exon 8, leading to a substitution from arginine to tryptophan (AGG > TGG: R377W), affecting a splice junction and protein function. The case herein reported further confirms the heterogeneity of PSEN1 mutations and the need to take into account genetic screening in those cases with atypical presentation. PMID- 21822700 TI - Treatment of Chiari malformation: who, when and how. AB - There is no effective alternative to surgery in the treatment of the symptomatic cases of chiari malformation. Nonetheless, in literature there is no unanimous consensus about what is the surgical "gold standard" and which are the candidates for surgery. No doubt that intracranial hypertension and ventricular dilatation have to be investigated and treated before considering decompression. It is also very important to keep in mind that a surgery does not guarantee a complete recovery from every symptoms. We report our experience about who are the candidates for surgery, which is the most appropriate surgical technique and when is the correct time for surgery along the natural history of the disease. PMID- 21822701 TI - Commentary on "expression of dopamine 2 receptor subtypes mRNA in clinically nonfunctioning pituitary adenomas". PMID- 21822702 TI - Chronic daily headache in the adults: differential diagnosis between symptomatic Chiari I malformation and spontaneous intracranial hypotension. AB - This article briefly reviews the spectrum of headaches associated with Chiari type I malformation (CMI) and specifically analyzes the current data on the possibility of this malformation as an etiology for some cases of chronic daily headache (CDH). CMI is definitely associated with cough headache and not with primary episodic headaches, with the rare exception of basilar migraine-like cases. With regard to CDH, there is no clear evidence supporting an association with CMI. A magnetic resonance imaging (MRI) study would be justified only in patients showing either a Valsalva-aggravating component or cervicogenic features. Hydrocephalus and low-intracranial pressure syndrome should be ruled out in patients showing tonsillar herniation in an MRI study and consulting due to daily headache. PMID- 21822703 TI - Headache and Chiari malformation in young age: clinical aspects and differential diagnosis. AB - Migraine and tension-type headache are common problems in children and adolescents. If we consider the possible differential diagnosis in the case of headache in children, we cannot exclude a symptomatic origin of the problem and in this case Chiari malformation can be the reason for an unrevealed organic cause of headache itself. Proper diagnosis and management of headache in young age depends on taking through history and comprehensive clinical examination. The clinical screening includes a complete neurological, mental status and physical examination and in some cases neuroimaging help is needed. Important suggestions in case of children with headache are: reassure the family about the benignity of the condition (by excluding organic diseases); educate the patients and their parents about the pathogenesis and natural history of headache; establish realistic goals for treatment according to age. PMID- 21822704 TI - Anatomy and development of the craniovertebral junction. AB - The occipital bone is the upper end of the somatic spine, limited cranially by the tentorium. The bony craniovertebral junction (caudal occiput, atlas, and axis) is interposed between the unsegmented occipital and the intersegmental spinal sclerotomes, separated from the occiput and C3 by the intrasegmental clefts of O4 and C2 sclerotomes, respectively. It retains a primitive segmental hypocentrum (anterior arch of C1) and is unsegmented from caudal O4 to cranial C2 half-sclerotomes (axis). Its morphology relates to the dual function of providing support and mobility (visual/olfactory/auditory pursuit, oral prehension) to the head. The early notochord passes through the odontoid tip to the basiocciput surface before entering the clivus up to the craniopharyngeal canal; later, the rostralmost chordal remnant is the C2/3 nucleus pulposus. Chondrification starts in the second fetal month and ossification in the fetal or postnatal periods depending on the structure. PMID- 21822705 TI - The complex Chiari: issues and management strategies. AB - "Complex Chiari" malformations may be defined as cerebellar tonsil herniation combined with one or more of the following radiographic findings: brainstem herniation through the foramen magnum (Chiari 1.5 malformation), medullary kink, retroflexed odontoid, abnormal clival-cervical angle, occipitalization of the atlas, basilar invagination, syringomyelia or scoliosis. Patients with "complex Chiari" malformation are different from those with typical Chiari 1 malformation in that their management strategy has a higher chance of including other operative interventions aside from a typical suboccipital decompression. These other operative procedures include odontoid resection and craniocervical fusion. This paper outlines specific scenarios where these other operative procedures must be considered and carried out. PMID- 21822706 TI - Partial anomalous pulmonary venous return: transcatheter repair. AB - This report describes a case of partial anomalous pulmonary venous return in a young white girl for whom transcatheter intervention successfully replaced surgical correction. This intervention was feasible because the left lung had dual pulmonary venous drainage. PMID- 21822707 TI - Occlusion of pulmonary arteriovenous malformations using the Amplatzer vascular plug/duct occluder for a family with hereditary hemorrhagic telangiectasia. PMID- 21822708 TI - Association between deteriorated renal function and long-term clinical outcomes after percutaneous coronary intervention. AB - Acute renal insufficiency after percutaneous coronary artery intervention (PCI) is a strong predictor of adverse events. However, the effect of chronic renal impairment on the long-term outcomes after PCI has not been well established. The aim of this study was to evaluate the incidence of deteriorated renal function during the chronic phase after PCI and its impact on clinical outcomes. We enrolled 282 consecutive patients who underwent PCI and had serum creatinine measured during the chronic phase (at least 3 months after PCI). We divided the study population into two groups: an advanced group that had an increase in stage of chronic kidney disease during the chronic phase, and a preserved group that included the remainder of the study population. There were 43 patients in the advanced group. We evaluated the incidence of major adverse cardiac events (MACE) that included all-cause death, nonfatal myocardial infarction, and rehospitalization with heart failure or angina pectoris. The rate of rehospitalization for heart failure and angina pectoris was significantly higher in the advanced group than in the preserved group (19.0% vs 6.8%, P < 0.01). In multivariate Cox regression analysis, the advanced group was associated with MACE (hazard ratio 3.50, 95% confidence interval 1.49-8.22, P < 0.01). Deterioration of renal function during long-term follow-up after percutaneous coronary intervention was associated with adverse cardiac events. PMID- 21822709 TI - Reversibility of Tau-related cognitive defects in a regulatable FTD mouse model. AB - The accumulation of proteins such as Tau is a hallmark of several neurodegenerative diseases, e.g., frontotemporal dementia (FTD). So far, many mouse models of tauopathies have been generated by the use of mutated or truncated human Tau isoforms in order to enhance the amyloidogenic character of Tau and to mimic pathological processes similar to those in FTD patients. Our inducible mice express the repeat domain of human Tau (Tau(RD)) carrying the FTDP 17 mutation DeltaK280 in a "pro-aggregant" and an "anti-aggregant" version. Based on the enhanced tendency of Tau to aggregate, only the "pro-aggregant" Tau(RD) mice develop Tau pathology (hyperphosphorylation, coassembly of human and mouse Tau, synaptic loss, and neuronal degeneration). We have now carried out behavioral and electrophysiological analyses showing that only the pro-aggregant Tau(RD) mice have impaired learning/memory and a distinct loss of LTP. Remarkably, after suppressing the pro-aggregant human Tau(RD), memory and LTP recover, while neuronal loss persists. Aggregates persist as well but change their composition from mixed human/mouse to mouse Tau only. The rescue of cognition and synaptic plasticity is explained by a partial recovery of spine synapses in the hippocampus. These results indicate a tight relationship between the amyloidogenic character of Tau and brain malfunction, and suggest that the cognitive impairment is caused by toxic human Tau(RD) species rather than by mouse Tau aggregates. PMID- 21822711 TI - Comparison of the puborectal muscle on MRI in women with POP and levator ani defects with those with normal support and no defect. AB - INTRODUCTION AND HYPOTHESIS: The objective of this study was to compare puborectal muscle integrity and bulk in women with both major levator ani (LA) defects on MRI and pelvic organ prolapse (POP) to women with normal LA muscle and normal support. METHODS: This is a case-control study comparing 24 cases with known major LA defects and POP to 24 controls with normal LA and normal support. Axial T-2 weighted MRI scans of the pelvis were evaluated for integrity of the puborectal muscle and degree of muscle bulk. RESULTS: There were no significant group differences in age, body mass index, vaginal deliveries, or hysterectomy status. In all 48 subjects, the puborectal muscle was visible and had no disruption noted. There was no difference in muscle bulk between groups (control/case, thin 42% vs. 25%, average 42% vs. 38%, thick-17% vs. 38%; P = 0.47). CONCLUSIONS: Defects and loss of muscle bulk in the puborectal muscle are not seen on MRI in women with major LA defects and POP. PMID- 21822710 TI - Can pelvic floor injury secondary to delivery be prevented? AB - The number of women suffering from pelvic floor disorders (PFD) is likely to grow significantly in the coming years with a growing older population. There is an urgent need to investigate factors contributing to the development of PFD and develop preventative strategies. We have reviewed the literature and analyzed results from our own study regarding the association between delivery mode, obstetrical practice and fetal measurements, and damage to the pelvic floor. Based on our findings, we have suggested a flowchart helping the obstetrician to conduct vaginal delivery with minimal pelvic floor insult. Primiparity, instrumental delivery, large fetal head circumference, and prolonged second stage of delivery are risk factors for PFD. Pelvic floor integrity should always be seriously considered in every primiparous woman. All efforts should be aimed at minimizing any insult, which might have a significant impact on the woman's pelvic integrity and future quality of life. PMID- 21822712 TI - Avulsion of puborectalis muscle and other risk factors for cystocele recurrence: a 2-year follow-up study. AB - INTRODUCTION AND HYPOTHESIS: This study aimed to determine the relationship of recurrent cystocele with avulsion of puborectalis muscle and other risk factors. METHODS: In this prospective observational cohort study, 245 women undergoing anterior colporrhaphy were invited for a 2-year follow-up visit consisting of a questionnaire, physical examination, and translabial 3D ultrasonography. Women with and without recurrent cystocele were compared to identify recurrence risk factors. RESULTS: Of the 245 women, 156 agreed to the follow-up visit (63.7%). Objective recurrence rate was 80 of 156 (51.3%). Seventeen of the 156 (10.9%) reported subjective recurrence. Risk factors for anatomical recurrence were complete avulsion of puborectalis muscle (OR, 2.4; 95% CI, 1.3, 4.7), advanced preoperative stage (OR, 2.0; 95% CI, 1.0, 4.1), family history of prolapse (OR, 2.4; 95% CI, 1.2, 4.9), and sacrospinous fixation (OR, 6.5; 95% CI, 2.0, 21.2). CONCLUSIONS: Risk factors for anatomical cystocele recurrence after anterior colporrhaphy were complete avulsion of puborectalis muscle, advanced preoperative stage, family history of prolapse, and sacrospinous fixation. PMID- 21822713 TI - Comparison of short-term outcomes following pelvic reconstruction with Perigee and Apogee systems: hysterectomy or not? AB - INTRODUCTION AND HYPOTHESIS: This study aims to compare the surgical outcomes between hysterectomy and uterine preservation in pelvic reconstruction with Perigee and Apogee systems for severe pelvic organ prolapse. METHODS: Ninety-one women who have undergone transvaginal pelvic reconstructive surgery with Perigee and Apogee systems for severe pelvic organ prolapse were divided into two groups: hysterectomy (n = 39) and uterine preservation (n = 52). The pre-operative and post-operative assessments include subjective urinary and prolapse symptoms, objective pelvic organ prolapse quantification (POP-Q) system, urodynamic examination, and complications. RESULTS: The mean follow-up period was 8.9 months (range, 0.9-26.5). There were no anatomical differences between the two groups other than a longer perineal body in the hysterectomy group (3.9 vs. 3.6, p < 0.05) and a longer total vaginal length in the uterine preservation group (8.2 vs. 7.8, p < 0.05). Preservation of uterus has significantly reduced operative time, blood loss, and days of urine indwelling catheter (p < 0.001). CONCLUSIONS: Hysterectomy and uterine preservation have comparable anatomical outcomes and post-operative complications in pelvic reconstruction with Perigee and Apogee systems at short-term follow-up. PMID- 21822714 TI - A prospective study on the prevalence of hydronephrosis in women with pelvic organ prolapse and their outcomes after treatment. AB - INTRODUCTION AND HYPOTHESIS: This work aims to study the prevalence of hydronephrosis and its associated factors in women with pelvic organ prolapse (POP) and to assess the effect on hydronephrosis following treatment for POP. METHODS: In this prospective observational study, 233 patients with POP were staged by the Pelvic Organ Prolapse-Quantification system, followed by sonographic measurement of bilateral renal pelvis to identify presence of hydronephrosis. Follow-up scan for hydronephrosis was performed after patients were treated for the POP. RESULTS: The prevalence of hydronephrosis was 10.3% (95% confidence interval (CI), 6% and 14%). Although patient's age, higher parity, and the presence of diabetes mellitus and hypertension were more common in the group with hydronephrosis, logistic regression analysis indicated that only the severity of POP was an independent risk factor for hydronephrosis. The odds ratio in stages 3 to 4 POP for hydronephrosis was 3.4 (95% CI, 1.3 and 9.2). Hydronephrosis resolved in 95% of patients after they received treatment for POP. CONCLUSIONS: The prevalence of hydronephrosis was 10.3% in patients with POP and patients with stages 3 to 4 POP were at particular higher risk. Hydronephrosis resolved in most of the patients after treatment for the prolapse. PMID- 21822715 TI - Peculiarities of the extracellular matrix in the interstitium of the renal stem/progenitor cell niche. AB - The development of the nephron is piloted by interactions between epithelial and surrounding mesenchymal stem/progenitor cells. Data show that an astonishingly wide interstitial space separates both kinds of stem/progenitor cells. A simple contrasting procedure was applied to visualize features that keep renal epithelial and mesenchymal stem/progenitor cells in distance. The kidney of neonatal rabbits was fixed in solutions containing glutaraldehyde (GA) in combination with alcian blue, lanthanum, ruthenium red, or tannic acid. To obtain a comparable view to the renal stem/progenitor cell niche, the tissue was exactly orientated along the axis of collecting ducts. Fixation with GA or in combination with alcian blue or lanthanum revealed an inconspicuous interstitial space. In contrast, fixation with GA containing ruthenium red exhibits strands of extracellular matrix lining from epithelial stem/progenitor cells through the interstitium up to the surface of mesenchymal stem/progenitor cells. Fixation with GA containing tannic acid shows that the basal lamina of epithelial stem/progenitor cells, the adjacent interstitial space and also the surface of mesenchymal stem/progenitor cells are connected over a net of extracellular matrix. The applied technique appears to be a suitable method to illuminate the interstitium in stem/progenitor cell niches of specialized tissues, the microenvironment of tumors and extension of degeneration. PMID- 21822716 TI - Expression of mechanogated two-pore domain potassium channels in mouse lungs: special reference to mechanosensory airway receptors. AB - Afferent activities arising from sensory nerve terminals located in lungs and airways are carried almost exclusively by fibres travelling through the vagus nerve. Based on electrophysiological investigations, intrapulmonary airway related vagal afferent receptors have been classified into three main subtypes, two of which are myelinated and mechanosensitive, i.e., rapidly and slowly adapting receptors. To allow for a full functional identification of the distinct populations of airway receptors, morphological and neurochemical characteristics still need to be determined. Nerve terminals visualised using markers for myelinated vagal afferents seem to be almost uniquely associated with two morphologically well-formed airway receptor end organs, smooth muscle-associated airway receptors (SMARs) and neuroepithelial bodies (NEBs), localised in airway smooth muscle and epithelium, respectively. Due to the lack of a selective marker for SMARs in mice, no further neurochemical coding is available today. NEBs are extensively innervated diffusely spread groups of neuroendocrine cells in the airway epithelium, and are known to receive at least two separate populations of myelinated vagal afferent nerve terminals. So far, however, no evidence has been reported for the expression of channels that may underlie direct sensing and transduction of mechanical stimuli by the receptor terminals in NEBs and SMARs. This study focused on the expression of mechanogated two-pore domain K(+) (K(2P)) channels, TREK-1 and TRAAK, in mouse airways and more particular in the NEB micro environment and in SMARs by multiple immunostaining. TREK-1 could be detected on smooth muscle cells surrounding intrapulmonary airways and blood vessels, while TRAAK was expressed on myelinated vagal afferents terminating both in SMARs and in the NEB micro-environment. Co-stainings with known markers for subpopulations of myelinated vagal afferents and general neuronal markers revealed that all identified SMARs exhibit TRAAK immunoreactivity, and that at least three subpopulations exist in mouse airways. Also, the intraepithelial terminals of both subpopulations of NEB-associated myelinated vagal sensory nerve fibres were shown to express TRAAK. In conclusion, the present study finally characterised an intrinsically mechanosensitive ion channel, the K(2P) channel TRAAK, on the terminals of identified myelinated vagal nodose airway afferents, organised as SMARs and as components of the innervation of NEBs. These data support the hypothesis that both SMARs and NEBs harbour the morphological counterparts of electrophysiologically identified myelinated vagal airway mechanoreceptors. TRAAK appears to be strongly involved in regulating airway mechanosensing since it was found to be expressed on the terminals of all subpopulations of potential vagal mechanosensors. PMID- 21822717 TI - Impact of time since last caloric intake on blood glucose levels. AB - Blood glucose (BG) is usually measured after a caloric restriction of at least 8 h; however evidence-based recommendations for the duration of a fasting status are missing. Here we analyze the effect of fasting duration on levels of BG to determine the minimal fasting duration to achieve comparable BG levels to conventional fasting measurements. We used data of a cross-sectional study on primary care patients, performed in October 2005. We included 28,024 individuals (age-range 18-99 years; 63% women) without known diabetes mellitus and without missing data for BG and fasting status. We computed general linear models, adjusting for age, sex, time of blood withdrawal, systolic blood pressure, waist circumference, total- and HDL-cholesterol, physical activity, smoking, intake of beta-blocker and alcohol. We tested the intra-individual variability with respect to fasting status. Overall, the mean BG differed only slightly between individuals fasting >= 8 h and those fasting <8 h (men: 5.1 +/- 0.8 mmol/L versus 5.2 +/- 1.2 mmol/L; women: 4.9 +/- 0.7 mmol/L, 5.0 +/- 1.0 mmol/L). After 3 h of fasting differences of BG diminished in men to -0.08 mmol/L (95%-CI: -0.15; -0.01 mmol/L), in women to -0.07 mmol/L (-0.12; -0.03 mmol/L) compared to individuals fasting >= 8 h. Noteworthy, age, time of day of blood withdrawal, physical activity, and intake of hard liquor influenced BG levels considerably. Our data challenge the necessity for a fasting duration of >= 8 h when measuring blood glucose, suggesting a random sampling or a fasting duration of 3 h as sufficient. Rather, our study indicates that essentially more effort on the assessment of additional external/internal factors on BG levels is necessary. PMID- 21822719 TI - Renal hyperperfusion injury resulting in transient proteinuria post renal artery angioplasty for fibromuscular dysplasia. AB - Renovascular hypertension (RVH) can be treated utilizing medical, surgical or endovascular techniques. We present a case in which severe exacerbation of pre existing proteinuria followed percutaneous transluminal angioplasty of a highly stenotic renal artery to relieve RVH caused by fibromuscular dysplasia. We propose that the worsening proteinuria post-angioplasty was caused by a transient renal hyperperfusion injury that overcame the glomerular autoregulatory mechanisms, thereby leading to raised intraglomerular pressures and loss of proteins through the glomerular filtration barrier until the vascular autoregulatory ability of the glomeruli was successfully re-established. PMID- 21822720 TI - Acinic cell carcinoma of the retromolar trigone region: expanding the tumor phenotype in Cowden syndrome? AB - Cowden syndrome (CS) is a cancer predisposition syndrome caused by germline mutations in the PTEN tumor suppressor gene. It is associated with an increased risk of thyroid, breast and endometrial cancer but many manifestations can be found in the head and neck region, some of which are pathognomonic. Here we report a 35-year-old male referred by his dentist for evaluation of a lesion located near the retromolar trigone. Comprehensive clinical examination revealed papillomatous skin lesions, macrocephaly and gingival hypertrophy. Histopathological examination of the lesion showed an acinic cell carcinoma (ACC) of minor salivary gland origin. Analysis of the PTEN gene identified a germline R130Q mutation in exon 5, confirming the diagnosis of CS, but no loss of heterozygosity was seen in DNA extracted from tumor tissue. This is to our knowledge the first case describing an association of ACC of the minor salivary gland with a PTEN-gene related disorder. It emphasizes the importance of head and neck examination in these patients. PMID- 21822721 TI - Microsatellite instability analysis in uterine cavity washings as a screening tool for endometrial cancer in Lynch syndrome. AB - Although patients with Lynch syndrome (LS) are at high risk of endometrial cancer, gynecologic screening has been poorly investigated and diagnostic value of current screening tests remains unclear. Microsatellite instability (MSI) phenotype is found in more than 90% of endometrial cancers developed in LS patients. Here we report the first two cases of unstable endometrial tumors with detection of MSI in uterine cavity washings cells. This new technique may be a promising screening tool in LS. PMID- 21822723 TI - Improving the accuracy of ultrafast ligand-based screening: incorporating lipophilicity into ElectroShape as an extra dimension. AB - In a previous paper, we presented the ElectroShape method, which we used to achieve successful ligand-based virtual screening. It extended classical shape based methods by applying them to the four-dimensional shape of the molecule where partial charge was used as the fourth dimension to capture electrostatic information. This paper extends the approach by using atomic lipophilicity (alogP) as an additional molecular property and validates it using the improved release 2 of the Directory of Useful Decoys (DUD). When alogP replaced partial charge, the enrichment results were slightly below those of ElectroShape, though still far better than purely shape-based methods. However, when alogP was added as a complement to partial charge, the resulting five-dimensional enrichments shows a clear improvement in performance. This demonstrates the utility of extending the ElectroShape virtual screening method by adding other atom-based descriptors. PMID- 21822722 TI - Computational investigation of the binding mode of bis(hydroxylphenyl)arenes in 17beta-HSD1: molecular dynamics simulations, MM-PBSA free energy calculations, and molecular electrostatic potential maps. AB - 17beta-Hydroxysteroid dehydrogenase type 1 (17beta-HSD1) catalyzes the last step of the estrogen biosynthesis, namely the reduction of estrone to the biologically potent estradiol. As such it is a potentially attractive drug target for the treatment of estrogen-dependent diseases like breast cancer and endometriosis. 17beta-HSD1 belongs to the bisubstrate enzymes and exists as an ensemble of conformations. These principally differ in the region of the betaFalphaG'-loop, suggesting a prominent role in substrate and inhibitor binding. Although several classes of potent non-steroidal 17beta-HSD1 inhibitors currently exist, their binding mode is still unclear. We aimed to elucidate the binding mode of bis(hydroxyphenyl)arenes, a highly potent class of 17beta-HSD1 inhibitors, and to rank these compounds correctly with respect to their inhibitory potency, two essential aspects in drug design. Ensemble docking experiments resulted in a steroidal binding mode for the closed enzyme conformations and in an alternative mode for the opened and occluded conformers with the inhibitors placed below the NADPH interacting with it synergically via pi-pi stacking and H-bond formation. Both binding modes were investigated by MD simulations and MM-PBSA binding free energy estimations using as representative member for this class compound 1 (50 nM). Notably, only the alternative binding mode proved stable and was energetically more favorable, while when simulated in the steroidal binding mode compound 1 was displaced from the active site. In parallel, ab initio studies of small NADPH-inhibitor complexes were performed, which supported the importance of the synergistic interaction between inhibitors and cofactor. PMID- 21822725 TI - Dew water isotopic ratios and their relationships to ecosystem water pools and fluxes in a cropland and a grassland in China. AB - Dew formation has the potential to modulate the spatial and temporal variations of isotopic contents of atmospheric water vapor, oxygen and carbon dioxide. The goal of this paper is to improve our understanding of the isotopic interactions between dew water and ecosystem water pools and fluxes through two field experiments in a wheat/maize cropland and in a short steppe grassland in China. Measurements were made during 94 dew events of the D and (18)O compositions of dew, atmospheric vapor, leaf, xylem and soil water, and the whole ecosystem water flux. Our results demonstrate that the equilibrium fractionation played a dominant role over the kinetic fractionation in controlling the dew water isotopic compositions. A significant correlation between the isotopic compositions of leaf water and dew water suggests a large role of top-down exchange with atmospheric vapor controlling the leaf water turnover at night. According to the isotopic labeling, dew water consisted of a downward flux of water vapor from above the canopy (98%) and upward fluxes originated from soil evaporation and transpiration of the leaves in the lower canopy (2%). PMID- 21822726 TI - Seasonal photosynthetic gas exchange and water-use efficiency in a constitutive CAM plant, the giant saguaro cactus (Carnegiea gigantea). AB - Crassulacean acid metabolism (CAM) and the capacity to store large quantities of water are thought to confer high water use efficiency (WUE) and survival of succulent plants in warm desert environments. Yet the highly variable precipitation, temperature and humidity conditions in these environments likely have unique impacts on underlying processes regulating photosynthetic gas exchange and WUE, limiting our ability to predict growth and survival responses of desert CAM plants to climate change. We monitored net CO(2) assimilation (A(net)), stomatal conductance (g(s)), and transpiration (E) rates periodically over 2 years in a natural population of the giant columnar cactus Carnegiea gigantea (saguaro) near Tucson, Arizona USA to investigate environmental and physiological controls over carbon gain and water loss in this ecologically important plant. We hypothesized that seasonal changes in daily integrated water use efficiency (WUE(day)) in this constitutive CAM species would be driven largely by stomatal regulation of nighttime transpiration and CO(2) uptake responding to shifts in nighttime air temperature and humidity. The lowest WUE(day) occurred during time periods with extreme high and low air vapor pressure deficit (D(a)). The diurnal with the highest D(a) had low WUE(day) due to minimal net carbon gain across the 24 h period. Low WUE(day) was also observed under conditions of low D(a); however, it was due to significant transpiration losses. Gas exchange measurements on potted saguaro plants exposed to experimental changes in D(a) confirmed the relationship between D(a) and g(s). Our results suggest that climatic changes involving shifts in air temperature and humidity will have large impacts on the water and carbon economy of the giant saguaro and potentially other succulent CAM plants of warm desert environments. PMID- 21822727 TI - Nematode and snail metallothioneins. AB - Metallobiologists have, at large, neglected soil dwelling invertebrates; exceptions are the nematode (Caenorhabditis elegans) and snails (Helix pomatia and Cantareus aspersus). This review aims to compare and contrast the molecular, protein and cellular mechanisms of the multifunctional nematode and snail metallothioneins (MTs). The C. elegans genome contains two MT genes, mtl-1, which is constitutively expressed in the pharynx and likely to act as an essential and/or toxic metal sensor, and mtl-2, which plays a negligible role under normal physiological conditions but is strongly induced (as mtl-1) in intestinal cells upon metal exposure. It has been possible to follow the intricate phenotypic responses upon the knockdown/knockout of single and multiple MT isoforms and we have started to decipher the multifunctional role of C. elegans MTs. The snails have contributed to our understanding regarding MT evolution and diversity, structure and metal-specific functionality. The H. pomatia and C. aspersus genomes contain at least three MT isoform genes. CdMT is responsible for cadmium detoxification, CuMT is involved in copper homeostasis and Cd/CuMT is a putative ancestral MT possibly only of minor importance in metal metabolism. Further investigations of nematode, snail and other invertebrate MTs will allow the development of alternative biomarker approaches and lead to an improved understanding of metallobiology, protein evolution and toxicogenomics. PMID- 21822728 TI - CYP1A1 is overexpressed upon incubation of breast cancer cells with a polyphenolic cocoa extract. AB - PURPOSE: To evaluate the effect of cocoa flavonoids in breast cancer cells at the molecular level, a functional genomic analysis was performed using a polyphenolic cocoa extract (PCE) in MCF-7 and SKBR3 cell lines. METHODS: The expression profile of 84 genes included in the Stress & Toxicity PathwayFinderTM PCR Array was analyzed after PCE incubation for 24 h. mRNA and protein levels were analyzed by RT-PCR and western blot, respectively. Gel shift assays were used to evaluate DNA-protein complexes. Protein complexes were identified by co immunoprecipitation. Cell viability was evaluated by MTT assays. RESULTS: Upon PCE incubation, 7 genes were overexpressed and 1 underexpressed in MCF-7 cells, whereas 9 genes were overexpressed in SKBR3 cells. Among the differentially expressed genes in both cell lines, cytochrome P450, family 1, subfamily A, polypeptide 1 (CYP1A1) was chosen for further study. CYP1A1 mRNA and protein levels and enzymatic activity increased upon PCE incubation. CYP1A1 transcriptional activation by PCE was mediated through AhR binding to XRE elements within the CYP1A1 promoter in MCF-7 cells. A protein complex including AhR and ERalpha was detected. The combination of PCE with tamoxifen caused a synergistic cytotoxicity in both cell lines and was due to an increase in apoptosis in MCF-7 cells. CONCLUSIONS: The interaction between ERalpha and AhR upon incubation with PCE leads to CYP1A1 induction in breast cancer cells. The synergy between PCE and non-cytotoxic tamoxifen concentrations opens the possibility for a combination therapy based on polyphenols from cocoa that increased tamoxifen efficacy. PMID- 21822729 TI - Disease progression and costs of care in Alzheimer's disease patients treated with donepezil: a longitudinal naturalistic cohort. AB - BACKGROUND/AIMS: Improved data and methods are needed for modeling disease progression in Alzheimer's disease (AD) for economic evaluation of treatments. The aim is to estimate prediction models for long-term AD progression and subsequently economic outcomes. METHODS: Three-year follow-up data on 435 patients treated with the cholinesterase inhibitor donepezil in clinical practise were analyzed. Regression models were estimated for long-term prediction of decline in cognitive function (ADAS-cog) and activities in daily living (ADL) ability, risk of institutionalization and costs of care. RESULTS: The cognitive deterioration was estimated at between 1.6 and 4 ADAS-cog points per every 6 months, increasing with disease severity. Cognitive function was an important predictor of ADL-ability, which itself was the most important predictor of the risk of institutionalization and costs of care. Combining all models in a cross validation process generated accurate predictions of costs of care at each 6 months follow-up. CONCLUSION: The proposed methods for representing AD progression and economic outcomes can be used in micro-simulation models for the economic evaluation of new treatments. PMID- 21822731 TI - Cross-linking of wheat gluten proteins during production of hard pretzels. AB - The impact of the hot alkaline dip, prior to pretzel-baking, on the types and levels of cross-links between wheat proteins was studied. Protein extractability of pretzel dough in sodium dodecyl sulfate containing buffer decreased during alkaline dipping [45 s, 1.0% (w/v) NaOH, 90 degrees C], and even more during baking (3 min at 250 degrees C) and drying (10 min at 135 degrees C). Reducing agent increased the extractability partly, indicating that both reducible (disulfide, SS) and non-reducible (non-SS) protein cross-links had been formed. The decrease in cystine levels suggested beta-elimination of cystine releasing Cys and dehydroalanine (DHA). Subsequent reaction of DHA with Lys and Cys, induced the unusual and potentially cross-linking amino acids lysinoalanine (LAL) and lanthionine (LAN), respectively, in alkaline dipped dough (7 MUmol LAN/g protein) and in the end product (9 MUmol LAL and 50 MUmol LAN/g protein). The baking/drying step increased sample redness, decreased Lys levels more than expected based on LAL formation (57 MUmol/g protein), and induced a loss of reducing sugars (99 MUmol/g protein), which suggested the potential contribution of Maillard-derived cross-links to the observed extractability loss. However, levels of Maillard products which possibly cross-link proteins, are small compared to DHA-derived cross-links. Higher dipping temperatures, longer dipping times, and higher NaOH concentrations increased protein extractability losses and redness, as well as LAL and LAN levels in the end product. No indications for Maillard-derived cross-links or LAL in pretzel dough immediately after dipping were found, even when severe dipping conditions were used. PMID- 21822730 TI - eIF5A interacts functionally with eEF2. AB - eIF5A is highly conserved from archaea to mammals, essential for cell viability and the only protein known to contain the essential amino acid residue hypusine, generated by a unique posttranslational modification. eIF5A was originally identified as a translation initiation factor due to its ability to stimulate the formation of the first peptide bond. However, recent studies have shown that depletion of eIF5A causes a significant decrease in polysome run-off and an increase in the ribosome transit time, suggesting that eIF5A is actually involved in the elongation step of protein synthesis. We have previously shown that the depletion mutant tif51A-3 (eIF5A(C39Y/G118D)) shows a sicker phenotype when combined with the dominant negative mutant eft2 ( H699K ) of the elongation factor eEF2. In this study, we used the eIF5A(K56A) mutant to further investigate the relationship between eIF5A and eEF2. The eIF5A(K56A) mutant is temperature sensitive and has a defect in protein synthesis, but instead of causing depletion of the eIF5A protein, this mutant has a defect in hypusine modification. Like the mutant tif51A-3, the eIF5A(K56A) mutant is synthetic sick with the mutant eft2 ( H699K ) of eEF2. High-copy eEF2 not only improves cell growth of the eIF5A(K56A) mutant, but also corrects its increased cell size defect. Moreover, eEF2 suppression of the eIF5A(K56A) mutant is correlated with the improvement of total protein synthesis and with the increased resistance to the protein synthesis inhibitor hygromycin B. Finally, the polysome profile defect of the eIF5A(K56A) mutant is largely corrected by high-copy eEF2. Therefore, these results demonstrate that eIF5A is closely related to eEF2 function during translation elongation. PMID- 21822732 TI - A deconvolution method to improve automated 3D-analysis of dendritic spines: application to a mouse model of Huntington's disease. AB - Dendritic spines are postsynaptic structures the morphology of which correlates with the strength of synaptic efficacy. Measurements of spine density and spine morphology are achievable using recent imaging and bioinformatics tools. The three-dimensional automated analysis requires optimization of image acquisition and treatment. Here, we studied the critical steps for optimal confocal microscopy imaging of dendritic spines. We characterize the deconvolution process and show that it improves spine morphology analysis. With this method, images of dendritic spines from medium spiny neurons are automatically detected by the software Neuronstudio, which retrieves spine density as well as spine diameter and volume. This approach is illustrated with three-dimensional analysis of dendritic spines in a mouse model of Huntington's disease: the transgenic R6/2 mice. In symptomatic mutant mice, we confirm the decrease in spine density, and the method brings further information and show a decrease in spine volume and dendrite diameter. Moreover, we show a significant decrease in spine density at presymptomatic age which so far has gone unnoticed. PMID- 21822733 TI - Activation of ERK1/2 and PI3K/Akt by IGF-1 on GAP-43 expression in DRG neurons with excitotoxicity induced by glutamate in vitro. AB - Insulin-like growth factor-1 (IGF-1) is a neurotrophic factor and plays an important role in promoting axonal growth from dorsal root ganglion (DRG) neurons. Whether IGF-1 influences growth-associated protein 43 (GAP-43) expression and activates the extracellular signal-regulated protein kinase (ERK1/2) and the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways in DRG neurons with excitotoxicity induced by glutamate (Glu) remains unknown. In this study, embryonic 15-day-old rat DRG explants were cultured for 48 h and then exposed to IGF-1, Glu, Glu + IGF-1, Glu + IGF-1 + PD98059, Glu + IGF-1 + LY294002, Glu + IGF-1 + PD98059 + LY294002 for additional 12 h. The DRG explants were continuously exposed to growth media as control. The levels of GAP-43 mRNA were detected by real time-PCR analysis. The protein levels of GAP-43, phosphorylated ERK1/2, phosphorylated Akt, total ERK1/2, and total Akt were detected by Western blot assay. GAP-43 expression in situ was determined by immunofluorescent labeling. Apoptotic cell death was monitored by Hoechst 33342 staining. IGF-1 alone increased GAP-43 and its mRNA levels in the absence of Glu. The decreased GAP-43 and its mRNA levels caused by Glu could be partially reversed by the presence of IGF-1. IGF-1 rescued neuronal cell death caused by Glu. Neither the ERK1/2 inhibitor PD98059 nor the PI3K inhibitor LY294002 blocked the effect of IGF-1, but both inhibitors together were effective. To validate the impact of GAP-43 expression by IGF-1, GAP-43 induction was blocked by administration of dexamethasone (DEX). IGF-1 partially rescued the decrease of GAP-43 and its mRNA levels induced by DEX. DEX induced an increase of cell apoptosis. IGF-1 may play an important role in neuroprotective effects on DRG neurons through regulating GAP-43 expression with excitotoxicity induced by Glu and the process was involved in both ERK1/2 and PI3K/Akt signaling pathways. PMID- 21822734 TI - Anxiety and reading difficulties in early elementary school: evidence for unidirectional- or bi-directional relations? AB - The present study examined competing models of the bi-directional influences of anxiety and reading achievement. Participants were 153 ethnically-diverse children (84 male, 69 female) from general education classes evaluated in the winter and spring of their first-grade academic year. Children completed standardized measures of reading achievement involving decoding and fluency along with an anxiety rating scale. Hierarchical linear regression analyses revealed that separation anxiety symptoms were negatively predicted by fluency performance and harm avoidance symptoms were positively predicted by decoding performance. Fluency performance was positively predicted by harm avoidance and total anxiety (for girls only) symptoms, while decoding was not predicted by any anxiety subscale. PMID- 21822735 TI - Comparing longitudinal assessments of quality of life by patient and parent in newly diagnosed children with cancer: the value of both raters' perspectives. AB - PURPOSE: Health-related quality of life (HRQoL) information from children facing rare and/or life-threatening disease serves important clinical functions. Longitudinal HRQoL ratings from 222 child-parent dyads collected at four time points during the first 16 weeks of cancer treatment are presented. Patient and parent HRQoL reports at the domain level, based on the Pediatric Quality of Life InventoryTM 4.0 Generic Core Scales, were compared over time, and variation in child/parent agreement by age, treatment intensity, and time on treatment was explored. PATIENTS AND METHODS: Analyses included consideration of missingness, differences between child and parent group mean domain scores averaged over assessments, agreement between individual child and parent, compared to group averages, and within-subject changes between assessments. RESULTS: Children consistently reported higher functioning than their parents with differences varying by child age and HRQoL domain and diminishing over time. No differences were found by intensity of treatment. The between-subject correlation ranged from 0.61 (social functioning) to 0.86 (physical functioning) across time. Agreement within groups, defined by age, treatment intensity, and time were generally similar. CONCLUSIONS: Results indicate moderate-to-good child/parent agreement with variability by domain of HRQoL. Findings underscore the complexity of self- and proxy-based report and support the use of information from both raters. PMID- 21822736 TI - A mixed methods approach to adapting health-related quality of life measures for use in routine oncology clinical practice. AB - PURPOSE: The current study reviewed and adapted existing health-related quality of life (HRQoL) instruments for use in routine clinical practice delivering outpatient chemotherapy for colorectal, breast and gynaecological cancers. METHODS: 564 (288 gynaecological, 208 breast and 68 colorectal) outpatient consultations of 141 patients were audio-recorded and analysed to identify discussed issues. Issues were ranked from most to least commonly discussed within each disease group. Existing HRQoL instruments were evaluated against these lists and best fitting items entered into cancer-specific item banks. Item banks were evaluated during semi-structured interviews by twenty-one oncologists (13 consultants and 8 specialist registrars), four clinical nurse specialists and thirty patients, from breast, gynaecological and colorectal cancer practices. Pilot questionnaires were completed by 448 (145 breast, 148 gynaecological and 155 colorectal) patients attending outpatient clinics. Item selection and scale reliability was explored using descriptive data and psychometric methods alongside qualitative patient and clinician ratings. RESULTS: Each questionnaire includes five physical and three psychosocial function scales each with good internal consistency reliability (alpha > 0.70) plus disease-specific individual symptom items identified as useful in clinical practice. CONCLUSIONS: Three cancer-specific health-related quality of life measures were developed for use in routine clinical practice. Initial analyses suggest good clinical utility and acceptable psychometric properties for the new instruments. PMID- 21822737 TI - Lack of association of primary iron overload and common HFE gene mutations with liver cirrhosis in adult Indian population. AB - AIM: To find out the association of common HFE mutations (viz., C282Y and H63D) with primary iron overload (PIL) in liver cirrhosis (CLD) patients of Indian origin. METHODS: Polymerase chain reaction-restriction fragment length polymorphism method was used for screening C282Y and H63D mutation in 496 CLD patients (hepatitis B virus associated cirrhosis (HBVc) = 74, hepatitis C virus associated cirrhosis (HCV) = 50, alcoholic cirrhosis with hepatitis (ALcW) = 38, alcoholic cirrhosis without hepatitis (ALc) = 92, cryptogenic cirrhosis (CC) = 242) and 502 healthy controls. Transferrin saturation of >45 or serum ferritin of >300 ng/mL (males)/>200 ng/mL (females) with normal total exogenous iron intake was suggestive of PIL. Histological liver iron grading was done by Perl's Prussian blue stain. RESULTS: Of 496 patients, 13 (2.6; 9 CC, 2 ALc, 1 HBVc, 1 AlcW) had PIL. However, only two (15.3) of 13 patients (1 CC and 1 HBVc) were positive for H63D heterozygous mutation. All the subjects were found to be C282Y wild type, except a single case of double heterozygous (C282Y/H63D) who however, did not have PIL. Overall frequency of H63D allele in patients and controls was not significantly different (5.95 and 4.58 respectively, p = 0.17). A highly significant H63D allele frequency (p < 0.005) was observed in HBVc (10.82) and ALcW (11.84) groups but they were not associated with PIL. CONCLUSION: The frequency of PIL, and the HFE gene mutaion (C282Y) are both rare in Indian patients and explain why hemochromatosis is a rare cause of liver cirrhosis in India. A highly significant H63D allele frequency in HBV and alcohol-related cirrhosis suggest a possible predisposing role for liver fibrosis of this allele. PMID- 21822738 TI - The impact of 2011! PMID- 21822739 TI - A linear, biphasic model incorporating a brinkman term to describe the mechanics of cell-seeded collagen hydrogels. AB - Protein-based hydrogels are commonly used as in vitro models of native tissues because they can mimic specific aspects of the three-dimensional extracellular matrix present in vivo. Bulk mechanical stimulation is often applied to these gels to determine the response of embedded cells to biomechanical factors such as stress and strain. This study develops and applies a linear, biphasic formulation of hydrogel mechanics that includes a Brinkman term to account for viscous effects. The model is used to predict fluid pressure, relative velocity, and estimated shear stress exerted on cells seeded within a cyclically strained collagen hydrogel with and without imposed cross flow. The model was validated using a confined compression creep test of a cardiac fibroblast-seeded collagen type I hydrogel, and the effect of the added Brinkman term was assessed. The model indicated that the effects of strain and interstitial fluid flow are strongly interdependent in the collagen hydrogel. Our results suggest that the contribution of the Brinkman term is greater in protein hydrogels than in native tissues, and that studies that apply cyclic strain to cell-seeded hydrogels should account for the induced interstitial fluid flow. This study, therefore, has relevance to the increasing number of studies that examine cellular responses to mechanical stresses using in vitro hydrogel models. PMID- 21822740 TI - Three-dimensional modeling and quantitative analysis of gap junction distributions in cardiac tissue. AB - Gap junctions play a fundamental role in intercellular communication in cardiac tissue. Various types of heart disease including hypertrophy and ischemia are associated with alterations of the spatial arrangement of gap junctions. Previous studies applied two-dimensional optical and electron-microscopy to visualize gap junction arrangements. In normal cardiomyocytes, gap junctions were primarily found at cell ends, but can be found also in more central regions. In this study, we extended these approaches toward three-dimensional reconstruction of gap junction distributions based on high-resolution scanning confocal microscopy and image processing. We developed methods for quantitative characterization of gap junction distributions based on analysis of intensity profiles along the principal axes of myocytes. The analyses characterized gap junction polarization at cell ends and higher-order statistical image moments of intensity profiles. The methodology was tested in rat ventricular myocardium. Our analysis yielded novel quantitative data on gap junction distributions. In particular, the analysis demonstrated that the distributions exhibit significant variability with respect to polarization, skewness, and kurtosis. We suggest that this methodology provides a quantitative alternative to current approaches based on visual inspection, with applications in particular in characterization of engineered and diseased myocardium. Furthermore, we propose that these data provide improved input for computational modeling of cardiac conduction. PMID- 21822741 TI - Animal models of temporomandibular joint disorders: implications for tissue engineering approaches. AB - Animal models for temporomandibular joint disorder (TMD) or degradation are necessary for assessing the value of current and future tissue engineering therapies. After reviewing the literature, it is quite apparent that most TMD animal studies can be categorized into chemical approaches or surgical/mechanical approaches. Overall, it was found that the top five cited manuscripts for all chemical models were cited by almost 40% more manuscripts than the top five manuscripts for surgical/mechanical models. It is clear that the chemical approaches have focused on the inflammatory aspect of TMDs and its relationship to pain. However, chemical irritants must be tested in larger animal models, and the effect of short-term inflammation on the mechanical properties of the fibrocartilage must be examined. Nevertheless, therapeutic approaches aimed at reducing or controlling inflammation could use the established chemical methods. Surgical/mechanical methods can be used as negative controls for first generation TMJ tissue engineering approaches when the therapy is applied immediately after injury. Next generation tissue engineering approaches will require testing on tissues degenerated for a few months after the surgical/mechanical methods, with enhanced functional assessment techniques. PMID- 21822742 TI - Deep infiltrating endometriosis of the bowel: MR imaging as a method to predict muscular invasion. AB - PURPOSE: To evaluate magnetic resonance (MR) imaging morphologic- and signal intensity abnormalities of deep infiltrating endometriosis (DIE) of the bowel wall and to assess its value in predicting depth and extent of bowel wall infiltration. MATERIALS AND METHODS: This single-center study was performed in a tertiary referral center for endometriosis. All patients (n = 28) who underwent segmental bowel resection (2004-2010) were retrospectively studied. MR images were analyzed by two experienced readers independently (number of lesions, location, size, signal intensity, and depth of bowel wall infiltration) and this was correlated with histopathology. RESULTS: The sensitivity, specificity, positive and negative predictive values, and accuracy for diagnosis of endometriosis infiltrating the muscular layer of the bowel were 100%, 75%, 96%, 100%, and 96%, respectively. The inter-rater agreement was 0.84. "Fan shaped" configurations with hypointensity on T2- and T1-weighted imaging were characteristic for thickening of indigenous smooth muscle and smooth muscle hyperplasia at histopathology, as a consequence of infiltration by endometriosis. Thickening of the (sub)mucosa corresponded to edema with or without infiltration of endometriosis. CONCLUSION: MR imaging at 1.5 Tesla is useful to predict muscular infiltration of the bowel in endometriosis, whereas it is of limited value in diagnosis of (sub)mucosal infiltration. PMID- 21822743 TI - Religiosity, spirituality, sexual attitudes, and sexual behaviors among college students. AB - The purpose of this study was to determine whether religiosity, spirituality, and sexual attitudes accounted for differences in sexual behaviors among college students. The sample included 960 college students enrolled at four northeastern colleges. Results indicated differences in sexual attitudes, religiosity, and spirituality by gender. Moreover, sexual attitudes, religiosity, and spirituality were associated with sexual behaviors among college students. Sexual behaviors among males were influenced by their sexual attitudes, religiosity, and spirituality, while for females, their sexual behaviors were mostly influenced by their sexual attitudes. College health professionals can use these findings when discussing sexual practices with students. PMID- 21822744 TI - Religious coping and psychological distress in military veteran cancer survivors. AB - Research on the relationship between religious coping and psychological well being in cancer survivors is limited. Forty-eight veteran cancer survivors completed measures of psychological distress, posttraumatic growth, and positive and negative religious coping. Negative religious coping was associated with greater distress and growth. Positive religious coping was associated with greater growth. Gender, race, and religious affiliation were significant predictors of positive and negative religious coping. Veteran cancer survivors who utilize negative religious coping may benefit from referral to clergy or a mental health professional. Assessment of religious coping may be particularly important for female, non-White, and Christian cancer survivors. PMID- 21822746 TI - Abstracts fo the XXXVIth Sir Peter Freyer Memorial Lecture and Surgical Symposium. September 2-3, 2011. Galway, Ireland. PMID- 21822745 TI - Effects of carbonated liquids on oropharyngeal swallowing measures in people with neurogenic dysphagia. AB - Aspiration is common in adults with neurogenic dysphagia and pharyngeal delay. This can lead to dehydration, malnutrition, and aspiration pneumonia. Diet modifications aimed at reducing thin liquid aspiration are partially successful or unpalatable or both. Carbonated liquids show some potential in influencing swallowing behavior. However, there is a paucity of evidence to support this intervention. This study compares the effects of carbonated thin liquids (CTL) with that of noncarbonated thin liquids (NCTL) on oropharyngeal swallowing in adults with neurogenic dysphagia and examines the palatability of the CTL stimulus. Seventeen people with pharyngeal delay attended for videofluoroscopy (VFSS). Outcome measures were oral transit time (OTT), pharyngeal transit time (PTT), stage transition duration (STD), initiation of the pharyngeal swallow (IPS), penetration-aspiration scale (PENASP), and pharyngeal retention (PR). A modification of Quartermaster Hedonic Scale (AQHS) was employed to assess palatability of the CTL. CTL vs. NCTL significantly decreased penetration and aspiration on 5-ml (P = 0.028) and 10-ml (P = 0.037) swallows. CTL had no significant effect on OTT, PTT, IPS, and PR for any volume of bolus. Only one participant disliked the CTL stimulus. These findings support the hypothesis that oropharyngeal swallowing can be modulated in response to sensory stimuli. Implications for research and clinical practice are discussed. PMID- 21822747 TI - Cerebral salt wasting syndrome in post-operative pediatric brain tumor patients. AB - BACKGROUND: Cerebral salt wasting syndrome (CSWS) and the syndrome of inappropriate antidiuretic hormone (SIADH) are both causes of hyponatremia in pediatric neurosurgical patients often with similar presenting symptoms; however, despite similar clinical characteristics the treatment for CSWS and SIADH can be drastically different, which makes the distinction critical for post-operative treatment. Further complicating matters, are the exact mechanism for CSWS which remains unclear, and the incidence and severity of CSWS is not well studied in pediatric neurosurgical patients. We hypothesized that CSWS occurs frequently in post-operative brain tumor patients and is an important cause of post-operative hyponatremia in these patients. METHODS: We designed a single institution retrospective cohort study of all pediatric brain tumor patients undergoing craniotomy for tumor resection at our institution between January 2005 and December 2009. RESULTS: Of the 282 patients undergoing 291 operations, post operative CSWS was identified in 15 cases (5%), and was more frequently observed than SIADH (nine cases, 3%). Median onset of CSWS was on post-operative day 3, lasting a median of 2.5 days. Patients with CSWS were more likely to have suffered post-operative stroke (40 vs. 4.6%, P < 0.001), have chiasmatic/hypothalamic tumors (40 vs. 3.8%, P = 0.002), and be younger (mean age 5.9 vs. 9.7 years, P = 0.01) than eunatremic patients. In addition, nearly half of the patients with CSWS (47%) had post-operative hyponatremic seizures. CONCLUSION: The diagnosis of CSWS should be strongly considered in hyponatremic pediatric patients with significant natriuresis following brain tumor resection, and a treatment initiated promptly to prevent neurologic sequeleae. PMID- 21822748 TI - Ongoing abdominal status myoclonus in postanoxic coma. AB - We present the video of a patient who presented massive and ongoing rhythmic abdominal myoclonus in postanoxic coma. PMID- 21822749 TI - Treatment-related optimism protects quality of life in a phase II clinical trial for metastatic renal cell carcinoma. AB - BACKGROUND: Patients on clinical trials often experience declining quality of life (QOL). Little is known about the psychosocial variables that buffer against decline. PURPOSE: This study aims to examine correlations between psychosocial variables and QOL over the course of a clinical trial in patients with metastatic renal cell cancer. METHODS: At baseline, 114 participants completed measures of treatment-related optimism, social support, and QOL (Functional Assessment of Cancer Therapy-General). QOL was also assessed 2, 4, and 8 weeks after the start of treatment with low-dose or intermediate-dose interferon. RESULTS: QOL decreased significantly in the intermediate-dose group but not in the low-dose group (p < .01). The decline was less severe for patients who had high rather than low treatment optimism (p = .03). A higher level of social support was significantly associated with higher baseline QOL (p < .05) but a more rapid decline in QOL over time (p < .01). CONCLUSION: Treatment optimism was favorably associated with QOL. PMID- 21822750 TI - Outcomes of a 12-month web-based intervention for overweight and obese men. AB - BACKGROUND: This study assessed the effect of a 1-year internet-based weight loss intervention for men. METHODS: Four hundred forty-one overweight and obese men were randomized to intervention or delayed treatment. Participants completed a Web-based assessment of diet and physical activity behaviors and weekly tailored Web modules addressing weight-related behaviors. RESULTS: At 12 months compared to controls, intervention men decreased percent of energy from saturated fat and increased grams of fiber and fruit/vegetable servings per 1.000 kcal (p values < 0.001) and walked 16 min more per day (p < 0.05). No between-group differences in body mass index (BMI), weight, or waist circumference were seen, but among completers, men in the highest tertile of intervention participation had lower weight (98.74 vs. 102.37 kg), BMI (32.38 vs. 33.46), and waist circumference (42.17 vs. 43.47 cm) compared to men who participated less often. CONCLUSIONS: The intervention improved diet and activity behaviors, but weight loss occurred only for those with the highest adherence. PMID- 21822751 TI - Adult health in the context of everyday family life. AB - BACKGROUND: Characteristics of family life are linked both cross-sectionally and prospectively to adult mental and physical health. PURPOSE: This paper discusses social and biological processes that may explain how families influence the health of their members. METHODS: We review naturalistic studies of short-term biopsychosocial processes as they unfold within the family. RESULTS: Day-to-day fluctuations in stressors, demands, and social and emotional experiences in the family are reflected in short-term changes in adult members' affect and in the activity of biological stress-response systems, particularly the hypothalamic pituitary-adrenal axis. CONCLUSIONS: To learn how family environments are linked to health, researchers should study the interlacing of different aspects of the everyday lives of family members, including their physiology, emotions, behavior, activities, and experiences. PMID- 21822752 TI - Assessment of recanalization of chronic total occlusions on left ventricular function in patients with or without previous myocardial infarction by real-time three-dimensional echocardiography. AB - The changes of left ventricular ejection fraction (LVEF) were assessed after successful recanalization of chronic total occlusions (CTO) with or without previous myocardial infarction (MI) by real-time three-dimensional echocardiography (RT3DE). 32 patients with a successfully recanalyzed CTO were included in the present prospective study. The patients were divided into group 1 without previous MI and group 2 with previous MI in the territories of total occlusion vessel that was recanalized. In addition, there was a subgroup composed of 14 patients with collateral flow or retrograde flow in group 2. In all patients, LVEF was determined by RT3DE at baseline and after 6 weeks. In group 1, the evolution of LVEF increased significantly from 59.9 +/- 7.2-67.5 +/- 8.7% (P < 0.05). In group 2, the evolution of LVEF increased from 48.6 +/- 6.1-50.1 +/- 6.4%, however, it was without statistic significance (P > 0.05). The evolution of LVEF increased from 46.8 +/- 7.1-53.0 +/- 7.2% (P < 0.05) in the subgroup of group 2. Left ventricular function in patients with CTO can be feasibility and actually evaluated by RT3DE. The influence of recanalization of CTO on the improvement of left ventricular function was different between MI and non-MI patients. The left ventricular function did not improve in MI patients, but improved significantly in the patients having rich collateral circulation. PMID- 21822753 TI - Q2N and S65D substitutions of ubiquitin unravel functional significance of the invariant residues Gln2 and Ser65. AB - Ubiquitin is a small, globular protein, structure of which has been perfected and conserved through evolution to manage diverse functions in the macromolecular metabolism of eukaryotic cells. Several non-homologous proteins interact with ubiquitin through entirely different motifs. Though the roles of lysines in the multifaceted functions of ubiquitin are well documented, very little is known about the contribution of other residues. In the present study, the importance of two invariant residues, Gln2 and Ser65, have been examined by substituting them with Asn and Asp, respectively, generating single residue variants of ubiquitin UbQ2N and UbS65D. Gln2 and Ser65 form part of parallel G1 beta-bulge adjacent to Lys63, a residue involved in DNA repair, cell-cycle regulated protein synthesis and imparting resistance to protein synthesis inhibitors. The secondary structure of variants is similar to that of UbF45W, a structural homologue of wild-type ubiquitin (UbWt). However, there are certain functional differences observed in terms of resistance to cycloheximide, while there are no major differences pertaining to growth under normal conditions, adherence to N-end rule and survival under heat stress. Further, expression of UbQ2N impedes protein degradation by ubiquitin fusion degradation (UFD) pathway. Such differential responses with respect to functions of ubiquitin produced by mutations may be due to interference in the interactions of ubiquitin with selected partner proteins, hint at biomedical implications. PMID- 21822754 TI - Management of a patient with tracheomalacia and supraglottic obstruction after thyroid surgery. AB - PURPOSE: We describe an unusual combination of dynamic supraglottic, glottic, subglottic, and intrathoracic airway obstructions following a total thyroidectomy. These problems were anticipated, documented videographically, and managed preemptively. CLINICAL FEATURES: Following a total thyroidectomy, we replaced the endotracheal tube with a laryngeal mask airway, namely, the LMA ClassicTM, in a patient with symptomatic tracheal compression and probable obstructive sleep apnea. Spontaneous ventilation was observed bronchoscopically through the LMA-Classic. Supraglottic swelling, extraglottic collapse on inspiration, and intrathoracic collapse on expiration were documented prior to recovery. These observations were of sufficient concern to warrant reinsertion of the endotracheal tube and subsequent tracheal extubation over a tube exchanger. Thereafter, we provided face-mask continuous positive airway pressure using a Boussignac mask with an endotracheal ventilation catheter in situ. CONCLUSIONS: Acute airway collapse following thyroid surgery is a rare and potentially serious complication. Diagnosis by conventional methods may be insensitive. Difficulties may not be apparent until the patient becomes distressed after tracheal extubation, and this circumstance will worsen airway compromise. In such a state, re-establishing the airway can become life-threatening. We describe the preemptive identification, physiologic manifestations, and management of the supraglottic and subglottic obstruction exemplified by this case. PMID- 21822755 TI - Type A aortic dissection during late pregnancy in a patient with Marfan syndrome. AB - PURPOSE: To report the management of a 38-yr-old patient with known Marfan syndrome who presented with acute Stanford type A dissection of the aorta in the 34(th) week of pregnancy. CLINICAL FEATURES: A Cesarean delivery was performed under deep general anesthesia with high-dose opioid administration to avoid tachycardia and hypertension during tracheal intubation and obstetric surgery. Delivery took place less than five minutes after induction of anesthesia, and tracheal intubation of the newborn was required due to opioid-induced hypoventilation. Subsequently, aortic arch repair was performed in the mother after connection to extracorporal bypass. Despite extensive replacement of coagulation factors, severe vaginal bleeding persisted after weaning from extracorporal bypass, and the bleeding stopped only after a hysterectomy was performed. Postoperatively, after a short period in the intensive care unit, mother and child were discharged from hospital in excellent condition ten days after surgery. CONCLUSION: Deep general anesthesia for emergency Cesarean delivery while accepting the risk of respiratory depression in the newborn is a viable option for the anesthetic management of life-threatening events such as Stanford type A dissection. PMID- 21822756 TI - Easily adoptable total joint arthroplasty program allows discharge home in two days. AB - PURPOSE: A safe efficient care pathway is needed to address the increasing need for arthroplasty surgery in Canada. Our primary objective was to determine whether a fast-track model of care can reduce length of hospital stay following total hip and knee arthroplasty while maintaining patient safety and satisfaction. METHODS: In this historical cohort study, 100 patients treated in a newly implemented fast-track program for total joint arthroplasty were compared with 100 patients treated before the introduction of the program. The fast-track program emphasizes preoperative patient education, postoperative multimodal analgesia with periarticular injections, early physiotherapy and rehabilitation, and discharge home with an outpatient rehabilitation program. The primary outcome was hospital length of stay. Secondary outcomes were concerned with patient safety and involved evaluating postoperative side effects, transfers to the tertiary care hospital, and emergency department (ED) visits and readmissions to hospital within 30 days of discharge. RESULTS: Length of hospital stay adjusted for age, sex, smoking, comorbidities, American Society of Anesthesiologists' physical status classification, body mass index, and surgical procedure was reduced significantly for patients in the fast-track program compared with the standard program (mean 47 hr; 95% confidence interval [CI] 41 to 53 vs mean 116 hr; 95% CI 110 to 122, respectively). Patients in the fast-track program were discharged from hospital 69 hr earlier than patients in the standard program (95% CI -60 to -78). Despite significantly less morphine utilization, pain scores trended lower in the fast-track patients, both at rest and with activity, than in patients in the standard group (median 7.5 vs 35 mg, respectively). There were no significant differences between the two groups in the rate of ED visits or readmissions in the first 30 days. CONCLUSION: Our multimodal multidisciplinary fast-track protocol reduced hospital stay and opioid consumption while maintaining a high level of patient safety. Program implementation is feasible both in tertiary care and in community hospitals. PMID- 21822757 TI - Usefulness of histopathological examination in nontraumatic perforation of small intestine. AB - INTRODUCTION: Nontraumatic perforation of small intestine (NTPSI) is a fairly common cause of peritonitis in developing world requiring early surgical intervention. Various etiological factors have been proposed for the cause of small bowel perforation. This retrospective study was conceded with an aim to determine the prevalence patterns of the different etiologies of NTPSI. MATERIALS AND METHODS: A total of 164 patients were included in the study who had segments of small intestine removed for perforation during emergency procedures. Preoperative definitive diagnoses were not known in these cases. On gross examination, most of the small intestine perforations, n = 110 (67%), were found in the terminal ileum. On microscopy, the most frequent category was that of ulcers of nonspecific etiology, n = 61 (37.2%), which showed general features like inflammatory granulation tissue, serositis, and foreign body giant cell reaction. RESULTS: In cases where a definite opinion could be established, infection was the commonest cause, n = 71 (43.3%), wherein tuberculosis (49, 29.9%) and typhoid (22, 13.4%) constituted the greatest number of cases. There were two cases of lymphoma and one case of metastatic adenocarcinoma involving the small intestine. Thus, histopathological examination of operated specimen is a useful guide for the surgeon to decide further management of the patient especially in the case of infections. PMID- 21822758 TI - Effect of aspartame on oxidative stress and monoamine neurotransmitter levels in lipopolysaccharide-treated mice. AB - This study aimed at investigating the effect of the sweetener aspartame on oxidative stress and brain monoamines in normal circumstances and after intraperitoneal (i.p.) administration of lipopolysaccharide (LPS; 100 MUg/kg) in mice. Aspartame (0.625-45 mg/kg) was given via subcutaneous route at the time of endotoxin administration. Mice were euthanized 4 h later. Reduced glutathione (GSH), lipid peroxidation (thiobarbituric acid-reactive substances; TBARS), and nitrite concentrations were measured in brain and liver. Tumor necrosis factor alpha (TNF-alpha) and glucose were determined in brain. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) were measured in liver. The administration of only aspartame (22.5 and 45 mg/kg) increased brain TBARS by 17.7-32.8%, decreased GSH by 25.6-31.6%, and increased TNF-alpha by 16.7-44%. Aspartame caused dose-dependent inhibition of brain serotonin, noradrenaline, and dopamine. Aspartame did not alter liver TBARS, nitrite, GSH, AST, ALT, or ALP. The administration of LPS increased nitrite in brain and liver by 26.8 and 37.1%, respectively; decreased GSH in brain and liver by 21.6 and 31.1%, respectively; increased brain TNF-alpha by 340.4%, and glucose by 39.9%, and caused marked increase in brain monoamines. LPS increased AST, ALT, and ALP in liver tissue by 84.4, 173.7, and 258.9%, respectively. Aspartame given to LPS-treated mice at 11.25 and 22.5 mg/kg increased brain TBARS by 15.5-16.9%, nitrite by 12.6-20.1%, and mitigated the increase in monoamines. Aspartame did not alter liver TBARS, nitrite, GSH, ALT, AST, or ALP. Thus, the administration of aspartame alone or in the presence of mild systemic inflammatory response increases oxidative stress and inflammation in the brain, but not in the liver. PMID- 21822760 TI - Effect of pre- and postnatal manganese exposure on brain histamine content in a rodent model of Parkinson's disease. AB - Rats lesioned shortly after birth with 6-hydroxydopamine (6-OHDA; 134 MUg icv) represent a near-ideal model of severe Parkinson's disease because of the near total destruction of nigrostriatal dopaminergic fibers. There are scarce data that in Parkinson's disease, activity of the central histaminergic system is increased. The element manganese, an essential cofactor for many enzymatic reactions, itself in toxic amount, replicates some clinical features similar to those of Parkinson's disease. The aim of this study was to examine the effect of neonatal manganese exposure on 6-OHDA modeling of Parkinson's disease in rats, and to determine effects on histamine content in the brain of these rats in adulthood. Manganese (MnCl2.4H2O; 10,000 ppm) was included in the drinking water of pregnant Wistar rats from the time of conception until the 21st day after delivery, the age when neonatal rats were weaned. Control rats consumed tap water. Other groups of neonatal rat pups, on the 3rd day after birth, were pretreated with desipramine (20 mg/kg ip 1 h) prior to bilateral icv administration of 6-OHDA (60 or 134 MUg) or its vehicle saline-ascorbic (0.1%) (control). At 2 months after birth, in rats lesioned with 60 or 134 MUg 6-OHDA, endogenous striatal dopamine (DA) content was reduced, respectively, by 92 and 98% (HPLC/ED), while co-exposure of these groups to perinatal manganese did not magnify the DA depletion. However, there was prominent enhancement of histamine content in frontal cortex, hippocampus, hypothalamus, and medulla oblongata of adult rat brain after 6-OHDA (60 and 134 MUg) injection on the day 3rd postnatal day. These findings indicate that histamine and the central histaminergic system are altered in the brain of rats lesioned to model Parkinson's disease, and that manganese enhances effects of 6-OHDA on histamine in brain. PMID- 21822761 TI - Characteristics and quality of autism websites. AB - The World Wide Web is a common method for obtaining information on autism spectrum disorders, however, there are no guidelines for finding websites with high quality. We conducted two studies examining the characteristics and/or quality of autism websites in 2009 and 2010. We found websites with a .gov top level domain had a statistically significant association with high quality websites and websites offering a product or service and websites promoting a non evidence-based practice had a statistically significant association with poor quality websites. Based on our work we concluded that online information should not replace the information consumers obtain from professionals. Further implications for practice, overview of study limitations and future directions are provided. PMID- 21822762 TI - Predictors and moderators of parent training efficacy in a sample of children with autism spectrum disorders and serious behavioral problems. AB - The Research Units on Pediatric Psychopharmacology--Autism Network reported additional benefit when adding parent training (PT) to antipsychotic medication in children with autism spectrum disorders and serious behavior problems. The intent-to-treat analyses were rerun with putative predictors and moderators. The Home Situations Questionnaire (HSQ) and the Hyperactivity/Noncompliance subscale of the Aberrant Behavior Checklist were used as outcome measures. Candidate predictors and moderators included 21 demographics and baseline measures of behavior. Higher baseline HSQ scores predicted greater improvement on the HSQ regardless of treatment assignment, but no other predictors of outcome were observed. None of the variables measured in this study moderated response to PT. Antipsychotic medication plus PT appears to be equally effective for children with a wide range of demographic and behavioral characteristics. PMID- 21822763 TI - Valence scaling of dynamic facial expressions is altered in high-functioning subjects with autism spectrum disorders: an fMRI study. AB - FMRI was performed with the dynamic facial expressions fear and happiness. This was done to detect differences in valence processing between 25 subjects with autism spectrum disorders (ASDs) and 27 typically developing controls. Valence scaling was abnormal in ASDs. Positive valence induces lower deactivation and abnormally strong activity in ASD in multiple regions. Negative valence increased deactivation in visual areas in subjects with ASDs. The most marked differences between valences focus on fronto-insular and temporal regions. This supports the idea that subjects with ASDs may have difficulty in passive processing of the salience and mirroring of expressions. When the valence scaling of brain activity fails, in contrast to controls, these areas activate and/or deactivate inappropriately during facial stimuli presented dynamically. PMID- 21822764 TI - Using the transporters DVD as a learning tool for children with Autism Spectrum Disorders (ASD). AB - Data from two groups of children who were randomly allocated to those groups showed that the ability of children with ASD to identify and label basic and complex facial expressions following a 3-week home based DVD intervention significantly improved when viewing The Transporters DVD. Improvements in emotion recognition appear related to the content of the DVD as participants in a control group who observed an alternate DVD showed no such improvement. Although social behaviour improved significantly as a result of watching The Transporters, a significant improvement in social behaviour was however, also observed in the Thomas the Tank Engine condition suggesting the unique content of The Transporters DVD was not pivotal to the improvement of social behaviour in general. PMID- 21822766 TI - Periodic multidrug therapy in a within-host virus model. AB - Floquet theory and perturbation techniques are used to analyze a classical within host virus model with periodic drug treatment. Both single and multidrug treatment strategies are investigated. Specifically, the effects of both RT inhibitors and P-inhibitors on the stability of the infection-free steady state are studied. It is found that when both classes of drugs have periodic drug efficacy functions, then shifting the phase of these functions can critically affect the stability of the infection-free steady state. A numerical study is conducted to illustrate the theoretical results and provide additional insights. PMID- 21822765 TI - Mental states inside out: switching costs for emotional and nonemotional sentences that differ in internal and external focus. AB - Mental states-such as thinking, remembering, or feeling angry, happy, or dizzy have a clear internal component. We feel a certain way when we are in these states. These internal experiences may be simulated when people understand conceptual references to mental states. However, mental states can also be described from an "external" perspective, for example when referring to "smiling." In those cases, simulation of visible outside features may be more relevant for understanding. In a switching costs paradigm, we presented semantically unrelated sentences describing emotional and nonemotional mental states while manipulating their internal or external focus. The results show that switching costs occur when participants shift between sentences with an internal and an external focus. This suggests that different forms of simulation underlie understanding these sentences. In addition, these effects occurred for emotional and nonemotional mental states, suggesting that they are grounded in a similar way-through the process of simulation. PMID- 21822767 TI - Development and evaluation of a prototype of a novel clotting time test to monitor enoxaparin. AB - PURPOSE: Dosing of the anticoagulant enoxaparin may result in bleeding following excessive doses or thrombosis if dose is too low. Rarely, anti-Xa activity is used to assess the dose for enoxaparin, but its utility to predict clotting or bleeding remains uncertain. We aimed to develop a clotting time test to monitor enoxaparin therapy. METHODS: A previously developed mathematical model of the coagulation network was used to identify suitable targets for monitoring enoxaparin therapy. In vitro experiments were then carried out to demonstrate proof of mechanism of the clotting time test activated by the new target activator. RESULTS: Using the mathematical model, we identified Xa as a plausible activating agent for a clotting time test for enoxaparin. In vitro experiments showed a prolongation of the Xa clotting time of 4.6-fold in the presence of enoxaparin (0.5 IU/ml) where 10 nM Xa was used to activate clotting. CONCLUSIONS: Using both simulations and in vitro experiments, we provide a proof of mechanism for the Xa clotting time (XaCT) test, which can be considered for further development to provide a biomarker of the effect of enoxaparin on the clotting system. PMID- 21822768 TI - Myocardial perfusion GSPECT imaging in patients with myocardial bridging. AB - BACKGROUND: The aim of this study was to investigate the incidence, reversibility, and severity of LV perfusion abnormalities in patients with isolated myocardial bridges using a gated myocardial perfusion SPECT study (GSPECT). METHODS: A retrospective study involved 42 patients without history of myocardial infarction, with isolated myocardial bridges detected in coronary angiography and no substantial evidence of atherosclerotic changes in coronary arteries. In all patients a gated SPECT study was performed at both rest and stress, after intravenous administration of (99m)Tc MIBI. Reconstructed slices were analyzed using a 20-segment model of the left ventricle. RESULTS: Incidence and severity of stress-induced ischemia were related to degree of artery constriction (P = .002 and .00014, respectively). Perfusion abnormalities were detected only in patients with critical narrowing (>= 50%) of artery (in 12 out of 28, i.e., 43% of patients). Summed stress scores (SSS) ranged from 4 to 11 (mean 7), indicating slight or moderate defect intensity. Only 1 patient presented with a SSS value of 31 (severe defect). Perfusion defects were stress induced in 70 out of 72 (97%) segments with abnormal perfusion. CONCLUSION: Perfusion abnormalities were observed in ab. 40% of patients with critical (>= 50%) narrowing of artery affected by bridging and were mild, stress induced. PMID- 21822769 TI - Real-time 3D fluoroscopy-guided large core needle biopsy of renal masses: a critical early evaluation according to the IDEAL recommendations. AB - INTRODUCTION: Three-dimensional (3D) real-time fluoroscopy cone beam CT is a promising new technique for image-guided biopsy of solid tumors. We evaluated the technical feasibility, diagnostic accuracy, and complications of this technique for guidance of large-core needle biopsy in patients with suspicious renal masses. METHODS: Thirteen patients with 13 suspicious renal masses underwent large-core needle biopsy under 3D real-time fluoroscopy cone beam CT guidance. Imaging acquisition and subsequent 3D reconstruction was done by a mobile flat panel detector (FD) C-arm system to plan the needle path. Large-core needle biopsies were taken by the interventional radiologist. Technical success, accuracy, and safety were evaluated according to the Innovation, Development, Exploration, Assessment, Long-term study (IDEAL) recommendations. RESULTS: Median tumor size was 2.6 (range, 1.0-14.0) cm. In ten (77%) patients, the histological diagnosis corresponded to the imaging findings: five were malignancies, five benign lesions. Technical feasibility was 77% (10/13); in three patients biopsy results were inconclusive. The lesion size of these three patients was <2.5 cm. One patient developed a minor complication. Median follow-up was 16.0 (range, 6.4 19.8) months. CONCLUSIONS: 3D real-time fluoroscopy cone beam CT-guided biopsy of renal masses is feasible and safe. However, these first results suggest that diagnostic accuracy may be limited in patients with renal masses<2.5 cm. PMID- 21822770 TI - Chemoembolization for hepatocellular carcinoma supplied exclusively by the hepatic falciform artery. AB - PURPOSE: The purpose of this study was to describe imaging appearances of hepatocellular carcinoma (HCC) supplied exclusively by the hepatic falciform artery (HFA) and safety of chemoembolization via the HFA. METHODS: During the past 6 years, we have performed chemoembolization for the treatment of 12 patients with HCCs supplied exclusively by the HFA. Computed tomography (CT) scans, digital subtraction angiograms, and medical records were retrospectively reviewed by consensus. RESULTS: Tumors were located in Couinaud segments IV (n = 7) and III (n = 5) and in subcapsular areas around the falciform ligaments. Tumor size ranged from 1.0 to 1.8 cm (mean, 1.3 cm; median, 1.3 cm). HFAs originated from A4 (n = 7), A3 (n = 4), and the left hepatic artery near the umbilical point (n = 1). All tumors were supplied exclusively by the HFA. Prophylactic embolization of the distal HFA before chemoembolization was performed using gelatin sponge particles in only one patient, and selective chemoembolization via the HFA was achieved in all patients. One patient suffered from a skin rash after chemoembolization and recovered after conservative management. Individual responses of tumors supplied exclusively by the HFA were complete response (n = 8), partial response (n = 1), and stable disease (n = 2) at the first follow-up enhanced CT scan. CONCLUSIONS: The HFA can supply HCC located in subcapsular areas around the falciform ligament, and the tumors can be safely chemoembolized without significant complications. PMID- 21822771 TI - Ten years of experience with the GORE EXCLUDER(r) stent-graft for the treatment of aortic and iliac aneurysms: outcomes from a single center study. AB - PURPOSE: This study was designed to assess the long-term outcome of selected patients with aortic, aortoiliac, and isolated common iliac aneurysms treated with the GORE EXCLUDER(r) stent-graft. METHODS: Between December 1998 and June 2010, 121 nonconsecutive patients underwent insertion of a GORE EXCLUDER(r) stent graft to treat an aortic (n=80; 66%), aortoiliac (n=25; 21%), or isolated common iliac (n=16; 13%) aneurysm. Procedural and follow-up data were collected prospectively. Primary endpoints are overall survival, intervention-free survival, and freedom from aneurysm rupture. Secondary endpoints are device- and procedure-related complications, including all types of endoleaks or endotension, and reintervention. RESULTS: The mean follow-up is 4.98 years (standard deviation, 3.18; median follow-up, 4.05 years). The estimated percentage overall survival (with 95% confidence interval) after respectively 5 and 10 years of follow-up is 74.5% (65.8; 81.3) and 57.8% (47.7; 66.7). The estimated intervention-free survival after respectively 5 and 10 years is 90% (84.3; 96.1) and 77.7% (67; 88.4). There was no aneurysm rupture during follow-up. Early postoperative complications occurred in 16 patients (13%); none were fatal. Late reinterventions were performed in 18 patients (15%). Finally, throughout the follow-up period, endoleaks were identified: type I (n=4; 3%); type II (n=39; 32%); type III (n=0; 0%); endotension was seen in 11 patients (9%). CONCLUSIONS: Aneurysm exclusion with use of the GORE EXCLUDER(r) stent-graft is durable through a mean follow-up of nearly 5 years. There was no postprocedural aneurysm rupture. Complications occurred throughout the follow-up period, requiring continued clinical and radiological surveillance. PMID- 21822772 TI - Carbon monoxide exposure enhances arrhythmia after cardiac stress: involvement of oxidative stress. AB - Arrhythmias following cardiac stress are a key predictor of death in healthy population. Carbon monoxide (CO) is a ubiquitous pollutant promoting oxidative stress and associated with hospitalization for cardiovascular disease and cardiac mortality. We investigated the effect of chronic CO exposure on the occurrence of arrhythmic events after a cardiac stress test and the possible involvement of related oxidative stress. Wistar rats exposed chronically (4 weeks) to sustained urban CO pollution presented more arrhythmic events than controls during recovery after cardiac challenge with isoprenaline in vivo. Sudden death occurred in 22% of CO-exposed rats versus 0% for controls. Malondialdehyde (MDA), an end-product of lipid peroxidation, was increased in left ventricular tissue of CO-exposed rats. Cardiomyocytes isolated from CO-exposed rats showed higher reactive oxygen species (ROS) production (measured with MitoSox Red dye), higher diastolic Ca(2+) resulting from SR calcium leak and an higher occurrence of irregular Ca(2+) transients (measured with Indo-1) in comparison to control cells after a high pacing sequence. Acute treatment with a ROS scavenger (N-acetylcysteine, 20 mmol/L, 1 h) prevented this sequence of alterations and decreased the number of arrhythmic cells following high pacing. Chronic CO exposure promotes oxidative stress that alters Ca(2+) homeostasis (through RYR2 and SERCA defects) and thereby mediates the triggering of ventricular arrhythmia after cardiac stress that can lead to sudden death. PMID- 21822773 TI - Providers' perceptions and practices regarding BRCA1/2 genetic counseling and testing in African American women. AB - We examined healthcare providers' perceptions of genetic counseling and testing in African American women at moderate to high-risk of carrying a BRCA1/2 mutation. We conducted 20 in-depth interviews with genetic counselors (n = 5), medical oncologists (n = 8), obstetrician/gynecologists (n = 2) and surgeons (n = 5). Interviews were audiotaped, transcribed and independently coded by two individuals using a content analysis approach. Seven themes emerged relevant to providers' perceptions of African American women's use of BRCA1/2 genetic services: access factors, cultural beliefs and preferences, effects of testing, patient motivators for genetic counseling and testing, patient-provider communication, reasons for provider referral, and reasons for patient refusal. Providers identified individual- and system-level barriers to African American women's use of genetic services, including lack of follow-up after referrals to genetic specialists and challenges to obtaining financial coverage for under- and uninsured high-risk women. Results have implications for physician and patient education regarding appropriate referrals to and uptake of genetic services in at risk African American women. PMID- 21822775 TI - A zebrafish scale assay to monitor dioxin-like activity in surface water samples. AB - New regulations on water quality require a close control of the possible biological activities known or unexpected pollutants may bring about. We present here a protocol based on the direct exposure of zebrafish to river water and the analysis of expression of specific genes in their scales to determine the presence of compounds with dioxin-like biological activity. The method does not require the killing of animals and allows detection of the biological activity after a single day of exposure. When tested, the method with real samples from the Llobregat River, clear temporal and spatial variations were observed, demonstrating its suitability for monitoring natural variations in water quality linked to specific discharges. High biological activities were unrelated to the currently checked water quality parameters (macropollutants, turbidity, TOC, etc.), but they did correlate with the presence of micropollutants (estrogens, detergents, etc.) related to domestic and/or industrial runoffs. The scale assay therefore provides a new tool to evaluate water quality changes that cannot be easily derived from the existing standard analytical procedures. It ranks among the very few described protocols able to detect biological effects from natural water samples, without a pre-concentration step, and after only 24 h of exposure. PMID- 21822776 TI - Development of a monoclonal antibody-based, congener-specific and solvent tolerable direct enzyme-linked immunosorbent assay for the detection of 2,2',4,4' tetrabromodiphenyl ether in environmental samples. AB - A sensitive direct enzyme-linked immunosorbent assay (ELISA) for the specific detection of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) in environmental samples was developed. A hapten mimicking BDE-47 was synthesized by introducing a butyric acid spacer into 5-hydroxy-BDE-47 and coupled to keyhole limpet hemocyanin to form an immunogen for the production of monoclonal antibodies (Mabs) against BDE 47. The most sensitive direct ELISA was formatted with a Mab, designated as 4F2, in combination with 5-(2,4-dibromophenoxy)pentanoic acid peroxidase as a tracer. The inhibition half-maximum concentrations and limit of detection of BDE-47 in phosphate buffered saline with 25% DMSO were 1.4 +/- 0.05 and 0.1 ng mL(-1), respectively. Cross-reactivity values of the ELISA with the tested BDE congeners and metabolites were <=5.8%. This assay was used to determine BDE-47 in soil, sediment and house dust samples after ultrasonic extraction, simple cleanup and concentration steps. The average recoveries, repeatabilities (intraday extractions and analyses), and intra-laboratory reproducibilities (interday extractions and analyses) were in a range of 92-126%, 8-19% and 9-25%, respectively. Applied to 44 real samples, the results of this assay displayed a statistically significant correlation with those of a gas chromatography-mass spectrometry method (R(2)=0.79-0.85), indicating this ELISA is a suitable tool for environmental analyses of BDE-47. PMID- 21822774 TI - AAV8-mediated long-term expression of human LCAT significantly improves lipid profiles in hCETP;Ldlr(+/-) mice. AB - Lecithin:cholesterol acyltransferase (LCAT) is the key circulating enzyme responsible for high-density lipoprotein (HDL) cholesterol esterification, HDL maturation, and potentially reverse cholesterol transport. To further explore LCAT's mechanism of action on lipoprotein metabolism, we employed adeno associated viral vector (AAV) serotype 8 to achieve long-term (32-week) high level expression of human LCAT in hCETP;Ldlr(+/-) mice, and characterized the lipid profiles in detail. The mice had a marked increase in HDL cholesterol, HDL particle size, and significant reduction in low-density lipoprotein (LDL) cholesterol, plasma triglycerides, and plasma apoB. Plasma LCAT activity significantly increased with humanized substrate specificity. HDL cholesteryl esters increased in a fashion that fits human LCAT specificity. HDL phosphatidylcholines trended toward decrease, with no change observed for HDL lysophosphatidylcholines. Triglycerides reduction appeared to reside in all lipoprotein particles (very low-density lipoprotein (VLDL), LDL, and HDL), with HDL triglycerides composition highly reflective of VLDL, suggesting that changes in HDL triglycerides were primarily driven by the altered triglycerides metabolism in VLDL. In summary, in this human-like model for lipoprotein metabolism, AAV8-mediated overexpression of human LCAT resulted in profound changes in plasma lipid profiles. Detailed lipid analyses in the lipoprotein particles suggest that LCAT's beneficial effect on lipid metabolism includes not only enhanced HDL cholesterol esterification but also improved metabolism of apoB containing particles and triglycerides. Our findings thus shed new light on LCAT's mechanism of action and lend support to its therapeutic potential in treating dyslipidemia. PMID- 21822777 TI - Fluorescence dye as novel label molecule for quantitative SERS investigations of an antibiotic. AB - Within this contribution, the proof-of-principle for a new concept for indirect surface-enhanced Raman spectroscopy (SERS) detection is presented. The fluorescence dye FR-530 is applied as a label molecule for the antibiotic erythromycin. The antibiotic binds directly to the label molecule. Changes within the SERS spectrum of the fluorescence dye appearing with the presence of the antibiotic are utilized for the detection and quantitative investigations of erythromycin. With the new concept of binding the label molecule directly to the analyte molecule, the application of linkage compounds like antibodies or any other recognition molecules becomes dispensable. PMID- 21822778 TI - Focus on analytical chemistry to illuminate the past. PMID- 21822779 TI - Process for detecting Helicobacter pylori using aliphatic amides. AB - Helicobacter pylori diagnosis is fundamental in the management of gastrointestinal pathologies, whose current clinical guidelines support a non invasive 'test-and-treat' strategy. As such, the present work reports the basis of a new, low-cost, specific breath test based on the detection of volatile carboxylic acids resulting from the hydrolysis of short-chain aliphatic amides by H. pylori amidases. Propionamide and butyramide, which are metabolized by amidases to propionic and butyric acids, were elected for this study. Conditions for the extraction of these acids from a vapour phase were optimized concerning the use of solid-phase microextraction (SPME) followed by gas chromatography quadrupole mass spectrometry (GC-qMS) analysis. SPME-GC-qMS was then used to detect the acids released into a vapour phase upon incubation of a H. pylori reference strain J99 or a clinical specimen with the amides. These experiments have demonstrated that the administration of less than 9 mg of propionamide and/or butyramide to H. pylori cultures, in loads recognized to cause infection (10(6)-10(9) cells), resulted in the formation of detectable and/or quantifiable amounts of propionic and/or butyric acids after 30 min incubation. As such, propionic and butyric acids can be used as biomarkers for H. pylori upon incubation with the corresponding amides. SPME-GC-qMS was also used to verify the hepatic stability of the acids. These experiments were conducted in mouse liver cells and revealed no signs of metabolization that could compromise their bioavailability in future in vivo assays. Moreover, SPME-GC-qMS permitted the detection of both acids in amounts as low as 0.8 MUg in systems mimicking exhaled breath, demonstrating the sensitivity of the method for these compounds. PMID- 21822780 TI - Dexamethasone inhibits ICAM-1 and MMP-9 expression and reduces brain edema in intracerebral hemorrhagic rats. AB - BACKGROUND: The molecular mechanism of hemorrhagic stroke is unclear, and the identification of therapeutic agents for attenuating post-stroke brain damage remains an unresolved challenge. Dexamethasone (DEX) is used clinically to treat spinal cord injury and brain tumor patients by reducing edema formation, but has produced conflicting results in stroke management. METHODS: In this study, intracerebral hemorrhage (ICH) was induced in rats by intracranial stereotactic injection of collagenase into the caudate nucleus. DEX was given immediately and 3 days after ICH. The expression of intercellular adhesion molecule-1 (ICAM-1), matrix metalloproteinase-9 (MMP-9), nuclear factor (NF)-kappaB, and IkappaB were analyzed by Western blotting, and perihematomal edema formation was evaluated by magnetic resonance imaging. RESULTS: The results showed that ICH caused an increase of ICAM-1 and MMP-9 expression from 4 h to 7 days, which was inhibited following the administration of DEX. The perihematomal edema volume in ICH rats was high, with two peak periods at 12 h and 3 days, which was also reduced in DEX treated groups. Furthermore, the administration of DEX not only maintained IkappaB in cytoplasm, but also decreased NF-kappaB elevation in the nucleus at 3 and 5 days in ICH rats. CONCLUSIONS: In conclusion, these data show that DEX successfully reduced post-stroke brain edema by decreasing MMP-9 and ICAM-1 levels, partially through the IkappaB/NF-kappaB signaling pathway. The timing of DEX administration in relation to the onset of brain injury may be critical. PMID- 21822781 TI - Epidural capillary hemangioma of the thoracic spine with proximal nerve root involvement and extraforaminal extension. PMID- 21822782 TI - Central and peripheral neurotoxicity of metronidazole after treatment for brain abscess. PMID- 21822783 TI - Rupture of an internal carotid artery aneurysm within a clinoidal meningioma following stereotactic radiosurgery. PMID- 21822785 TI - Raw data-based iterative reconstruction in body CTA: evaluation of radiation dose saving potential. AB - OBJECTIVE: To evaluate prospectively, in patients undergoing body CTA, the radiation dose saving potential of raw data-based iterative reconstruction as compared to filtered back projection (FBP). METHODS: Twenty-five patients underwent thoraco-abdominal CTA with 128-slice dual-source CT, operating both tubes at 120 kV. Full-dose (FD) images were reconstructed with FBP and were compared to half-dose (HD) images with FBP and HD-images with sinogram-affirmed iterative reconstruction (SAFIRE), both reconstructed using data from only one tube-detector-system. Image quality and sharpness of the aortic contour were assessed. Vessel attenuation and noise were measured, contrast-to-noise-ratio was calculated. RESULTS: Noise as image quality deteriorating artefact occurred in 24/25 (96%) HD-FBP but not in FD-FBP and HD-raw data-based iterative reconstruction datasets (p < 0.001). Other artefacts occurred with similar prevalence among the datasets. Sharpness of the aortic contour was higher for FD FBP and HD-raw data-based iterative reconstruction as compared to HD-FBP (p < 0.001). Aortoiliac attenuation was similar among all datasets (p > 0.05). Lowest noise was found for HD-raw data-based iterative reconstruction (7.23HU), being 9.4% lower than that in FD-FBP (7.98HU, p < 0.05) and 30.8% lower than in HD-FBP images (10.44HU, p < 0.001). Contrast-to-noise-ratio was lower in HD-FBP (p < 0.001) and higher in HD-raw data-based iterative reconstruction (p < 0.001) as compared to FD-FBP. CONCLUSION: Intra-individual comparisons of image quality of body CTA suggest that raw data-based iterative reconstruction allows for dose reduction >50% while maintaining image quality. Key Points * Raw data-based iterative reconstruction reduces image noise and improves image quality as compared to filtered back projection * At a similar radiation dose, raw data based iterative reconstruction improves the sharpness of vessel contours * In body CTA a dose reduction of >50% might be possible when using raw data-based iterative reconstructions, while image quality can be maintained. PMID- 21822784 TI - Functional imaging of lung cancer using dual energy CT: how does iodine related attenuation correlate with standardized uptake value of 18FDG-PET-CT? AB - OBJECTIVES: To investigate the correlation between maximum standardized uptake value (SUV(max)) of (18)FDG PET-CT and iodine-related attenuation (IRA) of dual energy CT (DECT) of primary tumours and (18)FDG PET-CT positive thoracic lymph nodes (LN) in patients with lung cancer. METHODS: 37 patients with lung cancer (27 NSCLC, 10 SCLC, 86 (18)FDG PET-CT positive thoracic LN) who underwent both (18)FDG PET-CT and DECT were analyzed. The mean study interval between (18)FDG PET-CT and DECT was <=21 days in 17 patients. The mean and maximum IRA of DECT as well as of virtual unenhanced and virtual 120 kV images of DECT was analyzed and correlated to the SUV(max) of (18)FDG PET-CT in all tumours and (18)FDG PET-CT positive thoracic lymph nodes. Further subgroup analysis was performed for histological subtypes in all groups. RESULTS: A moderate correlation was found between SUV(max) and maximum IRA in all tumours (n = 37;r = 0.507;p = 0.025) whereas only weak or no correlation were found between SUV(max) and all other DECT measurements. A strong correlation was found in patients with study intervals <=21 days (n = 17; r = 0.768;p = 0.017). Analysis of histological subtypes of lung cancer showed a strong correlation between SUV(max) and maximum IRA in the analysis of all patients with NSCLC (r = 0.785;p = 0.001) and in patients with NSCLC and study intervals <=21 days (r = 0.876;p = 0.024). Thoracic LN showed moderate correlation between SUV(max) and maximum IRA in patients with study intervals <=21 days (r = 0.654; p = 0.010) whereas a weak correlation was found between SUV(max) and maximum IRA in patients with study intervals >21 days (r = 0.299; p = 0.035). CONCLUSIONS: DECT could serve as a valuable functional imaging test for patients with NSCLC as the IRA of DECT correlates with SUV(max) of (18)FDG PET-CT. PMID- 21822786 TI - Trigeminal neuralgia: assessment with T2 VISTA and FLAIR VISTA fusion imaging. AB - OBJECTIVE: To evaluate the neurovascular compression (NVC) in patients with trigeminal neuralgia (TN) using T2 VISTA and FLAIR VISTA fusion imaging. METHODS: Sixty-six consecutive patients with TN who underwent MR imaging at 3-T between April 2008 and December 2010 were retrospectively reviewed. Multiplanar reconstructions (MPR) of T2 VISTA and FLAIR VISTA fusion imaging were used for image interpretation. The frequency of vascular contact, the segment of compression and the type of vessel were compared between the ipsilateral symptomatic side and the contralateral asymptomatic side. RESULTS: The frequency of vascular contact on the ipsilateral side and the contralateral side were 95.5% (63/66) and 74.2% (49/66), respectively. The frequency of indentation on the ipsilateral side and contralateral side were 74.2% (49/66) and 21.2% (14/66), and showed a statistically significant difference (p < 0.05). The sensitivity, specificity and odds ratio were 77.8%, 71.4% and 10.7, respectively. There were no significant differences in the involved segment or type of vessel between the ipsilateral side and contralateral side. CONCLUSION: MPR of T2 VISTA and FLAIR VISTA fusion imaging is useful in the detection of NVC in patients with TN. Vascular indentation can predict the presence of symptoms in patients with TN. Key Points *Fusion MRI with multiplanar reconstruction can detect neurovascular compression in patients with trigeminal neuralgia *Vascular indentation can predict the presence of symptoms in patients with trigeminal neuralgia *In patients with trigeminal neuralgia, neurovascular indentation is commoner on the symptomatic side. PMID- 21822787 TI - Sp1king out cancer (....and fibrosis?). AB - It is becoming increasingly apparent that many of the basic mechanisms underlying cancers also underlie fibrotic diseases. For example, the Sp1 family of transcription factors plays an essential role in controlling the gene expression of proteins that promote both oncogenesis and fibrogenesis. The drug mithramycin, which prevents Sp1 binding to DNA, has been in use clinically for some cancers, but has side-effects. However, other drugs exist that affect Sp1 activity through promoting Sp1 protein degradation. Evidence has emerged that low levels of mithramycin can be combined with these drugs to result in potent antitumorigenic effects without resulting in obvious toxicity (Gao et al. Cancer Res 2011 Jun 20; Jia et al. Cancer Res 70:1111-1119, 2010). Given that Sp1 proteins also promote expression of profibrotic genes such as collagen type I and CCN2, it is possible that this combinatorial approach may be taken in the future to block not only cancer but also fibrosis. PMID- 21822788 TI - Role of Streptococcus intermedius DnaK chaperone system in stress tolerance and pathogenicity. AB - Streptococcus intermedius is a facultatively anaerobic, opportunistic pathogen that causes purulent infections and abscess formation. The DnaK chaperone system has been characterized in several pathogenic bacteria and seems to have important functions in stress resistance and pathogenicity. However, the role of DnaK in S. intermedius remains unclear. Therefore, we constructed a dnaK knockout mutant that exhibited slow growth, thermosensitivity, accumulation of GroEL in the cell, and reduced cytotoxicity to HepG2 cells. The level of secretion of a major pathogenic factor, intermedilysin, was not affected by dnaK mutation. We further examined the function and property of the S. intermedius DnaK chaperone system by using Escherichia coli DeltadnaK and DeltarpoH mutant strains. S. intermedius DnaK could not complement the thermosensitivity of E. coli DeltadnaK mutant. However, the intact S. intermedius DnaK chaperone system could complement the thermosensitivity and acid sensitivity of E. coli DeltadnaK mutant. The S. intermedius DnaK chaperone system could regulate the activity and stability of the heat shock transcription factor sigma(32) in E. coli, although S. intermedius does not utilize sigma(32) for heat shock transcription. The S. intermedius DnaK chaperone system was also able to efficiently eliminate the aggregated proteins from DeltarpoH mutant cells. Overall, our data showed that the S. intermedius DnaK chaperone system has important functions in quality control of cellular proteins but has less participation in the modulation of expression of pathogenic factors. PMID- 21822789 TI - No beta cell desensitisation after a median of 68 months on glibenclamide therapy in patients with KCNJ11-associated permanent neonatal diabetes. PMID- 21822790 TI - Community-acquired enterococcal urinary tract infections in hospitalized children. AB - The objectives of this study were to characterize community-acquired (CA) enterococcal urinary tract infections (UTIs) in a tertiary pediatric center and to determine risk factors for their occurrence, their association with renal abnormalities, their antibiotic susceptibility profile, and the appropriateness of the empiric antibiotic treatment, in comparison to those of Gram-negative UTIs. In a 5-year prospective clinical and laboratory study, we found that enterococcal UTIs caused 6.2% (22/355) of culture-proven CA UTIs. Compared with Gram-negative UTI, enterococcal UTI was associated with male predominance, higher rates of underlying urinary abnormalities (70 vs. 43.7%; p = 0.03) and inappropriate empiric antibiotic therapy (22 vs. 5.6%; p = 0.02), and mainly vesicoureteral reflux (53% of cases). This study highlights the importance of early detection of CA enterococcal UTIs because of their association with underlying urinary abnormalities and a high rate of inappropriate empiric antibiotic therapy. Renal imaging is recommended for children with enterococcal UTIs; Gram stain is suggested in selected cases to detect Gram-positive cocci for early diagnosis of enterococcal UTIs and initiation of appropriate antibiotics. PMID- 21822791 TI - Seroprevalence and risk factors associated with bovine viral diarrhea virus (BVDV) infection in non-vaccinated dairy and dual purpose cattle herds in Ecuador. AB - A cross-sectional study was carried out to determine the seroprevalence and risk factors associated with Bovine viral diarrhea virus (BVDV) infection in non vaccinated dairy and dual-purpose cattle herds from Ecuador. A total of 2,367 serum samples from 346 herds were collected from June 2008 through February 2009. A questionnaire, which included variables related to cattle, health, management measures, and the environment, was filled out in each herd. A commercial indirect enzyme-linked immunosorbent assay test was used to determine the seropositivity. A logistic regression model was used to determine risk factors at herd level. The individual seroprevalence for BVDV in non-vaccinated herds in Ecuador was 36.2% (857/2,367; CI(95%), 34.3-38.1%). The herd prevalence was 74% (256/346; CI(95%), 69.4-78.6%) and the intra-herd prevalence ranged between 11.1% and 100% (mean = 51.6%). The logistic regression model showed that the density of cattle farms in the area (more than 70%; OR, 1.94; CI(95%), 1.21-3.2) and the altitude (higher than 2,338 m above sea level; 2.33; CI(95%), 1.4-3.9) are potential risk factors associated with BVDV infection. PMID- 21822792 TI - Heat-related mortality in the Florentine area (Italy) before and after the exceptional 2003 heat wave in Europe: an improved public health response? AB - High ambient temperatures have been associated with increased mortality across the world. Several studies suggest that timely preventive measures may reduce heat-related excess mortality. The main aim of this study was to detect the temporal modification of heat-related mortality, in older adults (aged 65-74) and in elderly >=75 years old, in the Florentine area by comparing previous (1999 2002) and subsequent (2004-2007) periods to the summer of 2003, when a regional Heat-Health Warning System (HHWS) was set up. Mortality data from 1999 to 2007 (May-September) were provided by the Mortality Registry of the Tuscany Region (n = 21,092). Weather data were used to assess daily apparent temperatures (AT). Case-crossover time-stratified designs and constrained segmented distributed lag models were applied. No significant heat-related mortality odds ratio (OR) variations were observed among the sub-periods. Nevertheless, a general OR decrease dating from 1999-2002 (OR 1.23; lack of HHWS) to 2004-2005 (OR 1.21; experimental HHWS running only for Florence) and to 2006-2007 (OR 1.12; official HHWS extended to the whole Florentine area) was observed when the maximum AT was considered. This modification was only evident in subjects >=75 years old. The heat effect was higher and sustained for more days (until lag 9) during the period 1999-2002 than 2004-2007. The decrease of the excessive heat effect on mortality between periods with the absence and existence of a HHWS is also probably due to the mitigation of preventive measures and the implementation of a HHWS with specific interventions for safeguarding the health of the "frail elderly". PMID- 21822793 TI - Cell wall polysaccharide distribution in Sandersonia aurantiaca flowers using immuno-detection. AB - The localization of cell wall polysaccharides of the fused petals of monocotyledonous Sandersonia aurantiaca flowers has been identified using antibodies directed to pectin and xyloglucan epitopes and detection by fluorescence microscopy. Cross sections of the petal tissue were taken from cut flowers in bud and at various stages of maturity and senescence. Patterns of esterification in pectin backbones were identified by JIM5 and 2F4 labelling. Pectic galactan and arabinan side branches were detected by LM5 and LM6, respectively, while fucosylated xyloglucan was identified by CCRC-M1. The labelling patterns highlighted compositional differences between walls of the outer/inner epidermis compared to the spongy parenchyma cells of the interior mesophyll for fucosylated xyloglucan and arabinan. Partially esterified homogalacturonan was present in the junction zones of the outer epidermis and points of contact between cells of the mesophyll, and persisted throughout senescence. Pectic galactans were ubiquitous in the outer and inner epidermal cell walls and walls of the interior mesophyll at flower opening, whereas pectic arabinan was found predominantly in the epidermal cells. Galactan was lost from walls of all cells as flowers began to senesce, while fucosylated xyloglucan appeared to increase over this time. Such differences in the location of polysaccharides and the timing of changes suggest distinct combinations of certain polysaccharides offer mechanical and rheological advantages that may assist with flower opening and senescence. PMID- 21822796 TI - Yinglai Wang: an admirable biochemist for his foresightedness and selflessness. PMID- 21822795 TI - EmmdR, a new member of the MATE family of multidrug transporters, extrudes quinolones from Enterobacter cloacae. AB - We cloned a gene, ECL_03329, from the chromosome of Enterobacter cloacae ATCC13047, using a drug-hypersensitive Escherichia coli KAM32 cell as the host. We show here that this gene, designated as emmdR, is responsible for multidrug resistance in E. cloacae. E. coli KAM32 host cells containing the cloned emmdR gene (KAM32/pEMMDR28) showed decreased susceptibilities to benzalkonium chloride, norfloxacin, ciprofloxacin, levofloxacin, ethidium bromide, acriflavine, rhodamine6G, and trimethoprim. emmdR-deficient E. cloacae cells (EcDeltaemmdR) showed increased susceptibilities to several of the antimicrobial agents tested. EmmdR has twelve predicted transmembrane segments and some shared identity with members of the multidrug and toxic compound extrusion (MATE) family of transporters. Study of the antimicrobial agent efflux activities revealed that EmmdR is an H+-drug antiporter but not a Na+ driven efflux pump. These results indicate that EmmdR is responsible for multidrug resistance and pumps out quinolones from E. cloacae. PMID- 21822797 TI - Perspectives on the role of mTORC2 in B lymphocyte development, immunity and tumorigenesis. AB - Mammalian target of rapamycin complex 2 (mTORC2) is a key downstream mediator of phosphoinositol-3-kinase (PI3K) dependent growth factor signaling. In lymphocytes, mTORC2 has emerged as an important regulator of cell development, homeostasis and immune responses. However, our current understanding of mTORC2 functions and the molecular mechanisms regulating mTORC2 signaling in B and T cells are still largely incomplete. Recent studies have begun to shed light on this important pathway. We have previously reported that mTORC2 mediates growth factor dependent phosphorylation of Akt and facilitates Akt dependent phosphorylation and inactivation of transcription factors FoxO1 and FoxO3a. We have recently explored the functions of mTORC2 in B cells and show that mTORC2 plays a key role in regulating survival and immunoglobulin (Ig) gene recombination of bone marrow B cells through an Akt2-FoxO1 dependent mechanism. Ig recombination is suppressed in proliferating B cells to ensure that DNA double strand breaks are not generated in actively dividing cells. Our results raise the possibility that genetic or pharmacologic inhibition of mTORC2 may promote B cell tumor development as a result of inefficient suppression of Ig recombination in dividing B cells. We also propose a novel strategy to treat cancers based on our recent discovery that mTORC2 regulates Akt protein stability. PMID- 21822798 TI - Thiabendazole inhibits ubiquinone reduction activity of mitochondrial respiratory complex II via a water molecule mediated binding feature. AB - The mitochondrial respiratory complex II or succinate: ubiquinone oxidoreductase (SQR) is a key membrane complex in both the tricarboxylic acid cycle and aerobic respiration. Five disinfectant compounds were investigated with their potent inhibition effects on the ubiquinone reduction activity of the porcine mitochondrial SQR by enzymatic assay and crystallography. Crystal structure of the SQR bound with thiabendazole (TBZ) reveals a different inhibitor-binding feature at the ubiquinone binding site where a water molecule plays an important role. The obvious inhibitory effect of TBZ based on the biochemical data (IC(50) ~100 MUmol/L) and the significant structure-based binding affinity calculation (~94 MUmol/L) draw the suspicion of using TBZ as a good disinfectant compound for nematode infections treatment and fruit storage. PMID- 21822799 TI - Cdk2 acts upstream of mitochondrial permeability transition during paclitaxel induced apoptosis. AB - Sequential activation of cyclin-dependent kinases (Cdks) controls mammalian cell cycle. Here we demonstrate that the upregulation of cyclin-dependent kinase 2 (Cdk2) activity coincides with the loss of mitochondrial membrane potential (MMP) in paclitaxel-induced apoptosis. Ectopic expression of the dominant negative Cdk2 (Cdk2-dn) and a specific Cdk2 inhibitor, p21( WAF1/CIP1 ), effectively suppresses the loss of MMP, the release of cytochrome c, and subsequent activation of caspase-3 in paclitaxel-treated cells. Whereas forced activation of Cdk2 by overexpression of cyclin A dramatically promotes these events. We further show that Cdk2 activation status does not interfere with a procedure that lies downstream of cytochrome c release induced by Bax protein. These findings suggest that Cdk2 kinase can regulate apoptosis at earlier stages than mitochondrial permeability transition and cytochrome c release. PMID- 21822800 TI - Antioxidant proteins TSA and PAG interact synergistically with Presenilin to modulate Notch signaling in Drosophila. AB - Alzheimer's disease (AD) pathogenesis is characterized by senile plaques in the brain and evidence of oxidative damage. Oxidative stress may precede plaque formation in AD; however, the link between oxidative damage and plaque formation remains unknown. Presenilins are transmembrane proteins in which mutations lead to accelerated plaque formation and early-onset familial Alzheimer's disease. Presenilins physically interact with two antioxidant enzymes thiol-specific antioxidant (TSA) and proliferation-associated gene (PAG) of the peroxiredoxin family. The functional consequences of these interactions are unclear. In the current study we expressed a presenilin transgene in Drosophila wing and sensory organ precursors of the fly. This caused phenotypes typical of Notch signaling loss-of-function mutations. We found that while expression of TSA or PAG alone produced no phenotype, co-expression of TSA and PAG with presenilin led to an enhanced Notch loss-of-function phenotype. This phenotype was more severe and more penetrant than that caused by the expression of Psn alone. In order to determine whether these phenotypes were indeed affecting Notch signaling, this experiment was performed in a genetic background carrying an activated Notch (Abruptex) allele. The phenotypes were almost completely rescued by this activated Notch allele. These results link peroxiredoxins with the in vivo function of Presenilin, which ultimately connects two key pathogenetic mechanisms in AD, namely, antioxidant activity and plaque formation, and raises the possibility of a role for peroxiredoxin family members in Alzheimer's pathogenesis. PMID- 21822801 TI - AMPD3 is involved in anthrax LeTx-induced macrophage cell death. AB - The responses of macrophages to Bacillus anthracis infection are important for the survival of the host, since macrophages are required for the germination of B. anthracis spores in lymph nodes, and macrophage death exacerbates anthrax lethal toxin (LeTx)-induced organ collapse. To elucidate the mechanism of macrophage cell death induced by LeTx, we performed a genetic screen to search for genes associated with LeTx-induced macrophage cell death. RAW264.7 cells, a macrophage-like cell line sensitive to LeTx-induced death, were randomly mutated and LeTx-resistant mutant clones were selected. AMP deaminase 3 (AMPD3), an enzyme that converts AMP to IMP, was identified to be mutated in one of the resistant clones. The requirement of AMPD3 in LeTx-induced cell death of RAW 264.7 cells was confirmed by the restoration of LeTx sensitivity with ectopic reconstitution of AMPD3 expression. AMPD3 deficiency does not affect LeTx entering cells and the cleavage of mitogen-activated protein kinase kinase (MKK) by lethal factor inside cells, but does impair an unknown downstream event that is linked to cell death. Our data provides new information regarding LeTx-induced macrophage death and suggests that there is a key regulatory site downstream of or parallel to MKK cleavage that controls the cell death in LeTx-treated macrophages. PMID- 21822802 TI - Pharmacological applications of a novel neoepitope antibody to a modified amyloid precursor protein-derived beta-secretase product. AB - We have previously described a novel artificial NFEV beta-secretase (BACE1) cleavage site, which when introduced into the amyloid-beta precursor protein (APP), significantly enhances APP cleavage by BACE1 in in vitro and cellular assays. In this study, we describe the identification and characterization of a single chain fragment of variable region (scFv), specific to the EV neo-epitope derived from BACE1 cleavage of the NFEV-containing peptide, and its conversion to IgG1. Both the scFv displayed on phage and EV-IgG1 show exquisite specificity for binding to the EV neoepitope without cross-reactivity to other NFEV containing peptides or WT-APP KMDA cleavage products. EV-IgG1 can detect as little as 0.3 nmol/L of the EV peptide. EV-IgG1 antibody was purified, conjugated with alkaline phosphatase and utilized in various biological assays. In the BACE1 enzymatic assay using NFEV substrate, a BACE1 inhibitor MRK-3 inhibited cleavage with an IC(50) of 2.4 nmol/L with excellent reproducibility. In an APP_NFEV stable SH SY5Y cellular assay, the EC(50) for inhibition of EV-Abeta peptide secretion with MRK-3 was 236 nmol/L, consistent with values derived using an EV polyclonal antibody. In an APP_NFEV knock-in mouse model, both Abeta_EV40 and Abeta_EV42 peptides in brain homogenate showed excellent gene dosage dependence. In conclusion, the EV neoepitope specific monoclonal antibody is a novel reagent for BACE1 inhibitor discovery for both in vitro, cellular screening assays and in vivo biochemical studies. The methods described herein are generally applicable to novel synthetic substrates and enzyme targets to enable robust screening platforms for enzyme inhibitors. PMID- 21822813 TI - Primitive interactions between inclusions on a fluid membrane: the role of thermal fluctuations. AB - Consider a fluid membrane decorated by moving hard or soft inclusions. The aim of this work is a quantitative study of the influence of thermal fluctuations on the three-dimensional primitive forces between these inclusions. Integrating over all membrane fluctuations, we obtain a general form giving the modified primitive interactions upon the transverse distance. The established formalism enables us to obtain the modified expression of some standard interaction potentials. In particular, for power-like potentials, we found a modified expression featuring the Whittaker function. The present formalism may be extended to other primitive interaction potentials. Finally, the main conclusion is that, decorated fluid membranes may be regarded as effective two-dimensional colloidal solutions where inclusions interact via the computed effective interactions. PMID- 21822803 TI - Selective expansion and enhanced anti-tumor effect of antigen-specific CD4(+) T cells by retrovirus-mediated IL-15 expression. AB - Mounting evidence has demonstrated that CD4(+) T cells play an important role in anti-tumor immune responses. Thus, adoptive transfer of these cells may have great potential for anti-cancer therapy. However, due to the difficulty to generate sufficient tumor-specific CD4(+) T cells, the use of CD4(+) T cells in tumor therapy is limited. It has been found that IL-15 transfection enhances the proliferation and anti-tumor activity of tumor-specific CD8(+) T cells, but the effect of IL-15 transfection on CD4(+) T cells remains unknown. Here, the effects of retrovirus-mediated IL-15 expression in Ova-specific CD4(+) T cells from Do11.10 mice were evaluated and it was discovered that IL-15 transfected CD4(+) T cells expressed both soluble and membrane-bound IL-15. Retrovirus-mediated IL-15 expression led to a selective expansion of antigen-specific CD4(+) T cells by inhibiting their apoptosis. In vivo IL-15 transfected CD4(+) T cells were more effective in suppressing tumor growth than control retroviral vector transfected ones. To ensure the safety of the method, the employment of thymidine kinase gene made it possible to eliminate these transgenic CD4(+) T cells following ganciclovir treatment. Together, we show that IL-15 transfection induced a selective expansion of antigen-specific CD4(+) T cells ex vivo and enhanced their tumor-suppression effects in vivo. This has an important significance for improving the efficacy of adoptive T cell therapy. PMID- 21822814 TI - Droplet breakup in an asymmetric microfluidic T junction. AB - Breakup of non-uniform droplets in an asymmetric T junction consisting of an inlet channel and two different-size outlet channels has been investigated numerically. Also, an analytical approach in the limit of the lubrication approximation has been extended to provide some analytical relations to study the system and verify the numerical results. Parameters that are important in the performance of the system have been determined and discussed. Our results indicate that smaller droplets can be produced by increasing the capillary number. As the geometry becomes symmetric the pressure drop decreases. Our results also reveal that the breakup time and the pressure drop for this system are smaller than the previous suggested method for producing non-uniform droplets, i.e., a uniform size T junction with different-length outlet channels. PMID- 21822815 TI - Molecular level dynamics of genetic oscillator--the effect of protein-protein interaction. AB - Uncovering how interactions of a set of molecular components influence the system's dynamic behavior is important for understanding intracellular processes and elucidating design principles, but unfortunately, there are limited efforts for studying this issue. Here, we study the effect of distinct post-translational dynamics controlled by protein dimerization on oscillations in the repressilator. For this, we propose three biologically motivated model scenarios of the repressilator with monomer or dimer being the active form of repressor, and with protein-protein interactions. It is found that the dimer dissociation constant can tune oscillatory regions, frequency and amplitude. Introducing a modified linear noise approximation to evaluate fluctuations of amplitude and period in the oscillatory systems, we show that different dimerization leads to a different effect on period and amplitude in reducing noise. The manipulation of the circuit's biochemical properties provides a practical strategy for designing a robust and tunable oscillator. PMID- 21822816 TI - Dry powder vaccines for mucosal administration: critical factors in manufacture and delivery. AB - Dry powder vaccine formulations have proved effective for induction of systemic and mucosal immune responses. Here we review the use of dry vaccines for immunization in the respiratory tract. We discuss techniques for powder formulation, manufacture, characterization and delivery in addition to methods used for evaluation of stability and safety. We review the immunogenicity and protective efficacy of dry powder vaccines as compared to liquid vaccines delivered by mucosal or parenteral routes. Included is information on mucosal adjuvants and mucoadhesives that can be used to enhance nasal or pulmonary dry vaccines. Mucosal immunization with dry powder vaccines offers the potential to provide a needle-free and cold chain-independent vaccination strategy for the induction of protective immunity against either systemic or mucosal pathogens. PMID- 21822817 TI - Basic concepts of inflammation and its role in carcinogenesis. AB - While the normal inflammatory cascade is self-limiting and crucial for host protection against invading pathogens and in the repair of damaged tissue, a wealth of evidence suggests that chronic inflammation is the engine driving carcinogenesis. Over a period of almost 150 years the link between inflammation and cancer development has been well established. In this chapter we discuss the fundamental concepts and mechanisms behind normal inflammation as it pertains to wound healing. We further discuss the association of inflammation and its role in carcinogenesis, highlighting the different stages of cancer development, namely tumour initiation, promotion and progression. With both the innate and adaptive arms of the immune system being central to the inflammatory process, we examine the role of a number of immune effectors in contributing to the carcinogenic process. In addition, we highlight the influences of host genetics in altering cancer risk. PMID- 21822818 TI - Inherited Syndromes Predisposing to Inflammation and GI Cancer. AB - Cancers arising within the gastrointestinal (GI) tract are commonly associated with an immune component at their inception and later in their maintenance. While many of the immune factors and immune cell types surrounding these lesions have been highlighted, the underlying pre-dispositions in immunesupported carcinogenesis are not well characterised. Inherited Mendelian GI disorders such as polyposis syndromes, while classically due to germline mutations in non-immune genes, commonly demonstrate alterations in key immune and inflammatory genes. In some cases immune based therapies have been shown to provide at least some benefit in animal models of these syndromes. The advent of genome wide association studies has begun to powerfully examine the genetic nature of complex non-Mendelian GI diseases highlighting polymorphisms within immune related genes and their potential to provide the niche in which GI cancers may originate. Here in the role in which Mendelian and non-Mendelian genetics of immune related factors supporting GI malignancy will be presented and discussed. PMID- 21822819 TI - Stem cells and inflammation in the intestine. AB - Knowledge of stem cell biology in the intestine is increasing exponentially and it is one of the current hot topics 'of the day'. Yet it is only recently that molecules such as Lgr5 and Bmi1 have been shown to reliably mark stem cells and have revealed the stem cell location throughout the murine gastrointestinal tract. However, there is a scarcity of meaningful work within their human counterpart. Nevertheless, recent studies have demonstrated the processes of niche succession, where one stem cell takes over the entire population of stem cells within a crypt; and monoclonal conversion, whereby the entire crypt becomes a clonal population of cells, are present in the human crypt. This work has also shown how crypts themselves divide and expand in the human colon. PMID- 21822820 TI - Acid reflux and oesophageal cancer. AB - Barrett's metaplasia is one of the commonest premalignant lesions in the western world following colorectal adenomas. One in 50 of the adult population develops Barrett's as a consequence of chronic gastro-oesophageal reflux. The mucosal inflammation seen within patients with gastro-oesophageal reflux seems likely to drive the growth of the metaplastic mucosa and also help direct further oncological change, yet the molecular events that characterize the pathway from inflammation to metaplasia to dysplasia and adenocarcinoma are poorly understood. There is hope that understanding the role of oesophageal inflammation will provide important insight into the development of Barrett's metaplasia and oesophageal cancer. This chapter will discuss the inflammation seen within context of Barrett's oesophagus and also clinical trials which hope to address this common premalignant disease. There are several ongoing clinical trials which are aiming to provide data using anti-inflammatory therapies to tackle this important premalignant condition. There is new data presented which suggests that data from the aspirin esomeprazole chemoprevention trial (AspECT) may hold the clue to disease treatment and that the cytokine TNF-alpha seems to be a key signalling molecule in the metaplasia-dysplasia-carcinoma sequence. Specifically it appears that both epigenetic and inherited genetics cooperate to modulate the prognosis. PMID- 21822821 TI - Helicobacter pylori and gastric cancer. AB - Gastric cancer remains a major cause of cancer death worldwide. The discovery of Helicobacter pylori Helicobacter pylori and its association with gastric cancer has opened up new insights into its pathogenesis. Gastric cancer pathogenesis is the result of a complex interplay between bacterial, host and environmental factors resulting in a step wise histological progression to neoplasia. H. pylori is a major factor in the early stages of cancer development and the mechanism of action of its virulence factors are being steadily unravelled. It is also now recognised that host genetic polymorphisms also play a complex role interacting synergistically with the bacterial virulence factors. The role of H. pylori in the causation of gastric cancer also raises the possibility of cancer prevention through screening and eradication, actions which may improve outcomes in high risk populations but which may not be cost-effective in areas of low risk. Ultimately, despite the vast improvements in knowledge, as yet there has not been a corresponding improvement in terms of gastric cancer survival rates. PMID- 21822822 TI - Inflammatory bowel disease and colon cancer. AB - The inflammatory bowel diseases (IBD); Crohn's and Ulcerative colitis, result from an altered host response to intestinal flora. Recurrent inflammation with ulceration and tissue restitution confers an increased risk of cancer in both UC and Crohns, and genome wide searches have identified a number of disease susceptibility alleles. The carcinogenesis pathway in colitis-associated colorectal cancer (CACRC) is less clearly understood than it's sporadic counterpart. Clonal ordering experiments have indicated the order and timing of chromosomal instability and common genetic mutations. Epigenetic changes such as DNA methylation and histone modification are thought to play an increasingly important role in inflammation induced carcinogenesis. Clonal expansion of procarcinogenic mutations can lead to large fields of mutant tissue from which colitis associated cancers can arise (field cancerisation). Endoscopic screening is the mainstay of surveillance in high-risk patients although the development of appropriate, clinically applicable biomarkers remains a research priority. Despite the expanding field of biological therapy in inflammatory bowel disease the ASA compounds remain the best-studied and most efficacious chemopreventive agents. Colitis associated CRC appears to have a different aetiology, carcinogenesis pathway and clinical course to its sporadic counterpart. Further research including long-term follow up of patient cohorts taking biological therapies will improve the detection and treatment of these important, inflammation-induced malignancies. PMID- 21822823 TI - Primary sclerosing cholangitis. AB - Primary sclerosing cholangitis (PSC) is a chronic liver condition which may affect both intra and extrahepatic biliary tree. Etiology of PSC remains to be fully elucidated but genetic, autoimmune, inflammatory and possibly infective factors could all contribute to its development. More than two-thirds of patients are males and the most commonly associated condition is an inflammatory bowel disease which occurs in up to 70% of affected subjects. Endoscopic cholangiopancreatography (ERCP) and magnetic resonanse cholangiopancreatography (MRCP) remain a gold standard in the diagnosis of this condition. No curative treatment of PSC exists and a proportion of patients who develop liver failure or suffer from recurrent episodes of cholangitis requires liver transplantation. PSC is associated with increased risk of malignancies, in particular cholangiocarcinoma which may arise in 12% of patients. The main aim of this chapter is to review the current knowledge on pathogenesis and clinical aspects of PSC as well as its associated malignancies. PMID- 21822825 TI - Gastrointestinal cancer: current screening strategies. AB - The prevention and chemoprevention of cancer is based on identifying a pre neoplastic lesion and altering the outcome by early intervention. Many of the gastrointestinal epithelial cancers are related to chronic inflammatory conditions for many years prior to cancer development. It is clear that treatment of the inflammatory condition can prevent and indeed reverse changes that predispose to cancer. This is most notable for helicobacter pylori infection of the stomach. Screening for Barrett's oesophagus and other conditions are more controversial and the results of large scale clinical trials are awaited. Nevertheless preventive strategies are highly attract health care interventions and are being actively considered. PMID- 21822824 TI - Chronic inflammation and hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) invariably develops within a setting of chronic inflammation caused by either hepatotropic viruses, toxins, metabolic liver disease or autoimmunity. Mechanisms that link these two processes are not completely understood, but transcription factors of the NF-kappaB family and signal transducer and activator of transcription 3 (STAT3), cytokines such as IL 6 and IL-1alpha and ligands of the epidermal growth factor receptor (EGFR) family are clearly pivotal players. HCC may have its origins in either hepatocytes or hepatic progenitor cells (HPCs), and HCCs, like other solid tumours appear to be sustained by a minority population of cancer stem cells. PMID- 21822826 TI - Targeted drug therapies and cancer. AB - With the progress of research in molecular biology and greater understanding of cell signalling systems emerge an increasing array of potential targets for the therapy of cancer. While traditional chemotherapy aims to elicit tumour cell death, it also produces undesirable side effects on physiologically proliferating cells. By isolating cell surface receptors which link specific intracellular secondary messenger pathways, researchers are increasingly able to define the biological network which drives cellular function. Of importance are routes involved in malignant transformation, proliferation, survival and angiogenesis. Thus targeted therapy is directed to specific differential growth processes particular to malignant tumours. The principle mode of action generally involves the "lock-and-key" mechanism and identifying the "Achilles' heel" for drug action. Various targeted agents have been studied and many have translated into significant clinical benefit. This chapter will describe some examples which illustrate the role of this approach in gastrointestinal cancers. PMID- 21822828 TI - Endoscopic methods. AB - Endoscopic methods to recognise and treat early gastrointestinal malignancies have increased in recent years. This has resulted in more lesions being diagnosed at an early stage and a shift away from invasive surgery towards endoscopic resection. However, it is necessary for the endoscopist to understand the key principles behind advanced endoscopic diagnosis and the new therapeutic options available. This chapter will review the advances in endoscopic techniques and methods which are changing the way we diagnose and treat these cancers. It will examine the general principles behind advanced endoscopy and then examine their application in Barrett's neoplasia, gastric cancer and the dysplasia associated lesions or masses associated with ulcerative colitis. It will focus on the best techniques for each of the above pathology. PMID- 21822827 TI - Genetics of inflammation in the gastrointestinal tract and how it can cause cancer. AB - Genetic epidemiology is an important discipline that is helping to unravel the aetiology and pathogenesis of complex human diseases. In the context of gastrointestinal malignancy, the paradigm model of host genetic influence on disease outcome is H. pylori-associated gastric adenocarcinoma. This cancer represents a classic example of an inflammation-induced malignancy and highlights the importance of host genetics in disease development. This chapter gives an insight into how genetic epidemiology can play an important role in the development of gastric cancer. Increasing our understanding of host genetics in cancer development may allow particularly susceptible individuals to be targeted for screening or treatment to reduce risk of future malignant transformation. PMID- 21822829 TI - Screening or selection for chloroplast biogenesis mutants of Arabidopsis, following chemical or insertional mutagenesis. AB - The power of Arabidopsis as a model organism lies in the depth and breadth of genetic tools available for its study. This also applies to the study of chloroplast biology. Although vast numbers of mutants have been identified in Arabidopsis, the continued use of forward-genetic screening approaches remains valuable for the isolation and study of previously overlooked mutants and novel mutations in sensitised backgrounds (i.e., suppressors or enhancers of previously known mutants). In addition, reverse-genetic collections of insertional mutants are now extensive and provide unique opportunities for gene function discovery. Here, we describe methods for the chemical mutagenesis of Arabidopsis, the screening of mutants visually, on the basis of gene-expression phenotypes (scored as reduced or enhanced activity of reporter genes), and the use of databases to select for existing mutations from historic collections or insertional mutagenesis programmes. PMID- 21822830 TI - Analysis of plastid number, size, and distribution in Arabidopsis plants by light and fluorescence microscopy. AB - Methods are described which allow one to observe chloroplasts in mesophyll cells from leaves of Arabidopsis, determine their number per cell, measure their area, and determine a value for chloroplast coverage inside mesophyll cells. Non-green plastids can also be imaged either by using staining, or by exploiting fluorescent proteins targeted to the plastid in non-green parts of the plant, such as the roots, in transgenic Arabidopsis. PMID- 21822831 TI - Immunofluorescence microscopy for localization of Arabidopsis chloroplast proteins. AB - Immunofluorescence microscopy reveals localization of proteins in cells and tissues by means of highly specific, fluorescently labeled antibodies. This technique is an important complement to localization methods that use genetically encoded fluorescent tags. This chapter describes the five stages of immunofluorescence localization of proteins in plant chloroplasts in sectioned leaf tissue: (1) fixation, (2) tissue embedding and sectioning, (3) treatment of sections prior to immunolabeling, (4) immunostaining, and (5) fluorescence microscopy and image capture. Protocols for both cryosectioning and sectioning of low-melting-point wax-embedded samples are described. Immunofluorescence localization in chloroplasts is complicated by their intense autofluorescence background. Measures to suppress nonspecific background staining, confirm specificity of the fluorescence signal, and optimize imaging conditions are described. PMID- 21822832 TI - Transient expression and analysis of chloroplast proteins in Arabidopsis protoplasts. AB - Although chloroplasts have their own genome, most chloroplast proteins are encoded in the nuclear genome and are targeted to chloroplasts posttranslationally. In vitro import studies with isolated chloroplasts have been widely used and have helped to elucidate the complex mechanisms involved in protein targeting to chloroplasts. Recently, an in vivo targeting method using protoplasts emerged as an alternative method to investigate protein targeting into chloroplasts. The present study describes a set of principles and methods, including polyethylene glycol-mediated reporter plasmid transformation, fluorescence microscopy, immunocytochemistry, and Western blotting, for studying chloroplast interior and envelope membrane protein targeting using protoplasts isolated from Arabidopsis thaliana leaf tissues. PMID- 21822833 TI - Visualisation of stromules on Arabidopsis plastids. AB - Stromules are thin stroma-filled tubules that extend from all plastid types in all multicellular plants examined. They are most easily visualised by epifluorescence or confocal microscopy of plastids containing green fluorescent protein (GFP) or other fluorescent proteins. Transient expression of gene constructs encoding plastid-targeted GFP following bombardment of whole plants or organs of Arabidopsis with gold or tungsten particles coated with plasmid DNA is a relatively rapid and simple means of producing material for observation of stromules. PMID- 21822834 TI - Analysis of chloroplast movement and relocation in Arabidopsis. AB - Chloroplast photorelocation movement is essential for the sessile plant survival and plays a role for efficient photosynthesis and avoiding photodamage of chloroplasts. There are several ways to observe or detect chloroplast movement directly or indirectly. Here, techniques for the induction of chloroplast movement and how to detect the responses, as well as various points of attention and advice for the experiments, are described. PMID- 21822835 TI - Studying starch content and sedimentation of amyloplast statoliths in Arabidopsis roots. AB - Amyloplasts, organelles responsible for the synthesis and storage of starch, are of critical importance to gravitropism in higher plants. We discuss two methods that are useful for describing the histology and behavior of amyloplasts. First, because mutants with little or no plastidic starch accumulation are defective in their gravitropic response, we review a method to observe starch accumulation quickly in plant tissue. Second, we discuss a method for measuring amyloplast sedimentation in the dynamic environment of Arabidopsis root columella cells, which is thought to provide a directional cue to a reoriented plant. PMID- 21822836 TI - Studying Arabidopsis chloroplast structural organisation using transmission electron microscopy. AB - Chloroplasts, as well as other, non-photosynthetic types of plastid, are characteristic structures within plant cells. They are relatively large organelles (typically 1-5 MUm in diameter), and so can readily be analysed by electron microscopy. Chloroplast structure is remarkably complex, comprising at least six distinct sub-organellar compartments, and is sensitive to developmental changes, environmental effects, and genetic lesions. Transmission electron microscopy (TEM), therefore, represents a powerful technique for monitoring the effects of various changing parameters or treatments on the development and differentiation of these important organelles. We describe a method for the analysis of Arabidopsis plant material by TEM, primarily for the assessment of plastid ultrastructure. PMID- 21822837 TI - Transplastomics in Arabidopsis: progress toward developing an efficient method. AB - Protocols developed for plastome engineering in Nicotiana tabacum rely on biolistic delivery of the transforming DNA to chloroplasts in intact leaf tissue; integration of the foreign DNA into the plastid genome by homologous recombination via flanking plastid DNA (ptDNA) targeting regions; and gradual dilution of non-transformed ptDNA during cultivation in vitro. Plastid transformation in Arabidopsis was obtained by combining the tobacco leaf transformation protocol with Arabidopsis-specific tissue culture and plant regeneration protocols. Because the leaf cells in Arabidopsis are polyploid, this protocol yielded sterile plants. Meristematic cells in a shoot apex or cells of a developing embryo are diploid. Therefore, we developed a regulated embryogenic root culture system that will generate diploid tissue for plastid transformation. This embryogenic culture system is created by steroid-inducible expression of the BABY BOOM transcription factor. Plastid transformation in Arabidopsis will enable the probing of plastid gene function, and the characterization of posttranscriptional mechanisms of gene regulation and the regulatory interactions of plastid and nuclear genes. PMID- 21822838 TI - Isolation, quantification, and analysis of chloroplast DNA. AB - Many areas of chloroplast research require methods that can assess the quality and quantity of chloroplast DNA (cpDNA). The study of chloroplast functions that depend on the proper maintenance and expression of the chloroplast genome, understanding cpDNA replication and repair, and the development of technologies for chloroplast transformation are just some of the disciplines that require the isolation of high-quality cpDNA. Arabidopsis thaliana offers several advantages for studying these processes because of the sizeable collection of mutants and natural varieties (accessions) available from stock centers and a broad community of researchers that has developed many other genetic resources. Several approaches for the isolation and quantification of cpDNA have been developed, but little consideration has been given to the strengths and weaknesses and the type of information obtained by each method, especially with respect to A. thaliana. Here, we provide protocols for obtaining high-quality cpDNA for PCR and other applications, and we evaluate several different isolation and analytical methods in order to build a robust framework for the study of cpDNA with this model organism. PMID- 21822839 TI - Measurement of transcription rates in Arabidopsis chloroplasts. AB - The regulation of gene expression is still one of the major issues in modern plant molecular biology. The amount of RNA in a cell is regulated by both transcriptional and posttranscriptional events. Methods to determine these steady state levels of RNAs, such as Northern analysis, ribonuclease protection assay (RPA), and quantitative real-time PCR, do not discriminate between regulation by de novo RNA synthesis and the influence by degradation or stabilization. To assess the rate of transcription of individual genes, run-on transcription is utilized. To this end, isolated chloroplasts are used in brief in vitro transcription reactions in the presence of radiolabeled nucleotides, with a subsequent hybridization of the isolated RNA with DNA fragments spotted on membranes. Here, we describe a protocol for run-on transcription in chloroplasts isolated from Arabidopsis leaves and present data on the transcriptional activity of several plastid genes in detached leaves of different Arabidopsis ecotypes. PMID- 21822840 TI - Studying the structure and processing of chloroplast transcripts. AB - Most chloroplast genes in land plants are represented by multiple transcript isoforms that arise via differential splicing, endo- and exo-nucleolytic processing, and/or RNA editing. Exploration of the functional significance and mechanisms of these processing events is an active area of current research. This chapter focuses on methods that can be used to define the termini of chloroplast RNAs, quantify the relative levels of alternative processed RNA isoforms, and identify the binding sites of proteins that mediate chloroplast RNA processing. Various approaches for defining the sequence specificity of chloroplast RNA binding proteins are discussed, as are the parameters to consider in designing in vitro assays for RNA binding activities. A protocol is provided for a poisoned primer extension assay for quantifying different splice isoforms. PMID- 21822841 TI - In vitro RNA-binding assay for studying trans-factors for RNA editing in chloroplasts. AB - In plant organelles, specific C residues are modified to U by RNA editing. Short RNA sequences surrounding the target site (i.e., cis-elements) are recognized by trans-factors, which were recently shown to be pentatricopeptide repeat (PPR) proteins. PPR proteins consist of tandem arrays of a highly degenerate unit of 35 (pentatrico) amino acids, and PPR motifs are believed to recognize specific RNA sequences. In Arabidopsis thaliana, more than 450 sites are edited in mitochondria and plastids, and a similar number of PPR proteins are encoded in the nuclear genome. To study how the tandem array of a PPR motif facilitates the recognition of RNA sequences, an efficient biochemical strategy is an in vitro binding assay of recombinant PPR proteins with target RNA. This analysis is especially powerful with a combination of in vivo analyses based on the phenotypes of mutants and transgenic plants. In this chapter, we describe methods for the expression of recombinant PPR proteins in Escherichia coli, preparation of probe RNAs, and RNA gel shift assays. These methods can also be utilized for other RNA-binding proteins. PMID- 21822842 TI - Studying translation in Arabidopsis chloroplasts. AB - Chloroplasts as descendents of a cyanobacterial endosymbiont have retained, during evolution, their own genome together with the gene expression machinery, including the translation apparatus. Therefore, chloroplast protein synthesis is not only a key process in organello biogenesis and maintenance, but it also represents the major regulatory step in chloroplast gene expression. In fact, several independent evidences have shown that the accumulation of template messengers is not limiting in the expression of chloroplast genes. On the contrary, translation regulatory processes based on selection of translatable mRNA by either nucleus-encoded activation factors or sensors of the assembly status of chloroplast multiprotein complexes have been reported. Additionally, we have shown that organelle translation rate triggers an organelle-to-nucleus signaling cascade aimed to modulate nuclear gene expression according to the organelle's needs. Therefore, the study of chloroplast translation appears to be essential for the comprehension of several aspects of chloroplast activity. Here, we describe the in vivo pulse-chase and the polysome isolation approaches. Taken together, the two methods allow one to assess rates of protein synthesis and degradation as well as defects during the initial steps of protein synthesis. PMID- 21822843 TI - Studying proteases and protein turnover in Arabidopsis chloroplasts. AB - Proteolysis is a key process for maintaining homeostasis in all living cells. The ability to degrade specific metabolic enzymes and regulatory proteins is essential for both cellular integrity and function. Equally important is the efficient removal of damaged or otherwise inactive polypeptides, especially during periods of developmental change or stress adaptation. Being one of the most metabolically active plant organelles, chloroplasts require various proteases to control overall protein quality. Much has been revealed about these chloroplast proteases over the last decade, and yet the identity of their native protein substrates remains elusive. In this chapter, we describe a variation upon a classic genetic approach to identify protease substrates based on the comparative protein degradation rates in wild-type and transgenic lines with impaired proteolytic activity. We have successfully used this approach with an in organello assay to identify numerous substrates for the stromal Clp protease from Arabidopsis thaliana, using both gene knockout mutants and antisense repression lines. In principle, the technique can be readily adapted for the study of other chloroplast proteases, and in other plant and algal species as the necessary genetic resources become available. PMID- 21822844 TI - In silico methods for identifying organellar and suborganellar targeting peptides in Arabidopsis chloroplast proteins and for predicting the topology of membrane proteins. AB - Numerous experimental and in silico approaches have been developed for attempting to identify the -subcellular localisation of proteins. Approximately 2,000-4,000 proteins are thought to be targeted to plastids in plants, but a complete and unambiguous catalogue has yet to be drawn up. This article reviews the various prediction methods that identify plastid targeting sequences, and those that can help estimate location and topology within the plastid or plastid membranes. The most successful approaches are described in detail, with detailed notes to help avoid common pitfalls and advice on interpreting conflicting or ambiguous results. In most cases, it is best to try multiple approaches, and we also cover the powerful new integrated databases that provide a selected blend of experimental data and predictions. PMID- 21822845 TI - Rapid isolation of Arabidopsis chloroplasts and their use for in vitro protein import assays. AB - In vitro chloroplast protein import assays have been performed since the late 1970s, initially with plant species (e.g., pea and spinach) that readily provide an abundant source of starting material and also, subsequently, a good yield of chloroplasts for import assays. However, the sequencing of the Arabidopsis genome paved the way for an additional model system that is more amenable to genetic analysis, as a complement to the more biochemically orientated models such as pea and spinach. A prerequisite for this change was an efficient and reliable protocol for the isolation of chloroplasts for use in protein import assays, enabling biochemical approaches to be combined with the genetic potential of the plant. The method described here was developed as a rapid and low-cost procedure that can be accessed by everyone due to its simplicity. Despite its rapidity and simplicity, the method yields highly pure chloroplasts, and in addition works well with mutant plants that exhibit pale or chlorotic phenotypes. The protocol is also optimized for work with material from young plants (10-14 days old), when protein import is believed to be at its peak, and so plant growth can be conducted in vitro on Murashige and Skoog medium. The isolation method has been used not only for protein import assays, but also for proteomic analysis and further subfractionation studies. PMID- 21822846 TI - Energetic manipulation of chloroplast protein import and the use of chemical cross-linkers to map protein-protein interactions. AB - Most chloroplast proteins are synthesized in the cytosol as preproteins with N terminal cleavable transit peptides and are imported into the organelle through the TOC-TIC translocon system. Import involves a complex set of recognition and membrane translocation steps that ensure the fidelity and unidirectional transport of the polypeptide across the double-membrane chloroplast envelope. To understand the mechanism of import, the molecular interactions and energetics of each step must be defined. Here, we describe the methods for capturing intermediates in the import process through the manipulation of the energy state of chloroplasts, and the use of two different chemical cross-linking approaches to examine the molecular interactions that mediate the import process and to assess the assembly state of the translocons. These approaches can be employed to identify sequential protein-protein interactions, and thereby dissect the pathway and roles of import components during protein import into chloroplasts. PMID- 21822847 TI - Isolation of Arabidopsis thylakoid membranes and their use for in vitro protein insertion or transport assays. AB - This chapter focuses on the techniques of chloroplast isolation; their fractionation into envelopes, stroma, and thylakoids; and their further use for in vitro protein transport assays. In addition to the isolation of thylakoids, this chapter also describes the experimental steps of both protein translocation across the thylakoid membrane and protein integration into the membrane. Protein translocation and integration can be analysed by the radioactive labelling of substrate proteins using an in vitro transcription and translation system. The translocated or integrated proteins can then be detected by autoradiography. Our protocol allows the analysis of these transport systems in wild-type Arabidopsis or mutants that lack or overexpress soluble or membrane transport factors that could be of potential interest. PMID- 21822848 TI - Determining the location of an Arabidopsis chloroplast protein using in vitro import followed by fractionation and alkaline extraction. AB - Chloroplasts have one of the most complicated structures among organelles. They have three membrane systems, the outer and inner envelope membranes and the thylakoid membrane, which enclose three aqueous spaces: the intermembrane space between the two envelope membranes, the stroma, and the thylakoid lumen. Each of the chloroplast's sub-organellar compartments houses a distinct set of proteins that perform distinct functions. Determining the sub-organellar location of a protein in the chloroplast is vital for understanding or verifying the function of the protein. Here, we present protocols for determining the sub-organellar location of a chloroplast protein. The protein of interest is synthesized and labeled with [(35)S]methionine by an in vitro translation system, and imported into isolated chloroplasts. The location of the protein is then identified by fractionation of the chloroplasts through differential and sucrose step-gradient centrifugations. The various sub-chloroplast fractions are analyzed by SDS-PAGE and autoradiography, so no specific antibody against the protein of interest is required. For membrane proteins, an alkaline extraction protocol is provided to further determine whether the protein is a peripheral or an integral membrane protein. The fractionation and extraction procedures presented can also be used in conjunction with immunoblotting, if an antibody against the protein of interest is available, enabling analyses of endogenous proteins. PMID- 21822849 TI - Studying Arabidopsis envelope protein localization and topology using thermolysin and trypsin proteases. AB - Chloroplasts are metabolically important organelles that perform many essential functions within plant cells. The chloroplasts can be subdivided into six distinct sub-compartments to which a protein may be ultimately targeted. These sub-compartments are defined as the outer envelope membrane (OEM), the inner envelope membrane (IEM), the thylakoid membrane, and three aqueous sub compartments - the intermembrane space (IMS), the stroma, and the thylakoid lumen. The process by which proteins are targeted to the chloroplastic envelope membrane remains a challenging question in cell biology. Our understanding of protein targeting to the OEM is very limited, whereas targeting of membrane proteins to the IEM appears to utilize at least two targeting pathways called the stop-transfer and the conservative sorting (or post-import) pathways. Furthermore, once a membrane protein arrives at the envelope membrane, our understanding of how it achieves its final topology remains limited. One method that can be used to determine the topology of an envelope membrane protein is to apply the "dual protease" strategy. This approach involves several steps: first, performing an in vitro import assay; second, applying a "dual protease" protection assay using thermolysin and trypsin; and finally, isolating and analyzing chloroplastic subcellular fractionations (i.e., total membrane and soluble fractions). By using this multistep approach, one can gain critical information regarding the final topology of an OEM or IEM protein. Likewise, the "dual protease" approach may help in elucidating the possible targeting pathway that a membrane protein utilizes prior to its insertion into the envelope membrane. PMID- 21822852 TI - Severe dyspnoea during late pregnancy in a woman with history of asthma. PMID- 21822853 TI - Efficacy of reperfusion with primary percutaneous coronary intervention in patients with acute ST segment elevation myocardial infarction. PMID- 21822854 TI - The clinicopathologic differences in papillary thyroid carcinoma with or without co-existing chronic lymphocytic thyroiditis. AB - The goal of this study is to determine the clinicopathologic differences in patients with papillary thyroid carcinoma (PTC) with or without chronic lymphocytic thyroiditis (CLT). We reviewed the medical records of 195 consecutive PTC patients who underwent total thyroidectomy and bilateral central lymph node dissection from April 2008 to March 2010. The differences in clinicopathologic factors, such as age, gender, size of primary tumor, perithyroidal invasion, lymphovascular invasion, capsular invasion, and central lymph node (CLN) metastasis, were analyzed in PTC patients with or without CLT. Among 195 patients, 56 (28.7%) had co-existing CLT. Patients with CLT had the following characteristics as compared to patients without CLT: significantly younger, female predominance, smaller tumor size, and lower incidence of capsular invasion (p = 0.038, 0.006, 0.037, and 0.026, respectively). Also, patients with CLT (12.5%) had a significantly lower incidence of CLN metastases than patients without CLT (28.1%; p = 0.025) based on univariate analysis. Moreover, multivariate analysis showed that younger age (p = 0.042, odds ratio = 1.033) and female gender (p = 0.012, odds ratio = 6.865) are independent clinical factors in patients with CLT compared to patients without CLT. CLT was shown to be commonly associated with PTC. Compared to patients with PTC without CLT, patients with CLT were younger with a female predominance, which are the most important and well known prognostic variables for thyroid cancer mortality. PMID- 21822855 TI - Audiological implications of earplugs used for the prevention of aural exostoses. AB - External auditory canal exostoses may be a preventable disease, so it is surprising that the regular use of water precautions is not greater among surfers. One reason for this is the impairment of hearing whilst wearing earplugs. The objective of this study is to establish the hearing impairment of commonly available earplugs used by surfers. Staff and patients with normal hearing were recruited to have pure tone audiometry performed multiple times, initially with no earplugs, and subsequently with earplugs. Three earplug types were tested which differed in their nature and material (prefabricated elastomer, custom-fitted silicone, and custom-fitted acrylic). Vented and non-vented forms of the earplugs were tested. 30 normal hearing ears were included. Two-tailed paired t-tests comparing hearing thresholds between different earplugs identified that the elastomer earplugs caused the least hearing impairment (p < 0.001). There was no significant difference in hearing thresholds between vented and non vented elastomer earplugs (p = 0.148), but the difference between vented and non vented forms of other earplugs was statistically significant (silicone p = 0.010, acrylic p = 0.018). Prefabricated ear plugs produce less hearing impairment than other commonly available earplugs. A customised earplug made of hard material causes the greatest impairment of hearing. We therefore recommend that for aquatic sports where hearing is important, a soft prefabricated earplug is preferable. PMID- 21822856 TI - Endoscopic DCR without stents: clinical guidelines and procedure. AB - It is a retrospective analysis of cases of endoscopic Dacryocystorhinostomy (DCR) in whom stents were not inserted after completion of surgery for the last 2 years. Thirty-five patients were included in this study, and selection of patients was done depending on both clinical findings preoperatively and on the operative findings during surgery. These criteria ensure that the level of obstruction is postsaccal, and good surgical procedure with maximal sac exposure and marsupialization. When all criteria were present, stents were not inserted. Follow-ups range from 6 to 12 months (average of 8 months). Success was determined by symptomatic relief of epiphora and dacryocystitis, together with the endoscopic findings of free passage of the fluorescein dye that is applied to the conjunctiva to the nasal cavity. In this study, all the patients had both symptomatic and clinical improvements making the success rate 100%. As a conclusion, stents are not always necessary after endoscopic DCR. PMID- 21822858 TI - Responses of soil CO(2) efflux to precipitation pulses in two subtropical forests in southern China. AB - This study was designed to examine the responses of soil CO(2) efflux to precipitation pulses of varying intensities using precipitation simulations in two subtropical forests [i.e., mixed and broadleaf forests (MF and BF)] in southern China. The artificial precipitation event was achieved by spraying a known amount of water evenly in a plot (50 * 50 cm(2)) over a 30 min period, with intensities ranging from 10, 20, 50 and 100 mm within the 30 min. The various intensities were simulated in both dry season (in December 2007) and wet (in May 2008) season. We characterized the dynamic patterns of soil CO(2) efflux rate and environmental factors over the 5 h experimental period. Results showed that both soil moisture and soil CO(2) efflux rate increased to peak values for most of the simulated precipitation treatments, and gradually returned to the pre-irrigation levels after irrigation in two forests. The maximum peak of soil CO(2) efflux rate occurred at the 10 mm precipitation event in the dry season in BF and was about 3.5 times that of the pre-irrigation value. The change in cumulative soil CO(2) efflux following precipitation pulses ranged from -0.68 to 1.72 g CO(2) m( 2) over 5 h compared to the pre-irrigation levels and was generally larger in the dry season than in the wet season. The positive responses of soil CO(2) efflux to precipitation pulses declined with the increases in precipitation intensity, and surprisingly turned to negative when precipitation intensity reached 50 and 100 mm in the wet season. These findings indicated that soil CO(2) efflux could be changed via pulse-like fluxes in subtropical forests in southern China as fewer but extreme precipitation events occur in the future. PMID- 21822857 TI - Are all prognostic factors in parotid gland carcinoma well recognized? AB - The aim of his study was to assess the treatment results and prognostic factors in patients with parotid gland carcinoma. The material consisted of 109 patients treated surgically, with or without complementary radiotherapy, between 1978 and 2008 (follow-up at least 5-years). 5-year overall and disease-specific survival were observed in 57.0% of the patients and 5-year disease-free survival was achieved in 50.0%. Univariate analysis including ten clinical and pathological features to assess their prognostic value was done. Parapharyngeal space invasion, facial nerve palsy, and high grade of tumor malignancy were the factors with the highest influence on the treatment results, because their presence decreased the chance for recovery 9.8, 9.7, and 8.2 times, respectively. Histologically positive cervical lymph nodes and extraparenchymal extension were the other factors connected with poor prognosis (prognosis worse 6.7 and 5.4 times, respectively). Clinically positive cervical lymph nodes, positive/uncertain microscopic margin, involvement of the deep lobe, or the whole gland increased the risk of treatment failure 3.4, 3.1, and 2.8, respectively. The age >= 60 years and male gender were statistically significant factors, correlated with poor prognosis and decreased chance for recovery 2.4 and 2.6 times. T-status and clinical stage had important influence on 5-year disease-free survival rate because there were significant differences in the treatment results between individual stages. Multivariate analysis proved that the independent prognostic value, among anatomic structures involved by the neoplasm, had mandible, facial nerve, and skin infiltration. Among tumor-related factors, T stage and grade had the statistically significant influence on treatment results, and stage and lymph nodes metastases among clinical and pathological features. These results confirm the value of actually used TNM classification (2002). Although the parapharyngeal space invasion is a factor, which seems to have a significant, poor prognostic value, it was not included in this classification. PMID- 21822859 TI - Developing effective research-practice partnerships for creating a culture of evidence-based decision making. AB - With growing evidence that treatment as usual may have limited effectiveness in mental health the pressure on service providers to be accountable and produce evidence as to the effectiveness of their services has increased. Measurement Feedback Systems, such as the Contextualized Feedback System (CFS), have the potential to be powerful tools for service providers in assessing their own effectiveness at multiple levels with an organization. These systems represent an amalgamation of the data driven world of science and the experience driven world of clinical practice. However, the synthesis of these two worlds is not without significant challenges as these two very different cultures can easily clash. The key for successful collaboration in developing and implementing Measurement Feedback Systems is a good university-practice partnership that has a strong foundation in common goals and the positive relationships among its members. In addition, the partnership needs to be flexible so that it can adapt to new challenges and continuously grow with each obstacle. These are some of several lessons learned the authors of this article will share as part of their experience with developing and implementing CFS in one of the largest behavioral health service providers in the U.S. PMID- 21822860 TI - Molality-molarity challenge. PMID- 21822861 TI - Solution to Hofmeister effect challenge. PMID- 21822862 TI - Solution to radioactive Jeopardy challenge. PMID- 21822863 TI - The stem cell laboratory: design, equipment, and oversight. AB - This chapter describes some of the major issues to be considered when setting up a laboratory for the culture of human pluripotent stem cells (hPSCs). The process of establishing a hPSC laboratory can be divided into two equally important parts. One is completely administrative and includes developing protocols, seeking approval, and establishing reporting processes and documentation. The other part of establishing a hPSC laboratory involves the physical plant and includes design, equipment and personnel. Proper planning of laboratory operations and proper design of the physical layout of the stem cell laboratory so that meets the scope of planned operations is a major undertaking, but the time spent upfront will pay long-term returns in operational efficiency and effectiveness. A well-planned, organized, and properly equipped laboratory supports research activities by increasing efficiency and reducing lost time and wasted resources. PMID- 21822864 TI - Stem cell banks: preserving cell lines, maintaining genetic integrity, and advancing research. AB - The ability to cryopreserve and successfully recover cell lines has been critical to the conservation of all cell lines, especially the preservation of pristine early-stage cultures and the preparation of well-characterized cell banks. Indeed, the systematic storage and establishment of cryopreserved banks of cells for the stem cell research community is fundamental to the promotion of standardisation in stem cell research and their use in clinical applications. In spite of the significant potential for the use of stem cells in research and therapy, they are challenging to maintain and have been shown to be unstable after prolonged culture that often results in permanent alterations in their genetic make-up, which ultimately alters the phenotype of the culture. This chapter will review the principles of cell bank production, techniques for the scale-up of human pluripotent stem cells, quality control, and characterisation methods for banked cell lines. PMID- 21822865 TI - Embryonic stem cell derivation from human embryos. AB - Human embryonic stem cells (hESCs) are self-renewing, pluripotent cells that serve as a valuable research tool and hold promise for use in regenerative medicine. Most hESC lines are derived from cryopreserved human embryos that were created during in vitro fertilization (IVF) and are in excess of clinical need. Embryos that are discarded during the IVF procedure are also a viable source of hESCs. hESCs can be derived from pre-blastocyst embryos and even from single blastomeres. However, hESC line derivation efficiency is greatest using embryos that have reached the blastocyst stage. This chapter describes a protocol for the derivation of pluripotent stem cell lines from human embryos. PMID- 21822866 TI - Derivation of human parthenogenetic stem cell lines. AB - Pluripotent stem cells (PSCs) derived from parthenogenetically activated human oocytes demonstrate the typical characteristics displayed by human embryonic stem cells (hESCs) including infinite division and in vitro and in vivo differentiation into cells of all germ lineages. Different activation techniques allow the creation of either human leukocyte antigen (HLA) heterozygous human parthenogenetic stem cell (hpSC) lines, which are HLA-matched/histocompatible with the oocyte donor, or HLA-homozygous hpSC lines, which may be histocompatible to significant segments of the human population. This immune-matching advantage, combined with the advantage of derivation from nonviable human embryos that originate from unfertilized parthenogenetically activated oocytes, makes hpSCs a promising source of PSCs for cell-based transplantation therapy. This chapter describes two approaches for the parthenogenetic activation of human oocytes, their cultivation to the blastocyst stage, and the subsequent derivation of PSC lines. PMID- 21822867 TI - Generation of induced pluripotent stem cell lines from human fibroblasts via retroviral gene transfer. AB - This chapter describes a protocol for deriving induced pluripotent stem cells (iPSCs) from human fibroblasts. Human fibroblasts, cultured in fibroblast medium, are infected with a cocktail of retroviral vectors expressing the transcription factors OCT4, SOX2, KLF4, and MYC. The culture conditions are then switched to conditions that support human embryonic stem cell growth and emerging iPSC colonies that morphologically resemble human embryonic stem cell (hESC) colonies and have silenced the retroviral vectors (as evidenced by downregulation of retroviral GFP expression) that are mechanically isolated and subsequently cultured in identical fashion to hESCs. Putative iPSC lines are validated to be bona fide human iPSC lines by analyzing them for the expression of pluripotency markers and by differentiation in vitro and in vivo. PMID- 21822868 TI - Derivation of induced pluripotent stem cells by lentiviral transduction. AB - This chapter provides a method for reprogramming human dermal fibroblasts into induced pluripotent stem cells (iPSCs) using three lentiviruses containing cDNAs for OCT4 and SOX2, KLF4 and C-MYC, and NANOG and LIN28, respectively. Lentiviral vectors are based on the human immunodeficiency virus (HIV) and provide an effective means for the delivery, integration, and expression of exogenous genes in mammalian cells. Lentiviruses are attractive gene delivery vehicles as they are able to infect both proliferating and nonproliferating cells. Lentiviruses stably integrate into the genome without incurring cellular toxicity and can maintain sustained transgene expression during prolonged host cell proliferation and differentiation. In this protocol, we describe how to prepare lentiviruses, stably transduce human fibroblasts, and identify bona fide iPSC colonies based on morphological similarity to human embryonic stem cell (ESC) colonies and live cell immunological staining using cell-surface markers of human PSCs such as Tra 1-60 and Tra-1-81. PMID- 21822869 TI - Transgene-free production of pluripotent stem cells using piggyBac transposons. AB - Reprogramming of somatic cells to induced pluripotent stem cells (iPSCs) allows the derivation of -personalized stem cells. Transposon transgenesis is a novel and viable alternative to viral transduction methods for the delivery of reprogramming factors (Oct4, Sox2, Klf4, c-Myc) to somatic cells. Since transposons can be introduced as naked DNA using common plasmid transfection protocols, they provide a safer alternative to viral methods. piggyBac transposons are host-factor independent and integrate stably into the target genome, yet benefit from the unique characteristic of seamless removal mediated by transient expression of piggyBac transposase. Thus, piggyBac transposition provides an effective means to generate human, transgene-free iPSCs. The protocol describes the production of iPSCs from human embryonic fibroblasts, delivering reprogramming factors via plasmid transfection and piggyBac transposition. PMID- 21822870 TI - Traditional human embryonic stem cell culture. AB - Culturing human embryonic stem cells (hESCs) requires a significant commitment of time and resources. It takes weeks to establish a culture, and the cultures require daily attention. Once hESC cultures are established, they can, with skill and the methods described, be kept in continuous culture for many years. hESC lines were originally derived using very similar culture medium and conditions as those developed for the derivation and culture of mouse ESC lines. However, these methods were suboptimal for hESCs and have evolved considerably in the years since the first hESC lines were derived. Compared with mouse ESCs, hESCs are very difficult to culture - they grow slowly, and most importantly, since we have no equivalent assays for germline competence, we cannot assume that the cells that we have in our culture dishes are either stable or pluripotent. This makes it far more critical to assay the cells frequently using the characterization methods, such as karyotyping, immunocytochemistry, gene expression analysis, and flow cytometry, provided in this manual. PMID- 21822871 TI - Xeno-free culture of human pluripotent stem cells. AB - Stem cell culture systems that rely on undefined animal-derived components introduce variability to the cultures and complicate their therapeutic use. The derivation of human embryonic stem cells and the development of methods to produce induced pluripotent stem cells combined with their potential to treat human diseases have accelerated the drive to develop xenogenic-free, chemically defined culture systems that support pluripotent self-renewal and directed differentiation. In this chapter, we describe four xeno-free culture systems that have been successful in supporting undifferentiated growth of hPSCs as well as methods for xeno-free subculture and cryopreservation of hPSCs. Each culture system consists of a xeno-free growth medium and xeno-free substratum: (1) TeSR2TM with human recombinant laminin (LN-511); (2) NutriStemTM with LN-511; (3) RegESTM with human foreskin fibroblasts (hFFs); (4) KO-SR Xeno-FreeTM/GF cocktail with CELLstartTM matrix. PMID- 21822872 TI - Adaptation of human pluripotent stem cells to feeder-free conditions in chemically defined medium with enzymatic single-cell passaging. AB - This protocol describes the culture of human pluripotent stem cells (PSCs) under feeder-free conditions in a commercially available, chemically defined, growth medium, using Matrigel as a substrate and the enzyme solution Accutase for single cell passaging. This system is strikingly different from traditional PSC culture, where the cells are co-cultured with feeder cells and in medium containing serum replacement. PSCs cultured in this new system have a different morphology than those cultured on feeder cells but retain their characteristic pluripotency. This feeder-free PSC culture system is conceptually similar to feeder-free systems that use mouse embryonic fibroblast (MEF)-conditioned medium (MEF-CM) and Matrigel substratum. Instead of MEF-CM, a very complex and undefined medium, this new system uses StemPro SFM, a chemically defined medium that permits enzymatic passaging with Accutase to disaggregate the colonies into single cells. Accutase passaging has been used in conjunction with Stempro in our hands for 20+ passages without detectable karyotypic abnormalities. We will also review techniques for adapting cultures previously grown on MEFs, routine passaging of the cells, and cryopreservation. PMID- 21822873 TI - GMP scale-up and banking of pluripotent stem cells for cellular therapy applications. AB - Human pluripotent stem cells (PSCs), which include human embryonic stem cells (ESCs) as well as induced pluripotent stem cells (iPSCs), represent an important source of cellular therapies in regenerative medicine and the study of early human development. As such, it is becoming increasingly important to develop methods for the large-scale banking of human PSC lines. There are several well established methods for the propagation of human PSCs. The key to development of a good manufacturing practice (GMP) bank is to determine a manufacturing method that is amenable to large-scale production using materials that are fully documented. We have developed several banks of hESCs using animal feeder cells, animal-based matrices, or animal-free matrices. Protocols for growing hESCs on mouse embryonic fibroblasts (MEFs) are well established and are very helpful for producing research grade banks of cells. As most human ESCs cultured by research laboratories have been exposed to xenogeneic reagents, it is not imperative that all materials used in the production of a master cell bank be animal-free in origin. Nevertheless, as the field develops, it will no doubt become increasingly important to produce a bank of cells for clinical use without xenogeneic reagents, particularly nonhuman feeder cells which might harbor viruses with potential risk to human health or cell product integrity. Thus, even for cell lines previously exposed to xenogeneic reagents, it is important to minimize any subsequent exposure of the cell lines to additional adventitious agents. We have specifically described procedures for the growth of hESCs on Matrigel, an animal matrix, and CELLstart, an animal-free matrix, and these can be used to produce hESCs as part of a clinical manufacturing process. PMID- 21822874 TI - Culture of human pluripotent stem cells on glass slides for high-resolution imaging. AB - For certain applications, particularly experiments involving high-resolution imaging, it is necessary to culture cells on glass slides or cover glasses. This chapter describes techniques for successfully growing human embryonic stem cells (hESCs) on glass surfaces under three different conditions - serum-containing, serum-free, and following single-cell dissociation. It is anticipated that these techniques will extrapolate to other types of pluripotent stem cells such as induced pluripotent stem cells (iPSCs) and embryonic germ cells (EGCs). PMID- 21822875 TI - Classical cytogenetics: karyotyping techniques. AB - Classical cytogenetics by karyotyping has been utilized in clinical research laboratories for more than 50 years and remains the key method used in the stem cell laboratory to assess the genetic stability of stem cell cultures. It is currently the most readily accessible method for detecting chromosomal abnormalities in pluripotent stem cell cultures. This chapter will describe (1) how to prepare a culture to maximize the number of metaphase cells, (2) how to prepare slides containing chromosome spreads (3) methods used to stain chromosomes, and (4) how to interpret the cytogenetic report. PMID- 21822876 TI - FISH analysis of human pluripotent stem cells. AB - Human pluripotent stem cells (PSCs) hold promise for treating a multitude of diseases. These fascinating cells are unique in their ability to both self-renew and differentiate into cells from all three germ layers. However, PSCs, as well as other cultured cells, are prone to genetic instability. Given the possibility that these cells may one day be used clinically, identifying, and perhaps preventing, genetic instability is of particular concern for human PSC researchers. One type of genetic alteration that has been observed in PSCs is aneuploidy. Aneuploidy is defined as any divergence from the normal diploid number of chromosomes. So for human cells, any cell with more or less than 46 chromosomes would be considered aneuploid. Interestingly, there is a tendency for human PSCs, regardless of culture conditions, to gain specific chromosomes. In particular, gains of chromosomes 12, 17, 1, and X have been reported from labs all over the world. Since gains of these specific chromosomes are by far the most common aneuploidy seen in human PSCs, it is relatively easy and inexpensive to screen for these using fluorescent in situ hybridization (FISH). Here we will describe a cytogenetic method for screening human PSCs using FISH. PMID- 21822877 TI - Immunocytochemical analysis of human pluripotent stem cells. AB - This chapter will describe the most common immunocytochemical method utilized in the stem cell field - using fluorescently tagged secondary antibodies to detect a primary antibody that is bound to an epitope on a molecule of interest. Secondary antibodies recognize the heavy chain of the primary antibody's isotype. Generally, these methods employ an incubation period of the sample with the primary antibody, a series of washes to remove unbound primary antibody, a secondary incubation period of the sample with the fluorescently conjugated secondary antibody, followed by washes and preparation for microscopy. PMID- 21822878 TI - Flow cytometric analysis of human pluripotent stem cells. AB - Human pluripotent stem cells, human embryonic stem cells and induced pluripotent stem cells, represent an exciting new era in regenerative medicine and drug discovery. However, prior to their clinical translation, there is a need to gain an in-depth understanding of human pluripotent stem cell biology by characterizing these potentially heterogeneous populations of cells. Flow cytometry provides a rapid and efficient approach with which to isolate, purify, and study the functional properties of defined pluripotent stem cell types. PMID- 21822879 TI - The teratoma assay: an in vivo assessment of pluripotency. AB - A teratoma is a nonmalignant tumor comprised of a disorganized mixture of cells and small foci of tissue comprised of cells from all three of the embryonic germ layers. By definition, a cell is pluripotent if it can differentiate into cells derived from all three of the embryonic germ-layers: ectoderm, mesoderm, and endoderm. In the teratoma assay, putative pluripotent stem cells (PSCs) are implanted into an immune-compromised mouse where they may proliferate and differentiate to form a teratoma. The PSCs grow at the implantation site supported by a complex mixture of factors from the local milieu, as well as circulating factors that are vital components of normal mammalian physiology. After a predetermined time of 6-12 weeks or when the tumor has reached sufficient size, it is removed and subjected to histopathological analysis. The teratoma may be further processed by immunocytochemistry and gene expression profiling. This chapter describes methods to generate teratomas through the implantation of putative PSC lines in the SCID mouse. Implantation at the following sites is described: (1) intramuscular, (2) subcutaneous, (3) under the testis capsule, and (4) under the kidney capsule. PMID- 21822880 TI - Detection of copy number variation using SNP genotyping. AB - Genetic diversity among human genomes comes in many forms, including single nucleotide polymorphisms (SNPs) and small insertions and deletions on the order of one to several basepairs. More recently, large, >1 kb copy number changes have been identified as an important source of normal genomic variation as well as disease-causing variation. The ability to perform genome-wide discovery of large copy number variants (CNVs) has been facilitated by advances in two technologies array comparative genomic hybridization and SNP genotyping platforms. Here, we discuss the general principles and strategies underlying CNV detection with SNP genotyping platforms, which are widely used and capable of providing both SNP and CNV genotyping information. PMID- 21822881 TI - Genome-wide epigenetic analysis of human pluripotent stem cells by ChIP and ChIP Seq. AB - Chromatin immunoprecipitation (ChIP) is used to evaluate the interaction of proteins and genomic DNA. In eukaryotic cells, the DNA is highly compacted with the evolutionarily conserved histone proteins (which together with DNA form the nucleosome) and other chromosomal-associated proteins to form the chromatin structure. Chromatin structure is dynamically regulated by several mechanisms including transcription factor binding and various posttranslational modifications of the histone proteins. The chromatin structure can be affected by environmental factors, such as those that induce differentiation or promote self renewal in stem cells. Using very specific antibodies, one can evaluate the specific amino acids within the histones and each one of these modifications is associated with a distinct DNA-templated process, including transcription. Therefore, determining the location of transcription factors and histone modifications can yield important insights into the DNA-associated activities that are occurring at that particular region of the genome at that time. ChIP followed by high-throughput DNA sequencing (ChIP-Seq) provides a means to rapidly determine the precise genomic location of transcription factor binding sites and histone modifications on a genome-wide scale. Genome-wide mapping of histone modifications and chromatin-associated proteins have already begun to reveal the mechanisms responsible for regulating the pattern of gene expression in mouse embryonic stem cells. However, similar studies in human embryonic stem cells are currently lacking due to the difficulty in obtaining the large number of purified cells typically required for ChIP and ChIP-Seq experiments. Here, we describe a detailed method for determining the locations of specific histone modifications using only one million cells. PMID- 21822882 TI - Basic approaches to gene expression analysis of stem cells by microarrays. AB - This chapter covers gene expression analysis by microarray to study and characterize stem cells. In a case-study scenario, we describe basic bioinformatic methodologies used to answer common questions in microarray experiments involving one or more stem cell populations. Service providers or departmental core labs usually carry out sample preparation, hybridization, and scanning of microarrays. Therefore, in this chapter, we focus on the state-of-the art data analysis that avoids common pitfalls and introduces the reader to important controls that yield robust biologically relevant results. We describe evaluation of differentially expressed genes, clustering methods, gene-set enrichment analysis, and gene network discovery methods that can be used to formulate meaningful biological insights as well as suggest new wet lab experiments. PMID- 21822883 TI - Human pluripotent stem cells: the development of high-content screening strategies. AB - High-content screening (HCS) permits simultaneous observation and analysis of multiple cellular variables including cell morphology, survival, and differentiation in live cells at the single-cell level, at the level of the culture well, and across the entire culture. By combining high-throughput technologies such as robotics, chemical libraries, and automated high-resolution microscopy, scientists are able to evaluate a much broader array of experimental conditions than can be studied using conventional cell biological techniques that study fewer parameters at any one time. Thus, HCS assays provide a means to vastly improve our basic understanding of stem cell biology. We have developed a HCS assay that allows the study of the effects of hundreds of small molecules in parallel. The protocol described in this chapter was developed to assess the effects of small molecules on the survival, proliferation, and expression of pluripotent markers following single-cell dissociation of human embryonic stem cells, but can be applied to the study of other types of stem cells including induced pluripotent stem cells. A detailed protocol for the setup of HCS assays and the parameters used to identify chemical modifiers of survival in human pluripotent stem cells, as well as secondary assays used to validate the small molecule "hits" obtained during the high-content screen, are described. PMID- 21822884 TI - Quantitative proteome and phosphoproteome analysis of human pluripotent stem cells. AB - Understanding the signaling pathways governing pluripotency and self-renewal is a prerequisite for better controlling stem cell differentiation to specific fates. Reversible protein phosphorylation is one of the most important posttranslational modifications regulating signaling pathways in biological processes. Global analysis of dynamic changes in protein phosphorylation is, therefore, key to understanding signaling at the system level. Here, we describe a generic mass spectrometry (MS)-based phosphoproteomics strategy applied to monitor phosphorylation dynamics after bone morphogenetic protein 4 (BMP4)-induced differentiation of human embryonic stem cells (hESCs). Our method combines the use of strong cation exchange (SCX) and titanium dioxide (TiO(2)) for phosphopeptide enrichment, high-resolution MS for peptide and protein identification, and stable isotope labeling by amino acids in cell culture (SILAC) for quantification. This approach allows us to identify thousands of phosphorylation sites and profile their relative abundance during differentiation. This systems-biology-based approach provides new insights into how human pluripotent stem cells exit the pluripotent state. PMID- 21822885 TI - Lentivirus-mediated modification of pluripotent stem cells. AB - Relatively safe, HIV-1-based lentiviral vectors have served as an efficient means of transducing human embryonic stem cells (hESCs). Here we describe the variety of lentiviral vector systems available with the basic strategy for designing viral vectors and methods for generating viruses for efficiently infecting and selecting transduced hESCs. PMID- 21822886 TI - Nucleofection of human embryonic stem cells. AB - The ability to realize the full potential of human pluripotent stem cells (hPSCs) as tools for -understanding human development and advancing the field of regenerative medicine is dependent on efficient methods to genetically manipulate these cells. There are several methods for introducing foreign DNA into cells such as electroporation, lipid-based transfection technology, and viral transduction. We describe here a method to transfect human embryonic stem cells (hESCs) using nucleofection technology. This unique method uses the Nucleofector II Device that combines the use of a cell type-specific Nucleofector Solution and preprogrammed electrical parameters to efficiently deliver DNA into the cell nucleus. The use of this technology allows high-efficiency transfer of nucleic acids into hESCs enabling both transient and stable manipulation of gene expression in these cells. PMID- 21822887 TI - Nonviral gene delivery in neural progenitors derived from human pluripotent stem cells. AB - Human pluripotent stem cells (hPSCs) have been used to derive self-renewing neural progenitor (NP) cell lines. Here we describe methods to genetically modify these cells. Detailed methods for transfection and nucleofection in PSC-derived NP cells are presented. We have shown that nucleofection results in higher yield of GFP(+) NP cells as compared with transfection. However, nucleofection leads to higher cell death than transfection. Application of these methods allows for the development of novel tools to study human development and cellular differentiation. Genetically modified NPs have direct application in neural imaging, tracking neural cells, and for drug delivery to target organs using neural progenitor cells as carriers. PMID- 21822888 TI - Gene targeting in human pluripotent stem cells. AB - Targeted homologous recombination (HR) is an essential tool in stem cell biology. It can be used to study gene function and is a highly developed technology in the mouse where precise genetic modifications are introduced into the genome via HR in mouse embryonic stem cells (mESCs). However, gene targeting has not been widely applied to the study of human pluripotent stem cells (hPSCs) due to its relatively low efficiency in human cell lines. To overcome this technical hurdle, we have developed and established a protocol that allows efficient gene targeting in hPSC lines. This chapter provides a detailed protocol for efficiently performing gene targeting in hPSCs by electroporation. The protocol describes methods for cell preparation, antibiotic selection, and excision of the selectable marker following gene targeting. While we can only target one allele at a time, HR covers a broad range of important applications including making knock-in reporter lines and knock-in lineage tracers, generating disease models that are caused by dominant mutants, repair of patient-derived induced PSCs that only involve a single allele mutation, and knocking out genes that are located on the X chromosome in male lines. When targeting to both alleles is needed, such as generation of a knockout cell line, the cells can be electroporated twice with targeting vectors designed to target each of the alleles. This protocol will find broad applications in generating lineage-specific reporter lines and point mutations in genetic repair in disease models using hPSCs. PMID- 21822889 TI - Episomal transgene expression in pluripotent stem cells. AB - Herpes simplex type 1 (HSV-1) amplicon vectors possess a number of features that make them excellent vectors for the delivery of transgenes into stem cells. HSV-1 amplicon vectors are capable of efficiently transducing both dividing and nondividing cells and since the virus is quite large, 152 kb, it is of sufficient size to allow for incorporation of entire genomic DNA loci with native promoters. HSV-1 amplicon vectors can also be used to incorporate and deliver to cells a variety of sequences that allow extrachromosomal retention. These elements offer advantages over integrating vectors as they avoid transgene silencing and insertional mutagenesis. The construction of amplicon vectors carrying extrachromosomal retention elements, their packaging into HSV-1 viral particles, and the use of HSV-1 amplicons for stem cell transduction will be described. PMID- 21822890 TI - The generation of embryoid bodies from feeder-based or feeder-free human pluripotent stem cell cultures. AB - Embryoid body (EB) formation is a traditional method of inducing differentiation of pluripotent stem cells (PSCs). It is a routine in vitro test of pluripotency as well as the first stage in many differentiation protocols targeted toward the production of a specific lineage or cellular population, as in neural differentiation (see Chapters 29 and 30). The induction of differentiation via EB formation is fairly straightforward. However, depending on the specific PSC culture conditions - substrate, feeders, medium, and eventual cell type of interest - various methods are applied in order to most routinely obtain healthy EB cultures. PMID- 21822891 TI - Derivation of oligodendrocyte progenitor cells from human embryonic stem cells. AB - The directed differentiation of human pluripotent stem cells into specific, determined, and high-purity cell types can provide a means to study the cellular and molecular mechanisms of development and to generate cells for potential therapeutic applications. The ability to derive homogeneous cell populations obviates the need for transgene expression or cell sorting methods and can improve selection efficiency, lineage differentiation, cell viability, and clinical utility. Compared to undifferentiated pluripotent stem cells, high purity cell phenotypes for clinical therapeutic strategies are expected to enhance engraftment, potentiate clinical efficacy, and decrease the risk of adverse effects such as dedifferentiation or teratoma formation. Clinical interest in the derivation of oligodendrocyte progenitor cells from pluripotent stem cells is based on research that demonstrates the effectiveness of progenitor cell transplants to improve outcomes after spinal cord injury. Here, we describe a protocol to generate oligodendroglial lineage-specific cells in high purity from human embryonic stem cells. PMID- 21822892 TI - Directed differentiation of dopamine neurons from human pluripotent stem cells. AB - Midbrain dopaminergic (mDA) neurons play a critical role in regulating postural reflexes and movement as well as modulating psychological processes. Dysfunction or degeneration of mDA neurons is involved in a number of neurological disorders including Parkinson's disease. Availability of large quantities of human mDA neurons would greatly enhance our ability to reveal pathological processes underlying mDA neuron degeneration and to identify treatments for these neurological conditions. Human pluripotent stem cells (PSCs), including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), provide an unlimited source for mDA neurons. Here we describe a chemically defined protocol for mDA neuron differentiation. PSCs are first converted to neuroepithelia in a chemically defined medium without any growth factors, followed by patterning the neuroepithelia to midbrain progenitors with fibroblast growth factor 8 (FGF8) and sonic hedgehog (SHH) and subsequent differentiating to functional mDA neurons. This protocol typically yields about half of the neuronal population being mDA neurons, determined by expression of mDA markers, electrophysiological recordings, and the ability to reverse functional deficit in a rat model of Parkinson's disease. PMID- 21822893 TI - Methods for the derivation and use of cardiomyocytes from human pluripotent stem cells. AB - The availability of human cardiomyocytes derived from embryonic stem cells (ESCs) has generated -considerable excitement, as these cells are an excellent model system for studying myocardial development and may have eventual application in cell-based cardiac repair. Cardiomyocytes derived from the related induced pluripotent stem cells (iPSCs) have similar properties, but also offer the prospects of patient-specific disease modeling and cell therapies. Unfortunately, the methods by which cardiomyocytes have been historically generated from pluripotent stem cells are unreliable and typically result in preparations of low cardiac purity (typically <1% cardiomyocytes). We detail here the methods for a recently reported directed cardiac differentiation protocol, which involves the serial application of two growth factors known to be involved in early embryonic heart development, activin A, and bone morphogenetic protein-4 (BMP-4). This protocol reliably yields preparations of 30-60% cardiomyocytes, which can then be further enriched to >90% cardiomyocytes using straightforward physical methods. PMID- 21822894 TI - In vivo evaluation of putative hematopoietic stem cells derived from human pluripotent stem cells. AB - Efficient derivation and isolation of hematopoietic stem cells (HSCs) from human pluripotent stem cell (hPSC) populations remains a major goal in the field of developmental hematopoiesis. These enticing pluripotent stem cells (comprising both human embryonic stem cells and induced pluripotent stem cells) have been successfully used to generate a wide array of hematopoietic cells in vitro, from primitive hematoendothelial precursors to mature myeloid, erythroid, and lymphoid lineage cells. However, to date, PSC-derived cells have demonstrated only limited potential for long-term multilineage hematopoietic engraftment in vivo - the test by which putative HSCs are defined. Successful generation and characterization of HSCs from hPSCs not only requires an efficient in vitro differentiation system that provides insight into the developmental fate of hPSC-derived cells, but also necessitates an in vivo engraftment model that allows identification of specific mechanisms that hinder or promote hematopoietic engraftment. In this chapter, we will describe a method that utilizes firefly luciferase-expressing hPSCs and bioluminescent imaging to noninvasively track the survival, proliferation, and migration of transplanted hPSC-derived cells. Combined with lineage and functional analyses of engrafted cells, this system is a useful tool to gain insight into the in vivo potential of hematopoietic cells generated from hPSCs. PMID- 21822895 TI - Differentiation of dendritic cells from human embryonic stem cells. AB - Improving our understanding of the interactions between human dendritic cells (DCs) and T cells may contribute to the development of therapeutic strategies for a variety of immune-mediated disorders. The possibility of using DCs themselves as tools to manipulate immune responses opens even greater therapeutic avenues. Current methods of generating human DCs are both inadequate and susceptible to high levels of variability between individuals. DCs differentiated from human embryonic stem cells (hESCs) could provide a more reliable, consistent solution. DCs have now successfully been differentiated from hESCs and more recently this has been repeated using protocols that avoid the inclusion of animal products, an important modification for clinical use. We have developed a novel method for the generation of DCs from hESCs in the absence of animal products that does not necessitate a separate embryoid body (EB) generation step. The technique involves the use of four growth factors and their successive removal from culture, resulting in accumulation of DCs with phenotypic, morphological, and immunostimulatory properties comparable to those of classical human monocyte derived DCs. In addition to the application of hESC-derived DCs in basic research and novel approaches to cancer immunotherapy, they may also play a central role in the field of regenerative medicine. Tolerogenic DCs differentiated from hESCs may be used to persuade the immune system of the recipients of cell replacement therapy to tolerate allogeneic tissues differentiated from the same hESC line. Such an approach may help to address the immunological barriers that threaten to derail the clinical application of hESCs. PMID- 21822896 TI - Late-onset Alzheimer's disease is associated with mitochondrial DNA 7028C/haplogroup H and D310 poly-C tract heteroplasmy. PMID- 21822897 TI - The role of non-epistemic values in engineering models. AB - We argue that non-epistemic values, including moral ones, play an important role in the construction and choice of models in science and engineering. Our main claim is that non-epistemic values are not only "secondary values" that become important just in case epistemic values leave some issues open. Our point is, on the contrary, that non-epistemic values are as important as epistemic ones when engineers seek to develop the best model of a process or problem. The upshot is that models are neither value-free, nor depend exclusively on epistemic values or use non-epistemic values as tie-breakers. PMID- 21822898 TI - Twisted nose: a new simple classification and surgical algorithm in Asians. AB - The purpose of this study was to present our experiences with correction of twisted nose in Asian patients using a new and simple classification and a surgical algorithm. A classification and standard surgical algorithm was followed to determine treatment strategies for 384 patients with twisted nose between June 2001 and July 2009. A retrospective chart review from the Tri-Service General Hospital archives was performed to collect patients' data and surgical details. A follow-up self-evaluation survey regarding satisfaction with nasal function and esthetics was distributed to all participants. Preoperative and postoperative standardized photography of the face were evaluated to judge objectively the esthetic outcomes of the surgery. There were 147, 131, and 106 patients in Type I, Type II, and Type III patients, respectively. The percentages of functionally satisfied and very satisfied patients were 95.2, 93.9, and 93.4% in Type I, Type II, and Type III groups, respectively. The percentages of esthetically satisfied or very satisfied patients were 89.1, 88.5, and 87.7% in Type I, Type II, and Type III groups, respectively. There were only 2 patients with type III deviation with residual deviation of dorsum objectively who were satisfied with the results after undergoing a revision rhinoplasty. Aside from residual deviation, the postoperative periods were uneventful and without major complications. We propose a new and simple classification and surgical algorithm to optimally correct twisted nose deformities for Asian patients. The classification and surgical algorithm, which is simple and reproducible especially for beginner, guides surgical decisions that yield consistently satisfactory functional and esthetic results. PMID- 21822899 TI - Site-specific recombinases as tools for heterologous gene integration. AB - Site-specific recombinases are the enzymes that catalyze site-specific recombination between two specific DNA sequences to mediate DNA integration, excision, resolution, or inversion and that play a pivotal role in the life cycles of many microorganisms including bacteria and bacteriophages. These enzymes are classified as tyrosine-type or serine-type recombinases based on whether a tyrosine or serine residue mediates catalysis. All known tyrosine-type recombinases catalyze the formation of a Holliday junction intermediate, whereas the catalytic mechanism of all known serine-type recombinases includes the 180 degrees rotation and rejoining of cleaved substrate DNAs. Both recombinase families are further subdivided into two families; the tyrosine-type recombinases are subdivided by the recombination directionality, and the serine-type recombinases are subdivided by the protein size. Over more than two decades, many different site-specific recombinases have been applied to in vivo genome engineering, and some of them have been used successfully to mediate integration, deletion, or inversion in a wide variety of heterologous genomes, including those from bacteria to higher eukaryotes. Here, we review the recombination mechanisms of the best characterized recombinases in each site-specific recombinase family and recent advances in the application of these recombinases to genomic manipulation, especially manipulations involving site-specific gene integration into heterologous genomes. PMID- 21822900 TI - ATP-dependent fructose uptake system in Deinococcus radiodurans. AB - The bacterial phosphoenolpyruvate (PEP)-dependent group translocation system (PTS) requires the presence of both membrane-bound and cytoplasmic components to phosphorylate and translocate sugar. Deinococcus radiodurans has a functional fruA gene coding for the membrane-bound components of the fructose-specific PTS. However, fruB gene coding for the fructose-specific cytosolic components of PTS is a pseudogene. Yet, this bacterium metabolized fructose readily. In vitro studies showed that both cell membranes and cytoplasmic fractions of the cells were needed for fructose phosphorylation. Further studies showed that fructose phosphorylation required ATP, not PEP, as the phosphate donor. Unlike most PEP dependent PTS systems, fructose phosphorylation is sensitive to sodium fluoride, a kinase inhibitor. Fructose phosphorylation was also inhibited in the presence of antiserum against a kinase phosphorylation site. Rhodobacter capsulatus has a functional fruA-fruB system. Complementation assays by reconstituting the membrane fraction of D. radiodurans to the cytoplasmic fraction of R. capsulatus resulted in a PEP-dependent fructose phosphorylation, whereas mixing the membranes of R. capsulatus and the deinococcal cytosol in vitro resulted in an ATP-dependent fructose phosphorylation. PMID- 21822901 TI - Refolding of proteins from inclusion bodies: rational design and recipes. AB - The need to develop protein biomanufacturing platforms that can deliver proteins quickly and cost-effectively is ever more pressing. The rapid rate at which genomes can now be sequenced demands efficient protein production platforms for gene function identification. There is a continued need for the biotech industry to deliver new and more effective protein-based drugs to address new diseases. Bacterial production platforms have the advantage of high expression yields, but insoluble expression of many proteins necessitates the development of diverse and optimised refolding-based processes. Strategies employed to eliminate insoluble expression are reviewed, where it is concluded that inclusion bodies are difficult to eliminate for various reasons. Rational design of refolding systems and recipes are therefore needed to expedite production of recombinant proteins. This review article discusses efforts towards rational design of refolding systems and recipes, which can be guided by the development of refolding screening platforms that yield both qualitative and quantitative information on the progression of a given refolding process. The new opportunities presented by light scattering technologies for developing rational protein refolding buffer systems which in turn can be used to develop new process designs armed with better monitoring and controlling functionalities are discussed. The coupling of dynamic and static light scattering methodologies for incorporation into future bioprocess designs to ensure delivery of high-quality refolded proteins at faster rates is also discussed. PMID- 21822902 TI - Kinetics of CO conversion into H2 by Carboxydothermus hydrogenoformans. AB - The objective of this study was to improve the biological water-gas shift reaction for producing hydrogen (H(2)) by conversion of carbon monoxide (CO) using an anaerobic thermophilic pure strain, Carboxydothermus hydrogenoformans. Specific hydrogen production rates and yields were investigated at initial biomass densities varying from 5 to 20 mg volatile suspended solid (VSS) L(-1). Results showed that the gas-liquid mass transfer limits the CO conversion rate at high biomass concentrations. At 100-rpm agitation and at CO partial pressure of 1 atm, the optimal substrate/biomass ratio must exceed 5 mol CO g(-1) biomass VSS in order to avoid gas-liquid substrate transfer limitation. An average H(2) yield of 94 +/- 3% and a specific hydrogen production rate of ca. 3 mol g(-1) VSS day( 1) were obtained at initial biomass densities between 5 and 8 mg VSS(-1). In addition, CO bioconversion kinetics was assessed at CO partial pressure from 0.16 to 2 atm, corresponding to a dissolved CO concentration at 70 degrees C from 0.09 to 1.1 mM. Specific bioactivity was maximal at 3.5 mol CO g(-1) VSS day(-1) for a dissolved CO concentration of 0.55 mM in the culture. This optimal concentration is higher than with most other hydrogenogenic carboxydotrophic species. PMID- 21822903 TI - Expression of a lipid-inducible, self-regulating form of Yarrowia lipolytica lipase LIP2 in Saccharomyces cerevisiae. AB - Saccharomyces cerevisiae is frequently used as a bioreactor for conversion of exogenously acquired metabolites into value-added products, but has not been utilized for bioconversion of low-cost lipids such as triacylglycerols (TAGs) because the cells are typically unable to acquire these lipid substrates from the growth media. To help circumvent this limitation, the Yarrowia lipolytica lipase 2 (LIP2) gene was cloned into S. cerevisiae expression vectors and used to generate S. cerevisiae strains that secrete active Lip2 lipase (Lip2p) enzyme into the growth media. Specifically, LIP2 expression was driven by the S. cerevisiae PEX11 promoter, which maintains basal transgene expression levels in the presence of sugars in the culture medium but is rapidly upregulated by fatty acids. Northern blotting, lipase enzyme activity assays, and gas chromatographic measurements of cellular fatty acid composition after lipid feeding all confirmed that cells transformed with the PEX11 promoter-LIP2 construct were responsive to lipids in the media, i.e., cells expressing LIP2 responded rapidly to either free fatty acids or TAGs and accumulated high levels of the corresponding fatty acids in intracellular lipids. These data provided evidence of the creation of a self regulating positive control feedback loop that allows the cells to upregulate Lip2p production only when lipids are present in the media. Regulated, autonomous production of extracellular lipase activity is a necessary step towards the generation of yeast strains that can serve as biocatalysts for conversion of low value lipids to value-added TAGs and other novel lipid products. PMID- 21822904 TI - Sequencing and analysis of three plasmids from Lactobacillus casei TISTR1341 and development of plasmid-derived Escherichia coli-L. casei shuttle vectors. AB - Pyrosequencing followed by conventional PCR and sequencing was used to determine the complete nucleotide sequence of three plasmids (pRCEID2.9, pRCEID3.2, and pRCEID13.9) from the Lactobacillus casei strain TISTR1341. The plasmid sequences were found to be almost identical, respectively, to those of pLA106, pLA105, and pLA103 from Lactobacillus acidophilus strain TK8912, suggesting that these strains may be related. Sequence analysis and comparison indicated that pRCEID2.9 replicates by a rolling circle (RC) mechanism, while pRCEID3.2 and pRCEID13.9 probably follow a theta-type mode of replication. Replicons of pRCEID2.9 and pRCEID13.9 were used to develop Escherichia coli/L. casei compatible shuttle vectors, which were stably maintained in different genetic backgrounds. Real-time quantitative PCR analysis showed copy numbers of around 4 and 15, respectively, for the pRCEID13.9- and pRCEID2.9-derived shuttle vectors per chromosome equivalent. The functionality of vector pRCEID-LC13.9 was proved by cloning and expressing in L. casei of a green fluorescent protein gene variant from Aequorea victoria under the control of the promoter from a homologous lactate dehydrogenase gene. The new vectors might complement those currently in use for the exploitation of L. casei as a cellular factory and in other biotechnological applications. PMID- 21822906 TI - Uncommon vascular tumor of the ovary. Primary ovarian epithelioid hemangioendothelioma or vascular sarcomatous transformation in ovarian germ cell tumor? AB - Epithelioid hemangioendothelioma (EHE) is an unusual vascular tumor, which usually occurs in the soft tissue, liver, breast, lung and bone. We submit a case of EHE, a tumor never before reported in the ovary. A 20-year-old woman was admitted with a medical history of unilateral ovarian tumor. The right ovary was totally removed and histologically, the tumor was composed of epithelioid cells with eosinophilic cytoplasm and prominent intracytoplasmic vacuoles associated with myxohyaline matrix. No morphologic evidence of germ cell tumor was observed. Immunohistochemically, the tumor cells were positive for CD31 and CD34. However, all germ cell tumor markers were negative. The final diagnosis was EHE of the ovarian gland and sarcomatous transformation in ovarian germ cell tumor was excluded after extensive histopathological and immunohistochemical study. EHE is an uncommon vascular tumor, which is rarely seen in female genital tract and this is the first report of EHE in ovarian gland. Final diagnosis depends on histopathological and immunohistochemical features. PMID- 21822905 TI - Detection and identification of microorganisms in wine: a review of molecular techniques. AB - The microbial ecology of wine is complex. Microbes can play both positive and negative roles in the quality of the final product. Due to this impact, the microbial ecology of wine has been well studied. Traditional indirect methods, such as plating, have largely been replaced by a number of molecular methods. These methods are typically either indirect methods used for identification of cultured organisms, or direct methods used to profile whole populations or identify specific microbes in a mixed population. These molecular methods offer a number of advantages over traditional methods including speed and precision. This review will examine both direct and indirect molecular methods, provide examples of their impact on the study of the microbial ecology of wine, and also discuss their strengths and limitations. PMID- 21822907 TI - Three Dimensional Power Doppler evaluation of human endometrium after administration of oxytocine receptor antagonist (OTRa) in an IVF program. AB - PURPOSE: To compare endometrial and subendometrial morphological changes and vascularity as measured by 3D Power Doppler sonography, based on a specific scoring system between women subjected or not to oxytocine receptor antagonist (OTRa) during IVF cycles. METHODS: Twenty-six women were divided into groups according to OTRa (Atosiban tractocide) administration. The first group (control n = 13 women) was examined with 3D Power Doppler 3 days after embryo transfer. The second group (n = 13 women) was administered 7.5 mg intravenous tractocide 2 days after embryo transfer and a 3D Power Doppler was performed after a day. RESULTS: The control group presented the following ultrasonographic characteristics: (a) echogenic endometrium in all cases, (b) endometrial thickness >7 mm in all cases (84.6%), (c) endometrial volume >2.31 cm(3) in 5 cases (38.5%), (d) abnormal sub-endometrial halo in 3 cases (23.1%), (e) endometrial blood flow in 6 cases (46.2%) and (f) complex vessel's architecture in 2 cases (15.4%). In women who underwent OTRa administration were observed: (a) echogenic endometrium in 1 case (7.7%), triple line endometrium in 12 cases (92.3%), (b) endometrial thickness >7 mm in all cases, (c) endometrial volume >2.31 cm(3) in 11 cases (84.6%), (d) abnormal sub-endometrial halo in 3 cases (23.1%), (e) endometrial blood flow in 11 cases (84.6%) and (f) complex vessel's architecture in 6 cases (46.2%). CONCLUSIONS: Women who have taken OTRa presented an endometrium with characteristics more predictive of implantation. PMID- 21822908 TI - Age and gender may affect posterior reversible encephalopathy syndrome in renal disease. AB - It remains elusive what factors affect posterior reversible encephalopathy syndrome (PRES). Eleven PRES children, all with acute glomerulonephritis, Alport syndrome, and lupus nephritis, 5 with nephrosis, and 3 renal transplant recipients, were studied. PRES recurred in 1 patient. Neurological symptoms were graded as 1: mild (headache, nausea/vomiting, or tremor), 2: moderate (vision change), and 3: severe (mental dysfunction, cerebellar symptoms, seizures, recurrence of seizures, and coma). Magnetic resonance imaging was graded as 1: subtle change, 2: abnormal large areas, and 3: complete involvement of the regions. The common symptoms were seizures (100%), headache (82%), nausea/vomiting (73%), coma (55%), and vision change (46%). Seizures recurred in 7 (64%). All but one (91%) developed hypertension and 7 (64%) received calcineurin inhibitors (CNI). Edema occurred in 7 (64%) and renal insufficiency/end-stage renal disease (ESRD) in 4 (36%). Seizures recurred frequently in younger patients. Symptoms were severe in girls. Duration or severity of the condition with predisposing factors (hypertension, CNI, nephrosis or renal insufficiency/ERSD) did not make a difference in the symptoms and neuroimaging. Two patients developed chronic epilepsy. Age and gender may affect PRES symptoms. Our results are limited by small sample size and should be determined using larger numbers of patients. PMID- 21822909 TI - Increased bacterial translocation in gluten-sensitive mice is independent of small intestinal paracellular permeability defect. AB - AIM: We investigated whether treatment with gliadin induces a paracellular permeability defect that enhances bacterial translocation to mesenteric lymph nodes (MLN) via resident dendritic cells (DC) expressing TLR-2 or 4 in HCD4/HLA DQ8 transgenic mice. METHODS: HLA-DQ8 transgenic mice were sensitized and subsequently gavaged with gliadin, in the presence or absence of AT1001 (paracellular permeability inhibitor). Non-sensitized mice were gavaged with indomethacin (permeability inducer) or rice cereal. CD11c and CD103 (DC markers) and TLR-2 and 4 were investigated by immunostaining. Intestinal permeability was assessed by paracellular flux of (51)Cr-EDTA in Ussing chambers. Bacterial translocation to MLN was performed by plate counting on aerobic and anaerobic conditions. RESULTS: In gliadin-treated mice, both (51)Cr-EDTA flux in jejunal mucosa and aerobic and anaerobic bacterial counts in MLN were increased (p < 0.05) compared to indomethacin-treated mice and controls. The inhibitor AT1001 normalized (51)Cr-EDTA flux, but had no effect on bacterial translocation in gliadin-treated mice. In addition, changes in mucosal DC marker distribution such as increased (p < 0.05) trans-epithelial CD103(+) cells and reduction (p < 0.05) of CD11c immunostaining were detected in gliadin-treated mice. Moreover, changes in DC markers and TLR-2 or 4 immunophenotypes were not associated. CONCLUSIONS: Pharmacological restoration of paracellular permeability was not sufficient to prevent bacterial translocation in gluten-sensitive mice. We hypothesize that transcellular mechanisms involving CD103(+)DC and CD11c(+)DC may explain in gluten-sensitive HCD4/HLA-DQ8 transgenic mice the sustained increased bacterial translocation observed in the absence of a significant inflammatory response. PMID- 21822910 TI - Deterioration of glycemic control after corticosteroid administration in islet autotransplant recipients: a cautionary tale. AB - Islet autotransplantation (IAT) is performed at the time of total pancreatectomy (TP) to prevent or minimize post-surgical diabetes. Corticosteroids induce insulin resistance and present a risk to islet autografts, through glucotoxicity and increased metabolic demand on a marginal islet mass. We present four IAT recipients treated with oral or injected corticosteroids after transplant for medical conditions unrelated to chronic pancreatitis or TPIAT. Hyperglycemia or insulin resistance was evident in all four patients, including reversion to long term insulin therapy in two patients. One patient receiving corticosteroid injections had a transient increase in hemoglobin A1c (+0.6% above baseline), and one patient given a one time dose of oral dexamethasone exhibited hyperglycemia despite high insulin (>200 mU/L) and C-peptide (15.3 ng/mL) production on an oral glucose tolerance test. IAT recipients have insufficient islet mass to compensate for the insulin resistance induced by corticosteroids. Caution should be given to using these agents in IAT recipients. When corticosteroids are medically necessary, insulin therapy should be administered temporarily to compensate for the increased metabolic demand and minimize long-term risks on the islet graft. PMID- 21822911 TI - Down-regulation of TWIST decreases migration and invasion of laryngeal carcinoma Hep-2 cells by regulating the E-cadherin, N-cadherin expression. AB - PURPOSE: The transcription factor TWIST is an important factor in regulation of the epithelial-mesenchymal transition (EMT), which represents the primary stages during the metastasis of tumors. To identify the role of TWIST in the regulation of metastasis in laryngeal carcinoma Hep-2 cells, we investigated whether the alteration of TWIST has an effect on the Hep-2 cells morphology and whether the alteration of TWIST has an effect on the expression of E-cadherin, N-cadherin as well as the ability of cell motion, migration, and invasion. METHODS: Morphological changes of Hep-2 cells that were transfected a mircoRNA against TWIST vector were observed by the reserved microscope. Reverse transcription polymerase chain reaction was performed in order to examine the mRNA expression of TWIST, E-cadherin, and N-cadherin. Western blotting was performed to examine the protein expression of TWIST, E-cadherin, and N-cadherin. Cell motion ability was examined by Scratch-wound assay. Transwell(TM) chamber assays were used to determine cell migration and invasion. RESULTS: Transfecting a mircoRNA down regulated TWIST expression at mRNA and protein levels. Down-regulation of TWIST expression induced morphological changes, such as the inversion of the EMT. Moreover, down-regulation of TWIST expression up-regulated E-cadherin and down regulated N-cadherin expressions at mRNA and protein levels, respectively. Furthermore, we confirmed that down-regulation of TWIST expression decreased the motion, invasion, and migration ability of the Hep-2 cells. CONCLUSIONS: Down regulation of TWIST expression decreases migration and invasion of laryngeal carcinoma Hep-2 cells by regulation of the E-cadherin, N-cadherin expression. PMID- 21822912 TI - Tuberculosis infection in rheumatic patients with infliximab therapy: experience with 157 patients. AB - It is recommended to evaluate the presence of latent tuberculosis infection (LTBI) prior to the use of antitumor necrosis factor alpha. The aim of this study is to assess the presence of LTBI in patients with rheumatic diseases undergoing treatment with infliximab in an endemic area for tuberculosis (TB). LTBI was searched through the contact history, chest X-ray and tuberculin skin test with purified protein derivative (PPD) >=5 mm. We studied 157 patients in the period from May 2005 to October 2008, 99 (63.1%) were women with average age of 49 years and 58 (36.9%) were men with average age of 41 years. The group comprising 90 patients (57.3%) with rheumatoid arthritis (RA), 54 (34.4%) with ankylosing spondylitis (AS) and 13 (8.3%) with psoriatic arthritis (PsA) had PPD reactor 13.4% (21/157), being prevented by isoniazid (INH) in these patients. There are dissimilar responsiveness to the PPD between the three pathologies, and the reactivity was lower in RA (RA * AS: chi(2) = 12; P = 0.0004; and RA * PsA: chi(2) with Yates' correction = 3.6; P = 0.05). No significant difference between the reactivity of the PPD and the use of immunosuppressive drugs (P = 0.81) is observed. The immunoprophylaxis with INH showed an efficacy of 95% (20/21); three (1.9%) patients developed active TB (spondylodiscitis, meningitis and lymphadenopathy) after the use of infliximab, reaffirming extrapulmonary involvement. These results suggest that PPD has a low sensitivity for detection of LTBI in RA and that the previous use of immunosuppressive drugs does not affect the response to PPD. PMID- 21822913 TI - Single-dose intravenous casopitant in combination with ondansetron and dexamethasone for the prevention of oxaliplatin-induced nausea and vomiting: a multicenter, randomized, double-blind, active-controlled, two arm, parallel group study. AB - PURPOSE: The primary objective was to determine if a single dose of casopitant 90 mg added to ondansetron and dexamethasone would improve the control of chemotherapy-induced nausea and vomiting (CINV) over 0-120 h following initiation of oxaliplatin-based moderately emetic chemotherapy (MEC) compared to ondansetron and dexamethasone alone. METHODS: Patients with colorectal cancer received either casopitant or placebo intravenously (IV) added to ondansetron 8 mg bid oral on study days 1 to 3 and one dose of dexamethasone 8 mg IV given prior to starting the oxaliplatin on day 1. The primary endpoint was the percentage of subjects achieving complete response (CR; no vomiting/retching or use of rescue medication) during 120 h after initiation of chemotherapy in cycle 1. RESULTS: No difference in the rate of CR was noted in the casopitant group compared to the placebo group for the overall (placebo 85%, casopitant 86%, p = 0.7273), acute (placebo 96%, casopitant 97%), or delayed phases (placebo 85%, casopitant 86%). The average area under curve (0-infinity) of casopitant after a single 90-mg IV dose was 8,390 ng h/mL. At 24 h after casopitant 90-mg IV dosing, the plasma casopitant concentration was 24% lower than the values noted in prior studies with 150 mg oral administration, and the plasma exposure of the major metabolite (GSK525060) was 18% lower. CONCLUSIONS: Addition of single-dose casopitant 90 mg IV did not improve the control of CINV at any time during 120 h following initiation of oxaliplatin-based MEC. Excellent control of CINV was achieved in this study population with the combination of ondansetron and dexamethasone alone. PMID- 21822914 TI - Life events as environmental States and genetic traits and the role of personality: a longitudinal twin study. AB - The occurrence of many life events is not entirely random but genetically influenced. The current study examined the sources underlying the stability or recurrence of life events and the developmental interplay between personality traits and life events. In a longitudinal study of 338 adult twin pairs we estimated (1) the genetic and environmental sources of continuity in aggregates of life events, (2) the sources through which personality influences the experience of life events, and (3) the sources through which life events influence personality. Unlike personality which showed both genetic and environmental influences on substantial continuity over time, stability of life events was moderate and mainly influenced by genetic factors. Significant associations between personality and life events were specific to certain personality traits and qualitative aspects of life events (controllable positive, controllable negative, and less controllable negative), primarily directional from personality to life events, and basically genetically mediated. Controlled for these genetic associations, we also found some small and basically environmentally mediated effects of life events on personality traits. The results support the concept of genotype-environment correlation as a propulsive mechanism of development. PMID- 21822915 TI - Acetabular orientation: anatomical and functional measurement. AB - PURPOSE: Acetabular orientation is important to consider in hip joint pathology and treatment. This study aims to describe the functional orientation of the acetabulum as a representative measure of force transmitted through the hip joint generated from bone density mapping and compare it to landmark-based anatomical orientation measures. METHODS: CT scans of 38 non-pathologic individuals were analyzed. Functional orientation was computed as the density-weighted average of the acetabular surface normals based on surface density maps. Two anatomical measures were also used to describe the orientation of each acetabulum: the normal to the acetabular rim plane and the abduction angle based on AP pelvic "Radiographs" generated from the CT data. RESULTS: The average functional and anatomic abduction and anteversion angles ranged from 32 degrees -58 degrees and 22 degrees -31 degrees , respectively, with significant side-to-side correlation in individual patients for the majority of measures. Functional acetabular orientation was weakly correlated only with the rim plane measure. Native acetabular abduction in the 3D anatomic and functional methods was significantly shallower than the 2D "Radiographic" measure. The vector generated to describe functional acetabular orientation was found to be more vertically and posteriorly oriented than the anatomic measures. CONCLUSIONS: Functional acetabular orientation, reflecting the calculated directionality of the subchondral bone density, yields a more posterior and vertical measure of acetabular orientation as compared to the direction of load transmission suggested by the anatomic methods. PMID- 21822917 TI - Immunotherapy with MVA-BN(r)-HER2 induces HER-2-specific Th1 immunity and alters the intratumoral balance of effector and regulatory T cells. AB - MVA-BN(r)-HER2 is a new candidate immunotherapy designed for the treatment of HER 2-positive breast cancer. Here, we demonstrate that a single treatment with MVA BN(r)-HER2 exerts potent anti-tumor efficacy in a murine model of experimental pulmonary metastasis. This anti-tumor efficacy occurred despite a strong tumor mediated immunosuppressive environment characterized by a high frequency of regulatory T cells (T(reg)) in the lungs of tumor-bearing mice. Immunogenicity studies showed that treatment with MVA-BN(r)-HER2 induced strongly Th1-dominated HER-2-specific antibody and T-cell responses. MVA-BN(r)-HER2-induced anti-tumor activity was characterized by an increased infiltration of lungs with highly activated, HER-2-specific, CD8+CD11c+ T cells accompanied by a decrease in the frequency of T(reg) cells in the lung, resulting in a significantly increased ratio of effector T cells to T(reg) cells. In contrast, administration of HER2 protein formulated in Complete Freund's Adjuvant (CFA) induced a strongly Th2 biased immune response to HER-2. However, this did not lead to significant infiltration of the tumor-bearing lungs by CD8+ T cells or the decrease in the frequency of T(reg) cells nor did it result in anti-tumor efficacy. In vivo depletion of CD8+ cells confirmed that CD8 T cells were required for the anti tumor activity of MVA-BN(r)-HER2. Furthermore, depletion of CD4+ or CD25+ cells demonstrated that tumor-induced T(reg) cells promoted tumor growth and that CD4 effector cells also contribute to MVA-BN(r)-HER2-mediated anti-tumor efficacy. Taken together, our data demonstrate that treatment with MVA-BN(r)-HER2 controls tumor growth through mechanisms including the induction of Th1-biased HER-2 specific immune responses and the control of tumor-mediated immunosuppression. PMID- 21822918 TI - Akt signalling parameters are different in oncocytomas compared to renal cell carcinoma. AB - PURPOSE: Renal oncocytomas are assigned as benign tumours, and their detailed molecular mechanism is poorly characterised. Activation of the PKB/Akt pathway is assumed to contribute to the pathogenesis and progression of malignant disease. For oncocytomas, hardly any data are available for Akt signalling parameters. Aim of the present work was to determine the alterations of Akt parameters PTEN, phosphorylated Akt (p-Akt) and p27(Kip1) in oncocytoma to better understand the dedifferentiation of renal tumours. METHODS: By tissue microarray analysis 15 oncocytoma, 18 clear cell renal cell carcinoma (ccRCC) and the corresponding benign tissue were investigated. Significant expression differences between PTEN, p-Akt and p27(Kip1) were determined by immunohistochemistry using One-way ANOVA with all pairs Tukey-Kramer as post hoc analyses. To investigate Akt parameter interactions in the oncocytoma, linear regression analyses were performed. RESULTS: Expression of all proteins was significantly different between the groups and in all groups the lowest for oncocytoma: PTEN: 32.9 +/- 13.0 versus 75.5 +/- 8.0 versus 123.7 +/- 8.8; p < 0.001 for oncocytoma, benign parenchyma and ccRCC and 2.7 +/- 1.2 versus 40.8 +/- 9.5 versus 143.6 +/- 12.2; p < 0.001 for p27(Kip1). p-Akt expression was significantly different between oncocytoma and ccRCC (67.3 +/- 15.7 vs. 144.0 +/- 26.6; p < 0.05). CONCLUSION: All three investigated parameters were the lowest in oncocytoma when compared to ccRCC. Expression of PTEN and p27(Kip1) seems to be exceedingly associated with malignant conditions of ccRCC. These findings might contribute to the understanding of tumorous signalling of the PKB/Akt axis in renal tumours. PMID- 21822919 TI - Results of the Total Evolutive Shoulder System (TESS): a single-centre study of 56 consecutive patients. AB - BACKGROUND: Shoulder arthroplasty surgery has undergone remarkable progress. New concepts like reverse and stemless shoulder prostheses have been widely used. The Total Evolutive Shoulder System (TESS) is a new innovative system that provides the surgeon with different prosthetic versions. The purpose of the present study was to evaluate our short-term results and complications of the TESS. PATIENTS AND METHODS: 56 consecutive patients were operated with one of the two versions of TESS (anatomical or reverse) between October 2007 and December 2009. Preoperative and postoperative evaluation of the function and life quality was achieved by the Quick Disability of the Arm, Shoulder and Hand (DASH) index and EQ-5D self-report questionnaire, respectively. Radiographic follow-up by anteroposterior, axillary and lateral views was done. The anterosuperior approach was used in all cases. We compared the outcome in fracture patients with other categories. RESULTS: 49 patients were available for 9-24 months (mean 14) clinical and radiographic postoperative follow-up. The mean of quick DASH improved from 56 preoperatively to 34 postoperatively (p < 0.001) and EQ-5D from 0.36 preoperatively to 0.73 postoperatively (p < 0.001). The complications were few and we had no radiolucencies or scapular notching during the study period. Fracture patients did worse compared to other categories. CONCLUSIONS: TESS prosthesis showed promising short-term results with few complications. The reverse version could be implanted without stem if initial stability was adequate. Long-term follow-up is required to confirm the results of this innovative system in the long run. PMID- 21822920 TI - [+]-Huperzine A protects against soman toxicity in guinea pigs. AB - The chemical warfare nerve agent (CWNA) soman irreversibly inhibits acetylcholinesterase (AChE) causing seizure, neuropathology and neurobehavioral deficits. Pyridostigmine bromide (PB), the currently approved pretreatment for soman, is a reversible AChE inhibitor that does not cross the blood-brain barrier (BBB) to protect against central nervous system damage. [-]-Huperzine A, a natural reversible AChE inhibitor, rapidly passes through the BBB and has numerous neuroprotective properties that are beneficial for protection against soman. However, [-]-Huperzine A is toxic at higher doses due to potent AChE inhibition which limits the utilization of its neuroprotective properties. [+] Huperzine A, a synthetic stereoisomer of [-]-Huperzine A and a weak inhibitor of AChE, is non-toxic. In this study, we evaluated the efficacy of [+]-Huperzine A for protection against soman toxicity in guinea pigs. Pretreatments with [+] Huperzine A, i.m., significantly increased the survival rate in a dose-dependent manner against 1.2* LD(50) soman exposures. Behavioral signs of soman toxicity were significantly reduced in 20 and 40 mg/kg [+]-Huperzine A treated animals at 4 and 24 h compared to vehicle and PB controls. Electroencephalogram (EEG) power spectral analysis showed that [+]-Huperzine A significantly reduces soman-induced seizure compared to PB. [+]-Huperzine A (40 mg/kg) preserved higher blood and brain AChE activity compared to PB in soman exposed animals. These data suggest that [+]-Huperzine A protects against soman toxicity stronger than PB and warrant further development as a potent medical countermeasure against CWNA poisoning. PMID- 21822921 TI - Antioxidants prevent memory deficits provoked by chronic variable stress in rats. AB - Learning and memory deficits occur in depression and other stress related disorders. Although the pathogenesis of cognitive impairment after stress has not been fully elucidated, factors such as oxidative stress and neurotrophins are thought to play possible roles. Here we investigated the effect of treatment with vitamin E (40 mg/kg) and vitamin C (100 mg/kg) on the effects elicited by chronic variable stress on rat performance in Morris water maze. Brain-derived neurotrophic factor (BDNF) immunocontent was also evaluated in hippocampus of rats. Sixty-day old Wistar rats were submitted to different stressors for 40 days (stressed group). Half of stressed group received administration of vitamins once a day, during the period of stress. Chronically stressed rats presented a marked decrease in reference memory in the water maze task as well as a reduced efficiency to find the platform in the working memory task. Rats treated with vitamins E and C had part of the above effects prevented, suggesting the participation of oxidative stress in such effects. The BDNF levels were not altered in hippocampus of stressed group when compared to controls. Our findings lend support to a novel therapeutic strategy, associated with these vitamins, to the cognitive dysfunction observed in depression and other stress related diseases. PMID- 21822922 TI - Soluble NgR fusion protein modulates the proliferation of neural progenitor cells via the Notch pathway. AB - NogoA, myelin-associated glycoprotein (MAG) and oligodendrocyte myelin glycoprotein are CNS myelin molecules that bind to the neuronal Nogo-66 receptor (NgR) and inhibit axon growth. The NgR antagonist, soluble NgR1-Fc protein (sNgR Fc), facilitates axon regeneration by neutralizing the inhibitory effects of myelin proteins in experimental models of CNS injury. Here we aim to investigate the effect of sNgR-Fc on the proliferation of neural progenitor cells (NPCs). The hippocampus cells of embryonic rats were isolated and cultured in vitro. The expression of nestin, betaIII-Tubulin, GFAP and Nogo-A on these cells was observed using immunocytochemistry. In order to investigate the effect on proliferation of NPCs, sNgR-Fc, MAG-Fc chimera and Notch1 blocker were added respectively. The total cell number for the proliferated NPCs was counted. BrdU was applied and the rate of proliferating cells was examined. The level of Notch1 was analyzed using Western blotting. We identified that NogoA is expressed in NPCs. sNgR-Fc significantly enhanced the proliferation of NPCs in vitro as indicated by BrdU labeling and total cell count. This proliferation effect was abolished by the administration of MAG suggesting specificity. In addition, we demonstrate that sNgR-Fc is a potent activator for Notch1 and Notch1 antagonist reversed the effect of sNgR-Fc on NPC proliferation. Our results suggest that sNgR-Fc may modulate Nogo activity to induce NPC proliferation via the Notch pathway. PMID- 21822923 TI - Longitudinal changes of bone ultrasound measurements in healthy infants during the first year of life: influence of gender and type of feeding. AB - There is evidence suggesting that early events in life may predispose the adult to osteoporosis. We assessed bone status by quantitative ultrasonography in healthy neonates, and we report the changes occurring during the first year of life, according to the type of early feeding. We measured the speed of sound (SOS) of the left tibia in 116 full-term infants (0-9 days of age) and in their mothers (21-42 years of age). SOS values did not correlate with gestational age of the study subjects (r = 0.08) or anthropometric measurements. The SOS measurements of the mothers did not correlate with those of their children (r = 0.01). Fifty-seven infants had SOS measurements performed at 4 and 12 months. Twenty-five infants were exclusively breast-fed, 12 received formula milk from birth, and 20 received human and formula milk. SOS measurements at 4 months were comparable with those at baseline, whereas at 12 months they were significantly higher. No effect of type of feeding was observed, indicating that SOS changes may be independent of the type of early diet. PMID- 21822924 TI - Lymphocyte alpha-kinase is a gout-susceptible gene involved in monosodium urate monohydrate-induced inflammatory responses. AB - The molecular functions and pathophysiologic role of the lymphocyte alpha-kinase gene (ALPK1) in gout are unknown. We aimed to examine ALPK1 expression in patients with gout and investigate its role in monosodium urate monohydrate (MSU) induced inflammatory responses. Microarray data mining was performed with six datasets containing three clinical gout and three volunteer samples. Real-time quantitative polymerase chain reaction (qPCR) assay was used to profile ALPK1 mRNA expression in 62 independent samples. RNA interference for ALPK1 suppression in THP1 cells (human monocytic cell line) was used to scrutinize the functional role of ALPK1 in MSU-mediated inflammatory responses, and ALPK1 expression in MSU treated THP1 cells was determined by qPCR and Western blot analysis. Cytokine mRNA expression in HEK293 cells after incubation with different concentrations of MSU crystals in the presence or absence of ALPK1 was also detected by qPCR, and ERK1/2, p38, and JNK expressions were investigated by Western blot analysis. ALPK1 mRNA was overexpressed in the clinical gout samples. MSU treatment promoted ALPK1 expression at the mRNA and protein levels. Furthermore, ALPK1 knockdown in THP1 cells resulted in a markedly decreased IL-1beta, TNF-alpha, and IL-8 mRNA expression; plasmid ALPK1 transfection and MSU stimulation synergistically increased the mRNA expression of these cytokines in a concentration-dependent manner. The synergistic effect also led to ERK1/2 activation. ALPK1 is a gout susceptible gene involved in MSU-induced inflammatory responses. It may contribute to the development of gout by enhancing the inflammatory responses via the mitogen-activated protein kinase pathway. PMID- 21822925 TI - Does a small difference in iodine status among children in two regions of Belgium translate into a different prevalence of thyroid nodular diseases in adults? AB - PURPOSE: To explore whether there are regional differences in iodine status and in prevalence of thyroid diseases in the two main regions of Belgium. METHODS: A national survey of iodine status among children was performed in 1998. The raw data of this survey were reanalyzed to explore regional differences. The total number of thyroidectomies, carried out for multinodular goiter or solitary nodules, was obtained from the Minimal Clinical Summary hospital discharge database. Percentage of people with thyroid diseases going to the general practitioner or the specialist was assessed by means of data about the number of adults using anti-thyroid medications. Food consumption patterns were explored using national food consumption data. RESULTS: In Flanders, median urinary iodine concentration (UIC) was higher than in Wallonia, 84 MUg/L (n = 1,316) and 78 MUg/L (n = 1,268), respectively (p < 0.001). There were no differences in goiter prevalence and thyroid volume between the regions among children. Data from the food consumption survey showed a significant higher consumption of seafood in Flanders compared to Wallonia. Further, it was observed that the number of thyroidectomies, carried out for MNG or solitary nodules, and the use of anti thyroid medication were significantly higher in Wallonia than in Flanders. CONCLUSION: Iodine status in children was found slightly different in both regions of the country. This finding is in agreement with a higher incidence of thyroidectomies and more extensive use of anti-thyroid medications in the adult population in the region with the lowest iodine excretion. PMID- 21822926 TI - Genotoxicity associated with oxidative damage in the liver and kidney of mice exposed to dimethoate subchronic intoxication. AB - BACKGROUND AND AIMS: Because of the widespread use of pesticides for domestic and industrial applications, the evaluation of their toxic effects is of major concern to public health. The aim of the present study was to investigate the propensity of dimethoate (DM), an organophosphorus pesticide, to cause oxidative damage in the liver and kidney of mice and its associated genotoxic effect. METHODS: DM was administered intraperitoneally at doses of 1, 5, 10, 15, and 30 mg/kg body weight for 30 consecutive days in BALB/c mice. Oxidative stress was monitored in the kidney and liver by measuring malondialdehyde level, protein carbonyl concentration, and the catalase activity. The genotoxicity of DM was assessed by the comet assay in vivo. RESULTS AND DISCUSSION: Our results indicated that DM inhibited acetylcholinesterase activities in the liver and kidney of treated mice. DM increased lipid peroxidation and protein carbonyl levels in the liver and kidney in a dose-dependent manner. Catalase activity was found to be significantly increased in the liver and kidney at doses higher than 5 mg/kg body weight. CONCLUSIONS: Our study demonstrated that DM induced DNA damage in the liver and kidney of treated mice in a dose-dependent manner; this induction was associated to DM-induced oxidative stress. Further investigations are needed to prove the implication of oxidative stress in genotoxicity induced by DM. PMID- 21822927 TI - Automatic pH control system enhances the dechlorination of 2,4,4' trichlorobiphenyl and extracted PCBs from contaminated soil by nanoscale Fe0 and Pd/Fe0. AB - PURPOSE: Dechlorination of polychlorinated biphenyls (PCBs) by nanoscale zerovalent iron (NZVI) is often strongly hindered by increased pH because large amounts of H(+) ions were consumed during the surface reaction. The main objective of this work was to evaluate the effect of pH control in acid on the dechlorination processes of PCBs and to compare the dechlorination efficiency between 2,4,4'-trichlorobiphenyl (2,4,4'-CB) and the extracted PCBs from the field PCBs-contaminated soil in this system. METHODS: The reaction solution pH was controlled to be weakly acid (4.90-5.10) with an automatic pH control system, in which the dechlorination of 2,4,4'-CB and extracted PCBs from a PCBs contaminated soil by NZVI and palladized nanoscale zerovalent iron (NZVI/Pd) was investigated. RESULTS: To control the reaction solution pH to be acid actually increased the dechlorination rate of PCBs by NZVI and NZVI/Pd. The observed normalized pseudo-first-order dechlorination rate constants (k (obs)) of 2,4,4' CB increased from 0.0029 min(-1) (no pH control) to 0.0078 min(-1) (pH control) by NZVI and from 0.0087 min(-1) (no pH control) to 0.0108 min(-1) (pH control) by NZVI/Pd. In the case of NZVI/Pd, the chlorines in the para position were much more easily dechlorinated than ortho position, and biphenyl was the dominating product. As the solution pH was controlled at 4.90-5.10, the dechlorination rate constants of PCB congeners extracted from soil (k (obs)) were 0.0027-0.0033 min( 1) and 0.0080-0.0098 min(-1) by NZVI and NZVI/Pd, respectively. CONCLUSIONS: To keep the reaction solution to be weakly acid markedly increased the dechlorination rate of PCBs, which may offer a novel technology in the remediation of PCBs-contaminated soil. PMID- 21822928 TI - Analytical improvements of hybrid LC-MS/MS techniques for the efficient evaluation of emerging contaminants in river waters: a case study of the Henares River (Madrid, Spain). AB - PURPOSE: Instrumental capabilities and software tools of modern hybrid mass spectrometry (MS) instruments such as high-resolution mass spectrometry (HRMS), quadrupole time-of-flight (QTOF), and quadrupole linear ion trap (QLIT) were experimentally investigated for the study of emerging contaminants in Henares River water samples. METHODS: Automated screening and confirmatory capabilities of QTOF working in full-scan MS and tandem MS (MS/MS) were explored when dealing with real samples. Investigations on the effect of sensitivity and resolution power influence on mass accuracy were studied for the correct assignment of the amoxicillin transformation product 5(R) amoxicillin-diketopiperazine-2',5' as an example of a nontarget compound. On the other hand, a comparison of quantitative and qualitative strategies based on direct injection analysis and off-line solid phase extraction sample treatment were assayed using two different QLIT instruments for a selected group of emerging contaminants when operating in selected reaction monitoring (SRM) and information-dependent acquisition (IDA) modes. RESULTS AND DISCUSSION: Software-aided screening usually needs a further confirmatory step. Resolving power and MS/MS feature of QTOF showed to confirm/reject most findings in river water, although sensitivity-related limitations are usually found. Superior sensitivity of modern QLIT-MS/MS offered the possibility of direct injection analysis for proper quantitative study of a variety of contaminants, while it simultaneously reduced the matrix effect and increased the reliability of the results. Confirmation of ethylamphetamine, which lacks on a second SRM transition, was accomplished by using the IDA feature. CONCLUSION: Hybrid MS instruments equipped with high resolution and high sensitivity contributes to enlarge the scope of targeted analytes in river waters. However, in the tested instruments, there is a margin of improvement principally in required sensitivity and data treatment software tools devoted to reliable confirmation and improved automated data processing. PMID- 21822929 TI - Petroleum hydrocarbon contamination of the Southern Black Sea Shelf, Turkey. AB - INTRODUCTION: In this study, total petroleum hydrocarbon (TPH) contents and some aliphatic and aromatic hydrocarbon concentrations were analysed in coastal sediments of hot points collected from along the Southern Black Sea Shelf. MATERIALS AND METHODS: Surface sediment (0-2 cm) samples were collected from the locations using a Van Veen type grab sampler in September 2008 during a cruise on the Pollution Monitoring R/V ARAR. All sampling procedures were carried out according to internationally recognized guide-lines (UNEP 1991). Samples were analysed using a UV-fluorescence spec-trophotometry (UNEP/IOC/IAEA 1992) and gas chromatog- raphy (GC) via a Hewlett-Packard HP6890N series with a selective detector (GC-MSD) after hexane/ dichloromethane extraction. RESULTS AND DISCUSSION: The ratio C(17)/C(18) varied between 2.2 and 2.9 for the surface sediments of TRK 34Y (Samsun), TRK46 (Giresun), and TRK55 (Rize), respectively. These results showed higher marine organic matter accumulation. However, pyrolytic PAHs were found predominant in these areas. In contrast, petrogenic contributions were found at Stations TRK1 (Igneada), TRK13 (Zonguldak), TRK53 (Trabzon) and TRK61 (Hopa). TPH contents of surface sediments varied between 0.29 and 363 MUg g(-1) (dry wt) throughout the shelf. The lowest values were measured at Stations TRK1 (Igneada) and TRK 19 (Bartin), whereas the highest values were found at Stations TRK13 (Zonguldak) and TRK 53 (Trabzon). PMID- 21822930 TI - Evaluation of phenol detoxification by Brassica napus hairy roots, using Allium cepa test. AB - INTRODUCTION: Meristematic mitotic cells of Allium cepa constitute an adequate material for cytotoxicity and genotoxicity evaluation of environmental pollutants, such as phenol, which is a contaminant frequently found in several industrial effluents. RESULTS AND DISCUSSION: In the present work, Brassica napus hairy roots (HR) were used for phenol removal assays. The toxicity of post removal solutions (PRS) and phenol solutions was analyzed. These HR removed the contaminant with high efficiency (100-80% for phenol solutions containing 10-250 mg/L, respectively). Phenol solutions treated with B. napus HR showed a significant reduction of general toxicity compared to untreated phenol solutions, since the IC50 values were 318.39 and 229.02 mg/L, respectively. Moreover, PRS presented lower cytotoxicity and genotoxicity than that found in phenol solutions untreated. The mitotic index (MI) observed in meristematic cells treated with PRS (100 and 250 mg/L of phenol) showed an increase of 35% and 42%, whereas the chromosome aberrations showed a significant decrease. According to these results, B. napus HR cultures could be used for the treatment of solutions contaminated with phenol, since we observed not only high removal efficiency, but also an important reduction of the general toxicity, cytotoxicity, and genotoxicity. PMID- 21822931 TI - Homozygous carriers of the G allele of rs4664447 of the glucagon gene (GCG) are characterised by decreased fasting and stimulated levels of insulin, glucagon and glucagon-like peptide (GLP)-1. AB - AIMS/HYPOTHESIS: The glucagon gene (GCG) encodes several hormones important for energy metabolism: glucagon, oxyntomodulin and glucagon-like peptide (GLP)-1 and 2. Variants in GCG may associate with type 2 diabetes, obesity and/or related metabolic traits. METHODS: GCG was re-sequenced as a candidate gene in 865 European individuals. Twenty-nine variants were identified. Four variants that were considered to have a likelihood for altered functionality: rs4664447, rs7581952, Ile158Val and Trp169Ter, were genotyped in 17,584 Danes. RESULTS: When examined in 5,760 treatment-naive individuals, homozygous carriers of the low frequency (minor allele frequency 2.3%) G allele of rs4664447, predicted to disrupt an essential splice enhancer binding site, had lower levels of fasting plasma glucose (mean +/- SD, 4.8 +/- 1.2 vs 5.5 +/- 0.8 mmol/l, p = 0.004); fasting serum insulin (22 +/- 14 vs 42 +/- 27 pmol/l, p = 0.04); glucose stimulated serum insulin (159 +/- 83 vs 290 +/- 183 pmol/l, p = 0.01) and adult height (165 +/- 10 vs 172 +/- 9 cm, p = 0.0009) compared with A allele carriers. During oral glucose tolerance and hyperglycaemic arginine stimulation tests, the plasma AUC for GLP-1 (730 +/- 69 vs 1,334 +/- 288 pmol/l * min, p = 0.0002) and basal and stimulated levels of serum insulin and plasma glucagon were ~50% decreased (p < 0.001) among three homozygous carriers compared with nine matched wild-type carriers. rs7581952, Ile158Val and Trp169Ter (where 'Ter' indicates 'termination') variants of GCG did not significantly associate or co-segregate with the metabolic traits examined. CONCLUSIONS/INTERPRETATION: Re-sequencing of GCG revealed a low frequency intronic variant, rs4664447, and follow-up physiological studies suggest that this variant in homozygous form may cause decreased fasting and stimulated levels of insulin, glucagon and GLP-1. Overall, our findings suggest that variation in GCG has no major impact on carbohydrate metabolism in the study populations examined. PMID- 21822932 TI - A retrospective clinical study of the treatment of slow-channel congenital myasthenic syndrome. AB - Slow-channel congenital myasthenic syndrome (CMS) is a rare subtype of CMS caused by dominant "gain of function" mutations in the acetylcholine receptor. Clinically, the cervical and forearm extensor muscles seem to be preferentially weaker; and conventional treatment with anticholinesterases fails to improve symptoms. In contrast, open channel blockers such as fluoxetine and quinidine have been shown to be of benefit. The objectives of our study were to provide further insight into the clinical features of slow-channel CMS and evaluate response to recommended therapy. We carried out a retrospective clinical follow up study of 15 slow-channel CMS patients referred to the Munich CMS Centre. Detailed clinical data were collected by clinicians involved in the care of each patient, with a particular focus on response and tolerability to recommended therapy. Patients varied widely as regard onset of symptoms, severity of disease and mutations involved. Patients received up to four different medications and some had none. Our results strengthen previous reported findings in terms of clinical phenotype variability and the poor response to pyridostigmine. Although treatment with fluoxetine was beneficial in most patients, a number of our patients suffered significant adverse effects that hindered optimum dose titration or led to treatment cessation. Slow-channel CMS is rare and exhibits distinct clinical and genetic characteristics. Our study suggests that fluoxetine, despite being effective in most patients, can be associated with significant side effects, thus reducing treatment effectiveness in clinical practice. PMID- 21822933 TI - Late-onset Alexander disease with a V87L mutation in glial fibrillary acidic protein (GFAP) and calcifying lesions in the sub-cortex and cortex. AB - Glial fibrillary acidic protein (GFAP) mutation has been reported in Alexander disease. We report a 31-year-old woman suffering from Alexander disease with a V87L mutation in GFAP. She showed psychomotor regression and a history of seizures, in addition to pendular nystagmus, dysarthria, spastic gait, and bladder dysfunction. Brain magnetic resonance imaging (MRI) showed atrophy of the medulla oblongata and mild cervical cord atrophy, deep white matter abnormalities, periventricular rim, and signal changes of the medulla oblongata and dentate hilum. Sequence analysis of her GFAP gene showed a heterozygous c.273G>C mutation predictive of a p.V87L amino acid substitution. We concluded that she was actually affected with Alexander disease. Twenty months later she fell down and sustained a head contusion. Urgent head computed tomography (CT) showed calcification in the subcortical and cortical regions, which may relate to the psychomotor regression and history of seizures. Calcification in the subcortical and cortical regions on head CT has not been reported in Alexander disease; this may be associated with a V87L mutation in GFAP. PMID- 21822934 TI - Challenges of clinical trial design when there is lack of clinical equipoise: use of a response-conditional crossover design. AB - Clinical equipoise is widely accepted as the basis of ethics in clinical research and requires investigators to be uncertain of the relative therapeutic merits of trial comparators. When clinical equipoise is in question, innovative trial designs are needed to reduce ethical tension while satisfying regulators' requirements. We report a novel response-conditional crossover study design used in a Phase 3, randomized, double-blind, placebo-controlled clinical trial of intravenous 10% caprylate-chromatography purified immunoglobulin for chronic inflammatory demyelinating polyradiculoneuropathy. During the initial 24-week period, patients crossed over to the alternative treatment at the first sign of deterioration or if they failed to improve or were unable to maintain improvement at any time after 6 weeks. This trial design addressed concerns about lack of equipoise raised by physicians interested in trial participation and proved acceptable to regulatory authorities. The trial design may be applicable to other studies where clinical equipoise is in question. PMID- 21822935 TI - Decompressive hemicraniectomy followed by endovascular thrombosuction in a patient with cerebral venous thrombosis. PMID- 21822936 TI - Negative mood, craving, and alcohol relapse: can treatment interrupt the process? PMID- 21822937 TI - Effects of amyloid-beta peptides on voltage-gated L-type Ca(V)1.2 and Ca(V)1.3 Ca(2+) channels. AB - Overload of intracellular Ca(2+) has been implicated in the pathogenesis of neuronal disorders, such as Alzheimer's disease. Various mechanisms produce abnormalities in intracellular Ca(2+) homeostasis systems. L-type Ca(2+) channels have been known to be closely involved in the mechanisms underlying the neurodegenerative properties of amyloid-beta (Abeta) peptides. However, most studies of L-type Ca(2+) channels in Abeta-related mechanisms have been limited to Ca(V)1.2, and surprisingly little is known about the involvement of Ca(V)1.3 in Abeta-induced neuronal toxicity. In the present study, we examined the expression patterns of Ca(V)1.3 after Abeta(25-35) exposure for 24 h and compared them with the expression patterns of Ca(V)1.2. The expression levels of Ca(V)1.3 were not significantly changed by Abeta(25-35) at both the mRNA levels and the total protein level in cultured hippocampal neurons. However, surface protein levels of Ca(V)1.3 were significantly increased by Abeta(25-35), but not by Abeta(35-25). We next found that acute treatment with Abeta(25-35) increased Ca(V)1.3 channel activities in HEK293 cells using whole-cell patch-clamp recordings. Furthermore, using GTP pulldown and co-immunoprecipitation assays in HEK293 cell lysates, we found that amyloid precursor protein interacts with beta(3) subunits of Ca(2+) channels instead of Ca(V)1.2 or Ca(V)1.3 alpha(1) subunits. These results show that Abeta(25-35) chronically or acutely upregulates Ca(V)1.3 in the rat hippocampal and human kidney cells (HEK293). This suggests that Ca(V)1.3 has a potential role along with Ca(V)1.2 in the pathogenesis of Alzheimer's disease. PMID- 21822938 TI - Spontaneous orbital haemorrhage in a healthy young male. PMID- 21822939 TI - Technical innovation: digital tomosynthesis of the hip following intra-articular administration of contrast. AB - OBJECTIVE: To demonstrate the clinical use of digital tomosynthesis in the depiction of labral and chondral pathology in the setting of post-operative CAM type impingement of the hip following intra-articular administration of dilute iodinated contrast. MATERIALS AND METHODS: We present images from a 46 year-old African American female with suspected CAM-type femoroacetabular impingement (FAI) following percutaneous pinning of the right hip for slipped capital femoral epiphysis (SCFE). RESULTS: A partial tear of the labrum and clinically significant acetabular chondral abnormalities were demonstrated with the use of digital tomosynthesis with superb anatomic detail. CONCLUSION: Digital tomosynthesis can be of great clinical utility and can depict pathology in superb anatomic detail, particularly in situations in which MRI is not available as well as under circumstances in which artifact due to orthopedic hardware is of concern as shown in this case. PMID- 21822940 TI - Unusual supero-medial iliac fatigue stress fracture. AB - Fatigue stress fractures are quite common in athletes, especially in women. They typically involve the lower extremities, but they have also been described in the pelvis and sacrum. Most of the time, they are radiographically occult at the beginning, and become visible only when the callus is detected. They are suspected owing to their clinical features, and investigated using magnetic resonance imaging (MRI) and computed tomography (CT). We present a case of unusual supero-medial iliac fatigue stress fracture in a 58-year-old amateur marathon runner woman presenting with a history of 1-month's worsening pain in the right buttock. Diagnosis was challenging. The early radiograph was normal, and the stress fracture was suspected by clinical features and MRI. Although the fracture was evident on the MRI, the findings were subtle and overlooked. The fracture was later confirmed by CT and radiograph, showing the reparative process. PMID- 21822941 TI - 1H, 13C and 15N NMR assignments of inactive form of P1 endolysin Lyz. AB - Lysozyme (Lyz) encoded by phage P1 is required for host cell lysis upon infection. Lyz has a N-terminal Signal Anchor Release (SAR) domain, responsible for its secretion into the periplasm and for its accumulation in a membrane tethered inactive form. Here, we report sequence-specific (1)H, (13)C and (15)N resonance assignments for secreted inactive form of Lyz at pH 4.5. PMID- 21822942 TI - Population structure and marker-trait association analysis of the US peanut (Arachis hypogaea L.) mini-core collection. AB - Peanut (Arachis hypogaea L.) is one of the most important oilseed and nutritional crops in the world. To efficiently utilize the germplasm collection, a peanut mini-core containing 112 accessions was established in the United States. To determine the population structure and its impact on marker-trait association, this mini-core collection was assessed by genotyping 94 accessions with 81 SSR markers and two functional SNP markers from fatty acid desaturase 2 (FAD2). Seed quality traits (including oil content, fatty acid composition, flavonoids, and resveratrol) were obtained through nuclear magnetic resonance (NMR), gas chromatography (GC), and high-performance liquid chromatography (HPLC) analysis. Genetic diversity and population structure analysis identified four major subpopulations that are related to four botanical varieties. Model comparison with different levels of population structure and kinship control was conducted for each trait and association analyses with the selected models verified that the functional SNP from the FAD2A gene is significantly associated with oleic acid (C18:1), linoleic acid (C18:2), and oleic-to-linoleic (O/L) ratio across this diverse collection. Even though the allele distribution of FAD2A was structured among the four subpopulations, the effect of FAD2A gene remained significant after controlling population structure and had a likelihood-ratio based R ( 2 ) (R ( LR ) ( 2 ) ) value of 0.05 (oleic acid), 0.09 (linoleic acid), and 0.07 (O/L ratio) because the FAD2A alleles were not completely fixed within subpopulations. Our genetic analysis demonstrated that this peanut mini-core panel is suitable for association mapping. Phenotypic characterization for seed quality traits and association testing of the functional SNP from FAD2A gene provided information for further breeding and genetic research. PMID- 21822943 TI - Statistical energy potential: reduced representation of Dehouck-Gilis-Rooman function by selecting against decoy datasets. AB - Statistical effective energy function (SEEF) is derived from the statistical analysis of the database of known protein structures. Dehouck-Gilis-Rooman (DGR) group has recently created a new generation of SEEF in which the additivity of the energy terms was manifested by decomposing the total folding free energy into a sum of lower order terms. We have tried to optimize the potential function based on their work. By using decoy datasets as screening filter, and through modification of algorithms in calculation of accessible surface area and residue residue interaction cutoff, four new combinations of the energy terms were found to be comparable to DGR potential in performance test. Most importantly, the term number was reduced from the original 30 terms to only 5 in our results, thereby substantially decreasing the computation time while the performance was not sacrificed. Our results further proved the additivity and manipulability of the DGR original energy function, and our new combination of the energy could be used in prediction of protein structures. PMID- 21822944 TI - Eicosapentaenoic acid and docosahexaenoic acid regulate modified LDL uptake and macropinocytosis in human macrophages. AB - There is evidence that long chain n-3 PUFA (such as from fish oils) provide atheroprotection through, in part, changes in macrophage function although it has not been fully determined whether these n-3 PUFA target cellular mechanisms that control macrophage foam cell formation. Therefore, we investigated whether the n 3 PUFA, EPA and DHA, modulate modified low-density lipoprotein (LDL) uptake by human macrophages. The uptake of fluorophore labeled acetylated LDL (AcLDL) and/or oxidized LDL (OxLDL) by THP-1 macrophages and primary human monocyte derived macrophages were measured by flow cytometry following co-incubation with EPA or DHA in vitro. DHA inhibited both AcLDL and OxLDL uptake in human macrophages whilst EPA reduced AcLDL and increased OxLDL uptake. These effects were only partly explained by changes in the mRNA and protein expression of key scavenger receptors, such as CD36 and scavenger receptor-A, in these cells suggesting the involvement of a scavenger receptor-independent mechanism. EPA and DHA inhibited macropinocytosis, as measured by Lucifer Yellow uptake, in human macrophages and attenuated the expression of Syndecan-4, which has been implicated in the uptake of other modified forms of LDL. EPA and DHA reduced modified LDL uptake by human macrophages through a mechanism that is in part scavenger receptor-independent and may involve inhibition of macropinocytosis and Syndecan-4 expression. This suggests that both EPA and DHA are capable of regulating macrophage foam cell formation and adds to the evidence describing an atheroprotective role for n-3 PUFA, implicating them as potential therapeutic agents for the treatment of clinical atherosclerosis. PMID- 21822946 TI - Tumour ADC measurements in rectal cancer: effect of ROI methods on ADC values and interobserver variability. AB - OBJECTIVES: To assess the influence of region of interest (ROI) size and positioning on tumour ADC measurements and interobserver variability in patients with locally advanced rectal cancer (LARC). METHODS: Forty-six LARC patients were retrospectively included. Patients underwent MRI including DWI (b0,500,1000) before and 6-8 weeks after chemoradiation (CRT). Two readers measured mean tumour ADCs (pre- and post-CRT) according to three ROI protocols: whole-volume, single slice or small solid samples. The three protocols were compared for differences in ADC, SD and interobserver variability (measured as the intraclass correlation coefficient; ICC). RESULTS: ICC for the whole-volume ROIs was excellent (0.91) pre-CRT versus good (0.66) post-CRT. ICCs were 0.53 and 0.42 for the single-slice ROIs versus 0.60 and 0.65 for the sample ROIs. Pre-CRT ADCs for the sample ROIs were significantly lower than for the whole-volume or single-slice ROIs. Post-CRT there were no significant differences between the whole-volume ROIs and the single-slice or sample ROIs, respectively. The SDs for the whole-volume and single-slice ROIs were significantly larger than for the sample ROIs. CONCLUSIONS: ROI size and positioning have a considerable influence on tumour ADC values and interobserver variability. Interobserver variability is worse after CRT. ADCs obtained from the whole tumour volume provide the most reproducible results. Key Points * ROI size and positioning influence tumour ADC measurements in rectal cancer * ROI size and positioning influence interobserver variability of tumour ADC measurements * ADC measurements of the whole tumour volume provide the most reproducible results * Tumour ADC measurements are more reproducible before, rather than after, chemoradiation treatment * Variations caused by ROI size and positioning should be taken into account when using ADC as a biomarker for tumour response. PMID- 21822945 TI - Mechanisms by which the extracellular matrix and integrin signaling act to regulate the switch between tumor suppression and tumor promotion. AB - Cell adhesion to the extracellular matrix (ECM) is necessary for development of the mammary gland, and to maintain the normal architecture and function of the gland. Cells adhere to the ECM via the integrin family of trans-membrane receptors, which signal to control mammary-specific gene expression and regulate cell proliferation and survival. During tumor formation, the ECM is extensively remodeled and signaling through integrins is altered such that cells become proliferative and invasive. A key regulator of whether integrin-mediated adhesion will promote tumor suppression or tumor formation is the stiffness of the stromal ECM. The normal mammary gland is typically surrounded by a loose collagenous stroma. An increase in the deposition of collagen and other stromal components is associated with mammographic density, which is one of the greatest risk factors for developing breast carcinoma. Several groups have demonstrated that increased stromal ECM density results in a matrix that is stiffer. Cells sense the stiffness of their surrounding ECM by Rho-mediated contraction of the actin myosin cytoskeleton. If the surrounding ECM is stiffer than the cell's ability to contract it, then the tensile forces that result are able to drive the clustering of integrins and assemble adhesion signaling complexes. The result is subsequent activation of signaling pathways including FAK, ERK, and PI3K that drive cell proliferation and survival. In contrast, focal complexes are not formed in a compliant matrix, and activation of FAK and pERK is diminished, resulting in control of proliferation. Signaling from FAK moreover regulates p53 and miR-200 members, which control apoptosis and epithelial phenotype, such that a compliant matrix is predicted to promote normal mammary gland architecture and suppress tumor formation. PMID- 21822947 TI - Height restoration and wedge angle correction effects of percutaneous vertebroplasty: association with intraosseous clefts. AB - OBJECTIVE: To evaluate effects of vertebroplasty on restoration of vertebral body height and wedge angle and relief from pain in patients with osteoporotic compression fractures. METHODS: A retrospective study of 156 patients (232 levels) who had undergone vertebroplasty was conducted. Treated vertebrae with cleft included 49 patients (49 levels) and that without cleft 107 patients (183 levels). Effects on restoration of vertebral body height and wedge angle, and pain scores between pre- and post-procedure were statistically analyzed by using a paired-sample t test, and Kruskal Wallis test. RESULTS: The height and wedge angle of the fractured vertebral body, and pain score, improved significantly after vertebroplasty. On a vertebra-by-vertebra analysis, the vertebral body height and wedge angle in the cleft group, were statistically significantly better post-procedure (P < 0.01); in the non-cleft group, there was nosignificant improved (P > 0.05). Pain relief was not statistically significant different between the two groups (P > 0.05). CONCLUSION: Most patients experienced pain relief after vertebroplasty. After vertebroplasty, the height and wedge angle were significantly improved in the cleft group (p < 0.01), with no significant improvement in the non-cleft group (p > 0.05). Key Points * Vertebra with cleft is attributed to improvement of the spinal deformity * Vertebra without cleft was not associated with improvement of the spinal deformity * Vertebroplasty is an effective treatment strategy for osteoporotic compression fractures. PMID- 21822948 TI - Radio-opaque ethylcellulose-ethanol is a safe and efficient sclerosing agent for venous malformations. AB - OBJECTIVE: To evaluate the efficacy and safety of gelified ethanol, a newly developed sclerosing agent for slow-flow vascular malformations. METHODS: Seventy nine sclerotherapy procedures were performed on 44 patients with 37 venous malformations, 2 glomuvenous malformations, 2 lymphatic malformations, 2 lymphatico-venous malformations, and 1 Klippel-Trenaunay syndrome. The median injected volume was 1.00 mL/site of injection. Effects of sclerotherapy on pain, functional and cosmetic disturbance were statistically evaluated with a final result score. Local and systemic complications were recorded. RESULTS: The mean Visual Analogue Scores were 5.20 +/- 2.81 before and 1.52 +/- 1.25 after treatment (p < 0.001). Functional and aesthetic improvement was achieved in 31/35 patients (89%) and in 33/41 (80%), respectively. Minor local side effects included necrosis with or without issue of ethylcellulose, palpable residue, and hematoma. No systemic side-effects occurred. CONCLUSION: Per mL used, radio opaque gelified ethanol is at least as effective as absolute ethanol. No systemic complication was observed, as only a low dose of ethanol was injected. Indications for sclerotherapy can be widened to areas with higher risk for local side effects (hands and periocular region), as ethanol is trapped in the lesion. Careful injection procedure is though necessary, because only a limited amount of ethylcellulose can be used per puncture. Key Points * Development of a new sclerosing agent for venous malformations. * Interesting novel way to deliver alcohol to slow-flow vascular malformations. * Alcohol-based with less local and systemic side-effects. PMID- 21822950 TI - Mechanistic clues in the protective effect of ellagic acid against apoptosis and decreased mitochondrial respiratory enzyme activities in myocardial infarcted rats. AB - Our previous study described the cardioprotective effects of ellagic acid in an isoproterenol-induced myocardial infarction model. In this study, we are reporting the mechanism of protective action of ellagic acid with respect to apoptosis and mitochondrial respiratory enzymes. Ellagic acid (7.5 and 15 mg/kg) was administered orally as a pretreatment for 10 days. Then, isoproterenol (100 mg/kg) was injected subcutaneously to rats at an interval of 24 h for 2 days. Myocardial infarction was quantified by planimetry. Apoptosis was measured by apoptotic gene expressions. The levels of mitochondrial respiratory enzymes were also measured. Isoproterenol-induced myocardial infarcted rats showed increased infarct size, a decrease in myocardial expression of the Bcl-2 gene and an increase in myocardial expression of the BAX gene. Fas ligand and caspases were markedly elevated along with compromised respiratory marker enzymes in isoproterenol-induced rats. Ellagic acid pretreatment reduced the infarct size, regulated apoptotic gene expressions and enhanced the activities of mitochondrial respiratory marker enzymes and cell viability, thereby protecting the myocardium against isoproterenol-induced myocardial infarction. The decreased infarct size associated with inhibited apoptosis and increased respiratory marker enzymes provide insight on the role of ellagic acid in antiapoptotic mechanism, and it may be the reason for its cardioprotective activity. PMID- 21822949 TI - Acute exacerbation of idiopathic pulmonary fibrosis: high-resolution CT scores predict mortality. AB - OBJECTIVES: To determine high-resolution computed tomography (HRCT) findings helpful in predicting mortality in patients with acute exacerbation of idiopathic pulmonary fibrosis (AEx-IPF). METHODS: Sixty patients with diagnosis of AEx-IPF were reviewed retrospectively. Two groups (two observers each) independently evaluated pattern, distribution, and extent of HRCT findings at presentation and calculated an HRCT score at AEx based on normal attenuation areas and extent of abnormalities, such as areas of ground-glass attenuation and/or consolidation with or without traction bronchiectasis or bronchiolectasis and areas of honeycombing. The correlation between the clinical data including the HRCT score and mortality (cause-specific survival) was evaluated using the univariate and multivariate Cox-regression analyses. RESULTS: Serum KL-6 level, PaCO(2), and the HRCT score were statistically significant predictors on univariate analysis. Multivariate analysis revealed that the HRCT score was an independently significant predictor of outcome (hazard ratio, 1.13; 95% confidence interval, 1.06-1.19, P = 0.0002). The area under receiver operating characteristics curve for the HRCT score was statistically significant in the classification of survivors or nonsurvivors (0.944; P < 0.0001). Survival in patients with HRCT score >=245 was worse than those with lower score (log-rank test, P < 0.0001). CONCLUSION: The HRCT score at AEx is independently related to prognosis in patients with AEx-IPF. PMID- 21822951 TI - Remember the touch: tactile distractors retrieve previous responses to targets. AB - In selection tasks where target stimuli are accompanied by distractors, responses to target stimuli, target stimuli and the distractor stimuli can be encoded together as one episode in memory. Subsequent repetition of any aspect of such an episode can lead to the retrieval of the whole episode including the response. Thus, repeating a distractor can retrieve responses given to previous targets; this mechanism was labeled distractor-response binding and has been evidenced in vision and audition. Yet, previous research suggests possibly different distractor processing in the tactile as compared to the visual modality. In the present study, we therefore used a selection task in which participants always responded to one tactile stimulus while ignoring another. Evidence for the integration of tactile distractors with target responses was found in response times and errors. Our results indicate that binding of responses to distractors is a cognitive process that is independent of the stimulus' modality. PMID- 21822952 TI - As(2)O (3) oxidation by vitamin C: cell culture studies. AB - The ability of As(2)O(3) to induce apoptosis in various malignant cell lines has made it a potential treatment agent for several malignancies. In this study the chemical stability of As(2)O(3) (As(III)) in cell-free growth media with various compositions was studied (MEM with different amount of amino acids and DMEM). Special attention was given to evaluate the influence of serum (FBS; fetal bovine serum) absence and vitamin C addition on the oxidation of As(III) to As(V) in cell-free growth media. FBS is an important source of antioxidants and vitamin C (ascorbic acid) is acting as a prooxidant in millimolar concentrations. Media were incubated with As(III) (0.6, 2 and 7 MUmol l(-1)) up to 72 h. Experiments were performed at 37 degrees C in light or/and in the dark, with or without added serum (10%) or vitamin C (1.4, 0.14 mM). Metabolites were followed with high performance liquid chromatography directly coupled to a hydride generation-atomic fluorescence spectrometry system. After 72 h up to 30% of As(III) was transformed into As(V) in MEMs and up to 35% in DMEM when exposed in dark. Light had no influence on transformations in MEMs, but changed the situation dramatically in DMEM where almost all As(III) was oxidized to As(V) after 72 h when exposed to light. Except for some faster oxidation rate the absence of FBS had little effect on the transformation rate in all media. The most visible impact on As(III) oxidation was observed by addition of vitamin C. Addition of vitamin C (1.4 mM) transformed almost all As(III) to As(V) within 72 h. In lower concentrations (0.14 mM) a pro-oxidative effect was still observed reaching approximately 60% oxidation of As(III) during 72 h. All oxidation processes could be explained by pseudo first order reaction kinetics, yielding reaction rates increasing with initial As(III) concentration and vitamin C concentration whereas the FBS content additionally increased the As(III) oxidation rate in the DMEM (light). The temporal oxidation of As(III) to As(V) in various cell-free growth media necessitates routine checking of the valence state of arsenic during cell culture experiments and the results of biological effects attributed to As(III) should be interpreted with caution. Special attention is needed particularly in cases with vitamin C which was acting pro-oxidatively in all conditions examined. PMID- 21822953 TI - Assessment of the efficacy of Aspergillus sp. EL-2 in textile waste water treatment. AB - Fungal biomass has the ability to decolorize a wide variety of dyes successfully through a number of mechanisms. A brown rot isolate, previously identified as Aspergillus sp. EL-2, was used in the aerobic treatment of textile waste water efficiently. In the current work, the treated waste water was tested chemically using more than one combined treatment. Microbial toxicity, phytotoxicity, genotoxicity and cytotoxicity were also studied to assess the toxicity level for each treatment. The obtained data suggest that the contribution of more than one mode of treatment is essential to ensure complete destruction of the by-products. The use of gamma irradiation (25 kGy) after the bioremediation step led to the decrease of the by-products of biodegradation as observed by visible spectrum and Fourier transfer infra red spectroscopy (FT-IR). The toxicity assessment presented variable results indicating the need for more than one toxicity test to confirm the presence or absence of hazardous compounds. Brown rot fungus could be used efficiently in the treatment of textile waste water without the risk of obtaining high carcinogenic or genotoxic compounds, especially if combined treatment is employed. PMID- 21822954 TI - Investigating partner abuse among HIV-positive men who have sex with men. AB - High rates of partner abuse (PA) of all types-physical, sexual, and psychological have been identified in studies of HIV-positive individuals. We examined both the prevalence and correlates of same-sex PA in HIV-positive men who have sex with men (MSM). Participants recruited from public outpatient HIV clinics (N = 168) completed CASI surveys about PA and current physical and mental health. Electronic medical record data were obtained for HIV biomarkers. Results indicate high rates of past year PA (physical, 19%; sexual, 17%; psychological, 51%; any, 54%), with rates comparable to, or higher than, those reported in recent studies of HIV-positive women and older studies of HIV-positive MSM. Overall, participants endorsing past year PA reported poorer mental but not physical health. Participants who endorsed past year physical PA, specifically, reported the largest number of mental health problems. HIV care providers should routinely assess PA, especially physical PA, in all MSM patients. PMID- 21822955 TI - On a communitarian approach to bioethics. AB - A communitarian approach to bioethics adds a core value to a field that is often more concerned with considerations of individual autonomy. Some interpretations of liberalism put the needs of the patient over those of the community; authoritarian communitarianism privileges the needs of society over those of the patient. Responsive communitarianism's main starting point is that we face two conflicting core values, autonomy and the common good, and that neither should be a priori privileged, and that we have principles and procedures that can be used to work out this conflict but not to eliminate it. This discussion uses the debate in the US over funding for entitlements as a case study to apply the values of communitarian bioethics. PMID- 21822956 TI - Macrocephaly in neurofibromatosis type 1: a sign post for optic pathway gliomas? AB - PURPOSE: Optic pathway gliomas, which occur in 15-20% of paediatric patients with neurofibromatosis type 1, are the most common central nervous system tumour associated with this neurocutaneous disorder. The detection of optic pathway gliomas is essential for further management but is often delayed in infancy due to oligosymptomatic progression and difficulties in clinical detection. Therefore, the aim of our study was to find a clinical indicator for the presence of optic pathway gliomas in children with neurofibromatosis type 1 in order to facilitate early diagnosis and initiate further ophthalmological and neuroimaging investigations. METHODS: We retrospectively evaluated 70 patients (mean age of 10.5 years; SD of 4.3 years; range of 0.5-19.6 years; 35 females) with neurofibromatosis type 1 seen at the University Children's Hospital of Bern, Switzerland, between January 1998 and December 2008 regarding clinical features of neurofibromatosis type 1 in relation to the presence of optic pathway gliomas. RESULTS: Fifty-seven of the 70 patients (81.4%) had no clinical or radiological signs of optic pathway gliomas [magnetic resonance imaging (MRI) of the brain in 26/57], whereas 13/70 patients (18.6%) were diagnosed with optic pathway gliomas by MRI. Patients with optic pathway gliomas showed macrocephaly significantly more often compared to patients without optic pathway gliomas (8/13 vs. 9/57, respectively; p = 0.004). CONCLUSION: Macrocephaly significantly correlates with the incidence of optic pathway gliomas in children with neurofibromatosis type 1. We therefore hypothesise that in otherwise asymptomatic patients, macrocephaly is an additional indicator for performing MRI to detect optic pathway gliomas. PMID- 21822957 TI - Ventriculoperitoneal shunt catheter protrusion through the anus: case report of an uncommon complication and literature review. PMID- 21822958 TI - eNOS polymorphisms and moyamoya disease. PMID- 21822959 TI - Hydrocephalus in toddlers: the place of shunts in sub-Sahara African countries. AB - PURPOSE: This study describes the epidemiological patterns of hydrocephalus in toddlers in our setting in order to determine the proportion of those who could benefit from endoscopic third ventriculostomy (ETV). METHODS: This prospective and descriptive study included all toddlers operated on for hydrocephalus from 1 March 2008 to 31 March 2010 at the Yaounde Central Hospital. RESULTS: Forty-six toddlers were included representing 72% of all hydrocephalus cases managed at the Neurosurgery Unit during the study period. The mean age was 6.9 +/- 1.6 months. The delay before treatment varied from 5 days to 15.8 months (mean = 3.7 +/- 0.5 months). The commonest clinical presentation was macrocrania (78.3%). Of the toddlers, 58.7% presented with a probable blindness (loss of ocular pursuit); dilated and non-reactive pupils were found in nine patients (19.6%). The diagnosis was based on transfontanellar echography (TFE), CT scan or combined TFE and CT scan. Identified aetiologies were aqueduct stenosis (28.7%), haemorrhage (18%), Dandy-Walker's syndrome (14.3%), meningitis (10.8%), myelomeningocele (10.8%), agenesis of Monro's foramen (3.6%), brain abscess (3.2%) and posterior fossa tumour (3.6%). No specific cause was found in 7% of cases. The treatment was ventriculoperitoneal shunting in 42 cases (91.3%) and ETV in two cases (4.3%). Infections (11.1%) and shunts' obstruction (5.4%) were the main complications. CONCLUSION: Cases of hydrocephalus in toddlers are frequent in our setting. Regardless of the patient's age, the most prevailing aetiologies (infections, haemorrhage, myelomeningocele) and technological conditions (neuroendoscope) are less favourable for ETV. The use of ETV in the treatment of hydrocephalus in sub-Saharan Africa is still marginal and needs to be encouraged in selected cases. The prevention of non-tumoral hydrocephalus is of critical importance. PMID- 21822960 TI - Clonal trisomies 7,10 and 12, normal 3p and absence of VHL gene mutation in a clear cell tubulopapillary carcinoma of the kidney. PMID- 21822961 TI - Comparison of two mathematical models for correlating the organic matter removal efficiency with hydraulic retention time in a hybrid anaerobic baffled reactor treating molasses. AB - A modelling of the anaerobic digestion process of molasses was conducted in a 70 L multistage anaerobic biofilm reactor or hybrid anaerobic baffled reactor with six compartments at an operating temperature of 26 degrees C. Five hydraulic retention times (6, 16, 24, 72 and 120 h) were studied at a constant influent COD concentration of 10,000 mg/L. Two different kinetic models (one was based on a dispersion model with first-order kinetics for substrate consumption and the other based on a modification of the Young equation) were evaluated and compared to predict the organic matter removal efficiency or fractional conversion. The first-order kinetic constant obtained with the dispersion model was 0.28 h(-1), the Peclet dispersion number being 45, with a mean relative error of 2%. The model based on the Young equation predicted the behaviour of the reactor more accurately showing deviations lower than 10% between the theoretical and experimental values of the fractional conversion, the mean relative error being 0.9% in this case. PMID- 21822962 TI - Comparison of metals in tissues of fish from Paradeniz Lagoon in the coastal area of northern east Mediterranean. AB - Present study was performed to examined the metal concentrations in muscle, liver, gonad and gill of gilthead seabream, European seabass, Leaping mullet and Flathead grey mullet from Paradeniz Lagoon, Mediterranean coastal area. The metal concentrations found in muscle tissue varied for Fe: 2.3-51.4, Zn: 6.63-14.8, Cu: 0.38-1.10, Mn: 0.38-1.06, Cr: 0.34-1.13, Ni: 0.58-.074, Pb: 0.32-1.02, Cd: 0.20 0.67 and Co: 0.30-0.61 mg/kg wet weight. Iron showed the highest levels in all tissues, and generally followed by zinc. On the other hand, cadmium, cobalt and lead showed lower levels than other metals. Statistically significant differences were observed in the mean metal values obtained from investigated fish species and their tissues. The levels of metals in the examined fish were well below the regulatory values of various govermental agencies. PMID- 21822963 TI - Pregnant and recently pregnant women's perceptions about influenza a pandemic (H1N1) 2009: implications for public health and provider communication. AB - The objective of this study was to explore pregnant and recently pregnant women's perceptions of influenza vaccine and antivirals during the 2009 H1N1 pandemic. We conducted 18 focus groups with pregnant and recently pregnant women in three US cities in September 2009. Participants were segmented into groups by insurance status (no or public insurance vs. private insurance), vaccine attitudes (higher vs. lower likelihood of acceptance of any vaccines, not only influenza vaccines), and parity (first child vs. other children in the home) based on information they provided on the screening questionnaire at the time of recruitment. We found that women are not well informed about influenza vaccinations and antiviral medicine and have significant concerns about taking them during pregnancy. An interest in their infant's well-being, however, can be strong motivation to adopt preventive recommendations, including vaccination. A woman's health care provider is a highly trusted source of information about the 2009 H1N1. Pregnant women have unique communication needs for influenza. Messages directing pregnant women to adopt public health recommendations, particularly for vaccination or prophylactic medication should include a detailed description of the benefits or lack of risk to the fetus and the safety of breastfeeding. Additionally, messages should recognize that pregnant women are taught to be selective about taking medication and provide a clear rationale for why the medicine or vaccine is necessary. PMID- 21822964 TI - Exploring the concept of positive deviance related to breastfeeding initiation in black and white WIC enrolled first time mothers. AB - Positive deviance inquiry is effective in identifying advantageous health behaviors and improving health outcomes among disadvantaged resource-poor populations. The objective of this study was to apply the positive deviance concept to explore the characteristics of positive deviants for breastfeeding among WIC-enrolled first-time mothers in Louisiana. The cross sectional study included data on 2,036 WIC-enrolled first time mothers (52.6% black) from the LaPRAMs, 2000-2004. Chi-square test was used to compare groups. Multivariable logistic regression was applied to calculate adjusted OR and 95% CI by breastfeeding initiation status. The average age was 21.3 years, 31.5% had less than 12 years of education, and 44.6% of the sample reported having initiated breastfeeding. Black mothers were less likely to initiate breastfeeding than their white counterparts (OR 0.39 (95% CI: 0.31, 0.48)). Among 641 WIC-enrolled first time mothers with less than 12 years of education, 28.4% were identified as positive deviants for breastfeeding initiation. Among the black mothers 19.8% were positive deviants compared to 40.3% of the white mothers. Breastfeeding in the hospital after delivery (P < 0.0001) and having received help on how to breastfeed in the hospital (P < 0.0001) were significantly associated with breastfeeding initiation in white and black mothers. In addition, the black positive deviants were more likely, OR 2.80 (95% CI: 1.20, 6.56) to have initiated breastfeeding if their baby was low birth weight. Breastfeeding practices shortly after delivery including assistance and education from staff in the hospital, are related to breastfeeding initiation among less educated WIC enrolled mothers. PMID- 21822965 TI - The GAL10 gene is located 40 kbp away from the GAL7-GAL1 region in the yeast Kazachstania naganishii. AB - Of the genes involved in galactose metabolism, GAL7, GAL10, and GAL1 are tightly linked in this order on chromosome II in Saccharomyces cerevisiae. While several species of the order Saccharomycetales have similar gene organization, Kazachstania naganishii is unique, in which GAL7 and GAL1 are close to each other whereas GAL10 is substantially apart from them on chromosome XI. In this study, we inserted the recognition sequence of I-SceI homing-endonuclease into GAL10 and also into the intervening segment of GAL7-GAL1. By cleaving chromosome DNA of the gene-manipulated strain with I-SceI, we obtained evidence that chromosome XI (610 kbp) was replaced with three fragments (305, 265, and 40 kbp). Using appropriate probes, we further found that GAL10 was about 40 kbp apart from the GAL7-GAL1 cluster and that orientation of GAL10 was reversed comparing to the S. cerevisiae counter part. We, therefore, contend that comparison of the organization of the GAL cluster among Saccharomycetales is of importance to elucidate evolution of chromosomes and that the experimental scheme developed in this study is useful for this line of investigation. PMID- 21822966 TI - Side-chain to backbone correlations from solid-state NMR of perdeuterated proteins through combined excitation and long-range magnetization transfers. AB - Proteins with excessive deuteration give access to proton detected solid-state NMR spectra of extraordinary resolution and sensitivity. The high spectral quality achieved after partial proton back-exchange has been shown to start a new era for backbone assignment, protein structure elucidation, characterization of protein dynamics, and access to protein parts undergoing motion. The large absence of protons at non-exchangeable sites, however, poses a serious hurdle for characterization of side chains, which play an important role especially for structural understanding of the protein core and the investigation of protein protein and protein-ligand interactions, e.g. This has caused the perdeuteration approach to almost exclusively be amenable to backbone characterization only. In this work it is shown that a combination of isotropic (13)C mixing with long range (1)H/(13)C magnetization transfers can be used effectively to also access complete sets of side-chain chemical shifts in perdeuterated proteins and correlate these with the protein backbone with high unambiguity and resolution. COmbined POlarization from long-Range transfers And Direct Excitation (COPORADE) allows this strategy to yield complete sets of aliphatic amino acid resonances with reasonable sensitivity. PMID- 21822967 TI - Gastric subepithelial masses: evaluation of multidetector CT (multiplanar reconstruction and virtual gastroscopy) versus endoscopic ultrasonography. AB - OBJECTIVES: To assess the role of multidetector computed tomography (MDCT) with multiplanar reconstruction (MPR) and virtual gastroscopy (VG) for detection and differentiation of gastric subepithelial masses (SEMs) by comparison with endoscopic ultrasonography (EUS). METHODS: Forty-one patients with a suspected SEM were evaluated using EUS and MDCT. MDCT findings were analyzed based on the consensus of two radiologists who were blinded to the EUS findings. The analysis of the CT features included the location, size, and contours of the tumor, the presence of central dimpling, as well as the growth pattern, enhancement pattern, and enhancement degree. The long diameter (LD) and the short diameter (SD) of each lesion were measured and the LD/SD ratios were calculated. EUS and MDCT results were compared with histopathology for the pathologically proven lesions. For the non-pathologically proven lesions, MDCT results were compared with EUS. RESULTS: Among the 41 patients, 34 SEMs were detected using EUS. For the detection of SEMs with MDCT, a sensitivity of 85.3%, a specificity of 85.7%, a positive predictive value of 96.7%, and a negative predictive value of 54.5% were calculated. The overall accuracy of MDCT for detecting and classifying the SEMs was 85.3 and 78.8%, respectively. CONCLUSIONS: MDCT with MPR and VG is a valuable method for the evaluation of SEMs. Specific MDCT criteria for various SEMs may be helpful in making an accurate diagnosis. PMID- 21822968 TI - Gastric bypass does not influence olfactory function in obese patients. AB - Morbidly obese individuals have altered sense of taste and smell. Gastric bypass (GBP) alters taste but olfactory function has not been evaluated. Changes in these senses may influence dietary preferences following GBP. Our aim was to evaluate the effect of abdominal operation, specifically GBP, and weight loss on olfactory function. Fifty-five persons undergoing GBP and cholecystectomy and 40 persons undergoing cholecystectomy (CC) alone were administered the Cross Cultural Smell Identification Test (CC-SIT) preoperatively and 2 and 6 weeks postoperatively. Patients undergoing GBP underwent further tests at 3, 6, 9, and 12 months. Body mass index (BMI) was also assessed. Mean BMI was significantly greater preoperatively in the GBP group (50.6 +/- 8.0 vs. 30.6 +/- 7.3 kg/m(2), p < 0.05). Significantly more GBP patients had abnormal CC-SIT results preoperatively (12.7% vs. 5.0%). There were no significant differences in percentage of abnormal tests at 2 and 6 weeks within groups but remained lower in CC patients (2 weeks, GBP 6.2% vs. CC 5.7%; 6 weeks, GBP 9.8% vs. CC 3.2%, p < .05). BMI decreased in the GBP group at 12 months (50.6 +/- 8.0 preoperatively to 31.9 +/- 6.9 p < 0.05). Absolute olfactory dysfunction (AOD) was present at each interval up to 12 months after GBP. Only 22% of patients with AOD remained obese. GBP does not appear to influence olfactory function. AOD present in morbidly obese persons is not affected by weight loss. These findings support that olfactory dysfunction may be a contributing factor to the development of obesity. PMID- 21822969 TI - Impact of pump flow fluctuations on post column online ID-ICP-MS. AB - In post column online isotope dilution mass spectrometry (IDMS), the stability of the spike mass flow is a key element. Changes in viscosity or fluctuations in the pump rate of the peristaltic pump may affect the results of post column online IDMS measurements. It was shown by simulating random fluctuations and studying the changes in the resulting integrals of the isotope ratio chromatogram of the sample that even small fluctuations, observable when using peristaltic pumps, can influence the result and especially its uncertainty. The use of a balance to continuously monitor the mass flow of the spike during the measurement which we presented in a previous publication allows now to correct the isotope ratio chromatogram for these fluctuations. Subsequently, the simulated effect was verified experimentally for the determination of Se-Met in the human serum reference material BCR 637, where the corrected mass fraction was plainly closer to the mass fraction obtained by species specific IDMS. Additional attention was paid to the fact that there is a time shift between the observation of the fluctuations in the pump rate and the detection of these fluctuations in the ICP MS. PMID- 21822970 TI - Exploring the limits of robust detection of incorporation of 13C by mass spectrometry in protein-based stable isotope probing (protein-SIP). AB - One of the features of protein-based stable isotope probing is the parallel identification of differentially labeled peptide forms and the accurate calculation of their relative isotope abundances. The level of incorporation is informative of the metabolic activity of the species that synthesized the said protein and peptide. To model the carbon flux in a microbial community, an accurate assessment is crucial. Since the initial processes in carbon consumption are one of the most interesting objectives in microbial ecology, the methodology to detect low amounts of incorporation was tuned, and the limits of robust detection were analyzed. For this, Pseudomonas fluorescens DSM 50090T was grown on galactose using different ratios of (12)C/(13)C galactose from 10% down to 0.1% labeled galactose. After prolonged cultivation to ensure complete labeling, protein samples were separated by one-dimensional gel electrophoresis, subsequently tryptically digested and analyzed by ultra-performance liquid chromatography (UPLC) Orbitrap tandem mass spectrometry (MS/MS) measurements. The isotopic patterns from identified peptides in the mass spectra were used to calculate the (13)C relative isotope abundance (RIA) in the respective peptides. The statistic distribution of the RIA values in dependence of the number of analyzed peptides was compared between the different ratios of unlabeled/labeled substrate. The acquired data showed that the applied method is capable of detecting a difference in (13)C incorporation of +/-0.1% RIA based on at least 20 peptides. This sensitivity makes protein-stable isotope probing a valuable method for quantitative assessment of species specific metabolic activity in metaproteomics. PMID- 21822971 TI - A rapid analytical method based on microwave-assisted extraction for the determination of drugs of abuse in vitreous humor. AB - Robust and simple validated analytical methods are required in postmortem toxicology to confirm immunoassay screening analysis of drugs of abuse. In this work, microwave-assisted extraction (MAE) was evaluated as an alternative method for extraction of target compounds such as cocaine, benzoylecgonine, cocaethylene, morphine, codeine, 6-monoacetylmorphine, methadone, and 2 ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine from vitreous humor. The MAE procedure parameters, namely, extraction temperature, time, and solvent volume, were optimized using a central composite design and applying desirability functions. The optimal conditions for extraction were 80 degrees C, 8 min, and 15 mL of dichloromethane solvent. The MAE-high-performance liquid chromatography diode-array detection method was validated, showing its capability for the detection of concentrations in the range from 33 to 76 ng mL(-1) and recoveries in the range from 87 to 99.3% for all drugs. The MAE-based method was tested for 15 vitreous humor samples from forensic cases and its performance was compared with that of a solid-phase extraction method previously developed by our group. In general, better recovery and precision were achieved with the use of the MAE based procedure. PMID- 21822972 TI - Neutral loss and precursor ion scan tandem mass spectrometry for study of activated benzopyrene-DNA adducts. AB - Methodology for detection of activated benzo[a]pyrene (B[a]P)-nucleoside adducts by liquid chromatography-tandem mass spectrometry is reported. Adducts of B[a]P dihydrodiol epoxide (B[a]PDE) with guanosine and adenosine have been detected for the first time by use of precursor ion scan and neutral loss scan. B[a]P was then activated by use of UV irradiation and some of the products obtained have been identified by taking advantage of the information obtained for B[a]PDE. Photoactivation has also been carried out in the presence of hydrogen peroxide; this resulted in a higher yield of products with increased production of BaP diones. The reactivity of these compounds toward nucleosides has been tested. The proposed method was successfully used for detection of one stable guanosine-B[a]P dione adduct. PMID- 21822973 TI - Development of highly fluorescent silica nanoparticles chemically doped with organic dye for sensitive DNA microarray detection. AB - Increasing the sensitivity in DNA microarray hybridization can significantly enhance the capability of microarray technology for a wide range of research and clinical diagnostic applications, especially for those with limited sample biomass. To address this issue, using reverse microemulsion method and surface chemistry, a novel class of homogenous, photostable, highly fluorescent streptavidin-functionalized silica nanoparticles was developed, in which Alexa Fluor 647 (AF647) molecules were covalently embedded. The coating of bovine serum albumin on the resultant fluorescent particles can greatly eliminate nonspecific background signal interference. The thus-synthesized fluorescent nanoparticles can specifically recognize biotin-labeled target DNA hybridized to the microarray via streptavidin-biotin interaction. The response of this DNA microarray technology exhibited a linear range within 0.2 to 10 pM complementary DNA and limit of detection of 0.1 pM, enhancing microarray hybridization sensitivity over tenfold. This promising technology may be potentially applied to other binding events such as specific interactions between proteins. PMID- 21822974 TI - Changing Italian nosocomial-community trends and heteroresistance in Staphylococcus aureus from bacteremia and endocarditis. AB - Bloodstream infections due to Staphylococcus aureus (BSI) are serious infections both in hospitals and in the community, possibly leading to infective endocarditis (IE). The use of glycopeptides has been recently challenged by various forms of low-level resistance. This study evaluated the distribution of MSSA and MRSA isolates from BSI and IE in 4 Italian hospitals, their antibiotic susceptibility--focusing on the emergence of hVISA--and genotypic relationships. Our results demonstrate that the epidemiology of MRSA is changing versus different STs possessing features between community-acquired (CA)- and hospital acquired (HA)-MRSA groups; furthermore, different MSSA isolated from BSI and IE were found, with the same backgrounds of the Italian CA-MRSA. The hVISA phenotype was very frequent (19.5%) and occurred more frequently in isolates from IE and in both the MSSA and MRSA strains. As expected, hVISA were detected in MRSA with vancomycin minimum inhibitory concentrations (MICs) of 1-2 mg/l, frequently associated with the major SCCmec I and II nosocomial clones; this phenotype was also detected in some MSSA strains. The few cases of MR-hVISA infections evaluated in our study demonstrated that 5 out of 9 patients (55%) receiving a glycopeptide, died. Future studies are required to validate these findings in terms of clinical impact. PMID- 21822975 TI - Emerging knowledge from genome sequencing of crop species. AB - Extensive insights into the genome composition, organization, and evolution have been gained from the plant genome sequencing and annotation ongoing projects. The analysis of crop genomes provided surprising evidences with important implications in plant origin and evolution: genome duplication, ancestral re arrangements and unexpected polyploidization events opened new doors to address fundamental questions related to species proliferation, adaptation, and functional modulations. Detailed paleogenomic analysis led to many speculation on how chromosomes have been shaped over time in terms of gene content and order. The completion of the genome sequences of several major crops, prompted to a detailed identification and annotation of transposable elements: new hypothesis related to their composition, chromosomal distribution, insertion models, amplification rate, and evolution patterns are coming up. Availability of full genome sequence of several crop species as well as from many accessions within species is providing new keys for biodiversity exploitation and interpretation. Re-sequencing is enabling high-throughput genotyping to identify a wealth of SNP and afterward to produce haplotype maps necessary to accurately associate molecular variation to phenotype. Conservation genomics is emerging as a powerful tool to explain adaptation, genetic drift, natural selection, hybridization and to estimate genetic variation, fitness and population's viability. PMID- 21822977 TI - Friedreich's Ataxia: a review from a cardiology perspective. AB - BACKGROUND: Neuromuscular disorders are not among the common causes of cardiomyopathy in the general population; however, cardiomyopathy is known to occur in several neuromuscular disorders including Friedreich's Ataxia (FA). In patients with neuromuscular disorders, concomitant cardiac involvement contributes significantly to morbidity and mortality and often leads to premature death. METHODS: An extensive literature search of Medline and Pubmed was conducted to include all published reports on cardiac involvement in FA. Secondary articles were identified from key paper reference listings. CONCLUSION: Hypertrophic cardiomyopathy is a cardinal feature of FA; therefore all FA patients should be screened for cardiomyopathy. A cardiac examination, ECG and ECHO are advised at diagnosis, and also on the development of any cardiac symptoms. Treatment is determined by the presence of symptoms, the presence of left ventricular outflow gradient and the sudden death risk. Institution of aggressive medical therapy early in the course of the disease may help improve quality of life and provide survival benefit. PMID- 21822978 TI - Post-TACE combination therapy of heparin and octreotide results in decreased tumor metastasis in extrahepatic tumorigenesis. AB - Primary hepatocarcinoma is the most common type of malignant tumor and a leading cause of cancer mortality. Standard treatment for patients with advanced primary hepatocarcinoma for whom surgery is not recommended includes transcatheter arterial chemoembolization (TACE). Within these patients 44% develop metastasis within 1 year. Thus, understanding the events underlying the recurrent tumors and developing therapies in conjunction with TACE would be of great benefit. Reducing tumor angiogenesis by combining the somatostatin analog octreotide with small doses of heparin is one approach in decreasing metastasis rates by targeting VEGF and heparinase, respectively. Given this, we investigated whether a heparin and octreotide combination treatment administered post-TACE would decrease the tumor metastasizing rate in primary hepatocarcinoma. A total of 147 patients diagnosed with primary hepatocarcinoma were admitted to the study and received 2-4 TACE treatments and were monitored for 1 year. Of these 84 received the heparin plus octreotide combination treatment and 63 did not (control group). All patients were monitored for adverse reactions, coagulation ability, and tumor metastasis. We found a significant decrease in the incidence of tumor metastasis in patients receiving the combination treatment post-TACE for up to 1 year with no significant toxic or adverse effects. Thus, we propose using the combination treatment of heparin and octreotide post-TACE in the treatment of recurrent tumorigenesis in primary hepatocarcinoma. PMID- 21822976 TI - Mammalian metallothionein in toxicology, cancer, and cancer chemotherapy. AB - The present paper centers on mammalian metallothionein 1 and 2 in relationship to cell and tissue injury beginning with its reaction with Cd2+ and then considering its role in the toxicology and chemotherapy of both metals and non-metal electrophiles and oxidants. Intertwined is a consideration of MTs role in tumor cell Zn2+ metabolism. The paper updates and expands on our recent review by Petering et al. (Met Ions Life Sci 5:353-398, 2009). PMID- 21822979 TI - Familia adelante: a multi-risk prevention intervention for Latino families. AB - A comprehensive approach for providing behavioral health services to youth is becoming increasingly emphasized. Latino youth are at increased risk for substance abuse, mental health concerns, unsafe sexual practices and HIV, and these outcomes have been empirically connected to individual, family and community-based stress. Despite this knowledge, there is a lack of evidence-based approaches that target these negative outcomes by reducing stress in Latino families in a culturally relevant manner. The current study examined the use of research-based strategies for reducing multiple risk behaviors in a predominantly Mexican-American sample of families. Through a modular approach, participants engaged in a psycho-educational curriculum to enhance communication and psychosocial coping, increase substance abuse and HIV knowledge and perception of harm, and improve school behavior. Over 12 sessions, the curriculum aimed to achieve these outcomes through an overall decrease in family and community-based stress by focusing on acculturative stress. Findings indicate that communication and perception of substance use harm were significantly enhanced, while social norms regarding sexual behavior, HIV anxiety and past use of marijuana and other illegal drugs were significantly reduced. While many of measures were reliable (alpha > .80), further changes are necessary to improve the accuracy of future studies. Despite these limitations, Familia Adelante improves many areas of participant's family life, and points toward the feasibility of multi-risk reduction behavioral health prevention approaches. PMID- 21822980 TI - Planning and self-efficacy can increase fruit and vegetable consumption: a randomized controlled trial. AB - Fruit and vegetable consumption represents a nutritional goal to prevent obesity and chronic illness. To change dietary behaviors, people must be motivated to do so, and they must translate their motivation into actual behavior. The present experiment aims at the psychological mechanisms that support such changes, with a particular focus on dietary self-efficacy and planning skills. A randomized controlled trial compared a theory-based psychological intervention with a health education session in 114 participants. Dependent variables were fruit and vegetable consumption, intention to consume more fruit and vegetables, planning to consume more, and dietary self-efficacy, assessed before the intervention, 1 week afterwards, and at 6-week follow up. Significant group by time interactions for all four dependent variables documented superior treatment effects for the psychological intervention group, with substantially higher scores at posttest and follow-up for the experimental group, although all students benefited from participation. To identify the contribution of the main intervention ingredients (self-efficacy and planning), regression analyses yielded mediator effects for these two factors. A social-cognitive intervention to improve fruit and vegetable consumption was superior to a knowledge-based education session. Self-efficacy and planning seem to play a major role in the mechanisms that facilitate dietary changes. PMID- 21822981 TI - Large woody debris input and its influence on channel structure in agricultural lands of Southeast Brazil. AB - Riparian forests are important for the structure and functioning of stream ecosystems, providing structural components such as large woody debris (LWD). Changes in these forests will cause modifications in the LWD input to streams, affecting their structure. In order to assess the influence of riparian forests changes in LWD supply, 15 catchments (third and fourth order) with riparian forests at different conservation levels were selected for sampling. In each catchment we quantified the abundance, volume and diameter of LWD in stream channels; the number, area and volume of pools formed by LWD and basal area and tree diameter of riparian forest. We found that riparian forests were at a secondary successional stage with predominantly young trees (diameter at breast height <10 cm) in all studied streams. Results showed that basal area and diameter of riparian forest differed between the stream groups (forested and non forested), but tree density did not differ between groups. Differences were also observed in LWD abundance, volume, frequency of LWD pools with subunits and area and volume of LWD pools. LWD diameter, LWD that form pools diameter and frequency of LWD pools without subunits did not differ between stream groups. Regression analyses showed that LWD abundance and volume, and frequency of LWD pools (with and without subunits) were positively related with the proportion of riparian forest. LWD diameter was not correlated to riparian tree diameter. The frequency of LWD pools was correlated to the abundance and volume of LWD, but characteristics of these pools (area and volume) were not correlated to the diameter of LWD that formed the pools. These results show that alterations in riparian forest cause modifications in the LWD abundance and volume in the stream channel, affecting mainly the structural complexity of these ecosystems (reduction in the number and structural characteristics of LWD pools). Our results also demonstrate that riparian forest conservation actions must consider not only its extension, but also successional stage to guarantee the quantity and quality of LWD necessary to enable the structuring of stream channels. PMID- 21822982 TI - Assessment of DDT and DDE levels in soil, dust, and blood samples from Chihuahua, Mexico. AB - The aim of this study was to assess levels of DDT and DDE in two environmental matrices (soil and dust) and to investigate the blood levels of these insecticides in exposed children living in a north Mexican state (Chihuahua) where DDT was sprayed several years ago during (1) health campaigns for the control of malaria and (2) agricultural activities. DDT and DDE were analyzed by gas chromatography/mass spectrometry. In general, lower levels were found in household outdoor samples. The levels in outdoor samples ranged from 0.001 to 0.788 mg/kg for DDT and from 0.001 to 0.642 mg/kg for DDE. The levels in indoor samples ranged from 0.001 to 15.47 mg/kg for DDT and from 0.001 to 1.063 mg/kg for DDE. Similar results to those found in indoor soil were found in dust, in which the levels ranged from 0.001 to 95.87 mg/kg for DDT and from 0.001 to 0.797 mg/kg for DDE. Moreover, blood levels showed that all of the communities studied had been exposed to DDT and/or DDE, indicating a general past or present exposure to DDT. It is important to note that the quotient DDT/DDE in all matrices was always >1. Whether the people living in our study area are at risk is an issue that deserves further analysis. However, applying precautionary principles, it is important to initiate a risk-reduction program to decrease exposure to DDT and its metabolites in people living in this area. PMID- 21822983 TI - Three cases of superficial siderosis of the central nervous system and review of the literature. AB - Superficial siderosis of the central nervous system results from chronic or intermittent hemorrhage into the subarachnoid space that causes hemosiderin deposition in subpial layers of the brain and the spinal cord leading to neuronal damage. Patients present with progressive and debilitating symptoms that typically include adult-onset slowly progressive cerebellar gait ataxia and sensorineural hearing impairment. Regardless of extensive investigations, the origin of the hemorrhage is often not clear. Because of the good availability of magnetic resonance imaging, asymptomatic cases of superficial siderosis of the central nervous system are increasingly discovered. SS cases are increasingly reported in the literature. We present three new cases. The etiology, pathogenesis, clinical features, and treatment options of SS are reviewed. PMID- 21822984 TI - De novo basilar artery aneurysm formation after placement of a Wingspan stent. AB - Report the de novo formation of an aneurysm after wingspan placement and describe the treatment modality. We report a patient with symptomatic basilar stenosis who underwent placement of a wingspan stent. On 9-month follow-up, the patient was found to have a new 5-mm aneurysm adjacent to the proximal tines of the stent. The patient subsequently underwent placement of an enterprise stent and coils for aneurysm occlusion. We reviewed the literature and discussed possible etiologies for the development of this unique de novo aneurysm. PMID- 21822985 TI - Local feeding strategies and milk composition in small-scale dairy production systems during the rainy season in the highlands of Mexico. AB - The objective of the work was to identify local feeding strategies in small-scale dairy production systems during the rainy season in the highlands of Mexico, and to determine their effects on milk yields (MY), milk composition and economic viability. Twenty-two dairy farms were monitored by monthly visits, recording and sampling milk from between two and six cows in each farm, live-weight was also recorded. Samples from feeds used in that month were taken and feeds given to the dairy herd were weighed. Economic data was also recorded. Milk composition and milk urea nitrogen were determined, as well as chemical composition of feeds. Eighteen feedstuffs were identified, grouped in: HNH feeds-high in neutral detergent fibre (NDF) and in DM matter; HNL feeds-high in NDF but low in DM; HCh feeds-high in non-fibrous carbohydrates; and HCP feeds-high in crude protein. Four feeding strategies were identified: strategy 1 uses HND, HNL and HCP; strategy 2-HND, HNL, HCh and HCP; strategy 3 HNH and HCP; and strategy 4 HNL and HCP. Of participating farms, 73.4% followed strategy 1, 11.3% strategy 2, 11.3% strategy 4 and 3.8% strategy 3. There were no statistical differences (P > 0.05) between strategies for MY and milk composition, but there were differences (P < 0.05) for ration costs. Multiple regression analysis showed no significative (P > 0.05) model relating intake of feed groups and milk fat content, but milk protein and SNF contents were significantly explained by intake of HCP. When expressed as MY and milk components yield, milk fat yield was significantly explained by intake of all four feed groups, but milk protein and SNF yields were explained only by intake of HCP and LW. MUN excretion was explained also by HCP intake. All feeding strategies produced positive economic returns, on average generating the equivalent of 3.45 minimum wages of the area. PMID- 21822986 TI - Brain-derived neurotrophic factor and suicidal behavior in adolescents. PMID- 21822987 TI - An overview of morbidity, mortality and long-term outcome of late preterm birth. AB - BACKGROUND: Preterm birth rate continues to rise around the world mainly at the expense of late preterm newborns, recently defined as births between the gestational age of 34 weeks and 36-6/7 weeks. Late preterm infants are considered to have significantly more short-term and longterm adverse outcomes than term infants. DATA SOURCES: Articles concerning morbidity, mortality and long-term outcomes of late preterm infants were retrieved from PubMed/MEDLINE published during the period of 2000-2010. RESULTS: Late preterm infants are the fastest growing subgroup of neonates, comprising the majority of all preterm births. Compared with term infants, they have significantly higher risk of morbidity, mortality and adverse long-term outcomes well beyond infancy into adulthood. However, epidemiology and etiology of late preterm births, the magnitude of their morbidity, the long-term life quality, and public health impact have not been well studied. CONCLUSIONS: The growing number of late preterm neonates substantiates the importance to better understand and medically approach this special preterm subgroup. A long-term evaluation, monitoring and follow-up of late preterm infants are needed to optimize neonatal care and improve human health status. PMID- 21822988 TI - Posterior urethral valve. AB - BACKGROUND: Posterior urethral valve (PUV) is a significant cause of morbidity, mortality and ongoing renal damage in children. It accounts for end-stage renal disease in a proportion of children. This article aims at highlighting the current trend in the management of boys with posterior urethral valve. DATA SOURCES: PubMed/Medline and bibliographic search for posterior urethral valve was done. Relevant literatures on presentation, pathology, evaluation, management and outcomes of PUV were reviewed. RESULTS: PUV which is increasingly diagnosed prenatally presents a spectrum of severity. The varied severity and degree of obstruction caused by this abnormality depend on the configuration of the obstructive membrane within the urethra. The decision to intervene prenatally is dependent on gestational age, amniotic volume, and renal function of fetal urine aspiration. Identification of the patients who may benefit from early intervention remains inconclusive. Endoscopic ablation of the valve is the gold standard of treatment but use of Mohan's valvotome and other modalities are invaluable in developing countries where endoscopic facilities are limited. Proximal urinary diversion may result in poor bladder compliance and should be reserved for patients with persisting or increasing upper urinary tract dilatation, increasing serum creatinine or inappropriate instruments. The behavior of the bladder and its subsequent management after valve ablation may influence the long-term renal outcome in PUV patients. CONCLUSIONS: The care of children with PUV continues to improve as a result of earlier diagnosis by ultrasound, developments in surgical technique and meticulous attention to neonatal care. The ultimate goal of management should be to maximize renal function, maintain normal bladder function, minimize morbidity and prevent iatrogenic problems. PMID- 21822990 TI - Epidemiological characteristics and meteorological factors of childhood Mycoplasma pneumoniae pneumonia in Hangzhou. AB - BACKGROUND: Mycoplasma pneumoniae (M. pneumoniae) is an important pathogen of pediatric respiratory infections and the relation of M. pneumoniae pneumonia (MPP) with meteorological factors remains obscure. This study aims to investigate the epidemiological characteristics of childhood MPP and observe if there is a relationship between epidemiological characteristics and meteorological factors in Hangzhou. METHODS: M. pneumoniae DNA in nasopharyngeal aspirates of hospitalized pneumonia children were detected by polymerase chain reaction from January 1, 2007 to December 31, 2009. The positive rates of MPP (MPP rates) in different years, seasons and ages were compared. The relationship between MPP rates and meteorological data, including mean air temperature ( degrees C), mean relative humidity (%), monthly precipitation (mm) and raining days were analyzed. RESULTS: In 14 799 pneumonia cases found from 2007 to 2009, the MPP rate was 18.5%. Altogether 1610 boys (16.9%) and 1134 girls (21.4%) suffered from MPP with a significant difference between both genders (chi(2)=45.68, P<0.001). In children younger than 1 year, 1-2 years, 3-6 years, and older than 7 years, the MPP rates were 9.8%, 21.1%, 44.4% and 61.6%, respectively. The MPP rates were significantly higher in older children than in younger ones (trends test chi(2)=46.72, P<0.001). In a descending order, the MPP rates in summer, autumn, spring, and winter were 27.8%, 23.9%, 18.0% and 11.6%, respectively (chi(2)=372.75, P<0.001). The MPP rates in 2007 to 2009 were 12.9%, 19.3% and 23.6%, respectively (trends test chi(2)=13.72, P<0.001). Of the four meteorological factors, only monthly mean air temperature was included in the multiple linear regression model (P<0.001). CONCLUSIONS: This study showed that the MPP rate was higher in older children than in younger ones. Girls had a higher positive rate of MPP than boys. In Hangzhou, MPP was more prevalent in summer and autumn. Air temperature was the only meteorological factor affecting the prevalence of MPP. PMID- 21822989 TI - Micronutrients deficiency and associated sociodemographic factors in Chinese children. AB - BACKGROUND: Although the prevalence of malnutrition has decreased, micronutrient deficiency still exists among children. While iron level has been studied, limited information on serum levels of zinc in Chinese children is available. This study aims to describe the status of micronutrients and its association with sociodemographic factors, and to assess associated risk factors. METHODS: A cross sectional study was performed on 1375 Chinese preschool children. Venous blood samples were collected and analyzed for zinc and iron by atomic absorption spectrophotometry. Sociodemographic information was obtained from self administered questionnaires given to the parents. RESULTS: The high prevalence of low serum zinc (38.2%) and iron (24.3%) was found. Children from rural preschools had the lowest zinc levels, whereas those from urban preschools had the lowest iron levels. Children living in small houses had the highest prevalence of low serum zinc (47.1%), and children from small families (<=3 persons) had a higher prevalence of low serum zinc than those from large families (41.8% vs. 34.1%). CONCLUSIONS: Our findings in the recent socioeconomic development of China suggest the need for continuous monitoring of nutritional factors and highlight the importance of public health implication in preschool children even in developed regions. PMID- 21822991 TI - Gastroesophageal reflux scintigraphy: interpretation methods and inter-reader agreement. AB - BACKGROUND: Scintigraphic imaging is a useful screening tool for patients with suspected gastroesophageal reflux. New scintigraphic interpretation methods have recently been introduced. This study was undertaken to evaluate the efficiency of various scintigraphic interpretation methods in the detection of gastroesophageal reflux and to measure their influence on inter-reader agreement. METHODS: Scintigraphic images of 49 children with suspected gastroesophageal reflux were interpreted by three different methods: visual interpretation, time activity curves, and condensed images. The readings were performed by three specialists and a resident. The discordant results were resolved by a consensus reading done together by all interpreters based on the three different methods. The gastroesophageal refluxes were grouped according to their number, location and intensity. RESULTS: Gastroesophageal reflux scintigraphy revealed 22 patients with negative results and 27 with positive results. The sensitivity, positive predictive value and specificity for each of the three specialists vs. the resident were 96%, 96% and 81% vs. 96%; 93%, 90% and 96% vs. 81%; and 90%, 86%, and 95% vs. 73%, respectively. The mean inter-observer reproducibility (kappa value) was 0.910 for visual interpretation, 0.652 for time activity curves and 0.789 for condensed images. Twenty-seven percent of the results were discordant and most of these refluxes were of low grade (92%), low intensity (77%) and localization in the distal esophagus (54%). CONCLUSION: Gastroesophageal scintigraphy is a useful tool for detecting patients with suspected reflux, and visual interpretation is better than the other two methods in terms of accuracy and inter-observer reproducibility. PMID- 21822992 TI - Experience in minimally invasive Nuss operation for 406 children with pectus excavatum. AB - BACKGROUND: This study was to investigate the advantages of thoracoscopy-assisted minimally invasive Nuss operation for the treatment of pectus excavatum (PE) in children. METHODS: A total of 406 patients with PE (female: 93; male: 313) with an average age of 6.8 years (range: 3.5-17.5 years) were included in this study. Associated diseases included congenital heart disease in 9 patients and congenital pulmonary cyst in 2. The Haller index of the patients ranged from 3.35 to 7.23, with an average of 5.17+/-1.64. Minimally invasive Nuss operation was performed for all the patients. RESULTS: The operations were performed successfully and no operative mortality occurred. The average blood loss during the operation was less than 10 mL and the operating time ranged from 30 to 85 minutes with an average of 45 minutes. The length of hospital stay ranged from 5 to 9 days with an average of 7 days. Struts were implanted in 12 (3.0%) of the 406 patients. Injury of the pericardium occurred in 1 patient during the operation. Early post-operative complications occurred in 9 patients with pneumothorax and 6 patients with pleural effusion, which were cured by puncture or drainage. Poor wound healing occurred in 4 patients (1.0%) and was cured by nutritional support. During a 3-month to 6-year follow-up, 2 patients had scoliosis and 3 patients had displacement of the strut, which was cured by a second Nuss operation. Allergy occurred in 2 patients: the symptoms were improved in 1 patient after conservative treatment, but the strut was removed in advance due to allergy in the other patient. Totally 154 patients (40.0%) underwent operation for strut removal. Excellent repair results were achieved in 387 (95.3%) patients, good repair results in 12 (3.0%), and fair results in 7 (1.7%). CONCLUSIONS: Thoracoscopy-assisted Nuss operation has many advantages including small and masked incision, short operative time, minimal blood loss, fast recovery, less trauma, and satisfactory outcomes of repair. Nuss is a safe and reliable technique for repair of PE. PMID- 21822993 TI - Dying with parents: an extreme form of child abuse. AB - BACKGROUND: Filicide is the tragic crime of murdering one's own child. This report aims to summarize all such cases involving filicide with suicide and analyze possible risk factors pertinent to the city of Hong Kong. METHODS: All cases involving filicide with suicide between 1998 and 2010 were reviewed and possible risk factors pertinent to the city of Hong Kong were analyzed. RESULTS: During the study period, there were 14 cases of parents committing suicide and filicide in Hong Kong. Sixteen victims (9 boys and 7 girls, ages range from 2 months to 33 years) and a three-month fetus were involved; only two survived. The parents (12 mothers and 3 fathers, ages range from 25 years to 64 years) all died. The majority of perpetrators (n=7) had alleged history of psychiatric illness or post-puerperal depression. The majority jumped from heights (n=11 off tall buildings, n=1 off a bridge), one father used town-gas, and one couple burned charcoal (carbon monoxide poisoning). CONCLUSIONS: These rare but tragic cases involved children of both sexes and all ages. Although psychosocial risk factors may be clues for interventions, the rarity of these incidents and the impulsiveness of the act make preventive measures virtually impossible in a city full of high-rise buildings. PMID- 21822994 TI - Laparoscopic cholecystostomy and bile duct lavage for treatment of inspissated bile syndrome: a single-center experience. AB - BACKGROUND: We aim to describe our experience of laparoscopic cholecystostomy and bile duct lavage in the treatment of inspissated bile syndrome. METHODS: Between January 2005 and December 2009, 16 infants with inspissated bile syndrome underwent laparoscopic cholecystostomy and bile duct lavage in our department. They were 7 males and 9 females, aged 40 days to 3 months, with an average of 65+/-23.4 days. A laparoscopic aided cholecystostomy was done. Cholangiography and bile duct lavage were performed during the operation. One week after the operation, bile duct lavage with saline was repeated every 2 to 3 days. According to bilirubin levels and liver function, the tube was kept for 2-4 weeks. RESULTS: The level of bilirubin decreased and liver function was greatly improved after bile duct lavage. Direct bilirubin level, aspartate aminotransferase and gamma-GT were significantly decreased 1-2 months after the operation compared with those before surgery (P<0.05). CONCLUSIONS: The treatment strategy for inspissated bile syndrome with laparoscopic cholecystostomy and biliary duct lavage is feasible and effective. PMID- 21822995 TI - Congenital intrathoracic neuroblastoma presenting as persistent pulmonary hypertension in a newborn. PMID- 21822996 TI - Botryoid Wilms' tumor: report of two cases. AB - BACKGROUND: Botryoid Wilms' tumor is a rare kind of Wilms' tumor. We report two cases of this tumor. METHODS: Case 1, a 2-year-old boy, was admitted with macrohematuria for 5 months. Case 2, a 19-month-old boy, was referred for a palpable abdominal mass. The two cases were checked by 64-row multi-slice spiral CT (MSCT) and scanned with the dynamic contrast enhancement. The masses were excised and pathologically confirmed. RESULTS: In case 1, the mass occurred in the renal pelvis and calyx bilaterally, with heterogeneous density and prominent calcification. By contrast enhanced CT scan, the mass was mildly enhanced. In case 2, the left renal pelvis and ureter were filled with the tumor. Unenhanced scan revealed that the mass was homogeneous and non-calcified. In contrast, the mass was slightly and heterogeneously enhanced. Macroscopically, the mass filled in the pelvicalyceal system and had a botryoid appearance. Microscopically, the typical features of Wilms' tumor with blastemal, epithelial, and stromal components were evident. CONCLUSION: Botryoid Wilms' tumor should be included in the differential diagnosis of tumors in the pelvicalyceal system no matter it is unilateral or bilateral. PMID- 21822997 TI - OCRL1 mutation in a boy with Dent disease, mild mental retardation, but without cataracts. AB - BACKGROUND: Oculocerebrorenal (Lowe) syndrome is an X-linked multisystem disease characterized by renal proximal tubulopathy, mental retardation, and congenital cataracts. We present a 19-year-old boy who was found to have low molecular weight proteinuria, hypercalciuria, mild generalized hyperaminoaciduria and intermittent microscopic hematuria at the age of 3. METHODS: Standard clinical and biochemical examinations and mutational analysis of the CLNC5 and OCRL1 gene were performed for the patient. RESULTS: The patient fulfilled diagnostic criteria for Dent disease, but lacked mutation in CLCN5. Sequencing of candidate genes revealed a mutation in his OCRL1 gene, which encodes for enzyme PIP2 5 phosphatase. The enzyme was not detected by western blot analysis, and decreased activity of the enzyme PIP2 5-phosphatase was observed in cultured skin fibroblasts. The boy had only mild mental retardation, mildly elevated muscle enzymes, but no neurological deficit or congenital cataracts, which are typical for Lowe syndrome. CONCLUSIONS: Children with Dent phenotype who lack CLCN5 mutation should be tested for OCRL1 mutation. OCRL1 mutations may present with mild clinical features and are not necessarily associated with congenital cataracts. PMID- 21822999 TI - Exploring China's western and central county systems performance measured by outcomes framework scores-a cross-sectional survey of routine healthcare data. AB - This study was designed to measure the performance of county health systems in central and western China utilizing routine healthcare data. Drawing on a literature review and expert consultation, the study established a theoretical framework and an indicator system for performance review. Questionnaires were designed and disseminated to collect empirical data on health system performance in four counties of two central and western provinces. Quantitative data were subjected to descriptive statistical analysis through SPSS12.0. Three dimensions were introduced in the performance review framework-health outcomes, financial risk protection and consumer and provider satisfaction. Health outcomes were assessed from four secondary indicators: infant mortality rate; maternal mortality rate; under-5 child mortality rate; and the incidence of Class A and Class B notifiable diseases. Financial risk was assessed using two secondary indicators: the proportion of the cost of inpatient care that was reimbursed under the New Cooperative Medical System (NCMS) insurance scheme, and the rate of NCMS funds utilization. The assessment of satisfaction was made using two secondary indicators: the overall satisfaction of local residents with healthcare services, and the satisfaction of health practitioners at the township and village level. The study indicated better health system performance in the two counties in Chongqing than those in Shanxi. It was concluded that outcome framework scores can fairly reveal performance differences among county health systems in central and western China, and can provide practical evidence for optimizing the operation and inputs of county health systems. Caution needs to be exercised in generalizing such performance outcomes as many factors such as spending and organization that contribute to county health system performance were not included in the study. PMID- 21822998 TI - Different physiology of interferon-alpha/-gamma in models of liver regeneration in the rat. AB - Liver regeneration may take place after liver injury through replication of hepatocytes or hepatic progenitor cells called oval cells. Interferons (IFN) are natural cytokines with pleiotrophic effects including antiviral and antiproliferative actions. No data are yet available on the physiology and cellular source of natural IFNs during liver regeneration. To address this issue, we have analyzed the levels and biologic activities of IFN-alpha/IFN-gamma in two models of partial hepatectomy. After 2/3rd partial hepatectomy (PH), hepatic levels of IFN-alpha and IFN-gamma declined transiently in contrast to a transient increase of the IFN-gamma serum level. After administration of 2 acetylaminofluorene and partial hepatectomy (AAF/PH model), however, both IFN alpha and IFN-gamma expression were up-regulated in regenerating livers. Again, the IFN-gamma serum level was transiently increased. Whereas hepatic IFN-gamma was up-regulated early (day 1-5), but not significantly, in the AAF/PH model, IFN alpha was significantly up-regulated at later time points in parallel to the peak of oval cell proliferation (days 7-9). Biological activity of IFN-alpha was shown by activation of IFN-alpha-specific signal transduction and induction of IFN alpha specific-gene expression. We found a significant infiltration of the liver with inflammatory monocyte-like mononuclear phagocytes (MNP) concomitant to the frequency of oval cells. We localized IFN-alpha production only in MNPs, but not in oval cells. These events were not observed in normal liver regeneration after standard PH. We conclude that IFN-gamma functions as an acute-phase cytokine in both models of liver regeneration and may constitute a systemic component of liver regeneration. IFN-alpha was increased only in the AAF/PH model, and was associated with proliferation of oval cells. However, oval cells seem not to be the source of IFN-alpha. Instead, inflammatory MNP infiltrating AAF/PH-treated livers produce IFN-alpha. These inflammatory MNPs may be involved in the regulation of the oval cell compartment through local expression of cytokines, including IFN-alpha. PMID- 21823000 TI - Urgent need for contraceptive education and services in Chinese unmarried undergraduates: a multi-campus survey. AB - In order to ascertain prevalence rate of premarital sexual intercourse, unintended pregnancy and abortion, and evaluate associated factors of unintended pregnancy among undergraduates from all over China, the representative sample of unmarried undergraduates was obtained by using a multi-stage, stratified, probability cluster design, and data were collected by using a survey questionnaire. 62 326 available responders were gained. 11.6% of them acknowledged having experiences of premarital sexual intercourse (standardized prevalence rate of sexual intercourse was 13.8%). 31.5% of students active in premarital sex acknowledged undergoing unintended pregnancy. 76.2% of pregnant students selected abortion to end it. Of students active in premarital sex, 46.2% used contraception at the first sexual intercourse, 28.2% replied "always" using contraception in sexual intercourse. The rate of using condoms, oral contraceptives (OCs), and withdrawal among students who had used contraception was 52.0%, 31.0%, and 27.2% respectively. "No preparation for sex" (40.3%), "pleasure decrement" (32.1%), "won't-be-pregnancy in occasional sexual intercourse" (30.2%) were their common excuses for using no contraception. The identified risk factors for unintended pregnancy among students active in premarital sex by multivariate analysis were as follows: having no steady lover [having no steady lover vs having a steady lover: odds ratio (OR), 1.875; 95% confidence interval (CI), 1.629-2.158], unaware of the course of conception (unaware vs aware: OR, 2.023; 95% CI, 1.811-2.260), considering abortion not endanger women's physical and mental health (no endangerment vs endangerment: OR, 2.659; 95% CI, 2.265-3.121), nonuse of contraception (never use vs always use: OR, 1.682; 95% CI, 1.295-2.185). Medical students were not less likely to experience an unintended pregnancy than nonmedical students (OR, 1.111; 95% CI, 0.906-1.287). The substantial proportion of unintended pregnancy among undergraduates indicates a need for convenient and targeted contraceptive education and services. PMID- 21823001 TI - Epidemiological features of allergic rhinitis in four major cities in Western China. AB - Allergic rhinitis (AR), with an increasing uptrend of the prevalence in many developed and developing countries, is a global health problem that affects people of all ages and ethnic groups. However, data on the prevalence of self reported AR in western China are rare. This study investigated the epidemiological features of self-reported AR in western China. In the cross sectional, population-based study, a validated questionnaire survey on self reported AR was carried out in 4 major cities in western China by multistage, stratified and cluster sampling, from January to December 2008. The total prevalence rate was 34.3%, with 32.3% (Chongqing), 34.3% (Chengdu), 37.9% (Urumqi), 30.3% (Nanning), respectively. The prevalence presented to increase with age before 30 years old while decrease with age after 30 years old, and the highest prevalence was in 19-30 years group in Chongqing, Chengdu and Nanning which significantly showed "persistent and moderate-severe" type (P<0.0001); In Urumqi, there wasn't a significant increasing or decreasing trend of prevalence rate with age but with an "intermittent and mild"predominance (P<0.0001). There were no distinct sexual differences in prevalence rates in the 4 cities. The morbidity was positively related to monthly average temperature and sunshine (r=0.76645, P=0.0036; r=0.67303, P=0.0165), but negatively associated with relative humidity (r=-0.64391, P=0.0238) in Urumqi. Interestingly, the monthly morbidity was negatively associate with average temperature, sunshine and precipitation in Nanning (r=-0.81997, P=0.0011; r=-0.60787, P=0.0360; r=-0.59443, P=0.0415). Self-reported AR is becoming common in western China with a rapid development in recent years, affecting about three persons out of ten. The climatic factors may have an indirect impact on the prevalence rate through the effects on the local allergens. PMID- 21823002 TI - Protective effect and mechanism of sodium tanshinone II A sulfonate on microcirculatory disturbance of small intestine in rats with sepsis. AB - To explore the protective effect of sodium tanshinone IIA sulfonate (STS) on microcirculatory disturbance of small intestine in rats with sepsis, and the possible mechanism, a rat model of sepsis was induced by cecal ligation and puncture (CLP). Rats were randomly divided into 3 groups: sham operated group (S), sepsis group (CLP) and STS treatment group (STS). STS (1 mg/kg) was slowly injected through the right external jugular vein after CLP. The histopathologic changes in the intestinal tissue and changes of mesenteric microcirculation were observed. The levels of tumor necrosis factor-alpha (TNF-alpha) in the intestinal tissue were determined by using enzyme-linked immunoabsorbent assay (ELISA). The expression of intercellular adhesion molecule-1 (ICAM-1) in the intestinal tissue was detected by using immunohistochemisty and Western blot, that of nuclear factor kappaB (NF-kappaB) and tissue factor (TF) by using Western blot, and the levels of NF-kappaB mRNA expression by using RT-PCR respectively. The microcirculatory disturbance of the intestine was aggravated after CLP. The injury of the intestinal tissues was obviously aggravated in CLP group as compared with S group. The expression levels of NF-kappaB p65, ICAM-1, TF and TNF alpha were upregulaed after CLP (P<0.01). STS post-treatment could ameliorate the microcirculatory disturbance, attenuate the injury of the intestinal tissues induced by CLP, and decrease the levels of NF-kappaB, ICAM-1, TF and TNF-alpha (P<0.01). It is suggested that STS can ameliorate the microcirculatory disturbance of the small intestine in rats with sepsis, and the mechanism may be associated with the inhibition of inflammatory responses and amelioration of coagulation abnormality. PMID- 21823003 TI - Triptolide-induced apoptosis by inactivating nuclear factor-kappa B apoptotic pathway in multiple myeloma in vitro. AB - The effect of triptolide on proliferation and apoptosis of human multiple myeloma RPMI-8226 cells in vitro, as well as the roles of nuclear factor-kappa B (NF kappaB) and IkappaBalpha was investigated. The effect of tritptolide on the growth of RPMI-8226 cells was studied by MTT assay. Apoptosis was detected by Hoechest 33258 staining and Annexin V/PI double staining assay. The expression of NF-kappaB and IkappaBalpha was observed by Western blot and confocal microscopy. The results showed that triptolide inactivated NF-kappaB apoptotic pathway in human multiple myeloma RPMI-8226 cells. Triptolide at nM range induced proliferation inhibition in a dose- and time-dependent manner and apoptosis in a dose-dependent fashion in RPMI-8226 cells. Besides, we observed the inhibition of NF-kappaB /p65 in the nuclear fraction was correlated with the increase in the protein expression of IkappaBalpha in the cytosol. These results suggested that triptolide might exhibit its strong anti-tumor effects via inactivation of NF kappaB/p65 and IkappaBalpha. PMID- 21823004 TI - Effects of SNPs at newly identified lipids loci on blood lipid levels and risk of coronary heart disease in Chinese Han population: a case control study. AB - Associations between "lipid-related" candidate genes, blood lipid concentrations and coronary artery disease (CHD) risk are not clear. We aimed to investigate the effect of three newly identified lipids loci from genome-wide association studies on CHD and blood lipid levels in Chinese Han population. The genotypes of SNPs at three newly identified lipid loci and blood lipids concentrations were examined in 1360 CHD patients and 1360 age- and sex-frequency matched controls from an unrelated Chinese Han population. Allele T of rs16996148 occurred less frequently in CHD patients with the odds ratio (OR) being 0.64 (95% CI 0.50 to 0.81), after adjusting for conventional risk factors and was associated with a 33% decreased CHD risk (P<0.01) comparing with the major allele G. Individuals with GT genotype had the lowest CHD risk. No associations were found between the polymorphisms of other two loci with CHD risk and all three SNPs had no effect on lipid profile in this population. SNP rs16996148 on chromosome 19p13 is significantly associated with lower risk for CHD in Chinese Han population. However, it remains unresolved why these lipid-related loci had significantly less effects than the correspondingly expected effects on blood lipids levels in this population. PMID- 21823005 TI - Everolimus vs. rapamycin for treating diabetic nephropathy in diabetic mouse model. AB - In order to evaluate the effectiveness of everolimus vs. rapamycin in the treatment of diabetic nephropathy, 8-week old diabetic (db/db) mice received everolimus (2 mg/kg every day) or rapamycin (2 mg/kg every day) for 4 weeks or 12 weeks respectively. Blood and 24-h urine samples were collected for biochemical tests. One kidney from each mouse was homogenized for protein analysis and the other was removed for histological analysis. The expression levels of transforming growth factor-beta1 (TGF-beta1)and phospho-p70s6k were detected by using ELISA and Western blot, respectively in the renal tissue as well as in mesengial cell culture samples. Everolimus was significantly more effective than rapamycin in improving indexes of renal function and glomerular hypertrophy, and in decreasing accumulation and expansion of the extracellular matrix. However, everolimus inhibited TGF-beta1 secretion and p70s6k phosphorylation induced by high glucose in vitro less efficiently than rapamycin at the same dose. Everolimus was more effective than rapamycin in preventing diabetic nephropathy in vivo, which may be contributed to the fact that everolimus has better bioavailability and a higher oral absorption rate. PMID- 21823006 TI - Effect of tiotropium bromide on expression of CD(8) (+)CD (25) (+)FoxP (3) (+) regulatory T cells in patients with stable chronic obstructive pulmonary disease. AB - The expression of CD(8) (+)CD(25) (+)FoxP(3) (+) regulatory T cells (CD(8) (+)Tregs) in the peripheral blood of patients with stable chronic obstructive pulmonary disease (COPD), and the effect of muscarinic cholinergic receptor antagonist tiotropium bromide on the expression of CD(8) (+)Tregs were investigated. Twenty-three patients with moderate to severe stable COPD were enrolled in this study. All patients inhaled tiotropium bromide (18 MUg daily) for 3 months. Before and after inhalation of tiotropium bromide, peripheral blood samples were collected from the patients, and T cells were labeled by three-color labeled monoclonal antibodies. Flow cytometry was used to detect the quantity and percentage of CD(8) (+)T cells, CD(8) (+)CD(25) (+)T cells, CD(8) (+)Tregs, CD(4) (+)T cells, CD(4) (+)CD(25) (+)T cells and CD(4) (+)CD(25) (+)FoxP(3) (+) regulatory T cells (CD(4) (+)Tregs) respectively. The percentage of CD(4) (+)T cells was increased from (27.82+/-2.18)% to (35.53+/-1.3)% (t=3.20, P=0.004) in the peripheral blood of patients with stable COPD after inhalation of tiotropium bromide for 3 months, that of CD(4) (+)CD(25) (+)T cells was decreased from (10.03 +/-1.42)% to (4.21 +/-0.65)% (t=3.78, P=0.001), and that of CD(8) (+)Tregs was increased from (8.41 +/-1.68)% to (21.34 +/-4.20)% (t=2.72, P=0.013). At baseline, CD(8) (+)T cells, CD(8) (+)CD(25) (+)T cells and CD(4) (+)Tregs were detectable in the peripheral blood, but no significant changes were observed after treatment. Linear correlation analysis revealed that the difference before and after treatment in CD(4) (+)T cells and CD(4) (+)CD(25) (+)T cells was negatively correlated with the ratio of change in CD(8) (+)Tregs before and after treatment (r=-0.61, P=0.013; r=-0.72, P=0.001 respectively). In the peripheral blood of patients with stable COPD, there was the expression of CD(8) (+)Tregs and CD(4) (+)Tregs. Muscarinic receptor antagonist, tiotropium bromide, can promote the amplification of CD(4) (+)T cells, inhibit the expression of CD(25) (+)T cells, and enhance the expression of CD(8) (+)Tregs. CD(8) (+)Tregs and CD(4) (+)Tregs can be used as new indicators to understand the immune status of patients. They are helpful in judging the treatment efficacy and disease immunophenotype. PMID- 21823007 TI - Upregulated DJ-1 promotes renal tubular EMT by suppressing cytoplasmic PTEN expression and Akt activation. AB - Recently, phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is suggested as a new agent in the fighting against fibrogenesis. In tumor, DJ-1 is identified as a negative regulator of PTEN. But the expression of DJ-1 and the regulation of PTEN in fibrosis are unclear. Renal fibrosis was induced in 5/6 subtotal nephrectomy rat model. Human proximal tubular epithelial cells (HKC) were treated with transforming growth factor-beta 1 (TGF-beta1), or transfected with DJ-1 or PTEN. Confocal microscope was used to investigate the localization of DJ-1 and PTEN. The selective phosphoinositide-3 kinase (PI3K) inhibitor, LY294002, was administered to inhibit PI3K pathway. The DJ-1 and PTEN expression, markers of epithelial-mesenchymal transition (EMT) and Akt phosphorylation were measured by RT-PCR, Western blotting or immunocytochemistry. In vitro, after HKC cells were stimulated with 10 ng/mL TGF-beta1 for 72 h, the expression of DJ-1 was increased, and that of PTEN was decreased. In vivo, the same results were identified in 5/6-nephrectomized rats. In normal HKC cells, most of DJ-1 protein localized in cytoplasm, and little in nucleus. TGF-beta1 upregulated DJ-1 expression in both cytoplasma and nuclei. In contrary, TGF-beta1 emptied cytoplasmic PTEN protein into nucleus. Overexpression of DJ-1 decreased the expression of PTEN, promoted the activation of Akt and the expression of vimentin, and also led to the loss of cytoplasmic PTEN. Contrarily, overexpression of PTEN protected HKC cells from TGF-beta1-induced EMT. In conclusion, DJ-1 is upregulated in renal fibrosis and DJ-1 mediates EMT by suppressing cytoplasmic PTEN expression and Akt activation. PMID- 21823008 TI - Relatively increased number of liver Foxp(3+) regulatory T cells against hepatic lesions in murine lupus. AB - Systemic lupus erythematosus (SLE) is a multiple organ autoimmune disorder, including the liver, but the possible reason in impairment in the liver is still unclear. Our present study assessed alterations of transcription factor Foxp3(+) regulatory T cells (Tregs) and several other immune molecules [programmed cell death 1 and its ligand (PD1 and PD-L1), and interleukin 10 (IL-10) and transform growth factor beta (TGF-beta)] in the liver and other major organs of lupus-prone BXSB mice by flow cytometry, real-time quantitative reverse transcription PCR, and enzyme-linked immunosorbent assay. Results showed that both frequency and number of Foxp3(+) Tregs were dramatically reduced in the thymus, spleen and kidney of the BXSB mice (P<0.05), but those in the liver were kept in nearly normal range, when compared to negative control C57BL/6 mice. In comparison to control mice, the mRNA levels of Foxp3, PD1 and PD-L1 were significantly decreased in the kidneys of BXSB mice (P<0.05), but there was no significant difference in the livers of the BXSB mice (P>0.05). Protein levels of IL-10 and TGF-beta in serum showed no significant difference between BXSB and C57BL/6 mice, but were significantly increased in the kidneys and livers of BXSB mice as compared with those in C57BL/6 mice (P<0.05). These results suggest that reduced Foxp3(+) Tregs are involved in the pathogenesis of SLE in BXSB mice, and relatively higher number of these cells in the livers than in the other target organs could constitute a protective mechanism against hepatic lesions in lupus prone mice, which may provide insights into development of new therapeutic approaches in SLE patients. PMID- 21823009 TI - Effects of variant rs346473 in ARHGAP24 gene on disease progression of HBV infection in Han Chinese population. AB - Host genetic, environmental and viral factors are classified as three categories that determine clinical outcomes of hepatitis B virus (HBV) infection. The objective of this study was to detect the associations between polymorphisms rs346473 and rs346482 in Rho GTPase-activating protein 24 (ARHGAP24) gene and disease progression of HBV infection in Han Chinese population. These two SNPs were found by our DNA pooling using Affymetrix Genome-Wide Human Mapping SNP6.0 Array in HBV carriers, and verified by using TaqMan 7900HT Sequence Detection System with 758 progressed HBV carriers versus 300 asymptomatic HBV carriers (AsC) in a discovery phase and 971 progressed HBV carriers versus 328 AsC in a replication phase. Multivariable logistic regression revealed that individuals with genotype TT at variant rs346473 displayed remarkable correlations with disease progression of HBV infection both in the discovery phase (OR, 2.693; 95% CI, 1.928-3.760; P=6.2*10(-9); additive model) and the replication phase (OR, 1.490; 95% CI, 1.104-2.012; P=9.0*10(-3); additive model). These two SNPs were in strong linkage disequilibrium with D'=0.99 and r (2)=0.951, and haplotype TT disclosed an increased susceptibility to HBV progression (OR, 1.980; 95% CI, 1.538-2.545; P=8.1*10(-8)). These findings suggest that polymorphism rs346473 in the ARHGAP24 gene might be a part of the genetic variants underlying the susceptibility of HBV carriers to disease progression. PMID- 21823010 TI - Synergistic effect of hyperthermia and neferine on reverse multidrug resistance in adriamycin-resistant SGC7901/ADM gastric cancer cells. AB - Multidrug resistance (MDR) plays a major obstacle to successful gastric cancer chemotherapy. The purpose of this study was to investigate the MDR reversal effect and mechanisms of hyperthermia in combination with neferine (Nef) in adriamycin (ADM) resistant human SGC7901/ADM gastric cancer cells. The MDR cells were heated at 42 degrees C and 45 degrees C for 30 min alone or combined with 10 MUg/mL Nef. The cytotoxic effect of ADM was evaluated by MTT assay. Cellular plasma membrane lipid fluidity was detected by fluorescence polarization technique. Intracellular accumulation of ADM was monitored with high performance liquid chromatography. Mdr-1 mRNA, P-glycoprotein (P-gp), gammaH2AX expression and gammaH2AX foci formation were determined by real-time PCR, Western blot and immunocytochemical staining respectively. It was found that different heating methods induced different cytotoxic effects. Water submerged hyperthermia had the strongest cytotoxicity of ADM and Nef combined with hyperthermia had a synergistic cytotoxicity of ADM in the MDR cells. The water submerged hyperthermia increased the cell membrane fluidity. Both water submerged hyperthermia and Nef increased the intracellular accumulation of ADM. The water submerged hyperthermia and Nef down-regulated the expression of mdr-1 mRNA and P gp. The water submerged hyperthermia could damage DNA and increase the gammaH2AX expression of SGC7901/ADM cells. The higher temperature was, the worse effect was. Our results show that combined treatment of hyperthermia with Nef can synergistically reverse MDR in human SGC7901/ADM gastric cancer cells. PMID- 21823011 TI - Suppression of breast cancer proliferation and induction of apoptosis via AKT and ERK1/2 signal transduction pathways by synthetic polypeptide derived from viral macrophage inflammatory protein II. AB - SDF-1alpha, a ligand for the chemokine receptor CXCR4, is well known for mediating the migration of breast cancer cells. In a previous study we demonstrated that a synthetic 21-mer peptide antagonist of CXCR4 (NT21MP) derived from the viral macrophage inflammatory protein II could antagonize tumor growth in vivo by inhibiting cellular proliferation and inducing apoptosis in breast cancer cells. However, the role of SDF-1alpha in the signaling pathways underlying the proliferation of human breast cancer cells and associated signaling pathways and inhibiting signal pathways of NT21MP remained unclear. The present study investigated the mechanism of NT21MP on anti-tumor in breast cancer in vitro. The effect of NT21MP on the viability of cells was determined by the MTT assay. Annexin V-FITC and PI staining was performed to detect early stage apoptosis in SKBR3 cells treated with SDF-1alpha and AMD3100 or NT21MP. Western blotting techniques were used to assay the composition of phosphoproteomics and total proteins present in the SKBR3 breast cancer cells. RT-PCR and Western blotting technique were used to detect the effect of NT21MP and AMD3100 on Bcl-2 and Bax expression. The results indicated that SDF-1alpha prevented apoptosis and promoted the proliferation of SKBR3 human breast cancer cells. As compared with untreated SKBR3 cells, Treatment with SDF-1alpha significantly increased cell viability, and NT21MP abolished the protective effects of SDF-1alpha dose dependently (P<0.05). There was a significant decrease in the percentage of apoptotic cells after SDF-1alpha treatment as compared with control group (2.7%+/ 0.2% vs. 5.7%+/-0.4%, P<0.05). But pretreatment of SKBR3 cells with NT21MP significantly attenuated the antiapoptotic effects of SDF-1alpha as compared with SKBR3 cells without NT21MP pretreatment. The proliferative and anti-apoptotic effects of SDF-1alpha in SKBR3 cells were associated with an increase in AKT and ERK1/2 phosphorylation as well as a decrease in Bax expression and an increase in Bcl-2 expression. These changes in intracellular processes were blocked by NT21MP in a dose-dependent manner(P<0.05). In conclusion, NT21MP efficiently inhibits SDF-1alpha-induced proliferation and antiapoptosis in SKBR3 cells by reducing the levels of phosphorylated AKT and ERK1/2, as well as decreasing the ratio of expression of Bcl-2 relative to Bax. PMID- 21823012 TI - Effect of omega-3 polyunsaturated fatty acid on toll-like receptors in patients with severe multiple trauma. AB - This study examined the effects of omega-3 polyunsaturated fatty acid (omega 3PUFA) on the expression of toll-like receptor 2 (TLR2), toll-like receptor 4 (TLR4) and some related inflammatory factors in peripheral blood mononuclear cells (PBMCs) of patients with early-stage severe multiple trauma. Thirty-two patients who were admitted to the Department of Traumatic Surgery, Tongji Hospital (Wuhan, China) between May 2010 and November 2010, and diagnosed as having severe multiple trauma with a injury severity score (ISS) no less than 16, were enrolled in the study and divided into two groups at random (n=16 in each): omega-3PUFA group and control group in which routine parenteral nutrition supplemented with omega-3PUFA or not was administered to the patients in two groups for consecutive 7 days. Peripheral blood from these patients was collected within 2 h of admission (day 0), and 1, 3, 5 and 7 days after the nutritional support. PBMCs were isolated and used for detection of the mRNA and protein expression of TLR2 and TLR4 by using real-time PCR and flow cytometry respectively, the levels of NF-kappaB by quantum dots-based immunofluorescence assay, the levels of TNF-alpha, IL-2, IL-6 and COX-2 by ELISA, respectively. The results showed that the mRNA and protein expression of TLR2 and TLR4 in PBMCs was significantly lower in omega-3PUFA group than in control group 5 and 7 days after nutrition support (both P<0.05). The levels of TNF-alpha, IL-2, IL-6 and COX-2 were found to be substantially decreased in PBMCs in omega-3PUFA group as compared with control group at 5th and 7th day (P<0.05 for all). It was concluded that omega-3PUFA can remarkably decrease the expression of TLR2, TLR4 and some related inflammatory factors in NF-kappaB signaling pathway in PBMCs of patients with severe multiple trauma, which suggests that omega-3PUFA may suppress the excessive inflammatory response meditated by the TLRs/NF-kappaB signaling pathway. PMID- 21823013 TI - Inhibitory effects of miR-146b-5p on cell migration and invasion of pancreatic cancer by targeting MMP16. AB - Previous studies have shown that miRNAs participate in a wide range of biological functions and play important roles in various human diseases including cancer. We found miR-146b-5p significantly dysregulated in human pancreatic cancer cells by qRT-PCR. To demonstrate its function and regulation mechanism, we overexpressed miR-146-5p by transfecting the mimics. Our data showed that miR-146b-5p overexpression significantly reduced the abilities of migration and invasion of MIA PaCa-2 pancreatic cancer cells. Furthermore, we found that matrix metalloproteinase 16 (MMP16) was a downstream target of miR-146b-5p by dual luciferase reporter assay. Altogether, our findings suggest that miR-146b-5p may be involved in pancreatic cancer cell migration and invasion by targeting MMP16, and miR-146b-5p may be a potential therapeutic target for the pancreatic cancer. PMID- 21823014 TI - Different optical properties between human hepatocellular carcinoma tissues and non-tumorous hepatic tissues in vitro. AB - There has been an ongoing search for clinically acceptable methods for the accurate, efficient and simple diagnosis and prognosis of hepatocellular carcinoma (HCC). Optical spectroscopy is a technique with potential clinical applications to diagnose cancer diseases. The purpose of this study was to obtain the optical properties of HCC tissues and non-tumorous hepatic tissues and identify the difference between them. A total of 55 tissue samples (HCC tissue, n=38; non-tumorous hepatic tissue, n=17) were surgically resected from patients with HCC. The optical parameters were measured in 10-nm steps using single integrating-sphere system in the wavelength range of 400 to 1800 nm. It was found that the optical properties and their differences varied with the wavelength for the HCC tissue and the non-tumorous hepatic tissue in the entire wavelength range of research. The absorption coefficient of the HCC tissue (1.48+/-0.99, 1.46+/ 0.88, 0.86+/-0.61, 2.15+/-0.53, 0.54+/-0.10, 0.79+/-0.15 mm(-1)) was significantly lower than that of the non-tumorous hepatic tissue (2.79+/-1.73, 3.13+/-1.47, 3.06+/-2.79, 2.57+/-0.55, 0.62+/-0.10, 0.93+/-0.16 mm(-1)) at wavelengths of 400, 410, 450, 1450, 1660 and 1800 nm, respectively (P<0.05). The reduced scattering coefficient of HCC tissue (5.28+/-1.70, 4.91+/-1.54, 1.26+/ 0.35 mm(-1)) and non-tumorous hepatic tissue (8.14+/-3.70, 9.27+/-3.08, 2.55+/ 0.57 mm(-1)) was significantly different at 460, 500 and 1800 nm respectively (P<0.05). These results show different pathologic liver tissues have different optical properties. It provides a better understanding of the relationship between optical parameters and physiological characteristics in human liver tissues. And it would be very useful for developing a non-invasive, real-time, simple and efficient way for medical management of HCC in the future. PMID- 21823016 TI - Construction of eukaryotic expression plasmid of hTGF-beta3 and its inducing effect on differentiation of precartilaginous stem cells into chondroblasts. AB - This study examined the construction of eukaryotic expression plasmid of human transforming growth factor-beta3 (hTGF-beta3) and its inducing effect on the differentiation of precartilaginous stem cells (PSCs) into chondroblasts. hTGF beta3 gene was amplified by using polymerase chain reaction (PCR) and then inserted into the eukaryotic expression plasmid pcDNA3.1 to construct the eukaryotic expression plasmid pcDNA3.1(+)-hTGF-beta3. Rat PSCs were isolated and purified by employing an immunomagnetic cell sorting system. pcDNA3.1(+)-hTGF beta3 was transfected into purified PSCs with the use of linear polyamines. The expression of TGF-beta3 and cartilage-specific extracellular matrix (ECM) components was detected after transfection by real-time quantitative PCR, ELISA, immunochemistry and Western blotting, respectively. The results showed that the eukaryotic expression plasmid pcDNA3.1(+)-hTGF-beta3 was successfully established as identified by enzyme digestion and DNA sequencing. Real-time quantitative PCR and ELISA revealed that hTGF-beta3 was strongly expressed in pcDNA3.1(+)-hTGF beta3-transfected PSCs. Real-time quantitative PCR, immunochemistry and Western blotting showed that the cartilage-specific ECM markers, i.e., cartilage oligomeric matrix protein (COMP), Aggrecan, collagen type X and II were intensely expressed in the pcDNA3.1(+)-hTGF-beta3-transfected cells. It was concluded that hTGF-beta3 could be stably expressed in pcDNA3.1(+)-hTGF-beta3-transfected PSCs and induce the differentiation of PSCs into chondroblasts. PMID- 21823015 TI - Association of expression of Leucine-rich repeats and immunoglobulin-like domains 2 gene with invasiveness of pituitary adenoma. AB - The Leucine-rich repeats and immunoglobulin-like domains-2 (LRIG2) gene expression in pituitary adenoma and its correlation with tumor invasiveness were studied. The expression of LRIG2 mRNA and protein in human pituitary adenoma obtained surgically was detected by RT-PCR (39 cases) and immunohistochemical staining (30 cases). It was found that LRIG2 was mostly localized at the nucleus of the pituitary adenoma cells. Its expression was significantly higher in the invasive cases than in the non-invasive cases. LRIG2 protein was positive in 14 cases out of 21 cases of invasive adenoma, but only 2 cases were positive in 9 cases of non-invasive adenoma. The positive expression rate of LRIG2 mRNA was 91.3% in invasive cases (total 23 cases) and 62.5% in non-invasive cases (total 16 cases), respectively. LRIG2 gene is overexpressed in invasive pituitary adenoma. It may play an important role in pituitary adenoma invasiveness and further studies are necessary to elucidate the mechanism under this phenomenon. PMID- 21823017 TI - Anti-tumor activity of curcumin against androgen-independent prostate cancer cells via inhibition of NF-kappaB and AP-1 pathway in vitro. AB - The anti-tumor activity of curcumin against androgen-independent prostate cancer cells in vitro and the possible mechanism were investigated. After curcumin treatment, the effect of curcumin on the proliferation of prostate cancer PC-3 cells was assessed by CFSE staining. Flow cytometery (FCM) was performed to analyze the cell cycle and the induction of apoptosis of tumor cells. A luciferase reporter gene assay was used to determine the effects of curcumin on the activities of intracellular NF-kappaB and AP-1 signaling pathways. The results showed curcumin could effectively inhibit the proliferation of PC-3 cells in vitro (P<0.05). Cells were arrested at G(2)/M phase. After curcumin treatment, the percentage of apoptotic cells was significantly higher than in control group (P<0.05). The results of the luciferase assay revealed that curcumin selectively inhibited the activities of the NF-kappaB and AP-1 signaling pathways in PC-3 cells significantly. It was suggested that curcumin could exert anti-tumor activity against androgen-independent prostate cancer cells in vitro by inhibiting cellular proliferation and inducing apoptosis, which was probably contributed to the inhibition of transcription factors NF-kappaB and AP-1. PMID- 21823018 TI - Association of controlled ovarian hyperstimulation treatment with down-regulation of key regulators involved in embryonic implantation in mice. AB - The debate exists whether or not gonadotropin-releasing hormone (GnRH) analogs used in controlled ovarian hyperstimulation (COH) impair endometrial receptivity. Homeobox A11 (Hoxa11), Meis homeobox 1 (Meis1), cadherin 1 (Cdh1), and catenin beta 1 (Ctnnb1) are well known to be involved in successful implantation. In this study, the endometrial expression of Hoxa11, Meis1, Cdh1, and Ctnnb1 during the peri-implantation period was investigated in an in vitro fertilization (IVF) mouse model by real-time RT-PCR and Western blot to evaluate the relationship between Hoxa11, Meis1, Cdh1, and Ctnnb1 expression and the impact of the COH on endometrial receptivity. The mimic COH protocols included GnRH agonist plus human menopausal gonadotropin (HMG) (GnRH agonist group), GnRH antagonist plus HMG (GnRH antagonist group), and HMG alone (HMG group). The expression levels of Hoxa11, Meis1, Cdh1, and Ctnnb1 mRNA and protein were decreased in all of the COH groups. The expression levels of Hoxa11 and Ctnnb1 were the lowest in the GnRH agonist group, and those of Meis1 and Cdh1 were lower in the GnRH analog groups than the HMG group. There were positive correlations between the expression of Hoxa11 and Ctnnb1, as well as the expression of Meis1 and Cdh1 among all the groups. In conclusion, the COH protocols, particularly with GnRH analogs, suppressed Hoxa11, Meis1, Ctnnb1 and Cdh1 expression, in mouse endometrium during the peri-implantation period. Our data reveal a novel molecular mechanism by which the COH protocols might impair endometrial receptivity. PMID- 21823019 TI - miR-125b confers resistance of ovarian cancer cells to cisplatin by targeting pro apoptotic Bcl-2 antagonist killer 1. AB - Chemotherapy is the preferred therapeutic approach for advanced ovarian cancer, but a successful long-term treatment is prevented by the development of drug resistance. Recent works have underlined the involvement of non-coding RNAs, microRNAs (miRNAs) in cancer development, with several conjectures regarding their possible involvement in the evolution of drug resistance. This study is to investigate the promoting effects and mechanism of miR-125b involved in the development of chemoresistance in ovarian cancer. The different expression of miR 125b in cisplatin-sensitive ovarian cancer cell line (OV2008) and its resistant variant (C13*) was identified by real-time PCR. An in vitro cytotoxicity assay and apoptosis assay using CCK-8 assay and flow cytometry, were carried out to detect the effect of miR-125b and Bak1 on cisplatin resistance of cells. Real time PCR, Western blotting and luciferase reporter assay were used to detect whether Bak1 is a target of miR-125b. As compared with OV2008 cells, the expression levels of miR-125b in C13* cells were increased. It was found that the up-regulation of microRNA-125b caused a marked inhibition of cisplatin-induced cytotoxicity and apoptosis and a subsequent increase in the resistance to cisplatin in OV2008 and C13* cells. Moreover, Bak1 was a direct target of miR 125b, and down-regulation of Bak1 suppressed cisplatin-induced apoptosis and led to an increased resistance to cisplatin. Our study indicates that miR-125b has a significantly promoting effect on chemoresistance of C13* cells and up-regulation of miR-125b expression contributes to cisplatin resistance through suppression of Bak1 expression. This finding has important implications in the development of targeted therapeutics for overcoming cisplatin resistance in ovarian cancer. PMID- 21823020 TI - TLR9 expression and its role in chemosensitivity to DDP in human cervical cancer cells in vitro. AB - Inflammation and infection play an important role in the pathogenesis of many cancers. Toll-like receptors (TLRs) are a class of pattern recognition receptors that recognize conserved components of microbes and trigger the immune response against invading microorganisms. Toll-like receptor 9 (TLR9) recognizes non methylated cytosine-phosphateguanosine (CpG) DNA sequences which are the surrogate for viral DNA. TLR9 may react to tumor development and progression during chronic inflammation that involves the tumor microenvironment. In order to study the role of TLR9 in cervical cancer, we analyzed the TLR9 expression in different types of HPV infection cervical cancer cells. Then we detected if CpG sequences influenced the TLR9 expression and the sensitivity to cisplatin (DDP) of these cervical cancer cells in vitro. The expression of TLR9 mRNA and protein in SiHa, Hela and C33A cells was detected by RT-PCR and Western blotting. Real time PCR was used to examine the TLR9 expression changes induced by CpG. Chemosensitivity of the cervical cancer cells to cisplatin (DDP) was measured by MTT. It was observed that the expression of TLR9 mRNA and protein was increased gradually in SiHa (HPV16+), Hela (HPV18+) and C33A (HPV-) cells. Low doses of CpG increased the TLR9 expression only in C33A (HPV-) cells, but not in SiHa (HPV16+) and Hela (HPV18+) cells. Furthermore, low dose of CpG significantly increased the sensitivity of C33A (HPV-) cells, but not that of SiHa (HPV16+) and Hela (HPV18+) cells. These results indicated that TLR9 may serve as a protective agent in HPV negative cervical cancer cells. It was concluded that TLR9 could improve the sensitivity to DDP in HPV negative cervical cancer cells and might represent a potential therapeutic option in clinical practice. PMID- 21823021 TI - Effects of rapamycin on expression of Bcl-2 and Bax in human lens epithelial cells and cell cycle in rats. AB - The effects of rapamycin on the expression of Bcl-2 and Bax protein in in vitro cultured human lens epithelial cells (LECs) and cell cycle were investigated in order to provide the theoretical basis for the development of new inhibitory drugs for clinical prevention and treatment of after-cataract. The cultured LECs of second and third passages were collected and treated with rapamycin. The LECs were transferred into 96-well culture plates and divided into 6 groups, and each group was set to have 8 duplicate wells. In the negative control group, the LECs were given culture medium only, and in the blank control group, only culture medium was given. In the four rapamycin-treated groups, different concentrations (20, 40, 60 and 80 ng/mL) of rapamycin were given. After treatment for 24, 48 and 72 h, the absorbance (A) values in each well were determined by MTT assay. The cell cycles of all groups were detected by using flow cytometry. Real-time fluorescent quantitative polymerase chain reaction (RFQ-PCR) and Western blot were used to detect the mRNA and protein expression of Bcl-2 and Bax respectively. MTT assay showed that rapamycin could inhibit proliferation of LECs in a time- and dose-dependent manner. Flow cytometry revealed that rapamycin could block the conversion of LECs from G1 phase to S phase, resulting in the increase of cells in G(1) phase and the decrease of the cells in S phase. RFQ-PCR indicated that rapamycin could down-regulate the expression of Bcl-2 mRNA, but up regulate the expression of Bax mRNA, suggesting it could induce apoptosis of LECs. Western blot demonstrated that rapamycin could suppress the expression of Bcl-2 protein, but promote the expression of Bax protein. It is concluded that rapamycin could inhibit proliferation of LECs probably not only by blocking the progression of cell cycle, but also by promoting the induction of apoptosis. PMID- 21823022 TI - Correlation of vascular endothelial growth factor and CD105-microvascular density in primary pterygium. AB - The relationship between the expression of vascular endothelial growth factor (VEGF) and microvascular density (MVD) marked by CD105 (CD105-MVD), and that between CD105-MVD and the clinicopathological characteristics of primary pterygium were investigated. The streptavidin-biotin complex (SABC) immunohistochemical staining in paraffin-embedded tissues was used to detect the expression of VEGF in 23 cases of primary pterygia and 7 normal conjunctival specimens. The antibody against CD105 was used to display vascular endothelial cells, and MVD was examined by counting the CD105-positive vascular endothelial cells. The correlations of VEGF and CD105-MVD, and those of CD105-MVD and clinicopathological data were analyzed by using SPSS 12.0. The expression of VEGF was significantly increased in epithelia (P=0.000), endothelia and stroma cells (P=0.005) in primary pterygia as compared with normal conjunctivae. The CD105-MVD in pterygia (mean 19.22+/-6.68) was higher than that in normal conjunctivae (mean 4.00+/-2.15, P=0.000). MVD in pterygia was significantly associated with the Tan classification (P=0.000) and the VEGF expression level in the stroma (P=0.020), but not with sex (P=0.61), age (P=0.150) or the VEGF expression level in the epithelia (P=0.518). Our results suggest that over-expression of VEGF and high CD105-MVD in primary pterygium may contribute to the progression by increasing angiogenesis and growth of primary pterygium. PMID- 21823023 TI - Inhibition of melanoma cell proliferation by targeting Wnt/beta-catenin pathway through Sox4 RNA interference. AB - The effect of siRNA-mediated Sox4 gene silencing on Wnt/beta-catenin signaling pathway of human malignant melanoma cell line A375 was investigated. Two types of dsRNA targeting Sox4 were constructed and transfected into A375 cells, and untreated cells and cells transfected with scramble RNA were used as blank control and negative control respectively. The expression levels of mRNA and protein of Sox4, Wnt3a, beta-catenin and Wnt/beta-catenin signaling target gene Survivin were detected after real-time PCR and Western blot respectively. MTT assay was used to measure cell proliferation after Sox4 knockdown. beta catenin/TCF transcription reporter assay was used for assessing Wnt/beta-catenin signaling pathway activity. Our results showed that the two types of Sox4 siRNA were transfected into A375 cells successfully. As compared with untreated cells, Sox4 siRNAs had no significant influence on Wnt3a expression, and Sox4 siRNAs led to the decrease of beta-catenin at protein level. Wnt/beta-catenin signaling pathway activity was inhibited significantly. As a target of Wnt/beta-catenin signaling, Survivin was decreased at both mRNA and protein levels, and cell proliferation was attenuated. Our study suggests that Sox4 may play an important role in Wnt/beta-catenin signaling pathway in human malignant melanoma cells by regulating beta-catenin protein level, indicating that Sox4 is involved in the progression of malignant melanoma through Wnt/beta-catenin signaling pathway. PMID- 21823024 TI - Molecular genetic analysis of partial 9p trisomy in two Chinese families with mental retardation and facial anomaly. AB - Mental retardation is defined by significant limitations in intellectual function and adaptive behavior that occur before 18 years of age. Many chromosomal diseases come with mental retardation. We reported two Chinese families with partial trisomy 9p and other chromosome partial monosomy, clinical features of mental retardation and mild facial and pinkie anomalies. In the family 1, we showed that the proband carried a trisomy 9p21.3->pter and monosomy 21q22.3->qter by using fluorescence in situ hybridization analysis. Molecular genetic analysis defined the precise breakpoint on chromosome 9p between markers D9S1846 and D9S171, an interval of about 2.9 Mb on 9p21.3, and the breakpoint on chromosome 21q between markers D21S1897 and D21S1446, a region of about 1.5 Mb on 21q22.3. In the family 2, a patient with trisomy 9p21.3->pter and monosomy 5p15.33->pter, and a de novo maternal balanced translocation between chromosomes 5 and 9 was identified in his mother. Cytogenetic and molecular genetic analysis defined the precise breakpoints on chromosome 9p21.3 and chromosome 5p15.33. Further clinical investigation found that any individual had no refractoriness eczema disease except the proband in this family. These results further implicate that trisomy 9p is associated with mental retardation, and that there may be key gene duplication on chromosome 9p21.3->9pter responsible for mental retardation and mild facial anomaly. This result has been applied successfully in prenatal diagnosis of the second family. PMID- 21823025 TI - Investigation on positive correlation of increased brain iron deposition with cognitive impairment in Alzheimer disease by using quantitative MR R2' mapping. AB - Brain iron deposition has been proposed to play an important role in the pathophysiology of Alzheimer disease (AD). The aim of this study was to investigate the correlation of brain iron accumulation with the severity of cognitive impairment in patients with AD by using quantitative MR relaxation rate R2' measurements. Fifteen patients with AD, 15 age- and sex-matched healthy controls, and 30 healthy volunteers underwent 1.5T MR multi-echo T2 mapping and T2* mapping for the measurement of transverse relaxation rate R2' (R2'=R2*-R2). We statistically analyzed the R2' and iron concentrations of bilateral hippocampus (HP), parietal cortex (PC), frontal white matter (FWM), putamen (PU), caudate nucleus (CN), thalamus (TH), red nucleus (RN), substantia nigra (SN), and dentate nucleus (DN) of the cerebellum for the correlation with the severity of dementia. Two-tailed t-test, Student-Newman-Keuls test (ANOVA) and linear correlation test were used for statistical analysis. In 30 healthy volunteers, the R2' values of bilateral SN, RN, PU, CN, globus pallidus (GP), TH, and FWM were measured. The correlation with the postmortem iron concentration in normal adults was analyzed in order to establish a formula on the relationship between regional R2' and brain iron concentration. The iron concentration of regions of interest (ROI) in AD patients and controls was calculated by this formula and its correlation with the severity of AD was analyzed. Regional R2' was positively correlated with regional brain iron concentration in normal adults (r=0.977, P<0.01). Iron concentrations in bilateral HP, PC, PU, CN, and DN of patients with AD were significantly higher than those of the controls (P<0.05); Moreover, the brain iron concentrations, especially in parietal cortex and hippocampus at the early stage of AD, were positively correlated with the severity of patients' cognitive impairment (P<0.05). The higher the R2' and iron concentrations were, the more severe the cognitive impairment was. Regional R2' and iron concentration in parietal cortex and hippocampus were positively correlated with the severity of AD patients' cognitive impairment, indicating that it may be used as a biomarker to evaluate the progression of AD. PMID- 21823026 TI - Intravenous leiomyomatosis with right heart involvement-a report of 4 cases and literature review. AB - Intravenous leiomyomatosis (IVL) is a rare benign neoplasm which originates from the smooth muscle cells and is usually confined to the pelvic venous system. Rarely, intracaval and intracardiac extension has been described. Death can occur as a result of intracardiac involvement. We reported 4 cases of IVL with right heart involvement (intracardiac leiomyomatosis, ICL). Three of them suffered recurrent sudden syncope, and the other one was totally asymptomatic. All of them were successfully treated through one-stage operation under extracorporeal circulation. PMID- 21823027 TI - Deep vein thrombosis: related to anemophilous pollen? AB - The etiology of deep vein thrombosis (DVT) is still not elucidated nowadays. Based on the accordance between DVT incidence and the anemophilous pollen concentration in the air, we proposed the hypothesis that allergic reaction induced by anemophilous pollen may cause "idiopathic" DVT, and proinflammatory factors may play an important role in the thrombosis process. PMID- 21823028 TI - JAK-mutant myeloproliferative neoplasms. AB - Although the Janus family of kinases (JAK1, JAK2, JAK3, and TYK2) has been extensively characterized and investigated, the role of Janus kinase activation in the pathogenesis and therapy of human malignancies was not fully appreciated until recently when multiple studies identified a recurrent somatic mutation in the JAK2 tyrosine kinase (JAK2V617F) in the majority of patients with BCR-ABL negative myeloproliferative neoplasms (MPN), polycythemia vera, essential thrombocytosis, and primary myelofibrosis. Other mutations that activate the JAK STAT signaling pathway have since been identified in JAK2V617F-negative MPN patients and in a subset of patients with acute myeloid leukemia and acute lymphoid leukemia. In addition, dysregulated JAK-STAT signaling has been implicated in the pathogenesis of a spectrum of epithelial neoplasms. In this chapter, we will review the recent studies that identified genetic alterations that activate JAK signaling in different malignancies, and discuss the recent efforts aimed at developing small-molecule inhibitors of JAK kinase activity for the treatment of MPNs and other malignancies. PMID- 21823029 TI - Drug efficacy testing in mice. AB - The traditional path of drug development passes from in vitro screening and response assessment to validation of drug efficacy in cell line xenografts. While xenografts have their merits, historically, more often than not, they have not served as an accurate predictor of drug efficacy in humans. The refinement and increased availability of genetically engineered mouse models (GEMMs) of cancer has made GEMMs an attractive avenue for the preclinical testing of therapeutic agents. The histopathologic and genetic resemblance of GEMMs to human cancer are an important measure to evaluate their suitability for pre-clinical studies and a number of studies using kinase inhibitors have now been performed in GEMMs. We have highlighted several of the salient advantages and challenges associated with GEMM studies. Well-characterized GEM models of human cancer should aide in the prioritization of both established and novel therapeutics. PMID- 21823030 TI - The influence of silicon substitution on the properties of spherical- and whisker like biphasic alpha-calcium-phosphate/hydroxyapatite particles. AB - In this work, the influence of the morphology of hydroxyapatite particles on silicon substitution through hydrothermal synthesis performed under the same conditions was investigated. Spherical- and whisker-like hydroxyapatite particles were obtained starting from calcium-nitrate, sodium dihydrogen phosphate, disodium-ethylenediaminetetraacetic acid and urea (used only for the synthesis of whisker-like particles) dissolved in aqueous solutions. Silicon was introduced into the solution using tetraethylorthosilicate. X-ray diffraction, infrared spectroscopy, scanning electron microscopy, energy-dispersive X-ray spectroscopy and transmission electron microscopy indicate that silicon doping induce different phase compositions and bioactivity of spherical- and whisker-like hydroxyapatite particles obtained under the same hydrothermal conditions. Silicon substituted, spherical hydroxyapatites particles showed greater phase transformation to silicon-substituted alpha- calcium-phosphate compared with whiskers-like hydroxyapatite particles synthesized with the same amount of added silicon. Metabolic activity assay performed with SaOs2 osteosarcoma cells showed better biocompatibility of annealed biphasic spherical-like particles compared with annealed whiskerlike particles while dried spherical-like particles induce high cytotoxicity effect. PMID- 21823031 TI - Epitaxial growth of the zinc oxide nanorods, their characterization and in vitro biocompatibility studies. AB - Here, we have synthesized Zinc Oxide (ZnO) nanorods at room temperature using zinc acetate and hexamethylenetetramine as precursors followed by characterization using X-ray diffraction (XRD), fourier transform infra red spectroscopy, scanning electron microscopy (SEM) and transmission electron microscopy. The growth of the synthesized ZnO was found to be very close to its hexagonal nature, which is confirmed by XRD. The nanorods were grown perpendicular to the long-axis and grew along the [001] direction, which is the nature of ZnO growth. The morphology of the synthesized ZnO nanorods was also confirmed by SEM. The size of the nanorod was estimated to be around 20-25 nm in diameter and approximately 50-60 nm in length. Our biocompatibility studies using synthesized ZnO showed no significant dose- or time-dependent increase in the formation of free radicals, accumulation of peroxidative products, antioxidant depletion or loss of cell viability on lung epithelial cells. PMID- 21823032 TI - A case of cor triatriatum with an abnormal P wave: the pacemaker action from the specialized tissue in the abnormal septum. AB - A boy presented with an abnormal P wave shown on an electrocardiogram (ECG) checkup at school. An echocardiogram and contrast-enhanced computed tomography (CT) showed cor triatriatum with a slit-like opening between the accessory chamber and the left atrium located along the interatrial septum. The boy underwent open heart surgery for excision of the anomalous membrane, and a postoperative ECG showed normal P waves. The excised tissue was examined immnunohistopathologically using antihyperpolarization-activated cyclic nucleotide-gated potassium channel 4 (HCN4) antibody and other staining. The authors confirmed the existence of cells positive to HCN4, indicating that they were sinoatrial node cells or at least cells with electrical automaticity. PMID- 21823033 TI - Cardiac-related varicella mortality in childhood: a literature review with clinical experience. AB - Among unvaccinated populations, primary varicella zoster virus (VZV) infection results in a minor childhood illness for the majority of individuals. Mortality is rare, and fatalities associated with cardiac complications are exceptional. In a population where routine VZV vaccination is not practised, we report a death in a previously healthy child secondary to VZV myocarditis. A literature review of cardiac-related VZV mortality in childhood is included. This identified a further 13 cases where death was associated with or attributable to, direct involvement of the myocardium or conducting system with what is frequently considered a benign childhood illness. PMID- 21823034 TI - NT-proBNP as a biomarker for the assessment of a potential cardiovascular drug induced liability in beagle dogs. AB - The amino-terminal pro-brain natriuretic peptide (NT-proBNP) is released into the plasma predominantly from ventricular cardiomyocytes, particularly in patients with chronic cardiac diseases, although small amounts are detectable in the plasma of healthy subjects. While NT-proBNP has been widely exploited in human medicine, limited literature is available related to its characterization in veterinary medicine (e.g., correlation with damage and specificity) and, particularly, in the context of preclinical drug safety assessment. This paper describes the analytical performance characteristics and the biological variability of NT-proBNP in male beagle dogs by using a commercially available enzyme-linked immunosorbent assay. Male beagle dogs were treated with Casopitant, an NK1 receptor antagonist under development for depression and anxiety, which, when administered chronically to dogs, caused cardiac toxicity. Heart weight increase, myocardial necrosis, degeneration, and inflammation associated with high serum levels of cardiac troponin I characterized the end stage pathology observed in dogs treated orally at 40 mg/kg for 39 weeks. Based on these data, ad hoc studies were designed in order to evaluate the possible relationship between NT-proBNP serum levels and both standard toxicology endpoints, such as the organ weight and histology, as well as nonstandard endpoints such as macroscopic morphometry and echocardiography. Early changes of NT-proBNP serum levels were observed following 2 weeks of treatment onward, preceding most, if not all of the anatomical and functional changes. The results obtained demonstrate that NT proBNP acts as an early biomarker of cardiac changes, representing a sensitive and predictive marker of drug-induced cardiac liability. PMID- 21823035 TI - Responsiveness of the Oswestry Disability Index and the Roland Morris Disability Questionnaire in Italian subjects with sub-acute and chronic low back pain. AB - INTRODUCTION: An ability to assess longitudinal changes in health status is crucial for the outcome measures used in treatment efficacy trials. The aim of this study was to verify the responsiveness of the Italian versions of the Oswestry Disability Index (ODI) and the Roland Morris Disability Questionnaire (RMDQ) in subjects with subacute or chronic low back pain (LBP). MATERIAL AND METHODS: At the beginning and end of an 8 week rehabilitation programme, 179 patients completed a booklet containing the ODI, the RMDQ, a 0-10 numerical rating scale (NRS), and the 36-item Short-Form Health Survey (SF-36). A global perception of change scale was also completed at the end of the programme, and collapsed to produce a dichotomous outcome (i.e. improved vs. not improved). Responsiveness was assessed by means of distribution methods [minimum detectable change (MDC); effect size (ES); standardised response mean (SRM)] and anchor based methods (ROC curves). RESULTS: The MDC for the ODI and RMDQ was, respectively, 13.67 and 4.87; the ES was 0.53 and 0.68; and the SRM was 0.80 and 0.81. ROC analysis revealed an area under the curve of 0.71 for the ODI and 0.64 for the RMDQ, thus indicating discriminating capacity; the best cut-off point for the dichotomous outcome was 9.5 for the ODI (sensitivity 76% and specificity 63%) and 2.5 for the RMDQ (sensitivity 62% and specificity 55%). These estimates were comparable between the subacute and chronic subjects. Both the ODI and the RMDQ moderately correlated with the SF-36 and NRS (Spearman's and Pearson's correlation coefficients of >0.30). CONCLUSION: The Italian ODI and RMDQ proved to be sensitive in detecting clinical changes after conservative treatment for subacute and chronic LBP. Our findings are consistent with those published in the literature, thus allowing cross-cultural comparisons and stimulating cross national studies. PMID- 21823036 TI - Modified technique for C1-2 screw-rod fixation and fusion using autogenous bicortical iliac crest graft. AB - INTRODUCTION: Various techniques have been described for posterior atlantoaxial fusion. Sublaminar passage of the wire/cable is cumbersome with a risk of spinal cord injury. Packing morselized bone grafts into the C1-2 facet joints may be difficult and it may cause massive bleeding and neuropathic pain or posterior scalp numbness postoperatively. We introduce a modified method by using C1-2 screw-rod fixation (SRF) to compress a structural iliac bone graft between the posterior elements of C1 and C2 without supplemental wiring construct. MATERIALS AND METHODS: From December 2006 to May 2009, 35 consecutive patients with atlantoaxial instability treated by this method were reviewed retrospectively. Clinical and radiographic history was recorded. Patients with neck pain had relieved significantly after surgery and the neurologic status was also improved greatly. Thirty-three (94.3%) patients gained bony fusion at 3 months postoperatively. No vertebral artery and spinal cord injuries were noted. There was no instrumentation failure during the observation period. CONCLUSION: We conclude that the C1-2 SRF with construct-compression structural bone grafting can be used for C1-2 fusion with relatively simple performance and less time consuming in selected cases. PMID- 21823037 TI - Effects of transforming growth factor-beta (TGF-beta1) on satellite cell activation and survival during oxidative stress. AB - The regulation of adult skeletal muscle repair and regeneration is largely due to the contribution of resident adult myogenic precursor cells called satellite cells. The events preceding their participation in muscle repair include activation (exit from quiescence), proliferation, and differentiation. This study examined the effects of transforming growth factor-beta (TGF-beta1) on satellite cell activation, determined whether TGF-beta1 could maintain quiescence in the presence of hepatocyte growth factor (HGF), and whether the regulation of satellite cell activation with TGF-beta1 improves the ability of satellite cells to withstand oxidative stress. The addition of TGF-beta1 during early satellite cell activation (0-48 h) or during the proliferative phase (48-96 h) maintained and induced satellite cell quiescence, respectively, as determined by myogenic differentiation (MyoD) protein expression. TGF-beta1 also attenuated satellite cell activation when used with HGF. Finally, the role of quiescence in protecting cells against oxidative stress was examined. TGF-beta1 treatment and the low pH satellite cell preparation procedure, a technique that forestalls spontaneous activation in vitro, both enhanced survival of cultured satellite cells following hydrogen peroxide treatment. These findings indicate that TGF-beta1 is capable of maintaining and inducing satellite cell quiescence and suggest methods to maintain satellite cell quiescence may improve their transplantation efficiency. PMID- 21823038 TI - Zn- and Cu-thioneins: a functional classification for metallothioneins? AB - This report intends to provide the reader with a deeper insight in the chemical, and extensively biological, characteristics of the metallothionein (MT) system. We have devoted nearly 20 years to the study of MTs and this has allowed us to form what we believe is a more complete picture of this peculiar family of metalloproteins. At the beginning of the 1990s, the landscape of this field was quite different from the overall picture we have now. Many researchers have contributed to the readjustment of this part of scientific knowledge. In our case, we implemented a unified method for obtaining MTs, for characterizing their metal-binding features, and for applying a unified research rationale. All this has helped to enlarge the initial picture that was mainly dominated by mammalian MT1/MT2 and yeast Cup1, by introducing approximately 20 new MTs. It has also allowed some characteristics to be clarified and examined in more detail, such as the cooperativity or the coexistence of multiple species in the metal substitution reactions, the availability of Ag(I) or Cd(II) for use as respective probes for the Cu(I) and Zn(II) binding sites, the participation of chloride or sulfide ligands in the metal coordination spheres, and the feasibility of using in vitro data as representative of in vivo scenarios. Overall, the results yield enough data to consider new criteria for a proposal of classification of MTs based on MT metal-binding features, which complements the previous classifications, and that can shed light on the still controversial physiological functions of this peculiar superfamily of metalloproteins. PMID- 21823039 TI - Utility and cost of a renal transplant transition clinic. AB - Successful transition from paediatric-centred to adult-oriented healthcare positively influences health outcomes for youth with chronic illness. The primary objective is to evaluate outcomes pre- and post provision of multidisciplinary transition clinic (TC) care to renal transplant recipients. We compared patient and allograft survival in renal transplant recipients at British Columbia Children's Hospital who received care within a transition clinic (TC) to a cohort of patients transferred prior to establishment of the TC, pre-TC (PTC) in 2007. Baseline characteristics, allograft function, and survival data were collected prospectively via a validated provincial database for 2 years posttransfer. We also estimated and compared the average yearly per-patient cost during the 2-year follow-up period. Thirty-three patients were transferred (PTC) and 12 transitioned (TC). In the PTC cohort, there was a combined poor outcome (death or allograft loss) incidence of 24% within 2 years posttransfer compared with no death or allograft loss in the TC cohort. Cost estimates indicate the average yearly per-patient cost was Canadian dollars (CAD) $17,127-$38,909 for the PTC and CAD $11,380-$34,312 for the TC cohort. For PTC patients who lost their allograft and returned to dialysis, the per-patient cost was CAD $40,956-$61,470. Our results indicate improved allograft and patient survival posttransfer of care in renal transplant recipients who attended TCs, and we found that providing TCs is economically feasible. PMID- 21823040 TI - High serum adiponectin concentration in children with chronic kidney disease. AB - Adiponectin (ADPN) counteracts the inflammatory response of the endothelium, which plays an important role in the development of atherosclerosis in patients with chronic kidney disease (CKD). Data in children with CKD are scarce. We examined serum ADPN concentration in 90 children with various renal disorders: 28 with CKD on conservative treatment (CKD), 21 on regular dialysis treatment (D), and 41 after kidney transplantation (Tx); 27 age-matched healthy children served as controls (C). Body mass index (BMI), estimated glomerular filtration rate (eGFR), lipids, homocysteine, high sensitivity CRP (hsCRP), and systolic blood pressure (SBP) were also measured. Mean serum ADPN concentration was significantly higher in patients with CKD (27.3 MUg/ml +/-15.0), on D (34.2 MUg/ml +/-14.9), and after Tx (23.6 MUg/ml +/-9.5) compared with ADPN levels in C (13.5 MUg/ml +/-6.1) (p < 0.0001). Serum ADPN concentration was inversely related to BMI (p = 0.001) and SBP (p = 0.004). In the multiple linear regression analysis, only SBP remained independently associated with ADPN plasma levels. Data show that children with CKD have significantly higher serum ADPN, even after Tx. The protective antiarthrosclerotic effect of ADPN may be mediated by lower SBP, a finding that deserves further study. PMID- 21823041 TI - Inflammatory myofibroblastic tumor of the mesentery: a clinical dilemma. AB - Although rare, extra-pulmonary inflammatory myofibroblastic tumors (IMTs) are becoming increasingly recognized. While surgical resection is currently an effective and accepted treatment for IMTs, the optimal management of unresectable or residual IMTs remains a clinical dilemma. We present the case of an incompletely resected IMT treated successfully with anti-inflammatory therapy alone, and describe the rationale for this approach. PMID- 21823042 TI - Deregulated transcription factors in leukemia. AB - Specific chromosomal translocations and other mutations associated with acute myeloblastic leukemia (AML) often involve transcription factors and transcriptional coactivators. Such target genes include AML1, C/EBPalpha, RARalpha, MOZ, p300/CBP, and MLL, all of which are important in the regulation of hematopoiesis. The resultant fusion or mutant proteins deregulate the transcription of the affected genes and disrupt their essential role in hematopoiesis, causing differentiation block and abnormal proliferation and/or survival. This review focuses on such transcription factors and coactivators, and describes their roles in leukemogenesis and hematopoiesis. PMID- 21823044 TI - Induction of remission following a single dose of rituximab alone in a patient with minimal change nephrotic syndrome. AB - Treatment with a single dose of rituximab alone induced remission in a patient with relapsed minimal change nephrotic syndrome (MCNS). A 27-year-old man was given corticosteroid (prednisolone; PSL) and cyclosporine (CyA) therapy combined with rituximab for his fifth relapse in 2008. Thereafter, complete remission was achieved and maintained despite eventual discontinuation of the PSL and CyA. In 2010, we treated his sixth relapse with a single dose of rituximab. Complete remission was obtained 32 days later. This is the first report of rituximab monotherapy in the treatment of MCNS. PMID- 21823043 TI - Pioglitazone reduces urinary albumin excretion in renin-angiotensin system inhibitor-treated type 2 diabetic patients with hypertension and microalbuminuria: the APRIME study. AB - BACKGROUND: The aim of his study was to compare the efficacy of pioglitazone with metformin on the reduction of albuminuria in type 2 diabetic patients with hypertension and microalbuminuria treated with renin-angiotensin system inhibitors (RAS-Is). METHODS: The open-label, randomized trial was performed in type 2 diabetic patients with hypertension and microalbuminuria. On the basis of the treatment with RAS-Is, 68 patients with microalbuminuria received either pioglitazone (15-30 mg/day; n = 32) or metformin (500-750 mg/day; n = 31) for 52 weeks. Urinary albumin-to-creatinine ratio (UACR) was measured every 12 weeks. RESULTS: After 52 weeks of treatment, the changes in the log-UACR from baseline were -8.3% in the pioglitazone group and +4.2% in the metformin group (p = 0.01), with similar glycemic and blood pressure changes. CONCLUSION: The combination of pioglitazone and RAS-Is showed therapeutic benefit in the reduction of urinary albumin excretion for type 2 diabetic patients with hypertension and microalbuminuria. PMID- 21823045 TI - Tubulointerstitial nephritis and uveitis syndrome with transient hyperthyroidism in an elderly patient. AB - A 69-year-old Japanese woman without any specific medical or family history was admitted to our hospital for renal insufficiency with proteinuria. On laboratory examinations, deteriorated renal function (blood urea nitrogen level was 34.9 mg/dL and creatinine level was 1.78 mg/dL) and elevated urinary levels of N acetyl-beta-D-glucosaminidase (23.4 U/L) and beta2-microgloblin (20200 MUg/L) were observed. We performed a renal biopsy. The biopsied specimen showed severe diffuse infiltration of mononuclear cells into the interstitium, with normal glomeruli, and these findings were compatible with acute tubulointerstitial nephritis (ATIN). At that time, ATIN seemed to be idiopathic. We performed gallium scintigraphy, and the results revealed uptake by the bilateral kidneys, thyroid gland, and right parotid gland. Serum thyroid stimulating hormone (TSH) was undetectable, free triiodothyronine was normal (3.11 pg/mL), and free thyroxine was elevated to 2.4 ng/dL. The titers of antithyroglobulin and antithyroid microsomal and TSH-receptor antibodies were not elevated. Two months later, burning pain and conjunctival congestion developed in both eyes. She had uveitis, as diagnosed by slit-lamp examination. Topical corticosteroid was used for the uveitis with success. We could not detect any cause of the uveitis, so a diagnosis of tubulointerstitial nephritis and uveitis syndrome (TINU syndrome) with associated hyperthyroidism was made. Treatment was started with 15 mg/day of prednisolone. Now her renal function is slowly recovering. There are few reports of TINU syndrome with transient hyperthyroidism. This case suggests the possibility of thyroid dysfunction in patients with TINU syndrome. A laboratory evaluation of thyroid function should be considered in the diagnostic evaluation of TINU syndrome. PMID- 21823046 TI - Impact of intensive horticulture practices on groundwater content of nitrates, sodium, potassium, and pesticides. AB - A monitoring program of nitrate, nitrite, potassium, sodium, and pesticides was carried out in water samples from an intensive horticulture area in a vulnerable zone from north of Portugal. Eight collecting points were selected and water analyzed in five sampling campaigns, during 1 year. Chemometric techniques, such as cluster analysis, principal component analysis (PCA), and discriminant analysis, were used in order to understand the impact of intensive horticulture practices on dug and drilled wells groundwater and to study variations in the hydrochemistry of groundwater. PCA performed on pesticide data matrix yielded seven significant PCs explaining 77.67% of the data variance. Although PCA rendered considerable data reduction, it could not clearly group and distinguish the sample types. However, a visible differentiation between the water samples was obtained. Cluster and discriminant analysis grouped the eight collecting points into three clusters of similar characteristics pertaining to water contamination, indicating that it is necessary to improve the use of water, fertilizers, and pesticides. Inorganic fertilizers such as potassium nitrate were suspected to be the most important factors for nitrate contamination since highly significant Pearson correlation (r = 0.691, P < 0.01) was obtained between groundwater nitrate and potassium contents. Water from dug wells is especially prone to contamination from the grower and their closer neighbor's practices. Water from drilled wells is also contaminated from distant practices. PMID- 21823047 TI - Assessing the potentials of Lemna minor in the treatment of domestic wastewater at pilot scale. AB - Water crisis is one of the most serious problems faced by the world today. Phytoremediation is one of the serious efforts towards sustainability. Macrophyte based wastewater treatment systems have several potential advantages compared with conventional treatment systems. Duckweeds (Lemna spp., Spirodela spp., Wolffia spp.) are small, green freshwater, free-floating aquatic plants. The primary objective of this work was to analyze the role of duckweeds in organic waste and nutrient removal from domestic wastewater being generated from hostels of Birla Institute of Technology, Mesra, Ranchi (India). Interesting results were obtained in which the BOD value reduced by 94.45% and the level of orthophosphate at the end of the work was found to be reduced by 79.39%. The duckweeds flourished well during the experimental period in the pH range of 7 to 8; it can be said that, other factors remaining favorable, the optimum pH for duckweed growth ranges from 7 to 8. Therefore, it can be concluded that this treatment can be successfully carried out on a large scale. Also, it is a low-cost solution to wastewater treatment problems and could satisfy the discharge standards. PMID- 21823048 TI - Spatial and temporal variation of metal concentrations in adult honeybees (Apis mellifera L.). AB - Honeybees (Apis mellifera L.) have great potential for detecting and monitoring environmental pollution, given their wide-ranging foraging behaviour. Previous studies have demonstrated that concentrations of metals in adult honeybees were significantly higher at polluted than at control locations. These studies focused at a limited range of heavy metals and highly contrasting locations, and sampling was rarely repeated over a prolonged period. In our study, the potential of honeybees to detect and monitor metal pollution was further explored by measuring the concentration in adult honeybees of a wide range of trace metals, nine of which were not studied before, at three locations in the Netherlands over a 3 month period. The specific objective of the study was to assess the spatial and temporal variation in concentration in adult honeybees of Al, As, Cd, Co, Cr, Cu, Li, Mn, Mo, Ni, Pb, Sb, Se, Sn, Sr, Ti, V and Zn. In the period of July-September 2006, replicated samples were taken at 2-week intervals from commercial-type bee hives. The metal concentration in micrograms per gram honeybee was determined by inductive coupled plasma-atomic emission spectrometry. Significant differences in concentration between sampling dates per location were found for Al, Cd, Co, Cr, Cu, Mn Sr, Ti and V, and significant differences in average concentration between locations were found for Co, Sr and V. The results indicate that honeybees can serve to detect temporal and spatial patterns in environmental metal concentrations, even at relatively low levels of pollution. PMID- 21823049 TI - Study of the PM10 concentration variations along two intra-urban roads within a compact city. AB - Eighty-five measurement campaigns were performed repeatedly to compare the concentration variation profiles along two intra-urban roads-one with open configuration and the other with street canyon effect. Fixed-effects panel data analysis was applied for formulating a model to express the PM(10) concentrations along intra-urban roads in terms of parameters like nearby central monitoring data, traffic counts and meteorological conditions with an objective to analyze the PM(10) concentration variation patterns along the two roads. Our findings reveal that traffic intensity and metrological conditions exert influence on concentration variation for both types of road configurations while wind velocity only affect the pollutants removal effectiveness of open road configuration. Further analysis unveils that the PM(10) concentration distribution profiles within a compact city environment are not always uniform and are dependent on the road configuration. Considerable PM(10) concentration differences were observed along the street canyon, and 70% of their variations are attributed to variations in their road aspect ratios. By contrast, no significant concentration difference is observed at open road configurations. PMID- 21823050 TI - Development and validation of a macroinvertebrate index of biotic integrity (IBI) for assessing urban impacts to Northern California freshwater wetlands. AB - Despite California policies requiring assessment of ambient wetland condition and compensatory wetland mitigations, no intensive monitoring tools have been developed to evaluate freshwater wetlands within the state. Therefore, we developed standardized, wadeable field methods to sample macroinvertebrate communities and evaluated 40 wetlands across Northern California to develop a macroinvertebrate index of biotic integrity (IBI). A priori reference sites were selected with minimal urban impacts, representing a best-attainable condition. We screened 56 macroinvertebrate metrics for inclusion in the IBI based on responsiveness to percent urbanization. Eight final metrics were selected for inclusion in the IBI: percent three dominant taxa; scraper richness; percent Ephemeroptera, Odonata, and Trichoptera (EOT); EOT richness; percent Tanypodinae/Chironomidae; Oligochaeta richness; percent Coleoptera; and predator richness. The IBI (potential range 0-100) demonstrated significant discriminatory power between the reference (mean = 69) and impacted wetlands (mean = 28). It also declined with increasing percent urbanization (R (2) = 0.53, p < 0.005) among wetlands in an independent validation dataset (n = 14). The IBI was robust in showing no significant bias with environmental gradients. This IBI is a functional tool to determine the ecological condition at urban (stormwater and flood control ponds), as well as rural freshwater wetlands (stockponds, seasonal wetlands, and natural ponds). Biological differences between perennial and non perennial wetlands suggest that developing separate indicators for these wetland types may improve applicability, although the existing data set was not sufficient for exploring this option. PMID- 21823051 TI - East Coast fever immunisation field trial in crossbred dairy cattle in Hanang and Handeni districts in northern Tanzania. AB - East Coast fever (ECF) causes considerable mortality and production losses in the Tanzania smallholder dairy sector and limits the introduction of improved dairy breeds in areas where the disease is present. The infection and treatment method (ITM) was adopted by smallholder dairy farms for ECF immunisation in Hanang and Handeni districts of Tanzania. This study recorded incidence rates for ECF and other tick-borne diseases (TBDs) for ECF-immunised and non-immunised cattle between 1997 and 2000. Approximately 80% of smallholder households from both sites (n = 167) participated in this longitudinal study, with immunisations carried out at the request of the livestock owners. Efficacy of ITM for preventing ECF cases in these crossbred dairy cattle was estimated at 97.6%, while that for preventing ECF deaths was 97.9%. One percent of the cattle developed clinical ECF as a result of immunisation. Since ECF immunisation permits a reduction in acaricide use, an increase in other TBDs is a potential concern. Sixty-three percent of farmers continued to use the same acaricide after immunisation, with 80% of these reducing the frequency of applications. Overall, 78% of farmers increased the acaricide application interval after immunisation beyond that recommended by the manufacturer, resulting in annual savings in the region of USD 4.77 per animal. No statistical difference was observed between the immunised and non-immunised animals in the incidence of non-ECF TBDs. However, immunised animals that succumbed to these diseases showed fewer case fatalities. ITM would therefore appear to be a suitable method for ECF control in Tanzania's smallholder dairy sector. PMID- 21823052 TI - Physical training increases osteoprotegerin in postmenopausal women. AB - The purpose of this study was to explore whether mechanical loading by exercise over a 1-year period in postmenopausal women had an effect on the receptor activator for nuclear factor kappa B ligand/osteoprotegerin (RANKL/OPG) system or the levels of the Wnt-signaling antagonist sclerostin. A total of 112 postmenopausal were randomized to either sedentary life (controls) or physical activity (training group). Ninety-two women fulfilled the study protocol. The training program consisted of three fast 30-min walks and one or two 1-h aerobic training sessions per week. The effect on the bone mineral density of the hip assessed with dual X-ray absorptiometry was positive as reported earlier. Blood samples were taken from participants at baseline and after 1 year and serum levels of OPG, RANKL and sclerostin were quantified together with the bone metabolism markers C-terminal telopeptide of collagen type I (CTX) and bone specific alkaline phosphatase (BALP). The results were analyzed using an analysis of covariance model using baseline values as the covariate. The training group displayed a clear mean increase of OPG +7.55 pg/ml compared to controls (p = 0.007). The mean changes for RANKL +0.19 pg/ml (square-root transformed data) and sclerostin +0.62 pmol/l were non-significant (p = 0.13 and p = 0.34). The changes in bone turnover markers CTX and BALP showed a tendency to decrease in the training group versus controls but the changes were small and non-significant. Although our study is limited in number of participating women, we have been able to show an OPG-associated, and RANKL- and sclerostin-independent, training induced inhibition of postmenopausal bone loss. PMID- 21823053 TI - Prolactin and lactation as modifiers of diabetes risk in gestational diabetes. AB - Pregnancy and puerperium are periods of intense hormonal changes. Maternal metabolism adapts to spare the mother from harm on behalf of her developing offspring and major alterations maintain normal glucose tolerance. Insulin secretion increases during a normal pregnancy to compensate for pregnancy-induced insulin resistance and maintain euglycemia. Women at risk for gestational diabetes have insulin resistance before conception. Gestational diabetes develops when a woman at risk is unable to meet the insulin secretory demands imposed by the additional insulin resistance characteristic of pregnancy. The lactogens, human placental lactogen and prolactin, are major stimuli for the adaptation of the endocrine pancreas during gestation. This review discusses the role of lactogens on glucose homeostasis during pregnancy and proposes a mechanism by which the hormonal control of lactation, led by prolactin, may regulate adipocyte biology, glucose and lipid metabolism, and guard postpartum women against type 2 diabetes. PMID- 21823054 TI - Stimulation of fat oxidation, but no sustained reduction of hepatic lipids by prolonged pharmacological inhibition of acetyl CoA carboxylase. AB - Acetyl CoA carboxylase isoforms 1 and 2 (ACC1/2) are key enzymes of fat metabolism and their inhibition has been postulated to be beneficial for the treatment of the metabolic syndrome by decreasing ectopic fat accumulation. In order to validate this approach pharmacologically, we characterized the chronic effect of the small molecule ACC1/2 inhibitor SAR210 in 2 rodent models of fatty liver. Chronic administration of SAR210 increased serum ketone levels in both diet-induced obese mice and female ZDF rats. The inhibitor neither reduced hepatic triglycerides nor influenced body weight in either diet-induced obese mice or female ZDF rats. Thus, chronic pharmacological inhibition of ACC1/2 stimulated fat oxidation, which was, however, not sufficient to reduce hepatic triglycerides. PMID- 21823055 TI - Enhanced oxidative stress and platelet activation combined with reduced antioxidant capacity in obese prepubertal and adolescent girls with full or partial metabolic syndrome. AB - In adults, obesity is a main factor implicated in increased oxidative stress (OS), platelet activation (PA) and impaired antioxidant status (AS), all predisposing factors for cardiovascular disease leading to increased morbidity and mortality. Furthermore, the metabolic syndrome (MetS) is an important cardiovascular risk factor, which progressively develops and may already be present during late childhood or adolescence. However, scarce data exist on oxidative-antioxidant balance and PA in childhood and adolescence in the presence of partial (PMetS) or full MetS. The aim of the study was to evaluate OS, PA, and AS in prepubertal and adolescent obese girls with partial or full MetS. 96 girls with a clinical and metabolic evaluation for obesity and 44 healthy normal-weight sex- and age-matched girls were studied. IDF-adopted criteria were used to define full and partial MetS and the patient population was divided into 4 groups: the first comprised 31 pre-pubertal girls with PMetS (PR-PMetS), the second 37 adolescents with PMetS (AD-PMetS), the third 10 prepubertal girls with full MetS (PR-MetS), and the fourth 18 adolescents with full MetS (AD-MetS). The OS was evaluated by measuring plasma 15-F(2t)-Isoprostane levels (15-F(2t)-IsoP) and protein carbonyls, PA by thromboxane B(2) levels (TXB(2)), and AS by serum vitamin E and plasma total antioxidant capacity (TAC) levels. 15-F(2t)-IsoP, protein carbonyls, and TXB(2) levels were significantly gradually amplified, and vitamin E and TAC reduced, and significantly correlated with obesity from childhood to adolescence and from partial to full MetS. This study demonstrates the loss of the normal homeostatic balance between oxidant-antioxidant state in obese children and adolescents with manifestations of partial and full MetS. PMID- 21823056 TI - Estrogen attenuates VEGF-initiated blood-retina barrier breakdown in male rats. AB - 17beta-Estradiol has been demonstrated to protect blood-brain barrier from disruption and attenuate brain injury in various conditions. The aim of this study was to investigate the effect of 17beta-estradiol on the blood-retina barrier (BRB) breakdown induced by intravitreous injection of vascular endothelial growth factor (VEGF), a significant mediator of vascular permeability. Intravitreous injection of VEGF was performed to initiate BRB breakdown in male rats with PBS in the contralateral eye as control. 2 doses of 17beta-estradiol and vehicle control were given to 3 groups of rats. The integrity of the BRB was quantified by Evans blue technique and assessed by fluorescent dyes in retinal sections and wholemounts. BRB breakdown was achieved by VEGF as retinal vascular permeability was increased compared with control eyes (14.66+/-4.09 vs. 4.94+/-1.20 MUl/g/h, p<0.01). Vascular permeability in the 2 groups treated with 17beta-estradiol was reduced compared with control (14.66+/ 4.09 vs. 10.26+/-3.67 vs. 7.37+/-2.22 MUl/g/h, p<0.01). Rhodamine isothiocyanate (RhIC) extravasation in retinal sections and Evans blue-albumin complex leakage in retinal wholemounts were also decreased in the 2 treatment groups. These results suggest that 17beta-estradiol attenuates BRB breakdown induced by VEGF in male rats, which may provide a new role of 17beta-estradiol in ocular diseases. PMID- 21823057 TI - Rosuvastatin blocks advanced glycation end products-elicited reduction of macrophage cholesterol efflux by suppressing NADPH oxidase activity via inhibition of geranylgeranylation of Rac-1. AB - Adenosine triphosphate-binding membrane cassette transporter A1 (ABCA1) and ABCG1 play a crucial role in macrophage cholesterol efflux, which is a novel therapeutic target for atherosclerosis. Advanced glycation end products (AGE) and their receptor RAGE axis is involved in accelerated atherosclerosis in diabetes as well. However, the role of AGE-RAGE axis in macrophage cholesterol efflux is not fully understood. We examined here whether AGE-RAGE axis could impair cholesterol efflux from human macrophage cells, THP-1 cells by suppressing ABCA1 and ABCG1 expression. We further investigated the effects of rosuvastatin on cholesterol efflux from AGE-exposed THP-1 cells. AGE increased reactive oxygen species generation in THP-1 cells, which was completely inhibited by rosuvastatin, anti-RAGE-antibody or diphenylene iodonium chloride (DPI), an inhibitor of NADPH oxidase. The antioxidative effect of rosuvastatin on AGE exposed THP-1 cells was significantly prevented by geranylgeranyl pyrophosphate (GGPP). AGE decreased ABCA1 and ABCG1 mRNA levels, and subsequently reduced cholesterol efflux from THP-1 cells, which was prevented by GGPP. DPI mimicked the effects of rosuvastain. The results demonstrated that rosuvastatin could inhibit the AGE-induced reduction of THP-1 macrophage cholesterol efflux by suppressing NADPH oxidase activity via inhibition of geranylgeranylation of Rac 1. Our present study provides a novel beneficial aspect of rosuvastatin in diabetes; rosuvastain may prevent the development and progression of atherosclerosis in diabetes by not only reducing serum cholesterol level, but also by improving cholesterol efflux from foam cells of the arterial wall via blocking the harmful effects of AGE on macrophages. PMID- 21823058 TI - Decrease of blood lipids induced by Shan-Zha (fruit of Crataegus pinnatifida) is mainly related to an increase of PPARalpha in liver of mice fed high-fat diet. AB - Hyperlipidemia is an important risk factor for cardiovascular diseases. Agents for the treatment of hyperlipidemia are well-developed in the clinic while PPARalpha is a target for lipid-lowering agents. Shan-Zha (Crataegus pinnatifida) is a traditional Chinese medicine used to increase digestion. Also, Shan-Zha fruit extract showed merit to improve obesity and hyperlipidemia in hamsters; however, the mechanism remained obscure. In the present study, hypertriglycemia and hypercholesterolemia were induced by high fat diet in C57BL/6 J male mice. Then, they were orally administered with Shan-Zha fruit extract at an effective dose of 250 mg/kg for 7 days. The liver was removed to estimate the expressions of PPARalpha and beta-oxidation-related enzyme. Oral intake of Shan-Zha extract significantly improved hyperlipidemia in high fat diet-fed mice with an increase of PPARalpha expression in liver. Also, expression of PPARalpha-regulated beta oxidation-related enzymes was raised in liver by Shan-Zha extract. However, adipose tissue and others were not modified by this treatment of Shan-Zha fruit extract. Thus, Shan-Zha can increase the expression of PPARalpha to facilitate beta-oxidation-related enzymes in liver for lipid degradation and blood lipid decrement. Also, this is the first report showing Shan-Zha fruit extract can influence liver to lower hyperlipidemia prior to the action in adipose tissue. PMID- 21823059 TI - Maternal prolactin inhibition during lactation is associated to renal dysfunction in their adult rat offspring. AB - The renal function of rats whose mothers had hypoprolactinemia at the end of lactation was evaluated during development. Lactating Wistar rats were treated with bromocriptine (BRO, 1 mg twice a day, s.c.) or saline on days 19, 20, and 21 of lactation, and their male offspring were followed from weaning until 180 days old. 1 rat from each of the 12 litters/group was evaluated at 2 time points (90 and 180 days). Body and kidney weights, sodium, potassium, and creatinine were measured. Values were considered significant when p<0.05. Adult BRO-treated offspring presented higher body weight (+10%), lower relative renal weight at 90 and 180 days (-9.2% and -15.7%, respectively), glomerulosclerosis, and peritubular fibrosis. At 90 and 180 days, creatinine clearance was lower (-32% and -30%, respectively), whereas serum potassium was higher (+19% and +29%, respectively), but there were no changes in serum sodium. At 180 days, higher proteinuria (+36%) and serum creatinine levels (+20%) were detected. Our data suggest that prolactin inhibition during late lactation programs renal function damage in adult offspring that develops gradually, first affecting the creatinine clearance and potassium serum levels with further development of hyperproteinuria and higher serum creatinine, without affecting sodium. Thus, precocious weaning programs some components of the metabolic syndrome, which can be a risk factor for further development of kidney disease. PMID- 21823060 TI - Elevated levels of macrophage migration inhibitory factor in women with metabolic syndrome. AB - Metabolic syndrome is a complex clinical disorder characterized by obesity, a disturbance of glucose metabolism, dyslipidemia, and hypertension, leading to increased cardiovascular risk. Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine produced both by innate immune cells and by adipocytes, and it plays an important role in inflammatory and cardiovascular diseases. The goal of this study was to evaluate the expression of circulating MIF in patients with metabolic syndrome. A study was conducted involving 172 persons who attended the Jeju National University Hospital Health Promotion Center. Among the 172 subjects, 88 patients with metabolic syndrome and 84 healthy control subjects were included. Serum MIF levels were considerably higher in patients with metabolic syndrome than in healthy subjects (mean+/-SEM, 1413.0-pg/ml+/-102.6 vs. 1077.0-pg/ml+/--91.3, p=0.016). Among the metabolic syndrome patients, MIF levels were significantly increased in women (1403.0-pg/ml+/-114.2 vs. 921.3 pg/ml+/ 117.3, p=0.005), but not in men. Even after further linear regression adjustment for age and body mass index, the expression of MIF for women with metabolic syndrome was still clearly elevated when compared to healthy subjects (p=0.011). Circulating MIF concentrations showed a gender disparity between healthy and metabolic syndrome subjects. An elevation of systemic MIF in women with metabolic syndrome may contribute to pathogenesis of metabolic syndrome or to the development of metabolic syndrome-related diseases, such as atherosclerosis and type 2 diabetes mellitus. PMID- 21823061 TI - Maintained serum sodium in male ultra-marathoners--the role of fluid intake, vasopressin, and aldosterone in fluid and electrolyte regulation. AB - Exercise-associated hyponatremia (EAH) is a well know electrolyte disorder in endurance athletes. Although fluid overload is the most like etiology, recent studies, however, argued whether EAH is a disorder of vasopressin secretion. The aims of the present study were to investigate (i) the prevalence of EAH in male ultra-marathoners and (ii) whether fluid intake, aldosterone or vasopressin, as measured by copeptin, were associated with post-race serum sodium concentration ([Na+]). In 50 male ultra-marathoners in a 100 km ultra-marathon, serum [Na+], aldosterone, copeptin, serum and urine osmolality, and body mass were measured pre- and post-race. Fluid intake, renal function parameters and urine excretion were measured. No athlete developed EAH. Copeptin and aldosterone increased; a significant correlation was found between the change in copeptin and the change in serum [Na+], no correlation was found between aldosterone and serum [Na+]. Serum [Na+] increased by 1.6%; body mass decreased by 1.9 kg. The change in serum [Na+] and body mass correlated significantly and negatively. The fluid intake of ~ 0.58 l/h was positively related to the change in body mass and negatively to both post-race serum [Na+] and the change in serum [Na+]. We conclude that serum [Na+] was maintained by both the mechanisms of fluid intake and the hormonal regulation of vasopressin. PMID- 21823062 TI - Cardiovascular events in thyroid disease: a population based, prospective study. AB - No consensus exists whether subclinical thyroid disease should be treated or just observed. Untreated overt thyroid disease is associated with increased risk of cardiovascular disease, and this study was conducted to assess the risk of cardiovascular events in subclinical thyroid disease. The population-based prospective study was conducted in Denmark. A total of 609 subjects from general practice aged 50 years or above with normal left ventricular function were examined. During a median of 5 years of follow-up, major cardiovascular events were documented. In subjects with abnormal TSH at baseline, information about potential thyroid treatment during follow-up was obtained from case reports and mailings. At baseline, 549 (90.7%) were euthyroid (TSH 0.40-4.00 mU/l), 31 (5.1%) were subclinical hypothyroid (TSH>4.00 mU/l), and 25 (4.1%) were subclinical hyperthyroid (TSH<0.40 mU/l). 1 overt hyperthyroid and 3 overt hypothyroid participants were excluded from the analyses. At baseline, the levels of NT proBNP were inversely associated with the levels of TSH; the lower the levels of TSH, the higher the NT-proBNP concentration. During follow-up, 88 participants died, 81 had a major cardiovascular event, and 28 had a stroke. The incidence of stroke was increased among subjects with subclinical hyperthyroidism, HR 3.39 (95% CI 1.15-10.00, p=0.027) after adjusting for sex, age, and atrial fibrillation. Subclinical hypothyroidism was not related with any of the outcome measurements. Subclinical hyperthyroidism seems to be a risk factor of developing major cardiovascular events, especially stroke in older adults from the general population with normal left ventricular function. PMID- 21823063 TI - Adipokine serum concentrations, anthropometric measurements and socio-economic status in two ethnic groups with different prevalence levels for cardiovascular diseases and type 2 diabetes. AB - Obesity is more common in African than Asian-Indian populations and yet type 2 diabetes and cardiovascular diseases are more common in the latter populations. The main purpose of the current study was therefore to determine whether ethnic differences in body fat distribution, adipokine levels, and socio-economic status may explain population differences in the prevalence of these metabolic disorders. Leptin, IL-6, CRP, visceral fat, education level, and socio-economic status were measured in 50 African and the same number of Indian women residing in Johannesburg, South Africa. Serum leptin levels were significantly higher in Indian than African subjects (41.3+/-2.0 and 34.2+/-2.9 ng/ml, respectively; p<0.05). TNF-alpha levels were significantly higher in the African group, (5.22+/ 0.86 vs. 2.54+/-0.52 pg/ml; p<0.05), whilst visceral fat levels were significantly lower (56.1+/-5.5 vs. 77.9+/-6.5 cm(2); p<0.05). The CRP and IL-6 levels were not different between groups. Education levels (p<0.005) and socio economic status (p<0.0001) were both lower in the African subjects, however, adjusting for these variables in ANCOVA did not attenuate differences in adipokine or visceral fat levels. We hypothesise that one of the reasons for the higher prevalence of obesity in the African than Indian population may be related to lower leptin levels, whilst ethnic differences in the prevalence of metabolic disorders cannot be explained by differences in adipokine levels, but maybe related to higher visceral adiposity in the Indian group. PMID- 21823064 TI - [Dolle and Bowlby--discourses about sensitivity]. AB - Based upon biographical information and a summary of E.A. Dolle's contributions to psychotherapy research, this paper describes how Dolle - obviously during his time in a British war prison - had some encounters with John Bowlby, father of attachment theory, and how these encounters might have influenced Dolle during his later years. These years were spent at the Catholic University Eichstatt, where Dolle tried to positively influence the development of values and their "sensitivity for sensitivity" among Catholic students. The paper concludes that Dolle probably would be disappointed if he could see current developments within science and - even more - within society. PMID- 21823065 TI - [Neurousurpation--the expropriation and suppression of Dolle's neurobiological pioneer work]. AB - The discovery of a hitherto unpublished dissertational thesis in the archive of a publishing house has lead to a lost publication by Ernst August Dolle. In this manuscript, the author reports on the stimulation of a cerebral libido area in the dog, long before Olds and Milner published their work on the discovery of the rewarding area. The reasons for the suppression of this early publication by Dolle are investigated and are ascribed to an effort to use his neurobiologic research for secret mental manipulation experiments of the CIA at the beginning of the Cold War. PMID- 21823066 TI - [The outpatient provision of care for mental disorders in a rural area. An analysis of reimbursement claims in Mecklenburg-West Pomerania]. AB - Mental disorders cause a substantial amount of the burden of disease. Although they are less frequent in rural areas, their provision of care is disproportionately lower. Reimbursement claims in the federal state of Mecklenburg-West Pomerania of the years 2006/2007 serve as the basis for the descriptive distribution of subgroups on the total number of mental disorders and their outpatient care. Of all claims, 35,3% were allotted to neurotic, stress related and somatoform disorders, 24,2% to affective disorders and 12,5% to substance use disorders. Claims for reimbursement were made for 44,7% by general practitioners, 15,1% by neurologists and psychiatrists, 12,6% by gynaecologists, and 8,1% by internists. Psychotherapists claimed 3,1%. These results cause considerations regarding the establishment of psychotherapeutic and neurological/psychiatric practices as well as the significance of mental disorders in the training of general practitioners. PMID- 21823067 TI - [Patient participation in medical decision making among breast cancer patients--a comparison of breast centre care units and non-centre hospitals]. AB - This study investigated the extent of involvement of breast cancer patients in medical decisions in comparison between certified breast cancer centres vs. non centres. Data on the participation in medical decision making were collected in a retrospective cross-sectional design from 652 breast cancer patients. 9 different dimensions of participation were analysed. In the descriptive analysis, there is only one significant difference in participation between breast centres and non centres (dimension: time of treatment). In multivariate analysis, the treatment in a breast cancer centre was a predictor for increased patient participation in 3 dimensions of participation in medical decisions (p <0.05). In particular, younger age and good health are of statistical significance for participation in medical decision making. There is a higher participation of patients in breast centres in only few subdimensions of medical decision making, but not in general. PMID- 21823068 TI - Peroral cholangioscopy for diagnosis and therapy of biliary tract disease using an ultra-slim gastroscope. AB - High-resolution video cholangioscopy is expected to improve diagnostic validity for diseases of the biliary tract. We report our experience in using an ultra slim gastroscope for diagnosis and treatment of biliary tract disease. Cholangioscopy was attempted in 25 cases (22 patients) and succeeded in 22 cases (success rate 88%; 19 patients). Cholangiocellular carcinoma (CCC) was diagnosed by cholangioscopy in five of 10 cases (histopathologically confirmed in four), or ruled out in five. Cholangioscopy was used to detect stones in mega-choledochus (n=3), to clarify the postoperative condition of the bile ducts (n=2), to diagnose bile duct varices (n=1), and to release a dislodged self-expanding metal stent (n=1), and others. Argon plasma coagulation was successfully completed in a patient with mucin-producing adenomatosis of the bile ducts. One case of non fatal air embolism occurred before replacing air with CO2 insufflation. In summary, peroral cholangioscopy with an ultra-slim gastroscope is feasible and helpful in selected patients, improving diagnostic validity, and offering new therapeutic interventions. This technique should only be performed using CO2 insufflation. PMID- 21823069 TI - Interventional cardiology in 2011- a look back. PMID- 21823070 TI - Future directions in cardiac surgery-part II. PMID- 21823071 TI - A genomic revolution for cardiovascular disease-a progress report at five years. PMID- 21823072 TI - Cell therapy-a 21st century hope for treating cardiovascular disease-a five-year retrospective and predictive view. PMID- 21823073 TI - Biomarkers associated with cardiometabolic risk in obesity. AB - BACKGROUND: The US is facing an obesity epidemic. Recognizing the biomarkers associated with adipose tissue may impact physicians' management of cardiometabolic disease greatly. EVIDENCE OF ACQUISITION: We searched PubMed for keywords 'obesity', 'leptin', and 'adiponectin', reviewed national surveys, and searched reference articles used in review articles retrieved via the PubMed search. We included articles with multiple relevant citations. Observational data acquired from two sources, not previously published, were also used to support our conclusion. RESULTS: Literature review and analysis of observational data showed that the level of leptin increases with the increase in weight gain, while adiponectin decreases. The roles of these adipokines in the body have been defined. With the increase in leptin levels, the incidence and prevalence of the components of the metabolic syndrome were seen to be higher, resulting in higher cardiovascular disease, while adiponectin was seen to play a more protective role in the body against developing such disease. CONCLUSIONS: Measuring circulating levels of leptin and adiponectin as a screening tool may help recognize those individuals who do not only have obesity as a major risk factor toward developing cardiometabolic disease but also may have an unfavorable 'biomarker profile', putting them at highest risk. This may encourage the mobilization of resources to help these individuals lose weight rapidly with possibly aggressive measures such as bariatric surgery. PMID- 21823074 TI - Approach to the differentiation of wide QRS complex tachycardias. PMID- 21823075 TI - High prevalence of obesity in young patients with ST elevation myocardial infarction. AB - BACKGROUND: There is growing concern about increasing rates of obesity in young people, and increasing ST elevation myocardial infarction (STEMI) at a younger age. There are only a few studies performed to study the risk factors in STEMI among young populations. METHODS: Retrospective chart reviews on all first event STEMI patients between December 2005 and July 2007 were performed. A young population was defined as: men <45 years of age and women <55 years of age. RESULTS: Among 206 patients with STEMI, 36 were young. In young patients with STEMI, 78 % were obese compared with 35 % obese, non-young (p<0.001). Also, among young patients with STEMI, family history of coronary heart disease (CHD) was positive in 39 %, compared with 19 % in non-young patients (p=0.009). This significance for obesity and family history persisted after adjusting for other risk factors using logistic regression (OR 2.96 to 17.75, 95 % CI, p<0.0001 and OR 1.36 to 7.47, 95 % CI, p=0.008, respectively). CONCLUSION: Obesity and family history of CHD were major risk factors with a higher prevalence in young patients with STEMI than non-young patients. PMID- 21823076 TI - Cardiac resynchronization therapy for non-ischemic cardiomyopathy-immediate changes in QRS duration, with left bundle branch block pattern on electrocardiogram. AB - BACKGROUND: We evaluated mean QRS duration improvement immediately after cardiac resynchronization therapy (CRT) in patients with non-ischemic cardiomyopathy (NICM), with a left bundle branch block (LBBB) pattern on electrocardiogram (ECG), owing to obligatory right ventricular pacing or as a new finding; and to what extent. METHODS AND RESULTS: We tabulated ECGs of 18 subjects, 24 hours before and after receiving CRT, for both groups. The percentage decreases of QRS duration in all groups were statistically similar (p<0.05). There was a significant negative correlation (p<0.05) between age and the percentage of the QRS decrease. CONCLUSIONS: The study showed a greater reduction in QRS duration with CRT for younger subjects. PMID- 21823077 TI - Angiographic success and successful stent delivery for complex lesions using the GuideLinerTM five-in-six system- a case report. AB - In this report, we describe two cases of transradial intervention of chronic total occlusions assisted by the GuideLiner catheter when the guide catheter support was suboptimal. This novel coaxial system can provide additional support for more complex lesions and, in our cases, allowed the procedure to be completed via the transradial approach rather than having to change to transfemoral access. PMID- 21823078 TI - Diffuse coronary ectasia complicated by myocardial infarction in a patient with multiple sclerosis-transradial dethrombosis and one-year coronary computed tomography angiography follow-up. AB - Coronary artery ectasia (CAE) is frequently considered an incidental finding during coronary angiography, however, several reports have shown an association with myocardial ischemia and infarction. When acute myocardial infarction (AMI) occurs in cases of CAE, current reperfusion therapies, due to the large arterial size and the massive intracoronary thrombus, when used alone are limited in preventing the development of distal embolization and 'no reflow phenomenon.' In this article, we described the case of a multiple sclerosis (MS) patient with diffuse CAE and ST elevation AMI, treated by coronary dethrombosis multistrategy (mechanical and pharmacologic) during a transradial primary angioplasty. The higher thrombotic burden in MS with CAE was analyzed and possible common pathophysiologic pathways were discovered in the imbalance between proteolytic activities of metalloproteinases and endogenous tissue inhibitor, with subsequent increased proteolysis leading to a risk for coronary plaque rupture. The one-year clinical and angiographic follow-up with coronary computed tomography (CT) angiography, together with long-term antiplatelet therapy, was also evaluated. PMID- 21823079 TI - Saphenous vein graft aneurysm-an unusual cause of mediastinal mass. AB - We report the case of a 78-year-old man who was incidentally found to have a large, ovoid mass on a chest X-ray. Nineteen years before, he had undergone a coronary artery bypass graft (CABG). A chest computed tomography (CT) scan revealed a 6.8 x 6.7 cm aneurysm of the saphenous vein bypass graft anastomosed to the distal right coronary artery with contrast filling only the proximal end of the graft. The inferior wall of the left ventricle was akinetic on echocardiography, suggesting prior myocardial infarction of this vascular bed. Because of the patient's comorbidities, occlusion of the graft, and prior inferior infarction, clinical observation was elected. PMID- 21823080 TI - Spontaneous calcific coronary embolus from a degenerative calcific aortic valve-a rare cause of acute ST segment elevation myocardial infarction. AB - This case report describes pathology-proven spontaneous coronary embolization from a calcific aortic valve resulting in an acute ST segment elevation myocardial infarction. It serves as an important reminder that, especially for elderly patients with coexisting aortic valvular disease, initial treatment for abrupt coronary artery occlusion with aspiration thrombectomy catheterization is standard of care. PMID- 21823081 TI - A five-year retrospective on futures in cardiology-part one. PMID- 21823083 TI - A peculiar case of very late restenosis in a drug-eluting stent. PMID- 21823082 TI - Mycotic aneurysm of the ulnar artery. AB - CONTEXT: Mycotic aneurysm of the ulnar artery is extremely rare. We report a case of mycotic aneurysm of the ulnar artery due to subacute bacterial endocarditis (SBE) presenting with a painful pulsatile mass in hypotenar region. CASE REPORT: In a 39-year-old man, treated as a case of SBE, a painful progressive pulsatile mass appeared in the left hypotenar region. Ultrasonography and angiography showed an aneurysm of ulnar artery in this region. The aneurysm was resected by surgery. CONCLUSION: Since the diagnosis may be difficult at the early phase and in some cases limb loss may occur, there should be high clinical suspicion to make a prompt diagnosis. PMID- 21823084 TI - The future was here and now, and has passed you by. PMID- 21823085 TI - Cardiovascular imaging-reflecting on 2006 predictions and new predictions for 2016. AB - Cardiovascular imaging has advanced at breakneck speed over the past five years. With the steadily improving capability to image the cardiovascular system has come the appreciation that imaging is not an end in itself, but must lead to more effective and appropriate therapy in order to be clinically justified. Current economic challenges are particularly relevant to healthcare and will have major influence on further technical development and clinical application of advanced cardiovascular imaging modalities. PMID- 21823086 TI - Genetic variability of NaCl tolerance in tomato. AB - Cultivation of crops in soils with high salt (NaCl) content can affect plant development. We examined the morphological and physiological mechanisms of salt tolerance in tomato. The responses of 72 accessions of tomato (Solanum lycopersicum) to salinity were compared by measuring shoot and root lengths, and fresh shoot and root weights relative to those of controls (plants grown in normal salt levels). All traits were reduced at the seedling stage when salinity levels were increased. The accession x salinity interaction was significant for all traits. Root length had higher heritability than other traits and was used as a selection criterion to identify salt-tolerant and -non-tolerant accessions. On the basis of root length, accessions LA2661, CLN2498A, CLN1621L, BL1176, 6233, and 17870 were considered to be more tolerant than accessions 17902, LO2875 and LO4360. The degree of salt tolerance was checked by analyzing K+ and Na+ concentrations and K+/Na+ ratio in tissues of plants treated with 10 and 15 dS/m salinity levels. Tolerance of these accessions to salinity was most associated with low accumulation of Na+ and higher K+/Na+ ratios. PMID- 21823087 TI - Phylogenetic analysis reveals gene conversions in multigene families of rhizobia. AB - Gene families are an important and intrinsic trait of rhizobial species. These gene copies can participate in non-reciprocal recombination events, also called gene conversions. Gene conversion has diverse roles, but it is usually implicated in the evolution of multigene families. Here, we searched for gene conversions in multigene families of six representative rhizobial genomes. We identified 11 gene families with different numbers of copies, genome location and function in CFN42 and CIAT652 strains of Rhizobium etli, Rhizobium sp NGR234, Mesorhizobium loti MAFF303099, Sinorhizobium meliloti 1021, and Bradyrhizobium japonicum USDA110. Gene conversions were detected by phylogenetic inference in the nifD and nifK gene families in R. etli. Sequence analysis confirmed multiple gene conversions in these two gene families. We suggest that gene conversion events have an important role in homogenizing multigene families in rhizobia. PMID- 21823088 TI - Population genetics analysis of Podocnemis sextuberculata (Testudines, Podocnemidae): lack of population structure in the central Amazon Basin. AB - The chelonians are, in general, important for the economy of the traditional populations of the Amazon region, especially as a source of animal protein. Furthermore, sub-products, such as eggs and fat, are utilized in the manufacture of cosmetics, and the plastron and carapace are used in the manufacture of adornments. The freshwater turtle species Podocnemis sextuberculata, locally known as "iaca" or "pitiu", is widely distributed in the Amazon Basin in Brazil and also in Colombia and Peru. This species is on the International Union for Conservation of Nature Red List in the category of vulnerable species. We examined the genetic variability and population structure of three populations represented by 64 individuals sampled from Reserva Federal de Abufari, Tapaua, Amazonas State; Reserva de Desenvolvimento Sustentavel Mamiraua, Tefe, Amazonas State, and Terra Santa, Para State. All of these are over 1000 km from each other. A partial 415-bp sequence of the mitochondrial gene ND1 was utilized as a molecular marker. Seven haplotypes were observed; the most common haplotype was shared by all the areas sampled, while the rarest haplotypes were represented by a single individual and were thus restricted to a single locality. The sharing of the most common haplotype, the high number of migrants (Nm) and the AMOVA results indicate a lack of genetic structure among the sampling localities. The levels of genetic variability observed were homogeneous among the sampling localities. These results (?(ST) and Nm) are compatible with what is known about the ecology of this species, which has a great migratory capacity. PMID- 21823089 TI - Heterologous amplification and characterization of microsatellite markers in the Neotropical fish Leporinus friderici. AB - Leporinus friderici, native to the Amazon Basin and popularly known as "piau-tres pintas", has great ecological and economic importance; it is widely fished and consumed throughout much of tropical South America. Knowledge of the genetic diversity of this native species is important to support management and conservation programs. We evaluated microsatellite loci amplification, using heterologous primers, in 31 individuals of L. friderici. These samples were collected from natural populations of the Araguaia River basin, in central Brazil, and the DNA was extracted from samples of muscle tissue. Eight loci were successfully analyzed. Six of them were polymorphic, and the number of alleles ranged from three to 10. Values of expected heterozygosities for these polymorphic loci ranged from 0.488 to 0.795. Exclusion probability (0.983), the identity probability (0.000073), and the mean genetic diversity values were high, showing that these microsatellite markers are suitable for assessing the genetic variability of L. friderici populations. There is a growing interest in studies that evaluate the genetic variability of natural populations for various purposes, such as conservation. Here, we showed that a viable alternative to the costly development of specific primers for fish populations is simply testing for heterologous amplification of microsatellite markers available from research on other species. PMID- 21823090 TI - Identification of a DNA methylation point in the promoter region of the bovine CYP21 gene. AB - The CYP21 (steroid 21-hydroxylase) gene is involved in the synthesis of steroid hormones. Bov-A2 is a retroposon that is common in ruminant genomes. The promoter region of bovine CYP21 contains a short interspersed nucleotide element of Bov A2, which overlaps a putative Sp1 binding site. We looked for RFLP/HpaII polymorphism in the Bov-A2 element in bovine Zebu breeds by PCR-RFLP, and examined whether polymorphism in this element is associated with methylation. Among DNA samples from 135 Brazilian Zebu breed cattle, we identified an RFLP/HpaII polymorphism (T/C), which, based on a restriction methylation sensitive assay employing HpaII and isoschizomer MspI enzymes (methylation sensitive and -non-sensitive enzymes, respectively), appears to be a DNA methylation point. This is the first report of this polymorphism and on DNA methylation in the bovine CYP21 promoter region in Brazilian Zebu cattle. PMID- 21823091 TI - Efficacy of random primer-pair arrays in plant genome analysis: a case study of Cucumis (Cucurbitaceae) for identification of wild and cultivated species. AB - The efficacy of random primer-pair arrays compared to conventional RAPD method with a single decamer primer was evaluated using DNA from two species of Cucumis. The banding patterns of amplicons revealed enhanced utility of primer-pair arrays over conventional RAPDs, producing more bands and a higher degree of polymorphism, both at intra- and inter-specific levels. Amplification produced by both methods clearly distinguished a wild from a cultivated species of the genus Cucumis. The main advantage of the primer-pair RAPD over single-primer-based RAPD is the increase in the number of reactions and amplification products in the form of novel/unique bands with a limited number of primers. It also enables the generation of reliable amplicons with a large number of polymorphic bands, which can be linked to gene-governing traits, allowing sequence-characterized partial genome analysis. PMID- 21823092 TI - Genetic linkage analysis of oral lichen planus in a Chinese family. AB - Oral lichen planus (OLP) is a common oral inflammatory disease affecting about 1 2% of the general adult population. As with European families who are diagnosed with OLP, the Chinese family who we studied was diagnosed with a severe form of oral reticular and erosive lesions; moreover, two of the five affected individuals developed oral cancer at an early age. A whole-genome genotyping scan with linkage analysis was performed using the 10K SNP array to investigate the genetic susceptibility of the Chinese family to OLP, which revealed one maximal nonparametric LOD score of 2.32 (P = 0.0156) for SNP marker rs2372736, defined at the chromosome 3p14-3q13 region encompassing 19 SNPs. Blood samples were obtained from 10 members of the family, which included the grandmother, father and mother, and the children altogether. The grandfather is dead, but the family members remembered he also suffered from the same disease. Chromosome 3p14-3q13 was identified as the candidate gene region for OLP; this information provides a foundation for further identification of the gene responsible for OLP. PMID- 21823093 TI - Study of closely related species within the Physalaemus cuvieri group (Anura): contribution of microsatellite markers. AB - Various species of the Physalaemus cuvieri group of frogs are difficult to distinguish morphologically, making molecular analysis an attractive alternative for indentifying members of this group, which is considered to be at risk because of loss of habitat. The genetic structure of natural populations of P. ephippifer and P. albonotatus species was investigated and analyzed, together with that of five previously studied populations of P. cuvieri. Nine microsatellite loci were used in the analyses. The overall G(ST) value (0.46) revealed high genetic variation among the populations, as expected for different species. Bayesian analysis implemented by the STRUCTURE software clustered the seven populations into seven groups (K = 7). All the P. albonotatus and P. ephippifer specimens were grouped into a single cluster, both species showing clear differentiation from P. cuvieri. The different grouping based on these microsatellites of some P. cuvieri individuals from Porto Nacional and from Passo Fundo suggests that they could be a new species, indicating a necessity for taxonomic reevaluation. Despite the intrinsic difficulties in analyzing closely related species, the nine microsatellite loci were found to be adequate for distinguishing these three species of the P. cuvieri group and their populations. PMID- 21823094 TI - Cloning of the nptII gene of Escherichia coli and construction of a recombinant strain harboring functional recA and nptII antibiotic resistance. AB - In an attempt to clone the ORF of the nptII gene of Escherichia coli K12 (ATCC 10798), two degenerate primers were designed based on the nptII sequence of its Tn5 transposon. The nptII ORF was placed under the control of the E. coli hybrid trc promoter, in the pKK388-1 vector, transformed into E. coli DH5alpha DeltarecA (recombinant, deficient strain). Transferred cells were tested for ampicillin, tetracycline, kanamycin, neomycin, geneticin, paromomycin, penicillin, and UV resistance. The neomycin phosphotransferase gene of E. coli was cloned successfully and conferred kanamycin, neomycin, geneticin, and paromomycin resistance to recombinant DH5alpha; this did not inhibit insertion of additional antibiotic resistance against ampicillin and tetracycline, meaning the trc promoter can express two different genes carried by two different plasmids harbored in the same cell. This resistance conferral process could be considered as an emulation of horizontal gene transfer occurring in nature and would be a useful tool for understanding mechanisms of evolution of multidrug-resistant strains. PMID- 21823095 TI - Development and testing of 13 polymorphic microsatellite markers in Larimichthys polyactis (Sciaenidae) using 5' anchored PCR. AB - Larimichthys polyactis is a commercially important marine fish species in southeast Asia. The population crashed due to overfishing in the 1970s, but has since recovered. We developed 13 novel polymorphic microsatellite markers in L. polyactis using 5' anchored PCR. The characteristics of these loci were estimated by analyzing a sample of 30 individuals. A total of 74 alleles were detected, with a mean of 5.7 alleles per locus. There were 2 to 12 alleles, 0.2760 to 0.8247 polymorphism information content, and 0.3214 to 1.000 observed and 0.3097 to 0.8567 expected heterozygosity per locus. The mean observed and expected heterozygosity was 0.6816 and 0.6724, respectively. Three loci deviated significantly from Hardy-Weinberg equilibrium after Bonferroni's correction, and no significant linkage disequilibrum between pairs of loci was found. This information will be useful for the analysis of population genetic diversity, and the management of this important fish resource. PMID- 21823096 TI - Assessing genetic diversity of cotton cultivars using genomic and newly developed expressed sequence tag-derived microsatellite markers. AB - Estimations of genetic diversity and of relationships between varieties are crucial for cotton breeding. The genetic diversity of 59 core cotton cultivars, most of which were collected from China's main cotton-growing areas, was analyzed based on genomic and newly developed expressed sequence tag-derived microsatellite markers, using total DNA extracted from fresh leaf tissue. Three hundred and two fragments were detected, of which 255 were polymorphic. The number of amplification products generated by each primer varied from 2 to 14, with a mean of 5.08 bands/primer. The polymorphism information content was 0.50 to 0.90, with a mean of 0.80. The genetic similarity coefficients were calculated and dendrograms were constructed by the unweighted pair group with arithmetic mean method; the resulting distance matrix gave a dendrogram with four main clusters. Some cultivars with similar pedigrees could be clustered. For example, Zhong206 and Shanmian4, both derived from Deltapine15, were clustered. The genetic similarity coefficient of the 59 core cultivars ranged from 0.53 to 0.99, with a mean of 0.72, indicating that there was a relatively high level of genetic variation. PMID- 21823097 TI - Molecular genetic analysis of the yellow-breasted capuchin monkey: recommendations for ex situ conservation. AB - The yellow-breasted capuchin monkey, Cebus xanthosternos, is one of the most endangered species of the Brazilian Atlantic Forest. In situ conservation for this species is problematic due to habitat destruction; therefore, captive conservation has been considered as an alternative strategy. A Studbook for C. xanthosternos has been kept for more than 20 years; however, no genetic data has been collected. Our aim was to provide a preliminary assessment of the genetic variability of C. xanthosternos in captivity in Brazil and compare it with data from the wild. Microsatellite and mtDNA sequencing were carried out in 40 samples from five Brazilian institutions registered in the international Studbook and compared with 8 samples collected in a wild population from REBIO-Una/BA. DNA for analysis was extracted from hair, feces and blood. Our results showed that two of the five captive groups assessed had a genetic variability comparable to wild animals. However, the other three groups apparently require urgent management to improve its genetic variability. Considering that inbreeding effects are more pronounced in captivity due to lack of gene flow, our data indicate a need to increase population size by introducing newly rescued individuals into these captive groups. Our results are the first attempt to provide genetic information for captive C. xanthosternos in Brazil. PMID- 21823098 TI - Influence of the halothane gene (HAL) on pork quality in two commercial crossbreeds. AB - We evaluated the effect of the halothane (HAL) gene on the quality of pork in domestic pigs. Half-carcasses from two different commercial pig (Sus domestica) crossbreeds were analyzed, 46 of which were homozygous dominant (HAL(NN)) and 69 of which were heterozygous (HAL(Nn)) for the halothane gene. The measures included backfat thickness, lean meat percentage, carcass weight, pH 24 h after slaughtering, color, and drip loss; DNA was extracted from the haunch muscle. Swine with the HAL(Nn) genotype had less backfat thickness and higher lean meat percentages than swine with the HAL(NN) genotype. Yet, swine with the HAL(Nn) genotype had lower quality meat than those with the HAL(NN) swine. The pH at 24 h was lower in HAL(Nn) swine. The meat color was paler in HAL(Nn) animals, the drip loss was greater in those animals bearing the n allele, and the amount of intramuscular fat was not related to the halothane genotype. We conclude that bearers of the recessive allele of the halothane gene produce more meat, but with quality parameters that are inferior to those sought by consumers and industry. PMID- 21823099 TI - Genetic evaluation of Jatropha curcas: an important oilseed for biodiesel production. AB - Jatropha curcas, internationally and locally known, respectively, as physic nut and pinhao manso, is a highly promising species for biodiesel production in Brazil and other countries in the tropics. It is rustic, grows in warm regions and is easily cultivated. These characteristics and high-quality oil yields from the seeds have made this plant a priority for biodiesel programs in Brazil. Consequently, this species merits genetic investigations aimed at improving yields. Some studies have detected genetic variability in accessions in Africa and Asia. We have made the first genetic evaluation of J. curcas collected from Brazil. Our objective was to quantify genetic diversity and to estimate genetic parameters for growth and production traits and seed oil content. We evaluated 75 J. curcas progenies collected from Brazil and three from Cambodia. The mean oil content in the seeds was 31%, ranging from 16 to 45%. No genetic correlation between growth traits and seed oil content was found. However, high coefficients of genetic variation were found for plant height, number of branches, height of branches, and stem diameter. The highest individual narrow-sense heritabilities were found for leaf length (0.35) and width (0.34), stem diameter (0.24) and height of branches (0.21). We used a clustering algorithm to genetically identify the closest and most distant progenies, to assist in the development of new cultivars. Geographical diversity did not necessarily represent the genetic diversity among the accessions collected. These results are important for the continuity of breeding programs, aimed at obtaining cultivars with high grain yield and high oil content in seeds. PMID- 21823100 TI - mtDNA variation of the critically endangered hawksbill turtle (Eretmochelys imbricata) nesting on Iranian islands of the Persian Gulf. AB - Genetic diversity of sea turtles (hawksbill turtle) was studied using sequencing of mitochondrial DNA (mtDNA, D-loop region). Thirty dead embryos were collected from the Kish and Qeshm Islands in the Persian Gulf. Analysis of sequence variation over 890 bp of the mtDNA control region revealed five haplotypes among 30 individuals. This is the first time that Iranian haplotypes have been recorded. Nucleotide and haplotype diversity was 0.77 and 0.001 for Qeshm Island and 0.64 and 0.002 for Kish Island, respectively. Total haplotype diversity was calculated as 0.69, which demonstrates low genetic diversity in this area. The data also indicated very high rates of migration between the populations of these two islands. A comparison of our data with data from previous studies downloaded from a gene bank showed that turtles of the Persian Gulf migrated from the Pacific and the Sea of Oman into this area. On the other hand, evidence of migration from populations to the West was not found. PMID- 21823101 TI - Molecular cloning and sequence analysis of follicle-stimulating hormone beta polypeptide precursor cDNA from the bovine pituitary gland. AB - Follicle-stimulating hormone (FSH) plays an essential role in mammalian spermatogenesis and follicular development. In a previous study, we demonstrated that some bulls carry numerous linked mutations in the FSH beta-subunit (FSHB) gene, and that these bulls have poor-quality semen, low fertility, and slightly lower serum FSH concentration compared to those without such mutations. Here, we identified the different FSHB mRNA transcripts in such individuals and analyzed the evolutionary pattern of the FSHB open reading frame (ORF) in different species. Two different lengths of FSHB mRNA transcripts corresponding to two different polyadenylation sites in the 3'-UTR were detected in wild-type bull pituitary glands, and four different mRNA transcripts resulting from the different polyadenylation sites and linked mutations were identified in mutation bearing bull pituitaries. All transcripts had almost the same putative FSHB precursor molecule. When the ORF sequences of wild-type and mutation-bearing genes were compared with those of other tetrapod species, the leopard frog had the lowest level of homology (57.8 and 58.1%) and the buffalo had the highest level (95.9 and 96.7%), respectively. These results indicated that the bovine FSHB gene transcribes at least two classes of mRNA in the wild-type and four classes of mRNA in the mutation-bearing individuals, which provides a new insight into the bovine FSHB evolutionary pattern. In addition, these findings lay a foundation for further study of gene expression regulation and the effects of mutations on male fertility traits in cattle. PMID- 21823102 TI - Isolation and characterization of microsatellite loci in the fish Coilia mystus (Clupeiformes: Engraulidae) using PCR-based isolation of microsatellite arrays. AB - Coilia mystus is the most important harvested fish species in China; it inhabits quite different water environments during the different life history stages. Populations of C. mystus have dropped sharply due to overharvesting and water pollution. We developed eight microsatellite loci in C. mystus for conservation genetics studies. These new markers were tested in 20 individuals from the Min River in ChangLe. The number of alleles ranged from 3 to 8, the expected heterozygosity from 0.621 to 0.853 and the observed heterozygosity from 0.473 0.800. Only two loci deviated significantly from Hardy-Weinberg expectations due to heterozygote deficiency. These primers may provide a tool for understanding demography and population structure of this economically important and threatened species. PMID- 21823103 TI - Complementary medicine for fatigue and cortisol variability in breast cancer survivors: a randomized controlled trial. AB - BACKGROUND: Fatigue is a chief complaint in cancer patients, and warrants effective treatment. Biofield therapies are complementary medicine approaches used by cancer populations. There is little information about their efficacy. METHODS: This blinded, randomized controlled trial examined the effects of 4 weeks (eight 1-hour sessions) of biofield healing compared with mock healing and a waitlist control group on fatigue in 76 fatigued breast cancer survivors (stages I-IIIa). Secondary outcomes were diurnal cortisol variability (via estimates of cortisol slope), depression, and quality of life (QOL). Treatment belief was assessed to explore whether belief predicted outcomes. Data were analyzed via hierarchical linear modeling. RESULTS: There were no significant differences between biofield healing and mock healing on belief; 75% thought they received biofield healing. Compared with controls, biofield healing significantly decreased total fatigue (P < .0005, Cohen's d = 1.04), as did mock healing (P = .02, Cohen's d = 0.68), with no significant differences between biofield healing and mock healing. Cortisol slope significantly decreased for biofield healing versus both mock healing and control (P < .04 in both cases; Cohen's d = 0.58). Belief predicted changes in QOL over and above group (P = .004, Cohen's d = 0.84). Belief did not impact fatigue or cortisol variability. CONCLUSIONS: Nonspecific factors are important in responses to biofield interventions for fatigue. Belief predicts QOL responses but not fatigue or cortisol variability. Biofield therapies increase cortisol variability independent of belief and other nonspecific factors. There is a need to further examine the effects of specific processes of biofield healing on outcomes for cancer populations. PMID- 21823104 TI - Exposure to bisphosphonates and risk of colorectal cancer: a population-based nested case-control study. AB - BACKGROUND: Chemoprevention is a potentially attractive strategy for decreasing the burden of colorectal cancer (CRC). Preclinical studies suggest that bisphosphonates (BPs) may have direct antitumour effects against CRC. The objective of this study was to determine the effect of exposure to BPs on the incidence of CRC. METHODS: The Manitoba Cancer Registry was used to identify patients who were diagnosed with CRC from 2000 to 2009 who had been living in Manitoba for at least 5 years before diagnosis (cases). Each case was matched to 10 controls of similar age, sex, and duration of residence in Manitoba using incidence density sampling. Exposure to BPs was determined using the provincial Drug Program Information Network database. Conditional logistic regression analysis was performed to determine the effect of exposure to BPs on CRC incidence with adjustment for health care use, medical procedures (including lower gastrointestinal endoscopy), socioeconomic status, and pre-existing health conditions. RESULTS: In total, 5425 patients with CRC were matched to 54,242 controls. In the multivariate analysis, exposure to BPs was associated with a reduction in the risk of CRC (2-13 BP prescriptions over >=5 years: odds ratio [OR] 0.84; 95% confidence interval [CI], 0.71-1.00; >=14 BP prescriptions over >=5 years: OR, 0.78; 95% CI, 0.65-0.94). When the effect of specific BP agents was evaluated, the effect was significant only for exposure to risedronic acid (OR, 0.50; 95% CI, 0.30-0.85). There was no significant effect of increasing duration or cumulative dose of alendronic acid. CONCLUSIONS: The results from this study suggested that exposure to BPs, especially risedronic acid, may be associated with a decreased risk of developing CRC. PMID- 21823105 TI - Limited evidence of human papillomavirus in [corrected] breast tissue using molecular in situ methods. AB - BACKGROUND: Human papillomavirus (HPV) has been proposed as an etiologic agent of breast cancer based on numerous reports of high-risk (oncogenic) HPV types in malignant breast tissues. However, most of those studies used standard and nested solution polymerase chain reaction (PCR) techniques, both of which are disadvantaged by vulnerability to laboratory contamination from positive control DNA and the inability to localize the signal to a specific cell type. To overcome these drawbacks, the authors of this report explored the use of in situ molecular methods of viral detection to reassess the frequency of HPV in malignant breast tissue. METHODS: In situ hybridization (ISH) was used with probes that were specific for the capsid region of 12 oncogenic HPV types, and in situ PCR (IS PCR) was used with primers that were specific for the capsid region of HPV-16, which is the most common oncogenic HPV type. These methods were resistant to molecular contamination and allowed identification of the positive cell type. The specimens examined were malignant tissues from patients with 70 breast cancer patients at The University of Texas M. D. Anderson Cancer Center in Houston, Texas. RESULTS: HPV was observed in 4 of 70 specimens (5.7%) using ISH and in 2 of 70 specimens (2.9%) of specimens using IS-PCR. Concordance between the 2 methods was high for negative specimens; both methods yielded negative results in 66 of 70 specimens (94.3%). However, there was no concordance for the few positive specimens, probably because of differences in sensitivity and the targeted HPV types. CONCLUSIONS: Oncogenic (high-risk) HPV types were present in malignant breast epithelium very infrequently and, thus, may be causative agents of only a relatively small proportion of all breast cancers. PMID- 21823106 TI - Cancer survivorship and sexual orientation. PMID- 21823107 TI - Quality of care in patients with bladder cancer: a case report? AB - BACKGROUND: Although there is level I evidence demonstrating the superiority of intravesical therapy in patients with bladder cancer, surveillance strategies are primarily founded on expert opinion. The authors examined compliance with surveillance and treatment strategies and the pursuant impact on survival in patients with high-grade disease. METHODS: Using linked Surveillance, Epidemiology, and End Results (SEER)-Medicare data, the authors identified subjects with a diagnosis of high-grade, non-muscle-invasive disease between 1992 and 2002 who survived 2 years and did not undergo definitive treatment during that time. Nonlinear mixed-effects regression analyses was used to examine compliance with surveillance and treatment strategies. After adjusting for confounders using a propensity score-weighted approach, the authors determined whether individual and comprehensive strategies during the initial 2 years after diagnosis were associated with survival after 2 years. RESULTS: Of 4790 subjects, only 1 received all the recommended measures. Although mean utilization for most measures significantly increased after 1997, only compliance with an induction course of bacillus Calmette-Guerin (BCG) increased (13% to 20%; P < .001). On multivariate analysis, compliance with >= 4 cystoscopies, >= 4 cytologies, and BCG instillation was found to be lower among octogenarians and higher among those with undifferentiated, Tis, and T1 tumors, and among those individuals diagnosed after 1997. Subjects compliant with these measures had a lower hazard of mortality (hazard ratio, 0.41; 95% confidence interval, 0.18-0.93) than those who received < 4 cystoscopies, < 4 cytologies, and no BCG. CONCLUSION: There was a statistically significant survival advantage found among those who received at least half of the recommended care. Improving compliance with these process-of care measures via systematic quality improvement initiatives serves as the primary target to meliorate bladder cancer care. PMID- 21823108 TI - Effect of CYP2D6 polymorphisms on breast cancer recurrence. AB - BACKGROUND: Previous studies evaluating the effect of cytochrome P450 2D6 (CYP2D6) polymorphisms on outcomes of adjuvant tamoxifen therapy have been conflicting due to differences in study design, concomitant medications that alter CYP2D6 metabolism, and tamoxifen adherence. METHODS: The authors performed CYP2D6 genotyping from whole blood and fresh frozen tumor samples (n 106) in patients at The University of Texas MD Anderson Cancer Center who were receiving, or had received, tamoxifen as adjuvant therapy for early breast cancer (EBC), using the AmpliChip CYP450 Test. Each patient's medical history was assessed for drugs that affected CYP2D6. Fifty-five patients who had experienced breast cancer recurrence were matched (by date of diagnosis, menopausal status, clinical stage [TNM Staging System], and race) to patients without recurrence. RESULTS: Unadjusted for other patient characteristics, the odds ratio for disease recurrence associated with CYP2D6 functional status was 1.0 (95% confidence interval, 0.35-2.85). After adjustment for stage, CYP2D6 inhibitors (moderate or strong vs none), and follow-up time, no significant association was found between CYP2D6 genotype and breast cancer recurrence in patients who were treated with adjuvant tamoxifen for EBC. CONCLUSIONS: This case-control study demonstrated no significant effect of CYP2D6 genotype on risk of recurrence in breast cancer patients who received adjuvant tamoxifen therapy. PMID- 21823110 TI - Efficacy of imatinib mesylate for the treatment of locally advanced and/or metastatic tenosynovial giant cell tumor/pigmented villonodular synovitis. AB - BACKGROUND: Pigmented villonodular synovitis (PVNS) (also known as diffuse-type giant cell tumor) and tenosynovial giant cell tumors (TGCT) are rare, usually benign neoplasms that affect the synovium and tendon sheaths in young adults. These tumors are driven by the overexpression of colony stimulating factor-1 (CSF1). CSF1 is expressed by a minority of tumor cells, which, in turn attract non-neoplastic inflammatory cells that express CSF1 receptor (CSF1R) through a paracrine effect. METHODS: Imatinib mesylate (IM) blocks CSF1R, and previous case reports indicated that it also exerts antitumor activity in PVNS. The authors conducted a multi-institutional retrospective study to assess the activity of IM in patients with locally advanced/metastatic PVNS/TGCT. RESULTS: Twenty-nine patients from 12 institutions in Europe, Australia, and the United States were included. There were 13 men, the median age was 41 years, and the most common site of disease was the knee (n = 17; 59%). Two patients had metastatic disease to the lung and/or bone. Five of 27 evaluable patients had Response Evaluation in Solid Tumor (RECIST) responses (overall response rate, 19%; 1 complete response and 4 partial responses), and 20 of 27 patients (74%) had stable disease. Symptomatic improvement was noted in 16 of 22 patients (73%) who were assessable for symptoms. Despite a high rate of symptomatic improvement and a favorable safety profile, 6 patients discontinued because of toxicity, and 4 patients decided to discontinue IM for no clear medical reason. CONCLUSIONS: IM displayed interesting activity in patients with PVNS/TGCT, providing proof of concept for targeting CSF1R in this disease. The authors concluded that the benefits of alleviating morbidity in patients with localized PVNS/TGCT must be balanced against the potential toxicity of chronic drug therapy. PMID- 21823111 TI - Validation of the Royal Marsden Hospital prognostic score in patients treated in the Phase I Clinical Trials Program at the MD Anderson Cancer Center. AB - BACKGROUND: The authors validated the Royal Marsden Hospital (RMH) prognostic score in patients with advanced lung, pancreatic, and head and neck cancers who were enrolled on phase 1 trials in the MD Anderson Cancer Center Phase I Clinical Trials Program. METHODS: The RMH score uses albumin (>=3.5 g/dL vs <3.5 g/dL), lactate dehydrogenase (less than or equal to the upper limit of normal [<=ULN] vs >ULN), and the number of metastatic sites (<=2 sites vs >=3 sites) to predict patient survival in phase 1 trials. The authors of this report retrospectively reviewed the outcomes of 229 consecutive patients with lung, pancreatic, and head and neck tumors who were treated on 57 phase 1 trials. RESULTS: Two hundred twenty-nine consecutive patients with lung cancer (N = 85), pancreatic cancer (N = 83), and head and neck tumors (N = 61) were treated. The median patient age was 60 years (range, 26-85 years), and 63% of the patients were men. Patients with a good RMH prognostic score (0-1) at baseline had a longer median survival than patients with a poor prognostic score (2-3; 33.9 weeks vs 21.1 weeks; P < .0001). The RMH score was an independent variable that predicted survival in multivariate analysis. Other independent variables that predicted better survival were hemoglobin level (>=10.5 g/dL), Eastern Cooperative Oncology Group performance status (0-1), and tumor type. Patients who were treated on first-in-human trials did not fare worse compared with those who were not treated on first-in-human trials. CONCLUSIONS: For patients with lung, pancreatic, and head and neck tumors who were treated on phase 1 trials, survival was predicted accurately by the RMH prognostic score. PMID- 21823112 TI - Inappropriate utilization of radiographic imaging in men with newly diagnosed prostate cancer in the United States. AB - BACKGROUND: The use of radiographic imaging (bone scan and computerized tomography) is only recommended for men diagnosed with high-risk prostate cancer characteristics. The authors sought to characterize utilization patterns of imaging in men with newly diagnosed prostate cancer. METHODS: The authors performed a population-based observational cohort study using the US Surveillance, Epidemiology, and End Results-Medicare linked data to identify 30,183 men diagnosed with prostate cancer during 2004 to 2005. RESULTS: Thirty four percent of men with low-risk and 48% with intermediate-risk prostate cancer underwent imaging, whereas only 60% of men with high-risk disease received imaging before treatment. Radiographic imaging utilization was greater for men who were older than 75 years (odds ratio [OR], 1.28; 95% confidence interval [CI], 1.20-1.37; P < .001), were black (OR, 1.11; 95% CI, 1.01-1.21; P = .030), resided in wealthier areas (OR, 1.19; 95% CI, 1.08-1.32 for median income >$60,000 vs <$35,000; P < .001), lived in rural regions (OR, 1.23; 95% CI, 1.12 1.36; P < .001), or underwent standard radiation therapies (OR, 1.71; 95% CI, 1.60-1.84; P < .001). Imaging utilization was less for men living in areas with greater high school education (OR, 0.83; 95% CI, 0.75-0.91 between highest and lowest graduation rates; P < .001) or opting for active surveillance (OR, 0.17; 95% CI, 0.15-0.19 vs radical prostatectomy; P < .001). The estimated cost of unnecessary imaging over this 2-year period exceeded $3.6 million. CONCLUSIONS: In the United States, there is widespread overutilization of imaging for low-risk and intermediate-risk prostate cancer, whereas a worrisome number of men with high-risk disease did not receive appropriate imaging studies to exclude metastases before therapy. PMID- 21823113 TI - Educational achievement in Swiss childhood cancer survivors compared with the general population. AB - BACKGROUND: The objective of this study was to describe educational achievements of childhood cancer survivors in Switzerland compared with the general population. In particular, the authors investigated educational problems during childhood, final educational achievement in adulthood, and its predictors. METHODS: Childhood cancer survivors who were aged <16 years at diagnosis from 1976 to 2003 who had survived for >=5 years and were currently ages 20 to 40 years received a postal questionnaire during 2007 to 2009. Controls were respondents of the Swiss Health Survey ages 20 to 40 years. Educational achievement included compulsory schooling, vocational training, upper secondary schooling, and university degree. The analysis was weighted to optimize comparability of the populations. The authors analyzed the association between demographic and clinical predictors and educational achievement using multivariable logistic regression. Subgroup analyses focused on survivors aged >=27 years. RESULTS: One-third of survivors encountered educational problems during schooling (30% repeated 1 year, and 35% received supportive tutoring). In the total sample, more survivors than controls achieved compulsory schooling only (8.7% vs 5.2%) and fewer acquired a university degree (7.3% vs 11%), but more survivors than controls achieved an upper secondary education (36.1 vs 24.1%). In those aged >=27 years, differences in compulsory schooling and university education largely disappeared. In survivors and controls, sex, nationality, language region, and migration background were strong predictors of achievement. Survivors of central nervous system tumors or those who had a relapse had poorer outcomes (P < .05). CONCLUSIONS: Childhood cancer survivors encountered problems during schooling and completed professional education with some delay. However, with the exception of patients who had central nervous system tumors and those who experienced a relapse, the final educational achievement in survivors of child cancer was comparable to that of the general population. PMID- 21823115 TI - Relationship between sunbed use and melanoma risk in a large case-control study in the United Kingdom. PMID- 21823114 TI - Modifying effect of MDM4 variants on risk of HPV16-associated squamous cell carcinoma of oropharynx. AB - BACKGROUND: The p53 pathway plays a critical role in maintaining genomic stability and preventing tumor formation. Given the roles of both MDM4 and HPV16 E6 oncoproteins in inhibition of p53 activity, we tested the hypothesis that MDM4 polymorphisms are associated with the risk of HPV16-associated squamous cell carcinoma of head and neck (SCCHN). METHODS: Genotyping was conducted on 3 tagging single nucleotide polymorphisms (rs11801299 G>A, rs10900598 G>T, and rs1380576 C>G) in MDM4, and serology was used to determine HPV 16 exposure in 380 cases and 335 cancer-free controls that were frequency-matched by age, sex, smoking, and drinking status. RESULTS: None of 3 MDM4 polymorphisms alone was significantly associated with risk of overall SCCHN. With further analysis stratified by HPV16 serology and tumor site, we found that each polymorphism individually modified the risk of HPV16-associated squamous cell carcinoma of the oropharynx (SCCOP), and such effect modification was particularly pronounced in never smokers and never drinkers. CONCLUSION: The risk of HPV16-associated SCCOP could be modified by MDM4 polymorphisms. Large and prospective studies are needed to validate our findings. PMID- 21823116 TI - Vegetable and fruit intake after diagnosis and risk of prostate cancer progression. AB - Cruciferous vegetables, tomato sauce and legumes have been associated with reduced risk of incident advanced prostate cancer. In vitro and animal studies suggest these foods may inhibit progression of prostate cancer, but there are limited data in men. Therefore, we prospectively examined whether intake of total vegetables, and specifically cruciferous vegetables, tomato sauce and legumes, after diagnosis reduce risk of prostate cancer progression among 1,560 men diagnosed with non-metastatic prostate cancer and participating in the Cancer of the Prostate Strategic Urologic Research Endeavor, a United States prostate cancer registry. As a secondary analysis, we also examined other vegetable subgroups, total fruit and subgroups of fruits. The participants were diagnosed primarily at community-based clinics and followed from 2004 to 2009. We assessed vegetable and fruit intake via a semi-quantitative food frequency questionnaire, and ascertained prostate cancer outcomes via urologist report and medical records. We observed 134 events of progression (53 biochemical recurrences, 71 secondary treatments likely due to recurrence, 6 bone metastases and 4 prostate cancer deaths) during 3,171 person-years. Men in the fourth quartile of post diagnostic cruciferous vegetable intake had a statistically significant 59% decreased risk of prostate cancer progression compared to men in the lowest quartile (hazard ratio (HR): 0.41; 95% confidence interval (CI): 0.22, 0.76; p trend: 0.003). No other vegetable or fruit group was statistically significantly associated with risk of prostate cancer progression. In conclusion, cruciferous vegetable intake after diagnosis may reduce risk of prostate cancer progression. PMID- 21823118 TI - Neuropeptide Y stimulates proliferation and migration in the 4T1 breast cancer cell line. AB - Stress has long been thought of to be associated with increased risk of cancer. Chronic stress is associated with elevated levels of sympathetic neurotransmitter (norepinephrine and neuropeptide Y: NPY) release and immunosuppression. The expression of NPY receptors has been reported in human breast carcinomas. Recently, activation of the NPY Y5 receptor was shown to stimulate cell growth and increase migration in human breast cancer cells; however the effects of NPY have yet to be investigated in a murine model of breast cancer. Thus, the specific aims of the current study were to: (i) characterize NPY receptor expression in 4T1 breast cancer cells and orthotopic tumors grown in BALB/c mice and (ii) investigate the impact of NPY receptor activation on 4T1 cell proliferation and migration in vitro. Positive expression of NPY receptors (Y1R, Y2R and Y5R) was observed in cells and tumor tissue. As well, NPY treatment of 4T1 cells promoted a concentration-dependent increase in proliferation, through increased phosphorylation of ERK 1/2. Using NPY receptor antagonists (Y1R:BIBP3226, Y2R:BIIE0246 and Y5R:L-152,804), we found the proliferative response to be Y5R mediated. Additionally, NPY increased chemotaxis through Y2R and Y5R activation. These data are in congruence with those from human cell lines and highlight the 4T1 cell line as a translatable model of breast cancer in which the effects of NPY can be studied in an immunocompetent system. PMID- 21823117 TI - Long-term risk of recurrent cervical human papillomavirus infection and precancer and cancer following excisional treatment. AB - Risk of recurrent CIN2+ (including cervical intraepithelial neoplasia grade 2 [CIN2], CIN3, carcinoma and in situ, adenocarcinoma in situ or cancer) remains elevated for years following treatment. The role of long-term post-treatment human papillomavirus (HPV) presence on subsequent risk of CIN2+ was evaluated in the 10,049-women Guanacaste cohort. Six hundred eighty-one women were referred to colposcopy because of high-grade cytology, positive cervicography and/or suspicion of cancer based on visual assessment; 486 were judged to require treatment. After excluding women with <12 months of follow-up (N = 88), prior cancer or hysterectomy (N = 37) or other reasons (N = 14), 347 were included in the analysis. Infections were categorized as persistent if present at both pre- and post-treatment visits and new if detected only post-treatment. Median time between the treatment and post-treatment visits was 6.7 years (interquartile range 3.8-7.8). At the post-treatment visit, 8 (2.4%), 2 (0.6%) and 8 (2.4%) of the 347 treated women had persistent HPV16, HPV18 or other carcinogenic HPV, respectively. Two (0.8%), 3 (1.0%) and 13 (4.0%) had new HPV16, HPV18 and other carcinogenic HPV, respectively. Six CIN2+ cases were identified at the post treatment visit, all with persistent infections (three HPV16, one HPV18 and two other carcinogenic HPV). No recurrent disease was observed among women with new HPV infections during the follow-up period. Thus, persistence of HPV infection a median of six years after treatment was uncommon but, when present, posed a substantial risk of subsequent CIN2+. Serial follow-up data from other studies would further strengthen these conclusions. PMID- 21823119 TI - The role of focal adhesion kinase catalytic activity on the proliferation and migration of squamous cell carcinoma cells. AB - Focal adhesion kinase (FAK) is upregulated in several epithelial tumours and there has been considerable interest in developing small molecule kinase inhibitors of FAK. However, FAK also has important adaptor functions within the cell, integrating signals from both integrins and growth factors. To investigate the role of FAKs kinase domain, we generated fak-deficient squamous cell carcinoma (SCC) cell lines. Re-expression of a wild type or kinase dead FAK allowed us to delineate its kinase dependent functions. In addition, we used the novel FAK kinase inhibitor PF-562,271. The kinase activity of FAK was important for tumour cell migration and polarity but more striking was its requirement for the anchorage independent 3 dimensional (3D) proliferation of SCC cells and their growth as xenografts in mice. Inhibition of FAK activity and prevention of growth in 3D correlated with Src inhibition. We further identified a mechanism whereby FAK regulates proliferation in 3D via regulation of the kinase activity of Src. This was dependent on the kinase activity of FAK and its resulting phosphorylation on Y397 that provides a high affinity binding site for Src. These data support the further development of FAK kinase inhibitors as agents that have the potential to inhibit both tumour cell migration and proliferation. PMID- 21823120 TI - Matched-pair analysis comparing the outcomes of primary breast and nodal diffuse large B-cell lymphoma in patients treated with rituximab plus chemotherapy. AB - Primary breast diffuse large B-cell lymphoma (DLBCL) is an extremely rare presentation of non-Hodgkin's lymphoma that has been associated with poorer clinical outcomes compared with nodal DLBCL in the pre-rituximab era. The aim of this study was to investigate the impact of rituximab on clinical outcomes in patients with primary breast DLBCL. Data from 25 female patients with primary breast DLBCL receiving rituximab plus chemotherapy were matched to 75 female patients (1:3) with nodal DLBCL by following five established prognostic factors (age, Ann Arbor stage, Eastern Cooperative Oncology Group performance status, serum lactate dehydrogenase level and B symptoms). Overall survival (OS) was similar between primary breast and nodal DLBCL groups (3-year OS rate, 82.2% vs. 90.7%, respectively; p = 0.345). In the analysis of immunohistochemically defined prognostic subgroups, 19 of 20 available cases in the primary breast DLBCL group displayed a non-germinal center (GC) phenotype. Compared with patterns of recurrence, extranodal progression in the breast or central nervous system (CNS) was significantly higher in the primary breast DLBCL group than in the nodal DLBCL group (p < 0.001). Additionally, the stage-modified International Prognostic Index was the only independent prognostic factor for OS in this population. This suggests that clinical outcomes of primary breast DLBCL might no longer be inferior to those of nodal DLBCL in the rituximab era, which might be associated with the intrinsic biologic characteristics of the non-GC phenotype. However, despite including rituximab, extranodal progression in the breast or CNS was problematic. This study was registered at www.clinicaltrials.gov as no. NCT01266668. PMID- 21823121 TI - Recombinant canstatin inhibits angiopoietin-1-induced angiogenesis and lymphangiogenesis. AB - We describe the effect of recombinant canstatin, the NC1 domain of the alpha2 chain of Type IV collagen, on suppression of angiogenesis and lymphangiogenesis both in vitro and in vivo. Recombinant canstatin produced from stably transformed Drosophila S2 cells reduced the expression of angiopoietin-1 in hypoxia mimetic agent, CoCl(2) -treated CT-26 cells. Recombinant canstatin inhibited proliferation, tube formation and migration of human angiopoietin-1 (rhAngpt-1) treated human umbilical vein endothelial cells (HUVEC) and lymphatic endothelial cells (LEC). Recombinant canstatin suppressed the expression of Tie-2 and vascular endothelial growth factor-3 (VEGFR-3) transcripts in rhAngpt-1-treated HUVEC and LEC, respectively. The inhibitory effect of recombinant canstatin on tumor growth was also investigated using a heterotopic CT-26 colon carcinoma animal (BALB/c mice) model. Recombinant canstatin reduced the final volume and weight of tumors, and blood and lymphatic vessel densities of tumors, which were evaluated by CD-31 and LYVE-1 immunostaining. Immunohistochemical analysis showed that recombinant canstatin dramatically reduced the expression of angiopoietin-1 in CT-26 colon carcinoma-induced tumor, but not the expression of VEGF-C. Tie-2 and VEGFR-3 expressions were also reduced in recombinant canstatin-treated tumors. These results indicate that recombinant canstatin has anti-tumoral activities against CT-26 colon carcinoma cells. Recombinant canstatin reduces the expression of angiopoietin-1 in hypoxia-induced CT-26 cells and inhibits the angiogenic and lymphangiogenic signaling induced by angiopoietin-1. Recombinant canstatin probably inhibits angiogenesis and lymphangiogenesis via suppression of the integrin-dependent FAK signaling induced by angiopoietin-1/Tie-2 and/or VEGFR 3. PMID- 21823122 TI - Differential glycosylation of MUC1 and CEACAM5 between normal mucosa and tumour tissue of colon cancer patients. AB - Altered glycosylation in epithelial cancers may play an important role in tumour progression, as it may affect tumour cell migration and antigen presentation by antigen presenting cells. We specifically characterise the glycosylation patterns of two tumour antigens that are highly expressed in cancer tissue and often detected in their secreted form in serum: the epithelial mucin MUC1 and carcinoembryonic antigen (CEA, also called CEACAM5). We analysed 48 colorectal cancer patients, comparing normal colon and tumour epithelium within each patient. Lectin binding was studied by a standardised CEA/MUC1 capture ELISA, using several plant lectins, and the human C-type lectins MGL and DC-SIGN, and Galectin-3. Peanut agglutinin (PNA) bound to MUC1 from tumour tissue in particular, suggests increased expression of the Thomsen-Friedenreich antigen (TF antigen) (Core 1, Galbeta1-3GalNAc-Ser/Thr). Only small amounts of Tn-antigen (GalNAcalpha-Ser/Thr) expression was observed, but the human C-type lectin MGL showed increased binding to tumour-associated MUC1. Furthermore, sialylation was greatly enhanced. In sharp contrast, tumour-associated CEA (CEACAM5) contained high levels of the blood-group related carbohydrates, Lewis X and Lewis Y. This correlated strongly with the interaction of the human C-type lectin DC-SIGN to tumour-associated CEA, suggesting that CEA can be recognized and taken up by antigen presenting cells. In addition, increased mannose expression was observed and branched N-glycans were prominent, and this correlated well with human Galectin-3 binding. These data demonstrate that individual tumour antigens contain distinct glycan structures associated with cancer and, since glycans affect cellular interactions with its microenvironment, this may have consequences for progression of the disease. PMID- 21823123 TI - Tumor-dependent down-regulation of the zeta-chain in T-cells is detectable in early breast cancer and correlates with immune cell function. AB - Suppressive factors produced by tumors or tumor-associated cells represent a major obstacle to immune-mediated tumor eradication and immunotherapy. We studied tumor-dependent changes in expression of the zeta-chain, a key molecule for the transduction of stimulatory signals through the T-cell receptor and activating receptors on natural killer (NK) cells, in patients with early (stages 1 and 2) breast cancer. Ex-vivo levels of zeta-chain expression, proliferation and cytokine expression in lymphocyte subpopulations were measured in breast tumors, their draining lymph nodes and in pre- and postoperative blood samples of cancer patients and healthy controls by multi-parametric flow cytometry. We found that T cell zeta-chain expression in peripheral blood of breast cancer patients (n = 29) was down-regulated compared with healthy controls (n = 10) (p <= 0.033), which was most pronounced in stage 2 (n = 15, p <= 0.004). T- and NK-cell zeta-chain loss was most distinct in the tumor and decreased with increasing distance (p <= 0.015). After surgical tumor resection, peripheral blood zeta-chain levels normalized to those observed in healthy controls. zeta-chain expression in peripheral blood T-cells correlated with lymphocytic proliferative activity (p <= 0.035), and with the expression of proinflammatory cytokines in CD8+ T-cells (p <= 0.035). Breast cancer patients had lower numbers of circulating early memory CD8+ T-cells than healthy donors (p <= 0.000), correlating with lower T-cell zeta chain levels (p <= 0.011). Our findings suggest that phenotypic and functional alterations in lymphocytes can be detected even in early stage breast cancer patients. The observed immunosuppression appears to be systemic and tumor dependent, as it is strongest in the tumor, correlates with tumor stage and normalizes after surgery. PMID- 21823124 TI - Data mining: comparing the empiric CFS to the Canadian ME/CFS case definition. AB - This article contrasts two case definitions for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). We compared the empiric CFS case definition (Reeves et al., 2005) and the Canadian ME/CFS clinical case definition (Carruthers et al., 2003) with a sample of individuals with CFS versus those without. Data mining with decision trees was used to identify the best items to identify patients with CFS. Data mining is a statistical technique that was used to help determine which of the survey questions were most effective for accurately classifying cases. The empiric criteria identified about 79% of patients with CFS and the Canadian criteria identified 87% of patients. Items identified by the Canadian criteria had more construct validity. The implications of these findings are discussed. PMID- 21823125 TI - Effect of cultivar and roasting technique on sensory quality of Bierzo roasted pepper. AB - BACKGROUND: Pepper (Capsicum annuum L.) is one of the main horticultural products in the world. Roasted pepper is a high quality transformed product in the Iberian Peninsula, and obtained the recognition of 'Protected Geographical Indication' (PGI) of 'Pimiento Asado del Bierzo' in 2002. Roasted pepper has been traditionally processed with a steel-sheet hob. However, there are no data available about the effect of roasting technique in the quality of roasted pepper. The objective of this work was to compare the sensory quality of roasted pepper using industrial roasting techniques. RESULTS: Sensory properties that showed significant differences between roasting techniques were colour, thickness and charred remains (appearance descriptors), bitterness (taste descriptor) and smokiness (after-taste descriptor). Higher value of descriptors such as colour, charred remains and smokiness for peppers elaborated in a rotary oven, helped roasted pepper to reach a higher level of overall quality, although rotary oven samples reached the lowest roast yield. CONCLUSION: Roasting technique, rather than landrace, had the greatest effect on the sensory quality of roasted pepper, so the rotary oven was the roasting technique that achieved the highest quality score. This will contribute to improve sensory quality and marketing of PGI 'Pimiento Asado del Bierzo' in high quality markets. PMID- 21823126 TI - Changes in volatile compound composition of Antrodia camphorata during solid state fermentation. AB - BACKGROUND: Although the volatiles present in mushrooms and fungi have been investigated by many researchers, including Antrodia camphorata in submerged fermentation, there are few data available regarding changes in volatile compounds during fermentation. Our research has revealed that solid state fermentation of A. camphorata is highly odiferous compared with submerged cultures and the odor changed with increasing culture time. Therefore the aim of this study was to investigate the changes in volatile compound composition of A. camphorata during solid state fermentation. RESULTS: Altogether, 124 major volatile compounds were identified. The volatile compounds produced by A. camphorata during growth in solid state fermentation were quite different. Oct-1 en-3-ol, octan-3-one and methyl 2-phenylacetate were predominant in exponential growth phase production, while the dominant volatiles produced in stationary phase were octan-3-one and methyl 2-phenylacetate. In stationary phase, lactone compounds in A. camphorata, such as 5-butyloxolan-2-one, 5-heptyloxolan-2-one, 6 heptyloxan-2-one, contributed greatly to peach and fruit-like flavor. Terpene and terpene alcohol compounds, such as 1-terpineol, L-linalool, T-cadinol, (E, E) farnesol, beta-elemene, cis-alpha-bisabolene and alpha-muurolene, made different contributions to herbal fresh aroma in A. camphorata. Nineteen volatile sesquiterpenes were detected from solid state fermentation of A. camphorata. The compounds 5-n-butyl-5H-furan-2-one, beta-ionone, (-)-caryophyllene oxide, aromadendrene oxide, diepi-alpha-cedrene epoxide, beta-elemene, alpha-selinene, alpha-muurolene, azulene, germacrene D, gamma-cadinene and 2-methylpyrazine have not hitherto been reported in A. camphorata. CONCLUSION: The preliminary results suggest that the aroma-active compounds produced by A camphorata in solid state fermentation might serve as an important source of natural aroma compounds for the food and cosmetic industries or antibiotic activity compounds. The sesquiterpenes could be identified as possible taxonomic markers for A. camphorata. PMID- 21823127 TI - A novel bioabsorbable drug-eluting tracheal stent. AB - OBJECTIVES/HYPOTHESIS: Currently available silicone and metallic stents for tracheal stenosis are associated with problems of granulations, mucus trapping, and difficult removals. Our aim was to develop a novel bioabsorbable tracheal stent with mitomycin C (MMC) drug elution to circumvent such problems. STUDY DESIGN: A randomized animal study. METHODS: Twenty-five rabbits were randomly assigned into five test groups: 1) controls (without stent), 2) silicone tubular stents (commercially available currently); 3) bioabsorbable helical stents; 4) bioabsorbable tubular stents; and 5) bioabsorbable tubular stents with MMC. Weekly tracheal endoscopy to document granulation, mucus plugging, and extent of tracheal stenosis was performed for 12 weeks. One rabbit was euthanized every 3 weeks for histological analysis of the trachea. In vitro MMC-release profiles in conditions mimicking tracheal conditions were studied. RESULTS: The bioabsorbable tubular stents with 0.1 mg MMC drug elution performed the best, with the least mucus trapping and airway obstruction due to tracheal stenosis. Tracheal stenosis was most significant for the bioabsorbable helical stents, followed by the control group without stent, the group of bioabsorbable tubular stents, and then the silicone stents. After 12 weeks, tracheal stenosis for the bioabsorbable tubular stents with MMC was only half that of the silicone stents. CONCLUSIONS: This study reports on the development of a novel bioabsorbable tracheal stent with sustained MMC drug elution for preventing tracheal stenosis. Further studies are warranted to optimize stent design and drug dosage. PMID- 21823128 TI - Dielectrophoretic capture of E. coli cells at micropatterned nanoelectrode arrays. AB - This paper reports capture and detection of pathogenic bacteria based on AC dielectrophoresis (DEP) and electrochemical impedance spectroscopy (EIS) employing an embedded vertically aligned carbon nanofiber (VACNF) nanoelectrode array (NEA) versus a macroscopic indium-tin-oxide (ITO) transparent electrode in "points-and-lid" configuration. The nano-DEP device was fabricated using photolithography processes to define an exposed active region on a randomly distributed NEA and a microfluidic channel on ITO to guide the flow of labeled Escherichia coli cells, respectively, and then bond them into a fluidic chip. A high-frequency (100 kHz) AC field was applied to generate positive DEP at the tips of exposed CNFs. Enhanced electric field gradient was achieved due to reduction in electrode size down to nanometer scale which helped to overcome the large hydrodynamic drag force experienced by E. coli cells at high flow velocities (up to 1.6 mm/s). This DEP device was able to effectively capture a significant number of E. coli cells. Significant decrease in the absolute impedance at the NEA was observed in EIS experiments. The results obtained in this study suggest the possibility of integration of a fully functional electronic device for rapid, reversible and label-free capture and detection of pathogenic bacteria. PMID- 21823129 TI - Dielectrophoretic mobility determination in DC insulator-based dielectrophoresis. AB - Insulator-based dielectrophoresis (iDEP) is a powerful tool for separating and characterizing particles, yet it is limited by a lack of quantitative characterizations. Here, this limitation is addressed by employing a method capable of quantifying the DEP mobility of particles. Using streak-based velocimetry the particle properties are deduced from their motion in a microfluidic channel with a constant electric field gradient. From this approach, the DEP mobility of 1 MUm polystyrene particles was found to be -2+/-0.4 10(-8) cm4 /(V2 s). In the future, such quantitative treatment will allow for the elucidation of unique insights and rational design of devices. PMID- 21823130 TI - Double-layer polarization of a non-conducting particle in an alternating current field with applications to dielectrophoresis. AB - Dielectrophoresis is becoming one of the most important techniques in particle manipulation including particle separation, particle assembly, and biomolecule characterization. Understanding dielectrophoretic properties of particles is a key step toward effective and efficient particle manipulation. Theoretical studies of polarization of a particle can help to understand experimental observations and also go beyond to develop a predictive theory to guide the experimental design. This article discusses recent theoretical advances in the polarization of a dielectric particle, in particular, the polarization of the electric double layer. The double-layer polarization is critical to determine particle dynamics in dielectrophoresis. The dipole moment characterizing the strength of this polarization depends on the double-layer thickness, the electric field frequency, the particle's surface charge, and other surface's properties (Pohl, H. A., Dielectrophoresis, Cambridge University Press, New York 1978). After a brief review of the mathematical model, the focus is on the following problems: (i) the polarization of a spherical particle; (ii) the polarization of an elongated cylindrical particle; (iii) the effect of the slip on the polarization of a particle. The double-layer polarization is examined here in the context of high-frequency and low-frequency dispersions induced by surface conduction and diffusion, respectively. PMID- 21823131 TI - Cascade and staggered dielectrophoretic cell sorters. AB - We have developed two new microfluidic cell sorters based on conventional negative dielectrophoresis (DEP) for continuous flow operations. The first is a cascade configuration sorter designed to increase purity of isolated target cell. The second has two staggered side channels in opposite side walls to increase sample throughput without compromising enrichment factor. Particles (carboxylate microspheres) of different sizes were first used to demonstrate the feasibility of the present DEP sorters for cell isolation. Then biological cells, i.e. human prostate cancer cell line LNCaP and human colorectal cancer cell line HCT116 were used to test the performance of the DEP sorters. In the present work, applied voltage was in the range of 0-20 V(p-p) , and frequency was from 0 to 10 MHz. Comparing to a single side channel DEP cell sorter, the isolation purity was improved from 80 to 96% by a single cascade sorter and the sample throughput was increased from 0.2 to 0.65 MUL/min by a single staggered side channel sorter. In this article, we report the cell sorter designs, cell separation and enrichment factors. PMID- 21823132 TI - Dielectrophoretic particle-particle interaction under AC electrohydrodynamic flow conditions. AB - We used the Maxwell stress tensor method to understand dielectrophoretic particle particle interactions and applied the results to the interpretation of particle behaviors under alternating current (AC) electrohydrodynamic conditions such as AC electroosmosis (ACEO) and electrothermal flow (ETF). Distinct particle behaviors were observed under ACEO and ETF. Diverse particle-particle interactions observed in experiments such as particle clustering, particles keeping a certain distance from each other, chain and disc formation and their rotation, are explained based on the numerical simulation data. The improved understanding of particle behaviors in AC electrohydrodynamic flows presented here will enable researchers to design better particle manipulation strategies for lab-on-a-chip applications. PMID- 21823133 TI - Dielectrophoretic monitoring of microorganisms in environmental applications. AB - Dielectrophoresis (DEP) is the motion of polarizable particles in the presence of nonuniform electric fields. This novel electrokinetic technique has successfully been employed in many miniaturized systems for the manipulation and detection of microbes. This review article depicts the application of dielectrophoresis for the monitoring of microorganisms in microfluidic devices for environmental applications. The research studies described here are mainly conceived for water- and air-monitoring assessments, and are classified considering the target aimed to detect, concentrate, and/or separate, including chemical and toxicant agents, and microorganisms ranging from virus to protozoa. Dielectrophoresis has also played an important role in biofilm formation studies. This review article comprises mainly studies published from 2000 to present. Even in this relatively short time frame, there have been many significant contributions of this powerful and nascent technique related to environmental monitoring; thus, unveiling its great potential for future research directions. PMID- 21823134 TI - Geometric measures of large biomolecules: surface, volume, and pockets. AB - Geometry plays a major role in our attempts to understand the activity of large molecules. For example, surface area and volume are used to quantify the interactions between these molecules and the water surrounding them in implicit solvent models. In addition, the detection of pockets serves as a starting point for predictive studies of biomolecule-ligand interactions. The alpha shape theory provides an exact and robust method for computing these geometric measures. Several implementations of this theory are currently available. We show however that these implementations fail on very large macromolecular systems. We show that these difficulties are not theoretical; rather, they are related to the architecture of current computers that rely on the use of cache memory to speed up calculation. By rewriting the algorithms that implement the different steps of the alpha shape theory such that we enforce locality, we show that we can remediate these cache problems; the corresponding code, UnionBall has an apparent O(n) behavior over a large range of values of n (up to tens of millions), where n is the number of atoms. As an example, it takes 136 sec with UnionBall to compute the contribution of each atom to the surface area and volume of a viral capsid with more than five million atoms on a commodity PC. UnionBall includes functions for computing analytically the surface area and volume of the intersection of two, three and four spheres that are fully detailed in an appendix. UnionBall is available as an OpenSource software. PMID- 21823135 TI - Exact and efficient calculation of Lagrange multipliers in biological polymers with constrained bond lengths and bond angles: proteins and nucleic acids as example cases. AB - To accelerate molecular dynamics simulations, it is common to impose holonomic constraints on the hardest degrees of freedom. In this way, the time step used to integrate the equations of motion can be increased, thereby allowing longer total simulation times. The imposition of such constraints results in an aditional set of N(c) equations (the equations of constraint) and unknowns (their associated Lagrange multipliers), whose solution is closely related to any algorithm implementing the constraints in Euclidean coordinates. In this work, it is shown that, due to the essentially linear structure of typical biological polymers the algebraic equations that need to be solved involve a matrix which is not only sparse, but also banded if the constraints are indexed in a skilful way. This allows the Lagrange multipliers to be obtained through a noniterative procedure, which can be considered exact up to machine precision, and which takes O(N(c)) operations, instead of the usual O(N c3) for generic molecular systems. We develop the formalism, and describe the appropriate indexing for a number of model molecules. Finally, we provide a numerical example of the technique in a series of polyalanine peptides of different lengths. Although a use of the Lagrange multipliers without any modification in the solution of the underlying ordinary differential equations yields unstable integration algorithms, the central role of these quantities makes their efficient calculation useful for the improvement of methods that correctly enforce the exact satisfaction of the constraints at each time step. We provide several examples of this. PMID- 21823136 TI - Bond indices in solids: extended analytical model. AB - The analytical model suggested some time ago for the calculation of bond indices in infinite periodical structures was reconsidered and extended so as to provide not only realistic estimate of the extent of electron sharing localized among individual pairs of the atoms in the lattice but also to detect the eventual presence of multicenter bonding in metallic solids. PMID- 21823137 TI - An LC-MS/MS method for simultaneous determination of vincristine and verapamil in rat plasma after oral administration of a dual agent formulation. AB - A rapid and sensitive method for simultaneous determination of vincristine and verapamil in rat plasma was first developed and validated, using high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) in multiple reaction monitoring (MRM) mode via electrospray ionization (ESI). The method, which required a small sample volume (25 uL) of plasma, was linear in the concentration range of 0.5-500 ng/mL for vincristine and 0.1-100.0 ng/mL for verapamil. Finally, the method was successfully employed in a pharmacokinetic study of vincristine and verapamil in rats after an oral administration of a dual-agent formulation containing vincristine and verapamil. PMID- 21823138 TI - Health-service use in women with binge eating disorders. AB - OBJECTIVE: To compare health-care utilization between participants who met DSM-IV criteria for binge eating disorder (BED) and those engaged in recurrent binge eating (RBE) and to evaluate whether objective binge eating (OBE) days, a key measurement for diagnosing BED, predicted health-care costs. METHOD: We obtained utilization and cost data from electronic medical records to augment patient reported data for 100 adult female members of a large health maintenance organization who were enrolled in a randomized clinical trial to treat binge eating. RESULTS: Total costs did not differ between the BED and RBE groups (beta = -0.117, z = -0.48, p = .629), nor did the number of OBE days predict total costs (beta = -0.017, z = -1.01, p = .313). DISCUSSION: Findings suggest that the medical impairment, as assessed through health care costs, caused by BED may not be greater than impairment caused by RBE. The current threshold number of two OBE days/week as a criterion for BED may need to be reconsidered. PMID- 21823139 TI - Changes of orexin A plasma levels in girls with anorexia nervosa during eight weeks of realimentation. AB - OBJECTIVE: Orexin A (OXA) is a hypothalamic neuropeptide involved in regulation of food intake and nutritional status. There are multiple disturbances of neuropeptide signaling described in girls with anorexia nervosa (AN), but OXA levels have not been addressed in this population to date. Therefore, we analyzed OXA levels of AN girls in this study. METHOD: OXA (radioimmunoassay/RIA/method), leptin, insulinlike growth factor-1 (IGF-1), and insulinlike growth factor-1 binding protein-3 (IGFBP-3) levels were measured before and after 8 weeks of realimentation in 36 girls with AN and in 14 healthy controls (control group: CG). RESULTS: Average weight increased significantly in AN during the study (p < .0001), while plasma levels of OXA decreased (before realimentation: 56.2 +/- 2.4 pg/ml; after realimentation: 47.5 +/- 1.4 pg/ml; p = .0025). OXA levels before realimentation differed from levels in the CG (47.15 +/- 2.6 pg/ml, p = .034), but not afterward. We did not find any correlation between OXA and age, height, weight, BMI; or IGF-1, IGFBP-3, and leptin levels. DISCUSSION: OXA levels in untreated AN patients differ significantly from healthy subjects and decrease during realimentation. These findings indicate that OXA may be involved in the nutritional regulation of malnourished children and adolescents. PMID- 21823140 TI - Behavioral symptoms of eating disorders in Native Americans: results from the ADD Health Survey Wave III. AB - OBJECTIVE: To examine prevalence and correlates (gender, Body Mass Index) of disordered eating in American Indian/Native American (AI/NA) and white young adults. METHOD: We examined data from the 10,334 participants (mean age 21.93 years, SD = 1.8) of the National Longitudinal Study of Adolescent Health (ADD Health) Wave III for gender differences among AI/NA participants (236 women, 253 men) and ethnic group differences on measures of eating pathology. RESULTS: Among AI/NA groups, women were significantly more likely than men to report loss of control and embarrassment due to overeating. In gender-stratified analyses, a significantly higher prevalence of AI/NA women reported disordered eating behaviors compared with white women; there were no between group differences in prevalence for breakfast skipping or having been diagnosed with an eating disorder. Among men, disordered eating behaviors were uncommon and no comparison was statistically significant. DISCUSSION: Our study offers a first glimpse into the problem of eating pathology among AI/NA individuals. Gender differences among AI/NA participants are similar to results reported in white samples. That AI/NA women were as likely as white women to have been diagnosed with an eating disorder is striking in light of well documented under-utilization of mental health care among AI/NA individuals. PMID- 21823141 TI - Adolescent-adult discrepancies on the eating disorder examination: a function of developmental stage or severity of illness? AB - OBJECTIVE: Across studies, adolescents score lower on measures of eating disorder pathology than adults, but it is unclear whether such findings reflect discrepancies inherent to site/study or true developmental differences. The aim of this study was to determine whether age predicts subscale and diagnostic scores of the Eating Disorder Examination (EDE) in adolescents and adults with anorexia nervosa (AN) admitted to a single research center within the same period of time. METHOD: The sample consisted of 16 adolescent and 20 adult consecutive admissions to parallel, age-specific, research-based AN treatment programs. Participants completed a baseline evaluation at admission that included the EDE, depression measures, and global assessment of functioning scales. RESULTS: Age significantly predicted EDE scores in univariate regression analyses. However, in multivariate models that included severity indices of general and specific psychopathology as covariates, age was no longer a significant predictor of severity of eating disorder symptoms. DISCUSSION: This study adds to the growing body of data showing lower scores on the EDE for adolescents with AN relative to their adult counterparts, while eliminating potential site confounds. Results indicate that the higher adult scores may be carried in part by a more overall severe and chronic general clinical profile. PMID- 21823142 TI - Interval estimation in two-stage, drop-the-losers clinical trials with flexible treatment selection. AB - In a two-stage, drop-the-losers clinical trial, researchers choose the 'best' among a number of treatments at an interim analysis after the first stage. The selected treatment continues to the second stage for confirmation of efficacy, and the remaining treatments (the 'losers') are dropped from the study. Wu et al. (Biometrika 2010; 97:405-418) showed how to construct confidence limits for the mean difference between the selected treatment and the control when the treatment is chosen after the first stage based on the highest efficacy in the primary clinical endpoint. In this article, we show how to construct a lower confidence limit for the mean difference when the treatment is chosen based on first-stage safety data, early endpoint efficacy data, a combination of safety and efficacy data or any other prespecified selection rule. The result extends the applicability of drop-the-losers designs, for in practice, the 'best' treatment often is not chosen for efficacy alone. PMID- 21823143 TI - Second-order spatial analysis of epidermal nerve fibers. AB - Breakthroughs in imaging of skin tissue reveal new details on the distribution of nerve fibers in the epidermis. Preliminary neurologic studies indicate qualitative differences in the spatial patterns of nerve fibers based on pathophysiologic conditions in the subjects. Of particular interest is the evolution of spatial patterns observed in the progression of diabetic neuropathy. It appears that the spatial distribution of nerve fibers becomes more 'clustered' as neuropathy advances, suggesting the possibility of diagnostic prediction based on patterns observed in skin biopsies. We consider two approaches to establish statistical inference relating to this observation. First, we view the set of locations where the nerves enter the epidermis from the dermis as a realization of a spatial point process. Secondly, we treat the set of fibers as a realization of a planar fiber process. In both cases, we use estimated second-order properties of the observed data patterns to describe the degree and scale of clustering observed in the microscope images of blister biopsies. We illustrate the methods using confocal microscopy blister images taken from the thigh of one normal (disease-free) individual and two images each taken from the thighs of subjects with mild, moderate, and severe diabetes and report measurable differences in the spatial patterns of nerve entry points/fibers associated with disease status. PMID- 21823146 TI - Optimal response-adaptive randomized designs for multi-armed survival trials. AB - We considered design issues for multiple treatment arms in survival intervention trials and used optimal design theory to allocate patients adaptively in such trials. We proposed three types of optimal designs: one ensures that we have the most precise estimates of the treatment effects, another guarantees that we have the minimal sample size subject to user-specified allocation ratio assignments among treatment arms, and the third ensures that the design has minimal total hazard for the cohort. The latter two types of optimal designs are also subject to user-specified power constraints for testing contrasts among treatment effects. The operating characteristics of these optimal designs along with balanced designs are compared theoretically and by simulation, including their robustness properties with respect to model misspecifications. Our results show that the proposed optimal designs are frequently unbalanced and that they are generally more efficient and more ethical than the popular balanced designs. We also apply our response-adaptive allocation strategy to redesign a three-arm head and neck cancer trial and make comparisons. PMID- 21823147 TI - Researchers take on a preventable dementia: brain bank is giving researchers new understanding of chronic traumatic encephalopathy. PMID- 21823150 TI - The beautiful and ethereal neurological exam: an appeal for research. PMID- 21823151 TI - Neurovascular coupling: key to gait slowing in aging? PMID- 21823152 TI - Is antiepileptic drug generic substitution always safe? Slow progress toward definitive answers. PMID- 21823153 TI - Acute ischemic stroke in children versus young adults. AB - OBJECTIVE: The aim of this study was to compare children and young adults with acute ischemic stroke (AIS) in 2 large registries. METHODS: We compared clinical characteristics, stroke etiology, workup, and outcome (modified Rankin scale score [mRS] at 3-6 months) in children (1 month-16 years) and young adults (16.1 45 years) with AIS. Data of children were collected prospectively in the nationwide Swiss NeuroPediatric Stroke Registry, young adults in the Bernese stroke database. Outcome (mRS) and stroke severity (pediatric adaptation of the National Institutes of Health stroke scale [PedNIHSS]) in children were calculated retrospectively. RESULTS: From January 2000 to December 2008, 128 children and 199 young adults suffered from an AIS. Children were more likely to be male than young adults (62%/49%, p = 0.023) and less frequently had hypertension (p = 0.001), hypercholesterolemia (p = 0.003), and a family history of stroke (p = 0.048). Stroke severity was similar in children and young adults (median PedNIHSS/NIHSS 5/6; p = 0.102). Stroke etiology (original TOAST classification) was more likely to be "other determined cause" in children than in young adults (51%/29%; p < .001). Cervicocerebral artery dissections were less frequent in children than in young adults (10%/23%; p = 0.005). Outcome at 3 to 6 months did not differ between children and young adults (p = 0.907); 59% of children and 60% of young adults had a favorable outcome (mRS 0-1). Mortality was similar among children and young adults (4%/6%; p = 0.436). In multivariate analysis, low PedNIHSS/NIHSS was the most important predictor of favorable outcome (p < 0.001). INTERPRETATION: Although stroke etiology and risk factors in children and young adults are different, stroke severity and clinical outcome were similar in both groups. PMID- 21823154 TI - Plasma tissue kallikrein level is negatively associated with incident and recurrent stroke: a multicenter case-control study in China. AB - OBJECTIVE: Tissue kallikrein (TK) cleaves kininogen to produce the potent bioactive compounds kinin and bradykinin, which lower blood pressure and protect the heart, kidneys, and blood vessels. Reduction in TK levels is associated with cardiovascular disease and diabetes in animal models. In this study, we investigated the association of TK levels with event-free survival over 5 years in Chinese first-ever stroke patients. METHODS: We conducted a case-control study with 1,268 stroke patients (941 cerebral infarction, 327 cerebral hemorrhage) and 1,210 controls. Plasma TK levels were measured with an enzyme-linked immunosorbent assay. We used logistic regression and Cox proportional hazards models to assess the relationship between TK levels and risk of first-time or recurrent stroke. RESULTS: Plasma TK levels were significantly lower in stroke patients (0.163 +/- 0.064mg/l vs 0.252 +/- 0.093mg/l, p < 0.001), especially those with ischemic stroke. After adjustment for traditional risk factors, plasma TK levels were negatively associated with the risk of first-ever stroke (odds ratio [OR], 0.344; 95% confidence interval [CI], 0.30-0.389; p < 0.001) and stroke recurrence and positively associated with event-free survival during 5 years of follow-up (relative risk, 0.82; 95% CI, 0.74-0.90; p < 0.001). Compared with the first quartile of plasma TK levels, the ORs for first-ever stroke patients were as follows: second quartile, 0.77 (95% CI, 0.56-1.07); third quartile, 0.23 (95% CI, 0.17-0.32); fourth quartile, 0.04 (95% CI, 0.03-0.06). INTERPRETATION: Lower plasma TK levels are independently associated with first ever stroke and are an independent predictor of recurrence after an initial stroke. PMID- 21823156 TI - Application of immunosignatures to the assessment of Alzheimer's disease. AB - OBJECTIVE: Accurate assessment of Alzheimer's disease (AD), both presymptomatically and at different disease stages, will become increasingly important with the expanding elderly population. There are a number of indications that the immune system is engaged in AD. Here we explore the ability of an antibody-profiling technology to characterize AD and screen for peptides that may be used for a simple diagnostic test. METHODS: We developed an array based system to profile the antibody repertoire of transgenic mice with cerebral amyloidosis (TG) and elderly individuals with or without AD. The array consists of 10,000 random sequence peptides (20-mers) capable of detecting antibody binding patterns, allowing the identification of peptides that mimic epitopes targeted by a donor's serum. RESULTS: TG mice exhibited a distinct immunoprofile compared to nontransgenic littermates. Further, we show that dementia patients, including autopsy-confirmed AD subjects, have distinguishable profiles compared to age-matched nondemented people. Using antibodies to different forms of Abeta peptide and blocking protocols, we demonstrate that most of this signature is not due to the subject's antibodies raised against Abeta. INTERPRETATION: We propose that "immunosignaturing" technology may have potential as a diagnostic tool in AD. PMID- 21823155 TI - Visinin-like protein-1: diagnostic and prognostic biomarker in Alzheimer disease. AB - OBJECTIVE: There is a growing need to identify cerebrospinal fluid (CSF) markers that can detect Alzheimer's disease (AD) pathology in cognitively normal individuals because it is in this population that disease-modifying therapies may have the greatest chance of success. While AD pathology is estimated to begin ~10 15 years prior to the onset of cognitive decline, substantial neuronal loss is present by the time the earliest signs of cognitive impairment appear. Visinin like protein-1 (VILIP-1) has demonstrated potential utility as a marker of neuronal injury. Here we investigate CSF VILIP-1 and VILIP-1/amyloid-beta42 (Abeta42) ratio as diagnostic and prognostic markers in early AD. METHODS: We assessed CSF levels of VILIP-1, tau, phosphorylated-tau181 (p-tau181), and Abeta42 in cognitively normal controls (CNC) (n = 211), individuals with early symptomatic AD (n = 98), and individuals with other dementias (n = 19). Structural magnetic resonance imaging (n = 192) and amyloid imaging with Pittsburgh Compound-B (n = 156) were obtained in subsets of this cohort. Among the CNC cohort, 164 individuals had follow-up annual cognitive assessments for 2 3 years. RESULTS: CSF VILIP-1 levels differentiated individuals with AD from CNC and individuals with other dementias. CSF VILIP-1 levels correlated with CSF tau, p-tau181, and brain volumes in AD. VILIP-1 and VILIP-1/Abeta42 predicted future cognitive impairment in CNC over the follow-up period. Importantly, CSF VILIP 1/Abeta42 predicted future cognitive impairment at least as well as tau/Abeta42 and p-tau181/Abeta42. INTERPRETATION: These findings suggest that CSF VILIP-1 and VILIP-1/Abeta42 offer diagnostic utility for early AD, and can predict future cognitive impairment in cognitively normal individuals similarly to tau and tau/Abeta42, respectively. PMID- 21823157 TI - Progressive multifocal leukoencephalopathy in transplant recipients. AB - OBJECTIVE: Transplant recipients are at risk of developing progressive multifocal leukoencephalopathy (PML), a rare demyelinating disorder caused by oligodendrocyte destruction by JC virus. METHODS: Reports of PML following transplantation were found using PubMed Entrez (1958-July 2010). A multicenter, retrospective cohort study also identified all cases of PML among transplant recipients diagnosed at Mayo Clinic, Johns Hopkins University, Washington University, and Amsterdam Academic Medical Center. At 1 institution, the incidence of posttransplantation PML was calculated. RESULTS: A total of 69 cases (44 solid organ, 25 bone marrow) of posttransplantation PML were found including 15 from the 4 medical centers and another 54 from the literature. The median time to development of first symptoms of PML following transplantation was longer in solid organ vs bone marrow recipients (27 vs 11 months, p = 0.0005, range of <1 to >240). Median survival following symptom onset was 6.4 months in solid organ vs 19.5 months in bone marrow recipients (p = 0.068). Case fatality was 84% (95% confidence interval [CI], 70.3-92.4%) and survival beyond 1 year was 55.7% (95% CI, 41.2-67.2%). The incidence of PML among heart and/or lung transplant recipients at 1 institution was 1.24 per 1,000 posttransplantation person-years (95% CI, 0.25-3.61). No clear association was found with any 1 immunosuppressant agent. No treatment provided demonstrable therapeutic benefit. INTERPRETATION: The risk of PML exists throughout the posttransplantation period. Bone marrow recipients survive longer than solid organ recipients but may have a lower median time to first symptoms of PML. Posttransplantation PML has a higher case fatality and may have a higher incidence than reported in human immunodeficiency virus (HIV) patients on highly-active antiretroviral therapy (HAART) or multiple sclerosis patients treated with natalizumab. PMID- 21823159 TI - Reply to Schutzer et al. PMID- 21823160 TI - Prymnesium parvum: an emerging threat to inland waters. PMID- 21823158 TI - Clinicopathological correlations in corticobasal degeneration. AB - OBJECTIVE: To characterize cognitive and behavioral features, physical findings, and brain atrophy patterns in pathology-proven corticobasal degeneration (CBD) and corticobasal syndrome (CBS) with known histopathology. METHODS: We reviewed clinical and magnetic resonance imaging data in all patients evaluated at our center with either an autopsy diagnosis of CBD (n = 18) or clinical CBS at first presentation with known histopathology (n = 40). Atrophy patterns were compared using voxel-based morphometry. RESULTS: CBD was associated with 4 clinical syndromes: progressive nonfluent aphasia (n = 5), behavioral variant frontotemporal dementia (n = 5), executive-motor (n = 7), and posterior cortical atrophy (n = 1). Behavioral or cognitive problems were the initial symptoms in 15 of 18 patients; less than half exhibited early motor findings. Compared to controls, CBD patients showed atrophy in dorsal prefrontal and perirolandic cortex, striatum, and brainstem (p < 0.001 uncorrected). The most common pathologic substrates for clinical CBS were CBD (35%), Alzheimer disease (AD, 23%), progressive supranuclear palsy (13%), and frontotemporal lobar degeneration (FTLD) with TDP inclusions (13%). CBS was associated with perirolandic atrophy irrespective of underlying pathology. In CBS due to FTLD (tau or TDP), atrophy extended into prefrontal cortex, striatum, and brainstem, whereas in CBS due to AD, atrophy extended into temporoparietal cortex and precuneus (p < 0.001 uncorrected). INTERPRETATION: Frontal lobe involvement is characteristic of CBD, and in many patients frontal, not parietal or basal ganglia, symptoms dominate early stage disease. CBS is driven by medial perirolandic dysfunction, but this anatomy is not specific to a single underlying histopathology. Antemortem prediction of CBD will remain challenging until clinical features of CBD are redefined, and sensitive, specific biomarkers are identified. PMID- 21823161 TI - Optimal choice of pH for toxicity and bioaccumulation studies of ionizing organic chemicals. AB - It is recognized that the pH of exposure solutions can influence the toxicity and bioaccumulation of ionizing compounds. The present study investigates whether it can be considered a general rule that an ionizable compound is more toxic and more bioaccumulative when in the neutral state. Three processes were identified to explain the behavior of ionizing compounds with changing pH: the change in lipophilicity when a neutral compound becomes ionized, electrical attraction, and the ion trap. The literature was screened for bioaccumulation and toxicity tests of ionizing organic compounds performed at multiple pH levels. Toxicity and bioconcentration factors (BCFs) were higher for acids at lower pH values, whereas the opposite was true for bases. The effect of pH was most pronounced when pH - pK(a) was in the range of -1 to 3 for acids, and -3 to 1 for bases. The factor by which toxicity and BCF changed with pH was correlated with the lipophilicity of the compound (log K(OW) of the neutral compound). For both acids and bases, the correlation was positive, but it was significant only for acids. Because experimental data in the literature were limited, results were supplemented with model simulations using a dynamic flux model based on the Fick-Nernst-Planck diffusion equation known as the cell model. The cell model predicts that bases with delocalized charges may in some cases show declining bioaccumulation with increasing pH. Little information is available for amphoteric and zwitterionic compounds; however, based on simulations with the cell model, it is expected that the highest toxicity and bioaccumulation of these compounds will be found where the compounds are most neutral, at the isoelectric point. PMID- 21823162 TI - Sorption of triclosan onto sediments and its distribution behavior in sediment water-rhamnolipid systems. AB - Triclosan has been commonly used as an antimicrobial and disinfectant agent. Distribution between water and sediment plays a key role in its occurrence, transfer, and fate in the aquatic environment. Sorption of triclosan onto sediments and the effect of the biosurfactant rhamnolipid on distribution were studied in the present work. Batch equilibrium experiments were performed on three different sediments, with a wide triclosan concentration range. S-shaped equations can be used to describe the sorption behavior when triclosan concentration is relative high (50-250 ug . g-1). The Pearl River, China (PR), sediment, which has the largest cumulative volume of pores, appeared to have great capability for continuously capturing triclosan. In the lower concentration range (10-150 ug . g-1) assays, linear and Freundlich equations fitted the sorption isotherm data well. The pH value of sediment appeared to have a significant influence on sorption of low triclosan concentrations. Formation of rhamnolipid micelle remarkably decreased the sediment-water distribution ratio, K(d)*. Evaluation of the distribution efficiency, E, suggested that pores of sediment might have played a role in triclosan distribution, whereas sediment organic matter bound triclosan and reduced solubilization of triclosan. Rhamnolipid appears to be a good sorbent for triclosan. The findings of the present study suggest that, to understand the sorption and distribution of triclosan fully, studies should be carried out over a relatively broad concentration range. PMID- 21823164 TI - DFT studies of ESR parameters for N-O centered radicals, N-alkoxyaminyl and aminoxyl radicals. AB - Theoretical calculations of ESR parameters for aminoxyl radicals have been widely studied using the density functional theory (DFT) calculations. However, the isomer N-alkoxyaminyl radicals have been limitedly studied. With the use of experimental data for 46 N-alkoxyaminyl and 38 aminoxyl radicals, the isotropic (14)N hyperfine coupling constants (aN ) and g-factors have been theoretically estimated by several DFT calculations. The best calculation scheme of aN for N alkoxyaminyl radicals was PCM/B3LYP/6-31 + + G(d,p) (R(2) = 0.9519, MAE = 0.034 mT), and that for aminoxyl radicals was PCM/BHandHLYP/6-31 + + G(3df,3pd) (R(2) = 0.9336, MAE = 0.057 mT). For aminoxyl radicals, the solvation models in calculations enhanced the accuracy of reproducibility. In contrast, for N alkoxyaminyl radicals the calculations with solvation models provided no improvement. The differences in the best functionals between two types of radicals were thought to come from the contribution ratios of neutral and dipolar canonical structures in resonance forms. The aN for N-alkoxyaminyl radicals that were stabilized by small contribution of dipolar canonical structures could be precisely reproduced by B3LYP with only 20% HF exact exchange. In contrast, the aN for aminoxyl radicals stabilized by large contribution of dipolar canonical structures was well reproduced by BHandHLYP with 50% HF exchange. The best calculation scheme of g-factors was IEFPCM/B3LYP/6-31 + G(d,p) (R(2) = 0.9767, MAE = 0.0001) for not only aminoxyl but also N-alkoxyaminyl radicals. PMID- 21823165 TI - Ferric reductase genes involved in high-affinity iron uptake are differentially regulated in yeast and hyphae of Candida albicans. AB - The pathogenic yeast Candida albicans possesses a reductive iron uptake system which is active in iron-restricted conditions. The sequestration of iron by this mechanism initially requires the reduction of free iron to the soluble ferrous form, which is catalysed by ferric reductase proteins. Reduced iron is then taken up into the cell by a complex of a multicopper oxidase protein and an iron transport protein. Multicopper oxidase proteins require copper to function and so reductive iron and copper uptake are inextricably linked. It has previously been established that Fre10 is the major cell surface ferric reductase in C. albicans and that transcription of FRE10 is regulated in response to iron levels. We demonstrate here that Fre10 is also a cupric reductase and that Fre7 also makes a significant contribution to cell surface ferric and cupric reductase activity. It is also shown, for the first time, that transcription of FRE10 and FRE7 is lower in hyphae compared to yeast and that this leads to a corresponding decrease in cell surface ferric, but not cupric, reductase activity. This demonstrates that the regulation of two virulence determinants, the reductive iron uptake system and the morphological form of C. albicans, are linked. PMID- 21823166 TI - Application of the FLP/FRT system for conditional gene deletion in yeast Saccharomyces cerevisiae. AB - The yeast Saccharomyces cerevisiae has proved to be an excellent model organism to study the function of proteins. One of the many advantages of yeast is the many genetic tools available to manipulate gene expression, but there are still limitations. To complement the many methods used to control gene expression in yeast, we have established a conditional gene deletion system by using the FLP/FRT system on yeast vectors to conditionally delete specific yeast genes. Expression of Flp recombinase, which is under the control of the GAL1 promoter, was induced by galactose, which in turn excised FRT sites flanked genes. The efficacy of this system was examined using the FRT site-flanked genes HSP104, URA3 and GFP. The pre-excision frequency of this system, which might be caused by the basal activity of the GAL1 promoter or by spontaneous recombination between FRT sites, was detected ca. 2% under the non-selecting condition. After inducing expression of Flp recombinase, the deletion efficiency achieved ca. 96% of cells in a population within 9 h. After conditional deletion of the specific gene, protein degradation and cell division then diluted out protein that was expressed from this gene prior to its excision. Most importantly, the specific protein to be deleted could be expressed under its own promoter, so that endogenous levels of protein expression were maintained prior to excision by the Flp recombinase. Therefore, this system provides a useful tool for the conditional deletion of genes in yeast. PMID- 21823167 TI - Health insurance for undocumented immigrants: opportunities and barriers on the Mexican side of the US border. AB - OBJECTIVE: This article aims to identify opportunities, barriers and challenges in Mexico's policy networks for the development of healthcare programs for undocumented migrants in the USA and their families. METHODS: We used policy analysis, in-depth interviews and a case study. Key stakeholders at the federal, state and municipal levels in one major migrant-sending state were interviewed. We also conducted an in-depth case study of one community to obtain the perceptions of local health workers, migrant families and local nongovernmental organizations. RESULTS: Findings identified opportunities and barriers involving the stakeholders, institutions, social interactions and types of relationships necessary for further progress on binational policies. There was wide interest in creating binational health insurance with different degrees of potential involvement by political actors and variation in local actors' willingness to be covered by some type of health insurance scheme. CONCLUSIONS: The use of the opportunities to overcome barriers depends on the identification of high, medium or low interaction among key stakeholders, integration of coalitions and negotiating skills of all stakeholders involved. PMID- 21823168 TI - Dose-dependent effects of olanzapine on QT intervals and plasma prolactin levels in Japanese patients with stable schizophrenia. AB - OBJECTIVES: There have been few reports regarding olanzapine (OLZ)-related QT prolongation and hyperprolactinemia. This study evaluated the dose-dependent effect of OLZ on QT interval and plasma prolactin (PRL) level in a single sample of patients with schizophrenia. METHODS: Twenty-six subjects treated with varying starting doses of OLZ were enrolled in the study. Following baseline assessments, which included completion of the Brief Psychiatric Rating Scale (BPRS), measurements of Body Mass Index (BMI), QT interval, electrolytes, fasting plasma glucose, PRL, hemoglobin A1c (HbA1c), total cholesterol (TC), triglyceride (TG), high density lipoprotein (HDL), and low density lipoprotein (LDL), the dose of OLZ was increased for each subject. The same parameters were evaluated following the increased dose treatment. RESULTS: A significant decrease was observed in BPRS score (p = 0.01) following treatment with an increased dose of OLZ. Significant increases were observed in BMI (p = 0.032), QTc (p = 0.031), and plasma PRL level (p = 0.028). The mean values of electrolytes, fasting plasma glucose, HbA1c, TC, TG, HDL and LDL treatment were unchanged by the switch to increased-dose OLZ treatment. CONCLUSION: We have demonstrated the dose-dependent effect of OLZ on the QT interval and the plasma PRL level of patients with schizophrenia. PMID- 21823169 TI - Genetic interactions in the adrenergic system genes: analysis of antipsychotic induced weight gain. AB - Atypical antipsychotics (AP) have high affinity for many neurotransmitter receptors. Among these receptors, APs are antagonist at alpha-adrenergic and beta adrenergic receptors, and this pharmacological property has been postulated to be involved in the mechanism of action of these drugs with respect to both clinical response and adverse effects. OBJECTIVE: We tested the hypotheses that AP-induced weight gain is associated with genetic variation in adrenergic receptors and pathway enzymes. We analyzed nine genetic polymorphisms across seven adrenergic genes (ADRA1A, ADRA2A, ADRA2C, ADRB3, DBH, MAOA and COMT). METHODS: One hundred thirty-nine patients with schizophrenia were prospectively assessed for AP induced weight gain. The HelixTree software (Golden Helix, Bozeman, MT, USA) was employed to detect differences in genotypic distribution between weight gainer and non-weight gainer groups. Furthermore, for the dopamine beta-hydroxylase haplotype, we were able to obtain both the molecular and the statistical phases, analyzing the phenotype considering both phases. RESULTS: Weight gain was not associated with any adrenergic gene. CONCLUSIONS: Our results suggest that genetic polymorphisms in the adrenergic system may not play a major role in AP induced weight gain; however, adrenergic 2A receptor gene that produced previously the most consistent associations with this phenotype showed a significant interaction with the monoamine oxidase A in weight gainers. PMID- 21823170 TI - Longitudinal patterns of benzodiazepine consumption in a German cohort of methadone maintenance treatment patients. AB - OBJECTIVE: Cross-sectional studies show that considerable proportions of opiate dependents in methadone maintenance treatment (MMT) consume benzodiazepines (BZD). The longitudinal patterns of BZD use over time were described here. METHODS: After admission to MMT, patients from two outpatient MMT clinics (n = 345) were observed for up to 2 years whilst in treatment. The use of BZD, cannabis, opiates and cocaine was assessed by urine sampling carried out twice a month. RESULTS: For the whole sample, the mean BZD-positive urine specimen rate was 0.36 during the first 3 months. Rates slightly decreased during the first year and remained stable afterwards (last observation carried forward). For study completers (n = 152), the rate decreased over time, from 0.31 (first 3-month period) to 0.19 (last period; p < 0.001). According to a longitudinal cluster analysis, 26% of all patients showed a pattern of constantly high BZD-positivity rates, mostly in combination with other substances. Inpatient detoxifications from BZD (carried out in 18% of cases) did not have a sustained effect on levels of BZD use. CONCLUSIONS: BZD consumption in MMT is often part of a polydrug consumption pattern and is associated with poorer treatment retention. It is necessary to further investigate the reasons for BZD use in MMT patients and to develop effective interventions to reduce levels of BZD consumption. PMID- 21823171 TI - Impact of treatment approach on maternal and neonatal outcome in pregnant opioid maintained women. AB - OBJECTIVE: The objective of this study is to compare maternal and neonatal outcome of opioid-dependent women maintained on buprenorphine or methadone throughout pregnancy in a randomized double-blind double-dummy clinical trial (CT) with a comparison group undergoing a structured standard protocol (SP) at the Medical University of Vienna, Austria. METHODS: One hundred and fourteen subjects were included in the analysis, with 77 in SP (n = 51 methadone, n = 26 buprenorphine), and 37 in CT (n = 19 methadone, n = 18 buprenorphine), comparing maternal concomitant consumption during third trimester, demographic birth data, duration of treatment for neonatal abstinence syndrome (NAS), morphine dose for NAS treatment and length of hospital stay (LOS). RESULTS: Both study groups yielded healthy neonates with no significant demographic differences and equivalently low rates of positive maternal urine toxicologies. However, NAS parameters were significantly better in CT regarding total medication dose administered to neonates (p = 0.014) and LOS (p = 0.015). Superior results were achieved in buprenorphine compared with methadone-exposed neonates regarding gestational age at birth (p = 0.003), birth weight (p = 0.011), total morphine dose administered (p = 0.008), NAS treatment duration (p = 0.008) and LOS (p = 0.001). CONCLUSIONS: Comparably favorable outcome for mothers and infants and efficacy and safety of opioid medications were shown in both treatment approaches. Neonatal care could benefit from transferring successful CT procedures into clinical practice. PMID- 21823172 TI - Comparison of metabolic changes in patients with schizophrenia during randomized treatment with intramuscular olanzapine long-acting injection versus oral olanzapine. AB - Metabolic changes were examined in patients with schizophrenia during treatment with either oral olanzapine or olanzapine long-acting injection (LAI). Data were collected from patients who had been stabilized on oral olanzapine (10, 15, or 20 mg/day) for >=4 weeks and then randomized to either continued olanzapine oral treatment (n = 322) or LAI (n = 599; 150 mg/2 weeks, 405 mg/4 weeks, or 300 mg/2 weeks) for up to 24 weeks. Mean and categorical changes in metabolic parameters were analyzed. Mean changes in weight, glucose, and most lipids were generally not significantly different between treatment groups. Weight changes over time followed similar patterns and were not significantly different at endpoint between the two treatment-formulation groups. Low-density lipoprotein cholesterol decreased significantly less among olanzapine LAI-treated patients. Percentages of patients with potentially clinically significant changes in blood glucose and lipid concentrations were similar for the two treatments. Percentages of patients experiencing adverse events related to weight, diabetes, or dyslipidemia were also not significantly different between treatments. Metabolic changes in patients with schizophrenia appeared generally similar during treatment with oral olanzapine or olanzapine LAI. PMID- 21823173 TI - Effects of alcohol on highway driving in the STISIM driving simulator. AB - OBJECTIVE: The STISIM driving simulator is widely used. To enhance its usefulness in pharmacological research, a calibration study was performed to test a standardized highway driving test scenario after administration of three different dosages of alcohol and placebo. METHODS: Twenty-seven healthy young adults (14 men and 13 women; mean age (SD) = 22.8 (1.4)) participated in this randomized, single-blind crossover trial. Subjects received alcohol to gain a blood alcohol concentration (BAC) of 0.05%, 0.08%, and 0.11%, or placebo-alcohol. In each condition, subjects completed a 100-km highway driving simulator test. The standard deviation of lateral position, the weaving of the car, was the primary parameter of the test. RESULTS: Alcohol produced dose-dependent driving impairment. Standard deviation of lateral position and standard deviation of speed were significantly increased relative to placebo (p < 0.05). Subjective driving assessments were in line with the objective driving measurements. CONCLUSION: The STISIM highway driving simulator test is able to differentiate dose-dependent impairment after administration of alcohol. The highway driving test scenario is suitable for future psychopharmacological research. PMID- 21823175 TI - Efficient separation of dyes by mucin: toward bioinspired white-luminescent devices. PMID- 21823174 TI - A group music intervention using percussion instruments with familiar music to reduce anxiety and agitation of institutionalized older adults with dementia. AB - OBJECTIVE: This experimental study aimed to evaluate the effects of a group music intervention on anxiety and agitation of institutionalized older adults with dementia. METHODS: A total of 60 participants were randomly assigned to an experimental or a control group. The experimental group received a 30-min music intervention using percussion instruments with familiar music in a group setting in mid afternoon twice weekly for 6 weeks, whereas the control group received usual care with no music intervention. The Rating of Anxiety in Dementia scale was used to assess anxiety, and Cohen-Mansfield Agitation Inventory was used to assess agitation at baseline, week 4 and week 6. RESULTS: Repeated measures analysis of covariance indicated that older adults who received a group music intervention had a significantly lower anxiety score than those in the control group while controlling for pre-test score and cognitive level (F = 8.98, p = 0.004). However, the reduction of agitation between two groups was not significantly different. CONCLUSIONS: Anxiety and agitation are common in older adults with dementia and have been reported by caregivers as challenging care problems. An innovative group music intervention using percussion instruments with familiar music as a cost-effective approach has the potential to reduce anxiety and improve psychological well-being of those with dementia. PMID- 21823176 TI - Electrical characteristics of molybdenum disulfide flakes produced by liquid exfoliation. PMID- 21823177 TI - In situ gelation of electrolytes for highly efficient gel-state dye-sensitized solar cells. PMID- 21823178 TI - Enhanced differentiation of human neural stem cells into neurons on graphene. PMID- 21823179 TI - Reversible tuning of SERS hot spots with aptamers. PMID- 21823180 TI - Optical interference lithography using azobenzene-functionalized polymers for micro- and nanopatterning of silicon. PMID- 21823181 TI - Effects of pyruvate dose on in vivo metabolism and quantification of hyperpolarized 13C spectra. AB - Real-time in vivo measurements of metabolites are performed by signal enhancement of [1-(13)C]pyruvate using dynamic nuclear polarization, rapid dissolution and intravenous injection, acquisition of free induction decay signals and subsequent quantification of spectra. The commonly injected dose of hyperpolarized pyruvate is larger than typical tracer doses, with measurement before complete dilution of the injected bolus. Pyruvate is in exchange with its downstream metabolites lactate, alanine and bicarbonate. A transient exposure to high pyruvate blood concentrations may cause the saturation of cellular uptake and metabolic conversion. The goal of this study was to examine the effects of a [1 (13)C]pyruvate bolus on metabolic conversion in vivo. Spectra were quantified by three different methods: frequency-domain fitting with LCModel, time-domain fitting with AMARES and simple linear least-squares fitting in the time domain. Since the simple linear least-squares approach showed bleeding artifacts and LCModel produced noisier time signals. AMARES performed best in the quantification of in vivo hyperpolarized pyruvate spectra. We examined pyruvate doses of 0.1-0.4 mmol/kg (body mass) in male Wistar rats by acquiring slice selective free induction decay signals in slices dominated by heart, liver and kidney tissue. Dose effects were noted in all cases, except for alanine in the cardiac slice below the dose of 0.2 mmol/kg. Our results indicate unlimited cellular uptake of pyruvate up to this dose and limited enzymatic activity of lactate dehydrogenase. In the cardiac slice above 0.2 mmol/kg and in liver and kidney slices, reflect limited cellular uptake or enzymatic activity, or a combination of both effects. The results indicate that the dose of pyruvate must be recognized as an important determinant for metabolic tissue kinetics, and saturation effects must be taken into account for the quantitative interpretation of the observed results. PMID- 21823182 TI - Effect of implantation site and growth of hepatocellular carcinoma on apparent diffusion coefficient of water and sodium MRI. AB - Hepatocellular carcinoma (HCC) and liver metastases are an increasing problem worldwide. Non-invasive methods for the early detection of HCC and understanding of the tumor growth mechanisms are highly desirable. Both the diffusion-weighted (1)H (DWI) and (23)Na MRI reflect alterations in tissue compartment volumes in tumors, as well as physiological and metabolic transformation in cells. Effects of untreated growth on apparent diffusion coefficient of water (ADC), single quantum (SQ) and triple quantum-filtered (TQF) (23)Na MRI were compared in intrahepatically and subcutaneously implanted HCCs in rats. Animals were examined weekly for 4 weeks after injection of N1S1 cells. ADC of intrahepatic HCC was 1.5 times higher compared to the nearby liver tissue, and with growth, the ADC did not increase. ADC of subcutaneous HCC was lower compared to intrahepatic HCC and it increased with growth. Untreated growth of both intrahepatic and subcutaneous HCCs was associated with an increase in SQ and TQF (23)Na signal intensity suggesting an increase in tissue Na(+) and intracellular Na(+) (Na(+)(i)), respectively, most likely due to an increase in relative extracellular space and Na(+)(i) concentration as a result of changes in tissue structure and cellular metabolism. Thus, SQ and TQF (23)Na MRI may be complementary to diffusion imaging in areas susceptible to motion for characterizing hepatic tumors and for other applications, such as, predicting and monitoring therapy response. PMID- 21823183 TI - Predicting long-term survival and treatment response in breast cancer patients receiving neoadjuvant chemotherapy by MR metabolic profiling. AB - PURPOSE: This study aimed to evaluate whether MR metabolic profiling can be used for prediction of long-term survival and monitoring of treatment response in locally advanced breast cancer patients during neoadjuvant chemotherapy (NAC). METHODS: High resolution magic angle spinning (HR MAS) MR spectra of pre- and post-treatment biopsies from 33 patients were acquired. Tissue concentrations of choline-containing metabolites (tCho), glycine and taurine were assessed using electronic reference to access in vivo concentration (ERETIC) of the signal and receiver operating characteristic (ROC) curves was used to define their potential to predict patient survival and treatment response. The metabolite profiles obtained by HR MAS spectroscopy were related to long-term survival and treatment response by genetic algorithm partial least squares discriminant analysis (GA PLS DA). RESULTS: Different pre-treatment MR metabolic profiles characterized by higher levels of tCho and lower levels of lactate were observed in patients with long-term survival (>=5 years, survivors) compared to patients who died of cancer recurrence (<5 years, non-survivors). A significant decrease in glycerophosphocholine (GPC) post-treatment was associated with long-term survival (p = 0.046) and partial response (p = 0.014) to NAC. Long-term survival was best predicted by GPC using ROC analyses (sens. 66.7%, spec. 62.5%), while taurine had the best predictive value of treatment response (sens. 72.7%, spec. 63.2%). GA PLS-DA multivariate classification models successfully discriminated between survivors and non-survivors, resulting in 82.7% and 90.2% cross-validation (CV) classification accuracy, pre- and post-treatment, respectively. Classification of treatment response using GA PLS-DA was not successful for this patient cohort. CONCLUSIONS: Our results demonstrate that HR MAS MR metabolic profiles consisting of important metabolic characteristics of breast cancer tumors could potentially assist the classification and prediction of long-term survival in locally advanced breast cancer patients, in addition to being used as an adjunct for evaluation of treatment response to NAC. PMID- 21823184 TI - Individual-level interventions for alcohol-related violence: a rapid evidence assessment. AB - BACKGROUND: Alcohol-related violence is of major concern to society. Around half of all violent crimes are alcohol related, and yet interventions for alcohol related violence are under-developed. Often, offenders receive treatment for substance use or violence, but not the two in nexus. AIM: My aim was to conduct a Rapid Evidence Assessment of interventions with a focus on treating established nonsexual violence in the context of alcohol use, to describe the content of these interventions, where they take place and their effectiveness in reducing alcohol problems and/or violence. METHODS: The electronic databases Embase, Medline, National Criminal Justice Reference Service, Cumulative Index to Nursing and Allied Health Literature were searched together with the Campbell Collaboration; Cochrane Reviews and selected government websites using terms for alcohol, violence and treatment/interventions. The search excluded sexual and intimate partner violence. The focus was on psychosocial interventions with people already in difficulties, not prevention. All empirical study types with people of any age and in any setting (criminal justice, health, social services or education) were included. The principal outcomes of interest were change in alcohol use, violence and alcohol-related violence. RESULTS: Only four studies of two different interventions were identified. Control of Violence for Angry Impulsive Drinkers has been evaluated with small samples using a nonequivalent comparison group and a single case methodology. Changes were evident on measures of alcohol-related aggression. In a randomised controlled trial, SafERteens participants showed greater improvements in attitudes to alcohol and violence compared with a leaflet only condition. DISCUSSION: Directions for developing interventions based on alcohol and aggression research are discussed. Interventions targeting primarily alcohol consumption, primarily violence and alcohol-related violence in nexus should be compared. In evaluating these interventions, robust outcome measures should be used across studies to allow comparisons to be made. CLINICAL IMPLICATIONS: Skills for coping with perceived provocation may be taught, so that nonviolent options are available and so that they become more accessible when people are under the influence of alcohol. Alcohol's effect on reducing self-awareness may be counteracted by teaching mindfulness techniques and the ability to 'act sober' in provocative situations. Setting individual implementation intentions may facilitate harm avoidance in high-risk social situations through preplanning of specific sensible behavioural strategies. PMID- 21823185 TI - Pure, transparent-melting starch esters: synthesis and characterization. AB - Long chain starch esters were prepared by a new method using molten imidazole as solvent for the biopolymer. The advantage is the simplicity of the reaction mixture. Imidazole is acting not only as solvent, but also as reagent and base. The reaction succeeds via the imidazolide, which is formed in situ with an acid chloride. It yields highly pure derivatives, as could be shown by NMR spectroscopy and elemental analysis. No hints for desoxychloro substituents or other impurities could be found. The high quality of the products prepared is responsible for the occurrence of colorless melts. Although DSC measurements show a variety of thermal transitions, the formation of melts in the range of 40 to 255 degrees C could be observed with a hot stage microscope. The melting behavior can be adjusted by the type of ester moiety and the amount of ester functions introduced. In case of starch palmitates completely transparent melts are obtained within two distinct DS regions namely around 1.5 and 2.2 to 3.0. Upon cooling the melts form homogeneous films on different supports including glass. They show good adhesion and should therefore be a suitable basic material for the preparation of composites like laminated glass. PMID- 21823186 TI - One-pot synthesis of colloidal nanobowls and hybrid multipod-like nanoparticles by radiation miniemulsion polymerization. AB - A facile approach is proposed to one-pot synthesis of two kinds of nanoparticles: a new type of PS nanobowls (a hole appearing at the bottom of nanobowl) and PS/silica hybrid multipod-like nanoparticles. The two type of nanoparticles generated together during polymerization could be separated easily by centrifugation. Furthermore, the structure of nanobowls could be easily controlled by the weight ratio of monomer/silica. In addition, we find that the multipod-like nanoparticles play important roles in hydrophobic properties. The water contact angle increased from 24.0 degrees to 143.3 degrees after coated with the multipod-like nanoparticles. PMID- 21823187 TI - PLCzeta and its role as a trigger of development in vertebrates. AB - A major unresolved issue in developmental biology is the precise mechanism whereby the sperm activates the oocyte. With the discovery that calcium signals are the primary trigger for oocyte activation, a key remaining question became the identification of the signaling protein that mediates such calcium signals at fertilization. A major step forward came in 2002 with the discovery of a sperm specific mammalian phospholipase C called phospholipase C zeta (PLCzeta), which had the expected properties of the mammalian oocyte activation factor and was subsequently identified in other vertebrate groups. Most recently, defects in PLCzeta have been shown to be linked to certain types of male infertility in humans. Despite these advances, many questions remain about the precise mechanism of action of PLCzeta and the extent of its role during oocyte activation in the vertebrate kingdom. In this review, we will look at the current state of understanding of PLCzeta's mechanism of action and physiological role in mammals and other vertebrates, and identify areas of uncertainty that still remain to be resolved. PMID- 21823189 TI - Dicer gene expression during early bovine embryo development. PMID- 21823188 TI - The multiple hats of Vasa: its functions in the germline and in cell cycle progression. AB - Vasa, an ATP-dependent RNA helicase, is broadly conserved among various organisms from cnidarians to mammals. It has a rich history of utility as a germline marker, and is believed to function as a positive translational regulator in the determination and maintenance of germline cells. Studies in non-model organisms, however, revealed that Vasa is also present in somatic cells of many tissues. In many cases these cells are multipotent, are non-germline associated, and give rise to a variety of different tissue types. Recent work now also demonstrates that Vasa functions in the regulation of the cell cycle. Here, we discuss this newly described function of Vasa in mitotic and meiotic cell cycles, and we address the conundrum created within these observations, that is, that most cells are mitotically independent of Vasa, yet when Vasa is present in a cell, it appears to be essential for cell cycle progression. PMID- 21823190 TI - Polymorphisms of estrogen receptors alpha and beta in idiopathic, infertile Brazilian men: a case-control study. AB - Estrogen plays an important role in the human reproductive system and its action is mediated mainly by two specific receptors: alpha (ERalpha) and beta (ERbeta). There are polymorphic variants in both ER genes, and studies showed their association with reproductive outcomes. We aimed to determine the distribution of ERalpha and ERbeta gene polymorphisms in idiopathic, infertile Brazilian patients in a case-control study comprising 187 idiopathic, infertile Brazilian men with nonobstructive azoospermia (NOA, n = 78) or severe oligozoospermia (SO, n = 109) and 216 fertile men. Detection of ERalpha (PvuII and XbaI) and ERbeta (AluI and RsaI) gene polymorphisms were performed using TaqMan PCR. The results were analyzed statically, and a P-value < 0.05 was considered significant. Single marker analysis revealed that neither PvuII nor XbaI polymorphisms of the ERalpha gene were associated either with NOA group (P = 0.662 and P = 0.527, respectively) or SO group (P = 0.777 and P = 1.0, respectively). Regarding ERbeta polymorphisms, no statistical difference was observed between the AluI polymorphism and NOA group compared to controls (P = 1.0) or between SO group and controls (P = 0.423). We found similar results with the RsaI polymorphism. Statistical analysis did not reveal a difference between NOA (P = 0.740) and SO (P = 0.920) groups compared to controls. Combined genotypes of ERalpha and ERbeta polymorphisms did not identify a haplotype associated with idiopathic infertility. Thus, in the Brazilian population, genetic variations in both estrogen receptors alpha (PvuII and XbaI) and beta (AluI and RsaI) were not relevant to idiopathic infertility. PMID- 21823191 TI - Measuring use of services for mental health problems in epidemiological surveys. AB - The use of services for mental problems is generally reported as being relatively low. However, the methods used for data collection in surveys may have influenced the quality of self-reported service use. This study compares the information on recourse to physicians for mental problems reported in different sections of a survey conducted in six European countries. Thus, 5545 respondents were asked questions on contacts with physicians at least twice: (1) after the symptoms checklist in any completed diagnostic section, and (2) in a section devoted to use of care for mental problems. Of these 39.3% reported contacts with physicians about mental problems in the diagnostic sections, whereas 29.5% did so in the use of-care section. Inconsistencies concerned 20.1% of participants, among whom those reporting consultations in diagnostic sections without reporting them in the use-of-care section represented the majority (74.4%). Multiple logistic regression analysis revealed that age, marital status, educational level and country were associated with under-reporting in the use-of-care section, as well as having mood or sleep problems. In conclusion, services used for mental health reasons when measured through a question referring to use of care due to the presence of a mental problem may underestimate the care people received for their problems. PMID- 21823192 TI - The host interactome of influenza virus presents new potential targets for antiviral drugs. AB - Increasing antiviral drug resistance is a major concern for treating influenza, especially in a pandemic setting when the availability of a protective vaccine is uncertain. Resistance is often an issue with drugs directed at viral proteins and for small RNA viruses; there are also a limited number of viral proteins that are amenable to inhibition by a small molecule. A new approach that is gaining support is that cellular proteins, which facilitate virus replication, may be used as alternative targets. Whereas drugs directed at viral proteins tend to be virus-specific, drugs directed at host targets have the potential to have broad spectrum antiviral activity as many viruses may share a dependency on that host function. For influenza virus, we have very limited knowledge of which cellular factors are involved in virus replication, let alone which of these have suitable properties to serve as drug targets. Through the use of high-throughput RNA interference screens, several studies have addressed this gap in our knowledge. The resulting datasets provide new insight into host pathways that are involved in the influenza virus replication cycle and identify specific host factors in these pathways that may serve as potential targets for future antiviral drug development. PMID- 21823193 TI - Drug utilization according to reason for prescribing: a pharmacoepidemiologic method based on an indication hierarchy. AB - PURPOSE: To develop a pharmacoepidemiologic method for drug utilization analysis according to indication, gender, and age by means of register-based information. Statin utilization in 2005 was applied as an example. METHODS: Following the recommendations for statin therapy, we constructed an indication hierarchy with eight mutually exclusive levels of register markers of cardiovascular disease and diabetes. Danish residents, as of January 1, 1996, were followed at the individual level in nationwide registers with respect to dispensed prescriptions of cardiovascular drugs and antidiabetics (1996-2005) along with discharge diagnoses and surgical procedures (1977-2005). The highest current possible indication level was assigned to all cohort members. Stratified by indication, gender, and age, statin treatment prevalence and incidence were calculated. RESULTS: Statin treatment prevalence was highest among individuals with myocardial infarction and tended to be higher among men with indications in the upper part of the hierarchy, but it was higher among women (especially the elderly) in the lower part of the hierarchy. Treatment incidence rates followed roughly the same pattern. Women with no register marker or primary hypertension accounted for almost 50% of all incident female users; among men, the figure was 35%. The proportion of incident users with ischemic heart disease or myocardial infarction increased with age. CONCLUSION: The proposed indication hierarchy provided new insight into prescription patterns of statins. The method can be implemented for other drug categories and could be useful for studying trends in drug utilization, differential drug adherence, and cross-national comparisons. PMID- 21823194 TI - Hospitalised ischaemic cerebrovascular accident and risk factors in a primary care database. AB - PURPOSE: Ischaemic cerebrovascular accident (ICVA) is a common cause of morbidity and mortality. Identification of risk factors can reduce its incidence. We aim to estimate the incidence rate (IR) of hospitalised ICVA in the general population by sex and quantify its risk associated with several factors. METHODS: We followed up 907, 001 individuals aged 40-84 years during a mean of 3.63 years to ascertain the first episode of hospitalised ICVA between 2000 and 2004 using a UK primary care database. We evaluated the risk factors for ICVA through unconditional logistic regression (OR) with a nested case-control analysis, using 2953 incident cases and 10, 000 random controls frequency-matched by age, sex and year. RESULTS: The IR of hospitalised ICVA was 1.94 (95%CI: 1.87-2.01) per 1000 person-years in men and 1.59 (95%CI: 1.53-1.65) in women. The IR ratio adjusted by age was 1.35 (95%CI: 1.28-1.43). Major risk factors for the first ICVA were atrial fibrillation (AF) (OR of 1.96 (95%CI: 1.59-2.42) for men and 3.54 (95%CI: 2.85-4.39) for women), smoking, epilepsy and hypertension. AF patients on anticoagulant therapy presented a reduced risk of ICVA (OR: 0.39; 95%CI: 0.27 0.56) in both sexes. Hypertensive women that discontinued the treatment had an increased risk (OR: 2.53; 95%CI: 1.63-3.91). CONCLUSIONS: Men had higher incidence of hospitalised ICVA than women. AF was the major risk factor for ICVA (more in women than men), followed by smoking. Among AF patients, those under anticoagulant therapy showed a significant reduced risk of first ICVA. Antihypertensive drug discontinuation increased the risk of ICVA among women. PMID- 21823195 TI - Relationship between cardiovascular outcomes and proton pump inhibitor use in patients receiving dual antiplatelet therapy after acute coronary syndrome. AB - BACKGROUND: There is conflicting evidence regarding the potential interaction between clopidogrel and proton pump inhibitors (PPIs), with observational studies suggesting an increased risk of adverse cardiovascular (CV) outcomes and clinical trials suggesting there is no such risk. METHODS: We conducted a retrospective cohort study to assess CV outcomes of 9753 patients taking dual antiplatelet therapy of aspirin plus clopidogrel with or without a PPI after hospitalization for acute coronary syndrome (ACS). Cox proportional hazards models were used to assess our primary endpoint of re-hospitalization for ACS in overall sample and a propensity score matching subsample. RESULTS: Among patients taking clopidogrel plus aspirin, concomitant use of PPI was not associated with the risk of re hospitalization for ACS (adjusted hazard ratio [HR] 1.12 [95%CI 0.72-1.73]). The findings were consistent in the propensity score matching cohort (adjusted HR 0.82 [95%CI 0.43-1.54]). Compared with PPI nonusers, there is no significant association between each specific PPI users and the risk of re-hospitalization for ACS (adjusted HR; omeprazole 0.96 [95%CI 0.35-2.66], pantoprazole 1.05 [95%CI 0.38-2.92], rabeprazole 0.60 [95%CI 0.17-2.17], esomeprazole 0.31 [95%CI 0.10 0.99], and lansoprazole 0.82 [95%CI 0.32-2.07]). CONCLUSION: In conclusion, this population-based cohort study found that concomitant use of clopidogrel and PPI in patients who received dual antiplatelet therapy after ACS was not associated with risk of ACS re-hospitalization. Together, our study and findings of recently published clinical trials suggest that there was no apparent CV interaction between clopidogrel and PPI in patients who received dual antiplatelet therapy. PMID- 21823196 TI - The incidence of hepatosplenic T-cell lymphoma in a large managed care organization, with reference to anti-tumor necrosis factor therapy, Northern California, 2000-2006. AB - BACKGROUND: Hepatosplenic T-cell lymphoma (HSTCL), a rare and rapidly progressive subtype of peripheral T-cell lymphoma, has been reported following TNF-alpha blocker therapy. To better understand this relationship, we conducted an epidemiologic study in the Kaiser Permanente membership. METHODS: The retrospective cohort study was conducted among Northern California members of all ages. The Kaiser Permanente Cancer Registry, supplemented with review of medical charts and pathology slides, was used to identify and confirm cases of HSTCL. Medical histories were obtained, and we computed the standardized incidence rate for the 7-year period 2000-2006, when immunohistochemical staining was fully established throughout the health plan for diagnosing lymphoma. RESULTS: Six cases were diagnosed during 2000-2006, for an annual age-standardized incidence rate of 0.3 (95%CI, 0.11-0.65) per million person-years. One case had a prior diagnosis of human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS); another had a prior diagnosis of Crohn's disease treated with steroids, thiopurine and infliximab. CONCLUSION: Prior cases of HIV/AIDS-linked HSTCL are uncommon in the existing literature. Multiple case reports of HSTCL in the setting of Crohn's disease treated with anti-TNF plus thiopurine have been published, but HSTCL is rare, making epidemiologic assessments difficult. PMID- 21823197 TI - Quality of life and mental health in the bereaved family members of patients with terminal cancer. AB - OBJECTIVE: This study specifically aimed to compare quality of life (QOL) and mental health in bereaved family members of patients with cancer with that of the general population and to examine factors associated with QOL and mental health in this population. DESIGN: A nationwide multicenter, cross-sectional survey was administered to the bereaved family members of patients with terminal cancer. SETTING: Thirty-three palliative care centers designated by the Ministry of Health and Welfare participated in this study. PARTICIPANTS: The participants in this study were 501 bereaved family members of patients with terminal cancer and matched control individuals from the Korean National Health and Nutrition Examination Survey. MEASUREMENT: EQ-5D and several questions used in Korean National Health And Nutrition Examination Survey were used in to measure health related QOL and mental health. RESULTS: Health-related QOL, as determined by EQ 5D, was significantly lower in bereaved family members than in controls (0.88 +/- 0.20 vs 0.93 +/- 0.13, p = 0.002). Bereaved family members experienced more frequent episodes of depression (33.1% vs 12.5%, p < 0.001) and suicidal thoughts (31.4% vs 16.4%, p < 0.001) during the previous year than did controls. Female sex, lower income, spousal relationship, and longer duration of survival after palliative care referral were negatively correlated with health-related QOL. Younger age and higher mental burden of caregiving were associated with a higher risk of impaired mental health. DISCUSSION: Our results confirm that bereaved family members of patients with cancer have lower health-related QOL and mental health than the general population. Healthcare providers should focus more attention on this vulnerable group, and various support programs should be developed to improve their health-related QOL. PMID- 21823198 TI - Psychometric properties of the Chinese version of Sense of Coherence Scale in women with cervical cancer. AB - PURPOSE: The purpose of this study was to test the psychometric properties of a Chinese version of the Sense of Coherence Scale (C-SOC-13) in women with cervical cancer in Mainland China. METHODS: The C-SOC-13 and Health-related Quality of Life scale (Functional Assessment of Cancer Therapy-Cervix) were administered to 238 women with cervical cancer. Validity was assessed in terms of factor validity, predictive validity, divergent validity and stability, whereas reliability was evaluated using Cronbach's alpha coefficient. RESULTS: This study showed that in confirmatory factor analysis, the first-order interrelated three factor model and second-order model were performed based on Antonovsky's theoretical structure of Sense of Coherence (SOC). Both models fitted the data satisfactorily when the largest modification index was released. The chi-square value/degrees of freedom was 2.120, the goodness-of-fit index was 0.919, the root mean square error of approximation was 0.069, and the comparative fit index was 0.911. The Pearson correlation coefficient between SOC and Functional Assessment of Cancer Therapy-Cervix was 0.611. Enter multiple regression with SOC as a dependent variable and medical and socio-economic variables as independent variables showed no statistically significant partial coefficient of any independent variable in regression equation except for age. The Cronbach's alpha coefficient for the scale was 0.824. CONCLUSION: The factor validity, predictive validity and divergent validity of C-SOC-13 were reasonable, as well as the internal consistency. In general, C-SOC-13 showed to be suitable as an SOC measurement for women with cervical cancer in Mainland China. However, SOC may have a different meaning to Chinese people because of the philosophy and culture that shape the context of their lives. Generalizing the findings to other populations requires further psychometric evaluation of C-SOC-13. Further longitudinal studies are also needed to explore the stability. PMID- 21823199 TI - Cognitive-behavioural group therapy versus guided self-help for compulsive buying disorder: a preliminary study. AB - Compulsive buying (CB) is defined as extreme preoccupation with buying/shopping and frequent buying that causes substantial negative psychological, social, occupational and financial consequences. There exists preliminary evidence that group cognitive-behavioural therapy (CBT) is effective in the treatment of CB. The present pilot study made a first attempt to compare group CBT for CB with telephone-guided self-help (GSH). Fifty-six patients were allocated randomly to one of the three conditions: (1) group CBT (n = 22); (2) GSH (n = 20); and (3) a waiting list condition (n = 14). The results indicate that face-to-face group CBT is superior not only to the waiting list condition but also to GSH. Patients who received GSH tended to have more success in overcoming CB compared with the waiting list controls. Given the sample size, the results must be considered as preliminary and further research is needed to address the topic whether GSH also could be a helpful intervention in reducing CB. PMID- 21823200 TI - Fipronil (active ingredient of acaricide Frontline(r)) acting on the mice thyroid. AB - Fipronil, active ingredient of Frontline(r) acaricide, is a phenyl-pyrazolic derivative, and its efficacy in the elimination of several plagues, even in lower concentrations, has already been demonstrated; however, its effect on nontarget organisms has not been thoroughly explained. In this sense, the present study had the objective to evaluate the effects of different doses of fipronil in mice and determine its cytotoxic potential and possible compromises on nontarget organisms in artificial conditions. The results showed that animals exposed to fipronil presented significant alterations in the thyroidean tissue with evident follicular disorganization, decreased in the size of most follicles culminating with the rupture of smaller follicles and still with posterior fusion in a big and irregular "follicle" filled with colloid. The present study also revealed that the action of fipronil not only causes disorganization in the thyroidean tissue but alsoalters the chemical composition of the colloid itself (prehormone), modifying its proteic basis, which was confirmed by histochemical test for protein detection, making it clear that, in thyroids exposed to fipronil, the colloid was weakly positive or even negative for the presence of proteins in its constitution. PMID- 21823201 TI - Rab7 and actin cytoskeleton participate during mobilization of beta1EHFNR in fibronectin-stimulated Entamoeba histolyticatrophozoites. AB - In vitro interaction of Entamoeba histolytica trophozoites with fibronectin (FN) induces redistribution of the amoebic fibronectin receptor (beta1EhFNR). Trafficking of beta1 integrins is important for cell adhesion and migration in higher eukaryotes and requires the participation of Rab proteins. In E. histolytica, the machinery involved in integrin trafficking is not completely known. EhRab7 is a 24.5-kDa protein whose alignment with other Rab7 proteins demonstrated that it shared significant homology with Rab7 proteins from other organisms, including humans. Using different types of microscopy (fluorescence and confocal microscopy), it was established that Rab7 and the actin cytoskeleton participated in the mobilization of beta1EhFNR in FN-stimulated trophozoites. beta1EhFNR and Rab7 co-localized only in vesicular structures at 5 min, and at longer time (1 h), both co-localized in both plasma membrane and in vesicular structures; at the same time, Rab7 co-localized with specific actin structures (phagocytic vacuoles). At 5 h the beta1EhFNR, Rab7, and actin co-localized at the plasma membrane, and only beta1EhFNR and Rab7 decorated vesicles of different sizes. Actin and Rab7 co-localized in a cap-like structure at one end of the cell. Fluorescence resonance energy transfer and electron microscopy confirmed the close interaction between beta1EhFNR and Rab7. Moreover, the use of a lysosome-specific marker (LysoTracker) and a Golgi-specific marker (NBD C(6) ceramide) allowed us to establish that, at some point within the endocytic route, beta1EhFNR and Rab7 co-localized within a lysosome-type organelle, but not a Golgi-like organelle, which indicated that this integrin-like molecule was returned to the plasma membrane via exocytic or secretory vesicles. PMID- 21823202 TI - Anisotropic properties of bovine nasal cartilage. AB - To investigate the structural anisotropy in bovine septal cartilage, quantitative procedures in microscopic magnetic resonance imaging (MUMRI), polarized light microscopy (PLM), and mechanical indentation were used to measure the tissue in three orthogonal planes: vertical, medial, and caudocephalic. The quantitative T2 imaging experiments in MUMRI found strong anisotropy in the images of both vertical and caudocephalic planes but little anisotropy in the images from the medial plane. The PLM birefringent experiments found that the retardation values in the medial section were only about 10% of these in the vertical and caudocephalic sections and that the angle values in all three sections followed the rotation of the tissue section in the microscope stage. The stress relaxation experiments in mechanical indentation showed reduced stiffness in the medial plane compared to stiffness in either the vertical or caudocephalic planes. Collectively, the results in this project coherently indicate a marked structural anisotropy in cartilage from the nasal septum, where the long axis of the collagen fibrils is oriented in parallel with the medial axis. PMID- 21823203 TI - Intravital dual-colored visualization of colorectal liver metastasis in living mice using two photon laser scanning microscopy. AB - A major challenge of cancer biology is to visualize the dynamics of the metastatic process in secondary organs at high optical resolution in vivo real time. Here, we presented intravital, dual-colored imaging of liver metastasis formation from a single cancer cell to metastatic colonies in the living liver of living mice using two photon laser scanning microscopy (TPLSM). Red fluorescent protein expressing murine (SL4) or human (HT29) colorectal cancer cell lines were inoculated to the spleen of green fluorescent protein expressing mice. Intravital TPLSM was performed by exteriorizing and fixing the liver lobe of living mice. This was repeated several times for the long-term imaging of the same mouse. Viable cancer cells in the living liver of living mice were visualized intravitally at a magnification of over 600*. Single cancer cells were arrested within hepatic sinusoids 2 h after injection. Platelet aggregation surrounding a cancer cell was observed, indicating a phenomenon of tumor-cell induced platelet aggregation. Cancer cells were extravasated from hepatic sinusoids to the space of Disse. Protrusions of Kupffer cells surrounding a cancer cell were observed, indicating that Kupffer cells appear to phagocytose cancer cells. SL4 cells formed liver metastatic colonies with extensive stromal reaction. Liver metastases by HT29 cells were observed as a cluster of micrometastatic nodules. High-resolution, dual-colored, real-time visualization of cancer metastasis using intravital TLPSM can help to understand spatiotemporal tumor-host interactions during metastatic processes in the living organs of living animals. PMID- 21823205 TI - Letter to the editor: Brain iron mapping using MRI relaxation rate or R2* revisited. PMID- 21823204 TI - Use of different morphological techniques to analyze the cellular composition of the adult zebrafish optic tectum. AB - Cellular composition of the adult zebrafish (Danio rerio) optic tectal cortex was examined in this study. Morphological techniques such as 1 MUm thick serial plastic sections stained with osmium tetroxide and toluidine blue, modified rapid Golgi silver impregnation, GFAP immunohistochemistry, confocal microscopy, as well as scanning and transmission electron microscopy were used. Neuronal and glial components are described and the layers of the cortex are revisited. Specific neuronal arrangements as well as unique glial/ependymal cells are described. A three dimensional rendering of the astrocytic fiber arrangement in the marginal zone is presented and a composite drawing summarizes the cellular composition of the optic tectum. PMID- 21823206 TI - Human cortical theta reactivity to high-frequency repetitive transcranial magnetic stimulation. AB - Electroencephalography (EEG) can directly monitor the temporal progression of cortical changes induced by repetitive Transcranial Magnetic Stimulation (rTMS) and facilitate the understanding of cortical and subcortical influences in the genesis of oscillations. In this combined rTMS/EEG study, we aimed to investigate changes in oscillatory activity after high-frequency (~11 Hz) rTMS relative to the number of applied pulses. Twenty intermittent trains of 20 or 60 rTMS pulses were delivered over the human primary motor cortex at rest and tuned to individual mu frequency. The regional and interregional oscillatory neural activity after stimulation were evaluated using event-related power (ERPow) and event-related coherence (ERCoh) transformations. The most prominent changes for ERPow were observed in the theta band (4-7 Hz), as an increase in ERPow up to 20 s following 60 rTMS pulses, whereas ERPow increases were smaller in mu (10-12 Hz) and beta (13-30 Hz). ERCoh revealed that rTMS 60 modulated the connectivity in the theta band for up to 20 s. The topography of mu and theta changes were not identical; mu was more focal and theta was more global. Our data suggested the presence of independent cortical theta and mu generators with different reactivity to rTMS but could not rule out possible thalamocortical contributions in generating theta and mu over the motor network. PMID- 21823207 TI - Look at me, I'll remember you: the perception of self-relevant social cues enhances memory and right hippocampal activity. AB - Being looked at by a person enhances the subsequent memorability of her/his identity. Here, we tested the specificity of this effect and its underlying brain processes. We manipulated three social cues displayed by an agent: Gaze Direction (Direct/Averted), Emotional Expression (Anger/Neutral), and Pointing gesture (Presence/Absence). Our behavioral experiment showed that direct as compared with averted gaze perception enhanced subsequent retrieval of face identity. Similar effect of enhanced retrieval was found when pointing finger was absent as compared with present but not for anger as compared with neutral expression. The fMRI results revealed amygdala activity for both Anger and Direct gaze conditions, suggesting emotional arousal. Yet, the right hippocampus, known to play a role in self-relevant memory processes, was only revealed during direct gaze perception. Further investigations suggest that right hippocampal activity was maximal for the most self-relevant social event (i.e. actor expressing anger and pointing toward the participant with direct gaze). Altogether, our results suggest that the perception of self-relevant social cues such as direct gaze automatically prompts "self-relevant memory" processes. PMID- 21823208 TI - Face-likeness and image variability drive responses in human face-selective ventral regions. AB - The human ventral visual stream contains regions that respond selectively to faces over objects. However, it is unknown whether responses in these regions correlate with how face-like stimuli appear. Here, we use parameterized face silhouettes to manipulate the perceived face-likeness of stimuli and measure responses in face- and object-selective ventral regions with high-resolution fMRI. We first use "concentric hyper-sphere" (CH) sampling to define face silhouettes at different distances from the prototype face. Observers rate the stimuli as progressively more face-like the closer they are to the prototype face. Paradoxically, responses in both face- and object-selective regions decrease as face-likeness ratings increase. Because CH sampling produces blocks of stimuli whose variability is negatively correlated with face-likeness, this effect may be driven by more adaptation during high face-likeness (low variability) blocks than during low face-likeness (high-variability) blocks. We tested this hypothesis by measuring responses to matched-variability (MV) blocks of stimuli with similar face-likeness ratings as with CH sampling. Critically, under MV sampling, we find a face-specific effect: responses in face-selective regions gradually increase with perceived face-likeness, but responses in object selective regions are unchanged. Our studies provide novel evidence that face selective responses correlate with the perceived face-likeness of stimuli, but this effect is revealed only when image variability is controlled across conditions. Finally, our data show that variability is a powerful factor that drives responses across the ventral stream. This indicates that controlling variability across conditions should be a critical tool in future neuroimaging studies of face and object representation. PMID- 21823209 TI - Memory training impacts short-term changes in aging white matter: a longitudinal diffusion tensor imaging study. AB - A growing body of research indicates benefits of cognitive training in older adults, but the neuronal mechanisms underlying the effect of cognitive intervention remains largely unexplored. Neuroimaging methods are sensitive to subtle changes in brain structure and show potential for enhancing our understanding of both aging- and training-related neuronal plasticity. Specifically, studies using diffusion tensor imaging (DTI) suggest substantial changes in white matter (WM) in aging, but it is not known whether cognitive training might modulate these structural alterations. We used tract-based spatial statistics (TBSS) optimized for longitudinal analysis to delineate the effects of 8 weeks intensive memory training on WM microstructure. 41 participants (mean age 61 years) matched for age, sex and education were randomly assigned to an intervention or control group. All participants underwent MRI-scanning and neuropsychological assessments at the beginning and end of the study. Longitudinal analysis across groups revealed significant increase in frontal mean diffusivity (MD), indicating that DTI is sensitive to WM structural alterations over a 10-week interval. Further, group analysis demonstrated positive effects of training on the short-term changes. Participants in the training group showed a relative increase in fractional anisotropy (FA) compared with controls. Further, a significant relationship between memory improvement and change in FA was found, suggesting a possible functional significance of the reported changes. The training effect on FA seemed to be driven by a relative decrease in radial diffusivity, which might indicate a role for myelin-related processes in WM plasticity. PMID- 21823210 TI - Concise review: Genomic stability of human induced pluripotent stem cells. AB - The usefulness of human induced pluripotent stem cells (hiPSCs) in research and therapeutic applications highly relies on their genomic integrity and stability. Many laboratories including ours have addressed this concern by comparing genomic (at both karyotypic and subkaryotypic levels) and epigenomic abnormalities of hiPSC lines (derived via either DNA- or non-DNA-based methods), as well as human embryonic stem cell lines during long-term culture. A variety of methods have been used for this purpose, such as karyotyping and fluorescent in situ hybridization to detect karyotypic abnormalities, array-based comparative genomic hybridization to detect copy number variations (CNVs), single-nucleotide polymorphism-based microarrays to detect both CNVs and loss of heterozygosity, analysis of integration sites in the genome, and whole genome sequencing for protein-coding exome and DNA methylome profiling. Here, we summarize the progresses in this dynamically evolving field and also discuss how the findings apply to the study and application of hiPSCs. PMID- 21823211 TI - Lineage specific methylation of the Elf5 promoter in mammary epithelial cells. AB - Recent characterization of mammary stem and progenitor cells has improved our understanding of the transcriptional network that coordinates mammary development; however, little is known about the mechanisms that enforce lineage commitment and prevent transdifferentiation in the mammary gland. The E-twenty six transcription factor Elf5 forces the differentiation of mammary luminal progenitor cells to establish the milk producing alveolar lineage. Methylation of the Elf5 promoter has been proposed to act as a lineage gatekeeper during embryonic development. We used bisulphite sequencing to investigate in detail whether Elf5 promoter methylation plays a role in lineage commitment during mammary development. An increase in Elf5 expression was associated with decreasing Elf5 promoter methylation in differentiating HC11 mammary cells. Similarly, purified mammary epithelial cells from mice had increased Elf5 expression and decreased promoter methylation during pregnancy. Finally, analysis of epithelial subpopulations revealed that the Elf5 promoter is methylated and silenced in the basal, stem cell-containing population relative to luminal cells. These results demonstrate that Elf5 promoter methylation is lineage-specific and developmentally regulated in the mammary gland in vivo, and suggest that loss of Elf5 methylation specifies the mammary luminal lineage, while continued Elf5 methylation maintains the stem cell and myoepithelial lineages. PMID- 21823212 TI - History of eating disorder in mothers of children with early onset eating disorder or disturbance. AB - The literature suggests that there is significant familial aggregation of eating disorders. A specific association has also been reported between childhood feeding problems and maternal eating disorder. This study investigates whether subgroups of children with early onset eating disturbance are distinguished by maternal eating disorder history. The mothers of 66 children with either anorexia nervosa (AN), food avoidance emotional disorder (FAED) or selective eating (SE) were interviewed to ascertain eating disorder history. Seventeen per cent of mothers reported a history of eating disorder, compared with 3%-5% reported for community samples. A history of eating disorder was reported by 5.9% of mothers of children with SE, 12.9% of mothers of children with AN and 33.3% of mothers of children with FAED. The findings, based on this small sample, suggest that children with FAED are especially likely to have grown up in a dysfunctional food environment. PMID- 21823213 TI - Do men with eating disorders differ from women in clinics, psychopathology and personality? AB - OBJECTIVE: To determine if male and female eating disorders differ in clinics, psychopathology and personality traits when compared with a healthy group. METHODS: Sixty male and 60 female eating disorder individuals (16% anorexia nervosa, 42% bulimia nervosa and 42% eating disorder not otherwise specified), matched for age and diagnostic, were compared with 120 healthy-eating participants (60 male and 60 female participants). All were diagnosed according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Assessment measures included Eating Disorder Inventory--2, Symptom Checklist--Revised and Temperament and Character Inventory- Revised, as well as other clinical and psychopathological indices. RESULTS: Male eating disorder participants reported significant lower laxative abuse (p = 0.020) and significant higher vomiting episodes (p = 0.019) than female eating disorder participants. Differences on drive for thinness, body dissatisfaction and some Symptom Checklist--Revised scales were found across genders in eating disorder participants. Male eating disorder participants scored significantly lower than female participants with eating disorders on harm avoidance, reward dependence and cooperativeness. CONCLUSIONS: Although eating disorder clinical features were similar across genders, male eating disorder participants had less body image concern and general psychopathology than female eating disorder participants. PMID- 21823215 TI - Aberrant expression profiles of isoproterenol-induced endoplasmic reticulum stress response genes in mouse myocardium. AB - In this study, we identified the aberrant expression profiles of isoproterenol- (ISO; synthetic catecholamine)induced endoplasmic reticulum (ER) stress response genes in mouse myocardium. Mouse models of acute catecholamine cardiotoxicity were induced by ISO for 6, 12, and 24 h. We performed whole genome oligo microarrays of damaged mouse cardiac tissues, and we found 26 ER stress-related genes whose expression changed significantly for at least one time point. The functional analysis of those genes indicated that myocardial cells were protected by increasing folding capacity, inhibiting general protein translation, and promoting the degradation of misfolded proteins; however, some of them underwent apoptosis in the early stage of ER stress after ISO induced. PMID- 21823214 TI - Serum analysis of tryptophan catabolism pathway: correlation with Crohn's disease activity. AB - BACKGROUND: Indoleamine 2,3 dioxygenase-1 (IDO1) is a tryptophan catabolizing enzyme with immunotolerance-promoting functions. We sought to determine if increased gut expression of IDO1 in Crohn's disease (CD) would result in detectable changes in serum levels of tryptophan and the initial IDO1 pathway catabolite, kynurenine. METHODS: Individuals were prospectively enrolled through the Washington University Digestive Diseases Research Center. The Montreal Classification was used for disease phenotyping. Disease severity was categorized by the Physician's Global Assessment. Serum tryptophan and kynurenine were measured by high-pressure liquid chromatography. IDO1 immunohistochemical staining was performed on formalin-fixed tissue blocks. RESULTS: In all, 25 CD patients and 11 controls were enrolled. Eight CD patients had serum collected at two different timepoints and levels of disease activity compared. Strong IDO1 expression exists in both the lamina propria and epithelium during active CD compared to controls. Suppressed serum tryptophan levels and an elevated kynurenine/tryptophan (K/T) ratio were found in individuals with active CD as compared to those in remission or the control population. K/T ratios correlated positively with disease activity as well as with C-reactive protein and erythrocyte sedimentation rate. In the subgroup of CD patients with two serum measurements, tryptophan levels were elevated while kynurenine levels and the K/T ratio lowered as the disease activity lessened. CONCLUSIONS: IDO1 expression in CD is associated with lower serum tryptophan and an elevated K/T ratio. These levels may serve as a reasonable objective marker of gut mucosal immune activation and as a surrogate for CD activity. PMID- 21823216 TI - Hepatoprotective activity of quercetin against acrylonitrile-induced hepatotoxicity in rats. AB - Acrylonitrile is a potent hepatotoxic, mutagen, and carcinogen. A role for free radical-mediated lipid peroxidation in the toxicity of acrylonitrile has been suggested. The present study was designed to assess the hepatoprotective effect of quercetin against acrylonitrile-induced hepatotoxicity in rats. Liver damage was induced by oral administration of acrylonitrile (50 mg/kg/day/5 weeks). Acrylonitrile produced a significant elevation of malondialdehyde (138.9%) with a marked decrease in reduced glutathione (72.4%), and enzymatic antioxidants; superoxide dismutase (81%), and glutathione peroxidase (53.2%) in the liver. Serum aspartate aminotransferase, alanine aminotransferases, direct bilirubin, and total bilirubin showed a significant increase in acrylonitrile alone treated rats (115.5%, 110.8%, 1006.8%, and 1000.8%, respectively). Pretreatment with quercetin (70 mg/kg/day/6 weeks) and its coadministration with acrylonitrile prevented acrylonitrile-induced alterations in hepatic lipid peroxides and enzymatic antioxidants as well as serum aminotransferases and bilirubin. Histopathological findings supported the biochemical results. We suggest that querectin possess hepatoprotective effect against acrylonitrile-induced hepatotoxicity through its antioxidant activity. PMID- 21823217 TI - Furthering the link between the sarcomere and primary cardiomyopathies: restrictive cardiomyopathy associated with multiple mutations in genes previously associated with hypertrophic or dilated cardiomyopathy. AB - Mutations in genes that encode components of the sarcomere are well established as the cause of hypertrophic and dilated cardiomyopathies. Sarcomere genes, however, are increasingly being associated with other cardiomyopathies. One phenotype more recently recognized as a disease of the sarcomere is restrictive cardiomyopathy (RCM). We report on two patients with RCM associated with multiple mutations in sarcomere genes not previously associated with RCM. Patient 1 presented with NYHA Class III/IV heart failure at 22 years of age. She was diagnosed with RCM and advanced heart failure requiring heart transplantation. Sequencing of sarcomere genes revealed previously reported homozygous p.Glu143Lys mutations in MYL3, and a novel heterozygous p.Gly57Glu mutation in MYL2. The patient's mother is a double heterozygote for these mutations, with no evidence of cardiomyopathy. Patient 2 presented at 35 years of age with volume overload while hospitalized for oophorectomy. She was diagnosed with RCM and is being evaluated for heart transplantation. Sarcomere gene sequencing identified homozygous p.Asn279His mutations in TPM1. The patient's parents are consanguineous and confirmed heterozygotes. Her father was diagnosed with HCM at 42 years of age. This is the first report of mutations in TPM1, MYL3, and MYL2 associated with primary, non-hypertrophied RCM. The association of more sarcomere genes with RCM provides further evidence that mutations in the various sarcomere genes can cause different cardiomyopathy phenotypes. These cases also contribute to the growing body of evidence that multiple mutations have an additive effect on the severity of cardiomyopathies. PMID- 21823219 TI - Stimulation of erythrocyte phospholipid scrambling by enniatin A. AB - SCOPE: Enniatin A, a peptide antibiotic and common food contaminant, triggers mitochondrial dysfunction and apoptosis. Even though lacking mitochondria, erythrocytes may similarly undergo suicidal cell death or eryptosis. Eryptosis is characterized by cell shrinkage and cell membrane phospholipid scrambling. Triggers of phospholipid scrambling include energy depletion and increase in cytosolic Ca(2+) activity ([Ca(2+) ](i) ). The present study explored whether enniatin A triggers phospholipid scrambling. METHODS AND RESULTS: Phospholipid scrambling was estimated from annexin-V-binding, cell volume from forward scatter (FSC), [Ca(2+) ](i) from Fluo3-fluorescence, cytosolic ATP-concentration ([ATP](i) ) using a luciferase assay and hemolysis from hemoglobin release. Exposure of erythrocytes for 48 h to enniatin A (>= 2.5 MUM) significantly increased [Ca(2+) ](i) , decreased [ATP](i) , decreased FSC, triggered annexin-V binding and elicited hemolysis. Annexin-V-binding affected 25%, and hemolysis 2% of treated erythrocytes. Decreased [ATP](i) by glucose depletion for 48 h was similarly followed by increased [Ca(2+) ](i) , decreased FSC and annexin-V binding. Enniatin A augmented the effect on [Ca(2+) ](i) and annexin-V-binding, but not on FSC. Annexin-V-binding was blunted by Ca(2+) removal, by the cation channel inhibitor amiloride (1 mM), by the protein kinase C inhibitor staurosporine (500 nM) but not by the pancaspase inhibitor zVAD (10 MUM). CONCLUSION: The food contaminant enniatin A triggers ATP depletion and increases cytosolic Ca(2+) activity, effects resulting in suicidal erythrocyte death. PMID- 21823220 TI - Alkaloids in the human food chain--natural occurrence and possible adverse effects. AB - Alkaloid-containing plants are an intrinsic part of the regular Western diet. The present paper summarizes the occurrence of alkaloids in the food chain, their mode of action and possible adverse effects including a safety assessment. Pyrrolizidine alkaloids are a reason for concern because of their bioactivation to reactive alkylating intermediates. Several quinolizidine alkaloids, beta carboline alkaloids, ergot alkaloids and steroid alkaloids are active without bioactivation and mostly act as neurotoxins. Regulatory agencies are aware of the risks and have taken or are considering appropriate regulatory actions for most alkaloids. These vary from setting limits for the presence of a compound in feed, foods and beverages, trying to define safe upper limits, advising on a strategy aiming at restrictions in use, informing the public to be cautious or taking specific plant varieties from the market. For some alkaloids known to be present in the modern food chain, e.g., piperine, nicotine, theobromine, theophylline and tropane alkaloids risks coming from the human food chain are considered to be low if not negligible. Remarkably, for many alkaloids that are known constituents of the modern food chain and of possible concern, tolerable daily intake values have so far not been defined. PMID- 21823222 TI - Soy food supplementation, dietary fat reduction and peripheral blood gene expression in postmenopausal women--a randomized, controlled trial. AB - SCOPE: The effect of soy food supplementation or dietary fat reduction on gene expression is not well studied. METHODS AND RESULTS: We evaluated the potential of gene expression profiling in peripheral blood mononuclear cells (PBMCs) collected at baseline and at the completion of an 8-wk controlled dietary intervention. Healthy postmenopausal women were randomized to a very-low-fat diet (VLFD; 11% of energy as fat) (n=21), a Step 1 diet (25% energy as fat) supplemented with soy food (SFD; 50 mg isoflavones per day) (n=20), or a control Step 1 diet (CD; 27% energy as fat) with no SFD (n=18). All diets were prepared at the General Clinical Research Center of the University of Southern California. We did not observe any gene that showed variable response across the three dietary interventions. However, there were notable changes in gene expression associated with the intervention in the VLFD and SFD groups. Our findings suggest that the expression of nicotinamide phosphoribosyltransferase (NAMPT) and genes related to Fc gamma R-mediated phagocytosis and cytokine interactions may be significantly altered in association with dietary fat reduction and soy supplementation. Gene expression changes in NAMPT were somewhat dampened with adjustment for weight but changes related to Fc gamma R-mediated phagocytosis and cytokine interactions remained largely unchanged. CONCLUSION: PBMCs can reveal novel gene expression changes in association with controlled dietary intervention. PMID- 21823221 TI - Acrolein-mediated injury in nervous system trauma and diseases. AB - Acrolein, an alpha,beta-unsaturated aldehyde, is a ubiquitous pollutant that is also produced endogenously through lipid peroxidation. This compound is hundreds of times more reactive than other aldehydes such as 4-hydroxynonenal, is produced at much higher concentrations, and persists in solution for much longer than better known free radicals. It has been implicated in disease states known to involve chronic oxidative stress, particularly spinal cord injury and multiple sclerosis. Acrolein may overwhelm the anti-oxidative systems of any cell by depleting glutathione reserves, preventing glutathione regeneration, and inactivating protective enzymes. On the cellular level, acrolein exposure can cause membrane damage, mitochondrial dysfunction, and myelin disruption. Such pathologies can be exacerbated by increased concentrations or duration of exposure, and can occur in normal tissue incubated with injured spinal cord, showing that acrolein can act as a diffusive agent, spreading secondary injury. Several chemical species are capable of binding and inactivating acrolein. Hydralazine in particular can reduce acrolein concentrations and inhibit acrolein mediated pathologies in vivo. Acrolein scavenging appears to be a novel effective treatment, which is primed for rapid translation to the clinic. PMID- 21823223 TI - Integrative metabolome and transcriptome profiling reveals discordant energetic stress between mouse strains with differential sensitivity to acrolein-induced acute lung injury. AB - SCOPE: This investigation sought to better understand the metabolic role of the lung and to generate insights into the pathogenesis of acrolein-induced acute lung injury. A respiratory irritant, acrolein is generated by overheating cooking oils or by domestic cooking using biomass fuels, and is in environmental tobacco smoke, a health hazard in the restaurant workplace. METHODS AND RESULTS: Using SM/J (sensitive) and 129X1/SvJ (resistant) inbred mouse strains, the lung metabolome was integrated with the transcriptome profile before and after acrolein exposure. A total of 280 small molecules were identified and mean values (log 2 >0.58 or <-0.58, p<0.05) were considered different for between-strain comparisons or within-strain responses to acrolein treatment. At baseline, 24 small molecules increased and 33 small molecules decreased in the SM/J mouse lung as compared to 129X1/SvJ mouse lung. Notable among the increased compounds was malonylcarnitine. Following acrolein exposure, several molecules indicative of glycolysis and branched chain amino acid metabolism increased similarly in both strains, whereas SM/J mice were less effective in generating metabolites related to fatty acid beta-oxidation. CONCLUSION: These findings suggest management of energetic stress varies between these strains, and that the ability to evoke auxiliary energy generating pathways rapidly and effectively may be critical in enhancing survival during acute lung injury in mice. PMID- 21823224 TI - Characterization and identification of multiple constituents in Yinhuang granules by high-performance liquid chromatography with diode-array and time-of-flight mass spectrometry detection. AB - A fast high-performance liquid chromatography (HPLC) method with diode-array detection (DAD) and time-of-flight mass spectrometry (TOF/MS) has been developed for the analysis of multi-constituent in Yinhuang granules, a well-known combined herbal remedy prepared from the extract mixtures of Flos Lonicerae and Radix Scutellariae. The fast HPLC analysis was performed on an Agilent ZorBax SB-C(18) column (4.6*50 mm, 1.8 MUm) and 0.2% aqueous formic acid and acetonitrile was the optimum mobile phase for gradient elution in 17 min, which is five times faster than the performance of conventional columns packed with 5.0 MUm particles. With various fragmentor voltages in TOF/MS, accurate mass measurements (<5 ppm error) for molecular ions and characteristic fragment ions represented reliable identification criteria for different constituents. A total of 28 compounds, including nine phenolic acids, three iridoid glycosides and nine saponins from Flos Lonicerae and seven flavonoids from Radix Scutellariae, were identified or tentatively characterized in the extract of Yinhuang granules. The established fast HPLC-DAD-TOF/MS method turns out to be useful and efficient for quality control of this commonly used Chinese herbal preparation. PMID- 21823225 TI - RNA nucleotide methylation. AB - Methylation of RNA occurs at a variety of atoms, nucleotides, sequences and tertiary structures. Strongly related to other posttranscriptional modifications, methylation of different RNA species includes tRNA, rRNA, mRNA, tmRNA, snRNA, snoRNA, miRNA, and viral RNA. Different catalytic strategies are employed for RNA methylation by a variety of RNA-methyltransferases which fall into four superfamilies. This review outlines the different functions of methyl groups in RNA, including biophysical, biochemical and metabolic stabilization of RNA, quality control, resistance to antibiotics, mRNA reading frame maintenance, deciphering of normal and altered genetic code, selenocysteine incorporation, tRNA aminoacylation, ribotoxins, splicing, intracellular trafficking, immune response, and others. Connections to other fields including gene regulation, DNA repair, stress response, and possibly histone acetylation and exocytosis are pointed out. WIREs RNA 2011 2 611-631 DOI: 10.1002/wrna.79 For further resources related to this article, please visit the WIREs website. PMID- 21823227 TI - tRNA mimicry in translation termination and beyond. AB - The mechanism of translation termination has long been a puzzle. The release factor (RF) class of translation factors plays a key role in terminating protein synthesis. Bacteria have two RFs, RF1 and RF2, with high specificity to decipher three stop codons. Decades ago, an idea was formulated that RFs may be protein analogs of tRNA. This idea gained substantial support 10 years ago by the identification of two classes of crucial RF peptide motifs, P(A/V)T/SPF and GGQ, in bacteria. These motifs were functionally equivalent to the anticodon and aminoacyl-CCA terminus of tRNA, although the processes these molecules function in are different. These findings reinforced the 'molecular mimicry' or 'tRNA mimicry' hypothesis. Since then, the RF-tRNA mimicry hypothesis has played a crucial role to elucidate the mechanism of translation termination. In the past decade, the crystal structure of the translation termination complex between the ribosome and RFs has been determined at atomic resolution. Overall, the structural data strongly support the RF-tRNA mimicry hypothesis, with shared as well as distinct ribosomal conformations induced by RF or tRNA binding. In this review, we re-evaluate the structural data from the genetic and biochemical viewpoint as our initial functional evidence were not fully interpreted in the previous reports. Recent structural and functional studies of the translation machinery have uncovered that the concept of tRNA mimicry can be expanded for factors beyond translation termination and into translation initiation, elongation, as well as mRNA surveillance pathways for protein synthesis. WIREs RNA 2011 2 647-668 DOI: 10.1002/wrna.81 For further resources related to this article, please visit the WIREs website. PMID- 21823226 TI - RITS-connecting transcription, RNA interference, and heterochromatin assembly in fission yeast. AB - In recent years, a bevy of evidence has been unearthed indicating that 'silent' heterochromatin is not as transcriptionally inert as once thought. In the unicellular yeast Schizosaccharomyces pombe, the processing of transcripts derived from centromeric repeats into homologous short interfering RNA (siRNA) is essential for the formation of centromeric heterochromatin. Deletion of genes required for siRNA biogenesis showed that core components of the canonical RNA interference (RNAi) pathway are essential for centromeric heterochromatin assembly as well as for centromere function. Subsequent purification of the RNA induced initiation of transcriptional gene silencing (RITS) complex provided the critical link between siRNAs and heterochromatin assembly, with RITS acting as a physical bridge between noncoding RNA scaffolds and chromatin. Here, we review current understanding of how RITS promotes heterochromatin formation and how it participates in transcription-coupled silencing. WIREs RNA 2011 2 632-646 DOI: 10.1002/wrna.80 For further resources related to this article, please visit the WIREs website. PMID- 21823228 TI - Uridine insertion/deletion editing in trypanosomes: a playground for RNA-guided information transfer. AB - RNA editing is a collective term referring to enzymatic processes that change RNA sequence apart from splicing, 5' capping or 3' extension. In this article, we focus on uridine insertion/deletion mRNA editing found exclusively in mitochondria of kinetoplastid protists. This type of editing corrects frameshifts, introduces start and stops codons, and often adds much of the coding sequence to create an open reading frame. The mitochondrial genome of trypanosomatids, the most extensively studied clade within the order Kinetoplastida, is composed of ~50 maxicircles with limited coding capacity and thousands of minicircles. To produce functional mRNAs, a multitude of nuclear encoded factors mediate interactions of maxicircle-encoded pre-mRNAs with a vast repertoire of minicircle-encoded guide RNAs. Editing reactions of mRNA cleavage, U-insertions or U-deletions, and ligation are catalyzed by the RNA editing core complex (RECC, the 20S editosome) while each step of this enzymatic cascade is directed by guide RNAs. These 50-60 nucleotide (nt) molecules are 3' uridylated by RET1 TUTase and stabilized via association with the gRNA binding complex (GRBC). Remarkably, the information transfer between maxicircle and minicircle transcriptomes does not rely on template-dependent polymerization of nucleic acids. Instead, intrinsic substrate specificities of key enzymes are largely responsible for the fidelity of editing. Conversely, the efficiency of editing is enhanced by assembling enzymes and RNA binding proteins into stable multiprotein complexes. WIREs RNA 2011 2 669-685 DOI: 10.1002/wrna.82 For further resources related to this article, please visit the WIREs website. PMID- 21823229 TI - Emerging roles for the Ro 60-kDa autoantigen in noncoding RNA metabolism. AB - All cells contain an enormous variety of ribonucleoprotein (RNP) complexes that function in diverse processes. Although the mechanisms by which many of these RNPs contribute to cell metabolism are well understood, the roles of others are only now beginning to be revealed. A member of this latter category, the Ro 60 kDa protein and its associated noncoding Y RNAs, was discovered because the protein component is a frequent target of the autoimmune response in patients with the rheumatic diseases systemic lupus erythematosus and Sjogren's syndrome. Recent studies have shown that Ro is ring shaped, binds the single-stranded ends of misfolded noncoding RNAs in its central cavity, and may function in noncoding RNA quality control. Although Ro is not present in yeast, many bacterial genomes contain potential Ro orthologs. In the radiation-resistant eubacterium Deinococcus radiodurans, the Ro ortholog functions with exoribonucleases during stress-induced changes in RNA metabolism. Moreover, in both D. radiodurans and animal cells, Ro is involved in the response to multiple types of environmental stress. Finally, Y RNAs can influence the subcellular location of Ro, inhibit access of the central cavity to other RNAs, and may also act as binding sites for proteins that influence Ro function. WIREs RNA 2011 2 686-699 DOI: 10.1002/wrna.85 For further resources related to this article, please visit the WIREs website. PMID- 21823231 TI - Biogenesis of spliceosomal small nuclear ribonucleoproteins. AB - Virtually, all eukaryotic mRNAs are synthesized as precursor molecules that need to be extensively processed in order to serve as a blueprint for proteins. The three most prevalent processing steps are the capping reaction at the 5'-end, the removal of intervening sequences by splicing, and the formation of poly (A)-tails at the 3'-end of the message by polyadenylation. A large number of proteins and small nuclear ribonucleoprotein complexes (snRNPs) interact with the mRNA and enable the different maturation steps. This chapter focuses on the biogenesis of snRNPs, the major components of the pre-mRNA splicing machinery (spliceosome). A large body of evidence has revealed an intricate and segmented pathway for the formation of snRNPs that involves nucleo-cytoplasmic transport events and elaborates assembly strategies. We summarize the knowledge about the different steps with an emphasis on trans-acting factors of snRNP maturation of higher eukaryotes. WIREs RNA 2011 2 718-731 DOI: 10.1002/wrna.87 For further resources related to this article, please visit the WIREs website. PMID- 21823230 TI - Pre-mRNA splicing during transcription in the mammalian system. AB - Splicing of RNA polymerase II transcripts is a crucial step in gene expression and a key generator of mRNA diversity. Splicing and transcription have generally been studied in isolation, although in vivo pre-mRNA splicing occurs in concert with transcription. The two processes appear to be functionally connected because a number of variables that regulate transcription have been identified as also influencing splicing. However, the mechanisms that couple the two processes are largely unknown. This review highlights the observations that implicate splicing as occurring during transcription and describes the evidence supporting functional interactions between the two processes. I discuss postulated models of how splicing couples to transcription and consider the potential impact that such coupling might have on exon recognition. WIREs RNA 2011 2 700-717 DOI: 10.1002/wrna.86 For further resources related to this article, please visit the WIREs website. PMID- 21823234 TI - Polypyrrole/graphene composite-coated fiber for the solid-phase microextraction of phenols. AB - A polypyrrole (Ppy)/graphene (G) composite was developed and applied as a novel coating for use in solid-phase microextraction (SPME) coupled with gas chromatography (GC). The Ppy/G-coated fiber was prepared by electrochemically polymerizing pyrrole and G on a stainless-steel wire. The extraction efficiency of Ppy/G-coated fiber for five phenols was the highest compared with the fibers coated with either Ppy or Ppy/graphene oxide (GO) using the same method preparation. Significantly, compared with various commercial fibers, the extraction efficiency of Ppy/G-coated fiber is better than or comparable to 85 MUm CAR/PDMS fiber (best extraction efficiency of phenol, o-cresol, and m-cresol in commercial fibers) and 85 MUm polyacrylate (PA) fiber (best extraction efficiency of 2,4-dichlorophenol and p-bromophenol in commercial fibers). The effects of extraction and desorption parameters such as extraction time, stirring rate, and desorption temperature and time on the extraction/desorption efficiency were investigated and optimized. The calibration curves were linear from 10 to 1000 MUg/L for o-cresol, m-cresol, p-bromophenol, and 2,4-dichlorophenol, and from 50 to 1000 MUg/L for phenol. The detection limits were within the range 0.34 3.4 MUg/L. The single fiber and fiber-to-fiber reproducibilities were <8.3 (n=7) and 13.3% (n=4), respectively. The recovery of the phenols spiked in natural water samples at 200 MUg/L ranged from 74.1 to 103.9% and the relative standard deviations were <3.7%. PMID- 21823233 TI - Small RNA and transcriptional upregulation. AB - Small RNA molecules, such as microRNA and small interfering RNA, have emerged as master regulators of gene expression through their ability to suppress target genes in a phenomenon collectively called RNA interference (RNAi). There is growing evidence that small RNAs can also serve as activators of gene expression by targeting gene regulatory sequences. This novel mechanism, known as RNA activation (RNAa), appears to be conserved in at least mammalian cells and triggered by both endogenous and artificially designed small RNAs. RNAa depends on Argonaute proteins, but possesses kinetics distinct from that of RNAi. Epigenetic changes are associated with RNAa and may contribute to transcriptional activation of target genes, but the underlying mechanism remains elusive. Given the potential of RNAa as a molecular tool for studying gene function and as a therapeutic for disease, further research is needed to completely elucidate its molecular mechanism in order to refine the rules for target selection and improve strategies for exploiting it therapeutically. WIREs RNA 2011 2 748-760 DOI: 10.1002/wrna.90 For further resources related to this article, please visit the WIREs website. PMID- 21823232 TI - Structural biology of poly(A) site definition. AB - 3' processing is an essential step in the maturation of all messenger RNAs (mRNAs) and is a tightly coupled two-step reaction: endonucleolytic cleavage at the poly(A) site is followed by the addition of a poly(A) tail, except for metazoan histone mRNAs, which are cleaved but not polyadenylated. The recognition of a poly(A) site is coordinated by the sequence elements in the mRNA 3' UTR and associated protein factors. In mammalian cells, three well-studied sequence elements, UGUA, AAUAAA, and GU-rich, are recognized by three multisubunit factors: cleavage factor I(m) (CFI(m) ), cleavage and polyadenylation specificity factor (CPSF), and cleavage stimulation factor (CstF), respectively. In the yeast Saccharomyces cerevisiae, UA repeats and A-rich sequence elements are recognized by Hrp1p and cleavage factor IA. Structural studies of protein-RNA complexes have helped decipher the mechanisms underlying sequence recognition and shed light on the role of protein factors in poly(A) site selection and 3' processing machinery assembly. In this review we focus on the interactions between the mRNA cis elements and the protein factors (CFI(m) , CPSF, CstF, and homologous factors from yeast and other eukaryotes) that define the poly(A) site. WIREs RNA 2011 2 732-747 DOI: 10.1002/wrna.88 For further resources related to this article, please visit the WIREs website. PMID- 21823235 TI - Determination of darusentan enantiomers in rat plasma by enantioselective liquid chromatography with tandem mass spectrometry using cellulose-based chiral stationary phase. AB - A sensitive, specific and rapid liquid chromatography-mass spectrometry (LC MS/MS) method has been developed and validated for enantioselective determination of darusentan enantiomers, orally active potent endothelin-A receptor antagonist, in rat plasma. The plasma samples were pretreated by protein precipitation with methanol and baseline chromatographic separation was performed on a Chiralcel OD RH column with a mobile phase consisting of acetonitrile/water/formic acid (50:50:0.1, v/v/v) at a flow rate of 0.5 mL/min. The detection was accomplished by multiple-reaction monitoring (MRM) scanning via electrospray ionization (ESI) source operating in the negative ionization mode. The calibration curve was linear over the investigated concentration from 0.500 to 2500 ng/mL (r>=0.995) for each enantiomer using 50 MUL of rat plasma. The lower limit of quantitation (LLOQ) for each enantiomer was 0.500 ng/mL. The intra- and inter-day precisions were not more than 10.2% and the accuracy was within the range from -5.4 to 6.3% for darusentan enantiomers. No chiral inversion was observed during the plasma preparation, storage and analysis. The method proved adequate for enantioselective pharmacokinetic studies of darusentan enantiomers after oral administration of three different doses of racemic darusentan. PMID- 21823239 TI - Towards faster bioprocess development. PMID- 21823236 TI - In vivo biocompatibility of three potential intraperitoneal implants. AB - The intraperitoneal biocompatibility of PDMS, polyHEMA and pEVA was investigated in rats, rabbits and rhesus monkeys. No inflammation was evidenced by hematological analyses and measurement of inflammatory markers throughout the experiment and by post-mortem examination of the pelvic cavity. After 3 or 6 months, histological analysis revealed fibrous tissue encapsulating PDMS and PEVA implants in all species and polyHEMA implants in rabbits and monkeys. Calcium deposits were observed inside polyHEMA implants. The intraperitoneal biocompatibility of all 3 polymers makes them suitable for the design of drug delivery systems, which may be of great interest for pathologies confined to the pelvic cavity. PMID- 21823242 TI - New biotechnological production systems. PMID- 21823243 TI - National Postdoctoral Association 9(th) Annual Meeting (NPA2011). PMID- 21823244 TI - Autism and cancer risk. AB - A literature review was conducted on the genetic and developmental bases of autism in relation to genes and pathways associated with cancer risk. Convergent lines of evidence from four types of analysis: (1) recent theoretical studies on the causes of autism, (2) epidemiological studies, (3) genetic analyses linking autism with mutations in tumor suppressor genes and other cancer-associated genes and pathways, and (4) contrasts with schizophrenia, Parkinson's, and Alzheimer's disease indicate that autism may involve altered cancer risk. This evidence should motivate further epidemiological studies, and it provides useful insights into the nature of the genetic, epigenetic, and environmental factors underlying the etiologies of autism, other neurological conditions, and carcinogenesis. PMID- 21823247 TI - Two faces of patient safety and care quality: a Franco-American comparison. AB - Patient safety, and more broadly the quality of care, is typically discussed with reference to the reduction of preventable adverse events within hospitals and adherence to practice guidelines on care processes. We call it the 'care-centered approach' and recognize that the United States is a leader in the field. Another face of patient safety and care quality may be defined as the 'system-centered approach'. It focuses on access to a timely and effective continuum of health care services--clinical prevention, primary care and appropriate referral to and receipt of specialty care. Although France's efforts to pursue a care-centered approach to patient safety are limited, its system-centered approach yields some benefits. Based on the evidence we have reviewed for access to primary care (hospital discharges for avoidable hospital conditions), mortality amenable to medical intervention and consumer satisfaction, in the United States and France, there appear to be good grounds for bolstering the system-centered approach in the United States. PMID- 21823248 TI - Tailoring nanostructured, graded, and particle-reinforced Al laminates by accumulative roll bonding. AB - Accumulative roll bonding (ARB) is a very attractive process for processing large sheets to achieve ultrafine-grained microstructure and high strength. Commercial purity Al and many Al alloys from the 5xxx and the precipitation strengthened 6xxx alloy series have been successfully processed by the ARB process into an ultrafine-grained state and superior ductility have been achieved for some materials like technical purity Al. It has also been shown that the ARB process can be successfully used to produce multi-component materials with tailored properties by reinforcement or grading, respectively. This allows optimizing the properties based on two or more materials/alloys. For example, to achieve high corrosion resistance and good visual surface properties it is interesting to produce a composite of two different Al alloys, where for example a high strength alloy of the 5xxx series is used as the core material and a 6xxx series alloy as the clad material. It has been shown that such a composite achieves more or less the same strength as the core material although 50% of the composite consists of the significant softer clad alloy. Furthermore, it has been found, that the serrated yielding which typically appears in 5xxx series alloys and limits applications as outer skin materials completely disappears. Moreover, the ARB process allows many other attractive ways to design new composites and graded material structures with unique properties by the introduction of particles, fibres and sheets. Strengthening with nanoparticles for example is a very attractive way to improve the properties and accelerate the grain refining used in the severe plastic deformation process. With an addition of only 0.1 vol.-% Al2O3 nanoparticles a significantly accelerated grain refinement has been found which reduces the number of ARB passes necessary to achieve the maximum in strength. The paper provides a short review on recent developments in the field of ARB processing for producing multicomponent ultrafine-grained sheet materials with tailored properties. PMID- 21823249 TI - Rare-earth ion doped up-conversion materials for photovoltaic applications. AB - With the aim of utilizing the infrared region of solar radiation to improve solar cell performance, significant progress, including theoretical analysis and experimental achievement, has been made in the field of up-conversion for photovoltaic applications. This Research News article reviews recent progress in the development of rear-earth (RE) ion doped up-conversion materials for solar cell applications. In addition, new trends for RE-ion-doped phosphors are briefly discussed, among them trivalent RE-ion-doped up-conversion materials for organic solar cell applications. PMID- 21823250 TI - The potential of molecular self-assembled monolayers in organic electronic devices. AB - Functionalized molecules that organize to self-assembled monolayers (SAMs) are gaining importance in organic electronic devices. They are fully compatible with flexible substrates, are amenable to low-cost processing, and show reliable film forming behavior. Highly integrated devices, such as sensor arrays or memories, have also been demonstrated. Starting from auxiliary layers, which improve and modify surfaces and interfaces in traditional thin-film devices, the applications of SAMs develop towards molecular scale electronics, including active molecular device layers and multifunctional SAMs, which fulfill several layer functions of a device within one monolayer. Mixed SAMs make new and tunable device features possible, by stoichiometric control of the composition of different SAM-forming molecules. PMID- 21823251 TI - Interpretation of complex phenotypes: lessons from the Mitf gene. AB - SUMMARY: Mutations provide important structure-function relationships by allowing the correlation of phenotypes to the underlying genotypes. Knockout mutations that lead to loss-of-function are important and informative in this respect. However, spontaneous and induced mutations sometimes provide surprising phenotypes, which lead to unexpected functional insights and novel biochemical pathways, especially when multiple mutations(alleles) exist at a locus. An excellent example is provided by the microphthalmia (Mitf) locus in the mouse.The multiple Mitf alleles have their own phenotypic properties, most of which have been explained by the underlying mutation. However, one allele, the Mitf (Mi White) (Mitf (Mi-Wh)) mutation, exhibits phenotypes that have not yet been fully explained. Here, the molecular, genetic, and phenotypic properties of this mutation are reviewed and an attempt made to explain the underlying biochemical reason for its observed effects. PMID- 21823252 TI - Indian insulin guidelines: a year later and the road ahead. AB - There are various regimens available for prescribing insulin, which include but are not limited to basal bolus, split mixed, premix, and prandial therapy. Basal bolus, although termed ideal for people with type 1 diabetes, is often perceived as complex for management of T2DM. In order to provide primary care physicians with a simple algorithm for initiation and titration of insulin therapy, the Indian National Consensus Group (INCG), formulated a guideline on premixed insulin therapy, which was published in 2009. They recommended premixed insulin as simple, safe, easy to start and stay, and a more physiological option for treating type 2 diabetes. The Indian insulin guideline has evoked a good deal of participation and has been discussed at various forums including national conferences, continuing medical education programs, and institutional seminars. The initial feedback on the utility of the guideline from the medical fraternity has been very encouraging. PMID- 21823253 TI - Management of diabetes in pregnancy. AB - Diabetes in pregnancy is associated with risks to the woman and to the developing fetus. Miscarriage, pre-eclampsia, preterm labour and congenital malformations in fetus are more common in women with pre-existing diabetes. Insulin requirement increases with each trimester of pregnancy in diabetic females. Treatment of gestational diabetes consists of medical nutrition therapy but insulin treatment forms the mainstay of the therapy. Monitoring glycemic control is essential in treatment of gestational diabetes. HbA1c level is helpful to differentiate between a pre-GDM and GDM. Majority of pregnant women with diabetes fail to achieve optimum glycemic control, mostly the postprandial plasma glucose with conventional insulin. In them, the best option is to administer ultra-short acting analogs, insulin lispro or insulin aspart. These analogs improve the postprandial glucose control during pregnancy in both type 1 and type 2 diabetes and are considered safe and effective. PMID- 21823254 TI - Insulin pens: the modern delivery devices. AB - Strict glycemic control helps in reducing complications and mortality in patients with diabetes. Insulin remains the mainstay in treatment of diabetes. One of the most important barriers to insulin therapy is the use of conventional insulin delivery system, which remains time-consuming, cumbersome, inconvenient and painful. Insulin dosing via syringe is associated with a high risk of dosage errors. The modern pen devices have various advantages over the conventional insulin delivery methods. The user-friendliness and comfort of injection makes the initiation of insulin easier. The ease of use of insulin pens and the flexibility of incorporating insulin injections into a busy lifestyle may improve diabetes control with much less effort, while maintaining the quality of life for the diabetic patients. Reusable and prefilled pens are available. PMID- 21823255 TI - Think thyroid. PMID- 21823256 TI - Clinical approach to thyroid disease. PMID- 21823257 TI - Laboratory evaluation of thyroid function. PMID- 21823258 TI - Nodular diseases in the thyroid. PMID- 21823259 TI - Guidelines in the management of thyroid cancer. PMID- 21823260 TI - Why basic microbiology still matters. AB - Microbiology has been a foundation of our investigation into the basic principles of life, but much remains to be discovered. Therefore, the focus on basic microbiology research cannot be lost. PMID- 21823261 TI - Microvascular sequestration of Plasmodium falciparum. PMID- 21823262 TI - Finding auxetic frameworks in periodic tessellations. AB - It appears that most models for micro-structured materials with auxetic deformations were found by clever intuition, possibly combined with optimization tools, rather than by systematic searches of existing structure archives. Here we review our recent approach of finding micro-structured materials with auxetic mechanisms within the vast repositories of planar tessellations. This approach has produced two previously unknown auxetic mechanisms, which have Poisson's ratio nuss=-1 when realized as a skeletal structure of stiff incompressible struts pivoting freely at common vertices. One of these, baptized Triangle-Square Wheels, has been produced as a linear-elastic cellular structure from Ti-6Al-4V alloy by selective electron beam melting. Its linear-elastic properties were measured by tensile experiments and yield an effective Poisson's ratio nuLE~ 0.75, also in agreement with finite element modeling. The similarity between the Poisson's ratios nuSS of the skeletal structure and nuLE of the linear-elastic cellular structure emphasizes the fundamental role of geometry for deformation behavior, regardless of the mechanical details of the system. The approach of exploiting structure archives as candidate geometries for auxetic materials also applies to spatial networks and tessellations and can aid the quest for inherently three-dimensional auxetic mechanisms. PMID- 21823263 TI - Complex Faraday rotation in microstructured magneto-optical fiber waveguides. AB - Magneto-optical glasses are of considerable current interest, primarily for applications in fiber circuitry, optical isolation, all-optical diodes, optical switching and modulation. While the benchmark materials are still crystalline, glasses offer a variety of unique advantages, such as very high rare-earth and heavy-metal solubility and, in principle, the possibility of being produced in fiber form. In comparison to conventional fiber-drawing processes, pressure assisted melt-filling of microcapillaries or photonic crystal fibers with magneto optical glasses offers an alternative route to creating complex waveguide architectures from unusual combinations of glasses. For instance, strongly diamagnetic tellurite or chalcogenide glasses with high refractive index can be combined with silica in an all-solid, microstructured waveguide. This promises the implementation of as-yet-unsuitable but strongly active glass candidates as fiber waveguides, for example in photonic crystal fibers. PMID- 21823264 TI - Edgar Allan Poe: a case description of the Marfan syndrome in an obscure short story. AB - In the obscure short story "A Tale of the Ragged Mountains," Edgar Allen Poe meticulously described a character with features remarkably consistent with the Marfan syndrome. This description appeared in fiction >50 years before the celebrated index description in the published medical research by Professor Antoine Marfan in Paris in 1896. PMID- 21823265 TI - [Human value in health care]. PMID- 21823266 TI - New Zealand Medical Association. Health equity position statement. PMID- 21823267 TI - Medicare program; prospective payment system and consolidated billing for skilled nursing facilities for FY 2012. Final rule. AB - This final rule updates the payment rates used under the prospective payment system for skilled nursing facilities (SNFs) for fiscal year 2012. In addition, it recalibrates the case-mix indexes so that they more accurately reflect parity in expenditures between RUG-IV and the previous case-mix classification system. It also includes a discussion of a Non-Therapy Ancillary component currently under development within CMS. In addition, this final rule discusses the impact of certain provisions of the Affordable Care Act, and reduces the SNF market basket percentage by the multi-factor productivity adjustment. This rule also implements certain changes relating to the payment of group therapy services and implements new resident assessment policies. Finally, this rule announces that the proposed provisions regarding the ownership disclosure requirements set forth in section 6101 of the Affordable Care Act will be finalized at a later date. PMID- 21823268 TI - Fascist political athletes and the body politic: Bulgaria reborn. PMID- 21823269 TI - The iconic symbolism of Niels Bukh: Aryan body culture, Danish gymnastics and Nordic tradition. PMID- 21823270 TI - "Now if you have only sons you are dead": migration, gender, and family economy in twentieth century northwestern Ghana. AB - This article explores the interconnectedness between labor migration, gender, and the family economy in northwestern Ghana in the 20th century. It focuses specifically on the Dagaaba of the Nadowli and Jirapa administrative districts of what is now the Upper West Region (UWR). It examines how the relationships between men and women in terms of roles, status, access to productive resources and inheritance, changed in tandem with broader changes in society in the 20th century; changes that over time produced enhanced value and elevated status for women in the family. These changes in gender relations are reflected increasingly in the belief among elderly men that 'now if you have only sons, you are dead'. By focusing on the lived experiences of ordinary women and men in the migration process, it argues that even though indigenous social structures privileged men over women in almost all spheres of life, Dagaaba women were nonetheless significantly active in shaping the history of their communities and that gender relations in Dagaaba communities were not static - they changed over time and generation. This article contributes to the ongoing discussion of the internal migration phenomenon in West Africa, which has so far attracted scant historical analysis. PMID- 21823271 TI - An interview with professor Ridwaan Omar. PMID- 21823272 TI - [Specificity of acupuncture-moxibustion effect and its research value]. AB - Acupuncture-moxibustion is the major method and process in acupuncture treatment. And obvious therapeutic effect can be found toward different phases of syndromes or various diseases. The concept of specificity of acupuncture-moxibustion effect is firstly put forward by this article, which refers to the corresponding relationship between different acupuncture and moxibustion techniques and the best indications or phases of syndromes. Meanwhile, through analysis of literatures concerning comparison on effects of different acupuncture-moxibustion techniques, different manipulations of the same acupuncture technique and different parameters of the same technique, the subjective existence of the specificity of acupuncture-moxibustion effect is approved. The recognition on specificity of acupuncture-moxibustion effect by domestic experts is also expounded. It is demonstrated that the study of specificity of acupuncture moxibustion effect can be advanced through revealing of the law and features of its specificity, which is considered to be significant for clinical decision, educational implement and scientific research designation of acupuncture and moxibustion. PMID- 21823274 TI - [Acupoint sticking therapy for 100 cases of infants asthmatic bronchitis]. PMID- 21823273 TI - [Effect of electroacupuncture in different frequencies on electromyography and ambulation in stroke patients with lower-extremity spasticity: a randomized controlled study]. AB - OBJECTIVE: To assess the effect of electroacupuncture in different frequencies by electromyography and walking function measure in post-stroke patients with lower extremity (OLE) spasticity and hemiparesis. METHODS: Fifty cases of post-stroke whose motor deficit was classified into Brunnstrom stage II - IV were randomly divided into a 100 Hz group, a 50 Hz group and a 2 Hz group. They were accepted 100 Hz, 50 Hz or 2 Hz of electroacupuncture (EA) therapy combined with standard rehabilitation program. Main outcome measures included integrated electromyography (IEMG) score during maximum isometric voluntary contraction (MIVC) of the knee flexors and extensors, ankle dorsiflexors and planterflexors in the affected LE recorded by surface EMG, Co-contraction ratio calculated by IEMG score of the antagonist over that of the agonist plus antagonist, Composite Spasticity Scale (CSS), Fugl-Meyer Motor Scale (FMS) and Functional Ambulation Categories (FAC) on LE. All outcomes were assessed at the baseline and after treatment by the professional practitioners who blinded to the treatment. RESULTS: After EA treatment, IEMG of rectus femoris were decreased in 100 Hz and 50 Hz groups (P < 0.01, P < 0.05), and better than that in 2 Hz group (both P < 0.05); gastrocnemius IEMG were decreased in 100 Hz and 50 Hz groups (P < 0.05, P < 0.01); but IEMG of tibialis anterior muscle was increased only in 50 Hz group (P < 0.05). During knee flexion, EMG co-contraction ratio in MIVC declined in 100 Hz and 50 Hz groups were decreased significantly (P < 0.05, P < 0.01), and the co contraction ratio between the non-affected and affected side were increased significantly in all the 3 groups after treatment (P < 0.01, P < 0.05). During ankle dorsiflexion, co-contraction ratio were decreased significantly in all the 3 groups (P < 0.05, P < 0.01), and cocontraction ratio between the non-affected and affected side was increased significantly only in 100 Hz after treatment (P < 0.01). FMS score, CSS and FAC were improved in all the 3 groups after treatment (all P < 0.01), but only FAC in 100 Hz group showed better effect than that in 50 Hz group or 2 Hz group (both P < 0.05). CONCLUSION: Electroacupuncture therapy combined with rehabilitation program is effective for the spasticity status of lower-extremity in post-stroke. The therapeutic effect of EA in the frequencies of 100 Hz or 50 Hz is superior to that of 2 Hz stimulation and parameter of 100 Hz may be optimal. PMID- 21823275 TI - [Observation on therapeutic effect of acupuncture on spontaneous facial paralysis in acute stage]. AB - OBJECTIVE: To observe the therapeutic effect and to explore the best opportunity of acupuncture on spontaneous facial paralysis in acute stage. METHODS: By prospective cohort study, 80 patients were divided into an observation group (n = 59) and a control group (n = 21). The course of disease was less than 5 days in the observation group and more than 7 days in the control group and had not received acupuncture treatment. They were all treated with acupuncture at Sibai (ST 2), Dicang (ST 4), Jiache (ST 6) and Cuanzhu (BL 2) etc. for 8 weeks. The facial nerve function grading (House-Brackmann, HB) and facial disable index (FDI) before treatment, 8 days after onset, 2, 4, 6, 8 weeks and 3 months after treatment were evaluated. RESULTS: Both two groups could decrease HB grading and increase FDI score (all P < 0.05), and the observation group was superior to the control group in improvement degree (all P < 0.05). The cured rate of 86.4% (51/59) in the observation group was superior to that of 76.2% (16/21) in the control group, with significant difference between the two groups (P < 0.05). Compared with the control group, the treatment time of cured patients in the observation group was shorter [(25.98 +/- 11.25) days vs (39.31 +/- 13.07) days, P < 0.01], and the incidence of sequelae of 5.1% (3/59) in the observation group was lower than that of 9.5% (2/21) in the control group (P < 0.05). CONCLUSION: Acupuncture can improve the therapeutic effect, shorten the treatment course and reduce the sequelae incidence of spontaneous facial paralysis in acute stage. PMID- 21823276 TI - [Observation on therapeutic effects of electroacupuncture at Neiguan (PC 6) on silent myocardial ischemia]. AB - OBJECTIVE: To observe the therapeutic effects of acupuncture at Neiguan (PC 6) on silent myocardial ischemia (SMI). METHODS: Forty patients with SMI were randomly divided into an electroacupuncture group and a medicine group, 20 cases in each group. The Electroacupuncture group was treated with electroacupuncture and Neiguan (PC 6) was selected as the main acupoint, and the other acupoints were selected by syndrome differentiation. The medicine group was treated with oral administration of compound Danshen dripping pill. The total effective rate, heart rate, blood pressure and dynamic electrocardiogram in 24 h were compared. RESULTS: The total effective rate of 95.0% (19/20) in the electroacupuncture group was better than that of 75.0% (15/20) in the medicine group (P < 0.05). After treatment, the heart rate, systolic blood pressure and diastolic blood pressure in the two groups were decreased significantly (P < 0.01, P < 0.05) and the electroacupuncture group was superior to the medicine group (all P < 0.05). The SMI duration and the number of ST segment depression were decreased significantly in both groups after treatment (P < 0.01, P < 0.05) and the electroacupuncture group was superior to the medicine group (P < 0.05). CONCLUSION: Acupuncture at Neiguan (PC 6) has a good therapeutic effect on SMI. It can decrease the heart rate and blood pressure, reduce the afterload in left ventricular and is superior to that of compound Danshen dripping pill. PMID- 21823277 TI - [Chronic pelvic inflammation treated with herbal cake-separated moxibustion]. PMID- 21823278 TI - [Comparative study on acupoint pressing and medication for angina pectoris due to coronary heart disease]. AB - OBJECTIVE: To observe the differences of therapeutic effect of acupoint pressing, Nitroglycerin and Suxiaojiuxin pill on angina pectoris (AP) due to coronary heart disease (CHD). METHODS: One hundred and six ty-eight patients with AP due to CHD were randomly divided into an acupoint pressing group (n = 58), a Nitro glycerin group (n = 56) and a Suxiaojiuxin pill group (n = 54) and were treated with acupoint pressing at Danzhong (CV 17) for 5-10 minutes, sublingual administration of Nitroglycerin and sublingual administration of Suxiaojiuxin pill, respectively. Symptoms, improvements in ECG, the time of producing effectiveness and adverse effects in all the groups were observed. RESULTS: The total effective rate and the effective rate of ECG were 93.1% (54/58) and 86.2% (50/58) in the acupoint pressing group respectively, 92.9% (52/56) and 85.7% (48/56) in the Nitroglycerin group, and 87.0% (47/54) and 75.9% (41/54) in the Suxiaojiuxin pill group, with no significant differences among the three groups (all P > 0.05). The average time of producing effectiveness was (1.67 +/- 2.45) min in the acupoint pressing group which was shorter than (2.89 +/- 2.64) min in the Nitroglycerin group and (3.75 +/- 2.99) min in the Suxiaojiuxin pill group (P < 0.05, P < 0.001). During the treatment, there were no adverse effects in the acupoint pressing group, which less than 19 cases in the Nitroglycerin group and 12 cases in the Suxiaojiuxin pill group (both P < 0.05). CONCLUSION: Acupoint pressing can significantly improve symptoms of AP patients with a similar therapeutic effect to Nitroglycerin and Suxiaojiuxin pill, but it has more rapid therapeutic effect without adverse effects. PMID- 21823279 TI - [Acupuncture at Hegu (LI 4) combined with manual reduction for intractable shoulder dislocation]. PMID- 21823280 TI - [Clinical observation on ankylosing spondylitis treated with acupoint catgut embedding combined vessel pricking therapy]. AB - OBJECTIVE: To explore the efficacy and safety of acupoint catgut embedding combined with vessel pricking therapy for ankylosing spondylitis (AS). METHODS: Eighty-six cases of AS were randomly divided into an acupoint catgut embedding combined vessel pricking group (group A) and a medication group(group B), 43 cases in each group. In the group A, acupoint catgut embedding combined with vessel pricking therapy were applied at Shenshu(BL 23), Dazhu (BL 11) and Jiaji (EX-B 2) etc. The group B was treated with oral administration of Sulfasalazine (SASP). The treatment lasted for 8 weeks. Symptom score, Visual Analogue Scale(VAS), the indices of morning stiff duration, Schober test, occiput to wall distance, chest expansion, erythrocyte sedimentation rate (ESR) and C-response protein (CRP) were compared before and after treatment between two groups. RESULTS: After treatment, the total effective rate was 83.7% (36/43) in the group A, which was superior to that of 70.0% (28/40) in the group B (P < 0.05). The improvements of all indices in two groups were more significant than those before treatment (all P < 0.01), and symptom score, Schober test score and VAS score in group A were superior to those in the group B (P < 0.01, P < 0.05). No adverse reaction occurred in the group A. CONCLUSION: The therapeutic effect of acupoint catgut embedding combined with vessel pricking therapy for AS is preferable without any adverse effects, which is superior to that of oral administration of SASP. PMID- 21823281 TI - [Fifty cases of irritable bowel syndrome of diarrhea type treated with scalp acupuncture]. PMID- 21823282 TI - [Comparative study on irritable bowel syndrome treated with acupuncture and western medicine]. AB - OBJECTIVE: To compare the differences in the therapeutic effect on irritable bowel syndrome (IBS) between acupuncture at Tianshu (ST 25) and Dachangshu (BL 25) and western medication with Trimebutine Maleate. METHODS: Forty cases were divided randomly into an acupuncture group and a western medication group, 20 cases in each one. In acupuncture group, acupuncture was applied to Tianshu (ST 25) and Dachangshu (BL 25). Ziwu Daojiu needling technique was adopted, once daily. In western medication group, Trimebutine Maleate capsule was administered, 2 capsules in each time, 3 times per day. The assessment on the therapeutic effect was performed in 4 weeks of treatment in two groups. RESULTS: As compared with those before treatment, the time of abdominal pain, the frequency of abdominal pain, the morbidity of abnormal stool appearance, the morbidity of defecation abnormality, the morbidity of mucus stool and the score of bloating or abdominal pain on bowel movement were all reduced after treatment in two groups (all P < 0.01). The results in acupuncture group were much more significant than those in western medication group (the total score: 16.70 +/- 2.40 vs 15.70 +/- 3.01, P < 0.01). The total effective rate in acupuncture group was 95.0% (19/20), which was superior to that of 70.0% (14/20) in western medication group (P < 0.05). CONCLUSION: Acupuncture at Tianshu (ST 25) and Dachangshu (BL 25) may remarkably relieve the clinical symptoms of IBS and its efficacy is superior to that of oral medication with Trimebutine Maleate. PMID- 21823283 TI - [Observation on therapeutic effect of acupoint injection desensitization with autoblood on chronic urticaria]. AB - OBJECTIVE: To compare the effect of acupoint injection desensitization with autoblood and routine combined therapy for treatment of chronic urticaria. METHODS: Two hundred patients with chronic urticaria were randomly divided into an acupoint injection with autoblood (AJA) group and a medicine group, 100 cases in each group. The AJA group was treated by acupoint injection desensitization with autoblood and Dazhui (GV 14), Fengfu (GV 16), Feishu (BL 13), Neiguan (PC 6) and etc. were selected, 3-5 acupoints each time, once every three days, 30 days for a course. The therapeutic effect was assessed after one course. The medicine group was treated with external application of Dexamethasone Acetate cream, twice a day, and oral administration of Setastine Hydrochloride, twice a day, 1 mg each time and the treatment duration was the same as that in the AJA group. RESULTS: The clinical cured rate was 66.0% (66/100) in the AJA group, which was superior to that of 0 (0/100) in the medicine group (P < 0.05). CONCLUSION: The acupoint injection desensitization with autoblood has obvious therapeutic effect on chronic urticaria with no apparent dependence and rebound problem. PMID- 21823284 TI - [Clinical observation on diabetic peripheral neuropathy treated with electroacupuncture and acupoint injection]. AB - OBJECTIVE: To compare the differences in the therapeutic effect on diabetic peripheral neuropathy between the combined therapy of electroacupuncture and acupoint injection and the simple acupoint injection. METHODS: Under the satisfactory control of blood glucose, 60 cases of diabetic peripheral neuropathy were divided randomly into two groups, 30 cases in each one. In electroacupuncture plus acupoint injection group (group A), electroacupuncture and acupoint injection with Methylcobalamin were administered. Penetrating acupuncture was applied from Gongsun (SP 4) to Quanzhong (Extra) and from Yongquan (KI 1) to Taichong (LR 3) mainly. Acupoint injection was administered on Sanyinjiao (SP 6). In acupoint injection group (group B), only acupoint injection with Methylcobalamin was provided on Sanyinjiao (SP 6). After 2 sessions of treatment, the conduction velocity of ulnar nerve and tibial nerve was measured. The scores of Chinese medicine syndrome and diabetic peripheral neuropathy were recorded before and after treatment in two groups. RESULTS: The effective rates were 90.0% (27/30) and 63.3% (19/30) in group A and group B respectively, presenting significant statistical difference (P < 0.05). After treatment, the motor nerve conduction velocity (MCV) and sensory nerve conduction velocity (SCV) of ulnar nerve and tibial nerve in group A were higher than those in group B (P < 0.05, P < 0.01). After treatment, the score of Chinese medicine syndrome in group A was lower than that in group B (14.36 +/- 1.88 vs 26.58 +/- 3.52, P < 0.01), the score of diabetic peripheral neuropathy in group A was lower than that in group B (12.86 +/- 4.28 vs 17.89 +/- 4.35, P < 0.01). CONCLUSION: Electroacupuncture and acupoint injection with Methylcobalamin achieve a significant clinical efficacy on diabetic neuropathy and its efficacy is superior to that of simple acupoint injection with Methylcobalamin. This therapy can effectively increase nerve conduction velocity, control and relieve the symptoms of diabetic peripheral neuropathy. PMID- 21823285 TI - [Quality control on acupuncture treatment]. AB - The theory and practice of acupuncture treatment are explored and summarized in this article from the viewpoint of clinical practice. And three major principles of quality control on acupuncture treatment is put forward, namely intensive control according to individuals, which divides patients into six categories based on their body constitutions of extreme sensitive, super sensitive, sensitive, normal, dull and super dull; intensive control according to diseases, which adjusts the intensive of acupuncture treatment according to diseases, stage of diseases and progress of diseases; and intensive control according to practitioners, which regulates acupuncture intensive according to techniques of practitioners, opportunities of treatment (season, temperature and condition of the patients, etc.) as well as treating methods. And it is concluded that appropriate intensive is the key point for the best therapeutic effect of acupuncture treatment. PMID- 21823286 TI - [Clinical observation on warming-promotion acupuncture for lumbar muscle strain]. AB - OBJECTIVE: To observe the theraputic effect of warming-promotion acupuncture for lumbar muscle strain. METHODS: Sixty-four cases were randomly divided into a warming-promotion acupuncture group(group A) and a routine acupuncture group (group B), 32 cases in each group. The group A was treated with acupuncture at Shenshu (BL 23) and Guanyuanshu (BL 26) with warming-promotion acupuncture method, (Guanyuanshu (BL 26), Yaoyangguan (GV 3), Weizhong (BL 40) with twirling uniform reinforcing-reducing method. The group B was treated with acupuncture at same acupoints only with twirling uniform reinforcing-reducing method. After four session treatment, the theraputic effect of two groups was compared. RESULTS: The cured and markedly effective rate of 65.6% (21/32) in the group A, which was superior to that of 40.6% (13/32)in the group B (P < 0.05). CONCLUSION: The efficiency on lumbar muscle strain treated with warming-promotion acupuncture is superior to that with routine acupuncture, means a suitable manipulation can enhance the therapeutic effect. PMID- 21823287 TI - [Case of infertility]. PMID- 21823288 TI - [Cardiac protective effects of transcutaneous electrical acupoint stimulation combined with general anesthesia for controlled hypotension]. AB - OBJECTIVE: To explore the protective effect and the mechanism of controlled hypotension induced by transcutaneous electrical acupoint stimulation (TEAS) combined with general anesthesia. METHODS: Sixteen male Beagles were randomly divided into a group of controlled hypotension induced by simple general anesthesia (control group) and a group of controlled hypotension induced by TEAS combined with general anesthesia (observation group). All the animals were administered with combination of Isoflurane and Sodium Nitroprusside (SNP) for controlled hypotension without TEAS until the arterial pressure was lowered to 30% basic mean arterial pressure (MAP) for 60 min. In the observation group, TEAS (2 Hz/100 Hz, 3-5 mA) was applied to "Hegu" (LI 4) "Zusanli" (ST 36), "Sanyinjiao" (SP 6) and "Quchi" (LI 11) from the beginning of physiological conditions stability to the end of maintained low MAP for 60 min, but there was no TEAS in control group. The changes of MAP, the left intraventricular pressure (LIVP), T wave and ST-T segment of II lead electrocardiogram (ECG) were monitored with the physiological signal acquisition system, and myocardial apoptosis was detected by TUNEL method. RESULTS: All the animals could maintain stable required low blood pressure. At one hour after cease of controlled hypotension, MAP of (109.56 +/- 6.14) mmHg returned to the basic level in the observation group, while MAP of (84.91 +/- 6.36) mmHg was still lower than its basic MAP of (111.02 +/- 4.15) mmHg in the control group (P < 0.05), showing significant difference in MAP between the two groups (P < 0.05). -dp/dtmax of (3156.32 +/- 332.82) mmHg/s showed significant lower than its basic value of (4585.33 +/- 638.55) mmHg/s when blood pressure increased for 1 h in the control group (P < 0.05), but there was no difference in the observation group. When the objective low MAP maintaining for 60 min the ST segment was decreased significantly in the control group (P < 0.05), but there was no difference in the observation group. The numbers of positive apoptosis cardiocytes in the observation group were (24.67 +/- 2.45) cells/mm2, which were significantly fewer than (37.89 +/- 1.90) cells/mm2 in the control group (P < 0. 05). CONCLUSIONS: TEAS combined with general anesthesia for controlled hypotension can significantly shorten restoration time of MAP, help to improve myocardial ischemia and the cardiac functional recovery and reduce myocardial apoptosis so as to produce myocardial protection. PMID- 21823289 TI - [Case of radial nerve damage caused by improper massage for ganglion cyst]. PMID- 21823290 TI - [Brief analysis on professor WU Lian-Zhong's academic thought]. AB - Professor WU Lian-zhong's academic thought and relevant theories of WU's mind regulation needling technique, the needling technique of ascending the clear and descending the turbid, clinical evidence-based needling technique at special acupoints, as well as the operation methods are introduced in this paper. In application of The mind regulation needling technique and the needling technique of ascending the clear and descending the turbid, He emphasizes the and highlights the importance of the people and the interaction between physician and patient. The needling techniques lay the stresses on motivating meridian qi, adjusting the antipathogenic qi in the core of resuscitation and mind regulation. These needling techniques bring the obvious efficacy on difficultly-treated diseases, such as stroke, dementia and tumor, etc. PMID- 21823291 TI - [Professor LI Zhi-Dao's clinical experiences in acupuncture]. AB - The outstanding experiences of Professor LI Zhi-dao in acupuncture clinic practices are stated in this paper. He believes acupoint and manipulation are the key factors which determine the clinical efficacy. He explains that the accurate acupoint location is the basis of acupuncture manipulation. He clarifies that acupoint location is located by tactile perception with hands. You should touch a wider area around the acupoint; the accurate acupoint location is mainly around or among the edges of bones, tendons and muscles; you should continually press, push and touch. The direction, angle and depth of needle insertion are the guarantee of the safety and efficacy of acupuncture clinic practices. Furthermore, the needling sensation and its transmission are crucial to the clinical efficacy. PMID- 21823292 TI - [Triple needling at Jianyu (LI 15) for 63 cases of supraspinatus tendinitis]. PMID- 21823293 TI - [Clinical application of bloodletting method on the face]. AB - The clinical practice of bloodletting method on the face is introduced in this paper through 4 medical cases: post-operative periarthritis of the shoulder in lung cancer, dizziness and vertigo, protrusion of lumbar intervertebral disc and keratitis. It is believed that the change in facial luster, vein condition on the face, the site with the most obvious change in facial luster and local skin abnormality are commonly regarded as the reaction points or areas of facial disease. According to the reaction points or areas on the face and in association with the syndrome differentiation in Lingshu: Wuse (Miraculous Pivot : Five Colors), the acupoints are selected and stimulated with bloodletting method in the treatment of some difficult and complicated cases, and the good efficacy could be obtained. But, this therapeutic method needs a further research and deserves to be promoted in practice. PMID- 21823294 TI - [Moxibustion with Zhuang medicated thread for 70 cases of cyclomastopathy]. PMID- 21823295 TI - [Problems and countermeasures of assessment standard on manipulative skill in Acupuncture and Moxibustion Manipulations]. AB - In order to construct a scientific, objective and quantitative assessment standard of operating skills, characteristics of operation test in Acupuncture and Moxibustion Manipulations are analyzed and problems of assessment standard in appendix of the textbooks of various types and levels are discussed. It is concluded that improvement should be made through compiling an operation manual, drawing up a specification operation steps and quantitative indices. At the same time, a problem-oriented test on people-oriented service should be added as well. And it is held that only through the innovation of assessment standard of skills operation in Acupuncture and Moxibustion Manipulations, the comprehensive quality and application ability of students can be promoted. PMID- 21823296 TI - [Case of atrial fibrillation]. PMID- 21823297 TI - [Study on lower He-sea points]. AB - The development of the theory of lower He-sea points is analyzed, and the indication law of acupoints as well as its significance on understanding of meridians are discussed in this article. It is concluded that the application experiences of Zusanli (ST 36) has great significance to the recognition of major points for diseases of fu organs. However, it is held that the relationship between the major indications of Xiajuxu (ST 39) and the relation between Weiyang (BL 39) and Sanjiao are not the complete embodiment of application experiences. There is a precedence relationship between the formation consequence of the five shu points and the lower He-sea points, which concerning the formation of the concept that He-sea points can treat diseases of their corresponding fu organs and the incomplete theory of the lower He-sea points. The formation of the theory of lower He-sea points also indicates the change of recognition of the relation between yang meridians and internal organs. Therefore, it is held that the relation between meridians and internal organs as well as the indication law of acupoints can be studied on the base of the above theory. PMID- 21823298 TI - [Professor LI Ding's understanding on the eight extra meridians]. AB - Through his long-term acupuncture-moxibustion teaching and academic research, professor LI Ding from Shanghai University of TCM had conducted a profound research on the theory of the eight extra meridians, named Governor Vessel, Conception Vessel, Thoroughfare Vessel, Belt Vessel, Link Vessels and Heel Vessels, as well as their relationship with the regular meridians. He rectified the miss-understanding on the courses of Governor Vessel and Conception Vessel determined by the ancient medical masters, and had a further analysis on some different views, such as the running course of Governor Vessel and the flowing direction of meridian qi in Governor Vessel and Conception Vessel. He proposed that the nutrient qi flew up to down in Governor Vessel and down to up in Conception Vessel. His research and discovery much perfected the theory of the eight extra meridians and provided a significant instruction for the research on the eight extra meridians in the later generations. PMID- 21823299 TI - [Elucidation of the national standard for Standardized Manipulation of Acupuncture and Moxibustion, Part VII: Skin needle]. AB - The importance of standardization, the main content and important cautions in the Standardized Manipulation of Acupuncture and Moxibustion, Part VII: Skin Needle are introduced briefly in this paper. It standardizes the stimulation intensity, the tapped needling location, the course of treatment and the interval between treatments. It elucidates the key points, the difficulty and the important cautions in clinical practices. In order to promote the standardization and its implementation, it also states the experiences of establishing the national standard of acupuncture and moxibustion manipulations. PMID- 21823300 TI - [Elucidation of the national standard for Standard ized Manipulation of Acupuncture and Moxibustion, Part VII: Skin needle]. PMID- 21823301 TI - [Study on meridians and collaterals through ying-qi and wei-qi]. AB - Assisted with inference, and approved by the ancient medical classics, it is concluded that meridians and collaterals are often felt in the form of qi through imitation of the methods of life experiencing of the ancient people. Ying-qi is considered as jing-qi (meridian qi), which originates from the experiences of respiration. And wei-qi relates with experiences of sleep. Part of meridian theory originated from the traditional Chinese thought of seeking the internal cause but not the external manifestations, and paying attention to the self adjustment, accomplishment and comprehension. It is also believed that the theory of ying-qi traveling inside the meridians and wei-qi outside the meridians is based on the theory that needling sensation has close relationship with wei-qi. PMID- 21823302 TI - [Analysis and strategy report on overseas large-scale systematic evaluation on clinical effectiveness of acupuncture]. AB - In recent years, studies of large-scale systematic evaluation on clinical effectiveness of acupuncture were carried out in overseas. The literatures were conducted in Cochrane Library and overseas journals about systematic review of clinical effectiveness of acupuncture. The Cochrane Library contained a series of systematic reviews for the treatment of 67 kinds of diseases by acupuncture in 2009. Preliminary evaluations of clinical effectiveness of acupuncture on 37 kinds of disease were conducted. The results indicated that acupuncture therapy was effective for 7 kinds of disease, such as idiopathic headache, neck disorders, glaucoma, rheumatoid arthritis, chemotherapy-induced nausea or vomiting, primary dysmenorrhoea with TENS and knee osteoarthritis with TENS. However, these studies still need improved research designs and sufficient research evidence. The results also indicated that acupuncture was indecisive for the other 30 kinds of disease because of insufficient evidence. Through analysis, results of most systematic reviews indicated that there were no significant difference between therapeutic effects of acupuncture treatment and pseudo acupuncture treatment. Effect of acupuncture treatment was equivalent to therapeutic effect of placebo. The likely reasons may be that some important clinical factors are disregarded in these researches, such as selection of acupoints, treatment with syndrome differentiation, the angel and depth of needle insertion, the proper time for treatment and so on. Therefore, the large-scale systematic evaluation on clinical effectiveness of acupuncture was criticized by acupuncturists. Thus, the pressing problem is to establish a rational evaluation system of clinical acupuncture. The suggestions are strengthening the research on diagnosis and treatment standard, strengthening the quality control of clinical acupuncture and establishing sound acupuncture control group and placebo acupuncture group. The basic researches on the relationship between diseases and acupoints need to be strengthened in order to explore the mechanism of acupoints reaction on diseases. PMID- 21823303 TI - [Acupuncture resources in Cochrane Library]. AB - To identify acupuncture resources in six databases of Cochrane Library (CL) with computer retrieve. Seventy-two literatures were identified in Cochrane Database of Systematic Reviews (CDSR). Among them, 12 Cochrane systematic review (CSR) verified the effectiveness of acupuncture, 29 concerning the indeterminacy of the efficacy of acupuncture with 1 didn't support acupuncture for epilepsy and 31 remained as protocols; 121 literatures were found in Database of Abstracts of Reviews of Effects (DARE) with more types of diseases or symptoms and rich modality comparing to CSR; 4218 randomized controlled trials and clinical controlled trials were identified in Cochrane Central Register of Controlled Trials (CCRCT); 43 literatures in Cochrane Methodology Register Database (CMRD) which focused on blindness study, quality assessment of methodology of research and publication bias and so on; 25 literatures in Health Technology Assessment Database (HTAD) and 18 in NHS Economic Evaluation Database (NHS EED) which were centered on acupuncture analgesia. Consequently, acupuncture literatures in 6 databases of CL do provide good resources for acupuncture researchers due to its abundant content, concrete classification and high quality evidence. PMID- 21823304 TI - Uncertain times. PMID- 21823305 TI - A safe place. PMID- 21823306 TI - Staffing levels required for major bowel surgery. PMID- 21823307 TI - Infection control beyond our control? PMID- 21823308 TI - Perioperative implications of surgery in elderly patients with hip fractures: an evidence-based review. AB - Hip fracture is a major cause of morbidity, mortality and loss of independence for the elderly. Surgical fixation of the fractured hip remains the standard of care to allow for early mobilisation and a return to independence. Operative management in this population carries its own set of problems. The altered physiological state of the older person, often coupled with significant comorbidity, can present challenges for the anaesthetist, the surgeon and the rest of the perioperative team. This article provides an evidence-based review of the important perioperative factors associated with hip fractures in the older person and their management. PMID- 21823309 TI - Perioperative management of liver resection surgery. AB - Advances in liver resection surgery have lead to reductions in both mortality and morbidity. However morbidity remains high so effective multidisciplinary teamwork is essential to optimise the perioperative care of this patient group. In this article we review the current literature on the perioperative management of patients undergoing liver resection surgery. PMID- 21823310 TI - 'Pass the buzzy thing, please.' Recognising and understanding information: an essential non-technical skill element for the efficient scrub practitioner. AB - Adverse events are unintended injuries or complications that are caused by the management of a patient's care rather than by their underlying medical condition. Research into adverse events in hospitals has demonstrated that the operating theatre is one area of healthcare where there is room for improvement, with 41% of all adverse events occurring in the operating theatre, according to one systematic review (deVries et al 2008). Despite technical guidelines, there are still instances of sponges and instruments being retained within patients (Gawande et al 2003) and the factors contributing to this may include assertiveness issues and communication between perioperative and medical staff, i.e. non-technical skills. PMID- 21823311 TI - Prevention of infection in orthopaedic joint replacement. AB - Infection of a prosthetic joint is a significant adverse event, affecting the patient, the surgical team, and consuming hospital resources. The patient faces multiple operations, a prolonged hospital stay and a more challenging period of rehabilitation. The surgeon must perform longer and more technically demanding revision operations in order to remove the infected prosthesis, increasing the burden on hospital resources. It has been estimated that that the cost of managing an infected total hip replacement (THR) is four times greater than for a primary procedure (Dreghorn & Hamblen 1989). The personal cost to the patient must also be emphasised. PMID- 21823312 TI - The development of an extended care facility in the recovery unit: the post anaesthesia care unit. AB - This article describes the development of a new service - the post-anaesthesia care unit (PACU) - that provides extended care in a recovery unit for patients who would have formerly been 'fast-tracked' through a high dependency unit (HDU). Patients requiring major surgery who stay in the recovery unit overnight are invasively monitored, have tight fluid management, blood chemistry analysis and frequently have pharmacological support. However, our overnight recovery service is not considered suitable for ventilated patients. Over 90% of patients are able to be discharged to a surgical ward within 24 hours of admission, following medical review. PMID- 21823313 TI - The early days of thyroidectomy. AB - Although the normal thyroid gland is invisible and impalpable, its enlargement gives such an obvious swelling in the front of the neck that this pathology has been observed from ancient times. Old names for the swollen gland included 'bronchocele', which means a cystic mass in the neck, 'struma', (Latin for a swollen gland) and 'goitre', which comes from the Latin word 'gutta', the throat, and which is a term which is still used today. The term 'thyroid' was introduced by the 17th century anatomist Thomas Wharton, of London, and is derived from the Greek word thyreos, a shield, based on its shield-like appearance wrapped over the front of the trachea. He believed that its function was to give women a beautifully rounded neck! PMID- 21823314 TI - [Malaria situation in the People's Republic Of China in 2009]. AB - Totally 14,491 malaria cases and 59 741 suspected cases with 12 deaths were reported by the annual case reporting system in 1171 counties of 23 Provinces/Municipalities/Autonomous Regions (P/M/A) in 2009, and the annual incidence was 0.11/10,000. Through the internet reporting system, 14,140 malaria cases were reported from 956 counties of 30 P/M/ A. The number of malaria cases and the rank of P/M/A were basically in concordance in the two systems. Among the 1171 counties with reported malaria cases, 4 counties with an incidence of more than 10/10,000 distributed in Yunnan (3 counties) and Tibet (1). There were 59 counties in which the malaria incidence was between 1/ 10,000 and 10/10,000. A total of 1027 Plasmodium falciparum malaria cases accounted for 7.1% of the total cases, of which 87.3% (897) were imported cases reported in 326 counties/cities of 21 P/M/A. Indigenous falciparum malaria was found in 18 counties/cities of Yunnan and Hainan Provinces, of which 16 counties/cities were in Yunnan and 2 counties/cities were in Hainan, 3 or 6 less respectively in comparison to that of 2008. No focal outbreaks occurred in the whole country in 2009. Although a considerable decrease in malaria incidence contributed to the implementation of the National Malaria Control Program and the project supported by the Global Fund to Fight AIDS, Tuberculosis and Malaria, Yunnan and Hainan Provinces are still the relatively high transmission areas. Yunnan ranked No.2 in the country in terms of the number of cases, while Hainan ranked down to No.6 by malaria incidence in 2009. Three thousand nine hundred and twenty two malaria cases were reported from the two provinces in 2009, accounting for 27.1% of the total reported cases in the country. There were 3 237 cases with 3 deaths reported from Yunnan, the incidence was 0.96/10,000, a decrease of 17.2% than that in the last year. Among the reported cases, 567 were falciparum malaria with 49.7% imported cases. The number of reported cases in Hainan was 685, with an incidence of 0.79/10,000, 63.8% decrease than the last year. In central China, the resurgence of malaria was suppressed and the number of malaria cases was considerably decreased in 2009, but the incidence in Anhui Province has still been the first in the country. A total of 5 918 malaria cases were reported from Anhui Province in 2009, accounting for 40.8% of the total cases in the country, with an incidence of 1.19/10,000 which decreased by 50.8% than that in 2008. The number of reported cases in Henan Province was 1 611, decreased by 40.8% in incidence. Hubei Province reported 709 malaria cases with an incidence of 0.12/10,000, decreased by 34.8%. There were 389 cases reported from Jiangsu Province, decreased by 41.8% compared to that in 2008. Cases reported from other P/M/A occupied about 13.4% of the total. Above hundred were reported from Shandong and less than 100 cases were reported from each of Fujian, Chongqing, Shanghai, Jiangxi, Liaoning, Shaanxi, Jilin, Heilongjiang, Gansu and Tibet in 2009. In summary, the re-emergence of malaria has been restrained through several years' efforts, but malaria is still an important problem of public health in China, especially in the southern and central parts. Yunnan and Hainan still face the spread of Plasmodium falciparum, especially imported malaria in the border areas. In the central parts of the country, Anhui Province is still with the highest incidence in 2009. In addition, imported malaria cases in those provinces with a low transmission or without local transmission may become a new challenge to the National Malaria Control Program. PMID- 21823315 TI - [Therapeutic effect on murine asthma with sublingual use of Dermatophagoides farinae/chitosan nanoparticle vaccine]. AB - OBJECTIVE: To prepare Dermatophagoides farinae (Der f)/chitosan nanoparticle vaccine (DCN), and to investigate the effect of sublingual administration with DCN in asthma mice model. METHODS: DCN were prepared by ionotropic gelation. 30 BALB/c mice were randomly divided into 5 groups: normal control group(A), PBS control group (B), Chitosan group (C), Der f group (D), DCN group (E). Group A were treated with normal saline (100 microl) all the time. Mice in other groups were sensitized intraperitoneally with 50 microg dust mite extracts plus 2 mg Al(OH)3, and on day 28 given a sublingual vaccination of PBS(group B), or empty CS nanoparticles (group C), or Der f (group D, 1 mg Der f) or DCN (group E, loaded with 1 mg Der f). All the mice received 18 doses at 1-day intervals. One week after the last immunization, mice in group B, C, D, and E were intranasally challenged with 50 microg Der f extract daily for seven days. Twenty-four hours after the last challenge, airway hyper-responsiveness (AHR) was assessed by using whole-body plethysmography. Two days post challenge, mice were sacrificed and bronchoalveolar lavage fluid (BALF) was collected. Number of the total cells and eosinophils was determined. Level of cytokines in the supernatant of splenocyte culture was assayed by ELISA. Level of Der f specific IgE, IgG2a and IgA in the sera was determined by ELISA. Airway inflammation was analyzed by HE staining. Spleen lymphocyte proliferation responses were analyzed by MTT colorimetry. RESULTS: Compared with group B, AHR and the lung inflammation in groups D and E were greatly reduced. Numbers of total cells and eosinophils in BALF of groups D (36.50 x 10(4)/ml, 3.72 x 10(4)/ml) and E (34.25 x 10(4)/ml, 2.25 x 10(4)/ml) were significantly lower than that of group B (61.67 x 10(4)/ml, 14.17 x 10(4)/ml) (P < 0.05). The level of specific IgE was significantly lower in groups D (0.22) and E (0.22), and that of IgA in groups D (0.88) and E (1.03) was significantly higher than that in group B (0.79). The level of IL-4 in BALF (D: 28.49 pg/ml, E: 20.93 pg/ml) and cultured splenocytes (D: 27.82 pg/ml, E: 20.80 pg/ml) of groups D and E was significantly lower than that of group B (56.33 pg/ml, 45.84 pg/ml) (P < 0.05). While IFN-gamma (D: 18.80 pg/ml, E: 37.32 pg/nml) and IL-10 (D: 118.90 pg/ml, E: 129.15 pg/ml) in BALF in groups D and E were significantly higher than that of group B (13.60 pg/ml, 29.61 pg/ml) (P < 0.05), and same with IFN-y (D: 20.68 pg/ml, E: 42.42 pg/ml) and IL-10 (D: 36.31 pg/ml, E: 161.37 pg/ml) in spleen cultured supernatants of groups D and E (P < 0.05). The allergen-specific splenocyte proliferation was inhibited in groups D (SI: 0.14) and E (SI: 0.13), and there was no significant difference between group C (SI: 0.22) and group B (SI: 0.23). CONCLUSION: Dermatophagoides farinae (Der f)/chitosan nanoparticle vaccine has therapeutic effect on murine asthma. PMID- 21823316 TI - [In vitro effect of seven anthelmintic agents against adult Clonorchis sinensis]. AB - OBJECTIVE: To observe the in vitro effect of praziquantel, tribendimidine, levamisole, artemether, artesunate, albendazole and mebendazole against adult Clonorchis sinensis. METHODS: Seventy rats infected with 50-100 C. sinensis metacercariae for 5-7 weeks were euthanized, and adult C. sinensis were collected from the common bile duct Three to four worms were placed in each well of a 24 well falcon plate, and treated by Hanks' balanced salt solution-20% calf serum containing aforementioned drugs at various concentrations. The motor activity and morphology change of the worms were observed under an inverted microscope at 4, 24, 48 and 72 h post treatment. RESULTS: Praziquantel could reduce the motor activity of the worms rapidly which resulted in detachment of oral sucker from the well wall, curl of the worm body and emergence of vacuoles from the tegument. The minimal concentration of praziquantel to kill adult C. sinensis was 0.1 g/ml. After adult C. sinensis exposed to tribendimidine at concentrations of 0.5, 1 and 10 g/ml, they revealed in paralysis, looseness and stretch of the worm body rapidly or immediately. The minimal concentration of tribendimidine to kill adult worms was 0.05 g/ml. When worms exposed to levamisole at 10 and 20 g/ml, there was a gradual decrease in the worm's motor activity accompanied by looseness of the worm body. But 48 h post exposure, most worms showed apparently recovery of motor activity. In a higher levamisole concentration of 50 g/ml, all worms revealed in stretch and paralysis which was similar to that induced by tribendimidine. When adult C. sinensis were exposed to artemether or artesunate 10 and 50 g/ml, the motor activity of worm body and oral sucker reduced which accompanied by worm contraction, then followed by looseness of the worm body and emergence of vacuoles along the tegument. At 72h post exposure, the worm mortalities induced by the two concentrations of the two drugs were about half, respectively. In adult C. sinensis exposed to albendazole and mebendazole at concentrations of 10 and 50 g/ml, only stimulation of motor activity of oral sucker was seen which revealed in vigorous contraction within 24 h post exposure. During 72 h observation period, no any other changes in worm activity and morphology were seen. CONCLUSION: Praziquantel and tribendimidine exhibit strong in vitro killing effect on adult C. sinensis. The minimal concentration of levamisole used to kill adult worm is 50 times higher than that of tribendimidine. The higher concentrations of artemether and artesunate show slower action to reduce the worm activity and kill part of the worms. Higher concentrations of albendazole and mebendazole exhibit no killing effect on C. sinensis, besides stimulating the motor activity of worm oral sucker. PMID- 21823317 TI - [Recombinant plasmid ZLW/pEGFP-C2 transfection into schistosomula of Schistosoma japonicum]. AB - OBJECTIVE: To study the efficiency of ZLW/pEGFP-C2 plasmid transfection into Schistosoma japonicum schistosomula and observe its in vitro effect of anti schistosomula. METHODS: Recombinant plasmid ZLW/pEGFP-C2 was transfected into mechanically transformed schistosomula by immersion in 0.75% DMSO and high concentration of plasmid. Enhanced green fluorescent protein (EGFP) transfected cells were observed under inverted fluorescence microscope. At 48 hours after culture, total RNA and proteins from transfected schistosomula were extracted, and the presence of the transgenes (ZLW and EGFP) in schistosomula were confirmed by RT-PCR and Western blotting. At 24, 48, 72, and 96 hours after transfection, the schistosomula were counted by light microscope with methylene blue staining. pEGFP-C2 empty plasmid group and TBS group served as controls. RESULTS: The transfection rate was about 10%. The fluorescence of ZLW/EGFP protein was mainly localized in the tegument of the worms, especially abundant around oral sucker and ventral sucker. The expected size of 259 bp fragment was successfully amplified by RT-PCR and confirmed by DNA sequencing. Western blotting analysis showed that ZLW/EGFP was expressed in schistosomula. No statistically significant difference was established for schistosomula mortality among ZLW/pEGFP-C2 group (14.0%, 48.8%), pEGFP-C2 group (15.9%, 45.7%) and TBS group (16.9%, 50.3%) at 24 and 48 hours after transfection (P > 0.05). At 72 hours after transfection the mortality rate of ZLW/pEGFP-C2 group (92.7%) was significantly higher than that of pEGFP-C2 group (73.2%) (P < 0.01), and after 96 h the mortality in ZLW/pEGFP C2 group increased to 100%. CONCLUSION: ZLW/pEGFP-C2 plasmid has been introduced into juvenile S. japonicum by immersion in 0.75% DMSO and high concentration of plasmid, and was expressed in the parasite. PMID- 21823318 TI - [Detection of specific IgG in the sera of patients with chronic schistosomiasis japonica by dot-ELISA with the recombinant Sj26-Sj32 fusion protein]. AB - OBJECTIVE: To study the diagnostic value of the Dot ELISA with rSj26-Sj32 fusion protein for chronic schistosomiasis japonica. METHODS: rSj26-Sj32 fusion protein and SjAWA were used to establish the HRP-IgG-Dot-ELISA. Serum samples from patients with chronic schistosomiasis japonica (40 cases), clonorchiasis sinensis (21 cases), paragonimiasis westermani(13 cases), alveolar echinococcosis (10 cases), cystic echinococcosis(9 cases), hepatitis B(20 cases), pulmonary tuberculosis (20 cases) and healthy persons (43 cases) were examined. RESULTS: Sensitivity and specificity were respectively 92.5% (37/40) and 95.4% (41/43) for rSj26-Sj32-Dot-ELISA and 95.0% (38/40) and 93.0% (40/43) for SjAWA-Dot-ELISA, and there was no significant difference between two antigens (P > 0.05). There were different cross reactions to the sera of patients with clonorchiasis sinensis, paragonimiasis westermani or alveolar echinococcosis, but no cross reaction to the sera of patients with cystic echinococcosis, hepatitis B or pulmonary tuberculosis. The positive and negative predictive value and efficiency of diagnosis of rSj26-Sj32-Dot-ELISA for chronic schistosomiasis japonica were 84.1% (37/44), 97.7% (129/132), and 94.3% (166/176), respectively, and those of SjAWA Dot-ELISA were 77.6% (38/49), 98.4% (125/127), and 92.6% (163/176), respectively. There was no significant difference between the two methods (P > 0.05). CONCLUSION: rSi26-Si32 fusion protein can be applied to immunodiagnosis for chronic schistosomiasis japonica. PMID- 21823319 TI - [Function of TEP1 gene during Plasmodium yoelii infection in Anopheles dirus]. AB - OBJECTIVE: To study the role of TEP1 gene from Anopheles dirns during Plasmodium yoelii infection by RNA interference. METHODS: TEP1 primers with T7 promoter were designed based on the sequence of An. dirus TEP1 gene from GenBank database. PCR amplification of TEP1 gene was completed with An. dirus cDNA as template. The AdTEP1 double-stranded RNA was synthesized by using in vitro transcription kit with purified PCR products. Female An. dirus emerged for 1-2 days were divided into three groups each with 200 mosquitoes: TEP1 interference group, EGFP interference group and control. Mosquitoes in TEP1 and EGFP interference groups were microinjected in chest with 147 ng of AdTEP1 and EGFP double-stranded RNA, respectively, while those of control group were untreated. Effect of TEP1 interference on P. yoelii in An. dirus was estimated through semi-quantitative PCR with internal reference AdS7 at 3 d after injection. On 4 d after injection, mosquitoes were infected by EGFP-expressing P. yoelii BY265. The infection rate and infectivity of mosquitoes were observed through anastomosing 25 midguts from each group at 9 d post-infection. RESULTS: The AdTEP1 double-stranded RNA did well in the interference of TEP1 expression in An. dirus. The infection rate in the groups of control, EGFP and TEP1 interference was (24 +/- 2.83)%, (24 +/- 0.71)%, and (80 +/- 3.54)%, respectively; and the infectivity of the three groups was 0.32 +/- 0.7, 0.44 +/- 0.85, and 5.52 +/- 4.84, respectively. CONCLUSION: AdTEP1 interference increases the infection rate and infectivity of An. dirus by P. yoelii, and raises the susceptibility of An. dirus to P. yoelii significantly. TEP1 plays a critical role in the process of P. yoelii infection. PMID- 21823320 TI - [Prokaryotic expression and identification of S-dsRNA gene from Cryptosporidium parvum virus]. AB - OBJECTIVE: To clone and express S-dsRNA gene of Cryptosporidium parvum virus, and investigate the reactogenicity of the recombinant. METHODS: Total RNA was extracted from Cryptosporidium parvum and S-dsRNA gene was amplified by RT-PCR. The PCR product was cloned into pET-28a(+) expression vector. The recombinant plasmid pET-28a(+)-S was transformed into E. coli BL21 (DE3) and induced with IPTG. The expression situation of recombinant protein was analyzed by SDS-PAGE. Its reactogenicity was examined by Western blotting analysis. RESULTS: pET-28a (+)-S was identified by PCR and double endonuclease digestion. SDS-PAGE result showed that the recombinant protein (M, 37,000) was expressed in the form of inclusion body. High level expression of recombinant protein was found at 1 mmol/L IPTG condition after incubation at 37 degrees C for 4 h and reached up to 72.6% of the total protein. The protein was recognized by the antisera from mice immunized with antigens from Cryptosporidium parvum oocysts. CONCLUSION: The S dsRNA gene of Cryptosporidium parvum virus has been expressed with adequate reactogenicity. PMID- 21823321 TI - [The correlation between osteopontin and metastasis of hepatic Echinococcus multilocularis infection]. AB - OBJECTIVE: To investigate the expression and distribution of osteopontin (OPN) in Echinococcus multilocularis cyst, and explore the role of OPN in the metastasis of hepatic E. multilocularis infection. METHODS: Forty gerbils were infected with 20% E. multilocularis suspension (0.1 ml per gerbil) through abdominal opening injection in liver. Gerbils were sacrificed at 100 days postinfection for observing the growth and metastasis of hepatic echinococcus cyst. The liver, hepatic echinococcus cyst and metastasis tissue were observed on HE stain; the expression of OPN were measured by immunohistochemistry staining (SP method). RESULTS: E. multilocularis were spread over the liver and abdominal cavity. Expression of OPN was found at different degree in echinococcus cysts. The positive expression rate of OPN in echinococcus cysts was 70% (28/40). OPN was mainly distributed in the germinal layer, inflammatory cells and some liver cells. 60% (24/40) occurred thoracic lymph node metastases. The OPN expression rate in hepatic echinococcus cysts with thoracic lymph node metastases (83%, 20/24) was significantly higher than that of hepatic echinococcus cysts without thoracic lymph node metastases (50%, 8/16) (P < 0.05). The positive expression of OPN in lymph node metastases (92%, 22/24) was higher than that of hepatic echinococcus cyst (70%, 28/40) (P < 0.05). CONCLUSION: Osteopontin mainly distributes in the germinal layer of hepatic echinococcus cyst and inflammatory cells, which might be involved in metastasis of hepatic E. multilocularis infection. PMID- 21823323 TI - [Two cases of alveolar echinococcosis in Minle County of Gansu province ]. PMID- 21823322 TI - [Cloning and expression of var2csa DBL domains from Plasmodium falciparum hainan isolate and functional analysis of the recombinant protein]. AB - OBJECTIVE: To clone and express three VAR2CSA duffy antigen-binding ligand (DBL) domains (DBL4/ 5/6) encoded by var2csa gene of a Hainan isolate of Plasmodium falciparum, and study the difference of chondroitin sulfate A (CSA)-binding activity among them. METHODS: Three DBL domains was amplified by PCR and cloned into the vector pMD18-T. The recombinant plasmids were identified by enzyme digestion and sequencing, and then subcloned into the prokaryotic expression vector pET-22b. The recombinant plasmid was transformed into E. coli BL21 (DE3) and followed by expression of the protein induced by IPTG. The recombinant protein was purified with His GraciTrap kit and identified by SDS-PAGE and Western blotting. CSA-binding activity of the three recombinant DBL domains was assayed by ELISA. RESULTS: The target genes were amplified with the length of 996 bp, 859 bp and 894 bp. The constructed recombinant plasmids were identified by enzyme digestion and DNA sequencing. The recombinant proteins (DBL4/5/6) were purified, the relative molecular mass of DBLfA, DBL5 and DBL6 was Mr 439 800, Mr 34,500 and Mr 36,000, respectively. The purified protein has been confirmed with immunogenicity by Western blotting. The results of adhesion experiment indicated that A405 values of DBL5 domain with different concentration were significantly higher than that of DBLA and DBL6. CONCLUSION: The three recombinant proteins (DBLA/5/6) of VAR2CSA DBL domains were expressed, and DBL5 domain has high binding affinity with CSA. PMID- 21823324 TI - [Application of nested PCR in diagnosis of imported malaria]. AB - OBJECTIVE: To evaluate the usefulness of nested PCR method in the diagnosis of imported malaria. METHODS: A total of 210 blood smears and blood samples on filter paper were taken from persons returned from highly malaria endemic countries. The results of both nested PCR and microscopy for 210 samples were compared. RESULTS: Among the 210 persons, 43 were hospitalized due to malaria, and positive by nested PCR test Among the rest 157 people at high risk of getting malaria, 3 were found plasmodium-positive by microscope (1.91%), and 5 were positive by nested PCR (3.18%). In four samples with discrepancy between the two methods, 1 was microscopy positive and PCR negative, and 3 were microscopy negative and PCR positive. Positive and negative coincidence rate between the two tests was 66.7% and 98.1%, respectively. The coincidence between the two methods was 97.5%. CONCLUSION: Nested PCR is useful for monitoring, identification and diagnosis of imported malaria. PMID- 21823325 TI - [Non-surgical treatment for nonresectable advanced hepatic alveolar echinococcosis]. AB - OBJECTIVE: To investigate the therapeutic methods of nonresectable advanced hepatic alveolar echinococcosis. METHODS: A retrospective study was carried out to analyze 25 cases of nonresectable advanced hepatic alveolar echinococcosis in the Fourth Hospital of PLA from 2006 to 2009. RESULTS: There were 18 male and 7 female patients with a mean age of 41 years. Twelve cases were treated with albendazole alone. Eleven patients were treated with albendazole combined with percutaneous puncture. Two cases were treated with albendazole combined with other intervention. A course of albendazole administration lasted 2 weeks with a dose of 15-20 mg/(kg x d) for 3 course in general. Eighteen patients were followed up for 1-4 years. In albendazole group, 2 cases were effective and 7 cases were symptom-improved. Five patients got improved and 2 cases showed effective in albendazole combined with percutaneous puncture group. Two cases of albendazole combined with intervention group showed no efficacy. CONCLUSIONS: Long-term use of albendazole is the main treatment for nonresectable advanced hepatic alveolar echinococcosis. PMID- 21823326 TI - [Application of artificial neural networks in infectious diseases]. AB - With the development of information technology, artificial neural networks has been applied to many research fields. Due to the special features such as nonlinearity, self-adaptation, and parallel processing, artificial neural networks are applied in medicine and biology. This review summarizes the application of artificial neural networks in the relative factors, prediction and diagnosis of infectious diseases in recent years. PMID- 21823327 TI - [Malaria epidemic trend and characteristics at monitoring sites in Yunnan province in 2008]. AB - Malaria situation in 5 monitoring sites of Yunnan showed a decline trend from 2005 to 2008. The average malaria incidence in 2008 was 11.84/10,000 with a decrease of 66.1% in comparison to 2005. The seropositive rate with immuno fluorescence assay (IFA) was 4.61% for pupils. 82% of the cases chose town or township hospitals as the first place of seeking diagnosis and treatment. 83.6% cases were diagnosed over 3 days of symptom appearing. The main clinical manifestation was fever every other day attack (occupied 72.7%). 98.4% of the cases were with light symptoms. The proportion of primary attacks and relapses among malaria patients were 95.3% and 4.7%, respectively. Plasmodium vivax was the main malaria parasite, occupying 81.2%. 97.2% of the local infected cases were found in the bordering areas of the country. The mosquito net utilization rate was 51.4%. Results showed that malaria has been effectively controlled in the monitoring sites of Yunnan. PMID- 21823328 TI - [Progress on functional genomics of some important zoonotic parasites]. AB - With the development of molecular biology, genomics research has been expanded from structural genomics to functional genomics, and from single gene to massive batch. This paper summarizes the progress of structural genomics of some zoonotic parasites and major technical methods. PMID- 21823329 TI - [Immunopathological mechanism of cerebral malaria]. AB - Cerebral malaria is a severe complication of malaria. Early studies suggest that cerebral malaria is related to cytoadherence of parasitized red blood cells to the microvessel endothelium of brain. However, more and more evidence supported that the cause of cerebral malaria is uncontrolled inflammatory cytokines and infiltration of lymphocytes in brain microvessel. The article summarizes the research progress on immunological mechanism of cerebral malaria. PMID- 21823330 TI - [Cloning and sequence analysis of thioredoxin peroxidase gene from Taenia multiceps]. AB - Protoscoleces of Taenia multiceps were collected from the naturally infected sheep and total RNA was extracted. Specific primers were designed according to TaHe2-D11 mRNA sequence and T. multiceps thioredoxin peroxidase gene (TmTPx) was amplified by RT-PCR. PCR products were ligated into pMD18-T vector and transformed to E. coli DH5alpha. The recombinant plasmids were identified by restriction digestion and sequencing. A 614 bp cDNA was amplified. The TmTPx open reading frame (591 bp) encoded a 196-amino acid protein with Mr 21,690, pI 7.61. Bioinformatics analysis indicated that TmTPx had a typical 2-Cys Prx conserved domain. Phylogenetic tree revealed that T. multiceps had the closest relationship to T. asiatica, followed by T. solium and T. crassiceps, E. granulosus and E. multilocularis. PMID- 21823331 TI - [Localization of acetylcholinesterase in the nervous system of Cotylophoron indicum]. AB - The nervous system of Cotylophoron indicum was studied by using acetylcholine esterase histochemical staining techniques. Cranial ganglia and transverse commissure situate at dorso-lateral body between oral sucker and genital sucker. From the cranial ganglia four pairs of nerves proceed cephalad and connect with nerve network of the oral sucker. The posterior nerve cords from the cranial ganglia consist of 3 pairs and the ventral ones are the stoutest and longest nerves. A few branches from the 3 pairs of nerve cords connect to ventral sucker. There is a developed nerve network distributed in its genital sucker. The nerve fibers on body surface in pairs and parallel are diagonal and cross to form a nerve network on body surface. Three kinds of neurocytes distribute at the prosomal region. Results show that the nervous system structure of C. indicum is consistent with the essential features of Digenea, but more special and complicated around genital sucker. PMID- 21823332 TI - [Investigation on serology, risk factor and awareness of angiostrongylus cantonensis in Hainan province]. AB - Five survey sites were selected from Hainan Province and one village were randomly extracted in each site. A survey that covered knowledge and risk factor on angiostrongyliasis cantonensis was conducted and infection rate of Angiostrongylus cantonensis tested by ELISA. Among 393 sampled people, the sero positive IgG rate was 20.6% and about 39.7% residents were found with a history of eating snails in recent half year, 12.5% from respondents had the habit of eating raw snails. Questionnairing showed that the ratio of awareness on A. cantonensis was 8.4%. All factors were analyzed by multi-logistic module and showed that the history of snail-eating and resident area may be the risk factors. PMID- 21823333 TI - [Death due to imported falciparum malaria in Shiyan City]. PMID- 21823334 TI - [Two cases infected by Echinostoma hortense in Guangxi]. PMID- 21823335 TI - [Severe multiple hepatic-celiac-pulmonary hydatid disease: one case report]. PMID- 21823336 TI - [One case of breast sparganosis mansoni]. PMID- 21823337 TI - [Serum testosterone reduction and metabolism in aging male rats: correlation and mechanism]. AB - OBJECTIVE: To investigate the mechanism of serum testosterone reduction, its relationship with metabolism, changes in the number and morphology of Leydig cells and endocrine function in aging male rats. METHODS: The levels of serum total testosterone (tT), LH, FSH, HDL, LDL, TG, TC, Glu, INS, IRG and LP were determined in young (9 mo) and aging rats (12, 15, 18 and 21 mo), with 6 in each group. The morphological changes of Leydig cells were observed under the microscope. The concentrations of testosterone secreted from the cultured Leydig cells with the stimulation of hCG and Forskolin were assayed. The apoptosis rates of Leydig cells were detected by TUNEL. The visceral fat was isolated and weighed, and the Lee's index calculated. All the above indexes were recorded and compared among different age groups. RESULTS: The aging rats showed a significant decrease in the levels of serum tT and TSI ([1.26 +/- 0.65] ng/ml and [0.07 +/- 0.65] ng/mIU) as compared with the young rats ([3.24 +/- 0.38] ng/ml and [0.21 +/ 0.01] ng/mIU) (P < 0.01). Obvious differences were found in the morphology of Leydig cells among different age groups. The T secretion of Leydig cells at 24, 48 and 72 h in aging rats was markedly decreased (P < 0.05) while their TUNEL positive rate remarkably increased in the aging rats (17.36% +/- 1.31%) compared with the young ones (7.02% +/- 1.05%) (P < 0.05). There were statistically significant differences between the young and aging rats in all the biochemical parameters including IRG, HDL, LDL, TG, TC and visceral fat content (P < 0.05), except the levels of serum Glu, INS and LP (P > 0.05). CONCLUSION: The serum T level and secreting capacity of Leydig cells are significantly lower in aging rats than in young ones, and the metabolic parameters undergo regular changes with the decreasing level of serum T. The reduction of testosterone in aging male rats may be associated with the decreased secreting capacity and number of Leydig cells and declined function of the pituitary. PMID- 21823338 TI - [Establishment of a nonbacterial prostatitis model in rats using the autoimmune method: a dose-effect study]. AB - OBJECTIVE: To establish an animal model of chronic nonbacterial prostatitis (CNP) using different doses of purified prostate protein with Freund's complete adjuvant (FCA), and to investigate the relationship of the doses with the success of the model construction. METHODS: Thirty male Wistar rats were divided into a control (A) and 4 experimental groups (B, C, D and E) of equal number. The latter 4 groups were given multi-loci intracutaneous injection of 1.0 ml of a 1:1 mixture of purified prostate protein at 20, 40, 60 and 80 mg/ml with Freund's complete adjuvant (FCA), and meanwhile intraperitoneally injected with 0.5 ml of pertussis-diphtheria-tetanus vaccine at 0 and 30 days. On the 45th day, the rats were sacrificed for observation of the pathomorphological changes in the prostate glands with the naked eyes and microscope. RESULTS: Different degrees of chronic inflammation were observed with different degrees of lymphocyte infiltration and interstitial hyperplasia in the experimental rats. More obvious changes were found in Groups C and D than in A, and even more significant in Group E (P < 0.05). CONCLUSION: The rat model of CNP can be successfully established by multi loci intracutaneous injection of 1.0 ml of a 1: 1 mixture of purified prostate protein at 40 - 60 mg/ml with FCA, and simultaneously intraperitoneal injection of 0.5 ml of pertussis-diphtheria-tetanus vaccine twice within 30 days. PMID- 21823339 TI - [Cloning and prokaryotic expression of the outer membrane protein gene PorB of Neisseria gonorrhoeae]. AB - OBJECTIVE: To construct a fused expression vector of the outer membrane protein gene PorB of Neisseria gonorrhoeae, express the fusion protein in the prokaryotic system, and obtain a gene recombination protein, for the purpose of preparing the ground for further research on the pathopoiesis and immune protective response of PorB. METHODS: A pair of primers were designed according to the known sequence of the PorB gene, and the PorB gene was amplified by PCR from the genome of Neisseria gonorrhoeae 29403 and cloned into the prokaryotic expression plasmid pGEX-4T-1 to generate pGEX-4T-PorB recombinants. The recombinant plasmid pGEX4T PorB was transferred into competent cells E. coli BL21. After confirmed by restriction endonuclease digestion, PCR and DNA sequencing analysis, the recombinant protein was induced to express by isopropyl-beta-D-thiogalactoside (IPTG), and examined by SDS-PAGE and Western blotting. RESULTS: Restriction endonuclease digestion, PCR amplification and DNA sequencing analysis showed that the PorB gene of 1 047 bp was amplified from Neisseria gonorrhoeae DNA, and the recombinant plasmid pGEX-4T-PorB was successfully constructed and highly expressed in E. coli. CONCLUSION: The prokaryotic expression vector of pGEX-4T PorB was successfully constructed and efficiently expressed in the prokaryotic system, which has provided a basis for further study on the biological activity of the PorB protein, as well as animal immune experiment and detection of Neisseria gonorrhoeae, and its application as a mucosal immune vaccine. PMID- 21823340 TI - [Recurrent miscarriage and the quality of semen and sperm: a case-control study]. AB - OBJECTIVE: To analyze the relation between recurrent miscarriage and routine semen parameters. METHODS: We compared the semen parameters of normal healthy men with those of the spouses of recurrent miscarriage women through 1: 1 age-matched case-control study. RESULTS: Compared with the healthy controls, the men of the case group showed a significantly lower mean semen volume ([1.95 +/- 1.11] ml vs [2.74 +/- 1.43] ml), sperm concentration ([48.68 +/- 20.07] x 10(6)/ml vs [59.26 +/- 25.35] x 10(6)/ml), percentage of grade b sperm ([12.07 +/- 3.34] % vs [16.18 +/- 6.74] %), fruit-sugar content ([1.73 +/- 0.64] g/L vs [2.21 +/- 0.75] g/L), acrosomal enzyme activity ([84.34 +/- 26.69] U/mg prot vs [94.20 +/- 26.35] U/mg prot), alpha-glucuronidase (alpha-GLU) content ([36.28 +/- 15.98] U/ml vs [44.45 +/- 12. 54] U/ml), and acid phosphatase (ACP) content ([68.55 +/- 35.45] U/ml vs [84.78 +/- 51. 10] U/ml) (P < 0.05), but remarkably higher percentages of head teratospermia ([47.36 +/- 4.59] % vs [46.50 +/- 6.32] %) and tail teratospermia ([7.56 +/- 2.27] % vs [7.28 +/- 3.10] %), and elastase content ([885.64 +/- 1 272.30] ng/ml vs [661.08 +/- 764.64] ng/ml) (P < 0.05). Based on the results of discriminant analysis, the semen volume, percentages of grade b sperm and combined teratospermia, and contents of fruit-sugar, alpha-GLU and ACP could be used to evaluate the semen and sperm quality of the spouses of recurrent miscarriage women. CONCLUSION: Routine semen and sperm tests might help evaluate the seminal factors of recurrent miscarriage, but they lack specificity and need comprehensive analysis. Poorer semen quality is associated with higher incidence of recurrent miscarriage. PMID- 21823341 TI - [Semen analysis training and its evaluation]. AB - OBJECTIVE: To establish the methods for training green-hand laboratorians in standard semen analysis and evaluating the training results, and afford some reference for internal quality control and training in andrology laboratories in China. METHODS: We trained the green-hand technicians in standard semen analysis recommended by WHO Laboratory Manual for the Examination and Processing of Human Semen (5th ed), and evaluated the training results by assessing the trainees' performance in the examination of sperm concentration and motility by statistic analysis. RESULTS: After training, the coefficients of variation of the semen samples with high, middle and low sperm concentration achieved by the trainees were 7.72% and 3.38% and 4.49%, and those with high, middle and high motility were 7.82%, 8.09% and 6.62%, respectively. We used Bland-Altman's method to evaluate the consistency between the results obtained by the trainees and those by the trainers. For sperm concentration, 4.77% of the datum points were out of the 95% consistency interval, and the absolute value of the biggest difference between the trainees and trainers was 8 x 10(6)/ml within the 95% consistency interval. For sperm motility, 7.15% of the data points were out of the 95% consistency interval, and the absolute value of the biggest difference between the trainees and trainers was 10% within the 95% consistency interval. Two-way analysis of variance showed no significant differences in the results of sperm concentration and motility analyses between the trainees and trainers (P > 0.05). CONCLUSION: Training in standard semen analysis significantly improved the precision of semen analysis among the green-hand laboratorians. The training and assessment methods we established proved to be effective and feasible. PMID- 21823342 TI - [Application of tubularized incised plate in one-stage urethroplasty for hypospadia accompanied with anatomic kak-factors]. AB - OBJECTIVE: To investigate the application of tubularized incised plate (TIP) in urethroplasty for hypospadia accompanied with anatomic kak-factors. METHODS: We retrospectively studied 191 cases of hypospadia treated by one-stage TIP urethroplasty. Taking the position of the urinary meatus, the development of the glans penis and urethral plate, and the degree of penile ventral curvature as anatomic kak-factors inducing postoperative complications and affecting the appearance, we conducted correlation analyses on the clinical effects of the procedure using SPSS 10.0 statistics. RESULTS: Postoperative complications were closely correlated with the position of the urinary meatus, the nearer its position to the coronary sulcus, the higher the incidence of complications (chi2 = 24.291, P < 0.01). And so were they with the development of the glans penis and urethral plate and the degree of penile ventral curvature. The incidence of postoperative complications was significantly higher in the hypospadia patients with small glans, maldeveloped urethral plate and severe penile ventral curvature than in those with straight penis and well-developed glans and urethral plate (chi2 = 25.419, P < 0.01). CONCLUSION: Tubularized incised plate urethroplasty for hyper-spadias should be chosen according to the position of the meatus, the development of urethral mucous membrane, the degree of ventral curvature and surgery experience in order to achieve a high cure rate and good cosmetic effect. PMID- 21823343 TI - [Combination therapy of biofeedback with electrical stimulation for chronic prostatitis/chronic pelvic pain syndrome]. AB - OBJECTIVE: To investigate the effect of the combination therapy of biofeedback with electrical stimulation on chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) through clinical trials. METHODS: A total of 140 cases of diagnosed CP/CPPS were randomly divided into a control group (n = 20), a biofeedback group (BF, n = 40), an electrical stimulation group (ES, n = 40), and a biofeedback plus electrical stimulation group (BF + ES, n = 40). The latter three groups were treated by corresponding methods 5 times a week for 2 weeks, while the controls left untreated. After the treatment, all the patients were followed up for 30 days. The NIH chronic prostatitis symptom index (NIH-CPSI) scores and the results of uroflowmetry were obtained and compared before and after the treatment. RESULTS: Compared with the control group, the scores on pain, urinary symptoms and quality of life (QOL) and the total NIH-CPSI scores were obviously decreased (P < 0.05), and the maximum flow rate (MFR) markedly improved (P < 0.05) in the BF, ES and BF + ES groups after the treatment, with significant differences between the former two and the latter one (P < 0.05), but not between the BF and ES groups (P > 0.05), nor in the control group before and after the treatment (P > 0.05). CONCLUSION: The combination therapy of biofeedback with electrical stimulation has a synergistic effect on CP/CPPS by alleviating pain and urinary symptoms, improving QOL and elevating MFR. PMID- 21823344 TI - [Tamoxifen combined with coenzyme Q10 for idiopathic oligoasthenospermia]. AB - OBJECTIVE: To investigate the effects of tamoxifen (TMX) combined with coenzyme Q10 (CoQ10) on idiopathic oligoasthenospermia. METHODS: A total of 183 patients with idiopathic oligoasthenospermia were randomly divided into a TMX + CoQ10 group (n = 63), a TMX group (n = 61) and a CoQ10 group (n = 59). At the end of 3 and 6 months of treatment, semen analyses and hormone tests were performed, and the results were compared with those obtained before the treatment. RESULTS: Compared with the pre-treatment results, the levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH) and testosterone (T) and sperm concentration were significantly elevated in the TMX + CoQ10 and TMX groups (P < 0.05), but showed no significant difference in the CoQ10 group (P > 0.05); sperm motility and morphologically normal sperm were increased significantly in the TMX + CoQ10 and CoQ10 groups (P < 0.05), and slightly in the TMX group but with no statistically significant difference (P > 0.05). CONCLUSION: Tamoxifen combined with CoQ10 can significantly improve sperm concentration, motility and morphology in patients with idiopathic oligoasthenospermia. PMID- 21823345 TI - [Sperm DNA damage and unexplained recurrent spontaneous abortion]. AB - OBJECTIVE: To explore the relationship of sperm DNA damage with unexplained recurrent spontaneous abortion (URSA). METHODS: Sperm DNA fragmentation was evaluated by sperm chromatin dispersion (SCD), and the results were expressed in terms of DNA fragmentation index (DFI). DFIs were measured in the male partners of 56 women with URSA (the experiment group) and of 31 without URSA (the control group). RESULTS: The DFI was shown to be (11.0% - 56.9%) in the experiment group, 21 (37.5%) of the subjects over 30%, as compared with (10.0% -36.8%) in the control group, only 8 (25.8%) of the subjects over 30%, significantly higher in the former than in the latter (29.4% vs 25.5%, P < 0.05). CONCLUSION: There is a relationship between sperm DNA damage and URSA. PMID- 21823346 TI - [Transverse preputial island flap technique (Duckett's procedure) for hypospadias repair: a report of 356 cases]. AB - OBJECTIVE: To evaluate the effect of the transverse preputial island flap technique (Duckett's procedure) for hypospadias repair. METHODS: A total of 356 patients with hypospadias were treated by Duckett's procedure from March 1995 to December 2010, of whom 324 (91.0%) were younger than 14 years. The length of urethra repair ranged from 1.5 to 10 cm. RESULTS: The total success rate of Duckett's procedure was 91.0%. Urethra fistula occurred in 30 cases, external orifice stricture in 1, and urethral anastomosis stricture in another. There were no significant differences in the rate of complications among either different age groups or different surgical times (P > 0.05). CONCLUSION: Duckett's procedure remains the first choice for the one-stage repair of hypospadias, especially applicable to hypospadias with chordee. PMID- 21823347 TI - [Devine's technique with free skin grafting for concealed penis with prepuce deficit]. AB - OBJECTIVE: To investigate the clinical effect of Devine's technique with free skin grafting in the treatment of concealed penis with prepuce deficit. METHODS: This study included 7 children with concealed penis, aged 6 - 15 (mean 8.6) years, 6 of them treated by circumcision previously. All the patients underwent Devine's operation to resect the inelasticity sarcolemma and lengthen the penis. The length of prepuce deficit ranged from 2 to 4 cm. Intermediate split thickness skin grafts of the corresponding length were taken from the femoribus internus to wrap up the tunica albuginea penis, followed by the procedures of saturation, encapsulation and fixation. RESULTS: Surgery time ranged from 70 to 120 minutes, averaging 90.5 minutes. The penis was prolonged about 2 - 4 cm after surgery. A 6 month follow-up revealed desirable penile appearance and normal penile erection. CONCLUSION: Devine's technique with free skin grafting from the femoribus internus is an ideal treatment for concealed penis with prepuce deficit. PMID- 21823348 TI - [Regulatory effect of GDNF on the proliferation and differentiation of mammalian spermatogonial stem cells]. AB - The glial cell-derived neurotrophic factor (GDNF) is a member of the transforming growth factor beta (Tgf-beta) superfamily, which is produced by Sertoli cells and plays an important role in the proliferation and differentiation of spermatogonial stem cells (SSC). The addition of proper amount of GDNF to the culture media can promote SSC proliferation in vitro. Besides, GDNF regulates the self-renewal and differentiation of SSCs through various signaling pathways. This review focuses on the effects of GDNF on the proliferation and differentiation of mammalian SSCs and GDNF-mediated signaling pathways. PMID- 21823349 TI - [ATM/H2AX and repair of sperm-DNA damage during cryopreservation]. AB - Semen cryopreservation is an important method in assisted reproductive technology, but meanwhile it is complicated by cryodamage to spermatozoa. Mechanisms behind the cryodamage to spermatozoa are thought to be multifactorial, and the excessive generation of reactive oxygen species (ROS) has been suggested as a major contributing factor. DNA-damaged sperm is also capable of fertilizing oocytes, significantly affecting the outcome of reproduction. As a sensor of DNA damage responses, protein kinase ATM (ataxia telangiectasia mutated) can be initiated through rapid intermolecular autophosphorylation induced by DNA damage, phosphorylate various proteins, and amplify the responses to DNA damage. After DNA damage, histone H2AX is activated by ATM, which contributes to the repair of sperm-DNA damage after fertilization and regulates the cell cycle during embryo development. Given the important role of the ATM/H2AX signaling pathway in the response to and repair of DNA damage induced by oxidative stress, it may mediate the repair of sperm-DNA damage resulting from cryopreservation. PMID- 21823350 TI - [Application of Online Mendelian Inheritance in Man to medical genetics]. AB - Online Mendelian Inheritance in Man (OMIM, http://omim. org/) is a comprehensive, authoritative, practical and timely knowledgebase of human genes and genetic disorders. OMIM, as a genetic encyclopedia, provides an easy and straightforward access to information on human genetics to students, researchers and clinicians. This article presents an overview on the contents of OMIM and its application to medical genetics. PMID- 21823351 TI - [Reconstruction of resected cavernous nerve]. AB - The injury of the penile cavernous nerve is a common cause of erectile dysfunction (ED). Reconstruction of the resected cavernous nerve can restore penile erectile function to normal. The methods for cavernous nerve repair include direct anastomosis, autotransplantation of the nerve, and substitution of the biodegradable artificial nerve, among which only autotransplantation of the sural nerve is used clinically at present. Besides, the nerve growth factor plays an important role in nerve reconstruction. This paper summarizes the methods of cavernous nerve reconstruction in the recent years. PMID- 21823352 TI - [Androgen receptor mutation and progression of prostate cancer]. AB - Prostate cancer growth is almost wholly dependent on the route of the androgen receptor and most therapies aimed at blocking this signaling axis are useful tools in the management of this disease. Unfortunately such therapies invariably fail, and the cancer progresses to an androgen-independent stage. In such cases, androgen receptor mutation almost always occurs and much evidence suggests the continuous growth of the tumor. One mechanism by which the receptor is thought to remain active is mutation. This paper reviews the molecular mechanism of tumor growing after androgen receptor mutation and some of the promising management principles and systemic chemotherapy options against prostate cancer. PMID- 21823353 TI - [Impact of Cryptotanshinone on the reproductivity and metabolism of male mice with Akt2 deletion]. AB - OBJECTIVE: To investigate the impact of protein kinase B (Akt2) allele deletion on testicular reproductive function, and to discuss the regulatory effect of Cryptotanshinone on the reproductivity of male mice with Akt2 allele deletion and its molecular mechanism. METHODS: Fifteen Akt2 +/+ male mice were randomly divided into Groups A (baseline control, n = 7) and B (stimulation, n = 8), and another 29 Akt2 -/- male mice into C (baseline control, n = 7), D (stimulation, n = 8), E (solvent, n = 7) and F (Cryptotanshinone, n = 7). Groups B and D underwent human chorionic gonadotropin (HCG) stimulation tests at 5 IU / 20 g, while A and C received physiological saline, all for 4 hours; Group F were given gastric lavage of Cryptotanshinone, while E solvent only, at 600 mg/kg twice a day for 8 weeks, both subjected to oral glucose tolerance tests (OGTT) at 2 g/kg before and after the treatment. The body and bilateral testis weights were obtained, the serum testosterone (T) level measured, and the expressions of testicular steroid hormone synthesis and glycometabolism-related genes determined by RT-PCR. RESULTS: OGTT showed that the level of blood glucose was significantly higher in Groups C and D than in A and B ([10.38 +/- 1.42] and [10.96 +/- 1.81] mmol/L vs [7.92 +/- 0.63] and [8.32 +/- 0.44] mmol/L, P < 0.05), but had no significant differences at different time points in E and F (P > 0.05). The testis weight was remarkably higher in Groups C and D than in A and B ([0.17 +/- 0.01] and [0.17 +/- 0.01] g vs [0.15 +/- 0.01] and [0.15 +/- 0.02] g, P < 0.05), but exhibited no obvious difference in E and F, nor were there any significant differences in body weight among different groups (P > 0.05). The serum T level was markedly higher in Group C than in A ([9.08 +/- 1.59] nmol/L vs [6.42 +/- 0.95] nmol/L, P < 0.05), but evidently lower in F than in E ([5.94 +/- 0.49] nmol/L vs [8.18 +/- 1.44] nmol/L, P < 0.05). The baseline expression levels of Cyp11, Cyp17, 3B-HSD, Star, Gsk3beta, Erk-1, and MCM2 mRNA were significantly higher in Group C than in A (P < 0.05). After HCG stimulation, the expressions of Cyp11, Cyp17, 3B-HSD, and Star mRNA were remarkably increased in B and D, but with no obvious difference between the two groups (P > 0.05), while the expressions of Cyp11, Cyp17, 3B-HSD, Star, Gsk3beta, Erk-1, and MCM2 mRNA markedly decreased in F as compared with E (P < 0.05). CONCLUSION: Akt2 gene deletion may affect glycometabolism and testicular function, and cause abnormal glycometabolism and androgen secretion in male mice, whose molecular mechanism is associated with the elevated expressions of the key glycometabolic molecules and of the key enzymes for androgen synthesis. Cryptotanshinone can reduce the levels of androgens by down-regulating the expressions of the key enzymes for androgen synthesis. PMID- 21823354 TI - ["Pneumologia" journal turns 60!]. PMID- 21823355 TI - [The long way of TB eradication versus TB elimination, from utopia to reality]. PMID- 21823356 TI - [Variability of cardiac rate in patients with obstructive sleep apnea/hypopnea]. AB - BACKGROUND: Obstructive sleep apnea-hypopnea syndrome (OSAHS) is characterized by repeated breathing pauses caused by upper airway collapse during sleep, leading to intermittent hypoxemia, sleep fragmentation and autonomic dysfunction. The gold standard for the treatment of OSAHS is ventilation with continuous positive airway pressure (CPAP). AIM: To study the effect of CPAP on autonomic dysfunction in patients OSAHS, by assessing the heart rate variability (HRV) parameters before the initiation of CPAP and under CPAP during the first week and at 3 months. MATERIAL, METHODS: We have assessed HRV parametrs by 24 hours ECG Holter monitoring in 42 patients with moderate and severe OSAHS (apnea-hypopnea index AHI > or = 15/h) without other causes of autonomic neuropathy. The assessment was made at diagnosis, during the first week of CPAP use and at 3 months of CPAP use. RESULTS. Both time domain and frequency domain HRV parameters decreased significantly during the first week of CPAP use and increased back to normal values at 3 months. Initially and during the first week of treatment, HRV parameters correlated negatively with the severity of OSAHS expressed by AHI. CONCLUSIONS: Patients with OSAHS present an alteration of HRV, proportionally with disease severity. The decrease in HRV is revealed by the absence of apneas during the initiation of CPAP. After 3 months of CPAP treatment, the HRV parmeters are normalized independently of the disease severity. PMID- 21823357 TI - Efficacy and safety of iodopovidone pleurodesis through chest tube in spontaneous pneumothorax. AB - Pleurodesis is one of the best methods of controlling malignant pleural effusions and pneumothorax. Recently Iodopovidone (IP) which is cheap and easily available was used for pleurodesis and demonstrated low morbidity with good results similar to talcum powder. However, in those studies a wide range of pleural diseases were included, and heterogeneity makes it difficult to draw conclusions about spontaneous pneumothorax (SP). The aim of this study was to evaluate the efficacy and safety of IP pleurodesis in SP. METHODS: In 29 patients, we instilled 20 ml IP 10% diluted with 80 ml of normal saline through a chest tube, clamped for 4 h. Data on adverse events including chest pain, respiratory distress, allergic reactions, hypotension and failure of PD (the requirement for additional pleural procedures and recurrence) were collected. The follow-up period was 3 to 21 months. RESULTS: Complete response with no recurrence was obtained in 27 (93% percent) patients. One patient with bone marrow transplantation with cystic lung changes in lungs returned two months later with bilateral pneumothoraces. A case of Wegener's granulomatosis on corticosteroids and immunosuppressive therapy returned with SP on the same side four months later. Five (13%) patients experienced chest pain with visual scale measurment 1 to 5. No hypotension, allergic reaction, visual impairment were observed. CONCLUSIONS: Pleurodesis with IP was successful and was associated with only minor complication. It appears to be a good option for the pleurodesis in SP. PMID- 21823358 TI - Acute massive pulmonary embolism associated with olanzapine therapy and no significant personal history in a young male--case report and literature review. AB - We report the case of a 28 years old, non-smoker male with a massive pulmonary embolism and left pleural effusion associated and probably induced by olanzapine 10 mg once daily in the previous 4 months, completely recovered after 18 days of stopping the antipsychotic and trombolytic treatment. Thrombotic events have been reported with the use of antipsychotic compounds, although the incidence, predisposing factors, and biological mechanisms associated with these events in psychiatric patients are subject to debate. PMID- 21823359 TI - Aquatic leech as a rare cause of respiratory distress and hemoptysis. AB - This paper presents a 73 years old male with three weeks history of intermittent hemoptysis, dysphagia, dyspnea, stridor, and suffocations sensation. By means of fibrotic bronchoscopic examination, the cause was found to be a leech in the glottis. It was removed by injection of 4 ml lidocaine 2%. Infestation into the respiratory tract by a leech may become lethal because of hypoxia and death secondary to airway obstruction. A high index of suspicion of leech infestation sould be considered in patients presenting with hemoptysis, hoarseness and respiratory distress and a history of recent contact with fresh water streams. PMID- 21823360 TI - [Rare case of multiple pulmonary nodules--a case report]. AB - The article presents the case of a 44 years old female patient admitted in the hospital for a solitary pulmonary nodule discovered through a chest X-ray performed for left thoracic pain. Despite the young age, a lot of comorbidities were present: severe dyslipidemia, ischemic right cerebellar lesion, degenerative periventricular lesions, chronic autoimmune thyroiditis, uterine fibroma, fibrocystic mastitis, polyglobulia of uncertain etiology and Rendu-Osler disease. The investigation which showed the nature of the pulmonary nodule was the CT scan with intravenous contrast, which demonstrated that the nodules were in fact arterial-venous malformations as part of the Rendu-Osler disease. This case offers the opportunity to discuss about etiopathogeny, morphopathology, criteria of diagnosis and treatment principles in Rendu-Osler disease. PMID- 21823361 TI - [Natural course of preneoplastic bronchial lesions]. AB - Advances in endoscopic technology have improved the detection of precancerous bronchial lesions associated with the occurence of proximal squamous cell lung cancer (SCC) in high-risk individuals for broncho-pulmonary neoplasm. The debates and controversies regarding the control and treatment of intraepitelial bronchial lesions is due to the fact that the regression rate of all preneoplastic bronchial lesions is 54%. But the progression to carcinoma in situ or to cancer is significantly higher for severe dysplasia, than for preneoplastic lesions showing lower-grade dysplasia, such as squamous metaplasia and mild or moderate dysplasia. The progression rate to carcinoma in situ or cancer with squamous cells varies between 19% and 46% for patients with severe dysplasia. The diagnosis and resection of pulmonary cancer in incipient stages increases spectacularly the survival rates of the resected patients, by comparison to the non-operated patients. PMID- 21823362 TI - [The fundamental mechanisms of metastatic spread and chemotherapy resistance in lung cancer]. AB - Lung cancer is the leading cause of cancer-related death in the European Union and the United States, accounting for about one third of all cancer deaths. Primary lung cancer may arise from the central (bronchial) or peripheral (bronchiolo-alveolar) compartment of the lung, but the origins of the different histological types of primary lung tumours are not well understood and described in medical literature. Current investigation in the field of cancer research have focused on the "cancer stem cell" hypothesis as stem cells are belived to be crucial players in the homeostasis of all adult tissues. Even if the role of stem cells in lung carcinogenesis is not clear yet, numerous studies indicate that lung cancer is not the result of a sudden transforming event, but of a multistep process of molecular changes of the primordial stem cell niche, leading to the development of noeplasia. In the current review, we present state-of-the-art research in the field of lung stem cell biology, with a special emphasis on lung cancer emergence, development, metastasis and multidrug resistance. PMID- 21823363 TI - [Asthma patients compliance--who is to blame?]. AB - Compliance to treatment in the case of patients with bronchial asthma remains a permanent problem. The author is looking to the possible answers to the multiple causes what can influence the compliance and the modalities to correct them. PMID- 21823364 TI - School-based smoking prevention programmes: ethical aspects. AB - School-based health education has the potential to inform and educate young people, in order to promote healthy behaviours among them, which will help to prevent diseases and social problems. The present study gives an overview of several ethical issues which must be considered in different phases of school based smoking prevention programs. This will help health educators, public health professionals and researchers in their activity of health education in schools. The ethical issues must be taken into consideration during all the activities and refer to the involvement of officials, schools, parents, young people who participate into the program, authors and persons/institutions responsible with the implementation, evaluation or funding of the programs. The application into practice of these ethical principles, influence the quality of the health education, its acceptability BY the target group and the correctness of results. Also, it prevents possible problems and misunderstandings between persons and institutions involved in the health education and smoking prevention process, which could seriously affect and even destroy implementation of such health education activities. PMID- 21823365 TI - [How to build up a scientific poster]. PMID- 21823366 TI - The history of pain measurement. PMID- 21823367 TI - Anaesthetists: still the airway experts? PMID- 21823368 TI - Ethics and evidence. PMID- 21823369 TI - What do "triage" and "informed consent" really mean in practice? PMID- 21823370 TI - Opioids, ventilation and acute pain management. AB - Despite the increasing use of a variety of different analgesic strategies, opioids continue as the mainstay for management of moderate to severe acute pain. However concerns remain about their potential adverse effects on ventilation. The most commonly used term, respiratory depression, only describes part of that risk. Opioid-induced ventilatory impairment (OIVI) is a more complete term encompassing opioid-induced central respiratory depression (decreased respiratory drive), decreased level of consciousness (sedation) and upper airway obstruction, all of which, alone or in combination, may result in decreased alveolar ventilation and increased arterial carbon dioxide levels. Concerns about OIVI are warranted, as deaths related to opioid administration in the acute pain setting continue to be reported. Risks are often said to be higher in patients with obstructive sleep apnoea. However, the tendency to use the term 'obstructive sleep apnoea' to encompass the much broader spectrum of sleep- and obesity related hypoventilation syndromes and the related misuse of terminology in papers relating to obstructive sleep apnoea and sleep-disordered breathing remain significant problems in discussions of opioid-related effects. Opioids given for management of acute pain must be titrated to effect for each patient. However strategies aiming for better pain scores alone, without highlighting the need for appropriate monitoring of OIVI, can and will lead to an increase in adverse events. Therefore, all patients must be monitored appropriately for OIVI (at the very least using sedation scores as a '6th vital sign') so that it can be detected at an early stage and appropriate interventions triggered. PMID- 21823371 TI - Obesity and obstetric anaesthesia. AB - Obesity is increasing in the population as a whole, and especially in the obstetric population, among whom pregnancy-induced physiological changes impact on those already present due to obesity. In particular, changes in the cardiovascular and respiratory systems during pregnancy further alter the physiological effects and comorbidities of obesity. Obese pregnant women are at increased risk of diabetes, hypertensive disorders of pregnancy, ischaemic heart disease, congenital malformations, operative delivery postpartum infection and thromboembolism. Regional analgesia and anaesthesia is usually preferred but may be challenging. Obese pregnant women appear to have increased morbidity and mortality associated with caesarean delivery and general anaesthesia for caesarean delivery in particular, and more anaesthesia-related complications. This article summarises the physiological and pharmacological implications of obesity and pregnancy and describes the issues surrounding the management of these women for labour and delivery. PMID- 21823372 TI - Brugada syndrome--a review of the implications for the anaesthetist. AB - Brugada syndrome is characterised by specific electrocardiogram changes in the right precordial leads, a structurally normal heart and susceptibility to ventricular arrhythmias that may cause syncope or sudden death in otherwise fit young adults. Perioperative pharmacological and physiological changes may precipitate these events. Arrhythmias and symptoms typically occur at rest or sleep when vagal activity predominates. Although the condition is rare, the implications are serious and may result in death. Individual case reports describe diverse anaesthetic management. In this paper we critically appraise the literature to identify unifying features and determine whether specific management can be recommended. We found 18 clinical reports of anaesthesia including a total of 28 patients, most under general anaesthesia. Those with an implanted defibrillator should have it deactivated. All patients should have external defibrillator pads applied continuously throughout the perioperative period. Electrolyte imbalances should be corrected preoperatively. Propofol infusions for maintenance of general anaesthesia are probably safe if duration and dose are limited. Sevoflurane may be the preferred volatile anaesthetic. Autonomic changes, inadequate analgesia, light anaesthesia and postural changes should be all be minimised. The patient should be warmed or cooled to maintain normothermia. An isoprenaline infusion is advocated for intraoperative ST changes. Regional anaesthesia is possible if the dose is limited and systemic absorption restricted. Lignocaine is the drug of choice while bupivacaine is relatively contraindicated. Ropivacaine is possibly also not safe. Prolonged regional anaesthesia may therefore require continuous catheter techniques. Five lead electrocardiogram monitoring and ST trend analysis should continue into the postoperative period. PMID- 21823373 TI - Emergency surgical airway in life-threatening acute airway emergencies--why are we so reluctant to do it? AB - 'Can't intubate, can't oxygenate' scenarios are rare but are often poorly managed, with potentially disastrous consequences. In our opinion, all doctors should be able to create a surgical airway if necessary. More practically, at least all anaesthetists should have this ability. There should be a change in culture to one that encourages and facilitates the performance of a life-saving emergency surgical airway when required. In this regard, an understanding of the human factors that influence the decision to perform an emergency surgical airway is as important as technical skill. Standardisation of difficult airway equipment in areas where anaesthesia is performed is a step toward ensuring that an emergency surgical airway will be performed appropriately Information on the incidence and clinical management of 'can't intubate, can't oxygenate' scenarios should be compiled through various sources, including national coronial inquest databases and anaesthetic critical incident reporting systems. A systematic approach to teaching and maintaining human factors in airway crisis management and emergency surgical airway skills to anaesthetic trainees and specialists should be developed: in our opinion participation should be mandatory. Importantly, the view that performing an emergency surgical airway is an admission of anaesthetist failure should be strongly countered. PMID- 21823374 TI - Changing patterns in endotracheal intubation for anaesthesia trainees: a retrospective analysis of 80,000 cases over 10 years. AB - Several overseas studies have suggested that opportunities for anaesthesia trainees to learn and practise endotracheal intubation have decreased over time. We analysed the operating theatre data collection system at a large Australian metropolitan teaching hospital from 1998 to 2008 to determine if numbers for trainees' caseloads in general, and endotracheal intubation in particular had changed. The total caseload per trainee of approximately 800 cases per year was stable throughout the study period. The number of gastrointestinal endoscopies per trainee increased significantly with a corresponding decrease in the number of other cases. The mean number of endotracheal intubations per trainee per year fell by 10% and of supraglottic devices by 16%, neither of which was statistically significant. Endotracheal intubation for caesarean sections did however fall significantly from an average of nine to an average of six cases per trainee per year. Our findings contrast with other reports of much larger decreases in the number of endotracheal intubations performed by trainees over the last decade, but suggest that our local practice is similar to the international experience of decreasing opportunities for endotracheal intubation in obstetric anaesthesia. PMID- 21823375 TI - Comparison of cardiac output measurements in critically ill patients: FloTrac/Vigileo vs transthoracic Doppler echocardiography. AB - Measurement of cardiac output is an integral part of patient management in the intensive care unit. FloTrac/Vigileo is a continuous cardiac output monitoring device that does not need re-calibration. However its reliability has been questioned in some studies, especially involving surgical patients. In this study, we evaluated the comparability of FloTrac/Vigileo and transthoracic Doppler echocardiography in 53 critically ill patients requiring continuous cardiac output monitoring. Most of these patients had septic or cardiogenic shock. Cardiac output was measured by both FloTrac/Vigileo and transthoracic Doppler echocardiography. The bias and precision (mean and SD) between the two devices was 0.35 +/- 1.35 l/minute. The limits of agreement were -2.3 to 3.0 l/minute (%error = 49.3%). When patients with irregular heart rhythms and aortic stenosis were excluded, the bias and precision was 0.02 +/- 0.80 l/minute (n = 42). The limits of agreement were -1.55 to 1.59 l/minute (%error = 29.5%). Patient demographics (body surface area, gender and age) did not affect the bias, but there was a mild tendency for FloTrac/ Vigileo to register a higher cardiac output at high heart rates. Changes in cardiac output for two consecutive days correlated well between the two methods (r = 0.86; P < 0.001). In summary, with the exceptions of patients with irregular heart rhythms and significant aortic stenosis, FloTrac/Vigileo is clinically comparable to transthoracic Doppler echocardiography in cardiac output measurements in critically ill patients. PMID- 21823376 TI - Comparison of actual tidal volume in neonatal lung model volume control ventilation using three ventilators. AB - In neonates, small changes in tidal volumes (V(T)) may lead to complications. Previous studies have shown a significant difference between ventilator-measured tidal volume and tidal volume delivered (actual V(T)). We evaluated the accuracy of three different ventilators to deliver small V(T) during volume-controlled ventilation. We tested Servo 300, 840 ventilator and Evita 4 Neoflow ventilators with lung models simulating normal and injured neonatal lung compliance models. Gas volume delivered from the ventilator into the test circuit (V(TV)) and actual V(T) to the test lung were measured using Ventrak respiration monitors at set V(T) (30 ml). The gas volume increase of the breathing circuit was then calculated. Tidal volumes of the SV300 and PB840 in both lung models were similar to the set V(T) and the actual tidal volumes in the injured model (20.7 ml and 19.8 ml, respectively) were significantly less than that in the normal model (27.4 ml and 23.4 ml). PB840 with circuit compliance compensation could not improve the actual V(T). V(TV) of the EV4N in the normal and the injured models (37.8 ml and 46.6 ml) were markedly increased compared with set V(T), and actual V(T) were similar to set V(T) in the normal and injured model (30.2 ml and 31.9 ml, respectively). EV4N measuring V(T) close to the lung could match actual V(T) to almost the same value as the set V(T) however the gas volume of the breathing circuit was increased. If an accurate value for the patient's actual V(T) is needed, this V(T) must be measured by a sensor located between the Y-piece and the tracheal tube. PMID- 21823377 TI - Effect of epidural levobupivacaine on recovery from vecuronium-induced neuromuscular block in patients undergoing lower abdominal surgery. AB - The aim of this study was to evaluate the effect of epidural levobupivacaine on recovery from vecuronium-induced neuromuscular block. Ninety patients undergoing lower abdominal surgery were randomised into two groups after an epidural test dose: the epidural group (n = 45) received a bolus of 15 ml of 0.5% levobupivacaine whereas the control group (n = 45) did not. Anaesthesia was induced and maintained with propofol, fentanyl, vecuronium and nitrous oxide. Neuromuscular block was induced with vecuronium 0.1 mg/kg and monitored with acceleromyographic train-of-four at the adductor pollicis. Patients in each group received neostigmine at 25% recovery of the first twitch of train-of-four during recovery from anaesthesia. The effect of epidural levobupivacaine on the speed of recovery of neuromuscular function was evaluated. The lag time, onset time and time from vecuronium administration until 25% T1 recovery did not differ between the groups. The times of the recovery index (the time from 25% to 75% recovery of T1) and of the DUR 25-train-of-four 90 (time from 25% T1 to train-of-four ratio of 0.9) in the epidural group were significantly longer than those for the control group (5.2 [2.1] vs 3.04 [1.02] minutes and 10.8 [3.3] vs 8.2 [2.3] minutes, P < 0.001). This study shows that epidural levobupivacaine significantly delays the train-of-four recovery from vecuronium-induced block. Although the interaction is small in the clinical setting, anaesthetists should take this interaction into consideration when combining general and epidural anaesthesia during surgery. PMID- 21823378 TI - Comparison of the effect-site concentrations of remifentanil for Streamlined Liner of the Pharynx Airway (SLIPA) versus laryngeal mask airway SoftSealTM insertion during target-controlled infusion of propofol. AB - This study was designed to determine the optimal dose of remifentanil required for the successful insertion of Streamlined Liner of the Pharynx Airway (SLIPA) and to compare it to that required for laryngeal mask airway (LMA) insertion in patients receiving a propofol infusion at a standard effect-site concentration. Fifty-eight patients scheduled to undergo general anaesthesia were randomly assigned to either the SLIPA (n = 29) or LMA (n = 29) group. All patients were premedicated with midazolam 0.05 mg x kg(-1) and glycopyrrolate 0.004 mg x kg(-1) intramuscularly. After the administration of lignocaine 1 mg x kg(-1) intravenously, a propofol infusion was started at an effect-site concentration of 3.5 microg x ml(-1) with a remifentanil infusion without a neuromuscular blocking agent. The remifentanil dose was determined by the modified up-and-down method starting in each group at 4 ng x ml(-1). Six minutes after induction, the airway device was inserted. Airway device insertion was classified as 'success' or 'failure' based on patient response. From the isotonic regression analysis and bootstrap distribution, the EC50 of remifentanil for SLIPA and LMA were 0.93 ng x ml(-1) (95% confidence interval [CI] 0.81 to 1.50 ng x ml(-1) and 1.36 ng x ml( 1) (95% CI 1.19 to 2.06 ng x ml(-1)) respectively, and the EC95 for SLIPA and LMA insertions were 1.90 ng x ml(-1) (95% CI 1.39 to 1.95) and 2.43 ng x ml(-1) (95% CI 1.80 to 2.46 ng x ml(-1)) respectively. Using the 83% CIs from the bootstrap distribution, EC50 for SLIPA was significantly less than that of LMA (0.83 to 1.23 vs 1.26 to 2.00, respectively) (P < 0.05). These findings suggest that the insertion of SLIPA needs about a 32% lower depth of anaesthesia than LMA insertion. PMID- 21823379 TI - Effectiveness of the Streamlined Liner of the Pharynx Airway (SLIPATM) in allowing positive pressure ventilation during gynaecological laparoscopic surgery. AB - The aim of this study was to assess whether the Streamlined Liner of the Pharynx Airway (SLIPA) performed as well as an endotracheal tube for positive pressure ventilation in gynaecological laparoscopic surgery in the Trendelenburg position. Forty patients (American Society of Anesthesiologists physical status I to III) were randomly divided into two groups: SLIPA (n = 20) or endotracheal tube group (n = 20). Lung mechanics and severity of postoperative sore throat were assessed in both groups. In the SLIPA group, the oropharyngeal leak pressure was also measured. There were no significant differences between groups in the lung mechanics. In the SLIPA group, oropharyngeal leak pressure and peak inspiratory pressure increased significantly after gas insufflation compared to 10 minutes after patient positioning in the lithotomy position (P < 0.05). The difference between oropharyngeal leak pressure and peak inspiratory pressure (approximately 10 cmH2O throughout the procedure) remained suitable for airway maintenance. The incidence of sore throat was similar in both groups but the severity was less in the SLIPA group 24 hours after surgery (P < 0.05). There were no other complications such as regurgitation noted in either group. In the study population, the SLIPA performed as well as an endotracheal tube in allowing positive pressure ventilation without gas leak during gynaecological laparoscopy. The way in which the SLIPA increases its resistance to gas leak as the inspiratory pressure rises may account for this. PMID- 21823380 TI - Clinical prediction of weaning and extubation in Australian and New Zealand intensive care units. AB - Our objective was to describe, in Australian and New Zealand adult intensive care units, the relative frequency in which various clinical criteria were used to predict weaning and extubation, and the weaning methods employed. Participant intensivists at 55 intensive care units completed a self-administered questionnaire, using visual analogue scales (0 = not at all predictive, 10 = perfectly predictive, not used = null score) to record the perceived utility of 30 potential predictors. Survey response rate was 71% (164/230). Those variables thought most predictive of weaning readiness were respiratory rate (median score 8.0, interquartile range 7.0 to 8.6) effective cough (7.3, 5.9 to 8.2) and pressure support setting (7.2, 6.0 to 8.0). The most highly rated predictors of extubation success were effective cough (8.0, 7.0 to 9.0), respiratory rate (8.0, 7.0 to 8.5) and Glasgow Coma Score (7.9, 6.1 to 8.3). Variables perceived least predictive of weaning and extubation success were P0.1, Acute Physiological and Chronic Health Evaluation score II, mean arterial pressure, electrolytes and maximum inspiratory pressure (individual median scores < 5). Most popular clinical criteria were those perceived to have high predictive accuracy, both for weaning (respiratory rate 96%, pressure support setting 94% and Glasgow coma score 91%) and extubation readiness (respiratory rate 98%, effective cough 94% and Glasgow Coma Score 92%). Weaning mostly employed pressure support ventilation (55%), with less use of synchronised intermittent mandatory ventilation (32%) and spontaneous breathing trials (13%). Classic ventilatory performance predictors including respiratory rate and effective cough were reported to be of greater clinical utility than other more recently proposed measures. PMID- 21823381 TI - The efficacy of ultrasound-guided transversus abdominis plane block in patients undergoing hysterectomy. AB - The study objective of this prospective, double-blind randomised controlled study was to evaluate the efficacy of ultrasound guided transversus abdominis plane (TAP) block and bupivacaine infiltration of the skin and subcutaneous tissue of the wound in patients undergoing hysterectomy. Patients were randomly allocated to three groups: a control group (n = 18) and TAP block group (n = 18) received bilateral TAP blocks with saline and bupivacaine respectively, and an infiltration group (n = 19) received skin and subcutaneous wound tissue infiltration with bupivacaine at the end of surgery. After surgery patients received patient-controlled intravenous tramadol and were assessed for pain and tramadol consumption at 1, 2, 4, 6 and 24 hours. Both the TAP and infiltration groups had lower movement and rest pain scores than the control group, with lower scores in the TAP group than the infiltration group at 6 and 24 hours. Total tramadol consumption was significantly lower in the TAP group than in the other groups at all time points. We concluded that ultrasound-guided TAP block reduced rest and movement pain after total abdominal hysterectomy and was more effective than superficial wound infiltration for postoperative pain management. PMID- 21823382 TI - Ciprofloxacin in critically ill children. AB - Data regarding the use of fluoroquinolones in critically ill children are scarce. We present our experience regarding the use of ciprofloxacin in this specific patient population. We prospectively identified all paediatric patients who received ciprofloxacin treatment in the intensive care unit of the tertiary care P. & A. Kyriakou Children's Hospital during a three year period (2005 to 2008). Eighteen paediatric patients (mean age 23 months, 12 females) who received intravenous ciprofloxacin were identified. Various underlying diseases, including malignancy and immunodeficiency, were observed. None of the evaluated patients had cystic fibrosis. Fourteen patients had bacteraemia (mainly caused from Gram negative pathogens), one had Stenotrophomonas maltophilia pneumonia, while no pathogen was identified in three patients. The latter patients received ciprofloxacin due to the severity of their clinical manifestations. All patients with microbiologically documented infections recovered. Three deaths attributed to the underlying diseases were noted. Within a 10-day follow-up, two cases of diarrhoea, one case of vomiting and one case of reversible supraventricular tachycardia were noted. No case of QT prolongation was noted. The short-term follow-up hampered any assessment of joint and cartilage toxicity, potentially associated with ciprofloxacin treatment. Our study suggests that ciprofloxacin may be a useful option for critically ill children without cystic fibrosis. Even though firm conclusions regarding the safety profile of ciprofloxacin in critically ill children could not be drawn, our study provides useful information regarding short-term adverse events associated with ciprofloxacin. PMID- 21823383 TI - Ondansetron does not modify emergence agitation in children. AB - In this prospective, placebo-controlled study, we evaluated the effect of prophylactic ondansetron therapy on emergence agitation of children who underwent minor surgery below the umbilicus. Seventy children aged one to six years and American Society of Anesthesiologists physical status I were studied. Children were premedicated with midazolam rectally and were randomly assigned to receive either ondansetron (Group O) or placebo (Group P) in combination with caudal anaesthesia. Children in Group O received intravenous ondansetron (0.1 mg/kg for children weighing < 40 kg, 4 mg for children weighing > 40 kg) and Group P (n = 35) received normal saline 2 ml following anaesthesia induction with sevoflurane. Airway management was provided with LMA-Proseal without muscle relaxation and anaesthesia maintenance was provided with a 60:40 N2O:O2 mixture and sevoflurane. Emergence agitation was evaluated with a ten point scale and pain level was assessed every 10 minutes for the first 30 minutes after admission to the recovery room. There were no significant differences between the placebo and ondansetron groups with respect to demographic, anaesthetic and surgical details. Incidences of emergence agitation in ondansetron and placebo groups were similar (32.4% and 30.3% at 10 minutes respectively). Mean modified Children's Hospital of Eastern Ontario pain scale scores and mean ten-point scale scores and emergence agitation incidences decreased similarly after 10 minutes in both groups. Ready time for discharge was similar between the groups. Agitated patients had significantly increased ready time for discharge compared to non agitated patients (P = 0.001). Prophylactic intravenous ondansetron administration does not reduce emergence agitation comparing to placebo after sevoflurane anaesthesia. PMID- 21823384 TI - Comparison of predicted and perceived pain from epidural and spinal puncture in patients undergoing elective caesarean section. AB - The intensity of pain expected by patients before an epidural and/or a spinal puncture is uncertain. The main purpose of this study was to identify and compare the intensity of pain predicted and perceived by patients having an epidural and a spinal procedure. After screening for relevant exclusion criteria, 50 women who were undergoing elective caesarean section under combined spinal-epidural anaesthesia (double-segment technique) were enrolled in the study. Infiltration anaesthesia prior to needle insertion was performed for the epidural but not the spinal puncture. Pain assessments, using a 100 mm visual analogue pain scale, were made before (predicted pain) and after (perceived pain) the epidural and the spinal puncture. Predicted pain for epidural and spinal insertion (epidural 60.6 +/- 20.5 mm, spinal: 55.1 +/- 24 mm) was significantly higher than the pain perceived (epidural 36.3 +/- 20 mm, spinal 46.1 +/- 23.2 mm) (epidural P < 0.001, spinal P = 0.031). Patients who were scheduled for an elective caesarean section under combined spinal-epidural anaesthesia predicted 1.2- to 1.7-fold stronger pain intensity than they perceived during the procedure. Patients should be informed that a regional anaesthetic, especially epidural, procedure is often less painful than the patient's expectation. PMID- 21823385 TI - Observational study of admission and triage decisions for patients referred to a regional intensive care unit. AB - The objectives of this study were to identify factors associated with decisions concerning triage and admission to the intensive care unit and to describe the outcome of patients referred to intensive care unit for admission. The study was a single-centre, prospective, observational study. It was performed in the general intensive care unit of a tertiary regional hospital, over the period of February to June 2009. The patients were non-elective, acute medical in-patients. For 100 patients referred, only 36 were admitted to the intensive care unit. The remaining 64 were declined admission: nine were declined admission because they were assessed as too sick to benefit, 41 were declined admission because they were assessed as too well to benefit and 14 were deemed to potentially benefit from intensive care unit admission but were not admitted ('triage'). Patients most likely to receive triage decisions were medical in-patients who had expressed wishes about end-of-life care, who were functionally limited with co morbid conditions affecting their performance status. Patients referred by Resident Medical Officers were also more likely to receive a triage decision. Age, gender Aboriginal and Torres Strait Islander status, diagnostic category and reason for referral did not impact on admission or triage decisions. Bed status in intensive care unit at the time of referral affected neither admission nor triage decisions. Hospital mortality in patients deemed too well to benefit from intensive care unit was 7.3%, suggesting that all patients referred for consideration of admission to intensive care unit should be classified as 'high risk'. PMID- 21823386 TI - The influence of objective prognostic information on the likelihood of informed consent for decompressive craniectomy: a study of Australian anaesthetists. AB - The aim of this study was to assess the influence of detailed prognostic information on the likelihood of informed consent for decompressive craniectomy for severe traumatic brain injury. The study was a simulation exercise, asking anaesthetists to give opinions as if they themselves were the injured party. Anaesthetists were chosen as they represent a distinct group likely to be familiar with the procedure and the decision-making process, but not necessarily aware of the longer-term outcomes. A two-part structured interview was used. Seventy-five anaesthetists were shown three cases of differing severity of traumatic brain injury. A visual analogue scale (1 to 10) was used to assess the strengths of their opinion. Initially they were asked their opinion with no predictive outcome data. They were then shown the prediction of an unfavourable outcome (Glasgow Outcome Scale severely disabled, vegetative state or dead) and the observed outcome at 18-month follow-up from a cohort of 147 patients (who had had a decompressive craniectomy for severe traumatic brain injury in Perth, Western Australia between the years 2004 and 2008). The opinions of the participants before and after seeing the prediction outcome data were compared. The participants' preferences to consent to the procedure changed after being informed of the predicted risks of unfavourable outcomes (P values < 0.01). The changes in attitude appeared to be independent of age group, amount of experience in caring for similar patients and religious background. These findings suggest that access to objective information on risks of unfavourable outcomes may influence opinions in relation to consent for decompressive craniectomy for traumatic brain injury. PMID- 21823387 TI - Remifentanil patient-controlled analgesia for labour: a complete audit cycle. AB - Remifentanil patient-controlled analgesia (PCA) was introduced to a small maternity unit where an extensive epidural service was difficult to provide. This was a new service and the New Zealand College of Midwives had serious doubts about the efficacy and safety of remifentanil, so auditing its use was important. In a two-stage audit, clinical notes of 244 consecutive remifentanil users were studied between January 2008 and November 2009. We developed a questionnaire to assess the parturients' satisfaction with remifentanil PCA and designed a proforma to evaluate it against four standards of best practice. During the two audit periods, timely commencement of PCA was achieved in 65% and 82% of cases, respectively. A 70% compliance rate with monitoring standards fell to 10% after the withdrawal of supervision by an acute pain team, but improved to 91% following implementation of regular midwifery training sessions and a redesigned partogram and prescription flowchart. Ninety-four percent of women rated remifentanil PCA as excellent, very good or good. Maternal side-effects were nausea, pruritus and drowsiness. A comparison of Apgar scores of consecutive neonates born by normal vaginal delivery to women receiving no analgesia, with those born to women using remifentanil PCA, demonstrated no difference. As a result of our audit, remifentanil PCA is now viewed by our midwives as an effective and safe method when accompanied by 1:1 care and appropriate monitoring. With our input other maternity units have introduced it, especially where epidural service provision is limited, and for patients in whom epidural analgesia is contraindicated. PMID- 21823388 TI - Intraoperative thrombolysis in a patient with cardiopulmonary arrest undergoing caesarean delivery. AB - Thromboembolic events during pregnancy remain a major cause of morbidity and mortality with possible catastrophic sequelae for the patient. The decision whether to use high-risk therapeutic thrombolytics during pregnancy or perinatally is complicated and many considerations pertain. We report on the thrombolytic management of a 34-year-old woman who had an asystolic cardiac arrest secondary to massive pulmonary embolism while undergoing emergency caesarean delivery. The patient was thrombolysed during successful cardiopulmonary resuscitation. Return of spontaneous circulation was accompanied by massive uterine bleeding. Instead of performing a postpartum hysterectomy, the uterus was preserved through continuous manual pressure and packing for four hours by the obstetric team until haemostasis was achieved. The patient survived and was later discharged without any major neurological deficit. PMID- 21823389 TI - Failure to ventilate with supraglottic airways after drowning. AB - We report the failure of an i-gel and an Ambu AuraOnce supraglottic airway to ventilate a drowning victim. Failure was attributed to changes in lung physiology following submersion and inhalation of water that may have required ventilation pressures up to 40 cmH2O to treat the victim's hypoxaemia. The ease of use and rapid insertion of supraglottic airways without interrupting cardiac compression has prompted recommendations for their use during resuscitation. The relatively low leak pressures attainable from many supraglottic airways, however may cause inadequate lung ventilation and entrainment of air into the stomach when these devices are used in drowning victims. PMID- 21823390 TI - Oesophageal balloon tracheoplasty in early tracheal stenosis following percutaneous tracheostomy. AB - Percutaneous tracheostomy is an efficient technique used in intensive care units. Although a safe procedure, serious early and late complications can occur. A rare complication is suprastomal stenosis following inadvertent tracheal cartilage fracture resulting in stenosis. Management is complicated, often requiring specialised equipment. While surgical treatment techniques are evolving, none are universally applicable. We report a case of early tracheal stenosis following percutaneous tracheostomy, treated successfully using a novel technique of oesophageal balloon tracheoplasty. To our knowledge, this is the first reported case of immediate post percutaneous tracheostomy suprastomal stenosis treated with balloon tracheoplasty using an oesophageal balloon catheter which is readily available in most endoscopy units. PMID- 21823391 TI - Calcitonin for acute neuropathic pain associated with spinal cord injury. AB - Neuropathic pain associated with spinal cord injury is caused by complex neural mechanisms and is often refractory to standard therapy. Salmon calcitonin was an effective treatment for neuropathic symptoms in this case series of three patients with recent spinal cord injury. Salmon calcitonin is already used to help manage pain after limb amputation and also after vertebral fractures and it is perhaps surprising that it has not been trialled previously for spinal cord injury pain. Calcitonin is thought to exert its effect by modulation of the serotonergic system and is generally well tolerated and convenient to administer. This underutilised drug may be a very useful adjuvant for neuropathic pain associated with spinal cord injury. PMID- 21823392 TI - Changes in microvascular blood flow during coupled plasma filtration and adsorption. AB - A 51-year-old man with septic shock underwent three consecutive sessions of coupled plasma filtration-adsorption each lasting 12 hours. Sublingual microvascular perfusion was assessed using the orthogonal polarisation spectral imaging technique at three different times: immediate pre-coupled plasma filtration-adsorption phase, two hours following commencement and two hours after its termination. The video images of the sublingual microcirculation were analysed by an investigator blinded to the time of image acquisition. The De Backer's score was calculated. During the coupled plasma filtration-adsorption, the number of perfused vessels increased compared with the pre-coupled plasma filtration-adsorption period, but decreased again after its termination. It is arguable that the elimination of septic mediators during the procedure could account for the observed variations. PMID- 21823393 TI - Residual neuromuscular blockade in myotonic dystrophy: lessons unlearned and sugammadex. PMID- 21823394 TI - A limitation to use a gum elastic bougie through Murphy's eye for difficult intubation. PMID- 21823395 TI - Anaphylaxis and patent Blue V. PMID- 21823396 TI - The Proseal laryngeal mask airway and elective caesarean section. PMID- 21823397 TI - Electroconvulsive therapy using rocuronium and sugammadex in patient with neuroleptic malignant syndrome. PMID- 21823398 TI - Sugammadex in the management of a failed intubation in a morbidly obese patient. PMID- 21823399 TI - Rocuronium and sugammadex as a novel management strategy in a patient with plasmacholinesterase deficiency presenting for electroconvulsive therapy. PMID- 21823400 TI - A rapid high-dose infusion of remifentanil. PMID- 21823401 TI - Tracheal intubation with the Airway Scope in congestive heart failure patients. PMID- 21823402 TI - Upper airway obstruction due to retropharyngeal haematoma after posterior cervical spine surgery. PMID- 21823403 TI - Successful spinal administration is related to the angle formed between the skin and a spinal needle. A geometric model. PMID- 21823404 TI - Recombinant human activated protein C in a liver transplant recipient in the immediate postoperative period. PMID- 21823405 TI - Uvular and tonsillar pillar mucosal necrosis as a cause of severe sore throat after orotracheal intubation. PMID- 21823406 TI - Profound bradycardia during skin preparation for inguinal herniorrhaphy. PMID- 21823407 TI - Maximisation of maternal cardiac output during labour might help to prevent not only foetal hypoxaemia but also myometrial ischaemia, dysfunctional labour, uterine atony and postpartum endometritis. PMID- 21823408 TI - Kaolin activated thromboelastography can result in false positive fibrinolytic trace. PMID- 21823409 TI - Tube feeding and drugs in intensive care unit. PMID- 21823410 TI - [Problems in post-stroke dysphagia by acupuncture]. PMID- 21823411 TI - [Current situation and prospect on post-surgery assessment of peri-operative gastrointestinal functions]. AB - Under the guidance of the concept of fast tract surgery (FTS), peri-operative managements including pre-operative, intra-operative and post-operative treatments can be optimized to accelerate the rehabilitation of surgery patients. Post-operative recovery of gastrointestinal functions is one of the key links of FTS, in which Chinese medicine has certain features and advantages over it. Current assessments on post-operative gastrointestinal functions recovery include clinical and laboratory assessments, but there is still no industrial assessment received by all. The current situation of post-surgery assessment of peri operative gastrointestinal functions was studied in this paper, and the research orientation of this field was analyzed and prospected. PMID- 21823412 TI - [Treatment of coronary heart disease angina by mutual complementation of Chinese medicine and western medicine]. PMID- 21823413 TI - [Effect of acupuncture on dysphagia of convalescent stroke patients]. AB - OBJECTIVE: To discuss the therapeutic effect on dysphagia of the convalescent stroke by combination of the body acupuncture, the scalp acupuncture and the electric acupuncture could be better than that by routine rehabilitation training. METHODS: 148 patients with dysphagia of convalescent stroke were randomly assigned to the acupuncture group and rehabilitation group, 74 in each group. Fengchi (GB20), Wangu (GB12), Yifeng (SJ17), Lian-quan (RN23), Jinjin (EX HN12), Yuye (EX-HN12) on the affected side were needled, and the scalp acupuncture was needled. The body acupuncture, the electric acupuncture, and the scalp acupuncture were applied in combination in the acupuncture group. The acupuncture was performed once a day, five times as one therapeutic course, 2 -4 courses totally. Rehabilitation training was performed by language therapists in the control group. The main outcomes were assessed with both intention-to-treat analysis and on-treatment/per-protocol analysis at the same time. The value of number needed to treat (NNT)/number needed to harm (NNH) and their 95% confidence intervals were also reported. The secondary outcomes were assessed by the end of the treatment. RESULTS: The recovery rate assessed by Watian swallowing ability, water drinking test in the acupuncture group were better than those of the control group by the end of the treatment and three months after treatment (P<0.05). There was no statistical significance in the pulmonary infection rate and the mortality or in the 6-month mortality after treatment by the end of the treatment between the two groups (P>0.05). The compliance was 100% in the two groups. No adverse reaction occurred in the acupuncture group. CONCLUSION: Acupuncture for dysphagia of convalescent stroke was better than routine rehabilitation training with safety and high tolerance. PMID- 21823414 TI - [Dynamic observation on therapeutic features of thalamic pain by mind calming, blood activating and pain relief acupuncture and carbamazepine]. AB - OBJECTIVE: To observe therapeutic features of thalamic pain by mind Calming, blood activating and pain relief acupuncture and Carbamazepine. METHODS: Crossover trial design was adopted. Eleven patients with confirmed diagnosis of thalamic pain were randomly assigned to two groups according to the minimal unbalance index method, i.e., Group I (Six patients received acupuncture first and then Western medicine.) and Group II (Five patients received Western medicine first and then acupuncture). The therapeutic course for each group was ten days. There was a ten-day elution phase between the two therapeutic methods. The total therapeutic course was thirty days. Eleven patients were enrolled in the two groups for statistical analysis. The therapeutic efficacy was assessed with visual analogue scale (VAS) and the pain assessment scale of Anderson Cancer Center in the USA (MD Pain Evaluation value) respectively. The VAS and MD values of the two groups were recorded every day to get the dynamic curve. RESULTS: The VAS and MD values obviously decreased in the two groups after treatment (P<0.05). The pain curves of the two groups showed a declining trend during the treatment. A gradual and stable descending process was shown in the acupuncture group. But a greater decrease first appeared in the Western medicine group, then a comparatively greater decrease occurred after one platform stage, showing ladder shaped curve. CONCLUSIONS: Cumulative potency may be the main analgesic effects of acupuncture. Western medicine may possibly play a role by rapid initiate effect. PMID- 21823415 TI - [Effect on the motor function of stroke patients by combination of needling at Back-shu point and trunk exercise]. AB - OBJECTIVE: To study the effect on the motor function of stroke patients by combination of needling at Back-shu point and trunk exercise. METHODS: Ninety stroke hemiplegic patients were randomly assigned to the conventional treatment group (as the convention group), the Back-shu point needling group, and the combination of Back-shu point needling and the trunk exercise group, 30 patients in each group. They were treated with the conventional treatment, needling at Back-shu point, and the combination of needling at Back-shu point and trunk exercise. The Fugl-Meyer score (FMA) and modified Barthel index (MBI) score were assessed before treatment and two months after treatment. RESULTS: The three rehabilitation treatment methods were all effective in improving the motor function of stroke hemiplegic patients (P<0.05). The effects in the Back-shu point needling group and the combination of Back-shu point needling and the trunk exercise group were respectively superior to that in the conventional treatment group (P<0.05). The effect in the combination of Back-shu point needling and the trunk exercise group was superior to that in the Back-shu point needling group (P<0.05). CONCLUSION: The combination of Back-shu point needling and the trunk exercise could improve the motor function of stroke hemiplegic patients, and its effect was better than needling at Back-shu point alone. PMID- 21823416 TI - [Study on the correlation between Chinese medical syndrome types and serum levels of PLTP and CETP in coronary heart disease patients]. AB - OBJECTIVE: To study the correlation between the serum levels of phospholipid transfer protein (PLTP), cholesteryl ester transfer protein (CETP), and Chinese medical syndrome types of coronary heart disease (CHD) patients, thus probing a new pathway for the objectivity of CHD syndrome typing and developing therapeutic drugs. METHODS: 201 patients with CHD confirmed by coronary angiography were selected. The comprehensive analysis database by the four examination methods was established using generally accepted standard for Chinese medical syndrome typing. Twenty healthy subjects were randomly recruited as the control group. Serum samples were separated from venous blood. The serum activities of PLTP and CETP were assayed by ELISA. The triglyceride (TG) content was determined using acetic acetone coloring method. Contents of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were determined using precipitation floating enzyme couplet method. RESULTS: Serum levels of PLTP, CETP, and TC of CHD patients of all Chinese medical syndrome types were significantly higher than those of the control group, showing statistical difference (P<0.05, P<0.01). Statistical difference existed in serum levels of TG, HDL-C, and LDL-C of all Chinese medical syndrome types when compared with the control group (P<0.05, P<0.01). Statistical difference existed in serum levels of PLTP between the sthenia in superficiality groups of all Chinese medical syndrome types and the asthenia in origin groups of all Chinese medical syndrome types (P< 0.05). Statistical difference existed in serum levels of TG, HDL-C, and LDL-C between the sthenia in superficiality groups of all Chinese medical syndrome types and the asthenia in origin groups of all Chinese medical syndrome types (P<0.05, P<0.01). CONCLUSIONS: The serum PLTP levels of CHD patients of sthenia in superficiality significantly increased. Changes in serum lipids was more significant in CHD patients of the sthenia in superficiality syndrome than in those of the asthenia in origin syndrome. PMID- 21823417 TI - [Analysis of Chinese syndrome features and combination laws of 2029 patients with coronary heart disease angina]. AB - OBJECTIVE: To explore the element distribution features and syndrome combination laws of coronary heart disease angina. METHODS: The syndrome database of 2 029 patients with coronary heart disease angina was established to study the syndrome elements and syndrome combination laws. RESULTS: (1) The syndrome element distribution of coronary heart disease angina was featured as: blood stasis > qi deficiency > phlegm turbid > yin deficiency > phlegm turbid with more warm property > yang deficiency > stagnant qi > phlegm turbid with more cold > cold coagulation. Of them, qi deficiency and blood stasis were the main two syndrome elements, and phlegm turbid with more warm and yin deficiency also occupied important positions. (2) Syndrome combination laws of coronary heart disease angina: three elements syndrome and two elements syndrome were dominant. The combination of sthenia syndrome element and asthenia syndrome element was the most important combination laws. Qi deficiency and blood stasis was the main combination form. CONCLUSIONS: Qi deficiency, yin deficiency, phlegm turbid, and blood stasis form four key links of its pathogenesis, in which, qi deficiency and blood stasis was the most basic pathogenesis. The syndrome element combination had some laws. PMID- 21823418 TI - [Study on Chinese medical syndrome distribution laws in 507 coronary heart disease patients of the Han nationality in Fuzhou city]. AB - OBJECTIVE: To explore Chinese medical syndrome distribution laws in coronary heart disease (CHD) patients of the Han nationality in Fuzhou city. METHODS: A questionnaire on Chinese medical syndrome was carried out in 507 patients with confirmed CHD from different regions of Fuzhou city. The correlation analyses of Chinese medical syndrome distribution laws, the Chinese medical syndrome types and complications, gender, age, the body mass index (BMI) were conducted. RESULTS: Viewed from elements of deficiency in origin or excess in superficiality, blood stasis syndrome was the most often seen syndrome in patients with CHD (accounting for 63.1%), followed by qi deficiency syndrome (accounting for 59.4%) and phlegm turbidity syndrome (accounting for 45.6%). Among syndrome types, qi deficiency blood stasis syndrome was the most often seen syndrome (accounting for 12.2%), followed by qi deficiency, blood stasis and phlegm turbidity syndrome (accounting for 9.1%), and qi deficiency and phlegm turbidity syndrome (accounting for 8.1%). The distribution of various Chinese medical syndrome types showed significant difference in different ages (P<0.05), but no obvious difference was shown in different genders, body mass index, or complications (P>0.05). CONCLUSIONS: Blood stasis, qi deficiency, and phlegm turbidity were the basic pathogeneses of CHD patients of the Han nationality in Fuzhou city. Syndrome with intermingled blood stasis, qi deficiency, and phlegm turbidity was the main Chinese medical syndrome pattern. The combination of syndrome showed certain regularity. PMID- 21823419 TI - [Correlation between essential elements of Chinese medicine syndrome and the lung function in patients with acute aggravating chronic obstructive pulmonary disease]. AB - OBJECTIVE: To study the correlation between essential elements of Chinese medicine syndrome (EECMS) and the lung function in patients with acute aggravating chronic obstructive pulmonary disease (AACOPD). METHODS: Adopting clinical epidemiological method, the Chinese medicine syndrome of 199 AACOPD patients with various grades of the lung function was differentiated, and EECMS in them were picked up, summarized and analyzed statistically. RESULTS: Along with the deteriorating of the lung ventilation, the EECMS of disease-position was progressed correspondingly, i.e. in patients with lung function of grade I, disease was positioned mainly on Fei (88.89%); in patients of grade II, on Fei Shen (25.97%), Fei-Pi (9.09%), and Fei-Gan (3.90%); in those of grade III, on Fei Shen (51.32%), Fei-Pi (7.89%), Fei-Pi-Shen (19.74%), and Fei-Pi-Shen-Xin (2.63%); in those of grade IV: on Fei-Shen (56.76%), Fei-Pi-Shen (27.03%). The EECMS of disease-property was also progressed, that for excessive syndromes were disposed as: grade I - II, phlegm (23.76%); grade III: phlegm-heat (30.26%), phlegm-stasis (15.79%), and phlegm-retention (9.21%); grade IV: phlegm-stasis (24.32%), phlegm heat-stasis (29.73%), phlegm-retention-stasis (2.70%); and for deficiency syndromes were arranged as qi-deficiency --> qi-yin deficiency --> qi-yang deficiency --> qi-yin-yang deficiency. CONCLUSION: The lung function could be taken as the objective and quantitative index for the progression of Chinese medicine syndromes in patients with AACOPD. PMID- 21823420 TI - [Effects of bushen huoxue recipe on urinary levels of albumin, IL-6, TGF-beta1 and MCP-1 in chronic nephritis patients of shen-deficiency blood-stasis syndrome]. AB - OBJECTIVE: To observe the effect of Bushen Huoxue Recipe (BSHXR, a Chinese medicine recipe for Shen reinforcing and blood circulation activating) on the levels of urinary albumin, interleukin-6 (IL-6), transforming growth factor-beta1 (TGF-beta1), and monocyte chemotactic protein-1 (MCP-1) in chronic nephritis patients of Shen-deficiency blood-stasis syndrome. METHODS: Forty-five patients were blocking assigned randomly to two groups, fifteen patients in the control group and thirty in the treatment group. All orally took Monopril 10 mg, once daily. But BSHXR was given additionally to patients in the treatment group after decocting,one dose per day (taken in two times). The treatment course for both groups was eight weeks. Besides, a normal control group consisting of six healthy subjects from health examination of Shuguang Hospital was set up. The 24-h urinary albumin and contents of TGF-beta1, IL-6 and MCP-1 in urine of all subjects were observed. RESULTS: Compared with before treatment the 24-h urinary albumin was obviously reduced in the treatment group, showing significant difference (P<0.01). The urinary 24-h albumin decreased in the control group, with statistical significance (P<0.05). Statistical difference existed between the treatment group and the control group after treatment (P<0.01). Compared with before treatment, urinary levels of IL-6, TGF-beta1, and MCP-1 were all down regulated in the treatment group and the control group after treatment (P<0.01), and the decreasing of IL-6 and TGF-beta1, levels was more significant in the treatment group statistically (P<0.05). CONCLUSIONS: BSHXR could attenuate the albuminuria in patients of chronic nephritis. Its mechanism might be possibly correlated with its down-regulation of IL-6, TGF-beta1, and MCP-1 levels. PMID- 21823421 TI - [Multi-center clinical study on therapeutic effect of kunxian capsule on rheumatoid arthritis]. AB - OBJECTIVE: To assess the therapeutic efficacy and safety of Kunxian Capsule (KXC) in treatment of rheumatoid arthritis (RA). METHODS: Randomized positive parallel controlled and multi-center open test method was adopted. 240 RA patients of mild/moderate degree were randomly assigned to three groups equally, i.e., KXC group (who took KXC), the methotrexate (MTX) group (who took MTX), and the KXC + MTX group (who took KXC and MTX simultaneously), respectively. The therapeutic course for them all was 12 weeks. The effect of the treatment was assessed in items of DAS28, ACR20, and ACR50; number of joints with pain and swelling; VAS score of pain, tiredness, and general condition; time of morning stiffness; bilateral grip strength; HAQ score, as well as blood levels of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), anti CCP antibody, and platelet count. RESULTS: By the end of the 4th week, the improvement of ACR20, ACR50, DAS28 efficacy judgment, and DAS28 score in the KXC + MTX group were much better than those in the other two groups, with statistical difference (P<0.05). The total effective rate was 88. 6% and the markedly effective rate was 51.8% in the KXC + MTX group at the 12 th week. The Improvement was more obviously shown in all groups after treatment (all P<0.05). Better effects in reducing VAS scores of pain and tiredness were shown in the KXC group and the KXC + MTX group. The effects of KXC + MTX were superior to the other two groups in terms of swollen joint numbers, pain joints, grip strength (assessed by researcher), as well as VAS score of general condition and HAQ score (assessed by both patients and researcher, P<0.05). But the differences among groups in improving morning stiffness and the incidence rate of adverse events were in- significant. CONCLUSIONS: KXC could relieve symptoms, improve joint functions, physical signs, and laboratory indices of RA patients with less adverse reaction. It was synergistic with MTX. PMID- 21823422 TI - [Effect of tangzu yuyang ointment on the outcome event of patients with chronic diabetic foot ulcers]. AB - OBJECTIVE: To assess the efficacy and safety of Tangzu Yuyang Ointment (TYO) for treatment of chronic diabetic foot ulcers. METHODS: Fifty-seven patients with chronic diabetic foot ulcers of Wagner's ulcer grade 1 to 3 were randomly assigned to the control group (29 cases) and the treatment group (28 cases). Patients in the control group received the standard wound therapy (SWT), while those in the treatment group received SWT plus TYO. The ulcer healing rate, the ulcer improvement rate and the incidence of adverse events were compared between the two groups. Totally 48 patients finished the final follow-ups and entered the data analysis. RESULTS: The ulcer improvement rate was 79.2% in the TYO group and 41.7% in the SWT group (P=0.017) at the 12th week, and 91.7% vs. 62.5% (P=0.036) at the 24th week. There was no statistical difference in the ulcer healing rate and the incidence of adverse events between the two groups at week 4, 12, and 24, respectively. The ulcer healing time was 96 +/- 56 days in the TYO group and 75 +/- 53 days in the SWT group, showing insignificant difference (P=0.271). CONCLUSION: TYO plus SWT was more safe and effective than SWT alone in the treatment of chronic diabetic foot ulcers. PMID- 21823423 TI - [Effect of bushen tiaojing recipe on growth differentiation factor-9 in tubal infertility patients undergoing in vitro fertilization-embryo transfer]. AB - OBJECTIVE: To study the effect and mechanism of Bushen Tiaojing Recipe on improving oocyte and embryo qualities in patients undergoing in vitro fertilization-embryo transfer (IVF-ET) at the super-ovulatory cycle. METHODS: Fifty-eight tubal infertility patients undergoing IVF-ET were randomly assigned to two groups. Thirty patients in the treatment group were treated with Bushen Tiaojing Recipe and GnRHa/FSH/hCG, and twenty-eight patients in the control group were treated with GnRHa/FSH/hCG. Contents of GDF-9 in the mature follicular fluid were detected by Western blot. The expressions of GDF-9 in granulose cells were detected by Real-time PCR. The dose of gonadotropin (Gn), the number of oocytes obtained, the fertilization rate, the oocyte cleavage rate, the high quality embryo rate, and the pregnancy rate were compared. RESULTS: The contents of GDF-9 in the follicular fluid and its expression in granulosa cells were significantly higher in the treatment group than in the control group (P<0.05). The number of oocytes obtained, the fertilization rate, the high quality embryo rate, and the pregnancy rate were significantly higher in the treatment group than in the control group. There was no significant difference in the dose of Gn or the oocyte cleavage rate. CONCLUSIONS: Bushen Tiaojing Recipe could improve the pregnancy rate of IVF-ET. Its mechanism might be possibly through regulating the GDF-9 contents in the follicular fluid and granulosa cells. PMID- 21823424 TI - [Effect of electroacupuncture on nitric oxide synthase in rats with cerebral ischemia-reperfusion injury]. AB - OBJECTIVE: To study the effect of electroacupuncture on nitric oxide synthase (NOS) in rats with cerebral ischemia-reperfusion injury. METHODS: Focal cerebral ischemia-reperfusion model was established using modified intravascular suture technique. The NO content in the brain tissue was detected by nitrite reduction and the expressions of nNOS and iNOS were detected by immunohistochemistry. Eighty rats in this experiment were divided into the normal group, the cerebral ischemia-reperfusion injury model group (as the model group), the cerebral ischemia-reperfusion injury + electroacupuncture group (as the acupuncture group), and the cerebral ischemia-reperfusion injury + phosphatidylinositol 3 kinase (PI3-K) inhibitor group (as the inhibitor group). Each group consisted of twenty rats. Five microL PI3-K inhibitor LY294002 (400 microL) was slowly injected at the lateral cerebral ventricle of rats in the inhibitor group at a constant speed using microinjector according to Konig Klippel atlas of the stereotaxis instrument. Shuigou (DU26) and Chengjiang (RN24) were selected to determine levels of NO and NOS. RESULTS: After 24-h ischemia-reperfusion, the NO levels of the hippocampus and the cerebral cortex increased abnormally, and the expressions of nNOS and iNOS increased, showing significant difference when compared with those of the normal group (P<0.05). By electroacupuncture at Shuigou (DU26) and Chengjiang (RN24), the ischemic cerebral ischemia-reperfusion injury neuron loss was inhibited. Meanwhile, the high levels of NO, nNOS and iNOS in the cerebral cortex and the hippocampus were significantly inhibited (P<0.05). The abnormally increased expressions of nNOS and iNOS were reversed, showing significant difference when compared with the model group (P<0.05). But when compared with the normal group, there was no significant difference (P>0.05). The effects of electroacupuncture reversed the abnormally increased NO levels of the hippocampus and the cerebral cortex and expressions of nNOS and iNOS after LY294002 oppressed anti-PI3K to block the TrkA acceptor circuit. The NO levels of the hippocampus and the cerebral cortex and expressions of nNOS and iNOS increased again, showing significant difference when compared with the acupuncture group (P<0.05). CONCLUSIONS: Acupuncture fought against cerebral ischemia and reperfusion in the loss of neurons, at the same time, the abnormal regulation of NOS had reverse effect partly through TrkA/PI3K mediated signal transduction pathway. PMID- 21823425 TI - [Effect of scutellarin on expressions of nicotinic acetylcholine receptor protein and mRNA in the brains of dementia rats]. AB - OBJECTIVE: To observe the effect of Scutellarin (Scu) on expressions of nicotinic acetylcholine receptor (nAChR) subunit protein and mRNA in dementia rats, and to study its possible mechanism on dementia. METHODS: Forty-two Wistar rats were randomly divided into 5 groups, i.e., the normal control group (n=6), the sham operative group (n=6), the memory deficit model group, the Scu treatment group (n=10), and the positive drug (piracetam) control group (n=10). The dementia rat model was established by bilateral ventricle injection with beta-amyloid peptide (Abeta)(25-35) and abdominal cavity injection with D-galactose. Rats in the Scu treatment group or the piracetam control group were treated with Scu or piracetam by gastrogavage. The learning and memory ability of rats were detected by Morris water maze test, nAChR alpha4, alpha7, and beta2 subunits at protein and mRNA levels were detected by Western blot and Real-time PCR respectively. RESULTS: Compared with the normal control group and the sham-operative group, the learning and memory ability decreased in rats of the model group (P<0.05). nAChR alpha4 and alpha7 subunit protein expressions were obviously lowered (P<0.05), but changes of beta2 were not obvious. No obvious change of mRNA expressions in all three nAChR subunits was seen (P>0.05). After treatment of Scu, the learning and memory ability was greatly improved, nAChRs alpha4 and alpha7 subunit protein expressions increased in rats with dementia (all P<0.05). No obvious change of mRNA expressions in all three nAChR subunits was seen (P>0.05). No obvious difference of each index was shown between the Scu treatment group and the positive drug (piracetam) control group. CONCLUSIONS: Scutellarin could improve the learning and memory ability of dementia rats. Its mechanism might be associated with its up-regulation of nAChR expressions. PMID- 21823426 TI - [Effects of bushen huoxue decoction on neurobiochemical markers in the hippocampus of female rats with repeated immobilization stress]. AB - OBJECTIVE: To study the effect o f Bushen Huoxue Decoction (BHD) on neurobiochemical markers in the hippocampus of female rats with repeated immobilization stress. METHODS: Sixty female rats were randomly divided into the normal group, the model group, the positive control group (treated with Liuwei Dihuang Pill at the dose of 3.3 g crude drug/kg), and the high, middle, and low BHD treated groups (at the dose of 8, 4, 2 g crude drug/kg), ten in each group. Chronic psychological stress was induced using repeated immobilization stress in rats. Medication was conducted by gastrogavage while modeling once a day for twenty successive days. The hippocampal neurohumoral levels were detected with high-performance liquid chromatography. The expression levels of BDNF and its receptor in the hippocampus were detected by Westem blot. Effect of BHD on neurobiochemical markers in the hippocampus of rats with repeated immobilization stress was observed. RESULTS: The levels of Glu, GABA, and BDNF in the hippocampus of the normal group were 1280.0 +/- 258.3 ng/mg, 588.3 +/- 115.1 ng/mg, and 13.26 +/- 2.57 gray value, respectively. But the hippocampal neurohumoral levels and the expression of BDNF in the model group obviously decreased when compared with the normal group, being 1016.9 +/- 215.9 ng/mg, 485.1 +/- 71.0 ng/mg, and 7.23 +/- 0.61 gray value, respectively. The levels of Glu (ng/mg) in hippocampus of the three BHD treated groups were 1459.1 +/- 413.5, 1894.7 +/- 542.8, and 1373.3 +/- 345.7, respectively. GABA levels (ng/mg) inthe hippocampus were 631.6 +/- 161.4, 899.1 +/- 262.1, and 656.4 +/- 140.8, respectively. BDNF levels (gray value) were 16.57 +/- 1.52, 29.85 +/- 1.37, and 24.44 +/- 3.81, respectively, significantly higher than that of the model group (P<0.05, P<0.01). The level of Glu in the positive control group (1216.5 +/- 193.8 ng/mg) was significantly higher than that of model group (P<0.05). CONCLUSION: BHD showed significant accommodation on the hippocampal neurohumoral levels and the expression of BDNF in the female rats with repeated immobilization stress. PMID- 21823427 TI - [Effect of ginsenoside Rg1 on the spatial learning-memory ability in dementia rats after transplanted with bone marrow mesenchymal stem cells]. AB - OBJECTIVE: To study the effect and mechanism of ginsenoside Rg1 on the spatial learning-memory ability in rats with Alzheimer's disease after transplanted with bone marrow mesenchymal stem cells (BMSCs). METHODS: Using digital randomization table method, seventy-five male SD rats were divided into the bilateral FF transection model group (as the model group: ambi-hippocampal fimbria-fomix transected), the sham-operative control group (the SOC group: receiving the same modeling process as the model group, but without ambi-hippocampal fimbria-fomix transected), the ginsenoside Rg1 treatment group (as the treatment group: Two weeks after modeling ginsenoside Rg1 was peritoneally injected at the dose of 5 mg/kg, once daily for four weeks in total), the BMSCs transplanted treatment group [as the control group: Two weeks after modeling every rat received transplantation of BMSCs (10 microL, 1 x 10(6) cells)], and the ginsenoside Rg1 + BMSCs treatment group (as the combination group: They received both transplantation of BMSCs and peritoneal injection of ginsenoside Rgl). The spatial learning-memory ability of rats was detected by Morris water maze and the escape latency (s) was recorded, mRNA expression of nerve growth factor (NGF) was detected using Real-time PCR. RESULTS: Six weeks after the hippocampal fimbria fomix (FF) transection, the escape latency o feach medication group was obviously shorter than that of the model group, and the spatial learning-memory ability of dementia rats was somewhat improved. The spatial learning-memory ability of rats in the combination group was (29.95 +/- 2.03) and the mRNA expression level of NGF was (1.13 +/- 0.15), better than those in the BMSCs group (44.36 +/- 1.43, 0.78 +/- 0.09, P<0.05). CONCLUSIONS: Ginsenoside Rg1 could strengthen the spatial learning-memory ability in dementia rats after transplanted with BMSCs. Its mechanism might be possibly correlated with up-regulating mRNA expression of NGF in basal forebrain after BMSCs transplantation. PMID- 21823428 TI - [Effects of scutellaria stem-leaf total flavonoids on cardiocyte apoptosis induced by hypoxia/reoxygenation]. AB - OBJECTIVE: To study the effect of Scutellaria baicalensis stem-leaf total flavonoids (SSTF) on cardiocyte apoptosis of neonatal rats induced by hypoxia/reoxygenation and its action of mechanism. METHODS Sixty one to two days old rats, male or female, were selected. Hypoxia/reoxygenation injured model was established in cultured cardiocytes of neonate rats. The cultured neonatal rat cardiocytes were divided into 5 groups, i.e., the normal control group, the hypoxia/reoxygenation injury group (as the model group, cultured cardiocytes were exposed to hypoxia 2 h and subsequently reoxygenated for 4 h), the hypoxia/reoxygenation injury plus 50 mg/L SSTF group (as the low dose SSTF group), the hypoxia/reoxygenation plus 100 mg/L SSTF group (as the middle dose SSTF group), and the hypoxia/reoxygenation plus 200 mg/L SSTF group (as the high dose SSTF group). The cell viability was detected by methyl thiazolyl tetrazolium (MTT) colorimetry. The apoptosis of cardiocytes was determined by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and the apoptosis rate calculated. The Bcl-2 and Bax protein expressions were determined by immunohistochemistry. RESULTS: Compared with the normal control group, the cell viability, Bcl-2 protein contents and Bcl-2/Bax decreased, the apoptosis rate and Bax protein contents increased in the model group (all P<0.01). Compared with the model group, the cell viability, Bcl-2 protein contents and Bcl-2/Bax increased, while the apoptosis rate and Bax protein contents decreased in each SSTF treated group (P<0.05, P<0.01). Compared with the low dose SSTF group, significant difference existed in each index of the high dose SSTF group (all P<0.05). CONCLUSIONS: SSTF had protection on hypoxia/reoxygenation induced cardiocyte apoptosis. Its protective mechanism might be correlated with its up regulation of the expression of Bcl-2 protein ahd down-regulation of the expression of Bax protein. PMID- 21823429 TI - [Effect of astragaloside against the oxidative damage on endothelial cells]. AB - OBJECTIVE: To observe the effect of astragaloside on oxidative low-density lipoprotein (Ox-LDL) mediated oxidative damage of endothelial progenitor cells (EPCs). METHODS: Peripheral blood mononuclear cells(PBMCs) were isolated by Ficoll density gradient centrifugation, and EPCs were identified by flow cytometry. Adherent cells were collected after seven-day incubation and randomly divided into the normal control group, the Ox-LDL group (as the model group, at the dose of 100 microg/mL), the low, middle, and high astragaloside groups (with 100 microg/mL Ox-LDL plus 2, 10, and 50 microg/mL astragaloside). Twenty-four h later, the proliferation and adhesion capabilities of EPCs were observed using MTT colorimetry and the adhesion capability detection. Levels of superoxide dismutase (SOD) and malonaldehyde (MDA) in the cell supernate of each group were determined. RESULTS: After Ox-LDL damage, the proliferative and adhesive capacities of EPCs were significantly injured (53 +/- 8 vs 42 +/- 6, 0.49 +/- 0.12 vs 0.37 +/- 0.02, both P<0.05). The SOD content obviously decreased (21.95 +/- 1.43 vs 14.76 +/- 3.99, P<0.01), the MDA content obviously increased (3.72 +/ 0.30 vs 5.57 +/- 0.64, P<0.01). After intervened by astragaloside for 24 h, the proliferative and adhesive capacities of EPCs were significantly improved. The SOD contents of astragaloside intervention groups were obviously improved and the MDA content obviously lowered. CONCLUSIONS: Astragaloside showed significant protection on Ox-LDL damaged EPCs. Its mechanism might be correlated with antioxidative damage. PMID- 21823430 TI - [Effect of banxia baizhu tianma decoction on the vascular endothelial function of spontaneous hypertensive rats]. AB - OBJECTIVE: To study the vascular endothelial function recovery and its mechanism of Banxia Baizhu Tianma Decoction (BBTD). METHODS: 54 SH rats were randomly divided into three groups: the blank control group, BBTD group and Captopril treatment group. BBTD (at the daily dose of 4. 320 g crude drug/kg) and Captopril (at the daily dose of 3.375 g/kg) was administered from the 7th week to the 24th week. Another eighteen Wistar-Kyoto rats of the same ages were taken as the control. Medication was discontinued and effects were observed until the 32nd week. The blood pressure was determined by arterial carotis cannula. The concentration of serum NO2(-) and total anti-oxidation were determined by Griess and fluorescence recovery after photobleaching (FRAP). The acetylcholine (Ach) dependent relaxation of superior mesenteric artery was detected using in vitro vascular ring. The mRNA expressions of IL-1, IL-6 and iNOS were detected by Real time PCR at the 18th, 24th, and 32nd week. RESULTS: BBTD could significantly lower blood pressure of SHR and the concentration of serum NO2(-) at the 18th and 24th week (P<0.05). The total anti-oxidation of SH rats increased at the 18th week (P<0.01), and ACh-dependent relaxation of superior mesenteric artery increased at the 24th week. The mRNA expressions of IL-1 was markedly suppressed by BBTD at the 18th, 24th, and 32nd week (P<0.05), while IL-6 and iNOS mRNA expression were significantly lowered only at the 32nd week (P< 0.01). Captopril could significantly lower blood pressure of SHR at the 18th and 24th week (P<0.05). It significantly increased the total anti-oxidation of SH rats at the 18th week (P<0.01). However, it could not increase ACh-dependent relaxation of superior mesenteric artery and regulate the concentration of NO2(-) at the 18th, 24th, and 32nd week. The mRNA expression of iNOS was markedly suppressed by Captopril at the 24th and 32nd week, while mRNA expressions of IL-1 and IL-6 were significantly lower only at the 32nd week (P<0.01). CONCLUSIONS: BBTD showed similar effect in decreasing the blood pressure to captopril, but it showed better effect in improving the mesenteric endothelial dysfunction of SHR, which may be associated with its inhibition on NO and IL-1 expression, and improvement of the oxidative stress state. PMID- 21823431 TI - [Effect of modified zhenzhu tiaozhi capsule on lipid peroxidation and endothelial functions in atherosclerotic rabbits]. AB - OBJECTIVE: To observe the anti-atherosclerotic effect and its possible mechanisms of Modified Zhenzhu Tiaozhi Capsule (MZTC) in rabbits. METHODS: 50 rabbits were divided into five groups, i.e., the normal group, the model group, the simvastatin group (3 mg/kg), the high dose MZTC group (1.6 g crude drug/kg), and the low dose MZTC group (1.6 g crude drug/kg), respectively, ten in each group. The atherosclerosis (AS) model was established by feeding rabbits with high fat diet. Corresponding medicines were administrated on the basis of high fat diet for twelve successive weeks. Levels of blood lipids, serum superoxide dismutase (SOD), malondialdehyde (MDA), and nitric oxide (NO) were detected. The area of the aortic tunica intima plaque was determined. The pathological changes of the aorta were observed. RESULTS: Compared with the model group, serum levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), MDA, and atherosclerotic index (AI) were significantly lowered in the MZTC groups (P<0.05, P<0.01), while serum levels of high-density lipoprotein cholesterol (HDL-C), SOD, and NO obviously increased (P<0.05, P<0.01). Serum levels of TC, TG, LDL-C, and in the MZTC groups were obviously higher than those of the simvastatin group (P<0.01), and there was insignificant difference in other indices. The ratio of the aortic tunica intima plaque percentage to the total tunica intima area was also markedly lower than that of the model group (P<0.05, P<0.01). Results under light microscope indicated the pathological changes of the aorta was obviously attenuated. CONCLUSIONS: MZTC could inhibit the formation and development of AS plaque. Its mechanism might be associated with regulating lipids metabolism, antioxidation, and improving endothelial functions. PMID- 21823432 TI - [Study on two strains of mouse developing dampness-heat models infected by Dengue virus]. AB - OBJECTIVE: To establish two strains of mouse developing dampness-heat syndrome models infected by Dengue virus and to compare the difference in infection, so as to choose a suitable mouse strain for modeling. METHODS: According to the modeling methods of the seasonal febrile disease of the dampness-heat syndrome in Chinese medicine, BALB/C and C57BL/6 mice were respectively treated with complex factors as the high glucose and high fat forage + high-temperature chamber + Dengue virus. At the same time a normal control group, the virus infection group (modeled by Dengue virus infection), and the dampness-heat group (modeling by pure dampness heat circumstance) were set up. Changes of the body temperature, platelet counts, virus in the separate serum, pathological changes of the liver, and serological indicators were observed to compare the modeling difference. RESULTS: After modeling low-grade fever appeared in mice in the high-temperature chamber. Compared with the normal control group, the platelet count decreased in mice of the BALB/C model group. AST increased in both BALB/C and C57BL/6 mice and the virus infection group. TC and TG increased in BALB/C model group and the dampness-heat group, with statistical significance (P<0.05). Various degrees of pathological changes were shown in the liver tissue of each group, with the most severe one in the BALB/C model group. The serum virus titers were detected with Real-time PCR after modeling. The virus load was 2.9 x 10(4) - 5.5 x 10(4) copies/mL. No significant difference was found among these groups. CONCLUSIONS: The mouse model of dampness-heat syndrome infected by Dengue virus was primarily established. When compared the infection between BALB/C mice and C57BL/6 mice, BALB/C mice were more suitable for modeling. PMID- 21823433 TI - [Research of cardiovascular effects and mechanism of Panax quinquefolius saponin]. AB - Panax quinquefolium L., also named American ginseng, is a valuable tonic medicine. Because of its main active ingredient ginsenoside's extensive biological effects, researches on the Panax quinquefolius saponin have important clinical and scientific value. Its basic components, bioactivities, cardiovascular effects and mechanisms will be covered in this paper. PMID- 21823434 TI - [Thinking on dose-effect relationship of Chinese herbal compounds in clinical studies]. AB - Dose-effect relationship is an important topic as well as difficulties in clinical studies on Chinese herbal compounds. The relevant concepts of the dose effect relationship, its features, its backgrounds, directions and roles of clinical studies on the dose-effect relationship of Chinese herbal compounds were discussed in this essay. The current state of clinical studies was introduced. The confronting challenges of clinical studies were also analyzed, thus providing references for the establishment of appropriate clinical research methods in line with Chinese medicine features. PMID- 21823435 TI - [Consensus on developing the integrative medicine]. PMID- 21823436 TI - [Diagnosis and treatment guidance for blood stasis syndrome by integrative medicine]. PMID- 21823437 TI - [Current status and prospect of methods for studying Chinese medicine syndrome evolution laws]. PMID- 21823438 TI - [Study on anti-arrhythmia mechanisms of Chinese materia medica by blocking multiple ion channels]. PMID- 21823439 TI - [Cerebrovascular diseases and activating blood and removing stasis method]. PMID- 21823440 TI - [Nausea and vomiting rational in the community pharmacy setting]. PMID- 21823441 TI - [Efficacy and safety of ibuprofen and paracetamol in fever among children]. PMID- 21823442 TI - [Role of the hospital pharmacist in the management of chemotherapy-induced nausea and vomiting]. PMID- 21823443 TI - [Docosanol (Erazaban), dermal use]. PMID- 21823444 TI - [ Erdosteine (Mucodox), oral administration]. PMID- 21823445 TI - [Effects of different light and GA3 on the germination and seedling growth of Rhodiola sachalinensis]. AB - OBJECTIVE: To improve germination rate and research the seed germination character of Rhodiola sachalinensis. METHODS: Made seed germinated under water or with moisture, at light or dark condition, effects of 6 different light qualities (black, white, blue, green, red and far red light) illumination on seed germination were studied. The seedling growth at different temperature were studied as well. RESULTS: The results indicated that light was required for Rhodiola sachalinensis seeds germinate, 83.3% germination rate at light and soaking in watercondition; Seed germination were improved to 84%, 70.7% and 52.0% respectively in white, red and green light quality illumination, the germination rate reached 84% after 9 h of white light illumination. Germination rate were 80% after 100 mg/L GA3 treatment for 3 h under dark condition. 20 degrees C was the optimal temperature for Rhodiola sachalinensis seedling growth, under with the plant height, fresh weight and dry weight of plant were the best. Seedling growth rate and the dry weight increased obviously at 35 d and 50 d. CONCLUSION: The experiment definited the best condition for Rhodiola sachalinensis seed germination and seedling growth, supplied basic data for large scale planting Rhodiola sachalinensis using seed propagation technology. PMID- 21823447 TI - [Study on the net photosynthesis rate of Coptis chinensis from different types and production places]. AB - OBJECTIVE: Evaluate the photosynthesis characteristics of Coptis chinensis and provide theoretical basis for the optimization of Coptis chinensis germplasm resources and variety. METHODS: The daily variation of the net photosynthetic rate, transpiration rate, stomatal conductance and intercellular CO2 density in leaf blade were determined by Photosynthesis analyzer, and the net photosynthesis rate of Coptis chinensis from different plant ages, types and production places was compared. RESULTS: The light saturation point in Coptis chinensis was about 500 micromol/m2 x s, light compensation point was about 12.04 micromol/(m2 x s), apparent quantum yield was 0.011. When the temperature was above 33 degrees C, the transpiration rate increased but the net photosynthesis rate decreased. There was no significant difference (P > 0.05) among the net photosynthesis rate of Coptis chinensis from different plant ages. The net photosynthesis rate of the type DA-YE and ZHI-HUA was significantly higher than that of other types (P < 0.05); The net photosynthesis rates of specimens from Fubao mountain in Lichuan county of Hubei and Fengmu village in Shizhu county of Chongqing were significantly higher than that of others. CONCLUSIONS: The net photosynthesis rate of Coptis chinensis decreased under hight temperation and hight light. Different germplasm resources of Coptis chinensis, the net photosynthetic rate had certain differences. PMID- 21823446 TI - [Effects of spraying uniconazole on plant morphology and total alkaloid content of Aconitum carmichaeli]. AB - OBJECTIVE: To study the effects of spraying uniconazole on plant morphology and total alkaloid content of Aconitum carmichaeli for providing theory base for establishment of planting measure. METHODS: The mainly morphological character and total alkaloid content of Radix Aconiti Lateralis Praeparata were studied under different uniconazole spraying time and density. RESULTS: Unieonazole could decrease plant height and leaf area, increase stem diameter, leaves and fibril roots, and the amount of dry matter. The difference in total alkaloid was not significant. CONCLUSION: In this experiment,Spraying uniconazole has no significant effect on total alkaloid content of Aconitum carmichaeli. It is better for increasing yield per plant to applied 120 mg/L unieonazole at sub-root enlargement stage than sub-root formation stage, and it is better to applied the same density at another stage for adjusting the plant morphology. PMID- 21823448 TI - [Effect of sodium cantharidinate on the angiogenesis of nude mice with human gastric cancer]. AB - OBJECTIVE: To study the effect of sodium cantharidinate on the angiogenesis of nude mice with human gastric cancer. METHODS: Nude mice xenograft models of human gastric cancer were established by injecting gastric carcinoma cell BGC823 into peritoneal. Expression of VEGF and MVD labeling by CD34 in human gastric cancer cells were measured by immunohistochemistry. RESULTS: Expression scores of VEGF in medium dose and high dose group with sodium cantharidinate treatment were lower than those in low dose and control group (P < 0.01). There was no significant difference between medium dose and high dose group or low dose and control group (P > 0.05). MVD values in medium and high dose group with sodium cantharidinate treatment were lower than those in low dose and control group (P < 0.01), but there was no significant difference between medium dose and high dose group (P > 0.05). CONCLUSIONS: sodium cantharidinate can inhibit the growth of the tumor by down-regulating VEGF expression of the tumour cell and the angiogenesis of the tumour. PMID- 21823449 TI - [Pharmacognostical studies on imported and cultivated Citrullus colocynthis]. AB - OBJECTIVE: In order to use Citrullus colocynthis safety and correctly,The pharmacognosy of imported and cultivated Citrullus colocynthis was systematically studied. METHODS: The morphological characters, microscopical identification, and thin layer Chromatograpy (TLC) were studied. RESULTS: The characters of import and cultivated Citrullus colocynthis were approximately identical, but there were still some differences between them, such as: the fruit size of cultivated Citrullus colocynthis was largish, granulose were more, trachea were thicker, collenchyma were longer, the colour of spots in TCL were more clear. CONCLUSION: There were seldon difference between import and cultivated Citrullus colocynthis, and cultivated Citrullus colocynthis could take the place of import's if planted on a large scale. PMID- 21823450 TI - [Contents comparision of atractylode I, II, III in rhizoma atractylodis macrocephalae and the processed with soils]. AB - OBJECTIVE: To research the effect of processing with soils on the contents of Atractylode I, II, III of Rhizoma Atractylodis Macrocephalae. METHODS: Contents of Atractylode I, II, III were determined by HPLC. Hypersil-ODS C18 (200 mm x 4.6 mm, 5 microm) column was used; The mobile phase consisted of acetonitrile-water; The flow rate was 1.0 mL/min; The detection wavelength was 220 nm and 276 nm,the column temperature was 30 degrees C. RESULTS: All the indexes of Atractylode I, II, III peak were qualified; The result of methodological study was met the requirement of HPLC; The average contents of Atractylode I , II , II in raw Rhizoma Atractylodis Macrocephalae were 0.4365, 0.2878, 0.4140 mg/g, the soil processed Rhizoma Atractylodis Macrocephalae were 0.5503, 0.3013, 0.8403 mg/g, the processed Rhizoma Atractylodis Macrocephalae were 0.5386, 0.2958, 0.7399 mg/g. CONCLUSION: The content of Atractylode II is no significant difference among the raw Rhizoma Atractylodis Macrocephalae and the Processed. The contents of both Atractylode I and III increased after processed. However, there is no significant difference between the soil-processed and the processed Rhizoma Atractylodis Macrocephalae with nothing. PMID- 21823451 TI - [Studies on the chemical constituents of Coleus forskohlii transplanted in Tongcheng and their antitumor activity]. AB - OBJECTIVE: To study the chemical constituents of Coleus forskohlii. METHODS: Isolation and purification were carried out by silica gel column chromatographic and Toyopearl HW-40F. Compounds were identified and elucidated by spectral and chemical methods. RESULTS: Seven compounds were obtained from ethyl acetate extract fraction. Their structures were identified as lupeol (1), oleanolic acid (2), uvalo(3), beta-sitosterol (4), colonic acid (5), demethylcryptojaponol (6), coleolic acid (7). Compounds 1, 2, 6, 7 showed obviously antitumor activity. CONCLUSION: Compound 1 and 3 are isolated from the genus for the first time. Moreover, compound 1 is firstly found to have antitumor activity from the plants. PMID- 21823452 TI - [Studies on the chemical constituents of Ligusticum sinense]. AB - OBJECTIVE: To study the chemical constituents of Ligusticum sinense. METHODS: The chemical constituents were isolated and purified by column chromatography on silica gel and Sephadex LH-20; Using spectroscopy methods to elucidate their structures. RESULTS: Nine compounds were isolated and identified as levistolide A (1), (Z)-3-butylidene-7-hydroxyphthalide (2), senkyunolide B (3), 3 butylphthalide(4), (Z)-ligustilide (5), riligustilide (6), neocnidilide (7), senkyunolide A (8), beta-sitostesol (9). CONCLUSION: Compounds 2 and 3 are obtained from this plant for the first time. PMID- 21823453 TI - [Studies on the chemical constituents of Ardisia tenera]. AB - OBJECTIVE: To investigate the chemical constituents of Ardisia tenera Mez. METHODS: Compounds were isolated by normal phase silica gel, MCI GEL and Sephadex LH-20 gel column chromatography. Their structures were elucidated by analyses of spectroscopic data. RESULTS: Eight compounds were isolated, and their structures were elucidated as bauerenol (I), myristic acid (II), 11-phenyl-1-(2',6' dihydroxy-4'-methoxy-phenyl)-undecan-1 -one (III), ardisinone A( IV), ardisinone B( V ), ardisinone C( VI), ardisinone F (VI), beta-sitosterol (VIII). CONCLUSION: All of these compounds are obtained from this plant for the first time. PMID- 21823454 TI - [Studies on the diterpenoids of Wedelia prostrata]. AB - OBJECTIVE: To study the chemical constituents of Wedelia prostrata. METHODS: Chromatography and spectroscopic analysis were employed to isolate and elucidate the chemical constituents in the plant. RESULTS: Seven compounds were obtained and identified as ent-kaur-16-en-19-oic acid (I), ent-kaur-16alpha, 17-dihydroxy 19-oic acid (II), ent-kaur-15alpha-senecioyloxy-16-en-19-oic acid (III), beta sitosterol (IV), stigmasterol (V), stigmasterol-3-O-beta-D-glucopyranoside (VI) and n-hexacosanol (VII). CONCLUSION: Compounds I-III are isolated from this plant for the first time. PMID- 21823455 TI - [Study on the chemical constituents from Melicope ptelefolia]. AB - OBJECTIVE: To study the chemical constituents from Melicope ptelefolia. METHODS: Several chromatographic methods were applied to isolate and purify compounds. Their structures were identified on the basis of physicochemical properties and spectroscopic data. RESULTS: Seven compounds were isolated and elucidated as n octadecanyl palmitate (I), beta-sitosterol (II), palmitic acid (III), 3, 5,3' trihydroxy-8,4'-dimethoxy-7-(3-methylbut-2-enyloxy) flavone (IV), daucosterol (V), salylic acid (VI), kaempferol-3-O-alpha-D-arabinpyranoside (VII). CONCLUSION: Compound VII is isolated from the genus for the first time, Compounds V and VI are isolated from Melicope ptelefolia for the first time. PMID- 21823456 TI - [Studies on the chemical constituents of Paris bashanensis]. AB - OBJECTIVE: Study the chemical constituents of the rhizomes of Paris bashanensis to search after the alternative resourc for the Chinese medicinal material Rhizoma Paridis. METHODS: The n-BuOH extracts of P. bashanensis was applied to silica gel column and eluted with EtOAc-EtOH,then the gained fractions were further purified by chromatography on Sephadex LH-20 column and PreRP-HPLC to give pure compounds whose structures were elucidated mainly on the basis of analyzing the spectral data of MS,1H-NMR, 13C-NMR,2D-NMR. RESULTS: Five compounds were isolated and identified as P-ecdysone (1), pinnatasterone(2), pennogenin-3-0 alpha-L-rhamnopyranosyl (1-->2)-[alpha-L-arabinofuranosyl ( 1- -4) ] -pf-D glycopyranoside (3), diosgenin-3-O-alpha-L-rhamnopyranosyl (1-->2) - [ a-L arabinofuranosyl (1-->4)]-beta-D-glycopyranoside(4), pennogenin-3-O-alpha-L rhamnopyranosyl (1-->4) -a-L-rhamnopyranosyl (1-4)-[alpha-L-rhamnopyranosyl (1- >2)]-beta-D-glycopyranoside (5). CONCLUSION: Compound 1-5 are obtained from this plant for the first time. PMID- 21823457 TI - [Analysis of the chemical constituents of essential oil from Anaphalis aureopunctata by GC-MS]. AB - OBJECTIVE: The chemical components of essential oil from Anaphalis aureopunctata were analyzed by GC-MS. METHODS: Essential oil was extracted by stem distillation (SD). The chemical components of essential oil were analyzed by GC-MS. RESULTS: The main components in the oil were Eudesma-4(14), 11-diene, alpha Bisabolol,6,10,14-trimethyl- 2-Pentadecanone,Caryophyllene oxide,alpha-Selinene and so on. CONCLUSION: This is the first time to adopt GC-MS to analyze the chemical components of volatile oil of Anaphalis au-reopunctata, and this study can provide science basis for further research development of Anaphalis aureopunctata. PMID- 21823458 TI - [Effects and mechanism of Plastrum testudinis extracts on PC12 apoptosis]. AB - OBJECTIVE: To observe the inhibitive effects of Plastrum testudinis Extracts (PTE) on 6-Hydroxydopamine (6-OHDA) induced PC12 cells apoptosis and explore its mechanism. METHODS: PC12 apoptosis model was established by serum starvation and damaged for 24 hours. The cells were randomly divided into four groups:control group, 6-OHDA group, PTE 3, 30 microg/mL group. Cell optical density was determined by MTT; Ratio of cell apoptosis was examined by Annexin V/PI double stain flow cytometry (FCM), and Western blot was applied to detect the BCL-X/L expression. RESULTS: MTT and FCM analysis demonstrated that PTE can elevate PC12 cells viability and reduce their apoptotic ratio in a dose dependent manner. Western blot showed that PTE promoted the expression of BCL-X/L. CONCLUSION: PTE can inhibit the apoptosis of PC12 induced by 6-OHDA in a dose dependent manner, and its mechanism maybe associated partially with up-regulating BCL-X/L signaling pathway. PMID- 21823459 TI - [Effect of isopsoralen on the proliferation and differentiate of osteoblasts in vitro]. AB - OBJECTIVE: To investigate the effect of isopsoralen on proliferation, osteogenic differentiation and calcification capacity of rat calvarial osteoblasts (ROB). METHODS: Segregated neonatal SD rat skull,and digestion with enzyme to obtain bone cells and cultured in MEM containing 10% FBS. Exchange the medium after three days, proceeded serial subcultivation when cells covered with 90% culture dish. Proliferation analysis was performed in 96-well plates use MTT method, isopsoralen's final concentration were 1 x 10(-4), 1 x10(-5), 1 x 10(-6), 1 x 10( 7) mmol/L. Differentiation analysis was performed in 24-well plates, the Alkaline phosphatase activity and calcium salt sediment yield and osteocalcin measured at the 4th, 8th, 12th, 16th day. At 12th day, proceeded ALP stain, and at 14th day for alizarin red staining and calcified nodule count. RESULTS: When the Isopsoralen's final concentration was 1 x 10(-5) mmol/L, there was no significant effect on the ROB's proliferation, but it could promote osteogenesis. It also could raise the ALP activity and calcium salt sediment yield and osteocalcin, increase calcified tubercle amount. CONCLUSION: When the isopsoralen final concentration is 1 x 10(-5) mmol/L, it promoted ROB differentiation and maturation. Isopsoralen may be the active ingredients of preventing anti osteoporosis in Psoralea corylifolia. PMID- 21823460 TI - [Determination of cinnamic acid and glycyrrhizic acid in rat serum and its pharmacokinetics after oral administration of Dangguisini decoction]. AB - OBJECTIVE: To mensurate concentrations and pharmacokinetics of cinnamic acid and glycyrrhizic acid in rats after oral adiministration Dangguisini decoction. METHODS: To Determine serum concentration of cinnamic acid and glycyrrhizic acid by High-Performance Liquid Chromatography and calculate its parameter of pharmacokinetics in rats after oral administration of Dangguisini decoction via 3P97 software. RESULTS: Parameters of Pharmacokinetics of cinnamic acid and glycyrrhizic acid were Cmax 9.2008 (mg/L), AUC 304.0734 (mg/L) x min and Cmax 51.1330(mg/L), AUC 21476.9688 (mg/L) x min respectively in rats after oral administration of Dangguisini decoction. CONCLUSION: Absorption of cinnamic acid is quick and its metabolize is quick too, but metabolism of glycyrrhizic acid is oppositely slow in rats after oral administration of Dangguisini decoction. PMID- 21823461 TI - [Effects and mechanism of berberine on the hypertensive renal injury rats induced by enriched high fat-salt-fructose diet]. AB - OBJECTIVE: To study the effects of berberine on hypertensive renal injury model in rats fed by enriched high fat-salt-fructose diet . METHODS: hypertensive renal injury model was esteblished by feeding enriched high fat-salt-fructose diet for 8 weeks. On the basis of animal blood pressure, hypertensive rats were randomly divided into model group (10 rats, distilled water), captopril group (10 rats,25 mg/kg), berberine high dose group (10 rats, 300 mg/kg) and low dose group (10 rats, 100 mg/kg). These rats were fed by enriched high fat-salt-fructose diet and treated by intragastric administration with drugs for 4 weeks. And normal control group (10 rats) was set Blood pressure was determined at 0, 4, 8, 10, 12 weekend,and after 4 weeks of drugs treatment, getting urine to determine urine protein, taking blood serum to determine blood urea nitrogen, serum creatinine,GHb,MDA and activity of SOD. The content of H2O2 and GSH-Px and activity of CAT in kidney tissues were determined also. RESULTS: Compared with normal control group, blood pressure, urine protein, blood urea nitrogen, serum creatinine and MDA and GHb in serum of model rats obviously increased (P < 0.01), the activity of SOD decreased (P < 0.01), higher content of H2O2 and lower content of GSH-Px and activity of CAT (P < 0.01) in the kidney tissues. Treated with berberine for 4 weeks, elevated blood pressure and heightened levels of urine protein, blood urea nitrogen and serum creatinine in model rats were depressed significantly (P < 0.01), and elevated the activity of SOD, lowed the levels of MDA and GHb in blood serum (P < 0.01). At the same time, berberine increased the activities of GSH-Px and CAT (P < 0.01) and slightly lowed the content of H2O2 in the kidney tissues. CONCLUSION: Berberine has protecting effects on the hypertensive renal impairment model rats fed by enriched high fat salt-fructose diet, which are concerned with elevated antioxidant capability in body and kidney tissues. PMID- 21823462 TI - [Study on the ultraviolet protective effects of the cream of the total flavonoids from Oxytropis falcata]. AB - OBJECTIVE: To study the protective effects of the cream of the total flavonoids from Oxytropis falcata on the destructed skin of mice induced by moderate-wave ultraviolet (UVB) irradiation. METHODS: Dorsal skin of Wistar mice were treated with the cream of the total flavonoids from Oxytropis falcata and then irradiated with UVB in the dosage of 5 min once a day for one week. The tissue of skin was pathological diagnosed and the activities or contents of superoxide dismutase (SOD), malondialdehyde (MDA), hydroxyproline (Hyp), glutathione peroxidease (GSH Px), glutathione (GSH), glutathion-s-transferase (GST), catalase (CAT) and hydroxy radical (*OH) were determined with chromatometry. RESULTS: The ultraviolet protective effects of the cream could be observed with appearance and pathology examine. The cream could increase the activities of SOD (P < 0.001), GSH-Px (P < 0.001), GST (P < 0.05) and CAT (P < 0.01), raise the content of Hyp (P < 0.001) significantly. The cream could also decrease the contents of MDA and *OH (P < 0.001), and the activities of GSH significantly (P < 0.001). CONCLUSION: The cream of the total flavonoids from Oxytropis falcata has protective effect on the destructed skin of mice induced by moderate-wave ultraviolet (UVB) irradiation. PMID- 21823463 TI - [Study on molecular recognition technology in active constituents extracted and isolated from Aconitum pendulum]. AB - OBJECTIVE: To investigate CD molecular recognition technology applied in active constituents extracted and isolated from traditional Chinese medicine--Aconitum pendulum. METHODS: The inclusion constant and form probability of the inclusion complex of Aconitum pendulum with p-CD was calculated by UV spectra method. The active constituents of Aconitum pendulum were extracted and isolated by molecular recognition technology. The inclusion complex was identified by UV. The chemical constituents of Aconitum pendulum and inclusion complex was determined by HPLC. The analgesic effects of inclusion complex was investigated by experiment of intraperitoneal injection of acetic acid in rats. RESULTS: The inclusion complex was identified and confirmed by UV spectra method, the chemical components of inclusion complex were simple, and the content of active constituents increased significantly, the analgesic effects of inclusion complex was well. CONCLUSION: The molecular recognition technology can be used for extracting and isolating active constituents of Aconitum pendulum, and the effects are obvious. PMID- 21823464 TI - [Study on extraction and purification techniques and free radical scavenging activity of total flavonoids from Fissistigma oldhamii]. AB - OBJECTIVE: To optimize the extraction and purification techniques of total flavonoids in Fissistigma oldhamii. The scavenging activity to DPPH of the total flavonoids and the extraction were studied in vitro. METHODS: By orthogonal design, we investigated the effects of concentration of ethanol, temperature, ratio of solid to liquid and time of extraction on the total flavonoids extraction rate. The total flavonoids was separated and purified by AB-8 macroporous resin absorption. RESULTS: The optimum extraction condition was that at extraction time of 3 h, concentration of alcohol 90%, solid/liquid ratio of 1:10 and temperature of 70 degrees C. The content of total flavonoids in the refined product was above 55%. The GFM-2 fraction showed antioxidant capacity in vitro. CONCLUSION: The optimum extraction condition and purification experiment are very useful for further development of industrial process. Meantime, the result may be helpful for further development of Fissistigma oldhamii as health protection foods. PMID- 21823465 TI - [Effect of separation and purification processes on extraction ratio of polysaccharides in Rabdosia rubescens and immunocompetence]. AB - OBJECTIVE: To select a good method for purifying polysaccharides from Rabdosia rubescens, and study their immunological activity. METHODS: DEAE-Sepharose Fast Flow (Cl-) weak polar anion-exchange chromatography and stepwise ethanol precipitation were used to isolate and purify the polysaccharides from Rabdosia rubescens, respectively. MTT method was used to evaluate the immune activity. RESULTS: Five components were obtained from DEAE-Sepharose Fast Flow (Cl-) weak polar anion-exchange chromatography and four polysaccharides were obtained through alcohol precipitation. CONCLUSION: Polysaccharides from Rabdosia rubescens by stepwise ethanol precipitation show stronger immunological activity. Their immunomodulatory effect and related mechanism will be researched further. PMID- 21823466 TI - [Study on optimization of formulation of Danggui Liuhuang effervescent granules]. AB - OBJECTIVE: To optimize the formulation of Danggui Liuhuang effervescent granules. METHODS: By means of quadratic regression rotation-orthogonal combination design, the effect of the proper proportion between citric acid and sodium bicarbonate, as well as the proper quantity of polyethylene glycol 6000 and sodium cyclamate on the dissolubility and pH of effervescent granules was studied. RESULTS: The best formulation was as follows: citric acid: sodium bicarbonate = 0.75: 1, the percentage of polyethylene glycol 6000 and cyclamate was 3.25% and 0.89%, respectively. CONCLUSION: The dissolubility and pH of the effervescent granules are better and the taste is satisfactory. PMID- 21823467 TI - [Dispersion behavior of effective ingredients in Chinese medicine decoctions]. AB - OBJECTIVE: To research the disperse behavior of many Chinese medicine decoctions. METHODS: Through the analysis of the dispersible attributes of 22 kinds of Chinese medicine decoctions including Radix Salviae Miltiorrhizae by means of turbidity, ultramicroscope and TEM, we found that a lot of nanometer particles existed in these decoctions after 4000 r/min centrifugation. Based on the model of Radix Salviae Miltiorrhizae, we analyzed the influence on the loss of effective ingredients by way of centrifugation, alcohol precipitation, flocculation and salting-out edulcoration. RESULTS: The removal of infinite nanometer particles from these decoctions led to the greater loss of water soluble and fat-soluble ingredients,and the latter accounts for the major loss. CONCLUSION: Oral liquid preparation of traditional Chinese medicine is a kind of nano-pharmaceutics with nanometer particles dispersed in the water as the carriers of effective ingredients in medicine. PMID- 21823468 TI - [Molecular identification of geminivirus inducing vein yellowing in Abelmoschus manihot]. AB - OBJECTIVE: The virus isolate H was identified by molecular biology,it was collected from Abelmoschus manihot plant showing leaf curl,yellow vein symptoms in Guangxi Botanical Garden of Medicinal Plant. METHODS: The virus isolate H was observed in electron micrograph, and conformed detected by PCR using universal primer pair for the genus Geminivirus. RESULTS: The results indicated that all sequences homologous to the specific fragment belonged to the genus Begomovirus of the family Geminiviridae. There was the highest similarity shared 95% homology at nucleotide between the specific fragment and DNA-A of Emilia yellow vein virus isolates. CONCLUSION: These findings suggested that there was geminiviridea in Abelmoschus manihot, and the disease probably caused by Emilia yellow vein virus. PMID- 21823469 TI - [Effects of "3414" fertilizer application on the yield of Fagopyrum cymosum]. AB - OBJECTIVE: To study the effects of different fertilizer applications on the yield of Fagopyrum cymosum and explore the hese scheme for getting the maximum yield on purple soil in the Chongqing-west. METHODS: Experiment with implementing plan of "3414"; The quality Assessment by the contents of bipoly-chrysanthemin; The data process program under the Excel 2003, SPSS 13.0, MatlaB 7.0, Word 2003 environments. RESULTS: Various fertilizer combinations had different transformation efficiency which the N3P2K2 combination was the maximum 97.09% and the NOP2K2 combination was the minimum 4.32%; The NOP2K2 combination had the lowest yield except of the bland group which was 186 kg/667 m2; When the N fertilizer Rate was controlled in the level of 15 kg/667 m2 The yied had no obvious change as the increase of another two kinds fertilizer rate; Three kinds of function could better reflect the relationships between fertilizer and yields, which all of the R2 value were above 0.88; The best one was N K function with the maximum R2; The blank group had maximum content 8.67% of bipoly-chrysanthemin and the content had a little decrease as the increase of N or K, but all higher than 7.14% which were planted in Bei Jing area. CONCLUSIONS: Various fertilizer combinations influenced the transformation efficiency of N, P, K;N is the key fertilizer on purple soil; Reconmentation funtion was N,K function which could be as the guiding function; F; Fertilizer would not influence the quality of Fagopyrum cymosum. PMID- 21823470 TI - [Sterols of marine bryozoan Bugula neritina from the South China Sea]. AB - OBJECTIVE: To study the sterol constituents of Bugula neritina from the South China Sea. METHODS: The alcohol extract of Bugula neritina was purified by silica gel column and Sephadex LH-20 column chromatography, and structures of the isolated compounds were identified by spectroscopic analysis and comparison with those of literatures. RESULTS: Ten sterols were isolated and identified from the petroleum ether fraction of alcohol extract of B. neritina L.:Cholest-4-en-3 one(I); cholesterol(II);3beta,5alpha,9alpha-trihydroxy-(22E,24R)-ergosta-7,22 dien-6-one(III); 24-methyl-5alpha-cholesta-7,22-diene-3beta,5,6beta-triol(IV); 3beta-Hydroxy-7-methoxy-Cholesta-5-en(V);5alpha, 8alpha-epidioxy-(22E,24R) ergosta-6, 22-dien-3beta-ol(VI); 3beta-hydroxycholest-5-en-7-one (VII); and 6beta hydroxy-cholest-4-en-3-one(VIII); Cholesta-5-ene-3beta,7beta-diol(IX); Cholesta 5,22(E)-dien-3beta,7alpha-diol(X). CONCLUSION: Compounds IV-X were isolated from Bugula neritina for the first time. PMID- 21823471 TI - [Study on the production of alkaloid by cell mass suspension culture of Fritillaria cirrhosa]. AB - OBJECTIVE: Set up Fritillaria cirrhosa cell mass suspension culture system to rapidly screen the best culture conditions for cell mass proliferation and hormone combination. METHODS: Using MS medium as the basic medium, the impact of inoculum size, hormone combination, growth regulators for Fritillaria cirrhosa cell mass suspension culture were compared, and also the growth of cell mass at different culture conditions was compared, and the total alkaloids content in proliferative cell mass was measured. RESULTS AND CONCLUSION: Fritillaria cirrhosa grow significantly faster in cell mass suspension culture than in the solid culture. The total alkaloid content in cell mass is higher than commercial and wild bulb of Fritillaria cirrhosa. The optimal inoculum size for cell mass suspension culture is 30 g/L and the optimal culture media is MS +6-BA 2.0 mg/L + NAA 0.2 mg/L. PMID- 21823472 TI - [Determination of ergosterol in Ganoderma lucidum from different varieties and cultured tree species by HPLC]. AB - OBJECTIVE: HPLC method for determining ergosterol was established to evaluate the quality of Ganoderma lucidum and to analyze of the ergosterol in different varieties and cultrued tree species. METHODS: Samples from 17 different varieties and 14 different tree species were quantified by HPLC. The RP-HPLC was conducted on Diamonsil C18 column with acetonitrile as the mobile phase at 40 degrees C. The flow rate was 1.0 mL/min; and the detection wavelength was 282 nm. RESULTS: The fluctuations of ergosterol content was 0.093%-0.243% among different varieties and 0.080%-0.227% among different tree species. Hanzhi-2, Yuanzhi, Ming 1, Yesheng-1 hao were excellent at both ergosterol content and conversion rate among all the varieties, and Bai Li, Yang Mei have comparatively more ergosterol and high conversion rate among all the tree species in this study. CONCLUSIONS: This method is simple, sensitive and accurate. It could be used to determine the contents of ergosterol and the evaluation of the quality in Ganoderma. It also provides references for choosing varieties and tree species when culture Ganoderma. PMID- 21823473 TI - [HPLC fingerprint of Pericarpium Citri Reticultae from Guangdong province]. AB - OBJECTIVE: To establish chromatographic fingerprint of Pericarpium Citri Reticultae from Guangdong province by HPLC and comparison of citrus herbs similarity with different strains and different origin, it was expected to fix standard of quality control. METHODS: 26 samples' analysis was performed on Diamonsil C18 column (250 mm x 4.6 mm, 5 microm) with gradient mobile phase of acetonitrile-1% acetic acid,fingerprint was finished in 65 min, the monitoring wavelength was at 330 nm with the flow rate of 1.0 mL/min. RESULTS: Establishing the fingerprint of Pericarpium Citri Reticultae from Guangdong province, 17 common peaks were found in the HPLC fingerprints from different sources, the similarity of Pericarpium Citri Reticultae from Guangdong province above 0.975 and quite different for different origin drugs. CONCLUSION: This method is simple, accurate with good reproducibility, and can be used specifically for the quality control of Pericarpium Citri Reticultae from Guangdong province. PMID- 21823474 TI - [Optimization of processing technology for semen cuscuta by uniform and regression analysis]. AB - OBJECTIVE: To optimize the best preparation technology for the contains of total flavornoids, polysaccharides, the percentage of water and alcohol-soluble components in Semen Cuscuta herb processing. METHODS: UV-spectrophotometry was applied to determine the contains of total flavornoids and polysaccharides, which were extracted from Semen Cuscuta. And the processing was optimized by the way of uniform design and contour map. RESULTS: The best preparation technology was satisfied with some conditions as follows: baking temperature 150 degrees C, baking time 140 seconds. CONCLUSION: The regression models are notable and reasonable, which can forecast results precisely. PMID- 21823475 TI - [FTIR fingerprints-chemical pattern recognition research of three kinds of Chimonanthus and fried samples]. AB - OBJECTIVE: To classify the leaves of Chimonanthus nitens, Chimonanthus Salicifolius, Chimonanthus zhejiang and their fried samples, Discriminating equation was established to distinguish categories of raw materials. METHODS: The spectra of three kinds of Chimonanthus and fried samples were determined by FTIR. Principal component analysis, clustering analysis and discriminative analysis were applied to classify three kinds of Chimonanthus leaves and fried samples from different areas according to the relative absorbance of common peaks between 400 to 4000 cm(-1). RESULTS: 26 samples were divided into four classes, the discriminating accuracy was 96%. CONCLUSION: The method is rapid, simple and could be applied to evaluate the quality of Chimonanthus leaves without damaging to sample, and it is easy to identify the adulteration. PMID- 21823476 TI - [Studies on the chemical constituents from stems and leaves of Lonicera macranthoides]. AB - OBJECTIVE: To research the chemical constituents from stems and leaves of Lonicera macranthoides. METHODS: Various column chromatographies were employed to isolate and purify the constituents. Their structures were elucidated by spectral analysis (IR, MS, 1H-NMR, 13 C-NMR) and chemical evidence. RESULTS: Nine constituents were obtained and identified as loganin (I), loganic acid (II), morroniside (III),7-O-ethyl-morroniside (IV), scopoletin (V), caffeic acid (VI), chlorogenic acid (VII), beta-sitosterol (VIII), daucosterol (IX). CONCLUSION: Compounds I-VI are isolated from the plant for the first time. All the compounds are found for the first time from the stems and leaves of Lonicera macranthoides. PMID- 21823477 TI - [Study on the chemical constituents of endophytic fungus Fimetariella rabenhorstii isolated from Aquilaria sinensis]. AB - OBJECTIVE: To study the chemical constituents of endophytic fungus Fimetariella rabenhorsti isolated from Aquilaria sinensis. METHODS: Chemical constituents of the fungus were isolated and purified by column chromatography and their structures were elucidated on the basis of spectral data. RESULTS: Five compounds were isolated and identified as 4-hydroxy-phenylethyl alcohol (1),nicotinic acid (2), D-galacitol(3), 2-anilino-1,4-naphthoquinone (4), N-phenylacetamide (5). CONCLUSION: Compounds 1-5 are isolated from the genus Fimetariella for the first time, compound 5 is rare in natural products. PMID- 21823478 TI - [Studies on the chemical constituents of Laportea bulbifera]. AB - OBJECTIVE: To study the chemical constituents of Laportea bulbifera. METHODS: 70% EtOH was used for constituent extraction, silica gel column chromatography for constituent seperation, physical and chemical properties together with spectroscopic methods for chemical structure identification. RESULTS: six compounds were obtained from root of L. bulbifera. Their chemical structures were elucidated as p3-sitosterol(1) , P-daucosterol (2), 2,2'-oxy-bis(1-phenylethanol (3), 1-(2-phenylcarbonyloxy acetyl) benzene (4) , methyl linoleate(5),1,4 diphenyl-1,4-butanedione(6). CONCLUSION: All compounds are isolated from L. bulbifera and among compounds 3 and 4 are reported as natural products for the first time. PMID- 21823479 TI - [Studies on the chemical constituents in fruits of Acanthopanax gracilistylus]. AB - OBJECTIVE: To study the chemical constituents in the fruits of Acanthopanax gracilistylus. METHODS: The chemical components were isolated and purified by silica gel, ODS C-18, and Sephadex LH-20 column chromatogram. The chemical structures were elucidated on the basis of physicochemical properties and spectral data. RESULTS: Ten compounds were isolated and identified as acankoreoside D(1), 3alpha, 11alpha-dihydroxylup-20(29)-en-28-oic acid(2), 3/3 ([O-beta-D-glucopyranuronosyl] oxy) -olean-12-ene-28-olc acid (3),3beta-([O-beta D-glucopyranuronosyl]oxy)-28-O-P3-D-glucopyranosyl-olean-12-ene-28-olc acid(4),oleanolic acid-3-O-6'-O-methyl-beta-D-glucuronopyranoside(5), acantrifoside A(6), acankoreoside A(7), (-)-kaur-16-en-19-oic acid(8), protocatechuic acid (9),beta-sitosterol(10). CONCLUSION: Compounds 2-5 are obtained from the fruits of the plant for the first time. PMID- 21823480 TI - [Studies on the chemical constituents of Salsola collina]. AB - OBJECTIVE: To study the chemical constituents of Salsola collina. METHODS: The compounds were isolated by column chromatography, and their structures were identified by physical and chemical properties and spectral data. RESULTS: Seven compounds were isolated and identified as n-lignoceric acid (1), n-dotriacontanic acid (2), beta-sitosterol (3), 5, 2'-dihydroxy-6, 7-methylenedioxy-isoflavone (4), vanillic acid (5), (-)syringaresinol 4,4'-bis-O-beta-D-glucopyranoside (6), salicylic acid (7). CONCLUSION: The compounds of 1, 2, 4, 5 and 6 are isolated from the plant for the first time. PMID- 21823481 TI - [Studies on the chemical constituents from the leave of Paulownia tomentosa]. AB - OBJECTIVE: To study the chemical constituents of the leave of Paulownia tomentosa. METHODS: The constituents were isolated by column chromatography and their structures were elucidated through spectroscopic analysis. RESULTS: The compounds were identified as apigenin(I), uteolin(II), homoeriodictyol(III), 3alpha-hydroxyurs-12-en-28-oic acid (IV),3beta,19alpha-dihydroxyurs-12en-28-oic acid (pomolic acid)(V),2alpha,3a-dihydroxyurs-12-en-28-oic acid(VI),ursolic acid (VII),2alpha,3beta-dihydroxyolean-12-en-28-oic acid (maslinic acid) (VIII), daucosterol(IX),beta-sitosterol(X). CONCLUSION: The compound I-X are obtained from the leave of Paulownia tomentosa (Thunb.) Steud for the first time. PMID- 21823482 TI - [Studies on the chemical constituents of Artemisia lavandulaefolia]. AB - OBJECTIVE: To investigate the chemical constituents from aerial part of Aremisia lavandulaefolia. METHODS: Compounds were isolated by using silicagel, Sephadex LH 20 chromatography and their structures were elucidated by means of spectral data analysiy. RESULTS: Eight compounds were isolated and identifies as P-amyrin(1), P sitosterol(2), ursolic acid(3), erpatilin(4), naringenin(5), apigenin(6), luteolin(7), quercetin(8). CONCLUSION: All these compounds are isolated from this plant for the first time. PMID- 21823483 TI - [Influence of scutellarin on oxidative stress and neuronal apoptosis of rats with dementia]. AB - OBJECTIVE: To investigate the influence of Scutellarin on the oxidative stress and neuronal apoptosis in rats with dementia and to reveal therapeutic mechanism of the drug to Alzheimer's disease. METHODS: Wistar rats were randomly divided into 5 groups: normal control group, sham group, model group,scutellarin group and positive control group. The animal model with dementia was by bilateral ventricle injection with beta-amyloid peptide (AP) 25-35 and intraperitoneal injection with D-galactose. Learning and memory ability of rats were detected by Morris Water Maze test; Histopathology of the cerebral cortex and hippocampus were observed under light microscope; Changes of Nissl's body in the hippocampus were survey by Nissl staining; The activities of SOD and MAO were detected by xanthinoxidase method and chemical method, respectively, and neuronal apoptosis was measured using flow cytometry. RESULTS: Compared with control group and sham group, the ability of learning and memory of the rats in model group was decreased; Neuropathological changes were observed in the hippocampus; The activity of SOD was decreased while the activity of MAO increased in brain tissues; Neuronal apoptosis percentage was increased. After treated with Scutellarin, learning and memory ability of rats with dementia was improved; The pathologic changes were alleviated; The activity of SOD was up-regulation and the activity of MAO was decreased; Neuronal apoptosis percentage was declined. No significant difference between the scutellarin group and positive drug control group was found. CONCLUSION: Scutellarin might play an therapeutic role by inhibiting oxidative stress and apoptosis in AD treatment. PMID- 21823484 TI - [In vitro study on the anti-HSV-1 and HBV activities of extracts from the fruit of Eucalyptus maidenii]. AB - OBJECTIVE: To investigate the antiviral activities of three kinds of extracts from the fruit of Eucalyptus maidenii against herpes simplex virus typel and Hepatitis B Virus. METHODS: Cytotoxicity of extracts on Vero cell lines were estimated using MTT method and anti-HSV-1 activity was observed and determined with CPE and plaque reduction assay. The inhibitory effects of extracts on HBsAg and HBeAg secretion in HepG2.2.15 cell culture were detected using ELISA. RESULTS: Aqueous extract (pl8-E3) had conspicuous anti-HSV-1 activity, the IC50 was 126.77 microg/mL,but the EtOAc extracts( pl8-E1 )and MeOH extracts (pl8-E2) showed little anti-HSV-1 activity. None of these extracts had significant inhibitory eflect on HBsAg and HBeAg secretion in HepG2.2.15 cell culture. CONCLUSION: Aqueous extract(p18-E3) from the fruit of Eucalyptus maidenii has conspicuous anti-HSV-1 activity. It could inactivate virus directly,and inhibit virus attachment,but had no influence on virus penetration. The mechanism that p18-E3 inactivates virus might involve in viral envelope alteration. PMID- 21823485 TI - [Study of galic acid extracted from the leaves of Phyllanthus emblica on apoptotic mechanism of human hepatocellular carcinoma cells BEL-7404]. AB - OBJECTIVE: To explore the mechanism of apoptosis of human hepatocellular carcinoma cells BEL-7404 induced by Galic acid extracted from leaves of Phyllanthus emblica. METHODS: PI/Hoechst33342 double staining method was utilized to observe the influence on cell life cycle. The expressions of Bax and Bcl-2 protein were determined by fluorescence immunostaining and Western blot. RESULTS: The results from PI/Hoechst33342 double staining method indicated that the percentage of cells G2/M phases increased after treated for 72 h, the phenomenon of blockage appeared and cell death was induced. Fluorescence immunostaining showed that the expression of Bax was up-regulated, and the expression of Bcl-2 was down-regulated. Western blot also showed that the the expression of Bax was up-regulated. CONCLUSION: The mechanism of human hepatoma BEL-7404 cells apoptosis induced by Galic acid from leaves of Phyllanthus emblica may be blocking G2/M period in cell life cycle, up-regulating the expression of Bax and down-regulating the expression of Bcl-2, that can decrease membrane potential of mitochondria,and triggered the caspases of activation of cascade and induced cell death. PMID- 21823486 TI - [Study on the effects of hematopoiesis of anemic mice after marrow-suppressed treated by tonifying kidney, invigorating spleen, and removing blood stasis]. AB - OBJECTIVE: To observe the effects of tonifying kidney,tonifying spleen,invigorating the circulation of blood on the expression of hematopooietic cytokines of bone marrow suppression induced by chemotherapy. METHODS: Automated blood analyzer was used to detect the level of RBC and HGB, 14th and 28 days, while real time quantitative RT-PCR was used to detect EPO, EPOR mRNA expression. RESULTS: Liuwei Dihuang Tang, Buzhong Yiqi Tang and Compound Danshen Decoction group could increase the level of RBC and HGB significantly. Liuwei Dihuang Tang and Buzhong Yiqi Tang groups could increase the mRNA expression level of EPO and EPOR significantly. However, there was no significantly difference when Compound Danshen Decoction group compared with control group on EPO, EPOR mRNA expression level. CONCLUSION: The tonifying kidney, tonifying spleen, invigorate the circulation of blood are stable and reliable as to enhance the role of peripheral blood; tonifying kidney, tonifying spleen can improve EPO, EPOR mRNA expression levels, and promote the proliferation of bone marrow hematopoietic stem cells, and promote the differentiation of erythroid blood cells to increase red blood cell line; And invigorate the circulation of blood promote hematopoietic mechanisms have to be further studied. PMID- 21823487 TI - [Study on the toxic reaction induced by single dose of qingkailing injection]. AB - OBJECTIVE: To study the toxic reaction induced by Qingkailing Injection. METHODS: Kunming mice were injected single dose of Qingkailing Injection via tail vein and observed for 14 days to test the toxic reaction of the drug. According to Chinese Pharmacopoeia, hemolysis tests were conducted on the injections of different lots and each ingredient of the injection. RESULTS: Toxic reaction induced by single dose of injection--with dose increasing,mice quickly showed different responses such as hypodynamia, convulsion, syncope and even death after injection. In the high dose group, blood routine detection showed that mice have lower counts of RBC, WBC and lower content of hemoglobin; The pulmonary pathological sections of dead mice showed significant hyperemia. And there were no significant difference in the contents of serum electrolyte (K+, Na+, Ca2+) between normal saline control group and Qingkailing injection group. Hemolysis test in vitro- Honeysuckle extraction (significantly) and gardenia extraction which were components of Qing-kailing injection caused hemolysis in certain dose; While gardenia, pearl shell and isatis root extraction caused RBC agglutination. With higher concentration, the Qingkailing injections of different lot caused different degree of hemolysis. There was no significant difference in the hemolysis test in vitro between the group of Balb/C mice which were sensitized by Qingkailing injection or not. CONCLUSION: In clinical practice some adverse reactions induced by Qingkailing injection occurred concomitantly with acute hemolysis within vessels, which might be caused by honeysuckle and gardenia. And the hemolysis was independent of allergy. PMID- 21823488 TI - [Study on intra-gastric floating beads of naringenin]. AB - OBJECTIVE: To prepare calcium alginate-chitosan intra-gastric floating beads of naringenin combining with the solid dispersion method and investigate the in vitro floating characteristics, entrapment efficiency and drug release property of the beads. METHODS: The solid dispersion of naringenin was prepared by the Eudragit RLPO. Sodium alginate solution mixed with the powder of the solid dispersion of naringenin and frother was slowly dripped into chitosan-calcium chloride solution added with acetic acid. Calcium alginatechitosan intra-gastric floating beads of naringenin were obtained after drying. The effects of solid dispersion on in vitro release of naringenin were investigated. RESULTS: Intra gastric floating beads of naringenin were acquired successfully. More than 70% of the beads kept floating in artificial gastric juice in 9 h, the release ratio of naringenin during 9 h was 65%-70% and the entrapment efficiency was about 70% 80%. CONCLUSION: The sustained release of naringenin in the calcium alginate chitosan intra-gastric floating beads could be achieved by using the solid dispersion method and it provides some ideas of intra-gastric floating preparations. PMID- 21823489 TI - [Studies on optimizing preparation technics of wumeitougu oral liquid by response surface methodology]. AB - OBJECTIVE: To optimize the preparation technics of wumeitougu oral liquid (WTOL) by response surface methodology. METHODS: Based on the single-factor tests, the times of WTOL extraction, alcohol precipitation concentration and pH value were selected as three factors for box-behnken central composite design. The response surface methodology was used to optimize the parameters of the preparation. RESULTS: Under the condition of extraction time 1.5 h, extraction times 2.772, the relative density 1.12, alcohol precipitation concentration 68.704%, and pH value 5.0, he theory highest content of Asperosaponin VI was up to 549.908 mg/L. Considering the actual situation, the conditions were amended to three extract times, alcohol precipitation concentration 69%, pH value 5.0, and the content of Dipsacaceae VI saponin examined was 548.63 mg/L which was closed to the theoretical value. CONCLUSION: The optimized preparation technics of WTOL by response surface methodology is reasonable and feasible. PMID- 21823490 TI - [Comparison on extraction of volatile oils from Lithospermum erythrorhizon by different methods]. AB - OBJECTIVE: To extract the volatile oils from Lithospermum erythrorhizon via ultrasound-enhanced sub-critical water extraction (USWE) and compare with ultrasound-enhanced solvent extraction (USE) and steam distillation extraction (SD). METHODS: The extraction yield of the volatile oils, the containing components of extract, the effect of scanvenging activities on free radical DPPH and reducing activities as well as the inhibitory on escherichia coli and staphylococcus aureus were investigated. RESULTS: The extraction yield of volatile oils by USWE, USE and SD were 2.39%, 1.93% and 0.62%, respectively, the extracts by three methods all contained six major components, but the extracts by SD and USE contained more impurities. The inhibitory effect on escherichia coli and staphylococcus aureus of the extract by SD and its reducing action were the best,but those by USWE were the worst. CONCLUSION: the extraction yield of volatile oils by USWE is the highest, and it contains less impurities based on the worst in reducing power and inhibitory effects. PMID- 21823491 TI - [Study on methods of deproteinization from Phellinus baumii polysaccharide]. AB - OBJECTIVE: To study and compare different methods and influencing factors of deproteinization from Phellinus baumii polysaccharide. METHODS: Sevag method and TCA method were used to remove protein from crude polysaccharide of Phellinus baumii, respectively. RESULTS: The effect of TCA method on removing protein was superior to that of Sevag method,and the optimum conditions of removing protein with TCA were as follows: 30 min treating time, 5% trichloroacetic acid,3 times treatemt. Under these conditions the rate of protein-removed was 82% and the rate of polysaccharide-lost was 10.8%. CONCLUSION: TCA method is the optimal mean for deproteinization from Phellinus baumii polysaccharide. PMID- 21823492 TI - Bumble bee: my nemesis. PMID- 21823493 TI - Dental home needed earlier for children. PMID- 21823494 TI - Aggressive periodontitis. PMID- 21823495 TI - Aggressive periodontitis: the historic quest for understanding. AB - Aggressive periodontitis has had many names as well as theories behind its etiology. The current paper looks to investigate this history and show the evolution of both nomenclature and understanding. Going beyond academic debates, emerging trends and conventions are also examined and placed into a clinical perspective. The aim of the paper is to recognize the origins of the elusive disease in order to form a concrete understanding of this multifactorial phenomenon. PMID- 21823496 TI - Latin America: native populations affected by early onset periodontal disease. AB - Millions of individuals are affected by early onset periodontal disease in Latin America, a continent that includes more than 20 countries. The decision-makers claim that the disease is not commonly encountered. In 2009, 280,919 authorized immigrants were registered in the United States versus 5,460,000 unauthorized (2,600,000 in California). The objective of the present article is to raise awareness about the high prevalence of the disease among Latin Americans and the good prognosis of preventive measures associated with minimal financial cost. PMID- 21823497 TI - Herpesvirus periodontitis: infection beyond biofilm. AB - Herpesviruses, including Epstein-Barr virus and cytomegalovirus, occur at high copy counts in aggressive periodontitis, and may interact synergistically with periodontopathic bacteria in the etiology of the disease. Herpesvirus active periodontal infections may impair local host defenses and thus increase the aggressiveness of resident periodontopathic bacteria. The bacteria, in turn, may augment the virulence of the herpesviruses. The abundance of herpesviruses in periodontitis redefines the pathogenic paradigm of the disease and may have significant clinical implications. PMID- 21823498 TI - Dynamic therapeutic approach for individuals affected with aggressive periodontitis. AB - Management of patients affected with aggressive periodontitis is complicated by several poorly understood etiological and modifying factors that create difficulty in establishing a universal treatment recommendation. The goal of this manuscript is to underscore the complexity of therapy and to provide some guidelines in the decision-making process and interdisciplinary therapy. A dynamic approach is presented to formulate strategies in diagnosis and treatment planning that is both patient-and site-specific. PMID- 21823499 TI - Peri-implant management of patients with aggressive periodontitis. AB - Peri -implant mucositis has been a common clinical finding around implant supported restorations. More recently, several publications have documented progressive bone loss around implants. A peri-implant tissue maintenance protocol seems essential to maintain health postimplant therapy among patients affected with aggressive periodontitis. PMID- 21823500 TI - In development: jiggle and moosh to be caries foe. PMID- 21823501 TI - Team training simulation in perioperative nursing education. AB - The current traditional apprenticeship model in healthcare is no longer meeting the needs of our learners. This model requires learners to master various core skills, carry out a procedure under supervision, and relate simultaneously to other staff in the complex operating room. The approach of "see one, do one, teach one" is considered, by some, to no longer be acceptable. Perioperative nursing educators are, as a result, now faced with the challenge of finding education modalities that will facilitate the learner's journey to competence and the delivery of safe patient care. The purpose of this paper is to discuss team training simulation in the competence development of perioperative nursing learners at the Registered Nurses Professional Development Centre (RNPDC) in Halifax, Nova Scotia. PMID- 21823502 TI - PNEC perspective. PMID- 21823503 TI - Is stainless steel really "stainless"? AB - Initial purchase and replacement costs for surgical instrumentation are significant components in today's operating room budgets. OR staff and medical device reprocessing personnel work together as a team to ensure effective management of this valuable commodity. The purpose of this article is to discuss the composition of stainless steel surgical instruments, to identify processes to minimize damage to instruments caused by staining, corrosion, and pitting, and to utilize that information to describe effective measures to manage instrumentation in both the OR and reprocessing areas. PMID- 21823504 TI - [Clinical characteristics and treatment of dystonia]. AB - Dystonia is defined as a syndrome of sustained muscle contractions, frequently causing twisting and repetitive movements, or abnormal postures. Its diagnosis is based on clinical characteristics. In dystonia, the pattern of abnormal posture or movement tends to be constant during the short term even if its severity fluctuates. This stereotypy often helps differentiate dystonia from psychogenic reaction. Dystonia may appear only during some specific task (task specificity) especially in its early phase, although it often becomes obscure during the long clinical course, resulting in persistent dystonic posture. Sensory trick or geste antagoniste means the change of severity triggered by some sensory input Overflow phenomenon is the activation of muscles unnecessary to a task, hampering purposeful movement. Symptoms tend to be milder in the morning, with large individual variation of its duration (morning benefit). Symptoms of dystonia may abruptly appear or disappear (flip-flop phenomenon). Cocontraction, believed as an essential feature of dystonia, reflects a loss of reciprocal inhibition of muscle activities, causing involuntary simultaneous contractions of agonists and antagonists. "Negative dystonia," still an unaccepted feature of dystonia, is defined as non-paretic loss of central driving of muscle activities necessary to a task. Apraxia of lid opening/closure, paretic form of hand dystonia, dropped head syndrome, camptocormia, Pisa syndrome, cervical dystonia with limited range of head movement, or mandibular dystonia without cocontractions of masticatory muscles, can be explained with this concept at least in a subset of cases. Treatment of dystonia includes medication, botulinum toxin injection, intrathecal baclofen, surgical intervention, acupuncture and other alternative therapies, rehabilitation, and psychotherapy. Oral medication is usually an adjunct to more potent therapeutic options except for some specific indications like dopa responsive dystonia. Botulinum toxin is usually the treatment of choice for focal dystonia. Deep brain stimulation can be considered for both focal and non-focal phenotypes of dystonia. PMID- 21823505 TI - [Clinicoepidemiological analysis of genetic testing in 1,000 cases of hereditary neurological disorders]. AB - A total of 1,000 neurological patients were examined for genetic testings at the Department of Neurology, Okayama University, from 1992 to 2010. To investigate the role and significance of genetic testings in neurological diagnostic consultation, we divided the analysis period into two, the former period (1992 to 2000) and the latter period (2001 to 2010). The number of genetic testings was 669 cases in the former period, and 331 cases in the latter period. However, the positive rate of genetic testings was 25.3% in the former period, and 48.1% in the latter period. The reason of this remarkable rise of the positive rate in the latter period was mainly attributable to our feedback inquiry to the doctors from 2001, noticing them the total number of test in a year, positive rate with or without family history, and an encouragement to examine more clinical details of their patients. The genetic testing plays an essential role in clinical neurology. It is important that the application of genetic testing to each case should be considered more carefully and properly. PMID- 21823506 TI - [Good response to intravenous immunoglobulin therapy in sensory dominant distal variant of chronic inflammatory demyelinating polyneuropathy]. AB - A 46-year-old man experienced numbness and muscle weakness in the distal portions of both hands, which progressed over following three months. Neurological examination showed mild muscle weakness only in distal arms, hypoflexia or areflexia, and hypesthesia in glove and stocking distribution. Motor conduction study revealed markedly prolonged distal latency and abnormal temporal dispersion. Sensory nerve potentials were reduced or could not be recorded. Histopathlogical findings of the sural nerve showed several nerve fibers with thinning myelin sheath and mild reduction of myelinated fibers. These results suggested the diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP). Two weeks after intravenous immunoglobulin therapy, neurological deficits rapidly improved and electrophysiological abnormalities were also ameliorated. Thereafter, there was no clinical deterioration for two years without further treatment. Our patient suggested that immunomodulating treatment is needed for stopping the initial progression of neurological deficits, but maintenance therapy is not always necessary for keeping the remitting state in distal variant of CIDP. PMID- 21823507 TI - [A case of neurosarcoidosis with swelling and gadolinium enhancement of spinal nerve roots on magnetic resonance imaging]. AB - An 80-year-old woman was admitted to our hospital because of developed sense of constriction in the trunk and gradually progressive numbness and muscle weakness in the upper and lower extremities. Cerebrospinal fluid analysis showed increased cell count and protein level. Gadolinium enhanced magnetic resonance imaging (MRI) of spine showed the enhancement and swelling of bilateral nerve root in the cervical and lumbar segments. Although chest computed tomography showed neither bilateral hilar lymphoadenopathy nor lung lesions and serum angiotensin converting enzyme and lysozyme (ACE) were normal, tuberculin skin test was negative and cell count and CD4/CD8 elevated in bronchoalveolar lavage fluid. Biopsy specimen of scalene lymph node showed noncaseating granuloma. The patient was treated with oral predonisolone, which improved her symptoms and abnormalities on MRI. It is important to consider neurosarcoidosis in the differential diagnosis of polyradiculopathy with swelling and gadolinium enhancement of spinal nerve roots. PMID- 21823508 TI - [A case of Castleman disease with status epileptics originating from focal cortical dysplasia]. AB - A 55-year-old man was admitted to our hospital because of prolonged consciousness disturbance after generalized convulsions. He had been afflicted with chronic inflammatory symptoms since 43 years of age, while multiple abdominal lymphadenopathy with a high level of serum IL-6 was revealed at the age of 53. FDG-PET/CT showed hypermetabolism in the left medial portion of the frontal lobe. Biopsy specimens of this lesion revealed a pathology of focal cortical dysplasia (FCD). Non-convulsive status epileptics continued despite enhanced treatment with antiepileptic drugs, while cortical T2 hyperintense lesions developed and expanded. Castleman disease was confirmed by pathological findings of abdominal lymph node biopsy specimens. The patient showed a higher level of IL-6 in cerebrospinal fluid (1,400 pg/dl) than in serum (720 pg/dl), thus indicating intrathecal production of this proinflammatory cytokine. We concluded that continuous exposure of FCD tissue to IL-6 may have augmented epileptogenesis of the originally silent congenital lesion. PMID- 21823509 TI - [Group B streptococcus meningitis and infection surrounding the spinal canal caused by bacterial transmission from rectal ulcer via Batson's plexus]. AB - A 62-year-old man was admitted to our hospital because of fever and disturbed consciousness. He suffered from persistent constipation due to diabetic autonomic neuropathy. On admission, neck stiffness and weakness of the lower extremities were observed. Cerebrospinal fluid (CSF) pleocytosis and decreased CSF glucose concentration showed the presence of meningitis. Bacterial culture of CSF was negative. One week after admission, he suddenly suffered from massive bleeding from the rectum, where a hemorrhagic ulcer caused by severe persistent constipation was observed. Contrast-enhanced CT scans and gadolinium-enhanced MR scans demonstrated a lumbar spinal epidural abscess, paraspinal muscle abscess, and cervical osteomyelitis. Streptococcus agalactiae, a bacterial species belonging to the group B streptococci, was isolated from pus obtained by needle puncture of the paraspinal muscle abscess. His entire condition was treated successfully with ampicillin and cefotaxime. Group B streptococci normally colonize the mucous membrane of the genital or lower gastrointestinal regions and rarely cause a spinal epidural abscess. However, in this case, the existence of a rectal ulcer probably made it possible for S. agalactiae to cause an infection of the epidural space or paraspinal muscles via the spinal valveless venous system named Batson's plexus communicating with the sacral, pelvic, and prostatic venous plexus. Our case indicated the importance of Batson's plexus in group B streptococcus infections surrounding the spinal canal and the necessity to explore for intrapelvic lesions including a rectal ulcer. PMID- 21823510 TI - [A case of anti-N-methyl-D-aspartate receptor encephalitis with ovarian teratoma showing excellent recovery with decreasing of anti-N-methyl-D-aspartate receptor antibody]. AB - We report a case of a 17-year-old woman with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, who developed psychiatric symptoms. Pelvic MRI revealed a right ovarian tumor that was suspected of being an ovarian teratoma. On the 27th day after onset, the patient underwent right salpingo-oophorectomy. The histopathological diagnosis was immature ovarian teratoma. Subsequently, 4 double filtration plasmapheresises (DFPP) were performed from day 34 to day 43. Methylprednisolone (1,000 mg/day for 3 days) was started on day 38. With these treatments, consciousness disturbance completely improved, and the patient was discharged on day 50. The serum and cerebrospinal fluid were positive for antibodies against the GluRzeta1 (NR1)-EGFP/GluRepsilon2 (NR2B) heteromer and the GluRzeta1 (NR1) subunit of NMDAR. The patient was hence diagnosed as having anti NMDAR encephalitis with ovarian teratoma Serial analysis show that the antibodies against NMDAR decreased with improvement of symptoms after the immunotherapy including DFPP treatment. PMID- 21823511 TI - [A case of occipital epilepsy with anti-GluRepsilon2 antibody in cerebrospinal fluid, presenting as repeated visual disturbance and headache]. AB - A 78-year-old man was admitted to our hospital with repeated attacks of headache and visual hallucinations, which had begun 10 days before. He also displayed left hemispatial neglect and left homonymous hemianopsia during attacks. Brain magnetic resonance imaging (MRI) showed an abnormal high-intense area in the right occipital lobe on diffusion weighted imaging (DWI) and fluid attenuated inversion recovery (FLAIR) weighted imaging; this lesion was demonstrated as an area of hyperperfusion on ECD-single photon emission computed tomography (SPECT) and hypoperfusion on 123I-BZ-SPECT. Electroencephalography during an attack demonstrated epileptogenic discharges in the right occipital region. Acute urinary retention due to meningoencephalitis appeared 2 weeks after onset of the first attack. Autoantibodies against glutamate receptor epsilon2 were detected in cerebrospinal fluid. We diagnosed the patient with occipital epilepsy due to anti NMDA receptor antibody encephalitis. Epileptic attacks diminished and MRI and SPECT findings improved following two administrations of intravenous bolus steroid therapy. PMID- 21823512 TI - [A case of clinically mild encephalitis/encephalopathy with a reversible splenial lesion associated with anti-glutamate receptor antibody]. AB - We report the case of an 18-year-old boy who presented with disturbance of consciousness and generalized seizures following flu-like symptoms such as high fever and arthralgia. T2 and diffusion weighted brain magnetic resonance images showed a hyperintense ovoid lesion in the splenium of the corpus callosum and T, weighted images showed a hypointense lesion; the lesion completely disappeared on repeat imaging after 3 days. Antiglutamate epsilon2 receptor antibodies were detected in his cerebrospinal fluid. Although the patient had several episodes of generalized seizures, he completely recovered within 3 months. Our patient had a clinically mild encephalitis/encephalopathy with a reversible splenial lesion following flu-like symptoms, which indicated viral infection. As compared to previously reported cases, our case was characteristic because of the protracted recovery shown by the patient. Anti-glutamate epsilon2 receptor antibodies may be associated with prolonged generalized seizures in the case of our patient. Our results also suggest that anti-glutamate epsilon2 receptor antibodies may play a role in the pathogenesis of this condition. PMID- 21823513 TI - [Primary care of epilepsy and recent topics]. PMID- 21823514 TI - [Molecular biology-based diagnosis and therapy for pancreatic cancer]. PMID- 21823515 TI - Inhalative administration of insulin using a new bubble jet atomization device. AB - OBJECTIVES: In this study, we attempted to perform inhalative administration of insulin using a new "bubble jet" atomization device based on ink jet printing technology and developed by Canon Inc. The aim of this study was to confirm the usefulness of the new device for achieving a hypoglycemic effect by insulin inhalation in normal rats. METHODS: Inhaled insulin (15 U/kg) or a control solution without insulin was administrated to each Wistar rat intratracheally using the bubble-jet atomization device. Blood glucose concentrations were measured at 0, 10, 20, 30, 60, 90 and 120 min after administration of insulin or control solution. RESULTS: The blood glucose concentrations in the inhaled insulin group were 63 +/- 10 mg/dl (20 min), 43 +/- 8 mg/dl (60 min) and 35 +/- 9 mg/dl (120 min), while those in the control solution group were 80 +/- 9 mg/dl (p = 0.016), 75 +/- 10 mg/dl (p < 0.001) and 85 +/- 27 mg/dl (p < 0.001). The blood glucose concentrations after administration of inhaled insulin were significantly lower than those after administration of control solution at all time points (p < 0.05) except 0 and 10 min. CONCLUSIONS: We confirmed the hypoglycemic effect of inhaled insulin using the new bubble jet atomization device. These results proved that the new device could atomize insulin while maintaining its bioactivity. PMID- 21823516 TI - Nurse fatigue: an NCNA survey. PMID- 21823517 TI - The damage caused by incomplete and uncontrolled medical information. PMID- 21823518 TI - Dorsolumbar kyphosis: diagnostic value of hook shaped vertebra. PMID- 21823519 TI - Are adolescent weight-related problems and general well-being essentially an issue of age, gender or rather a pubertal timing issue? AB - OBJECTIVE: To compare the characteristics of a set of weight-related and well being variables among adolescents according to gender and age. It was hypothesised that time of puberty, not age in itself, might be the turning point for gender dissimilarities. METHODS: Data were drawn from the Portuguese 2006 HBSC/WHO database and were disaggregated by gender and age group. Groups were compared for dieting, body image, health perception and happiness variables on the bivariate level using cross-tabulations. Separate analysis of the dependent variables was further conducted for 11-year-olds comparing males with pre- and post-menarche females. RESULTS: Dieting and a negative body image were consistently more prevalent among girls and increased with age. At 11 years significantly more post-menarche girls were dieting and dissatisfied with their body image than boys and their pre-menarche counterparts. A poor self-rated health and the perception of unhappiness tended to be more common among older adolescents and among girls. CONCLUSIONS: Pubertal timing, and not age in itself, appears as the turning point for gender dissimilarities. Both gender- and age specific differences as well as pubertal timing have to be taken into account by any physician when assessing an adolescent in order to be able to adapt the intervention. PMID- 21823520 TI - Comparison of methimazole and propylthiouracil in the management of children and adolescents with Graves' disease: efficacy and adverse reactions during initial treatment and long-term outcome. AB - OBJECTIVE: The aim of this study was to compare the efficacy and adverse reactions during initial treatment and long-term outcome between children and adolescents with Graves' disease (GD) treated with propylthiouracil (PTU) and those treated with methimazole (MMI). DESIGN, SETTING AND PARTICIPANTS: Retrospective and collaborative study. Children and adolescents with GD were divided into group M (MMI: n=64) and group P (PTU: n=69) and into four subgroups by initial dose: group M1 (<0.75 mg/kg of MMI, n=34), group M2 (> or = 0.75 mg/kg, n=30), group P1 (<7.5 mg/kg of PTU, n=24) and group P2 (> or = 7.5 mg/kg, n=45). MAIN OUTCOME MEASURES: The duration for normalization of serum T4 on initial treatment, the incidence of adverse effects for one year and outcomes at 10 years after were compared. RESULTS: Mean durations for normalization of T4 (+/ SD) were 1.7 +/- 1.0 months in group M and 2.3 +/- 2.4 in group P [not significant (NS)], while the mean duration in group P1 (3.1 +/- 3.3) was significantly longer than those in the other subgroups (M1: 1.9 +/- 1.2; M2: 1.4 +/- 0.7; P2; 1.7 +/- 1.3). No major adverse reaction was observed. Minor adverse effects occurred in 25.0% of cases in group M and 31.9% in group P (NS). The incidence in group P2 (44.4%) was significantly higher than those in group M1 (20.6%) and group P1 (8.3%). Remission rates did not differ between the MMI treated group (35.0%, n=20) and PTU-treated group (50.0%, n=40). CONCLUSIONS: PTU may not be suitable for initial use in children and adolescents with GD, even with the risk of major adverse reactions such as liver failure excluded. PMID- 21823521 TI - The effect of glucocorticoid replacement therapy on bone mineral density in children with congenital adrenal hyperplasia. AB - OBJECTIVES: 1) To evaluate the effects of glucocorticoid (GC) doses on bone mineral density (BMD) in children with congenital adrenal hyperplasia (CAH), 2) Investigate other factors influencing BMD. METHODS: Twenty-six children with CAH and 11 healthy controls included in the study. All of the patients were examined with dual-energy X-ray absorptiometry (DXA) using a Hologic QDR 1000/W densitometer. The metabolic control state, age at diagnosis GC dose (mg/m2/day), pubertal status, 17 hydroxyprogesterone (17 OHP) levels, bone age (BA), and lumber BMD were evaluated in all cases. BMD (g/cm2), BMD z-score corrected to National Standards (cNS-BMD z-score), BMD z-score corrected to BA (cBABMD), bone mineral content (BMC), BMC corrected to puberty (cPBMC), and bone area (BAR) values were determined. Patients were grouped according to mean on-therapy serum 17 OHP levels as tight control (17 OHP<10 nmol/L) (n:13) and poor control (17 OHP>10 nmol/L) (n:13). All groups were compared with each other. RESULTS: The age range was 2.1-15.7 years and the mean age (+/- SD) 9.3 (+/- 3.5) years. There were no significant differences between the groups in terms of GC doses, lumbar BMD values [BMD (g/cm2), BMD z-score corrected to National Standards (cNS-BMD z score), BMD z-score corrected to BA (cBABMD), bone mineral content (BMC), BMC corrected to puberty (cPBMC), and bone area (BAR)]. However, the BMI value was higher in children with CAH than normal healthy controls. The BA of the poor control, late diagnosed groups and male patients were higher than tight control, early diagnosed group and female patients, respectively. BMC and BA were lower than the control group in tight control with early diagnosed patients. The cBABMD z-score was lower in males with poor control than males with tight control. There were no similar results in female patients. CONCLUSIONS: Although GC treatment seems not to influence BMD in CAH patients in our study, further studies are needed to additionally evaluate daily calcium (Ca) intake, polymorphism of vitamin D receptor, ethnic factors (strict Islamic dress, etc.), socioeconomic status, and 24-h urinary free cortisol level. PMID- 21823522 TI - Treatment of symptomatic osteoporosis in children: a comparison of two pamidronate dosage regimens. AB - Bisphosphonate treatment for bone fragility has expanded beyond children with osteogenesis imperfecta (OI) to those with other causes of low bone mass. However, clinical efficacy and optimal dosing in non-OI patients has not been established. We conducted a retrospective descriptive study of patients with non OI-related bone fragility to describe the effects of two different pamidronate treatment regimens on the bone mineral density (BMD) and fracture rate of these children. Between 2000 and 2009, 15 non-OI patients aged 8-16 years received pamidronate 1 mg/kg intravenously for 1 day every 3 months (4 mg/kg/year) or 1 mg/kg/day for 3 days every 4 months (9 mg/kg/year). After 1 year of pamidronate, the two groups had a comparable increase in adjusted BMD and reduction in fragility fractures. No serious adverse effects were observed. Since the long term effects of bisphosphonate are unknown, large trials are needed to delineate the minimal effective dose in these patients. PMID- 21823523 TI - Stanozolol regulates proliferation of growth plate chondrocytes via activation of ERalpha in GnRHa-treated adolescent rats. AB - Improving the final adult height is one of the most important aims for treatment of central precocious puberty. Stanozolol (ST) is a synthetic derivative of androgen. In this study, we investigated the effects and the mechanisms of ST on the proliferation of growth plate chondrocytes isolated from adolescent rats treated with gonadotropin-releasing hormone analogue (GnRHa). Treatment with ST resulted in time- and concentration-dependent effects on proliferation as determined by MTT and proliferating cell nuclear antigen (PCNA) assays. Western blotting showed that ST increased the phosphorylation level of the estrogen receptor alpha (ERalpha), but not the androgen receptor (AR). Pharmacological inhibition of ERalpha and mitogen-activated protein kinase (MAPK) attenuated the effects of ST on the proliferation of growth plate chondrocytes. A molecular dynamics simulation showed hydrophobic interactions between ST and ERalpha. These results suggested that ERalpha, but not AR, partially mediates the ST-driven proliferation of growth plate chondrocytes, and that multiple pathways may be involved in the mechanism of action of ST. PMID- 21823524 TI - A case of McCune-Albright syndrome associated with pituitary GH adenoma: therapeutic process and autopsy. AB - BACKGROUND: McCune-Albright syndrome (MAS) is a clinical syndrome with low incidence, and its concurrence with pituitary GH adenoma is rare. Little of the history, treatment and outcome has been studied. METHOD: Follow-up of a 37-year old male patient of MAS associated with pituitary GH adenoma was performed continuously recording the disease development and the treatment process until death, after which an autopsy was performed. RESULTS: Radiation therapy (RT) efficaciously controlled GH hypersecretion, however, it may have been the cause of the malignant transformation of the dysplastic bone tissue, which eventually caused brain hernia and death; autopsy demonstrated that the cranium had significant thickening (as much as 10 cm), the pathological diagnosis was fibrous dysplasia of bone associated with chondrosarcoma; and undifferentiated chondrosarcoma with malignant fibrous histocytoma subtype in the sellar region; nodular goiter with the thyroid gland, one nodus was pathologically demonstrated as papillary carcinoma. CONCLUSION: GH adenoma, present in a patient with MAS, might be cured by RT; but the risk of malignant transformation of the dysplastic bone tissue in the field of irradiation make it controversial. Lessons from the case reported here told us that we should take great caution when recommending RT for patients like this. PMID- 21823525 TI - The role of metabolic syndrome components and adipokines in insulin resistance in prepubertal children. AB - OBJECTIVE: Insulin resistance has a central role in the pathophysiology of cardiovascular atherosclerotic disease. Adipose tissue is of capital importance in view of its production of adipokines. The present study aims to determine the association of metabolic syndrome components, which constitute risk factors for cardiovascular atherosclerotic disease, and leptin and adiponectin with insulin resistance in prepubertal children. METHODS: We conducted a cross-sectional study involving 197 children. Of these, 112 children were obese, 36 were overweight and 49 had normal weight. The association of sex, waist circumference, Acanthosis nigricans, age, BMI Z-score, serum lipids, leptin and adipocytokines with insulin resistance [defined as the homeostatic model assessment for insulin resistance (HOMA-IR) index higher than or equal to 2.5] was investigated using logistic regression. RESULTS: There was positive association of sex (female), age, BMI Z score, triglycerides and leptin with insulin resistance (p<0.05). CONCLUSION: Among the conventional components of metabolic syndrome, the role of BMI Z-score and triglycerides stands out in insulin resistance of prepubertal children. Sex (female), age and leptin also showed to be of major importance. PMID- 21823526 TI - A new heterozygous mutation (D196N) in the Gs alpha gene as a cause for pseudohypoparathyroidism type IA in a boy who had gallstones. AB - BACKGROUND: Pseudohypoparathyroidism (PHP) is characterized by hypocalcemia and hyperphosphatemia in association with an increased secretion of parathyroid hormone (PTH) due to decreased target tissue responsiveness to PTH. Patients with PHP type Ia are not only resistant to PTH, but also to other hormones that bind to receptors coupled to stimulatory G protein (Gsalpha). PHP Ia and Albright hereditary osteodystrophy (AHO) are caused by a reduced activity of the Gsalpha protein. Heterozygous inactivating Gs alpha (GNAS) gene mutations have been identified in these patients. METHODS: We studied a boy with PHP Ia. During follow-up the patient developed elevated liver enzyme serum levels and abdominal discomfort. Gsalpha activity was measured in erythrocyte membranes from the patient and the GNAS coding region of Gsalpha sequenced. RESULTS: Gsalpha activity was reduced (62%) and molecular analysis revealed a new heterozygous GNAS gene mutation (D196N). Gallstones were diagnosed and cholecystectomy was performed. Biochemical analysis revealed cholesterol stones, a condition that was not reported before in PHP Ia. CONCLUSIONS: Cholesterol gallstones may rarely be associated with PHP Ia and should be taken into account. PMID- 21823527 TI - Causes and patterns of referral to a tertiary, multidisciplinary program for the treatment of childhood obesity. AB - BACKGROUND: Despite the childhood obesity epidemic, few obese children receive therapy and relatively few weight management multidisciplinary programs exist. OBJECTIVE AND METHODS: The objective of this study was to examine the patterns and causes for obese children referrals to a tertiary multidisciplinary childhood obesity treatment program. A total of 227 children (10.6 +/- 2.6 years; 108 boys, 119 girls) were evaluated at the beginning of the programs for personal and familial demographic and anthropometric details, the referring agent to the program, and the main reasons for participation and for the child's desire to lose weight. RESULTS: The majority of participants had an obese family member (83%), in particular an obese parent (62%). The majority of patients were self referred (86.8%), mainly by their mothers (74%). Only a small fraction were referred by healthcare providers (15.4%). The desire to improve appearance (44.5%), social/psychological issues (39.2%) and the will to improve fitness (29.5%) were the main reasons for joining the program. CONCLUSION: Understanding the motives for participation and referral patterns can improve recruitment and participation of obese children in weight reduction intervention programs. PMID- 21823528 TI - Vitamin D receptor genotypes are associated with bone mass in patients with Turner syndrome. AB - BACKGROUND: Turner syndrome (TS) patients present low bone mineral density (BMD) and increased fracture risk, probably due to a genetic defect aggravated by hormonal deficiency. AIM: To study the relationship between vitamin D receptor (VDR) gene polymorphisms and BMD and bone parameters in TS patients. METHODS: DNA from 65 TS patients and 110 controls was amplified by PCR and digested with FokI, BsmI and ApaI restrictases. Lumbar and femoral BMD were determined by DEXA and serum intact parathyroid hormone, osteocalcin and beta-CrossLaps by electrochemiluminescence. RESULTS: Genotype distribution within the ApaI site was different in both groups: genotype Aa was more abundant in TS (63.8% vs. 41.3%; p<0.01), whereas AA predominated in controls (33.9% vs. 15.5%; p<0.01). Patients carrying genotype bb (BsmI) or ff (FokI) had lower BMD than those with other genotypes (p<0.01 and p<0.05, respectively). CONCLUSION: BsmI and FokI polymorphic sites of VDR could be genetic determinants of BMD in TS patients. PMID- 21823529 TI - Plasma leptin and adiponectin concentrations in healthy, non-obese children. AB - BACKGROUND: Alterations in plasma leptin and adiponectin concentrations are associated with an adverse metabolic profile in obese children. OBJECTIVE: To simultaneously assess multiple factors with possible effects on plasma leptin and adiponectin concentrations in healthy, non-obese children. SUBJECTS: We studied 170 healthy non-obese children (86 males, age 10+1.5 years), with available medical records from birth. METHODS: Plasma leptin and adiponectin concentrations were assessed by immunoassay. The ratio of current weight/birth weight (WBWR) was used as an index of children growth from birth. Children's intensity of physical activity and parental characteristics were also assessed. RESULTS: Leptin was positively associated with WBWR (p<0.0001); parental smoking (analysis of variance, ANOVA; p-=0.03) and parental obesity (ANOVA; p<0.001) were negatively associated with breastfeeding (p<0.01) and children's access to exercise (p<0.0001). Adiponectin was negatively associated with WBWR (p<0.0001) and parental smoking (p=0.04), with an additive negative effect of parental smoking status and parental obesity on children's adiponectin levels (ANOVA; p=0.02). CONCLUSIONS: Children's and parental factors are related and could possibly influence leptin and adiponectin concentrations in healthy non-obese children. Early preventive strategies that target both children and parents could improve the profile of adipocytokine in these children. PMID- 21823530 TI - Puberty and pubertal growth dynamics in children with idiopathic short stature. AB - OBJECTIVE: As the prognosis for final height is unfavorable for children with idiopathic short stature (ISS), we studied the pubertal growth dynamics in these children, which is a determinant factor in final height. SUBJECTS/METHODS: In a retrospective cohort study, we analyzed the pubertal period, age of puberty and peripubertal growth in 50 children with ISS. RESULTS: The onset of puberty occurred later. Growth rate tended to become increasingly subnormal in the prepubertal period and height was -2.45 SD at puberty onset. Growth reaccelerated at this point, which tended to correct the deviation from the mean height, but it was insufficient to obtain a normal final height. CONCLUSIONS: The dynamics of growth in children with ISS showed a distinct pattern in the prepubertal and pubertal periods and puberty is significantly delayed in this population. These patterns could explain the unfavorable prognosis for children with ISS. PMID- 21823531 TI - Endocrine complications following pediatric bone marrow transplantation. AB - Pediatric bone marrow transplantation (BMT) for various diseases can lead to endocrine system dysfunction owing to preparative regimens involving chemotherapy and radiation therapy. We assessed the prevalence of post-BMT endocrine complications in children treated at the Alberta Children's Hospital (ACH) from 1991 to 2001. Time of onset of endocrine dysfunction, underlying disease processes, chemotherapy, radiation therapy and age at BMT were characterized. Subjects of <18 years of age at the time of allogeneic or autologous BMT for whom 1-year follow-up through the ACH and a chart were available for review were included in the study. Subjects with a pre-existing endocrine condition were excluded. Of the 194 pediatric BMT procedures performed at the ACH between January 1, 1991 and December 31, 2001, 150 complete charts were available for review. Sixty five subjects received follow-up care at other centers and were excluded. Therefore, a total of 85 subjects were included in the review. The prevalence of endocrine complications identified was: primary hypothyroidism 1.2%, compensated hypothyroidism 7.0%, hyperthyroidism 2.4%, hypergonadotrophic hypogonadism 22.4%, abnormal bone density 2.4%, and secondary diabetes mellitus 1.2%. These findings emphasize the need to screen for endocrine system dysfunction, particularly hypergonadotrophic hypogonadism, in children who have undergone BMT. Children need long-term follow-up so that endocrine complications can be diagnosed and treated promptly. PMID- 21823532 TI - Rare hypertension as a result of 17alpha-hydroxylase deficiency. AB - PURPOSE: To investigate CYP 7A1 gene mutations in Chinese patients with 17alpha hydroxylase deficiency. METHODS: Clinical data were retrospectively analyzed. CYP17A1 mutations were detected in two cases with 17alpha-hydroxylase deficiency. Genomic DNA was isolated from blood samples and eight primers pairs were used to amplify eight exons and exon-intron boundaries of the CYP17A1 gene. The amplified PCR products were purified by agarose gel electrophoresis and then directly sequenced. Sequencing results were compared to the established human CYP17A1 sequence. RESULTS: Two compound mutations were identified: TAC --> AA at codons 436-438 on exon 6, causing the amino acid missense mutation Y329K/418X; and deletion of the 9-bp sequence GACTCTTTC at codons 487-489 on exon 8, causing deletion of three amino acids (Asp-Ser-Phe). CONCLUSION: D487_F489del and Y329K, 418X CYP17A1 mutations were identified in our two patients. A literature review revealed that the main CYP17A1 mutations in the Chinese population are missense and splicing defects, and exons 8 and 6 are most frequently involved. PMID- 21823533 TI - Girls with early puberty attain a near-final height similar to their target height. AB - BACKGROUND: The median age at thelarche in Thai girls has decreased from 10.3 to 9.4 years over the last 20 years. An age at thelarche of 7.0-9.0 years, which is earlier than in the general population, is considered as early puberty. OBJECTIVE: To study the pattern of pubertal development in Thai girls with early puberty. STUDY DESIGN: A total of 104 girls with breast development at 7.0-9.0 years who attended Songklanagarind Hospital between 2003 and 2005 were followed up until they attained their near-final height (NFH). RESULTS: The mean age at initial evaluation was 8.5 +/- 1.0 years. The average age at menarche and on attaining NFH was 10.2 +/- 0.9 and 12.6 +/- 0.4 years, respectively. The average NFH was 154.0 +/- 4.9 cm, which was similar to the target height of 153.1 +/- 4.8 cm. Comparison of girls who were normal weight and obese (weight-for-height >120%) revealed that the latter had an earlier age at menarche (9.8 +/- 0.8 vs. 10.5 +/- 0.8 years, p<0.01) and reached their NFH at a younger age (12.2 +/- 0.4 vs. 12.9 +/- 0.4 years, p=0.02). However, normal-weight and obese girls reached approximately the same NFH (155.8 +/- 4.8 vs. 153.1 +/- 4.0 cm, p=0.058). CONCLUSION: Girls with early puberty attained NFH similar to their genetic potential. Obese girls attained NFH at an earlier age and had the same NFH as normal-weight girls. PMID- 21823534 TI - Persistent hyperthyrotropinemia in congenital hypothyroidism: successful combination treatment with levothyroxine and liothyronine. AB - BACKGROUND: Some children with congenital hypothyroidism (CH), have persistent hyperthyrotropinemia despite good compliance with levothyroxine. OBJECTIVE: To evaluate combination therapy of liothyronine (cytomel) with levothyroxine in CH with persistent hyperthyrotropinemia. PATIENTS AND METHODS: Files were reviewed retrospectively. Eight female patients with persistently high levels of TSH and upper normal FT4 levels were given either 6.25 or 12 microg liothyronine and the levothyroxine dose was reduced appropriately. Pre- and post-intervention hormone levels and drug doses were evaluated. RESULTS: TSH decreased in 8/8 and normalized in 6/8 patients. FT4 and free tri-iodothyronine (FT3) remained normal. The levothyroxine-equivalent dose on the combination was 5.0 +/- 0.3 microg/kg/day in infants and 3.4 +/- 0.4 microg/kg/day in children above 2.5 years. Infants required higher liothyronine doses compared with older children (0.66 +/- 0.01 vs. 0.3 +/- 0.05 microg/kg/day). CONCLUSIONS: Combined therapy can achieve normal TSH levels with normal FT4 and FT3. Further long-term research is required to investigate effects on neurodevelopmental outcome. PMID- 21823535 TI - Benign transient hyperphosphatasemia in infants and children: a prospective cohort. AB - A total of 20 children with benign transient hyperphosphatasemia were prospectively evaluated with no additional investigations recommended except repeat serologic evaluation in 2-3 months. The average age of our patients was 2.5 years (range 1 year 2 months-5 years 10 months). The serum levels of alkaline phosphatase averaged 2383 IU/L (range 1013-5700 IU/L). Levels returned to normal within several months. This condition should be recognized by the clinician in order not to put patients through lengthy, expensive and unnecessary investigations. PMID- 21823536 TI - The relation between 25-hydroxyvitamin D with peak bone mineral density and body composition in healthy young adults. AB - OBJECTIVE: The associations between peak bone mineral density (BMD) and body composition with 25 hydroxyvitamin D (25OHD) levels in healthy young adults were evaluated. METHODS: The number of participants was 464; 347 women and 117 men. The mean age was 24.3 years (range 17-31 years). BMD of the lumbar spine, total body and femoral neck (FN) and body composition were measured by dual energy X ray absorptiometry. Volumetric BMD, bone mineral apparent density (BMAD), of the lumbar spine and FN was calculated. RESULTS: In females, 25OHD level was positively associated with FN BMD and BMAD (both p<0.01) and negatively with percentage body fat (p<0.001). In males, 25OHD levels had a positive association with total body BMD and lean body mass (p=0.03 and p=0.01). CONCLUSIONS: 25OHD level is a determinant of peak BMD in both sexes. Vitamin D status was associated with body fat in females and with lean body mass in males. PMID- 21823537 TI - Childhood obesity: evidence of an association between plasminogen activator inhibitor-1 levels and visceral adiposity. AB - BACKGROUND: Plasminogen activator inhibitor-1 (PAI-1) has been considered as a cardiovascular risk factor, mainly because of its strong association with insulin resistance. METHODS: To detect independent predictors of circulating PAI-1 levels in obese pediatric patients, we evaluated 86 subjects (mean age 10.7 +/- 2.8 years), 42 of whom were male (49%). Subjects were divided in two groups according to body mass index (BMI): obese subjects (n=61) and healthy non-obese controls (n=25). They were also divided by pubertal status. Besides anthropometric data, levels of PAI-1, leptin and biochemical markers of metabolic syndrome were measured. RESULTS: The obese group had higher levels of PAI-1, leptin and biochemical markers of metabolic syndrome than nonobese controls (p<0.05). However, multivariate regression analysis showed that only puberty progression (p=0.005) and abdominal circumference/height index (p=0.002) remained independent predictors of PAI-1 levels. CONCLUSION: In pediatric obesity, fat mass accumulation, mainly of visceral fat, and puberty progression were related to high PAI-1 levels, which might in turn contribute to cardiovascular risk. PMID- 21823538 TI - Glargine basal-bolus insulin regimen versus insulin pump therapy: comparison of glycemic control. AB - BACKGROUND: Study results have varied when blood sugar control for subjects using a glargine basal-bolus insulin regimens (GBBIR) have been compared with those using continuous subcutaneous insulin infusion (CSII). Of 12 studies comparing GBBIR with CSII, six found improved glycemic control with CSII and six found no significant difference. These studies were often limited by small numbers of subjects and other study design parameters. METHODS: We reviewed hemoglobin (Hb) A1c data for youths with type 1 diabetes (n=43) changing from conventional split mix insulin regimens (CSMIR) to GBBIR and subsequently to CSII at 3, 6 and 12 months after each transition. All subjects had a diabetes duration of at least 1 year before initiating GBBIR. RESULTS: HbAlc levels at 3 months, 6 months and 1 year were not significantly different for GBBIR and CSII regimens. HbAlc increased significantly during GBBIR (p=0.036) and marginally during CSII (p=0.058) when 3-month and 1-year values were compared. CONCLUSIONS: We found no significant difference in glycemic control, as reflected by HbAlc, in youths with type 1 diabetes treated with GBBIR and CSII for up to 1 year. Blood sugar control waned by 12 months in both the GBBIR (p=0.036) and CSII (p=0.058) groups, which suggests that "burn out" qually affects those on each regimen. Additional investigation of glycemic variability and quality of life for those on GBBIR and CSII would be clinically relevant. PMID- 21823539 TI - A new variant of a known mutation in two siblings with permanent neonatal diabetes mellitus. AB - Permanent neonatal diabetes mellitus is a rare disorder usually presenting within the first few weeks or months of life. This disorder is genetically heterogeneous and has been associated with mutations in various genes. The genetic cause remains mostly unknown although several genes have been linked to this disorder. Mutations in KCNJ11, ABCC8, or INS are the cause of permanent neonatal diabetes mellitus in about 50%-60% of the patients. With genetic studies, we hope to increase our knowledge of neonatal diabetes, whereby new treatment models can become possible. Here, we defined a new variant of a known mutation, INS Exon 1-3 homozygous deletion, in two siblings diagnosed with permanent neonatal diabetes mellitus. PMID- 21823540 TI - HNF1A mutation presenting with fetal macrosomia and hypoglycemia in childhood prior to onset of overt diabetes. AB - BACKGROUND: HNF1A-MODY (MODY3) is a common subtype of autosomal dominant diabetes. Unlike HNF4-MODY where fetal macrosomia and early postnatal hyperinsulinemic hypoglycemia have been reported, a history of transient insulin overproduction has not been recognized in individuals with HNF1A-MODY yet. CASE REPORT: Here, we report a 40-year-old male patient with HNFJA mutation p.Arg272His (c.815G>A) with a history of fetal macrosomia (4750 g, 59 cm) and, at least, one attack of symptomatic hypoglycemia in childhood. Diabetes was subsequently diagnosed at 19 years. The proband's daughter who developed diabetes at 16 years carries the same mutation, but her birth weight and length were in the upper normal range, and she never experienced hypoglycemic symptoms. CONCLUSION: The observation of fetal macrosomia and hypoglycemia in childhood is suggestive of a biphasic impact of the HNF1A mutation on beta-cell function over the lifespan, leading from inappropriate insulin oversecretion to final clinical diabetes. PMID- 21823541 TI - A newborn case with perinatal-lethal Gaucher disease due to R463H homozygosity complicated by C677T homozygosity in the MTHFR gene. AB - Perinatal-lethal Gaucher disease is very rare and is considered a variant of type 2 Gaucher disease that occurs in the neonatal period. The most distinct features of perinatal-lethal Gaucher disease are non-immune hydrops fetalis, in utero fetal demise and neonatal distress. In some cases without hydrops, neurological signs occur in the first week of life and lead to death within 3 months. Less common signs of the disease are hepatosplenomegaly, ichthyosis, arthrogryposis and facial dysmorphy. We describe a preterm neonate with Gaucher disease homozygous for R463H mutation in GBA gene who showed severe neurologic signs in addition to refractory thrombocytopenia, hepatosplenomagaly, direct hyperbilirubinemia, facial dysmorphy and ichthyosiform skin abnormalities in addition to having thrombosis in portal and splenic veins possibly due to homozygosity for C677T mutation in MTHFR gene. To the best of our knowledge, this is the first case homozygous for the GBA R463H mutation resulting in Gaucher disease with a concomitant homozygous MTHFR C677T mutation. PMID- 21823542 TI - Hyperthyroidism presenting with hyperglycemia in an adolescent female. AB - A 15-year-old female presented to a pediatric emergency department with glycosuria, ketonuria, and hyperglycemia and was admitted with a presumed diagnosis of diabetes mellitus. The patient required no insulin therapy and only minor dietary modification to maintain euglycemia. Clinical examination and laboratory findings revealed a primary diagnosis of Graves' hyperthyroidism with associated impaired glucose tolerance. Here, we review the mechanisms of thyrotoxicosis resulting in impaired glucose metabolism. PMID- 21823543 TI - A single base-pair deletion in the WFS1 gene causes Wolfram syndrome. AB - Wolfram syndrome is a progressive neurodegenerative disorder also known as DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy and deafness). The majority of cases are caused by mutations in the WFS1 gene. WFS1 is located at 4p16.1 and encodes wolframin, a transmembrane endoplasmic reticulum (ER) protein involved in the negative regulation of ER stress signalling. To date, over 120 WFS1 mutations have been described. In this study, we report a consanguineous family with three siblings affected by Wolfram syndrome. A homozygous single base pair deletion (c.877delC, L293fsX303) was found in the WFS1 gene in all three affected siblings. PMID- 21823544 TI - Growth suppression caused by corticosteroid eye drops. AB - Scarce data on systemic activity of corticosteroid eye drops are available in children. Two weeks treatment with fluorometholone eye drops in a case series of five children caused growth suppression detected by knemometry. The suppression had no impact on height growth during the following year. PMID- 21823545 TI - Familial glucocorticoid deficiency due to compound heterozygosity of two novel MC2R mutations. AB - Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder characterized by isolated glucocorticoid deficiency. Mutations in the ACTH receptor (melanocortin 2 receptor, MC2R) or the MC2R accessory protein (MRAP) cause FGD types 1 and 2, respectively. A 2-year-old adopted Chinese girl presented with hypertonic seizures associated with hypoglycemia, skin hyperpigmentation, muscle weakness and mild jaundice. Hormonal analyses revealed high ACTH, low serum cortisol along with normal blood electrolytes. On hydrocortisone supplementation, the disease symptoms disappeared and the child recovered, although further episodes occurred with infection. To date, her physical and neurocognitive development progress is normal. A clinical diagnosis of FGD was given. We undertook MC2R and MRAP mutation screening. Two novel MC2R mutations were identified: p.D107G localized in the transmembrane region, predicted to be trafficking-competent but is unable to bind to ACTH, and p.R145C, situated in the second intracellular loop, predicted to be trafficking-defective. PMID- 21823546 TI - Isovaleric acidemia. PMID- 21823547 TI - Current concepts in the management of opioid-induced constipation: a perfect review with an imperfect concept. PMID- 21823548 TI - Considerations for the upcoming FDA REMS proposal. PMID- 21823550 TI - Efficacy and safety of an extended-release oxycodone (Remoxy) formulation in patients with moderate to severe osteoarthritic pain. AB - OBJECTIVE: To evaluate the efficacy and safety of an encapsulated, highly viscous formulation of extended-release oxycodone designed to resist common physical manipulation and chemical challenges (Remoxy; King Pharmaceuticals, Inc., Bristol, TV, which was acquired by Pfizer Inc. in March 2011). DESIGN: An enriched enrollment randomized withdrawal trial design was used whereby patients entered a double-blind, multicenter, placebo-controlled trial after completing an open-label titration phase. SETTING: Sixty-one US clinics. PATIENTS: All patients (40-75 years) had experienced moderate to severe chronic osteoarthritic pain in the hip or knee for > or = 3 months. INTERVENTIONS: During 2 weeks of open-label treatment (N = 558), patients were titrated from Remoxy 5 mg twice daily (bid) to 20 mg bid. Patients who tolerated the drug were randomly assigned to Remoxy or placebo bid for 12 weeks. Dose titration was permitted during weeks 1-4 (range, 10-80 mg/d) and fixed thereafter. MAIN OUTCOME MEASURES: The area under the curve (AUC) for change in pain intensity (PI) scores from prerandomization to the end of the 12-week period was the primary endpoint. Patient assessment of quality of analgesia, global assessment of study medication, quality of life, and safety were also evaluated. RESULTS: The mean AUC for change in PI score was significantly greater for Remoxy than for placebo (p = 0.007). Patients receiving Remoxy reported significantly better scores on quality of analgesia (p = 0.004) and global assessment of study medication (p = 0.007) when compared with patients receiving placebo. Remoxy had a safety profile consistent with other opioids. CONCLUSIONS: Remoxy significantly improved analgesia among patients with moderate to severe chronic osteoarthritic pain with an adverse event profile similar to other opioids. PMID- 21823549 TI - Positive and negative subjective effects of extended-release oxymorphone versus controlled-release oxycodone in recreational opioid users. AB - OBJECTIVE: To compare the subjective effects of oxymorphone extended release (OM ER) versus oxycodone controlled release (OC-CR). DESIGN: Randomized, double blind, crossover study. SETTING: Inpatient unit. SUBJECTS: Healthy, nondependent recreational opioid users. INTERVENTIONS: Single intact oral tablets that were placebo or contained OM-ER (15 and 30 mg) or OC-CR (30 and 60 mg). Doses were representative of mid-range doses for chronic pain and were calculated using an established opioid conversion table. MAIN OUTCOME MEASURES: Visual Analog Scales, Subjective Drug Value (SDV), and Addiction Research Center Inventory (ARCI) measured positive, negative, and balance effects and pupillometry. Equianalgesic comparisons were between OM-ER 15 mg versus OC-CR 30 mg (low doses) and OM-ER 30 mg versus OC-CR 60 mg (high doses). RESULTS: Thirty-five subjects received all five treatments. Positive subjective effects were lower for OM-ER 15 mg versus OC CR 30 mg and for OM-ER 30 mg versus OC-CR 60 mg in ARCI Morphine Benzedrine Group (< or = 0.01 for both), Good Effects (p < 0.001 for both), Rush (p < 0.001 for both), and High VAS (p < 0.001 for both). Nausea was higher with OC-CR (p < or = 0.02), and Bad Effects were higher for OC-CR 60 mg versus OM-ER 30 mg (p < 0.001). Balance effects were lower for OM-ER versus OC-CR (Drug Liking, p < 0.001; Overall Drug Liking, p < or = 0.006; SDV, p < or = 0.008), except for Take Drug Again (p < 0.001 for OC-CR 30 mg versus OM-ER 15 mg; p = 0.18 for high-dose group). Euphoric mood, nausea, somnolence, vomiting, and dizziness were more common with OC-CR than OM-ER. LIMITATIONS: Single-dose design; use of healthy, recreational opioid users. CONCLUSIONS: At equianalgesic doses, single oral intact OM-ER produced lower positive, negative, and balance subjective effects than OC-CR, indicating that analgesic potency may not necessarily be reflected in subjective/objective effects. PMID- 21823551 TI - Oxycodone-related side effects: impact on degree of bother, adherence, pain relief, satisfaction, and quality of life. AB - OBJECTIVES: Oxycodone immediate-release, alone or in combination (hereafter, oxycodone), is widely used to treat pain and is often associated with bothersome side effects. The objective was to assess side effect frequency, degree of bother, and impact on health-related quality of life (HRQoL). METHODS: An online survey was completed by a nationwide convenience sample of patients currently taking oxycodone for nonmalignant pain. Detailed data on any oxycodone-related side effects were collected. Relationships between side effects, pain relief and HRQoL (Physical Component Summary [PCS] and Mental Component Summary [MCS] of the Short Form 12-Item Health Survey) were explored. RESULTS: Among 601 respondents (average 45 years, 85.0 percent Caucasian, 69.1 percent female, 61.1 percent on oxycodone > 30 days), 84.0 percent were bothered by side effects with 30.8 percent quite a bit or extremely bothered. Over half were bothered by drowsiness (56.2 percent) and constipation (53.1 percent), over two-fifths by lightheadedness (43.6 percent) and dizziness (42.1 percent), approximately one third by headache (33.1 percent) and nausea (31.3 percent), 27.6 percent itching, and 14.8 percent vomiting, which affected adherence to prescribed dosing regimens and, thus, is inversely associated with the level of pain relief. Patients who experienced less than 50 percent pain relief from oxycodone had worse PCS (33.9 vs 35.7; p = 0.038) and MCS (38.5 vs 42.4; p < 0.001) scores when compared with those who experienced 50 percent or more pain relief CONCLUSIONS: The majority of survey respondents experienced side effects of oxycodone, with a majority being bothered by side effects and impacting their QoL. This raises a question about the unmet need for pain medications with improved side effect profiles. PMID- 21823552 TI - Analgesic and adverse effects of a fixed-ratio morphine-oxycodone combination (MoxDuo) in the treatment of postoperative pain. AB - OBJECTIVE: To compare efficacy and safety profiles of an immediate-release morphine and oxycodone Dual-Opioid combination (MoxDuo) versus its individual components and versus its morphine-equivalent doses in moderate to severe postoperative pain patients. DESIGN: Randomized, double-blind, 48-hour, parallel treatment, multicenter, six-arm study of MoxDuo. SETTING: Six US centers. PATIENTS: Within 6 hours after bunionectomy surgery, patients were eligible if they reported pain intensity > or = 2 on the 4-point Likert scale and > or = 4 on an 11-point Numerical Pain Rating Scale (197 randomly assigned; 175 completers). INTERVENTIONS: MoxDuo 12 mg/8 mg, MoxDuo 6 mg/4 mg, morphine 12 mg, oxycodone 8 mg, morphine 6 mg, or oxycodone 4 mg (all administered q6h). MAIN OUTCOME MEASURE: Sum of pain intensity differences 0-24 hours after the first dose of study medication (SPID24) and percentage of patients with moderate to severe nausea, emesis, or dizziness. RESULTS: SPID24 was significantly better in the MoxDuo 12 mg/8 mg group when compared with its individual components (morphine 12 mg [p = 0.009] and oxycodone 8 mg [p = 0.037]), and when compared with MoxDuo 6 mg/4 mg (p = 0.011; 54.3 vs 28.5, 35.7, and 30.0, respectively). MoxDuo6 mg/4 mg and its morphine-equivalent doses (morphine 12 mg and oxycodone 8 mg) had comparable analgesic effects. There was a 50-75 percent reduction in moderate to severe adverse events (AEs) commonly associated with opioids (ie, nausea, vomiting, and dizziness) in the MoxDuo 6 mg/4 mg group when compared with its morphine-equivalent dose groups. CONCLUSIONS: MoxDuo produced superior analgesic effects when compared with its individual components, but comparable efficacy when compared with its morphine-equivalent doses. Common AEs were reduced at least 50 percent with MoxDuo when compared with its morphine-equivalent doses. MoxDuo may be an improved intervention in the management of moderate to severe acute pain. PMID- 21823553 TI - Analysis of the paramedic administration of fentanyl. AB - INTRODUCTION: Pain is a common complaint among emergency medical services patients. When compared with the most commonly used morphine, fentanyl has a shorter onset of action, shorter duration, and far fewer side effects making it an appealing candidate for prehospital pain management. This study's intent is to prospectively assess the feasibility and safety of fentanyl for pain in prehospital patients in comparison with morphine. METHODS: Observational trial to evaluate select characteristics of fentanyl administration. The primary outcome measure was the reduction of pain from time of initial patient assessment to transfer of care (TOC) to emergency department (ED) staff. Secondary outcome measures included the development of adverse outcomes and side effects related to fentanyl administration. Additionally, data obtained were compared with morphine retrospectively from an identical prior time period, ie, 1 year earlier. RESULTS: About 16.6 percent of the patients who received fentanyl reported subjective pain relief in less than 1 minute, 47 percent in 1-2 minutes, 19.9 percent in 2-3 minutes, and 16.6 percent at greater than 3 minutes. The reduction of pain after fentanyl administration, on a scale of 1-10, was 3.82 points in TOC at the ED. No significant adverse clinical outcomes or incidents of diversion were reported during the trial period. CONCLUSIONS: Fentanyl can be used safely and effectively for pain control in the prehospital setting. PMID- 21823554 TI - Current status and evolving role of abuse-deterrent opioids in managing patients with chronic pain. AB - Opioids are widely used for the treatment of patients with chronic pain; yet, the increase in their abuse, misuse, and diversion is an ongoing focus of regulatory, governmental, and legal scrutiny. As a consequence, clinicians are faced with numerous challenges in an effort to use opioids in appropriate patients with pain while minimizing the potential for opioid abuse, misuse, and diversion. Policies and programs such as state prescription monitoring programs, which have been in existence for decades, are but one attempt to address some of the issues regarding the prescribing of opioids. Another is a risk evaluation and mitigation strategy for opioids under consideration by the US Food and Drug Administration. At the clinical level, a universal precautions and risk management package that includes risk assessment and patient monitoring is a recommended approach. This approach can also include the use of abuse-deterrent and abuse-resistant formulations designed to reduce the nonmedical use of opioids. Several of these opioid formulations have been approved or should soon be on the market for use in the United States; however, their role and other questions regarding their use remain unanswered. The authors offer their clinical perspective on several of these key questions. PMID- 21823555 TI - House of delegates. The times they are a-changing. PMID- 21823556 TI - I'm growing older but not up. PMID- 21823557 TI - 2011-2012 AMS President Stephen Magie, MD. "It's all about relationships". PMID- 21823558 TI - Women's health: 2011 updates. PMID- 21823559 TI - Legislative review. PMID- 21823560 TI - Good practice in wound closure. PMID- 21823561 TI - Children, parents and teachers back lessons in resuscitation. PMID- 21823562 TI - Organ donation rate raised by dedicated nurse-led service. PMID- 21823563 TI - Treating burns caused by hydrofluoric acid. AB - Hydrofluoric acid is an ingredient of many common household and industrial solutions. Even seemingly minor burns caused by this acid can have catastrophic effects if they are treated inappropriately or late. This article describes the signs and symptoms, the pathophysiology and the emergency management of hydrofluoric acid burns. PMID- 21823564 TI - Documenting and treating acute pain in children. AB - Pain management for children in emergency departments is often inconsistent or inadequate due to a lack of appropriate protocols. This article discusses the development of such a protocol in an ED in Sydney, Australia, and how its implementation led to a huge improvement in documentation of pain scores and in the appropriateness of pain relief given. PMID- 21823565 TI - Using a patient at risk tool in the community. AB - This article discusses the development and implementation of a patient at risk tool for use in the community by members of a multidisciplinary rapid response team. It also discusses the results of a pilot study, which show that the tool can help staff identify patients whose conditions are most likely to deteriorate, and thereby ensure that these patients receive appropriate and timely care. PMID- 21823566 TI - Diagnosis and management of acute angle-closure glaucoma. AB - This article discusses a potential diagnosis and different methods of treatment for eye pain and blurred vision. PMID- 21823567 TI - Responses to a recurring admission alert system. AB - This article presents and discusses a service improvement project to introduce an automated alert system that notifies a nominated healthcare worker that a cancer patient has attended the emergency department (ED). The recurring admission patient alert (RAPA) system was introduced in one trust and alerts were sent and monitored for 16 weeks. During this period 155 alerts were received by eight clinical nurse specialists (CNSs) representing nine different tumour sites. At the same time a focus group was held with four of the CNSs. The RAPA system demonstrated a decrease in mean length of stay. The focus group highlighted that the system was integrated into the working lives of the CNSs. Further work is required to define the CNS role in the ED and also to share and spread the software to other specialties. PMID- 21823568 TI - Comparison of suture types in the closure of scalp wounds. AB - Innovation in practice can benefit patients and healthcare providers but must be evidence based. This article describes a quantitative study of whether absorbable sutures are as beneficial as non-absorbable sutures in the management of simple scalp lacerations in adults. The results suggest that absorbable sutures can provide the same cosmetic and functional results as non-absorbable sutures. Their use can also reduce patient returns and save money and resources. PMID- 21823569 TI - Investigation of the utility of laser-secondary neutral mass spectrometry for the detection of polyaromatic hydrocarbons in individual atmospheric aerosol particles. AB - The distribution of polyaromatic hydrocarbons (PAHs) in ambient aerosol particles is of importance to both human health and climate forcing. Although time-of flight secondary ion mass spectrometry (ToF-SIMS) has proven useful for studying the distribution of organic compounds in individual aerosol particles, it is difficult to detect PAHs at relevant concentrations in individual aerosol particles because of their low ion yield. In this study, we explore the potential of using laser secondary neutral mass spectrometry (Laser-SNMS) to study three PAHs: pyrene, anthracene, and naphthalene. Because of the high volatility of PAHs, a cryostage was required for the analysis to prevent sublimation of the molecules into the vacuum chamber. We studied two laser systems, a 157 nm excimer laser, which is capable of single-photon ionization of the PAHs, and a 193 nm laser, which requires multiphoton ionization. Under optimized conditions for laser power density and primary ion pulse length, 193 nm postionization resulted in a 2-50-fold increase in ion yield over ToF-SIMS. Using the 157 nm laser, the yield was increased by more than 3 orders of magnitude for all 3 PAHs studied. The single-photon postionization process proved superior in terms of both yield enhancement and reduced fragmentation. By using the optimized 157 nm laser system and a cryostage, we were able to detect PAHs on the surface of 2 MUm diameter ambient aerosol particles. PMID- 21823570 TI - Isomer-specific degradation of branched and linear 4-nonylphenol isomers in an oxic soil. AB - Using (14)C- and (13)C-ring-labeling, degradation of five p-nonylphenol (4-NP) isomers including four branched (4-NP(38), 4-NP(65), 4-NP(111), and 4-NP(112)) and one linear (4-NP(1)) isomers in a rice paddy soil was studied under oxic conditions. Degradation followed an availability-adjusted first-order kinetics with the decreasing order of half-life 4-NP(111) (10.3 days) > 4-NP(112) (8.4 days) > 4-NP(65) (5.8 days) > 4-NP(38) (2.1 days) > 4-NP(1) (1.4 days), which is in agreement with the order of their reported estrogenicities. One metabolite of 4-NP(111) with less polarity than the parent compound occurred rapidly and remained stable in the soil. At the end of incubation (58 days), bound residues of 4-NP(111) amounted to 54% of the initially applied radioactivity and resided almost exclusively in the humin fraction of soil organic matter, in which chemically humin-bound residues increased over incubation. Our results indicate an increase of specific estrogenicity of the remaining 4-NPs in soil as a result of the isomer-specific degradation and therefore underline the importance of understanding the individual fate (including degradation, metabolism, and bound residue formation) of isomers for risk assessment of 4-NPs in soil. 4-NP(1) should not be used as a representative of 4-NPs for studies on their environmental behavior. PMID- 21823572 TI - Self-assembled hierarchical MoO2/graphene nanoarchitectures and their application as a high-performance anode material for lithium-ion batteries. AB - Self-assembled hierarchical MoO(2)/graphene nanoarchitectures have been fabricated on a large scale through a facile solution-phase process and subsequent reduction of the Mo-precursor/graphene composite. The as-formed MoO(2)/graphene nanohybrid as an anode material for lithium-ion batteries exhibits not only a highly reversible capacity but also an excellent cycling performance as well as good rate capability. Results show that the hierarchical rods made of primary MoO(2) nanocrystals are uniformly encapsulated within the graphene sheets. The synergistic effect of the hierarchical nanoarchitecture and the conducting graphene support may contribute to the enhanced electrochemical performances of the hybrid MoO(2)/graphene electrode. This work presents a facile synthetic strategy that is potentially competitive for scaling-up industrial production. Besides, the MoO(2)/graphene hybrids with a well-defined hierarchical topology not only provide flexible building blocks for advanced functional devices, but are also ideal candidates for studying their nanoarchitecture dependent performances in catalytic and electronic applications. PMID- 21823571 TI - Accumulation dynamics of chlordanes and their enantiomers in cockerels (Gallus gallus) after oral exposure. AB - After a single oral exposure of technical chlordane, levels of cis-chlordane (CC), trans-chlordane (TC), heptachlor (HEP), heptachlorepoxide (HEPX), and oxychlordane (OXY) were determined in gastrointestinal residues, droppings, and various tissues of cockerels at times of 60, 120, 160, 200, 300, 500, 1000, and 2000 min. Over 98% of CC and TC were found to be bioaccessible; only 1.1% of CC and TC were directly excreted through droppings without further biotransformation. According to the single-compartment toxicokinetic modeling, CC and TC shared similar absorption rates in the whole body while TC showed a slightly more rapid elimination rate, with a half-life of 13.4 h for CC and 12.5 h for TC. The metabolites HEPX and OXY appeared quickly in tissues 60 min after exposure and were mainly accumulated in fat and liver tissues. Concentrations of CC, TC, and HEP in cockerel tissues roughly followed the order as fat > intestine > skin > liver> brain > muscle > blood. Levels of CC, TC, and HEP in various tissues showed significant correlation with the lipid contents of the tissues (p < 0.05) for samples beginning 500 min after exposure. A multicompartment toxicokinetic model was developed to characterize the accumulation dynamics of CC and TC in the various tissues. All tissues of cockerels enantioselectively accumulated (-)-CC and (+)-TC, and fat, skin, and liver tissues showed a relatively stronger capacity of enantioenrichment. The enantiomer fractions (EFs) of droppings remained nearly racemic at first but gradually decreased to less than 0.5 for CC and increased to more than 0.5 for TC, which could rule out enantioselective absorption and excretion of CC and TC in cockerels. The one compartment toxicokinetic model was applied to the individual enantiomers of CC and TC. Different elimination rates but similar absorption rates were observed between the enantiomers for both CC and TC. PMID- 21823573 TI - Bond shortening (1.4 A) in the singlet and triplet excited states of [Ir2(dimen)4]2+ in solution determined by time-resolved X-ray scattering. AB - Ground- and excited-state structures of the bimetallic, ligand-bridged compound Ir2(dimen)4(2+) are investigated in acetonitrile by means of time-resolved X-ray scattering. Following excitation by 2 ps laser pulses at 390 nm, analysis of difference scattering patterns obtained at eight different time delays from 250 ps to 300 ns yields a triplet excited-state distance between the two Ir atoms of 2.90(2) A and a triplet excited-state lifetime of 410(70) ns. A model incorporating the presence of two ground-state structures differing in Ir-Ir separation is demonstrated to fit the obtained data very well, in agreement with previous spectroscopic investigations. Two ground-state isomers with Ir-Ir separations of 3.60(9) and 4.3(1) A are found to contribute equally to the difference scattering signal at short time delays. Further studies demonstrate the feasibility of increasing the effective time resolution from the 100 ps probe width down to the 10 ps regime by positioning the laser pump pulse at selected points in the X-ray probe pulse. This approach is used to investigate the structures of both the singlet and the triplet excited states of Ir2(dimen)4(2+). PMID- 21823574 TI - On the formation of "hypercoordinated" uranyl complexes. AB - Recent gas-phase experimental studies suggest the presence of hypercoordinated uranyl complexes. Coordination of acetone (Ace) to uranyl to form hypercoordinated species is examined using density functional theory (DFT) with a range of functionals and second-order perturbation theory (MP2). Complexes with up to eight acetones were studied. It is shown that no more than six acetones can bind directly to uranium and that the observed uranyl complexes are not hypercoordinated. In addition, other more exotic species involving proton transfer between acetones and species involving enol tautomers of acetone are high-energy species that are unlikely to form. PMID- 21823575 TI - Swerilactones L-O, secoiridoids with C12 and C13 skeletons from Swertia mileensis. AB - Swerilactones L-O (1-4), four unusual secoiridoids with unprecedented C12 and C13 skeletons, were isolated from the traditional Chinese herb Swertia mileensis. Compounds 1 and 2 had moderate inhibitory activities against the secretion of hepatitis B virus surface antigen (IC50 = 1.47 and 1.20 mM, with SI < 1 and 1.53, respectively) and hepatitis B virus e antigen (IC50 = 0.88 and >2.69 mM, with SI 1.62 and <1, respectively) in an antihepatitis B virus assay on the Hep G 2.2.15 cell line in vitro. PMID- 21823576 TI - N-heterocyclic carbene ligands as mimics of imidazoles/histidine for the stabilization of di- and trinitrosyl iron complexes. AB - N-heterocyclic carbenes (NHCs) are shown to be reasonable mimics of imidazole ligands in dinitrosyl iron complexes determined through the synthesis and characterization of a series of {Fe(NO)(2)}(10) and {Fe(NO)(2)}(9) (Enemark Feltham notation) complexes. Monocarbene complexes (NHC-iPr)(CO)Fe(NO)(2) (1) and (NHC-Me)(CO)Fe(NO)(2) (2) (NHC-iPr = 1,3-diisopropylimidazol-2-ylidene and NHC-Me = 1,3-dimethylimidazol-2-ylidene) are formed from CO/L exchange with Fe(CO)(2)(NO)(2). An additional equivalent of NHC results in the bis-carbene complexes (NHC-iPr)(2)Fe(NO)(2) (3) and (NHC-Me)(2)Fe(NO)(2) (4), which can be oxidized to form the {Fe(NO)(2)}(9) bis-carbene complexes 3(+) and 4(+). Treatment of complexes 1 and 2 with [NO]BF(4) results in the formation of uncommon trinitrosyl iron complexes, (NHC-iPr)Fe(NO)(3)(+) (5(+)) and (NHC Me)Fe(NO)(3)(+) (6(+)), respectively. Cleavage of the Roussin's Red "ester" (MU SPh)(2)[Fe(NO)(2)](2) with either NHC or imidazole results in the formation of (NHC-iPr)(PhS)Fe(NO)(2) (7) and (Imid-iPr)(PhS)Fe(NO)(2) (10) (Imid-iPr = 2 isopropylimidazole). The solid-state molecular structures of complexes 1, 2, 3, 4, 5(+), and 7 show that they all have pseudotetrahedral geometry. Infrared spectroscopic data suggest that NHCs are slightly better electron donors than imidazoles; electrochemical data are also consistent with what is expected for typical donor/acceptor abilities of the spectator ligands bound to the Fe(NO)(2) unit. Although the monoimidazole complex (Imid-iPr)(CO)Fe(NO)(2) (8) was observed via IR spectroscopy, attempts to isolate this complex resulted in the formation of a tetrameric {Fe(NO)(2)}(9) species, [(Imid-iPr)Fe(NO)(2)](4) (9), a molecular square analogous to the unsubstituted imidazole reported by Li and Wang et al. Preliminary NO-transfer studies demonstrate that the {Fe(NO)(2)}(9) bis-carbene complexes can serve as a source of NO to a target complex, whereas the {Fe(NO)(2)}(10) bis-carbenes are unreactive in the presence of a NO-trapping agent. PMID- 21823577 TI - Modulation of metal-metal separations in a series of Ag(I) and intensely blue photoluminescent Cu(I) NHC-bridged triangular clusters. AB - A series of picolyl-substituted NHC-bridged triangular complexes of Ag(I) and Cu(I) were synthesized upon reaction of the corresponding ligand precursors, [Him(CH(2)py)(2)]BF(4) (1a), [Him(CH(2)py-3,4-(OMe)(2))(2)]BF(4) (1b), [Him(CH(2)py-3,5-Me(2)-4-OMe)(2)]BF(4) (1c), [Him(CH(2)py-6-COOMe)(2)]BF(4) (1d), and [H(S)im(CH(2)py)(2)]BF(4) (1e), with Ag(2)O and Cu(2)O, respectively. Complexes [Cu(3)(im(CH(2)py)(2))(3)](BF(4))(3) (2a), [Cu(3)(im(CH(2)py-3,4 (OMe)(2))(2))(3)](BF(4))(3) (2b), [Cu(3)(im(CH(2)py-3,5-Me(2)-4 OMe)(2))(3)](BF(4))(3), (2c), [Ag(3)(im(CH(2)py-3,4-(OMe)(2))(2))(3)](BF(4))(3), (3b), [Ag(3)(im(CH(2)py-3,5-Me(2)-4-OMe)(2))(3)](BF(4))(3) (3c), [Ag(3)(im(CH(2)py-6-COOMe)(2))(3)](BF(4))(3) (3d), and [Ag(3)((S)im(CH(2)py)(2))(3)](BF(4))(3) (3e) were easily prepared by this method. Complex 2e, [Cu(3)((S)im(CH(2)py)(2))(3)](BF(4))(3), was synthesized by a carbene transfer reaction of 3e, [Ag(3)((S)im(CH(2)py)(2))(3)](BF(4))(3), with CuCl in acetonitrile. The ligand precursor 1d did not react with Cu(2)O. All complexes were fully characterized by NMR, UV-vis, and luminescence spectroscopies and high resolution mass spectrometry. Complexes 2a-2c, 2e, and 3b-3e were additionally characterized by single-crystal X-ray diffraction. Each metal complex contains a nearly equilateral triangular M(3) core wrapped by three bridging NHC ligands. In 2a-2c and 2e, the Cu-Cu separations are short and range from 2.4907 to 2.5150 A. In the corresponding Ag(I) system, the metal-metal separations range from 2.7226 to 2.8624 A. The Cu(I)-containing species are intensely blue photoluminescent at room temperature both in solution and in the solid state. Upon UV excitation in CH(3)CN, complexes 2a-2c and 2e emit at 459, 427, 429, and 441 nm, whereas in the solid state, these bands move to 433, 429, 432, and 440 nm, respectively. As demonstrated by (1)H NMR spectroscopy, complexes 3b-3e are dynamic in solution and undergo a ligand dissociation process. Complexes 3b-3e are weakly photoemissive in the solid state. PMID- 21823578 TI - Facilitated ion transport in all-solid-state flexible supercapacitors. AB - The realization of highly flexible and all-solid-state energy-storage devices strongly depends on both the electrical properties and mechanical integrity of the constitutive materials and the controlled assembly of electrode and solid electrolyte. Herein we report the preparation of all-solid-state flexible supercapacitors (SCs) through the easy assembly of functionalized reduced graphene oxide (f-RGO) thin films (as electrode) and solvent-cast Nafion electrolyte membranes (as electrolyte and separator). In particular, the f-RGO based SCs (f-RGO-SCs) showed a 2-fold higher specific capacitance (118.5 F/g at 1 A/g) and rate capability (90% retention at 30 A/g) compared to those of all-solid state graphene SCs (62.3 F/g at 1A/g and 48% retention at 30 A/g). As proven by the 4-fold faster relaxation of the f-RGO-SCs than that of the RGO-SCs and more capacitive behavior of the former at the low-frequency region, these results were attributed to the facilitated ionic transport at the electrical double layer by means of the interfacial engineering of RGO by Nafion. Moreover, the superiority of all-solid-state flexible f-RGO-SCs was demonstrated by the good performance durability under the 1000 cycles of charging and discharging due to the mechanical integrity as a consequence of the interconnected networking structures. Therefore, this research provides new insight into the rational design and fabrication of all-solid-state flexible energy-storage devices as well as the fundamental understanding of ion and charge transport at the interface. PMID- 21823579 TI - Flexible and hydrophobic Zn-based metal-organic framework. AB - A zinc-based metal-organic framework Zn(2)(adb)(2)(dabco).4.5 DMF (K) (DUT 30(Zn), DUT = Dresden University of Technology, adb = 9,10-anthracene dibenzoate, dabco =1,4-diazabicyclo[2.2.2]octane, DMF = N,N-dimethylformamide) was synthesized using a solvothermal route. This MOF exhibits six crystallographic guest dependent phases. Two of them were characterized via single crystal X-ray analysis. The as-synthesized phase K crystallizes in the orthorhombic space group Fmmm, with a = 9.6349(9), b = 26.235(3), and c = 28.821(4) A and consists of two interpenetrated pillar-layer networks with pcu topology. When the substance loses 0.5 DMF molecules per formula unit, a phase transition from the kinetic phase K to a thermodynamic phase T occurs. Zn(2)(adb)(2)(dabco).4 DMF (T) crystallizes in the tetragonal space group I4/mmm, with a = 19.5316(8) and c = 9.6779(3) A. During the evacuation the DUT-30(Zn) undergoes again the structural transformation to A. The activated compound A shows the gate pressure effect in the low pressure region of nitrogen physisorption isotherm and has a BET surface area of 960 m(2 )g(-1) and a specific pore volume of 0.43 cm(3) g(-1). Furthermore, DUT-30(Zn) exhibits a hydrogen storage capacity of 1.12 wt % at 1 bar, a CO(2) uptake of 200 cm(3) g(-1) at -78 degrees C and 0.9 bar, and a n butane uptake of 3.0 mmol.g(-1) at 20 degrees C. The N(2) adsorption process was monitored in situ via X-ray powder diffraction using synchrotron radiation. A low temperature induced transformation of phase A to phase V could be observed if the compound was cooled under vacuum to -196 degrees C. A further crystalline phase N could be identified if the framework was filled with nitrogen at -196 degrees C. Additionally, the treatment of activated phase A with water leads to the new phase W. PMID- 21823580 TI - Design and synthesis of C2-symmetric N-heterocyclic carbene precursors and metal carbenoids. AB - Chiral, C(2)-symmetric imidazolium and imidazolinium ions, as well as the corresponding copper- or silver-bound carbenoids, have been prepared. Structural study of these compounds by X-ray crystallography reveals a chiral pocket that surrounds the putative carbene site or the metal-carbene bond, at carbon 2, in three of the four ligands prepared. Preliminary investigation into the application of these complexes has shown one of them to be highly enantioselective in the hydrosilylation of acetophenone. PMID- 21823582 TI - Low dose gamma-irradiation as a suitable solution for chestnut (Castanea sativa Miller) conservation: effects on sugars, fatty acids, and tocopherols. AB - Along with dehydration, the development of insects and microorganisms is the major drawback in chestnut conservation. Irradiation has been regaining interest as an alternative technology to increase food product shelf life. In the present work, the effects of low dose gamma irradiation on the sugar, fatty acid, and tocopherol composition of chestnuts stored at 4 degrees C for different storage periods (0, 30, and 60 days) was evaluated. The irradiations were performed in a 60Co experimental equipment, for 1 h (0.27+/-0.04 kGy) and 2 h (0.54+/-0.04 kGy). Changes in sugars and tocopherols were determined by high performance liquid chromatography coupled to refraction index and fluorescence detections, respectively, while changes in fatty acids were analyzed by gas-chromatography coupled to flame ionization detection. Regarding sugar composition, storage time proved to have a higher effect than irradiation treatment. Fructose and glucose increased after storage, with the corresponding decrease of sucrose. Otherwise, the tocopherol content was lower in nonirradiated samples, without a significant influence of storage. Saturated, monounsaturated, and polyunsaturated fatty acids levels were not affected, either by storage or irradiation. Nevertheless, some individual fatty acid concentrations were influenced by one of two factors, such as the increase of palmitic acid in irradiated samples or the decrease of oleic acid after 60 days of storage. Overall, the assayed irradiation doses seem to be a promising alternative treatment to increase chestnut shelf life, without affecting the profile and composition in important nutrients. PMID- 21823581 TI - A general method for copper-catalyzed arene cross-dimerization. AB - A general method for a highly regioselective copper-catalyzed cross-coupling of two aromatic compounds using iodine as an oxidant has been developed. The reactions involve an initial iodination of one arene followed by arylation of the most acidic C-H bond of the other coupling component. Cross-coupling of electron rich arenes, electron-poor arenes, and five- and six-membered heterocycles is possible in many combinations. Typically, a 1/1.5 to 1/3 ratio of coupling components is used, in contrast to existing methodology that often employs a large excess of one of the arenes. Common functionalities such as ester, ketone, aldehyde, ether, nitrile, nitro, and amine are well-tolerated. PMID- 21823583 TI - Poisson-Boltzmann theory of pH-sensitive (annealing) polyelectrolyte brush. AB - We present a self-consistent field analytical theory of a polymer brush formed by weakly charged pH-sensitive (annealing) polyelectrolytes tethered to a solid liquid interface and immersed in buffer solution of low molecular weight salt. We use the Poisson-Boltzmann framework, applied by us previously to polyelectrolyte (PE) brushes with quenched charge (Zhulina, E. B.; Borisov, O. V. J. Chem. Phys. 1997, 107, 5952). This approach allows for detailed analysis of the internal structure of annealing PE brush in terms of polymer density distribution, profiles of electrostatic potential and of local degree of chain ionization as a function of buffer ionic strength and pH without any assumptions on mobile ion distribution imposed in earlier scaling-type models. The presented analytical theory recovers all major asymptotic dependences for average brush properties predicted earlier. In particular, a nonmonotonic dependence of brush thickness on ionic strength and grafting density is confirmed and specified with accuracy of numerical coefficients including crossover regions. Moreover, the theory predicts qualitatively new effects, such as, e.g., disproportionation of tethered polyions into weakly charged concentrated proximal and strongly charged sparse distal brush domains at low salt and moderate grating densities. The presented results allow us to quantify responsive features of annealing PE brushes whose large scale and local conformational properties can be manipulated by external stimuli. PMID- 21823584 TI - Intrinsic reaction parameters for electron transfer from aromatic radical anions to vicinal dibromoalkanes in alkane solutions. AB - In diffusion-assisted bimolecular reactions, the elementary reaction mechanism is typically difficult to study, because the kinetics of the intrinsic reaction is masked by the diffusive motion of the reactants. One of the possible experimental approaches to solve the problem is the precise determination of the effective reaction radii, R = k/(4piD(S)), where k is the stationary value of the reaction rate constant and D(S) is the sum of the diffusion coefficients of the reactants involved. In this work, this approach has been applied to study the reaction between radical anions of aromatic compounds (diphenylacetylene and diphenylsilane) and vicinal dibromoalkanes (1,2-dibromoethane and trans-1,2 dibromocyclohexane) in liquid alkanes. The reaction rates were determined using the effect that the bromoalkanes exert on the decay kinetics of the fluorescence from the irradiated solutions of the aromatics. The effect of the external electric field on the fluorescence decays was exploited to measure aromatic radical ion mobilities. Diffusion coefficients of the bromoalkane molecules were determined by means of the thermal diffusion forced Rayleigh scattering technique. The experimental radii obtained in the temperature range of 273-333 K were compared with those calculated from the diffusion equation with a distance dependent relative diffusion coefficient and electron-transfer rate. The most important factors that have been taken into account are (i) the ion-dipole interaction between the reagents, (ii) the shift of the equilibrium between rotational isomers of dibromoalkanes in the electric field of its charged partner, and (iii) the hydrodynamic interaction. The study shows that the apparent activation energy of the intrinsic electron-transfer rate from the anions to the dibromoalkanes does not exceed a few kilocalories per mole, in agreement with the results of quantum chemical calculations within the DFT approach. The evaluated electron-transfer rates at the reagents' contact (intrinsic rate) were estimated to be on the order 5 * 10(11) s(-1), corresponding to transfer matrix elements of about 30-50 cm(-1). PMID- 21823586 TI - Air-stable Pd(R-allyl)LCl (L= Q-Phos, P(t-Bu)3, etc.) systems for C-C/N couplings: insight into the structure-activity relationship and catalyst activation pathway. AB - A series of Pd(R-allyl)LCl complexes [R = H, 1-Me, 1-Ph, 1-gem-Me(2), 2-Me; L = Q Phos, P(t-Bu)(3), P(t-Bu)(2)(p-NMe(2)C(6)H(4)), P(t-Bu)(2)Np] have been synthesized and evaluated in the Buchwald-Hartwig aminations in detail, in addition to the preliminary studies on Suzuki coupling and alpha-arylation reactions. Pd(crotyl)Q-PhosCl (9) was found to be a superior catalyst to the other Q-Phos-based catalysts, and the reported in situ systems, in model coupling reactions involving 4-bromoanisole substrate with either N-methylaniline or 4 tert-butylbenzeneboronic acid. Precatalyst 9 also performed better than the catalysts bearing P(t-Bu)(2)(p-NMe(2)C(6)H(4)) ligand; however, it is comparable to the new crotyl catalysts bearing P(t-Bu)(3) or P(t-Bu)(2)Np ligands. In alpha arylation of a biologically important model substrate, 1-tetralone, Pd(allyl)P(t Bu)(2)(p-NMe(2)C(6)H(4))Cl (15) was found to be the best catalyst. The reason for the relatively higher activity of the crotyl complexes in comparison to the allyl derivatives in C-N bond formation reactions was investigated using X-ray crystallography in conjunction with NMR spectroscopic studies. PMID- 21823587 TI - Structural basis for a Kolbe-type decarboxylation catalyzed by a glycyl radical enzyme. AB - 4-Hydroxyphenylacetate decarboxylase is a [4Fe-4S] cluster containing glycyl radical enzyme proposed to use a glycyl/thiyl radical dyad to catalyze the last step of tyrosine fermentation in clostridia. The decarboxylation product p-cresol (4-methylphenol) is a virulence factor of the human pathogen Clostridium difficile . Here we describe the crystal structures at 1.75 and 1.81 A resolution of substrate-free and substrate-bound 4-hydroxyphenylacetate decarboxylase from the related Clostridium scatologenes . The structures show a (betagamma)(4) tetramer of heterodimers composed of a catalytic beta-subunit harboring the putative glycyl/thiyl dyad and a distinct small gamma-subunit with two [4Fe-4S] clusters at 40 A distance from the active site. The gamma-subunit comprises two domains displaying pseudo-2-fold symmetry that are structurally related to the [4Fe-4S] cluster-binding scaffold of high-potential iron-sulfur proteins. The N terminal domain coordinates one cluster with one histidine and three cysteines, and the C-terminal domain coordinates the second cluster with four cysteines. Whereas the C-terminal cluster is buried in the betagamma heterodimer interface, the N-terminal cluster is not part of the interface. The previously postulated decarboxylation mechanism required the substrate's hydroxyl group in the vicinity of the active cysteine residue. In contrast to expectation, the substrate-bound state shows a direct interaction between the substrate's carboxyl group and the active site Cys503, while His536 and Glu637 at the opposite side of the active site pocket anchor the hydroxyl group. This state captures a possible catalytically competent complex and suggests a Kolbe-type decarboxylation for p cresol formation. PMID- 21823585 TI - Environmentally persistent free radicals (EPFRs). 1. Generation of reactive oxygen species in aqueous solutions. AB - Reactive oxygen species (ROS) generated by environmentally persistent free radicals (EPFRs) of 2-monochlorophenol, associated with CuO/silica particles, were detected using the chemical spin trap, 5,5-dimethyl-1-pyrroline-N-oxide (DMPO), in conjunction with electron paramagnetic resonance (EPR) spectroscopy. Yields of hydroxyl radical ((*)OH), superoxide anion radical (O(2)(*-)), and hydrogen peroxide (H(2)O(2)) generated by EPFR-particle systems were reported. Failure to trap superoxide radicals in aqueous solvent, formed from reaction of EPFRs with molecular oxygen, results from fast transformation of the superoxide to hydrogen peroxide. However, formation of superoxide as an intermediate product in hydroxyl radical formation in aprotic solutions of dimethyl sulfoxide (DMSO) and acetonitrile (AcN) was observed. Experiments with superoxide dismutase (SOD) and catalase (CAT) confirmed formation of superoxide and hydrogen peroxide, respectively, in the presence of EPFRs. The large number of hydroxyl radicals formed per EPFR and monotonic increase of the DMPO-OH spin adduct concentration with incubation time suggest a catalytic cycle of ROS formation. PMID- 21823588 TI - Chemical-biological studies of subcellular organization in bacteria. AB - The subcellular organization of biological molecules is a critical determinant of many bacterial processes, including growth, replication of the genome, and division, yet the details of many mechanisms that control intracellular organization remain unknown. Decoding this information will impact the field of bacterial physiology and can provide insight into eukaryotic biology, including related processes in mitochondria and chloroplasts. Small molecule probes provide unique advantages in studying these mechanisms and manipulating the organization of biomolecules in live bacterial cells. In this review, we describe small molecules that are available for investigating subcellular organization in bacteria, specifically targeting FtsZ, MreB, peptidoglycan, and lipid bilayers. We discuss how these probes have been used to study microbiological questions and conclude by providing suggestions about important areas in which chemical biological approaches will have a revolutionary impact on the study of bacterial physiology. PMID- 21823589 TI - Current status and research strategies in tuberculosis drug development. PMID- 21823590 TI - Reaction of beta-lactam carbenes with 2-pyridyl isonitriles: a one-pot synthesis of 2-carbonyl-3-(pyridylamino)imidazo[1,2-a]pyridines useful as fluorescent probes for mercury ion. AB - The one-pot reaction of beta-lactam carbenes with 2-pyridyl isonitriles followed by an acidic hydrolysis was reported, which produced 2-carbonyl-3 (pyridylamino)imidazo[1,2-a]pyridines in moderate to good yields. Among the resulting novel imidazo[1,2-a]pyridine derivatives, 1-(6-chloro-3-(5 chloropyridin-2-ylamino)imidazo[1,2-a]pyridin-2-yl)-2-ethylbutan-1-one was demonstrated to be an efficient fluorescent probe for mercury ion both in acetonitrile and in buffered aqueous solution. PMID- 21823591 TI - Pinene-derived iminodiacetic acid (PIDA): a powerful ligand for stereoselective synthesis and iterative cross-coupling of C(sp3) boronate building blocks. AB - Efficient access to chiral C(sp(3)) boronates in stereochemically pure form is critical for realizing the substantial potential of such building blocks in complex-molecule synthesis. We herein report that a pinene-derived iminodiacetic acid (PIDA) ligand enables the highly diastereoselective synthesis of a wide range of oxiranyl C(sp(3)) boronates from the corresponding olefins. These oxiranyl PIDA boronates, in turn, can be readily transformed into unprecedented stable alpha-boryl aldehydes via a novel 1,2-migration of the boronate group that proceeds with complete maintenance of stereochemical purity. B-Protected haloboronic acids containing dual sp(3)-hybridized C centers are readily accessible via this platform, and the herein demonstrated capacity for stereocontrolled iterative C(sp(3)) cross-coupling with this novel type of bifunctional reagent to access a medicinally important chiral small-molecule target in highly enantioenriched form represents a substantial advance for the building-block-based approach to synthesis. PMID- 21823592 TI - PBu3-mediated vinylogous Wittig reaction of alpha-methyl allenoates with aldehydes and mechanistic investigations. AB - A highly stereoselective PBu(3)-mediated vinylogous Wittig olefination between alpha-methyl allenoates and a variety of aldehydes is presented as the first example of a practical and synthetically useful vinylogous Wittig reaction. Mechanistic experiments including deuterium-labeling, intermediate entrapment, and NMR monitoring have been deliberately conducted. On the basis of mechanistic investigations, a reliable mechanism for the vinylogous Wittig reaction is proposed, which features a water/phosphine-coassisted allylic phosphorus ylide 1,3-rearrangement pathway, rather than previous retro-Diels-Alder ones. It is noteworthy that mechanistic findings in this work also provide supportive evidence for typical mechanisms of important phosphine-mediated reactions of allenoates. PMID- 21823593 TI - Theranostic magnetic nanoparticles. AB - Early detection and treatment of disease is the most important component of a favorable prognosis. Biomedical researchers have thus invested tremendous effort in improving imaging techniques and treatment methods. Over the past decade, concepts and tools derived from nanotechnology have been applied to overcome the problems of conventional techniques for advanced diagnosis and therapy. In particular, advances in nanoparticle technology have created new paradigms for theranostics, which is defined as the combination of therapeutic and diagnostic agents within a single platform. In this Account, we examine the potential advantages and opportunities afforded by magnetic nanoparticles as platform materials for theranostics. We begin with a brief overview of relevant magnetic parameters, such as saturation magnetization, coercivity, and magnetocrystalline anisotropy. Understanding the interplay of these parameters is critical for optimizing magnetic characteristics needed for effective imaging and therapeutics, which include magnetic resonance imaging (MRI) relaxivity, heat emission, and attractive forces. We then discuss approaches to constructing an MRI nanoparticle contrast agent with high sensitivity. We further introduce a new design concept for a fault-free contrast agent, which is a T1 and T2 dual mode hybrid. Important capabilities of magnetic nanoparticles are the external controllability of magnetic heat generation and magnetic attractive forces for the transportation and movement of biological objects. We show that these functions can be utilized not only for therapeutic hyperthermia of cancer but also for controlled release of cancer drugs through the application of an external magnetic field. Additionally, the use of magnetic nanoparticles to drive mechanical forces is demonstrated to be useful for molecular-level cell signaling and for controlling the ultimate fate of the cell. Finally, we show that targeted imaging and therapy are made possible by attaching a variety of imaging and therapeutic components. These added components include therapeutic genes (small interfering RNA, or siRNA), cancer-specific ligands, and optical reporting dyes. The wide range of accessible features of magnetic nanoparticles underscores their potential as the most promising platform material available for theranostics. PMID- 21823594 TI - Effect-directed analysis of municipal landfill soil reveals novel developmental toxicants in the zebrafish Danio rerio. AB - Effect-directed analysis (EDA) is an approach used to identify (unknown) contaminants in complex samples which cause toxicity, using a combination of biology and chemistry. The goal of this work was to apply EDA to identify developmental toxicants in soil samples collected from a former municipal landfill site. Soil samples were extracted, fractionated, and tested for developmental effects with an embryotoxicity assay in the zebrafish Danio rerio. Gas chromatograph mass selective detection (GC-MSD) chemical screening was used to reveal candidate developmental toxicants in fractions showing effects. In a parallel study, liquid chromatography-hybrid linear ion trap Orbitrap mass spectrometry was also applied to one polar subfraction (Hoogenboom et al. J. Chromatogr. A2009, 1216, 510-519). EDA resulted in the identification of a number of previously unknown developmental toxicants, which were confirmed to be present in soil by GC-MS. These included 11H-benzo[b]fluorene, 9-methylacridine, 4 azapyrene, and 2-phenylquinoline, as well as one known developmental toxicant (retene). This work revealed the presence of novel contaminants in the environment that may affect vertebrate development, which are not subject to monitoring or regulation under current soil quality assessment guidelines. PMID- 21823595 TI - Atomistic structure of a micelle in solution determined by wide Q-range neutron diffraction. AB - The accepted picture of the structure of a micelle in solution arises from the idea that the surfactant molecules self-assemble into a spherical aggregate, driven by the conflicting affinity of their head and tail groups with the solvent. It is also assumed that the micelle's size and shape can be explained by simple arguments involving volumetric packing parameters and electrostatic interactions. By using wide Q-range neutron diffraction measurements of H/D isotopically substituted solutions of decyltrimethylammonimum bromide (C(10)TAB) surfactants, we are able to determine the complete, atomistic structure of a micelle and its surroundings in solution. The properties of the micelle we extract are in agreement with previous experimental studies. We find that ~45 surfactant molecules aggregate to form a spherical micelle with a radius of gyration of 14.2 A and that the larger micelles are more ellipsoidal. The surfactant tail groups are hidden away from the solvent to form a central dry hydrophobic core. This is surrounded by a disordered corona containing the surfactant headgroups, counterions, water, and some alkyl groups from the hydrophobic tails. We find a Stern layer of 0.7 bromide counterion per surfactant molecule, in which the bromide counterions maintain their hydration shells. The atomistic resolution of this technique provides us with unprecedented detail of the physicochemical properties of the micelle in its solvent. PMID- 21823596 TI - A highly oriented cubic phase formed by lipids under shear. AB - We demonstrate the formation of a macroscopically oriented inverse bicontinuous cubic (Q(II)) lipid phase from a sponge (L(3)) phase by controlled hydration during shear flow. The L(3) phase was the monoolein/butanediol/water system; the addition of water reduces the butanediol concentration, inducing the formation of a diamond (Q(II)(D)) cubic phase, which is oriented by the shear flow. The phenomenon was reproduced in both capillary and Couette geometries, indicating that this represents a robust general route for the production of highly aligned bulk Q(II) samples, with applications in nanomaterial templating and protein research. PMID- 21823597 TI - Design and synthesis of novel arylpiperazine derivatives containing the imidazole core targeting 5-HT(2A) receptor and 5-HT transporter. AB - Serotonin antagonist reuptake inhibitor (SARI) drugs that block both 5-HT(2) receptors and the serotonin transporters have been developed. The human 5 HT(2A/2C) receptor has been implicated in several neurological conditions, and potent selective 5-HT(2A/2C) ligands may have therapeutic potential for treatment of CNS diseases such as depression. An imidazole moiety usually provides good pharmacokinetic properties as a drug substance, and thus considerable efforts have been devoted to develop imidazole derivatives into drug candidates. The imidazole series of compounds was evaluated against 5-HT(2A/2C) and serotonin reuptake inhibition. A few of the compounds in the series showed promising IC(50) values and antidepressant-like effect in in vivo forced swimming test (FST). On the basis of these results, further lead optimization studies resulted in identifying promising compounds potentially for therapeutic use. PMID- 21823598 TI - Ethylene irradiation: a new route to grow graphene on low reactivity metals. AB - A novel technique for growing graphene on relatively inert metals, consisting in the thermal decomposition of low energy ethylene ions irradiated on hot metal surfaces in ultrahigh vacuum, is reported. By this route, we have grown graphene monolayers on Cu(111) and, for the first time, on Au(111) surfaces. For both noble metal substrates, but particularly for Au(111), our scanning tunneling microscopy and spectroscopy measurements provide sound evidence of a very weak graphene-metal interaction. PMID- 21823600 TI - Articular cartilage proteoglycans as boundary lubricants: structure and frictional interaction of surface-attached hyaluronan and hyaluronan--aggrecan complexes. AB - Mammalian synovial joints are extremely efficient lubrication systems reaching friction coefficient MU as low as 0.001 at high pressures (up to 100 atm) and shear rates (up to 10(6) to 10(7) Hz); however, despite much previous work, the exact mechanism responsible for this behavior is still unknown. In this work, we study the molecular mechanism of synovial joint lubrication by emulating the articular cartilage superficial zone structure. Macromolecules extracted and purified from bovine hip joints using well-known biochemical techniques and characterized with atomic force microscope (AFM) have been used to reconstruct a hyaluronan (HA)--aggrecan layer on the surface of molecularly smooth mica. Aggrecan forms, with the help of link protein, supramolecular complexes with the surface-attached HA similar to those at the cartilage/synovial fluid interface. Using a surface force balance (SFB), normal and shear interactions between a HA- aggrecan-coated mica surface and bare mica have been examined, focusing, in particular, on the frictional forces. In each stage, control studies have been performed to ensure careful monitoring of the macromolecular surface layers. We found the aggrecan--HA complex to be a much better boundary lubricant than the HA alone, an effect attributed largely to the fluid hydration sheath bound to the highly charged glycosaminoglycan (GAG) segments on the aggrecan core protein. A semiquantitative model of the osmotic pressure is used to describe the normal force profiles between the surfaces and interpret the boundary lubrication mechanism of such layers. PMID- 21823601 TI - Direct observation of a noncatalytic growth regime for GaAs nanowires. AB - We identify a new noncatalytic growth regime for molecular beam epitaxially grown GaAs nanowires (NWs) that may provide a route toward axial heterostructures with discrete material boundaries and atomically sharp doping profiles. Upon increase of the As/Ga flux ratio, the growth mode of self-induced GaAs NWs on SiO(2) masked Si(111) is found to exhibit a surprising discontinuous transition in morphology and aspect ratio. For effective As/Ga ratios <1, in situ reflection high-energy electron diffraction measurements reveal clear NW growth delay due to formation of liquid Ga droplets since the growth proceeds via the vapor-liquid solid mechanism. In contrast, for effective As/Ga ratios >1 an immediate onset of NW growth is observed indicating a transition to droplet-free, facet-driven selective area growth with low vertical growth rates. Distinctly different microstructures, facet formation and either the presence or absence of Ga droplets at the apex of NWs, are further elucidated by transmission electron microscopy. The results show that the growth mode transition is caused by an abrupt change from As- to Ga-limited conditions at the (111)-oriented NW growth front, allowing precise tuning of the dominant growth mode. PMID- 21823599 TI - Cancer-targeted optical imaging with fluorescent zinc oxide nanowires. AB - Herein we demonstrate that intrinsically fluorescent zinc oxide (ZnO) nanowires (NWs) can be adopted for molecularly targeted imaging of cancer cells, after they are functionalized to render water solubility, biocompatibility, and low cellular toxicity. Optical imaging of integrin alpha(v)beta(3) on U87MG human glioblastoma cells was achieved with RGD peptide-conjugated green fluorescent ZnO NWs, which opened up new avenues of research for investigating ZnO NW-based agents in tumor vasculature-targeted molecular imaging and drug delivery. PMID- 21823602 TI - Gas dwell time control for rapid and long lifetime growth of single-walled carbon nanotube forests. AB - The heat history (i.e., "dwell time") of the carbon source gas was demonstrated as a vital parameter for very rapid single-walled carbon nanotube (SWNT) forest growth with long lifetime. When the dwell time was raised to 7 s from the 4 s used for standard growth, the growth rate increased to 620 MUm/min: a benchmark for SWNT forest growth on substrates. Importantly, the increase in growth rate was achieved without decreasing either the growth lifetime or the quality of the SWNTs. We interpret that the conversion rate of the carbon feedstock into CNTs was selectively increased (versus catalyst deactivation) by delivering a thermally decomposed carbon source with the optimum thermal history to the catalyst site. PMID- 21823603 TI - Long-lived photoacid based upon a photochromic reaction. AB - A visible-light activatable photoacid has been studied, which upon irradiation, changes from a weak acid, with a pK(a) of 7.8, to a strong acid, which achieves nearly complete proton dissociation. This process is reversible and the half-life of the proton-dissociation state is ~70s. The long lifetime of the proton dissociation state is due to a sequential intramolecular photochromic reaction. Using this photoacid, a pH change of 2.2 units has been achieved. In addition, we demonstrated that the photoinduced proton concentration can catalyze an esterification reaction, and greatly alter the volume of a pH-sensitive polymer. This work shows that acid-catalyzed and pH-sensitive processes can be photochemically controlled by using this type of photoacid. PMID- 21823605 TI - Enhancing light emission of ZnO microwire-based diodes by piezo-phototronic effect. AB - Light emission from semiconductors depends not only on the efficiency of carrier injection and recombination but also extraction efficiency. For ultraviolet emission from high band gap materials such as ZnO, nanowires have higher extraction efficiencies than thin films, but conventional approaches for creating a p-n diode result in low efficiency. We exploited the noncentral symmetric nature of n-type ZnO nanowire/p-type GaN substrate to create a piezoelectric potential within the nanowire by applying stress. Because of the polarization of ions in a crystal that has noncentral symmetry, a piezoelectric potential (piezopotential) is created in the crystal under stress. The piezopotential acts as a "gate" voltage to tune the charge transport and enhance carrier injection, which is called the piezo-phototronic effect. We propose that band modification traps free carriers at the interface region in a channel created by the local piezoelectric charges. The emission intensity and injection current at a fixed applied voltage have been enhanced by a factor of 17 and 4, respectively, after applying a 0.093% compressive strain and improved conversion efficiency by a factor of 4.25. This huge enhanced performance is suggested arising from an effective increase in the local "biased voltage" as a result of the band modification caused by piezopotential and the trapping of holes at the interface region in a channel created by the local piezoelectric charges near the interface. Our study can be extended from ultraviolet range to visible range for a variety of optoelectronic devices that are important for today's safe, green, and renewable energy technology. PMID- 21823606 TI - 7-azaindenoisoquinolines as topoisomerase I inhibitors and potential anticancer agents. AB - A series of 7-azaindenoisoquinoline topoisomerase I (Top1) inhibitors have been prepared to investigate the effect of increased electron affinity of the aromatic system on the ability to stabilize the Top1-DNA cleavage complex. Ab initio calculations suggest that introduction of nitrogen into the aromatic system of the indenoisoquinolines would facilitate charge transfer complex formation with DNA, thus improving the pi-pi stacking interactions. The present study shows that 7-azaindenoisoquinolines demonstrate improved water solubility without any decrease in Top1 inhibitory activity or cytotoxicity. Analysis of the biological results reveals that smaller lactam ring substituents enable intercalation into both free DNA and Top1-DNA cleavage complex, whereas larger substituents only allow binding to the cleavage complex but not free DNA. Free DNA binding suppresses Top1-catalyzed DNA cleavage at high drug concentrations, whereas DNA cleavage and inhibition of religation occurs at low drug concentration. PMID- 21823607 TI - Comment on "Effect of dissolved organic matter on the transformation of contaminants induced by excited triplet states and the hydroxyl radical". PMID- 21823608 TI - Interaction of monovalent ions with hydrophobic and hydrophilic colloids: charge inversion and ionic specificity. AB - Here we study experimentally and by simulations the interaction of monovalent organic and inorganic anions with hydrophobic and hydrophilic colloids. In the case of hydrophobic colloids, our experiments show that charge inversion is induced by chaotropic inorganic monovalent ions but it is not induced by kosmotropic inorganic anions. For organic anions, giant charge inversion is observed at very low electrolyte concentrations. In addition, charge inversion disappears for both organic and inorganic ions when turning to hydrophilic colloids. These results provide an experimental evidence for the hydrophobic effect as the driving force for both ion specific effects and charge inversion. In the case of organic anions, our molecular dynamics (MD) simulations with full atomic detail show explicitly how the large adsorption free energies found for hydrophobic colloids are transformed into large repulsive barriers for hydrophilic colloids. Simulations confirm that solvation free energy (and hence the hydrophobic effect) is responsible for the build up of a Stern layer of adsorbed ions and charge inversion in hydrophobic colloids and it is also the mechanism preventing charge inversion in hydrophilic colloids. Overall, our experimental and simulation results suggest that the interaction of monovalent ions with interfaces is dominated by solvation thermodynamics, that is, the chaotropic/kosmotropic character of ions and the hydrophobic/hydrophilic character of surfaces. PMID- 21823609 TI - Kinetic resolution of N-acyl-beta-lactams via benzotetramisole-catalyzed enantioselective alcoholysis. AB - The first nonenzymatic kinetic resolution of beta-lactams has been achieved. Alcoholysis of their N-aroyl derivatives in the presence of a simple chiral acyl transfer catalyst, benzotetramisole, produces beta-amino acid derivatives with excellent enantioselectivity. PMID- 21823610 TI - Deactivation efficiency of stabilized bactericidal emulsions. AB - Biocide emulsions stabilized with various stabilizing agents were prepared and characterized, and their efficiency in bacteria deactivation was evaluated. A number of stabilizing agents were tested for their stabilizing effect on emulsions of thiocyanomethylthiobenzothiazole (TCMTB) biocide. Two agents, the most successful in stabilizing the biocide, were chosen for further studies: high molecular weight polyethyleneimine (PEI) and an amphiphilic block copolymer of poly(caprolactone)-b-poly(acrylic acid) (PCL(33)-b-PAA(33)). The emulsion droplet sizes varied between 325 and 500 nm. Deactivation of bacteria was studied by exposing E. coli ATCC 11229 bacteria dispersions to emulsions stabilized by positively charged PEI or negatively charged PCL-b-PAA micelles and by measuring their absorbance; E. coli do not grow with time in the presence of biocide emulsions. PEI molecules alone act as biocide and deactivate the bacteria. PCL-b PAA micelles as stabilizing agent do not affect the growth of the E. coli ; bacteria are deactivated by TCMTB released from the emulsion droplets. The kinetics of emulsion dissolution studies revealed for both stabilizing agents a decrease in droplet size with time while the emulsions were subjected to dialysis. The biocide was released from the emulsions within ~250 min; the droplet shells consist mostly of PEI or PCL-b-PAA insoluble complexes with the biocide, which do not dissolve during dialysis. SEM images confirm the presence of residual crumbled shells with holes after 24 h of dialysis. PMID- 21823611 TI - Adiabatic and nonadiabatic bond cleavages in Norrish type I reaction. AB - One of the fundamental photoreactions for ketones is Norrish type I reaction, which has been extensively studied both experimentally and theoretically. Its alpha bond-cleavage mechanisms are usually explained in an adiabatic picture based on the involved excited-state potential energy surfaces, but scarcely investigated in terms of a nonadiabatic picture. In this work, the S(1) alpha bond-cleavage reactions of CH(3)OC(O)Cl have been investigated by using the CASSCF and MRCI-SD calculations, and the ab initio based time-dependent quantum wavepacket simulation. The numerical results indicate that the photoinduced dissociation dynamics of CH(3)OC(O)Cl could exhibit strong nonadiabatic bond fission characteristics for the S(1) alpha C-Cl bond cleavage, while the dynamics of the S(1) alpha C-O bond cleavage is mainly of adiabatic characteristics. This nonadiabatic mechanism for Norrish type I reaction of CH(3)OC(O)Cl is uncovered for the first time. The quantum wavepacket dynamics, based on the reduced dimensional coupled potential energy surfaces, to some extent illustrates the significance of the nonadiabatic effect in the transition-state region on the dynamics of Norrish type I reaction. PMID- 21823613 TI - Three-dimensional multiple-order twinning of self-catalyzed GaAs nanowires on Si substrates. AB - In this paper we introduce a new paradigm for nanowire growth that explains the unwanted appearance of parasitic nonvertical nanowires. With a crystal structure polarization analysis of the initial stages of GaAs nanowire growth on Si substrates, we demonstrate that secondary seeds form due to a three-dimensional twinning phenomenon. We derive the geometrical rules that underlie the multiple growth directions observed experimentally. These rules help optimizing nanowire array devices such as solar or water splitting cells or of more complex hierarchical branched nanowire devices. PMID- 21823612 TI - Cell death induced by the Jak2 inhibitor, G6, correlates with cleavage of vimentin filaments. AB - Hyperkinetic Jak2 tyrosine kinase signaling has been implicated in several human diseases including leukemia, lymphoma, myeloma, and the myeloproliferative neoplasms. Using structure-based virtual screening, we previously identified a novel Jak2 inhibitor named G6. We showed that G6 specifically inhibits Jak2 kinase activity and suppresses Jak2-mediated cellular proliferation. To elucidate the molecular and biochemical mechanisms by which G6 inhibits Jak2-mediated cellular proliferation, we treated Jak2-V617F expressing human erythroleukemia (HEL) cells for 12 h with either vehicle control or 25 MUM of the drug and compared protein expression profiles using two-dimensional gel electrophoresis. One differentially expressed protein identified by electrospray mass spectroscopy was the intermediate filament protein, vimentin. It was present in DMSO treated cells but absent in G6 treated cells. HEL cells treated with G6 showed both time- and dose-dependent cleavage of vimentin as well as a marked reorganization of vimentin intermediate filaments within intact cells. In a mouse model of Jak2 V617F mediated human erythroleukemia, G6 also decreased the levels of vimentin protein, in vivo. The G6-induced cleavage of vimentin was found to be Jak2 dependent and calpain-mediated. Furthermore, we found that intracellular calcium mobilization is essential and sufficient for the cleavage of vimentin. Finally, we show that the cleavage of vimentin intermediate filaments, per se, is sufficient to reduce HEL cell viability. Collectively, these results suggest that G6-induced inhibition of Jak2-mediated pathogenic cell growth is concomitant with the disruption of intracellular vimentin filaments. As such, this work describes a novel pathway for the targeting of Jak2-mediated pathological cell growth. PMID- 21823614 TI - Copper-mediated aerobic synthesis of 3-azabicyclo[3.1.0]hex-2-enes and 4 carbonylpyrroles from N-allyl/propargyl enamine carboxylates. AB - Synthetic methods for 3-azabicyclo[3.1.0]hex-2-enes and 4-carbonylpyrroles have been developed that use copper-mediated/catalyzed reactions of N-allyl/propargyl enamine carboxylates under an O(2) atmosphere and involve intramolecular cyclopropanation and carbooxygenation, respectively. These methodologies take advantage of orthogonal modes of chemical reactivity of readily available N allyl/propargyl enamine carboxylates; the complementary pathways can be accessed by slight modification of the reaction conditions. PMID- 21823615 TI - Selective reduction of methylsulfinyl-containing compounds by mammalian MsrA suggests a strategy for improved drug efficacy. AB - Identification of pathways of drug metabolism provides critical information regarding efficacy and safety of these compounds. Particularly challenging cases involve stereospecific processes. We found that broad classes of compounds containing methylsulfinyl groups are reduced to methylsulfides specifically by methionine sulfoxide reductase A, which acts on the S-stereomers of methionine sulfoxides, whereas the R-stereomers of these compounds could not be efficiently reduced by any methionine sulfoxide reductase in mammals. The findings of efficient reduction of S-methylsulfinyls and deficiency in the reduction of R methylsulfinyls by methionine sulfoxide reductases suggest strategies for improved efficacy and decreased toxicity of drugs and natural compounds containing methylsulfinyls through targeted use of their enantiomers. PMID- 21823616 TI - Identification and characterization of a novel integrin-linked kinase inhibitor. AB - Integrin-linked kinase (ILK) represents a relevant target for cancer therapy in light of its role in promoting oncogenesis and tumor progression. Through the screening of an in-house focused compound library, we identified N-methyl-3-(1-(4 (piperazin-1-yl)phenyl)-5-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)-1H-pyrazol 3-yl)propanamide (22) as a novel ILK inhibitor (IC(50), 0.6 MUM), which exhibited high in vitro potency against a panel of prostate and breast cancer cell lines (IC(50), 1-2.5 MUM), while normal epithelial cells were unaffected. Compound 22 facilitated the dephosphorylation of Akt at Ser-473 and other ILK targets, including glycogen synthase kinase-3beta and myosin light chain. Moreover, 22 suppressed the expression of the transcription/translation factor YB-1 and its targets HER2 and EGFR in PC-3 cells, which could be rescued by the stable expression of constitutively active ILK. Evidence indicates that 22 induced autophagy and apoptosis, both of which were integral to its antiproliferative activity. Together, this broad spectrum of mechanisms underlies the therapeutic potential of 22 in cancer treatment, which is manifested by its in vivo efficacy as a single oral agent in suppressing PC-3 xenograft tumor growth. PMID- 21823617 TI - 9-substituted 6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazoles as highly selective and potent anaplastic lymphoma kinase inhibitors. AB - 9-Substituted 6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazoles were discovered as highly selective and potent anaplastic lymphoma kinase (ALK) inhibitors by structure-based drug design. The high target selectivity was achieved by introducing a substituent close to the E(0) region of the ATP binding site, which has a unique amino acid sequence. Among the identified inhibitors, compound 13d showed highly selective and potent inhibitory activity against ALK with an IC(50) value of 2.9 nM and strong antiproliferative activity against KARPAS-299 with an IC(50) value of 12.8 nM. The compound also displayed significant antitumor efficacy in an established ALK fusion gene-positive anaplastic large-cell lymphoma (ALCL) xenograft model in mice without body weight loss. PMID- 21823618 TI - Graphene surface-enabled lithium ion-exchanging cells: next-generation high-power energy storage devices. AB - Herein reported is a fundamentally new strategy for the design of high-power and high energy-density devices. This approach is based on the exchange of lithium ions between the surfaces (not the bulk) of two nanostructured electrodes, completely obviating the need for lithium intercalation or deintercalation. In both electrodes, massive graphene surfaces in direct contact with liquid electrolyte are capable of rapidly and reversibly capturing lithium ions through surface adsorption and/or surface redox reaction. These devices, based on unoptimized materials and configuration, are already capable of storing an energy density of 160 Wh/kg(cell), which is 30 times higher than that (5 Wh/kg(cell)) of conventional symmetric supercapacitors and comparable to that of Li-ion batteries. They are also capable of delivering a power density of 100 kW/kg(cell), which is 10 times higher than that (10 kW/kg(cell)) of supercapacitors and 100 times higher than that (1 kW/kg(cell)) of Li-ion batteries. PMID- 21823619 TI - Modeling the RNA 2'OH activation: possible roles of metal ion and nucleobase as catalysts in self-cleaving ribozymes. AB - The RNA 2'OH activation as taking place in the first chemical step of self cleaving ribozymes is studied theoretically by DFT and MP2 methods using a continuum solvation model (CPCM). The reaction of proton transfer is studied in the presence of two kinds of catalysts: a fully hydrated metal ion (Mg(2+)) or partially hydrated nucleobase (guanine), taken separately or together leading to three different modes of activation. The metal ion is either directly bound (inner-sphere) or indirectly bound (outer-sphere) to the 2'OH group and a hydroxide ion acts as a general or specific base; the nucleobase is taken in anionic or in neutral enol-tautomeric forms playing itself the role of general base. The presence of a close metal ion (outer-sphere) lowers the pK(a) value of the 2'OH group by several log units in both metal-ion and nuleobase catalysis. The direct metal coordination to the 2'OH group (inner-sphere) further stabilizes the developing negative charge on the nucleophile. The switching from the inner sphere to the outer-sphere coordination appears to be driven by the energy cost for reorganizing the first coordination shell rather than by the electrostatic repulsion between the ligands. The metal-ion catalysis is more effective with a specific base in the dianionic mechanism. On the other hand, the nucleobase catalysis is more effective in the monoanionic mechanism and in the presence of a metal ion acting as a cofactor through nonspecific electrostatic interactions. The results establish a baseline to study the possible roles of metal and nucleobase catalysts and their environment in more realistic models for self cleaving ribozymes. PMID- 21823620 TI - Hierarchical nanomorphologies promote exciton dissociation in polymer/fullerene bulk heterojunction solar cells. AB - PTB7 semiconducting copolymer comprising thieno[3,4-b]thiophene and benzodithiophene alternating repeat units set a historic record of solar energy conversion efficiency (7.4%) in polymer/fullerene bulk heterojunction solar cells. To further improve solar cell performance, a thorough understanding of structure-property relationships associated with PTB7/fullerene and related organic photovoltaic (OPV) devices is crucial. Traditionally, OPV active layers are viewed as an interpenetrating network of pure polymers and fullerenes with discrete interfaces. Here we show that the active layer of PTB7/fullerene OPV devices in fact involves hierarchical nanomorphologies ranging from several nanometers of crystallites to tens of nanometers of nanocrystallite aggregates in PTB7-rich and fullerene-rich domains, themselves hundreds of nanometers in size. These hierarchical nanomorphologies are coupled to significantly enhanced exciton dissociation, which consequently contribute to photocurrent, indicating that the nanostructural characteristics at multiple length scales is one of the key factors determining the performance of PTB7 copolymer, and likely most polymer/fullerene systems, in OPV devices. PMID- 21823621 TI - Microwave-assisted decarboxylative three-component coupling of a 2-oxoacetic acid, an amine, and an alkyne. AB - A novel and efficient microwave-assisted decarboxylative three-component coupling of a 2-oxoacetic acid, an amine, and an alkyne (OA(2)-coulpling) has been developed. This new multicomponent coupling constitutes an efficient approach for the synthesis of polysubstituted propargylamines in the presence of a catalytic amount of copper(I) catalyst. PMID- 21823623 TI - Tough blends of polylactide and castor oil. AB - Poly(l-lactide) (PLLA) is a renewable resource polymer derived from plant sugars with several commercial applications. Broader implementation of the material is limited due to its inherent brittleness. We show that the addition of 5 wt % castor oil to PLLA significantly enhances the overall tensile toughness with minimal reductions in the modulus and no plasticization of the PLLA matrix. In addition, we used poly(ricinoleic acid)-PLLA diblock copolymers, synthesized entirely from renewable resources, as compatibilizers for the PLLA/castor oil blends. Ricinoleic acid, the majority fatty acid comprising castor oil, was polymerized through a lipase-catalyzed condensation reaction. The resulting polymers contained a hydroxyl end-group that was subsequently used to initiate the ring-opening polymerization of l-lactide. The binary PLLA/castor oil blend exhibited a tensile toughness seven times greater than neat PLLA. The addition of block copolymer allowed for control over the morphology of the blends, and even further improvement in the tensile toughness was realized-an order of magnitude larger than that of neat PLLA. PMID- 21823624 TI - Oxidative intramolecular bromo-amination of N-alkenyl sulfonamides via umpolung of alkali metal bromides. AB - The oxidative intramolecular bromo-amination of various N-alkenyl sulfonamides and N-alkenoxyl sulfonamides via umpolung of alkali metal bromides occurred exo selectively to generate cyclic bromoamides in high yields with good diastereoselectivities. This method provided the desired products without elaborating the stoichiometric amount of corresponding organic waste. PMID- 21823622 TI - Discovery of a cytokinin deaminase. AB - An enzyme of unknown function within the amidohydrolase superfamily was discovered to catalyze the hydrolysis of N-6-substituted adenine derivatives, several of which are cytokinins. Cytokinins are a common type of plant hormone and N-6-substituted adenines are also found as modifications to tRNA. Patl2390, from Pseudoalteromonas atlantica T6c, was shown to hydrolytically deaminate N-6 isopentenyladenine to hypoxanthine and isopentenylamine with a k(cat)/K(m) of 1.2 * 10(7) M(-1) s(-1). Additional substrates include N-6-benzyl adenine, cis- and trans-zeatin, kinetin, O-6-methylguanine, N-6-butyladenine, N-6-methyladenine, N,N-dimethyladenine, 6-methoxypurine, 6-chloropurine, and 6-thiomethylpurine. This enzyme does not catalyze the deamination of adenine or adenosine. A comparative model of Patl2390 was computed using the three-dimensional crystal structure of Pa0148 (PDB code 3PAO ) as a structural template, and docking was used to refine the model to accommodate experimentally identified substrates. This is the first identification of an enzyme that will hydrolyze an N-6 substituted side chain larger than methylamine from adenine. PMID- 21823625 TI - Mechanical properties of bamboo-like boron nitride nanotubes by in situ TEM and MD simulations: strengthening effect of interlocked joint interfaces. AB - Understanding the influence of interfacial structures on the nanoarchitecture mechanical properties is of particular importance for its mechanical applications. Due to a small size of constituting nanostructural units and a consequently high volume ratio of such interfacial regions, this question becomes crucial for the overall mechanical performance. Boron nitride bamboo-like nanotubes, called hereafter boron nitride nanobamboos (BNNBs), are composed of short BN nanotubular segments with specific interfaces at the bamboo-shaped joints. In this work, the mechanical properties of such structures are investigated by using direct in situ transmission electron microscopy tensile tests and molecular dynamics simulations. The mechanical properties and deformation behaviors are correlated with the interfacial structure under atomic resolution, and a geometry strengthening effect is clearly demonstrated. Due to the interlocked joint interfacial structures and compressive interfacial stresses, the deformation mechanism is switched from an interplanar sliding mode to an in-plane tensile elongation mode. As a result of such a specific geometry strengthening effect, the BNNBs show high tensile fracture strength and Young's modulus up to 8.0 and 225 GPa, respectively. PMID- 21823626 TI - Influence of solvent and intramolecular hydrogen bonding on the conformational properties of o-linked glycopeptides. AB - A detailed investigation of the conformational properties of all the biologically relevant O-glycosidic linkages using the Hamiltonian replica exchange (HREX) simulation methodology and the recently developed CHARMM carbohydrate force field parameters is presented. Fourteen biologically relevant O-linkages between the five sugars N-acetylgalactosamine (GalNAc), N-acetylglucosamine (GlcNAc), D glucose (Glc), D-mannose (Man), and L-fucose (Fuc) and the amino acids serine and threonine were studied. The force field was tested by comparing the simulation results of the model glycopeptides to various NMR (3)J coupling constants, NOE distances, and data from molecular dynamics with time-averaged restraints (tar MD). The results show the force field to be in overall agreement with experimental and previous tar-MD simulations, although some small limitations are identified. An in-depth hydrogen bond and bridging water analysis revealed an interplay of hydrogen bonding and bridge water interactions influencing the geometry of the underlying peptide backbone, with the O-linkages favoring extended beta-sheet and polyproline type II (PPII) conformations over the compact alpha(R)-helical conformation. The newly developed parameters were also able to identify hydrogen bonding and water mediated interactions between O-linked sugars and proteins. These results indicate that the newly developed parameters in tandem with HREX conformational sampling provide the means to study glycoproteins in the absence of targeted NMR restraint data. PMID- 21823627 TI - A crossed molecular beams and ab initio study on the formation of C6H3 radicals. an interface between resonantly stabilized and aromatic radicals. AB - The crossed molecular beams reaction of dicarbon molecules, C(2)(X(1)Sigma(g)(+)/a(3)Pi(u)) with vinylacetylene was studied under single collision conditions at a collision energy of 31.0 kJ mol(-1) and combined with electronic structure calculations on the singlet and triplet C(6)H(4) potential energy surfaces. The investigations indicate that both reactions on the triplet and singlet surfaces are dictated by a barrierless addition of the dicarbon unit to the vinylacetylene molecule and hence indirect scattering dynamics via long lived C(6)H(4) complexes. On the singlet surface, ethynylbutatriene and vinyldiacetylene were found to decompose via atomic hydrogen loss involving loose exit transition states to form exclusively the resonantly stabilized 1-hexene-3,4 diynyl-2 radical (C(6)H(3); H(2)CCCCCCH; C(2v)). On the triplet surface, ethynylbutatriene emitted a hydrogen atom through a tight exit transition state located about 20 kJ mol(-1) above the separated stabilized 1-hexene-3,4-diynyl-2 radical plus atomic hydrogen product; to a minor amount (<5%) theory predicts that the aromatic 1,2,3-tridehydrobenzene molecule is formed. Compared to previous crossed beams and theoretical investigations on the formation of aromatic C(6)H(x) (x = 6, 5, 4) molecules benzene, phenyl, and o-benzyne, the decreasing energy difference from benzene via phenyl and o-benzyne between the aromatic and acyclic reaction products, i.e., 253, 218, and 58 kJ mol(-1), is narrowed down to only ~7 kJ mol(-1) for the C(6)H(3) system (aromatic 1,2,3 tridehydrobenzene versus the resonantly stabilized free radical 1-hexene-3,4 diynyl-2). Therefore, the C(6)H(3) system can be seen as a "transition" stage among the C(6)H(x) (x = 6-1) systems, in which the energy gap between the aromatic isomer (x = 6, 5, 4) is reduced compared to the acyclic isomer as the carbon-to-hydrogen ratio increases and the acyclic isomer becomes more stable (x = 1, 2). PMID- 21823628 TI - Baseline correction method using an orthogonal basis for gas chromatography/mass spectrometry data. AB - A baseline correction method that uses basis set projection to estimate spectral backgrounds has been developed and applied to gas chromatography/mass spectrometry (GC/MS) data. An orthogonal basis was constructed using singular value decomposition (SVD) for each GC/MS two-way data object from a set of baseline mass spectra. A novel aspect of this baseline correction method is the regularization parameter that prevents overfitting that may produce negative peaks in the corrected mass spectra or ion chromatograms. The number of components in the basis, the regularization parameter, and the mass spectral range from which the spectra were sampled to construct the basis were optimized so that the projected difference resolution (PDR) or signal-to-noise ratio (SNR) was maximized. PDR is a metric similar to chromatographic resolution that indicates the separation of classes in a multivariate data space. This new baseline correction method was evaluated with two synthetic data sets and a real GC/MS data set. The prediction accuracies obtained by using the fuzzy rule building expert system (FuRES) and partial least-squares-discriminant analysis (PLS-DA) as classifiers were compared and validated through bootstrapped Latin partition (BLP) between data before and after baseline correction. The results indicate that baseline correction of the two-way GC/MS data using the proposed methods resulted in a significant increase in average PDR values and prediction accuracies. PMID- 21823629 TI - Binary optical encoding strategy for multiplex assay. AB - A binary optical encoding strategy is proposed to meet the increasing requirements of multiplex bioassays. As illustrated in fluorescence immunodetection of multiplex antigen molecules, photonic crystal beads (PCBs) and quantum dots (QDs) can be used as biomolecular microcarriers and fluorescence labels, respectively. The categories of antigens were deciphered by the binary combination of optical spectra of PCBs and QDs as independent encoding elements. The number of categories that could be detected was theoretically m * n, where m and n represent the number of encoding PCBs and QDs, respectively. In addition, the concentrations of the antigens were determined by the fluorescence signals of the QDs. Results of sensitivity analysis indicate that a low-level detection of 58 pg/mL was achieved. Because of the special nanostructures of these two encoding elements, the binary encoding strategy demonstrated its superiority and practicability when compared with single PCB or QD encoding. This supports potential application in multiplex bioassays. PMID- 21823630 TI - Functional magnetic nanoparticle assemblies: formation, collective behavior, and future directions. AB - This Perspective describes recent progress in the development of functional magnetic nanoparticle assemblies. After describing the formation of two- and three-dimensional particle arrays in terms of the size-dependent driving forces, we focus on magnetic nanoparticle arrays. We discuss how the self-organized structure can modify the magnetic behavior, relative to that of isolated particles. We highlight an important development, described in this issue of ACS Nano by Kostiainen and co-workers, who have demonstrated not only the novel aqueous self-assembly of magnetic particles but also controlled and reversible disassembly. Finally, we explore two inter-related future directions for self assembly of magnetic nanoparticles: the formation of more complex, hierarchical structures and the integration of self-assembly with fabrication techniques for electronic devices. PMID- 21823631 TI - Two-dimensional IR spectroscopy of protein dynamics using two vibrational labels: a site-specific genetically encoded unnatural amino acid and an active site ligand. AB - Protein dynamics and interactions in myoglobin (Mb) were characterized via two vibrational dynamics labels (VDLs): a genetically incorporated site-specific azide (Az) bearing unnatural amino acid (AzPhe43) and an active site CO ligand. The Az-labeled protein was studied using ultrafast two-dimensional infrared (2D IR) vibrational echo spectroscopy. CO bound at the active site of the heme serves as a second VDL located nearby. Therefore, it was possible to use Fourier transform infrared (FT-IR) and 2D IR spectroscopic experiments on the Az in unligated Mb and in Mb bound to CO (MbAzCO) and on the CO in MbCO and MbAzCO to investigate the environment and motions of different states of one protein from the perspective of two spectrally resolved VDLs. A very broad bandwidth 2D IR spectrum, encompassing both the Az and CO spectral regions, found no evidence of direct coupling between the two VDLs. In MbAzCO, both VDLs reported similar time scale motions: very fast homogeneous dynamics, fast, ~1 ps dynamics, and dynamics on a much slower time scale. Therefore, each VDL reports independently on the protein dynamics and interactions, and the measured dynamics are reflective of the protein motions rather than intrinsic to the chemical nature of the VDL. The AzPhe VDL also permitted study of oxidized Mb dynamics, which could not be accessed previously with 2D IR spectroscopy. The experiments demonstrate that the combined application of 2D IR spectroscopy and site-specific incorporation of VDLs can provide information on dynamics, structure, and interactions at virtually any site throughout any protein. PMID- 21823633 TI - Chemical synthesis of cell-permeable apoptotic peptides from in vivo produced proteins. AB - In vivo synthesis of peptides by bacterial expression has developed into a reliable alternative to solid-phase peptide synthesis. A significant drawback of in vivo methods is the difficulty with which gene products can be modified post translationally. Here, we present a method for the facile modification of peptides generated in bacterial hosts after cyanogen bromide cleavage at C terminal methionines. Reaction of the resulting homoserine lactones with propargylamine allows efficient and selective modification with a wide variety of chemicals such as fluorescent dyes, biotin derivatives, polyprenyls, lipids, polysaccharides, or peptides. Attachment of the cell penetrating peptide octa arginine (R(8)) to peptides derived from the proapoptotic tumor suppressor Bak BH3 led to efficient cellular uptake and subsequent cytochrome c release from mitochondria, culminating in induction of apoptosis similar to that observed with peptides linked to R(8) via the peptide backbone. These results highlight the significant potential for use of such tools in live cells. PMID- 21823632 TI - Utilizing cell-matrix interactions to modulate gene transfer to stem cells inside hyaluronic acid hydrogels. AB - The effective delivery of DNA locally would increase the applicability of gene therapy in tissue regeneration, where diseased tissue is to be repaired in situ. One promising approach is to use hydrogel scaffolds to encapsulate and deliver plasmid DNA in the form of nanoparticles to the diseased tissue, so that cells infiltrating the scaffold are transfected to induce regeneration. This study focuses on the design of a DNA nanoparticle-loaded hydrogel scaffold. In particular, this study focuses on understanding how cell-matrix interactions affect gene transfer to adult stem cells cultured inside matrix metalloproteinase (MMP) degradable hyaluronic acid (HA) hydrogel scaffolds. HA was cross-linked to form a hydrogel material using a MMP degradable peptide and Michael addition chemistry. Gene transfer inside these hydrogel materials was assessed as a function of polyplex nitrogen to phosphate ratio (N/P = 5 to 12), matrix stiffness (100-1700 Pa), RGD (Arg-Gly-Asp) concentration (10-400 MUM), and RGD presentation (0.2-4.7 RGDs per HA molecule). All variables were found to affect gene transfer to mouse mensenchymal stem cells culture inside the DNA loaded hydrogels. As expected, higher N/P ratios lead to higher gene transfer efficiency but also higher toxicity; softer hydrogels resulted in higher transgene expression than stiffer hydrogels, and an intermediate RGD concentration and RGD clustering resulted in higher transgene expression. We believe that the knowledge gained through this in vitro model can be utilized to design better scaffold mediated gene delivery for local gene therapy. PMID- 21823634 TI - Pharmacological characterization of a recombinant, fluorescent somatostatin receptor agonist. AB - Somatostatin (SST) is a peptide neurotransmitter/hormone found in several mammalian tissue types. Apart from its natural importance, labeled SST/analogues are utilized in clinical applications such as targeting/diagnosis of neuroendocrine tumors. We report on the development and characterization of a novel, recombinant, fluorescent somatostatin analogue that has potential to elucidate somatostatin-activated cell signaling. SST was genetically fused with a monomeric-red fluorescent protein (mRFP) as the fluorescent label. The attachment of SST to mRFP had no detectable effect on its fluorescent properties. This analogue's potency to activate the endogenous and transfected somatostatin receptors was characterized using assays of membrane potential and Ca(2+) mobilization and immunocytochemistry. SST-mRFP was found to be an effective somatostatin receptor agonist, able to trigger the membrane hyperpolarization, mobilization of the intracellular Ca(2+) and receptor-ligand internalization in cells expressing somatostatin receptors. This complex represents a novel optical reporter due to its red emission spectral band suitable for in vivo imaging and tracking of the somatostatin receptor signaling pathways, affording higher resolution and sensitivity than those of the state-of-the-art radiolabeling bioassays. PMID- 21823635 TI - Experimental and theoretical investigations of the autoxidation of geranial: a dioxolane hydroperoxide identified as a skin sensitizer. AB - The autoxidation of geranial with O(2) was studied both experimentally and using density functional theory. Computational results were used to interpret experimentally observed product ratios. Geranial was found to autoxidize, forming 6,7-epoxygeranial as the main oxidation product. Hydroperoxides corresponding to those identified as important skin sensitizers in previous studies of fragrance terpenes could not be detected. Instead, a dioxolan derivative and its corresponding hydroperoxide were identified and detected in high concentrations. The distribution of products in autoxidation generally depends on the stabilities of the intermediate peroxyl radicals. In this study, the formation of a peracyl radical was found to be highly favored. This radical forms peracid which epoxidizes geranial. The epoxide thus produced can react with acyl radical to yield the dioxolan hydroperoxide. The dioxolan derivative is believed to form in an acid catalyzed closed shell reaction between 6,7-epoxygeranial and geranial. The dioxolan hydroperoxide and 6,7-epoxygeranial are strong sensitizers and are considered to be the compounds mainly responsible for the skin sensitization potency of air-exposed geranial. PMID- 21823636 TI - Molecular dynamics simulations of nanoparticle self-assembly at ionic liquid water and ionic liquid-oil interfaces. AB - We have studied the self-assembly of hydrophobic nanoparticles at ionic liquid (IL)-water and IL-oil (hexane) interfaces using molecular dynamics (MD) simulations. For the 1-butyl-3-methylimidazolium hexafluorophosphate ([BMIM][PF(6)])/water system, the nanoparticles rapidly approached the IL-water interface and equilibrated more into the IL phase although they were initially in the water phase. In contrast, when the nanoparticles were dispersed in the hexane phase, they slowly approached the IL-hexane interface but remained primarily in the hexane phase. Consequently, the IL-hexane interface was rather undisturbed by the nanoparticles whereas the IL-water interface changed significantly in width and morphology to accommodate the presence of the nanoparticles. The equilibrium positions of the nanoparticles were also supported and explained by potential of mean force (PMF) calculations. Interesting ordering and charge distributions were observed at the IL-liquid interfaces. At the IL-hexane interface, the [BMIM] cations preferentially oriented themselves so that they were immersed more in the hexane phase and packed efficiently to reduce steric hindrance. The ordering likely contributed to a heightened IL density and a slightly positive charge at the IL-hexane interface. In contrast, the cations at the IL-water interface were oriented isotropically unless in the presence of nanoparticles, where the cations aligned across the nanoparticle surfaces. PMID- 21823637 TI - Metallic and insulating interfaces of amorphous SrTiO3-based oxide heterostructures. AB - The conductance confined at the interface of complex oxide heterostructures provides new opportunities to explore nanoelectronic as well as nanoionic devices. Herein we show that metallic interfaces can be realized in SrTiO(3) based heterostructures with various insulating overlayers of amorphous LaAlO(3), SrTiO(3), and yttria-stabilized zirconia films. On the other hand, samples of amorphous La(7/8)Sr(1/8)MnO(3) films on SrTiO(3) substrates remain insulating. The interfacial conductivity results from the formation of oxygen vacancies near the interface, suggesting that the redox reactions on the surface of SrTiO(3) substrates play an important role. PMID- 21823638 TI - Chiral signatures show volatilization from soil contributes to polychlorinated biphenyls in grass. AB - Enantiomer fractions (EFs) of PCB 95 and concentrations of PCBs 28/31, 52, 101, 118, 138, 153, and 180 were determined in air. Samples were taken at ~14 day intervals on a vertical gradient at an urban background site in Birmingham U.K. in summer 2009 (114 days) and spring 2010 (84 days). EFs in air at 3 cm height were nonracemic (average 0.453 (2009) and 0.468 (2010)) and differed significantly (p < 0.05) from the racemic EFs in air at 10, 40, 90, and 130 cm. EFs in soil (average 0.452 (2009) and 0.447 (2010)) closely matched those in air at 3 cm, while those in grass (average 0.468 (2009) and 0.484 (2010)) were intermediate between those in soil and the racemic EFs in air at >= 10 cm. This implies that at the study site, PCBs volatilize from soil to an extent discernible only at the soil:air interface, and that PCBs in grass arise due to foliar uptake of volatile emissions from soil. Atmospheric concentrations of SigmaPCBs increased significantly (p < 0.05) with increasing height. Combined with the chiral signature data, this suggests the influence of PCB emissions from soil on airborne concentrations decreases with altitude, while that of emissions from the built environment increases. PMID- 21823639 TI - Chemoenzymatic synthesis of cryptophycin anticancer agents by an ester bond forming non-ribosomal peptide synthetase module. AB - Cryptophycins (Crp) are a group of cyanobacterial depsipeptides with activity against drug-resistant tumors. Although they have been shown to be promising, further efforts are required to return these highly potent compounds to the clinic through a new generation of analogues with improved medicinal properties. Herein, we report a chemosynthetic route relying on the multifunctional enzyme CrpD-M2 that incorporates a 2-hydroxy acid moiety (unit D) into Crp analogues. CrpD-M2 is a unique non-ribosomal peptide synthetase (NRPS) module comprised of condensation-adenylation-ketoreduction-thiolation (C-A-KR-T) domains. We interrogated A-domain 2-keto and 2-hydroxy acid activation and loading, and KR domain activity in the presence of NADPH and NADH. The resulting 2-hydroxy acid was elongated with three synthetic Crp chain elongation intermediate analogues through ester bond formation catalyzed by CrpD-M2 C domain. Finally, the enzyme bound seco-Crp products were macrolactonized by the Crp thioesterase. Analysis of these sequential steps was enabled through LC-FTICR-MS of enzyme-bound intermediates and products. This novel chemoenzymatic synthesis of Crp involves four sequential catalytic steps leading to the incorporation of a 2-hydroxy acid moiety in the final chain elongation intermediate. The presented work constitutes the first example where a NRPS-embedded KR domain is employed for assembly of a fully elaborated natural product, and serves as a proof-of-principle for chemoenzymatic synthesis of new Crp analogues. PMID- 21823640 TI - Preparation and characterization of multilayered polymer nanotube dispersions. AB - Despite considerable efforts to synthesize nanotubes using porous alumina or polycarbonate membrane templates, few studies have addressed the resulting nanotube dispersion. We prepared dispersions of multilayered polyethylenimine/maleic anhydride alternating copolymer (PEI/MAAC) nanotubes synthesized with porous alumina templates. After mechanical polishing to remove the residual polymer surface layer from templates and subsequent template dissolution, the multilayered PEI/MAAC nanotubes were easily dispersed in water at neutral pH by polyelectrolyte adsorption, producing nanotube dispersions that were stable for at least 3 months. We characterized the dispersions using phase contrast optical microscopy, electro-optics, electrophoresis, and viscometry to help understand their colloidal properties in the dilute and semidilute regimes. The dispersions were resistant to salt-induced aggregation up to at least 1 mM NaCl and were optically anisotropic when subjected to an electric field or flow. Interestingly, the electrophoretic mobility of polystyrene sulfonate (PSS) stabilized nanotubes increases with increasing ionic strength, because of the high surface charge and softness of the adsorbed polyelectrolyte. Furthermore, unlike many rod-like colloid systems, the polymer nanotube dispersion has low viscosity because of weak rotary Brownian motions and strong tendency to shear thinning. At the high shear rates achieved in capillary viscometry experiments, however, we observed a slight shear thickening, which can be attributed to transient hydrocluster formation. PMID- 21823641 TI - Fine-tuned nanostructures assembled from L-lysine-functionalized perylene bisimides. AB - Controllable nanostructures with tunable dimensions were obtained via self assembly of CBZ-L-lysine-functionalized tetrachloroperylene bisimides (4ClPBI Lys). Depending on the nature of substitute, solvent polarity, and sample concentration, 4ClPBI-Lys could form nanosphere, nanowire, nanobelt, and nanosheet, which were found to have different degree of molecular ordering. The effects of substitution position with respect to L-lysine on 4ClPBI were also explored in terms of assembly nanostructures. Hydrogen bonding was important to promote formation of long-range ordering. The nanostructures of different assemblies were characterized using SEM, TEM, XRD, UV-vis, and FTIR spectroscopy. For each obtained supramolecular assembly, we also found that the molecular packing motif ultimately determined the corresponding devices' electronic properties. PMID- 21823642 TI - Novel system for controlled investigation of environmental partitioning of hydrophobic compounds in water. AB - Partitioning behavior of hydrophobic and semivolatile chemicals (such as many POPs and PAHs) in water is key in controlling their environmental distribution and fate. A new equilibrium method is presented here which allows determination of the equilibrium partition coefficient of hexachlorobenzene with suspended particle (K(SPM)~ 337 L gOC(-1)) in a complex bulk water sample by correcting for a number of sampling artifacts and for the presence of dissolved matter. The method provides simultaneous experimental determination of the fraction of chemical truly dissolved in water (representing in this case about 54% of the bulk water concentration) and that associated to DM (21%). The Henry's law constant was also experimentally determined during the K(SPM) measurements, providing information on the occurrence of partitioning equilibrium in the system for each single observation. Results showed that the high level of quality control and accuracy provided confidence intervals for the K(SPM) estimates within 1 order of magnitude. PMID- 21823643 TI - Five-fold-symmetric macrocyclic aromatic pentamers: high-affinity cation recognition, ion-pair-induced columnar stacking, and nanofibrillation. AB - Described in this study is a conceptually new class of five-fold-symmetric cavity containing planar pentameric macrocycles with their interior decorated by five convergently aligned, properly spaced carbonyl oxygen atoms. These cation-binding oxygens enclose a hydrophilic lumen of 2.85 A in radius and thus display high affinity binding toward alkali metal cations, and possibly many other cations, too. Arising from their high-affinity recognition of metal ions, these planar macrocycles form cation- or ion-pair-induced one-dimensional columnar aggregates, and subsequently fascinating fibrillation results. PMID- 21823645 TI - Comparison of multiple prompt gamma-ray analysis and prompt gamma-ray analysis for the elemental analysis of geological and cosmochemical samples. AB - Multiple prompt gamma-ray analysis (MPGA) and conventional neutron-induced prompt gamma-ray analysis (PGA) are nondestructive analytical methods for bulk chemical compositions, and their analytical capabilities were compared for elemental analyses of geological and cosmochemical samples. Detection sensitivities of PGA are often restricted by poor signal-to-noise ratios and interferences from different origins. MPGA can substantially reduce the background level, especially for hydrogenous samples, relative to PGA, which opens up a possibility to use lower energy prompt gamma-rays of some trace elements. Although it is one of the major constituent elements of rock samples, Mg is hard to be determined by PGA. With MPGA, Mg contents could be determined with reasonable consistency with their corresponding recommended values in geological and cosmochemical samples by carefully selecting suitable coincident prompt gamma-ray energy pairs without interference correction. MPGA was applied to a hydrogenous meteorite, Ivuna, which contains H at 2% mass level. MPGA detection limits for most of the elements studied can be reduced up to 1 order of magnitude when compared with PGA detection limits under the present experimental conditions. PMID- 21823646 TI - Self-assembling nanofibers from thiophene-peptide diblock oligomers: a combined experimental and computer simulations study. AB - We report herein the synthesis of a novel type of hybrid compound that consists of a poly(ethylene oxide) (PEO) functionalized beta-sheet peptide sequence covalently linked to an alkylated quaterthiophene moiety. Compounds of this class are highly promising for technological applications because their self-assembly and stimuli-responsive behavior, which is mainly caused by the peptide moieties, combined with the potential semiconducting properties of oligothiophenes provides unprecedented opportunities for the design of advanced materials at the nanoscale in such areas as, for example, organic electronics and sensor design for chemical and biomedical applications. The compound presented herein is experimentally shown to form stable fibrillar aggregates that are visualized by both transmission electron and atomic force microscopy. We developed a theoretical methodology to study the possible intermolecular arrangements and their characteristic features with the help of all-atom MD simulations, while simultaneously incorporating available experimental data into the model. Large scale atomistic simulations of several fibrillar aggregates with different molecular arrangements were performed. The results of the simulations are compared with experimental data, which leads to the proposition of a likely model for the arrangement of the individual molecules within the observed aggregates. PMID- 21823644 TI - Probing single-molecule enzyme active-site conformational state intermittent coherence. AB - The relationship between protein conformational dynamics and enzymatic reactions has been a fundamental focus in modern enzymology. Using single-molecule fluorescence resonance energy transfer (FRET) with a combined statistical data analysis approach, we have identified the intermittently appearing coherence of the enzymatic conformational state from the recorded single-molecule intensity time trajectories of enzyme 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) in catalytic reaction. The coherent conformational state dynamics suggests that the enzymatic catalysis involves a multistep conformational motion along the coordinates of substrate-enzyme complex formation and product releasing, presenting as an extreme dynamic behavior intrinsically related to the time bunching effect that we have reported previously. The coherence frequency, identified by statistical results of the correlation function analysis from single-molecule FRET trajectories, increases with the increasing substrate concentrations. The intermittent coherence in conformational state changes at the enzymatic reaction active site is likely to be common and exist in other conformation regulated enzymatic reactions. Our results of HPPK interaction with substrate support a multiple-conformational state model, being consistent with a complementary conformation selection and induced-fit enzymatic loop-gated conformational change mechanism in substrate-enzyme active complex formation. PMID- 21823647 TI - Orbital reconstruction and interface ferromagnetism in self-assembled nanosheet superlattices. AB - We have investigated the interface electronic states in self-assembled (Ti(0.8)Co(0.2)O(2)/Ti(0.6)Fe(0.4)O(2))(n) superlattices by X-ray photoelectron spectroscopy. A charge of about -0.3 electron is transferred from Fe to Co ions across the interface and induces a major reconstruction of the orbital occupation at the interfacial (Ti(0.8)Co(0.2)O(2)/Ti(0.6)Fe(0.4)O(2)) layers. Supported by first-principles calculations, the Co(3+) state is partially occupied at the interface by superlattice formation, and this new magnetic state directly influences the coupling between Ti(0.8)Co(0.2)O(2) and Ti(0.6)Fe(0.4)O(2) nanosheets. These data indicate that the orbital reconstruction is indeed realized by the interface charge transfer between Co and Fe ions in the adjoined nanosheets, and the generic feature of engineered interfaces can be extended to self-assembled superlattices of oxide nanosheets. PMID- 21823648 TI - Reaction kinetics of catalyzed competitive heteropolymer cleavage. AB - A theoretical formulation for complete heteropolymer degradation is developed in terms of Michaelis-Menten reaction kinetics under the quasi-steady-state approximation. This allows the concentration of the entire intermediate decomposition cascade to be accounted for as well as each species of emerging final product. The formulation is implemented computationally and results in stable reaction kinetics across a range of orders of magnitude for K(M) and k(cat). The model is compared with experiment, specifically in vitro HIV-1 protease-catalyzed retroviral Gag-polyprotein processing. Using an experimentally determined cleavage-polypeptide parameter set, good qualitative agreement is reached with Gag degradation kinetics, given the difference in experimental conditions. A parameter search within 1 order of magnitude of variation of the experimental set results in the determination of an optimal parameter set in complete agreement with experiment which allows the time evolution of each individual as well as intermediate species in Gag to be accurately followed. Future investigations that determine the required enzymatic parameters to populate such a scheme will allow for the model to be refined in order to track the time for viral maturation and infectivity. PMID- 21823649 TI - Structural evolution during evaporation of a 3-glycidoxypropyltrimethoxysilane film studied in situ by time resolved infrared spectroscopy. AB - Time resolved infrared spectroscopy has been applied to study in situ the evaporation process of a 3-glycidoxypropyltrimethoxysilane hybrid sol by casting a droplet on a ZnSe substrate; the analysis has been performed in the middle infrared range and in the near-infrared range. The experiment has allowed following the structural changes induced by water evaporation and the formation of ordered structures within the cast film; the CH(2) scissoring bands have been used as a fingerprint for the disorder to order transition of the hybrid. The experiment has been done using both a fresh sol and an aged sol which produce respectively an amorphous material and a crystalline hybrid material. The analysis has shown that the epoxy groups do not react during the evaporation while the silica structure shows only a slight condensation and an increase in open cage-like species. At the end of evaporation the hybrid has a "soft-like" state which allows structural rearrangements to self-order. PMID- 21823651 TI - Radiation and radical chemistry of NO3(-), HNO3, and dialkylphosphoric acids in room-temperature ionic liquids. AB - Hydrophobic room-temperature ionic liquids (ILs) are considered as possible replacements for molecular diluents for nuclear separations, as well as the basis of new separations processes. Such applications may put the solvents both in high radiation fields and in contact with aqueous raffinate containing 1-6 M HNO(3). In this study, we address the effect of the extracted nitrate and nitric acid on the radiation chemistry of hydrophobic ILs composed of 1-alkyl-3 methylimidazolium cations (and closely related systems). We demonstrate that the nitrate anion competes with the solvent cation as an electron scavenger, with most of the primary radical species converted to NO(3)(*2-) and NO(2)(*) that initiate a complex sequence of radical reactions. In hydrophobic ILs equilibrated with 3 M HNO(3), nearly all electrons released by the ionizing radiation are converted to NO(2)(*). While the reductive pathway is strongly affected by the nitrate and there is also some N-O bond scission via direct excitation, the extent of interference with the oxidative pathway is relatively small; the cation damage is not dramatically affected by the presence of nitrate as most of the detrimental radiolytic products are generated via the oxidative pathway. These results are contrasted with the behavior of dialkylphosphoric acids (a large class of extraction agents for trivalent metal ions). We demonstrate that IL solvents protect these dialkylphosphoric acids against radiation-induced dealkylation. PMID- 21823650 TI - Thrombospondin-1 and angiotensin II inhibit soluble guanylyl cyclase through an increase in intracellular calcium concentration. AB - Nitric oxide (NO) regulates cardiovascular hemostasis by binding to soluble guanylyl cyclase (sGC), leading to cGMP production, reduced cytosolic calcium concentration ([Ca(2+)](i)), and vasorelaxation. Thrombospondin-1 (TSP-1), a secreted matricellular protein, was recently discovered to inhibit NO signaling and sGC activity. Inhibition of sGC requires binding to cell-surface receptor CD47. Here, we show that a TSP-1 C-terminal fragment (E3CaG1) readily inhibits sGC in Jurkat T cells and that inhibition requires an increase in [Ca(2+)](i). Using flow cytometry, we show that E3CaG1 binds directly to CD47 on the surface of Jurkat T cells. Using digital imaging microscopy on live cells, we further show that E3CaG1 binding results in a substantial increase in [Ca(2+)](i), up to 300 nM. Addition of angiotensin II, a potent vasoconstrictor known to increase [Ca(2+)](i), also strongly inhibits sGC activity. sGC isolated from calcium treated cells or from cell-free lysates supplemented with Ca(2+) remains inhibited, while addition of kinase inhibitor staurosporine prevents inhibition, indicating inhibition is likely due to phosphorylation. Inhibition is through an increase in K(m) for GTP, which rises to 834 MUM for the NO-stimulated protein, a 13-fold increase over the uninhibited protein. Compounds YC-1 and BAY 41-2272, allosteric stimulators of sGC that are of interest for treating hypertension, overcome E3CaG1-mediated inhibition of NO-ligated sGC. Taken together, these data suggest that sGC not only lowers [Ca(2+)](i) in response to NO, inducing vasodilation, but also is inhibited by high [Ca(2+)](i), providing a fine balance between signals for vasodilation and vasoconstriction. PMID- 21823652 TI - Novel polypropylene/inorganic fullerene-like WS2 nanocomposites containing a beta nucleating agent: dynamic crystallization and melting behavior. AB - The dynamic crystallization and melting behavior of isotactic polypropylene tungsten disulfide (iPP/IF-WS(2)) nanocomposites incorporating a beta-nucleating agent is investigated by X-ray diffraction and differential scanning calorimetry. A conventional melt-processing strategy is employed to generate new materials that exhibit variable alpha and beta polymorphism under the appropriate kinetic conditions. The results show that when the dual additive system is employed the nucleation ability on isotactic polypropylene not only depends on the nucleation efficiency (NE) and relative content of the individual alpha and beta-nucleating agents, but also on the cooling rates employed. The nucleating behavior of the additives is explained by competitive nucleation, and the correlation between crystallization and melting temperatures and relative content of alpha and beta crystals of iPP in the nanocomposites is discussed. PMID- 21823653 TI - Pericyclic reactions catalyzed by chorismate-utilizing enzymes. AB - One of the fundamental questions of enzymology is how catalytic power is derived. This review focuses on recent developments in the structure--function relationships of chorismate-utilizing enzymes involved in siderophore biosynthesis to provide insight into the biocatalysis of pericyclic reactions. Specifically, salicylate synthesis by the two-enzyme pathway in Pseudomonas aeruginosa is examined. The isochorismate-pyruvate lyase is discussed in the context of its homologues, the chorismate mutases, and the isochorismate synthase is compared to its homologues in the MST family (menaquinone, siderophore, or tryptophan biosynthesis) of enzymes. The tentative conclusion is that the activities observed cannot be reconciled by inspection of the active site participants alone. Instead, individual activities must arise from unique dynamic properties of each enzyme that are tuned to promote specific chemistries. PMID- 21823655 TI - Hierarchical mesoporous silica nanotubes derived from natural cellulose substance. AB - Bioinspired synthesis of hierarchical mesoporous silica nanotubes by using natural cellulose substance (filter paper) and cetyltrimethylammonium bromide (CTAB) micelles as dual templates was achieved. CTAB micelles were adsorbed onto the surfaces of ultrathin titania film precoated cellulose nanofibers, followed by hydrolysis and condensation of tetraethyl orthosilicate around these micelles to form silica. After calcination and sulfuric acid treatment to remove the organic templates and the thin titania film, bulk white sheets composed of natural hierarchical silica nanotubes with mesopores in the walls were obtained, to which silver nanoparticles were further induced to give a silica nanotube/metal-nanoparticle hybrid. PMID- 21823654 TI - The reconstituted Escherichia coli Bam complex catalyzes multiple rounds of beta barrel assembly. AB - beta-Barrel proteins are folded and inserted into the outer membranes of Escherichia coli by the Bam complex. The Bam complex has been purified and functionally reconstituted in vitro. We report conditions for reconstitution that increase the folding yield 10-fold and allow us to monitor the time course of folding directly. We use these conditions to analyze the effect of a mutation in the Bam complex and to demonstrate the ability of the reconstituted complex to catalyze more than one round of substrate assembly. PMID- 21823656 TI - Superhydrophobic films on glass surface derived from trimethylsilanized silica gel nanoparticles. AB - The paper deals with the fabrication of sol-gel-derived superhydrophobic films on glass based on the macroscopic silica network with surface modification. The fabricated transparent films were composed of a hybrid -Si(CH(3))(3) functionalized SiO(2) nanospheres exhibiting the desired micro/nanostructure, water repellency, and antireflection (AR) property. The wavelength selective AR property can be tuned by controlling the physical thickness of the films. Small angle X-ray scattering (SAXS) studies revealed the existence of SiO(2) nanoparticles of average size ~9.4 nm in the sols. TEM studies showed presence of interconnected SiO(2) NPs of ~10 nm in size. The films were formed with uniformly packed SiO(2) aggregates as observed by FESEM of film surface. FTIR of the films confirmed presence of glasslike Si-O-Si bonding and methyl functionalization. The hydrophobicity of the surface was depended on the thickness of the deposited films. A critical film thickness (>115 nm) was necessary to obtain the air push effect for superhydrophobicity. Trimethylsilyl functionalization of SiO(2) and the surface roughness (rms ~30 nm as observed by AFM) of the films were also contributed toward the high water contact angle (WCA). The coated glass surface showed WCA value of the droplet as high as 168 +/- 3 degrees with 6 MUL of water. These superhydrophobic films were found to be stable up to about 230-240 degrees C as confirmed by TG/DTA studies, and WCA measurements of the films with respect to the heat-treatment temperatures. These high water repellant films can be deposited on relatively large glass surfaces to remove water droplets immediately without any mechanical assistance. PMID- 21823657 TI - Preparation and optical properties of indium tin oxide/epoxy nanocomposites with polyglycidyl methacrylate grafted nanoparticles. AB - Visibly highly transparent indium tin oxide (ITO)/epoxy nanocomposites were prepared by dispersing polyglycidyl methacrylate (PGMA) grafted ITO nanoparticles into a commercial epoxy resin. The oleic acid stabilized, highly crystalline, and near monodisperse ITO nanoparticles were synthesized via a nonaqueous synthetic route with multigram batch quantities. An azido-phosphate ligand was synthesized and used to exchange with oleic acid on the ITO surface. The azide terminal group allows for the grafting of epoxy resin compatible PGMA polymer chains via Cu(I) catalyzed alkyne-azide "click" chemistry. Transmission electron microscopy (TEM) observation shows that PGMA grafted ITO particles were homogeneously dispersed within the epoxy matrix. Optical properties of ITO/epoxy nanocomposites with different ITO concentrations were studied with an ultraviolet-visible-near infrared (UV-vis-NIR) spectrometer. All the ITO/epoxy nanocomposites show more than 90% optical transparency in the visible light range and absorption of UV light from 300 to 400 nm. In the near-infrared region, ITO/epoxy nanocomposites demonstrate low transmittance and the infrared (IR) transmission cutoff wavelength of the composites shifts toward the lower wavelength with increased ITO concentration. The ITO/epoxy nanocomposites were applied onto both glass and plastic substrates as visibly transparent and UV/IR opaque optical coatings. PMID- 21823658 TI - Artificial extracellular matrix proteins containing phenylalanine analogues biosynthesized in bacteria using T7 expression system and the PEGylation. AB - In vivo incorporation of phenylalanine (Phe) analogues into an artificial extracellular matrix protein (aECM-CS5-ELF) was accomplished using a bacterial expression host that harbors the mutant phenylalanyl-tRNA synthetase (PheRS) with an enlarged binding pocket. Although the Ala294Gly/Thr251Gly mutant PheRS (PheRS**) under the control of T5 promoter allows incorporation of some Phe analogues into a protein, the T5 system is not suitable for material science studies because the amount of materials produced is not sufficient due to the moderate strength of the T5 promoter. This limitation can be overcome by using a pair of T7 promoter and T7 RNA polymerase instead. In the T7 expression system, it is difficult, however, to achieve a high incorporation level of Phe analogues, due to competition of Phe analogues for incorporation with the residual Phe that is required for synthesis of active T7 RNA polymerase. In this study, we prepared the PheRS** under T7 promoter and optimized culture condition to improve both the incorporation level of recombinant aECM protein and the incorporation level of Phe analogues. Incorporation and expression levels tend to increase in the case of p-azidophenylalanine, p-iodophenylalanine, and p-acetylphenylalanine. We evaluated the lower critical transition temperature, which is dependent on the incorporation ratio and the turbidity decreased when the incorporation level increased. Circular dichromism measurement indicated that this tendency is based on conformational change from random coil to beta-turn structure. We demonstrated that polyethylene glycol (PEG) can be conjugated at reaction site of Phe analogues incorporated. We also demonstrated that the increased hydrophilicity of elastin-like sequences in the aECM-CS5-ELF made by PEG conjugation could suppress nonspecific adhesion of human umbilical vein endothelial cells (HUVEC). PMID- 21823659 TI - Ordered blue luminescent ultrathin films by the effective coassembly of tris(8 hydroxyquinolate-5-sulfonate)aluminum and polyanions with layered double hydroxides. AB - This article reports a novel method to assemble a small anion with exfoliated Mg Al-layered double hydroxide (LDH) nanosheets into ordered ultrathin films (UTFs) by employing the layer-by-layer assembly technique. The premixing solution of tris(8-hydroxyquinolate-5-sulfonate)aluminum(III) (AQS(3-)) with three kinds of polyanions-poly(acrylic acid), ((C(3)H(4)O(2))(n), PAA), poly(styrene 4 sulfonate) ([CH(2)CH(C(6)H(4))SO(3)](m), PSS), and poly[5-methoxy-2-(3 sulfopropoxy)-1,4-phenylene vinylene] (C(12)H(13)O(5)S)(n), PPV)-has been used as building blocks to assemble alternatively with LDH nanosheets. The UV-vis absorption and fluorescence spectroscopy of (AQS-polyanion/LDH)(n) UTFs presents stepwise growth upon increasing deposited cycles in comparison with the (AQS/LDH)(n) film under the same experimental process. (AQS-PPV/LDH)(n) UTF displays complex fluorescence originating from AQS and PPV. The (AQS/LDH)(n) and (AQS-polyanion/LDH)(n) UTFs exhibit higher blue-polarized photoemission character with a luminescence anisotropy (r) of ca. 0.12-0.20 and a longer fluorescence lifetime than that of the Na(3)AQS film with r = 0.04. X-ray diffraction, scanning electron microscopy, and atomic force microscopy demonstrated that the UTFs were orderly periodically layered structures with a thickness of ca. 3.0 nm per bilayer. Therefore, this work gives a feasible method for immobilizing small anions into the gallery of LDHs. PMID- 21823660 TI - Ferroelectric control of magnetic anisotropy. AB - We demonstrate unambiguous evidence of the electric field control of magnetic anisotropy in a wedge-shaped Co film of varying thickness. A copolymer ferroelectric of 70% vinylidene fluoride with 30% trifluoroethylene, P(VDF-TrFE) overlays the Co wedge, providing a large switchable electric field. As the ferroelectric polarization is switched from up to down, the magnetic anisotropy of the Co films changes by as much as 50%. At the lowest Co thickness the magnetic anisotropy switches from out-of-plane to in-plane as the ferroelectric polarization changes from up to down, enabling us to rotate the magnetization through a large angle at constant magnetic field merely by switching the ferroelectric polarization. The large mismatch in the stiffness coefficients between the polymer ferroelectric and metallic ferromagnet excludes typical magnetoelectric strain coupling; rather, the magnetic changes arise from the large electric field at the ferroelectric/ferromagnet interface. PMID- 21823661 TI - Cross-linked, heterogeneous colloidosomes exhibit pH-induced morphogenesis. AB - Inspired by morphogenesis in biology, we present a strategy for developing functional 3D materials with the capacity to morph based on environmental cues. We utilized local mechanical stresses to cause global shape changes in colloidosomes. Colloidosomes were assembled from pH-sensitive calcium alginate particles (CAPs) with high and low swelling ratios. Colloidosomes were subsequently cross-linked via diamine compounds with varying carbon chain lengths. New colloidosome isoforms were generated from heterogeneous mixtures of CAPs, which resulted in nonuniform stresses. Our study demonstrated that coordinated networks of heterogeneous subunits may be used to design programmable materials. PMID- 21823662 TI - A redesigned vancomycin engineered for dual D-Ala-D-ala And D-Ala-D-Lac binding exhibits potent antimicrobial activity against vancomycin-resistant bacteria. AB - The emergence of bacteria resistant to vancomycin, often the antibiotic of last resort, poses a major health problem. Vancomycin-resistant bacteria sense a glycopeptide antibiotic challenge and remodel their cell wall precursor peptidoglycan terminus from d-Ala-d-Ala to d-Ala-d-Lac, reducing the binding of vancomycin to its target 1000-fold and accounting for the loss in antimicrobial activity. Here, we report [Psi[C(?NH)NH]Tpg(4)]vancomycin aglycon designed to exhibit the dual binding to d-Ala-d-Ala and d-Ala-d-Lac needed to reinstate activity against vancomycin-resistant bacteria. Its binding to a model d-Ala-d Ala ligand was found to be only 2-fold less than vancomycin aglycon and this affinity was maintained with a model d-Ala-d-Lac ligand, representing a 600-fold increase relative to vancomycin aglycon. Accurately reflecting these binding characteristics, it exhibits potent antimicrobial activity against vancomycin resistant bacteria (MIC = 0.31 MUg/mL, VanA VRE). Thus, a complementary single atom exchange in the vancomycin core structure (O -> NH) to counter the single atom exchange in the cell wall precursors of resistant bacteria (NH -> O) reinstates potent antimicrobial activity and charts a rational path forward for the development of antibiotics for the treatment of vancomycin-resistant bacterial infections. PMID- 21823663 TI - Thermodynamic modeling and investigation of the formation of electrospun collagen fibers. AB - Electrospun type I collagen fibers are very promising materials for tissue scaffold applications, but are typically fabricated from toxic solvents. Recently, electrospinning of type I collagen fibers by using environmentally friendly phosphate buffer saline (PBS)/ethanol solution has been explored. PBS/ethanol solvent systems offer better cell compatibility, but the high surface tension and high boiling point of the solvent system make the collagen difficult to electrospin and can cause inferior fiber morphology. In this study, the influence of solvent surface tension on the morphology of electrospun collagen fibers has been experimentally investigated and analyzed from a thermodynamics perspective. The analytical results indicate that solvents with high surface tension drive the formation of beads along the smaller, thinner fibers. In addition, beads with relatively small angular eccentricity were thermodynamically favorable. The experimental results presented herein corroborate the theoretical analysis and conclusions drawn from this study. The surface tension of the solvent has significant influence on the bead formation, especially in an aqueous system. The environmental humidity for the electrospinning process and the collagen concentration were also investigated. These parameters may result in variations of the evaporation-solidification rates, which consequently impact the formation and morphologies of electrospun collagen fibers. According to the thermodynamic analysis, uniform electrospun collagen fibers without beads can be obtained by manipulating solvent surface tension during the electrospinning process. PMID- 21823664 TI - Identification of hnRNPH1, NF45, and C14orf166 as novel host interacting partners of the mature hepatitis C virus core protein. AB - The hepatitis C virus core protein (HCVc) forms the viral nucleocapsid and is involved in viral persistence and pathogenesis, possibly by interacting with host factors to modulate viral replication and cellular functions. Here, we identified 36 cellular protein candidates by one-dimensional SDS-PAGE and LC-MS/MS-based proteomics after affinity purification with HCVc174, a matured form of HCVc from HCV-1b genotype, tagged with biotin and calmodulin-binding peptide/protein A at N and C-termini, respectively. By pull-down and confocal imaging techniques, we confirmed that heterogeneous nuclear ribonucleoprotein H1 (hnRNPH1), nuclear factor 45 (NF45), and C14orf166 are novel HCVc174-interacting host proteins, known to participate in mRNA metabolism, gene regulation, and microtubule organization, respectively. Unlike the other 2 proteins, NF45 interacted with HCVc174 in an RNA-dependent manner. These 3 proteins colocalized with ectopic HCVc-1b in both the cytoplasm and nucleus, which demonstrated their spatial interaction with naturally translocated HCVc174 after HCVc biogenesis. Such colocalization, however, shifted to the cytoplasm in cells with replicating virus of 1b or 2a genotype, indicating that active viral replication confined these interacting proteins in the cytoplasm. Collectively, our findings suggest that spatial interactions of hnRNPH1, NF45, and C14orf166 with HCVc174 likely modulate HCV or cellular functions during acute and chronic HCV infection. PMID- 21823665 TI - Magnetically responsive pickering foams. AB - We introduce a new class of Pickering foams which can be manipulated using a magnetic field. These foams are stabilized by a mixture of magnetic and nonmagnetic particles. They exhibit excellent stability in the absence of a magnetic field, but can be rapidly destroyed on demand with the application of a threshold field. We characterize their stability in the absence of a magnetic field by measuring the rate of water drainage from the foam as a function of time. We also correlate their collapse behavior under a magnetic field to the foam liquid fraction, as well as the concentration of magnetic particles in the foam. This novel system can be used to study the properties of Pickering foams, and has potential applications in noncontact defoaming processes. PMID- 21823666 TI - Structural basis of substrate recognition in human nicotinamide N methyltransferase. AB - Nicotinamide N-methyltransferase (NNMT) catalyzes the N-methylation of nicotinamide, pyridines, and other analogues using S-adenosyl-l-methionine as donor. NNMT plays a significant role in the regulation of metabolic pathways and is expressed at markedly high levels in several kinds of cancers, presenting it as a potential molecular target for cancer therapy. We have determined the crystal structure of human NNMT as a ternary complex bound to both the demethylated donor S-adenosyl-l-homocysteine and the acceptor substrate nicotinamide, to 2.7 A resolution. These studies reveal the structural basis for nicotinamide binding and highlight several residues in the active site which may play roles in nicotinamide recognition and NNMT catalysis. The functional importance of these residues was probed by mutagenesis. Of three residues near the nicotinamide's amide group, substitution of S201 and S213 had no effect on enzyme activity while replacement of D197 dramatically decreased activity. Substitutions of Y20, whose side chain hydroxyl interacts with both the nicotinamide aromatic ring and AdoHcy carboxylate, also compromised activity. Enzyme kinetics analysis revealed k(cat)/K(m) decreases of 2-3 orders of magnitude for the D197A and Y20A mutants, confirming the functional importance of these active site residues. The mutants exhibited substantially increased K(m) for both NCA and AdoMet and modestly decreased k(cat). MD simulations revealed long-range conformational effects which provide an explanation for the large increase in K(m)(AdoMet) for the D197A mutant, which interacts directly only with nicotinamide in the ternary complex crystal structure. PMID- 21823667 TI - Coating process regimes in particulate film production by forced-convection assisted drag-out. AB - Operating conditions for the deposition of monolayer and bilayer particulate coatings from aqueous 20-nm-diameter silica dispersions are identified in the context of a drag-out operation assisted by forced convection. The dry film thickness, uniformity, and morphology are assessed within an operating window parametrized by the capillary number and silica dispersion weight fraction. Three film deposition regimes with respect to the capillary number are observed: convective film deposition at low process rates, film entrainment at moderate process rates, and a thin-film transition regime at intermediate process rates. Locally ordered particulate films of variable layering thickness, including (i) a discontinuous submonolayer or (ii) a mixed submonolayer and monolayer, (iii) a mixed monolayer and bilayer, and (iv) multilayers, are dominant under convective deposition conditions. A map of morphologies is presented within the capillary number-weight fraction operating window, where monolayer and mixed monolayer bilayer films are demonstrated in the thin-film transition regime at an intermediate dispersion weight fraction. A complementary map of the morphologies formed by the drag-out of 110 nm silica dispersions reveals a broader applicability to this type of operability diagram. These operating maps are constructed using model silica dispersions and are therefore relevant to particulate coatings of other inorganic materials. PMID- 21823668 TI - Ultra high-resolution NMR: sustained induction decays of long-lived coherences. AB - Long-lived coherences (LLCs) in homonuclear pairs of chemically inequivalent spins can be excited and sustained during protracted radio frequency irradiation periods that alternate with brief windows for signal observation. Fourier transformation of the sustained induction decays recorded in a single scan yields NMR spectra with line-widths in the range 10 < Deltanu < 100 mHz, even in moderately inhomogeneous magnetic fields. The resulting doublets, which are reminiscent of J-spectra, allow one to determine the sum of scalar and residual dipolar interactions in partly oriented media. The signal intensity can be boosted by several orders of magnitude by "dissolution" dynamic nuclear polarization (DNP). PMID- 21823669 TI - Electrochemical analysis of proton and electron transfer equilibria of the reducible moieties in humic acids. AB - Humic substances play a key role in biogeochemical and pollutant redox reactions. The objective of this work was to characterize the proton and electron transfer equilibria of the reducible moieties in different humic acids (HA). Cyclic voltammetry experiments demonstrated that diquat and ethylviologen mediated electron transfer between carbon working electrodes and HA. These compounds were used also to facilitate attainment of redox equilibria between redox electrodes and HA in potentiometric E(h) measurements. Bulk electrolysis of HA combined with pH-stat acid titration demonstrated that electron transfer to the reducible moieties in HA also resulted in proton uptake, suggesting decreasing reduction potentials E(h) of HA with increasing pH. This was confirmed by potentiometric E(h)-pH titrations of HA at different redox states. E(h) measurements of HA samples prereduced to different redox states by bulk electrolysis revealed reducible moieties in HA that cover a wide range of apparent standard reduction potentials at pH 7 from E(h)(0)* = +0.15 to -0.3 V. Modeling revealed an overall increase in the relative abundance of reducible moieties with decreasing E(h). The wide range of HA is consistent with its involvement in numerous environmental electron transfer reactions under various redox conditions. PMID- 21823670 TI - Developing visible fluorogenic 'click-on' dyes for cellular imaging. AB - New fluorogenic dyes were designed and synthesized based on Cu(I)-catalyzed 'click' reaction. Conjugating weakly fluorescent benzothiazole derivatives with an electron-deficient alkyne group at the 2-position with azide-containing molecules in aqueous solution form 'click-on' fluorescent adducts. Model reactions and cell culture experiment indicated that the developed 'click-on' dye could be applied to labeling various biomolecules, such as nucleic acids, proteins, and other molecules, in cells. PMID- 21823671 TI - Rapid, biomimetic degradation in water of the persistent drug sertraline by TAML catalysts and hydrogen peroxide. AB - Iron TAML activators (oxidation catalysts based upon tetraamido macrocyclic ligands) at nanomolar concentrations in water activate hydrogen peroxide to rapidly degrade sertraline, the persistent, active pharmaceutical ingredient (API) in the widely used drug Zoloft. Although all the API is readily consumed, degradation slows significantly at one intermediate, sertraline ketone. The process occurs from neutral to basic pH. The pathway has been characterized through four early intermediates which reflect the metabolism of sertraline, providing further evidence that TAML activator/peroxide reactive intermediates mimic those of cytochrome P450 enzymes. TAML catalysts have been designed to exhibit considerable variability in reactivity and this provides an excellent tool for observing degradation intermediates of widely differing stabilities. Two elusive, hydrolytically sensitive intermediates and likely human metabolites, sertraline imine and N-desmethylsertraline imine, could be identified only by using a fast-acting catalyst. The more stable intermediates and known human metabolites, desmethylsertraline and sertraline ketone, were most easily detected and studied using a slow-acting catalyst. The resistance of sertraline ketone to aggressive TAML activator/peroxide treatment marks it as likely to be environmentally persistent and signals that its environmental effects are important components of the full implications of sertraline use. PMID- 21823673 TI - Nitrate in the Mississippi River and its tributaries, 1980 to 2008: are we making progress? AB - Changes in nitrate concentration and flux between 1980 and 2008 at eight sites in the Mississippi River basin were determined using a new statistical method that accommodates evolving nitrate behavior over time and produces flow-normalized estimates of nitrate concentration and flux that are independent of random variations in streamflow. The results show that little consistent progress has been made in reducing riverine nitrate since 1980, and that flow-normalized concentration and flux are increasing in some areas. Flow-normalized nitrate concentration and flux increased between 9 and 76% at four sites on the Mississippi River and a tributary site on the Missouri River, but changed very little at tributary sites on the Ohio, Iowa, and Illinois Rivers. Increases in flow-normalized concentration and flux at the Mississippi River at Clinton and Missouri River at Hermann were more than three times larger than at any other site. The increases at these two sites contributed much of the 9% increase in flow-normalized nitrate flux leaving the Mississippi River basin. At most sites, concentrations increased more at low and moderate streamflows than at high streamflows, suggesting that increasing groundwater concentrations are having an effect on river concentrations. PMID- 21823674 TI - Spectroscopic detection of DNA quadruplexes by vibrational circular dichroism. AB - The four-stranded G-quadruplex motif is a conformation frequently adopted by guanine-rich nucleic acids that plays an important role in biology, medicine, and nanotechnology. Although vibrational spectroscopy has been widely used to investigate nucleic acid structure, association of particular spectral features with the quadruplex structure has to date been ambiguous. In this work, experimental IR absorption and vibrational circular dichroism (VCD) spectra of the model quadruplex systems d(G)(8) and deoxyguanosine-5'-monophosphate (5' dGMP) were analyzed using molecular dynamics (MD) and quantum-chemical modeling. The experimental spectra were unambiguously assigned to the quadruplex DNA arrangement, and several IR and VCD bands related to this structural motif were determined. Involvement of MD in the modeling was essential for realistic simulation of the spectra. The VCD signal was found to be more sensitive to dynamical structural variations than the IR signal. The combination of the spectroscopic techniques with multiscale simulations provides extended information about nucleic acid conformations and their dynamics. PMID- 21823676 TI - 1H NMR metabolite fingerprint and pattern recognition of mullet (Mugil cephalus) bottarga. AB - Nuclear magnetic resonance (NMR) spectroscopy combined with multivariate data analysis (MVA) was used to investigate the molecular components of the aqueous extract of samples of bottarga, that is, salted and dried mullet (Mugil cephalus) roe, manufactured in Sardinia (Italy) from mullets of known and unknown geographical provenience. Principal component analysis (PCA) applied to the processed (1)H NMR spectra indicated that samples tend to cluster according to their geographical origin and also on the basis of storage and manufacturing procedures. The most important metabolites that characterized grouping of samples are the free amino acids methionine (Met), glutamate (Glu), histidine (His), phenylalanine (Phe), tyrosine (Tyr), and isoleucine (Ile); trimethylamine (TMA) and dimethylamine (DMA), both biomarkers of degradation; nucleotides and derivatives; choline (Cho) and phosphorylcholine (P-cho); and lactate (Lac). PMID- 21823675 TI - Combined proteomic and metabolomic profiling of serum reveals association of the complement system with obesity and identifies novel markers of body fat mass changes. AB - Obesity is associated with multiple adverse health effects and a high risk of developing metabolic and cardiovascular diseases. Therefore, there is a great need to identify circulating parameters that link changes in body fat mass with obesity. This study combines proteomic and metabolomic approaches to identify circulating molecules that discriminate healthy lean from healthy obese individuals in an exploratory study design. To correct for variations in physical activity, study participants performed a one hour exercise bout to exhaustion. Subsequently, circulating factors differing between lean and obese individuals, independent of physical activity, were identified. The DIGE approach yielded 126 differentially abundant spots representing 39 unique proteins. Differential abundance of proteins was confirmed by ELISA for antithrombin-III, clusterin, complement C3 and complement C3b, pigment epithelium-derived factor (PEDF), retinol binding protein 4 (RBP4), serum amyloid P (SAP), and vitamin-D binding protein (VDBP). Targeted serum metabolomics of 163 metabolites identified 12 metabolites significantly related to obesity. Among those, glycine (GLY), glutamine (GLN), and glycero-phosphatidylcholine 42:0 (PCaa 42:0) serum concentrations were higher, whereas PCaa 32:0, PCaa 32:1, and PCaa 40:5 were decreased in obese compared to lean individuals. The integrated bioinformatic evaluation of proteome and metabolome data yielded an improved group separation score of 2.65 in contrast to 2.02 and 2.16 for the single-type use of proteomic or metabolomics data, respectively. The identified circulating parameters were further investigated in an extended set of 30 volunteers and in the context of two intervention studies. Those included 14 obese patients who had undergone sleeve gastrectomy and 12 patients on a hypocaloric diet. For determining the long-term adaptation process the samples were taken six months after the treatment. In multivariate regression analyses, SAP, CLU, RBP4, PEDF, GLN, and C18:2 showed the strongest correlation to changes in body fat mass. The combined serum proteomic and metabolomic profiling reveals a link between the complement system and obesity and identifies both novel (C3b, CLU, VDBP, and all metabolites) and confirms previously discovered markers (PEDF, RBP4, C3, ATIII, and SAP) of body fat mass changes. PMID- 21823677 TI - Poly(ethylene oxide) layers grafted to dopamine-melanin anchoring layer: stability and resistance to protein adsorption. AB - In this study, we propose substrate-independent modification for creating a protein-repellent surface based on dopamine-melanin anchoring layer used for subsequent binding of poly(ethylene oxide) (PEO) from melt. We verified that the dopamine-melanin layer can be formed on literally any substrate and could serve as the anchoring layer for subsequent grafting of PEO chains. Grafting of PEO from melt in a temperature range 70-110 degrees C produces densely packed PEO layers showing exceptionally low protein adsorption when exposed to the whole blood serum or plasma. The PEO layers prepared from melt at 110 degrees C retained the protein repellent properties for as long as 10 days after their exposure to physiological-like conditions. The PEO-dopamine-melanin modification represents a simple and universal surface modification method for the preparation of protein repellent surfaces that could serve as a nonfouling background in various applications, such as optical biosensors and tissue engineering. PMID- 21823678 TI - Hydrated magnesium cations Mg+(H2O)n, n ~ 20-60, exhibit chemistry of the hydrated electron in reactions with O2 and CO2. AB - Ion-molecule reactions of Mg(+)(H(2)O)(n), n ~ 20-60, with O(2) and CO(2) are studied by Fourier-transform ion cyclotron resonance (FT-ICR) mass spectrometry. O(2) and CO(2) are taken up by the clusters. Both reactions correspond to the chemistry of hydrated electrons (H(2)O)(n)(-). Density functional theory calculations predicted that the solvation structures of Mg(+)(H(2)O)(16) contain a hydrated electron that is solvated remotely from a hexa-coordinated Mg(2+). Ion molecule reactions between Mg(+)(H(2)O)(16) and O(2) or CO(2) are calculated to be highly exothermic. Initially, a solvent-separated ion pair is formed, with the hexa-coordinated Mg(2+) ionic core being well separated from the O(2)(*-) or CO(2)(*-). Rearrangements of the solvation structure are possible and produce a contact-ion pair in which one water molecule in the first solvation shell of Mg(2+) is replaced by O(2)(*-) or CO(2)(*-). PMID- 21823679 TI - Effect of saccharide structure and size on the degree of substitution and product dispersity of alpha-lactalbumin glycated via the Maillard reaction. AB - The course of the Maillard reaction between alpha-lactalbumin and various mono- and oligosaccharides in the solid state was studied using UPLC-ESI-TOF-MS. Individual reaction products were monitored for their degree of substitution per protein molecule (DSP). The Maillard reaction rate depended on the saccharide type and decreased when the saccharide size increased. Conjugation with charged saccharides was hindered when a specific average DSP was reached, probably resulting from electrostatic repulsion. The DSP varied between 0 and 15, and the standard deviation of the average DSP, which is a measure for product dispersity, increased to 1.9. Similar experiments were performed with a dipeptide. Relative reaction rates in these experiments were 1 for glucose, 0.28 for maltose, and 0.16 for maltotriose. Comparison of the results obtained using alpha-lactalbumin and the dipeptide made clear that the Maillard reaction rate is determined by a number of factors, including saccharide reactivity and lysine accessibility. PMID- 21823680 TI - Hybrid organic/inorganic molecular heterojunctions based on strained nanomembranes. AB - In this work, we combine self-assembly and top-down methods to create hybrid junctions consisting of single organic molecular monolayers sandwiched between metal and/or single-crystalline semiconductor nanomembrane based electrodes. The fabrication process is fully integrative and produces a yield loss of less than 5% on-chip. The nanomembrane-based electrodes guarantee a soft yet robust contact to the molecules where the presence of pinholes and other defects becomes almost irrelevant. We also pioneer the fabrication and characterization of semiconductor/molecule/semiconductor tunneling heterojunctions which exhibit a double transition from direct tunneling to field emission and back to direct tunneling, a phenomenon which has not been reported previously. PMID- 21823681 TI - Sequential melting of two hydrophobic clusters within the green fluorescent protein GFP-cycle3. AB - The analysis of the three-dimensional structure of green fluorescent protein (GFP cycle3) revealed the presence of two well-defined hydrophobic clusters located on the opposite sides of the GFP beta-can that might contribute to the formation of partially folded intermediate(s) during GFP unfolding. The microcalorimetric analysis of the nonequilibrium melting of GFP-cycle3 and its two mutants, I14A and I161A, revealed that due to the sequential melting of the mentioned hydrophobic clusters, the temperature-induced denaturation of this protein most likely occurs in three stages. The first and second stages involve melting of a smaller hydrophobic cluster formed around the residue I161, whereas a larger hydrophobic cluster (formed around the residues I14) is melted only at the last GFP-cycle3 denaturation step or remains rather structured even in the denatured state. PMID- 21823682 TI - Perspective: The dawning of the age of graphene. AB - Graphene is a single sheet of carbon atoms that constitutes the basic building block of macroscopic graphite crystals. Held together by a backbone of overlapping sp(2) hybrids, graphene's 2p orbitals form pi state bands that delocalize over an entire 2-dimensional macroscopic carbon sheet leading to a number of unusual characteristics that include large electrical and thermal conductivities. Recent discoveries have provided simple methods (e.g., mechanical cleavage of graphite) for preparing laboratory scale samples that can be used to investigate the fundamental physical and chemical characteristics of graphene. In addition, a number of techniques have emerged that show promise for producing large-scale samples with the ultimate goal of developing devices that take advantage of graphene's unusual properties. As large samples become available, the possibility grows for applications of this material in solar cell technology (as flexible, transparent electrodes), in composite material development, and in electronic devices. PMID- 21823683 TI - Communication: Effective temperature and glassy dynamics of active matter. AB - A systematic expansion of the many-body master equation for active matter, in which motors power configurational changes as in the cytoskeleton, is shown to yield a description of the steady state and responses in terms of an effective temperature. The effective temperature depends on the susceptibility of the motors and a Peclet number which measures their strength relative to thermal Brownian diffusion. The analytic prediction is shown to agree with previous numerical simulations and experiments. The mapping also establishes a description of aging in active matter that is also kinetically jammed. PMID- 21823684 TI - A new internally contracted multi-reference configuration interaction method. AB - We present a new internally contracted multi-reference configuration interaction (MRCI) method which, at the same time, efficiently handles large active orbital spaces, long configuration expansions, and many closed-shell orbitals in the reference function. This is achieved by treating the closed-shell orbitals explicitly, so that all required coupling coefficients and density matrices only depend on active orbital labels. As a result, closed-shell orbitals are handled as efficiently as in a closed-shell single-reference program, and this opens up the possibility to perform high-accuracy MRCI calculations for much larger molecules than before. The enormously complex equations are derived using a new domain-specific computer algebra system and semi-automatically implemented using a newly developed integrated tensor framework. The accuracy and efficiency of the MRCI method is demonstrated with applications to dioxygen-copper complexes with different ligands, some of which involve more than 30 atoms, and to spin-state splittings of ferrocene. PMID- 21823685 TI - Soret motion in non-ionic binary molecular mixtures. AB - We study the Soret coefficient of binary molecular mixtures with dispersion forces. Relying on standard transport theory for liquids, we derive explicit expressions for the thermophoretic mobility and the Soret coefficient. Their sign depends on composition, the size ratio of the two species, and the ratio of Hamaker constants. Our results account for several features observed in experiment, such as a linear variation with the composition; they confirm the general rule that small molecules migrate to the warm, and large ones to the cold. PMID- 21823686 TI - Quantum optimal control for the full ensemble of randomly oriented molecules having different field-free Hamiltonians. AB - We have presented the optimal control theory formulation to calculate optimal fields that can control the full ensemble of randomly oriented molecules having different field-free Hamiltonians. The theory is applied to the fifty-fifty mixture of randomly oriented (133)CsI and (135)CsI isotopomers and an optimal field is sought to achieve isotope-selective vibrational excitations with high efficiency. Rotational motion is frozen and two total times (T's) of electric field duration, 460,000 and 920,000 a.u. (11.1 and 22.2 ps), are chosen in the present calculation. As a result, the final yields for T = 460,000 and 920,000 a.u. are calculated to be 0.706 and 0.815, respectively. The relatively high final yield obtained for T = 920,000 a.u. strongly suggests that a single laser pulse can control the full ensemble of randomly oriented non-identical molecules. The result is quite encouraging in terms of the application to isotope-separation processes. PMID- 21823687 TI - Inherent structures for soft long-range interactions in two-dimensional many particle systems. AB - We generate inherent structures, local potential-energy minima, of the "k-space overlap potential" in two-dimensional many-particle systems using a cooling and quenching simulation technique. The ground states associated with the k-space overlap potential are stealthy (i.e., completely suppress single scattering of radiation for a range of wavelengths) and hyperuniform (i.e., infinite wavelength density fluctuations vanish). However, we show via quantitative metrics that the inherent structures exhibit a range of stealthiness and hyperuniformity depending on the fraction of degrees of freedom chi that are constrained. Inherent structures in two dimensions typically contain five-particle rings, wavy grain boundaries, and vacancy-interstitial defects. The structural and thermodynamic properties of the inherent structures are relatively insensitive to the temperature from which they are sampled, signifying that the energy landscape is relatively flat along the directions sampled, with wide shallow local minima and devoid of deep wells. Using the nudged-elastic-band algorithm, we construct paths from ground-state configurations to inherent structures and identify the transition points between them. In addition, we use point patterns generated from a random sequential addition (RSA) of hard disks, which are nearly stealthy, and examine the particle rearrangements necessary to make the configurations absolutely stealthy. We introduce a configurational proximity metric to show that only small local, but collective, particle rearrangements are needed to drive initial RSA configurations to stealthy disordered ground states. These results lead to a more complete understanding of the unusual behaviors exhibited by the family of "collective-coordinate" potentials to which the k-space overlap potential belongs. PMID- 21823688 TI - Time-dependent density functional theory excited state nonadiabatic dynamics combined with quantum mechanical/molecular mechanical approach: photodynamics of indole in water. AB - We present a combination of time-dependent density functional theory with the quantum mechanical/molecular mechanical approach which can be applied to study nonadiabatic dynamical processes in molecular systems interacting with the environment. Our method is illustrated on the example of ultrafast excited state dynamics of indole in water. We compare the mechanisms of nonradiative relaxation and the electronic state lifetimes for isolated indole, indole in a sphere of classical water, and indole + 3H(2)O embedded in a classical water sphere. In the case of isolated indole, the initial excitation to the S(2) electronic state is followed by an ultrafast internal conversion to the S(1) state with a time constant of 17 fs. The S(1) state is long living (>30 ps) and deactivates to the ground state along the N-H stretching coordinate. This deactivation mechanism remains unchanged for indole in a classical water sphere. However, the lifetimes of the S(2) and S(1) electronic states are extended. The inclusion of three explicit water molecules opens a new relaxation channel which involves the electron transfer to the solvent, leading eventually to the formation of a solvated electron. The relaxation to the ground state takes place on a time scale of 60 fs and contributes to the lowering of the fluorescence quantum yield. Our simulations demonstrate the importance of including explicit water molecules in the theoretical treatment of solvated systems. PMID- 21823689 TI - Alternative wavefunction ansatz for including explicit electron-proton correlation in the nuclear-electronic orbital approach. AB - The nuclear-electronic orbital (NEO) approach treats specified nuclei quantum mechanically on the same level as the electrons with molecular orbital techniques. The explicitly correlated Hartree-Fock (NEO-XCHF) approach was developed to incorporate electron-nucleus dynamical correlation directly into the variational optimization of the nuclear-electronic wavefunction. In the original version of this approach, the Hartree-Fock wavefunction is multiplied by (1+G), where G is a geminal operator expressed as a sum of Gaussian type geminal functions that depend on the electron-proton distance. Herein, a new wavefunction ansatz is proposed to avoid the computation of five- and six-particle integrals and to simplify the computation of the lower dimensional integrals involving the geminal functions. In the new ansatz, denoted NEO-XCHF2, the Hartree-Fock wavefunction is multiplied by ?(1+G) rather than (1+G). Although the NEO-XCHF2 ansatz eliminates the integrals that are quadratic in the geminal functions, it introduces terms in the kinetic energy integrals with no known analytical solution. A truncated expansion scheme is devised to approximate these problematic terms. An alternative hybrid approach, in which the kinetic energy terms are calculated with the original NEO-XCHF ansatz and the potential energy terms are calculated with the NEO-XCHF2 ansatz, is also implemented. Applications to a series of model systems with up to four electrons provide validation for the NEO-XCHF2 approach and the treatments of the kinetic energy terms. PMID- 21823690 TI - Rigorous coarse-graining for the dynamics of linear systems with applications to relaxation dynamics in proteins. AB - Reduced-dimensionality, coarse-grained models are commonly employed to describe the structure and dynamics of large molecular systems. In those models, the dynamics is often described by Langevin equations of motion with phenomenological parameters. This paper presents a rigorous coarse-graining method for the dynamics of linear systems. In this method, as usual, the conformational space of the original atomistic system is divided into master and slave degrees of freedom. Under the assumption that the characteristic timescales of the masters are slower than those of the slaves, the method results in Langevin-type equations of motion governed by an effective potential of mean force. In addition, coarse-graining introduces hydrodynamic-like coupling among the masters as well as non-trivial inertial effects. Application of our method to the long timescale part of the relaxation spectra of proteins shows that such dynamic coupling is essential for reproducing their relaxation rates and modes. PMID- 21823691 TI - Ab initio quantum Monte Carlo study of the binding of a positron to alkali-metal hydrides. AB - Quantum Monte Carlo methods are used to investigate the binding of a positron to the alkali-metal hydrides, XH (X = Na and K). We obtain positron affinities for the NaH and KH molecules of 1.422(10) eV and 2.051(39) eV, respectively. These are considerably larger than the previous results of 1.035 eV and 1.273 eV obtained from multireference single- and double-excitation configuration interaction calculations. Together with our previous results for [LiH;e(+)] [Y. Kita et al., J. Chem. Phys. 131, 134310 (2009)], our study confirms the strong correlation between the positron affinity and dipole moment of alkali-metal hydrides. PMID- 21823692 TI - Fractional spin in reduced density-matrix functional theory. AB - We study the behavior of different functionals of the one-body reduced density matrix (1RDM) for systems with fractional z-component of the total spin. We define these systems as ensembles of integer spin states. It is shown that, similarly to density functional theory, the error in the dissociation of diatomic molecules is directly related to the deviation from constancy of the atomic total energies as functions of the fractional spin. However, several functionals of the 1RDM show a size inconsistency which leads to additional errors. We also investigate the difference between a direct evaluation of the energy of an ensemble of integer-spin systems and a direct minimization of the energy of a fractional-spin system. PMID- 21823693 TI - Nuclear magnetic relaxation in water revisited. AB - In this study, we revisited nuclear magnetic relaxation of (1)H in water at very low Larmor frequencies that has been studied intensively in earlier years. We make use of the recently developed superconducting quantum interference device based ultra-low field NMR technique, which enables much easier access to the longitudinal spin-lattice relaxation time T(1) and the transversal spin-spin relaxation time T(2) below several kHz than traditional field cycling methods. Our data reproduce and complement the earlier results, in that they corroborate the finding of an exchange process with a correlation time of about 0.34 ms at room temperature which can be attributed to the migration of hydronium and hydroxyl ions in neutral water via hydrogen bridges. The corresponding relaxation process is driven by the interaction of the protons with (17)O and contributes to the T(1) and the T(2) relaxation rate by about 0.12 s(-1). In addition, we found evidence of a very slow exchange process at about 100 Hz that has hitherto not been reported. PMID- 21823694 TI - Least-squares analysis of overlapped bound-free absorption spectra and predissociation data in diatomics: the C(1Piu) state of I2. AB - Absorption spectra are recorded at low resolution but high quantitative precision for I(2) vapor at 35 degrees C and 64 degrees C. These and literature spectra are analyzed by least-squares quantum spectral simulation of the overlapped A <- X, B <- X, and C((1)Pi(u)) <- X transitions, with the aid of a pseudocontinuum model for the discrete regions of the A <- X and B <- X spectra. The analysis yields improved descriptions of the small-R regions of the A- and B-state potentials, which are known precisely at larger R from discrete spectroscopy. The C potential is determined at small R from its C <- X absorption, at intermediate R from literature data for B -> C predissociation, and at large R from its known van der Waals well. The estimates of the electronic transition moment function ?MU(e)(R)? for the B-X transition expand upon precise results from a recent determination by a different method. For the C-X and A-X transitions, the R dependence of the transition moment functions resembles that found previously for these systems in Br(2). Of the spectroscopic properties, the C <- X spectrum is most altered from the previous analysis, being now ~20% weaker. For B -> C predissociation, no derived C potential has yielded computed rates in adequate statistical agreement with the analyzed experimental data. PMID- 21823695 TI - Collision limited reaction rates for arbitrarily shaped particles across the entire diffusive Knudsen number range. AB - Aerosol particle reactions with vapor molecules and molecular clusters are often collision rate limited, hence determination of particle-vapor molecule and particle-molecular cluster collision rates are of fundamental importance. These collisions typically occur in the mass transfer transition regime, wherein the collision kernel (collision rate coefficient) is dependent upon the diffusive Knudsen number, Kn(D). While this alone prohibits analytical determination of the collision kernel, aerosol particle- vapor molecule collisions are further complicated when particles are non-spherical, as is often the case for particles formed in high temperature processes (combustion). Recently, through a combination of mean first passage time simulations and dimensional analysis, it was shown that the collision kernel for spherical particles and vapor molecules could be expressed as a dimensionless number, H, which is solely a function of Kn(D). In this work, it is shown through similar mean first passage times and redefinitions of H and Kn(D) that the H(Kn(D)) relationship found for spherical particles applies for particles of arbitrary shape, including commonly encountered agglomerate particles. Specifically, it is shown that to appropriately define H and Kn(D), two geometric descriptors for a particle are necessary: its Smoluchowski radius, which defines the collision kernel in the continuum regime (Kn(D)->0) and its orientationally averaged projected area, which defines the collision kernel in the free molecular regime (Kn(D) >infinity). With these two parameters, as well as the properties of the colliding vapor molecule (mass and diffusion coefficient), the particle-vapor molecule collision kernel in the continuum, transition, and free molecular regimes can be simply calculated using the H(Kn(D)) relationship. PMID- 21823696 TI - Full-dimensional multi configuration time dependent Hartree calculations of the ground and vibrationally excited states of He2,3Br2 clusters. AB - Quantum dynamics calculations are reported for the tetra-, and penta-atomic van der Waals He(N)Br(2) complexes using the multiconfiguration time-dependent Hartree (MCTDH) method. The computations are carried out in satellite coordinates, and the kinetic energy operator in this set of coordinates is given. A scheme for the representation of the potential energy surface based on the sum of the three-body HeBr(2) interactions at CSSD(T) level plus the He-He interaction is employed. The potential surfaces show multiple close lying minima, and a quantum description of such highly floppy multiminima systems is presented. Benchmark, full-dimensional converged results on ground vibrational/zero-point energies are reported and compared with recent experimental data available for all these complexes, as well as with previous variational quantum calculations for the smaller HeBr(2) and He(2)Br(2) complexes on the same surface. Some low lying vibrationally excited eigenstates are also computed by block improved relaxation calculations. The binding energies and the corresponding vibrationally averaged structures are determined for different conformers of these complexes. Their relative stability is discussed, and contributes to evaluate the importance of the multiple-minima topology of the underlying potential surface. PMID- 21823697 TI - Revisiting falloff curves of thermal unimolecular reactions. AB - Master equations for thermal unimolecular reactions and the reverse thermal recombination reactions are solved for a series of model reaction systems and evaluated with respect to broadening factors. It is shown that weak collision center broadening factors F(cent) (wc) can approximately be related to the collision efficiencies beta(c) through a relation F(cent) (wc) ~ max {beta(c) (0.14), 0.64(+/-0.03)}. In addition, it is investigated to what extent weak collision falloff curves in general can be expressed by the limiting low and high pressure rate coefficients together with central broadening factors F(cent) only. It is shown that there cannot be one "best" analytical expression for broadening factors F(x) as a function of the reduced pressure scale x = k(0)/k(infinity). Instead, modelled falloff curves of various reaction systems, for given k(0), k(infinity), and F(cent), fall into a band of about 10% width in F(x). A series of analytical expressions for F(x), from simple symmetric to more elaborate asymmetric broadening factors, are compared and shown to reproduce the band of modelled broadening factors with satisfactory accuracy. PMID- 21823698 TI - Geometrical structure of benzene and naphthalene: ultrahigh-resolution laser spectroscopy and ab initio calculation. AB - Geometrical structures of the isolated benzene and naphthalene molecules have been accurately determined by using ultrahigh-resolution laser spectroscopy and ab initio calculation in a complementary manner. The benzene molecule has been identified to be planar and hexagonal (D(6h)) and the structure has been determined with accuracies of 2 * 10(-14) m (0.2 mA; 1 A = 1 * 10(-10) m) for the C-C bond length and 1.0 * 10(-13) m (1.0 mA) for the C-H bond length. The naphthalene molecule has been identified to be symmetric with respect to three coordinate axes (D(2h)) and the structure has been determined with comparable accuracies. We discuss the effect of vibrational averaging that is a consequence of zero-point motions on the uncertainty in determining the bond lengths. PMID- 21823699 TI - Pressure and temperature dependence of dissociative and non-dissociative electron attachment to CF3: experiments and kinetic modeling. AB - The kinetics of electron attachment to CF(3) as a function of temperature (300 600 K) and pressure (0.75-2.5 Torr) were studied by variable electron and neutral density attachment mass spectrometry exploiting dissociative electron attachment to CF(3)Br as a radical source. Attachment occurs through competing dissociative (CF(3) + e(-) -> CF(2) + F(-)) and non-dissociative channels (CF(3) + e(-) -> CF(3)(-)). The rate constant of the dissociative channel increases strongly with temperature, while that of the non-dissociative channel decreases. The rate constant of the non-dissociative channel increases strongly with pressure, while that of the dissociative channel shows little dependence. The total rate constant of electron attachment increases with temperature and with pressure. The system is analyzed by kinetic modeling in terms of statistical theory in order to understand its properties and to extrapolate to conditions beyond those accessible in the experiment. PMID- 21823700 TI - Experimental and theoretical studies of neutral MgmCnHx and BemCnHx clusters. AB - Neutral Mg(m)C(n)H(x) and Be(m)C(n)H(x) clusters are investigated both experimentally and theoretically for the first time. Single photon ionization at 193 nm is used to detect neutral cluster distributions through time of flight mass spectrometry. Mg(m)C(n)H(x) and Be(m)C(n)H(x) clusters are generated through laser ablation of Mg or Be foil into CH(4)/He expansion gas. A number of members of each cluster series are identified through isotopic substitution experiments employing (13)CH(4) and CD(4) instead of CH(4) in the expansion gas. An oscillation of the vertical ionization energies (VIEs) of Mg(m)C(n)H(x) clusters is observed in the experiments. The VIEs of Mg(m)C(n)H(x) clusters are observed to vary as a function of the number of H atoms in the clusters. Density functional theory (DFT) and ab initio (MP2) calculations are carried out to explore the structures and ionization energies of Mg(m)C(n)H(x) clusters. Many Be(m)C(n)H(x) clusters are also generated and detected in the experiments. The structures and VIEs of Be(m)C(n)H(x) clusters are also studied by theoretical calculations. Calculational results provide a good and consistent explanation for the experimental observations, and are in general agreement with them for both series of clusters. PMID- 21823701 TI - Ultrafast dynamics of aniline in the 294-234 nm excitation range: the role of the pisigma* state. AB - The ultrafast relaxation of jet-cooled aniline was followed by time-resolved ionization, after excitation in the 294-234 interval. The studied range of energy covers the absorption of the two bright pipi* excitations, S(1) and S(3), and the almost dark S(2) (pisigma*) state. The employed probe wavelengths permit to identify different ultrafast time constants related with the coupling of the involved electronic surfaces. A tau(1) = 165 +/- 30 fs lifetime is attributed to dynamics along the S(2) (pisigma*) repulsive surface. Other relaxation channels as the S(1)->S(0) and S(3)->S(1) internal conversion are also identified and characterized. The work provides a general view of the photophysics of aniline, particularly regarding the role of the pisigma* state. This state appears as minor dissipation process due to the ineffective coupling with the bright S(1) and S(3) states, being the S(1)->S(0) internal conversion the main non-radiative process in the full studied energy range. Additionally, the influence of the off resonance adiabatic excitation of higher energy electronic states, particularly S(3), is also observed and discussed. PMID- 21823702 TI - Electronic spectroscopy of the previously unknown arsenic carbide (AsC) free radical. AB - The previously unknown arsenic carbide (AsC) free radical has been identified in the gas phase through a combination of laser-induced fluorescence (LIF), single vibronic level emission, and stimulated emission pumping (SEP) spectroscopy in a supersonic expansion. The As(12)C and As(13)C isotopologues have been detected as products of an electric discharge in mixtures of arsine (AsH(3)) and carbon dioxide ((12)CO(2) or (13)CO(2)) in high pressure argon. The B (2)Sigma(+)-X (2)Sigma(+) band system was recorded by LIF spectroscopy and emission transitions from the B state down to the ground state and to the low-lying A (2)Pi(i) state were observed. High resolution studies of the B-X 0-0 band by LIF and the B-A 0-0 band by SEP spectroscopy enabled a determination of the molecular structures in the three states. Although CN, CP, and AsC have similar X (2)Sigma(+) and A (2)Pi(i) states, the B (2)Sigma(+) state molecular orbital configuration of CP and AsC differs from that of the CN free radical. PMID- 21823703 TI - Relativistic contributions to single and double core electron ionization energies of noble gases. AB - We have performed relativistic calculations of single and double core 1s hole states of the noble gas atoms in order to explore the relativistic corrections and their additivity to the ionization potentials. Our study unravels the interplay of progression of relaxation, dominating in the single and double ionization potentials of the light elements, versus relativistic one-electron effects and quantum electrodynamic effects, which dominate toward the heavy end. The degree of direct relative additivity of the relativistic corrections for the single electron ionization potentials to the double electron ionization potentials is found to gradually improve toward the heavy elements. The Dirac Coulomb Hamiltonian is found to predict a scaling ratio of ~4 for the relaxation induced relativistic energies between double and single ionization. Z-scaling of the computed quantities were obtained by fitting to power law. The effects of nuclear size and form were also investigated and found to be small. The results indicate that accurate predictions of double core hole ionization potentials can now be made for elements across the full periodic table. PMID- 21823704 TI - Energy transfer of highly vibrationally excited naphthalene: collisions with CHF3, CF4, and Kr. AB - Energy transfer of highly vibrationally excited naphthalene in the triplet state in collisions with CHF(3), CF(4), and Kr was studied using a crossed-beam apparatus along with time-sliced velocity map ion imaging techniques. Highly vibrationally excited naphthalene (2.0 eV vibrational energy) was formed via the rapid intersystem crossing of naphthalene initially excited to the S(2) state by 266 nm photons. The shapes of the collisional energy-transfer probability density functions were measured directly from the scattering results of highly vibrationally excited naphthalene. In comparison to Kr atoms, the energy transfer in collisions between CHF(3) and naphthalene shows more forward scatterings, larger cross section for vibrational to translational (V -> T) energy transfer, smaller cross section for translational to vibrational and rotational (T -> VR) energy transfer, and more energy transferred from vibration to translation, especially in the range -DeltaE(d) = -100 to -800 cm(-1). On the other hand, the difference of energy transfer properties between collisional partners Kr and CF(4) is small. The enhancement of the V -> T energy transfer in collisions with CHF(3) is attributed to the large attractive interaction between naphthalene and CHF(3) (1-3 kcal/mol). PMID- 21823706 TI - Small polaron hopping conduction mechanism in Fe doped LaMnO3. AB - The structural and electrical transport properties of LaMn(1-x)Fe(x)O(3) (0.1 <= x <= 0.6) bulk samples have been investigated. The powder x-ray diffraction patterns at room temperature show that all samples are formed in single phase. The temperature dependent resistivity data have been fitted with the Mott's variable-range hopping (VRH) model for an entire studied range of the temperature (77-300 K) to calculate the hopping distance (R(h)) and the density of states at Fermi level (N(E(F))). It is found that all parameters vary systematically with the increase in Fe concentration. Moreover, the resistivity data were also fitted in the small polaron hopping (SPH) model. The non-adiabatic SPH conduction mechanism is followed by all samples. This type conduction mechanism is far accompanied by subtle electronically induced structural changes involving in Fe-O Fe and Fe-O-Mn bond angles and bond lengths. Thus we suggest that the transport properties can be explained according to the additional localization of charge carriers induced by Fe doping. PMID- 21823705 TI - Delocalized electronic behavior observed in transition metal oxide clusters under strong-field excitation. AB - Heterogeneously composed clusters are exposed to intensity resolved, 100 fs laser pulses to reveal the energy requirements for the production of the high charge states of both metal and nonmetal ions. The ionization and fragmentation of group V transition metal oxide clusters are here examined with laser intensities ranging nearly four orders in magnitude (~3 * 10(11) W/cm(2) to ~2 * 10(15) W/cm(2)) at 624 nm. The ionization potentials of the metal atoms are measured using both multiphoton ionization and tunneling ionization models. We demonstrate that the intensity selective scanning method can be utilized to measure the low ionization potentials of transition metals (~7 eV). The high charge states demonstrate an enhancement in ionization that is three orders of magnitude lower in laser intensity than predicted for the atomic counterparts. Finally, the response from the various metals and the oxygen is compared to elucidate the mechanism of enhanced ionization that is observed. Specifically, the sequence of ion appearances demonstrates delocalized electron behavior over the entire cluster. PMID- 21823707 TI - A refined potential for hydroxylamine clusters and the liquid phase. AB - A detailed study including ab initio calculations and classic Monte-Carlo simulations of hydroxylamine in the gas and liquid phases is presented. A classical interaction potential for hydroxylamine, which includes polarizability, many-body effects, and intramolecular relaxation, was constructed. The results of the simulation were compared to the available experimental data in order to validate the model. We conclude that liquid hydroxylamine has a multitude of hydrogen bonds leading to a large density where the existence of cis conformers and clusters of these conformers is possible. This explains the occurrence of the classical [R. Nast and I. Z. Foppl, Z. Anorg. Allg. Chem. 263, 310 (1950)] scheme for the molecule's decomposition at room temperature and its large exothermicity and instability. PMID- 21823708 TI - DFT+U calculations of crystal lattice, electronic structure, and phase stability under pressure of TiO2 polymorphs. AB - This work investigates crystal lattice, electronic structure, relative stability, and high pressure behavior of TiO(2) polymorphs (anatase, rutile, and columbite) using the density functional theory (DFT) improved by an on-site Coulomb self interaction potential (DFT+U). For the latter the effect of the U parameter value (0 < U < 10 eV) is analyzed within the local density approximation (LDA+U) and the generalized gradient approximation (GGA+U). Results are compared to those of conventional DFT and Heyd-Scuseria-Ernzehorf screened hybrid functional (HSE06). For the investigation of the individual polymorphs (crystal and electronic structures), the GGA+U/LDA+U method and the HSE06 functional are in better agreement with experiments compared to the conventional GGA or LDA. Within the DFT+U the reproduction of the experimental band-gap of rutile/anatase is achieved with a U value of 10/8 eV, whereas a better description of the crystal and electronic structures is obtained for U < 5 eV. Conventional GGA/LDA and HSE06 fail to reproduce phase stability at ambient pressure, rendering the anatase form lower in energy than the rutile phase. The LDA+U excessively stabilizes the columbite form. The GGA+U method corrects these deficiencies; U values between 5 and 8 eV are required to get an energetic sequence consistent with experiments (E(rutile) < E(anatase) < E(columbite)). The computed phase stability under pressure within the GGA+U is also consistent with experimental results. The best agreement between experimental and computed transition pressures is reached for U ~ 5 eV. PMID- 21823709 TI - Density dependence of hydrogen bonding and the translational-orientational structural order in supercritical water: a molecular dynamics study. AB - Molecular dynamics simulation have been performed with a wide range of densities along a near critical isotherm of supercritical water (SCW) in order to study the density dependence of the structure order and hydrogen bonding (HB). It is revealed that the translational structure order is nearly invariant while the orientational tetrahedral structure order is very sensitive to the bulk density under supercritical conditions. Meanwhile, some energetically unfavorable intermediate water dimer structures are found to appear under supercritical conditions due to the reduced energy difference and the enhanced energy fluctuation. As a consequence, a general geometrical criterion or the inclusion of a energy-based criterion instead of currently widely adopted pure r(OH)-based geometric criterion is suggested to be used in the HB statistics under supercritical conditions. It is found that the average HB number per H(2)O molecule (n(HB)) reduces with the decreasing SCW bulk density although a given pair of H(2)O molecules are shown to have a stronger ability to form a hydrogen bond under lower SCW bulk densities. Accordingly, the orientational tetrahedral structure order q decreases with the reducing bulk density under supercritical conditions. However, when the fluid is dilute with rho <= 0.19rho(c) (rho(c) = 0.322 g/cm(3)), the energy fluctuation increases sharply and the short-range order is destroyed, signifying the supercritical fluid (SCF)-gas state transition. Accordingly, the orientational tetrahedral structure order q gets reversal around rho = 0.19rho(c) and approaches zero under very dilute conditions. The sensitivity of the orientational order to the density implies the microscopic origin of the significant dependence of SCF's physicochemical properties on the pressure. PMID- 21823710 TI - Ion-water clusters, bulk medium effects, and ion hydration. AB - Thermochemistry of gas-phase ion-water clusters together with estimates of the hydration free energy of the clusters and the water ligands are used to calculate the hydration free energy of the ion. Often the hydration calculations use a continuum model of the solvent. The primitive quasichemical approximation to the quasichemical theory provides a transparent framework to anchor such efforts. Here we evaluate the approximations inherent in the primitive quasichemical approach and elucidate the different roles of the bulk medium. We find that the bulk medium can stabilize configurations of the cluster that are usually not observed in the gas phase, while also simultaneously lowering the excess chemical potential of the ion. This effect is more pronounced for soft ions. Since the coordination number that minimizes the excess chemical potential of the ion is identified as the optimal or most probable coordination number, for such soft ions the optimum cluster size and the hydration thermodynamics obtained with and without account of the bulk medium on the ion-water clustering reaction can be different. The ideas presented in this work are expected to be relevant to experimental studies that translate thermochemistry of ion-water clusters to the thermodynamics of the hydrated ion and to evolving theoretical approaches that combine high-level calculations on clusters with coarse-grained models of the medium. PMID- 21823711 TI - Experimental and theoretical analysis of the rotational Raman spectrum of hydrogen molecules in clathrate hydrates. AB - The Raman spectra of H(2) and HD molecules in simple hydrogen and binary hydrogen tetrahydrofuran clathrate hydrates have been measured at temperatures as low as 20 K. The rotational bands of trapped molecules in simple and binary hydrates have been analyzed, and the contributions originating from hydrogen molecules in the large cages have been separated from those in the small cages. A theoretical model, consisting in rigid cages enclosing interacting hydrogen molecules, has been exploited to calculate, on the basis of quantum mechanics, the Raman intensity of the rotational transitions for up to two interacting molecules in one cage. A comparison with experiment leads to a clear interpretation of sidebands appearing in the Raman rotational lines. The quantitative agreement between theory and experiment obtained in some cases clarifies the importance of the choice of the interaction potential, and of the proton disorder in the clathrate crystal. PMID- 21823712 TI - Isotropic reorientations of fullerene C70 triplet molecules in solid glassy matrices revealed by light-induced electron paramagnetic resonance. AB - Continuous-wave X-band electron paramagnetic resonance (EPR) of fullerene C(70) molecules excited to a triplet state by continuous light illumination was studied in molecular glasses of o-terphenyl and cis/trans-decaline and in the glassy polymers polymethylmethacrylate (PMMA) and polystyrene (PS). Above ~100 K, a distinct narrowing of EPR lineshape of the triplet was observed, which was very similar for all systems studied. EPR lineshape was simulated reasonably well within a framework of a simple model of random jumps, which implies that the C(70) molecule performs isotropic orientational motion by sudden jumps of arbitrary angles. In simulations, a single correlation time tau(c) was used, varying in the range of 10(-7)-10(-8) s. Near and below 100 K electron spin echo (ESE) signals were also obtained which were found to decay exponentially. Correlation times tau(c) obtained from simulation of the EPR spectra in the slow motion limit (tau(c) close to 10(-7) s) turned out to be in good agreement with the phase memory times T(M) of the ESE decay, which additionally supports the employed simple model. The observed motional effects provide evidence that the nanostructure of the solid glassy media of different origins is soft enough to allow a large asymmetric C(70) molecule to reorient rapidly. Except for the EPR spectra of the triplet, in the center of the spectra, a small admixture of a narrow line was also observed; its possible nature is briefly discussed. PMID- 21823713 TI - Hierarchical structure and dynamics of an ionic liquid 1-octyl-3 methylimidazolium chloride. AB - We have performed the heat capacity, neutron diffraction, and neutron quasielastic scattering measurements of an ionic liquid 1-octyl-3 methylimidazolium chloride (C8mimCl). The heat capacity data revealed that C8mimCl exhibits a glass transition with a large heat capacity jump at T(g) = 214 K, which is lower than T(g) of C4mimCl with a shorter alkyl-chain. In the neutron diffraction measurement for a deuterated analogue, d-C8mimCl, the peaks associated with the inter-domain, inter-ionic, and inter-alkyl-chain correlations appeared at (3, 11, and 14) nm(-1), respectively. The temperature dependence of these peaks indicates that the packing of the alkyl-chains becomes more compact and the domains become more vivid and larger as decreasing temperature. The quasielastic neutron scattering measurements using neutron spin echo and time-of flight type instruments demonstrated that C8mimCl has faster relaxations probably owing to the alkyl-group and a slower relaxation owing to the ions. The latter relaxation, which is related to the glass transition, is of non-exponential as in the alpha relaxation of glass-forming molecular liquids. The relaxation of domains could not be observed in the present experiment but should have relaxation times longer than 100 ns. This is the first report to clarify temperature dependence of the hierarchical structure and relaxations simultaneously for a typical ionic liquid. PMID- 21823714 TI - Ultrafast 2D IR anisotropy of water reveals reorientation during hydrogen-bond switching. AB - Rearrangements of the hydrogen bond network of liquid water are believed to involve rapid and concerted hydrogen bond switching events, during which a hydrogen bond donor molecule undergoes large angle molecular reorientation as it exchanges hydrogen bonding partners. To test this picture of hydrogen bond dynamics, we have performed ultrafast 2D IR spectral anisotropy measurements on the OH stretching vibration of HOD in D(2)O to directly track the reorientation of water molecules as they change hydrogen bonding environments. Interpretation of the experimental data is assisted by modeling drawn from molecular dynamics simulations, and we quantify the degree of molecular rotation on changing local hydrogen bonding environment using restricted rotation models. From the inertial 2D anisotropy decay, we find that water molecules initiating from a strained configuration and relaxing to a stable configuration are characterized by a distribution of angles, with an average reorientation half-angle of 10 degrees , implying an average reorientation for a full switch of >=20 degrees . These results provide evidence that water hydrogen bond network connectivity switches through concerted motions involving large angle molecular reorientation. PMID- 21823715 TI - Optimization of linear and branched alkane interactions with water to simulate hydrophobic hydration. AB - Previous studies of simple gas hydration have demonstrated that the accuracy of molecular simulations at capturing the thermodynamic signatures of hydrophobic hydration is linked both to the fidelity of the water model at replicating the experimental liquid density at ambient pressure and an accounting of polarization interactions between the solute and water. We extend those studies to examine alkane hydration using the transferable potentials for phase equilibria united atom model for linear and branched alkanes, developed to reproduce alkane phase behavior, and the TIP4P/2005 model for water, which provides one of the best descriptions of liquid water for the available fixed-point charge models. Alkane site/water oxygen Lennard-Jones cross interactions were optimized to reproduce the experimental alkane hydration free energies over a range of temperatures. The optimized model reproduces the hydration free energies of the fitted alkanes with a root mean square difference between simulation and experiment of 0.06 kcal/mol over a wide temperature range, compared to 0.44 kcal/mol for the parent model. The optimized model accurately reproduces the temperature dependence of hydrophobic hydration, as characterized by the hydration enthalpies, entropies, and heat capacities, as well as the pressure response, as characterized by partial molar volumes. PMID- 21823716 TI - Structural behaviour of alkaline sulfides under compression: high-pressure experimental study on Cs2S. AB - The high-pressure behaviour of cesium sulphide Cs(2)S has been studied up to 19 GPa at room temperature using angle-dispersive x-ray powder diffraction in a diamond-anvil cell. X-ray results show that the initial anticotunnite-type structure (S.G. Pnma) seems to undertake a continuous transformation to a distorted Ni(2)In-type structure (also with S.G. Pnma), starting below 1 GPa and being almost completed at 5 GPa. The profile of the x-ray diffraction patterns did not change noticeably from this pressure to 17 GPa. The observed structural changes in Cs(2)S are discussed in relation to the high-pressure behaviour of the rest of alkaline sulfides and their systematic trends are pointed out. Finally, we discuss the analogies between the structures of alkaline-metal chalcogenides and those of the cationic arrays of their corresponding oxides (sulfates, selenates, and tellurates) comparing the insertion of oxygen and the application of pressure. PMID- 21823717 TI - Cavitation and crystallization in a metastable Lennard-Jones liquid at negative pressures and low temperatures. AB - Molecular dynamics simulations have been used to investigate the kinetics of spontaneous cavitation and crystallization in a Lennard-Jones liquid at negative pressures in the temperature range where these processes compete with each other. The nucleation rate has been calculated in NVE and NpT ensembles by the method of mean lifetime and the transition interface sampling method with parallel path swapping. The data obtained have been used to determine in the framework of classical nucleation theory the value of the ratio of the solid-liquid and the liquid-void interfacial free energy for critical crystals and cavities and the values of their volumes at points where the cavitation rate of the liquid is equal to the rate of its crystallization. PMID- 21823718 TI - Fourier transform infrared matrix and density functional theory study of the vibrational spectrum of the linear MgC3(-) anion. AB - The linear MgC(3)(-) anion has been identified in the products from the dual Nd:YAG laser ablation of carbon and magnesium rods trapped in solid Ar at ~12 K. Measurements of (13)C isotopic shifts confirm the identification of the nu(1)(sigma) vibrational fundamental at 1797.5 cm(-1). A second fundamental nu(2)(sigma) has been tentatively identified at 1190.1 cm(-1). The results are in good agreement with the predictions of density functional theory calculations using the B3LYP functional with the 6-311+G(d) basis set. This is the first optical detection of the linear isomer of MgC(3)(-). PMID- 21823719 TI - How close to two dimensions does a Lennard-Jones system need to be to produce a hexatic phase? AB - We report on a computer simulation study of a Lennard-Jones liquid confined in a narrow slit pore with tunable attractive walls. In order to investigate how freezing in this system occurs, we perform an analysis using different order parameters. Although some of the parameters indicate that the system goes through a hexatic phase, other parameters do not. This shows that to be certain whether a system of a finite particle number has a hexatic phase, one needs to study not only a large system, but also several order parameters to check all necessary properties. We find that the Binder cumulant is the most reliable one to prove the existence of a hexatic phase. We observe an intermediate hexatic phase only in a monolayer of particles confined such that the fluctuations in the positions perpendicular to the walls are less than 0.15 particle diameters, i.e., if the system is practically perfectly 2D. PMID- 21823720 TI - Entropic effects in the electric double layer of model colloids with size asymmetric monovalent ions. AB - The structure of the electric double layer of charged nanoparticles and colloids in monovalent salts is crucial to determine their thermodynamics, solubility, and polyion adsorption. In this work, we explore the double layer structure and the possibility of charge reversal in relation to the size of both counterions and coions. We examine systems with various size-ratios between counterions and coions (ion size asymmetries) as well as different total ion volume fractions. Using Monte Carlo simulations and integral equations of a primitive-model electric double layer, we determine the highest charge neutralization and electrostatic screening near the electrified surface. Specifically, for two binary monovalent electrolytes with the same counterion properties but differing only in the coion's size surrounding a charged nanoparticle, the one with largest coion size is found to have the largest charge neutralization and screening. That is, in size-asymmetric double layers with a given counterion's size the excluded volume of the coions dictates the adsorption of the ionic charge close to the colloidal surface for monovalent salts. Furthermore, we demonstrate that charge reversal can occur at low surface charge densities, given a large enough total ion concentration, for systems of monovalent salts in a wide range of ion size asymmetries. In addition, we find a non-monotonic behavior for the corresponding maximum charge reversal, as a function of the colloidal bare charge. We also find that the reversal effect disappears for binary salts with large-size counterions and small-size coions at high surface charge densities. Lastly, we observe a good agreement between results from both Monte Carlo simulations and the integral equation theory across different colloidal charge densities and 1:1-electrolytes with different ion sizes. PMID- 21823721 TI - Dewetting growth of crystalline water ice on a hydrogen saturated Rh(111) surface at 135 K. AB - We investigated the water (D(2)O) adsorption at 135 K on a hydrogen pre-adsorbed Rh(111) surface using temperature programmed desorption and infrared reflection absorption spectroscopy (IRAS) in ultrahigh vacuum. With increasing the hydrogen coverage, the desorption temperature of water decreases. At the saturation coverage of hydrogen, dewetting growth of water ice was observed: large three dimensional ice grains are formed. The activation energy of water desorption from the hydrogen-saturated Rh(111) surface is estimated to be 51 kJ/mol. The initial sticking probability of water decreases from 0.46 on the clean surface to 0.35 on the hydrogen-saturated surface. In IRAS measurements, D-down species were not observed on the hydrogen saturated surface. The present experimental results clearly show that a hydrophilic Rh(111) clean surface changes into a hydrophobic surface as a result of hydrogen adsorption. PMID- 21823722 TI - Unusual mechanism of capillary condensation in pores modified with chains forming pillars. AB - Density functional approach is applied to study the phase behavior of Lennard Jones(12,6) fluid in pillared slit-like pores. Our focus is in the evaluation of phase transitions in fluid adsorbed in the pore of a fixed width. If the length of pillars is sufficiently large, we observe additional phase transitions of the first and second order due to the symmetry breaking of the distribution of chain segments and fluid species with respect to the slit-like pore center. Re-entrant symmetry changes and additional critical, critical end points and tricritical points then are observed. The scenario of phase changes is sensitive to the energy of fluid-solid interaction, the amount, and the length of the pillars. Quantitative trends and qualitative changes of the phase diagrams topology are examined depending on the values of these parameters. PMID- 21823723 TI - Molecular dynamics study of nanoparticle stability at liquid interfaces: effect of nanoparticle-solvent interaction and capillary waves. AB - While the interaction of colloidal particles (sizes in excess of 100 nm) with liquid interfaces may be understood in terms of continuum models, which are grounded in macroscopic properties such as surface and line tensions, the behaviour of nanoparticles at liquid interfaces may be more complex. Recent simulations [D. L. Cheung and S. A. F. Bon, Phys. Rev. Lett. 102, 066103 (2009)] of nanoparticles at an idealised liquid-liquid interface showed that the nanoparticle-interface interaction range was larger than expected due, in part, to the action of thermal capillary waves. In this paper, molecular dynamics simulations of a Lennard-Jones nanoparticle in a binary Lennard-Jones mixture are used to confirm that these previous results hold for more realistic models. Furthermore by including attractive interactions between the nanoparticle and the solvent, it is found that the detachment energy decreases as the nanoparticle solvent attraction increases. Comparison between the simulation results and recent theoretical predictions [H. Lehle and M. Oettel, J. Phys. Condens. Matter 20, 404224 (2008)] shows that for small particles the incorporation of capillary waves into the predicted effective nanoparticle-interface interaction improves agreement between simulation and theory. PMID- 21823724 TI - Atomic imaging of nucleation of trimethylaluminum on clean and H2O functionalized Ge(100) surfaces. AB - The direct reaction of trimethylaluminum (TMA) on a Ge(100) surface and the effects of monolayer H(2)O pre-dosing were investigated using ultrahigh vacuum techniques, such as scanning tunneling microscopy (STM), scanning tunneling spectroscopy (STS), and x-ray photoelectron spectroscopy (XPS), and density functional theory (DFT). At room temperature (RT), a saturation TMA dose produced 0.8 monolayers (ML) of semi-ordered species on a Ge(100) surface due to the dissociative chemisorption of TMA. STS confirmed the chemisorption of TMA passivated the bandgap states due to dangling bonds. By annealing the TMA-dosed Ge surface, the STM observed coverage of TMA sites decreased to 0.4 ML at 250 degrees C, and to 0.15 ML at 450 degrees C. XPS analysis showed that only carbon content was reduced during annealing, while the Al coverage was maintained at 0.15 ML, consistent with the desorption of methyl (-CH(3)) groups from the TMA adsorbates. Conversely, saturation TMA dosing at RT on the monolayer H(2)O pre dosed Ge(100) surface followed by annealing at 200 degrees C formed a layer of Ge-O-Al bonds with an Al coverage a factor of two greater than the TMA only dosed Ge(100), consistent with Ge-OH activation of TMA chemisorption and Ge-H blocking of CH(3) chemisorption. The DFT shows that the reaction of TMA has lower activation energy and is more exothermic on Ge-OH than Ge-H sites. It is proposed that the H(2)O pre-dosing enhances the concentration of adsorbed Al and forms thermally stable Ge-O-Al bonds along the Ge dimer row which could serve as a nearly ideal atomic layer deposition nucleation layer on Ge(100) surface. PMID- 21823726 TI - Slow dynamics of the high density Gaussian core model. AB - We numerically study crystal nucleation and glassy slow dynamics of the one component Gaussian core model (GCM) at high densities. The nucleation rate at a fixed supercooling is found to decrease as the density increases. At very high densities, the nucleation is not observed at all in the time window accessed by long molecular dynamics (MD) simulation. Concomitantly, the system exhibits typical slow dynamics of the supercooled fluids near the glass transition point. We compare the simulation results of the supercooled GCM with the predictions of mode-coupling theory (MCT) and find that the agreement between them is better than any other model glassformers studied numerically in the past. Furthermore, we find that a violation of the Stokes-Einstein relation is weaker and the non Gaussian parameter is smaller than canonical glassformers. Analysis of the probability distribution of the particle displacement clearly reveals that the hopping effect is strongly suppressed in the high density GCM. We conclude from these observations that the GCM is more amenable to the mean-field picture of the glass transition than other models. This is attributed to the long-ranged nature of the interaction potential of the GCM in the high density regime. Finally, the intermediate scattering function at small wavevectors is found to decay much faster than its self part, indicating that dynamics of the large-scale density fluctuations decouples with the shorter-ranged caging motion. PMID- 21823725 TI - High resolution photoemission and x-ray absorption spectroscopy of a lepidocrocite-like TiO2 nanosheet on Pt(110) (1 * 2). AB - The electronic structure of TiO(2) nanosheets on the Pt(110)-(1 * 2) surface has been investigated by using high resolution photoemission spectroscopy and x-ray absorption spectroscopy (XAS). The Ti 2p XAS spectra of the deposited TiO(2) films have been theoretically evaluated and, from the comparison with the experimental data, the assignment to a lepidocrocite-like structure is confirmed. Coexistence of TiO(2) islands with PtO(2) stripes for incomplete nanosheets is confirmed by high resolution photoemission data. The location of the valence and conduction band edges of the nanosheet has been experimentally determined allowing us to describe in details subtle electronic effects due to the interface with the substrate. The locations of the valence band maximum and the leading peak in the O 1s XAS spectrum indicate a band gap similar to anatase but with the Fermi level closer to mid-gap than found for bulk, n-type TiO(2). PMID- 21823727 TI - The molecular kink paradigm for rubber elasticity: numerical simulations of explicit polyisoprene networks at low to moderate tensile strains. AB - Based on recent molecular dynamics and ab initio simulations of small isoprene molecules, we propose a new ansatz for rubber elasticity. We envision a network chain as a series of independent molecular kinks, each comprised of a small number of backbone units, and the strain as being imposed along the contour of the chain. We treat chain extension in three distinct force regimes: (Ia) near zero strain, where we assume that the chain is extended within a well defined tube, with all of the kinks participating simultaneously as entropic elastic springs, (II) when the chain becomes sensibly straight, giving rise to a purely enthalpic stretching force (until bond rupture occurs) and, (Ib) a linear entropic regime, between regimes Ia and II, in which a force limit is imposed by tube deformation. In this intermediate regime, the molecular kinks are assumed to be gradually straightened until the chain becomes a series of straight segments between entanglements. We assume that there exists a tube deformation tension limit that is inversely proportional to the chain path tortuosity. Here we report the results of numerical simulations of explicit three-dimensional, periodic, polyisoprene networks, using these extension-only force models. At low strain, crosslink nodes are moved affinely, up to an arbitrary node force limit. Above this limit, non-affine motion of the nodes is allowed to relax unbalanced chain forces. Our simulation results are in good agreement with tensile stress vs. strain experiments. PMID- 21823728 TI - Density functional theory for rod-coil polymers with different size segments. AB - A polymer density functional theory (PDFT) for rod-coil copolymers with different size segments is proposed, in which the PDFT approach combines a modified fundamental measure theory for the excluded-volume effects, Wertheim's first order thermodynamics perturbation theory for the chain connectivity and the mean field approximation for van der Waals attraction. First, for testing the PDFT derived, we compare the density profiles from present theory to simulation data, and find that the present theory successfully reproduces the simulation data. Therefore, we use the PDFT to further investigate the local density and solvation forces of rod-coils with different size (A(5)D(3)) and the same size (A(5)B(3)) segments. Results indicate that the excluded volume effect from the coil part determines the solvation force profiles of two rod-coil brushes at strong surface energy. In addition, owing to the vacuum effect, the weak attraction around the classical contact of the rod-coil brushes is also observed. In short, the present theory can be easily applied to the other architecture polymers containing different size segments. It is expected that the calculation results in this work could provide useful reference to select the rod-coils as stabilizer for the protection of surfaces or the colloidal stabilization. PMID- 21823729 TI - Effective static and high-frequency viscosities of concentrated suspensions of soft particles. AB - We obtain an analytic expression that allows to determine the static eta and high frequency eta(infinity) viscosities as function of the volume fraction phi of a concentrated suspension of soft spherical particles in a liquid of viscosity eta(0). The particles consist of a hard core of radius a covered by a porous layer of thickness d. Suspensions of hard spheres and homogeneous porous particles are limiting cases of the model. The proposed expression incorporates the results for the intrinsic viscosity obtained on the basis of a cell model [H. Ohshima, Langmuir 26, 6287 (2010)] into a recently obtained relation for the effective viscosity of concentrated colloidal suspensions [C. I. Mendoza and I. Santamaria-Holek, J. Chem. Phys. 130, 044904 (2009); J. Colloid. Interface Sci. 346, 118 (2010)]. In this model, the correlations between the particles due to crowding effects are introduced through an effective volume fraction phi(eff) which is then used as integration variable in a differential effective medium procedure. The final expression is simple, accurate, and allows to collapse all the data in a universal master curve that is independent of the parameters characterizing the system. The only difference between the static and high frequency cases is that in the later case phi(eff) also incorporates hydrodynamic interactions arising from the so-called relaxation term. We have tested the accuracy of our model comparing with experimental results for spherical polymeric brushes and simulations for the high-frequency viscosity of homogeneous porous particles. In all cases the agreement with the data is extremely good. PMID- 21823730 TI - Colloidal rotation near the colloidal glass transition. AB - We compare, using single-particle optical imaging, trajectories of rotation and translation for micron-sized spheres in index-matched colloidal suspensions near their glass transition. Rotational trajectories, while they show intermittent caged behavior associated with supercooled and glassy behavior, explore a sufficiently wider phase space such that in the averaged mean-square angular displacement there appears no plateau regime, but instead sub-Fickian angular diffusion that follows an apparent power law in time. We infer translation and rotation time constants, the former being the time to diffuse a particle diameter and the latter being the time to rotate a full revolution. Correlation between time constants increases with increasing volume fraction, but unlike the case for molecular glasses, the rotation time constant slows more weakly than the translation time. PMID- 21823731 TI - Vibronic coupling in quantum wires: applications to polydiacetylene. AB - A theory describing vibronic coupling in direct band gap, one-dimensional semiconductors is developed to account for the photophysical properties of isolated, defect-free conjugated polymers. A Holstein-like Hamiltonian represented in a multi-particle basis set is used to evaluate absorption and emission due to Wannier-Mott excitons. The photophysical properties of such quantum wires are shown to strongly resemble those of Frenkel exciton J aggregates. The 1(1)B(u) exciton coherence length and effective mass are readily determined from the ratio of the 0-0 and 0-1 line strengths, I(0 - 0)/I(0 - 1), in the photoluminescence spectrum. I(0 - 0)/I(0 - 1) is shown to follow a T(-1/2) dependence, in an excellent agreement with experiments on the red-phase of polydiacteylene. PMID- 21823732 TI - Energy maps, side chain conformational flexibility, and vibrational features of polar amino acids L-serine and L-threonine in aqueous environment. AB - A comprehensive description of the energetic, conformational, and vibrational features of the two amino acids (AAs) with polar side chains, i.e., serine and threonine, in aqueous environment, is provided. To adequately analyze the side chain conformational flexibility of these amino acids, we resorted to quantum mechanical calculations with the use of density functional theory, which allowed the determination of the energetic features of these AAs through 236 clusters. Each cluster contains a zwitterionic AA surrounded by seven explicit water molecules. The obtained data could evidence the effect of the side chain conformational angle (chi(1) and chi(2)) as well as the location of water molecules on the energy landscapes of both AAs. Four of the lowest energy clusters of each AA, which give rise to distinct side chain conformations, were selected in order to reproduce the FT-IR and Raman spectra recorded in aqueous solutions and to assign the vibrational modes responsible of the main observed bands. PMID- 21823733 TI - An effective continuum approach for modeling non-equilibrium structural evolution of protein nanofiber networks. AB - We quantify the formation and evolution of protein nanofibers using a new phase field modeling framework and compare the results to transmission electron microscopy measurements (TEM) and time-dependent growth measurements given in the literature. The modeling framework employs a set of effective continuum equations combined with underlying nanoscale forces and chemical potential relations governing protein nanofiber formation in solution. Calculations based on the theoretical framework are implemented numerically using a nonlinear finite element phase field modeling approach that couples homogenized protein molecular structure via a vector order parameter with chemical potential relations that describe interactions between the nanofibers and the surrounding solution. Homogenized, anisotropic molecular and chemical flux relations are found to be critical in obtaining nanofiber growth from seed particles or a random monomer bath. In addition, the model predicts both sigmoidal and first-order growth kinetics for protein nanofibers for unseeded and seeded models, respectively. These simulations include quantitative predictions on time scales of typical protein self-assembly behavior which qualitatively match TEM measurements of the RADA16-I protein and growth rate measurements for amyloid nanofibers from the literature. For comparisons with experiments, the numerical model performs multiple nanofiber protein evolution simulations with a characteristic length scale of ~2.4 nm and characteristic time scale of ~9.1 h. These results provide a new modeling tool that couples underlying monomer structure with self-assembling nanofiber behavior that is compatible with various external loadings and chemical environments. PMID- 21823734 TI - Numerical and theoretical study on the mechanism of biopolymer translocation process through a nano-pore. AB - We conducted a numerical study on the translocation of a biopolymer from the cis side to the trans side of a membrane through a synthetic nano-pore driven by an external electric field in the presence of hydrodynamic interactions (HIs). The motion of the polymer is simulated by 3D Langevin dynamics technique using a worm like chain model of N identical beads, while HI between the polymer and fluid are incorporated by the lattice Boltzmann equation. The translocation process is induced by electrophoretic force, which sequentially straightens out the folds of the initial random configuration of the polymer chain on the cis side. Our simulation results on translocation time and velocity are in good quantitative agreement with the corresponding experimental ones when the surface charge on the nano-pore and the HI effect are considered explicitly. We found that the translocation velocity of each bead inside the nano-pore mainly depends upon the length of the straightened portion of the polymer in forced motion near the pore. We confirmed this by a theoretical formula. After performing simulations with different pore lengths, we observed that translocation velocity mainly depends upon the applied potential difference rather than upon the electric field inside the nano-pore. PMID- 21823735 TI - Adapting Poisson-Boltzmann to the self-consistent mean field theory: application to protein side-chain modeling. AB - We present an extension of the self-consistent mean field theory for protein side chain modeling in which solvation effects are included based on the Poisson Boltzmann (PB) theory. In this approach, the protein is represented with multiple copies of its side chains. Each copy is assigned a weight that is refined iteratively based on the mean field energy generated by the rest of the protein, until self-consistency is reached. At each cycle, the variational free energy of the multi-copy system is computed; this free energy includes the internal energy of the protein that accounts for vdW and electrostatics interactions and a solvation free energy term that is computed using the PB equation. The method converges in only a few cycles and takes only minutes of central processing unit time on a commodity personal computer. The predicted conformation of each residue is then set to be its copy with the highest weight after convergence. We have tested this method on a database of hundred highly refined NMR structures to circumvent the problems of crystal packing inherent to x-ray structures. The use of the PB-derived solvation free energy significantly improves prediction accuracy for surface side chains. For example, the prediction accuracies for chi(1) for surface cysteine, serine, and threonine residues improve from 68%, 35%, and 43% to 80%, 53%, and 57%, respectively. A comparison with other side chain prediction algorithms demonstrates that our approach is consistently better in predicting the conformations of exposed side chains. PMID- 21823736 TI - First order melting transitions of highly ordered dipalmitoyl phosphatidylcholine gel phase membranes in molecular dynamics simulations with atomistic detail. AB - Molecular dynamics simulations with atomistic detail of the gel phase and melting transitions of dipalmitoyl phosphatidylcholine bilayers in water reveal the dependency of many thermodynamic and structural parameters on the initial system ordering. We quantitatively compare different methods to create a gel phase system and we observe that a very high ordering of the gel phase starting system is necessary to observe behavior which reproduces experimental data. We performed heating scans with speeds down to 0.5 K/ns and could observe sharp first order phase transitions. Also, we investigated the transition enthalpy as the natural intrinsic parameter of first order phase transitions, and obtained a quantitative match with experimental values. Furthermore, we performed systematic investigations of the statistical distribution and heating rate dependency of the microscopic phase transition temperature. PMID- 21823737 TI - Two-dimensional infrared spectroscopy of azido-nicotinamide adenine dinucleotide in water. AB - Mid-IR active analogs of enzyme cofactors have the potential to be important spectroscopic reporters of enzyme active site dynamics. Azido-nicotinamide adenine dinucleotide (NAD(+)), which has been recently synthesized in our laboratory, is a mid-IR active analog of NAD(+), a ubiquitous redox cofactor in biology. In this study, we measure the frequency-frequency time correlation function for the antisymmetric stretching vibration of the azido group of azido NAD(+) in water. Our results are consistent with previous studies of pseudohalides in water. We conclude that azido-NAD(+) is sensitive to local environmental fluctuations, which, in water, are dominated by hydrogen-bond dynamics of the water molecules around the probe. Our results demonstrate the potential of azido-NAD(+) as a vibrational probe and illustrate the potential of substituted NAD(+)-analogs as reporters of local structural dynamics that could be used for studies of protein dynamics in NAD-dependent enzymes. PMID- 21823738 TI - Robustness of multidimensional Brownian ratchets as directed transport mechanisms. AB - Brownian ratchets have recently been considered as models to describe the ability of certain systems to locate very specific states in multidimensional configuration spaces. This directional process has particularly been proposed as an alternative explanation for the protein folding problem, in which the polypeptide is driven toward the native state by a multidimensional Brownian ratchet. Recognizing the relevance of robustness in biological systems, in this work we analyze such a property of Brownian ratchets by pushing to the limits all the properties considered essential to produce directed transport. Based on the results presented here, we can state that Brownian ratchets are able to deliver current and locate funnel structures under a wide range of conditions. As a result, they represent a simple model that solves the Levinthal's paradox with great robustness and flexibility and without requiring any ad hoc biased transition probability. The behavior of Brownian ratchets shown in this article considerably enhances the plausibility of the model for at least part of the structural mechanism behind protein folding process. PMID- 21823740 TI - A new material mapping procedure for quantitative computed tomography-based, continuum finite element analyses of the vertebra. AB - Inaccuracies in the estimation of material properties and errors in the assignment of these properties into finite element models limit the reliability, accuracy, and precision of quantitative computed tomography (QCT)-based finite element analyses of the vertebra. In this work, a new mesh-independent, material mapping procedure was developed to improve the quality of predictions of vertebral mechanical behavior from QCT-based finite element models. In this procedure, an intermediate step, called the material block model, was introduced to determine the distribution of material properties based on bone mineral density, and these properties were then mapped onto the finite element mesh. A sensitivity study was first conducted on a calibration phantom to understand the influence of the size of the material blocks on the computed bone mineral density. It was observed that varying the material block size produced only marginal changes in the predictions of mineral density. Finite element (FE) analyses were then conducted on a square column-shaped region of the vertebra and also on the entire vertebra in order to study the effect of material block size on the FE-derived outcomes. The predicted values of stiffness for the column and the vertebra decreased with decreasing block size. When these results were compared to those of a mesh convergence analysis, it was found that the influence of element size on vertebral stiffness was less than that of the material block size. This mapping procedure allows the material properties in a finite element study to be determined based on the block size required for an accurate representation of the material field, while the size of the finite elements can be selected independently and based on the required numerical accuracy of the finite element solution. The mesh-independent, material mapping procedure developed in this study could be particularly helpful in improving the accuracy of finite element analyses of vertebroplasty and spine metastases, as these analyses typically require mesh refinement at the interfaces between distinct materials. Moreover, the mapping procedure is not specific to the vertebra and could thus be applied to many other anatomic sites. PMID- 21823741 TI - Remodeling of the collagen fiber architecture due to compaction in small vessels under tissue engineered conditions. AB - Mechanical loading protocols in tissue engineering (TE) aim to improve the deposition of a properly organized collagen fiber network. In addition to collagen remodeling, these conditioning protocols can result in tissue compaction. Tissue compaction is beneficial to tissue collagen alignment, yet it may lead to a loss of functionality of the TE construct due to changes in geometry after culture. Here, a mathematical model is presented to relate the changes in collagen architecture to the local compaction within a TE small blood vessel, assuming that under static conditions, compaction is the main factor responsible for collagen fiber organization. An existing structurally based model is extended to incorporate volumetric tissue compaction. Subsequently, the model is applied to describe the collagen architecture of TE constructs under either strain based or stress based stimulus functions. Our computations indicate that stress based simulations result in a helical collagen fiber distribution along the vessel wall. The helix pitch angle increases from a circumferential direction in the inner wall, over about 45 deg in the middle vessel layer, to a longitudinal direction in the outer wall. These results are consistent with experimental data from TE small diameter blood vessels. In addition, our results suggest a stress dependent remodeling of the collagen, suggesting that cell traction is responsible for collagen orientation. These findings may be of value to design improved mechanical conditioning protocols to optimize the collagen architecture in engineered tissues. PMID- 21823742 TI - FSI analysis of a human trachea before and after prosthesis implantation. AB - In this work we analyzed the response of a stenotic trachea after a stent implantation. An endotracheal stent is the common treatment for tracheal diseases such as stenosis, chronic cough, or dispnoea episodes. Medical treatment and surgical techniques are still challenging due to the difficulties in overcoming potential complications after prosthesis implantation. A finite element model of a diseased and stented trachea was developed starting from a patient specific computerized tomography (CT) scan. The tracheal wall was modeled as a fiber reinforced hyperelastic material in which we modeled the anisotropy due to the orientation of the collagen fibers. Deformations of the tracheal cartilage rings and of the muscular membrane, as well as the maximum principal stresses, are analyzed using a fluid solid interaction (FSI) approach. For this reason, as boundary conditions, impedance-based pressure waveforms were computed modeling the nonreconstructed vessels as a binary fractal network. The results showed that the presence of the stent prevents tracheal muscle deflections and indicated a local recirculatory flow on the stent top surface which may play a role in the process of mucous accumulation. The present work gives new insight into clinical procedures, predicting their mechanical consequences. This tool could be used in the future as preoperative planning software to help the thoracic surgeons in deciding the optimal prosthesis type as well as its size and positioning. PMID- 21823743 TI - Contact pressure in the facet joint during sagittal bending of the cadaveric cervical spine. AB - The facet joint contributes to the normal biomechanical function of the spine by transmitting loads and limiting motions via articular contact. However, little is known about the contact pressure response for this joint. Such information can provide a quantitative measure of the facet joint's local environment. The objective of this study was to measure facet pressure during physiologic bending in the cervical spine, using a joint capsule-sparing technique. Flexion and extension bending moments were applied to six human cadaveric cervical spines. Global motions (C2-T1) were defined using infra-red cameras to track markers on each vertebra. Contact pressure in the C5-C6 facet was also measured using a tip mounted pressure transducer inserted into the joint space through a hole in the postero-inferior region of the C5 lateral mass. Facet contact pressure increased by 67.6 +/- 26.9 kPa under a 2.4 Nm extension moment and decreased by 10.3 +/- 9.7 kPa under a 2.7 Nm flexion moment. The mean rotation of the overall cervical specimen motion segments was 9.6 +/- 0.8 degrees and was 1.6 +/- 0.7 degrees for the C5-C6 joint, respectively, for extension. The change in pressure during extension was linearly related to both the change in moment (51.4 +/- 42.6 kPa/Nm) and the change in C5-C6 angle (18.0 +/- 108.9 kPa/deg). Contact pressure in the inferior region of the cervical facet joint increases during extension as the articular surfaces come in contact, and decreases in flexion as the joint opens, similar to reports in the lumbar spine despite the difference in facet orientation in those spinal regions. Joint contact pressure is linearly related to both sagittal moment and spinal rotation. Cartilage degeneration and the presence of meniscoids may account for the variation in the pressure profiles measured during physiologic sagittal bending. This study shows that cervical facet contact pressure can be directly measured with minimal disruption to the joint and is the first to provide local pressure values for the cervical joint in a cadaveric model. PMID- 21823744 TI - Impact of stents and flow diverters on hemodynamics in idealized aneurysm models. AB - Cerebral aneurysms constitute a major medical challenge as treatment options are limited and often associated with high risks. Statistically, up to 3% of patients with a brain aneurysm may suffer from bleeding for each year of life. Eight percent of all strokes are caused by ruptured aneurysms. In order to prevent this rupture, endovascular stenting using so called flow diverters is increasingly being regarded as an alternative to the established coil occlusion method in minimally invasive treatment. Covering the neck of an aneurysm with a flow diverter has the potential to alter the hemodynamics in such a way as to induce thrombosis within the aneurysm sac, stopping its further growth, preventing its rupture and possibly leading to complete resorption. In the present study the influence of different flow diverters is quantified considering idealized patient configurations, with a spherical sidewall aneurysm placed on either a straight or a curved parent vessel. All important hemodynamic parameters (exchange flow rate, velocity, and wall shear stress) are determined in a quantitative and accurate manner using computational fluid dynamics when varying the key geometrical properties of the aneurysm. All simulations are carried out using an incompressible, Newtonian fluid with steady conditions. As a whole, 72 different cases have been considered in this systematic study. In this manner, it becomes possible to compare the efficiency of different stents and flow diverters as a function of wire density and thickness. The results show that the intra aneurysmal flow velocity, wall shear stress, mean velocity, and vortex topology can be considerably modified thanks to insertion of a suitable implant. Intra aneurysmal residence time is found to increase rapidly with decreasing stent porosity. Of the three different implants considered in this study, the one with the highest wire density shows the highest increase of intra-aneurysmal residence time for both the straight and the curved parent vessels. The best hemodynamic modifications are always obtained for a small aneurysm diameter. PMID- 21823745 TI - Influence of experimental protocols on the mechanical properties of the intervertebral disc in unconfined compression. AB - The lack of standardization in experimental protocols for unconfined compression tests of intervertebral discs (IVD) tissues is a major issue in the quantification of their mechanical properties. Our hypothesis is that the experimental protocols influence the mechanical properties of both annulus fibrosus and nucleus pulposus. IVD extracted from bovine tails were tested in unconfined compression stress-relaxation experiments according to six different protocols, where for each protocol, the initial swelling of the samples and the applied preload were different. The Young's modulus was calculated from a viscoelastic model, and the permeability from a linear biphasic poroviscoelastic model. Important differences were observed in the prediction of the mechanical properties of the IVD according to the initial experimental conditions, in agreement with our hypothesis. The protocol including an initial swelling, a 5% strain preload, and a 5% strain ramp is the most relevant protocol to test the annulus fibrosus in unconfined compression, and provides a permeability of 5.0 +/ 4.2e(-14)m(4)/N[middle dot]s and a Young's modulus of 7.6 +/- 4.7 kPa. The protocol with semi confined swelling and a 5% strain ramp is the most relevant protocol for the nucleus pulposus and provides a permeability of 10.7 +/- 3.1 e( 14)m(4)/N[middle dot]s and a Young's modulus of 6.0 +/- 2.5 kPa. PMID- 21823746 TI - Effect of storage duration on the mechanical behavior of mouse carotid artery. AB - Determining arterial mechanical properties is important for understanding the work done by the heart and how it changes with cardiovascular disease. Ex vivo tests are necessary to apply various loads to the artery and obtain data to model and predict the behavior under any load. Most ex vivo tests are performed within 24 h of dissection, so the tissue is still "alive." For large elastic arteries; however, the passive mechanical behavior is attributed mostly to the very stable proteins, elastin, and collagen. If the testing equipment fails, is in use, or is located at another facility, it would be useful to store the vessels and postpone the tests until the equipment is available. The goal of this study is to determine the effects of storage time on the mechanical behavior of the common carotid artery from adult mice. Each artery was tested after storage for 1-28 days in physiologic saline at 4 degrees C. There were no significant effects of storage time on the arterial diameter or force at each pressure, but there were significant effects on the stretch ratio and stress at each pressure. The significant effects on the stretch ratio and stress were due to decreases in the unloaded dimensions with storage time, when measured from cut arterial rings. When the unloaded dimensions were measured instead from histology sections, there were no significant changes with storage time. We conclude that histology sections yield a more consistent measurement of the unloaded dimensions and that there are no significant changes in the mechanical behavior of mouse carotid artery with storage up to 28 days. PMID- 21823747 TI - A wearable system to assess risk for anterior cruciate ligament injury during jump landing: measurements of temporal events, jump height, and sagittal plane kinematics. AB - The incidence of anterior cruciate ligament (ACL) injury remains high, and there is a need for simple, cost effective methods to identify athletes at a higher risk for ACL injury. Wearable measurement systems offer potential methods to assess the risk of ACL injury during jumping tasks. The objective of this study was to assess the capacity of a wearable inertial-based system to evaluate ACL injury risk during jumping tasks. The system accuracy for measuring temporal events (initial contact, toe-off), jump height, and sagittal plane angles (knee, trunk) was assessed by comparing results obtained with the wearable system to simultaneous measurements obtained with a marker-based optoelectronic reference system. Thirty-eight healthy participants (20 male and 18 female) performed drop jumps with bilateral and unilateral support landing. The mean differences between the temporal events obtained with both systems were below 5 ms, and the precisions were below 24 ms. The mean jump heights measured with both systems differed by less than 1 mm, and the associations (Pearson correlation coefficients) were above 0.9. For the discrete angle parameters, there was an average association of 0.91 and precision of 3.5 degrees for the knee flexion angle and an association of 0.77 and precision of 5.5 degrees for the trunk lean. The results based on the receiver-operating characteristic (ROC) also demonstrated that the proposed wearable system could identify movements at higher risk for ACL injury. The area under the ROC plots was between 0.89 and 0.99 for the knee flexion angle and between 0.83 and 0.95 for the trunk lean. The wearable system demonstrated good concurrent validity with marker-based measurements and good discriminative performance in terms of the known risk factors for ACL injury. This study suggests that a wearable system could be a simple cost effective tool for conducting risk screening or for providing focused feedback. PMID- 21823748 TI - Dynamic, regional mechanical properties of the porcine brain: indentation in the coronal plane. AB - Stress relaxation tests using a custom designed microindentation device were performed on ten anatomic regions of fresh porcine brain (postmortem time <3 h). Using linear viscoelastic theory, a Prony series representation was used to describe the shear relaxation modulus for each anatomic region tested. Prony series parameters fit to load data from indentations performed to ~10% strain differed significantly by anatomic region. The gray and white matter of the cerebellum along with corpus callosum and brainstem were the softest regions measured. The cortex and hippocampal CA1/CA3 were found to be the stiffest. To examine the large strain behavior of the tissue, multistep indentations were performed in the corona radiata to strains of 10%, 20%, and 30%. Reduced relaxation functions were not significantly different for each step, suggesting that quasi-linear viscoelastic theory may be appropriate for representing the nonlinear behavior of this anatomic region of porcine brain tissue. These data, for the first time, describe the dynamic and short time scale behavior of multiple anatomic regions of the porcine brain which will be useful for understanding porcine brain injury biomechanics at a finer spatial resolution than previously possible. PMID- 21823750 TI - Accurate prediction of wall shear stress in a stented artery: newtonian versus non-newtonian models. AB - A significant amount of evidence linking wall shear stress to neointimal hyperplasia has been reported in the literature. As a result, numerical and experimental models have been created to study the influence of stent design on wall shear stress. Traditionally, blood has been assumed to behave as a Newtonian fluid, but recently that assumption has been challenged. The use of a linear model; however, can reduce computational cost, and allow the use of Newtonian fluids (e.g., glycerine and water) instead of a blood analog fluid in an experimental setup. Therefore, it is of interest whether a linear model can be used to accurately predict the wall shear stress caused by a non-Newtonian fluid such as blood within a stented arterial segment. The present work compares the resulting wall shear stress obtained using two linear and one nonlinear model under the same flow waveform. All numerical models are fully three-dimensional, transient, and incorporate a realistic stent geometry. It is shown that traditional linear models (based on blood's lowest viscosity limit, 3.5 Pa s) underestimate the wall shear stress within a stented arterial segment, which can lead to an overestimation of the risk of restenosis. The second linear model, which uses a characteristic viscosity (based on an average strain rate, 4.7 Pa s), results in higher wall shear stress levels, but which are still substantially below those of the nonlinear model. It is therefore shown that nonlinear models result in more accurate predictions of wall shear stress within a stented arterial segment. PMID- 21823751 TI - A continuous method to compute model parameters for soft biological materials. AB - Developing appropriate mathematical models for biological soft tissues such as ligaments, tendons, and menisci is challenging. Stress-strain behavior of these tissues is known to be continuous and characterized by an exponential toe region followed by a linear elastic region. The conventional curve-fitting technique applies a linear curve to the elastic region followed by a separate exponential curve to the toe region. However, this technique does not enforce continuity at the transition between the two regions leading to inaccuracies in the material model. In this work, a Continuous Method is developed to fit both the exponential and linear regions simultaneously, which ensures continuity between regions. Using both methods, three cases were evaluated: idealized data generated mathematically, noisy idealized data produced by adding random noise to the idealized data, and measured data obtained experimentally. In all three cases, the Continuous Method performed superiorly to the conventional technique, producing smaller errors between the model and data and also eliminating discontinuities at the transition between regions. Improved material models may lead to better predictions of nonlinear biological tissues' behavior resulting in improved the accuracy for a large array of models and computational analyses used to predict clinical outcomes. PMID- 21823752 TI - A preliminary biomechanical assessment of a polymer composite hip implant using an infrared thermography technique validated by strain gage measurements. AB - With the resurgence of composite materials in orthopaedic applications, a rigorous assessment of stress is needed to predict any failure of bone-implant systems. For current biomechanics research, strain gage measurements are employed to experimentally validate finite element models, which then characterize stress in the bone and implant. Our preliminary study experimentally validates a relatively new nondestructive testing technique for orthopaedic implants. Lock-in infrared (IR) thermography validated with strain gage measurements was used to investigate the stress and strain patterns in a novel composite hip implant made of carbon fiber reinforced polyamide 12 (CF/PA12). The hip implant was instrumented with strain gages and mechanically tested using average axial cyclic forces of 840 N, 1500 N, and 2100 N with the implant at an adduction angle of 15 deg to simulate the single-legged stance phase of walking gait. Three-dimensional surface stress maps were also obtained using an IR thermography camera. Results showed almost perfect agreement of IR thermography versus strain gage data with a Pearson correlation of R(2) = 0.96 and a slope = 1.01 for the line of best fit. IR thermography detected hip implant peak stresses on the inferior-medial side just distal to the neck region of 31.14 MPa (at 840 N), 72.16 MPa (at 1500 N), and 119.86 MPa (at 2100 N). There was strong correlation between IR thermography measured stresses and force application level at key locations on the implant along the medial (R(2) = 0.99) and lateral (R(2) = 0.83 to 0.99) surface, as well as at the peak stress point (R(2) = 0.81 to 0.97). This is the first study to experimentally validate and demonstrate the use of lock-in IR thermography to obtain three-dimensional stress fields of an orthopaedic device manufactured from a composite material. PMID- 21823754 TI - Validation and invalidation of systems biology models using robustness analysis. AB - Robustness, the ability of a system to function correctly in the presence of both internal and external uncertainty, has emerged as a key organising principle in many biological systems. Biological robustness has thus become a major focus of research in Systems Biology, particularly on the engineering-biology interface, since the concept of robustness was first rigorously defined in the context of engineering control systems. This review focuses on one particularly important aspect of robustness in Systems Biology, that is, the use of robustness analysis methods for the validation or invalidation of models of biological systems. With the explosive growth in quantitative modelling brought about by Systems Biology, the problem of validating, invalidating and discriminating between competing models of a biological system has become an increasingly important one. In this review, the authors provide a comprehensive overview of the tools and methods that are available for this task, and illustrate the wide range of biological systems to which this approach has been successfully applied. PMID- 21823753 TI - Adaptation of a planar microbiaxial optomechanical device for the tubular biaxial microstructural and macroscopic characterization of small vascular tissues. AB - Murine models of disease are a powerful tool for researchers to gain insight into disease formation, progression, and therapies. The biomechanical indicators of diseased tissue provide a unique insight into some of these murine models, since the biomechanical properties in scenarios such as aneurysm and Marfan syndrome can dictate tissue failure and mortality. Understanding the properties of the tissue on the macroscopic scale has been shown to be important, as one can then understand the tissue's ability to withstand the high stresses seen in the cardiac pulsatile cycle. Alterations in the biomechanical response can foreshadow prospective mechanical failure of the tissue. These alterations are often seen on the microstructural level, and obtaining detailed information on such changes can offer a better understanding of the phenomena seen on the macroscopic level. Unfortunately, mouse models present problems due to the size and delicate features in the mechanical testing of such tissues. In addition, some smaller arteries in large-animal studies (e.g., coronary and cerebral arteries) can present the same issues, and are sometimes unsuitable for planar biaxial testing. The purpose of this paper is to present a robust method for the investigation of the mechanical properties of small arteries and the classification of the microstructural orientation and degree of fiber alignment. This occurs through the cost-efficient modification of a planar biaxial tester that works in conjunction with a two-photon nonlinear microscope. This system provides a means to further investigate how microstructure and mechanical properties are modified in diseased transgenic animals where the tissue is in small tube form. Several other hard-to-test tubular specimens such as cerebral aneurysm arteries and atherosclerotic coronary arteries can also be tested using the described modular device. PMID- 21823755 TI - Flux balance analysis for ethylene formation in genetically engineered Saccharomyces cerevisiae. AB - Biosynthesis of ethylene (ethene) is mainly performed by plants and some bacteria and fungi, via two distinct metabolic routes. Plants use two steps, starting with S-adenosylmethionine, while the ethylene-forming microbes perform an oxygen dependent reaction using 2-oxoglutarate and arginine. Introduction of these systems into Saccharomyces cerevisiae was studied in silico. The reactions were added to a metabolic network of yeast and flux over the two networks was optimised for maximal ethylene formation. The maximal ethylene yields obtained for the two systems were similar in the range of 7-8 mol ethylene/10 mol glucose. The microbial metabolic network was used for testing different strategies to increase the ethylene formation. It was suggested that supplementation of exogenous proline, using a solely NAD-coupled glutamate dehydrogenase, and using glutamate as the nitrogen source, could increase the ethylene formation. Comparison of these in silico results with published experimental data for yeast expressing the microbial system confirmed an increased ethylene formation when changing nitrogen source from ammonium to glutamate. The theoretical analysis methods indicated a much higher maximal yield per glucose for ethylene than was experimentally observed. However, such high ethylene yields could only be obtained with a concomitant very high respiration (per glucose). Accordingly, when ethylene production was optimised under the additional constraint of restricted respiratory capacity (i.e. limited to experimentally measured values) the theoretical maximal ethylene yield was much lower at 0.2/10 mol glucose, and closer to the experimentally observed values. PMID- 21823749 TI - Spinal facet joint biomechanics and mechanotransduction in normal, injury and degenerative conditions. AB - The facet joint is a crucial anatomic region of the spine owing to its biomechanical role in facilitating articulation of the vertebrae of the spinal column. It is a diarthrodial joint with opposing articular cartilage surfaces that provide a low friction environment and a ligamentous capsule that encloses the joint space. Together with the disc, the bilateral facet joints transfer loads and guide and constrain motions in the spine due to their geometry and mechanical function. Although a great deal of research has focused on defining the biomechanics of the spine and the form and function of the disc, the facet joint has only recently become the focus of experimental, computational and clinical studies. This mechanical behavior ensures the normal health and function of the spine during physiologic loading but can also lead to its dysfunction when the tissues of the facet joint are altered either by injury, degeneration or as a result of surgical modification of the spine. The anatomical, biomechanical and physiological characteristics of the facet joints in the cervical and lumbar spines have become the focus of increased attention recently with the advent of surgical procedures of the spine, such as disc repair and replacement, which may impact facet responses. Accordingly, this review summarizes the relevant anatomy and biomechanics of the facet joint and the individual tissues that comprise it. In order to better understand the physiological implications of tissue loading in all conditions, a review of mechanotransduction pathways in the cartilage, ligament and bone is also presented ranging from the tissue-level scale to cellular modifications. With this context, experimental studies are summarized as they relate to the most common modifications that alter the biomechanics and health of the spine-injury and degeneration. In addition, many computational and finite element models have been developed that enable more-detailed and specific investigations of the facet joint and its tissues than are provided by experimental approaches and also that expand their utility for the field of biomechanics. These are also reviewed to provide a more complete summary of the current knowledge of facet joint mechanics. Overall, the goal of this review is to present a comprehensive review of the breadth and depth of knowledge regarding the mechanical and adaptive responses of the facet joint and its tissues across a variety of relevant size scales. PMID- 21823756 TI - Biomolecular implementation of linear I/O systems. AB - Linear I/O systems are a fundamental tool in systems theory, and have been used to design complex circuits and control systems in a variety of settings. Here we present a principled design method for implementing arbitrary linear I/O systems with biochemical reactions. This method relies on two levels of abstraction: first, an implementation of linear I/O systems using idealised chemical reactions, and second, an approximate implementation of the ideal chemical reactions with enzyme-free, entropy-driven DNA reactions. The ideal linear dynamics are shown to be closely approximated by the chemical reactions model and the DNA implementation. We illustrate the approach with integration, gain and summation as well as with the ubiquitous robust proportional-integral controller. PMID- 21823757 TI - Integrated analysis of the gene neighbouring impact on bacterial metabolic networks. AB - Different levels of abstraction are needed to represent a living system. Unfortunately information of different nature is not superposable in an obvious way, but requires a dedicated framework. Because biological abstractions, i.e., genomic or metabolic information, can be easily represented as graphs, it is intuitive to integrate them into a unique graph, in which one can perform graph analysis for investigating a given biological assumption. This study follows such a philosophy and completes a genome and metabolome combination. In a such integrated framework and as illustration, we applied a graph analysis that automatically investigates impacts of the gene adjacency to predict functional relationships between genes and reactions. Our approach, called SIPPER, creates a weighted graph, in which the weights rely on the given relationship between genes, and computes (alternative) chains of reactions catalysed by genes. This method, as a generalisation of methods already published, can be easily adapted to several biological assumptions, properties or measures. This paper evaluates SIPPER on Escherichia coli. We automatically extract subgraphs, called k-SIPs, and quantify their interest in both genomic and metabolic contexts by showing functional compounds like operons or functional modules. PMID- 21823758 TI - Adaptation as a genome-wide autoregulatory principle in the stress response of yeast. AB - The gene expression response of yeast to various types of stresses/perturbations shows a common functional and dynamical pattern for the vast majority of genes, characterised by a quick transient peak (affecting primarily short genes) followed by a return to the pre-stimulus level. Kinetically, this process of adaptation following the transient excursion can be modelled using a genome-wide autoregulatory mechanism by means of which yeast aims at maintaining a preferential concentration in its mRNA levels. The resulting feedback system explains well the different time constants observable in the transient response, while being in agreement with all the known experimental dynamical features. For example, it suggests that a very rapid transient can be induced also by a slowly varying concentration of the gene products. PMID- 21823759 TI - Friend influence over adolescent problem behaviors as a function of relative peer acceptance: to be liked is to be emulated. AB - Friend influence over alcohol intoxication and delinquent behavior was examined as a function of relative peer acceptance in a 3-year study of Swedish youth (N = 184 girls, 145 boys). Participants were in the first year of secondary school (7th grade, M = 11.7 years old) or the first year of high school (10th grade, M = 15.3 years old) at the outset. Friends resembled one another before the friendship; resemblances were even greater after the friendship began. Resemblances continued to grow among those who remained friends one year later, but declined among those whose friendships dissolved. Partners were not equally responsible for increases in similarity. In stable friendships, the more accepted partner exerted greater influence over the less accepted partner, such that the greatest increases in problem behaviors were found among less accepted youth whose friends had higher initial levels of delinquency and alcohol intoxication. Unstable friends resembled random pairs of youth in that more- and less-accepted partners were comparably uninfluential. PMID- 21823760 TI - Disentangling the prospective relations between maladaptive cognitions and depressive symptoms. AB - In a four-wave, cohort-longitudinal design with a community sample of 515 children and adolescents (grades 2 through 9), this study examined the longitudinal structure of and prospective interrelations between maladaptive cognitions and depressive symptoms. Multigroup structural equation modeling generated four major findings. First, the longitudinal structures of maladaptive cognitions and depressive symptoms consist of a single time-invariant factor and a series of time-varying factors. Second, evidence supported a model in which depressive symptoms predicted negative cognitions but not the reverse. Third, the time-invariant components of cognition and depression were highly correlated. Fourth, the strength of the depression-to-cognition relation increased with age. Implications regarding the mechanisms underlying clinical interventions with depressed children are discussed. PMID- 21823761 TI - Affect and alcohol use: an ecological momentary assessment study of outpatients with borderline personality disorder. AB - Alcohol use may be viewed as an attempt (albeit maladaptive) to regulate negative emotional states. We examined associations between both negative and positive affects and alcohol use in outpatient women diagnosed with borderline personality disorder (BPD; n=74), a prototype of emotional dysregulation, as well as a psychiatric control group of women with current depressive disorder (major depressive disorder/dysthymic disorder [MDD?DYS]; n=50). Participants completed randomly prompted reports of mood and alcohol use up to six times a day over a 28 day period using electronic diaries. Mean levels of either positive or negative affects did not distinguish between drinkers and nondrinkers in either diagnostic group. However, levels of both negative and positive affects were positively associated with alcohol use at the momentary level in BPD drinkers. More robust findings were obtained with respect to within-person affective variability, which was related to alcohol use in multiple ways. BPD drinkers showed higher within person variability for most negative affects than BPD nondrinkers; MDD?DYS drinkers in general showed less within-person variability than MDD?DYS nondrinkers for negative affects. Multilevel lagged analyses for BPD drinkers indicated that alcohol use was positively related to variability in all affects, concurrently, but fewer significant effects of affect variability on the next day's drinking or significant effects of alcohol use on the next day's affect variability were observed. Among MDD?DYS drinkers, we observed more significant associations between affect variability on next day's alcohol use and of alcohol use on next day's affect variability. We discuss theoretical and methodological issues relevant to these findings as well as implications for future research. PMID- 21823763 TI - Domain-general and domain-specific strategies for the assessment of distress intolerance. AB - Recent research has provided evidence that distress intolerance-the perceived inability to tolerate distressing states-varies based on the domain of distress (e.g., pain, anxiety). Although domain-specific assessment strategies may provide information targeted to specific disorders or maladaptive behaviors, domain general measures have the potential to facilitate comparisons across studies, disorders, and populations. The current study evaluated the utilization of self report measures of distress intolerance as domain-general measures by examining their association with indices of behavioral avoidance and substance craving. Two groups of participants (N = 55) were recruited including a substance-dependent group and a comparison group equated based on the presence of an affective disorder. Results provided support for the validity of domain-general measures for assessing distress intolerance across varied domains. The importance of both domain-general and domain-specific measurement of distress intolerance is discussed. PMID- 21823762 TI - An internalizing pathway to alcohol use and disorder. AB - Research emanating from the field of developmental science indicates that initial risk factors for alcohol use and disorder can be evident in early childhood. One dominant developmental pathway connecting these initial risk factors with subsequent alcohol involvement focuses on the central role of disinhibited or externalizing behaviors. In the current paper, we delineate a second pathway that focuses on internalizing symptomatology. Several studies indicate that internalizing symptoms in early and middle childhood predict alcohol involvement in adolescence and young adulthood. We use a developmental psychopathology framework to describe a risk model that traces the potential developmental markers of this internalizing pathway and to consider the relation between the internalizing pathway and the more widely researched externalizing pathway. We outline the markers of risk in this pathway and conclude with a discussion of the implications of this model for prevention efforts and future research. In this manner, we strive for a translational goal, linking our existing understanding of internalizing processes and alcohol use and disorder with our efforts to develop effective prevention programs. PMID- 21823764 TI - Gaming machine addiction: the role of avoidance, accessibility and social support. AB - Commonality in etiology and clinical expression plus high comorbidity between pathological gambling and substance use disorders suggest common underlying motives. It is important to understand common motivators and differentiating factors. An overarching framework of addiction was used to examine predictors of problem gambling in current electronic gaming machine (EGM) gamblers. Path analysis was used to examine the relationships between antecedent factors (stressors, coping habits, social support), gambling motivations (avoidance, accessibility, social) and gambling behavior. Three hundred and forty seven (229 females: M = 29.20 years, SD = 14.93; 118 males: M = 29.64 years, SD = 12.49) people participated. Consistent with stress, coping and addiction theory, situational life stressors and general avoidance coping were positively related to avoidance-motivated gambling. In turn, avoidance-motivated gambling was positively related to EGM gambling frequency and problems. Consistent with exposure theory, life stressors were positively related to accessibility motivated gambling, and accessibility-motivated gambling was positively related to EGM gambling frequency and gambling problems. These findings are consistent with other addiction research and suggest avoidance-motivated gambling is part of a more generalized pattern of avoidance coping with relative accessibility to EGM gambling explaining its choice as a method of avoidance. Findings also showed social support acted as a direct protective factor in relation to gambling frequency and problems and indirectly via avoidance and accessibility gambling motivations. Finally, life stressors were positively related to socially motivated gambling but this motivation was not related to either social support or gambling behavior suggesting it has little direct influence on gambling problems. PMID- 21823765 TI - Childhood religious affiliation and alcohol use and abuse across the lifespan in alcohol-dependent men. AB - The current study examined the relationship between childhood religious affiliation and alcohol use across the life span. A sample of 931 men (average age of 51) from the Vietnam Era Twin Registry, which includes an overrepresentation of alcohol-dependent men, completed the Lifetime Drinking History interview, which assessed drinking across the life span. Childhood religious affiliation was obtained from the men's spouse/partner. Affiliations were subdivided into four categories: nonreligious, accommodating (religions that are relatively more accepting of the larger culture), differentiating (religions that set themselves apart from the larger culture), and Catholic. Differences in a variety of alcohol use variables by religious affiliation were examined, as well as the protective effect of childhood religious affiliation on three alcohol use variables at 5-year intervals from age 20 to age 50. Significant differences were found for abstinence, regular drinking, and current quantity-frequency (QFI) scores, with individuals in differentiating religions having the highest rates of abstinence/nonregular drinking and the lowest consumption levels. When examining QFI and alcohol dependence symptoms and diagnoses over time, the nonreligious group had more alcohol use than the religious groups, with the differentiating affiliations showing the least alcohol use. The differences between affiliations were not always significant, but the consistent pattern suggests that childhood religious affiliation may continue to affect alcohol use even into adulthood. PMID- 21823766 TI - Predictors of postdeployment alcohol use disorders in National Guard soldiers deployed to Operation Iraqi Freedom. AB - Alcohol use in the military is a significant problem. The goal of this study was to examine the associations between personality, posttraumatic stress disorder (PTSD) symptoms, and postdeployment alcohol use disorders (AUDs) among a group of Operation Iraqi Freedom (OIF) deployed National Guard soldiers, with a focus on differentiating predeployment and postdeployment onset AUDs. Participants were 348 National Guard soldiers deployed to Iraq from March 2006 to July 2007 drawn from the Readiness and Resilience in National Guard Soldiers (RINGS) study. Participants completed self-report measures one month before deployment and 3 to 6 months postdeployment; current and lifetime history of AUDs were assessed 6 to 12 months postdeployment, using the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders (4th ed. text rev.; DSM-IV; American Psychiatric Association, 2000). Overall, 13% of the panel was diagnosed with a current AUD. Of those who met criteria for a current AUD, 38% had an AUD that developed following return from deployment (new onset AUD). The development of new onset AUDs was uniquely predicted by higher levels of PTSD symptom severity, higher levels of avoidance-specific PTSD symptoms, and lower levels of positive emotionality. AUDs with onset prior to deployment were predicted by higher levels of negative emotionality and disconstraint. Results of this study suggest that combat deployed soldiers with current AUDs are a heterogeneous group and point to the influence of combat-related PTSD symptoms in the development of AUDs following deployment. PMID- 21823767 TI - Drinking refusal self-efficacy and tension-reduction alcohol expectancies moderating the relationship between generalized anxiety and drinking behaviors in young adult drinkers. AB - Despite the substantial comorbidity between generalized anxiety disorder (GAD) and alcohol use disorders (AUD), little is known about contributing factors to this relationship. This lack of knowledge has limited the development of theoretical models explicating the interesting yet complex relationship between GAD and AUD. The current study examined the roles of generalized anxiety, tension reduction alcohol expectancies, and drinking refusal self-efficacy in accounting for the variance of alcohol consumption and alcohol-related consequences in a sample of young adult drinkers (N = 474; 18-25 years of age, median age 19, 66% female) from a large, urban Midwestern university. Results showed that generalized anxiety level interacted with both tension-reduction alcohol expectancies and drinking refusal self-efficacy to predict alcohol consumption and alcohol-related consequences. Findings support the assessment of both alcohol related consequences and alcohol consumption, and highlight the importance of drinking refusal self-efficacy, which is a currently underexamined variable. Study results also enhance the knowledge about the underlining mechanisms of GAD and AUD comorbidity, which facilitates the development of an empirically based theoretical paradigm for their relationship. PMID- 21823768 TI - Intimate partner violence and specific substance use disorders: findings from the National Epidemiologic Survey on Alcohol and Related Conditions. AB - The association between substance use and intimate partner violence (IPV) is robust. It is less clear how the use of specific substances relates to relationship violence. This study examined IPV perpetration and victimization related to the following specific substance use disorders: alcohol, cannabis, cocaine, and opioid. The poly substance use of alcohol and cocaine, as well as alcohol and marijuana, were also examined. Data were analyzed from wave two of the National Epidemiologic Survey on Alcohol and Related Conditions (2004-2005). Associations between substance use disorders and IPV were tested using logistic regression models while controlling for important covariates and accounting for the complex survey design. Alcohol use disorders and cocaine use disorders were most strongly associated with IPV perpetration, while cannabis use disorders and opioid use disorders were most strongly associated with IPV victimization. A diagnosis of both an alcohol use disorder and cannabis use disorder decreased the likelihood of IPV perpetration compared to each individual substance use disorder. A diagnosis of both an alcohol use disorder and cocaine use disorder increased likelihood of reporting IPV perpetration compared with alcohol use disorders alone but decreased likelihood of perpetration compared with a cocaine use disorder diagnosis alone. Overall, substance use disorders were consistently related to intimate partner violence after controlling for important covariates. These results provide further evidence for the important link between substance use disorders and IPV and add to our knowledge of which specific substances may be related to relationship violence. PMID- 21823770 TI - Impacts of psychological science on national security agencies post-9/11. AB - Psychologists have been an integral part of national security agencies since World War I, when psychological science helped in personnel selection. A robust infrastructure supporting wider applications of psychology to military and intelligence problems developed further during World War II and the years following, primarily in the areas of testing, human factors, perception, and the decision sciences. Although the nature of the attacks on 9/11 raised the level of perceived need for increased human-based intelligence, the impacts of psychologists on the policies and practices of national security agencies in the decade since have not increased significantly. PMID- 21823769 TI - The college drinker's check-up: outcomes of two randomized clinical trials of a computer-delivered intervention. AB - The objective of the study was to evaluate the effectiveness of a computer delivered intervention (CDI) to reduce heavy drinking and alcohol-related problems in college students in two randomized clinical trials. In Experiment 1, we randomized 144 students to either the CDI or an assessment-only control group with follow-ups at 1 and 12 months. In Experiment 2, we randomized 82 students to either the CDI or a delayed-assessment control group with follow-up at 1 month. In Experiment 1, participants in both groups significantly reduced their drinking at both follow-ups. Compared to the control group, the CDI group reduced their drinking significantly more at 1 and 12 months on three drinking measures at alpha < .05. Using a more conservative, Bonferroni-adjusted criterion yielded one significant difference in a measure of heavier drinking at the 1 month follow-up. The mean between-groups effect sizes were d = .34 and .36 at 1 and 12 months, respectively. Experiment 2. Compared to the delayed assessment control group, the CDI group significantly reduced (by the Bonferroni-adjusted criterion) their drinking on all consumption measures. These results support the effectiveness of the CDI with heavy drinking college students when used in a clinical setting. In addition, the significant reductions in typical drinking in the control group in Experiment 1 and not in Experiment 2 combined with comparable baseline characteristics suggests that the control group in Experiment 1 demonstrated assessment reactivity. PMID- 21823771 TI - What should we expect after the next attack? AB - A test of any science is its ability to predict events under specified conditions. A test for the psychology represented in this special issue of the American Psychologist is its ability to predict individual and social behavior in the aftermath of a next terror attack. This article draws on that science to make such predictions. These predictions are conditioned on both the nature of the attack and our institutional preparations for it. Some attacks will test our resilience more than others. Whatever the attack, we will reduce its impacts if our institutions take advantage of psychological science. That science can reduce the scope of attacks by limiting terrorists' ability to organize their operations and by enhancing our ability to restrain them. It can reduce the impacts of any attacks that do occur by strengthening the institutions and civil society that must respond to them. Realizing these possibilities will require our social institutions to rely on science, rather than intuition, in dealing with these threats. It will require our profession to provide psychologists with rewards for public service, applied research, and interdisciplinary collaboration, as demanded by complex problems. Responding to these challenges could strengthen society and psychology. PMID- 21823773 TI - Psychology out of the laboratory: the challenge of violent extremism. AB - The idea that people inevitably act in accordance with their self-interest on the basis of a calculation of costs and benefits does not constitute an adequate framework for understanding political acts of violence and self-sacrifice. Recent research suggests that a better understanding is needed of how sacred values and notions of self and group identity lead people to act in terms of principles rather than prospects when the two come into conflict. Perhaps the greatest challenge is to better understand how sacred causes and moral imperatives diffuse through a population and motivate some (usually small) segment of it to commit violent actions. The challenge to psychology is to adopt an interdisciplinary focus drawing on a range of research methods and to become bolder in its choices of study populations if it is to be relevant to real-world problems. PMID- 21823772 TI - Posttraumatic stress disorder following the September 11, 2001, terrorist attacks: a review of the literature among highly exposed populations. AB - The September 11, 2001 (9/11), terrorist attacks were unprecedented in their magnitude and aftermath. In the wake of the attacks, researchers reported a wide range of mental and physical health outcomes, with posttraumatic stress disorder (PTSD) the one most commonly studied. In this review, we aim to assess the evidence about PTSD among highly exposed populations in the first 10 years after the 9/11 attacks. We performed a systematic review. Eligible studies included original reports based on the full Diagnostic and Statistical Manual of Mental Disorders (4th ed., rev.; American Psychiatric Association, 2000) criteria of PTSD among highly exposed populations such as those living or working within close proximity to the World Trade Center (WTC) and the Pentagon in New York City and Washington, DC, respectively, and first responders, including rescue, cleaning, and recovery workers. The large body of research conducted after the 9/11 attacks in the past decade suggests that the burden of PTSD among persons with high exposure to 9/11 was substantial. PTSD that was 9/11-related was associated with a wide range of correlates, including sociodemographic and background factors, event exposure characteristics, loss of life of significant others, and social support factors. Few studies used longitudinal study design or clinical assessments, and no studies reported findings beyond six years post 9/11, thus hindering documentation of the long-term course of confirmed PTSD. Future directions for research are discussed. PMID- 21823774 TI - Intelligence gathering post-9/11. AB - The gathering of information for intelligence purposes often comes from interviewing a variety of individuals. Some, like suspects and captured prisoners, are individuals for whom the stakes are especially high and who might not be particularly cooperative. But information is also gathered from myriad individuals who have relevant facts to provide, and occasionally the smallest details can be important. In gathering this information from both groups of informants, investigators need to worry about memory distortion, especially the extent to which memories can be contaminated by poor questioning or other sources of postevent information. Moreover, they need to worry about the potential for poor methods and other forms of influence to create false confessions, thereby leading investigators astray. A third area in which psychological science can contribute is in the detection of deception. Recent science in these domains can improve the quality of information that investigators gather and the inferences that they draw. PMID- 21823775 TI - Roles of human factors and ergonomics in meeting the challenge of terrorism. AB - Human factors and ergonomics research focuses on questions pertaining to the design of devices, systems, and procedures with the goal of making sure that they are well suited to human use and focuses on studies of the interaction of people with simple and complex systems and machines. Problem areas studied include the allocation of function to people and machines, person-system interface design, accident prevention, risk assessment, human performance under various types of stress, crisis management, search and rescue operations, decision aiding, the training and coordination of teams, and negotiation and conflict resolution, among many others. Much human factors and ergonomics work has been directed at responding to accidents (train wrecks, airplane crashes, nuclear plant mishaps) and natural disasters (hurricanes, earthquakes, floods). Although most of this work has not been motivated by the reality of terrorism or, in particular, by the attacks of 9/11, much of it is relevant to one or another aspect of terrorism in its various manifestations, and human factors and ergonomics researchers are increasingly making the connection. The purpose of this article is to illustrate this relevance by noting a few studies, from among the many that could be cited, that have implications for helping to prevent terrorism or for dealing with the effects of terrorist incidents when they occur. PMID- 21823776 TI - Postdisaster psychological intervention since 9/11. AB - A wealth of research and experience after 9/11 has led to the development of evidence-based and evidence-informed guidelines and strategies to support the design and implementation of public mental health programs after terrorism and disaster. This article reviews advances that have been made in a variety of areas, including development of improved metrics and methodologies for conducting needs assessment, screening, surveillance, and program evaluation; clarification of risk and resilience factors as these relate to varying outcome trajectories for survivors and inform interventions; development and implementation of evidence-based and evidence-informed early, midterm, and late interventions for children, adults, and families; adaptation of interventions for cultural, ethnic, and minority groups; improvement in strategies to expand access to postdisaster mental health services; and enhancement of training methods and platforms for workforce development among psychologists, paraprofessionals, and other disaster responders. Continuing improvement of psychologists' national capacity to respond to catastrophic events will require more systematic research to strengthen the evidence base for postdisaster screening and interventions and effective methods and platforms for training. Policy decisions are clearly needed that enhance federal funding to increase availability and access to services, especially for longer term care. Traumatic bereavement represents a critical area for future research, as much needs to be done to clarify issues related to reactions and adaptation to a traumatic death. PMID- 21823777 TI - Americans respond politically to 9/11: understanding the impact of the terrorist attacks and their aftermath. AB - The 9/11 terrorist attacks have had profound effect on U.S. domestic and foreign security policy, leading to several expensive wars and the erosion of civil liberties (under the USA PATRIOT Act). We review evidence on political reactions to the 9/11 attacks and conclude that subjective reactions to terrorism played an important role in shaping support for national security policy in the wake of 9/11. Support for a strong national security policy was most pronounced among Americans who perceived the nation as at threat from terrorism and felt angry at terrorists. In contrast, Americans who were personally affected by the attacks were more likely to feel anxious about terrorism, and this anxiety translated into less support for overseas military action. In addition, Americans who felt insecure after the 9/11 attacks and perceived a high future threat of terrorism were more likely than others to support strong foreign and domestic national security policies. Overall, research on American political reactions to 9/11 suggests that support for a strong government response to terrorism is most likely when members of a population perceive a high risk of future terrorism and feel angry at terrorists. PMID- 21823778 TI - The expulsion from Disneyland: the social psychological impact of 9/11. AB - People expressed many different reactions to the events of September 11th, 2001. Some of these reactions were clearly negative, such as political intolerance, discrimination, and hate crimes directed toward targets that some, if not many, people associated with the attackers. Other reactions were more positive. For example, people responded by donating blood, increasing contributions of time and money to charity, and flying the American flag. The goal of this article is to review some of Americans' negative and positive reactions to 9/11. We also describe two frameworks, value protection and terror management theory, that provide insights into Americans' various reactions to the tragedy of 9/11. PMID- 21823779 TI - Growing up in the shadow of terrorism: youth in America after 9/11. AB - Research conducted in the aftermath of the September 11th terrorist attacks (9/11) suggests that, except for those who directly witnessed or suffered loss from the attacks, for most children the emotional impact was relatively transitory. We review this literature as well as consider other ways in which the attacks may have played a role in the development of adolescents and young adults as they came of age in the shadow of 9/11 in the United States. Specifically, we discuss the potential impact of the collective trauma of 9/11 on children's coping and emotional regulation, their sociopolitical attitudes, and their general beliefs about the world. Developmental issues and the role of parents in shaping their children's responses to 9/11 are also addressed. Researchers interested in children's social, emotional, and psychological development have much to learn about children's reactions to events like 9/11 and factors that might mitigate the negative consequences of such events on children's development. PMID- 21823780 TI - Communicating about the risks of terrorism (or anything else). AB - Communication is essential to preventing terrorists from achieving their objectives. Effective communication can reduce terrorists' chances of mounting successful operations, creating threats that disrupt everyday life, and undermining the legitimacy of the societies that they attack. Psychological research has essential roles to play in that communication, identifying the public's information needs, designing responsive communications, and evaluating their success. Fulfilling those roles requires policies that treat two-way communication with the public as central to ensuring that a society is strengthened, rather than weakened, by its struggle with terror. There are scientific, organizational, and political barriers to achieving those goals. Psychological research can help to overcome them-and advance its science in the process. PMID- 21823781 TI - An introduction to "9/11: ten years later". PMID- 21823782 TI - Intelligent management of intelligence agencies: beyond accountability ping-pong. AB - The intelligence community (IC) is asked to predict outcomes that may often be inherently unpredictable-and is blamed for the inevitable forecasting failures, be they false positives or false negatives. To move beyond blame games of accountability ping-pong that incentivize bureaucratic symbolism over substantive reform, it is necessary to reach bipartisan agreements on performance indicators that are transparent enough to reassure clashing elites (to whom the IC must answer) that estimates have not been politicized. Establishing such transideological credibility requires (a) developing accuracy metrics for decoupling probability and value judgments; (b) using the resulting metrics as criterion variables in validity tests of the IC's selection, training, and incentive systems; and (c) institutionalizing adversarial collaborations that conduct level-playing-field tests of clashing perspectives. PMID- 21823783 TI - Mechanisms of symptom reduction in treatment for obsessions. AB - OBJECTIVE: We explored the dynamic relationship between cognition and obsession severity during 2 different treatments for primary obsessions, examining evidence for the hypothesis that symptom reduction would be mediated by appraisals about the meaning of unwanted intrusive thoughts. METHOD: Data from a recent randomized controlled trial were analyzed with traditional mediation analyses and latent difference scores. The trial had compared cognitive behavioral therapy and stress management training among 73 patients with primary obsessions. Mediation analyses were conducted with pre-, post-, and follow-up scores on the Obsessions subscale of the Yale-Brown Obsessive Compulsive Scale and 2 self-report measures of cognitions related to obsessive-compulsive disorder. Bivariate dual change score (BDCS) analyses were conducted with weekly assessments of obsession severity and appraisals of personal significance. RESULTS: Change in most cognitions related to obsessive-compulsive disorder accounted for reduction in obsession severity during the course of treatment and follow-up. BDCS analyses of the longitudinal data, however, indicated prior obsession severity is a leading indicator of subsequent change in appraisals, rather than the reverse. Analyses also suggested cognitive behavioral therapy is more effective than stress management training when symptoms are severe and that stress management training is more advantageous in the context of mild-to-moderate obsessions. CONCLUSIONS: The traditional mediation analysis indicated that appraisal change is a tenable mediator of obsession reduction, but the BDCS results raise doubts about the causal direction. The results highlight the importance of examining the dynamic relationship between putative mediators and outcome variables, and they suggest interesting hypotheses about mechanisms in treatment of obsessions. PMID- 21823785 TI - Family conflict and academic performance of first-year Asian American undergraduates. AB - This three-study investigation examined risk and protective factors for poor academic performance among Asian American first-year undergraduates. Students were surveyed prior to starting college and their GPA was collected after their first semester in college. Family conflict as a significant risk factor for poor academic performance was examined in all three studies. The results indicate that higher family conflict prior to college was related to lower first-semester college GPA, after controlling for standardized test scores and high school rank (Studies 1-3). Even though psychological distress was related to both family conflict and GPA, it did not mediate the relationship between family conflict and GPA (Studies 2 and 3). In terms of protective factors, the results indicate that life satisfaction buffered the negative effects of family conflict on first semester college GPA (Study 3). Together, these findings support the need to take into account family variables and psychological well-being in the academic performance of Asian American students as they transition from high school to college. PMID- 21823784 TI - Marriage as a risk factor for internalizing disorders: clarifying scope and specificity. AB - OBJECTIVE: Marital discord has been linked to both depression and anxiety; however, our understanding of how marriage contributes to the development of internalizing symptoms is limited in scope and lacking specificity. First, it is unclear whether the marital relationship contributes to the broad dimension of internalizing symptoms as opposed to specific diagnoses. Second, it is unclear how the marital relationship contributes to internalizing symptoms: through global marital dissatisfaction or through specific relationship processes (and which processes). The purpose of the present study was to address these 2 issues and, more generally, to develop a comprehensive and refined framework within which to understand the role of marriage in the developmental course of internalizing symptoms. METHOD: Questionnaire and interview data were collected from 102 husbands and wives 5 times over the first 7 years of marriage. RESULTS: Results indicated that marital discord during the transition into marriage was associated with the broad dimension of internalizing symptoms for husbands but not for wives. Further, both global marital dissatisfaction and an imbalance of power and control put husbands at significant risk for symptoms over the first 7 years of marriage, whereas low levels of emotional intimacy put wives at significant risk. CONCLUSIONS: Results exemplify the need to routinely consider intimate relationship processes in etiological models of depression and anxiety and to identify specific clinical targets that can be prioritized in interventions aimed at preventing internalizing disorders. PMID- 21823786 TI - Concreteness effects in short-term memory: a test of the item-order hypothesis. AB - The following experiments explore word length and concreteness effects in short term memory within an item-order processing framework. This framework asserts order memory is better for those items that are relatively easy to process at the item level. However, words that are difficult to process benefit at the item level for increased attention/resources being applied. The prediction of the model is that differential item and order processing can be detected in episodic tasks that differ in the degree to which item or order memory are required by the task. The item-order account has been applied to the word length effect such that there is a short word advantage in serial recall but a long word advantage in item recognition. The current experiment considered the possibility that concreteness effects might be explained within the same framework. In two experiments, word length (Experiment 1) and concreteness (Experiment 2) are examined using forward serial recall, backward serial recall, and item recognition. These results for word length replicate previous studies showing the dissociation in item and order tasks. The same was not true for the concreteness effect. In all three tasks concrete words were better remembered than abstract words. The concreteness effect cannot be explained in terms of an item-order trade off. PMID- 21823787 TI - The use of the bared-teeth display during play fighting in Tonkean macaques (Macaca tonkeana): sometimes it is all about oneself. AB - Play signals are viewed as important means by which animals inform each other that bites, strikes, and throws that occur during play fighting are indeed playful rather than serious. One such signal is the open mouth play face that is common in primates and many other mammals. Unfortunately, as most play fighting involves biting, it can be ambiguous as to whether any instance of opening the mouth is performed to communicate playful intent or is simply a preparation for biting. In this study, open mouths co-occurring with the bared-teeth display (teeth-baring) in Tonkean macaques were used to assess the context in which facial gestures only relevant for signaling (i.e., teeth-baring is not necessary for biting) are used during play. Two predictions arising from the hypothesis that play signals are used to facilitate playful contact were tested: that the open mouth with teeth-baring should (1) be most frequent preceding contact, and (2) that it should be performed most often when bites are directed at orientations that is visible to the recipient. The data only partially support these predictions. The open mouth with teeth-baring is also frequently used when a monkey withdraws from playful contact. Moreover, it is associated with bites to body targets, such as the rump, that offer little prospect for detection by the recipient; this supports the possibility that play signals may sometimes be emitted not to communicate with the partner but with the performer itself. Thus, play signals serve multiple functions during play fighting. PMID- 21823788 TI - Challenges and resilience in the lives of urban, multiracial adults: an instrument development study. AB - Multiracial Americans represent a rapidly growing population (Shih & Sanchez, 2009); however, very little is known about the types of challenges and resilience experienced by these individuals. To date, few psychological measures have been created specifically to investigate the experiences of multiracial people. This article describes 2 studies focused on the development and psychometric properties of the Multiracial Challenges and Resilience Scale (MCRS). The MCRS was developed using a nationwide Internet sample of urban, multiracial adults. Exploratory factor analyses revealed 4 Challenge factors (Others' Surprise and Disbelief Regarding Racial Heritage, Lack of Family Acceptance, Multiracial Discrimination, and Challenges With Racial Identity) and 2 Resilience factors (Appreciation of Human Differences and Multiracial Pride). A confirmatory factor analysis with data from a second sample provided support for the stability of this factor structure. The reliability and validity of the measure, implications of these findings, and suggestions for future research are discussed. PMID- 21823789 TI - The contributions of parental attachment bonds to college student development and adjustment: a meta-analytic review. AB - We report findings from a meta-analysis of 156 studies conducted between 1987 and 2009 (N = 32,969) that examined the relationship between self-reported parental attachment and multiple adjustment outcomes and developmental advances during the college years. Overall, a small-to-medium relationship was found between indicators of parental attachment quality and favorable adjustment outcomes (r = .23). Effect sizes were of similar magnitude for mother and father attachment relationships, for male and female students, and across ethnicity and nationality of the sample. The attachment-adjustment relationship varied somewhat according to the developmental task being investigated in the study, showing the strongest association for the task of separation-individuation. Additionally, we found stronger attachment-adjustment links for students residing away from their parents when compared with students living at home during college. PMID- 21823790 TI - Illusory contour figures are perceived as occluding contours by 4-month-old infants. AB - Although 4-month-olds perceive continuity of an object's trajectory through occlusion, little is known about the information specifying an occluding surface at this age. We investigated this in 3 experiments involving 84 participants. Testing the claim that 5-month-olds are unable to perceive the Kanizsa figure as an occluding surface (Csibra, 2001), we demonstrated that 4-month-olds perceived trajectory continuity behind this figure providing its horizontal extent was small. We demonstrated that the presence of visible occluding edges or occlusion of background was insufficient to specify an occluding surface but that their combination was sufficient. Thus, beyond object deletion and accretion, both visible occluding edges and occlusion of background are necessary for perception of occluding surfaces at this age. PMID- 21823791 TI - Relations among conceptual knowledge, procedural knowledge, and procedural flexibility in two samples differing in prior knowledge. AB - Competence in many domains rests on children developing conceptual and procedural knowledge, as well as procedural flexibility. However, research on the developmental relations between these different types of knowledge has yielded unclear results, in part because little attention has been paid to the validity of the measures or to the effects of prior knowledge on the relations. To overcome these problems, we modeled the three constructs in the domain of equation solving as latent factors and tested (a) whether the predictive relations between conceptual and procedural knowledge were bidirectional, (b) whether these interrelations were moderated by prior knowledge, and (c) how both constructs contributed to procedural flexibility. We analyzed data from 2 measurement points each from two samples (Ns = 228 and 304) of middle school students who differed in prior knowledge. Conceptual and procedural knowledge had stable bidirectional relations that were not moderated by prior knowledge. Both kinds of knowledge contributed independently to procedural flexibility. The results demonstrate how changes in complex knowledge structures contribute to competence development. PMID- 21823792 TI - Differential expression of social dominance as a function of age and maltreatment experience. AB - Recent perspectives on social dominance in normative populations have suggested a developmental progression from using primarily coercive strategies to incorporation of more socially competent strategies to attain material and social resources. Parental influences on the resource control strategies children use have been proposed but not investigated empirically. The present study examined age- and gender-related differences in dominance strategies in 470 children from high-risk neighborhoods who were between 6 and 13 years of age, approximately half of whom had experienced maltreatment. A Q-sort measure of social dominance was developed and received preliminary support. Consistent with predictions from resource control theory, age-related differences in dominance-related behavior were demonstrated in both nonmaltreated and maltreated children. Maltreated children were more likely than nonmaltreated children to be identified as dominant bullies at any age. Dominance and bullying were not more likely to be associated for children who had experienced physical and sexual abuse relative to those who were neglected or emotionally maltreated. Results are discussed in terms of the influence of maltreatment on the social development of children, and intervention approaches for limiting these deleterious effects are recommended. PMID- 21823794 TI - Gender differences in the reciprocal relationships between parental physical aggression and children's externalizing problem behavior in China. AB - The study examines gender differences in the reciprocal relations between parental physical aggression and child externalizing problem behavior in China. Four hundred fifty-four Chinese elementary school-age children reported on three forms of their parents' physical aggression toward them (i.e., mild corporal punishment, severe corporal punishment, and physical abuse) and their externalizing problem behavior at two time points, 6 months apart. Structural equation modeling revealed that the three types of parental physical aggression predicted child externalizing problem behavior for girls but not boys, whereas child externalizing problem behavior predicted severe corporal punishment and physical abuse for boys but not girls; child externalizing problem behavior did not predict mild corporal punishment for either gender. The findings suggest that the intervention for and prevention of child externalizing problem behavior may be somewhat different for boys and girls in China. PMID- 21823793 TI - Longitudinal associations among child maltreatment, social functioning, and cortisol regulation. AB - Child maltreatment increases the risk for impaired social functioning and cortisol regulation. However, the longitudinal interplay among these factors is still unclear. This study aimed to shed light on the effect of maltreatment on social functioning and cortisol regulation over time. The sample consisted of 236 children (mean age 7.64 years, SD = 1.36; 125 maltreated children and 111 nonmaltreated children, 128 boys and 108 girls) who attended a week-long summer camp for 2 consecutive years. Saliva was collected during 5 days at 9:00 a.m. and 4:00 p.m. Means of morning and afternoon cortisol levels and cortisol change (difference between morning and afternoon levels, controlled for morning levels) were used to group the children into low-, medium-, and high-cortisol groups. Prosocial, disruptive/aggressive, and withdrawn behaviors were assessed using information from peers and counselors. Maltreated children showed less prosocial and more disruptive/aggressive and withdrawn behavior. Results of structural equation modeling analyses indicated that there were indirect effects of maltreatment on Year 2 morning cortisol via prosocial and disruptive/aggressive behavior: Lower levels of prosocial behavior and higher levels of disruptive/aggressive behavior were related to lower morning cortisol levels 1 year later. Withdrawn behavior was related to higher afternoon cortisol values 1 year later. Results of this study suggest that maltreated children are more likely to experience difficulties in social functioning, which in turn is related to cortisol regulation 1 year later. This altered hypothalamic-pituitary adrenocortical (HPA) axis functioning may put children at risk for later psychopathology. PMID- 21823795 TI - Daily support in couples coping with early stage breast cancer: maintaining intimacy during adversity. AB - OBJECTIVE: Recent work has identified intimacy as a potentially important determinant of psychological adjustment in couples coping with cancer. Little work has examined specific social support processes within the context of the everyday life of couples' cancer experience. Specifically, we examined the links between breast cancer patient reports of receiving support from one's spouse/partner (support receipt) and spouse reports of providing support to the patient (support provision) with daily intimacy outcomes. We hypothesized that both patient and spouse would benefit from support receipt and support provision. METHOD: Forty-five women with early stage breast cancer and their spouses independently completed an Internet-based electronic diary assessing support receipt, support provision, and relationship intimacy for seven consecutive evenings shortly after surgery. Study outcomes consisted of daily relationship intimacy reported by each partner. RESULTS: As hypothesized, when controlling for patient report of support receipt, spouse report of support provision was uniquely associated with a significant additional increase in feelings of relationship intimacy for patients. Moreover, the independent effects of support receipt and support provision were also found to be beneficial for nonpatient spouses' daily feelings of intimacy. CONCLUSION: Findings highlight the use of dyadic diary methods and corresponding modeling to uncover the unique benefits of support provision that may sometimes occur outside the awareness of the recipient. Results are discussed in terms of conceptualizing the cancer experience in a shared interpersonal context, whereby patients and their spouses can both benefit from support as they adjust to cancer together. PMID- 21823796 TI - A hierarchical latent stochastic differential equation model for affective dynamics. AB - In this article a continuous-time stochastic model (the Ornstein-Uhlenbeck process) is presented to model the perpetually altering states of the core affect, which is a 2-dimensional concept underlying all our affective experiences. The process model that we propose can account for the temporal changes in core affect on the latent level. The key parameters of the model are the average position (also called home base), the variances and covariances of the process, and the regulatory mechanisms that keep the process in the vicinity of the average position. To account for individual differences, the model is extended hierarchically. A particularly novel contribution is that in principle all parameters of the stochastic process (not only the mean but also its variance and the regulatory parameters) are allowed to differ between individuals. In this way, the aim is to understand the affective dynamics of single individuals and at the same time investigate how these individuals differ from one another. The final model is a continuous-time state-space model for repeated measurement data taken at possibly irregular time points. Both time-invariant and time-varying covariates can be included to investigate sources of individual differences. As an illustration, the model is applied to a diary study measuring core affect repeatedly for several individuals (thereby generating intensive longitudinal data). PMID- 21823797 TI - Still young at heart: negative age-related information motivates distancing from same-aged people. AB - Research on subjective age has shown that most older adults feel significantly younger than their chronological age. One of the proposed mechanisms for this subjective age effect is that distancing oneself from an age group that is associated with decline in functioning helps older adults maintain a positive view of themselves. Providing negative age-related information, then, should lead older adults to direct their attention away from stimuli that remind them of their age and to distance themselves from same-aged people. In 2 experiments (N1 = 78, 65-83 years of age, M = 71.67, SD = 4.81; N2 = 98, 65-87 years of age, M = 70.52, SD = 4.89), older adults were confronted with positive, neutral, or negative age-related information. The salience of age increased after receiving negative age-related information. Furthermore, older adults directed their gaze away from pictures of older adults and looked longer at middle-aged adults after being confronted with negative age-related information. In addition, Study 2 showed that negative age-related information led older adults to distance themselves from same-aged people. Moreover, they perceived themselves as being more similar to middle-aged than to older adults. These findings highlight the motivational processes that might contribute to the discrepancy between chronological and subjective age in older adults and the psychological function of this discrepancy. Feeling younger might allow older adults to maintain a positive view of themselves despite age-related losses. PMID- 21823799 TI - Examination of the structural, convergent, and incremental validity of the Reynolds Intellectual Assessment Scales (RIAS) with a clinical sample. AB - Empirical examination of the Reynolds Intellectual Assessment Scales (RIAS; C. R. Reynolds & R. W. Kamphaus, 2003a) has produced mixed results regarding its internal structure and convergent validity. Various aspects of validity of RIAS scores with a sample (N = 521) of adolescents and adults seeking psychological evaluations at a university-based clinic were examined. Results from exploratory factor analysis indicated only 1 factor, and confirmatory factor analysis (CFA) indicated that the 1-factor model was a good fit and a better fit than the 2 factor model. Hierarchical factor analysis indicated the higher order, general intelligence factor accounted for the largest amount of variance. Correlations with other measures of verbal/crystallized and nonverbal/fluid intelligence were supportive of the convergent validity of the Verbal Intelligence Index but not the Nonverbal Intelligence Index. Joint CFA with these additional measures resulted in a superior fit of the 2-factor model compared with the 1-factor model, although the Odd-Item-Out subtest was found to be a poor measure of nonverbal/fluid intelligence. Incremental validity analyses indicated that the Composite Intelligence Index explained a medium to large portion of academic achievement variance; the NIX and VIX explained a small amount of remaining variance. Implications regarding interpretation of the RIAS when assessing similar individuals are discussed. PMID- 21823798 TI - Electrophysiological evidence for age effects on sensory memory processing of tonal patterns. AB - In older adults, difficulties processing complex auditory scenes, such as speech comprehension in noisy environments, might be due to a specific impairment of temporal processing at early, automatic processing stages involving auditory sensory memory (ASM). Even though age effects on auditory temporal processing have been well-documented, there is a paucity of research on how ASM processing of more complex tone-patterns is altered by age. In the current study, age effects on ASM processing of temporal and frequency aspects of two-tone patterns were investigated using a passive listening protocol. The P1 component, the mismatch negativity (MMN) and the P3a component of event-related brain potentials (ERPs) to tone frequency and temporal pattern deviants were recorded in younger and older adults as a measure of auditory event detection, ASM processing, and attention switching, respectively. MMN was elicited with smaller amplitude to both frequency and temporal deviants in older adults. Furthermore, P3a was elicited only in the younger adults. In conclusion, the smaller MMN amplitude indicates that automatic processing of both frequency and temporal aspects of two tone patterns is impaired in older adults. The failure to initiate an attention switch, suggested by the absence of P3a, indicates that impaired ASM processing of patterns may lead to less distractibility in older adults. Our results suggest age-related changes in ASM processing of patterns that cannot be explained by an inhibitory deficit. PMID- 21823800 TI - Effects of validity screening items on adolescent survey data. AB - In 2 studies, we examined the use of validity screening items in adolescent survey data. In each study, adolescent respondents were asked whether they were telling the truth and paying attention in answering survey questions. In Study 1 (N = 7,801), the prevalence rates of student risk behaviors were significantly lower after inappropriate (invalid) responders were screened out of the sample. In addition, confirmatory and multigroup factor analyses demonstrated significant differences between the factor structures of school climate scales with valid versus invalid responders. In Study 2, student perceptions of school climate were correlated with teacher perceptions in 291 schools. A bootstrap resampling procedure compared the correlations obtained with valid versus invalid responding students in each school and found that valid responders had more positive views of school conditions and produced higher correlations with teacher perceptions. These findings support the value of validity screening items in improving the quality of adolescent survey data. PMID- 21823802 TI - Putting the brakes on aggression toward a romantic partner: the inhibitory influence of relationship commitment. AB - Why do people behave aggressively toward romantic partners, and what can put the brakes on this aggression? Provocation robustly predicts aggression in both intimate and nonintimate relationships. Four methodologically diverse studies tested the hypothesis that provocation severity and relationship commitment interact to predict aggression toward one's romantic partner, with the aggression promoting effects of provocation diminishing as relationship commitment increases. Across all four studies, commitment to one's romantic relationship inhibited aggression toward one's partner when individuals were severely (but not mildly) provoked. Study 4 tested the hypothesis that this Partner Provocation * Commitment interaction effect would be strong among individuals high in dispositional tendencies toward retaliation but weak (perhaps even nonexistent) among individuals low in such tendencies. Discussion emphasizes the importance of understanding instigating, impelling, and inhibiting processes in the perpetration of aggression toward intimate partners. PMID- 21823803 TI - Paying for positive group esteem: how inequity frames affect whites' responses to redistributive policies. AB - This article finds that, when faced with racial inequity framed as White advantage, Whites' desire to think well of their racial group increases their support for policies perceived to harm Whites. Across 4 studies, the article provides evidence that (a) relative to minority disadvantage, White advantage increases Whites' support for policies perceived to reduce their group's economic opportunities, but does not increase support for policies perceived to increase minority opportunities; and (b) the effect of White advantage on Whites' esteem for their ingroup drives the effect of inequity frame on support for policies perceived to reduce Whites' opportunities. PMID- 21823804 TI - Letters in time and retinotopic space. AB - Various phenomena in tachistoscopic word identification and priming (WRODS and LTRS are confused with and prime WORDS and LETTERS) suggest that position specific channels are not used in the processing of letters in words. Previous approaches to this issue have sought alternative matching rules because they have assumed that these phenomena reveal which stimuli are good but imperfect matches to a particular word-such imperfect matches being taken by the word recognition system as partial evidence for that word. The new Letters in Time and Retinotopic Space model (LTRS) makes the alternative assumption that these phenomena reveal the rates at which different features of the stimulus are extracted, because the stimulus is ambiguous when some features are missing from the percept. LTRS is successfully applied to tachistoscopic identification and form priming data with manipulations of duration and target-foil and prime-target relationships. PMID- 21823805 TI - Effect size estimates: current use, calculations, and interpretation. AB - The Publication Manual of the American Psychological Association (American Psychological Association, 2001, American Psychological Association, 2010) calls for the reporting of effect sizes and their confidence intervals. Estimates of effect size are useful for determining the practical or theoretical importance of an effect, the relative contributions of factors, and the power of an analysis. We surveyed articles published in 2009 and 2010 in the Journal of Experimental Psychology: General, noting the statistical analyses reported and the associated reporting of effect size estimates. Effect sizes were reported for fewer than half of the analyses; no article reported a confidence interval for an effect size. The most often reported analysis was analysis of variance, and almost half of these reports were not accompanied by effect sizes. Partial eta2 was the most commonly reported effect size estimate for analysis of variance. For t tests, 2/3 of the articles did not report an associated effect size estimate; Cohen's d was the most often reported. We provide a straightforward guide to understanding, selecting, calculating, and interpreting effect sizes for many types of data and to methods for calculating effect size confidence intervals and power analysis. PMID- 21823806 TI - The effect of mental progression on mood. AB - Mood affects the way people think. But can the way people think affect their mood? In the present investigation, we examined this promising link by testing whether mood is influenced by the presence or absence of associative progression by manipulating the scope of participants' information processing and measuring their subsequent mood. In agreement with our hypothesis, processing that involved associative progression was associated with relatively better moods than processing that was restricted to a single topic (Experiment 1). Experiment 2 ruled out the possibility that conceptual plurality alone accounted for these mood differences; results converge with the view that mood is affected by the degree to which thoughts advance conceptually. PMID- 21823807 TI - Predicting premeditation: future behavior is seen as more intentional than past behavior. AB - People's intuitions about the underlying causes of past and future actions might not be the same. In 3 studies, we demonstrate that people judge the same behavior as more intentional when it will be performed in the future than when it has been performed in the past. We found this temporal asymmetry in perceptions of both the strength of an individual's intention and the overall prevalence of intentional behavior in a population. Because of its heightened intentionality, people thought the same transgression deserved more severe punishment when it would occur in the future than when it did occur in the past. The difference in judgments of both intentionality and punishment was partly explained by the stronger emotional reactions that were elicited in response to future actions than in response to past actions. We consider the implications of this temporal asymmetry for legal decision making and theories of attribution more generally. PMID- 21823808 TI - Visual temporal processing in dyslexia and the magnocellular deficit theory: the need for speed? AB - A controversial question in reading research is whether dyslexia is associated with impairments in the magnocellular system and, if so, how these low-level visual impairments might affect reading acquisition. This study used a novel chromatic flicker perception task to specifically explore temporal aspects of magnocellular functioning in 40 children with dyslexia and 42 age-matched controls (aged 7-11). The relationship between magnocellular temporal resolution and higher-level aspects of visual temporal processing including inspection time, single and dual-target (attentional blink) RSVP performance, go/no-go reaction time, and rapid naming was also assessed. The Dyslexia group exhibited significant deficits in magnocellular temporal resolution compared with controls, but the two groups did not differ in parvocellular temporal resolution. Despite the significant group differences, associations between magnocellular temporal resolution and reading ability were relatively weak, and links between low-level temporal resolution and reading ability did not appear specific to the magnocellular system. Factor analyses revealed that a collective Perceptual Speed factor, involving both low-level and higher-level visual temporal processing measures, accounted for unique variance in reading ability independently of phonological processing, rapid naming, and general ability. PMID- 21823809 TI - Independent influences of verbalization and race on the configural and featural processing of faces: a behavioral and eye movement study. AB - Describing a face in words can either hinder or help subsequent face recognition. Here, the authors examined the relationship between the benefit from verbally describing a series of faces and the same-race advantage (SRA) whereby people are better at recognizing unfamiliar faces from their own race as compared with those from other races. Verbalization and the SRA influenced face recognition independently, as evident on both behavioral (Experiment 1) and eye movement measures (Experiment 2). The findings indicate that verbalization and the SRA each recruit different types of configural processing, with verbalization modulating face learning and the SRA modulating both face learning and recognition. Eye movement patterns demonstrated greater feature sampling for describing as compared with not describing faces and for other-race as compared with same-race faces. In both cases, sampling of the eyes, nose, and mouth played a major role in performance. The findings support a single process account whereby verbalization can influence perceptual processing in a flexible and yet fundamental way through shifting one's processing orientation. PMID- 21823810 TI - Orthography influences the perception and production of speech. AB - One intriguing question in language research concerns the extent to which orthographic information impacts on spoken word processing. Previous research has faced a number of methodological difficulties and has not reached a definitive conclusion. Our research addresses these difficulties by capitalizing on recent developments in the area of word learning. Participants were trained to criterion on a set of associations between novel pictures and novel spoken words. Spelling sound consistent or spelling-sound inconsistent spellings were introduced on the 2nd day, and the influence of these spellings on speech processing was assessed on the 3rd day. Results showed significant orthographic effects on speech perception and speech production in a situation in which spelling-sound consistency was manipulated with perfect experimental control. Results are discussed in terms of a highly interactive language system in which there is a rapid and automatic flow of activation in both directions between orthographic and phonological representations. PMID- 21823811 TI - Semantic processing in the production of numerals across notations. AB - In the present work, we conducted a series of experiments to explore the processing stages required to name numerals presented in different notations. To this end, we used the semantic blocking paradigm previously used in psycholinguist studies. We found a facilitative effect of the semantic blocked context relative to the mixed context for Arabic digits and number words. However, the blocked context produced an interference effect for physical numerosity and Roman numbers. Our results provided further evidence to models suggesting that Arabic digits may be named through an asemantic route similar to that of number words, whereas a semantic route is mandatory to name physical numerosity and Roman numerals. PMID- 21823812 TI - Variation in working memory capacity and temporal-contextual retrieval from episodic memory. AB - Unsworth and Engle (2007) recently proposed a model of working memory capacity characterized by, among other things, the ability to conduct a strategic, cue dependent search of long-term memory. Although this ability has been found to mediate individual variation in a number of higher order cognitive tasks, the component processes involved remain unclear. The current study was designed to investigate individual variation in successfully retrieving information from episodic memory by examining various aspects of the retrieval process. Both high- and low-working memory capacity participants were found to initiate recall in a similar fashion; however, low-working memory capacity participants did not show the classic asymmetry in their conditional-response probabilities that is typically observed. Overall, the retrieval deficits observed in low-working memory capacity individuals appear to be rooted in their inability to use the products of retrieval to further aid their search. PMID- 21823814 TI - Memory as discrimination: a challenge to the encoding-retrieval match principle. AB - Four experiments contrasted the predictions of a general encoding-retrieval match hypothesis with those of a view claiming that the distinctiveness of the cue target relationship is the causal factor in retrieval. In Experiments 1, 2, and 4 participants learned the relationships between 4 targets and trios of cues; in Experiment 3 there were 3 targets, each associated with a pair of cues. A learning phase was followed by a cued-recognition task where the correct target had to be identified based on 1 or more of the cues. The main performance measurement was response time. Learning was designed to lead to high accuracy so effects could be attributed to retrieval efficiency rather than to variations in encoding. The nature of the cues and targets was varied across experiments. The critical factor was whether each cue was uniquely associated with the to-be recalled target. All experiments orthogonally manipulated (a) how discriminative or uniquely associated with a target-each cue was and (b) the degree of overlap between the cues present during learning and those present at retrieval. The novel finding reported here is that increasing the encoding-retrieval match can hinder performance if the increase simultaneously reduces how well cues predict a target-that is, a cue's diagnostic value. Encoding-retrieval match was not the factor that determined the effectiveness of retrieval. Our findings suggest that increasing the encoding-retrieval match can lead to no change, an increase, or a decrease in retrieval performance. PMID- 21823813 TI - Effect of grouping of evidence types on learning about interactions between observed and unobserved causes. AB - When a cause interacts with unobserved factors to produce an effect, the contingency between the observed cause and effect cannot be taken at face value to infer causality. Yet it would be computationally intractable to consider all possible unobserved, interacting factors. Nonetheless, 6 experiments found that people can learn about an unobserved cause participating in an interaction with an observed cause when the unobserved cause is stable over time. Participants observed periods in which a cause and effect were associated followed by periods of the opposite association ("grouped condition"). Rather than concluding a complete lack of causality, participants inferred that the observed cause does influence the effect (Experiment 1), and they gave higher causal strength estimates when there were longer periods during which the observed cause appeared to influence the effect (Experiment 2). Consistent with these results, when the trials were grouped, participants inferred that the observed cause interacted with an unobserved cause (Experiments 3 and 4). Indeed, participants could even make precise predictions about the pattern of interaction (Experiments 5 and 6). Implications for theories of causal reasoning are discussed. PMID- 21823815 TI - Comparative treatment of multiple vellus hair cysts with the 2940 nm Er:YAG and 1540 nm Er:Glass laser. AB - Eruptive vellus hair cysts occur sporadically, hereditarily or in association with other diseases due to developmental anomalies of vellus hair follicles. Here, we report on a 41-year-old male with multiple vellus hair cysts of the forehead, who was successfully treated three times with a non-ablative, non fractional 1540 nm Er:Glass laser on one side of his face, and with an ablative non-fractional 2940 nm Er:YAG laser on the other side, at intervals of 6-12 weeks. Over the whole treatment period of about 9 months, we could observe a marked reduction in the total number of cysts. The bigger and painful inflammatory cysts were reduced significantly. There was a slight tendency for better clinical outcome in the area in which the Er:YAG laser had been used. Clinical and histopathological findings, pathogenesis and treatment options are discussed with a review of the literature. PMID- 21823816 TI - The validity of temperature-sensitive ingestible capsules for measuring core body temperature in laboratory protocols. AB - The human core body temperature (CBT) rhythm is tightly coupled to an endogenous circadian pacemaker located in the suprachiasmatic nucleus of the anterior hypothalamus. The standard method for assessing the status of this pacemaker is by continuous sampling of CBT using rectal thermometry. This research sought to validate the use of ingestible, temperature-sensitive capsules to measure CBT as an alternative to rectal thermometry. Participants were 11 young adult males who had volunteered to complete a laboratory protocol that extended across 12 consecutive days. A total of 87 functional capsules were ingested and eliminated by participants during the laboratory internment. Core body temperature samples were collected in 1-min epochs and compared to paired samples collected concurrently via rectal thermistors. Agreement between samples that were collected using ingestible sensors and rectal thermistors was assessed using the gold-standard limits of agreement method. Across all valid paired samples collected during the study (n = 120,126), the mean difference was 0.06 degrees C, whereas the 95% CI (confidence interval) for differences was less than +/-0.35 degrees C. Despite the overall acceptable limits of agreement, systematic measurement bias was noted across the initial 5 h of sensor-transit periods and attributed to temperature gradations across the alimentary canal. PMID- 21823817 TI - Calculating the dim light melatonin onset: the impact of threshold and sampling rate. AB - The dim light melatonin onset (DLMO) is the most reliable circadian phase marker in humans, but the cost of assaying samples is relatively high. Therefore, the authors examined differences between DLMOs calculated from hourly versus half hourly sampling and differences between DLMOs calculated with two recommended thresholds (a fixed threshold of 3 pg/mL and a variable "3k" threshold equal to the mean plus two standard deviations of the first three low daytime points). The authors calculated these DLMOs from salivary dim light melatonin profiles collected from 122 individuals (64 women) at baseline. DLMOs derived from hourly sampling occurred on average only 6-8 min earlier than the DLMOs derived from half-hourly saliva sampling, and they were highly correlated with each other (r >= 0.89, p < .001). However, in up to 19% of cases the DLMO derived from hourly sampling was >30 min from the DLMO derived from half-hourly sampling. The 3 pg/mL threshold produced significantly less variable DLMOs than the 3k threshold. However, the 3k threshold was significantly lower than the 3 pg/mL threshold (p < .001). The DLMOs calculated with the 3k method were significantly earlier (by 22 24 min) than the DLMOs calculated with the 3 pg/mL threshold, regardless of sampling rate. These results suggest that in large research studies and clinical settings, the more affordable and practical option of hourly sampling is adequate for a reasonable estimate of circadian phase. Although the 3 pg/mL fixed threshold is less variable than the 3k threshold, it produces estimates of the DLMO that are further from the initial rise of melatonin. PMID- 21823819 TI - Retraction. Relative biological effectiveness (RBE) of fast neutrons in trabecular bone architecture in mice. PMID- 21823820 TI - Calculation of the biological effects of ion beams based on the microscopic spatial damage distribution pattern. AB - PURPOSE: To present details of the recent version of the 'Local Effect Model' (LEM), that has been developed and implemented in treatment planning for the ion beam therapy pilot project performed at GSI Helmholtzzentrum fur Schwerionenforschung in Darmstadt, Germany. MATERIALS AND METHODS: The new version of the model is based on a detailed consideration of the spatial distribution of the initial damages, i.e., double-strand breaks (DSB). This spatial distribution of DSB is obtained from the radial dose profile of the ion track using Monte Carlo methods. These distributions are then analyzed with regard to the proximity of DSB. This version of the model also facilitates the calculation of full dose response curves up to arbitrary high doses, thus allowing to thoroughly check the approximations previously used to estimate the quadratic term (beta-term) for the linear-quadratic description of dose response curves. RESULTS: The accuracy of the model predictions is demonstrated by good agreement of the relative biological effectiveness (RBE) as a function of the linear energy transfer (LET) with experimental data obtained for V79 cells after carbon irradiation. The beta-values predicted by the full simulation tend to be larger as compared to the approximation in the intermediate LET range. CONCLUSION: The new version of the model allows a more mechanistic description of the biological effects of ion radiation. The full simulation is a prerequisite for tests of the validity of the approach at high doses, which are of particular interest for application in hypofractionation studies. PMID- 21823821 TI - Monte Carlo simulations of therapeutic proton beams for relative biological effectiveness of double-strand break. AB - PURPOSE: The relative biological effectiveness (RBE) values relative to (60)Co for the induction of double-strand breaks (DSB) were calculated for therapeutic proton beams. RBE-weighted absorbed doses were determined at different depths in a water phantom for proton beams. MATERIALS AND METHODS: The depth-dose distributions and the fluence spectra for primary protons and secondary particles were calculated using the FLUKA (FLUktuierende KAskade) MC (Monte Carlo) transport code. These spectra were combined with the MCDS (Monte Carlo damage simulation) code to simulate the spectrum-averaged yields of clustered DNA lesions. RBE for the induction of DSB were then determined at different depths in a water phantom for the unmodulated and modulated proton beams. RESULTS: The maximum RBE for the induction of DSB at 1 Gy absorbed dose was found about 1.5 at 0.5 cm distal to the Bragg peak maximum for an UNMODULATED 160 MeV proton beam. The RBE-weighted absorbed dose extended the biologically effective range of the proton beam by 1.9 mm. The corresponding maximum RBE value was inversely proportional to the proton beam energy, reaching a value of about 1.9 for 70 MeV proton beam. For a modulated 160 MeV proton beam, the RBE weightings were more pronounced near the spread-out Bragg peak (SOBP) distal edge. CONCLUSIONS: It was demonstrated that a fast MCDS code could be used to simulate the DNA damage yield for therapeutic proton beams. Simulated RBE for the induction of DSB were comparable to RBE measured in vitro and in vivo. Depth dependent RBE values in the SOBP region might have to be considered in certain treatment situations. PMID- 21823822 TI - Determination of DNA structural detail using radioprobing. AB - PURPOSE: To put radioprobing into context as a relatively new method of determining structural detail in deoxyribonucleic acid (DNA), and to review its use since first proposed in 1997. The key feature of the method is that, by experiment or simulation, a radionuclide such as iodine-125 ((125)I) is placed near the DNA at a known point relative to the DNA base sequence, and the number of resulting strand breaks in each nucleotide is determined. As the intensity of damage declines consistently with distance from the radionuclide, relative distances between the emitter and the nucleotides can be deduced, and hence potentially the topology or structural detail of the DNA. For simulation, appropriate software includes a Molecular Dynamics package, analysis and visualization tools, and a Monte Carlo track structure program. CONCLUSIONS: A review of published work and our own recent unpublished studies have shown that radioprobing is sufficiently sensitive and consistent to determine structural detail such as internal folding topology and flexing behavior, and can be applied to DNA or a DNA-protein complex in an approximation to its normal biological environment. PMID- 21823823 TI - Applications of the microdosimetric function implemented in the macroscopic particle transport simulation code PHITS. AB - PURPOSE: Microdosimetric quantities such as lineal energy are generally considered to be better indices than linear energy transfer (LET) for expressing the relative biological effectiveness (RBE) of high charge and energy particles. To calculate their probability densities (PD) in macroscopic matter, it is necessary to integrate microdosimetric tools such as track-structure simulation codes with macroscopic particle transport simulation codes. METHODS: As an integration approach, the mathematical model for calculating the PD of microdosimetric quantities developed based on track-structure simulations was incorporated into the macroscopic particle transport simulation code PHITS (Particle and Heavy Ion Transport code System). The improved PHITS enables the PD in macroscopic matter to be calculated within a reasonable computation time, while taking their stochastic nature into account. APPLICATIONS: The microdosimetric function of PHITS was applied to biological dose estimation for charged-particle therapy and risk estimation for astronauts. The former application was performed in combination with the microdosimetric kinetic model, while the latter employed the radiation quality factor expressed as a function of lineal energy. CONCLUSION: Owing to the unique features of the microdosimetric function, the improved PHITS has the potential to establish more sophisticated systems for radiological protection in space as well as for the treatment planning of charged-particle therapy. PMID- 21823824 TI - Stochastic modelling of DSB repair after photon and ion irradiation. AB - PURPOSE: To test the stochastic model for DNA double-strand break (DSB) repair via non-homologous end joining (NHEJ) implemented in the Monte Carlo code PARTRAC (PARticle TRACks) against measured repair kinetics after nitrogen ion and (60)Co gamma reference irradiation. MATERIAL AND METHODS: By combining Monte Carlo track structure calculations with multi-scale models of cellular DNA, yields of DSB are calculated for N ion and (60)Co gamma-irradiation. The NHEJ model in PARTRAC is used to determine rejoining kinetics of the DNA ends and DNA fragment distributions after certain repair times. Model parameters are adapted to the measured rejoining kinetics for the different radiation types. RESULTS: DSB rejoining kinetics after low- and high-linear energy transfer (LET) irradiation have been reproduced after refinements of the DNA repair model, in particular by considering an ongoing production of detectable DSB in the initial phase, e.g., by enzymatic processing of labile sites, and by assuming a limited availability of repair enzymes needed for processing complex lesions during the slow repair phase. CONCLUSIONS: The need for certain model refinements suggests mechanisms that may significantly contribute to the DSB rejoining kinetics during both initial and later phases of NHEJ. PMID- 21823825 TI - Simulation of ionisation clusters formed in nanometric volumes of the deoxyribose substitute tetrahydrofuran. AB - PURPOSE: To investigate the implications of using interaction cross sections of liquid water for the target volume when studying radiation action at the DNA level by particle track structure simulations. MATERIALS AND METHODS: Absolute interaction cross sections for low energy electrons between 20 eV and 1 keV were measured for tetrahydrofuran (THF), which is a substitute for deoxyribose. From these data a complete interaction cross section data set was derived and integrated in our PTB Track structure Monte Carlo code 'PTra'. Simulations of electron track structure in THF and water were performed and ionisation cluster size distributions in nanometric target volumes were determined. From these a nanodosimetric estimate for the probability to produce a double strand break was derived. RESULTS: The probability distribution of ionisation cluster sizes was found to be shifted towards smaller values for a THF-filled target as compared to a water-filled one. For all electron energies investigated, the nanodosimetric estimates for double-strand break probability in the THF-filled target have lower values than for a target of liquid water. CONCLUSION: The preliminary results indicate that simulations based on cross sections of water would overestimate the initial direct radiation damage to the DNA. PMID- 21823826 TI - Polymorphisms and evolutionary history of retrotransposon insertions in rice promoters. AB - Retrotransposons are ubiquitous in higher plant genomes. The presence or absence of retrotransposons in whole genome and high throughput genomic sequence (HTGS) from cultivated and wild rice was investigated to understand the organization and evolution of retrotransposon insertions in promoter regions. Approximately half of the Oryza sativa subsp. japonica 'Nipponbare' promoters with retrotransposons conserved in Oryza sativa subsp. indica '93-11' and four wild rice species showed higher sequence conservation in retrotransposon than nonretrotransposon regions. We further investigated, in detail, the evolutionary dynamics of five retrotransposons in the promoter regions of 95 rice genotypes. Our data suggest that four of five insertions (Rp2-Rp5) occurred in the ancestor of AA genome, while the other insertion (Rp1) predates the ancestral divergence of Oryza officinalis (CC genome). Four retrotransposons (Rp2-Rp5) were present in 52% (Rp2), 29% (Rp3), 53% (Rp4), and 43% (Rp5) of the rice genotypes with AA genome type, and the fifth retrotransposon (Rp1) was present in 95% of the rice genotypes with AA, BBCC, or CC genome types. Furthermore, most of these retrotransposons were found to evolve slower than flanking promoter regions, suggesting a role in promoter function for regulating downstream genes. PMID- 21823827 TI - Presurgical orthopedics has no effect on archform in unilateral cleft lip and palate. AB - OBJECTIVE: Evaluation of the effect of presurgical orthopedics on maxillary archform up to 6 months of age. DeSIGN: Retrospective, single-blinded, case control study. PARTICIPANTS: Study model sets of 75 infants with consecutive, nonsyndromic, complete unilateral cleft lip and palate (excluding Simonart bands) from 1995 to 2005. INTERVENTIONS: All patients (PSO group, n = 14; non-PSO group, n = 61) received lip repair/vomer flap at 3 months and soft palate repair at 6 months by the same consultant surgeon. The two groups were comparable at birth (p > .01) in all archform variables. MAIN OUTCOME MEASURES: Sixteen variables were computed, following single-blinded analysis using the Reflex Microscope to describe the archform in the transverse, anteroposterior, and vertical dimensions and the arch circumference. Data were analyzed using a repeated-measures hierarchical analysis of variance with a significance level of 1%. RESULTS: Repeatability studies showed good measurement precision. Presurgical orthopedics produced no statistically significant mean change in any archform variable when compared with the non-PSO group. The difference in the mean reduction in the alveolar cleft width between the groups was 0.69 mm (95% confidence interval, -0.89 to 2.28 mm, p = .52). Lip repair produced greater change in archform than did presurgical orthopedics, reducing the mean alveolar cleft width by 4.45 mm (95% confidence interval, 3.53 to 5.37 mm; p < .001). CONCLUSIONS: There was no evidence that presurgical orthopedics produced any significant effect on archform, raising questions for its continued use in this context. Lip repair had a greater impact on arch dimensions than did presurgical orthopedics. PMID- 21823828 TI - Lack of recurrence of imatinib-induced interstitial lung disease with nilotinib. PMID- 21823830 TI - Genomic stratification of multiple myeloma treated with novel agents. AB - Cytogenetic testing is now routinely performed for the prognostic work-up of multiple myeloma (MM). The abnormalities del(17p), t(4;14) and del(13q) have been established as predictors of poor outcome in patients with MM treated with conventional chemotherapy or stem cell transplant; chromosome 1q gains and 1p losses have also been identified as novel prognostic factors. In recent years, bortezomib and lenalidomide have emerged as effective treatments for both relapsed/refractory and newly diagnosed MM. However, the effect of cytogenetic abnormalities is unclear among patients with MM treated with these novel agents. Here we review recent studies that analyze the impact of specific genomic aberrations on the outcome of MM treated with bortezomib and/or lenalidomide. PMID- 21823829 TI - A phase 2 study of vorinostat for treatment of relapsed or refractory Hodgkin lymphoma: Southwest Oncology Group Study S0517. AB - We performed a phase II study of oral vorinostat (200 mg twice daily, days 1-14 of a 21-day cycle), a histone and protein deacetylase inhibitor, to examine efficacy and tolerability in patients with relapsed/refractory Hodgkin lymphoma (HL) with <= 5 prior therapies. The primary endpoint was the objective response rate (ORR), with secondary endpoints of progression-free survival (PFS), overall survival (OS), safety and tolerability. A two-stage design was used for patient accrual. Twenty-five eligible patients were accrued in the first stage. Median time on treatment was 3.8 months. The ORR was 4% (one partial response). Median PFS was 4.8 months. The drug was well tolerated. The second stage of accrual was not opened due to few objective responses. Oral vorinostat has limited single agent activity in relapsed/refractory HL. There was one partial response, while seven other patients had stable disease for > 1 year, including two with stable disease for nearly 3 years, suggesting that further studies in combination with other active agents in this setting may be warranted. PMID- 21823831 TI - Monosomal karyotype routinely defines a poor prognosis subgroup in acute myeloid leukemia and is frequently associated with TP53 deletion. PMID- 21823832 TI - Breaking bad news in onco-hematology: new hope, new words? PMID- 21823833 TI - High prevalence of hepatitis B virus infection in multiple myeloma. AB - The aim of the present study was to verify the potential association between multiple myeloma (MM) and hepatitis B/C virus (HBV/HCV) infection. This retrospective case-control trial included 299 patients with MM and 299 patients with acute leukemia (AL). Age and sex were matched between the two groups. The hepatitis B surface antigen (HBsAg) positivity rate was significantly higher in the MM group (19.4% vs. 12.0% in patients with AL; p = 0.014). The rate of HCV infection did not differ between the two groups. The incidence of cirrhosis was significantly higher in HBsAg+ patients (17.2% vs. 6.2% in HBsAg- patients; p = 0.011). The rate of hepatitis E virus (HEV) infection was also significantly higher in HBsAg+ patients (5.2% vs. 0.4% in HBsAg- patients; p = 0.025). Hepatic damage was much more common in HBsAg+ patients than in HBsAg- patients both prior to (22.4% vs. 8.7%; p = 0.006) and during chemotherapy for MM (67.2% vs. 28.6%; p < 0.001). ISS stage, HBsAg+, the use of bortezomib and thalidomide and autologous stem cell transplant were significant factors for overall survival in univariate analysis. In the Cox regression analysis, ISS stage (p = 0.027), HBsAg+ (p = 0.042) and the use of thalidomide (p = 0.001) showed a significant effect on the OS of these patients. The prevalence of HBV infection is higher in patients with MM than in subjects with other hematological malignancies such as AL. Hepatic injury is more common in patients with MM with HBV infection, particularly during chemotherapeutic treatment. HBsAg positivity may be a prognosis factor in patients with MM in HBV endemic areas. PMID- 21823834 TI - Reversible nicorandil induced perianal ulceration in acute myeloid leukemia. PMID- 21823835 TI - Synthesis, biological screening and molecular modeling studies of novel 3-chloro 4-substituted-1-(2-(1H-benzimidazol-2-yl)phenyl))-azetidin-2-ones. AB - In the present investigation synthesis of some novel 1-(2-(1H-benzimidazol-2 yl)phenyl)-3-chloro-4-(Un/substitutedphenyl)azetidin-2-one (3a-3h) antibacterial are reported. Structures of synthesized compounds were confirmed by spectral techniques (IR, Mass, (1)H-NMR) All reactions were monitored with analytical thin layer chromatography. Synthesized compounds were docked in to the active site of enzyme transpeptidase. Compounds 3a, 3b, 3d and 3g were found to have good affinity for transpeptidase with potent antibacterial activity. A good correlation is found between in silico docking analysis and in vitro antibacterial activity. PMID- 21823836 TI - Studies on collagen-tannic acid-collagenase ternary system: Inhibition of collagenase against collagenolytic degradation of extracellular matrix component of collagen. AB - We report the detailed studies on the inhibitory effect of tannic acid (TA) on Clostridium histolyticum collagenase (ChC) activity against degradation of extracellular matrix component of collagen. The TA treated collagen exhibited 64% resistance against collagenolytic hydrolysis by ChC, whereas direct interaction of TA with ChC exhibited 99% inhibition against degradation of collagen and the inhibition was found to be concentration dependant. The kinetic inhibition of ChC has been deduced from the extent of hydrolysis of N-[3-(2-furyl) acryloyl]-Leu Gly-Pro-Ala (FALGPA). This data provides a selective competitive mode of inhibition on ChC activity seems to be influenced strongly by the nature and structure of TA. TA showed inhibitor activity against the ChC by molecular docking method. This result demonstrated that TA containing digalloyl radical possess the ability to inhibit the ChC. The inhibition of ChC in gaining new insight into the mechanism of stabilization of collagen by TA is discussed. PMID- 21823837 TI - Synthesis of some N-[4-(benzothiazole-2yl) phenyl]-2-aryloxyacetamide derivatives and their anticancer activities. AB - In this study, some N-[4-(Benzothiazole-2-yl) phenyl]-2-aryloxyacetamide derivatives were prepared by reacting N-[4-(benzothiazole-2yl)phenyl]-2 chloroacetamide and different substituent phenol or thiophenol derivatives. The anticancer activities of the compounds obtained were investigated. It was observed that some of the compounds, namely 25 and 38, showed notable anticancer activity. PMID- 21823839 TI - Teratogenicity of angiotensin converting enzyme inhibitors or receptor blockers. AB - Studies of 1st trimester exposure to ACE inhibitors and angiotensin receptor blockers examining teratogenicity have shown conflicting results. We systematically reviewed the literature and performed a meta-analysis evaluating the risk of major malformations. For the meta-analysis, we included studies comparing 1st trimester exposure to no exposure, or to exposure to other antihypertensives. Additionally, we conducted a qualitative analysis of studies that did not meet the inclusion criteria for the meta-analysis. A significant risk ratio was found when the exposed group was compared with healthy controls but not when compared with other antihypertensives. The qualitative analysis did not demonstrate a specific pattern of major malformations. Our results suggest that 1st trimester exposure to ACE inhibitors and angiotensin receptor blockers is not associated with an elevated risk of major malformations compared with other antihypertensives. A 1st trimester exposure to antihypertensives in general may be associated with an elevated risk of major malformations. PMID- 21823840 TI - Diagnosis and treatment of Zoon's vulvitis. PMID- 21823841 TI - Lifelong learning in obstetrics and gynaecology: how theory can influence clinical practice. AB - Lifelong learning refers to the systematic acquisition, renewal, updating and completion of knowledge. It is synonymous with the term 'self-directed learning'. This is a new educational strategy meant to consolidate knowledge in a fashion that is reproducible for a lifetime with successful application to both known and unknown clinical exercises. The development of lifelong learning is based on the principles of andragogy (autonomy and independence in one's learning activities), reflection and learning from experience. This paper deals with the development of these theories culminating in the advent of self-directed learning. Evidence to support experiential, reflective and self-directed learning is provided, including the use of rating scales. An example from obstetrics is used to highlight the application of these principles. There are barriers to adopting a new educational paradigm, however, lifelong learning remains an excellent tool for continuous professional development. PMID- 21823842 TI - The obstetric performance of Chinese immigrants residing in the UK. AB - Although the Confidential Enquiry into Maternal Deaths raised concerns that immigrant women have significantly poorer obstetric outcomes when compared to native women, there is little published data on the obstetric outcomes of Chinese immigrants living in the UK. This retrospective, case-control study compared maternal demographics and obstetric outcomes of Chinese with British Caucasian women matched for parity and age, who served as controls. Data from 125 index and 125 control cases were analysed. A total of 74% of the Chinese women had little or no understanding of English. The Chinese women were more likely to be non smokers, have a lower BMI and be unemployed than their British counterparts (p<0.001). They booked later (21.01 vs 15.35 weeks, p<0.0001) and attended on average one less antenatal clinic than controls (p<0.001). Chinese women were also less likely to deliver by caesarean section (p<0.05), but more likely to have a perineal tear (p<0.005). Pre-defined risk, gestation at delivery, birth weight, duration of labour, estimated blood loss and mean 5 min Apgar scores were comparable in both groups (p>0.05). In conclusion, there are significant differences in access to healthcare and the method of delivery, but overall, the obstetric outcomes of both ethnic groups are highly similar. This may be due to the 'healthy immigrant effect' or the increased use of interpreters and linkworkers in obstetric healthcare. PMID- 21823843 TI - Comparison in maternal body composition between Caucasian Irish and Indian women. AB - The use of body mass index (BMI) for the diagnosis of obesity has limitations, especially when comparing ethnic groups with different body proportions. The aim of this prospective study was to compare maternal body composition in early pregnancy between Caucasian Irish and Indian women. A total of 81 Indian women and 81 Irish Caucasian women were matched for age, parity and BMI. Maternal weight and height were measured, and body composition analysed using bioelectrical impedance. The Irish women were taller and weighed more than the Indian women (p<0.001). At any given BMI, the Indian women had a higher total body fat percentage, visceral fat level and high fat percentage than the Irish women (p=0.024, 0.001 and 0.001, respectively). Our findings suggest that lower BMI cut-offs should be used for screening for gestational diabetes mellitus in Indian women attending our antenatal services. PMID- 21823844 TI - Spousal disclosure of HIV serostatus among women attending antenatal care in urban Nigeria. AB - About 80% of HIV-positive pregnant women in our unit have a seronegative spouse. The prevalence, pattern and determinants of spousal disclosure of HIV serostatus was evaluated among 166 HIV-positive pregnant women receiving antiretroviral treatment. Although 146 women (88%) disclosed their HIV serostatus, 20 women (12%) did not disclose their status to their spouse. Non-disclosure was significantly associated with nulliparous (p=0.024) and unmarried women (p=0.026). Fear, regarding spread of the information (57.8%), stigmatisation (53%) and deterioration in the relationship with the spouse (47%) were the three commonest reasons for non-disclosure. Disclosure of HIV-positive status remains a sensitive issue among infected pregnant women. Strategies to reduce the stigma associated with HIV infection, appropriate management of the information following disclosure of seropositive status by HIV-infected persons are necessary to encourage disclosure to sexual partners and ultimately prevent new HIV infections. PMID- 21823845 TI - Sleep disturbance in late pregnancy and type and duration of labour. AB - In this study, the relationship between sleep quality and type and duration of labour has been evaluated. A total of 88 pregnant women completed the Pittsburgh Sleep Questionnaire three times during their last 3 weeks of pregnancy at their prenatal visits and once postpartum. A mean score of >5 was considered as poor quality sleep. Duration of labour, type of delivery and weight of the newborn at delivery was considered. Of the study population, 56.2% were categorised as the good-quality sleep group and 43.8% as the poor-quality sleep group. The reported sleeping time per day was 8.47+/-1.86 hours for the good-quality sleep group and 6.45+/-2.07 hours for the poor-quality sleep group. The poor-quality sleep women were 20% more likely to undergo caesarean section and had a longer labour duration. Gestational age at delivery and mean gravidity was respectively 38.53+/ 1.17 weeks and 1.91+/-1.03 in the good-quality sleep group and 38.36+/-1.59 weeks and 1.86+/-1.07 in the poor-quality sleep group. Thus, it was found that women with sleep problems experience longer labour duration and are more likely to undergo a caesarean section. PMID- 21823846 TI - Induction of labour with vaginal prostaglandin tablet vs gel. AB - The objective of this study was to compare outcomes in women whose labour was induced with vaginal prostaglandin E2 tablets with those induced with prostaglandin gel. We compared outcomes of induction during two audits conducted in 2005 (PGE2 gel) and 2009 (PGE2 tablets). We found that there was no difference in induction rates; 21% in 2005 and 24% in 2009. The recommended dose of prostaglandin E2 was exceeded in 6% and 17% of women induced with gel and tablets, respectively (p=0.007). There was a difference in use of syntocinon to augment uterine contractions, 39% vs 58% for women induced with gel and tablets, respectively (p=0.001). There was no difference in overall operative delivery, 37% in gel and 38% in tablets. There was no difference in the proportion of women who had vaginal birth within 24 h; 50% vs 42% for gel and tablet, respectively (p=0.187). We conclude that compared to prostaglandin gel, women who received prostaglandin tablets were more likely to require syntocinon to augment contractions. PMID- 21823847 TI - Does caesarean section provide the best outcome for mother and baby in breech presentation? A perspective from the developing world. AB - This is a retrospective analysis of vaginal breech delivery from January 2006 to December 2008 at a maternity hospital in New Delhi. The hospital has approximately 6,000 deliveries per year, and serves a low income population. Most patients are unbooked, have had no antenatal care and attend in an advanced stage of labour, delivering within 2-3 h of admission. The mode of delivery for breech presentation is one of the most controversial in modern obstetrics. The impact of a caesarean section involves not only immediate risk but complications in future pregnancies and on health costs. Outcome measures were expressed in terms of Apgar, SCBU admission, intrapartum death and birth trauma. Caesarean sections should be performed in selected cases after full discussion with the patient. We are ignoring maternal risks and concentrating on a small subset to reduce perinatal morbidity and mortality. PMID- 21823848 TI - A case series of interventional radiology in postpartum haemorrhage. AB - Postpartum haemorrhage (PPH) remains a significant cause of maternal morbidity and mortality in both developed and developing countries. In some instances, PPH can be anticipated and recent improvements in obstetric imaging techniques allow earlier and more reliable diagnosis of abnormalities associated with haemorrhage such as morbid placentation. However, the majority of PPH is unpredicted. Good practice notes published by the Royal College of Obstetricians and Gynaecologists state interventional radiology should be used as emergency intervention in PPH and should be considered when primary management has failed allowing arteries to be embolised to achieve haemostasis. Through collaboration between interventional radiology and maternity, appropriate guidelines need to be developed, on both emergency and elective of interventional radiology in the prevention and management of PPH. As there is mapping for neonatal services, in the future there should be consideration to develop obstetric trauma units. Maternity units which lack facilities for interventional radiology would be able to refer their cases (like placenta accreta) for safe management in units with 24 h interventional radiology services. PMID- 21823849 TI - The possibility of vertical transmission of human papillomavirus through maternal milk. AB - Human papillomavirus (HPV) DNA has been detected in the oral cavity of infants and breast cancer tissue, suggesting its vertical transmission through maternal milk. We determined whether HPV is detected in maternal milk and is vertically transmitted by breast-feeding. Informed consent was obtained, and maternal milk samples (n=80) were analysed for high-risk HPV DNA. In 43 women, this DNA was measured in the uterine cervix. In women with positive samples, this DNA was measured in the oral cavities of their children. The domain including HPV E6 and E7 was amplified by polymerase chain reaction using consensus primers, and HPV serotype determined by electrophoresis after restriction enzyme digestion. High risk HPV-16 was detected in two of 80 samples (2.5%), and in these two cases, high-risk HPV was not detected in the uterine cervix or oral cavity of the child. It was concluded that the infection of HPV in maternal milk is rare (2/80); vertical transmission through maternal milk was not detected in this study (0/80). HPV infection through maternal milk may occur, but its likelihood is low. PMID- 21823850 TI - Social disparity and intrauterine death: from politics to policies. AB - Correlation between intrauterine demise (IUD) and social disparity, based on maternal post-code of residence, is assessed in this study in order to find out if there is any correlation between IUD and geographical area. A total of 190 IUD cases from September 2002 to August 2004 were collected retrospectively from the IUD register. The maternity computer health record programme (Terranova Healthware) was used for the assessment of area of residence of the patient and GP, patient demography and pregnancy details. Data were then entered onto a MS Excel spreadsheet and analysed by a public health statistician and a consultant obstetrician using the IMD-Index of Multiple Deprivation and then on to a graph. The results of this study show that there was a strong correlation between the IMD and the distribution of IUDs. Disparities come at a personal, midwifery and obstetric price. Differential access may lead to disparities in quality. PMID- 21823851 TI - Forceps holding the cervix for postpartum haemorrhage. PMID- 21823852 TI - A prospective audit of the quality of documentation of gynaecological operations. AB - There is a paucity of audits in the speciality of Obstetrics and Gynaecology to estimate the standard of documentation of operation notes. Evidence from several audits across all specialities indicates the overall standard of reporting and documentation in medicine is poor, with many reports failing to contain important and pertinent data. Various attempts have been made to address these shortcomings. To estimate the degree of non-compliance in gynaecological practice, we set out to prospectively audit the standard of documentation of operation notes in a busy District General Hospital serving the largest Borough in terms of population in the city of London. An initial prospective audit was carried out in July 2008; and this was re-audited after 12 months using a standardised proforma based on the Royal College of Surgeons of England guidelines. There was evidence of significant improvement with the use of a standardised proforma. PMID- 21823853 TI - How do urogynaecologists treat failed suburethral slings? Experience from the British Society of Urogynaecology database and literature review. AB - Midurethral urethral sling (MUS) procedures have high success and satisfaction rates. A small percentage of MUS operations will fail and most centres have limited experience of treating this outcome. The aim of this study was to review the British Society of Urogynaecology (BSUG) database for women who underwent repeat anti-incontinence surgery after failed MUS. A total of 313 repeat surgical procedures were identified. For any failed MUS, the commonest second surgical intervention was a repeat retropubic MUS and was used in 54% (170/313) of repeat procedures. Bladder neck injections were the second commonest repeat procedure (43/313 cases: 14%). TVT-Os were used as repeat surgery in 12% (38/313) and TOTs in 8% (25/313). Small numbers of colposuspensions (20/313, 6%) and Aldridge slings (6/313, 2%) were also used. A variety of different surgical treatments are used for failed MUSs. From the BSUG database review, the commonest second surgical intervention was a repeat retropubic MUS. PMID- 21823854 TI - Comparison of transobturator tape (TOT) vs Burch method in treatment of stress urinary incontinence. AB - This study aim was to compare the efficacy of transobturator tape (TOT) as a new sling procedure, and Burch colposuspension as the gold standard surgical technique, in the treatment of stress urinary incontinence (SUI). This prospective randomised clinical trial was conducted on 62 women with SUI diagnosed with urodynamic test in Vali-e-Asr Hospital, Tehran, Iran. Patients were allocated into two surgery groups, randomly; TOT and Burch (31 patients in each group). After treatment, they were followed-up for long-term outcome. The average duration of follow-up was 22 and 28 months in the TOT and Burch group, respectively. Operation duration and hospital stay in the TOT group was significantly less than the Burch group (p=0.001). The rate of complete cure, improvement and failure in the TOT group was 90.3%, 9.7% and 0%, respectively, as well as 74.2%, 19.4% and 6.5% in the Burch group. In the TOT group, 90.3% of patients were very satisfied, 6.5% moderately satisfied and 3.2% were less satisfied; none of them were unsatisfied. It is concluded that the TOT procedure is a safe and effective option with less operation time and shorter in-hospital stay for SUI treatment. PMID- 21823855 TI - A series of Advantage suburethral slings. AB - Since the introduction of original tension-free vaginal tape in 1995, a number of different suburethral slings have been marketed. Much of the published literature on midurethral sling procedures relates to the original TVT. Although there has been a considerable number of publications comparing different routes of tape insertion, there is relatively little published identifying the efficacy of different retropubic slings. This study was designed to identify the success rate and complications in a case series of Advantage slings. A total of 70 women were assessed 6 months after insertion of an Advantage midurethral sling by questionnaire. The absence of stress incontinence was reported in 94% of women. There were no intraoperative complications. Only 3% had short-term voiding dysfunction (<6 weeks). De novo overactive bladder symptoms developed in 3% of women. The Advantage sling has a good success rate, with low complications. PMID- 21823856 TI - Inserting the tunneller during an outside-in transobturator tape procedure by syringe-needle guidance. AB - The objective of this study was to determine the feasibility of a novel syringe needle guidance technique (SNG), and its impact on the perioperative variables and outcomes of patients undergoing an outside-in transobturator tape procedure (TOT). Between November 2006 and May 2008, 48 consecutive women who underwent TOT with SNG were included. Another 25 women without SNG between March 2004 and October 2006 were included as a historical control. There were no significant differences in hospital stays and complication rates between the two groups. However, the operating time was shorter (mean 23.0 vs 28.3 min, p=0.008) in the SNG group than in the control group. The presence of the SNG technique was the sole predictor of the operating time (p=0.003). In conclusion, the SNG technique is a feasible method to provide help in inserting the tunneller of TOT through the transobturator foramen, and did not compromise the outcome. PMID- 21823857 TI - Abortion treatment by health professionals in south-eastern Nigeria. AB - Studies assessing the various modes of treatment for abortion and its associated complications remain relevant in the generation of data that will aid policy formulation for abortion management. This descriptive cross-sectional study was undertaken to determine the common methods of, together with the complications associated with, abortion treatment among healthcare practitioners in south eastern Nigeria. There were 230 males and 207 females, with a mean age of 38.23+10.4 years. General practitioners accounted for 214 (49.0%) respondents; nurses, 161 (36.8%); specialist doctors, 56 (12.8%); resident doctors, 5 (1.1%); and community health officers, 1 (0.02%). As high as 388 (88.8%) of the respondents had treated abortion. Manual vacuum aspiration (MVA), and sharp curettage were the commonest methods of treatment accounting for 36.0% and 34.1%, respectively, while medication treatment was employed by 15.0% of the respondents. Only 41.0% of the respondents had been formally trained on the use of MVA. Some 285 (65.2%) of the respondents recorded complications during abortion treatment and these included incomplete evacuation, 30.2%; haemorrhage, 26.0%; and infection, 22.2%. A significantly higher number of complications occurred following sharp metal curretage compared to MVA, and includes incomplete evacuation, 54 (62.5%) vs 33 (38.0%) (p<0.05); and haemorrhage, 32 (43.2%) vs 15 (20.5%) (p<0.05). Syncope, 2 (100%) and uterine perforation, 23 (100%) occurred solely from sharp metal curettage. Building capacity of health professionals on the use of MVA, and ensuring the universal access to the equipment will enable safer abortion treatment and reduce maternal morbidity and mortality from abortion-related complications. PMID- 21823858 TI - Vaginal route for breast cancer induced hysterectomy with oophorectomy. AB - A previous history of breast cancer can induce problems in some women, which may necessitate hysterectomy as well as oophorectomy. This study included 20 women with a history of breast cancer with endometrial hyperplasia and recurrent vaginal bleeding or the need for oophorectomy because of metastatic breast cancer along with concomitant hysterectomy. The aim of this study is to show that benign indications for hysterectomy with oophorectomy, arising out of management of breast cancer in the past, can be dealt with by the least invasive approach via the vaginal route, provided vaginal hysterectomy is not contraindicated and the abdomino-pelvic area is free of metastasis. All 20 women had an uneventful postoperative period with rapid recovery, economic benefit and short hospital stay. PMID- 21823859 TI - Comparing ascitic aspirate and tissue biopsy in the diagnosis of ovarian malignancy. AB - The objective of this retrospective study was to assess the role of tissue biopsy in ovarian cancer where a diagnosis had been made from cytological assessment of ascites. A total of 63 women had been coded for ovarian carcinoma during the period; 48 had undergone cytological or histological investigation, of which six had undergone tissue biopsy, despite having had a cytological diagnosis. In all six cases (100%), the tissue biopsy concurred with the original diagnosis. We conclude that, where a clinically- and radiologically-correlated cytological diagnosis is made, the benefits of an invasive procedure to obtain tissue samples do not outweigh the risks to the patient. PMID- 21823860 TI - Rescue cerclage at 13 weeks' gestation. PMID- 21823861 TI - Phaeochromocytoma in pregnancy can mimic severe hypertensive disorders. PMID- 21823862 TI - Type 2 diabetes identified in pregnancy secondary to Cushing's syndrome. PMID- 21823863 TI - Prenatal diagnosis of extrahepatic umbilicoportosystemic shunt: impact on postnatal management. PMID- 21823864 TI - Uterine rupture following previous uterine compression suture. PMID- 21823865 TI - Successful pregnancy reaching 36 weeks in a patient with previous recurrent uterine ruptures. PMID- 21823866 TI - Term pregnancy with LNG-IUS embedded in the rectal mucosa. PMID- 21823867 TI - Intrauterine death and growth restriction at term, secondary to an umbilical cord amniotic band. PMID- 21823868 TI - Postpartum rupture of ovarian artery. PMID- 21823869 TI - Spontaneous bilateral femoral neck fractures in a young primigravida. PMID- 21823870 TI - The case of the lost Mirena. PMID- 21823871 TI - Primary ectopic breast cancer mimicking as vulval malignancy. PMID- 21823872 TI - Angiomyofibroblastoma of the vulva. PMID- 21823873 TI - Cervical angioleiomyoma. PMID- 21823874 TI - Pre-peritoneal lipoleiomyoma with hyperoestrogenism in a postmenopausal woman. PMID- 21823875 TI - Re: Rohilla M, Raveendran A, Dhaliwal LK, Chopra S. 2010. Severe anaemia in pregnancy: a tertiary hospital experience from northern India. Journal of Obstetrics and Gynaecology 30:694-696. PMID- 21823880 TI - Using the sociological imagination in the interprofessional field. PMID- 21823881 TI - The devil is in the details: the seven deadly sins of organizing and continuing interprofessional education in the US. AB - In spite of increased calls for expanding interprofessional practice (IPP) in the US health care system to address concerns about patient safety and quality of care, there has not been a corresponding dramatic growth in interprofessional education (IPE) programs. Indeed, the history of IPE in the US has been a roller coaster ride of gains and losses, successes and failures. Understanding why this has been so requires the development of a personal and political economy framework, based on an understanding of the structural, ideological, and economic factors and forces that characterize IPE in American higher education. Using a metaphor of the seven deadly sins (lust, pride, greed, gluttony, envy, sloth, and wrath), this discussion focuses on both things that should not be done (sins of commission) and those that should be done but are not (sins of omission) to create successful and sustainable IPE programs. Taken together, these factors help to frame a perspective on IPE that highlights the essential knowledge, attitudes, and skills needed by faculty and administrators to create, implement, and - most importantly - sustain successful programs. Implications of this framework for promoting increased IPE are discussed, particularly with respect to insuring its successful continuation into the future. PMID- 21823882 TI - Neophyte facilitator experiences of interprofessional education: implications for faculty development. AB - The facilitation of learners from different professional groups requires a range of interprofessional knowledge and skills (e.g. an understanding of possible sources of tension between professions) in addition to those that are more generic, such as how to manage a small group of learners. The development and delivery of interprofessional education (IPE) programs tends to rely on a small cohort of facilitators who have typically gained expertise through 'hands-on' involvement in facilitating IPE and through mentorship from more experienced colleagues. To avoid burn-out and to meet a growing demand for IPE, a larger number of facilitators are needed. However, empirical evidence regarding effective approaches to prepare for this type of work is limited. This article draws on data from a multiple case study of four IPE programs based in an urban setting in North America with a sample of neophyte facilitators and provides insight into their perceptions and experiences in preparing for and delivering IPE. Forty-one semi-structured interviews were conducted before (n = 20) and after (n = 21) program delivery with 21 facilitators. Findings indicated that despite participating in a three-fold faculty development strategy designed to support them in their IPE facilitation work, many felt unprepared and continued to have a poor conceptual understanding of core IPE and interprofessional collaboration principles, resulting in problematic implications (e.g. 'missed teachable moments') within their IPE programs. Findings from this study are discussed in relation to the IPE, faculty development and wider educational literature before implications are offered for the future delivery of interprofessional faculty development activities. PMID- 21823886 TI - An essential role for programmed death-1 in the control of autoimmunity: implications for the future of hematopoietic stem cell transplantation. PMID- 21823888 TI - Lyso-thermosensitive liposomal doxorubicin: an adjuvant to increase the cure rate of radiofrequency ablation in liver cancer. AB - Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer death worldwide. No more than 30% of HCC patients are considered suitable for curative treatment because of tumor size and severity of liver impairment, among other factors. Radiofrequency ablation (RFA) monotherapy can cure small (<3 cm) HCC tumors. An adjuvant that interacts synergistically with RFA might enable curative therapy for many HCC patients with lesions >3 cm. Lyso-thermosensitive liposomal doxorubicin (LTLD) consists of the heat-enhanced cytotoxic doxorubicin within a heat-activated liposome. LTLD is infused intravenously prior to RFA. When heated to >39.5 degrees C, LTLD releases doxorubicin in high concentrations into the tumor and the tumor margins. The RFA plus LTLD combination has shown a statistically significant dose-response effect for time to treatment failure in a Phase I trial in which most subjects (62.5%) had tumors >3 cm. RFA plus LTLD is currently being evaluated in a 600-patient randomized, double-blind, dummy controlled trial. PMID- 21823889 TI - Crizotinib: an anaplastic lymphoma kinase inhibitor. AB - Crizotinib is an oral small-molecule inhibitor of ALK and c-Met tyrosine kinases that is being developed by Pfizer. ALK mutations or gene rearrangements result in growth factor-independent ALK activation. Most of the available clinical data with crizotinib are in patients with tumors that have an activated ALK, and the drug has shown very promising clinical benefit in these patients. ALK gene rearrangement occurs in approximately 3-5% of non-small-cell lung cancer patients, most of whom are never- or light smokers and have adenocarcinoma histology. In these patients, crizotinib at a dose of 250 mg twice daily demonstrated a response rate of 56% and a disease control rate of 87% in previously treated patients. The drug is generally well tolerated, with the most common adverse events being nausea, vomiting and some minor visual disturbances that are fleeting. Grade 3/4 elevations in hepatic transaminases occurred in 6% of the patients, which in most patients resolved with dose reduction. Ongoing studies will define the true utility of this drug in ALK-rearranged non-small cell lung cancer patients and in patients with other tumors that also have ALK activation. Preliminary data suggest that the drug may also be active in tumors with an activated c-Met pathway. PMID- 21823890 TI - Diagnosis and local management of breast cancer: part I. AB - This is the first of a two-part conference report and focuses primary on newer technologies (e.g., molecular methods for intraoperative nodal assessment and MRI/PET imaging) and surgical management in the context of neoadjuvant chemotherapy. A notable feature of the Second Kyoto Breast Cancer Consensus Conference was a consensus session for which a series of key clinical questions in the aforementioned areas formed the basis for discussion. Preconference questionnaires had been issued to all delegates and the final consensus sessions focused on more controversial and problematic areas where there is divergence of opinion and clinical management. PMID- 21823891 TI - Diagnosis and local management of breast cancer: part II. AB - This is the second of a two-part conference report and covers the other main themes of the Second Kyoto Breast Cancer Consensus Conference (KBCCC) including ductal carcinoma in situ, sentinel lymph node biopsy and therapeutic algorithms for local management of breast cancer. Once again, this report emphasizes conclusions from the consensus sessions that were a key feature of the KBCCC. PMID- 21823892 TI - Update on novel monoclonal antibodies and immunoconjugates for the treatment of lymphoproliferative disorders. AB - The year 1997 was pivotal in lymphoma research, as it was the year that the US FDA approved rituximab. Rituximab significantly altered clinical management and outcomes of patients with B-cell malignancies. Despite a high initial response rate, the majority of patients subsequently develop variable degrees of therapeutic resistance to rituximab. Research attempting to understand the mechanisms of rituximab resistance and potential ways to overcome them has given rise to the development of novel targeted immunotherapeutics. This article will update the readers on advances in bioengineering of monoclonal antibodies and immunoconjugates that target CD20, as well as other surface antigens. Some additional novel immunotherapeutics, including small modular immunopharmaceuticals, bispecific monoclonal antibodies, T-cell engaging antibodies and immunoconjugates, will also be discussed. PMID- 21823893 TI - Field cancerization in the GI tract. AB - The widely accepted paradigm for tumorigenesis begins with rate-limiting mutations in a key growth control gene resulting in immediate lesion growth. Tumor progression occurs as cells within the tumor acquire additional carcinogenic mutations. However, there is clear evidence that the road to cancer can begin long before the growth of a clinically detectable lesion - indeed, long before any of the usual morphological correlates of preneoplasia are recognizable. Field cancerization, the replacement of the normal cell population by a histologically nondysplastic but protumorigenic mutant cell clone, underlies the development of many cancer types, and in this article we review field cancerization in the GI tract. We present the evidence that field cancerization can underpin tumorigenesis in all gastrointestinal compartments, discuss the homeostatic mechanisms that could permit clone spread and highlight how an understanding of the mechanisms driving field cancerization is a means to study human stem cell biology. Finally, we discuss how appropriate recognition of the role of field cancerization in tumorigenesis could impact patient care. PMID- 21823894 TI - Cancer stem cells in the human mammary gland and regulation of their differentiation by estrogen. AB - The identification and characterization of normal and breast cancer stem cells have provided a new vision of breast tumorigenesis. Cancer stem cells may be responsible for breast tumor initiation, progression and development of resistance to therapy. Most breast cancers express the estrogen receptor, and several studies have linked long-term estrogen exposure to enhanced breast cancer risk; however, estrogen receptor-positive tumors usually present a better prognosis than estrogen receptor-negative ones. The finding that estrogen reduces the pool of human breast stem cells may explain the more differentiated phenotype observed in estrogen receptor-positive tumors. In this article, our current understanding of the complex role of estrogen in human breast stem cells is discussed in the context of breast malignancy. PMID- 21823895 TI - Interaction of natural products with cell survival and signaling pathways in the biochemical elucidation of drug targets in cancer. AB - The use of natural products with therapeutic properties is as ancient as human civilization and for a long time mineral, plant and animal products were the main sources of drugs. Worldwide sales of medicinal plants, crude extracts and finished products amounted to US$15 billion in 1999 and it increased to $23 billion in 2002. More interestingly, the influence of natural products upon anticancer drug discovery and design cannot be underestimated. Approximately 60% of all drugs in clinical trials are either a natural product, compounds derived from natural products or contain pharmacophores derived from active natural products. Thus, even today, in the presence of massive numbers of agents from combinatorial libraries, compounds from natural sources are still in the forefront of cancer chemotherapeutics as sources of active drug types, as well as being involved in drug discovery in diseases such as microbial and parasitic infections and the control of cholesterol/lipids, among other functions. PMID- 21823897 TI - In vitro primary cell culture as a physiologically relevant method for preclinical testing of human oncolytic adenovirus. AB - Ad[I/PPT-E1A] is an oncolytic adenovirus that specifically kills prostate cells via restricted replication by a prostate-specific regulatory element. Off-target replication of oncolytic adenoviruses would have serious clinical consequences. As a proposed ex vivo test, we describe the assessment of the specificity of Ad[I/PPT-E1A] viral cytotoxicity and replication in human nonprostate primary cells. Four primary nonprostate cell types were selected to mimic the effects of potential in vivo exposure to Ad[I/PPT-E1A] virus: bronchial epithelial cells, urothelial cells, vascular endothelial cells, and hepatocytes. Primary cells were analyzed for Ad[I/PPT-E1A] viral cytotoxicity in MTS assays, and viral replication was determined by hexon titer immunostaining assays to quantify viral hexon protein. The results revealed that at an extreme multiplicity of infection of 500, unlikely to be achieved in vivo, Ad[I/PPT-E1A] virus showed no significant cytotoxic effects in the nonprostate primary cell types apart from the hepatocytes. Transmission electron microscopy studies revealed high levels of Ad[I/PPT-E1A] sequestered in the cytoplasm of these cells. Adenoviral green fluorescent protein reporter studies showed no evidence for nuclear localization, suggesting that the cytotoxic effects of Ad[I/PPT-E1A] in human primary hepatocytes are related to viral sequestration. Also, hepatocytes had increased amounts of coxsackie adenovirus receptor surface protein. Active viral replication was only observed in the permissive primary prostate cells and LNCaP prostate cell line, and was not evident in any of the other nonprostate cells types tested, confirming the specificity of Ad[I/PPT-E1A]. Thus, using a relevant panel of primary human cells provides a convenient and alternative preclinical assay for examining the specificity of conditionally replicating oncolytic adenoviruses in vivo. PMID- 21823898 TI - Changes over time in the bacterial communities associated with fluid and food particles and the ruminal parameters in the bovine rumen before and after a dietary change. AB - This work aimed to study the changes over time in the bacterial communities associated with the fluid and food particle fractions of the cow rumen following a change in diet. Four cannulated cows were fed a hay-based diet for 21 days and were then switched to a corn-silage-based diet for 33 days. The bacterial communities were regularly characterized by capillary electrophoresis - single strand conformation polymorphism (CE-SSCP) and qPCR, and the main ruminal parameters were determined. The dietary change led to slight reductions in the diversity index, bacterial concentration, pH, and NH(3)-N concentration, and to an increase in the redox potential and volatile fatty acid concentrations. CE SSCP profiles were not significantly affected by the dietary change but did change over time, with frequent fluctuations in both fluid and food particle fractions before and after the dietary change. The food particle fraction had a higher diversity index of bacterial community (+1.2 points, P < 0.001) and slightly more total bacteria than the fluid fraction of the rumen. PMID- 21823899 TI - The value of clinical case management in a methadone maintenance treatment program. AB - BACKGROUND/OBJECTIVE: This study sought to determine whether case management was positively associated with improved outcomes and treatment compliance in those enrolled in a methadone maintenance treatment (MMT) program. METHODS: An intervention group (n = 396) received case management while the other group (n = 1308) did not. Total N = 1704. RESULTS: Statistically significant reductions were seen in the intervention group, in the proportion of urine samples positive for drugs of abuse (relative risk reduction = -15.4% (95% confidence interval (CI): 17.7, -13.1)), missed daily methadone doses (-1.9% (95% CI: -2.4, -1.4)), and missed physician appointments (-40.1% (95% CI: -43.7, -36.3)). CONCLUSIONS/SCIENTIFIC SIGNIFICANCE: Case management appears to be a very valuable tool in MMT programs. PMID- 21823900 TI - Kidney function and histological damage in autopsy subjects with myocardial infarction. AB - OBJECTIVES: Chronic kidney disease (CKD) is a major risk factor for cardiovascular disease (CVD). We previously reported renal parenchymal damage in autopsy subjects with stroke or abdominal aortic aneurysm. The aim of this study is to evaluate the relationship between renal histology and clinical characteristics of patients with myocardial infarction (MI). METHODS: A total of 699 subjects were autopsied at the National Cerebral and Cardiovascular Center Hospital. We retrospectively evaluated all autopsy cases with MI (n = 123). Estimated glomerular filtration rate (eGFR) was calculated using the Japanese formula. Subjects were classified into four groups: 25 subjects with eGFR >= 60 mL/min/1.73 m(2) and no proteinuria (no CKD), 10 subjects with eGFR >= 60 and proteinuria (CKD1/2), 65 subjects with 60 > eGFR >= 30 (CKD3), and 23 subjects with eGFR < 30 (CKD4/5). Renal parenchymal damage was evaluated using a semi quantitative histological score (score 0-3) for glomerulosclerosis, interstitial fibrosis, tubular atrophy, arteriolar hyalinosis, and arteriosclerosis of medium sized artery (maximum score = 15). RESULTS: The mean histological score was significantly higher in patients with CKD3 and CKD4/5 and was associated with age, hypertension, diabetes, kidney function, proteinuria, and other CVD. CONCLUSIONS: In patients with MI, renal parenchymal damage and deteriorating kidney function are closely associated. PMID- 21823901 TI - The ability of polycyclic aromatic hydrocarbons to alter physiological factors underlying drug disposition. AB - As part of everyday life, people are exposed to polycyclic aromatic hydrocarbons (PAHs). Sources of PAHs include cigarette smoke, ingestion of contaminated food and water or specifically charcoal-grilled meat, and occupational exposure (e.g., the coal industry). PAH compounds are well known to have enzyme-inducing effects, especially on the cytochrome P450 (CYP) family of enzymes, including CYP1A. Enhanced clearance of CYP1A-metabolized drugs as a result of PAH exposure is well established. However, there are examples where PAH-containing sources enhanced the clearance or altered the disposition of some non-CYP1A-metabolized drugs. It has been shown that not only do these compounds induce CYP1A isoforms, but they also can alter the expression of other CYPs, such as 1B1/2 and 2E1, certain phase II enzymes, some transport proteins (in animal models and cell lines), levels of plasma proteins (e.g., alpha1-acid glycoprotein and lipoproteins), and liver mass. Changes in any of these parameters can lead to changes in the biological disposition of a wide variety of drugs by altering either their concentrations in blood or tissues. Identification of patients with elevated enzyme activities or otherwise altered physiological parameters as a consequence of exposure to PAH could serve to lessen the risks and optimize therapeutic benefits of drug therapy. In this article, the pharmacokinetic properties of PAH, the possible mechanisms by which they can alter drug disposition, and specific examples are discussed. PMID- 21823902 TI - Disruption of virus-host cell interactions and cell signaling pathways as an anti viral approach against influenza virus infections. AB - Influenza is still one of the major plagues worldwide with the threatening potential to cause pandemics. In recent years, increasing levels of resistance to the four FDA approved anti-influenza virus drugs have been described. This situation underlines the urgent need for novel anti-virals in preparation for future influenza epidemics or pandemics. Although the anti-virals currently in use target viral factors such as the neuraminidase or the M2 ion channel, there is an increase in pre-clinical approaches that focus on cellular factors or pathways that directly or indirectly interact with virus replication. This does not only include inhibitors of virus-supportive signaling cascades but also interaction blockers of viral proteins with host cell proteins. This review aims to highlight some of these novel approaches that represent a paradigm change in anti-viral strategies against the influenza virus. Although most of these approaches are still in an early phase of preclinical development they might be very promising particularly with respect to the prevention of viral resistance to potential drugs. PMID- 21823903 TI - Utilizing new evidence in the prevention of recurrent preterm birth. AB - OBJECTIVE: Treatments that have proven to be effective in large randomized controlled trials are implemented in clinical practice at varying rates. We measured to what extent new and established strategies were applied to prevent recurrent preterm birth in the Netherlands. METHODS: In two academic hospitals, two non-academic teaching hospitals and two non-academic, non-teaching hospitals, we reviewed charts of all women who had delivered in 2006 and at that time had a history of spontaneous preterm birth before 34 weeks. We compared the application of preventive treatments between different types of hospitals. RESULTS: Ninety one records were identified. In academic centers, screening for bacterial vaginosis and progesterone treatment were applied more often than in other centers (49 vs. 14%, p-value 0.001 and 63 vs. 22%, p-value <0.001, respectively). Cervical length measurement was applied more often in non-academic hospitals (58 vs. 39%, p-value 0.07), but with fewer measurements per patient (average of 3.3 vs. 5.8). CONCLUSION: In the management of women with a history of preterm birth, there is large practice variation. Relatively new treatments such as progesterone injections and screening for bacterial vaginosis are applied more frequently in academic centers, whereas cervical length measurement is more often performed in non-academic hospitals. PMID- 21823904 TI - Fetal congenital heart disease and intrauterine growth restriction: a retrospective cohort study. AB - OBJECTIVE: Fetal congenital heart disease may lead to abnormal fetal growth. Our objective was to estimate the association between fetal congenital heart disease (CHD) and intrauterine growth restriction (IUGR) in an effort to better inform clinical management of continuing pregnancies complicated by fetal congenital heart disease. METHODS: In a retrospective cohort study, outcome data was collected from singleton pregnancies undergoing routine anatomic survey at a tertiary medical center between 1990 and 2008. Dedicated research nurses collected information on delivery outcomes in an on-going manner. Subjects with a prenatal diagnosis of fetal CHD were compared to those without CHD. Stratified analyses for isolated fetal CHD and major CHD were performed. The primary outcome was IUGR less than 10th percentile by the Alexander growth standard. Logistic regression was used to adjust for confounding variables and refine the estimates of risk. RESULTS: Among 67,823 patients, there were 193 cases of fetal CHD (0.3%) and 5,669 cases of IUGR (8.4%). Prenatal diagnosis of CHD was associated with an increased risk of IUGR (23.8% vs. 8.5%, adjusted odds ratio [aOR] 3.3, 95% confidence interval [CI] 2.4-4.6), and the risk was greatest in fetuses with major CHD (16.5% vs. 8.5%, aOR 2.1, 95% CI 1.3-3.2). Isolated CHD was also associated with an increased risk of IUGR (17.8% vs. 8.5%, aOR 2.2, 95% CI 1.4 3.7). CONCLUSION: Patients with a prenatal diagnosis of fetal CHD have a three fold increase in risk of developing IUGR; patients with isolated fetal CHD are twice as likely to develop IUGR. Based on our findings, serial growth assessment may be a reasonable option for patients with fetal CHD diagnosed at routine anatomic survey. PMID- 21823905 TI - Effects of diabetes and ovariectomy on rat hippocampus (a biochemical and stereological study). AB - Oxidative stress is one of the main reasons of both menopause and diabetes. So, it plays crucial role in the pathogeneses of that condition and disease. Therefore, the objective of the present study was to investigate the effects of menopause and diabetes upon the hippocampus using a rat model. Adult female Sprague Dawley rats (n = 24) were allocated randomly as follows; control (C group) ovariectomized (O group), diabetic (D group) and ovariectomy plus diabetic groups (DO group) (n = 6; in each group), respectively. For evaluating the results, tissue biochemistry and stereological analysis were made. Biochemistry results (lipid peroxidase (LPO); catalase (CAT); superoxide dismutase (SOD); total glutatyon (GSH); and myeloperoxidase (MPO) values) in Group C-DO were determined as 12.27, 21.88, 23.08 and 29.90 nmol/gr tissue; 59.3, 70.06, 69.7 and 78.1 mmol/min/mg tissue; 174.2, 156.4, 159.7 and 154.6 mmol/min/mg tissue; 3.63, 3.61, 4.21 and 3.97 nmol/mg tissue; and 5.05, 5.68, 5.58 and 6.19 umol/min/mg tissue, respectively. Moreover, both menopause and diabetes led to change of lipid profiles. There were significant differences between the control and other groups (Group C and D-DO) (p < 0.01) and among experimental groups (p < 0.01) in terms of neuron number. When the volumes of the hippocampus were compared, there were no significant differences between the all groups (P > 0.05). At this point, we suggested that diabetes could aggravate deleterious effects of ovariectomy. PMID- 21823906 TI - Massachusetts' Pediatric Palliative Care Network: successful implementation of a novel state-funded pediatric palliative care program. AB - BACKGROUND: U.S. children with life-limiting illness face barriers to accessing palliative care. In 2006, Massachusetts signed into law a statute providing for the creation and funding of the Pediatric Palliative Care Network (PPCN). This innovative, exclusively state-funded program provides comprehensive direct and consultative community-based pediatric palliative care services including: (1) pain and symptom management, (2) case management and assessment, (3) social services, counseling, and bereavement services, (4) volunteer support services, (5) respite services, and (6) complementary therapies. Provision of care is through a network of state-licensed hospice programs, and an array of professional and volunteer services. OBJECTIVE: To describe Massachusetts' experience in implementing a novel pediatric palliative care program. DESIGN: Enrollment and service trends were identified using Massachusetts Department of Public Health administrative data. Responses to a written family satisfaction survey provided to each family enrolled on PPCN are summarized. RESULTS: In fiscal year 2010, PPCN partnered with 11 hospice programs to provide services to 227 children with life-limiting illness. A total of $680,850 (86.7%) of state funding went to direct contract funds for hospices. Admitting diagnoses included cancer (30%), chromosomal abnormalities (17%), neurodegenerative disorders (15%), and other (38%). There were 11 deaths, 100% of which occurred in the family's requested location. Median length of stay on service prior to death was 233 days. Families most commonly implemented psychosocial and case management services, followed by complementary therapies, and volunteer services. CONCLUSIONS: Successful implementation of a statewide pediatric palliative care program as modeled in Massachusetts is highly feasible at relatively low cost. PMID- 21823907 TI - Patient and provider characteristics associated with the decision of HIV coinfected patients to start hepatitis C treatment. AB - Hepatitis C (HCV) and HIV coinfection is common and liver disease is a leading cause of morbidity and mortality among coinfected patients. Despite advances in HCV treatment, few HIV coinfected patients actually initiate treatment. We examined patient and provider characteristics associated with a patient's decision to accept or refuse HCV treatment once offered. We conducted patient chart abstraction and surveys with 127 HIV coinfected patients who were offered HCV treatment by their provider and surveys of their HCV care providers at three HIV clinics. Participants were mostly male (87%), minority (66%), and had a history of injection drug use (60%). Most had been diagnosed with HIV for several years (X=13.7 years) and reported HIV transmission through unprotected sex (47%). Of the 127 patients, 79 accepted treatment. In multivariate analysis, patients who had a CD4 greater than 200 cells/mm(3) and a provider with more confidence about HCV treatment were more likely to accept the recommendation to start treatment; younger age was marginally associated with treatment acceptance. In bivariate analysis, added correlates of treatment acceptance included male gender, no recent drug use, and several provider attitudes regarding treatment and philosophy about determination of patient treatment readiness. Patient and provider characteristics are important when understanding a patient's decision to start or defer HCV treatment. Further research is needed to better understand barriers to treatment uptake as new and more effective HCV treatments will soon be available. PMID- 21823908 TI - HIV knowledge and attitudes among providers in aging: results from a national survey. AB - Within 5 years, half the U.S. HIV-infected population will be over age 50, and providers caring for older adults must deal with this reality. This study assessed attitudes toward people with HIV/AIDS and knowledge of HIV/AIDS among physicians with a geriatrics specialty, and nurses and social workers who specialize in gerontology. A survey mailed in 2008 to a random sample of U.S. providers yielded a 60% response rate. Main outcome measures included: Knowledge of HIV/AIDS, attitudes toward people with HIV/AIDS, and knowledge of issues related to HIV in older adults. General knowledge of HIV/AIDS was good with scores of 89%, 84%, and 81% for physicians, nurses, and social workers, respectively; groups differed significantly (F(2, 483)=18.626, p<0.0005). Attitudes were positive, with a significant main effect of profession on the attitude subscales (F(4, 952)=6.84, p<0.0005). Eighty-three percent of the sample were unaware that dementia due to HIV may be reversible; no significant differences by profession (chi(2)=4.50, p=0.105). The sample had difficulty ranking the four most common risk factors for HIV infection in older adults, with no significant differences among the professions (F(2, 483)=1.22, p=0.296). Only 6% of the sample correctly ranked all four risk factors. Estimates of the percent of U.S. AIDS cases in people over age 50 varied widely; few answered correctly, with no significant differences by professional group (F(2,319)=2.82, p=0.06). These findings highlight the need for further education among providers who specialize in aging. PMID- 21823909 TI - Barriers to and facilitators of adherence to pediatric antiretroviral therapy in a sub-Saharan setting: insights from a qualitative study. AB - Despite the need for HIV-positive children to adhere effectively to antiretroviral treatment (ART), a guiding theory for pediatric ART in resource limited settings is still missing. Understanding factors that influence pediatric ART adherence is critical to developing adequate strategies. In-depth qualitative interviews were undertaken in Kinshasa, Democratic Republic of the Congo, with 20 sets of HIV disclosed and nondisclosed children along with respective caregivers to better characterize barriers, facilitators, and adherence experiences in children taking ART. Commonly cited barriers included lack of food or nutritional support, lack of assistance or supervision for children, lack of assistance for caregivers, and being unable to remember to take medicines on a consistent basis. Facilitators included having a strong caregiver-child relationship and support system along with strategies for maintaining adherence. Similar themes arose within the child-caregiver sets, but were often characterized differently between the two. Children who were aware of their HIV status displayed fewer instances of frustration and conflict concerning taking medicines and within the child caregiver relationship. Continued study on pediatric ART adherence should account for differing perspectives of children and caregivers, as well as between status disclosed and nondisclosed children. Areas of future intervention should focus on child-caregiver relationships, disclosure of HIV status, and available nutritional and psychosocial support for children and their caregivers. PMID- 21823910 TI - Antipsychotic drug administration does not correlate with prolonged rate corrected QT interval in children and adolescents: results from a nested case control study. AB - BACKGROUND: The rate-corrected QT interval (QTc) prolongation is a risk factor for sudden cardiac death and may be induced by antipsychotic drugs. OBJECTIVE: To determine the clinical characteristics associated with QTc prolongation (440 msec or greater) in children and adolescents hospitalized for treatment of psychiatric disorders. METHOD: We determined the frequency of baseline prolongation of QTc in 811 psychiatric pediatric inpatients (15.5 +/- 2.4 years of age). QTc duration was 440 msec or greater (range 441-481 msec) in 16 patients (1.97%). In a 1:5 nested case-control design, the 16 patients with prolonged QTc were age- and gender-matched with 80 patients with QTc of <421 msec. RESULTS: Patients with normal and prolonged QTc had similar utilization of antipsychotics (43.8% vs. 40.8%) and daily chlorpromazine equivalents (165 +/- 110 vs. 168 +/- 218 mg). Hypokalemia (p = 0.009) and obesity (p = 0.032) were more common among patients with prolonged QTc. The correlation between obesity and QTc prolongation was confirmed in logistic regression analysis. CONCLUSIONS: In a large cohort of youth hospitalized for treatment of psychiatric disorders, a prolonged QTc on admission was rare and correlated with the presence of obesity, but not with current use of antipsychotic drugs. PMID- 21823911 TI - Young mania rating scale line item analysis in pediatric subjects with bipolar I disorder treated with aripiprazole in a short-term, double-blind, randomized study. AB - OBJECTIVE: The aim of this study was to evaluate the effects of aripiprazole treatment on individual Young Mania Rating Scale (YMRS) line items in pediatric subjects with manic or mixed episodes associated with bipolar I disorder to better understand the discrete symptom improvements. METHODS: This was a post hoc analysis of the YMRS line item data from a 4-week, multicenter, randomized, double-blind, placebo-controlled study. Two hundred ninety-six eligible subjects were randomized to aripiprazole 10 mg/day (n = 98), aripiprazole 30 mg/day (n = 99), or placebo (n = 99). The primary endpoint was the mean change in YMRS total scores from baseline to week 4. Effect sizes and treatment effect on individual line items were calculated. RESULTS: Of the 296 subjects, 237 (80.1%) completed the 4-week study. Seven of the 11 YMRS line items showed a statistically significant improvement in both aripiprazole treatment groups versus placebo. Using the data for the pooled doses, the three YMRS line items with the greatest effect size at week 4 were irritability (effect size = 0.7; treatment effect = 1.43; p < 0.001), aggressive behavior (effect size = 0.7; treatment effect = 1.38; p < 0.001), and increased motor activity/energy (effect size = 0.6; treatment effect = 0.86; p < 0.001). CONCLUSION: Aripiprazole improved a broad spectrum of symptoms across the YMRS scale. PMID- 21823912 TI - An open-label study of aripiprazole in children with a bipolar disorder. AB - OBJECTIVE: The purpose of this open-label study was to describe the effectiveness of aripiprazole (APZ) in the treatment of children with bipolar disorders suffering from manic symptomatology. METHOD: Symptomatic outpatients (Young Mania Rating Scale [YMRS] score >=15) meeting strict, unmodified, Diagnostic and Statistical Manual of Mental Disorders, 4th edition, diagnostic symptom criteria for a bipolar disorder, ages 4-9 years, were eligible. Subjects were treated prospectively with flexible doses of APZ (maximum daily dose of 15 mg/day), for up to 16 weeks or until a priori response criteria were met. Outcome measures included the YMRS, Clinical Global Impressions Scale-Severity, Children's Global Assessment Scale (CGAS), and the Children's Depression Rating Scale-Revised (CDRS R). A priori response criteria consisted of 3 of 4 consecutive weeks with (1) CDRS-R <29; (2) YMRS <10; and (3) CGAS >50. RESULTS: Ninety-six children (62 males; mean age of 6.9 (SD = 1.7), received APZ for an average length of treatment of 12.5 (SD = 3.9) weeks. Significant improvements in YMRS, CDRS-R, CGAS, and Clinical Global Impressions Scale-Severity scores (p < 0.001) were noted at the end of study participation. Sixty of the subjects (62.5%) met a priori response criteria at study's end. The most common side effects noted were stomachache, increased appetite, and headache. Two subjects were removed from the study due to side effects [epistaxis (n = 1); akathisia (n = 1)]. Subjects experienced an average weight gain of 2.4 (SD = 1.9) kg. CONCLUSION: APZ may be effective in the acute treatment of symptoms of children with bipolar illnesses. PMID- 21823913 TI - Pyromania associated with escitalopram in a child. PMID- 21823914 TI - The impact of conduct disorder and stimulant medication on later substance use in an ethnically diverse sample of individuals with attention-deficit/hyperactivity disorder in childhood. AB - OBJECTIVE: To examine late adolescent substance use outcomes in relation to childhood conduct disorder (CD) and psychostimulant treatment in urban youth found to have attention-deficit/hyperactivity disorder (ADHD) in childhood. METHODS: Ninety-seven adolescents, evaluated during childhood, were seen for follow-up on average 9.30 (SD = 1.65) years later along with a well-matched never ADHD control group. Stimulant treatment history was coded: Never (n = 28), up to 1 year (n = 19), 1 to 5 years (n = 28), and greater than 5 years (n = 22). Substance use at outcome was coded dimensionally for severity (frequency * intensity) and categorically for substance use disorders (SUDs). RESULTS: Individuals with ADHD+CD in childhood had significantly higher rates of SUD and substance use severity than those with childhood ADHD and controls. The ADHD and control groups did not differ significantly. Among those with childhood ADHD, there were no significant differences in SUD status or substance use severity as a function of medication history. CONCLUSIONS: Within an ethnically diverse urban sample, the increased rate of substance use associated with ADHD was fully accounted for by the presence of CD. These results extend previous findings indicating little impact of psychostimulant treatment on later substance use to an ethnically diverse urban sample and to individuals who received treatment for up to 12 years. PMID- 21823915 TI - Riluzole in autistic disorder. PMID- 21823916 TI - An adolescent with kleptomania and attention-deficit/hyperactivity disorder treated with methylphenidate. PMID- 21823917 TI - A randomized phase I trial of a brief computer-delivered intervention for alcohol use during pregnancy. AB - BACKGROUND: Drinking alcohol during pregnancy has a range of negative consequences for the developing fetus. Screening and brief intervention approaches have significant promise, but their population impact may be limited by a range of challenges to implementation. We, therefore, conducted preliminary acceptability and feasibility evaluation of a computer-delivered brief intervention for alcohol use during pregnancy. METHODS: Participants were 50 pregnant women who screened positive for risky drinking during a routine prenatal clinic visit and were randomly assigned to computer-delivered brief intervention or assessment-only conditions. RESULTS: Ratings of intervention ease of use, helpfulness, and other factors were high (4.7-5.0 on a 1-5 scale). Participants in both conditions significantly decreased alcohol use at follow-up, with no group differences; however, birth weights for infants born to women in the intervention group were significantly higher (p<0.05, d = 0.62). CONCLUSIONS: Further development and study of computer-delivered screening and intervention for alcohol use during pregnancy are warranted. PMID- 21823919 TI - Depot-medroxyprogesterone acetate contraception use among Salvadoran women: an in depth analysis of attitudes and experiences. AB - OBJECTIVE: To survey a cross-section of reproductive-age Salvadoran women in order to assess the factors that influence their decision to use depot medroxyprogesterone acetate (DMPA), an injectable form of contraception. METHODS: Reproductive-age women at three rural Salvadoran health clinics were asked to participate in a study to assess their current and past experiences using DMPA contraception. Verbal informed consent was obtained, and research coordinators administered a 23-question survey. RESULTS: Surveys were completed in 425 women with an average age of 27.36 years. Average duration of DMPA contraception use was 2.89 years. The majority (84%) of past and present users were very satisfied with DMPA contraception, most commonly because they did not have to remember to use it daily (44.9%). The side effects of DMPA appear to be a significant indicator of whether women heard about and wanted to use other forms of long-term reversible contraception, such as an intrauterine device (IUD) or implant. CONCLUSIONS: The main reason Salvadoran women chose to use DMPA is because they do not have to think about it on a daily basis. However, many women do not like the side effects and may be open to explore using other long-term reversible methods of contraception, such as IUDs or implants. It is possible that with increased access to educational information about IUD use, safety, and effectiveness, more women would use this form of long-term contraception as opposed to sterilization. PMID- 21823918 TI - The influence of depression and anxiety on risk of adult onset vulvodynia. AB - BACKGROUND: Studies have shown that women with vulvodynia are more psychologically distressed than women without vulvodynia. These studies, however, have not effectively established temporal associations between diagnosed psychiatric disorders and vulvodynia. METHODS: The Structured Clinical Interview for DSM-IV Axis I Disorders (SCID) was administered to 240 case-control pairs of women with and without vulvodynia. Interviews established age at first onset of diagnosed mood and anxiety disorder. Age information was used to determine whether the first episode of mood and/or anxiety was antecedent or subsequent to the first onset of vulvodynia symptoms. Conditional logistic regressions tested whether antecedent depression or anxiety was more likely among women with or without vulvodynia. Cox proportional hazards modeling was then used to estimate risk of subsequent new or recurrent onset of mood or anxiety disorder. RESULTS: After adjusting for education, race, age at menarche, age at first tampon use, and age at first sexual intercourse, odds of vulvodynia were four-times more likely among women with antecedent mood or anxiety compared to women without (95% confidence interval [CI] 2.1-7.5). Vulvodynia was associated with new or recurrent onset of mood or anxiety disorder after adjustment (hazard ratio [HR] 1.7, 95% CI 1.1-2.6) and did not significantly change after including history of mood or anxiety disorder before the onset of vulvodynia or reference age of controls in the models. CONCLUSIONS: This is the first community-based epidemiologic study demonstrating that DSM-IV-diagnosed antecedent depression and anxiety disorders influence the risk of vulvodynia and that vulvodynia increases the risk of both new and recurrent onset of psychopathology. PMID- 21823920 TI - Sex bias in studies selected for clinical guidelines. AB - OBJECTIVE: To determine the proportions of female participants in research studies selected to inform the development of national clinical guidelines and to assess these against the proportions of women affected by the conditions. METHODS: We assessed 392 published articles, involving a total of 5.2 million participants, cited as references in five influential clinical guidelines addressing the use of antiarrhythmics, chronic fatigue, depression, diabetes, and colorectal cancer. For each article, we extracted the number of female participants to determine any discrepancies in the sex of participants and if the proportion of female participants as research subjects reflected the sex distribution of patients affected by the condition. RESULTS: The overall and median percentages (per study) of females per guideline were: use of antiarrhythmics (35%, median 38%), chronic fatigue (70%, median 73%), colorectal cancer (67%, median 46%), depression (66%, median 66%), and diabetes (63%, median 50%). The baseline prevalence rates used for comparison purposes were (percentage female): antiarrhythmics (60% of patients 75(+) years); chronic fatigue (66%), colorectal cancer (46%), depression (66%), and diabetes (46%). CONCLUSIONS: The colorectal cancer, depression, and chronic fatigue guidelines were based on research populations that accurately reflected the sex distribution of the condition in the general population. Women were slightly overrepresented in the research studies supporting the diabetes guidelines and were significantly underrepresented in the research studies supporting the guidelines on the use of antiarrhythmics. Guideline developers should be aware of and comment on the potential impact of sex. Where the evidence base is lacking, guideline developers should highlight this and, where necessary, limit their specific conclusions to populations on whom the research was performed. PMID- 21823921 TI - Identification of TDRP1 gene and its association with pig reproduction traits. AB - This study was performed to identify and characterize the pig TDRP1 gene and to investigate its association with reproduction traits. The obtained pig TDRP1 cDNA (713 base pair [bp]) comprises a 561-bp open reading frame, which encodes a peptide of 187 amino acids. The identities of pig TDRP1 cDNA were 84.6%, 75.7%, and 77.4% with its counterparts in human, rat, and mice, respectively. Real-time polymerase chain reaction indicated that pig TDRP1 gene was highly expressed in pituitary of male and uterus of female animals. The pig TDRP1 gene contains three exons and two introns. A total of 13 single-nucleotide polymorphisms (SNPs) and 1 indel were identified in the screened partial genomic sequence, with most polymorphisms in introns. Allelic frequencies of five SNPs among eight pig breeds were further investigated, and it indicated that Landrace had the lowest genetic diversity. In Yorkshire, three SNPs (c.215+144T>C, c.215+249A>G, and c.215+672T>C) exhibited complete linkage disequilibrium in one haplotype block, and association analyses showed that all of them were significantly associated with number born alive of first parity (NBA1) (p<0.05). c.215+672T>C was also significantly associated with NBA6 (p<0.05). In addition, these three SNPs and two other ones (c.215+1001G>A and c.215+1026C>T) were associated with total born alive of second parity (TBA2) and TBA6 at the suggestive level (0.05=20 years, selected through a multistage sampling technique. Blood samples were collected after overnight fasting and subjected to biochemical quantification such as fasting blood glucose, triglycerides, and high density lipoprotein cholesterol (HDL-C). Data were analyzed using updated National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) definition by modifying the waist circumference cutoffs as per Asia-Pacific guidelines. RESULTS: Overall metabolic syndrome was observed in 12.0% [95% confidence interval (CI); 8.5-16.8] of the rural women population. Women in the age group >=60 years had the highest prevalence (27.8%), whereas those in the age group 20-39 years had the lowest prevalence (4.2%). At least one component of metabolic syndrome was present in nearly 95% of the study respondents; 41.6% had at least two, 12.0% had at least three, and 2.6% had at least four components of metabolic syndrome. None of the participants had all the five components. CONCLUSION: The current prevalence of metabolic syndrome in women in rural communities of the selected area, although less than that in their urban counterparts, could be a serious problem in the future. It is incumbent on government agencies and the medical community to address this issue to prevent the consequences of its increased burden. PMID- 21823924 TI - A systematic methodology for selecting decontamination strategies following a biocontamination event. AB - Decontamination and recovery of a facility or outdoor area after a wide-area biological incident involving a highly persistent agent (eg, Bacillus anthracis spores) is a complex process that requires extensive information and significant resources, which are likely to be limited, particularly if multiple facilities or areas are affected. This article proposes a systematic methodology for evaluating information to select the decontamination or alternative treatments that optimize use of resources if decontamination is required for the facility or area. The methodology covers a wide range of approaches, including volumetric and surface decontamination, monitored natural attenuation, and seal and abandon strategies. A proposed trade-off analysis can help decision makers understand the relative appropriateness, efficacy, and labor, skill, and cost requirements of the various decontamination methods for the particular facility or area needing treatment- whether alone or as part of a larger decontamination effort. Because the state of decontamination knowledge and technology continues to evolve rapidly, the methodology presented here is designed to accommodate new strategies and materials and changing information. PMID- 21823922 TI - Role of cytokines in the pathogenesis and suppression of thyroid autoimmunity. AB - Autoimmune thyroid diseases (AITD) are one of the most common organ-specific autoimmune disorders, of which Hashimoto's thyroiditis (HT) and Graves' disease (GD) are 2 of the most common clinical expressions. HT is characterized by hypothyroidism that results from the destruction of the thyroid by thyroglobulin specific T cell-mediated autoimmune response. In contrast, GD is characterized by hyperthyroidism due to excessive production of thyroid hormone induced by thyrotropin receptor-specific stimulatory autoantibodies. Cytokines play a crucial role in modulating immune responses that affect the balance between maintenance of self-tolerance and initiation of autoimmunity. However, the role of cytokines is often confusing and is neither independent nor exclusive of other immune mediators. A regulatory cytokine may either favor induction of tolerance against thyroid autoimmune disease or favor activation and/or exacerbation of autoimmune responses. These apparently contradictory functions of a given cytokine are primarily influenced by the nature of co-signaling delivered by other cytokines. Consequently, a thorough understanding of the role of a particular cytokine in the context of a specific immune response is essential for the development of appropriate strategies to modulate cytokine responses to maintain or restore health. This review provides a summary of recent research pertaining to the role of cytokines in the pathogenesis of AITD with a particular emphasis on the therapeutic applications of cytokine modulation. PMID- 21823925 TI - Adverse effects in hospice patients with chronic kidney disease receiving hydromorphone. AB - BACKGROUND: Pain is one the most common symptoms experienced by palliative care patients. The treatment of pain involves the use of strong opioids such as hydromorphone, morphine, methadone, fentanyl, oxycodone, oxymorphone, or levorphanol for moderate to severe pain. Hydromorphone is metabolized by the liver to hydromorphone-3-glucuronide (H3G), a compound that can potentially cause neuroexcitatory phenomena with accumulation. Pharmacokinetic studies have shown that H3G levels in patients with renal insufficiency are 4 times as high as those with normal renal function; however, reports have been conflicting as to whether or not it is safe to use hydromorphone in renal insufficiency. METHODS: In this study we sought to determine the prevalence of neuroexcitation in patients with renal insufficiency who were given hydromorphone, as measured by the glomerular filtration rate (GFR), and to investigate factors associated with increased risk of neuroexcitation in this patient group. For the 12- month period from June 2007 through June 2008, charts of inpatient hospice patients that showed a glomerular filtration rate of <60 (mL/min/1.73 m(2)) and hydromorphone administration for pain control via continuous infusion were reviewed for the occurrence of neuroexcitatory effects, including tremor, myoclonus, agitation, cognitive dysfunction, and seizures. RESULTS: Overall prevalence of neuroexcitatory effects were: tremor 11 (20%), myoclonus 11 (20%), agitation 26 (48%), and cognitive dysfunction 21 (39%). No seizures were observed. No neuroexcitatory effects were observed for the lowest quartile of dose or duration of hydromorphone. There was a strong and graded increase in neuroexcitatory effects with increasing quartile of dose or duration of hydromorphone for agitation (dose, p<0.0001; duration, p<0.0001) and cognitive dysfunction (dose, p<0.0002; duration, p<0.002). Consistent but weaker trends were observed for tremor and myoclonus. CONCLUSION: Parenteral hydromorphone has few neuroexcitatory symptoms until H3G accumulates past a neurotoxic threshold, such as might occur with increasing dose or duration, which, when exceeded, causes neuroexcitatory symptoms to manifest. PMID- 21823926 TI - N-trimethyl chitosan-modified liposomes as carriers for oral delivery of salmon calcitonin. AB - Therapeutic peptide and protein drugs have high specificity and activity in their functions but present challenges in their administration route, requiring development of new delivery systems to improve their bioavailability. The aim of this work was to investigate the role of N-trimethyl chitosan- (TMC-) coated liposomes in the oral administration of calcitonin. TMC with a degree of quaternization around 78% was synthesized and its mucoadhesive properties were examined in vitro using the mucin-particle method, which confirmed that TMC showed mucoadhesion comparable to that of chitosan. TMC-coated liposomes containing calcitonin were prepared and characterized as having a particle size of 262 nm, zeta potential of 35.8 mV and high entrapment efficiency (89.1%). The in vivo evaluation of mucoadhesion was carried out using confocal laser microscopy to observe the residence time and permeation extent after intragastric administration. The results showed that TMC-coated liposomes prolonged the residence time and increased the penetration effect of the liposomal system compared to non-coated liposomes. The study of pharmacological effects confirmed that TMC-coated liposomes increased the area above the blood calcium concentration-time curves (AAC) from 3.13 +/- 20.50 to 448.84 +/- 103.56 compared to the calcitonin solution. These results support the feasibility of TMC-coated liposomes as a new oral delivery system for peptide and protein drugs. PMID- 21823927 TI - The burden of cholera. AB - Cholera is an acute secretory diarrheal disease that is perceived by World Health Organization (WHO) to be a highly contagious threat. Firstly discovered by an Italian physician, Filippo Pacini, the disease gains a reputation as the most feared epidemic diarrheal disease encountered in developing countries. Despite effort taken by WHO to reduce the incidence rate, cholera-endemic prevail in certain regions. Factors that contribute to the disease transmission and ongoing spreading in cholera-prone areas remain as elusive. Should an awareness and knowledge of cholera be developed, it is the residents of developing nation that stand to benefit the most. This review gives insight into the disease prevalence, pandemic, epidemiology, pathogenesis, disease transmission, major strategies and steps to be pursued toward controlling cholera. PMID- 21823928 TI - Reimbursement for EMS response, medical care, and transport. AB - The National Association of EMS Physicians (NAEMSP) believes that emergency medical services (EMS) response, care, and transport should be fairly reimbursed based on the prudent layperson standard. This paper is the official position of the NAEMSP. Key words: EMS; reimbursement; medical care; position statement; NAEMSP. PMID- 21823929 TI - Out-of-hospital lingual dystonia resulting in airway obstruction. AB - This article discusses a case of antipsychotic-induced, focal lingual dystonia causing airway obstruction that was managed completely in the out-of-hospital environment by emergency medical services (EMS) providers. With the ever increasing use of antipsychotic medications by the general population, it is important for EMS providers and emergency medicine physicians to be aware of rare presentations of dystonic reactions that can sometimes be life-threatening when they involve the lingual, pharyngeal, or laryngeal musculature. This article identifies the medications most likely to induce dystonic reactions, risk factors that predispose individuals to the development of dystonia, and the pathophysiology behind these adverse reactions. It also discusses differential diagnoses to consider, and emergent treatment options. PMID- 21823930 TI - The use of epinephrine for out-of-hospital treatment of anaphylaxis: resource document for the National Association of EMS Physicians position statement. AB - Anaphylaxis is a potentially life-threatening condition that requires both prompt recognition and treatment with epinephrine. All levels of emergency medical services (EMS) providers, with appropriate physician oversight, should be able to carry and properly administer epinephrine safely when caring for patients with anaphylaxis. EMS systems and EMS medical directors should develop a mechanism to review the charts of patients who received epinephrine and were not in cardiac arrest. This will help to ensure the safe and appropriate use of epinephrine in order to provide continued quality improvement. Despite the safety of epinephrine, EMS systems that carry epinephrine autoinjectors should establish protocols to deal with patients or emergency responders who have an unintentional injection of epinephrine into the hand or digit. Continued research is needed to better define the role that EMS plays in the management of anaphylaxis. This paper serves as a resource document to the National Association of EMS Physician position on the use of epinephrine for the out-of-hospital treatment of anaphylaxis. Key words: EMS; prehospital; anaphylaxis; epinephrine; intramuscular epinephrine. PMID- 21823931 TI - Mooren's-type ulceration associated with severe hidradenitis suppurativa: a case report and literature review. AB - PURPOSE: To report a case of bilateral Mooren's-type corneal ulcers associated with severe hidradenitis suppurativa. DESIGN: Case report and literature review. METHODS: Detailed clinical course including presentation, medical, and surgical treatment. RESULTS: A 47-year-old African American male with severe hidradenitis suppurativa presented with bilateral Mooren's-type corneal ulcers. His systemic workup was unrevealing. Progression led to bilateral corneal perforations. Systemic immunosuppression and surgical intervention were needed to control his disease. CONCLUSIONS: Severe hidradenitis suppurativa should be considered as a risk factor for Mooren's-type corneal ulcer. PMID- 21823932 TI - Rapid and sustained resolution of serous retinal detachment in Sturge-Weber syndrome after single injection of intravitreal bevacizumab. AB - PURPOSE: To report the effect of a single intravitreal bevacizumab injection on serous retinal detachment (SRD) in Sturge-Weber syndrome (SWS). DESIGN: Interventional case report. METHODS: A 15-year-old boy with history of SWS was referred with a complaint of sudden visual loss 2 days before, having choroidal hemangioma accompanied with SRD. Visual acuity was 20/160. RESULTS: He was treated with 1.25 mg of bevacizumab injected intravitreally. One week later, the retina was completely attached and visual acuity was 20/20. After 20 months, without repeating the injection, the retina remained attached and vision was stable. CONCLUSIONS: An early single dose of intravitreal bevacizumab is effective in the treatment of serous retinal detachment in SWS with good long term results. PMID- 21823933 TI - Pars plana vitrectomy for vitreo-retinal complications of birdshot chorioretinopathy. AB - PURPOSE: To evaluate the anatomical and functional outcomes of pars plana vitrectomy (PPV) in the treatment of vitreoretinal complications of birdshot chorioretinopathy (BCR). METHODS: The clinical records of 9 consecutive patients (16 eyes) with vitreo retinal complications in BCR refractory to medical therapy who underwent pars plana vitrectomy were reviewed. RESULTS: Indications for PPV were macular edema in 9 eyes (56.2%), and persistent vitreous opacities in 7 (43.8%). At a mean postoperative follow-up of 44.1 months, best-corrected visual acuity improved >=2 Snellen lines in 9 eyes (56.2%), remained stable in 6 (37.5%) and worsened in 1 eye (11.1%). Systemic medication was significatively reduced after surgery (p = .020) and macular thickness on optical coherence tomography exams decreased significatively in eyes with macular edema (p= .0039). CONCLUSIONS: In this small series of eyes with limited follow-up PPV seems to be a safe and effective for treatment of vitreoretinal complications in patients with BCR. PMID- 21823934 TI - Presumed tubercular retinal vasculitis with serpiginous-like choroiditis in the other eye. AB - A 17-year old boy, with decreased vision in right eye for 15 days, presented with retinal periphlebitis in multiple quadrants of the right eye and partially active serpiginous-like choroiditis in the left eye. Tuberculin test was positive (16 mm induration), and chest X-ray showed hilar lymphadenopathy. The patient was treated with a 9-month course of anti-tubercular therapy and a tapering dose of oral corticosteroids. Both retinal vasculitis and choroiditis lesions resolved over 3-4 months. Retinal neovascularization in the right eye was treated with laser photocoagulation. There was no recurrence over an 18-month follow-up. The probable pathogenic mechanism for such a presentation is discussed. PMID- 21823935 TI - Survey of expert practice and perceptions of the supporting clinical evidence for the management of uveitis-related cataract and cystoid macular oedema. AB - PURPOSE: To survey the practice of uveitis experts in the management of uveitic cataract and cystoid macular oedema (CMO). METHODS: A structured questionnaire containing two clinical scenarios was sent to members of the International Uveitis Study Group (IUSG). The questionnaire surveyed both respondents' current practice and their perception of the supporting clinical evidence. RESULTS: For uveitic cataract, 70% required a 3-month inflammation-free period before surgery, and 76% gave a prophylactic preoperative systemic corticosteroid. For uveitic CMO, 87% gave corticosteroids, usually orally. Preferred second-line agents were methotrexate (39%), cyclosporin (24%), azathioprine (17%), and mycophenolate (7%). Respondents suggested the evidence underlying their decisions was either absent or relatively weak (levels III or IV), and in most cases personal experience was a factor. CONCLUSIONS: This survey highlights areas of consensus and variation among uveitis experts in managing uveitic cataract and CMO, and emphasizes the need for further clinical trials to establish the best practice. PMID- 21823936 TI - Latency periods between alcohol-related traffic violations: implications for recidivism. AB - OBJECTIVE: Before October 1, 2002, Maryland's regulations for relicensing drivers with 2 recorded alcohol-related traffic violations distinguished between offenders with 5 or more years between their first and second violations and those with less than 5 years. Our research examined whether this policy was supported by differential probabilities of recidivism and violation-free survival. METHODS: We compared recidivism rates and survival probabilities among the 2 latency subgroups and 2 control groups (first offenders and drivers with no previous alcohol-related traffic violation). Data were extracted from Maryland's driver record database and segregated files and analyzed by age quintiles using Cox proportional hazards models containing identifiers for risk factors, including prior violations. All drivers (N = 64,536) were matched on age quintile, gender, and month of offenders' index violations. Effects of violation histories on survival and recidivism probabilities were measured by contrasts of regression coefficients. RESULTS: Among second offenders, the shorter latency subgroup consistently had higher recidivism and lower violation-free survival than the longer latency subgroup, whose rates fell between those of first offenders and the shorter latency subgroup. Although highly significant, the subgroup differences were small and paled by comparison to differences between first and zero offenders in probability of a subsequent violation. CONCLUSIONS: An earlier study that showed similar overall recidivism for these latency subgroups helped encourage Maryland to change its regulations governing license reinstatement. New regulations issued October 1, 2002, focused on 2 alcohol violations "during any period of time" where investigation indicated alcoholism or unaddressed alcohol problems. To obtain relicensure, these offenders could be required to enter or complete a lengthy certified alcohol treatment program. Our current results are consistent with these requirements. License reinstatement should be primarily guided by the extent of alcohol impairment, especially because both latency subgroups showed higher risks of recidivism than first offenders, who themselves had comparatively high risk. PMID- 21823937 TI - A descriptive analysis of the social context of drinking among first-time DUI offenders. AB - OBJECTIVE: To understand the role of social context in contributing to the incidence of alcohol-impaired driving. METHODS: Telephone interviews were conducted with 161 individuals who received a first-time DUI citation. They were predominantly white (70%), male (62%) and 21 to 45 years of age (62%). They were paid $25 for their participation. Questions were asked about their social network, the social context in which they typically drink, the specific location and circumstances where they were drinking at the time of their citation, risky driving behaviors, in the last month as well as the number of traffic tickets they received and crashes they have been involved in since they started to drive. RESULTS: Two reliable social contexts of drinking were identified through principle components factors analysis: emotional pain and social facilitation. Analyses of variance showed that drinking in a context of emotional pain (eg, to deal with depression, stress) was related to drinking alone at this location and driving when they know they have had too much to drink. Drinking in a context of social facilitation (eg, with friends, to be sociable) was related to drinking more frequently and with others (versus alone) at this location. Social facilitation was also positively related to driving over the speed limit and running a red light/stop sign. CONCLUSIONS: The social context of drinking is important for understanding the social network of drinking drivers, because most (86%) said that someone from their social network was with them at this drinking location. The need to understand how significant others influence the context of drinking as well as the likelihood of impaired driving is critical for program development. These results suggest that different types of interventions are needed for offenders depending on their social context of drinking. PMID- 21823938 TI - Teenagers' licensing decisions and their views of licensing policies: a national survey. AB - OBJECTIVE: One objective was to determine teenage licensing rates on a national basis, interest in early licensure, and reasons for delay. A second objective was to learn teenagers' opinions about licensing policies, important in states considering ways to upgrade their current licensing systems. METHODS: One thousand three hundred eighty-three 15- to 18-year-olds completed an online survey in November 2010. They were drawn from a nationally representative panel of US households recruited using probability-based sampling. The panel included cell phone-only households, and Internet access was provided to those without it. Weighting procedures were applied so that the study population represented the national US population of 15- to 18-year-olds. RESULTS: Most teens said that they were interested in getting a license as soon as legally possible, but many had not started the process. At 16, teens were about equally divided among those who had not started, those in the learner stage, and those with a restricted or full license. At 18, 62 percent had full licenses; 22 percent had not started. For those old enough to start, lack of a car, costs, parent availability, ability to get around without a car, and being busy with other activities were leading reasons for delay. The majority of teens were not in favor of higher licensing ages. Forty-six percent thought the minimum learner age should be 16; 30 percent thought the full license age should be 18 or older. The majority approved of night (78%) and passenger (57%) restrictions, and 85 and 93 percent endorsed cell phone and texting bans, respectively. When these policies were packaged together in a single law that included an age 16 start, night, passenger, cell phone and texting bans, and a full license at age 18, 74 percent of teens were in favor. CONCLUSIONS: Teenagers are not as supportive of strong licensing policies as parents of teens, but there is evidence that they will support comprehensive policies likely to lead to further reductions in teen crash rates. PMID- 21823939 TI - Relationship between road traffic accidents and conflicts recorded by drive recorders. AB - OBJECTIVE: Road traffic conflicts can be used to estimate the probability of accident occurrence, assess road safety, or evaluate road safety programs if the relationship between road traffic accidents and conflicts is known. To this end, we propose a model for the relationship between road traffic accidents and conflicts recorded by drive recorders (DRs). METHODS: DRs were installed in 50 cars in Beijing to collect records of traffic conflicts. Data containing 1366 conflicts were collected in 193 days. The hourly distributions of conflicts and accidents were used to model the relationship between accidents and conflicts. To eliminate time series and base number effects, we defined and used 2 parameters: average annual number of accidents per 10,000 vehicles per hour and average number of conflicts per 10,000 vehicles per hour. A model was developed to describe the relationship between the two parameters. RESULTS: If A(i) = average annual number of accidents per 10,000 vehicles per hour at hour i, and E(i) = average number of conflicts per 10,000 vehicles per hour at hour i, the relationship can be expressed as [Formula in text] (alpha>0, beta>0). The average number of traffic accidents increases as the number of conflicts rises, but the rate of increase decelerates as the number of conflicts increases further. CONCLUSIONS: The proposed model can describe the relationship between road traffic accidents and conflicts in a simple manner. According to our analysis, the model fits the present data. PMID- 21823940 TI - Department of Transportation vs self-reported data on motor vehicle collisions and driving convictions for stroke survivors: do they agree? AB - OBJECTIVE: Research on stroke survivors' driving safety has typically used either self-reports or government records, but the extent to which the 2 may differ is not known. We compared government records and self-reports of motor vehicle collisions and driving convictions in a sample of stroke survivors. METHODS: The 56 participants were originally recruited for a prospective study on driving and community re-integration post-stroke; the study population consisted of moderately impaired stroke survivors without severe communication disorders who had been referred for a driving assessment. The driving records of the 56 participants for the 5 years before study entry and the 1-year study period were acquired with written consent from the Ministry of Transportation of Ontario (MTO), Canada. Self-reports of collisions and convictions were acquired via a semistructured interview and then compared with the MTO records. RESULTS: Forty three participants completed the study. For 7 (13.5%) the MTO records did not match the self-reports regarding collision involvement, and for 9 (17.3%) the MTO records did not match self-reports regarding driving convictions. The kappa coefficient for the correlation between MTO records and self-reports was 0.52 for collisions and 0.47 for convictions (both in the moderate range of agreement). When both sources of data were consulted, up to 56 percent more accidents and up to 46 percent more convictions were identified in the study population in the 5 years before study entry compared to when either source was used alone. CONCLUSION: In our population of stroke survivors, self-reports of motor vehicle collisions and driving convictions differed from government records. In future studies, the use of both government and self-reported data would ensure a more accurate picture of driving safety post-stroke. PMID- 21823941 TI - Census study of fatal car-to-car intersection crashes in Sweden involving modern vehicles. AB - OBJECTIVE: Intersections are challenging for many road users. According to US, European, and global statistics, intersection-related crashes with fatal outcome represent approximately 20 percent of all traffic fatalities. The aim of this study was to use Swedish data to investigate and characterize fatal car-to-car intersection crashes for modern cars equipped with frontal and side air bags. METHOD: The Swedish Transport Administration (STA) national database on fatal crashes was searched to find vehicle-to-vehicle intersection crashes involving modern cars that occurred between 2003 and 2009 that resulted in fatal injuries for at least one of the involved passengers. From all intersection crashes, the car-to-car crashes from the sample were analyzed at an occupant level. Occupant location in the target vehicle with respect to impact direction as well as AIS3+ injuries to body regions was examined for the total car-to-car sample. Crashes involving a target vehicle equipped with front and side air bags were then selected for an in-depth study. RESULTS: In the STA database, 39 vehicle-to vehicle crashes matched the search criteria. Of 39 crashes, 17 involved a heavy goods vehicle (HGV) as the striking vehicle, and 17 were car-to-car crashes. All car-to-car crashes were side impacts, occurring at rural intersections, involving 20 (12 female and 8 male) fatally injured occupants, 15 of whom were 61 years or older and classified as senior occupants. A majority of fatally injured occupants sustained combined AIS3+ injuries to more than one body region. CONCLUSIONS: All modern car-to-car crashes with a fatal outcome occurring at Swedish intersections from 2003 to 2009 were side impacts. The crashes were characterized by a senior front seat driver, traveling with a front seat passenger, hit on the left side at approximately 70 km/h. In this study all fatal crashes occurred at severities beyond those currently evaluated in side impact rating procedures but were within survivable limits for a non-senior occupant in a majority of cases. PMID- 21823942 TI - BioRID dummy responses in matched ABTS and conventional seat tests on the IIHS rear sled. AB - OBJECTIVE: This study analyzed matched rear sled tests with all belts to seat (ABTS) and conventional seats from the same vehicle model to determine differences in BioRID IIg dummy responses. METHODS: The BioRID IIg rear impact dummy was placed on ABTS or conventional seats and subjected to 10 mph rear sled tests using the Insurance Institute for Highway Safety (IIHS) whiplash assessment protocol. Measurements in the dummy included head and pelvis triaxial accelerations, T1 and L1 biaxial accelerations, and upper and lower neck triaxial forces and moments. High-speed video captured the dummy and seat kinematics during seat loading and rebound into the lap-shoulder belts. Four vehicles were available with conventional and ABTS seats in the same model. They were the 2007 2008 Chrysler Sebring, 2006 Ford F-150, 2005-2007 Saab 9-3, and 2006-2007 BMW 3 series. Confidence intervals were used to determine significant differences between the matched ABTS and conventional seat responses. RESULTS: Ten sled tests were available for the 4 vehicle models with ABTS and conventional seats. The upper neck rearward shear force was 75 percent higher (range 17%-156%, P < .05) in the matched ABTS compared to conventional seats. The upper neck tension was 44 percent higher (range 24%-94%, P < .05) and the lower neck extension moment was 102 percent higher (range 38%-187%, P < .05). The Saab 9-3 responses were lower than the 3 other vehicles for both the conventional and ABTS seats. There was less rearward shear and extension of the neck in the Saab seats. CONCLUSIONS: The tests show that ABTS seats involved significantly higher neck tensions, rearward shear forces, and extension moments than matched conventional seats. Overall, ABTS seats applied more load on the head and spine, had less control of neck kinematics, and had higher risks for whiplash and more severe injury than conventional seats in the same vehicle model. PMID- 21823943 TI - Dynamic kinematic responses of female volunteers in rear impacts and comparison to previous male volunteer tests. AB - OBJECTIVES: The objective was to quantify dynamic responses of 50th percentile females in rear impacts and compare to those from similar tests with males. The results will serve as a basis for future work with models, criteria, and safety systems. METHODS: A rear impact sled test series with 8 female volunteers was performed at velocity changes of 5 and 7 km/h. The following dynamic response corridors were generated for the head, T1 (first thoracic vertebra) and head relative to T1: (1) accelerations in posterior-anterior direction, (2) horizontal and vertical displacements, (3) angular displacements for 6 females close to the 50th percentile in size. Additionally, the head-to-head restraint distance and contact time and neck injury criterion (NIC) were extracted from the data set. These data were compared to results from previously performed male volunteer tests, representing the 50th percentile male, in equivalent test conditions. T tests were performed with the statistical significance level of .05 to quantify the significance of the parameter value differences for the males and females. RESULTS: At 7 km/h, the females showed 29 percent earlier head-to-head restraint contact time (p = .0072); 27 percent shorter horizontal rearward head displacement (p = .0017); 36 percent narrower head extension angle (p = .0281); and 52 percent lower NIC value (p = .0239) than the males in previous tests. This was mainly due to 35 percent shorter initial head-to-head restraint distance for the females (p = .0125). The peak head acceleration in the posterior-anterior direction was higher and occurred earlier for the females. CONCLUSIONS: The overall result indicated differences in the dynamic response for the female and male volunteers. The results could be used in developing and evaluating a mechanical and/or mathematical average-sized female dummy model for rear impact safety assessment. These models can be used as a tool in the design of protective systems and for further development and evaluation of injury criteria. PMID- 21823944 TI - Necessity of an integrated road traffic injuries surveillance system: a community based study. AB - OBJECTIVES: A prerequisite to improving the situation of traffic accidents and injury prevention is to set up a road traffic accident and victim information system (RTAVIS), which does not exist in Iran. The objective of this study was to compare the 3 major sources of information, including police, emergency medical services (EMS), and hospitals, to show the necessity of an integrated road traffic injury surveillance system. METHOD: This prospective cohort study was performed by pursuing all road traffic accident (RTA) cases during one year (May 2008 to May 2009) within 30 days of their occurrence by a draft questionnaire and data pooling from participating sources. RESULTS: After pooling the data from all organizations, it was revealed that during one year, 245 road traffic accidents occurred in Tehran-Abali route (with a 45-km radius) in which 434 people were either injured or deceased. Out of these crash injuries, police and EMS were unaware of 67 and 51 cases, respectively. In other words, police, pre-hospital emergency services and hospitals reported 56.2, 82.9, and 76.4 percent of the entire number of injuries or deaths, respectively. CONCLUSION: None of the organizations investigated, that is, police, EMS, and health care facilities, have complete records on injuries and deaths caused by traffic accidents. We recommend the formulation and implementation of an integrated and multidisciplinary data collection system of national traffic accidents with the collaboration of police, Ministry of Health and Medical Education (EMS and hospitals), forensic medicine, and the Iranian Red Crescent. PMID- 21823945 TI - The social context of motorcycle riding and the key determinants influencing rider behavior: a qualitative investigation. AB - OBJECTIVE: Given the increasing popularity of motorcycle riding and heightened risk of injury or death associated with being a rider, this study explored rider behavior as a determinant of rider safety and, in particular, key beliefs and motivations that influence such behavior. To enhance the effectiveness of future education and training interventions, it is important to understand riders' own views about what influences how they ride. Specifically, this study sought to identify key determinants of riders' behaviors in relation to the social context of riding, including social and identity-related influences relating to the group (group norms and group identity) as well as the self (moral/personal norm and self-identity). METHOD: Qualitative research was undertaken via group discussions with motorcycle riders (n = 41). RESULTS: The findings revealed that those in the group with which one rides represent an important source of social influence. Also, the motorcyclist (group) identity was associated with a range of beliefs, expectations, and behaviors considered to be normative. Exploration of the construct of personal norm revealed that riders were most cognizant of the "wrong things to do" when riding; among those issues raised was the importance of protective clothing (albeit for the protection of others and, in particular, pillion passengers). Finally, self-identity as a motorcyclist appeared to be important to a rider's self-concept and was likely to influence on-road behavior. CONCLUSION: Overall, the insight provided by the current study may facilitate the development of interventions including rider training as well as public education and mass media messages. The findings suggest that these interventions should incorporate factors associated with the social nature of riding in order to best align it with some of the key beliefs and motivations underpinning riders' on road behaviors. PMID- 21823946 TI - Biomechanical response of ribs under quasistatic frontal loading. AB - OBJECTIVE: The goal of the present study was to identify rib-level differences in fracture characteristics for individual ribs subjected to anterior-posterior loading. METHODS: Twenty-seven individual ribs were extracted from levels 2 to 10 from 3 postmortem human subjects (2 females and one male) and subjected to anterior-posterior loading at a quasistatic (2 mm/s) loading rate. The ribs were placed in a fixture that provided a pinned boundary condition at each extremity, and each specimen was loaded to failure. Reaction force and strains on the internal and external cortical surfaces of the ribs were measured. RESULTS: Rib 2 was found to be 3 to 4 times stiffer than rib 3, whereas all other ribs were comparable in stiffness to rib 3. Fracture forces, fracture displacement, and work to fracture showed no clear rib-level trends, although the young male subject consistently exhibited higher fracture force and work values than the elderly female subjects for a given rib level. The cortical strains on the external surface of the rib remained in tension during the loading, whereas the internal surface strains were in compression. The data from the present study were compared to a similar study performed at dynamic loading rates (1.43-1.85 m/s). The quasistatic tests exhibited lower peak force and greater normalized fracture displacement than the dynamic tests, though the work was comparable between the 2 studies. CONCLUSIONS: The present study is one of the few that focuses on testing the rib as an entire structure and can contribute to understanding of how the structural behavior of an individual rib contributes to the fracture tolerance of the overall thorax when undergoing frontal loading. PMID- 21823947 TI - An analysis of head impact severity in simulations of collisions between pedestrians and SUVs/work utility vehicles, and sedans. AB - OBJECTIVE: To describe the determinants of the severity of the head kinematics of a pedestrian when struck by common sport utility vehicles (SUV) and work utility vehicles (WUVs) to assess how effective assessment protocols are in assessing injury risk for SUVs and work utilities. METHODS: Three hundred twenty-four simulations of pedestrian collisions with SUVs, work utility vehicles, and sedans were performed using several vehicle geometries, pedestrian orientations, speeds, and braking levels. Contact stiffnesses in the models were based on impact test results with exemplar vehicle structures. A single contact characteristic was used for all head-to-hood contacts to allow the effects of other factors on head injury risk to be compared. Simulations of standard headform tests on the same hood characterized the structure from a subsystem test perspective. RESULTS: Head injury criterion values were higher in SUV/WUV simulations than sedan simulations because of high neck tension rather than through higher contact forces with the hood. In fact, the severity of the impact between the head and hood was slightly less in SUV/WUV simulations. Sedan and SUV/WUV simulations produced lower head injury criterion (HIC) values than did the subsystem tests. CONCLUSIONS: High bonnet leading edges led to increased neck loads in these simulations of pedestrian collisions. Neck loads were influential on head injury risk in the SUV/work utility simulations but not in sedan simulations. Subsystem impact tests may overestimate head impact risk from the hood itself but fail to capture a potentially important injury mechanism in collisions with vehicles with high leading edges and thus fail to differentiate completely risks posed by such vehicles. These results may have implications for the interpretation of pedestrian subsystem test results: a given HIC value in an SUV/WUV test may represent a relatively higher risk of injury than the same results recorded in a sedan test. PMID- 21823948 TI - Potential of pedestrian protection systems--a parameter study using finite element models of pedestrian dummy and generic passenger vehicles. AB - OBJECTIVE: To study the potential of active, passive, and integrated (combined active and passive) safety systems in reducing pedestrian upper body loading in typical impact configurations. METHODS: Finite element simulations using models of generic sedan car fronts and the Polar II pedestrian dummy were performed for 3 impact configurations at 2 impact speeds. Chest contact force, head injury criterion (HIC(15)), head angular acceleration, and the cumulative strain damage measure (CSDM(0.25)) were employed as injury parameters. Further, 3 countermeasures were modeled: an active autonomous braking system, a passive deployable countermeasure, and an integrated system combining the active and passive systems. The auto-brake system was modeled by reducing impact speed by 10 km/h (equivalent to ideal full braking over 0.3 s) and introducing a pitch of 1 degree and in-crash deceleration of 1 g. The deployable system consisted of a deployable hood, lifting 100 mm in the rear, and a lower windshield air bag. RESULTS: All 3 countermeasures showed benefit in a majority of impact configurations in terms of injury prevention. The auto-brake system reduced chest force in a majority of the configurations and decreased HIC(15), head angular acceleration, and CSDM in all configurations. Averaging all impact configurations, the auto-brake system showed reductions of injury predictors from 20 percent (chest force) to 82 percent (HIC). The passive deployable countermeasure reduced chest force and HIC(15) in a majority of configurations and head angular acceleration and CSDM in all configurations, although the CSDM decrease in 2 configurations was minimal. On average a reduction from 20 percent (CSDM) to 58 percent (HIC) was recorded in the passive deployable countermeasures. Finally, the integrated system evaluated in this study reduced all injury assessment parameters in all configurations compared to the reference situations. The average reductions achieved by the integrated system ranged from 56 percent (CSDM) to 85 percent (HIC). CONCLUSIONS: Both the active (autonomous braking) and passive deployable system studied had a potential to decrease pedestrian upper body loading. An integrated pedestrian safety system combining the active and passive systems increased the potential of the individual systems in reducing pedestrian head and chest loading. PMID- 21823949 TI - Influence of curbs on traffic crash frequency on high-speed roadways. AB - OBJECTIVE: Curbs are commonly used on roadways for drainage management, access control, and other positive functions. However, curbs may also bring about unfavorable effects on drivers' behavior and vehicle stability when hitting curbs, especially for high-speed roadways. The objective of this article is to investigate whether the presence of curbs along outside shoulders has produced adverse effects on traffic safety on high-speed roadways and whether increasing speed limits has created any further harmful effects. METHODS: In this study, the Illinois Highway Safety Database from 2003 to 2007 was selected to evaluate the effects of curbs over traffic safety on 2-lane and 4-lane non-freeways with speed limits of 45, 50, and 55 mph. Wilcoxon/Kruskal-Wallis nonparametric tests were conducted to compare the road-segment crash rates between 3 types of outside shoulders (curbed shoulder, soft flush shoulder, and hard flush shoulder) and 3 speed limits. In addition, the zero-inflated negative binomial models were developed for all of the roadway segments combined, as well as the curbed outside shoulder-only segments. The models were used to estimate the influences of curbed outside shoulder, speed limit level, as well as other roadway characteristics on crash frequency. RESULTS: It was found that road segments with different types of outside shoulders were from different populations in terms of the distribution of crash rates, so did segments with different speed limits. Further, the crash frequency analysis indicates that the curbed outside shoulders did not induce a higher crash frequency compared to the other 2 types of outside shoulders. In addition, there was no evidence that a decrease in speed limit results in reduction in crash frequencies for road segments with curbed outside shoulders. CONCLUSIONS: The findings of this study suggest that the employment of curbed outside shoulders on high-speed roadways would not pose any significantly harmful effect on the occurrence of crashes, and on high-speed roadways with curbed outside shoulders, reducing the speed limit from 55 to 45 mph would not achieve any safety benefit. PMID- 21823950 TI - Behavioral consequences of conflict-oriented health news coverage: the 2009 mammography guideline controversy and online information seeking. AB - Building on channel complementarity theory and media-system dependency theory, this study explores the impact of conflict-oriented news coverage of health issues on information seeking online. Using Google search data as a measure of behavior, we demonstrate that controversial news coverage of the U.S. Preventive Services Task Force's November 2009 recommendations for changes in breast cancer screening guidelines strongly predicted the volume of same-day online searches for information about mammograms. We also found that this relationship did not exist 1 year prior to the coverage, during which mammography news coverage did not focus on the guideline controversy, suggesting that the controversy frame may have driven search behavior. We discuss the implications of these results for health communication scholars and practitioners. PMID- 21823951 TI - Suicide ideation among college students evidencing subclinical depression. AB - Identifying elevated suicide ideation in college students is a critical step in preventing suicide attempts and deaths by suicide on college campuses. Although suicide ideation may be most prominent in students with severe depression, this should not suggest that only students with severe depression experience significant risk factors for suicide. OBJECTIVE: The purpose of these 3 studies was to explore the relation between suicide ideation and severity of depressive symptoms in college students. PARTICIPANTS: In each study a sample of college students were recruited for participation. METHODS: Participants completed self report assessments of depressive symptoms and suicide ideation. RESULTS: The results of these studies suggest that although the greatest elevation in suicide ideation occurs at the highest depressive symptoms, significant suicide ideation is also experienced by college students with mild and moderate depressive symptoms. CONCLUSIONS: The implications of these findings for the assessment of suicide ideation are discussed. PMID- 21823952 TI - Reporting rape in a national sample of college women. AB - BACKGROUND: Studies indicate that a small percentage of rapes are reported to law enforcement officials. Research also suggests that rapes perpetrated by a stranger are more likely to be reported and that rapes involving drugs and/or alcohol are less likely to be reported. College women represent a unique and understudied population with regard to reporting rape. METHODS: In the current study, the authors interviewed a national sample of 2,000 college women about rape experiences in 2006. RESULTS: Only 11.5% of college women in the sample reported their most recent/only rape experience to authorities, with only 2.7% of rapes involving drugs and/or alcohol reported. Minority status (ie, nonwhite race) was associated with lower likelihood of reporting, whereas sustaining injuries during the rape was associated with increased likelihood of reporting. DISCUSSION: Reporting, particularly for rapes involving drugs and alcohol, is low among college women. Implications for policy are discussed. PMID- 21823954 TI - Examining the relationships between resilience, mental health, and academic persistence in undergraduate college students. AB - OBJECTIVE: In this study, the relationships between measures of interpersonal resilience, intrapersonal resilience, and mental health were examined with respect to academic and social integration, key determinants of academic persistence. PARTICIPANTS: A sample (n = 605) of undergraduate students was recruited from 2 midwestern universities during the 2007-2008 academic year. METHODS: Hierarchal (or sequential) regression analysis examined whether the inter- and intrapersonal resilience and mental health measures contributed to explaining variance in the response variables of university cumulative grade point average (GPA) and university sense of belonging. RESULTS: The intrapersonal resilience factors contributed to explaining variance in cumulative GPA in addition to aptitude and achievement. Furthermore, there was a strong statistical correlation between the inter- and intrapersonal resilience factors and mental health. CONCLUSIONS: The demands in college are significant and there is a need for more research on the concept of resilience as it relates to college health and academic persistence. PMID- 21823953 TI - Self-rated health in relation to rape and mental health disorders in a national sample of college women. AB - OBJECTIVE: The purpose of this study was to employ a multivariate approach to examine the correlates of self-rated health in a college sample of women, with particular emphasis on sexual assault history and related mental health outcomes. PARTICIPANTS: A national sample of 2,000 female college students participated in a structured phone interview between January and June 2006. METHODS: Interview modules assessed demographics, posttraumatic stress disorder, major depressive episode, substance use, rape experiences, and physical health. RESULTS: Logistic regression analyses showed that poor self-rated health was associated with low income (odds ratio [OR] = 2.70), lifetime posttraumatic stress disorder (OR = 2.47), lifetime major depressive episode (OR = 2.56), past year illicit drug use (OR = 2.48), and multiple rape history (OR = 2.25). CONCLUSIONS: These findings highlight the need for university mental health and medical service providers to assess for rape history, and to diagnose and treat related psychiatric problems in order to reduce physical morbidity. PMID- 21823955 TI - Active commuting patterns at a large, midwestern college campus. AB - OBJECTIVE: To understand patterns and influences on active commuting (AC) behavior. PARTICIPANTS: Students and faculty/staff at a university campus. METHODS: In April-May 2008, respondents answered an online survey about mode of travel to campus and influences on commuting decisions. Hierarchical regression analyses predicted variance in walking and biking using sets of demographic, psychological, and environmental variables. RESULTS: Of 898 respondents, 55.7% were female, 457 were students (50.4%). Students reported more AC than faculty/staff. For students, the models explained 36.2% and 29.1% of the variance in walking and biking, respectively. Among faculty/staff, the models explained 45% and 25.8% of the variance in walking and biking. For all models, the psychological set explained the greatest amount of variance. CONCLUSIONS: With current economic and ecological concerns, AC should be considered a behavior to target for campus health promotion. PMID- 21823956 TI - The state of sleep among college students at a large public university. AB - OBJECTIVE: Data about college student sleep were collected and used to develop an education campaign to improve sleep. PARTICIPANTS: On-campus residents at a large state university were surveyed on 4 occasions, October 2005 to April 2007. Sample size was 675 to 1,823 students. Fall 2005 mean age = 18.5 years, SD = 1.03 (range 18-30) years. Initial survey included 935 males and 1,859 females (2005-2006). Matched pairs data (2006-2007) included 91 males and 107 females. Twenty-six males and 22 females participated in interviews. METHODS: A survey administered online included the Pittsburgh Sleep Quality Index, along with an 8-question in person interview. RESULTS: Poor sleep interacted with academics and mental health, and an education campaign positively affected student sleep. CONCLUSIONS: Teaching students how to effectively manage sleep can improve their well-being. Sleep may also be a gateway topic for health care professionals to address sensitive health issues such as depression. PMID- 21823957 TI - Alcohol consumption among university students in North Rhine-Westphalia, Germany- results from a multicenter cross-sectional study. AB - OBJECTIVE: To assess alcohol use and problem drinking among university students in the German Federal State of North Rhine-Westphalia (NRW) and to examine the associated factors. METHOD: A multicenter cross-sectional study was conducted in 16 universities in 2006-2007 in NRW by a standardized questionnaire and 3,306 students provided information (response rate of 88%). Problem drinking was measured by the CAGE questionnaire. RESULTS: Alcohol consumption in the last 3 months was reported by >90 % of students. About 80% reported heavy drinking, and 20% displayed problem drinking. Male students, students living in residence halls, and students from sport faculties had a higher risk of heavy drinking and problem drinking. When students were compared across study years, frequency of heavy drinking decreased with higher semesters. CONCLUSIONS: Overall, heavy drinking and problem drinking are common among university students in this sample. Intervention programs should be designed for students at a particularly high risk. PMID- 21823958 TI - A pilot for improving depression care on college campuses: results of the College Breakthrough Series-Depression (CBS-D) project. AB - OBJECTIVE: To implement a pilot quality improvement project for depression identification and treatment in college health. PARTICIPANTS: Eight college health center teams composed primarily of primary care and counseling service directors and clinicians. METHODS: Chronic (Collaborative) Care Model (CCM) used with standardized screening to identify, treat, and track depressed students for 12 weeks to monitor predetermined process and clinical outcomes. RESULTS: Of all students receiving primary medical care services between January 2007 and May 2008, 69% (n = 71,908) were screened for depression. A total of 801 depressed students were treated and tracked; most predetermined treatment process and clinical outcome targets were achieved. CONCLUSION: The CCM for depression shows promise for improving depression identification and care for college students. PMID- 21823959 TI - US female college students' breast health knowledge, attitudes, and determinants of screening practices: new implications for health education. AB - OBJECTIVE: This study examined female college students' knowledge, attitudes, and breast cancer screening and determined significant predictors of breast self examination, clinical breast examination, and mammography among this population. PARTICIPANTS: A convenience sample of 1,074 college women from 3 universities participated in the research. METHODS: Respondents completed an online version of the Toronto Breast Self-examination Instrument as well as questions developed by the authors. RESULTS: Descriptive statistics showed gaps in college women's knowledge of breast health and negative attitudes toward screening that were relative to age. Multiple linear and logistic regression analyses revealed that knowledge, attitudes, and copay were significant predictors of screening, whereas family history and ethnicity were not. CONCLUSIONS: This study supported previous smaller-sample studies that showed college women to be a priority population for breast health education and revealed new significant factors that should be addressed in health education for this group. PMID- 21823960 TI - An examination of drinkers' consequences by sexual orientation. AB - OBJECTIVE: This study examined college student drinkers by sexual orientation (SO), alcohol use, and negative consequences in a national sample that self identified gender and SO. PARTICIPANTS: Students completing the Spring 2005 National College Health Assessment (N = 54,111). METHODS: A secondary analysis was conducted examining student responses by SO to items regarding negative consequences associated with alcohol. RESULTS: Bisexual students had the highest mean scores on an index of alcohol-related harm. Significant differences were found by SO among male high-risk drinkers for alcohol-related consequences of "fighting" and "injuring another," and females for "injuring another" and "unprotected sex." Bisexual students had significantly greater than expected cell counts for significant results, including a significant finding for bisexual low risk female students for alcohol-related "regret." CONCLUSION: These findings suggest that more research is necessary to discern real differences in alcohol related risk among college students by sexual orientation. PMID- 21823961 TI - Implications for sexual assault prevention: college students as prosocial bystanders. AB - Prosocial bystander interventions are promising approaches to sexual assault prevention on college campuses. OBJECTIVE: To assess bystander attitudes among undergraduate students at a northeastern university. PARTICIPANTS: A convenience sample of 188 students from 4 undergraduate classes was surveyed during regularly scheduled class sessions. METHODS: Participants completed a short survey on bystander efficacy, readiness to change, and barriers to intervention prior to the start of class. RESULTS: The majority of students were not involved in activities or programs focused on sexual assault prevention. Although students agreed that violence could be prevented, they perceived many barriers to their own participation in intervention. CONCLUSIONS: There is a need for gender targeted prevention programming that introduces the idea of prosocial bystander intervention, with a focus on increasing self-efficacy and lowering barriers. PMID- 21823962 TI - Psychotropic drug use among college students: patterns of use, misuse, and medical monitoring. AB - OBJECTIVE: To assess whether college students who use psychotropic drugs are (1) aware of potential side effects, (2) appropriately monitored by prescribing physicians, and (3) taking medications as prescribed. PARTICIPANTS: Fifty-five college students, currently taking psychotropic medications, were recruited between Summer 2008 and Fall 2009. METHODS: Participants were given interviews assessing (1) interactions with prescribing physicians, (2) patterns of psychotropic drug use, and (3) Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV) substance use disorders. RESULTS: Twenty-five percent of participants did not remember being assessed for suicidal ideation. A large number of participants took their medications in different quantities or frequencies than prescribed and 35% of participants met DSM criteria for substance dependence. CONCLUSIONS: Many students are misusing psychotropic medications and this misuse is not being communicated with prescribing physicians. PMID- 21823963 TI - Exercise motivation of college students in online, face-to-face, and blended basic studies physical activity and wellness course delivery formats. AB - OBJECTIVE: The purpose of this study was to assess exercise motivation among college students self-selected into 4 online (OL) and face-to-face (F2F) basic studies' physical activity and wellness course delivery formats. PARTICIPANTS/METHODS: Out of 1,037 enrolled students during the Spring 2009 semester, 602 responded online to demographic questions and to the Behavioural Regulation in Exercise Questionnaire, which assessed exercise motivation on 5 subscales. RESULTS: There were no significant differences (p > .05) in exercise motivation for students across course delivery formats, but there was a significant difference in age and employment status between the completely OL and F2F course formats. CONCLUSIONS: Health and physical educators can utilize these findings to better understand that physical activity and wellness students are not necessarily trying to avoid physical activity when selecting the OL course format, but are more likely trying to balance work and school responsibilities and need greater flexibility in time and location. PMID- 21823964 TI - Special considerations in the treatment of college students with bipolar disorder. AB - Bipolar disorder is a relatively common mental disorder that often has its onset during the college years. This means that students simultaneously face both the challenge of late adolescent development and the challenge of adapting to a major mental illness. As a further complication, the college environment is not well suited to the kinds of lifestyle changes that add stability to the lives of people with bipolar disorder. Treatment involves establishing an alliance, education about lifestyle changes, aiding adaptation to the illness, careful medication to minimize side effects, and loosening the affective constriction that can result from fear of relapse. Both the health care provider and student can use the culture of learning and self-discovery in the college setting to the treatment's benefit. As well, the provider can use the time-limited nature of college to lessen ambivalence about making long-term changes. PMID- 21823965 TI - Tuberculosis screening and targeted testing of college and university students. PMID- 21823966 TI - "Alcohol-related vehicular death rates for college students in the Commonwealth of Virginia". PMID- 21823968 TI - Justifying age thresholds for mammographic screening: an application of pragma dialectical argumentation theory. AB - Information campaigns on breast cancer screening in the Netherlands need to convince women above 50 years of age to have biannual mammography, and women below 50 years of age that regular mammograms are not recommended for them. This article reports the results of two experiments in which the construction of the persuasive messages was informed by argumentation-theoretical insights. No differences were found between either statistical and anecdotal evidence or gain- and loss-framing in the attempt to convince women under 50 that they normally do not need regular mammography. A striking contrast emerged, however, between the overwhelming acceptance of breast cancer screening for women above 50 and the relative restraint and reluctance to consent that mammography is usually not recommended for women under 50. The reluctance to accept that regular mammography is not recommended for women under 50 is traced back to ego involvement. PMID- 21823969 TI - Chronotherapy with valsartan/hydrochlorothiazide combination in essential hypertension: improved sleep-time blood pressure control with bedtime dosing. AB - Administration of angiotensin receptor blockers at bedtime results in greater reduction of nighttime blood pressure than dosing upon awakening, independent of the terminal half-life of each individual medication. To obtain blood pressure (BP) target goals most patients require treatment with more than one hypertension medication. However, the potential differing effects on BP regulation of combination therapy depending on the time-of-day of administration have scarcely been investigated. Accordingly, the authors prospectively evaluated the administration-time-dependent BP-lowering efficacy of valsartan/hydrochlorothiazide (HCTZ) combination therapy. The authors conducted a randomized, open-label, blinded-endpoint trial on 204 subjects with essential hypertension (95 men/109 women), 49.7 +/- 11.1 (mean +/- SD) yrs of age. The BP of participants in this trial was not properly controlled with respect to published ambulatory BP criteria after initially randomized to valsartan monotherapy (160 mg/day), whether routinely ingested upon awakening by one group or at bedtime by another group for 12 wks. Thus, HCTZ (12.5 mg/day) was added to valsartan as a single-pill formulation, maintaining the original treatment-time, i.e., upon awakening or at bedtime, of participants of the two groups, for another 12 wks. BP was measured by ambulatory monitoring for 48 h at inclusion and after each 12-wk span of therapy. Physical activity was simultaneously monitored every minute by wrist actigraphy to accurately define the beginning and end of daytime activity and nocturnal sleep so that the respective BP means for every participant at each evaluation could be precisely determined. Combination therapy resulted in a similar statistically significant reduction of the 48-h BP mean from baseline for both treatment-time groups (17.0/11.5 mm Hg in systolic/diastolic BP after combination therapy on awakening; 17.9/12.1 mm Hg reduction after combination treatment at bedtime; p > .542 between groups). The awake BP mean was reduced to a comparable extent in both treatment-time groups (p > .682). However, bedtime compared to morning dosing better reduced the asleep means of systolic BP (20.1 vs. 16.0 mm Hg; p = .015) and pulse pressure (6.5 vs. 4.0 mm Hg; p = .007 between groups). Accordingly, the proportion of subjects with a baseline non-dipper BP profile was significantly reduced from 59% to 23% only after bedtime combination treatment (p < .001). Moreover, the proportion of subjects with properly controlled ambulatory BP after combination therapy was significantly greater with bedtime than upon-awakening treatment (55 vs. 40%, p = .037). The improved efficacy in lowering the asleep BP mean, increased sleep-time relative BP decline, and greater proportion of controlled patients suggest that valsartan/HCTZ combination should be preferably administered at bedtime for treatment of subjects with essential hypertension requiring combination therapy to achieve proper BP control. PMID- 21823970 TI - Antifungal activity of a Pinus monticola antimicrobial peptide 1 (Pm-AMP1) and its accumulation in western white pine infected with Cronartium ribicola. AB - Pinus monticola antimicrobial peptide 1 (Pm-AMP1) was expressed and purified from bacterial cell lysate and its identity and purity confirmed by Western blot analysis using the Pm-AMP1 antibody. Application of Pm-AMP1 resulted in visible hyphal growth inhibition of Cronartium ribicola , Phellinus sulphurascens , Ophiostoma montium , and Ophiostoma clavigerum 3-12 days post-treatment. Pm AMP1 also inhibited spore germination of several other phytopathogenic fungi by 32%-84% 5 days post-treatment. Microscopic examination of C. ribicola hyphae in contact with Pm-AMP1 showed distinct morphological changes. Seven western white pine ( Pinus monticola Douglas ex D. Don) families (Nos. 1, 2, 5, 6, 7, 8, 10) showing partial resistance to C. ribicola in the form of bark reaction (BR) were assessed by Western immunoblot for associations between Pm-AMP1 accumulation and family, phenotype, canker number, and virulence of C. ribicola. There was a significant difference (p < 0.001) in mean Pm-AMP1 protein accumulation between families, with higher levels detected in the full-sib BR families (Nos. 1, 2, 5) than the half-sib BR families (Nos. 6, 7). Family 8, previously described as a Mechanism 'X' BR family, had the highest number of BR seedlings and displayed high Pm-AMP1 levels, whereas the susceptible family (No. 10) showed the lowest levels (p < 0.05). Family 1 showed a significant association between Pm-AMP1 accumulation and overall seedling health (p < 0.01, R = 0.533), with higher protein levels observed in healthy versus severely infected seedlings. In general, low Pm-AMP1 levels were observed with an increase in the number of cankers per seedling (p < 0.05), and seedlings inoculated with the avirulent source of C. ribicola showed significantly higher Pm-AMP1 levels (p < 0.05) in the majority of BR families. Cis-acting regulatory elements, such as CCAAT binding factors, and an AG-motif binding protein were identified in the Pm-AMP1 promoter region. Multiple polymorphic sites were identified within the 5' untranslated region and promoter regions. Our results suggest that Pm-AMP1 is involved in the western white pine defense response to fungal infection, as observed by its antifungal activity on C. ribicola and a range of phytopathogens as well as through its association with different indicators of resistance to C. ribicola. PMID- 21823972 TI - Effects of radiation quality and oxygen on clustered DNA lesions and cell death. AB - Radiation quality and cellular oxygen concentration have a substantial impact on DNA damage, reproductive cell death and, ultimately, the potential efficacy of radiation therapy for the treatment of cancer. To better understand and quantify the effects of radiation quality and oxygen on the induction of clustered DNA lesions, we have now extended the Monte Carlo Damage Simulation (MCDS) to account for reductions in the initial lesion yield arising from enhanced chemical repair of DNA radicals under hypoxic conditions. The kinetic energy range and types of particles considered in the MCDS have also been expanded to include charged particles up to and including (56)Fe ions. The induction of individual and clustered DNA lesions for arbitrary mixtures of different types of radiation can now be directly simulated. For low-linear energy transfer (LET) radiations, cells irradiated under normoxic conditions sustain about 2.9 times as many double strand breaks (DSBs) as cells irradiated under anoxic conditions. New experiments performed by us demonstrate similar trends in the yields of non-DSB (Fpg and Endo III) clusters in HeLa cells irradiated by gamma rays under aerobic and hypoxic conditions. The good agreement among measured and predicted DSBs, Fpg and Endo III cluster yields suggests that, for the first time, it may be possible to determine nucleotide-level maps of the multitude of different types of clustered DNA lesions formed in cells under reduced oxygen conditions. As particle LET increases, the MCDS predicts that the ratio of DSBs formed under normoxic to hypoxic conditions by the same type of radiation decreases monotonically toward unity. However, the relative biological effectiveness (RBE) of higher-LET radiations compared to (60)Co gamma rays (0.24 keV/MUm) tends to increase with decreasing oxygen concentration. The predicted RBE of a 1 MeV proton (26.9 keV/MUm) relative to (60)Co gamma rays for DSB induction increases from 1.9 to 2.3 as oxygen concentration decreases from 100% to 0%. For a 12 MeV (12)C ion (681 keV/MUm), the 'predicted RBE for DSB induction increases from 3.4 (100% O(2)) to 9.8 (0% O(2)). Estimates of linear-quadratic (LQ) cell survival model parameters (alpha and beta) are closely correlated to the Monte Carlo-predicted trends in DSB induction for a wide range of particle types, energies and oxygen concentrations. The analysis suggests alpha is, as a first approximation, proportional to the initial number of DSBs per cell, and beta is proportional to the square of the initial number of DSBs per cell. Although the reported studies provide some evidence supporting the hypothesis that DSBs are a biologically critical form of clustered DNA lesion, the induction of Fpg and Endo III clusters in HeLa cells irradiated by gamma rays exhibits similar trends with oxygen concentration. Other types of non-DSB cluster may still play an important role in reproductive cell death. The MCDS captures many of the essential trends in the formation of clustered DNA lesions by ionizing radiation and provides useful information to probe the multiscale effects and interactions of ionizing radiation in cells and tissues. Information from Monte Carlo simulations of cluster induction may also prove useful for efforts to better exploit radiation quality and reduce the impact of tumor hypoxia in proton and carbon-ion radiation therapy. PMID- 21823973 TI - Evolving strategies in epidemiologic research on radiation and cancer. PMID- 21823974 TI - Sensitivity of alanine dosimeters with gadolinium exposed to 6 MV photons at clinical doses. AB - In this study we analyzed the ESR signal of alanine dosimeters with gadolinium exposed to 6 MV linear accelerator photons. We observed that the addition of gadolinium brings about an improvement in the sensitivity to photons because of its high atomic number. The experimental data indicated that the addition of gadolinium increases the sensitivity of the alanine to 6 MV photons. This enhancement was better observed at high gadolinium concentrations for which the tissue equivalence is heavily reduced. However, information about the irradiation setup and of the radiation beam features allows one to correct for this difference. Monte Carlo simulations were carried out to obtain information on the expected effect of the addition of gadolinium on the dose absorbed by the alanine molecules inside the pellets. These results are compared with the experimental values, and the agreement is discussed. PMID- 21823976 TI - Effects of 56Fe-particle cranial radiation on hippocampus-dependent cognition depend on the salience of the environmental stimuli. AB - Ionizing radiation reduces the numbers of neurons expressing activity-regulated cytoskeleton-associated protein (Arc) in the hippocampal dentate gyrus (DG). It is currently unclear if that change relates to cognitive function. We assessed the effects of 1 Gy of head-only 56Fe-particle irradiation on hippocampus dependent and hippocampus-independent fear conditioning and determined how those changes related to Arc expression within the DG. Irradiated mice that did not receive tone-shock pairings on day 1 showed less freezing in the same context on a second day and a lower fraction of Arc-expressing neurons in the free (lower) blade of the DG than sham-irradiated mice. Those data suggested reduced hippocampus-dependent spatial habituation learning. Changes in Arc expression in the free blade correlated positively with freezing in mice that did not receive tone-shock pairings. However, irradiated mice that did receive tone-shock pairings showed enhanced contextual freezing but a reduced percentage of Arc expressing neurons in the enclosed (upper) blade. Changes in Arc expression correlated negatively with freezing in mice that received tone-shock pairings. In animals receiving cued fear conditioning, radiation did not affect cognitive performance or the fractions of Arc-expressing neurons. While the relationship between Arc expression and cognitive performance is complex, our data suggest that radiation effects on hippocampus-dependent cognition might depend on the prominence (salience) of environmental stimuli and blade-specific Arc expression. PMID- 21823977 TI - Genes differentially expressed under naphthoquinone-producing conditions in the entomopathogenic fungus Ophiocordyceps unilateralis. AB - The ant-pathogenic fungus Ophiocordyceps unilateralis BCC1869 produces six naphthoquinone (NQ) derivatives. These NQs can be found in fungal-infected ants or produced in culture. Also, the NQs have antibacterial, anticancer, and antimalarial activities and are red pigments with potential for use as natural colorants. Suppressive subtractive hybridization identified genes that were expressed under NQ-producing conditions but not under nonproducing conditions. On potato dextrose agar, the mycelia produced red pigments and secreted them into the medium and as droplets on top of the colony. High-performance liquid chromatography analysis indicated that the red pigment was predominantly erythrostominone with small amounts of its derivatives. For suppressive subtractive hybridization, the cDNA from O. unilateralis cultures on complete medium agar cultures (lacking NQs) were subtracted from those on potato dextrose agar (which produce and secrete NQs). Sixty-six unique expressed sequence tags (ESTs) were identified and include five transporter genes, two transcriptional regulator genes, and several genes in secondary metabolism and biodegradation. The transporter genes include an ATP-binding cassette transporter gene OuAtr1 and a major facilitator superfamily transporter gene OuMfs1. Expression of selected ESTs was further validated using quantitative reverse transcription PCR. Gene expression result indicates that OuAtr1 and OuMfs1 were dramatically upregulated (136- and 29-fold increase, respectively) during the NQ-producing stage compared with the NQ-nonproducing stage. Upregulation of other genes was also detected. This EST collection represents the first group of genes identified from this potential biocontrol agent and includes candidate genes for production and secretion of the red NQs. Roles of these genes could be further determined using a functional analysis. PMID- 21823978 TI - Fungal diversity in activated sludge from membrane bioreactors in Berlin. AB - The objective of this study was to evaluate the occurrence of fungi in aerobic and anoxic activated sludge from membrane bioreactors. Thirty-six samples from each aerobic and anoxic activated sludge were taken from two membrane bioreactors treating domestic wastewater. Over a period of 9 months, four samples from each plant were taken per month. The samples were prepared for count and identification of fungi. Sixty species belonging to 30 genera were collected from activated sludge samples under aerobic and anoxic conditions. In terms of fungal identification, under aerobic conditions Geotrichum candidum was found at 94.4% followed by Penicillium species at 80.6%, yeasts at 75.0%, and Trichoderma species at 50.0%; under anoxic conditions G. candidum at 86.1%, yeasts at 66.6%, and Penicillium species at 61.1% were the most prevalent. The results indicate that activated sludge is a habitat for growth and sporulation of different groups of fungi, both saprophytic and pathogenic. PMID- 21823979 TI - Measurement error in environmental epidemiology and the shape of exposure response curves. AB - Both classical and Berkson exposure measurement errors as encountered in environmental epidemiology data can result in biases in fitted exposure-response relationships that are large enough to affect the interpretation and use of the apparent exposure-response shapes in risk assessment applications. A variety of sources of potential measurement error exist in the process of estimating individual exposures to environmental contaminants, and the authors review the evaluation in the literature of the magnitudes and patterns of exposure measurement errors that prevail in actual practice. It is well known among statisticians that random errors in the values of independent variables (such as exposure in exposure-response curves) may tend to bias regression results. For increasing curves, this effect tends to flatten and apparently linearize what is in truth a steeper and perhaps more curvilinear or even threshold-bearing relationship. The degree of bias is tied to the magnitude of the measurement error in the independent variables. It has been shown that the degree of bias known to apply to actual studies is sufficient to produce a false linear result, and that although nonparametric smoothing and other error-mitigating techniques may assist in identifying a threshold, they do not guarantee detection of a threshold. The consequences of this could be great, as it could lead to a misallocation of resources towards regulations that do not offer any benefit to public health. PMID- 21823980 TI - A randomized, double-blind clinical trial comparing the effects of continuous and pulsed ultrasound in patients with chronic rhinosinusitis. AB - The objective of the present study was to compare the effects of continuous ultrasound (CUS) with pulsed ultrasound (PUS) in patients with chronic rhinosinusitis (CRS). In this prospective, randomized, double-blind, parallel group study, 40 patients (10 losses) with CRS participated. Patients received either continuous or pulsed (1:9) 1 MHz ultrasound (US) using a US head of 1 cm2 at 1 W/cm2 and 0.5 W/cm2 for the maxillary and frontal sinuses, respectively. Treatment was performed in 10 sessions, 3 days per week, with US given every other day. The primary outcome measure was percent improvement in the Sinusitis Symptom Score. Measurements were taken before and after 10 treatment sessions. The patients were followed up monthly for 2 months. After treatment, both groups improved significantly on the Sinusitis Symptoms Score. Patients who received PUS had significantly decreased total symptom scores compared with patients receiving CUS (mean change 9.8 vs. 5.6, p = 0.049). The percent improvement in the Sinusitis Symptom Score between the PUS group (65.2 SD 23.1) and the CUS group (43.9 SD 40.7) was not statistically significant (p = 0.09). The effect size for each treatment was large; PUS: d = 3.92 and CUS: d = 1.93. Symptom improvement in both groups was similar at the 2-month follow-up. These results support the use of therapeutic US for CRS. This pilot study gives only marginal evidence to favor PUS over CUS. PMID- 21823981 TI - Percutaneous nephrolithotripsy in patients with urinary diversions: a case control comparison of perioperative outcomes. AB - PURPOSE: To compare the operative techniques and perioperative outcomes of patients with urinary intestinal diversions undergoing percutaneous nephrolithotripsy (PCNL), to a control cohort of patients without diversions. PATIENTS AND METHODS: The medical records of all patients who were treated with PCNL from 1990 to 2009 were retrospectively reviewed. Each urinary diversion patient's first PCNL was age-matched with four controls who were undergoing PCNL. The perioperative outcomes were compared between the diversion and control cohorts. RESULTS: Twenty-five patients with a urinary diversion who had undergone 33 PCNLs were identified. The mean age was 49.3 (8-85) years for the diversion group and 48.9 (4-84) for the control group. Urinary tract infection (64% vs 15% patients, P<0.0001), neurologic disease (64% vs 2%, P<0.0001), previous procedure for the same calculus (24% vs 4%, P=0.0004), urinary tract abnormalities (56% vs 14%, P<0.0001), solitary kidney (20% vs 3%, P=0.0081), and struvite stones (80% vs 12.5%, P=0.0006) were more commonly observed in the diversion group. Percutaneous access gained by a radiologist (40% vs 0%, P<0.0001), second-look nephroscopy (36% vs 16%, P=0.0466), and an increase in the frequency of fever or sepsis (8% vs 0%, P=0.0387) were identified more frequently in the diversion group. CONCLUSIONS: Patients with upper tract calculi and urinary diversions are challenging to the endourologist because of anatomic factors that can make percutaneous access more difficult; ultrasonography-guided access can be helpful in this setting. Patients with urinary diversions can be treated as safely and effectively by PCNL as nondiverted patients. PMID- 21823982 TI - Laparoendoscopic single-site varicocele repair in adolescents-initial experience at a single institution. AB - BACKGROUND AND PURPOSE: Laparoendoscopic single-site (LESS) varicocele repair is a modification of standard laparoscopic varicocele repair that uses a single port. We describe our initial experience with LESS varicocele repair. PATIENTS AND METHODS: During a 1-year period, all patients who presented for varicocele repair underwent LESS repair. We evaluated our initial experience by determining operative time, operative and postoperative complications, and overall cost of the procedure. RESULTS: A total of 11 adolescents underwent LESS varicocele repair. There were no intraoperative complications, and there were no conversions to open surgery or traditional laparoscopy. Estimated blood loss was minimal, and mean operative time was 66.9 minutes (range 48-91 min). The varicocele was corrected in all cases. During the 4 to 14 month follow-up, there was no recurrence, testis atrophy, or hernia in any patient. One subclinical hydrocele developed postoperatively that has not been repaired. CONCLUSION: Our experience with LESS varicocele repair in adolescents suggests it to be a safe and effective method for varicocele repair in adolescents. PMID- 21823983 TI - Prospective study comparing two techniques of renal clamping in laparoscopic partial nephrectomy: impact on perioperative parameters. AB - PURPOSE: To compare en bloc and artery-only clamping techniques on renal function and perioperative outcomes after laparoscopic partial nephrectomy (LPN). PATIENTS AND METHODS: From March 2003 to December 2008, 205 patients underwent LPN by one surgeon in a single institution. The first 103 LPNs were achieved with artery only clamping (AO), and the last 102 LPNs were realized under control of the renal hilum (artery and vein [AV] clamping). Renal function was evaluated by creatinine changes, estimation of the glomerular filtration rate (eGFR), and assessment of split renal function using renal mercaptoacetyl triglycine-Lasix scintigraphy. Sixty-two of 205 patients had renal scintigraphy before and after surgery. RESULTS: There was no significant difference between the two groups regarding demographic data and renal mass characteristics. Warm ischemia time (WIT) was higher in the AO group: 30.4 +/- 8.2 vs 23.3 minutes +/- 10.0 (P<0.0001). The eGFR change was significantly lower in the AV group during the postoperative period: 10.2 mL/min vs 13.7 mL/min (P=0.0472). Operative blood loss, operative time, and complication rate were not statistically different between groups. Average loss of differential function of the operated kidney was 13.6 +/- 9.2% for the AO group and 14.3 +/- 12.3% for the AV group (P=0.8016). On multivariate analysis, clamping technique was not a predictive factor of renal function reduction. CONCLUSION: AV and AO techniques are associated with similar renal function outcomes in patients who were undergoing LPN. In our series, the AV technique was associated with a lower WIT, an important predictor of decrease in renal function. PMID- 21823984 TI - Polyglyconate unidirectional barbed suture for posterior reconstruction and anastomosis during robot-assisted prostatectomy: effect on procedure time, efficacy, and minimum 6-month follow-up. AB - BACKGROUND AND PURPOSE: With widespread implementation of posterior rhabdosphincter reconstruction (RSR) followed by urethrovesical anastomosis (UVA), reconstruction has become a significant portion of robot-assisted laparoscopic prostatectomy (RALP). Successful anastomosis can be measured by time for reconstruction and the absence of urinary leak. We prospectively evaluated the experience of a single surgeon (KKB) in using the V-LocTM wound closure device for the posterior RSR and UVA, and compared it with a standard reconstruction and anastomosis. PATIENTS AND METHODS: A total of 84 patients divided into two groups underwent RALP, undergoing RSR and UVA using a Van Velthoven technique with the V-Loc or with a standard 3-0 monofilament suture. The primary end point was the time to complete RSR, UVA, and the total reconstruction. As a secondary end point, the clinical evidence of an anastomotic leak was also documented. RESULTS: The mean RSR, UVA, and total times were 9, 18, and 27 minutes for the control group, and 6, 12 and 18 minutes for the V-Loc group, respectively. The time differences between the two groups for RSR, UVA, and total time were 3 minutes (P<0.01), 6 minutes (P<0.01), and 9 minutes (P<0.001), respectively. There was no clinical evidence of anastomotic leak in either group. Continence recovery was equivalent between the groups at 6 weeks and 6 months. At a 9-month follow-up, no patients in either group had a clinical UVA stricture necessitating intervention. CONCLUSIONS: The V-Loc suture is associated with a significantly shorter time for the RSR and UVA compared with the traditional suture and is not associated with a higher incidence of clinical urinary leak; however, a larger randomized study with long-term follow-up is necessary to confirm these results. PMID- 21823985 TI - Intravitreal bevacizumab for retinopathy of prematurity. AB - BACKGROUND: To evaluate the therapeutic effect of a single intravitreal injection of bevacizumab for treatment of threshold retinopathy in retinopathy of prematurity (ROP). METHODS: The retrospective study consisted of all infants who developed threshold ROP in fundus zone I or zone II and who consecutively received an intravitreal injection of bevacizumab (0.375 mg, 0.03 mL) in local anesthesia. RESULTS: Twelve infants (23 eyes) were included into the study. The mean birth weight was 625+/-187 g (mean+/-standard deviation; range: 450-810 g), mean gestational age was 25.1+/-1.4 weeks (range: 24.0-28.7 weeks), mean age at the time of intervention was 38.1+/-3.7 gestational weeks (range: 32.1-45.6 weeks), and mean follow-up was 30.4+/-25.9 weeks. Three children (6 eyes) showed aggressive posterior ROP. After the injection, all eyes showed a regression of plus disease within 2-6 days, a decrease in pupillary rigidity, a resolution of any tunica vasculosa lentis, and a complete regression of the retinal neovascularization within 2-3 weeks. In none of the children a second intravitreal injection of bevacizumab was performed. CONCLUSIONS: A single intravitreal bevacizumab injection of 0.375 mg in 0.03 mL appears to be potentially helpful for the therapy of threshold ROP avoiding side effects of conventional retinal laser coagulation such as irreversible retinal scarring. Long-term effects and side effects may be assessed in future prospective randomized trials. PMID- 21823986 TI - Intravitreal bevacizumab for treatment of macular edema secondary to central retinal vein occlusion: eighteen-month results of a prospective trial. AB - PURPOSE: The purpose of this article was to evaluate the efficacy and safety of intravitreal bevacizumab (Avastin) in eyes with macular edema secondary to central retinal vein occlusion (CRVO). METHODS: Forty-five consecutive eyes with macular edema secondary to CRVO were included in a prospective clinical trial. Eyes were treated with 3 initial intravitreal bevacizumab injections of 1.25 mg at monthly intervals. Retreatment was based on central retinal thickness (CRT) measured by optical coherence tomography (OCT). OCT was performed monthly; fluorescein angiography was performed every 3 months. Main outcome parameters were visual acuity (VA, using the Early Treatment of Diabetic Retinopathy Study protocol) and CRT in an 18-month follow-up period. RESULTS: After 18 months of follow-up, mean VA increased from 40.9 letters at baseline to 61.9 letters (+21 letters; P<0.001) at month 18; CRT decreased from 572.3 MUm at baseline to 273.2 MUm at month 18 (-299.1 MUm; P<0.001). Neither age, duration of CRVO, baseline VA, nor baseline CRT was correlated with the change in VA. No drug-related systemic or ocular side effects were observed following intravitreal bevacizumab treatment. CONCLUSIONS: Intravitreal bevacizumab is generally well tolerated and may improve VA and decrease CRT in patients with macular edema secondary to CRVO over a period of 18 months. PMID- 21823987 TI - Suppression of inflammation by recombinant Salmonella typhimurium harboring CCL22 microRNA. AB - Atopic dermatitis (AD) is an inflammatory, chronically relapsing, puritic skin disorder. These syndromes result from multifactorial inheritance, with interaction between genetic and environmental factors. In particular, the macrophage-derived chemokine CCL22 is directly implicated in skin inflammatory reactions and its levels are significantly elevated in serum and correlated with disease severity in AD. We tested the suppression of the CCL22 gene by microRNA (miRNA) and observed the effects in mice with inflammation similar to AD. We used Salmonella as a vector to deliver miRNA. The recombinant strain of Salmonella typhimurium expressing CCL22 miRNA (ST-miRCCL22) was prepared for in vivo knockdown of CCL22. ST-miRCCL22 was orally inoculated into mice and the CCL22 gene suppressed with CCL22 miRNA in the activated lymphocytes. IgE and interleukin-4 were inhibited and interferon-gamma was induced after treatments with ST-miRCCL22 and CCL22 was suppressed. Further, Th17 cells were suppressed in the atopic mice treated with ST-miRCCL22. These results suggested that suppression of the CCL22 gene using Salmonella induced anti-inflammatory effects. PMID- 21823988 TI - Susceptibility to breast cancer and three polymorphisms of GSTZ1. AB - Glutathione S-transferases class zeta (GSTzeta) is involved in the detoxification of xenobiotic compounds and catalyzes the biotransformation of a variety of alpha haloacids including dichloroacetic acid and chlorofluoroacetic acid. It has been reported that, in mice, deficiency of Gstz1 (a member of GSTzeta) resulted in the generation of a constant level of oxidative stress. The present study was carried out to investigate the association between genetic polymorphisms of GSTZ1 (in promoter site G-1002A and in coding sites Glu32Lys and Gly42Arg) and risk of breast cancer. We included 106 females with breast cancer and 106 healthy females frequency matched for age. The study polymorphisms were not associated with risk of breast cancer (p>0.05). The polymorphisms of GSTZ1 showed strong linkage disequilibrium among cancer patients and control subjects (p<0.0001). There was no significant difference between cancer patients and controls for frequencies of the GSTZ1 haplotypes (p>0.05). It seems there is no meaningful relationship between the genetic polymorphisms of GSTZ1 and risk of breast cancer. PMID- 21823989 TI - Characterization and molecular epidemiology of extended spectrum beta-lactamase producing Enterobacter cloacae isolated from a Tunisian hospital. AB - In 2009, out of the 66 nonrepetitive Enterobacter cloacae collected at Charles Nicolle hospital in Tunisia, 44 were extended spectrum beta-lactamase (ESBL) producers. The aim of the current study was to detect and characterize the genes encoding the ESBLs including blaTEM, blaSHV, and blaCTX-M groups by polymerase chain reaction and sequencing. Pulsed-field gel electrophoresis (PFGE) analysis was used to determine the genetic relatedness between isolates. All strains were susceptible to carbapenems. They were resistant to fluoroquinolones, gentamicin, tobramycin, and trimethoprim+sulfamethoxazole but variably resistant to netilmicin, amikacin, and tetracyclines. Sequence analysis of the polymerase chain reaction products revealed the presence of blaCTX-M-15 (39 strains), blaSHV 12 (6 strains), and blaSHV-27 (1 strain). The coexistence of two ESBLs was observed in two isolates harboring, respectively, SHV-12+CTX-M-15 and SHV-27+CTX M-15. PFGE revealed 36 unrelated profiles. Diffusion of E. cloacae producing CTX M-15 ESBL in our hospital is the consequence of dissemination of identical or related plasmids harboring the CTX-M-15 gene. PMID- 21823991 TI - Physiotherapy for patients following coronary artery bypass graft (CABG) surgery: limited uptake of evidence into practice. AB - The efficacy of physiotherapy techniques used for patients following uncomplicated coronary artery bypass surgery (CABG) is well documented. Previous research showed that some of this evidence was not rapidly adopted into practice by cardiothoracic physiotherapists; however, there has been no recent evaluation of the uptake of evidence. Our aim was to identify current physiotherapy interventions in use for patients following uncomplicated CABG surgery. A survey was sent to senior cardiothoracic physiotherapists from all Australian and New Zealand hospitals that perform CABG surgery. Fifty-four surveys were returned (response rate 88%). The most common treatments used were mobilisation (94% of hospitals), range of motion exercises (79%), deep breathing and/or cough (77%), cardiovascular exercise (42%), and incentive spirometry (40%). Respondents with a bachelor or diploma in physiotherapy were more likely to implement deep breathing exercises or coughing than those who obtained a postgraduate degree (p = 0.045). Respondents perceived personal experience as the most influential factor on postoperative treatment choices. Physiotherapists treating patients following uncomplicated CABG surgery continue to use interventions such as deep breathing exercises that are not supported by best available evidence. Standardised guidelines may be required to better match clinical practice with current literature. PMID- 21823990 TI - Control of neural cell composition in poly(ethylene glycol) hydrogel culture with soluble factors. AB - Poly(ethylene glycol) (PEG) hydrogels are being developed as cell delivery vehicles that have great potential to improve neuronal replacement therapies. Current research priorities include (1) characterizing neural cell growth within PEG hydrogels relative to standard culture systems and (2) generating neuronal enriched populations within the PEG hydrogel environment. This study compares the percentage of neural precursor cells (NPCs), neurons, and glia present when dissociated neural cells are seeded within PEG hydrogels relative to standard monolayer culture. Results demonstrate that PEG hydrogels enriched the initial cell population for NPCs, which subsequently gave rise to neurons, then to glia. Relative to monolayer culture, PEG hydrogels maintained an increased percentage of NPCs and a decreased percentage of glia. This neurogenic advantage of PEG hydrogels is accentuated in the presence of basic fibroblast growth factor and epidermal growth factor, which more potently increase NPC and neuronal expression markers when applied to cells cultured within PEG hydrogels. Finally, this work demonstrates that glial differentiation can be selectively eliminated upon supplementation with a gamma-secretase inhibitor. Together, this study furthers our understanding of how the PEG hydrogel environment influences neural cell composition and also describes select soluble factors that are useful in generating neuronal-enriched populations within the PEG hydrogel environment. PMID- 21823992 TI - Reliability and validity of measurement and associations between disability and behavioural factors in patients with Colles' fracture. AB - The aims of the study were to 1) investigate the test-retest reliability, the internal consistency in instruments that measure behavioural factors and disability as well as to investigate convergent validity between the Disabilities of the Arm, Shoulder, and Hand Outcome Questionnaire (DASH) and the Patient-Rated Wrist Evaluation (PRWE), in patients with Colles' fracture; and 2) assess the relationship between the behavioural measures and the region-specific measures addressing the patient perceptions of impairment, functional loss, and disability. Two samples (sample 1 = 16; sample 2 = 16) of patients with the fracture immobilised in plaster cast were included. The participants answered the Patient-Rated Wrist Evaluation (PRWE), Disabilities of the Arm, Shoulder, and Hand Outcome Questionnaire (DASH), Tampa Scale of Kinesophobia (TSK), Catastrophizing Subscale (CAT) of the Coping Strategies Questionnaire (CSQ), and Self-Efficacy Scale (SES) twice. Test-retest reliability was satisfactory for all instruments. The internal consistency examined with Cronbach's alpha was between 0.68 and 0.97. Because acceptable to good test-retest reliability and internal consistency were demonstrated for the PRWE, DASH, TSK, CAT of the CSQ, and SES, they can be used to detect and monitor fear of movement/(re)injury, catastrophic cognitions, and self-efficacy in patients with radius fracture in the acute and subacute phase. Generally low to moderate correlations were found between behavioural and region-specific measures, indicating that there are two distinct concepts that are not interchangeable. PMID- 21823993 TI - Exercise maintenance: COPD patients' perception and perspectives on elements of success in sustaining long-term exercise. AB - Our goal was to elucidate how patients with COPD who successfully maintain a long term exercise programme understand concordance with maintenance exercise and see potential solutions. The information, collected from 11 individuals through six in-depth interviews and one focus-group interview, was analysed by means of qualitative content analysis. Four themes were identified: (1) perception and acknowledgement of the disease; (2) the personal manner and empowering skills of the therapist; (3) perception of the exercise programme; and (4) left to myself-a pitfall in maintenance. Motivation to continue long-term exercise was related to how the patient is empowered to come to terms with the situation, the relational skills and expert competence of the physiotherapist, the patient's perceived mastery of the intensity of the exercise programme, and the physiotherapist's ability to individualize the exercise, peer support, and the availability and continuity of the programme. More attention should be paid to the link between PR programs and follow-up programmes. Crucial factors in this context are guidance of a municipal physiotherapist or instructor with extensive knowledge of exercise for patients with COPD, social interaction with peers in the exercise setting, enthusiasm, support, and ongoing communication between patients and practitioners across an entire continuum of care. PMID- 21823994 TI - Responses to superficial heating and cooling differ in men and women with knee osteoarthritis. AB - This investigation assessed differences between the response of men and women with knee osteoarthritis to superficial heat, cold, or contrast therapy applied with a water-circulating system or a standard heating pad, and rest. We further analyzed data from a previous study to better understand the influence of gender on the response to treatment based on Knee Injury and Osteoarthritis Outcome Score (KOOS) subscales and a visual analog pain scale (VAS). Using a within subject, randomized order design, 34 patients received each treatment in 1-week blocks. A KOOS questionnaire and VAS were completed at baseline and twice each week. Women were more likely to report clinically meaningful improvement in pain and symptoms on the KOOS with the use of heat, cold, and a heating pad. There were no significant differences in response to treatment between men and women for the function-daily living and quality of life subscales or percent pain reduction on the VAS. Men and women reported improved quality of life with intervention. Women are more likely to report clinically meaningful improvement in pain and symptoms associated with knee OA following the use of superficial heat, cold, or a heating pad than men. PMID- 21823995 TI - Gene expression patterns of insulin-like growth factor 1, insulin-like growth factor 2 and insulin-like growth factor binding protein 3 in human placenta from pregnancies with intrauterine growth restriction. AB - INTRODUCTION: In this study, we compared insulin-like growth factor (IGF)-gene expression patterns and characteristics of glucose and insulin metabolism in human placenta from pregnancies with or without intrauterine growth restriction (IUGR). MATERIALS AND METHODS: We compared 101 human placentas from intrauterine growth restriction pregnancies to those of 140 normal pregnancies treated at our department in a one-year period. We have also assessed the serum glucose and insulin levels of the IUGR and control groups. Several possible predicting factors of IUGR were also investigated. RESULTS: Risk for IUGR was suggested by gestational weight gain and gestational increase in maternal body mass index (BMI) as well as maternal birthweight. In pregnancies without IUGR, umbilical cord glucose and insulin levels were significantly higher than in pregnancies with IUGR. In placentas from pregnancies with IUGR an overexpression of the IGF-2 and the insulin-like growth factor binding protein (IGFBP)-3 genes was found. In placentas from pregnancies with male fetal gender we found a significant overexpression of the IGF-2 gene. DISCUSSION: Gestational weight gain and BMI increase seem to predict the development of IUGR. Insulin and carbohydrate metabolism are also impaired in IUGR fetuses. In the placentas from pregnancies with IUGR, IGF-2 is overexpressed reflecting its physiological role in optimizing energy distribution in a low-energy environment. PMID- 21823996 TI - Preserved autonomic regulation in patients undergoing transcatheter aortic valve implantation (TAVI): a prospective, comparative study. AB - Heart rate and blood pressure variability as well as baroreflex sensitivity (BRS) lead to additional insights on the patients' prognosis after cardiovascular events. The following study was performed to assess the differences in the postoperative recovery of the autonomic regulation after transcatheter aortic valve implantation (TAVI) and surgical aortic valve replacement (SAVR). Fifty eight consecutive patients were enrolled in a prospective study; 24 underwent TAVI and 34 SAVR. BRS was calculated according to the Dual Sequence Method, heart rate variability (HRV) was evaluated using standard linear as well as nonlinear parameters. HRV and BRS parameters were reduced after surgery in patients with SAVR only (meanNN: p<0.001, sdNN: p<0.05, Shannon: p<0.01, BRS: p<0.01), while these indexes were preserved in patients after TAVI. Simultaneously, an increased complexity of blood pressure (BP) in SAVR patients (fwShannon: p<0.001, fwRenyi4: p<0.001), but not in TAVI patients was recorded. In this study we were able to demonstrate for the first time that, in contrast to patients undergoing conventional open surgery, there are fewer alterations of the cardiovascular autonomic system in patients with TAVI. PMID- 21823997 TI - Cardiovascular regulation in different sleep stages in the obstructive sleep apnea syndrome. AB - Heart rate and blood pressure variability analysis as well as baroreflex sensitivity have been proven to be powerful tools for the assessment of autonomic control in clinical practice. Their ability to detect systematic changes caused by different states, diseases and treatments shall be shown for sleep disorders. Therefore, we consider 18 normotensive and 10 hypertensive patients suffering from obstructive sleep apnea syndrome (OSAS) before and after a three-month continuous positive airway pressure (CPAP) therapy. Additionally, an age and sex matched control group of 10 healthy subjects is examined. Linear and nonlinear parameters of heart rate and blood pressure fluctuation as well as the baroreflex sensitivity are used to answer the question whether there are differences in cardiovascular regulation between the different sleep stages and groups. Moreover, the therapeutic effect of CPAP therapy in OSAS patients shall be investigated. Kruskal-Wallis tests between the sleep stages for each group show significant differences in the very low spectral component of heart rate (VLF/P: 0.0033-0.04 Hz, p<0.01) which indicates differences in metabolic activity during the night. Furthermore, the decrease of Shannon entropy of word distribution as a parameter of systolic blood pressure during non-REM sleep reflects the local dominance of the vagal system (p<0.05). The increased sympathetic activation of the patients leads to clear differences of cardiovascular regulation in different sleep stages between controls and patients. We found a significant reduction of baroreflex sensitivity in slow wave sleep in the OSAS patients (Mann-Whitney test, p<0.05) compared to controls, which disappeared after three months of CPAP therapy. Hence, our results demonstrate the ability of cardiovascular analyzes to separate between healthy and pathological regulation as well as between different severities of OSAS in this retrospective study. PMID- 21823998 TI - Analysis of nocturnal pulse oximetry in sleep medicine. AB - Oxygen saturation obtained from nocturnal pulse oximetry is a significant evaluation parameter for sleep related breathing disorders, especially in the diagnosis of the obstructive sleep apnea syndrome (OSA). Today clinical interpretation relies mainly on the number of desaturation events per hour (oxygen desaturation index, ODI). In this study various alternatives were established and their applicability for OSA screening was evaluated. The discussed methods include time-based approaches (Delta-index), non-linear analysis (central tendency measure, approximate entropy), and spectral methods (Welch transform, wavelet transform). When applied to 192 data sets (132 male, 60 female, 47.9+/-15.5 years, BMI 27.4+/-6.5 kg/m(2)) these methods showed good correlation with clinical findings. When discriminating between non-OSA and OSA patients the approaches under investigation yield sensitivity values between 96.6% and 100% and specificity values between 97.4% and 100%. Particularly spectral methods could provide parameters for an optimized OSA screening based on nocturnal pulse oximetry. PMID- 21823999 TI - Analysis on subtracting projection of extracted independent components from EEG recordings. AB - Event-related potentials of electroencephalography (EEG) recordings can be assumed as mixtures of sources of electrical brain activities. To reject artifact sources, the projection of the estimated counterpart by independent component analysis (ICA) is often subtracted from EEG recordings. However, the association of performance of ICA decomposition and the subtraction has never been analyzed before. Coincidently, we find that a source can be completely removed from EEG recordings through the subtraction theoretically. The necessary condition of such results is that the estimated ICA model for every source should be entirely correct, that is, each estimated source is just the scaled version of one source. Meanwhile, we also find that the subtraction cannot sufficiently reject one source practically. This is because the estimated ICA model for some sources is inevitably incorrect, that is, some estimated sources are still the mixture of a few sources. To improve the accuracy of the subtraction, it is first necessary to develop better ICA algorithms to separate mixtures as sufficiently as possible and secondly it is necessary to modify the abnormal polarity of the projection of the estimated source in the electrode field. Numerical simulations validate the effectiveness of the modification on the abnormal polarity in rejecting one source. PMID- 21824000 TI - Surface-enhanced Raman scattering using silver nanocluster on anodic aluminum oxide template sensor toward protein detection. AB - The affordable surface-enhanced Raman scattering (SERS) substrates, with a structure consisting of densely distributed round-shape silver nanoclusters on anodic aluminum oxide (AAO) template, is fabricated by magnetron sputtering and anodization processes. The physical investigations show that the silver nanoclusters with size distribution ranging from 10 to 30 nm uniformly distributed on the top and in the bottom of the AAO nanochannels. The SERS activities from adsorbed probe molecules, i.e., methylene blue, on the SERS substrate surface indicate a high Raman enhancement factor for trace organic analysis. The SERS substrate is successfully utilized in the detection of a trace amount of three different proteins, bovin serum albumin, immunoglobulin G, and cardiac troponin T, also adsorbed on the substrate surface. Several spectral bands containing important molecular structures of these proteins are clearly observed and identified. The obtained results indicated a step forward to label free biomolecular detections in chip-based biosensors. PMID- 21824001 TI - Highlight on septins. PMID- 21824002 TI - New insights into the phylogenetic distribution and evolutionary origins of the septins. AB - Until recently, it had appeared that the septin family of proteins was restricted to the opisthokont eukaryotes (the fungi and animals and their close relatives the microsporidia and choanoflagellates). It has now become apparent that septins are also present in several other widely divergent eukaryotic lineages (chlorophyte algae, brown algae, and ciliates). This distribution and the details of the non-opisthokont septin sequences appear to require major revisions to hypotheses about the origins and early evolution of the septins. PMID- 21824004 TI - Septin9 is involved in septin filament formation and cellular stability. AB - Septin9 (Sept9) is a member of the filament-forming septin family of structural proteins and is associated with a variety of cancers and with hereditary neuralgic amyotrophy. We have generated mice with constitutive and conditional Sept9 knockout alleles. Homozygous deletion of Sept9 results in embryonic lethality around day 10 of gestation whereas mice homozygous for the conditional allele develop normally. Here we report the consequences of homozygous loss of Sept9 in immortalized murine embryonic fibroblasts. Proliferation rate was not changed but cells without Sept9 had an altered morphology compared to normal cells, particularly under low serum stress. Abnormal, fragmented, and multiple nuclei were more frequent in cells without Sept9. Cell migration, as measured by gap-filling and filter-invasion assays, was impaired, but individual cells did not move less than wild-type cells. Sept9 knockout cells showed a reduced resistance to hypo-osmotic stress. Stress fiber and vinculin staining at focal adhesion points was less prominent. Long septin filaments stained for Sept7 disappeared. Instead, staining was found in short, often curved filaments and rings. Furthermore, Sept7 was no longer localized to the mitotic spindle. Together, these data reveal the importance of Sept9 for septin filament formation and general cell stability. PMID- 21824005 TI - Lethal phenotype of mice carrying a Sept11 null mutation. AB - Septins are cytoskeletal GTP-binding proteins involved in processes characterized by active membrane movement, such as cytokinesis, vesicle trafficking and exocytosis. Most septins are expressed ubiquitously, however, some septins accumulate in particular tissues. The ubiquitous SEPT11 also shows high expression levels in the central nervous system and in platelets. Here, SEPT11 is involved in vesicle trafficking and may play a role in synaptic connectivity. Interestingly, mice that harbor a homozygous Sept11 null mutation, die in utero. From day 11.5 post coitum onwards, development of homozygous embryos seems to be retarded and the embryos from day 13.5 onwards were dead. PMID- 21824003 TI - Genetic interactions with mutations affecting septin assembly reveal ESCRT functions in budding yeast cytokinesis. AB - Membrane trafficking via targeted exocytosis to the Saccharomyces cerevisiae bud neck provides new membrane and membrane-associated factors that are critical for cytokinesis. It remains unknown whether yeast plasma membrane abscission, the final step of cytokinesis, occurs spontaneously following extensive vesicle fusion, as in plant cells, or requires dedicated membrane fission machinery, as in cultured mammalian cells. Components of the endosomal sorting complexes required for transport (ESCRT) pathway, or close relatives thereof, appear to participate in cytokinetic abscission in various cell types, but roles in cell division had not been documented in budding yeast, where ESCRTs were first characterized. By contrast, the septin family of filament-forming cytoskeletal proteins were first identified by their requirement for yeast cell division. We show here that mutations in ESCRT-encoding genes exacerbate the cytokinesis defects of cla4Delta or elm1Delta mutants, in which septin assembly is perturbed at an early stage in cell division, and alleviate phenotypes of cells carrying temperature-sensitive alleles of a septin-encoding gene, CDC10. Elevated chitin synthase II (Chs2) levels coupled with aberrant morphogenesis and chitin deposition in elm1Delta cells carrying ESCRT mutations suggest that ESCRTs normally enhance the efficiency of cell division by promoting timely endocytic turnover of key cytokinetic enzymes. PMID- 21824006 TI - ARTS, the unusual septin: structural and functional aspects. AB - The human Septin 4 gene (Sept4) encodes two major protein isoforms; Sept4_i1 (H5/PNUTL2) and Sept4_i2/ARTS. Septins have been traditionally studied for their role in cytokinesis and their filament-forming abilities, but subsequently have been implicated in diverse functions, including membrane dynamics, cytoskeletal reorganization, vesicle trafficking, and tumorigenesis. ARTS is localized at mitochondria and promotes programmed cell death (apoptosis). These features distinguish ARTS from any other known human septin family member. This review compares the structural and functional properties of ARTS with other septins. In addition, it describes how a combination of two distinct promoters, differential splicing, and intron retention leads to the generation of two different Sept4 variants with diverse biological activity. PMID- 21824007 TI - Structural and biochemical properties of Sept7, a unique septin required for filament formation. AB - Septins constitute a family of conserved guanine nucleotide binding proteins found in a wide range of organisms from fungi to mammals. Members of the family share a canonical G-domain with N- and C-terminal extensions. G-domains assemble into hetero-oligomeric complexes which form non-polarised filaments or rings. Linear filaments are formed between the G-domains using either the guanine nucleotide binding site (G interface) or N- and C-terminal extensions (NC interface). Sept7 is a unique among the 13 human septins in that it occupies the ends of hexameric building blocks which assemble into non-polarised filaments. To gain insight into its particular properties we performed structural and biochemical studies on Sept7. We solved the crystal structure of a Sept7 dimer in the GDP-bound state. The structure and biochemistry of Sept7 provide new insights into the dynamics of the G interface and outline the differences in the properties of Sept7 compared to the members of group 2 septins. PMID- 21824008 TI - The mother-bud neck as a signaling platform for the coordination between spindle position and cytokinesis in budding yeast. AB - During asymmetric cell division, spindle positioning is critical for ensuring the unequal inheritance of polarity factors. In budding yeast, the mother-bud neck determines the cleavage plane and a correct nuclear division between mother and daughter cell requires orientation of the mitotic spindle along the mother-bud axis. A surveillance device called the spindle position/orientation checkpoint (SPOC) oversees this process and delays mitotic exit and cytokinesis until the spindle is properly oriented along the division axis, thus ensuring genome stability. Cytoskeletal proteins called septins form a ring at the bud neck that is essential for cytokinesis. Furthermore, septins and septin-associated proteins are implicated in spindle positioning and SPOC. In this review, we discuss the emerging connections between septins and the SPOC and the role of the mother-bud neck as a signaling platform to couple proper chromosome segregation to cytokinesis. PMID- 21824009 TI - Evidence that a septin diffusion barrier is dispensable for cytokinesis in budding yeast. AB - Septins are essential for cytokinesis in Saccharomyces cerevisiae, but their precise roles remain elusive. Currently, it is thought that before cytokinesis, the hourglass-shaped septin structure at the mother-bud neck acts as a scaffold for assembly of the actomyosin ring (AMR) and other cytokinesis factors. At the onset of cytokinesis, the septin hourglass splits to form a double ring that sandwiches the AMR and may function as diffusion barriers to restrict diffusible cytokinesis factors to the division site. Here, we show that in cells lacking the septin Cdc10 or the septin-associated protein Bud4, the septins form a ring-like structure at the mother-bud neck that fails to re-arrange into a double ring early in cytokinesis. Strikingly, AMR assembly and constriction, the localization of membrane-trafficking and extracellular-matrix-remodeling factors, cytokinesis, and cell-wall-septum formation all occur efficiently in cdc10Delta and bud4Delta mutants. Thus, diffusion barriers formed by the septin double ring do not appear to be critical for S. cerevisiae cytokinesis. However, an AMR mutation and a septin mutation have synergistic effects on cytokinesis and the localization of cytokinesis proteins, suggesting that tethering to the AMR and a septin diffusion barrier may function redundantly to localize proteins to the division site. PMID- 21824010 TI - The impact of a multimodal Summer Camp Training on neuropsychological functioning in children and adolescents with ADHD: an exploratory study. AB - This study examined the combined effects of methylphenidate (MPD) and response cost and token strategy (RCT), administered in an intensive ADHD Summer Camp Training (ASCT) format, on neuropsychological functions. Forty children with ADHD were randomly assigned to either the ASCT treatment (MPD plus RCT) or a control group (MPD plus a 1-hour session of standardized parental education/counselling [SPC]). This latter group was structured to be similar to the more typical current treatment. The ASCT treatment was administered for 21/2 weeks and included RCT, consisting of elements of social skill training, attention training, and sports participation. RCT was systematically applied in all daily situations and activities. Executive functions and state of regulation using the Test for Attention Performance (TAP) and the Trail-Making Test (TMT) were assessed before training and at a 6-month follow-up. Participants receiving the ASCT improved specific neuropsychological functions in attention regulation and inhibitory control tasks at the 6-month follow-up. No changes occurred for participants assigned to the control condition. The data suggest that an intensive multimodal summer camp treatment program including strategies of instrumental learning can lead to substantial and enduring improvements in neuropsychological functioning of children and adolescents with ADHD. PMID- 21824011 TI - Injury among migrant workers in Changning district, Shanghai, China. AB - The objective of this study was to characterise the injury epidemic and injury prevention needs of migrant workers in Shanghai. Cluster random sampling was applied in selecting subjects in migrant gathering areas, and face-to-face interview survey was conducted in this study. In this survey, 1256 migrant workers were included, among which the injury incidence in last one year was 38.3%. The first four injuries were incised and penetrating injury (9.5%), falls (7.2%), traffic injury (6.3%) and burns (5.3%). The injury incidence of male workers was significantly higher than that of female workers (chi(2) = 22.7, P < 0.01). Electricians, safeguards and construction workers were at the highest risk of getting injured. About 60.7% of injury episodes happened at a residence. The longest period of absence from work was up to 3 months due to falls, while the highest medical expense was near 9999 CNY ($1464.2) caused by traffic injury. About 62.9% of migrant workers need services on injury prevention. It is concluded that compared with urban registered residents, migrant workers have significantly higher incidence of injury in Shanghai. Injury prevention services are in urgent demand among the migrant workers. PMID- 21824012 TI - Pleasant emotional induction broadens the visual world of young children. AB - These experiments aimed at studying the influence of emotional context on global/local visual processing in children. Children 5 years old, known to present an immature global visual bias, and 8 years old, known to pay attention predominantly to global information, were placed in either a neutral or pleasant emotional context and subsequently presented with a global/local visual judgement task. As with previous findings for adults, both age groups presented a pronounced perceptual bias toward global information following exposure to emotionally pleasant pictures. Interestingly, younger children, who do not present a global bias during the neutral exposure, presented the same preference for global information as older children when exposed to the pleasant context. These findings indicate that emotion may strongly affect visual perception in children, with important implications for educational practice and models of cognition. PMID- 21824013 TI - When believing is seeing: the role of predictions in shaping visual perception. AB - The study investigated the influence of predictions on perception-in particular, how strong but erroneous prediction coupled with poor sensory data can trigger misperceptions. Using signal detection, we tested whether predictions induced by a semantic cue change the recognition threshold (criterion) or the subjectively perceived differences between stimuli (sensitivity). In a series of 3 experiments, participants observed pictures of (a) real objects distorted to various extents (targets), (b) noise with elements corresponding to meaningful objects (foils), or (c) nonsense images (noise). Stimuli were preceded either by a semantic cue or by a blank screen with equal probability. Presence of the cue resulted in a more liberal criterion, but only for targets and foils. The cue decreased sensitivity between the distorted targets, but increased sensitivity between the targets and noise-that is, the cue increased between-class differences, but decreased within-class differences. When there was no correspondence between prediction and the sensory input, prediction actually increased the chances of correctly rejecting noise. The influence of the cue was strongest for the moderately distorted targets and foils-when uncertainty related to the bottom-up input was the highest. PMID- 21824014 TI - Bicultural adolescents' anger regulation: in between two cultures? AB - This study explored the anger-regulation strategies of bicultural individuals who are brought up with two distinct cultures that might carry contradictory demands about how to regulate emotions. With a sample of 525 adolescents in the Netherlands and Morocco, we found that bicultural Moroccan-Dutch adolescents' anger regulation in response to hypothetical peer conflict were largely similar to those of their Dutch peers. In fact, both the Dutch and the Moroccan-Dutch adolescents' anger regulation differed in the same ways from the Moroccan group, with greater acting out and less calm verbalisation, reflection, and diversion in the former than in the latter. Additionally, our findings indicate that Moroccan Dutch adolescents' identification with the Dutch as well as with the Moroccan culture is related to more anger verbalisation and less externalising anger regulation. These results are interpreted in light of the complex cultural position faced by bicultural adolescents. PMID- 21824015 TI - Categorical and dimensional perceptions in decoding emotional facial expressions. AB - We investigated whether categorical perception and dimensional perception can co occur while decoding emotional facial expressions. In Experiment 1, facial continua with endpoints consisting of four basic emotions (i.e., happiness-fear and anger-disgust) were created by a morphing technique. Participants rated each facial stimulus using a categorical strategy and a dimensional strategy. The results show that the happiness-fear continuum was divided into two clusters based on valence, even when using the dimensional strategy. Moreover, the faces were arrayed in order of the physical changes within each cluster. In Experiment 2, we found a category boundary within other continua (i.e., surprise-sadness and excitement-disgust) with regard to the arousal and valence dimensions. These findings indicate that categorical perception and dimensional perception co occurred when emotional facial expressions were rated using a dimensional strategy, suggesting a hybrid theory of categorical and dimensional accounts. PMID- 21824016 TI - You don't act like you trust me: dissociations between behavioural and explicit measures of source credibility judgement. AB - This study compared explicit and behavioural measures of source credibility judgements based on two factors: a source's past record of accuracy and its production of predictions that participants would like to believe. The former is considered to be a rational factor for judging credibility, while the latter is considered nonrational (i.e., it does not predict actual credibility). In Experiments 1 and 2, participants saw an equal number of predictions from two sources, one of which was either highly or slightly more accurate/desirable than the other. In Experiment 3, either one source was high accuracy and the other high desirability, or one source was higher on both measures. For all experiments, participants then saw new accurate and inaccurate predictions and said which source they thought was most likely to produce each (behavioural task). Participants then gave a percentage rating for each source's perceived accuracy (explicit judgement task). Participants showed sensitivity to past accuracy differences using both tasks, but not to the size of the differences. Desirability influenced performance only on the behavioural task. However, when the two factors conflicted, participants responded solely using past accuracy information. Behaviours reflect source credibility judgements based on both rational and irrational factors, but participants appear to be both more strongly influenced by the rational factor and more aware of that influence. PMID- 21824017 TI - 'It's my inner strength': spirituality, religion and HIV in the lives of young African American men who have sex with men. AB - Young black men who have sex with men account for 48% of 13-29-year-old HIV positive men who have sex with men in the USA. It is important to develop an effective HIV prevention approach that is grounded in the context of young men's lives. Towards this goal, we conducted 31 interviews with 18-30-year-old men who have sex with men in the San Francisco-Oakland Bay Area. This paper examines the roles of religion and spirituality in men who have sex with men's lives, which is central in the lives of many African Americans. Six prominent themes emerged: (1) childhood participation in formal religious institutions, (2) the continued importance of spirituality among men who have sex with men, (3) homophobia and stigmatisation in traditional black churches, (4) tension between being a man who has sex with men and being a Christian, (5) religion and spirituality's impact on men's sense of personal empowerment and coping abilities and (6) treatment of others and building compassion. Findings suggest that integrating spiritual practice into HIV prevention may help programmes be more culturally grounded, thereby attracting more men and resonating with their experiences and values. In addition, faith-based HIV/AIDS ministries that support HIV-positive men who have sex with men may be particularly helpful. Finally, targeting pastors and other church leaders through anti-stigma curricula is crucial. PMID- 21824018 TI - Perceptions about safety and risks in gender-based violence research: implications for the ethics review process. AB - Does research on gender-based violence (GBV) pose greater than minimal risk to researchers and participants? This question needs to be understood particularly in light of hesitancy by Institutional Review Boards to approve research on GBV. The safety and risks of doing GBV studies and the implications for the ethical review process have not been a focus of much research. This qualitative study collected data through in-depth interviews with 12 experienced GBV researchers from various countries and a desk review. This paper explores researchers' interpretation of and meanings of the safety recommendations as provided in the WHO guidelines and whether there is empirical evidence on the presence of risks and safety concerns unique to GBV research. Informants raised a number of safety concerns about GBV research, yet in the interviews there were very few examples of problems having occurred, possibly because of the precautions applied. This paper argues that the notion that GBV studies carry greater than minimal risk when ethics precautions are followed is based on speculation, not evidence. It highlights the need for empirical evidence to support assertions of risk in research. PMID- 21824019 TI - Cognition and Emotion Lecture at the 2010 SPSP Emotion Preconference. AB - One of the most fundamental distinctions in the field of emotion is the distinction between emotion generation and emotion regulation. This distinction fits comfortably with folk theories, which view emotions as passions that arise unbidden and then must be controlled. But is it really helpful to distinguish between emotion generation and emotion regulation? In this article, we begin by offering working definitions of emotion generation and emotion regulation. We argue that in some circumstances, the distinction between emotion generation and emotion regulation is indeed useful. We point both to citation patterns, which indicate that researchers from across a number of sub-areas within psychology are making this distinction, and to empirical studies, which indicate the utility of this distinction in many different research contexts. We then consider five ways in which the distinction between emotion generation and emotion regulation can be problematic. We suggest that it is time to move beyond debates about whether this distinction is useful to a more specific consideration of when and in what ways this distinction is useful, and in this spirit, we offer recommendations for future research. PMID- 21824020 TI - An emotion perspective on emotion regulation. PMID- 21824021 TI - Better safe than sorry: simplistic fear-relevant stimuli capture attention. AB - It has been consistently demonstrated that fear-relevant images capture attention preferentially over fear-irrelevant images. Current theory suggests that this faster processing could be mediated by an evolved module that allows certain stimulus features to attract attention automatically, prior to the detailed processing of the image. The present research investigated whether simplified images of fear-relevant stimuli would produce interference with target detection in a visual search task. In Experiment 1, silhouettes and degraded silhouettes of fear-relevant animals produced more interference than did the fear-irrelevant images. Experiment 2, compared the effects of fear-relevant and fear-irrelevant distracters and confirmed that the interference produced by fear-relevant distracters was not an effect of novelty. Experiment 3 suggested that fear relevant stimuli produced interference regardless of whether participants were instructed as to the content of the images. The three experiments indicate that even very simplistic images of fear-relevant animals can divert attention. PMID- 21824022 TI - Attentional bias in high- and low-anxious individuals: evidence for threat induced effects on engagement and disengagement. AB - Attentional bias to threatening visual stimuli (words or pictures) is commonly present in anxious individuals, but not in non-anxious people. There is evidence to show that attentional bias to threat can be induced in all individuals when threat is imposed by threat not of symbolic nature, but by cues that predict aversive stimulation (loud noise or electric shock). However, it is not known whether attentional bias in such situations is still influenced by individual differences in anxiety. This question was addressed in two experiments using a spatial cuing task in which visual cues predicted the occurrence of an aversive event consisting of a loud human scream. Speeded attentional engagement to threat cues was positively correlated with trait anxiety in Experiment 1. Experiment 2 showed that speeded attentional engagement was present only in participants selected for high anxiety but not in low-anxious participants. In both experiments, slower disengagement from threat cues was found in all participants, irrespective of their trait anxiety levels. PMID- 21824023 TI - Emotion and narrative fiction: Interactive influences before, during, and after reading. AB - Emotions are central to the experience of literary narrative fiction. Affect and mood can influence what book people choose, based partly on whether their goal is to change or maintain their current emotional state. Once having chosen a book, the narrative itself acts to evoke and transform emotions, both directly through the events and characters depicted and through the cueing of emotionally valenced memories. Once evoked by the story, these emotions can in turn influence a person's experience of the narrative. Lastly, emotions experienced during reading may have consequences after closing the covers of a book. This article reviews the current state of empirical research for each of these stages, providing a snapshot of what is known about the interaction between emotions and literary narrative fiction. With this, we can begin to sketch the outlines of what remains to be discovered. PMID- 21824024 TI - Emotional speech processing: disentangling the effects of prosody and semantic cues. AB - To inform how emotions in speech are implicitly processed and registered in memory, we compared how emotional prosody, emotional semantics, and both cues in tandem prime decisions about conjoined emotional faces. Fifty-two participants rendered facial affect decisions (Pell, 2005a), indicating whether a target face represented an emotion (happiness or sadness) or not (a facial grimace), after passively listening to happy, sad, or neutral prime utterances. Emotional information from primes was conveyed by: (1) prosody only; (2) semantic cues only; or (3) combined prosody and semantic cues. Results indicated that prosody, semantics, and combined prosody-semantic cues facilitate emotional decisions about target faces in an emotion-congruent manner. However, the magnitude of priming did not vary across tasks. Our findings highlight that emotional meanings of prosody and semantic cues are systematically registered during speech processing, but with similar effects on associative knowledge about emotions, which is presumably shared by prosody, semantics, and faces. PMID- 21824025 TI - Reversed mnemic neglect of self-threatening memories in dysphoria. AB - Previous research has suggested that people have difficulties remembering information which is threatening to the self--an effect known as mnemic neglect. Three experiments are presented that examined mnemic neglect in dysphoria and whether dysphoric individuals show enhanced memory for self-threatening information. Pilot work determined that dysphoric participants rated central negative traits as more important than nondysphoric participants. In Experiment 1, dysphoric participants were found to have better memory for self-threatening information than nondysphoric participants. Enhanced recall of self-threatening memories was also found for unmodifiable (Experiment 2), and highly diagnostic (Experiment 3) self-threatening traits. The findings suggest that dysphoric participants show reversed mnemic neglect effects indicating enhanced access to negative information relating to the self. PMID- 21824026 TI - Depressive symptoms and cognitive control in a mixed antisaccade task: specific effects of depressive rumination. AB - Growing empirical evidence suggests that cognitive and affective problems in depression may be a reflection of cognitive control impairments. However, to date, the nature of such impairments is still poorly understood and further investigation of this topic is required to advance current knowledge on the underlying vulnerability factors for depression. Using a mixed antisaccade paradigm, the present study examined if depressive symptoms in general, and more specifically rumination, are related to impairments in cognitive control functions such as inhibition and switching. The results on antisaccade latency and error rates indicated that depressive symptoms in general were not related to impairments in inhibition and switching. However, rumination was associated with impaired inhibition such that high, compared to low, ruminators had slower antisaccade latencies. No group differences were observed on antisaccade error rates. Implications for understanding the underlying vulnerability factors for the development of depressive symptoms are discussed. PMID- 21824027 TI - Do proposed facial expressions of contempt, shame, embarrassment, and compassion communicate the predicted emotion? AB - Shame, embarrassment, compassion, and contempt have been considered candidates for the status of basic emotions on the grounds that each has a recognisable facial expression. In two studies (N=88, N=60) on recognition of these four facial expressions, observers showed moderate agreement on the predicted emotion when assessed with forced choice (58%; 42%), but low agreement when assessed with free labelling (18%; 16%). Thus, even though some observers endorsed the predicted emotion when it was presented in a list, over 80% spontaneously interpreted these faces in a way other than the predicted emotion. PMID- 21824028 TI - Oh, it's you again: memory interference from irrelevant emotional and neutral faces. AB - In two experiments, repeated runs of a continuous recognition task were employed to assess healthy participants' ability to handle interference from irrelevant emotional and neutral memories. Presumably, such interference can be due to salience from either emotional or mnemonic processing. In both experiments, participants made more false alarms to emotional faces that were familiar from preceding runs (i.e., emotion-induced temporal-context confusion). Participants performed well for neutral faces in the first experiment including only two runs. However, increasing the number of runs to four in the second experiment induced temporal context confusion also for neutral faces. The findings suggest that memory interference can be induced when the salience of irrelevant information is erroneously considered diagnostic for memory judgements. PMID- 21824029 TI - Prospective memory, emotional valence and ageing. AB - Emotional factors have been found to be an important influence on memory. The current study investigated the influence of emotional salience and age on a laboratory measure of prospective memory (PM); Virtual Week. Thirty young and 30 old adults completed Virtual Week, in which the emotional salience of the tasks at encoding was manipulated to be positive, negative or neutral in content. For event-based, but not time-based tasks, positivity enhancement in both age groups was seen, with a greater number of positive PM tasks being performed relative to neutral tasks. There was no negativity enhancement effect. Older adults showed generally poorer levels of PM, but they also demonstrated greater beneficial effects of positive valence compared to young. These effects of emotion on PM accuracy do not appear to reflect the retrospective component of the task as a different pattern of emotion effects was seen on the recall of PM content. Results indicate that older adults' difficulties in prospective remembering can be reduced where the tasks to be remembered are positive. PMID- 21824030 TI - Experimental manipulations of perspective taking and perspective switching in expressive writing. AB - Previous studies suggest that those who naturally vary their pronoun use over the course of expressive writing subsequently report the greatest improvements in physical and mental health. To explore possible perspective taking or perspective switching effects, two studies manipulated writing perspectives about emotional events from either a first-person, second-person, or third-person perspective. In Study 1, 55 students were randomly assigned to one of the three writing perspectives and were asked to write from the same perspective for three 5-minute writing sessions. In Study 2, 129 students wrote for three 5-minute sessions, one from each perspective in a counterbalanced order. The results showed that writing from a first-person perspective conferred more perceived benefits and was associated with using more cognitive mechanism words, whether engaged in perspective taking or perspective switching. PMID- 21824031 TI - A functionalist account of shame-induced behaviour. AB - Recent research has shown that shame activates both a restore and a protect motive (De Hooge, Zeelenberg, & Breugelmans, 2010), explaining the hitherto unexpected finding that shame can lead to both approach and avoidance behaviours. In the present article we show a clear difference in priority and development of restore and protect motives over time. Our experiment reveals that shame mainly motivates approach behaviour to restore the damaged self, but that this restore motive decreases when situational factors make it too risky or difficult to restore. In contrast, the motive to protect one's damaged self from further harm is not influenced by such situational factors. As a consequence, the approach behaviour that shame activates may change over time. These findings add to our understanding of the motivational processes and behaviours following from shame. PMID- 21824032 TI - The understanding and self-reported use of emotional display rules in children with autism spectrum disorders. AB - Two studies examined the understanding and self-reported use of rules for the expressive display of emotions in children with high functioning autism spectrum disorders (HFASD) and in typically developing children. In Study 1, children from the two groups reported display rules equally often when presented with hypothetical situations that provided clear motives for using display rules, although emotion-masking displays were more commonly identified for vignettes with prosocial rather than self-protective motives. In Study 2, children were interviewed about display rule use in real life. Children with HFASD reported display rules less often, included more prototypical examples, and referred less often to prosocial motives than typically developing children. Children with HFASD appear to be aware of display rules, but are less adept at identifying the interpersonal functions of such rules than their typically developing peers. PMID- 21824033 TI - Older Chinese men and women's experiences and understanding of sexuality. AB - This study explored the meaning of sexuality for older Chinese people from diverse backgrounds and the role of traditional Chinese cultural values in shaping sexual expression. A total of 20 Hong Chinese elders were interviewed. Most reported a rigid definition of sexual behaviour, confining it to heterosexual sexual intercourse. Kissing, hugging and caressing were not considered 'sexual', and same-sex relationships were virtually absent from respondents' conceptions of sexuality. Traditional patriarchal values in relation to sexuality prevailed. Men and women attached different meanings to sexuality. Neither believed that sex was enjoyable for women or that women needed sex in the same way as men. Female participants saw sex as part of their responsibility to procreate and to fulfill their husband's needs. Male participants considered sex to be important for fulfilling their physical drives. The lack of an appropriate partner due to widowhood, the partner's physical condition or a poor spousal relationship apparently accounted for the low levels of sexual activity reported by informants. PMID- 21824034 TI - Mountain high, valley low: direction-specific effects of articulation on reaching. AB - Representations underpinning action and language overlap and interact very closely. There are bidirectional interactions between word and action comprehension, semantic processing of language, and response selection. This study extends our understanding of the influence of speech on concurrent motor execution. Participants reached-to-grasp the top or bottom of a vertically oriented bar in response to the location of a word on a computer screen (top/bottom). Words were synonyms for "up" or "down", and participants were required to articulate the word during movement. We were particularly interested in the influence of articulated word semantics on the transport component of the reach. Using motion capture to analyse action kinematics, we show that irrespective of reach direction, saying "up" synonyms led to greater height of the hand, while saying "down" synonyms was associated with reduced height. This direction-specific influence of articulation on the spatial parameters of the hand supports the idea that linguistic systems are tightly integrated and influence each other. PMID- 21824035 TI - Conflict in object affordance revealed by grip force. AB - Viewing objects can result in automatic, partial activation of motor plans associated with them-"object affordance". Here, we recorded grip force simultaneously from both hands in an object affordance task to investigate the effects of conflict between coactivated responses. Participants classified pictures of objects by squeezing force transducers with their left or right hand. Responses were faster on trials where the object afforded an action with the same hand that was required to make the response (congruent trials) compared to the opposite hand (incongruent trials). In addition, conflict between coactivated responses was reduced if it was experienced on the preceding trial, just like Gratton adaptation effects reported in "conflict" tasks (e.g., Eriksen flanker). This finding suggests that object affordance demonstrates conflict effects similar to those shown in other stimulus-response mapping tasks and thus could be integrated into the wider conceptual framework on overlearnt stimulus-response associations. Corrected erroneous responses occurred more frequently when there was conflict between the afforded response and the response required by the task, providing direct evidence that viewing an object activates motor plans appropriate for interacting with that object. Recording continuous grip force, as here, provides a sensitive way to measure coactivated responses in affordance tasks. PMID- 21824036 TI - Controlled and uncontrolled allergic asthma in routine respiratory specialist care - a clinical-epidemiological study in Germany. AB - BACKGROUND: Studies in the last decade showed high rates of poorly treated and poorly controlled asthma in the community. Extending these findings we describe the more recent situation in specialist respiratory care as the most frequent source of treatment provision using comprehensive clinical and patient assessments and exploring predictors for poor control. METHODS: This is a German cross-sectional, clinical epidemiological study in a nationally representative stratified treatment prevalence sample of N = 572 outpatients diagnosed with allergic asthma (AA; females 58.2%, aged 47.5 +/- 16.3 (16-81 years). Treating physicians completed standardized clinical assessments (lung function, laboratory, clinical findings, severity, illness and treatment history, asthma control [GINA]), supplemented by patients' self-report measures (EQ5-D, AQLQ, ACT) and mental health module (CIDI-SF). RESULTS: A total of 65.4% of patients were rated (GINA) as controlled, 30.3% partially controlled, and 4.4% uncontrolled; the patient-rated ACT showed lower rates of control (19.9% controlled, 44.2% partial, 35.8% uncontrolled, kappa: 0.2). Consistent with findings of clinical measures, controlled asthma was highest among patients with pre-treatment stage I severity (83.6%) and decreased by pre-treatment severity (stage IV patients: 29.3%). Poorer control was associated with pre-treatment severity, nocturnal attacks, diminished adherence and comorbid anxiety/depression. Patients received complex multiple drug and non-drug interventions, largely consistent with guidelines. Degree of asthma control was associated with improved and even normalized quality of life findings. CONCLUSION: In this representative sample of longterm treated AA patients in specialist respiratory care we find better control rates and better adherence to guidelines as previous studies. Despite remarkable differences in clinician- vs patient-rated control ratings even the initially most severe stage IV patients (12.9% of patients) showed remarkable control rates and close to normal quality of life. Intensified treatment (e.g. omalizumab) was associated with improved control. Poorer control was associated with higher initial severity, diminished adherence, comorbid anxiety/depression and old age. LIMITATION: Findings apply to AA patients in respiratory specialist care sector which is likely to treat the more severely affected patients. Thus, findings cannot be generalized to the general population, other treatment settings or asthma types. PMID- 21824037 TI - The effect of antibiotics on bone healing: current evidence. AB - INTRODUCTION: Bone healing is a complex cascade of events that involves the proliferation and differentiation of osteoblastic cells under the influence of signals from growth factors, cytokines and mechanical loading. Several medications have been found to interact negatively with this process including cytostatics, NSAIDs and corticosteroids; however, the effect of antibiotics on bone repair processes remains obscure. AREAS COVERED: The authors offer a comprehensive review of the existing literature on the in vivo and in vitro effect of antibiotics on bone, bone cells and fracture healing. The authors describe the pharmacokinetic characteristics of antibiotics after parenteral administration as well as their levels when applied locally together with a delivery vehicle. EXPERT OPINION: The available experimental data and clinical evidence are rather limited to allow safe conclusions. In vitro studies indicate that high doses administered after systemic administration have little or no direct effect on bone cells. Further studies are desirable to define the effect of higher or prolonged concentrations on bone biology and especially that of high concentrations released by locally implanted antibiotic-delivery systems, that is, bone cement, spacers and beads. PMID- 21824038 TI - TAXTOX - a retrospective study regarding the side effects of docetaxel given as part of the adjuvant treatment to patients with primary breast cancer in Denmark from 2007 to 2009. AB - BACKGROUND: In 2007 docetaxel was introduced as part of the adjuvant setting offered to high risk breast cancer patients in Denmark. Meta-analyses had shown that taxane-containing chemotherapy reduced the relative risk of relapse and death by 20-30%, apparently with moderate side effects. The treatment was given as three cycles of cyclophosphamide (600 mg/m(2)) and epirubicin (90 mg/m(2)) followed by three cycles of docetaxel (100 mg/m(2)). Because of an apparent high incidence of side effects, especially febrile neutropenia (FN) and non hematologic side effects, the DBCG (The Danish Breast Cancer Cooperative Group) initiated a retrospective study of adverse reactions to the newly introduced regime and all patients were offered primary prophylaxis with growth factors (G CSF) pr 1/1-2008. MATERIAL AND METHODS: Two medical doctors examined available journals and nurse charts from the 13 oncology departments in Denmark, and graded all side effects according to NCI CTC version 2.0. To be enrolled, the patients should have received three cycles of EC and at least one cycle of docetaxel. The side effects were investigated before and after routine use of G-CSF. RESULTS: One thousand one hundred and forty-three patients entered the study. In 2007 (before G-CSF) the incidence of FN was 25% and 90.6% of the patients completed the planned treatment. In 2008 (after the introduction of G-CSF) the incidence of FN was 10% and 94.5% completed the treatment. The incidence of non-hematological adverse events, in 2007 and 2008 combined, was for neuropathy 35%, mucositis 75%, muscle and joint pain 53%, skin rash 25% and fatigue 43% (all grades). CONCLUSION: The introduction of G-CSF was justified because of the high incidence of FN. However, it could not have been predicted after reviewing the published literature. The incidence of non-hematological adverse events had been reported in some, but not all adjuvant taxanes studies. In the future, focus should be more on the side effects, especially when introducing new toxic systemic regimes. PMID- 21824039 TI - The effect of maternal number of births on oxidative and antioxidative systems in cord blood. AB - OBJECTIVE: The aim of this study is to evaluate the relationship between cord blood oxidative and antioxidative status and maternal parity number. METHODS: Patients are grouped according to the maternal parity number: primiparous group (n = 36), multiparous group (n = 40), and grand multiparous group (n = 26). Cord blood samples are obtained in all subjects and assessed for total antioxidant capacity (TAC), total oxidant status (TOS) and oxidative stress index (OSI). The serum TAC and TOS were evaluated by using an automated colorimetric measurement method. RESULTS: TAC levels are significantly higher and oxidative stress indicators are significantly lower in newborns of primiparous women compared to multiparous women p < 0.05 for all). TAC level is increased, whereas TOS and OSI levels are decreased in newborns of grand multiparous mothers compared to primiparous mothers. TAC level is significantly higher, whereas TOS and OSI levels are significantly lower in newborns of grand multiparous women compared to multiparous women (p < 0.05 for all). CONCLUSIONS: These results suggest a relation between higher maternal parity and increased oxidative stress and decreased antioxidant defense capacity. On the other hand, the compensatory mechanisms improve the antioxidant defense system in newborns of grand multiparous women and may prevent oxidative stress. PMID- 21824040 TI - Brachial artery endothelial function predicts platelet function in control subjects and in patients with acute myocardial infarction. AB - Platelet activation occurs in an endothelium-dependent flow-mediated dilation (FMD) impairment environment. The aim of this study was to explore the association between platelet reactivity and brachial artery FMD in individuals without established cardiovascular disease (controls) and acute myocardial infarction (AMI) patients. We prospectively assessed brachial artery FMD in 151 consecutive subjects, 104 (69%) controls, and 47 (31%) AMI patients; 115 (76%) men, mean age 53 +/- 11 years. Following overnight fasting and discontinuation of all medications for >= 12 h, percent change in brachial artery FMD (%FMD) and endothelium-independent, nitroglycerin-mediated vasodilation (%NTG) were assessed. Platelet aggregation was assessed by conventional aggregometry, and platelet adhesion and aggregation under flow conditions by cone-and-plate(let) technology (Impact-R). Smoking, diabetes, and hypertension were more common in AMI compared to control subjects (p < 0.01 for all). Furthermore, aspirin, clopidogrel, beta-blockers, angiotensin-converting enzyme inhibitors, and statin administration were more common in AMI compared to controls (p < 0.01 for all). %FMD but not %NTG was significantly lower in AMI patients compared to controls (10.2 +/- 4.2% vs. 15.4 +/- 4.4%; p < 0.001 and 17.2 +/- 3.9% vs. 18.0 +/- 3.7%, p = 0.803, respectively). %FMD was significantly and inversely associated with all platelet functions tests (p < 0.001) in all study participants. In a multivariate logistic regression (unadjusted and adjusted for age, gender, smoking status, diabetes mellitus, hypertension, hypercholesterolemia, overweight, family history, and concomitant medications), %FMD remained the best predictor of platelet function, irrespective of group allocation (AMI patients or controls). In conclusion, FMD is inversely correlated to platelet reactivity in both controls and AMI patients. PMID- 21824041 TI - Displays mounted on cutting blocks reduce the learning curve in navigated total knee arthroplasty. AB - The use of computer navigation in total knee arthroplasty (TKA) improves the implant alignment but increases the operation time. Studies have shown that the operation time is further prolonged due to the surgeon's learning curve, and longer operation times have been associated with higher morbidity risks. It has been our hypothesis that an improvement in the human-machine interface might reduce the time required during the learning curve. Accordingly, we asked whether the use of navigation devices with a display fixed on the surgical instruments would reduce the operation time in navigated TKAs performed by navigation beginners. Thirty medical students were randomized and used two navigation devices in rotation: these were the Kolibri(r) device with an external display and the Dash(r) device with a display that was fixed on the cutting blocks. The time for adjustment of the tibial and femoral cutting blocks on knee models while using these devices was measured. A significant time reduction was demonstration when the Dash(r) device was used: The time reduction was 21% for the tibial block (p = 0.007), 40% for the femoral block (p < 0.001), and 32% for the whole procedure (p < 0.001). The integrated display, fixed on surgical instruments in a manner similar to a spirit level, seems to be more user-friendly for navigation beginners. Hence, unproductive time losses during the learning curve may be diminished. PMID- 21824042 TI - Pain cognitions as predictors of the request for pain relief during the first stage of labor: a prospective study. AB - BACKGROUND: It is thought that pain cognitions determine coping behavior and success in adapting to labor. The aim of this study was to examine whether pain cognitions assessed by the labor pain coping and cognition list (LPCCL) predict the request for pain relief during the first stage of labor and which pain cognition is the strongest predictor of a request for pain relief over and above, and independent of, other pain cognitions. METHODS: Participants in this prospective study were 177 low-risk nulliparous pregnant women. Data were collected on two different occasions. The numerical pain intensity scale (NPS) anticipated and the LPCCL were administered at 34-36 weeks' gestation followed by the NPS-during labor. RESULTS: Catastrophizing and external pain control predicted the request for pain relief during labor after adjustment for relevant demographic and clinical characteristics, respectively (adjusted odds ratio [OR] 2.61 [95% CI 1.45-4.68] and adjusted OR 1.90 [95% CI 1.16-3.10]). Catastrophizing was found to be the strongest and independent predictor among the pain cognitions while controlling for significant background variables (adjusted OR 2.61 p-value < 0.001). CONCLUSION: Catastrophizing seems to have a substantial impact on the request for pain relief in low-risk pregnant women. PMID- 21824043 TI - Symptoms of post-traumatic stress after preeclampsia. AB - This study describes the prevalence of postpartum post-traumatic stress disorder (PTSD) based on the DSM-IV criteria, including its symptoms of intrusion, avoidance and hyperarousal after pregnancies complicated by preeclampsia, and examines which variables are associated with PTSD and its symptoms. Women whose pregnancies were complicated by preeclampsia completed the Self-Rating Inventory for PTSD at 6 and 12 weeks postpartum: 149 women completed this questionnaire on at least one time point. Logistic regression analyses were used to examine associations with PTSD and its symptoms. Results showed that the prevalence of PTSD was 8.6% at 6 weeks, and 5.1% at 12 weeks postpartum; 21.9% of the study sample experienced postpartum symptoms of intrusion at 6 weeks postpartum (11.7% at 12 weeks), 9.4% symptoms of avoidance (8.0% at 12 weeks), and 28.9% symptoms of hyperarousal (20.4% at 12 weeks). Younger age, severe preeclampsia, cesarean section, lower gestational age, lower birth weight, admission to the neonatal intensive care unit, and perinatal death were found to be associated with PTSD and its symptoms. There was a relatively high prevalence of postpartum symptoms of PTSD among women after preeclampsia. The prevalence was highest among younger women who experienced more adverse pregnancy outcomes. PMID- 21824044 TI - Post-traumatic stress symptoms, parenting stress and mother-child relationships following childbirth and at 2 years postpartum. AB - This study examined the prevalence of childbirth-related post-traumatic stress (PTS) symptoms at 2 years postpartum and the relationship between such symptoms and both self-reported parenting stress and perceptions of the mother-child relationship. 81 women completed measures of childbirth-related PTS symptoms at 6 weeks and 3 months postpartum; these results were used in an exploration of their predictive links with mother-child relationship and parenting measures at 2 years. 17.3% of respondents reported some PTS symptoms at a clinically significant level at 2 years postpartum. However, these symptoms were only weakly linked to parenting stress and were not related to mothers' perceptions of their children. However earlier PTS symptoms within 3 months of childbirth did show limited associations with parenting stress at 2 years but no association with child relationship outcomes once current depression was taken into account. Implications for clinical practice and the concept of childbirth-related post traumatic stress disorder are discussed. PMID- 21824045 TI - "We feel rejected": experiences of women with hirsutism consulting physicians. AB - The aim of the study was to describe how women with hirsutism experience their relationship with health care. Data were collected by tape-recorded individual interviews, which were analyzed by means of qualitative content analysis. The results showed that the relationship with health care, from the perspective of patients with hirsutism, is suboptimal. PMID- 21824047 TI - Genetic polymorphisms associated with steroids metabolism and insulin action in polycystic ovary syndrome. AB - Polycystic ovary syndrome (PCOS) is an endocrinopathy associated with infertility, diabetes and cardiovascular events. This study aimed to correlate polymorphisms of genes involved in the biosynthesis and metabolism of steroids and insulin action (CYP17A1, CYP19A1, AR, ESR1, ESR2, INSR, IGF2 and PAI1) with clinical and biochemical parameters of PCOS. DNA was extracted from peripheral blood samples obtained from 117 PCOS and 105 healthy women. The PAI1 insertion/deletion (-675 ins/delG) polymorphism (rs1799768) was genotyped by PCR SSCP. CYP19A1 [TTTA](n), AR [CAG](n), ESR1 [TA](n), and ESR2 [CA](n) genes were evaluated by PCR-based GeneScan analysis, while CYP17A1 5'UTR (rs743572), INSR 1058 CT (rs1799817), and IGF2 3'UTR GA (rs680) polymorphisms were evaluated by PCR-RFLP. The results showed a prevalence of PAI1 4G5G+4G4G genotypes in PCOS (p = 0.025). Younger PCOS women showed a predominance of CT+TT, GA+AA and 4G5G+4G4G genotypes of INSR, IGF2, and PAI1 (p = 0.0499, p = 0.0300, p = 0.0350, respectively). AR shorter alleles (<= 20 repeats) were significantly associated with higher serum levels of total testosterone (TT, p = 0.0086). In conclusion, PAI1 polymorphism seems to be associated with the risk of PCOS development. Younger PCOS women had specific genotypes of INSR, IGF2 and PAI1 genes. AR shorter alleles can be associated with higher serum levels of TT in PCOS patients. PMID- 21824048 TI - Evaluation of the relationship between endogenous gonadotropins and female sexual function and psychological status in predialysis and hemodialysis patients. AB - OBJECTIVES: To evaluate sexual function and psychological state and the factors affecting female sexual dysfunction in predialysis and hemodialysis patients. DESIGN AND METHODS: Forty-seven women with chronic renal failure including 22 predialysis patients, 25 hemodialysis patients, and 30 healthy controls were included in this study. Demographic and clinical variables of the patients were recorded. The sexual functions and psychological states of the patients, assessed by the Arizona Sexual Experiences Scale (ASEX) and Beck Depression Inventory (BDI), respectively, were compared between the groups. RESULTS: Total ASEX scores, ability to reach orgasm, and BDI scores were significantly higher in predialysis and hemodialysis patients than controls, reflecting sexual dysfunction. The patients in the predialysis group were 6 and 3.8 times more likely to develop depressive symptoms compared to the controls and hemodialysis patients, respectively. The predialysis patients who showed depressive symptoms were 24 times more likely to develop sexual dysfunction compared to those without depression. Serum FSH and LH levels were also positively correlated with arousal and erection/lubrication scores in the predialysis patients with depressive symptoms. CONCLUSION: Female predialysis rather than dialysis patients might be more likely to develop depression. Those patients with depressive symptoms may also be at greater risk of developing sexual dysfunction in which increased gonadotropin levels and age may also be contributing factors. Therefore, psychiatric and gynecologic consultations may be beneficial. PMID- 21824049 TI - Telomere length and type 2 diabetes in males, a premature aging syndrome. AB - BACKGROUND: Increased telomere shortening has been demonstrated in several diseases including type 2 diabetes. However, it is not known whether telomere length changes during the course of type 2 diabetes. OBJECTIVE: To determine telomere length at different stages of type 2 diabetes, including early and late stages. METHODS: A total of 93 males with type 2 diabetes and 10 years or more since original diagnosis; 96 males with less than one year of diagnosis; 98 age matched healthy males. Telomere length was estimated by means of real-time polymerase chain reaction. Fasting venous blood samples were obtained for measurement of lipid peroxidation and inflammation markers. RESULTS: We found a greater telomere shortening in group (A) with type 2 diabetes of 10 years or more since original diagnosis, compared with the control group (C) of healthy males (5.4 vs 9.6 Kb) (p = 0.04) and with group B (5.4 vs 8.7 kb) (p = 0.05). With regard to inflammatory markers TNF-alpha, malondialdehyde peroxidation and adiponectin we found significant differences. CONCLUSION: Telomere shortening increases with the duration of diabetes. The time of exhibition suggests in parallel that the progressive increase of inflammation and/or oxidative stress plays a direct role in telomere shortening. PMID- 21824050 TI - Cost-effectiveness of adding rituximab to fludarabine and cyclophosphamide for the treatment of previously untreated chronic lymphocytic leukemia. AB - A recent phase III trial demonstrated improved progression-free survival (PFS) and overall survival (OS) associated with adding rituximab to fludarabine and cyclophosphamide (R-FC) compared to FC in treatment of previously untreated chronic lymphocytic leukemia (CLL). A cost-effectiveness analysis of R-FC over FC was performed from a US third-party payer perspective over a lifetime horizon in the base case. One-way, two-way and probabilistic sensitivity analyses were conducted to assess the robustness of the results. A secondary analysis was performed by also considering a societal perspective. R-FC was associated with an incremental 1.15 quality-adjusted life-years (QALYs) compared to FC and resulted in an incremental cost-effectiveness ratio of $23 530 per QALY in the base case and $31 513 per QALY considering a societal perspective. Results were most sensitive to time horizon, discount rate and unit drug cost for rituximab. Within the limitations of modeling long-term outcomes, R-FC is cost-effective for previously untreated CLL. PMID- 21824051 TI - Bortezomib, liposomal doxorubicin and dexamethasone followed by thalidomide and dexamethasone is an effective treatment for patients with newly diagnosed multiple myeloma with Internatinal Staging System stage II or III, or extramedullary disease. AB - We evaluated sequential bortezomib, liposomal doxorubicin and dexamethasone (BDD) followed by thalidomide and dexamethasone (TD) if >= partial response (PR) or bortezomib and TD (BTD) if < PR in untreated patients with multiple myeloma with International Staging System stage II/III or extramedullary disease. Of the 42 patients enrolled, two-thirds had cytogenetic abnormalities including high-risk findings [del(13q) by karyotype, t(4;14), loss of p53 or gain 1q] in one-third. After the planned three cycles of BDD, the overall response rate (ORR) was 81% with 40% >= very good partial response (VGPR), including 26% near complete and complete responses (nCR/CR). After the additional two cycles of TD or BTD, ORR was 83% with 60% >= VGPR including 43% nCR/CR, indicating deeper responses following sequential therapy (p = 0.008). Two-thirds of patients who presented with significant renal impairment had improved renal function. All patients undergoing stem cell harvest had a successful collection. BDD followed by TD or BTD is effective initial therapy for this population with higher-risk myeloma and results in rapid disease control and a high response rate. PMID- 21824052 TI - A NME1 promoter SNP predicts Ara-C associated neurotoxicity in AML patients. PMID- 21824053 TI - Gastric mucosa-associated lymphoid tissue lymphoma: how to attack the T... for two? PMID- 21824054 TI - The toxicity lies not with the alcohol, but with the mixers. PMID- 21824055 TI - Bringing greater transparency to "black box" warnings. AB - The number of drugs with boxed warnings and the detail in the box are much greater in the USA than Australia. US warnings are up to ten times longer and often include a great deal of detail and qualified advice. Australian warnings are usually just a few sentences long and the expected response unequivocal. Other details are relegated to the relevant section within the product information. The restriction of warnings such that they are succinct and used sparingly are explicitly highlighted in the guidelines for boxed warnings in Australia. In addition, the range of other risk management strategies used may be broader. Widespread prescription drug subsidies and mechanisms set up to implement the "Quality Use of Medicines" policy provide a complementary range of options. Withdrawal of registration, removal of subsidies for all or selected indications, changed product information and labels, consumer-targeted information, prescriber mail outs, education programmes, restriction to authorised prescribers, and changed pack size and packaging have all been applied at some time in response to safety concerns. The diversity of approaches around the world provides an opportunity for a systematic approach to look at the effects of boxed warnings on prescribing practices so that we might discover what works best. While there are many studies on the effect of warnings from the USA, there are few comparable studies done where different approaches are used. Further, it is not possible to easily examine the total number and purpose of boxed warnings via any government websites. If there were always explicit and potentially verifiable changes in practice as the stated goal for each boxed warning in each jurisdiction and a requirement that the effectiveness of the intervention was measured against these goals, then we might have the evidence base for better policy around boxed warnings. PMID- 21824056 TI - Clinical toxicology and drug regulation: a United Kingdom perspective. AB - The Medicines and Healthcare products Regulatory Authority (MHRA) is the government body with responsibility for regulating new and existing medicines and medical devices in the United Kingdom. The Yellow Card scheme is a well established pharmacovigilance system that collects voluntary reports of adverse effects associated with therapeutic drug use. In contrast, data concerning clinical toxicological effects are more poorly characterised. No comparable surveillance processes exist in the United Kingdom or elsewhere in Europe that might allow systematic collection of clinical data and outcomes after drug overdose. Toxicological effects are normally ascertained from individual patient reports or small case series from a few specialised poisons units, so that these data are generally under-represented in post-marketing consideration of risks and benefits. Safety concerns may lead to withdrawal of the Marketing Authorisation or restricted prescribing conditions, which are conveyed to health care professionals by means of safety warnings. These may have a variable impact, and three selected examples are presented to illustrate the complex interaction between drug regulation and clinical toxicology. First, the effects of the withdrawal of rofecoxib in 2004 shows that regulatory responses may reduce the prescribing of drugs across a particular class, and this has resulted in fewer enquiries to Poisons Control Centres regarding all cyclooxygenase-2 selective inhibitors. Secondly, data concerning the impact of safety warnings about antipsychotic medications illustrate that regulatory decisions may have a variable impact due to other factors that influence prescribing, including clinical guidelines, marketing pressures, and lack of alternative safe medications. Finally, the recent withdrawal of co-proxamol serves as an example of how clinical toxicology data can inform the drug regulation process and improve safety by minimising the risk of death associated with overdose. Greater reliance on clinical toxicology data could better inform the drug regulation process, perhaps through coordinated data collection systems that already exist in certain national poisons centres. Routine collection of high quality data concerning the effects of drug overdose could allow a more comprehensive review of risk and benefit by the regulatory authorities. PMID- 21824057 TI - Mechanisms of toxicity of Cleistanthus collinus: vacuolar ATPases are a putative target. AB - Ingestion of Cleistanthus collinus, a shrub native to South India, either intentionally or accidentally, is a common cause of death in the area. Consumption of a boiled decoction of leaves is highly toxic, but medical management of patients is mainly supportive because the molecular mechanisms of toxin action are unknown. Distal renal tubular acidosis is one of the symptoms of poisoning in patients and adenosine triphosphate (ATP) requiring proton pumps is important for acid secretion in the kidney. Hence, we hypothesized that these may be putative targets for C. collinus action and we tested this by exposing rat renal brush border membrane (BBM) as well as cultured kidney cells to a boiled decoction of C. collinus. Exposure to the C. collinus decoction resulted in significant inhibition of vacuolar type H(+)-ATPase (V-ATPase) activity in renal BBM as well as blocking of the proton pump in renal BBM vesicles. C. collinus decoction was also found to inhibit acidification of intracellular organelles in cells in culture, similar to the effect seen with either bafilomycin or concanamycin - specific inhibitors of the V-ATPase. This was accompanied by a decrease in V-ATPase activity, but an increase in protein levels. These results demonstrate that the V-ATPase in renal cells is a putative target for the toxins in C. collinus and the inhibition of this important proton pump probably plays a role in the development of distal renal tubular acidosis and subsequent renal failure seen in poisoned patients. PMID- 21824058 TI - Studies on ethylene glycol poisoning: one patient - 154 admissions. AB - OBJECTIVE: Fomepizole is the antidote of choice in toxic alcohol poisonings. Potential side effects from frequent use of fomepizole were studied in a patient admitted 154 times with ethylene glycol (EG) poisoning. The intra-individual correlation between the serum-ethylene glycol (serum-EG) and the osmolal gap (OG) EG-kinetics, and other laboratory parameters were also studied. METHODS: Combined pro- and retrospective collection of material from three different hospitals, and results from autopsy. RESULTS: A 26-year-old female with a dissociative disorder was admitted with EG poisoning a total of 154 times. Her admission data revealed a median pH of 7.31 (range 6.87-7.49), pCO(2): 4.2 kPa (1.2-6.7) (32 mmHg [9 50]), HCO-3: 15 mmol/L (4-26) (15 mEq/L [4-26]), base deficit (BD): 10 mmol/L (- 4 to 27) (10 mEq/L [-4 to 27]), serum-creatinine 65 MUmol/L (40-133) (0.74 mg/dL [0.45-1.51]), OG 81 mOsm/kgH(2)O (25-132), and serum-EG 44 mmol/L (4-112) (250 mg/dL [25-700]). She was treated with fomepizole 99 times, ethanol 60 times (with a combination of both six times), and dialysis 73 times. The correlation between serum-EG and OG was good (r(2) = 0.76). She was finally found dead outside hospital with an EG blood concentration of 81 mmol/L (506 mg/dL). An autopsy revealed calcium oxalate crystals in the kidneys, slight liver steatosis, and slight edema of the lungs. DISCUSSION: The frequent use of fomepizole in this young patient was not associated with any detectable side effects; neither on clinical examination and lab screening, nor on the later autopsy. Regarding the sequelae from the repetitive EG-poisoning episodes, her kidney function seemed to normalize after each overdose. She was treated with buffer and antidote without hemodialysis 81 times without complications, supporting the safety of this approach in selected cases. PMID- 21824059 TI - The epidemiology and type of medication errors reported to the National Poisons Information Centre of Ireland. AB - INTRODUCTION: Medication errors are widely reported for hospitalised patients, but limited data are available for medication errors that occur in community based and clinical settings. Epidemiological data from poisons information centres enable characterisation of trends in medication errors occurring across the healthcare spectrum. AIM: The objective of this study was to characterise the epidemiology and type of medication errors reported to the National Poisons Information Centre (NPIC) of Ireland. METHODS: A 3-year prospective study on medication errors reported to the NPIC was conducted from 1 January 2007 to 31 December 2009 inclusive. Data on patient demographics, enquiry source, location, pharmaceutical agent(s), type of medication error, and treatment advice were collated from standardised call report forms. Medication errors were categorised as (i) prescribing error (i.e. physician error), (ii) dispensing error (i.e. pharmacy error), and (iii) administration error involving the wrong medication, the wrong dose, wrong route, or the wrong time. RESULTS: Medication errors were reported for 2348 individuals, representing 9.56% of total enquiries to the NPIC over 3 years. In total, 1220 children and adolescents under 18 years of age and 1128 adults (>= 18 years old) experienced a medication error. The majority of enquiries were received from healthcare professionals, but members of the public accounted for 31.3% (n = 736) of enquiries. Most medication errors occurred in a domestic setting (n = 2135), but a small number occurred in healthcare facilities: nursing homes (n = 110, 4.68%), hospitals (n = 53, 2.26%), and general practitioner surgeries (n = 32, 1.36%). In children, medication errors with non-prescription pharmaceuticals predominated (n = 722) and anti-pyretics and non-opioid analgesics, anti-bacterials, and cough and cold preparations were the main pharmaceutical classes involved. Medication errors with prescription medication predominated for adults (n = 866) and the major medication classes included anti-pyretics and non-opioid analgesics, psychoanaleptics, and psychleptic agents. Approximately 97% (n = 2279) of medication errors were as a result of drug administration errors (comprising a double dose [n = 1040], wrong dose [n = 395], wrong medication [n = 597], wrong route [n = 133], and wrong time [n = 110]). Prescribing and dispensing errors accounted for 0.68% (n = 16) and 2.26% (n = 53) of errors, respectively. CONCLUSION: Empirical data from poisons information centres facilitate the characterisation of medication errors occurring in the community and across the healthcare spectrum. Poison centre data facilitate the detection of subtle trends in medication errors and can contribute to pharmacovigilance. Collaboration between pharmaceutical manufacturers, consumers, medical, and regulatory communities is needed to advance patient safety and reduce medication errors. PMID- 21824060 TI - Increased adolescent opioid use and complications reported to a poison control center following the 2000 JCAHO pain initiative. AB - CONTEXT: Adolescents are at risk to abuse opioid analgesics for many reasons, including inaccurate perception of risk and increased drug availability. In 2000, the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) released pain management standards that emphasized pain control as a patient rights issue. This focus on analgesia may have increased both the prescribing and use of opioid analgesics, thereby increasing availability. OBJECTIVE: Using data from a US poison center, this study aims to compare the number of adolescent opioid cases and their outcome severity before and after the 2000 JCAHO pain initiative. METHODS: Retrospective case series of opioid exposures involving persons 12-18 years of age reported to a US poison center from 1994 to 2007. The main outcome measure was the number of adolescent opioid cases reported for 1994 2000 compared to 2001-2007. Secondary outcomes included outcome severity, number of cases involving specific opioids, and correlation between the number of cases and the amount of opioids distributed to the state. RESULTS: There were 1634 adolescent opioid-related cases with 187 cases developing medical complications. Compared with 1994-2000, the rate ratio of cases involving adolescents and opioid analgesics for the years 2001-2007 was 1.69 (95% CI: 1.53, 1.86), and these cases were 2.84 (95% CI: 2.06, 3.91) times more likely to have had medical complications. Medical complications involving methadone (p =0.001) increased after the JCAHO initiative, while complications related to codeine (p =0.001) and propoxyphene (p =0.030) decreased. There were 15 deaths in 2001-2007 and none in 1994-2000 (p =0.012). Lastly, there was a correlation between the rate of adolescent opioid cases and the amount of opioids distributed to the state (r(2) =0.90; p < 0.001). CONCLUSION: In the 7 years following the JCAHO pain standards, there was an increase in the number and severity of adolescent opioid-related poison center cases. The increase correlates with statewide availability of opioids. These data may prove useful in drug education and prevention programs targeting adolescents. PMID- 21824061 TI - Clinical experience with and analytical confirmation of "bath salts" and "legal highs" (synthetic cathinones) in the United States. AB - Recently, there has been a worldwide rise in the popularity and abuse of synthetic cathinones. In 2009 and 2010, a significant rise in the abuse of a new group of synthetic cathinones was reported in Western Europe. In 2010, the rapid emergence of a new drug of abuse, referred to as bath salts or "legal high," occurred in the USA. The growing number of cases along with the alarming severity of the effects caused by the abuse of these substances prompted significant concern from both healthcare providers and legal authorities. We report the experience of the first 8 months of two regional poison centers after the emergence of a new group of substances of abuse. METHOD: This was a retrospective case series of patients reported to two poison centers with exposures to bath salts. Additionally, 15 "product samples" were obtained and analyzed for drug content using GC/MS. RESULTS: There were 236 patients of which 184 (78%) were male. Age range was 16-64 years (mean 29 years, SD 9.4). All cases were intentional abuse. There were 37 separate "brand" names identified. Clinical effects were primarily neurological and cardiovascular and included: agitation (n = 194), combative behavior (n = 134), tachycardia (n = 132), hallucinations (n = 94), paranoia (n = 86), confusion (n = 83), chest pain (n = 40), myoclonus (n = 45), hypertension (n = 41), mydriasis (n = 31), CPK elevations (n = 22), hypokalemia (n = 10), and blurred vision (n = 7). Severe medical outcomes included death (n = 1), major (n = 8), and moderate (n = 130). Therapies included benzodiazepines (n = 125), antipsychotics (n = 47), and propofol (n = 10). Primary dispositions of patients were: 116 (49%) treated and released from ED, 50 (21%) admitted to critical care, 29 (12%) admitted to psych, and 28 (12%) lost to follow up. Nineteen patients had blood and/or urine analyzed using GC/MS. MDPV was detected in 13 of 17 live patients (range 24-241 ng/mL, mean 58 ng/mL). The four samples with no drug detected, reported last use of bath salts >20 h prior to presentation. Three of five patients had MDPV detected in urine (range 34-1386 ng/mL, mean 856 ng/mL). No mephedrone or methylone was detected in any sample. Quantitative analysis performed on postmortem samples detected MDPV in blood at 170 ng/mL and in urine at 1400 ng/mL. No other synthetic cathinones were detected. DISCUSSION: This is the first report of MDPV exposures with quantitative blood level confirmation. Clinical effects displayed a sympathomimetic syndrome, including psychotic episodes often requiring sedation, movement disorders, and tachycardia. Within 8 months of their appearance, 16 states had added synthetic cathinones to the controlled substances list as a Schedule I drug. CONCLUSION: We report the emergence of a new group of substances of abuse in the USA, known as bath salts, with quantitative results in 18 patients. State and federal authorities used timely information from poison centers on the bath salt outbreak during investigations to help track the extent of use and the effects occurring from these new drugs. Close collaboration between state authorities and poison centers enhanced a rapid response, including legislation. PMID- 21824062 TI - Occupational exposure to toluene diisocyanate and neutrophilic bronchitis without asthma. AB - CONTEXT: Isocyanates represent a leading cause of occupational asthma, and sputum neutrophilia or eosinophilia has been described in subjects with isocyanate induced occupational asthma after exposure to these chemicals. One case of non asthmatic eosinophilic bronchitis due to methylene diphenil isocyanates has been reported, but a similar condition in the instance of neutrophilic bronchial inflammation has never been described. CASE DETAILS: We report a 34-year-old woman, who, 18 months after beginning work in a plastic industry, reported the onset of dry cough at work. Spirometry was normal, reversibility and methacholine challenge tests were negative. A specific inhalation challenge with toluene diisocyanate elicited dry cough without significant changes in respiratory function. Sputum induction showed a post-challenge neutrophil increase. DISCUSSION: The results of our case suggest that the occurrence of a neutrophilic bronchial inflammation without the functional characteristics of occupational asthma as a consequence of exposure to toluene diisocyanate may also be considered, suggesting a diagnosis of occupational non-asthmatic neutrophilic bronchitis. PMID- 21824063 TI - "Hyperammonemia following glufosinate-containing herbicide poisoning: a potential marker of severe neurotoxicity" by Yan-Chido Mao et al., Clin Toxicol (Phila) 2011; 49:48-52. PMID- 21824065 TI - Use of intravenous lipid 20% emulsion for the treatment of a voluntary intoxication of flecainide with refractory shock. PMID- 21824067 TI - Feasibility and optimization study of using cold-forming extrusion process for agglomerating and microencapsulating ferrous fumarate for salt double fortification with iodine and iron. AB - A microencapsulation-based technology platform has been developed for salt double fortification with iron and iodine, aiming to address two globally prevalent micronutrient deficiencies simultaneously. Specifically, ferrous fumarate was microencapsulated into a form of salt grain-sized premix, and then added into iodised salt. The earlier process involved fluidised-bed agglomeration followed by lipid coating. To improve physico-chemical properties of the iron premix, the use of cold-forming extrusion for agglomerating and microencapsulating ferrous fumarate was investigated and optimized in this study, leading to optimal formulations and operation parameters. Grain flours were suitable for forming an extrudable dough incorporating high percentages of ferrous fumarate. All extruded iron particles, regardless of binders used, were rich in iron and had excellent iron in vitro digestibility. The extruded iron particles formed the basis of the final, microencapsulated iron premixes with desired particle size (300-700 um), and other physical, chemical, nutritional, and organoleptic properties suitable for salt fortification. PMID- 21824068 TI - Chitosan microparticles for sustaining the topical delivery of minoxidil sulphate. AB - Given the hypothesis that microparticles can penetrate the skin barrier along the transfollicular route, this work aimed to obtain and characterise chitosan microparticles loaded with minoxidil sulphate (MXS) and to study their ability to sustain the release of the drug, attempting a further application utilising them in a targeted delivery system for the topical treatment of alopecia. Chitosan microparticles, containing different proportions of MXS/polymer, were prepared by spray drying and were characterised by yield, encapsulation efficiency, size and morphology. Microparticles selected for further studies showed high encapsulation efficiency (~82%), a mean diameter of 3.0 um and a spherical morphology without porosities. When suspended in an ethanol/water solution, chitosan microparticles underwent instantaneous swelling, increasing their mean diameter by 90%. Release studies revealed that the chitosan microparticles were able to sustain about three times the release rate of MXS. This feature, combined with suitable size, confers to these microparticles the potential to target and improve topical therapy of alopecia with minoxidil. PMID- 21824069 TI - Eudragit(r) S100 coated calcium pectinate microspheres of curcumin for colon targeting. AB - Currently, colon-specific drug delivery systems have been investigated for drugs that can exert their bioactivities in the colon. In this study, Eudragit(r) S100 coated calcium pectinate microsphere, a pH-dependent and enzyme-dependent system, as colon-specific delivery carrier for curcumin was investigated. Curcumin-loaded calcium pectinate microspheres were prepared by emulsification-linkage method, and the preparation technology was optimised by uniform experimental design. The morphology of microspheres was observed under scanning electron microscopy. Interactions between drug and polymers were investigated with differential scanning calorimetry (DSC) and X-ray diffraction. In vitro drug release studies were performed in simulated colonic fluid in the presence of Pectinex Ultra SP-L or 1% (w/v) rat caecal content, and the results indicated that the release of curcumin was significantly increased in the presence of 1% (w/v) rat caecal contents. It could be concluded that Eudragit(r) S100 coated calcium pectinate microsphere was a potential carrier for colon delivery of curcumin. PMID- 21824070 TI - The plasma membrane: a catalyst in the decision to die or not to die? PMID- 21824071 TI - Gut inflammation in response to injury: potential target for therapeutic intervention. AB - Traumatic injuries present a major public health concern worldwide. A role of gut and/or its derived factors has been suggested in the pathogenesis associated with injury. Injury causes the activation of various signaling pathways along with the release and activation of pro-inflammatory cytokines, chemokines and adhesion molecules in the intestine. This mediates infiltration of neutrophils into the intestine. Primed and subsequently activated neutrophils release various proteolytic enzymes and superoxide anion which ultimately result in intestinal inflammation and/or injury. This review will discuss the various factors contributing to intestinal inflammation following injury. Some of the patents relevant to intestinal inflammation have also been discussed in the present manuscript. PMID- 21824072 TI - Current update on eosinophilic lung diseases and anti-IL-5 treatment. AB - Peripheral blood eosinophilia and eosinophilic lung inflammation are common in a variety of pulmonary conditions, including eosinophilic pneumonia and asthma, hypereosinophilic syndrome and Churg-Strauss syndrome. Therapy in most of these clinical entities consists of long-term treatment with systemic corticosteroids, which is not always successful and has substantial side-effects. Interest has increased considerably regarding alternative corticosteroid-sparing "smart" regimens in these diseases that target IL-5, an important regulator of eosinophilic development and function. To date, two humanized monoclonal antibodies, mepolizumab and reslizumab, have been developed that bind to human IL 5. In addition a new monoclonal antibody (MEDI-563) has been recently developed targeting the IL-5 receptor. This review will investigate the current status on IL-5 targeted therapy and related patents regarding eosinophil-driven respiratory diseases, primarily eosinophilic asthma but also CSS and HES. Recent advances and information from clinical trials will be presented in a way that will allow the reader to approach the role of the eosinophil in the lung diseases presented in this review. PMID- 21824073 TI - A decade of targets and patented drugs for chemotherapy of Chagas disease. AB - Chagas disease, a parasitic infection typically spread by triatomine bugs, affects millions of people throughout Latin America. Current chemotherapy based on the nitroaromatic compounds, benzonidazole and nifurtimox provides unsatisfactory results and suffers from considerable side effects. Therefore, there is still an urgent need for new drugs to treat this neglected disease. During the last decade, the advances and understanding in the biology and biochemistry of Trypanosoma cruzi have allowed the identification of multiple new targets for Chagas' disease chemotherapy. Among the most promising targets for antiparasitic drugs are: cruzipain, the main cysteine protease of T. cruzi, essential for parasite survival and proliferation in mammalian host; ergosterol biosynthesis pathway; trypanothione synthesis and thiol-dependant redox metabolism. Specific enzymes of the glycolytic, pentose phosphate, polyisoprenoid (farnesylpyrophosphate synthase) and other particular biosynthetic pathways as well as enzymes from purine salvage (hypoxanthine-guanine phosphoribosyl transferase, dihydrofolate reductase) have also been intensively studied in T. cruzi. In particular, trypanocidal agents that target the validated biochemical pathways of the parasite including cysteine proteinase inhibitors and inhibitors capable to block ergosterol biosynthesis are currently in the pipeline. Among the latter, posaconazole and ravuconazole, are planned to enter in clinical trials for trypanocidal chemotherapy in the near future. This review will summarize advances on antichagasic agents directed to specific parasite targets such as metabolic pathways or specific enzymes. Related patents filed and issued from 2000 to 2010 claiming inhibitors for specific parasite targets will be also discussed. Among them, the most represented were those related with cysteine proteinase inhibitors. PMID- 21824074 TI - Insulin resistance and diabetes in HIV infection. AB - Insulin resistance is an important and under recognized consequence of HIV treatment. Different studies have yielded widely varying estimates of the prevalence of impaired glucose metabolism in people on highly active antiretroviral therapy (HAART). The risk increases further with hepatitis C co infection. Although Protease inhibitors (PIs) are the main drug class implicated in insulin resistance, some studies have shown an association of increased risk of diabetes with cumulative exposure of nucleoside reverse transcriptase inhibitors (NRTIs). The effect of switching to other antiretrovirals has not been fully determined and the long-term consequences of insulin resistance in this population are not known. Treatment of established diabetes mellitus should generally follow existing guidelines. It is therefore reasonable to recommend general measures to increase insulin sensitivity in all patients infected with HIV, such as regular aerobic exercise and weight reduction for overweight persons. The present review article has the information of some recent patents regarding the insulin resistance in HIV infection. PMID- 21824075 TI - Animal venoms: from deadly arsenals (toxins) to therapeutic drug candidates. PMID- 21824076 TI - Wedding bells: animal venoms and therapeutic drug candidate. PMID- 21824078 TI - Interactions of cnidarian toxins with the immune system. AB - Cnidarians comprise four classes of toxic marine animals: Anthozoa, Cubozoa, Scyphozoa and Hydrozoa. They are the largest and probably the oldest phylum of toxic marine animals. Any contact with a cnidarian, especially the box jellyfish (Chironex fleckeri), can be fatal, but most cnidarians do not possess sufficiently strong venomous apparatus to penetrate the human skin, whereas others rarely come into contact with human beings. Only a small, almost negligible percentage of the vast wealth of cnidarian toxins has been studied in detail. Many polypeptide cnidarian toxins are immunogenic, and cross-reactivity between several jellyfish venoms has been reported. Cnidarians also possess components of innate immunity, and some of those components have been preserved in evolution. On the other hand, cnidarian toxins have already been used for the design of immunotoxins to treat cancer, whereas other cnidarian toxins can modulate the immune system in mammals, including man. This review will focus on a short overview of cnidarian toxins, on the innate immunity of cnidarians, and on the mode of action of cnidarian toxins which can modulate the immune system in mammals. Emphasis is palced on those toxins which block voltage activated potassium channels in the cells of the immune system. PMID- 21824077 TI - Immunological and toxinological responses to jellyfish stings. AB - Just over a century ago, animal responses to injections of jellyfish extracts unveiled the phenomenon of anaphylaxis. Yet, until very recently, understanding of jellyfish sting toxicity has remained limited. Upon contact, jellyfish stinging cells discharge complex venoms, through thousands of barbed tubules, into the skin resulting in painful and, potentially, lethal envenomations. This review examines the immunological and toxinological responses to stings by prominent species of jellyfish including Physalia sp (Portuguese Man-o-War, Blue bottle), Cubozoan jellyfish including Chironex fleckeri, several Carybdeids including Carybdea arborifera and Alatina moseri, Linuche unguiculta (Thimble jellyfish), a jellyfish responsible for Irukandji syndrome (Carukia barnesi) and Pelagia noctiluca. Jellyfish venoms are composed of potent proteinaceous porins (cellular membrane pore-forming toxins), neurotoxic peptides, bioactive lipids and other small molecules whilst the tubules contain ancient collagens and chitins. We postulate that immunologically, both tubular structural and functional biopolymers as well as venom components can initiate innate, adaptive, as well as immediate and delayed hypersensitivity reactions that may be amenable to topical anti-inflammatory-immunomodifier therapy. The current challenge for immunotoxinologists is to deconstruct the actions of venom components to target therapeutic modalities for sting treatment. PMID- 21824079 TI - From the stretcher to the pharmacy's shelf: drug leads from medically important brazilian venomous arachnid species. AB - Accidents involving venomous animals have always caught the attention of mankind due to their lethality and other clinical implications. However, since the molecules obtained from animal venoms have been the product of millions of years of evolutionary process, toxins could be used to probe physiological mechanisms and could serve as leads for drug development. The present work reviews the state of the art pertaining to venom molecules from Brazilian medically important arachnid species bearing potential biotechnological applications. Special focus is given to toxins isolated from the scorpion Tityus serrulatus and the spiders Phoneutria nigriventer and Lycosa erythrognatha, whose venoms possess molecules acting as erectile function modulators and as antihypertensive, analgesic, neuroprotective and antimicrobial agents. PMID- 21824080 TI - Venom Peptide modulators of the immune system. AB - Venomous animals produce a diverse range of peptides and small molecules that are of both therapeutic and pharmacologic value. One such animal, the cone snail, produces peptides known as conotoxins, which may be of interest to those studying the mammalian immune system. Conotoxins are a family of venom peptides that display extraordinary diversity and often exquisite specificity for membrane protein targets, especially voltage and ligand activated ion channels. Conopeptides are proving to be important pharmacological tools to probe human physiology, with some showing promise as therapeutics for conditions such as neuropathic pain. The potential of these peptides to interact and modulate the human immune system has not been investigated despite literature suggesting that conotoxins could be valuable research tools and potential therapeutics in area of immunology. Known pharmacological targets of conopeptides expressed by immunocompetent cells include voltage-gated potassium channel (Kv), voltage-gated calcium channel (Cav), nicotinic and acetylcholine receptors. In addition, the 5 HT3, GABAB and NMDA receptors that are not considered classic immunomodulators but may play a secondary role in modulating immune responses. This review highlights venom peptides with potential to act at immunological targets within the mammalian immune system. PMID- 21824081 TI - Immune response towards snake venoms. AB - The immune response involves a complex repertoire of innate and adaptive responses to foreign agents in the organism. The present review focuses on the immune response to snake venoms, including those occurring in snakebite accidental envenomation, experimental vaccination and animal hyperimmunization for snake antivenom production. The following aspects are considered: (a) the structural characteristics of snake toxins and their relationship to immunogenicity, (b) the effects that factors such as administration route, venom dose, type of adjuvant, and individual and species characteristics of the immunized animal have on the immune response, (c) the initial venom-induced inflammatory response, (d) the process by which specific antibodies towards individual toxins are produced, and (e) the techniques currently used to evaluate the antibody response. Understanding the immune response to snake venoms is highly relevant for improving antivenom production and for gaining a more complete view of snakebite envenoming. PMID- 21824082 TI - The humoral immune response induced by snake venom toxins. AB - This review summarizes the key contributions to our knowledge regarding the immune response induced by snake venom toxins, focusing particularly on the production of antibodies and their venom-neutralizing effects. We cover the past and present state of the art of anti-snake venom production, followed by an overview of the venomous snakes and their venoms. The toxic properties of relevant snake venom toxins are approached in some details, with particular emphasis on the molecular domains responsible for binding to cells or plasma components in victims. The interactions of these domains are also reviewed, particularly the putatively relevant epitopes, along with the immune system and the resulting antibodies. We also review trials aimed at reducing the quantities of non-relevant antibodies in the antivenoms by substituting whole venoms with purified toxins to immunize animals, or the immunogenicity of the heterologous antivenom antibodies by humanizing their molecules. PMID- 21824084 TI - High-Throughput, 384-Well, LC-MS/MS CYP Inhibition Assay Using Automation, Cassette-Analysis Technique, and Streamlined Data Analysi. AB - Here we describe a high capacity and high-throughput, automated, 384-well CYP inhibition assay using well-known HLM-based MS probes. We provide consistently robust IC(50) values at the lead optimization stage of the drug discovery process. Our method uses the Agilent Technologies/Velocity11 BioCel 1200 system, timesaving techniques for sample analysis, and streamlined data processing steps. For each experiment, we generate IC(50) values for up to 344 compounds and positive controls for five major CYP isoforms (probe substrate): CYP1A2 (phenacetin), CYP2C9 ((S)-warfarin), CYP2C19 ((S)-mephenytoin), CYP2D6 (dextromethorphan), and CYP3A4/5 (testosterone and midazolam). Each compound is incubated separately at four concentrations with each CYP probe substrate under the optimized incubation condition. Each incubation is quenched with acetonitrile containing the deuterated internal standard of the respective metabolite for each probe substrate. To minimize the number of samples to be analyzed by LC-MS/MS and reduce the amount of valuable MS runtime, we utilize timesaving techniques of cassette analysis (pooling the incubation samples at the end of each CYP probe incubation into one) and column switching (reducing the amount of MS runtime). Here we also report on the comparison of IC(50) results for five major CYP isoforms using our method compared to values reported in the literature. PMID- 21824083 TI - Analogs of the sea anemone potassium channel blocker ShK for the treatment of autoimmune diseases. AB - CCR7- effector memory T (TEM) lymphocytes are involved in autoimmune diseases such as multiple sclerosis, type 1 diabetes mellitus and rheumatoid arthritis. These cells express Kv1.3 potassium channels that play a major role in their activation. Blocking these channels preferentially inhibits the activation of CCR7- TEM cells, with little or no effects on CCR7+ naive and central memory T cells. Blockers of lymphocyte Kv1.3 channels therefore show considerable potential as therapeutics for autoimmune diseases. ShK, a 35-residue polypeptide isolated from the Caribbean sea anemone Stichodactyla helianthus, blocks Kv1.3 channels at picomolar concentrations. Although ShK was effective in treating rats with delayed type hypersensitivity and a model of multiple sclerosis, it lacks selectivity for Kv1.3 channels over closely-related Kv1 channels. Extensive mutagenesis studies combined with elucidation of the structure of ShK led to models of ShK docked with the channel. This knowledge was valuable in the development of new ShK analogs with improved selectivity and increasing stability, which have proven efficacious in preventing and/or treating animal models of delayed type hypersensitivity, type 1 diabetes, rheumatoid arthritis, and multiple sclerosis without inducing generalized immunosuppression. They are currently undergoing further evaluation as potential immunomodulators for the treatment of autoimmune diseases. PMID- 21824085 TI - Hypercholesterolemia: chemical aspect of approach. AB - This review is the first attempt at systematization and analysis of the literature data (covering the last decade) on the chemical structures and specific activities of cholesterol-regulating agents. Six of thirty currently known biological targets for treating hyperlipidemia were selected and considered. All of the chemical structures under study are divided into two classes with different mechanisms of their activity: cholesterol biosynthesis blockers (HMG-CoA reductase and squalene 2,3-oxide-lanosterol cyclase inhibitors) and regulators of cholesterol transformations in the organism (PPARalpha and PPARalpha/gamma agonists, inhibitors of intestinal absorption of cholesterol, cholesteryl ester transfer protein (CETP) inhibitors, and regulators of low density-lipoprotein receptor (LDLR) expression). PMID- 21824086 TI - Differential anti-cancer effects of purified EPA and DHA and possible mechanisms involved. AB - As the concepts of pharmaconutrition are receiving increasing attention, it seems essential to clearly assess the effects of specific dietary compounds in specific groups of patients or clinical conditions. We are herein interested in better defining the differential anti-neoplastic effects of the two major n-3 long chain polyunsaturated fatty acids present in fish oil, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The efficiency of these fatty acids represents a subject of intense interest and debate, and whereas plenty of preclinical studies have strongly demonstrated their preventive and therapeutic effect in different kinds of cancers, the results of the epidemiologic studies are still controversial, and only a few trials have been performed. It has been reported that EPA and DHA may act either through the same or different mechanisms, thus suggesting that a differential efficacy could exist. At present, however, this point has not been clarified, although its better comprehension would allow a more proper and effective use of these fatty acids in the human interventional studies. In an attempt to elucidate this aspect we have herein analyzed the data obtained in the studies which have directly compared the antitumor effects of separate treatments with EPA or DHA. Most of the in vitro data indicate DHA as the more powerful antineoplastic agent. However, an equivalent efficiency of EPA and DHA is suggested by the few in vivo studies. Possible reasons for this discrepancy are discussed and pathways of cell growth that could be differentially influenced by EPA and DHA are described. PMID- 21824087 TI - Targeting mitochondrial dysfunction and neurodegeneration by means of coenzyme Q10 and its analogues. AB - Coenzyme Q10 is a small electron carrier of the respiratory chain with antioxidant properties, widely used for the treatment of mitochondrial disorders. Mitochondrial diseases are neuromuscular disorders caused by impairment of the respiratory chain and increased generation of reactive oxygen species. Coenzyme Q10 supplementation is fundamental in patients with primary coenzyme Q10 deficiency. Furthermore, coenzyme Q10 and its analogues, idebenone and mitoquinone (or MitoQ), have been also used in the treatment of other neurogenetic/neurodegenerative disorders. In Friedreich ataxia idebenone may reduce cardiac hypertrophy and, at higher doses, also improve neurological function. These compounds may also play a potential role in other conditions which have been linked to mitochondrial dysfunction, such as Parkinson disease, Huntington disease, amyotrophic lateral sclerosis and Alzheimer disease. This review introduces mitochondrial disorders and Friedreich ataxia as two paradigms of the tight links existing between oxidative stress, respiratory chain dysfunction and neurodegeneration, and focuses on current and emerging therapeutic uses of coenzyme Q10 and idebenone in neurology. PMID- 21824088 TI - Advances in bile acid medicinal chemistry. AB - Bile acids (BAs) are a family of steroidal molecules derived from cholesterol and biosynthesised in the pericentral hepatocytes of the liver. Structurally they may be regarded as consisting of two components, a rigid steroid nucleus and a short aliphatic side chain terminating in an alcohol or carboxyl group. Traditionally BAs are known for their ability to act as solubilising agents in the gut, aiding in the absorption of dietary lipids through the formation of mixed micelles. However the identification of BAs as ligands of the farnesoid X receptor (FXR) has lead to the realisation that these molecules have a wider range of biological effects. BAs regulate lipid and glucose homeostasis through activation of the FXR and the G-protein coupled receptor, TGR5. They can activate apoptotic, inflammatory and carcinogenic signalling pathways. BAs have also been shown to have anti-inflammatory effects. Interestingly, BAs are not restricted to the hepatic-intestinal system. Plasma BAs regulate BA synthesis and metabolism. BAs have recently been identified in cerebrospinal fluid. The BA, ursodeoxycholic acid has a potential role as a neuroprotectant in Huntington's disease and its taurine conjugate exhibits neuro-protective effects in vitro that may be relevant to Alzheimer's disease. This renaissance in BA biology has lead to the development of numerous medicinal chemistry programmes with different therapeutic targets, using BAs as lead structures. BA derivatives with increased efficacy and potency for FXR and TGR5 hold significant promise for the treatment of metabolic disorders. The peculiar effects of BAs on cell viability have been exploited for the design of selective cytocidal agents for treatment of various cancers. BA derivatives have also been screened with much success for anti-microbial and antifungal properties. Other targets include carbonic anhydrase for treatment of glaucoma and the glucocorticoid receptor for antiinflammatory effects. In this review interesting recent developments in the medicinal chemistry of these eclectic substances will be discussed. PMID- 21824089 TI - Insight into the structural requirements of benzothiadiazine scaffold-based derivatives as hepatitis C virus NS5B polymerase inhibitors using 3D-QSAR, molecular docking and molecular dynamics. AB - Hepatitis C virus (HCV) infection is a significant world health threat with frequently ineffective problem existed in the present treatment, thus representing a major unmet medical need. The nonstructural viral protein 5B (NS5B), one of the best-studied polymerase, has emerged as an attractive target for the development of novel therapeutics against hepatitis C virus. In this work, both ligand- and receptor- based three-dimensional quantitative structure activity relationship (3D-QSAR) studies were carried out using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques on 360 benzothiadiazine scaffold-based derivatives as HCV GT-1b NS5B polymerase allosteric inhibitors. The resultant optimum 3D-QSAR model exhibited R(2)(ev) of 0.54, R(2)(nev) of 0.72 and the predictive ability was validated by using an independent test set of 90 compounds which gave R(2)(pred) value of 0.64. In addition, docking analysis and molecular dynamics simulation (MD) were also applied to elucidate the probable binding modes of these inhibitors at the allosteric site of the enzyme. Interpretation of the 3D contour maps in context of the topology of the allosteric binding site of NS5B provided insight into NS5B-inhibitor interactions. The information obtained from this work can be utilized to accurately predict the binding affinity of related analogues and also facilitate the future rational design of novel inhibitors with improved activity. PMID- 21824090 TI - Small molecule inhibitors of STAT3 for cancer therapy. AB - Aberrant activation of the signal transducer and activator of transcription (STAT) 3 occurs in many human tumors. Constitutive STAT3 activity induces specific target genes that stimulate cell proliferation, prevent apoptosis, promote angiogenesis and facilitate tumor immune evasion. Thus, STAT3 is an attractive molecular target for the development of novel cancer therapeutics. Targeting and disruption of oncogenic STAT3 signaling may theoretically be accomplished through various approaches, involving direct and indirect strategies. Small molecular weight compounds have been used for this purpose. This review is intended to be full coverage of the small molecular inhibitors to develop direct STAT3 as a target for cancer therapy and will provide a discussion on the inhibitory modalities developed to date. At present, we retrieved related small molecular inhibitors experimental research papers about STAT3 as a cancer therapy target, the rationale to pursue the protein for the discovery and development of novel anticancer strategies and agents. PMID- 21824091 TI - Quinone methides and their prodrugs: a subtle equilibrium between cancer promotion, prevention, and cure. AB - The importance of reactive drug metabolites in the pathogenesis of drug-induced toxicity has been investigated since the early 1950s, mainly to reveal the link between toxic metabolites and chemical carcinogenesis. This review mainly focuses on biologically active compounds, which generate reactive quinone methide (QM) intermediates either directly or after bioactivation. Several examples of anticancer drugs acting through the generation of QM electrophiles are given. The use of those drugs for chemotherapeutic purposes is also discussed. The key feature of those QM-generating drugs is their reactivity toward specific nucleophilic biological targets. Modulation of their reactivity represents a challenge for medicinal chemists because, depending on the reactivity of these QM intermediates, their interaction with critical proteins can alter the function of these key proteins and induce a wide variety of responses with functional consequences. Among the possible consequences, antiproliferative effects could be exploited for chemotherapeutic purposes. Information on how such QM-generating drugs can affect individual target proteins and their functional consequences are required to help the medicinal chemist in the design of more specific QM generating molecules for chemotherapeutic use. PMID- 21824092 TI - Advances in dendritic cell-based vaccines for HIV. AB - HIV remains one of the most important deadly infections today, due to the lack of a preventive vaccine and limited access to medical care in developing countries. In developed countries antiretroviral therapy is available but the regime is unable to eliminate the virus, implying that life-long therapy is necessary. Dendritic cells (DCs) are important mediators of cellular and humoral immune responses and hence offer a promising therapeutic vaccination strategy to attenuate disease progression. The current knowledge in DC subsets and their functional plasticity are prominent determinants in harnessing the full immunostimulatory potential of dendritic cells. Type of antigen, immunogen delivery method, optimal interaction of antigenic peptide and T cells, and avoidance of tolerogenic responses are some of the elements that need to be considered to develop an efficient immunotherapy. Novel strategies that modulate DC functions that eventually trigger a robust cellular response against a broad T cell repertoire are needed. This review focuses on current DC-based vaccine strategies for optimal induction of immune responses. PMID- 21824093 TI - The "STEP-wise" future of adenovirus-based HIV vaccines. AB - The HIV pandemic continues to be a public health crisis with over 30 million people currently living with the disease and, depending on the estimate, another 2 - 2.8 million infected annually. The disappointing results of the first Phase II study of a highly immunogenic adenovirus-vectored vaccine, named the STEP trial, was a wake up call to both the clinical and preclinical HIV vaccine fields. A vaccine designed only to elicit T cells and including a single HIV gene insert, will not be sufficient to reduce transmission or lower viremia in people. Additionally, future use of adenovirus-based vectored vaccines needs to be carefully planned with respect to vector type, gene inserts, route of immunization and risk factors among subject volunteers. The initial observation of a transient, increased risk of infection in Ad5 seropositive, uncircumcised men who have sex with men (MSM) is still unexplained, and may yet be considered simply a random event. The vaccine field has not given up on adenoviruses and there is continued interest in pursuing these highly immunogenic vectors, either in combination approaches with DNA, use of rare serotypes with low seroprevalence, or those derived from simian origin. Finally, evaluation of replicating adenovirus vectors known to be capable of inducing potent cellular, humoral, and mucosal immunity will be vital to meeting our future goal of an effective HIV vaccine. PMID- 21824094 TI - PD-1 signaling in HIV and chronic viral infection--potential for therapeutic intervention? AB - Programmed death-1 (PD-1) is a negative immunoregulatory cell surface receptor molecule whose interaction with its ligands PD-L1 and PD-L2 downmodulates T-cell immune responses. Originally investigated in the context of self-tolerance, PD-1 has more recently been discovered to be upregulated on T cells of HIV-infected individuals. High levels of PD-1 on HIV-infected T cells are correlated with viral load and with a state of cellular anergy, or ' exhaustion' that results in decreased cellular proliferation, cytotoxic function and cytokine secretion. The finding that interruption of PD-1 with its ligand PD-L1 rescues HIV-infected cells from this state of anergy or ' exhaustion' presents the promise for therapeutic intervention. Understanding the molecular signaling pathway(s) of PD 1 may provide opportunities for therapeutic intervention, that may serve as adjunctive therapies to HIV vaccine development. Evidence to date suggests that PD-1 exerts its regulatory effect by interfering with T cell receptor signaling. While certain molecular signals in the PD-1 pathway have been identified, their precise roles and mechanisms of action remain poorly understood. This article reviews what is currently known about PD-1 signaling in human T cells, and more specifically in T cells of individuals chronically infected with certain viruses such as HIV. PMID- 21824095 TI - Immune correlates of HIV control. AB - The development of an effective HIV vaccine is still hampered by the lack of clearly defined immune correlates of HIV control. Although a number of immune markers have been associated over last years with relative viral control and slower HIV disease progression, these associations are oftentimes complicated by the causality dilemma that does not allow to directly assign cause or effect to the identified parameters. In addition, many of these immune markers may act in concert or represent surrogate makers for otherwise controlled HIV infection. This review will revisit the current knowledge of host genetic and immune markers and their associations with HIV control, particularly examining the roles of virus-specific T cells and humoral immune responses and testing their role as direct correlates of control. PMID- 21824096 TI - Simultaneous approach using systemic, mucosal and transcutaneous routes of immunization for development of protective HIV-1 vaccines. AB - Mucosal tissues are major sites of HIV entry and initial infection. Induction of a local mucosal cytotoxic T lymphocyte response is considered an important goal in developing an effective HIV vaccine. In addition, activation and recruitment of memory CD4(+) and CD8(+) T cells in systemic lymphoid circulation to mucosal effector sites might provide the firewall needed to prevent virus spread. Therefore a vaccine that generates CD4(+) and CD8(+) responses in both mucosal and systemic tissues might be required for protection against HIV. However, optimal routes and number of vaccinations required for the generation of long lasting CD4(+) and CD8(+) CTL effector and memory responses are not well understood especially for mucosal T cells. A number of studies looking at protective immune responses against diverse mucosal pathogens have shown that mucosal vaccination is necessary to induce a compartmentalized immune response including maximum levels of mucosal high-avidity CD8(+) CTL, antigen specific mucosal antibodies titers (especially sIgA), as well as induction of innate anti viral factors in mucosa tissue. Immune responses are detectable at mucosal sites after systemic delivery of vaccine, and prime boost regimens can amplify the magnitude of immune responses in mucosal sites and in systemic lymphoid tissues. We believe that the most optimal mucosal and systemic HIV/SIV specific protective immune responses and innate factors might best be achieved by simultaneous mucosal and systemic prime and boost vaccinations. Similar principals of vaccination may be applied for vaccine development against cancer and highly invasive pathogens that lead to chronic infection. PMID- 21824097 TI - Update on HIV vaccines: which way now? PMID- 21824098 TI - Coumarins as antioxidants. AB - Coumarins, a well-known class of naturally occurring compounds, display a remarkable array of biochemical and pharmacological actions, some of which suggest that certain members of this group of compounds may significantly affect the function of various mammalian cellular systems. The development of coumarins as antioxidant agents has attracted much attention in recent years. Coumarins afford an opportunity for the discovery of new antioxidants with truly novel mechanisms of action. This review updates and expands the 2006 review by the same author. The review considers and incorporates the most recently published literature on coumarins as related to their antioxidant properties. A lot of coumarins have been identified from natural sources, especially green plants. These natural compounds have served as valuable leads for further design and synthesis of more active analogues. Beyond doubt, a deep understanding of the mechanisms of existing synthetic and natural coumarins will build the basis for the rational design. PMID- 21824099 TI - Medicinal chemistry perspectives of trioxanes and tetraoxanes. AB - Trioxane based compounds such as artemisinin and its synthetic and semi-synthetic analogues constitute promising class of antimalarial agents. The pharmaceutical development of artemisinin was started in 1971 after the isolation from Chinese medicinal plant Artemisia annua and this compound has drawn much attention from medical chemist and pharmacologist worldwide. Researchers from across the globe have independently and collaboratively conducted various studies on the artemisinin system in an attempt to identify lead molecules for malaria chemotherapy. This systematic study led to the discovery of artemether, arteether, dihydroartemisinin, and sodium artesunate which are being used as antimalarial drug for the treatment of Plasmodium falciparum related infections. These studies also revealed that the trioxane bridge is essential for the antimalarial activity of this class of compounds. Another class of structurally simple peroxides that emerged from these studies was the 1,2,4,5-tetraoxanes. Some of the tetraoxane based compounds have shown promising antimalarial potential, and much of work has been done on this type of compound in recent years. Apart from their antimalarial activity, these classes of compounds have also shown promising anticancer and antibacterial activity. To this end, an attempt has been made to describe the medicinal potential of trioxane and tetraoxane-based compounds. Literature from 1999 has been critically reviewed and an attempt has been made to discuss structure activity relationship study among the series of trioxane and tetraoxane based compounds. PMID- 21824100 TI - Antioxidant therapy: current status and future prospects. AB - Reactive oxygen species (ROS) are widely believed to cause or aggravate several human pathologies such as neurodegenerative diseases, cancer, stroke and many other ailments. Antioxidants are assumed to counteract the harmful effects of ROS and therefore prevent or treat oxidative stress-related diseases. In this report, recent human studies exploring the efficiency of antioxidants in prevention and treatment of various diseases are reviewed. Few antioxidants including edaravone (for ischemic stroke in Japan), Nacetylcysteine (for acetaminophen toxicity), alfa-lipoic acid (for diabetic neuropathy) and some flavonoids (polyphenolic compounds present in dietary plants), such as micronized purified flavonoid fraction (diosmin and hesperidin) and oxerutins (for chronic venous insufficiency) as well as baicalein and catechins (for osteoarthritis) have found accepted clinical use. However, despite much enthusiasm in the 1980s and 1990s, many well-known agents such as antioxidant vitamins and also more recently developed compounds such as nitrones have not successfully passed the scrutiny of clinical trials for prevention and treatment of various diseases. This has given rise to a pessimistic view of antioxidant therapy, however, the evidence from human epidemiological studies about the beneficial effects of dietary antioxidants and preclinical in vitro and animal data are compelling. We have probably wasted too much time on agents like antioxidant vitamins instead of focusing on more disease specific, target-directed, highly bioavailable antioxidants. We here discuss possible reasons for the lack of success in some clinical trials and seek to provide some suggestions to be considered if antioxidant therapy is to succeed as an effective therapeutic strategy. PMID- 21824101 TI - Synthetic and application perspectives of azapodophyllotoxins: alternative scaffolds of podophyllotoxin. AB - Podophyllotoxin (1) has been known to possess anti-tumor activity and is still considered an important lead for research and development of antineoplastic agents. Derivatives of podophyllotoxin, namely etoposide (2), etopophos (3) and teniposide (4) have been developed and are currently used in clinic for the treatment of a variety of malignancies. These agents are also used in combination therapies with other drugs. Due to the drug resistance developed by cancer cells as well as side effects associated with the use of these agents in clinic, the search for new effective anticancer analogues of podophyllotoxin remains an intense area of research. The structural complexity of podophyllotoxin, arising from the presence of four stereogenic carbons in ring C has restricted most of the structural activity relationship (SAR) studied by derivatization of the parent natural product rather than by de novo multi-step chemical synthesis. These issues provide strong impetus to a search for analogues of 1 with simplified structures, which can be accessible via short synthetic sequences from simple starting materials. Even if such initial compounds might have diminished cytotoxic potencies compared with the parent cyclolignan, the ease of preparation of carefully designed libraries of analogues would lead to more informative SAR studies and expeditious structure optimization. In this regard, during the last two decades considerable efforts have been made to synthesize aza- analogs of podophyllotoxin, i. e. aza-podophyllotoxins, with hetero atoms at different positions of the podophyllotoxin skeleton, while keeping the basic podophyllotoxin structure. Recently, there have been significant efforts towards the convenient synthesis of aza-analogs of 1. The use of multicomponent reactions (MCRs) and the synergies of ultrasound and microwave irradiations have increased the synthetic speed and variety of azapodophyllotoxins which are and will be available to be tested against a diverse population of carcinomas and other diseases. It has been reported that several aza-podophyllotoxins retain a great fraction of the cytotoxicity associated with the parent lignan. This review focuses on the strategies towards synthesis of various aza-podophyllotoxin analogues and their biological activities. PMID- 21824102 TI - An update on natural occurrence and biological activity of chromones. AB - The chemistry of chromones is very well known. This system is widely used in organic chemistry as an intermediate compound for the synthesis of numerous hetrocycles. On the other hand, chromones were extensively studied as bioactive compounds. They possess remarkable biological activities, such as antimicrobial, antiviral, anticancer, anti-inflammatory, antioxidant, etc. This comprehensive review describes the current status and knowledge of natural occurrence, and biological activities of chromones. Recent advances made over the last decade i.e. January 1999 to December 2009 are critically discussed and we have covered about 176 references and more than 350 compounds reported during this period. PMID- 21824103 TI - Small molecule drug agents. PMID- 21824104 TI - Treatment of cardiovascular calcification in uremia. AB - Uremic subjects, in addition to accelerated atherosclerosis, develop diffuse media vascular calcification (VC) which, in turn, is associated with increased vascular stiffness and mortality risk. Two sets of risk factors for VC can be considered: passive deposition of calcium-phosphate and active transformation of vascular smooth muscle cells into osteoblastic- like cells. The former is linked with the metabolic imbalance in divalent ions that affects renal patients at any stage of the disease; the latter is secondary to a recently discovered mechanism of cellular trans-differentiation caused by deranged local concentration of divalent ions. Also, the role of inhibitors of calcification is under investigation. These include circulating or local, substances like fetuin, matrix GLA protein or osteoprotegerin. Their biologic importance is supported by the occurrence of calcification in transgenic animals lacking these factors. Accordingly, VC is a complex biologic and incompletely understood process that deserves further research, in order to develop specific therapeutic strategies. In general, once established, these calcifications are not considered to be reversible; therefore, prevention is the main treatment option. With this aim, in uremic patients it is now recommended to adopt restricted ranges of serum concentrations for calcium, phosphate and parathyroid hormone which are associated with a lower rate of calcification. To target these recommended ranges, new drugs, like selective vitamin D receptor activators, calcium sensing receptor modulators and calcium free intestinal phosphate binders, have been introduced. Moreover new possible pathogenetic pathways are considered (e.g. vitamin K deficiency). Further, in patients with calciphylaxis, the most severe form of VC, experimental therapies are suggested, with drugs like sodium thiosulphate or bisphosphonates. Drugs capable of reversing the process of trans differentiation from osteoblast-like to vascular smooth muscle cells could be developed in the future. PMID- 21824105 TI - Risk factors for cardiovascular events in Japanese patients treated with fluvastatin from the long-term event monitoring (LEM) study. AB - OBJECTIVE: The long-term event monitoring (LEM) study evaluated the lipid lowering efficacy and safety of fluvastatin in Japanese patients with hypercholesterolemia. The present sub-analysis focused on the impact of risk factors on event prevention. METHODS: In the LEM study, patients (n=21,139) who started fluvastatin between 2000/4/1 and 2002/3/31 in Japan were prospectively registered and followed up for 3 years (secondary prevention cohort) or 5 years (primary prevention cohort). RESULTS: Of the patients registered, 19,084 were included in this sub-analysis. The secondary prevention group, demonstrated 8.27- and 2.89-fold higher incidence in cardiac events and cerebral events, respectively compared with the primary prevention group (P < 0.001). Complications of cerebrovascular disease demonstrated a 2.22- and 5.29-fold higher incidence in cardiac events and cerebral events (P < 0.01 and P < 0.001, respectively). Presence of diabetes mellitus (DM) in patients without complication significantly increased the incidence in both cardiac events (2.37) and cerebral events (2.15) as compared with non-DM patients for primary prevention (P < 0.001 and P < 0.01, respectively). For the secondary prevention, DM patients with complication of cardiac disease showed a significantly higher incidence in both cardiac events (1.59) and cerebral events (3.79) compared with non-DM patients (P < 0.05 and P < 0.01, respectively). In contrast, DM patients with complications of cerebrovascular disease showed a significantly higher incidence in cerebral events (2.58, P < 0.05), but not cardiac events compared with non-DM patients. Similarly, the presence of hypertension significantly increased the incidence in both cardiac (1.64) and cerebral events (1.81) for primary prevention (P < 0.01 and P < 0.05, respectively). For secondary prevention, hypertension in patients with complication of cardiac or cerebrovascular disease did not affect incidence in both cardiac and cerebral events. In the patients without complication, high triglycerides and low high density lipoprotein cholesterol (HDL-C), but not low density lipoprotein cholesterol (LDL-C), increased cerebral events, while only LDL-C significantly increased cardiac events. For secondary prevention, high triglycerides or low HDL C, but not LDL-C, significantly increased the relative risk of cardiac events in the patients with complication of cardiac disease. CONCLUSIONS: The LEM study, a large-scale prospective study of long-term fluvastatin treatment for hypercholesterolemia in Japanese patients, demonstrated high impact of complications such as DM and hypertension as well as high triglycerides or low HDL-C on cardiac and cerebral events. After long-term statin treatment, the control of other factors rather than LDL-C alone might be important to avoid vascular events. PMID- 21824106 TI - Progress of computer-aided drug design (CADD) of proteasome inhibitors. AB - The target proteasome has been the focus of drug discovery since the first drug bortezomib was launched in 2003. Many structurally diverse proteasome inhibitors were discovered and even some of them entered the clinical trials. Due to rapid technological progress in chemistry, bioinformatics, structural biology and computer technology, computer-aided drug design (CADD) plays a more and more important role in today's drug discovery. Many CADD technologies were employed in designing various inhibitors of proteasome in the past years. This review gives a global description of the development of computer-aided proteasome inhibitor design by using different commercial or academic software. The binding modes of some structurally novel inhibitors with proteasome were visualized with these new technologies. PMID- 21824107 TI - The immunoproteasome: an emerging therapeutic target. AB - The proteasome, a large multisubunit protease complex, has been extensively investigated over the years, greatly enhancing our understanding of critical roles that the proteasome plays in cells. The FDA approval of bortezomib for the treatment of multiple myeloma and mantle cell lymphoma has validated the proteasome as an anticancer target. However, the undesirable toxicities of these agents limit their broad utility. The immunoproteasome, an alternative form of the constitutive proteasome, has recently been explored as a therapeutic target. While the immunoproteasome, normally expressed in cells of hematopoietic origin, has been shown to be associated with various types of cancer and inflammatory diseases, its multifaceted function is not fully understood due to the lack of appropriate molecular probes. In this review, recent advances in the immunoproteasome field are covered, including potential implications in disease states. In particular, recent developments in immunoproteasome-specific inhibitors are emphasized. PMID- 21824108 TI - Synthesis of salinosporamide A and its analogs as 20S proteasome inhibitors and SAR summarization. AB - Salinosporamide A (4), a secondary metabolite of the marine actinomycete Salinispora tropica, is a potent inhibitor of 20S proteasome that is currently in clinical trials for the treatment of cancers. Herein, we described various synthetic strategies of 4 and summarized the SAR of 4 and its analogs. PMID- 21824109 TI - Targeting the ubiquitin-proteasome pathway: an emerging concept in cancer therapy. AB - Selective degradation of proteins by the ubiquitin-proteasome pathway is a critical determinant for maintaining cellular homeostasis. Most intracellular proteins are degraded by the proteasome, a multicatalytic enzyme complex containing a 20S catalytic core and two 19S regulatory complexes. Many proteasome target proteins are involved in the regulation of important processes of carcinogenesis and cancer cell survival, such as cell cycle progression, cell proliferation, differentiation and apoptosis. Indeed, the ubiquitin-proteasome dependent degradation pathway plays an essential role in both the up-regulation of cell proliferation and down-regulation of cell death in human cancer cells. Both in vitro and in vivo experimental and clinical results have demonstrated the potential use of proteasome inhibitors as novel anticancer drugs. Proteasome inhibition in cancer cells leads to accumulation of pro-apoptotic target proteins followed by induction of cell death. The clinical efficacy of the proteasome inhibitor bortezomib toward multiple myeloma and other hematologic malignancies provides the "proof of concept" that targeting the proteasome is a promising strategy for cancer treatment. Several other proteasome inhibitors have also been identified from natural resources, such as marine microbial metabolites, green tea polyphenols, flavonoids, and medicinal compounds. Additionally, the use of metal complexes as proteasome inhibitors has also been investigated as a potential anticancer strategy. The clinical significance of targeting the tumor survival-associated proteasome pathway for cancer treatment, intervention and prevention will be discussed. PMID- 21824110 TI - Ubiquitination in Rho signaling. AB - The Rho family small GTPases of the Ras superfamily play key roles in regulating diverse signaling pathways that control a myriad of fundamental cellular processes such as cytoskeletal dynamics, cell cycle progression, gene expression, cell polarity, migration and cell transformation. The Rho GTPases cycle between an active GTP-bound and an inactive GDP-bound form, which is controlled by many regulators including GEFs, GAPs and GDIs. Recent studies have revealed a new layer of regulation for Rho GTPases, indicating that several members of the Rho family of small GTPases including RhoA, Rac1, and RhoBTB, as well as the Ras family member Rap1B, are also regulated by the ubiquitin-proteasome pathway, which plays important roles in controlling cell polarity, migration, cell transformation and actin dynamics. Importantly, regulators for Rho GTP-GDP cycling such as RhoGDI and Rho-GEF ECT2 were also found to be modulated by the ubiquitin pathway. In this review, we focus on how ubiquitin signaling guides the fate and function of Rho GTPases and their regulators, especially how the E3 ubiquitin ligase Smurf1 regulates cell polarity and motility through targeting RhoA for ubiquitination and degradation. PMID- 21824111 TI - Proteasome structure, function, and lessons learned from beta-lactone inhibitors. AB - The 26S proteasome is the enzymatic core engine of the ubiquitin and proteasome dependent proteolytic system (UPS), the major eukaryotic pathway for regulated protein degradation. The UPS plays a pivotal role in cellular protein turnover, protein quality control, antigen processing, signal transduction, cell cycle regulation, cell differentiation and apoptosis, inspiring in-depth studies of proteasome structure and function and the search for selective inhibitors. Structural studies revealed that the 26S proteasome comprises up to two 19S regulatory caps flanking a cylindrical 20S core particle, which houses the proteolytic subunits and is present in all kingdoms of life. This review highlights current understanding of 20S architecture, maturation and assembly, the mechanism for selective degradation of protein substrates targeted for destruction, and relationships to other proteases. This knowledge base has benefited from structurally diverse proteasome inhibitors discovered from unique sources, including terrestrial and marine actinomycetes that produce the beta lactone-gamma- lactam superfamily of inhibitors, including omuralide, salinosporamide A (marizomib; NPI-0052) and the cinnabaramides. These "minimalist inhibitors" utilize dense functionality to maximum efficiency for potent and selective proteasome inhibition and have advanced from biochemical tools to potential agrochemicals and anticancer agents. In this review, lessons learned from the beta-lactone-gamma-lactam superfamily are presented, with an emphasis on their unique binding mechanisms elucidated through structural biology in concert with medicinal chemistry. Distinctions between slowly reversible and irreversible inhibitors are discussed, together with the relationship of irreversible binding at the molecular level to prolonged duration proteasome inhibition in tumor cells, and in vitro and in vivo efficacy. PMID- 21824112 TI - Editorial [Hot topic: The medicinal chemistry of ubiquitin-proteasome pathway (UPP) and its relevance in drug discovery (guest editor: Yongqiang Zhu)]. PMID- 21824113 TI - Expression of hepatocyte growth factor in the skin of amyotrophic lateral sclerosis. AB - OBJECTIVES: Hepatocyte growth factor (HGF) is one of the most potent survival promoting factors for motor neurons. Overexpression of neuronal HGF has been shown to result in the attenuation of neuronal cell death and progression of disease in a familial amyotrophic lateral sclerosis (ALS) transgenic mouse model. HGF might be beneficial for motor neuron survival and is a good candidate agent for the treatment of ALS. So far, studies of the skin of ALS have shown unique pathological and biochemical abnormalities. However, there has been no study of HGF in ALS skin. MATERIALS AND METHODS: We made a quantitative immunohistochemical study of the expression of HGF in the skin from 19 patients with sporadic ALS and 16 controls. RESULTS: Hepatocyte growth factor immunoreactivity was positive in the epidermis, some dermal blood vessels, and glands in patients with ALS. These findings became more conspicuous as ALS progressed. The optical density for HGF immunoreactivity of the nucleus and the cytoplasm in the epidermis in ALS was significantly higher (P < 0.001 and P < 0.001) than in controls. There was a significant positive relation (r = 0.53, P < 0.02 and r = 0.73, P < 0.001) between HGF immunoreactivity and duration of illness in the nucleus and the cytoplasm in the epidermis in patients with ALS. CONCLUSIONS: These findings suggest that changes in HGF in ALS skin are related to the disease process and that metabolic alterations of HGF may take place in the skin of patients with ALS. PMID- 21824114 TI - Impact of screening with thyroid ultrasonography in myasthenia gravis patients. AB - OBJECTIVES: This study was conducted to screen thyroid abnormality evaluated with ultrasonography (US) in patients with myasthenia gravis (MG) and investigate further when malignancy is suspected. METHODS: Thyroid screening using US was conducted in 162 patients with MG. In cases where malignancy was suspected, further investigations were performed. RESULTS: Abnormal US findings were detected in 125 of 162 patients with MG (72 patients with nodules, 74 patients with cysts, 27 patients with diffuse findings such as enlargement, atrophy, a hypoechoic pattern or a heterogenous echoic pattern, and 28 patients with calcification). From among these 125 subjects, 30 patients underwent further examinations such as needle aspiration cytology. As a result, six patients (3.7% of 162 cases) were positive for papillary carcinoma. The size of the carcinoma in three patients was <10 mm, yet the stage of thyroid carcinomas was high (stage III or IVa) in all six cases. CONCLUSIONS: Our data suggest that the prevalence of thyroid carcinoma in cases of MG may be higher than that of the general population. Furthermore, in patients with MG, there is a possibility that the stage of the carcinoma is higher even when the carcinoma is of a very small size. Patients with MG, when diagnosed, should be advised to undergo US screening of the thyroid because most cases of thyroid carcinoma are highly curable. PMID- 21824115 TI - Family recurrence and oligo-anuria predict uremic restless legs syndrome. AB - OBJECTIVES: To determine clinical and laboratory predictors of restless legs syndrome (RLS) in patients with end-stage kidney disease (ESKD) undergoing long term hemodialysis (HD). MATERIALS AND METHODS: One hundred and sixty-two consecutive patients were assessed. History of sleep disturbances, neurological examination, clinical, and laboratory data were collected. Patients with and without RLS were compared, and a logistic regression model described the relations between independent predictors and RLS. RESULTS: Fifty-one patients (32%) currently had RLS (RLS+). RLS+ vs RLS- patients were more frequently women (49% vs 29%, P = 0.012), had first-degree relative with RLS (22% vs 6%, P = 0.004), insomnia (59% vs 36%, P = 0.007), peripheral neuropathy (41% vs 21%, P = 0.006), and low residual diuresis (92% vs 68% with below 500 ml/24 h, P = 0.001). Low (OR = 8.71, CI = 2.27-33.41; P = 0.002) and absent (OR = 4.96, CI = 1.52 16.20; P = 0.008) residual diuresis, peripheral neuropathy (OR = 4.00, CI = 1.44 11.14; P = 0.008), and first-degree relative with RLS (OR = 3.82, CI = 1.21 12.13; P = 0.023) significantly predicted RLS in ESKD patients undergoing HD. CONCLUSION: Positive family history for RLS together with reduced/absent residual renal function and peripheral neuropathy predicts the risk for RLS in ESKD patients undergoing HD. Longitudinal studies are warranted to correlate RLS occurrence with genetic and environmental factors. PMID- 21824116 TI - Acute stroke centre - the changing focus of stroke unit care. The Bergen NORSTROKE Study. AB - OBJECTIVES: The basic stroke unit studies selected patients primarily for rehabilitation and did not deal with the critical first hours after stroke. The aim of this study was to analyse a unselected cohort of patients admitted to an acute stroke centre with primary focus on emergency diagnosis and treatment. MATERIALS AND METHODS: All patients with suspected stroke were admitted as emergencies. Patients with definite cerebrovascular disease were prospectively included in the Bergen Stroke Study, patients with other diseases were excluded, but final diagnosis was registered. RESULTS: Fifty per cent of the admitted patients had other diagnosis than stroke. Of 1267 consecutive patients with cerebrovascular disease, 70% had no or minor neurological deficits on admission. After 1 week, 56% were independent, 30% needed long-term rehabilitation, 10% were bedridden and 4% were dead. CONCLUSION: An acute stroke centre today requires a high degree of neurological expertise in assessing patients admitted with possible stroke. Most patients with stroke have no or mild deficits and need above all rapid diagnostic work-up, acute and prophylactic treatment. In-hospital rehabilitation is essential for a smaller number of patients who suffer from persisting neurological deficits after stroke. PMID- 21824117 TI - Inclusion body myositis in Alzheimer's disease. AB - BACKGROUND: The prevalence of Alzheimer's disease is increasing. Could findings of similar deposits in brain and muscle tissue explain this increase? The purpose of this report is to illustrate that Alzheimer's disease and inclusion body myositis may share a common aetiology. RESULTS: We present a case where Alzheimer's disease and inclusion body myositis coexist in the same patient. Amyloid-beta deposition and the presence of phosphorylated tau protein have been noted in brain tissue and in muscle biopsy from patients with these disorders. METHODS: Electrophysiological methods are needed for proper diagnosis of this brain and muscle disorder. Recent data on deposit structures in both conditions may indicate an environmental aetiology for Alzheimer's disease and inclusion body myositis. CONCLUSION: By combining electrophysiological methods with muscle biopsy in cases of Alzheimer's disease, the possible aetiological connection between simultaneous affection of both muscle and brain in this condition can be established. PMID- 21824118 TI - Trauma, exile and mental health in young refugees. AB - OBJECTIVE: To review evidence of trauma and exile-related mental health in young refugees from the Middle East. METHOD: A review of four empirical studies: i) a qualitative study of 11 children from torture surviving families, ii) a cohort study of 311 3-15-year-old asylum-seeking children, iii) a qualitative study of 14 members of torture surviving families and iv) a follow-up study of 131 11-23 year-old refugees. RESULTS: The reactions of the children were not necessarily post-traumatic stress disorder specific. Seventy-seven per cent suffered from anxiety, sleep disturbance and/or depressed mood at arrival. Sleep disturbance (prevalence 34%) was primarily predicted by a family history of violence. At follow-up, 25.9% suffered from clinically relevant psychological symptoms. Traumatic experiences before arrival and stressful events in exile predicted internalizing behaviour, witnessing violence and frequent school changes in exile predicted externalizing behaviour. School participation, Danish friends, language proficiency and mother's education predicted less long-term psychological problems. CONCLUSION: Psychological problems are frequent in refugee children, but the extents are reduced over time in exile. Traumatic experience before arrival is most important for the short-term reaction of the children while aspects of life in exile are important for the children's ability to recover from early traumatization. PMID- 21824119 TI - Cardiac structure and function and dependency in the oldest old. AB - OBJECTIVES: To examine the association between cardiac function and activities of daily living (ADLs) in an age-homogenous, community-dwelling population born in 1920 and 1921. DESIGN: Cross-sectional analysis of a prospective cohort study. SETTING: Community-dwelling elderly population. PARTICIPANTS: Participants were recruited from the Jerusalem Longitudinal Cohort Study, which has followed an age homogenous cohort of Jerusalem residents born in 1920 and 1921. Four hundred eighty-nine of the participants (228 male, 261 female) from the most recent set of data collection in 2005 and 2006 underwent echocardiography at their place of residence in addition to structured interviews and physical examination. MEASUREMENTS: A home-based comprehensive assessment was performed to assess health and functional status, including performance of ADLs. Dependence was defined as needing assistance with one or more basic ADLs. Standard echocardiographic assessment of cardiac structure and function, including ejection fraction (EF) and diastolic function as assessed using early diastolic mitral annular tissue velocity measurements obtained using tissue Doppler, was performed. RESULTS: Of the participants with limitation in at least one ADL, significantly more had low EF (< 55%) than the group that was independent (52.6 % vs 39.1%; P=.01). In addition, participants with dependence in ADL had higher left ventricular mass index (LVMI) (129.3 vs 119.7 g/m2) and left atrial volume index (LAVI) (41.3 vs 36.7 mL/m2). There were no differences between the groups in percentage of participants with impaired diastolic function or average ratio of early diastolic transmitral flow velocity to early diastolic mitral annular tissue velocity (11.5 vs 11.8; P=.64). CONCLUSION: In this age-homogenous cohort of the oldest old, high LVMI and LAVI and indices of systolic but not diastolic function as assessed according to Doppler were associated with limitations in ADLs. PMID- 21824121 TI - Creating a geriatric medicine fellowship program in 10 "easy" steps. AB - The aging of the U.S. population poses one of the greatest future challenges for family medicine and internal medicine residency training. One important barrier to providing quality education and training in geriatric medicine to residents is a serious and growing shortage of practicing geriatricians and geriatrics faculty. The Accreditation Council for Graduate Medical Education currently accredits 45 family medicine-based and 107 internal medicine-based geriatric medicine fellowships in the United States. There are 13 American Osteopathic Association-certified geriatric medicine fellowship programs. In this article, the authors examine the rationale for the development of additional geriatric medicine fellowship programs and offer some practical suggestions and pointers for those interested in developing their own geriatric medicine fellowships. The authors write from the perspective of their own recent experiences with the development and accreditation of a family medicine residency-affiliated fellowship in geriatrics. Other residencies may find this article useful in determining the feasibility of developing a geriatric medicine fellowship for their programs and communities and will find practical guidance for beginning the process. PMID- 21824120 TI - Potential underuse, overuse, and inappropriate use of antidepressants in older veteran nursing home residents. AB - OBJECTIVES: To examine prevalence and resident- and site-level factors associated with potential underuse, overuse, and inappropriate use of antidepressants in older Veterans Affairs (VA) Community Living Center (CLC) residents. DESIGN: Longitudinal study. SETTING: One hundred thirty-three VA CLCs. PARTICIPANTS: Three thousand six hundred ninety-two veterans aged 65 and older admitted between January 1, 2004, and June 3, 2005, with long stays (>= 90 days). MEASUREMENTS: Prevalence of potential underuse, inappropriate use, and overuse of antidepressants in residents with and without depression (as documented according to International Classification of Diseases, Ninth Revision, Clinical Modification, codes or Depression Rating Scale). RESULTS: Selective serotonin reuptake inhibitors were the most commonly prescribed antidepressant. Of the 877 residents with depression, 25.4% did not receive an antidepressant, suggesting potential underuse. Of residents with depression who received antidepressants, 57.5% had potential inappropriate use due primarily to problems seen with drug drug and drug-disease interactions. Of the 2,815 residents who did not have depression, 1,190 (42.3%) were prescribed one or more antidepressants; only 48 (4.0%) of these had a Food and Drug Administration-approved labeled indication, suggesting potential overuse. Overall, only 17.6% of antidepressant use was appropriate (324/1,844). The only consistent resident factor associated with potential underuse and overuse use was taking an antipsychotic without evidence of schizophrenia (underuse: adjusted relative risk ratio (ARRR)=0.56, 95% confidence interval (CI)=0.33-0.94; overuse: adjusted odds ratio=1.52, 95% CI=1.21-1.91). Having moderate to severe pain (ARRR=1.54, 95% CI=1.08-2.20) and the prescribing of an anxiolytic or hypnotic (ARRR=1.33, 95% CI=1.02-1.74) increased the risk of potential inappropriate antidepressant use. CONCLUSION: Potential problems with the use of antidepressants were frequently observed in older U.S. veteran CLC residents. Future studies are needed to examine the true risks and benefits of antidepressant use in CLC and non-VA nursing homes. PMID- 21824122 TI - Tattoo inks in general usage contain nanoparticles. AB - BACKGROUND: To our knowledge tattooing has never been thought of as a method of introducing nanoparticles (NPs) into the human body by the intradermal route, and as such it has never been a topic of research in nanotoxicology. The content of NPs in tattoo inks is unknown. OBJECTIVES: To classify the particle sizes in tattoo inks in general usage. METHODS: The particle size was measured by laser diffraction, electron microscopy and X-ray diffraction. RESULTS: The size of the pigments could be divided into three main classes. The black pigments were the smallest, the white pigments the largest and the coloured pigments had a size in between the two. The vast majority of the tested tattoo inks contained significant amounts of NPs except for the white pigments. The black pigments were almost pure NPs, i.e. particles with at least one dimension <100 nm. CONCLUSIONS: The finding of NPs in tattoo inks in general usage is new and may contribute to the understanding of tattoo ink kinetics. How the body responds to NP tattoo pigments should be examined further. PMID- 21824123 TI - Advances in Merkel cell carcinoma pathogenesis and management: a recently discovered virus, a new international consensus staging system and new diagnostic codes. AB - Merkel cell carcinoma is a rare but aggressive neuroendocrine carcinoma of the skin with a rising incidence and a high mortality rate. It occurs primarily in sun-exposed skin of older individuals. It is characterized by a high rate of local recurrence, regional lymph node metastases and distant metastases, occurring even after prompt treatment. Many controversies exist regarding its pathogenesis and optimal management. The discovery of Merkel cell polyomavirus has been a major breakthrough in understanding the aetiology of the disease. A recently adopted new international consensus staging system in combination with new international diagnostic codes are expected to facilitate future clinical trials and improve the management of patients. According to recent (2010) guidelines, most patients should be managed with a combination of surgery and radiotherapy. PMID- 21824124 TI - Effect of a preceding laser dermabrasion on the outcome of combined therapy with narrowband ultraviolet B and potent topical steroids for treating nonsegmental vitiligo in resistant localizations. AB - BACKGROUND: The treatment of vitiligo remains unsatisfactory. OBJECTIVES: To assess in patients with vitiligo the effect of a laser dermabrasion in addition to the association of topical steroids and ultraviolet (UV) B in difficult-to treat areas. METHODS: This was a single-centre prospective randomized trial including patients with nonsegmental vitiligo who had at least two symmetrical lesions located on bony prominences and/or extremities. An erbium laser-assisted dermabrasion was first performed on one side (randomly assigned). After 48 h, hydrocortisone 17-butyrate cream applied daily for three periods of 3weeks followed by a 1-week steroid-free interval and narrowband UVB treatment was performed on both sides twice weekly for 12weeks. The evaluation was performed on standardized pictures by two physicians blinded to the type of treatment received. The criterion of success was a repigmentation of at least 50%, 1month after the end of the treatment. RESULTS: Eighteen patients were included (24 paired lesions treated). Two patients dropped out for personal reasons. Almost 50% of lesions achieved at least 50% repigmentation in the dermabrasion side while only 4.2% did so with topical steroids and UVB alone (P<10(-4) ). Side effects were delayed healing, pain and two hypertrophic scars. The tolerance and patient satisfaction were 4.2 and 4/10 for the laser-treated side and 8.4 and 3/10 in the UVB+ steroids alone group, respectively. CONCLUSIONS: Laser dermabrasion significantly improves the repigmentation rate in vitiligo lesions. Despite a high rate of repigmentation in such difficult-to-treat areas the high rate of side-effects and the poor tolerance strongly limit its use in current practice. PMID- 21824125 TI - Evaluation of Bowen disease by in vivo reflectance confocal microscopy. PMID- 21824126 TI - Pyoderma gangrenosum: a retrospective review of patient characteristics, comorbidities and therapy in 103 patients. AB - BACKGROUND: Pyoderma gangrenosum (PG) is an uncommon and challenging disease, highly associated with comorbidities, but poorly characterized from a diagnostic and therapeutic perspective. OBJECTIVES: To describe the epidemiology of PG in a hospital-based retrospective review, focusing on demographics, comorbidities and treatments. METHODS: We conducted a retrospective chart review. Patient data were taken from the Research Patient Data Repository of Brigham and Women's Hospital and Massachusetts General Hospital from 1 January 2000 to 31 December 2007. We identified and confirmed 103 cases of PG, and collected data on anatomical location, number and size of the PG lesions, patient demographics, comorbidities, mortality rate and treatments. RESULTS: Of the 103 patients, 78 (76%) were female, and only 7% had a biopsy suggestive of PG. The lower leg was the most common location with 78% of PG ulcers occurring there, and 67 (65% of patients) had two or more ulcers at some point. Thirty-five individuals (34%) had inflammatory bowel disease (IBD), 21 (20%) had haematological disorders, 14 (14%) had major depression, 20 (19%) had seronegative arthritis, 11 (11%) had psoriasis, and nine (9%) had hepatitis. Therapy was generally multimodal. The mortality rate during the 8-year study period was 16%. CONCLUSIONS: We present one of the largest PG case series to date. In our study, we found that biopsy of a PG lesion rarely yielded characteristic features of the disease and tissue pathology should not be used to exclude a PG diagnosis. We also found a female predominance and associations with IBD and haematological disorders. Patients with PG in this series had high rates of depression and hepatitis. Further work is needed to establish the mechanism(s) underlying these findings. PMID- 21824127 TI - Tumescent liposuction in lipoedema yields good long-term results. AB - BACKGROUND: Lipoedema is a painful disease in women with circumscribed increased subcutaneous fatty tissue, oedema, pain and bruising. Whereas conservative methods with combined decongestive therapy (manual lymphatic drainage, compression garments) have been well established over the past 50years, surgical therapy with tumescent liposuction has only been used for about 10years and long term results are unknown. OBJECTIVES: To determine the efficacy of liposuction concerning appearance (body shape) and associated complaints after a long-term period. METHODS: A total of 164 patients who had undergone conservative therapy over a period of years, were treated by liposuction under tumescent local anaesthesia with vibrating microcannulas. In a monocentric study, 112 could be re evaluated with a standardized questionnaire after a mean of 3years and 8months (range 1year and 1month to 7years and 4months) following the initial surgery and a mean of 2years and 11months (8months to 6years and 10months) following the last surgery. RESULTS: All patients showed a distinct reduction of subcutaneous fatty tissue (average 9846mL per person) with improvement of shape and normalization of body proportions. Additionally, they reported either a marked improvement or a complete disappearance of spontaneous pain, sensitivity to pressure, oedema, bruising, restriction of movement and cosmetic impairment, resulting in a tremendous increase in quality of life; all these complaints were reduced significantly (P<0.001). Patients with lipoedema stage II and III showed better improvement compared with patients with stage I. Physical decongestive therapy could be either omitted (22.4% of cases) or continued to a much lower degree. No serious complications (wound infection rate 1.4%, bleeding rate 0.3%) were observed following surgery. CONCLUSIONS: Tumescent liposuction is a highly effective treatment for lipoedema with good morphological and functional long term results. PMID- 21824128 TI - Benign mucinous metaplasia of the genital mucosa: histomorphological and immunohistochemical features and criteria for differentiation from extramammary Paget disease. AB - BACKGROUND: Benign mucinous metaplasia of the genitalia (BMM) is a rare condition typified by cells with foamy mucinous cytoplasm. Differential diagnoses include extramammary Paget disease (PD) and human papillomavirus (HPV)-induced vulval intraepithelial neoplasia (VIN) with mucinous differentiation. OBJECTIVES: To characterize histopathological and immunohistochemical features of BMM and to forge criteria for differentiation from PD and VIN with mucinous differentiation. METHODS: Eight biopsy specimens of BMM were stained with haematoxylin and eosin, periodic acid-Schiff and alcian blue, and for cytokeratin (CK) 7, CK10, CK14, CK20, carcinoembryonic antigen (CEA), epithelial membrane antigen (EMA), S100, gross cystic disease fluid protein-15 (GCDFP-15), lysozyme and Ki67 and compared with PD. Polymerase chain reaction was performed in order to identify HPV specific DNA. RESULTS: BMM showed mucin deposition in superficial epithelial layers ranging from numerous large goblet cells to subtle deposits. The epithelium often showed polygonal (squamoid) or cuboidal differentiation while columnar differentiation was an inconsistent feature. A band-like inflammatory infiltrate was consistently present. Metaplastic epithelium consistently expressed CK7, CEA and EMA either in the entire epithelium or in a superficial band, while CK14, CK10, GCDFP-15 and lysozyme were largely not expressed, and staining for CK20 and S100 was negative. Comparison with PD demonstrated similar staining characteristics, but in a scattered pattern of mucinous cells within preserved squamous epithelium and not in a band-like pattern as in BMM. Nuclear pleomorphism and Ki67-positive mucinous cells in superficial epithelial layers were seen only in PD; GCDFP-15 and/or lysozyme were expressed in the majority of cases of PD. No evidence of HPV-specific DNA was found in BMM. CONCLUSIONS: The spectrum of changes in BMM is distinctive, and BMM can be differentiated with surety from both PD and VIN with mucinous differentiation. PMID- 21824129 TI - MicroRNAs as novel players in skin development, homeostasis and disease. AB - MicroRNAs (miRNAs) are a group of newly discovered small (~19-24 nucleotides), noncoding RNAs that modulate gene expression by interacting with the 3' untranslated region of the corresponding target gene messenger RNA (mRNA). miRNAs have been estimated to regulate more than one-third of protein-encoding mRNAs. As a consequence, cellular protein expression and a large number of biological processes are influenced by miRNA-mediated post-transcriptional regulation of gene expression. The severe phenotype of mice lacking key enzymes of the miRNA biogenesis pathway (Dgcr8 and Dicer) in the skin confirmed the essential function of miRNAs in this tissue. In addition, a growing number of reports has identified miRNAs as regulators of the morphogenesis and homeostasis of the skin and its appendages, and miRNA deregulation was shown to be associated or even causally related to several skin diseases. Profiling studies have identified numerous differentially regulated miRNAs associated with physiological (e.g. keratinocyte differentiation) and pathological (e.g. psoriasis, melanoma) processes. These data bear enormous potential for further studies. Because of the easy accessibility of the skin, it is plausible to anticipate that, once efficient and safe methods for the topical delivery of substances mimicking or modulating miRNA activity become available, skin diseases will be among the first to be approached with miRNA-based therapies. This review article gives a short introduction to miRNA biology and summarizes and discusses existing evidence for a role of these molecules in the skin. PMID- 21824130 TI - The development of distrust. AB - Preschool-age children's reasoning about the reliability of deceptive sources was investigated. Ninety 3- to 5-year-olds watched several trials in which an informant gave advice about the location of a hidden sticker. Informants were either helpers who were happy to give correct advice, or trickers who were happy to give incorrect advice. Three-year-olds tended to accept all advice from both helpers and trickers. Four-year-olds were more skeptical but showed no preference for advice from helpers over trickers, even though they differentiated between helpers and trickers on metacognitive measures. Five-year-olds systematically preferred advice from helpers. Selective trust was associated with children's ability to make mental state inferences. PMID- 21824131 TI - Nonlinear growth curves in developmental research. AB - Developmentalists are often interested in understanding change processes, and growth models are the most common analytic tool for examining such processes. Nonlinear growth curves are especially valuable to developmentalists because the defining characteristics of the growth process such as initial levels, rates of change during growth spurts, and asymptotic levels can be estimated. A variety of growth models are described beginning with the linear growth model and moving to nonlinear models of varying complexity. A detailed discussion of nonlinear models is provided, highlighting the added insights into complex developmental processes associated with their use. A collection of growth models are fit to repeated measures of height from participants of the Berkeley Growth and Guidance Studies from early childhood through adulthood. PMID- 21824132 TI - Preservation of acidified cucumbers with a combination of fumaric acid and cinnamaldehyde that target lactic acid bacteria and yeasts. AB - The naturally occurring compound, fumaric acid, was evaluated as a potential preservative for the long-term storage of cucumbers. Fumaric acid inhibited growth of lactic acid bacteria (LAB) in an acidified cucumber juice medium model system resembling conditions that could allow preservation of cucumbers in the presence of sodium benzoate. Forty millimolars of fumaric acid were required to inhibit growth of an extremely aciduric Lactobacillus plantarum LA0445 strain at pH 3.8. Half of this concentration was required to achieve inhibition of L. plantarum LA0445 at pH 3.5. As expected growth of the spoilage yeasts Zygosaccharomyces globiformis and Z. bailii was not inhibited by fumaric acid at near saturation concentrations in the same cucumber juice medium. To usefully apply fumaric acid as a preservative in acidified foods it will be necessary to combine it with a food grade yeast inhibitor. The antimicrobial agent, cinnamaldehyde (3.8 mM) prevented growth of Z. globiformis as well as the yeasts that were present on fresh cucumbers. Acidified cucumbers were successfully preserved, as indicated by lack of yeasts or LAB growth and microbial lactic acid or ethanol production by a combination of fumaric acid and cinnamaldehyde during storage at 30 degrees C for 2 mo. This combination of 2 naturally occurring preservative compounds may serve as an alternative approach to the use of sodium benzoate, potassium sorbate, or sodium metabisulfite for preservation of acidified vegetables without a thermal process. PRACTICAL APPLICATION: This study evaluates the potential application of alternative preservatives for the long term storage of cucumbers in a reduced NaCl cover brine solution and without a thermal process. PMID- 21824133 TI - Survival of Escherichia coli O157:H7 in meat product brines containing antimicrobials. AB - Brine solution injection of beef contaminated with Escherichia coli O157:H7 on its surface may lead to internalization of pathogen cells and/or cross contamination of the brine, which when recirculated, may serve as a source of new product contamination. This study evaluated survival of E. coli O157:H7 in brines formulated without or with antimicrobials. The brines were formulated in sterile distilled water (simulating the composition of freshly prepared brines) or in a nonsterile 3% meat homogenate (simulating the composition of recirculating brines) at concentrations used to moisture-enhance meat to 110% of initial weight, as follows: sodium chloride (NaCl, 5.5%) + sodium tripolyphosphate (STP, 2.75%), NaCl + sodium pyrophosphate (2.75%), or NaCl + STP combined with potassium lactate (PL, 22%), sodium diacetate (SD, 1.65%), PL + SD, lactic acid (3.3%), acetic acid (3.3%), citric acid (3.3%), nisin (0.0165%) + ethylenediamine tetraacetic acid (EDTA, 200 mM), pediocin (11000 AU/mL) + EDTA, sodium metasilicate (2.2%), cetylpyridinium chloride (CPC, 5.5%), or hops beta acids (0.0055%). The brines were inoculated (3 to 4 log CFU/mL) with rifampicin resistant E. coli O157:H7 (8-strain composite) and stored at 4 or 15 degrees C (24 to 48 h). Immediate (0 h) pathogen reductions (P < 0.05) of 1.8 to >= 2.4 log CFU/mL were observed in brines containing CPC or sodium metasilicate. Furthermore, brines formulated with lactic acid, acetic acid, citric acid, nisin + EDTA, pediocin + EDTA, CPC, sodium metasilicate, or hops beta acids had reductions (P < 0.05) in pathogen levels during storage; however, the extent of pathogen reduction (0.4 to > 2.4 log CFU/mL) depended on the antimicrobial, brine type, and storage temperature and time. These data should be useful in development or improvement of brine formulations for control of E. coli O157:H7 in moisture-enhanced meat products. PRACTICAL APPLICATION: Results of this study should be useful to the meat industry for developing or modifying brine formulations to reduce the risk of E. coli O157:H7 in moisture-enhanced meat products. PMID- 21824134 TI - Mechanochemistry in thermomechanical processing of foods: kinetic aspects. AB - In some food processing operations, raw materials sustain shearing and heating simultaneously. These thermomechanical treatments will induce chemical, physicochemical, and biochemical changes, such as starch degradation and gelatinization, protein denaturalization, loss of nutritious components, and inactivation of enzymes and their inhibitors. In this article, only kinetic aspects of these changes are reviewed. The Basedow and Zhurkov models are commonly used to describe shear effects on the rate constants of mechanochemical reactions. After a brief description of these 2 models, their applications in food are reviewed deeply, with emphasis on the activation energy reduction in the Zhurkov model and the shear activation energy in the Basedow model. Since the changes occurring in food systems often involve various interactions at the atomic, molecular, and supramolecular levels, they were described only phenomenonlogically by the mechanochemical kinetic models. The limitation, opportunity, and extension of the mechanochemical approach to modeling food kinetics are discussed. PMID- 21824135 TI - Antioxidant and antiinflammation capacities of some pear cultivars. AB - Five commercial pear cultivars were investigated for total phenolics and flavonoids contents, the main phenolic compounds, and their antioxidant and antiinflammation capacities. Four in vitro oxidant and 2 in vivo antiinflammation models were used to evaluate the pharmacological activities of the different pears. The main phenolic compounds were determined by high-performance liquid chromatography with diode-array detector, which result indicated that gallic acid ranged from 5.23 to 10.72 MUg/g, catechin from 0.41 to 28.83 MUg/g, chlorogenic acid from 485.11 to 837.03 MUg/g, caffeic acid from 0 to 1.16 MUg/g, epicatechin from 6.73 to 131.49 MUg/g, and rutin from 0.92 to 104.64 MUg/g. The total antioxidant capacity was in descending order: Shuijing > Fengshui > Xuehua > Ya > Xiang pear, which was consistent with the total phenol and flavonoid contents. Thus, the antioxidant capacity of pears may be attributed to their high contents of phenolics and flavonoids. However, the antiinflammation activity was in decreasing order: Xuehua > Xiang > Ya > Fengshui > Shuijing pear, which indicates that compounds other than antioxidants may be responsible for the antiinflammation effect. PRACTICAL APPLICATION: The importance on antioxidant activities of phenolic compounds in foods and vegetables as natural antioxidants has reached a new high in recent years. In this study, the total phenol and flavonoid contents, and the antioxidant and antiinflammation activities of 5 different types of commercial pears in China were investigated, which may be the experimental basis for the further development and utilization of the pears. PMID- 21824136 TI - Prevalence, characterization, and antimicrobial resistance of Aeromonas strains from various retail food products in Mumbai, India. AB - A total of 154 food samples (chicken, fish, and ready-to-eat sprouts) from various retail outlets in Mumbai, India, were analyzed for the presence of Aeromonas spp. over a period of 2 y (January 2006 to March 2008). Twenty-two Aeromonas isolates belonging to 7 different species were isolated from 18 (11.7%) food samples. The highest percentages of isolation were from chicken (28.6%) followed by fish (20%) and sprout (2.5%) samples. Aeromonas caviae, A. veronii bv. sobria, and A. salmonicida were the most frequently isolated species from sprouts, chicken, and fish samples, respectively. The genes encoding for putative virulence factors, cytotoxic enterotoxin (act), hemolysin (hly), aerolysin (aer), elastase (ahyB), and lipase (lip) were detected using polymerase chain reaction method in 59.1%, 40.9%, 22.7%, 54.5%, and 31.8% of the strains, respectively. The isolated Aeromonas strains were found to be positive for virulence factors, that is, amylase, DNase, gelatinase, protease, and lipase production. More than 60% isolates were also positive for beta-hemolytic activity. All these food isolates were found to be resistant to ampicillin and bacitracin, and sensitive to gentamicin, 3rd-generation cephalosporins (ceftazidime, cephotaxime, ceftriaxone), and chloramphenicol. Seventeen (77.2%) isolates harbored single and/or multiple plasmids (approximately 5 to >16 kb). The XbaI digestion patterns of chromosomal DNA of these isolates, using pulsed field gel electrophoresis, showed high genetic diversity among these isolates. Our results demonstrate the presence of various Aeromonas spp. with virulence potential and antimicrobial resistance in different food products marketed in Mumbai, India. The potential health risks posed by consumption of these raw or undercooked food products should not be underestimated. PMID- 21824137 TI - Blackberry seed extracts and isolated polyphenolic compounds showing protective effect on human lymphocytes DNA. AB - The tentative identification of seed extracts from 3 cultivars of blackberry (blackberry seed extracts [BSEs]) constituents was performed by LC/UV/MS technique. The identified compounds belonged to ellagitannins, galic acid derivatives, and ellagic acid derivatives. Two ellagitannins, Lambertianin C and Sanguiniin H-6, and an ellagic acid derivative, 4-alpha-L-arabinofuranosylellagic acid, were isolated using semipreparative High-performance liquid chromatography. The structure elucidations were based on high resolution-mass spectrometry and nuclear magnetic resonance studies. The BSEs and 3 isolated pure compounds were tested for in vitro protective effect on chromosome aberrations in peripheral human lymphocytes using cytochalasin-B blocked micronucleus (MN) assay. The frequency of MN was scored in binucleated cells, and nuclear proliferation index was calculated. Among the tested extracts, the seeds of cv. Thornfree at concentration of 1 MUg/mL exhibit the most prominent effect decreasing the frequency of MN by 62.4%, when compared with the controls cell cultures. Antioxidant potential of pure ellagitannins cannot explain the strong effect of BSEs. The assumption was that better antioxidant effect of BSEs result from synergistic effects of individual compounds contained in the extracts and/or some minor components possessed strong activity. PraCTICAL APPLICATION: Our results provide evidence of protective effects of BSEs and isolated pure compounds on cytogenetic damages in human lymphocytes. Thus, BSEs could exert beneficial effects in quite a few diseases, because many of the biological actions have been attributed to their antioxidant properties. PMID- 21824138 TI - Supercritical CO2 decaffeination of unroasted coffee beans produces melanoidins with distinct NF-kappaB inhibitory activity. AB - The supercritical CO(2)-decaffeination process causes unroasted coffee beans to turn brown. Therefore, we suspected that the decaffeinated beans contained melanoidins. Decaffeinated unroasted coffee extract absorbed light at 405 nm with a specific extinction coefficient, K(mix 405 nm), of 0.02. Membrane dialysis (molecular weight cut-off, 12 to 14 kDa) increased the K(mix 405 nm) value 15 fold. Gel filtration chromatography showed that the high-MW fraction (MW > 12 kDa) had an elution profile closer to that of melanoidins of medium-roast coffee than to the corresponding fraction of unroasted coffee, indicating the presence of melanoidins in decaffeinated unroasted beans. Using murine myoblast C2C12 cells with a stably transfected nuclear factor-kappaB (NF-kappaB) luciferase reporter gene, we found that the high-MW fraction of decaffeinated unroasted beans had an NF-kappaB inhibitory activity of IC(50) = 499 MUg/mL, more potent than that of regular-roast coffee (IC(50) = 766 MUg/mL). Our results indicate that melanoidins form during the supercritical CO(2)-decaffeination process and possess biological properties distinct from those formed during the regular roasting process. PRACTICAL APPLICATION: We discovered the roasting effect of decaffeination process, reporting the discovery of melanoidins in green (unroasted) decaf coffee beans. Our results indicated that melanoidins form during the supercritical CO2-decaffeination process and possess biological properties distinct from those formed during the regular roasting process. Our results offer new insights into the formation of bioactive coffee components during coffee decaffeination process. PMID- 21824139 TI - Comprehensive analysis of umami compounds by ion-pair liquid chromatography coupled to mass spectrometry. AB - An ion-pair LC-ESI-MS method was developed capable of analyzing various reported umami or umami-enhancing compounds, including glutamic acid and 5' ribonucleotides. The method was validated using tomato and potato samples and showed overall good analytical performance with respect to selectivity, detection limit, linearity, and repeatability. The method was applied to various tomato samples resulting in concentrations of glutamic acid and 5'-ribonucleotides that were in good comparison with literature. The methodology might also be used for the discovery of new umami (enhancing) compounds in an untargeted mode. This was to a certain extent demonstrated for tomato samples by correlating all peaks observed with the ion-pair liquid chromatography-mass spectrometry (LC-MS) method to sensory properties using multivariate statistics. PRACTICAL APPLICATION: This study describes the development and application of a LC-MS method, which can be used to quantify several known umami (enhancing) compounds in various foods. Furthermore, the method might be useful for the discovery of new umami (enhancing) compounds. PMID- 21824140 TI - Decreased alpha4beta2 nicotinic receptor number in the absence of mRNA changes suggests post-transcriptional regulation in the spontaneously hypertensive rat model of ADHD. AB - The spontaneously hypertensive rat (SHR) is widely used as a model of attention deficit/hyperactivity disorder (ADHD). Deficits in central nicotinic receptors (nAChRs) have been previously observed in SHRs, which is interesting since epidemiological studies have identified an association between smoking and ADHD symptoms in humans. Here, we examine whether nAChR deficits in SHRs compared with Wistar Kyoto rat (WKY) controls are nAChR subtype-specific and whether these deficits correlate with changes at the level of mRNA transcription in specific brain regions. Levels of binding sites (B(max) ) and dissociation constants (K(d)) for nAChRs were determined from saturation curves of high-affinity [3H]epibatidine- and [3H] Methyllycaconitine (MLA) binding to membranes from cortex, striatum, hippocampus and cerebellum. In additional brain regions, nAChRs were examined by autoradiography with [125I]A-85380 and [125I]alpha-bungarotoxin. Levels of mRNA encoding nAChR subunits were measured using quantitative real-time PCR (qPCR). We showed that the number of alpha4beta2 nAChR binding sites is lower globally in the SHR brain compared with WKY in the absence of significant differences in mRNA levels, with the exception of lower alpha4 mRNA in cerebellum of SHR compared with WKY. Furthermore, nAChR deficits were subtype- specific because no strain difference was found in alpha7 nAChR binding or alpha7 mRNA levels. Our results suggest that the lower alpha4beta2 nAChR number in SHR compared with WKY may be a consequence of dysfunctional post-transcriptional regulation of nAChRs. PMID- 21824141 TI - Biphasic effects of copper on neurotransmission in rat hippocampal neurons. AB - The importance of copper in the CNS is well documented, but the mechanisms related to its brain functions are poorly understood. Copper is released at the synaptic cleft, where it may modulate neurotransmission. To understand the functional impact of copper on the neuronal network, we have analyzed the synaptic activity of primary rat hippocampal neurons by using different approaches including whole cell patch clamp, recording of calcium transients, immunofluorescence and western blot. Here, we show that copper produces biphasic changes in neurotransmission. When copper is acutely applied to the plate it blocks neurotransmission. Interestingly, when it is applied for 3 h to hippocampal neurons it mainly increases the frequency and amplitude of alpha amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)ergic currents (control: 0.21 +/- 0.05 Hz/22.9 +/- 1.3 pA; copper: 0.68 +/- 0.16 Hz/30.5 +/- 2.5 pA), intracellular calcium transients (control: 0.05 +/- 0.013 Hz; copper: 0.11 +/- 0.02 Hz) and evoked AMPA currents (control: EC50 8.3 +/- 0.5 MUM; copper: EC50 2.9 +/- 0.2 MUM). Moreover, our results suggest that copper increases GluA1 subunit levels of the AMPA receptor through the anchorage of AMPA receptors to the plasma membrane as a result of PSD-95 accumulation. We also found that copper treated neurons displayed an undistinguishable neurotransmission to control neurons after 24 h of treatment, indicating that changes in neurotransmission induced by copper at 3 h of incubation are homeostatically regulated after long term exposure to the metal. Together, our data reveal an unexpected biphasic effect of copper on neurotransmission, which may be relevant to understand the effects of this ion in brain diseases that display copper dyshomeostasis such as that observed in Alzheimer's disease (AD). PMID- 21824142 TI - A human IgM signals axon outgrowth: coupling lipid raft to microtubules. AB - Mouse and human IgMs support neurite extension from primary cerebellar granule neurons. In this study using primary hippocampal and cortical neurons, we demonstrate that a recombinant human IgM, rHIgM12, promotes axon outgrowth by coupling membrane domains (lipid rafts) to microtubules. rHIgM12 binds to the surface of neuron and induces clustering of cholesterol and ganglioside GM1. After cell binding and membrane fractionation, rHIgM12 gets segregated into two pools, one associated with lipid raft fractions and the other with the detergent insoluble cytoskeleton-containing pellet. Membrane-bound rHIgM12 co-localized with microtubules and co-immuno precipitated with beta3-tubulin. rHIgM12-membrane interaction also enhanced the tyrosination of alpha-tubulin indicating a stabilization of new neurites. When presented as a substrate, rHIgM12 induced axon outgrowth from primary neurons. We now demonstrate that a recombinant human mAb can induce signals in neurons that regulate membrane lipids and microtubule dynamics required for axon extension. We propose that the pentameric structure of the IgM is critical to cross-link membrane lipids and proteins resulting in signaling cascades. PMID- 21824143 TI - Methamphetamine exposure during brain development alters the brain acetylcholine system in adolescent mice. AB - Children exposed to methamphetamine during brain development as a result of maternal drug use have long-term hippocampus-dependent cognitive impairments, but the mechanisms underlying these impairments are not understood. The acetylcholine system plays an important role in cognitive function and potential methamphetamine-induced acetylcholine alterations may be related to methamphetamine-induced cognitive impairments. In this study, we investigated the potential long-term effects of methamphetamine exposure during hippocampal development on the acetylcholine system in adolescence mice on postnatal day 30 and in adult mice on postnatal day 90. Methamphetamine exposure increased the density of acetylcholine neurons in regions of the basal forebrain and the area occupied by acetylcholine axons in the hippocampus in adolescent female mice. In contrast, methamphetamine exposure did not affect the density of GABA cells or total neurons in the basal forebrain. Methamphetamine exposure also increased the number of muscarinic acetylcholine receptors in the hippocampus of adolescent male and female mice. Our results demonstrate for the first time that methamphetamine exposure during hippocampal development affects the acetylcholine system in adolescent mice and that these changes are more profound in females than males. PMID- 21824145 TI - Identification and characterization of a neuronal enriched novel transcript encoding the previously described p60Fe65 isoform. AB - Fe65 is a multimodular adaptor protein that interacts with the cytosolic domain of the beta-amyloid precursor protein (APP), the major component of Alzheimer's disease (AD) senile plaques. In the work here presented, we describe the existence of a new Fe65 transcript variant (GenBank Accession EF103274). A unique 5' sequence of 69 nucleotides, spanning a region between exons 2 and 3 of the FE65 gene, was present in a yeast two-hybrid (YTH) clone from a human brain cDNA library. In silico analysis and RT-PCR revealed the presence of a novel exon of 133 bp, and we redefined the structure of the human FE65 gene. The novel exon 3a inclusive transcript generates a shorter isoform, p60Fe65. The migration pattern of the p60Fe65 isoform was observed previously and attributed to an alternative translation initiation site within the p97Fe65 transcript. Here, we provide evidence for the origin of the previously unexplained p60Fe65 isoform. Moreover, Fe65E3a is expressed preferentially in the brain and the p60Fe65 protein levels increased during PC12 cell differentiation. This novel Fe65 isoform and the regulation of the splicing events leading to its production, may contribute to elucidating neuronal specific roles of Fe65 and its contribution to AD pathology. PMID- 21824146 TI - Idiopathic osseous hyperplasia of the nasal turbinates in a Welsh terrier. AB - A three-year-old Welsh terrier was presented with a 6-month history of progressive stertor, exercise intolerance and sneezing which was unresponsive to symptomatic treatment. A large calcified mass occupying the entire rostral right nasal cavity was defined with computed tomography. The mass was completely removed via a dorsal rhinotomy. Histopathological examination of the mass revealed osseous hyperplasia of the nasal turbinates. The excision led to complete resolution of clinical signs and there has been no recurrence 18 months after surgery. PMID- 21824144 TI - FE65 proteins regulate NMDA receptor activation-induced amyloid precursor protein processing. AB - Amyloid precursor protein (APP) family members and their proteolytic products are implicated in normal nervous system function and Alzheimer's disease pathogenesis. APP processing and Abeta secretion are regulated by neuronal activity. Various data suggest that NMDA receptor (NMDAR) activity plays a role in both non-amyloidogenic and amyloidogenic APP processing depending on whether synaptic or extrasynaptic NMDARs are activated, respectively. The APP-interacting FE65 proteins modulate APP trafficking and processing in cell lines, but little is known about their contribution to APP trafficking and processing in neurons, either in vivo or in vitro. In this study, we examined the contribution of the FE65 protein family to APP trafficking and processing in WT and FE65/FE65L1 double knockout neurons under basal conditions and following NMDAR activation. We report that FE65 proteins facilitate neuronal Abeta secretion without affecting APP fast axonal transport to pre-synaptic terminals. In addition, FE65 proteins facilitate an NMDAR-dependent non-amyloidogenic APP processing pathway. Generation of high-molecular weight (HMW) species bearing an APP C-terminal epitope was also observed following NMDAR activation. These HMW species require proteasomal and calpain activities for their accumulation. Recovery of APP polypeptide fragments from electroeluted HMW species having molecular weights consistent with calpain I cleavage of APP suggests that HMW species are complexes formed from APP metabolic products. Our results indicate that the FE65 proteins contribute to physiological APP processing and accumulation of APP metabolic products resulting from NMDAR activation. PMID- 21824147 TI - Antimicrobial usage in dogs and cats in first opinion veterinary practices in the UK. AB - OBJECTIVES: To provide baseline data on patterns of antimicrobial usage in dogs and cats through the analysis of data stored in electronic practice management systems. METHODS: Clinical data from 11 first opinion veterinary practices were extracted for the year 2007. Descriptive statistical analysis was performed to assess the usage of antimicrobials. RESULTS: Widespread usage of systemic broad spectrum antimicrobials was observed. Antimicrobials most frequently used in both species were potentiated amoxicillin (44.4% and 46.1% in cats and dogs, respectively) and amoxicillin (14.3% and 20.7%). Cephalexin (13.4%) and cefovecin (15.0%) were also commonly used in dogs and cats, respectively. Systemic critically important antimicrobials in human medicine were widely used in dogs (60.5%) and cats (82.7%). Topical antimicrobials used in both species included fusidic acid (48.4% and 54.8%), framycetin (20.4% and 13.4%), polymyxin B (12.6% and 9.3%) and neomycin (6.5% and 6.6%). CLINICAL SIGNIFICANCE: Inappropriate usage of broad-spectrum antimicrobials may contribute to the development of antimicrobial resistance and loss of efficacy of antimicrobials in veterinary settings. Data recorded in practice management systems were demonstrated to be a practical source for monitoring antimicrobial usage in pets. PMID- 21824148 TI - Ventral fixation of chronic atlanto-occipital luxation in a dog. AB - A 4.5-year-old male Australian Kelpie was presented for evaluation of ambulatory tetraparesis and neck pain of five weeks duration. Atlanto-occipital luxation was diagnosed by computed tomography. The joint was unstable following closed reduction, and a ventral surgical approach to the cranial cervical spine and occiput permitted manual reduction and stabilisation of the atlanto-occipital joint. The thickened joint capsule and articular cartilage were removed to promote AO arthrodesis. Eight cortical screws, inserted into the occipital condyles and C1, were embedded in polymethylmethacrylate to stabilise the atlanto occipital articulation. The dog recovered uneventfully after it was placed in a neck brace and rested for six weeks. Neurologic examination at six weeks was normal and the dog returned to normal farm work 12 weeks after surgery. PMID- 21824149 TI - Bacterial and fungal colonisation of peripheral intravenous catheters in dogs and cats. AB - OBJECTIVES: The purposes of this study were to determine the prevalence of intravenous catheter colonisation in a routine clinical setting, to identify pathogens involved and to explore factors associated with an increased risk of colonisation. METHODS: A prospective study of 100 peripherally placed intravenous catheters from 13 cats and 78 dogs was conducted. The distal two-thirds were removed and submitted for bacterial and fungal cultures. Antimicrobial susceptibility of each isolate was determined. RESULTS: Nineteen peripheral catheters were positive for microbiologic culture from 14 animals. Twenty organisms were isolated among which Staphylococcus species was the most common. Isolates displayed lower levels of resistance against the antimicrobial agents amoxicillin-clavulanate, cephalosporins and gentamicin than against other agents tested. Major risk factors predisposing to catheter-related colonisation included dextrose infusion, duration of catheter placement, local complications and immunosuppressive diseases or drugs. CLINICAL SIGNIFICANCE: In a routine clinical setting, the prevalence of microbial colonisation of peripheral intravenous catheters is comparable to that found in an intensive care unit. However, consequences on morbidity and mortality rates differ. PMID- 21824150 TI - Three-dimensional visualization and quantification of water content in the rhizosphere. AB - * Despite the importance of rhizosphere properties for water flow from soil to roots, there is limited quantitative information on the distribution of water in the rhizosphere of plants. * Here, we used neutron tomography to quantify and visualize the water content in the rhizosphere of the plant species chickpea (Cicer arietinum), white lupin (Lupinus albus), and maize (Zea mays) 12 d after planting. * We clearly observed increasing soil water contents (theta) towards the root surface for all three plant species, as opposed to the usual assumption of decreasing water content. This was true for tap roots and lateral roots of both upper and lower parts of the root system. Furthermore, water gradients around the lower part of the roots were smaller and extended further into bulk soil compared with the upper part, where the gradients in water content were steeper. * Incorporating the hydraulic conductivity and water retention parameters of the rhizosphere into our model, we could simulate the gradual changes of theta towards the root surface, in agreement with the observations. The modelling result suggests that roots in their rhizosphere may modify the hydraulic properties of soil in a way that improves uptake under dry conditions. PMID- 21824151 TI - Clastogenic plasma factors in psoriasis--comparison of phototherapy and anti-TNF alpha treatments. AB - As previously described, Psoralen plus UVA (PUVA) therapy induces chromosome damage in psoriatic patients. This study evaluates whether these effects are transitory or persistent. In addition, we studied these effects after narrowband UVB (nUVB) and anti-tumor necrosis factor (TNF)-alpha treatments. Among 40 responder patients, 10 received PUVA, 10 nUVB, 10 Infliximab and 10 Etanercept. Disease activity was determined with Psoriasis Area and Severity Index. Chromosomal breakage was evaluated by the clastogenic factor (CF) test. Potential clastogenic agents, malondialdehyde (MDA) and TNF-alpha were measured. Before treatment, the plasma-adjusted clastogenic scores (ACS) of patients were increased. During treatment, a further increase in ACS was observed in both phototherapy groups. Chromosome damage persisted for PUVA patients at week 32, while it diminished after nUVB to ACS values lower than before treatment. MDA and TNF-alpha values were also increased at baseline. MDA decreased during treatment in all groups, but without reaching normal levels. Plasma TNF-alpha remained unchanged in PUVA and nUVB but decreased in both anti-TNF-alpha treatment groups. Psoriasis is accompanied by CF-induced chromosomal breakage that increases during PUVA and nUVB treatments. Plasma clastogenic activity persisted in the follow-up after PUVA, while after nUVB ACS returned to values even lower than baseline. Clastogenic activity during the induction phase with anti-TNF-alpha remained unchanged. PMID- 21824152 TI - The predictive value of low heart rate and heart rate variability during stress for reoffending in delinquent male adolescents. AB - Low autonomic (re)activity is a consistent correlate of antisocial behavior in juveniles. However, longitudinal research relating autonomic measures to persistent antisocial behavior has remained scarce. Therefore, in the present study we examined the predictive value of heart rate (HR) and heart rate variability (HRV, often studied as respiratory sinus arrhythmia) for reoffending in delinquent male adolescents. At initial assessment, HR and HRV were measured at rest and in response to a public speaking task. Registered reoffending was assessed after 5-year follow-up. Attenuated HR response and stronger HRV response to stress predicted higher reoffending rates. Results provide evidence that HR/HRV reactivity are neurobiological markers for persistent juvenile antisocial behavior. Although effect sizes were small to moderate, our findings underscore the consistency of the relationship between autonomic markers and antisocial behavior. PMID- 21824153 TI - Electrophysiological correlates of the maintenance of the representation of pitch objects in acoustic short-term memory. AB - We studied the neuronal mechanisms that implement acoustic short-term memory (ASTM) for pitch using event-related potentials (ERP). Experiment 1 isolated an ERP component, the sustained anterior negativity (SAN), that increased in amplitude with increasing memory load in ASTM using stimuli with equal duration at all memory loads. The SAN load effect found in Experiment 1, when pitch had to be remembered to perform the task, was absent in Experiment 2 using the same sounds when memory was not required. In Experiment 3, the memory task was performed without or with concurrent articulatory suppression during the retention interval to prevent rehearsal via an articulatory loop. Load-related effects observed in Experiment 1 were found again, whether participants engaged in concurrent suppression or not. The results suggest that the SAN reflects activity required to maintain pitch objects in an ASTM system that is distinct from articulatory rehearsal. PMID- 21824154 TI - Neurophysiological markers of retrieval-induced forgetting in multiplication fact retrieval. AB - Event-related potential (ERP) counterparts of practice effects in multiplication fact retrieval were examined. Participants performed a multiplication verification task after having practiced a specific problem set. Practice was either active (retrieval of solutions to multiplication problems) or passive (reexposure to the same operands plus the correct result). Behavioral data showed retrieval-induced facilitation for practiced items and retrieval-induced forgetting for related, unpracticed items, irrespective of practice type. ERPs revealed that, for the active practice group, forgetting was reflected in a reduced N100 component time-locked to result onset. Irrespective of practice type, forgetting was also reflected in a reduced result-locked P350 component, whereas facilitation was associated with an increased amplitude of the same component. These results suggest that beneficial and detrimental effects of practice may be mediated by partially distinct processes. PMID- 21824155 TI - In the face of fear: anxiety sensitizes defensive responses to fearful faces. AB - Fearful faces readily activate the amygdala. Yet, whether fearful faces evoke fear is unclear. Startle studies show no potentiation of startle by fearful faces, suggesting that such stimuli do not activate defense mechanisms. However, the response to biologically relevant stimuli may be sensitized by anxiety. The present study tested the hypothesis that startle would not be potentiated by fearful faces in a safe context, but that startle would be larger during fearful faces compared to neutral faces in a threat-of-shock context. Subjects viewed fearful and neutral faces in alternating periods of safety and threat of shock. Acoustic startle stimuli were presented in the presence and absence of the faces. Startle was transiently potentiated by fearful faces compared to neutral faces in the threat periods. This suggests that although fearful faces do not prompt behavioral mobilization in an innocuous context, they can do so in an anxiogenic one. PMID- 21824156 TI - Alpha modulation in parietal and retrosplenial cortex correlates with navigation performance. AB - The present study investigated the brain dynamics accompanying spatial navigation based on distinct reference frames. Participants preferentially using an allocentric or an egocentric reference frame navigated through virtual tunnels and reported their homing direction at the end of each trial based on their spatial representation of the passage. Task-related electroencephalographic (EEG) dynamics were analyzed based on independent component analysis (ICA) and subsequent clustering of independent components. Parietal alpha desynchronization during encoding of spatial information predicted homing performance for participants using an egocentric reference frame. In contrast, retrosplenial and occipital alpha desynchronization during retrieval covaried with homing performance of participants using an allocentric reference frame. These results support the assumption of distinct neural networks underlying the computation of distinct reference frames and reveal a direct relationship of alpha modulation in parietal and retrosplenial areas with encoding and retrieval of spatial information for homing behavior. PMID- 21824157 TI - Preface for the evolution of infectious agents in relation to sex. PMID- 21824160 TI - Introduction to the evolution of infectious agents in relation to sex. PMID- 21824161 TI - Evolutionary approaches to sexually transmitted infections. AB - Evolutionary approaches are particularly valuable for studies of sexually transmitted diseases. Methods for tracing evolutionary phylogenies have powerful new applications that use genetic data to trace the history of pathogens across millions of years, within outbreaks lasting years, and even within individuals. Equally valuable are less widely appreciated evolutionary methods for analyzing how host-pathogen co-evolution shapes extreme traits whose costs can be substantial. These and other applications of Darwinian medicine will improve understanding and treatment of sexually transmitted diseases. PMID- 21824162 TI - One health-one medicine: unifying human and animal medicine within an evolutionary paradigm. AB - One health is a concept since early civilization, which promoted the view that there was no major distinction between animal and human medicine. Although persisting through the 19th century, this common vision was then all but forgotten in the early 20th century. It is now experiencing a renaissance, coincident with an awakening of the role that evolutionary biology plays in human and animal health, including sexually transmitted infections (STIs). A number of STIs in humans have comparable infections in animals; likewise, both humans and animals have STIs unique to each mammalian camp. These similarities and differences offer opportunities for basic medical and public health studies, including evolutionary insights that can be gleaned from ongoing interdisciplinary investigation--especially with the molecular analytical tools available--in what can become a golden age of mutually helpful discovery. PMID- 21824163 TI - Biology and evolution of sexual transmission. AB - Sexual reproduction brings together and recombines different genomes. Associated with these contacts is transmission of microorganisms and selfish genetic elements, many of which can be harmful to the host. In organisms with internal fertilization, sexually transmitted infections are caused by pathogens transmitted between the parents participating in mating. Sexual transmission has different epidemiological dynamics from nonsexual transmission in that it is less likely to be dependent on host density, there may be no population density threshold for disease increase, and it is more likely to lead to host extinction. Analysis of the evolutionary pathways that have led to the sexual mode of transmission in pathogens indicates that sexual transmission appears more often to be derived from nonsexual transmission, although the pathways are highly variable, and several groups of pathogens are exceptions to this rule. Sexual transmission has evolved from a wide variety of alternative transmission modes, although rarely from aerially transmitted diseases. More data are needed on the phylogeny and transmission mode of the relatives of sexually transmitted pathogens in order to guide development of animal models and comparative studies. PMID- 21824164 TI - Evolutionary-developmental perspectives on immune system interactions among the pregnant woman, placenta, and fetus, and responses to sexually transmitted infectious agents. AB - A balance has evolved over deep time between the various immune systems of the "triad" that is linked together for a short period: the pregnant woman, the fetus, and the placenta. This balance is affected by, and helps to determine, the immune responses to maternal infectious agents that may be transmitted to the fetus/infant transplacentally, intrapartum, or via breast milk. This review identifies newer evolutionary concepts and processes related particularly to the human placenta, innate and adaptive immune systems involved in tolerance, and in responses to sexually transmitted infectious (STI) agents that may be pathogenic to the fetus/infant at different gestational periods and in the first year of life. An evolutionary-developmental (EVO-DEVO) perspective has been applied to the complexities within, and among, the different actors and their beneficial or deleterious outcomes. Such a phylogenetic and ontogenic approach has helped to stimulate several basic questions and suggested possible explanations and novel practical interventions. PMID- 21824165 TI - The genital econiche: focus on microbiota and bacterial vaginosis. AB - Ecological and evolutionary forces shaping the normal and abnormal microflora of the genital econiche are discussed, in particular those related to bacterial vaginosis, which worldwide is the most common vaginal infection, with numerous obstetrical and gynecological complications, including acquisition and transmission of HIV and other sexually transmitted infections (STIs). Characterized by a heavy overgrowth of Gram-negative and Gram-positive anaerobes with no signs of inflammation, bacterial vaginosis has been regarded a microbiological and immunological enigma. Immune tolerance to both normal and abnormal vaginal microbiota, mainly derived from gut microflora, as a result of coevolution with humans might explain the absence of inflammation, supported by short-chain fatty acids, known to modulate immune responses, that are produced in large quantities by anaerobes. Recent studies have implicated the development of a vaginal biofilm with Gardnerella vaginalis and Atopobium vaginae as main players in the pathogenesis of bacterial vaginosis. Supporting this conclusion are data such as those demonstrating heavy growth of G. vaginalis and diversified anaerobes with numerous "clue cells" that are sloughing off from the biofilm. Gardnerella and Atopobium organisms attached to these clue cells can be demonstrated in the male genital econiche, likely reflecting a heterosexual transmission of the disorder. PMID- 21824166 TI - Society, sex, and STIs: human behavior and the evolution of sexually transmitted diseases and their agents. AB - The last few decades have provided new perspectives on the increasingly complex interrelationships between the evolutionary epidemiology of STDs and their agents, human sexuality, and economic, social, cultural, and technological developments. Rapidly emerging HIV/AIDS, globalization, migration, and information technology are some factors that stress the importance of focusing on how old and new sexually transmitted infections (STIs) are spread, both in and between networks and populations. This review of determinants of STI transmission emphasizes their impact on disease prevalence and transmission, as well as their potential for affecting the agents themselves--directly or indirectly. Interventions aiming to control the spread of STIs and HIV on the different levels of society need to be adapted to the specific environment and need to integrate social structures, such as economic and gender inequality and mobility, as well as the great variability and complexity of sexual behavior. PMID- 21824168 TI - HIV-1 evolution in relation to molecular epidemiology and antiretroviral resistance. AB - HIV/AIDS has become one of the most important infectious diseases with a cumulative number of almost 60 million infections worldwide. The prevalence and epidemiological patterns are unevenly distributed across the globe and also within countries. HIV is one of the fastest evolving organisms known. Several genetically distinct subtypes are present and new circulating recombinant forms are continuously emerging. This review discusses HIV-1 evolution in relation to molecular epidemiology and antiretroviral resistance. Factors and concepts that influence global spread and within-patient evolution of HIV-1 are discussed as well as future perspectives on the use of phylodynamics in HIV epidemiology. PMID- 21824169 TI - Urinary mRNA markers of epithelial-mesenchymal transition correlate with progression of diabetic nephropathy. AB - OBJECTIVE: Epithelial-mesenchymal transition (EMT) plays an important role in the pathogenesis and progression of diabetic nephropathy (DN). Quantification of messenger RNA (mRNA) expression in urinary sediment is emerging as a noninvasive method of screening DN-associated biomarkers. The aim of our study was to examine whether urinary mRNA profile of EMT-associated genes may provide valuable clinical insight into the different stages of DN. DESIGN AND METHODS: Diabetic nephropathy patients (n = 44) and healthy controls (n = 12) were enrolled in this study. DN patients were divided into three groups according to the levels of estimated glomerular filtration rate (eGFR): Group A (eGFR > 60 ml/min per 1.73 m(2), n = 27), Group B (45 < eGFR < 60 ml/min per 1.73 m(2), n = 9), and Group C (eGFR < 45 ml/min per 1.73 m(2), n = 8). Relative mRNA abundance of alpha-smooth muscle actin (alpha-SMA), fibronectin, FSP1 and matrix metalloproteinase-9 (MMP 9) were quantified, and correlations between target mRNAs and clinical parameters were examined. RESULTS: The urinary mRNA levels of alpha-SMA, fibronectin and MMP 9 were significantly higher in the DN group compared with controls (P < 0.05), and mRNA levels increased with DN progression. Urinary mRNA levels of all target genes positively correlated with both urinary albumin excretion (UAE) and blood urea nitrogen (BUN). Moreover, the expression of alpha-SMA, fibronectin and MMP-9 mRNA correlated with serum creatinine levels (r = 0.514, r = 0.53 and r = 0.469, all P < 0.001) and GFR levels (r = -0.374, r = -0.392 and r = -0.487, all P < 0.01). CONCLUSIONS: Quantification of EMT-associated genes in urinary sediment may be a novel approach for searching new biomarkers of DN. PMID- 21824167 TI - The evolution of infectious agents in relation to sex in animals and humans: brief discussions of some individual organisms. AB - The following series of concise summaries addresses the evolution of infectious agents in relation to sex in animals and humans from the perspective of three specific questions: (1) what have we learned about the likely origin and phylogeny, up to the establishment of the infectious agent in the genital econiche, including the relative frequency of its sexual transmission; (2) what further research is needed to provide additional knowledge on some of these evolutionary aspects; and (3) what evolutionary considerations might aid in providing novel approaches to the more practical clinical and public health issues facing us currently and in the future? PMID- 21824170 TI - Acromegaly surgery in Manchester revisited--the impact of reducing surgeon numbers and the 2010 consensus guidelines for disease remission. AB - INTRODUCTION: Surgical remission rates for acromegaly vary and are dependent on the tumour morphology, biochemical definition of disease remission and surgical expertise. A previous report from the Manchester region in 1998 reported an overall surgical remission rate of 27% using accepted criteria for biochemical remission at the time. The establishment of the 2010 Consensus guidelines further tightens biochemical criteria for remission. This report aims to assess the impact of establishing a specialist pituitary surgery service in Manchester in 2005, with reduced surgeon numbers on the remission rates for acromegaly surgery. METHODS: Patients with acromegaly undergoing first time endoscopic transsphenoidal surgery between 2005 and 2010 were studied. Surgery was performed by a single surgeon. Review of a prospectively collected acromegaly surgery database was performed with documentation of pre- and postoperative biochemical tests [oral glucose tolerance test (oGTT) and IGF-1], as well as clinical, pathological and radiological data. Definition of disease remission was according to the 2010 Consensus criteria (GH nadir <0.4 MUg/l following an oGTT and normalized population matched IGF-1). RESULTS: There were 43 consecutive patients with acromegaly, with 13 (30%) microadenomas and 12 (28%) invasive adenomas. Overall, surgical remission was achieved in 29 (67%) patients. The remission rates were similar between micro (77%), macro (63%) and giant (67%) adenomas. There were nonsignificant trends towards higher remission rates for noninvasive tumours compared with invasive tumours (74%vs 50%) and for patients with a preoperative GH nadir <10 MUg/l (73%vs 54%) and IGF-1 standard deviation score <15 (72%vs 54%). CONCLUSIONS: Remission rates for acromegaly surgery have improved following establishment of a specialist surgical service, with a reduction in surgeon numbers. Endoscopic trans-sphenoidal surgery remains an effective first-line treatment for achieving biochemical remission in acromegaly, despite the introduction of the more stringent 2010 consensus guidelines. PMID- 21824171 TI - Application of complementary luminescent and fluorescent imaging techniques to visualize nuclear and cytoplasmic Ca2+ signalling during the in vivo differentiation of slow muscle cells in zebrafish embryos under normal and dystrophic conditions. AB - 1. Evidence is accumulating for a role for Ca2+ signalling in the differentiation and development of embryonic skeletal muscle. 2. Imaging of intact, normally developing transgenic zebrafish that express the protein component of the Ca2+ sensitive complex aequorin, specifically in skeletal muscle, show that two distinct periods of spontaneous synchronised Ca2+ transients occur in the trunk: one at approximately 17.5-19.5 h post-fertilization (h.p.f.; termed signalling period SP1) and the other after approximately 23 h.p.f. (termed SP2). These periods of intense Ca2+ signalling activity are separated by a quiet period. 3. Higher-resolution confocal imaging of embryos loaded with the fluorescent Ca2+ reporter calcium green-1 dextran shows that the Ca2+ signals are generated almost exclusively in the slow muscle cells, the first muscle cells to differentiate, with distinct nuclear and cytoplasmic components. 4. Here, we show that coincidental with the SP1 Ca2+ signals, dystrophin becomes localized to the vertical myoseptae of the myotome. Introduction of a dmd morpholino (dmd-MO) resulted in no dystrophin being expressed in the vertical myoseptae, as well as a disruption of myotome morphology and sarcomere organization. In addition, the Ca2+ signalling signatures of dmd-MO-injected embryos or homozygous sapje mutant embryos were abnormal such that the frequency, amplitude and timing of the Ca2+ signals were altered compared with controls. 5. Our new data suggest that, in addition to a structural role, dystrophin may function in the regulation of [Ca2+](i) during the early stages of slow muscle cell differentiation when the Ca2+ signals generated in these cells coincide with the first spontaneous contractions of the trunk. PMID- 21824172 TI - Pet ownership and cardiovascular risk reduction: supporting evidence, conflicting data and underlying mechanisms. AB - 1. It is widely believed that pet ownership is beneficial to humans and that some of this benefit is through favourable effects on cardiovascular risk. In the present review, we critically examine the evidence in support of this hypothesis and present the available data with respect to major cardiovascular risk factors. 2. There is evidence that dog owners are less sedentary and have lower blood pressure, plasma cholesterol and triglycerides, attenuated responses to laboratory-induced mental stress and improved survival following myocardial infarction compared with non-pet owners. However, conflicting data exist with regard to the association between pet ownership and each of these risk factors. 3. Numerous non-cardiovascular effects of pet ownership have been reported, largely in the psychosocial domain, but the relationship is complex and can vary with demographic and social factors. 4. A unifying hypothesis is presented, linking improved mood and emotional state to decreased central and regional autonomic activity, improved endothelial function and, thus, lower blood pressure and reduced cardiac arrhythmias. 5. Overall, ownership of domestic pets, particularly dogs, is associated with positive health benefits. PMID- 21824173 TI - Protective effects of propofol on endotoxemia-induced acute kidney injury in rats. AB - 1. Animal studies suggest that propofol protects against endotoxaemia-induced lung and kidney injury. Upregulation of aquaporin expression in lung tissue mediates these effects, but the mechanism of action in the kidney is unclear. The present study examined the protective effects of propofol on endotoxaemia-induced acute kidney injury in rats. 2. A rat model of endotoxaemia was established using lipopolysaccharide (LPS). We determined the effects of 10% propofol administration 1 h before, during and 1 h after LPS-induced endotoxaemia on expression of aquaporin (AQP)-2, tumour necrosis factor (TNF)-alpha, intercellular adhesion molecule (ICAM)-1, caspase 3, Bcl-2 and Bax using reverse transcription-polymerase chain reaction, western blotting and immunocytochemistry. Renal morphology, superstructure, apoptosis and function were also assessed. 3. Normal renal tubular structure was seen in the propofol pretreated group, but LPS treatment resulted in changes to renal tissue morphology. Propofol treatment improved renal function in LPS-treated rats. Pretreatment with propofol 1 h before LPS normalized urine and serum osmolality, serum creatinine and blood urea nitrogen to control levels. Lipopolysaccharide downregulated expression of AQP-2 and downregulated the expression of ICAM-1 and TNF-alpha. These effects were reversed by propofol treatment. Lipopolysaccharide reduced the Bcl2 : Bax ratio and induced renal cell apoptosis and these effects were reduced by propofol treatment. Overall, propofol pretreatment had greater effects than concurrent treatment or propofol administration after LPS induction of endotoxaemia. 4. In conclusion, propofol pretreatment protected renal function in a rat model of endotoxaemia. Further studies are necessary to confirm this effect in other experimental models and in humans. PMID- 21824175 TI - MDLChunker: a MDL-based cognitive model of inductive learning. AB - This paper presents a computational model of the way humans inductively identify and aggregate concepts from the low-level stimuli they are exposed to. Based on the idea that humans tend to select the simplest structures, it implements a dynamic hierarchical chunking mechanism in which the decision whether to create a new chunk is based on an information-theoretic criterion, the Minimum Description Length (MDL) principle. We present theoretical justifications for this approach together with results of an experiment in which participants, exposed to meaningless symbols, have been implicitly encouraged to create high-level concepts by grouping them. Results show that the designed model, called hereafter MDLChunker, makes precise quantitative predictions both on the kind of chunks created by the participants and also on the moment at which these creations occur. They suggest that the simplicity principle used to design MDLChunker is particularly efficient to model chunking mechanisms. The main interest of this model over existing ones is that it does not require any adjustable parameter. PMID- 21824174 TI - Naja nigricollis CMS-9 enhances the mitochondria-mediated death pathway in adaphostin-treated human leukaemia U937 cells. AB - 1. The aim of the present study was to explore the effect of the Naja nigricollis phospholipase A(2) CMS-9 on adaphostin-induced death of human leukaemia U937 cells. 2. Leukaemia U937 cells (Bcr/Abl-negative cells) were treated with adaphostin (0-10 MUmol/L) and CMS-9 (0-1 MUmol/L). The effects of CMS-9, adaphostin and their combination on cell viability, the generation reactive oxygen species (ROS), [Ca(2+) ](i) , p38 mitogen-activated protein kinase (MAPK) activation, Akt and extracellular signal-regulated kinase (ERK) inactivation, mitochondrial membrane potential (DeltaPsi(m) ) and Bcl-2 family proteins were analysed. 3. Both adaphostin and CMS-9 induced U937 cell apoptosis, characterized by dissipation of DeltaPsi(m) and ROS generation. Combined treatment further increased DeltaPsi(m) loss and reduced the viability of adaphostin-treated cells. Unlike in CMS-9-treated cells, in adaphostin-treated cells ROS-induced increases in [Ca(2+) ](i) were observed. CMS-9-induced ROS generation resulted in p38 MAPK activation, whereas adaphostin treatment elicited ROS/Ca(2+) -mediated inactivation of Akt and ERK. Moreover, Akt was found to be involved in ERK phosphorylation. Suppression of p38 MAPK activation blocked CMS-9-induced DeltaPsi(m) loss and Bcl-xL downregulation. Overexpression of constitutively active Akt and mitogen-activated protein kinase kinase (MEK) 1 rescued adaphostin induced DeltaPsi(m) loss and Bcl-2 downregulation. Similarly, CMS-9 augmented adaphostin toxicity in human leukaemia K562 cells via increased mitochondrial alterations. 4. The results suggest that two distinct pathways mediate adaphostin and CMS-9-induced mitochondrial damage (i.e. the ROS-Ca(2+) -Akt-ERK and ROS-p38 MAPK pathways, respectively). These distinct pathway explain the augmentation by CMS-9 of DeltaPsi(m) loss and apoptosis in adaphostin-treated U937 cells. PMID- 21824176 TI - Impact, orthodoxy and peer review. PMID- 21824178 TI - Poverty of the stimulus revisited. AB - A central goal of modern generative grammar has been to discover invariant properties of human languages that reflect "the innate schematism of mind that is applied to the data of experience" and that "might reasonably be attributed to the organism itself as its contribution to the task of the acquisition of knowledge" (Chomsky, 1971). Candidates for such invariances include the structure dependence of grammatical rules, and in particular, certain constraints on question formation. Various "poverty of stimulus" (POS) arguments suggest that these invariances reflect an innate human endowment, as opposed to common experience: Such experience warrants selection of the grammars acquired only if humans assume, a priori, that selectable grammars respect substantive constraints. Recently, several researchers have tried to rebut these POS arguments. In response, we illustrate why POS arguments remain an important source of support for appeal to a priori structure-dependent constraints on the grammars that humans naturally acquire. PMID- 21824179 TI - Criteria for the design and evaluation of cognitive architectures. AB - Cognitive architectures are unified theories of cognition that take the form of computational formalisms. They support computational models that collectively account for large numbers of empirical regularities using small numbers of computational mechanisms. Empirical coverage and parsimony are the most prominent criteria by which architectures are designed and evaluated, but they are not the only ones. This paper considers three additional criteria that have been comparatively undertheorized. (a) Successful architectures possess subjective and intersubjective meaning, making cognition comprehensible to individual cognitive scientists and organizing groups of like-minded cognitive scientists into genuine communities. (b) Successful architectures provide idioms that structure the design and interpretation of computational models. (c) Successful architectures are strange: They make provocative, often disturbing, and ultimately compelling claims about human information processing that demand evaluation. PMID- 21824180 TI - Screening tools used for measuring depression among people with Type 1 and Type 2 diabetes: a systematic review. AB - BACKGROUND: Depression is common in patients with Type 1 or Type 2 diabetes, has a strong negative impact on the quality of life of patients and is associated with poor outcomes and higher mortality rates. Several guidelines encourage screening of patients with diabetes for depression. It is unclear which depression screening tools are currently being used in people with diabetes and which are most appropriate. METHODS: A systematic review was conducted to examine which depression screening instruments are currently being used in diabetes research, and the operating characteristics of these tools in diabetes populations. Literature searches for the period January 1970 to October 2010 were conducted using MEDLINE, PSYCH-INFO, ASSIA, SCOPUS, ACADEMIC SEARCH COMPLETE, CINAHL and SCIENCE DIRECT. RESULTS: Data are presented for the 234 published studies that were examined. The Beck Depression Inventory and the Centre for Epidemiologic Studies Depression Scale were the most popular screening tools (used in 24% and 21% of studies). Information on the cultural applicability of screening tools was mostly unavailable and, where reported, included only details of the language translation process. A small number of studies reported reliability data, most of which showed moderate-good sensitivity and specificity but a high rate of false positives. CONCLUSIONS: Although a range of depression screening tools have been used in research, there remains few data on their reliability and validity. Information on the cultural applicability of these instruments is even scantier. Further research is required in order to determine the suitability of screening tools for use in clinical practice and to address the increasing problem of co-morbid diabetes and depression. PMID- 21824181 TI - BEVA: the next 50 years: who has a crystal ball? PMID- 21824182 TI - New developments at EVJ's Wiley Online Library site. PMID- 21824183 TI - EVJ literary prizes. PMID- 21824184 TI - Quality assurance in the diabetic retinopathy screening programme: evaluating the benefit of universal regrading of the normal primary grade. PMID- 21824186 TI - Comparing incident diabetes as defined by fasting plasma glucose or by HbA(1c). The AusDiab, Inter99 and DESIR studies. AB - AIM: We examined the ability of fasting plasma glucose and HbA(1c) to predict 5 year incident diabetes for an Australian cohort and a Danish cohort and 6-year incident diabetes for a French cohort, as defined by the corresponding criteria. METHODS: We studied 6025 men and women from AusDiab (Australian), 4703 from Inter99 (Danish) and 3784 from DESIR (French), not treated for diabetes and with fasting plasma glucose < 7.0 mmol/l and HbA(1c) < 48 mmol/mol (6.5%) at inclusion. Diabetes was defined as fasting plasma glucose >= 7.0 mmol/l and/or treatment for diabetes or as HbA(1c) >= 48 mmol/mol (6.5%) and/or treatment for diabetes. RESULTS: For AusDiab, incident fasting plasma glucose-defined diabetes was more frequent than HbA(1c) -defined diabetes (P(McNemar)<0.0001), the reverse applied to Inter99 (P(McNemar) < 0.007) and for DESIR there was no difference (P(McNema)=0.17). Less than one third of the incident cases were detected by both criteria. Logistic regression models showed that baseline fasting plasma glucose and baseline HbA(1c) predicted incident diabetes defined by the corresponding criteria. The standardized odds ratios (95% confidence interval) for HbA(1c) were a little higher than for fasting plasma glucose, but not significantly so. They were respectively, 5.0 (4.1-6.1) and 4.1 (3.5-4.9) for AusDiab, 5.0 (3.6-6.8) and 4.8 (3.6-6.3) for Inter99, 4.8 (3.6-6.5) and 4.6 (3.6-5.9) for DESIR. CONCLUSIONS: Fasting plasma glucose and HbA(1c) are good predictors of incident diabetes defined by the corresponding criteria. Despite Diabetes Control and Complications Trial-alignment of the three HbA(1c) assays, there was a large difference in the HbA(1c) distributions between these studies, conducted some 10 years ago. Thus, it is difficult to compare absolute values of diabetes prevalence and incidence based on HbA(1c) measurements from that time. PMID- 21824185 TI - Comparison of longitudinal point-of-care and high-performance liquid chromatography HbA1c measurements in a multi-centre trial. AB - AIMS: Point-of-care HbA(1c) is routine in clinical practice. Comparison of point of-care HbA(1c) against laboratory measurements across sites and over time is warranted. METHODS: One hundred and twenty-one young persons with Type 1 diabetes from four centres provided 450 paired samples collected over 10 months for point of-care HbA(1c) and central laboratory-based high-performance liquid chromatography (HPLC) HbA(1c) determinations. Change in HbA(1c) over time was assessed by difference from initial to final HbA(1c) and by growth modelling with annualized slope calculation. Change in HbA(1c) was categorized as improved (decrease of >= 0.5% or negative slope), no change (+/- 0.4% of initial HbA(1c) or slope = 0) or worsened (increase of >= 0.5% or positive slope). RESULTS: The 450 paired samples (median of four pairs/patient) were highly correlated (r = 0.97, P < 0.0001), as were time-specific and site-specific pairs (r = 0.94 to 0.98, P < 0.0001). Initial-to-final point-of-care HbA(1c) and HPLC HbA(1c) changes were 0.3 +/- 1.1% (range -2.7 to 4.1) and 0.4 +/- 1.2% (-3.9 to 4.5), respectively, with 21% of patients (n = 26) discordant for change categories. DeltaHbA(1c) by point-of-care HbA(1c) vs. HPLC HbA(1c) differed across the HbA(1c) range and by >= 0.5% absolute difference in DeltaHbA(1c) in 14 (54%) of the 26 patients discordant for HbA(1c) change categories. Mean annual HbA(1c) slope was 0.4 +/- 1.5% (-5.4 to 4.8) for point-of-care HbA(1c) and 0.4 +/- 1.6% ( 6.9 to 5.2) for HPLC HbA(1c), with 18% (n = 22 pairs) discordant for change categories. CONCLUSIONS: Assessment of absolute HbA(1c) change may not be different for point-of-care HbA(1c) compared with HPLC HbA(1c); however, misclassification of patients by discrete cut-off values may occur with point-of care HbA(1c) compared with HPLC HbA(1c) determinations. PMID- 21824187 TI - Effectiveness of medical nutrition treatment delivered by dietitians on glycaemic outcomes and lipid profiles of Arab, Omani patients with Type 2 diabetes. AB - AIMS: In this randomized controlled trial we evaluated the effectiveness of medical nutritional therapy on Arab patients with Type 2 diabetes in Oman delivered by a dietitian. METHODS: Patients with Type 2 diabetes (n = 170) were randomly assigned to a group receiving usual nutritional care (n = 85) or a group receiving practice guidelines nutritional care (n = 85). Anthropometric (weight, height, BMI and waist circumference) and biochemical (fasting blood glucose, HbA1c ) variables were measured at baseline and after each appointment. Patients were given 1-3 appointments with a dietitian over 6 months. RESULTS: Those in the group receiving practice guidelines nutritional care (n = 85) had significant changes in HbA(1c) (-0.8%, P = 0.001), fasting plasma glucose (-1.3 mmol?l, P = 0.003) and weight (-5.1 kg, P = 0.05), whereas the patients in the usual nutritional care group (n = 85) had no significant improvements in either HbA(1c) (-0.4%, P = 0.248) or fasting plasma glucose (-0.2 mmol/l, P = 0.638) during the same period. We also found a significant difference between the group receiving practice guidelines nutritional care and the usual nutritional care group, respectively, in waist circumference (96.9 +/- 7.9 vs. 100.0 +/- 8.7 cm, P = 0.019), triglycerides levels (1.42 +/- 0.58 vs. 1.98 +/- 0.96 mmol?l, P = 0.001), cholesterol levels (5.1 +/- 1.0 vs. 5.5 +/- 0.9 mmol/l, P = 0.009) and LDL cholesterol levels (3.58 +/- 0.98 vs. 3.89 +/- 0.98 mmol/l, P = 0.046). CONCLUSIONS: Medical nutrition therapy provided by dietitians to Arab patients with Type 2 diabetes in Oman resulted in significant improvements in anthropometric and biochemical outcomes in both the usual nutritional care group and the group receiving practice guidelines nutritional care. Subjects with Type 2 diabetes tended to do better with practice guidelines nutritional care than with usual nutritional care. Ongoing medical counselling in nutrition by a trained dietitian is important for better long-term metabolic control. PMID- 21824188 TI - Precision and accuracy of blood glucose measurements using three different instruments. AB - AIMS: Assessment of insulin sensitivity by dynamic metabolic tests such as the hyperinsulinemic euglycemic clamp critically relies on the reproducible and fast measurement of blood glucose concentrations. Although various instruments have been developed over the last decades, little is known as to the accuracy and comparability. We therefore compared the best new instrument with the former gold standard instruments to measure glucose concentrations in metabolic tests. METHODS: Fasting blood samples of 15 diabetic and 10 healthy subjects were collected into sodium-fluoride tubes, spiked with glucose (0, 2.8, 6.9 and 11.1 mmol/l) and measured either as whole blood (range 3.3-26.3 mmol/l) or following centrifugation as plasma (range 3.9-32.0 mmol/l). Plasma samples were analyzed in the YSI-2300 STAT plus (YSI), EKF Biosen C-Line (EKF) and the reference method, Beckman Glucose analyzer-II (BMG), whole blood samples in EKF instruments with YSI as reference method. RESULTS: The average deviation of the EKF from the reference, BMG, was 3.0 +/- 3.5% without any concentration-dependent variability. Glucose measurements by YSI were in good agreement with that by BMG (plasma) and EKF (plasma and whole blood) up to concentrations of 13.13 mmol/l (0.5 +/- 3.7%), but deviation increased to -6.2 +/- 3.8% at higher concentrations. Precision (n = 6) was +/-2.2% (YSI), +/-3.9% (EKF) and +/-5.2% (BMG). CONCLUSIONS: The EKF instrument is comparable regarding accuracy and precision to the reference method BMG and can be used in metabolic tests, while the YSI showed a systematic shift at higher glucose concentrations. Based on these results we decided to replace BMG with EKF instrument in metabolic tests. PMID- 21824189 TI - Coeliac disease in children: a social epidemiological study in Sweden. AB - AIM: Little is known on the possible existence of socioeconomic and geographical differences in early coeliac disease (CD) risk. Therefore, we investigated these aspects in children before age two. METHODS: Linking the Swedish Medical Birth Registry to several other national registries, we identified all singletons born in Sweden from 1987 to 1993 (n = 792,401) and followed them until 2 years of age to identify cases of CD. Applying multilevel logistic regression analysis, we investigated the association between socioeconomic position (SEP) and CD in children and also whether a possible geographical variation in CD risk was explained by individual characteristics. RESULTS: Low SEP was associated with CD in boys OR 1.37 (95% CI 1.03-1.82), but not in girls OR 0.87 (95% CI 0.68-1.12). We found a considerable geographical variation in disease risk (i.e. intra municipality correlation ~ 10%) that was not explained by individual characteristics. CONCLUSIONS: Low SEP is associated with CD in boys but not in girls. Also, CD appears to be conditioned by geographical area of residence. While our study represents an innovative contribution to the epidemiology of CD in children, the reasons for the observed geographical and socioeconomic differences could be speculated but are still unknown. PMID- 21824190 TI - Motor examination in children with Attention-deficit/hyperactivity Disorder and Asperger Syndrome. AB - AIM: Evaluating whether motor skills could differentiate drug-naive subjects with two neurodevelopmental disorders: Attention-Deficit Hyperactivity Disorder (ADHD) and Asperger Syndrome (AS). METHODS: Thirty-six boys (12 with ADHD, 12 with AS and 12 with typical development) aged 8-12 were evaluated using the Physical and Neurological Examination for Subtle Signs. Three primary outcome variables were obtained as follows: (i) total speed of timed activities, (ii) total overflow and (iii) total dysrhythmia. RESULTS: Children with AS performed more slowly than those with ADHD and healthy children independently of age and IQ. Total dysrhythmia differentiates ADHD and AS children from controls. CONCLUSION: Dysfunction of the fronto-striatal-cerebellar networks related to motor control could be the physiopathological basis of the reported findings. PMID- 21824191 TI - Lung function in children born after foetal growth restriction and very preterm birth. AB - AIMS: To assess lung function at early school age in children delivered at very early gestation owing to intrauterine growth restriction and abnormal foetal blood flow (IUGR). METHODS: Spirometry was performed at median age 8.4 (range 6.5 10.7) years in 31 children born preterm with IUGR (PT-IUGR) with a median (range) birth weight (BW) of 650 (395-976) g and median (range) gestational age 27 (24 29) weeks. Control groups were matched for gender and age and had BW appropriate for gestational age (AGA); 31 children born preterm (PT-AGA) with BW of 1010 (660 1790) g matched for gestational age at birth, and 31 children born at term (T AGA) with BW of 3530 (3000-4390) g. RESULTS: The PT-IUGR group had lower mean (SD) values of z-scores for FEV(1), FEV(1)/FVC and forced mid-expiratory flow rate (FEF(25-75%)) compared to the T-AGA group, p = 0.003, p = 0.032 and p < 0.001, respectively, but did not differ from the PT-AGA group. PT-IUGR children delivered at >=26 gestational weeks (GW) had lower FEF(25-75%) than PT-AGA children of corresponding GA, p = 0.014. CONCLUSION: Lung function was reduced in the PT-IUGR group at early school age compared to controls born at term. The influence of IUGR on later lung function was only apparent in children born preterm after 26 GW. PMID- 21824192 TI - Incidence and pattern of hearing impairment in children with <= 800 g birthweight in British Columbia, Canada. AB - AIM: This study aimed to evaluate changes over time in the characteristics of permanent hearing impairment (HI) in extremely low-birthweight (ELBW <=800 g) children. METHODS: Data from sequential visits up to 5 years of age assessing hearing and other neurodevelopmental outcomes were extracted from a cohort of ELBW subjects born between 1983 and 2006 at a single Canadian site. Trends in HI incidence, severity and association with other impairments were analysed in three 8-year epochs. RESULTS: Fifty of 586 ELBW children had a HI. HI rates increased from 5% in epoch 1 to 7% in epoch 2-13% in epoch 3 (p = 0.01). Mild HI decreased from 78% in epoch 1 to 35% in epoch 3 (p = 0.03). Median age at diagnosis decreased from 13 to 8 months. Comorbidities were more common in HI children than non-HI children: cerebral palsy (40% vs 14%, p < 0.0001)), cognitive (38% vs 12%, p < 0.0001) and visual impairments (16% vs 6%, p = 0.009). CONCLUSION: The incidence and severity of hearing impairment in a cohort of extremely low birthweight children increased significantly from 5% to 13% (p = 0.01) over a 24 year period. Comorbidities were common. Potentially modifiable causes are explored. PMID- 21824193 TI - Procalcitonin and valuable clinical symptoms in the early detection of neonatal late-onset bacterial infection. AB - AIM: To evaluate which clinical symptoms indicate proven neonatal bacterial infection (NBI) and whether measuring procalcitonin aside from C-reactive protein and interleukin 6 improves sensitivity and specificity in diagnosis. METHODS: In a prospective observational study, clinical symptoms and procalcitonin, C reactive protein and interleukin 6 were simultaneously determined from the 4th day of life in 170 preterm and term neonates at the first time of suspicion of NBI. Proven NBI was defined as a positive culture of otherwise sterile body fluids or radiologically verified pneumonia in combination with elevated inflammatory markers. RESULTS: Fifty-eight (34%) patients were diagnosed with proven late-onset NBI. In case of proven NBI, odds ratio and 95% confidence intervals were 2.64 (1.06-6.54) for arterial hypotension, 5.16 (2.55-10.43) for feeding intolerance and 9.18 (4.10-20.59) for prolonged capillary refill. Sensitivity of combined determination of C-reactive protein (>10 mg/L) and interleukin 6 (>100 pg/mL) was 91.4%, specificity 80.4%, positive predictive value 70.7% and negative predictive value 94.7%. The additional determination of procalcitonin (>0.7 ng/mL) resulted in 98.3%, 65.2%, 58.8% and 98.6%, respectively. CONCLUSION: Arterial hypotension, feeding intolerance and especially prolonged capillary refill indicate proven neonatal late-onset bacterial infection, even at the time of first suspicion. Additional measurement of procalcitonin does indeed improve sensitivity to nearly 100%, but is linked to a decline in specificity. Nevertheless, in the high-risk neonatal population, additional procalcitonin measurement can be recommended because all infants with NBI have to be identified. PMID- 21824194 TI - Overweight does not increase asthma risk but may decrease allergy risk at school age after infantile bronchiolitis. AB - AIM: Increasing evidence suggests that overweight children are at increased risk of asthma. The association between weight gain and allergy is more complex. The aim was to evaluate the association between overweight or obesity and asthma, allergy, bronchial reactivity or atopic sensitization at school age in children with bronchiolitis in infancy. SUBJECTS AND METHODS: Eighty-one children hospitalized for bronchiolitis at <24 months of age attended control visits at 7.2 and 12.3 years of ages. The visits consisted of medical examinations, weight and height measurements, body mass index (BMI) calculations, skin prick tests and exercise challenge tests. BMI >1.3 SD from age- and gender-specific references meant overweight and BMI >2.0 SD obesity. RESULTS: Current or previous overweight or obesity did not increase the risk of asthma, allergy, bronchial reactivity or atopic sensitization at 7.2 or 12.3 years of age. Previous and current obesity decreased the risk of atopic dermatitis, and current overweight and obesity decreased the risk of sensitization to outdoor allergens at 12.3 years of age. CONCLUSION: Previous or current overweight does not increase asthma or allergy risk but current obesity may decrease allergy risk at school age after bronchiolitis in infancy. PMID- 21824195 TI - Shortened treatment duration of glucocorticoid-induced skin atrophy in rats. AB - Glucocorticoids (GCs) belong to the most widely used anti-inflammatory drugs at all. However, their topical use is limited by their side effect potential, with skin atrophy being the most prominent one. Thus, determining the atrophogenic potential of novel compounds is of importance for drug development. Currently, the most frequently performed model in the base and pharmaceutical research is the hr/hr rat model of GC-induced skin atrophy that lasts for 19 days. In this study, we analysed statistically skin atrophy experiments retrospectively to ascertain (i) the earliest time-point, at which skin atrophy is significantly induced; and (ii) whether the differences between the GC treatment groups change until the end of the experiment. We show here that the treatment duration of rat skin atrophy models might be reduced to 5 days for economical and ethical reasons. PMID- 21824196 TI - Mitochondrial function evaluation in epidermal cells ex vivo after ultraviolet irradiation. AB - Ultraviolet radiation (UVR) effects on skin have been extensively studied. However, mitochondrial dysfunction and superoxide () production have only been studied using cell cultures, which are useful models, but do not consider the crosstalk between tissues or cellular differentiation. We aimed to evaluate the usefulness of fluorescent dyes to study skin ex vivo. Mitochondrial alterations were evaluated in epidermal cells isolated from UVR-exposed mice. Furthermore, a combination of dyes and antibodies was tested to analyse specific skin cell types. UVR caused a decrease in the percentage of total cells with polarized mitochondria, but did not change the mitochondrial production. However, this production was increased significantly in cells. Furthermore, it was possible to evaluate the cellular damage produced to basal keratinocytes and Langerhans cells. The results show that fluorescent dyes - alone or in combination with antibodies - are useful to analyse cellular events that take place in whole organs. PMID- 21824197 TI - Hedgehog pathway does not play a role in hidradenitis suppurativa pathogenesis. AB - Hidradenitis suppurativa is a chronically relapsing skin disorder with onset after puberty and is characterized by inflammatory lesions in hair follicle and apocrine sweat gland-bearing skin that manifests as abscesses with formation of cysts and sinus tracts. Hedgehog family genes are required in normal embryonic skin, hair follicle, sebaceous and sweat gland development. Mutations of hedgehog pathway in adult skin have previously been found in basal cell carcinomas and in alopecia as well as in epidermal cysts and in odontogenic keratocysts. Therefore, we suggested that the hedgehog pathway might play a role in formation of sinus tracts and cysts as newly formed structures in hidradenitis suppurativa patients. None of the sinus tracts or cysts in 81 hidradenitis suppurativa histological slides from 34 patients showed positive finding for sonic hedgehog mutation. According to our findings, we have to conclude that there is no evidence that sonic hedgehog pathway is part of hidradenitis suppurativa pathogenesis. PMID- 21824198 TI - Statins inhibit chemotactic interaction between CCL20 and CCR6 in vitro: possible relevance to psoriasis treatment. AB - Psoriasis is a chronic IL-23/Th17 pathway-associated skin disease. An increased expression of lesional CCL20 can recruit CCR6+ Th17, and lesional cytokine milieu persistently activates keratinocytes to produce CCL20. Lipid-lowering drugs, statins, are known to possess immune-modulating functions. In this study, we explored an inhibitory effect of statins on CCL20/CCR6 interaction. We demonstrated that IL-1beta, TNF-alpha, and IL-17A significantly increased CCL20 production from HaCaT cells. However, these increments were markedly inhibited by fluvastatin and simvastatin, but not by pravastatin. In the chemotaxis migration assay, pretreatment with fluvastatin and simvastatin inhibited the migration of human CD4+ T cells towards CCL20. However, the level of CCR6 surface expression in memory CD4+ T cells was not affected. Our results suggest that not all, but specific types of statins may be of benefit in alleviating psoriasis partially via interrupting CCL20/CCR6 chemotactic interaction, the mechanism which may eventually lessen the infiltration of Th17 cells. PMID- 21824199 TI - Involvement of leukotriene B4 in spontaneous itch-related behaviour in NC mice with atopic dermatitis-like skin lesions. AB - To elucidate the mechanisms of severe itch in atopic dermatitis, we investigated the role of leukotriene B(4) , a potent itch mediator, in spontaneous itch related behaviour in NC mice with atopic dermatitis-like skin lesions. Topical application of the BLT leukotriene B(4) receptor antagonist ONO-4057 inhibited spontaneous itch-related behaviour. The concentration of leukotriene B(4) was significantly increased in the lesional skin. The expression levels of 5 lipoxygenase were also elevated in the lesional skin, yet present throughout the epidermis of both healthy and lesional skin. These results suggest a role for leukotriene B(4) in chronic dermatitis-related itch. Sphingosylphosphorylcholine (SPC) was increased in the epidermis of the lesional skin. Moreover, intradermal injection of SPC elicited itch-related behaviours in healthy mice. Because SPC induces itch-related responses through the production of leukotriene B(4) in keratinocytes (J Invest Dermatol, 129, 2009, 2854), these results suggest that an increase in SPC induces leukotriene B(4) -mediated itching in chronic dermatitis. BLT1 receptor and 5-lipoxygenase in the skin may be effective pharmacological targets for the treatment of itch in atopic dermatitis. PMID- 21824200 TI - Photoprotection against UVAR: effective triterpenoids require a lipid raft stabilizing chemical structure. AB - UVA(Ultraviolet A)-induced gene expression is supposed to be a hallmark for inflammation, for immunosuppression and in long-term cancer formation. In previous studies, we have shown for keratinocytes that physiological doses of UVA radiation result in the upregulation of gene expression mediated by ceramide formation from sphingolipids/cholesterol-rich microdomains (rafts), which can be blocked by preloading keratinocytes with cholesterol or plant sterols. Here, we show that besides stigmasterol and beta-sitosterol, also sterols like 14 dehydroergosterol, ergosterol-peroxide and 29-norcycloartenol inhibit the UVA response. Moreover, we present evidence that natural material-derived triterpenoids such as oleanolic acid can abrogate UVA-induced gene expression by raft stabilization. This effect depends on the structure of the molecule, because its isomer ursolic acid also integrates within the rafts without inhibiting ceramide formation and upregulation of gene expression. PMID- 21824201 TI - Key role of heparan sulfate chains in assembly of anchoring complex at the dermal epidermal junction. AB - Epidermal basement membrane forms anchoring complex composed of hemidesmosomes, anchoring filaments, lamina densa and anchoring fibrils to link epidermis to dermis. However, the anchoring complex is rarely formed in skin equivalent models, probably because of degradation of extracellular matrix (ECM) proteins and heparan sulfate chains by matrix metalloproteinases (MMPs) and heparanase, respectively. To explore the roles of ECM proteins and heparan sulfate in anchoring complex assembly, we used specific inhibitors of MMPs and heparanase, and the formation of anchoring complex was analysed in terms of polarized deposition of collagen VII, BP180 and beta4 integrin at the dermal-epidermal junction (DEJ) by means of immunohistochemistry and transmission electron microscopy (TEM). The deposition of collagen VII was polarized to the basal side by the addition of MMP inhibitor, and the staining intensity was increased by combined treatment with MMP inhibitor and heparanase inhibitor, which enhanced anchoring fibril formation as observed by TEM. BP180 was polarized to the basal side by heparanase inhibitor, which protects HS chains, but not by MMP inhibitor. MMP inhibitor improved the polarization of beta4 integrin. Hemidesmosomes were formed in the presence of each inhibitor, as observed by TEM, and formation was greatly enhanced by the combined treatment. These findings suggest that heparan sulfate chains, in addition to ECM proteins at the DEJ, play an important role in the assembly of anchoring complex, especially hemidesmosomes and anchoring fibrils. PMID- 21824202 TI - Training-induced modifications of circadian rhythmicity of peroxidative parameters in horses. AB - The aim of this study was to evaluate the daily rhythms of peroxidative parameters in untrained and trained horses. Blood samples were collected every 4 h for a 48-h period for the determination of reactive oxygen metabolites test (d ROMs), antioxidant barrier (Oxy-ads), thiol antioxidant barrier (SHp) and lipid peroxidation (LPO). Two-way anova showed a significant effect of time of day on all parameters studied, except on LPO. Higher values of Oxy-ads and SHp were observed in trained horses during both days of monitoring (p < 0.01). All studied parameters, except for LPO, showed robust daily rhythms. Their acrophases occurred during the day in untrained horses and in the evening in trained horses. Our results showed that training increases antioxidative capacity and demonstrated that the daily rhythms of antioxidative parameters can be modified by training. PMID- 21824203 TI - Journal of neuroendocrinology impact factor reaches 4.65! Who cares? PMID- 21824205 TI - Plasticity of the parental brain: a case for neurogenesis. AB - Profound behavioural changes occur in the mother at parturition, together with extensive remodelling of neural circuits. These changes include neurochemical, morphological and functional plasticity. The continuous generation of new neurones in the hippocampus and the olfactory system is an additional form of neuroplasticity that contributes to motherhood. This review describes the reciprocal relationships between hippocampal and olfactory neurogenesis and parental behaviour. Studies in rodents demonstrate that parturition and interactions with the young affect both cell proliferation and survival in a different manner across neurogenic zones. Species in which an individual recognition of the offspring is formed, such as sheep, show a down-regulation of neurogenesis during the perinatal period. This would function to decrease cell competition, favouring the selection of newborn neurones involved in olfactory recognition of the young. Also, in biparental species, increases in olfactory neurogenesis occur in the father in response to pup exposure during the early postpartum period. Oestradiol, corticosterone and prolactin changes associated with parturition are the main physiological factors involved in the regulation of neurogenesis that have been determined so far. In the father, prolactin mediates an enhancement of olfactory neurogenesis. Contradictory evidence indicates a functional link between neurogenesis and parenting behaviour. Mice receiving focal irradiation of the olfactory neurogenic subventricular zone show few disturbances in the expression of maternal behaviour, whereas a reduction of both hippocampal and olfactory neurogenesis as a result of the infusion of an anti mitotic agent induces behavioural deficits. Disrupting prolactin signalling abolished increased paternal neurogenesis and offspring recognition by the father, and rescuing this neurogenesis restored recognition behaviour. More studies that selectively suppress the changes of neurogenesis are needed to confirm the role of new neurones in regulating parenting behaviour. PMID- 21824204 TI - Pituitary adenylate cyclase-activating polypeptide controls stimulus transcription coupling in the hypothalamic-pituitary-adrenal axis to mediate sustained hormone secretion during stress. AB - External and internal stimuli that threaten homeostasis trigger coordinated stress responses through activation of specialised neuroendocrine circuits. In mammals, the hypothalamic-pituitary-adrenal (HPA) axis mediates responses to stressors such as restraint, ultimately enhancing adrenocortical hormone secretion. Pituitary adenylate cyclase-activating polypeptide (PACAP) has been implicated in central control of the HPA axis, and we have recently shown PACAP dependent expression of corticotropin-releasing hormone (CRH) and secretion of corticosterone in response to restraint. We now provide a more detailed analysis of PACAP-dependent HPA axis stimulation in the mouse, indicating that the hypothalamic paraventricular nucleus (PVN) is the primary site of action. We demonstrate by quantitative polymerase chain reaction and in situ hybridisation that up-regulation of mRNAs encoding CRH and inducible transcription factors, from the Nr4a family (Nur77, Nor1) in the PVN is PACAP-dependent. Furthermore, CRH hnRNA is rapidly up-regulated in cultured hypothalamic neurones after treatment with PACAP. Induction of Nr4a factors (Nur77, Nurr1) in response to restraint is attenuated in the pituitary gland of PACAP-deficient mice. In the adrenal glands, restraint elicits a marked PACAP-dependent increase in adrenocortical mRNA levels of all three Nr4a transcription factors, steroidogenic factor 1 (Nr5a1), steroidogenic acute regulatory protein and steroid 21 hydroxylase. Taken together, our results show that PACAP controls HPA responses to restraint primarily at the level of the hypothalamus by up-regulating CRH, possibly involving transcription factors such as Nur77 and Nor1. Subsequent adrenocortical steroidogenesis also appears to involve PACAP-dependent stimulus transcription coupling, suggesting a mechanism by which PACAP exerts control over HPA axis function during stress. PMID- 21824206 TI - Differential changes in the hypothalamic-pituitary-adrenal axis and prolactin responses to stress in early pregnant mice. AB - Stress can cause pregnancy failure but it is unclear how the mother's neuroendocrine system responds to stress to impair mechanisms establishing implantation. We analysed stress-evoked hypothalamic-pituitary-adrenal (HPA) axis responses in early pregnant mice. HPA axis secretory responses to immune stress in early-mid pregnancy were strong and similar to that in virgins, although activation of hypothalamic vasopressin neurones, rather than corticotrophin releasing hormone neurones, may be more important in the stress response in pregnancy. The site and mode of detrimental glucocorticoid action in pregnancy is not established. Because circulating prolactin is important for progesterone secretion and pregnancy establishment, we also hypothesised that stress negatively impacts on prolactin and its neuroendocrine control systems in early pregnant mice. Basal prolactin secretion was profoundly inhibited by either immune or fasting stress in early pregnancy. Prolactin release is inhibited by tonic dopamine release from tuberoinfundibular (TIDA) neurones. However, immune stress did not increase TIDA neurone activity in the median eminence in pregnant mice [measured by 3,4-dihydroxyphenylacetic acid (DOPAC) content and the DOPAC:dopamine ratio]. By contrast, both immune stress and fasting caused weak induction of Fos in TIDA neurones. However, Fos induction does not always reflect dopamine secretion. Taken together, the data suggest that the stress-evoked profound reduction in prolactin secretion does not involve substantially increased dopamine activity as anticipated. In pregnancy, there was also attenuated recruitment of parvocellular paraventricular nucleus neurones and increased activation of brainstem noradrenergic nuclei after immune stress, indicating that other mechanisms may be involved in the suppression of prolactin secretion. In summary, low prolactin and increased circulating glucocorticoids together may partly explain how a mother's endocrine system mediates stress induced pregnancy failure. PMID- 21824208 TI - Risk of injury from alcohol and drug use in the emergency department: a case crossover study. AB - INTRODUCTION AND AIMS: A substantial literature exists demonstrating the risk of injury from alcohol, but less is known about the association of alcohol in combination with other drugs and injury. This study examined the risk of injury associated with alcohol and drug use prior to the event. DESIGN AND METHODS: Case crossover analysis was used to estimate the relative risk (RR) of injury due to alcohol use alone, compared with alcohol in combination with other drug use in a sample of emergency department injured patients from two sites in Vancouver, British Columbia (n = 443). Alcohol and drug use in the 6 h prior to injury was compared with the patient's use of these substances during the same 6 h period the day prior and the week prior to injury. RESULTS: Using multiple matching for the two control time periods, RR of injury was significantly related to both alcohol use (RR = 3.3) and to alcohol combined with drug use (RR = 3.0), but not to drug use alone. Effect modification was found only for age for alcohol combined with drug use, with a significant increase in injury risk (P = 0.087) for those over 30. DISCUSSION AND CONCLUSION: While a similar elevated risk of injury was found for alcohol use alone and alcohol used with other drugs, the literature suggests that alcohol in combination with some drugs may be potentially more risky for injury occurrence. Findings suggest the need for future research on risk of injury for specific alcohol and drug combinations. PMID- 21824209 TI - An exploratory study of drinkers views of health information and warning labels on alcohol containers. AB - INTRODUCTION AND AIMS: To identify general and specific features of health information warning labels on alcohol beverage containers that could potentially inform the development and implementation of a new labelling regime in Australia. DESIGN AND METHODS: Mixed methods, including a cross-sectional population survey and a qualitative study of knowledge, attitudes and behaviours regarding alcohol beverage labelling. The population survey used computer-assisted telephone interviews of 1500 persons in Victoria, Australia to gauge the level of support for health information and warning labels. The qualitative study used six focus groups to test the suitability of 12 prototype labels that were placed in situ on a variety of alcohol beverage containers. RESULTS: The telephone survey found 80% to 90% support for a range of information that could potentially be mandated by government authorities for inclusion on labels (nutritional information, alcohol content, health warning, images). Focus group testing of the prototype label designs found that labels should be integrated with other alcohol-related health messages, such as government social advertising campaigns, and specific labels should be matched appropriately to specific consumer groups and beverage types. DISCUSSION AND CONCLUSION: There are high levels of public support for health information and warning labels on alcohol beverages. This study contributes much needed empirical guidance for developing alcohol beverage labelling strategies in an Australian context. PMID- 21824210 TI - Hierarchical polygyny in multiparous lesser flat-headed bats. AB - How males gain access to mates and the potential for female choice will determine whether polygyny can operate at several levels, from within litters and groups to the wider population. Female lesser flat-headed bats (Tylonycteris pachypus) form maternity groups in bamboo stems. Unusually for bats, they are multiparous, providing the opportunity to test whether multi-level polygyny differs among males depending on whether they roost with females, with males or are solitary. We genotyped 662 individuals from 54 internodes and analysed parentage of 165 litters. Our results revealed 170 sets of paternal twins/triplets, of which 96 were full-sibs and 74 were half-sibs. We found that males captured roosting with females typically sired more offspring overall than did other males and also showed a greater tendency to monopolize paternity within both litters and roosting groups. In comparison, males that sired fewer full-sibs were assigned more maternal half-sibs. These latter individuals, which included solitary males and those from all-male groups, might gain copulations either via roaming with furtive mating or during visits by females. Indeed, female lesser flat-headed bats store sperm, so could benefit from multiple mating to reduce genetic incompatibilities. At the same time, however, we found no evidence of outbreeding. Finally, relatedness and mtDNA analyses revealed that polygyny also operated within matrilineal kin, suggesting a system that might promote social cohesiveness. Future studies of individual movements will help to determine the extent to which mixed paternities in litters, matrilines and groups are driven by male or female behaviour. PMID- 21824211 TI - Effects of Pleistocene climatic fluctuations on the phylogeographic and demographic histories of Pacific herring (Clupea pallasii). AB - We gathered mitochondrial DNA sequences (557 bp from the control region in 935 specimens and 668 bp of the cytochrome b gene in 139 specimens) of Pacific herring collected from 20 nearshore localities spanning the species' extensive range along the North Pacific coastlines of Asia and North America. Haplotype diversity and nucleotide diversity were high, and three major phylogeographic lineages (sequence divergences ca. 1.5%) were detected. Using a variety of phylogenetic methods, coalescent reasoning, and molecular dating interpreted in conjunction with paleoclimatic and physiographic evidence, we infer that the genetic make-up of extant populations of C. pallasii was shaped by Pleistocene environmental impacts on the historical demography of this species. A deep genealogical split that cleanly distinguishes populations in the western vs. eastern North Pacific probably originated as a vicariant separation associated with a glacial cycle that drove the species southward and isolated two ancestral populations in Asia and North America. Another deep genealogical split may have involved either a vicariant isolation of a third herring lineage (perhaps originally in the Gulf of California) or it may have resulted simply from the long coalescent times that are possible in large populations. Coalescent analyses showed that all the three evolutionary lineages of C. pallasii experienced major expansions in their most recent histories after having remained more stable in the preceding periods. Independent of the molecular calibration chosen, populations of C. pallasii appear to have remained stable or grown throughout the periods that covered at least two major glaciations, and probably more. PMID- 21824212 TI - Utility of endtidal carbon dioxide monitoring in detection of hypoxia during sedation for brain magnetic resonance imaging in children with developmental disabilities. AB - BACKGROUND: We have shown previously that children with developmental disabilities have three times higher incidence of sedation-related hypoxia when compared with normal children. OBJECTIVES: Our objectives were to describe the changes in endtidal carbon dioxide (ETCO(2)) values and the utility of ETCO(2) monitoring in earlier identification of hypoxia during sedation for brain magnetic resonance imaging (MRI) in children with developmental disabilities. METHODS: We conducted a prospective observational study of a convenience sample of 150 children with developmental disabilities aged 1-10 years who received intravenous sedation for brain MRI. Children were sedated and monitored according to the institution's sedation protocol. We recorded ETCO(2) levels, hypoxia, and adverse events during sedation. Hypoxia was defined as SpO(2) < 93%. A change in ETCO(2) level >= 10 mm Hg from presedation baseline, an intra-sedation >= 50 mm Hg, and loss of capnographic waveform were considered as significant ETCO(2) abnormalities. RESULTS: Of the children, 80.7% (121/150) were sedated with a combination of pentobarbital and fentanyl. ETCO(2) abnormalities were noted in 42.6% (64/150) of sedation encounters. Hypoxia occurred in 18% (27/150) of subjects. ETCO(2) abnormalities were documented in 19(70%) patients with hypoxia before changes in pulse oximetry were noted. ETCO(2) changes were noted a mean of 4.38 +/- 1.89 min prior to occurrence of hypoxia. CONCLUSIONS: ETCO(2) abnormalities and hypoxia occur commonly during sedation in children with developmental disabilities. ETCO(2) monitoring is useful in early recognition of impending hypoxia during sedation in children with developmental disabilities. PMID- 21824213 TI - Retrospective review of ilioinguinal-iliohypogastric nerve block with general anesthesia for herniotomy in ex-premature neonates. AB - OBJECTIVES AND AIMS: We examine the efficacy and complications of general anesthesia with ilioinguinal-iliohypogastric nerve block performed on ex premature neonates undergoing inguinal herniotomy. BACKGROUND: The ex-premature neonate has many co-morbidities and is at risk of postoperative apnea and bradycardia. Anesthesia techniques aimed to provide good surgical conditions include general anesthesia and central neuroaxial techniques. There are still significant complications after these techniques and none is superior. METHODS/MATERIALS: A retrospective search of our department's computer database was conducted on ex-premature neonates, post-menstrual age of 48 weeks and under, who received general anesthesia and ilioinguinal-iliohypogastric nerve block for bilateral inguinal herniotomy from 1997 to 2009. RESULTS: Eighty-two neonates were selected. All medical notes were traced and information including the demographics, co-morbidities and perioperative data were obtained. The mean gestational age was 30.3 weeks (sd +/- 3.2) and the mean post-conception age was 40.0 weeks (sd +/- 3.1). Mean birth weight was 1284 g (sd +/- 518) and mean weight at the time of surgery was 2795 g (sd +/- 958). Thirty-two (39.0%) neonates had apnea of prematurity, which required caffeine treatment. Thirty-five (42.7%) neonates required intubation for ventilatory support preoperatively. There was a good success rate of the ilioinguinal-iliohypogastric nerve block in 73 (89.0%) patients. They were deemed successful clinically by the attending anesthesiologist. No perioperative rescue opioid was required. Four neonates had postoperative apnea requiring intervention. CONCLUSION: Ilioinguinal iliohypogastric nerve block has a success rate similar to other techniques and when combined with general anesthesia, provides a viable alternative technique of anesthesia in these high-risk patients. PMID- 21824214 TI - Ultrasound guided lower extremity blocks. PMID- 21824215 TI - Caudal blocks. AB - Caudal anesthesia is the single most important pediatric regional anesthetic technique. The technique is relatively easy to learn (1), has a remarkable safety record (2), and can be used for a large variety of procedures. The technique has been reviewed in the English (3) and French (4) literature, as well as in German guidelines (5) and in pediatric anesthesia textbooks (6). PMID- 21824216 TI - Manifestation of Long QT syndrome with normal QTc interval under anesthesia: a case report. AB - Patients with congenital Long QT are known to have normal QT interval in symptom free period and in the early years of life. Precipitating factors like surgical stress, interactions with anesthetic agents prolonging QT interval, and electrolyte imbalances can manifest with life threatening arrhythmias in congenital or acquired Long QT syndrome. We report a case of concealed LQTS manifesting under anesthesia and its subsequent perioperative course. PMID- 21824217 TI - Respirology: a thank you note from the outgoing editor. PMID- 21824218 TI - The importance of epigenetics in the development of chronic obstructive pulmonary disease. AB - It is generally accepted that genetic predisposition plays a role in COPD development in susceptible individuals. Therefore, many candidate genes that could be linked to the development of disease have been examined in COPD. However, inconsistent results in different study populations often limit this approach, suggesting that not only genetics, but also other factors, may be contributed to the susceptibility to COPD. Epigenetic mechanisms can affect the transcriptional activity of specific genes, at different points in time, and in different organs. Moreover, these mechanisms can have an effect on people's health. Recently, there is emerging evidence supporting a role of epigenetics for the regulation of inflammatory genes in diseases such as asthma and COPD. Moreover, recent studies suggest that the currently used treatments including corticosteroids may work through epigenetic mechanisms. Epigenetic regulation can be reprogrammed, potentially affecting the risk, aetiology and treatment of various disease states. The epigenetically influenced phenotype could be reversed with demethylating or deacetylating agents, consistent with epigenetic plasticity. The postnatal reversibility of these methylation or acetylation events may therefore provide good opportunities for intervention. The recognition of the role of genetic and epigenetic mechanisms in the development of COPD may identify novel targets that hatch new therapies for patients with COPD. PMID- 21824219 TI - Heaves, an asthma-like disease of horses. AB - Animal models have been developed to investigate specific components of asthmatic airway inflammation, hyper-responsiveness or remodelling. However, all of these aspects are rarely observed in the same animal. Heaves is a naturally occurring disease of horses that combines these features. It is characterized by stable dust-induced inflammation, bronchospasm and remodelling. The evaluation of horses during well-controlled natural antigen exposure and avoidance in experimental settings allows the study of disease mechanisms in the asymptomatic and symptomatic stages, an approach rarely feasible in humans. Also, the disease can be followed over several years to observe the cumulative effect of repeated episodes of clinical exacerbation or to evaluate long-term treatment, contrasting most murine asthma models. This model has shown complex gene and environment interactions, the involvement of both innate and adaptive responses to inflammation, and the contribution of bronchospasm and tissue remodelling to airway obstruction, all occurring in a natural setting. Similarities with the human asthmatic airways are well described and the model is currently being used to evaluate airway remodelling and its reversibility in ways that are not possible in people for ethical reasons. Tools including antibodies, recombinant proteins or gene arrays, as well as methods for sampling tissues and assessing lung function in the horse are constantly evolving to facilitate the study of this animal model. Research perspectives that can be relevant to asthma include the role of neutrophils in airway inflammation and their response to corticosteroids, systemic response to pulmonary inflammation, and maintaining athletic capacities with early intervention. PMID- 21824220 TI - Evaluation of antitumor effects following tumor necrosis factor-alpha gene delivery using nanobubbles and ultrasound. AB - The antitumor effects of tumor necrosis factor (TNF-alpha) were evaluated following transfection of TNF-alpha plasmid DNA into solid mouse tumors using the nanobubbles (NBs) and ultrasound (US) gene delivery system. Murine breast carcinoma (EMT6) cells expressing luciferase (1 * 10(6) cells) were injected intradermally into the flanks of 6-7-week-old male SCID mice on day 0. Ten microliters of TNF-alpha (5 MUg/MUL) or TNF-alpha mock plasmid DNA (5 MUg/MUL) with/without NBs (15 MUL) and saline was injected intratumorally in a total volume of 30 MUL, and tumors were exposed to US (frequency, 1 MHz; intensity, 3.0 W/cm(2); duty cycle, 20%; number of pulses, 200; and exposure time, 60 s) on days 2, 4, 7, and 9. Changes in tumor size were measured with an in vivo bioluminescent imaging system and a mechanical caliper. Changes in tumor vessel area were quantified using contrast-enhanced US imaging with Sonazoid and a high frequency US imaging system (40 MHz) and immunohistochemistry (CD31). At the mRNA level, expression of TNF-alpha, caspase-3, and p53 were quantified using real time quantitative RT-PCR. At the protein level, expression of caspase-3 and p53 were confirmed by immunohistochemistry. We show that repeated TNF-alpha gene delivery using NBs and US can lead to the local production of TNF-alpha. This results in antitumor effects, including activation of p53-dependent apoptosis, decrease in tumor vessel density, and suppression of tumor size. In this study, we showed the effectiveness of using NBs and US for TNF-alpha gene delivery into tumor cells. PMID- 21824221 TI - Evaluation of [125I]IPOS as a molecular imaging probe for hypoxia-inducible factor-1-active regions in a tumor: comparison among single-photon emission computed tomography/X-ray computed tomography imaging, autoradiography, and immunohistochemistry. AB - To image hypoxia-inducible factor-1 (HIF-1)-active tumors, we previously developed a chimeric protein probe ([(123/125) I]IPOS) that is degraded in the same manner as HIF-1alpha under normoxic conditions. In the present study, we aim to show that the accumulation of radioiodinated POS reflects the expression of HIF-1. In vivo single-photon emission computed tomography (SPECT)/X-ray CT (CT) imaging, autoradiography, and double-fluorescent immunostaining for HIF-1alpha and pimonidazole (PIMO) were carried out 24 h after the injection of [(125) I]IPOS. Tumor metabolite analysis was also carried out. A tumor was clearly visualized by multi-pinhole, high-resolution SPECT/CT imaging with [(125) I]IPOS. The obtained images were in accordance with the corresponding autoradiograms and with the results of ex vivo biodistribution. A metabolite analysis revealed that 77% of the radioactivity was eluted in the macromolecular fraction, suggesting that the radioactivity mainly existed as [(125) I]IPOS in the tumors. Immunohistochemistry revealed that the HIF-1alpha-positive areas and PIMO positive areas were not always identical, only some of the regions were positive for both markers. The areas showing [(125) I]IPOS accumulation were positively and significantly correlated with the HIF-1alpha-positive areas (R = 0.75, P < 0.0001). The correlation coefficient between [(125) I]IPOS-accumulated areas and HIF-1alpha-positive areas was significantly greater than that between the [(125) I]IPOS-accumulated areas and the PIMO-positive areas (P < 0.01). These findings indicate that [(125) I]IPOS accumulation reflects HIF-1 expression. Thus, [(123/125) I]IPOS can serve as a useful probe for the molecular imaging of HIF-1 active tumors. PMID- 21824222 TI - Prevention of hematogenous metastasis by neutralizing mice and its chimeric anti Aggrus/podoplanin antibodies. AB - The platelet aggregation-inducing factor, Aggrus (also known as podoplanin), is reported to contribute to cancer metastasis by mediating cancer cell-platelet interaction. Aggrus has been shown to be upregulated in many different types of cancers. Thus, not only the functional inhibition of Aggrus, but also its application as a cancer-specific antigen has therapeutic potential. Among a series of anti-Aggrus mAb established previously, no mouse anti-human Aggrus mAb exists that possesses the ability to neutralize platelet aggregation. For precise preclinical examinations of mouse and monkey models, the establishment of Aggrus neutralizing mouse mAb and their chimeric Abs is needed. In this study, we established two mouse anti-human Aggrus mAb, P2-0 and HAG-3. A precise analysis of their epitopes revealed that P2-0 recognized the conformation near the bioactive O-glycosylation site at the Thr(52) residue. In contrast, HAG-3 recognized the amino-terminus side at a short distance from the conformation recognized by P2-0. We observed that only P2-0 attenuated Aggrus-induced platelet aggregation and Aggrus binding to its platelet receptor, that is, the C-type lectin-like receptor-2. Consistent with these data, only P2-0 prevented the experimental metastasis of human Aggrus-overexpressing CHO cells. Subsequently, we cloned the complementary determining region of P2-0 and produced the murine/human chimeric P2-0 antibody. This chimeric antibody maintained its inhibitory activity of Aggrus-induced platelet aggregation and experimental metastasis. Thus, P2-0 and its chimeric antibody are expected to aid the development of preclinical and clinical examinations of Aggrus-targeted cancer therapy. PMID- 21824223 TI - The state of hepatitis B and C in Europe: report from the hepatitis B and C summit conference*. AB - Worldwide, the hepatitis B virus (HBV) and the hepatitis C virus (HCV) cause, respectively, 600,000 and 350,000 deaths each year. Viral hepatitis is the leading cause of cirrhosis and liver cancer, which in turn ranks as the third cause of cancer death worldwide. Within the WHO European region, approximately 14 million people are chronically infected with HBV, and nine million people are chronically infected with HCV. Lack of reliable epidemiological data on HBV and HCV is one of the biggest hurdles to advancing policy. Risk groups such as migrants and injecting drug users (IDU) tend to be under-represented in existing prevalence studies; thus, targeted surveillance is urgently needed to correctly estimate the burden of HBV and HCV. The most effective means of prevention against HBV is vaccination, and most European Union (EU) countries have universal vaccination programmes. For both HBV and HCV, screening of individuals who present a high risk of contracting the virus is critical given the asymptomatic, and thereby silent, nature of disease. Screening of migrants and IDUs has been shown to be effective and potentially cost-effective. There have been significant advances in the treatment of HCV and HBV in recent years, but health care professionals remain poorly aware of treatment options. Greater professional training is needed on the management of hepatitis including the treatment of liver cancer to encourage adherence to guidelines and offer patients the best possible outcomes. Viral hepatitis knows no borders. EU Member States, guided by the EU, need to work in a concerted manner to implement lasting, effective policies and programmes and make tackling viral hepatitis a public health priority. PMID- 21824224 TI - Nursing in Critical Care. What's in this issue? PMID- 21824225 TI - The future of nursing: leading change, advancing health stories to ignite the transformation. PMID- 21824226 TI - 'The big three': quality, safety & cost. PMID- 21824227 TI - The ventilator care bundle and its impact on ventilator-associated pneumonia: a review of the evidence. AB - AIMS AND OBJECTIVES: The aim of this review was to critically analyse recent research that has investigated ventilator care bundle (VCB) use, with the objective of analysing its impact on ventilator-associated pneumonia (VAP) outcomes. BACKGROUND: The VCB is a group of four evidence-based procedures, which when clustered together and implemented as an 'all or nothing' strategy, may result in substantial clinical outcome improvement. VAP is a nosocomial lung infection associated with endotracheal tube use in ventilated patients. Since the VCB was introduced there have been several studies that have reported significant VAP rate reductions. SEARCH STRATEGY: A comprehensive search for research, published between 2004 and 2009, was conducted using Medline and PubMed. Key words were used to identify English language studies reporting VCB implementation within adult intensive care units (ICU) and associated clinical outcomes. Studies that implemented bundle variations that did not include all four elements were excluded. CONCLUSIONS: Because of the limitations of the observational designs used in the studies retrieved, a definitive causal relationship between VCB use and VAP reduction cannot be stated. However, the evidence to date is strongly indicative of a positive association. Several studies reported the use of additional VCB elements. In these cases it is difficult to establish which elements are related to the measured outcomes. Further research is recommended to establish baseline outcome measures using the four-element VCB, before adding further processes singly, as well as research investigating the effect of audit and feedback on VCB compliance and its effect on clinical outcomes. RELEVANCE TO CLINICAL PRACTICE: A reduction in VAP is associated with VCB use. The evidence to date, whilst not at the highest experimental level, is at the highest ethically permissible level. In the absence of contradictory research, the current evidence suggests that use of the VCB represents best practice for all eligible adult ventilated patients in ICU. PMID- 21824228 TI - The implementation of a bowel management protocol in an adult intensive care unit. AB - AIM: A study to explore the impact of implementing a bowel management protocol in a tertiary referral intensive care unit (ICU) in the West of Scotland. METHODS: A three phase study was implemented. Phase 1 - a baseline audit reviewing 26 patients' medical notes and a baseline focus group reviewing the multidisciplinary team's (MDT's) opinions with regard to bowel care management in the ICU. Phase 2 - the implementation of a protocol, updated bowel care chart and education sessions for members of the MDT. Phase 3 - an end of study audit reviewing 27 patients' notes after the implementation of phase 2. Additionally, a further focus group examined the MDT's experiences of the protocol in clinical practice. RESULTS AND FINDINGS: During the phase 1 data collection period, it was evident that there was a haphazard approach to bowel care in the ICU, resulting in poor bowel care documentation and a high incidence of constipation and diarrhoea days. After the interventions of phase 2, bowel care documentation days increased by 13% (p = 0.0003), constipation incidence decreased by 20.7% (p = 0.13) and diarrhoea days reduced by 15.2% (p = 0.18). CONCLUSION: Although further evaluation is planned, the protocol implemented in this particular study appears to be a useful tool for the delivery of bowel care in the ICU. RELEVANCE TO CLINICAL PRACTICE: Ensuring appropriate and timely bowel care in the ICU has major implications for the critically ill patients. PMID- 21824229 TI - Risk factors for prolonged stay in cardiac surgery intensive care units. AB - AIMS AND OBJECTIVES: To identify the factors that might affect the length of stay in the intensive care unit (ICU-LOS) among cardiac surgery patients. BACKGROUND: ICU-LOS forms an important factor for assessing the effectiveness of the provided nursing care. A number of factors can be accused for increasing patient hospitalization. The nursing workload (NWL), among others, was found to play a significant role as it is closely associated with the quality of care. DESIGN: An observational cohort study among 313 consecutive patients who were admitted to the cardiac surgery intensive care unit of a general, tertiary hospital of Athens, Greece from November 2008 to November 2009. METHODS: Data collection was performed by using a short questionnaire (for basic demographic information) and two instruments, the Nursing Activities Score (NAS) and the logistic EuroSCORE, for assessing the NWL and the perioperative risk for each patient respectively. RESULTS: ICU-LOS of more than 2 days increased with age and was more common among females (p < 0.001 and p = 0.02, respectively). Multivariate logistic regression analysis revealed a positive association between increased perioperative risk and the increased ICU-LOS [odd ratio (OR) 1.9, 95% confidence interval (CI) 1.0-3.5, p = 0.04], while patients with a first day NAS of more than 61.6% had an almost 5.2 times greater probability to stay in the cardiac surgery unit for more than 2 days (OR 5.2, 95% CI 3.0-8.8, p < 0.001). CONCLUSIONS: Increased level of NWL and patient perioperative risk are closely associated with increased ICU-LOS. RELEVANCE TO CLINICAL PRACTICE: The correlation between patient perioperative risk and ICU-LOS encourages the early identification of high-risk patients for prolonged hospitalization. Furthermore, the relationship between NWL and ICU-LOS allows the early identification of these patients with the use of an independent nursing tool. PMID- 21824230 TI - An observational pilot study of CSF diversion in subarachnoid haemorrhage. AB - BACKGROUND: A primary focus of hospital treatment following admission for subarachnoid haemorrhage (SAH) is a prevention of cerebral artery vasospasm, which may result in ischaemic stroke. Intraventricular catheter (IVC) insertion to facilitate cerebral spinal fluid (CSF) drainage and intracranial pressure (ICP) monitoring may reduce the incidence or severity of vasospasm, but insufficient evidence exists from which clinicians may determine the best practice of CSF management. AIMS: The aim of this study was to provide the pilot data to explore the impact of different methods of CSF drainage on outcomes in patients with SAH. METHODS: In this non-randomized observational study, patients diagnosed with SAH who had ICP monitoring in situ were prospectively enrolled. Group assignment was determined by the method of external ventricular drainage (EVD) management prescribed by the attending physician prior to enrollment. RESULTS: The 37 subjects were disproportionately divided: open-EVD group (N = 24) and monitor-ICP group (N = 13). There were no statistically significant differences by group assignment with respect to vasospasm, length of stay (LOS), highest average ICP, total CSF drained and disability upon discharge between groups. CONCLUSIONS: Although not significant, our results show that the monitor ICP group trended towards improved clinical outcomes. These results provide sufficient equipoise to support further research in ICP management in patients with SAH using a randomized clinical trial. RELEVANCE TO CLINICAL PRACTICE: This study provides a solid foundation for the development of a randomized trial exploring two different methods of ICP monitoring and CSF diversion during the acute phase of care following aneurysm rupture. PMID- 21824231 TI - An evaluation of a critical care course for undergraduate nursing students. AB - AIM: The aim of this paper was to evaluate a 2-day critical care course (CCC) delivered to a cohort of adult branch nursing students. BACKGROUND: In today's health care system there is an increase in the number of critically ill patients being cared for in a ward environment. As a result, nurses require the knowledge and skills to effectively manage this patient group. Skills such as prompt recognition of the sick patient, effective communication and performing basic management care skills are necessary. METHODS: The CCC was provided to final year adult branch nursing students (n = 182) within a university in the UK. On completion of the course, participants were invited to undertake a Likert scale questionnaire. The questionnaire also contained a free response section to elicit qualitative information. Quantitative data were analysed using SPSS version 17.0 and descriptive statistics produced. Qualitative responses were analysed thematically. RESULTS: There was a 73.7% (n = 135) response rate. Overall, there was a positive evaluation of the course. Students (89.6%; n = 121) reported a perceived increase in confidence when caring for critically ill patients following the course and 88.2% (n = 119) felt that their knowledge and skills had improved at the end of the 2-day course. CONCLUSION: This study supports the implementation of critical care training for undergraduate nursing students. There are implications for the development of specific modules, aiming to improve undergraduate nursing students' recognition, assessment and management of the critically ill patient. RELEVANCE TO CLINICAL PRACTICE: There is a shortage of critical care practice placements for undergraduate nursing students. It is essential that an undergraduate curriculum incorporates critical care teaching so that critical care skills are evident at the point of registration. PMID- 21824239 TI - Molecular typing of Candida albicans isolates from patients and health care workers in a neonatal intensive care unit. AB - AIMS: The aim of this study was to investigate the genetic relatedness between Candida albicans isolates and to assess their nosocomial origin and the likeliness of cross-transmission between health care workers (HCWs) and hospitalized neonates in a neonatal intensive care unit (NICU). METHODS: We retrospectively analysed 82 isolates obtained from 40 neonates and seven isolates from onychomycosis of the fingers of five HCWs in a Tunisian NICU by using pulsed field gel electrophoresis (PFGE) and randomly amplified polymorphic DNA (RAPD) analysis with CA1 and CA2 as primers. RESULTS: In RAPD analysis, the discriminatory power (DP) of CA1 and CA2 primers was 0.86 and 0.81, respectively. A higher DP was achieved by combining patterns generated by both primers (0.92), while PFGE karyotyping exhibited the lowest DP (0.62). The RAPD-CA1/CA2 analysis revealed that 65.8% of isolates obtained from neonates derived from a limited number (6) of groups of genetically identical strains, that five temporal clusterings occurred during the study period and that three HCWs' isolates and 11 isolates obtained from six neonates were identical. CONCLUSIONS: These findings argue for the nosocomial transmission of C. albicans in our NICU and for the transfer of strains from HCWs to patients. SIGNIFICANCE AND IMPACT OF THE STUDY: Identification of relatedness between Candida species obtained from neonates and health care workers by using molecular techniques with high discriminatory power is essential for setting up specific control measures in order to reduce the incidence of nosocomial candidiasis. PMID- 21824240 TI - Decontamination of a hard surface contaminated with Bacillus anthracisDeltaSterne and B. anthracis Ames spores using electrochemically generated liquid-phase chlorine dioxide (eClO2). AB - AIMS: To evaluate the inactivation of Bacillus anthracisDeltaSterne and Ames spores using electrochemically generated liquid-phase chlorine dioxide (eClO(2)) and compare two sporulation and decontamination methods with regard to cost, safety and technical constraints. METHODS AND RESULTS: Spores were prepared via agar and broth methods and subsequently inoculated and dried onto clean, autoclave-sterilized glass coupons. Bacillus anthracis spore inactivation efficacy was evaluated using the modified three-step method (AOAC 2008.05) and a single-tube extraction method. Spores (7.0 +/- 0.5 logs) were inactivated within 1 min at room temperature using freshly prepared eClO(2). Bacillus anthracisDeltaSterne spores decreased in size after eClO(2) treatment as measured using a Beckman Coulter Multisizer. CONCLUSIONS: eClO(2) saturation of a hard surface was an effective B. anthracis sporicide. Broth sporulation and the single tube extraction method required less time and fewer steps, yielded a higher percentage of phase-bright spores and showed higher spore recovery efficiency compared with AOAC 2008.05, making it more amenable to biosafety level 3 (BSL3) testing of virulent spores. SIGNIFICANCE AND IMPACT OF THE STUDY: Two test methods demonstrated the sporicidal efficacy of eClO(2). A new single-tube extraction test protocol for decontaminants was introduced. PMID- 21824241 TI - Nocardia infection in kidney transplant recipients: case report and analysis of 66 published cases. AB - Nocardiosis is a rare but life-threatening opportunistic infection, especially in immune compromised patients, including kidney transplant recipients. Primary pulmonary infection is the most common clinical pattern, and can easily result in disseminated Nocardia infection if treatment therapy is not adequate at the beginning. In this article, we report a new case of disseminated nocardiosis (lungs, skin, and pericardium) after renal allograft transplantation. We also review the English literature published from 1980 to 2010 and analyze the clinical characteristics of nocardiosis in kidney transplant recipients. PMID- 21824243 TI - Separation of fluorescence-labelled terminal restriction fragment DNA on a two dimensional gel (T-RFs-2D) - an efficient approach for microbial consortium characterization. AB - Fingerprinting techniques provide access to understanding the ecology of uncultured microbial consortia. However, the application of current techniques such as terminal restriction fragment length polymorphism (T-RFLP) and denaturing gradient gel electrophoresis (DGGE) has been hindered due to their limitations in characterizing complex microbial communities. This is due to that different populations possibly share the same terminal restriction fragments (T-RFs) and DNA fragments may co-migrate on DGGE gels. To overcome these limitations, a new approach was developed to separate terminal restriction fragments (T-RFs) of 16S rRNA genes on a two-dimensional gel (T-RFs-2D). T-RFs-2D involves restriction digestion of terminal fluorescence-labelled PCR amplified 16S rRNA gene products and their high-resolution separation via a two-dimensional (2D) gel electrophoresis based on the T-RF fragment size (1(st) D) and its sequence composition on the denaturing gradient gel (2(nd) D). The sequence information of interested T-RFs on 2D gels can be obtained through serial poly(A) tailing reaction, PCR amplification and subsequent DNA sequencing. By employing the T-RFs 2D method, bacteria with MspI digested T-RF size of 436 (+/-1) bp and 514 (+/-1) bp were identified to be a Lysobacter sp. and a Dehalococcoides sp. in a polychlorinated biphenyl (PCB) dechlorinating culture. With the high resolution of 2D separation, T-RFs-2D separated 63 DNA fragments in a complex river-sediment microbial community, while traditional DGGE detected only 41 DNA fragments in the same sample. In all, T-RFs-2D has its advantage in obtaining sequence information of interested T-RFs and also in characterization of complex microbial communities. PMID- 21824242 TI - Massive dominance of Epsilonproteobacteria in formation waters from a Canadian oil sands reservoir containing severely biodegraded oil. AB - The subsurface microbiology of an Athabasca oil sands reservoir in western Canada containing severely biodegraded oil was investigated by combining 16S rRNA gene- and polar lipid-based analyses of reservoir formation water with geochemical analyses of the crude oil and formation water. Biomass was filtered from formation water, DNA was extracted using two different methods, and 16S rRNA gene fragments were amplified with several different primer pairs prior to cloning and sequencing or community fingerprinting by denaturing gradient gel electrophoresis (DGGE). Similar results were obtained irrespective of the DNA extraction method or primers used. Archaeal libraries were dominated by Methanomicrobiales (410 of 414 total sequences formed a dominant phylotype affiliated with a Methanoregula sp.), consistent with the proposed dominant role of CO(2) -reducing methanogens in crude oil biodegradation. In two bacterial 16S rRNA clone libraries generated with different primer pairs, > 99% and 100% of the sequences were affiliated with Epsilonproteobacteria (n = 382 and 72 total clones respectively). This massive dominance of Epsilonproteobacteria sequences was again obtained in a third library (99% of sequences; n = 96 clones) using a third universal bacterial primer pair (inosine-341f and 1492r). Sequencing of bands from DGGE profiles and intact polar lipid analyses were in accordance with the bacterial clone library results. Epsilonproteobacterial OTUs were affiliated with Sulfuricurvum, Arcobacter and Sulfurospirillum spp. detected in other oil field habitats. The dominant organism revealed by the bacterial libraries (87% of all sequences) is a close relative of Sulfuricurvum kujiense - an organism capable of oxidizing reduced sulfur compounds in crude oil. Geochemical analysis of organic extracts from bitumen at different reservoir depths down to the oil water transition zone of these oil sands indicated active biodegradation of dibenzothiophenes, and stable sulfur isotope ratios for elemental sulfur and sulfate in formation waters were indicative of anaerobic oxidation of sulfur compounds. Microbial desulfurization of crude oil may be an important metabolism for Epsilonproteobacteria indigenous to oil reservoirs with elevated sulfur content and may explain their prevalence in formation waters from highly biodegraded petroleum systems. PMID- 21824244 TI - The RNA chaperone, Hfq, controls two luxR-type regulators and plays a key role in pathogenesis and production of antibiotics in Serratia sp. ATCC 39006. AB - Serratia sp. ATCC 39006 (S39006) is a Gram-negative bacterium that is virulent in plant (potato) and animal (Caenorhabditis elegans) models. It produces two secondary metabolite antibiotics, a prodigiosin and a carbapenem, and the exoenzymes, pectate lyase and cellulase. A complex regulatory network that includes quorum sensing (QS) controls production of prodigiosin. While many aspects of the regulation of the metabolites and exoenzymes are well understood, the potential role in this network of the RNA chaperone Hfq and dependent small regulatory RNAs has not been characterized. Hfq is an RNA chaperone involved in post-transcriptional regulation that plays a key role in stress response and virulence in diverse bacterial species. To explore whether Hfq-dependent processes might contribute to the regulation of antibiotic production we constructed an S39006 Deltahfq mutant. Production of prodigiosin and carbapenem was abolished in this mutant strain, while production of the QS signalling molecule, butanoyl homoserine lactone (BHL), was unaffected. Using transcriptional fusions, we found that Hfq regulates the QS response regulators, SmaR and CarR. Additionally, exoenzyme production and swimming motility were decreased in a Deltahfq mutant, and virulence was attenuated in potato and C. elegans models. These results suggest that an Hfq-dependent pathway is involved in the regulation of virulence and secondary metabolite production in S39006. PMID- 21824245 TI - HIF-1alpha is involved in mediating apoptosis resistance to Chlamydia trachomatis infected cells. AB - Chlamydiae are obligate intracellular Gram-negative bacteria that cause widespread diseases in humans. Due to the intimate association between bacterium and host, Chlamydia evolved various strategies to protect their host cell against death-inducing stimuli, allowing the bacterium to complete its development cycle. An RNA interference (RNAi)-based screen was used to identify host cell factors required for apoptosis resistance of human epithelial cells infected with Chlamydia trachomatis serovar L2. Among the 32 validated hits, the anti-apoptotic Bcl-2 family member Mcl-1 was identified as a target. Protein network analyses implicated the transcription factor hypoxia-induced factor 1 alpha (HIF-1alpha) to be central to the regulation of many of the identified targets. Further mechanistic investigations showed that HIF-1alpha was stabilized within the host cell cytoplasm during early infection time points, followed by its translocation to the nucleus and eventual transcriptional activation of Mcl-1. siRNA-mediated depletion of HIF-1alpha led to a drastic decrease in Mcl-1, rendering the cell sensitive to apoptosis induction. Taken together, our findings identify HIF 1alpha as responsible for upregulation of Mcl-1 and the maintenance of apoptosis resistance during Chlamydia infection. PMID- 21824246 TI - How can microbial interactions with the blood-brain barrier modulate astroglial and neuronal function? AB - The vascular endothelium of the blood-brain barrier (BBB) is regarded as a part of the neurovascular unit (NVU). This emerging NVU concept emphasizes the need for homeostatic signalling among the neuronal, glial and vascular endothelial cellular compartments in maintaining normal brain function. Conversely, dysfunction in any component of the NVU affects another, thus contributing to disease. Brain endothelial activation and dysfunction is observed in various neurological diseases, such as (ischemic) stroke, seizure, brain inflammation and infectious diseases and likely contributes to or exacerbates neurological conditions. The role and impact of brain endothelial factors on astroglial and neuronal activation is unclear. Similarly, it is not clear which stages of BBB endothelial activation can be considered beneficial versus detrimental. Although the BBB plays an important role in context of encephalopathies caused by neurotropic microbes that must first penetrate into the brain, a crucial role of the BBB in contributing to neurological dysfunction may be seen in cerebral malaria (CM), where the Plasmodium parasite remains sequestered in the brain vasculature, does not enter the brain parenchyma, and yet causes coma and seizures. In this minireview some of the scenarios and factors that may play a role in BBB as a relay station to modulate astroneuronal functioning are discussed. PMID- 21824247 TI - Salmonella typhimurium is pathogenic for Dictyostelium cells and subverts the starvation response. AB - In unicellular amoebae, such as Dictyostelium discoideum, bacterial phagocytosis is a food hunting device, while in higher organisms it is the first defence barrier against microbial infection. In both cases, pathogenic bacteria exploit phagocytosis to enter the cell and multiply intracellularly. Salmonella typhimurium, the agent of food-borne gastroenteritis, is phagocytosed by both macrophages and Dictyostelium cells. By using cell biological assays and global transcriptional analysis with DNA microarrays covering the Dictyostelium genome, we show here that S. typhimurium is pathogenic for Dictyostelium cells. Depending on the degree of virulence, which in turn depended on bacterial growth conditions, Salmonella could kill Dictyostelium cells or inhibit their growth and development. In the early phase of infection in non-nutrient buffer, the ingested bacteria escaped degradation, induced a starvation-like transcriptional response but inhibited selectively genes required for chemotaxis and aggregation. This way differentiation of the host cells into spore and stalk cells was blocked or delayed, which in turn is likely to be favourable for the establishment of a replicative niche for Salmonella. Inhibition of the aggregation competence and chemotactic streaming of aggregation-competent cells in the presence of Salmonella suggests interference with cAMP signalling. PMID- 21824248 TI - Salmonella exploits Arl8B-directed kinesin activity to promote endosome tubulation and cell-to-cell transfer. AB - The facultative intracellular pathogen Salmonella enterica serovar Typhimurium establishes a replicative niche, the Salmonella-containing vacuole (SCV), in host cells. Here we demonstrate that these bacteria exploit the function of Arl8B, an Arf family GTPase, during infection. Following infection, Arl8B localized to SCVs and to tubulated endosomes that extended along microtubules in the host cell cytoplasm. Arl8B(+) tubules partially colocalized with LAMP1 and SCAMP3. Formation of LAMP1(+) tubules (the Salmonella-induced filaments phenotype; SIFs) required Arl8B expression. SIFs formation is known to require the activity of kinesin-1. Here we find that Arl8B is required for kinesin-1 recruitment to SCVs. We have previously shown that SCVs undergo centrifugal movement to the cell periphery at 24 h post infection and undergo cell-to-cell transfer to infect neighbouring cells, and that both phenotypes require kinesin-1 activity. Here we demonstrate that Arl8B is required for migration of the SCV to the cell periphery 24 h after infection and for cell-to-cell transfer of bacteria to neighbouring cells. These results reveal a novel host factor co-opted by S. Typhimurium to manipulate the host endocytic pathway and to promote the spread of infection within a host. PMID- 21824249 TI - Long in the shade, glucagon re-occupies centre court. PMID- 21824250 TI - Early milestones in glucagon research. AB - As an introduction to the Symposium, we have reviewed the early steps in glucagon research from its discovery in 1923 to the establishment of the basics of the physiology and pathophysiology of the hormone after the description of a sensitive and specific radioimmunoassay by Unger and his co-workers in 1959. PMID- 21824252 TI - Transcriptional regulation of alpha-cell differentiation. AB - The development of the endocrine pancreas and the differentiation of its five cell types, alpha, beta, delta, epsilon and pancreatic polypeptide (PP) cells, are a highly complex and tightly regulated process. Proper differentiation and function of alpha- and beta-cells are critical for blood glucose homeostasis. These processes are governed by multiple transcription factors and other signalling systems, and its dysregulation results in diabetes. The differentiation of alpha-cells and the maintenance of alpha-cell function can be influenced at several stages during development and in the maturing islet. Many transcription factors, such as neurogenin 3 (Ngn3), pancreatic duodenal homeobox 1 (Pdx1) and regulatory factor x6 (Rfx6), play a crucial role in the determination of the endocrine cell fate, while other transcription factors, such as aristaless-related homeobox (Arx) and forkhead box A2 (Foxa2), are implicated in the initial or terminal differentiation of alpha-cells. In vivo and in vitro studies have shown that preproglucagon transcription, and therefore the maintenance of alpha-cell function, is regulated by several factors, including forkhead box A1 (Foxa1), paired box 6 (Pax6), brain4 (Brn4) and islet-1 (Isl-1). Detailed information about the regulation of normal and abnormal alpha-cell differentiation gives insight into the pathogenesis of diabetes, identifies further targets for diabetes treatment and provides clues for the reprogramming of alpha- to beta-cells for replacement therapy. PMID- 21824251 TI - Basic helix-loop-helix transcription factors and enteroendocrine cell differentiation. AB - For over 30 years it has been known that enteroendocrine cells derive from common precursor cells in the intestinal crypts. Until recently little was understood about the events that result in commitment to endocrine differentiation or the eventual segregation of over 10 different hormone-expressing cell types in the gastrointestinal tract. Enteroendocrine cells arise from pluripotent intestinal stem cells. Differentiation of enteroendocrine cells is controlled by the sequential expression of three basic helix-loop-helix transcription factors, Math1, Neurogenin 3 (Neurog3) and NeuroD. Math1 expression is required for specification and segregation of the intestinal secretory lineage (Paneth, goblet,and enteroendocrine cells) from the absorptive enterocyte lineage. Neurog3 expression represents the earliest stage of enteroendocrine differentiation and in its absence enteroendocrine cells fail to develop. Subsequent expression of NeuroD appears to represent a later stage of differentiation for maturing enteroendocrine cells. Enteroendocrine cell fate is inhibited by the Notch signalling pathway, which appears to inhibit both Math1 and Neurog3. Understanding enteroendocrine cell differentiation will become increasingly important for identifying potential future targets for common diseases such as diabetes and obesity. PMID- 21824253 TI - Growth factor signalling in the regulation of alpha-cell fate. AB - Glucagon plays critical roles in regulating glucose homeostasis, mainly by counteracting the effects of insulin. Consequently, the dysregulated glucagon secretion that is evident in type 2 diabetes has significant implications in the pathophysiology of the disease. Glucagon secretion from pancreatic alpha-cells has been suggested to be modulated by blood glucose, signals from the nervous system and endocrine components. In addition to these regulators, intraislet factors acting in a paracrine manner from neighbouring beta-cells are emerging as central modulator(s) of alpha-cell biology. One of the most important of these paracrine factors, insulin, modulates glucagon secretion. Indeed, the alpha-cell specific insulin receptor knockout (alphaIRKO) mouse manifests hypersecretion of glucagon in the postprandial stage and exhibits defective secretion in fasting induced hypoglycaemia, together mimicking the alpha-cell defects observed in type 2 diabetes. Interestingly, alphaIRKO mice display a progressive increase in beta cell mass and a concomitant decrease in alpha-cells. Lineage trace analyses reveal that the new beta-cells originate, in part, from the insulin receptor deficient alpha-cells indicating a critical role for alpha-cell insulin signalling in determining beta-cell origin. Our studies also reveal that glucagon like peptide-1 (GLP-1) treatment of alphaIRKO mice suppresses glucagon secretion despite absence of functional insulin receptors precluding a role for insulin in GLP-1 action on alpha-cells in this model. These findings highlight the significance of insulin signalling in the regulation of alpha-cell biology. PMID- 21824254 TI - Glucagon gene expression in the endocrine pancreas: the role of the transcription factor Pax6 in alpha-cell differentiation, glucagon biosynthesis and secretion. AB - The glucagon gene is expressed in alpha-cells of the pancreas, L cells of the intestine and the hypothalamus. The determinants of the alpha-cell-specific expression of the glucagon gene are not fully characterized, although Arx, Pax6 and Foxa2 are critical for alpha-cell differentiation and glucagon gene expression; in addition, the absence of the beta-cell-specific transcription factors Pdx1, Pax4 and Nkx6.1 may allow for the glucagon gene to be expressed. Pax6, along with cMaf and MafB, binds to the DNA control element G(1) which confers alpha-cell specificity to the promoter and to G(3) and potently activates glucagon gene transcription. In addition, to its direct role on the transcription of the glucagon gene, Pax6 controls several transcription factors involved in the activation of the glucagon gene such as cMaf, MafB and NeuroD1/Beta2 as well as different steps of glucagon biosynthesis and secretion. We conclude that Pax6 independently of Arx and Foxa2 is critical for alpha-cell function by coordinating glucagon gene expression as well as glucagon biosynthesis and secretion. PMID- 21824255 TI - Longevity of human islet alpha- and beta-cells. AB - Pancreatic islet cell regeneration is considered to be important in the onset and progression of diabetes and as a potential cell therapy. Current hypotheses, largely based on rodent studies, indicate continuous turnover and plasticity of alpha- and beta-cells in adults; cell populations in rodents respond to increased secretory demand in obesity (30-fold beta-cell increase) and pregnancy. Turnover and plasticity of islet cells decrease in mice within >1 year. In man, morphometric observations on postmortem pancreas have indicated that the cellular expansion is much smaller than the increased insulin secretion that accompanies obesity. Longevity of beta-cells in humans >20-30 years has been shown by (14) C measurements and bromo-deoxyuridine (BrdU) incorporation and there is an age related decline in the expression of proteins associated with cell division and regeneration including cyclin D3 and PDX-1. Quantitative estimation and mathematical modelling of the longevity marker, cellular lipofuscin body content, in islets of subjects aged 1-84 years indicated an age-related increase and that 97% of the human beta-cell population was established by the age of 20. New data show that human alpha-cell lipofuscin content is less than that seen in beta cells, but the age-related accumulation is similar; lipofuscin-positive (aged) cells form >= 95% of the population after 20 years. Increased turnover of cellular organelles such as mitochondria and endoplasmic reticulum could contribute to lipofuscin accumulation with age in long-lived cells. Induction of regeneration of human islet cells will require understanding of the mechanisms associated with age-related senescence. PMID- 21824257 TI - Reprogramming gut and pancreas endocrine cells to treat diabetes. AB - Multiple approaches have been investigated with the ultimate goal of providing insulin independence to patients with either type 1 or type 2 diabetes. Approaches to produce insulin-secreting cells in culture, convert non-beta-cells into functional beta-cells or engineer autologous cells to express and secrete insulin in a meal-responsive manner have all been described. This research has been facilitated by significant improvements in both viral and non-viral gene delivery approaches that have enabled new experimental strategies. Many studies have examined possible avenues to confer islet cytoprotection against immune rejection, inflammation and apoptosis by genetic manipulation of islet cells prior to islet transplantation. Here we review several reports based on the reprogramming of pancreas and gut endocrine cells to treat diabetes. PMID- 21824256 TI - In vivo conversion of adult alpha-cells into beta-like cells: a new research avenue in the context of type 1 diabetes. AB - Type 1 diabetes is caused by the loss of insulin-producing beta-cells as a result of an autoimmune condition. Despite current therapeutic approaches aimed at restoring the insulin supply, complications caused by variations in glycaemia may still arise with age. There is therefore mounting interest in the establishment of alternative therapies. Most current approaches consist in designing rational protocols for in vitro or in vivo cell differentiation/reprogramming from a number of cell sources, including stem, progenitor or differentiated cells. Towards this ultimate goal, it is clear that we need to gain further insight into the interplay between signalling events and transcriptional networks that act in concert throughout pancreatic morphogenesis. This short review will therefore focus on the main events underlying pancreatic development with particular emphasis on the genetic determinants implicated, as well as on the relatively new concept of endocrine cell reprogramming, that is the conversion of pancreatic alpha-cells into cells displaying a beta-cell phenotype. PMID- 21824258 TI - Foetal proglucagon processing in relation to adult appetite control: lessons from a transplantable rat glucagonoma with severe anorexia. AB - We have previously reported severe anorexia abruptly induced in rats 2-3 weeks after they have been transplanted subcutaneously with the glucagonoma MSL-G-AN. Vagotomy did not affect the time of onset and severity of anorexia, and the anorectic state resembles hunger with strongly elevated neuropeptide Y (NPY) mRNA levels in the nucleus arcuatus. We now show that circulating levels of bioactive glucagon-like peptide-1 (GLP-1) (7-36amide) start to increase above control levels exactly at the time of onset of anorexia. At this time-point, bioactive glucagon as well as total glucagon precursors and GLP-1 metabolites are already vastly elevated compared to controls. We further show that intravenous administration of very high concentrations of GLP-1 to hungry schedule-fed rats causes anorexia in a dose-dependent manner, which is blocked by the GLP-1 receptor antagonist exendin (9-39). GLP-1 (7-36amide) has a well-characterized anorectic effect but also causes taste aversion when administered centrally. The anorectic effect is blocked in rats treated neonatally by monosodium glutamate (MSG). We show that MSG treatment does not prevent the MSL-G-AN-induced anorexia, thereby suggesting a different type of anorectic function. We show a very strong component of taste aversion as anorectic rats, when presented to novel or known alternative food items, will resume normal feeding for 1 day, and then redevelop anorexia. We hypothetize that the anorexia in MSL-G-AN tumour-bearing rats correlates with a foetal processing pattern of proglucagon to both glucagon and GLP-1 (7-36amide), and is due to taste aversion. The sudden onset is characterized by a dramatic increase in circulating levels of biologically active GLP-1 (7-36amide), suggesting eventual saturation of proteolytic inactivation of its N-terminus. PMID- 21824259 TI - Incretin hormones and the expanding families of glucagon-like sequences and their receptors. AB - Peptide hormones encoded by the proglucagon (Gcg) and glucose-dependent insulinotropic polypeptide (Gip) genes are evolutionarily related glucagon-like sequences and act through a subfamily of G-protein-coupled receptors. A better understanding of the evolutionary history of these hormones and receptors should yield insight into their biological functions. The availability of a large number of near-complete vertebrate genome sequences is a powerful resource to address questions concerning the evolution of sequences; here, we utilize these resources to examine the evolution of glucagon-like sequences and their receptors. These studies led to the discovery of novel genes for a glucagon receptor-like receptor (Grlr) and a glucagon-like sequence (exendin) in vertebrates. Both exendin and GRLR have ancient origins, early in vertebrate evolution, but have been lost on the ancestral lineage leading to extant mammals. We also show that exendin and GRLR are both expressed in the brain of the chicken and Xenopus tropicals, results that suggest that the products of these genes function in this tissue. The lack of exendin or Grlr genes in mammals suggests that other genes may have acquired the functions of exendin and Grlr during mammalian evolution. PMID- 21824260 TI - Brain glucose sensing and neural regulation of insulin and glucagon secretion. AB - Glucose homeostasis requires the tight regulation of glucose utilization by liver, muscle and white or brown fat, and glucose production and release in the blood by liver. The major goal of maintaining glycemia at ~ 5 mM is to ensure a sufficient flux of glucose to the brain, which depends mostly on this nutrient as a source of metabolic energy. This homeostatic process is controlled by hormones, mainly glucagon and insulin, and by autonomic nervous activities that control the metabolic state of liver, muscle and fat tissue but also the secretory activity of the endocrine pancreas. Activation or inhibition of the sympathetic or parasympathetic branches of the autonomic nervous systems are controlled by glucose-excited or glucose-inhibited neurons located at different anatomical sites, mainly in the brainstem and the hypothalamus. Activation of these neurons by hyper- or hypoglycemia represents a critical aspect of the control of glucose homeostasis, and loss of glucose sensing by these cells as well as by pancreatic beta-cells is a hallmark of type 2 diabetes. In this article, aspects of the brain-endocrine pancreas axis are reviewed, highlighting the importance of central glucose sensing in the control of counterregulation to hypoglycemia but also mentioning the role of the neural control in beta-cell mass and function. Overall, the conclusions of these studies is that impaired glucose homeostasis, such as associated with type 2 diabetes, but also defective counterregulation to hypoglycemia, may be caused by initial defects in glucose sensing. PMID- 21824261 TI - Regulation of glucagon secretion by incretins. AB - Glucagon secretion plays an essential role in the regulation of hepatic glucose production, and elevated fasting and postprandial plasma glucagon concentrations in patients with type 2 diabetes (T2DM) contribute to their hyperglycaemia. The reason for the hyperglucagonaemia is unclear, but recent studies have shown lack of suppression after oral but preserved suppression after isoglycaemic intravenous glucose, pointing to factors from the gut. Gastrointestinal hormones that are secreted in response to oral glucose include glucagon-like peptide-1 (GLP-1) that strongly inhibits glucagon secretion, and GLP-2 and GIP, both of which stimulate secretion. When the three hormones are given together on top of isoglycaemic intravenous glucose, glucagon suppression is delayed in a manner similar to that observed after oral glucose. Studies with the GLP-1 receptor antagonist, exendin 9-39, suggest that endogenous GLP-1 plays an important role in regulation of glucagon secretion during fasting as well as postprandially. The mechanisms whereby GLP-1 regulates glucagon secretion are debated, but studies in isolated perfused rat pancreas point to an important role for a paracrine regulation by somatostatin from neighbouring D cells. Clinical studies of the antidiabetic effect of GLP-1 in T2DM suggest that the inhibition of glucagon secretion is as important as the stimulation of insulin secretion. PMID- 21824262 TI - Regulation of glucagon secretion by glucose: paracrine, intrinsic or both? AB - Glucagon secretion is regulated by glucose but the mechanisms involved remain hotly debated. Both intrinsic (within the alpha-cell itself) and paracrine (mediated by factors released beta- and/or delta-cells) have been postulated. Glucagon secretion is maximally suppressed by glucose concentrations that do not affect insulin and somatostatin secretion, a finding that highlights the significance of intrinsic regulation of glucagon secretion. Experiments on islets from mice lacking functional ATP-sensitive potassium channels (K(ATP)-channels) indicate that these channels are critical to the alpha-cell's capacity to sense changes in extracellular glucose. Here, we review recent data on the intrinsic and paracrine regulation of glucagon secretion in human pancreatic islets. We propose that glucose-induced closure of the K(ATP)-channels, via membrane depolarization, culminates in reduced electrical activity and glucagon secretion by voltage-dependent inactivation of the ion channels involved in action potential firing. We further demonstrate that glucagon secretion measured in islets isolated from donors with type-2 diabetes is reduced at low glucose and that glucose stimulates rather than inhibits secretion in these islets. We finally discuss the relative significance of paracrine and intrinsic regulation in the fed and fasted states and propose a unifying model for the regulation of glucagon secretion that incorporates both modes of control. PMID- 21824263 TI - A role for zinc in pancreatic islet beta-cell cross-talk with the alpha-cell during hypoglycaemia. AB - Signalling by intraislet beta-cells to neighbouring alpha-cells was recognized almost 40 years ago, leading to the hypothesis that this is an essential mechanism to regulate the glucagon counterregulatory response to hypoglycaemia. The thesis was that during normoglycaemia or hyperglycaemia insulin secretion from beta-cells would enter the islet periportal circulation and travel downstream to alpha-cells to dampen glucagon secretion. As a corollary, during hypoglycaemia beta-cells would stop secreting insulin, which would permit alpha cells to release glucagon into the hepatic portal circulation so it could travel to the liver to increase glucose production and thereby correct hypoglycaemia. This mini-review briefly mentions the early work that established this hypothesis and more extensively examines more recent work that has provided direct evidence supporting the hypothesis. A new twist has been introduced based on the fact that zinc is bound to insulin within beta-cells and co-secreted with insulin. Zinc is released from insulin when it reaches the higher pH of blood, and zinc has recently been shown to negatively regulate alpha-cell secretion. It is now suggested that a switch-off signal provided by a sudden cessation of zinc secretion from beta-cells during hypoglycaemia may play a critical role in stimulating glucagon secretion that is independent of the effect of insulin. PMID- 21824264 TI - Regulation of glucagon secretion by zinc: lessons from the beta cell-specific Znt8 knockout mouse model. AB - In type-2 diabetes, hyperglucagonaemia aggravates elevated blood glucose levels. Relative to our knowledge of the beta-cell and insulin secretion, there remains a limited understanding of glucagon secretion in alpha-cells. Regulation of glucagon may be dependent on a combination of factors, which include direct glucose sensing by the alpha-cell, innervations from the autonomic nervous system and potential 'paracrine' actions by hormones and factors that are released by adjacent endocrine cells within the islets. The list of potential 'paracrine' regulators within the islet includes insulin, somatostatin, gamma-aminobutyric acid, glutamate and zinc. Zinc crystallises with insulin in beta-cells and is co secreted with insulin. In the scientific literature, the effect of exogeneous zinc on glucagon secretion has been debated. Here, we confirm that an increase in exogeneous zinc does inhibit glucagon secretion. To determine if there are physiological effects of zinc on glucagon secretion we used a beta-cell-specific ZnT8 knockout (Znt8BKO) mouse model. Znt8BKO mice, despite showing lower granular zinc content in beta-cells, showed no changes in fasted plasma glucagon levels and glucose regulated glucagon secretion. These findings suggest that zinc secreted from beta-cell does not regulate glucagon secretion. PMID- 21824265 TI - Physiologic action of glucagon on liver glucose metabolism. AB - Glucagon is a primary regulator of hepatic glucose production (HGP) in vivo during fasting, exercise and hypoglycaemia. Glucagon also plays a role in limiting hepatic glucose uptake and producing the hyperglycaemic phenotype associated with insulin deficiency and insulin resistance. In response to a physiological rise in glucagon, HGP is rapidly stimulated. This increase in HGP is entirely attributable to an enhancement of glycogenolysis, with little to no acute effect on gluconeogenesis. This dramatic rise in glycogenolysis in response to hyperglucagonemia wanes with time. A component of this waning effect is known to be independent of hyperglycemia, though the molecular basis for this tachyphylaxis is not fully understood. In the overnight fasted state, the presence of basal glucagon secretion is essential in countering the suppressive effects of basal insulin, resulting in the maintenance of appropriate levels of glycogenolysis, fasting HGP and blood glucose. The enhancement of glycogenolysis in response to elevated glucagon is critical in the life-preserving counterregulatory response to hypoglycaemia, as well as a key factor in providing adequate circulating glucose for working muscle during exercise. Finally, glucagon has a key role in promoting the catabolic consequences associated with states of deficient insulin action, which supports the therapeutic potential in developing glucagon receptor antagonists or inhibitors of glucagon secretion. PMID- 21824266 TI - The role of dysregulated glucagon secretion in type 2 diabetes. AB - Excessive production of glucose by the liver contributes to fasting and postprandial hyperglycaemia, hallmarks of type 2 diabetes. A central feature of this pathologic response is insufficient hepatic insulin action, due to a combination of insulin resistance and impaired beta-cell function. However, a case can be made that glucagon also plays a role in dysregulated hepatic glucose production and abnormal glucose homeostasis. Plasma glucagon concentrations are inappropriately elevated in diabetic individuals, and alpha-cell suppression by hyperglycaemia is blunted. Experimental evidence suggests that this contributes to greater rates of hepatic glucose production in the fasting state and attenuated reduction after meals. Recent studies in animal models indicate that reduction of glucagon action can have profound effects to mitigate hyperglycaemia even in the face of severe hypoinsulinaemia. While there are no specific treatments for diabetic patients yet available that act specifically on the glucagon signalling pathway, newer agents including glucagon-like peptide-1 (GLP 1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors reduce plasma glucagon and this is thought to contribute to their action to lower blood glucose. The alpha-cell and glucagon receptor remain tempting targets for novel diabetes treatments, but it is important to understand the magnitude of benefit new strategies would provide as preclinical models suggest that chronic interference with glucagon action could entail adverse effects as well. PMID- 21824267 TI - Optimizing reduction in basal hyperglucagonaemia to repair defective glucagon counterregulation in insulin deficiency. AB - In health, the pancreatic islet cells work as a network with highly co-ordinated signals over time to balance glycaemia within a narrow range. In type 1 diabetes (T1DM), with autoimmune destruction of the beta-cells, lack of insulin is considered the primary abnormality and is the primary therapy target. However, replacing insulin alone does not achieve adequate glucose control and recent studies have focused on controlling the endogenous glucagon release as well. In T1DM, glucagon secretion is disordered but not absolutely deficient; it may be excessive postprandially yet it is characteristically insufficient and delayed in response to hypoglycaemia. We review our system-level analysis of the pancreatic endocrine network mechanisms of glucagon counterregulation (GCR) and their dysregulation in T1DM and focus on possible use of alpha-cell inhibitors (ACIs) to manipulate the glucagon axis to repair the defective GCR. Our results indicate that the GCR abnormalities are of 'network origin'. The lack of beta-cell signalling is the primary deficiency that contributes to two separate network abnormalities: (i) absence of a beta-cell switch-off trigger and (ii) increased intraislet basal glucagon. A strategy to repair these abnormalities with ACI is proposed, which could achieve better control of glycaemia with reduced hypoglycaemia risk. PMID- 21824269 TI - Metabolic impact of glucagon deficiency. AB - Multiple bioactive peptides are produced from proglucagon encoded by glucagon gene (Gcg). Glucagon is produced in islet alpha-cells through processing by prohormone convertase 2 (Pcsk2) and exerts its action through the glucagon receptor (Gcgr). Although it is difficult to produce a genetic model that harbours isolated glucagon deficiency without affecting the production of other peptides derived from proglucagon, three different animal models that harbour deficiencies in glucagon signalling have been generated by gene targeting strategy. Although both Pcsk2(-/-) and Gcgr(-/-) mice display lower blood glucose levels, homozygous glucagon-GFP knock-in mice (Gcg(gfp/gfp) ) display normoglycaemia despite complete glucagon deficiency. In Gcg(gfp/gfp) mice, the metabolic impact of glucagon deficiency is probably ameliorated by lower plasma insulin levels and glucagon-independent mechanisms that maintain gluconeogenesis. As both Pcsk2(-/-) and Gcgr(-/-) mice exhibit increased production of glucagon like peptide-1 (GLP-1), which is absent in Gcg(gfp/gfp), GLP-1 is the likely cause of the difference in metabolic impact of glucagon deficiency in these animal models. Although all the three models display islet 'alpha'-cell hyperplasia, the mechanisms involved remain to be elucidated. Studies using Pcsk2(-/-), Gcgr(-/-) and Gcg(gfp/gfp) mice, especially in combination with alpha cell ablation models such as pancreas-specific aristaless-related homeobox (ARX) knockout mice, should further clarify the physiological and pathological roles of glucagon in the regulation of metabolism and the control of islet cell differentiation and proliferation. PMID- 21824268 TI - Novel insight into glucagon receptor action: lessons from knockout and transgenic mouse models. AB - Using knockout and transgenic technology, genetically modified animal models allowed us to understand the role of glucagon signalling in metabolism. Mice with a global deletion of the glucagon receptor gene (Gcgr) were designed using gene targeting. The phenotype of Gcgr(-/-) mouse provided important clues about the role of Gcgr in foetal growth, pancreatic development and glucose and lipid homeostasis. The lack of Gcgr activation was associated with: (i) hypoglycaemic pregnancies, poor foetal growth and increased foetal-neonatal demise; (ii) altered cytoarchitecture of pancreatic islets; (iii) altered glucose, lipid and hormonal milieu; (iv) reduced gastric emptying; (v) altered body composition and protection from diet-induced obesity; (vi) altered energy state; (vii) impaired hepatocyte survival; (viii) altered metabolic response to prolonged fasting and exercise and (ix) prevented development of diabetes in insulin-deficient mice. In contrast, mice overexpressing the Gcgr on pancreatic beta-cells displayed an increase insulin secretion, pancreatic insulin content and beta-cell mass, and partially protected against hyperglycaemia and impaired glucose tolerance when fed a high-fat diet. These findings suggest that glucagon signalling plays a significant role in the regulation of glucose and lipid homeostasis. Treatment options designed to block Gcgr activation may have negative implications in the treatment of diabetes. PMID- 21824270 TI - The future of incretin-based therapy: novel avenues--novel targets. AB - Incretin-based therapy for type 2 diabetes is based on the antidiabetic effects of glucagon-like peptide-1 (GLP-1) and instituted by GLP-1 receptor agonists and dipeptidyl peptidase-4 inhibitors targeting the key islet defects of the disease. The treatment is clinically efficient and safe, and associated with a low risk of adverse events. It can be used both in early and late stages of the disease and both as monotherapy and add-on to other therapies. Current research on the future of incretin-based therapy focuses on optimizing its place in diabetes treatment and examines its potential in type 1 diabetes, in subjects with obesity without type 2 diabetes and in cardiovascular and neurodegenerative disorders. Other studies aim at prolonging the duration of action of the GLP-1 receptor agonists to allow weekly administration, and to develop orally GLP-1 receptor agonists. Furthermore, other investigators focus on stimulation of GLP-1 secretion by activating GLP-1-producing L-cells or using gene therapy. Finally, also other gastro-entero-pancreatic bioactive peptides are potential targets for drug development as are synthetic peptides engineered as co-agonists stimulating more than one receptor. We can therefore expect a dynamic development within this field in the coming years. PMID- 21824273 TI - Extracorporeal artificial liver support in hepatic failure: pathfinder, bridge to recovery or dead end street? PMID- 21824271 TI - Age-related decline in osteoblastogenesis and 1alpha-hydroxylase/CYP27B1 in human mesenchymal stem cells: stimulation by parathyroid hormone. AB - With aging, there is a decline in bone mass and in osteoblast differentiation of human mesenchymal stem cells (hMSCs) in vitro. Osteoblastogenesis can be stimulated with 1,25-dihydroxyvitamin D(3) [1,25(OH)(2) D(3) ] and, in some hMSCs, by the precursor 25-hydroxyvitamin D(3) (25OHD(3) ). CYP27B1/1alpha hydroxylase activates 25OHD(3) and, to a variable degree, hMSCs express CYP27B1. In this study, we tested the hypotheses (i) that age affects responsiveness to 25OHD(3) and expression/activity of CYP27B1 in hMSCs and (ii) that parathyroid hormone (PTH) upregulates CYP27B1 in hMSCs, as it does in renal cells. There were age-related declines in osteoblastogenesis (n=8, P=0.0286) and in CYP27B1 gene expression (n=27, r= -0.498; P=0.008) in hMSCs. Unlike hMSCs from young subjects (<=50 years), hMSCs from older subjects (>=55 years) were resistant to 25OHD(3) stimulation of osteoblastogenesis. PTH1-34 (100 nm) provided hMSCs with responsiveness to 25OHD(3) (P=0.0313, Wilcoxon matched pairs test) and with two episodes of increased 1,25(OH)(2) D(3) synthesis, of cAMP response element binding protein (CREB) activation, and of CYP27B1 upregulation. Both increases in CYP27B1 expression by PTH were obliterated by CREB-siRNA or KG-501 (which specifically inhibits the downstream binding of activated CREB). Only the second period of CREB signaling was diminished by AG1024, an inhibitor of insulin-like growth factor-I receptor kinase. Thus, PTH stimulated hMSCs from elders with responsiveness to 25OHD(3) by upregulating expression/activity of CYP27B1 and did so through CREB and IGF-I pathways. PMID- 21824272 TI - Oncogenes induce senescence with incomplete growth arrest and suppress the DNA damage response in immortalized cells. AB - Activation of the Her2 (ErbB2) oncogene is implicated in the development of breast, ovary and other cancers. Here, we show that expression of NeuT, a mutant activated rodent isoform of Her2, in immortalized breast epithelial cells, while promoting senescence-associated morphological changes, up-regulation of senescence-associated beta-galactosidase activity, and accumulation of the cyclin dependent kinase inhibitor p21, failed to trigger the major senescence end-point, i.e. permanent growth arrest. Similar senescence-associated phenotype with incomplete growth arrest, which we dubbed senescence with incomplete growth arrest (SWING), could also be triggered by the expression of the Ras oncogene. SWING phenotype was stable, and persisted in tumor xenografts established from NeuT-transduced cells. Furthermore, a significant population of cells in SWING state was found in tumors in the MMTV/NeuT transgenic mouse model. SWING cells showed downregulation of histone H2AX, critical for repair of double-stranded DNA breaks, and impaired activation of Chk1 kinase. Overall, SWING cells were characterized by increased DNA instability and hypersensitivity to genotoxic stresses. We propose that the SWING state could be a stage in the process of cancer development. PMID- 21824274 TI - Detoxification as a treatment goal in hepatic failure. AB - Acute liver failure (ALF) is a dramatic clinical syndrome with high mortality because of cerebral oedema (type A hepatic encephalopathy) and multi-organ failure. With intensive care medicine and emergent liver transplantation being the mainstay of treatment, alternatives to transplantation are increasingly needed. Ammonia has been recognised as a major toxin in patients with ALF. It can be effectively removed by haemodialysis, haemofiltration and artificial liver support (a combination of extracorporeal toxin absorption and haemodialysis). Previous studies of extracorporeal detoxification, however, have either not specifically targeted ammonia or were hampered by poor biocompatibility and obsolete pathophysiological assumptions, ultimately failing to improve the prognosis. Moreover, most patients were treated only late after the emergence of advanced HE and multi-organ failure, while detoxification should prevent these complications. Acute-on-chronic liver failure (AOCLF) occurs in the setting of chronic liver disease and has an equally poor prognosis. Here, the goals of extracorporeal blood detoxification are renal support and haemodynamic stabilisation in order to support recompensation. Patients with AOCLF, unfortunately, are at a risk for treatment-related complications including bleeding, thrombocytopenia, hypotension and acute renal failure, making biocompatibility a critical issue. Peritoneal dialysis could possibly emerge as a more biocompatible way of treating refractory hepatorenal syndrome. This article will critically analyse the pathophysiological concepts and goals of extracorporeal detoxification in acute and chronic liver diseases. PMID- 21824275 TI - Clearing of toxic substances: are there differences between the available liver support devices? AB - Toxins accumulating in liver failure split into water solved (e.g. ammonia) and albumin bound substances (e.g. bilirubin). Because the latter cannot be removed by conventional haemodialysis, special liver support systems have been developed. The majority of data concerning elimination efficiency exist for the cell-free devices Molecular Adsorbent Recirculating System (MARS) and Prometheus, as they have been commercially available in Europe since many years. Overall, Prometheus provides higher clearances for most liver toxins, especially if they are tightly albumin bound. However, for bile acids and cytokines no such differences could be found. Single pass albumin dialysis (SPAD) can be assumed to be equally effective as MARS. None of the bioartificial liver support systems being developed is on the market today and published clearance data are scarce. In general, clearance efficiency for albumin bound substances is relatively low in all systems currently available. Besides optimizing biocompatibility and selectivity, future technologies should also focus on improved detoxification efficiency of liver support devices. PMID- 21824276 TI - Albumin dialysis: current practice and future options. AB - The current management of patients with severe liver failure encompasses treatment of the precipitating event and supportive therapy for extra-hepatic end organ dysfunction while waiting for the liver to recover or for a suitable graft to become available. Molecular Adsorbent Recirculating System (MARS) is an extracorporeal detoxification device that allows the save and effective removal of albumin-bound as well as water-soluble substances in an effort to overcome phases of critical organ dysfunction or to bridge patients until transplantation. MARS has proven to be a useful treatment in patients with acute-on-chronic liver failure and acute liver failure for improving biochemical parameters and clinical symptoms but benefits in patient outcome have not yet been fully demonstrated. The optimal timing for initiation, frequency and duration of MARS treatment, and the biochemical and clinical parameters on which to base clinical decisions, remain partially unanswered issues. PMID- 21824277 TI - Fractionated plasma separation and adsorption: current practice and future options. AB - Fractionated plasma separation and adsorption (FPSA) is a method of albumin dialysis that is integrated into an extracorporeal liver support device (Prometheus((r))). This concept allows the effective removal of both protein bound and water-soluble substances without the need for external albumin. Several studies comparing the in vivo extraction capacities of FPSA and molecular adsorbent recirculating system (MARS) concluded that detoxification by FPSA seems to be more effective than by MARS. Overall, FPSA therapy has been shown to be safe. Over the last few years, the anticoagulation protocol for FPSA therapy was optimised by using regional anticoagulation with citrate to avoid clotting of system components. Recently, the results of a large randomised-controlled multicentre trial (HELIOS) have been presented. Survival after 1 and 3 months was evaluated in 145 patients with acute-on-chronic liver failure comparing FPSA therapy with standard medical treatment versus standard medical treatment alone. There was no statistically significant survival benefit for patients undergoing FPSA therapy. However, patients with hepatorenal syndrome type I or MELD score >30 showed a significant survival benefit under FPSA in a predefined subgroup analysis. Furthermore, there have been promising results with FPSA in the treatment of refractory cholestatic pruritus. Regarding acute liver failure, only few data are currently available. PMID- 21824278 TI - Extracorporeal liver support with multipass albumin dialysis or plasmapheresis and filtering systems in acute liver failure. AB - Acute liver failure is a very complex type of disease with a mortality of up to 90%, leading to numerous severe disturbances of the whole organism. Bleeding because of absent synthesis of various coagulation factors and disseminated intravascular coagulation, acute kidney failure, circulatory failure with vasopressor dependence, respiratory failure with adult respiratory distress syndrome, neurological failure up to coma because of hepatic encephalopathy, and a very high risk of infection and sepsis frequently result from the initial state of isolated liver failure. High urgency liver transplantation is a highly efficient therapy if performed in time. However, increasing the rate of spontaneous recovery of the patients' own liver, and reducing the need for liver transplantation is preferable and would further improve the outcome of acute liver failure. Extracorporeal liver support by multipass albumin dialysis or plasmapheresis and filtering systems may offer a possibility to fulfill these aims of therapy. A prospective study in 88 patients with acute liver failure has shown a nonsignificant trend in improvement of survival after acute liver failure by multipass albumin dialysis and filtering. Other retrospective studies have shown benefits in improving hepatic encephalopathy and brain oedema. Further, an increase in the rate of spontaneous recovery of liver function has been described. With regional citrate anticoagulation for multipass albumin dialysis and filtering, the need for systemic anticoagulation - a potentially very harmful measure in these patients - can be eliminated and the rate of filter clotting can extremely effectively be reduced. PMID- 21824279 TI - Extracorporeal artificial liver support in hypoxic liver injury. AB - The incidence of hypoxic liver injury, most commonly referred to as hypoxic hepatitis (HH), is up to 10% in critically ill patients. In the majority of cases, HH occurs as a consequence of haemodynamic impairment following cardiogenic or septic shock. A marked, dramatic increase in the aminotransferase levels in a setting of cardiocirculatory failure is the key characteristic of HH. HH may contribute to several complications such as hepatopulmonary syndrome and hypoglycaemia. The overall mortality after the onset of HH is approximately 50 60% within 1 month. We report a case of severe HH that was successfully bridged using the Molecular Adsorbent Recirculating System. In addition to the possible effects of extracorporeal liver support devices, the recognition of HH and therapy of the underlying disease that led to the occurrence of HH is of central importance. PMID- 21824280 TI - The clinical challenges of acute on chronic liver failure. AB - Acute on chronic liver failure (ACLF) encompasses patients with previously well compensated liver disease in whom an acute decompensation of liver function occurs because of a precipitating event. There are emerging data on the presentation and course of patients with this profile of liver disease; a clear definition based on precise diagnostic criteria, however, remains difficult to establish. In a high percentage of patients, ACLF is associated with the development of multi-organ failure leading to high in-hospital mortality despite costly intensive care therapy. Liver transplantation remains the only curative therapeutic option for the majority of these patients. Therefore, early identification of the precipitating events inducing ACLF and better understanding of the underlying mechanism are key issues for the prevention and treatment of ACLF. However, although there is increasing evidence that cytokines play a major role in the development of ACLF, the pathophysiology remains complex and poorly understood. PMID- 21824281 TI - New insights into the management of hepato-renal syndrome. AB - Hepato-renal syndrome (HRS) is a serious complication in patients with advanced liver disease indicating a very poor prognosis. Nevertheless, effective treatment strategies have been introduced into clinical practice over the last decade. The combined treatment with terlipressin/albumin has been proven to be effective in most published studies and should be regarded as the standard of care. Norepinephrine or midodrine are possible alternatives when terlipressin is not available. Although there is presently not enough evidence to recommend extracorporeal liver support therapy as a standard procedure in patients with HRS, these concepts constitute promising options that need to be studied in prospective clinical trials. PMID- 21824282 TI - Extracorporeal artificial liver support systems in the management of intractable cholestatic pruritus. AB - Pruritus can occur as a severe complication of cholestasis. Several hypotheses suggest an important role for the accumulation of bile acids, endogenous opioids and - mire recently - lysophosphatidic acid. Bile acid sequestrants are the first line therapeutic agents. In refractory cases, a stepwise approach using rifampicin, oral opiate antagonists and the selective serotonin reuptake inhibitor sertraline should be tested. Recent case series reported effective relief of pruritus using extracorporal liver support systems and plasmapheresis. PMID- 21824283 TI - Validation of an automated latex particle-enhanced immunoturbidimetric von Willebrand factor activity assay. AB - BACKGROUND: Laboratory diagnosis of von Willebrand disease (VWD) requires accurate measurement of plasma von Willebrand factor (VWF) activity. OBJECTIVES: To evaluate laboratory characteristics, diagnostic accuracy and testing utilities of an automated latex particle-enhanced immunoturbidimetric VWF assay (VWF:Lx) based on a monoclonal antibody recognizing the VWF-platelet glycoprotein (GP) Ib binding domain. METHODS: Laboratory characteristics including lower detection limit, linearity, precision, sample stability, and method comparison between VWF:Lx and VWF ristocetin cofactor activity by platelet aggregometry (VWF:RCo) were examined. To assess VWF:Lx diagnostic accuracy, 492 patient plasma samples, including 40 previously characterized VWD patient samples, were tested for VWF antigen (VWF:Ag) and VWF:RCo by either aggregometry or flow cytometry, and VWF:Lx with supplemental VWF multimer analysis when indicated. Based on results of VWF:Ag, VWF:RCo and VWF multimer analysis, and available clinical information, samples were categorized as: normal; VWD types 1, 2A/B, 2M, or severe 1 vs. 2M; or acquired VWF abnormalities (AVWA) due to subtle loss of highest molecular weight multimers. RESULTS: VWF:Lx had excellent laboratory characteristics and linear correlation with VWF:RCo (R(2) = 0.93). VWF:Lx accurately classified virtually all normal and VWD patient samples. Compared with VWF:RCo, VWF:Lx had superior sensitivity and specificity for distinguishing severe type 1 vs. 2M VWD and identifying AVWA. A proposed screening panel comprising VWF:Ag and VWF:Lx had 100% and 83% sensitivity for detecting VWD and AVWA, respectively. CONCLUSIONS: VWF:Lx has excellent laboratory characteristics and diagnostic accuracy compared with VWF:RCo, and can be used as part of an initial VWD screening panel and as a supplementary test. PMID- 21824284 TI - Mutations in disguise. PMID- 21824285 TI - Streptococcus sanguinis-induced cytokine release from platelets. AB - BACKGROUND: There is increasing evidence that both chronic and acute infections play a role in the development and progression of atherothrombotic disorders. One potential mechanism is the direct activation of platelets by bacteria. A wide range of bacterial species activate platelets through heterogeneous mechanisms. The oral micro-organism S. sanguinis stimulates platelet aggregation in vitro in a strain-dependent manner, although there are no reports of associated cytokine production. OBJECTIVE: The aim of the present study was to determine whether platelet activation by S. sanguinis involved the release of pro-inflammatory and immune modulating factors, and whether activation was enhanced by epinephrine. METHODS AND RESULTS: Four strains of S. sanguinis and one of S. gordonii stimulated the release of RANTES, PF4, sCD40L and PDGF-AB, whereas only one S. sanguinis strain caused the release of sCD62p. Epinephrine enhanced S. sanguinis induced platelet aggregation and phosphorylation of phospholipase Cgamma2 and Erk, but inhibited RANTES, PF4, sCD40L and PDGF-AB release. Wortmannin inhibited S. sanguinis-induced aggregation and release; however, only aggregation was partially reversed by epinephrine. CONCLUSIONS: The present study demonstrates that platelets respond to S. sanguinis with both prothrombotic and pro inflammatory/immune-modulating responses. Epinephrine, potentially released in response to infection and/or stress, can significantly enhance the prothrombotic response, thereby providing a putative link between bacteraemia and acute coronary events during stress. In contrast, epinephrine inhibited the pro inflammatory/immune-modulating response by an undetermined mechanism. PMID- 21824286 TI - Mutant telomerase RNAs induce DNA damage and apoptosis via the TRF2-ATM pathway in telomerase-overexpressing primary fibroblasts. AB - Mutant template human telomerase RNAs (MT-hTers) have been shown to induce apoptosis in various cancer cells with high telomerase activity. However, the mechanism by which MT-hTers inhibit the growth of cancer cells and their effects on normal cells remain unknown. To determine the effects of MT-hTers on normal cells, MT-hTer-47A and -AU5 were introduced into IMR90 lung fibroblasts, which have low telomerase levels. Growth of IMR90 cells after MT-hTers infection was not significantly impaired; however, similar treatments in telomerase overexpressing IMR90 [IMR90 wild-type (WT)hTERT] cells inhibited cell proliferation and induced apoptosis. Confocal microscopy showed that MT-hTers induced DNA damage foci (i.e. 53BP1 and gamma-H2AX) in IMR90 WThTERT cells. Microarray analysis revealed that GADD45gamma was significantly elevated in MT hTer-treated IMR90 WThTERT cells. MT-hTers also induced ATM phosphorylation at Ser1981 in IMR90 WThTERT cells, and western blot analysis revealed high levels of phosphorylated p53 after the down-regulation of cellular TRF2 expression in MT hTer-treated IMR90 WThTERT cells. Taken together, we have shown that MT-hTers induce double-stranded DNA break-like damages in telomerase positive IMR90 WThTERT cells after phosphorylation of ATM and p53 via suppression of TRF2, which may eventually lead to apoptosis via elevation of GADD45gamma. PMID- 21824287 TI - Proteomic reactors and their applications in biology. AB - Proteomic analysis requires the combination of an extensive suite of technologies including protein processing and separation, micro-flow HPLC, MS and bioinformatics. Although proteomic technologies are still in flux, approaches that bypass gel electrophoresis (gel-free approaches) are dominating the field of proteomics. Along with the development of gel-free proteomics, came the development of devices for the processing of proteomic samples termed proteomic reactors. These microfluidic devices provide rapid, robust and efficient pre-MS sample procession by performing protein sample preparation/concentration, digestion and peptide fractionation. The proteomic reactor has advanced in two major directions: immobilized enzyme reactor and ion exchange-based proteomic reactor. This review summarizes the technical developments and biological applications of the proteomic reactor over the last decade. PMID- 21824288 TI - High-pressure analysis of a hammerhead ribozyme from Chrysanthemum chlorotic mottle viroid reveals two different populations of self-cleaving molecule. AB - The activity of the full-length hammerhead ribozyme requires a tertiary interaction between its distal loops leading to the closure of the molecule and its stabilization in the active conformation. In this study, the conformational changes accompanying the cis-cleavage reaction of Chrysanthemum chlorotic mottle viroid hammerhead ribozyme were investigated by high-pressure experiments on the complete cleavage reaction. Two activation volumes (DeltaV(?)) were measured, pointing to the presence of two different populations of molecules corresponding to fast-cleaving and slow-cleaving ribozymes in the reaction mixture. The fast population, with a small DeltaV(?) of 2.6 mL.mol(-1), most likely represents molecules in the near-active conformation, whereas the slow population, with a larger DeltaV(?) of 11.6 mL.mol(-1 , represents molecules that need a larger conformational change to induce activity. In addition, pH-dependence experiments suggest that the group whose deprotonation is required for activity intervenes in the formation of the transition state or in the chemistry of the reaction, but not in the conformational change that precedes it. PMID- 21824289 TI - Assessing the patterns of linkage disequilibrium in genic regions of the human genome. AB - We used the genotyping data generated by the International HapMap Project to study the patterns of linkage disequilibrium (LD) in human genic regions. LD patterns for 11,998 genes from 11 HapMap populations were identified by analyzing the distribution of haplotype blocks. The genes were prioritized using LD levels. The results showed that there were significant differences in the degree of LD between genes. Genes with high or low LD (the upper and lower quartiles of the LD levels) fell into different Gene Ontology functional categories. The high LD genes clustered preferentially in the metabolic process, macromolecule localization and cell-cycle categories, whereas the low LD genes clustered in the developmental process, ion transport, and immune and regulation system categories. Furthermore, we subdivided the genic region into 3'-UTR, 5'-UTR and CDS (coding region), and compared the different LD patterns in these subregions. We found that the LD patterns in low LD genes had a more interspersed block structure compared with the high LD genes. This was especially true in the CDS and 5'-UTR. The extent of LD was somewhat higher in 5'-UTRs compared with 3'-UTRs for both high and low LD genes. In addition, we assessed the overlap for the intragenic LD regions and found that the LD regions in high LD genes were more consistent among populations. Comprehensive information about the distribution of LD patterns in gene regions in populations may provide insights into the evolutionary history of humans and help in the selection of biomarkers for disease association studies. PMID- 21824290 TI - Protein engineering to stabilize soluble amyloid beta-protein aggregates for structural and functional studies. AB - The molecular biology underlying protein aggregation and neuronal death in Alzheimer's disease is not yet completely understood, but small soluble nonamyloid aggregates of the amyloid beta-protein (Abeta) have been shown to play a fundamental neurotoxic role. The composition and biological action of such aggregates, known as oligomers and protofibrils, are therefore areas of intense study. However, research is complicated by the multitude of different interconverting aggregates that Abeta can form in vitro and in vivo, and by the inhomogeneity and instability of in vitro preparations. Here we review recent studies in which protein engineering, and in particular disulfide engineering, has been applied to stabilize different Abeta aggregates. For example, several techniques now exist to obtain stable and neurotoxic protofibrillar forms of Abeta, and engineered Abeta dimers, or larger aggregates formed by these, have been shown to specifically induce neuronal damage in a way that mimics Alzheimer's disease pathology. Disulfide engineering has also revealed structural properties of neurotoxic aggregates, for instance that Abeta in protofibrils and globular oligomers adopts a beta-hairpin conformation that is similar to, but topologically distinct from, the conformation of Abeta in mature amyloid fibrils. Protein engineering is therefore a workable strategy to address many of the outstanding questions relating to the structure, interconversion and biological effects of oligomers and protofibrils of Abeta. PMID- 21824291 TI - Barnase and binase: twins with distinct fates. AB - RNases are enzymes that cleave RNAs, resulting in remarkably diverse biological consequences. Many RNases are cytotoxic. In some cases, they attack selectively malignant cells triggering an apoptotic response. A number of eukaryotic and bacterial RNase-based strategies are being developed for use in anticancer and antiviral therapy. However, the physiological functions of these RNases are often poorly understood. This review focuses on the properties of the extracellular RNases from Bacillus amyloliquefaciens (barnase) and Bacillus intermedius (binase), the characteristics of their biosynthesis regulation and their physiological role, with an emphasis on the similarities and differences. Barnase and binase can be regarded as molecular twins according to their highly similar structure, physical-chemical and catalytic properties. Nevertheless, the 'life paths' of these enzymes are not the same, as their expression in bacteria is controlled by diverse signals. Binase is predominantly synthesized under phosphate starvation, whereas barnase production is strictly dependent on the multifunctional Spo0A regulator controlling sporulation, biofilm formation and cannibalism. Barnase and binase also have some distinctions in practical applications. Barnase was initially suggested to be useful in research and biotechnology as a tool for studying protein-protein interactions, for RNA elimination from biological samples, for affinity purification of RNase fusion proteins, for the development of cloning vectors and for sterility acquisition by transgenic plants. Binase, as later barnase, was tested for antiviral, antitumour and immunogenic effects. Both RNases have found their own niche in cancer research as a result of success in targeted delivery and selectivity towards tumour cells. PMID- 21824292 TI - What's new in the Australasian Paediatric Resuscitation Guidelines 2010. PMID- 21824293 TI - Troponin: a risk-defining biomarker for emergency department physicians. PMID- 21824294 TI - Chest pain research in Australasian emergency medicine: putting our mark on the world stage. PMID- 21824295 TI - Introduction to paediatric advanced life support. ARC and NZRC Guideline 2010. AB - * Introduction to Paediatric Advanced Life Support. ARC and NZRC Guideline 2010 * Advanced Life Support for Infants and Children Diagnosis and Management. ARC and NZRC Guideline 2010 * Flowchart for the Sequential Management of Life-threatening Dysrhythmias in Infants and Children. ARC and NZRC Guideline 2010 * Medications and Fluids in Paediatric Advanced Life Support. ARC and NZRC Guideline 2010 * Management of Specific Dysrhythmias in Paediatric Advanced Life Support. ARC and NZRC Guideline 2010 * Techniques in Paediatric Advanced Life Support. ARC and NZRC Guideline 2010 * Management after Resuscitation in Paediatric Advanced Life Support. ARC and NZRC Guideline 2010. PMID- 21824296 TI - Advanced life support for infants and children diagnosis and management. ARC and NZRC Guideline 2010. PMID- 21824297 TI - Flowchart for the sequential management of life-threatening dysrhythmias in infants and children. ARC and NZRC Guideline 2010. PMID- 21824298 TI - Medications and fluids in paediatric advanced life support. ARC and NZRC Guideline 2010. PMID- 21824299 TI - Management of specific dysrhythmias in paediatric advanced life support. ARC and NZRC Guideline 2010. PMID- 21824300 TI - Techniques in paediatric advanced life support. ARC and NZRC Guideline 2010. PMID- 21824301 TI - Management after resuscitation in paediatric advanced life support. ARC and NZRC Guideline 2010. PMID- 21824302 TI - Introduction to resuscitation of the newborn infant. ARC and NZRC Guideline 2010. AB - * Introduction to Resuscitation of the Newborn Infant. ARC and NZRC Guideline 2010 * Planning for Neonatal Resuscitation and Identification of the Newborn Infant at Risk. ARC and NZRC Guideline 2010 * Assessment of the Newborn Infant. ARC and NZRC Guideline 2010 * Airway Management and Mask Ventilation of the Newborn Infant. ARC and NZRC Guideline 2010 * Tracheal Intubation and Ventilation of the Newborn Infant. ARC and NZRC Guideline 2010 * Chest Compressions during Resuscitation of the Newborn Infant. ARC and NZRC Guideline 2010 * Medication or Fluids for the Resuscitation of the Newborn Infant. ARC and NZRC Guideline 2010 * The Resuscitation of the Newborn Infant in Special Circumstances. ARC and NZRC Guideline 2010 * After the Resuscitation of a Newborn Infant. ARC and NZRC Guideline 2010 * Ethical Issues in Resuscitation of the Newborn Infant. ARC and NZRC Guideline 2010. PMID- 21824303 TI - Planning for neonatal resuscitation and identification of the newborn infant at risk. ARC and NZRC Guideline 2010. PMID- 21824304 TI - Assessment of the newborn infant. ARC and NZRC Guideline 2010. PMID- 21824305 TI - Airway management and mask ventilation of the newborn infant. ARC and NZRC Guideline 2010. PMID- 21824306 TI - Tracheal intubation and ventilation of the newborn infant. ARC and NZRC Guideline 2010. PMID- 21824307 TI - Chest compressions during resuscitation of the newborn infant. ARC and NZRC Guideline 2010. PMID- 21824308 TI - Medication or fluids for the resuscitation of the newborn infant. ARC and NZRC Guideline 2010. PMID- 21824309 TI - The resuscitation of the newborn infant in special circumstances. ARC and NZRC Guideline 2010. PMID- 21824310 TI - After the resuscitation of a newborn infant. ARC and NZRC Guideline 2010. PMID- 21824311 TI - Ethical issues in resuscitation of the newborn infant. ARC and NZRC Guideline 2010. PMID- 21824312 TI - Review article: Prophylactic metoclopramide for patients receiving intravenous morphine in the emergency setting: a systematic review and meta-analysis of randomized controlled trials. AB - The objective of the present study was to conduct a systematic review and meta analysis of randomized controlled trials, comparing metoclopramide with placebo, for preventing vomiting in patients who have received i.v. morphine for acute pain in the emergency setting, and to determine the level of evidence supporting the use of prophylactic metoclopramide in this population. Comprehensive systematic electronic searches were conducted of MEDLINE, EMBASE and the Cochrane Library for randomized controlled trials addressing the clinical question. Reference lists of identified articles were hand-searched. Methodologically appropriate clinical trials identified in the search process were included in a meta-analysis to provide a pooled estimate of effect. Three randomized controlled trials fulfilled the search criteria. All three studies were included in the final meta-analysis that demonstrated an overall result of no difference between metoclopramide and placebo for the primary outcome of vomiting (odds ratios 0.72; 95% confidence intervals 0.11-4.58). There was little evidence that routine prophylactic administration of metoclopramide following the administration of i.v. morphine for acute pain management in the emergency setting is clinically beneficial. Routine metoclopramide administration might expose patients to a risk of harm which is not justifiable given a lack of evidence of benefit. PMID- 21824313 TI - Procedural sedation practices in Australian Emergency Departments. AB - OBJECTIVE: The aim of the present study was to describe procedural sedation practices undertaken in a spectrum of Australian EDs. METHODS: Eleven Australian EDs enrolled consecutive adult and paediatric patients between January 2006 and December 2008. Patients were included if a sedative drug was administered for an ED procedure. Data collection was prospective and used a specifically designed data collection document. RESULTS: 2623 patients were enrolled. 1581 were male (60.3%, 95% CI 58.4-62.2) and the mean patient age was 39.2 (SD 25.2) years. Reductions of fracture/dislocated shoulders (694 cases, 26.7%), wrist/forearm fractures (403, 15.5%) and tibia/fibula fractures (341, 13.1%) were the most common procedures. Procedures were supervised by consultants and registrars in 1424 (54.3%) and 1025 (39.1%) cases, respectively. Of 2413 patients with complete fasting status data, 1252 (51.9%, 95% CI 49.9-53.9) patients had consumed food or fluid in the previous 6 h. 1399 (53.3%, 95% CI 51.4-55.3) patients received pre procedural medication. Pre-procedural morphine (894, 34.1%) exceeded fentanyl use (323, 12.3%), both as a sole agent and in combination with another agent. The principal sedatives used alone were propofol (857, 38.5%), midazolam (224, 10%) and ketamine (165, 7.4%). Ketamine and nitrous oxide were most commonly used in children with propofol, midazolam and opiates largely restricted to adults (P < 0.001). The intra-procedural use of adjunct fentanyl exceeded that of morphine (ratio 4:1). CONCLUSIONS: Procedural sedation practice across Australian EDs is varies considerably. Procedural sedation 'best practice' guidelines, based upon the findings of the present study and the available evidence, are recommended. PMID- 21824314 TI - Risk factors for sedation-related events during procedural sedation in the emergency department. AB - OBJECTIVE: To determine the nature, incidence and risk factors for sedation related events during ED procedural sedation, with particular focus on the drugs administered. METHODS: Eleven Australian EDs enrolled consecutive adult and paediatric patients between January 2006 and December 2008. Patients were included if a sedative drug was administered for an ED procedure. Data collection was prospective and employed a specifically designed form. Multivariate logistic regression was employed to determine risk factors for sedation-related events. RESULTS: Two thousand, six hundred and twenty-three patients were enrolled (60.3% male, mean age 39.2 years). Reductions of fracture/dislocations of shoulders, wrists and ankles were most common. Four hundred and sixty-one (17.6%) cases experienced at least one airway event that required intervention. Airway obstruction, hypoventilation and desaturation occurred in 12.7%, 6.4% and 3.7% of all patients, respectively. Two thousand, one hundred and forty-six cases had complete datasets for further analyses. Increasing age and level of sedation, pre medication with fentanyl, and sedation with propofol, midazolam or fentanyl were risk factors for an airway event (P < 0.05). Ketamine was a protective factor. Hypotension (systolic pressure <80 mmHg) occurred in 34 (1.6%) cases with midazolam being a significant risk factor (P < 0.001). Vomiting also occurred in 34 (1.6%) cases, 12 of whom required an intervention. One patient aspirated. Vomiting occurred after administration of all drugs but was not associated with fasting status. Other events were rare. CONCLUSIONS: Sedation-related events, especially airway events, are common but very rarely have an adverse outcome. Elderly patients, deeply sedated with short-acting agents, are at particular risk. The results will help tailor sedation to individual patients. PMID- 21824315 TI - Factors associated with failure to successfully complete a procedure during emergency department sedation. AB - OBJECTIVE: To determine factors associated with failure to successfully complete a procedure during sedation in the ED. METHODS: Eleven Australian EDs enrolled consecutive adult and paediatric patients between January 2006 and December 2008. Patients were included if a sedative drug was administered for an ED procedure and the success or failure of the procedure was recorded. RESULTS: Data were available for 2567 patients. Of these, 1548 (60.3%, 95% CI 58.4-62.2) were male and 456 (17.8%, 95% CI 16.3-19.3) were age <16 years. The most common procedures performed were reduction of major joints and laceration repair. A total of 149 procedures (5.8%, 95% CI 5.0-6.8) failed. There were significant differences in failure rates between the types of procedure undertaken, with reduction of hips, digits and mandibles associated with the highest failure rates (P < 0.001). In adults, body weight >100 kg was also associated with increased risk of procedural failure (odds ratio 2.3, 95% CI 1.3-4.1). Ketamine used as a single agent had the lowest procedural failure rate (2.5%, 95% CI 1.1-5.4) whereas propofol had the highest (5.9%, 95% CI 4.6-7.6). However, these two drugs were generally used in different age groups and for different procedures. CONCLUSIONS: Procedures performed under sedation in the ED have a low failure rate. However, increased body weight and specific procedures, such as hip reduction, are associated with significantly higher failure rates. Special consideration should be given to these patient groups before undertaking sedation in the ED. PMID- 21824316 TI - Hazardous alcohol use interventions with emergency patients: Self-reported practices of nurses, and predictors of behaviour. AB - OBJECTIVES: The present study examined Australian ED nurses' practices in asking patients about alcohol and assisting them to manage their alcohol consumption. It also investigated strategies to support ED nurses in these interventions. METHODS: A two-stage survey was administered to ED nurses. The first questionnaire measured theoretical and organizational predictors of behaviour, and underlying beliefs, and the subsequent questionnaire explored rates of asking and assisting patients. RESULTS: A total of 125 nurses returned the first questionnaire. Participants held generally positive attitudes, perceived norms, feelings of legitimacy and perceived ability to ask about and intervene for alcohol, but lower role adequacy. The 71 ED nurses who completed the second questionnaire had intervened with almost 500 patients concerning alcohol in the previous week. Participants asked approximately one in four patients about alcohol (median = 26.3% of patients, 1095/4279 total patients asked). The Theory of Planned Behaviour did not predict rates of asking or assisting patients. Several strategies were identified that might increase rates: identify environmental factors that prevent nurses acting on their intentions to ask and intervene, raise confidence and skills, make asking about alcohol part of routine assessment, make supports such as drug and alcohol units or nurses available, and implement organizational policies on alcohol. CONCLUSIONS: Nurses appear positively disposed to engage with patients in regard to alcohol. However, greater support is needed to achieve the considerable significant public health benefits from this engagement. The findings point to several practical strategies that could be pursued to provide this support. PMID- 21824317 TI - Clinical diagnosis and outcomes for Troponin T 'positive' patients assessed by a high sensitivity compared with a 4th generation assay. AB - BACKGROUND: High sensitivity troponin T (hsTnT) detects lower levels of troponin T with greater precision than the 4th generation (cTnT) assay. However, the clinical implications of this are uncertain. OBJECTIVES: Primary: Describe the proportion of patients who test 'positive' with hsTnT but negative with cTnT. Secondary: Determine proportion in each group with an adverse event (representation, AMI or died) within 90 days of the index test. METHOD: 161 patients samples were tested with cTnT and hsTNT assays. McNemar's test was used to compare paired samples. Electronic medical records were reviewed, with discharge diagnosis and 90 day outcomes determined blind to hsTnT results. Patients were then classified as 'TnT negative' (hsTnT was <0.014 mcg/mL), 'new positive' (hsTnT was >= 0.014 mcg/mL and cTnT <0.03 mcg/mL) and 'TnT positive' (cTNT was >= 0.03 mcg/mL). RESULTS: Positive results more than doubled with the hsTnT assay (50% vs 22%, P < 0.001). 81 patients were 'TnT negative', 44 were 'new positive' and 36 'cTnT positive'. The discharge diagnosis for 'new positives' was AMI in 4 (9%), other cardiac in 13 (30%) and non-cardiac in 27 (61%). At 90 days adverse events occurred in 30%, 54% and 50% of the groups respectively. There were no late cases of AMI or cardiovascular death in 'new positive' patients. CONCLUSION: Many patients with diagnoses other than AMI will have hsTNT above the reference level. Indiscriminate testing with hsTnT might lead to more patients requiring serial troponin testing and/or invasive further tests, which will have process and resource implications for EDs and health services. PMID- 21824318 TI - Quantitative rt-PCR holds promise as a screening tool for patients with severe sepsis. AB - OBJECTIVE: The aim of the present study was to determine if the quantification of bacterial 16S rDNA could be clinically useful in predicting patients at increased risk of developing septic shock. METHODS: A retrospective study of patients with positive blood cultures taken on arrival to the ED. An EDTA sample was collected simultaneously with blood cultures and assayed by polymerase chain reaction to quantitate the bacterial 16S rDNA load. Descriptive and clinical data were collected from the medical record and this was blinded to the 16S rDNA result. Subsequently, the 16S rDNA result was compared with illness severity markers including septic shock and death to determine the relationship between the 16S rDNA load and illness severity. RESULTS: 98 patients (mean age 61 +/- 20 years, range 18-92) with positive blood cultures were studied, most commonly growing Escherichia coli (n= 25) and Staphylococcus aureus (n= 23). 16 (16%) died. There were 42 (43%) 16S rDNA positive patients. A high 16S rDNA load was associated with an increased risk of developing delayed septic shock (OR 21.9, 95% CI 2.5 192.6) in comparison with either a low or negative 16S rDNA load; with a mortality OR 4.6 (95% CI 0.9-23.5). CONCLUSIONS: The quantitative assay for 16S rDNA might be a useful screening tool to detect severe sepsis in those whom it might not be clinically suspected. However, prospective studies are required to further assess the clinical usefulness of this assay. PMID- 21824319 TI - Necrotizing enterocolitis in a 16-day-old, term neonate. AB - Necrotizing enterocolitis in a term neonate is a rare presentation to the ED. Prompt diagnosis and management is critical because of its rarity and the reported mortality of 5-20%. We report a case of necrotizing enterocolitis in a term neonate who presented at 16 days of age with bloody stool. PMID- 21824320 TI - Bilateral luxatio erecta: recognition and reduction. AB - Luxatio erecta is the rarest form of shoulder dislocation, accounting for 0.5% of all glenohumeral dislocations. Bilateral cases are rarer still with only 12 accounts described in medical literature. We describe an unusual case and its management. PMID- 21824321 TI - A light-hearted look at patient overcrowding: the extended Emergency Department Cardiology Analogy Model (e-EDCAM). PMID- 21824322 TI - Usage and efficacy of airway adjuncts in an emergency intubation kit. PMID- 21824323 TI - Estimate of emergency department patients who could be seen by GPs is best available. PMID- 21824325 TI - Pharmacogenetics of toxicity, plasma trough concentration and treatment outcome with nevirapine-containing regimen in anti-retroviral-naive HIV-infected adults: an exploratory study of the TRIANON ANRS 081 trial. AB - The aim of this exploratory study was to investigate in a homogeneous population of anti-retroviral naive HIV-1-infected adults, the relationships between genetic polymorphisms involved in nevirapine metabolism [CYP2B6 516G>T, 785A>G and 1459C>T; CYP3A5 6986A>G (CYP3A5*3)], transport (ABCB1 2677G>T/A and 3435C>T), and antigen recognition (HLA-DRB1*0101), and the hepatic and/or cutaneous toxicity occurring within the first 8 or 72 weeks of treatment, plasma trough concentrations (C(trough) ) at week 8 and immuno-virological response to nevirapine at week 24. Associations between genetic polymorphisms and toxicity, C(trough) and response to nevirapine were performed in a population of 72 HIV-1 positive and nevirapine-treated patients followed during 72 weeks, as part of the previous study called: ANRS081 'Trianon' trial. Among the 18 patients who developed toxicity events during the 72 weeks of the study, 12 patients exhibited early toxicity before week 8. No significant association could be evidenced between any of the analysed single nucleotide polymorphisms (SNPs) and nevirapine early or global toxicity, pharmacokinetics and immuno-virological responses even though a possible association between CYP2B6 516G>T and 1459C>T and the trough level of nevirapine was suggested. PMID- 21824328 TI - Metabolic stability of peptidomimetics: N-methyl and aza heptapeptide analogs of a PKB/Akt inhibitor. AB - Linear peptides suffer from poor pharmacokinetic and pharmacodynamic properties. Peptidomimetics are designed to overcome these pharmacological drawbacks while maintaining the biological effects of the parent peptides. Aza-peptides, in which an alpha carbon is replaced with nitrogen, are promising peptidomimetic analogs; however, little is known about the stability of these analogs toward enzymatic degradation. We performed systematic aza and N-methyl scans of a PKB/Akt inhibitor, PTR6154. We evaluated the stability of the aza-scan and N-methyl scan libraries toward enzymatic degradation by trypsin/chymotrypsin. Our results indicate that the modification site is important for metabolic stability and that aza-peptides have a more global effect than N-methylation, affecting cleavage sites distant from the modification site. PMID- 21824329 TI - Computational-aided design for dopamine prodrugs based on novel chemical approach. AB - The goal of this project was to design novel dopamine prodrugs for the treatment of Parkinson's disease that can improve the overall biopharmaceutical profile of the current medications to enhance effectiveness and to ease the use of the medications. Based on Menger's study and other's kinetic studies on the cleavage reactions of some Kemp's acid amides to the corresponding amines and anhydrides, DFT calculations were made to find a candidate to be used as an efficient dopamine prodrug. The proposed dopamine prodrugs have a carboxylic group as a hydrophilic moiety and a hydrocarbon skeleton as a lipophilic moiety, where the combination of both groups ensures a moderate hydrophilic lipophilc balance value. The potential prodrugs are expected to give better bioavailability than the parental drug owing to improved absorption. Furthermore, the proposed prodrugs are believed to be more effective than l-dopa because the latter undergoes decarboxylation in the periphery before reaching the blood-brain barrier. Additionally, the predicted prodrugs can be used in different dosage forms (I.V., S.C., tablets, and others) because of their potential solubility in organic and aqueous media. It is expected that the proposed prodrugs will undergo cleavage reactions to release the parental dopamine drug with half-life time (t(1/2) ) of 12-20 h. PMID- 21824330 TI - Window-type patent ductus arteriosus with acquired rheumatic mitral stenosis. AB - An 18-year-old patient with a window type of patent ductus arteriosus and acquired rheumatic mitral stenosis is reported for its rarity. The pitfalls in the diagnosis and surgical management of this condition are discussed. PMID- 21824331 TI - Design and synthesis of a series of novel bisquinazoline glycosides as epidermal growth factor receptor inhibitors. AB - A new series of potential epidermal growth factor receptor inhibitors possessing bisquinazoline and saccharide moieties were designed and synthesized. The biological results demonstrated that the synthetic derivatives significantly inhibited epidermal growth factor receptor enzymatic activity in vitro. Of them, compound 14b showed the highest inhibitory rate toward epidermal growth factor receptor protein tyrosine kinase (81.36%) at a concentration of 1 MUM. Further molecular simulation predicted that 14b offered its saccharide moieties hydrogen bonding to ATP-binding pocket. PMID- 21824332 TI - Delayed repair of hemitruncus in an extremely low birth weight infant. AB - We present a case of a premature female infant, with a delayed diagnosis of hemitruncus, who underwent primary repair at 105 days of life. There have been few published reports of premature infants with hemitruncus, and none to our knowledge who underwent repair that was significantly delayed. PMID- 21824333 TI - Staged single-ventricle palliation in 2011: outcomes and expectations. AB - Outcomes for staged palliation for single-ventricle heart disease have improved over the past two decades. As outcomes improve, parental expectations for survival and quality of life have risen accordingly. Nevertheless, the number of interventions and complications these patients must endure remain high. The final surgical destination of the single-ventricle patient, the total cavopulmonary connection (or Fontan operation) successfully separates systemic venous and pulmonary venous blood flow but does so at great cost. Fontan patients remain at significant risk of complications despite what are perceived to be "favorable" hemodynamics. The outcomes in this population are discussed in this review, with particular attention to the history behind our current strategies as well as to recent salient studies. PMID- 21824334 TI - DNA barcoding of European Herbertus (Marchantiopsida, Herbertaceae) and the discovery and description of a new species. AB - DNA barcoding of a group of European liverwort species from the genus Herbertus was undertaken using three plastid (matK, rbcL and trnH-psbA) and one nuclear (ITS) marker. The DNA barcode data were effective in discriminating among the sampled species of Herbertus and contributed towards the detection of a previously overlooked European Herbertus species, described here as H. norenus sp. nov. This species shows clear-cut differences in DNA sequence for multiple barcode regions and is also morphologically distinct. The DNA barcode data were also useful in clarifying taxonomic relationships of the European species with some species from Asia and North America. In terms of the discriminatory power of the different barcode markers, ITS was the most informative region, followed closely by matK. All species were distinguishable by ITS alone, rbcL + matK and various other multimarker combinations. PMID- 21824335 TI - COI is better than 16S rRNA for DNA barcoding Asiatic salamanders (Amphibia: Caudata: Hynobiidae). AB - The 5' region of the mitochondrial DNA (mtDNA) gene cytochrome c oxidase I (COI) is the standard marker for DNA barcoding. However, because COI tends to be highly variable in amphibians, sequencing is often challenging. Consequently, another mtDNA gene, 16S rRNA gene, is often advocated for amphibian barcoding. Herein, we directly compare the usefulness of COI and 16S in discriminating species of hynobiid salamanders using 130 individuals. Species identification and classification of these animals, which are endemic to Asia, are often based on morphology only. Analysis of Kimura 2-parameter genetic distances (K2P) documents the mean intraspecific variation for COI and 16S rRNA genes to be 1.4% and 0.3%, respectively. Whereas COI can always identify species, sometimes 16S cannot. Intra- and interspecific genetic divergences occasionally overlap in both markers, thus reducing the value of a barcoding gap to identify genera. Regardless, COI is the better DNA barcoding marker for hynobiids. In addition to the comparison of two potential markers, high levels of intraspecific divergence in COI (>5%) suggest that both Onychodactylus fischeri and Salamandrella keyserlingii might be composites of cryptic species. PMID- 21824336 TI - Infection by spotted fever rickettsiae in people, dogs, horses and ticks in Londrina, Parana State, Brazil. AB - Spotted fever is a disease caused by bacteria from the genus Rickettsia of the spotted fever group (SFG). Rickettsia rickettsii is likely the main agent of Brazilian spotted fever (BSF). With the objective of gathering information on the circulation of SFG rickettsiae in Londrina, Parana state, ticks from dogs and horses and also blood from dogs, horses and humans were collected in a neighbourhood of the city which presented potential for circulation of rickettsiae between hosts and vectors. Amblyomma cajennense, Dermacentor nitens, and Rhipicephalus sanguineus ticks were subjected to Polymerase Chain Reaction targeting a fragment of the Rickettsia gltA gene. This specific gene encodes the enzyme citrate synthase of Rickettsia spp., and results on all ticks were negative. Human and animal sera were tested by Indirect Immunofluorescence Assay in which R. rickettsii and R. parkeri were used as antigens. Sera from 4.7% human, 2.7% canine and 38.5% equine were positive for R. rickettsii. For R. parkeri, 0.9% human, 2.7% canine and 11.5% equine samples were positive. All samples reactive to R. parkeri also reacted to R. rickettsii. An epidemiological questionnaire was applied, but there were no statistically significant results. Comparison of our serological results with previous studies in Brazil, among BSF endemic and non-endemic areas, indicates that there is no established rickettsial infection in the study area, a statement corroborated with our molecular analysis. Nonetheless, as humans of the present study are highly exposed to tick infestations, health education within the population is needed to obtain efficient tick control. PMID- 21824337 TI - Prevalence of Salmonella, Yersinia and Campylobacter spp. in feral raccoons (Procyon lotor) and masked palm civets (Paguma larvata) in Japan. AB - To estimate the public and animal health risk that alien species pose, the prevalence of Salmonella, Yersinia, and Campylobacter spp. in feral raccoons (Procyon lotor, n=459) and masked palm civets (Paguma larvata, n=153), which are abundant alien species in Japan, was investigated in urban and suburban areas of Japan. Salmonella enterica was detected from 29 samples [26 raccoons, 5.7%, 95% confidence interval (CI) 7.8-3.5%; three masked palm civets, 2.0%, 95% CI 4.2 0%]. Many of the isolates belonged to serovars that are commonly isolated from human gastroenteritis patients (e.g. S. Infantis, S. Typhimurium, and S. Thompson). The antimicrobial susceptibility test showed that 26.9 % of the isolates from raccoons were resistant to at least one antimicrobial agent, whereas none of the isolates from masked palm civets were resistant. Yersinia sp. was detected from 193 samples (177 raccoons, 38.6%, 95% CI 43.0-34.1%; 16 masked palm civets, 10.5%, 95% CI 15.3-5.6%). All virulent Yersinia strains belonged to Yersinia pseudotuberculosis, which was isolated from seven (1.5%, 95% CI 2.6 0.4%) raccoons and six (3.9%, 95% CI 7.0-0.8%) masked palm civets. According to the detection of virulence factors, all the Y. pseudotuberculosis isolates belonged to the Far Eastern systemic pathogenicity type. Campylobacter spp. was detected from 17 samples (six raccoons, 1.3%, 95% CI 2.3-0.3%; 11 masked palm civets, 7.2%, 95% CI 11.3-3.1%). Among these, three isolates from raccoons were identified as C. jejuni. These results showed that these pathogens can be transmitted by human activities, other wild animals, and the environment to feral raccoons and masked palm civets, and vice versa. As these animals have omnivorous behaviour and a wide range of habitats, they can play an important role in the transmission of the enteric pathogens. PMID- 21824338 TI - Distribution of Campylobacter jejuni isolates from turkey farms and different stages at slaughter using pulsed-field gel electrophoresis and flaA-short variable region sequencing. AB - The aim of this study was to assess the diversity of thermotolerant Campylobacter spp. isolated from turkey flocks at six rearing farms 1-2 weeks prior to slaughter (360 faecal swab samples) and from 11 different stages at the slaughterhouse (636 caecal, environmental, neck skin and meat samples). A total of 121 Campylobacter isolates were identified to species level using a multiplex PCR assay and were typed by pulsed-field gel electrophoresis (PFGE) and flaA short variable region (SVR) sequencing. All Campylobacter isolates were identified as Campylobacter jejuni. PFGE analysis with KpnI restriction enzyme resulted in 11 PFGE types (I-XI) and flaA SVR typing yielded in nine flaA-SVR alleles. The Campylobacter-positive turkey flocks A, C and E were colonized by a limited number of Campylobacter clones at the farm and slaughter. The present study confirms the traceability of flock-specific strains (PFGE types I, V and IX; flaA types 21, 36 and 161) from the farm along the entire processing line to meat cuts. It seems that stress factors such as high temperature of the defeathering water (54-56 degrees C), drying of the carcass skin during air chilling (24 h at 2 degrees C), and oxygen in the air could not eliminate Campylobacter completely. Campylobacter-negative flocks became contaminated during processing by the same subtypes of Campylobacter introduced into the slaughter house by preceeding positive flocks even if they were slaughtered on subsequent days. Proper and efficient cleaning and disinfection of slaughter and processing premises are needed to avoid cross-contamination, especially in countries with a low prevalence of Campylobacter spp. The majority of flaA SVR alleles displayed a distinct association with a specific PFGE type. However, a linear relationship for all strains among both typing methods could not be established. To specify genetic relatedness of strains, a combination of different genotyping methods, is needed. PMID- 21824339 TI - Simulation model for Campylobacter cross-contamination during poultry processing at slaughterhouses. AB - Broiler meat is regarded as the most common source of Campylobacter infection and risk management measures are required to reduce broiler meat contamination. Among the quantitative risk assessments for Campylobacter in broiler meat, evaluation of the poultry processing stage is particularly important for predicting the contamination level of broiler meat and the effects of control measures. In this study, we built a simulation model for cross-contamination during poultry processing focusing on Campylobacter contamination at the individual carcass level. Using this model, we examined changes in the prevalence of contaminated carcasses and the number of Campylobacter per carcass after processing. As a result, it was found that the prevalence and number of Campylobacter after processing were largely influenced by the number of Campylobacter on the contaminated carcasses before processing. In the baseline model, where it was assumed that the mean number of Campylobacter on contaminated carcasses before processing was 4.7 log10 cfu per carcass, the prevalence after processing was less than that before processing. Although the median value of Campylobacter on contaminated carcasses was reduced after processing, the distributions after processing became wider and the upper limit of the 95% credible interval of Campylobacter on contaminated carcasses remained elevated. The individual-based simulation model can trace individual level changes considering discrete interactions, while models tracing mean values cannot handle these interactions in detail. The individual-based approach is considered useful for modelling cross contamination among individual carcasses during poultry processing. PMID- 21824340 TI - Agroenvironmental determinants associated with the presence of antimicrobial resistant Escherichia coli in beach waters in Quebec, Canada. AB - Exposure to microorganisms resistant to antimicrobials may constitute a health risk to human populations. It is believed that one route of exposure occurs when people engage in recreational activities in water contaminated with these microorganisms. The main objective of this study was to explore population-level and environmental determinants specifically associated with the presence of antimicrobial resistant (AMR) generic Escherichia coli isolated from recreational waters sampled from beaches located in southern Quebec, Canada. Water samples originated from the Quebec provincial beach surveillance program for the summers of 2004 and 2005. This study focused on three classes of determinants, namely: agricultural, population-level and beach characteristics for a total of 19 specific factors. The study was designed as a retrospective observational analysis and factors were assessed using logistic regression methods. From the multivariable analysis, the data suggested that the percentage of land used for spreading liquid manure was a significant factor associated with the presence of AMR E. coli (OR=27.73). Conceptually, broad factors potentially influencing the presence of AMR bacteria in water must be assessed specifically in addition to factors associated with general microbial contamination. Presence of AMR E. coli in recreational waters from beaches in southern Quebec may represent a risk for people engaging in water activities and this study provides preliminary evidence that agricultural practices, specifically spreading liquid manure in agricultural lands nearby beaches, may be linked to the contamination of these waters by AMR E. coli. PMID- 21824341 TI - A national epidemic of campylobacteriosis in Iceland, lessons learned. AB - Epidemics often result in organizational, policy and technical changes within a country. In 1999, an epidemic of campylobacteriosis was reported in Iceland. The recent availability of fresh poultry products in the marketplace was suggested as the source of infection. This paper reports on the context of the epidemic, reviews interventions implemented to prevent campylobacteriosis, and discusses lessons learned. A retrospective study of interventions implemented in Iceland from June 1995 to December 2007 was conducted by interviewing key informants and reviewing Iceland's literature. Cumulative incidence rates of domestic campylobacteriosis by year and average incidence rates per epidemic period were calculated. Interventions included on-farm surveillance of Campylobacter, producer education, enhanced biosecurity measures, changes in poultry processing, a leak-proof packaging policy, a freezing policy for products from Campylobacter positive poultry flocks, consumer education, and the creation of a legislated inter-organizational response committee. These interventions appear to have collectively contributed to a decrease in campylobacteriosis' incidence rate near pre-epidemic baseline levels. Expert consultations revealed that the implementation of a Campylobacter surveillance program in poultry and the freezing policy were critical to controlling the disease in the Icelandic population. It was also recognized that new multidisciplinary collaborations among public health, veterinary, and food safety authorities and a sustained co operation from the poultry industry were integral factors to the mitigation of the epidemic. Iceland's response to the campylobacteriosis epidemic is a lesson learned of inter-disciplinary and inter-organizational precautionary public health action in the face of a complex public health issue. PMID- 21824342 TI - Exposure of uninfected poultry farms to HPAI (H7N7) virus by professionals during outbreak control activities. AB - With an extensive data set on visits made to control the H7N7 avian influenza epidemic in The Netherlands in 2003 we investigate the potential role of the persons involved in the control activities as vectors for disease transmission. We hypothesized that people can spread the virus on the same day mechanically, or till 10 days if they have become infected themselves. Taken into account was the estimated time of introduction of the virus into a poultry flock back-calculated from mortality data. We identified 19 visits from a person that went on the same day from an infected (source) farm to a (target) farm that was before infection and a further 197 visits were made to (target) farms that remained uninfected. Of the 19 visits, eight were made within 3 days before an infection started on the target farm. If we assume that these eight visits were the primary reason the visited farms became infected, then we can calculate an upper estimate for the probability of transmission by a person per visit of 0.037. In addition we identified visits were a person first visited an infected source farm and up to 10 days after visited a target farm that either remained uninfected or was before infection. Most visits to infected source farms were made just after infection. Animals on these farms were likely not yet symptomatic, thus escaping diagnosis. Such events may be difficult to prevent, although awareness of this possibility is already a major step towards prevention. Most of these visits involved tracing and screening and were made by a relatively small number of trained veterinarians. This makes it possible to focus training efforts specifically on these persons and make sure they stringently use the personal protective equipment and strictly follow the hygiene protocol, to protect them and prevent them from spreading the disease. PMID- 21824343 TI - Zoonotic disease awareness in animal shelter workers and volunteers and the effect of training. AB - Animal shelter workers are a vulnerable population whose exposure to zoonotic disease may be greater compared with the general population. The aim of this project was to identify baseline zoonotic disease knowledge of animal shelter workers and to develop and evaluate zoonotic disease awareness training. Ten animal shelters in six western states were randomly selected. One hundred and eleven trainees were evaluated by identical pre- and post-training tests. Training topics included identification of clinical signs, susceptible species, and transmission of disease to animals and to humans. Zoonotic diseases included rabies, plague, leptospirosis, internal parasites, methicillin-resistant Staphylococcus aureus (MRSA) and salmonella. A statistically significant difference in overall total scores between pre-test (58.5%) and post-test (69.5%) was observed (P = 0.0001). No association was observed between test scores and length of time working in animal shelters, or with the participants' role at the animal shelter. Overall test scores were raised by 11%. The lowest baseline levels of knowledge were found with leptospirosis, MRSA, plague and rabies, emerging diseases with increasing prevalence and high consequence. Zoonotic disease awareness training is a valuable service to animal shelters. In the current study, training was modestly successful in transferring short-term knowledge to animal shelter workers. To understand and evaluate the effectiveness of training completely, observable or measureable behaviours should be compared before and after training. Long-term assessment with measureable outcomes is needed. PMID- 21824344 TI - Serological and virological surveillance of swine H1N1 and H3N2 influenza virus infection in two farms located in Hubei province, central China. AB - Swine influenza viruses H1N1 and H3N2 have been reported in the swine population worldwide. From June 2008 to June 2009, we carried out serological and virological surveillance of swine influenza in the Hubei province in central China. The serological results indicated that antibodies to H1N1 swine influenza virus in the swine population were high with a 42.5% (204/480) positive rate, whereas antibodies to H3N2 swine influenza virus were low with a 7.9% (38/480) positive rate. Virological surveillance showed that only one sample from weanling pigs was positive by RT-PCR. Phylogenetic analysis of the hemagglutinin and neuraminidase genes revealed that the A/Sw/HB/S1/2009 isolate was closely related to avian-like H1N1 viruses and seemed to be derived from the European swine H1N1 viruses. In conclusion, H1N1 influenza viruses were more dominant in the pig population than H3N2 influenza viruses in central China, and infection with avian like H1N1 viruses persistently emerged in the swine population in the area. PMID- 21824345 TI - Fatal pandemic (H1N1) 2009 influenza A virus infection in a Pennsylvania domestic cat. AB - We report the earliest recognized fatality associated with laboratory-confirmed pandemic H1N1 (pH1N1) influenza in a domestic cat in the United States. The 12 year old, indoor cat died on 6 November 2009 after exposure to multiple family members who had been ill with influenza-like illness during the peak period of the fall wave of pH1N1 in Pennsylvania during late October 2009. The clinical presentation, history, radiographic, laboratory and necropsy findings are presented to assist veterinary care providers in understanding the features of this disease in cats and the potential for transmission of infection to pets from infected humans. PMID- 21824346 TI - Antimicrobial susceptibility of canine and human Staphylococcus aureus collected in Saskatoon, Canada. AB - Staphylococcus aureus is one of the most common causes of infection in people and is increasingly recognized in dogs. The increasing prevalence of methicillin resistant S. aureus (MRSA) is complicating the treatment of these infections. Panton Valentine leukocidin (PVL), a toxin involved in the pathogenesis of necrotic syndromes in people may be partially responsible for the rise of MRSA. Canine and human S. aureus from the same geographic area are genetically similar, indicating a common population and likely transmission. The implications of increasing antimicrobial resistance complicated by interspecies transmission, necessitates including both dogs and humans in S. aureus resistance surveillance studies. A collection of 126 S. aureus isolates from people (n = 99) and dogs (n = 27) were included, minimum inhibitor concentrations to a panel of 33 antimicrobials used in human and veterinary medicine were determined. No resistance to vancomycin, linezolid, daptomycin, quinupristin/dalfopristin or nitrofurantoin was found. A wide range of antibiograms were found; including resistance to 0-12 drugs (0-6 drug classes). Outstanding antibiograms included a canine MRSA resistant to rifampin and a human MRSA resistant to chloramphenicol. Inducible clindamycin resistance was found among 78% and 4% of canine and human MRSA and 17% and 25% of canine colonizing and human methicillin susceptible S. aureus (MSSA), respectively. Resistance to mupirocin was only found among human isolates including 20% of MRSA and 4% of MSSA. While no canine isolates were PVL positive, 39% of human MRSA and 2% of MSSA carried the gene. The bidirectional transmission of S. aureus between people and dogs necessitates the inclusion of isolates from both species in future studies. PMID- 21824347 TI - Identification of Anaplasma spp. rickettsia isolated from horses from clinical disease cases in Poland. AB - This study was aimed at determining the cause of the diseases in five horses exhibiting symptoms of fever, joint oedema and ataxia and thrombocytopenia. The PCR technique revealed the presence in the blood of 16S RNA Anaplasma/Ehrlichia spp. genetic material. DNA amplification with primers EHR 521 and EHR 747 gave a product with a size of 247 bp. The sequence of the PCR product obtained showed a 97.6-99.6% similarity with a sequence of a fragment of 16S RNA Anaplasma phagocytophilum, gene number EU 090186 from GenBank. Intravenous administration of oxytetracycline at a dose of 8 mg/kg of body mass for 7 days resulted in a gradual recovery. PMID- 21824348 TI - Toxoplasma gondii in Switzerland: a serosurvey based on meat juice analysis of slaughtered pigs, wild boar, sheep and cattle. AB - Toxoplasmosis is one of the most important zoonotic diseases worldwide and is caused by the protozoan Toxoplasma gondii. Besides vertical infection during pregnancy, humans can get infected post-natally either by peroral uptake of sporulated Toxoplasma oocysts or by ingestion of tissue cysts upon consumption of raw or undercooked meat. The aim of this study was to approximate the risk of human infection via meat consumption by estimating the seroprevalence of T. gondii in slaughtered animals in Switzerland and to compare data with prevalences assessed 10 years ago. The study included pigs, cattle, sheep and wild boar of different age groups and housing conditions whenever possible and applicable. A P 30-ELISA was used to detect T. gondii-specific antibodies and to determine seroprevalences in meat juice of slaughtered animals. A total of 270 domestic pigs (120 adults, 50 finishing, 100 free-ranging animals), 150 wild boars, 250 sheep (150 adults, 100 lambs) and 406 cattle (47 calves, 129 heifers, 100 bulls, 130 adult cows) were tested. Seropositivity increased with the age of the assessed animals. Independent of the age-group, the overall seroprevalence was lowest in wild boars (6.7%), followed by pigs (23.3%), cattle (45.6%) and sheep (61.6%), respectively. Conventional fattening pigs and free-ranging pigs surprisingly had comparable seroprevalences (14.0% and 13.0%, respectively). Unlike in other European countries, where generally a decrease in the number of seropositive animals had been observed, we found that the prevalence of seropositive animals, when compared with that of 10 years ago, had increased for most species/age groups. Conclusively, the results demonstrated a high seroprevalence of T. gondii in animals slaughtered for meat production and revealed that increasing age of the animals is a more important risk factor than housing conditions in Switzerland. PMID- 21824349 TI - Corynebacterium ulcerans from diseased wild boars. AB - Two Corynebacterium strains were isolated from lymph nodes of wild boars showing severe alterations caused by caseous lymphadenitis. The wild boars came from different districts in southern Germany; one was found dead, the other had been shot. The two Corynebacterium strains obtained were both positive for phospholipase D. Further analysis of biochemical profiles did not allow unambiguous differentiation between Corynebacterium ulcerans and Corynebacterium pseudotuberculosis. Fourier-transformed infrared spectroscopy as well as partial sequencing of the genes for 16S rRNA and RNA polymerase beta subunit (rpoB) clearly identified both strains as Corynebacterium ulcerans. The tox gene for diphtheria toxin (DT) could be detected in both porcine isolates by PCR. Partial DNA sequencing of this tox gene showed significant differences from sequences described for other Corynebacterium ulcerans strains and a higher degree of similarity to that of Corynebacterium diphtheria. Production of diphtheria toxin could not be detected. These results indicate that wild game could be a reservoir for zoonotic Corynebacterium ulcerans. PMID- 21824350 TI - Carriage of methicillin-resistant Staphylococcus pseudintermedius in small animal veterinarians: indirect evidence of zoonotic transmission. AB - Methicillin-resistant Staphylococcus pseudintermedius (MRSP) is increasingly reported in small animals and cases of human infections have already been described despite its recent emergence in veterinary practice. We investigated the prevalence of MRSP and methicillin-resistant Staphylococcus aureus (MRSA) among small animal dermatologists attending a national veterinary conference in Italy. Nasal swabs were obtained from 128 veterinarians, seven of which harboured MRSP (n = 5; 3.9%) or MRSA (n = 2; 1.6%). A follow-up study of two carriers revealed that MRSP persisted for at least 1 month in the nasal cavity. Methicillin-susceptible S. aureus (MSSA) was isolated from 32 (25%) conference participants, whereas methicillin-susceptible S. pseudintermedius (MSSP) was not detected, suggesting that MRSP may have a particular ability to colonize humans compared to MSSP. All isolates were characterized by spa typing. Methicillin resistant isolates were further typed by antimicrobial susceptibility testing, SCCmec and multi-locus sequence typing. Two lineages previously associated with pets were identified among the five MRSP isolates; the European epidemic clone ST71-SCCmec II-III and ST106-SCCmec IV. One of the two MRSA isolates displayed a genotype (ST22- SCCmecIV) frequently reported in dogs and cats. MRSP isolates were resistant to more antimicrobial agents compared with MRSA isolates and displayed the typical multidrug resistance patterns of MRSP in pets. The 32 MSSA isolates belonged to 20 spa types and the most frequent types (t12, t15 and t166) were associated with common S. aureus lineages in humans (CC30 and CC45). Although low, the 3.9% MRSP carriage rate found among small animal dermatologists was surprising in consideration of the rare occurrence of S. pseudintermedius in humans, the lack of MSSP detection and the recent appearance of MRSP in Europe. As cases of human MRSP infection have been linked with pets, veterinarians should be aware of this zoonotic risk and proper preventative measures should be taken to avoid MRSP transmission from animal patients. PMID- 21824351 TI - Chlamydophila felis in cats--are the stray cats dangerous source of infection? AB - Chlamydophila felis is a causative agent of acute or chronic conjunctivitis, and pneumonia in cats. Natural transmission mostly occurs consequently to close contact with other infected cats, their aerosol and fomites. We have examined 93 cats with symptoms of acute or chronic conjunctivitis, from Kosice region in Slovakia, during the period of 2 years. Conjunctival samples were obtained from 55 domestic cats (59.14%) and 38 stray cats (40.86%). Of the total number of 93 examined animals, 42 cats were positive, which represents 45.16% overall positivity. Out of the 42 positive cats, 25 cats were stray and 17 positive cats were classified as domestic, which means that of 38 stray cats, 25 were positive (which represented 65.78% positivity) and of 55 domestic cats, 17 were positive (positivity was 30.90%). Our results showed that cats, especially stray cats, could be a dangerous source of chlamydiosis for humans. PMID- 21824352 TI - Brucella melitensis infection following military duty in Iraq. AB - Brucellosis is a common zoonotic disease worldwide; however, few cases are reported in the US. Brucella melitensis infections are primarily acquired via consumption of high-risk foods or travel to endemic areas. We describe a case of B. melitensis infection in a Tennessee soldier following deployment in Iraq. Initial symptoms included knee and back pain. Culture of an aspirate of the left sacroiliac joint yielded B. melitensis. Genetic analysis indicated that this isolate came from the Middle East. Investigation of laboratory workers identified risky exposures and positive serology prompting post-exposure prophylaxis. Military personnel and other travellers should be advised to reduce risk regarding food consumption and animal contact in endemic areas. Additionally, medical providers should remain vigilant for non-endemic zoonoses among recent travellers. PMID- 21824353 TI - Exploitation of intestinal colonization-inhibition between salmonella organisms for live vaccines in poultry: potential and limitations. AB - Immunization represents one of the most important methods to increase the resistance of chickens against Salmonella infection. In addition to the development of an adaptive immune response, oral administration of live Salmonella strains to day-old chicks provides protection against infection within hours by intestinal colonization-inhibition. For the exploitation of this phenomenon, practical information on colonization-inhibition between Salmonella organisms is needed. Colonization-inhibition capacity between Salmonella strains from serogroups B, C1, C2, D and G was assessed in chickens. The most profound level of intestinal colonization-inhibition occurred between isogenic strains. Inhibition between strains of the same serovar was greater than that between strains of different serovars. The degree of inhibition between different serovars was not sufficiently high to identify a single strain which might inhibit a wide range of other Salmonella organisms. However, as Salmonella Enteritidis is the dominant serovar in poultry in many countries and because of the profound colonization-inhibition within this serovar there is a considerable potential to exploit this phenomenon in the development of novel live S. Enteritidis vaccines. Treatment of young chicks with mixtures of different Salmonella serovars resulted not only in a very strong growth inhibition of the isogenic strains but also in a substantial inhibition of heterologous serovars. The potential of mixtures of heterologous Salmonella strains as a 'Salmonella Inhibition Culture' and as a 'live Salmonella vaccine' should be further explored. PMID- 21824354 TI - State-level zoonotic disease surveillance in the United States. AB - Most emerging infectious diseases are zoonotic, yet recent commissions have highlighted deficiencies in their surveillance. We conducted a survey to understand the needs of state agencies for zoonotic disease surveillance. The findings will hopefully support the development of biomedical informatics applications that can link animal and human data for surveillance. PMID- 21824355 TI - Salmonella serovars and antimicrobial resistance patterns on a sample of high seroprevalence pig farms in England and Wales (2003-2008). AB - Following the introduction of a national abattoir-based monitoring programme for Salmonella in pigs, advisory visits were made to pig farms in England and Wales with high Salmonella seroprevalence assessed by muscle tissue fluid (meat juice) ELISA. Samples (n = 15 790), including pooled pen floor faeces (n = 12 136), were collected for Salmonella culture from 296 farms, between October 2003 and February 2008. Salmonella was isolated from 4489 (28%) of all samples collected, including 3301 (27%) of pooled pen floor faecal samples, from 270 (91%) of farms visited. Salmonella Typhimurium and S. Derby were the most prevalent serovars, representing 64% and 16% of isolates serotyped, respectively. The main phage types of S. Typhimurium identified were U288 and DT193. Antimicrobial resistance (AMR) was seen in 92% of isolates tested, with the highest frequencies of resistance occurring to tetracyclines (T), sulphonamide compounds (SU), ampicillin (AM), sulphamethoxazole/trimethoprim (SXT), streptomycin (S) and chloramphenicol (C). Fifty-nine AMR patterns were observed, the most frequent of these being T, AM, SXT, C, S, SU, seen in 35% of isolates tested. Multi-drug resistance was commonly found, with 67% of isolates submitted for AMR testing showing resistance to between four and nine antimicrobials. PMID- 21824356 TI - Foodborne outbreak of Salmonella subspecies IV infections associated with contamination from bearded dragons. AB - Approximately 1.4 million Salmonella infections and 400 deaths occur annually in the United States. Approximately 6% of human Salmonella cases are thought to be associated with reptiles; Salmonella enterica subspecies IV is primarily reptile associated. During 1-4 December, 2009, three isolates of Salmonella IV 6,7:z4,z24:- with indistinguishable pulsed-field gel electrophoresis (PFGE) patterns were identified through Minnesota Department of Health laboratory-based surveillance. None of the three patients associated with the isolates reported reptile contact; however, all had attended the same potluck dinner. Dinner attendees were asked questions regarding illness history, foods they prepared for and consumed at the event, and pet ownership. Cases were defined as illness in a person who had eaten potluck food and subsequently experienced fever and diarrhoea (three or more loose stools in 24 h) or laboratory-confirmed infection with Salmonella IV matching the outbreak PFGE subtype. Nineteen days after the event, environmental samples were collected from a food preparer's house where two pet bearded dragons were kept. Sixty-six of 73 potluck food consumers were interviewed; 19 cases were identified; 18 persons reported illness but did not meet the case definition. Median incubation period was 19 h (range: 3-26 h). Median duration of illness was 5 days (range: 1-11 days). Consumption of gravy, prepared by the bearded dragons' asymptomatic owner, was associated with illness (16/32 exposed versus 1/12 unexposed; risk ratio: 6.0; exact P = 0.02). Salmonella Labadi was recovered from 10 samples, including from one bearded dragon, the bathroom door knob and sink drain, and the kitchen sink drain. The outbreak PFGE subtype of Salmonella subspecies IV was isolated from vacuum cleaner bag contents. This foodborne outbreak probably resulted from environmental contamination from bearded dragons. Reptiles pose a community threat when food for public consumption is prepared in households with reptiles. PMID- 21824357 TI - Prevention educational program of human rabies transmitted by bats in rain forest preserved area of southern Brazilian coast. AB - Guaraquecaba city is a rain forest environmental protected area located on the southern coast of Brazil. Recently, the local Animal Health Service has noticed haematophagous bats feeding from humans and domestic animals, as well as bat colonies located in houses and public schools. In 2007, two non-haematophagous bats were tested positive by direct immunofluorescence for rabies in a nearby city. Native fauna and environmental laws protect non-haematophagous bats in Brazilian preserved areas such as Guaraquecaba, making non-haematophagous bat population control almost impossible. Accordingly, the aim of this study was to evaluate a simple and feasible educational protocol applied by a multi institutional task force in local elementary schools to prevent rabies transmitted by bats. Information was transmitted to children by video, lectures and oral question-answer section; evaluation was made by written questionnaires to teachers and students. Interinstitutional task force included public and animal health public services, a federal university and the city secretary of environment, of education, of agriculture and of animal health, and also participation of local community. Information was effectively absorbed by children when evaluated just after being given. As important, questionnaires showed that handling and playing with bats at day time was common in several elementary school students, exposing themselves to what may represent higher risk of rabies transmission than haematophagous bat feeding directly from humans. Training of teachers and students may effectively prevent rabies by bats in such communities. Insertion of this subject into science content of local elementary school educational programme was proposed in order to establish a continuing education programme on rabies transmitted by bats in environmental preserved areas. PMID- 21824358 TI - Desperately seeking diarrhoea: outbreak of haemolytic uraemic syndrome caused by emerging sorbitol-fermenting shiga toxin-producing Escherichia coli O157:H-, Germany, 2009. AB - Infection with sorbitol-fermenting Shiga toxin-producing Escherichia coli O157:H- (sf STEC O157:H-) is rare, but emerging in Europe. The pathogen is typically isolated from paediatric patients with life-threatening haemolytic uraemic syndrome (HUS). It is unclear whether this observation primarily reflects the pathogen's virulence or its complex laboratory diagnosis, not routinely conducted in diarrhoeal patients. In summer 2009, four boys living in the same suburb in Germany developed diarrhoea-associated HUS: three were infected by sf STEC O157:H and one died. We conducted two analytical epidemiological studies, an extensive search for diarrhoeal cases in potentially exposed groups, and an environmental investigation. Outbreak cases were residents of the suburb diagnosed with HUS, sf STEC O157:H- infection, or both between 24 July 2009 and 25 August 2009. Overall, we ascertained eight cases with a median age of 4 years (range: from 8 months to 9 years). Stool screening of 220 persons led to the identification of only four additional cases: two asymptomatic carriers and two diarrhoeal cases. HUS was strongly associated with visiting a local playground in July, particularly on 16th July (odds ratio = 42.7, P = 0.002). No other commonality, including food, was identified, and all environmental samples (n = 24) were negative. In this localized non-foodborne outbreak, the place of likely infection was a local playground. Sf STEC O157:H- infection apparently limits itself rarely to diarrhoeal illness and progresses frequently to HUS. Therefore, detection of and response to this hypervirulent pathogen primarily relies on HUS surveillance. PMID- 21824359 TI - Influenza A pandemic (H1N1) 2009 virus outbreak in a cat colony in Italy. AB - In April 2009, a novel H1N1 influenza A virus (pH1N1) was recognized as the cause of the flu pandemic in humans. Here, we report the isolation of pH1N1 virus from the lung homogenates of two cats, which died after severe respiratory symptoms. The cats belonged to a cat colony consisting of 90 caged cats and were found dead following a 2-week period of respiratory and gastrointestinal diseases in the colony. During the outbreak, 25 cats died and 50% of the animal colony showed anorexia, depression, respiratory and gastrointestinal symptoms. Histological examination of the lungs of the two tested cats displayed lesions centred on terminal airways with epithelial bronchiolar hyperplasia and alveolar necrosis. Influenza A virus was detected in the lung tissues by immunohistochemistry and real-time RT-PCR (rRT-PCR). Partial sequences of haemagglutinin (HA) genes and complete sequences of neuraminidase (NA) genes of the two isolates displayed high similarity to the pH1N1 viruses circulating in humans (99% for HA gene and 100% for NA gene). To determine whether the pandemic virus had circulated among cats, serum samples and pharyngeal swabs were collected from 38 cats of the colony. Serum samples were tested by ELISA to detect antibodies against pH1N1 nucleoprotein and by hemagglutination-inhibition test, while pharyngeal swabs were examined by pH1N1 specific rRT-PCR. Twenty-one (55%) of the tested cats carried antibodies against the isolated strain and two swabs were positive for the presence of pH1N1 RNA. Our results confirm that the pH1N1 virus was able to infect cats and raise the hypothesis of the circulation of the virus within the colony being due to cat-to-cat transmission. The case reported here provides, to the best of the authors' knowledge, the first description of the pH1N1 infection involving numerous cats that lived in a restricted area with limited contact with humans. PMID- 21824360 TI - A nationwide outbreak of Salmonella bovismorbificans associated with sprouted alfalfa seeds in Finland, 2009. AB - Salmonella enterica serotype Bovismorbificans is a rare serotype in Finland. In June 2009, a nationwide outbreak of S. Bovismorbificans infections occurred, and 42 clinical isolates were identified. We conducted a case-control study enrolling 28 cases and 48 matched controls, and found ready-to-eat alfalfa sprouts associated with the infection (odds ratio = 35.2, 95% confidence interval 2.8 435). The sprouts were traced back to a domestic producer, with the seeds originating in Italy. Although finding microbiological evidence for sprouts as a source of this outbreak was very challenging, S. Bovismorbificans was finally found in sprouts germinated in the laboratory, and in soaking and rinse waters during the germination process. The pulsed field gel electrophoresis showed that these isolates were identical to the human outbreak isolates. Before sampling, it is important to mix the seeds well and to take several large-size samples from different seed lots. Instead of analysing seeds, the analysis should be targeted to soaking or rinse water samples and to the sprouts germinated in a laboratory. Accordingly, the sprout producers should only buy seeds that have been analysed for Salmonella. The producers have to include Salmonella testing in their internal quality control to ensure that Salmonella is absent from sprouts placed on the market during their shelf-life. In order to reduce the health hazard caused by sprouts, an effective and safe decontamination procedure should also be developed for the seeds. PMID- 21824361 TI - Sonographical and serological survey of human cystic echinococcosis and analysis of risk factors associated with seroconversion in rural communities of Kerman, Iran. AB - Cystic echinococcosis (CE) caused by larval stage of Echinococcus granulosus, is an endemic zoonosis in Iran particularly in rural regions. The objective of this study was to determine the prevalence of CE among rural communities in Kerman using ultrasonography (US) and serology. Kerman Province, in southeastern Iran, is the largest province, with 2.9 million inhabitants. A sample of 1140 individuals (200 males and 940 females) was selected by randomized cluster sampling in 2006-2008. After acquiring informed consent for each participant a questionnaire was filled, complete abdominal US in supine position was carried out and 5 ml blood was collected for ELISA test. Two hydatid cases (0.2%) were detected by ultrasound. Serological results showed 7.3% seropositivity, and females (8.3%) were significantly more positive than males (2.1%). There were significant difference between CE seropositivity and sex, age and occupation. Residents of desert regions (Shahdad, Andouhjerd and Golbaf) were 2.5 times more likely to be seropositive than mountainous regions with better socioeconomic status (OR = 2.5; 95% CI = 1.09-5.95). Dog ownership does not appear to be a significant risk factor for CE in the region. Only about 10% of households own dogs, usually only one dog. However, the stray dog population of Kerman province is estimated at 145 000-480 000 (3.5-11.5 times the owned dog population). Infection in humans and animals would appear to come mostly from infected stray dogs. Management of stray dog population could make major progress in control of hydatid disease. In addition, proper washing of vegetables decreased probability of infection by 53% (OR = 0.47; 95% CI = 0.26-0.84). The serological study showed that many people, especially women, had been exposed to Echinococcus eggs and had seroconverted but were not infected. PMID- 21824362 TI - Seasonal dynamics of house dust mites in dust samples collected from sleeping places in north-western Poland. AB - The most common families of mites found in house dust are Pyroglyphidae, Glycyphagidae and Acaridae; all are a source of many antigens responsible for allergic diseases. The aim of this study was to examine the seasonal dynamics of allergenic mite populations in dust samples collected from sleeping places in apartments in north-western Poland. The mites were isolated from the dust using a saturated saline floating method. In 132 dust samples we determined: Dermatophagoides farinae, Dermatophagoides pteronyssinus, Euroglyphus maynei, Hirstia sp., Chortoglyphus arcuatus, Lepidoglyphus destructor, Gohieria fusca and Cheyletus sp. The greatest frequency was observed for D. farinae, D. pteronyssinus, Ch. arcuatus and Cheyletus sp., in the fourth quarter and D. farinae in the third quarter. Smaller coefficients of dominance were found for D. pteronyssinus, Ch. arcuatus and Cheyletus sp., and their greatest mean concentrations were found in the first and fourth quarters. Given the division of the year into heating and non-heating seasons, mites D. farinae and D. pteronyssinus achieved the highest mean concentration in the first season, and Cheyletus sp. in the second season. The analysis of the participation of developmental stages showed that the adults of D. farinae were more prevalent than juveniles in the first, second and third quarters, and imago stages of D. pteronyssinus were more numerous in relation to juveniles in the first, third and fourth quarters. The results confirm the high incidence of house dust mites in sleeping places in north-western Poland dwellings; the best conditions for the development of these mites, mainly D. farinae and D. pteronyssinus, occur in the fourth quarter and are the least favourable in the second quarter. In many cases, these results are consistent with data from other parts of Poland collected by various authors. PMID- 21824363 TI - Candida species isolated from urban bats of Londrina-Parana, Brazil and their potential virulence. AB - The aim of this study was to isolate yeasts from the faeces of urban bats inhabiting the city of Londrina, Parana, Brazil and to determine their potential virulence attributes. Seven (12.3%) of 57 bats screened in this study showed yeasts in their faeces. Five species of the genus Candida were isolated: C. guilliermondii, C. krusei, C. lusitaniae, C. parapsilosis, and C. pelliculosa. No phospholipase activity was detected in the egg yolk plate assay; however, all isolates demonstrated protease secretion in skim milk agar. Yeasts isolated from bats produced biofilm on the surface of polystyrene plates and all were classified as intermediate biofilm producers. Minimal inhibitory concentration (MIC) values for fluconazole in the yeasts varied according to the species. Only one isolate (M34 - C. lusitaniae) was considered susceptible dose-dependent to fluconazole. The yeasts were injected intravenously into Swiss mice, and at 15 days post-infection, the animals were killed and portions of their kidneys cultured on Sabouraud dextrose agar medium. All tissues analysed showed positive cultures of Candida spp. This is the first study evaluating the presence of fungi in the faeces of bats in an urban region, where the yeast species found were shown to be potentially pathogenic. As bats are commonly found in cities, these findings indicate the need for continuous surveillance concerning environmental contamination by their excreta. PMID- 21824364 TI - Detection of zoonotic intestinal parasites in public parks of Spain. Potential epidemiological role of microsporidia. AB - Several studies have demonstrated that the soil of public parks presents an important source of infection which has a significant impact on public health. Children are the main group affected by accidentally ingestion of contaminated soil. This study was performed in order to identify the presence of zoonotic parasites in dog and cat faecal and soil samples from public parks of Madrid, Spain. Six hundred twenty-five and seventy-nine soil and faecal samples (presumably from dogs and cats) respectively were collected from 67 parks. Intestinal parasites were identified in 27 parks (40.3%), which were contamined with Giardia sp. (19.4%), microsporidia (19.4%), Toxocara spp. (16.4%), Cryptosporidium sp. (6%), Entamoeba histolytica (3%) and Ancylostomidae (3%). Combinations of two or more intestinal parasites were found in 11 parks, and it was common to find Giardia and microsporidia together in samples. Intestinal parasites were detected in 18% (112/625) of soil samples. The most frequent parasite species found in the examined soil samples were Toxocara spp. (16.4%), followed by Giardia sp. (4.5%) and Strongyloides sp. larvae (3%). The zoonotic parasites found in the 79 faecal samples were Giardia sp. (17.7%), Cryptosporidium sp. (9%), E. histolytica (2.5%), Trichuris vulpis (1.3%), Toxascaris leonina (1.3%) and microsporidia spores (28%). Microsporidia characterization by amplification of DNA confirmed 10 samples as positive, eight for E. bieneusi and two for E. hellem by PCR. The role of those parasites in the environment are discussed. PMID- 21824365 TI - Leptospirosis and tularaemia in raccoons (Procyon lotor) of Larimer County, [corrected] Colorado. AB - Raccoons (Procyon lotor) are commonly implicated as carriers of many zoonotic pathogens. The purpose of this cross-sectional study was to look for Leptospira interrogans and Francisella tularensis in opportunistically sampled, free-ranging raccoons of Larimer Country, Colorado, USA. Sixty-five animals were included in the study and testing consisted of gross post-mortem examination, histopathology, and both immunohistochemistry and PCR for L. interrogans and F. tularensis. No significant gross lesions were identified and the most common histological lesions were lymphoplasmacytic interstitial nephritis and pulmonary silicosis; rare periportal hepatitis, splenic lymphoid hyperplasia and small pulmonary granulomas were also identified. Of 65 animals, 20 (30%) were positive for Leptospira on IHC but only one by PCR. Animals with inflammation in their kidneys were seven times more likely to be positive for Leptospira than animals without inflammation. The severity of inflammation was variable but often mild with minimal associated renal pathology. One animal was positive for Francisella on both IHC and PCR; IHC staining was localized to histiocytic cells within a pulmonary granuloma. In Colorado the significance and epidemiology of Leptospira is poorly understood. The high prevalence of infection in raccoons in this study population suggests that this species may be important in the regional epidemiology or could be used to estimate risk to domestic animals and humans. Identification of a single Francisella positive animal is significant as this is an uncommon disease in terrestrial animals within the state; the apparently higher prevalence in this peridomestic species implies that raccoons may be good indicators of the pathogen in the region. The results of this study suggest that raccoons may serve as effective sentinels for both Leptospira and Francisella in the state of Colorado. Further studies are needed to better characterize the prevalence and epidemiology of both organisms within the region. PMID- 21824366 TI - Prevalence of methicillin-resistant Staphylococci on a farm: staff can harbour MRS when animals do not. AB - The aim of this work was to establish the prevalence of methicillin-resistant Staphylococci (MRS) in the animals and staff of a teaching and research farm. Samples of dairy cattle (36), beef cattle (26), sheep (19), horses (21), pigs (23), goats (23) and humans (13) were collected and screened for the presence of MRS. The detection of mecA gene was performed by PCR to determine the resistance of the samples to methicillin. Antimicrobial-resistance testing to penicillin, meropenem, ceftriaxone, cephalothin, oxacillin, levofloxacin, enrofloxacin, chloramphenicol, ciprofloxacin, gentamicin, clindamycin, erytromycin, linezolid, sulfamethoxazole/trimethoprim, tetracycline, doxycycline and vancomycin was performed on the mecA+ isolates. From the 161 samples, four methicillin-resistant coagulase-negative Staphylococci (MRCoNS) were isolated from human beings (31%), whereas none was isolated from animals (0%). No methicillin-resistant Staphylococcus aureus (MRSA) were isolated. All of the MRCoNS isolates from this work presented different antimicrobial resistance patterns. MRCoNS may be present in humans associated with animals while not present in the animals. Selective pressure outside of the farm and a lack of MRCoNS transmission between humans and animals may be responsible for this lack of correlation. PMID- 21824367 TI - Tick infestation and spotted-fever group Rickettsia in shelter dogs, California, 2009. AB - In response to an outbreak of Rocky Mountain spotted fever (RMSF) in Baja California in early 2009, dogs at two shelters in neighbouring Imperial County, California, were evaluated for ectoparasites. Brown dog ticks (Rhipicephalus sanguineus), a recognized vector for RMSF, were found on 35 (30%) of 116 dogs but all ticks tested negative for Rickettsia rickettsii by PCR. PMID- 21824368 TI - Risk factors for human rabies in China. AB - In China, we have witnessed an increasing incidence of rabies in recent years and the number of deaths ranked first among the 39 notifiable infectious diseases. We conducted a case-control study to identify risk factors for human rabies infection and disease to recommend prevention and treatment among people exposed to rabies. Exposure site, pre-exposure prophylaxis and post-exposure prophylaxis were significantly associated with rabies infection. Exposure site at upper limb and trunk or at lower limb were at lower risk as compared with head-exposed patients. The OR was 0.09(95% CI: 0.009-0.93) and 0.01(95% CI: 0.001-0.115) respectively. Pre-exposure prophylaxis (OR = 0.05, 95% CI: 0.03-0.11) and post exposure prophylaxis (OR = 0.02, 95% CI: 0.01-0.40) were both protective factors as compared with no prophylaxis. For patients who had post-exposure prophylaxis, dose for the first injection and immunity procedure were significantly associated with rabies infection. PMID- 21824369 TI - Effects of pine processionary caterpillar Thaumetopoea pityocampa contact in dogs: 41 cases (2002-2006). AB - The pine processionary caterpillar, Thaumetopoea pityocampa, is considered an emerging pine pest in Mediterranean countries, with high medical relevance. In recent years, adverse reactions reports in humans following contact with T. pityocampa have been increasingly reported. Dogs living in pinewood areas are also frequently exposed to the caterpillar. This work consisted on a retrospective study of 41 cases of lepidopterism. All dogs presented drooling, dysphagia, submandibular lymphadenomegaly and clinical signs of pain. The animals were distributed in three groups, according to the time span from exposure to the caterpillar until presentation: up to 2 h (group 1), 2-5 h (group 2) and more than 5 h (group 3). All animals from groups 2 (n = 5) and 3 (n = 9), and eight dogs from group 1 (n = 27) developed lingual necrosis. Lepidopterism coursed through a predictable clinical pattern. The evolution was mainly dependent on the time span between exposure to the caterpillar and medical intervention, which should take place earlier than 2 h from exposure. PMID- 21824370 TI - Reportable animal diseases in the United States. AB - Timely reporting of animal diseases is fundamental to the detection of emerging threats, rapid and effective outbreak response, and ultimately the health of both animals and humans. In the United States, each state has the authority to regulate reporting of diseases. While past research has reviewed reportable human diseases, the research on reportable animal diseases has assessed only veterinarian knowledge and understanding of law rather than identifying the actual statutes and regulation that exists. Therefore, this article reviewed the statutes, regulations, and online reportable animal disease lists from the 50 states and District of Columbia to describe the legal landscape of animal disease reporting. The findings suggest wide variation in state animal disease reporting requirements. Three hundred and forty distinct diseases, agents, and categories were identified, with only 15 diseases being listed by 40 or more states. States typically require reporting of animal diseases within 48 h. Substantial consideration needs to be given to the implications of these variations for rapid and effective animal and zoonotic disease detection and reporting in the United States, particularly in light of One Health initiatives and international obligations. PMID- 21824371 TI - Epidemiology and clinical features of human infection with Coxiella burnetii in Denmark during 2006-07. AB - Query (Q) fever was virtually unknown in Denmark in 2005, when, after the introduction of new sensitive diagnostic methods for Coxiella burnetii, an increasing number of positive cattle created concern among people with frequent exposure. This led to a dramatic rise in examinations for Q fever among humans in the following 2 years. The aim of our study was to assess indication for testing and symptoms in individuals with serological signs of infection with C. burnetii. We performed a case-review study of seropositives among all humans tested for Q fever in 2006-07 in Denmark. Seropositive cases were categorized with acute infection: 4-fold increase in immunoglobulin G (IgG) phase II or concomitant IgM phase II >= 1 : 256 and IgG phase II >= 1 : 1024; and previous infection: IgG phase II >= 1 : 1024. A borderline result was defined as: IgG phase II = 1 : 512. Physicians completed a questionnaire retrospectively. Of the 1613 people tested, 177 (11%) were seropositive [37 (2%) acute infection, 140 (9%) previous infection], 180 had a borderline result. Among 127 seropositives responders, 31% were tested due to symptoms compatible with Q fever after a possible exposure to C. burnetii, 64% were asymptomatic and were tested following relevant exposure only; 64% were males, 43% farmers, 39% veterinarians, 84% had been exposed to cattle. The most frequently reported symptoms were asthenia (25%), myalgia (21%), fever (17%) and headache (13%). About two-thirds of seropositives reported asymptomatic infections, and were tested for Q fever because of concern for occupational exposure to cattle. One-third of the seropositives reported symptoms consistent with Q fever, the majority being mild. Our study provided important evidence that increased requests for Q fever testing in 2006-07 arose from heightened public awareness of the disease, and not from an outbreak of clinical disease. Nonetheless, Q fever should be considered endemic in Denmark. PMID- 21824372 TI - The prevalence and genetic diversity of Campylobacter spp. in domestic 'backyard' poultry in Canterbury, New Zealand. AB - Campylobacteriosis is the most commonly notified illness in New Zealand. Whilst the importance of commercial poultry in campylobacteriosis is well established, little is known about the possible role of chickens kept at home as a direct animal/faecal contact or consumption exposure pathway. The aim of this study was to determine the prevalence and genetic diversity of Campylobacter spp. in domestic backyard chicken flocks in the Canterbury region of New Zealand. Poultry faecal samples were collected from 35 domestic 'backyard' poultry flocks from urban and rural properties around the Canterbury Region of New Zealand. A total of 291 samples were collected and tested for the presence of thermotolerant Campylobacter spp. and positive isolates were analysed using pulsed-field gel electrophoresis (PFGE) using both SmaI and KpnI enzymes. There was a high prevalence of Campylobacter spp. with 86% of flocks testing positive. Campylobacter jejuni alone, Campylobacter coli alone and both C. jejuni and C. coli were detected in 20 (57%), 2 (6%) and 8 (23%) of the flocks respectively. SmaI/KpnI PFGE analysis identified 50 different genotypes across the 35 flocks. Genotype diversity richness was highest on the lifestyle block and farm properties with 43 different genotypes isolated, whilst urban properties displayed the least richness with 12 genotypes isolated. Rural flocks tended to have more different genotypes in a given flock than urban flocks. Comparison of the genotypes with the PulseNet Aotearoa Campylobacter database showed that 28 of the genotypes had previously been isolated from human cases of campylobacteriosis. Many of these were also indistinguishable from Campylobacter spp. previously isolated from retail chicken. Therefore, contact with backyard poultry or their faecal material is a potential additional infection pathway outside of exposure to the established pathways associated with the consumption of Campylobacter-contaminated commercial meat or foods cross-contaminated from contaminated poultry. PMID- 21824373 TI - Prevalence of Coxiella burnetii in ticks after a large outbreak of Q fever. AB - Q fever has emerged as an important human and veterinary public health problem in the Netherlands with major outbreaks in three consecutive years. Goat farms are probably the prime source from which Coxiella burnetii have spread throughout the environment, infecting people living in the vicinity. Coxiella burnetii infection not only spilled over from animal husbandry to humans but could also have spread to neighbouring wildlife and pets forming novel reservoirs and consequently posing another and lingering threat to humans, companion animals and livestock. In these cases, transmission routes other than airborne spread of contaminated aerosols may become significant. Therefore, the role of ticks in the transmission of Coxiella burnetii in the current situation was investigated. A total of 1891 questing Ixodes ricinus ticks and 1086 ticks feeding on pets, wildlife and livestock were tested by a recently developed multiplex Q-PCR. All ticks were negative, except for a few ticks feeding on a herd of recently vaccinated sheep. Coxiella-positive ticks were not detected after resampling this particular herd three months later. Based on these data we conclude that the current risk of acquiring Q fever from questing ticks in the Netherlands is negligible. However, for future risk assessments, it might be relevant to sample more ticks in the vicinity of previously C. burnetii infected goat farms and to assess whether C. burnetii can be transmitted transovarially and transstadially in I. ricinus ticks. PMID- 21824374 TI - Seroprevalence of tularemia in wild bears and hares in Japan. AB - Tularemia is a zoonotic disease caused by Francisella tularensis. The distribution of the pathogen in Japan has not been studied well. In this study, seroprevalence of tularemia among wild black bears and hares in Japan was determined. Blood samples collected from 431 Japanese black bears (Ursus thibetanus japonicus) and 293 Japanese hares (Lepus brachurus) between 1998 and 2009 were examined for antibodies against F. tularensis by micro-agglutination test (MA) or enzyme-linked immunosorbent assay. By subsequent confirmatory tests using western blot (WB) and indirect immunofluorescence assay (IFA), eight sera from Japanese black bears were definitely shown to be seropositive. All of these eight bears were residents of the northeastern part of main-island of Japan, where human tularemia had been reported. On the other hand, no seropositive Japanese hares were found. These results suggest that Japanese black bears can serve as sentinel for tularemia surveillance and may help understand the distribution of F. tularensis throughout the country. This is the first report on detection of antibody to F. tularensis in black bears of Japan. PMID- 21824375 TI - Characterization of influenza a outbreaks in Minnesota swine herds and measures taken to reduce the risk of zoonotic transmission. AB - Influenza A virus infections commonly cause respiratory disease in swine and can be transmitted between people and pigs, with potentially novel strains introduced into herds and spilling back into the human population. The goals of this study were to characterize influenza infections in Minnesota pigs and assess biosecurity measures used by swine workers. Veterinarians submitting influenza positive swine samples to the University of Minnesota Veterinary Diagnostic Laboratory between October 2007 and April 2009 were surveyed regarding disease related information and biosecurity procedures at each farm. Influenza-positive samples were submitted year-round, peaking in spring and fall. H1N1 was the most commonly detected subtype (56%), followed by H3N2 (14%) and H1N2 (12%). Most positive submissions were associated with illness in growing pigs (median age 8.8 weeks, IQR 5-15). Median morbidity and mortality were 25% (IQR 10-48) and 2% (IQR 0.5-3.5), respectively. Vaccination of sows and growing pigs was conducted at 71% and 7.9% of the swine farms, respectively. Specialized footwear was reported as the most common form of protective equipment used by workers. Employee vaccination for seasonal influenza was 19%. The sow vaccination rate in this study is consistent with national data, although growing pig vaccination is lower than the national average. Seasonal and age trends identified here may provide diagnostic guidance when growing pigs experience respiratory disease. Inconsistent use of protective equipment and employee vaccination at swine farms indicates the need for further discussion and research of approaches to minimize interspecies influenza transmission on swine farms. PMID- 21824376 TI - Seroprevalence of seven zoonotic infections in Nunavik, Quebec (Canada). AB - In Nunavik, common practices and food habits such as consumption of raw meat and untreated water place the Inuit at risk for contracting zoonotic diseases. The aim of this study was to determine the seroprevalence of seven zoonotic infections among the permanent residents of Nunavik. The study was conducted in the fall 2004 as part of the Nunavik Health Survey. Blood samples from adults aged 18-74 years (n = 917) were collected and analysed for the presence of antibodies against Trichinella spp., Toxocara canis, Echinococcus granulosus, Brucella spp., Coxiella burnetii, Leptospira spp. and Francisella tularensis. Information on sociodemographic characteristics, traditional activities, drinking water supply and nutrition was gathered using english/inuktitut bilingual questionnaires. The chi-squared test was used to evaluate associations between seropositivity and other measured variables. Statistically significant variables were included in a multivariate logistic regression model to control for confounding factors. Estimated seroprevalences were 8.3% for E. granulosus, 3.9% for T. canis, 5.9% for Leptospira spp. and 18.9% for F. tularensis. Seroprevalence was <= 1% for Trichinella spiralis, Brucella spp. and C. burnetii. For most infections, seropositivity tended to increase with age. In multivariate analyses, seroprevalence was positively (i.e. directly) associated with age and residence in the Ungava coast area for F. tularensis; age and residence in the Hudson coast area for T. canis; female gender, lower level of schooling and frequent cleaning of water reservoirs for E. granulosus. No risk factor for Leptospira spp. infection was identified. No associations were detected with regards to food habits or environmental exposures. A small but significant portion of the Nunavik population has serologic evidence of exposure to at least one of the pathogenic microorganisms investigated. Further studies are needed to better understand the mechanisms for transmission of zoonotic infections and their potential reservoirs in Nunavik. PMID- 21824377 TI - Risk factors for symptoms of gastrointestinal illness in rural town Isiolo, Kenya. AB - This study assesses risk factors for food-borne gastrointestinal illness indicated by diarrhoea and/or vomiting using 14-day recalls among children and young adults. The study was set in Isiolo, a rural town of Kenya, inhabited mainly by pastoralists of different ethnic groups. The preparation methods of milk at the household level were also investigated. The study was cross-sectional and involved 900 participants from randomly selected households. They were interviewed using a structured questionnaire. An unmatched nested case-control study was constructed by randomly selecting three controls for each case. Potential risk factors for gastrointestinal illness were analysed using both univariate and multivariate logistic regression models with random effect on ethnic groups. The study results showed that consumption of mutton, carrots, Irish potatoes, raw camel milk, boiled camel milk and fermented camel milk were important risk factors for diarrhoea and/or vomiting, whereas the consumption of boiled goat milk, boiled cow milk, spinach, washing of hands with soap and the presence of proper drainage system had protective effects (odds ratio < 1). We conclude that in this setting, primarily vegetables and the camel milk market chain pose the greatest risks for symptoms of food-borne gastrointestinal illness. PMID- 21824378 TI - A systematic review of vaccinations to reduce the shedding of Escherichia coli O157 in the faeces of domestic ruminants. AB - The objective of this study was to conduct a systematic review and meta-analysis of the published literature to evaluate the efficacy of vaccines in reducing faecal shedding of Escherichia coli O157 in ruminants. A systematic search of eight databases and land-grant university research reports using an algorithm adapted from a previous systematic review of pre-harvest interventions against E. coli O157 was conducted to locate all reports of in vivo trials of E. coli O157 vaccines in ruminants published between 1990 and 2010. All located references were screened by two independent reviewers, and data were extracted from all relevant papers, with treatment effect measured in odds ratios. For trials with a faecal prevalence outcome that did not involve mixing of treated and untreated cattle in the same pen, efficacy was explored using random-effects meta-analysis. Funnel plots were used to evaluate publication bias, and random-effects meta regression was performed to explore heterogeneity. The search located 20 relevant manuscripts which detailed 24 trials and 46 treatment comparisons; all but one trial involved cattle. There were 9 deliberate challenge trials (19 comparisons), and 15 natural exposure trials (27 comparisons). For Type III protein vaccines, there were 9 natural exposure trials detailing 17 comparisons, and meta-analysis of 8 comparisons revealed that vaccine treatment resulted in a statistically significant reduction in E. coli O157 faecal prevalence [odds ratio (OR)=0.38, 95% confidence interval (CI)=0.29, 0.51]. Siderophore receptor and porin protein (SRP) vaccines (three trials/four comparisons) also reduced faecal prevalence (OR=0.42, 95% CI=0.20, 0.61); however, none of the bacterin vaccine trials (n=3, six comparisons) resulted in a statistically significant reduction in prevalence. The results suggest that Type III protein and SRP vaccines significantly reduce faecal shedding in cattle; however, caution should be taken in interpreting the results because of the heterogeneity in the results. PMID- 21824379 TI - Antibody prevalence of low-pathogenicity avian influenza and evaluation of management practices in Minnesota backyard poultry flocks. AB - Low-pathogenicity avian influenza (LPAI) viruses have caused illness in poultry and humans with poultry contact. To determine whether there is evidence of exposure to avian influenza viruses (AIV) among backyard poultry in Minnesota and their human caretakers, 150 flocks of backyard birds were sampled for antibodies to AIV from August 2007 through December 2008. One hundred flocks were tested through routine slaughter surveillance by the Minnesota Board of Animal Health and an additional 50 flocks were contacted and sampled by study investigators. Blood was collected from 10 to 13 birds from each flock and a survey of biosecurity and management practices was administered to the flock owner. Blood samples were tested by agar gel immunodiffusion (AGID) for influenza A antibodies. Tested flocks had a median flock size of 100 birds (range: 12-800 birds), and were most commonly owned for meat for personal use (81% of respondents), fun or hobby (58%) and eggs for personal use (56%). Although 7% of flock owners reported that their birds had shown respiratory signs in the previous 3 months, only 1 of 150 flocks tested positive for influenza by AGID. Antibodies to LPAI H6N1 were detected in the positive flock. The owner of the positive flock did not have antibodies to H6 or other common AIV. Based on the findings of this study, the risk of transmission of LPAI viruses from backyard poultry to owners in Minnesota appears to be low under current conditions and management practices. PMID- 21824380 TI - The prevalence of methicillin-resistant Staphylococcus aureus colonization in feedlot cattle. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is an important human pathogen and recent evidence has implicated food animals in the epidemiology of human infections in some regions. While the role of food in MRSA transmission and human health relevance are unclear, MRSA can be found in retail meat products internationally, including beef, yet there has been minimal investigation of MRSA in beef cattle. This study involved screening feedlot cattle for nasal and gastrointestinal colonization with MRSA shortly before the time of slaughter. Methicillin-resistant S. aureus was not isolated from any of 491 nasal swabs and 488 faecal samples. This finding is in contrast to studies that have isolated MRSA from retail beef in Canada, performed in the same laboratory using comparable culture techniques. The reason for this discrepancy is unclear but it demonstrates that further study of MRSA in livestock as well as slaughter, processing and retail environments is needed to elucidate the epidemiology of MRSA contamination of meat. PMID- 21824381 TI - Computerized clinical decision support systems for primary preventive care: a decision-maker-researcher partnership systematic review of effects on process of care and patient outcomes. AB - BACKGROUND: Computerized clinical decision support systems (CCDSSs) are claimed to improve processes and outcomes of primary preventive care (PPC), but their effects, safety, and acceptance must be confirmed. We updated our previous systematic reviews of CCDSSs and integrated a knowledge translation approach in the process. The objective was to review randomized controlled trials (RCTs) assessing the effects of CCDSSs for PPC on process of care, patient outcomes, harms, and costs. METHODS: We conducted a decision-maker-researcher partnership systematic review. We searched MEDLINE, EMBASE, Ovid's EBM Reviews Database, Inspec, and other databases, as well as reference lists through January 2010. We contacted authors to confirm data or provide additional information. We included RCTs that assessed the effect of a CCDSS for PPC on process of care and patient outcomes compared to care provided without a CCDSS. A study was considered to have a positive effect (i.e., CCDSS showed improvement) if at least 50% of the relevant study outcomes were statistically significantly positive. RESULTS: We added 17 new RCTs to our 2005 review for a total of 41 studies. RCT quality improved over time. CCDSSs improved process of care in 25 of 40 (63%) RCTs. Cumulative scientifically strong evidence supports the effectiveness of CCDSSs for screening and management of dyslipidaemia in primary care. There is mixed evidence for effectiveness in screening for cancer and mental health conditions, multiple preventive care activities, vaccination, and other preventive care interventions. Fourteen (34%) trials assessed patient outcomes, and four (29%) reported improvements with the CCDSS. Most trials were not powered to evaluate patient-important outcomes. CCDSS costs and adverse events were reported in only six (15%) and two (5%) trials, respectively. Information on study duration was often missing, limiting our ability to assess sustainability of CCDSS effects. CONCLUSIONS: Evidence supports the effectiveness of CCDSSs for screening and treatment of dyslipidaemia in primary care with less consistent evidence for CCDSSs used in screening for cancer and mental health-related conditions, vaccinations, and other preventive care. CCDSS effects on patient outcomes, safety, costs of care, and provider satisfaction remain poorly supported. PMID- 21824382 TI - Can computerized clinical decision support systems improve practitioners' diagnostic test ordering behavior? A decision-maker-researcher partnership systematic review. AB - BACKGROUND: Underuse and overuse of diagnostic tests have important implications for health outcomes and costs. Decision support technology purports to optimize the use of diagnostic tests in clinical practice. The objective of this review was to assess whether computerized clinical decision support systems (CCDSSs) are effective at improving ordering of tests for diagnosis, monitoring of disease, or monitoring of treatment. The outcome of interest was effect on the diagnostic test-ordering behavior of practitioners. METHODS: We conducted a decision-maker researcher partnership systematic review. We searched MEDLINE, EMBASE, Ovid's EBM Reviews database, Inspec, and reference lists for eligible articles published up to January 2010. We included randomized controlled trials comparing the use of CCDSSs to usual practice or non-CCDSS controls in clinical care settings. Trials were eligible if at least one component of the CCDSS gave suggestions for ordering or performing a diagnostic procedure. We considered studies 'positive' if they showed a statistically significant improvement in at least 50% of test ordering outcomes. RESULTS: Thirty-five studies were identified, with significantly higher methodological quality in those published after the year 2000 (p = 0.002). Thirty-three trials reported evaluable data on diagnostic test ordering, and 55% (18/33) of CCDSSs improved testing behavior overall, including 83% (5/6) for diagnosis, 63% (5/8) for treatment monitoring, 35% (6/17) for disease monitoring, and 100% (3/3) for other purposes. Four of the systems explicitly attempted to reduce test ordering rates and all succeeded. Factors of particular interest to decision makers include costs, user satisfaction, and impact on workflow but were rarely investigated or reported. CONCLUSIONS: Some CCDSSs can modify practitioner test-ordering behavior. To better inform development and implementation efforts, studies should describe in more detail potentially important factors such as system design, user interface, local context, implementation strategy, and evaluate impact on user satisfaction and workflow, costs, and unintended consequences. PMID- 21824383 TI - Computerized clinical decision support systems for drug prescribing and management: a decision-maker-researcher partnership systematic review. AB - BACKGROUND: Computerized clinical decision support systems (CCDSSs) for drug therapy management are designed to promote safe and effective medication use. Evidence documenting the effectiveness of CCDSSs for improving drug therapy is necessary for informed adoption decisions. The objective of this review was to systematically review randomized controlled trials assessing the effects of CCDSSs for drug therapy management on process of care and patient outcomes. We also sought to identify system and study characteristics that predicted benefit. METHODS: We conducted a decision-maker-researcher partnership systematic review. We updated our earlier reviews (1998, 2005) by searching MEDLINE, EMBASE, EBM Reviews, Inspec, and other databases, and consulting reference lists through January 2010. Authors of 82% of included studies confirmed or supplemented extracted data. We included only randomized controlled trials that evaluated the effect on process of care or patient outcomes of a CCDSS for drug therapy management compared to care provided without a CCDSS. A study was considered to have a positive effect (i.e., CCDSS showed improvement) if at least 50% of the relevant study outcomes were statistically significantly positive. RESULTS: Sixty five studies met our inclusion criteria, including 41 new studies since our previous review. Methodological quality was generally high and unchanged with time. CCDSSs improved process of care performance in 37 of the 59 studies assessing this type of outcome (64%, 57% of all studies). Twenty-nine trials assessed patient outcomes, of which six trials (21%, 9% of all trials) reported improvements. CONCLUSIONS: CCDSSs inconsistently improved process of care measures and seldomly improved patient outcomes. Lack of clear patient benefit and lack of data on harms and costs preclude a recommendation to adopt CCDSSs for drug therapy management. PMID- 21824384 TI - Computerized clinical decision support systems for therapeutic drug monitoring and dosing: a decision-maker-researcher partnership systematic review. AB - BACKGROUND: Some drugs have a narrow therapeutic range and require monitoring and dose adjustments to optimize their efficacy and safety. Computerized clinical decision support systems (CCDSSs) may improve the net benefit of these drugs. The objective of this review was to determine if CCDSSs improve processes of care or patient outcomes for therapeutic drug monitoring and dosing. METHODS: We conducted a decision-maker-researcher partnership systematic review. Studies from our previous review were included, and new studies were sought until January 2010 in MEDLINE, EMBASE, Evidence-Based Medicine Reviews, and Inspec databases. Randomized controlled trials assessing the effect of a CCDSS on process of care or patient outcomes were selected by pairs of independent reviewers. A study was considered to have a positive effect (i.e., CCDSS showed improvement) if at least 50% of the relevant study outcomes were statistically significantly positive. RESULTS: Thirty-three randomized controlled trials were identified, assessing the effect of a CCDSS on management of vitamin K antagonists (14), insulin (6), theophylline/aminophylline (4), aminoglycosides (3), digoxin (2), lidocaine (1), or as part of a multifaceted approach (3). Cluster randomization was rarely used (18%) and CCDSSs were usually stand-alone systems (76%) primarily used by physicians (85%). Overall, 18 of 30 studies (60%) showed an improvement in the process of care and 4 of 19 (21%) an improvement in patient outcomes. All evaluable studies assessing insulin dosing for glycaemic control showed an improvement. In meta-analysis, CCDSSs for vitamin K antagonist dosing significantly improved time in therapeutic range. CONCLUSIONS: CCDSSs have potential for improving process of care for therapeutic drug monitoring and dosing, specifically insulin and vitamin K antagonist dosing. However, studies were small and generally of modest quality, and effects on patient outcomes were uncertain, with no convincing benefit in the largest studies. At present, no firm recommendation for specific systems can be given. More potent CCDSSs need to be developed and should be evaluated by independent researchers using cluster randomization and primarily assess patient outcomes related to drug efficacy and safety. PMID- 21824385 TI - Computerized clinical decision support systems for acute care management: a decision-maker-researcher partnership systematic review of effects on process of care and patient outcomes. AB - BACKGROUND: Acute medical care often demands timely, accurate decisions in complex situations. Computerized clinical decision support systems (CCDSSs) have many features that could help. However, as for any medical intervention, claims that CCDSSs improve care processes and patient outcomes need to be rigorously assessed. The objective of this review was to systematically review the effects of CCDSSs on process of care and patient outcomes for acute medical care. METHODS: We conducted a decision-maker-researcher partnership systematic review. MEDLINE, EMBASE, Evidence-Based Medicine Reviews databases (Cochrane Database of Systematic Reviews, DARE, ACP Journal Club, and others), and the Inspec bibliographic database were searched to January 2010, in all languages, for randomized controlled trials (RCTs) of CCDSSs in all clinical areas. We included RCTs that evaluated the effect on process of care or patient outcomes of a CCDSS used for acute medical care compared with care provided without a CCDSS. A study was considered to have a positive effect (i.e., CCDSS showed improvement) if at least 50% of the relevant study outcomes were statistically significantly positive. RESULTS: Thirty-six studies met our inclusion criteria for acute medical care. The CCDSS improved process of care in 63% (22/35) of studies, including 64% (9/14) of medication dosing assistants, 82% (9/11) of management assistants using alerts/reminders, 38% (3/8) of management assistants using guidelines/algorithms, and 67% (2/3) of diagnostic assistants. Twenty studies evaluated patient outcomes, of which three (15%) reported improvements, all of which were medication dosing assistants. CONCLUSION: The majority of CCDSSs demonstrated improvements in process of care, but patient outcomes were less likely to be evaluated and far less likely to show positive results. PMID- 21824387 TI - Regulation of DMD pathology by an ankyrin-encoded miRNA. AB - BACKGROUND: Duchenne muscular dystrophy (DMD) is an X-linked myopathy resulting from the production of a nonfunctional dystrophin protein. MicroRNA (miRNA) are small 21- to 24-nucleotide RNA that can regulate both individual genes and entire cell signaling pathways. Previously, we identified several mRNA, both muscle enriched and inflammation-induced, that are dysregulated in the skeletal muscles of DMD patients. One particularly muscle-enriched miRNA, miR-486, is significantly downregulated in dystrophin-deficient mouse and human skeletal muscles. miR-486 is embedded within the ANKYRIN1(ANK1) gene locus, which is transcribed as either a long (erythroid-enriched) or a short (heart muscle- and skeletal muscle-enriched) isoform, depending on the cell and tissue types. RESULTS: Inhibition of miR-486 in normal muscle myoblasts results in inhibited migration and failure to repair a wound in primary myoblast cell cultures. Conversely, overexpression of miR-486 in primary myoblast cell cultures results in increased proliferation with no changes in cellular apoptosis. Using bioinformatics and miRNA reporter assays, we have identified platelet-derived growth factor receptor beta, along with several other downstream targets of the phosphatase and tensin homolog deleted on chromosome 10/AKT (PTEN/AKT) pathway, as being modulated by miR-486. The generation of muscle-specific transgenic mice that overexpress miR-486 revealed that miR-486 alters the cell cycle kinetics of regenerated myofibers in vivo, as these mice had impaired muscle regeneration. CONCLUSIONS: These studies demonstrate a link for miR-486 as a regulator of the PTEN/AKT pathway in dystrophin-deficient muscle and an important factor in the regulation of DMD muscle pathology. PMID- 21824386 TI - Computerized clinical decision support systems for chronic disease management: a decision-maker-researcher partnership systematic review. AB - BACKGROUND: The use of computerized clinical decision support systems (CCDSSs) may improve chronic disease management, which requires recurrent visits to multiple health professionals, ongoing disease and treatment monitoring, and patient behavior modification. The objective of this review was to determine if CCDSSs improve the processes of chronic care (such as diagnosis, treatment, and monitoring of disease) and associated patient outcomes (such as effects on biomarkers and clinical exacerbations). METHODS: We conducted a decision-maker researcher partnership systematic review. We searched MEDLINE, EMBASE, Ovid's EBM Reviews database, Inspec, and reference lists for potentially eligible articles published up to January 2010. We included randomized controlled trials that compared the use of CCDSSs to usual practice or non-CCDSS controls. Trials were eligible if at least one component of the CCDSS was designed to support chronic disease management. We considered studies 'positive' if they showed a statistically significant improvement in at least 50% of relevant outcomes. RESULTS: Of 55 included trials, 87% (n = 48) measured system impact on the process of care and 52% (n = 25) of those demonstrated statistically significant improvements. Sixty-five percent (36/55) of trials measured impact on, typically, non-major (surrogate) patient outcomes, and 31% (n = 11) of those demonstrated benefits. Factors of interest to decision makers, such as cost, user satisfaction, system interface and feature sets, unique design and deployment characteristics, and effects on user workflow were rarely investigated or reported. CONCLUSIONS: A small majority (just over half) of CCDSSs improved care processes in chronic disease management and some improved patient health. Policy makers, healthcare administrators, and practitioners should be aware that the evidence of CCDSS effectiveness is limited, especially with respect to the small number and size of studies measuring patient outcomes. PMID- 21824388 TI - Estimating travel reduction associated with the use of telemedicine by patients and healthcare professionals: proposal for quantitative synthesis in a systematic review. AB - BACKGROUND: A major benefit offered by telemedicine is the avoidance of travel, by patients, their carers and health care professionals. Unfortunately, there is very little published information about the extent of avoided travel. We propose to undertake a systematic review of literature which reports credible data on the reductions in travel associated with the use of telemedicine. METHOD: The conventional approach to quantitative synthesis of the results from multiple studies is to conduct a meta analysis. However, too much heterogeneity exists between available studies to allow a meaningful meta analysis of the avoided travel when telemedicine is used across all possible settings. We propose instead to consider all credible evidence on avoided travel through telemedicine by fitting a linear model which takes into account the relevant factors in the circumstances of the studies performed. We propose the use of stepwise multiple regression to identify which factors are significant. DISCUSSION: Our proposed approach is illustrated by the example of teledermatology. In a preliminary review of the literature we found 20 studies in which the percentage of avoided travel through telemedicine could be inferred (a total of 5199 patients). The mean percentage avoided travel reported in the 12 store-and-forward studies was 43%. In the 7 real-time studies and in a single study with a hybrid technique, 70% of the patients avoided travel. A simplified model based on the modality of telemedicine employed (i.e. real-time or store and forward) explained 29% of the variance. The use of store and forward teledermatology alone was associated with 43% of avoided travel. The increase in the proportion of patients who avoided travel (25%) when real-time telemedicine was employed was significant (P = 0.014). Service planners can use this information to weigh up the costs and benefits of the two approaches. PMID- 21824390 TI - Cross-sectional evaluation of a longitudinal consultation skills course at a new UK medical school. AB - BACKGROUND: Good communication is a crucial element of good clinical care, and it is important to provide appropriate consultation skills teaching in undergraduate medical training to ensure that doctors have the necessary skills to communicate effectively with patients and other key stakeholders. This article aims to provide research evidence of the acceptability of a longitudinal consultation skills strand in an undergraduate medical course, as assessed by a cross sectional evaluation of students' perceptions of their teaching and learning experiences. METHODS: A structured questionnaire was used to collect student views. The questionnaire comprised two parts: 16 closed questions to evaluate content and process of teaching and 5 open-ended questions. Questionnaires were completed at the end of each consultation skills session across all year groups during the 2006-7 academic year (5 sessions in Year 1, 3 in Year 2, 3 in Year 3, 10 in Year 4 and 10 in Year 5). 2519 questionnaires were returned in total. RESULTS: Students rated Tutor Facilitation most favourably, followed by Teaching, then Practice & Feedback, with suitability of the Rooms being most poorly rated. All years listed the following as important aspects they had learnt during the session: * how to structure the consultation * importance of patient-centredness * aspects of professionalism (including recognising own limits, being prepared, generally acting professionally). All years also noted that the sessions had increased their confidence, particularly through practice. CONCLUSIONS: Our results suggest that a longitudinal and integrated approach to teaching consultation skills using a well structured model such as Calgary-Cambridge, facilitates and consolidates learning of desired process skills, increases student confidence, encourages integration of process and content, and reinforces appreciation of patient-centredness and professionalism. PMID- 21824389 TI - Pre-referral rectal artesunate in severe malaria: flawed trial. AB - BACKGROUND: Immediate injectable treatment is essential for severe malaria. Otherwise, the afflicted risk lifelong impairment or death. In rural areas of Africa and Asia, appropriate care is often miles away. In 2009, Melba Gomes and her colleagues published the findings of a randomized, placebo-controlled trial of rectal artesunate for suspected severe malaria in such remote areas. Enrolling nearly 18,000 cases, the aim was to evaluate whether, as patients were in transit to a health facility, a pre-referral artesunate suppository blocked disease progression sufficiently to reduce these risks. The affirmative findings of this, the only trial on the issue thus far, have led the WHO to endorse rectal artesunate as a pre-referral treatment for severe malaria. In the light of its public health importance and because its scientific quality has not been assessed for a systematic review, our paper provides a detailed evaluation of the design, conduct, analysis, reporting, and practical features of this trial. RESULTS: We performed a checklist-based and an in-depth evaluation of the trial. The evaluation criteria were based on the CONSORT statement for reporting clinical trials, the clinical trial methodology literature, and practice in malaria research. Our main findings are: The inclusion and exclusion criteria and the sample size justification are not stated. Many clearly ineligible subjects were enrolled. The training of the recruiters does not appear to have been satisfactory. There was excessive between center heterogeneity in design and conduct. Outcome evaluation schedule was not defined, and in practice, became too wide. Large gaps in the collection of key data were evident. Primary endpoints were inconsistently utilized and reported; an overall analysis of the outcomes was not done; analyses of time to event data had major flaws; the stated intent to-treat analysis excluded a third of the randomized subjects; the design indicated stratified or multi-variate analysis was not done; many improper subgroups were analyzed in a post-hoc fashion; the analysis and reporting metric was deficient. There are concerns relating to patient welfare at some centers. Exclusion of many cases from data analysis compromised external validity. A bias controlled reanalysis of available data does not lend support to the conclusions drawn by the authors. CONCLUSIONS: This trial has numerous serious deficiencies in design, implementation, and methods of data analysis. Interpretation and manner of reporting are wanting, and the applicability of the findings is unclear. The trial conduct could have been improved to better protect patient welfare. The totality of these problems make it a flawed study whose conclusions remain subject to appreciable doubt. PMID- 21824391 TI - High-speed shaking of frozen blood clots for extraction of human and malaria parasite DNA. AB - BACKGROUND: Frozen blood clots remaining after serum collection is an often disregarded source of host and pathogen DNA due to troublesome handling and suboptimal outcome. METHODS: High-speed shaking of clot samples in a cell disruptor manufactured for homogenization of tissue and faecal specimens was evaluated for processing frozen blood clots for DNA extraction. The method was compared to two commercial clot protocols based on a chemical kit and centrifugation through a plastic sieve, followed by the same DNA extraction protocol. Blood clots with different levels of parasitaemia (1-1,000 p/MUl) were prepared from parasite cultures to assess sensitivity of PCR detection. In addition, clots retrieved from serum samples collected within two epidemiological studies in Kenya (n = 630) were processed by high speed shaking and analysed by PCR for detection of malaria parasites and the human alpha-thalassaemia gene. RESULTS: High speed shaking succeeded in fully dispersing the clots and the method generated the highest DNA yield. The level of PCR detection of P. falciparum parasites and the human thalassaemia gene was the same as samples optimally collected with an anticoagulant. The commercial clot protocol and centrifugation through a sieve failed to fully dissolve the clots and resulted in lower sensitivity of PCR detection. CONCLUSIONS: High speed shaking was a simple and efficacious method for homogenizing frozen blood clots before DNA purification and resulted in PCR templates of high quality both from humans and malaria parasites. This novel method enables genetic studies from stored blood clots. PMID- 21824392 TI - Mutual regulation between deubiquitinase CYLD and retroviral oncoprotein Tax. AB - BACKGROUND: Oncoprotein Tax, encoded by the human T-cell leukemia virus type 1 (HTLV1), persistently induces NF-kappaB activation, which contributes to HTLV1 mediated T-cell transformation. Recent studies suggest that the signaling function of Tax requires its ubiquitination, although how the Tax ubiquitination is regulated remains unclear. RESULTS: We show here that the deubiquitinase CYLD physically interacts with Tax and negatively regulates the ubiquitination of this viral protein. This function of CYLD is associated with inhibition of Tax mediated activation of IKK although not that of Tak1. Interestingly, CYLD undergoes constitutive phosphorylation in HTLV1-transformed T cells, a mechanism known to inactivate the catalytic activity of CYLD. Consistently, a phospho mimetic CYLD mutant fails to inhibit Tax ubiquitination. CONCLUSION: These findings suggest that CYLD negatively regulates the signaling function of Tax through inhibition of Tax ubiquitination. Conversely, induction of CYLD phosphorylation may serve as a mechanism by which HTLV1 overrides the inhibitory function of CYLD, leading to the persistent activation of NF-kappaB. PMID- 21824393 TI - Porn video shows, local brew, and transactional sex: HIV risk among youth in Kisumu, Kenya. AB - BACKGROUND: Kisumu has shown a rising HIV prevalence over the past sentinel surveillance surveys, and most new infections are occurring among youth. We conducted a qualitative study to explore risk situations that can explain the high HIV prevalence among youth in Kisumu town, Kenya METHODS: We conducted in depth interviews with 150 adolescents aged 15 to 20, held 4 focus group discussions, and made 48 observations at places where youth spend their free time. RESULTS: Porn video shows and local brew dens were identified as popular events where unprotected multipartner, concurrent, coerced and transactional sex occurs between adolescents. Video halls - rooms with a TV and VCR - often show pornography at night for a very small fee, and minors are allowed. Forced sex, gang rape and multiple concurrent relationships characterised the sexual encounters of youth, frequently facilitated by the abuse of alcohol, which is available for minors at low cost in local brew dens. For many sexually active girls, their vulnerability to STI/HIV infection is enhanced due to financial inequality, gender-related power difference and cultural norms. The desire for love and sexual pleasure also contributed to their multiple concurrent partnerships. A substantial number of girls and young women engaged in transactional sex, often with much older working partners. These partners had a stronger socio-economic position than young women, enabling them to use money/gifts as leverage for sex. Condom use was irregular during all types of sexual encounters. CONCLUSIONS: In Kisumu, local brew dens and porn video halls facilitate risky sexual encounters between youth. These places should be regulated and monitored by the government. Our study strongly points to female vulnerabilities and the role of men in perpetuating the local epidemic. Young men should be targeted in prevention activities, to change their attitudes related to power and control in relationships. Girls should be empowered how to negotiate safe sex, and their poverty should be addressed through income-generating activities. PMID- 21824394 TI - Increased complexity of Tmem16a/Anoctamin 1 transcript alternative splicing. AB - BACKGROUND: TMEM16A (Anoctamin 1; ANO1) is an eight transmembrane protein that functions as a calcium-activated chloride channel. TMEM16A in human exhibits alternatively spliced exons (6b, 13 and 15), which confer important roles in the regulation of channel function. Mouse Tmem16a is reported to consist of 25 exons that code for a 956 amino acid protein. In this study our aim was to provide details of mouse Tmem16a genomic structure and to investigate if Tmem16a transcript undergoes alternative splicing to generate channel diversity. RESULTS: We identified Tmem16a transcript variants consisting of alternative exons 6b, 10, 13, 14, 15 and 18. Our findings indicate that many of these exons are expressed in various combinations and that these splicing events are mostly conserved between mouse and human. In addition, we confirmed the expression of these exon variants in other mouse tissues. Additional splicing events were identified including a novel conserved exon 13b, tandem splice sites of exon 1 and 21 and two intron retention events. CONCLUSION: Our results suggest that Tmem16a gene is significantly more complex than previously described. The complexity is especially evident in the region spanning exons 6 through 16 where a number of the alternative splicing events are thought to affect calcium sensitivity, voltage dependence and the kinetics of activation and deactivation of this calcium-activated chloride channel. The identification of multiple Tmem16a splice variants suggests that alternative splicing is an exquisite mechanism that operates to diversify TMEM16A channel function in both physiological and pathophysiological conditions. PMID- 21824396 TI - Isolates from hospital environments are the most virulent of the Candida parapsilosis complex. AB - BACKGROUND: Candida parapsilosis is frequently isolated from hospital environments, like air and surfaces, and causes serious nosocomial infections. Molecular studies provided evidence of great genetic diversity within the C. parapsilosis species complex but, despite their growing importance as pathogens, little is known about their potential to cause disease, particularly their interactions with phagocytes. In this study, clinical and environmental C. parapsilosis isolates, and strains of the related species C. orthopsilosis and C. metapsilosis were assayed for their ability to induce macrophage cytotocixity and secretion of the pro-inflammatory cytokine TNF-alpha, to produce pseudo-hyphae and to secrete hydrolytic enzymes. RESULTS: Environmental C. parapsilosis isolates caused a statistically significant (p = 0.0002) higher cell damage compared with the clinical strains, while C. orthopsilosis and C. metapsilosis were less cytotoxic. On the other hand, clinical isolates induced a higher TNF alpha production compared with environmental strains (p < 0.0001). Whereas the amount of TNF-alpha produced in response to C. orthopsilosis strains was similar to the obtained with C. parapsilosis environmental isolates, it was lower for C. metapsilosis strains. No correlation between pseudo-hyphae formation or proteolytic enzymes secretion and macrophage death was detected (p > 0.05). However, a positive correlation between pseudo-hyphae formation and TNF-alpha secretion was observed (p = 0.0119). CONCLUSIONS: We show that environmental C. parapsilosis strains are more resistant to phagocytic host defences than bloodstream isolates, being potentially more deleterious in the course of infection than strains from a clinical source. Thus, active environmental surveillance and application of strict cleaning procedures should be implemented in order to prevent cross-infection and hospital outbreaks. PMID- 21824395 TI - The emphysematous lung is abnormally sensitive to TRAIL-mediated apoptosis. AB - BACKGROUND: Alveolar apoptosis is increased in the emphysematous lung. However, mechanisms involved are not fully understood. Recently, we demonstrated that levels of TRAIL receptor 1 and 2, levels of p53, and Bax/Bcl-xL ratio were elevated in the lung of subjects with emphysema, despite smoking cessation. Thus, we postulate that due to chronic pulmonary oxidative stress, the emphysematous lung would be abnormally sensitive to TRAIL-mediated apoptosis. METHODOLOGY: A549 cells were exposed to rTRAIL, cigarette smoke extract, and/or H2O2 prior to caspase-3 activity measurement and annexin V staining assessment. In addition, freshly resected lung samples were obtained from non-emphysematous and emphysematous subjects and exposed ex vivo to rTRAIL for up to 18 hours. Lung samples were harvested and levels of active caspase-3 and caspase-8 were measured from tissue lysates. RESULTS: Both cigarette smoke extract and H2O2 were able to sensitize A549 cells to TRAIL-mediated apoptosis. Moreover, following exposure to rTRAIL, caspase-3 and -8 were activated in lung explants from emphysematous subjects while being decreased in lung explants from non-emphysematous subjects. SIGNIFICANCE OF THE STUDY: Alveolar sensitivity to TRAIL-mediated apoptosis is strongly increased in the emphysematous lung due to the presence of oxidative stress. This might be a new mechanism leading to increased alveolar apoptosis and persistent alveolar destruction following smoking cessation. PMID- 21824398 TI - Preparation of monolayers of [MnIII6CrIII]3+ single-molecule magnets on HOPG, mica and silicon surfaces and characterization by means of non-contact AFM. AB - We report on the characterization of various salts of [MnIII6CrIII]3+ complexes prepared on substrates such as highly oriented pyrolytic graphite (HOPG), mica, SiO2, and Si3N4. [MnIII6CrIII]3+ is a single-molecule magnet, i.e., a superparamagnetic molecule, with a blocking temperature around 2 K. The three positive charges of [MnIII6CrIII]3+ were electrically neutralized by use of various anions such as tetraphenylborate (BPh4-), lactate (C3H5O3-), or perchlorate (ClO4-). The molecule was prepared on the substrates out of solution using the droplet technique. The main subject of investigation was how the anions and substrates influence the emerging surface topology during and after the preparation. Regarding HOPG and SiO2, flat island-like and hemispheric-shaped structures were created. We observed a strong correlation between the electronic properties of the substrate and the analyzed structures, especially in the case of mica where we observed a gradient in the analyzed structures across the surface. PMID- 21824397 TI - Lamivudine plus adefovir combination therapy versus entecavir monotherapy for lamivudine-resistant chronic hepatitis B: a systematic review and meta-analysis. AB - BACKGROUND: Chronic hepatitis B virus (HBV) infection represents a serious global health problem and resistance to lamivudine (LAM) has become a serious clinical challenge. Previous rescue therapy for the treatment of chronic LAM-resistant hepatitis B infected patients included switching to entecavir (ETV) and adding adefovir (ADV) or tenofovir (TFV). At present, switching to ETV is not recommended for rescue therapy for LAM-resistant chronic hepatitis B (CHB). The aim of this report was to determine whether add-on ADV was a superior rescue strategy in the treatment of CHB patients with LAM resistance. METHODS: We searched Medline/PubMed, EMBASE, Web of Knowledge, and the Cochrane Library. Relative risks (RRs) of virologic response, virologic breakthrough, normalization of serum alanine aminotransferase (ALT) levels and HBeAg seroconversion rates were studied. Factors predicting virologic response, standardized mean differences (SMD) in HBV DNA levels and safety were reviewed. RESULTS: Six eligible trials (451 patients in total) were included in the analysis. The rate of virologic breakthrough in the ETV group was higher than that in the LAM plus ADV group. There were no statistical differences in virologic response, ALT normalization and HBeAg seroconversion in either group 48 weeks post treatment. LAM plus ADV combination therapy produced faster and greater HBV DNA reduction rates 24 weeks post therapy compared to ETV monotherapy. HBV DNA baseline levels and the initial virologic response (IVR) were predictive of the virologic response. Additionally, combination therapy or monotherapy were both well tolerated. CONCLUSIONS: LAM plus ADV combination therapy was more effective and produced longer-lasting effects than switching to ETV monotherapy in treating CHB patients with LAM resistance. However, considering the practical benefits and limitations of ADV, individualized therapy will be needed in patients with prior history of LAM resistant infections. PMID- 21824399 TI - Cardiac arrest associated with sildenafil ingestion in a patient with an abnormal origin of the left coronary artery: case report. AB - BACKGROUND: Left coronary artery arising from the right sinus of Valsalva is an uncommon congenital coronary anomaly that seems to be associated with sudden death in young patients. CASE PRESENTATION: We report a case of cardiac arrest in a 59-year-old patient after sexual intercourse and Sildenafil ingestion. A coronary arteriography and an angiographic computed tomography scan subsequently revealed a LCA origin from the right aortic sinus along with an intramural course of the left main stem. In addition a distal stenosis of the right coronary artery was detected. After successful resuscitation without neurological deficits coronary artery bypass surgery was performed. CONCLUSION: To our knowledge, this is the first report demonstrating sudden cardiac arrest associated with Sildenafil ingestion in a patient with this type of coronary anomaly. The question arises, whether a cardiac screening is necessary before a Sildenafil therapy is initiated. PMID- 21824400 TI - Therapeutic promise and challenges of targeting DLL4/NOTCH1. AB - DLL4-mediated NOTCH1 signaling represents an essential pathway for vascular development and has emerged as an attractive target for angiogenesis-based cancer therapies. However, newly reported toxicity findings raise safety concerns of chronic pathway blockade. Lessons learned from the development of gamma-secretase inhibitors (GSIs) might offer insights into how to safely harness this important signaling pathway. PMID- 21824401 TI - Metabolic alteration of urinary steroids in pre- and post-menopausal women, and men with papillary thyroid carcinoma. AB - BACKGROUND: To evaluate the metabolic changes in urinary steroids in pre- and post-menopausal women and men with papillary thyroid carcinoma (PTC). METHODS: Quantitative steroid profiling combined with gas chromatography-mass spectrometry was used to measure the urinary concentrations of 84 steroids in both pre- (n = 21, age: 36.95 +/- 7.19 yr) and post-menopausal female (n = 19, age: 52.79 +/- 7.66 yr), and male (n = 16, age: 41.88 +/- 8.48 yr) patients with PTC. After comparing the quantitative data of the patients with their corresponding controls (pre-menopause women: n = 24, age: 33.21 +/- 10.48 yr, post-menopause women: n = 16, age: 49.67 +/- 8.94 yr, male: n = 20, age: 42.75 +/- 4.22 yr), the levels of steroids in the patients were normalized to the mean concentration of the controls to exclude gender and menopausal variations. RESULTS: Many urinary steroids were up-regulated in all PTC patients compared to the controls. Among them, the levels of three active androgens, androstenedione, androstenediol and 16alpha-hydroxy DHEA, were significantly higher in the pre-menopausal women and men with PTC. The corticoid levels were increased slightly in the PTC men, while progestins were not altered in the post-menopausal PTC women. Estrogens were up regulated in all PTC patients but 2-hydroxyestrone and 2-hydroxy-17beta-estradiol were remarkably changed in both pre-menopausal women and men with PTC. For both menopausal and gender differences, the 2-hydroxylation, 4-hydroxylation, 2 methoxylation, and 4-methoxylation of estrogens and 16alpha-hydroxylation of DHEA were differentiated between pre- and post-menopausal PTC women (P < 0.001). In particular, the metabolic ratio of 2-hydroxyestrone to 2-hydroxy-17beta estradiol, which could reveal the enzyme activity of 17beta-hydroxysteroid dehydrogenase, showed gender differences in PTC patients (P < 1 * 10-7). CONCLUSIONS: These results are expected be helpful for better understanding the pathogenic differences in PTC according to gender and menopausal conditions. PMID- 21824402 TI - A computational approach to identify point mutations associated with occult hepatitis B: significant mutations affect coding regions but not regulative elements of HBV. AB - BACKGROUND: Occult Hepatitis B Infection (OBI) is characterized by absence of serum HBsAg and persistence of HBV-DNA in liver tissue, with low to undetectable serum HBV-DNA. The mechanisms underlying OBI remain to be clarified. To evaluate if specific point mutations of HBV genome may be associated with OBI, we applied an approach based on bioinformatics analysis of complete genome HBV sequences. In addition, the feasibility of bioinformatics prediction models to classify HBV infections into OBI and non-OBI by molecular data was evaluated. METHODS: 41 OBI and 162 non-OBI complete genome sequences were retrieved from GenBank, aligned and subjected to univariable analysis including statistical evaluation. Their S coding region was analyzed for Stop codon mutations too, while S amino acid variability could be evaluated for genotype D only, due to the too small number of available complete genome OBI sequences from other genotypes.Prediction models were derived by multivariable analysis using Logistic Regression, Rule Induction and Random Forest approaches, with extra-sample error estimation by Multiple ten fold Cross-Validation (MCV). Models were compared by t-test on the Area Under the Receiver Operating Characteristic curve (AUC) distributions obtained from the MCV runs for each model against the best-performing model. RESULTS: Variations in seven nucleotide positions were significantly associated with OBI, and occurred in 11 out of 41 OBI sequences (26.8%): likely, other mutations did not reach statistical significance due to the small size of OBI dataset. All variations affected at least one HBV coding region, but none of them mapped to regulative elements. All viral proteins, with the only exception of the X, were affected. Stop codons in the S, that might account for absence of serum HBsAg, were not significantly enriched in OBI sequences. In genotype D, amino acid variability in the S was higher in OBI than non-OBI, particularly in the immunodominant region. A Random Forest prediction model showed the best performance, but all models were not satisfactory in terms of specificity, due to the small sample size of OBIs; however results are promising in the perspective of a broader dataset of complete genome OBI sequences. CONCLUSIONS: Data suggest that point mutations rarely occur in regulative elements of HBV, if ever, and contribute to OBI by affecting different viral proteins, suggesting heterogeneous mechanisms may be responsible for OBI, including, at least in genotype D, an escape mutation mechanism due to imperfect immune control. It appears possible to derive prediction models based on molecular data when a larger set of complete genome OBI sequences will become available. PMID- 21824403 TI - A survey of schoolchildren's exposure to secondhand smoke in Malaysia. AB - BACKGROUND: There is a lack of data describing the exposure of Malaysian schoolchildren to Secondhand Smoke (SHS). The aim of this study is to identify factors influencing schoolchildren's exposures to SHS in Malaysia. METHOD: This cross-sectional study was carried out to measure salivary cotinine concentrations among 1064 schoolchildren (10-11 years) attending 24 schools in Malaysia following recent partial smoke-free restrictions. Parents completed questionnaires and schoolchildren provided saliva samples for cotinine assay. RESULTS: The geometric mean (GM) salivary cotinine concentrations for 947 non smoking schoolchildren stratified by household residents' smoking behaviour were: for children living with non-smoking parents 0.32 ng/ml (95% CI 0.28-0.37) (n = 446); for children living with a smoker father 0.65 ng/ml (95% CI 0.57-0.72) (n = 432); for children living with two smoking parents 1.12 ng/ml (95% CI 0.29-4.40) (n = 3); for children who live with an extended family member who smokes 0.62 ng/ml (95% CI 0.42-0.89) (n = 33) and for children living with two smokers (father and extended family member) 0.71 ng/ml (95% CI 0.40-0.97) (n = 44). Parental-reported SHS exposures showed poor agreement with children's self reported SHS exposures. Multiple linear regression demonstrated that cotinine levels were positively associated with living with one or more smokers, urban residence, occupation of father (Armed forces), parental-reported exposure to SHS and education of the father (Diploma/Technical certificate). CONCLUSIONS: This is the first study to characterise exposures to SHS using salivary cotinine concentrations among schoolchildren in Malaysia and also the first study documenting SHS exposure using salivary cotinine as a biomarker in a South-East Asian population of schoolchildren. Compared to other populations of similarly aged schoolchildren, Malaysian children have higher salivary cotinine concentrations. The partial nature of smoke-free restrictions in Malaysia is likely to contribute to these findings. Enforcement of existing legislation to reduce exposure in public place settings and interventions to reduce exposure at home, especially to implement effective home smoking restriction practices are required. PMID- 21824404 TI - Profiling and quantitative evaluation of three nickel-coated magnetic matrices for purification of recombinant proteins: helpful hints for the optimized nanomagnetisable matrix preparation. AB - BACKGROUND: Several materials are available in the market that work on the principle of protein magnetic fishing by their histidine (His) tags. Little information is available on their performance and it is often quoted that greatly improved purification of histidine-tagged proteins from crude extracts could be achieved. While some commercial magnetic matrices could be used successfully for purification of several His-tagged proteins, there are some which have been proved to operate just for a few extent of His-tagged proteins. Here, we address quantitative evaluation of three commercially available Nickel nanomagnetic beads for purification of two His-tagged proteins expressed in Escherichia coli and present helpful hints for optimized purification of such proteins and preparation of nanomagnetisable matrices. RESULTS: Marked differences in the performance of nanomagnetic matrices, principally on the basis of their specific binding capacity, recovery profile, the amount of imidazole needed for protein elution and the extent of target protein loss and purity were obtained. Based on the aforesaid criteria, one of these materials featured the best purification results (SiMAG/N-NTA/Nickel) for both proteins at the concentration of 4 mg/ml, while the other two (SiMAC-Nickel and SiMAG/CS-NTA/Nickel) did not work well with respect to specific binding capacity and recovery profile. CONCLUSIONS: Taken together, functionality of different types of nanomagnetic matrices vary considerably. This variability may not only be dependent upon the structure and surface chemistry of the matrix which in turn determine the affinity of interaction, but, is also influenced to a lesser extent by the physical properties of the protein itself. Although the results of the present study may not be fully applied for all nanomagnetic matrices, but provide a framework which could be used to profiling and quantitative evaluation of other magnetisable matrices and also provide helpful hints for those researchers facing same challenge. PMID- 21824405 TI - Technology-assisted education in graduate medical education: a review of the literature. AB - Studies on computer-aided instruction and web-based learning have left many questions unanswered about the most effective use of technology-assisted education in graduate medical education. OBJECTIVE: We conducted a review of the current medical literature to report the techniques, methods, frequency and effectiveness of technology-assisted education in graduate medical education. METHODS: A structured review of MEDLINE articles dealing with "Computer-Assisted Instruction," "Internet or World Wide Web," "Education" and "Medical" limited to articles published between 2002-2007 in the English language was performed. RESULTS: The two literature searches returned 679 articles; 184 met our inclusion and exclusion criteria. In 87 articles, effectiveness was measured primarily using self-reported results from a survey of subjects. Technology-assisted education was superior to traditional methods in 42 of the 64 direct comparison articles (66%, 95% CI 53-77%). Traditional teaching methods were superior to technology-assisted education in only 3/64 (5%, 95% CI 1-13%). The remaining 19 direct comparison articles showed no difference. A detailed review of the 64 comparative studies (technology-assisted education versus traditional teaching methods) also failed to identify a best method or best uses for technology assisted education. CONCLUSIONS: Technology-assisted education is used in graduate medical education across a variety of content areas and participant types. Knowledge gain was the predominant outcome measured. The majority of studies that directly compared knowledge gains in technology-assisted education to traditional teaching methods found technology-assisted education equal or superior to traditional teaching methods, though no "best methods" or "best use" was found within those studies. Only three articles were specific to Emergency Medicine, suggesting further research in our specialty is warranted. PMID- 21824406 TI - A genomic biomarker signature can predict skin sensitizers using a cell-based in vitro alternative to animal tests. AB - BACKGROUND: Allergic contact dermatitis is an inflammatory skin disease that affects a significant proportion of the population. This disease is caused by an adverse immune response towards chemical haptens, and leads to a substantial economic burden for society. Current test of sensitizing chemicals rely on animal experimentation. New legislations on the registration and use of chemicals within pharmaceutical and cosmetic industries have stimulated significant research efforts to develop alternative, human cell-based assays for the prediction of sensitization. The aim is to replace animal experiments with in vitro tests displaying a higher predictive power. RESULTS: We have developed a novel cell based assay for the prediction of sensitizing chemicals. By analyzing the transcriptome of the human cell line MUTZ-3 after 24 h stimulation, using 20 different sensitizing chemicals, 20 non-sensitizing chemicals and vehicle controls, we have identified a biomarker signature of 200 genes with potent discriminatory ability. Using a Support Vector Machine for supervised classification, the prediction performance of the assay revealed an area under the ROC curve of 0.98. In addition, categorizing the chemicals according to the LLNA assay, this gene signature could also predict sensitizing potency. The identified markers are involved in biological pathways with immunological relevant functions, which can shed light on the process of human sensitization. CONCLUSIONS: A gene signature predicting sensitization, using a human cell line in vitro, has been identified. This simple and robust cell-based assay has the potential to completely replace or drastically reduce the utilization of test systems based on experimental animals. Being based on human biology, the assay is proposed to be more accurate for predicting sensitization in humans, than the traditional animal-based tests. PMID- 21824407 TI - Self-assembly of copper and cobalt complexes with hierarchical size and catalytic properties for hydroxylation of phenol. AB - A feasible and effective self-assembly method to synthesize different scale coordination polymers in highly dilute solution (from nanocrystals to microcrystals and to bulk crystals) without any blocking agent has been described. The growth of crystalline particles was controlled by removing the particles at different reaction times to interrupt the growth at the desired size. The nano and microscale particles show better catalytic conversions and selectivities in the hydroxylation of phenols than the bulk crystals. PMID- 21824408 TI - Growth mechanism and magnon excitation in NiO nanowalls. AB - The nanosized effects of short-range multimagnon excitation behavior and short circuit diffusion in NiO nanowalls synthesized using the Ni grid thermal treatment method were observed. The energy dispersive spectroscopy mapping technique was used to characterize the growth mechanism, and confocal Raman scattering was used to probe the antiferromagnetic exchange energy J2 between next-nearest-neighboring Ni ions in NiO nanowalls at various growth temperatures below the Neel temperature. This study shows that short spin correlation leads to an exponential dependence of the growth temperatures and the existence of nickel vacancies during the magnon excitation. Four-magnon configurations were determined from the scattering factor, revealing a lowest state and monotonic change with the growth temperature.PACS: 75.47.Lx; 61.82.Rx; 75.50.Tt; 74.25.nd; 72.10.Di. PMID- 21824409 TI - BKM-react, an integrated biochemical reaction database. AB - BACKGROUND: The systematic, complete and correct reconstruction of genome-scale metabolic networks or metabolic pathways is one of the most challenging tasks in systems biology research. An essential requirement is the access to the complete biochemical knowledge - especially on the biochemical reactions. This knowledge is extracted from the scientific literature and collected in biological databases. Since the available databases differ in the number of biochemical reactions and the annotation of the reactions, an integrated knowledge resource would be of great value. RESULTS: We developed a comprehensive non-redundant reaction database containing known enzyme-catalyzed and spontaneous reactions. Currently, it comprises 18,172 unique biochemical reactions. As source databases the biochemical databases BRENDA, KEGG, and MetaCyc were used. Reactions of these databases were matched and integrated by aligning substrates and products. For the latter a two-step comparison using their structures (via InChIs) and names was performed. Each biochemical reaction given as a reaction equation occurring in at least one of the databases was included. CONCLUSIONS: An integrated non redundant reaction database has been developed and is made available to users. The database can significantly facilitate and accelerate the construction of accurate biochemical models. PMID- 21824410 TI - Changes in sexual desires and behaviours of people living with HIV after initiation of ART: implications for HIV prevention and health promotion. AB - BACKGROUND: As immune compromised HIV sero-positive people regain health after initiating antiretroviral treatment (ART), they may seek a return to an active 'normal' life, including sexual activity. The aim of the paper is to explore the changing sexual desires and behaviour of people on ART in Uganda over a 30 month period. METHODS: This study employed longitudinal qualitative interviews with forty people starting ART. The participants received their ART, adherence education and counselling support from The AIDS Support Organisation (TASO). The participants were selected sequentially as they started ART, stratified by sex, ART delivery mode (clinic or home-based) and HIV progression stage (early or advanced) and interviewed at enrolment, 3, 6, 18 and 30 months of their ART use. RESULTS: Sexual desire changed over time with many reporting diminished desire at 3 and 6 months on ART compared to 18 and 30 months of use. The reasons for remaining abstinent included fear of superinfection or infecting others, fear that engaging in sex would awaken the virus and weaken them and a desire to adhere to the counsellors' health advice to remain abstinent. The motivations for resumption of sexual activity were: for companionship, to obtain material support, social norms around marriage, desire to bear children as well as to satisfy sexual desires. The challenges for most of the participants were using condoms consistently and finding a suitable sexual partner (preferably someone with a similar HIV serostatus) who could agree to have a sexual relationship with them and provide for their material needs. CONCLUSIONS: These findings point to the importance of tailoring counselling messages to the changing realities of the ART users' cultural expectations around child bearing, marriage and sexual desire. People taking ART require support so they feel comfortable to disclose their HIV status to sexual partners. PMID- 21824411 TI - Heterologous production of active ribonuclease inhibitor in Escherichia coli by redox state control and chaperonin coexpression. AB - BACKGROUND: Eukaryotic Ribonuclease inhibitor (RI), belonging to the RNH1 family, is distinguished by unique features--a high sensitivity to oxidation due to the large number of reduced cysteins and a high hydrophobicity, which made most production approaches so far unsuccessful or resulted in very low yields. In this work efficient in vivo folding of native RI in the Escherichia coli cytoplasm was obtained by external addition of a reducing agent in tandem with oxygen limitation and overproduction of a molecular chaperonin. After optimisation of the production conditions in the shake flask scale the process was scaled up to high cell densities by applying a glucose limited fed-batch procedure. RESULTS: RI production in a T7 RNA polymerase based system results in accumulation of aggregated inactive product in inclusion bodies. Combination of addition of the reductant DTT, low production temperature and coexpression of the chaperonin GroELS resulted in high level production of approximately 25 mg g(-1) CDW active RI in E. coli ER2566 pET21b, corresponding to approximately 800 kU g(-1) cell wet weight. Further conditional screening under fed-batch-like conditions with the EnBase(r) technology and scale up into the bioreactor scale resulted in an efficient high cell density glucose and oxygen limited fed-batch process with a final cell dry weight of 25 g L(-1) and a total RI yield of app. 625 mg L(-1) (volumetric activity of 80,000 kU L(-1)). The E. coli based production constructs showed a very high robustness. The recombinant culture maintained its productivity despite the combination of the toxic growth conditions, the substrate limited production mode in tandem with a high level expression of several recombinant proteins, the set of molecular chaperonins and the target protein (RI). CONCLUSIONS: High level production of active RI in E. coli in a T7 RNA polymerase expression system depends on the following factors: (i) addition of a reducing agent, (ii) low production temperature, (iii) oxygen limitation, and (iii) co-overexpression of the chaperonin GroELS. The study indicates the strength of applying fed-batch cultivation techniques for the efficient optimisation of production factors already at the screening stage for fast and straight forward bioprocess development even for target proteins which show a complex folding behaviour. In our case none of the approaches alone would have resulted in significant accumulation of active RI. PMID- 21824412 TI - Differential expression of HIF-1alpha in CD44+CD24-/low breast ductal carcinomas. AB - BACKGROUND: Cancer stem cell (CSC) hypothesis postulates that tumors are maintained by a self-renewing CSC population that is also capable of differentiating into non-self-renewing cell populations that constitute the bulk of tumor. Stem cells renewal and differentiation can be directly influenced by the oxygen levels of determined tissues, probably by the reduction of oxidative DNA damage in hypoxic regions, thus leading to a friendlier microenvironment, regarding to clonal expansion and for resistance to chemotherapeutic regimens. Furthermore, there have been strong data indicating a pivotal role of hypoxic niche in cancer stem cells development. There are evidence that hypoxia could drive the maintenance of CSC, via HIF-1alpha expression, but it still to be determined whether hypoxia markers are expressed in breast tumors presenting CD44+CD24-/low immunophenotype. METHODS: Immunohistochemical analysis of CD44+CD24-/low expression and its relationship with hypoxia markers and clinical outcome were evaluated in 253 samples of breast ductal carcinomas. Double immunolabeling was performed using EnVision Doublestain System (Dako, Carpinteria, CA, USA). Slides were then scanned into high-resolution images using Aperio ScanScope XT and then, visualized in the software Image Scope (Aperio, Vista, CA, USA). RESULTS: In univariate analysis, CD44+CD24-/low expression showed association with death due to breast cancer (p = 0.035). Breast tumors expressing CD44+CD24-/low immunophenotype showed relationship with HIF-1alpha (p = 0.039) and negativity for HER-2 (p = 0.013). CONCLUSION: Considering that there are strong evidences that the fraction of a tumour considered to be cancer stem cells is plastic depending upon microenvironmental signals, our findings provide further evidence that hypoxia might be related to the worse prognosis found in CD44+CD24-/low positive breast tumors. PMID- 21824413 TI - The Chinese version of the Obsessive-Compulsive Inventory-Revised scale: replication and extension to non-clinical and clinical individuals with OCD symptoms. AB - BACKGROUND: The Obsessive-Compulsive Inventory-Revised (OCI-R) was designed to evaluate the severity of obsessive-compulsive symptoms in both clinical and non clinical samples. The aim of the study was to evaluate the psychometric properties of a Chinese version of this scale. METHODS: The Chinese version of the OCI-R was administered to both a non-clinical sample (209 undergraduate students) and a clinical sample (56 obsessive-compulsive disorder (OCD) patients). Confirmatory factor analysis was conducted to examine the construct validity of the OCI-R in the non-clinical sample. The internal consistency at baseline and test-retest reliabilities at 4-week interval was examined in both the non-clinical and clinical samples. RESULTS: The confirmatory factor analysis of the non-clinical sample confirmed a 6-factor model suggested by the original authors of the instrument (df = 120, RMSEA = 0.068, CFI = 0.88, NNFI = 0.85, GFI = 0.89). The internal consistency and test-retest reliability were at an acceptable range for both the non-clinical and clinical samples. The OCI-R also showed good clinical discrimination for patients with OCD from healthy controls. CONCLUSIONS: The Chinese version of the OCI-R is a valid and reliable instrument for measuring OCD symptoms in the Chinese context. PMID- 21824416 TI - Auricular squamous cell carcinoma. AB - Squamous cell carcinoma is a common cancer to the head and neck region that is typically diagnosed when it is 2 cm in size. This case report illustrates a patient who had neglected an auricular carcinoma for over a year. At the time of presentation the entire ear was infected with pseudomonas and yeast and chronic friability and bleeding caused an anemia which required blood transfusion. PMID- 21824414 TI - Complete genome and comparative analysis of Streptococcus gallolyticus subsp. gallolyticus, an emerging pathogen of infective endocarditis. AB - BACKGROUND: Streptococcus gallolyticus subsp. gallolyticus is an important causative agent of infectious endocarditis, while the pathogenicity of this species is widely unclear. To gain insight into the pathomechanisms and the underlying genetic elements for lateral gene transfer, we sequenced the entire genome of this pathogen. RESULTS: We sequenced the whole genome of S. gallolyticus subsp. gallolyticus strain ATCC BAA-2069, consisting of a 2,356,444 bp circular DNA molecule with a G+C-content of 37.65% and a novel 20,765 bp plasmid designated as pSGG1. Bioinformatic analysis predicted 2,309 ORFs and the presence of 80 tRNAs and 21 rRNAs in the chromosome. Furthermore, 21 ORFs were detected on the plasmid pSGG1, including tetracycline resistance genes telL and tet(O/W/32/O). Screening of 41 S. gallolyticus subsp. gallolyticus isolates revealed one plasmid (pSGG2) homologous to pSGG1. We further predicted 21 surface proteins containing the cell wall-sorting motif LPxTG, which were shown to play a functional role in the adhesion of bacteria to host cells. In addition, we performed a whole genome comparison to the recently sequenced S. gallolyticus subsp. gallolyticus strain UCN34, revealing significant differences. CONCLUSIONS: The analysis of the whole genome sequence of S. gallolyticus subsp. gallolyticus promotes understanding of genetic factors concerning the pathogenesis and adhesion to ECM of this pathogen. For the first time we detected the presence of the mobilizable pSGG1 plasmid, which may play a functional role in lateral gene transfer and promote a selective advantage due to a tetracycline resistance. PMID- 21824415 TI - The protocadherins, PCDHB1 and PCDH7, are regulated by MeCP2 in neuronal cells and brain tissues: implication for pathogenesis of Rett syndrome. AB - BACKGROUND: Rett syndrome is a neurodevelopmental and autistic disease caused by mutations of Methyl-CpG-binding protein 2 (MECP2) gene. MeCP2 protein is mainly expressed in neurons and binds to methylated gene promoters to suppress their expression, indicating that Rett syndrome is caused by the deregulation of target genes in neurons. However, it is likely that there are more unidentified neuronal MeCP2-targets associated with the neurological features of RTT. RESULTS: Using a genome-microarray approach, we found 22 genomic regions that contain sites potentially regulated by MeCP2 based on the features of MeCP2 binding, DNA methylation, and repressive histone modification in human cell lines. Within these regions, Chromatin immunoprecipitation (ChIP) analysis revealed that MeCP2 binds to the upstream regions of the protocadherin genes PCDHB1 and PCDH7 in human neuroblastoma SH-SY5Y cells. PCDHB1 and PCDH7 promoter activities were down regulated by MeCP2, but not by MBD-deleted MeCP2. These gene expression were up regulated following MeCP2 reduction with siRNA in SH-SY5Y cells and in the brains of Mecp2-null mice. Furthermore, PCDHB1 was up-regulated in postmortem brains from Rett syndrome patients. CONCLUSIONS: We identified MeCP2 target genes that encode neuronal adhesion molecules using ChIP-on-BAC array approach. Since these protocadherin genes are generally essential for brain development, aberrant regulation of these molecules may contribute to the pathogenesis of the neurological features observed in Rett syndrome. PMID- 21824417 TI - Strong differences in the clonal variation of two Daphnia species from mountain lakes affected by overwintering strategy. AB - BACKGROUND: The population structure of cyclical parthenogens such as water fleas is strongly influenced by the frequency of alternations between sexual and asexual (parthenogenetic) reproduction, which may differ among populations and species. We studied genetic variation within six populations of two closely related species of water fleas of the genus Daphnia (Crustacea, Cladocera). D. galeata and D. longispina both occur in lakes in the Tatra Mountains (Central Europe), but their populations show distinct life history strategies in that region. In three studied lakes inhabited by D. galeata, daphnids overwinter under the ice as adult females. In contrast, in lakes inhabited by D. longispina, populations apparently disappear from the water column and overwinter as dormant eggs in lake sediments. We investigated to what extent these different strategies lead to differences in the clonal composition of late summer populations. RESULTS: Analysis of genetic variation at nine microsatellite loci revealed that clonal richness (expressed as the proportion of different multilocus genotypes, MLGs, in the whole analysed sample) consistently differed between the two studied species. In the three D. longispina populations, very high clonal richness was found (MLG/N ranging from 0.97 to 1.00), whereas in D. galeata it was much lower (0.05 to 0.50). The dominant MLGs in all D. galeata populations were heterozygous at five or more loci, suggesting that such individuals all represented the same clonal lineages rather than insufficiently resolved groups of different clones. CONCLUSIONS: The low clonal diversities and significant deviations from Hardy Weinberg equilibrium in D. galeata populations were likely a consequence of strong clonal erosion over extended periods of time (several years or even decades) and the limited influence of sexual reproduction. Our data reveal that populations of closely related Daphnia species living in relatively similar habitats (permanent, oligotrophic mountain lakes) within the same region may show strikingly different genetic structures, which most likely depend on their reproductive strategy during unfavourable periods. We assume that similar impacts of life history on population structures are also relevant for other cyclical parthenogen groups. In extreme cases, prolonged clonal erosion may result in the dominance of a single clone within a population, which might limit its microevolutionary potential if selection pressures suddenly change. PMID- 21824418 TI - On the quest for selective constraints shaping the expressivity of the genes casting retropseudogenes in human. AB - BACKGROUND: Pseudogenes, the nonfunctional homologues of functional genes are now coming to light as important resources regarding the study of human protein evolution. Processed pseudogenes arising by reverse transcription and reinsertion can provide molecular record on the dynamics and evolution of genomes. Researches on the progenitors of human processed pseudogenes delved out their highly expressed and evolutionarily conserved characters. They are reported to be short and GC-poor indicating their high efficiency for retrotransposition. In this article we focused on their high expressivity and explored the factors contributing for that and their relevance in the milieu of protein sequence evolution. RESULTS: We here, analyzed the high expressivity of these genes configuring processed or retropseudogenes by their immense connectivity in protein-protein interaction network, an inclination towards alternative splicing mechanism, a lower rate of mRNA disintegration and a slower evolutionary rate. While the unusual trend of the upraised disorder in contrast with the high expressivity of the proteins encoded by processed pseudogene ancestors is accredited by a predominance of hub-protein encoding genes, a high propensity of repeat sequence containing genes, elevated protein stability and the functional constraint to perform the transcription regulatory jobs. Linear regression analysis demonstrates mRNA decay rate and protein intrinsic disorder as the influential factors controlling the expressivity of these retropseudogene ancestors while the latter one is found to have the most significant regulatory power. CONCLUSIONS: Our findings imply that, the affluence of disordered regions elevating the network attachment to be involved in important cellular assignments and the stability in transcriptional level are acting as the prevailing forces behind the high expressivity of the human genes configuring processed pseudogenes. PMID- 21824419 TI - Response to: Pre-referral rectal artesunate in severe malaria: a flawed trial. AB - A response to and comment on Pre-referral rectal artesunate in severe malaria: a flawed trial, by Karim F Hirji and Zulfiqarali G Premji. PMID- 21824420 TI - Managing daily intensive care activities: an observational study concerning ad hoc decision making of charge nurses and intensivists. AB - INTRODUCTION: Management of daily activities in ICUs is challenging. ICU shift leaders, charge nurses and intensivists have to make several immediate ad hoc decisions to enable the fluent flow of ICU activities. Even though the management of ICU activities is quite well delineated by international consensus guidelines, we know only a little about the content of the real clinical decision making of ICU shift leaders. METHODS: We conducted an observational study with the think aloud technique to describe the ad hoc decision making of ICU shift leaders. The study was performed in two university-affiliated hospital ICUs. Twelve charge nurses and eight intensivists were recruited. Observations were recorded and transcribed for qualitative content analysis using the protocol analysis method. The software program NVivo 7 was used to manage the data. The interrater agreement was assessed with percentages and by Cohen's kappa. RESULTS: We identified 463 ad hoc decisions made by the charge nurses and 444 made by the intensivists. During our data collection time, this breaks down to over 230 immediately made decisions per day (24 hours). We divided the ad hoc decision making of ICU shift leaders into two types: process-focused and situation focused. Process-focused decision making included more permanent information, such as human resources, know-how and material resources, whereas situation focused decision making included decisions about single events, such as patient admission. We named eight different categories for ICU ad hoc decision making: (1) adverse events, (2) diagnostics, (3) human resources and know-how, (4) material resources, (5) patient admission, (6) patient discharge, (7) patient information and vital signs and (8) special treatments. CONCLUSIONS: ICU shift leaders make a great number of complex ad hoc decisions throughout the day. Often this decision making involves both intensivists and charge nurses. It forms a bundle that requires versatile, immediate information for a successful outcome. In the future, we need to investigate which information is crucial for ad hoc decision making. These challenges should also be emphasised when information technology programs for ICU care management are developed. PMID- 21824421 TI - Can an online clinical data management service help in improving data collection and data quality in a developing country setting? AB - BACKGROUND: Data collection by electronic medical record (EMR) systems have been proven to be helpful in data collection for scientific research and in improving healthcare. For a multi-centre trial in Indonesia and the Netherlands a web based system was selected to enable all participating centres to easily access data. This study assesses whether the introduction of a clinical trial data management service (CTDMS) composed of electronic case report forms (eCRF) can result in effective data collection and treatment monitoring. METHODS: Data items entered were checked for inconsistencies automatically when submitted online. The data were divided into primary and secondary data items. We analysed both the total number of errors and the change in error rate, for both primary and secondary items, over the first five month of the trial. RESULTS: In the first five months 51 patients were entered. The primary data error rate was 1.6%, whilst that for secondary data was 2.7% against acceptable error rates for analysis of 1% and 2.5% respectively. CONCLUSION: The presented analysis shows that after five months since the introduction of the CTDMS the primary and secondary data error rates reflect acceptable levels of data quality. Furthermore, these error rates were decreasing over time. The digital nature of the CTDMS, as well as the online availability of that data, gives fast and easy insight in adherence to treatment protocols. As such, the CTDMS can serve as a tool to train and educate medical doctors and can improve treatment protocols. PMID- 21824422 TI - Detection of HIV-1 dual infections in highly exposed treated patients. AB - BACKGROUND: Genetic characterization of HIV-1 in Argentina has shown that BF recombinants predominate among heterosexuals and injecting drug users, while in men who have sex with men the most prevalent form is subtype B. OBJECTIVES: The aim of this work was to investigate the presence of HIV dual infections in HIV infected individuals with high probability of reinfection STUDY DESIGN: Blood samples were collected from 23 HIV positive patients with the risk of reinfection from Buenos Aires. A fragment of the HIV gene pol was amplified and phylogenetic analyses were performed. Antiretroviral drug resistance patterns of all the sequences were analyzed. RESULTS: Five dual infections were detected with four patients coinfected with subtype B and BF recombinants and one patient was coinfected with two BF recombinants presenting different recombination patterns. Prolonged infection with a stable clinical condition was observed in the five individuals. Resistance mutation patterns were different between the predominant and the minority strains. CONCLUSIONS: Our results show that HIV dual infection can occur with closely related subtypes, and even with different variants of the same recombinant form in certain populations. Clinical observations showed neither aggressive disease progression nor impact on the resistance patterns in the dually-infected patients. PMID- 21824423 TI - BLAST Ring Image Generator (BRIG): simple prokaryote genome comparisons. AB - BACKGROUND: Visualisation of genome comparisons is invaluable for helping to determine genotypic differences between closely related prokaryotes. New visualisation and abstraction methods are required in order to improve the validation, interpretation and communication of genome sequence information; especially with the increasing amount of data arising from next-generation sequencing projects. Visualising a prokaryote genome as a circular image has become a powerful means of displaying informative comparisons of one genome to a number of others. Several programs, imaging libraries and internet resources already exist for this purpose, however, most are either limited in the number of comparisons they can show, are unable to adequately utilise draft genome sequence data, or require a knowledge of command-line scripting for implementation. Currently, there is no freely available desktop application that enables users to rapidly visualise comparisons between hundreds of draft or complete genomes in a single image. RESULTS: BLAST Ring Image Generator (BRIG) can generate images that show multiple prokaryote genome comparisons, without an arbitrary limit on the number of genomes compared. The output image shows similarity between a central reference sequence and other sequences as a set of concentric rings, where BLAST matches are coloured on a sliding scale indicating a defined percentage identity. Images can also include draft genome assembly information to show read coverage, assembly breakpoints and collapsed repeats. In addition, BRIG supports the mapping of unassembled sequencing reads against one or more central reference sequences. Many types of custom data and annotations can be shown using BRIG, making it a versatile approach for visualising a range of genomic comparison data. BRIG is readily accessible to any user, as it assumes no specialist computational knowledge and will perform all required file parsing and BLAST comparisons automatically. CONCLUSIONS: There is a clear need for a user-friendly program that can produce genome comparisons for a large number of prokaryote genomes with an emphasis on rapidly utilising unfinished or unassembled genome data. Here we present BRIG, a cross-platform application that enables the interactive generation of comparative genomic images via a simple graphical-user interface. BRIG is freely available for all operating systems at http://sourceforge.net/projects/brig/. PMID- 21824424 TI - Context-based FISH localization of genomic rearrangements within chromosome 15q11.2q13 duplicons. AB - BACKGROUND: Segmental duplicons (SDs) predispose to an increased frequency of chromosomal rearrangements. These rearrangements can cause a diverse range of phenotypes due to haploinsufficiency, in cis positional effects or gene interruption. Genomic microarray analysis has revealed gene dosage changes adjacent to duplicons, but the high degree of similarity between duplicon sequences has confounded unequivocal assignment of chromosome breakpoints within these intervals. In this study, we localize rearrangements within duplicon enriched regions of Angelman/Prader-Willi (AS/PWS) syndrome chromosomal deletions with fluorescence in situ hybridization (FISH). RESULTS: Breakage intervals in AS deletions were localized recursively with short, coordinate-defined, single copy (SC) and low copy (LC) genomic FISH probes. These probes were initially coincident with duplicons and regions of previously reported breakage in AS/PWS. Subsequently, probes developed from adjacent genomic intervals more precisely delineated deletion breakage intervals involving genes, pseudogenes and duplicons in 15q11.2q13. The observed variability in the deletion boundaries within previously described Class I and Class II deletion AS samples is related to the local genomic architecture in this chromosomal region. CONCLUSIONS: Chromosome 15 abnormalities associated with SDs were precisely delineated at a resolution equivalent to genomic Southern analysis. This context-dependent approach can define the boundaries of chromosome rearrangements for other genomic disorders associated with SDs. PMID- 21824425 TI - Troponin elevation in acute ischemic stroke (TRELAS)--protocol of a prospective observational trial. AB - BACKGROUND: Levels of the cardiac muscle regulatory protein troponin T (cTnT) are frequently elevated in patients with acute ischemic stroke and elevated cTnT predicts poor outcome and mortality. The pathomechanism of troponin release may relate to co-morbid coronary artery disease and myocardial ischemia or, alternatively, to neurogenic cardiac damage due to autonomic activation after acute ischemic stroke. Therefore, there is uncertainty about how acute ischemic stroke patients with increased cTnT levels should be managed regarding diagnostic and therapeutic workup. METHODS/DESIGN: The primary objective of the prospective observational trial TRELAS (TRoponin ELevation in Acute ischemic Stroke) is to investigate the frequency and underlying pathomechanism of cTnT elevation in acute ischemic stroke patients in order to give guidance for clinical practice. All consecutive patients with acute ischemic stroke admitted within 72 hours after symptom onset to the Department of Neurology at the Campus Benjamin Franklin of the University Hospital Charite will be screened for cTnT elevations (i.e. >= 0.05 MUg/l) on admission and again on the following day. Patients with increased cTnT will undergo coronary angiography within 72 hours. Diagnostic findings of coronary angiograms will be compared with age- and gender-matched patients presenting with Non-ST-Elevation myocardial infarction to the Department of Cardiology. The primary endpoint of the study will be the occurrence of culprit lesions in the coronary angiogram indicating underlying co-morbid obstructive coronary artery disease. Secondary endpoints will be the localization of stroke in the cerebral imaging and left ventriculographic findings of wall motion abnormalities suggestive of stroke-induced global cardiac dysfunction. DISCUSSION: TRELAS will prospectively determine the frequency and possible etiology of troponin elevation in a large cohort of ischemic stroke patients. The findings are expected to contribute to clarify pathophysiologic concepts of co morbid cardiac damage in ischemic stroke patients and also to provide a basis for clinical recommendations for cardiac workup of such patients. TRIAL REGISTRATION: clinicaltrials.gov NCT01263964. PMID- 21824426 TI - NETGEM: Network Embedded Temporal GEnerative Model for gene expression data. AB - BACKGROUND: Temporal analysis of gene expression data has been limited to identifying genes whose expression varies with time and/or correlation between genes that have similar temporal profiles. Often, the methods do not consider the underlying network constraints that connect the genes. It is becoming increasingly evident that interactions change substantially with time. Thus far, there is no systematic method to relate the temporal changes in gene expression to the dynamics of interactions between them. Information on interaction dynamics would open up possibilities for discovering new mechanisms of regulation by providing valuable insight into identifying time-sensitive interactions as well as permit studies on the effect of a genetic perturbation. RESULTS: We present NETGEM, a tractable model rooted in Markov dynamics, for analyzing the dynamics of the interactions between proteins based on the dynamics of the expression changes of the genes that encode them. The model treats the interaction strengths as random variables which are modulated by suitable priors. This approach is necessitated by the extremely small sample size of the datasets, relative to the number of interactions. The model is amenable to a linear time algorithm for efficient inference. Using temporal gene expression data, NETGEM was successful in identifying (i) temporal interactions and determining their strength, (ii) functional categories of the actively interacting partners and (iii) dynamics of interactions in perturbed networks. CONCLUSIONS: NETGEM represents an optimal trade-off between model complexity and data requirement. It was able to deduce actively interacting genes and functional categories from temporal gene expression data. It permits inference by incorporating the information available in perturbed networks. Given that the inputs to NETGEM are only the network and the temporal variation of the nodes, this algorithm promises to have widespread applications, beyond biological systems.The source code for NETGEM is available from https://github.com/vjethava/NETGEM. PMID- 21824427 TI - Integrative network analysis identifies key genes and pathways in the progression of hepatitis C virus induced hepatocellular carcinoma. AB - BACKGROUND: Incidence of hepatitis C virus (HCV) induced hepatocellular carcinoma (HCC) has been increasing in the United States and Europe during recent years. Although HCV-associated HCC shares many pathological characteristics with other types of HCC, its molecular mechanisms of progression remain elusive. METHODS: To investigate the underlying pathology, we developed a systematic approach to identify deregulated biological networks in HCC by integrating gene expression profiles with high-throughput protein-protein interaction data. We examined five stages including normal (control) liver, cirrhotic liver, dysplasia, early HCC and advanced HCC. RESULTS: Among the five consecutive pathological stages, we identified four networks including precancerous networks (Normal-Cirrhosis and Cirrhosis-Dysplasia) and cancerous networks (Dysplasia-Early HCC, Early-Advanced HCC). We found little overlap between precancerous and cancerous networks, opposite to a substantial overlap within precancerous or cancerous networks. We further found that the hub proteins interacted with HCV proteins, suggesting direct interventions of these networks by the virus. The functional annotation of each network demonstrates a high degree of consistency with current knowledge in HCC. By assembling these functions into a module map, we could depict the stepwise biological functions that are deregulated in HCV-induced hepatocarcinogenesis. Additionally, these networks enable us to identify important genes and pathways by developmental stage, such as LCK signalling pathways in cirrhosis, MMP genes and TIMP genes in dysplastic liver, and CDC2 mediated cell cycle signalling in early and advanced HCC. CDC2 (alternative symbol CDK1), a cell cycle regulatory gene, is particularly interesting due to its topological position in temporally deregulated networks. CONCLUSIONS: Our study uncovers a temporal spectrum of functional deregulation and prioritizes key genes and pathways in the progression of HCV induced HCC. These findings present a wealth of information for further investigation. PMID- 21824428 TI - Serum neuron-specific enolase as predictor of outcome in comatose cardiac-arrest survivors: a prospective cohort study. AB - BACKGROUND: The prediction of neurological outcome in comatose patients after cardiac arrest has major ethical and socioeconomic implications. The purpose of this study was to assess the capability of serum neuron-specific enolase (NSE), a biomarker of hypoxic brain damage, to predict death or vegetative state in comatose cardiac-arrest survivors. METHODS: We conducted a prospective observational cohort study in one university hospital and one general hospital Intensive Care Unit (ICU). All consecutive patients who suffered cardiac arrest and were subsequently admitted from June 2007 to February 2009 were considered for inclusion in the study. Patients who died or awoke within the first 48 hours of admission were excluded from the analysis. Patients were followed for 3 months or until death after cardiopulmonary resuscitation. The Cerebral Performance Categories scale (CPC) was used as the outcome measure; a CPC of 4-5 was regarded as a poor outcome, and a CPC of 1-3 a good outcome. Measurement of serum NSE was performed at 24 h and at 72 h after the time of cardiac arrest using an enzyme immunoassay. Clinicians were blinded to NSE results. RESULTS: Ninety-seven patients were included. All patients were actively supported during the first days following cardiac arrest. Sixty-five patients (67%) underwent cooling after resuscitation. At 3 months 72 (74%) patients had a poor outcome (CPC 4-5) and 25 (26%) a good outcome (CPC 1-3). The median and Interquartile Range [IQR] levels of NSE at 24 h and at 72 h were significantly higher in patients with poor outcomes: NSE at 24 h: 59.4 ng/mL [37-106] versus 28.8 ng/mL [18-41] (p < 0.0001); and NSE at 72 h: 129.5 ng/mL [40-247] versus 15.7 ng/mL [12-19] (p < 0.0001). The Receiver Operator Characteristics (ROC) curve for poor outcome for the highest observed NSE value for each patient determined a cut-off value for NSE of 97 ng/mL to predict a poor neurological outcome with a specificity of 100% [95% CI = 87-100] and a sensitivity of 49% [95% CI = 37-60]. However, an approach based on a combination of SSEPs, NSE and clinical-EEG tests allowed to increase the number of patients (63/72 (88%)) identified as having a poor outcome and for whom intensive treatment could be regarded as futile. CONCLUSION: NSE levels measured early in the course of patient care for those who remained comatose after cardiac arrest were significantly higher in patients with outcomes of death or vegetative state. In addition, we provide a cut-off value for NSE (> 97 ng/mL) with 100% positive predictive value of poor outcome. Nevertheless, for decisions concerning the continuation of treatment in this setting, we emphasize that an approach based on a combination of SSEPs, NSE and clinical EEG would be more accurate for identifying patients with a poor neurological outcome. PMID- 21824429 TI - Prescribing patterns in dementia: a multicentre observational study in a German network of CAM physicians. AB - BACKGROUND: Dementia is a major and increasing health problem worldwide. This study aims to investigate dementia treatment strategies among physicians specialised in complementary and alternative medicine (CAM) by analysing prescribing patterns and comparing them to current treatment guidelines in Germany. METHODS: Twenty-two primary care physicians in Germany participated in this prospective, multicentre observational study. Prescriptions and diagnoses were reported for each consecutive patient. Data were included if patients had at least one diagnosis of dementia according to the 10th revision of the International Classification of Diseases during the study period. Multiple logistic regression was used to determine factors associated with a prescription of any anti-dementia drug including Ginkgo biloba. RESULTS: During the 5-year study period (2004-2008), 577 patients with dementia were included (median age: 81 years (IQR: 74-87); 69% female). Dementia was classified as unspecified dementia (57.2%), vascular dementia (25.1%), dementia in Alzheimer's disease (10.4%), and dementia in Parkinson's disease (7.3%). The prevalence of anti dementia drugs was 25.6%. The phytopharmaceutical Ginkgo biloba was the most frequently prescribed anti-dementia drug overall (67.6% of all) followed by cholinesterase inhibitors (17.6%). The adjusted odds ratio (AOR) for receiving any anti-dementia drug was greater than 1 for neurologists (AOR = 2.34; CI: 1.59 3.47), the diagnosis of Alzheimer's disease (AOR = 3.28; CI: 1.96-5.50), neuroleptic therapy (AOR = 1.87; CI: 1.22-2.88), co-morbidities hypertension (AOR = 2.03; CI: 1.41-2.90), and heart failure (AOR = 4.85; CI: 3.42-6.88). The chance for a prescription of any anti-dementia drug decreased with the diagnosis of vascular dementia (AOR = 0.64; CI: 0.43-0.95) and diabetes mellitus (AOR = 0.55; CI: 0.36-0.86). The prescription of Ginkgo biloba was associated with sex (female: AOR = 0.41; CI: 0.19-0.89), patient age (AOR = 1.06; CI: 1.02-1.10), treatment by a neurologist (AOR = 0.09; CI: 0.03-0.23), and the diagnosis of Alzheimer's disease (AOR = 0.07; CI: 0.04-0.16). CONCLUSIONS: This study provides a comprehensive analysis of everyday practice for treatment of dementia in primary care in physicians with a focus on CAM. The prescribing frequency for anti-dementia drugs is equivalent to those found in other German studies, while the administration of Ginkgo biloba is significantly higher. PMID- 21824430 TI - Multiple search methods for similarity-based virtual screening: analysis of search overlap and precision. AB - BACKGROUND: Data fusion methods are widely used in virtual screening, and make the implicit assumption that the more often a molecule is retrieved in multiple similarity searches, the more likely it is to be active. This paper tests the correctness of this assumption. RESULTS: Sets of 25 searches using either the same reference structure and 25 different similarity measures (similarity fusion) or 25 different reference structures and the same similarity measure (group fusion) show that large numbers of unique molecules are retrieved by just a single search, but that the numbers of unique molecules decrease very rapidly as more searches are considered. This rapid decrease is accompanied by a rapid increase in the fraction of those retrieved molecules that are active. There is an approximately log-log relationship between the numbers of different molecules retrieved and the number of searches carried out, and a rationale for this power law behaviour is provided. CONCLUSIONS: Using multiple searches provides a simple way of increasing the precision of a similarity search, and thus provides a justification for the use of data fusion methods in virtual screening. PMID- 21824432 TI - Structural diversity of biologically interesting datasets: a scaffold analysis approach. AB - BACKGROUND: The recent public availability of the human metabolome and natural product datasets has revitalized "metabolite-likeness" and "natural product likeness" as a drug design concept to design lead libraries targeting specific pathways. Many reports have analyzed the physicochemical property space of biologically important datasets, with only a few comprehensively characterizing the scaffold diversity in public datasets of biological interest. With large collections of high quality public data currently available, we carried out a comparative analysis of current day leads with other biologically relevant datasets. RESULTS: In this study, we note a two-fold enrichment of metabolite scaffolds in drug dataset (42%) as compared to currently used lead libraries (23%). We also note that only a small percentage (5%) of natural product scaffolds space is shared by the lead dataset. We have identified specific scaffolds that are present in metabolites and natural products, with close counterparts in the drugs, but are missing in the lead dataset. To determine the distribution of compounds in physicochemical property space we analyzed the molecular polar surface area, the molecular solubility, the number of rings and the number of rotatable bonds in addition to four well-known Lipinski properties. Here, we note that, with only few exceptions, most of the drugs follow Lipinski's rule. The average values of the molecular polar surface area and the molecular solubility in metabolites is the highest while the number of rings is the lowest. In addition, we note that natural products contain the maximum number of rings and the rotatable bonds than any other dataset under consideration. CONCLUSIONS: Currently used lead libraries make little use of the metabolites and natural products scaffold space. We believe that metabolites and natural products are recognized by at least one protein in the biosphere therefore, sampling the fragment and scaffold space of these compounds, along with the knowledge of distribution in physicochemical property space, can result in better lead libraries. Hence, we recommend the greater use of metabolites and natural products while designing lead libraries. Nevertheless, metabolites have a limited distribution in chemical space that limits the usage of metabolites in library design. PMID- 21824431 TI - Understanding the impact of 1q21.1 copy number variant. AB - BACKGROUND: 1q21.1 Copy Number Variant (CNV) is associated with a highly variable phenotype ranging from congenital anomalies, learning deficits/intellectual disability (ID), to a normal phenotype. Hence, the clinical significance of this CNV can be difficult to evaluate. Here we described the consequences of the 1q21.1 CNV on genome-wide gene expression and function of selected candidate genes within 1q21.1 using cell lines from clinically well described subjects. METHODS AND RESULTS: Eight subjects from 3 families were included in the study: six with a 1q21.1 deletion and two with a 1q21.1 duplication. High resolution Affymetrix 2.7M array was used to refine the 1q21.1 CNV breakpoints and exclude the presence of secondary CNVs of pathogenic relevance. Whole genome expression profiling, studied in lymphoblast cell lines (LBCs) from 5 subjects, showed enrichment of genes from 1q21.1 in the top 100 genes ranked based on correlation of expression with 1q21.1 copy number. The function of two top genes from 1q21.1, CHD1L/ALC1 and PRKAB2, was studied in detail in LBCs from a deletion and a duplication carrier. CHD1L/ALC1 is an enzyme with a role in chromatin modification and DNA damage response while PRKAB2 is a member of the AMP kinase complex, which senses and maintains systemic and cellular energy balance. The protein levels for CHD1L/ALC1 and PRKAB2 were changed in concordance with their copy number in both LBCs. A defect in chromatin remodeling was documented based on impaired decatenation (chromatid untangling) checkpoint (DCC) in both LBCs. This defect, reproduced by CHD1L/ALC1 siRNA, identifies a new role of CHD1L/ALC1 in DCC. Both LBCs also showed elevated levels of micronuclei following treatment with a Topoisomerase II inhibitor suggesting increased DNA breaks. AMP kinase function, specifically in the deletion containing LBCs, was attenuated. CONCLUSION: Our studies are unique as they show for the first time that the 1q21.1 CNV not only causes changes in the expression of its key integral genes, associated with changes at the protein level, but also results in changes in their known function, in the case of AMPK, and newly identified function such as DCC activation in the case of CHD1L/ALC1. Our results support the use of patient lymphoblasts for dissecting the functional sequelae of genes integral to CNVs in carrier cell lines, ultimately enhancing understanding of biological processes which may contribute to the clinical phenotype. PMID- 21824433 TI - The mosaicism of plasmids revealed by atypical genes detection and analysis. AB - BACKGROUND: From an evolutionary viewpoint, prokaryotic genomes are extremely plastic and dynamic, since large amounts of genetic material are continuously added and/or lost through promiscuous gene exchange. In this picture, plasmids play a key role, since they can be transferred between different cells and, through genetic rearrangement(s), undergo gene(s) load, leading, in turn, to the appearance of important metabolic innovations that might be relevant for cell life. Despite their central position in bacterial evolution, a massive analysis of newly acquired functional blocks [likely the result of horizontal gene transfer (HGT) events] residing on plasmids is still missing. RESULTS: We have developed a computational, composition-based, pipeline to scan almost 2000 plasmids for genes that differ significantly from their hosting molecule. Plasmids atypical genes (PAGs) were about 6% of the total plasmids ORFs and, on average, each plasmid possessed 4.4 atypical genes. Nevertheless, conjugative plasmids were shown to possess an amount of atypical genes than that found in not mobilizable plasmids, providing strong support for the central role suggested for conjugative plasmids in the context of HGT. Part of the retrieved PAGs are organized into (mainly short) clusters and are involved in important biological processes (detoxification, antibiotic resistance, virulence), revealing the importance of HGT in the spreading of metabolic pathways within the whole microbial community. Lastly, our analysis revealed that PAGs mainly derive from other plasmid (rather than coming from phages and/or chromosomes), suggesting that plasmid-plasmid DNA exchange might be the primary source of metabolic innovations in this class of mobile genetic elements. CONCLUSIONS: In this work we have performed the first large scale analysis of atypical genes that reside on plasmid molecules to date. Our findings on PAGs function, organization, distribution and spreading reveal the importance of plasmids-mediated HGT within the complex bacterial evolutionary network and in the dissemination of important biological traits. PMID- 21824434 TI - In silico predicted epitopes from the COOH-terminal extension of cysteine proteinase B inducing distinct immune responses during Leishmania (Leishmania) amazonensis experimental murine infection. AB - BACKGROUND: Leishmania parasites have been reported to interfere and even subvert their host immune responses to enhance their chances of survival and proliferation. Experimental Leishmania infection in mice has been widely used in the identification of specific parasite virulence factors involved in the interaction with the host immune system. Cysteine-proteinase B (CPB) is an important virulence factor in parasites from the Leishmania (Leishmania) mexicana complex: it inhibits lymphocytes Th1 and/or promotes Th2 responses either through proteolytic activity or through epitopes derived from its COOH-terminal extension. In the present study we analyzed the effects of Leishmania (Leishmania) amazonensis CPB COOH-terminal extension-derived peptides on cell cultures from murine strains with distinct levels of susceptibility to infection: BALB/c, highly susceptible, and CBA, mildly resistant. RESULTS: Predicted epitopes, obtained by in silico mapping, displayed the ability to induce cell proliferation and expression of cytokines related to Th1 and Th2 responses. Furthermore, we applied in silico simulations to investigate how the MHC/epitopes interactions could be related to the immunomodulatory effects on cytokines, finding evidence that specific interaction patterns can be related to in vitro activities. CONCLUSIONS: Based on our results, we consider that some peptides from the CPB COOH-terminal extension may influence host immune responses in the murine infection, thus helping Leishmania survival. PMID- 21824435 TI - Tropically stable novel oral lipid formulation of amphotericin B (iCo-010): biodistribution and toxicity in a mouse model. AB - BACKGROUND: The purpose of this study was to evaluate the biodistribution and toxicity of amphotericin B (AmB) following multiple oral administrations of a novel tropically stable lipid-based formulation (iCo-010). METHODS: BALB/c mice were allocated into six groups: oral iCo-010 twice daily for 5 days in the dose of 20, 10, 5 and 2.5 mg/kg; vehicle control; and intravenous boluses of Fungizone 2 mg/kg once daily for 5 days. The animals were sacrificed 12 h following the last administration and blood and tissues were collected. RESULTS: The plasma concentrations of AmB were similar to previously reported after administration of iCo-009. Somewhat lower concentrations of AmB were detected in reticulo endothelial system in the case of iCo-010 when compared with iCo-009. The concentration in kidney was higher with iCo-010 than with iCo-009. The creatinine levels in all oral treatment groups were in a normal range as in the case of iCo 009. Administration of Fungizone resulted in elevated plasma creatinine levels. Histopathology analysis detected no GI, liver or kidney toxicity following multiple dose oral administration of iCo-010. Fungizone treatment induced necrotic changes in hepatic and kidney tissues. CONCLUSIONS: Given the tropical stability of iCo-010, near identical activity against visceral leishmaniasis and significant concentrations in target organs this formulation has a potential to become a treatment of choice in tropical developing countries. PMID- 21824436 TI - Differential gene expression in male and female rainbow trout embryos prior to the onset of gross morphological differentiation of the gonads. AB - BACKGROUND: There are large differences between the sexes at the genetic level; these differences include heterogametic sex chromosomes and/or differences in expression of genes between the sexes. In rainbow trout (Oncorhynchus mykiss) qRT PCR studies have found significant differences in expression of several candidate sex determining genes. However, these genes represent a very small fraction of the genome and research in other species suggests there are large portions of the transcriptome that are differentially expressed between the sexes. These differences are especially noticeable once gonad differentiation and maturation has occurred, but less is known at earlier stages of development. Here we use data from a microarray and qRT-PCR to identify genes differentially expressed between the sexes at three time points in pre-hatch embryos, prior to the known timing of sexual differentiation in this species. RESULTS: The microarray study revealed 883 differentially expressed features between the sexes with roughly equal numbers of male and female upregulated features across time points. Most of the differentially expressed genes on the microarray were not related to sex function, suggesting large scale differences in gene expression between the sexes are present early in development. Candidate gene analysis revealed sox9, DMRT1, Nr5a1 and wt1 were upregulated in males at some time points and foxl2, ovol1, fst and cyp19a1a were upregulated in females at some time points. CONCLUSION: This is the first study to identify sexual dimorphism in expression of the genome during embryogenesis in any fish and demonstrates that transcriptional differences are present before the completion of gonadogenesis. PMID- 21824437 TI - Mesenchymal stem cell transplantation ameliorates motor function deterioration of spinocerebellar ataxia by rescuing cerebellar Purkinje cells. AB - BACKGROUND: Spinocerebellar ataxia (SCA) refers to a disease entity in which polyglutamine aggregates are over-produced in Purkinje cells (PCs) of the cerebellum as well as other neurons in the central nervous system, and the formation of intracellular polyglutamine aggregates result in the loss of neurons as well as deterioration of motor functions. So far there is no effective neuroprotective treatment for this debilitating disease although numerous efforts have been made. Mesenchymal stem cells (MSCs) possess multi-lineage differentiation potentials as well as immuno-modulatory properties, and are theoretically good candidates for SCA treatment. The purpose of this study is to investigate whether transplantation of human MSCs (hMSCs) can rescue cerebellar PCs and ameliorate motor function deterioration in SCA in a pre-clinical animal model. METHOD: Transgenic mice bearing poly-glutamine mutation in ataxin-2 gene (C57BL/6J SCA2 transgenic mice) were serially transplanted with hMSCs intravenously or intracranially before and after the onset of motor function loss. Motor function of mice was evaluated by an accelerating protocol of rotarod test every 8 weeks. Immunohistochemical stain of whole brain sections was adopted to demonstrate the neuroprotective effect of hMSC transplantation on cerebellar PCs and engraftment of hMSCs into mice brain. RESULTS: Intravenous transplantation of hMSCs effectively improved rotarod performance of SCA2 transgenic mice and delayed the onset of motor function deterioration; while intracranial transplantation failed to achieve such neuroprotective effect. Immunohistochemistry revealed that intravenous transplantation was more effective in the preservation of the survival of cerebellar PCs and engraftment of hMSCs than intracranial injection, which was compatible to rotarod performance of transplanted mice. CONCLUSION: Intravenous transplantation of hMSCs can indeed delay the onset as well as improve the motor function of SCA2 transgenic mice. The results of this preclinical study strongly support further exploration of the feasibility to transplant hMSCs for SCA patients. PMID- 21824438 TI - Diet-induced bacterial immunogens in the gastrointestinal tract of dairy cows: impacts on immunity and metabolism. AB - Dairy cows are often fed high grain diets to meet the energy demand for high milk production or simply due to a lack of forages at times. As a result, ruminal acidosis, especially subacute ruminal acidosis (SARA), occurs frequently in practical dairy production. When SARA occurs, bacterial endotoxin (or lipopolysaccharide, LPS) is released in the rumen and the large intestine in a large amount. Many other bacterial immunogens may also be released in the digestive tract following feeding dairy cows diets containing high proportions of grain. LPS can be translocated into the bloodstream across the epithelium of the digestive tract, especially the lower tract, due to possible alterations of permeability and injuries of the epithelial tissue. As a result, the concentration of blood LPS increases. Immune responses are subsequently caused by circulating LPS, and the systemic effects include increases in concentrations of neutrophils and the acute phase proteins such as serum amyloid-A (SAA), haptoglobin (Hp), LPS binding protein (LBP), and C-reactive protein (CRP) in blood. Entry of LPS into blood can also result in metabolic alterations. Blood glucose and nonesterified fatty acid concentrations are enhanced accompanying an increase of blood LPS after increasing the amount of grain in the diet, which adversely affects feed intake of dairy cows. As the proportions of grain in the diet increase, patterns of plasma beta-hydroxybutyric acid, cholesterol, and minerals (Ca, Fe, and Zn) are also perturbed. The bacterial immunogens can also lead to reduced supply of nutrients for synthesis of milk components and depressed functions of the epithelial cells in the mammary gland. The immune responses and metabolic alterations caused by circulating bacterial immunogens will exert an effect on milk production. It has been demonstrated that increases in concentrations of ruminal LPS and plasma acute phase proteins (CRP, SAA, and LBP) are associated with declines in milk fat content, milk fat yield, 3.5% fat corrected milk yield, as well as milk energy efficiency. PMID- 21824439 TI - Significance of differential expression of thymidylate synthase in normal and primary tumor tissues from patients with colorectal cancer. AB - The role of thymidylate synthase (TS) is essential as a key rate-limiting enzyme in DNA synthesis. It is the primary target of fluorouracil and its derivates in colorectal cancer. In this study, TS mRNA expression was examined in primary tumor and normal tissues from 76 patients with high- risk stage II/III colorectal cancer by laser capture microdissection and polymerase chain reaction. Thirty (39.47%) patients were found to have higher TS expression in primary tumors with earlier stage (P = 0.018), lower histological grades (P = 0.001) and high frequency microsatellite instability (P = 0.000). Multivariate analysis showed that microsatellite instability, histological grade and number of lymph nodes examined are independent prognostic markers. PMID- 21824440 TI - Adrenomedullin in rat follicles and corpora lutea: expression, functions and interaction with endothelin-1. AB - BACKGROUND: Adrenomedullin (ADM), a novel vasorelaxant peptide, was found in human/rat ovaries. The present study investigated the interaction of ADM and endothelin-1 (ET-1) in follicles and newly formed corpora lutea (CL) and the actions of ADM on progesterone production in CL during pregnancy. METHODS: The peptide and gene expression level of adrenomedullin in small antral follicles, large antral follicles and CL was studied by real-time RT-PCR and EIA. The effect of ADM treatment on oestradiol production in 5-day follicular culture and on progesterone production from CL of different pregnant stages was measured by EIA. The interaction of ADM and ET-1 in follicles and CL at their gene expression level was studied by real-time RT-PCR. RESULTS: In the rat ovary, the gene expression of Adm increased during development from small antral follicles to large antral follicles and CL. In vitro treatment of preantral follicular culture for 5 days with ADM increased oestradiol production but did not affect follicular growth or ovulation rate. The regulation of progesterone production by ADM in CL in culture was pregnancy-stage dependent, inhibitory at early and late pregnancy but stimulatory at mid-pregnancy, which might contribute to the high progesterone production rate of the CL at mid-pregnancy. Moreover, the interaction between ADM and ET-1 at both the production and functional levels indicates that these two vasoactive peptides may form an important local, fine-tuning regulatory system together with LH and prolactin for progesterone production in rat CL. CONCLUSIONS: As the CL is the major source of progesterone production even after the formation of placenta in rats, ADM may be an important regulator in progesterone production to meet the requirement of pregnancy. PMID- 21824441 TI - Ovarian sensitivity index is strongly related to circulating AMH and may be used to predict ovarian response to exogenous gonadotropins in IVF. AB - BACKGROUND: Serum anti-Mullerian hormone (AMH) is currently considered the best marker of ovarian reserve and of ovarian responsiveness to gonadotropins in in vitro fertilization (IVF). AMH assay, however, is not available in all IVF Units and is quite expensive, a reason that limits its use in developing countries. The aim of this study is to assess whether the "ovarian sensitivity index" precisely reflects AMH so that this index may be used as a surrogate for AMH in prediction of ovarian response during an IVF cycle. METHODS: AMH serum levels were measured in 61 patients undergoing IVF with a "long" stimulation protocol including the GnRH agonist buserelin and recombinant follicle-stimulating hormone (rFSH). Patients were divided into four subgroups according to the percentile of serum AMH and their ovarian stimulation was prospectively followed. Ovarian sensitivity index (OSI) was calculated dividing the total administered FSH dose by the number of retrieved oocytes. RESULTS: AMH and OSI show a highly significant negative correlation (r = -0.67; p = 0.0001) that is stronger than the one between AMH and the total number of retrieved oocytes and than the one between AMH and the total FSH dose. CONCLUSIONS: OSI reflects quite satisfactory the AMH level and may be proposed as a surrogate of AMH assay in predicting ovarian responsiveness to FSH in IVF. Being very easy to calculate and costless, its use could be proposed where AMH measurement is not available or in developing countries where limiting costs is of primary importance. PMID- 21824442 TI - Detecting transmission and reassortment events for influenza A viruses with genotype profile method. AB - Evolutionary events of transmission and reassortment for influenza A viruses were traditionally detected by phylogenetic analysis for influenza viruses' eight gene segments. Because the phylogenetic analysis can be complex, we developed genotype profile method which packaged the phylogenetic algorithms to analyze combination patterns of gene segments and integrated epidemiology knowledge. With the method, the analysis of reassortment and transmission becomes a simple and reliable process that combines genotypes, which is identical for the biological process of the virus. An application called IVEE that implements the method is available for all academic users to apply the method http://snptransformer.sourceforge.net. Furthermore, we found that a previous summary of the reassortment events in swine influenza A viruses may be inaccurate. PMID- 21824443 TI - Development of a rapid dipstick with latex immunochromatographic assay (DLIA) for diagnosis of schistosomiasis japonica. AB - BACKGROUND: Schistosomiasis japonica (schistosomiasis) is a zoonosis that can seriously affect human health. At present, the immunodiagnostic assays for schistosomiasis detection are time-consuming and require well-trained personnel and special instruments, which can limit their use in the field. Thus, there is a pressing need for a simple and rapid immunoassay to screen patients on a large scale. In this study, we developed a novel rapid dipstick with latex immunochromatographic assay (DLIA) to detect anti-Schisaosoma japonicum antibodies in human serum. RESULTS: Using latex microspheres as a color probe, DLIA was established to test standard positive and negative sera, in comparison with the classical enzyme-linked immunosorbent assay (ELISA). The sensitivity and specificity of DLIA were 95.10% (97/102) and 94.91% (261/275), respectively. The cross-reaction rates with clonorchiosis, intestinal nematodes, Angiostrongylus cantonensis and paragonimiasis were 0, 0, 0 and 42.11% respectively. All the results showed no significant difference to the ELISA. In field tests, 333 human serum samples from an endemic area were tested with DLIA, and compared with ELISA and Kato-Katz method. There was no significant difference between DLIA and ELISA on positive and negative rates of detection; however, significant differences existed between DLIA and Kato-Katz method, and between ELISA and Kato-Katz method. The kappa value between DLIA and ELISA was 0.90. CONCLUSIONS: This is the first study in which DLIA was used to detect anti-Schistosoma japonicum antibody. The results show that DLIA is a simple, rapid, convenient, sensitive and specific assay for the diagnosis of schistosomiasis and is therefore very suitable for large-scale field applications and clinical detection. PMID- 21824444 TI - Oral hydroxycitrate supplementation enhances glycogen synthesis in exercised human skeletal muscle. AB - Glycogen stored in skeletal muscle is the main fuel for endurance exercise. The present study examined the effects of oral hydroxycitrate (HCA) supplementation on post-meal glycogen synthesis in exercised human skeletal muscle. Eight healthy male volunteers (aged 22.0 (se 0.3) years) completed a 60-min cycling exercise at 70-75 % VO2max and received HCA or placebo in a crossover design repeated after a 7 d washout period. They consumed 500 mg HCA or placebo with a high-carbohydrate meal (2 g carbohydrate/kg body weight, 80 % carbohydrate, 8 % fat, 12 % protein) for a 3-h post-exercise recovery. Muscle biopsy samples were obtained from vastus lateralis immediately and 3 h after the exercise. We found that HCA supplementation significantly lowered post-meal insulin response with similar glucose level compared to placebo. The rate of glycogen synthesis with the HCA meal was approximately onefold higher than that with the placebo meal. In contrast, GLUT4 protein level after HCA supplementation was significantly decreased below the placebo level, whereas expression of fatty acid translocase (FAT)/CD36 mRNA was significantly increased above the placebo level. Furthermore, HCA supplementation significantly increased energy reliance on fat oxidation, estimated by the gaseous exchange method. However, no differences were found in circulating NEFA and glycerol levels with the HCA meal compared with the placebo meal. The present study reports the first evidence that HCA supplementation enhanced glycogen synthesis rate in exercised human skeletal muscle and improved post-meal insulin sensitivity. PMID- 21824445 TI - Home and neighbourhood correlates of BMI among children living in socioeconomically disadvantaged neighbourhoods. AB - A detailed understanding of the underlying drivers of obesity-risk behaviours is needed to inform prevention initiatives, particularly for individuals of low socioeconomic position who are at increased risk of unhealthy weight gain. However, few studies have concurrently considered factors in the home and local neighbourhood environments, and little research has examined determinants among children from low socioeconomic backgrounds. The present study examined home, social and neighbourhood correlates of BMI (kg/m2) in children living in disadvantaged neighbourhoods. Cross-sectional data were collected from 491 women with children aged 5-12 years living in forty urban and forty rural socioeconomically disadvantaged areas (suburbs) of Victoria, Australia in 2007 and 2008. Mothers completed questionnaires about the home environment (maternal efficacy, perceived importance/beliefs, rewards, rules and access to equipment), social norms and perceived neighbourhood environment in relation to physical activity, healthy eating and sedentary behaviour. Children's height and weight were measured at school or home. Linear regression analyses controlled for child sex and age. In multivariable analyses, children whose mothers had higher efficacy for them doing physical activity tended to have lower BMI z scores (B = 0.04, 95 % CI - 0.06, - 0.02), and children who had a television (TV) in their bedroom (B = 0.24, 95 % CI 0.04, 0.44) and whose mothers made greater use of food as a reward for good behaviour (B = 0.05, 95 % CI 0.01, 0.09) tended to have higher BMI z scores. Increasing efficacy among mothers to promote physical activity, limiting use of food as a reward and not placing TV in children's bedrooms may be important targets for future obesity prevention initiatives in disadvantaged communities. PMID- 21824446 TI - Prevalence of vitamin D deficiency and secondary hyperparathyroidism during winter in pre-menopausal Bangladeshi and Somali immigrant and ethnic Finnish women: associations with forearm bone mineral density. AB - Secondary hyperparathyroidism (SHPT) is one of the outcomes of vitamin D deficiency that negatively affects bone metabolism. We studied the ethnic differences in vitamin D status in Finland and its effect on serum intact parathyroid hormone (S-iPTH) concentration and bone traits. The study was done in the Helsinki area (60 degrees N) during January-February 2008. A total of 143 healthy women (20-48 years of age) from two groups of immigrant women (Bangladeshi, n 34 and Somali, n 48), and a group of ethnic Finnish women (n 61) were studied in a cross-sectional setting. Serum concentrations of 25 hydroxyvitamin D (S-25OHD) and S-iPTH were measured. Peripheral quantitative computed tomography measurements were taken at 4 and 66 % of the forearm length. In all groups, the distribution of S-25OHD was shifted towards the lower limit of the normal range. A high prevalence of vitamin D insufficiency (S-25OHD < 50 nmol/l) was observed (89.6 %) in the Somali group. The prevalence of SHPT (S iPTH>65 ng/l) was higher (79.1 %) in Somali women than in Finnish women (16 %). There was a significant association between S-25OHD and S-iPTH (r - 0.49, P < 0.001). Ethnicity and S-25OHD together explained 30 % of the variation in S-iPTH. The total bone mass at all sites of the forearm, fracture load and stress-strain index was higher (P < 0.001) in Bangladeshi and Finnish women than in Somali women. The high prevalence of hypovitaminosis D, SHPT and low bone status in Somali women indicates a higher risk of osteoporosis. PMID- 21824447 TI - Low-surfactant microemulsions for enhanced topical delivery of poorly soluble drugs. AB - PURPOSE: To develop and characterize low-surfactant microemulsion (ME) gels to enhance topical delivery of poorly soluble drugs. METHOD: Five low surfactant ME formulations were manufactured following the construction of pseudo-ternary phase diagrams. The MEs were screened for their ability to dissolve a poorly soluble new chemical entity (Model Drug X). Various viscosity imparting agents like Carbopol 934, Colloidal Silica, HPMC K100M, Lubrajel NP, and Xanthan Gum were evaluated for the manufacture of these ME gels. Each ME gel was then further evaluated for physical stability, including assessing rheological profiles. In vitro release profiles were also determined and compared to a conventional ointment. RESULTS: Three of the five low surfactant MEs developed (ME1, ME4 and ME5) were capable of dissolving Model Drug X up to 14 fold higher than the conventional ointment formulation. ME1 and ME4 gels comprising Xanthan gum or Carbopol 934 were physically stable, while ME5 gel was stable only with Colloidal Silica. The ME5 gel with Colloidal Silica showed an irreversible increase in its elastic modulus when exposed to high temperature, indicating that the formulation would be less suitable for commercial use. The Xanthan Gum and Colloidal Silica gels yielded significantly higher release rates (8 - 10 fold) compared to a conventional ointment and formulations containing Carbopol 934. The significant difference in drug release rates between Xanthan Gum and Carbopol 934 indicated that choice of viscosity imparting agent played an important role in governing drug release from ME gels. CONCLUSION: ME gels were developed with low surfactant concentrations and improved formulation characteristics, which increased the solubility and subsequent release of a poorly soluble drug. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 21824448 TI - Transport characteristics of tryptanthrin and its inhibitory effect on P-gp and MRP2 in Caco-2 cells. AB - PURPOSE. Tryptanthrin, an indole quinazoline alkaloid with multiple medical activities, has been recently under preclinical development as an anti tuberculosis and anti-tumor drug. The aims of this study are to characterize the intestinal transport of tryptanthrin in Caco-2 cells, to determine whether P glycoprotein (P-gp) and multidrug resistance-associated protein 2 (MRP2) are involved in this issue, and to evaluate the potential influence of tryptanthrin on the function of P-gp and MRP2. METHODS. Transport assays of tryptanthrin were performed in Caco-2 monolayers with or without the supplement of P-gp and MRP2 inhibitors. Transport assays of P-gp and MRP2 substrates were also performed in the presence of tryptanthrin. The effect of tryptanthrin on the expression of P gp and MRP2 was analyzed by reverse transcriptase-PCR. RESULTS. Both absorption and secretion of tryptanthrin were concentration-independent at a low concentration range of 0.8-20 uM. The apparent permeability (Papp) for the apical (AP) to basolateral (BL) was 6.138 +/- 0.291 * 10-5. The ratio of Papp (BL->AP) to Papp (AP->BL) was 0.77, suggesting greater permeability in the absorptive direction. Both the P-gp inhibitor, verapamil, and the MRP2 inhibitor, glibenclamide, didn't affect the efflux transport of tryptanthrin. The efflux transport of the P-gp substrate, digoxin, and the MRP2 substrate, pravastatin sodium, decreased when tryptanthrin was present. However, tryptanthrin didn't change the expression of P-gp and MRP2. CONCLUSIONS. Tryptanthrin was well absorbed across the Caco-2 monolayers, and its transepithelial transports were dominated by passive diffusion. Tryptanthrin was not a substrate, but a potential inhibitor of P-gp and MRP2. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 21824449 TI - Pharmacy patrons 'awareness of pharmacists' education and routine patient care responsibilities. AB - PURPOSE: To assess the similarities between pharmacists' and pharmacy patrons' views of pharmacists' roles and to explore the extent to which persons actually see pharmacists assuming certain roles. METHOD: Cross-sectional survey was administered to pharmacists and patients who were filling prescriptions or seeking nonprescription medications in 9 community pharmacies in Morgantown, West Virginia. The survey assessed 11 routine patient care services. Main outcome measures include opinions of pharmacists and patients about responsibility for providing 11 routine care services and the extent to which these services are provided. RESULTS: Pharmacists and patients had similar opinions about services that pharmacists should provide for 7 of the 11 services evaluated. For the other 4 items for which opinions were divergent, the mean scores for the extent to which pharmacists provide these services indicated that pharmacists do not always provide these services. CONCLUSION: Pharmacy patrons might not attribute certain patient-related functions to pharmacists because pharmacists do not frequently perform these routine care-related services in actual practice. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 21824450 TI - Fluorescence detection of Zabofloxacin, a novel fluoroquinolone antibiotic, in plasma, bile, and urine by HPLC: the first oral and intravenous applications in a pharmacokinetic study in rats. AB - PURPOSE: To develop an HPLC method using fluorescence detection for the pharmacokinetic evaluation of levels of zabofloxacin, a novel broad spectrum fluoroquinolone antibiotic, in the plasma, bile and urine of rats. METHODS: A simple reversed-phase HPLC method using a C18 column with fluorescence detection was developed and validated for the simultaneous determination of zabofloxain and enrofloxacin as an internal standard. The plasma sample was treated with methanol for protein precipitation, and treatment of the bile and urine samples included deproteinization and extraction using chloroform. The applicability of the developed assay method to pharmacokinetic studies of zabofloxacin in rats was examined. Zabofloxacin was intravenously and orally administered to rats at a dose of 20 mg/kg. RESULTS: The limits of quantification (LOQ) was determined to be 50 ng/mL for the plasma with acceptable linearity ranging from 50 to 25,000 ng/mL (R>0.999), and 0.5 MUg/mL for the bile and urine samples with acceptable linearity ranging from 0.5 to 100 MUg/mL (R>0.999). The validation parameters for zabofloxacin were found to be acceptable according to FDA assay validation (2001). While zabofloxacin in plasma and urine has been stable in all tested handling conditions, it has been unstable in bile during freeze-thaw cycles for 24 h at room temperature. Following intravenous and oral administration of zabofloxacin to rats at a dose of 20 mg/kg, concentration was quantifiable in plasma for up to 8 h. The bioavailability of zabofloxacin was 27.7%, and it was excreted into bile and urine at about 8% each per oral administration. CONCLUSIONS: These observations suggest that a validated assay can be used in pharmacokinetic studies of zabofloxacin in small animals. Due to the limited stability of zabofloxcin in rat bile, freeze-thaw cycles or prolonged handling at room temperature is not recommended. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 21824451 TI - Strategies for the early recognition of bipolar disorder. AB - Bipolar disorder often exists for 10 or more years without being correctly diagnosed or treated. Early-onset bipolar disorder is associated with longer treatment delay and a worse outcome than adult-onset bipolar disorder. This activity describes various risk factors for the development of bipolar disorder and discusses possible solutions to the challenges surrounding timely diagnosis. PMID- 21824452 TI - Performance improvement CME: schizoaffective disorder. AB - Correctly diagnosing schizoaffective disorder depends on having an accurate history of the patient's signs and symptoms, including documentation from medical and psychiatric records and information gathered from patients and their family members or caregivers. Placing the patient's symptoms within a diagnostic framework helps to differentiate schizoaffective disorder from other psychotic disorders so that an individualized, evidence-based treatment plan can be formulated. Clinicians should monitor treatment adherence, which is closely correlated with treatment outcomes; using multiple, objective measures to assess adherence is optimal. This performance improvement activity provides opportunities to improve strategies for diagnosing schizoaffective disorder, individualizing treatment, and assessing and managing medication nonadherence. PMID- 21824453 TI - Using moderator-based algorithms and electronic medical records to achieve optimal outcomes in depression. AB - Moderator-based treatment algorithms for depression are available to assist clinicians by providing a highly structured approach for the monitoring and assessment of medication efficacy and risks. Algorithm-based treatment strategies provide consistent care and improve outcomes, and patients treated with measurement-based care experience greater reduction of symptoms, faster remission rates, and better overall efficacy than care as usual. Additionally, electronic medical records have the potential to provide interactive guidance on optimal treatment choices during patient follow-up visits. This Webcast focuses on evaluating predictors of treatment response within the context of using algorithms and integrating this information into clinical practice via electronic medical records. PMID- 21824454 TI - Impact of stimulant pharmacotherapy on sleep quality: post hoc analyses of 2 large, double-blind, randomized, placebo-controlled trials. AB - BACKGROUND: Sleep disturbances may cause distress among individuals with attention-deficit/hyperactivity disorder (ADHD), but few studies have examined the impact of stimulant pharmacotherapy for ADHD on sleep in adults. METHOD: These post hoc analyses included sleep data collected with the Pittsburgh Sleep Quality Index (PSQI), a self-rated questionnaire, from 831 adults with DSM-IV-TR defined ADHD in 2 large, randomized, double-blind, placebo-controlled, forced dose titration studies of lisdexamfetamine (N = 420; conducted from May 25, 2006, to November 16, 2006) and triple-bead mixed amphetamine salts (MAS) (N = 411; conducted from April 25, 2005, to November 4, 2005). Change from baseline to endpoint in PSQI clinically meaningful change categories (ie, "decrease," "no change," or "increase") was analyzed by treatment group in each study using the chi2 test. The Cochran-Mantel-Haenszel method was used (1) to determine whether there was a statistically significant difference in Clinical Global Impressions Improvement (CGI-I) score of 1 or 2 (improved) versus > 2 (not improved) relative to a decrease or an increase in PSQI and (2) to analyze shifts from good sleep at baseline (PSQI <= 5) to poor sleep at endpoint (PSQI > 5). RESULTS: Impaired sleep (PSQI score > 5) relative to baseline was demonstrated in 8.3% and 9.7% of the treatment and placebo groups, respectively (P = .18), in the MAS study and 7.7% and 8.2%, respectively (P = .03), in the lisdexamfetamine study. Clinically meaningful change in baseline to endpoint PSQI was not statistically significantly different between treatment and placebo groups in either study. A significant difference in CGI-I 1 and 2 relative to an increase or decrease in PSQI was found in both the triple-bead MAS (P < .0001) and the lisdexamfetamine (P = .0008) trials. More subjects with improved CGI-I rating of 1 or 2 had improvement in PSQI than had worsening. CONCLUSIONS: Approximately one-third of subjects receiving treatment or placebo had clinically meaningful sleep improvement, emphasizing that change in sleep quality during treatment may not necessarily be related to stimulant therapy. When managing complaints of sleep difficulties in ADHD subjects, clinicians should undertake a broad assessment and consider underlying conditions that may contribute to sleep disruption. TRIAL REGISTRATION: clinicaltrials.gov Identifiers: NCT00334880 and NCT00152022. PMID- 21824455 TI - Late-life health consequences of exposure to trauma in a general elderly population: the mediating role of reexperiencing posttraumatic symptoms. AB - OBJECTIVE: A history of trauma is associated with poor mental and physical health, but the specific impact of posttraumatic stress disorder (PTSD) symptoms on physical health using objective indicators of health status has rarely been evaluated in elderly civilians. This study investigates the long-term consequences of a lifetime exposure to trauma on health in a French elderly general population. METHOD: Data from this retrospective study were derived from a longitudinal study (the Enquete de Sante Psychologique-Risques, Incidence et Traitement [ESPRIT]) of community-dwelling participants. Psychiatric health, medical history, and clinical examination (ICD-10 criteria) were assessed in 1,662 subjects (mean [SD] age = 72.5 [5.2] years). Lifetime traumatic exposure, PTSD, and psychiatric diagnoses were obtained using the Watson PTSD Inventory and the Mini-International Neuropsychiatric Interview. The outcome measures used were the Mini-International Neuropsychiatric Interview, Center for Epidemiologic Studies Depression Scale, Mini-Mental State Examination, and measures of physical health. RESULTS: We observed an increase in the number and severity of health related outcomes between groups, with nontraumatized subjects having the lowest risk and those with trauma leading to recurrent reexperiencing of events (nonresilient subjects) having the highest risk. Traumatized persons who did not report reexperiencing symptoms (resilient subjects) showed better current mental health than traumatized subjects who did and nontraumatized subjects. Nonresilient subjects were more likely to have current depressive symptoms (P = .003), current major depression (P < .0001), current anxiety disorder (P = .032), and psychiatric comorbidity (P = .002) than nontraumatized subjects. Resilient subjects differed from nontraumatized subjects in having significantly less current suicidal ideation (P = .054) and psychiatric comorbidity (P = .035). Both groups of traumatized subjects showed a higher rate of cardio-ischemic diseases, notably current angina pectoris (multivariate, adjusted OR = 2.27; 95% CI, 1.31 3.91; and OR = 2.34; 95% CI, 1.22-4.49; for resilient and nonresilient groups, respectively). Traumatized persons, specifically those nonresilient, showed a higher waist-hip ratio, higher triglyceride levels, and a greater frequency of hypertension. CONCLUSIONS: Our findings suggest that trauma could be associated with cardio-ischemic diseases independently of PTSD symptoms expression. However, the presence of these symptoms appears associated with additional metabolic risk factors. PMID- 21824456 TI - Efficacy of antipsychotic drugs against hostility in the European First-Episode Schizophrenia Trial (EUFEST). AB - OBJECTIVE: To compare the effects of haloperidol, amisulpride, olanzapine, quetiapine, and ziprasidone on hostility in first-episode schizophrenia, schizoaffective disorder, or schizophreniform disorder. METHOD: We used the data acquired in the European First-Episode Schizophrenia Trial, an open, randomized trial (conducted in 14 countries) comparing 5 antipsychotic drugs in 498 patients aged 18-40 years with first-episode schizophrenia, schizoaffective disorder, or schizophreniform disorder. DSM-IV diagnostic criteria were used. Patients were assessed between December 23, 2002 and January 14, 2006. Most subjects joined the study as inpatients and then continued with follow-ups in outpatient clinic visits. The Positive and Negative Syndrome Scale (PANSS) was administered at baseline and at 1, 3, 6, 9, and 12 months after randomization. We analyzed the scores on the PANSS hostility item in a subset of 302 patients showing at least minimal hostility (a score > 1) at baseline. We hypothesized (1) that the treatments would differ in their efficacy for hostility and (2) that olanzapine would be superior to haloperidol. Our primary statistical analysis tested the null hypothesis of no difference among the treatment groups in change in hostility over time. Secondary analysis addressed the question of whether the effects on hostility found in the primary analysis were specific to this item. All our analyses were post hoc. RESULTS: The primary analysis of hostility indicated an effect of differences between treatments (F(4,889) = 4.02, P = .0031). Post hoc treatment-group contrasts for hostility change showed that, at months 1 and 3, olanzapine was significantly superior (P < .05) to haloperidol, quetiapine, and amisulpride in reducing hostility. Secondary analyses demonstrated that these results were at least partly specific to hostility. CONCLUSIONS: Both hypotheses were supported. Olanzapine appears to be a superior treatment for hostility in early phases of therapy for first-episode schizophrenia, schizoaffective disorder, and schizophreniform disorder. This efficacy advantage of olanzapine must be weighed against its adverse metabolic effects and propensity to cause weight gain. TRIAL REGISTRATION: ISRCTN Register Identifier: ISRCTN68736636. PMID- 21824457 TI - Antidepressant medication treatment during pregnancy: prevalence of use, clinical implications, and alternatives. PMID- 21824459 TI - Optimizing clinical outcomes across domains of life in adolescents and adults with ADHD. PMID- 21824458 TI - Mother-infant antidepressant concentrations, maternal depression, and perinatal events. AB - OBJECTIVE: The authors explored the relationship of cord-maternal antidepressant concentration ratios and maternal depression with perinatal events and preterm birth. METHOD: The investigators examined 21 mother-infant pairs that had antidepressant exposure during pregnancy. The antidepressants included serotonin reuptake inhibitors (SRIs) and nortriptyline (a norepinephrine inhibitor and mild SRI). The mothers were evaluated with the Structured Clinical Interview for DSM IV. Depression ratings were repeated at 20, 30, and 36 weeks' pregnancy. At delivery, investigators assessed cord and maternal antidepressant concentrations, neonatal outcomes on the Peripartum Events Scale (PES), and gestational weeks at birth. The investigators performed this study at the Women's Behavioral HealthCARE Program, Western Psychiatric Institute and Clinic, University of Pittsburgh Medical Center, Pennsylvania, from April 2003 until September 2006. RESULTS: Mean +/- SD cord-to-maternal concentration ratios were 0.52 +/- 0.35 (range, 0.00-1.64) for the parent drug and 0.54 +/- 0.17 (range, 0.28-0.79) for the metabolite. Nine of 21 mothers (43%) had a major depressive episode. From examining the maximum depression ratings, the mean +/- SD Structured Interview Guide for the Hamilton Depression Rating Scale, Atypical Depression Symptoms Version score was 16.0 +/- 7.6. One third (7/21) of infants had at least 1 perinatal event (PES >= 1). The frequency of deliveries complicated by any perinatal event was similar in depressed and nondepressed mothers. There was no significant association between perinatal events and cord-to-maternal antidepressant concentration ratios or maternal depression levels. Exposure to short half-life antidepressants compared to fluoxetine resulted in more perinatal events (7/16 = 44% vs 0/5 = 0%; P = .06). Fourteen percent (3/21) of infants were preterm. Preterm birth was not associated with cord-to-maternal metabolite concentration ratios, depression levels, or exposure to fluoxetine. CONCLUSIONS: Antidepressant-exposed infants experienced a limited number of transient perinatal events. No association between cord-maternal concentration ratios or maternal depression and perinatal events could be identified. Contrary to other reports, we detected no increased risk for perinatal events with fluoxetine therapy compared to the short half-life antidepressants. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00279370. PMID- 21824461 TI - Keeping 'em honest: the current crisis of confidence in antidepressants. PMID- 21824463 TI - The emerging role of atypical antipsychotics in the treatment of tardive dyskinesia induced by other atypical antipsychotics. PMID- 21824465 TI - Effect of valproic acid on acute lung injury in a rodent model of intestinal ischemia reperfusion. AB - OBJECTIVES: Acute lung injury (ALI) can develop during the course of many clinical conditions, and is associated with significant morbidity and mortality. Valproic acid (VPA), a well-known anti-epileptic drug, has been shown to have anti-oxidant and anti-inflammatory effects in various ischemia/reperfusion (I/R) models. The purpose of this study was to investigate whether VPA could affect survival and development of ALI in a rat model of intestinal I/R. METHODS: Two experiments were performed. Experiment I: Male Sprague-Dawley rats (250-300 g) were subjected to intestinal ischemia (1h) and reperfusion (3h). They were randomized into 2 groups (n=7 per group) 3 min after ischemia: Vehicle (Veh) and VPA (300 mg/kg, IV). Primary end-point for this study was survival over 4h from the start of ischemia. Experiment II: The histological and biochemical effects of VPA treatment on lungs were examined 3h (1h ischemia+2h reperfusion) after intestinal I/R injury (Veh vs. VPA, n=9 per group). An objective histological score was used to grade the degree of ALI. Enzyme linked immunosorbent assay (ELISA) was performed to measure serum levels of interleukins (IL-6 and 10), and lung tissue of cytokine-induced neutrophil chemoattractant (CINC) and myeloperoxidase (MPO). In addition, the activity of 8-isoprostane was analyzed for pulmonary oxidative damage. RESULTS: In Experiment I, 4-h survival rate was significantly higher in VPA treated animals compared to Veh animals (71.4% vs. 14.3%, p=0.006). In Experiment II, ALI was apparent in all of the Veh group animals. Treatment with VPA prevented the development of ALI, with a reduction in the histological score (3.4 +/- 0.3 vs. 5.3 +/- 0.6, p=0.025). Moreover, compared to the Veh control group the animals from the VPA group displayed decreased serum levels of IL-6 (952 +/- 213 pg/ml vs. 7709 +/- 1990 pg/ml, p=0.011), and lung tissue concentrations of CINC (1188 +/- 28 pg/ml vs. 1298 +/- 27 pg/ml, p<0.05), MPO activity (368 +/- 23 ng/ml vs. 490 +/- 29 ng/ml, p<0.05) and 8-isoprostane levels (1495 +/- 221 pg/ml vs. 2191 +/- 177 pg/ml, p<0.05). CONCLUSION: VPA treatment improves survival and attenuates ALI in a rat model of intestinal I/R injury, at least in part, through its anti-oxidant and anti-inflammatory effects. PMID- 21824466 TI - Probing membrane permeabilization by the antimicrobial peptide distinctin in mercury-supported biomimetic membranes. AB - The mechanism of membrane permeabilization by the antimicrobial peptide distinctin was investigated by using two different mercury-supported biomimetic membranes, namely a lipid self-assembled monolayer and a lipid bilayer tethered to the mercury surface through a hydrophilic spacer (tethered bilayer lipid membrane: tBLM). Incorporation of distinctin into a lipid monolayer from its aqueous solution yields rapidly ion channels selective toward inorganic cations, such as Tl(+) and Cd(2+). Conversely, its incorporation in a tBLM allows the formation of ion channels permeable to potassium ions only at non-physiological transmembrane potentials, more negative than -340mV. These channels, once formed, are unstable at less negative transmembrane potentials. The kinetics of their formation is consistent with the disruption of distinctin clusters adsorbed on top of the lipid bilayer, incorporation of the resulting monomers and their aggregation into hydrophilic pores by a mechanism of nucleation and growth. Comparing the behavior of distinctin in tBLMs with that in conventional black lipid membranes strongly suggests that distinctin channel formation in lipid bilayer requires the partitioning of distinctin molecules between the two sides of the lipid bilayer. We can tentatively hypothesize that an ion channel is formed when one distinctin cluster on one side of the lipid bilayer matches another one on the opposite side. PMID- 21824467 TI - Engineering and screening the N-terminus of chemokines for drug discovery. AB - Chemokines are small chemoattractive proteins involved in many important physiological and pathological processes such as leukocyte mobilisation, inflammation, cancer and HIV-1 infection. The N-terminus of chemokines was shown to be crucial for interaction and activation with their cognate receptors. Therefore, multiple strategies including elongation, truncation, mutagenesis or chemical modifications of chemokine N-terminus were developed to identify analogues with modified selectivity displaying antagonist or enhanced agonist activities. Library approaches allowed fast screening of a large number of such chemokine variants and led to the identification of promising therapeutic candidates. Additional studies were able to reduce the chemokine to the size of a peptide while retaining its receptor affinity and selectivity. In analogy to full length chemokines, peptides derived from the chemokine N-terminal sequence were improved by mutagenesis, elongation and truncation approaches to develop potential therapeutic molecules used in various clinical trials. Altogether these studies demonstrated the pharmacophore potential of the chemokine N-terminus and its vast modulation properties to develop analogues with great therapeutic value for a large set of pathologies. PMID- 21824468 TI - Redox regulation of cellular stress response in multiple sclerosis. AB - Multiple sclerosis (MS) is an autoimmune-mediated neurodegenerative disease with characteristic foci of inflammatory demyelination in the brain, spinal cord, and optic nerves. Recent studies have demonstrated not only that axonal damage and neuronal loss are significant pathologic components of MS, but that this neuronal damage is thought to cause the permanent neurologic disability often seen in MS patients. Emerging finding suggests that altered redox homeostasis and increased oxidative stress, primarily implicated in the pathogenesis of MS, are a trigger for activation of a brain stress response. Relevant to maintenance of redox homeostasis, integrated mechanisms controlled by vitagenes operate in brain in preserving neuronal survival during stressful conditions. Vitagenes encode for heat shock proteins (Hsp) Hsp32, Hsp70, the thioredoxin and the sirtuin protein systems. In the present study we assess stress response mechanisms in the CSF, plasma and lymphocytes of control patients compared to MS patients. We found that the levels of vitagenes Hsp72, Hsc70, HO-1, as well as oxidative stress markers carbonyls and hydroxynonenals were significantly higher in the blood and CSF of MS patients than in control patients. In addition, an increased expression of Trx and sirtuin 1, together with a decrease in the expression of TrxR were observed. Our data strongly support a pivotal role for redox homeostasis disruption in the pathogenesis of MS and, consistently with the notion that new therapies that prevent neurodegeneration through nonimmunomodulatory mechanisms can have a tremendous potential to work synergistically with current MS therapies, unravel important targets for new cytoprotective strategies. PMID- 21824469 TI - Comparison of three assays for quantifying S-100B in serum. AB - BACKGROUND: Serum S-100B has clinical value in monitoring malignant melanoma and in monitoring and predicting outcomes in patients with traumatic brain injury. METHODS: Analytical performance characteristic and split-sample method comparison studies for three commercial S-100B immunoassays (CanAg(r) S100, Sangtec(r) 100, YK150 Human S-100 beta) were performed. Reference intervals (97.5th percentile) for each assay were established by non-parametric analysis of results from healthy volunteers. RESULTS: Linearity results were slope=1.014, intercept=65.1, r(2)=0.999 for the Sangtec assay; slope=1.038, intercept=31.1, r(2)=0.999 for the CanAg assay; slope=1.123, intercept=-105.4, r(2)=0.997 for the YK150 assay. Within-run CVs were <=5.7, <=6.3 and <=10.8 for the Sangtec, CanAg and YK150 ELISAs, respectively. Between-run CVs were <=11.3, <=5.9 and <=9.5, respectively. Upper reference interval limits of 141, 96 and 735 ng/l S-100B were established for the Sangtec, CanAg and YK150 ELISAs, respectively. Deming regression generated the following: CanAg vs. Sangtec, slope=0.339, intercept=24.1, r(2)=0.932; YK150 vs. Sangtec, slope=0.266, intercept=-140.0, r(2)=0.690; YK150 vs. CanAg, slope=1.376, intercept=-13.1, r(2)=0.860. CONCLUSIONS: The configurations, procedures and performance characteristics of the Sangtec and CanAg S-100B ELISAs are comparable and better than those of the YK150 assay. Poor agreement and large biases prevent interchangeable use of results. PMID- 21824470 TI - Discovery of a novel neuroprotective compound, AS1219164, by high-throughput chemical screening of a newly identified apoptotic gene marker. AB - We have reported that tacrolimus (FK506), an immunosuppressive drug, and diclofenac, a non-steroidal anti-inflammatory drug, possess different modes of neuroprotective action. FK506 suppresses only thapsigargin-induced apoptosis in neuroblastoma SH-SY5Y cells while diclofenac reverses tunicamycin-induced as well as thapsigargin-induced apoptosis. The aim of this study is to discover novel compounds that exert neuroprotective properties by using the transcriptional response of a newly identified gene, which was regulated by both FK506 and diclofenac, as a surrogate screening marker in high-throughput chemical screening and characterize the compounds in comparison with FK506 and diclofenac. Using a microarray with 4504 human cDNAs and quantitative RT-PCR, two genes as apoptotic markers, transmembrane protein 100 (TMEM100) and limb-bud and heart (LBH), were identified because the thapsigargin-induced elevations in their mRNA levels were reversed by both FK506 and diclofenac. A luciferase reporter assay with a TMEM100 promoter region was applied to high-throughput chemical screening. AS1219164, {3 [(E)-2-{5-[(E)-2-pyridin-4-ylvinyl]pyridin-3-yl} vinyl]aniline}, suppressed thapsigargin-induced transactivation of the TMEM100 gene and reversed thapsigargin-induced increases in TMEM100 and LBH mRNA levels in SH-SY5Y cells, similar to the effects of FK506 and diclofenac. Furthermore, AS1219164 protected against SH-SY5Y cell death induced by four apoptotic agents including thapsigargin, similar to diclofenac, but was more potent than diclofenac, while FK506 only showed protective effects against thapsigargin-induced cell death. In conclusion, a novel neuroprotecitve compound, AS1219164, was discovered by high throughput chemical screening using a reporter assay with the TMEM100 gene promoter regulated by both FK506 and diclofenac. Reporter assay using the promoter region of a gene under pharmacological and physiological transcriptional regulation would be well suit for use in high-throughput chemical screening. PMID- 21824471 TI - Mechanotransduction activates alpha5beta1 integrin and PI3K/Akt signaling pathways in mandibular osteoblasts. AB - It is unclear how bone cells at different sites detect mechanical loading and how site-specific mechanotransduction affects bone homeostasis. To differentiate the anabolic mechanical responses of mandibular cells from those of calvarial and long bone cells, we isolated osteoblasts from C57B6J mouse bones, cultured them for 1week, and subjected them to therapeutic low intensity pulsed ultrasound (LIPUS). While the expression of the marker proteins of osteoblasts and osteocytes such as alkaline phosphatase and FGF23, as well as Wnt1 and beta catenin, was equally upregulated, the expression of mandibular osteoblast messages related to bone remodeling and apoptosis differed from that of messages of other osteoblasts, in that the messages encoding the pro-remodeling protein RANKL and the anti-apoptotic protein Bcl-2 were markedly upregulated from the very low baseline levels. Blockage of the PI3K and alpha(5)beta(1) integrin pathways showed that the mandibular osteoblast required mechanotransduction downstream of alpha(5)beta(1) integrin to upregulate expression of the proteins beta-catenin, p-Akt, Bcl-2, and RANKL. Mandibular osteoblasts thus must be mechanically loaded to preserve their capability to promote remodeling and to insure osteoblast survival, both of which maintain intact mandibular bone tissue. In contrast, calvarial Bcl-2 is fully expressed, together with ILK and phosphorylated mTOR, in the absence of LIPUS. The antibody blocking alpha(5)beta(1) integrin suppressed both the baseline expression of all calvarial proteins examined and the LIPUS-induced expression of all mandibular proteins examined. These findings indicate that the cellular environment, in addition to the tridermic origin, determines site-specific bone homeostasis through the remodeling and survival of osteoblastic cells. Differentiated cells of the osteoblastic lineage at different sites transmit signals through transmembrane integrins such as alpha(5)beta(1) integrin in mandibular osteoblasts, whose signaling may play a major role in controlling bone homeostasis. PMID- 21824472 TI - Protective effects of catalase on retinal ischemia/reperfusion injury in rats. AB - Retinal ischemia/reperfusion (I/R) injury causes profound tissue damage, especially retinal ganglion cell (RGC) death. The aims of the study were to investigate whether catalase (CAT) has a neuroprotective effect on RGC after I/R injury in rats, and to determine the possible antioxidant mechanism. Wistar female rats were randonmized into four groups: normal control group (Control group), retinal I/R with vehicle group (I/R with vehicle group), retinal I/R with AAV-CAT group (I/R with AAV-CAT group), and normal retina with AAV-CAT group (normal with AAV-CAT group). One eye of each rat was pretreated with recombinant adeno-associated virus containing catalase gene (I/R with AAV-CAT group or normal with AAV-CAT group) and recombinant adeno-associated virus containing GFP gene (I/R with vehicle group) by intravitreal injection 21 days before initiation of I/R injury. Retinal I/R injury was induced by elevating intraocular pressure to 100mmHg for 1h. The number of RGC and inner plexiform layer (IPL) thickness were measured by fluorogold retrograde labeling and hematoxylin and eosin staining at 6h, 24h, 72 h and 5d after injury. Hydrogen peroxide (H(2)O(2)), the number of RGC, IPL thickness, malondialdehyde(MDA), 8-hydroxy-2-deoxyguanosine (8-OHdG), CAT activity and nitrotyrosine were measured by fluorescence staining, immunohistochemistry and enzyme-linked immunosorbent assay analysis at 5 days after injury. Electroretinographic (ERG) evaluation was also used. Pretreatment of AAV-CAT significantly decreased the levels of H(2)O(2), MDA, 8-OHdG and nitrotyrosine, increased the catalase activity, and prevented the reduction of a- and b- waves in the I/R with AAV-CAT group compare with the I/R with vehicle group (p<0.01). Catalase attenuated the I/R-induced damage of RGC and IPL and retinal function. Therefore, catalase can protect the rat retina from I/R-induced injury by enhancing the antioxidative ability and reducing oxidative stress, which suggests that catalase may be relevant for the neuroprotection of inner retina from I/R-related diseases. PMID- 21824474 TI - Styrax japonica supplementation diet enhances the innate immune response in Epinephelus bruneus against bacterial and protozoan infections. AB - Kelp grouper, Epinephelus bruneus, fed for 30 days with 0% (control), 0.1%, 1.0%, and 2.0% of Styrax japonica supplementation diets, led to reductions in mortality after being challenged with a bacterium (Vibrio harveyi) and a ciliate protozoan (Uronema marinum). The enriched diets significantly increased the survival rate as compared to the controls. The phagocytic and respiratory activities were significantly increased in kelp groupers given 1.0% and 2.0% enriched diets. The complement activity, lysozyme activity, serum bactericidal activity, and total protein level significantly increased with any enriched diet against the pathogens; however antiprotease activity and myeloperoxidase levels significantly increased only with 1.0% and 2.0% enriched diets while the alpha2-macroglobulin level was significantly enhanced with 1.0% enriched diet. The study suggests that incorporation of S. japonica at 1.0% and 2.0% level in the diet significantly enhances the immune responses in the kelp grouper E. bruneus against V. harveyi and U. marinum. PMID- 21824475 TI - Conserved features of chronic stress across phyla: the effects of long-term stress on behavior and the concentration of the neurohormone octopamine in the cricket, Gryllus texensis. AB - Many of the deleterious effects of chronic stress in vertebrates are caused by the long-term elevation of stress hormones. These negative effects are thought to be unavoidable by-products of sustained activation of the stress response, but the details remain unclear. A comparative perspective may help in understanding chronic stress. We exposed crickets (Gryllus texensis) to a mock predator. A single exposure to a mock predator induced a transient increase in the hemolymph (blood) concentration of the insect stress neurohormone, octopamine. Repeated exposure to the mock predator increased basal levels of octopamine, similar to the effects of chronic stress on the basal levels of vertebrate stress hormones. This study is the first to report an increase in the basal levels of an invertebrate stress hormone in response to repeated flight-or-fight stress. Chronic stress reduced weight gain, and decreased feeding and enhanced weight loss after food deprivation in adult female crickets. However, chronic stress also increased the tendency of crickets to produce sustained flight. Therefore, this study supports the hypothesis that increasing basal levels of stress hormones may be a phylogenetically common response to chronically stressful conditions. It also demonstrates that chronic stress has both positive and negative effects in insects. PMID- 21824473 TI - The retina of the PCD/PCD mouse as a model of photoreceptor degeneration. A structural and functional study. AB - In this work, we used the pcd (Purkinje cell degeneration) mutant mouse with a slow temporal progression of photoreceptor degeneration in order to analyze the structural and functional modifications in the neuronal populations of the outer and inner retina. Retinal immunocytochemistry and functional electroretinography were performed on the pcd/pcd mutant mice and control wild type animals of the C57/DBA strain at 45, 90, 180 and 270 post-natal days. Immunohistochemical studies were performed for a series of protein markers: calbindin, calretinin, PKCalpha, bassoon, synapsin, syntaxin and islet1. Full field electroretinography recordings were performed on control and dystrophic mice. Rod and mixed responses, and oscillatory potentials, were recorded in dark adapted conditions; cone and flicker responses were recorded under light adaptation. Our results show significant structural modifications in the photoreceptor populations and neurons of the inner retina. Changes in cell morphology affect mainly to the bipolar cells, which gradually lose their dendritic tufts. The electroretinography records reveal that in the pcd retinas the rod and cone systems show a reduction in the amplitude of the electrical signals. This decrease progresses slowly with the passage of time, although for the most advanced stage of photoreceptor degeneration considered, 270 post-natal days, it is still possible to record light induced responses. We conclude that pcd mice experience a loss of retinal function in correlation with the loss of photoreceptors with age, and significant changes in retinal synaptic processes. PMID- 21824476 TI - Assessment of cyclobutane pyrimidine dimers by digital photography in human skin. AB - UV-mediated DNA damage and repair are important mechanisms in research on UV induced carcinogenesis. UV-induced DNA-damage and repair can be determined by immunohistochemical staining of photoproduct positive nuclei of keratinocytes in the epidermis. We developed a new method of analysing and quantifying thymine dimer (TT-CPD) positive cells in the epidermis. Normal skin of healthy controls was exposed to UVB ex vivo and in vivo. Skin samples were immunohistochemically stained for TT-CPDs. Digital images of the epidermis were quantified for TT-CPDs both visually and digitally. There was a UVB-dose dependent induction of TT-CPDs present in the ex vivo UVB-irradiated skin samples. The linear measurement range of the digital quantification was increased compared to the manual counting. The average 24-hour repair rate of the initiated TT-CPDs elicited by the UVB irradiation at T=0 of the 8 HCs showed a 34% decrease of TT-CPD photoproducts by the manual counting method and a 51% decrease determined by digital counting. The digital quantification method improves immunohistochemical quantification of DNA photo damage. It is more sensitive in measuring the extent of DNA-damage per nucleus. PMID- 21824477 TI - Differential effect of drug interference in immunogenicity assays. AB - The presence of anti-drug antibodies (ADA) in adalimumab-treated patients is associated with reduced serum adalimumab levels and a lower clinical response. Currently, there is no standard for measurement of anti-drug antibodies and many factors influence the results. Consequently, the incidence of ADA as reported in different studies varies considerably. Here we investigated the differential effect of drug interference in two common types of assays used to measure anti adalimumab: an antigen binding test (ABT) and a more often-used bridging elisa. We measured ADA to adalimumab in a cohort of 216 rheumatoid arthritis patients treated with adalimumab for 28 weeks. Only 15 samples (7%) were positive in the bridging elisa, compared to 29 (13%) in the ABT, despite the fact that the bridging elisa was the most sensitive assay. Furthermore, in an ABT specific for IgG4, 48 samples (22%) were found positive. The bridging elisa was found to detect only the bivalent form of (drug-specific) IgG4, resulting in an underestimation of ADA levels. However, the predominant reason for the different outcomes of these assays was a differential susceptibility to drug interference. In particular, the bridging elisa only detected ADA in the absence of detectable amounts of circulating adalimumab and is therefore not suited for measurement of ADA in complex with the drug. In summary, we showed that a bridging elisa is susceptible to drug interference and typically measures ADA only in absence of detectable drug levels. PMID- 21824478 TI - Specific binding of activated Vip3Aa10 to Helicoverpa armigera brush border membrane vesicles results in pore formation. AB - Helicoverpa armigera is one of the most harmful pests in China. Although it had been successfully controlled by Cry1A toxins, some H. armigera populations are building up resistance to Cry1A toxins in the laboratory. Vip3A, secreted by Bacillus thuringiensis, is another potential toxin against H. armigera. Previous reports showed that activated Vip3A performs its function by inserting into the midgut brush border membrane vesicles (BBMV) of susceptible insects. To further investigate the binding of Vip3A to BBMV of H. armigera, the full-length Vip3Aa10 toxin expressed in Escherichia coli was digested by trypsin or midgut juice extract, respectively. Among the fragments of digested Vip3Aa10, only a 62kDa fragment (Vip3Aa10-T) exhibited binding to BBMV of H. armigera and has insecticidal activity. Moreover, this interaction was specific and was not affected by the presence of Cry1Ab toxin. Binding of Vip3Aa10-T to BBMV resulted in the formation of an ion channel. Unlike Cry1A toxins, Vip3Aa10-T was just slightly associated with lipid rafts of BBMV. These data suggest that although activated Vip3Aa10 specifically interacts with BBMV of H. armigera and forms an ion channel, the mode of action of it may be different from that of Cry1A toxins. PMID- 21824479 TI - Unique utilization of a phosphoprotein phosphatase fold by a mammalian phosphodiesterase associated with WAGR syndrome. AB - Metallophosphoesterase-domain-containing protein 2 (MPPED2) is a highly evolutionarily conserved protein with orthologs found from worms to humans. The human MPPED2 gene is found in a region of chromosome 11 that is deleted in patients with WAGR (Wilms tumor, aniridia, genitourinary anomalies, and mental retardation) syndrome, and MPPED2 may function as a tumor suppressor. However, the precise cellular roles of MPPED2 are unknown, and its low phosphodiesterase activity suggests that substrate hydrolysis may not be its prime function. We present here the structures of MPPED2 and two mutants, which show that the poor activity of MPPED2 is not only a consequence of the substitution of an active site histidine residue by glycine but also due to binding of AMP or GMP to the active site. This feature, enhanced by structural elements of the protein, allows MPPED2 to utilize the conserved phosphoprotein-phosphatase-like fold in a unique manner, ensuring that its enzymatic activity can be combined with a possible role as a scaffolding or adaptor protein. PMID- 21824480 TI - Disease embryo development network reveals the relationship between disease genes and embryo development genes. AB - A basic problem for contemporary biology and medicine is exploring the correlation between human disease and underlying cellular mechanisms. For a long time, several efforts were made to reveal the similarity between embryo development and disease process, but few from the system level. In this article, we used the human protein-protein interactions (PPIs), disease genes with their classifications and embryo development genes and reconstructed a human disease embryo development network to investigate the relationship between disease genes and embryo development genes. We found that disease genes and embryo development genes are prone to connect with each other. Furthermore, diseases can be categorized into three groups according to the closeness with embryo development in gene overlapping, interacting pattern in PPI network and co-regulated by microRNAs or transcription factors. Embryo development high-related disease genes show their closeness with embryo development at least in three biological levels. But it is not for embryo development medium-related disease genes and embryo development low-related disease genes. We also found that embryo development high related disease genes are more central than other disease genes in the human PPI network. In addition, the results show that embryo development high-related disease genes tend to be essential genes compared with other diseases' genes. This network-based approach could provide evidence for the intricate correlation between disease process and embryo development, and help to uncover potential mechanisms of human complex diseases. PMID- 21824481 TI - A thermodynamic perspective of immune capabilities. AB - We consider the mutual interactions, via cytokine exchanges, among helper lymphocytes, B lymphocytes and killer lymphocytes, and we model them as a unique system by means of a tripartite network. Each part includes all the different clones of the same lymphatic subpopulation, whose couplings to the others are either excitatory or inhibitory (mirroring elicitation and suppression by cytokine). First of all, we show that this system can be mapped into an associative neural network, where helper cells directly interact with each other and are able to secrete cytokines according to "strategies" learn by the system and profitable to cope with possible antigenic stimulation; the ability of such a retrieval corresponds to a healthy reaction of the immune system. We then investigate the possible conditions for the failure of a correct retrieval and distinguish between the following outcomes: massive lymphocyte expansion/suppression (e.g. lymphoproliferative syndromes), subpopulation unbalance (e.g. HIV, EBV infections) and ageing (thought of as noise growth); the correlation of such states to autoimmune diseases is also highlighted. Lastly, we discuss how self-regulatory effects within each effector branch (i.e. B and killer lymphocytes) can be modeled in terms of a stochastic process, ultimately providing a consistent bridge between the tripartite-network approach introduced here and the immune networks developed in the last decades. PMID- 21824482 TI - Modeling population patterns of chemotactic bacteria in homogeneous porous media. AB - The spatio-temporal distribution of subsurface microorganisms determines their efficiency in providing essential ecosystem services such as the degradation of organic matter, the remineralization of carbon and nitrogen, or the remediation of anthropogenic contaminants. Populations of motile, chemotactic bacteria have been shown to be capable of pattern formation even in the absence of environmental heterogeneities. Focusing on the water saturated domain of the subsurface (e.g., aquatic sediments, porous aquifers), we analyze this innate capability of bacterial populations in an idealized model of a homogeneous, saturated porous medium. Considering a linear array of connected, identical microhabitats populated by motile, chemotactic bacterial cells, we identify prerequisites for pattern formation, analyze types of patterns, and assess their impact on substrate utilization. In our model, substrate supplied to the microhabitats facilitates bacterial growth, and microbial cells can migrate between neighboring microhabitats due to (i) random motility, (ii) chemotaxis towards substrate, and (iii) self-attraction. A precondition for inhomogeneous population patterns is analytically derived, stating that patterns are possible if the self-attraction exceeds a threshold defined by the random motility and the steady state population density in the microhabitats. An individual-based implementation of the model shows that static and dynamic population patterns can unfold. Degradation efficiency is highest for homogeneous bacterial distributions and decreases as pattern formation commences. If during biostimulation efforts the carrying capacity of the microhabitats is successively increased, simulation results show that degradation efficiency can unexpectedly decrease when the pattern formation threshold is crossed. PMID- 21824483 TI - Replicator dynamics in public goods games with reward funds. AB - Which punishment or rewards are most effective at maintaining cooperation in public goods interactions and deterring defectors who are willing to freeload on others' contribution? The sanction system is itself a public good and can cause problematic "second-order free riders" who do not contribute to the provisions of the sanctions and thus may subvert the cooperation supported by sanctioning. Recent studies have shown that public goods games with punishment can lead to a coercion-based regime if participation in the game is optional. Here, we reveal that even with compulsory participation, rewards can maintain cooperation within an infinitely large population. We consider three strategies for players in a standard public goods game: to be a cooperator or a defector in a standard public goods game, or to be a rewarder who contributes to the public good and to a fund that rewards players who contribute during the game. Cooperators do not contribute to the reward fund and are therefore classified as second-order free riders. The replicator dynamics for the three strategies exhibit a rock-scissors paper cycle, and can be analyzed fully, despite the fact that the expected payoffs are nonlinear. The model does not require repeated interaction, spatial structure, group selection, or reputation. We also discuss a simple method for second-order sanctions, which can lead to a globally stable state where 100% of the population are rewarders. PMID- 21824484 TI - Genotoxicity screening via the gammaH2AX by flow assay. AB - The measurement of serine139-phosphorylated histone H2AX (gammaH2AX) provides a biomarker of DNA double-strand breaks (DSBs) and may identify potential genotoxic activity. In order to evaluate a flow cytometry assay for gammaH2AX detection (hereafter termed the gammaH2AX by flow assay), 6 prototypical (3 pro- and 3 proximate) genotoxins, i.e. dimethylbenz[a]anthracene (DMBA), 2 acetylaminofluorene (2-AAF), benzo[a]pyrene (B[a]P), methyl methane sulphonate (MMS), methyl nitrosourea (MNU) and 4-nitroquinoline oxide (4NQO), were selected to define assay evaluation criteria. In addition, 3 non-genotoxic cytotoxins (phthalic anhydride, n-butyl chloride and hexachloroethane) were included to investigate the influence of cytotoxicity on assay performance. At similar cytotoxicity levels (relative cell counts; RCC 75-40%) all prototypical genotoxins induced marked concentration-dependent increases in gammaH2AX compared with the non-genotoxins. As a result, assay evaluation criteria for a positive effect were defined as >1.5-fold gammaH2AX @ RCC >25%. Twenty five additional chemicals with diverse structures and genotoxic activity were selected to evaluate the gammaH2AX by flow assay. Results were compared with Ames bacterial and in vitro mammalian genotoxicity tests (mouse lymphoma assay and/or chromosome aberration assay). gammaH2AX by flow assay results were highly predictive of Ames (sensitivity 100%; specificity 67%; concordance 82%) and in vitro mammalian genotoxicity tests (sensitivity 91%; specificity 89%; concordance 91%) and provide additional evidence that gammaH2AX is a biomarker of potential genotoxic activity, underpinned mechanistically by the cellular response to DSBs. Discordant findings were predominately attributed to differences in specificity for some mammalian cell genotoxins that are Ames non-mutagens or for "biologically-irrelevant" positives in the mammalian tests. Simple anilines were classified as genotoxic following rat liver S9-mediated bioactivation, however, effects on gammaH2AX were atypical and limited to a small sub-population of S phase nuclei. Nevertheless, the gammaH2AX by flow assay represents a novel genotoxicity assay with the potential to flag both pro- and proximate genotoxins. PMID- 21824485 TI - Carisbamate (RWJ-333369) inhibits glutamate transmission in the granule cell of the dentate gyrus. AB - Carisbamate (CRS, RWJ-333369) is a novel antiepileptic drug awaiting approval for use in the treatment of partial and generalized seizures. Our aim was to determine whether CRS modulates synaptic transmission in the dentate gyrus (DG) and the underlying mechanism. The whole-cell patch-clamp method was used to record AMPA receptor- and NMDA receptor-mediated excitatory postsynaptic currents (EPSC(AMPA) and EPSC(NMDA)) and GABA(A) receptor-mediated inhibitory postsynaptic currents (IPSCs) in granule cells of the DG in brain slices prepared from 3- to 5 week-old male Wistar rats. CRS (30-300 MUM) inhibited the evoked EPSC(AMPA) and EPSC(NMDA) by the same extent (20%) with significantly altered CV(-2), suggesting presynaptic modulation. It did not significantly change the inward currents induced by AMPA application. The inhibitory effect of CRS on the evoked EPSC(AMPA) was not occluded by selective voltage-gated Ca(2+) channel blockers, ruling out the involvement of presynaptic Ca(2+) channels. The frequency, but not the amplitude, of spontaneous EPSC(AMPA) was significantly reduced by CRS. However, CRS did not alter either the frequency or the amplitude of TTX insensitive miniature EPSC(AMPA), indicating an action potential-dependent mechanism was involved. In addition, CRS (100 or 300 MUM) did not significantly change the amplitude of the evoked IPSCs. To summarize, our results suggest that CRS reduces glutamatergic transmission by an action potential-dependent presynaptic mechanism and consequently inhibits excitatory synaptic strength in the DG without affecting GABAergic transmission. This effect may contribute to the antiepileptic action observed clinically at therapeutic concentrations of CRS. PMID- 21824486 TI - Fasting of 3-day-old chicks leads to changes in histone H3 methylation status. AB - Unfavorable nutritional conditions during early developmental periods may cause neuronal network remodeling in the hypothalamus, which influences subsequent adaptability to those same stressful conditions. Alterations in hypothalamic plasticity as a result of neuronal remodeling are achieved by variations in the repertoire of proteins expressed via gene transcriptional activation or repression, both of which are modulated by histone methylation status. This study demonstrates that fasting had a stimulatory effect on dimethylation and trimethylation of histone 3 at lysine 27 (H3K27) in preoptic/anterior hypothalamus (PO/AH) of 3-day-old chicks. The expression of enhancer of zeste 2 (EZH2), a H3K27-specific histone methyltransferase (HMT), was significantly increased by fasting in the paraventricular nucleus (PVN) and PO/AH, which is consistent with the upregulation of H3K27 dimethylation and trimethylation. Furthermore, in the PVN, corticotrophin-releasing hormone (CRH) mRNA expression was significantly inhibited, while mRNA expressions of thyrotropin-releasing hormone (TRH) and type 2 deiodinase (D2) were significantly stimulated by fasting. These findings highlight the potential role of H3K27 methylation status in early feed stress responses in chicks and may be indicative of an epigenetic mechanism for later adaptation to feed intake stress. PMID- 21824487 TI - Histopathological analysis and in situ localisation of Australian tiger snake venom in two clinically envenomed domestic animals. AB - OBJECTIVE: To assess histopathological changes in clinically envenomed tiger snake patients and identify tissue specific localisation of venom toxins using immunohistochemistry. SAMPLES: One feline and one canine patient admitted to the Murdoch Pet Emergency Centre (MPEC), Murdoch University with tiger snake (Notechis sp.) envenoming. Both patients died as a result of envenomation. Non envenomed tissue was also collected and used for comparison. METHODOLOGY: Biopsy samples (heart, lung, kidney andskeletal muscle tissue) were retrieved 1-2 h post death and processed for histopathological examination using Haemotoxylin and Eosin, Martius Scarlet Blue and Periodic Acid Schiff staining. Tissues were examined by light microscopy and tissue sections subjected to immunohistochemical staining using in-house generated monoclonal and polyclonal antibodies against Notechis venoms. RESULTS: Venom-induced pathological changes were observed in the lungs, kidneys and muscle tissue of both patients. Evidence, not previously noted, of procoagulant venom effects were apparent, with formed thrombi in the heart, lungs (small fibrillar aggregates and larger, discrete thrombi) and kidneys. Immunohistochemical assays revealed venom present in the pulmonary tissue, in and around the glomerular capsule and surrounding tubules in renal tissue and scattered throughout the Gastrocnemius muscle tissue. CONCLUSION: This work has shown pathological evidence of procoagulant venom activity supporting previous suggestions that an initial thrombotic state occurs in envenomed patients. We have shown that venom toxins are able to be localised to specific tissues, in this case, venom was detected in the lung, kidney and muscle tissues of clinically envenomed animals. Future work will examine specific toxin localisation using monoclonal antibodies and identify if antivenom molecules are able to reach their target tissues. PMID- 21824489 TI - Why the prevention paradox is a paradox, and why we should solve it: a philosophical view. AB - This paper provides some philosophical comments on Rose's prevention paradox, suggesting why that paradox seems so difficult, and why policy-makers should care about solving it. The assumptions underlying the paradox section sets out two ways of understanding the notion of "benefit" in public health programmes, and shows how the prevention paradox arises from combining both understandings. Thinking through the paradox section argues that if we find the second understanding of benefit appealing, then we should rethink how we typically assess preventive public health measures. The implications section shows how these theoretical arguments imply that public health practitioners should care about solving the prevention paradox, rather than simply denying the legitimacy of one of the two views from which it arises. PMID- 21824488 TI - Modeling binge-like ethanol drinking by peri-adolescent and adult P rats. AB - Alcohol binge-drinking, especially among adolescents and young adults, is a serious public health concern. The present study examined ethanol binge-like drinking by peri-adolescent [postnatal days (PNDs 30-72)] and adult (PNDs 90-132) alcohol-preferring (P) rats with a drinking-in-the-dark-multiple-scheduled-access (DID-MSA) procedure used by our laboratory. Male and female P rats were provided concurrent access to 15% and 30% ethanol for three 1-h sessions across the dark cycle 5 days/week. For the 1st week, adolescent and adult female P rats consumed 3.4 and 1.6g/kg of ethanol, respectively, during the 1st hour of access, whereas for male rats the values were 3.5 and 1.1g/kg of ethanol, respectively. Adult intakes increased to ~2.0 g/kg/h and adolescent intakes decreased to ~2.5 g/kg/h across the 6 weeks of ethanol access. The daily ethanol intake of adult DID-MSA rats approximated or modestly exceeded that seen in continuous access (CA) rats or the selection criterion for P rats (>=5 g/kg/day). However, in general, the daily ethanol intake of DID-MSA peri-adolescent rats significantly exceeded that of their CA counterparts. BELs were assessed at 15-min intervals across the 3rd hour of access during the 4th week. Ethanol intake was 1.7 g/kg vs. 2.7 g/kg and BELs were 57 mg% vs. 100mg% at 15- and 60-min, respectively. Intoxication induced by DID-MSA in female P rats was assessed during the 1st vs. 4th week of ethanol access. Level of impairment did not differ between the 2 weeks (106 vs. 97 s latency to fall, 120 s criterion) and was significant (vs. naive controls) only during the 4th week. Overall, these findings support the use of the DID-MSA procedure in rats, and underscore the presence of age- and sex-dependent effects mediating ethanol binge-like drinking in P rats. PMID- 21824490 TI - Until the lab takes it away from epidemiology. AB - BACKGROUND: It is proposed that, historically, when the conditions are right for laboratory sciences to contribute to causal knowledge, they take the place of epidemiology as leaders in a given field. METHODS: Review examples of cholera, pellagra, and Kaposi's sarcoma. RESULTS: In the cases of cholera, pellagra, and Kaposi's sarcoma, epidemiology ceased to be at the forefront of knowledge acquisition when laboratory sciences identified more proximate causes than those that epidemiologic group comparisons could reveal. CONCLUSION: These three examples deal with diseases, which, at the individual level, appear to rely predominantly on a single factor. For diseases whose causes still elude specific identification by the laboratory sciences, epidemiology may be uniquely equipped to play a leading role. PMID- 21824491 TI - A novel immune-related gene, microtubule aggregate protein homologue, is up regulated during IFN-gamma-related immune responses in Japanese flounder, Paralichthys olivaceus. AB - Delayed-type hypersensitivity (DTH) response mediated by antigen-specific Th1 cells is used as a test to detect exposure to tuberculosis in humans. Japanese flounder (Paralichthys olivaceus) microtubule aggregate protein homologue (PoMTAP) was identified as a gene strongly induced during fish DTH response. In this study, PoMTAP gene was cloned and its expression profile was analyzed. The PoMTAP gene has a transcriptional regulatory region that includes two interferon stimulated response elements and two IFN-gamma activated sites. Expressions of PoMTAP and IFN-gamma genes were up-regulated at the same time points during the DTH response, Edwardsiella tarda infection and VHSV infection. Furthermore, PoMTAP gene expressing cells also expressed CD3epsilon, confirming that PoMTAP is expressed by T lymphocytes. These results suggest that PoMTAP is a novel immune related gene expressed by T lymphocytes that is preferentially induced by IFN gamma and has a role in Th1-mediated immune responses in Japanese flounder. PMID- 21824492 TI - Molecular antifungal defenses in subterranean termites: RNA interference reveals in vivo roles of termicins and GNBPs against a naturally encountered pathogen. AB - Subterranean termites face strong pathogenic pressures from the ubiquitous soil fungus Metarhizium anisopliae, and rely on innate humoral and cellular, as well as behavioral immune defenses for protection. Reticulitermes termites secrete antifungal enzymes that exhibit strong beta-1,3-glucanase activity associated with Gram-negative bacteria binding proteins (GNBPs), which prevent M. anisopliae from invading the hemocoel where it can evade immune responses. Molecular evolutionary studies of Reticulitermes termicin genes, which code for defensin like antifungal peptides, suggest that these proteins may be important effector molecules in antifungal defenses. In this study we show that the RNAi knockdown of termicin and GNBP2 expression via the ingestion of dsRNA significantly increases mortality in termites exposed to a naturally encountered strain of M. anisopliae. Termicin and GNBP2 knockdown also decrease external cuticular antifungal activity, indicating a direct role for these proteins in an external antifungal defense strategy that depends on the active dissemination of antifungal secretions among nestmates. PMID- 21824493 TI - Piecing together the puzzle of acetaldehyde as a neuroactive agent. AB - Mainly known for its more famous parent compound, ethanol, acetaldehyde was first studied in the 1940s, but then research interest in this compound waned. However, in the last two decades, research on acetaldehyde has seen a revitalized and uninterrupted interest. Acetaldehyde, per se, and as a product of ethanol metabolism, is responsible for many pharmacological effects which are not clearly distinguishable from those of its parent compound, ethanol. Consequently, the most recent advances in acetaldehyde's psychopharmacology have been inspired by the experimental approach to test the hypothesis that some of the effects of ethanol are mediated by acetaldehyde and, in this regard, the characterization of metabolic pathways for ethanol and the localization within discrete brain regions of these effects have revitalized the interest on the role of acetaldehyde in ethanol's central effects. Here we present and discuss a wealth of experimental evidence that converges to suggest that acetaldehyde is an intrinsically active compound, is metabolically generated in the brain and, finally, mediates many of the psychopharmacological properties of ethanol. PMID- 21824494 TI - The Occupational JP8 Exposure Neuroepidemiology Study (OJENES): repeated workday exposure and central nervous system functioning among US Air Force personnel. AB - One of the most prevalent workplace chemical exposures historically and currently confronting the global military and civilian workforce is jet propellant (JP) fuel (e.g., JP4, JP5, JP8, jet A1), a complex mixture of numerous hydrocarbon compounds and additives. To date, numerous protective and preventive strategies (e.g., federal exposure limits, workplace procedure protocols, protective gear such as goggles, respirator use, gloves, and coveralls) have been put in place to minimize acutely toxic exposure levels. However, questions remain regarding the effect of repeated exposures at lower (than regulated) levels of JP fuel. The Occupational JP8 Exposure Neuroepidemiology Study (OJENES) was designed to examine the relationships between occupational JP8 exposure over multiple, repeated workdays and specific aspects of central nervous system (CNS) functioning among Air Force (AF) personnel. In this report, we present the OJENES methodology, descriptive findings related to participant characteristics, JP8 exposure levels observed over a work week among higher and lower exposure groups, and neuropsychological task performances at the first study assessment. Results indicated minimal differences between participants in the high and lower exposure groups in terms of descriptive characteristics, other than daily JP8 exposure levels (p<0.001). In addition, neuropsychological task performances for most task measures were not found to be significantly different from reported reference ranges. These findings demonstrated that confounding and misclassification of exposure and outcome status are not major concerns for the study. Therefore, future OJENES analyses targeting the more focused research questions regarding associations between JP8 exposure and CNS functioning are likely to provide valid conclusions, as they will be less influenced by these research biases. PMID- 21824495 TI - Clinical and laboratory findings of a sandfly fever Turkey Virus outbreak in Ankara. AB - Sandfly fever (SF) is an arthropod-borne disease, which has not yet been reported from Ankara. In the summer of 2007, the disease started to be seen in our region, surprisingly causing severe clinical presentations. This report reviews the clinical and laboratory findings of patients with sandfly virus infection of disease outbreaks in 2008 and 2009. A retrospective single-centre descriptive study was performed. Clinically suspected cases were defined on the basis of epidemiologic history and clinical and laboratory findings. The sera samples of the suspected patients were sent to Germany for diagnostic assistance. 50 patients were included in the study. Fever, headache, photophobia, conjunctivitis, myalgia, arthralgia, nausea, abdominal pain and anorexia were common symptoms. Although the fever lasted only 3-6 days, complete recovery required up to 30 days. Leukopenia, thrombocytopenia and elevated serum aspartate aminotransferase and alanine-aminotransferase levels were remarkable findings. The viral-load of Sandfly fever Turkey Virus (SFTV) was detected in the serum of acute patients ranged from 3.19*10(6) to 2.79*10(9) viral RNA molecules/ml. As a result we want to underline that the new type of sandfly virus causes a severe clinical picture with elevated liver enzymes and thrombocytopenia, to an extent not described before in the literature, which might be due to the elevated viral load observed. PMID- 21824496 TI - Escitalopram reduces circulating pro-inflammatory cytokines and improves depressive behavior without affecting sleep in a rat model of post-cardiac infarct depression. AB - Myocardial infarction (MI) in rats is followed by a behavioral syndrome similar to human post-MI depression. We tested the effects of escitalopram, a selective serotonin reuptake inhibitor, on this syndrome. MI was induced in 19 Sprague Dawley rats by occluding the left anterior descending coronary artery for 40min, followed by reperfusion. A sham-operated group of 20 rats was submitted to the same protocol without coronary artery occlusion. Fifteen minutes after the onset of reperfusion, escitalopram (10mg/kg/day, i.p.) or saline was infused continuously through osmotic minipumps. After 2weeks of treatment, the rats were tested for behavioral despair and anhedonia by the forced swimming and sucrose preference tests, respectively. They were then sacrificed, and blood levels of pro-inflammatory cytokines (IL-1beta, IL-6, TNF-alpha), PGE(2) and corticosterone were measured. In a separate cohort of 24 rats, sleep was recorded after 2weeks of post-MI treatment with escitalopram or saline. In MI rats, behavioral despair and anhedonia were blocked by escitalopram but prolonged sleep latency, low total sleep time and short latency to paradoxical sleep (PS) were not; escitalopram decreased PS in sham controls. Plasma TNF-alpha, PGE(2), and corticosterone levels were higher in MI rats than in the controls. Escitalopram lowered TNF alpha, IL-1beta, and PGE(2) levels in both groups of rats while IL-6 showed no differences whatsoever. Escitalopram reverses post-MI behavioral syndrome in rats through a mechanism that could involve a reduction of pro-inflammatory cytokines and PGE(2). It has limited effects on sleep disorders in MI rats but reduces PS in control rats. PMID- 21824497 TI - Ceftriaxone prevents the induction of cocaine sensitization and produces enduring attenuation of cue- and cocaine-primed reinstatement of cocaine-seeking. AB - Ceftriaxone is a beta-lactam antibiotic which has been found to increase the expression and function of the major glutamate transporter, GLT-1. It has previously been shown that GLT-1 expression is decreased in the nucleus accumbens following cocaine self-administration and extinction training; ceftriaxone given in the days immediately prior to reinstatement testing attenuates both cue- and cocaine-primed reinstatement. Here we tested the ability of ceftriaxone pre treatment (for 5 days prior to the first cocaine exposure) to prevent the induction of cocaine sensitization and the acquisition of cocaine self administration. We also tested whether ceftriaxone administered only during self administration attenuates the reinstatement of extinguished cocaine-seeking. We found that ceftriaxone did not affect the acquisition of cocaine self administration but was able to attenuate reinstatement weeks after ceftriaxone administration ceased. This attenuation in reinstatement was accompanied by a restoration of GLT-1 expression in the nucleus accumbens. Ceftriaxone also attenuated locomotor behavior following the first cocaine injection and prevented the induction of cocaine but not caffeine sensitization. While ceftriaxone treated animals did not sensitize to caffeine, they displayed reduced caffeine induced locomotion following repeated caffeine treatment, indicating a possible dopaminergic effect of ceftriaxone. Taken together, these results indicate that ceftriaxone produces enduring changes in glutamate homeostasis in the nucleus accumbens which counteract addiction-related behaviors. PMID- 21824498 TI - Inhibition of 5-lipoxygenase triggers apoptosis in prostate cancer cells via down regulation of protein kinase C-epsilon. AB - Previous studies have shown that human prostate cancer cells constitutively generate 5-lipoxygenase (5-LOX) metabolites from arachidonic acid, and inhibition of 5-LOX blocks production of 5-LOX metabolites and triggers apoptosis in prostate cancer cells. This apoptosis is prevented by exogenous metabolites of 5 LOX, suggesting an essential role of 5-LOX metabolites in the survival of prostate cancer cells. However, downstream signaling mechanisms which mediate the survival-promoting effects of 5-LOX metabolites in prostate cancer cells are still unknown. Recently, we reported that MK591, a specific inhibitor of 5-LOX activity, induces apoptosis in prostate cancer cells without inhibition of Akt, or ERK, two well-characterized regulators of pro-survival mechanisms, suggesting the existence of an Akt and ERK-independent survival mechanism in prostate cancer cells regulated by 5-LOX. Here, we report that 5-LOX inhibition-induced apoptosis in prostate cancer cells occurs via rapid inactivation of protein kinase C epsilon (PKCepsilon), and that exogenous 5-LOX metabolites prevent both 5-LOX inhibition-induced down-regulation of PKCepsilon and induction of apoptosis. Interestingly, pre-treatment of prostate cancer cells with diazoxide (a chemical activator of PKCepsilon), or KAE1-1 (a cell-permeable, octa-peptide specific activator of PKCepsilon) prevents 5-LOX inhibition-induced apoptosis, which indicates that inhibition of 5-LOX triggers apoptosis in prostate cancer cells via down-regulation of PKCepsilon. Altogether, these findings suggest that metabolism of arachidonic acid by 5-LOX activity promotes survival of prostate cancer cells via signaling through PKCepsilon, a pro-survival serine/threonine kinase. PMID- 21824499 TI - c-Jun N-terminal kinase induces axonal degeneration and limits motor recovery after spinal cord injury in mice. AB - c-Jun N-terminal kinase (JNK) mediates neuronal death in response to stress and injury in the CNS and peripheral nervous system. Here, we show that JNK also regulates retrograde axonal degeneration (axonal dieback) after spinal cord injury (SCI) in mice. Activated phospho-JNK was highly expressed in damaged corticospinal tract (CST) axons after thoracic SCI by hemisection. Local administration of SP600125, a JNK inhibitor, prevented accumulation of amyloid beta precursor protein and retraction of the severed CST axons as well as preserved the axonal arbors rostral to the injury site. The treatment with SP600125 also improved functional recovery of the hindlimbs, assessed by Basso mouse scale open-field scores and the grid-walking test. In Jnk1(-/-) and Jnk3(-/ ) mice, we observed prevention of axonal degeneration and enhancement of motor recovery after SCI. These results indicate that both JNK1 and JNK3 induce axonal degeneration and limit motor recovery after SCI. Thus, a JNK inhibitor may be a suitable therapeutic agent for SCI. PMID- 21824500 TI - Metabolic flux analysis gives an insight on verapamil induced changes in central metabolism of HL-1 cells. AB - Verapamil has been shown to inhibit glucose transport in several cell types. However, the consequences of this inhibition on central metabolism are not well known. In this study we focused on verapamil induced changes in metabolic fluxes in a murine atrial cell line (HL-1 cells). These cells were adapted to serum free conditions and incubated with 4 MUM verapamil and [U-13C5] glutamine. Specific extracellular metabolite uptake/production rates together with mass isotopomer fractions in alanine and glutamate were implemented into a metabolic network model to calculate metabolic flux distributions in the central metabolism. Verapamil decreased specific glucose consumption rate and glycolytic activity by 60%. Although the HL-1 cells show Warburg effect with high lactate production, verapamil treated cells completely stopped lactate production after 24 h while maintaining growth comparable to the untreated cells. Calculated fluxes in TCA cycle reactions as well as NADH/FADH2 production rates were similar in both treated and untreated cells. This was confirmed by measurement of cell respiration. Reduction of lactate production seems to be the consequence of decreased glucose uptake due to verapamil. In case of tumors, this may have two fold effects; firstly depriving cancer cells of substrate for anaerobic glycolysis on which their growth is dependent; secondly changing pH of the tumor environment, as lactate secretion keeps the pH acidic and facilitates tumor growth. The results shown in this study may partly explain recent observations in which verapamil has been proposed to be a potential anticancer agent. Moreover, in biotechnological production using cell lines, verapamil may be used to reduce glucose uptake and lactate secretion thereby increasing protein production without introduction of genetic modifications and application of more complicated fed-batch processes. PMID- 21824501 TI - Oral drug delivery utilizing intestinal OATP transporters. AB - Transporters play important roles in tissue distribution and urinary- and biliary excretion of drugs and transporter molecules involved in those processes have been elucidated well. Furthermore, an involvement of efflux transporters such as P-glycoproteins, multidrug resistance associated protein 2, and breast cancer resistance protein as the intestinal absorption barrier and/or intestinal luminal secretion mechanisms has been demonstrated. However, although there are many suggestions for the contribution of uptake/influx transporters in intestinal absorption of drugs, information on the transporter molecules responsible for the intestinal absorptive process is limited. Among them, most studied absorptive drug transporter is peptide transporter PEPT1. However, utilization of PEPT1 for oral delivery of drugs may not be high due to the chemical structural requirement of PEPT1 limited to peptide-mimetics. Recently, organic anion transporting polypeptide (OATP) family such as OATP1A2 and OATP2B1 has been suggested to mediate intestinal absorption of several drugs. Since OATPs exhibit species difference in expressed tissues and functional properties between human and animals, human studies are essential to clarify the intestinal absorption mechanisms of drugs via OATPs. Recent pharmacogenomic studies demonstrated that OATP2B1 is involved in the drug absorption in human. In addition, information of drug-juice interaction in the intestine also uncovered the contribution of OATP1A2 and OATP2B1 in drug absorption. Since OATP1A2 and OATP2B1 exhibit broader substrate selectivity compared with PEPT1, their potential to be applied for oral delivery should be high. In this review, current understanding of characteristics and contribution as the absorptive transporters of OATPs in small intestine in human is described. Now, it is getting clearer that OATPs have significant roles in intestinal absorption of drugs, therefore, there are higher possibility to utilize OATPs as the tools for oral delivery. PMID- 21824502 TI - Crossmodal correspondences in product packaging. Assessing color-flavor correspondences for potato chips (crisps). AB - We report a study designed to investigate consumers' crossmodal associations between the color of packaging and flavor varieties in crisps (potato chips). This product category was chosen because of the long-established but conflicting color-flavor conventions that exist for the salt and vinegar and cheese and onion flavor varieties in the UK. The use of both implicit and explicit measures of this crossmodal association revealed that consumers responded more slowly, and made more errors, when they had to pair the color and flavor that they implicitly thought of as being "incongruent" with the same response key. Furthermore, clustering consumers by the brand that they normally purchased revealed that the main reason why this pattern of results was observed could be their differing acquaintance with one brand versus another. In addition, when participants tried the two types of crisps from "congruently" and "incongruently" colored packets, some were unable to guess the flavor correctly in the latter case. These strong crossmodal associations did not have a significant effect on participants' hedonic appraisal of the crisps, but did arouse confusion. These results are relevant in terms of R&D, since ascertaining the appropriate color of the packaging across flavor varieties ought normally to help achieve immediate product recognition and consumer satisfaction. PMID- 21824503 TI - Food cravings mediate the relationship between rigid, but not flexible control of eating behavior and dieting success. AB - Both food cravings and rigid dietary control strategies have been implicated in low dieting success while flexible control often is associated with successful weight loss. An online survey was conducted (N=616) to test the mediational role of food cravings between dietary control strategies and self-perceived dieting success. Food cravings fully mediated the inverse relationship between rigid control and dieting success. Contrarily, flexible control predicted dieting success independently of food cravings, which were negatively associated with dieting success. Differential mechanisms underlie the relationship between rigid and flexible control of eating behavior and dieting success. PMID- 21824504 TI - Expectation of having consumed caffeine can improve performance and mood. AB - We explored whether caffeine, and expectation of having consumed caffeine, affects attention, reward responsivity and mood using double-blinded methodology. 88 participants were randomly allocated to 'drink-type' (caffeinated/decaffeinated coffee) and 'expectancy' (told caffeinated/told decaffeinated coffee) manipulations. Both caffeine and expectation of having consumed caffeine improved attention and psychomotor speed. Expectation enhanced self-reported vigour and reward responsivity. Self-reported depression increased at post-drink for all participants, but less in those receiving or expecting caffeine. These results suggest caffeine expectation can affect mood and performance but do not support a synergistic effect. PMID- 21824505 TI - Dual RNAs in plants. AB - Plants have remarkable developmental plasticity, and the same genotype can result in different phenotypes depending on environmental variation. Indeed, abiotic stresses or biotic interactions affect organogenesis and post-embryonic growth and significantly affect gene regulation. The large diversity of non-protein coding RNAs (npcRNAs) and genes containing only short open reading frames that are expressed during plant growth and development, contribute to the regulation of gene expression. Certain npcRNAs code for oligopeptides and may possess additional biological activity linked to the RNA moiety. The ENOD40 gene is a dual RNA that is activated during a symbiotic interaction leading to root nodule organogenesis. Both the oligopeptides encoded by ENOD40 and the structured regions of the ENOD40 RNA have been shown to interact with different proteins in the cell to control enzymatic activities or induce the relocalisation of ribonucleoproteins, respectively. Other npcRNAs encode for small signalling peptides or are the precursors of small RNAs involved in post-transcriptional or transcriptional gene silencing. They may have RNA-related activities or encode peptides (or even larger proteins), and therefore act as dual RNAs. In addition, long natural antisense RNAs with a coding function and a regulatory RNA-mediated action that are expressed in response to abiotic stress in plants have been identified. In certain cases, these RNAs lead to the synthesis of nat-siRNAs, that are small RNAs derived from the overlapping double-stranded RNA region of natural antisense RNAs, which facilitates the silencing of complementary mRNAs. Finally, the advent of deep sequencing technologies has identified a large number of non-protein-coding RNAs in plants, which could be a large reservoir for dual RNAs. PMID- 21824506 TI - Age-related changes in myelin morphology, electrophysiological property and myelin-associated protein expression of mouse sciatic nerves. AB - This study investigated the morphological and functional changes in peripheral nerves during the maturation and aging process. In a mouse sciatic nerve model, electron micrographs revealed that the number of myelin sheath lamellae gradually increased from 1 week through 12 months of age, when it reached the peak value, and then remained unchanged until 18 months of age; electrophysiological examinations showed that the amplitude of compound muscle action potentials gradually increased from 1 week through 18 months of age and displayed a positive linear correlation with the number of myelin sheath lamellae. Western blot analysis exhibited the age-related expression patterns of four myelin-associated proteins, i.e., myelin-associated glycoprotein (MAG), myelin basic protein (MBP), glycoprotein P0 (P0) and peripheral myelin protein 22 (PMP22). And MAG, MBP and PMP22 showed linear negative or positive correlations with the number of myelin sheath lamellae. Our results suggest that the morphological and functional changes in peripheral nerves are closely related to each other and the myelin associated proteins perform distinct actions on the formation, maturation, degeneration and regeneration of myelin sheaths. PMID- 21824507 TI - White matter asymmetry in healthy individuals: a diffusion tensor imaging study using tract-based spatial statistics. AB - The purpose of this study was to investigate white matter asymmetry across the whole brain and evaluate the effects of age and sex on white matter asymmetry in a large sample of healthy adults. A total of 857 normal subjects (310 females and 547 males, mean age=56.1+/-9.9 years, age range=24.9-84.8 years) were included in this study. With use of tract-based spatial statistics (TBSS), we investigated white matter fractional anisotropy (FA) asymmetry and evaluated the effects of age and sex on white matter FA asymmetry. The voxel-wise analysis showed a large number of white matter FA asymmetries including leftward asymmetry of the arcuate fasciculus and cingulum. The effects of age and sex on white matter FA asymmetry were minor compared to overall FA asymmetries. Small regions showed a significant effect of age or sex, due to the large sample, but this may not be relevant in practice. There was no significant interaction between age and sex. The results of our study demonstrate white matter asymmetry in healthy adults and suggest that white matter asymmetry is relatively stable during aging and not much different between males and females. PMID- 21824508 TI - Optic flow direction coding in area PEc of the behaving monkey. AB - The cortical representation of heading perception derives from several functional processes distributed across many cortical areas. The aim of the present study was to assess if the optic flow motion directions, expansion and contraction, differently modulate the firing activity of area PEc neurons. We determined the influence of the eye position and/or the spatial position of the focus of expansion (FOE) on this activity. Single neuron activity during radial optic flow stimulation was recorded in three behaving monkeys. The retinal FOE position and the spatial eye position were examined in order to study eye position's influence upon the directional selectivity for the radial stimuli. We observed that the neurons able to discriminate the retinotopic FOE position are differently modulated by expansion and contraction. One class of neurons exhibited a different preferred FOE position during expansion and contraction. A second class showed the same preferred position with similar firing activity in the two stimuli. A third class showed the same preferred position but different firing activity. Eye position affected the directional selectivity of most PEc cells. The main result of this study is that there is a continuum in cell modulation by optic flow direction, and it can be modified by the angle of gaze with respect to the FOE. These results shed light on potential cellular integrative mechanisms of area PEc in heading perception. PMID- 21824510 TI - Prescription patterns of Chinese herbal products for menopausal syndrome: analysis of a nationwide prescription database. AB - ETHNO-PHARMACOLOGICAL RELEVANCE: Chinese herbal products (CHP) are commonly used for menopausal syndrome in traditional Chinese medicine (TCM). AIM OF THE STUDY: Because menopausal syndrome is a common issue among women worldwide, this study analyzed the prescription patterns and frequencies of CHP in relieving menopausal syndrome in Taiwan. MATERIALS AND METHODS: Prescriptions of CHP for menopausal syndrome were obtained from the nationwide prescription database (National Health Insurance Research Database) of Taiwan. Every prescription with a leading diagnosis of menopausal syndrome made in the year 2002 for women out-patients aged 45-55 years was analyzed. Descriptive statistics and data mining method (association rule mining) were applied to the pattern of co-prescription. RESULTS: A total of 54456 prescriptions were made for 15486 subjects in clinical visits. Salvia miltiorrhiza and Dan-zhi-xiao-yao-san were the most commonly prescribed single herb (SH) and herbal formula (HF), respectively. For combinations of two CHP, Salvia miltiorrhiza with Dan-zhi-xiao-yao-san, Zhi-bai di-huang-wan with Dan-zhi-xiao-yao-san, and Ligustrum lucidum with Eclipta prostrata were the most frequently co-prescribed CHP couplets as SH-HF, HF-HF, and SH-SH, respectively. The most commonly used combination of three CHP was Eclipta prostrata with Ligustrum lucidum and Dan-zhi-xiao-yao-san. The core formula for menopausal syndrome was Dan-zhi-xiao-yao-san. CONCLUSIONS: Combinations of CHP are widely used for menopausal syndrome. Data mining analysis demonstrates the core formula and the commonly combined CHP in prescriptions. Further studies are needed to evaluate their efficacy for menopausal syndrome. PMID- 21824509 TI - Comparative genomic analysis of dinucleotide repeats in Tritryps. AB - The protozoans Trypanosoma cruzi, Trypanosoma brucei and Leishmania major (Tritryps), are evolutionarily ancient eukaryotes which cause worldwide human parasitosis. They present unique biological features. Indeed, canonical DNA/RNA cis-acting elements remain mostly elusive. Repetitive sequences, originally considered as selfish DNA, have been lately recognized as potentially important functional sequence elements in cell biology. In particular, the dinucleotide patterns have been related to genome compartmentalization, gene evolution and gene expression regulation. Thus, we perform a comparative analysis of the occurrence, length and location of dinucleotide repeats (DRs) in the Tritryp genomes and their putative associations with known biological processes. We observe that most types of DRs are more abundant than would be expected by chance. Complementary DRs usually display asymmetrical strand distribution, favoring TT and GT repeats in the coding strands. In addition, we find that GT repeats are among the longest DRs in the three genomes. We also show that specific DRs are non-uniformly distributed along the polycistronic unit, decreasing toward its boundaries. Distinctive non-uniform density patterns were also found in the intergenic regions, with predominance at the vicinity of the ORFs. These findings further support that DRs may control genome structure and gene expression. PMID- 21824511 TI - The apoptosis inducing effects of Sutherlandia spp. extracts on an oesophageal cancer cell line. AB - AIM OF STUDY: Oesophageal cancer is the ninth most common cancer in the world and the second most common cancer among South African men. It also has one of the lowest possibilities of cure, with the 5-year survival rate estimated to be only 10% overall. Sutherlandia frutescens, or the "cancer bush", is a medicinal plant indigenous to southern Africa that is believed to have anti-cancer and anti proliferative properties. The aim of this study was to investigate the potential apoptosis-inducing effects of two S. frutescens extracts and one Sutherlandia tomentosa extract on the SNO oesophageal cancer cell line. MATERIALS AND METHODS: Cell viability and morphology of SNO cells were evaluated following exposure to the extracts. Apoptotic markers including cytochrome c translocation and phosphatidylserine externalisation were quantified by flow cytometry. The activity of caspases 3 and 7 was evaluated with spectrofluorometry. Apoptosis was evaluated in the presence of the pan-caspase inhibitor, Z-VAD-fmk. The effect of the extracts was compared to non-cancerous peripheral blood mononuclear cells (PBMCs). RESULTS: Time- and dose-response studies were conducted to establish treatment conditions of 2.5 and 5mg/ml of crude plant extracts. Microscopy studies revealed that S. frutescens- and S. tomentosa-treated SNO cells had morphological features characteristic of apoptosis. Annexin V/propidium iodide flow cytometry confirmed that the extracts do, in fact, induce apoptosis in the SNO cells. Caspase inhibition studies seem to indicate that extracts A (S. frutescens (L.) R. Br. subsp. microphylla from Colesberg), B (S. frutescens (L.) R. Br. subsp. microphylla from Platvlei) and C (S. tomentosa Eckl. & Zeyh from Stil Bay) are able to induce caspase-dependent as well as -independent cell death. The S. frutescens and S. tomentosa extracts were found to be more cytotoxic to cancerous SNO cells when compared to the PBMCs. CONCLUSIONS: S. frutescens and S. tomentosa extracts show promise as apoptosis-inducing anti cancer agents. PMID- 21824512 TI - Disulfide bond formation and its impact on the biological activity and stability of recombinant therapeutic proteins produced by Escherichia coli expression system. AB - Therapeutic proteins require correct disulfide bond formation for biological activity and stability. This makes their manufacturing and storage inherently challenging since disulfide bonds can be aberrantly formed and/or undergo significant structural changes. In this paper the mechanisms of disulfide bond formation and scrambling are reviewed, with a focus on their impact on the biological activity and storage stability of recombinant proteins. After assessing the research progress in detecting disulfide bond scrambling, strategies for preventing this phenomenon are proposed. PMID- 21824513 TI - phiGENOME: an integrative navigation throughout bacteriophage genomes. AB - phiGENOME is a web-based genome browser generating dynamic and interactive graphical representation of phage genomes stored in the phiSITE, database of gene regulation in bacteriophages. phiGENOME is an integral part of the phiSITE web portal (http://www.phisite.org/phigenome) and it was optimised for visualisation of phage genomes with the emphasis on the gene regulatory elements. phiGENOME consists of three components: (i) genome map viewer built using Adobe Flash technology, providing dynamic and interactive graphical display of phage genomes; (ii) sequence browser based on precisely formatted HTML tags, providing detailed exploration of genome features on the sequence level and (iii) regulation illustrator, based on Scalable Vector Graphics (SVG) and designed for graphical representation of gene regulations. Bringing 542 complete genome sequences accompanied with their rich annotations and references, makes phiGENOME a unique information resource in the field of phage genomics. PMID- 21824514 TI - Medioventral part of the posterior thalamus in the mouse. AB - The posterior thalamus (Po) consists of heterogeneous groups of cells, which have not been clearly defined. In the present study, we focused on a part of the Po in the mouse brain, which is located caudally to the ventral posterior nucleus and rostromedially to the medial geniculate nucleus and shows distinct calretinin immunoreactivity. While we found the region had a considerable unity on the cytoarchitectural and histochemical grounds, it did not correspond to any particular nucleus but partially involved three structures in a widely used brain atlas (Franklin and Paxinos, 2008). Therefore, we tentatively designated the region as the medioventral part of the posterior thalamus (PoMV) and examined its anatomical features with immunohistochemistry and retrograde tract-tracing. The PoMV was appreciated as a reticular structure with prominent calretinin immunoreactivity, especially in horizontal sections, and displayed apparent differences in the cytoarchitecture from its surrounding regions. The PoMV had two divisions: the dorsal division (PoMVd), which contained parvalbuminimmunoreactive fibers, and the ventral division (PoMVv), which lacked these fibers. The tract-tracing studies showed that the somata retrogradely labeled from the injections in the insular cortex and some of the extended amygdalar regions were fairly concentrated within the PoMV, especially in the PoMVd. On the other hand, the labeling from the medial hypothalamus injections was found predominantly within the PoMVv. These findings indicate that the PoMV can be regarded as a distinct structure within the Po, and it may play a role in the emotional aspect of somatosensory processing. PMID- 21824515 TI - Zinc-desferrioxamine attenuates retinal degeneration in the rd10 mouse model of retinitis pigmentosa. AB - Iron-associated oxidative injury plays a role in retinal degeneration such as age related macular degeneration and retinitis pigmentosa. The metallo-complex zinc desferrioxamine (Zn/DFO) may ameliorate such injury by chelation of labile iron in combination with release of zinc. We explored whether Zn/DFO can affect the course of retinal degeneration in the rd10 mouse model of retinitis pigmentosa. Zn/DFO-treated animals showed significantly higher electroretinographic responses at 3 and 4.5 weeks of age compared with saline-injected controls. Corresponding retinal (photoreceptor) structural rescue was observed by quantitative histological and immunohistochemical techniques. When administered alone, the components of the complex, Zn and DFO, showed a lesser, partial effect. TBARS, a marker of lipid peroxidation, and levels of oxidative DNA damage as quantified by 8-OHdG immunostaining were significantly lower in Zn/DFO-treated retinas compared with saline-injected controls. Reduced levels of retinal ferritin as well as reduced iron content within ferritin molecules were measured in Zn/DFO-treated retinas. The data, taken together, suggest that the protective effects of the Zn/DFO complex are mediated through modulation of iron bioavailability, leading to attenuation of oxidative injury. Reducing iron-associated oxidative stress using complexes such as Zn/DFO may serve as a "common pathway" therapeutic approach to attenuate injury in retinal degeneration. PMID- 21824516 TI - Biomarkers of Oxidative Stress Study IV: ozone exposure of rats and its effect on antioxidants in plasma and bronchoalveolar lavage fluid. AB - The objective of this study was to determine whether acutely exposing rats to ozone would result in the loss of antioxidants from plasma and bronchoalveolar lavage fluid (BALF). Additional goals were to compare analyses of the same antioxidant concentration between different laboratories, to investigate which methods have the sensitivity to detect decreased levels of antioxidants, and to identify a reliable measure of oxidative stress in ozone-exposed rats. Male Fisher rats were exposed to either 2.0 or 5.0 ppm ozone inhalation for 2h. Blood plasma and BALF samples were collected 2, 7, and 16 h after the exposure. It was found that ascorbic acid in plasma collected from rats after the higher dose of ozone was lower at 2h, but not later. BALF concentrations of ascorbic acid were decreased at both 2 and 7h postexposure. Tocopherols (alpha, delta, gamma), 5 nitro-gamma-tocopherol, tocol, glutathione (GSH/GSSG), and cysteine (Cys/CySS) were not decreased, regardless of the dose or postexposure time point used for sample collection. Uric acid was significantly increased by the low dose at 2h and the high dose at the 7h point, probably because of the accumulation of blood plasma in the lung from ozone-increased alveolar capillary permeability. We conclude that measurements of antioxidants in plasma are not sensitive biomarkers for oxidative damage induced by ozone and are not a useful choice for the assessment of oxidative damage by ozone in vivo. PMID- 21824517 TI - Disruption of beta-arrestins blocks glucocorticoid receptor and severely retards lung and liver development in mice. AB - In this study, the role of beta-arrestin 1 and beta-arrestin 2 in fetal lung and liver development was examined using Arrb1(-/-)Arrb2(-/-) mouse embryos. beta Arrestin 1/2 dual-null mice died shortly after birth and morphological examination revealed an obvious pulmonary hypoplasia and severe hepatic impairment. Western blot analysis demonstrated that GR protein levels in Arrb1(-/ )Arrb2(-/-) lung and liver tissues were significantly decreased compared to wild type embryos. Expression of GR proteins was confirmed in the nuclei of type II pneumocytes of 18.5 day embryos (E18.5) by immunofluorescence. The production of hepatic glucose and mRNA level of gluconeogenic enzymes were dramatically reduced in E18.5 Arrb1(-/-)Arrb2(-/-) liver. These results suggest that GR is an important downstream effector of the beta-arrestin signaling pathway involved in regulation of lung and liver development. However, no obvious changes in GR expression following in vitro modulation of beta-arrestin 1/2 indicated the existence of an indirect regulatory relationship between GR and the beta-arrestin signaling pathway. PMID- 21824518 TI - Signaling functions of ubiquitin in the 17beta-estradiol (E2):estrogen receptor (ER) alpha network. AB - Protein posttranslational modifications (PTMs) are signaling alterations that allow coordinating the cellular responses with the changes in the extracellular environment. In this way, the posttranslationally-modified protein becomes a switch node in the transduction network activated by the specific extracellular stimuli. It is now clear that this is the case also for protein ubiquitination: this extremely versatile PTM controls cell physiology through the modulation of protein stability as well as through the modulation of the dynamics of the intracellular signaling cascades. Recent evidence clearly indicates that such a complex scheme appears to be valid also for the 17beta-estradiol (E2):estrogen receptor (ER) alpha signal transduction pathways. Indeed, beside the long standing notion that ERalpha ubiquitination is required for the regulation of receptor stability, several laboratories, including our own, have clearly indicated that ERalpha ubiquitination also serves non-degradative functions. This review will reconsider the role of ubiquitination in E2:ERalpha signaling by particularly highlighting how the functions of the non-degradative ubiquitination impact on ERalpha activities and contribute to the modulation of E2-dependent physiological processes. PMID- 21824519 TI - Deficiency in the inner mitochondrial membrane peptidase 2-like (Immp21) gene increases ischemic brain damage and impairs mitochondrial function. AB - Mitochondrial dysfunction plays an important role in mediating ischemic brain damage. Immp2l is an inner mitochondrial membrane peptidase that processes mitochondrial protein cytochrome c1 (Cyc1). Homozygous mutation of Immp2l (Immp2l(Tg(Tyr)979Ove) or Immp2l(-/-)) elevates mitochondrial membrane potential, increases superoxide (O(2)(-)) production in the brain and impairs fertility. The objectives of this study are to explore the effects of heterozygous mutation of Immp2l (Immp2l(+/-)) on ischemic outcome and to determine the influence of Immp2l deficiency on brain mitochondria after stroke. Male Immp2l(+/-) and wild-type (WT) mice were subjected to 1-h focal cerebral ischemia. Their brains were harvested after 5 and 24-h of reperfusion. The results showed that infarct volume and DNA oxidative damage significantly increased in the Immp2l(+/-) mice. There were no obvious cerebral vasculature abnormalities between the two types of mice viewed by Indian ink perfusion. The increased damage in Immp2l(+/-) mice was associated with early increase in O(2)(-) production. Mitochondrial respiratory rate, total mitochondrial respiratory capacity and mitochondrial respiratory complex activities were decreased at 5-h of recirculation in Immp2l(+/-) mice compared to WT mice. Our results suggest that Immp2l deficiency increases ischemic brain damage by enhancing O(2)(-) production and damaging mitochondrial functional performance. PMID- 21824520 TI - In vitro nuclear egress of herpes simplex virus type 1 capsids. AB - During their life cycles, viruses typically undergo many transport events throughout the cell. These events depend on a variety of both viral and host proteins and are often not fully understood. Such studies are often complicated by asynchronous infections and the concurrent presence of various viral intermediates in the cells, making it difficult to molecularly define each step. In the case of the herpes simplex virus type 1, the etiological agent of cold sores and many other illnesses, the viral particles undergo an intricate series of transport steps during its life cycle. Upon entry by fusion with a cellular membrane, they travel to the host cell nucleus where the virus replicates and assembles new viral particles. These particles then travel across the two nuclear envelopes and transit through the trans-Golgi network before finally being transported to and released at the cell surface. Though viral components and some host proteins modulating these numerous transport events have been identified, the details of these processes remain to be elucidated. To specifically address how the virus escapes the nucleus, we set up an in vitro model that reproduces the unconventional route used by herpes simplex type 1 virus to leave nuclei. This has not only allowed us to clarify the route of capsid egress of the virus but is now useful to define it at the molecular level. PMID- 21824521 TI - Plasma clusterin concentration is associated with longitudinal brain atrophy in mild cognitive impairment. AB - Recent genetic and proteomic studies demonstrate that clusterin/apolipoprotein-J is associated with risk, pathology, and progression of Alzheimer's disease (AD). Our main aim was to examine associations between plasma clusterin concentration and longitudinal changes in brain volume in normal aging and mild cognitive impairment (MCI). A secondary objective was to examine associations between peripheral concentration of clusterin and its concentration in the brain within regions that undergo neuropathological changes in AD. Non-demented individuals (N=139; mean baseline age 70.5 years) received annual volumetric MRI (912 MRI scans in total) over a mean six-year interval. Sixteen participants (92 MRI scans in total) were diagnosed during the course of the study with amnestic MCI. Clusterin concentration was assayed by ELISA in plasma samples collected within a year of the baseline MRI. Mixed effects regression models investigated whether plasma clusterin concentration was associated with rates of brain atrophy for control and MCI groups and whether these associations differed between groups. In a separate autopsy sample of individuals with AD (N=17) and healthy controls (N=4), we examined the association between antemortem clusterin concentration in plasma and postmortem levels in the superior temporal gyrus, hippocampus and cerebellum. The associations of plasma clusterin concentration with rates of change in brain volume were significantly different between MCI and control groups in several volumes including whole brain, ventricular CSF, temporal gray matter as well as parahippocampal, superior temporal and cingulate gyri. Within the MCI but not control group, higher baseline concentration of plasma clusterin was associated with slower rates of brain atrophy in these regions. In the combined autopsy sample of AD and control cases, representing a range of severity in AD pathology, we observed a significant association between clusterin concentration in the plasma and that in the superior temporal gyrus. Our findings suggest that clusterin, a plasma protein with roles in amyloid clearance, complement inhibition and apoptosis, is associated with rate of brain atrophy in MCI. Furthermore, peripheral concentration of clusterin also appears to reflect its concentration within brain regions vulnerable to AD pathology. These findings in combination suggest an influence of this multi-functional protein on early stages of progression in AD pathology. PMID- 21824522 TI - Reconstructing the colonisation and diversification history of the endemic freshwater crab (Seychellum alluaudi) in the granitic and volcanic Seychelles Archipelago. AB - The endemic, monotypic freshwater crab species Seychellum alluaudi was used as a template to examine the initial colonisation and evolutionary history among the major islands in the Seychelles Archipelago. Five of the "inner" islands in the Seychelles Archipelago including Mahe, Praslin, Silhouette, La Digue and Fregate were sampled. Two partial mtDNA fragments, 16S rRNA and cytochrome oxidase subunit I (COI) was sequenced for 83 specimens of S. alluaudi. Evolutionary relationships between populations were inferred from the combined mtDNA dataset using maximum parsimony, maximum likelihood and Bayesian inferences. Analyses of molecular variance (AMOVA) were used to examine genetic variation among and within clades. A haplotype network was constructed using TCS while BEAST was employed to date the colonisation and divergence of lineages on the islands. Phylogenetic analyses of the combined mtDNA data set of 1103 base pairs retrieved a monophyletic S. alluaudi group comprised three statistically well-supported monophyletic clades. Clade one was exclusive to Silhouette; clade two included samples from Praslin sister to La Digue, while clade three comprised samples from Mahe sister to Fregate. The haplotype network corresponded to the three clades. Within Mahe, substantial phylogeographic substructure was evident. AMOVA results revealed limited genetic variation within localities with most variation occurring among localities. Divergence time estimations predated the Holocene sea level regressions and indicated a Pliocene/Pleistocene divergence between the three clades evident within S. alluaudi. The monophyly of each clade suggests that transoceanic dispersal is rare. The absence of shared haplotypes between the three clades, coupled with marked sequence divergence values suggests the presence of three allospecies within S. alluaudi. PMID- 21824523 TI - Models and approaches to understand the role of airway remodelling in disease. AB - Airway remodelling is a collective term for changes in the amount or organisation of the cellular and molecular constituents of the airway wall. Remodelling occurs in and is associated with the pathophysiology of airways diseases including asthma and chronic obstructive pulmonary disease. The remodelling that occurs in these diseases exhibits both shared and distinct features. Remodelling is generally considered to be deleterious to airway function but recent studies also indicate potential protective effects. However, the true impact of different aspects of the remodelling process on lung function, both negative and positive, is poorly understood. In addition, the genetic susceptibility and processes by which environmental insults drive the cell and molecular events which result in airway remodelling and the potential for therapeutic reversibility are also incompletely understood. The last 10-15 years has seen the development of animal models of airway remodelling which have been refined and modified as new factors such as exacerbations and early life influences have been recognised as being of importance. In addition, invertebrate models have been put forward and complex in vitro culture systems and lung slice preparations developed. In parallel, imaging technology has developed to an extent where it is feasible using a combination of techniques to image structural components, cells and proteins in the airway wall as well as to analyse biological processes, cell and receptor activation non invasively over time. The integration of data from in vivo and in vitro models together with use of imaging techniques in man and animals should allow validation of models, further our understanding of the pathophysiology of airway remodelling and potentially improve predictive accuracy for the translation of novel therapeutic agents into the clinic. PMID- 21824524 TI - Tammar wallaby mammary cathelicidins are differentially expressed during lactation and exhibit antimicrobial and cell proliferative activity. AB - Cathelicidins secreted in milk may be central to autocrine feedback in the mammary gland for optimal development in addition to conferring innate immunity to both the mammary gland and the neonate. This study exploits the unique reproductive strategy of the tammar wallaby (Macropus eugenii) model to analyse differential splicing of cathelicidin genes and to evaluate the bactericidal activity and effect of the protein on mammary epithelial cell proliferation. Two linear peptides, Con73 and Con218, derived from the heterogeneous carboxyl end of cathelicidin transcripts, MaeuCath1 and MaeuCath7 respectively, were evaluated for antimicrobial activity. Both Con73 and Con218 significantly inhibited the growth of Staphylococcus aureus, Pseudomonas aureginosa, Enterococcus faecalis and Salmonella enterica. In addition both MaeuCath1 and MaeuCath7 stimulated proliferation of primary tammar wallaby mammary epithelial cells (WallMEC). Lactation-phase specific alternate spliced transcripts were determined for MaeuCath1 showing utilisation of both antimicrobial and proliferative functions are required by the mammary gland and the suckled young. The study has shown for the first time that temporal regulation of milk cathelicidins may be crucial in antimicrobial protection of the mammary gland and suckled young and mammary cell proliferation. PMID- 21824525 TI - Identification of Sc-type ILV6 as a target to reduce diacetyl formation in lager brewers' yeast. AB - Diacetyl causes an unwanted buttery off-flavor in lager beer. It is spontaneously generated from alpha-acetolactate, an intermediate of yeast's valine biosynthesis released during the main beer fermentation. Green lager beer has to undergo a maturation process lasting two to three weeks in order to reduce the diacetyl level below its taste-threshold. Therefore, a reduction of yeast's alpha acetolactate/diacetyl formation without negatively affecting other brewing relevant traits has been a long-term demand of brewing industry. Previous attempts to reduce diacetyl production by either traditional approaches or rational genetic engineering had different shortcomings. Here, three lager yeast strains with marked differences in diacetyl production were studied with regard to gene copy numbers as well as mRNA abundances under conditions relevant to industrial brewing. Evaluation of data for the genes directly involved in the valine biosynthetic pathway revealed a low expression level of Sc-ILV6 as a potential molecular determinant for low diacetyl formation. This hypothesis was verified by disrupting the two copies of Sc-ILV6 in a commercially used lager brewers' yeast strain, which resulted in 65% reduction of diacetyl concentration in green beer. The Sc-ILV6 deletions did not have any perceptible impact on beer taste. To our knowledge, this has been the first study exploiting natural diversity of lager brewers' yeast strains for strain optimization. PMID- 21824526 TI - Leukotriene B4 receptor BLT-mediated phosphorylation of NF-kappaB and CREB is involved in IL-8 production in human mast cells induced by Trichomonas vaginalis derived secretory products. AB - Trichomonas vaginalis is a protozoan parasite that causes acute tissue inflammation in vaginal trichomoniasis. In this study, we investigated the signaling mechanisms through which T. vaginalis-derived secretory products (TvSP) induce chemokine IL-8 production in human mast cells. Stimulation with TvSP induced up-regulation of IL-8 protein secretion in HMC-1 cells. In addition, TvSP induced phosphorylation of transcription factors NF-kappaB and CREB in HMC-1 cells. Pretreatment of TvSP with lipase, but not heat or proteinase K strongly abolished the stimulatory effect on IL-8 production. Moreover, TvSP-induced IL-8 production and phosphorylation of NF-kappaB or CREB were inhibited when HMC-1 cells were stimulated with modified TvSP collected from 5-lipooxygenase inhibitor treated trichomonads. Indeed, T. vaginalis-secreted lipid mediator LTB(4) (700pg/ml) from 1*10(7) trichomonads. Furthermore, pretreatment of HMC-1 cells with antagonists for LTB(4) receptors BLT1 or BLT2 abolished the stimulatory effects of TvSP. Finally, TvSP-induced IL-8 production was inhibited by pretreatment with IkappaB or CREB inhibitors. These results suggest that T. vaginalis-derived secretory lipid mediator LTB(4) induces IL-8 production in mast cells via BLT-dependent activation of NF-kappaB and CREB. PMID- 21824528 TI - Genetically manipulated adult stem cells for wound healing. AB - New knowledge of the signal controls and activities of adult stem cells (ASCs) involved in wound repair have led to extensive investigation of the topical delivery of biomacromolecules and multipotent stem cells to injured tissues for scar-less regeneration. The transplantation of genetically recombinant stem cells, which have roles as both therapeutics and carriers for gene delivery to wound sites, represents an attractive strategy for wound treatment. Here, we compare viral and non-viral vectors and three-dimensional scaffold-based transfection strategies in terms of their biosafety, recombinant efficiency and influence on the differentiation of ASCs, to indicate the future direction of the application of recombinant ASCs in wound treatment. PMID- 21824529 TI - Dancing with the sterols: critical roles for ABCG1, ABCA1, miRNAs, and nuclear and cell surface receptors in controlling cellular sterol homeostasis. AB - ATP binding cassette (ABC) transporters represent a large and diverse family of proteins that transport specific substrates across a membrane. The importance of these transporters is illustrated by the finding that inactivating mutations within 17 different family members are known to lead to specific human diseases. Clinical data from humans and/or studies with mice lacking functional transporters indicate that ABCA1, ABCG1, ABCG4, ABCG5 and ABCG8 are involved in cholesterol and/or phospholipid transport. This review discusses the multiple mechanisms that control cellular sterol homeostasis, including the roles of microRNAs, nuclear and cell surface receptors and ABC transporters, with particular emphasis on recent findings that have provided insights into the role(s) of ABCG1. This article is part of a Special Issue entitled Advances in High Density Lipoprotein Formation and Metabolism: A Tribute to John F. Oram (1945-2010). PMID- 21824530 TI - Antitumor and immunomodulatory properties of artemether and its ability to reduce CD4+ CD25+ FoxP3+ T reg cells in vivo. AB - BACKGROUND: Development of agents that specifically kill cancer cells and simultaneously elicit antitumor immune response is a step forward in cancer therapy. In the present study, we investigated whether the administration of artemether contributes to the augmentation of antitumor immunity and the regression of tumor tissues in a mouse model of breast cancer. METHODS: An optimal immunostimulatory dose of artemether (ART) was defined by DTH reaction and antibody production in sRBC-challenged mice. Subsequent experiments were carried out on tumor-bearing BALB/c mice. In the first group of tumor-bearing mice, the dose of 10 mg/kg/day of artemether were intraperitoneally administered to each animal for six times. The second group was treated with 20 mg/kg/day of cyclophosphamide as a positive control, and the last group (negative control) received the ART diluents. Tumor size was measured during the 10-day experiment; on the last day, mice were sacrificed and their splenocytes and tumor infiltrating lymphocytes were harvested. The concentration of IL-4 and IFN-gamma cytokines (using ELISA assay) and the percentage of splenic and tumor Treg cells (using Flowcytometry analysis) were measured. RESULTS: Artemether could increase both DTH reaction and the production of hemagglutinating antibody in normal mice. Administration of ART profoundly suppressed the progression of tumor tissues. As well, it was significantly effective in the depletion of splenic CD4+ CD25+ Foxp3+ Treg cells (p-value>0.05). ART also increased the production of IL-4 (p value<0.05) and IFN-gamma (p-value>0.05). As a conclusion, the cytotoxic and immunomodulatory properties of artemether were acknowledged in vivo. PMID- 21824531 TI - Neonatal stress and abnormal hypercapnic ventilatory response of adult male rats: the role of central chemodetection and pulmonary stretch receptors. AB - Neonatal maternal separation (NMS) is a form of stress that interferes with respiratory control development. At adulthood, the hypercapnic ventilatory response (HCVR) of male NMS rats is lower than controls both during wakefulness and anesthesia. To address the mechanisms underlying the respiratory phenotype of NMS rats, we first used phrenic nerve recording in anesthetised (urethane: 1.0 g/kg+isoflurane: 0.5%), vagotomised, and artificially ventilated (hyperoxic) animals, to test the hypothesis that the central chemodetection is altered by NMS. As no difference was observed between groups, we then tested the hypothesis that NMS affects respiratory modulation by pulmonary stretch receptors (PSRs). Experiments were performed on urethane/isoflurane anesthetised, spontaneously breathing rats (with vagi intact). The role of PSR and their implication was assessed during normo- and hypercapnia (+10 mm Hg above baseline) by the induction of a positive airway pressure (Paw). The slopes of the relationships between the ventilatory variables (frequency, amplitude, and minute activity) and the different levels of Paw in each group were compared between groups. During normocapnia, the decrease in breathing frequency induced by increasing Paw was greater in control than in NMS rats, thereby revealing that NMS reduces the Hering-Breuer reflex (HBR). During hypercapnia, however, the responses of control and NMS rats were similar indicating that the stimulation of chemoreceptors by CO(2) reduced the influence of stretch receptors on ventilation. These results indicate NMS does not affect central CO(2) chemosensitivity of this preparation but that differences in PSR function and/or signal integration contribute to the effects of NMS on respiratory regulation. PMID- 21824527 TI - The functional cycle of visual arrestins in photoreceptor cells. AB - Visual arrestin-1 plays a key role in the rapid and reproducible shutoff of rhodopsin signaling. Its highly selective binding to light-activated phosphorylated rhodopsin is an integral part of the functional perfection of rod photoreceptors. Structure-function studies revealed key elements of the sophisticated molecular mechanism ensuring arrestin-1 selectivity and paved the way to the targeted manipulation of the arrestin-1 molecule to design mutants that can compensate for congenital defects in rhodopsin phosphorylation. Arrestin 1 self-association and light-dependent translocation in photoreceptor cells work together to keep a constant supply of active rhodopsin-binding arrestin-1 monomer in the outer segment. Recent discoveries of arrestin-1 interaction with other signaling proteins suggest that it is a much more versatile signaling regulator than previously thought, affecting the function of the synaptic terminals and rod survival. Elucidation of the fine molecular mechanisms of arrestin-1 interactions with rhodopsin and other binding partners is necessary for the comprehensive understanding of rod function and for devising novel molecular tools and therapeutic approaches to the treatment of visual disorders. PMID- 21824532 TI - Cosmetic medicine and surgery: a shift in perspective. PMID- 21824533 TI - An overview of cosmetic medicine and surgery: past, present, and future. AB - The evolution of thought and process in cosmetic medicine and surgery has united specialists from various backgrounds with the goal of providing safe, reproducible techniques to improve the various elements of the aging face from within and without. The realization that the aging face is both vector and volume based has dramatically altered the approach to reversing the signs of aging. Ultimately, it was the joining of forces from multiple specialties that provided a blueprint for impressive improvement in the return of a youthful, natural look. PMID- 21824534 TI - The interface of cosmetic medicine and surgery: working from the inside and the outside. AB - Minimally invasive or noninvasive procedures account for an overwhelming majority of cosmetic procedures. These procedures include botulinum toxin injections, soft tissue fillers, chemical peel, dermabrasion, and laser hair removal. This article reviews some of the principles involved in these procedures. Plastic surgeons need to be equally familiar with surgical and nonsurgical approaches to cosmetic medicine to provide a complete set of therapeutic options to their patients. PMID- 21824535 TI - BeautiPHIcationTM: a global approach to facial beauty. AB - The recent availability of safe volumizing fillers has provided cosmetic physicians with the tools necessary to contour facial features non-surgically and cost-effectively. This review focuses on outlining objective parameters necessary for creating a template to maximize each individual's facial beauty. Phi relationships can be approached for all facial features and rely on the establishment of smooth ogee curves in all dimensions. Once goals have been determined and a budget established, a logical syntax is used to create an algorithm for selecting products and procedures. The methodology leads to consistent and pleasing results with a high rate of patient satisfaction. PMID- 21824536 TI - Volumizing the face with soft tissue fillers. AB - This article discusses the role of injectable soft-tissue fillers in the aging face, and their clinical and chemical behavior. Temporary and permanent fillers are discussed, namely hyaluronic acids, calcium hydroxylapatite, poly-l-lactic acid, liquid silicone, and polymethylmethacrylate. Techniques and outcomes are presented. PMID- 21824537 TI - Dermabrasion. AB - This review presents skin anatomy, dermabraders, indications for dermabrasion and microdermabrasion, and dermabrasion techniques for the face, along with potential complications. Dermabrasion is a minimally invasive technique used for skin resurfacing. Its applications include treatment of rhytids, abnormal scarring, and premalignant lesions. The risks of complications are low and include pigment changes, hypertrophic scarring, and infection. Despite the introduction of newer therapies, such as lasers and chemical peels, dermabrasion remains an effective tool for physicians to combat the effects of aging without the downtime required for surgery. PMID- 21824538 TI - The art and science of new advances in cosmeceuticals. AB - The need for cosmeceutical research is ever present. This article has tried to highlight the chemistry of botanic extracts in the current marketplace and review the best research available. In some ways, more questions have been raised than answered; yet, ideas for intellectual discourse have been provided. Herein lies the physician cosmeceutical challenge. PMID- 21824539 TI - An overview of botulinum toxins: past, present, and future. AB - Although the mechanism of action of botulinum toxin (BTX) has been intensively studied, many unanswered questions remain regarding the composition and clinical properties of the two formulations of BTX currently approved for cosmetic use. In the first half of this review, these questions are explored in detail, with emphasis on the most pertinent and revelatory studies in the literature. The second half delineates most of the common and some not so common uses of BTX in the face and neck, stressing important patient selection and safety considerations. Complications from neurotoxins at cosmetic doses are generally rare and usually technique dependent. PMID- 21824540 TI - Principles and practice of cutaneous laser and light therapy. AB - Laser technology has evolved rapidly in the last 2 decades. The theory of selective photothermolysis guides the proper selection and use of lasers to safely and effectively treat patients. This review summarizes the basic concepts and adjustable parameters for laser devices, emphasizing the importance of selective photothermolysis in clinical practice. It then covers the clinical applications of laser devices, including vascular lesions, hair removal, tattoo removal, facial rejuvenation, and fractional resurfacing. The authors intend to make the reader feel comfortable with the proper selection and application of lasers to treat their patients. PMID- 21824541 TI - Radio frequency energy for non-invasive and minimally invasive skin tightening. AB - This article reviews the non-invasive and minimally invasive options for skin tightening, focusing on peer-reviewed articles and presentations and those technologies with the most proven or promising RF non-excisional skin-tightening results for excisional surgeons. RF has been the mainstay of non-invasive skin tightening and has emerged as the "cutting edge" technology in the minimally invasive skin-tightening field. Because these RF skin-tightening technologies are capital equipment purchases with a significant cost associated, this article also discusses some business issues and models that have proven to work in the plastic surgeon's office for non-invasive and minimally invasive skin-tightening technologies. PMID- 21824542 TI - Fractionation: a new era in laser resurfacing. AB - Fractional photothermolysis combines the benefits of fully ablative lasers with significantly reduced downtime and fewer complications. Skin is treated in a fractional manner, with narrow cylinders of tissue being thermally heated and normal adjacent skin left unaffected, and the fractional devices have shown effectiveness in treating a variety of conditions, especially scarring and photodamage. There are many devices that use fractional photothermolysis, and practitioners are becoming more adept at using optimal parameters to induce near CO(2) laser benefits. Fractionated lasers have become the cornerstone of a minimally invasive treatment regimen and have ushered in a new era of laser skin rejuvenation. PMID- 21824543 TI - Laser, light, and energy devices for cellulite and lipodystrophy. AB - Cellulite affects all races, and it is estimated that 85% of women older than 20 years have some degree of cellulite. Many currently accepted cellulite therapies target deficiencies in lymphatic drainage and microvascular circulation. Devices using radiofrequency, laser, and light-based energies, alone or in combination and coupled frequently with tissue manipulation, are available for improving cellulite. Laser assisted liposuction may improve cellulite appearance. Although improvement using these devices is temporary, it may last several months. Patients who want smoother skin with less visible cellulite can undergo a series of treatments and then return for additional treatments as necessary. PMID- 21824544 TI - Sclerotherapy: it is back and better. AB - With the recent US Food and Drug Administration (FDA) approval of polidocanol in the United States, there has been a resurgence of interest in sclerotherapy. Despite the popularity of laser therapy, sclerotherapy remains the gold standard for treating spider and reticular veins. Although this traditional method of treatment has been around for more than 100 years, better sclerosing agents and newer techniques have made sclerotherapy safer and more efficacious than ever before. This article is a primer for physicians interested in updating their skills in sclerotherapy. It reviews common sclerosants, sclerotherapy techniques, patient evaluation, complications, and recent advancements in sclerotherapy. PMID- 21824545 TI - Injectable therapies for localized fat loss: state of the art. AB - This review presents mechanisms of action and a review of the clinical applications of injections currently in development for localized fat reduction. After being received with initial enthusiasm earlier in the decade, mesotherapy and other injectable methods for fat loss (Lipodissolve, PC/DC, DC, injection lipolysis, adipolysis) have been subjects of critical scrutiny by the media and the US Food and Drug Administration. Several medications with novel detergent and lipolytic activity are in development and have demonstrated potential as minimally invasive fat reducing treatments. PMID- 21824546 TI - Noninvasive body contouring with radiofrequency, ultrasound, cryolipolysis, and low-level laser therapy. AB - Noninvasive body contouring is perhaps one of the most alluring areas of esthetic surgery today. This article discusses current noninvasive body-contouring modalities, including suction massage devices, radiofrequency energy, high frequency focused ultrasound, cryolipolysis, and low-level light laser therapy devices. It also discusses imminent technologies awaiting approval by the Food and Drug Administration, reviews the basic science and clinical effects behind each of these existing and emerging technologies, addresses patient selection and clinical applications of each modality, and discusses the applicability and economics of providing noninvasive lipolysis services in office. PMID- 21824547 TI - Lifting and wound closure with barbed sutures. AB - The advent of barbed sutures has been a novel and useful adjunct for the aesthetic plastic surgeon in properly selected patients. The deployment of a barbed suture minimizes the risks of cheese wiring and stress relaxation, facilitating the minimally invasive repositioning of soft tissue in the head and neck, as well as optimizing and enhancing traditionally long and potentially tedious procedures in body contouring. This article highlights the advances, advantages, and efficacy associated with the use of barbed sutures in lifting and wound closure. PMID- 21824548 TI - Preface to South Pacific Environmental Radioactivity Association (SPERA). PMID- 21824550 TI - Sarcopenia: origins and clinical relevance. AB - To a considerable extent, the advent of the term sarcopenia has contributed to the focus on this important condition and its effects on the quality of life and care of older persons. It is hoped that the advances in our understanding of the etiology and treatment of sarcopenia will further contribute to placing this diagnosis and treatment at a higher priority in the management of older persons and prevention of disability. PMID- 21824551 TI - Toward a definition of sarcopenia. AB - The definition of sarcopenia has been thoroughly discussed by scientific stakeholders and industry representatives to increase the clinical applicability of the concept. The pooled consensus from 3 of 5 recent and parallel processes, of which 2 are pending, is that sarcopenia is mainly, but not only, an age related condition defined by the combined presence of reduced muscle mass and muscle function. Contributing factors to sarcopenia are senescence, chronic disease, physical inactivity, and poor food intake. Cachexia may be considered as one etiologic pathway of an accelerated sarcopenia. The adjusted and extended definitions of sarcopenia promote the clinical use of the concept. PMID- 21824552 TI - The epidemiology of sarcopenia. AB - The term sarcopenia was coined in 1989 and refers to the age-related loss in skeletal muscle mass. Operational definitions of sarcopenia have been used in research studies to identify older persons with healthy muscle mass values (normal) and older adults with unacceptably low muscle mass values (sarcopenic). Despite the enormous research on sarcopenia that has been completed in the past 20 years, sarcopenia currently receives little attention in the clinical setting. To address this issue, the European Working Group on Sarcopenia in Older People recently developed a consensus definition of sarcopenia. The availability of a consensus definition may assist with the integration of sarcopenia into mainstream geriatric assessment. PMID- 21824553 TI - Physiopathological mechanism of sarcopenia. AB - The etiology of sarcopenia is multifactorial but still poorly understood, and the sequelae of this phenomenon represent a major public health issue. Age-related loss of muscle mass can be counteracted by adequate metabolic interventions including nutritional intake and exercise training. Other strategies including changes in daily protein pattern, the speed of protein digestion, or specific amino acid supplementation may be beneficial to improve short-term muscle anabolic response in elderly people. A multimodal approach combining nutrition, exercise, hormones, and specific anabolic drugs may be an innovative treatment for limiting the development of sarcopenia with aging. PMID- 21824554 TI - Consequences of sarcopenia. AB - This article describes the relationship of sarcopenia and dynapenia with three important outcomes in aging research: functional status, falls, and mortality. The data from epidemiologic studies conducted in large samples of older men and women suggest that muscle functioning, as indicated by muscle strength or muscle power, has a strong impact on functional status, falls, and mortality. Furthermore, there is evidence that the relationship between poor muscle strength and these three different outcomes is not influenced by muscle size. For the prevention of functional decline, falls, and early mortality in older men and women a major focus on maintaining or increasing muscle strength instead of muscle size seems warranted. PMID- 21824555 TI - Sarcopenia and obesity. AB - Four body composition phenotypes exist in older adults: normal, sarcopenic, obese, and a combination of sarcopenic and obese. There is no consensus, however, on the definitions and classifications of these phenotypes and their etiology and consequences continue to be debated. The lack of standard definitions, particularly for sarcopenia and sarcopenic obesity, creates challenges for determining prevalence across different populations. The etiology of these phenotypes is multifactorial with complex covariate relationships. This review focuses on the current literature addressing the classification, prevalence, etiology, and correlates of sarcopenia, obesity, and the combination of sarcopenia and obesity, referred to as sarcopenic obesity. PMID- 21824556 TI - Current and future pharmacologic treatment of sarcopenia. AB - Sarcopenia is a complex multifactorial condition that can by treated with multimodal approaches. No pharmacologic agent to prevent or treat sarcopenia has been as efficacious as exercise (mainly resistance training) in combination with nutritional intervention (adequate protein and energy intake). However, performing resistance training sessions and following nutritional advice can be challenging, especially for frail, sarcopenic, elderly patients, and results remain only partial. Therefore, new pharmacologic agents may substantially reduce the functional decline in older people. This article reviews the new pharmacologic agents currently being assessed for treating sarcopenia. PMID- 21824557 TI - Physical activity and sarcopenia. AB - Physical activity can be a valuable countermeasure to sarcopenia in its treatment and prevention. In considering physical training strategies for sarcopenic subjects, it is critical to consider personal and environmental obstacles to access opportunities for physical activity for any patient with chronic disease. This article presents an overview of current knowledge of the effects of physical training on muscle function and the physical activity recommended for sarcopenic patients. So that this countermeasure strategy can be applied in practice, the authors propose a standardized protocol for prescribing physical activity in chronic diseases such as sarcopenia. PMID- 21824558 TI - Clinical trials on sarcopenia: methodological issues regarding phase 3 trials. AB - Phase 3 trials estimate the effectiveness of an intervention to prevent, delay the onset of, or treat sarcopenia. Participants should have sarcopenia or present a sarcopenia risk profile. Control group should be characterized by the best standard of clinical care. This article further develops issues on sarcopenia definition, target population, primary and secondary end points, duration of the trials, muscle mass assessment, strength and physical performance assessment, and control of possible confounders. The challenges to conduct phase 3 trials in the elderly should not offset the opportunities for the development of new strategies to counteract sarcopenia and prevent late-life disability. PMID- 21824559 TI - Early infantile Krabbe disease: results of the World-Wide Krabbe Registry. AB - New York State began screening for Krabbe disease in 2006 to identify infants with Krabbe disease before symptom onset. Because neither galactocerebrosidase activity nor most genotypes reliably predict phenotype, the World Wide Registry was developed to determine whether other clinical/neurodiagnostic data could predict early infantile Krabbe disease in the newborn screening population. Data on disease course, galactocerebrosidase activity, DNA mutations, and initial neurodiagnostic studies in 67 symptomatic children with early infantile Krabbe disease were obtained from parent questionnaires and medical records. Initial signs included crying/irritability, cortical fisting, and poor head control. Galactocerebrosidase activity was uniformly low. Eight of 17 manifested novel mutations. Ninety-two percent (n = 25) exhibited elevated cerebrospinal fluid protein; 76% (n = 42) demonstrated abnormal magnetic resonance images; 67% (n = 15) exhibited abnormal computed tomography findings; 43% (n = 28) produced abnormal electroencephalogram findings; 100% (n = 5) demonstrated abnormal nerve conduction velocities; 83% (n = 6) produced abnormal brainstem evoked responses; and 50% (n = 6) exhibited abnormal visual evoked responses. One, 2, and 3 year survivals were 60%, 26%, and 14%, respectively. Although most symptomatic patients with the early infantile phenotype manifested abnormal cerebrospinal fluid protein, magnetic resonance imaging, brainstem evoked responses, and nerve conduction velocities, studies of affected children may be normal. Other biomarkers are needed to predict phenotype in the newborn screening population. PMID- 21824560 TI - Laterality of brain and ocular lesions in Aicardi syndrome. AB - This study reports a large case series of children with Aicardi syndrome. A new severity scoring system is established to assess sidedness of ocular and brain lesions. Thirty-five children were recruited from Aicardi syndrome family conferences. All children received dilated ophthalmologic examinations, and brain magnetic resonance images (MRIs) were reviewed. Ocular and brain MRI Aicardi lesion severity scores were devised. A linear mixed model was used to compare each side for the ocular and brain MRI severity scores of Aicardi-associated disease. Twenty-six children met the inclusion criteria for the study. All subjects were female, ages 3 months to 19 years. Rates per child of optic nerve coloboma, severe lacunae, and microphthalmos in one or both eyes (among those with complete fundus examinations available) were 10/24 (42%), 8/22 (36%), and 7/26 (27%), respectively. Ocular and brain MRI asymmetry was found in 18% (4/22) and 58% (15/26) of subjects, respectively, with more right-sided brain lesions than left-sided ones (V = 52, P = 0.028). A significant correlation between sidedness of brain disease and microphthalmos was noted (T = 2.54, P = 0.02). This study substantiates the range and severity of Aicardi syndrome-associated ophthalmologic and brain MRI lesions from prior smaller case series. PMID- 21824561 TI - Inherited thrombophilia in childhood arterial stroke: data from Lebanon. AB - Pediatric ischemic stroke still represents a burden, and more than half of the survivors will experience cognitive or motor disabilities. The objective of this study was to investigate the role of thrombophilia in a cohort of children with arterial ischemic stroke. The records of infants and children with clinically and radiologically confirmed stroke were reviewed. Patients with venous or perinatal stroke were not included. Thirty-three patients were diagnosed with arterial ischemic stroke. The male/female ratio was 1.75:1. The median age was 4 years. The most frequent clinical manifestations were hemiparesis (54.5%) and seizures (33.3%). Genetic thrombophilia testing was available on 24 patients. Nine of the 24 patients (37.5%) were heterozygous for factor V Leiden. None of the patients carried the factor II G20210A variant. Ten patients (41.7%) were heterozygous and 3 (12.5%) were homozygous for methylenetetrahydrofolate reductase (MTHFR) C677T variant. Fifteen patients (62.5%) had one or more genetic polymorphism. Factor V Leiden was significantly associated with arterial ischemic stroke (P < 0.001). Stroke recurred in 2 children with multiple risk factors and MTHFR C677T mutation. Factor V Leiden is one of the major genetic risk factors for pediatric arterial ischemic stroke in Lebanon. MTHFR C677T was prevalent among patients with recurrent stroke. PMID- 21824562 TI - Thyroid hormone levels in children receiving carbamazepine or valproate. AB - Antiepileptic therapy is associated with alteration of thyroid hormone levels. We evaluated the effect of valproate and carbamazepine therapy on the thyroid hormone profile of epileptic children. Subjects included children aged 2-12 years receiving therapy for at least 6 months. Free triiodothyronine, free thyroxine, and thyroid-stimulating hormone were measured by electrochemiluminescent assay in 30 children receiving carbamazepine, 34 children receiving valproate, and 30 age- and sex-matched control subjects. Groups were similar for age, body mass index, and duration of therapy. Thyroid-stimulating hormone (mean +/- S.D.) was 2.67 +/- 1.66, 4.53 +/- 1.9, and 3.61 +/- 1.75 MU IU/mL in the control, valproate, and carbamazepine group, respectively (P < 0.001). Free thyroxine was 1.39 +/- 0.19, 1.40 +/- 0.63, 1.11 +/- 0.19 ng/dL (P = 0.009). Free triiodothyronine was 4.03 +/ 0.74, 4.14 +/- 0.94, 3.92 +/- 0.68 pg/mL (P = 0.54). When groups were compared 2 at a time, there was no difference in free triiodothyronine (P > 0.05). Free thyroxine levels in the carbamazepine group were significantly different from valproate (P = 0.015) and control (P = 0.027). Thyroid-stimulating hormone increased with both valproate and carbamazepine compared to control but was significant with valproate (P < 0.001). We conclude that carbamazepine and valproate therapy alters thyroid functions by decreasing free thyroxine levels. Compensation by increase in thyroid-stimulating hormone is better with valproate. The need for monitoring and supplementation should be assessed further. PMID- 21824563 TI - Quality of life in children and adolescents with cerebral palsy and myelomeningocele. AB - The aim of this study was to compare health-related quality of life in children with cerebral palsy and with myelomeningocele. Fifty-seven children with spastic cerebral palsy and 34 patients with myelomeningocele aged 5-16 years were included in the study. Their mothers completed standardized measures on the Revidierter Kinder Lebensqualitatsfragebogen (KINDL-R) parent questionnaire. The 2 groups were demographically comparable. The children with cerebral palsy were classified more frequently into levels II (n = 24) and III (n = 18) of the Gross Motor Function Classification System. Other patients were classified into levels IV (n = 5) and V (n = 10). Three patients with myelomeningocele were community walkers, 10 could walk with assistive devices, and 21 used a wheelchair. Lesion level was thoracic in 13 patients, lumbar in 17, and sacral in 4. Twenty-nine patients (85.3%) with myelomeningocele had hydrocephalus, and 27 had a shunt. Parents in the both studied groups reported similar overall quality of life of their children in the dimensions of physical and emotional well-being, self esteem, family, friends, and school. No significant correlations between the quality-of-life scores and age, walking ability, and mental development of the studied groups were found. PMID- 21824564 TI - Epileptic seizures in infants and children with mitochondrial diseases. AB - The purpose of this study is to describe the characteristics of epileptic seizures in infants and children with mitochondrial diseases. From 1984 to December 2010, data from 46 of 76 patients diagnosed as having mitochondrial diseases with epileptic seizures were reviewed. Age at seizure onset, epileptic phenotypes, electroencephalogram findings, magnetic resonance imaging features, and treatment outcome in patients with syndromic or nonsyndromic mitochondrial diseases were analyzed. Thirty (65%) of 46 patients manifested seizures before the age of 1 year; 43% had Leigh syndrome and 53% had nonsyndromic mitochondrial diseases. Twenty-eight (61%) of 46 patients exhibited seizures as the manifesting complaint. Nineteen (68%) of 28 patients had nonsyndromic mitochondrial diseases. The most frequently observed electroencephalogram finding was background slow activity (28/46; 61%) in both groups. The most common cortical abnormality relevant to clinical seizures was diffuse brain atrophy on the brain magnetic resonance imaging (26/45; 58%), which was commonly observed in patients with nonsyndromic mitochondrial diseases (16/26; 62%). Despite treatment, 49% of patients experienced less than 50% seizure reduction rate, 77% of whom had nonsyndromic mitochondrial diseases. Leigh syndrome and nonsyndromic mitochondrial diseases often manifest as infantile seizures. Epileptic seizure as the initial complaint, diffuse brain atrophy, and refractory epilepsy were more common in patients with nonsyndromic mitochondrial diseases. PMID- 21824565 TI - Selective serotonin reuptake inhibitors and periodic limb movements of sleep. AB - Serotonin reuptake inhibitors may induce periodic limb movements of sleep in adults. We undertook a retrospective review of polysomnography data of 1,023 children acquired at our institution over 1 year to assess whether children receiving serotonin reuptake inhibitors have a higher risk of periodic limb movements of sleep than children that are not treated with these medications. Periodic limb movements of sleep were found in 13 (31.7%) of 41 children receiving serotonin reuptake inhibitors and in 77 (7.8%) of 982 children not receiving serotonin reuptake inhibitors (odds ratio 5.45). Furthermore, the median periodic limb movement index in patients receiving serotonin reuptake inhibitors was significantly higher than patients not receiving serotonin reuptake inhibitors (11.2 and 6.5 respectively; P < 0.05). Children receiving serotonin reuptake inhibitors are at risk of periodic limb movements of sleep. Appropriate clinical judgment and medical management may result in better control of periodic limb movements of sleep and improved quality of life in these patients. PMID- 21824566 TI - Glioblastoma multiforme in children: report of 13 cases and review of the literature. AB - We present clinical and histopathologic data from 13 children who underwent craniotomy for newly diagnosed glioblastoma multiforme. Clinical characteristics were compared to those in adult patients (n = 403). The mean age of the children was 10.4 years. The male/female ratio was 3.3:1. The localization was infratentorial in 6 cases (brainstem, n = 4; cerebellum, n = 2) and supratentorial in 7 cases (frontal, n = 2; parietal, n = 3; temporal, n = 2). Infratentorial localization was observed solely in children from 0-10 years, whereas supratentorial location was found in children between the age of 11 and 21 years. Surgical resection was followed by radiotherapy in 11 cases and additional chemotherapy in 8 cases. Giant cell glioblastoma multiforme was found in 2 cases (15%, vs 1-5% in adults). The mean Ki-67 proliferation index was 29.4% (vs 25.6% in adults). There were no significant differences in histologic morphology between children and adults. The total survival time was 90 weeks (vs 47 weeks in adults). One patient is still alive after 8 years. Predictive factors of prolonged survival were the extent of tumor resection and radio- and/or chemotherapy after resection. Multidisciplinary treatment of glioblastoma in childhood might lead to better median survival than in adults. Infratentorial tumor location was observed exclusively in children younger than 11 years old. PMID- 21824567 TI - Hunter disease before and during enzyme replacement therapy. AB - Mucopolysaccharidosis type II (Hunter disease) is a lysosomal storage disease attributable to X-linked deficiency of the enzyme alpha-L-iduronate-sulfatase. Because of this deficiency, glycosaminoglycanes accumulate in various tissues and body fluids. We describe three patients representing the broad spectrum of Hunter disease and their response to enzyme replacement therapy. Patient 1 did not manifest central nervous system involvement, patient 2 manifested moderate neurologic disease, and patient 3 had already manifested a severe neurologic course during early infancy. In all patients, improvements in visceral organ size, physical capacity, and gastrointestinal functioning were reported. Moreover, all three patients demonstrated a gain in height, improved functioning of the upper limb, and a reduced need for antibiotics to treat upper airway infections. The response to enzyme replacement therapy occurred independent of type of genetic mutation (missense or frame shift), and we observed only mild infusion-related reactions. We conclude that all patients with mucopolysaccharidosis type II (those with and without clinical central nervous system involvement) may benefit from enzyme replacement therapy. PMID- 21824568 TI - Novel TSEN54 mutation causing pontocerebellar hypoplasia type 4. AB - Pontocerebellar hypoplasia exhibits a diverse range of etiologies, including six known autosomal recessive, single gene disorders. We describe a molecularly confirmed case of pontocerebellar hypoplasia type 4, a rare and severe neonatal phenotype with a novel TSEN54 mutation, presenting with polyhydramnios, hypertonia, and early neonatal death. The patient manifested severe hypoplasia of the cerebellum and brainstem. The neuropathologic findings in pontocerebellar hypoplasia type 4 develop late in gestation, and therefore prenatal diagnosis with ultrasonography is of limited use. Establishing a molecular diagnosis in the proband is critical for allowing couples to plan future pregnancies. PMID- 21824569 TI - Central nervous system vasculitis with positive antithyroid antibodies in an adolescent boy. AB - Hashimoto's encephalopathy is diagnosed when patients exhibit features of corticosteroid-responsive encephalopathy and positive antithyroid antibodies. The relationship between antithyroid antibodies and encephalopathy is subject to considerable debate. We describe corticosteroid-responsive encephalopathy in a 14 year-old boy with positive antimicrosomal antibodies. His history included subtle neurocognitive decline. He presented with seizures. He underwent a brain biopsy before initiating treatment after his third episode. That biopsy was consistent with central nervous system vasculitis. This report is unique because, to our knowledge, it describes the first pretreatment brain biopsy of a pediatric patient who fits the criteria for Hashimoto's encephalopathy. PMID- 21824570 TI - Hemiconvulsion-hemiplegia-epilepsy syndrome associated with CACNA1A S218L mutation. AB - Hemiconvulsion-hemiplegia-epilepsy syndrome involves sudden and prolonged unilateral seizures, followed by transient or permanent hemiplegia and epilepsy during infancy or early childhood. Some patients with familial hemiplegic migraine and demonstrating the S218L mutation in CACNA1A experience severe attacks with unilateral cerebral edema after trivial head trauma. We report on a 5-year-old Japanese girl presenting with hemiconvulsion-hemiplegia-epilepsy syndrome after infection with parvovirus B19. Magnetic resonance imaging performed 2 days after admission revealed cerebellar atrophy and marked hyperintensity in the left hemisphere on T(2)-weighted and diffusion-weighted imaging. Magnetic resonance angiography performed 7 days after admission demonstrated obliteration of the left proximal middle cerebral artery in the acute phase. However, this finding was not evident on brain angiography performed 25 hours after magnetic resonance angiography. Genetic analysis of familial hemiplegic migraine revealed a heterozygous S218L mutation in CACNA1A. Taken together, these results suggest that vasospasms of cerebral vascular smooth muscle, with possible cortical spreading depression, may have caused the hemiconvulsions and hemiplegia in the left hemisphere. This case report is the first, to the best of our knowledge, to associate CACNA1A with hemiconvulsion hemiplegia-epilepsy syndrome and familial hemiplegic migraine, and to suggest that similar pathogenic mechanisms may underlie these two disorders. PMID- 21824571 TI - Posterior fossa dermoid with Klippel-Feil syndrome in a child. AB - Intracranial dermoid tumors constitute a rare entity. Their association with Klippel-Feil anomaly is all the more rare. These lesions, if associated with dermal sinuses, receive attention when a patient presents with features of central nervous system infection. We describe a 5-year-old girl who presented with purulent discharge from an occipital dermal sinus with an infected posterior fossa dermoid associated with cerebellar abscesses and characteristic Klippel Feil anomaly. PMID- 21824572 TI - MRI findings and steroid therapy for neuralgic amyotrophy in children. AB - Neuralgic amyotrophy is not uncommon in adults but is relatively rare in children. We recently encountered 2 cases of neuralgic amyotrophy in children. Patient 1 was a 7-year-old girl who developed a right leg paralysis after an epileptic seizure. Lumbar plexus T(2)-weighted magnetic resonance imaging (MRI) revealed a hyperintense and thickened portion extending from the root to the knee region of the right sciatic nerve, and T(1)-weighted conventional spin echo with gadolinium administration revealed enhancement. Patient 2 was a 4-year-old boy who experienced a sudden onset of severe right arm pain and paralysis. T(2) weighted MRI with a short tau inversion recovery revealed a slightly thickened and high intensity region at the right C(6)-C(8) level. After high-dose methylprednisolone pulse therapy was performed in each case, patient 1 experienced complete recovery, whereas patient 2 experienced only amelioration of pain. A diagnosis of neuralgic amyotrophy in children was facilitated by an MRI study (T(2) weighed with short tau inversion recovery and T(1) weighted with gadolinium enhancement), and early steroid therapy might have improved the condition of these children. PMID- 21824573 TI - Rare magnetic resonance imaging findings in medium-chain acyl-coenzyme A dehydrogenase deficiency. AB - A 3-year-old boy receiving valproate for 1.5 months presented with sudden-onset unprovoked seizures and unconsciousness. Hypoketotic hypoglycemia, hyperammonemia, and deranged liver function were detected. Elevated medium-chain urinary acylglycines and plasma acylcarnitine were detected. His serum valproate level was elevated. Valproate toxicity had been precipitated in presence of medium-chain acyl-CoA dehydrogenase deficiency. Cranial magnetic resonance imaging brain indicated unilateral basal ganglia ischemia instead of the bilateral changes expected in metabolic disease. PMID- 21824574 TI - Congenital cataracts, facial dysmorphism, and neuropathy syndrome. AB - Congenital cataracts, facial dysmorphism, and neuropathy syndrome is a delineated genetic disease exclusively manifested in the Roma population. The pattern of inheritance is autosomal recessive, and a causative mutation is evident in the CTDP1 gene. Affected patients display congenital cataracts, microcornea, peripheral neuropathy, mild facial dysmorphism, hypogonadism, and psychomotor delay. We present the second case of this syndrome in a Greek Roma family, diagnosed in early infancy, along with the prenatal diagnosis in a subsequent pregnancy. PMID- 21824575 TI - Horner's syndrome in a child with otitis media: an unusual complication. PMID- 21824577 TI - Attention-deficit hyperactivity disorder in children with benign epilepsy and their siblings. PMID- 21824578 TI - Twenty years: long live NMCD! PMID- 21824579 TI - Management of neck pain. PMID- 21824580 TI - The anatomy and pathophysiology of neck pain. AB - Neck pain should not, and must not, be confused with cervical radicular pain. Equating the two conditions, or confusing them, results in misdiagnosis, inappropriate investigations, and inappropriate treatment that is destined to fail. So critical is the difference that pedagogically it is unwise to include the two topics in the same book, let alone the same article. However, traditions and expectations are hard to break. In deference to habit, this article addresses both entities, but does so by underplaying cervical radicular pain so as to retain the emphasis on neck pain. PMID- 21824581 TI - History, physical examination, and differential diagnosis of neck pain. AB - Neck pain is a common and costly problem in Western society. Nearly two-thirds of the US population will experience neck pain at some point in their lives, and at any one time about 5% of the US population has sufficient neck pain to cause disability. Although the likelihood of defining a precise cause of neck pain is low, if the etiology and structural source can be determined, they may be valuable in directing treatment. Patient history serves to identify red flags and yellow flags, whereas the physical examination, guided by the history, serves primarily to confirm those suspicions. PMID- 21824582 TI - Evaluation of the patient with neck versus shoulder pain. AB - Neck and shoulder pain are common complaints among the general population, being the second and third most common musculoskeletal complaints, respectively, after back pain in the primary care setting. Differentiating between neck and shoulder pain can be challenging, as both share symptoms and physical examination findings. The differential diagnoses of neck and shoulder pain are extensive. Providers are encouraged to develop a systematic, comprehensive, and reproducible approach, including thorough history taking and physical examination along with focused diagnostic testing. PMID- 21824583 TI - Radiologic evaluation of the neck: a review of radiography, ultrasonography, computed tomography, magnetic resonance imaging, and other imaging modalities for neck pain. AB - The patient with neck pain may pose a diagnostic dilemma for the treating physician. As with other areas of medicine, imaging is guided by the history and physical examination. The steady advance of 3-dimensional, functional, and nuclear medicine studies make it increasingly important that the ordering physician be aware of the potential benefits and disadvantages of imaging options. This article reviews the current literature on imaging for the patient with neck pain, illustrates several imaging abnormalities, and discusses the workup of commonly seen patient populations. PMID- 21824584 TI - The electrodiagnostic evaluation of neck pain. AB - Electrodiagnostic studies play an important role in the evaluation of radiculopathy. This article reviews the use of standard nerve conduction studies, late responses, evoked potentials, and needle electrode examination in the electrodiagnostic evaluation of neck pain. PMID- 21824585 TI - Cervical radiculopathy. AB - With regards to spinal disorders, neck pain is one of the most common presenting symptoms, only second to low back pain. When pain radiates down the arm and is associated with sensory and motor disturbances, cervical radiculopathy is suspected. PMID- 21824586 TI - Cervical facet-mediated pain. AB - The cervical zygapophyseal joints, or facet joints, have long been implicated as a source of neck pain. This article examines the epidemiology of pain arising from these joints and relevant anatomy and histology. An emphasis on clinical findings, examination, and imaging are presented, as well as a focus on whiplash associated pain. PMID- 21824587 TI - Cervical spine pain in the competitive athlete. AB - Cervical pain is a common complaint in both the well-conditioned athlete and the weekend warrior. Some injuries are mild in nature, responding to conservative treatment, including rest, medication, physical therapy, and time. However, more serious injuries, especially those involving the cervical spine, can have devastating consequences. Having a comprehensive understanding of the evaluation and management of cervical pain and cervical spine emergencies is crucial for physicians providing coverage for organized athletic events or for those who serve as team physicians. This article reviews the common causes of cervical spine pain in the competitive athlete. PMID- 21824588 TI - Thoracic outlet syndrome. AB - Of the many clinical entities involving the neck region, one of the most intriguing is thoracic outlet syndrome (TOS). TOS is an array of disorders that involves injury to the neurovascular structures in the cervicobrachial region. A classification system based on etiology, symptoms, clinical presentation, and anatomy is supported by most physicians. The first type of TOS is vascular, involving compression of either the subclavian artery or vein. The second type is true neurogenic TOS, which involves injury to the brachial plexus. Finally, the third and most controversial type is referred to as disputed neurogenic TOS. This article aims to provide the reader some understanding of the pathophysiology, workup, and treatment of this fascinating clinical entity. PMID- 21824589 TI - Neck pain from a rheumatologic perspective. AB - This article provides a comprehensive review of rheumatologic considerations for a clinician when evaluating a patient with neck pain. Clearly, anatomic derangements of the cervical spine should be considered when a patient complains of cervicalgia. However, one must also entertain the possibility of a systemic illness as the cause of the pain. Examples of diseases that may present with a prominent feature of neck pain are discussed, including rheumatoid arthritis, ankylosing spondylitis, diffuse idiopathic skeletal hyperostosis, myositis, and fibromyalgia. Evidence of an underlying rheumatic illness may guide the clinician in a different therapeutic direction. PMID- 21824590 TI - Conservative treatment for neck pain: medications, physical therapy, and exercise. AB - This article offers conservative treatment strategies for patients suffering from musculoskeletal causes of neck pain. Basic pharmacology is reviewed, including that of opioids, nonsteroidal anti-inflammatory drugs, adjuvants, and topical analgesics. Moreover, indications for therapeutic exercise, manual therapy, and modalities are reviewed, along with any supporting literature. Treatment considerations with each category of medication and physical therapy are discussed. This article is meant to serve as a resource for physicians to tailor conservative treatment options to their individual patients. PMID- 21824591 TI - Complementary and alternative treatment for neck pain: chiropractic, acupuncture, TENS, massage, yoga, Tai Chi, and Feldenkrais. AB - Of the multitude of treatment options for the management of neck pain, no obvious single treatment modality has been shown to be most efficacious. As such, the clinician should consider alternative treatment modalities if a modality is engaging, available, financially feasible, potentially efficacious, and is low risk for the patient. As evidence-based medicine for neck pain develops, the clinician is faced with the challenge of which treatments to encourage patients to pursue. Treatment modalities explored in this article, including chiropractic, acupuncture, TENS, massage, yoga, Tai Chi, and Feldenkrais, represent reasonable complementary and alternative medicine methods for patients with neck pain. PMID- 21824592 TI - Interventional procedures for cervical pain. AB - Percutaneous interventional spinal procedures have become ubiquitous in the management of cervical pain syndromes. This article reviews the indications, contraindications, patient selection, and potential complications of epidural injections, zygapophyseal joint and medial branch nerve injections, spinal cord stimulation, and radiofrequency neurotomy. PMID- 21824593 TI - Neck pain from a spine surgeon's perspective. AB - Through the myriad of abnormalities encountered by spine surgeons, neck pain is one of the most perplexing. The nature, onset, and location of the pain all provide information as to what the potential pain generator may be. By synthesizing data garnered from the physical examination, imaging studies, and history, a spine surgeon must formulate a differential diagnosis and treatment plan. The surgeon must determine whether the patient has cervical radiculopathy, myelopathy, or simply cervical spondylosis because the treatment of each of these is vastly different. PMID- 21824594 TI - Double contrast-enhanced ultrasonography for the preoperative evaluation of gastric cancer: a comparison to endoscopic ultrasonography with respect to histopathology. AB - BACKGROUND: This study was designed to compare the accuracy of endoscopic ultrasound (EUS) with double contrast-enhanced ultrasound (DCUS) in the staging of gastric malignancies. DCUS is a transabdominal ultrasound technique using both intravenous and intraluminal contrast to enhance sonographic visualization. METHODS: This retrospective study included 162 patients with biopsy-proven gastric cancer who underwent DCUS and EUS preoperatively with the ultrasound results compared with the pathologic findings of the resected specimens. RESULTS: The overall accuracy of DCUS and EUS for tumor (T) staging was 77.2% and 74.7%, respectively. Comparison of ultrasound techniques for T staging revealed that DCUS was superior to EUS only for a tumor depth of T3 (chi-square, P = .025). Lymph nodes were staged correctly with DCUS and EUS in 78.4% and 57.4% of cases, respectively (chi-square, P = .001). CONCLUSIONS: DCUS offers a noninvasive approach for the staging of gastric cancer. DCUS was comparable to EUS in tumor depth evaluation but offered an advantage in lymph node detection. PMID- 21824595 TI - The adoption of advanced surgical techniques: are surgical masterclasses enough? AB - BACKGROUND: The surgical master class is a traditional method for a surgeon to learn new operations. However, there is limited evidence to support that it can help a surgeon adopt a new technique. The aim of this study was to investigate the adoption of surgical techniques after attendance at a surgical master class. METHODS: A questionnaire was sent to surgeons attending surgical master classes in laparoscopic bariatric and colorectal surgery. The questionnaire examined operative experience before attending the master class and the consequent adoption of techniques. RESULTS: There was a significant adoption of colorectal procedures, from 33% to 79% (P = .00011), and bariatric procedures, from 27% to 66% (P = .014), after attendance at the surgical master classes. CONCLUSIONS: This study shows a significant increase in surgeons' performing advanced surgical procedures after attendance at a surgical master class. This is the first study to demonstrate the effectiveness of the master class in terms of surgeons' adopting new techniques. PMID- 21824597 TI - Program directors' views on general surgery resident travel for transplant rotations. AB - BACKGROUND: Some program directors in surgery (PDs) must maintain transplant rotations at nonintegrated (away) hospitals. This study investigated the opinions of PDs related to resident travel for transplant surgery experience. METHODS: An Internet-based survey was e-mailed to 251 PDs in the United States. RESULTS: Altogether, 131 PDs (52%) responded. Of those, 66% have a transplant service at integrated hospitals. Small majorities of PDs believed transplant rotations offer a good educational experience (59%) and comply with duty hours (71%). Few PDs believed transplant rotations provide excellent operative experience (47%) and mandate service over education (38%). PDs leading community-affiliated and smaller programs employed away rotations more commonly. Affected PDs used commuting (48%) and purchased temporary housing (52%). Most believed travel is a poor aspect of the experience (78%) and transplant rotations should become an optional component of residency training (60%). PDs using away hospitals more often believed this content area should be eliminated. CONCLUSIONS: Although away transplant rotations minimally impact opinions of PDs related to select educational issues, most PDs challenge the existing paradigm of transplant surgery as essential content. PMID- 21824596 TI - Outcomes after resection of locally advanced or borderline resectable pancreatic cancer after neoadjuvant therapy. AB - BACKGROUND: Neoadjuvant treatment frequently is performed in unresectable/borderline resectable pancreatic cancer. The aim of this study was to retrospectively compare postoperative outcomes and survival of patients who underwent pancreatectomy after neoadjuvant treatment for locally advanced/borderline resectable pancreatic cancer (neoadjuvant treatment group) with those of patients with resectable disease who underwent upfront surgery. METHODS: Between 2000 and 2008, there were 403 patients who underwent pancreatic cancer resection, 41 (10.1%) patients after neoadjuvant treatment for initially unresectable tumors and 362 (89.9%) patients had upfront surgery. Univariate and multivariable analyses were performed. RESULTS: Mortality/morbidity rates were similar in the 2 groups. Nodal metastases were significantly lower in the neoadjuvant treatment group (31.7% vs 86.2%; P < .001). A complete pathologic response was observed in 13.6% after neoadjuvant treatment. Median disease specific survival from resection was 35 and 27 months in the neoadjuvant treatment and upfront groups, respectively (P = .74). In the neoadjuvant treatment group survival rates were similar in N0/N1 patients. CONCLUSIONS: Postoperative mortality and morbidity do not significantly increase after neoadjuvant treatment. Neoadjuvant treatment in locally advanced pancreatic cancer can lead to an objective pathologic response, but this does not significantly improve survival after resection. PMID- 21824598 TI - The role of Ki-67 in predicting biological behavior of goblet cell carcinoid tumor in appendix. AB - BACKGROUND: The aim of this study was to examine the role of Ki-67, a cellular proliferation marker, in the prognosis of goblet cell appendiceal carcinoid tumor. METHODS: Twelve goblet cell appendiceal carcinoid tumors were stained with MIB-1, a monoclonal antibody of Ki-67, to assess their cell proliferation and correlations with clinical and histologic parameters. RESULTS: Among 12 patients studied, the mean MIB-1 index was 24%, with tumors ranging from .5 to 5.0 cm in size. No correlation was observed between tumor size and MIB-1 index. Two patients had metastatic disease on presentation (MIB-1 index 10% and 60%). All patients received surgical intervention according to extent of tumor invasion regardless of their MIB-1 index values. Median follow-up was 54 months, with a 75% follow-up rate and 1 death from metastasis. The overall survival rate was 76%, with a disease-specific survival rate of 87%. CONCLUSIONS: Ki-67 had no prognostic significance for goblet cell carcinoid tumors and should not be used solely to determine treatment and surgical approach. PMID- 21824599 TI - Steroid-refractory cryptogenic multifocal ulcerous stenosing enteritis. AB - Cryptogenic multifocal ulcerous stenosing enteritis (CMUSE) is a rare disease of unclear origin and pathophysiology. Treatment is symptomatic, with no particular medical therapy except for corticosteroids. We describe a patient with steroid refractory CMUSE. A 25-year-old woman underwent bowel surgery 4 times because of small-bowel obstruction. She was diagnosed with CMUSE. Despite steroid treatment and immunosuppressive therapy, she continued to complain of recurrent gastrointestinal symptoms and persistent anemia. To avoid short-bowel syndrome in our patient, new medical treatment is necessary for steroid-refractory CMUSE. PMID- 21824600 TI - Pseudo-Meigs syndrome caused by sigmoid colon cancer metastasis to the ovary. AB - We present a patient with pseudo-Meigs syndrome (PMS) secondary to sigmoid colon cancer metastasis to the ovary with elevated serum levels of carcinoembryonic antigen, CA19-9, and CA-125 who showed a marked change in pleural effusion before and after surgery. We have to consider PMS associated with colon cancer in patients with pleural effusion/ascites and ovarian tumors. PMID- 21824601 TI - Single gigantic calculus of common bile duct and multiple hepatolithiasis. AB - Choledocholithiasis is a very common surgical disease worldwide. Reports of a single calculus of the common bile duct >10 cm are very rare. The authors present a case of a single gigantic calculus in the common bile duct with multiple stones distributing in the left intrahepatic ducts. The patient was treated with left hemihepatectomy combined with Roux-en-Y hepaticojejunostomy, and the postoperative course was uneventful. Left hemihepatectomy combined with Roux-en-Y hepaticojejunostomy was the optimal treatment for this patient, with a satisfactory outcome. PMID- 21824602 TI - Comment on: laparoscopic colorectal surgery in elderly patients: a case-control study of 15 years of experience. PMID- 21824603 TI - Comment on: use of tumescent mastectomy technique as a risk factor for native breast skin flap necrosis after immediate breast reconstruction. PMID- 21824604 TI - Outcome of surgical resection for recurrent pulmonary metastasis from colorectal carcinoma. AB - BACKGROUND: The outcomes after repeat pulmonary resection for colorectal cancer (CRC) and the factors associated with the prognosis of these patients remain uncharacterized. METHODS: Data on 156 patients who underwent curative resection of pulmonary metastasis from CRC were reviewed. Repeat pulmonary resection was performed in 25 patients; the present study examined the outcomes and factors associated with prognosis after repeat pulmonary resection. RESULTS: The 5-year survival rate after the first pulmonary resection was 56.2%. A multivariate analysis identified a histological type other than well-differentiated adenocarcinoma, a high prethoracotomy serum carcinoembryonic antigen (CEA) level, and the presence of hilar or mediastinal lymph node metastasis as poor prognostic factors for the first pulmonary resection. The 5-year survival rate after repeat pulmonary resection was 42.1%. Hilar or mediastinal lymph node metastasis at the time of the repeat resection was significantly associated with poor survival. CONCLUSIONS: Repeat pulmonary resection for metastatic CRC provides satisfactory outcomes. Hilar or mediastinal lymph node involvement is consistently associated with a poor prognosis after the first and repeat pulmonary resections. PMID- 21824605 TI - Morphological evaluation of tongue mucosa in burning mouth syndrome. AB - OBJECTIVE: The aim of the present study was to perform a morphological evaluation by immunofluorescence of biomarkers of keratinocyte intercellular adhesion, and of differentiation in the tongue mucosa of burning mouth syndrome patients (BMS), compared with a control group. DESIGN: A prospective blinded evaluation of tongue mucosal specimens processed for light microscopy was performed. Intercellular adhesion was evaluated by investigating the expression of desmoglein 1, desmoglein 3, and of occludin. Keratin 10 and keratin 14 (markers of epithelial differentiation) were also evaluated, as keratin 16 (marker for activated keratinocytes after epithelial injury). Apoptotic cascade was investigated by p53 and activated caspase-3 expression. The basal membrane integrity was analysed through laminin immunoreactivity. RESULTS: In both groups, a preserved three dimensional architecture of the tongue was observed. Desmoglein 1 and desmoglein 3 epithelial distributions were similar in the desmosomes of patients and control subjects. Again, keratin 10 immunoreactivity and distribution pattern of keratin 14 in the epithelial compartment was similar in both groups. In control samples, keratin 16 immunoreactivity was scant throughout the epithelium with a punctuate and scattered cytoplasmic labelling. In contrast, in all BMS patients keratinocyte cytoplasm was homogeneously labelled for keratin 16, with a more intense staining than controls. Furthermore, keratin 16 staining progressively decreased proceeding towards the most superficial epithelial layers. CONCLUSIONS: The results of this study are consistent with and support the clinically normal features of oral mucosa in BMS, and suggest that keratin 16 may be involved in the cell mechanisms underlying the syndrome occurrence. PMID- 21824606 TI - Impairment of spatial learning and memory in transgenic mice overexpressing human fibroblast growth factor-23. AB - Fibroblast growth factor-23 (FGF-23) is a potent circulating phosphaturic factor associated with renal phosphate wasting. Effects of FGF-23 on skeleton, phosphate homeostasis, and cardiovascular system have been investigated; however, the effect of FGF-23 on the central nervous system (CNS) is unknown. To assess whether FGF-23 influences the function and structure of the CNS and whether the effect of FGF-23 on the CNS is mediated by FGF receptors directly or by hypophosphatemia indirectly, FGF-23 transgenic mice and their wild-type littermates were fed a normal diet or a high-phosphate diet containing a normal diet plus 1.25% phosphate in drinking water from weaning for 5weeks and the phenotypes of the CNS were compared between FGF-23 transgenic mice and their wild type littermates on the same diet. At the end of this time period, transgenic animals on the normal diet showed impaired spatial learning and memory. Furthermore, these mice exhibited the impairment of long-term potentiation in hippocampal CA1 region, and the reduction of hippocampal adenosine-triphosphate content and of choline acetyltransferase-positive neurons in basal forebrain, possibly as pathogenetic factors contributing to the cognitive deficit. The central nervous phenotypes of transgenic mice were rescued following improved hypophosphatemia by the high-phosphate diet intake. This study demonstrates that FGF-23 overexpression can result in abnormalities in the CNS mediated by the secondary severe hypophosphatemia. PMID- 21824607 TI - GABA-A receptors play a minor role in cortical epileptic afterdischarges in immature rats. AB - The role of inhibitory gamma-aminobutyric acid-A (GABA-A) system in the cortical epileptic afterdischarges (ADs) was studied at three different developmental stages of rats. Animals 12, 18 and 25days old with implanted epidural electrodes were pretreated with bicuculline (1 and 2mg/kgi.p.) and 15min later repeatedly stimulated with low frequency trains with stepwise increasing current intensity. Bicuculline only exceptionally decreased threshold current intensities necessary for elicitation of movements directly bound to stimulation, spike-and wave ADs, clonic seizures and transition into a limbic type of ADs. Duration of ADs was not systematically affected by either dose of bicuculline. In contrast, transcallosal evoked potentials exhibited under the influence of bicuculline steeper curve expressing relation between intensity of stimuli and amplitude of responses. In contrast to GABA-B receptors, GABA-A receptors do not play an important role in generation and arrest of cortical epileptic ADs in immature rats. PMID- 21824608 TI - One-pot fluorescent labeling of saccharides with fluorescein-5-thiosemicarbazide for imaging polysaccharides transported in living cells. AB - A simple and efficient procedure for the fluorescent labeling of saccharides is a prerequisite step for imaging the transport of polysaccharides in living cells. We report a one-pot strategy for the fluorescent labeling of saccharides with fluorescein-5-thiosemicarbazide (FTSC), which introduces the thiosemicarbazide group of FTSC to the aldehyde group at the reducing end of saccharides to form stable amino derivatives via reductive amination. The Glc-FTSC derivative was characterized by HPLC-MS, HRESIMS and NMR spectroscopy. Saccharides were quantitatively labeled with FTSC at 75 degrees C for 1 h under optimum reaction conditions. Fluorescence studies illustrated that the conjugation of FTSC to saccharides did not change its florescence properties (lambda(ex)=495 nm, lambda(em)=517 nm), presenting desirable compatibility with commonly used fluorescence equipment. Polysaccharide AAG-FTSC derivatives exhibited rather low levels of cytotoxicity against rat thymus cells, and the fluorescent labeling procedure had slight impact on their anti-tumor activity. Results indicate that the assay neither introduces discernible cytotoxicity against living cells nor obviously alters the functional activities of polysaccharides, and provides a convenient, highly efficient fluorescent labeling approach for imaging the transport of polysaccharides in living cells. PMID- 21824609 TI - The efficient structure elucidation of minor components in heparin digests using microcoil NMR. AB - The structural complexity and microheterogeneity of the glycosaminoglycans heparin and heparan sulfate make their characterization a daunting task. The methodology described herein utilizes a combination of enzymatic digestion, size exclusion chromatography, strong anion-exchange HPLC, reverse-phase ion-pair ultrahigh performance liquid chromatography-mass spectrometry, and microcoil NMR for the efficient sequencing of heparin-derived tetrasaccharides. The high mass sensitivity of microcoil NMR makes this technique well suited for the characterization of mass-limited samples removing a bottleneck in the analysis workflow and permitting structural characterization of minor components isolated from a heparin enzymatic digestion. Complete characterization of one tetrasulfonated, five pentasulfonated isomers and two hexasulfonated tetrasaccharide sequences is described. To our knowledge, two of the identified minor tetrasaccharides are unique, and have not been previously reported: IdoA(2S)-GlcNS(6S)-IdoA(2S)-GlcNS(6S) and DeltaUA(2S)-GlcNS(6S)-IdoA-GlcNS(6S). PMID- 21824610 TI - Gastric intramural hematoma caused by argon plasma coagulation: treated with endoscopic incision and drainage (with videos). PMID- 21824611 TI - Efficacy and safety of EMR to completely remove Barrett's esophagus: experience in 41 patients. AB - BACKGROUND: EMR is typically used to remove focal abnormalities of the esophageal mucosa. However, larger areas of Barrett's esophagus (BE) can be resected through side-by-side resections. OBJECTIVE: To assess the efficacy and safety of EMR to completely remove BE. DESIGN: Retrospective, single-center study. SETTING: University of Iowa Hospitals and Clinics. PATIENTS: Between January 2006 and December 2010, 46 patients underwent EMR for complete removal of BE. Three were lost to follow-up, one died of unrelated causes before completion, and one was still undergoing EMR treatment at the conclusion of the study. The remaining 41 patients were included for analysis. The worst histologic grade was low-grade dysplasia in 4 patients, high-grade dysplasia without cancer in 26 patients, and high-grade dysplasia with superficial adenocarcinoma in 11 patients. BE was circumferential in 65.9% of cases, and the mean (+/- SD) length was 3.3 +/- 2.3 cm. INTERVENTION: EMR was performed by using a cap (n = 4), a multiband ligator device (n = 31), or both (n = 6), with a mean (+/- SD) of 2.4 +/- 1.2 sessions per patient. MAIN OUTCOME MEASUREMENTS: Remission rates and complications. RESULTS: Remission of high-grade dysplasia and cancer, all dysplasia, and all BE was achieved in 94.6%, 85.4%, and 78.0%, respectively. Complications included minor bleeding (31.7%), perforations (4.9%), and strictures (43.9%). All complications were managed conservatively. LIMITATIONS: Retrospective design. CONCLUSION: Complete removal of BE with EMR is effective but associated with a high complication rate, which is mainly related to stricture formation. This needs to be considered when choosing between available treatment modalities. PMID- 21824612 TI - Usefulness of cap-assisted colonoscopy during colonoscopic EMR: a randomized, controlled trial. AB - BACKGROUND: Clinical demand for total colonoscopy is increasing. Several articles have reported on the usefulness of a cap for faster cecal intubation and reduced patient discomfort, but results for polyp and adenoma detection have been inconsistent. OBJECTIVE: To assess the efficacy of a cap attached to the tip of a colonoscope for detection and resection of polyps by experienced colonoscopists. DESIGN: Prospective, randomized, controlled trial. SETTING: A tertiary referral center. PATIENTS AND INTERVENTION: A total of 329 patients who underwent colonoscopic EMR were randomized to cap-assisted colonoscopy (CAC) (CAC group, n = 166) or regular colonoscopy (RC) (RC group, n = 163). MAIN OUTCOME MEASUREMENTS: Cecal intubation time, total procedure time, required time for colonoscopic EMR of each polyp, and missing polyp rate. RESULTS: The cecal intubation time in the CAC group and RC group was 5.3 +/- 3.3 minutes and 5.8 +/- 3.7 minutes, respectively (P = .170). The total procedure time in the CAC group and RC group was 23.0 +/- 15.5 minutes and 29.2 +/- 13.4 minutes, respectively (P = .626). The time required for colonoscopic EMR of each polyp in the CAC group and RC group was 3.5 +/- 4.5 minutes and 4.2 +/- 5.1 minutes, respectively (P = .010). The number of polyps during the initial colonoscopy in the CAC group and RC group was 2.2 +/- 1.7 and 2.0 +/- 1.8, respectively (P = .221). The number of detected polyps during colonoscopic EMR in the CAC group and RC group was 3.4 +/- 2.7 and 2.7 +/- 1.9 (P = .003). The number of missed polyps in the CAC group and RC group was 1.1 +/- 1.5 and 0.8 +/- 0.9 (P = .024). LIMITATION: Single-center experience. CONCLUSIONS: CAC may reduce the time required for colonoscopic EMR of each polyp and may also improve the polyp detection rate. PMID- 21824613 TI - Localized primary AL amyloidosis of the colon without other GI involvement. PMID- 21824614 TI - Esophageal web resolved by endoscopic incision in a patient with Plummer-Vinson syndrome. PMID- 21824615 TI - Biomechanical evaluation of the expansive cannulated screw for fixation of femoral neck fractures. AB - BACKGROUND: Femoral neck fracture is one of the common clinical traumas, especially amongst elder patients. This study aims to test, compare and evaluate the bone-screw interface strengths, the fatigue strengths, and the stabilities of our newly designed expansive cannulated screw (ECS) and the common cannulated compression screw (CCS) in the fixation of femoral neck fracture, which is a summary of recent research. METHODS: Twenty-four pairs (48) of fresh femur specimens were randomly divided into four groups with six pairs (12) in each. To simulate one-legged standing, the maximum compressive strength and the single screw axial pull-out force were compared between the fixed femoral necks treated with two ECSs and two CCSs, two ECSs and three CCSs or three ECSs and three CCSs, respectively. The screws were also subjected to 1,000,000 cycles of a loaded fatigue test and the results were recorded. FINDINGS: When the same number of screws was used, the ECS showed significantly greater maximum compressive strength than the CCS (P<0.05), but no significant difference in fixation effectiveness was detected between the two ECSs and the three CCSs groups. The maximum axial pull-out strength of the ECS was also significantly greater that of the CCS (P<0.01); however, there was no sign of fatigue in both the ECS and CCS after 1,000,000 cycles of loaded fatigue test. INTERPRETATION: The ECS shows better fixation performance than the currently and commonly used CCS; under certain circumstances, fixation with two ECSs can achieve the same effect as that with traditional three CCSs. PMID- 21824617 TI - Patient-specific prediction of intrinsic mechanical loadings on sub-muscular pectoral pacemaker implants based on an inter-species transfer function. AB - With the steady technological development enabling reduced device dimensions and new patient populations, detailed data on mechanical in vivo loads become increasingly important to ensure reliability of implantable medical devices. Based on an intra-species correlation of in-line and transverse force of the Pectoralis major established previously for the Chacma baboon (de Vaal et al., 2010a), a simplified physiological model and a mechanical equivalent model were developed for a sub-muscular pectoral device implant considering Pectoralis major, Pectoralis minor and rib cage. By assessing the morphometric and mechanical parameters of these musculo-skeletal structures and the associated model parameters, the intra-species correlation was shown to exhibit (a) robustness for a larger intra-species subject population and (b) linear scale variance allowing application for humans under consideration of the inter-species difference of the attachment angles of Pectoralis major. The transfer function provides a basis for the prediction of patient-specific maximum mechanical loadings on a sub-muscular pectoral cardiac pacemaker implant through non- or minimal invasive measurements on the patient. PMID- 21824616 TI - Differential effect of weight loss with low-fat diet or high-fat diet restriction on inflammation in the liver and adipose tissue of mice with diet-induced obesity. AB - OBJECTIVE: We studied the effects of weight loss induced by either a low-fat normal diet (ND) or restriction of high-fat diet (HFD) on hepatic steatosis, inflammation in the liver and adipose tissue (AT), and blood monocytes of obese mice. METHODS: In mice with HFD-induced obesity, weight loss was achieved by switching from HFD to ND and maintaining on ND ad libitum or by restricting HFD intake to match body weight of mice with ND-induced weight loss. After diet interventions for 4 weeks, hepatic steatosis, hepatic and AT inflammation, and blood CD11c(+) monocytes were examined. RESULTS: At 4 weeks after switching diets, body weight was reduced by 23% from baseline. To achieve the same reduced body weight required restricting calorie intake from HFD. Weight loss with either ND or HFD restriction decreased body fat mass and ameliorated liver steatosis; both effects were greater with ND-induced weight loss than HFD restriction induced weight loss. Weight loss with ND but not HFD restriction normalized blood CD11c(+) monocytes and attenuated hepatic inflammation assessed by chemokine and CD11c expression. In contrast, weight loss with HFD restriction significantly reduced chemokine levels and CD11c(+) cells in AT compared to obese controls, and tended to reduce AT chemokines and CD11c(+) cells more than ND-induced weight loss. CONCLUSION: In mice with diet-induced obesity, weight loss with ND was superior in alleviating hepatic inflammation and steatosis, whereas weight loss with HFD calorie restriction provided greater amelioration of AT inflammation. PMID- 21824618 TI - Kinematics and kinetics of an accidental lateral ankle sprain. AB - Ankle sprains are common during sporting activities and can have serious consequences. Understanding of injury mechanisms is essential to prevent injuries, but only two previous studies have provided detailed descriptions of the kinematics of lateral ankle sprains and measures of kinetics are missing. In the present study a female handball player accidentally sprained her ankle during sidestep cutting in a motion analysis laboratory. Kinematics and kinetics were calculated from 240 Hz recordings with a full-body marker setup. The injury trial was compared with two previous (non-injury) trials. The injury trial showed a sudden increase in inversion and internal rotation that peaked between 130 and 180 ms after initial contact. We observed an attempted unloading of the foot from 80 ms after initial contact. As the inversion and internal rotation progressed, the loads were likely to exceed injury threshold between 130 and 180 ms. There was a considerable amount of dorsiflexion in the injury trial compared to neutral flexion in the control trials, similar to the previously published kinematical descriptions of lateral ankle sprains. The present study also adds valuable kinetic information that improves understanding of the injury mechanism. PMID- 21824619 TI - Study of carotid arterial plaque stress for symptomatic and asymptomatic patients. AB - Stroke is one of the leading causes of death in the world, resulting mostly from the sudden ruptures of atherosclerosis carotid plaques. Until now, the exact plaque rupture mechanism has not been fully understood, and also the plaque rupture risk stratification. The advanced multi-spectral magnetic resonance imaging (MRI) has allowed the plaque components to be visualized in-vivo and reconstructed by computational modeling. In the study, plaque stress analysis using fully coupled fluid structure interaction was applied to 20 patients (12 symptomatic and 8 asymptomatic) reconstructed from in-vivo MRI, followed by a detailed biomechanics analysis, and morphological feature study. The locally extreme stress conditions can be found in the fibrous cap region, 85% at the plaque shoulder based on the present study cases. Local maximum stress values predicted in the plaque region were found to be significantly higher in symptomatic patients than that in asymptomatic patients (200 +/- 43 kPa vs. 127 +/- 37 kPa, p=0.001). Plaque stress level, defined by excluding 5% highest stress nodes in the fibrous cap region based on the accumulative histogram of stress experienced on the computational nodes in the fibrous cap, was also significantly higher in symptomatic patients than that in asymptomatic patients (154 +/- 32 kPa vs. 111 +/- 23 kPa, p<0.05). Although there was no significant difference in lipid core size between the two patient groups, symptomatic group normally had a larger lipid core and a significantly thinner fibrous cap based on the reconstructed plaques using 3D interpolation from stacks of 2D contours. Plaques with a higher stenosis were more likely to have extreme stress conditions upstream of plaque throat. The combined analyses of plaque MR image and plaque stress will advance our understanding of plaque rupture, and provide a useful tool on assessing plaque rupture risk. PMID- 21824620 TI - Electromembrane extraction of amino acids from body fluids followed by capillary electrophoresis with capacitively coupled contactless conductivity detection. AB - Electromembrane extraction (EME) proved to be a simple and rapid pretreatment method for analysis of amino acids and related compounds in body fluid samples. Body fluids were acidified to the final concentration of 2.5 M acetic acid and served as donor solutions. Amino acids, present as cations in the donor solutions, migrated through a supported liquid membrane (SLM) composed of 1-ethyl 2-nitrobenzene/bis-(2-ethylhexyl)phosphonic acid (85:15 (v/v)) into the lumen of a porous polypropylene hollow fiber (HF) on application of electric field. The HF was filled with 2.5 M acetic acid serving as the acceptor solution. Matrix components in body fluids were efficiently retained on the SLM and did not interfere with subsequent analysis. Capillary electrophoresis with capacitively coupled contactless conductivity detection was used for determination of 17 underivatized amino acids in background electrolyte solution consisting of 2.5 M acetic acid. Parameters of EME, such as composition of SLM, pH and composition of donor and acceptor solution, agitation speed, extraction voltage, and extraction time were studied in detail. At optimized conditions, repeatability of migration times and peak areas of 17 amino acids was better than 0.3% and 13%, respectively, calibration curves were linear in a range of two orders of magnitude (r(2)=0.9968-0.9993) and limits of detection ranged from 0.15 to 10 MUM. Endogenous concentrations of 12 amino acids were determined in EME treated human serum, plasma, and whole blood. The method was also suitable for simple and rapid pretreatment and determination of elevated concentrations of selected amino acids, which are markers of severe inborn metabolic disorders. PMID- 21824621 TI - Recombinant protein purification using gradient assisted simulated moving bed hydrophobic interaction chromatography. Part II: process design and experimental validation. AB - In the first part of this work adsorption isotherm parameters were acquired to describe the migration of recombinant streptokinase in Butyl Sepharose columns at different salt concentrations. Based on these results, a simulated moving bed (SMB) chromatographic process was designed and realised, which exploits a two step salt gradient and allows the continuous separation of streptokinase from contaminants present in a clarified Escherichia coli cell lysate solution. This second part describes the design of the three-zone open-loop gradient SMB process applying both equilibrium theory and an equilibrium stage model and presents results of a series of experiments aiming to obtain pure streptokinase. Moreover, the potential of the SMB process and the design approach are evaluated. PMID- 21824622 TI - Development of a multi-residue method for the determination of organic micropollutants in water, sediment and mussels using gas chromatography-tandem mass spectrometry. AB - This study describes the development of a multiresidue method based on gas chromatography-electron ionization-tandem mass spectrometry (GC-EI-MS/MS) for the detection of sixteen polycyclic aromatic hydrocarbons (PAHs), five phthalate esters (PEs), seven polychlorinated biphenyls (PCBs), six polybrominated diphenyl ethers (PBDEs), six alkylphenols (APs), three organochlorined pesticides and their isomers or degradation products (OCPs) and bisphenol A in seawater, river water, wastewater treatment plant (WWTP) effluents, sediments and mussels. Solid phase extraction (SPE) was used for the extraction of target analytes in aqueous samples, and ultrasound assisted extraction for solid samples. GC-EI-MS/MS acquisition conditions in selected reaction monitoring (SRM) using two transitions per compound were optimized. In this way, quantification and unequivocal identification of organic micropollutants were performed in compliance with the Decision 2002/657/EC. Good linearity responses with coefficients of determination higher than 0.99 were obtained. Methodological detection limits (MDLs) in seawater ranged from 0.1 to 6 ng L(-1); in river water from 0.1 to 4.8 ng L(-1); in WWTP effluents from 1 to 75 ng L(-1); in sediments from 1 to 150 ng g(-1) and in mussels from 1 to 125 ng g(-1). MDLs and recovery yields were compared with other published methods and similarities or even improvements were achieved. The optimized method was applied to analyze five samples from each matrix collected in coastal areas, showing its potential use for marine pollution monitoring. PMID- 21824624 TI - Mesoscopic simulations on the aggregation behavior of pH-responsive polymeric micelles for drug delivery. AB - Computer simulations, dissipative particle dynamics (DPD) and mesoscopic dynamics (MesoDyn), are performed to study the aggregation behavior of pH-sensitive micelles self-assembled from amphiphilic polymer poly(methyl methacrylate-co methacrylic acid)-b-poly(poly-(ethylene glycol) methyl ether monomethacrylate), P(MMA-co-MAA)-b-PPEGMA. Ibuprofen (IBU) is selected as the model drug. It can be seen from DPD simulations that P(MMA-co-MAA)-b-PPEGMA and IBU form spherical core shell micelles at certain compositions, and IBU molecules distribute inside the core formed by hydrophobic MMA. The polymer molecules aggregate first, and then IBU diffuses into the aggregate, forming drug-loaded nanoparticles. With different compositions of polymer and IBU, aggregate morphologies in water are observed as sphere, column and lamella. From MesoDyn results, with less hydrophobic MMA beads, the polymer chains are more difficult to form ordered aggregates, and the order parameters get equilibrated in a longer time. The pH value also affects the aggregate process. At pH<5, the polymer could form traditional core-shell micelles. But at pH>5, the morphology of micelles is found to be anomalous and loose for releasing drug. MAA aggregates on the surface, instead of the inside. The simulation results are qualitatively consistent with the experimental results. PMID- 21824623 TI - Fabrication, characterization, and application of greigite nanoparticles for cancer hyperthermia. AB - Greigite is a Fe-S-containing complex having magnetic properties mainly synthesized in the solution. In the present study, greigite was synthesized by a coprecipitation method at different pH's and reaction times. The greigite phase was analyzed by the X-ray diffraction (XRD) method at an optimum pH of 3.0 and reaction time of 10 min, respectively. The magnetization characterization by superconducting quantum interference device (SQUID) revealed that the magnetic saturation was obtained at 16.1538 (emu/g). The inductive heating property of the greigite nanoparticles was carried out by induction heater power cube (IHPC) in an alternating current magnetic field and the results indicated that the heating effect was significant. Transmission electron microscopy (TEM) revealed that the size of the greigite was around 50-100 nm and the edges of nanoparticles have no clear boundary or distinctive morphology. Studies on LDH and WST-I assay revealed low cytotoxicity at greigite concentrations of 1 mg/ml. In vitro experiments suggested that cancerous cells, human lung adenocarcinoma epithelial cell line (A549), had the ability to become more damaged under AC magnetic field than the normal human lung cells (HFL-1). PMID- 21824625 TI - Applications of nanotechnology in food packaging and food safety: barrier materials, antimicrobials and sensors. AB - In this article, several applications of nanomaterials in food packaging and food safety are reviewed, including: polymer/clay nanocomposites as high barrier packaging materials, silver nanoparticles as potent antimicrobial agents, and nanosensors and nanomaterial-based assays for the detection of food-relevant analytes (gasses, small organic molecules and food-borne pathogens). In addition to covering the technical aspects of these topics, the current commercial status and understanding of health implications of these technologies are also discussed. These applications were chosen because they do not involve direct addition of nanoparticles to consumed foods, and thus are more likely to be marketed to the public in the short term. PMID- 21824626 TI - A comparative study of the histopathology and immunohistochemistry of pythiosis in horses, dogs and cattle. AB - Twenty-one cases of pythiosis in horses (n = 10), dogs (n = 9) and cattle (n = 2) were investigated. The aetiology in all cases was confirmed by immunohistochemistry. Data related to the clinical course and outcome and localization of the lesions were obtained from pathology reports. The equine lesions consisted of fibrotic tissue with multiple, often coalescing, areas of immature granulation tissue encircling eosinophilic cores. Affected dogs had gastrointestinal and/or cutaneous lesions with either or both of a granulomatous/pyogranulomatous or necrotizing eosinophilic inflammatory reaction. In cattle, cutaneous lesions were characterized by multifocal to coalescing granulomas with surrounding fibrosis. The number of intralesional hyphae, the distribution of hyphae, the presence of angioinvasion and the nature of the local inflammatory reactions were associated with the different types of lesions observed. PMID- 21824627 TI - A cognitive comparison of pathological skin picking and trichotillomania. AB - OBJECTIVE: Pathological Skin Picking (PSP) and Trichotillomania (TTM) share overlapping comorbidity and phenomenology. The extent to which these disorders share a common cognitive phenotype, however, has yet to be examined. This study sought to compare inhibitory control processes in individuals with PSP or TTM. METHODS: Thirty-one subjects with PSP (mean age 31.2 +/- 12.5 years; 93.5% female), 39 subjects with TTM (mean age 35.9 +/- 10.7 years; 87.2% female), and 33 matched controls (mean age 31.9 +/- 9.9 years; 72.7% female) undertook cognitive assessments using the Stop-Signal Task (assessing response impulsivity) and the Intra-dimensional/Extra-dimensional (ID/ED) Set Shift task (assessing cognitive flexibility). Groups were matched for age, gender, race/ethnicity, and education. RESULTS: PSP was associated with significantly impaired stop-signal reaction times but intact ID/ED cognitive flexibility compared to controls. TTM occupied an intermediate position in terms of stop-signal reaction times between controls and PSP but did not differ significantly from either group on the ID/ED Set Shift Task. CONCLUSION: These results replicate the finding of impaired inhibitory control in PSP but suggest TTM may be heterogeneous with respect to such impairment. Future work should explore possible subgroups in TTM and whether cognitive variables are predictive of treatment outcomes. PMID- 21824628 TI - Reduced cerebellar left hemisphere and vermal volume in adults with PTSD from a community sample. AB - BACKGROUND: Traumatic events exposure is a necessary condition for developing posttraumatic stress disorder (PTSD), but not all individuals exposed to the same trauma will develop PTSD. Human studies have suggested that the cerebellum is involved in human fear perception, anticipation, and recollection. In this context, the current study evaluated whether cerebellar volume is associated with PTSD. METHODS: Eighty-four victims of violence, 42 who fulfilled the DSM-IV-TR criteria for PTSD and 42 resilient controls, were identified through an epidemiologic survey conducted in the city of Sao Paulo. Subjects were evaluated using the Clinician-Administered PTSD Scale (CAPS), Beck Anxiety Inventory (BAI), Beck Depression Inventory (BDI), and Early Trauma Inventory (ETI). All subjects underwent a magnetic resonance imaging (MRI) scan to evaluate their cerebellar hemispheres and vermis. RESULTS: PTSD subjects had relative smaller left hemisphere (p = 0.04) and vermis (p < 0.01) volumes persisted after controlling for gender, age, and brain volume. In PTSD group, left cerebellar hemisphere volume correlated negatively with PTSD (p = 0.01) and depressive symptoms (p = 0.04). Vermal volume correlated negatively with PTSD symptoms (p < 0.01), early traumatic life events (p < 0.01), depressive symptoms (p = 0.04) and anxiety (p = 0.01). CONCLUSION: The cerebellum is involved in emotion modulation, and our results suggest that cerebellar volumetric reduction is associated with mood, anxiety and PTSD symptoms. Early traumatic life experiences are related to vermal volume reduction and may be a risk factor for future PTSD development. PMID- 21824629 TI - Altered tryptophan metabolism in Parkinson's disease: a possible novel therapeutic approach. AB - Parkinson's disease (PD) is one of the most common disabling neurodegenerative diseases. Although several therapeutic approaches are available, there are two major unresolved issues: the lack of proved neuroprotective therapy and the treatment of L-dopa-induced motor complications. In the brain, 90% of the tryptophan is metabolized in the kynurenine pathway. Some of the intermediates, such as quinolinic acid and 3-hydroxy kynurenine, are neurotoxic, while others, such as kynurenic acid, are putative intrinsic neuroprotective compounds, mainly by acting as endogenous antagonists of ionotropic excitatory amino acid receptors. Alterations in the kynurenine pathway have been demonstrated in PD. Preclinical data suggest that intervention in the kynurenine pathway may result in neuroprotection and may alleviate L-dopa-induced dyskinesia. There are two alternative approaches for such intervention: the use of kynurenic acid analogues or pro-drugs, or modulation of the activities of the intrinsic enzymes of the pathway. PMID- 21824630 TI - Outcomes of total arch replacement with stepwise distal anastomosis technique and modified perfusion strategy. AB - OBJECTIVE: Total arch replacement has been reported to present high morbidity and mortality. We have introduced a stepwise distal anastomosis technique and modified perfusion strategy, including selective antegrade cerebral perfusion, moderate hypothermia, and separate lower-body perfusion, to minimize organ ischemia and secondary morbidities. We report the operative outcomes of total arch replacement with our modified perfusion strategy. METHODS: Between August 2006 and December 2008, 119 patients underwent total arch replacement with the current perfusion strategy. Of these patients, 56 (47%) underwent emergency operation for acute type A aortic dissection (n = 48) or ruptured thoracic aneurysm (n = 8). The mean age of patients was 68 years, and the mean follow-up period was 25 months. We analyzed operative mortality, morbidity, and 4-year survival of this patient group. RESULTS: The mean operation, cardiopulmonary bypass, and circulatory arrest times were 313, 183, and 47 minutes, respectively. Operative mortality was 3.4%. Operative mortality of elective cases was 1.6%. The incidences of permanent neurologic deficit, paraparesis, and renal insufficiency were 5.0%, 1.7%, and 7.6%, respectively. Actuarial 4-year survival was 86.5%. CONCLUSIONS: Total arch replacement with our modified perfusion strategy has demonstrated low operative mortality and morbidity. PMID- 21824631 TI - Persistent embryonic right venous valve giving a cor triatriatum dexter appearance in a cyanotic neonate. PMID- 21824632 TI - Down-regulation of UDP-arabinopyranose mutase reduces the proportion of arabinofuranose present in rice cell walls. AB - Arabinoxylans may account for up to 25% of the mass of grass cell walls. The interactions of these polysaccharides with themselves and with cellulose and lignin is believed to affect the walls physical properties and increase the walls resistance to biochemical conversion to fermentable sugars. Arabinoxylans have a backbone composed of 1,4-linked beta-D-xylosyl residues, some of which are substituted at O-2 or O-3 with single arabinofuranosyl (Araf) residues. The Araf residues are likely transferred from UDP-Araf to the xylan backbone by arabinofuranosyltransferases. UDP-Araf is itself formed from UDP-arabinopyranose (UDP-Arap) by UDP-arabinopyranose mutase (UAM). In this study, RNA interference (RNAi) was used to suppress UAM expression in rice plants and thereby reduce the amounts of UDP-Araf available for cell wall synthesis. Several of the transgenic plants had reduced proportions of Araf in their walls together with a decrease in the extent of substitution of the xylan backbone, and a reduction of between 25% and 80% in ferulic acid and p-coumaric acid contents of the cell walls. Those transgenic plants with >25% reduction in the amounts of Araf were dwarfed and infertile. PMID- 21824633 TI - The advantages of using a combination of LDL and glutamine in comparison with TRIS egg yolk and Equex(r) STAMP extenders in the cryopreservation of canine semen. AB - Twenty semen samples taken from 5 dogs were frozen in liquid nitrogen at -196 degrees C in four different extenders: one control extender based on 20% egg yolk, 6% LDL alone (low density lipoproteins: the active cryoprotective principle in chicken egg yolk), 6% LDL combined with 20 mmol glutamine, and Equex(r) (a reference extender that we wish to compare with the LDL-glutamine combination). After thawing, spermatozoal motility was evaluated using a HAMILTON THORNE CERROS 12 image analyzer; the percentage of motile spermatozoa was 27.7% in the egg yolk extender (p<0.05), 49.9% with 6% LDL alone (p>0.05), 54.7% in the 6% LDL+20 mmol glutamine extender, and 47.9% with Equex(r) (p>0.05). The motility parameters (VAP, VCL, VSL and ALH) were also superior in the 6% LDL+20 mmol glutamine extender in comparison with the other extenders. Finally, the spermatozoa were generally better protected during freezing with the 6% LDL+20 mmol glutamine association than with the egg yolk, 6% LDL, or Equex extenders in terms of the flagellar plasma membrane (HOS test), DNA (Acridine orange test), and acrosome integrity (Spermac(r) test: no significant difference). The Equex(r) extender obtained the best results for the acrosome, followed by 6% LDL+20 mmol glutamine (FITC-PSA test: p<0.05 between each extender). PMID- 21824634 TI - Occurrence of Bartonella henselae types I and II in Central Italian domestic cats. AB - Serological and molecular surveys were conducted to determine the occurrence of Bartonella henselae in domestic cats in Central Italy. Samples from 234 pet cats were tested for B. henselae antibodies by indirect immunofluorescence with 78 (33.3%) positive. A PCR assay specific for the Bartonella 16S rRNA gene was carried out on DNA samples extracted from blood of the 234 cats; 26 (11.1%) of the seropositive cats were positive. Two PCR protocols, which discriminate genotypes I and II of B. henselae, were performed on all DNA samples. Sixteen (6.8%) cats were infected by genotype I, 6 (2.5%) by genotype II, and two males (0.8%) by both genotypes. Two female (0.8%) cats which were Bartonella sp. PCR positive, gave negative results with the types I and II PCR. This protocol facilitates the direct and rapid detection of Bartonella DNA in feline blood samples, and differentiates B. henselae genotypes. PMID- 21824635 TI - Textural characterization of histopathological images for oral sub-mucous fibrosis detection. AB - In the field of quantitative microscopy, textural information plays a significant role very often in tissue characterization and diagnosis, in addition to morphology and intensity. The aim of this work is to improve the classification accuracy based on textural features for the development of a computer assisted screening of oral sub-mucous fibrosis (OSF). In fact, a systematic approach is introduced in order to grade the histopathological tissue sections into normal, OSF without dysplasia and OSF with dysplasia, which would help the oral onco pathologists to screen the subjects rapidly. In totality, 71 textural features are extracted from epithelial region of the tissue sections using various wavelet families, Gabor-wavelet, local binary pattern, fractal dimension and Brownian motion curve, followed by preprocessing and segmentation. Wavelet families contribute a common set of 9 features, out of which 8 are significant and other 61 out of 62 obtained from the rest of the extractors are also statistically significant (p<0.05) in discriminating the three stages. Based on mean distance criteria, the best wavelet family (i.e., biorthogonal3.1 (bior3.1)) is selected for classifier design. support vector machine (SVM) is trained by 146 samples based on 69 textural features and its classification accuracy is computed for each of the combinations of wavelet family and rest of the extractors. Finally, it has been investigated that bior3.1 wavelet coefficients leads to higher accuracy (88.38%) in combination with LBP and Gabor wavelet features through three-fold cross validation. Results are shown and discussed in detail. It is shown that combining more than one texture measure instead of using just one might improve the overall accuracy. PMID- 21824636 TI - Measurement of the sound velocity in fluids using the echo signals from scattering particles. AB - With conventional methods the sound velocity c in fluids can be determined using the back wall echo. This paper proposes a novel technique, in which the signals reflected by scattering particles suspended in a fluid are analysed instead. The basic idea is that the particles generate the strongest echo signal when being located in the sound field maximum. Therefore the position of the echo signal maximum is a measure for the propagation time to the sound field maximum. Provided that calibration data or sound field simulations for the ultrasonic transducer are available, this propagation time suffices to determine both sound velocity and the location of the sound field maximum. The feasibility of the new approach is demonstrated by different kinds of experiments: (i) Measurements of the sound velocity c in four fluids covering the wide range between 1116 and 2740m/s. The results show good agreement with values published elsewhere. (ii) Using the dependence of the sound velocity on temperature, it is possible to vary c over the comparatively small range between 1431 and 1555m/s with increments of less than 10m/s. The measured statistical variation of 1.4m/s corresponds to a relative uncertainty not worse than 0.1%. (iii) The focus position, i.e. the distance of the maximum of the sound field from the transducer, was varied by time-shifted superposition of the receive signals belonging to the different elements of an annular array. The results indicate that the novel method is even capable of measuring profiles of the sound velocity along the ultrasonic beam non invasively. PMID- 21824637 TI - Novel device to measure critical point "Onset" of capillary wave and interpretation of Faraday instability wave by numerical analysis. AB - A capillary wave was created on a surface by vibrating from the bottom of a container. When the amplitude of the container vibration approached the critical point, called the onset state, the surface broke up and bursted into very small drops on the air. The numerical analysis was used to determine the amplitude of the onset. The onset point was found to be 0.349MUm at f=500kHz. The critical amplitude h(cr) was determined by using a multi-Fourier horn nozzle (MFHN) device. The onset point was measured to be 0.37MUm using a laser Doppler vibrometer (LDV) with the MFHN at f=486kHz. These drops indicate that particle size distributions of 10.8MUm and 7.0MUm were produced by the MFHN at f=289kHz and f=486kHz, respectively. These results agreed with those obtained using Kelvin's equation, which predicted D=0.34lambda. PMID- 21824638 TI - Identification of cocaine and its metabolites in urban wastewater and comparison with the human excretion profile in urine. AB - The most relevant human urinary metabolites of cocaine (nine metabolites) were measured in urban wastewater in Italy and USA. A novel analytical method based on liquid chromatography tandem mass spectrometry allowed the identification of ecgonine, ecgonine methyl ester and the pyrolytic derivatives of cocaine in untreated wastewater. The aim of this study was to verify whether the pattern of cocaine metabolites in wastewater reflected the human excretion profile in urine. The performance of the method was good, with recoveries higher than 60% and limits of quantifications in the low ng/L range. The stability in untreated wastewater was assessed for all metabolites and the best storage condition resulted freezing samples immediately after collection and keep them frozen until analysis. All the selected compounds were measured in wastewater at concentrations up to 1.5 MUg/L and their weekly loads were calculated during a five weeks monitoring campaign in Milan (Italy). The profiles of cocaine metabolites in wastewater matched with those in human urine reported in the literature, suggesting that measures in wastewater reflect the real human excretion and that wastewater analysis is suitable for assessing drug consumption. Benzoylecgonine was confirmed as the best target for estimating cocaine use by wastewater analysis, while cocaine itself should not be considered because its amount in wastewater is affected by other environmental sources such as transport, handling and consumption. Results suggested that the measurement of other metabolites in combination with benzoylecgonine might reflect 60% of an administered dose of cocaine providing also information on different patterns of use. PMID- 21824640 TI - Modifications of black carbons and their influence on pyrene sorption. AB - Sorption of pyrene on black carbons (BCs) obtained by heating sawdust at two temperatures (400 and 700 degrees C, denoted as 400BC and 700BC, respectively), as well as on modified BCs (via oxidation, oximation, and hydrolysis) was studied to investigate the role of BC structural characteristics in sorption of hydrophobic organic compounds. Pyrene was bound strongly by 700BC and 400BC, with organic carbon normalized distribution coefficients (K(oc)) of 10(5.04)-10(5.86) and 10(4.65)-10(5.16), respectively, at equilibrium pyrene concentrations of 10 100 MUg L(-1). Both chemical composition and pore distribution of the two BCs changed after modifications, which led to changes in their sorption characteristics for pyrene. After modifications, the linearity of pyrene sorption isotherm increased for 700BC but decreased for 400BC. For 700BC, both oxidation and oximation reduced pyrene sorption, with K(oc) decreasing by 69.1-73.7% and 18.7-33.9%, respectively, whereas hydrolysis did not exert a significant influence. For 400BC, oxidation and hydrolysis reduced K(oc) by 2.28-25.9% and 29.2-33.9%, respectively, while oximation increased K(oc). In most cases, the change in sorption capacity could be explained by the changes in C content and type, polarity, surface area, and micropore volume of the BCs; however, the role of conformation (the accessibility to sorption sites) could not be ignored. PMID- 21824639 TI - Crystal structure and density functional theory studies of toxic quinone metabolites of polychlorinated biphenyls. AB - Lower chlorinated polychlorinated biphenyls (PCBs) are readily metabolized via hydroxylated metabolites to reactive PCB quinones. Although these PCB metabolites elicit biochemical changes by mechanisms involving cellular target molecules, such as the aryl hydrocarbon receptor, and toxicity by interacting with enzymes like topoisomerases, only few PCB quinones have been synthesized and their conformational properties investigated. Similar to the parent compounds, knowledge of the three-dimensional structure of PCB quinones may therefore be important to assess their fate and risk. To address this gap in our knowledge, the gas phase molecular structure of a series of PCB quinones was predicted using HF/3-21G, B3LYP/6-31G** and UB3LYP/6-311G** calculations and compared to the respective solid state structure. All three methods overestimated the Cl-C bond length, but otherwise provided a reasonable approximation of the solid state bond angles and bond lengths. Overall, the UB3LYP/6-311G** level of theory yielded the best approximation of the molecular structure of PCB quinones in the solid state. Chlorine addition at the ortho position of both rings was found to increase the dihedral angle of the resulting quinone compound, which may have important implications for their interaction with cellular targets and, thus, their toxicity. PMID- 21824642 TI - Association of GSTM1 and GSTT1 polymorphisms with DNA damage in coal-tar workers. AB - DNA damage was evaluated by alkaline comet assay in peripheral blood lymphocytes of 115 coal-tar workers occupationally exposed to polycyclic aromatic hydrocarbons (PAHs) and 105 control subjects. The effect of polymorphisms of glutathione S-transferase (GST) genotypes on the DNA damage was assessed. The mean tail moment (TM) value in the coal-tar workers was significantly higher as compared to the control subjects (12.06 +/- 0.55 versus 0.44 +/- 0.31; P<0.05). No significant association (P>0.05) between the GSTT1 and GSTM1 genotypes and the TM values was found, however highest mean rank TM value was reported in GSTM1 null and GSTT1 null genotypes in both control and exposed subjects. Our results suggest that there is increased DNA damage in coal-tar workers due to PAHs exposure. Polymorphisms in GSTM1 and GSTT1 genes do not show significant effect (P>0.05) on DNA damage. PMID- 21824641 TI - Heavy metal and pesticide content in commonly prescribed individual raw Chinese Herbal Medicines. AB - Heavy metal and pesticide contamination has previously been reported in Chinese Herbal Medicines (CHMs), in some cases at potentially toxic levels. This study was conducted to determine general patterns and toxicological significance of heavy metal and pesticide contamination in a broad sample of raw CHMs. Three hundred-thirty-four samples representing 126 species of CHMs were collected throughout China and examined for arsenic, cadmium, chromium, lead, and mercury. Of the total, 294 samples representing 112 species were also tested for 162 pesticides. At least 1 metal was detected in all 334 samples (100%) and 115 samples (34%) had detectable levels of all metals. Forty-two different pesticides were detected in 108 samples (36.7%), with 1 to 9 pesticides per sample. Contaminant levels were compared to toxicological reference values in the context of different exposure scenarios. According to a likely scenario of CHM consumption, only 3 samples (1%) with heavy metals and 14 samples (5%) with pesticides were found with concentrations that could contribute to elevated background levels of contaminant exposure. According to the most conservative scenario of CHM consumption, 231 samples (69%) with heavy metals and 81 samples (28%) with pesticides had contaminants that could contribute to elevated levels of exposure. Wild collected plants had higher contaminant levels than cultivated samples. Cadmium, chromium, lead, and chlorpyrifos contamination showed weak correlations with geographic location. Based on our assumptions of the likely mode of consumption of raw CHMs, the vast majority (95%) of the 334 samples in this study contained levels of heavy metals or pesticides that would be of negligible concern. However, given the number of samples with detectable contaminants and the range between the more likely and more conservative scenarios of contaminant exposure, more research and monitoring of heavy metals (especially cadmium and chromium) and pesticide residues (especially chlorpyrifos) in raw CHMs are advised. PMID- 21824643 TI - Pyrolysis and thermal-oxidation characterization of organic carbon and black carbon aerosols. AB - In this study, the pyrolytic behaviors and the thermal-oxidation decomposition characteristics of organic carbon (OC), pyrolytically generated elemental carbon (PEC) and black carbon (BC) particles have been studied in inert and air atmosphere respectively, in order to develop a new PEC correction method for the determination of BC by using thermal oxidation method. Our results indicated that: 1) a part of OC can be removed by heating it at 400 degrees C in inert atmosphere and another part of OC was charred to form PEC, whereas, the weight of BC particles approximately keeps no change in the same conditions. 2) PEC and BC began to decompose at a similar temperature in air atmosphere. However, the decomposition rate of PEC is quite different from that of BC in air atmosphere and the difference varied with the temperature. As maximum, the decomposition rate of PEC is 5.64 times faster than that of BC particles at 500 degrees C in air atmosphere. Based on the difference of the decomposition rate between PEC and BC, a new method of PEC correction was developed for the thermal oxidation method. With the help of the new PEC correction method and thermal analyzer, we successfully determined OC and BC concentrations in actual soot sample and artificial soot samples. The results obtained with our PEC correction method are consistent well with the real value or those analyzed with thermal-optical method, suggesting that the novel PEC correction method have a high accuracy. PMID- 21824644 TI - Elevated soluble endothelial cell protein C receptor (sEPCR) levels in women with preeclampsia: a marker of endothelial activation/damage? AB - The endothelial protein C receptor (EPCR) plays a crucial role in the anticoagulant and anti-inflammatory effects of the protein C pathway, whereas its soluble form (sEPCR) exhibits opposite properties. High plasma levels of sEPCR have been observed in subjects carrying the A3 haplotype of PROCR, the EPCR gene. Elevated plasma levels of sEPCR were also recently reported in women with preeclampsia (PE), a multisystemic syndrome involving inflammation, endothelial dysfunction and thrombosis. To determine whether this increase is genetically mediated or acquired, we analyzed sEPCR levels and the A3 haplotype distribution in 145 preeclamptic women and 145 age- and term-matched women with normal pregnancies enrolled in a case-control study. Plasma sEPCR levels were higher in the women with PE than in the controls, and this difference was not due to A3 haplotype over-representation. We observed a positive correlation between sEPCR levels and two markers of endothelium activation/damage (von Willebrand factor and soluble thrombomodulin), and a trend towards a third (sVCAM1). We also found an association between sEPCR levels in the highest quartile and the PE risk. The modest increase of sEPCR levels, together with the correlation with other endothelium activation/damage markers, suggest that it is more an innocent bystander of the endothelium activation/damage than an actor in PE. PMID- 21824645 TI - Platelet activation and induction of tissue factor in acute and chronic atrial fibrillation: involvement of mononuclear cell-platelet interaction. AB - BACKGROUND: Atrial fibrillation (AF) is associated with a prothrombotic state. The aim of this study was to analyze platelet activation and tissue factor (TF) induction in mononuclear cells (MNCs) and granulocytes downstream of cell-cell interactions in AF patients. METHODS: Blood samples were obtained from patients with paroxysmal AF (n=14) at sinus rhythm and at 15 min after induction of AF during an electrophysiological study, and from control subjects (n=13) and patients with chronic AF (n=14) in the outpatient clinic. The expression of CD41a, CD42b, P-selectin, and P-selectin glycoprotein ligand-1 (PSGL-1) on platelets and microparticles in platelet-rich plasma (PRP), and on MNCs and granulocytes in whole blood were examined by flow cytometry. MNC-platelet interaction was investigated ex vivo. RESULTS: The expression of CD41a and CD42b on platelets and microparticles was comparable between the control and chronic AF groups, and unchanged after AF induction. Acute induction of AF significantly increased the expression of P-selectin on platelets and microparticles, and to a similar extent, P-selectin-positive MNCs and granulocytes and P-selectin/PSGL-1 double positive MNCs. However, AF induction had no effect on platelet-MNC interactions ex vivo or TF expression on MNCs and granulocytes. Only patients with chronic AF showed platelet-MNC interaction ex vivo and TF overexpression on MNCs. CONCLUSIONS: Acute-onset AF activates platelets within minutes to initiate platelet-MNC interaction. The subsequent platelet binding induced TF expression in patients with chronic AF. These findings support the efficacy of anticoagulant therapeutics in chronic AF and suggest the underlying utility of antiplatelet therapeutics in early phase of AF occurrence. PMID- 21824646 TI - Comparison of a fluorogenic anti-FXa assay with a central laboratory chromogenic anti-FXa assay for measuring LMWH activity in patient plasmas. AB - INTRODUCTION: Low molecular weight heparins (LMWHs) are used worldwide for the treatment and prophylaxis of thromboembolic disorders. Routine laboratory tests are not required due to the predictable pharmacokinetics of LMWHs, with the exception of pregnant patients, children, patients with renal failure, morbid obesity, or advanced age. Anti-Factor Xa (anti-FXa) plasma levels are most often employed in the assessment and guidance of accurate dosing in these patient cohorts. MATERIALS AND METHODS: A LMWH calibration curve was generated using citrated human pooled plasma spiked with pharmacologically relevant concentrations (0-1.2U/ml) of two low molecular weight heparins; enoxaparin and tinzaparin. Least squares analysis determined the best curve fit for this set of data which returned low sum of squares (SS) values for the log linear fit with an R(2) value of 0.98. 30 patient samples were tested in the fluorogenic assay and concentrations were determined using the log linear regression equation and correlated with a standard chromogenic assay used for heparin monitoring. RESULTS: A statistically significant correlation was found between the fluorogenic and the chromogenic anti-FXa assays for 30 patient samples, with a slope of 0.829, offset of 0.258 and an R(2) value of 0.72 (p<0.0001). CONCLUSIONS: In the study presented here, a fluorogenic anti-FXa assay was correlated with a standard laboratory chromogenic anti-FXa assay using samples from patients on LMWH therapy. Significant correlations between the values derived by the fluorogenic and chromogenic anti-FXa assays were found for the patient cohort tested in this study. PMID- 21824647 TI - High-grade uterine sarcoma during pregnancy. PMID- 21824648 TI - Regulation of the immune response and inflammation by histamine and histamine receptors. AB - Histamine is a biogenic amine with extensive effects on many cell types, including important immunologic cells, such as antigen-presenting cells, natural killer cells, epithelial cells, and T and B lymphocytes. Histamine and its 4 receptors represent a complex system of immunoregulation with distinct effects dependent on receptor subtypes and their differential expression. These are influenced by the stage of cell differentiation, as well as microenvironmental influences, leading to the selective recruitment of effector cells into tissue sites accompanied by effects on cellular maturation, activation, polarization, and effector functions, which lead to tolerogenic or proinflammatory responses. In this review we discuss the regulation of histamine secretion, receptor expression, and differential activation of cells within both the innate and adaptive immune responses. It is clear that the effects of histamine on immune homeostasis are dependent on the expression and activity of the 4 currently known histamine receptors, and we also recognize that 100 years after the original identification of this biogenic amine, we still do not fully understand the complex regulatory interactions between histamine and the host immune response to everyday microbial and environmental challenges. PMID- 21824649 TI - Resilience in low-socioeconomic-status children with asthma: adaptations to stress. AB - BACKGROUND: Low socioeconomic status (SES) is a strong predictor of many health problems, including asthma impairment; however, little is understood about why some patients defy this trend by exhibiting good asthma control despite living in adverse environments. OBJECTIVE: This study sought to test whether a psychological characteristic, the shift-and-persist strategy (dealing with stressors by reframing them more positively while at the same time persisting in optimistic thoughts about the future), protects low-SES children with asthma. METHODS: One hundred twenty-one children aged 9 to 18 years with a physician's diagnosis of asthma were recruited from medical practices and community advertisements (mean age, 12.6 years; 67% male; 61% white). Shift-and-persist scores and asthma inflammation (eosinophil counts and stimulated IL-4 cytokine production) were assessed at baseline, and asthma impairment (daily diary measures of rescue inhaler use and school absences) and daily peak flow were monitored at baseline and at a 6-month follow-up. RESULTS: Children who came from low-SES backgrounds but who engaged in shift-and-persist strategies displayed less asthma inflammation at baseline (beta = 0.19, P < .05), as well as less asthma impairment (reduced rescue inhaler use and fewer school absences; beta = 0.32, P < .01) prospectively at the 6-month follow-up period. In contrast, shift and-persist strategies were not beneficial among high-SES children with asthma. CONCLUSION: An approach that focuses on the psychological qualities that low-SES children develop to adapt to stressors might represent a practical and effective starting point for reducing health disparities. Moreover, the approaches that are effective in low-SES communities might be different from those that are optimal in a high-SES context. PMID- 21824650 TI - Effects of particle size of silica filler on polymerization conversion in a light curing resin composite. AB - OBJECTIVES: The effect of visible light passing through a resin composite with different particle sizes of spherical silica filler on the curing depth and Knoop hardness of the resin composite was examined. The null hypotheses tested were that the particle size of silica filler has no effect on (1) the transmitted amount of visible light passing through the resin composite, (2) the curing depth of the resin composite, and (3) the ratio of the Knoop hardness of the hardened resin composite. METHODS: A series of different experimental resin composite pastes with different particle sizes of silica filler were prepared. The amount of visible light passing through each of the experimental resin pastes during the hardening process was determined. The curing depth and Knoop hardness of the resin composites were measured. Further, to characterize the polymerization conversion, the ratio of the Knoop hardness of the bottom surface against the irradiated surface of the hardened resin composites was determined. RESULTS: Increases in the particle size of the silica filler resulted in decreases in the transmitted amount of visible light, curing depth, and ratio of the Knoop hardness of the resin composite. The rate of polymerization conversion of the resin composite occurring deep within the cavity was found to be less than the rate of polymerization conversion occurring at the upper surface. SIGNIFICANCE: To increase the rate of polymerization conversion deep within the resin composite, it is important to reduce the particle size of the silica filler. PMID- 21824651 TI - Analysis of interfacial fracture in dental restorations. AB - OBJECTIVES: To provide a brief summary of the background theory of interfacial fracture mechanics and develop an analytical framework that identifies the critical factors for the analysis of the initiation and propagation of adhesion failure in composite restorations. METHODS: A conceptual framework utilizing interfacial fracture mechanics and Toya's solution for a partially delaminated circular inclusion in an elastic matrix, which can be applied (with caution) to approximate polymer curing induced cracking about composite resins for class 1 cavity restorations. RESULTS: The findings indicate that: (1) most traditional shear tests are not appropriate for the analysis of the interfacial failure initiation; (2) material properties of the restorative and tooth material have a strong influence on the energy realize rate; (3) there is a strong size effect; and (4) interfacial failure once initiated is characterized by unstable propagation along the interface almost completely encircling the composite. SIGNIFICANCE: The work is important for the analysis of the reliability of composite class I restorations and provides an adequate interpretation of recent adhesion debonding experimental results utilizing tubular geometry of specimens. The approach clearly identifies the critical parameters including; curing strain, material modulii, size and interfacial strain energy release rate for reliable development of advanced restorative materials. PMID- 21824652 TI - The intracellular uptake of CD95 modified paclitaxel-loaded poly(lactic-co glycolic acid) microparticles. AB - The CD95/CD95L receptor-ligand system is mainly recognised in the induction of apoptosis. However, it has also been shown that CD95L is over-expressed in many cancer types where it modulates immune-evasion and together with its receptor CD95 promotes tumour growth. Here, we show that CD95 surface modification of relatively large microparticles >0.5 MUm in diameter, including those made from biodegradable polylactic-co-glycolic acid (PLGA), enhances intracellular uptake by a range of CD95L expressing cells in a process akin to phagocytosis. Using this approach we describe the intracellular uptake of microparticles and agent delivery in neurons, medulloblastoma, breast and ovarian cancer cells in vitro. CD95 modified paclitaxel-loaded PLGA microparticles are shown to be significantly more effective compared to conventional paclitaxel therapy (Taxol) at the same dose in subcutaneous medulloblastoma (***P < 0.0001) and orthotopic ovarian cancer xenograft models where a >65-fold reduction in tumour bioluminescence was measured after treatment (*P = 0.012). This drug delivery platform represents a new way of manipulating the normally advantageous tumour CD95L over-expression towards a therapeutic strategy. CD95 functionalised drug carriers could contribute to the improved function of cytotoxics in cancer, potentially increasing drug targeting and efficacy whilst reducing toxicity. PMID- 21824653 TI - Adenylyl cyclase/cAMP-PKA-mediated phosphorylation of basal L-type Ca(2+) channels in mouse embryonic ventricular myocytes. AB - In fetal mammalian heart, constitutive adenylyl cyclase/cyclic AMP-dependent protein kinase A (cAMP-PKA)-mediated phosphorylation, independent of beta adrenergic receptor stimulation, could under such circumstances play an important role in sustaining the L-type calcium channel current (I(Ca,L)) and regulating other PKA dependent phosphorylation targets. In this study, we investigated the regulation of L-type Ca(2+) channel (LTCC) in murine embryonic ventricles. The data indicated a higher phosphorylation state of LTCC at early developmental stage (EDS, E9.5-E11.5) than late developmental stage (LDS, E16.5-E18.5). An intrinsic adenylyl cyclase (AC) activity, PKA activity and basal cAMP concentration were obviously higher at EDS than LDS. The cAMP increase in the presence of isobutylmethylxanthine (IBMX, nonselective phosphodiesterase inhibitor) was further augmented at LDS but not at EDS by chelation of intracellular Ca(2+) with 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA)-acetoxymethyl ester (BAPTA-AM). Furthermore, I(Ca,L) increased with time after patch rupture in LDS cardiomyocytes dialyzed with pipette solution containing BAPTA whereas not at EDS. Thus we conclude that the high basal level of LTCC phosphorylation is due to the high intrinsic PKA activity and the high intrinsic AC activity at EDS. The latter is possibly owing to the little or no effect of Ca(2+) influx via LTCCs on AC activity, leading to the inability to inhibit AC. PMID- 21824654 TI - Pneumocystis jirovecii pneumonia as a complication of bendamustine in a patient receiving bendamustine plus rituximab for marginal zone lymphoma. PMID- 21824655 TI - Changes in the prevalence of child sexual abuse, its risk factors, and their associations as a function of age cohort in a Finnish population sample. AB - OBJECTIVE: We examined (1) the prevalence of childhood sexual abuse (CSA) experiences as a function of cohort and gender, (2) the prevalence of factors associated with CSA as a function of cohort and whether the association of these factors with CSA remained the same irrespective of cohort, and (3) whether any cohort differences could be explainable by cohort differences in reporting bias. METHOD: We used the responses of 4,561 men (M=29, SD=7 years) and 8,361 female (M=29, SD=7 years) Finnish participants who responded to the Childhood Trauma Questionnaire-Short Form as well as questions regarding family structure. RESULTS: The prevalence of CSA experiences varied between 0.7-4.6% for men and 1.8-7.5% for women depending on the item. Younger cohorts reported less CSA as well as less of the risk factors (physical neglect and abuse, emotional neglect and abuse, parental substances abuse, not growing up with both biological parents) that were positively associated with the likelihood of CSA. The effects of these risk factors did not vary as a function of the cohort. Also, the declining trend was not explainable by social desirability being higher in the younger cohorts. CONCLUSIONS: The results suggest that there is a real decline in the prevalence of CSA and it is associated with a simultaneous decline in factors associated with CSA. PMID- 21824656 TI - Differential effects of psychological maltreatment on children of mothers exposed to intimate partner violence. AB - OBJECTIVE: Psychological maltreatment (PM) is the most prevalent form of child abuse, and is the core component of most of what is considered as child maltreatment. The aim of this work was to explore differential adverse outcomes of the different types of PM in the mental health and functioning of children living in homes in which they are exposed to intimate partner violence (IPV). METHOD: Participants were 168 children, aged between 4 and 17, whose mothers experienced IPV. They were assessed using different measures of psychopathology and functioning: Diagnostic Interview for Children and Adolescents-IV, Child Behavior Checklists and Child and Adolescent Functioning Assessment Scale. Furthermore, IPV was assessed with the Schedule for Assessment of Intimate Partner Violence Exposure in Children and the Index of Spouse Abuse. Statistical analyses were carried out with regression models adjusted by means of Generalized Estimating Equations. RESULTS: Spurning was the PM subtype with the greatest global effect on the children, as it was significantly associated with internalizing and externalizing problems. Denying emotional responsiveness specifically increased the risk of internalizing psychopathology and impairment in the emotional area. Terrorizing was not significantly associated with a greater number of negative outcomes in children's psychopathology or functioning in this population. IMPLICATIONS: The results suggest the importance of taking PM types into account in order to fully understand the problems of children exposed to IPV at home, and for the design of effective treatment and prevention programs. PMID- 21824657 TI - Green space, health inequality and pregnancy. AB - Green spaces have been suggested to improve physical and mental health and well being by increasing physical activity, reducing air pollution, noise, and ambient temperature, increasing social contacts and relieving psychophysiological stress. Although these mechanisms also suggest potential beneficial effects of green spaces on pregnancy outcomes, to our knowledge there is no available epidemiological evidence on this impact. We investigated the effects of surrounding greenness and proximity to major green spaces on birth weight and gestational age at delivery and described the effect of socioeconomic position (SEP) on these relationships. This study was based on a cohort of births (N=8246) that occurred in a major university hospital in Barcelona, Spain, during 2001 2005. We determined surrounding greenness from satellite retrievals as the average of Normalized Difference Vegetation Index (NDVI) in a buffer of 100 m around each maternal place of residence. To address proximity to major green spaces, a binary variable was used to indicate whether maternal residential address is situated within a buffer of 500 m from boundaries of a major green space. For each indicator of green exposure, linear regression models were constructed to estimate change in outcomes adjusted for relevant covariates including individual and area level SEP. None of the indicators of green exposure was associated with birth weight and gestational age. After assessing effect modification based on the level of maternal education, we detected an increase in birth weight (grams) among the lowest education level group (N=164) who had higher surrounding NDVI (Regression coefficient (95% confidence interval (CI) of 436.3 (43.1, 829.5)) or lived close to a major green space (Regression coefficient (95% CI)) of 189.8 (23.9, 355.7)). Our findings suggest a beneficial effect of exposure to green spaces on birth weight only in the lowest SEP group. PMID- 21824658 TI - Selenium exposure in subjects living in areas with high selenium concentrated drinking water: results of a French integrated exposure assessment survey. AB - BACKGROUND: Selenium is an essential element which can be toxic if ingested in excessive quantities. The main human exposure is food. In addition, intake may be boosted by consumption drinking water containing unusual high selenium concentration. OBJECTIVE: We measured the individual selenium level of people exposed to selenium concentration in drinking water greater than the maximum recommended limit which is 10 MUg/L. METHODS: We carried out a prospective cohort study on 80 adults (40 exposed subjects i.e. living in the involved area and 40 non-exposed ones i.e. living elsewhere) in western France. We used three different approaches: (1) direct measurement of ingested selenium by the duplicate portion method, (2) dietary reconstitution with a food frequency questionnaire (FFQ) and (3) evaluation of the individual selenium status by measuring the selenium content in toenail clippings. Analyses were performed by inductively coupled plasma-mass spectrometry. The association between toenail selenium concentration and area of residence was analyzed using linear regression with repeated measurements. RESULTS: We estimated selenium intake from FFQ at 64+/-14 MUg/day for exposed subjects as opposed to 52+/-14 MUg/day for the non exposed ones. On the basis of 305 duplicate diet samples, average intake was estimated at 64+/-26 MUg/day for exposed subjects. Area of residence (p=0.0030) and smoking (p=0.0054) were independently associated with toenail selenium concentration. CONCLUSION: Whatever method used for estimating selenium intake, the selenium level in this studied area with high selenium concentrated drinking water is much lower than in seleniferous areas. PMID- 21824659 TI - Risks and realities: dyadic interaction between 6-month-old infants and their mothers in opioid maintenance treatment. AB - A number of studies point to methadone exposure in utero as a possible risk factor in the developing mother-infant relationship in the first year of life. This study is part of a larger, national follow-up of 38 infants prenatally exposed to methadone or buprenorphine and 36 comparison, low-risk infants. The aim of the present paper is to assess the quality of mother-infant relationship when the infants are 6 months old. Videotaped mother-infant interactions were rated in a global scale (NICHD). Maternal and infant contributions collapsed into the variables "infant style" and "maternal style" showed that the only factor making significant contribution to the outcome measure "dyadic mutuality" was maternal style. The importance of group membership (exposed versus non-exposed), was reduced when controlling for maternal drug use prior to opioid maintenance treatment (OMT), maternal depression and parenting stress as well as infants' developmental status and sensory-integrative functions. This suggests that prediction of dyadic mutuality should be based on individual characteristics rather than group characteristics. These results support previous research findings that methadone and buprenorphine use per se does not have direct influence on the quality of early mother-infant relationship, but tailored follow up procedures targeting drug-free pregnancies and parenting support are beneficial for women in OMT and their children. PMID- 21824660 TI - A comparison of the clinical characteristics of Chinese patients with recurrent major depressive disorder with and without dysthymia. AB - BACKGROUND: The relationship between major depressive disorder (MDD) and dysthymia, a form of chronic depression, is complex. The two conditions are highly comorbid and it is unclear whether they are two separate disease entities. We investigated the extent to which patients with dysthymia superimposed on major depression can be distinguished from those with recurrent MDD. METHODS: We examined the clinical features in 1970 Han Chinese women with MDD (DSM-IV) between 30 and 60 years of age across China. Logistic regression was used to determine the association between clinical features of MDD and dysthymia and between dysthymia and disorders comorbid with major depression. RESULTS: The 354 cases with dysthymia had more severe MDD than those without, with more episodes of MDD and greater co-morbidity for anxiety disorders. Patients with dysthymia had higher neuroticism scores and were more likely to have a family history of MDD. They were also more likely to have suffered serious life events. LIMITATIONS: Results were obtained in a clinically ascertained sample of Chinese women and may not generalize to community-acquired samples or to other populations. It is not possible to determine whether the associations represent causal relationships. CONCLUSIONS: The additional diagnosis of dysthymia in Chinese women with recurrent MDD defines a meaningful and potentially important subtype. We conclude that in some circumstances it is possible to distinguish double depression from recurrent MDD. PMID- 21824662 TI - Increased risk of depressive disorder following the diagnosis of benign prostatic enlargement: one-year follow-up study. AB - PURPOSE: In previous studies, benign prostatic enlargement (BPE) and urinary tract symptoms were demonstrated to be associated with depressive symptoms. However, no longitudinal follow-up study to date has evaluated the relationship between BPE and the subsequent risk of developing depressive disorder. This nationwide, population-based study aimed to prospectively examine the relationship between a history of BPE and the risk of developing depressive disorder. MATERIALS AND METHODS: A total of 16,130 adult patients diagnosed with BPE for the first time between 2005 and 2007 were recruited along with a comparison cohort of 48,390 matched enrollees without a history of BPE. All the subjects were tracked for a one-year period following their index date to identify those who subsequently developed a depressive disorder. The Cox proportional hazards model was utilized to compute the risk difference for depressive disorder between cohorts. RESULTS: Of 64,520 sampled patients, 325 (2.01%) from the BPE cohort, and 531 (1.10%) from the comparison cohort were subsequently diagnosed with depressive disorder during the follow-up period. The risk of developing depressive disorder within one-year following diagnosis with BPE was found to be 1.87 (95% CI=1.63-2.16, p<0.001) times the risk in absence of BPE after adjusting for the patients' monthly income, and the geographical location and urbanization level of their place of residence. CONCLUSIONS: Our results suggest that patients with BPE are at an increased risk for contracting depressive disorder. PMID- 21824663 TI - Psychosocial risk factors for postpartum depression and their relation to timing of onset: the Hamamatsu Birth Cohort (HBC) Study. AB - BACKGROUND: The time frame for postpartum depression (PPD) defined in the literature differs among studies - either 4 weeks or 3 months after childbirth. To address potential difference in PPD in relation to onset of the illness, we investigated risk factors for early- and late-onset PPD using a representative birth cohort in Japan. METHODS: We evaluated 675 women who completed the Edinburgh Postnatal Depression Scale (EPDS) for two to three times within 3 months after childbirth. Mothers with an onset of PPD (>= 9 points on EPDS) within 4 weeks after childbirth were classified as having early-onset PPD, and those with PPD that occurred during the period of the 5th to 12th week after childbirth were classified as having late-onset PPD. We adopted multinomial logistic regression to investigate risk factors associated with each of early- and late-onset PPD, whilst simultaneously allowing for all risk factors a priori selected in the model. RESULTS: The period prevalence of early- and late-onset PPD was 11% and 4%, respectively. Primiparity was associated only with early onset PPD (OR=2.6, 95%CI 1.5-4.4). Younger (<25 years: OR=3.6, 95%CI 1.2-11.2) and advanced age (>= 35 years: OR=2.5, 95%CI 1.1-5.8) of the participating women was significantly associated only with late-onset PPD. Lack of emotional support and a history of depression/anxiety appeared to increase risk both for early- and late-onset PPD. LIMITATIONS: Moderate sample size and diagnosis of PPD without use of structured interviews may limit generalisability of the findings. CONCLUSION: The finding that risk sets for early- and late-onset PPD differ suggests that these two types may have different aetiology. PMID- 21824661 TI - The relationship between neuroticism, major depressive disorder and comorbid disorders in Chinese women. AB - OBJECTIVE: The personality trait of neuroticism is a risk factor for major depressive disorder (MDD), but this relationship has not been demonstrated in clinical samples from Asia. METHODS: We examined a large-scale clinical study of Chinese Han women with recurrent major depression and community-acquired controls. RESULTS: Elevated levels of neuroticism increased the risk for lifetime MDD (with an odds ratio of 1.37 per SD), contributed to the comorbidity of MDD with anxiety disorders, and predicted the onset and severity of MDD. Our findings largely replicate those obtained in clinical populations in Europe and US but differ in two ways: we did not find a relationship between melancholia and neuroticism; we found lower mean scores for neuroticism (3.6 in our community control sample). LIMITATIONS: Our findings do not apply to MDD in community acquired samples and may be limited to Han Chinese women. It is not possible to determine whether the association between neuroticism and MDD reflects a causal relationship. CONCLUSIONS: Neuroticism acts as a risk factor for MDD in Chinese women, as it does in the West and may particularly predispose to comorbidity with anxiety disorders. Cultural factors may have an important effect on its measurement. PMID- 21824664 TI - The impact of educational status on the clinical features of major depressive disorder among Chinese women. AB - BACKGROUND: Years of education are inversely related to the prevalence of major depressive disorder (MDD), but the relationship between the clinical features of MDD and educational status is poorly understood. We investigated this in 1970 Chinese women with recurrent MDD identified in a clinical setting. METHODS: Clinical and demographic features were obtained from 1970 Han Chinese women with DSM-IV major depression between 30 and 60 years of age across China. Analysis of linear, logistic and multiple logistic regression models were used to determine the association between educational level and clinical features of MDD. RESULTS: Subjects with more years of education are more likely to have MDD, with an odds ratio of 1.14 for those with more than ten years. Low educational status is not associated with an increase in the number of episodes, nor with increased rates of co-morbidity with anxiety disorders. Education impacts differentially on the symptoms of depression: lower educational attainment is associated with more biological symptoms and increased suicidal ideation and plans to commit suicide. LIMITATIONS: Findings may not generalize to males or to other patient populations. Since the threshold for treatment seeking differs as a function of education there may an ascertainment bias in the sample. CONCLUSIONS: The relationship between symptoms of MDD and educational status in Chinese women is unexpectedly complex. Our findings are inconsistent with the simple hypothesis from European and US reports that low levels of educational attainment increase the risk and severity of MDD. PMID- 21824666 TI - The face and its emotion: right N170 deficits in structural processing and early emotional discrimination in schizophrenic patients and relatives. AB - Previous studies have reported facial emotion recognition impairments in schizophrenic patients, as well as abnormalities in the N170 component of the event-related potential. Current research on schizophrenia highlights the importance of complexly-inherited brain-based deficits. In order to examine the N170 markers of face structural and emotional processing, DSM-IV diagnosed schizophrenia probands (n=13), unaffected first-degree relatives from multiplex families (n=13), and control subjects (n=13) matched by age, gender and educational level, performed a categorization task which involved words and faces with positive and negative valence. The N170 component, while present in relatives and control subjects, was reduced in patients, not only for faces, but also for face-word differences, suggesting a deficit in structural processing of stimuli. Control subjects showed N170 modulation according to the valence of facial stimuli. However, this discrimination effect was found to be reduced both in patients and relatives. This is the first report showing N170 valence deficits in relatives. Our results suggest a generalized deficit affecting the structural encoding of faces in patients, as well as the emotion discrimination both in patients and relatives. Finally, these findings lend support to the notion that cortical markers of facial discrimination can be validly considered as vulnerability markers. PMID- 21824665 TI - Clinical features and risk factors for post-partum depression in a large cohort of Chinese women with recurrent major depressive disorder. AB - BACKGROUND: Post partum depression (PPD) is relatively common in China but its clinical characteristics and risk factors have not been studied. We set out to investigate whether known risk factors for PPD could be found in Chinese women. METHODS: A case control design was used to determine the impact of known risk factors for PPD in a cohort of 1970 Chinese women with recurrent DSM-IV major depressive disorder (MDD). In a within-case design we examined the risk factors for PPD in patients with recurrent MDD. We compared the clinical features of MDD in cases with PPD to those without MDD. Odds ratios were calculated using logistic and ordinal regression. RESULTS: Lower occupational and educational statuses increased the risk of PPD, as did a history of pre-menstrual symptoms, stressful life events and elevated levels of the personality trait of neuroticism. Patients with PPD and MDD were more likely to experience a comorbid anxiety disorder, had a younger age of onset of MDD, have higher levels of neuroticism and dysthymia. LIMITATIONS: Results obtained in this clinical sample may not be applicable to PPD within the community. Data were obtained retrospectively and we do not know whether the correlations we observe have the same causes as those operating in other populations. CONCLUSIONS: Our results are consistent with the hypothesis that the despite cultural differences between Chinese and Western women, the phenomenology and risk factors for PPD are very similar. PMID- 21824667 TI - Relationships between season of birth, schizotypy, temperament, character and neurocognition in a non-clinical population. AB - While schizophrenia has been associated with a slight excess of winter/early spring birth, it is unclear whether there is such an association in relation to schizotypal personality traits. Season of birth has also been reported to relate to temperament and character personality dimensions and cognitive functioning. Moreover, non-clinical schizotypy has been shown to be associated with mild cognitive impairment, although its precise nature is yet to be elucidated. Here we examined the relationships between season of birth, schizotypal traits, temperament and character, and cognitive function. Four hundred and fifty-one healthy adults completed the Schizotypal Personality Questionnaire (SPQ). The Temperament and Character Inventory (TCI) and a neuropsychological test battery consisting of full versions of the Wechsler Memory Scale-Revised and the Wechsler Adult Intelligence Scale-Revised, and the Wisconsin Card Sorting Test, were also administered to most of the participants. The total SPQ score of those born in winter was significantly higher than that of the remaining participants. Season of birth was not significantly associated with any of the TCI dimensions or cognitive test results. Significant but mild relationships between higher SPQ scores and lower scores on some aspects of IQ were observed. These results support the notion that schizotypy and schizophrenia are neurodevelopmental conditions on the same continuum. PMID- 21824668 TI - The role of metformin and thiazolidinediones in the regulation of hepatic glucose metabolism and its clinical impact. AB - Fasting hyperglycemia in type 2 diabetes mellitus (T2DM) results from elevated endogenous glucose production (EGP), which is mostly due to augmented hepatic gluconeogenesis. Insulin-resistant humans exhibit impaired insulin-dependent suppression of EGP and excessive hepatic lipid storage (steatosis), which relates to abnormal supply of free fatty acids (FFA) and energy metabolism. Only two glucose-lowering drug classes, the biguanide metformin and the thiazolidendiones (TZDs), exert insulin- and glucagon-independent hepatic effects. Preclinical studies suggest that metformin inhibits mitochondrial complex I. TZDs, as peroxisome proliferator-activated receptor (PPAR) gamma-agonists, predominantly reduce the flux of FFA and cytokines from adipose tissue to the liver, but could also directly inhibit mitochondrial complex I. Although both metformin and TZDs improve fasting hyperglycemia and EGP in clinical trials, only TZDs decrease steatosis and peripheral insulin resistance. More studies are required to address their effects on hepatocellular energy metabolism with a view to identifying novel targets for the treatment of T2DM. PMID- 21824669 TI - Association of resident and room characteristics with antipsychotic use in long term care facilities (LTCF). AB - Inappropriate and widespread prescribing of antipsychotics in LTCF is of concern. This study aimed to explore the association of resident and room characteristics with antipsychotic use in this setting. This is cross-sectional secondary analysis of the baseline data of 280 residents >= 65 years old, from a prospective, observational, LTCF multi-site (n=7) cohort study on delirium. Demographic data included age, sex and length of stay. Resident characteristics assessed were presence of dementia, disruptive behavior, delirium and use of restraints. Room characteristics assessed were single room, clock/calendar, and telephone. Separate logistic regression models were used to explore the association of resident and room characteristics with antipsychotic use, adjusting for demographic variables. Mean age was 84.9 +/- 7.0 years (+/- S.D.) with 56% female. The mean prevalence of antipsychotics use was 31.1% (range: 25.6 50.0%). The regression model of resident characteristics revealed a significant association between disruptive behavior (OR=1.18, 95% CI=1.12-1.25) and antipsychotic use. The model of room characteristics revealed a significant association between absence of a clock or calendar (OR=1.93, 95% CI=1.04-3.56) and absence of a telephone (OR=2.79, 95% CI=1.48-5.25). Our results suggest that behavior problems are associated with a higher likelihood of antipsychotic use. Absence of a clock/calendar and of a telephone was related to antipsychotic use. Further research is needed to confirm these findings. PMID- 21824670 TI - Vanishing heart: a case report of a patient a life without heart sounds and a complete cardiac standstill on echocardiography. PMID- 21824671 TI - "Angiographic late catch-up" phenomenon after sirolimus-eluting stent implantation. AB - BACKGROUND: Although several randomized trials have shown that sirolimus-eluting stent (SES) substantially reduces in-stent restenosis, recent studies have suggested the possibility of late catch-up after SES implantation. We investigated long-term angiographic outcomes after SES implantation in real-world practice. METHODS: This study was conducted on 195 patients with 253 lesions who underwent the first and long-term angiographic follow-up after SES implantation. First follow-up was done at near 6 months after SES implantation. Long-term angiographic follow-up was defined as that performed at least 36 months after index procedure. Angiographies in patients who experienced target lesion revascularization at the time of the first angiographic follow-up were excluded from the current analysis. RESULTS: Minimal luminal diameter at long-term angiographic follow-up was significantly smaller compared with that at the first follow-up (2.21 +/- 0.65 vs. 2.40 +/- 0.55, p<0.001). In-stent late lumen loss between the first and long-term follow-up tended to be larger compared with that between SES implantation and the first follow-up (0.19 +/- 0.47 vs. 0.15 +/- 0.39, p=0.298). There was a trend for increased incidence of coronary artery aneurysm (1.6% and 7.5% at the first and long-term follow-up) and stent fracture (4.3% and 10.3%). Two stent aneurysms and one stent fracture were related with definite very late stent thrombosis. CONCLUSION: An "angiographic late catch-up" phenomenon and a trend toward increased incidence of coronary artery aneurysm and stent fracture were found at a median 46.5-month angiographic follow-up compared with a median 6-month follow-up. PMID- 21824672 TI - Variability in biofilm production by Listeria monocytogenes correlated to strain origin and growth conditions. AB - This study aimed to identify factors that influence the development of biofilm by Listeria monocytogenes strains and to determine the extent to which biofilm production protects against quaternary ammonium compound (QAC) disinfectant challenge. A total of 95 L. monocytogenes strains were studied and biofilm production was assessed as a function of incubation temperature, media pH, strain origin, serotype, and environmental persistence status. Attachment and biofilm development (inferred by the level of attached biomass) were measured in vitro using a colourimetric 96-well microtitre plate method in nutritive media (Brain Heart Infusion). Increased biofilm production correlated with increasing temperature and the most acidic, or most alkaline, growth conditions tested. Clinical and environmental (food factory) strains were observed to increase biofilm production at higher and lower incubation temperatures respectively, independent of their rate of planktonic growth. Serotype 1/2a strains produced significantly more biofilm. Biofilm maturity, rather than strain, was correlated with resistance to QAC. Carbohydrate containing exopolymeric material could not be detected in the biofilm of representative strains, and no correlation between strains recovered as persistent food factory contaminants and biofilm production was identified. Although limited to in vitro inference based on the assay system used, our results suggest that environmental conditions determine the level of biofilm production by L. monocytogenes strains, independent of the rate of planktonic growth, and that this may manifest from selection pressures to which a given strain grows optimally. PMID- 21824673 TI - Microbiology at first visit of moderate-to-severe diabetic foot infection with antimicrobial activity and a survey of quinolone monotherapy. AB - Samples from 1295 patients with diabetic foot infection were evaluated; 4332 samples were collected with an average of 3.3 samples per patient. Fifty-seven percent of patients had a 2B ulcer and 23% had a 3B ulcer according to Texas University Classification. In 64.2% of samples collected at first visit an etiologic agent was identified. About 40% of the positive samples were polymicrobial. Gram positive bacteria were more frequently isolated (52.6%), Staphylococcus aureus was the most frequently isolated single agent (29.9%) and MRSA was 22% of S. aureus. Enterococcus spp., mainly Enterococcus faecalis, were 9.9%, all vancomycin susceptible except 2 isolates. Streptococci were 4.6%, more than 60% Streptococcus agalactiae. Gram negative rods were 40.6%, with enterobacteria 23.5% and Pseudomonas aeruginosa 10.3%. Anaerobes were only 0.3%, probably due to culture methods applied in our laboratory. Cotrimoxazole, rifampin and doxycycline were still active against S. aureus. ESBL producers, among enterobacteria, were 10%, mainly Escherichia coli and Proteus spp. Only colistin had a rate of susceptibility against P. aeruginosa above 90%. Levofloxacin had the best clinical activity with respect to the other quinolones, but when it failed, selected more resistant strains with respect to moxifloxacin among S. aureus and with respect to ciprofloxacin among P. aeruginosa. PMID- 21824674 TI - Insulin resistance index (HOMA-IR) levels in a general adult population: curves percentile by gender and age. The EPIRCE study. AB - AIMS: To describe the distribution of HOMA-IR levels in a general nondiabetic population and its relationships with metabolic and lifestyles characteristics. METHODS: Cross-sectional study. Data from 2246 nondiabetic adults in a random Spanish population sample, stratified by age and gender, were analyzed. Assessments included a structured interview, physical examination, and blood sampling. Generalized additive models (GAMs) were used to assess the effect of lifestyle habits and clinical and demographic measurements on HOMA-IR. Multivariate GAMs and quantile regression analyses of HOMA-IR were carried out separately in men and women. RESULTS: This study shows refined estimations of HOMA-IR levels by age, body mass index, and waist circumference in men and women. HOMA-IR levels were higher in men (2.06) than women (1.95) (P=0.047). In women, but not men, HOMA-IR and age showed a significant nonlinear association (P=0.006), with increased levels above fifty years of age. We estimated HOMA-IR curves percentile in men and women. CONCLUSIONS: Age- and gender-adjusted HOMA-IR levels are reported in a representative Spanish adult non-diabetic population. There are gender-specific differences, with increased levels in women over fifty years of age that may be related with changes in body fat distribution after menopause. PMID- 21824675 TI - Speed-bumps ahead for the genetics of later-life diseases. PMID- 21824676 TI - Normal and hypoacoustic infant cry signal classification using time-frequency analysis and general regression neural network. AB - Crying is the most noticeable behavior of infancy. Infant cry signals can be used to identify physical or psychological status of an infant. Recently, acoustic analysis of infant cry signal has shown promising results and it has been proven to be an excellent tool to investigate the pathological status of an infant. This paper proposes short-time Fourier transform (STFT) based time-frequency analysis of infant cry signals. Few statistical features are derived from the time frequency plot of infant cry signals and used as features to quantify infant cry signals. General Regression Neural Network (GRNN) is employed as a classifier for discriminating infant cry signals. Two classes of infant cry signals are considered such as normal cry signals and pathological cry signals from deaf infants. To prove the reliability of the proposed features, two neural network models such as Multilayer Perceptron (MLP) and Time-Delay Neural Network (TDNN) trained by scaled conjugate gradient algorithm are also used as classifiers. The experimental results show that the GRNN classifier gives very promising classification accuracy compared to MLP and TDNN and the proposed method can effectively classify normal and pathological infant cries. PMID- 21824677 TI - Conservation successes at micro-, meso- and macroscales. AB - Although large-scale biodiversity declines are ongoing, certain conservation actions have made a positive difference. Rates of extinction and endangerment of vertebrate species, for instance, have probably been reduced via conservation interventions. Such conservation actions operate at different spatial scales. Habitat preservation and endangered species recovery are examples of conservation successes at microscales. Mesoscale conservation includes regional cooperation among neighboring countries that has arrested population declines of endangered species, such as mountain gorillas. At macroscales, public pressure on multinational corporations has sometimes resulted in their abandoning environmentally damaging practices or suppliers with poor environmental records. Overall, conservation projects such as these need more long-term funding and greater political and popular support, and must also include provisions to evaluate and document their outcomes. As we discuss here, a focus on conservation successes achieved at different scales can help to promote these aims and guide future conservation victories. PMID- 21824678 TI - Expression analysis of the gene family associated with raffinose accumulation in rice seedlings under cold stress. AB - A considerable increase in the concentration of raffinose was detected in rice seedlings exposed to chilling for more than 4 days. The content of raffinose in leaf blades increased from hardly detectable levels (0-1 days) to approximately 9 mg/g FW after 11 days of chilling treatment. Accumulation occurred in leaf blades but not in sheaths. Analysis of the expression of candidate genes related to galactinol and raffinose synthesis revealed that transcript levels of two galactinol synthase and four raffinose synthase genes increased in leaf blades before the accumulation of raffinose became detectable. PMID- 21824679 TI - Gastrophysa polygoni herbivory on Rumex confertus: single leaf VOC induction and dose dependent herbivore attraction/repellence to individual compounds. AB - We report large induction (>65(fold) increases) of volatile organic compounds (VOCs) emitted from a single leaf of the invasive weed mossy sorrel, Rumex confertus Willd. (Polygonaceae), by herbivory of the dock leaf beetle, Gastrophysa polygoni L. (Coleoptera: Chrysomelidae). The R. confertus VOC blend induced by G. polygoni herbivory included two green leaf volatiles ((Z)-3 hexenal, (Z)-3-hexen-1-yl acetate) and three terpenes (linalool, beta caryophyllene, (E)-beta-farnesene). Uninjured leaves produced small constitutive amounts of the GLVs and barely detectable amounts of the terpenes. A Y-tube olfactometer bioassay revealed that both sexes of adult G. polygoni were attracted to (Z)-3-hexenal and (Z)-3-hexen-1-yl acetate at a concentration of 300 ng h(-1). No significant G. polygoni attraction or repellence was detected for any VOC at other concentrations (60 and 1500 ng h(-1)). Yet, G. polygoni males and females were significantly repelled by (or avoided) at the highest test concentration (7500 ng h(-1)) of both GLVs and (E)-beta-farnesene. Mated male and female G. polygoni might be attracted to injured R. confertus leaves, but might avoid R. confertus when VOC concentrations (especially the terpene (E)-beta farnesene) suggest high overall plant injury from conspecifics, G. viridula, or high infestations of other herbivores that release (E)-beta-farnesene (e.g., aphids). Tests in the future will need to examine G. polygoni responses to VOCs emitted directly from uninjured (constitutive) and injured (induced) R. confertus, and examine whether R. confertus VOC induction concentrations increase with greater tissue removal on a single leaf and/or the number of leaves with feeding injury. PMID- 21824680 TI - [Retrobulbar optic neuropathy and non-Hodgkin lymphoma]. AB - INTRODUCTION: Non-Hodgkin lymphomas (NHLs) constitute a group of heterogeneous diseases that can arise in lymphatic nodal or extranodal sites. Ocular lymphomas account for 1% of all NHLs. Tumor of the orbit, which can lead to compression of the optic nerve, is the most frequent presentation of the disease. Primary infiltration of the optic nerve and its sheath remains exceptional. OBSERVATION: We report the case of a 51-year-old female patient treated for a NHL. While she was considered to be in remission after four courses of chemotherapy, she presented a right visual loss with hand motion acuity. Her examination revealed a right afferent pupillary defect. Brain MRI emphasized an infiltration of her right optic nerve with no other orbit abnormality. Cerebrospinal fluid analysis showed lymphomatous meningitis. She was then considered to have lymphomatous optic neuropathy (LON). Despite initial improvement of the visual acuity with treatment, the patient died of bone marrow aplasia 6 weeks later. CONCLUSION: LON can be suspected in a painful and sudden visual loss in a context of neoplasia. The diagnosis is confirmed by MRI and cerebrospinal fluid analysis. LON may occur as the sole ocular manifestation of disease recurrence in a patient with systemic NHL, otherwise thought to be in clinical remission. PMID- 21824681 TI - Evaluation of the biological efficacy of hydrogen peroxide vapour decontamination in wards of an Australian hospital. AB - This study assessed the efficacy of a 'dry' hydrogen peroxide vapour decontamination in an Australian hospital via a two-armed study. The in vivo arm examined the baseline bacterial counts in high-touch zones within wards and evaluated the efficacy of cleaning with a neutral detergent followed by either hydrogen peroxide vapour decontamination, or a manual terminal clean with bleach or Det-Sol 500. The in vitro arm examined the efficacy of hydrogen peroxide vapour decontamination on a variety of different surfaces commonly found in the wards of an Australian hospital, deliberately seeded with a known concentration of vancomycin-resistant enterococci (VRE). All bacterial counts were evaluated by a protocol of contact plate method. In the in vivo arm, 33.3% of the high-touch areas assessed had aerobic bacterial count below the detection limit (i.e. no bacteria recoverable) post hydrogen peroxide decontamination, and in all circumstances the highest microbial density was <=3 cfu/cm(2), while in the in vitro arm there was at least a reduction in bacterial load by a factor of 10 at all surfaces investigated. These results showed that dry hydrogen peroxide vapour room decontamination is highly effective on a range of surfaces, although the cleanliness data obtained by these methods cannot be easily compared among the different surfaces as recovery of organisms is affected by the nature of the surface. PMID- 21824682 TI - Epidemiology of central line-associated bloodstream infections in Quebec intensive care units: a 6-year review. AB - BACKGROUND: The burden of central line-associated bloodstream infections (CLABSI) in Canadian intensive care units (ICUs) is not well established. The present study aimed to describe CLABSI epidemiology in Quebec ICUs during 2003-2009. METHODS: The study population was a retrospective dynamic cohort of 58 ICUs that participated in the Surveillance Provinciale des Infections Nosocomiales program during 2003-2009. We calculated annual CLABSI incidence rates (IRs), central venous catheter (CVC) utilization ratios, and case-fatality proportions, and described the pathogens involved. We analyzed data using descriptive statistics and standardized incidence ratios. RESULTS: A total of 891 CLABSIs were identified during 446,137 CVC-days. In 2003-2009, CLABSI IRs were 1.67 CLABSI/1,000 CVC-days in adult ICUs, 2.20 CLABSIs/1,000 CVC-days in pediatric ICUs, and 4.40 CLABSIs/1,000 CVC-days in neonatal ICUs. Since 2007, CLABSI IRs in adult, pediatric and neonatal ICUs have decreased by 11%, 50%, and 18%, respectively. Pediatric ICUs had the highest CVC utilization ratio (median, 0.61; interquartile range, 0.57-0.66). Coagulase-negative staphylococci caused 53% of the CLABSIs. The proportion of methicillin-resistant Staphylococcus aureus declined from 70% to <40% after 2006. CONCLUSIONS: CLABSIs result in a considerable burden of illness in Quebec ICUs. However, CLABSI IRs have decreased since 2007, and the proportion of methicillin-resistant S aureus has remained <40% since 2006. Continuous surveillance is essential to determine whether these changes are sustainable. PMID- 21824683 TI - Disposal of sharps medical waste in the United States: impact of recommendations and regulations, 1987-2007. AB - BACKGROUND: To gauge the impact of regulatory-driven improvements in sharps disposal practices in the United States over the last 2 decades, we analyzed percutaneous injury (PI) data from a national surveillance network from 2 periods, 1993-1994 and 2006-2007, to see whether changes in disposal-related injury patterns could be detected. METHODS: Data were derived from the EPINet Sharps Injury Surveillance Research Group, established in 1993 and coordinated by the International Healthcare Worker Safety Center at the University of Virginia. For the period 1993-1994, 69 hospitals contributed data; the combined average daily census for the 2 years was 24,495, and the total number of PIs reported was 7,854. For the period 2006-2007, 33 hospitals contributed data; the combined average daily census was 6,800, and the total number of PIs reported was 1901. RESULTS: In 1992-1993, 36.8% of PIs reported were related to disposal of sharp devices. In 2006-2007, this proportion was 19.3%, a 53% decline. CONCLUSIONS: This comparison provides evidence that implementation of point-of-use, puncture resistant sharps disposal containers, combined with large-scale use of safety engineered sharp devices, has resulted in a marked decline in sharps disposal related injury rates in the United States. The protocol for removing and replacing full sharps disposal containers remains a critical part of disposal safety. PMID- 21824684 TI - Evaluation of pet contact as a risk factor for carriage of multidrug-resistant staphylococci in nursing home residents. AB - BACKGROUND: Pets, often used as companionship and for psychological support in the therapy of nursing home residents, have been implicated as reservoirs for antibiotic-resistant bacteria. We investigated the importance of pets as reservoirs of multidrug-resistant (MDR) staphylococci in nursing homes. METHODS: We assessed the carriage of MDR staphylococci in pets and in 2 groups of residents, those living in nursing homes with pets and those living without pet contacts. We collected demographic, health status, and human-pet contact data by means of questionnaires. We assessed potential bacteria transmission pathways by investigating physical resident-to-pet contact. RESULTS: The observed prevalence of MDR staphylococci carriage was 84/229 (37%) in residents living with pets and 99/216 (46%) in those not living with pets (adjusted odds ratio [aOR], 0.6; 95% confidence interval [CI], 0.4-0.9). Active pet contact was associated with lower carriage of MDR staphylococci (aOR, 0.5; 95% CI, 0.4-0.8). Antibiotic treatment during the previous 3 months was associated with significantly increased risk for MDR carriage in residents (aOR, 3.1; 95% CI, 1.8-5.7). CONCLUSIONS: We found no evidence that the previously reported benefits of pet contact are compromised by the increased risk of carriage of MDR staphylococci in residents associated with interaction with these animals in nursing homes. Thus, contact with pets, always under good hygiene standards, should be encouraged in these settings. PMID- 21824685 TI - Epidemiologic characteristics of resistant microorganisms present in reserves from an intensive care unit. AB - In this study, significant contamination in the intensive care unit environment was observed (P < .004). Sampling of inanimate surfaces and equipment found vancomycin-resistant Enterococcus faecalis, ciprofloxacin-resistant Staphylococcus aureus and S epidermidis, and multiresistant Acinetobacter baumannii with similarities (60%-80%) to blood culture isolates. PMID- 21824686 TI - [Editor response: the evidence of case reports in urology is, per se, scarcely defendable]. PMID- 21824687 TI - [Evidence-based defense of case reports in urology]. PMID- 21824689 TI - [Factors influencing influenza vaccination among primary care workers]. PMID- 21824690 TI - Comparative study on antioxidant capacity of flavonoids and their inhibitory effects on oleic acid-induced hepatic steatosis in vitro. AB - Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease and its incidence is rising worldwide. We compared the antioxidant capacity of seventeen flavonoids with their inhibitory effects on oleic acid-induced triglyceride (TG) over-accumulation in HepG2 cells. The results showed significant correlations (P < 0.01) between the inhibition of intracellular TG levels and the suppression effects on reactive oxygen species. Nevertheless, the radical-reducing activities of flavonoids assessed by chemical assays (cyclic voltammetry and Folin-Ciocalteu reagent assay) were poorly correlated with their intracellular TG inhibitory effects. The relationships between structural properties of flavonoids and their inhibitory effects on TG over-accumulation were discussed. PMID- 21824691 TI - Synthesis, computational studies and preliminary pharmacological evaluation of 2 [4-(aryl substituted) piperazin-1-yl] N, N-diphenylacetamides as potential antipsychotics. AB - A series of 2-[4-(aryl substituted) piperazin-1-yl] N, N-diphenylacetamides have been synthesized and the target compounds (3a-j) were evaluated for atypical antipsychotic activity in apomorphine induced climbing, 5-HTP induced head twitches behavior and catalepsy studies in mice. The physicochemical similarity of the target compounds with respect to standard drugs clozapine, ketanserin and risperidone was calculated by using software programs. Among them, compound 3e showed maximum atypical antipsychotic like profile. PMID- 21824692 TI - Tertiary amides with a five-membered heteroaromatic ring as new probes for the translocator protein. AB - In this study novel ligands of the translocator protein (TSPO), characterized by a five-membered aromatic heterocycle (i.e. oxazole, isoxazole, oxadiazole), a phenyl ring, and an amide side chain of carboxy or acetic type, were designed using a previously reported pharmacophore/topological model. Most of compounds showed significant TSPO binding affinity (K(i) values in the nanomolar/submicromolar range), the highest being displayed by oxazolacetamides 6. A number of compounds were tested for their ability to inhibit the proliferation/viability of human glioblastoma cell line U87MG. The dose-time dependent cell response to treatment with 6d demonstrated the specificity of the observed effect. The ability of 6d to induce mitochondrial membrane dissipation (DeltaPsim) substantiates the intracellular pro-apoptotic mechanism activated by ligand binding to TSPO. PMID- 21824693 TI - Unfolding case studies in pre-registration nursing education: lessons learned. AB - Nursing education is undergoing radical change worldwide. There is criticism surrounding the content of education and the delivery. As a result, traditional methods of teaching and learning have been replaced by strategies that place greater emphasis on active learner interaction, critical thinking, and decision making. Assisting pre-registration nurses to become competent and confident in clinical practice requires immersion in practice with sufficient support and coaching based on real life scenarios. Simulation via an unfolding case study approach is one way to provide interactive learning experiences where students acquire new skills that advance their clinical judgment with the aim of becoming safe, competent practitioners. Lessons learned from implementing an unfolding case study are discussed in this paper. PMID- 21824694 TI - Diclofenac sodium intramuscularly, or paracetamol intravenously? Question not answered. PMID- 21824695 TI - Implementation of electronic operating notes. PMID- 21824696 TI - A comparative biomechanical study of traditional and in-line plating systems following immediate stabilization of single and bi-level cervical segments. AB - BACKGROUND: Anterior cervical plate fixation has gained widespread acceptance for treatment of cervical spine pathologies by stabilizing the segment and enhancing fusion rates. While it is generally accepted that multiple fusion levels benefit from plating, few studies have compared plate designs. Wider plates can increase surgical complications and cost and are, therefore, not indicated unless biomechanical benefits exist. In this study, a cervical cadaver model is subjected to physiological loads and stabilized with in-line one-screw, and traditional two-screw per vertebral body plates. METHODS: Three groups of eight fresh frozen human cadaver cervical spines (C2-C7) were tested by applying pure moments of 1.5 Nm. Motion was obtained at C5-C6, and C4-C5/C5-C6 for single-level and bi-level experiments, respectively, in flexion-extension, lateral bending and axial rotation. Specimens were tested, 1) intact, 2) injured (anterior discectomy), 3) with interbody fusion spacer, 4) in-line one-screw plate+spacer, and 5) two-screw plate+spacer, using four available plate brands. FINDINGS: Single-level plating with interbody spacer restricted range-of-motion with respect to the spacer-alone construct in flexion-extension, regardless of one screw or two-screw plate design, or brand. Similar behavior was seen in axial rotation, but not in lateral bending, where significance reductions in motion were achieved only with respect to the intact spine, not the interbody spacer group. In bi-level experiments all plate types restricted range-of-motion below spacer-alone levels in all loading modes. INTERPRETATION: Anterior plating should be selected based on surgical requirements, as a wide (two-screw) over a narrow (one-screw) plating profile does not appear to provide a tangible biomechanical benefit. PMID- 21824697 TI - Biomechanical evaluation of bone-cement augmented Proximal Femoral Nail Antirotation blades in a polyurethane foam model with low density. AB - BACKGROUND: Helically shaped cephalic implants have proven their benefit to provide an improved stabilization of unstable hip fractures. However, cut out ratios up to 3.6% still occur. This in vitro study evaluated the biomechanical performance of a novel cement augmentation technique of the Proximal Femoral Nail Antirotation in surrogate femora. METHODS: Four study groups were formed out of 24 polyurethane foam specimens with low density. Proximal Femoral Nail Antirotation blades were implanted, either non-augmented, or augmented using 3ml of injectable Polymethylmethacrylate bone-cement. The influence of implant mal positioning was investigated by placing the blade either centered in the femoral head or off-centric in an anteroposterior direction. All specimens underwent cyclic loading under physiological conditions. Starting at 1000 N, the load was monotonically increased by 0.1N/cycle until construct failure. Movement of the head was identified by means of optical motion tracking. Non-parametric test statistics were carried out on the cycles to failure, to compare between study groups. FINDINGS: Compared to control samples; augmented samples showed a significantly increased number of cycles to failure (P=0.012). In the groups with centric position of the Proximal Femoral Nail Antirotation blade, cement augmentation led to an increase in loading cycles of 225%. In the groups with off centric positioning of the blade, this difference was even more accentuated (933%). INTERPRETATION: Cement augmentation of the Proximal Femoral Nail Antirotation blade with small amounts of bone-cement for treatment of osteoporotic hip fractures clearly enhances fixation stability and carries high potential for clinical application. PMID- 21824698 TI - Out of the reach of children? Young people's health-seeking practices and agency in Africa's newly-emerging therapeutic landscapes. AB - Despite a dominant view within Western biomedicine that children and medicines should be kept apart, a growing literature suggests that children and adolescents often take active roles in health-seeking. Here, we consider young people's health-seeking practices in Ghana: a country with a rapidly-changing therapeutic landscape, characterised by the recent introduction of a National Health Insurance Scheme, mass advertising of medicines, and increased use of mobile phones. Qualitative and quantitative data are presented from eight field-sites in urban and rural Ghana, including 131 individual interviews, focus groups, plus a questionnaire survey of 1005 8-to-18-year-olds. The data show that many young people in Ghana play a major role in seeking healthcare for themselves and others. Young people's ability to secure effective healthcare is often constrained by their limited access to social, economic and cultural resources and information; however, many interviewees actively generated, developed and consolidated such resources in their quest for healthcare. Health insurance and the growth of telecommunications and advertising present new opportunities and challenges for young people's health-seeking practices. We argue that policy should take young people's medical realities as a starting point for interventions to facilitate safe and effective health-seeking. PMID- 21824699 TI - Horses for courses: the need for pragmatism and realism as well as balance and caution. A commentary on Angel. PMID- 21824700 TI - "They arrested me for loving a schoolgirl": ethnography, HIV, and a feminist assessment of the age of consent law as a gender-based structural intervention in Uganda. AB - In 1990 women's rights activists in Uganda successfully lobbied to amend the Defilement Law, raising the age of sexual consent for adolescent females from fourteen to eighteen years old and increasing the maximum sentence to death by hanging. The amendment can be considered a macro-level intervention designed to address the social and health inequalities affecting young women and girls, particularly their disproportionately high rate of HIV as compared to their male counterparts. While the intention of the law and aggressive campaign was to prosecute "sugar daddies" and "pedophiles," the average age of men charged with defilement was twenty-one years old and many were believe to be "boyfriends" in consensual sexual liaisons with the alleged victims. This article uses court records, case studies, and longitudinal ethnographic data gathered in east central Uganda to examine the impact of the age of consent law at national and local levels, and specifically what the disjunctures between national intentions and local uses reveal about conflicting views about sexual privilege and rights. I argue that existing class, gender, and age hierarchies have shaped how the Defilement Law has been applied locally, such that despite the stated aim of "protecting" young women, the law reinstates patriarchal privilege (especially against men of lower social class) while simultaneously increasing the regulation of adolescent female sexuality and undermining their autonomy. This paper demonstrates how ethnography and critical gender theory-which emphasizes the intersectionality of gender, age, and class in the (re)production of inequalities can be used to examine consequences of macro-level interventions in ways that may be undetected in conventional public health evaluation techniques but that are crucial for designing and modifying effective interventions. PMID- 21824702 TI - Health and welfare effects of integrating AIDS treatment with food assistance in resource constrained settings: a systematic review of theory and evidence. AB - The article systematically reviews theory and existing empirical evidence on the health and welfare effects of integrating AIDS treatment with food assistance. While theoretical predictions point to possible improvements in health, consumption and ambiguous effects on labor supply, there are few empirical studies that used robust designs. Five empirical studies are reviewed and in two of them, food assistance improves nutritional status, especially when provided in the form of ready to use therapeutic feeding. However because of methodological concerns, the positive effects of food assistance on weight gain warrant cautious interpretation. One study found a positive association between food assistance and adherence. While no quantitative study evaluated welfare effects, respondents in a qualitative study self-reported the resumption of labor activities, increased dietary diversity and food consumption. There is still limited evidence on the role of duration of AIDS treatment and programmatic aspects like targeting, composition and duration of food assistance. The major conclusion of the paper is that there is still need for further research based on robust designs which investigates both health and household welfare effects. PMID- 21824703 TI - Inferior or double joint spaces injection versus superior joint space injection for temporomandibular disorders: a systematic review and meta-analysis. AB - PURPOSE: To compare the effect and safety of inferior or double temporomandibular joint spaces drug injection versus superior temporomandibular joint space injection in the treatment of temporomandibular disorders. MATERIALS AND METHODS: MEDLINE (via Ovid, 1948 to March 2011), CENTRAL (Issue 1, 2011), Embase (1984 to March 2011), CBM (1978 to March 2011), and World Health Organization International Clinical Trials Registry Platform were searched electronically; relevant journals as well as references of included studies were hand-searched for randomized controlled trials comparing effect or safety of inferior or double joint spaces drug injection technique with those of superior space injection technique. Risk of bias assessment with the tool recommended by Cochrane Collaboration, reporting quality assessment with CONSORT and data extraction, were carried out independently by 2 reviewers. Meta-analysis was delivered with RevMan 5.0.23. RESULTS: Four trials with 349 participants were included. All the included studies had moderate risk of bias. Meta-analysis showed that inferior or double spaces injection technique could significantly increase 2.88 mm more maximal mouth opening (P = .0001) and alleviate pain intensity in the temporomandibular area on average by 9.01 mm visual analog scale scores (P = .0001) compared with superior space injection technique, but could not markedly change synthesized clinical index (P = .05) in the short term; nevertheless, they showed more beneficial maximal mouth opening (P = .002), pain relief (P < .0001), and synthesized clinical variable (P < .0001) in the long term than superior space injection. No serious adverse events were reported. CONCLUSIONS: Inferior or double temporomandibular joint spaces drug injection technique shows better effect than superior space injection technique, and their safety is affirmative. However, more high-quality studies are still needed to test and verify the evidence. PMID- 21824704 TI - Mandible reconstruction assisted by preoperative simulation and transferring templates: cadaveric study of accuracy. AB - PURPOSE: In this study we tried to define tumor resection, fibula cutting, and positioning by surgical templates to perform the mandible reconstruction surgery according to the preoperative simulation. The accuracy was evaluated through cadaveric surgery. MATERIALS AND METHODS: Five cadaveric mandibles and fibulas were obtained. Preoperative surgical simulation was performed. Surgical templates that defined tumor resection, fibula cutting, and positioning were designed and fabricated. Translation, angular deviation, and rotation of bone grafts, as well as translation of condyles, were measured. RESULTS: The reconstructed mandibles showed high similarity to the surgical planning. The mean translation, angular deviation, and rotation of fibula segments of the reconstructed mandibles were 1.35 +/- 0.86 mm, 3.36 degrees +/- 1.86 degrees , and 8.13 degrees +/- 5.35 degrees , respectively. In the mandible remnants, the translation of condyles was measured, with a mean of 1.39 +/- 0.66 mm. CONCLUSIONS: Our method of defining the tumor resection, fibula cutting, and positioning by surgical templates was accurate enough for mandible reconstruction surgery. PMID- 21824705 TI - Surgical management of obstructive sleep apnea in acromegaly with mandibular prognathism and macroglossia: a treatment dilemma. PMID- 21824706 TI - Huge ameloblastoma associated with hypercalcemia, leukocytosis, and elevated tumor markers via production of parathyroid hormone-related protein and granulocyte colony-stimulating factor. PMID- 21824707 TI - SEPAR guidelines for lung cancer staging. AB - The latest tumour, lymph node and metastasis (TNM) classification by the International Association for the Study of Lung Cancer (IASLC), based on the analysis of patients from all over the world, has incorporated changes in the descriptors, especially those regarding tumor size, while proposing new group staging. A new lymph node map has also been developed with the intention of facilitating the classification of the "N" component. SEPAR recommends using this new classification. As for the procedures recommended for staging, in addition to the generalized use of computed tomography (CT), it points to the role of positron emission tomography (PET) or image fusion methods (PET/CT), which provide a better evaluation of the mediastinum and extrathoracic metastases. Endobronchial ultrasound (EBUS) and esophageal ultrasound (EUS) for obtaining cytohistological samples have been incorporated in the staging algorithm, and it emphasizes the importance of precise re-staging after induction treatment in order to make new therapeutic decisions. Comment is made on the foreseeable incorporation in the near future of molecular staging, and systematic lymph node dissection is recommended with the intention of making a more exact surgical pathological classification. PMID- 21824708 TI - Reassessing the value of cardiofemoral index in the management of Rh(D) alloimmunized pregnancies: a pilot study. PMID- 21824709 TI - Triggering final oocyte maturation with reduced doses of hCG in IVF/ICSI: a prospective, randomized and controlled study. AB - OBJECTIVE: To compare the effectiveness of urinary human chorionic gonadotropin (u-hCG) at reduced doses of 4000 IU and 6000 IU in inducing final oocyte maturation during in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) cycles. STUDY DESIGN: 164 patients with an indication for IVF or ICSI recruited in this randomized, single-blinded and controlled study in IVF clinic at the Sun Yat-sen Memorial Hospital. Patients were prospectively randomized to receive 4000 IU (Group A, n=83) and 6000 IU (Group B, n=81) of hCG for triggering final oocyte maturation. Number or percentage of mature oocytes retrieved per patient, fertilization rates, pregnancy rates were the main outcome measures. RESULTS: No evidence of statistically significant difference in the number or proportion of mature oocytes retrieved was observed in both groups. The lower fertilization rate and significantly lower clinical pregnancy rate were observed in Group A. The ovarian hyperstimulation syndrome (OHSS) rates in both groups were also similar. In the subgroup of BMI< 20 kg/m(2), fertilization rate were significantly higher in the administration group of hCG at the dose of 6000 IU when compared with the dose of 4000 IU (82.40% vs. 70.92%, P=0.017); in contrast, no significant difference in clinical pregnancy rates was observed in both groups. In the subgroup of BMI 20-25 kg/m(2), clinical pregnancy rates were significantly higher in patients treated with hCG at dose of 6000 IU than patients treated with hCG at dose of 4000 IU (65.3% vs. 35.0%, P=0.004); however, no significant difference in fertilization rates was observed. CONCLUSION: Both doses of u-hCG revealed an equal effect on the induction of final oocyte maturation in the patients with moderate or high ovarian response; however, the reduced dose of hCG could result in an obvious impact on clinical pregnancy rates and did not exhibit an obvious effect on OHSS rates. PMID- 21824710 TI - Relationship between oocyte abnormal morphology and intracytoplasmic sperm injection outcomes: a meta-analysis. AB - The aim of this study was to perform a meta-analysis of the potential effects of oocyte morphological abnormalities on ICSI outcomes. Relevant original papers reporting on the relation between oocyte morphology and ICSI outcomes were identified by searching MEDLINE, EMBASE and the Cochrane Library. The main outcome measures were fertilisation rate and embryo quality. A meta-analysis was performed and Mantel-Haenszel pooled odd ratios (ORs) with 95% confidence intervals (CIs) were calculated to express the relation between the oocyte morphology and the ICSI outcomes. A total of 14 studies reporting 3688 ICSI cycles were included. Our meta-analysis demonstrates that the probability of an oocyte becoming fertilised is significantly reduced by the presence of large IPB (OR: 0.29, CI: 0.09-0.90), large PVS (OR: 0.86, CI: 0.74-0.99), refractile bodies (OR: 0.66, CI: 0.51-0.84) or vacuoles (OR: 0.59, CI: 0.42-0.83). No other investigated morphological abnormalities demonstrated significant relationships with ICSI outcomes. Our data demonstrate that the presence of large IPB, large PVS, refractile bodies or vacuoles is associated with decreased oocyte fertilisation. Our findings might be of importance for selecting embryos for replacement because the effects of oocyte abnormalities on implantation and pregnancy rates remain unclear. PMID- 21824711 TI - Atypical squamous cells of undetermined significance in postmenopausal women: a comparative retrospective analysis. AB - OBJECTIVES: To determine the outcomes of women with a diagnosis of atypical squamous cells of undetermined significance (ASCUS) with respect to menopausal status. STUDY DESIGN: Between October 2006 and March 2010, the data of 214 postmenopausal women with ASCUS results on Pap smear were evaluated. Sociodemographic data and histopathological results were compared with those of 1018 premenopausal women with ASCUS cytology. RESULTS: At the final diagnosis, most histological findings were normal in pre- and postmenopausal women with ASCUS cytology (70% and 70.1%, respectively). In the premenopausal group, 23.1% of the women had cervical intra-epithelial neoplasia (CIN) 1 lesions and 6.7% had CIN 2/3 lesions. Similarly, CIN 1 and CIN 2/3 lesions were detected in 23.4% and 6.1% of postmenopausal women, respectively. No significant difference in the final diagnosis was found between the two groups (p=0.88). Two premenopausal women (0.2%) and one postmenopausal woman (0.5%) had micro-invasive cervical carcinoma. There were no cases of invasive carcinoma in either group. CONCLUSIONS: According to this study, the rates of pre-invasive and micro invasive cervical carcinoma were similar in pre- and postmenopausal women with ASCUS cytology. PMID- 21824712 TI - External validation of the adapted Risk of Malignancy Index incorporating tumor size in the preoperative evaluation of adnexal masses. AB - OBJECTIVE: The Risk of Malignancy Index (RMI) is a simple scoring system to standardize and improve the preoperative evaluation of adnexal masses. Since 1990, three versions of the RMI have been validated in different clinical studies. Recently, a fourth version of the RMI (RMI-4) was introduced that includes tumor size as an additional parameter. The aim of this study was to validate the ability of RMI-4 to discriminate between non-invasive lesions and invasive malignant adnexal masses, and to compare its performance with RMI-3. STUDY DESIGN: Women scheduled for surgery for an adnexal mass between 2005 and 2009 in 11 hospitals were included. Ultrasonographic characteristics, menopausal status and serum CA 125 level were registered preoperatively, and combined into the RMI. The performances of RMI-3 and RMI-4 were assessed and statistically tested for differences. RESULTS: A total of 643 patients were included: 469 benign, 73 borderline and 101 malignant tumors. The RMI-3 had a sensitivity of 76%, specificity of 82%, positive and negative predictive values (PPV and NPV) of 45% and 95%, and an accuracy of 81%. The RMI-4 had a sensitivity of 74%, specificity of 79%, PPV of 40%, NPV of 94%, and an accuracy of 78%. The accuracy of RMI-3 was significantly higher than the accuracy of RMI-4 (p=.001). Both models had an area under the curve of 0.86. CONCLUSION: Both RMI-3 and RMI-4 were able to discriminate between non-invasive lesions and invasive malignant adnexal masses, with similar performances. Including tumor size in the RMI does not improve its performance. PMID- 21824713 TI - Ovum donation: examining the new Israeli law. AB - Ovum donation affords countless couples that under natural circumstances would not be able to produce offspring the ability to carry out natural pregnancies. With advancements in biotechnology including egg collection and in vitro fertilization (IVF), physicians can now successfully implant fertilized embryos. Due to Israel's tremendous involvement in IVF for its own citizens, the national laws that govern egg donation are of great importance. On September 5th 2010, the Israeli Parliament (Knesset) passed a law that allows young women between the ages of 21 and 35 to donate their eggs for paid financial compensation. The new law allows infertile women between the ages of 18 and 54 to request egg donation and IVF, which will partially be covered under state insurance plans. This article provides a description of the new Israeli law regulating ovum donation and the practical, moral and ethical debate surrounding the new system. PMID- 21824714 TI - Mesh complications following prolapse surgery: management and outcome. AB - OBJECTIVE: This is a description of complications following prolapse surgery with the use of alloplastic materials, the management and outcome. STUDY DESIGN: 54 women have been referred to Mainz, urogynecology referral center due to complications following mesh-augmented prolapse surgery. RESULTS: The complaints who lead to the admission are expressed by the new terminology and standardized classification for complications arising directly from the insertion of prostheses and grafts in female pelvic floor surgery [1]. Pain (66.7%), mesh erosion (55.6%) and vaginal discharge (48.1%) were the most frequent complaints. Revision was performed after a median time of 27.2 months post mesh implantation. Nine patients underwent limited excision of the mesh, 49 had a vaginal revision with wide mesh removal and 10 had a laparotomy with wide mesh removal. After 3 months 48 patients had a follow-up, 25 could have been relieved from their complaints. CONCLUSION: Although the incidence is low, complications after prolapse repair with mesh use are difficult to prevent, affect quality of life and often require a new surgical intervention, which should be performed by an experienced and competent surgeon. PMID- 21824715 TI - Mycobacterium bovis BCG and purified protein derivative-induced reduction in the CD80 expression and the antigen up-take function of dendritic cells from patients with cervical cancer. AB - OBJECTIVE: Clinical diagnostic studies have reported that co-existence of malignancy and tuberculosis in regions with high incidence of tuberculosis may be possible. However, simultaneous occurrence of cervical cancer (CaCx) and tuberculosis has been reported for it rarity. Our analysis of prevalence of mycobacterial infection among the study group of patients with CaCx had revealed co-infection of mycobacterium species including Mycobacterium tuberculosis. Since M. tuberculosis potentially affects the dendritic cells-mediated protective immune response, the main aim of this study was to analyse the effect of the mycobacterial infection on the immunological functions of dendritic cells (DC) in patients with CaCx. STUDY DESIGN: Initially, the prevalence of mycobacterial infection was analysed in the blood samples of patients with CaCx using ELISA and PCR techniques. Later to determine the role of mycobacterial infection on immunosuppression of DC in the progression of CaCx, dendritic cell-mediated immune suppression induced by Mycobacterium bovis BCG (M. bovis BCG) and purified protein derivative (PPD) was studied in patients with CaCx. Expression of co stimulatory molecules CD80 and CD86, and the antigen processing function of the macrophage-derived immature dendritic cells (imDC) were analysed. RESULTS: When compared to untreated imDC, the PPD and M. bovis BCG-treated imDC displayed 15% and 46.7% reduced expression of CD80, respectively. However, the M. bovis BCG and PPD did not have any significant reduction in the CD86 expression. Moreover, the dextran up-take was reduced by 24.4% and 35.8% with PPD and M. bovis BCG treatment, respectively. In addition, the M. bovis BCG-treated imDC derived from patients with CaCx showed a marginal reduction of lymphocyte proliferation and the PPD-treated imDC did not show a significant stimulation of lymphocyte proliferation. CONCLUSION: These results indicate that the PPD and M. bovis BCG inhibit the maturation and antigen up-take property of macrophage-derived imDC in patients with cervical cancer, suggesting that the M. tuberculosis infection may favour the progression of cervical cancer through immunosuppressed imDC. PMID- 21824716 TI - Hydrosalpinx and infertility: what about conservative surgical management? AB - OBJECTIVE: The aim of this study was to assess and validate a management protocol for infertile patients affected by at least one hydrosalpinx. STUDY DESIGN: Eighty-one consecutive infertile normo-ovulatory patients with uni or bilateral hydrosalpinx planed to be surgically managed were included in the protocol from November 2003 to May 2007. During laparoscopy, a systematic evaluation of the tubes was firstly conducted and the local management protocol based on validated tubal prognostic scores was applied. Surgery for hydrosalpinx was either conservative by neosalpingostomy or radical by salpingectomy. The primary end point was the cumulative clinical pregnancy rate. RESULTS: 115 hydrosalpinges out of 153 present tubes were confirmed during laparoscopy. Neosalpingostomy was possible in 35 patients featuring 50 hydrosalpinges (43.2% and 43.5%, respectively). Salpingectomy was necessary for the others (46 patients representing 65 hydrosalpinges). The mean follow-up period was 31.8 +/- 12.4 months. The overall cumulative pregnancy rate was 61% per couple who completed the protocol (33/54 patients). The cumulative pregnancy rate was 50% after IVF in patients who underwent bilateral salpingectomy. Among patients with at least one functional tube, the overall cumulative pregnancy rate was 63.3%, with a spontaneous pregnancy rate of 30.4%. CONCLUSION: Hydrosalpinx management can be conservative with a tubal conservative of 43.5% and fair chances for spontaneous conception. An integrated management of hydrosalpinx including ART actually leads to a cumulative pregnancy rate of 61% per patient. PMID- 21824717 TI - Fuel derived pollutants and boating activity patterns in the Sea of Galilee. AB - MTBE (Methyl tert-Butyl Ether) is a fuel additive that replaced lead as an antiknock compound in internal combustion motors. Few years after its introduction, detectable levels of MTBE were found in various water bodies. MTBE has a very low taste and odor threshold and is a potential carcinogen. Another group of fuel derived toxic compounds that has been detected in water bodies is BTEX (Benzene, Toluene, Ethylbenzene and Xylene). Boating activity and allochthonous contributions from watersheds are the major sources of fuel derived pollutants in lakes. Their concentrations in lakes thus vary as a function of boating activity intensity, lake surface area and depth, weather and wind regime, land-use in the watershed, etc. The Sea of Galilee (Lake Kinneret) is the only recreational lake in Israel and an important freshwater source. In the current study, a sampling campaign was conducted in order to quantify MTBE and BTEX concentrations in Lake Kinneret, its marinas and its main contributing streams. In addition, a boating-use survey was performed in order to estimate MTBE and BTEX contribution of recreational boating. The sampling campaign revealed that, as expected, MTBE concentrations were higher than BTEX, and that near shore (i.e., marina) concentrations were higher than in-lake concentrations. Despite the clear contribution from boating, high MTBE concentrations were found following a major inflow event in winter, indicating the importance of the allochthonous contribution. The contribution from boating during summer, as measured indirectly by in-lake concentrations, is likely underestimated due to enhanced MTBE volatilization due to strong winds and high temperatures. May September was found to be the main recreational boating season, with continued boating year round. On average, a single boat is active 23 d/y, with 84% of the watercrafts being active only during weekends and holidays. The survey further indicated that boats stay in the lake for 4.5 h on average, which conforms to the unique winds regime that limits afternoon activity due to high winds, and have an average fuel consumption of 14 L/h. The annual load of MTBE and BTEX from recreational boating in Lake Kinneret was estimated at 4430 and 6220 kg/y respectively. PMID- 21824719 TI - Re: Gregory R. Pond, Andrew J. Armstrong, Brian A. Wood, et al. Evaluating the value of number of cycles of docetaxel and prednisone in men with metastatic castration-resistant prostate cancer. Eur Urol 2012;61:363-9. PMID- 21824718 TI - Recruitment of intracavernously injected adipose-derived stem cells to the major pelvic ganglion improves erectile function in a rat model of cavernous nerve injury. AB - BACKGROUND: Intracavernous (IC) injection of stem cells has been shown to ameliorate cavernous-nerve (CN) injury-induced erectile dysfunction (ED). However, the mechanisms of action of adipose-derived stem cells (ADSC) remain unclear. OBJECTIVES: To investigate the mechanism of action and fate of IC injected ADSC in a rat model of CN crush injury. DESIGN, SETTING, AND PARTICIPANTS: Sprague-Dawley rats (n=110) were randomly divided into five groups. Thirty-five rats underwent sham surgery and IC injection of ADSC (n=25) or vehicle (n=10). Another 75 rats underwent bilateral CN crush injury and were treated with vehicle or ADSC injected either IC or in the dorsal penile perineural space. At 1, 3, 7 (n=5), and 28 d (n=10) postsurgery, penile tissues and major pelvic ganglia (MPG) were harvested for histology. ADSC were labeled with 5-ethynyl-2-deoxyuridine (EdU) before treatment. Rats in the 28-d groups were examined for erectile function prior to tissue harvest. MEASUREMENTS: IC pressure recording on CN electrostimulation, immunohistochemistry of the penis and the MPG, and number of EdU-positive (EdU+) cells in the injection site and the MPG. RESULTS AND LIMITATIONS: IC, but not perineural, injection of ADSC resulted in significantly improved erectile function. Significantly more EdU+ ADSC appeared in the MPG of animals with CN injury and IC injection of ADSC compared with those injected perineurally and those in the sham group. One day after crush injury, stromal cell-derived factor-1 (SDF-1) was upregulated in the MPG, providing an incentive for ADSC recruitment toward the MPG. Neuroregeneration was observed in the group that underwent IC injection of ADSC, and IC ADSC treatment had beneficial effects on the smooth muscle/collagen ratio in the corpus cavernosum. CONCLUSIONS: CN injury upregulates SDF-1 expression in the MPG and thereby attracts intracavernously injected ADSC. At the MPG, ADSC exert neuroregenerative effects on the cell bodies of injured nerves, resulting in enhanced erectile response. PMID- 21824720 TI - Characterizing paramagnetic signal in a patient with Wilson's disease by susceptibility-weighted imaging. PMID- 21824721 TI - Intraparenchymal schwannomas: report of two new cases studied with MRI and review of the literature. AB - Intraparenchymal schwannomas are very rare tumours. We present two young adult patients operated for this type of lesion who show no signs of recurrence 2 years after surgery. These tumours have a bimodal peak of presentation: most occur in young patients under 25 years, and the rest present in the elderly. Characteristically they show both Antoni A and Antoni B areas, intense inmunoreactivity to S-100 and Vimentin protein, and none to EMA or CD34. Electron microscopy is diagnostic when basal membrane is found around the cytoplasmatic processes. MRI spectroscopy depicts increased myoinositol, choline and lipids, and perfusion MR demonstrates high rCBV with a characteristic curve due to the total absence of blood brain barrier. An origin in the Schwann cells of the perivascular nervous plexus in the subarachnoid space is the most accepted theory for the histogenesis of these tumours. We propose to perform the characterization of a series of markers such as SOX-10 in every new case in order to prove that theory. PMID- 21824722 TI - The prophylactic use of an antiepileptic drug in intracerebral hemorrhage. AB - OBJECTIVE: Patients with intracerebral hemorrhage (ICH) are at increased risk for both early seizures and later epilepsy. There is a common, but unproven, practice of prescribing a prophylactic antiepileptic drug (PAED) to prevent seizures, but the safety and efficacy of this practice is unclear, as is the optimal drug for this purpose. The objective of the study is to evaluate whether patients presenting with acute, spontaneous intracerebral hemorrhage (ICH) benefit from prescription of prophylactic antiepileptic drug (PAED). METHOD: All patients with a discharge diagnosis of acute, spontaneous ICH admitted to our institution in the calendar years 2004 and 2007 were included. We retrospectively reviewed the records for baseline characteristics, hospital course, PAED use, early seizures, length of stay, discharge disposition, and death. RESULTS: 157 patients met our criteria for review. 46 (29%) patients were placed on a PAED. 12 (7.6%) had early seizures. 11% of patients placed on a PAED had an early seizure versus 6.3% who not placed on a PAED. Death or hospice discharge was less common in patients prescribed a PAED, while length of stay was longer, however neither of these differences were significant after adjustment for multiple comparisons. INTERPRETATIONS: Our study confirms previous reports that patients with acute, spontaneous ICH are at an increased risk for early seizures. PAED use in our series was not significantly associated with the risk of early seizures, long term epilepsy, disability, or death. PMID- 21824723 TI - Suppression of carbonyl reductase expression enhances malignant behaviour in uterine cervical squamous cell carcinoma: carbonyl reductase predicts prognosis and lymph node metastasis. AB - Carbonyl reductase (CR) is an NADPH-dependent, mostly monomeric, cytosolic enzyme with broad substrate specificity for carbonyl compounds. CR appears to be involved in the regulation of tumour progression. However, molecular mechanisms of CR in tumour progression and clinical significance of CR status remain unclear in human uterine squamous cell carcinoma (SCC). Here, we investigated the clinical significance of CR using immunohistochemical analyses of human uterine cervical SCC tissues and how CR affects cancer cell behaviour in vitro. Paraffin sections from uterine cervical SCC tissues, FIGO stage Ib1-IIb (n = 67) were immunostained with anti-CR antibodies. Overall survival (OS) and progression-free survival (PFS) were analyzed by the Kaplan-Meier method. Sense and antisense CR cDNAs were transfected into a human uterine SCC cell line (SiHa) to investigate the role of CR in cancer cell invasion and metastasis. Immunohistochemical analyses showed that reduced CR expression patterns in primary cancer lesions were closely associated with a high incidence of pelvic lymph node metastasis, poor OS, and poor PFS. In an in vitro experiment, suppression of CR increased cancer cell invasion, secretion of MMP-2, -9 and cyclooxygenase-2 (COX-2) expression and decreased E-cadherin expression. On the other hand, over expression of CR increased E-cadherin expression and decreased MMP-2, -9 secretion and COX-2 expression. The reduced CR expression pattern, as measured by immunohistochemistry, can be a useful predictor of lymph node metastasis and poor prognosis in patients with uterine SCC. This clinical result is supported by the in vitro data which show that suppression of CR expression promotes cancer cell invasion with decreased E-cadherin expression and increased MMP-2, -9 secretion. PMID- 21824724 TI - Bystander cytotoxicity in human medullary thyroid carcinoma cells mediated by fusion yeast cytosine deaminase and 5-fluorocytosine. AB - In our work, we have evaluated efficiency of gene-directed enzyme/prodrug therapy (GDEPT) based on combination of fusion yeast cytosine deaminase (yCD) and 5 fluorocytosine (5FC) on model human medullary thyroid carcinoma (MTC) cell line TT. We determined the efficiency of this GDEPT approach in suicide and bystander cytotoxicity induction. We have shown significant bystander effect in vitro and 5FC administration resulted in potent antitumor effect in vivo. Furthermore, we have unraveled high efficiency of cell-mediated GDEPT, when human mesenchymal stromal cells (MSC) were used as delivery vehicles in direct cocultures in vitro. Nevertheless, effector MSC exhibited inhibitory effect on TT cell proliferation and abrogated TT xenotransplant growth in vivo. We suggest that yCD/5FC combination represents another experimental treatment modality to be tested in MTC and our data further support the exploration of MSC antitumor potential for future use in metastatic MTC therapy. PMID- 21824725 TI - Radiotherapy and TRAIL for cancer therapy. AB - The use of radiotherapy and concomitant chemotherapy substantially improved cure rates in patients with different malignant tumours. However, it is unlikely that further improvements based on conventional chemotherapy may be achieved in the future since increased rates of acute side effects already limit the value of these approaches. Additionally, the increased local control rates are counterweighted by still high rates of distant failures resulting in low net gains for the patients. Thus, there is a currently unmet need for the integration of target-specific drugs improving local control as well distant control into radiation based treatment protocols. In this regard, the death-receptor ligand TNF-alpha-related apoptosis-inducing ligand (TRAIL/Apo2L) and TRAIL-receptor agonistic antibodies were shown to display a high selectivity for tumour cells and act synergistically with conventional chemotherapy drugs and radiation. Up to now it has been shown that radiation strongly sensitises malignant cells to TRAIL and TRAIL-agonistic antibodies. Synergistic induction of apoptosis was demonstrated in a majority of malignant cell types and xenograft models. Especially in those cells types displaying only weak responses to either treatment alone, strong sensitising effects were described. Moreover, in merely all normal cells and tissues no synergistic effects were found. Depending on cell type and experimental setting, the efficacy of combined treatment is determined by the p53-status, the balance between pro- and anti-apoptotic Bcl-2 proteins and modulation of TRAIL-receptor signal transduction. PMID- 21824726 TI - Determination of trace bismuth in human serum by cloud point extraction coupled flow injection inductively coupled plasma optical emission spectrometry. AB - A cloud point extraction method for the preconcentration of ultra-trace bismuth in human serum prior to its determination by inductively coupled plasma optical emission spectrometry had been developed in this paper. The cloud point extraction method was based on the complex of Bi(III) with 8-hydroxyquinoline and Triton X-114 was used as non-ionic surfactant. The main factors affecting cloud point extraction efficiency, such as pH of solution, concentration of complexing agent, concentration of non-ionic surfactant, equilibration temperature and time were investigated in detail. An enrichment factor of 81 was obtained for the preconcentration of Bi(III) with 25 mL solution. Under the optimal conditions, the detection limit of Bi(III) is 0.12 MUg L(-1). The relative standard deviation (n = 7) of determination was 2.3%, values of recovery of bismuth were from 92.3% to 94.7% for three samples. This method is simple, accurate, sensitive and can be applied to the determination trace bismuth in human serum. PMID- 21824727 TI - Low-temperature selective catalytic reduction of NO with propylene in excess oxygen over the Pt/ZSM-5 catalyst. AB - A 0.5 wt% Pt/ZSM-5 catalyst was used for the low-temperature selective catalytic reduction (SCR) of NO with C(3)H(6) in the presence of excess oxygen. Under an atmosphere of 150 ppm NO, 150 ppm C(3)H(6) and 18 vol% O(2) (GHSV 72,000 h(-1)), Pt/ZSM-5 showed remarkably high catalytic performance giving 77.1% NO reduction to N(2) + N(2)O and 79.7% C(3)H(6) conversion to CO(2) simultaneously at 140 degrees C. The samples were characterized by means of NO temperature programmed desorption (TPD), NO/C(3)H(6) temperature programmed oxidation (TPO), BET surface area, XRD and TEM. The catalytic activities of C(3)H(6) combustion and NO oxidation are improved by well-dispersed platinum significantly. It is found that the enhanced activity of Pt/ZSM-5 for the low-temperature SCR is associated with its outstanding activities in the TPO processes of NO to NO(2) and C(3)H(6) to CO(2) in low temperature range. PMID- 21824728 TI - First report of a Rhipicephalus microplus tick population multi-resistant to acaricides and ivermectin in the Mexican tropics. AB - We document the presence of a Rhipicephalus microplus tick population resistant to acaricides (organophosphates (OP), synthetic pyrethroids (SP), amitraz) and macrocyclic lactones (ML) (ivermectin). Engorged females of R. microplus were collected from a cattle farm in Veracruz, Mexico, to evaluate acaricide and ivermectin resistance. The modified larval packet test (LPT) was used to detect OP (chlorpiriphos and diazinon) and SP (flumethrin, deltamethrin and cypermethrin) resistance and the larval immersion test (LIT) to detect resistance to amitraz and ivermectin. Both, LPT and LIT were performed twice at different times with different collected samples. Mortality data with ivermectin were subjected to probit analysis to obtain lethal concentrations and resistance ratios (RR) using an ivermectin-susceptible strain (Deutch) as a reference. The R. microplus population showed resistance to all acaricides tested, with different mortalities at the discriminate dose: chlorpiriphos (1%), diazinon (24.2%), flumethrin (92.8%), deltamethrin (94.2%), cypermethrin (98.0%) and amitraz (1.5%). The studied tick population also showed resistance to ivermectin with a resistance ratio at 99% of 9.58 and 6.52 in the first and second evaluation, respectively. We report for the first time a R. microplus population in Mexico with different levels of resistance to OP, SP, amidines (Am) and ivermectin. The uncontrolled use of these products in the study area may promote the complete failure of tick control within a short period of time. PMID- 21824729 TI - No loss of production due to larval challenge in sheep given continuous anthelmintic treatment via a controlled release capsule. AB - This study aimed to quantify production loss due to larval challenge in sheep administered a controlled release albendazole capsule (CRC) and thus determine the suitability of CRC treated sheep as a proxy for worm-free sheep in grazing experiments. The experiment used an incomplete 2 * 3 latin square design with 81 Merino wethers. Sheep were either infected (INF) with mixed oral infection of albendazole-susceptible Haemonchus contortus, Trichostrongylus colubriformis, and Teladorsagia circumcincta (initial bolus then thrice weekly maintenance) or remained uninfected (UINF). Worm control treatments were with a CRC (CRCT), threshold treatment with a short-acting anthelmintic when worm egg count (WEC) exceeded 1500 epg (TT) or untreated (UT). The experiment was conducted in two 63 day periods (separated by a 14 day washout period) with infection treatments swapped between periods. A subset of animals was killed at the end of each period for worm counts and tissue sampling. Faecal worm egg count in UINF-UT reached 10,204 and 6078 epg at day 63 in periods 1 and 2, respectively, and remained 0 throughout in the CRT treatments. There was no difference in live weight gain or wool growth of INF-CRCT sheep (67 and 70 g/d) relative to UINF-CRCT (67 and 76 g/d). Live weight gain was significantly lower in INF-UT (27 g/d) and INF-TT (55 g/d) than UINF-UT (88 g/d) or UINF-TT (81 g/d) treatments. During the first infection period, greasy fleece weight growth was significantly lower in INF-UT (6.33 g/d) and INF-TT (6.37 g/d) than UINF-UT (7.80 g/d) or UINF-TT (7.32 g/d) treatments. The effects of infection on production persisted in INF-UT, but not INF-TT sheep for several weeks after termination of infection. Eosinophil counts were elevated in all infected groups and the antibody response to T. colubriformis was greater in INF-CRCT and INF-TT groups compared to uninfected sheep. Together, these results indicate that larval challenge in sheep with a CRC is mildly immunogenic but is not associated with production loss. The results also showed that the CRC itself reduced live weight gain and that anthelmintic treatment at a WEC threshold of 1500 epg reduces production loss during infections and prevents persistence of adverse effects following infection. PMID- 21824731 TI - Cheyne-Stokes respiration: hypoxia plus a deep breath that interrupts hypoxic drive, initiating cyclic breathing. AB - In the 19th Century, Cheyne and Stokes independently reported cycles of respiration in patients with heart failure, beginning with apnea, followed by a few breaths. However Cheyne-Stokes respiration (C-SR) can also occur in healthy individuals with sleep, and was demonstrated in 1908 with voluntary hyperventilation, followed by apnea that Haldane blamed on hypoxia, subsequently called post-hyperventilation apnea. Additional theories explaining C-SR did not appear until 1954, based on control theory, specifically a feed-back regulator controlling CO(2). This certainly describes control of normal respiration, but to produce an unstable state such as C-SR requires either a very long transit time (31/2 min) or an increase of the controller gain (13 times), physiologically improbable. There is general agreement that apnea initiates C-SR but that has not been well explained except for post-hyperventilation apnea, and that explanation is not compatible with a study by Nielsen and Smith in 1951. They plotted the effects of diminished oxygen on ventilation (V) in relation to CO(2) (Fig. 1). They found that the slope of V/CO(2) (gain) increased with hypoxia, but it flattened at a moderate CO(2) level and had nointercept with zero (apnea). It is also incompatible with our published findings in 1975 that showed that apnea did not occur until an extreme level of hypoxia occurred (the PO(2) fell below 10 mmHg), followed shortly by gasping. Much milder hypoxia underlies most cases of C SR, when hypoxic drive replaces the normal CO(2)-based respiratory drive, in a failsafe role. I hypothesize that the cause of apnea is a brief interruption of hypoxic drive caused by a pulse of oxygen from a stronger than average breath, such as a sigh. The rapidity of onset of apnea in response to a pulse of oxygen, reflects the large pressure gradient for oxygen from air to lung with each breath, in contrast to CO(2). With apnea, there is a gradual fall in oxygen, resulting in a resumption of hypoxic drive, and the cycle of C-SR continues until the next large breath. This novel theory, that a pulse of oxygen interrupts hypoxic drive to cause the initiating apnea of C-SR, is compatible with the known causes of C-SR: onset of sleep, mild hypoxia with congestive heart failure, and neurologic disorders. It is also compatible with factors known to abolish C-SR: waking, oxygen supplementation, and drugs that increase alertness such as caffeine. Testing of the hypothesis would require beat by beat recording of respiration, and arterial oxygen with a response time fast enough to demonstrate the rapid suppression of hypoxic drive. Alternatively, using a different theoretical approach such as limit-cycle oscillators instead of control theory. PMID- 21824732 TI - Extracellular cyclophilin A may be a potential target to protect against myocardial reperfusion injury. AB - Myocardial reperfusion injury is increasingly recognized as an inflammatory process, characterized by neutrophil recruitment and subsequently excessive release of pro-inflammatory factors. Recently, the extracellular cyclophilin A (CypA) has been showed to play an important role in initiation and development of inflammation by chemo trafficking of leukocytes into inflamed tissues, eliciting massive release of pro-inflammatory cytokines, and inducing production of matrix metalloproteinases. Also, the agents targeting CypA have been demonstrated to promise anti-inflammatory effects in the different experimental models of inflammatory diseases including acute lung injury, rheumatoid arthritis, and atherosclerosis. Therefore, we hypothesize that the extracellular CypA may in some way implicated in the pathogenesis of reperfusion-induced inflammatory process, and the specific inhibitors of the extracellular CypA can provide a protection against the myocardial reperfusion injury. PMID- 21824733 TI - Evaluation of the efficacy of commercial vaccines against bluetongue virus serotypes 1 and 8 in experimentally infected red deer (Cervus elaphus). AB - Red deer (Cervus elaphus) is a widespread and abundant species susceptible to bluetongue virus (BTV) infection. Inclusion of red deer vaccination among BTV control measures should be considered. Four out of twelve BTV antibody negative deer were vaccinated against serotype 1 (BTV-1), and four against serotype 8 (BTV 8). The remaining four deer acted as unvaccinated controls. Forty-two days after vaccination (dpv), all deer were inoculated with a low cell passage of the corresponding BTV strains. Serological and virological responses were analyzed from vaccination until 28 days after inoculation (dpi). The vaccinated deer reached statistically significant (P<0.05) higher specific antibody levels than the non vaccinated deer from 34 (BTV-8) and 42 (BTV-1) dpv, maintaining stable neutralizing antibodies until 28 dpi. The non vaccinated deer remained seronegative until challenge, showing neutralizing antibodies from 7 dpi. BTV RNA was detected in the blood of the non vaccinated deer from 2 to 28 dpi, whereas no BTV RNA was found in the vaccinated deer. BTV was isolated from the blood of non vaccinated deer from 7 to 28 dpi (BTV-1) and from 9 to 11 dpi (BTV-8). BTV RNA could be identified by RT-PCR at 28 dpi in spleen and lymph nodes, but BTV could not be isolated from these samples. BT-compatible clinical signs were inapparent and no gross lesions were found at necropsy. The results obtained in the present study confirm that monovalent BTV-1 and BTV-8 vaccines are safe and effective to prevent BTV infection in red deer. This finding indicates that vaccination programs on farmed or translocated red deer could be a useful tool to control BTV. PMID- 21824730 TI - Population genetics of Toxoplasma gondii: new perspectives from parasite genotypes in wildlife. AB - Toxoplasma gondii, a zoonotic protozoal parasite, is well-known for its global distribution and its ability to infect virtually all warm-blooded vertebrates. Nonetheless, attempts to describe the population structure of T. gondii have been primarily limited to samples isolated from humans and domesticated animals. More recent studies, however, have made efforts to characterize T. gondii isolates from a wider range of host species and geographic locales. These findings have dramatically changed our perception of the extent of genetic diversity in T. gondii and the relative roles of sexual recombination and clonal propagation in the parasite's lifecycle. In particular, identification of novel, disease-causing T. gondii strains in wildlife has raised concerns from both a conservation and public health perspective as to whether distinct domestic and sylvatic parasite gene pools exist. If so, overlap of these cycles may represent regions of high probability of disease emergence. Here, we attempt to answer these key questions by reviewing recent studies of T. gondii infections in wildlife, highlighting those which have advanced our understanding of the genetic diversity and population biology of this important zoonotic pathogen. PMID- 21824734 TI - Actinobacillus pleuropneumoniae is impaired by the garlic volatile allyl methyl sulfide (AMS) in vitro and in-feed garlic alleviates pleuropneumonia in a pig model. AB - Decomposition products of ingested garlic are to a certain extent excreted via the lungs. If the supposed health-supporting capacities associated with garlic extend to these exhaled sulfurous compounds, they could have an effect on the course of pneumonia. In this study, the garlic-derived volatile allyl methyl sulfide (AMS) as a lead compound of volatile garlic metabolites was shown to exhibit an antibacterial effect against the pig pathogen Actinobacillus pleuropneumoniae serotype 9. AMS caused a delay in the appearance of the optical density-monitored growth of A. pleuropneumoniae in medium when compared to unaffected growth curves, yet without lowering the stationary phase yield at the concentration range tested. At 1.1mM, AMS impaired the in vitro growth rate of A. pleuropneumoniae serotype 9 by 8% compared to unimpeded growth. In an animal trial, a garlic-fed group of 15 pigs that received a diet with 5% garlic feed component and a control group of 15 pigs that received a diet without garlic were infected with A. pleuropneumoniae serotype 2 via an aerosol and subsequently followed for 4 days. At the day of the challenge, blood AMS in the garlic-fed group amounted to 0.32 +/- 0.13 MUM. A beneficial, alleviating effect of garlic on the course and severity of an A. pleuropneumoniae infection in pigs was indicated by the reduced occurrence of characteristic pleuropneumonia lesions (27% of the lungs affected in the garlic-fed group vs. 47% in the control group) and a near to significant (p=0.06) lower relative lung weight post mortem in the garlic-fed group. PMID- 21824735 TI - Detection of matrix metalloproteinase (MMP)-2 and MMP-9 in canine seminal plasma. AB - Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that play a central role in degradation of protein components of the extracellular matrix and basement membrane. Previous studies have shown that MMP-2 and MMP-9 are present in human seminal plasma, but there is little information available on the presence of MMPs in canine seminal plasma. This study aims to investigate the presence of MMPs in canine seminal plasma and their clinical manifestation at the level of various semen parameters in canine species. Latent and active forms of MMP-2 and MMP-9 were evaluated using gelatin zymography and their association with semen parameters was examined. Results demonstrate that both latent and active forms of MMP-2 and MMP-9 are present in canine seminal plasma and the latent forms are predominant. The latent and active MMP-9 activities were elevated in the semen with unsatisfactory quality traits and proMMP-2 was inversely correlated with semen quality whereas, MMP-2 was positively correlated with semen quality traits. These findings suggest that proMMP-9 and MMP-9 activation contributes to the variation in semen, while the activation of MMP-2 improves the sperm functionality. PMID- 21824736 TI - Analytical aspects in doping control: challenges and perspectives. AB - Since the first anti-doping tests in the 1960s, the analytical aspects of the testing remain challenging. The evolution of the analytical process in doping control is discussed in this paper with a particular emphasis on separation techniques, such as gas chromatography and liquid chromatography. These approaches are improving in parallel with the requirements of increasing sensitivity and selectivity for detecting prohibited substances in biological samples from athletes. Moreover, fast analyses are mandatory to deal with the growing number of doping control samples and the short response time required during particular sport events. Recent developments in mass spectrometry and the expansion of accurate mass determination has improved anti-doping strategies with the possibility of using elemental composition and isotope patterns for structural identification. These techniques must be able to distinguish equivocally between negative and suspicious samples with no false-negative or false-positive results. Therefore, high degree of reliability must be reached for the identification of major metabolites corresponding to suspected analytes. Along with current trends in pharmaceutical industry the analysis of proteins and peptides remains an important issue in doping control. Sophisticated analytical tools are still mandatory to improve their distinction from endogenous analogs. Finally, indirect approaches will be discussed in the context of anti-doping, in which recent advances are aimed to examine the biological response of a doping agent in a holistic way. PMID- 21824737 TI - Systemic hypoxia differentially affects neurogenesis during early mouse brain maturation. AB - BACKGROUND: Cerebral tissue oxygen level modifies crucial processes of neurogenesis, glial and neuronal development during physiological and hypoxic conditions. Whether hypoxia-sensitive factors such as doublecortin (DCX) and hypoxia-inducible transcription factor (HIF)-regulated CXCR4 and SDF-1 modify and activate adaptation to hypoxia in developing brain is not well understood. Present study investigated maturational regulation of oxygen-sensitive developmental genes and proteins in developing mouse brain in relation to the degree of hypoxia. METHODS: Physiological expression of HIF-1, CXCR4, SDF-1 and DCX were analyzed in the brain of C57/BL6 mice (P0-P60). In addition, mice (P0, P7) were exposed to normoxia, acute (8% O(2), 6 h) or chronic hypoxia (10% O(2), 7 d) followed by reoxygenation. Gene expression was analyzed by quantitative PCR, proteins were quantified by Western blot analysis and immunohistochemistry. RESULTS: Cerebral HIF-1alpha protein, CXCR4 and DCX mRNA levels showed maturational stage-related peak levels at P0/P1, whereas SDF-1 mRNA levels were highest at P17. CXCR4 and SDF-1 mRNA levels were not altered in response to hypoxia. Whereas DCX mRNA levels significantly increased during acute hypoxia, down-regulation of DCX transcripts was found in response to chronic hypoxia compared to controls, and these changes were related to specifically vulnerable brain regions. CONCLUSIONS: Maturational stage-related dynamic changes of HIF 1alpha, CXCR4, SDF-1 and DCX may reflect involvement of hypoxia-regulated systems in important developmental regulatory processes of the developing brain. Extending the knowledge of differential effects of hypoxia on neurogenesis and dynamic regulatory networks present data provide a basis for future research on gestational age-specific neuroprotective options. PMID- 21824738 TI - Association between nonverbal communication during clinical interactions and outcomes: a systematic review and meta-analysis. AB - OBJECTIVE: To conduct a systematic review and meta-analysis of studies reporting associations between patients' and clinicians' nonverbal communication during real clinical interactions and clinically relevant outcomes. METHODS: We searched 10 electronic databases, reference lists, and expert contacts for English language studies examining associations between nonverbal communication measured through direct observation and either clinician or patient outcomes in adults. Data were systematically extracted and random effects meta-analyses were performed. RESULTS: 26 observational studies met inclusion criteria. Meta analysis was performed for patient satisfaction, which was assessed in 65% of studies. Mental and physical health status were evaluated in 23% and 19% of included studies, respectively. Both clinician warmth and clinician listening were associated with greater patient satisfaction (p<0.001 both). Physician negativity was not related to patient satisfaction (p=0.505), but greater nurse negativity was associated with less patient satisfaction (p<0.001). Substantial differences in study design and nonverbal measures existed across studies. CONCLUSION: Greater clinician warmth, less nurse negativity, and greater clinician listening were associated with greater patient satisfaction. Additional studies are needed to evaluate the impact of nonverbal communication on patients' mental and physical health. PRACTICE IMPLICATIONS: Communication-based interventions that target clinician warmth and listening and nurse negativity may lead to greater patient satisfaction. PMID- 21824739 TI - More than words: patients' views on apology and disclosure when things go wrong in cancer care. AB - OBJECTIVE: Guidelines on apology and disclosure after adverse events and errors have been in place for over 5 years. This study examines whether patients consider recommended responses to be appropriate and desirable, and whether clinicians' actions after adverse events are consistent with recommendations. METHODS: Patients who believed that something had gone wrong during their cancer care were identified. During in-depth interviews, patients described the event, clinicians' responses, and their reactions. RESULTS: 78 patients were interviewed. Patients' valued apology and expressions of remorse, empathy and caring, explanation, acknowledgement of responsibility, and efforts to prevent recurrences, but these key elements were often missing. For many patients, actions and evidence of clinician learning were most important. CONCLUSION: Patients' reports of apology and disclosure when they believe something has gone wrong in their care suggest that clinicians' responses continue to fall short of expectations. PRACTICE IMPLICATIONS: Clinicians preparing to talk with patients after an adverse event or medical error should be aware that patients expect their actions to be congruent with their words of apology and caring. Healthcare systems need to support clinicians throughout the disclosure process, and facilitate both system and individual learning to prevent recurrences. PMID- 21824740 TI - Concurrent binge drinking and depression among Canadian youth: prevalence, patterns, and suicidality. AB - This study compared differences in risk for suicidality among youth living in the community who met criteria for comorbid depression and binge drinking, depression without binge drinking, and binge drinking without depression relative to a reference group with neither condition. Logistic regression analysis was used to analyze data from the Canadian Community Health Survey, Cycle 3.1 (CCHS 3.1, 2005): a cross-sectional survey of respondents from the Canadian population. To restrict the sample to youth, respondents were excluded who were younger than 15 or older than 24 years. Over 17,000 respondents were assessed to determine whether they met criteria for depression, binge drinking, the comorbid condition, or neither condition (reference group). Binge drinking was defined as five drinks or more on an occasion. The 12-month prevalence rates for comorbid binge drinking and depression were 2.7% for male respondents and 2.1% for female respondents. When adjusted for demographic factors and when compared with the reference group, the risk of suicidality was increased for the depressed group (odds ratio [OR] 5.23, 95% confidence interval [CI]: 3.34-8.2) and the comorbid group (OR 6.28, 95% CI: 3.68-10.70), but not for the binge-drinking group. With the exception of increasing age, sociodemographic factors were not correlates of comorbidity. In conclusion, binge drinking was not associated with an increased risk of suicidality among Canadian youth living in the community, although depression and comorbidity were associated with suicidality. PMID- 21824742 TI - Prognostic value of breast cancer subtypes on breast cancer specific survival, distant metastases and local relapse rates in conservatively managed early stage breast cancer: a retrospective clinical study. AB - AIM: To ascertain if breast cancer subtypes had prognostic effect on breast cancer specific survival, distant metastases and local relapse rates in women affected by early stage breast cancer. PATIENTS AND METHODS: Data of 774 patients affected by early stage breast cancer and treated with breast-conserving therapy were reviewed. Patients were grouped, based on steroid receptor status and HER2 status as: Luminal A (ER+/PR+/HER2-), Luminal B (ER+/PR+/HER2+), Basal-like (ER /PR-/HER2-) and HER2 (ER-/PR-/HER2+). Distribution of variables among subtypes was evaluated with Pearson's test. Survival rates were calculated with life tables; Cox regression stepwise method was used to identify predictive variables of survival. RESULTS: Median age was 55.0 years old (range 27-80) and median follow up time of 59.0 months (range 13.6-109.7). Breast cancer specific survival and distant metastases rates were different among breast cancer subtypes (both outcomes P=0.00001) but there was no difference regarding local relapse rates (P=0.07). Axillary nodes status (P=0.00001), adjuvant therapy (P=0.03) and breast cancer subtypes (P=0.03) resulted prognostic factors of breast cancer specific survival; axillary node status (P=0.00001) and breast cancer subtypes (P=0.00001) had an impact on distant metastases. Age (P=0.003), tumor size (P=0.0001), positive or close surgical margin (P=0.00001) and tumor grade 3 (P=0.049) resulted prognostic factors of local relapse. CONCLUSIONS: In our study, breast cancer subtype seems a prognostic factor of breast cancer specific survival and distant metastases rates, but not of local relapse rate. Patients could be submitted to conservative surgery, if feasible, but considering the differences in survivals, patients with worse prognosis should receive more aggressive adjuvant treatments. PMID- 21824741 TI - Chronic ethanol consumption reduces adrenomedullin-induced relaxation in the isolated rat aorta. AB - Adrenomedullin (AM) is a peptide that displays cardiovascular protective activity. We investigated the effects of chronic ethanol consumption on vascular reactivity to AM and the expression of AM system components in the rat aorta. Male Wistar rats were treated with ethanol (20% vol/vol) for 6 weeks. Vascular reactivity experiments were performed in the isolated rat aorta. Metalloproteinase-2 (MMP-2) levels were determined by gelatin zymography. Nitrite and nitrate generation was measured by chemiluminescence. Protein and mRNA levels of pre-pro-AM, calcitonin receptor-like receptor (CRLR) and RAMP1, 2, and 3 (receptor-activity-modifying proteins) were assessed by western blot and quantitative real-time polymerase chain reaction, respectively. Ethanol intake reduced AM-induced relaxation in endothelium-intact rat aortas, whereas calcitonin gene-related peptide-, acetylcholine-, and sodium nitroprusside induced relaxation were not affected by ethanol intake. N(G)-nitro-l-arginine methyl-ester (l-NAME), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, and tetraethylammonium reduced AM-induced relaxation in aortic rings from both control and ethanol-treated rats. Ethanol consumption did not alter basal levels of nitrate and nitrite, nor did it affect the expression of MMP-2 in the rat aorta. Ethanol consumption increased mRNA levels of pre-pro-AM and RAMP1. Protein levels of AM, CRLR, and RAMP1, 2, and 3 were not affected by ethanol consumption. The major findings of the present study are that ethanol consumption reduces the vascular relaxation induced by AM and changes the mRNA expression of the components of the AM system in the vasculature. This response could be one of the mechanisms by which ethanol predisposes individuals to vascular dysfunction and hypertension. PMID- 21824743 TI - Soft lens matter recurrence after congenital cataract surgery. AB - We report a case of soft lens matter recurrence 17 years after the original congenital cataract was removed. To our knowledge, this is the longest interval for soft lens matter to recur. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned. PMID- 21824744 TI - Piloting the perinatal obsessive-compulsive scale (POCS): development and validation. AB - Onset/worsening of obsessive-compulsive disorder (OCD) during the perinatal period are frequently seen clinically. No specific tool assessing the unique content, context, severity, and onset of perinatal OCD exists. A self-report scale of perinatal obsessions and compulsions, the Perinatal Obsessive-Compulsive Scale (POCS), was developed and validated. A total of 162 women (67 pregnant, 95 postpartum) participated in this pilot study. They completed the POCS as well as the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). The POCS has good construct validity, reflected by representative items, high internal consistency, good concurrent validity and discriminative capacity. The most common obsessions were fear of having an unhealthy baby at birth, contamination, the baby being taken away, and infant death. Behavioral compulsions such as repeating rituals, asking for reassurance, checking, and cleaning mirrored these obsessions. The POCS helps clinicians detect perinatal OCD while giving perinatal women an opportunity to openly discuss socially sensitive issues. PMID- 21824745 TI - The effects of gender and age on repetitive and/or restricted behaviors and interests in adults with autism spectrum disorders and intellectual disability. AB - Frequency of repetitive and/or restricted behaviors and interests (RRBIs) was assessed in 140 adults with autism spectrum disorders (ASDs) and severe or profound intellectual disability (ID). The associations of gender and age range were analyzed with RRBI frequency which was obtained using the Stereotypies subscale of the Diagnostic Assessment for the Severely Handicapped-II (DASH-II). A significant main effect of gender was found. Male participants had higher frequency of RRBIs than females regardless of age range. There was not a significant main effect of age range or a significant interaction between gender and age range. Results and implications are discussed. PMID- 21824746 TI - Teaching individuals with profound multiple disabilities to access preferred stimuli with multiple microswitches. AB - We replicated and extended previous research on microswitch facilitated choice making by individuals with profound multiple disabilities. Following an assessment of stimulus preferences, we taught 6 adults with profound multiple disabilities to emit 2 different responses to activate highly preferred stimuli. All participants learnt to activate both microswitches. Five participants showed a higher overall level of responding when both switches activating preferred stimuli were available concurrently. After completion of microswitch training, a choice assessment was conducted in which participants had access to 2 microswitches concurrently, with 1 connected to the most highly preferred stimulus and the other to a least preferred stimulus. Choice making behavior was shown in 3 participants and provided support for the preference assessment results. The results of the 3 remaining participants showed that both the most highly preferred and the least preferred stimuli may serve as reinforcers for microswitch activation responses. PMID- 21824747 TI - Psychometric properties and norms of the German ABC-Community and PAS-ADD Checklist. AB - AIM: The aim of the present study was to standardize and generate psychometric evidence of the German language versions of two well-established English language mental health instruments: the Aberrant Behavior Checklist-Community (ABC-C) and the Psychiatric Assessment Schedule for Adults with Developmental Disabilities (PAS-ADD) Checklist. New methods in this field were introduced: a simulation method for testing the factor structure and an exploration of long-term stability over two years. METHODS: The checklists were both administered to a representative sample of 270 individuals with intellectual disability (ID) and, two years later in a second data collection, to 128 participants of the original sample. Principal component analysis and parallel analysis were performed. Reliability measures, long-term stability, subscale intercorrelations, as well as standardized norms were generated. Prevalence of mental health problems was examined. RESULTS: Psychometric properties were mostly excellent, with long-term stability showing moderate to strong effects. The original factor structure of the ABC-C was replicated. PAS-ADD Checklist produced a similar, but still different structure compared with findings from the English language area. The overall prevalence rate of mental health problems in the sample was about 20%. CONCLUSION: Considering the good results on the measured psychometric properties, the two checklists are recommended for the early detection of mental health problems in persons with ID. PMID- 21824748 TI - Performance of 18F-FDG PET/contrast-enhanced CT in the staging of squamous cell carcinoma of the oral cavity and oropharynx. AB - The aim of this study was to assess the diagnostic value of integrated whole body positron emission tomography/contrast-enhanced CT (PET/CECT) as a one step examination in the initial staging of oral and oropharyngeal squamous cell carcinoma (OOSCC). Seventy three consecutive OOSCC patients who underwent PET/CECT for initial staging and tumour resection and neck dissection as primary treatment, were included. For each PET/CECT result, the contribution of fluorine 18 fluorodeoxyglucose ((18)F-FDG)-uptake and radiologic criteria was assessed. PET/CECT results were correlated to histological specimens obtained with tumour resection and neck dissection. For detecting the primary tumour PET/CECT showed a sensitivity of 96% and for detecting cervical metastases a sensitivity and specificity of 89% and 81%, respectively. In the clinically N0 subgroup (n=37), PET/CECT showed a sensitivity and specificity of 64% and 81%, respectively. In five of six patients PET/CECT detected a second primary tumour. The results show that the use of diagnostic PET/CECT as a one step examination is a reliable alternative for PET/CT in combination with a separate diagnostic CT in patients with OOSC for initial staging. The need for treatment of the neck in the clinically negative neck should not be based on PET/CECT results only, due to the risk of missing a small metastasis. PMID- 21824749 TI - Left atrial thrombus and prognosis after anticoagulation therapy in patients with atrial fibrillation. AB - BACKGROUND: Anticoagulation therapy reduces the risk of thromboembolic events by two-thirds in patients with atrial fibrillation (AF). The prevalence of left atrial thrombus (LAT) in AF patients with anticoagulation therapy has not been fully investigated. PURPOSE: To investigate the prevalence of LAT and its impact on the outcomes in patients with nonvalvular AF after anticoagulation therapy. METHODS: This study consisted of 231 patients with nonvalvular AF who had transthoracic (TTE) and transesophageal echocardiographic (TEE) examinations more than 3 weeks after anticoagulation therapy. The clinical and echocardiographic characteristics were evaluated. RESULTS: LAT was observed in 13 (8.8%) of 148 patients with sub-therapeutic anticoagulation, and in 3 (3.6%) of 83 patients with sufficient anticoagulation. The presence of LAT was associated with higher CHADS(2) score, decreased LA volume changes and the presence of spontaneous echocardiographic contrast (SEC) in patients with sub-therapeutic anticoagulation. Patients with LAT after sufficient anticoagulation were male with permanent AF who had decreased left ventricular systolic and diastolic function and dilated LA on TTE and SEC, and reduced appendage flow velocity on TEE. Patients with LAT had worse cardiovascular outcomes compared with those without LAT (p=0.02). CONCLUSIONS: We demonstrated that LAT was a univariate risk factor associated with worse cardiovascular outcomes, which was observed in 8.8% of patients with sub-therapeutic anticoagulation and 3.6% of patients with sufficient anticoagulation. PMID- 21824750 TI - Dynamic changes in plasma total and high molecular weight adiponectin levels in acute heart failure. AB - BACKGROUND: Elevated levels of total plasma adiponectin (APN) and high molecular weight (HMW)-APN have been observed in chronic heart failure (HF) and are associated with poor prognosis, however, the response of APN levels in acute HF is not known. The purpose of this study was to clarify the dynamic changes of the plasma total APN, HMW-APN levels, and the ratio of HMW-APN to total APN (HMWR) in acute HF. METHODS: From February 2006 to January 2007, 20 patients with acute HF (non-ischemic and non-valvular origin, 17 men, aged 63+/-11 years) were enrolled, and blood was sampled before the onset of the treatment and at discharge. Ten patients admitted for the treatment of supraventricular arrhythmia (8 men, aged 45+/-13 years) were included as controls. RESULTS: The medians and interquartile ranges of the plasma total APN, HMW-APN levels, and HMWR at admission were 20.8 (14.5-38.9) MUg/mL, 12.4 (7.7-23.3) MUg/mL, and 0.60 (0.50-0.69), respectively. The total APN and HMW-APN values were significantly higher than the values of the control. The plasma total APN, HMW-APN, and HMWR values at discharge decreased to 19.4 (7.2-27.3)MUg/mL, 10.5 (3.2-12.8) MUg/mL, and 0.52 (0.46-0.57), respectively. An exploratory survival analysis showed that the higher HMWR values at admission and the larger decrease in HMWR were associated with a better prognosis after discharge. CONCLUSION: Plasma total APN and HMW-APN values are elevated at the admission for acute HF. Plasma total APN, HMW-APN, and HMWR values decrease following treatment. Higher HMWR at admission and its larger decrease may be the signs of favorable treatment responsiveness in acute HF. PMID- 21824751 TI - Efficacy of anidulafungin against Aspergillus niger in vitro and in vivo. AB - In this study, anidulafungin (AFG) showed high in vitro activity against 10 isolates of Aspergillus niger by broth microdilution and disk diffusion methods. The efficacy of AFG at 1, 5 and 10 mg/kg was tested against six of the isolates in a murine model of disseminated infection. AFG was able to reduce mortality, showing survival rates of 70-100%, 60-100% and 30-60% in mice treated with AFG at 10, 5 and 1 mg/kg, respectively. AFG also showed a dose-response efficacy in reducing tissue burden in kidneys and spleen. A parallel experiment demonstrated that administration of AFG did not reduce serum concentrations of galactomannan in mice. Histopathological studies confirmed the efficacy of AFG. PMID- 21824752 TI - Interaction of mephedrone with dopamine and serotonin targets in rats. AB - INTRODUCTION: We described a first approach to the pharmacological targets of mephedrone (4-methyl-methcathinone) in rats to establish the basis of the mechanism of action of this drug of abuse. EXPERIMENTAL PROCEDURES: We performed in vitro experiments in isolated synaptosomes or tissue membrane preparations from rat cortex or striatum, studying the effect of mephedrone on monoamine uptake and the displacement of several specific radioligands by this drug. RESULTS: In isolated synaptosomes from rat cortex or striatum, mephedrone inhibited the uptake of serotonin (5-HT) with an IC 50 value lower than that of dopamine (DA) uptake (IC 50=0.31+/-0.08 and 0.97+/-0.0 5MUM, respectively). Moreover, mephedrone displaced competitively both [3H]paroxetine and [3H]WIN35428 binding in a concentration-dependent manner (Ki values of 17.55+/-0.78MUM and 1.53+/-0.47 MUM, respectively), indicating a greater affinity for DA than for 5 HT membrane transporters. The affinity profile of mephedrone for the 5-HT2 and D2 receptors was assessed by studying [3H]ketanserin and [3H] raclopride binding in rat membranes. Mephedrone showed a greater affinity for the 5-HT2 than for the D2 receptors. DISCUSSION: These results provide evidence that mephedrone, interacting with 5-HT and DA transporters and receptors must display a similar pattern of other psychoactive drugs such as amphetamine-like compounds. PMID- 21824753 TI - Default-mode network connectivity and white matter burden in late-life depression. AB - The brain's default-mode network has been the focus of intense research. This study characterizes the default-mode network activity in late-life depression and the correlation of the default-mode network activity changes with the white matter hyperintensities burden. We hypothesized that elderly depressed subjects would have altered default-mode network activity, which would correlate with the increased white-matter hyperintensities burden. Twelve depressed subjects (mean Hamilton Depression Rating Scale 19.8+/-4.1, mean age 70.5+/-4.9) and 12 non depressed, comparison subjects (mean age 69+/-6.5) were included. Functional magnetic resonance imaging (fMRI) data were collected while subjects performed a low cognitive load, event-related task. We compared the default-mode network activity in these groups (including depressed subjects pre- and post antidepressant treatment). We analyzed the resting connectivity patterns of the posterior cingulate cortex. Deconvolution was used to evaluate the correlation of resting-state connectivity scores with the white-matter hyperintensities burden. Compared with non-depressed elderly, depressed subjects pretreatment had decreased connectivity in the subgenual anterior cingulate cortex and increased connectivity in the dorsomedial prefrontal cortex and the orbito-frontal cortex. The abnormal connectivity was significantly correlated with the white-matter hyperintensities burden. Remitted elderly depressed subjects had improved functional connectivity compared to pretreatment, although alterations persisted in the anterior cingulate and the prefrontal cortex when remitted elderly depressed subjects were compared with non-depressed elderly. Our study provides evidence for altered default-mode network connectivity in late-life depression. The correlation between white-matter hyperintensities burden and default-mode network connectivity emphasizes the role of vascular changes in late-life depression etiopathogenesis. PMID- 21824755 TI - Consumption of fried foods and weight gain in a Mediterranean cohort: the SUN project. AB - BACKGROUND AND AIMS: The consumption of fried foods is believed to be linked with obesity and higher weight gain, however, the evidence from long-term randomized trials or prospective epidemiological studies is scarce. Therefore, the aim of our study was to prospectively evaluate the association between the consumption of fried foods and weight change and the incidence of overweight/obesity in a Mediterranean cohort. METHODS AND RESULTS: Prospective cohort study of 9850 men and women with a mean age of 38.1 years (SD 11.4) were followed-up for a median of 6.1 years to assess average yearly change in body weight, and incidence of overweight/obesity. The consumption of fried foods was associated with higher weight gain, but the differences were of small magnitude and statistically non significant. The incidence of overweight/obesity during follow-up was also assessed in the subset of 6821 participants with initial body mass index <25 kg/m(2) (initially free of overweight/obesity), after adjusting for potential confounders, the odds ratio for developing overweight/obesity among participants who consumed fried foods >4 times/week was 1.37 (95% confidence interval: 1.08 to 1.73) in comparison with those who consumed fried foods <2 times/week (p for trend = 0.02). CONCLUSION: In this Mediterranean prospective cohort, a more frequent consumption of fried foods at baseline was associated with a higher risk of subsequently developing overweight/obesity during follow-up. PMID- 21824754 TI - Resting EEG deficits in accused murderers with schizophrenia. AB - Empirical evidence continues to suggest a biologically distinct violent subtype of schizophrenia. The present study examined whether murderers with schizophrenia would demonstrate resting EEG deficits distinguishing them from both non-violent schizophrenia patients and murderers without schizophrenia. Resting EEG data were collected from five diagnostic groups (normal controls, non-murderers with schizophrenia, murderers with schizophrenia, murderers without schizophrenia, and murderers with psychiatric conditions other than schizophrenia) at a brain hospital in Nanjing, China. Murderers with schizophrenia were characterized by increased left-hemispheric fast-wave EEG activity relative to non-violent schizophrenia patients, while non-violent schizophrenia patients instead demonstrated increased diffuse slow-wave activity compared to all other groups. Results are discussed within the framework of a proposed left-hemispheric over processing hypothesis specific to violent individuals with schizophrenia, involving left hemispheric hyperarousal deficits, which may lead to a homicidally violent schizophrenia outcome. PMID- 21824757 TI - Lower endothelial progenitor cell number, family history of cardiovascular disease and reduced HDL-cholesterol levels are associated with shorter leukocyte telomere length in healthy young adults. AB - BACKGROUND AND AIMS: Leukocyte telomere length (LTL) is a novel marker of cardiovascular (CV) risk. The aim of the study was to investigate the major determinants of LTL in a healthy young population at very low CV risk. METHODS AND RESULTS: LTL was determined in 82 healthy subjects (49M/33F; age37 +/- 9yrs), normotensive and not taking any medication with different family history of cardiovascular disease (CVD) (24yes/58no). Fasting blood samples were drawn in all subjects for the determination of lipid profile, high sensitive C-reactive protein, uric acid, Plasminogen Activator Inhibitor-1 (PAI-1), LTL and Endothelial Progenitor Cell (EPC) number. LTL was assessed with a specific real time PCR reaction in leukocyte DNA samples. LTL resulted inversely correlated with family history of CVD (t = 2.70; p = 0.009), age (r = -0.238; p = 0.032), waist circumference (r = -0.256; p = 0.02), triglycerides (r = -0.218; p = 0.049), PAI-1 (r = -0.288; p = 0.009) and directly correlated with HDL cholesterol (r = 0.316; p = 0.004) and EPC number (r = 0.358; p = 0.002). At a multivariate analysis, family history of CVD (p = 0.013), EPC count (p = 0.003), and HDL-cholesterol (p = 0.017) were independently associated with LTL (r = 0.62). CONCLUSION: LTL is independently associated to CV risk factors also in healthy young adults. PMID- 21824756 TI - Cocoa consumption reduces NF-kappaB activation in peripheral blood mononuclear cells in humans. AB - BACKGROUND AND AIMS: Epidemiological studies have demonstrated an association between high-polyphenol intake and reduced incidence of atherosclerosis. The healthy effects of cocoa-polyphenols may be due to their antioxidant and anti inflammatory actions, although the exact mechanisms are unknown and depend on the matrix in which cocoa-polyphenols are delivered. Nuclear factor kappaB (NF kappaB) is a key molecule in the pathophysiology of atherosclerosis involved in the regulation of adhesion molecules(AM) and cytokine expression and its activation is the first step in triggering the inflammatory process. The aim of this study was to evaluate the effect of acute cocoa consumption in different matrices related to the bioavailability of cocoa-polyphenols in NF-kappaB activation and the expression of AM. METHODS AND RESULTS: Eighteen healthy volunteers randomly received 3 interventions: 40g of cocoa powder with milk (CM), with water (CW), and only milk (M). NF-kappaB activation in leukocytes and AM (sICAM, sVCAM, E-selectin) were measured before and 6h after each intervention. Consumption of CW significantly decreased NF-kappaB activation compared to baseline and to CM (P < 0.05, both), did not change after CM intervention, and significantly increased after M intervention (P = 0.014). sICAM-1 concentrations significantly decreased after 6h of CW and CM interventions (P <= 0.026; both) and E-selectin only decreased after CW intervention (P = 0.028). No significant changes were observed in sVCAM-1 concentrations. CONCLUSIONS: The anti inflammatory effect of cocoa intake may depend on the bioavailability of bioactive compounds and may be mediated at least in part by the modulation of NF kappaB activation and downstream molecules reinforcing the link between cocoa intake and health. PMID- 21824758 TI - Identification of fungal DNA in BALF from patients with home-related hypersensitivity pneumonitis. AB - BACKGROUND: In Japan, a major type of home-related hypersensitivity pneumonitis (HP) is summer-type HP, which is caused by Trichosporon asahii (T. asahii) or Trichosporon mucoides. Some patients with home-related HP test negative for antibodies against Trichosporon; yet, a causative mold antigen cannot be identified. METHODS: We analyzed 19 patients with home-related HP, 8 healthy volunteers, and 35 patients with other diseases. We extracted DNA from cell pellets of bronchoalveolar lavage fluid (BALF), amplified the DNA by PCR using Trichosporon-specific primers or other fungus-specific primers, and cloned as well as sequenced the PCR amplicon. Other primers used were specific for Acremonium chrysogenum, Aspergillus fumigatus, Aspergillus niger, Fusarium napiforme, Humicola fuscoatra, Penicillium corylophilum, and Pezizia domiciliana. RESULTS: We detected Trichosporon DNA (n = 17) and F. napiforme DNA (n = 2) by PCR in 19 patients with home-related HP; however, these species were not identified in healthy volunteers. After sequencing of the PCR amplicon for Trichosporon species, we identified T. asahii (n = 11), Trichosporon japonicum (n = 1), and Cryptococcus uzbekistanesis (n = 4). CONCLUSION: We could detect fungal DNA in BALF cell pellets from patients with home-related HP. These data suggest that this method might be useful to detect antigens responsible for home-related HP. PMID- 21824759 TI - Highly sensitive and selective detection of thiol-containing biomolecules using DNA-templated silver deposition. AB - In this work, we report a new fluorescent method for the label-free assay of thiol-containing amino acids and peptide by use of silver deposited DNA duplex and the intercalating dye. The sensing approach is based on the specific interactions between thiols and DNA-templated silver deposition via robust Ag-S bonds. In the presence of thiols, the intercalating dye gives a dramatic increase in fluorescence as a result of the strong interaction between the intercalator and the released DNA from silver surfaces. The detection limit of this method is lower than or at least comparable to previous fluorescence-based methods, and the turn-on sensing mode offers additional advantage to efficiently reduce background noise. Moreover, the detection and discrimination process can be observed by the naked eye with the aid of an UV transilluminator. This method also exhibits excellent selectivity for these thiol-containing biomolecules over various other amino acids. As far as we know, our method is the first example using the specific interaction between thiols and silver-coated DNA to fabricate a turn-on fluorescent sensor for biological thiols with high sensitivity and selectivity. PMID- 21824760 TI - Electrochemical sensor for dopamine based on a novel graphene-molecular imprinted polymers composite recognition element. AB - A novel composite of graphene sheets/Congo red-molecular imprinted polymers (GSCR MIPs) was synthesized through free radical polymerization (FRP) and applied as a molecular recognition element to construct dopamine (DA) electrochemical sensor. The template molecules (DA) were firstly absorbed at the GSCR surface due to their excellent affinity, and subsequently, selective copolymerization of methacrylic acid (MAA) and ethylene glycol dimethacrylate (EGDMA) was further achieved at the GSCR surface. Potential scanning was presented to extract DA molecules from the imprinted polymers film, and as a result, DA could be rapidly and completely removed by this way. With regard to the traditional MIPs, the GSCR MIPs not only possessed a faster desorption and adsorption dynamics, but also exhibited a higher selectivity and binding capacity toward DA molecule. As a consequence, an electrochemical sensor for highly sensitive and selective detection of DA was successfully constructed as demonstration based on the synthesized GSCR-MIPs nanocomposites. Under experimental conditions, selective detection of DA in a linear concentration range of 1.0 * 10(-7)-8.3 * 10(-4)M was obtained, which revealed a lower limit of detection and wider linear response compared to some previously reported DA electrochemical MIPs sensors. The new DA electrochemical sensor based on GSCR-MIPs composites also exhibited excellent repeatability, which expressed as relative standard deviation (RSD) was about 2.50% for 30 repeated analyses of 20 MUM DA. PMID- 21824761 TI - Aptamer beacons for visualization of endogenous protein HIV-1 reverse transcriptase in living cells. AB - Direct visualization of endogenous proteins in living cells remains a challenge. Aptamer beacon is a promising technique to resolve this problem by combining the excellent protein binding specificity of the aptamer with the sensitive signal transduction mechanism of the molecular beacon. In this study, aptamer 93 del against HIV-1 reverse transcriptase (RT) was engineered into aptamer beacons to recognize and image HIV-1 RT. The constructed aptamer beacons could specifically bind to HIV-1 RT and the beacon-RT binding showed effective fluorescence signal transduction in homogeneous solution. In solutions with 1 MUM of the aptamer beacon, the effective fluorescence signal increased with increasing concentration of HIV-1 RT from 0.5 MUM to 5 MUM. When the aptamer beacons were delivered into the living cells that transiently expressed HIV-1 RT, HIV-1 RT could be specifically labeled and imaged. The designed aptamer beacons were further successfully applied for RT imaging in HIV-1 integrated U1 cells. The method developed here may be extended to visualize many other endogenous proteins in living cells using appropriate aptamer beacons. PMID- 21824762 TI - X-ray crystallography at the heart of life science. AB - X-ray crystallography is the fundamental research tool that shaped our notion on biological structure & function at the molecular level. It generates the information vital to understand life processes by providing the information required for creating accurate three-dimensional models (namely mapping the position of each and every atom that makes up the studied object). The use of this method begun in the middle of last century following Max von Laue discovery of the phenomenon of diffraction of X-rays by crystals, and the successful application of this discovery for the determination of the electronic distribution within simple inorganic molecules by Sir William Henry Bragg and his son, William Lawrence Bragg. The idea of extension of this method to biological molecules met initially with considerable skepticism. For over two decades many respected scientists doubted whether it could be done. Yet, despite its bottlenecks (some of which are described below), the superiority of X-ray crystallography over all other approaches for shedding light on functional aspects at the molecular level became evident once the first structure was determined. The power of this method inspired continuous efforts and spectacular innovations, which vastly accelerated its incredible expansion. Consequently, over the last six decades biological crystallography has produced a constantly growing number of structures, some of which were considered formidable. This remarkable advance yielded numerous new insights into intricate functional aspects. Owing to space limitation this article focuses on selected studies performed recently and highlights some recent exciting developments. PMID- 21824763 TI - Long term survival in patients with hepatocellular carcinoma directly invading the gastrointestinal tract: case reports and literature review. AB - Hepatocellular carcinoma (HCC) directly invading the gastrointestinal (GI) organs is rare and is associated with poor survival outcome. We report two patients with good long-term outcome following resection of HCC that invaded the stomach and duodenum, respectively. A literature review was conducted to elucidate the course of patients with this pathology. Two cases (57-year-old and 72-year-old males) with enlarged hepatic tumors directly invading the stomach and duodenum underwent hepatectomies with en-bloc resection of the involved organs. Both patients are still alive at 80 and 68 months following the surgery. Our literature review showed that most of the patients with this pathology have manifested, and died of persistent GI bleeding. Patients who were treated surgically had a statistically significant longer survival than those who were treated with non-surgical palliative treatments (P < 0.001). In addition, patients who were treated with surgery with curative intent tend to have a longer survival times than those who were treated with surgery to palliate the bleeding but the difference was not statistically significant (P < 0.174). Removing the tumor completely could significantly prolong the survival of patients with HCC invading the GI tract. PMID- 21824764 TI - Degradation of pentachlorophenol with the presence of fermentable and non fermentable co-substrates in a microbial fuel cell. AB - Pentachlorophenol (PCP) was more rapidly degraded in acetate and glucose-fed microbial fuel cells (MFCs) than in open circuit controls, with removal rates of 0.12 +/- 0.01 mg/Lh (14.8 +/- 1.0 mg/g-VSS-h) in acetate-fed, and 0.08 +/- 0.01 mg/L h (6.9 +/- 0.8 mg/g-VSS-h) in glucose-fed MFCs, at an initial PCP concentration of 15 mg/L. A PCP of 15 mg/L had no effect on power generation from acetate but power production was decreased with glucose. Coulombic balances indicate the predominant product was electricity (16.1 +/- 0.3%) in PCP-acetate MFCs, and lactate (19.8 +/- 3.3%) in PCP-glucose MFCs. Current generation accelerated the removal of PCP and co-substrates, as well as the degradation products in both PCP-acetate and PCP-glucose reactors. While 2,3,4,5 tetrachlorophenol was present in both reactors, tetrachlorohydroquinone was only found in PCP-acetate MFCs. These results demonstrate PCP degradation and power production were affected by current generation and the type of electron donor provided. PMID- 21824765 TI - Response of lab-scale methanogenic reactors inoculated from different sources to organic loading rate shocks. AB - Anaerobic digester failure due to a pH drop may be overcome with the use of an acidotolerant methanogenic community. To test this, lab-scale reactors were inoculated from acidic bog sediments, a municipal sludge digester, or a combination of these inocula and challenged with glucose pulses without pH control. Only the bog reactor survived the first glucose shock, and the methanogen community was dominated by members of the acidic Fen Cluster. After restarting the digester and hybrid reactors, two subsequent glucose shocks were applied. Methanogenic communities converged in all reactors and were dominated by Methanosarcina and Methanobacteriaceae. The Fen Cluster was eventually nondetectable in bog and hybrid reactors, presumably due to periods of circumneutral pH with only intermittent periods of low pH following glucose shocks. Although the resultant communities required base addition, an increase in Methanosarcina numbers after glucose pulses resulted in decreased acetate and increased reactor pH and methane production. PMID- 21824766 TI - High titer ethanol production from simultaneous enzymatic saccharification and fermentation of aspen at high solids: a comparison between SPORL and dilute acid pretreatments. AB - Native aspen (Populus tremuloides) was pretreated using sulfuric acid and sodium bisulfite (SPORL) and dilute sulfuric acid alone (DA). Simultaneous enzymatic saccharification and fermentation (SSF) was conducted at 18% solids using commercial enzymes with cellulase loadings ranging from 6 to 15 FPU/g glucan and Saccharomyces cerevisiae Y5. Compared with DA pretreatment, the SPORL pretreatment reduced the energy required for wood chip size-reduction, and reduced mixing energy of the resultant substrate for solid liquefaction. Approximately 60% more ethanol was produced from the solid SPORL substrate (211 L/ton wood at 59 g/L with SSF efficiency of 76%) than from the solid DA substrate (133 L/ton wood at 35 g/L with SSF efficiency 47%) at a cellulase loading of 10 FPU/g glucan after 120 h. When the cellulase loading was increased to 15 FPU/g glucan on the DA substrate, the ethanol yield still remained lower than the SPORL substrate at 10 FPU/g glucan. PMID- 21824767 TI - Graphite oxide-supported CaO catalysts for transesterification of soybean oil with methanol. AB - Graphite oxide (GO) supported CaO catalysts were prepared and successfully applied to the transesterification of soybean oil with methanol. The supports and resultant catalysts were characterized using X-ray diffraction (XRD), transmission electron microscopy (TEM), N(2) adsorption, thermogravimetry (TG), X ray photoelectron spectroscopy (XPS), temperature-programed desorption (TPD) and Fourier-transform infrared spectroscopy (FT-IR). The GO supported CaO catalysts exhibited excellent catalytic activity and were easily regenerated by simple heat treatment. The oxygen-containing groups (i.e., hydroxyl, epoxide groups and carboxyl groups) present on the surface of GO likely act as anchoring centers for CaO. This work demonstrates that graphite oxide is an effective host material of catalytically active CaO nanoparticles for the transesterification of soybean oil with methanol to produce biodiesel. PMID- 21824768 TI - Competitive adsorption of Cu(II) and Cd(II) ions by chitosan crosslinked with epichlorohydrin-triphosphate. AB - In this study, chitosan (CTS) was crosslinked with both epichlorohydrin (ECH) and triphosphate (TPP), by covalent and ionic crosslinking reactions, respectively. The resulting adsorbent (CTS-ECH-TPP) was characterized by SEM, CHN, EDS, FT-IR and TGA analyses, and tested for metal adsorption. The adsorbent was used in batch experiments to evaluate the adsorption of Cu(II) and Cd(II) ions in single and binary metal solutions. In single metal solutions the maximum adsorption capacities for Cu(II) and Cd(II) ions, obtained by Langmuir model, were 130.72 and 83.75 mg g-1, respectively. Adsorption isotherms for binary solutions showed that the presence of Cu(II) decreased Cd(II) adsorption due to a significant competition effect, that is, the adsorbent was selective towards Cu(II) rather than Cd(II). PMID- 21824769 TI - A hybrid genetic--neural algorithm for modeling the biodegradation process of DnBP in AAO system. AB - A hybrid artificial neural network - genetic algorithm numerical technique was successfully developed to model, and to simulate the biodegradation process of di n-butyl phthalate in an anaerobic/anoxic/oxic (AAO) system. The fate of DnBP was investigated, and a removal kinetic model including sorption and biodegradation was formulated. To correlate the experimental data with available models or some modified empirical equations, the steady state model equations describing the biodegradation process have been solved using genetic algorithm (GA) and artificial neural network (ANN) from the water quality characteristic parameters. Compared with the kinetic model, the performance of the GA-ANN for modeling the DnBP was found to be more impressive. The results show that the predicted values well fit measured concentrations, which was also supported by the relatively low RMSE (0.2724), MAPE (3.6137) and MSE (0.0742)and very high R (0.9859) values, and which illustrates the GA-ANN model predicting effluent DnBP more accurately than the mechanism model forecasting. PMID- 21824770 TI - Significance of oxygen supply in production of a novel antibiotic by Pseudomonas sp. SJT25. AB - A new agricultural antibiotic, 2-heptyl-5-hexylfuran-3-carboxylic acid (HHCA), was recently discovered, but its further application was limited due to its low production titer. In shake flask fermentation, the effect of initial K(L)a within the range of 2.12-18.87 h-1 on HHCA production was investigated. The cell growth and glycerol consumption were faster at a higher initial K(L)a value, but the maximum production (14.43 mg/L) was attained at an initial K(L)a value of 12.46 h 1. The oxygen supply information was further applied to a 2-L bubble column bioreactor (BCB) by varying initial K(L)a from 1.45 to 30.18 h-1, and the hyperproduction of HHCA was achieved at a relatively low initial K(L)a around 5 10 h-1. The control of oxygen supply is considered to be an important strategy to enhance HHCA production, and the information obtained will be useful to production of this powerful new antibiotic on a large scale. PMID- 21824771 TI - Effect of a static magnetic field on formaldehyde biodegradation in wastewater by activated sludge. AB - The aim of this study was to determine the impact of a static magnetic field (MF) of 7 mT on formaldehyde (FA) biodegradation by activated sludge in synthetic wastewater. The MF had a positive effect on activated sludge biomass growth and dehydrogenase activity. The influence of the MF on the degradation process was observed with a FA concentration of 2400-2880 mg/l. Decreases in FA concentration and chemical oxygen demand (COD) were greater, by 30% and 26% respectively, than those in the control sample. At initial FA concentrations in raw wastewater of 2400 and 2880 mg/l, a decrease in the wastewater biodegradation efficiency was observed. This resulted in an increase of the ecotoxicity of the effluent to Daphnia magna. The value of the sludge biotic index (SBI) was dependent on the FA concentration in raw wastewater and the induction of the MF. PMID- 21824772 TI - Synthesis and biological evaluation of some novel N-aryl-1,4-dihydropyridines as potential antitubercular agents. AB - 1,4-Dihydropyridines are the emerging class of antitubercular agent. Recently, studies have revealed that 1,4-dihydropyridine-3,5-dicarbamoyl derivatives with lipophilic groups have demonstrated excellent antitubercular activity. We have synthesized new N-aryl-1,4-dihydropyridines bearing carbethoxy and acetyl group at C-3 and C-5 of the DHP ring. In addition, 1H-pyrazole ring is substituted at C 4 position. The lowest minimum inhibitory concentration value, 0.02 MUg/mL, was found for diethyl 1-(2-chlorophenyl)-1,4-dihydro-2,6-dimethyl-4-(1,3-diphenyl-1H pyrazol-4-yl)pyridine-3,5-dicarboxylate 4e making it more potent than first line antitubercular drug isoniazid. In addition, this compound exhibited relatively low cytotoxicity. PMID- 21824773 TI - 1,6-Disubstituted indole derivatives as selective human neuronal nitric oxide synthase inhibitors. AB - A series of 1,6-disubstituted indole derivatives was designed, synthesized and evaluated as inhibitors of human nitric oxide synthase (NOS). By varying the basic amine side chain at the 1-position of the indole ring, several potent and selective inhibitors of human neuronal NOS were identified. In general compounds with bulkier side chains displayed increased selectivity for nNOS over eNOS and iNOS isoforms. One of the compounds, (R)-8 was shown to reduce tactile hyperesthesia (allodynia) after oral administration (30 mg/kg) in an in vivo rat model of dural inflammation relevant to migraine pain. PMID- 21824774 TI - Synthesis and biological activity of a novel class nicotinic acetylcholine receptors (nAChRs) ligands structurally related to anatoxin-a. AB - The introduction of the isoxazole ring as bioisosteric replacement of the acetyl group of anatoxin-a led to a new series of derivatives binding to nicotinic acetylcholine receptors. Bulkier substitutions than methyl at the 3 position of isoxazole were shown to be detrimental for the activity. The binding potency of the most interesting compounds with alpha1, alpha7 and alpha3beta4 receptor subtypes, was, anyway, only at micromolar level. Moreover, differently from known derivatives with pyridine, isoxazole condensed to azabicyclo ring led to no activity. PMID- 21824775 TI - Substitution of the phosphonic acid and hydroxamic acid functionalities of the DXR inhibitor FR900098: an attempt to improve the activity against Mycobacterium tuberculosis. AB - Two series of FR900098/fosmidomycin analogs were synthesized and evaluated for MtDXR inhibition and Mycobacterium tuberculosis whole-cell activity. The design rationale of these compounds involved the exchange of either the phosphonic acid or the hydroxamic acid part for alternative acidic and metal-coordinating functionalities. The best inhibitors provided IC(50) values in the micromolar range, with a best value of 41 MUM. PMID- 21824776 TI - Amine-constrained pyridazinone histamine H3 receptor antagonists. AB - Pyridazinone 1 was recently reported as a potent H(3)R antagonist with good drug like properties and in vivo activity. A series of constrained amine analogs of 1 was synthesized to identify compounds with improved pharmacokinetic profiles. From these efforts, a new class of (S)-2-pyrrolidin-1-ylmethyl-1-pyrrolidinyl amides was identified. PMID- 21824777 TI - Characteristic of alkylated chalcones from Angelica keiskei on influenza virus neuraminidase inhibition. AB - As part of our ongoing effort to develop influenza virus neuraminidase (NA) inhibitors from various medicinal plants, we utilized bioassay-guided fractionation to isolated six alkylated chalcones (1-6) from Angelica keiskei. Xanthokeistal A (1) emerged as new compound containing the rare alkyl substitution, 6,6-dimethoxy-3-methylhex-2-enyl. When we tested the ability of these individual alkyl substituted chalcones to inhibit influenza virus NA hydrolysis, we found that 2-hydroxy-3-methyl-3-butenyl alkyl (HMB) substituted chalcone (3, IC(50)=12.3 MUM) showed most potent inhibitory activity. The order of potency of substituted alkyl groups on for NA inhibition was HMB>6-hydroxyl 3,7-dimethyl-octa-2,7-dienyl>dimethylallyl>geranyl. All NA inhibitors screened were found to be reversible noncompetitive inhibitors. PMID- 21824778 TI - Potent antimalarial 4-pyridones with improved physico-chemical properties. AB - Antimalarial 4-pyridones are a novel class of inhibitors of the plasmodial mitochondrial electron transport chain targeting Cytochrome bc1 (complex III). In general, the most potent 4-pyridones are lipophilic molecules with poor solubility in aqueous media and low oral bioavailability in pre-clinical species from the solid dosage form. The strategy of introducing polar hydroxymethyl groups has enabled us to maintain the high levels of antimalarial potency observed for other more lipophilic analogues whilst improving the solubility and the oral bioavailability in pre-clinical species. PMID- 21824779 TI - Design and synthesis of novel amide AKT1 inhibitors with selectivity over CDK2. AB - Through the analysis of X-ray crystallographic information and previous SAR studies, a novel series of protein kinase B (PKB/AKT) inhibitors was developed. The compounds showed nanomolar inhibition of AKT1 and were selective against cyclin-dependent kinase 2 (CDK2). PMID- 21824780 TI - Discovery of a novel series of selective HCN1 blockers. AB - The discovery of a series of novel, potent, and selective blockers of the cyclic nucleotide-modulated channel HCN1 is disclosed. Here we report an SAR study around a series of selective blockers of the HCN1 channel. Utilization of a high throughput VIPR assay led to the identification of a novel series of 2,2 disubstituted indane derivatives, which had moderate selectivity and potency at HCN1. Optimization of this hit led to the identification of the potent, 1,1 disubstituted cyclohexane HCN1 blocker, 2-ethoxy-N-((1-(4-isopropylpiperazin-1 yl)cyclohexyl)methyl)benzamide. The work leading to the discovery of this compound is described herein. PMID- 21824781 TI - Taking a "good" look at free radicals in the aging process. AB - The mitochondrial free radical theory of aging (MFRTA) proposes that aging is caused by damage to macromolecules by mitochondrial reactive oxygen species (ROS). This is based on the observed association of the rate of aging and the aged phenotype with the generation of ROS and oxidative damage. However, recent findings, in particular in Caenorhabditis elegans but also in rodents, suggest that ROS generation is not the primary or initial cause of aging. Here, we propose that ROS are tightly associated with aging because they play a role in mediating a stress response to age-dependent damage. This could generate the observed correlation between aging and ROS without implying that ROS damage is the earliest trigger or main cause of aging. PMID- 21824782 TI - Synthesis and structure-activity relationship of novel diarylpyrimidines with hydromethyl linker (CH(OH)-DAPYs) as HIV-1 NNRTIs. AB - A series of 26 diarylpyrimidines, characterized by the hydroxymethyl linker between the left wing benzene ring and the central pyrimidine, were synthesized and evaluated for in vitro anti-HIV activity. Most of the compounds exhibited moderate to excellent activities against wild-type HIV-1. Among them, compound 10i, bearing a chlorine atom at the C-2 position of left benzene ring, was the best congener and showed potent activity against wild-type HIV-1 with an EC(50) value of 0.009 MUM, along with moderate activities against the double RT mutant (K103N+Y181C) HIV-1(III(B)) and HIV-2(ROD) with an EC(50) value of 6.2 and 6.0 MUM, respectively. The preliminary structure-activity relationship (SAR) of this new series of compounds was also investigated. PMID- 21824783 TI - Synthesis and antimalarial evaluation of novel benzopyrano[4,3-b]benzopyran derivatives. AB - 7-Methoxyflavenes and 5,7,8-trimethoxyflavenes were found to undergo stereoselective acid-catalyzed rearrangement to generate the benzopyrano[4,3 b]benzopyran ring system present in the natural product, dependensin. Dependensin and its analogs were subjected to antimalarial growth inhibition assays against Plasmodium falciparum and found to have IC(50) values ranging between 1.9 and 3.9 MUM. PMID- 21824784 TI - The dynamics of the early inflammatory response in double-hit burn and sepsis animal models. AB - Severe burn trauma is generally associated with bacterial infections, which causes a more persistent inflammatory response with an ongoing hypermetabolic and catabolic state. This complex biological response, mediated by chemokines and cytokines, can be more severe when excessive interactions between the mediators take place. In this study, the early inflammatory response following the cecum ligation and puncture (CLP) or its corresponding control treatment (sham-CLP or SCLP) in burn (B) male rats was analyzed by measuring 23 different cytokines and chemokines. Cytokines and chemokines, including MCP-1, IP-10, leptin, TNF-alpha, MIP-1alpha, IL-18, GMCSF, RANTES and GCSF were significantly altered in both B+CLP and B+SCLP groups. IL-10 and IL-6 were significantly up-regulated in the B+CLP group when compared to the B+SCLP group. Down regulation of leptin and IP 10 concentrations were found to be related to surgery and/or infection. IL-18 and MCP-1 were elevated in all groups including previously published single injury models receiving similar treatments. In this study, insult-specific mediators with their characteristic temporal patterns were elucidated in double hit models. PMID- 21824785 TI - The role of IL-21 in hematological malignancies. AB - IL-21, the newest member of the common gamma-chain family of cytokines, has pleiotropic biological effects through regulating a variety of immune cells. Recently, the role of IL-21 in the treatment of cancers has been widely investigated. Conducted phase I trials in metastatic malignant melanoma and renal cell carcinoma have shown that rIL-21 has a favorable antitumor activity. Expression of IL-21 and IL-21R has also been found in many types of hematological malignancies, such as chronic lymphocytic leukemia (CLL), multiple myeloma (MM) and lymphoma. Through binding with IL-21R, IL-21 induces activation of different JAK/STAT signal transduction pathways and regulates proliferation or apoptosis of tumor cells. In this review, we will discuss the expression of IL-21/IL-21R and its effect in different types of hematological malignancies. PMID- 21824786 TI - Caspase-1-processed IL-1 family cytokines play a vital role in driving innate IL 17. AB - The interleukin (IL)-1 cyokine family plays a vital role in inflammatory responses during infection and in autoimmune diseases. The pro-inflammatory cytokines, IL-1beta and IL-18 are members of the IL-1 family that require cleavage by caspase-1 in the inflammasome to generate the mature active cytokines. Cells of the innate immune system, including gammadelta T cells and invariant natural killer T (iNKT) cells respond rapidly to invading pathogens by producing inflammatory cytokines, such as IFN-gamma and IL-17. IL-1beta or IL-18 in combination with IL-23 can induce IL-17 production by gammadelta T cells without T cell receptor (TCR) engagement. IL-1beta and IL-23 can also synergize to induce IL-17 production by iNKT cells. Furthermore, CD4+ alphabeta effector memory T cells secrete IL-17 in response to IL-23 in combination with either IL 1beta or IL-18, in the absence of any TCR stimulation. The early IL-17 produced by innate cells induces recruitment of neutrophils to the site of infection, stimulates local epithelial cells to secrete anti-microbial proteins, such as lipocalins and calgranulins, induces production of structural proteins important in tight junction stability, and promotes production of matrix metalloproteinases. Caspase-1 processed IL-1 family cytokines therefore play a vital role in the innate immune response and induction of IL-17 from innate immune cells which functions to fight infections and promote autoimmunity. PMID- 21824787 TI - Salary discrepancies between practicing male and female physician assistants. AB - BACKGROUND: Salary discrepancies between male and female physicians are well documented; however, gender-based salary differences among clinically practicing physician assistants (PAs) have not been studied since 1992 (Willis, 1992). Therefore, the objectives of the current study are to evaluate the presence of salary discrepancies between clinically practicing male and female PAs and to analyze the effect of gender on income and practice characteristics. METHODS: Using data from the 2009 American Academy of Physician Assistants' (AAPA) Annual Census Survey, we evaluated the salaries of PAs across multiple specialties. Differences between men and women were compared for practice characteristics (specialty, experience, etc) and salary (total pay, base pay, on-call pay, etc) in orthopedic surgery, emergency medicine, and family practice. FINDINGS: Men reported working more years as a PA in their current specialty, working more hours per month on-call, providing more direct care to patients, and more funding available from their employers for professional development (p < .001, all comparisons). In addition, men reported a higher total income, base pay, overtime pay, administrative pay, on-call pay, and incentive pay based on productivity and performance (p < .001, all comparisons). Multivariate analysis of covariance and analysis of variance revealed that men reported higher total income (p < .0001) and base pay (p = .001) in orthopedic surgery, higher total income (p = .011) and base pay (p = .005) in emergency medicine, and higher base pay in family practice (p < .001), independent of clinical experience or workload. CONCLUSION: These results suggest that certain salary discrepancies remain between employed male and female PAs regardless of specialty, experience, or other practice characteristics. PMID- 21824788 TI - Adaptations in the gait pattern with experimental hamstring pain. AB - Pain changes movement but most studies have focused on basic physiological adaptations during non-functional movement tasks. The existing studies on how pain affects lower extremity gross movement biomechanics have primarily involved movements in which the quadriceps is the primary muscle and little attention has been given to how pain in other muscles affects functional movement. The purpose of this study was to investigate the changes in the gait patterns of healthy subjects that occur during experimental muscle pain in the biceps femoris. In a cross-over study design, 14 healthy volunteers underwent EMG assisted 3D gait analyses before, during and after experimental biceps femoris pain induced by intramuscular injections of hypertonic saline. Isotonic saline injections were administered as a non-painful control. The experimental biceps femoris pain led to reductions in hip extensor moments, knee flexor and lateral rotator moments. No changes in lower extremity kinematics and EMG activity in any of the recorded muscles were observed. It is concluded that experimental muscle pain in the biceps femoris leads to changes in the gait pattern in agreement with unloading of the painful muscle. The changes are specific to the painful muscle. The present study provides support to the theory that musculoskeletal pain is a protective signal leading to changes in movement patterns that serve to unload the painful tissue. PMID- 21824789 TI - Fat mass limits lower-extremity relative strength and maximal walking performance in older women. AB - The purpose of this study was to determine if excess fat negatively affects relative strength and walking gait performance in overweight, older women. Twenty five older women (65-80 yr) were separated into normal weight (BMI<25 kg m(-2), n=11) and overweight groups (BMI 25 >= kg m(-2), n=14). Strength and rate of torque development (RTD) of the knee extensors and flexors, ankle plantarflexors and dorsiflexors were measured. Participants walked at standard and maximal speeds during which muscle activation, spatiotemporal and kinetic gait variables were measured. Relative to mass, overweight older women had 24% lower maximal torque and 38% lower RTD than normal weight women. Maximal walking speed was slower in overweight (1.25+/-0.22 vs. 1.54+/-0.25 m s(-1), P=0.004) and was correlated to strength (r=0.53, P<0.01) and fat mass (r=-0.65, P=0.001). At maximal speed, overweight had 11% lower vertical ground reaction force relative to mass, 8% slower stride rate, 12% shorter strides, 13% longer foot-ground contact times, 21% longer double-limb support times, 65% greater knee extensor and 78% greater plantarflexor activation (P<0.05). Overweight, older women demonstrated altered gait and reduced walking performance related to poor relative strength and rate of torque development of lower-extremity muscles. PMID- 21824790 TI - Measuring strategic control in artificial grammar learning. AB - In response to concerns with existing procedures for measuring strategic control over implicit knowledge in artificial grammar learning (AGL), we introduce a more stringent measurement procedure. After two separate training blocks which each consisted of letter strings derived from a different grammar, participants either judged the grammaticality of novel letter strings with respect to only one of these two grammars (pure-block condition), or had the target grammar varying randomly from trial to trial (novel mixed-block condition) which required a higher degree of conscious flexible control. Random variation in the colour and font of letters was introduced to disguise the nature of the rule and reduce explicit learning. Strategic control was observed both in the pure-block and mixed-block conditions, and even among participants who did not realise the rule was based on letter identity. This indicated detailed strategic control in the absence of explicit learning. PMID- 21824791 TI - Evaluating the feasibility of measures of motor threshold and cortical silent period as predictors of outcome after temporal lobe epilepsy surgery. AB - INTRODUCTION: Although it is well known that ES alters cortical excitability, little is known about the relationship between ES outcome and cortical excitability. Transcranial magnetic stimulation has been successfully used to evaluate cortical excitability in epilepsy patients. The present study aimed to assess the value of the motor threshold (MT) and cortical silent period (CSP) as predictors of the outcome of temporal lobe epilepsy surgery (TLES). MATERIALS AND METHODS: Epileptic foci in the epilepsy patients were identified via video electroencephalography (v-EEG) monitoring, brain magnetic resonance imaging (MRI), single-photon emission computed tomography (SPECT), and positron emission tomography (PET), and neurophysiological testing. MT, CSP-150, and CSP-max were measured in 10 epilepsy patients on both the ipsilateral and contralateral side of the epileptic focus 1 week before and 3 months after TLES. Pre- and post operative MT and CSP measurements were compared, and the results were interpreted based on the clinical outcome of TLES. RESULTS: Mean follow-up period was 28.8 months. In all, 8 patients were seizure-free post TLES, whereas in 2 patients seizures persisted. No significant differences were observed in ipsilateral or contralateral hemisphere MT measurements before and after surgery. Both CSP-150 and CSP-max values in the non-focal hemispheres decreased in the 8 patients that were seizure-free post TLES, whereas no differences were observed in the 2 patients with seizures that persisted post TLES. CONCLUSIONS: The present findings indicate that monitoring pre- and post-TLES CSP changes may be predictive of the early clinical outcome of TLES. PMID- 21824792 TI - Gender as a significant predictor of intravesical recurrence in patients with urothelial carcinoma of the upper urinary tract following nephroureterectomy. AB - OBJECTIVES: To retrospectively assess the significance of gender as a predictor of intravesical recurrence following nephroureterectomy for urothelial carcinoma of the upper urinary tract (UC-UUT). MATERIALS AND METHODS: This study included 502 consecutive patients (360 male and 142 female) who were diagnosed as having clinically localized UC-UUT and underwent nephroureterectomy. Clinicopathologic outcomes of these patients were analyzed focusing on the impact of gender. RESULTS: The incidence of intravesical recurrence in male patients (41.9%) was significantly greater than that in female patients (27.5%). Despite the lack of significant differences in cancer-specific and overall survivals with respect to gender, the intravesical recurrence-free survival in male patients was significantly worse than that in female patients. Of several parameters examined, univariate analysis identified gender, tumor site, and tumor focality as significant predictors of intravesical recurrence following nephroureterectomy. Of these, only gender and tumor site appeared to be independently associated with intravesical recurrence-free survival on multivariate analysis. Furthermore, there was a significant difference in intravesical recurrence-free survival according to positive numbers of these two independent factors; that is, intravesical recurrence occurred in 12 of 55 patients who were negative for both risk factors (21.8%), 96 of 280 positive for a single risk factor (34.3%), and 82 of 167 positive for both risk factors (49.1%). CONCLUSIONS: The incidence of intravesical recurrence following nephroureterectomy for UC-UUT is comparatively high. Therefore, it would be potentially important to perform careful follow-up targeting intravesical recurrence for such patients, particularly for male patients and/or patients with tumor located at the ureter. PMID- 21824793 TI - Smoking and adverse outcomes at radical prostatectomy. AB - BACKGROUND: Multiple large epidemiologic studies have examined the relationship between smoking and prostate cancer incidence and mortality only to arrive at contradictory results. In this series, we studied the effect of smoking on pathologic outcomes and biochemical recurrence in a cohort of men undergoing radical prostatectomy. METHODS: We identified 630 men who underwent radical prostatectomy between 1989 and 2005 who had detailed smoking histories. There were 321 smokers and 309 nonsmokers. Pathologic outcomes included prostate weight, volume of cancer, volume of high grade cancer, margin status, seminal vesicle involvement, extraprostatic extension, perineural invasion, angiolymphatic invasion, and the presence of nodal metastasis. Biochemical recurrence was defined as a postoperative PSA >= 0.1 ng/ml. Univariate analysis and multivariate linear and Cox regression were used to study the impact of smoking on these outcomes. RESULTS: The volume of cancer (2.54 vs. 2.16 ml, P = 0.016) and the volume of high grade cancer (0.58 vs. 0.28 ml, P = 0.004) were greater in smokers compared with nonsmokers. Smoking independently predicted greater volumes of cancer and high grade cancer in multivariate analysis. Heavy smokers (>=20 pack-year history) had a greater risk of biochemical recurrence on univariate survival analysis. Smoking also predicted a greater risk of biochemical recurrence on Cox regression, the magnitude of which was approximately 1% per pack-year smoked. CONCLUSIONS: Smoking is associated with adverse pathologic features and a higher risk of biochemical recurrence in men undergoing radical prostatectomy. If confirmed by additional studies, smoking history may need to be included into risk assessment models. PMID- 21824794 TI - Dynamic multi-coil shimming of the human brain at 7 T. AB - High quality magnetic field homogenization of the human brain (i.e. shimming) for MR imaging and spectroscopy is a demanding task. The susceptibility differences between air and tissue are a longstanding problem as they induce complex field distortions in the prefrontal cortex and the temporal lobes. To date, the theoretical gains of high field MR have only been realized partially in the human brain due to limited magnetic field homogeneity. A novel shimming technique for the human brain is presented that is based on the combination of non-orthogonal basis fields from 48 individual, circular coils. Custom-built amplifier electronics enabled the dynamic application of the multi-coil shim fields in a slice-specific fashion. Dynamic multi-coil (DMC) shimming is shown to eliminate most of the magnetic field inhomogeneity apparent in the human brain at 7 T and provided improved performance compared to state-of-the-art dynamic shim updating with zero through third order spherical harmonic functions. The novel technique paves the way for high field MR applications of the human brain for which excellent magnetic field homogeneity is a prerequisite. PMID- 21824795 TI - Exchange facilitated indirect detection of hyperpolarized 15ND2-amido-glutamine. AB - Hyperpolarization greatly enhances opportunities to observe in vivo metabolic processes in real time. Accessible timescales are, however, limited by nuclear spin relaxation times, and sensitivity is limited by magnetogyric ratios of observed nuclei. The majority of applications to date have involved direct (13)C observation of metabolites with non-protonated carbons at sites of interest ((13)C enriched carbonyls, for example), a choice that extends relaxation times and yields moderate sensitivity. Interest in (15)N containing metabolites is equally high but non-protonated sites are rare and direct (15)N observation insensitive. Here an approach is demonstrated that extends applications to protonated (15)N sites with high sensitivity. The normally short relaxation times are lengthened by initially replacing protons (H) with deuterons (D) and low sensitivity detection of (15)N is avoided by indirect detection through protons reintroduced by H/D exchange. A pulse sequence is presented that periodically samples (15)N polarization at newly protonated sites by INEPT transfer to protons while returning (15)N magnetization of deuterated sites to the +Z axis to preserve polarization for subsequent samplings. Applications to (15)ND(2)-amido glutamine are chosen for illustration. Glutamine is an important regulator and a direct donor of nitrogen in cellular metabolism. Potential application to in vivo observation is discussed. PMID- 21824796 TI - Vitamin B12 deficiency and phenylketonuria. AB - The literature regarding the vitamin B(12) status of patients with phenylketonuria was reviewed. Adequate amounts of B(12) are provided in products used in dietary treatment; however, a number of case reports and cohort studies document deficiency in those who have discontinued taking amino acid, mineral and vitamin supplements but who continue to eat only very limited amounts of natural protein. Symptoms and signs of B(12) deficiency are variable but severe deficiency may cause serious neurological disease. Nitrous oxide anaesthesia is a particular risk. It is recommended that plasma total homocysteine and plasma or urinary methylmalonate should be routinely measured, as they are more sensitive markers of deficiency than serum B(12) concentrations. Functional B(12) deficiency can occur in the presence of a normal B(12) concentration. PMID- 21824797 TI - Finite element prediction of proximal femur fracture pattern based on orthotropic behaviour law coupled to quasi-brittle damage. AB - The purpose of this study was to develop a finite element model based on continuum damage mechanics in order to simulate the profile of the fractured area of proximal femur and the complete force-displacement curve from the beginning until complete fracture. The model was developed in term of anisotropic behaviour law coupled to quasi-brittle damage to describe the progressive crack initiation and propagation within proximal femoral. A damage law was developed and implemented into a finite element code (Abaqus) based on experimental observations. To illustrate the potential of the current approach, the right adult human femur previously investigated by Keyak and Falkinstein (Model B: male, age 61) was simulated until complete fracture under one-legged stance load. The femur fracture profile was predicted and compared to clinical observed results. Good agreements were obtained suggesting that the proposed damage model could be used correctly to simulate the force-displacement curve, the fracture type and to simulate the progressive propagation of the crack paths. Present model can contribute towards the development of diagnostic tool that can detect osteoporotic fracture for aged patients in an early stage and predict bone strength accurately. PMID- 21824798 TI - Experimental investigation of the flow of a blood analogue fluid in a replica of a bifurcated small artery. AB - The scope of this work is to study the pulsatile flow of a blood mimicking fluid in a micro channel that simulates a bifurcated small artery, in which the Fahraeus-Lindqvist effect is insignificant. An aqueous glycerol solution with small amounts of xanthan gum was used for simulating viscoelastic properties of blood and in vivo flow conditions were reproduced. Local flow velocities were measured using micro Particle Image Velocimetry (MU-PIV). From the measured velocity distributions, the wall shear stress (WSS) and its variation during a pulse were estimated. The Reynolds numbers employed are relatively low, i.e. similar to those prevailing during blood flow in small arteries. Experiments both with a Newtonian and a non-Newtonian fluid (having asymptotic viscosity equal to the viscosity of the Newtonian one) proved that the common assumption that blood behaves as a Newtonian fluid is not valid for blood flow in small arteries. It was also shown that the outer wall of the bifurcation, which is exposed to a lower WSS, is more predisposed to atherosclerotic plaque formation. Moreover, this region in small vessels is shorter than the one in large arteries, as the developed secondary flow decays faster. Finally, the WSS values in small arteries were found to be lower than those in large ones. PMID- 21824799 TI - A randomized pilot trial of estrogen replacement therapy in post-menopausal women with Parkinson's disease. AB - OBJECTIVE: To assess short-term safety and tolerability of estrogen replacement therapy in post-menopausal women with Parkinson's disease (PD). METHODS: In a multi-center randomized, double-blind, placebo-controlled pilot trial, post menopausal women with PD and motor fluctuations received either 0.625 mg/day of conjugated equine estrogens or matching placebo for 8 weeks. The primary outcome was the ability of participants to complete the trial. Other outcome measures included adverse events and changes from baseline to Week 8 in Unified PD Rating Scale scores, "on" time, dyskinesia ratings, and neuropsychological test results. RESULTS: Twenty-three women (age 62.9(6.3) years, total Unified PD Rating 25.0(13.4), 8.8(6.0) years since symptom onset) were enrolled. There were no serious adverse events. One subject withdrew due to worsening of tremor and dystonia. The most commonly reported adverse events were vaginal spotting, breast enlargement and breast tenderness. The estrogen group showed improved total and motor Unified PD Rating scores although these did not reach statistical significance (mean changes from baseline, estrogen vs. placebo: Total -5.0 vs. 2.8, treatment effect = -7.8, p = 0.10; Motor -3.0 vs. 2.4, treatment effect = 5.4, p = 0.16). CONCLUSIONS: Estrogen replacement therapy was safe and well tolerated over 8 weeks in post-menopausal women with advanced PD. This pilot data suggests that estrogen replacement may be associated with improvement in motor symptoms. While larger studies of longer duration are necessary to determine the effects of estrogen in PD, the complex risk/benefit profile and continued controversy surrounding estrogen are obstacles to clinical trials. PMID- 21824800 TI - Absence of the inferior portion of the trapezius muscle in three family members. AB - Absence of the trapezius muscle is regarded as relatively rare. This report presents the clinical observations for absence of the inferior portion of the trapezius muscle in three family members that were later confirmed in vivo with magnetic resonance imaging. The absences occurred in two sisters and the son of one sister. The inferior portion of trapezius was absent bilaterally in the sisters but was absent on the left side only in the son. These findings support the notion of a genetic link as one of the possible causes of this aplasia. There were overt functional implications for the absence of the lower portion of the trapezius in one female where there was high demand on the upper limbs in competitive swimming. PMID- 21824801 TI - Gibberellin control of stamen development: a fertile field. AB - Stamen development is governed by a conserved genetic pathway, within which the role of hormones has been the subject of considerable recent research. Our understanding of the involvement of gibberellin (GA) signalling in this developmental process is further advanced than for the other phytohormones, and here we review recent experimental results in rice (Oryza sativa) and Arabidopsis (Arabidopsis thaliana) that have provided insight into the timing and mechanisms of GA regulation of stamen development, identifying the tapetum and developing pollen as major targets. GA signalling governs both tapetum secretory functions and entry into programmed cell death via the GAMYB class of transcription factor, the targets of which integrate with the established genetic framework for the regulation of tapetum function at multiple hierarchical levels. PMID- 21824802 TI - Mutational analysis of PTEN/PIK3CA/AKT pathway in oral squamous cell carcinoma. AB - The phosphoinositide 3-kinase (PI3K)/v-akt murine thymoma (AKT) viral oncogene pathway is involved in regulating the signaling of multiple biological processes such as apoptosis, metabolism, cell proliferation, and cell growth. Mutations in the genes associated with the PI3K/AKT pathway including PI3K, AKT, RAS and PTEN, are infrequently found within head and neck squamous cell carcinoma and more specifically are rarely reported in oral squamous cell carcinoma (OSCC) cases. We aimed to investigate the frequency of mutations in AKT1, PTEN, PIK3CA, and RAS (K RAS, N-RAS, H-RAS) genes in 37 cases of oral squamous cell carcinoma (OSCC). Mutational analysis of PTEN, RAS, PIK3CA and AKT genes was performed using chip based matrix-assisted laser desorption time-of-flight (MALDI-TOF) mass spectrometry and by direct sequencing. The only gene mutated in our series was the PIK3CA. Missense mutations of the PIK3CA gene were found in 4 of our cases (10.8%); no correlation has been found with oral location, stage and survival. The absence of mutations in AKT1, PTEN, and RAS genes in the present study is in accordance with previous studies confirming that these genes are rarely mutated in OSCC. Our data confirm that PIK3CA is important to OSCC tumorigenesis and can contribute to oncogene activation of the PIK3CA/AKT pathway in OSCC. The knowledge of the PIK3CA's involvement in OSCC is important because a specific kinase inhibitor could be considered as a future therapeutic option for OSCC patients with PIK3CA mutations. PMID- 21824803 TI - Personalized medicine for mucositis: Bayesian networks identify unique gene clusters which predict the response to gamma-D-glutamyl-L-tryptophan (SCV-07) for the attenuation of chemoradiation-induced oral mucositis. AB - Gamma-D-glutamyl-L-tryptophan (SCV-07) demonstrated an overall efficacy signal in ameliorating oral mucositis (OM) in a clinical trial of head and neck cancer patients. However, not all SCV-07-treated subjects responded positively. Here we determined if specific gene clusters could discriminate between subjects who responded to SCV-07 and those who did not. Microarrays were done using peripheral blood RNA obtained at screening and on the last day of radiation from 28 subjects enrolled in the SCV-07 trial. An analytical technique was applied that relied on learned Bayesian networks to identify gene clusters which discriminated between individuals who received SCV-07 and those who received placebo, and which differentiated subjects for whom SCV-07 was an effective OM intervention from those for whom it was not. We identified 107 genes that discriminated SCV-07 responders from non-responders using four models and applied Akaike Information Criteria (AIC) and Bayes Factor (BF) analysis to evaluate predictive accuracy. AIC were superior to BF: the accuracy of predicting placebo vs. treatment was 78% using BF, but 91% using the AIC score. Our ability to differentiate responders from non-responders using the AIC score was dramatic and ranged from 93% to 100% depending on the dataset that was evaluated. Predictive Bayesian networks were identified and functional cluster analyses were performed. A specific 10 gene cluster was a critical contributor to the predictability of the dataset. Our results demonstrate proof of concept in which the application of a genomics-based analytical paradigm was capable of discriminating responders and non-responders for an OM intervention. PMID- 21824804 TI - The role of Cripto-1 in the tumorigenesis and progression of oral squamous cell carcinoma. AB - Oral squamous cell carcinoma (OSCC), the most common malignancy of the oral cavity, remains a lethal disease in over 50% of cases diagnosed annually, due mostly to late detection of this cancer in its advanced stages despite the easy accessibility of the oral cavity for regular examinations. Cripto-1 is a member of the epidermal growth factor (EGF)-CFC protein family and is involved in the activation of several different signaling pathways during embryonic development and cellular transformation. Although the Cripto-1 protein is overexpressed in several human cancers including breast, colon, cervix, gastric, and pancreatic cancer, no prior study has evaluated Cripto-1 expression in OSCC. Therefore, our aims in this study were to examine Cripto-1 expression in clinical samples of OSCC patients using immunohistochemistry, to analyze the correlation between Cripto-1 expression and clinicopathologic parameters, and to identify the oncogenic roles of Cripto-1 in OSCC cell lines. Both epithelial dysplasia (73.3%) and OSCC (55.5%) tissue samples showed significantly higher expression of Cripto 1 than normal mucosa (20%) (p=0.031). In the OSCC samples, there was a significant correlation between Cripto-1 expression and the histological differentiation of OSCC (p=0.015) and a high PCNA index (p=0.011). The in vitro cell proliferation assays demonstrated that recombinant human Cripto-1 (rhCripto 1) induced both SCC-4 and SCC-25 cells to proliferate as compared with control cells (p<0.05 and p<0.01, respectively). In in vitro migration assays, treatment of SCC-4 and SCC-25 cells with rhCripto-1 protein induced a 2.4-fold and 1.7-fold increase in cell migration, respectively (p=0.000 and p=0.008, respectively). Taken together, our data suggest that Cripto-1 plays a role in the malignant transformation of the oral mucosa and is involved in the tumorigenesis and progression of OSCC by promoting the growth and migration of malignant cells. PMID- 21824805 TI - Viruses exploiting peroxisomes. AB - Viruses that are of great importance for global public health, including HIV, influenza and rotavirus, appear to exploit a remarkable organelle, the peroxisome, during intracellular replication in human cells. Peroxisomes are sites of lipid biosynthesis and catabolism, reactive oxygen metabolism, and other metabolic pathways. Viral proteins are targeted to peroxisomes (the spike protein of rotavirus) or interact with peroxisomal proteins (HIV's Nef and influenza's NS1) or use the peroxisomal membrane for RNA replication. The Nef interaction correlates strongly with the crucial Nef function of CD4 downregulation. Viral exploitation of peroxisomal lipid metabolism appears likely. Mostly, functional significance and mechanisms remain to be elucidated. Recently, peroxisomes were discovered to play a crucial role in the innate immune response by signaling the presence of intracellular virus, leading to the first rapid antiviral response. This review unearths, interprets and connects old data, in the hopes of stimulating new and promising research. PMID- 21824806 TI - Nucleoproteins and nucleocapsids of negative-strand RNA viruses. AB - A hallmark of negative-strand RNA viruses (NSVs) is that their genomes never exist as free RNA, but instead are always assembled with many copies of a single nucleoprotein (N) to form highly stable nucleocapsids. Moreover, viral genomes are the only RNAs in infected cells that are assembled with N. The mechanism by which this specific association occurs, for both the segmented (s) and non segmented (ns) viruses, has recently become clearer due to our expanding knowledge of N protein and nucleocapsid structures. PMID- 21824807 TI - Autoxidation of giant extracellular hemoglobin of Glossoscolex paulistus: molecular mechanism and oligomeric implications. AB - Giant extracellular hemoglobins present high redox stability due to their supramolecular architecture, high number of polypeptide chains and great compaction of protein subunits. The oligomeric assembly and the changes in the polypeptidic structure can influence the autoxidation rate of the heme proteins, being that different nucleophiles can act in this process due to pH alterations. In the present work, we have studied the autoxidation rate of whole Glossoscolex paulistus (HbGp) giant extracellular hemoglobin, as well as the autoxidation rate of the isolated d monomer of HbGp studied regarding pH variations. The kinetic decay behavior is dependent on pH, presenting mono-exponential or bi-exponential character, depending on the oligomeric state of the protein. Thus, the oligomeric dissociation in specific pH values demonstrated a bi-exponential kinetic decay. A mono-exponential kinetic behavior was verified in the pH range of 5.9-7.3, which is assigned to the native whole protein. In alkaline medium, the presence of hydroxide ions leads the autoxidation of whole hemoglobin to a complex behavior, which is described by the combination of two first-order kinetics. The slow process occurs due to the d monomer autoxidation. At pH 7.0, the kinetic is mono exponential, indicating a highly conserved oligomeric structure. In acid medium, the proton-catalyzed autoxidation occurs both on the whole hemoglobin and in the d monomer. It has been found that proximal and distal histidines develop determinant roles regarding the autoxidation rate, being that the distal histidine controls the contact of ligands with the ferrous center through a very interesting "swinging door" mechanism. Despite the significant sensitivity of the distal histidine to the presence of protons, water molecules and anions, the influence of chemical changes around the heme, such as pH changes, is much more effective in hemoproteins without this amino acid as distal residue. This fact denotes the ability of HbGp to adapt to environmental disturbances caused by the presence of the distal histidine, which is responsible for the great redox and oligomeric stabilities encountered in HbGp. PMID- 21824808 TI - Vibrational analysis of 4-amino pyrazolo (3,4-d) pyrimidine A joint FTIR, Laser Raman and scaled quantum mechanical studies. AB - The FTIR and Laser Raman spectra of 4-amino pyrazolo (3,4-d) pyrimidine have been measured in the regions 4000-400 cm(-1) and 3500-100 cm(-1), respectively. Utilizing the observed FTIR and Laser Raman data, a complete vibrational assignment and analysis of the fundamental modes of the title compound were carried out. The vibrational frequency which were determined experimentally are compared with those theoretically from force field calculation based on ab initio HF/6-311+G**(d,p) and standard B3LYP/6-311+G**(d,p) methods and basis set combinations for optimized geometries. The observed FTIR and Laser Raman vibrational frequencies were analysed and compared with the theoretically predicted vibrational frequencies. The assignments of bands to various normal modes of the molecules were also carried out. A detailed interpretation of the infrared and Raman spectra of 4-amino pyrazolo (3,4-d) pyrimidine [4AP(3,4-D)P] is also reported based on total energy distribution (TED). The calculated HOMO and LUMO energies shows that charge transfer occur within the molecule. The theoretical FT-IR and FT-Raman spectra for the title molecule have also been constructed. PMID- 21824809 TI - Comparison of structural, textural and thermal characteristics of pure and acid treated bentonites from Aleksinac and Petrovac (Serbia). AB - Bentonite samples collected from vicinity of Petrovac and Aleksinac were treated with different sulfuric acid molarities. Acid attack dissolved the octahedral sheets by interlayer and edge attack. The effects of the H(2)SO(4) acid caused an exchange of Al(3+), Fe(3+) and Mg(2+) with H(+) ions leading to a modification of the smectite crystalline structure. The Mg and Fe substitution in the octahedral sheets promoted the dispersion of corresponding layers and formation of amorphous silicon. The activated bentonites, after the treatment of sulfuric acid, exhibited a lower cation-exchange capacity (CEC) and significant increase of specific surface area from 6 to 387 m(2) g(-1) (bentonite from Petrovac) and from 11 to 306 m(2) g(-1) (bentonite from Aleksinac). The acid reaction caused a splitting of particles within the octahedral sheet which led to an increase in specific surface area and decrease in CEC in both bentonites. PMID- 21824810 TI - Solution-phase synthesis of silver nanodiscs in HPMC-matrix and simulation of UV vis extinction spectra using DDA based method. AB - Present investigation demonstrates a very simple seed-mediated route, using hydroxypropyl methyl cellulose (HPMC) as stabilizing agent, for the synthesis of silver nanodiscs in aqueous solution. Central to the concept of seed-mediated growth of nanoparticles is that small nanoparticle seeds serve as nucleation centres to grow nanoparticles to a desired size and shape. It is found that the additional citrate ions in the growth solution play the pivotal role in controlling the size of silver nanodiscs. Similar to the polymers in the solution, citrate ions could be likewise dynamically adsorbed on the growing silver nanoparticles and promote the two-dimensional (2D) growth of nanoparticles. Morphological, structural, and spectral changes associated with the seed-mediated growth of the nanoparticles in the presence of HPMC are characterized using UV-vis and TEM spectroscopic studies. Metal nanoparticles have received increasing attention for their peculiar capability to control local surface plasmon resonance (LSPR) when interacting with incident light waves. Extensive simulation study of the UV-vis extinction spectra of our synthesized silver nanodiscs has been carried out using discrete dipole approximation (DDA) methodology. PMID- 21824811 TI - Synthesis, characterization and biological activity of some new VO(IV), Co(II), Ni(II), Cu(II) and Zn(II) complexes of chromone based NNO Schiff base derived from 2-aminothiazole. AB - Coordination compounds of VO(IV), Co(II), Ni(II), Cu(II) and Zn(II) with the Schiff base obtained through the condensation of 2-aminothiazole with 3-formyl chromone were synthesized. The compounds were characterized by (1)H, (13)C NMR, UV-Vis, IR, Mass, EPR, molar conductance and magnetic susceptibility measurements. The Cu(II) complex possesses tetrahedrally distorted square planar geometry whereas Co(II), Ni(II), and Zn(II) show distorted tetrahedral geometry. The VO(IV) complex shows square pyramidal geometry. The cyclic voltammogram of Cu (II) complex showed a well defined redox couple Cu(II)/Cu(I) with quasireversible nature. The antimicrobial activity against the species Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus, Bacillus subtilis, Candida albigans and Aspergillus niger was screened and compared to the activity of the ligand. Emission spectrum was recorded for the ligand and the metal(II) complexes. The second harmonic generation (SHG) efficiency was measured and found to have one fourth of the activity of urea. The SEM image of the copper(II) complex implies that the size of the particles is 2 MUm. PMID- 21824812 TI - Clinical features and outcomes of acute kidney injury among patients with acute hepatitis A. AB - BACKGROUND: Although acute hepatitis A is usually self-limited, the clinical manifestations can vary from mild to severe liver dysfunction. However, little is known about risk factors for and outcomes of acute kidney injury (AKI) in acute hepatitis A. OBJECTIVES: To identify the risk factors for and outcomes of AKI in acute hepatitis A. STUDY DESIGN: We identified 396 patients with acute hepatitis A, which registered between January 2006 and June 2009 at a tertiary care university hospital. Retrospective case-control studies were conducted in order to identify risk factors for AKI. RESULTS: Thirty patients (7.6%) developed AKI. On multivariate analysis, fulminant hepatitis, leukocytosis, and elevated CRP were independent risk factors for AKI associated with hepatitis A, and higher total bilirubin, leukocytosis, and elevated CRP were independent risk factor for AKI within nonfulminant hepatitis A. Of the 30 patients with AKI, 23 (76.7%) patients fully recovered, 2 patients maintained hemodialysis after hospital discharge and 5 patients died due to hepatic failure without recovery from AKI. Among 20 patients with AKI in nonfulminant subgroup, 19 patients (95%) recovered without hemodialysis. CONCLUSIONS: AKI is not a rare complication of acute hepatitis A and severity of hepatitis and hepatic injury influence the development of AKI in acute hepatitis A. PMID- 21824813 TI - Dengue virus isolation relying on antibody-dependent enhancement mechanism using FcgammaR-expressing BHK cells and a monoclonal antibody with infection-enhancing capacity. AB - BACKGROUND: Virus isolation is the most reliable evidence of dengue virus (DENV) infection. However, conventional virus isolation methods generally posses lower sensitivity and are time consuming as compared to other diagnostic methods such as detection of viral genome by RT-PCR, and determination of NS1 antigen and anti DENV antibody by ELISA. OBJECTIVES: A virus isolation method relying on the antibody-dependent enhancement mechanism was established and the assay's efficacy in DENV isolation was confirmed. STUDY DESIGN: FcgammaR-expressing BHK cells were used for DENV isolation from patient serum samples in the presence of a flavivirus-group reactive monoclonal antibody, mAb4G2, which possesses DENV infection-enhancement activity. DENV genome copy numbers in the culture supernatant fluids of FcgammaR-expressing BHK cells were assessed and compared to those of parent BHK cells and C6/36 mosquito cells, a cell line commonly used for DENV isolation. RESULTS: The virus titer levels were higher in the culture supernatant fluid of FcgammaR-expressing BHK cells in the presence of enhancing antibody in comparison with other cell lines using laboratory-established strains and some clinical samples. DENV was isolated from 7 of 16 serum samples by using FcgammaR-expressing BHK cells in the presence of mAb4G2, but not by using cell lines commonly employed in conventional isolation assays, the FcgammaR-negative BHK cells and C6/36 cell lines. CONCLUSIONS: The results demonstrate that FcgammaR-expressing BHK cell line in the presence of antibodies, which possess antibody dependent enhancement (ADE) activity, is a useful tool for DENV isolation. PMID- 21824814 TI - Reorganization of multi-muscle and joint withdrawal reflex during arm movements in post-stroke hemiparetic patients. AB - OBJECTIVES: To investigate the behavior of the nociceptive withdrawal reflex (NWR) in the upper limb during reaching and grasping movements in post-stroke hemiparetic patients. METHODS: Eight patients with chronic stroke and moderate motor deficits were included. An optoelectronic motion analysis system integrated with a surface EMG machine was used to record the kinematic and EMG data. The NWR was evoked through a painful electrical stimulation of the index finger during a movement which consisted of reaching out, picking up a cylinder, and returning it to the starting position. RESULTS: We found that: (i) the NWR is extensively rearranged in hemiparetic patients, who were found to present different kinematic and EMG reflex patterns with respect to controls; (ii) patients partially lose the ability to modulate the reflex in the different movement phases; (iii) the impairment of the reflex modulation occurs at single-muscle, single-joint and multi-joint level. CONCLUSIONS: Patients with chronic and mild-moderate post stroke motor deficits lose the ability to modulate the NWR dynamically according to the movement variables at individual as well as at multi-muscle and joint levels. SIGNIFICANCE: The central nervous system is unable to use the NWR substrate dynamically and flexibly in order to select the muscle synergies needed to govern the spatio-temporal interaction among joints. PMID- 21824815 TI - Purification and characterization of a novel aspartic protease from basidiomycetous yeast Cryptococcus sp. S-2. AB - An aspartic protease (Cap1) was purified from basidiomycetous yeast Cryptococcus sp. S-2 (FERM ABP-10961) using HiTrap DEAE FF column and HiTrap Q HP column chromatography with azocasein as a substrate. Cap1 has a molecular mass of 34 kDa on SDS-PAGE. It was stable up to 50 degrees C with maximum activity at 30 degrees C. Maximum proteolytic activity was observed at pH 5.0. Cap1 was stable in the pH range 3.0-7.0. Its enzyme activity was strongly inhibited by pepstatin A, an inhibitor of aspartic proteases, indicating that Cap1 is an aspartic protease. Cap1 hydrolyzed protein substrates, including BSA, hemoglobin, alpha-casein, beta casein, and kappa-casein. It showed activity on synthetic substrates, such as MOCAc-Gly-Lys-Pro-Ile-Leu-Phe-Phe-Arg-Leu-Lys(Dnp)-D-Arg-NH2 and MOCAc-Ala-Pro Ala-Lys-Phe-Phe-Arg-Leu-Lys(Dnp)-NH2. Hydrolysis of the oxidized insulin B chain followed by amino acid sequencing analysis of the cleavage products revealed that 9 of its 30 peptide bonds were hydrolyzed by Cap1. This result was similar to that observed with pig pepsin A and human pepsin A. Cap1 also exhibited milk clotting activity. We cloned the cDNA of CAP1 gene, which contained a 1254 bp open reading frame encoding a protein of 417 amino acid residues. Homology search in the NCBI database revealed that the amino acid sequence of Cap1 showed less than 39% identity to other known proteins. Therefore, we proposed that Cap1 is a novel aspartic protease. PMID- 21824816 TI - Acetyl xylan esterase of Aspergillus ficcum catalyzed the synthesis of peracetic acid from ethyl acetate and hydrogen peroxide. AB - Recombinant acetyl xylan esterase (rAXE) of Aspergillus ficcum catalyzed the synthesis of peracetic acid (PAA) from ethyl acetate and hydrogen peroxide. Ten micrograms of rAXE catalyzed the synthesis of 1.34 mM of PAA, which can be used for the pretreatment of cellulosic biomass in situ. PMID- 21824817 TI - Activity and stability enhancement of alpha-amylase treated with sub- and supercritical carbon dioxide. AB - Various physical, chemical and genetic approaches have been applied in order to enhance enzyme stability and activity. In this study, the aim was to investigate the capability of sub- and supercritical carbon dioxide to alter the stability and activity of alpha-amylase as an alternative technique. The effects of operational parameters such as pressure (50-300 bar), temperature (28-80 degrees C), CO2 flow (2-10 g min-1) and time (60-180 min) were evaluated in regard to the activity and stability of fungal based alpha-amylase from Aspergillus oryzea. The activity of untreated enzyme was determined as 17,726 MUmol/ml/min. While both sub- and supercritical conditions enhanced the activity, the increase in flow rate had an adverse effect and the activity was decreased by 28.9% at a flow rate of 10 g min-1 under supercritical conditions. Nuclear magnetic resonance (NMR) spectra of untreated enzyme and treated samples exhibiting the lowest and the highest activities were almost identical except for the chemical shifts observed at the lowest activity sample from 4.0 to 4.4 ppm which were assigned to protons of hydrogen-bonded groups. Optimum conditions were determined as 240 bar, 41 degrees C, 4 g min-1 CO2 flow and 150 min of process duration yielding 67.7% (29,728 MUmol/ml/min) higher activity than the untreated enzyme providing fundamental basis for enzymatic applications. PMID- 21824818 TI - Prevalence of restless legs syndrome in the rural town of Cassia dos Coqueiros in Brazil. AB - OBJECTIVE: To estimate the prevalence and evaluate the characteristics and severity of restless legs syndrome (RLS) in an urban Brazilian community. METHODS: A transversal study was conducted over an 18-month period. A neurologist conducted 1155 interviews using the diagnostic criteria of the International Restless Legs Syndrome Study Group (IRLSSG). RESULTS: The lifetime prevalence of RLS was found to be 6.40%. Prevalence during the last year, the last month, and the last week were found to be 5.71%, 5.36%, and 4.15%, respectively. A greater proportion of women met diagnostic criteria for RLS compared to men (OR: 2.63, CI 95%: 1.54-4.51). Furthermore, participants with low monthly family income (<$1575 USD) had a lower prevalence of disease compared to those with a high monthly family income (>$1575 USD) (OR: 2.91, CI 95%: 1.41-5.98). CONCLUSIONS: This is the first epidemiologic study of RLS conducted in a Brazilian population. The overall prevalence of disease and the greater proportion of RLS in women found in this study are similar to the findings of other studies conducted in western countries. The association of RLS with high family income is unpublished and should be confirmed in subsequent studies. PMID- 21824819 TI - Development of a next day functioning measure to assess the impact of sleep disturbance due to restless legs syndrome: the restless legs syndrome-next day impact questionnaire. AB - OBJECTIVES: Symptoms of Restless Legs Syndrome (RLS) affect patients' quality and duration of sleep, which can have next day sequelae detrimental to daytime performance. To date, no measure sufficiently assesses such sequelae. This study aimed to develop a new self-reported outcome measure to assess the impact of disturbed sleep due to RLS on next day functioning and to support its content validity. METHODS: The development of the Restless Legs Syndrome-Next Day Impact (RLS-NDI) questionnaire included concept elicitation interviews with RLS patients in the United States (n=20); grounded theory data collection and analysis methods; and review by clinical and measurement experts to generate items, responses, and instructions. Cognitive interviews (n=15) were conducted to ensure understanding of the RLS-NDI, concept comprehensiveness, and identification of any necessary item revisions. RESULTS: Impacts on next day functioning attributed to disturbed sleep due to RLS symptoms included activities of daily living (i.e., work, household chores), cognitive functioning (i.e., concentration, forgetfulness, mental tiredness, alertness), emotional functioning (i.e., irritability, depressed mood), physical functioning (i.e., physical tiredness, active leisure activities), energy, daytime sleepiness, and social functioning (i.e., relationships, social activities/situations). The final measure consists of 14 items assessed "today" and rated on a numeric rating scale. CONCLUSIONS: The RLS-NDI is an evaluative tool with demonstrated content validity. PMID- 21824820 TI - Prevention of T cell activation by interference of internalized intravenous immunoglobulin (IVIg) with MHC II-dependent native antigen presentation. AB - Activation of self-reactive CD4(+) T cells plays a central role in the initiation and maintenance of autoimmune diseases. We recently reported that intravenous immunoglobulin (IVIg) inhibits the MHC II-restricted CD4(+) T cell activation induced by the presentation of immune complexes. Because native antigens can also play a role in the induction of several autoimmune diseases, we determined whether IVIg could also affect CD4(+) T cell activation following presentation of native antigens by APCs. Here we report that IVIg significantly reduces the activation of CD4(+) T cells by native ovalbumin. The inhibitory effect is FcgammaR-independent and occurs following internalization of IVIg inside APCs, where it interferes with the intracellular events leading to MHC II-dependent antigen presentation. The effect of IVIg on native antigen presentation could therefore contribute to dampen the autoimmune reaction by reducing CD4(+) T cell activation and the subsequent inflammatory response induced by these cells. PMID- 21824821 TI - Electroencephalography in clinical epilepsy research. AB - Electroencephalography (EEG) remains central to the investigation of epilepsy. This review discusses two clinical problems at the temporal extremes of neurophysiologic recording: evaluation of the clinical significance of individual spike discharges in benign epilepsy of childhood with centrotemporal spikes (BECTS), and prolonged (several days) continuous EEG monitoring in the ICU. BECTS is misdiagnosed often, and probably mis-treated often as well. Though the long term outcome is usually excellent, it remains unclear whether the individual epileptiform discharges have a clinical effect. Answering this question is difficult, in part because of the natural evolution of the epilepsy and its different appearance depending on wakefulness or sleep state, and also due to substantial methodologic problems in measuring short and long-term cognitive effects. Continuous EEG (CEEG) recording has grown remarkably over the last 10 years. It has proved crucial in the diagnosis of nonconvulsive status epilepticus (NCSE), especially in the ICU, given the usual lack of obvious clinical signs of seizures in most of these patients, many of whom are critically ill. Much progress has been made in agreeing on terminology for the EEG findings, but diagnosis is still complicated. More efficient and reliable technology is being developed to help process the massive amount of data captured by CEEG and make it more useful (and in a timely fashion) clinically. Still, it is not completely clear which patients should be monitored, for how long, and what is the best role for CEEG in assessing and adjusting treatment once the diagnosis has been made. Investigators are using CEEG to study "seizure burden," to help determine what are the long-term effects of nonconvulsive seizures and NCSE, and to help guide treatment and improve outcome. PMID- 21824822 TI - A qualitative assessment of a community pharmacy cognitive pharmaceutical services program, using a work system approach. AB - BACKGROUND: Although lack of time, trained personnel, and reimbursement have been identified as barriers to pharmacists providing cognitive pharmaceutical services (CPS) in community pharmacies, the underlying contributing factors of these barriers have not been explored. One approach to better understand barriers and facilitators to providing CPS is to use a work system approach to examine different components of a work system and how the components may impact care processes. OBJECTIVES: The goals of this study were to identify and describe pharmacy work system characteristics that pharmacists identified and changed to provide CPS in a demonstration program. METHODS: A qualitative approach was used for data collection. A purposive sample of 8 pharmacists at 6 community pharmacies participating in a demonstration program was selected to be interviewed. Each semistructured interview was audio recorded and transcribed, and the text was analyzed in a descriptive and interpretive manner by 3 analysts. Themes were identified in the text and aligned with 1 of 5 components of the Systems Engineering Initiative for Patient Safety (SEIPS) work system model (organization, tasks, tools/technology, people, and environment). RESULTS: A total of 21 themes were identified from the interviews, and 7 themes were identified across all 6 interviews. The organization component of the SEIPS model contained the most (n=10) themes. Numerous factors within a pharmacy work system appear important to enable pharmacists to provide CPS. Leadership and foresight by the organization to implement processes (communication, coordination, planning, etc.) to facilitate providing CPS was a key finding across the interviews. Expanding technician responsibilities was reported to be essential for successfully implementing CPS. CONCLUSIONS: To be successful in providing CPS, pharmacists must be cognizant of the different components of the pharmacy work system and how these components influence providing CPS. PMID- 21824823 TI - Separation of prescribing and dispensing in Malaysia: a summary of arguments. AB - The role of pharmacists has transformed significantly because of changes in pharmacists' training and population health demands. Within this context, community pharmacists are recognized as important health personnel for the provision of extended health services. Similarly, in Malaysia, the need to transform community pharmacy practice has been discussed by all interested parties; however, the transition has been slow due in part to the nonexistence of a dispensing separation policy between pharmacists and medical doctors in private community practices. For decades, medical doctors in private community practices have had the right to prescribe and dispense, thus diluting the role of community pharmacists because of overlapping roles. This article explores dispensing separation in Malaysia and, by taking into account the needs of health professionals and health care consumers, suggests a mechanism for how dispensing separation practice can be implemented. PMID- 21824824 TI - Characterizing specialized compounding in community pharmacies. AB - BACKGROUND: Compounding is a traditional role of pharmacists that declined with the availability of manufactured medicines. Compounding is now increasingly offered by community pharmacies as a specialized service, and there are calls for regulatory and practice standard changes. However, the characteristics of specialized compounding are not well understood. OBJECTIVES: The objective of this study was to conduct an in-depth exploration of the motivations, experiences, and practices of pharmacists who deliver "specialized compounding services" in Australian pharmacies. METHODS: In-depth interviews of 18 pharmacists responsible for compounding in pharmacies offering specialized compounding were conducted using a semistructured interview guide based on an organizational framework. Participants were selected using purposive sampling. Characteristics of specialized compounding practice compared with routine compounding and routine dispensing were explored. Interviews were audiotaped and transcribed verbatim, then analyzed using the method of "constant comparison" to identify emergent themes. RESULTS: Pharmacists providing specialized compounding reported that compared with their prior routine practice, they used a greater variety of ingredients and dosage forms for more clinical conditions, used different equipment and processes, and had upgraded facilities for handling compounded products. Patient and physician interactions were more involved and in the case of physicians, more collaborative compared with routine dispensing. Participants reported feeling more empowered in their roles, with improved professional satisfaction. CONCLUSIONS: Pharmacists in specialized compounding pharmacies report greater collaboration and interaction with prescribers and patients compared with their routine compounding and dispensing. This contributed to perceptions of empowerment and increased professional satisfaction. Specialized compounding may also be an avenue for reprofessionalization. The organization of compounding as a specialized service should be considered in proposed changes to compounding regulations and practice standards. PMID- 21824825 TI - COX-2 inhibition does not reverse the increased sympathetic modulation in MSG obese rats. AB - We evaluate the effects of chronic treatment with celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, on blood pressure (BP) and heart rate variability (HRV) in obese rats induced by neonatal monosodium glutamate (MSG). The animals were treated with celecoxib or saline for 30 days (from the 60th to the 90th day of age). On the 90th day, the MSG obesity induced an increase in the low-frequency (LF) component (CTR=5.69+/-18.30ms(2), MSG=38.49+/-6.27ms(2)) and a decrease in the high-frequency (HF) component of HRV (CTR=71.48+/-6.22ms(2), MSG=50.94+/ 7.03ms(2)), which were unchanged by celecoxib treatment. We suggest that HRV in MSG obesity involves a greater sympathetic modulation not related with COX-2 products. PMID- 21824826 TI - The profile of the extracellular matrix changes in the aorta after sympathectomy in the hypercholesterolemic rats. AB - We previously showed that sympathectomy induces thickened intima and decreases the expression of cytoskeletal proteins associated with a differentiated smooth muscle cell (SMC) phenotype in hypercholesterolemic rats. In the present study, we sought to determine the effect of sympathectomy on various components of the extracellular matrix (ECM) in the aorta from these animals, since the state of SMC differentiation depends on the nature of ECM components. Collagen types I and III, previously reported to be associated with SMC dedifferentiation, and collagen VI, elastin, laminin and elastin-laminin receptor (E/L-R), previously reported to be associated with SMC differentiation, were analyzed by western immunoblot and confocal microscopy in abdominal aortae from sham rats and hypercholesterolemic rats sympathectomized with guanethidine. Both western immunoblot and immunohistological analysis showed an increase in collagens I and III (more for collagen I), with abundant labeling in the media, adventitia and thickened intima in sympathectomized aortae. Collagen IV labeling was decreased in the media and adventitia and was weak in the thickened intima in sympathectomised aortae. The E/L-R increased and was abundantly labeled in the media and weakly in the thickened intima in sympathectomized aortae. Elastin and laminin decreased and appeared less labeled in the media in the sympathectomised aortae. In the thickened intima, laminin was slightly labeled while elastin was not obviously labeled. These data show that sympathectomy favors the ECM features reported in association with a dedifferentiated/immature SMC phenotype and intimal thickening, probably by actions on both SMCs and fibroblasts. PMID- 21824827 TI - Histone deacetylase inhibitor sodium butyrate enhances cellular radiosensitivity by inhibiting both DNA nonhomologous end joining and homologous recombination. AB - HDAC inhibitors have been proposed as radiosensitizers in cancer therapy. Their application would permit the use of lower radiation doses and would reduce the adverse effects of the treatment. However, the molecular mechanisms of their action remain unclear. In the present article, we have studied the radiosensitizing effect of sodium butyrate on HeLa cells. FACS analysis showed that it did not abrogate the gamma-radiation imposed G2 cell cycle arrest. The dynamics of gamma-H2AX foci disappearance in the presence and in the absence of butyrate, however, demonstrated that butyrate inhibited DSB repair. In an attempt to clarify which one of the two major DSBs repair pathways was affected, we synchronized HeLa cells in G1 phase and after gamma-irradiation followed the repair of the DSBs by agarose gel electrophoresis. Since HR is not operational during G1 phase, by this approach we determined the rates of NHEJ only. The results showed that NHEJ decreased in the presence of butyrate. In another set of experiments, we followed the dynamics of disappearance of RAD51 foci in the presence and in the absence of butyrate after gamma-radiation of HeLa cells. Since RAD51 takes part in HR only, this experiment allows the effect of butyrate on DSB repair by homologous recombination to be assessed. It showed that HR was also obstructed by butyrate. These results were confirmed by host cell reactivation assays in which the repair of plasmids containing a single DSB by NHEJ or HR was monitored. We suggest that after a DSB is formed, HDACs deacetylated core histones in the vicinity of the breaks in order to compact the chromatin structure and prevent the broken DNA ends from moving apart from each other, thus ensuring effective repair. PMID- 21824828 TI - [Epicardial adipose tissue and its association to plasma adrenomedullin levels in patients with metabolic syndrome]. AB - OBJECTIVE: To assess the association between epicardial adipose tissue thickness (EAT) and plasma adrenomedullin plasma levels in patients with metabolic syndrome (MS). METHODS: Twenty-one patients (12 females and 9 males) with MS according to the International Diabetes Federation guidelines, aged 22-58 years, were enrolled into the study and compared to 19 age-matched control subjects without MS. Plasma glucose, lipid, and adrenomedullin levels were assessed. EAT, left ventricular mass, and carotid intima-media thickness were evaluated by transthoracic two dimensional echocardiography. RESULTS: No statistically significant differences were found between the groups in age, sex, and height. Body weight, abdominal circumference (AC), body mass index (BMI), systolic blood pressure (SBP), and diastolic blood pressure (DBP) were significantly higher (p=0.0001) in MS patients; this group also showed significantly higher glucose (p=0.001), total cholesterol (p=0.01), LDL-C (p=0.03), VLDL-C (p=0.005), triglyceride (p=0.002), Tg/HDL ratio (p=0.0001), and plasma adrenomedullin (3.49+/-1.21 vs 1.69+/-0.92 ng/mL; p=0.0001) levels and lower HDL-C (p=0.02) levels as compared to the control group. EAT was significantly thicker in MS patients compared to the control group (8.45+/-3.14 vs 5.43+/-0.96; p=0.0001), showed a positive correlation to BMI (r=0.347; p=0.02), AC (r=0.350; p=0.02), DBP (r=0.346; p=0.02), and adrenomedullin levels (r=0.741; p=0.0001). In multiple linear regression analysis, adrenomedullin was the only parameter associated to EAT (R(2)=0.550; p=0.0001). CONCLUSION: In this small patient group, a statistically significant association was found between EAT and plasma adrenomedullin levels, which may be considered as a potential biomarker of MS. PMID- 21824829 TI - [Endocrine function in obesity]. AB - Obesity is associated to significant disturbances in endocrine function. Hyper insulinemia and insulin resistance are the best known changes in obesity, but their mechanisms and clinical significance are not clearly established. Adipose tissue is considered to be a hormone-secreting endocrine organ; and increased leptin secretion from the adipocyte, a satiety signal, is a well-established endocrine change in obesity. In obesity there is a decreased GH secretion. Impairment of somatotropic function in obesity is functional and may be reversed in certain circumstances. The pathophysiological mechanism responsible for low GH secretion in obesity is probably multifactorial. There are many data suggesting that a chronic state of somatostatin hypersecretion results in inhibition of GH release. Increased FFA levels, as well as a deficient ghrelin secretion, probably contribute to the impaired GH secretion. In women, abdominal obesity is associated to hyperandrogenism and low sex hormone-binding globulin levels. Obese men, particularly those with morbid obesity, have decreased testosterone and gonadotropin levels. Obesity is associated to an increased cortisol production rate, which is compensated for by a higher cortisol clearance, resulting in plasma free cortisol levels that do not change when body weight increases. Ghrelin is the only known circulating orexigenic factor, and has been found to be decreased in obese people. In obesity there is also a trend to increased TSH and free T3 levels. PMID- 21824830 TI - [Nutritional risk in hospitalized elderly patients]. PMID- 21824831 TI - Familial intraductal papillary mucinous neoplasms of the pancreas. AB - The prevalence of intraductal papillary mucinous neoplasms in patients with a high risk of pancreatic adenocarcinoma was estimated to be 15%. However, a familial form of intraductal papillary mucinous neoplasms was never described. METHODS: Three families (8 patients) with intraductal papillary mucinous neoplasms familial forms were described. Diagnosis was made according to radiological criteria and was confirmed by pathological data. Genetic predisposing factors of pancreatic cancer were searched for. RESULTS: Symptoms related to intraductal papillary mucinous neoplasms were recurrent acute pancreatitis (n=3) or fortuitous discovery (n=5). Number of cystic lesions was <=3 (n=4) or >3 (n=4). Intraductal papillary mucinous neoplasms involved branch ducts (n=7) or both main pancreatic duct and branch duct (n=1). Severe and moderate dysplasia was found on surgical specimens. No genetic alteration was found (BRCA2, p16 or CDKN2A genes). CONCLUSION: A familial form of intraductal papillary mucinous neoplasms was found in three families. No pancreatic cancer was found in relatives but an attentive survey has to be proposed. PMID- 21824832 TI - Clampless anastomosis with an intraluminal thermosensitive gel: first application in reconstructive microsurgery and literature review. AB - Microvascular clamps of various designs provide a bloodless field for a safe anastomosis but can cause intimal lesions, occupy space in confined sites and have a risk of backwalling due to vessel flattening. They are often insufficient in their haemostatic effect in plaque-filled atherosclerotic vessels. A new, CE certified thermosensitive gel (LeGooTM) clinically proven in cardiovascular surgery allows a clampless microanastomosis technique. We operated on a series of five consecutive patients aged 24-71 years with six flaps for lower-extremity reconstruction using a clampless anastomosis technique with LeGooTM. We transplanted one fabricated chimaeric fibula plus gracilis, three gracilis muscle and one anterolateral thigh (ALT) flap. Pre- and postoperative protocols were similar to a 'standard' procedure with micro-clamps. All flaps survived completely except for a small area on fibula skin island, which was unrelated to gel use. The gel-assisted technique has a quick learning curve, according to this case series. The veins should be sutured first to prevent stasis in the flap. The gel provides circular stenting and gentle distension of the vessels for a safe and blood-free anastomotic site. It is completely dissolved after completion of the anastomosis with cold saline irrigation. Repolymerisation in the periphery will not occur, making it safe for microvascular flap surgery. From the experiences from this series and other specialities, the use of the thermosensitive gel LeGooTM permits a safe clampless microanastomosis technique minimising mechanical vessel manipulation and compression. This makes it an attractive alternative to micro-clamps, especially for atherosclerotic arteries and confined anastomosis sites. PMID- 21824833 TI - Partial external mitral annuloplasty in dogs with myxomatous mitral valve degeneration and congestive heart failure: outcome in 9 cases. AB - OBJECTIVE: To report the outcome of partial external mitral annuloplasty in dogs with congestive heart failure (CHF) due to mitral regurgitation caused by myxomatous mitral valve degeneration (MMVD). ANIMALS, MATERIALS AND METHODS: Nine client-owned dogs with CHF due to mitral regurgitation caused by MMVD. Surgery consisted of a double row of pledget-butressed continuous suture lines placed into the left ventricle parallel and just ventral to the atrioventricular groove between the subsinuosal branch of the left circumflex coronary artery and the paraconal branch of the left coronary artery. RESULTS: Two dogs died during surgery because of severe hemorrhage. Two dogs died 12 and 36 h after surgery because of acute myocardial infarction. Three dogs were euthanized 2 and 4 weeks after surgery because of progression of CHF, 1 was euthanized 30 days after surgery for non-cardiac disease, and 1 survived for 48 months. In the 5 dogs that survived to discharge there was no significant change in the left atrium to aortic ratio with surgery (3.6 +/- 0.56 before surgery; 3.1 +/- 0.4 after surgery; p = 0.182), and no significant change in mitral regurgitant fraction in 4 dogs in which this measurement was made (78.7 +/- 2.0% before surgery; 68.7 +/- 7.5% after surgery; p = 0.09). CONCLUSIONS: Partial external mitral annuloplasty in dogs with CHF due to MMVD was associated with high perioperative mortality and most dogs that survived to discharge failed to show clinically relevant palliation from this procedure. Consequently, partial external mitral annuloplasty is not a viable option for dogs with mitral regurgitation due to MMVD that has progressed to the stage of CHF. PMID- 21824834 TI - Transient effects of 80 Hz stimulation on gait in STN DBS treated PD patients: a 15 months follow-up study. AB - BACKGROUND: Subthalamic nucleus deep brain stimulation (STN DBS) is an effective therapeutic option for advanced Parkinson's disease (PD). Nevertheless, some patients develop gait disturbances despite a persistent improvement of PD segmental symptoms. Recent studies reported that stimulation of STN with low frequencies produced a positive effect on gait disorders and freezing episodes. OBJECTIVE: To evaluate the effects of 80 Hz stimulation frequency on gait in PD patients undergoing STN DBS and to determine whether such effects are maintained over time. METHODS: We evaluated 11 STN DBS treated PD patients who had developed gait impairment several years after surgery. Gait was assessed by means of the Stand-Walk-Sit (SWS) test. Motor symptoms and activities of daily living were evaluated through the Unified PD Rating Scale (UPDRS). The stimulation frequency was switched from 130 Hz to 80 Hz, adapting the voltage to maintain the same total delivered energy. Patients were assessed at baseline and 3 hours after switching the stimulation frequency to 80 Hz. Follow-up evaluations were carried out after 1, 5, and 15 months. The clinical global improvement scale was rated at every follow-up visit. RESULTS: A significant improvement of gait (SWS test) was evident immediately after switching the stimulation frequency to 80 Hz, with no deterioration of PD segmental symptoms. However, gait improvement was no longer detectable by the SWS test at follow-up evaluations 1, 5, and 15 months later. Three patients were switched back to 130 Hz because of unsatisfactory control of motor symptoms. Of the eight patients maintained at 80 Hz up to 15 months, five showed a global improvement and three showed no change. CONCLUSIONS: Stimulation frequency at 80 Hz has an immediate positive effect on gait in STN DBS treated patients; however, the objective gait improvement is not maintained over time, limiting the use of this frequency modulation strategy in the clinical setting. PMID- 21824835 TI - Decoding emotional prosody: resolving differences in functional neuroanatomy from fMRI and lesion studies using TMS. AB - BACKGROUND: Prosody conveys information about the emotional state and intention of others. Lesion studies have shown that damage to the right posterior temporal region is associated with prosody decoding deficits. Dissimilarly to findings from lesion studies, neuroimaging data show substantial bilateral peri-Sylvian activation. OBJECTIVE: This study aimed to investigate the involvement of the left and right superior temporal gyrus (STG) in prosodic and semantic processing using transcranial magnetic stimulation (TMS). These two regions of interest were chosen for their correspondence to Wernicke's area in the left hemisphere and its analog in the right. METHODS: Offline TMS with a stimulation frequency of 1 Hz and intensity of 60% of stimulator output (approximately 1.1 Tesla) with one pulse applied per second for 10 minutes (600 pulses) was performed. Directly after TMS on the right STG, the left STG or sham-stimulation, participants completed a prosody decoding or a semantic judgment task (whether the tone/meaning was happy or sad). RESULTS: Reaction times (RT) for the prosodic task were significantly slower when TMS was applied in the right STG in comparison to left STG and sham conditions. TMS over both right and left STG delayed RT in the semantic task, significantly when the tone of voice was incongruent with the meaning. CONCLUSIONS: Our data strongly suggests that left temporal regions are not crucial to the basic task of prosody decoding per se; however, the analogous region on the right is. Hence, involvement of the left STG in prosodic decoding revealed in previous imaging data is incidental. PMID- 21824836 TI - The effect of propofol-remifentanil anesthesia on selected seizure quality indices in electroconvulsive therapy. AB - BACKGROUND: Use of a short-acting opiate to potentiate anesthetic induction agents has been shown to increase seizure duration in electroconvulsive therapy (ECT), but little is known of the effect of this combination on indices of seizure quality. OBJECTIVE: To determine whether anesthetic modality affects commonly provided indices of seizure quality. METHODS: Twenty-five subjects were given propofol 2 mg/kg body weight for their first ECT session, at which time seizure threshold was titrated. Subjects thereafter alternated between that anesthetic regimen or propofol 0.5 mg/kg plus remifentanil 1 mcg/kg. Linear mixed models with random subject effect, adjusting for electrode placement, electrical charge, and number of treatments, were fit to estimate effect of anesthesia on seizure duration and several standard seizure quality indices (average seizure energy, time to peak electroencephalography (EEG) power, maximum sustained power, interhemispheric coherence, early and midictal EEG amplitude, and maximum sustained interhemispheric EEG coherence). RESULTS: Propofol-remifentanil anesthesia significantly lengthened seizure duration and was associated with longer time to reach maximal EEG power and coherence as well as maximal degree of interhemispheric EEG coherence. No effect was seen on early ictal amplitude or average seizure energy index. CONCLUSIONS: Propofol-remifentanil anesthesia prolongs seizure duration and has a significant effect on some, but not all, measures of seizure quality. This effect may be of some benefit in cases where adequate seizures are otherwise difficult to elicit. Varying anesthetic technique may allow more precise investigation of the relationships between and relative impacts of commonly used seizure quality indices on clinical outcomes and ECT related cognitive side effects. PMID- 21824837 TI - Repetitive transcranial magnetic stimulation: hearing safety considerations. AB - BACKGROUND: The guidelines for use of repetitive transcranial magnetic stimulation (rTMS) advise frequent updating of rTMS safety guidelines and recommendations. Although rTMS can produce sound of more than 120 dB C, which is sufficient to induce hearing loss, the effect of rTMS noise on the hearing of both patients and rTMS practitioners is understudied. OBJECTIVE: This study investigated the effects of rTMS noise on subjects' hearing using otoacoustic emissions evoked by clicks (transiently evoked otoacoustic emissions, TEOAEs), which is an objective and sensitive method of cochlear exploration. METHODS: Hearing thresholds and TEOAEs were recorded in 24 normal-hearing healthy subjects before and after a real or sham rTMS session (a single 20-minute session applied to the superior temporal gyrus with 1200 pulses at 100% of the individual motor threshold). RESULTS: No significant difference in hearing thresholds was observed between subjects exposed to real or sham rTMS. However, the difference in TEOAE amplitude between pre- and post-rTMS sessions increased significantly with rTMS noise for those subjects the least protected by earplugs, showing a post-rTMS slight decrease of TEOAE amplitude for high rTMS intensities and hence minor hearing function alteration. However, this correlation was no longer found 1 hour after the rTMS session. CONCLUSIONS: These findings suggest that, even when rTMS is used within normal safety limits and with good hearing protection, rTMS noise can transiently disturb hearing mechanisms in normal-hearing healthy subjects. This transient effect of rTMS on hearing may be an important consideration for Institutional Review Boards when rTMS is used at higher stimulation intensities. PMID- 21824838 TI - LTI models for 3-iodothyronamine time dynamics: a multiscale view. AB - 3-Iodothyronamine (T(1)AM) is a novel relative of thyroid hormone that plays a role in critical body regulatory processes such as glucose metabolism, thermal regulation, and heart beating. This paper was aimed at characterizing time dynamics of T(1)AM and its catabolite 3-iodothyroacetic acid (TA(1)) in different biological scales with linear time-invariant models. Culture medium samples coming from culture of H9c2 murine cells and perfusion liquid samples from perfused rat heart were collected after the injection of a T(1)AM bolus. T(1)AM and TA(1) concentrations in the samples were assayed with high-performance liquid chromatography coupled to tandem mass spectrometry. Kinetic constants relative to T(1)AM transport and conversion were estimated with weighted least-squares method. We found that these constants can be related with an allometric power law depending on mass, with a negative exponent of -0.27 +/- 0.19, implying that the velocity of conversion and internalization of T(1)AM decreases with increasing of system mass. PMID- 21824839 TI - ECG on the road: robust and unobtrusive estimation of heart rate. AB - Modern automobiles include an increasing number of assistance systems to increase the driver's safety. This feasibility study investigated unobtrusive capacitive ECG measurements in an automotive environment. Electrodes integrated into the driving seat allowed to measure a reliable ECG in 86% of the drivers; when only (light) cotton clothing was worn by the drivers, this value increased to 95%. Results show that an array of sensors is needed that can adapt to the different drivers and sitting positions. Measurements while driving show that traveling on the highway does not distort the signal any more than with the car engine turned OFF, whereas driving in city traffic results in a lowered detection rate due to the driver's heavier movements. To enable robust and reliable estimation of heart rate, an algorithm is presented (based on principal component analysis) to detect and discard time intervals with artifacts. This, then, allows a reliable estimation of heart rate of up to 61% in city traffic and up to 86% on the highway: as a percentage of the total driving period with at least four consecutive QRS complexes. PMID- 21824840 TI - An ultrasonically powered implantable micro-oxygen generator (IMOG). AB - In this paper, we present an ultrasonically powered implantable micro-oxygen generator (IMOG) that is capable of in situ tumor oxygenation through water electrolysis. Such active mode of oxygen generation is not affected by increased interstitial pressure or abnormal blood vessels that typically limit the systemic delivery of oxygen to hypoxic regions of solid tumors. Wireless ultrasonic powering (2.15 MHz) was employed to increase the penetration depth and eliminate the directional sensitivity associated with magnetic methods. In addition, ultrasonic powering allowed for further reduction in the total size of the implant by eliminating the need for a large area inductor. IMOG has an overall dimension of 1.2 mm * 1.3 mm * 8 mm, small enough to be implanted using a hypodermic needle or a trocar. In vitro and ex vivo experiments showed that IMOG is capable of generating more than 150 MUA which, in turn, can create 0.525 MUL/min of oxygen through electrolytic disassociation. In vivo experiments in a well-known hypoxic pancreatic tumor models (1 cm (3) in size) also verified adequate in situ tumor oxygenation in less than 10 min. PMID- 21824841 TI - Target motion tracking in MRI-guided transrectal robotic prostate biopsy. AB - PURPOSE: MRI-guided prostate needle biopsy requires compensation for organ motion between target planning and needle placement. Two questions are studied and answered in this paper: 1) is rigid registration sufficient in tracking the targets with an error smaller than the clinically significant size of prostate cancer and 2) what is the effect of the number of intraoperative slices on registration accuracy and speed? METHODS: we propose multislice-to-volume registration algorithms for tracking the biopsy targets within the prostate. Three orthogonal plus additional transverse intraoperative slices are acquired in the approximate center of the prostate and registered with a high-resolution target planning volume. Both rigid and deformable scenarios were implemented. Both simulated and clinical MRI-guided robotic prostate biopsy data were used to assess tracking accuracy. RESULTS: average registration errors in clinical patient data were 2.6 mm for the rigid algorithm and 2.1 mm for the deformable algorithm. CONCLUSION: rigid tracking appears to be promising. Three tracking slices yield significantly high registration speed with an affordable error. PMID- 21824843 TI - Observer design for switched recurrent neural networks: an average dwell time approach. AB - This paper is concerned with the problem of observer design for switched recurrent neural networks with time-varying delay. The attention is focused on designing the full-order observers that guarantee the global exponential stability of the error dynamic system. Based on the average dwell time approach and the free-weighting matrix technique, delay-dependent sufficient conditions are developed for the solvability of such problem and formulated as linear matrix inequalities. The error-state decay estimate is also given. Then, the stability analysis problem for the switched recurrent neural networks can be covered as a special case of our results. Finally, four illustrative examples are provided to demonstrate the effectiveness and the superiority of the proposed methods. PMID- 21824842 TI - Removal of spurious coherence in MEG source-space coherence analysis. AB - Source-space coherence analysis has become a popular method to estimate functional connectivity based on MEG/EEG. Source-space analysis involves solving the inverse problem, estimating the time courses of specific brain regions, and then examining the coherence between activities at different brain regions. However, source-space coherence analysis can be confounded by spurious coherence caused due to the leakage properties of the inverse algorithm employed. Such spurious coherence is typically manifested as an artifactual large peak around the seed voxel, called seed blur, in the resulting coherence images. This seed blur often obscures important details of brain interactions. This paper proposes the use of the imaginary part of the coherence to remove the spurious coherence caused by the leakage of an imaging algorithm. We present a theoretical analysis that explains how the use of imaginary part can remove this spurious coherence. We then present results from both computer simulations and experiments using resting-state MEG data which demonstrate the validity of our analysis. PMID- 21824844 TI - Textual and visual content-based anti-phishing: a Bayesian approach. AB - A novel framework using a Bayesian approach for content-based phishing web page detection is presented. Our model takes into account textual and visual contents to measure the similarity between the protected web page and suspicious web pages. A text classifier, an image classifier, and an algorithm fusing the results from classifiers are introduced. An outstanding feature of this paper is the exploration of a Bayesian model to estimate the matching threshold. This is required in the classifier for determining the class of the web page and identifying whether the web page is phishing or not. In the text classifier, the naive Bayes rule is used to calculate the probability that a web page is phishing. In the image classifier, the earth mover's distance is employed to measure the visual similarity, and our Bayesian model is designed to determine the threshold. In the data fusion algorithm, the Bayes theory is used to synthesize the classification results from textual and visual content. The effectiveness of our proposed approach was examined in a large-scale dataset collected from real phishing cases. Experimental results demonstrated that the text classifier and the image classifier we designed deliver promising results, the fusion algorithm outperforms either of the individual classifiers, and our model can be adapted to different phishing cases. PMID- 21824845 TI - Incremental learning of concept drift in nonstationary environments. AB - We introduce an ensemble of classifiers-based approach for incremental learning of concept drift, characterized by nonstationary environments (NSEs), where the underlying data distributions change over time. The proposed algorithm, named Learn(++). NSE, learns from consecutive batches of data without making any assumptions on the nature or rate of drift; it can learn from such environments that experience constant or variable rate of drift, addition or deletion of concept classes, as well as cyclical drift. The algorithm learns incrementally, as other members of the Learn(++) family of algorithms, that is, without requiring access to previously seen data. Learn(++). NSE trains one new classifier for each batch of data it receives, and combines these classifiers using a dynamically weighted majority voting. The novelty of the approach is in determining the voting weights, based on each classifier's time-adjusted accuracy on current and past environments. This approach allows the algorithm to recognize, and act accordingly, to the changes in underlying data distributions, as well as to a possible reoccurrence of an earlier distribution. We evaluate the algorithm on several synthetic datasets designed to simulate a variety of nonstationary environments, as well as a real-world weather prediction dataset. Comparisons with several other approaches are also included. Results indicate that Learn(++). NSE can track the changing environments very closely, regardless of the type of concept drift. To allow future use, comparison and benchmarking by interested researchers, we also release our data used in this paper. PMID- 21824846 TI - Toward a unified color space for perception-based image processing. AB - Image processing methods that utilize characteristics of the human visual system require color spaces with certain properties to operate effectively. After analyzing different types of perception-based image processing problems, we present a list of properties that a unified color space should have. Due to contradictory perceptual phenomena and geometric issues, a color space cannot incorporate all these properties. We therefore identify the most important properties and focus on creating opponent color spaces without cross contamination between color attributes (i.e., lightness, chroma, and hue) and with maximum perceptual uniformity induced by color-difference formulas. Color lookup tables define simple transformations from an initial color space to the new spaces. We calculate such tables using multigrid optimization considering the Hung and Berns data of constant perceived hue and the CMC, CIE94, and CIEDE2000 color-difference formulas. The resulting color spaces exhibit low cross contamination between color attributes and are only slightly less perceptually uniform than spaces optimized exclusively for perceptual uniformity. We compare the CIEDE2000-based space with commonly used color spaces in two examples of perception-based image processing. In both cases, standard methods show improved results if the new space is used. All color-space transformations and examples are provided as MATLAB codes on our website. PMID- 21824847 TI - Histogram contextualization. AB - Histograms have been widely used for feature representation in image and video content analysis. However, due to the orderless nature of the summarization process, histograms generally lack spatial information. This may degrade their discrimination capability in visual classification tasks. Although there have been several research attempts to encode spatial context into histograms, how to extend the encodings to higher order spatial context is still an open problem. In this paper,we propose a general histogram contextualization method to encode efficiently higher order spatial context. The method is based on the cooccurrence of local visual homogeneity patterns and hence is able to generate more discriminative histogram representations while remaining compact and robust. Moreover, we also investigate how to extend the histogram contextualization to multiple modalities of context. It is shown that the proposed method can be naturally extended to combine both temporal and spatial context and facilitate video content analysis. In addition, a method to combine cross-feature context with spatial context via the technique of random forest is also introduced in this paper. Comprehensive experiments on face image classification and human activity recognition tasks demonstrate the superiority of the proposed histogram contextualization method compared with the existing encoding methods. PMID- 21824848 TI - Model-assisted adaptive recovery of compressed sensing with imaging applications. AB - In compressive sensing (CS), a challenge is to find a space in which the signal is sparse and, hence, faithfully recoverable. Since many natural signals such as images have locally varying statistics, the sparse space varies in time/spatial domain. As such, CS recovery should be conducted in locally adaptive signal dependent spaces to counter the fact that the CS measurements are global and irrespective of signal structures. On the contrary, existing CS reconstruction methods use a fixed set of bases (e.g., wavelets, DCT, and gradient spaces) for the entirety of a signal. To rectify this problem, we propose a new framework for model-guided adaptive recovery of compressive sensing (MARX) and show how a 2-D piecewise autoregressive model can be integrated into the MARX framework to make CS recovery adaptive to spatially varying second order statistics of an image. In addition, MARX offers a mechanism of characterizing and exploiting structured sparsities of natural images, greatly restricting the CS solution space. Simulation results over a wide range of natural images show that the proposed MARX technique can improve the reconstruction quality of existing CS methods by 2 7 dB. PMID- 21824849 TI - Precision-aware self-quantizing hardware architectures for the discrete wavelet transform. AB - This paper presents designs for both bit-parallel (BP) and digit-serial (DS) precision-optimized implementations of the discrete wavelet transform (DWT), with specific consideration given to the impact of depth (the number of levels of DWT) on the overall computational accuracy. These methods thus allow customizing the precision of a multilevel DWT to a given error tolerance requirement and ensuring an energy-minimal implementation, which increases the applicability of DWT-based algorithms such as JPEG 2000 to energy-constrained platforms and environments. Additionally, quantization of DWT coefficients to a specific target step size is performed as an inherent part of the DWT computation, thereby eliminating the need to have a separate downstream quantization step in applications such as JPEG 2000. Experimental measurements of design performance in terms of area, speed, and power for 90-nm complementary metal-oxide-semiconductor implementation are presented. Results indicate that while BP designs exhibit inherent speed advantages, DS designs require significantly fewer hardware resources with increasing precision and DWT level. A four-level DWT with medium precision, for example, while the BP design is four times faster than the digital-serial design, occupies twice the area. In addition to the BP and DS designs, a novel flexible DWT processor is presented, which supports run-time configurable DWT parameters. PMID- 21824850 TI - On the stress function-based OWA determination method with optimization criteria. AB - The ordered weighted averaging (OWA) determination method with stress function was proposed by Yager, and it makes the OWA operator elements scatter in the shape of the stress function. In this paper, we extend the OWA determination with the stress function method using an optimization model. The proposed method transforms the OWA optimal solution elements into the interpolation points of the stress function. The proposed method extends the basic form of the stress function method with both scale and vertical shift transformations. We also explore a number of properties of this optimization-based stress function method. The OWA operator optimal solution elements can distribute as the shape of the given stress function in a parameterized way, in which case, the solution always possesses the arithmetic average operator as a special case. PMID- 21824851 TI - A dynamic hybrid framework for constrained evolutionary optimization. AB - Based on our previous work, this paper presents a dynamic hybrid framework, called DyHF, for solving constrained optimization problems. This framework consists of two major steps: global search model and local search model. In the global and local search models, differential evolution serves as the search engine, and Pareto dominance used in multiobjective optimization is employed to compare the individuals in the population. Unlike other existing methods, the above two steps are executed dynamically according to the feasibility proportion of the current population in this paper, with the purpose of reasonably distributing the computational resource for the global and local search during the evolution. The performance of DyHF is tested on 22 benchmark test functions. The experimental results clearly show that the overall performance of DyHF is highly competitive with that of a number of state-of-the-art approaches from the literature. PMID- 21824852 TI - Telepresence index for bilateral teleoperations. AB - This paper proposes a performance index called telepresence index for bilateral teleoperation, which can be used both for the performance evaluation of bilateral control architectures and for design purposes. This index is intended to represent a comprehensive performance objective consisting of transparency and kinematic correspondence, which are two major performance objectives of bilateral teleoperation. In order to quantify the performance objective, telepresence index has employed the error vector magnitude, which enables a seamless combination of magnitude and phase errors and the accommodation of time delay. In comparison with existing performance indices, it was observed that telepresence index possesses the comprehensiveness of performance objectives, magnitude/phase integrity, and the capacity to include time delay, which the others lack in one way or another. The index was applied to evaluate the performances of two widely known control architectures: PD-type bilateral control and Ueda's ideal control. In all cases, telepresence index has been compared favorably with the other indices in terms of clarity, convenience, and accuracy, thereby demonstrating its superiority. PMID- 21824853 TI - Distributed Primal-Dual Subgradient Method for Multiagent Optimization via Consensus Algorithms. AB - This paper studies the problem of optimizing the sum of multiple agents' local convex objective functions, subject to global convex inequality constraints and a convex state constraint set over a network. Through characterizing the primal and dual optimal solutions as the saddle points of the Lagrangian function associated with the problem, we propose a distributed algorithm, named the distributed primal-dual subgradient method, to provide approximate saddle points of the Lagrangian function, based on the distributed average consensus algorithms. Under Slater's condition, we obtain bounds on the convergence properties of the proposed method for a constant step size. Simulation examples are provided to demonstrate the effectiveness of the proposed method. PMID- 21824854 TI - Fisher-Tippett region-merging approach to transrectal ultrasound prostate lesion segmentation. AB - In this paper, a computerized approach to segmenting prostate lesions in transrectal ultrasound (TRUS) images is presented. The segmentation of prostate lesions from TRUS images is very challenging due to issues, such as poor contrast, low SNRs, and irregular shape variations. To address these issues, a novel approach is employed to segment the lesions from the surrounding prostate, where region merging is performed via a region-merging likelihood function based on regional statistics, as well as Fisher-Tippett statistics. Experimental results using TRUS prostate images demonstrate that the proposed Fisher-Tippett region-merging approach achieves more accurate segmentation of prostate lesions when compared to other segmentation methods. PMID- 21824856 TI - [Editor's commentary]. PMID- 21824855 TI - Ambient temperature and morbidity: a review of epidemiological evidence. AB - OBJECTIVE: In this paper, we review the epidemiological evidence on the relationship between ambient temperature and morbidity. We assessed the methodological issues in previous studies and proposed future research directions. DATA SOURCES AND DATA EXTRACTION: We searched the PubMed database for epidemiological studies on ambient temperature and morbidity of noncommunicable diseases published in refereed English journals before 30 June 2010. Forty relevant studies were identified. Of these, 24 examined the relationship between ambient temperature and morbidity, 15 investigated the short-term effects of heat wave on morbidity, and 1 assessed both temperature and heat wave effects. DATA SYNTHESIS: Descriptive and time-series studies were the two main research designs used to investigate the temperature-morbidity relationship. Measurements of temperature exposure and health outcomes used in these studies differed widely. The majority of studies reported a significant relationship between ambient temperature and total or cause-specific morbidities. However, there were some inconsistencies in the direction and magnitude of nonlinear lag effects. The lag effect of hot temperature on morbidity was shorter (several days) compared with that of cold temperature (up to a few weeks). The temperature-morbidity relationship may be confounded or modified by sociodemographic factors and air pollution. CONCLUSIONS: There is a significant short-term effect of ambient temperature on total and cause-specific morbidities. However, further research is needed to determine an appropriate temperature measure, consider a diverse range of morbidities, and to use consistent methodology to make different studies more comparable. PMID- 21824857 TI - [Evaluation of fracture risk in osteoporosis]. AB - Osteoporotic fractures are associated with excess mortality. Effective treatment options are available, which reduce the risk of vertebral and non-vertebral fractures, but the identification of patients with high fracture risk is problematic. Low bone mineral density (BMD)--the basis for the diagnosis of osteoporosis--is an important, but not the only determinant of fracture risk. Several clinical risk factors are know that operate partially or completely independently of BMD, and affect the fracture risk. These include age, a prior fragility fracture, a parental history of hip fracture, use of corticosteroids, excess alcohol intake, rheumatoid arthritis, and different types of diseases which can cause secondary bone loss. The FRAX(r) tool integrates the weight of above mentioned clinical risk factors for fracture risk assessment with or without BMD value, and calculates the 10-year absolute risk of hip and major osteoporotic (hip, vertebral, humerus and forearm together) fracture probabilities. Although the use of data is not yet uniform, the FRAX(r) is a promising opportunity to identify individuals with high fracture risk. The accumulation of experience with FRAX(r) is going on and it can modify current diagnostic and therapeutic recommendations in Hungary as well. PMID- 21824858 TI - [Skeletal and extra-skeletal consequences of vitamin D deficiency]. AB - Vitamin D is obtained from cutaneous production when 7-dehydrocholesterol is converted to vitamin D(3) (cholecalciferol) by ultraviolet B radiation or by oral intake of vitamin D. Rickets appeared to have been conquered with vitamin D intake, and many health care professionals thought the major health problems resulting from vitamin D deficiency had been resolved. However, rickets can be considered the tip of the vitamin D deficiency iceberg. In fact, vitamin D deficiency remains common in children and adults. An individual's vitamin D status is best evaluated by measuring the circulating 25-hydroxyvitamin D (25(OH)D3) concentration. There is increasing agreement that the optimal circulating 25(OH)D3 level should be approximately 30 ng/mL or above. Using this definition, it has been estimated that approximately three-quarters of all adults have low levels. In utero and during childhood, vitamin D deficiency can cause growth retardation and skeletal deformities and may increase the risk of hip fracture later in life. Vitamin D deficiency in adults can exacerbate osteopenia and osteoporosis, cause osteomalacia and muscle weakness, and increase the risk of fracture. More recently, associations between low vitamin D status and increased risk for various non-skeletal morbidities have been recognized; whether all of these associations are causally related to low vitamin D status remains to be determined. The discovery that most tissues and cells in the body have vitamin D receptors and that several possess the enzymatic machinery to convert the 25 hydroxyvitamin D3, to the active form, 1,25-dihydroxyvitamin D3, has provided new insights into the function of this vitamin. Of great interest is its role in decreasing the risk of many chronic illnesses, including common cancers, autoimmune diseases, infectious diseases, and cardiovascular disease. In this review I consider the nature of vitamin D deficiency, discuss its role in skeletal and non-skeletal health, and suggest strategies for prevention and treatment. PMID- 21824859 TI - [Pharmacologic treatment of osteoporosis--2011]. AB - Osteoporosis affects approximately 9% of the population in Hungary resulting in about 100 000 osteoporotic fractures annually. Thirty-five percent of patients with hip fractures due to osteoporosis will die within 1 year. Direct costs of osteoporosis exceed 25 billion forints per year. Apparently, cost-effective reduction of bone loss and consequent fracture risk will add up to not only financial savings but improvement in quality of life, as well. A number of pharmacological modalities are available for this purpose. The mainstay of the treatment of osteoporosis is the bisphosphonate group that includes effective anti-resorptive compounds mitigating bone loss and fragility. The recently registered denosumab exhibits similar efficacy by neutralizing RANK ligand, however, marked differences can be observed between the two drug classes. Strontium has a unique mechanism of action by rebalancing bone turnover, and thus, providing an efficient treatment option for the not fast bone losers who are at high fracture risk. The purely anabolic teriparatide is available for the extremely severe osteoporotic patients and for those who do not respond to other types of therapy. Older treatment options such as hormone replacement therapy, raloxifene, tibolone or calcitonin may also have a restricted place in the management of osteoporosis. PMID- 21824860 TI - [Orthopedic treatment of vertebral compression fractures in osteoporosis]. AB - Vertebral compression fracture is the most common type of fractures in osteoporosis increasing the mortality and morbidity of the systemic disease. Adequate treatment of the vertebral compression fractures is always in the focus of the national and international spine meetings and one of the most innovative fields in the spine care is the surgical therapy of the osteoporotic spine. Here, the authors summarize the orthopedic treatment options for vertebral compression fractures based on a literature review and their own institutional experience. PMID- 21824861 TI - [Paget's disease: clinical update]. AB - Paget's disease is a chronic disorder of bone remodeling, characterized by an abnormal increase of osteoclast and, hence, osteoblast activity. The imbalance of bone turnover results in the formation of unhealthy and fragile bone. It also leads to impairment of adjacent joints and to a risk of various complications. Current research focuses on the elucidation of the etiologic role viral infection and predisposing genetic factors. Paget's disease is commonly discovered by chance; its suspicion is raised either by high level of alkaline phosphatase or by the X-ray of the pathological bone. Bisphosphonates have proven to be effective in controlling disease activity because they inhibit osteoclast function. Their use is recommended when bone-derived serum alkaline phosphatase is high and/or when disease localizations are highly suspected for the development of complications. PMID- 21824864 TI - Development of memory-like autoregulatory CD8+ T cells is CD4+ T cell dependent. AB - Progression of spontaneous autoimmune diabetes is associated with development of a disease-countering negative-feedback regulatory loop that involves differentiation of low-avidity autoreactive CD8(+) cells into memory-like autoregulatory T cells. Such T cells blunt diabetes progression by suppressing the presentation of both cognate and noncognate Ags to pathogenic high-avidity autoreactive CD8(+) T cells in the pancreas-draining lymph nodes. In this study, we show that development of autoregulatory CD8(+) T cell memory is CD4(+) T cell dependent. Transgenic (TG) NOD mice expressing a low-affinity autoreactive TCR were completely resistant to autoimmune diabetes, even after systemic treatment of the mice with agonistic anti-CD40 or anti-4-1BB mAbs or autoantigen-pulsed dendritic cells, strategies that dramatically accelerate diabetes development in TG NOD mice expressing a higher affinity TCR for the same autoantigenic specificity. Furthermore, whereas abrogation of RAG-2 expression, hence endogenous CD4(+) T cell and B cell development, decelerated disease progression in high-affinity TCR-TG NOD mice, it converted the low-affinity TCR into a pathogenic one. In agreement with these data, polyclonal CD4(+) T cells from prediabetic NOD mice promoted disease in high-affinity TCR-TG NOD.Rag2(-/-) mice, but inhibited it in low-affinity TCR-TG NOD.Rag2(-/-) mice. Thus, in chronic autoimmune responses, CD4(+) Th cells contribute to both promoting and suppressing pathogenic autoimmunity. PMID- 21824865 TI - Cyclophilin A is a damage-associated molecular pattern molecule that mediates acetaminophen-induced liver injury. AB - The immune system is alerted to cell death by molecules known as damage associated molecular patterns (DAMPs). These molecules partly mediate acetaminophen-induced liver injury, an archetypal experimental model of sterile cell death and the commonest cause of acute liver failure in the western world. Cyclophilin A (CypA) is an intracellular protein that is proinflammatory when released by cells. We hypothesized that CypA is released from necrotic liver cells and acts as a DAMP to mediate acetaminophen-induced liver injury. Our data demonstrated that mice lacking CypA (Ppia(-/-)) were resistant to acetaminophen toxicity. Antagonism of the extracellular receptor for CypA (CD147) also reduced acetaminophen-induced liver injury. When injected into a wild-type mouse, necrotic liver from Ppia(-/-) mice induced less of an inflammatory response than did wild-type liver. Conversely, the host inflammatory response was increased when CypA was injected with necrotic liver. Antagonism of CD147 also reduced the inflammatory response to necrotic liver. In humans, urinary CypA concentration was significantly increased in patients with acetaminophen-induced liver injury. In summary, CypA is a DAMP that mediates acetaminophen poisoning. This mechanistic insight presents an opportunity for a new therapeutic approach to a disease that currently has inadequate treatment options. PMID- 21824866 TI - Fungal chitin from asthma-associated home environments induces eosinophilic lung infiltration. AB - Development of asthma and allergic inflammation involves innate immunity, but the environmental contributions remain incompletely defined. Analysis of dust collected from the homes of asthmatic individuals revealed that the polysaccharide chitin is environmentally widespread and associated with beta glucans, possibly from ubiquitous fungi. Cell wall preparations of Aspergillus isolated from house dust induced robust recruitment of eosinophils into mouse lung, an effect that was attenuated by enzymatic degradation of cell wall chitin and beta-glucans. Mice expressing constitutively active acidic mammalian chitinase in the lungs demonstrated a significant reduction in eosinophil infiltration after fungal challenge. Conversely, chitinase inhibition prolonged the duration of tissue eosinophilia. Thus, fungal chitin derived from home environments associated with asthma induces eosinophilic allergic inflammation in the lung, and mammalian chitinases, including acidic mammalian chitinase, limit this process. PMID- 21824867 TI - Plasticity of Ly-6C(hi) myeloid cells in T cell regulation. AB - CD11b(+)Ly-6C(hi) cells, including inflammatory monocytes (IMCs) and inflammatory dendritic cells (IDCs), are important in infectious, autoimmune, and tumor models. However, their role in T cell regulation is controversial. In this article, we show that T cell regulation by IMCs and IDCs is determined by their activation state and is plastic during an immune response. Nonactivated IMCs and IDCs function as APCs, but activated IMCs and IDCs suppress T cells through NO production. Suppressive IMCs are induced by IFN-gamma, GM-CSF, TNF-alpha, and CD154 derived from activated T cells during their interaction. In experimental autoimmune encephalomyelitis, CD11b(+)Ly-6C(hi) cells in the CNS are increasingly activated from disease onset to peak and switch their function from Ag presentation to T cell suppression. Furthermore, transfer of activated IMCs or IDCs enhances T cell apoptosis in the CNS and suppresses experimental autoimmune encephalomyelitis. These data highlight the interplay between innate and adaptive immunity: immunization leads to the expansion of Ly-6C(hi) myeloid cells initially promoting T cell function. As T cells become highly activated in the target tissue, they induce activation and NO production in Ly-6C(hi) myeloid cells, which in turn suppress T cells and lead to the contraction of local immune response. PMID- 21824868 TI - Stability of mitochondrial membrane proteins in terrestrial vertebrates predicts aerobic capacity and longevity. AB - The cellular energy produced by mitochondria is a fundamental currency of life. However, the extent to which mitochondrial (mt) performance (power and endurance) is adapted to habitats and life strategies of vertebrates is not well understood. A global analysis of mt genomes revealed that hydrophobicity (HYD) of mt membrane proteins (MMPs) is much lower in terrestrial vertebrates than in fishes and shows a strong negative correlation with serine/threonine composition (STC). Here, we present evidence that this systematic feature of MMPs was crucial for the evolution of large terrestrial vertebrates with high aerobic capacity. An Arrhenius-type equation gave positive correlations between STC and maximum life span (MLS) in terrestrial vertebrates (with a few exceptions relating to the lifestyle of small animals with a high resting metabolic rate [RMR]) and negative correlations in secondary marine vertebrates, such as cetaceans and alligators (which returned from land to water, utilizing buoyancy with increased body size). In particular, marked STC increases in primates (especially hominoids) among placentals were associated with very high MLS values. We connected these STC increases in MMPs with greater stability of respiratory complexes by estimating the degradation of the Arrhenius plot given by accelerating mtRMR up to mt maximum metabolic rate. Both mtRMR and HYD in terrestrial vertebrates decreased with increasing body mass. Decreases in mtRMR raise MMP stability when high mobility is not required, whereas decreased HYD may weaken this stability under the hydrophobic environment of lipid bilayer. High maximal metabolic rates (5-10 RMR), which we postulate require high MMP mobility, presumably render MMPs more unstable. A marked rise in STC may therefore be essential to stabilize MMPs, perhaps as dynamic supercomplexes, via hydrogen bonds associated with serine/threonine motifs. PMID- 21824869 TI - Genome-wide heterogeneity of nucleotide substitution model fit. AB - At a genomic scale, the patterns that have shaped molecular evolution are believed to be largely heterogeneous. Consequently, comparative analyses should use appropriate probabilistic substitution models that capture the main features under which different genomic regions have evolved. While efforts have concentrated in the development and understanding of model selection techniques, no descriptions of overall relative substitution model fit at the genome level have been reported. Here, we provide a characterization of best-fit substitution models across three genomic data sets including coding regions from mammals, vertebrates, and Drosophila (24,000 alignments). According to the Akaike Information Criterion (AIC), 82 of 88 models considered were selected as best-fit models at least in one occasion, although with very different frequencies. Most parameter estimates also varied broadly among genes. Patterns found for vertebrates and Drosophila were quite similar and often more complex than those found in mammals. Phylogenetic trees derived from models in the 95% confidence interval set showed much less variance and were significantly closer to the tree estimated under the best-fit model than trees derived from models outside this interval. Although alternative criteria selected simpler models than the AIC, they suggested similar patterns. All together our results show that at a genomic scale, different gene alignments for the same set of taxa are best explained by a large variety of different substitution models and that model choice has implications on different parameter estimates including the inferred phylogenetic trees. After taking into account the differences related to sample size, our results suggest a noticeable diversity in the underlying evolutionary process. All together, we conclude that the use of model selection techniques is important to obtain consistent phylogenetic estimates from real data at a genomic scale. PMID- 21824870 TI - Comparison of results from quality control of physical parameters and results from clinical evaluation of mammographic images for the mammography screening facilities in Poland. AB - The material for this study comprised control protocols from 248 mammography screening facilities, prepared by physicists employed at 16 Regional Coordinating Centres and the results from the clinical evaluation of mammographic images in 248 facilities in Poland. All mammograms were evaluated independently by three experts selected from a list approved by the national consultant of radiology and diagnostic imaging. The requirements for proper breast positioning, selection of appropriate parameters for exposure and absence of artefacts were fulfilled only in 38 % of inspected mammography facilities. The requirements of the clinical audit were met only in 15 % of the mammography facilities. The requirements for the physical parameters of mammographic equipment were met only in 28 % of them. The requirements of the quality control (QC) tests and clinical audit were not fulfilled only in 19 % of the mammography facilities. Results from the QC of physical parameters are comparable with results from clinical evaluation of mammographic images in 57 % of the mammography facilities in Poland. PMID- 21824871 TI - Survey of practice in paediatric computed tomography. AB - The purpose of this study was to explore the frequency of paediatric computed tomography (CT) examinations in several hospitals in Bulgaria and to assess the current practice. The standard forms provided by the International Atomic Emergency Agency for survey of the paediatric CT practice were used. Six hospitals provided data on frequency of paediatric CT examinations performed in 2009. Large variations in dose, up to a factor of 4, were found among the centres within the same age group for a given procedure, and in one of the hospitals the paediatric dose was twice higher than the adult dose. Seven departments use dedicated CT protocols for children. Only 4 in 12 departments keep records of patient dose. Dose information for previous examinations is not required by the radiologists. The collected detailed data provided preliminary information how the patient doses in paediatric CT can be reduced. Recommendations were given based on the findings. PMID- 21824872 TI - Potential for optimisation of paediatric chest X-ray examination. AB - The purpose of this study was to compare the important aspects of paediatric radiological practice and the patient doses from chest X-ray examinations performed in three hospitals in Bulgaria. Data from 163 paediatric patients were recorded using a standardised form. Entrance surface air kerma (ESAK) to patient was calculated from the air-kerma air product (KAP) and field size measurements. Large variations were found for KAP and ESAK. Inappropriate film size and insufficient collimation were often used. Inappropriate use of automatic exposure control and antiscatter grid was found. In most cases, no attention was paid to reduce dose to sensitive organs by means of shielding or proper collimation. Recommendations were given to the hospitals on how to reduce patient doses in paediatric chest radiography. PMID- 21824873 TI - Practitioners education on medical exposure justification. AB - The knowledge of practitioners on justification of the individual medical exposure was assessed during education and training programmes. A survey containing questions on this issue was used. The results show that the Good Practice Guide should be disseminated and studied by radiation protection training programmes and such kind of training must be extended to prescribers because they have to be involved in the justification process. PMID- 21824874 TI - Real-time 3D transoesophageal measurement of the mitral valve area in patients with mitral stenosis. AB - AIMS: Planimetry measured by two-dimensional transthoracic echocardiography (TTE, MVA2D) is the reference method for the evaluation of the severity of mitral stenosis (MS) but requires experienced operators and good echocardiographic windows. Real-time three-dimensional transoesophageal echocardiography (3D-TEE, MVA3D) may overcome these limitations but its accuracy has never been evaluated. METHODS AND RESULTS: We prospectively enrolled 80 patients (58+/-15 years, 86% female) referred for MS evaluation who underwent, within 1 week, a clinically indicated TTE and TEE. MVA2D was measured by experienced operators (Level III), MVA3D by one experienced and one non-experienced (Level I) operators blinded of any clinical or TTE information. MVA3D measured by the experienced operator [1.11+/-0.32 cm2; median, 1.1 cm2; range (0.45-2.20)] did not differ from and correlated well with MVA2D [1.10+/-0.34 cm2; median, 1.05 cm2; range (0.45 2.30)], P=0.87; r=0.79, P<0.0001; ICC=0.79) and mean difference between methods was small (+0.004+/-0.21 cm2). MVA3D measured by the non-experienced operator [1.08+/-0.34 cm2; median 1.02 cm2; range (0.45-2.23)] also did not differ from and correlated well with MVA2D measured by experienced operators (P=0.25; r=0.86, P<0.0001; mean difference -0.02+/-0.18 cm2; ICC=0.86). Intra and interobserver variability were 0.02+/-0.25 and 0.01+/-0.33 cm2. CONCLUSION: 3D-TEE provides accurate and reproducible MVA measurements similar to 2D planimetry performed by experienced operators. Thus, 3D-TEE could be considered as a second-line alternative tool for the evaluation of MS severity in patients with poor echocardiographic windows or for team less accustomed to evaluate MS patients. PMID- 21824875 TI - Urinary N-terminal B-type natriuretic peptide predicts severe retinopathy of prematurity. AB - OBJECTIVE: The goal of this study was to evaluate urinary N-terminal fragment of B-type natriuretic peptide concentrations, normalized to creatinine (UNBCR), to predict morbidities at discharge in preterm infants. METHODS: UNBCR were determined in urine collected on day of life (DOL) 2, 7, 14, and 28 in 136 preterm infants <1500 g birth weight, 22 of whom developed bronchopulmonary dysplasia (BPD), defined as oxygen supplementation at 36 weeks' gestational age) and 11 infants developed severe retinopathy (ROP), defined as stage 3 or stage >= 2 requiring surgery). RESULTS: UNBCR on DOL 7, 14, and 28 was elevated in infants who developed BPD or ROP compared with controls (P <= .001). On multiple regression analysis including birth weight and gestational age, ROP but not BPD remained independently associated with UNBCR on DOL 14 and 28. Areas under receiver operating characteristic curves for UNBCR on DOL 14 and 28 to predict ROP were 0.938 (0.027) and 0.954 (0.021), respectively. UNBCR DOL 14 and 28 thresholds exceeded by all infants with severe ROP (100% sensitivity, 100% negative predictive value) had a specificity of 66% and 85%, respectively. CONCLUSIONS: UNBCR might hold promise to reduce unnecessary eye examinations by timely and accurate identification of infants at risk of severe ROP. PMID- 21824876 TI - Policy statement-Climatic heat stress and exercising children and adolescents. AB - Results of new research indicate that, contrary to previous thinking, youth do not have less effective thermoregulatory ability, insufficient cardiovascular capacity, or lower physical exertion tolerance compared with adults during exercise in the heat when adequate hydration is maintained. Accordingly, besides poor hydration status, the primary determinants of reduced performance and exertional heat-illness risk in youth during sports and other physical activities in a hot environment include undue physical exertion, insufficient recovery between repeated exercise bouts or closely scheduled same-day training sessions or rounds of sports competition, and inappropriately wearing clothing, uniforms, and protective equipment that play a role in excessive heat retention. Because these known contributing risk factors are modifiable, exertional heat illness is usually preventable. With appropriate preparation, modifications, and monitoring, most healthy children and adolescents can safely participate in outdoor sports and other physical activities through a wide range of challenging warm to hot climatic conditions. PMID- 21824877 TI - Advanced hemodynamic monitoring in critically ill children. AB - Circulatory shock is an important cause of pediatric morbidity and mortality and requires early recognition and prompt institution of adequate treatment protocols. Unfortunately, the hemodynamic status of the critically ill child is poorly reflected by physical examination, heart rate, blood pressure, or laboratory blood tests. Advanced hemodynamic monitoring consists, among others, of measuring cardiac output, predicting fluid responsiveness, calculating systemic oxygen delivery in relation to oxygen demand, and quantifying (pulmonary) edema. We discuss here the potential value of these hemodynamic monitoring technologies in relation to pediatric physiology. PMID- 21824878 TI - Temperature of foods sent by parents of preschool-aged children. AB - OBJECTIVE: To measure the temperatures of foods in sack lunches of preschool-aged children before consumption at child care centers. METHODS: All parents of 3- to 5-year-old children in full-time child care at 9 central Texas centers were invited to participate in the study. Foods packed by the parents for lunch were individually removed from the sack and immediately measured with noncontact temperature guns 1.5 hours before food was served to the children. Type of food and number of ice packs in the lunch sack were also recorded. Descriptive analyses were conducted by using SPSS 13.0 for Windows. RESULTS: Lunches, with at least 1 perishable item in each, were assessed from 235 parent-child dyads. Approximately 39% (n = 276) of the 705 lunches analyzed had no ice packs, 45.1% (n = 318) had 1 ice pack, and 88.2% (n = 622) of lunches were at ambient temperatures. Only 1.6% (n = 22) of perishable items (n = 1361) were in the safe temperature zone. Even with multiple ice packs, the majority of lunch items (>90%) were at unsafe temperatures. CONCLUSIONS: These results provide initial data on how frequently sack lunches sent by parents of preschool-aged children are kept at unsafe temperatures. Education of parents and the public must be focused on methods of packing lunches that allow the food to remain in the safe temperature zone to prevent foodborne illness. PMID- 21824879 TI - Receipt of health care transition counseling in the national survey of adult transition and health. AB - OBJECTIVE: The goal of this study was to examine factors associated with receiving health care transition counseling services as reported by young adults. METHODS: We analyzed data from the 2007 Survey of Adult Transition and Health, a nationwide survey of young adults aged 19 to 23 years conducted by the National Center for Health Statistics, to explore self-reported receipt of services to support transition from pediatric to adult health care. Multivariate logistic regression was used to identify whether sociodemographic characteristics, health status, or markers of provider-youth health communication were associated with the receipt of 3 key transition counseling services. RESULTS: Among the 1865 Survey of Adult Transition and Health respondents, 55% reported that their physicians or other health care providers had discussed how their needs would change with age, 53% reported that their physicians or other health care providers had discussed how to obtain health insurance as an adult, and 62% reported having participated in a transition plan in school. Only 24% reported receiving all 3 transition counseling services. In multivariate logistic regression analyses, although gender, age, and race were not associated with increased receipt of the transition-related outcomes, markers of strong communication with the health system were associated with increased rates of receiving transition guidance. CONCLUSIONS: Many young adults reported not having received health care transition counseling. Provider-youth communication was associated with increased health care transition guidance, and suggests that a medical home model that promotes anticipatory guidance for health care transition could promote improvements in the transition process. PMID- 21824880 TI - Intestinal parasite screening in internationally adopted children: importance of multiple stool specimens. AB - OBJECTIVE: Our goal was to determine the prevalence of intestinal parasites in internationally adopted children, to examine factors associated with infection, and to determine if evaluating multiple stool specimens increases the yield of parasite identification. METHODS: We evaluated internationally adopted children with at least 1 stool specimen submitted for ova and parasite testing within 120 days after arrival to the United States. In children submitting 3 stool specimens, in which at least 1 specimen was positive for the pathogen studied, we examined whether multiple stool specimens increased the likelihood of pathogen identification. RESULTS: Of the 1042 children studied, 27% had at least 1 pathogen identified; with pathogen-specific prevalence of Giardia intestinalis (19%), Blastocystis hominis (10%), Dientamoeba fragilis (5%), Entamoeba histolytica (1%), Ascaris lumbricoides (1%), and Hymenolepsis species (1%). The lowest prevalence occurred in South Korean (0%), Guatemalan (9%), and Chinese (13%) children, and the highest prevalence occurred in Ethiopian (55%) and Ukrainian (74%) children. Increasing age was significantly associated with parasite identification, whereas malnutrition and gastrointestinal symptoms were not. Overall, the yield of 1 stool specimen was 79% with pathogen recovery significantly increasing for 2 (92%) and 3 (100%) specimens, respectively (P < .0001). Pathogen identification also significantly increased with evaluation of additional stool specimens for children with and without gastrointestinal symptoms. CONCLUSIONS: We provide data for evidence-based guidelines for intestinal parasite screening in internationally adopted children. Gastrointestinal symptoms were not predictive of pathogen recovery, and multiple stool specimens increased pathogen identification in this high-risk group of children. PMID- 21824881 TI - Health behaviors and infant health outcomes in homeless pregnant women in the United States. AB - OBJECTIVE: To describe selected demographics; maternal health behaviors before, during, and after pregnancy; and infant health outcomes among homeless women in the United States. PATIENTS AND METHODS: Analyses are based on Pregnancy Risk Assessment Monitoring System data from 31 participating states from 2000 to 2007 that were linked to birth certificate data, which contain demographic and medical information collected through the state's vital records system. Responses were then weighted to be representative of all women who gave birth in each state during that year. Assessment of these data takes into account the complex sampling designs employed by the states. RESULTS: Four percent of women reported homelessness within 12 months before pregnancy, with the highest percentage in Illinois, followed by Oregon and Washington. Homeless women were younger, unmarried, uninsured, less educated, less likely to initiate and sustain breastfeeding, and had less prenatal care and well-visits. They were also more likely to be black, Hispanic, smoke cigarettes, be underweight or have class III obesity, and not take preconception multivitamins. Infants had lower birth weights, a longer hospital stay, and were more likely to receive neonatal intensive care. CONCLUSIONS: In this study we provide additional insight into homelessness in the perinatal period and provide information on ways to direct interventions aimed at improving the health of homeless mothers and infants. Additional research is needed to determine factors that influence pregnancy weight gain and infant feeding practices among homeless women and how this affects infant health. PMID- 21824882 TI - Gender- and gestational age-specific body fat percentage at birth. AB - BACKGROUND: There is increasing evidence that in utero growth has both immediate and far-reaching influence on health. Birth weight and length are used as surrogate measures of in utero growth. However, these measures poorly reflect neonatal adiposity. Air-displacement plethysmography has been validated for the measurement of body fat in the neonatal population. OBJECTIVE: The goal of this study was to show the normal reference values of percentage body fat (%BF) in infants during the first 4 days of life. METHODS: As part of a large population based birth cohort study, fat mass, fat-free mass, and %BF were measured within the first 4 days of life using air-displacement plethsymography. Infants were grouped into gestational age and gender categories. RESULTS: Of the 786 enrolled infants, fat mass, fat-free mass, and %BF were measured in 743 (94.5%) infants within the first 4 days of life. %BF increased significantly with gestational age. Mean (SD) %BF at 36 to 376/7 weeks' gestation was 8.9% (3.5%); at 38 to 39 weeks' gestation, 10.3% (4%); and at 40 to 416/7 weeks' gestation, 11.2% (4.3%) (P < .001). Female infants had significantly increased mean (SD) %BF at 38 to 396/7 (11.1% [3.9%] vs 9.8% [3.9%]; P = .012) and at 40 to 416/7 (12.5% [4.4%] vs 10% [3.9%]; P < .001) weeks' gestation compared with male infants. Gender- and gestational age-specific centiles were calculated, and a normative table was generated for reference. CONCLUSION: %BF at birth is influenced by gestational age and gender. We generated accurate %BF centiles from a large population-based cohort. PMID- 21824883 TI - Suicidal behavior differs among early and late adolescents treated with antidepressant agents. AB - OBJECTIVE: To identify circumstances and characteristics of suicidal behavior among early (aged 10-14 years) and late (aged 15-18 years) adolescents from a cohort of youth who were prescribed antidepressant medication. METHODS: In-depth reviews of all available medical records were performed for 250 randomly chosen confirmed episodes of suicidal behavior identified as part of a large retrospective cohort study of antidepressant users and suicidal behavior. Study data were obtained from Tennessee Medicaid records and death certificates from January 1, 1995, to December 31, 2006. Medical records and autopsy reports for cases identified from electronic data were adjudicated by 2 investigators blinded to exposure status and classified by using a validated scale. RESULTS: Of the 250 cases reviewed, 65.6% were female and 26.4% were aged 10 to 14 years. Medication ingestion was the most frequent method of suicidal behavior for both early and late adolescents; however, early adolescents were significantly more likely to use hanging as a method of suicide. Nearly one-half of the adolescents had previously attempted suicide. Early adolescents were significantly more likely to have a history of sexual abuse and significantly less likely to have a history of substance abuse. Early adolescents were also significantly more likely than older adolescents to have a history of a psychotic disorder and to report hallucinations before the suicide attempt. CONCLUSION: Suicidal behavior among early and late adolescents prescribed antidepressant medication differed in terms of methods used, previous psychiatric history, and proximal symptoms. PMID- 21824884 TI - Birth anomalies and obstetric history as risks for childhood tumors of the central nervous system. AB - OBJECTIVE: The causes of childhood central nervous system (CNS) tumors are largely unknown. Birth characteristics have been examined as possible risk factors for childhood CNS tumors, although the studies have been underpowered and inconclusive. We hypothesized that birth anomalies and a mother's history of previous pregnancy losses, as a proxy for genetic defects, increase the risk for CNS tumors. METHODS: From the California Cancer Registry, we identified 3733 patients aged 0 to 14 years with CNS tumors, diagnosed from 1988 through 2006 and linked to a California birth certificate. Four controls were matched to each patient. We calculated odds ratios (ORs) for the reported presence of a birth defect and for history of pregnancy losses by using logistic regression, adjusted for race, Hispanic ethnicity, maternal age, birth weight, and birth order. RESULTS: Offspring from mothers who had >= 2 fetal losses after 20 weeks' gestation had a threefold risk for CNS tumors (OR: 3.13 [95% confidence interval (CI): 1.32-7.41]) and a 14-fold risk for high-grade glioma (OR: 14.28 [95% CI: 1.56-130.65]). Birth defects increased risk for the CNS cancers medulloblastoma (OR: 1.70 [95% CI: 1.12-2.57]), primitive neuroectodermal tumor (OR: 3.64 [95% CI: 1.54-8.56]), and germ cell tumors (OR: 6.40 [95% CI: 2.09-19.56]). CONCLUSIONS: Multiple pregnancy losses after 20 weeks' gestation and birth defects increase the risk of a childhood CNS tumor. Previous pregnancy losses and birth defects may be surrogate markers for gene defects in developmental pathways that lead to CNS tumorigenesis. PMID- 21824885 TI - Quality-improvement initiative sustains improvement in pediatric health care worker hand hygiene. AB - OBJECTIVE: To use quality-improvement (QI) methods to develop and test a multimodal intervention to improve hand-hygiene compliance among health care workers (HCWs) to >90%. METHODS: We used a quasi-experimental staggered intervention that was conducted on 2 similar general pediatric units within a 475 bed tertiary children's hospital. Compliance was defined as acceptable hand hygiene both before and after contact with the patient or the patient's care environment. Measurement of HCW hand-hygiene compliance was performed by covert observations made during routine patient care. Twelve months of preintervention data were collected. QI methods were used to test and implement interventions sequentially in each unit. Interventions addressed leadership support, improving HCW knowledge, hand-hygiene supply availability, and HCW behavior. RESULTS: Interventions began on unit A on November 10, 2008. Similar interventions were later tested on unit B starting March 23, 2009. By April 1, 2009, compliance increased on unit A (from 65% to 91%) and unit B (from 74% to 92%). Improvement on each unit occurred only after the interventions were introduced. Identifying HCWs who failed to perform hand hygiene and offering alcohol-based hand rub to them before patient contact resulted in the greatest improvement. Improvements were sustained on both units for 18 months. CONCLUSIONS: Use of QI methods to implement a multimodal intervention resulted in sustained improvement in hand hygiene compliance. Real-time individual performance feedback or other high reliability human-factor interventions seem to be necessary to reach and sustain high levels of hand-hygiene compliance. PMID- 21824886 TI - Sickle cell trait screening in athletes: pediatricians' attitudes and concerns. AB - BACKGROUND: As part of a legal settlement in 2010, the National Collegiate Athletic Association (NCAA) adopted a recommendation that all Division I athletes be screened for sickle cell trait (SCT) or sign an exemption waiver. Pediatricians' attitudes about this policy are unknown. OBJECTIVE: We queried 3 specialty sections of the American Academy of Pediatrics (AAP)--the Section on Adolescent Health, the Council on Sports Medicine and Fitness (COSMF), and the Section on Bioethics-to determine attitudes about and knowledge of SCT testing of athletes. METHODS: Three e-mail surveys were sent to 600 members of the AAP chosen equally from the Section on Bioethics, the Section on Adolescent Health, and the COSMF. The survey queried respondents about their awareness of the NCAA policy and whether they supported universal or targeted screening based on gender, race/ethnicity, level of play, and type of sport. RESULTS: Usable responses from 254 of 574 eligible respondents (44%) were received. Respondents were 54% male and 84% white. Almost half were aware of the NCAA policy, with highest awareness in members of COSMF (P < .001). Only 40% supported universal screening, whereas 70% supported targeted screening of athletes in all NCAA divisions and would focus on black student-athletes more than on Hispanic or white-Mediterranean student-athletes (no differences among AAP sections/council). More than 75% of all respondents support allowing athletes or their parents to waive screening. A majority expressed some concern that athletes with SCT might experience discrimination in sports participation and/or insurance. Members of COSMF were least concerned about discrimination. CONCLUSIONS: The NCAA policy to universally screen Division I athletes is not uniformly supported by pediatricians, who prefer targeted screening based on race/ethnicity and sport in all NCAA divisions. We found little difference in policy considerations between members of the different AAP sections/council except that members of the COSMF were least concerned about discrimination. PMID- 21824887 TI - Undiagnosed heart disease leading to sudden unexpected death in childhood: a retrospective study. AB - OBJECTIVES: Heart disease accounts for a significant proportion of sudden unexpected deaths among children. We describe here demographic features, pathological conditions, and the frequency of premonitory symptoms in a retrospective series of cases of sudden unexpected cardiac death (SUCD) attributable to undiagnosed structural heart disease. METHODS: A chart review of autopsies involving children 0 to 17 years of age that were performed at the Hospital for Sick Children (Toronto, Ontario, Canada) between 1984 and 2003 was conducted. Cases of sudden unexpected death within 24 hours after clinical presentation with previously undetected fatal heart disease were included. Cases with multiple or thoracic trauma and chronic or multisystem disease were excluded. RESULTS: During the 20-year study period, 4926 autopsies were performed. A total of 103 cases (2.1%), involving 51 male patients and 52 female patients 1 day to 15 years of age (mean: 2.9 +/- 4.2 years), were diagnosed as having SUCD. The most common diagnoses were myocarditis (n = 37 [35.9%]), hypoplastic left heart syndrome (HLHS) (n = 19 [18.4%]), dilated cardiomyopathy (DCM) (n = 16 [16.5%]), coronary artery anomalies (n = 6 [5.8%]), and aortic stenosis (n = 5 [4.9%]). There was a significant difference in the mean age of presentation between leading causes of SUCD (6.5 days for HLHS, 1.7 years for DCM, and 5.4 years for myocarditis; P < .0001). Of 103 cases, 27 (26.2%) had premonitory symptoms documented. CONCLUSION: SUCD accounted for 2.1% of all autopsies, and HLHS, DCM, and myocarditis were the 3 most common diagnoses, which presented at increasing ages. PMID- 21824888 TI - Prospective longitudinal study of signs and symptoms associated with primary tooth eruption. AB - OBJECTIVE: To assess the association between primary tooth eruption and the manifestation of signs and symptoms of teething in infants. METHODS: An 8-month, longitudinal study was conducted with 47 noninstitutionalized infants (ie, receiving care at home) between 5 and 15 months of age in the city of Diamantina, Brazil. The nonrandomized convenience sample was based on the registry of infants in this age range provided by the Diamantina Secretary of Health. Eligible participants were infants with up to 7 erupted incisors and no history of chronic disease or disorders that could cause an increase in the signs and symptoms assessed in the study. Tympanic and axillary temperature readings and clinical oral examinations were performed daily. A daily interview with the mothers was conducted to investigate the occurrence of 13 signs and symptoms associated with teething presented by the infants in the previous 24 hours. RESULTS: Teething was associated with a rise in tympanic temperature on the day of the eruption (P = .004) and with the occurrence of other signs and symptoms. Readings of maximal tympanic and axillary temperatures were 36.8 degrees C and 36.6 degrees C, respectively. The most frequent signs and symptoms associated with teething were irritability (median: 0.60; P < .001), increased salivation (median: 0.50; P < .001), runny nose (median: 0.50; P < .001), and loss of appetite (median: 0.50; P < .001). CONCLUSIONS: Irritability, increased salivation, runny nose, loss of appetite, diarrhea, rash, and sleep disturbance were associated with primary tooth eruption. Results of this study support the concept that the occurrence of severe signs and symptoms, such as fever, could not be attributed to teething. PMID- 21824889 TI - Neurocytomas: long-term experience of a single institution. AB - There is a lack of studies reporting on outcomes of control and treatment toxicities for neurocytomas. A 25-year retrospective review of a tertiary center's experience with neurocytomas was completed to report on these outcomes. All cerebral neurocytoma cases (19 patients; median age, 31 years; range, 18-62 years; 18 intraventricular and 1 extraventricular) treated between 1984 and 2009 were analyzed, including central pathology and radiology reviews. Median follow up was 104.5 months (range, 0.75-261.7 months). Primary treatment was surgery alone (n = 18 patients), followed by surgery and adjuvant radiotherapy (n = 1). The crude local control rate after surgery was 68% for all cases (cerebral neurocytomas) and 74% for central neurocytomas. Salvage therapies included further surgery (n = 4), radiation (n = 3), and chemotherapy (n = 1). Ten-year Kaplan-Meier overall and relapse-free survival rates were 82% and 62% and 81% and 57%, respectively, for all cases and for central neurocytomas only. The median overall survival and relapse-free survival were 104.5 and 79.3 months, respectively, for all cases and for central neurocytomas. Ten patients had grade 3/4 toxicity, and 1 patient had a grade 5 perioperative hemorrhage that resulted in death 23 days after surgery. Late grade 3/4 toxicities occurred in 9 patients. Three patients had permanent grade 2 motor or cognitive deficits. We provide the first report outlining toxicities and survival outcomes in a series of 19 patients. Our experience suggests that initial surgery provides durable local control rates in two-thirds of patients, with low risk for significant permanent deficits. Salvage therapy with surgery and/or radiation provides durable local control in tumors that recur after surgery. PMID- 21824890 TI - Enhanced expression of coproporphyrinogen oxidase in malignant brain tumors: CPOX expression and 5-ALA-induced fluorescence. AB - In photodynamic diagnosis, 5-aminolevulinic acid (5-ALA) is widely used for the fluorescence-guided resection of malignant brain tumors, where 5-ALA is converted to protoporphyrin IX, which exhibits strong fluorescence. Little is known, however, about the detailed molecular mechanisms underlying 5-ALA-induced fluorescence. To resolve this issue, we analyzed transcriptome profiles for the genes encoding enzymes, transporters, and a transcription factor involved in the porphyrin-biosynthesis pathway. By quantitative real-time (qRT)-PCR, we measured the mRNA levels of those genes in a total of 20 tumor samples that had been surgically resected from brain tumor patients at the Department of Neurosurgery of Osaka Medical College from 2008 to 2009. We selected 10 tumor samples with no 5-ALA-induced fluorescence, among which 2 were glioblastomas and 8 were metastatic brain tumors. Another 10 tumor samples were selected with strong fluorescence, among which 7 were glioblastomas and 3 were metastatic brain tumors. The qRT-PCR analysis study of these latter 10 samples revealed predominantly high levels of the mRNA of the coproporphyrinogen oxidase (CPOX) gene. The high mRNA level of CPOX expression was significantly well correlated with the phenotype of strong 5-ALA-induced fluorescence (P = .0003). These findings were further confirmed by immunohistochemical studies with a CPOX specific antibody. It is concluded that induction of CPOX gene expression is one of the key molecular mechanisms underlying the 5-ALA-induced fluorescence of malignant brain tumors. The induction mechanism for the CPOX gene in brain tumors remains to be elucidated. PMID- 21824891 TI - The effectiveness of reintegrative shaming and restorative justice conferences: focusing on juvenile offenders' perceptions in Australian reintegrative shaming experiments. AB - This article examines the effectiveness of diversionary restorative justice (RJ) conferences through the eyes of juvenile offenders. In Australia, Reintegrative Shaming Experiments (RISE) are based on Braithwaite's theory of reintegrative shaming. Previous studies, although showing that RISE reported high levels of victim satisfaction and positive changes in the attitudes of offenders, also demonstrated that it has different outcomes for juvenile offenders depending on the type of offense with which they were charged. However, the effectiveness of RISE in terms of the offenders' perceptions has not been addressed, and the impact of the offenders' perceptions about RISE still remains under investigation. Using Australian data from RISE between 1995 and 1999, this article examines juvenile offenders' perceptions on preventing reoffending, repaying the victim and society, and the degree of repentance. The data were taken from interviews with juvenile offenders to measure their perceptions after the court or RISE processing. A comparison of standard court processing effects and RISE on juvenile offending, including property crime, shoplifting, and violent offenses, was undertaken. The results from this study were somewhat inconsistent with previous research. In this study, there was no significant relationship between RJ conference and the offenders' own perceptions on the prevention of future offending. However, it was found that there were treatment effects on repaying the victim, repaying society, and the degree of feeling repentance, and that younger offenders wanted to repay the victim/society and feel repentance. PMID- 21824892 TI - From the inside/out: Greene County jail inmates on restorative reentry. AB - The application of criminal justice sanctions is often misguided by a failure to recognize the need for a comprehensive approach in the transformation of offenders into law-abiding citizens. Restorative justice is a growing movement within criminal justice that recognizes the disconnect between offender rehabilitative measures and the social dynamics within which offender reentry takes place. By using restorative approaches to justice, what one hopes of these alternative processes is that the offenders become reconnected to the community and its values, something rarely seen in retributive models in which punishment is imposed and offenders can often experience further alienation from society. In this study, the authors wish to examine factors that contribute to failed prisoner reentry and reintegration and explore how restorative reintegration processes can address these factors as well as the needs, attitudes, and perceptions that help construct and maintain many of the obstacles and barriers returning inmates face when attempting to reintegrate into society. PMID- 21824894 TI - Does weight gain during pregnancy influence postpartum depression? AB - The goal of this study was to determine if weight gain during pregnancy has an effect on postpartum depression (PPD). Data were collected in a web survey from 238 women who had recently given birth. The data were analyzed for the total sample and also by body weight category before pregnancy. Findings revealed that weight gain was inversely associated with PPD for the obese women in our sample. For these women, the less weight they gained, the more likely they were to experience PPD. History of depression, partner support, and age were also predictors of PPD. PMID- 21824893 TI - Lung cancer survival with herbal medicine and vitamins in a whole-systems approach: ten-year follow-up data analyzed with marginal structural models and propensity score methods. AB - Complementary and alternative medicines are used by up to 48% of lung cancer patients but have seen little formal assessment of survival efficacy. In this 10 year retrospective survival study, the authors investigated Pan-Asian medicine + vitamins (PAM+V) therapy in a consecutive case series of all non-small-cell lung cancer patients (n = 239) presenting at a San Francisco Bay Area Chinese medicine center (Pine Street Clinic). They compared short-term treatment lasting the duration of chemotherapy/radiotherapy with long-term therapy continuing beyond conventional therapy. They also compared PAM+V plus conventional therapy with conventional therapy alone, using concurrent controls from the Kaiser Permanente Northern California and California Cancer Registries. They adjusted for confounding with Kaplan-Meier, Cox regression, and newer methods - propensity score and marginal structural models (MSMs), which when analyzing data from observational studies or clinical practice records can provide results comparable with randomized trials. Long-term use of PAM+V beyond completion of chemotherapy reduced stage IIIB deaths by 83% and stage IV by 72% compared with short-term use only for the duration of chemotherapy. Long-term PAM+V combined with conventional therapy reduced stage IIIA deaths by 46%, stage IIIB by 62%, and stage IV by 69% compared with conventional therapy alone. Survival rates for stage IV patients treated with PAM+V were 82% at 1 year, 68% at 2 years, and 14% at 5 years. PAM+V combined with conventional therapy improved survival in stages IIIA, IIIB, and IV, compared with conventional therapy alone. Prospective trials using PAM+V with conventional therapy for lung cancer patients are justified. PMID- 21824895 TI - Go fast! Reaction time differences between adults and adolescents in evaluating risky traffic situations. AB - This study investigated the hypothesis that adults are faster than adolescents in responding to risks. Twenty-six adolescents (M(age) = 15 years) and 26 adults (M(age) = 47 years) responded to risky situations (e.g. 'Is it a good idea to drive a car while having drunk alcohol?') and non-risky situations (e.g. '... wear a helmet while riding a moped?') in a choice reaction time task. Adults responded 110 ms faster to both risky and non-risky questions than adolescents. Both adolescents and adults responded on average 100 ms faster to risky questions than to non-risky questions. The results of this study suggest a possible explanation for the increased accident involvement of adolescents in traffic. PMID- 21824896 TI - How meaningful are data from Likert scales? An evaluation of how ratings are made and the role of the response shift in the socially disadvantaged. AB - Likert scales relating to quality of life were completed by the homeless (N = 75); first year students (N = 301) and a town population (N = 72). Participants also completed free text questions. The scale and free text data were often contradictory and the results highlighted three processes to account for these disparities: i) frame of reference: current salient issues influenced how questions were interpreted; ii) within-subject comparisons: ratings were based on expectations given past experiences; iii) time frame: those with more stable circumstances showed habituation to their level of deprivation. Likert scale data should be understood within the context of how ratings are made. PMID- 21824897 TI - A balancing act of optimising insulin dose and insulin sensitivity in type 1 diabetes. AB - The incidence and prevalence of type 1, insulin dependent, diabetes is increasing worldwide, spurring efforts to develop and improve therapeutic modalities to improve clinical outcomes for patients. Patients with type 1 diabetes are absolutely dependent on exogenous insulin replacement. Despite advances with novel rapid-acting and intermediate-acting insulin analogues, the net result of exogenous delivery is non-physiologic with respect to both timing and the circulating insulin concentrations achieved. This leads to periods of hyperglycaemia and hypoglycaemia, both of which contribute negatively to overall clinical outcome. Thus, better understanding of optimal insulin regimens is of clinical relevance for patients with type 1 diabetes. PMID- 21824898 TI - Influence of head positioning on the assessment of Chiari-like malformation in Cavalier King Charles spaniels. AB - Chiari-like malformation (CM) is almost omnipresent in the Cavalier King Charles spaniels (CKCS), often leading to syringomyelia (SM). Morphometric studies have produced variable results concerning relationship between the brain parenchyma within the caudal cranial fossa (CCF) and SM. The present study assesses the effect of head position, one potential confounder. Magnetic resonance images of CKCS with CM were reviewed in extended and flexed head positions. Volumes were calculated from transverse T2-weighted brain images. Mid-sagittal images were used for measurement of cerebellar herniation and CSF space between cerebellum and brainstem. Fourteen CKCS were included into the study, seven dogs with CM and seven with CM/SM. There was no difference between the relative brain parenchyma within the CCF in extended position and flexed position, or the brain parenchyma within the rostral and middle cranial fossae proportion. Cerebellar herniation and CSF space between cerebellum and brainstem were significantly increased in the flexed position. Cerebellar herniation and CSF space differed significantly between CM and CM/SM in a flexed head position. Volumetric measurements did not vary with head position. Cerebellar herniation and CSF space between the cerebellum and the brainstem were larger in a flexed head position. PMID- 21824899 TI - Endothelial nitric oxide synthase activation and nitric oxide function: new light through old windows. AB - The principle mechanisms operating at the level of endothelial nitric oxide synthase (eNOS) itself to control its activity are phosphorylation, the auto regulatory properties of the protein itself, and Ca(2)(+)/calmodulin binding. It is now clear that activation of eNOS is greatest when phosphorylation of certain serine and threonine residues is accompanied by elevation of cytosolic [Ca2+](i). While eNOS also contains an autoinhibitory loop, Rafikov et al. (2011) present the evidence for a newly identified 'flexible arm' that operates in response to redox state. Boeldt et al. (2011) also review the evidence that changes in the nature of endothelial Ca(2)(+) signaling itself in different physiologic states can extend both the amplitude and duration of NO output, and a failure to change these responses in pregnancy is associated with preeclampsia. The change in Ca(2)(+) signaling is mediated through altering capacitative entry mechanisms inherent in the cell, and so many agonist responses using this mechanism are altered. The term 'adaptive cell signaling' is also introduced for the first time to describe this phenomenon. Finally NO is classically regarded as a regulator of vascular function, but NO has other actions. One proposed role is regulation of steroid biosynthesis but the physiologic relevance was unclear. Ducsay & Myers (2011) now present new evidence that NO may provide the adrenal with a mechanism to regulate cortisol output according to exposure to hypoxia. One thing all three of these reviews show is that even after several decades of study into NO biosynthesis and function, there are clearly still many things left to discover. PMID- 21824900 TI - Altered urinary excretion of aquaporin 2 in IgA nephropathy. AB - OBJECTIVE: The intrarenal renin-angiotensin system (RAS) activation plays a pivotal role in immunoglobulin A nephropathy (IgAN) pathogenesis, which is still largely undefined. Recently, vasopressin (AVP) has been advocated to contribute to the genesis and progression of chronic kidney diseases (CKD) directly, and indirectly, via RAS activation. Our aim is to explore the intrarenal activity of AVP, its relationship with RAS activity, as well as its modulation by therapies in IgAN. DESIGN: In this observational study, we measured plasma copeptin, a surrogate marker of AVP, the urine excretion of aquaporin 2 (AQP2), a protein reflecting renal AVP action, and angiotensinogen (AGT), a parameter of renal RAS activation, and their relationship with renal function in 44 IgAN patients at the time of renal biopsy, without any drug therapy, and after 6-month treatment with ACEi or steroid+ACEi. Twenty-one patients with other CKD and 40 healthy subjects were recruited as controls. METHODS: ELISAs were used to measure all variables of interest. RESULTS: At baseline, IgAN patients showed higher urinary levels of AQP2, compared with controls and patients with other CKD. Urinary AQP2 and AGT levels strongly correlated with the presence of arterial hypertension. Steroids+ACEi caused the decrease of all the variables examined. The fall of urinary AQP2 and AGT following drug treatments was associated with the decrease of daily proteinuria. CONCLUSION: Our findings would support the involvement of AVP-AQP2 axis, interacting with the RAS, in the progression of IgAN and candidate AQP2 as a possible novel marker of the disease. PMID- 21824902 TI - Agencies warn of impending disaster on Sudan's disputed border. PMID- 21824901 TI - Management of adolescents and adults with febrile illness in resource limited areas. PMID- 21824903 TI - South Africa's rising maternal mortality is due to health system failures, says report. PMID- 21824904 TI - How to obtain the confidence interval from a P value. PMID- 21824906 TI - Intractable headache after lumbar puncture. PMID- 21824907 TI - Increased risk of glucose intolerance and type 2 diabetes with statins. PMID- 21824908 TI - Tar wars over smoking cessation. PMID- 21824909 TI - FDA is criticised for hinting it may loosen conflict of interest rules. PMID- 21824910 TI - Proposal to drop depression from GP quality indicators sparks outcry. PMID- 21824911 TI - NHS laboratories are infringing DNA patents with cheap "home brew" tests, says Human Genetics Commission. PMID- 21824912 TI - Impartial comparative analysis of measurement of leukocyte telomere length/DNA content by Southern blots and qPCR. AB - Telomere length/DNA content has been measured in epidemiological/clinical settings with the goal of testing a host of hypotheses related to the biology of human aging, but often the conclusions of these studies have been inconsistent. These inconsistencies may stem from various reasons, including the use of different telomere length measurement techniques. Here, we report the first impartial evaluation of measurements of leukocyte telomere length by Southern blot of the terminal restriction fragments and quantitative PCR (qPCR) of telomere DNA content, expressed as the ratio of telomeric product (T)/single copy gene (S) product. Blind measurements on the same samples from 50 donors were performed in two independent laboratories on two different occasions. Both the qPCR and Southern blots displayed highly reproducible results as shown by r values > 0.9 for the correlations between results obtained by either method on two occasions. The inter-assay CV measurement for the qPCR was 6.45%, while that of the Southern blots was 1.74%. The relation between the results generated by Southern blots versus those generated by qPCR deviated from linearity. We discuss the ramifications of these findings with regard to measurements of telomere length/DNA content in epidemiological/clinical circumstances. PMID- 21824913 TI - Clustering of Alpers disease mutations and catalytic defects in biochemical variants reveal new features of molecular mechanism of the human mitochondrial replicase, Pol gamma. AB - Mutations in Pol gamma represent a major cause of human mitochondrial diseases, especially those affecting the nervous system in adults and in children. Recessive mutations in Pol gamma represent nearly half of those reported to date, and they are nearly uniformly distributed along the length of the POLG1 gene (Human DNA Polymerase gamma Mutation Database); the majority of them are linked to the most severe form of POLG syndrome, Alpers-Huttenlocher syndrome. In this report, we assess the structure-function relationships for recessive disease mutations by reviewing existing biochemical data on site-directed mutagenesis of the human, Drosophila and yeast Pol gammas, and their homologs from the family A DNA polymerase group. We do so in the context of a molecular model of Pol gamma in complex with primer-template DNA, which we have developed based upon the recently solved crystal structure of the apoenzyme form. We present evidence that recessive mutations cluster within five distinct functional modules in the catalytic core of Pol gamma. Our results suggest that cluster prediction can be used as a diagnosis-supporting tool to evaluate the pathogenic role of new Pol gamma variants. PMID- 21824914 TI - A single methyltransferase YefA (RlmCD) catalyses both m5U747 and m5U1939 modifications in Bacillus subtilis 23S rRNA. AB - Methyltransferases that use S-adenosylmethionine (AdoMet) as a cofactor to catalyse 5-methyl uridine (m(5)U) formation in tRNAs and rRNAs are widespread in Bacteria and Eukaryota, and are also found in certain Archaea. These enzymes belong to the COG2265 cluster, and the Gram-negative bacterium Escherichia coli possesses three paralogues. These comprise the methyltransferases TrmA that targets U54 in tRNAs, RlmC that modifies U747 in 23S rRNA and RlmD that is specific for U1939 in 23S rRNA. The tRNAs and rRNAs of the Gram-positive bacterium Bacillus subtilis have the same three m(5)U modifications. However, as previously shown, the m(5)U54 modification in B. subtilis tRNAs is catalysed in a fundamentally different manner by the folate-dependent enzyme TrmFO, which is unrelated to the E. coli TrmA. Here, we show that methylation of U747 and U1939 in B. subtilis rRNA is catalysed by a single enzyme, YefA that is a COG2265 member. A recombinant version of YefA functions in an E. coli m(5)U-null mutant adding the same two rRNA methylations. The findings suggest that during evolution, COG2265 enzymes have undergone a series of changes in target specificity and that YefA is closer to an archetypical m(5)U methyltransferase. To reflect its dual specificity, YefA is renamed RlmCD. PMID- 21824915 TI - Cell type specific, traceable gene silencing for functional gene analysis during vertebrate neural development. AB - Many genes have several, sometimes divergent functions during development. Therefore, timing of gene knockdown for functional analysis during development has to be done with precise temporal control, as loss of a gene's function at early stages prevents its analysis later in development. RNAi, in combination with the accessibility of chicken embryos, is an effective approach for temporally controlled analysis of gene function during neural development. Here, we describe novel plasmid vectors that contain cell type-specific promoters/enhancers to drive the expression of a fluorescent marker, followed directly by a miR30-RNAi transcript for gene silencing. These vectors allow for direct tracing of cells experiencing gene silencing by the bright fluorescence. The level of knockdown is sufficient to reproduce the expected pathfinding defects upon perturbation of genes with known axon guidance functions. Mixing different vectors prior to electroporation enables the simultaneous knockdown of multiple genes in independent regions of the spinal cord. This permits complex cellular and molecular interactions to be examined during development, in a fast and precise manner. The advancements of the in ovo RNAi technique that we describe will not only markedly enhance functional gene analysis in the chicken, but also could be adapted to other organisms in developmental studies. PMID- 21824917 TI - Teaching medical professionals about suicide prevention: what's missing? PMID- 21824916 TI - Phosphorylation of polynucleotide kinase/ phosphatase by DNA-dependent protein kinase and ataxia-telangiectasia mutated regulates its association with sites of DNA damage. AB - Human polynucleotide kinase/phosphatase (PNKP) is a dual specificity 5'-DNA kinase/3'-DNA phosphatase, with roles in base excision repair, DNA single-strand break repair and non-homologous end joining (NHEJ); yet precisely how PNKP functions in the repair of DNA double strand breaks (DSBs) remains unclear. We demonstrate that PNKP is phosphorylated by the DNA-dependent protein kinase (DNA PK) and ataxia-telangiectasia mutated (ATM) in vitro. The major phosphorylation site for both kinases was serine 114, with serine 126 being a minor site. Ionizing radiation (IR)-induced phosphorylation of cellular PNKP on S114 was ATM dependent, whereas phosphorylation of PNKP on S126 required both ATM and DNA-PK. Inactivation of DNA-PK and/or ATM led to reduced PNKP at DNA damage sites in vivo. Cells expressing PNKP with alanine or aspartic acid at serines 114 and 126 were modestly radiosensitive and IR enhanced the association of PNKP with XRCC4 and DNA ligase IV; however, this interaction was not affected by mutation of PNKP phosphorylation sites. Purified PNKP protein with mutation of serines 114 and 126 had decreased DNA kinase and DNA phosphatase activities and reduced affinity for DNA in vitro. Together, our results reveal that IR-induced phosphorylation of PNKP by ATM and DNA-PK regulates PNKP function at DSBs. PMID- 21824918 TI - Aortic valve replacement in the elderly: determinants of late outcome. AB - BACKGROUND: Few data exist on long-term outcomes of elderly patients after aortic valve replacement. We evaluated latest follow-up information for patients >=70 years of age after aortic valve replacement. METHODS AND RESULTS: Late overall survival of 2890 consecutive patients >=70 years of age who underwent aortic valve replacement between January 1993 and December 2007 was reviewed retrospectively, analyzed, and stratified by preoperative and intraoperative variables. Observed 5-, 10-, and 15-year late postoperative survival was lower than generally expected (68%, 34%, and 8% versus 70%, 42%, and 20%, respectively; P<0.001). Independent predictors of late death included older age, renal failure, diabetes mellitus, stroke, myocardial infarction, immunosuppression, prior coronary artery bypass grafting, implanted pacemaker, lower ejection fraction, hypertension, and New York Heart Association class III or IV. After stratification by age-comorbidity risk score, 10-year survival for the lowest risk group (n=946 [33%]) was similar to expected survival (55% versus 55%; P=0.50), but for the highest-risk group (n=564 [20%]), survival was significantly lower than expected (9% versus 26%; P<0.001). For 229 pairs of propensity-matched patients with mechanical or biological prostheses, survival was not significantly different (67%, 40%, and 19% versus 71%, 45%, and 7% at 5, 10, and 15 years, respectively; P=0.81). Structural deterioration of bioprostheses occurred in 64 patients (2.4%). CONCLUSIONS: Survival of elderly patients after aortic valve replacement is influenced by age and preoperative comorbidities; 33% at lowest risk had overall survival similar to that of an age- and sex-matched general population. There was no sufficient evidence that valve type affected survival. Structural deterioration of aortic bioprostheses was rare. PMID- 21824919 TI - Age- and gender-specific familial risks for venous thromboembolism: a nationwide epidemiological study based on hospitalizations in Sweden. AB - BACKGROUND: This nationwide study sought to determine age- and gender-specific familial risks in siblings hospitalized for venous thromboembolism (VTE). METHODS AND RESULTS: The Swedish Multigeneration Register on 0- to 75-year-old subjects was linked to the Hospital Discharge Register for the years 1987-2007. Standardized incidence ratios were calculated for individuals whose siblings were hospitalized for VTE compared with those whose siblings were not affected. Among a total of 45 362 hospitalized cases with VTE, 2393 affected siblings were identified, with a familial standardized incidence ratio of 2.45 (95% confidence interval [CI], 1.66 to 3.61). Gender-specific differences in incidence rates were observed. The familial risks were significantly increased from the age of 10 to 69 years, with a familial standardized incidence ratio of 4.77 (95% CI, 1.96 to 10.83) at ages 10 to 19 years, which decreased to 2.08 (95% CI, 1.35 to 3.20) at ages 60 to 69 years, although the absolute risk increased with age. The familial standardized incidence ratios for siblings with 2 and >=3 affected probands were 51.87 (95% CI, 31.47 to 85.00) and 53.69 (95% CI, 25.59 to 108.50), respectively. Spouses had low familial risks (standardized incidence ratio=1.07; 95% CI, 1.04 to 1.10; observed spouse cases=3900). CONCLUSIONS: Familial factors, although influenced by age and gender, are important risk factors for VTE. The present study shows that VTE is aggregated in families and suggests that uncovering the sources of familial aggregation (genetic and nongenetic) may be worthwhile. Moreover, in a small fraction of siblings, the familial risk was very high, suggesting segregation of rare but strong genetic risk factors. PMID- 21824920 TI - Uncontrolled and apparent treatment resistant hypertension in the United States, 1988 to 2008. AB - BACKGROUND: Despite progress, many hypertensive patients remain uncontrolled. Defining characteristics of uncontrolled hypertensives may facilitate efforts to improve blood pressure control. METHODS AND RESULTS: Subjects included 13,375 hypertensive adults from National Health and Nutrition Examination Surveys (NHANESs) subdivided into 1988 to 1994, 1999 to 2004, and 2005 to 2008. Uncontrolled hypertension was defined as blood pressure >=140/>=90 mm Hg and apparent treatment-resistant hypertension (aTRH) when subjects reported taking >=3 antihypertensive medications. Framingham 10-year coronary risk was calculated. Multivariable logistic regression was used to identify clinical characteristics associated with untreated, treated uncontrolled on 1 to 2 blood pressure medications, and aTRH across all 3 survey periods. More than half of uncontrolled hypertensives were untreated across surveys, including 52.2% in 2005 to 2008. Clinical factors linked with untreated hypertension included male sex, infrequent healthcare visits (0 to 1 per year), body mass index <25 kg/m2, absence of chronic kidney disease, and Framingham 10-year coronary risk <10% (P<0.01). Most treated uncontrolled patients reported taking 1 to 2 blood pressure medications, a proxy for therapeutic inertia. This group was older, had higher Framingham 10-year coronary risk than patients controlled on 1 to 2 medications (P<0.01), and comprised 34.4% of all uncontrolled and 72.0% of treated uncontrolled patients in 2005 to 2008. We found that aTRH increased from 15.9% (1998-2004) to 28.0% (2005-2008) of treated patients (P<0.001). Clinical characteristics associated with aTRH included >=4 visits per year, obesity, chronic kidney disease, and Framingham 10-year coronary risk >20% (P<0.01). CONCLUSION: Untreated, undertreated, and aTRH patients have consistent characteristics that could inform strategies to improve blood pressure control by decreasing untreated hypertension, reducing therapeutic inertia in undertreated patients, and enhancing therapeutic efficiency in aTRH. PMID- 21824922 TI - Differential clinical responses to everolimus-eluting and Paclitaxel-eluting coronary stents in patients with and without diabetes mellitus. AB - BACKGROUND: Some (but not all) prior trials have reported differential outcomes after percutaneous coronary intervention with paclitaxel-eluting stents versus stents eluting rapamycin analogs according to the presence of diabetes mellitus. These studies lacked sufficient power to examine individual safety and efficacy end points. METHODS AND RESULTS: To determine whether an interaction exists between the presence of diabetes mellitus and treatment with everolimus-eluting stents compared with paclitaxel-eluting stents, we pooled the databases from the Clinical Evaluation of the Xience V Everolimus Eluting Coronary Stent System in the Treatment of Patients With De Novo Native Coronary Artery Lesions (SPIRIT) II, SPIRIT III, SPIRIT IV, and A Trial of Everolimus-Eluting Stents and Paclitaxel-Eluting Stents for Coronary Revascularization in Daily Practice (COMPARE) trials in which percutaneous coronary intervention was performed in 6780 patients, 1869 (27.6%) of whom had diabetes mellitus. Patients without diabetes mellitus treated with everolimus-eluting stents compared with paclitaxel eluting stents had significantly reduced 2-year rates of mortality (1.9% versus 3.1%; P=0.01), myocardial infarction (2.5% versus 5.8%; P<0.0001), stent thrombosis (0.3% versus 2.4%; P<0.0001), and ischemia-driven target lesion revascularization (3.6% versus 6.9%; P<0.0001). In contrast, among patients with diabetes mellitus, there were no significant differences between the 2 stent types in any measured safety or efficacy parameter. Significant interactions were present between diabetic status and stent type for the 2-year end points of myocardial infarction (P=0.01), stent thrombosis (P=0.0006), and target lesion revascularization (P=0.02). CONCLUSIONS: We have identified a substantial interaction between diabetes mellitus and stent type on clinical outcomes after percutaneous coronary intervention. In patients without diabetes mellitus, everolimus-eluting stents compared with paclitaxel-eluting stents resulted in substantial 2-year reductions in death, myocardial infarction, stent thrombosis, and target lesion revascularization, whereas no significant differences in safety or efficacy outcomes were present in diabetic patients. PMID- 21824921 TI - Striking In vivo phenotype of a disease-associated human SCN5A mutation producing minimal changes in vitro. AB - BACKGROUND: The D1275N SCN5A mutation has been associated with a range of unusual phenotypes, including conduction disease and dilated cardiomyopathy, as well as atrial and ventricular tachyarrhythmias. However, when D1275N is studied in heterologous expression systems, most studies show near-normal sodium channel function. Thus, the relationship of the variant to the clinical phenotypes remains uncertain. METHODS AND RESULTS: We identified D1275N in a patient with atrial flutter, atrial standstill, conduction disease, and sinus node dysfunction. There was no major difference in biophysical properties between wild type and D1275N channels expressed in Chinese hamster ovary cells or tsA201 cells in the absence or presence of beta1 subunits. To determine D1275N function in vivo, the Scn5a locus was modified to knock out the mouse gene, and the full length wild-type (H) or D1275N (DN) human SCN5A cDNAs were then inserted at the modified locus by recombinase mediated cassette exchange. Mice carrying the DN allele displayed slow conduction, heart block, atrial fibrillation, ventricular tachycardia, and a dilated cardiomyopathy phenotype, with no significant fibrosis or myocyte disarray on histological examination. The DN allele conferred gene dose-dependent increases in SCN5A mRNA abundance but reduced sodium channel protein abundance and peak sodium current amplitudes (H/H, 41.0+/-2.9 pA/pF at 30 mV; DN/H, 19.2+/-3.1 pA/pF, P<0.001 vs. H/H; DN/DN, 9.3+/-1.1 pA/pF, P<0.001 versus H/H). CONCLUSIONS: Although D1275N produces near-normal currents in multiple heterologous expression experiments, our data establish this variant as a pathological mutation that generates conduction slowing, arrhythmias, and a dilated cardiomyopathy phenotype by reducing cardiac sodium current. PMID- 21824923 TI - Arteriogenic therapy by intramyocardial sustained delivery of a novel growth factor combination prevents chronic heart failure. AB - BACKGROUND: Therapeutic angiogenesis is a promising approach for the treatment of cardiovascular diseases, including myocardial infarction and chronic heart failure. We aimed to improve proangiogenic therapies by identifying novel arteriogenic growth factor combinations, developing injectable delivery systems for spatiotemporally controlled growth factor release, and evaluating functional consequences of targeted intramyocardial growth factor delivery in chronic heart failure. METHODS AND RESULTS: First, we observed that fibroblast growth factor and hepatocyte growth factor synergistically stimulate vascular cell migration and proliferation in vitro. Using 2 in vivo angiogenesis assays (n=5 mice per group), we found that the growth factor combination results in a more potent and durable angiogenic response than either growth factor used alone. Furthermore, we determined that the molecular mechanisms involve potentiation of Akt and mitogen activated protein kinase signal transduction pathways, as well as upregulation of angiogenic growth factor receptors. Next, we developed crosslinked albumin alginate microcapsules that sequentially release fibroblast growth factor-2 and hepatocyte growth factor. Finally, in a rat model of chronic heart failure induced by coronary ligation (n=14 to 15 rats per group), we found that intramyocardial slow release of fibroblast growth factor-2 with hepatocyte growth factor potently stimulates angiogenesis and arteriogenesis and prevents cardiac hypertrophy and fibrosis, as determined by immunohistochemistry, leading to improved cardiac perfusion after 3 months, as shown by magnetic resonance imaging. These multiple beneficial effects resulted in reduced adverse cardiac remodeling and improved left ventricular function, as revealed by echocardiography. CONCLUSION: Our data showing the selective advantage of using fibroblast growth factor-2 together with hepatocyte growth factor suggest that this growth factor combination may constitute an efficient novel treatment for chronic heart failure. PMID- 21824925 TI - New and emerging weight management strategies for busy ambulatory settings: a scientific statement from the American Heart Association endorsed by the Society of Behavioral Medicine. PMID- 21824924 TI - Relation of obesity to circulating B-type natriuretic peptide concentrations in blacks: the Jackson Heart Study. AB - BACKGROUND: Lower plasma B-type natriuretic peptide (BNP) concentrations in obese individuals ("natriuretic handicap") may play a role in the pathogenesis of obesity-related hypertension. Whether this phenomenon may contribute to hypertension in blacks is unknown. We tested the hypothesis that body mass index is inversely related to BNP concentrations in blacks. METHODS AND RESULTS: We examined the relation of plasma BNP to body mass index in 3742 Jackson Heart Study participants (mean age, 55 +/- 13; 62% women) without heart failure using multivariable linear and logistic regression, adjusting for clinical and echocardiographic covariates. The multivariable-adjusted mean BNP was higher for lean participants compared with obese participants in both normotensive (P<0.0001) and hypertensive (P<0.0012) groups. In sex-specific analyses, the adjusted mean BNP was higher in lean hypertensive individuals compared with obese hypertensive individuals for both men (20.5 versus 10.9 pg/mL, respectively; P=0.0009) and women (20.0 versus 13.8 pg/mL; P=0.011). The differences between lean and obese participants were more pronounced in normotensive participants (men, 9.0 versus 4.4 pg/mL; P<0.0001; women, 12.8 versus 8.4 pg/mL; P=0.0005). For both hypertensive and normotensive individuals in the pooled sample, multivariable-adjusted BNP was significantly related to both continuous body mass index (P<0.05 and P<0.0001, respectively) and categorical body mass index (P for trend <0.006 and <0.0001, respectively). CONCLUSION: Our cross-sectional study of a large community-based sample of blacks demonstrates that higher body mass index is associated with lower circulating BNP concentrations, thereby extending the concept of a natriuretic handicap in obese individuals observed in non-Hispanic whites to this high-risk population. PMID- 21824926 TI - Cardiology patient page. What you need to know if you have coronary artery disease. PMID- 21824928 TI - Incomplete endothelialization and late dislocation after implantation of an Amplatzer septal occluder device. PMID- 21824929 TI - Letter by Shanmugam et al regarding article, "Primary results from the SmartDelay determined AV optimization: a comparison to other AV delay methods used in cardiac resynchronization therapy (SMART-AV) trial: a randomized trial comparing empirical, echocardiography-guided, and algorithmic atrioventricular delay programming in cardiac resynchronization therapy". PMID- 21824930 TI - Letter by Gasparovic et al regarding article, "Aspirin plus clopidogrel versus aspirin alone after coronary artery bypass grafting: the clopidogrel after surgery for coronary artery disease (CASCADE) trial". PMID- 21824931 TI - Letter by Bisdas et al regarding article, "Aspirin plus clopidogrel versus aspirin alone after coronary artery bypass grafting: the clopidogrel after surgery for coronary artery disease (CASCADE) trial". PMID- 21824932 TI - Biomarkers in clinical trials: can we move from fortune telling to disease profiling? PMID- 21824933 TI - Glycated hemoglobin as a prognostic risk marker in nondiabetic patients after acute myocardial infarction: what now? PMID- 21824934 TI - How important is the electrocardiogram in protecting and guiding the athlete? PMID- 21824935 TI - Integrating information from novel risk factors with calculated risks: the critical impact of risk factor prevalence. PMID- 21824936 TI - Interpretation of the electrocardiogram of young athletes. PMID- 21824937 TI - Retrocardiac textiloma mimicking a left atrium myxoma. PMID- 21824938 TI - Physician specialty and carotid stenting among elderly medicare beneficiaries in the United States. AB - BACKGROUND: The use of carotid stenting is rising across the United States. How physician specialty relates to its utilization rates or outcomes is uncertain. METHODS: We performed an observational analysis of fee-for-service Medicare beneficiaries 65 years or older undergoing carotid stenting between 2005 and 2007 in 306 hospital referral regions (HRRs). We first determined how frequently carotid stenting was performed by different specialists within each HRR and then used multivariable regression models to compare population-based utilization rates and 30-day outcomes for this procedure across HRRs based on the proportion performed by cardiologists, surgeons, radiologists, or a mix of specialists. RESULTS: In 272 HRRs where at least 15 procedures were performed during the study period, we identified 28 700 carotid stenting procedures performed by 2588 operators. While cardiologists made up approximately one-third of these operators, they were responsible for 14 919 (52.0%) procedures. Significant differences were noted in the characteristics of patients treated by cardiologists compared with other specialties, including higher rates of invasive cardiac procedures and lower rates of acute stroke or transient ischemic attacks in the 180 days prior to carotid stenting. Population-based utilization rates were significantly higher in HRRs where cardiologists performed most procedures relative to HRRs where most were done by other specialists or a mix of specialists (P < .001). In contrast, risk-standardized outcomes did not differ across HRRs based on physician specialty. CONCLUSIONS: Carotid stenting is being performed by operators from diverse specialties. Hospital referral regions where cardiologists perform most procedures have higher population-based utilization rates with similar outcomes. PMID- 21824939 TI - Hazards of hospitalization: more than just "never events". PMID- 21824940 TI - Diagnostic blood loss from phlebotomy and hospital-acquired anemia during acute myocardial infarction. AB - BACKGROUND: Hospital-acquired anemia (HAA) during acute myocardial infarction (AMI) is associated with higher mortality and worse health status and often develops in the absence of recognized bleeding. The extent to which diagnostic phlebotomy, a modifiable process of care, contributes to HAA is unknown. METHODS: We studied 17,676 patients with AMI from 57 US hospitals included in a contemporary AMI database from January 1, 2000, through December 31, 2008, who were not anemic at admission but developed moderate to severe HAA (in which the hemoglobin level declined from normal to <11 g/dL), a degree of HAA that has been shown to be prognostically important. Patients' total diagnostic blood loss was calculated by multiplying the number and types of blood tubes drawn by the standard volume for each tube type. Hierarchical modified Poisson regression was used to test the association between phlebotomy and moderate to severe HAA, after adjusting for site and potential confounders. RESULTS: Moderate to severe HAA developed in 3551 patients (20%). The mean (SD) phlebotomy volume was higher in patients with HAA (173.8 [139.3] mL) vs those without HAA (83.5 [52.0 mL]; P < .001). There was significant variation in the mean diagnostic blood loss across hospitals (moderate to severe HAA: range, 119.1-246.0 mL; mild HAA or no HAA: 53.0-110.1 mL). For every 50 mL of blood drawn, the risk of moderate to severe HAA increased by 18% (relative risk [RR], 1.18; 95% confidence interval [CI], 1.13-1.22), which was only modestly attenuated after multivariable adjustment (RR, 1.15; 95% CI, 1.12-1.18). CONCLUSIONS: Blood loss from greater use of phlebotomy is independently associated with the development of HAA. These findings suggest that HAA may be preventable by implementing strategies to limit blood loss from laboratory testing. PMID- 21824941 TI - The RAD-HOME project: a pilot study of home delivery of radiology services. PMID- 21824942 TI - Large T-wave inversion in a patient with a pacemaker. PMID- 21824944 TI - Is predialysis nephrology care worthwhile? PMID- 21824945 TI - Safety-net providers and preparation for health reform: staff down, staff up, staff differently. PMID- 21824946 TI - Procalcitonin algorithms for antibiotic therapy decisions: a systematic review of randomized controlled trials and recommendations for clinical algorithms. AB - Previous randomized controlled trials suggest that using clinical algorithms based on procalcitonin levels, a marker of bacterial infections, results in reduced antibiotic use without a deleterious effect on clinical outcomes. However, algorithms differed among trials and were embedded primarily within the European health care setting. Herein, we summarize the design, efficacy, and safety of previous randomized controlled trials and propose adapted algorithms for US settings. We performed a systematic search and included all 14 randomized controlled trials (N = 4467 patients) that investigated procalcitonin algorithms for antibiotic treatment decisions in adult patients with respiratory tract infections and sepsis from primary care, emergency department (ED), and intensive care unit settings. We found no significant difference in mortality between procalcitonin-treated and control patients overall (odds ratio, 0.91; 95% confidence interval, 0.73-1.14) or in primary care (0.13; 0-6.64), ED (0.95; 0.67 1.36), and intensive care unit (0.89; 0.66-1.20) settings individually. A consistent reduction was observed in antibiotic prescription and/or duration of therapy, mainly owing to lower prescribing rates in low-acuity primary care and ED patients, and shorter duration of therapy in moderate- and high-acuity ED and intensive care unit patients. Measurement of procalcitonin levels for antibiotic decisions in patients with respiratory tract infections and sepsis appears to reduce antibiotic exposure without worsening the mortality rate. We propose specific procalcitonin algorithms for low-, moderate-, and high-acuity patients as a basis for future trials aiming at reducing antibiotic overconsumption. PMID- 21824947 TI - Screening for colorectal cancer in the elderly population: how much is enough? PMID- 21824948 TI - Lifestyle modification and prevention of type 2 diabetes in overweight Japanese with impaired fasting glucose levels: a randomized controlled trial. AB - BACKGROUND: Previous studies demonstrated that intensive lifestyle modification can prevent type 2 diabetes mellitus among those with impaired glucose tolerance, but similar beneficial results have not been proved among those with impaired fasting glucose levels. We investigated the efficacy of lifestyle modification on type 2 diabetes incidence among those with impaired fasting glucose levels. METHODS: The present study was an unmasked, multicenter, randomized, controlled trial. A total of 641 overweight Japanese (aged 30-60 years) with impaired fasting glucose levels were recruited nationwide in Japan and randomly assigned to a frequent intervention group (n = 311) or a control group (n = 330). For 36 months after randomization, the frequent intervention group received individual instructions and follow-up support for lifestyle modification from the medical staff 9 times. The control group received similar individual instructions 4 times at 12-month intervals during the same period. The primary outcome was type 2 diabetes incidence in annual 75-g oral glucose tolerance tests, diagnosed according to World Health Organization criteria. RESULTS: There were no significant differences between the allocation groups in baseline characteristics and dropout rates. Estimated cumulative incidences of type 2 diabetes were 12.2% in the frequent intervention group and 16.6% in the control group. Overall, the adjusted hazard ratio in the frequent intervention group was 0.56 (95% confidence interval, 0.36-0.87). In the post hoc subgroup analyses, the hazard ratio reduced to 0.41 (95% confidence interval, 0.24-0.69) among participants with impaired glucose tolerance at baseline, and to 0.24 (0.12-0.48) among those with baseline hemoglobin A(1c) levels of 5.6% or more (the Japan Diabetes Society method). Such risk reduction was not observed among those with isolated impaired fasting glucose findings or baseline hemoglobin A(1c) levels of less than 5.6%. CONCLUSIONS: Lifestyle modifications can prevent type 2 diabetes among overweight Japanese with impaired fasting glucose levels. In addition, identifying individuals with more deteriorated glycemic status by using 75-g oral glucose tolerance test findings or, especially, measurement of hemoglobin A(1c) levels, could enhance the efficacy of lifestyle modifications. TRIAL REGISTRATION: umin.ac.jp/ctr Identifier: UMIN000001959. PMID- 21824949 TI - Prevention of type 2 diabetes: comment on "Lifestyle modification and prevention of type 2 diabetes in overweight Japanese with impaired fasting glucose levels". PMID- 21824950 TI - Soy isoflavones in the prevention of menopausal bone loss and menopausal symptoms: a randomized, double-blind trial. AB - BACKGROUND: Concerns regarding the risk of estrogen replacement have resulted in a significant increase in the use of soy products by menopausal women who, despite the lack of evidence of the efficacy of such products, seek alternatives to menopausal hormone therapy. Our goal was to determine the efficacy of soy isoflavone tablets in preventing bone loss and menopausal symptoms. METHODS: The study design was a single-center, randomized, placebo-controlled, double-blind clinical trial conducted from July 1, 2004, through March 31, 2009. Women aged 45 to 60 years within 5 years of menopause and with a bone mineral density T score of -2.0 or higher in the lumbar spine or total hip were randomly assigned, in equal proportions, to receive daily soy isoflavone tablets, 200 mg, or placebo. The primary outcome was changes in bone mineral density in the lumbar spine, total hip, and femoral neck at the 2-year follow-up. Secondary outcomes included changes in menopausal symptoms, vaginal cytologic characteristics, N -telopeptide of type I bone collagen, lipids, and thyroid function. RESULTS: After 2 years, no significant differences were found between the participants receiving soy tablets (n = 122) and those receiving placebo (n = 126) regarding changes in bone mineral density in the spine (-2.0% and -2.3%, respectively), the total hip (-1.2% and 1.4%, respectively), or the femoral neck (-2.2% and -2.1%, respectively). A significantly larger proportion of participants in the soy group experienced hot flashes and constipation compared with the control group. No significant differences were found between groups in other outcomes. CONCLUSIONS: In this population, the daily administration of tablets containing 200 mg of soy isoflavones for 2 years did not prevent bone loss or menopausal symptoms. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00076050. PMID- 21824951 TI - Soy isoflavones for prevention of menopausal bone loss and vasomotor symptoms: comment on "Soy isoflavones in the prevention of menopausal bone loss and menopausal symptoms". PMID- 21824952 TI - Predialysis nephrology care of older patients approaching end-stage renal disease. AB - BACKGROUND: Little is known about trends in the timing of first nephrology consultation and associated outcomes among older patients initiating dialysis. METHODS: Data from patients aged 67 years or older who initiated dialysis in the United States between January 1, 1996, and December 31, 2006, were stratified by timing of the earliest identifiable nephrology visit. Trends of earlier nephrology consultation were formally examined in light of concurrently changing case mix and juxtaposed with trends in 1-year mortality rates after initiation of dialysis. RESULTS: Among 323,977 older patients initiating dialysis, the proportion of patients receiving nephrology care less than 3 months before initiation of dialysis decreased from 49.6% (in 1996) to 34.7% (in 2006). Patients initiated dialysis with increasingly preserved kidney function, from a mean estimated glomerular filtration rate of 8 mL/min/1.73 m(2) in 1996 to 12 mL/min/1.73 m(2) in 2006. Patients were less anemic in later years, which was partly attributable to increased use of erythropoiesis-stimulating agents, and fewer used peritoneal dialysis as the initial modality. During the same period, crude 1-year mortality rates remained unchanged (annual change in mortality rate, +0.2%; 95% confidence interval, 0% to +0.4%). Adjustment for changes in demographic and comorbidity patterns yielded estimated annual reductions in 1 year mortality rates of 0.9% (95% confidence interval, 0.7% to 1.1%), which were explained only partly by concurrent trends toward earlier nephrology consultation (annual mortality reduction after accounting for timing of nephrology care was attenuated to 0.4% [0.2% to 0.6%]). CONCLUSIONS: Despite significant trends toward earlier use of nephrology consultation among older patients approaching maintenance dialysis, we observed no material improvement in 1-year survival rates after dialysis initiation during the same time period. PMID- 21824955 TI - The "top 5" health care activities for which less is more: comment on "The 'top 5' lists in primary care". PMID- 21824953 TI - Earlier nephrology consultation is not associated with improved survival: comment on "Predialysis nephrology care of older patients approaching end-stage renal disease". PMID- 21824954 TI - Safety-net providers after health care reform: lessons from Massachusetts. AB - BACKGROUND: National health reform is designed to reduce the number of uninsured adults. Currently, many uninsured individuals receive care at safety-net health care providers such as community health centers (CHCs) or safety-net hospitals. This project examined data from Massachusetts to assess how the demand for ambulatory and inpatient care and use changed for safety-net providers after the state's health care reform law was enacted in 2006, which dramatically reduced the number of individuals without health insurance coverage. METHODS: Multiple methods were used, including analyses of administrative data reported by CHCs and hospitals, case study interviews, and analyses of data from the 2009 Massachusetts Health Reform Survey, a state-representative telephone survey of adults. RESULTS: Between calendar years 2005 and 2009, the number of patients receiving care at Massachusetts CHCs increased by 31.0%, and the share of CHC patients who were uninsured fell from 35.5% to 19.9%. Nonemergency ambulatory care visits to clinics of safety-net hospitals grew twice as fast as visits to non-safety-net hospitals from 2006 to 2009. The number of inpatient admissions was comparable for safety-net and non-safety-net hospitals. Most safety-net patients reported that they used these facilities because they were convenient (79.3%) and affordable (73.8%); only 25.2% reported having had problems getting appointments elsewhere. CONCLUSIONS: Despite the significant reduction in uninsurance levels in Massachusetts that occurred with health care reform, the demand for care at safety-net facilities continues to rise. Most safety-net patients do not view these facilities as providers of last resort; rather, they prefer the types of care that are offered there. It will continue to be important to support safety-net providers, even after health care reform programs are established. PMID- 21824957 TI - Medical technology--still an adjunct to clinical skills in making a diagnosis: comment on "Utility of clinical examination in the diagnosis of emergency department patients admitted to the department of medicine of an academic hospital". PMID- 21824958 TI - The value of history taking in diagnosis: comment on "Utility of clinical examination in the diagnosis of emergency department patients admitted to the department of medicine of an academic hospital". PMID- 21824956 TI - Utility of clinical examination in the diagnosis of emergency department patients admitted to the department of medicine of an academic hospital. PMID- 21824959 TI - Changes in barriers to primary care and emergency department utilization. PMID- 21824960 TI - Patient concerns at hospital admission. PMID- 21824961 TI - The comparative safety of opioids for nonmalignant pain in older adults. PMID- 21824962 TI - What is a reasonable threshold for worries about health risks? PMID- 21824963 TI - Improving clinical practice guidelines--the answer is more clinical research. PMID- 21824964 TI - Evaluation of IDSA clinical practice guidelines: a call to re-GRADE underlying evidence. PMID- 21824965 TI - Does industry have a role in medical education? PMID- 21824966 TI - Ambiguous mechanisms of dysphagia in multiple system atrophy. PMID- 21824967 TI - Mental health professionals' perspectives of telemental health with remote and rural First Nations communities. AB - We conducted an online survey and interviews amongst mental health workers in Canada who reported experience in working with rural and remote First Nations (although not necessarily telemental health). Sixty-three respondents (of the 164) to the online survey reported experience in working with clients in remote and rural First Nations. Only 16 of the online survey respondents with remote and rural First Nations experience reported having received training in videoconferencing use. When asked how frequently they used videoconferencing with clients, 51% reported never using it, 19% used it once every few months and 10% reported using it a few times a month. Approximately 50% of participants reported finding it useful. Approximately 38% found the technology easy or very easy to use, and 15% found it very difficult. Individual in-depth interviews were also conducted with professionals who had First Nations telemental health experience specifically (n = 5). A quantitative data analysis was used to explore their perceptions of usefulness and ease of use of telemental health, as well as the relationships among these constructs. Advantages, disadvantages and challenges in using the technology were identified from the qualitative data. Promising ways forward include incorporating traditional practices and the Seven Teachings into telemental health services. PMID- 21824968 TI - Telemedicine in acute stroke care: the TESSA model. AB - We conducted a retrospective controlled study to assess the safety and effectiveness of intravenous thrombolysis via videoconferencing, followed by patient transport to a specialized stroke unit. Between 2006 and 2009, 47 stroke patients were treated in peripheral hospitals in the county of Salzburg in Austria by intravenous thrombolysis via telemedicine; 304 patients who were treated with intravenous thrombolysis at a stroke unit served as the control group. The mean age of the patients was 67 years in the telemedicine group and 71 years in the control group. Haemorrhagic bleeding occurred in 6.4% of the telemedicine group compared to 7.6% of the control group. The mean onset-to needle time was 113 min in the telemedicine group and 122 min in the control group (P = 0.263). At three-month follow-up, 47% of the patients in the telemedicine group had good functional outcomes (mRS, dichotomized analysis 0-1) versus 43% in the control group (P = 0.694). The overall mortality at three-month follow-up was 19% in the telemedicine group and 13% in the control group (P = 0.248). Telemedicine can be used to support regional areas with little experience in delivering intravenous thrombolysis, thus raising the standard of stroke care and minimizing inequalities. PMID- 21824969 TI - Telemonitoring improves home health utilization outcomes in rural settings. AB - We have examined the hypothesis that home telemonitoring, when added to conventional home care in rural settings, results in less acute care hospitalization and more discharge to the community. Five US rural home health agencies of different types participated in the study. All agencies were not-for profit and served low-income patients in designated health professional shortage areas or medically underserved areas/populations. A prospective treatment group was telemonitored daily in the home during the period 1 October 2006 to 31 May 2009 (n = 1419). An historical control group was selected sequentially backwards from 30 September 2006 (n = 1502). Both groups had home health services for approximately 50 days (P = 0.76). We used logistic regression modelling, with covariate data captured from the Outcome and Assessment Information Set (OASIS) data set, to assess the effect of group on outcome. Home telemonitoring was found to reduce the odds of any acute care hospitalization (OR = 0.59, P < 0.001) and to increase the odds of discharge to the community (OR = 1.36, P = 0.003). PMID- 21824970 TI - Inferring disease and gene set associations with rank coherence in networks. AB - MOTIVATION: To validate the candidate disease genes identified from high throughput genomic studies, a necessary step is to elucidate the associations between the set of candidate genes and disease phenotypes. The conventional gene set enrichment analysis often fails to reveal associations between disease phenotypes and the gene sets with a short list of poorly annotated genes, because the existing annotations of disease-causative genes are incomplete. This article introduces a network-based computational approach called rcNet to discover the associations between gene sets and disease phenotypes. A learning framework is proposed to maximize the coherence between the predicted phenotype-gene set relations and the known disease phenotype-gene associations. An efficient algorithm coupling ridge regression with label propagation and two variants are designed to find the optimal solution to the objective functions of the learning framework. RESULTS: We evaluated the rcNet algorithms with leave-one-out cross validation on Online Mendelian Inheritance in Man (OMIM) data and an independent test set of recently discovered disease-gene associations. In the experiments, the rcNet algorithms achieved best overall rankings compared with the baselines. To further validate the reproducibility of the performance, we applied the algorithms to identify the target diseases of novel candidate disease genes obtained from recent studies of Genome-Wide Association Study (GWAS), DNA copy number variation analysis and gene expression profiling. The algorithms ranked the target disease of the candidate genes at the top of the rank list in many cases across all the three case studies. AVAILABILITY: http://compbio.cs.umn.edu/dgsa_rcNet CONTACT: kuang@cs.umn.edu. PMID- 21824972 TI - Metannogen: annotation of biological reaction networks. AB - MOTIVATION: Semantic annotations of the biochemical entities constituting a biological reaction network are indispensable to create biologically meaningful networks. They further heighten efficient exchange, reuse and merging of existing models which concern present-day systems biology research more often. Two types of tools for the reconstruction of biological networks currently exist: (i) several sophisticated programs support graphical network editing and visualization. (ii) Data management systems permit reconstruction and curation of huge networks in a team of scientists including data integration, annotation and cross-referencing. We seeked ways to combine the advantages of both approaches. RESULTS: Metannogen, which was previously developed for network reconstruction, has been considerably improved. From now on, Metannogen provides sbml import and annotation of networks created elsewhere. This permits users of other network reconstruction platforms or modeling software to annotate their networks using Metannogen's advanced information management. We implemented word-autocompletion, multipattern highlighting, spell check, brace-expansion and publication management, and improved annotation, cross-referencing and team work requirements. Unspecific enzymes and transporters acting on a spectrum of different substrates are efficiently handled. The network can be exported in sbml format where the annotations are embedded in line with the miriam standard. For more comfort, Metannogen may be tightly coupled with the network editor such that Metannogen becomes an additional view for the focused reaction in the network editor. Finally, Metannogen provides local single user, shared password protected multiuser or public access to the annotation data. AVAILABILITY: Metannogen is available free of charge at: http://www.bioinformatics.org/strap/metannogen/ or http://3d-alignment.eu/metannogen/. CONTACT: christoph.gille@charite.de SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 21824971 TI - FDM: a graph-based statistical method to detect differential transcription using RNA-seq data. AB - MOTIVATION: In eukaryotic cells, alternative splicing expands the diversity of RNA transcripts and plays an important role in tissue-specific differentiation, and can be misregulated in disease. To understand these processes, there is a great need for methods to detect differential transcription between samples. Our focus is on samples observed using short-read RNA sequencing (RNA-seq). METHODS: We characterize differential transcription between two samples as the difference in the relative abundance of the transcript isoforms present in the samples. The magnitude of differential transcription of a gene between two samples can be measured by the square root of the Jensen Shannon Divergence (JSD*) between the gene's transcript abundance vectors in each sample. We define a weighted splice graph representation of RNA-seq data, summarizing in compact form the alignment of RNA-seq reads to a reference genome. The flow difference metric (FDM) identifies regions of differential RNA transcript expression between pairs of splice graphs, without need for an underlying gene model or catalog of transcripts. We present a novel non-parametric statistical test between splice graphs to assess the significance of differential transcription, and extend it to group-wise comparison incorporating sample replicates. RESULTS: Using simulated RNA-seq data consisting of four technical replicates of two samples with varying transcription between genes, we show that (i) the FDM is highly correlated with JSD* (r=0.82) when average RNA-seq coverage of the transcripts is sufficiently deep; and (ii) the FDM is able to identify 90% of genes with differential transcription when JSD* >0.28 and coverage >7. This represents higher sensitivity than Cufflinks (without annotations) and rDiff (MMD), which respectively identified 69 and 49% of the genes in this region as differential transcribed. Using annotations identifying the transcripts, Cufflinks was able to identify 86% of the genes in this region as differentially transcribed. Using experimental data consisting of four replicates each for two cancer cell lines (MCF7 and SUM102), FDM identified 1425 genes as significantly different in transcription. Subsequent study of the samples using quantitative real time polymerase chain reaction (qRT-PCR) of several differential transcription sites identified by FDM, confirmed significant differences at these sites. AVAILABILITY: http://csbio linux001.cs.unc.edu/nextgen/software/FDM CONTACT: darshan@email.unc.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 21824973 TI - A biclustering algorithm for extracting bit-patterns from binary datasets. AB - MOTIVATION: Binary datasets represent a compact and simple way to store data about the relationships between a group of objects and their possible properties. In the last few years, different biclustering algorithms have been specially developed to be applied to binary datasets. Several approaches based on matrix factorization, suffix trees or divide-and-conquer techniques have been proposed to extract useful biclusters from binary data, and these approaches provide information about the distribution of patterns and intrinsic correlations. RESULTS: A novel approach to extracting biclusters from binary datasets, BiBit, is introduced here. The results obtained from different experiments with synthetic data reveal the excellent performance and the robustness of BiBit to density and size of input data. Also, BiBit is applied to a central nervous system embryonic tumor gene expression dataset to test the quality of the results. A novel gene expression preprocessing methodology, based on expression level layers, and the selective search performed by BiBit, based on a very fast bit-pattern processing technique, provide very satisfactory results in quality and computational cost. The power of biclustering in finding genes involved simultaneously in different cancer processes is also shown. Finally, a comparison with Bimax, one of the most cited binary biclustering algorithms, shows that BiBit is faster while providing essentially the same results. AVAILABILITY: The source and binary codes, the datasets used in the experiments and the results can be found at: http://www.upo.es/eps/bigs/BiBit.html CONTACT: dsrodbae@upo.es SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 21824974 TI - Commentary: Pregnancy outcome--a fertile barometer for women's health. PMID- 21824975 TI - Macrophage-dependent cleavage of the laminin receptor alpha6beta1 in prostate cancer. AB - The laminin-binding integrin alpha6beta1 plays a major role in determining the aggressive phenotype of tumor cells during metastasis. Our previous work has shown that cleavage of the alpha6beta1 integrin to produce the structural variant alpha6pbeta1 on tumor cell surfaces is mediated by the serine protease urokinase plasminogen activator (uPA). Cleavage of alpha6beta1 increases tumor cell motility, invasion, and prostate cancer metastasis, and blockage of uPA inhibits alpha6pbeta1 production. In human tumors, uPA and uPAR are expressed in tumor cells and tumor-associated macrophages (TAM). TAMs localize to solid tumors and contribute to increased tumor growth and the metastatic phenotype. In this study, we utilized a coculture system of PC-3 prostate tumor cells and macrophages [12-O tetradecanoylphorbol-13-acetate (TPA)-differentiated human leukemia HL-60 cells] to investigate the hypothesis that macrophages stimulate the production of the prometastatic variant alpha6pbeta1 on human prostate cancer cells via the uPA/uPAR axis. Our results indicate that adherent macrophages cocultured with PC 3 cells increased PC-3 uPAR mRNA, uPAR cell surface protein expression and alpha6 integrin cleavage. The stimulation does not require macrophage/tumor cell contact because macrophage conditioned medium is sufficient for increased uPAR transcription and alpha6 cleavage-dependent PC-3 cell invasion. The increased cleavage was dependent on uPAR because production was blocked by silencing RNA targeting uPAR. These results indicate that macrophages can stimulate uPA/uPAR production in tumor cells which results in alpha6 integrin cleavage. These data suggest that TAMs promote prometastatic integrin-dependent pericellular proteolysis. PMID- 21824977 TI - Using the continual reassessment method to estimate the minimum effective dose in phase II dose-finding studies: a case study. AB - BACKGROUND: The Continual Reassessment Method typically is presented as the method of choice for the purpose of dose-finding based on a toxicity scale in phase I clinical trials. However, this adaptive statistical approach also can be applied easily to dose-finding experiments in phase II trials. PURPOSE: To provide a case study from a real clinical trial to illustrate the use of the Continual Reassessment Method in the context of phase II dose finding. METHODS: The Continual Reassessment Method was used to model the dose-failure relationship in order to estimate the minimal effective dose. This approach was retrospectively used to determine the minimal effective dose of granulocyte colony-stimulating factor for peripheral blood stem cell collection in allografted patients following chemotherapy. RESULTS: After the inclusion of 25 patients, the minimal effective dose was estimated to be the third dose level tested in the study. LIMITATIONS: The main limitation of the Continual Reassessment Method, which is not specific to the method but to the dose-finding setting, is that the empirical choice of the dose range can be either under or over-estimated. The method requires a calibration study prior to trial onset. CONCLUSIONS: Assuming that a dose-effect relationship is monotonically increasing, the use of the Continual Reassessment Method in phase II dose-finding studies allows the estimation of the minimum effective dose for further studies. Modeling the dose-failure relationship allows the direct use of available software developed for the Continual Reassessment Method in the context of phase I clinical trials. PMID- 21824976 TI - A genome-wide association study of bladder cancer identifies a new susceptibility locus within SLC14A1, a urea transporter gene on chromosome 18q12.3. AB - Genome-wide and candidate-gene association studies of bladder cancer have identified 10 susceptibility loci thus far. We conducted a meta-analysis of two previously published genome-wide scans (4501 cases and 6076 controls of European background) and followed up the most significant association signals [17 single nucleotide polymorphisms (SNPs) in 10 genomic regions] in 1382 cases and 2201 controls from four studies. A combined analysis adjusted for study center, age, sex, and smoking status identified a novel susceptibility locus that mapped to a region of 18q12.3, marked by rs7238033 (P = 8.7 * 10(-9); allelic odds ratio 1.20 with 95% CI: 1.13-1.28) and two highly correlated SNPs, rs10775480/rs10853535 (r(2)= 1.00; P = 8.9 * 10(-9); allelic odds ratio 1.16 with 95% CI: 1.10-1.22). The signal localizes to the solute carrier family 14 member 1 gene, SLC14A1, a urea transporter that regulates cellular osmotic pressure. In the kidney, SLC14A1 regulates urine volume and concentration whereas in erythrocytes it determines the Kidd blood groups. Our findings suggest that genetic variation in SLC14A1 could provide new etiological insights into bladder carcinogenesis. PMID- 21824978 TI - Boosting enrolment in clinical trials: validation of a regional network model. AB - BACKGROUND: Clinical trials of stroke therapy have been hampered by slow rates of enrolment. PURPOSE: Our purpose is to validate a previously developed model for accelerating enrolment in clinical trials by replicating it at new locations. The model employs coordinators who travel from a host institution to enrol participants from a network of participating hospitals. Active surveillance assures identification of all eligible patients. METHODS: Among 70 U.S. investigators participating in National Institutes of Health-funded trial of stroke prevention, five investigators were invited to develop local identification and outreach networks (LIONs). Each LION comprised a LION coordinating centre servicing multiple hospitals. Hospitals provided names of patients with stroke or transient ischaemic attack to researchers at the LION coordinating centre who initiated contact; patients were offered home visits for consent and randomization. Outcomes were feasibility, enrolment, data quality, and cost. RESULTS: Five LIONs varied in size from two to eight hospitals. All 24 hospitals we approached agreed to participate. The average monthly rate of enrolment at the research sites increased from 1.4 participants to 3.5 after expanding from a single institution model to the LION format (mean change = 2.1, range 0.9-3.7). Monthly performance improved over time. Data quality was similar for LIONs and non-LION sites, except for drug adherence which was lower at LIONs. The average cost to randomize and follow one participant during the study interval was 2.4 times the cost under the per-patient, cost-reimbursement strategy at non-LION sites. The cost ratio declined from 3.4 in year one to 1.8 in year two. LIMITATIONS: The LION strategy requires unprecedented collaboration and trust among institutions. Applicability beyond stroke requires confirmation. CONCLUSION: LIONs are a practical, reproducible method to increase enrolment in trial research. Twelve months were required for the average site to reach its potential. The per-participant cost at LIONs was higher than conventional sites but declined over time. PMID- 21824979 TI - Head roll influences perceived hand position. AB - Visual and proprioceptive sensory inputs are naturally coded in different reference frames, i.e., eye-centered and body-centered, respectively. To use these signals in conjunction for motor planning or perception ultimately requires converting them into a common frame of reference using estimates of the relative orientation of the eyes, head, and body. Here, we examine whether extraretinal signals-specifically head roll-alter multisensory perception through noisy reference frame transformations. To do so, we examine the accuracy of visual localization relative to proprioceptive hand position for different head roll orientations. Subjects were required to judge whether a visual target was located closer or further and left or right (4-alternative forced-choice task) from their unseen hand. This was done for three different head roll rotations (-30, 0, and 30 deg). We show that eccentric head roll increased the variability in the subjects' ability to discriminate target location relative to the fingertip. We conclude that sensory perception is sensitive to body-geometry-dependent noise affecting the coordinate matching transformations of sensory data. PMID- 21824980 TI - Crowding is tuned for perceived (not physical) location. AB - In the peripheral visual field, nearby objects can make one another difficult to recognize (crowding) in a manner that critically depends on their separation. We manipulated the apparent separation of objects using the illusory shifts in perceived location that arise from local motion to determine if crowding depends on physical or perceived location. Flickering Gabor targets displayed between either flickering or drifting flankers were used to (a) quantify the perceived target-flanker separation and (b) measure discrimination of the target orientation or spatial frequency as a function of physical target-flanker separation. Relative to performance with flickering targets, we find that flankers drifting away from the target improve discrimination, while those drifting toward the target degrade it. When plotted as a function of perceived separation across conditions, the data collapse onto a single function indicating that it is perceived and not physical location that determines the magnitude of visual crowding. There was no measurable spatial distortion of the target that could explain the effects. This suggests that crowding operates predominantly in extrastriate visual cortex and not in early visual areas where the response of neurons is retinotopically aligned with the physical position of a stimulus. PMID- 21824981 TI - Tolerability profile of aripiprazole in patients with Tourette syndrome. AB - Over the last few years, aripiprazole has been proposed as a potentially useful medication for tics in patients with Tourette syndrome (TS). Aripiprazole has been associated with fewer adverse effects compared with other atypicals; however, little is known about its tolerability profile in the TS population. This study assessed the prevalence and characteristics of adverse effects resulting from the use of aripiprazole in a retrospective chart review of 29 patients with TS. Six patients (20.7%) discontinued aripiprazole because of the severity of specific adverse effects. The most commonly reported adverse effects were sedation (n = 9, 30%) and sleep problems (n = 5, 17%). In the majority of cases, adverse effects were not severe. There were no differences in demographic or clinical variables between the patients who did or did not experience adverse effects. The discontinuation rate of 20.7% suggests that aripiprazole is safe and reasonably well tolerated for use in TS. The prevalence of adverse effects appears to increase with treatment duration. PMID- 21824982 TI - The role of the endocannabinoid system in the neuroendocrine regulation of energy balance. AB - Animal and human studies carried out so far have established a role for the endocannabinoid system (ECS) in the regulation of energy balance. Here we critically discuss the role of the endocannabinoid signalling in brain structures, such as the hypothalamus and reward-related areas, and its interaction with neurotransmitter and neuropeptide systems involved in the regulation of food intake and body weight. The ECS has been found to interact with peripheral signals, like leptin, insulin, ghrelin and satiety hormones and the resulting effects on both central and peripheral mechanisms affecting energy balance and adiposity will be described. Furthermore, ECS dysregulation has been associated with the development of dyslipidemia, glucose intolerance and obesity; phenomena that are often accompanied by a plethora of neuroendocrine alterations which might play a causal role in determining ECS dysregulation. Despite the withdrawal of the first generation of cannabinoid type 1 receptor (CB1) antagonists from the pharmaceutical market due to the occurrence of psychiatric adverse events, new evidence suggests that peripherally restricted CB1 antagonists might be efficacious for the treatment of obesity and its associated metabolic disorders. Thus, a perspective on new promising strategies to selectively target the ECS in the context of energy balance regulation is given. PMID- 21824983 TI - Reaching cost-saving effects by a mixed collection of light packagings together with residual household waste? AB - To enforce material recycling of household waste at high levels, separate collection schemes often under a producer's responsibility regime were implemented in Germany since the 1970s and 1990s, respectively. The separate collection of recyclables (Sorting-Transportation-Sorting-Recovery' system) is assumed, guaranteeing higher purities of the collected material streams but also causing higher costs for logistics and the processing of the waste fractions. Several authors argue that since the rapid development of automatic sorting systems in recent years, a mixed collection of recyclables and residual household waste with a downstream sorting strategy (Transportation-Sorting-Recovery system) is cheaper than the currents system while keeping the product quality constant. This paper evaluates the economic saving potentials in logistics and the extra costs for separation technologies when implementing a mixed collection system for light packagings together with residual household waste in an East German city. The results show that costs for process technologies in a mixed collection system can overcompensate cost-saving potentials in logistics. PMID- 21824984 TI - Life cycle assessment of a household solid waste source separation programme: a Swedish case study. AB - The environmental impact of an extended property close source-separation system for solid household waste (i.e., a systems for collection of recyclables from domestic properties) is investigated in a residential area in southern Sweden. Since 2001, households have been able to source-separate waste into six fractions of dry recyclables and food waste sorting. The current system was evaluated using the EASEWASTE life cycle assessment tool. Current status is compared with an ideal scenario in which households display perfect source-separation behaviour and a scenario without any material recycling. Results show that current recycling provides substantial environmental benefits compared to a non-recycling alternative. The environmental benefit varies greatly between recyclable fractions, and the recyclables currently most frequently source-separated by households are often not the most beneficial from an environmental perspective. With optimal source-separation of all recyclables, the current net contribution to global warming could be changed to a net-avoidance while current avoidance of nutrient enrichment, acidification and photochemical ozone formation could be doubled. Sensitivity analyses show that the type of energy substituted by incineration of non-recycled waste, as well as energy used in recycling processes and in the production of materials substituted by waste recycling, is of high relevance for the attained results. PMID- 21824985 TI - Practicalities of individual producer responsibility under the WEEE directive: experiences in Germany. AB - In theory, individual producer responsibility (IPR) creates incentives for 'design-for-recycling'. Yet in practice, implementing IPR is challenging, particularly if applied to waste electric and electronic equipment. This article discusses different options for implementing IPR schemes under German WEEE legislation. In addition, practical aspects of a German 'return share' brand sampling scheme are examined. Concerning 'new' WEEE put on the market after 13 August 2006, producers in Germany can choose between two different methods of calculating take-back obligations. These can be determined on the basis of 'return shares' or 'market shares'. While market shares are regularly monitored by a national clearing house, the 'return share' option requires sampling and sorting of WEEE. Herein it is shown that the specifics of the German WEEE take back scheme require high sample sizes and multi-step test procedures to ensure a statistically sound sampling approach. Since the market share allocation continues to apply for historic waste, producers lack incentives for choosing the costly brand sampling option. However, even return share allocation might not imply a decisive step towards IPR, as it merely represents an alternative calculation of market shares. Yet the fundamental characteristics of the German take-back system remain unchanged: the same anonymous mix of WEEE goes to the same treatment operations. PMID- 21824986 TI - Competition of different methods for recovering energy from waste. AB - Waste-to-energy (WtE) facilities have been established worldwide as a sustainable method for the disposal of residual waste. In the present study the following competing WtE systems were compared: (1) municipal solid waste incinerators (MSWIs) with energy recovery; (2) co-incineration of waste in old lignite or coal fired power plants; (3) substitute [refuse-derived fuel (RDF)] incinerators with energy recovery; and (4) co-incineration of defined waste fractions in cement kilns. In general the municipal solid waste incinerators in Europe are designed for a broad range of municipal and commercial waste without a pre-treatment of the waste. All other WtE processes including the cement kilns require a pre treatment and are more limited in terms of RDF composition; namely particle size, chlorine content, calorific value. As to Germany, the emission limit values for all facilities are similar. A sensitivity analysis of the economics of boilers using RDF and municipal solid waste leads to the conclusion that the feasibility of RDF incinerators might partially recover if the prices for primary energy increase again. On the other hand, pre-treatment of waste leads to higher costs for RDF. Incineration and recycling capacities are large enough in middle Europe to avoid landfilling of organic waste. The steep decline of gate fees observed in some national spot markets is a clear indicator of an already existing overcapacity. Considering the enormous amount of greenhouse gas emissions saved by WtE facilities in comparison with landfilling, free capacities of WtE installations should be used to incinerate waste from EU member states where waste disposal is still predominantly based on landfilling. PMID- 21824987 TI - One WEEE, many species: lessons from the European experience. AB - Electrical and electronic equipment (EEE) pervades modern lifestyles, but its quick obsolescence is resulting in huge quantities of EEE to be disposed of. This fast-growing waste stream has been recognized for its hazard potential. The European Union's (EU) Waste Electrical and Electronic Equipment (WEEE) Directive was essentially in response to the toxicity of e-waste - to ensure that it was collected and treated in an environmentally sound manner. Since then, the WEEE Directive has expanded its aims to include recovery of valuable resources as a means to reduce raw material extraction. With these objectives in mind, the Directive sets a common minimum legislative framework for all EU member states. However, the transposition of the Directive into national legislations has meant many differences in actual implementation models. There are 27 national transpositions of the Directive with different definitions, provisions and agreements. Each legislation reflects national situations, whether they are geographical considerations, legislative history, the influence of lobby groups and other national priorities. Although this diversity in legislations has meant massive problems in compliance and enforcement, it provides an opportunity to get an insight into the possible operational models of e-waste legislation. Building on the study by the United Nations University commissioned by the European Commission as part of its 2008 Review of the WEEE Directive, the paper identifies some key features of the Directive as well as legislative and operational differences in transposition and implementation in the various members states. The paper discusses the successes and challenges of the Directive and concludes with lessons learnt from the European experience. PMID- 21824988 TI - Dynamics of indigenous bacterial communities associated with crude oil degradation in soil microcosms during nutrient-enhanced bioremediation. AB - Bacterial population dynamics were examined during bioremediation of an African soil contaminated with Arabian light crude oil and nutrient enrichment (biostimulation). Polymerase chain reaction followed by denaturing gradient gel electrophoresis (DGGE) were used to generate bacterial community fingerprints of the different treatments employing the 16S ribosomal ribonucleic acid (rRNA) gene as molecular marker. The DGGE patterns of the nutrient-amended soils indicated the presence of distinguishable bands corresponding to the oil-contaminated nutrient-enriched soils, which were not present in the oil-contaminated and pristine control soils. Further characterization of the dominant DGGE bands after excision, reamplification and sequencing revealed that Corynebacterium spp., Dietzia spp., Rhodococcus erythropolis sp., Nocardioides sp., Low G+C (guanine plus cytosine) Gram positive bacterial clones and several uncultured bacterial clones were the dominant bacterial groups after biostimulation. Prominent Corynebacterium sp. IC10 sequence was detected across all nutrient-amended soils but not in oil-contaminated control soil. Total heterotrophic and hydrocarbon utilizing bacterial counts increased significantly in the nutrient-amended soils 2 weeks post contamination whereas oil-contaminated and pristine control soils remained fairly stable throughout the experimental period. Gas chromatographic analysis of residual hydrocarbons in biostimulated soils showed marked attenuation of contaminants starting from the second to the sixth week after contamination whereas no significant reduction in hydrocarbon peaks were seen in the oil-contaminated control soil throughout the 6-week experimental period. Results obtained indicated that nutrient amendment of oil-contaminated soil selected and enriched the bacterial communities mainly of the Actinobacteria phylogenetic group capable of surviving in toxic contamination with concomitant biodegradation of the hydrocarbons. The present study therefore demonstrated that the soil investigated harbours hydrocarbon-degrading bacterial populations which can be biostimulated to achieve effective bioremediation of oil-contaminated soil. PMID- 21824989 TI - Realizing the full potential of PET for measuring the biodistribution of novel anticancer agents. PMID- 21824990 TI - Impact of aliskiren treatment on urinary aldosterone levels in patients with type 2 diabetes and nephropathy: an AVOID substudy. AB - INTRODUCTION: Aldosterone blockade reduces albuminuria in diabetic patients with chronic kidney disease (CKD), and improves prognosis in chronic heart failure. This study assessed the effects of direct renin inhibition with aliskiren in combination with losartan and optimal antihypertensive therapy on urinary aldosterone, plasma renin activity (PRA) and plasma renin concentration (PRC). MATERIALS AND METHODS: In the AVOID study, 599 patients with type 2 diabetes, hypertension and nephropathy received 6 months aliskiren (150 mg force titrated to 300 mg once daily after 3 months) or placebo added to losartan 100 mg and optimal antihypertensive therapy. Urinary aldosterone excretion, PRA and PRC were measured at baseline and after 24 weeks in a prespecified subset of 133 patients. RESULTS: Aliskiren added to losartan provided reductions from baseline in urinary aldosterone compared with adding placebo (-24% vs. -4%, p = 0.017) at week 24. There was no significant difference between the aliskiren and placebo groups in the proportion of patients with aldosterone breakthrough (aliskiren 35%, placebo 46%, p = 0.199). Aliskiren treatment reduced PRA by 90% at 24 weeks and increased PRC by 328%. CONCLUSIONS: Adding aliskiren to recommended renoprotective treatment with losartan and optimal antihypertensive therapy provided significant reductions in urinary aldosterone excretion which may attenuate decline in kidney function. PMID- 21824991 TI - Is there a role of the local tissue RAS in the regulation of physiologic and pathophysiologic conditions in the reproductive tract? AB - The renin-angiotensin system is well known as a systemic endocrine pathway that regulates blood pressure and salt-water metabolism. In addition to the systemic renin-angiotensin system there is evidence in different species for the presence of a local tissue renin-angiotensin system, which allows local production of the bioactive peptides angiotensin II and angiotensin (1-7). The local renin angiotensin system has been found in a variety of tissues including tissue of the human reproductive tract. Thus, it was suspected that it may have important functions in the local hormonal microenvironment. Here, a systematic literature search was undertaken to review whether there is evidence for regulatory functions of the local tissue renin-angiotensin system in the human reproductive tract under physiological and pathological conditions. PMID- 21824992 TI - Abilities of candesartan and other AT(1) receptor blockers to impair angiotensin II-induced AT(1) receptor activation after wash-out. AB - Angiotensin II (Ang II) binds to Ang II type 1 (AT(1)) receptor and evokes cell signaling, and subsequently stimulates vasoconstriction and cell proliferation, which eventually lead to cardiovascular disease. Since most AT(1) receptor blockers (ARBs) have molecular (differential) effects, we evaluated the specific features of candesartan and compared the abilities of candesartan and other ARBs (olmesartan, telmisartan, valsartan, irbesartan and losartan) to bind to and activate AT(1) receptors using a cell-based wash-out assay. Each ARB blocked Ang II-induced extracellular signal-regulated kinase (ERK) activation and inositol phosphate production to different degrees after wash-out. In addition, a small difference in the molecular structure, i.e. a carboxyl group, between candesartan and candesartan-7H was associated with a difference in the degree of this blocking effect. In addition, interaction between Gln(257) in the AT(1) receptor and the carboxyl group of candesartan may be partially associated with the effect of candesartan after wash-out. Although our findings regarding the molecular effects of ARB are based on basic research, these findings may lead to an exciting new area in the clinical application of ARBs. PMID- 21824993 TI - Molecular characterization and regulation of the angiotensin-converting enzyme type 2/angiotensin-(1-7)/MAS receptor axis during the ovulation process in cattle. AB - The objective of this study was to characterize the profiles of Ang-(1-7), MAS receptor, ACE(2), NEP and PEP during the ovulatory process in cattle. For this study, 40 synchronized cows with follicular diameter >= 12 mm were ovariectomized at different time-points (0, 3, 6, 12 and 24 h) after i.m. application of gonadotropin-releasing hormone (GnRH) to induce a luteinizing hormone surge. Follicular fluid was collected for measuring Ang-(1-7) by radioimmunoassay. Theca and granulosa cells were isolated from the preovulatory follicles to evaluate the gene expression of MAS receptor, ACE(2), NEP and PEP by qRT-PCR assay. Cross contamination between theca and granulosa cells was tested by RT-PCR to detect cytochrome P450 aromatase (CYP19A1) and 17alpha-hydroxylase (CYP17A1) mRNA. Ang (1-7) levels were constant until 12 h and then increased (p < 0.05) at 24 h after GnRH. Messenger RNA expression of MAS, ACE(2), NEP and PEP was detected in theca and granulosa cells at all time-points after GnRH. In granulosa cells, ACE(2), NEP and PEP were differentially expressed after GnRH treatment (p < 0.05). In conclusion, the Ang-(1-7), MAS receptor, ACE(2), NEP and PEP profiles in preovulatory follicles indicate that Ang-(1-7) plays a role in the regulation of the ovulatory process in cattle. PMID- 21824994 TI - Copy number variation analysis in the great apes reveals species-specific patterns of structural variation. AB - Copy number variants (CNVs) are increasingly acknowledged as an important source of evolutionary novelties in the human lineage. However, our understanding of their significance is still hindered by the lack of primate CNV data. We performed intraspecific comparative genomic hybridizations to identify loci harboring copy number variants in each of the four great apes: bonobos, chimpanzees, gorillas, and orangutans. For the first time, we could analyze differences in CNV location and frequency in these four species, and compare them with human CNVs and primate segmental duplication (SD) maps. In addition, for bonobo and gorilla, patterns of CNV and nucleotide diversity were studied in the same individuals. We show that CNVs have been subject to different selective pressures in different lineages. Evidence for purifying selection is stronger in gorilla CNVs overlapping genes, while positive selection appears to have driven the fixation of structural variants in the orangutan lineage. In contrast, chimpanzees and bonobos present high levels of common structural polymorphism, which is indicative of relaxed purifying selection together with the higher mutation rates induced by the known burst of segmental duplication in the ancestor of the African apes. Indeed, the impact of the duplication burst is noticeable by the fact that bonobo and chimpanzee share more CNVs with gorilla than expected. Finally, we identified a number of interesting genomic regions that present high-frequency CNVs in all great apes, while containing only very rare or even pathogenic structural variants in humans. PMID- 21824996 TI - Acute life-threatening extrinsic allergic alveolitis in a paint controller. AB - BACKGROUND: Occupational diisocyanate-induced extrinsic allergic alveolitis (EAA) is a rare and probably underestimated diagnosis. Two acute occupational EAA cases have been described in this context, but neither of them concerned hexamethylene diisocyanate (HDI) exposure. AIMS: To investigate the cause of a life-threatening EAA arising at work in a healthy 30-year-old female paint quality controller. METHODS: Occupational medical assessment, workplace evaluation, airborne and biological monitoring and immunodermatological tests. RESULTS: Diagnosis of EAA relied on congruent clinical and radiological information, confirmed occupational HDI exposure and positive IgG antibodies and patch tests. The patient worked in a small laboratory for 7 years, only occasionally using HDI-containing hardeners. While working with HDI for 6 h, she developed breathlessness, rapidly progressing to severe respiratory failure. Workplace HDI airborne exposure values ranged from undetectable levels to 4.25 p.p.b. Biological monitoring of urinary hexamethylene diamine in co-workers ranged from <1.0 to 15.4 MUg/g creatinine. Patch tests 8 months later showed delayed skin reaction to HDI at 48 h. Subsequent skin biopsy showed spongiotic dermatitis with infiltration of CD4(+) and CD8(+) T cells. CONCLUSIONS: We believe this is the first reported case of acute life-threatening EAA following exposure to HDI. Low concentrations of airborne HDI and relatively high urinary hexamethylene diamine suggest significant skin absorption of HDI could have significantly contributed to the development of this acute occupational EAA. PMID- 21824995 TI - The Proteome Folding Project: proteome-scale prediction of structure and function. AB - The incompleteness of proteome structure and function annotation is a critical problem for biologists and, in particular, severely limits interpretation of high throughput and next-generation experiments. We have developed a proteome annotation pipeline based on structure prediction, where function and structure annotations are generated using an integration of sequence comparison, fold recognition, and grid-computing-enabled de novo structure prediction. We predict protein domain boundaries and three-dimensional (3D) structures for protein domains from 94 genomes (including human, Arabidopsis, rice, mouse, fly, yeast, Escherichia coli, and worm). De novo structure predictions were distributed on a grid of more than 1.5 million CPUs worldwide (World Community Grid). We generated significant numbers of new confident fold annotations (9% of domains that are otherwise unannotated in these genomes). We demonstrate that predicted structures can be combined with annotations from the Gene Ontology database to predict new and more specific molecular functions. PMID- 21824997 TI - High-pressure plastic injection injury of the hand: case report. AB - Occupational high-pressure injection injuries are not common but can be devastating, especially to the hand. Most of the time, full recovery does not occur. We present a case of high-pressure injection injury to the hand in a patient who worked in a shoe-making factory. As far as we know, this massive involvement of a limb in a high-pressure plastic injection injury has never been reported in the literature. Better controls are required to prevent injection injuries and when they do occur, a high index of suspicion is required with immediate referral for surgical review. PMID- 21824998 TI - Telemetric analysis of haemodynamic regulation during voluntary exercise training in mouse models. AB - Regular physical exercise reduces the risk of cardiovascular disease and improves outcome in patients with cardiovascular diseases. The dynamic changes in blood pressure and heart rate with acute exercise are independently predictive of prognosis. Quantification of the haemodynamic response to exercise training in genetically modified mouse models may provide insight into the molecular mechanisms underlying the beneficial effects of exercise. We describe, for the first time, the use of radiotelemetry to provide continuous blood pressure monitoring in C57BL/6J mice during a programme of voluntary wheel exercise with continuous simultaneous recording and analysis of wheel rotations and beat-by beat haemodynamic parameters. We define distinct haemodynamic profiles at rest, during normal cage activity and during episodes of voluntary wheel running. We show that whilst cage activity is associated with significant rises both in blood pressure and in heart rate, voluntary wheel running leads to a further substantial rise in heart rate with only a small increment in blood pressure. With 5 weeks of chronic exercise training, resting heart rate progressively falls, but heart rate during episodes of wheel running initially increases. In contrast, there are minimal changes in blood pressure in response to chronic exercise training. Finally, we have quantified the acute changes in heart rate at the onset of and recovery from individual episodes of wheel running, revealing that changes in heart rate are extremely rapid and that the peak rate of change of heart rate increases with chronic exercise training. The results of this study have important implications for the use of genetically modified mouse models to investigate the beneficial haemodynamic effects of chronic exercise on blood pressure and cardiovascular diseases. PMID- 21824999 TI - Regulation of hypothalamic renin-angiotensin system and oxidative stress by aldosterone. AB - In rats with salt-induced hypertension or postmyocardial infarction, angiotensin II type 1 receptor (AT(1)R) densities and oxidative stress increase and neuronal NO synthase (nNOS) levels decrease in the paraventricular nucleus (PVN). The present study was designed to determine whether these changes may depend on activation of the aldosterone -'ouabain' neuromodulatory pathway. After intracerebroventricular (i.c.v.) infusion of aldosterone (20 ng h(-1)) for 14 days, blood pressure (BP) and heart rate (HR) were recorded in conscious Wistar rats, and mRNA and protein for nNOS, endothelial NO synthase (eNOS), AT(1)R and NADPH oxidase subunits were assessed in brain tissue. Blood pressure and HR were significantly increased by aldosterone. Aldosterone significantly increased mRNA and protein of AT(1)R, P22phox, P47phox, P67phox and Nox2, and decreased nNOS but not eNOS mRNA and protein in the PVN, as well as increased the angiotensin converting enzyme and AT(1)R binding densities in the PVN and supraoptic nucleus. The increases in BP and HR, as well as the changes in mRNA, proteins and angiotensin-converting enzyme and AT(1)R binding densities were all largely prevented by concomitant i.c.v. infusion of Digibind (to bind 'ouabain') or benzamil (to block presumed epithelial sodium channels). These data indicate that aldosterone, via 'ouabain', increases in the PVN angiotensin-converting enzyme, AT(1)R and oxidative stress, but decreases nNOS, and suggest that endogenous aldosterone may cause the similar pattern of changes observed in salt-sensitive hypertension and heart failure postmyocardial infarction. PMID- 21825000 TI - Preclinical pharmacology and pharmacokinetics of AZD3783, a selective 5 hydroxytryptamine 1B receptor antagonist. AB - The preclinical pharmacology and pharmacokinetic properties of (2R)-6-methoxy-8 (4-methylpiperazin-1-yl)-N-(4-morpholin-4-ylphenyl)chromane-2-carboxamide (AZD3783), a potent 5-hydroxytryptamine 1B (5-HT(1B)) receptor antagonist, were characterized as part of translational pharmacokinetic/pharmacodynamic hypothesis testing in human clinical trials. The affinity of AZD3783 to the 5-HT(1B) receptor was measured in vitro by using membrane preparations containing recombinant human or guinea pig 5-HT(1B) receptors and in native guinea pig brain tissue. In vivo antagonist potency of AZD3783 for the 5HT(1B) receptor was investigated by measuring the blockade of 5-HT(1B) agonist-induced guinea pig hypothermia. The anxiolytic-like potency was assessed using the suppression of separation-induced vocalization in guinea pig pups. The affinity of AZD3783 for human and guinea pig 5-HT(1B) receptor (K(i), 12.5 and 11.1 nM, respectively) was similar to unbound plasma EC(50) values for guinea pig receptor occupancy (11 nM) and reduction of agonist-induced hypothermia (18 nM) in guinea pig. Active doses of AZD3783 in the hypothermia assay were similar to doses that reduced separation induced vocalization in guinea pig pups. AZD3783 demonstrated favorable pharmacokinetic properties. The predicted pharmacokinetic parameters (total plasma clearance, 6.5 ml/min/kg; steady-state volume of distribution, 6.4 l/kg) were within 2-fold of the values observed in healthy male volunteers after a single 20-mg oral dose. This investigation presents a direct link between AZD3783 in vitro affinity and in vivo receptor occupancy to preclinical disease model efficacy. Together with predicted human pharmacokinetic properties, we have provided a model for the quantitative translational pharmacology of AZD3783 that increases confidence in the optimal human receptor occupancy required for antidepressant and anxiolytic effects in patients. PMID- 21825001 TI - The soluble guanylate cyclase stimulator BAY 41-2272 inhibits vascular smooth muscle growth through the cAMP-dependent protein kinase and cGMP-dependent protein kinase pathways. AB - Vascular smooth muscle (VSM) proliferation and migration are key components in vessel remodeling. Cyclic nucleotide signaling is protective and has long-served as a therapeutic target against undesired VSM growth. The present work analyzed the effects of the soluble guanylate cyclase (sGC) stimulator 3-(4-amino-5 cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine [BAY 41 2272 (BAY)] on VSM growth, and we hypothesize that BAY has the capacity to reduce proliferation and migration via cyclic nucleotide-driven kinase signaling. Perivascular BAY postballoon injury reduced neointimal growth by ~ 40% compared with vehicle controls after 2 weeks. In VSM cells, BAY (10 MUM) reduced proliferation by ~ 40% after 72 h and migration by ~ 40% after 6 h and ~ 60% after 18 h without deleterious effects on cell viability. cGMP content peaked (248 *) 20 min after BAY treatment and remained elevated (140 *) through 60 min; however, BAY did not affect cAMP levels compared with controls. Conventional and In-Cell Western analyses showed increases in vasodilator-stimulated phosphoprotein (VASP) phosphorylation (pVASP) at serines 239 (3 *) and 157 (2 *), respective markers of cGMP- and cAMP-directed protein kinases (PKG and PKA, respectively). The PKG inhibitor YGRKKRRQRRRPPLRKKKKKH peptide (DT-2) completely reversed BAY-mediated increases in pVASPSer(239) and BAY-mediated inhibition of migration. In comparison, the PKA inhibitor peptide PKI further potentiated BAY stimulated pVASPSer(157) and pVASPSer(239) and partially reversed the antiproliferative effects of BAY. This is the first report demonstrating the effectiveness of BAY in reducing neointimal growth with direct evidence for PKG specific antimigratory and PKA-specific antiproliferative mechanisms. Conclusively, the sGC stimulator BAY reduces VSM growth through cGMP-dependent PKG and PKA processes, providing support for continued evaluation of its clinical utility. PMID- 21825002 TI - Building healthy public policy: don't believe the misdirection. PMID- 21825003 TI - All because of the mast cell: blocking the angiotensin receptor-1 should be better than inhibiting ACE (theoretically). PMID- 21825004 TI - Combined transcranial direct current stimulation and robot-assisted arm training in subacute stroke patients: an exploratory, randomized multicenter trial. AB - BACKGROUND: No rehabilitation intervention has effectively improved functional use of the arm and hand in patients with severe upper limb paresis after stroke. Pilot studies suggest the potential for transcranial direct current stimulation and bilateral robotic training to enhance gains. OBJECTIVE: In a double-blind, randomized trial the combination of these interventions was tested. METHODS: This study randomized 96 patients with an ischemic supratentorial lesion of 3 to 8 weeks' duration with severe impairment of motor control with a Fugl-Meyer score (FMS) for the upper limb <18 into 3 groups. For 6 weeks, group A received anodal stimulation of the lesioned hemisphere, group B received cathodal stimulation of the nonlesioned side for 20 minutes at 2.0 mA, and group C received sham stimulation. The electrodes were placed over the hand area and above the contralateral orbit. Contemporaneously, the subjects practiced 400 repetitions each of 2 different bilateral movements on a robotic assistive device. RESULTS: The groups were matched at onset. The FMS improved in all patients at 6 weeks (P < .001). No between-group differences were found; initial versus finish FMS scores were 7.8 +/- 3.8 versus 19.1 +/- 14.4 in group A, 7.9 +/- 3.4 versus 18.8 +/- 10.5 in group B, and 8.2 +/- 4.4 versus 19.2 +/- 15.0 in group C. No significant changes between groups were present at 3 months. CONCLUSIONS: Neither anodal nor cathodal transcranial direct current stimulation enhanced the effect of bilateral arm training in this exploratory trial of patients with cortical involvement and severe weakness. Unilateral hand training and upregulation of the nonlesioned hemisphere might also be tried in this population. PMID- 21825005 TI - Factors associated with health-related quality of life after stroke: a 1-year prospective cohort study. AB - BACKGROUND: In line with patient-centered health care, it is necessary to understand patients' perceptions of health. How stroke survivors perceive their health at different time points after stroke and which factors are associated with these feelings provide important information about relevant rehabilitation targets. OBJECTIVE: This study aimed to identify the independent factors of health-related quality of life (HRQoL) from a biopsychosocial perspective using the methods of multivariate regression at 3 different time points poststroke. METHODS: Included in the study were 99 patients from stroke units with diagnosed first-ever stroke. At admission and at 6 weeks, 3 months, and 1 year poststroke, HRQoL was assessed using the EuroQoL-5D Visual Analogue Scale (EQ-5D VAS). Consequences in Body Functions and Activities and Participation, and Environmental Factors were documented using 155 categories of the International Classification of Functioning, Disability and Health (ICF) Core Set for Stroke. RESULTS: For a period of 1 year, problems with recreation and leisure, personality functions, energy and drive functions, and gait pattern functions were repeatedly associated with worse HRQoL. Whereas Body Functions and Activities and Participation explained more than three-fourths of the variances of HRQoL at 6 weeks and 3 months (R2 = 0.80-0.93), the variation at 1 year was best explained by either Body Functions or Environmental Factors (R2 = 0.51). CONCLUSIONS: The results indicate the importance of Body Functions and Activities and Participation (mainly personality functions and recreation and leisure) on HRQoL within 3 months poststroke, but increased impact of Environmental Factors on HRQoL at 1 year. PMID- 21825006 TI - Inhibition of PARP-1 by olaparib (AZD2281) increases the radiosensitivity of a lung tumor xenograft. AB - PARP-1 is a critical enzyme in the repair of DNA strand breaks. Inhibition of PARP-1 increases the effectiveness of radiation in killing tumor cells. However, although the mechanism(s) are well understood for these radiosensitizing effects in vitro, the underlying mechanism(s) in vivo are less clear. Nicotinamide, a drug structurally related to the first generation PARP-1 inhibitor, 3 aminobenzamide, reduces tumor hypoxia by preventing transient cessations in tumor blood flow, thus improving tumor oxygenation and sensitivity to radiotherapy. Here, we investigate whether olaparib, a potent PARP-1 inhibitor, enhances radiotherapy, not only by inhibiting DNA repair but also by changing tumor vascular hemodynamics in non-small cell lung carcinoma (NSCLC). In irradiated Calu-6 and A549 cells, olaparib enhanced the cytotoxic effects of radiation (sensitizer enhancement ratio at 10% survival = 1.5 and 1.3) and DNA double strand breaks persisted for at least 24 hours after treatment. Combination treatment of Calu-6 xenografts with olaparib and fractionated radiotherapy caused significant tumor regression (P = 0.007) relative to radiotherapy alone. To determine whether this radiosensitization was solely due to effects on DNA repair, we used a dorsal window chamber model to establish the drug/radiation effects on vessel dynamics. Olaparib alone, when given as single or multiple daily doses, or in combination with fractionated radiotherapy, increased the perfusion of tumor blood vessels. Furthermore, an ex vivo assay in phenylephrine preconstricted arteries confirmed olaparib to have higher vasodilatory properties than nicotinamide. This study suggests that olaparib warrants consideration for further development in combination with radiotherapy in clinical oncology settings such as NSCLC. PMID- 21825007 TI - Targeting the microtubular network as a new antimyeloma strategy. AB - We identified nocodazole as a potent antimyeloma drug from a drug screening library provided by the Multiple Myeloma Research Foundation. Nocodazole is a benzimidazole that was originally categorized as a broad-spectrum anthelmintic drug with antineoplastic properties. We found that nocodazole inhibited growth and induced apoptosis of primary and multiresistant multiple myeloma cells cultured alone and in the presence of bone marrow stromal cells. Nocodazole caused cell-cycle prophase and prometaphase arrest accompanied by microtubular network disarray. Signaling studies indicated that increased expression of Bim protein and reduced X-linked inhibitor of apoptosis protein and Mcl-1(L) levels were involved in nocodazole-induced apoptosis. Further investigation showed Bcl-2 phosphorylation as a critical mediator of cell death, triggered by the activation of c-jun-NH(2) kinase (JNK) instead of p38 kinase or extracellular signal regulated kinases. Treatment with JNK inhibitor decreased Bcl-2 phosphorylation and subsequently reduced nocodazole-induced cell death. Nocodazole combined with dexamethasone significantly inhibited myeloma tumor growth and prolonged survival in a human xenograft mouse model. Our studies show that nocodazole has potent antimyeloma activity and that targeting the microtubular network might be a promising new treatment approach for multiple myeloma. PMID- 21825008 TI - Antitumor activity of ridaforolimus and potential cell-cycle determinants of sensitivity in sarcoma and endometrial cancer models. AB - Ridaforolimus is a nonprodrug rapamycin analogue that potently inhibits mTOR and has shown significant activity in patients with metastatic sarcoma and endometrial cancer, two diseases where high unmet need remains. Here, we evaluated the activity of ridaforolimus in preclinical models of these tumor types and used these models to explore molecular correlates of sensitivity. The in vitro sensitivity of a panel of sarcoma and endometrial cancer cell lines was established by measuring the effect of ridaforolimus on cell proliferation rate, revealing broad inhibition at low nanomolar concentrations. Additional benefit was found when ridaforolimus was combined with agents used to treat sarcoma and endometrial cancer patients. In vivo, potent antitumor activity of ridaforolimus associated with inhibition of mTOR signaling was observed in sarcoma and endometrial xenograft models. Immunoblot analysis was conducted to assess the expression and activation state of multiple signaling proteins in the phosphoinositide-3-kinase/AKT/mTOR and cell-cycle pathways. In endometrial but not sarcoma cell lines, the absence of PTEN or elevated levels of phosphorylated or total AKT was associated with greater sensitivity. However, in both tumor types, the proportion of cells in the G(0)-G(1) phase before treatment correlated significantly with ridaforolimus sensitivity. Consistent with this, expression of several G(1) phase cell-cycle proteins, notably p21 and p27, was higher in more sensitive lines. These results underscore the promise of ridaforolimus as a single agent or combination treatment of these tumor types and suggest novel potential predictive biomarkers of sensitivity to an mTOR inhibitor based on cell cycle status. PMID- 21825009 TI - The heat shock protein 90 inhibitor IPI-504 induces KIT degradation, tumor shrinkage, and cell proliferation arrest in xenograft models of gastrointestinal stromal tumors. AB - The activity of the receptor tyrosine kinase KIT is crucial for gastrointestinal stromal tumor (GIST) growth and survival. Imatinib and sunitinib are very effective in advanced GIST, but have no curative potential. The observation that heat shock protein 90 (HSP90) inhibition results in KIT degradation prompted us to assess the efficacy of the HSP90 inhibitor retaspimycin hydrochloride (IPI 504) alone or in combination with imatinib or sunitinib in two GIST xenografts with distinctive KIT mutations. Nude mice were grafted with human GIST carrying KIT exon 13 (GIST-882; n = 59) or exon 11 (GIST-PSW; n = 44) mutations and dosed with imatinib (50 mg/kg twice daily), sunitinib (40 mg/kg once daily), IPI-504 (100 mg/kg 3 times per week), IPI-504 + imatinib, or IPI-504 + sunitinib. We evaluated tumor volume, proliferation and apoptosis, KIT expression and activation, as well as adverse events during treatment. Treatment with IPI-504 alone resulted in tumor regression, proliferation arrest, and induction of tumor necrosis. We documented downregulation of KIT and its signaling cascade in IPI 504-treated animals. Treatment effects were enhanced by combining IPI-504 with imatinib or sunitinib. On histologic examination, liver damage was frequently observed in animals exposed to combination treatments. In conclusion, IPI-504 shows consistent antitumor activity and induces KIT downregulation in GIST, as a single agent, and is more potent in combination with imatinib or sunitinib. The sequence of drug administration in the combination arms warrants further studies. PMID- 21825010 TI - Unusual causes of carpal tunnel syndrome: space occupying lesions. AB - Space occupying lesions found at surgery caused or contributed to carpal tunnel syndrome in 23 of 779 patients operated for carpal tunnel syndrome from January 1999 to December 2008. The mean age of these 23 patients was 52.9 years, and in patients who had a local swelling or palpable mass, ultrasonography or magnetic resonance imaging (MRI) was done. All had open release of the transverse carpal ligament and lesions were removed. Histopathology showed tophaceous gout in 10 men, tenosynovitis in seven patients and tumors in eight. The tumors included ganglion cysts in two, lipoma in three and fibroma of the tendon sheath in one. The neurological symptoms subsided after surgery in all. In patients with gout, one had an infected wound and another had recurrence of symptoms 1 year after later. Carpal tunnel syndrome caused by a space occupying lesion is rare and more complicated than idiopathic carpal tunnel syndrome. PMID- 21825011 TI - Trifid median nerve. PMID- 21825012 TI - Scaphoid nonunion in the presence of a degenerate carpus: don't rush to salvage surgery. AB - We retrospectively studied 13 patients with degenerative change associated with a scaphoid nonunion treated by internal fixation and bone graft. All patients had radiological signs of radioscaphoid degenerative change (scaphoid nonunion advanced collapse--scaphoid nonunion advanced collapse-- grade II or more) and had surgery more than 2 years after injury. Ten of the 13 patients achieved union at 6 months with all but one of these demonstrating improvement on the Disability of Arm, Shoulder and Hand (DASH) score. Surgeons presented with this difficult patient group might consider reconstruction before salvage procedures. PMID- 21825013 TI - Morphological study of the proximal boundary of the flexor retinaculum and of its constituent parts. AB - The proximal boundary of the flexor retinaculum is not readily demarcated, and previous reports of three distinct regions of the flexor retinaculum were not consistent with the authors' experience. This study was undertaken to clarify the proximal boundary and the constituent parts of the flexor retinaculum. A total of 56 cadaveric wrists were used in the study. The proximal boundary of the flexor retinaculum was identified by a change in thickness and colour of the longitudinally sectioned surface of the continuous membranous sheet of the flexor retinaculum and antebrachial fascia. Steel wires were placed on the proximal and distal boundaries, and anteroposterior radiographic images were taken. MRI was carried out before dissection or serial section. The locations of the proximal and distal boundaries of the flexor retinaculum varied. The flexor retinaculum was comprised of two parts, which were distinguishable by thickness and transparency. These two parts were also identified on MR images and by light microscopy. PMID- 21825014 TI - Resuscitating cancer immunosurveillance: selective stimulation of DLL1-Notch signaling in T cells rescues T-cell function and inhibits tumor growth. AB - Deficiencies in immune function that accumulate during cancer immunoediting lead to a progressive escape from host immunosurveillance. Therapies that correct or overcome these defects could have a powerful impact on cancer management, but current knowledge of the types and mechanisms of immune escape is still incomplete. Here, we report a novel mechanism of escape from T-cell immunity that is caused by reduction in levels of the Delta family Notch ligands DLL1 and DLL4 in hematopoietic microenvironments. An important mediator of this effect was an elevation in the levels of circulating VEGF. Selective activation of the DLL1 Notch signaling pathway in bone marrow precursors enhanced T-cell activation and inhibited tumor growth. Conversely, tumor growth led to inhibition of Delta family ligand signaling through Notch in the hematopoietic environment, resulting in suppressed T-cell function. Overall, our findings uncover a novel mechanism of tumoral immune escape and suggest that a soluble multivalent form of DLL1 may offer a generalized therapeutic intervention to stimulate T-cell immunity and suppress tumor growth. PMID- 21825015 TI - Genome-wide methylation analysis identifies genes specific to breast cancer hormone receptor status and risk of recurrence. AB - To better understand the biology of hormone receptor-positive and-negative breast cancer and to identify methylated gene markers of disease progression, we carried out a genome-wide methylation array analysis on 103 primary invasive breast cancers and 21 normal breast samples, using the Illumina Infinium HumanMethylation27 array that queried 27,578 CpG loci. Estrogen and/or progesterone receptor-positive tumors displayed more hypermethylated loci than estrogen receptor (ER)-negative tumors. However, the hypermethylated loci in ER negative tumors were clustered closer to the transcriptional start site compared with ER-positive tumors. An ER-classifier set of CpG loci was identified, which independently partitioned primary tumors into ER subtypes. A total of 40 (32 novel and 8 previously known) CpG loci showed differential methylation specific to either ER-positive or ER-negative tumors. Each of the 40 ER subtype-specific loci was validated in silico, using an independent, publicly available methylome dataset from the Cancer Genome Atlas. In addition, we identified 100 methylated CpG loci that were significantly associated with disease progression; the majority of these loci were informative particularly in ER-negative breast cancer. Overall, the set was highly enriched in homeobox containing genes. This pilot study shows the robustness of the breast cancer methylome and illustrates its potential to stratify and reveal biological differences between ER subtypes of breast cancer. Furthermore, it defines candidate ER-specific markers and identifies potential markers predictive of outcome within ER subgroups. PMID- 21825016 TI - Constitutive intestinal NF-kappaB does not trigger destructive inflammation unless accompanied by MAPK activation. AB - Nuclear factor (NF)-kappaB, activated by IkappaB kinase (IKK), is a key regulator of inflammation, innate immunity, and tissue integrity. NF-kappaB and one of its main activators and transcriptional targets, tumor necrosis factor (TNF), are up regulated in many inflammatory diseases that are accompanied by tissue destruction. The etiology of many inflammatory diseases is poorly understood, but often depends on genetic factors and environmental triggers that affect NF-kappaB and related pathways. It is unknown, however, whether persistent NF-kappaB activation is sufficient for driving symptomatic chronic inflammation and tissue damage. To address this question, we generated IKKbeta(EE)(IEC) mice, which express a constitutively active form of IKKbeta in intestinal epithelial cell (IECs). IKKbeta(EE)(IEC) mice exhibit NF-kappaB activation in IECs and express copious amounts of inflammatory chemokines, but only small amounts of TNF. Although IKKbeta(EE)(IEC) mice exhibit inflammatory cell infiltration in the lamina propria (LP) of their small intestine, they do not manifest tissue damage. Yet, upon challenge with relatively mild immune and microbial stimuli, IKKbeta(EE)(IEC) mice succumb to destructive acute inflammation accompanied by enterocyte apoptosis, intestinal barrier disruption, and bacterial translocation. Inflammation is driven by massive TNF production, which requires additional activation of p38 and extracellular-signal-regulated kinase mitogen-activated protein kinases (MAPKs). PMID- 21825017 TI - Cytokine signals through PI-3 kinase pathway modulate Th17 cytokine production by CCR6+ human memory T cells. AB - Human memory T cells (T(M) cells) that produce IL-17 or IL-22 are currently defined as Th17 or Th22 cells, respectively. These T cell lineages are almost exclusively CCR6(+) and are important mediators of chronic inflammation and autoimmunity. However, little is known about the mechanisms controlling IL-17/IL 22 expression in memory Th17/Th22 subsets. We show that common gamma chain (gammac)-using cytokines, namely IL-2, IL-7, and IL-15, potently induce Th17 signature cytokine expression (Il17a, Il17f, Il22, and Il26) in CCR6(+), but not CCR6(-), T(M) cells, even in CCR6(+) cells lacking IL-17 expression ex vivo. Inhibition of phosphoinositide 3-kinase (PI-3K) or Akt signaling selectively prevents Th17 cytokine induction by gammac-cytokines, as does ectopic expression of the transcription factors FOXO1 or KLF2, which are repressed by PI-3K signaling. These results indicate that Th17 cytokines are tuned by PI-3K signaling in CCR6(+) T(M) cells, which may contribute to chronic or autoimmune inflammation. Furthermore, these findings suggest that ex vivo analysis of IL-17 expression may greatly underestimate the frequency and pathogenic potential of the human Th17 compartment. PMID- 21825018 TI - Preexisting helminth infection induces inhibition of innate pulmonary anti tuberculosis defense by engaging the IL-4 receptor pathway. AB - Tuberculosis and helminthic infections coexist in many parts of the world, yet the impact of helminth-elicited Th2 responses on the ability of the host to control Mycobacterium tuberculosis (Mtb) infection has not been fully explored. We show that mice infected with the intestinal helminth Nippostrongylus brasiliensis (Nb) exhibit a transitory impairment of resistance to airborne Mtb infection. Furthermore, a second dose of Nb infection substantially increases the bacterial burden in the lungs of co-infected mice. Interestingly, the Th2 response in the co-infected animals did not impair the onset and development of the protective Mtb-specific Th1 cellular immune responses. However, the helminth induced Th2 environment resulted in the accumulation of alternatively activated macrophages (AAMs) in the lung. Co-infected mice lacking interleukin (IL) 4Ralpha exhibited improved ability to control Mtb infection, which was accompanied by significantly reduced accumulation of AAMs. Moreover, IL-4Ralpha(-/-) mice adoptively transferred with wild-type macrophages had a significantly higher Mtb load in their lungs compared with those that received IL-4Ralpha(-/-) macrophages, suggesting a direct contribution for the IL-4R pathway to the heightened susceptibility of co-infected animals. The Th2 response can thus enhance the intracellular persistence of Mtb, in part by mediating the alternative activation of macrophages via the IL-4Ralpha signaling pathway. PMID- 21825019 TI - Coordinate regulation of tissue macrophage and dendritic cell population dynamics by CSF-1. AB - Tissue macrophages (Mphis) and dendritic cells (DCs) play essential roles in tissue homeostasis and immunity. How these cells are maintained at their characteristic densities in different tissues has remained unclear. Aided by a novel flow cytometric technique for assessing relative rates of blood-borne precursor recruitment, we examined Mphi and DC population dynamics in the pregnant mouse uterus, where rapid tissue growth facilitated a dissection of underlying regulatory mechanisms. We demonstrate how Mphi dynamics, and thus Mphi tissue densities, are locally controlled by CSF-1, a pleiotropic growth factor whose in situ level of activity varied widely between uterine tissue layers. CSF 1 acted in part by inducing Mphi proliferation and in part by stimulating the extravasation of Ly6C(hi) monocytes (Mos) that served as Mphi precursors. Mo recruitment was dependent on the production of CCR2 chemokine receptor ligands by uterine Mphis in response to CSF-1. Unexpectedly, a parallel CSF-1-regulated, but CCR2-independent pathway influenced uterine DC tissue densities by controlling local pre-DC extravasation rates. Together, these data provide cellular and molecular insight into the regulation of Mphi tissue densities under noninflammatory conditions and reveal a central role for CSF-1 in the coordination of Mphi and DC homeostasis. PMID- 21825020 TI - Protein solubility and protein homeostasis: a generic view of protein misfolding disorders. AB - According to the "generic view" of protein aggregation, the ability to self assemble into stable and highly organized structures such as amyloid fibrils is not an unusual feature exhibited by a small group of peptides and proteins with special sequence or structural properties, but rather a property shared by most proteins. At the same time, through a wide variety of techniques, many of which were originally devised for applications in other disciplines, it has also been established that the maintenance of proteins in a soluble state is a fundamental aspect of protein homeostasis. Taken together, these advances offer a unified framework for understanding the molecular basis of protein aggregation and for the rational development of therapeutic strategies based on the biological and chemical regulation of protein solubility. PMID- 21825021 TI - Protein misfolding and retinal degeneration. AB - The retina is a highly complex and specialized organ that performs preliminary analysis of visual information. Composed of highly metabolically active tissue, the retina requires a precise and well-balanced means of maintaining its functional activity during extended periods of time. Maintenance and regulation of a vast array of different structural and functional proteins is required for normal function of the retina. This process is referred to as protein homeostasis and involves a variety of activities, including protein synthesis, folding, transport, degradation, elimination, and recycling. Deregulation of any of these activities can lead to malfunctioning of the retina, from subtle subclinical signs to severe retinal degenerative diseases leading to blindness. Examples of retinal degenerative diseases caused by disruption of protein homeostasis include retinitis pigmentosa and Stargardt's disease. A detailed discussion of the role of disruption in protein homeostasis in these and other retinal diseases is presented, followed by examples of some existing and potential treatments. PMID- 21825024 TI - Changes of SERCA activity have only modest effects on sarcoplasmic reticulum Ca2+ content in rat ventricular myocytes. AB - Changes of the activity of the sarco-endoplasmic reticulum Ca(2+)-ATPase (SERCA) affect the amplitude of the systolic Ca(2+) transient and thence cardiac contractility. This is thought to be due to alterations of SR Ca(2+) content. Recent work on mice in which the expression of SERCA is decreased found that a large reduction of SERCA expression resulted in a proportionately much smaller decrease of SR Ca(2+) content. The aim of the current work was to investigate the quantitative nature of the dependence of both the amplitude of the systolic Ca(2+) transient and SR Ca(2+) content on SERCA activity during acute partial inhibition of SERCA. Experiments were performed on rat ventricular myocytes. Brief application of thapsigargin (1 MUm) resulted in a decrease of SERCA activity as measured from the rate of decay of the systolic Ca(2+) transient. This was accompanied by a decrease in the amplitude of the systolic Ca(2+) transient which was linearly related to that of SERCA activity. However, the fractional decrease in the SR Ca(2+) content was much less than that of SERCA activity. On average SR Ca(2+) content was proportional to SERCA activity raised to the 0.38 +/- 0.07 power. This shallow dependence of SR content on SERCA activity arises because Ca(2+) release is a steep function of SR Ca(2+) content. In contrast SR Ca(2+) content was increased 4.59 +/- 0.40 (n = 8)-fold by decreasing ryanodine receptor opening with tetracaine (1 mm). Therefore a modest decrease of SR Ca(2+) content results in a proportionately larger fall of Ca(2+) release from the SR which can balance a larger initiating decrease of SERCA. In conclusion, the shallow dependence of SR Ca(2+) content on SERCA activity is expected for a system in which small changes of SR Ca(2+) content produce larger effects on the amplitude of the systolic Ca(2+) transient. PMID- 21825022 TI - Distinct mechanisms regulate GABAA receptor and gephyrin clustering at perisomatic and axo-axonic synapses on CA1 pyramidal cells. AB - Pyramidal cells express various GABA(A) receptor (GABA(A)R) subtypes, possibly to match inputs from functionally distinct interneurons targeting specific subcellular domains. Postsynaptic anchoring of GABA(A)Rs is ensured by a complex interplay between the scaffolding protein gephyrin, neuroligin-2 and collybistin. Direct interactions between these proteins and GABA(A)R subunits might contribute to synapse-specific distribution of GABA(A)R subtypes. In addition, the dystrophin-glycoprotein complex, mainly localized at perisomatic synapses, regulates GABA(A)R postsynaptic clustering at these sites. Here, we investigated how the functional and molecular organization of GABAergic synapses in CA1 pyramidal neurons is altered in mice lacking the GABA(A)R alpha2 subunit (alpha2 KO). We report a marked, layer-specific loss of postsynaptic gephyrin and neuroligin-2 clusters, without changes in GABAergic presynaptic terminals. Whole cell voltage-clamp recordings in slices from alpha2-KO mice show a 40% decrease in GABAergic mIPSC frequency, with unchanged amplitude and kinetics. Applying low/high concentrations of zolpidem to discriminate between alpha1- and alpha2/alpha3-GABA(A)Rs demonstrates that residual mIPSCs in alpha2-KO mice are mediated by alpha1-GABA(A)Rs. Immunofluorescence analysis reveals maintenance of alpha1-GABA(A)R and neuroligin-2 clusters, but not gephyrin clusters, in perisomatic synapses of mutant mice, along with a complete loss of these three markers on the axon initial segment. This striking subcellular difference correlates with the preservation of dystrophin clusters, colocalized with neuroligin-2 and alpha1-GABA(A)Rs on pyramidal cell bodies of mutant mice. Dystrophin was not detected on the axon initial segment in either genotype. Collectively, these findings reveal synapse-specific anchoring of GABA(A)Rs at postsynaptic sites and suggest that the dystrophin-glycoprotein complex contributes to stabilize alpha1-GABA(A)R and neuroligin-2, but not gephyrin, in perisomatic postsynaptic densities. PMID- 21825025 TI - Endothelin B receptor contribution to peripheral microvascular function in women with polycystic ovary syndrome. AB - Endothelin-1 is elevated in women with polycystic ovary syndrome (PCOS), and may play a role in the endothelial dysfunction associated with PCOS. Endothelin-1 binds two receptor subtypes, endothelin A (ET-A) and endothelin B (ET-B). We hypothesized that ET-A mediates vasoconstriction in the cutaneous microvasculature in women with and without PCOS. We further hypothesized that while the ET-B receptors mediate vasodilatation in both groups of women, this response would be blunted in women with PCOS. During local skin warming, we used laser Doppler flowmetry combined with intradermal microdialysis to measure skin blood flow (SkBF) during graded ET-A (BQ-123) and ET-B (BQ-788) antagonist infusions in women with (n = 6) and without (n = 8) PCOS. In both groups, SkBF increased during local heating. The percentage of maximal SkBF-[BQ123] sigmoidal dose-response curve indicated a vasodilatory response as the concentration of the antagonist increased (Hill slope 4.96 +/- 4.77, 4.74 +/- 5.01; logED(50) 2.53 +/- 0.09, 2.49 +/- 0.09 nm, for PCOS and Control, respectively). In contrast, the % max SkBF-[BQ788] curve indicated a vasoconstrictive response (Hill slope -4.69 +/ 3.85, -4.03 +/- 3.85; logED(50), 2.56 +/- 0.09, 2.41 +/- 0.12 nm, in PCOS and Control). Moreover, the SkBF-[BQ788] curve shifted to the right in women with PCOS, suggesting attenuated ET-B receptor mediated vasodilatation during local skin warming compared to Controls. Thus, the endothelium located ET-B receptors function similarly in women with and without PCOS, although with blunted responsiveness in women with PCOS. Our studies suggest that the lower ET-B receptor responsiveness associated with PCOS may reflect lower endothelial mediated vasodilatation independent of generally lower vascular reactivity. PMID- 21825026 TI - Modulation of the myogenic response in renal blood flow autoregulation by NO depends on endothelial nitric oxide synthase (eNOS), but not neuronal or inducible NOS. AB - Nitric oxide (NO) blunts the myogenic response (MR) in renal blood flow (RBF) autoregulation. We sought to clarify the roles of NO synthase (NOS) isoforms, i.e. neuronal NOS (nNOS) from macula densa, endothelial NOS (eNOS) from the endothelium, and inducible NOS (iNOS) from smooth muscle or mesangium. RBF autoregulation was studied in rats and knockout (ko) mice in response to a rapid rise in renal artery pressure (RAP). The autoregulatory rise in renal vascular resistance within the first 6 s was interpreted as MR, from ~6 to ~30 s as tubuloglomerular feedback (TGF), and ~30 to ~100 s as the third regulatory mechanism. In rats, the nNOS inhibitor SMTC did not significantly affect MR (67 +/- 4 vs. 57 +/- 4 units). Inhibition of all NOS isoforms by l-NAME in the same animals markedly augmented MR to 78 +/- 4 units. The same was found when SMTC was combined with angiotensin II to reproduce the hypertension and vasoconstriction seen with l-NAME (58 +/- 3 vs. 54 +/- 7 units, l-NAME 81 +/- 2 units), or when SMTC was replaced by the nNOS inhibitor NPA (57 +/- 5 vs. 56 +/- 7 units, l-NAME 79 +/- 4 units) or by the iNOS inhibitor 1400W (50 +/- 1 vs. 55 +/- 4 units, l NAME 81 +/- 3 units). nNOS-ko mice showed the same autoregulation as wild-types (MR 36 +/- 4 vs. 38 +/- 3 units) and the same response to l-NAME (111 +/- 9 vs. 114 +/- 10 units). eNOS-ko had similar autoregulation as wild-types (44 +/- 8 vs. 33 +/- 4 units), but failed to respond to l-NAME (37 +/- 7 vs. 78 +/- 16 units). We conclude that the attenuating effect of NO on MR depends on eNOS, but not on nNOS or iNOS. In eNOS-ko mice MR is depressed by NO-independent means. PMID- 21825027 TI - In vivo passive mechanical behaviour of muscle fascicles and tendons in human gastrocnemius muscle-tendon units. AB - Ultrasound imaging was used to measure the length of muscle fascicles in human gastrocnemius muscles while the muscle was passively lengthened and shortened by moving the ankle. In some subjects the muscle belly 'buckled' at short lengths. When the gastrocnemius muscle-tendon unit was passively lengthened from its shortest in vivo length by dorsiflexing the ankle, increases in muscle-tendon length were not initially accompanied by increases in muscle fascicle lengths (fascicle length remained constant), indicating muscle fascicles were slack at short muscle-tendon lengths. The muscle-tendon length at which slack is taken up differs among fascicles: some fascicles begin to lengthen at very short muscle tendon lengths whereas other fascicles remain slack over a large range of muscle tendon lengths. This suggests muscle fascicles are progressively 'recruited' and contribute sequentially to muscle-tendon stiffness during passive lengthening of the muscle-tendon unit. Even above their slack lengths muscle fascicles contribute only a small part (<~30%) of the total change in muscle-tendon length. The contribution of muscle fascicles to muscle-tendon length increases with muscle length. The novelty of this work is that it reveals a previously unrecognised phenomenon (buckling at short lengths), posits a new mechanism of passive mechanical properties of muscle (recruitment of muscle fascicles), and confirms with high-resolution measurements that the passive compliance of human gastrocnemius muscle-tendon units is due largely to the tendon. It would be interesting to investigate if adaptations of passive properties of muscles are associated with changes in the distribution of muscle lengths at which fascicles fall slack. PMID- 21825028 TI - Effects of ageing on single muscle fibre contractile function following short term immobilisation. AB - Very little attention has been given to the combined effects of healthy ageing and short-term disuse on the contractile function of human single muscle fibres. Therefore, the present study investigated the effects of 2 weeks of lower limb cast immobilisation (i.e. disuse) on selected contractile properties of single muscle fibres (n = 378) from vastus lateralis of nine young (24 +/- 1 years) and eight old (67 +/- 2 years) healthy men with comparable levels of physical activity. Prior to immobilisation, MHC IIa fibres produced higher maximum Ca(2+) activated force (approx. 32%) and specific force (approx. 33%) and had lower Ca(2+) sensitivity than MHC I fibres (P < 0.05), with no differences between young and old. After immobilisation, the decline in single fibre force (MHC I: young 21% and old 22%; MHC IIa: young 22% and old 30%; P < 0.05) as well as specific force (MHC I: young 14% and old 13%; MHC IIa: young 18% and old 25%; P < 0.05) was more pronounced in MHC IIa fibres compared to MHC I fibres (P < 0.05), with no differences between young and old. Notably, there was a selective decrease in Ca(2+) sensitivity in MHC IIa fibres of young (P < 0.05) and in MHC I fibres of old individuals (P < 0.05), respectively. In conclusion, 2 weeks of lower limb immobilisation caused greater impairments in single muscle fibre force and specific force in MHC IIa than MHC I fibres independently of age. In contrast, immobilisation-induced changes in Ca(2+) sensitivity that were dependent on age and MHC isoform. PMID- 21825029 TI - Age-dependent remodelling of inhibitory synapses onto hippocampal CA1 oriens lacunosum moleculare interneurons. AB - Stratum oriens-lacunosum moleculare interneurons (O-LM INs) represent the major element of the hippocampal feedback inhibitory circuit, which provides inhibition to the distal dendritic sites of CA1 pyramidal neurons. Although the intrinsic conductance profile and the properties of glutamatergic transmission to O-LM INs have become a subject of intense investigation, far less is known about the properties of the inhibitory synapses formed onto these cells. Here, we used whole-cell patch-clamp recordings in acute mouse hippocampal slices to study the properties and plasticity of GABAergic inhibitory synapses onto O-LM INs. Surprisingly, we found that the kinetics of inhibitory postsynaptic currents (IPSCs) were slower in mature synapses (P26-40) due to the synaptic incorporation of the alpha5 subunit of the GABA(A) receptor (a5-GABA(A)R). Moreover, this age dependent synaptic expression of a5-GABA(A)Rs was directly associated with the emergence of long-term potentiation at IN inhibitory synapses. Finally, the slower time course of IPSCs observed in O-LM INs of mature animals had a profound effect on IN excitability by significantly delaying its spike firing. Our data suggest that GABAergic synapses onto O-LM INs undergo significant modifications during postnatal maturation. The developmental switch in IPSC properties and plasticity is controlled by the synaptic incorporation of the a5-GABA(A)R subunit and may represent a potential mechanism for the age-dependent modifications in the inhibitory control of the hippocampal feedback inhibitory circuit. PMID- 21825030 TI - Biophysical properties and functional consequences of reactive oxygen species (ROS)-induced ROS release in intact myocardium. AB - Reactive oxygen species (ROS)-induced ROS release (RIRR) is a fundamental mechanism by which cardiac mitochondria respond to elevated ROS levels by stimulating endogenous ROS production in a regenerative, autocatalytic process that ultimately results in global oxidative stress (OS), cellular dysfunction and death. Despite elegant studies describing the phenomenon of RIRR under artificial conditions such as photo-induced oxidation of discrete regions within cardiomyocytes, the existence, biophysical properties and functional consequences of RIRR in intact myocardium remain unclear. Here, we used a semi-quantitative approach of optical superoxide (O(2)(-)) mapping using dihydroethidium (DHE) fluorescence to explore RIRR, its arrhythmic consequences and underlying mechanisms in intact myocardium. Initially, perfusion of rat hearts with 200 MUM H(2)O(2) for 40 min (n = 4) elicited two distinct O(2)(-) peaks that were readily distinguished by their timing and amplitude. The first peak (P1), which was generated rapidly (within 5-8 min of H(2)O(2) perfusion) was associated with a relatively limited (10 +/- 2%) rise in normalized O(2)(-) levels relative to baseline. In contrast, the second peak (P2) occurred 19-26 min following onset of H(2)O(2) perfusion and was associated with a significantly greater amplitude compared to P1. Spatio-temporal ROS mapping during P2 revealed active O(2)(-) propagation across the myocardium at a velocity of ~20 MUm s(-1). Exposure of hearts (n = 18) to a short (10 min) episode of H(2)O(2) perfusion revealed consistent generation of P2 by high (>=200 MUM, 8/8) but not lower (<=100 MUM, 3/8) H(2)O(2) concentrations (P < 0.03). In these hearts, onset of P2 occurred following, not during, the 10 min OS protocol, consistent with RIRR. Importantly, P2 (+) hearts exhibited a markedly greater (by 3.8-fold, P < 0.001) arrhythmia score compared to P2 (-) hearts. To explore the mechanism underlying RIRR in intact myocardium, hearts were perfused with either cyclosporin A (CsA) or 4 chlorodiazepam (4-Cl-DZP) to inhibit the mitochondrial permeability transition pore (mPTP) or the inner membrane anion channel (IMAC), respectively. Surprisingly, perfusion with CsA failed to suppress (P = 0.75, n.s.) or even delay H(2)O(2)-induced P2 or the incidence of arrhythmias compared to untreated hearts. In sharp contrast, perfusion with 4-Cl-DZP markedly blunted O(2)(-) levels during P2, and suppressed the incidence of sustained ventricular tachycardia or ventricular fibrillation (VT/VF). Finally, perfusion of hearts with the synthetic superoxide dismutase/catalase mimetic EUK-134 completely abolished the H(2)O(2)-mediated RIRR response as well as the incidence of arrhythmias. These findings extend the concept of RIRR to the level of the intact heart, establish regenerative O(2)(-) production as the mediator of RIRR-related arrhythmias and reveal their strong dependence on IMAC and not the mPTP in this acute model of OS. PMID- 21825031 TI - Spinal direct current stimulation modulates the activity of gracile nucleus and primary somatosensory cortex in anaesthetized rats. AB - Afferent somatosensory activity from the spinal cord has a profound impact on the activity of the brain. Here we investigated the effects of spinal stimulation using direct current, delivered at the thoracic level, on the spontaneous activity and on the somatosensory evoked potentials of the gracile nucleus, which is the main entry point for hindpaw somatosensory signals reaching the brain from the dorsal columns, and of the primary somatosensory cortex in anaesthetized rats. Anodal spinal direct current stimulation (sDCS) increased the spontaneous activity and decreased the amplitude of evoked responses in the gracile nucleus, whereas cathodal sDCS produced the opposite effects. At the level of the primary somatosensory cortex, the changes in spontaneous activity induced by sDCS were consistent with the effects observed in the gracile nucleus, but the changes in cortical evoked responses were more variable and state dependent. Therefore, sDCS can modulate in a polarity-specific manner the supraspinal activity of the somatosensory system, offering a versatile bottom-up neuromodulation technique that could potentially be useful in a number of clinical applications. PMID- 21825032 TI - Calcitonin gene-related peptide restores disrupted excitation-contraction coupling in myotubes expressing central core disease mutations in RyR1. AB - Central core disease (CCD) is a congenital human myopathy associated with mutations in the gene encoding the skeletal muscle ryanodine receptor (RyR1), resulting in skeletal muscle weakness and lower limb deformities. The muscle weakness can be at least partially explained by a reduced magnitude of voltage gated Ca(2+) release (VGCR). To date, only a few studies have focused on identifying potential therapeutic agents for CCD. Therefore, in this work we investigated the potential use of the calcitonin gene related peptide (CGRP) to restore VGCR in myotubes expressing CCD RyR1 mutants. We also examined the influence of CCD mutants on Ca(2+)-dependent processes involved in myogenesis (myoblast fusion and sarcoendoplasmic reticulum Ca(2+)-ATPase isoform 2 (SERCA2) gene expression). C2C12 cells were transfected with cDNAs encoding either wild type RyR1 or CCD mutants, and then exposed to CGRP (100 nm, 1-4 h). Expression of the I4897T mutant significantly inhibited SERCA2 gene expression and myoblast fusion, whereas the Y523S mutant exerted the opposite effect. Interestingly, both mutants clearly inhibited VGCR (50%), due to a reduction in SR Ca(2+) content. However, no major changes due to CGRP or CCD mutants were observed in I(CaL). Our data suggest that the Y523S mutant results in store depletion via decompensated SR Ca(2+) leak, while the I4897T mutant inhibits SERCA2 gene expression. Remarkably, in both cases CGRP restored VGCR, likely to have been by enhancing phospholamban (PLB) phosphorylation, SERCA activity and SR Ca(2+) content. Taken together, our data show that in the C2C12 model system, changes in excitation contraction coupling induced by the expression of RyR1 channels bearing CCD mutations Y523S or I4897T can be reversed by CGRP. PMID- 21825034 TI - The vasostatin-1 fragment of chromogranin A preserves a quiescent phenotype in hypoxia-driven endothelial cells and regulates tumor neovascularization. AB - The angiogenic switch is a fundamental process for many diseases and for tumor growth. The main proangiogenic stimulus is hypoxia, through activation of the hypoxia-inducible factor (HIF)-1alpha pathway in endothelial cells (ECs). We have previously shown that the vasostatin-1 (VS-1) fragment of chromogranin A inhibits TNF-alpha-induced vessel permeability and VEGF-induced EC proliferation, together with migration and matrix invasion, which are all critical steps in angiogenesis. The present study was undertaken to investigate the effect of VS-1 on tumor angiogenesis. We found mouse mammary adenocarcinomas (TS/A), genetically engineered to secrete VS-1 (TS/A 1B8), to be characterized by reduced vascular density and more regular vessels, compared with nontransfected tumors [TS/A wild type (WT)]. Supernatants from TS/A WT cells, but not those from TS/A 1B8, generated tip cells and promoted the permeability of primary human umbilical vein ECs, via VE-cadherin redistribution and cytoskeletal disorganization. These effects were abrogated by mAb 5A8, a VS-1-blocking antibody. Furthermore, VS-1 inhibited hypoxia-driven EC morphological changes, VE-cadherin redistribution, intercellular gap formation, tube morphogenesis, and HIF-1alpha nuclear translocation in vitro. Our findings highlight a previously undescribed function of VS-1 as a regulator of tumor vascularization. PMID- 21825033 TI - Neuronal homeostasis: time for a change? AB - Homeostatic processes that regulate electrical activity in neurones are now an established aspect of physiology and rest on a large body of experimental evidence that points to roles in development, learning and memory, and disease. However, the concepts underlying homeostasis are too often summarized in ways that restrict their explanatory power and obviate important subtleties. Here, we present a review of the underlying theory of homeostasis--control theory--in an attempt to reconcile some existing conceptual problems in the context of neuronal physiology. In addition to clarifying the underlying theory, this review highlights the remaining challenges posed when analysing homeostatic phenomena that underlie the regulation of neuronal excitability. Moreover, we suggest approaches for future experimental and computational work that will further our understanding of neuronal homeostasis and the fundamental neurophysiological functions it serves. PMID- 21825035 TI - Behavioral deficit, oxidative stress, and mitochondrial dysfunction precede tau pathology in P301S transgenic mice. AB - Abnormal tau accumulation can lead to the development of neurodegenerative diseases. P301S mice overexpress the human tau mutated gene, resulting in tau hyperphosphorylation and tangle formation. Mice also develop synaptic deficits and microglial activation prior to any neurodegeneration and tangles. Oxidative stress can also affect tauopathy. We studied the role of oxidative stress in relationship to behavioral abnormalities and disease progression in P301S mice at 2, 7, and 10 mo of age. At 7 mo of age, P301S mice had behavioral abnormalities, such as hyperactivity and disinhibition. At the same age, we observed increased carbonyls in P301S mitochondria (~215 and 55% increase, males/females), and deregulation in the activity and content of mitochondrial enzymes involved in reactive oxygen species formation and energy metabolism, such as citrate synthase (~19 and ~5% decrease, males/females), MnSOD (~16% decrease, males only), cytochrome C (~19% decrease, females only), and cytochrome C oxidase (~20% increase, females only). These changes in mitochondria proteome appeared before tau hyperphosphorylation and tangle formation, which were observed at 10 mo and were associated with GSK3beta activation. At that age, mitochondria proteome deregulation became more apparent in male P301S mitochondria. The data strongly suggest that oxidative stress and mitochondrial abnormalities appear prior to tau pathology. PMID- 21825036 TI - Sphingosine-1-phospate receptor 4 (S1P4) deficiency profoundly affects dendritic cell function and TH17-cell differentiation in a murine model. AB - Although predominantly expressed on lymphocytic and hematopoietic cells, the role of sphingosine-1-phospate receptor 4 (S1P(4)) in immune homeostasis is still poorly understood. In this report, we used a S1P(4)-deficient murine model to characterize the biological role of S1P(4)-mediated S1P signaling in the immune system. S1p(4)(-/-) animals showed normal peripheral lymphocyte numbers and a regular architecture of secondary lymphoid organs. Interestingly, S1P(4) only marginally affects T-cell function in vivo. In contrast, dendritic cell (DC) migration and cytokine secretion are profoundly affected by S1P(4) deficiency. Lack of S1P(4) expression on DCs significantly reduces T(H)17 differentiation of T(H) cells. Furthermore, in various in vivo models of T(H)1- or T(H)2-dominated immune reactions, S1P(4) deficiency consistently increased the amplitude of T(H)2 dominated immune responses, while those depending on T(H)1-dominated mechanisms were diminished. Finally, S1p(4)(-/-) mice showed decreased pathology in a model of dextran sulfate sodium-induced colitis. In summary, for the first time, we show that S1P(4) signaling is involved in the regulation of DC function and T(H)17 T-cell differentiation. S1P(4)-mediated S1P signaling also modifies the course of various immune diseases in a murine model. We propose that S1P(4) may constitute an interesting target to influence the course of various autoimmune pathologies. PMID- 21825037 TI - Evaluation of a clinical pathway to improve colorectal cancer outcomes. AB - The aims of this preintervention and postintervention study were to monitor and evaluate the clinical pathway (CP) for colorectal cancer (CRC) over a 5-year period and to compare 2 groups of patients (before and after the intervention) with regard to different variables of effectiveness. Group I comprised 68 patients who underwent planned surgery between January 2002 and January 2003. Group II comprised a sample of 202 patients who underwent surgery between January 2004 and December 2008. No significant differences were found in the majority of the parameters measured: postoperative stay, compliance with antibiotic prophylaxis, compliance with the staging study, mortality, rate of infection, and reoperations. The mean length of stay (+/-standard deviation) for patients without complications was reduced significantly (9.2 +/- 3.6 in group I versus 7.7 +/- 1.7 in group II, P = .031). The CP for CRC did not achieve most of the objectives for which it was designed. PMID- 21825038 TI - Variation in public reporting of central line-associated bloodstream infections by state. AB - Central line-associated bloodstream infections (CLABSIs) are common, costly, and largely preventable. Consumers who want high-quality care should have access to CLABSI rates to make health care decisions. The authors searched state health department Web sites for publicly available CLABSI data. Fourteen states, all with mandatory CLABSI monitoring laws, had publicly available data. The authors identified significant variation in the presentation of infection rates, methods of risk adjustment, locations and care settings reported, time span of data collection, and time lag to reporting. The wide variation in availability and content of information illustrates the need for standardized CLABSI monitoring and reporting mechanisms. PMID- 21825039 TI - Autophagy activation in hepatocellular carcinoma contributes to the tolerance of oxaliplatin via reactive oxygen species modulation. AB - PURPOSE: Understanding the roles of mammalian autophagy in cancer highlights recent advances in the pharmacologic manipulation of autophagic pathways as a therapeutic strategy for cancer. However, autophagy status and corresponding functions in hepatocellular carcinoma (HCC) after therapeutic stress remain to be clarified. This study was to determine whether the autophagic machinery could be activated after chemotherapy and the contribution of autophagy to tolerance of oxaliplatin in HCC. EXPERIMENTAL DESIGN: Autophagy activation and cell death induced by oxaliplatin were examined in two HCC cell lines as well as in vivo using an HCC model in nude mice. HCC tissue samples with or without locoregional chemotherapy before surgery were also examined by immunohistochemical and electron microscopic analysis. RESULTS: Autophagy was functionally activated in HCC cell lines and xenografts after oxaliplatin treatment. Suppression of autophagy using either pharmacologic inhibitors or RNA interference of essential autophagy gene enhanced cell death induced by oxaliplatin in HCC cells. Generation of reactive oxygen species has an important role in the induction of cell death by oxaliplatin in combination with autophagy inhibitors. Critically, the combination of oxaliplatin with autophagy inhibitor chloroquine resulted in a more pronounced tumor suppression in HCC xenografts. Furthermore, autophagy specific protein LC3 and autophagic autophagosome formation were induced to a significantly higher level in HCC specimens that had been subjected to locoregional chemotherapy. CONCLUSIONS: Autophagy activation under therapy stress contributes to HCC tumor cell survival. Targeting the autophagy pathway is a promising therapeutic strategy to enhance the effects of chemotherapy and improve clinical outcomes in HCC patients. PMID- 21825040 TI - Cyclin-dependent kinase 5 is amplified and overexpressed in pancreatic cancer and activated by mutant K-Ras. AB - PURPOSE: To evaluate the nature of cyclin-dependent kinase 5 (CDK5) hyperactivity in pancreatic cancer progression. EXPERIMENTAL DESIGN: We used genetic, biochemical, and molecular biology methods to investigate the nature and function of overexpression of CDK5 and its activators p35 and p39 during the progression of pancreatic cancer. RESULTS: Amplification of the CDK5 gene or either of its main activators, p35 and p39, was observed in 67% of human pancreatic ductal adenocarcinoma (PDAC). CDK5, p35, and p39 were rarely expressed in pancreatic ducts whereas more than 90% of PDACs had increased levels of CDK5 and p35. Increased levels of CDK5, p35, and p39 protein were observed in several pancreatic cancer cell lines. Inhibition of CDK5 kinase activity using a CDK5 dominant-negative mutant or the drug roscovitine significantly decreased the migration and invasion of pancreatic cancer cells in vitro. Increased CDK5 kinase activity was also observed in immortalized human pancreatic nestin-expressing (HPNE) cells expressing a mutant form of K-Ras (G12D) compared with HPNE cells expressing native K-Ras. G12D K-Ras increased cleavage of p35 to p25, a stable and greater activator of CDK5, thus implicating a role for CDK5 in early progression of PDAC. Inhibition of the signaling cascade downstream of mutant K Ras (G12D) that involves mitogen-activated protein/extracellular signal-regulated kinase, phosphoinositide 3-kinase, or CDK5 decreased p25 protein levels. CONCLUSION: These results suggest that mutant K-Ras acts in concert with CDK5 and its activators to increase malignant progression, migration, and invasion of pancreatic cancer cells. PMID- 21825041 TI - Preclinical pharmacokinetics and safety of Sym004: a synergistic antibody mixture directed against epidermal growth factor receptor. AB - PURPOSE: Sym004 is a novel therapeutic antibody mixture product comprising two unmarketed monoclonal antibodies (mAb) targeting the epidermal growth factor receptor (EGFR). In previous preclinical proof-of-concept studies, Sym004 was shown to elicit superior cancer cell growth inhibition activities compared with marketed anti-EGFR mAbs. This article describes the design and results of the preclinical safety program conducted to support early clinical development of Sym004. EXPERIMENTAL DESIGN: Tissue cryosections from various species were stained with Sym004 to evaluate tissue cross reactivity. The pharmacokinetics of Sym004 were evaluated in a mouse xenograft model and in Cynomolgus monkeys. Monkeys received once weekly intravenous infusions of Sym004 in the range 2 to 24 mg/kg for 6 to 8 weeks. Cetuximab (a marketed anti-EGFR mAb) and the individual antibodies comprising Sym004 were included in the repeat-dose toxicity studies at single-dose level. RESULTS: Sym004 had a staining pattern similar to cetuximab in tissue panels from both human and non-human primates. Once weekly dosing of Sym004 to Cynomolgus monkeys did not cause accumulation, whereas administration of the individual antibodies resulted in prolonged half-life and accumulation. In direct comparisons with cetuximab, Sym004 did not induce any distinct or novel adverse findings in the animals. However, an early onset of pronounced, reversible, and anticipated anti-EGFR-mediated pharmacologic effects, such as skin rash, dehydration, and liquid feces, was observed. Only minor adverse effects were recorded in animals treated with the individual antibodies comprising Sym004. CONCLUSION: Sym004 was well tolerated and did not induce any unexpected toxicities. The preclinical safety data enabled initiation of the ongoing clinical development. PMID- 21825043 TI - Rwanda hikes premiums in health insurance overhaul. PMID- 21825042 TI - Upregulation of Rac GTPase-activating protein 1 is significantly associated with the early recurrence of human hepatocellular carcinoma. AB - PURPOSE: To assess the significance of Rac GTPase-activating protein 1 (RACGAP1) expression in identifying HBV-positive human hepatocellular carcinoma (HCC) patients who are at high risk for recurrent disease. EXPERIMENTAL DESIGN: The prognostic significance of RACGAP1 was compared with clinicopathologic parameters available at diagnosis using multivariate and log-rank test. RACGAP1 expression and outcome in recurrence was compared between 35 patients with recurrence and 41 patients without recurrence using Kaplan-Meier analysis. RACGAP1-targeted molecules and pathways were identified and characterized by inhibition with siRNA duplexes. RESULTS: Kaplan-Meier analysis showed that the level of RACGAP1 expression is sufficient to predict the early recurrence of HCC: high RACGAP1 expression correlates with high risk of postresection recurrent HCC (P < 0.0005). Silencing of RACGAP1 in Hep3B and MHCC97-H HCC cells with high endogenous RACGAP1 expression inhibited cell migration and invasion. Using Ingenuity Pathway Analysis, the target molecules silenced in the RACGAP1 interactome were mostly genes related to the mitotic roles of the polo-like kinases. These included PRC1, AURKB, CDC2, ECT2, KIF23, PAK1, and PPP2R5E. In providing clinical corroboration of these results, when expression of these transcripts was analyzed in an expression database that we have established previously for HBV-positive HCC patients, these genes was mostly upregulated in patients who exhibited early recurrent disease and hence provided important corroboration of these results. CONCLUSIONS: siRNA-silencing RACGAP1 mainly targeted genes in an interactome clinically relevant to early HCC recurrence. Besides being an independent informative prognostic biomarker, RACGAP1 could also be a potential molecular target for designing therapeutic strategies for HCC. PMID- 21825045 TI - Cataract surgery. PMID- 21825046 TI - Toilet training children: when to start and how to train. PMID- 21825047 TI - Making the snip hip: mass circumcision in Rwanda. PMID- 21825049 TI - The Skype solution. PMID- 21825050 TI - Hyperpigmentation in Laugier-Hunziker syndrome. PMID- 21825051 TI - A population-based profile of adult Canadians living with participation and activity limitations. AB - BACKGROUND: Currently, one out of every seven Canadians is affected by limitations to their participation and activity. This study describes the self reported main causes of these limitations in a national sample. METHODS: The 2006 Participation and Activity Limitation Survey was a two-phase stratified survey based on filter questions posed in the 2006 Census of Population conducted by Statistics Canada. Respondents to the survey represent 5,185,980 Canadian adults with activity and participation limitations. We used these data to develop a profile of our population of interest: adult Canadians with activity and participation limitations. Associations between demographic variables and self reported causes of activity and participation limitations were assessed using multiple logistic regression. RESULTS: One quarter of participants did not attribute their disability to any medical cause. The most prevalent medical conditions to which disabilities were attributed were musculoskeletal (46.1%), cardio/cerebrovascular (12.3%), mental health (8.4%), neurologic (6.0%), endocrine (6.0%) and respiratory (4.5%) conditions. Significant associations were noted between sociodemographic variables and participants' attributions of medical conditions as cause of disability. Multiple logistic regression with bootstrapping showed that people who reported a medical cause for their limitation were more likely (p < 0.05) to be female, widowed, 40 years of age or older, born in Canada or white and were less likely (p < 0.05) to be in the highest income category or to be employed (i.e., to work more than 0 h/w). INTERPRETATION: Most people living with activity and participation limitations report having a musculoskeletal disorder. However, a significant proportion of respondants did not attribute their limitations to a medical cause. PMID- 21825052 TI - Too heavy to save or be saved. PMID- 21825054 TI - Routine peripubertal circumcision? PMID- 21825055 TI - "Hari": not embedded needles. PMID- 21825056 TI - Antidepressants and spontaneous abortion. PMID- 21825057 TI - Antidepressants and spontaneous abortion. PMID- 21825058 TI - Empathetic responses. PMID- 21825059 TI - Enhanced neutrophil longevity and recruitment contribute to the severity of oviduct pathology during Chlamydia muridarum infection. AB - Our previous studies revealed that intravaginal infection of mice with a plasmid deficient strain of Chlamydia muridarum, CM3.1, does not induce the development of oviduct pathology. In this study, we determined that infection with CM3.1 resulted in a significantly reduced frequency and absolute number of neutrophils in the oviducts during acute infection. This reduction in neutrophils was associated with significantly lower levels of neutrophil chemokines in the oviducts and decreased production of neutrophil chemokines by oviduct epithelial cells infected with CM3.1 in vitro. Infection with CM3.1 also resulted in an increased frequency of late apoptotic/dead neutrophils in the oviduct. Examination of the ability of Chlamydia trachomatis to prevent neutrophil apoptosis in vitro revealed that C. trachomatis strain D/UW-3/Cx exhibited an enhanced ability to prevent neutrophil apoptosis compared to plasmid-deficient CTD153, and this effect was dependent on the presence of CD14(high) monocytes. The presence of monocytes also resulted in enhanced neutrophil cytokine production and increased production of tissue-damaging molecules in response to D/UW-3/Cx relative to results with CTD153. Attempts to use antibody-mediated depletion to discern the specific role of neutrophils in infection control and pathology in vivo revealed that although Ly6G(high) neutrophils were eliminated from the blood and oviducts with this treatment, immature neutrophils and high levels of tissue-damaging molecules were still detectable in the upper genital tract. These data support the role of neutrophils in chlamydia-induced pathology and reveal that novel methods of depletion must be developed before their role can be specifically determined in vivo. PMID- 21825060 TI - Tegumental phosphodiesterase SmNPP-5 is a virulence factor for schistosomes. AB - The intravascular trematode Schistosoma mansoni is a causative agent of schistosomiasis, a disease that constitutes a major health problem globally. In this study we cloned and characterized the schistosome tegumental phosphodiesterase SmNPP-5 and evaluated its role in parasite virulence. SmNPP-5 is a 52.5-kDa protein whose gene is rapidly turned on in the intravascular parasitic life stages, following invasion of the definitive host. Highest expression is found in mated adult males. As revealed by immunofluorescence analysis, SmNPP-5 protein is found prominently in the dorsal surface of the tegument of males. Localization by immuno-electron microscopy illustrates a unique pattern of immunogold-labeled SmNPP-5 within the tegument; some immunogold particles are scattered throughout the tissue, but many are clustered in tight arrays. To determine the importance of the protein for the parasites, RNA interference (RNAi) was employed to knock down expression of the SmNPP-5-encoding gene in schistosomula and adult worms. Both quantitative real-time PCR (qRT-PCR) and Western blotting confirmed successful and robust gene suppression. In addition, the suppression and the ectolocalization of this enzyme in live parasites were evident because of a significantly impaired ability of the suppressed parasites to hydrolyze exogenously added phosphodiesterase substrate p nitrophenyl 5'-dTMP (p-Nph-5'-TMP). The effects of suppressing expression of the SmNPP-5 gene in vivo were tested by injecting parasites into mice. It was found that, unlike controls, parasites whose SmNPP-5 gene was demonstrably suppressed at the time of host infection were greatly impaired in their ability to establish infection. These results demonstrate that SmNPP-5 is a virulence factor for schistosomes. PMID- 21825061 TI - The LuxS-dependent quorum-sensing system regulates early biofilm formation by Streptococcus pneumoniae strain D39. AB - Streptococcus pneumoniae is the leading cause of death in children worldwide and forms highly organized biofilms in the nasopharynx, lungs, and middle ear mucosa. The luxS-controlled quorum-sensing (QS) system has recently been implicated in virulence and persistence in the nasopharynx, but its role in biofilms has not been studied. Here we show that this QS system plays a major role in the control of S. pneumoniae biofilm formation. Our results demonstrate that the luxS gene is contained by invasive isolates and normal-flora strains in a region that contains genes involved in division and cell wall biosynthesis. The luxS gene was maximally transcribed, as a monocistronic message, in the early mid-log phase of growth, and this coincides with the appearance of early biofilms. Demonstrating the role of the LuxS system in regulating S. pneumoniae biofilms, at 24 h postinoculation, two different D39DeltaluxS mutants produced ~80% less biofilm biomass than wild-type (WT) strain D39 did. Complementation of these strains with luxS, either in a plasmid or integrated as a single copy in the genome, restored their biofilm level to that of the WT. Moreover, a soluble factor secreted by WT strain D39 or purified AI-2 restored the biofilm phenotype of D39DeltaluxS. Our results also demonstrate that during the early mid-log phase of growth, LuxS regulates the transcript levels of lytA, which encodes an autolysin previously implicated in biofilms, and also the transcript levels of ply, which encodes the pneumococcal pneumolysin. In conclusion, the luxS-controlled QS system is a key regulator of early biofilm formation by S. pneumoniae strain D39. PMID- 21825062 TI - Filifactor alocis has virulence attributes that can enhance its persistence under oxidative stress conditions and mediate invasion of epithelial cells by porphyromonas gingivalis. AB - Filifactor alocis, a Gram-positive anaerobic rod, is one of the most abundant bacteria identified in the periodontal pockets of periodontitis patients. There is a gap in our understanding of its pathogenicity and ability to interact with other periodontal pathogens. To evaluate the virulence potential of F. alocis and its ability to interact with Porphyromonas gingivalis W83, several clinical isolates of F. alocis were characterized. F. alocis showed nongingipain protease and sialidase activities. In silico analysis revealed the molecular relatedness of several virulence factors from F. alocis and P. gingivalis. In contrast to P. gingivalis, F. alocis was relatively resistant to oxidative stress and its growth was stimulated under those conditions. Biofilm formation was significantly increased in coculture. There was an increase in adherence and invasion of epithelial cells in coculture compared with P. gingivalis or F. alocis monocultures. In those epithelial cells, endocytic vesicle-mediated internalization was observed only during coculture. The F. alocis clinical isolate had an increased invasive capacity in coculture with P. gingivalis compared to the ATCC 35896 strain. In addition, there was variation in the proteomes of the clinical isolates compared to the ATCC 35896 strain. Hypothetical proteins and those known to be important virulence factors in other bacteria were identified. These results indicate that F. alocis has virulence properties that may enhance its ability to survive and persist in the periodontal pocket and may play an important role in infection-induced periodontal disease. PMID- 21825063 TI - Retracted science and the retraction index. AB - Articles may be retracted when their findings are no longer considered trustworthy due to scientific misconduct or error, they plagiarize previously published work, or they are found to violate ethical guidelines. Using a novel measure that we call the "retraction index," we found that the frequency of retraction varies among journals and shows a strong correlation with the journal impact factor. Although retractions are relatively rare, the retraction process is essential for correcting the literature and maintaining trust in the scientific process. PMID- 21825065 TI - Identification of an ATPase, MsmK, which energizes multiple carbohydrate ABC transporters in Streptococcus pneumoniae. AB - Streptococcus pneumoniae is the leading cause of community-acquired pneumonia and results in over 1 million deaths each year worldwide. Asymptomatic colonization of the airway precedes disease, and acquisition of carbohydrates from the host environment is necessary for bacterial survival. We previously demonstrated that S. pneumoniae cleaves sialic acid from human glycoconjugates to be used as a carbohydrate source. The satABC genes are required for growth and import of sialic acid. The satABC genes are predicted to encode components of an ABC transporter but not the ATPases essential to energize transport. As this subunit is essential, an ATPase must be encoded elsewhere in the genome. We identified msmK as a candidate based on similarity to other known carbohydrate ATPases. Recombinant MsmK hydrolyzed ATP, revealing that MsmK is an ATPase. An msmK mutant was reduced in growth on and transport of sialic acid, demonstrating that MsmK is the ATPase energizing the sialic acid transporter. In addition to satABC, S. pneumoniae contains five other loci that are predicted to encode CUT1 family carbohydrate ABC transporter components; each of these lacks a predicted ATPase. Data indicate that msmK is also required for growth on raffinose and maltotetraose, which are the substrates of two other characterized carbohydrate ABC transporters. Furthermore, an msmK mutant was reduced in airway colonization. Together, these data imply that in vivo, MsmK energizes multiple carbohydrate transporters in S. pneumoniae. This is the first demonstration of a shared ATPase in a pathogenic bacterium. PMID- 21825064 TI - Helicobacter pylori activates calpain via toll-like receptor 2 to disrupt adherens junctions in human gastric epithelial cells. AB - Helicobacter pylori is a risk factor for the development of gastritis, gastroduodenal ulcers, and gastric adenocarcinoma. H. pylori-induced disruption of epithelial adherens junctions (AJs) is thought to promote the development of severe disease; however, the mechanisms whereby H. pylori alters AJ structure remain incompletely understood. The present study demonstrates that H. pylori infection in human patients is associated with elevated serum levels of an 80-kDa E-cadherin ectodomain, whose presence is independent of the presence of serum antibodies against CagA. In vitro, a heat-labile H. pylori surface component activates the host protease calpain in human gastric MKN45 cells independently of the virulence factors CagA and VacA. H. pylori-induced calpain activation results in cleavage of E-cadherin to produce a 100-kDa truncated form and induce relocalization of E-cadherin and beta-catenin. Stimulation of MKN45 cells with the toll-like receptor 2 (TLR2) ligand P3C activated calpain and disrupted E cadherin and beta-catenin in a pattern similar to that induced by H. pylori. Inhibition of TLR2 prevented H. pylori-induced calpain activation and AJ disassembly. Together, these findings identify a novel pathway whereby H. pylori activates calpain via TLR2 to disrupt gastric epithelial AJ structure. PMID- 21825066 TI - Course of infection with the emergent pathogen Brucella microti in immunocompromised mice. AB - A new Brucella species, Brucella microti, has been isolated from wild rodents and found to be pathogenic in mice. The biological relevance of this new mouse pathogen is clear, as it allows us to study Brucella infection in a species specific model. The course of infection in wild-type (wt) and immunodeficient mice that lack B (Jh), T and B (SCID), or T, B, and NK (SCID.Beige) cells was analyzed over 3 weeks. wt mice completely cleared bacteria from the liver and spleen after that time. However, SCID mice showed a much higher bacterial load in the spleen and liver than wt and Jh mice after 1 week and maintained the same level during the next 2 weeks. All mice tested survived for the 3 weeks. In contrast, the bacterial levels in mice that lacked NK cell activity progressively increased and these mice succumbed to infection after 16 to 18 days. Histopathology analysis of infected mice showed extensive areas of necrotic tissue and thrombosis in liver after 1 week in all infected SCID.Beige mice but were not seen in either SCID or wt animals. These processes were dramatically increased after 21 days, corresponding with the death of SCID.Beige animals. Our results indicate that T and/or B cells are required for the control of infection with the mouse pathogen Brucella microti in liver and spleen but that NK cells are crucial for survival in the absence of B and T cells. In addition, they suggest that controlled granuloma formation is critical to clear this type of infection in wt mice. PMID- 21825067 TI - Pseudomonas aeruginosa suppresses interferon response to rhinovirus infection in cystic fibrosis but not in normal bronchial epithelial cells. AB - Despite increased morbidity associated with secondary respiratory viral infections in cystic fibrosis (CF) patients with chronic Pseudomonas aeruginosa infection, the underlying mechanisms are not well understood. Here, we investigated the effect of P. aeruginosa infection on the innate immune responses of bronchial epithelial cells to rhinovirus (RV) infection. CF cells sequentially infected with mucoid P. aeruginosa (MPA) and RV showed lower levels of interferons (IFNs) and higher viral loads than those of RV-infected cells. Unlike results for CF cells, normal bronchial epithelial cells coinfected with MPA/RV showed higher IFN expression than RV-infected cells. In both CF and normal cells, the RV-stimulated IFN response requires phosphorylation of Akt and interferon response factor 3 (IRF3). Preinfection with MPA inhibited RV-stimulated Akt phosphorylation and decreased IRF3 phosphorylation in CF cells but not in normal cells. Compared to normal, unstimulated CF cells or normal cells treated with CFTR inhibitor showed increased reactive oxygen species (ROS) production. Treatment of CF cells with antioxidants prior to MPA infection partially reversed the suppressive effect of MPA on the RV-stimulated IFN response. Together, these results suggest that MPA preinfection inhibits viral clearance by suppressing the antiviral response particularly in CF cells but not in normal cells. Further, increased oxidative stress in CF cells appears to modulate the innate immune responses to coinfection. PMID- 21825068 TI - Host cytosolic phospholipase A2alpha contributes to group B Streptococcus penetration of the blood-brain barrier. AB - Group B Streptococcus (GBS) is the most common bacterium causing neonatal meningitis, and neonatal GBS meningitis continues to be an important cause of mortality and morbidity. Here we provide the first direct evidence that host cytosolic phospholipase A2alpha (cPLA2alpha) contributes to type III GBS invasion of human brain microvascular endothelial cells (HBMEC), which constitute the blood-brain barrier and penetration into the brain, the key step required for the development of GBS meningitis. This was shown by our demonstration that pharmacological inhibition and gene deletion of cPLA2alpha significantly decreased GBS invasion of the HBMEC monolayer and penetration into the brain. cPLA2alpha releases arachidonic acid from membrane phospholipids, and we showed that the contribution of cPLA2alpha to GBS invasion of HBMEC involved lipoxygenated metabolites of arachidonic acid, cysteinyl leukotrienes (LTs). In addition, type III GBS invasion of the HBMEC monolayer involves protein kinase Calpha (PKCalpha), as shown by time-dependent PKCalpha activation in response to GBS as well as decreased GBS invasion in HBMEC expressing dominant-negative PKCalpha. PKCalpha activation in response to GBS, however, was abolished by inhibition of cPLA2alpha and cysteinyl LTs, suggesting that cPLA2alpha and cysteinyl LTs contribute to type III GBS invasion of the HBMEC monolayer via PKCalpha. These findings demonstrate that specific host factors involving cPLA2alpha and cysteinyl LTs contribute to type III GBS penetration of the blood brain barrier and their contribution involves PKCalpha. PMID- 21825070 TI - Ulrike Eggert: big things from small molecules. Interview by Caitlin Sedwick. PMID- 21825069 TI - Anaerobic respiration of Escherichia coli in the mouse intestine. AB - The intestine is inhabited by a large microbial community consisting primarily of anaerobes and, to a lesser extent, facultative anaerobes, such as Escherichia coli, which we have shown requires aerobic respiration to compete successfully in the mouse intestine (S. A. Jones et al., Infect. Immun. 75:4891-4899, 2007). If facultative anaerobes efficiently lower oxygen availability in the intestine, then their sustained growth must also depend on anaerobic metabolism. In support of this idea, mutants lacking nitrate reductase or fumarate reductase have extreme colonization defects. Here, we further explore the role of anaerobic respiration in colonization using the streptomycin-treated mouse model. We found that respiratory electron flow is primarily via the naphthoquinones, which pass electrons to cytochrome bd oxidase and the anaerobic terminal reductases. We found that E. coli uses nitrate and fumarate in the intestine, but not nitrite, dimethyl sulfoxide, or trimethylamine N-oxide. Competitive colonizations revealed that cytochrome bd oxidase is more advantageous than nitrate reductase or fumarate reductase. Strains lacking nitrate reductase outcompeted fumarate reductase mutants once the nitrate concentration in cecal mucus reached submillimolar levels, indicating that fumarate is the more important anaerobic electron acceptor in the intestine because nitrate is limiting. Since nitrate is highest in the absence of E. coli, we conclude that E. coli is the only bacterium in the streptomycin-treated mouse large intestine that respires nitrate. Lastly, we demonstrated that a mutant lacking the NarXL regulator (activator of the NarG system), but not a mutant lacking the NarP-NarQ regulator, has a colonization defect, consistent with the advantage provided by NarG. The emerging picture is one in which gene regulation is tuned to balance expression of the terminal reductases that E. coli uses to maximize its competitiveness and achieve the highest possible population in the intestine. PMID- 21825071 TI - The cell biology of disease: cellular mechanisms of cardiomyopathy. AB - The heart exhibits remarkable adaptive responses to a wide array of genetic and extrinsic factors to maintain contractile function. When compensatory responses are not sustainable, cardiac dysfunction occurs, leading to cardiomyopathy. The many forms of cardiomyopathy exhibit a set of overlapping phenotypes reflecting the limited range of compensatory responses that the heart can use. These include cardiac hypertrophy, induction of genes normally expressed during development, fibrotic deposits that replace necrotic and apoptotic cardiomyocytes, and metabolic disturbances. The compensatory responses are mediated by signaling pathways that initially serve to maintain normal contractility; however, persistent activation of these pathways leads to cardiac dysfunction. Current research focuses on ways to target these specific pathways therapeutically. PMID- 21825072 TI - Visualization of dynein-dependent microtubule gliding at the cell cortex: implications for spindle positioning. AB - Dynein motors move along the microtubule (MT) lattice in a processive "walking" manner. In the one-cell Caenorhabditis elegans embryo, dynein is required for spindle-pulling forces during mitosis. Posteriorly directed spindle-pulling forces are higher than anteriorly directed forces, and this imbalance results in posterior spindle displacement during anaphase and an asymmetric division. To address how dynein could be asymmetrically activated to achieve posterior spindle displacement, we developed an assay to measure dynein's activity on individual MTs at the embryo cortex. Our study reveals that cortical dynein motors maintain a basal level of activity that propels MTs along the cortex, even under experimental conditions that drastically reduce anaphase spindle forces. This suggests that dynein-based MT gliding is not sufficient for anaphase spindle pulling force. Instead, we find that this form of dynein activity is most prominent during spindle centering in early prophase. We propose a model whereby different dynein-MT interactions are used for specific spindle-positioning tasks in the one-cell embryo. PMID- 21825073 TI - The mitochondrial import protein Mim1 promotes biogenesis of multispanning outer membrane proteins. AB - The mitochondrial outer membrane contains translocase complexes for the import of precursor proteins. The translocase of the outer membrane complex functions as a general preprotein entry gate, whereas the sorting and assembly machinery complex mediates membrane insertion of beta-barrel proteins of the outer membrane. Several alpha-helical outer membrane proteins are known to carry multiple transmembrane segments; however, only limited information is available on the biogenesis of these proteins. We report that mitochondria lacking the mitochondrial import protein 1 (Mim1) are impaired in the biogenesis of multispanning outer membrane proteins, whereas overexpression of Mim1 stimulates their import. The Mim1 complex cooperates with the receptor Tom70 in binding of precursor proteins and promotes their insertion and assembly into the outer membrane. We conclude that the Mim1 complex plays a central role in the import of alpha-helical outer membrane proteins with multiple transmembrane segments. PMID- 21825074 TI - Multispan mitochondrial outer membrane protein Ugo1 follows a unique Mim1 dependent import pathway. AB - The mitochondrial outer membrane (MOM) harbors several multispan proteins that execute various functions. Despite their importance, the mechanisms by which these proteins are recognized and inserted into the outer membrane remain largely unclear. In this paper, we address this issue using yeast mitochondria and the multispan protein Ugo1. Using a specific insertion assay and analysis by native gel electrophoresis, we show that the import receptor Tom70, but not its partner Tom20, is involved in the initial recognition of the Ugo1 precursor. Surprisingly, the import pore formed by the translocase of the outer membrane complex appears not to be required for the insertion process. Conversely, the multifunctional outer membrane protein mitochondrial import 1 (Mim1) plays a central role in mediating the insertion of Ugo1. Collectively, these results suggest that Ugo1 is inserted into the MOM by a novel pathway in which Tom70 and Mim1 contribute to the efficiency and selectivity of the process. PMID- 21825075 TI - Rb and p130 control cell cycle gene silencing to maintain the postmitotic phenotype in cardiac myocytes. AB - The mammalian heart loses its regenerative potential soon after birth. Adult cardiac myocytes (ACMs) permanently exit the cell cycle, and E2F-dependent genes are stably silenced, although the underlying mechanism is unclear. Heterochromatin, which silences genes in many biological contexts, accumulates with cardiac differentiation. H3K9me3, a histone methylation characteristic of heterochromatin, also increases in ACMs and at E2F-dependent promoters. We hypothesize that genes relevant for cardiac proliferation are targeted to heterochromatin by retinoblastoma (Rb) family members interacting with E2F transcription factors and recruiting heterochromatin protein 1 (HP1) proteins. To test this hypothesis, we created cardiac-specific Rb and p130 inducible double knockout (IDKO) mice. IDKO ACMs showed a decrease in total heterochromatin, and cell cycle genes were derepressed, leading to proliferation of ACMs. Although Rb/p130 deficiency had no effect on total H3K9me3 levels, recruitment of HP1 gamma to promoters was lost. Depleting HP1-gamma up-regulated proliferation promoting genes in ACMs. Thus, Rb and p130 have overlapping roles in maintaining the postmitotic state of ACMs through their interaction with HP1-gamma to direct heterochromatin formation and silencing of proliferation-promoting genes. PMID- 21825076 TI - Formation of the postmitotic nuclear envelope from extended ER cisternae precedes nuclear pore assembly. AB - During mitosis, the nuclear envelope merges with the endoplasmic reticulum (ER), and nuclear pore complexes are disassembled. In a current model for reassembly after mitosis, the nuclear envelope forms by a reshaping of ER tubules. For the assembly of pores, two major models have been proposed. In the insertion model, nuclear pore complexes are embedded in the nuclear envelope after their formation. In the prepore model, nucleoporins assemble on the chromatin as an intermediate nuclear pore complex before nuclear envelope formation. Using live cell imaging and electron microscope tomography, we find that the mitotic assembly of the nuclear envelope primarily originates from ER cisternae. Moreover, the nuclear pore complexes assemble only on the already formed nuclear envelope. Indeed, all the chromatin-associated Nup107-160 complexes are in single units instead of assembled prepores. We therefore propose that the postmitotic nuclear envelope assembles directly from ER cisternae followed by membrane dependent insertion of nuclear pore complexes. PMID- 21825077 TI - Dynamics of the putative RNA helicase Spb4 during ribosome assembly in Saccharomyces cerevisiae. AB - Spb4 is a putative ATP-dependent RNA helicase that is required for proper processing of 27SB pre-rRNAs and therefore for 60S ribosomal subunit biogenesis. To define the timing of association of this protein with preribosomal particles, we have studied the composition of complexes that copurify with Spb4 tagged by tandem affinity purification (TAP-tagged Spb4). These complexes contain mainly the 27SB pre-rRNAs and about 50 ribosome biogenesis proteins, primarily components of early pre-60S ribosomal particles. To a lesser extent, some protein factors of 90S preribosomal particles and the 35S and 27SA pre-rRNAs also copurify with TAP-tagged Spb4. Moreover, we have obtained by site-directed mutagenesis an allele that results in the R360A substitution in the conserved motif VI of the Spb4 helicase domain. This allele causes a dominant-negative phenotype when overexpressed in the wild-type strain. Cells expressing Spb4(R360A) display an accumulation of 35S and 27SB pre-rRNAs and a net 40S ribosomal subunit defect. TAP-tagged Spb4(R360A) displays a greater steady-state association with 90S preribosomal particles than TAP-tagged wild-type Spb4. Together, our data indicate that Spb4 is a component of early nucle(ol)ar pre-60S ribosomal particles containing 27SB pre-rRNA. Apparently, Spb4 binds 90S preribosomal particles and dissociates from pre-60S ribosomal particles after processing of 27SB pre-rRNA. PMID- 21825078 TI - Averting a roadblock in transforming growth factor beta signaling. PMID- 21825079 TI - Studying the epigenome using next generation sequencing. AB - The advances in next generation sequencing (NGS) technologies have had a significant impact on epigenomic research. The arrival of NGS technologies has enabled a more powerful sequencing based method--that is, ChIP-Seq--to interrogate whole genome histone modifications, improving on the conventional microarray based method (ChIP-chip). Similarly, the first human DNA methylome was mapped using NGS technologies. More importantly, studies of DNA methylation and histone modification using NGS technologies have yielded new discoveries and improved our knowledge of human biology and diseases. The concept that cytosine methylation was restricted to CpG dinucleotides has only been recently challenged by new data generated from sequencing the DNA methylome. Approximately 25% of all cytosine methylation identified in stem cells was in a non-CG context. The non-CG methylation was more enriched in gene bodies and depleted in protein binding sites and enhancers. The recent developments of third generation sequencing technologies have shown promising results of directly sequencing methylated nucleotides and having the ability to differentiate between 5-methylcytosine and 5-hydroxymethylcytosine. The importance of 5-hydroxymethylcytosine remains largely unknown, but it has been found in various tissues. 5 hydroxymethylcytosine was particularly enriched at promoters and in intragenic regions (gene bodies) but was largely absent from non-gene regions in DNA from human brain frontal lobe tissue. The presence of 5-hydroxymethylcytosine in gene bodies was more positively correlated with gene expression levels. The importance of studying 5-methylcytosine and 5-hydroxymethylcytosine separately for their biological roles will become clearer when more efficient methods to distinguish them are available. PMID- 21825080 TI - Once-weekly risedronate for prevention of hip fracture in women with Parkinson's disease: a randomised controlled trial. AB - BACKGROUND: Incidence of a fracture, particularly in the hip joint, is high in Parkinson's disease (PD), owing to the immobilisation-induced bone resorption and vitamin D deficiency with reduced bone mineral density (BMD). The authors previously demonstrated the lowered incidence of hip fractures in PD by daily administration of risedronate and vitamin D. METHODS: This randomised, double blind, placebo-controlled study was conducted to determine the efficacy of 17.5 mg once-weekly risedronate in the prevention of hip fracture in women with PD. Patients were randomly assigned to 17.5 mg risedronate once a week (n=136) or a placebo (n=136) combined with daily 1000 IU of ergocalciferol. Incidence of hip fractures was compared between the two groups during the 2-year follow-up. RESULTS: Hip fractures occurred in 15 patients in the placebo group and 3 patients in the risedronate group. The RR for hip fractures in the risedronate group as compared with the placebo group was 0.20 (95% CI 0.06 to 0.66). In the risedronate group, serum calcium levels decreased during the follow-up, while the levels in the placebo group increased. BMD increased by 3.4% in the risedronate group and decreased by 3.2% in the placebo group (p<0.01). CONCLUSIONS: Treatment with once-weekly risedronate and ergocalciferol prevents hip fractures in older women with PD. PMID- 21825081 TI - Use of sputum eosinophil counts to guide management in children with severe asthma. AB - BACKGROUND: Previous studies in adults with asthma incorporating the control of sputum eosinophils into management strategies have shown significant reductions in exacerbations. A study was undertaken to investigate whether this strategy would be successful in children with severe asthma. METHODS: 55 children (7-17 years) with severe asthma were randomised to either a conventional symptom-based management strategy or to an inflammation-based strategy (principally sputum eosinophils). Children were seen 3-monthly over a 1-year period. RESULTS: The annual rate of total and major exacerbations (courses of oral corticosteroids) was non-significantly lower in the inflammatory management group compared with the symptom management group (3.6 vs. 4.8, incident rate ratio (IRR) 0.75, 95% CI 0.54 to 1.04, p=0.082; and 1.9 vs. 2.7 IRR 0.73, 95% CI 0.42 to 1.28, p=0.274 for total and major exacerbations, respectively). Significantly fewer subjects in the inflammatory management group experienced an exacerbation within 28 days of a study visit. There were small non-significant differences in measures of asthma control (symptom-free days and short-acting beta agonist use) favouring the inflammatory management group. There was no significant difference in the inhaled corticosteroid dose prescribed over the course of the study. CONCLUSION: Incorporating the control of sputum eosinophils into the management algorithm did not significantly reduce overall exacerbations or improve asthma control. Exacerbations were reduced in the short term, suggesting that more frequent measurements would be needed for a clinically useful effect and that controlling inflammation may have a role to play in subgroups of children with severe asthma. PMID- 21825082 TI - Are reference equations for spirometry an appropriate criterion for diagnosing disease and predicting prognosis? AB - In the last few years, there has been considerable debate on the use of threshold criteria for the diagnosis of obstructive lung disease based on FEV(1) and FEV(1)/FVC ratio. It has been argued that a fixed ratio and fixed percentage criterion result in misclassification. The author argues that this critique is based on a false presumption about the validity of reference equations as a criterion for normality. The flaw lies in the methods used to derive reference equations, which involve arbitrary and circular criteria for exclusion of some members of the population, use potentially non-representative reference populations and include predictive variables that are really risk factors for disease or for adverse outcomes of disease. The author argues for a new interpretative approach for the use of lung function data in clinical practice based on prognostic equations analogous to the Framingham cardiovascular risk factor equations. These interpretative equations should be based on data from cohort studies and randomised controlled trials, rather than cross-sectional studies, and if properly formulated, will prove to be valuable aids to clinical decision making. PMID- 21825084 TI - Regulation of inflammatory responses by the commensal microbiota. AB - It is well established that dysregulation of the interactions between the immune system and commensal bacteria is one factor that underpins the development and chronicity of a number of inflammatory diseases. Certain phyla of bacteria within the microbiota have been associated with 'health', but the mechanisms by which the presence of these bacteria supports a healthy environment are still being unravelled. Recent evidence indicates that one such mechanism involves the anti inflammatory properties of fermentation products of fibre, short-chain fatty acids and their signalling through the G-protein coupled receptor GPR43. Recent findings also indicate that, even in health, bacterial communities harbour in the airways, indicating that direct exposure to bacterial products at this site may provide a further explanation for how commensal bacteria can regulate chronic airway inflammation. PMID- 21825083 TI - Results of a phase IIa study of VX-809, an investigational CFTR corrector compound, in subjects with cystic fibrosis homozygous for the F508del-CFTR mutation. AB - BACKGROUND: VX-809, a cystic fibrosis transmembrane conductance regulator (CFTR) modulator, has been shown to increase the cell surface density of functional F508del-CFTR in vitro. METHODS: A randomised, double-blind, placebo-controlled study evaluated the safety, tolerability and pharmacodynamics of VX-809 in adult patients with cystic fibrosis (n=89) who were homozygous for the F508del-CFTR mutation. Subjects were randomised to one of four VX-809 28 day dose groups (25, 50, 100 and 200 mg) or matching placebo. RESULTS: The type and incidence of adverse events were similar among VX-809- and placebo-treated subjects. Respiratory events were the most commonly reported and led to discontinuation by one subject in each active treatment arm. Pharmacokinetic data supported a once daily oral dosing regimen. Pharmacodynamic data suggested that VX-809 improved CFTR function in at least one organ (sweat gland). VX-809 reduced elevated sweat chloride values in a dose-dependent manner (p=0.0013) that was statistically significant in the 100 and 200 mg dose groups. There was no statistically significant improvement in CFTR function in the nasal epithelium as measured by nasal potential difference, nor were there statistically significant changes in lung function or patient-reported outcomes. No maturation of immature F508del CFTR was detected in the subgroup that provided rectal biopsy specimens. CONCLUSIONS: In this study, VX-809 had a similar adverse event profile to placebo for 28 days in F508del-CFTR homozygous patients, and demonstrated biological activity with positive impact on CFTR function in the sweat gland. Additional data are needed to determine how improvements detected in CFTR function secondary to VX-809 in the sweat gland relate to those measurable in the respiratory tract and to long-term measures of clinical benefit. CLINICAL TRIAL NUMBER: NCT00865904. PMID- 21825085 TI - Urbanisation is associated with prevalence of childhood asthma in diverse, small rural communities in Ecuador. AB - BACKGROUND: Studies conducted in transitional communities from Africa and Asia have pointed to the process of urbanisation as being responsible for the increase in asthma prevalence in developing regions. In Latin America, there are few published data available on the potential impact of urbanisation on asthma prevalence. The aim of the present study was to explore how the process of urbanisation may explain differences in asthma prevalence in transitional communities in north-eastern Ecuador. METHODOLOGY/PRINCIPAL FINDINGS: An ecological study was conducted in 59 communities in Esmeraldas Province, Ecuador. Indicators of urbanisation were grouped into three indices representing the processes associated with urbanisation: socioeconomic, lifestyle and urban infrastructure. Categorical principal components analysis was used to generate scores for each index and a fourth index--a summary urbanisation index--was derived from the most representative variables in each of the three indices. The authors analysed the associations between community asthma prevalence and the indices, as well as with each indicator variable of every group. The overall prevalence of asthma was 10.1% (range 0-31.4% between communities). Three of the four indices presented significant associations with community asthma prevalence: socioeconomic (r = 0.295, p = 0.023), lifestyle (r = 0.342, p = 0.008) and summary urbanisation index (r = 0.355, p = 0.006). Variables reflecting better socioeconomic status and a more urban lifestyle were associated with greater asthma prevalence. CONCLUSIONS: These data provide evidence that the prevalence of asthma increases with increasing levels of urbanisation in transitional communities, and factors associated with greater socioeconomic level and changes towards a more urban lifestyle may be particularly important. PMID- 21825086 TI - Is indirect calorimetry a necessity or a luxury in the pediatric intensive care unit? AB - BACKGROUND: Critically ill children differ in their energy needs from healthy children in terms of underlying metabolic derangement, comorbidities, energy reserve, and response to illness. This study determined how many pediatric intensive care unit (PICU) patients were candidates for indirect calorimetry (IC), per American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.) recommendations. METHODS: Admission diagnosis, demographics, type/amount of nutrition support, length of intensive care unit/hospital stay were collected. Patients were classified as candidates for IC per A.S.P.E.N. guidelines. RESULTS: Mean (SD) age of patients (n = 150) was 6.7 (5.6) years, with PICU length of stay of 3.9 (5.3) days. IC was indicated in 72.0% (108/150) of patients during PICU days 1-7. Patients with miscellaneous (50%), neurological (73%), respiratory (81%), sepsis (83%), and oncology (100%) diagnoses were candidates for IC. Underweight/overweight/obese (32.4%), hypermetabolism (26.4%), and not meeting nutrition goals (13.7%) were the most frequent indications for IC (chi(2), P < .001). Patients (31%) met >=2 indications for IC. Patients with neurological disease (relative risk [RR], 4.8; 95% confidence interval [CI], 1.7-14.6), oncology patients (4.2; 1.1-15.9), respiratory patients (5.5; 2.0-16.9), and children with sepsis/septic shock/infection (5.6; 1.9-18.1) were more likely to have >=2 indications for IC compared to those with other diagnoses. CONCLUSIONS: Three of 4 patients were candidates for IC per A.S.P.E.N. guidelines. PICUs might have to prioritize performing IC in patients who are <2 years of age, malnourished (underweight/overweight) on admission, or PICU stay of >5 days. Future studies should determine the cost-benefit ratios of performing IC in PICU patients. PMID- 21825087 TI - Dosing and monitoring of trace elements in long-term home parenteral nutrition patients. AB - BACKGROUND: Trace elements (TEs) dosing and monitoring in home parenteral nutrition (PN) patients vary with their underlying conditions. METHODS: This retrospective observational study evaluated parenteral TE dosing, serum TE concentrations and monitoring, and dose-concentration relationships between TE doses and serum TE concentrations in 26 adult and adolescent home PN patients. RESULTS: There was a total of 40,493 PN days. Average parenteral zinc doses of 9.1 mg/d and 7.6 mg/d resulted in the majority of serum zinc concentrations (90%) within normal range in patients with and without short bowel syndrome (SBS), respectively. Selenium at about 70 mcg/d resulted in about 60% of serum selenium concentrations within normal range, with 38% of values below normal in patients with and without SBS alike. Copper at 1 mg/d resulted in 22.5% of serum copper concentrations above the normal range. The majority of serum manganese (94.6%) and chromium (96%) concentrations were elevated. Serum TE concentrations were infrequently monitored. Significant relationships existed between doses and serum concentrations for zinc (P < .0001), manganese (P = .012), and chromium (P < .0001) but not for selenium or copper. CONCLUSIONS: TE doses in home PN should be individualized and adjusted based on regular monitoring of TE status. In long term home PN patients, higher zinc and selenium doses may be necessary to maintain their normal serum concentrations. Lower copper doses and restrictions of manganese and chromium supplementation may be needed to avoid their accumulation. Relationships between TE doses and serum TE concentrations vary for each TE and underlying clinical conditions. PMID- 21825088 TI - The role of parenteral lipids in the development of advanced intestinal failure associated liver disease in infants: a multiple-variable analysis. AB - BACKGROUND: Given the recent interest in the role of omega-6 lipids in the development of intestinal failure-associated liver disease (IFALD), the authors sought to examine the role of parenteral lipids in the development of a serum conjugated bilirubin >100 umol/L (5.9 mg/dL; CB100) in infants. METHOD: Between 2003 and 2004, data were collected prospectively on infants undergoing an abdominal surgical procedure. Univariate logistic regression models for the prediction of CB100 by 1 year postoperatively were developed. Predictors significant at the 0.2 level on univariate analysis were entered into a backward stepwise multiple variable logistic regression. RESULTS: Of 152 infants who received parenteral nutrition (PN) postoperatively, 22 developed CB100. Predictors that met criteria for consideration in the multiple-variable model were age, weight, small bowel length, presence of a stoma, proportion of enteral feeds postoperatively, septic episodes, days of maximal PN amino acid (>2.5 g/kg/d), days of maximal lipid (>2.5 g/kg/d), and PN duration. The final model included septic episodes (odds ratio, 3.23; 95% confidence interval, 1.8-5.9) and days of lipid >2.5 g/kg/d (1.04; 1.003-1.06). At 60 days of maximal lipid, the odds of advanced IFALD were increased 10-fold. CONCLUSIONS: This model suggests a key role of parenteral lipids and septic events in the development of CB100 from IFALD. These data may provide targets, such as careful line care, reduction in maximal lipid dose, or alternate lipids such as omega-3 fatty acids, to prevent CB100, an identified marker of subsequent liver failure from IFALD. PMID- 21825089 TI - Nutrition in inflammatory bowel disease. AB - The diet of industrialized nations may contribute to the pathogenesis of both ulcerative colitis (UC) and Crohn disease (CD). Malnutrition is relatively unusual in UC, but in CD, which often affects the small intestine, it is frequent and may be severe. Nutrition support is therefore frequently indicated. First principles of artificial nutrition can be applied effectively using the gut whenever possible. Parenteral nutrition is generally required only in those with short bowel syndrome. An increasing literature (especially in pediatrics) favors the use of defined exclusive enteral nutrition (EN) in the primary treatment of active CD. Controlled trials are, however, lacking, and recommendations are accordingly not of the highest rank. It appears that in this context, simple polymeric regimens are usually sufficient, and there is currently insufficient evidence to make a strong recommendation for disease-specific feeds. In the maintenance of remission in CD, controlled data demonstrate that defined EN reduces the risk of relapse requiring steroid treatment. There are no data in support of primary nutrition therapy in UC either in management of the acute flare or in maintenance. In conclusion, nutrition therapy in adults with inflammatory bowel disease is probably both undervalued and underused, but the evidence base needs to be strengthened to confirm its efficacy, determine better those patients most likely to benefit, and optimize the regimens to be employed. PMID- 21825090 TI - Maintenance of parenteral nutrition volume reduction, without weight loss, after stopping teduglutide in a subset of patients with short bowel syndrome. AB - BACKGROUND: Teduglutide was discontinued after being tested for >= 24 weeks in patients with parenteral nutrition (PN) -dependent short bowel syndrome in a clinical trial for efficacy to reduce PN volume. This study was describes change in body mass index (BMI) and PN volume over 12 months in patients who stopped drug after the clinical trial. METHODS: Prescribed PN volume, weight, and complications were reported. Patients with stable (NEUT, n = 15) or decreased (DEC, n = 7) PN volume by 12 months after stopping drug (NEUT/DEC, n = 22) were compared to those who had increased PN volume (INC, n = 15). With drug response defined by >= 20% reduction from pre-drug PN volume to end of drug therapy, 12 INC and 13 NEUT/DEC patients were drug responders. RESULTS: Eleven of 20 eligible sites reported data for 39 of 53 eligible study participants, with follow-up data for 37. INC patients had shorter colon and less frequently had colon in continuity than NEUT/DEC. BMI was decreased at 3, 6, and 12 months relative to the first off-drug visit in INC patients (P = .001), but not in NEUT/DEC patients. Change in BMI off-drug was predicted by colon and small bowel length, baseline BMI, and on-drug change in PN volume (adjusted R2 = 0.708). CONCLUSIONS: Gastrointestinal anatomy, baseline BMI, and PN volume reduction on-drug predicted change in BMI off-drug. Whether this response would be maintained for a longer time or in the context of a challenging clinical situation has not been evaluated. PMID- 21825091 TI - An insulin protocol for management of hyperglycemia in patients receiving parenteral nutrition is superior to ad hoc management. AB - BACKGROUND: The authors investigated whether an insulin protocol for parenteral nutrition (PN)-induced hyperglycemia is superior to conventional management relying primarily on sliding-scale insulin at a large county hospital. METHODS: A prospective cohort study with historical controls was completed. Adult patients receiving PN were managed with a protocol that determined insulin doses based on carbohydrate delivery and capillary blood glucose (CBG) if half or more of CBG measurements in the first 24 hours after initiation of PN exceeded 140 mg/dL. Control data were obtained from records of patients who met study eligibility criteria but had been managed before implementation of the insulin protocol. RESULTS: Mean CBG after the start of insulin therapy was 138 +/- 37 mg/dL for protocol patients and 159 +/- 46 mg/dL for controls (P < .0001). Proportion of CBG values in the target range of 80-140 mg/dL was 60% in the protocol group and 35% in the control group (P < .0001). Hypoglycemia, defined as CBG <80 mg/dL, occurred infrequently but more often in the protocol group (3% vs 1%, P = .012). There was no difference in total daily insulin between groups, although protocol patients received mostly scheduled insulin (93% total daily dose), whereas control patients received predominantly supplemental insulin (66% total daily dose). CONCLUSIONS: Protocol-directed management of PN-induced hyperglycemia is superior to ad hoc insulin dosing. Linking insulin to carbohydrate in PN leads to improved glycemic control with a low rate of hypoglycemia. PMID- 21825092 TI - Contributing factors to aggressive behaviors in high school students in Turkey. AB - Violence among young people is an important public health topic as a universal problem. One of the recent issues concerning both the media and parents is the aggressive behavior among the high school students in Istanbul and the worldwide. The aim of this study was to investigate the types and rates of aggressive behavior and the contributing factors to this behavior among high school students. Sample was composed of 805 students of 14-18 ages attending five high schools in Istanbul. The most common aggressive behavior among the students was found to be "beating others," 34.5% (n = 278). Past experiences of violence of high school students (direct exposure to violence/witnessing violence/exposure to/witnessing attack with knife/gun) were determined as the most contributing factor to aggressive behavior. The present study investigated the nature of violent behaviors and associations between violent behaviors and contributing factors among high school students from Turkey. PMID- 21825093 TI - Effect of Jin Shin Jyutsu energy medicine treatments on women diagnosed with breast cancer. AB - PURPOSE: The purpose of the study was to evaluate the effectiveness of 10 weekly treatments of Jin Shin Jyutsu (JSJ), as practiced by a qualified practitioner, for women diagnosed with breast cancer. DESIGN: A pretest, posttest exploratory evaluation project design was used. Twenty-nine women provided complete data. METHOD: Adaptation, social support, activities of daily living, helpfulness of JSJ, and project participation goals were measured by an investigator-developed questionnaire prior to and at the end of the 10 JSJ sessions. FINDINGS: Nonparametric statistical analyses revealed that at the end of the JSJ sessions, women had higher levels of adaptation and performance of activities of daily living but no difference in satisfaction with social support than at the beginning of project participation. Descriptive analyses indicated that women reported that JSJ was helpful and that their goals had been met. Content analysis of goals revealed that the women wanted to feel better physically and emotionally and to live a fuller life and were seeking balance in life. CONCLUSIONS: JSJ may be an effective intervention for women with breast cancer. Although the sample size was small and a single practitioner provided treatment, the results indicate that a large-scale evaluation with multiple practitioners is warranted. PMID- 21825094 TI - Expression and distribution of nucleoside transporter proteins in the human syncytiotrophoblast. AB - The plasma membrane distribution and related biological activity of nucleoside transporter proteins (NTs) were investigated in human syncytiotrophoblast from term placenta using a variety of approaches, including nucleoside uptake measurements into vesicles from selected plasma membrane domains, NT immunohistochemistry, and subcellular localization (basal, heavy, and light apical membranes as well as raft-enriched membranes from the apical domain). In contrast with other epithelia, in this epithelium, we have identified the high affinity pyrimidine-preferring human concentrative nucleoside transporter (hCNT) 1 as the only hCNT-type protein expressed at both the basal and apical membranes. hCNT1 localization in lipid rafts is also dependent on its subcellular localization in the apical plasma membrane, suggesting a complex cellular and regional expression. Overall, this result favors the view that the placenta is a pyrimidine-preferring nucleoside sink from both maternal and fetal sides, and hCNT1 plays a major role in promoting pyrimidine salvage and placental growth. This finding may be of pharmacological relevance, because hCNT1 is known to interact with anticancer nucleoside-derived drugs and other molecules, such as nicotine and caffeine, for which a great variety of harmful effects on placental and fetal development, including intrauterine growth retardation, have been reported. PMID- 21825095 TI - A dynamic pharmacophore drives the interaction between Psalmotoxin-1 and the putative drug target acid-sensing ion channel 1a. AB - Acid-sensing ion channel 1a (ASIC1a) is a primary acid sensor in the peripheral and central nervous system. It has been implicated as a novel therapeutic target for a broad range of pathophysiological conditions including pain, ischemic stroke, depression, and autoimmune diseases such as multiple sclerosis. The only known selective blocker of ASIC1a is pi-TRTX-Pc1a (PcTx1), a disulfide-rich 40 residue peptide isolated from spider venom. pi-TRTX-Pc1a is an effective analgesic in rodent models of acute pain and it provides neuroprotection in a mouse model of ischemic stroke. Thus, understanding the molecular basis of the pi TRTX-Pc1a-ASIC1a interaction should facilitate development of therapeutically useful ASIC1a blockers. We therefore developed an efficient bacterial expression system to produce a panel of pi-TRTX-Pc1a mutants for probing structure-activity relationships as well as isotopically labeled toxin for determination of its solution structure and dynamics. We demonstrate that the toxin pharmacophore resides in a beta-hairpin loop that was revealed to be mobile over a wide range of time scales using molecular dynamics simulations in combination with NMR spin relaxation and relaxation dispersion measurements. The toxin-receptor interaction was modeled by in silico docking of the toxin structure onto a homology model of rat ASIC1a in a restraints-driven approach that was designed to take account of the dynamics of the toxin pharmacophore and the consequent remodeling of side chain conformations upon receptor binding. The resulting model reveals new insights into the mechanism of action of pi-TRTX-Pc1a and provides an experimentally validated template for the rational design of therapeutically useful pi-TRTX-Pc1a mimetics. PMID- 21825096 TI - Comparison of minimally invasive techniques in tongue base surgery in patients with obstructive sleep apnea. AB - OBJECTIVE: To compare the effectiveness and morbidity of 3 microinvasive tongue base surgical procedures combined with uvulopalatopharyngoplasty (UPPP) in supine dependent obstructive sleep apnea (OSA) patients. STUDY DESIGN: A prospective, randomized clinical study. SETTING: A tertiary referral center. METHODS: Fifty OSA patients were randomly advised to undergo UPPP combined with low-temperature bipolar radiofrequency (group 1), submucosal minimally invasive lingual excision with radiofrequency (SMILE-R; group 2), or submucosal minimally invasive lingual excision with a harmonic scalpel (SMILE-H; group 3). The Epworth Sleepiness Scale, the visual analog scale (VAS) for snoring, the pre- and postoperative 3 month polysomnography (PSG) findings, and the decrease in tongue volume using magnetic resonance imaging (MRI) were compared. The operation times, the postoperative pain VAS score, the analgesic requirement, and the time in commencing a normal diet were compared in the 3 groups. RESULTS: The decrease in apnea-hypopnea index (AHI) and supine AHI values at the postoperative 3-month time point was significant in group 2 (P < .05). The decrease in tongue volume at the 3-month postoperative time point according to the MRI evaluations was higher in groups 1 and 2 (P < .05). In the subjective comparison of effectiveness, there was no significant difference. The operation time was significantly lower in group 3. In the assessment of postoperative pain, no significant difference was found between the groups. CONCLUSION: When the PSG findings and MRI were evaluated, UPPP + SMILE-R were found to be more effective. No significant difference was found between the 3 techniques when morbidity and complications were compared. PMID- 21825097 TI - Modified mini-Lothrop/extended Draf IIB procedure for contralateral frontal sinus disease: a cadaveric feasibility study. PMID- 21825098 TI - Lack of association between eotaxin-1 gene polymorphisms and nasal polyposis. AB - OBJECTIVE: To examine whether there is an association of eotaxin-1 gene polymorphisms with nasal polyposis (NP). STUDY DESIGN: Cross-sectional study. SETTING: Tertiary referral center. SUBJECTS AND METHODS: The study group included 85 patients with NP and 93 controls without sinonasal disease. Genotypes of eotaxin-1 (-384 A>G and +67 G>A) were identified by restriction fragment length polymorphism analyses after polymerase chain reaction. RESULTS: The -384 A>G and +67 G>A single nucleotide polymorphisms were higher in patients with NP than in controls (P = .044 and P = .019, respectively). However, their relation was statistically poor (association coefficient = 0.18). Consistent with this result, comparisons of allele frequencies for both single nucleotide polymorphisms were not significantly different (-384 A>G, P = .164; +67 G>A, P = .144). CONCLUSION: In this study, eotaxin-1 -384 A>G or 67 G>A genotypes were not associated with susceptibility to NP. PMID- 21825099 TI - Therapy and prognosis of intracranial invasive olfactory neuroblastoma. AB - OBJECTIVE: There is currently no consensus on a standardized treatment strategy for olfactory neuroblastoma (ONB), especially for intracranial invasion. This purpose of this study is to explore the appropriate treatment modality and prognostic factors of intracranial invasive ONB. STUDY DESIGN: Case series with chart review. SETTING: The study was conducted at the Sun Yat-sen Memorial Hospital and the Cancer Center of Sun Yat-sen University, China. SUBJECTS AND METHODS: Twenty-five cases of intracranial invasive ONB were collected and investigated using a retrospective review analysis from patients diagnosed between 1980 and 2005. RESULTS: The 1-, 3-, and 5-year overall survival rates for the group were 55%, 46%, and 31%, respectively. The subgroups who did not receive surgical treatment had worse survival rates than those who did receive treatment. In particular, patients who did not receive any therapy did not live past 1 year. In contrast, the group of patients treated by intranasal resection in combination with radiotherapy and/or chemotherapy showed a slightly better survival rate. It is important to note that the group of patients treated by craniofacial surgery combined with radiotherapy and/or chemotherapy had a markedly favorable prognosis, with 1-, 3-, and 5-year overall survival rates of up to 100%, 88%, and 66%, respectively. CONCLUSIONS: Craniofacial surgery in combination with radiotherapy and/or chemotherapy was an effective treatment for intracranial invasive ONB. In addition, it was found that age may not be an important prognostic factor for intracranial invasive ONB; however, the rate of intracalvarial invasion was found to be a potent marker for predicting the prognosis of patients. PMID- 21825100 TI - Systematic functional assessment of nasal dyspnea: surgical outcomes and predictive ability. AB - OBJECTIVE: Evaluate the ability of a systematic preoperative evaluation to determine the most appropriate procedures for patients undergoing functional septorhinoplasty and to accurately predict postoperative outcomes. STUDY DESIGN: Case series with chart review. SETTING: Tertiary care military hospital. SUBJECTS AND METHODS: Fifty-nine consecutive patients from a quality control database who underwent functional rhinoplasties for nasal dyspnea were evaluated. All patients underwent a full preoperative assessment using intranasal manipulation to determine the area(s) contributing to their nasal dyspnea. Rates of success for the predictive ability and for the functional outcome were determined for each side of the nose by comparing preoperative visual analog scale (VAS) scores (1 10) to postoperative scores. RESULTS: Overall there was a 91% success rate in predicting the outcome of surgery and a 95% success rate in improving nasal dyspnea at 1 year. There was no statistically significant difference in improvement between different surgical groups (septoplasty +/- alar strut grafts +/- spreader grafts) or between primary surgeries and revisions. CONCLUSION: Using a systematic approach to evaluate patients for nasal dyspnea, it is possible to predict and improve outcomes by choosing the most appropriate surgery for each individual. PMID- 21825101 TI - Clinical value of circulating endothelial cell levels in metastatic colorectal cancer patients treated with first-line chemotherapy and bevacizumab. AB - BACKGROUND: We investigated whether circulating endothelial cells (CECs) predict clinical outcome of first-line chemotherapy and bevacizumab in metastatic colorectal cancer (mCRC) patients. PATIENTS AND METHODS: In a substudy of the randomized phase II FNCLCC ACCORD 13/0503 trial, CECs (CD45- CD31+ CD146+ 7-amino actinomycin- cells) were enumerated in 99 patients by four-color flow cytometry at baseline and after one cycle of treatment. We correlated CEC levels with objective response rate (ORR), 6-month progression-free survival (PFS) rate (primary end point of the trial), PFS, and overall survival (OS). Multivariate analyses of potential prognostic factors, including CEC counts and Kohne score, were carried out. RESULTS: By multivariate analysis, high baseline CEC levels were the only independent prognostic factor for 6-month PFS rate (P < 0.01) and were independently associated with worse PFS (P = 0.02). High CEC levels after one cycle were the only independent prognostic factor for ORR (P = 0.03). High CEC levels at both time points independently predicted worse ORR (P = 0.025), 6 month PFS rate (P = 0.007), and PFS (P = 0.02). Kohne score was the only variable associated with OS. CONCLUSION: CEC levels at baseline and after one treatment cycle may independently predict ORR and PFS in mCRC patients starting first-line bevacizumab and chemotherapy. PMID- 21825102 TI - Epidural anesthesia as a thromboembolic prophylaxis modality in plastic surgery. AB - BACKGROUND: Epidural anesthesia (EA) is known to reduce postoperative thromboembolic complications, but the mechanisms are poorly understood. Review of the literature revealed no reports about the ability of epidural anesthesia (EA) to reduce the risk of venous thromboembolism (VTE) in abdominal contouring surgery and/or liposuction. Most medical publications in this field are based on orthopedic cases. OBJECTIVES: The authors investigate the hypothesis that the differential nerve-blocking effect of bupivacaine, which spares motor function and permits leg movement during the operation, is the most important mechanism by which EA prevents thromboembolism. METHODS: From June 1992 to August 1995, 24 cases of abdominoplasty were performed under general anesthesia (Group 1). From September 1995 to December 2009, 371 cases of concurrent abdominoplasty and liposuction were performed under EA (Group 2). Eighteen cases (4.8%) from Group 2 were ultimately excluded from the study because of unsuccessful EA. All surgeries were performed by the senior author (FH). RESULTS: One thromboembolic event (pulmonary embolism [PE]) occurred in Group 1 (4%). No cases of deep vein thrombosis (DVT) or PE occurred among Group 2 patients. CONCLUSIONS: Together, differential epidural nerve blocks and purposeful intraoperative movement of lower-limb muscles represent an effective prophylactic mechanism that may prevent devastating DVT and resultant PE. PMID- 21825103 TI - Pathophysiology-based treatment of idiopathic calcium kidney stones. AB - Idiopathic calcium oxalate (CaOx) stone-formers (ICSFs) differ from patients who make idiopathic calcium phosphate (CaP) stones (IPSFs). ICSFs, but not IPSFs, form their stones as overgrowths on interstitial apatite plaque; the amount of plaque covering papillary surface is positively correlated with urine calcium excretion and inversely with urine volume. The amount of plaque predicts the number of recurrent stones. The initial crystal overgrowth on plaque is CaP, although the stone is mainly composed of CaOx, meaning that lowering supersaturation (SS) for CaOx and CaP is important for CaOx stone prevention. IPSFs, unlike ICSFs, have apatite crystal deposits in inner medullary collecting ducts, which are associated with interstitial scarring. ICSFs and IPSFs have idiopathic hypercalciuria, which is due to decreased tubule calcium reabsorption, but sites of abnormal reabsorption may differ. Decreased reabsorption in proximal tubules (PTs) delivers more calcium to the thick ascending limb (TAL), where increased calcium reabsorption can load the interstitium, leading to plaque formation. The site of abnormal reabsorption in IPSFs may be the TAL, where an associated defect in bicarbonate reabsorption could produce the higher urine pH characteristic of IPSFs. Preventive treatment with fluid intake, protein and sodium restriction, and thiazide will be effective in ICSFs and IPSFs by decreasing urine calcium concentration and CaOx and CaP SS and may also decrease plaque formation by increased PT calcium reabsorption. Citrate may be detrimental for IPSFs if urine pH rises greatly, increasing CaP SS. Future trials should examine the question of appropriate treatment for IPSFs. PMID- 21825104 TI - The small GTPase Rab5a is essential for intracellular transport of proglutelin from the Golgi apparatus to the protein storage vacuole and endosomal membrane organization in developing rice endosperm. AB - Rice (Oryza sativa) glutelins are synthesized on the endoplasmic reticulum as larger precursors, which are then transported via the Golgi to the protein storage vacuole (PSV), where they are processed into acidic and basic subunits. Three independent glutelin precursor mutant4 (glup4) rice lines, which accumulated elevated levels of proglutelin over the wild type, were identified as loss-of-function mutants of Rab5a, the small GTPase involved in vesicular membrane transport. In addition to the plasma membrane, Rab5a colocalizes with glutelins on the Golgi apparatus, Golgi-derived dense vesicles, and the PSV, suggesting that Rab5a participates in the transport of the proglutelin from the Golgi to the PSV. This spatial distribution pattern was dramatically altered in the glup4 mutants. Numerous smaller protein bodies containing glutelin and alpha globulin were evident, and the proteins were secreted extracellularly. Moreover, all three independent glup4 allelic lines displayed the novel appearance of a large dilated, structurally complex paramural body containing proglutelins, alpha globulins, membrane biomarkers for the Golgi apparatus, prevacuolar compartment, PSV, and the endoplasmic reticulum luminal chaperones BiP and protein disulfide isomerase as well as beta-glucan. These results indicate that the formation of the paramural bodies in glup4 endosperm was due to a significant disruption of endocytosis and membrane vesicular transport by Rab5a loss of function. Overall, Rab5a is required not only for the intracellular transport of proglutelins from the Golgi to the PSV in rice endosperm but also in the maintenance of the general structural organization of the endomembrane system in developing rice seeds. PMID- 21825105 TI - Genome-wide characterization of the HD-ZIP IV transcription factor family in maize: preferential expression in the epidermis. AB - Transcription factors of the plant-specific homeodomain leucine zipper IV (HD-ZIP IV) family have been found from moss to higher plants, and several family members have been associated with epidermis-related expression and/or function. In maize (Zea mays), four of the five characterized HD-ZIP IV family members are expressed specifically in the epidermis, one contributes to trichome development, and target genes of another one are involved in cuticle biosynthesis. Assessing the phylogeny, synteny, gene structure, expression, and regulation of the entire family in maize, 12 novel ZmHDZIV genes were identified in the recently sequenced maize genome. Among the 17 genes, eight form homeologous pairs duplicated after the split of maize and sorghum (Sorghum bicolor), whereas a fifth duplication is shared with sorghum. All 17 ZmHDZIV genes appear to be derived from a basic module containing seven introns in the coding region. With one possible exception, all 17 ZmHDZIV genes are expressed and show preferential expression in immature reproductive organs. Fourteen of 15 ZmHDZIV genes with detectable expression in laser-dissected tissues exhibit a moderate to very strong expression preference for the epidermis, suggesting that at least in maize, the majority of HD-ZIP IV family members may have epidermis-related functions. Thirteen ZmHDZIV genes carry conserved motifs of 19 and 21 nucleotides in their 3' untranslated region. The strong evolutionary conservation and the size of the conserved motifs in the 3' untranslated region suggest that the expression of HD ZIP IV genes may be regulated by small RNAs. PMID- 21825106 TI - Chromatin configuration as a battlefield in plant-bacteria interactions. PMID- 21825107 TI - Inhibition of protein synthesis by TOR inactivation revealed a conserved regulatory mechanism of the BiP chaperone in Chlamydomonas. AB - The target of rapamycin (TOR) kinase integrates nutritional and stress signals to coordinately control cell growth in all eukaryotes. TOR associates with highly conserved proteins to constitute two distinct signaling complexes termed TORC1 and TORC2. Inactivation of TORC1 by rapamycin negatively regulates protein synthesis in most eukaryotes. Here, we report that down-regulation of TOR signaling by rapamycin in the model green alga Chlamydomonas reinhardtii resulted in pronounced phosphorylation of the endoplasmic reticulum chaperone BiP. Our results indicated that Chlamydomonas TOR regulates BiP phosphorylation through the control of protein synthesis, since rapamycin and cycloheximide have similar effects on BiP modification and protein synthesis inhibition. Modification of BiP by phosphorylation was suppressed under conditions that require the chaperone activity of BiP, such as heat shock stress or tunicamycin treatment, which inhibits N-linked glycosylation of nascent proteins in the endoplasmic reticulum. A phosphopeptide localized in the substrate-binding domain of BiP was identified in Chlamydomonas cells treated with rapamycin. This peptide contains a highly conserved threonine residue that might regulate BiP function, as demonstrated by yeast functional assays. Thus, our study has revealed a regulatory mechanism of BiP in Chlamydomonas by phosphorylation/dephosphorylation events and assigns a role to the TOR pathway in the control of BiP modification. PMID- 21825108 TI - Seed storage oil mobilization is important but not essential for germination or seedling establishment in Arabidopsis. AB - Triacylglycerol (TAG) is a major storage reserve in many plant seeds. We previously identified a TAG lipase mutant called sugar-dependent1 (sdp1) that is impaired in TAG hydrolysis following Arabidopsis (Arabidopsis thaliana) seed germination (Eastmond, 2006). The aim of this study was to identify additional lipases that account for the residual TAG hydrolysis observed in sdp1. Mutants were isolated in three candidate genes (SDP1-LIKE [SDP1L], ADIPOSE TRIGLYCERIDE LIPASE-LIKE, and COMPARATIVE GENE IDENTIFIER-58-LIKE). Analysis of double, triple, and quadruple mutants showed that SDP1L is responsible for virtually all of the residual TAG hydrolysis present in sdp1 seedlings. Oil body membranes purified from sdp1 sdp1L seedlings were deficient in TAG lipase activity but could still hydrolyze di- and monoacylglycerol. SDP1L is expressed less strongly than SDP1 in seedlings. However, SDP1L could partially rescue TAG breakdown in sdp1 seedlings when expressed under the control of the SDP1 or 35S promoters and in vitro assays showed that both SDP1 and SDP1L can hydrolyze TAG, in preference to diacylglycerol or monoacylglycerol. Seed germination was slowed in sdp1 sdp1L and postgerminative seedling growth was severely retarded. The frequency of seedling establishment was also reduced, but sdp1 sdp1L was not seedling lethal under normal laboratory growth conditions. Our data show that together SDP1 and SDP1L account for at least 95% of the rate of TAG hydrolysis in Arabidopsis seeds, and that this hydrolysis is important but not essential for seed germination or seedling establishment. PMID- 21825110 TI - Cognitive responses to stress, depression, and anxiety and their relationship to ADHD symptoms in first year psychology students. AB - OBJECTIVE: To explore the relationship between levels of reported depression, anxiety, and stress with scores on the Conners's Adult ADHD Rating Scale (CAARS). METHOD: Information was obtained from 84 1st-year psychology students using the CAARS, the Depression Anxiety and Stress Scale (DASS), and the Life Experiences Survey (LES). RESULTS: Approximately 23%, 18%, and 12% of students scored above critical values on the Diagnostic and Statistical Manual of Mental Disorders (4th ed., DSM-IV) Inattention Symptoms, the DSM-IV ADHD Symptoms Total, and the Inattention/Restlessness subscales, respectively. CAARS scores were positively related to reported levels of depression, anxiety, and stress, which accounted for significant variance among the three subscales. Only 5% of participants scored above recommended critical values on the ADHD index; however, a significant amount of the variance on this measure was also attributable to the DASS. CONCLUSION: Mood symptoms such as depression, anxiety, and stress may obscure correct attribution of cause in those being evaluated for ADHD. PMID- 21825109 TI - Subtissue-specific evaluation of promoter efficiency by quantitative fluorometric assay in laser microdissected tissues of rapeseed. AB - beta-glucuronidase (GUS) is a useful reporter for the evaluation of promoter characteristics in transgenic plants. Here, we introduce an original technique to quantify the strength of promoters at subtissue resolution of cell clusters. The method combines cryotomy, laser microdissection, and improved fluorometric analysis of GUS activity using 6-chloro-4-methylumbelliferyl-beta-D-glucuronide as an efficient fluorogenic substrate for kinetic studies in plants. The laser microdissection/6-chloro-4-methylumbelliferyl-beta-D-glucuronide method is robust and reliable in a wide range of GUS expression levels and requires extremely low (few cells) tissue amounts. Suitability of the assay was demonstrated on rapeseed (Brassica napus) plants transformed with a P35S2::GUS construct. GUS expression patterns were visualized and quantified in approximately 30 tissues of vegetative and generative organs. Considerable differences in promoter activity within the tissues are discussed in relation to the cell type and developmental state. PMID- 21825111 TI - Assessing youth who sexually offended: the predictive validity of the ERASOR, J SOAP-II, and YLS/CMI in a non-Western context. AB - Recent research suggested that the predictive validity of adult sexual offender risk assessment measures can be affected when used cross-culturally, but there is no published study on the predictive validity of risk assessment measures for youth who sexually offended in a non-Western context. This study compared the predictive validity of three youth risk assessment measures (i.e., the Estimate of Risk of Adolescent Sexual Offense Recidivism [ERASOR], the Juvenile Sex Offender Assessment Protocol-II [J-SOAP-II], and the Youth Level of Service/Case Management Inventory [YLS/CMI]) for sexual and nonviolent recidivism in a sample of 104 male youth who sexually offended within a Singaporean context (M (follow up) = 1,637 days; SD (follow-up) = 491). Results showed that the ERASOR overall clinical rating and total score significantly predicted sexual recidivism but only the former significantly predicted time to sexual reoffense. All of the measures (i.e., the ERASOR overall clinical rating and total score, the J-SOAP-II total score, as well as the YLS/CMI) significantly predicted nonsexual recidivism and time to nonsexual reoffense for this sample of youth who sexually offended. Overall, the results suggest that the ERASOR appears to be suited for assessing youth who sexually offended in a non-Western context, but the J-SOAP-II and the YLS/CMI have limited utility for such a purpose. PMID- 21825112 TI - Preventive effect of eccentric training on acute hamstring injuries in men's soccer: a cluster-randomized controlled trial. AB - BACKGROUND: The incidence of acute hamstring injuries is high in several sports, including the different forms of football. PURPOSE: The authors investigated the preventive effect of eccentric strengthening of the hamstring muscles using the Nordic hamstring exercise compared with no additional hamstring exercise on the rate of acute hamstring injuries in male soccer players. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: Fifty Danish male professional and amateur soccer teams (942 players) were allocated to an intervention group (461 players) or a control group (481 players). Players in the intervention group conducted a 10-week progressive eccentric training program followed by a weekly seasonal program, whereas players in the control group followed their usual training program. The main outcome measures were numbers of overall, new, and recurrent acute hamstring injuries during 1 full soccer season. RESULTS: Fifty two acute hamstring injuries in the control group compared with 15 injuries in the intervention group were registered. Comparing intervention versus the control group, overall acute hamstring injury rates per 100 player seasons were 3.8 versus 13.1 (adjusted rate ratio [RR], 0.293; 95% confidence interval [CI], 0.150 0.572; P < .001). New injury rates per 100 player seasons were 3.1 versus 8.1 (RR, 0.410; 95% CI, 0.180-0.933; P = .034), whereas recurrent injury rates per 100 player seasons were 7.1 versus 45.8 (RR, 0.137; 95% CI, 0.037-0.509; P = .003). Number needed to treat [NNT] to prevent 1 acute hamstring injury (new or recurrent) is 13 (95% CI, 9-23) players. The NNT to prevent 1 new injury is 25 (95% CI, 15-72) players, and NNT to prevent 1 recurrent injury is 3 (95% CI, 2-6) players. CONCLUSION: IN male professional and amateur soccer players, additional eccentric hamstring exercise decreased the rate of overall, new, and recurrent acute hamstring injuries. PMID- 21825113 TI - Induction and repair of DNA strand breaks and oxidised bases in somatic and spermatogenic cells from the earthworm Eisenia fetida after exposure to ionising radiation. AB - Methods for analysing oxidised DNA lesions [formamidopyrimidine glycosylase (Fpg) sensitive sites] in coelomocytes and spermatogenic cells from the earthworm Eisenia fetida using the Fpg-modified comet assay were established. The DNA integrity (SSBs = strand breaks plus alkali labile sites and Fpg-sensitive sites) in cells from E. fetida continuously exposed to (60)Co gamma-radiation (dose rates 0.18-43 mGy/h) during two subsequent generations (F0 and F1) were measured and related to effects on reproduction end points which have already been reported. The data suggest a slight increase of Fpg-sensitive sites in spermatogenic cells from worms exposed at 11 mGy/h in the F0 generation but not in F1, whereas reduced reproduction had been observed at dose rates at or >4 mGy/h in F0 and at 11 mGy/h in F1. Using acute X-rays (41.9 Gy/h), dose-response relationships were established for SSBs in coelomocytes and spermatogenic cells exposed in vitro. In vivo DNA repair was studied by measuring the decrease in damage (SSBs and Fpg-sensitive sites) in coelomocytes and spermatogenic cells isolated from worms at different times (0-6 h) after acute X-ray exposure (4 Gy). SSBs were repaired in coelomocytes following biphasic kinetics, i.e. with a fast and a slow half-life (t(1/2)) of 36 min (95%) and 6.7 h (5%), respectively. Fpg sensitive sites were repaired at considerably lower rates (t(1/2) = 4-5 h). In spermatogenic cells, SSB repair during the first hour was observed but a half life could not be estimated. Repair of Fpg-sensitive sites could not be determined. In general, a reduced repair of Fpg-sensitive sites suggests a higher potential for accumulation of oxidised lesions, compared to SSBs, in earthworms exposed to radiation and other environmental contaminants. This is the first study comparing DNA damage with reproduction in earthworms exposed to ionising radiation. PMID- 21825114 TI - Hydroxymethyl-substituted furans: mutagenicity in Salmonella typhimurium strains engineered for expression of various human and rodent sulphotransferases. AB - 5-Hydroxymethylfurfural (HMF) and furfuryl alcohol (FFA) are present in numerous foodstuffs at high levels. FFA is also used for the production of polymers. Both compounds had demonstrated some evidence of carcinogenic activity in 2-year bioassays. We tested these compounds and four congeners for mutagenicity in Salmonella typhimurium TA100 and TA100-derived strains expressing human or rodent sulphotransferases (SULTs). 5-Hydroxymethylfuroic acid, a metabolite of HMF, was not mutagenic in any strain. 3-Hydroxymethylfuran was weakly mutagenic in all strains independently of SULT expression. HMF, 2,5-(bishydroxymethyl)furan (metabolite of HMF), FFA and 5-methyl-FFA were inactive in TA100 but strongly mutagenic when human SULT1C2 was expressed. This form has been detected in ovary, kidney and foetal tissues. Human SULT1A1, SULT1A2 and SULT1A3 as well as murine Sult1a1 and Sult1d1 also activated some hydroxymethyl-substituted furans to varying degrees. Whereas chemically synthesised 5-sulphooxymethylfurfural was mutagenic in TA100, furfuryl sulphate was bacteriotoxic, only leading to marginal increases in the number of revertants. Furfuryl acetate, an uncharged ester of FFA, used as fragrance and food flavouring, was clearly mutagenic. We determined half-life times of 120 min, 20 s and 10 h, respectively, for 5 sulphooxymethylfurfural, furfuryl sulphate and furfuryl acetate at 37 degrees C in water. It is likely that the short lifespan of furfuryl sulphate, together with its charge, led to insufficient penetration of the bacteria when added externally, although it was mutagenic when generated by appropriate SULTs from FFA within the cell. PMID- 21825115 TI - Progesterone receptor membrane component 1 modulates human cytochrome p450 activities in an isoform-dependent manner. AB - Cytochromes P450 (P450s) catalyze the metabolism of a wide spectrum of compounds. Recently, progesterone receptor membrane component 1 (PGRMC1), which shares a key structural motif with cytochrome b(5), has been reported to bind to sterol- or steroid-synthesizing P450s, enhancing their activities. In this study, we investigated whether PGRMC1 affects human drug-metabolizing P450 activities. Using coexpression systems for PGRMC1 and P450s (CYP3A4, CYP2C9, or CYP2E1) in HepG2 cells, we found that PGRMC1 decreased the V(max) values and increased the K(m) values of the CYP3A4 activities, and it decreased the V(max) values but did not affect the K(m) values of the CYP2C9 activities. In contrast, PGRMC1 hardly affected the CYP2E1 activities. These results suggest that PGRMC1 negatively modulates the drug-metabolizing activities of P450, although it was isoform but not substrate dependent. It is worth noting that coimmunoprecipitation analysis using coexpression systems for FLAG-PGRMC1 and Myc-P450s in human embryonic kidney 293 cells revealed that PGRMC1 interacts with all three P450s, although the affinity seemed to vary. In 29 human liver microsomes (HLMs), there was a 5 fold variability in the PGRMC1 protein levels. By the correlation analyses using the P450 activities and the PGRMC1 levels, we could neither observe the contribution of PGRMC1 to the P450 activities in HLMs nor that of the NADPH cytochrome P450 reductase or cytochrome b(5). In conclusion, in contrast to sterol- or steroid-synthesizing P450s, we found that PGRMC1 negatively modulates the human drug-metabolizing activities of P450 through direct interaction. Further studies are needed to determine the clinical significance of PGRMC1 in the pharmacokinetics of drugs. PMID- 21825116 TI - Effect of dimethyl sulfoxide on in vitro cytochrome P4501A2 mediated phenacetin O deethylation in human liver microsomes. AB - In this study, we report the effect of dimethyl sulfoxide (DMSO), acetonitrile, and methanol on the CYP1A2-mediated metabolism of phenacetin in human liver microsomes. Phenacetin O-deethylation is the preferred probe reaction for CYP1A2, in which the metabolite, acetaminophen, is quantified using liquid chromatography tandem mass spectrometry. DMSO was found to inhibit CYP1A2-mediated phenacetin O deethylation even at low concentrations (0.1%). Acetonitrile did not significantly change the phenacetin O-deethylation activity at concentrations up to 2%. There was no effect on the phenacetin O-deethylation when methanol was present at levels up to 2%. We found that the DMSO level should be kept lower than 0.05% because a concentration of 0.1% strongly affected the metabolism of phenacetin. These findings should be taken into consideration when designing in vitro metabolism studies, especially studies in which metabolism of the investigational compound needs to be evaluated, which would confound the results. The findings from this study indicate that methanol is the suitable solvent and has no significant effects on CYP1A2-mediated phenacetin O-deethylation. PMID- 21825117 TI - Carbon debt of Conservation Reserve Program (CRP) grasslands converted to bioenergy production. AB - Over 13 million ha of former cropland are enrolled in the US Conservation Reserve Program (CRP), providing well-recognized biodiversity, water quality, and carbon (C) sequestration benefits that could be lost on conversion back to agricultural production. Here we provide measurements of the greenhouse gas consequences of converting CRP land to continuous corn, corn-soybean, or perennial grass for biofuel production. No-till soybeans preceded the annual crops and created an initial carbon debt of 10.6 Mg CO(2) equivalents (CO(2)e).ha(-1) that included agronomic inputs, changes in C stocks, altered N(2)O and CH(4) fluxes, and foregone C sequestration less a fossil fuel offset credit. Total debt, which includes future debt created by additional changes in soil C stocks and the loss of substantial future soil C sequestration, can be constrained to 68 Mg CO(2)e.ha(-1) if subsequent crops are under permanent no-till management. If tilled, however, total debt triples to 222 Mg CO(2)e.ha(-1) on account of further soil C loss. Projected C debt repayment periods under no-till management range from 29 to 40 y for corn-soybean and continuous corn, respectively. Under conventional tillage repayment periods are three times longer, from 89 to 123 y, respectively. Alternatively, the direct use of existing CRP grasslands for cellulosic feedstock production would avoid C debt entirely and provide modest climate change mitigation immediately. Incentives for permanent no till and especially permission to harvest CRP biomass for cellulosic biofuel would help to blunt the climate impact of future CRP conversion. PMID- 21825118 TI - Marine microgels as a source of cloud condensation nuclei in the high Arctic. AB - Marine microgels play an important role in regulating ocean basin-scale biogeochemical dynamics. In this paper, we demonstrate that, in the high Arctic, marine gels with unique physicochemical characteristics originate in the organic material produced by ice algae and/or phytoplankton in the surface water. The polymers in this dissolved organic pool assembled faster and with higher microgel yields than at other latitudes. The reversible phase transitions shown by these Arctic marine gels, as a function of pH, dimethylsulfide, and dimethylsulfoniopropionate concentrations, stimulate the gels to attain sizes below 1 MUm in diameter. These marine gels were identified with an antibody probe specific toward material from the surface waters, sized, and quantified in airborne aerosol, fog, and cloud water, strongly suggesting that they dominate the available cloud condensation nuclei number population in the high Arctic (north of 80 degrees N) during the summer season. Knowledge about emergent properties of marine gels provides important new insights into the processes controlling cloud formation and radiative forcing, and links the biology at the ocean surface with cloud properties and climate over the central Arctic Ocean and, probably, all oceans. PMID- 21825119 TI - Genome-wide recombination drives diversification of epidemic strains of Acinetobacter baumannii. AB - Acinetobacter baumannii is an emerging human pathogen and a significant cause of nosocomial infections among hospital patients worldwide. The enormous increase in multidrug resistance among hospital isolates and the recent emergence of pan-drug resistant strains underscores the urgency to understand how A. baumannii evolves in hospital environments. To this end, we undertook a genomic study of a polyclonal outbreak of multidrug-resistant A. baumannii at the research-based National Institutes of Health Clinical Center. Comparing the complete genome sequences of the three dominant outbreak strain types enabled us to conclude that, despite all belonging to the same epidemic lineage, the three strains diverged before their arrival at the National Institutes of Health. The simultaneous presence of three divergent strains from this lineage supports its increasing prevalence in international hospitals and suggests an ongoing adaptation to the hospital environment. Further genomic comparisons uncovered that much of the diversification that occurred since the divergence of the three outbreak strains was mediated by homologous recombination across 20% of their genomes. Inspection of recombinant regions revealed that several regions were associated with either the loss or swapping out of genes encoding proteins that are exposed to the cell surface or that synthesize cell-surface molecules. Extending our analysis to a larger set of international clinical isolates revealed a previously unappreciated ability of A. baumannii to vary surface molecules through horizontal gene transfer, with subsequent intraspecies dissemination by homologous recombination. These findings have immediate implications in surveillance, prevention, and treatment of A. baumannii infections. PMID- 21825120 TI - Human herpesvirus-6 entry into the central nervous system through the olfactory pathway. AB - Viruses have been implicated in the development of neurodegenerative diseases, such as Alzheimer's, Parkinson's, and multiple sclerosis. Human herpesvirus-6 (HHV-6) is a neurotropic virus that has been associated with a wide variety of neurologic disorders, including encephalitis, mesial temporal lobe epilepsy, and multiple sclerosis. Currently, the route of HHV-6 entry into the CNS is unknown. Using autopsy specimens, we found that the frequency of HHV-6 DNA in the olfactory bulb/tract region was among the highest in the brain regions examined. Given this finding, we investigated whether HHV-6 may infect the CNS via the olfactory pathway. HHV-6 DNA was detected in a total of 52 of 126 (41.3%) nasal mucous samples, showing the nasal cavity is a reservoir for HHV-6. Furthermore, specialized olfactory-ensheathing glial cells located in the nasal cavity were demonstrated to support HHV-6 replication in vitro. Collectively, these results support HHV-6 utilization of the olfactory pathway as a route of entry into the CNS. PMID- 21825121 TI - Mutant alcohol dehydrogenase leads to improved ethanol tolerance in Clostridium thermocellum. AB - Clostridium thermocellum is a thermophilic, obligately anaerobic, gram-positive bacterium that is a candidate microorganism for converting cellulosic biomass into ethanol through consolidated bioprocessing. Ethanol intolerance is an important metric in terms of process economics, and tolerance has often been described as a complex and likely multigenic trait for which complex gene interactions come into play. Here, we resequence the genome of an ethanol tolerant mutant, show that the tolerant phenotype is primarily due to a mutated bifunctional acetaldehyde-CoA/alcohol dehydrogenase gene (adhE), hypothesize based on structural analysis that cofactor specificity may be affected, and confirm this hypothesis using enzyme assays. Biochemical assays confirm a complete loss of NADH-dependent activity with concomitant acquisition of NADPH dependent activity, which likely affects electron flow in the mutant. The simplicity of the genetic basis for the ethanol-tolerant phenotype observed here informs rational engineering of mutant microbial strains for cellulosic ethanol production. PMID- 21825122 TI - Structural and functional characterization of a single-chain peptide-MHC molecule that modulates both naive and activated CD8+ T cells. AB - Peptide-MHC (pMHC) multimers, in addition to being tools for tracking and quantifying antigen-specific T cells, can mediate downstream signaling after T cell receptor engagement. In the absence of costimulation, this can lead to anergy or apoptosis of cognate T cells, a property that could be exploited in the setting of autoimmune disease. Most studies with class I pMHC multimers used noncovalently linked peptides, which can allow unwanted CD8(+) T-cell activation as a result of peptide transfer to cellular MHC molecules. To circumvent this problem, and given the role of self-reactive CD8(+) T cells in the development of type 1 diabetes, we designed a single-chain pMHC complex (scK(d).IGRP) by using the class I MHC molecule H-2K(d) and a covalently linked peptide derived from islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP(206 214)), a well established autoantigen in NOD mice. X-ray diffraction studies revealed that the peptide is presented in the groove of the MHC molecule in canonical fashion, and it was also demonstrated that scK(d).IGRP tetramers bound specifically to cognate CD8(+) T cells. Tetramer binding induced death of naive T cells and in vitro- and in vivo-differentiated cytotoxic T lymphocytes, and tetramer-treated cytotoxic T lymphocytes showed a diminished IFN-gamma response to antigen stimulation. Tetramer accessibility to disease-relevant T cells in vivo was also demonstrated. Our study suggests the potential of single-chain pMHC tetramers as possible therapeutic agents in autoimmune disease. Their ability to affect the fate of naive and activated CD8(+) T cells makes them a potential intervention strategy in early and late stages of disease. PMID- 21825123 TI - Bacterial community assembly based on functional genes rather than species. AB - The principles underlying the assembly and structure of complex microbial communities are an issue of long-standing concern to the field of microbial ecology. We previously analyzed the community membership of bacterial communities associated with the green macroalga Ulva australis, and proposed a competitive lottery model for colonization of the algal surface in an attempt to explain the surprising lack of similarity in species composition across different algal samples. Here we extend the previous study by investigating the link between community structure and function in these communities, using metagenomic sequence analysis. Despite the high phylogenetic variability in microbial species composition on different U. australis (only 15% similarity between samples), similarity in functional composition was high (70%), and a core of functional genes present across all algal-associated communities was identified that were consistent with the ecology of surface- and host-associated bacteria. These functions were distributed widely across a variety of taxa or phylogenetic groups. This observation of similarity in habitat (niche) use with respect to functional genes, but not species, together with the relative ease with which bacteria share genetic material, suggests that the key level at which to address the assembly and structure of bacterial communities may not be "species" (by means of rRNA taxonomy), but rather the more functional level of genes. PMID- 21825124 TI - The aneurogenic limb identifies developmental cell interactions underlying vertebrate limb regeneration. AB - The removal of the neural tube in salamander embryos allows the development of nerve-free aneurogenic limbs. Limb regeneration is normally nerve-dependent, but the aneurogenic limb regenerates without nerves and becomes nerve-dependent after innervation. The molecular basis for these tissue interactions is unclear. Anterior Gradient (AG) protein, previously shown to rescue regeneration of denervated limbs and to act as a growth factor for cultured limb blastemal cells, is expressed throughout the larval limb epidermis and is down-regulated by innervation. In an aneurogenic limb, the level of AG protein remains high in the epidermis throughout development and regeneration, but decreases after innervation following transplantation to a normal host. Aneurogenic epidermis also shows a fivefold difference in secretory gland cells, which express AG protein. The persistently high expression of AG in the epithelial cells of an aneurogenic limb ensures that regeneration is independent of the nerve. These findings provide an explanation for this classical problem, and identify regulation of the epidermal niche by innervation as a distinctive developmental mechanism that initiates the nerve dependence of limb regeneration. The absence of this regulation during anuran limb development might suggest that it evolved in relation to limb regeneration. PMID- 21825125 TI - Broadly neutralizing human antibody that recognizes the receptor-binding pocket of influenza virus hemagglutinin. AB - Seasonal antigenic drift of circulating influenza virus leads to a requirement for frequent changes in vaccine composition, because exposure or vaccination elicits human antibodies with limited cross-neutralization of drifted strains. We describe a human monoclonal antibody, CH65, obtained by isolating rearranged heavy- and light-chain genes from sorted single plasma cells, coming from a subject immunized with the 2007 trivalent influenza vaccine. The crystal structure of a complex of the hemagglutinin (HA) from H1N1 strain A/Solomon Islands/3/2006 with the Fab of CH65 shows that the tip of the CH65 heavy-chain complementarity determining region 3 (CDR3) inserts into the receptor binding pocket on HA1, mimicking in many respects the interaction of the physiological receptor, sialic acid. CH65 neutralizes infectivity of 30 out of 36 H1N1 strains tested. The resistant strains have a single-residue insertion near the rim of the sialic-acid pocket. We conclude that broad neutralization of influenza virus can be achieved by antibodies with contacts that mimic those of the receptor. PMID- 21825126 TI - Craniometric ratios of microcephaly and LB1, Homo floresiensis, using MRI and endocasts. AB - The designation of Homo floresiensis as a new species derived from an ancient population is controversial, because the type specimen, LB1, might represent a pathological microcephalic modern Homo sapiens. Accordingly, two specific craniometric ratios (relative frontal breadth and cerebellar protrusion) were ascertained in 21 microcephalic infants and children by using MRI. Data on 118 age-equivalent control (normocephalic) subjects were collected for comparative purposes. In addition, the same craniometric ratios were determined on the endocasts of 10 microcephalic individuals, 79 normal controls (anatomically modern humans), and 17 Homo erectus specimens. These ratios were then compared with those of two LB1 endocasts. The findings showed that the calculated cerebral/cerebellar ratios of the LB1 endocast [Falk D, et al. (2007) Proc Natl Acad Sci USA 104:2513-2518] fall outside the range of living normocephalic individuals. The ratios derived from two LB1 endocasts also fall largely outside the range of modern normal human and H. erectus endocasts and within the range of microcephalic endocasts. The findings support but do not prove the contention that LB1 represents a pathological microcephalic Homo sapiens rather than a new species, (i.e., H. floresiensis). PMID- 21825127 TI - Multiple enhancers ensure precision of gap gene-expression patterns in the Drosophila embryo. AB - Segmentation of the Drosophila embryo begins with the establishment of spatially restricted gap gene-expression patterns in response to broad gradients of maternal transcription factors, such as Bicoid. Numerous studies have documented the fidelity of these expression patterns, even when embryos are subjected to genetic or environmental stress, but the underlying mechanisms for this transcriptional precision are uncertain. Here we present evidence that every gap gene contains multiple enhancers with overlapping activities to produce authentic patterns of gene expression. For example, a recently identified hunchback (hb) enhancer (located 5-kb upstream of the classic enhancer) ensures repression at the anterior pole. The combination of intronic and 5' knirps (kni) enhancers produces a faithful expression pattern, even though the intronic enhancer alone directs an abnormally broad expression pattern. We present different models for "enhancer synergy," whereby two enhancers with overlapping activities produce authentic patterns of gene expression. PMID- 21825128 TI - Arabidopsis hybrid speciation processes. AB - The genus Arabidopsis provides a unique opportunity to study fundamental biological questions in plant sciences using the diploid model species Arabidopsis thaliana and Arabidopsis lyrata. However, only a few studies have focused on introgression and hybrid speciation in Arabidopsis, although polyploidy is a common phenomenon within this genus. More recently, there is growing evidence of significant gene flow between the various Arabidopsis species. So far, we know Arabidopsis suecica and Arabidopsis kamchatica as fully stabilized allopolyploid species. Both species evolved during Pleistocene glaciation and deglaciation cycles in Fennoscandinavia and the amphi-Beringian region, respectively. These hybrid studies were conducted either on a phylogeographic scale or reconstructed experimentally in the laboratory. In our study we focus at a regional and population level. Our research area is located in the foothills of the eastern Austrian Alps, where two Arabidopsis species, Arabidopsis arenosa and A. lyrata ssp. petraea, are sympatrically distributed. Our hypothesis of genetic introgression, migration, and adaptation to the changing environment during the Pleistocene has been confirmed: We observed significant, mainly unidirectional gene flow between the two species, which has given rise to the tetraploid A. lyrata. This cytotype was able to escape from the narrow ecological niche occupied by diploid A. lyrata ssp. petraea on limestone outcrops by migrating northward into siliceous areas, leaving behind a trail of genetic differentiation. PMID- 21825129 TI - Synthesizing epidemiological and economic optima for control of immunizing infections. AB - Epidemic theory predicts that the vaccination threshold required to interrupt local transmission of an immunizing infection like measles depends only on the basic reproductive number and hence transmission rates. When the search for optimal strategies is expanded to incorporate economic constraints, the optimum for disease control in a single population is determined by relative costs of infection and control, rather than transmission rates. Adding a spatial dimension, which precludes local elimination unless it can be achieved globally, can reduce or increase optimal vaccination levels depending on the balance of costs and benefits. For weakly coupled populations, local optimal strategies agree with the global cost-effective strategy; however, asymmetries in costs can lead to divergent control optima in more strongly coupled systems--in particular, strong regional differences in costs of vaccination can preclude local elimination even when elimination is locally optimal. Under certain conditions, it is locally optimal to share vaccination resources with other populations. PMID- 21825130 TI - Iroquois homeobox gene 3 establishes fast conduction in the cardiac His-Purkinje network. AB - Rapid electrical conduction in the His-Purkinje system tightly controls spatiotemporal activation of the ventricles. Although recent work has shed much light on the regulation of early specification and morphogenesis of the His Purkinje system, less is known about how transcriptional regulation establishes impulse conduction properties of the constituent cells. Here we show that Iroquois homeobox gene 3 (Irx3) is critical for efficient conduction in this specialized tissue by antithetically regulating two gap junction-forming connexins (Cxs). Loss of Irx3 resulted in disruption of the rapid coordinated spread of ventricular excitation, reduced levels of Cx40, and ectopic Cx43 expression in the proximal bundle branches. Irx3 directly represses Cx43 transcription and indirectly activates Cx40 transcription. Our results reveal a critical role for Irx3 in the precise regulation of intercellular gap junction coupling and impulse propagation in the heart. PMID- 21825131 TI - Assessing the vulnerability of traditional maize seed systems in Mexico to climate change. AB - Climate change is predicted to have major impacts on small-scale farmers in Mexico whose livelihoods depend on rain-fed maize. We examined the capacity of traditional maize seed systems to provide these farmers with appropriate genetic material under predicted agro-ecological conditions associated with climate change. We studied the structure and spatial scope of seed systems of 20 communities in four transects across an altitudinal gradient from 10-2,980 m above sea level in five states of eastern Mexico. Results indicate that 90% of all of the seed lots are obtained within 10 km of a community and 87% within an altitudinal range of +/-50 m but with variation across four agro-climate environments: wet lowland, dry lowland, wet upper midlatitude, and highlands. Climate models suggest a drying and warming trend for the entire study area during the main maize season, leading to substantial shifts in the spatial distribution patterns of agro-climate environments. For all communities except those in the highlands, predicted future maize environments already are represented within the 10-km radial zones, indicating that in the future farmers will have easy access to adapted planting material. Farmers in the highlands are the most vulnerable and probably will need to acquire seed from outside their traditional geographical ranges. This change in seed sources probably will entail important information costs and the development of new seed and associated social networks, including improved linkages between traditional and formal seed systems and more effective and efficient seed-supply chains. The study has implications for analogous areas elsewhere in Mexico and around the world. PMID- 21825132 TI - Efficient transformation of an auditory population code in a small sensory system. AB - Optimal coding principles are implemented in many large sensory systems. They include the systematic transformation of external stimuli into a sparse and decorrelated neuronal representation, enabling a flexible readout of stimulus properties. Are these principles also applicable to size-constrained systems, which have to rely on a limited number of neurons and may only have to fulfill specific and restricted tasks? We studied this question in an insect system--the early auditory pathway of grasshoppers. Grasshoppers use genetically fixed songs to recognize mates. The first steps of neural processing of songs take place in a small three-layer feed-forward network comprising only a few dozen neurons. We analyzed the transformation of the neural code within this network. Indeed, grasshoppers create a decorrelated and sparse representation, in accordance with optimal coding theory. Whereas the neuronal input layer is best read out as a summed population, a labeled-line population code for temporal features of the song is established after only two processing steps. At this stage, information about song identity is maximal for a population decoder that preserves neuronal identity. We conclude that optimal coding principles do apply to the early auditory system of the grasshopper, despite its size constraints. The inputs, however, are not encoded in a systematic, map-like fashion as in many larger sensory systems. Already at its periphery, part of the grasshopper auditory system seems to focus on behaviorally relevant features, and is in this property more reminiscent of higher sensory areas in vertebrates. PMID- 21825133 TI - Modulation of pancreatic islets-stress axis by hypothalamic releasing hormones and 11beta-hydroxysteroid dehydrogenase. AB - Corticotropin-releasing hormone (CRH) and growth hormone-releasing hormone (GHRH), primarily characterized as neuroregulators of the hypothalamic-pituitary adrenal axis, directly influence tissue-specific receptor-systems for CRH and GHRH in the endocrine pancreas. Here, we demonstrate the expression of mRNA for CRH and CRH-receptor type 1 (CRHR1) and of protein for CRHR1 in rat and human pancreatic islets and rat insulinoma cells. Activation of CRHR1 and GHRH-receptor significantly increased cell proliferation and reduced cell apoptosis. CRH stimulated both cellular content and release of insulin in rat islet and insulinoma cells. At the ultrastructural level, CRHR1 stimulation revealed a more active metabolic state with enlarged mitochondria. Moreover, glucocorticoids that promote glucose production are balanced by both 11b-hydroxysteroid dehydrogenase (11beta-HSD) isoforms; 11beta-HSD-type-1 and 11beta-HSD-type-2. We demonstrated expression of mRNA for 11beta-HSD-1 and 11beta-HSD-2 and protein for 11beta-HSD-1 in rat and human pancreatic islets and insulinoma cells. Quantitative real-time PCR revealed that stimulation of CRHR1 and GHRH-receptor affects the metabolism of insulinoma cells by down-regulating 11beta-HSD-1 and up-regulating 11beta-HSD 2. The 11beta-HSD enzyme activity was analyzed by measuring the production of cortisol from cortisone. Similarly, activation of CRHR1 resulted in reduced cortisol levels, indicating either decreased 11beta-HSD-1 enzyme activity or increased 11beta-HSD-2 enzyme activity; thus, activation of CRHR1 alters the glucocorticoid balance toward the inactive form. These data indicate that functional receptor systems for hypothalamic-releasing hormone agonists exist within the endocrine pancreas and influence synthesis of insulin and the pancreatic glucocorticoid shuttle. Agonists of CRHR1 and GHRH-receptor, therefore, may play an important role as novel therapeutic tools in the treatment of diabetes mellitus. PMID- 21825134 TI - Inhibition of PI3K binding to activators by serine phosphorylation of PI3K regulatory subunit p85alpha Src homology-2 domains. AB - Class IA PI3Ks are activated by growth factor receptors and generate lipid second messengers that mediate downstream responses including cell growth, cell migration, and cell survival. The p85 regulatory subunit of PI3K contains Src homology-2 (SH2) domains that mediate binding to tyrosine-phosphorylated receptors or adaptor proteins to facilitate localization and activation of PI3K at the plasma membrane. We report here that persistent activation of PKC family members by phorbol ester stimulation in cells leads to phosphorylation of two serine residues at analogous sites on both SH2 domains of p85alpha (S361 and S652). The modified serine residues are located in the phospho-tyrosine binding pockets of the two SH2 domains, and in the crystal structures the phosphate moieties are predicted to occupy the same space as the phosphate moieties of bound phospho-tyrosine peptides. Consistent with this prediction, phosphorylation at these serine residues or mutation to aspartate inhibits binding of p85alpha to tyrosine-phosphorylated peptides. We provide evidence that protein kinase D, which is phosphorylated and activated by PKCs, mediates phosphorylation of S652 in the C-terminal SH2 domain. These results reveal cross talk between PKC signaling and PI3K signaling that impairs PI3K pathway activation under conditions of persistent PKC (and protein kinase D) activity. PMID- 21825135 TI - ADP ribosylation factor 6 (ARF6) controls amyloid precursor protein (APP) processing by mediating the endosomal sorting of BACE1. AB - Amyloid beta (Abeta) peptides, the primary constituents of senile plaques and a hallmark in Alzheimer's disease pathology, are generated through the sequential cleavage of amyloid precursor protein (APP) by beta-site APP cleaving enzyme 1 (BACE1) and gamma-secretase. The early endosome is thought to represent a major compartment for APP processing; however, the mechanisms of how BACE1 encounters APP are largely unknown. In contrast to APP internalization, which is clathrin dependent, we demonstrate that BACE1 is sorted to early endosomes via a route controlled by the small GTPase ADP ribosylation factor 6 (ARF6). Altering ARF6 levels or its activity affects endosomal sorting of BACE1, and consequently results in altered APP processing and Abeta production. Furthermore, sorting of newly internalized BACE1 from ARF6-positive towards RAB GTPase 5 (RAB5)-positive early endosomes depends on its carboxyterminal short acidic cluster-dileucine motif. This ARF6-mediated sorting of BACE1 is confined to the somatodendritic compartment of polarized neurons in agreement with Abeta peptides being primarily secreted from here. These results demonstrate a spatial separation between APP and BACE1 during surface-to-endosome transport, suggesting subcellular trafficking as a regulatory mechanism for this proteolytic processing step. It thereby provides a novel avenue to interfere with Abeta production through a selective modulation of the distinct endosomal transport routes used by BACE1 or APP. PMID- 21825136 TI - Spermless males elicit large-scale female responses to mating in the malaria mosquito Anopheles gambiae. AB - Anopheles gambiae sensu stricto is the major vector of malaria, a disease with devastating consequences for human health. Given the constant spread of the disease, alternative approaches to the use of insecticides are urgently needed to control vector populations. Females of this species undergo large behavioral changes after mating, which include a life-long refractoriness to further insemination and the induction of egg laying in blood-fed individuals. Genetic control strategies aimed at impacting Anopheles fertility through the release of sterile males are being advocated to reduce the size of mosquito field populations. Such strategies depend on the ability of the released sterile males to mate successfully with wild females and to switch off the female receptivity to further copulation. Here we evaluate the role of sperm in regulating female behavioral responses after mating in An. gambiae. We developed spermless males by RNAi silencing of a germ cell differentiation gene. These males mated successfully and preserved standard accessory gland functions. Females mated to spermless males exhibited normal postcopulatory responses, which included laying large numbers of eggs upon blood feeding and becoming refractory to subsequent insemination. Moreover, spermless males induced transcriptional changes in female reproductive genes comparable to those elicited by fertile males. Our data demonstrate that, in contrast to Drosophila, targeting sperm in An. gambiae preserves normal male and female reproductive behavior for the traits and time frame analyzed and validate the use of approaches based on incapacitation or elimination of sperm for genetic control of vector populations to block malaria transmission. PMID- 21825137 TI - A Unified attentional bottleneck in the human brain. AB - Human information processing is characterized by bottlenecks that constrain throughput. These bottlenecks limit both what we can perceive and what we can act on in multitask settings. Although perceptual and response limitations are often attributed to independent information processing bottlenecks, it has recently been suggested that a common attentional limitation may be responsible for both. To date, however, evidence supporting the existence of such a "unified" bottleneck has been mixed. Here, we tested the unified bottleneck hypothesis using time-resolved fMRI. Experiment 1 isolated brain regions involved in the response selection bottleneck that limits speeded dual-task performance. These same brain regions were not only engaged by a perceptual encoding task in Experiment 2, their activity also tracked delays to a speeded decision-making task caused by concurrent perceptual encoding (Experiment 3). We conclude that a unified attentional bottleneck, including the inferior frontal junction, superior medial frontal cortex, and bilateral insula, temporally limits operations as diverse as perceptual encoding and decision-making. PMID- 21825138 TI - Aryl hydrocarbon receptor deficiency in T cells suppresses the development of collagen-induced arthritis. AB - The contributions of aryl hydrocarbon receptor (Ahr) to the pathogenesis of rheumatoid arthritis have not been elucidated. Here, we show that Ahr deficiency ameliorated collagen-induced arthritis, a mouse model of RA. Collagen-immunized Ahr KO mice showed decreased serum levels of such proinflammatory cytokines as IL 1beta and IL-6. The Th17 and Th1 cell populations in lymph nodes from these mice decreased and increased, respectively, whereas the percentage of regulatory T cells was unchanged. Interestingly, a lack of Ahr specifically in T cells significantly suppressed collagen-induced arthritis development, whereas Ahr deficiency in macrophages had no effect. These finding indicate that the development of experimental autoimmune arthritis depends on the presence of Ahr in T cells, and that Th1/Th17 balance may be particularly important for this process. PMID- 21825139 TI - Exome sequencing and analysis of induced pluripotent stem cells identify the cilia-related gene male germ cell-associated kinase (MAK) as a cause of retinitis pigmentosa. AB - Retinitis pigmentosa (RP) is a genetically heterogeneous heritable disease characterized by apoptotic death of photoreceptor cells. We used exome sequencing to identify a homozygous Alu insertion in exon 9 of male germ cell-associated kinase (MAK) as the cause of disease in an isolated individual with RP. Screening of 1,798 unrelated RP patients identified 20 additional probands homozygous for this insertion (1.2%). All 21 affected probands are of Jewish ancestry. MAK encodes a kinase involved in the regulation of photoreceptor-connecting cilium length. Immunohistochemistry of human donor tissue revealed that MAK is expressed in the inner segments, cell bodies, and axons of rod and cone photoreceptors. Several isoforms of MAK that result from alternative splicing were identified. Induced pluripotent stem cells were derived from the skin of the proband and a patient with non-MAK-associated RP (RP control). In the RP control individual, we found that a transcript lacking exon 9 was predominant in undifferentiated cells, whereas a transcript bearing exon 9 and a previously unrecognized exon 12 predominated in cells that were differentiated into retinal precursors. However, in the proband with the Alu insertion, the developmental switch to the MAK transcript bearing exons 9 and 12 did not occur. In addition to showing the use of induced pluripotent stem cells to efficiently evaluate the pathogenicity of specific mutations in relatively inaccessible tissues like retina, this study reveals algorithmic and molecular obstacles to the discovery of pathogenic insertions and suggests specific changes in strategy that can be implemented to more fully harness the power of sequencing technologies. PMID- 21825140 TI - Chloroplast Omp85 proteins change orientation during evolution. AB - The majority of outer membrane proteins (OMPs) from gram-negative bacteria and many of mitochondria and chloroplasts are beta-barrels. Insertion and assembly of these proteins are catalyzed by the Omp85 protein family in a seemingly conserved process. All members of this family exhibit a characteristic N-terminal polypeptide-transport-associated (POTRA) and a C-terminal 16-stranded beta-barrel domain. In plants, two phylogenetically distinct and essential Omp85's exist in the chloroplast outer membrane, namely Toc75-III and Toc75-V. Whereas Toc75-V, similar to the mitochondrial Sam50, is thought to possess the original bacterial function, its homolog, Toc75-III, evolved to the pore-forming unit of the TOC translocon for preprotein import. In all current models of OMP biogenesis and preprotein translocation, a topology of Omp85 with the POTRA domain in the periplasm or intermembrane space is assumed. Using self-assembly GFP-based in vivo experiments and in situ topology studies by electron cryotomography, we show that the POTRA domains of both Toc75-III and Toc75-V are exposed to the cytoplasm. This unexpected finding explains many experimental observations and requires a reevaluation of current models of OMP biogenesis and TOC complex function. PMID- 21825141 TI - Nuclear membranes control symbiotic calcium signaling of legumes. AB - Nuclear-associated oscillations in calcium act as a secondary messenger in the symbiotic signaling pathway of legumes. These are decoded by a nuclear-localized calcium and calmodulin-dependent protein kinase, the activation of which is sufficient to drive downstream responses. This implies that the calcium oscillations within the nucleus are the predominant signals for legume symbiosis. However, the mechanisms that allow targeted release of calcium in the nuclear region have not been defined. Here we show that symbiosis-induced calcium changes occur in both the nucleoplasm and the perinuclear cytoplasm and seem to originate from the nuclear membranes. Reaction diffusion simulations suggest that spike generation within the nucleoplasm is not possible through transmission of a calcium wave from the cytoplasm alone and that calcium is likely to be released across the inner nuclear membrane to allow nuclear calcium changes. In agreement with this, we found that the cation channel DMI1, which is essential for symbiotic calcium oscillations, is preferentially located on the inner nuclear membrane, implying an essential function for the inner nuclear membrane in symbiotic calcium signaling. Furthermore, a sarco/endoplasmic reticulum calcium ATPase (SERCA) essential for symbiotic calcium oscillations is targeted to the inner nuclear membrane, as well as the outer nuclear membrane and endoplasmic reticulum (ER). We propose that release of calcium across the inner nuclear membrane allows targeted release of the ER calcium store, and efficient reloading of this calcium store necessitates the capture of calcium from the nucleoplasm and nuclear-associated cytoplasm. PMID- 21825142 TI - Cytoskeletal actin networks in motile cells are critically self-organized systems synchronized by mechanical interactions. AB - Growing networks of actin fibers are able to organize into compact, stiff two dimensional structures inside lamellipodia of crawling cells. We put forward the hypothesis that the growing actin network is a critically self-organized system, in which long-range mechanical stresses arising from the interaction with the plasma membrane provide the selective pressure leading to organization. We show that a simple model based only on this principle reproduces the stochastic nature of lamellipodia protrusion (growth periods alternating with fast retractions) and several of the features observed in experiments: a growth velocity initially insensitive to the external force; the capability of the network to organize its orientation; a load-history-dependent growth velocity. Our model predicts that the spectrum of the time series of the height of a growing lamellipodium decays with the inverse of the frequency. This behavior is a well-known signature of self-organized criticality and is confirmed by unique optical tweezer measurements performed in vivo on neuronal growth cones. PMID- 21825143 TI - Detection and formation scenario of citric acid, pyruvic acid, and other possible metabolism precursors in carbonaceous meteorites. AB - Carbonaceous meteorites deliver a variety of organic compounds to Earth that may have played a role in the origin and/or evolution of biochemical pathways. Some apparently ancient and critical metabolic processes require several compounds, some of which are relatively labile such as keto acids. Therefore, a prebiotic setting for any such individual process would have required either a continuous distant source for the entire suite of intact precursor molecules and/or an energetic and compact local synthesis, particularly of the more fragile members. To date, compounds such as pyruvic acid, oxaloacetic acid, citric acid, isocitric acid, and alpha-ketoglutaric acid (all members of the citric acid cycle) have not been identified in extraterrestrial sources or, as a group, as part of a "one pot" suite of compounds synthesized under plausibly prebiotic conditions. We have identified these compounds and others in carbonaceous meteorites and/or as low temperature (laboratory) reaction products of pyruvic acid. In meteorites, we observe many as part of three newly reported classes of compounds: keto acids (pyruvic acid and homologs), hydroxy tricarboxylic acids (citric acid and homologs), and tricarboxylic acids. Laboratory syntheses using (13)C-labeled reactants demonstrate that one compound alone, pyruvic acid, can produce several (nonenzymatic) members of the citric acid cycle including oxaloacetic acid. The isotopic composition of some of the meteoritic keto acids points to interstellar or presolar origins, indicating that such compounds might also exist in other planetary systems. PMID- 21825144 TI - Unveiling the structural basis for translational ambiguity tolerance in a human fungal pathogen. AB - In a restricted group of opportunistic fungal pathogens the universal leucine CUG codon is translated both as serine (97%) and leucine (3%), challenging the concept that translational ambiguity has a negative impact in living organisms. To elucidate the molecular mechanisms underlying the in vivo tolerance to a nonconserved genetic code alteration, we have undertaken an extensive structural analysis of proteins containing CUG-encoded residues and solved the crystal structures of the two natural isoforms of Candida albicans seryl-tRNA synthetase. We show that codon reassignment resulted in a nonrandom genome-wide CUG redistribution tailored to minimize protein misfolding events induced by the large-scale leucine-to-serine replacement within the CTG clade. Leucine or serine incorporation at the CUG position in C. albicans seryl-tRNA synthetase induces only local structural changes and, although both isoforms display tRNA serylation activity, the leucine-containing isoform is more active. Similarly, codon ambiguity is predicted to shape the function of C. albicans proteins containing CUG-encoded residues in functionally relevant positions, some of which have a key role in signaling cascades associated with morphological changes and pathogenesis. This study provides a first detailed analysis on natural reassignment of codon identity, unveiling a highly dynamic evolutionary pattern of thousands of fungal CUG codons to confer an optimized balance between protein structural robustness and functional plasticity. PMID- 21825145 TI - Glycosylation of the enhanced aromatic sequon is similarly stabilizing in three distinct reverse turn contexts. AB - Cotranslational N-glycosylation can accelerate protein folding, slow protein unfolding, and increase protein stability, but the molecular basis for these energetic effects is incompletely understood. N-glycosylation of proteins at naive sites could be a useful strategy for stabilizing proteins in therapeutic and research applications, but without engineering guidelines, often results in unpredictable changes to protein energetics. We recently introduced the enhanced aromatic sequon as a family of portable structural motifs that are stabilized upon glycosylation in specific reverse turn contexts: a five-residue type I beta turn harboring a G1 beta-bulge (using a Phe-Yyy-Asn-Xxx-Thr sequon) and a type II beta-turn within a six-residue loop (using a Phe-Yyy-Zzz-Asn-Xxx-Thr sequon) [Culyba EK, et al. (2011) Science 331:571-575]. Here we show that glycosylating a new enhanced aromatic sequon, Phe-Asn-Xxx-Thr, in a type I' beta-turn stabilizes the Pin 1 WW domain. Comparing the energetic effects of glycosylating these three enhanced aromatic sequons in the same host WW domain revealed that the glycosylation-mediated stabilization is greatest for the enhanced aromatic sequon complementary to the type I beta-turn with a G1 beta-bulge. However, the portion of the stabilization from the tripartite interaction between Phe, Asn(GlcNAc), and Thr is similar for each enhanced aromatic sequon in its respective reverse turn context. Adding the Phe-Asn-Xxx-Thr motif (in a type I' beta-turn) to the enhanced aromatic sequon family doubles the number of proteins that can be stabilized by glycosylation without having to alter the native reverse turn type. PMID- 21825146 TI - Direct inference of protein-DNA interactions using compressed sensing methods. AB - Compressed sensing has revolutionized signal acquisition, by enabling complex signals to be measured with remarkable fidelity using a small number of so-called incoherent sensors. We show that molecular interactions, e.g., protein-DNA interactions, can be analyzed in a directly analogous manner and with similarly remarkable results. Specifically, mesoscopic molecular interactions act as incoherent sensors that measure the energies of microscopic interactions between atoms. We combine concepts from compressed sensing and statistical mechanics to determine the interatomic interaction energies of a molecular system exclusively from experimental measurements, resulting in a "de novo" energy potential. In contrast, conventional methods for estimating energy potentials are based on theoretical models premised on a priori assumptions and extensive domain knowledge. We determine the de novo energy potential for pairwise interactions between protein and DNA atoms from (i) experimental measurements of the binding affinity of protein-DNA complexes and (ii) crystal structures of the complexes. We show that the de novo energy potential can be used to predict the binding specificity of proteins to DNA with approximately 90% accuracy, compared to approximately 60% for the best performing alternative computational methods applied to this fundamental problem. This de novo potential method is directly extendable to other biomolecule interaction domains (enzymes and signaling molecule interactions) and to other classes of molecular interactions. PMID- 21825147 TI - Antagonistic VEGF variants engineered to simultaneously bind to and inhibit VEGFR2 and alphavbeta3 integrin. AB - Significant cross-talk exists between receptors that mediate angiogenesis, such as VEGF receptor-2 (VEGFR2) and alpha(v)beta(3) integrin. Thus, agents that inhibit both receptors would have important therapeutic potential. Here, we used an antagonistic VEGF ligand as a molecular scaffold to engineer dual-specific proteins that bound to VEGFR2 and alpha(v)beta(3) integrin with antibody-like affinities and inhibited angiogenic processes in vitro and in vivo. Mutations were introduced into a single-chain VEGF (scVEGF) ligand that retained VEGFR2 binding, but prevented receptor dimerization and activation. Yeast-displayed scVEGF mutant libraries were created and screened by high-throughput flow cytometric sorting to identify several variants that bound with high affinity to both VEGFR2 and alpha(v)beta(3) integrin. These engineered scVEGF mutants were specific for alpha(v)beta(3) integrin and did not bind to the related integrins alpha(v)beta(5), alpha(iib)beta(3), or alpha(5)beta(1). In addition, surface plasmon resonance and cell binding assays showed that dual-specific scVEGF proteins can simultaneously engage both receptors. Compared to monospecific scVEGF mutants that bind VEGFR2 or alpha(v)beta(3) integrin, dual-specific scVEGF proteins more strongly inhibited VEGF-mediated receptor phosphorylation, capillary tube formation, and proliferation of endothelial cells cultured on Matrigel or vitronectin-coated surfaces. Moreover, dual specificity conferred strong inhibition of VEGF-mediated blood vessel formation in Matrigel plugs in vivo, whereas monospecific scVEGF mutants that bind VEGFR2 or alpha(v)beta(3) integrin were only marginally effective. Instead of relying on antibody associating domains or physical linkage, this work highlights an approach to creating dual-specific proteins where additional functionality is introduced into a protein ligand to complement its existing biological properties. PMID- 21825148 TI - Hierarchical self-assembly of amelogenin and the regulation of biomineralization at the nanoscale. AB - Enamel is a highly organized hierarchical nanocomposite, which consists of parallel arrays of elongated apatitic crystallites forming an intricate three dimensional microstructure. Amelogenin, the major extracellular matrix protein of dental enamel, regulates the formation of these crystalline arrays via cooperative interactions with forming mineral phase. Using cryoelectron microscopy, we demonstrate that amelogenin undergoes stepwise hierarchical self assembly. Furthermore, our results indicate that interactions between amelogenin hydrophilic C-terminal telopeptides are essential for oligomer formation and for subsequent steps of hierarchical self-assembly. We further show that amelogenin assemblies stabilize mineral prenucleation clusters and guide their arrangement into linear chains that organize as parallel arrays. The prenucleation clusters subsequently fuse together to form needle-shaped mineral particles, leading to the formation of bundles of crystallites, the hallmark structural organization of the forming enamel at the nanoscale. These findings provide unique insight into the regulation of biological mineralization by specialized macromolecules and an inspiration for bottom-up strategies for the materials design. PMID- 21825149 TI - Phenotype-information-phenotype cycle for deconvolution of combinatorial antibody libraries selected against complex systems. AB - Use of large combinatorial antibody libraries and next-generation sequencing of nucleic acids are two of the most powerful methods in modern molecular biology. The libraries are screened using the principles of evolutionary selection, albeit in real time, to enrich for members with a particular phenotype. This selective process necessarily results in the loss of information about less-fit molecules. On the other hand, sequencing of the library, by itself, gives information that is mostly unrelated to phenotype. If the two methods could be combined, the full potential of very large molecular libraries could be realized. Here we report the implementation of a phenotype-information-phenotype cycle that integrates information and gene recovery. After selection for phage-encoded antibodies that bind to targets expressed on the surface of Escherichia coli, the information content of the selected pool is obtained by pyrosequencing. Sequences that encode specific antibodies are identified by a bioinformatic analysis and recovered by a stringent affinity method that is uniquely suited for gene isolation from a highly degenerate collection of nucleic acids. This approach can be generalized for selection of antibodies against targets that are present as minor components of complex systems. PMID- 21825150 TI - Transformations, transport, and potential unintended consequences of high sulfur inputs to Napa Valley vineyards. AB - Unintended anthropogenic deposition of sulfur (S) to forest ecosystems has a range of negative consequences, identified through decades of research. There has been far less study of purposeful S use in agricultural systems around the world, including the application of elemental sulfur (S(0)) as a quick-reacting fungicide to prevent damage to crops. Here we report results from a three-year study of the transformations and flows of applied S(0) in soils, vegetation, and hydrologic export pathways of Napa Valley, CA vineyards, documenting that all applied S is lost from the vineyard ecosystem on an annual basis. We found that S(0) oxidizes rapidly to sulfate ( ) on the soil surface where it then accumulates over the course of the growing season. Leaf and grape tissues accounted for only 7-13% of applied S whereas dormant season cover crops accounted for 4-10% of applications. Soil S inventories were largely and ester bonded sulfates; they decreased from 1,623 +/- 354 kg ha(-1) during the dry growing season to 981 +/- 526 kg ha(-1) (0-0.5 m) during the dormant wet season. Nearly all S applied to the vineyard soils is transported offsite in dissolved oxidized forms during dormant season rainstorms. Thus, the residence time of reactive S is brief in these systems, and largely driven by hydrology. Our results provide new insight into how S use in vineyards constitutes a substantial perturbation of the S cycle in Northern California winegrowing regions and points to the unintended consequences that agricultural S use may have at larger scales. PMID- 21825152 TI - Dichroic coherent diffractive imaging. AB - Understanding electronic structure at the nanoscale is crucial to untangling fundamental physics puzzles such as phase separation and emergent behavior in complex magnetic oxides. Probes with the ability to see beyond surfaces on nanometer length and subpicosecond time scales can greatly enhance our understanding of these systems and will undoubtedly impact development of future information technologies. Polarized X-rays are an appealing choice of probe due to their penetrating power, elemental and magnetic specificity, and high spatial resolution. The resolution of traditional X-ray microscopes is limited by the nanometer precision required to fabricate X-ray optics. Here we present a novel approach to lensless imaging of an extended magnetic nanostructure, in which a scanned series of dichroic coherent diffraction patterns is recorded and numerically inverted to map its magnetic domain configuration. Unlike holographic methods, it does not require a reference wave or precision optics. In addition, it enables the imaging of samples with arbitrarily large spatial dimensions, at a spatial resolution limited solely by the coherent X-ray flux, wavelength, and stability of the sample with respect to the beam. It can readily be extended to nonmagnetic systems that exhibit circular or linear dichroism. We demonstrate this approach by imaging ferrimagnetic labyrinthine domains in a Gd/Fe multilayer with perpendicular anisotropy and follow the evolution of the domain structure through part of its magnetization hysteresis loop. This approach is scalable to imaging with diffraction-limited resolution, a prospect rapidly becoming a reality in view of the new generation of phenomenally brilliant X-ray sources. PMID- 21825151 TI - Iduna is a poly(ADP-ribose) (PAR)-dependent E3 ubiquitin ligase that regulates DNA damage. AB - Ubiquitin mediated protein degradation is crucial for regulation of cell signaling and protein quality control. Poly(ADP-ribose) (PAR) is a cell-signaling molecule that mediates changes in protein function through binding at PAR binding sites. Here we characterize the PAR binding protein, Iduna, and show that it is a PAR-dependent ubiquitin E3 ligase. Iduna's E3 ligase activity requires PAR binding because point mutations at Y156A and R157A eliminate Iduna's PAR binding and Iduna's E3 ligase activity. Iduna's E3 ligase activity also requires an intact really interesting new gene (RING) domain because Iduna possessing point mutations at either H54A or C60A is devoid of ubiquitination activity. Tandem affinity purification reveals that Iduna binds to a number of proteins that are either PARsylated or bind PAR including PAR polymerase-1, 2 (PARP1, 2), nucleolin, DNA ligase III, KU70, KU86, XRCC1, and histones. PAR binding to Iduna activates its E3 ligase function, and PAR binding is required for Iduna ubiquitination of PARP1, XRCC1, DNA ligase III, and KU70. Iduna's PAR-dependent ubiquitination of PARP1 targets it for proteasomal degradation. Via PAR binding and ubiquitin E3 ligase activity, Iduna protects against cell death induced by the DNA damaging agent N-methyl-N-nitro-N-nitrosoguanidine (MNNG) and rescues cells from G1 arrest and promotes cell survival after gamma-irradiation. Moreover, Iduna facilitates DNA repair by reducing apurinic/apyrimidinic (AP) sites after MNNG exposure and facilitates DNA repair following gamma-irradiation as assessed by the comet assay. These results define Iduna as a PAR-dependent E3 ligase that regulates cell survival and DNA repair. PMID- 21825153 TI - Snapshots of the maltose transporter during ATP hydrolysis. AB - ATP-binding cassette transporters are powered by ATP, but the mechanism by which these transporters hydrolyze ATP is unclear. In this study, four crystal structures of the full-length wild-type maltose transporter, stabilized by adenosine 5'-(beta,gamma-imido)triphosphate or ADP in conjunction with phosphate analogs BeF(3)(-), VO(4)(3-), or AIF(4)(-), were determined to 2.2- to 2.4-A resolution. These structures led to the assignment of two enzymatic states during ATP hydrolysis and demonstrate specific functional roles of highly conserved residues in the nucleotide-binding domain, suggesting that ATP-binding cassette transporters catalyze ATP hydrolysis via a general base mechanism. PMID- 21825154 TI - Dedicated ent-kaurene and ent-atiserene synthases for platensimycin and platencin biosynthesis. AB - Platensimycin (PTM) and platencin (PTN) are potent and selective inhibitors of bacterial and mammalian fatty acid synthases and have emerged as promising drug leads for both antibacterial and antidiabetic therapies. Comparative analysis of the PTM and PTN biosynthetic machineries in Streptomyces platensis MA7327 and MA7339 revealed that the divergence of PTM and PTN biosynthesis is controlled by dedicated ent-kaurene and ent-atiserene synthases, the latter of which represents a new pathway for diterpenoid biosynthesis. The PTM and PTN biosynthetic machineries provide a rare glimpse at how secondary metabolic pathway evolution increases natural product structural diversity and support the wisdom of applying combinatorial biosynthesis methods for the generation of novel PTM and/or PTN analogues, thereby facilitating drug development efforts based on these privileged natural product scaffolds. PMID- 21825155 TI - Hypoxia-induced methylation of a pontin chromatin remodeling factor. AB - Pontin is a chromatin remodeling factor that possesses both ATPase and DNA helicase activities. Although Pontin is frequently overexpressed in human cancers of various types and implicated in oncogenic functions, the upstream signaling network leading to the regulation of Pontin that in turn affects transcription of downstream target genes has not been extensively studied. Here, we identify Pontin is methylated by G9a/GLP methyltransferases in hypoxic condition and potentiates HIF-1alpha-mediated activation by increasing the recruitment of p300 coactivator to a subset of HIF-1alpha target promoters. Intriguingly, Pontin methylation results in the increased invasive and migratory properties by activating downstream target gene, Ets1. In contrast, inhibition of Pontin methylation results in the suppression of tumorigenic and metastatic properties. Together, our data provide new approaches by targeting Pontin methylation and its downstream targets for the development of therapeutic agents for human cancers. PMID- 21825156 TI - Biologically induced initiation of Neoproterozoic snowball-Earth events. AB - The glaciations of the Neoproterozoic Era (1,000 to 542 MyBP) were preceded by dramatically light C isotopic excursions preserved in preglacial deposits. Standard explanations of these excursions involve remineralization of isotopically light organic matter and imply strong enhancement of atmospheric CO(2) greenhouse gas concentration, apparently inconsistent with the glaciations that followed. We examine a scenario in which the isotopic signal, as well as the global glaciation, result from enhanced export of organic matter from the upper ocean into anoxic subsurface waters and sediments. The organic matter undergoes anoxic remineralization at depth via either sulfate- or iron-reducing bacteria. In both cases, this can lead to changes in carbonate alkalinity and dissolved inorganic pool that efficiently lower the atmospheric CO(2) concentration, possibly plunging Earth into an ice age. This scenario predicts enhanced deposition of calcium carbonate, the formation of siderite, and an increase in ocean pH, all of which are consistent with recent observations. Late Neoproterozoic diversification of marine eukaryotes may have facilitated the episodic enhancement of export of organic matter from the upper ocean, by causing a greater proportion of organic matter to be partitioned as particulate aggregates that can sink more efficiently, via increased cell size, biomineralization or increased CN of eukaryotic phytoplankton. The scenario explains isotopic excursions that are correlated or uncorrelated with snowball initiation, and suggests that increasing atmospheric oxygen concentrations and a progressive oxygenation of the subsurface ocean helped to prevent snowball glaciation on the Phanerozoic Earth. PMID- 21825157 TI - Microaerobic steroid biosynthesis and the molecular fossil record of Archean life. AB - The power of molecular oxygen to drive many crucial biogeochemical processes, from cellular respiration to rock weathering, makes reconstructing the history of its production and accumulation a first-order question for understanding Earth's evolution. Among the various geochemical proxies for the presence of O(2) in the environment, molecular fossils offer a unique record of O(2) where it was first produced and consumed by biology: in sunlit aquatic habitats. As steroid biosynthesis requires molecular oxygen, fossil steranes have been used to draw inferences about aerobiosis in the early Precambrian. However, better quantitative constraints on the O(2) requirement of this biochemistry would clarify the implications of these molecular fossils for environmental conditions at the time of their production. Here we demonstrate that steroid biosynthesis is a microaerobic process, enabled by dissolved O(2) concentrations in the nanomolar range. We present evidence that microaerobic marine environments (where steroid biosynthesis was possible) could have been widespread and persistent for long periods of time prior to the earliest geologic and isotopic evidence for atmospheric O(2). In the late Archean, molecular oxygen likely cycled as a biogenic trace gas, much as compounds such as dimethylsulfide do today. PMID- 21825158 TI - High-level recombinant protein expression in transgenic plants by using a double inducible viral vector. AB - We describe here a unique ethanol-inducible process for expression of recombinant proteins in transgenic plants. The process is based on inducible release of viral RNA replicons from stably integrated DNA proreplicons. A simple treatment with ethanol releases the replicon leading to RNA amplification and high-level protein production. To achieve tight control of replicon activation and spread in the uninduced state, the viral vector has been deconstructed, and its two components, the replicon and the cell-to-cell movement protein, have each been placed separately under the control of an inducible promoter. Transgenic Nicotiana benthamiana plants incorporating this double-inducible system demonstrate negligible background expression, high (over 0.5 * 10(4)-fold) induction multiples, and high absolute levels of protein expression upon induction (up to 4.3 mg/g fresh biomass). The process can be easily scaled up, supports expression of practically important recombinant proteins, and thus can be directly used for industrial manufacturing. PMID- 21825159 TI - Common-path interference and oscillatory Zener tunneling in bilayer graphene p-n junctions. AB - Interference and tunneling are two signature quantum effects that are often perceived as the yin and yang of quantum mechanics: a particle simultaneously propagating along several distinct classical paths versus a particle penetrating through a classically inaccessible region via a single least-action path. Here we demonstrate that the Dirac quasiparticles in graphene provide a dramatic departure from this paradigm. We show that Zener tunneling in gapped bilayer graphene, which governs transport through p-n heterojunctions, exhibits common path interference that takes place under the tunnel barrier. Due to a symmetry peculiar to the gapped bilayer graphene bandstructure, interfering tunneling paths form conjugate pairs, giving rise to high-contrast oscillations in transmission as a function of the gate-tunable bandgap and other control parameters of the junction. The common-path interference is solely due to forward propagating waves; in contrast to Fabry-Perot-type interference in resonant tunneling structures, it does not rely on multiple backscattering. The oscillations manifest themselves in the junction I-V characteristic as N-shaped branches with negative differential conductivity. The negative dI/dV, which arises solely due to under-barrier interference, can enable new high-speed active circuit devices with architectures that are not available in electronic semiconductor devices. PMID- 21825160 TI - Synthesis of unnatural alkaloid scaffolds by exploiting plant polyketide synthase. AB - HsPKS1 from Huperzia serrata is a type III polyketide synthase (PKS) with remarkable substrate tolerance and catalytic potential. Here we present the synthesis of unnatural unique polyketide-alkaloid hybrid molecules by exploiting the enzyme reaction using precursor-directed and structure-based approaches. HsPKS1 produced novel pyridoisoindole (or benzopyridoisoindole) with the 6.5.6 fused (or 6.6.5.6-fused) ring system by the condensation of 2-carbamoylbenzoyl CoA (or 3-carbamoyl-2-naphthoyl-CoA), a synthetic nitrogen-containing nonphysiological starter substrate, with two molecules of malonyl-CoA. The structure-based S348G mutant not only extended the product chain length but also altered the cyclization mechanism to produce a biologically active, ring-expanded 6.7.6-fused dibenzoazepine, by the condensation of 2-carbamoylbenzoyl-CoA with three malonyl-CoAs. Thus, the basic nitrogen atom and the structure-based mutagenesis enabled additional C?C and C?N bond formation to generate the novel polyketide-alkaloid scaffold. PMID- 21825161 TI - Fast-folding alpha-helices as reversible strain absorbers in the muscle protein myomesin. AB - The highly oriented filamentous protein network of muscle constantly experiences significant mechanical load during muscle operation. The dimeric protein myomesin has been identified as an important M-band component supporting the mechanical integrity of the entire sarcomere. Recent structural studies have revealed a long alpha-helical linker between the C-terminal immunoglobulin (Ig) domains My12 and My13 of myomesin. In this paper, we have used single-molecule force spectroscopy in combination with molecular dynamics simulations to characterize the mechanics of the myomesin dimer comprising immunoglobulin domains My12-My13. We find that at forces of approximately 30 pN the alpha-helical linker reversibly elongates allowing the molecule to extend by more than the folded extension of a full domain. High-resolution measurements directly reveal the equilibrium folding/unfolding kinetics of the individual helix. We show that alpha-helix unfolding mechanically protects the molecule homodimerization from dissociation at physiologically relevant forces. As fast and reversible molecular springs the myomesin alpha-helical linkers are an essential component for the structural integrity of the M band. PMID- 21825162 TI - Evolution of functional nucleic acids in the presence of nonheritable backbone heterogeneity. AB - Multiple lines of evidence support the hypothesis that the early evolution of life was dominated by RNA, which can both transfer information from generation to generation through replication directed by base-pairing, and carry out biochemical activities by folding into functional structures. To understand how life emerged from prebiotic chemistry we must therefore explain the steps that led to the emergence of the RNA world, and in particular, the synthesis of RNA. The generation of pools of highly pure ribonucleotides on the early Earth seems unlikely, but the presence of alternative nucleotides would support the assembly of nucleic acid polymers containing nonheritable backbone heterogeneity. We suggest that homogeneous monomers might not have been necessary if populations of heterogeneous nucleic acid molecules could evolve reproducible function. For such evolution to be possible, function would have to be maintained despite the repeated scrambling of backbone chemistry from generation to generation. We have tested this possibility in a simplified model system, by using a T7 RNA polymerase variant capable of transcribing nucleic acids that contain an approximately 11 mixture of deoxy- and ribonucleotides. We readily isolated nucleotide-binding aptamers by utilizing an in vitro selection process that shuffles the order of deoxy- and ribonucleotides in each round. We describe two such RNA/DNA mosaic nucleic acid aptamers that specifically bind ATP and GTP, respectively. We conclude that nonheritable variations in nucleic acid backbone structure may not have posed an insurmountable barrier to the emergence of functionality in early nucleic acids. PMID- 21825163 TI - Do lambda-IFNs IL28A and IL28B act on human natural killer cells? PMID- 21825164 TI - The conserved GTPase Gem1 regulates endoplasmic reticulum-mitochondria connections. AB - Mitochondria are connected to the endoplasmic reticulum (ER) through specialized protein complexes. We recently identified the ER-mitochondria encounter structure (ERMES) tethering complex, which plays a role in phospholipid exchange between the two organelles. ERMES also has been implicated in the coordination of mitochondrial protein import, mitochondrial DNA replication, and mitochondrial dynamics, suggesting that these interorganelle contact sites play central regulatory roles in coordinating various aspects of the physiology of the two organelles. Here we purified ERMES complexes and identified the Ca(2+)-binding Miro GTPase Gem1 as an integral component of ERMES. Gem1 regulates the number and size of the ERMES complexes. In vivo, association of Gem1 to ERMES required the first of Gem1's two GTPase domains and the first of its two functional Ca(2+) binding domains. In contrast, Gem1's second GTPase domain was required for proper ERMES function in phospholipid exchange. Our results suggest that ERMES is not a passive conduit for interorganellar lipid exchange, but that it can be regulated in response to physiological needs. Furthermore, we provide evidence that the metazoan Gem1 ortholog Miro-1 localizes to sites of ER-mitochondrial contact, suggesting that some of the features ascribed to Gem1 may be evolutionarily conserved. PMID- 21825165 TI - Anterograde or retrograde transsynaptic labeling of CNS neurons with vesicular stomatitis virus vectors. AB - To understand how the nervous system processes information, a map of the connections among neurons would be of great benefit. Here we describe the use of vesicular stomatitis virus (VSV) for tracing neuronal connections in vivo. We made VSV vectors that used glycoprotein (G) genes from several other viruses. The G protein from lymphocytic choriomeningitis virus endowed VSV with the ability to spread transsynaptically, specifically in an anterograde direction, whereas the rabies virus glycoprotein gave a specifically retrograde transsynaptic pattern. The use of an avian G protein fusion allowed specific targeting of cells expressing an avian receptor, which allowed a demonstration of monosynaptic anterograde tracing from defined cells. Synaptic connectivity of pairs of virally labeled cells was demonstrated by using slice cultures and electrophysiology. In vivo infections of several areas in the mouse brain led to the predicted patterns of spread for anterograde or retrograde tracers. PMID- 21825166 TI - Role of egg predation by haddock in the decline of an Atlantic herring population. AB - Theoretical studies suggest that the abrupt and substantial changes in the productivity of some fisheries species may be explained by predation-driven alternate stable states in their population levels. With this hypothesis, an increase in fishing or a natural perturbation can drive a population from an upper to a lower stable-equilibrium population level. After fishing is reduced or the perturbation ended, this low population level can persist due to the regulatory effect of the predator. Although established in theoretical studies, there is limited empirical support for predation-driven alternate stable states in exploited marine fish populations. We present evidence that egg predation by haddock (Melanogrammus aeglefinus) can cause alternate stable population levels in Georges Bank Atlantic herring (Clupea harengus). Egg predation by haddock explains a substantial decoupling of herring spawning stock biomass (an index of egg production) from observed larval herring abundance (an index of egg hatching). Estimated egg survival rates ranged from <2-70% from 1971 to 2005. A population model incorporating egg predation and herring fishing explains the major population trends of Georges Bank herring over four decades and predicts that, when the haddock population is high, seemingly conservative levels of fishing can still precipitate a severe decline in the herring population. These findings illustrate how efforts to rebuild fisheries can be undermined by not incorporating ecological interactions into fisheries models and management plans. PMID- 21825167 TI - Hemagglutinin-neuraminidase balance confers respiratory-droplet transmissibility of the pandemic H1N1 influenza virus in ferrets. AB - A novel reassortant derived from North American triple-reassortant (TRsw) and Eurasian swine (EAsw) influenza viruses acquired sustained human-to-human transmissibility and caused the 2009 influenza pandemic. To identify molecular determinants that allowed efficient transmission of the pandemic H1N1 virus among humans, we evaluated the direct-contact and respiratory-droplet transmissibility in ferrets of representative swine influenza viruses of different lineages obtained through a 13-y surveillance program in southern China. Whereas all viruses studied were transmitted by direct contact with varying efficiency, respiratory-droplet transmissibility (albeit inefficient) was observed only in the TRsw-like A/swine/Hong Kong/915/04 (sw915) (H1N2) virus. The sw915 virus had acquired the M gene derived from EAsw and differed from the gene constellation of the pandemic H1N1 virus by the neuraminidase (NA) gene alone. Glycan array analysis showed that pandemic H1N1 virus A/HK/415742/09 (HK415742) and sw915 possess similar receptor-binding specificity and affinity for alpha2,6-linked sialosides. Sw915 titers in differentiated normal human bronchial epithelial cells and in ferret nasal washes were lower than those of HK415742. Introducing the NA from pandemic HK415742 into sw915 did not increase viral replication efficiency but increased respiratory-droplet transmissibility, despite a substantial amino acid difference between the two viruses. The NA of the pandemic HK415742 virus possessed significantly higher enzyme activity than that of sw915 or other swine influenza viruses. Our results suggest that a unique gene constellation and hemagglutinin-neuraminidase balance play a critical role in acquisition of efficient and sustained human-to-human transmissibility. PMID- 21825168 TI - Fungal recognition is mediated by the association of dectin-1 and galectin-3 in macrophages. AB - Dectin-1, the major beta-glucan receptor in leukocytes, triggers an effective immune response upon fungal recognition. Here we use sortase-mediated transpeptidation, a technique that allows placement of a variety of probes on a polypeptide backbone, to monitor the behavior of labeled functional dectin-1 in live cells with and without fungal challenge. Installation of probes on dectin-1 by sortagging permitted highly specific visualization of functional protein on the cell surface and its subsequent internalization upon ligand presentation. Retrieval of sortagged dectin-1 expressed in macrophages uncovered a unique interaction between dectin-1 and galectin-3 that functions in the proinflammatory response of macrophages to pathogenic fungi. When macrophages expressing dectin-1 are exposed to Candida albicans mutants with increased exposure of beta-glucan, the loss of galectin-3 dramatically accentuates the failure to trigger an appropriate TNF-alpha response. PMID- 21825169 TI - Clearance of roadblocks in replication fork restart. PMID- 21825170 TI - A fitness trade-off between local competition and dispersal in Vibrio cholerae biofilms. AB - Bacteria commonly grow in densely populated surface-bound communities, termed biofilms, where they gain benefits including superior access to nutrients and resistance to environmental insults. The secretion of extracellular polymeric substances (EPS), which bind bacterial collectives together, is ubiquitously associated with biofilm formation. It is generally assumed that EPS secretion is a cooperative phenotype that benefits all neighboring cells, but in fact little is known about the competitive and evolutionary dynamics of EPS production. By studying Vibrio cholerae biofilms in microfluidic devices, we show that EPS producing cells selectively benefit their clonemates and gain a dramatic advantage in competition against an isogenic EPS-deficient strain. However, this advantage carries an ecological cost beyond the energetic requirement for EPS production: EPS-producing cells are impaired for dispersal to new locations. Our study establishes that a fundamental tradeoff between local competition and dispersal exists among bacteria. Furthermore, this tradeoff can be governed by a single phenotype. PMID- 21825171 TI - Protease phenotype of constitutive connective tissue and of induced mucosal mast cells in mice is regulated by the tissue. AB - Mouse mast cells (MCs) express a large number of serine proteases including tryptases, mouse mast cell protease (mMCP)-6 and -7; chymases, mMCP-1, -2, and 4; and an elastase, mMCP-5; along with carboxypeptidase-A3 (CPA3). In helminth infected mouse intestine, distinct protease phenotypes are observed for connective tissue MCs (CTMCs) (mMCP-4(+)-7(+), and CPA3(+)) and mucosal MCs (MMCs) (mMCP-1(+) and 2(+)). To determine whether the protease phenotype was regulated by the tissue, we compared the phenotype of constitutive CTMCs and induced MMCs in trachea and large airways in antigen-sensitized unchallenged and challenged mice to MCs in skin and helminthic-infected intestine. We found that in the trachea, unlike in skin and intestine, CTMCs and MMCs both express all six serine proteases and CPA3 (mMCP-1(+), -2(+), 4(+)-7(+), CPA3(+)). This phenotype also holds for the lung CTMCs in the proximal bronchi, whereas the induced MMCs express only four proteases, mMCP-1, -2, -6, and -7. Thus, the T-cell-dependent induction of MMCs in trachea, large bronchi, and small intestine provides numbers but does not determine the protease phenotype. Furthermore, the CTMCs, which are constitutive, also show striking differences at these tissue sites, supporting the view that the differences in expression are tissue directed and not dependent on inflammation. PMID- 21825172 TI - Bacteria-induced natural product formation in the fungus Aspergillus nidulans requires Saga/Ada-mediated histone acetylation. AB - Sequence analyses of fungal genomes have revealed that the potential of fungi to produce secondary metabolites is greatly underestimated. In fact, most gene clusters coding for the biosynthesis of antibiotics, toxins, or pigments are silent under standard laboratory conditions. Hence, it is one of the major challenges in microbiology to uncover the mechanisms required for pathway activation. Recently, we discovered that intimate physical interaction of the important model fungus Aspergillus nidulans with the soil-dwelling bacterium Streptomyces rapamycinicus specifically activated silent fungal secondary metabolism genes, resulting in the production of the archetypal polyketide orsellinic acid and its derivatives. Here, we report that the streptomycete triggers modification of fungal histones. Deletion analysis of 36 of 40 acetyltransferases, including histone acetyltransferases (HATs) of A. nidulans, demonstrated that the Saga/Ada complex containing the HAT GcnE and the AdaB protein is required for induction of the orsellinic acid gene cluster by the bacterium. We also showed that Saga/Ada plays a major role for specific induction of other biosynthesis gene clusters, such as sterigmatocystin, terrequinone, and penicillin. Chromatin immunoprecipitation showed that the Saga/Ada-dependent increase of histone 3 acetylation at lysine 9 and 14 occurs during interaction of fungus and bacterium. Furthermore, the production of secondary metabolites in A. nidulans is accompanied by a global increase in H3K14 acetylation. Increased H3K9 acetylation, however, was only found within gene clusters. This report provides previously undescribed evidence of Saga/Ada dependent histone acetylation triggered by prokaryotes. PMID- 21825173 TI - Expansion of a unique CD57+NKG2Chi natural killer cell subset during acute human cytomegalovirus infection. AB - During human CMV infection, there is a preferential expansion of natural killer (NK) cells expressing the activating CD94-NKG2C receptor complex, implicating this receptor in the recognition of CMV-infected cells. We hypothesized that NK cells expanded in response to pathogens will be marked by expression of CD57, a carbohydrate antigen expressed on highly mature cells within the CD56(dim)CD16(+) NK cell compartment. Here we demonstrate the preferential expansion of a unique subset of NK cells coexpressing the activating CD94-NKG2C receptor and CD57 in CMV(+) donors. These CD57(+)NKG2C(hi) NK cells degranulated in response to stimulation through their NKG2C receptor. Furthermore, CD57(+)NKG2C(hi) NK cells preferentially lack expression of the inhibitory NKG2A receptor and the inhibitory KIR3DL1 receptor in individuals expressing its HLA-Bw4 ligand. Moreover, in solid-organ transplant recipients with active CMV infection, the percentage of CD57(+)NKG2C(hi) NK cells in the total NK cell population preferentially increased. During acute CMV infection, the NKG2C(+) NK cells proliferated, became NKG2C(hi), and finally acquired CD57. Thus, we propose that CD57 might provide a marker of "memory" NK cells that have been expanded in response to infection. PMID- 21825175 TI - Spontaneous prosocial choice by chimpanzees. AB - The study of human and primate altruism faces an evolutionary anomaly: There is ample evidence for altruistic preferences in our own species and growing evidence in monkeys, but one of our closest relatives, the chimpanzee (Pan troglodytes), is viewed as a reluctant altruist, acting only in response to pressure and solicitation. Although chimpanzee prosocial behavior has been reported both in observational captive studies and in the wild, thus far Prosocial Choice Tests have failed to produce evidence. However, methodologies of previous Prosocial Choice Tests may have handicapped the apes unintentionally. Here we present findings of a paradigm in which chimpanzees chose between two differently colored tokens: one "selfish" token resulting in a reward for the actor only (1/0), and the other "prosocial" token rewarding both the actor and a partner (1/1). Seven female chimpanzees, each tested with three different partners, showed a significant bias for the prosocial option. Prosocial choices occurred both in response to solicitation by the partner and spontaneously without solicitation. However, directed requests and pressure by the partner reduced the actor's prosocial tendency. These results draw into question previous conclusions indicating that chimpanzees have a limited sensitivity to the needs of others and behave prosocially only in response to significant prompting. PMID- 21825176 TI - Informed consent and relational conceptions of autonomy. AB - The received view in medical contexts is that informed consent is both necessary and sufficient for patient autonomy. This paper argues that informed consent is not sufficient for patient autonomy, at least when autonomy is understood as a "relational" concept. Relational conceptions of autonomy, which have become prominent in the contemporary literature, draw on themes in the thought of Charles Taylor. I first identify four themes in Taylor's work that together constitute a picture of human agency corresponding to the notion of agency implicit in relational accounts of autonomy. Drawing on these themes, I sketch two arguments against the position that informed consent secures autonomy. The first is that informed consent is an "opportunity" concept whereas autonomy is an "exercise" concept; the second is that informed consent requires merely weak evaluation and not strong evaluation. On Taylor's analysis of agency, strong evaluation is required for agency and for autonomy. PMID- 21825174 TI - Leukocyte composition of human breast cancer. AB - Retrospective clinical studies have used immune-based biomarkers, alone or in combination, to predict survival outcomes for women with breast cancer (BC); however, the limitations inherent to immunohistochemical analyses prevent comprehensive descriptions of leukocytic infiltrates, as well as evaluation of the functional state of leukocytes in BC stroma. To more fully evaluate this complexity, and to gain insight into immune responses after chemotherapy (CTX), we prospectively evaluated tumor and nonadjacent normal breast tissue from women with BC, who either had or had not received neoadjuvant CTX before surgery. Tissues were evaluated by polychromatic flow cytometry in combination with confocal immunofluorescence and immunohistochemical analysis of tissue sections. These studies revealed that activated T lymphocytes predominate in tumor tissue, whereas myeloid lineage cells are more prominant in "normal" breast tissue. Notably, residual tumors from an unselected group of BC patients treated with neoadjuvant CTX contained increased percentages of infiltrating myeloid cells, accompanied by an increased CD8/CD4 T-cell ratio and higher numbers of granzyme B expressing cells, compared with tumors removed from patients treated primarily by surgery alone. These data provide an initial evaluation of differences in the immune microenvironment of BC compared with nonadjacent normal tissue and reveal the degree to which CTX may alter the complexity and presence of selective subsets of immune cells in tumors previously treated in the neoadjuvant setting. PMID- 21825177 TI - Influence of visual field testing frequency on detection of glaucoma progression with trend analyses. AB - OBJECTIVE: To explore whether increased frequency of visual field testing leads to earlier detection of glaucoma progression with trend analyses. METHODS: The visual fields of 468 eyes (381 patients) from the Advanced Glaucoma Intervention Study with 10 or more reliable visual field tests and 3 or more years of follow up were studied. Starting at year 1, every other visual field examination was deleted to create a low-frequency data set, and the original group was kept as the high-frequency data set. The proportion of progressing eyes and the time to progression were compared between the 2 data sets with global and pointwise linear regression criteria. RESULTS: The median number of visual field examinations was 20 and 12 for the high- and low-frequency data sets, respectively. Based on primary mean deviation criteria, 204 eyes (43.6%) in the high-frequency data set and 160 eyes (34.2%) in the low-frequency data set progressed (P < .001), whereas 185 eyes (39.5%) in the high-frequency data set and 167 eyes (35.7%) in the low-frequency data set progressed according to pointwise linear regression (P = .02). The high-frequency data set was more likely to detect progression with mean deviation (hazard ratio [HR], 1.69 [95% confidence interval {CI}, 1.36-2.10]) or pointwise linear regression criteria (HR, 1.52 [95% CI, 1.21-1.90]). A similar number of improving eyes were detected with mean deviation criteria (HR, 0.95 [95% CI, 0.58-1.60]), but pointwise linear regression criteria were more likely to detect improvement in the high-frequency data set (HR, 2.27 [95% CI, 1.43-3.62]). The results did not significantly change after censoring data at 5 years. CONCLUSIONS: Increasing the frequency of visual field testing leads to earlier detection of glaucoma progression, especially with global trend analyses. This finding has significant implications for the care of patients with glaucoma. PMID- 21825178 TI - Quality of vision in patients with fuchs endothelial dystrophy and after descemet stripping endothelial keratoplasty. AB - OBJECTIVE: To evaluate the quality of vision (visual acuity and straylight) in patients with Fuchs dystrophy and the improvement in visual quality after Descemet stripping endothelial keratoplasty (DSEK). METHODS: There was an observational case series (Amsterdam group) and a prospective interventional case series (Mayo group). Corrected distance visual acuity (CDVA), straylight, and corneal thickness were measured in patients with phakic and pseudophakic eyes with Fuchs dystrophy recruited at the Academic Medical Center, Amsterdam, the Netherlands (99 eyes), and at Mayo Clinic, Rochester, Minnesota (48 eyes). The Mayo group was also examined at 1, 3, 6, and 12 months after DSEK; all these eyes were rendered pseudophakic during DSEK. RESULTS: Eyes with Fuchs dystrophy had decreased CDVA (mean [SD], 0.42 [0.26] logMAR; Snellen equivalent 20/53) and increased straylight (mean [SD], 1.54 [0.24] logarithm of the straylight parameter) compared with normal eyes. Younger patients were affected more by increased straylight than by decreased CDVA. Corrected distance visual acuity (r = 0.26; P = .003; n = 135) and straylight (r = 0.26; P = .003; n = 133) were correlated with corneal thickness. Corrected distance visual acuity and straylight improved at all postoperative examinations (P < .001), and improvement in straylight from before DSEK to 12 months after DSEK correlated with recipient age (r = -0.43; P = .01; n = 33). Improvement in straylight was more predictable than that of CDVA and was associated with preoperative straylight more than 1.33 logarithm of the straylight parameter. CONCLUSIONS: Quality of vision is severely impaired in patients with Fuchs dystrophy and improves significantly after DSEK. Straylight improves more in younger than in older eyes after DSEK. Preoperative straylight can be a useful clinical metric to predict postoperative improvement, especially in cases where preoperative visual acuity is close to 20/20. PMID- 21825179 TI - Bacterial dispersal associated with speech in the setting of intravitreous injections. AB - OBJECTIVE: To investigate the amount of bacterial dispersal associated with speech in a simulated intravitreous injection. METHODS: Fifteen volunteers were recruited. Each volunteer was positioned over an open blood agar plate and did the following: read a 5-minute script with a face mask, read a 5-minute script without a face mask, read a 5-minute script with the face turned away from the plate without a face mask, and stood in silence for 5 minutes. Each volunteer then read a 5-minute script while reclined in a standard ophthalmic examination chair with an open blood agar plate secured to the forehead to simulate bacterial dispersal associated with a talking patient. Total numbers of colony-forming bacteria per plate were counted, and the bacteria were identified. RESULTS: Significantly less bacterial growth occurred in the face mask and silence conditions compared with the no face mask condition (both P < .001). Bacterial growth was significantly greater in the reclined condition compared with the room control (P = .02). Oral streptococcal species represented 66.7% to 82.6% of bacterial colonies in the no face mask, face turned, and reclined conditions. CONCLUSIONS: During simulated intravitreous injection, wearing a face mask or remaining silent significantly decreases culture plate contamination from talking. Talking from above and talking in the reclined position were associated with a significant increase in culture plate contamination. Physicians performing intravitreous injections should be aware of these patterns of bacterial contamination, should consider either wearing a face mask or minimizing speech, and should encourage patients to minimize speech during the procedure. PMID- 21825180 TI - Risk assessment model for development of advanced age-related macular degeneration. AB - OBJECTIVE: To design a risk assessment model for development of advanced age related macular degeneration (AMD) incorporating phenotypic, demographic, environmental, and genetic risk factors. METHODS: We evaluated longitudinal data from 2846 participants in the Age-Related Eye Disease Study. At baseline, these individuals had all levels of AMD, ranging from none to unilateral advanced AMD (neovascular or geographic atrophy). Follow-up averaged 9.3 years. We performed a Cox proportional hazards analysis with demographic, environmental, phenotypic, and genetic covariates and constructed a risk assessment model for development of advanced AMD. Performance of the model was evaluated using the C statistic and the Brier score and externally validated in participants in the Complications of Age-Related Macular Degeneration Prevention Trial. RESULTS: The final model included the following independent variables: age, smoking history, family history of AMD (first-degree member), phenotype based on a modified Age-Related Eye Disease Study simple scale score, and genetic variants CFH Y402H and ARMS2 A69S. The model did well on performance measures, with very good discrimination (C statistic = 0.872) and excellent calibration and overall performance (Brier score at 5 years = 0.08). Successful external validation was performed, and a risk assessment tool was designed for use with or without the genetic component. CONCLUSIONS: We constructed a risk assessment model for development of advanced AMD. The model performed well on measures of discrimination, calibration, and overall performance and was successfully externally validated. This risk assessment tool is available for online use. PMID- 21825181 TI - Alterations of tear neuromediators in dry eye disease. AB - OBJECTIVES: To evaluate tear levels of neuromediators in patients with dry eye disease and to identify statistical correlations with the clinical findings. METHODS: Nineteen patients with dry eye disease (Sjogren syndrome, n = 5 patients; non-Sjogren syndrome, n = 10; and ocular cicatricial pemphigoid, n = 4) and 12 healthy volunteers were enrolled. The eyes of all participants were evaluated by slitlamp examination, Schirmer testing, fluorescein staining, and tear film break-up time. Grading of dry eye severity was recorded. Tear samples were collected, and substance P, calcitonin gene-related peptide (CGRP), neuropeptide Y (NPY), vasoactive intestinal peptide, and nerve growth factor (NGF) concentrations were evaluated by enzyme-linked immunoassay and correlated with the clinical findings. RESULTS: Nerve growth factor tear levels were significantly increased in participants with dry eye disease; CGRP and NPY concentrations were significantly decreased when compared with those in healthy participants. Dry eye severity showed a direct correlation with NGF and an inverse correlation with CGRP and NPY tear levels. Nerve growth factor tear levels showed a direct correlation with conjunctival hyperemia and fluorescein staining results, CGRP directly correlated with Schirmer test values, and NPY inversely correlated with tear film break-up time. Subgroup analysis showed that CGRP and NPY but not NGF were changed in autoimmune (ie, Sjogren syndrome and ocular cicatricial pemphigoid) dry eye disease. CONCLUSIONS: The decreased tear levels of NPY and CGRP in dry eye disease are related to impaired lacrimal function, and tear levels of NGF are more closely related to corneal epithelial damage. Our findings suggest that NPY, CGRP, and NGF could become useful markers of dry eye severity. PMID- 21825182 TI - Supra-tenon capsule placement of original Molteno vs Molteno 3 tube implants in black patients with refractory glaucoma: a single-surgeon experience. AB - OBJECTIVE: To evaluate the efficacy of supra-Tenon capsule placement of original Molteno vs Molteno 3 tube implants (Molteno Ophthalmic, Dunedin, New Zealand) in black patients with refractory glaucoma. METHODS: A retrospective study comparing the efficacy of supra-Tenon capsule placement of the original Molteno tube implant (130-mm(2) plate size) with the newer Molteno 3 tube implant (175-mm(2) plate size). Original Molteno tube implants were placed into 17 eyes and Molteno 3 tube implants into 27 eyes. RESULTS: Success was defined as an intraocular pressure of 18 mm Hg or less with or without adjuvant medical therapy. The median follow-up periods were 24 months (range, 12-48 months) for the original Molteno implanted group (hereafter referred to as the original Molteno group) and 18 months (range, 12-48 months) for the Molteno 3-implanted group (hereafter referred to as the Molteno 3 group). The median preoperative intraocular pressures were 30 mm Hg for the original Molteno group and 24 mm Hg for the Molteno 3 group. The median postoperative intraocular pressures were 13 mm Hg for the original Molteno group and 14 mm Hg for the Molteno 3 group. Using Kaplan Meier analysis, survival percentages were 71% for the original Molteno group and 88% for the Molteno 3 group. Log-rank test for comparison of survival indicated no significant difference between the 2 groups (P > .25). CONCLUSIONS: Supra Tenon capsule placement of single-plate Molteno tube implants of different sizes can adequately control intraocular pressure in a group of patients with refractory glaucoma. Tenon capsule elimination seems to negate the effect of plate size. PMID- 21825183 TI - Outcome of toric intraocular lens implantation after adjusting for anterior chamber depth and intraocular lens sphere equivalent power effects. AB - OBJECTIVE: To describe the refractive outcome of toric intraocular lens (IOL) implantation by taking into account the effect on astigmatic outcome of the anterior chamber depth and the sphere power of the IOL, and to examine whether the predictability of the toric effect can be improved. METHOD: In a university department in a publicly funded hospital, 38 eyes of 29 patients underwent routine cataract surgery with insertion of a toric implant (SN60TT AcrySof Toric). The corneal plane effective cylinder power of the IOL was calculated, including the effect on this value of the anterior chamber depth and pachymetry and of the sphere power of the IOL. RESULTS: The mean (SD) corneal plane equivalent cylinder power of the IOL predicted preoperatively by the manufacturer as 1.58 (0.47) diopters (D) vs 2.02 (0.64) D by us (calculated using predicted postoperative anterior chamber depth and IOL sphere values). The mean (SD) measured postoperative value was 1.78 (0.89) D, which was better predicted by us. CONCLUSIONS: The manufacturer currently appears to underestimate the corneal plane effective cylinder power of its toric IOLs. Improved outcome could be achieved by estimating the effective corneal plane cylinder power of the IOL, as altered by the anterior chamber depth and pachymetry and by the IOL sphere power, but this is currently not addressed by the manufacturer. PMID- 21825184 TI - Toric intraocular lens outcome using the manufacturer's prediction of corneal plane equivalent intraocular lens cylinder power. AB - OBJECTIVES: To describe the refractive outcome of toric intraocular lens (IOL) implantation by comparing the postoperative refractive astigmatism with the preoperative keratometric astigmatism target. METHOD: In a university department of a publicly funded hospital, 38 eyes of 29 patients underwent routine cataract surgery with insertion of a toric implant (SN60TT AcrySof Toric). Surgically induced astigmatism was derived using vector analysis of refractive outcome vs predicted postoperative keratometric astigmatism and compared with the targeted induced astigmatism. RESULTS: Postoperative remaining refractive astigmatism of 0.97 diopters (D) was achieved vs a target of 0.61 D. A mean (SD) surgically induced astigmatism value of 1.78 (0.89) D was derived compared with a mean (SD) targeted induced astigmatism value of 1.58 (0.47) D (calculated by the manufacturer's online calculator, which predicts IOL corneal plane equivalent cylinder power and postoperative keratometric cylinder). CONCLUSIONS: Toric IOLs are a safe, predictable method of astigmatic correction. However, some remaining astigmatism is commonly present owing to the necessary nonzero astigmatic targets imposed by the steps between IOL cylinder powers, variability of axis, and power effects of surgical incisions as well as by underestimation of the corneal plane cylinder power of the IOLs by the manufacturer. PMID- 21825185 TI - Vision loss and recovery after trabeculectomy: risk and associated risk factors. AB - OBJECTIVES: To assess the risk of long-term vision loss after trabeculectomy and to determine the course of long-term vision loss vs transient loss and recovery. METHODS: The medical records of 301 eyes in 262 patients undergoing trabeculectomy between January 1999 and September 2003 were retrospectively reviewed. Postoperative vision loss was categorized as mild or moderate (decrease in Snellen visual acuity of 3-5 lines) vs severe (decrease of >5 lines). Postoperative vision loss was considered permanent if visual acuity did not have a return of 3 lines within a 6-month follow-up period. RESULTS: Permanent vision loss occurred in 24 of 301 eyes (8.0%): 13 (4.3%) had mild or moderate vision loss, and 11 (3.7%) had severe vision loss. Ten eyes (3.3%) with permanent mild or moderate vision loss and 6 eyes (2.0%) with permanent severe vision loss had no identifiable cause. Significant risk factors for permanent severe unexplained vision loss were preoperative split fixation on visual fields, preoperative number of quadrants with split fixation, and postoperative choroidal effusions with eventual resolution. Transient vision loss occurred in 170 of 301 eyes (56.5%): 79 (26.2%) had mild or moderate vision loss, with a mean time to recovery of 88 days (range, 6-720 days), and 91 (30.2%) had severe vision loss, with a mean time to recovery of 78 days (range, 6-720 days). CONCLUSIONS: Transient vision loss after trabeculectomy is common and may take up to 2 years for recovery. The risk of permanent vision loss is less common but significant. Two percent of our study population experienced permanent severe unexplained vision loss ("snuff-out"), and risk factors included preoperative split fixation on visual fields, preoperative number of quadrants with split fixation, and postoperative choroidal effusions with eventual resolution. PMID- 21825186 TI - Increased levator muscle function by supramaximal resection in patients with blepharophimosis-ptosis-epicanthus inversus syndrome. AB - OBJECTIVE: To study the efficacy and clinical and anatomical results of supramaximal levator resection in patients with blepharophimosis-ptosis epicanthus inversus syndrome (BPES) with severe congenital ptosis with poor levator function (LF). METHODS: Eleven patients with molecularly proven BPES underwent supramaximal levator resection. Palpebral fissure height and LF were measured preoperatively and postoperatively. RESULTS: All patients showed an excellent reduction in ptosis with a single intervention resulting in a clear visual axis. Palpebral fissure height improved from mean (SD) 3.3 (0.7) mm preoperatively to 7.1 (0.9) mm postoperatively (P value <.001). Four patients underwent additional surgery because of cosmetic issues with eyelid height asymmetry. All patients showed a marked, consistent, and lasting improvement in LF, going from mean (SD) 1.9 (0.9) mm preoperatively to 7.4 (1.1) mm postoperatively (P value <.001). This improvement could be attributed to the presence of a very long and thin tendon, as well as a striated muscle belly. This elongated aponeurosis inhibits the levator muscle from having sufficient impact on the vertical eyelid excursion. CONCLUSIONS: We demonstrated that supramaximal levator resection performed in patients with BPES not only results in good cosmetic appearance in terms of ptosis reduction in the majority of cases but also in a significant increase of the levator palpebrae superioris function. An anatomical substrate was found to explain these findings. To our knowledge, this is the first study to provide evidence of a marked increase in LF in BPES due to resection of the elongated tendon with reinsertion of the muscle belly. PMID- 21825187 TI - Prevention of experimental choroidal neovascularization and resolution of active lesions by VEGF trap in nonhuman primates. AB - OBJECTIVE: To evaluate the efficacy of systemic and intravitreous administration of VEGF Trap (aflibercept) in a nonhuman primate model of choroidal neovascularization (CNV). METHODS: VEGF Trap treatment on laser-induced CNV was evaluated in 48 adult cynomolgus monkeys. In the prevention arms of the study, VEGF Trap was administered by intravenous injection (3 or 10 mg/kg weekly) or intravitreous injection (50, 250, or 500 MUg/eye every 2 weeks) beginning before laser injury. In the treatment arm, a single intravitreous injection (500 MUg) was given 2 weeks following laser injury. Laser-induced lesions were scored from grade 1 (no hyperfluorescence) to grade 4 (clinically relevant leakage). Representative lesions were evaluated histologically. RESULTS: Grade 4 leakage developed at 32.4% and 45.4% of the laser sites in animals receiving intravitreous or intravenous administration of placebo at 2 weeks following laser injury, respectively. In contrast, the development of grade 4 lesions was completely or nearly completely prevented in all groups receiving intravenous or intravitreous injections of VEGF Trap. A single intravitreous injection of VEGF Trap (500 MUg) administered following the development of CNV reduced the frequency of grade 4 lesions from 44.4% to 0% within 14 days of treatment. Intravitreous VEGF Trap was well tolerated with either no or only mild ocular inflammation. Histological evaluation showed decreased scores for morphologic features of tissue proliferation in the VEGF Trap prevention groups. CONCLUSIONS: VEGF Trap prevented the development of clinically relevant CNV leakage when administered at the lowest doses tested. Moreover, a single intravitreous injection induced inhibition of active CNV leakage. CLINICAL RELEVANCE: The animal model used in this study has an established track record as a predictor of pharmacologic efficacy of antineovascular drugs in humans having the neovascular, or wet, form of age-related macular degeneration. PMID- 21825188 TI - Geographic and climatic factors associated with exfoliation syndrome. AB - OBJECTIVE: To identify geographic and climatic risk factors associated with exfoliation syndrome (ES). METHODS: A retrospective study of 626 901 eye care recipients, dating from 2001 to 2007 from 47 US states in a managed care network. Incident ES cases-patients (N = 3367) were identified by using billing codes. We assessed the risk of ES by geographic latitude tier in the continental United States and assigned state-level climatic data (eg, ambient temperature, elevation, and sun exposure) according to patients' residential location. The hazard of ES was calculated by using multivariable-adjusted Cox proportional hazards regression models. RESULTS: Compared with middle-tier residence, northern tier residence (above 42 degrees N) was associated with an increased hazard of ES (adjusted hazard ratio [HR], 2.14; 95% confidence interval [CI], 1.94-2.35). Southern-tier (below 37 degrees N) was associated with a reduced hazard of ES (HR, 0.83; 95% CI, 0.75-0.93). Excluding whites did not change these associations. After adjustment for joint environmental effects, for every 1 degrees increase in July high temperature, the hazard of ES decreased by 9% (HR, 0.91; 95% CI, 0.89-0.93); for every 1 degrees increase in January low temperature, the hazard decreased 3% (0.97; 0.96-0.98). For each additional sunny day annually, the hazard increased by 1.5% (HR, 1.02; 95% CI, 1.01-1.02) in locations with average levels of other climatic factors. CONCLUSION: Ambient temperature and sun exposure may be important environmental triggers of ES. PMID- 21825190 TI - The landers trunkless temporary keratoprosthesis. AB - OBJECTIVE: To demonstrate the watertight seal created by the new wide-angle Landers trunkless temporary keratoprosthesis (T-TKP). METHODS: In 20 enucleated, porcine eyes, a 7.5-mm trephination was made, followed by capsulorrhexis and lensectomy. The T-TKP was sutured securely onto each eye. Testing the watertight seal at an intraocular pressure of 100 mm Hg was performed before and after pars plana vitrectomy. RESULTS: In all 20 eyes, the T-TKP maintained its watertight seal at an intraocular pressure of 100 mm Hg before and after vitrectomy. CONCLUSION: The Landers T-TKP is a reusable device that provides a clear view and watertight eye in the presence of corneal trephinations up to 7.5 mm in diameter. Because of its unique trunkless design, as demonstrated in the laboratory, the T TKP should allow the surgeon greater flexibility than previous models in cases of ocular trauma. PMID- 21825189 TI - Complement factor H 402H variant and reticular macular disease. AB - OBJECTIVE: To determine the association of high-risk alleles in the complement factor H (CFH; Y402H, rs1061170) and age-related maculopathy susceptibility (ARMS2; A69S, rs10490924) genes with reticular macular disease (RMD), a major clinical subphenotype of age-related macular degeneration (AMD). METHODS: Using retinal images from the Columbia Macular Genetics Study, we identified 67 subject individuals with RMD. A comparison group of 64 subjects with AMD without RMD was matched by ethnicity, age, sex, and AMD clinical stage. RESULTS: In the RMD group, 53 of 67 subjects (79.1%) were female, the mean age was 83 years, and 47 of 67 (70.1%) had late AMD, with closely matched values in the non-RMD group. The frequencies of the CFH 402H allele were 39.6% in the RMD group (53 of 134 individuals) and 58.6% in the non-RMD group (75 of 128 individuals) (chi(2) = 8.8; P = .003; odds ratio, 0.46 [95% confidence interval, 0.28-0.76]). The corresponding frequencies of the risk allele for ARMS2 were 44.0% (40 of 128 individuals) and 31.3% (40 of 128 individuals), respectively (chi(2) = 4.0; P = .045; odds ratio, 1.73 [95% confidence interval, 1.04-2.90]). Homozygosity for 402H was particularly associated with the absence of RMD, occurring in 8 of 67 subjects (11.9%) with RMD vs 24 of 64 subjects (37.5%) without RMD (P < .001). Retinal macular disease also was associated with hypertension among male patients. CONCLUSIONS: The AMD-associated CFH 402H risk variant is significantly associated with the absence of RMD but enhanced risk for RMD is conferred by the ARMS2 69S AMD risk allele. These results are consistent with the hypothesis that 402H may confer a survival benefit against certain infections, some of which may cause RMD. CLINICAL RELEVANCE: Reticular macular disease may be genetically distinct from the rest of AMD. PMID- 21825191 TI - Transconjunctival plain gut "tape" for 23-gauge sclerotomy closure. AB - Small-incision "sutureless" vitrectomy has become increasingly popular, but wound leaks still occur in some cases. This can lead to postoperative hypotony and may increase the risk of endophthalmitis. I have developed a new wound closure method using transconjunctival 6-0 plain gut suture fashioned as a "tape." Since the suture ends remain under the conjunctiva, the risk of both wicking and foreign body sensation is minimized. The patients treated with 6-0 plain gut "tape" are more comfortable than those managed with transconjunctival polyglactin 910 sutures and have low rates of hypotony. The plain gut sutures are well tolerated, showing little postoperative inflammatory reaction. This is a low-cost, effective, and simple method for wound closure when needed in small-incision vitrectomy. PMID- 21825192 TI - Subtotal excision with adjunctive sclerosing therapy for the treatment of severe symptomatic orbital lymphangiomas. AB - Orbital lymphangiomas are congenital malformations with abnormal and dead-end lymphatic channels and present management challenges to ophthalmologists and orbital surgeons. Recurrent hemorrhage and expansion can lead to vision loss and disfigurement. We report our technique that uses adjunctive intraoperative injection of sodium morrhuate, 5%, under direct visualization into lymphangioma channels prior to excision. We believe that in the hands of experienced orbital surgeons, and with appropriate preoperative evaluation and careful surgical technique, this procedure is useful in saving vision and avoiding complications from orbital lymphangiomas. PMID- 21825194 TI - Anti-vascular endothelial growth factor therapy and renal thrombotic microangiopathy. PMID- 21825193 TI - What experimental embryology can teach us about the development of the extraocular muscles in anophthalmia: at the interface of basic and clinical sciences. PMID- 21825195 TI - Retinopathy of prematurity: do we still have a problem?: the Charles L. Schepens lecture. AB - OBJECTIVE: To assess the present-day prevalence of retinopathy of prematurity (ROP) worldwide. METHODS: A search of the literature was conducted to better define the worldwide experience with ROP. An interview was also conducted with 2 schools for the blind, Overbrook in Philadelphia, Pennsylvania, and Perkins in Watertown, Massachusetts. The study also is based on personal experience with ROP over the last 49 years. RESULTS: Worldwide, the prevalence of ROP is on the rise in developing countries, and some of those ROP-affected premature infants are heavier than 1500 g. In western countries, extremely low-birth-weight infants (<=1000 g) are also surviving. Currently, the Overbrook School for the Blind has 11 of 55 children between the ages of 3 and 5 years with ROP (20%). The Perkins School has 34 of 200 children from birth to age 3 years with ROP (17%). During 2009, 47 babies had laser treatment for ROP in the neonatal intensive care unit of Jefferson Medical College by physicians from Wills Eye Hospital. Twenty-four infants had been identified in a screening of 591 patients (4.1%). The other 23 had been referred in for treatment. In 2009, we had 187 outpatient visits related to ROP ranging from 6 months to 67 years of age. CONCLUSIONS: Because more and more extreme low-birth-weight infants are surviving in western countries and because of the rising numbers of surviving premature infants in emerging nations, we may be on the verge of an ROP epidemic. PMID- 21825196 TI - Cerebrotendinous xanthomatosis: a treatable disease with juvenile cataracts as a presenting sign. PMID- 21825197 TI - Childhood-onset autosomal recessive bestrophinopathy. PMID- 21825198 TI - Vitamin A deficiency in schoolchildren in urban central India: the central India children eye study. PMID- 21825199 TI - Peripapillary choroidal thickening and cavitation. PMID- 21825200 TI - Frequency of intraocular pressure increase within days after intravitreal triamcinolone injections in the diabetic retinopathy clinical research network. PMID- 21825201 TI - Selective abnormality of cone outer segment tip line in acute zonal occult outer retinopathy as observed by spectral-domain optical coherence tomography. PMID- 21825202 TI - Adult ovarian retinoblastoma genomic profile distinct from prior childhood eye tumor. PMID- 21825203 TI - Acute exudative polymorphous paraneoplastic vitelliform maculopathy in a patient with carcinoma, not melanoma. PMID- 21825204 TI - Early diabetes mellitus or hypertension is not significantly associated with severity of vision loss in nonarteritic anterior ischemic optic neuropathy. PMID- 21825205 TI - Acupuncture and the placebo effect. PMID- 21825206 TI - Pediatric horner syndrome. PMID- 21825208 TI - Rethinking surface tension and buoyancy. PMID- 21825210 TI - Pneumatic retinopexy. PMID- 21825213 TI - Ten-year outcome of subthalamic stimulation in Parkinson disease: a blinded evaluation. AB - OBJECTIVE: To assess the 10-year motor outcome of deep brain stimulation of the subthalamic nucleus (STN-DBS) in patients with Parkinson disease (PD). DESIGN: Patients with PD with bilateral STN-DBS were assessed according to the Core Assessment Program for Surgical Interventional Therapies in Parkinson's Disease protocol and videotaped at baseline and 1, 5, and 10 years after surgery. An independent rater blinded to stimulation and medication condition scored the 10 year video assessments. SETTING: Movement Disorders Centre, Toronto Western Hospital, University Health Network, University of Toronto. PATIENTS: Eighteen patients with advanced PD and 10-year follow-up of STN-DBS. INTERVENTION: Bilateral STN-DBS surgery. MAIN OUTCOME MEASURES: The primary outcome was the change in blinded Unified Parkinson's Disease Rating Scale (UPDRS) motor scores/subscores between the no medication/stimulation condition vs the no medication/no stimulation condition at 10 years. Secondary outcomes were the changes in blinded UPDRS motor scores between the medication/no stimulation and medication/stimulation conditions, UPDRS II scores, UPDRS IV dyskinesia and motor fluctuations scores, and anti-PD medication dose (levodopa equivalent daily dose) at different points. RESULTS: In the 18 patients available for follow-up at 10 years, STN-DBS still significantly improved the UPDRS total motor score (P = .007) and resting and action tremor (P < .01 and P = .02, respectively) and bradykinesia (P = .01) subscores. The UPDRS II scores in the medication and no medication conditions, UPDRS IV dyskinesia and motor fluctuations scores, and the levodopa equivalent daily dose were also significantly reduced compared with baseline. Axial signs showed the most progressive decline in stimulation and levodopa response over the years. CONCLUSION: This class III study provides evidence that stimulation-induced motor improvement was sustained overall at 10 years, although part of the initial benefit wore off mainly because of progressive loss of benefit on axial signs over time. PMID- 21825214 TI - Myasthenia gravis-associated neuromyelitis optica-like disease: an immunological link between the central nervous system and muscle? AB - BACKGROUND: Although overt involvement of the central nervous system (CNS) in myasthenia gravis (MG) is considered rare, hyperreflexia is a common and yet unexplained finding. Aquaporin 4 (AQP4), the target autoantigen in neuromyelitis optica, is expressed both in the CNS and in the neuromuscular junction. OBJECTIVES: To evaluate the prevalence of even mild CNS involvement in patients with MG and to identify features indicative of neuromyelitis optica-like disease. DESIGN: Cohort study. SETTING: Outpatient clinic. PATIENTS: A cohort of 164 patients with MG. METHODS: In 24 patients with MG, signs of CNS involvement were detected; 15 of these patients had at least 1 additional paraclinical indication of neuromyelitis optica-like disease (presence of antibodies against AQP4, pathological visual evoked potentials, or white matter lesions detected on brain and/or spinal magnetic resonance imaging scans) and fulfilled the inclusion and exclusion criteria for our study. RESULTS: Of the 15 patients who had at least 1 additional paraclinical indication of neuromyelitis optica-like disease, 14 had abnormal visual evoked potentials, and in 6 of 9 patients in whom magnetic resonance imaging was performed, there was evidence of lesions in the white matter of the brain and/or spinal cord. Anti-AQP4 antibodies were detected in 7 patients (out of the 14 tested). Thymic enlargement (hyperplasia or thymoma) was more frequent in patients with MG who had signs of CNS involvement than in patients with MG who did not. CONCLUSIONS: The incidence of CNS involvement in MG is higher than previously reported and is expressed predominantly as a pyramidal syndrome accompanied by optical tract involvement (frequently subclinical). These features bear some resemblance to neuromyelitis optica spectrum disease, supported also by the presence of anti-AQP4 antibodies in 7 of the 14 patients tested. This association may represent a new nosological entity or may indicate that an autoimmune process targeting AQP4 is an integral part of the immunopathogenetic mechanisms in MG. PMID- 21825216 TI - Neurological injury in adults treated with extracorporeal membrane oxygenation. AB - BACKGROUND: Extracorporeal membrane oxygenation (ECMO) may be urgently used as a last resort form of life support when all other treatment options for potentially reversible cardiopulmonary injury have failed. OBJECTIVE: To examine the range and frequency of neurological injury in ECMO-treated adults. DESIGN: Retrospective clinicopathological cohort study. SETTING: Mayo Clinic, Rochester, Minnesota. PATIENTS: A prospectively collected registry of all patients 15 years or older treated with ECMO for 12 or more hours from January 2002 to April 2010. INTERVENTION: Patients were analyzed for potential risk factors for neurological events and death using logistic regression and Cox proportional hazards models. MAIN OUTCOME MEASURES: Neurological diagnosis and/or death. RESULTS: A total of 87 adults were treated (35 female [40%]; median age, 54 years [interquartile range, 31]; mean duration of ECMO, 91 hours [interquartile range, 100]; overall survival >7 days after ECMO, 52%). Neurological events occurred in 42 patients who received ECMO (50%; 95% confidence interval [CI], 39%-61%). Diagnoses included subarachnoid hemorrhage, ischemic watershed infarctions, hypoxic ischemic encephalopathy, unexplained coma, and brain death. Death in patients who received ECMO who did not require antecedent cardiopulmonary resuscitation was associated with increased age (odds ratio, 1.24 per decade; 95% CI, 1.03-1.50; P = .02) and lower minimum arterial oxygen pressure (odds ratio, 0.79; 95% CI, 0.68 0.92; P = .03). Although stroke was rarely diagnosed clinically, 9 of 10 brains studied at autopsy demonstrated hypoxic-ischemic and hemorrhagic lesions of vascular origin. CONCLUSION: Severe neurological sequelae occur frequently in adult ECMO-treated patients with otherwise reversible cardiopulmonary injury (conservative estimate, 50%) and include a range of potentially fatal neurological diagnoses that may be due to the precipitating event and/or ECMO treatment. PMID- 21825215 TI - Evidence for ordering of Alzheimer disease biomarkers. AB - OBJECTIVE: To empirically assess the concept that Alzheimer disease (AD) biomarkers significantly depart from normality in a temporally ordered manner. DESIGN: Validation sample. SETTING: Multisite, referral centers. PARTICIPANTS: A total of 401 elderly participants in the Alzheimer's Disease Neuroimaging Initiative who were cognitively normal, who had mild cognitive impairment, or who had AD dementia. We compared the proportions of 3 AD biomarker values (the Abeta42 level in cerebrospinal fluid [CSF], the total tau level in CSF, and the hippocampal volume adjusted for intracranial volume [hereafter referred to as the adjusted hippocampal volume]) that were abnormal as cognitive impairment worsened. Cut points demarcating normal vs abnormal for each biomarker were established by maximizing diagnostic accuracy in independent autopsy samples. MAIN OUTCOME MEASURES: Three AD biomarkers (ie, the CSF Abeta42 level, the CSF total tau level, and the adjusted hippocampal volume). RESULTS: Within each clinical group of the entire sample (n = 401), the CSF Abeta42 level was abnormal more often than was the CSF total tau level or the adjusted hippocampal volume. Among the 298 participants with both baseline and 12-month data, the proportion of participants with an abnormal Abeta42 level did not change from baseline to 12 months in any group. The proportion of participants with an abnormal total tau level increased from baseline to 12 months in cognitively normal participants (P = .05) but not in participants with mild cognitive impairment or AD dementia. For 209 participants with an abnormal CSF Abeta42 level at baseline, the percentage with an abnormal adjusted hippocampal volume but normal CSF total tau level increased from baseline to 12 months in participants with mild cognitive impairment. No change in the percentage of MCI participants with an abnormal total tau level was seen between baseline and 12 months. CONCLUSIONS: A reduction in the CSF Abeta42 level denotes a pathophysiological process that significantly departs from normality (ie, becomes dynamic) early, whereas the CSF total tau level and the adjusted hippocampal volume are biomarkers of downstream pathophysiological processes. The CSF total tau level becomes dynamic before the adjusted hippocampal volume, but the hippocampal volume is more dynamic in the clinically symptomatic mild cognitive impairment and AD dementia phases of the disease than is the CSF total tau level. PMID- 21825217 TI - No cerebral or cervical venous insufficiency in US veterans with multiple sclerosis. AB - OBJECTIVE: To determine if chronic cerebral venous insufficiency exists in patients with multiple sclerosis (MS) using ultrasonography and 4-dimensional color Doppler ultrasonography examination and unverified criteria proposed by Zamboni et al. DESIGN: Patients with MS and clinically isolated syndrome were matched by age and sex with subjects with migraine or no neurological disease. All subjects underwent gray-scale, color, and spectral Doppler ultrasonography examination of the internal jugular veins (IJVs), vertebral veins, and deep cerebral veins for stenosis, absence of signal, and reflux. SETTING: Academic MS center. PATIENTS: All patients with MS fulfilled revised McDonald criteria for the diagnosis of MS. Patients with clinically isolated syndrome exhibited a typical transient focal neurological deficit and had magnetic resonance imaging lesions typical of MS. Control subjects were recruited from the VA migraine clinic or staff. MAIN OUTCOME MEASURES: Five parameters of venous outflow used by Zamboni et al were examined: (1) IJV or vertebral vein reflux, (2) deep cerebral vein reflux, (3) IJV stenosis, (4) absence of flow in IJVs or vertebral veins, and (5) change in cross-sectional area of the IJV with postural change. RESULTS: There was no significant difference in the number and type of venous outflow abnormalities in patients with MS compared with controls. CONCLUSION: This study does not support the theory that chronic cerebral venous insufficiency exists in MS. PMID- 21825218 TI - Thrombolytic treatment of patients with acute ischemic stroke related to underlying arterial dissection in the United States. AB - OBJECTIVE: To determine the outcomes related to thrombolytic treatment of an acute ischemic stroke secondary to an arterial dissection in a large national cohort. DESIGN: Retrospective database study. SETTING: Nationwide Inpatient Sample data files from 2005 to 2008. PATIENTS: We determined the frequency of underlying arterial dissection among patients with acute ischemic stroke treated with thrombolytic treatment and associated in-hospital outcomes. MAIN OUTCOME MEASURES: All the in-hospital outcomes were analyzed after adjusting for potential confounders using multivariate analysis. RESULTS: Of the 47,899 patients with ischemic stroke who received thrombolytic treatment, 488 (1%) had an underlying dissection. The intracranial hemorrhage rates did not differ between patients with ischemic stroke with or without underlying dissection who received thrombolytic treatment (6.9% vs 6.4%). After adjusting for age, sex, hypertension, diabetes mellitus, renal failure, congestive heart failure, and hospital teaching status, presence of dissection was associated with higher rates of moderate disability (odds ratio, 2.8; 95% confidence interval, 1.7-4.6; P < .001) at discharge. The interaction terms between dissection and thrombolytic treatment among all patients with ischemic stroke for predicting in-hospital mortality (P = .84) and minimal disability (P = .13) were not statistically significant. CONCLUSIONS: The adjusted rate of favorable outcomes is lower among patients with ischemic stroke with underlying arterial dissection following thrombolytic treatment compared with those without underlying dissections. However, the observed lower rates are not influenced by thrombolytic treatment. PMID- 21825220 TI - Primary hyperparathyroidism with concurrent primary aldosteronism. PMID- 21825219 TI - AMP activated protein kinase-alpha2 regulates expression of estrogen-related receptor-alpha, a metabolic transcription factor related to heart failure development. AB - The normal expression of myocardial mitochondrial enzymes is essential to maintain the cardiac energy reserve and facilitate responses to stress, but the molecular mechanisms to maintain myocardial mitochondrial enzyme expression have been elusive. Here we report that congestive heart failure is associated with a significant decrease of myocardial estrogen-related receptor-alpha (ERRalpha), but not peroxisome proliferator-activated receptor-gamma coactivator 1alpha, in human heart failure samples. In addition, chronic pressure overload in mice caused a decrease of ERRalpha expression that was significantly correlated to the degree of left ventricular dysfunction, pulmonary congestion, and decreases of a group of myocardial energy metabolism-related genes. We found that the metabolic sensor AMP activated protein kinase (AMPK) regulates ERRalpha expression in vivo and in vitro. AMPKalpha2 knockout decreased myocardial ERRalpha (both mRNA and protein) and its downstream targets under basal conditions, with no change in myocardial peroxisome proliferator-activated receptor-gamma coactivator 1alpha expression. Using cultured rat neonatal cardiac myocytes, we found that overexpression of constitutively active AMPKalpha significantly induced ERRalpha mRNA, protein, and promoter activity. Conversely, selective gene silencing of AMPKalpha2 repressed ERRalpha and its target gene levels, indicating that AMPKalpha2 is involved in the regulation of ERRalpha expression. In addition, overexpression of ERRalpha in AMPKalpha2 knockout neonatal cardiac myocytes partially rescued the repressed expression of some energy metabolism-related genes. These data support an important role for AMPKalpha2 in regulating the expression of myocardial ERRalpha and its downstream mitochondrial enzymes. PMID- 21825221 TI - Angiotensin II Deteriorates Endothelial Progenitor Cells: Good Intentions With Bad Consequences. PMID- 21825223 TI - Evaluating the true prevalence of resistant hypertension. PMID- 21825222 TI - Hypercalcemia reduces plasma renin via parathyroid hormone, renal interstitial calcium, and the calcium-sensing receptor. AB - Acute hypercalcemia inhibits plasma renin activity (PRA). How this occurs is unknown. We hypothesized that acute hypercalcemia inhibits PRA via the calcium sensing receptor because of parathyroid hormone-mediated increases in renal cortical interstitial calcium via TRPV5. To test our hypothesis, acute in vivo protocols were run in sodium-restricted, anesthetized rats. TRPV5 messenger RNA expression was measured with real-time quantitative RT-PCR. Acute hypercalcemia significantly decreased PRA by 37% from 32.0+/-3.3 to 20.3+/-2.6 ng of angiotensin I per milliliter per hour (P<0.001). Acute hypercalcemia also significantly increased renal cortical interstitial calcium by 38% (1.73+/-0.06 mmol/L) compared with control values (1.25+/-0.05 mmol/L; P<0.001). PRA did not decrease in hypercalcemia in the presence of a calcium-sensing receptor antagonist, Ronacaleret (22.8+/-4.3 versus 21.6+/-3.6 ng of angiotensin I per milliliter per hour). Increasing plasma calcium did not decrease PRA in parathyroidectomized rats (22.5+/-2.6 versus 22.0+/-3.0 ng of angiotensin I per milliliter per hour). Parathyroidectomized rats were unable to increase their renal cortical interstitial calcium in response to hypercalcemia (1.01+/-0.11 mmol/L). Acutely replacing plasma parathyroid hormone levels did not modify the hypercalcemic inhibition of PRA in parathyroid-intact rats (39.1+/-10.9 versus 16.3+/-3.2 ng of angiotensin I per milliliter per hour; P<0.05). Renal cortical TRPV5 messenger RNA expression decreased by 67% in parathyroidectomized (P<0.001) compared with intact rats. Our data suggest that acute hypercalcemia inhibits PRA via the calcium-sensing receptor because of parathyroid hormone-mediated increases in renal cortical interstitial calcium via TRPV5. PMID- 21825224 TI - Inhibition of prolyl hydroxylase domain-containing protein downregulates vascular angiotensin II type 1 receptor. AB - Inhibition of prolyl hydroxylase domain-containing protein (PHD) by hypoxia stabilizes hypoxia-inducible factor 1 and increases the expression of target genes, such as vascular endothelial growth factor. Although the systemic renin angiotensin system is activated by hypoxia, the role of PHD in the regulation of the renin-angiotensin system remains unknown. We examined the effect of PHD inhibition on the expression of angiotensin II type 1 receptor (AT(1)R). Hypoxia, cobalt chloride, and dimethyloxalylglycine, all known to inhibit PHD, reduced AT(1)R expression in vascular smooth muscle cells. Knockdown of PHD2, a major isoform of PHDs, by RNA interference also reduced AT(1)R expression. Cobalt chloride diminished angiotensin II-induced extracellular signal-regulated kinase phosphorylation. Cobalt chloride decreased AT(1)R mRNA through transcriptional and posttranscriptional mechanisms. Oral administration of cobalt chloride (14 mg/kg per day) to C57BL/6J mice receiving angiotensin II infusion (490 ng/kg per minute) for 4 weeks significantly attenuated perivascular fibrosis of the coronary arteries without affecting blood pressure level. These data suggest that PHD inhibition may be beneficial for the treatment of cardiovascular diseases by inhibiting renin-angiotensin system via AT(1)R downregulation. PMID- 21825225 TI - Inhibition of prolyl hydroxylase domain-containing protein: a novel therapy for cardiovascular diseases? PMID- 21825226 TI - Bedtime hypertension treatment increases ambulatory blood pressure control and reduces cardiovascular risk in resistant hypertension. PMID- 21825227 TI - Angiotensin II impairs endothelial progenitor cell number and function in vitro and in vivo: implications for vascular regeneration. AB - Endothelial progenitor cells (EPCs) contribute to endothelial regeneration. Angiotensin II (Ang II) through Ang II type 1 receptor (AT(1)-R) activation plays an important role in vascular damage. The effect of Ang II on EPCs and the involved molecular mechanisms are incompletely understood. Stimulation with Ang II decreased the number of cultured human early outgrowth EPCs, which express both AT(1)-R and Ang II type 2 receptor, mediated through AT(1)-R activation and induction of oxidative stress. Ang II redox-dependently induced EPC apoptosis through increased apoptosis signal-regulating kinase 1, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinase phosphorylation; decreased Bcl-2 and increased Bax expression; and activation of caspase 3 but had no effect on the low cell proliferation. In addition, Ang II impaired colony-forming and migratory capacities of early outgrowth EPCs. Ang II infusion diminished numbers and functional capacities of EPCs in wild-type (WT) but not AT(1)a-R knockout mice (AT(1)a(-/-)). Reendothelialization after focal carotid endothelial injury was decreased during Ang II infusion. Salvage of reendothelialization by intravenous application of spleen-derived progenitor cells into Ang II-treated WT mice was pronounced with AT(1)a(-/-) cells compared with WT cells, and transfusion of Ang II-pretreated WT cells into WT mice without Ang II infusion was associated with less reendothelialization. Transplantation of AT(1)a(-/-) bone marrow reduced atherosclerosis development in cholesterol-fed apolipoprotein E-deficient mice compared with transplantation of apolipoprotein E-deficient or WT bone marrow. Randomized treatment of patients with stable coronary artery disease with the AT(1)-R blocker telmisartan significantly increased the number of circulating CD34/KDR-positive EPCs. Ang II through AT(1)-R activation, oxidative stress, and redox-sensitive apoptosis signal-regulating kinase 1-dependent proapoptotic pathways impairs EPCs in vitro and in vivo, resulting in diminished vascular regeneration. PMID- 21825228 TI - Participation in a clinical trial enhances adherence and persistence to treatment: a retrospective cohort study. AB - Poor adherence to treatment is one of the major determinants of an uncontrolled blood pressure. Participation in a clinical trial may increase patient's adherence to treatment. This prompted us to investigate adherence and persistence profiles in patients with hypertension who had participated in a clinical trial, by collecting pharmacy refill data before, during, and after participation in the trial. Pharmacy refill data of 182 patients with hypertension who participated in the Home Versus Office Blood Pressure Measurements: Reduction of Unnecessary Treatment Study between 2001 and 2005 were obtained from 1999 until 2010. Refill adherence to treatment was compared for the periods before, during, and after this trial. Persistence to medication was investigated for the period after termination of the trial. Refill data were available for 22 600 prescriptions. Participation into the trial significantly increased refill adherence, from 90.6% to 95.6% (P<0.001). After the trial period, refill adherence decreased again to 91.8% (P<0.001), which did not differ from the adherence before the start of the trial (P=0.45). Except for adherence to trial medication, adherence to nontrial related drugs also increased as a consequence of trial participation, from 77.6% to 89.6% (P<0.001). After termination of the trial, median persistence was 1424 days. Participants classified as adherent (adherence: >90%) were less likely to discontinue treatment compared with nonadherent participants (odds ratio: 0.66 [95% CI: 0.45 to 0.98]). Participation in a clinical trial significantly increases adherence to both trial-related and nontrial-related treatment, suggesting that participants in a trial are more involved with their conditions and treatments. PMID- 21825229 TI - Expanding role for combination drug therapy in the initial treatment of hypertension? PMID- 21825230 TI - Antihypertensive effects of peroxisome proliferator-activated receptor-beta activation in spontaneously hypertensive rats. AB - Activation of nuclear hormone receptor peroxisome proliferator-activated receptor beta/delta (PPARbeta) has been shown to improve insulin resistance and plasma high-density lipoprotein levels, but nothing is known about its effects in genetic hypertension. We studied whether the PPARbeta agonist GW0742 might exert antihypertensive effects in spontaneously hypertensive rats (SHRs). The rats were divided into 4 groups, Wistar Kyoto rat-control, Wistar Kyoto rat-treated (GW0742, 5 mg . kg(-1) . day(-1) by oral gavage), SHR-control, and SHR-treated, and followed for 5 weeks. GW0742 induced a progressive reduction in systolic arterial blood pressure and heart rate in SHRs and reduced the mesenteric arterial remodeling, the increased aortic vasoconstriction to angiotensin II, and the endothelial dysfunction characteristic of SHRs. These effects were accompanied by a significant increase in endothelial NO synthase activity attributed to upregulated endothelial NO synthase and downregulated caveolin 1 protein expression. Moreover, GW0742 inhibited vascular superoxide production, downregulated p22(phox) and p47(phox) proteins, decreased both basal and angiotensin II-stimulated NADPH oxidase activity, inhibited extracellular regulated kinase 1/2 activation, and reduced the expression of the proinflammatory and proatherogenic genes, interleukin 1beta, interleukin 6, or intercellular adhesion molecule 1. None of these effects were observed in Wistar Kyoto rats. PPARbeta activation, both in vitro and in vivo, increased the expression of the regulators of G protein-coupled signaling proteins RGS4 and RGS5, which negatively modulated the vascular actions of angiotensin II. PPARbeta activation exerted antihypertensive effects, restored the vascular structure and function, and reduced the oxidative, proinflammatory, and proatherogenic status of SHRs. We propose PPARbeta as a new therapeutic target in hypertension. PMID- 21825231 TI - Cardiovascular protection by initial and subsequent combination of antihypertensive drugs in daily life practice. AB - Guidelines recommend a combination of 2 drugs to be used as first-step treatment strategy in high-risk hypertensive individuals to achieve timely blood pressure control and avoid early events. The evidence that this is associated with cardiovascular (CV) benefits compared with initial monotherapy is limited, however. The objective of this study was to assess whether, compared with antihypertensive monotherapy, a combination of antihypertensive drugs provides a greater CV protection in daily clinical practice. A population-based, nested case control study was carried out by including the cohort of 209 650 patients from Lombardy (Italy) aged 40 to 79 years who were newly treated with antihypertensive drugs between 2000 and 2001. Cases were the 10 688 patients who experienced a hospitalization for CV disease from initial prescription until 2007. Three controls were randomly selected for each case. Logistic regression was used to model the CV risk associated with starting on and/or continuing with combination therapy. A Monte-Carlo sensitivity analysis was performed to account for unmeasured confounders. Patients starting on combination therapy had an 11% CV risk reduction with respect to those starting on monotherapy (95% CI: 5% to 16%). Compared with patients who maintained monotherapy also during follow-up, those who started on combination therapy and kept it along the entire period of observation had 26% reduction of CV risk (95% CI: 15% to 35%). In daily life practice, a combination of antihypertensive drugs is associated with a great reduction of CV risk. The indication for using combination of blood pressure drugs should be broadened. PMID- 21825232 TI - Subtypes of resistant hypertension based on out-of-office blood pressure measurement. PMID- 21825234 TI - Reversible cerebral vasoconstriction syndrome: a rose by any other name? PMID- 21825233 TI - Contribution of central nervous system endothelial nitric oxide synthase to neurohumoral activation in heart failure rats. AB - Neurohumoral activation, a hallmark in heart failure (HF), is linked to the progression and mortality of HF patients. Thus, elucidating its precise underlying mechanisms is of critical importance. Other than its classic peripheral vasodilatory actions, the gas NO is a pivotal neurotransmitter in the central nervous system control of the circulation. While accumulating evidence supports a contribution of blunted NO function to neurohumoral activation in HF, the precise cellular sources, and NO synthase (NOS) isoforms involved, remain unknown. Here, we used a multidisciplinary approach to study the expression, cellular distribution, and functional relevance of the endothelial NOS isoform within the hypothalamic paraventricular nucleus in sham and HF rats. Our results show high expression of endothelial NOS in the paraventricular nucleus (mostly confined to astroglial cells), which contributes to constitutive NO bioavailability, as well as tonic inhibition of presympathetic neuronal activity and sympathoexcitatory outflow from the paraventricular nucleus. A diminished endothelial NOS expression and endothelial NOS-derived NO availability were found in the paraventricular nucleus of HF rats, resulting, in turn, in blunted NO inhibitory actions on neuronal activity and sympathoexcitatory outflow. Taken together, our study supports blunted central nervous system endothelial NOS derived NO as a pathophysiological mechanism underlying neurohumoral activation in HF. PMID- 21825235 TI - Rett syndrome: exploring the autism link. AB - The presence of autism in individuals with neurodevelopmental disorders, whether transient as in Rett syndrome (RTT) or enduring as in fragile X syndrome or Down syndrome, suggests the possibility of common neurobiologic mechanisms whose elucidation could fundamentally advance our understanding. This review explores the commonalities and differences between autism and RTT at clinical and molecular levels with respect to current status and challenges for each, highlights recent findings from the Rare Disease Network Natural History study on RTT, and summarizes the broad range of phenotypes resulting from mutations in the methyl-CpG-binding protein 2 gene (MECP2), which is responsible for RTT in 95% of individuals with the disorder. For RTT, animal models have been critical resources for advancing pathobiologic discovery and promise to be important test beds for evaluating new therapies. Fundamental understanding of autism based on unique genetic mechanism(s) must await similar advances. PMID- 21825236 TI - Association and expression analyses with single-nucleotide polymorphisms in TOMM40 in Alzheimer disease. AB - BACKGROUND: Apolipoprotein E (APOE) is the most statistically significant genetic risk factor for late-onset Alzheimer disease (LOAD). The linkage disequilibrium pattern around the APOE gene has made it difficult to determine whether all the association signal is derived from APOE or whether there is an independent signal from a nearby gene. OBJECTIVE: To attempt to replicate a recently reported association of APOE 3-TOMM40 haplotypes with risk and age at onset. DESIGN: We used standard techniques to genotype several polymorphisms in the APOE-TOMM40 region in a large case-control series, in a series with cerebrospinal fluid biomarker data, and in brain tissue. SETTING: Alzheimer's Disease Research Center. PARTICIPANTS: Research volunteers who were cognitively normal or had Alzheimer disease. MAIN OUTCOME MEASURES: Disease status and age at onset. RESULTS: We did not replicate the previously reported association of the polyT polymorphism (rs10524523) with risk and age at onset. We found a significant association between rs10524523 and risk of LOAD in APOE 33 homozygotes but in the opposite direction as the previously reported association (the very long allele was underrepresented in cases vs controls in this study (P = .004]). We found no association between rs10524523 and cerebrospinal fluid tau or beta-amyloid 42 levels or TOMM40 or APOE gene expression. CONCLUSIONS: Although we did not replicate the earlier association between the APOE 3-TOMM40 haplotypes and age at onset, we observed that the polyT polymorphism is associated with risk of LOAD in APOE 33 homozygotes in a large case-control series but in the opposite direction as in the previous study. PMID- 21825238 TI - Referring patients for deep brain stimulation: an improving practice. AB - BACKGROUND: Deep brain stimulation (DBS) is a recent treatment modality. Few studies have examined referral practices for DBS. OBJECTIVE: To review referral patterns to a large movement disorders center to investigate the current level of knowledge surrounding DBS candidacy. DESIGN: Retrospective analysis. SETTING: Tertiary care medical center. PATIENTS: Reviewed were 197 medical records of patients referred for DBS between December 1, 2005, and November 30, 2009. MAIN OUTCOME MEASURES: Standardized criteria for DBS patient selection were used to categorize referred DBS candidates as the following: good candidates, possible future candidates, poor candidates because of neurological contraindications, or poor candidates because of medical contraindications. Yearly percentages were computed. Referral sources were categorized as movement disorder specialists vs non-movement disorder physicians and self-referred. RESULTS: In total, 165 referrals (83.8%) had ailments for which DBS was indicated, and 100 referrals (50.8%) were good candidates (62 with idiopathic Parkinson disease, 35 with dystonia, and 3 with essential tremor). Referrals by movement disorder specialists vs other sources differed significantly in their percentages of good candidates (66.7% vs 40.4%, P = .002) and possible future candidates (14.7% vs 32.7%, P = .02) but not poor candidates (18.7% vs 25.0%, P = .60). Over the observed period of referrals, the yearly percentages significantly decreased for good candidates and increased for possible future candidates and poor candidates. CONCLUSIONS: Compared with findings in prior studies, the quality of DBS referrals has improved. The increase in referral of possible future candidates and poor candidates may reflect greater confidence in the procedure. PMID- 21825237 TI - Association of low ejection fraction with impaired verbal memory in older patients with heart failure. AB - BACKGROUND: Cognitive dysfunction has a major role in health outcomes for cardiac patients. The association of cognitive dysfunction with heart failure is well established, but the cardiac variables that contribute to cognition are not well understood. OBJECTIVES: To investigate the relationships among age, memory, and left ventricular ejection fraction (EF) in patients with heart failure. DESIGN: Retrospective study. SETTING: Academic medical center. PARTICIPANTS: A total of 207 patients with heart failure underwent neuropsychological assessment of memory on standardized tests. MAIN OUTCOME MEASURES: Patients were grouped by age quartiles, and memory function was compared in those with an EF below 30% vs those with an EF of 30% or higher. RESULTS: Demographic, cognitive, and medical variables having a significant association with a memory composite score were identified in a univariate linear regression analysis. In a multivariate linear model that adjusted for significant covariates, there was a significant interaction between age and EF for memory function. Patients younger than 63 years maintained stable memory function across EF levels, but patients 63 years or older showed a significant decline in memory performance when EF dropped below 30% (P < .02). Post hoc multivariate analysis showed that verbal delayed recall and recognition were the components of memory most affected by low EF. CONCLUSION: The effect of EF on memory differs by age such that older patients with lower EFs have significantly reduced verbal memory function. PMID- 21825239 TI - Deep brain stimulation in benign tremulous parkinsonism. AB - BACKGROUND: Benign tremulous parkinsonism (BTP) is characterized by prominent resting plus action tremor, mild parkinsonism with limited disability or progression apart from tremor, and a less-robust response to levodopa therapy. This disorder has an uncertain pathophysiologic relationship to idiopathic Parkinson disease. Deep brain stimulation (DBS) should be efficacious for this condition, but there is no previously published experience. OBJECTIVES: To assess the clinical outcomes and surgical complications of patients with BTP who underwent DBS. DESIGN: Retrospective case series. SETTING: Tertiary care medical center. PATIENTS: Twelve men and 3 women with BTP who underwent DBS for levodopa refractory tremor. MAIN OUTCOME MEASURES: Tremor status after DBS, preoperative vs postoperative scores on the Fahn-Tolosa-Marin tremor scale, and the presence of adverse events. RESULTS: Of the 15 patients, 8 underwent unilateral thalamic nucleus ventralis intermedius (VIM), 4 bilateral VIM, and 3 bilateral subthalamic nucleus DBS. At last follow-up at a median of 4 years post-DBS, 7 patients were tremor free, 6 had only trace tremor, and 2 were definitely improved but with residual tremor. The median preoperative Fahn-Tolosa-Marin tremor scale score was 17 (range, 11-21); the tremor scale score at the last videotaped follow-up was 1 (range, 0-6). Median time between the 2 videotapes was 11.5 months (range, 3-14 months). No patients experienced adverse events after the surgical procedure. CONCLUSIONS: These findings support the efficacy of DBS, with VIM and STN targets, in medically refractory BTP-related tremor. Further studies are needed to explore the long-term durability of response and to better compare the surgical targets. PMID- 21825240 TI - Resting tremor in Parkinson disease: a negative predictor of levodopa-induced dyskinesia. AB - BACKGROUND: It is unclear whether patients with different clinical subtypes of Parkinson disease (PD) differ in their risk of developing levodopa-induced dyskinesia (LID) and whether resting tremor is negatively correlated with this risk. OBJECTIVES: To determine whether resting tremor as an initial manifestation of PD negatively correlated with subsequent occurrence and severity of LID and to study the correlations between LID and other epidemiological factors (eg, age at onset of PD and duration of PD). DESIGN: Logistic regression analysis was used to determine predictive factors of LID. Spearman rank correlations between LID and epidemiological factors and motor signs (including tremor) were calculated. SETTING: Institutional tertiary referral center for movement disorders. PATIENTS: Cohort of 85 patients with PD. MAIN OUTCOME MEASURE: Occurrence of LID according to the Unified Parkinson Disease Rating Scale part IV. RESULTS: Resting tremor as an initial manifestation of PD was associated with reduced risk of developing LID independent of other predictors of LID (duration of PD, axial signs, and levodopa dose). CONCLUSION: Resting tremor as an initial manifestation of PD predicts lower probability of developing LID under levodopa treatment. PMID- 21825241 TI - The dynamics of cortical and hippocampal atrophy in Alzheimer disease. AB - OBJECTIVE: To characterize rates of regional Alzheimer disease (AD)-specific brain atrophy across the presymptomatic, mild cognitive impairment, and dementia stages. DESIGN: Multicenter case-control study of neuroimaging, cerebrospinal fluid, and cognitive test score data from the Alzheimer's Disease Neuroimaging Initiative. SETTING: Research centers across the United States and Canada. PATIENTS: We examined a total of 317 participants with baseline cerebrospinal fluid biomarker measurements and 3 T1-weighted magnetic resonance images obtained within 1 year. MAIN OUTCOME MEASURES: We used automated tools to compute annual longitudinal atrophy in the hippocampus and cortical regions targeted in AD. We used Mini-Mental State Examination scores as a measure of cognitive performance. We performed a cross-subject analysis of atrophy rates and acceleration on individuals with an AD-like cerebrospinal fluid molecular profile. RESULTS: In presymptomatic individuals harboring indicators of AD, baseline thickness in AD vulnerable cortical regions was significantly reduced compared with that of healthy control individuals, but baseline hippocampal volume was not. Across the clinical spectrum, rates of AD-specific cortical thinning increased with decreasing cognitive performance before peaking at approximately the Mini-Mental State Examination score of 21, beyond which rates of thinning started to decline. Annual rates of hippocampal volume loss showed a continuously increasing pattern with decreasing cognitive performance as low as the Mini-Mental State Examination score of 15. Analysis of the second derivative of imaging measurements revealed that AD-specific cortical thinning exhibited early acceleration followed by deceleration. Conversely, hippocampal volume loss exhibited positive acceleration across all study participants. CONCLUSIONS: Alzheimer disease-specific cortical thinning and hippocampal volume loss are consistent with a sigmoidal pattern, with an acceleration phase during the early stages of the disease. Clinical trials should carefully consider the nonlinear behavior of these AD biomarkers. PMID- 21825242 TI - Ecology of the aging human brain. AB - BACKGROUND: Alzheimer disease, cerebral vascular brain injury, and isocortical Lewy body disease (LBD) are the major contributors to dementia in community- and population-based studies. OBJECTIVE: To estimate the prevalence of clinically silent forms of these diseases in cognitively normal (CN) adults. DESIGN: Autopsy study. SETTING: Community- and population based. PARTICIPANTS: A total of 1672 brain autopsies from the Adult Changes in Thought study, Honolulu-Asia Aging Study, Nun Study, and Oregon Brain Aging Study, of which 424 met the criteria for CN. MAIN OUTCOME MEASURES: Of these, 336 cases had a comprehensive neuropathologic examination of neuritic plaque density, Braak stage for neurofibrillary tangles, LB distribution, and number of cerebral microinfarcts. RESULTS: Forty-seven percent of CN cases had moderate or frequent neuritic plaque density; of these, 6% also had Braak stage V or VI for neurofibrillary tangles. Fifteen percent of CN cases had medullary LBD; 8% also had nigral and 4% isocortical LBD. The presence of any cerebral microinfarcts was identified in 33% and of high-level cerebral microinfarcts in 10% of CN individuals. Overall, the burden of lesions in each individual and their comorbidity varied widely within each study but were similar across studies. CONCLUSIONS: These data show an individually varying complex convergence of subclinical diseases in the brain of older CN adults. Appreciating this ecology should help guide future biomarker and neuroimaging studies and clinical trials that focus on community- and population based cohorts. PMID- 21825243 TI - Differential involvement of optineurin in amyotrophic lateral sclerosis with or without SOD1 mutations. AB - BACKGROUND: Mutations in optineurin have recently been linked to amyotrophic lateral sclerosis (ALS). OBJECTIVE: To determine whether optineurin-positive skeinlike inclusions are a common pathologic feature in ALS, including SOD1 linked ALS. DESIGN: Clinical case series. SETTING: Academic referral center. SUBJECTS: We analyzed spinal cord sections from 46 clinically and pathologically diagnosed ALS cases and ALS transgenic mouse models overexpressing ALS-linked SOD1 mutations G93A or L126Z. RESULTS: We observed optineurin-immunoreactive skeinlike inclusions in all the sporadic ALS and familial ALS cases without SOD1 mutation, but not in cases with SOD1 mutations or in transgenic mice overexpressing the ALS-linked SOD1 mutations G93A or L126Z. CONCLUSION: The data from this study provide evidence that optineurin is involved in the pathogenesis of sporadic ALS and non- SOD1 familial ALS, thus supporting the hypothesis that these forms of ALS share a pathway that is distinct from that of SOD1-linked ALS. PMID- 21825244 TI - Encephalitis associated with glutamic acid decarboxylase autoantibodies in a child: a treatable condition? AB - OBJECTIVE: To increase the recognition of glutamic acid decarboxylase autoantibodies-related encephalitis in childhood. DESIGN: Case report and review of the literature. PATIENT: A 6-year-old girl who had developed refractory seizures, developmental regression, and type 1 diabetes mellitus at age 25 months. INTERVENTIONS: Blood analysis, electroencephalogram, cerebral magnetic resonance imaging, positron emission tomography scan, lumbar puncture, and measurement of glutamic acid decarboxylase activity were performed. Treatment with repeated plasmapheresis and rituximab, with concomitant antiepileptic drugs, was administered. RESULTS: Highly elevated titers of glutamic acid decarboxylase autoantibodies were found in the serum, as well as in the cerebrospinal fluid. Major clinical improvement in parallel with a decrease in the levels of serum and cerebrospinal fluid antibodies was observed with treatment. CONCLUSIONS: Encephalitis associated with glutamic acid decarboxylase autoantibodies is a severe epileptic disorder that occurs in young children as well as adults. It may be partially reversible with aggressive immunomodulatory treatment, including plasmapheresis and rituximab. Studies are warranted to determine whether early treatment leads to complete remission. PMID- 21825245 TI - N-methyl-D-aspartate receptor autoimmune encephalitis presenting with opsoclonus myoclonus: treatment response to plasmapheresis. AB - OBJECTIVES: To report the clinical, laboratory, and radiographic features and the response to plasmapheresis in a patient with encephalopathy, opsoclonus, and myoclonus whose cerebrospinal fluid was positive for N-methyl-D-aspartate receptor-IgG. DESIGN: Case report. SETTING: St Marys Hospital, Rochester, Minnesota. PATIENT: A 27-year-old woman with a history of episodic migraine developed subacute progressive myoclonus, opsoclonus, and encephalopathy. RESULTS: Magnetic resonance imaging demonstrated nodular leptomeningeal enhancement in the superior cerebellar folia and subsequent T2 hyperintensities in the periventricular regions and amygdala. A positron emission tomographic scan of the head demonstrated predominantly frontotemporoparietal cortical hypometabolism with sparing of the primary sensory and motor cortices. Cerebrospinal fluid examination revealed a lymphocytic pleocytosis, mildly elevated protein level, elevated IgG index, and positive oligoclonal banding. Autoimmune cerebrospinal fluid screening revealed a neural-specific IgG that bound to synapse-rich regions of mouse hippocampus and cerebellar granular layer; the neural-specific IgG was confirmed to be N-methyl-D-aspartate receptor specific. No neoplasm was detected by physical examination or by whole-body computed tomography and positron emission tomography. A 5-day course of high-dose intravenous methylprednisolone sodium succinate yielded limited improvement, and the patient subsequently required intensive care unit admission following a pulseless electrical activity arrest associated with pulmonary embolism. The encephalopathy improved dramatically after plasmapheresis. CONCLUSIONS: This case highlights opsoclonus and myoclonus as manifestations of autoimmune N-methyl-D aspartate receptor encephalitis in the setting of a novel appearance on positron emission tomography, and it shows a remarkable clinical response to plasmapheresis. PMID- 21825247 TI - Curing of oscillating larynx by levetiracetam. PMID- 21825246 TI - Isolated ZIC4 antibodies in paraneoplastic cerebellar syndrome with an underlying ovarian tumor. AB - OBJECTIVE: To describe a patient with paraneoplastic cerebellar syndrome and the uncommon association of isolated ZIC4 antibodies and ovarian cancer. DESIGN: Case report and review of the literature. SETTING: Hospitalized care, follow-up in private practice. PATIENT: A 60-year-old woman with severe paraneoplastic cerebellar syndrome and an underlying ovarian adenocarcinoma. INTERVENTIONS: Neurological examination, lumbar puncture, laboratory tests, radiological imaging, and histological examination. MAIN OUTCOME MEASURES: Clinical course and titer of anti- ZIC4 antibodies in serum. RESULTS: Laboratory and cerebrospinal fluid tests revealed the isolated presence of ZIC4 antibodies. Screening results for small cell lung carcinoma were negative, while abdominal computed tomographic scan was suggestive of ovarian adenocarcinoma, which was confirmed by histological examination. Glucocorticosteroid administration and chemotherapy led to complete remission of paraneoplastic cerebellar degeneration. CONCLUSION: To the best of our knowledge, this is the first case of paraneoplastic cerebellar degeneration in a patient with isolated ZIC4 antibodies associated with ovarian adenocarcinoma. PMID- 21825248 TI - Intra-arterial thrombus visualized on magnetic resonance imaging in internal carotid artery occlusion. PMID- 21825249 TI - The many faces of central nervous system tuberculosis. PMID- 21825250 TI - Incontinentia pigmenti: skin and magnetic resonance imaging findings. PMID- 21825251 TI - A case report of transverse myelitis following influenza vaccination. PMID- 21825252 TI - Use of mitoxantrone in neuromyelitis optica. PMID- 21825253 TI - Effect of pallidal deep brain stimulation on psychiatric symptoms in myoclonus dystonia due to epsilon-sarcoglycan mutations. PMID- 21825254 TI - Music and semantic dementia. PMID- 21825255 TI - Atrophy after traumatic axonal injury. PMID- 21825256 TI - Cause-specific colostomy rates after radiotherapy for anal cancer: a Danish multicentre cohort study. AB - PURPOSE: In anal cancer, colostomy-free survival is a measure of anal sphincter preservation after treatment with radiotherapy or chemoradiotherapy. Failure to control anal cancer and complications of treatment are alternative indications for colostomy. However, no data exist on cause-specific colostomy rates. We examined this in a cohort study. PATIENTS AND METHODS: Through national registries and review of medical records, we identified patients with anal cancer diagnosed from 1995 to 2003 who had curative-intent radiotherapy or chemoradiotherapy in four Danish centers. We computed cumulative incidence of tumor-related colostomy and therapy-related colostomy, treating colostomy and death as competing events. Follow-up started at completion of radiotherapy and continued throughout 2008. We used competing risk regression to compute hazard ratios (HRs) to compare the cumulative incidence of cause-specific colostomies between age, sex, tumor size, chemotherapy, and local excision before radiotherapy. RESULTS: We included 235 patients with anal cancer. The 5-year cumulative incidences of tumor-related and therapy-related colostomy were 26% (95% CI, 21% to 32%) and 8% (95% CI, 5% to 12%), respectively. Tumor size greater than 6 cm versus less than 4 cm was a risk factor for tumor-related colostomy (adjusted HR, 3.8; 95% CI, 1.7 to 8.1), and local excision before radiotherapy was a risk factor for therapy-related colostomy (adjusted HR, 4.5; 95% CI, 1.5 to 13.5). CONCLUSION: After curative-intent radiotherapy or chemoradiotherapy, one third of patients had a colostomy, of which one third were related to therapy. Large tumor size was associated with a higher risk of tumor-related colostomy, whereas history of prior excision was associated with an increased incidence of therapy-related colostomy. PMID- 21825257 TI - Active surveillance for prostate cancer: progress and promise. AB - Widespread prostate-specific antigen (PSA) -based screening and aggressive treatment of prostate cancer have reduced mortality rates substantially, but both remain controversial in large part because of high rates of overdiagnosis and overtreatment of otherwise indolent tumors. Active surveillance--or close monitoring of PSA levels combined with periodic imaging and repeat biopsies--is gaining acceptance as an alternative initial management strategy for men with low risk prostate cancer. In reported series, rates of progression to active treatment with intermediate-term follow-up have ranged from 14% to 41%, and likelihood of subsequent cure with surgery or radiation does not seem to be compromised by an initial trial of surveillance. Two related challenges to broader acceptance of surveillance are better characterization at time of diagnosis of the risk of progression (including likelihood that given tumor may have been undersampled by diagnostic biopsy) and validation of optimal end points once surveillance begins. Both are subjects of intense ongoing investigation, with emerging biomarkers and novel imaging tests expected to facilitate decision making substantially. Recent reports have suggested active surveillance can be a cost-effective approach and preserve quality of life, but these questions must be assessed more definitively in prospective cohorts. Ultimately, by minimizing the harms of overtreating low-risk prostate cancer, active surveillance may help settle the controversy surrounding prostate cancer screening and management. PMID- 21825258 TI - Clinical features and outcome of patients with non-small-cell lung cancer harboring BRAF mutations. AB - PURPOSE: To investigate the prevalence, distribution, and prognostic role of BRAF mutations in a large cohort of white patients with non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: A retrospective series of 1,046 NSCLCs-comprising 739 adenocarcinomas (ADCs) and 307 squamous cell carcinomas (SCCs)-was investigated for BRAF mutations. High-resolution melting analysis followed by sequencing and strip hybridization assay were used. All patients were also analyzed for KRAS and EGFR mutations. RESULTS: BRAF mutations were present in 36 ADCs (4.9%) and one SCC (0.3%; P = .001). Twenty-one of the mutations (56.8%) were V600E, and 16 (43.2%) were non-V600E. V600E mutations were significantly more prevalent in females (16 of 187 patients; 8.6%) than in males (five of 552 patients; 0.9%), as indicated by multivariate logistic regression analysis (hazard ratio [HR], 11.29; P < .001). V600E-mutated tumors showed an aggressive histotype characterized by micropapillary features in 80% of patients and were significantly associated with shorter disease-free and overall survival rates on both univariate (HR, 2.67; P < .001 and HR, 2.97; P < .001, respectively) and multivariate analyses (HR, 2.19; P = .011 and HR, 2.18; P = .014, respectively). All non-V600E mutations were found in smokers (P = .015) and were associated with neither clinicopathologic parameters nor prognosis. BRAF and EGFR were concomitantly mutated in two tumors. CONCLUSION: We report for the first time to our knowledge that V600E and non-V600E BRAF mutations affect different patients with NSCLC. V600E mutations are significantly associated with female sex and represent a negative prognostic factor. In addition, we identified a number of other clinicopathologic parameters potentially useful for the selection of patients carrying BRAF mutations. PMID- 21825259 TI - A randomized, phase II, biomarker-selected study comparing erlotinib to erlotinib intercalated with chemotherapy in first-line therapy for advanced non-small-cell lung cancer. AB - PURPOSE: Erlotinib prolongs survival in patients with advanced non-small-cell lung cancer (NSCLC). We report the results of a randomized, phase II study of erlotinib alone or intercalated with chemotherapy (CT + erlotinib) in chemotherapy-naive patients with advanced NSCLC who were positive for epidermal growth factor receptor (EGFR) protein expression and/or with high EGFR gene copy number. PATIENTS AND METHODS: A total of 143 patients were randomly assigned to either erlotinib 150 mg daily orally until disease progression (PD) occurred or to chemotherapy with paclitaxel 200 mg/m(2) intravenously (IV) and carboplatin dosed by creatinine clearance (AUC 6) IV on day 1 intercalated with erlotinib 150 mg orally on days 2 through 15 every 3 weeks for four cycles followed by erlotinib 150 mg orally until PD occurred (CT + erlotinib). The primary end point was 6-month progression-free survival (PFS); secondary end points included response rate, PFS, and survival. EGFR, KRAS mutation, EGFR fluorescent in situ hybridization and immunohistochemistry, and E-cadherin and vimentin protein levels were also assessed. RESULTS: Six-month PFS rates were 26% and 31% for the two arms (CT + erlotinib and erlotinib alone, respectively). Both were less than the historical control of 45% (P = .001 and P = .011, respectively). Median PFS times were 4.57 and 2.69 months, respectively. Patients with tumors harboring EGFR activating mutations fared better on erlotinib alone (median PFS, 18.2 months v 4.9 months for CT + erlotinib). CONCLUSION: The feasibility of a multicenter biomarker-driven study was demonstrated, but neither treatment arms exceeded historical controls. This study does not support combined chemotherapy and erlotinib in first-line treatment of EGFR-selected advanced NSCLC, and the patients with tumors harboring EGFR mutations had a better outcome on erlotinib alone. PMID- 21825260 TI - Immunotherapy for prostate cancer: biology and therapeutic approaches. AB - Although prostate cancer was not historically considered to be a particularly immune-responsive cancer, recent clinical trials have demonstrated that immunotherapy for prostate cancer can lead to improvements in overall survival (OS). These studies include randomized controlled trials with sipuleucel-T and another with PROSTVAC-VF, both of which rely on stimulating the immune system to target prostate proteins. This review discusses the most promising developments over the past year in immune-based therapy for prostate cancer and the opportunities that lie ahead. Recent randomized immunotherapy trials in prostate cancer have demonstrated improvements in OS but without the concomitant improvements in progression-free survival. This uncoupling of survival from clinical response poses challenges to clinical management, because conventional measures of objective response cannot be used to identify patients benefiting from treatment. There is a significant need to identify immunologic or clinical surrogates for survival so that clinical benefit can be assessed in a timely manner. Immunotherapy is now an established treatment approach for prostate cancer, with multiple clinical trials demonstrating improvements in OS. Significant challenges to this modality remain, including determining best clinical setting for immunotherapy, identifying patients who benefit, and defining relevant clinical and immunologic end points. Nevertheless, the broader availability of novel immunotherapies will provide opportunities not only to target different components of the immune system but also to combine immunotherapies with other treatments for improved clinical efficacy. PMID- 21825261 TI - Is computed tomography simulation associated with improved survival, or is this finding a result of confounding variables? PMID- 21825262 TI - [18F]Fluorodeoxyglucose positron emission tomography for detection of bone marrow involvement in children and adolescents with Hodgkin's lymphoma. AB - PURPOSE: Currently, a routine bone marrow biopsy (BMB) is performed to detect bone marrow (BM) involvement in pediatric Hodgkin's lymphoma (HL) stage greater than IIA. [(18)F]fluorodeoxyglucose positron emission tomography (FDG-PET) is increasingly used for the initial staging of HL. The value of using FDG-PET to detect BM involvement has not been sufficiently defined. We compared the results of BMBs and FDG-PET for the diagnosis of BM involvement in a large pediatric group with HL. PATIENTS AND METHODS: The initial staging of 175 pediatric patients with newly diagnosed classical HL stage greater than IIA was determined by using BMB, FDG-PET, chest computed tomography (CT), and magnetic resonance imaging (MRI) or CT of the neck, abdomen, and pelvis. Staging images were prospectively evaluated by a central review board. Skeletal regions that were suggestive of BM involvement by either method were re-evaluated by using different imaging modalities. In suspicious cases, bone scintigraphy was performed. If follow-up FDG-PET scans were available, the remission of skeletal lesions during treatment was evaluated. RESULTS: BMB results were positive in seven of 175 patients and were identified by FDG-PET. FDG-PET scans showed BM involvement in 45 patients. In addition, the lesions of 32 of these 45 patients had a typical multifocal pattern. In 38 of 39 follow-up positron emission tomography scans, most of the skeletal lesions disappeared after chemotherapy. There was no patient with skeletal findings suggestive of BM involvement by MRI or CT with a negative FDG-PET. CONCLUSION: FDG-PET is a sensitive and specific method for the detection of BM involvement in pediatric HL. The sensitivity of a BMB appears compromised by the focal pattern of BM involvement. Thus, FDG-PET may safely be substituted for a BMB in routine staging procedures. PMID- 21825263 TI - Phase I trial of lenalidomide and CCI-779 in patients with relapsed multiple myeloma: evidence for lenalidomide-CCI-779 interaction via P-glycoprotein. AB - PURPOSE: Multiple myeloma (MM) is an incurable plasma-cell neoplasm for which most treatments involve a therapeutic agent combined with dexamethasone. The preclinical combination of lenalidomide with the mTOR inhibitor CCI-779 has displayed synergy in vitro and represents a novel combination in MM. PATIENTS AND METHODS: A phase I clinical trial was initiated for patients with relapsed myeloma with administration of oral lenalidomide on days 1 to 21 and CCI-779 intravenously once per week during a 28-day cycle. Pharmacokinetic data for both agents were obtained, and in vitro transport and uptake studies were conducted to evaluate potential drug-drug interactions. RESULTS: Twenty-one patients were treated with 15 to 25 mg lenalidomide and 15 to 20 mg CCI-779. The maximum tolerated dose (MTD) was determined to be 25 mg lenalidomide with 15 mg CCI-779. Pharmacokinetic analysis indicated increased doses of CCI-779 resulted in statistically significant changes in clearance, maximum concentrations, and areas under the concentration-time curves, with constant doses of lenalidomide. Similar and significant changes for CCI-779 pharmacokinetics were also observed with increased lenalidomide doses. Detailed mechanistic interrogation of this pharmacokinetic interaction demonstrated that lenalidomide was an ABCB1 (P glycoprotein [P-gp]) substrate. CONCLUSION: The MTD of this combination regimen was 25 mg lenalidomide with 15 mg CCI-779, with toxicities of fatigue, neutropenia, and electrolyte wasting. Pharmacokinetic and clinical interactions between lenalidomide and CCI-779 seemed to occur, with in vitro data indicating lenalidomide was an ABCB1 (P-gp) substrate. To our knowledge, this is the first report of a clinically significant P-gp-based drug-drug interaction with lenalidomide. PMID- 21825264 TI - Phase I trial of MK-0752 in children with refractory CNS malignancies: a pediatric brain tumor consortium study. AB - PURPOSE: To estimate the maximum-tolerated dose (MTD), describe dose-limiting toxicities (DLTs), and characterize pharmacokinetic properties of MK-0752, a gamma secretase inhibitor, in children with refractory or recurrent CNS malignancies. PATIENTS AND METHODS: MK-0752 was administered once daily for 3 consecutive days of every 7 days at escalating dosages starting at 200 mg/m(2). The modified continual reassessment method was used to estimate the MTD. A course was 28 days in duration. Pharmacokinetic analysis was performed during the first course. Expression of NOTCH and hairy enhancer of split (HES) proteins was assessed in peripheral-blood mononuclear cells (PBMCs) before and following treatment with MK-0752. RESULTS: Twenty-three eligible patients were enrolled: 10 males (median age, 8.1 years; range, 2.6 to 17.7 years) with diagnoses of brainstem glioma (n = 6), ependymoma (n = 8), medulloblastoma/primitive neuroectodermal tumor (n = 4), glioblastoma multiforme (n = 2), atypical teratoid/rhabdoid tumor (n = 1), malignant glioma (n = 1), and choroid plexus carcinoma, (n = 1). Seventeen patients were fully evaluable for toxicity. No DLTs occurred in the three patients enrolled at 200 mg/m(2)/dose. At 260 mg/m(2)/dose, DLTs occurred in two of six patients, both of whom experienced grade 3 ALT and AST. There were no grade 4 toxicities; non-dose-limiting grade 3 toxicities included hypokalemia and lymphopenia. Population pharmacokinetic values (% coefficient of variation) for MK-0752 were apparent oral clearance, 0.444 (38%) L/h/m(2); apparent volume of distribution, 7.36 (24%) L/m(2); and k(a), 0.358 (99%) hr(-1). CONCLUSION: MK-0752 is well-tolerated in children with recurrent CNS malignancies. The recommended phase II dose using the 3 days on followed by 4 days off schedule is 260 mg/m(2)/dose once daily. PMID- 21825265 TI - Reversal of leukostasis-related pulmonary distress syndrome after leukapheresis and low-dose chemotherapy in acute myeloid leukemia. PMID- 21825267 TI - Natural course of insomnia comorbid with cancer: an 18-month longitudinal study. AB - PURPOSE: This study aimed to assess the prevalence and natural course (incidence, persistence, remission, and relapse) of insomnia comorbid with cancer during an 18-month period. PATIENTS AND METHODS: All patients scheduled to receive a curative surgery for a first diagnosis of nonmetastatic cancer were approached on the day of their preoperative visit to participate in the study. A total of 962 patients with cancer (mixed sites) completed an insomnia diagnostic interview at the perioperative phase (T1), as well as at 2 (T2), 6 (T3) 10 (T4), 14 (T5), and 18 (T6) months after surgery. RESULTS: Findings revealed high rates of insomnia at baseline (59%), including 28% with an insomnia syndrome. The prevalence of insomnia generally declined over time but remained pervasive even at the end of the 18-month period (36%). Rates were greater in patients with breast (42% to 69%) and gynecologic (33% to 68%) cancer and lower in men with prostate cancer (25% to 39%) throughout the study. Nearly 15% of patients had a first incidence of insomnia during the study, and 19.5% experienced relapse. The evolution of symptoms varied according to sleep status. Remissions (patients becoming good sleepers) were much less likely for patients with an insomnia syndrome (10.8% to 14.9%) than for those with insomnia symptoms (42.0% to 51.3%). Most frequently (37.6%), patients with an insomnia syndrome at baseline kept that status throughout the 18-month period. CONCLUSION: Insomnia is a frequent and enduring problem in patients with cancer, particularly at the syndrome level. Early intervention strategies, such as cognitive-behavioral therapy, could prevent the problem from becoming more severe and chronic. PMID- 21825266 TI - Inflammation and behavioral symptoms after breast cancer treatment: do fatigue, depression, and sleep disturbance share a common underlying mechanism? AB - PURPOSE: Fatigue, depression, and sleep disturbance are common adverse effects of cancer treatment and frequently co-occur. However, the possibility that inflammatory processes may underlie this constellation of symptoms has not been examined. PATIENTS AND METHODS: Women (N = 103) who had recently finished primary treatment (ie, surgery, radiation, chemotherapy) for early-stage breast cancer completed self-report scales and provided blood samples for determination of plasma levels of inflammatory markers: soluble tumor necrosis factor (TNF) receptor II (sTNF-RII), interleukin-1 receptor antagonist, and C-reactive protein. RESULTS: Symptoms were elevated at the end of treatment; greater than 60% of participants reported clinically significant problems with fatigue and sleep, and 25% reported elevated depressive symptoms. Women treated with chemotherapy endorsed higher levels of all symptoms and also had higher plasma levels of sTNF-RII than women who did not receive chemotherapy (all P < .05). Fatigue was positively associated with sTNF-RII, particularly in the chemotherapy treated group (P < .05). Depressive symptoms and sleep problems were correlated with fatigue but not with inflammatory markers. CONCLUSION: This study confirms high rates of behavioral symptoms in breast cancer survivors, particularly those treated with chemotherapy, and indicates a role for TNF-alpha signaling as a contributor to postchemotherapy fatigue. Results also suggest that fatigue, sleep disturbance, and depression may stem from distinct biologic processes in post treatment survivors, with inflammatory signaling contributing relatively specifically to fatigue. PMID- 21825268 TI - Specific training program improves oncologists' palliative care communication skills in a randomized controlled trial. AB - PURPOSE: The aim of the study was to demonstrate that COM-ON-p, concise and individualized communication skills training (CST), improves oncologists' communication skills in consultations focusing on the transition to palliative care. METHODS: Forty-one physicians were randomly assigned to a control (CG) or intervention group (IG). At t(0), all physicians held two video-recorded consultations with actor-patient pairs. Afterward, physicians in the IG participated in COM-ON-p. Five weeks after t(0), a second assessment took place (t(1)). COM-ON-p consists of an 11-hour workshop (1.5 days), pre- and postassessment (2 hours), and coaching (0.5 hours). Physicians focused on practicing individual learning goals with actor patients in small groups. To evaluate the training, blinded raters assessed communication behavior of the physicians in video-recorded actor-patient consultations using a specific checklist. Data were analyzed using a mixed model with baseline levels as covariates. RESULTS: Participants in the IG improved significantly more than those in the CG in all three sections of the COM-ON-Checklist: skills specific to the transition to palliative care, global communication skills, and involvement of significant others (all P < .01). Differences between the CG and IG on the global items of communication skills and involvement of significant others were also significant (P < .01). Effect sizes were medium to large, with a 0.5-point improvement on average on a five-point rating scale. CONCLUSION: Physicians can be trained to meet better core challenges during the transition to palliative care through developed concise CST. Generalization and transfer into clinical practice must be proven in additional studies. PMID- 21825269 TI - Retraction -- October 2011. PMID- 21825270 TI - Cross-cultural evaluation of the WHOQOL-BREF domains in primary care depressed patients using Rasch analysis. AB - BACKGROUND: The Rasch model prescribes procedures to ensure that a scale constructed from multiple items conforms to fundamental requirements of interval scales of measurement. OBJECTIVE: To test the Rasch properties of the domains of the World Health Organization Quality of Life Instrument-abbreviated version (WHOQOL-BREF) in depressed patients from primary care settings. DESIGN: Cross sectional, cross-national study. SETTING: Primary care. PATIENTS: The sample consisted of 1193 patients having a confirmed diagnosis of depression from 6 countries (Australia, Brazil, Israel, Russia, Spain, and the United States) involved in the Longitudinal Investigation of Depression Outcomes (LIDO) study. MEASUREMENTS: The Composite International Diagnostic Interview (CIDI) diagnosed depression, whereas the Center for Epidemiological Studies Depression Scale (CES D) assessed severity of depression. The WHOQOL-BREF measured generic quality of life (QOL). RESULTS: Three of the 4 WHOQOL-BREF domains (physical, psychological, and environment) conform to the Rasch model expectations, following adjustments required mainly because of individual item misfit or differential item functioning (DIF) due to age or country. The social domain showed relatively poor psychometric properties, as observed in previous studies. CONCLUSIONS: The Rasch analysis demonstrated that, with some modifications, all domains of the WHOQOL BREF, except for the social domain, provide an interval scale measure of generic subjective QOL in the context of depressed primary care patients in 6 countries worldwide. PMID- 21825271 TI - Teaching neuroimages: neuropathy caused by Mycobacterium leprae. PMID- 21825272 TI - Teaching neuroimages: numb chin syndrome in an edentulous patient. PMID- 21825273 TI - Teaching neuroimages: bilateral internal superior cerebellar artery watershed infarction. PMID- 21825275 TI - Intractable progressive pneumocephalus due to tuberculous meningoencephalitis. PMID- 21825276 TI - HLA B*44: protective effects in MS susceptibility and MRI outcome measures. PMID- 21825277 TI - Changes . People . Comments. PMID- 21825278 TI - Challenges facing providers caring for HIV/HCV-coinfected patients. AB - Despite the high prevalence of hepatitis C virus (HCV) infection among injection drug users also infected with human immunodeficiency virus (HIV), and the synergistic adverse effect of the two diseases on patients' health and survival, research on the clinical management of these patients and particularly the low uptake of HCV therapy is limited. We conducted qualitative interviews with 17 HIV providers from two urban public hospitals. We discovered that the limitations of the current state of medical knowledge, the severe side effects of HIV and HCV therapies, and the psychosocial vulnerability of HIV/HCV-coinfected patients combined with their resistance to becoming informed about HCV posed significant challenges for providers. To contend with these challenges, providers incorporated key dimensions of patient-centered medicine in their practice, such as considering their patients' psychosocial profiles and the meaning patients assign to being coinfected, and finding ways to engage their patients in a therapeutic alliance. PMID- 21825280 TI - The proteomic signature of Aspergillus fumigatus during early development. AB - Aspergillus fumigatus is a saprophytic fungus that causes a range of diseases in humans including invasive aspergillosis. All forms of disease begin with the inhalation of conidia, which germinate and develop. Four stages of early development were evaluated using the gel free system of isobaric tagging for relative and absolute quantitation to determine the full proteomic profile of the pathogen. A total of 461 proteins were identified at 0, 4, 8, and 16 h and fold changes for each were established. Ten proteins including the hydrophobin rodlet protein RodA and a protein involved in melanin synthesis Abr2 were found to decrease relative to conidia. To generate a more comprehensive view of early development, a whole genome microarray analysis was performed comparing conidia to 8 and 16 h of growth. A total of 1871 genes were found to change significantly at 8 h with 1001 genes up-regulated and 870 down-regulated. At 16 h, 1235 genes changed significantly with 855 up-regulated and 380 down-regulated. When a comparison between the proteomics and microarray data was performed at 8 h, a total of 22 proteins with significant changes also had corresponding genes that changed significantly. When the same comparison was performed at 16 h, 12 protein and gene combinations were found. This study, the most comprehensive to date, provides insights into early pathways activated during growth and development of A. fumigatus. It reveals a pathogen that is gearing up for rapid growth by building translation machinery, generating ATP, and is very much committed to aerobic metabolism. PMID- 21825279 TI - The stability and complexity of antibody responses to the major surface antigen of Plasmodium falciparum are associated with age in a malaria endemic area. AB - Individuals that are exposed to malaria eventually develop immunity to the disease with one possible mechanism being the gradual acquisition of antibodies to the range of parasite variant surface antigens in their local area. Major antibody targets include the large and highly polymorphic Plasmodium falciparum Erythrocyte Membrane Protein 1 (PfEMP1) family of proteins. Here, we use a protein microarray containing 123 recombinant PfEMP1-DBLalpha domains (VAR) from Papua New Guinea to seroprofile 38 nonimmune children (<4 years) and 29 hyperimmune adults (>=15 years) from the same local area. The overall magnitude, prevalence and breadth of antibody response to VAR was limited at <2 years and 2 2.9 years, peaked at 3-4 years and decreased for adults compared with the oldest children. An increasing proportion of individuals recognized large numbers of VAR proteins (>20) with age, consistent with the breadth of response stabilizing with age. In addition, the antibody response was limited in uninfected children compared with infected children but was similar in adults irrespective of infection status. Analysis of the variant-specific response confirmed that the antibody signature expands with age and infection. This also revealed that the antibody signatures of the youngest children overlapped substantially, suggesting that they are exposed to the same subset of PfEMP1 variants. VAR proteins were either seroprevalent from early in life, (<3 years), from later in childhood (>=3 years) or rarely recognized. Group 2 VAR proteins (Cys2/MFK-REY+) were serodominant in infants (<1-year-old) and all other sequence subgroups became more seroprevalent with age. The results confirm that the anti-PfEMP1-DBLalpha antibody responses increase in magnitude and prevalence with age and further demonstrate that they increase in stability and complexity. The protein microarray approach provides a unique platform to rapidly profile variant specific antibodies to malaria and suggests novel insights into the acquisition of immunity to malaria. PMID- 21825281 TI - Rapid response of the yeast plasma membrane proteome to salt stress. AB - The plasma membrane separates the cell from the external environment and plays an important role in the stress response of the cell. In this study, we compared plasma membrane proteome modifications of yeast cells exposed to mild (0.4 m NaCl) or high (1 m NaCl) salt stress for 10, 30, or 90 min. Plasma membrane enriched fractions were isolated, purified, and subjected to iTRAQ labeling for quantitative analysis. In total, 88-109 plasma membrane proteins were identified and quantified. The quantitative analysis revealed significant changes in the abundance of several plasma membrane proteins. Mild salt stress caused an increase in abundance of 12 plasma membrane proteins, including known salt responsive proteins, as well as new targets. Interestingly, 20 plasma membrane proteins, including the P-type H(+)-ATPase Pma1, ABC transporters, glucose and amino acid transporters, t-SNAREs, and proteins involved in cell wall biogenesis showed a significant and rapid decrease in abundance in response to both 0.4 m and 1 m NaCl. We propose that rapid protein internalization occurs as a response to hyper-osmotic and/or ionic shock, which might affect plasma membrane morphology and ionic homeostasis. This rapid response might help the cell to survive until the transcriptional response takes place. PMID- 21825282 TI - Recovery from an at-risk state: clinical and functional outcomes of putatively prodromal youth who do not develop psychosis. AB - BACKGROUND: The "clinical high risk" (CHR) construct was developed to identify individuals at imminent risk of developing psychosis. However, most individuals identified as CHR do not convert to psychosis, and it is unknown whether these nonconverting individuals actually recover from an at-risk state. METHODS: Eighty four prospectively identified patients meeting CHR criteria, and 58 healthy comparison subjects were followed in a 2-year longitudinal study. Analyses examined rates of conversion, clinical, and functional recovery. Proportional cause-specific hazard models were used to examine the effects of baseline and time-varying predictors on conversion and remission. Trajectories of symptoms and psychosocial functioning measures were compared across outcome groups. RESULTS: Competing risk survival analyses estimated that 30% of CHR subjects convert to psychosis by 2 years, while 36% symptomatically remit and 30% functionally recover by 2 years. Lower levels of negative and mood/anxiety symptoms were related to increased likelihood of both symptomatic and functional recovery. CHR subjects who remitted symptomatically were more similar to healthy controls in terms of both their baseline and longitudinal symptoms and functioning than the other outcome groups. CONCLUSIONS: Nonconverting CHR cases represented a heterogeneous group. Given that nonconverted subjects who remitted symptomatically also presented initially with less severe prodromal symptomatology and showed a distinct normative trajectory of both symptoms and psychosocial functioning over time, it may be possible to refine the CHR criteria to reduce the number of "false positive" cases by eliminating those who present with less severe attenuated positive symptoms or show early improvements in terms of symptoms or functioning. PMID- 21825284 TI - Structural and biochemical characterization of the C3-C4 intermediate Brassica gravinae and relatives, with particular reference to cellular distribution of Rubisco. AB - On the basis of its CO(2) compensation concentration, Brassica gravinae Ten. has been reported to be a C(3)-C(4) intermediate. This study investigated the structural and biochemical features of photosynthetic metabolism in B. gravinae. The cellular distribution of ribulose 1,5-bisphosphate carboxylase/oxygenase (Rubisco) was also examined in B. gravinae, B. napus L. (C(3)), Raphanus sativus L. (C(3)), and Diplotaxis tenuifolia (L.) DC. (C(3)-C(4)) by immunogold electron microscopy to elucidate Rubisco expression during the evolution from C(3) to C(3) C(4) intermediate plants. The bundle sheath (BS) cells of B. gravinae contained centrifugally located chloroplasts as well as centripetally located chloroplasts and mitochondria. Glycine decarboxylase P-protein was localized in the BS mitochondria. Brassica gravinae had low C(4) enzyme activities and high activities of Rubisco and photorespiratory enzymes, suggesting that it reduces photorespiratory CO(2) loss by the glycine shuttle. In B. gravinae, the labelling density of Rubisco was higher in the mesophyll chloroplasts than in the BS chloroplasts. A similar cellular pattern was found in other Brassicaceae species. These data demonstrate that, during the evolution from C(3) to C(3)-C(4) intermediate plants, the intercellular pattern of Rubisco expression did not change greatly, although the amount of chloroplasts in the BS cells increased. It also appears that intracellular variation in Rubisco distribution may occur within the BS cells of B. gravinae. PMID- 21825285 TI - Adjunctive rifampin is crucial to optimizing daptomycin efficacy against rabbit prosthetic joint infection due to methicillin-resistant Staphylococcus aureus. AB - Daptomycin is an attractive option for treating prosthetic joint infection, but the 6-mg/kg of body weight/day dose was linked to clinical failure and emergence of resistance. Using a methicillin-resistant Staphylococcus aureus (MRSA) knee prosthesis infection in rabbits, we studied the efficacies of high-dose daptomycin (22 mg/kg given intravenously [i.v.] once daily [o.d.]; equivalent to 8 mg/kg/day in humans) or vancomycin (60 mg/kg given intramuscularly [i.m.] twice daily [b.i.d.]), both either alone or with adjunctive rifampin (10 mg/kg i.m. b.i.d.). After partial knee replacement with a silicone implant, 10(7) MRSA CFU was injected into the knees. Treatment started 7 days postinoculation and lasted 7 days. Positive cultures were screened for the emergence of mutant strains, defined as having 3-fold-increased MICs. Although in vivo mean log(10) CFU/g of daptomycin-treated (4.23 +/- 1.44; n = 12) or vancomycin-treated (4.63 +/- 1.08; n = 12) crushed bone was significantly lower than that of controls (5.93 +/- 1.15; n = 9) (P < 0.01), neither treatment sterilized bone (2/12 and 0/12 rabbits with sterile bone, respectively). Daptomycin mutant strains were found in 6/12, 3/12, and 2/9 daptomycin-treated, vancomycin-treated, and control rabbits, respectively; no resistant strains emerged (MIC was always <1 mg/liter). Adjunctive rifampin with daptomycin (1.47 +/- 0.04 CFU/g of bone [detection threshold]; 11/11 sterile bones) or vancomycin (1.5 +/- 0.12 CFU/g of bone; 6/8 sterile bones) was significantly more effective than monotherapy (P < 0.01) and prevented the emergence of daptomycin mutant strains. In this MRSA joint prosthesis infection model, combining rifampin with daptomycin was highly effective. Daptomycin mutant strains were isolated in vivo even without treatment, but adjunctive rifampin prevented this phenomenon, previously found after monotherapy in humans. PMID- 21825287 TI - Impact of carbapenem resistance and receipt of active antimicrobial therapy on clinical outcomes of Acinetobacter baumannii bloodstream infections. AB - Nosocomial Acinetobacter baumannii bloodstream infections occur with significant prevalence and mortality. The relationship between carbapenem resistance in A. baumannii and patient outcomes remains unclear. A retrospective cohort study was conducted on patients with A. baumannii bacteremia. Outcomes, controlling for confounders, were compared for carbapenem-nonresistant A. baumannii (CNRAB) and carbapenem-resistant A. baumannii (CRAB). The primary outcome studied was all cause hospital mortality, and the secondary endpoints evaluated were time to mortality, time to negative cultures, and length of stay postinfection for survivors. A total of 79 patients, 37 infected with CRAB and 42 with CNRAB, were studied. Hospital mortality was greater in the CRAB group as determined based on bivariate analysis (P < 0.01); however, this effect was nullified when controlling for relevant confounders with logistic regression and a Cox proportional-hazards model (P = 0.71 and 0.75, respectively). Values for time to mortality and time to negative cultures did not differ between the groups. The median number of days of stay postinfection for survivors was greater for the CRAB group than the CNRAB group (14 versus 6.5; P < 0.01). Patients who received active antimicrobial therapy were less likely to die (93.5% versus 74.2%; P = 0.02), regardless of carbapenem susceptibility classifications, and this result was robust in the multivariate model (P = 0.02). Trends existed for improved outcomes in patients receiving an active beta-lactam, and patients fared worse if they had received a polymyxin as an active agent. Patients with CRAB bloodstream infections were more chronically ill and had more comorbidities. Inactive therapy was more important than carbapenem susceptibility with respect to outcomes, was a strong predictor of death, and is potentially modifiable. PMID- 21825286 TI - Impaired parasite attachment as fitness cost of metronidazole resistance in Giardia lamblia. AB - Infections with the diarrheagenic protozoan pathogen Giardia lamblia are most commonly treated with metronidazole (Mz). Treatment failures with Mz occur in 10 to 20% of cases and Mz resistance develops in the laboratory, yet clinically, Mz resistant (Mz(r)) G. lamblia has rarely been isolated from patients. To understand why clinical Mz(r) isolates are rare, we questioned whether Mz resistance entails fitness costs to the parasite. Our studies employed several newly generated and established isogenic Mz(r) cell lines with stable, high-level resistance to Mz and significant cross-resistance to tinidazole, nitazoxanide, and furazolidone. Oral infection of suckling mice revealed that three of five Mz(r) cell lines could not establish infection, while two Mz(r) cell lines infected pups, albeit with reduced efficiencies. Failure to colonize resulted from a diminished capacity of the parasite to attach to the intestinal mucosa in vivo and to epithelial cells and plastic surfaces in vitro. The attachment defect was related to impaired glucose metabolism, since the noninfectious Mz(r) lines consumed less glucose, and glucose promoted ATP-independent parasite attachment in the parental lines. Thus, resistance of Giardia to Mz is accompanied by a glucose metabolism-related attachment defect that can interfere with colonization of the host. Because glucose-metabolizing pathways are important for activation of the prodrug Mz, it follows that a fitness trade-off exists between diminished Mz activation and reduced infectivity, which may explain the observed paucity of clinical Mz(r) isolates of Giardia. However, the data also caution that some forms of Mz resistance do not markedly interfere with in vivo infectivity. PMID- 21825288 TI - Effect of the hepatitis C virus protease inhibitor telaprevir on the pharmacokinetics of amlodipine and atorvastatin. AB - Telaprevir is a hepatitis C virus protease inhibitor that is both a substrate and an inhibitor of CYP3A. Amlodipine and atorvastatin are both substrates of CYP3A and are among the drugs most frequently used by patients with hepatitis C. This study was conducted to examine the effect of telaprevir on atorvastatin and amlodipine pharmacokinetics (PK). This was an open-label, single sequence, nonrandomized study involving 21 healthy male and female volunteers. A coformulation of 5 mg amlodipine and 20 mg atorvastatin was administered on day 1. Telaprevir was taken with food as a 750-mg dose every 8 h from day 11 until day 26, and a single dose of the amlodipine-atorvastatin combination was readministered on day 17. Plasma samples were collected for determination of the PK of telaprevir, amlodipine, atorvastatin, ortho-hydroxy atorvastatin, and para hydroxy atorvastatin. When administration with telaprevir was compared with administration without telaprevir, the least-square mean ratios (90% confidence limits) for amlodipine were 1.27 (1.21, 1.33) for the maximum drug concentration in serum (C(max)) and 2.79 (2.58, 3.01) for the area under the concentration-time curve from 0 h to infinity (AUC(0-infinity)); for atorvastatin, they were 10.6 (8.74, 12.9) for the C(max) and 7.88 (6.84, 9.07) for the AUC(0-infinity). Telaprevir significantly increased exposure to amlodipine and atorvastatin, consistent with the inhibitory effect of telaprevir on the CYP3A-mediated metabolism of these agents. PMID- 21825283 TI - The Lifestyle Interventions and Independence for Elders Study: design and methods. AB - BACKGROUND: As the number of older adults in the United States rises, maintaining functional independence among older Americans has emerged as a major clinical and public health priority. Older people who lose mobility are less likely to remain in the community; demonstrate higher rates of morbidity, mortality, and hospitalizations; and experience a poorer quality of life. Several studies have shown that regular physical activity improves functional limitations and intermediate functional outcomes, but definitive evidence showing that major mobility disability can be prevented is lacking. A Phase 3 randomized controlled trial is needed to fill this evidence gap. METHODS: The Lifestyle Interventions and Independence for Elders (LIFE) Study is a Phase 3 multicenter randomized controlled trial designed to compare a supervised moderate-intensity physical activity program with a successful aging health education program in 1,600 sedentary older persons followed for an average of 2.7 years. RESULTS: LIFE's primary outcome is major mobility disability, defined as the inability to walk 400 m. Secondary outcomes include cognitive function, serious fall injuries, persistent mobility disability, the combined outcome of major mobility disability or death, disability in activities of daily living, and cost-effectiveness. CONCLUSIONS: Results of this study are expected to have important public health implications for the large and growing population of older sedentary men and women. PMID- 21825289 TI - Once-daily amikacin dosing in burn patients treated with continuous venovenous hemofiltration. AB - Amikacin clearance can be increased in burn injury, which is often complicated by renal insufficiency. Little is known about the impact of renal replacement therapies, such as continuous venovenous hemofiltration (CVVH), on amikacin pharmacokinetics. We retrospectively examined the clinical pharmacokinetics, bacteriology, and clinical outcomes of 60 burn patients given 15 mg/kg of body weight of amikacin in single daily doses. Twelve were treated with concurrent CVVH therapy, and 48 were not. The pharmacodynamic target of >=10 for the maximum concentration of drug in serum divided by the MIC (C(max)/MIC) was achieved in only 8.5% of patients, with a small reduction of C(max) in patients receiving CVVH and no difference in amikacin clearance. Mortality and burn size were greater in patients who received CVVH. Overall, 172 Gram-negative isolates were recovered from the blood cultures of 39 patients, with amikacin MIC data available for 82 isolates from 24 patients. A 10,000-patient Monte Carlo simulation was conducted incorporating pharmacokinetic and MIC data from these patients. The cumulative fraction of response (CFR) was similar in CVVH and non CVVH patients. The CFR rates were not significantly improved by a theoretical 20 mg/kg amikacin dose. Overall, CVVH did not appear to have a major impact on amikacin serum concentrations. The low pharmacodynamic target attainment appears to be primarily due to higher amikacin MICs rather than more rapid clearance of amikacin related to CVVH therapy. PMID- 21825290 TI - International pneumococcal clones match or exceed the fitness of other strains despite the accumulation of antibiotic resistance. AB - A few international pneumococcal clones dominate the population of antibiotic resistant pneumococci. Despite the scientific paradigm that a loss in fitness is the price for acquisition of resistance, these clones spread successfully. One hundred fifty-four isolates from adult patients with community-acquired pneumonia (CAP) were analyzed. Thirty percent showed a close relationship to international clones and had fitness equal to or exceeding that of other strains (P = 0.015); these factors may result in the endurance of these strains despite a reduction of antibiotic usage. PMID- 21825291 TI - In vitro activity of E1210, a novel antifungal, against clinically important yeasts and molds. AB - E1210 is a new antifungal compound with a novel mechanism of action and broad spectrum of antifungal activity. We investigated the in vitro antifungal activities of E1210 compared to those of fluconazole, itraconazole, voriconazole, amphotericin B, and micafungin against clinical fungal isolates. E1210 showed potent activities against most Candida spp. (MIC(90) of <=0.008 to 0.06 MUg/ml), except for Candida krusei (MICs of 2 to >32 MUg/ml). E1210 showed equally potent activities against fluconazole-resistant and fluconazole-susceptible Candida strains. E1210 also had potent activities against various filamentous fungi, including Aspergillus fumigatus (MIC(90) of 0.13 MUg/ml). E1210 was also active against Fusarium solani and some black molds. Of note, E1210 showed the greatest activities against Pseudallescheria boydii (MICs of 0.03 to 0.13 MUg/ml), Scedosporium prolificans (MIC of 0.03 MUg/ml), and Paecilomyces lilacinus (MICs of 0.06 MUg/ml) among the compounds tested. The antifungal action of E1210 was fungistatic, but E1210 showed no trailing growth of Candida albicans, which has often been observed with fluconazole. In a cytotoxicity assay using human HK-2 cells, E1210 showed toxicity as low as that of fluconazole. Based on these results, E1210 is likely to be a promising antifungal agent for the treatment of invasive fungal infections. PMID- 21825292 TI - The MUT056399 inhibitor of FabI is a new antistaphylococcal compound. AB - MUT056399 is a highly potent new inhibitor of the FabI enzyme of both Staphylococcus aureus and Escherichia coli. In vitro, MUT056399 was very active against S. aureus strains, including methicillin-susceptible S. aureus (MSSA), methicillin-resistant S. aureus (MRSA), linezolid-resistant, and multidrug resistant strains, with MIC(90)s between 0.03 and 0.12 MUg/ml. MUT056399 was also active against coagulase-negative staphylococci, with MIC(90)s between 0.12 and 4 MUg/ml. The antibacterial spectrum is consistent with specific FabI inhibition with no activity against bacteria using FabK but activity against FabI-containing Gram-negative bacilli. In vitro, resistant clones of S. aureus were obtained at a low frequency. All of the resistant clones analyzed were found to contain mutations in the fabI gene. In vivo, MUT056399, administered subcutaneously, protected mice from a lethal systemic infection induced by MSSA, MRSA, and vancomycin-intermediate S. aureus strains (50% effective doses ranging from 19.3 mg/kg/day to 49.6 mg/kg/day). In the nonneutropenic murine thigh infection model, the same treatment with MUT056399 reduced the bacterial multiplication of MSSA and MRSA in the thighs of immunocompetent mice. These properties support MUT056399 as a very promising candidate for a novel drug to treat severe staphylococcal infections. PMID- 21825293 TI - Nonconcordance with surgical site infection prevention guidelines and rates of surgical site infections for general surgical, neurological, and orthopedic procedures. AB - Surgical site infection (SSI) is a common and preventable complication of surgery, but the relative importance of individual measures recommended by guidelines has not been determined. Elective general surgical, neurological, and orthopedic procedures requiring antibiotic prophylaxis from a 3-month period were retrospectively studied to determine concordance with SSI prevention guidelines and to identify factors which predicted the development of SSIs. A total of 216 surgeries were reviewed, with 18 SSIs (8.3%). A mean of 1.4 antibiotic prophylaxis errors per surgery were identified, with correct antibiotic type identified for 64%, antibiotic timing for 83%, supplemental antibiotic dosing for 34%, and antibiotic duration of less than 24 h for 44%. Normothermia was present in 79% of surgeries, and normoglycemia was present in 17%. Univariate analysis of the SSI rate identified four significant factors. Antibiotic prophylaxis for less than 24 h postoperatively (odds ratio [OR], 0.213; 95% confidence interval [95% CI]0.060 to 0.757) and neurosurgery (OR, 0.118; 95% CI, 0.15 to 0.903) correlated with a reduced risk of SSI. The mean number of prophylaxis errors (OR, 1.6; 95% CI, 1.02 to 2.4) and a duration of surgical drainage for more than 3 days (OR, 2.679; 95% CI, 1.009 to 7.113) predicted SSI. By multivariate analysis, errors in individual antibiotic prophylaxis measures were not significantly associated with SSI; however, the presence of more than two errors was significant (OR, 4.030; 95% CI, 1.018 to 15.96). A strong correlation was identified between the degree of concordance to SSI prevention guidelines and the SSI rate (P = 0.001, Mantel Haenszel linear-by-linear association chi-square test). PMID- 21825294 TI - Prediction of failure in vancomycin-treated methicillin-resistant Staphylococcus aureus bloodstream infection: a clinically useful risk stratification tool. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is a common cause of bloodstream infection (BSI) and is often associated with invasive infections and high rates of mortality. Vancomycin has remained the mainstay of therapy for serious Gram-positive infections, particularly MRSA BSI; however, therapeutic failures with vancomycin have been increasingly reported. We conducted a comprehensive evaluation of the factors (patient, strain, infection, and treatment) involved in the etiology and management of MRSA BSI to create a risk stratification tool for clinicians. This study included consecutive patients with MRSA BSI treated with vancomycin over 2 years in an inner-city hospital in Detroit, MI. Classification and regression tree analysis (CART) was used to develop a risk prediction model that characterized vancomycin-treated patients at high risk of clinical failure. Of all factors, the Acute Physiology and Chronic Health Evaluation II (APACHE-II) score, with a cutoff point of 14, was found to be the strongest predictor of failure and was used to split the population into two groups. Forty-seven percent of the population had an APACHE-II score < 14, a value that was associated with low rates of clinical failure (11%) and mortality (4%). Fifty-four percent of the population had an APACHE-II score >= 14, which was associated with high rates of clinical failure (35%) and mortality (23%). The risk stratification model identified the interplay of three other predictors of failure, including the vancomycin MIC as determined by Vitek 2 analysis, the risk level of the source of BSI, and the USA300 strain type. This model can be a useful tool for clinicians to predict the likelihood of success or failure in vancomycin-treated patients with MRSA bloodstream infection. PMID- 21825295 TI - Impairment of swimming motility by antidiarrheic Lactobacillus acidophilus strain LB retards internalization of Salmonella enterica serovar Typhimurium within human enterocyte-like cells. AB - We report that both culture and the cell-free culture supernatant (CFCS) of Lactobacillus acidophilus strain LB (Lacteol Boucard) have the ability (i) to delay the appearance of Salmonella enterica serovar Typhimurium strain SL1344 induced mobilization of F-actin and, subsequently, (ii) to retard cell entry by S. Typhimurium SL1344. Time-lapse imaging and Western immunoblotting showed that S. Typhimurium SL1344 swimming motility, as represented by cell tracks of various types, was rapidly but temporarily blocked without affecting the expression of FliC flagellar propeller protein. We show that the product(s) secreted by L. acidophilus LB that supports the inhibitory activity is heat stable and of low molecular weight. The product(s) caused rapid depolarization of the S. Typhimurium SL1344 cytoplasmic membrane without affecting bacterial viability. We identified inhibition of swimming motility as a newly discovered mechanism by which the secreted product(s) of L. acidophilus strain LB retards the internalization of the diarrhea-associated pathogen S. enterica serovar Typhimurium within cultured human enterocyte-like cells. PMID- 21825296 TI - Dissemination of an NDM-2-producing Acinetobacter baumannii clone in an Israeli rehabilitation center. AB - New Delhi metallo-beta-lactamase (NDM-1) was initially identified in various Enterobacteriaceae and recently in Acinetobacter baumannii. This study described the clonal dissemination of an NDM-2-producing A. baumannii isolate in an Israeli rehabilitation ward and the genetic surroundings of the gene. The bla(NDM-2) gene was surrounded by the ble and trpF genes downstream and two copies of the ISAba125 on both sides. These are the first NDM-producing A. baumannii strains in Israel from patients with no previous travel or hospitalization on the Indian subcontinent. PMID- 21825297 TI - In vitro and in vivo activities of novel, semisynthetic thiopeptide inhibitors of bacterial elongation factor Tu. AB - Recently, we identified aminothiazole derivatives of GE2270 A. These novel semisynthetic congeners, like GE2270 A, target the essential bacterial protein elongation factor Tu (EF-Tu). Medicinal chemistry optimization of lead molecules led to the identification of preclinical development candidates 1 and 2. These cycloalklycarboxylic acid derivatives show activity against difficult to treat Gram-positive pathogens and demonstrate increased aqueous solubility compared to GE2270 A. We describe here the in vitro and in vivo activities of compounds 1 and 2 compared to marketed antibiotics. Compounds 1 and 2 were potent against clinical isolates of methicillin-resistant Staphylococcus aureus and vancomycin resistant enterococci (MIC(90) <= 0.25 MUg/ml) but weaker against the streptococci (MIC(90) >= 4 MUg/ml). Like GE2270 A, the derivatives inhibited bacterial protein synthesis and selected for spontaneous loss of susceptibility via mutations in the tuf gene, encoding EF-Tu. The mutants were not cross resistant to other antibiotic classes. In a mouse systemic infection model, compounds 1 and 2 protected mice from lethal S. aureus infections with 50% effective doses (ED(50)) of 5.2 and 4.3 mg/kg, respectively. Similarly, compounds 1 and 2 protected mice from lethal systemic E. faecalis infections with ED(50) of 0.56 and 0.23 mg/kg, respectively. In summary, compounds 1 and 2 are active in vitro and in vivo activity against difficult-to-treat Gram-positive bacterial infections and represent a promising new class of antibacterials for use in human therapy. PMID- 21825299 TI - Is cefazolin inferior to nafcillin for treatment of methicillin-susceptible Staphylococcus aureus bacteremia? AB - About 20% of methicillin-susceptible Staphylococcus aureus (MSSA) isolates have a substantial inoculum effect with cefazolin, suggesting that cefazolin treatment may be associated with clinical failure for serious MSSA infections. There are no well-matched controlled studies comparing cefazolin with nafcillin for the treatment of MSSA bacteremia. A retrospective propensity-score-matched case control study was performed from 2004 to 2009 in a tertiary care hospital where nafcillin was unavailable from August 2004 to August 2006. The cefazolin group (n = 49) included MSSA-bacteremic patients treated with cefazolin during the period of nafcillin unavailability, while the nafcillin group (n = 84) comprised those treated with nafcillin. Treatment failure was defined as a composite outcome of a change of antibiotics due to clinical failure, relapse, and mortality. Of 133 patients, 41 patients from each group were matched by propensity scores. There were no significant differences in baseline characteristics between the matched groups. The treatment failure rates were not significantly different at 4 or 12 weeks (10% [4/41] versus 10% [4/41] at 4 weeks [P > 0.99] and 15% [6/41] versus 15% [6/41] at 12 weeks [P > 0.99]). Cefazolin treatment was interrupted less frequently than nafcillin treatment due to drug adverse events (0% versus 17%; P = 0.02). Cefazolin had clinical efficacy similar to that of nafcillin and was more tolerable than nafcillin for the treatment of MSSA bacteremia. PMID- 21825300 TI - Comparison of drug resistance scores for tipranavir in protease inhibitor-naive patients infected with HIV-1 B and non-B subtypes. AB - Genotypes of samples from protease inhibitor-naive patients in Frankfurt's HIV Cohort were analyzed with five tipranavir resistance prediction algorithms. Mean scores were higher in non-B than in B subtypes. The proportion of non-B subtypes increased with increasing scores, except in weighted algorithms. Virtual and in vitro phenotype analyses of samples with increased scores showed no reduced tipranavir susceptibility. Current algorithms appear suboptimal for interpretation of resistance to tipranavir in non-B subtypes; increased scores might reflect algorithm bias rather than "natural resistance." PMID- 21825298 TI - Phase III randomized, double-blind study comparing single-dose intravenous peramivir with oral oseltamivir in patients with seasonal influenza virus infection. AB - Antiviral medications with activity against influenza viruses are important in controlling influenza. We compared intravenous peramivir, a potent neuraminidase inhibitor, with oseltamivir in patients with seasonal influenza virus infection. In a multinational, multicenter, double-blind, double-dummy randomized controlled study, patients aged >= 20 years with influenza A or B virus infection were randomly assigned to receive either a single intravenous infusion of peramivir (300 or 600 mg) or oral administration of oseltamivir (75 mg twice a day [b.i.d.] for 5 days). To demonstrate the noninferiority of peramivir in reducing the time to alleviation of influenza symptoms with hazard model analysis and a noninferiority margin of 0.170, we planned to recruit 1,050 patients in South Korea, Japan, and Taiwan. A total of 1,091 patients (364 receiving 300 mg and 362 receiving 600 mg of peramivir; 365 receiving oseltamivir) were included in the intent-to-treat infected population. The median durations of influenza symptoms were 78.0, 81.0, and 81.8 h in the groups treated with 300 mg of peramivir, 600 mg of peramivir, and oseltamivir, respectively. The hazard ratios of the 300- and 600-mg-peramivir groups compared to the oseltamivir group were 0.946 (97.5% confidence interval [CI], 0.793, 1.129) and 0.970 (97.5% CI, 0.814, 1.157), respectively. Both peramivir groups were noninferior to the oseltamivir group (97.5% CI, <1.170). The overall incidence of adverse drug reactions was significantly lower in the 300-mg-peramivir group, but the incidence of severe reactions in either peramivir group was not different from that in the oseltamivir group. Thus, a single intravenous dose of peramivir may be an alternative to a 5-day oral dose of oseltamivir for patients with seasonal influenza virus infection. PMID- 21825301 TI - Characterization of the retrocyclin analogue RC-101 as a preventative of Staphylococcus aureus nasal colonization. AB - Nasal colonization of Staphylococcus aureus is a risk factor for pathogenic autoinfection, particularly in postoperative patients and the immunocompromised. As such, standardized preoperative nasal decolonization of S. aureus has become a major consideration for the prevention of nosocomial infection. However, only a few treatment options for nasal decolonization are currently available, with resistance to these approaches already a concern. Here we have identified the macrocyclic -defensin analogue RC-101 as a promising anti-S. aureus agent for nasal decolonization. RC-101 exhibits bactericidal effects against S. aureus with the use of in vitro epithelium-free systems, while also preventing the pathogen's proliferation and attachment in an ex vivo human nasal epithelial cell adhesion model and an organotypic model of human airway epithelia. Peptide concentrations as low as 2.5 MUM elicited significant reductions in S. aureus growth in epithelium-free systems, with 10 MUM concentrations being completely bactericidal for all strains tested, including USA300. In ex vivo nasal colonization models, RC-101 significantly reduced adherence, survival, and proliferation of S. aureus on human nasal epithelia. Reductions in S. aureus viability were evident in these assays, with as little as 1 MUg of peptide per tissue, while 10 MUg of RC-101 completely prevented adhesion of all strains tested. Furthermore, RC-101 did not exhibit cellular toxicity to human nasal epithelia at concentrations up to 200 MUM, nor did it induce a proinflammatory response in these cells. Collectively, the findings of this study identify RC-101 as a potential preventative of S. aureus nasal colonization. PMID- 21825302 TI - Development of peptide-conjugated morpholino oligomers as pan-arenavirus inhibitors. AB - Members of the Arenaviridae family are a threat to public health and can cause meningitis and hemorrhagic fever, and yet treatment options remain limited by a lack of effective antivirals. In this study, we found that peptide-conjugated phosphorodiamidate morpholino oligomers (PPMO) complementary to viral genomic RNA were effective in reducing arenavirus replication in cell cultures and in vivo. PPMO complementary to the Junin virus genome were designed to interfere with viral RNA synthesis or translation or both. However, only PPMO designed to potentially interfere with translation were effective in reducing virus replication. PPMO complementary to sequences that are highly conserved across the arenaviruses and located at the 5' termini of both genomic segments were effective against Junin virus, Tacaribe virus, Pichinde virus, and lymphocytic choriomeningitis virus (LCMV)-infected cell cultures and suppressed viral titers in the livers of LCMV-infected mice. These results suggest that arenavirus 5' genomic termini represent promising targets for pan-arenavirus antiviral therapeutic development. PMID- 21825303 TI - Longitudinal assessment of noise exposure in a cohort of construction workers. AB - OBJECTIVES: To address questions surrounding noise-induced hearing loss (NIHL) from variable noise, we have been evaluating noise exposures and changes in hearing in a prospective cohort of construction workers (representing eight trades) and controls. In this paper, we develop and explore several long-term exposure estimates for cohort members. METHODS: We followed cohort members between 1999 and 2009 and interviewed them approximately annually to obtain a detailed work history for the previous subject-interval while also collecting tests of hearing sensitivity. Over the same period, we also collected a sample of full-shift average noise measurements and activity information. We used data from these two sources to develop various exposure estimates for each subject for specific subject intervals and for the duration of the study. These estimates included work duration, trade-mean (TM)-equivalent continuous exposure level (L(EQ)), task-based (TB) L(EQ), a hybrid L(EQ) combining TB and subjective information, and an estimate of noise exposure 'peakiness'. RESULTS: Of the 456 subjects enrolled in the study, 333 had at least 2 interviews and met several inclusion criteria related to hearing sensitivity. Depending on the metric used, between one-third and three-quarters of 1310 measured full-shift noise exposures exceeded permissible and recommended exposure limits. Hybrid and TB exposure estimates demonstrated much greater variability than TM estimates. Work duration and estimates of exposure peakiness showed poor agreement with average exposures, suggesting that these metrics evaluate different aspects of exposure and may have different predictive value for estimating NIHL. CONCLUSIONS: Construction workers in the cohort had subject-interval and study-average exposures which present a substantial potential risk of NIHL. In a subsequent paper, we will use these estimates to evaluate the exposure-response relationship between noise and NIHL. PMID- 21825304 TI - Parathyroid hormone and phosphorus overload in uremia: impact on cardiovascular system. AB - BACKGROUND: Cardiac remodeling in uremia is characterized by left ventricular hypertrophy, interstitial fibrosis and microvascular disease. Cardiovascular disease is the leading cause of death in uremic patients, but coronary events alone are not the prevalent cause, sudden death and heart failure are. We studied the cardiac remodeling in experimental uremia, evaluating the isolated effect of parathyroid hormone (PTH) and phosphorus. METHODS: Wistar rats were submitted to parathyroidectomy (PTx) and 5/6 nephrectomy (Nx); they also received vehicle (V) and PTH at normal (nPTH) or high (hPTH) doses. They were fed with a poor phosphorus (pP) or rich-phosphorus (rP) diet and were divided into the following groups: 'Sham': G1 (V+normal-phosphorus diet (np)) and 'Nx+PTx': G2 (nPTH+pP), G3 (nPTH+rP), G4 (hPTH+pP) and G5 (hPTH+rP). After 8 weeks, biochemical analysis, myocardium morphometry and arteriolar morphological analysis were performed. In addition, using immunohistochemical analysis, we evaluated angiotensin II, alpha actin, transforming growth factor-beta (TGF-beta) and nitrotyrosine, as well as fibroblast growth factor-23 (FGF-23), fibroblast growth factor receptor-1 (FGFR 1) and runt-related transcription factor-2 (Runx-2) expression. RESULTS: Nx animals presented higher serum creatinine levels as well as arterial hypertension. Higher PTH levels were associated with myocardial hypertrophy and fibrosis as well as a higher coronary lesion score. High PTH animals also presented a higher myocardial expression of TGF-beta, angiotensin II, FGF-23 and nitrotyrosine and a lower expression of alpha-actin. Phosphorus overload was associated with higher serum FGF-23 levels and Runx-2, as well as myocardial hypertrophy. FGFR-1 was positive in the cardiomyocytes of all groups as well as in calcified coronaries of G4 and G5 whereas Runx-2 was positive in G3, G4 and G5. CONCLUSION: In uremia, PTH and phosphorus overload are both independently associated with major changes related to the cardiac remodeling process, emphasizing the need for a better control of these factors in chronic kidney disease. PMID- 21825305 TI - Annual variation in body fat is associated with systemic inflammation in chronic kidney disease patients Stages 3 and 4: a longitudinal study. AB - BACKGROUND: In dialysis patients, cross-sectional studies show that total and abdominal body fat associate with inflammatory markers. Whether this is true in earlier disease stages is unknown. We evaluated the cross-sectional and longitudinal (12-month interval) association between body fat markers and C reactive protein (CRP) in pre-dialysis chronic kidney disease (CKD) patients. METHODS: We studied, over a period of 1 year, clinically stable CKD patients at Stages 3-4 who were under treatment in a single outpatient clinic. Fifty-seven patients were included and 44 concluded the observational period [males: 66%; age: 62.9+/-13.9 years; body mass index (BMI): 25.5+/-5.1 kg/m2; estimated glomerular filtration rate (eGFR): 34+/-12.3 mL/min/1.73 m2]. Total body fat (skinfold thicknesses), waist circumference (WC), laboratory measurements (serum creatinine, total cholesterol, albumin, high-sensitivity CRP and leptin) and food intake (24-h food recall) were assessed at baseline and after 12+/-2 months. RESULTS: Most patients had anthropometric parameters in the range of overweight/obesity and none had signs of protein-energy wasting. In univariate analysis, changes (delta: end-baseline) in CRP were associated (P<0.05) with changes in BMI (r=0.39) and WC (r=0.33). In multiple regression analysis, these associations remained significant (P<0.05) even after adjusted by potential confounders (sex, diabetes, baseline age and eGFR). CONCLUSIONS: During a follow up of 12 months, changes in BMI and WC were directly associated with changes in CRP. Our results support the concept that interventions aimed at reducing weight and/or abdominal adiposity in pre-dialysis CKD patients may also translate into reduced systemic inflammation. PMID- 21825306 TI - Influence of physical activity on cardiorespiratory fitness in children after renal transplantation. AB - BACKGROUND: Cardiorespiratory fitness is significantly reduced in children with end-stage renal disease. The role of renal transplantation in improving cardiorespiratory fitness has not been thoroughly investigated. METHODS: In this work, we wanted to assess whether, in children after a successful renal transplant, the amount of weekly physical exercise affects cardiorespiratory fitness and left ventricular mass (LVM). The study was conducted on 16 children after renal transplantation and 36 matching healthy controls. Four groups were formed according to the weekly amount of physical exercise; all children received an echocardiogram and underwent a treadmill exercise test according to the Bruce protocol. RESULTS: Cardiorespiratory fitness is worst in renal transplant children with a weekly physical exercise<3 h; renal transplant children with a physical exercise of 3-5 h per week attain a cardiorespiratory fitness comparable to controls with a sedentary lifestyle (<3-h exercise per week); healthy controls with a weekly physical exercise of 3-5 h per week show the highest levels of cardiorespiratory fitness; the LVM assessed via echocardiography follows the same pattern. CONCLUSIONS: In children with a successful renal transplant, a weekly physical exercise of 3-5 h significantly improves the cardiorespiratory fitness and the LVM, up to the level of matching healthy controls with a sedentary lifestyle (<3 h exercise per week). PMID- 21825307 TI - Saccharomyces as a vaccine against systemic aspergillosis: 'the friend of man' a friend again? AB - The mortality of clinical Aspergillus infections necessitates consideration of the utility of a vaccine. We have found that Saccharomyces species can act as a protective vaccine against a lethal systemic Aspergillus infection, and describe experiments optimizing a subcutaneous regimen with killed yeast. Three injections of 2.5 mg given a week apart, 2 weeks prior to challenge, consistently, significantly, provided survival protection and reduction of infection in organs in survivors. The protection was independent of the strain of Saccharomyces, and possibly even the species, and could be demonstrated in several inbred (including C'-deficient) and outbred mouse strains. The protective moiety(ies) appeared to reside in the cell wall and was resistant to 100 degrees C, but not to protease or formalin. Alum potentiated the protection. The protection was comparable or superior to that of several Aspergillus-specific preparations described in the literature. Other studies have indicated that heat-killed Saccharomyces can protect against infection with at least three other fungal genera, raising the possibility of development of a panfungal vaccine, and such a vehicle has been studied in clinical trials, without dose-limiting toxicity. PMID- 21825308 TI - Hepatic peroxisome proliferator-activated receptor-gamma-fat-specific protein 27 pathway contributes to obesity-related hypertension via afferent vagal signals. AB - AIMS: Obesity is commonly associated with hypertension. Increased sympathetic tonus in obese subjects contributes to the underlying mechanism. However, the precise mechanisms whereby obesity induces this sympathetic activation remain unclear. Hepatic peroxisome proliferator-activated receptor (PPAR)-gamma2 expression, which is reportedly upregulated during obesity development, affects sympathetic activation via hepatic vagal afferents. Herein, we report involvement of this neuronal relay in obesity-related hypertension. METHODS AND RESULTS: Peroxisome proliferator-activated receptor-gamma and a direct PPARgamma target, fat-specific protein 27 (Fsp27), were adenovirally overexpressed or knocked down in the liver, in combination with surgical dissection or pharmacological deafferentation of the hepatic vagus. Adenoviral PPARgamma2 expression in the liver raised blood pressure (BP) in wild-type but not in beta1/beta2/beta3 adrenergic receptor-deficient mice. In addition, knockdown of endogenous PPARgamma in the liver lowered BP in murine obesity models. Either surgical dissection or pharmacological deafferentation of the hepatic vagus markedly blunted BP elevation in mice with diet-induced and genetically-induced obesity. In contrast, BP was not elevated in other models of hepatic steatosis, DGAT1 and DGAT2 overexpressions, in which PPARgamma is not upregulated in the liver. Thus, hepatic PPARgamma upregulation associated with obesity is involved in BP elevation during obesity development. Furthermore, hepatic expression of Fsp27 raised BP and the effect was blocked by hepatic vagotomy. Hepatic Fsp27 is actually upregulated in murine obesity models and its knockdown reversed BP elevation. CONCLUSION: The hepatic PPARgamma-Fsp27 pathway plays important roles in the development of obesity-related hypertension via afferent vagal signals from the liver. PMID- 21825309 TI - Pathologic lesions caused by coinfection of Mycoplasma gallisepticum and H3N8 low pathogenic avian influenza virus in chickens. AB - Chickens were infected under experimental conditions with Mycoplasma gallisepticum and low pathogenic avian influenza (LPAI) strain A/mallard/Hungary/19616/07 (H3N8). Two groups of chickens were aerosol challenged with M. gallisepticum strain 1226. Seven days later, one of these groups and one mycoplasma-free group was challenged with LPAI H3N8 virus; one group without challenge remained as negative control. Eight days later, the birds were euthanized and examined for gross pathologic and histologic lesions. The body weight was measured, and the presence of antimycoplasma and antiviral antibodies was tested before the mycoplasma challenge, before the virus challenge, and at the end of the study to confirm both infections. Chickens in the mycoplasma infected group developed antibodies against M. gallisepticum but not against the influenza virus. Chickens of the group infected with the influenza virus became serologically positive only against the virus, while the birds in the coinfected group developed antibodies against both agents. The LPAI H3N8 virus strain did not cause decrease in body weight and clinical signs, and macroscopic pathological lesions were not present in the chickens. The M. gallisepticum infection caused respiratory signs, airsacculitis, and peritonitis characteristic of mycoplasma infection. However, the clinical signs and pathologic lesions and the reduction in weight gain were much more significant in the group challenged with both M. gallisepticum and LPAI H3N8 virus than in the group challenged with M. gallisepticum alone. PMID- 21825311 TI - Internet and print resources to facilitate pathology analysis when phenotyping genetically engineered rodents. AB - Genetically engineered mice and rats are increasingly used as models for exploring disease progression and mechanisms. The full spectrum of anatomic, biochemical, and functional changes that develop in novel, genetically engineered mouse and rat lines must be cataloged before predictions regarding the significance of the mutation may be extrapolated to diseases in other vertebrate species, including humans. A growing list of reference materials, including books, journal articles, and websites, has been produced in the last 2 decades to assist researchers in phenotyping newly engineered rodent lines. This compilation provides an extensive register of materials related to the pathology component of rodent phenotypic analysis. In this article, the authors annotate the resources they use most often, to allow for quick determination of their relevance to research projects. PMID- 21825310 TI - Metastatic melanomas in young broiler chickens (Gallus gallus domesticus). AB - Four young broiler chickens affected by multiple melanotic tumors are described. Grossly, there were multiple tumors composed of melanocytes within the skin, skeletal muscle, and multiple visceral organs. Tumors ranged from flattened macules to masses that extensively replaced viscera. Microscopically, melanocytes were often well pigmented, and while there was moderate nuclear anisokaryosis, mitotic rates were low. Immunohistochemical staining of some melanomas with antibodies to S100 proteins, Melan-A, vimentin, or neuron-specific enolase after bleaching of tumor cells with potassium permanganate revealed lack of immunostaining of tumor cells with antibodies to S100, strong positive staining of tumor cells for neuron-specific enolase, moderate staining with antibodies to vimentin, and faint staining for Melan-A. Only neuron-specific enolase staining was evident in unbleached tumor cells. Attempts to identify exogenous avian leukosis viruses in these tumors were unsuccessful. PMID- 21825312 TI - Pathologic findings and toxin identification in cyanobacterial (Nodularia spumigena) intoxication in a dog. AB - A 3-year-old Cairn Terrier dog that had been in contact with sea water containing cyanobacteria (blue-green algae) was euthanized because of acute hepatic failure and anuria after a 5-day illness. Histologic findings included lytic and hemorrhagic centrilobular hepatocellular necrosis and renal tubular necrosis. The cyanotoxin nodularin was detected in liver and kidney by high-performance liquid chromatography-mass spectrometry. Nodularin is a potent hepatotoxin produced by the algal species Nodularia spumigena. The intensity of algal blooms has increased during the past decades in the Baltic Sea region, thus increasing the risk for intoxications in domestic and wild animals. The authors describe the pathologic findings of cyanobacterial toxicosis in a dog with direct identification of the toxin from organ samples. PMID- 21825313 TI - Postnatal neurogenesis: of mice, men, and macaques. AB - Over the past 20 years, the conception of brain development has radically changed from a fixed and limited hierarchical process to a more plastic and continuous one. Most surprising, the field has learned that postnatal neurogenesis is not just a seasonal phenomenon in songbirds but a process that occurs across species and seasons. Astrocytes, whose primary role in the central nervous system was thought to be strictly supportive, have emerged as a heterogeneous population, a subset of which is the neural stem cell. Postnatal neurogenesis persists in specialized niches within the rostral subventricular zone and hippocampal dentate gyrus and, for a limited period, within the white matter tracts and external granular layer of the cerebellum. These specialized microenvironments are influenced by factors in the blood, cerebrospinal fluid, and local extracellular matrix. This article reviews the current understanding of adult neurogenesis, which is conserved across many vertebrate species, underscoring the value of animal models in past and present studies of human neurogenesis and neurogenic disease. PMID- 21825314 TI - C-kit expression in canine mucosal melanomas. AB - The c-kit receptor is responsible for transmission of promigration signals to melanocytes; its downregulation may be involved in malignant progression of human melanocytic neoplasms. Expression of this receptor has not been examined in normal or neoplastic melanocytes from dogs. In this study, 14 benign dermal and 61 malignant mucosal melanocytic tumors were examined for c-kit (KIT) expression. Sites of the mucosal melanomas were gingiva (not further specified; n = 30), buccal gingiva (n = 6), soft palate (n = 4), hard palate (n = 5), tongue (n = 7), lip (n = 6), and conjunctiva (n = 3). Melan A was expressed in all 14 dermal melanocytomas and in 59 of 61 (96.7%) tumors from oral or conjunctival mucosa, confirming melanocytic origin. C-kit receptor expression was strong and diffuse throughout the cytoplasm in all 14 dermal melanocytomas and was identified in basilar mucosal melanocytes over submucosal neoplasms (27 of 61, 44.3%), junctional (neoplastic) melanocytes (17 of 61, 27.9%), and, less commonly, neoplastic melanocytes of the subepithelial tumors (6 of 61, 9.8%). KIT expression anywhere within the resected melanomas correlated with significantly longer survival. These results suggest that c-kit receptor expression may be altered in canine melanomas and may have potential as a prognostic indicator for mucosal melanomas. PMID- 21825315 TI - Calculated chiral and magneto-electric dichroic signals for copper metaborate (CuB(2)O(4)) in an applied magnetic field. AB - Expressions for dichroic signals in terms of electron multipoles have been used to analyse optical data gathered on a crystal of copper metaborate in the presence of a magnetic field. Calculated signals comply with the established crystal and magnetic structures of CuB(2)O(4), and respect the global symmetries of parity-even and parity-odd dichroic signals in full. We have success in describing five different experiments in total. The claim by Saito et al (2008 Phys. Rev. Lett. 101 117402) that they observe magnetic control of crystal chirality in one of their five experiments is challenged. PMID- 21825316 TI - Q-dependence of spin excitations in high-T(C) cuprates from spin-phonon coupling. AB - An understanding of spin excitations in cuprates is essential since the mechanism of high-T(C) superconductivity might be linked to spin fluctuations. Band calculations for 'one-dimensional' unit cells of La(2)CuO(4) show larger coupling (spin-phonon coupling, SPC) between anti-ferromagnetic spin waves and O-phonons than for Cu- or La-phonons. When this result is applied to a two-dimensional, free-electron like band, it leads to an 'hourglass' shape of the spin excitation spectrum, as in recent experiments. Isotope shifts and doping dependences of the excitations are discussed. PMID- 21825317 TI - Superconductivity at 56 K in samarium-doped SrFeAsF. AB - We synthesized the samples Sr(1-x)Sm(x)FFeAs with a ZrCuSiAs-type structure. These samples were characterized by resistivity and susceptibility. It is found that substitution of rare earth metal for alkaline earth metal in this system suppresses the anomaly in resistivity and induces superconductivity. Superconductivity at 56 K in nominal composition Sr(0.5)Sm(0.5)FFeAs is realized, indicating that the superconducting transition temperatures in the iron arsenide fluorides can reach as high as that in oxypnictides with the same structure. PMID- 21825318 TI - The effect of normal load on polytetrafluoroethylene tribology. AB - The tribological behavior of oriented poly(tetrafluoroethylene) (PTFE) sliding surfaces is examined as a function of sliding direction and applied normal load in classical molecular dynamics (MD) simulations. The forces are calculated with the second-generation reactive empirical bond-order potential for short-range interactions, and with a Lennard-Jones potential for long-range interactions. The range of applied normal loads considered is 5-30 nN. The displacement of interfacial atoms from their initial positions during sliding is found to vary by a factor of seven, depending on the relative orientation of the sliding chains. However, within each sliding configuration the magnitude of the interfacial atomic displacements exhibits little dependence on load over the range considered. The predicted friction coefficients are also found to vary with chain orientation and are in excellent quantitative agreement with experimental measurements. PMID- 21825319 TI - Effective slip lengths for flows over surfaces with nanobubbles: the effects of finite slip. AB - We consider effective slip lengths for flows of simple liquids over surfaces contaminated by gaseous nanobubbles. In particular, we examine whether the effects of finite slip over the liquid-bubble interface are important in limiting effective slip lengths over such surfaces. Using an expression that interpolates between the perfect slip and finite slip regimes for flow over bubbles, we conclude that for the bubble dimensions and coverages typically reported in the literature the effects of finite slip are secondary, reducing effective slip lengths by only 10%. Further, we find that nanobubbles do not significantly increase slip lengths beyond those reported for bare hydrophobic surfaces. PMID- 21825320 TI - Thermodynamic stability and electronic structure of small carbon nitride nanotubes. AB - In order to tune the electronic properties of carbon-based nanotubes, attention is now turning to new avenues based on chemical manipulation. The introduction of nitrogen at either doping or alloying concentrations has been shown to give rise to new tubular structures and desirable electronic properties, but a detailed understanding of the strain and thermodynamic properties is still lacking. In this paper a systematic computational study of the structure and thermodynamics of small C(x)N nanotubes is presented (x = 1, 2, 3, 5, and 7). The aim of this work is to investigate which stoichiometries and atomic distributions are likely to be stable under ambient and operating conditions, thereby offering viable candidates for future synthesis efforts. In addition to this, the electronic properties of stable structures are briefly examined, to establish whether small carbon nitride nanotubes may be tailored for emerging technological applications. PMID- 21825321 TI - Molecular dynamics study of the melting of a supported 887-atom Pd decahedron. AB - We employ classical molecular dynamics simulations to investigate the melting behaviour of a decahedral Pd(887) cluster on a single layer of graphite (graphene). The interaction between Pd atoms is modelled with an embedded-atom potential, while the adhesion of Pd atoms to the substrate is approximated with a Lennard-Jones potential. We find that the decahedral structure persists at temperatures close to the melting point, but that just below the melting transition, the cluster accommodates to the substrate by means of complete melting and then recrystallization into an fcc structure. These structural changes are in qualitative agreement with recently proposed models, and they verify the existence of an energy barrier preventing softly deposited clusters from 'wetting' the substrate at temperatures below the melting point. PMID- 21825322 TI - Modelling the relative stability of carbon nanotubes exposed to environmental adsorbates and air. AB - In parallel with the development of technological applications for carbon nanotubes, issues related to toxicology and environmental impact are also under increased scrutiny. It is clear from the available literature that the integrity of future carbon nanotube-based devices, our ability to anticipate failure of these devices, and our ability to manage the toxicological and environmental impacts require a detailed understanding of the stability of pure and functionalized carbon nanotubes under a full range of environmental conditions. Motivated by this endeavour, the present study uses a general thermodynamic model to predict the relative stability of carbon nanotubes exposed to a variety of atmospheric adsorbates, and uses them to examine the stability of nanotubes in air, as a function of the relative humidity. In general the results indicate that the adsorption of a sparse coverage of air is thermodynamically favoured, depending on the humidity, and the stability of small diameter nanotubes may be improved by exposure to humid air. PMID- 21825323 TI - Comparison of embedded atom method potentials for small aluminium cluster simulations. AB - In this paper, we present a comparison of the performance of a series of embedded atom method potentials for the evaluation of bulk and small aluminium cluster geometries and relative energies, against benchmark density functional theory calculations. In general, the non-pairwise potential-B (NP-B), which was parametrized against Al cluster data, performs the best. PMID- 21825324 TI - Modeling the crystallization of gold nanoclusters-the effect of the potential energy function. AB - The crystallization dynamics of 5083 atom gold nanoclusters, which were quenched from the melt, were studied by molecular dynamics (MD) using the EAM 'Glue' and 'Force-matched' potentials to compare and contrast how the crystallization dynamics is affected by these potential energy functions. MD simulations from each potential showed the formation of gold nanoclusters of icosahedral morphology during the quenching process, which is in good agreement with the experimental studies of gold nanoclusters formed under vacuum. The effect of the potential on the evolution of cluster (surface and interior) morphology during the crystallization process is discussed. PMID- 21825325 TI - Adsorption of atomic nitrogen and oxygen on [Formula: see text] surface: a density functional theory study. AB - The adsorption of atomic nitrogen and oxygen on the ([Formula: see text]) crystal face of zinc oxide (ZnO) was studied. Binding energies, workfunction changes, vibrational frequencies, charge density differences and electron localization functions were calculated. It was elucidated that atomic oxygen binds more strongly than nitrogen, with the most stable [Formula: see text] structure exhibiting a binding energy of -2.47 eV, indicating chemisorption onto the surface. Surface reconstructions were observed for the most stable minima of both atomic species. Positive workfunction changes were calculated for both adsorbed oxygen and nitrogen if the adsorbate interacted with zinc atoms. Negative workfunction changes were calculated when the adsorbate interacted with both surface oxygen and zinc atoms. Interactions between the adsorbate and the surface zinc atoms resulted in ionic-type bonding, whereas interactions with oxygen atoms were more likely to result in the formation of covalent-type bonding. The positive workfunction changes correlate with an experimentally observed increase in resistance of ZnO conductometric sensor devices. PMID- 21825326 TI - Quantum mechanical study of atomic hydrogen interaction with a fluorinated boron substituted coronene radical. AB - In this work we study the transmission of atomic hydrogen across a fluorinated boron-substituted coronene radical (C(19)H(12)BF(6)) as a model for partially fluorinated and boron-doped nanotubes or fullerenes. Complete active space self consistent field (CASSCF) and multi-reference configuration interaction (MRCI) methods are employed to calculate the potential energy surfaces for both ground and excited electronic states, and one-dimensional R-matrix propagation is utilized to investigate the transmission/reflection dynamics of atomic hydrogen, through the central six-member ring of the fluorinated boron-substituted coronene radical. The quantum scattering includes resonance effects as well as non adiabatic transitions between the ground and excited electronic states. Within the sudden approximation, both centre and off-centre approach trajectories have been investigated. Implications for atomic hydrogen encapsulation by carbon nanotube and fullerene are discussed. PMID- 21825327 TI - Impact of the carbon pore size and topology on the equilibrium quantum sieving of hydrogen isotopes at zero coverage and finite pressures. AB - Carbonaceous slit-shaped and square-shaped pores efficiently differentiate adsorbed hydrogen isotopes at 77 and 33 K. Extensive path integral Monte Carlo simulations revealed that the square-shaped carbon pores enhanced the selectivity of deuterium over hydrogen in comparison to equivalent slit-shaped carbon pores at zero coverage as well as at finite pressures (i.e. quantum sieving of hydrogen isotopes is pore-topology-dependent). We show that this enhancement of the D(2)/H(2) equilibrium selectivity results from larger localization of hydrogen isotopes in square-shaped pores. The operating pressures for efficient quantum sieving of hydrogen isotopes are strongly dependent on the topology as well as on the size of the carbon pores. However, for both considered carbon pore topologies the highest D(2)/H(2) separation factor is observed at zero-coverage limit. Depending on carbon pore size and topology we predicted monotonic decreasing and non-monotonic shape of the D(2)/H(2) equilibrium selectivity at finite pressures. For both kinds of carbonaceous pores of molecular sizes we predict high compression of hydrogen isotopes at 77 and 33 K (for example, the pore density of compressed hydrogen isotopes at 77 K and 0.25 MPa in a square-shaped carbon pore of size 2.6 A exceeds 60 mmol cm(-3); for comparison, the liquid density of para H(2) at 30 K and 30 MPa is 42 mmol cm(-3)). Finally, by direct comparison of simulation results with experimental data it is explained why 'ordinary' carbonaceous materials are not efficient quantum sieves. PMID- 21825328 TI - Optical properties of intermetallic compounds from first principles calculations: a search for the ideal plasmonic material. AB - First principles calculations have been used to predict the optical properties for a range of intermetallic compounds for which little or no experimental optical data are currently available. Density functional theory combined with the random phase approximation is used to calculate the dielectric functions for these compounds. The aim of this work is to investigate how the band edge and plasma frequency vary with composition in order to identify materials with promising plasmonic properties. Towards this end the intermetallic compounds chosen are composed of elements which on their own have reasonable optical properties for plasmonic applications. The position of the band edge relative to the plasma frequency is most favourable in the simple binary compounds formed from the alkali plus noble metals NaAu, KAu and KAg. In particular, for KAu the band edge and plasma frequency occur at almost the same frequency, and hence the imaginary part of the dielectric function is practically zero for frequencies below the plasma frequency. In addition, the plasma frequency in this compound is at relatively low frequency, promising a material with strong plasmon response in the infrared. PMID- 21825329 TI - The effect of small elongations on the electronic and optical signatures in InAs nanocrystal quantum dots. AB - We present a detailed theoretical investigation of the electronic structure and optical properties of InAs nanocrystals at the transition from spheres to rods. Using a semiempirical pseudopotential approach, we predict that, despite the qualitative similarity of both intra- and inter-band optical spectra, for NCs with R>15 A even slight elongations should result in shifts of the order of hundreds of meV in the spacings between STM peaks measured in the positive bias regime, in the position of the intra-band absorption peaks associated with transitions within the conduction band and in the separation between the first and the fifth peak in PLE experiments. Our results show that, based on the spectroscopic data, it should be possible to discriminate between spherical and elongated NCs with aspect ratios of length over diameter as small as 1.2. Indeed our results suggest that many nominally spherical experimental samples contained a large fraction of slightly elongated structures. PMID- 21825330 TI - Application of coupled nanoscale resonators for spectral sensing. AB - In this paper we propose a method to perform tunable spectral sensing using globally inhibitory coupled oscillators. The suggested system may operate in the analog radio frequency (RF) domain without high speed ADC and heavy digital signal processing. Oscillator arrays may be made of imprecise elements such as nanoresonators. Provided there is a proper coupling, the system dynamics can be made stable despite the imprecision of the components. Global coupling could be implemented using a common load and controlled by digital means to tune the bandwidth. This method may be used for spectral sensing in cognitive radio terminals. PMID- 21825331 TI - Oscillation of carbon molecules inside carbon nanotube bundles. AB - In this paper, we investigate the mechanics of a nanoscaled gigahertz oscillator comprising a carbon molecule oscillating within the centre of a uniform concentric ring or bundle of carbon nanotubes. Two kinds of oscillating molecules are considered, which are a carbon nanotube and a C(60) fullerene. Using the Lennard-Jones potential and the continuum approach, we obtain a relation between the bundle radius and the radii of the nanotubes forming the bundle, as well as the optimum bundle size which gives rise to the maximum oscillatory frequency for both the nanotube-bundle and the C(60)-bundle oscillators. While previous studies in this area have been undertaken through molecular dynamics simulations, this paper emphasizes the use of applied mathematical modelling techniques, which provides considerable insight into the underlying mechanisms of the nanoscaled oscillators. The paper presents a synopsis of the major results derived in detail by the present authors (Cox et al 2007 Proc. R. Soc. A 464 691-710 and Cox et al 2007 J. Phys. A: Math. Theor. 40 13197-208). PMID- 21825333 TI - Lattice dielectric and thermodynamic properties of yttria stabilized zirconia solids. AB - A study of lattice dielectric and thermodynamic properties of yttria stabilized zirconia (YSZ) crystals as a function of yttria concentration is reported. This study is based on density functional perturbation theory, using ABINIT. Within the local density approximation and the harmonic approximation, we find excellent agreement between calculated and low temperature experimental specific heat and dielectric constants. From the variation of the specific heat of YSZ with the yttria composition, we propose a simple additivity rule that estimates the dependence of the specific heat of YSZ on the yttria concentration, whereas for the dielectric constants of YSZ, the values are bounded by the dielectric constants of cubic and amorphous zirconia. PMID- 21825332 TI - The effect of Nd and Mg doping on the micro-Raman spectra of LiNbO(3) single crystals. AB - The LiNbO(3) congruent crystals doped with small Nd concentrations, <1 mol% Nd, and co-doped with Mg ions, 0-9 mol% Mg, were systematically investigated by means of micro-Raman spectroscopy in the Y and Z crystal directions. Results obtained from an undoped congruent crystal, an Nd-doped crystal, a Mg-doped crystal and Nd, Mg-co-doped crystals are compared. From the analyses of the results obtained in the Y direction, the Nd and Mg content dependence of the two lowest-Raman A(1)(TO(1)) and A(1)(TO(2)) modes, the half-width composition and the area ratio of the A(1)(TO(4)) and E(TO(8)) bands, we reached several conclusions about the incorporation mechanism of the Nd and Mg ions into the LiNbO(3) lattice. Likewise the Raman shift and half-width of the E(TO(1)) and E(TO(7)) modes were investigated in the Z direction. Results indicate that Mg and Nd ions are located in the Li site for low doping concentrations and for larger concentrations there is a replacement in both Li and Nb ion sites. PMID- 21825334 TI - A new EXAFS investigation of local structural changes in amorphous and crystalline GeO(2) at high pressure. AB - Structural transformations at high pressure in amorphous and quartz-like crystalline GeO(2) have been investigated by using a Paris-Edinburgh press coupled to EXAFS spectroscopy. From both the germanium absorption edge position and the Ge-O distance evolution, new detailed information has been obtained about the pressure behavior of the short range order. Crystalline GeO(2) undergoes a transformation from four- to six-fold coordination at about 8.5 GPa, but at least the whole 6-12 GPa pressure range should be considered as the transition region. On the other hand, amorphous GeO(2) is characterized by a much more gradual structural change and the full octahedral state is not reached at 13 GPa as commonly believed. Furthermore, no support to the recently claimed fully pentahedral intermediate state can be given. EXAFS signals of glassy GeO(2) beyond the first Ge-O shell qualitatively confirm the continuous breakdown of the intermediate range order up to 10 GPa. PMID- 21825335 TI - Ab initio calculations of the structure and mechanical properties of vanadium oxides. AB - VO, V(2)O(3), VO(2), V(6)O(13), V(4)O(9), V(3)O(7) and V(2)O(5) have been investigated in terms of structure, bulk modulus B and elastic constant C(44) using ab initio calculations. The C(44) values for V(6)O(13), V(4)O(9), V(3)O(7) and V(2)O(5) are significantly lower than those for V(2)O(3) and VO(2). As the V valency is increased from 3 to 5, C(44) decreases by 83%, whereas the bulk modulus decreases by 61%, leading to an increase in the B/C(44) ratio from 1.4 to 3.4. This is consistent with calculated decohesion energies for cleavage in VO(2) and V(2)O(5). When cleaving V(2)O(5), decohesion energies are considerably lower than those of VO(2). This behaviour may be understood based on V valency induced changes in the crystal and electronic structure as well as in the chemical bonding. As the V valency is increased, the bond strength decreases. The phases with a V valency >4 exhibit low C(44) values, large anisotropy and possess weak ionic bonding between the layers. The formation of easily plastically deformable structures is enabled by the screened Coulomb potential. The largest distance and therefore weakest bond strength is observed for V(2)O(5) in the (002) plane. PMID- 21825336 TI - Anomalous thermal expansion in rare-earth gallium perovskites: a comprehensive powder diffraction study. AB - Crystal structures of rare-earth gallium perovskites LaGaO(3), PrGaO(3), NdGaO(3) and Pr(1-x)Nd(x)GaO(3) (x = 0.25, 0.50, 0.75) solid solutions were investigated in the temperature range 12-300 K by high-resolution powder diffraction using synchrotron or neutron radiation. The previously reported negative thermal expansion in the b direction of the PrGaO(3) lattice has been found to be persistent in Pr(1-x)Nd(x)GaO(3) solid solutions and its magnitude has been revealed as proportional to the amount of praseodymium. Evaluation of the obtained temperature evolution of cell dimensions indicated a weak anomalous behaviour of the b lattice parameter in NdGaO(3), and its origin is supposed to be the same as in PrGaO(3), i.e. a coupling of the crystal electric field levels with phonon excitations of about 23-25 meV energy. The performed bond length analysis revealed an anomalous behaviour of both LnO(12) (Ln-rare-earth) and GaO(6) coordination polyhedra, which can be a structural manifestation of anomalous thermal expansion in the considered compounds. PMID- 21825337 TI - The theoretical tensile strength of fcc crystals predicted from shear strength calculations. AB - This work presents a simple way of estimating uniaxial tensile strength on the basis of theoretical shear strength calculations, taking into account its dependence on a superimposed normal stress. The presented procedure enables us to avoid complicated and time-consuming analyses of elastic stability of crystals under tensile loading. The atomistic simulations of coupled shear and tensile deformations in cubic crystals are performed using first principles computational code based on pseudo-potentials and the plane wave basis set. Six fcc crystals are subjected to shear deformations in convenient slip systems and a special relaxation procedure controls the stress tensor. The obtained dependence of the ideal shear strength on the normal tensile stress seems to be almost linearly decreasing for all investigated crystals. Taking these results into account, the uniaxial tensile strength values in three crystallographic directions were evaluated by assuming a collapse of the weakest shear system. Calculated strengths for [Formula: see text] and [Formula: see text] loading were found to be mostly lower than previously calculated stresses related to tensile instability but rather close to those obtained by means of the shear instability analysis. On the other hand, the strengths for [Formula: see text] loading almost match the stresses related to tensile instability. PMID- 21825338 TI - A quantum transfer matrix method for one-dimensional disordered electronic systems. AB - We develop a novel quantum transfer matrix method to study thermodynamic properties of one-dimensional (1D) disordered electronic systems. It is shown that the partition function can be expressed as a product of 2 * 2 local transfer matrices. We demonstrate this method by applying it to the 1D disordered Anderson model. Thermodynamic quantities of this model are calculated and discussed. PMID- 21825339 TI - In-depth investigation of EPR spectra of Mn(2+) ions in ZnS single crystals with pure cubic structure. AB - The X (9.8 GHz)-band electron paramagnetic resonance (EPR) properties of substitutional Mn(2+) ions in high quality cubic ZnS single crystals grown from PbCl(2) flux have been thoroughly investigated. Accurate spin Hamiltonian (SH) parameters: g = 2.002 25 +/- 0.000 06; a = (7.987 +/- 0.008) * 10(-4) cm(-1) and A = -(63.88 +/- 0.02) * 10(-4) cm(-1) were obtained by simulation and fitting to the experimentally allowed transitions recorded for the magnetic field aligned within +/- 0.25 degrees along the main crystal axes. The normally forbidden hyperfine [Formula: see text], Deltam = +/- 1 transitions were also observed. Their position was found to be in agreement, within the experimental accuracy of DeltaH = +/- 0.01 mT, with calculations using the same SH parameters. The angular variation of the ratios of the intensities of the central forbidden to the allowed transitions could be accounted for only by including an additional constant contribution. The observed line broadening of the [Formula: see text] and [Formula: see text] fine structure transitions and their line width variation in a (110) plane have been quantitatively described by considering a random distribution of lattice strains at the Mn(2+) impurity ions. The influence of the forbidden transitions and line broadening on the EPR spectra line shape of the Mn(2+) ions in cubic ZnS crystalline powders is also examined. PMID- 21825340 TI - Calculation of the solvent and solute enhancement factors in BCC metals assuming a hypothetical structure with fourteen first nearest neighbors. AB - In this paper the solute and solvent enhancement factors in a hypothetical body centered cubic (b.c.c) structure having fourteen first nearest neighbors are calculated by using a statistical model for diffusion in dilute alloys. Inherent to the model is the assumption of the equality of the first and second nearest neighbor jump distances, since in the b.c.c structure the difference between these distances, respectively, is only ~13.5%. The number of parameters required for fitting to evaluate the enhancement factors (b and B) is substantially reduced in comparison to existing models and therefore fewer experiments are necessary. Correlation effects are implicit in the calculated values of b and B. The results of the fitting provide values for the frequency ratios, the additional energies required to form a vacancy in the vicinity of a solute and for the binding energies between solute pairs, i.e., between the reference and tracer solute. Values of b and B in several dilute alloys were calculated at different temperatures. In general there is a good agreement between experimental and calculated values of b and B in the alloys tested. The equations for b and B can be used for temperatures where no experimental data exist. PMID- 21825341 TI - Noise characteristics of the Fano effect and the Fano-Kondo effect in triple quantum dots. AB - We theoretically compare transport properties of the Fano-Kondo effect with those of the Fano effect, focusing on the effect of a two-level state in a triple quantum dot (QD) system. We analyze shot noise characteristics in the Fano-Kondo region at zero temperature, and discuss the effect of strong electronic correlation in QDs. We found that the modulation of the Fano dip is strongly affected by the on-site Coulomb interaction in QDs, and stronger Coulomb interaction (Fano-Kondo case) induces larger noise. PMID- 21825342 TI - The size effects of electrodes in molecular devices: an ab initio study on the transport properties of C(60). AB - The role of electrodes in the transport properties of molecular devices is investigated by taking C(60) as an example and using gold nanowire and a gold atomic chain as the electrodes. The calculations are done by an ab initio method combined with the non-equilibrium Green function technique. We find that devices in which a single C(60) molecule is connected with different electrodes show completely different transport behavior. In the case of nanowire/C(60)/nanowire the device shows a metallic behavior with a big equilibrium conductance (about 2.18G(0)) and the current increases rapidly and almost linearly starting from zero. The transmission function shows wide peaks and platforms around the Fermi level. While in the atomic-chain/C(60)/atomic-chain case, the device shows resonant tunneling behavior and the Fermi level lies between the HOMO (highest occupied molecular orbital) and LUMO (lowest unoccupied molecular orbital) transmission peaks. This results in a current that is one order of magnitude smaller than that in the nanowire/C(60)/nanowire system and the current increases very slowly until the bias is big enough to include the LUMO peak in the bias window. The big difference in the conductance and the current arises from the different coupling between the electrodes and the C(60) and the different number of channels in the electrodes. PMID- 21825343 TI - Magnetic properties of undoped Cu(2)O fine powders with magnetic impurities and/or cation vacancies. AB - Fine powders of micron- and submicron-sized particles of undoped Cu(2)O semiconductor, with three different sizes and morphologies, have been synthesized by different chemical processes. These samples include nanospheres 200 nm in diameter, octahedra of size 1 um and polyhedra of size 800 nm. They exhibit a wide spectrum of magnetic properties. At low temperature, T = 5 K, the octahedron sample is diamagnetic with the magnetic susceptibility chi(OH) = -9.5 * 10(-6) emu g(-1) Oe(-1). The nanosphere is paramagnetic with chi(NS) = 2.2 * 10(-5) emu g(-1) Oe(-1). The other two polyhedron samples synthesized in different runs by the same process are found to show different magnetic properties. One of them exhibits weak ferromagnetism with T(C)~455 K and saturation magnetization M(S)~0.19 emu g(-1) at T = 5 K, while the other is paramagnetic with chi = 1.0 * 10(-5) emu g(-1) Oe(-1). The total magnetic moment estimated from the detected impurity concentration of Fe, Co and Ni, is too small to account for the observed magnetism by one to two orders of magnitude. Calculations by density functional theory (DFT) reveal that cation vacancies in the Cu(2)O lattice are one of the possible causes of induced magnetic moments. The results further predict that the defect-induced magnetic moments favour a ferromagnetically coupled ground state if the local concentration of cation vacancies, n(C), exceeds 12.5%. This offers a possible scenario to explain the observed magnetic properties. The limitations of the investigations in the present work, in particular in the theoretical calculations, are discussed and possible areas for further study are suggested. PMID- 21825344 TI - Anisotropic intermediate coupling superconductivity in Cu(0.03)TaS(2). AB - The anisotropic superconducting state properties in Cu(0.03)TaS(2) have been investigated by magnetization, magnetoresistance and specific heat measurements. They clearly show that Cu(0.03)TaS(2) undergoes a superconducting transition at T(C) = 4.03 K. The obtained superconducting parameters demonstrate that Cu(0.03)TaS(2) is an anisotropic type-II superconductor. Combining specific heat jump DeltaC/gamma(n)T(C) = 1.6(4), gap ratio 2Delta/k(B)T(C) = 4.0(9) and the estimated electron-phonon coupling constant lambda~0.68, the superconductivity in Cu(0.03)TaS(2) is explained within the intermediate coupling BCS scenario. First principles electronic structure calculations suggest that copper intercalation of 2H-TaS(2) causes a considerable increase of the Fermi surface volume and the carrier density, which suppresses the CDW fluctuation and favors the raise of T(C). PMID- 21825345 TI - Electromagnetic pulse-driven spin-dependent currents in semiconductor quantum rings. AB - We investigate the non-equilibrium charge and spin-dependent currents in a quantum ring with a Rashba spin-orbit interaction (SOI) driven by two asymmetric picosecond electromagnetic pulses. The equilibrium persistent charge and persistent spin-dependent currents are investigated as well. It is shown that the dynamical charge and the dynamical spin-dependent currents vary smoothly with a static external magnetic flux and the SOI provides a SU(2) effective flux that changes the phases of the dynamic charge and the dynamic spin-dependent currents. The period of the oscillation of the total charge current with the delay time between the pulses is larger in a quantum ring with a larger radius. The parameters of the pulse fields control to a certain extent the total charge and the total spin-dependent currents. The calculations are applicable to nanometre rings fabricated in heterojunctions of III-V and II-VI semiconductors containing several hundreds of electrons. PMID- 21825346 TI - Tunneling of large polarons in semiconducting zinc vanadate glasses. AB - The ac electrical properties of several compositions of the semiconducting zinc vanadate glasses have been studied in the frequency range 10 Hz-2 MHz and in the temperature range 93-423 K. It has been observed that the ac conductivity shows power law dependence. The experimental data for the conductivity have been analyzed in the framework of several theoretical models based on quantum mechanical tunneling and classical hopping over barriers in order to determine the conduction mechanism. It has been observed that the model based on the tunneling of large polarons, out of the several models discussed, could explain adequately the temperature and frequency dependence of the ac conductivity and its power law exponent. The parameters obtained from the fits of this model with the experimental results are reasonable. PMID- 21825347 TI - Structure and magnetic properties of Fe-doped ZnO prepared by the sol-gel method. AB - Zn(0.97)Fe(0.03)O nanoparticles were synthesized by the sol-gel method. X-ray diffraction (XRD) and transmission electron microscope (TEM) analysis revealed that the samples had pure ZnO wurtzite structure and Fe ions were well incorporated into the ZnO crystal lattice. X-ray photoelectron spectroscopy (XPS) showed that both Fe(2+) and Fe(3+) existed in Zn(0.97)Fe(0.03)O. The result of x ray absorption near-edge structure (XANES) further testified that Fe ions took the place of Zn sites in our samples. Magnetic measurements indicated that Zn(0.97)Fe(0.03)O was ferromagnetic at room temperature. PMID- 21825348 TI - Magneto-elastic interaction in cubic helimagnets with B20 structure. AB - The magneto-elastic interaction in cubic helimagnets with B 20 symmetry is considered. It is shown that this interaction is responsible for a negative contribution to the square of the spin-wave gap Delta and it alone appears to disrupt the assumed helical structure. It is suggested that competition between the positive part of Delta(I)(2), which stems from magnon-magnon interaction, and its negative magneto-elastic part leads to the quantum phase transition observed at high pressure in MnSi and FeGe. This transition has to occur when [Formula: see text]. For MnSi it was shown using rough estimations that at ambient pressure both parts Delta(I) and |Delta(ME)| are comparable with the experimentally observed gap. The magneto-elastic interaction is responsible for 2k modulation of the lattice where k is the helix wavevector and contributes to the magnetic anisotropy. Properties of the magnetic state above the quantum phase transition are also discussed. Experimental observation of the lattice modulation by x-ray and neutron scattering allows the determination of the strength of the anisotropic part of the magneto-elastic interaction responsible for the above phenomena and the lattice helicity. PMID- 21825349 TI - The quantum-mechanical basis of an extended Landau-Lifshitz-Gilbert equation for a current-carrying ferromagnetic wire. AB - An extended Landau-Lifshitz-Gilbert (LLG) equation is introduced to describe the dynamics of inhomogeneous magnetization in a current-carrying wire. The coefficients of all the terms in this equation are calculated quantum mechanically for a simple model which includes impurity scattering. This is done by comparing the energies and lifetimes of a spin wave calculated from the LLG equation and from the explicit model. Two terms are of particular importance since they describe non-adiabatic spin-transfer torque and damping processes which do not rely on spin-orbit coupling. It is shown that these terms may have a significant influence on the velocity of a current-driven domain wall and they become dominant in the case of a narrow wall. PMID- 21825350 TI - Alternating current driven instability in magnetic junctions. AB - An effect is considered of alternating (high-frequency) current on the spin-valve type magnetic junction configuration. The stability with respect to small fluctuations is investigated in the macrospin approximation. When the current frequency is close to the eigenfrequency (precession frequency) of the free layer, parametric resonance occurs. Both collinear configurations, antiparallel and parallel, can become unstable under resonance conditions. The antiparallel configuration can also become unstable under non-resonant conditions. The threshold current density amplitude is of the order of the dc current density for switching of the magnetic junction. PMID- 21825351 TI - Green's function method applied to the paramagnetic properties of R(1 x)X(x)MnO(3). AB - The magnetic properties of the isotropic manganites R(1-x)X(x)MnO(3) are studied in the paramagnetic regime using the Green's function method. The Curie-Weiss and critical temperatures, Theta and T(c), are obtained within the random phase approximation, as well as the high-temperature susceptibility. Our results are in agreement with other theoretical and experimental results. PMID- 21825352 TI - A high-field magnetization study of a Nd(2)Fe(14)Si(3) single crystal. AB - Magnetization study of a single crystal of Nd(2)Fe(14)Si(3) (with the rhombohedral Th(2)Zn(17)-type structure) reveals that the compound is a ferromagnet with a spontaneous magnetic moment of 32.3MU(B) per formula unit (at T = 2 K) and a Curie temperature equal to 495 K. The easy-magnetization direction lies close to the b-axis, tilting slightly towards the c-axis. (The b-axis [120] is not a high-symmetry direction in the crystallographic class D(3d).) The observed strong magnetic anisotropy is attributed almost entirely to the Nd sublattice, as concluded from comparison with a Y(2)Fe(14)Si(3) single crystal. A magnetic field applied along the c-axis induces a first-order spin reorientation transition at B(FOMP) = 20 T. In the process of magnetization the Nd and Fe sublattices behave as essentially non-collinear. This is manifest particularly in the downward curvature of the first (pre-FOMP) stage of the magnetization curve. It is proposed to regard this curvature as a validity criterion for the single sublattice approximation. PMID- 21825353 TI - On the dielectric dispersion and absorption in nanosized manganese zinc mixed ferrites. AB - The temperature and frequency dependence of dielectric permittivity and dielectric loss of nanosized Mn(1-x)Zn(x)Fe(2)O(4) (for x = 0, 0.2, 0.4, 0.6, 0.8, 1) were investigated. The impact of zinc substitution on the dielectric properties of the mixed ferrite is elucidated. Strong dielectric dispersion and broad relaxation were exhibited by Mn(1-x)Zn(x)Fe(2)O(4). The variation of dielectric relaxation time with temperature suggests the involvement of multiple relaxation processes. Cole-Cole plots were employed as an effective tool for studying the observed phenomenon. The activation energies were calculated from relaxation peaks and Cole-Cole plots and found to be consistent with each other and indicative of a polaron conduction. PMID- 21825354 TI - Couette flow of a smectic A liquid crystal. AB - This paper considers the dynamics of cylindrically arranged parallel layers of smectic A liquid crystal subjected to Couette flow. Governing equations are constructed using a recently developed dynamic theory for smectic A (Stewart 2007 Contin. Mech. Thermodyn. 18 343-60). These equations are solved to provide analytical solutions for the smectic layer undulations and velocity profiles. Results show the dependence of the response time of the smectic layers upon the permeation constant and the layer compression modulus. The relaxation times for the flow profiles are shown to depend upon two viscosities; estimates for these times are shown to be shorter than that for a typical approximation to the relaxation time of the smectic layer undulations. PMID- 21825355 TI - Effect of the reservoir size on gas adsorption in inhomogeneous porous media. AB - We study the influence of the relative size of the reservoir on the adsorption isotherms of a fluid in disordered or inhomogeneous mesoporous solids. We consider both an atomistic model of a fluid in a simple, yet structured pore, whose adsorption isotherms are computed by molecular simulation, and a coarse grained model for adsorption in a disordered mesoporous material, studied by a density functional approach in a local mean-field approximation. In both cases, the fluid inside the porous solid exchanges matter with a reservoir of gas that is at the same temperature and chemical potential and whose relative size can be varied, and the control parameter is the total number of molecules present in the porous sample and in the reservoir. Varying the relative sizes of the reservoir and the sample within experimental range may change the shape of the hysteretic isotherms, leading to a 're-entrant' behavior compared to the grand-canonical isotherm when the latter displays a jump in density. We relate these phenomena to the organization of the metastable states that are accessible for the adsorbed fluid at a given chemical potential or density. PMID- 21825356 TI - Structural and optical properties of Tb-doped Na-Gd metaphosphate glasses and glass-ceramics. AB - The optical and structural properties of terbium doped sodium gadolinium phosphate glasses of three different compositions subjected to a crystallization process were studied and compared with those of the parent glassy samples. The structural characteristics of the glassy and crystallized phases were determined by Raman spectroscopy and the results showed a remarkable reduction in the full width at half maximum of the Raman peaks after crystallization. Radio luminescence measurements revealed the emissions of both Gd(3+) and Tb(3+) ions. Their intensities strongly increased and their intensity ratio was modified by the crystallization. The luminescence temperature dependence investigated by radio-luminescence measurements in the temperature interval from 10 to 310 K became more complicated after crystallization. The role of free carrier trapping phenomena in the modification of the radio-luminescence efficiency was also studied by thermally stimulated luminescence. PMID- 21825357 TI - Bending elasticity of saturated and monounsaturated phospholipid membranes studied by the neutron spin echo technique. AB - We have used neutron spin echo (NSE) spectroscopy to study the effect of bilayer thickness and monounsaturation (existence of a single double bond on one of the aliphatic chains) on the physical properties of unilamellar vesicles. The bending elasticity of saturated and monounsaturated phospholipid bilayers made of phospholipids with alkyl chain length ranging from 14 to 20 carbons was investigated. The bending elasticity kappa(c) of phosphatidylcholines (PCs) in the liquid crystalline (L(alpha)) phase ranges from 0.38 * 10(-19) J for 1,2 dimyristoyl-sn-glycero-3-phosphocholine to 0.64 * 10(-19) J for 1,2-dieicosenoyl sn-glycero-3-phosphocholine. It was confirmed that, contrary to the strong effect on the main transition temperature, the monounsaturation has a limited influence on the bending elasticity of lipid bilayers. In addition, when the area modulus K(A) varies little with chain unsaturation or length, the elastic ratios (kappa(c)/K(A))(1/2) of saturated and monounsaturated phospholipid bilayers varies linearly with lipid hydrophobic thickness d which agrees well with the theory of ideal fluid membranes. PMID- 21825358 TI - Differences between pressure-induced densification of LiCl-H(2)O glass and polyamorphic transition of H(2)O. AB - We perform volumetric measurements of LiCl aqueous solution up to 1.00 GPa in the 100-170 K range, examine the pressure-induced vitrification and densification, and draw the pressure-temperature-volume surface. The pressure-induced vitrification of the solution corresponds to the cooling-induced vitrification of the liquid. We found that the volumetric decrease of glassy solution during the densification is continuous and this behavior depends on the glassy state before the compression. Raman profiles of the glassy solutions before and after the densification are similar. In contrast, the polyamorphic transition from low density amorphous ice (LDA) to high-density amorphous ice (HDA) is discontinuous and their Raman profile before and after the transition is distinct. These results suggest that the densification relates to the structural relaxation and differs intrinsically from the polyamorphic transition. Furthermore, the densification of HDA is observed under high pressure, suggesting that very high density amorphous ice (VHDA) may be the densified HDA. In order to recognize a polyamorphic transition under a non-equilibrium condition correctly, evidence of not only large volume change but also some distinct structural changes in glassy state is necessary. PMID- 21825359 TI - The complex structure of liquid Cu(6)Sn(5) alloy. AB - By applying ab initio molecular dynamics simulation to liquid Cu(6)Sn(5) alloy, the hetero-coordination tendency is discovered by Bathia-Thornton partial correlation functions and a chemical short-range parameter. However the local structural environment of Sn in l-Cu(6)Sn(5) alloy resembles that of liquid Sn by Voronoi analysis. A new feature, i.e. a subpeak in between the first and second peaks, is discovered by the present method which implies that topologically disordered beta-Sn-type structural units may exist in l-Cu(6)Sn(5) alloy. The local density states of electrons show that both Cu-Sn and Sn-Sn bonding exist in l-Cu(6)Sn(5) alloy. This work suggests that chemical short-range order between unlike atoms and self-coordination between Sn atoms coexists in l-Cu(6)Sn(5) alloy. PMID- 21825360 TI - Ground state configurations and melting of two-dimensional non-uniformly charged classical clusters. AB - We consider classical two-dimensional (2D) Coulomb clusters consisting of two species containing five particles with charge q(1) and five with charge q(2), respectively. Using Monte Carlo and molecular dynamics (MD) simulations, we investigated the ground state configurations as well as radial and angular displacements of particles as a function of temperature and their dependence on the ratio q = q(2)/q(1). We found new configurations and a new multi-step melting behavior for q sufficiently different from the uniform charge limit q = 1. PMID- 21825361 TI - Temperature-dependent EXAFS analysis of embedded Pt nanocrystals. AB - The vibrational and thermal properties of embedded Pt nanocrystals (NCs) have been investigated with temperature-dependent extended x-ray absorption fine structure (EXAFS) spectroscopy. NCs of diameter 1.8-7.4 nm produced by ion implantation in amorphous SiO(2) were analysed over the temperature range 20-295 K. An increase in Einstein temperature (~194 K) relative to that of a Pt standard (~179 K) was evident for the smallest NCs while those larger than ~2.0 nm exhibited values comparable to bulk material. Similarly, the thermal expansion of interatomic distances was lowest for small NCs. While the amorphous SiO(2) matrix restricted the thermal expansion of interatomic distances, it did not have a significant influence on the mean vibrational frequency of embedded Pt NCs. Instead, the latter was governed by finite-size effects or, specifically, capillary pressure. PMID- 21825362 TI - Pressure-induced structural phase transitions on Na(0.5)CoO(2): a first principles study. AB - First principles calculations have been carried out to study the pressure effects on the structural, electronic and magnetic properties of Na(0.5)CoO(2). An unexpected Na ion structural transformation has been predicted from our calculations. The main factor for such a transformation has been attributed to the increasing Coulomb repulsion between the Na1 and Co ions with the increase of pressure. The experimentally observed insulator-metal transition has been found to be induced by this structural transformation. Furthermore, due to the strong coupling between Na ordering and Co magnetic ordering, a magnetic phase transition follows after the structural transformation. PMID- 21825363 TI - Elastic scattering of 200 keV electrons in elemental solids: experimental observation of atomic-number-dependent oscillatory behavior. AB - Mean free path of elastic electron scattering lambda(el) has been measured with a 200 keV transmission electron microscope for a wide range of stable elemental solids. An oscillating behavior versus atomic number Z has been revealed, such that, within one row of the periodic table, lambda(el) exhibits minimum (maximum) for elements with completed (empty) outer d shells. These lambda(el)(Z) oscillations are attributed to Z dependence of the atomic density, and their importance for the interpretation of electron microscope images is demonstrated. PMID- 21825364 TI - Self-similar optical transmittance for a deterministic aperiodic multilayer structure. AB - We study theoretically the spectral transmission properties of a multilayer structure in which the refractive index of the layers follows a self-similar arithmetical sequence named 'The 1s-counting sequence', which is related to the Pascal's triangle. The transmittance spectrum is intermediate between that of a periodic structure and that of a random structure, and shows clearly properties of scaling and self-similarity for all incident angles and TE and TM polarizations. PMID- 21825365 TI - Effective parameters for periodic photonic structures of resonant elements. AB - We report on the effective electromagnetic parameters of metamaterials consisting of resonant building units, through systematic full-electrodynamic calculations by the layer-multiple-scattering method on a model system: a photonic crystal of metallic nanoshells. The results obtained by the S-matrix retrieval procedure for single- and multi-layer slabs of ordered arrays of such nanoshells are analysed in conjunction with the complex band structure of the corresponding infinite crystal and the Maxwell-Garnett effective-medium approximation. We discuss conditions that must be fulfilled in order for an effective-medium description of a metamaterial to be valid and explain artefacts which often occur in numerical calculations of the effective parameters. In particular, we propose a method to resolve ambiguities in the determination of the effective refractive index, which become prominent for thick slabs, based on the complex band structure of the infinite crystal. PMID- 21825366 TI - Spin transport properties of a quantum dot coupled to ferromagnetic leads with noncollinear magnetizations. AB - A correct general formula for the spin current through an interacting quantum dot coupled to ferromagnetic leads with magnetization at an arbitrary angle theta is derived within the framework of the Keldysh formalism. Under asymmetric conditions, the spin current component J(z) may change sign for 0r(S)(c). This signals the formation of an electron Wigner crystal pinned by the impurity potential. The electron density, homogeneous below r(S)(c), indeed shows a periodic modulation at r(S)>r(S)(c). The modulation amplitude follows a (r(S)-r(S)(c))((1)/(2)) behaviour which is characteristic for a second-order phase transition, as expected in the mean-field-type DFT-OEP approach. Our calculation shows that the macroscopic current, which is a quantity directly accessible in DFT, can serve as an indicator of the formation of a correlated electron state. PMID- 21825371 TI - (93)Nb NMR study of the charge density wave state in NbSe(2). AB - (93)Nb NMR studies were carried out for a single crystal of NbSe(2) at 73.328 MHz in the temperature range 9-300 K to investigate the normal and charge density wave (CDW) states. Detailed analysis of the NMR line shape of the central transition using a classical incommensurate model reveals the change in the conduction electron spin dynamics from above T(CDW). An increase of the Knight shift below T(CDW) reflects modification to the uniform part of the conduction electron density of states. As suggested theoretically, the Knight shift distribution is found to be directly proportional to the square of the amplitude of the CDW. The results further indicate an incommensurate CDW state in 2H NbSe(2). Analysis of the NMR spectra using the McMillan incommensurate model suggests a large value of the discommensuration parameter (gamma) which is almost temperature independent, in contrast to the much smaller value previously reported in the case of 2H-TaSe(2). PMID- 21825372 TI - Infrared switching from resonant to passive photonic bandgaps: transition from purely photonic to hybrid electronic/photonic systems. AB - Coherently controlled optical processes have been extensively studied in various systems including atoms, quantum wells and quantum dots. In this study we investigate such processes in Bragg multi-quantum well resonant (active) photonic bandgaps, wherein the dipole-dipole interwell interaction couples different quantum wells together, forming supperradiant exciton modes. Our results show that in such systems one can use an infrared laser beam to replace the collective superradiant mode with an electromagnetically induced transparency mode, demonstrating infrared switching of an active photonic bandgap to a hybrid system. Such a hybrid system consists of a passive photonic bandgap and an electromagnetically induced transparency band window superimposed on each other. A detailed study of the interplay between the collective and infrared-induced exciton excitations of quantum wells in Bragg multi-quantum well resonant photonic bandgap structures is presented. PMID- 21825373 TI - Peltier's and Thomson's coefficients of thermoelectric phenomena in the observable formulation. AB - Four transport coefficients characterize the thermoelectric properties of materials. Three of them are widely measured and studied. But the number of references on the Peltier coefficient are very limited. This unequal result is a consequence of the Onsager reciprocal relation (ORR). A review on the preciseness and accuracy of Peltier coefficient measurements has been developed in this paper. Thus we can appreciate a low level in the experimental confirmation for the ORR. In order to describe the thermoelectric processes in an advantageous way, the observable formulation has been used. This is characterized by the electric potential measured at the probe terminals and for the heat flux which the conductor laterally dissipates. The energy balance provides the basic relationships among the observables and the Peltier and Thomson coefficients. A new way for measuring the Peltier coefficient has been suggested. PMID- 21825374 TI - Perfect light transmission in Fibonacci arrays of dielectric multilayers. AB - In this paper we study the propagation of light through an asymmetric array of dielectric multilayers built by joining two porous silicon substructures in a Fibonacci sequence. Each Fibonacci substructure follows the well-known recursive rule but in the second substructure dielectric layers A and B are exchanged. Even without mirror symmetry, this array gives rise to multiple transparent states, which follow the scaling properties and self-similar spectra of a single Fibonacci multilayer. We apply the transfer matrix formalism to calculate the transmittance. By setting the transfer matrix of the array equal to +/- I, the identity matrix, frequencies of perfect light transmission are reproduced in our theoretical calculations. Although the light absorption of porous silicon in the optical range limits our experimental study to low Fibonacci generations, the positions of the transparent states are well predicted by the above-mentioned condition. We conclude that mirror symmetry in arrays of Fibonacci multilayers is sufficient but not necessary to generate multiple transparent states, opening broader applications of quasiperiodic systems as filters and microcavities of multiple frequencies. PMID- 21825375 TI - First order phase transition in deuterated triglycine selenate under an electric field: experimental study and analysis in the frame of Landau theory. AB - The influence of electric fields lower than the critical field in the ferroelectric phase transition in deuterated triglycine selenate has been studied by means of thermal and dielectric properties. The latent heat, specific heat and dielectric constant have been measured and compared to the theoretical expectations from the Landau theory under an electric field. A full agreement has been found on cooling experiments. PMID- 21825376 TI - Pressure and magnetic field tuned quantum critical point in the Kondo antiferromagnet CePtZn. AB - We report magnetization, heat capacity and electrical resistivity measurements on CePtZn, which crystallizes in the orthorhombic TiNiSi type structure. Magnetization and electrical resistivity on the iso-structural series of compounds Ce(1-x)La(x)PtZn (x = 0.1, 0.2 0.5 and 1) were also carried out. The electrical resistivity of CePtZn was also measured in external magnetic fields up to 12 T and under pressures up to 2.66 GPa. We find that CePtZn is a dense Kondo lattice, ordering antiferromagnetically at T(N) = 1.7 K, with a comparable Kondo temperature. The magnetic transition temperature, T(N), is continuously suppressed both by the magnetic field and pressure and [Formula: see text] around 5-6 T and at 1.2 GPa, respectively. Non-Fermi liquid behavior of resistivity at 4 T and 1.2 GPa and logarithmic divergence of the heat capacity, C(4f)/T, at 6 T in a limited temperature region strongly suggest the emergence of a quantum critical point as [Formula: see text]. PMID- 21825377 TI - Structure and magnetic properties of Ni/Cu/Fe/MgO(001) films. AB - The structural and magnetic properties of thin Ni films grown on Cu/Fe/MgO(001) and Cu/MgO(001) buffer layers are investigated and compared to those grown on Cu/Si(001). The use of an Fe seed layer a few monolayers thick leads to the epitaxial growth of high surface quality Cu(001) buffer layers on MgO(001), while Cu growth on the bare MgO(001) substrate results in polycrystalline films. Magneto-optic Kerr effect magnetometry shows that Ni films grown on Cu/Fe/MgO(001) exhibit dominant perpendicular magnetic anisotropy up to ~90 A, which is similar to that of Ni films grown on Cu/Si(001). The polycrystalline Ni films also exhibit perpendicular magnetic remanence, but with a dominant in-plane magnetization component. PMID- 21825378 TI - Grain-boundary-induced spin disorder in nanocrystalline gadolinium. AB - Based on experimental magnetic-field-dependent neutron scattering data, we have calculated the autocorrelation function of the spin misalignment of nanocrystalline (160)gadolinium. The analysis suggests the existence of two characteristic length scales in the spin system: the smaller one is about 5 nm and is attributed to the defect cores of the grain boundaries, whereas the larger length scale is of the order of the average crystallite size D = 21 nm and presumably describes the response of the magnetization to the magnetic anisotropy field of the individual crystallites. PMID- 21825379 TI - Neutron diffraction study and magnetic properties of La(1-x)Ba(x)CoO(3) (x = 0.2 and 0.3). AB - The magnetic properties together with the crystal and magnetic structures of the cobaltites La(1-x)Ba(x)CoO(3) (for x = 0.2 and 0.3) are determined by DC magnetization, AC magnetic susceptibility and neutron powder diffraction measurements over a broad spectrum of temperatures. For x = 0.3 a rhombohedral structure with space group [Formula: see text] is maintained at all temperatures below 300 K. On the other hand, for x = 0.2 the refinement of the neutron data below 150 K indicates the coexistence of two structures, [Formula: see text] (rhombohedral) and Pbnm (orthorhombic), respectively, in a ratio of ~48/52. Both compounds (x = 0.2 and 0.3) show a ferromagnetic long range order. The data fit well with the Co(3+) ions in the intermediate spin state and the Co(4+) ions in a low spin state. PMID- 21825380 TI - Co-publication with Journal of Physics: Conference Series. AB - The 25th International Conference on Low Temperature Physics (LT25) was held in Amsterdam between 6-13 August 2008. The majority of the special invited lectures are published in Journal of Physics: Condensed Matter. Papers relating to the oral and poster presentations will appear in part II of the proceedings in a dedicated open access issue of Journal of Physics: Conference Series. PMID- 21825382 TI - Homogeneously precessing domain in (3)He-B: formation and properties. AB - The long-range order realized in the superfluid phases of (3)He leads to a nonlocal motion of spin in these phases. In the B phase the nonlocality manifests itself in the formation of a homogeneously precessing domain (HPD). This domain is formed under conditions of nuclear magnetic resonance. Within the domain spin precesses coherently-with the same frequency and phase even though the steady magnetic field can be nonuniform. Coherence of precession is maintained by the spin current carried by the condensate of Cooper pairs. The key experiments, revealing the main properties of the HPD and the underlying theory are briefly reviewed in this paper. PMID- 21825381 TI - Spin superfluidity and coherent spin precession. AB - The spontaneous phase coherent precession of the magnetization in superfluid (3)He-B was discovered experimentally in 1984 at the Institute for Physical Problems, Moscow by Borovik-Romanov, Bunkov, Dmitriev and Mukharsky and simultaneously explained theoretically by Fomin (Institut Landau, Moscow). Its formation is a direct manifestation of spin superfluidity. The latter is the magnetic counterpart of mass superfluidity and superconductivity. It is also an example of the Bose-Einstein condensation of spin-wave excitations (magnons). The coherent spin precession opened the way for investigations of spin supercurrent magnetization transport and other related phenomena, such as spin-current Josephson effect, process of phase slippage at a critical value of spin supercurrent, spin-current vortices, non-topological solitons (analogous to Q balls in high energy physics) etc. New measuring techniques based on coherent spin precession made the investigation of mass counterflow and mass vortices possible owing to the spin-mass interaction. New phenomena were observed: mass spin vortices, the Goldstone mode of the mass vortex with non-axisymmetric core, superfluid density anisotropy etc. Different types of coherent spin precession were later found in superfluid (3)He-A and (3)He-B confined in anisotropic aerogel, in the states with counterflow and in (3)He with reduced magnetization. Finally, spin superfluidity investigations developed the basis for a modern investigation of electron spin supercurrent and spintronics. PMID- 21825383 TI - Unconventional superconductivity of NpPd(5)Al(2). AB - The high quality single crystals of NpPd(5)Al(2) with the body-centered tetragonal structure were grown by the Pb flux method. NpPd(5)Al(2) was found to be the first Np-based heavy fermion superconductor with the relatively high critical temperature T(sc) = 4.9 K. The upper critical field H(c2) is large and highly anisotropic. Corresponding to the heavy electronic state, the initial slope of H(c2) is large, but H(c2) at low temperatures is suppressed by the magnetic field, indicating a strong Pauli paramagnetic effect and the first-order transition at H(c2). These results imply that NpPd(5)Al(2) is located at the proximity of the antiferromagnetic ordering, which might be hidden by the superconductivity. The d-wave superconductivity with a spin singlet state is most likely realized in NpPd(5)Al(2). PMID- 21825384 TI - Elastic properties of solid helium. AB - Following recent torsional oscillator measurements which appear to show the 'non classical rotational inertia' which characterizes a supersolid, a number of experiments have searched for evidence of unusual behavior in other properties. We have developed a new technique for measuring the shear modulus of solid helium at low frequencies and small strains. In hexagonal close packed (4)He, the shear modulus increases dramatically below 200 mK, the temperature range where decoupling is seen in torsional oscillators. The modulus anomaly is frequency independent, depends strongly on strain amplitude, and is very sensitive to (3)He impurities. In these and other ways, the shear modulus closely mirrors the torsional oscillator behavior and it is clear that the two phenomena are closely related. We attribute the shear modulus effects to the elastic response of mobile dislocations and their pinning by (3)He impurities at low temperatures. A question then arises: are the modulus increases responsible for the frequency changes seen in torsional oscillator experiments? The expected frequency shifts appear to be much too small to explain the apparent decoupling, nor can elastic effects explain the 'blocked annulus' results or the behavior in small pores. In order to clarify the relationship between the shear modulus and torsional oscillator behaviors, we have recently made modulus measurements on (3)He, where no supersolid response is expected. Since dislocation motion depends on crystal structure it was important that these measurements be extended to the hexagonal close packed phase of (3)He, not just the body centered cubic phase. PMID- 21825385 TI - Classical and quantum physics of hydrogen clusters. AB - We present results of a comprehensive theoretical investigation of the low temperature (T) properties of clusters of para-hydrogen (p-H(2)), both pristine as well as doped with isotopic impurities (i.e., ortho-deuterium, o-D(2)). We study clusters comprising up to N = 40 molecules, by means of quantum simulations based on the continuous-space Worm algorithm. Pristine p-H(2) clusters are liquid like and superfluid in the [Formula: see text] limit. The superfluid signal is uniform throughout these clusters; it is underlain by long cycles of permutation of molecules. Clusters with more than 22 molecules display solid-like, essentially classical behavior at temperatures down to T~1 K; some of them are seen to turn liquid-like at sufficiently low T (quantum melting). PMID- 21825386 TI - Superfluidity in a gas of strongly interacting fermions. AB - After an introduction into 100 years of research on superfluidity and the concept of the BCS-BEC crossover, we describe recent experimental studies of a spin polarized Fermi gas with strong interactions. Tomographically resolving the spatial structure of an inhomogeneous trapped sample, we have mapped out the superfluid phases in the parameter space of temperature, spin polarization, and interaction strength. Phase separation between the superfluid and the normal component occurs at low temperatures, showing spatial discontinuities in the spin polarization. The critical polarization of the normal gas increases with stronger coupling. Beyond a critical interaction strength all minority atoms pair with majority atoms, and the system can be effectively described as a boson-fermion mixture. Pairing correlations have been studied by rf spectroscopy, determining the fermion pair size and the pairing gap energy in a resonantly interacting superfluid. PMID- 21825387 TI - Quantum turbulence-from superfluid helium to atomic Bose-Einstein condensates. AB - This paper reviews recent developments in the physics of quantum turbulence (QT). QT was discovered in superfluid (4)He in the 1950s, while the research has taken a new direction since the middle of the 1990s. QT is comprised of quantized vortices that are definite topological defects and expected to give a prototype of turbulence much simpler than usual classical turbulence. We give a general introduction and brief review of classical turbulence followed by a description of the dynamics of quantized vortices. After mentioning the modern research trends in QT, we discuss the energy spectra, the energy cascade and the possible dissipation mechanism of QT at very low temperatures. The last part is devoted to QT in atomic Bose-Einstein condensates. PMID- 21825388 TI - Odd-frequency pairing in superconducting heterostructures. AB - We review the theory of odd-frequency pairing in superconducting heterostructures, where an odd-frequency pairing component is induced near interfaces. A general description of the superconducting proximity effect in a normal metal or a ferromagnet attached to an unconventional superconductor (S) is given within quasiclassical kinetic theory for various types of symmetry state in S. Various possible symmetry classes in a superconductor are considered which are consistent with the Pauli principle: even-frequency spin-singlet even-parity (ESE) state, even-frequency spin-triplet odd-parity (ETO) state, odd-frequency spin-triplet even-parity (OTE) state and odd-frequency spin-singlet odd-parity (OSO) state. As an example, we consider a junction between a diffusive normal metal (DN) and a p-wave superconductor (even-frequency spin-triplet odd-parity symmetry), where the pairing amplitude in DN belongs to an odd-frequency spin triplet even-parity symmetry class. We also discuss the manifestation of odd frequency pairing in conventional superconductor/normal (S/N) proximity systems and its relation to the classical McMillan-Rowell oscillations. PMID- 21825389 TI - Multiband superconductivity in Pb, H under pressure and CaBeSi from ab initio calculations. AB - Superconductivity in Pb, H under extreme pressure and CaBeSi, in the framework of the density functional theory for superconductors, is discussed. A detailed analysis on how the electron-phonon and electron-electron interactions combine together to determine the superconducting gap and critical temperature of these systems is presented. Pb, H under pressure and CaBeSi are multigap superconductors. We will address the question under which conditions does a system exhibits this phenomenon. The presented results contribute to the understanding of multiband and anisotropic superconductivity, which has received a lot of attention since the discovery of MgB(2), and show how it is possible to describe the superconducting properties of real materials on a fully ab initio basis. PMID- 21825390 TI - Is Sr(2)RuO(4) a chiral p-wave superconductor? AB - Much excitement surrounds the possibility that strontium ruthenate exhibits chiral p-wave superconducting order. Such order would be a solid state analogue of the A phase of He-3, with the potential for leading to exotic physics relevant to quantum computing. We take a critical look at the evidence for such time reversal symmetry breaking order. The possible superconducting order parameter symmetries and the evidence for and against chiral p-wave order are reviewed, with an emphasis on the most recent theoretical predictions and experimental observations. In particular, attempts to reconcile experimental observations and theoretical predictions for the spontaneous supercurrents expected at sample edges and domain walls of a chiral p-wave superconductor and for the polar Kerr effect, a key signature of broken time reversal symmetry, are discussed. PMID- 21825391 TI - Coexistence and interplay of superconductivity and ferromagnetism in URhGe. AB - As ferromagnetism and superconductivity are usually considered to be antagonistic, the discovery of their coexistence in UGe(2), URhGe, UIr and UCoGe has attracted a lot of interest. The mechanism to explain such a state has, however, not yet been fully elucidated. In these compounds superconductivity may be unconventional: Cooper pairs could be formed by electrons with parallel spins and magnetic fluctuations might be involved in the pairing mechanism. URhGe becomes ferromagnetic below a Curie temperature of 9.5 K, with a spontaneous moment aligned to the c-axis. For temperatures below 260 mK and fields lower than 2 T, superconductivity was first observed in 2001. Recently, we discovered a second pocket of superconductivity. This new pocket of superconductivity appears at higher fields applied close to the b-axis, enveloping a sudden magnetic moment rotation transition at H(R) = 12 T. Detailed studies of the field induced metamagnetic transition and superconductivity are presented. The possibility that magnetic fluctuations emerging from a quantum critical point provide the pairing mechanism for superconductivity is discussed. PMID- 21825392 TI - Fermi surface reconstruction in high-T(c) superconductors. AB - The recent observation of quantum oscillations in underdoped high-T(c) superconductors, combined with their negative Hall coefficient at low temperature, reveals that the Fermi surface of hole-doped cuprates includes a small electron pocket. This strongly suggests that the large hole Fermi surface characteristic of the overdoped regime undergoes a reconstruction caused by the onset of some order which breaks translational symmetry. Here we consider the possibility that this order is 'stripe' order, a form of combined charge/spin modulation observed most clearly in materials like Eu-doped and Nd-doped LSCO (La(2-x)Sr(x)CuO(4)). In these materials, the onset of stripe order coincides with major changes in transport properties, providing strong evidence that stripe order is indeed the cause of Fermi surface reconstruction. We identify the critical doping where this reconstruction occurs and show that the temperature dependence of transport coefficients at that doping is typical of metals at a quantum critical point. We discuss how the pseudogap phase may be a fluctuating precursor of the stripe-ordered phase. PMID- 21825393 TI - Superconductivity at the LaAlO(3)/SrTiO(3) interface. AB - We report on the structural characterization of LaAlO(3)/SrTiO(3) interfaces and on their transport properties. LaAlO(3) films were prepared using pulsed laser deposition onto TiO(2) terminated (001) SrTiO(3) substrates inducing a metallic conduction at the interface. Resistance and Hall effect measurements reveal a sheet carrier density between 0.4 and 1.2 * 10(14) electrons cm(-2) at room temperature and a mobility of ~300 cm(2) V(-1) s(-1) at low temperatures. A transition to a superconducting state is observed at a temperature of ~200 mK. The superconducting characteristics display signatures of 2D superconductivity. PMID- 21825394 TI - Visualizing pair formation on the atomic scale and the search for the mechanism of superconductivity in high-T(c) cuprates. AB - We have developed several new experimental techniques, based on the scanning tunneling microscope, to visualize the process of pair formation on the atomic scale and to probe with high precision what controls the strength of pairing in high-T(c) cuprate superconductor compounds. These new experiments provide evidence that pairing in these exotic superconductors occurs above the bulk transition temperature and in nanoscale regions with sizes of 1-3 nm. The high temperature nucleation and proliferation of these nanoscale puddles have a strong connection to the temperature-doping phase diagram of these superconductors. On average we have found that the pairing gap Delta and the temperature at which they first nucleate T(p) follow the simple relation: 2Delta/k(B)T(p)~8. Moreover, the variations of the pairing strength on the nanoscale can be examined to find microscopic clues to the mechanism of pairing. Specifically, we have found evidence that suggests that strong electronic correlation, as opposed to coupling of electrons to bosons, is responsible for the pairing mechanism in the cuprates. Surprisingly, we have found that nanoscale measurements of electronic correlations in the normal state (at temperatures as high as twice T(c)) can be used to predict the strength of the local pairing interaction at low temperatures. PMID- 21825395 TI - Quantum order in the chiral magnet MnSi. AB - Systems lacking inversion symmetry, such as selected three-dimensional compounds, multilayers and surfaces support Dzyaloshinsky-Moriya (DM) spin-orbit interactions. In recent years DM interactions have attracted great interest, because they may stabilize magnetic structures with a unique chirality and non trivial topology. The inherent coupling between the various properties provided by DM interactions is potentially relevant for a variety of applications including, for instance, multiferroic and spintronic devices. The, perhaps, most extensively studied material in which DM interactions are important is the cubic B20 compound MnSi. We review the magnetic field and pressure dependence of the magnetic properties of MnSi. At ambient pressure this material displays helical order. Under hydrostatic pressure a non-Fermi liquid state emerges, where a partial magnetic order, reminiscent of liquid crystals, is observed in a small pocket. Recent experiments strongly suggest that the non-Fermi liquid state is not due to quantum criticality. Instead it may be the signature of spin textures and spin excitations with a non-trivial topology. PMID- 21825396 TI - Quantum criticality and black holes. AB - Many condensed matter experiments explore the finite temperature dynamics of systems near quantum critical points. Often, there are no well-defined quasiparticle excitations, and so quantum kinetic equations do not describe the transport properties completely. The theory shows that the transport coefficients are not proportional to a mean free scattering time (as is the case in the Boltzmann theory of quasiparticles), but are completely determined by the absolute temperature and by equilibrium thermodynamic observables. Recently, explicit solutions of this quantum critical dynamics have become possible via the anti-de Sitter/conformal field theory duality discovered in string theory. This shows that the quantum critical theory provides a holographic description of the quantum theory of black holes in a negatively curved anti-de Sitter space, and relates its transport coefficients to properties of the Hawking radiation from the black hole. We review how insights from this connection have led to new results for experimental systems: (i) the vicinity of the superfluid-insulator transition in the presence of an applied magnetic field, and its possible application to measurements of the Nernst effect in the cuprates, (ii) the magnetohydrodynamics of the plasma of Dirac electrons in graphene and the prediction of a hydrodynamic cyclotron resonance. PMID- 21825397 TI - A brief update of angle-resolved photoemission spectroscopy on a correlated electron system. AB - In this paper, we briefly summarize the capabilities of state-of-the-art angle resolved photoemission spectroscopy (ARPES) in the field of experimental condensed matter physics. Due to the advancement of the detector technology and the high flux light sources, ARPES has become a powerful tool to study the low energy excitations of solids, especially those novel quantum materials in which many-body physics are at play. To benchmark today's state-of-the-art ARPES technique, we demonstrate that the precision of today's ARPES has advanced to a regime comparable to the bulk-sensitive de Haas-van Alphen (dHvA) measurements. Finally, as an example of new discoveries driven by the advancement of the ARPES technique, we summarize some of our recent ARPES measurements on underdoped high T(c) superconducting cuprates, which have provided further insight into the complex pseudogap problem. PMID- 21825398 TI - Pumping energy and charge by hybrid tunnel junctions. AB - Following the outline of my talk at LT25 I give a brief review of hybrid tunnel junctions as electronic refrigerators and as single-electron sources. PMID- 21825399 TI - Cryocoolers: the state of the art and recent developments. AB - Cryocooler performance and reliability are continually improving. Consequently, they are more and more frequently implemented by physicists in their laboratory experiments or for commercial and space applications. The five kinds of cryocoolers most commonly used to provide cryogenic temperatures for various applications are the Joule-Thomson, Brayton, Stirling, Gifford-McMahon, and pulse tube cryocoolers. Many advances in all types have occurred in the past 20 years that have allowed all of them to be used for a wide variety of applications. The present state of the art and on-going developments of these cryocoolers are reviewed in this paper. In the past five years new research on these cryocoolers has offered the potential to significantly improve them and make them suitable for even more applications. The general trend of this new cryocooler research is also presented. PMID- 21825400 TI - New light on the intriguing history of superfluidity in liquid (4)He. AB - Surprisingly, it was 30 years after the first liquefaction of (4)He in 1908 that the discovery that liquid (4)He is not just a 'cold' liquid was made. Below T = 2.18 K, it is a 'quantum' liquid which exhibits spectacular macroscopic quantum behaviour that can be seen with the naked eye. Since the observation of superfluidity in liquid (4)He is one of the greatest discoveries in modern physics, we present a day-to-day chronology of the tangled events which preceded the seminal discovery of zero viscosity in 1938 by Kapitza in Moscow and by Allen and Misener in Cambridge. On the theory side, London argued in 1938 that the microscopic basis for this new superfluid phase was the forgotten phenomenon of Bose-Einstein condensation (BEC) first suggested by Einstein in 1925. In 1941, Landau developed a very successful theory of superfluid (4)He, but it was not anchored in a microscopic theory of interacting atoms. It took another 20 years for theorists to unify the two seemingly different theories of Landau and London. Experiments on trapped superfluid atomic gases since 1995 have shone new light on superfluid (4)He. In the mid-1930s, London had emphasized that superconductivity in metals and superfluidity in liquid (4)He were similar. Experiments on trapped two-component Fermi gases in the last five years have shown that a Bose condensate is indeed the basis of both of these superfluid phases. This confirms the now famous Bardeen-Cooper-Schrieffer-BEC crossover scenario developed for superfluidity by Leggett and Nozieres in the early 1980s but largely ignored until a few years ago. The study of superfluid (4)He will increasingly overlap with strongly interacting dilute quantum gases, perhaps opening up a new era of research on this most amazing liquid. PMID- 21825401 TI - Cryogenics at the end of the 19th and the first half of the 20th century (1880 1940). AB - On the 10 July 1908 Heike Kamerlingh Onnes succeeded in the first liquefaction of helium. A very long preparation was necessary before Onnes succeeded. The underlying technological framework from his predecessors was mainly formed by the ingenious discoveries of Dewar. Onnes started with his cascade process of air liquefaction in 1892. In 1898 Dewar liquefied hydrogen for the first time and in 1906 the large hydrogen liquefier of Onnes was ready for use. The main part of this review concerns the first liquefaction of helium, for which the preparation of helium gas from monazite sand was needed, the construction of the liquefier and the mercury compressor of Cailletet, eventually rewarded with the first successful liquefaction. Subsequently, the later developments will be reviewed, i.e. Simon's expansion apparatus (1932), the helium liquefier of Kapitza (1934), and finally the Collins liquefier (1940-1947). This concludes the first half of the history of low temperature physics, after which a new area starts. PMID- 21825402 TI - A gas that sinks in a liquid-the first helium experiment published by Kamerlingh Onnes. AB - The year 1906 was a year of many remarkable achievements in the laboratory of Kamerlingh Onnes and his staff. They put into operation a hydrogen liquefier producing 4 l h(-1), followed by a liquid-hydrogen cryostat for work below 21 K. They prepared their first sample of 2 l of helium gas. Pressure-volume temperature measurements down to 54 K were in progress for hydrogen, and initiated for helium, in order to obtain an estimate for the critical temperature of helium; this estimate was urgently needed for design of a helium liquefier. Towards the end of 1906, Kamerlingh Onnes performed the first helium experiment at liquid-hydrogen temperature: a test of the phase behaviour of a mixture of hydrogen and helium. In the process, he discovered what he termed the barotropic effect: at increasing pressure, the helium-rich vapour phase sank to the bottom, having become heavier than the hydrogen-rich liquid phase. This paper describes the experiment and the resulting flurry of activity by Van der Waals, Kamerlingh Onnes, Keesom and Van Laar, all trying to understand and model the curious phase behaviour, as well as earlier relevant work by Van der Waals, Korteweg, Kuenen and Van Laar. PMID- 21825403 TI - Hendrik Antoon Lorentz: his role in physics and society. AB - Hendrik Antoon Lorentz (1853-1928) was appointed in 1878 to a chair of theoretical physics at the University of Leiden, one of the first of such chairs in the world. A few years later Heike Kamerlingh Onnes became his experimental colleague, after vehement discussions in the faculty. Lorentz strongly supported Kamerlingh Onnes then, and proved subsequently to be an ideal colleague. With Lorentz's electron theory the classical theory of electromagnetism obtained its final form, at the time often called the Maxwell-Lorentz theory. In this theory the Zeeman effect could be explained: the first glimpse of the electron. The Nobel Prize followed in 1902. The Lorentz transformation, established in 1904, preceded the special theory of relativity. Later on, Lorentz played a much admired role in the debate on the new developments in physics, in particular as chairman of a series of Solvay conferences. Gradually his stature outside of physics grew, both nationally as chairman of the Zuiderzee committee and internationally as president of the International Commission on Intellectual Cooperation of the League of Nations. At his funeral the overwhelming tribute was the recognition of his unique greatness. Einstein said about him 'He meant more to me personally than anyone else I have met on my life's journey'. PMID- 21825404 TI - Proposal for a [111] magnetization plateau in the spin liquid state of Tb(2)Ti(2)O(7). AB - Despite a Curie-Weiss temperature theta(CW)~-14 K, the Tb(2)Ti(2)O(7) pyrochlore magnetic material lacks long range magnetic order down to at least T(*)~50 mK. It has recently been proposed that the low temperature collective paramagnetic or spin liquid regime of this material may be akin to a spin ice state subject to both thermal and quantum fluctuations-a quantum spin ice (QSI) of sorts. Here we explore the effect of a magnetic field B along the [111] direction on the QSI state. To do so, we investigate the magnetic properties of a microscopic model of Tb(2)Ti(2)O(7) in an independent tetrahedron approximation in a finite field B along [111]. Such a model describes semi-quantitatively the collective paramagnetic regime where nontrivial spin correlations start to develop at the shortest length scale, that is over a single tetrahedron, but where no long range order is yet present. Our results show that a magnetization plateau develops at low temperatures as the system develops B = 0 ferromagnetic spin ice like 'two in/two-out' correlations at the shortest length scale. From these results, we are led to propose that the observation of such a [111] magnetization plateau in Tb(2)Ti(2)O(7) would provide compelling evidence for a QSI at B = 0 in this material and help guide the development of a theory for the origin of its spin liquid state. PMID- 21825405 TI - Unintentional conductivity of indium nitride: transport modelling and microscopic origins. AB - A three-region model for the high n-type conductivity in InN, including contributions from the bulk, surface and buffer layer interface of the sample, is considered. In particular, a parallel conduction analysis is used to show that this model can account for the carrier concentration and mobility variation with film thickness that has previously been determined from single-field Hall effect measurements. Microscopic origins for the donors in each region are considered, and the overriding tendency towards n-type conductivity is discussed in terms of the bulk band structure of InN. PMID- 21825406 TI - Studies of electron-phonon and phonon-phonon interactions in InN using ultrafast Raman spectroscopy. AB - Subpicosecond time-resolved Raman spectroscopy has been employed to investigate electron-phonon interactions and phonon dynamics in InN. The electron longitudinal optical phonon scattering rate and the decay dynamics of longitudinal optical phonons in InN have been directly measured. Our results indicate that hot-phonon effects can play an important role in the electron relaxation and transport in InN. The carrier dependence of the lifetime of the longitudinal optical phonons has also been measured. The results suggest that more theoretical work is needed to account for the dependence of the lifetime of longitudinal optical phonons on the photoexcited carrier density. PMID- 21825407 TI - GaN-based two-dimensional channels: hot-electron fluctuations and dissipation. AB - Ultrafast electronic and phononic processes are investigated in voltage-biased GaN-based two-dimensional channels of interest for heterostructure field-effect transistors. The accumulation of non-equilibrium longitudinal optical phonons (hot phonons) is treated for AlGaN/GaN, AlGaN/AlN/GaN, AlGaN/GaN/AlN/GaN, and AlInN/AlN/GaN structures in terms of the hot-phonon temperature and hot-phonon lifetime. The hot-phonon effect on hot-electron energy relaxation and hot-phonon number relaxation is extracted from an experimental investigation of hot-electron fluctuations and power dissipation. The measured equivalent hot-phonon temperature is nearly equal to the hot-electron temperature. The hot-phonon lifetime varies in the range from 150 to 800 fs and depends on electron density, temperature, and supplied electric power. The experimental dependence of the hot phonon lifetime on the hot-phonon mode occupancy is unique-neither Raman optical photon scattering nor optical-phonon-assisted intersubband absorption has, as yet, provided any experimental data of this sort. PMID- 21825408 TI - Phonon-plasmon coupled modes in GaN. AB - The phonon lifetime in GaN is known to exhibit a dependence on electron density. Recent noise measurements have also shown the lifetime to be temperature dependent. The source of these dependences is the coupling of the phonon and plasmon populations through the dielectric function. The effect of this anharmonicity is illustrated by comparing the frequency and wavevector dependent coupled-mode momentum relaxation rate with the phonon momentum relaxation rate obtained by Callen. A simple model that includes the anharmonic interaction and phonon migration yields phonon lifetimes depending on both electron density and temperature. PMID- 21825409 TI - The anharmonic phonon decay rate in group-III nitrides. AB - Measured lifetimes of hot phonons in group-III nitrides have been explained theoretically by considering three-phonon anharmonic interaction processes. The basic ingredients of the theory include full phonon dispersion relations obtained from the application of an adiabatic bond charge model and crystal anharmonic potential within the isotropic elastic continuum model. The role of various decay routes, such as Klemens, Ridley, Vallee-Bogani and Barman-Srivastava channels, in determining the lifetimes of the Raman active zone-centre longitudinal optical (LO) modes in BN (zincblende structure) and A(1)(LO) modes in AlN, GaN and InN (wurtzite structure) has been quantified. PMID- 21825410 TI - Rigid ion model of high field transport in GaN. AB - Here we report on high field transport in GaN based on the rigid ion model of the electron-phonon interaction within the cellular Monte Carlo (CMC) approach. Using the rigid pseudo-ion method for the cubic zinc-blende and hexagonal wurtzite structures, the anisotropic deformation potentials are derived from the electronic structure, the atomic pseudopotential and the full phonon dispersion and eigenvectors for both acoustic and optical modes. Several different electronic structure and lattice dynamics models are compared, as well as different models for the interpolation of the atomic pseudopotentials required in the rigid pseudo-ion method. Piezoelectric as well as anisotropic polar optical phonon scattering is accounted for as well. In terms of high field transport, the peak velocity is primarily determined by deformation potential scattering described through the rigid pseudo-ion model. The calculated velocity is compared with experimental data from pulsed I-V measurements. Good agreement is found using the rigid ion model to the measured velocity-field characteristics with the inclusion of dislocation and ionized impurity scattering. The crystal orientation of the electric field is investigated, where very little difference is observed in the velocity-field characteristics. We simulate the effects of nonequilibrium hot phonons on the energy relaxation as well, using a detailed balance between emission and absorption during the simulation, and an anharmonic decay of LO phonons to acoustic phonons, as reported previously. Nonequilibrium phonons are shown to result in a significant degradation of the velocity-field characteristics for high carrier densities, such as those encountered at the AlGaN/GaN interface due to polarization effects. PMID- 21825411 TI - Quantitative study of the enhancement of the thermal conductivity of AlN ceramics by nanoscale processing. AB - We have theoretically studied and quantitatively analysed the enhancement of the thermal conductivity of AlN microceramics (i.e. commercially available powder) by the insertion of AlN nanosized particles of high-specific surface area, and of Y(2)O(3) and CaO as sintering additives. We have also studied the enhancement of the thermal conductivity of AlN nanoceramics by using Y(2)O(3) as the sintering additive. Thermal conductivity calculations have been carried out by applying the Callaway theory in its full form and by incorporating a detailed and accurate account of three-phonon processes. The role of densification of the AlN ceramic samples in enhancing the thermal conductivity has been quantified at low, intermediate and high temperatures. In addition to explaining the experimentally observed room-temperature conductivity results, the conductivity variation has been predicted over a large temperature range. PMID- 21825412 TI - Photodetectors based on intersubband transitions using III-nitride superlattice structures. AB - We review our recent progress on the fabrication of near-infrared photodetectors based on intersubband transitions in AlN/GaN superlattice structures. Such devices were first demonstrated in 2003, and have since then seen a quite substantial development both in terms of detector responsivity and high speed operation. Nowadays, the most impressive results include characterization up to 3 GHz using a directly modulated semiconductor laser and up to 13.3 GHz using an ultra-short pulse solid state laser. PMID- 21825413 TI - Tailoring the electrical conductivity of GaAs by nitrogen incorporation. AB - We investigate the electrical conductivity of the dilute nitride alloy GaAs(1 x)N(x), focusing on the range of concentrations of N over which this material system behaves as a good conductor. We report a large increase of the resistivity for x>0.2% and a strong reduction of the electron mobility, MU, at x~0.1%. In the ultra-dilute regime (x~0.1%) and at low electric fields (<1 kV cm(-1)), the electrical conductivity retains the characteristic features of electron transport through extended states, albeit with relatively low mobility (MU~0.1 m(2) V(-1) s(-1) at T = 293 K) due to scattering of electrons by N atoms. In contrast, at large electric fields (>1 kV cm(-1)), the conduction electrons gain sufficient energy to approach the energy of the resonant N level, where they become spatially localized. This resonant electron localization in an electric field (RELIEF) leads to negative differential velocity. The RELIEF effect could be observed in other III-N-V compounds, such as InAs(1-x)N(x) and InP(1-x)N(x), and has potential for applications in terahertz electronics. PMID- 21825414 TI - Electronic transport in n- and p-type modulation doped Ga(x)In(1-x)N(y)As(1-y)/ GaAs quantum wells. AB - We present a comprehensive study of longitudinal transport of two-dimensional (2D) carriers in n- and p-type modulation doped Ga(x)In(1-x)N(y)As(1-y) /GaAs quantum well structures. The Hall mobility and carrier density of electrons in the n-modulation doped quantum wells (QWs) decreases with increasing nitrogen composition. However, the mobility of the 2D holes in p-modulation doped wells is not influenced by nitrogen and it is significantly higher than that of 2D electrons in n-modulation doped material. The observed behaviour is explained in terms of increasing electron effective mass as well as enhanced N-related alloying scattering with increasing nitrogen content. In order to determine the conduction band (CB) and valence band (VB) structures as well as electron and hole effective masses, the band anticrossing model with an eight-band [Formula: see text] approximation in the Luttinger-Kohn approach is used. The effects of strain, quantum confinement and the strong coupling between the localized nitrogen states and the CB extended states of GaInAs are considered in the calculations. The results indicate that the nitrogen induces a strong perturbation to the CB of the matrix semiconductor whilst the VB remains unaffected. The temperature dependent mobility of 2D electron gas is discussed using an analytical model that accounts for the most important scattering mechanisms. The results indicate that the interface roughness and N-related alloy scattering are the dominant mechanisms at low temperatures, while polar optical phonon and N-related alloy scattering limit mobility at high temperatures. PMID- 21825415 TI - Electron spin control in dilute nitride semiconductors. AB - We report on a study of spin-dependent recombination processes (SDR) for conduction band electrons on deep paramagnetic centers in a series of GaAs(1 y)N(y) epilayers by time-resolved optical orientation experiments. We demonstrate that this dilute nitride compound can be used as an effective electron spin filter under a polarized optical excitation of appropriate intensity. This optimum intensity can moreover be controlled by adjusting the nitrogen composition in the layer. PMID- 21825416 TI - Radiative energy transfer in disordered photonic crystals. AB - The difficulty of description of the radiative transfer in disordered photonic crystals arises from the necessity to consider on an equal footing the wave scattering by periodic modulations of the dielectric function and by its random inhomogeneities. We resolve this difficulty by approaching this problem from the standpoint of the general multiple scattering theory in media with an arbitrary regular profile of the dielectric function. We use the general asymptotic solution of the Bethe-Salpeter equation in order to show that for a sufficiently weak disorder the diffusion limit in disordered photonic crystals is presented by incoherent superpositions of the modes of the ideal structure with weights inversely proportional to the respective group velocities. The radiative transfer and the diffusion equations are derived as a relaxation of long scale deviations from this limiting distribution. In particular, it is shown that in general the diffusion is anisotropic unless the crystal has sufficiently rich symmetry, say, the square lattice in 2D or the cubic lattice in 3D. In this case, the diffusion is isotropic and only in this case can the effect of the disorder be characterized by a single mean free path depending on frequency. PMID- 21825417 TI - Dynamical stabilization of the body centered cubic phase in lanthanum and thorium by phonon-phonon interaction. AB - A recently developed self-consistent ab initio lattice dynamical method has been applied to the high temperature body centered cubic (bcc) phase of La and Th, which are dynamically unstable at low temperatures. The bcc phase of these metals is found to be stabilized by phonon-phonon interactions. The calculated high temperature phonon frequencies for La are found to be in good agreement with the corresponding experimental data. PMID- 21825418 TI - Equilibrium structure of delta-Bi(2)O(3) from first principles. AB - Using ab initio calculations, we have systematically studied the structure of delta-Bi(2)O(3) (fluorite prototype, 25% oxygen vacancies) probing [Formula: see text] and combined [Formula: see text] and [Formula: see text] oxygen vacancy ordering, random distribution of oxygen vacancies with two different statistical descriptions as well as local relaxations. We observe that the combined [Formula: see text] and [Formula: see text] oxygen vacancy ordering is the most stable configuration. Radial distribution functions for these configurations can be classified as discrete (ordered configurations) and continuous (random configurations). This classification can be understood on the basis of local structural relaxations. Up to 28.6% local relaxation of the oxygen sublattice is present in the random configurations, giving rise to continuous distribution functions. The phase stability obtained may be explained with the bonding analysis. Electron lone-pair charges in the predominantly ionic Bi-O matrix may stabilize the combined [Formula: see text] and [Formula: see text] oxygen vacancy ordering. PMID- 21825419 TI - NMR investigations of Li(+) ion dynamics in the NASICON ionic conductors [Formula: see text]. AB - NMR studies of (7)Li and (31)P nuclei are reported in the 150-900 K temperature range for the [Formula: see text] NASICON compounds with x = 0.8, 0.7, 0.6 and 0.3. Magic angle spinning (MAS mode) experiments were performed at room temperature on the (7)Li and (31)P nuclei. The linewidth and the spin lattice relaxation times of these nuclei are studied versus temperature in the static mode. The spectra recorded in the MAS mode show that the (7)Li ions occupy three chemical sites, the occupation of which being very sensitive to the x values but not sensitive to the coexistence of the two varieties [Formula: see text] and [Formula: see text] observed at room temperature in compounds with x<=0.5. On the other hand, the (31)P nucleus MAS spectra are very sensitive to lithium content but also to the variety coexistence. T(1) measurements were performed in a static mode on the (7)Li and (31)P nuclei. In all the compounds, the (7)Li spin lattice relaxation time exhibits two branches with several minima, indicating the complex dynamics for this ion. One of these minima appears in the same temperature range as the minimum of the (31)P nucleus T(1), strongly suggesting a cross-relaxation process between these nuclei. T(1rho) measurements on (7)Li (static mode) allow us to show a slow motion different from the one probed by the T(1). The analysis of the T(1rho) behaviour with temperature and composition allows us to ascribe the motion probed by this time to the oxygen ion motion which monitors the opening and closing of the lithium pathways. A qualitative interpretation of the (7)Li T(1) results is done; it takes into account the cross-relaxation phenomena between (31)P and (7)Li and quadrupolar fluctuations. PMID- 21825420 TI - (N-Me-2,6-di-Me-Pz) (TCNQ)(2)-genuine organic anion-radical salt: a spin-ladder? AB - The room temperature Raman spectra investigations on single crystals of an anion radical salt (N-Me-2,6-di-Me-Pz) (TCNQ)(2) with a pyrazine-based cation were performed. The infrared reflection spectra of the sample were recorded in the frequency range from 400 to 7500 cm(-1), at room temperature. Magnetization measurements were performed as a function of temperature in magnetic fields up to 5 T. The heat capacity and magnetic susceptibility were measured in the temperature range from 2 to 300 K. The results are studied in terms of quasi-one dimensional magnetic theoretical models and they indicate behavior close to a spin-ladder system. PMID- 21825421 TI - Structural, electronic, elastic and optical properties of Cd(x)Zn(1-x)Te mixed crystals. AB - The structural, electronic, elastic and optical properties of Cd(x)Zn(1-x)Te ternary mixed crystals are investigated by the first-principles plane-wave pseudopotential method within the LDA approximations. Basic physical properties, such as lattice constant, bulk modulus, second-order elastic constants (C(ij)) and the electronic band structures, are calculated. We also predict the shear modulus, Young's modulus and Poisson's ratio. Moreover, we have calculated the optical properties (dielectric functions, refractive index, extinction coefficient and energy loss function) of these ternary mixed crystals. Our results agree well with the available data in the literature. PMID- 21825422 TI - First-principles characterization of the anisotropy of theoretical strength and the stress-strain relation for a TiAl intermetallic compound. AB - We perform first-principles computational tensile and compressive tests (FPCTT and FPCCT) to investigate the intrinsic bonding and mechanical properties of a gamma-TiAl intermetallic compound (L 1(0) structure) using a first-principles total energy method. We found that the stress-strain relations and the corresponding theoretical tensile strengths exhibit strong anisotropy in the [001], [100] and [110] crystalline directions, originating from the structural anisotropy of gamma-TiAl. Thus, gamma-TiAl is a representative intermetallic compound that includes three totally different stress-strain modes. We demonstrate that all the structure transitions in the FPCTT and FPCCT result from the breakage or formation of bonds, and this can be generalized to all the structural transitions. Furthermore, based on the calculations we qualitatively show that the Ti-Al bond should be stronger than the Ti-Ti bond in gamma-TiAl. Our results provide a useful reference for understanding the intrinsic bonding and mechanical properties of gamma-TiAl as a high-temperature structural material. PMID- 21825423 TI - Structural phase transition of ultra thin PrO(2) films on Si(111). AB - Ultra thin heteroepitaxial PrO(2) films on Si(111) were annealed under UHV conditions and investigated by x-ray diffraction (XRD), x-ray reflectometry (XRR) and spot profile analysis low energy electron diffraction (SPALEED) with regard to structural stability and phase transitions due to the high oxygen mobility of the oxide. This gives information about the manageability of the material and its application as a model catalyst system in surface science. While the samples are stable in UHV at room temperature, annealing at 300 degrees C exhibits a terminated phase transition from PrO(2) and PrO(2-Delta) to cub-Pr(2)O(3) with an increase in the silicate at the interface and a decrease in the crystalline praseodymia layer mainly due to atomic diffusion of silicon into the oxide film. Strain effects during the phase transition also cause mosaic formation at the surface. Further annealing up to 600 degrees C shows only little change in the film structure. This will finally lead to a model of the film structure during the annealing process. PMID- 21825424 TI - Dispersionless motion and ratchet effect in a square-wave-driven inertial periodic potential system. AB - The underdamped Langevin equation of motion of a particle, in a symmetric periodic potential and subjected to a symmetric periodic forcing with mean zero over a period, with nonuniform friction, is solved numerically. The particle is shown to acquire a steady state mean velocity at asymptotically large timescales. At these large timescales the position dispersion grows proportionally with time, t, allowing for calculating the steady state diffusion coefficient D. Interestingly, D shows a peaking behaviour around the same F(0) where the net current peaks. The net (ratchet) current, however, turns out to be largely coherent. At an intermediate timescale, which bridges the small timescale behaviour of dispersion ~t(2) to the large time one, the system shows periodic oscillation between dispersionless and steeply growing dispersion depending on the amplitude and frequency of the forcing. The contribution of these different dispersion regimes to ratchet current is analysed. PMID- 21825425 TI - Quasielastic neutron scattering study of hydrogen motion in NbC(0.71)H(0.28). AB - In order to study the mechanism and parameters of H jump motion in the nonstoichiometric Nb carbides, we have performed quasielastic neutron scattering (QENS) measurements for NbC(0.71)H(0.28) over the temperature range 11- 475 K. Our results indicate that about 30% of H atoms in this system participate in a fast diffusive motion. The temperature dependence of the corresponding H jump rate in the range 298-475 K follows the Arrhenius law with an activation energy of 328 +/- 9 meV. The Q dependence of the QENS data suggests that the observed jump motion corresponds to long-range diffusion of H atoms along chains of the off-centre sites in carbon vacancies. PMID- 21825426 TI - Optical in situ study of the reduction/oxidation processes in YAlO(3):Mn crystals. AB - The paper presents experimental results on an in situ optical absorption study of the reduction/oxidation processes in YAlO(3):Mn crystals that are visible in the [Formula: see text] recharging of manganese ions. The appearance of the Mn(5+) absorption during annealing in an oxidizing atmosphere as well as its bleaching during annealing of the crystal in a reducing atmosphere have been studied in the temperature range from 800 to 1250 K. The oxidation and reduction kinetics are analyzed in the framework of the vacancies diffusion model and compared with the nominally pure and Nd-doped YAlO(3) crystals studied previously. PMID- 21825427 TI - Lattice relaxation at V(-), NV(-), and NVN(-) defects in diamond investigated by positron annihilation. AB - Experimental positron lifetime data for three vacancy-related defects in synthetic type Ib diamonds with well known structures are uniquely suitable for comparison with theoretical investigations of lattice relaxation. PMID- 21825428 TI - State mixing and the cubic crystal field approximation for rare earth ions: the case of the Er(3+) ion in axial crystal fields. AB - The validity of the cubic crystal field (CCF) approximation for the interpretation of the magnetic resonance properties of the Er(3+) ion in crystal fields with tetragonal and trigonal symmetry is examined. The ground state paramagnetic resonance principal g values are explicitly calculated in terms of the cubic crystal field eigenstates as a function of axial crystal field strength. It is shown that, depending on the ground state crystal field eigenstate, the widely accepted CCF approximation of simply taking the average of the trace of the g tensor and equating it to the g value found in cubic symmetry can lead to a misinterpretation of the ground state Stark level and the lattice coordination of the ion. The implications for experimentally reported results are discussed. PMID- 21825429 TI - Coupling of conduction electrons to two-level systems formed by hydrogen: a scattering approach. AB - An effective Hamiltonian for a two-level system (TLS) which could model the interaction between a tunneling proton and the conduction electrons of a metal is investigated in a comparative way. In the conventional first-order Born approximation with plane waves, and for small-distance displacement of the tunneling particle, a simple correlation between the atomic motion and angular momentum change of the scattering electron is deduced. For such a displacement, and within a distorted wave Born approximation for initial and final states, the change in the scattering amplitude is expressed via bounded trigonometric functions of the corresponding difference of scattering phase shifts. The numerical value of this amplitude change is analyzed in the framework of a self consistent screening description for an impurity embedding in a paramagnetic electron gas. The coupling thus obtained of the tunneling proton to a homogeneous electron gas is too weak to be in the range required for realization of the two channel Kondo effect. PMID- 21825430 TI - Pairing state symmetries of high- T(c) superconductors: a comparative study using two Ginzburg-Landau models. AB - An attempt has been made to resolve the issue regarding the pairing symmetry of high- T(c) superconducting materials (cuprates). The properties of high- T(c) superconductors, which are the signatures of the pairing symmetry of these materials, are being calculated by using the anisotropic s-wave Ginzburg-Landau (GL) theory, i.e. the anisotropic single-order parameter GL theory (ASGL), and is compared with those calculated in a recent work (Karmakar and Dey 2008 J. Phys.: Condens. Matter 20 255218) by the isotropic d-wave GL theory involving mixed symmetry states of the order parameters, i.e. the isotropic two-order parameter GL theory (TIGL), over the entire range of applied magnetic field and temperature for arbitrary values of the GL parameter kappa and vortex lattice symmetry. The results are further compared with suitable experimental data on the high- T(c) superconducting cuprate YBa(2)Cu(3)O(7-delta). It has been found that the TIGL model definitely gives a better match with the experimental data and is thus more suitable to describe the pairing state symmetries of the high- T(c) superconducting cuprates. PMID- 21825431 TI - Thermoelectric power in alloys with phase separation (composites). AB - A thermopower formula is derived for composites: [Formula: see text] (kappa(i) and kappa are the specific thermal conductivities, S(i) and S are the Seebeck coefficients of the phase i and the composite, respectively, and upsilon(i) is the volume fraction of the phase i). This formula can be applied for calculating the Seebeck coefficient (thermoelectric power) of amorphous transition-metal metalloid alloys, for which amorphous phase separation occurs for large ranges of concentration. There are two contributions to S(i), a scattering term and a contribution due to electron transfer between the phases maintaining a common electrochemical potential MU. The theory predicts discontinuities in the concentration dependence of the Seebeck coefficient of metallic composites. It is argued that in amorphous composites these discontinuities occur very precisely at upsilon(i) = 1/3. This phenomenon can be used to characterize the crystallization kinetics of amorphous alloys. The theory is applied to a- Cr(1-x)Si(x) alloys for calculation of S versus x. Both the calculated S(x) dependence and the discontinuities agree very well with the experimental data, as long as x<0.67; the deviations at x>0.67 are interpreted to be caused by the p-d bonds at the phase boundaries. PMID- 21825432 TI - Acoustic metamaterial with negative modulus. AB - We present experimental and theoretical results on an acoustic metamaterial that exhibits a negative effective modulus in a frequency range from 0 to 450 Hz. A one-dimensional acoustic metamaterial with an array of side holes on a tube was fabricated. We observed that acoustic waves above 450 Hz propagated well in this structure, but no sound below 450 Hz passed through. The frequency characteristics of the metamaterial has the same form as that of the permittivity in metals due to the plasma oscillation. We also provide a theory to explain the experimental results. PMID- 21825433 TI - Upper critical field, superconducting energy gaps and the Seebeck coefficient in La(0.8)Th(0.2)FeAsO. AB - We report the synthesis and characterization of a new electron-doped La oxypnictide superconductor by partial substitution of lanthanum by thorium. The superconducting transition temperature at about 30.3 K was observed in La(0.8)Th(0.2)FeAsO, which is the highest in La-based oxypnictide superconductors synthesized at ambient pressure. We find that the decrease in lattice parameters with Th doping in LaOFeAs is more drastic as compared to that obtained by high pressure (6 GPa) synthesis of oxygen-deficient LaOFeAs. The resistivity and magnetic susceptibility measurements yield an upper critical field H(c2)(0) of 47 T. Partial substitution of Th in place of La induces electron doping, as shown by a negative Seebeck coefficient. The temperature-dependent magnetic penetration depth data provides strong evidence for a nodeless low energy gap of 1.4 meV. PMID- 21825434 TI - Antiresonance and bound states in the continuum in electron transport through parallel-coupled quantum-dot structures. AB - In this paper we make a theoretical study of electron transport through a multi quantum-dot system, in which the peripheral quantum dots of a one-dimensional chain are embodied in the two arms of an Aharonov-Bohm interferometer. It is found that, in the absence of magnetic flux, all the even molecule states of odd numbered quantum-dot structures decouple from the leads and in even-numbered quantum-dot systems all the odd molecule states decouple from the leads, which indicates the formation of remarkable bound states in the continuum. Meanwhile, what is interesting is that apparent antiresonance occurs in electron transport through this structure, the positions of which are accordant with all even (odd) eigenenergies of the sub-molecule of the even (odd)-numbered quantum dots without the peripheral dots. All these results are efficiently modified by the presence of magnetic flux through this system. PMID- 21825435 TI - Isolation and aggregation of substituent Co in ZnO:Co diluted magnetic semiconductors. AB - Distribution of magnetic ions in a semiconducting host is critical for the functionality of diluted magnetic semiconductors. By investigating the temperature- and field-dependent magnetization of single-phase polycrystalline ZnO:Co oxides, the substitution of Co at the Zn site is found not to occur randomly but Co ions appear to have a tendency for aggregation via oxygen with an antiferromagnetic coupling, in contrast to paramagnetic isolated free Co. The experimental findings are justified through first-principles density functional calculations based on the generalized gradient approximation. It suggests that Co dopants in ZnO:Co have a tendency towards staying close to each other along the ab plane. PMID- 21825436 TI - Raman scattering of perovskite DyScO(3) and GdScO(3) single crystals. AB - We report an investigation of DyScO(3) and GdScO(3) single crystals by Raman scattering in various scattering configurations and at various wavelengths. The Raman spectra are well defined and the reported spectral signature together with the mode assignment set the basis for the use of Raman scattering for the investigation of rare earth scandates. The observed positions of Raman modes for DyScO(3) are for most bands in reasonable agreement with recent theoretical ab initio predictions of the vibrational spectrum for the same material. Further to the phonon signature, a luminescence signal is observed for both scandates. While the luminescence is weak for DyScO(3), it is very intense for GdScO(3) when using a 488 or 514 nm excitation line, which in turn inhibits full analysis of the phonon spectrum. We show that a meaningful phonon Raman analysis of GdScO(3) samples can be done by using a 633 nm excitation. PMID- 21825437 TI - The Yb(2)Al(1-x)Mg(x)Si(2) series from a spin fluctuation (x = 0) to a magnetically ordered ground state (x = 1). AB - The structural and magnetic properties of Yb(2)Al(1-x)Mg(x)Si(2) (x = 0, 0.5 and 1), crystallizing in the tetragonal Mo(2)FeB(2)-type structure, are reported in this work. Yb(2)AlSi(2) exhibits a Pauli paramagnetic ground state arising due to spin/valence fluctuations induced by a significant Yb 4f conduction band hybridization. High-field magnetization (up to 120 kOe) indicates a nearly temperature-independent susceptibility of 8.6 * 10(-3) emu/Yb mol below 10 K. On the other hand, Yb ions in Yb(2)MgSi(2) order antiferromagnetically at a relatively high temperature T(N) of 9.5 K. The intermediate composition alloy Yb(2)Al(0.5)Mg(0.5)Si(2) is a Kondo lattice, antiferromagnet with T(N) = 5.5 K. The coefficient of the linear term of the electronic heat capacity, gamma, of Yb(2)AlSi(2) is found to be 305 mJ mol(-1) K(-2), indicating a significant electronic mass enhancement due to strong electronic correlations. Below 12 K, an additional contribution to the heat capacity of the form T(3)lnT is observed. The (170)Yb Mossbauer spectra in the ordered state of Yb(2)MgSi(2) indicate a strong coupling of the 4f quadrupolar moment with the magnetic moment through a magneto elastic coupling. PMID- 21825438 TI - Magnetoelectric and multiferroic properties of ternary copper chalcogenides Cu(2)M(II)M(IV)S(4). AB - We investigate theoretically the ternary copper chalcogenides with the general formula Cu(2)M(II)M(IV)S(4). This family of compounds can crystallize in two different non-centrosymmetric structures, [Formula: see text] or Pnm 2(1). We show that all the reported members of Cu(2)M(II)M(IV)S(4) having the Pnm 2(1) symmetry exhibit a large spontaneous polarization. This result suggests that several of these materials are likely to be multiferroics since they order magnetically at low temperature. We discuss in detail in the framework of Landau theory the members Cu(2)MnSnS(4) and Cu(2)MnGeS(4) which should present both a linear magnetoelectric effect and multiferroic behavior. PMID- 21825439 TI - Induced motion of domain walls in multiferroics. AB - We study the dynamics of a 180 degrees domain wall of ab-type in external alternating magnetic and electrical fields in magnetic materials with linear magnetoelectric interaction. We discuss the features of oscillatory and drift motion of domain wall and stripe structure depending on the parameters of external fields and characteristics of the material. PMID- 21825440 TI - A new Kondo antiferromagnet Ce(Ni(0.25)In(1.75)). AB - We find that Ce(Ni(0.25)In(1.75)) crystallizes in the hexagonal AlB(2)-type structure with lattice parameters a = 0.4850(5) nm and c = 0.3908(5) nm. Magnetic susceptibility, electrical resistivity and low-temperature specific heat data reveal that the bulk phase transition at 3.7 +/- 0.2 K in Ce(Ni(0.25)In(1.75)) is to an antiferromagnetic state. The magnetic contribution to the resistivity rho(mag) of Ce(Ni(0.25)In(1.75)) increases as ln(T) when temperature is lowered from room temperature and reaches a plateau at 9 K, followed by a rapid decrease around 4 K. These results associated with a reduction of the Ce magnetic moment and of the magnetic entropy at T(N) suggest that Ce(Ni(0.25)In(1.75)) could be a Kondo antiferromagnet. The Kondo temperature is estimated to be of order 6 K. PMID- 21825441 TI - Effects of magnetic interactions in antiferromagnetic ferrihydrite particles. AB - The effects of magnetic interactions in the magnetic properties of six-line ferrihydrite particles were investigated by studying the behavior of aggregated versus coated particles. Four different coating agents (sugar, alginate, lactate and ascorbate) were employed in order to obtain dispersed particles and prevent particle agglomeration; one sub-sample was allowed to dry with no coating agent. The five sets of ferrihydrite particles were from the same batch and the size was estimated as 3.6 +/- 0.4 nm in length. Low temperature magnetization, ac susceptibility and Mossbauer spectroscopy data showed contrasting blocking temperatures for uncoated and coated samples with a decrease of T(P) from about 50 K to 12 K, respectively. The contributions from magnetic interactions were recognized in magnetic measurements and the effective anisotropy constant for non interacting ferrihydrite was estimated as (100 +/- 10) * 10(3) J m(-3). Overall, employing sugar and alginate as coating agents was more successful in preventing particle aggregation and magnetic interactions. In contrast, ascorbate and lactate were unsuitable due to the chemical reaction between the coating agent and ferrihydrite surface. PMID- 21825442 TI - Epitaxial TbMnO(3) thin films on SrTiO(3) substrates: a structural study. AB - TbMnO(3) films have been grown under compressive strain on (001)-oriented SrTiO(3) crystals. They have an orthorhombic structure and display the (001) orientation. With increasing thickness, the structure evolves from a more symmetric (tetragonal) to a less symmetric (bulk-like orthorhombic) structure, while keeping constant the in-plane compression, thereby leaving the out-of-plane lattice spacing unchanged. The domain microstructure of the films is also revealed, showing an increasing number of orthorhombic domains as the thickness is decreased: we directly observe ferroelastic domains as narrow as 4 nm. The high density of domain walls may explain the induced ferromagnetism observed in the films, while both the decreased anisotropy and the small size of the domains could account for the absence of a ferroelectric spin spiral phase. PMID- 21825443 TI - Localized magnetic states in biased bilayer and trilayer graphene. AB - We study the localized magnetic states of an impurity in biased bilayer and trilayer graphene. It is found that the magnetic boundary for bilayer and trilayer graphene shows mixed features of Dirac and conventional fermions. For zero gate bias, as the impurity energy approaches the Dirac point, the impurity magnetization region diminishes for bilayer and trilayer graphene. When a gate bias is applied, the dependence of impurity magnetic states on the impurity energy exhibits a different behavior for bilayer and trilayer graphene due to the opening of a gap between the valence and the conduction band in the bilayer graphene with an applied gate bias. The magnetic moment and the corresponding magnetic transition of the impurity in bilayer graphene are also investigated. PMID- 21825444 TI - Weak dimers and soft phonons on the beta-SiC(100) surface. AB - We study the beta-SiC(100) [Formula: see text] reversible phase transition, using first-principles molecular dynamics simulations to search for the ground state atomic structure as well as to investigate the dynamics of this surface. We find that this surface consists of weakly bonded asymmetric Si dimers that exhibit a complex atomic motion, associated with a surface soft phonon. This soft phonon is strongly coupled to the electrons in dangling bond states close to the Fermi level, explaining the observed insulator-metal transition. We identify the dynamical processes responsible for the phase transition and predict that this surface should undergo another reversible phase transition at low T. PMID- 21825445 TI - Silicon oxidation by ozone. AB - Understanding the oxidation of silicon has been an ongoing challenge for many decades. Ozone has recently received considerable attention as an alternative oxidant in the low temperature, damage-free oxidation of silicon. The ozone-grown oxide was also found to exhibit improved interface and electrical characteristics over a conventionally dioxygen-grown oxide. In this review article, we summarize the key findings about this alternative oxidation process. We discuss the different methods of O(3) generation, and the advantages of the ozone-grown Si/SiO(2) interface. An understanding of the growth characteristics is of utmost importance for obtaining control over this alternative oxidation process. PMID- 21825446 TI - Extended x-ray absorption fine structure studies of the atomic structure of nanoparticles in different metallic matrices. AB - It has been appreciated for some time that the novel properties of particles in the size range 1-10 nm are potentially exploitable in a range of applications. In order to ultimately produce commercial devices containing nanosized particles, it is necessary to develop controllable means of incorporating them into macroscopic samples. One way of doing this is to embed the nanoparticles in a matrix of a different material, by co-deposition for example, to form a nanocomposite film. The atomic structure of the embedded particles can be strongly influenced by the matrix. Since some of the key properties of materials, including magnetism, strongly depend on atomic structure, the ability to determine atomic structure in embedded nanoparticles is very important. This review focuses on nanoparticles, in particular magnetic nanoparticles, embedded in different metal matrices. Extended x-ray absorption fine structure (EXAFS) provides an excellent means of probing atomic structure in nanocomposite materials, and an overview of this technique is given. Its application in probing catalytic metal clusters is described briefly, before giving an account of the use of EXAFS in determining atomic structure in magnetic nanocomposite films. In particular, we focus on cluster-assembled films comprised of Fe and Co nanosized particles embedded in various metal matrices, and show how the crystal structure of the particles can be changed by appropriate choice of the matrix material. The work discussed here demonstrates that combining the results of structural and magnetic measurements, as well as theoretical calculations, can play a significant part in tailoring the properties of new magnetic cluster-assembled materials. PMID- 21825447 TI - Glutamic acid adsorbed on Ag(110): direct and indirect molecular interactions. AB - First-principles calculations are used to rationalize the adsorption geometry and long-range order observed for (s)-glutamic acid rows adsorbed on Ag(110). Hydrogen bonds and van der Waals interactions are found to be important for the direct molecular interaction within the molecular rows. Adsorption induced charge density waves in the substrate lead to an indirect interaction between the adsorbates, resulting in the formation of long-range order. Remarkably, structural relaxation effects also play a decisive role in the indirect interactions. PMID- 21825448 TI - On the transition from boundary lubrication to hydrodynamic lubrication in soft contacts. AB - We consider the contact between elastically soft solids with randomly rough surfaces in sliding contact in a fluid, which is assumed to be Newtonian with constant (pressure-independent) viscosity. We discuss the nature of the transition from boundary lubrication at low sliding velocity, where direct solid solid contact occurs, to hydrodynamic lubrication at high sliding velocity, where the solids are separated by a thin fluid film. We consider both hydrophilic and hydrophobic systems, and cylinder-on-flat and sphere-on-flat sliding configurations. We show that, for elastically soft solids such as rubber, including cavitation or not results in nearly the same friction. PMID- 21825449 TI - Phases and phase transitions of hexagonal cobalt oxide films on Ir(100)-(1 * 1). AB - Cobalt oxides on the unreconstructed Ir(100) surface were prepared by reactive deposition of Co established by simultaneous oxygen flux at about 50 degrees C and subsequent annealing. The films were investigated by low-energy electron diffraction (LEED), scanning tunnelling microscopy (STM) and thermal desorption spectroscopy (TDS). We show that in spite of the quadratic unit mesh of the substrate, oxide films of (111) orientation develop. As long as oxygen-rich conditions are maintained they are of spinel-type Co(3)O(4)(111). They are non pseudomorphic and transform to rocksalt-type CoO(111) when oxygen loss is induced by annealing at elevated temperatures. Thin films of CoO(111) are commensurate, and so, in order to realize that, they exhibit a slightly distorted unit cell when below a thickness equivalent to about seven cobalt monolayers. With increasing film thickness the uniaxial strain accompanied by the commensurability is gradually relieved by the insertion of dislocations so that eventually the film assumes ideal hexagonality. All CoO(111)-type surfaces are reconstructed at low sample temperatures equivalent to a [Formula: see text] superstructure. They reversibly transform into a (1 * 1) phase at about 50 degrees C. PMID- 21825450 TI - Magnetic domain coupling study in single-crystalline Fe/CoO bilayers. AB - We report on a study of the magnetic domain coupling in epitaxial wedge-shaped Fe layers deposited onto CoO/Ag(001). By using photoelectron emission microscopy (PEEM) in combination with x-ray magnetic circular and linear dichroism (XMCD, XMLD), we imaged the ferromagnetic and antiferromagnetic domains present in the Fe and CoO layers, respectively, below the CoO magnetic ordering temperature. The uncompensated Co spins at the Fe/CoO interface were revealed by XMCD-PEEM and were found to be coupled parallel to the magnetization of the Fe layer. An increase of the CoO XMLD contrast is visible for Fe thicknesses below 2 ML, where the Fe layer lacks magnetic long-range order. PMID- 21825451 TI - NEXAFS and XMCD studies of single-phase Co doped ZnO thin films. AB - A study of the electronic structure and magnetic properties of Co doped ZnO thin films synthesized by ion implantation followed by swift heavy ion irradiation is presented using near-edge x-ray absorption fine structure (NEXAFS) and x-ray magnetic circular dichroism (XMCD) measurements. The spectral features of NEXAFS at the Co L(3,2)-edge show entirely different features than that of metallic Co clusters and other Co oxide phases. The atomic multiplet calculations are performed to determine the valence state, symmetry and the crystal field splitting, which show that in the present system Co is in the 2+ state and substituted at the Zn site in tetrahedral symmetry with 10Dq = -0.6 eV. The ferromagnetic character of these materials is confirmed through XMCD spectra. To rule out the possibilities of defect induced magnetism, the results are compared with Ar annealed and Ar-ion implanted pure ZnO thin films. The presented results confirm the substitution of Co at the Zn site in the ZnO matrix, which is responsible for room temperature ferromagnetism. PMID- 21825452 TI - First principles studies of an Si tip on an Si(100)2 * 1 reconstructed surface. AB - We present a systematic study of the interaction between a silicon tip and a reconstructed Si(100)2 * 1 surface by means of total energy calculations using density functional theory. We perform geometry optimization to obtain the reconstructed Si surface using the local density approximation and the generalized gradient approximation methods and compare our results with those obtained experimentally. We then study the effects of the tip of a scanning probe of an atomic force microscope (AFM) on the behaviour of atoms on the reconstructed surface when the tip translates at distances close to it. Our results show that at certain positions of the tip relative to the surface and depending on the direction of the scan, the Si dimer on the surface flips, resulting in a local reconstruction of the surface into p(2 * 2) or c(4 * 2) configurations. These configurations exhibit energies lower by 0.05 eV/dimer than the Si(100)2 * 1 structure. PMID- 21825453 TI - Fano resonances in low-energy electron transmission through crystalline films. AB - It is shown that in crystalline films with a definite lattice symmetry there exist one-dimensional bands of bound electron states above the boundary of the continuous spectrum. The intensity of electron reflection near the state of complete transmission of low-energy electrons is found to have the form of a Fano resonance. We obtain the relationship between the Fano function parameters and physical characteristics of the system. The conditions for the electron transparency to arise near the bound state bands in the continuum are determined. PMID- 21825454 TI - Magnetic anisotropy of epitaxially grown Co and its alloy thin films. AB - We have performed a systematic study on the correlation between magnetic anisotropy energy (MAE) and crystal structures, such as lattice parameters, stacking fault densities, lattice strain, and so on, for epitaxially grown Co, Co Pt, and Co-Pd alloy thin films, and have found that the MAE strongly depends on the axial ratio c/a of the hcp crystal lattice. As the c/a of hcp Co decreases down to ~1.61 which is smaller than 1.622 for bulk Co, the MAE becomes significantly enhanced up to ~10(6) J m(-3). Similar trends have also been verified for hcp Co-Pt and -Pd. These results, which are qualitatively consistent with the classic single-ion anisotropy model and the recent first principles calculation, suggest a new effective way to control the MAE of magnetic thin films. PMID- 21825455 TI - Swift heavy ion irradiation of Cu-Zn-Al and Cu-Al-Ni alloys. AB - The effects produced by swift heavy ions in the martensitic (18R) and austenitic phase (beta) of Cu based shape memory alloys were characterized. Single crystal samples with a surface normal close to [210](18R) and [001](beta) were irradiated with 200 MeV of Kr(15+), 230 MeV of Xe(15+), 350 and 600 MeV of Au(26+) and Au(29+). Changes in the microstructure were studied with transmission electron microscopy (TEM) and high resolution transmission electron microscopy (HRTEM). It was found that swift heavy ion irradiation induced nanometer sized defects in the 18R martensitic phase. In contrast, a hexagonal close-packed phase formed on the irradiated surface of beta phase samples. HRTEM images of the nanometer sized defects observed in the 18R martensitic phase were compared with computer simulated images in order to interpret the origin of the observed contrast. The best agreement was obtained when the defects were assumed to consist of local composition modulations. PMID- 21825456 TI - Complete surface plasmon-polariton band gap and gap-governed waveguiding, bending and splitting. AB - We show theoretically that a complete band gap for surface plasmon-polaritons (SPPs) can exist in a flat metal surface coated with a two-dimensional periodic array of dielectric cylinders. Based on the SPP band gap, gap-governed SPP waveguides, bends and splitters at telecom wavelengths can be achieved by introducing line defects. Numerical simulations show that the proposed SPP waveguides have a very low loss, while SPP bends and splitters can bend and split guided SPPs efficiently. The proposed SPP waveguides, bends and splitters could thus be exploited to construct compact integrated optical circuits in the emerging field of plasmonics. PMID- 21825457 TI - Low pressure oxidation of ordered Sn/Pd(110) surface alloys. AB - The reaction of oxygen at low pressure with the Sn/Pd(110) system has been examined by photoelectron spectroscopy using synchrotron radiation. The c(2 * 2) and (3 * 1) reconstructions of the Sn/Pd(110) surface at 0.5 and 0.7 monolayers (ML) Sn coverage and a 1.75 ML Sn overlayer on the Pd(110) surface after flashing to 470 K were studied. The Sn 4d core level is strongly affected by O(2) adsorption while the Pd 3d core level shows very little change other than a decrease in intensity. Starting with a 10 L dose of oxygen, prominent changes in the spectra were observed for all Sn/Pd(110) surface alloys. Analysis of the Sn 4d core levels indicates that oxidation proceeds with the formation of well defined states of Sn, which were identified as a Pd-Sn-O interface layer, SnO and SnO(2) oxides. The valence band spectra confirm this assignment. The Sn(2+) and Sn(4+) component signals originate from the topmost surface layer, i.e. tin atoms in more highly oxidized states constitute the topmost surface layer on top of the Pd-Sn-O interface. The presence of a sub-surface PdSn intermetallic alloy facilitates the tin oxide formation; the Sn-O phase formation is accompanied by Pd-Sn bond dissociation. PMID- 21825458 TI - Investigation of the structure of thin HfO(2) films by soft x-ray reflectometry techniques. AB - HfO(2) thin films of different thicknesses and deposited by two methods (ALD and MOCVD) were studied. The microstructure of films was characterized by reflection spectroscopy, x-ray diffraction (XRD), and soft x-ray reflectometry. It was established that the HfO(2) film microstructure is closely dependent on film thickness. The 5 nm thick film synthesized by ALD shows an amorphous phase while the film prepared by MOCVD was inhomogeneous in depth and showed signs of crystalline structure. First results on the reconstruction of the depth distribution of chemical elements based on the analysis of reflectivity curves are discussed. PMID- 21825459 TI - Magnetic properties of a novel quasi-2D Cu(II)-trimer system. AB - We present structural and magnetic data of a new Cu(2+)(S = 1/2)-containing magnetic trimer system 2b.3CuCl(2).2H(2)O (b = betaine, C(5)H(11)NO(2)). The trimers form a quasi-2D quantum spin system with an unusual intra-layer exchange coupling topology, which, in principle, supports diagonal four-spin exchange. To describe the magnetic properties, a 2D effective interacting-trimer model has been developed including an intra-trimer coupling J and two inter-trimer couplings J(a) and J(b). The low-energy description and effective parameters are obtained from numerical calculations based on four coupled trimers (with periodic boundary conditions). Fits to the experimental data using this model yield the magnetic coupling constants J/k(B) = -15 K and J(a)/k(B) = J(b)/k(B) = -4 K. These parameters describe the susceptibility and magnetization data very well over the whole temperature and field range investigated. Moreover, the model calculations indicate that, for certain ranges of the ratio J(b)/J(a), which might be accessible by either chemical substitution and/or hydrostatic pressure, the low-energy properties of 2b.3CuCl(2).2H(2)O will be dominated by non-trivial four-spin exchange processes. PMID- 21825460 TI - Angular distribution of positrons in coherent pair production in deformed crystals. AB - We investigate the angular distribution of positrons in the coherent process electron-positron pair creation process by high-energy photons in a periodically deformed single crystal with a complex base. The formula for the corresponding differential cross section is derived for an arbitrary deformation field. The case is considered in detail when the photon enters into the crystal at small angles with respect to a crystallographic axis. The results of the numerical calculations are presented for SiO(2) and diamond single crystals and Moliere parameterization of the screened atomic potentials in the case of the deformation field generated by an acoustic wave of S-type. PMID- 21825461 TI - Slow dynamics in hard condensed matter: a case study of the phase separating system NdNiO(3). AB - We report the time dependent response of electrical resistivity in the non magnetic perovskite oxide NdNiO(3) in its phase separated state and provide a physical explanation of the observations. We also model the system and make an accurate Monte Carlo simulation of the observed behavior. While cooling, a phase separation takes place in the system below its metal-insulator transition temperature and in this state the material exhibits various dynamical phenomena such as relaxation of resistivity, dependence of resistivity on cooling rate and rejuvenation of the material after ageing. These phenomena signal that the phase separated state of NdNiO(3) is not in thermodynamic equilibrium, and we conjecture that it consists of supercooled paramagnetic metallic and antiferromagnetic insulating phases. The supercooled phases are metastable and they switch over to the insulating equilibrium state stochastically, and this can account for the slow dynamics observed in our system. We also verify the predictive power of our model by simulating the result of a new experiment and confirming it by actual measurements. PMID- 21825462 TI - Pressure-induced phase transitions of AX(2)-type iron pnictides: an ab initio study. AB - An investigation into the high-pressure behavior of AX(2)-type iron pnictides was conducted using first-principles calculations based on density functional theory within the generalized gradient approximation. Our results demonstrate that a phase transition from the marcasite to the CuAl(2) occurs at 108 GPa for FeP(2), at 92 GPa for FeAs(2), and at 38 GPa for FeSb(2), accompanying a semiconductor-to metal crossover. A linear relationship between bulk moduli and the inverse specific volume is proposed to be B(0) = 17 498/V(0)-45.9 GPa for the marcasite type phase and B(0) = 31 798/V(0)-67.5 GPa for the CuAl(2)-type phase. According to the observed structural evolutions, we claim that the regular marcasite transforms to the CuAl(2)-type phase and the anomalous marcasite transforms to the pyrite-type phase at high pressures. PMID- 21825463 TI - Narrow band exciton coupled with acoustical anharmonic phonons: application to the vibrational energy flow in a lattice of H-bonded peptide units. AB - A time-convolutionless master equation is established for describing the transport properties of amide-I vibrons coupled with acoustic phonons in a lattice of H-bonded peptide units. Within the non-adiabatic weak coupling limit, it is shown that the vibron dynamics strongly depends on the nature of the phonons and two distinct mechanisms have been identified. Harmonic phonons, which support spatial correlations over an infinite length scale, induce a fast dephasing-rephasing mechanism in the short time limit. Consequently, the vibron keeps its wavelike nature and a coherent vibrational energy flow takes place whatever the temperature. By contrast, anharmonic phonons carry spatial correlations over a finite length scale, only. As a result, the rephasing process no longer compensates the dephasing mechanism so that dephasing-limited band motion occurs. It gives rise to the incoherent diffusion of the vibron characterized by a diffusion coefficient whose temperature dependence scales as 1/T(alpha). In the weak anharmonicity limit, the exponent alpha is about 2. It becomes smaller than unity in the strong anharmonicity limit, indicating that the diffusion coefficient behaves as a slowly decaying function of the temperature. PMID- 21825464 TI - Ab initio study on the electronic structure and vibration modes of alkali and alkaline-earth amides and alanates. AB - We study the electronic structure and vibrational modes of several amides M(NH(2))(n) and alanates M(AlH(4))(n) (M = K, Na, Li, Ca and Mg), focusing on the role of cation states. Calculated breathing stretching vibration modes for these compounds are compared with measured infrared and Raman spectra. In the amides, we find a significant tendency such that the breathing mode frequencies and the structural parameters of NH(2) vary in accordance with the ionization energy of cation. The tendency may be explained by the strength in hybridization between cation orbitals and molecular orbitals of (NH(2))(-). The microscopic mechanism of correlations between the vibration frequencies and structural parameters is elucidated in relation to the electronic structure. A possible similar tendency in the alanates is also discussed. PMID- 21825465 TI - Peculiarities of ionic transport in Li(1.3)Al(0.15)Y(0.15)Ti(1.7)(PO(4))(3) ceramics. AB - A powder of Li(1.3)Al(0.15)Y(0.15)Ti(1.7)(PO(4))(3) has been synthesized by solid state reaction. The powder was a single phase material and had rhombohedral symmetry (space group [Formula: see text]) with six formula units in the unit cell. Impedance spectra of Li(1.3)Al(0.15)Y(0.15)Ti(1.7)(PO(4))(3) ceramics were recorded in the frequency range from 10(6) to 1.2 * 10(9) Hz and temperature range from 300 to 600 K. Two relaxation type dispersions of electrical quantities in the frequency range were found. The dispersion regions are presumably related to the ionic transport processes in bulk and grain boundaries of the ceramics. The activation energy of the conductivity of the bulk and the activation energy of the characteristic relaxation frequency, at which the dispersion sets in, has the same value of 0.25 eV. The only contribution of the mobility of Li(+) ions defines the temperature dependence of the bulk conductivity in the investigated temperature range. The values of epsilon(') may be related to the contributions of the polarization of the fast ionic migration, vibrations of the lattice and electronic polarization. Nuclear magnetic resonance (NMR) investigation shows that the T(1) of (7)Li and (6)Li at room temperature are 6 ms and 2 s respectively. This result confirms that the relaxation of the (7)Li nucleus occurs through quadrupolar fluctuations although the relaxation of the (6)Li nucleus occurs via dipolar fluctuations. Furthermore, the T(1) minimum allows us to evidence a motion with a characteristic frequency in the range of the Larmor frequency. PMID- 21825466 TI - Substantial stabilization of ferromagnetism in ZnO:Mn induced by N codoping. AB - Electronic structures and magnetic properties of ZnO:Mn and ZnO:Mn+N systems are investigated using first-principles density functional calculations with generalized gradient approximation. The results provide a fundamental theoretical understanding in the substantial ferromagnetic stability induced by N codoping in the ZnO:Mn system observed experimentally. They demonstrate that the ferromagnetic interaction is due to the hybridization between N 2p and Mn 3d states and is very sensitive to the geometrical configurations of dopants in the ZnO host lattice. The most stable ferromagnetic configuration corresponds to the Mn-N-Mn cluster, energetically strong enough to lead to hole-mediated ferromagnetism at room temperature. PMID- 21825467 TI - A study of the high temperature spin reorientation in YCoFe(3)B. AB - The iron-57 Mossbauer spectra of YCoFe(3)B have been measured between 4.2 and 480 K and reveal that YCoFe(3)B exhibits an axial orientation of the iron magnetic moments below 450 K and a basal orientation above 450 K. This spin reorientation, also observed in the thermomagnetic curves, results from the different signs of the contributions to the magnetic anisotropy of the 2c and 6i sites that are occupied by iron. The neutron diffraction patterns of YCoFe(3)B have been measured at 2 K and between 290 and 770 K and have been successfully analyzed with a model compatible with the magnetic orientation obtained from the Mossbauer spectra. The hybridization between the cobalt or iron 3d orbitals and the boron 2p orbitals leads to a larger magnetic moment and hyperfine field on the 2c site as compared to the 6i site. PMID- 21825468 TI - In situ x-ray reflectivity and grazing incidence x-ray diffraction study of L 1(0) ordering in (57)Fe/Pt multilayers. AB - In situ high temperature x-ray reflectivity and grazing incidence x-ray diffraction measurements in the energy dispersive mode are used to study the ordered face-centered tetragonal (fct) L 1(0) phase formation in [Fe(19 A)/Pt(25 A)]( * 10) multilayers prepared by ion beam sputtering. With the in situ x-ray measurements it is observed that (i) the multilayer structure first transforms to a disordered FePt and subsequently to an ordered fct L 1(0) phase, (ii) the ordered fct L 1(0) FePt peaks start to appear at 320 degrees C annealing, (iii) the activation energy of the interdiffusion is 0.8 eV and (iv) ordered fct FePt grains have preferential out-of-plane texture. The magneto-optical Kerr effect and conversion electron Mossbauer spectroscopies are used to study the magnetic properties of the as-deposited and 400 degrees C annealed multilayers. The magnetic data for the 400 degrees C annealed sample indicate that the magnetization is at an angle of ~50 degrees from the plane of the film. PMID- 21825470 TI - Low temperature conductivity in ferromagnetic manganite thin films: quantum corrections and inter-granular transport. AB - The interplay between inter-granular transport and quantum corrections to low temperature transport properties of La(0.67)Sr(0.33)MnO(3) (LSMO) and Nd(0.67)Sr(0.33)MnO(3) (NSMO) thin films has been discussed. All the samples exhibit characteristics of renormalized electron-electron interaction in two dimensions. The contrasting response of the low temperature transport to magnetic field in the LSMO and NSMO films is attributed to the strikingly different magnetic field sensitivity of the inter-granular transport. PMID- 21825469 TI - High-pressure synthesis of the double perovskite Sr(2)FeMoO(6): increment of the cationic ordering and enhanced magnetic properties. AB - The double perovskite Sr(2)FeMoO(6) has been prepared in polycrystalline form by high-pressure methods, starting from a precursor developed via a citrate technique, containing an elevated degree of anti-site disordering. The application of high external pressure (2 GPa) to Sr(2)FeMoO(6) promotes the long distance Fe/Mo cationic order, due to the smaller lattice volume of the ordered sample. Both the disordered perovskite obtained at ambient pressure and the sample synthesized under high-pressure methods have been characterized by means of x-ray diffraction, neutron powder diffraction and magnetic measurements. The magnetic properties of the two oxides have been compared; the specimen prepared under high pressure not only presents an improved cationic ordering, but also displays a superior saturation magnetization and a sharpener ferromagnetic transition at a significantly high temperature of 430 K. PMID- 21825471 TI - Determining the in-plane Fermi surface topology in high T(c) superconductors using angle-dependent magnetic quantum oscillations. AB - We propose a quantum oscillation experiment by which the rotation of an underdoped YBa(2)Cu(3)O(6+x) sample about two different axes with respect to the orientation of the magnetic field can be used to infer the shape of the in-plane cross-section of corrugated Fermi surface cylinder(s). Deep corrugations in the Fermi surface are expected to give rise to nodes in the quantum oscillation amplitude that depend on the magnitude and orientation of the magnetic induction B. Because the symmetries of electron and hole cylinders within the Brillouin zone are expected to be very different, the topology can provide essential clues as to the broken symmetry responsible for the observed oscillations. The criterion for the applicability of this method to the cuprate superconductors (as well as other layered metals) is that the difference in quantum oscillation frequency 2DeltaF between the maximum (belly) and minimum (neck) extremal cross sections of the corrugated Fermi surface exceeds |B|. PMID- 21825472 TI - Itinerant spin excitations near the hidden order transition in URu(2)Si(2). AB - By means of neutron scattering we show that the high temperature precursor to the hidden order state of the heavy fermion superconductor URu(2)Si(2) exhibits heavily damped incommensurate paramagnons whose strong energy dispersion is very similar to that of the long-lived longitudinal f spin excitations that appear below T(0). This suggests that there is a strongly hybridized character to the itinerant excitations observed previously above the hidden order transition. Here we present evidence that the itinerant excitations, like those in chromium, are due to Fermi surface nesting of hole and electron pockets; hence the hidden order phase probably originates from a Fermi surface instability. We identify wavevectors that span nested regions of a f-d hybridized band calculation and that match the neutron spin crossover from incommensurate to commensurate on approach to the hidden order phase. PMID- 21825473 TI - Colossal piezoresistance in phase separated manganites. AB - We have measured the strain dependent transport properties of phase separated manganite thin films. We subjected (La(1-y)Pr(y))(1-x)Ca(x)MnO(3) thin films grown on NdGaO(3)(110) substrates to direct external mechanical stress using a three-point beam bending method. The resultant change in resistance reveals a colossal piezoresistance (CPR) in manganites. Our experiments reveal that phase separation is a necessary but not sufficient condition for CPR. The maximum CPR is observed only when the phase boundaries are free to move in the fluid-like phase separated state. Our results show that both long-range strain interactions and quenched disorder play an important role in micrometer scale phase separation in manganites, albeit in different temperature ranges. PMID- 21825474 TI - Singular responses of spin-incoherent Luttinger liquids. AB - When a local potential changes abruptly in time, an electron gas responds by shifting to a new state which at long times is orthogonal to the one in the absence of the local potential. This is known as Anderson's orthogonality catastrophe and it is relevant for the so-called x-ray edge or Fermi-edge singularity, and for tunneling into an interacting one-dimensional system of fermions. It often happens that the finite frequency response of the photon absorption or the tunneling density of states exhibits a singular behavior as a function of frequency: [Formula: see text], where omega(th) is a threshold frequency and alpha is an exponent characterizing the singular response. In this review singular responses of spin-incoherent Luttinger liquids are reviewed. Such responses most often do not fall into the familiar form above, but instead typically exhibit logarithmic corrections and display a much higher universality in terms of the microscopic interactions in the theory. Specific predictions are made, the current experimental situation is summarized and key outstanding theoretical issues related to spin-incoherent Luttinger liquids are highlighted. PMID- 21825475 TI - Hydroxyl vacancies in single-walled aluminosilicate and aluminogermanate nanotubes. AB - We report a theoretical study of hydroxyl vacancies in aluminosilicate and aluminogermanate single-walled metal-oxide nanotubes. Defects are introduced on both sides of the tube walls and lead to occupied and empty states in the band gap which are highly localized both in energy and in real space. Different magnetization states are found depending on both the chemical composition and the specific side with respect to the tube cavity. The defect-induced perturbations to the pristine electronic structure are related to the electrostatic polarization across the tube walls and the ensuing change in Lewis acid-base reactivity. A general approach towards a quantitative evaluation of both the polarization across the tube walls and the tube excluded volume is also proposed and discussed on an electrostatic basis. PMID- 21825476 TI - Electron transfer from a carbon nanotube into vacuum under high electric fields. AB - The transfer of an electron from a carbon nanotube (CNT) tip into vacuum under a high electric field is considered beyond the usual one-dimensional semi-classical approach. A model of the potential energy outside the CNT cap is proposed in order to show the importance of the intrinsic CNT parameters such as radius, length and vacuum barrier height. This model also takes into account set-up parameters such as the shape of the anode and the anode-to-cathode distance, which are generically portable to any modelling study of electron emission from a tip emitter. Results obtained within our model compare well to experimental data. Moreover, in contrast to the usual one-dimensional Wentzel-Kramers-Brillouin description, our model retains the ability to explain non-standard features of the process of electron field emission from CNTs that arise as a result of the quantum behaviour of electrons on the surface of the CNT. PMID- 21825477 TI - Acoustic phonon modes and dispersion relations of nanowire superlattices. AB - We study theoretically acoustic phonon modes in nanowire superlattices (NWSLs) composed of cubic materials. We classify the acoustic phonon modes in rectangular and square cross-section NWSLs, based on group theory. For NWSLs consisting of GaAs and AlAs, we calculate numerically the dispersion relations of each phonon mode and corresponding displacement fields. We examine the effects of both the lateral confinement and superlattice modulation along the wire axis. The results suggest that peculiar electron-phonon interactions occur because the vibrations of both the lateral and longitudinal confining potentials induce scattering potential in addition to the deformation and piezoelectric potentials. PMID- 21825478 TI - Current-assisted cooling in atomic wires. AB - The effects of inelastic interactions between current-carrying electrons and vibrational modes of a nanoscale junction are a major limiting factor on the stability of such devices. A method for dynamical simulation of inelastic electron-ion interactions in nanoscale conductors is applied to a model system consisting of an adatom bonded to an atomic wire. It is found that the vibrational energy of such a system may decrease under bias, and furthermore that, as the bias is increased, the rate of cooling, within certain limits, will increase. This phenomenon can be understood qualitatively through low-order perturbation theory, and is due to the presence of an anti-resonance in the transmission function of the system at the Fermi level. Such current-assisted cooling may act as a stabilization mechanism, and may form the basis for a nanoscale cooling 'fan'. PMID- 21825479 TI - First principle calculations of structural, electronic, thermodynamic and optical properties of Pb(1-x)Ca(x)S,Pb(1-x)Ca(x)Se and Pb(1-x)Ca(x)Te ternary alloys. AB - Using first principles total energy calculations within the full potential linearized augmented plane wave (FP-LAPW) method, we have investigated the structural, electronic, thermodynamic and optical properties of Pb(1-x)Ca(x)S, Pb(1-x)Ca(x)Se and Pb(1-x)Ca(x)Te ternary alloys. The effect of composition on lattice parameter, bulk modulus, band gap, refractive index and dielectric function was investigated. Deviations of the lattice constants from Vegard's law and the bulk modulus from linear concentration dependence were observed for the three alloys. Using the approach of Zunger and co-workers, the microscopic origins of band gap bowing have been detailed and explained. The disorder parameter (gap bowing) was found to be mainly caused by the chemical charge transfer effect. On the other hand, the thermodynamic stability of these alloys was investigated by calculating the excess enthalpy of mixing, DeltaH(m), as well as the phase diagram. It was shown that all of these alloys are stable at low temperature. The calculated refractive indices and optical dielectric constants were found to vary nonlinearly with Ca composition. PMID- 21825480 TI - The differential atomic response of the topmost graphene layer on graphite. AB - The atomic response of the topmost graphene layer on graphite was studied by using scanning tunneling microscopy (STM) as a function of tunneling gap distance, gap voltage and bias polarity. The contrast of the site-dependent topographical image depends on the gap distance, and the site-dependent tunneling current order of magnitude at a given gap distance is switched with the gap voltage (i.e. the contrast is significantly altered). The site-dependent current order is altered at the lower positive gap voltage as the gap distance is reduced between the probe and the carbon atoms of the topmost graphene layer. The switching in the atomic image contrast and the current order of magnitude is directly related to the differential atomic response of carbon atoms to the STM probe originating from the electronically active and mechanically soft beta carbon atoms. PMID- 21825481 TI - First-principles study of diffusion of oxygen vacancies and interstitials in ZnO. AB - A comprehensive investigation of oxygen vacancy and interstitial diffusion in ZnO has been performed using ab initio total energy calculations with both the local density approximation (LDA) and the generalized gradient approximation (GGA). Based on our calculation results, oxygen octahedral interstitials are fast diffusers, contributing to annealing processes, as well as being responsible for the self-diffusion of oxygen for n-type ZnO, and oxygen vacancies are responsible for the self-diffusion of oxygen for p-type ZnO. PMID- 21825482 TI - Phase stability of lithium azide at pressures up to 60 GPa. AB - We studied lithium azide (LiN(3)) by x-ray diffraction and Raman spectroscopy at hydrostatic compression up to pressures above 60 GPa at room temperature. The results of x-ray diffraction analyses reveal the stability of the ambient pressure C 2/m crystal structure up to the highest pressure. The pressure dependence of librational modes provides evidence for an order-disorder transition at low pressures (below 3 GPa), similar to the transition observed previously at low temperatures. The observed structure stability indicates that this transition is not associated with structural changes. The phase stability of LiN(3) is in contrast to that of sodium azide (which is isostructural at ambient pressure), for which a set of phase transitions has been reported at pressures below 50 GPa. PMID- 21825483 TI - The origin of oxygen vacancy induced ferromagnetism in undoped TiO(2). AB - Using the full-potential linearized augmented plane wave method, we have investigated the oxygen vacancy defect induced ferromagnetism in both rutile and anatase TiO(2). It has been found that the oxygen vacancy induces lattice distortion in rutile TiO(2), whereas there is no such meaningful change in the anatase structure. Interestingly, the lattice distorted rutile TiO(2) shows an oxygen vacancy induced ferromagnetic state with a magnetic moment of 0.22 u(B) in the Ti atom neighboring the vacancy site, while only 0.06 u(B) is observed in the Ti atom in anatase TiO(2). We attribute the sizable magnetic moment due to the oxygen vacancy in rutile TiO(2) to the charge redistribution owing to lattice distortion. Experimentally measured magnetic hysteresis curves for undoped rutile and anatase TiO(2) films clearly display ferromagnetic behavior at room temperature. The observed magnetic strength of the rutile sample turns out to be larger than that of the anatase sample, in accordance with the theoretical calculations. PMID- 21825484 TI - Vibrational, optical and structural studies of an amorphous Se(0.90)S(0.10) alloy produced by mechanical alloying. AB - The local atomic order of an amorphous Se(0.90)S(0.10) alloy produced by mechanical alloying was studied by x-ray diffraction and extended x-ray absorption fine structure (EXAFS) data obtained at three temperatures, T = 300, 200 and 30 K. From the cumulant analysis of the EXAFS data, structural properties such as average interatomic distances, average coordination numbers, Debye-Waller factors and anharmonicity, given by the third cumulant, were obtained. The results found indicate that there is alloying at an atomic level, and Se-S pairs are more disordered and distorted than Se-Se ones due to the milling process. PMID- 21825485 TI - Light scattering from an isotropic layer between uniaxial crystals. AB - We develop a model for the reflection and transmission of plane waves by an isotropic layer sandwiched between two uniaxial crystals of arbitrary orientation. In the laboratory frame, reflection and transmission coefficients corresponding to the principal polarization directions in each crystal are given explicitly in terms of the [Formula: see text] axis and propagation directions. The solution is found by first deriving explicit expressions for reflection and transmission amplitude coefficients for waves propagating from an arbitrarily oriented uniaxial anisotropic material into an isotropic material. By combining these results with Lekner's (1991 J. Phys.: Condens. Matter3 6121-33) earlier treatment of waves propagating from isotropic media to anisotropic media and employing a matrix method we determine a solution to the general form of the multiple reflection case. The example system of a wetted interface between two ice crystals is used to contextualize the results. PMID- 21825486 TI - Structural transitions in a crystalline bilayer: the case of Lennard-Jones and Gaussian core models. AB - We study structural transitions in a system of interacting particles arranged as a crystalline bilayer, as a function of the density rho and the distance d between the layers. As d is decreased a sequence of transitions involving triangular, rhombic, square and centred rectangular lattices is observed. The sequence of phases and the order of transitions depends on the nature of the interactions. PMID- 21825487 TI - Cluster glass properties and magnetic phase separation studies of Nd(x)Bi(0.5 x)Sr(0.5)MnO(3) (x = 0.1, 0.2, 0.3 and 0.4). AB - The crystal structure, dc and ac magnetic susceptibility, electron spin resonance and magnetoresistive behavior of Nd(x)Bi(0.5-x)Sr(0.5)MnO(3) (x = 0.1, 0.2, 0.3 and 0.4) compounds are studied. The Rietveld analysis of the XRD data shows that the samples crystallize in an orthorhombic perovskite structure, with Pbnm space group for x = 0.1 and 0.2 and Imma space group for x = 0.4 and 0.3. Magnetic studies reveal that substituting Bi with Nd collapses the robust charge ordered AFM state of Bi(0.5)Sr(0.5)MnO(3) to an inhomogeneous magnetic state. As Nd concentration increases there is a gradual appearance of cluster glass behavior. ESR studies reveal that the NBSMO system phase separates into ferromagnetic and antiferromagnetic regions below the transition temperature. PMID- 21825488 TI - Computation of Mossbauer isomer shifts from first principles. AB - Computation of the observables of a Mossbauer spectrum, primarily the isomer shift, from a first-principles approach is described. The framework used is density functional theory using the projector augmented wave formalism (DFT PAW), which enables efficient computation even of many-electron solids such as SnCl(2). The proper PAW version of the isomer shift is derived and shown to be correct through comparison of computed shifts and experiment in a variety of compounds based on tin, germanium and zinc. The effects of pressure are considered as well as motional effects including the Lamb-Mossbauer factor and the second-order Doppler shift. PMID- 21825489 TI - Local structure of Sr(2)FeMo(x)W(1-x)O(6) double perovskites across the composition-driven metal to insulator transition. AB - Sr(2)FeMoO(6) oxides exhibit a half-metallic ferromagnetic (HM-FM) ground state and peculiar magnetic and magnetotransport properties, which are interesting for applications in the emerging field of spintronics and attractive for fundamental research in the field of heavily correlated electron systems. Sr(2)FeWO(6) is an insulator with an antiferromagnetic (I-AFM) ground state. The solid solutions Sr(2)FeMo(x)W(1-x)O(6) also have peculiar properties-W doping enhances chemical order which allows stabilization of the HM-FM state; as the W content exceeds a certain value a metal to insulator transition (MIT) occurs. The role of W in determining the physical properties of Sr(2)FeMo(x)W(1-x)O(6) systems has been a matter of intense investigation. This work deals with the problem of the structural and electronic changes related to the MIT from a local perspective by means of x-ray absorption spectroscopy (XAS). This technique allows one to probe in detail the local structure and electronic modifications around selected absorber ions (W, Mo, Fe and Sr in our case). The results of XAS analysis in the whole composition range (0<=x<=1), in the near edge (XANES) and extended (EXAFS) regions, demonstrate an abrupt change of the local structure around the Fe and Mo sites at the critical composition, x(c). This change represents the microstructural counterpart associated with the MIT. Conversely, the local structure and electronic configuration of W ions remain unaltered in the whole composition range, suggesting indirect participation of W in the MIT. PMID- 21825490 TI - An augmented space approach to the study of random ternary alloys: I. Electronic structure with uncorrelated disorder and short ranged order. AB - We present here a generalized augmented space recursive technique which includes the effects of diagonal and environmental disorder explicitly: an analytic, lattice translational invariant, multiple scattering theory for the study of short range ordering in random ternary alloys. Our generalized augmented space formalism includes atomic correlations over a finite cluster including short range order (SRO). We propose the augmented space recursion (ASR), a computationally fast and accurate technique which incorporates configuration fluctuations over a large local environment. We apply the formalism to a tight binding linear muffin-tin orbital (LMTO) study of stainless steel Fe(80 x)Ni(x)Cr(20) (x = 14 and 17). We have demonstrated the effects of short range ordering by calculating the configuration averaged density of states with and without SRO and with different kinds of cluster environment embedded in an averaged medium. PMID- 21825491 TI - An augmented space approach to the study of random ternary alloys: II. Optical response. AB - The augmented space approach to the study of random ternary alloys, described in an earlier paper (Alam and Mookerjee 2009 J. Phys.: Condens. Matter 21 195503), has been combined with the generalized recursion method of Viswanath and Muller (1993 The User Friendly Recursion Method, (Troisieme Cycle de la Physique, en Suisse Romande)) and the tight-binding linear muffin-tin orbitals technique (TB LMTO) to study the optical response in disordered Cu(x)Ni(y)Zn(z) alloys, and compared with existing experimental results. PMID- 21825492 TI - Vertex corrections and the Korringa ratio in strongly correlated electron materials. AB - We show that the Korringa ratio, associated with nuclear magnetic resonance in metals, is unity if vertex corrections to the dynamic spin susceptibility are negligible, the hyperfine coupling is momentum independent, and there exists an energy scale below which the density of states is constant. In the absence of vertex corrections we also find a Korringa behaviour for T(1), the nuclear spin relaxation rate, i.e., [Formula: see text], and a temperature independent Knight shift. These results are independent of the form and magnitude of the self-energy (so far as is consistent with neglecting vertex corrections) and of the dimensionality of the system. PMID- 21825493 TI - Electronic structure of pyrochlore Cd(2)Re(2)O(7). AB - Detailed band structure calculations have been performed for Cd(2)Re(2)O(7) in high-, middle- and low-temperature (T) phases. The calculations are based on the observed lattice structures from x-ray diffraction measurements. The spin-orbit interaction is incorporated self-consistently in both the generalized gradient approximation (GGA) and the GGA plus Hubbard U (GGA+U) approaches. It is found that the on-site U has negligible effects on the Re 5d band structures; therefore both the GGA and GGA+U Re 5d band energies agree well with the observed O K-edge x-ray absorption spectroscopy (XAS) spectrum, whereas the Cd 4d band energy observed from photoemission spectroscopy can only be correctly reproduced by GGA+U calculations, indicating the relatively itinerant Re 5d and localized Cd 4d electrons. On the other hand, the spin-orbit coupling gives rise to nontrivial spin and orbital magnetic moments for the middle- T phase. Most unexpectedly, we found that the low- T phase exhibits quasi-two-dimensional Fermi surfaces. The calculated carrier numbers for the three phases are, at least qualitatively, consistent with the measured Hall coefficient. PMID- 21825494 TI - Electronic band effects on the spin disorder resistivity of Gd(4)(Co(1 x)Cu(x))(3) compounds. AB - We present a study of the spin disorder resistivity ([Formula: see text]) and the electronic specific heat coefficient (gamma) in Gd(4)(Co(1-x)Cu(x))(3) compounds, with x = 0.00, 0.05, 0.10, 0.20 and 0.30. The experimental results show a strongly nonlinear dependence of [Formula: see text] on the average de Gennes factor (G(av)) which, in similar intermetallic compounds, is usually attributed to the existence of spin fluctuations on the Co 3d bands. Values of gamma were found around 110 mJ mol(-1) K(-2) for the Gd(4)(Co(1-x)Cu(x))(3) compounds, much larger than 38.4 mJ mol(-1) K(-2) found for the isostructural nonmagnetic Y(4)Co(3) compound. Using a novel type of analysis we show that the ratio [Formula: see text] follows a well-defined linear dependence on G(av), which is expected when appropriate dependencies with the effective electron mass are taken into account. This indicates that band structure effects, rather than spin fluctuations, could be the main cause for the strong electron scattering and gamma enhancement observed in the Gd(4)(Co(1-x)Cu(x))(3) compounds. A discussion on relevant features of magnetization and electrical resistivity data, for the same series of compounds, is also presented. PMID- 21825495 TI - Temperature-dependent striped antiferromagnetism of LaFeAsO in a Green's function approach. AB - We use a Green's function method to study the temperature-dependent average moment and magnetic phase-transition temperature of the striped antiferromagnetism of LaFeAsO, and other similar compounds, as the parents of FeAs-based superconductors. We consider the nearest and the next-nearest couplings in the FeAs layer, and the nearest coupling for inter-layer spin interaction. The dependence of the transition temperature T(N) and the zero temperature average spin on the interaction constants is investigated. We obtain an analytical expression for T(N) and determine our temperature-dependent average spin from zero temperature to T(N) in terms of unified self-consistent equations. For LaFeAsO, we obtain a reasonable estimation of the coupling interactions with the experimental transition temperature T(N) = 138 K. Our results also show that a non-zero antiferromagnetic (AFM) inter-layer coupling is essential for the existence of a non-zero T(N), and the many-body AFM fluctuations reduce substantially the low-temperature magnetic moment per Fe towards the experimental value. Our Green's function approach can be used for other FeAs-based parent compounds and these results should be useful to understand the physical properties of FeAs-based superconductors. PMID- 21825496 TI - pi-conjugation and conformation in a semiconducting polymer: small angle x-ray scattering study. AB - Small angle x-ray scattering (SAXS) in a poly[2-methoxy-5-(2'-ethyl-hexyloxy)-1,4 phenylene vinylene] (MEH-PPV) solution has shown the important role of pi electron conjugation in controlling the chain conformation and assembly. By increasing the extent of conjugation from 30 to 100%, the persistence length (l(p)) increases from 20 to 66 A. Moreover, a pronounced second peak in the pair distribution function has been observed in a fully conjugated chain, at larger length scales. This feature indicates that the chain segments tend to self assemble as the conjugation along the chain increases. Xylene enhances the rigidity of the PPV backbone to yield extended structures, while tetrahydrofuran solvates the side groups to form compact coils in which the l(p) is much shorter. PMID- 21825497 TI - Superfluorescent pulsed emission from biexcitons in an ensemble of semiconductor quantum dots. AB - Picosecond time-resolved photoluminescence from biexcitons in CuCl quantum dots (QDs) embedded in a NaCl matrix has been measured using an optical Kerr gate method. Ultrafast pulsed emission from the biexciton states was observed for the first time, only under resonant two-photon excitation of biexcitons. This implies that complete population inversion between the biexciton and exciton states is necessary in order to trigger the pulsed emission. In addition, the nature of the dependence of the time profiles of the pulsed emission on the excitation intensity reveals that the peak intensity is directly proportional to the square of the number of excited QDs. We conclude that this phenomenon is caused by superfluorescence, that is, the cooperative spontaneous radiative decay of many isolated excited states coupled by a resonant electromagnetic wave. Such a phenomenon has been observed for the first time in an ensemble of semiconductor QDs in this study. The results presented in this paper show that it is possible to control the microscopic coherent dynamics of electronic excited states in a QD ensemble. PMID- 21825498 TI - A plasmonic terahertz detector with a monolithic hot electron bolometer. AB - A plasmonic terahertz detector that integrates a voltage-controlled planar barrier into a grating gated GaAs/AlGaAs high electron mobility transistor has been fabricated and experimentally characterized. The plasmonic response at fixed grating gate voltage has a full width at half-maximum of 40 GHz at ~405 GHz. Substantially increased responsivity is achieved by introducing an independently biased narrow gate that produces a lateral potential barrier electrically in series with the resonant grating gated region. DC electrical characterization in conjunction with bias-dependent terahertz responsivity and time constant measurements indicate that a hot electron bolometric effect is the dominant response mechanism at 20 K. PMID- 21825499 TI - Ultrasonic studies of the magnetic phase transition in MnSi. AB - Measurements of the sound velocities in a single crystal of MnSi were performed in the temperature range 4-150 K. Elastic constants, controlling propagation of longitudinal waves, reveal significant softening at a temperature of about 29.6 K and small discontinuities at ~28.8 K, which corresponds to the magnetic phase transition in MnSi. In contrast, the shear elastic moduli do not show any softening at all, reacting only to the small volume deformation caused by the magneto-volume effect. The current ultrasonic study exposes an important fact that the magnetic phase transition in MnSi, occurring at 28.8 K, is just a minor feature of the global transformation marked by the rounded maxima or minima of heat capacity, thermal expansion coefficient, sound velocities and absorption, and the temperature derivative of resistivity. PMID- 21825500 TI - Magnetism in graphene due to single-atom defects: dependence on the concentration and packing geometry of defects. AB - The magnetism in graphene due to single-atom defects is examined by using spin polarized density functional theory. The magnetic moment per defect due to substitutional atoms and vacancy defects is dependent on the density of defects, while that due to adatom defects is independent of the density of defects. It reduces to zero with decrease in the density of substitutional atoms. However, it increases with decrease in density of vacancies. The graphene sheet with B adatoms is nonmagnetic, but with C and N adatoms it is magnetic. The adatom defects distort the graphene sheet near the defect perpendicular to the sheet. The distortion in graphene due to C and N adatoms is significant, while the distortion due to B adatoms is very small. The vacancy and substitutional atom (B, N) defects in graphene are planar in the sense that there is in-plane displacement of C atoms near the vacancy and substitutional defects. Upon relaxation the displacement of C atoms and the formation of pentagons near the vacancy site due to Jahn-Teller distortion depends upon the density and packing geometry of vacancies. PMID- 21825501 TI - Full potential results on the magneto-optical properties of the Heusler compounds Co(2)FeX (X = Al, Ga, Si and Ge). AB - We have calculated the magneto-optical (MO) properties of Co(2)FeX (X = Al, Ga, Si and Ge) Heusler compounds using the full potential linearized augmented plane wave (FPLAPW) method as implemented in the WIEN2K code using the local spin density approximation (LSDA) and also by using the generalized gradient approximation (GGA) for the electronic exchange and correlation. In all the compounds, Kerr rotation theta(K) has a strong minimum near 2 eV, the value of |theta(K)| corresponding to this minimum being almost as large as in pure Co-Fe compounds. The calculated MO spectra help to identify the features of the experimental spectra. A comparison of the results shows that the Kerr spectrum is quite similar from both LSDA and GGA but the latter gives better agreement with experiment. Moreover, we find that inclusion of correlation effects using GGA+U removes the discrepancy in magnetic moment of Co(2)FeX (X = Si, Ge) though it has an insignificant effect on the Kerr spectra. PMID- 21825502 TI - Structure, transport and magnetic properties of electron-doped perovskites R(x)Ca(1-x)MnO(3) (R = La, Y and Ce). AB - In this study, the transport and magnetic properties of electron-doped perovskites R(x)Ca(1-x)MnO(3) (R = La, Y and Ce) were investigated. As the R ion content increases, the crystal structure, resistivity, magnetoresistance, magnetization and related characteristic temperature of these systems all vary systematically. The data show that the variations in the electrical transport properties are mainly dependent on carrier concentration, whereas the magnetic properties of these systems are also dependent on crystal structure. When the carrier concentration exceeds a certain level, charge ordering occurs, leading to the localized electronic state and peaks in the magnetization curves. The magnetic transition temperature T(N) can be well described by crystal structural parameters, suggesting that crystal structure and magnetic properties are strongly coupled to each other. PMID- 21825503 TI - Realizing the 'hindered charge ordered phase' in nanoscale charge ordered manganites: magnetization, magneto-transport and EPR investigations. AB - We report three prominent observations made on the nanoscale charge ordered (CO) manganites RE(1-x)AE(x)MnO(3) (RE = Nd,Pr; AE = Ca; x = 0.5) probed by temperature dependent magnetization and magneto-transport, coupled with electron magnetic/paramagnetic resonance spectroscopy (EMR/EPR). First, evidence is presented to show that the predominant ground state magnetic phase in nanoscale CO manganites is ferromagnetic and it coexists with a residual anti-ferromagnetic phase. Secondly, the shallow minimum in the temperature dependence of the EPR linewidth shows the presence of a charge ordered phase in nanoscale manganites which was shown to be absent from the DC static magnetization and transport measurements. Thirdly, the EPR linewidth, reflective of spin dynamics, increases significantly with a decrease of particle size in CO manganites. We discuss the interesting observations made on various samples of different particle sizes and give possible explanations. We have shown that EMR spectroscopy is a highly useful technique to probe the 'hindered charge ordered phase' in nanoscale CO manganites, which is not possible by static DC magnetization and transport measurements. PMID- 21825504 TI - Comment on 'Modelling of surface energies of elemental crystals'. AB - Jiang et al (2004 J. Phys.: Condens. Matter 16 521) present a model based on the traditional broken-bond model for predicting surface energies of elemental crystals. It is found that bias errors can be produced in calculating the coordination numbers of surface atoms, especially in the prediction of high Miller-index surface energies. PMID- 21825505 TI - Reply to comment on 'Modelling of surface energies of elemental crystals'. AB - In reply to the comment by Luo et al, our theoretical model for the surface energy of elemental crystals is further developed to improve the prediction accuracy of the surface energy of the high-Miller-index facets. It is considered that the previous predicted unit surface area could not denote the actual one since the facets now are uneven. With the modification, the accuracy for the prediction of surface energy in units of J m(-2) is improved. PMID- 21825506 TI - 1/t pressure and fermion behaviour of water in two dimensions. AB - A variety of metal vacuum systems display the celebrated 1/t pressure, namely power-law dependence on time t, with the exponent close to unity, the origin of which has been a long-standing controversy. Here we propose a chemisorption model for water adsorbates, based on the argument for fermion behaviour of water vapour adsorbed on a stainless-steel surface, and obtain analytically the power-law behaviour of pressure, with an exponent of unity. Further, the model predicts that the pressure should depend on the temperature T according to T(3/2), which is indeed confirmed by our experiment. Our results should help elucidate the unique characteristics of the adsorbed water. PMID- 21825507 TI - Crystallization in three- and two-dimensional colloidal suspensions. AB - Despite progress in the understanding of crystal nucleation and crystal growth since the first theories for nucleation were developed, an exact quantitative prediction of the nucleation rates in most systems has remained an unsolved problem. Colloidal suspensions show a phase behavior that is analogous to atomic or molecular systems and serve accordingly as ideal model systems for studying crystal nucleation with an accuracy and depth on a microscopic scale that is hard to reach for atomic or molecular systems. Due to the mesoscopic size of colloidal particles they can be studied in detail on the single-particle level and their dynamics is strongly slowed down in comparison with atomic or molecular systems, such that the formation of a crystal nucleus can be followed in detail. In this review, recent progress in the study of homogeneous and heterogeneous crystal nucleation in colloids and the controlled growth of crystalline colloidal structures is reviewed. All this work has resulted in unprecedented insights into the early stage of nucleation and it is also relevant for a deeper understanding of soft matter materials in general as well as for possible applications based on colloidal suspensions. PMID- 21825508 TI - Polyelectrolyte-induced aggregation of liposomes: a new cluster phase with interesting applications. AB - Different charged colloidal particles have been shown to be able to self assemble, when mixed in an aqueous solvent with oppositely charged linear polyelectrolytes, forming long-lived finite-size mesoscopic aggregates. On increasing the polyelectrolyte content, with the progressive reduction of the net charge of the primary polyelectrolyte-decorated particles, larger and larger clusters are observed. Close to the isoelectric point, where the charge of the adsorbed polyelectrolytes neutralizes the original charge of the particles' surface, the aggregates reach their maximum size, while beyond this point any further increase of the polyelectrolyte-particle charge ratio causes the formation of aggregates whose size is progressively reduced. This re-entrant condensation behavior is accompanied by a significant overcharging. Overcharging, or charge inversion, occurs when more polyelectrolyte chains adsorb on a particle than are needed to neutralize its original charge so that, eventually, the sign of the net charge of the polymer-decorated particle is inverted. The stability of the finite-size long-lived clusters that this aggregation process yields results from a fine balance between long-range repulsive and short-range attractive interactions, both of electrostatic nature. For the latter, besides the ubiquitous dispersion forces, whose supply becomes relevant only at high ionic strength, the main contribution appears due to the non-uniform correlated distribution of the charge on the surface of the polyelectrolyte-decorated particles ('charge-patch' attraction). The interesting phenomenology shown by these system has a high potential for biotechnological applications, particularly when the primary colloidal particles are bio-compatible lipid vesicles. Possible applications of these systems as multi-compartment vectors for the simultaneous intra-cellular delivery of different pharmacologically active substances will be briefly discussed. PMID- 21825509 TI - Space and time dynamical heterogeneity in glassy relaxation. The role of democratic clusters. AB - In this work we review recent computational advances in the understanding of the relaxation dynamics of supercooled glass-forming liquids. In such a supercooled regime these systems experience a striking dynamical slowing down which can be rationalized in terms of the picture of dynamical heterogeneities, wherein the dynamics can vary by orders of magnitude from one region of the sample to another and where the sizes and timescales of such slowly relaxing regions are expected to increase considerably as the temperature is decreased. We shall focus on the relaxation events at a microscopic level and describe the finding of the collective motions of particles responsible for the dynamical heterogeneities. In so doing, we shall demonstrate that the dynamics in different regions of the system is not only heterogeneous in space but also in time. In particular, we shall be interested in the events relevant to the long-time structural relaxation or alpha relaxation. In this regard, we shall focus on the discovery of cooperatively relaxing units involving the collective motion of relatively compact clusters of particles, called 'democratic clusters' or d-clusters. These events have been shown to trigger transitions between metabasins of the potential energy landscape (collections of similar configurations or structures) and to consist of the main steps in the alpha relaxation. Such events emerge in systems quite different in nature such as simple model glass formers and supercooled amorphous water. Additionally, another relevant issue in this context consists in the determination of a link between structure and dynamics. In this context, we describe the relationship between the d-cluster events and the constraints that the local structure poses on the relaxation dynamics, thus revealing their role in reformulating structural constraints. PMID- 21825510 TI - Simulation of a model microswimmer. AB - We discuss the modelling of a microswimmer that operates in a 'squirmer' mode, by means of stochastic rotation dynamics. The squirmer that we model can easily be tuned between a 'pusher' and a 'puller'. We examine the flows produced by the squirmer and find that there is good agreement between both the predicted and simulated velocities of locomotion and the resulting flow field. PMID- 21825511 TI - Hydrodynamic orienting of asymmetric microobjects under gravity. AB - It is shown that non-symmetric microobjects orient while settling under gravity in a viscous fluid. To analyze this process, a simple shape is chosen: a non deformable 'chain'. The chain consists of two straight arms, made of touching solid spheres. In the absence of external torques, the spheres are free to spin along the arms. The motion of the chain is evaluated by solving the Stokes equations with the use of the multipole method. It is demonstrated that the spinning beads speed up sedimentation by a small amount and increase the orientation rate significantly in comparison to the corresponding rigid chain. It is shown that chains orient towards the V-shaped stable stationary configuration. In contrast, rods and star-shaped microobjects do not rotate. The hydrodynamic orienting is relevant for efficient swimming of non-symmetric microobjects and for sedimenting suspensions. PMID- 21825512 TI - Reciprocal locomotion of dense swimmers in Stokes flow. AB - Due to the kinematic reversibility of Stokes flow, a body executing a reciprocal motion (a motion in which the sequence of body configurations remains identical under time reversal) cannot propel itself in a viscous fluid in the limit of negligible inertia; this result is known as Purcell's scallop theorem. In this limit, the Reynolds numbers based on the fluid inertia and on the body inertia are all zero. Previous studies characterized the breakdown of the scallop theorem with fluid inertia. In this paper we show that, even in the absence of fluid inertia, certain dense bodies undergoing reciprocal motion are able to swim. Using Lorentz's reciprocal theorem, we first derive the general differential equations that govern the locomotion kinematics of a dense swimmer. We demonstrate that no reciprocal swimming is possible if the body motion consists only of tangential surface deformation (squirming). We then apply our general formulation to compute the locomotion of four simple swimmers, each with a different spatial asymmetry, that perform normal surface deformations. We show that the resulting swimming speeds (or rotation rates) scale as the first power of a properly defined 'swimmer Reynolds number', demonstrating thereby a continuous breakdown of the scallop theorem with body inertia. PMID- 21825513 TI - Stochastic low Reynolds number swimmers. AB - As technological advances allow us to fabricate smaller autonomous self-propelled devices, it is clear that at some point directed propulsion could not come from pre-specified deterministic periodic deformation of the swimmer's body and we need to develop strategies for extracting a net directed motion from a series of random transitions in the conformation space of the swimmer. We present a theoretical formulation for describing the 'stochastic motor' that drives the motion of low Reynolds number swimmers based on this concept, and use it to study the propulsion of a simple low Reynolds number swimmer, namely, the three-sphere swimmer model. When the detailed balanced is broken and the motor is driven out of equilibrium, it can propel the swimmer in the required direction. The formulation can be used to study optimal design strategies for molecular scale low Reynolds number swimmers. PMID- 21825514 TI - Lagrangian coherent structures in low Reynolds number swimming. AB - This work explores the utility of the finite-time Lyapunov exponent (FTLE) field for revealing flow structures in low Reynolds number biological locomotion. Previous studies of high Reynolds number unsteady flows have demonstrated that ridges of the FTLE field coincide with transport barriers within the flow, which are not shown by a more classical quantity such as vorticity. In low Reynolds number locomotion (O(1)-O(100)), in which viscous diffusion rapidly smears the vorticity in the wake, the FTLE field has the potential to add new insight to locomotion mechanics. The target of study is an articulated two-dimensional model for jellyfish-like locomotion, with swimming Reynolds number of order 1. The self propulsion of the model is numerically simulated with a viscous vortex particle method, using kinematics adapted from previous experimental measurements on a live medusan swimmer. The roles of the ridges of the computed forward- and backward-time FTLE fields are clarified by tracking clusters of particles both backward and forward in time. It is shown that a series of ridges in front of the jellyfish in the forward-time FTLE field transport slender fingers of fluid toward the lip of the bell orifice, which are pulled once per contraction cycle into the wake of the jellyfish, where the fluid remains partitioned. A strong ridge in the backward-time FTLE field reveals a persistent barrier between fluid inside and outside the subumbrellar cavity. The system is also analyzed in a body fixed frame subject to a steady free stream, and the FTLE field is used to highlight differences in these frames of reference. PMID- 21825515 TI - Swimming and peristaltic pumping between two plane parallel walls. AB - Swimming at low Reynolds number in a fluid confined between two plane walls is studied for an infinite plane sheet located midway between the walls and distorted with a transverse propagating wave. It is shown that the flow pattern is closely related to that for peristaltic pumping. The hydrodynamic interaction between two flexible sheets swimming parallel in infinite space is related to the problem of peristaltic pumping in a planar channel with two wavy walls. PMID- 21825516 TI - Dynamics of confined suspensions of swimming particles. AB - Low Reynolds number direct simulations of large populations of hydrodynamically interacting swimming particles confined between planar walls are performed. The results of simulations are compared with a theory that describes dilute suspensions of swimmers. The theory yields scalings with concentration for diffusivities and velocity fluctuations as well as a prediction of the fluid velocity spatial autocorrelation function. Even for uncorrelated swimmers, the theory predicts anticorrelations between nearby fluid elements that correspond to vortex-like swirling motions in the fluid with length scale set by the size of a swimmer and the slit height. Very similar results arise from the full simulations indicating either that correlated motion of the swimmers is not significant at the concentrations considered or that the fluid phase autocorrelation is not a sensitive measure of the correlated motion. This result is in stark contrast with results from unconfined systems, for which the fluid autocorrelation captures large-scale collective fluid structures. The additional length scale (screening length) introduced by the confinement seems to prevent these large-scale structures from forming. PMID- 21825517 TI - Hydrodynamics of linked sphere model swimmers. AB - We describe in detail the hydrodynamics of a simple model of linked sphere swimmers. We calculate the asymptotic form of both the time averaged flow field generated by a single swimmer and the interactions between swimmers in a dilute suspension, showing how each depends on the parameters describing the swimmer and its swimming stroke. We emphasize the importance of time reversal symmetry in determining the far field flow around a swimmer and show that the interactions between swimmers are highly dependent on the relative phase of their swimming strokes. PMID- 21825518 TI - Helical beating of an actuated elastic filament. AB - We investigate the propulsive force resulting from the rotation of a flexible filament in the low Reynolds number regime. Using a simple linear model, we establish the nonlinear torque-force relations for two torque-driven actuation modes. When the rotation of the filament is induced by two perpendicular transverse oscillating torques, the propulsive force increases monotonically with the torque amplitude. Conversely, when a constant axial torque is applied, the torque-force characteristics displays an unstable branch, related to a discontinuous transition in the shape of the filament. We characterize this shape transition using two geometrical parameters, quantifying the wrapping around and the collapse on the axis of the filament. The proposed theoretical description correctly accounts for our experimental observations and reveals a strong dependence of the filament dynamics on the anchoring conditions. PMID- 21825519 TI - Propulsion of flexible polymer structures in a rotating magnetic field. AB - We demonstrate a new concept for the propulsions of abiological structures at low Reynolds numbers. The approach is based on the design of flexible, planar polymer structures with a permanent magnetic moment. In the presence of an external, uniform, rotating magnetic field these structures deform into three-dimensional shapes that have helical symmetry and translate linearly through fluids at Re between 10(-1) and 10. The mechanism for the motility of these structures involves reversible deformation that breaks their planar symmetry and generates propulsion. These elastic propellers resemble microorganisms that use rotational mechanisms based on flagella and cilia for their motility in fluids at low Re. PMID- 21825520 TI - In situ measurements of the D(1) and D(2) Raman band intensities of vitreous and molten silica in the 77-2150 K temperature range. AB - In situ quantitative Raman spectra of vitreous and molten silica were measured from LN(2) temperatures up to above melting and used to calculate the intensities of the two 'defect peaks' D(1) and D(2) associated with the corresponding four- and three-membered ring structures. The D(1) intensity decreases with increasing temperature while the D(2) intensity appears to be invariant to temperature. The data are in disagreement with the quenching/fictive temperature experiments and show definitely no abrupt intensity changes at any temperature. PMID- 21825521 TI - A molecular dynamics simulation interpretation of neutron and x-ray diffraction measurements on single phase Y(2)O(3)-Al(2)O(3) glasses. AB - Molecular dynamics simulations and complementary neutron and x-ray diffraction studies have been carried out within the single phase glass forming range of (Y(2)O(3))(x)(Al(2)O(3))((100-x)), for x = 27 and 30. For x = 27, the experimental Al-O and Y-O coordination numbers are found to be 4.9 +/- 0.2 and 6.9 +/- 0.4 respectively, compared to 4.4 and 6.8 obtained from the simulation. Similar results were found for x = 30. An R-factor analysis showed that the simulation models agreed to within ~6% of the diffraction data in both cases. The Al-O polyhedra are dominated by fourfold and fivefold species and the Y-O local coordinations are dominated by sixfold, sevenfold and eightfold polyhedra. Analysis of the oxygen environments reveals a large number of combinations, which explains the high entropy of single phase yttrium aluminate glasses and melts. Of these, the largest variation between x = 27 and 30 is found in the number of aluminum oxygen triclusters (oxygens bonded to three Al) and oxygens surrounded by three Y and a single Al. The most abundant connections are between the AlO(x) and YO(y) polyhedra of which 30% are edge shared. The majority of AlO(x)-AlO(x) connections were found to be corner shared. PMID- 21825522 TI - The effect of tensile and compressive loading on the hierarchical strength of idealized tropocollagen-hydroxyapatite biomaterials as a function of the chemical environment. AB - Hard biomaterials such as bone, dentin and nacre have primarily a polypeptide phase (e.g. tropocollagen (TC)) and a mineral phase (e.g. hydroxyapatite (HAP) or aragonite) arranged in a staggered manner. It has been observed that the mechanical behaviour of such materials changes with the chemical environment and the direction of applied loading. In the presented investigation, explicit three dimensional molecular dynamics (MD) simulations based analyses are performed on idealized TC-HAP composite biomaterial systems to understand the effects of tensile and compressive loadings in three different chemical environments: (1) unsolvated, (2) solvated with water and (3) calcinated and solvated with water. The MD analyses are performed on two interfacial supercells corresponding to the lowest structural level (level n) of TC-HAP interactions and on two other supercells with HAP supercells arranged in a staggered manner (level n+1) in a TC matrix. The supercells at level n+1 are formed by arranging level n interfacial supercells in a staggered manner. Analyses show that at level n, the presence of water molecules results in greater stability of TC molecules and TC-HAP interfaces during mechanical deformation. In addition, water also acts as a lubricant between adjacent TC molecules. Under the application of shear stress dominated loading, water molecules act to strengthen the TC-HAP interfacial strength in a manner similar to the action of glue. An overall effect of the observed mechanisms is that, in a staggered arrangement, tensile strength increases in the presence of water and calcinated water environments. On the other hand, corresponding compressive strength decreases under similar circumstances. Fundamentally, supercells with primarily normal load transfer at the TC-HAP interfaces are stronger in tensile shear loading. On the other hand, supercells with primarily tangential or shear load transfer at the TC-HAP interfaces are stronger in compressive shear loading. A combination of changes in chemical environment from vacuum to calcinated water and changes in interfacial configurations in a staggered arrangement could be chosen to make the TC-HAP material stronger under applied deformation. PMID- 21825523 TI - Scaling and branching in wet sonogels as a function of the volume fraction of the liquid phase. AB - The structural properties of wet silica sonogels prepared with different volume fractions of the liquid phase were studied by small-angle x-ray scattering (SAXS) and thermogravimetry (TG). The SAXS intensity curves of aged wet gels were all found to be well fitted by the form factor for scattering from non-randomly branched polymers in solution. The radius of gyration (R(g)) of the polycondensates and the branching density were found to increase with the volume fraction of the liquid phase of the wet gels. The molecular weight (M) of the branched polycondensates was found to scale as M~R(g)(alpha) with alpha quite close to 2 in the studied range. PMID- 21825524 TI - Regular to chaotic transition of stick-slip motion in sliding friction of an adhesive gel-sheet. AB - Spatio-temporal pattern of the stick-slip motion of a gel-sheet pulled on a glass substrate is observed. The sliding takes place via the propagation of the wave of detachment (Schallamach wave). At large pull velocity, the detached region is a stripe which moves regularly with constant speed and the frictional force shows a periodic time dependence. As the pull velocity is decreased, the detached region is separated into bubbles which move around irregularly. In the irregular state, the frictional force shows chaotic time dependence and the statistics of the event of the force drop obeys a power law similar to the Gutenberg-Richter law known in earthquakes. In the regular region, the detachment wave is analyzed theoretically and the velocity and lengths are obtained as a function of the pull velocity. The transition from the regular to chaotic behavior is shown to be related to the spontaneous wetting of the gel. PMID- 21825525 TI - Elastic flexibility, fast-ion conduction, boson and floppy modes in AgPO(3)-AgI glasses. AB - Raman scattering, IR reflectance and modulated-DSC measurements are performed on specifically prepared dry (AgI)(x)(AgPO(3))(1-x) glasses over a wide range of compositions 0%37.8% are elastically flexible. Raman optical elasticity power laws, trends in the nature of the glass transition endotherms, corroborate the three elastic phase assignments. Ionic conductivities reveal a step-like increase when glasses become stress-free at x>x(c)(1) = 9.5% and a logarithmic increase in conductivity (sigma~(x-x(c)(2))(MU)) once they become flexible at x>x(c)(2) = 37.8% with a power law MU = 1.78. The power law is consistent with percolation of 3D filamentary conduction pathways. Traces of water doping lower T(g) and narrow the reversibility window, and can also completely collapse it. Ideas on network flexibility promoting ion conduction are in harmony with the unified approach of Ingram et al (2008 J. Phys. Chem. B 112 859), who have emphasized the similarity of process compliance or elasticity relating to ion transport and structural relaxation in decoupled systems. Boson mode frequency and scattering strength display thresholds that coincide with the two elastic phase boundaries. In particular, the scattering strength of the boson mode increases almost linearly with glass composition x, with a slope that tracks the floppy mode fraction as a function of mean coordination number r predicted by mean-field rigidity theory. These data suggest that the excess low frequency vibrations contributing to the boson mode in flexible glasses come largely from floppy modes. PMID- 21825526 TI - Low temperature magnetoresistance measurements on bismuth nanowire arrays. AB - We present low temperature resistance R(T) and magnetoresistance measurements for Bi nanowires with diameters between 100 and 500 nm, which are close to being single-crystalline. The nanowires were fabricated by electrochemical deposition in pores of polycarbonate membranes. R(T) varies as T(2) in the low temperature range 1.5 K1 decreases approaching one, and above some critical value of the exchange constant there is only one phase T(N) = T(*), and the magnetization temperature curve has the typical Curie-Weiss profile. When the intra-exchange constant of the sublattice with stronger intra-exchange interaction increases the Neel temperature increases while T(*) remains unchanged. Finally, when the magnetic order of the sublattice with smaller magnetic order decreases, T(*) decreases. The theoretical predictions are utilized to interpret the experimentally measured magnetization-temperature curves. PMID- 21825569 TI - Observation of a Griffiths-like phase in the paramagnetic regime of ErCo(2). AB - A systematic x-ray magnetic circular dichroism study of the paramagnetic phase of ErCo(2) has recently allowed us to identify the inversion of the net magnetization of the Co net moment with respect to the applied field well above the ferrimagnetic ordering temperature, T(c). The study of small-angle neutron scattering measurements has also shown the presence of short range order correlations in the same temperature region. This phenomenon, which we have denoted parimagnetism, may be related to the onset of a Griffiths-like phase in paramagnetic ErCo(2). We have measured ac susceptibility on ErCo(2) as a function of temperature, applied field and excitation frequency. Several characteristics shared by systems showing a Griffiths phase are present in ErCo(2), namely the formation of ferromagnetic clusters in the disordered phase, the loss of analyticity of the magnetic susceptibility and its extreme sensitivity to an applied magnetic field. The paramagnetic susceptibility allows us to establish that the magnetic clusters are only formed by Co moments as well as the intrinsic nature of those Co moments. PMID- 21825570 TI - Field-induced ferromagnetic structure in Er(2)Ni(2)Pb. AB - We have studied the effect of magnetic fields up to 4.5 T on the ground-state structure in Er(2)Ni(2)Pb using powder neutron diffraction measurements at low temperatures. The zero-field magnetic state that itself is not uniform and consists of different magnetic phases is rather unstable against the magnetic field. As the field is increased, the magnetic reflections of the zero-field structure disappear and a new magnetic phase with commensurate propagation vector is clearly observed in a field of 0.5 T. At higher fields a ferromagnetic state is established in Er(2)Ni(2)Pb, which can be fully described only by a model that combines at least two irreducible representations. The refined Er magnetic moment magnitude of 9.10 +/- 0.07 u(B) is very close to the Er(3+) free ion value of 9.0 u(B). PMID- 21825571 TI - On the ferromagnetic structure of the intermetallic borocarbide TbCo(2)B(2)C. AB - Based on magnetization, specific heat, magnetostriction and neutron-diffraction studies on single-crystal TbCo(2)B(2)C, it is found out that the paramagnetic properties, down to liquid nitrogen temperatures, are well described by a Curie Weiss behavior of the Tb(3+) moments. Furthermore, below T(c) = 6.3 K, the Tb sublattice undergoes a ferromagnetic (FM) phase transition with the easy axis being along the (100) direction and, concomitantly, the unit cell undergoes a tetragonal-to-orthorhombic distortion. The manifestation of an FM state in TbCo(2)B(2)C is unique among all other isomorphous borocarbides, in particular TbNi(2)B(2)C (T(N) = 15 K, incommensurate modulated magnetic state) even though the Tb ions in both isomorphs have almost the same crystalline electric field properties. The difference among the magnetic modes of these Tb-based isomorphs is attributed to a difference in their exchange couplings which are in turn caused by a variation in their lattice parameters and in the position of their Fermi levels. PMID- 21825572 TI - Magnetic phase evolution in the spinel compounds Zn(1-x)Co(x)Cr(2)O(4). AB - We present the magnetic properties of complete solid solutions of ZnCr(2)O(4) and CoCr(2)O(4): two well studied oxide spinels with very different magnetic ground states. ZnCr(2)O(4), with non-magnetic d(10) cations occupying the A site and magnetic d(3) cations on the B site, is a highly frustrated antiferromagnet. CoCr(2)O(4), with magnetic d(7) cations (three unpaired electrons) on the A site as well, exhibits Neel ferrimagnetism as well as commensurate and incommensurate non-collinear magnetic order. More recently, CoCr(2)O(4) has been studied extensively because of its polar behavior which arises from conical magnetic ordering. Gradually introducing magnetism on the A site of ZnCr(2)O(4) results in a transition from frustrated antiferromagnetism to glassy magnetism at low concentrations of Co, and eventually to ferrimagnetic and conical ground states at higher concentrations. Real-space Monte Carlo simulations of the magnetic susceptibility suggest that the first magnetic ordering transition and features of the susceptibility across x are captured by near-neighbor self-couplings and cross-couplings between the magnetic A and B atoms. We present, as a part of this study, a method for displaying the temperature dependence of magnetic susceptibility in a manner which helps distinguish between compounds possessing purely antiferromagnetic interactions from compounds where other kinds of ordering are present. PMID- 21825573 TI - Probing and comparing electron doping and miss-site effects in Re-based double perovskites. AB - We have studied the Sr(2-x)La(x)Fe(1+x/2)Re(1-x/2)O(6) series in order to check how the increase in the number of Fe-O-Fe superexchange interactions affects the magnetic properties of this family of double perovskites. In these compounds the addition of La(3+) can be compensated by an increase of the Fe(3+) ratio leading to a non-electron-doped system. The unit cell of these samples expands on replacing Sr by La and the cationic ordering disappears for x>1 samples. Spontaneous magnetization at 5 K is observed in a wide range of concentrations but the magnetization at 5 T decreases as the La content increases. This result may be explained in terms of a ferrimagnetic ground state of the double perovskite. The magnetic ordering temperature increases with increasing the La and Fe content in agreement with an increase in the number of Fe-O-Fe interactions. The comparison to the electron-doped samples suggests that this effect is not enough to explain on its own the stronger T(C)-rise in Sr(2 x)La(x)FeReO(6) compounds. PMID- 21825574 TI - Instability of the collinear phase in a two-dimensional ferromagnet in a strong in-plane magnetic field. AB - It is well-known that in a thin ferromagnetic film with a net magnetization perpendicular to the film the collinear arrangement of spins is unstable in an in plane field H smaller than its saturation value H(c). The existence of a stripe phase was proposed with elongated domains of alternating direction of the magnetization component perpendicular to the film. We consider in the present paper the strong-field regime H10(4) and maximum subthreshold swings of 170 mV/dec. The local bottom-gated DEP-assembled CNT-FETs will facilitate large-scale fabrication of complementary metal-oxide-semiconductor (CMOS) compatible nanoelectronic devices. PMID- 21825664 TI - Global and local charge trapping in carbon nanotube field-effect transistors. AB - The influences of trapped charges on carrier transport in carbon nanotubes (CNTs) are studied using CNT field-effect transistors with a partial top-gate and a global back-gate. Trapped charges induced by the global back-gate voltage sweeping (+/- 20 V) promote the device from 'ON' states to near 'OFF' states at zero gate voltage. The channel conductance and field-effect mobility of the device are significantly affected by the pre-trapped charges induced by global back-gate voltage pulses. When the partial top-gate is swept, the pre-trapped charges induced by the global back-gate voltage pulses change the conduction type of the device. In contrast, the pre-trapped charges induced by the partial top gate voltage pulses could force the device to the 'ON' or 'OFF' state during the top-gate sweeping (+/- 4 V). PMID- 21825665 TI - The systematic tunability of nanoparticle dimensions through the controlled loading of surface-deposited diblock copolymer micelles. AB - The continuous tunability of iron oxide nanoparticle dimensions is demonstrated using the pH controlled loading of ferric nitrate from aqueous solution into polystyrene-block-polyacrylic acid reverse micelles deposited on a silicon substrate. Quasi-hexagonally ordered two-dimensional arrays of iron oxide nanoparticles with a systematic tunability of particle heights in the sub-10 nm regime and a constant periodicity are obtained and characterized with atomic force microscopy and x-ray photoelectron spectroscopy. PMID- 21825666 TI - Creation of damage-free ferroelectric nanostructures via focused ion beam milling. AB - We present a novel method for creating damage-free ferroelectric nanostructures with a focused ion beam milling machine. Using a standard e-beam photoresist followed by a dilute acid wash, nanostructures ranging in size from 1 um down to 250 nm were created in a 90 nm thick lead zirconate titanate (PZT) wafer. Transmission electron microscopy and piezoresponse force microscopy (PFM) confirmed that the surfaces of the nanostructures remained damage free during fabrication, and showed no gallium implantation, and that there was no degradation of ferroelectric properties. In fact DC strain loops, obtained using PFM, demonstrated that the nanostructures have a higher piezoresponse than unmilled films. As the samples did not have any top hard mask, the method presented is unique as it allows for imaging of the top surface to understand edge effects in well-defined nanostructures. In addition, as no post-mill annealing was necessary, it facilitates investigation of nanoscale domain mechanisms without process-induced artefacts. PMID- 21825667 TI - Synthesis and photoluminescence of a full zinc blende phase ZnO nanorod array. AB - A single-crystalline ZnO nanorod array with rectangular cross-sections has been synthesized, in which the as-obtained products are a complete metastable zinc blende (ZB) phase. X-ray powder diffraction, electron microscopy, and elemental maps have been used to show that the ZB-ZnO samples have a lattice constant a = 4.580 A, and are free from contamination by hexagonal wurtzite (HW) ZnO. Based on our experimental data, the associated growth mechanism is tentatively suggested. In addition, the photoluminescence (PL) spectrum (about 400 nm (3.1 eV)) of the as-fabricated ZB-ZnO products was detected; this is the first experimental report of the optical properties of ZB-ZnO nanorod arrays. PMID- 21825668 TI - One-dimensional magnetopolymeric nanostructures with tailored sizes. AB - Ultra-high aspect ratio nanofibers composed of poly(vinyl alcohol) and CoFe(2)O(4) nanoparticles (PVA/CoFe(2)O(4)) and moderate aspect ratio nanofibers composed of poly(vinyl chloride) and Fe(3)O(4) nanoparticles (PVC/Fe(3)O(4)) have been prepared. Magnetopolymeric one-dimensional (1D) nanostructures with any diameter and length can be prepared by template synthesis using anodic aluminum oxide (AAO) followed by the replication methods presented in this work. These replication methods are very effective, and allow the nanomoulding of any polymer nanoparticle 1D composite. A first magnetic characterization of the nanostructured composites reveals a modest magnetic anisotropy. The development of magnetopolymeric nanofibers with adjusted length and diameter opens new opportunities in a wide range of applications. PMID- 21825669 TI - Fabrication of vertically aligned ultrafine ZnO nanorods using metal-organic vapor phase epitaxy with a two-temperature growth method. AB - We report the fabrication of vertically aligned ultrafine ZnO nanorods using metal-organic vapor phase epitaxy and applying a two-temperature growth method. First, thick nanorods were grown vertically on the substrate at a lower temperature. Then, ultrafine ZnO nanorods with an average diameter of 17.7 nm were grown from the tips of the thick nanorods at a higher temperature. The direction of the ultrafine ZnO nanorods followed that of the preformed vertically aligned thick nanorods. Electron microscopy revealed that the ultrafine nanorods were single crystals and the growth direction was along the c axis. Excellent photoluminescence characteristics of the nanorods were confirmed. PMID- 21825670 TI - Design of hybrid sol-gel films for direct x-ray and electron beam nanopatterning. AB - New epoxy based sol-gel organic inorganic materials, showing lithographic resist like properties without the addition of any photocatalysts, are presented. To obtain a material sensitive to radiation, specific sol-gel syntheses based on an organically modified alkoxide containing an epoxy ring, 3 glycidoxypropyltrimethoxysilane (GPTMS), have been developed. The synthesis and the patternability of hybrid materials have been obtained controlling the inorganic crosslinking degree and with an almost total absence of organic polymerization. Two examples of directly patternable hybrid films, called GB and GGe, have been synthesized using acidic (GGe) and basic (GB) conditions and obtaining different compositions. After electron beam lithography (EBL) or x-ray synchrotron radiation lithography (XRL) the polymerization of the organic component of the sol-gel film occurs, generating a hardening of the structure after post-exposure baking. The exposed polymerized material becomes insoluble, determining a negative resist-like behaviour of the film: the lithographic process of nanopatterning results from the dissolution of the unexposed areas in proper solvents (developers). Spatial resolution of the order of 200 nm is reported and a contrast of 2.2 is achieved. The novelty of this work is that epoxy based materials, which have enhanced thermomechanical stability with respect to the more usual acrylic based resins, are directly nanopatterned for the first time by electron beam (EB) and/or x-ray beam radiation exposure without the aid of catalysts for polymerization. In contrast to common resists that are sacrificial layers of the fabrication process, direct patternable sol-gel hybrids constitute the final material of the devices. In fact, an example of doping with a light emitting dye is reported together with the achievement of directly patterned structures by EBL and XRL. PMID- 21825671 TI - Selective etching of n-type silicon in pn junction structure in hydrofluoric acid and its application in silicon nanowire fabrication. AB - Boron is selectively implanted on the surface of an n-type silicon wafer to form a p-type area surrounded by an n-type area. The wafer is then put into a buffered oxide etch solution. It is found that the n-type area can be selectively etched without illumination, with an etching rate lower than 1 nm min(-1), while the p type area can be selectively etched under illumination with a much higher etching rate. The possible mechanism of the etching phenomenon is discussed. A simple fabrication process of silicon nanowires is proposed according to the above phenomenon. In this process only traditional micro-electromechanical system technology is used. Dimensions of the fabricated nanowire can be controlled well. A 50 nm wide and 50 nm thick silicon nanowire has been formed using this method. PMID- 21825672 TI - A novel gas sensor based on field ionization from ZnO nanowires: moderate working voltage and high stability. AB - We report a kind of gas sensor using ZnO nanowires as the field ionization anode. The sharp tips of nanowires generate very high electric fields at relatively low voltages. The sensors show good sensitivity and selectivity. Moreover, the detection limitation of the field ionization based ZnO nanowire gas sensors is about 5%. More importantly, a sensor with ZnO nanowires as the anode exhibits an impressive performance with respect to stability and anti-oxidation behavior, which are significantly better than those of carbon nanotubes (CNTs) as electrodes. Therefore, the simple, low-cost, sensors described here could be deployed for a variety of applications. PMID- 21825673 TI - Highly sensitive ZnO nanowire CO sensors with the adsorption of Au nanoparticles. AB - In this study, the growth of high density single-crystalline ZnO nanowires on patterned ZnO:Ga/SiO(2)/Si templates was reported. We also adsorbed Au nanoparticles onto nanowire surfaces and fabricated ZnO nanowire CO sensors. With 50 ppm CO gas, it was found that we could enhance the device sensitivities at 350 degrees C from 4.2% to 46.5% by the adsorption of Au nanoparticles. It was also found that measured sensitivities were around 30%, 37%, 46.5% and 53% when concentration of the injected CO gas was 5, 20, 50 and 100 ppm, respectively. PMID- 21825674 TI - 1, 3-dipolar cycloaddition as a general route for functionalization of Fe(3)O(4) nanoparticles. AB - Triazole formation by 1, 3-dipolar cycloaddition reactions has been used to functionalize the surface of Fe(3)O(4) nanoparticles. Fe(3)O(4) particle samples with diameters around 22 nm were synthesized without any additional stabilizer, and were then treated with silane coupling agent to react with propargyl acid. The alkynyl group on the Fe(3)O(4) surface provides better conjugation efficiency with azide derivative molecules, which led to their attachment through the formation of a 1, 2, 3-triazole ring. PMID- 21825675 TI - Aligned silane-treated MWCNT/liquid crystal polymer films. AB - We report on a method to preferentially align multiwall carbon nanotubes (MWCNTs) in a liquid crystalline matrix to form stable composite thin films. The liquid crystalline monomeric chains can be crosslinked to form acrylate bridges, thereby retaining the nanotube alignment. Further post-treatment by ozone etching of the composite films leads to an increase in bulk conductivity, leading to higher emission currents when examined under conducting scanning probe microscopy. The described methodology may facilitate device manufacture where electron emission from nanosized tips is important in the creation of new display devices. PMID- 21825676 TI - Precise size control of hydrophobic gold nanoparticles using cooperative effect of refluxing ripening and seeding growth. AB - We describe herein a synthetic technology for precise size control of monodispersed hybrid gold nanoparticles, which combines seeding growth and digestive ripening. In this procedure, alkyl amines allow the solubilization and thermal reduction of HAuCl(4) while 2.1 nm gold nanoparticles capped by thiol functions are used as seeds. By carefully controlling the HAuCl(4)/seeds ratio, highly monodisperse gold nanoparticles with various sizes (from 2.1 to 8.8 nm) can be generated. Variation of the alkyl amines as well as optimization of the growth procedure allows the precise tuning of particle size within a 0.5 nm range. On the basis of XPS and TEM studies, a mechanism for nanoparticle formation is proposed. PMID- 21825677 TI - Synthesis and characterization of iodine molecular wires in channels of zeolite AEL single crystals. AB - Well-aligned iodine molecular wires were synthesized by means of loading iodine molecules in the elliptical nanometer-scale channels of AlPO(4)-11 (AEL) single crystals. Polarized Raman spectra reveal that the iodine molecular wires are oriented along the crystal channel direction by lining iodine molecules on the yz plane, where y and z represent the channel direction and the major-axial direction of the elliptical rings, respectively. Natural iodine wires are unstable, but they are very stable in the AEL channels. The template technique offers us an ideal platform to study the novel properties of these molecular wires. PMID- 21825678 TI - Effect of seeding on formation of silicon carbide nanostructures from mesoporous silica-carbon nanocomposites. AB - Mesoporous silica-carbon nanocomposites (C-SiO(2)) were synthesized for the fabrication of highly crystalline silicon carbide (SiC) nanoparticles and nanofibers via carbothermal reduction. SiC nuclei were introduced into the mesopores as seeds by infiltration of preceramic precursor polycarbosilane (PCS) prior to the heat treatment of carbothermal reduction. When PCS with a mass percentage of 11-13% was infiltrated into the mesoporous C-SiO(2), SiC nanofibers and nanoparticles were produced at 1450 degrees C, even in the sample with low carbon content. The major morphology formed from the mesoporous C-SiO(2) nanocomposites without PCS infiltration was nanoparticles, while nanofibers dominated in the products of PCS-infiltrated compositions. The results indicate that the conversion of PCS into SiC nuclei in mesopores prior to carbothermal reduction has facilitated the formation of SiC nanofibers. Therefore infiltration of seeds into mesopores of C-SiO(2) precursors appears to be an effective means of accelerating the reaction and controlling SiC nanostructures. PMID- 21825679 TI - Nanoparticle formation by swift heavy ion irradiation of indium oxide thin film. AB - In this study, a novel approach for the formation of indium oxide (IO) nanoparticles by irradiating IO thin film using 100 MeV Ag(8+) ions has been reported. High resolution transmission electron microscopy and energy dispersive x-ray analysis confirm the presence of single-crystalline IO nanoparticles after irradiation. The electronic excitations induced by 100 MeV Ag(8+) ions followed by thermal relaxation of the energy spike in IO thin film is responsible for the formation of latent tracks in the film. The electronic energy loss (S(e)) of 100 MeV Ag(8+) ions in IO is greater than the threshold electronic energy loss (S(eth)) required for the track formation in IO film, but is less than S(eth) required for crystalline silicon. Therefore, the tracks are formed in the IO film and not in the silicon substrate. This results in a stress induced at the IO film and silicon substrate interface which is responsible for dewetting of the tracks and the formation of nanoparticles. The theoretically calculated value of nanoparticle diameter using the thermal spike model is found to be in good agreement with the experimentally observed value of 30 nm. PMID- 21825680 TI - Surface plasmon resonance and magnetism of thiol-capped gold nanoparticles. AB - Surface plasmon resonance measurements and magnetic characterization studies have been carried out for two types of thiol-capped gold nanoparticles (NPs) with similar diameters between 2.0 and 2.5 nm and different organic molecules linked to the sulfur atom: dodecanethiol and tiopronin. In addition, Au NPs capped with tetraoctyl ammonium bromide have also been included in the investigation since such capping molecules weakly interact with the gold surface atoms and, therefore, this system can be used as a model for naked gold NPs; such particles presented a bimodal size distribution with diameters around 1.5 and 5 nm. The plasmon resonance is non-existent for tiopronin-capped NPs, whereas a trace of such a feature is observed for NPs covered with dodecanethiol molecules and a bulk-like feature is measured for NPs capped with tetralkyl ammonium salts. These differences would indicate that the modification of the surface electronic structure of the Au NPs depends on the geometry and self-assembling capabilities of the capping molecules and on the electric charge transferred between Au and S atoms. Regarding the magnetization, dodecanethiol-capped NPs have a ferromagnetic like behaviour, while the NPs capped with tiopronin exhibit a paramagnetic behaviour and tetralkyl ammonium-protected NPs are diamagnetic across the studied temperature range; straight chains with a well-defined symmetry axis can induce orbital momentum on surface electrons close to the binding atoms. The orbital momentum not only contributes to the magnetization but also to the local anisotropy, giving rise to permanent magnetism. Due to the domain structure of the adsorbed molecules, orbital momentum is not induced for tiopronin-capped NPs and the charge transfer only induces a paramagnetic spin component. PMID- 21825681 TI - The electronic structure of a single-walled aluminosilicate nanotube. AB - The geometric structure and electronic structure of an imogolite nanotube have been studied using density functional theory (DFT). The calculation results indicate that the deformation of the material leads to structural electric charges on the tube wall. This hydrous aluminosilicate single-walled nanotube is a wide gap semiconductor with a direct band gap, E(g)~3.67 eV at the Gamma point, which may be promising for application in optoelectronic devices. In conjunction with the DFT calculations, molecular dynamics simulations based on empirical potentials are also performed to evaluate the mechanical properties of this material. PMID- 21825682 TI - A numerical study of the growth process of Au nanometre-sized particles in liquid phases. AB - Molecular dynamics simulations have been employed to study the growth of faceted and spherical gold (Au) nanometre-sized particles in undercooled Au melts and supersaturated Kr-, Xe- and Rn-based liquid solutions at different degrees of undercooling and supersaturation. Different mechanisms have been observed depending on the chemical environment and temperature. At relatively high temperatures, surface adsorption is shown to critically depend on the dynamics of surface species with low coordination number. At low temperatures, adsorption occurs instead with no selective feature. Dendritic structures are formed at the particle surface at high adsorption rates. PMID- 21825683 TI - The coordinated buckling of carbon nanotube turfs under uniform compression. AB - Complex structures consisting of intertwined, nominally vertical carbon nanotubes (CNTs), referred to as turfs, have unique properties that arise from their complex nanogeometry and interactions between individual CNT segments. For applications such as contact switches for electrical or thermal transfer it is necessary to understand the properties that arise from the collective behavior of an assemblage of CNTs rather than the properties of a single tube. In this study, the mechanical response of turfs bonded to substrates under compressive loading is demonstrated experimentally; coordinated alignment and buckling takes place under uniform loads. The mechanical response of turf structures provides some surprising results regarding parameters that control permanent deformation and buckling in assemblages of nanostructures; buckling of the turf structure is controlled by the height and effective modulus of the turf, but not the aspect ratio of the structure. We present and verify a model which describes the coordinated buckling phenomena relevant for applications such as CNT turfs for thermal transfer media. PMID- 21825684 TI - Novel drug nanocarriers combining hydrophilic cyclodextrins and chitosan. AB - The aim of this study was to explore the possibility of obtaining nanoparticles (NPs) containing high amounts of cyclodextrin (CD) derivatives such as carboxymethyl-beta-CD and sulphobutyl ether-beta-CD. The rationale used was to combine the drug solubilizing and stabilizing properties of cyclodextrins (CDs) with the mucoadhesive properties of chitosan (CS) in a unique nanoparticulate drug delivery system. The size of the resulting NPs was affected by the nature of the CDs, ranging between 275 and 550 nm, whereas the zeta potential of the NPs was always positive and close to +35 mV. The positive zeta values, together with the results from NMR studies, suggest that CS is the major compound on the surface of the NPs, while CD molecules are strongly associated with the NP matrix. The empirical composition of the NPs was quantified by elemental analysis and the results indicated that the amount of CD associated with the NPs was strictly dependent on its electrostatic charge. Finally, in vitro stability studies indicated that the presence of CDs in the NP structure can prevent the aggregation of this nanometric carrier system in simulated intestinal fluid. Overall, this new type of NP represents an attractive drug delivery platform of particular interest for the oral administration of drugs with low bioavailability. PMID- 21825685 TI - A study on the mechanical and electrical reliability of individual carbon nanotube field emission cathodes. AB - Individual carbon nanotube (CNT) field emission characteristics present a number of advantages for potential applications in electron microscopy and electron beam lithography. Mechanical and electrical reliability of individual CNT cathodes, however, remains a challenge and thus device integration of these cathodes has been limited. In this work, we present an investigation into the reliability issues concerning individual CNT field emission cathodes. We also introduce and analyze the reliability of a novel individual CNT cathode. The cathode structure is composed of a multi-walled carbon nanotube (MWNT) attached by Joule heating to a nickel-coated Si microstructure. The junction of the CNT and the Si microstructure is mechanically and electrically robust to withstand the strong electric field conditions that are typical for field emission devices. An optimal Ni film coating of 25 nm on the Si microstructure is required for mechanical and electrical stability. Experimental current-voltage data for the new cathode structure definitively demonstrates carbon nanotube field emission. Additionally, we demonstrate that our new nanofabrication method is capable of producing sophisticated cathode structures that were previously not realizable, such as one consisting of two parallel MWNTs, with highly controlled CNT lengths with 40 nm accuracy and nanotube-to-nanotube separations of less than 10 um. PMID- 21825686 TI - Architecture design of resistor/FET-logic demultiplexer for hybrid CMOS/nanodevice circuit interconnect. AB - Hybrid nanoelectronics consisting of nanodevice crossbars on top of CMOS backplane circuits is emerging as one viable option to sustain Moore's law after the CMOS scaling limit is reached. One main design challenge in such hybrid nanoelectronics is the interface between the highly dense nanowires in nanodevice crossbars and relatively coarse microwires in the CMOS domain. Such an interface can be realized through a logic circuit called a demultiplexer (demux). In this context, all the prior work on demux design uses a single type of device, such as resistor, diode or field effect transistor (FET), to realize the demultiplexing function. However, different types of devices have their own advantages and disadvantages in terms of functionality, manufacturability, speed and power consumption. This makes none of them provide a satisfactory solution. To tackle this challenge, this work proposes to combine resistor with FET to implement the demux, leading to the hybrid resistor/FET-logic demux. Such hybrid demux architecture can make these two types of devices complement each other well to improve the overall demux design effectiveness. Furthermore, due to the inevitable fabrication process variations at the nanoscale, the effects of resistor conductance and FET threshold voltage variability are analyzed and evaluated based on computer simulations. The simulation results provide the requirement on the fabrication process to ensure a high demux reliability, and promise the hybrid resistor/FET-logic demux an improved addressability and process variance tolerance. PMID- 21825687 TI - Enhanced light output from a nitride-based power chip of green light-emitting diodes with nano-rough surface using nanoimprint lithography. AB - Enhanced light extraction from a GaN-based power chip (PC) of green light emitting diodes (LEDs) with a rough p-GaN surface using nanoimprint lithography is presented. At a driving current of 350 mA and with a chip size of 1 mm * 1 mm packaged on transistor outline (TO)-cans, the light output power of the green PC LEDs with nano-rough p-GaN surface is enhanced by 48% when compared with the same device without a rough p-GaN surface. In addition, by examining the radiation patterns, the green PC LED with nano-rough p-GaN surface shows stronger light extraction with a wider view angle. These results offer promising potential to enhance the light output powers of commercial light-emitting devices by using the technique of nanoimprint lithography under suitable nanopattern design. PMID- 21825688 TI - Three-dimensional analysis of the guided-assembled growth of heteroepitaxial islands on imperfectly pre-patterned surfaces. AB - We simulate the guided-assembled heteroepitaxial growth of quantum dot arrays on an imperfectly pre-patterned substrate, revealing the existence of different growth regimes, such as defect tolerant regimes and defect sensitive and responsive regimes. These regimes can potentially be used to grow different designed surface patterns. PMID- 21825689 TI - The role of substrate surface alteration in the fabrication of vertically aligned CdTe nanowires. AB - Previously we have described the deposition of vertically aligned wurtzite CdTe nanowires derived from an unusual catalytically driven growth mode. This growth mode could only proceed when the surface of the substrate was corrupted with an alcohol layer, although the role of the corruption was not fully understood. Here, we present a study detailing the remarkable role that this substrate surface alteration plays in the development of CdTe nanowires; it dramatically improves the size uniformity and largely eliminates lateral growth. These effects are demonstrated to arise from the altered surface's ability to limit Ostwald ripening of the catalytic seed material and by providing a surface unable to promote the epitaxial relationship needed to sustain a lateral growth mode. The axial growth of the CdTe nanowires is found to be exclusively driven through the direct impingement of adatoms onto the catalytic seeds leading to a self-limiting wire height associated with the sublimation of material from the sidewall facets. The work presented furthers the development of the mechanisms needed to promote high quality substrate-based vertically aligned CdTe nanowires. With our present understanding of the growth mechanism being a combination of selective area epitaxy and a catalytically driven vapour-liquid-solid growth mode, these results also raise the intriguing possibility of employing this growth mode in other material systems in an effort to produce superior nanowires. PMID- 21825690 TI - The preparation of highly active antimicrobial silver nanoparticles by an organometallic approach. AB - Silver nanoparticles of small size with a high surface to volume ratio have been prepared using an organometallic approach. For this, the complex NBu(4)[Ag(C(6)F(5))(2)] has been treated with AgClO(4) in a 1:1 molar ratio, giving rise to the nanoparticle precursor [Ag(C(6)F(5))] in solution. Addition of one equivalent of hexadecylamine (HDA) and 5 h of reflux in toluene leads to a deep yellow solution containing monodisperse silver nanoparticles (Ag NPs) of ca. 10 nm. This approach leads to nanoparticles with almost uncontaminated surfaces which make them very reactive. Antimicrobial studies show that these nanoparticles are very active as antimicrobial agents. Very low concentrations between 12 and 25 ug ml(-1) of Ag NPs are enough to produce bacteriostatic and bactericidal effectiveness. PMID- 21825691 TI - Mesoporous silica-magnetite nanocomposite synthesized by using a neutral surfactant. AB - Magnetite nanoparticles coated by mesoporous silica were synthesized by an alternative chemical route using a neutral surfactant and without the application of any functionalization method. The magnetite (Fe(3)O(4)) nanoparticles were prepared by precipitation from aqueous media, and then coated with mesoporous silica by using nonionic block copolymer surfactants as the structure-directing agents. The mesoporous SiO(2)-coated Fe(3)O(4) samples were characterized by x ray diffraction, Fourier-transform infrared spectroscopy, N(2) adsorption desorption isotherms, transmission electron microscopy, (57)Fe Mossbauer spectroscopy, and vibrating sample magnetometry. Our results revealed that the magnetite nanoparticles are completely coated by well-ordered mesoporous silica with free pores and stable (~8 nm thick) pore walls, and that the structural and magnetic properties of the Fe(3)O(4) nanoparticles are preserved in the applied synthesis route. PMID- 21825692 TI - The direct synthesis of mesoporous structured MnO(2)/TiO(2) nanocomposite: a novel visible-light active photocatalyst with large pore size. AB - A series of visible-light-driven mesoporous structured MnO(2)/TiO(2) nanocrystal photocatalysts have been synthesized through a modified sol-gel method, and the N(2) adsorption-desorption isotherm confirms that the mesoporous materials possess large pore size (up to 9.2 nm) and a narrow pore size distribution. X-ray powder diffraction (XRD) analyses and complementary x-ray photoelectron spectroscopy (XPS) measurements reveal that the doping of the transition metal Mn inhibits the growth of TiO(2) anatase nanocrystals and the Mn species are highly dispersed on the surface of TiO(2). The ultraviolet (UV)-vis spectrum demonstrates the excellent adsorption properties of MnO(2)/TiO(2) over the whole region of visible light, which enables this novel photocatalysis material to possess remarkable activity in the photocatalytic degradation of methylene blue under visible light radiation. Moreover, a 'coating mechanism' based on the nucleation of titania nanocrystals along with the interaction between the dopant precursors and titania clusters has been suggested. PMID- 21825693 TI - Microwave plasma enhanced chemical vapor deposition growth of few-walled carbon nanotubes using catalyst derived from an iron-containing block copolymer precursor. AB - The microwave plasma enhanced chemical vapor deposition (MPECVD) method is now commonly used for directional and conformal growth of carbon nanotubes (CNTs) on supporting substrates. One of the shortcomings of the current process is the lack of control of the diameter and diameter distribution of the CNTs due to difficulties in synthesizing well-dispersed catalysts. Recently, block copolymer derived catalysts have been developed which offer the potential of fine control of both the size of and the spacing between the metal clusters. In this paper we report the successful growth of CNTs with narrow diameter distribution using polystyrene-block-polyferrocenylethylmethylsilane (PS-b-PFEMS) as the catalyst precursor. The study shows that higher growth pressure leads to better CNT growth. Besides the pressure, the effects on the growth of CNTs of the growth parameters, such as temperature and precursor gas ratio, are also studied. PMID- 21825695 TI - Bending and bundling of metal-free vertically aligned ZnO nanowires due to electrostatic interaction. AB - Bending and bundling was observed from vertically aligned arrays of ZnO nanowires with flat (0001) top surfaces, which were synthesized using a vapor-phase method without metal catalysts. Sufficient evidence was found to exclude electron-beam bombardment during scanning electron microscopy as a cause for bending and bundling. We attribute the bending and bundling to electrostatic interactions due to charged (0001) polar surfaces, and also discussed the threshold surface charge densities for the bending and bundling based on a simple cantilever-bending model. Some growth features were indicative of the operation of electrostatic interactions during the growth. PMID- 21825694 TI - Synthesis of erbium hydroxide microflowers and nanostructures in subcritical water. AB - The effects of temperature, pressure, pH, residence time and reactant concentrations, as well as the presence or absence of CO(2), on the size and morphology of erbium hydroxide particles synthesized in a hydrothermal batch reactor and a diamond-anvil cell (DAC) reactor have been investigated. Several new erbium-based microstructures and nanostructures were obtained that encompass different phases and shapes, including crystalline microflowers, hexagonal microlayers, microsticks and microspheres made from nanoparticles, as well as nanofibers, nanorods and nanolayers. The Er(2)OCO(3)(OH)(2) microflowers are pure, structurally uniform, and mostly free from dislocations. Their crystallinity, morphology, optical properties and structural features have been examined and compared with those of the other phases by field-emission scanning electron microscopy (SEM), x-ray diffraction (XRD), and energy-dispersive x-ray (EDX) analysis, and by Raman, infrared, UV-visible and fluorescence spectroscopy. PMID- 21825696 TI - Superparamagnetic bimetallic iron-palladium nanoalloy: synthesis and characterization. AB - Iron-palladium nanoalloy in the particle size range of 15-30 nm is synthesized by the relatively low temperature thermal decomposition of coprecipitated [Fe(Bipy)(3)]Cl(2) and [Pd(Bipy)(3)]Cl(2) in an inert ambient of dry argon gas. The silvery black Fe-Pd alloy nanoparticles are air-stable and have been characterized by EDX-RF, XRD, AFM, TEM, magnetometry, (57)Fe Mossbauer and impedance spectroscopy. This Fe-Pd nanoalloy is in single phase and contains iron sites having up to 11 nearest-neighboring atoms. It is superparamagnetic in nature with high magnetic susceptibility, low coercivity and hyperfine field. PMID- 21825697 TI - Device fabrication with solid-liquid-solid grown silicon nanowires. AB - High quality, single-crystal silicon nanowires were successfully grown from silicon wafers with a nickel catalyst by utilizing a solid-liquid-solid (SLS) mechanism. The nanowires were composed of a crystalline silicon core with an average diameter of 10 nm and a thick outer oxide layer of between 20 and 30 nm at a growth temperature of 1000 degrees C. When utilizing the SLS growth mechanism, the diameter of the silicon nanowire is dependent solely upon the growth temperature, and has no relation to either the size or the shape of the catalyst. The characteristics of the silicon nanowires are highly dependent upon the properties of the silicon substrate, such as the crystal phase of silicon itself, as well as the doping type. The possibility of doping of silicon nanowires grown via the SLS mechanism without any external dopant source was demonstrated by measuring the electrical properties of a silicon nanowire field effect transistor. PMID- 21825698 TI - Surface spin-glass freezing in interacting core-shell NiO nanoparticles. AB - Magnetization and AC susceptibility measurements have been performed on ~3 nm NiO nanoparticles in powder form. The results indicate that the structure of the particles can be considered as consisting of an antiferromagnetically ordered core, with an uncompensated magnetic moment, and a magnetically disordered surface shell. The core magnetic moments block progressively with decreasing temperature, according to the distribution of their anisotropy energy barriers, as shown by a broad maximum of the low field zero-field-cooled magnetization (M(ZFC)) and in the in-phase component chi' of the AC susceptibility, centred at ~70 K. On the other hand, surface spins thermally fluctuate and freeze in a disordered spin-glass-like state at much lower temperature, as shown by a peak in M(ZFC) (at 17 K, for H = 50 Oe) and in chi'. The temperature of the high temperature chi' peak changes with frequency according to the Arrhenius law; instead, for the low temperature maximum a power law dependence of the relaxation time was found, tau = tau(0)(T(g)/(T(nu)-T(g)))(alpha), where alpha = 8, like in spin glasses, tau(0) = 10(-12) s and T(g) = 15.9 K. The low temperature surface spin freezing is accompanied by a strong enhancement of magnetic anisotropy, as shown by the rapid increase of coercivity and high field susceptibility. Monte Carlo simulations for core/shell antiferromagnetic particles, with an antiferromagnetic core and a disordered shell, reproduce the qualitative behaviour of the temperature dependence of the coercivity. Interparticle interactions lead to a shift to a high temperature of the distribution of the core moment blocking temperature and to a reduction of magnetization dynamics. PMID- 21825699 TI - Scale effect on wave propagation of double-walled carbon nanotubes with initial axial loading. AB - This paper studies the vibrational characteristics of double-walled carbon nanotubes (DWNTs) with initial stress using a nonlocal Euler-Bernoulli beam model. Both the effect of initial stress and the effect of small length scale are discussed in detail. The effect of van der Waals forces is incorporated in the formulation. The corresponding resonant vibrational characteristics are presented in detail; they are shown to be very different from those predicted by classical elasticity theory when nonlocal effects are significant. The influence of initial stress in carbon nanotubes on their flexural vibration modes is dependent on the tension or compression form of the initial stress. The investigation of the effects of initial stress on transverse wave propagation in carbon nanotubes may be used as a useful reference for the application and the design of nanoelectronic and nanodrive devices, nano-oscillators, and nanosensors, in which carbon nanotubes act as basic elements. PMID- 21825700 TI - The interaction of nitrogen molecules with (4, 0) single-walled carbon nanotube: electronic and structural effects. AB - The electronic structure and energetics of (4, 0) single-walled carbon nanotubes (CNTs) interacting with nitrogen have been studied using density-functional calculations. We show that the nanotubes become covered with a stable sheath of N(2) molecules. We have constructed potential energy curves which can be used for the thermodynamic analysis of N(2) adsorption and desorption processes. Our results show that any analysis of the observed properties (for example thermodynamics, stability, and photoluminescence) of air-exposed CNTs needs to consider the N(2) adsorbed on the CNTs. PMID- 21825701 TI - The template-free synthesis of square-shaped SnO(2) nanowires: the temperature effect and acetone gas sensors. AB - Square-shaped single-crystalline SnO(2) nanowires and their sphere-like hierarchical structures were synthesized successfully with a template-free hydrothermal approach. It was found that an intermediate phase-Na(2)Sn(OH)(6)-is first produced because it is slow to dissolve in ethanol/water media. The intermediate phase gradually decomposes and converts into SnO(2) at temperatures higher than 200 degrees C. The reaction temperature also affects the microstructure of SnO(2) nanomaterials. Uniform square-shaped SnO(2) nanowires, which form sphere-like hierarchical structures in 100% structure yield, can be produced at 285 degrees C on a large scale. The diameter of the nanowires shows a decrease accompanying the increase of the reaction temperature. The temperature effect could be a result of the faster and oriented growth of SnO(2) nanowires along their [Formula: see text] direction at higher temperature. Chemical sensors constructed with square-shaped SnO(2) nanowires exhibit excellent stability, good sensitivity and selectivity, as well as a quick response and short recovery times under exposure to acetone gas in practical applications. PMID- 21825702 TI - Industrially synthesized single-walled carbon nanotubes: compositional data for users, environmental risk assessments, and source apportionment. AB - Commercially available single-walled carbon nanotubes (SWCNTs) contain large percentages of metal and carbonaceous impurities. These fractions influence the SWCNT physical properties and performance, yet their chemical compositions are not well defined. This lack of information also precludes accurate environmental risk assessments for specific SWCNT stocks, which emerging local legislation requires of nanomaterial manufacturers. To address these needs, we measured the elemental, molecular, and stable carbon isotope compositions of commercially available SWCNTs. As expected, catalytic metals occurred at per cent levels (1.3 29%), but purified materials also contained unexpected metals (e.g., Cu, Pb at 0.1-0.3 ppt). Nitrogen contents (up to 0.48%) were typically greater in arc produced SWCNTs than in those derived from chemical vapor deposition. Toluene extractable materials contributed less than 5% of the total mass of the SWCNTs. Internal standard losses during dichloromethane extractions suggested that metals are available for reductive dehalogenation reactions, ultimately resulting in the degradation of aromatic internal standards. The carbon isotope content of the extracted material suggested that SWCNTs acquired much of their carbonaceous contamination from their storage environment. Some of the SWCNTs, themselves, were highly depleted in (13)C relative to petroleum-derived chemicals. The distinct carbon isotopic signatures and unique metal 'fingerprints' may be useful as environmental tracers allowing assessment of SWCNT sources to the environment. PMID- 21825703 TI - In vivo non-invasive optical imaging of temperature-sensitive co-polymeric nanohydrogel. AB - Assessment of hyperthermia in pathological tissue is a promising strategy for earlier diagnosis of malignant tumors. In this study, temperature-sensitive co polymeric nanohydrogel poly(N-isopropylacrylamide-co-acrylic acid) (PNIPA-co-AA) was successfully synthesized by the precipitation polymerization method. The diameters of nanohydrogels were controlled to be less than 100 nm. Also the lower critical solution temperature (LCST, 40 degrees C) was manipulated above physiological temperature after integration of near-infrared (NIR) organic dye (heptamethine cyanine dye, HMCD) within its interior cores. NIR laser light (765 nm), together with sensitive charge coupled device (CCD) cameras, were designed to construct an NIR imaging system. The dynamic behaviors of PNIPA-co-AA-HMCD composites in denuded mice with or without local hyperthermia treatment were real time monitored by an NIR imager. The results showed that the PNIPA-co-AA-HMCD composites accumulated in the leg treated with local heating and diffused much slower than that in the other leg without heating. The results demonstrated that the temperature-responsive PNIPA-co-AA-HMCD composites combining with an NIR imaging system could be an effective temperature mapping technique, which provides a promising prospect for earlier tumor diagnosis and thermally related therapeutic assessment. PMID- 21825704 TI - High resolution LT-STM imaging of PTCDA molecules assembled on an InSb(001) c(8 * 2) surface. AB - The self-assembling of 3,4,9,10-perylene-tetracarboxylic-dianhydride (PTCDA) molecules deposited on an InSb(001) c(8 * 2) surface at sub-monolayer quantities has been investigated at low temperature (77 K) using scanning tunnelling microscopy. Sub-molecular resolution was obtained on PTCDA molecules. The results reveal that individual PTCDA molecules are arranged on the substrate in chains parallel to the [110] crystallographic direction, correlated with characteristic features of the low temperature InSb(001) c(8 * 2) surface electronic structure. A structural model for PTCDA molecules adsorbed on InSb is proposed. PMID- 21825705 TI - Second order optical effects in Au nanoparticle-deposited ZnO nanocrystallite films. AB - Photoinduced second harmonic generation (SHG) in Au nanoparticle-deposited ZnO nanocrystallite (NC) films was explored by applying bicolor coherent treatment of a Nd-YAG laser with wavelength 1.06 um and its SHG. We have established that coexistence of the ZnO and Au nanoparticles gives a substantially larger SHG output with respect to pure ZnO NC deposited on the glass substrate. It was established that the value of the second order susceptibility is about 23 pm V( 1). Better nonlinear optical susceptibilities were obtained during phototreatment at temperatures near 30-35 degrees C for the Au doped samples. The samples without gold NCs are temperature independent. Generally an increasing temperature leads to a decrease of the optical SHG. PMID- 21825706 TI - The high current-carrying capacity of various carbon nanotube-based buckypapers. AB - Buckypapers (BPs) are thin films made up of carbon nanomaterials, such as single walled carbon nanotubes (SWCNTs) or mixtures of SWCNTs with multi-walled carbon nanotubes (MWCNTs) or vapor-grown carbon nanofibers (VGCNFs). In this research, BPs were exposed to high electrical current densities under different environments, and the effects on nanotube and BP breakdown were observed. In ambient conditions, SWCNT BP breakdown happened at around 430 degrees C with a flash of light. Mixed BPs of SWCNTs/MWCNTs and SWCNTs/VGCNFs showed higher ignition temperatures of over 500 degrees C. The results were compared to those from thermogravimetric analysis. In a vacuum, current-driven thermal heating from the samples can generate temperatures greater than 2000 degrees C. The breakdown current density increased to more than three times that in open air. The breakdown current density of a BP sample increased proportionally to its conductivity. A finite-element model based on Joule heating and heat convection was used to explain this relationship. Further experiments also proved that the high current-carrying capacity of microscale nanotube array samples improved to 10(6) A cm(-2) due to increased heat dissipation through the substrate. PMID- 21825707 TI - Anomalous electrical transport behavior in nanocrystalline nickel. AB - We have prepared nanocrystalline Ni (n-Ni) samples of grain sizes 40-100 nm using a polyol method and investigated the electrical transport on their compacted pellets in the temperature range 3-300 K. The resistivity, rho, decreases nearly linearly with increase in compaction pressure but without a change in its slope, drho/dT. rho is anomalously large, and is strongly temperature and grain-size dependent. The resistivity at room temperature, rho(300 K), is in the range ~40 759 uOmega cm but with a positive coefficient of resistivity alpha (metallic). This is associated with the significantly enhanced drho/dT with increase in residual resistivity rho(0). These characteristics are attributed to the disorder in the grain boundaries that represents effectively a series resistor network. PMID- 21825708 TI - The effect of high energy mechanochemical processing on the microstructure, piezoelectric, ferroelectric and mechanical properties of PLZT ceramics. AB - Lead lanthanum zirconate titanate (PLZT) ceramics were synthesized using a high energy mechanochemical processing technique, using tungsten carbide grinding vials and balls. The ceramic powders were prepared using the constituent oxide powders, which were subjected to high energy milling, without the use of any excess PbO in the starting composition. TEM studies revealed the formation of very fine particles of the order of 30 nm, due to the milling effect. Highly dense ceramics could be prepared via sintering which resulted in ultra-high strains in these piezoelectric samples of up to 0.25%, a value which has not been reported hitherto by any other known process. The effect of the reduction in particle size on the microstructure, mechanical and electrical properties of PLZT ceramics were studied and are discussed herein. PMID- 21825709 TI - A hybrid light source with integrated inorganic light-emitting diode and organic polymer distributed feedback grating. AB - We report a compact light source that incorporates a semiconductor light-emitting diode, nanostructured distributed feedback (DFB) Bragg grating and spin-coated thin conjugated polymer film. With this hybrid structure, we transferred electrically generated 390 nm ultraviolet light to an organic polymer via optical pumping and out-couple green luminescence to air through a second-order DFB grating. We demonstrate the feasibility of electrically driven, hybrid, compact light-emitting devices and lasers in the visible range. PMID- 21825710 TI - Carbon nanotube-nanocrystal heterostructures fabricated by electrophoretic deposition. AB - Alternating layer, carbon nanotubes-nanocrystal composite films, comprising multi walled carbon nanotubes (MWCNTs) and iron oxide (Fe(3)O(4)) nanocrystals, have been fabricated via electrophoretic deposition (EPD) on stainless steel and gold substrates. Low field-high current and high field-low current EPD schemes were integrated to produce the composite films. The low field-high current EPD approach produced porous mats from an aqueous suspension of the MWCNTs, while the high field-low current EPD approach produced tightly packed nanocrystal films from a dispersion of the nanocrystals in hexane. Large electric fields applied during the nanocrystal EPD and strong van der Waals interactions among the nanocrystals facilitated the formation of tightly packed nanocrystal films atop the MWCNT mats to create CNT mat-nanocrystal film composites. The surface coverage and homogeneity of the nanocrystal films improved with repeated deposition of the nanocrystals on the same mat. The assembly of nanotube mats on top of the CNT mat-nanocrystal film composite confirmed the feasibility of multilayered CNT mat-nanocrystal film heterostructures suitable for a range of devices. Scanning electron microscopy (SEM) and atomic force microscopy (AFM) techniques were employed to characterize the surface coverage, homogeneity, and topology of these composite films. PMID- 21825711 TI - Gold nanowires fabricated by immersion plating. AB - The growth mechanism of oriented Au nanowires fabricated by immersion plating was investigated. Both n-type crystal Si (c-Si) and amorphous Si (a-Si) with an electron-beam (E-beam) patterned resist nanotrench were immersed into the plating bath HAuCl(4)/HF. For the Au nanowires fabricated on c-Si, voids, nanograins, and clusters were observed at various plating conditions, time and temperature. The voids were often found in the center of the Au nanowires due to there being fewer nucleation sites on the c-Si surface. However, Au can easily nucleate on the surface of a-Si and form continuous Au nanowires with grain sizes about 10-50 nm. The resistivities of Au nanowires with width 105 nm fabricated on a-Si are about 4.4-6.5 uOmega cm. After annealing at 200 degrees C for 30 min in N(2) ambient, the resistivities are lowered to about 3.0-3.9 uOmega cm, measured in an atomic force microscope (AFM) in contact mode. The grain size of Au is in the range of ~50-100 nm. A scanning electron microscope (SEM) examination and grazing incident x-ray diffraction (GIXRD) analysis were also carried out to study the morphology and crystalline structure of the Au nanowires. PMID- 21825712 TI - Growth of carbon nanostructures on carbonized electrospun nanofibers with palladium nanoparticles. AB - This paper studies the mechanism of the formation of carbon nanostructures on carbon nanofibers with Pd nanoparticles by using different carbon sources. The carbon nanofibers with Pd nanoparticles were produced by carbonizing electrospun polyacrylonitrile (PAN) nanofibers including Pd(Ac)(2). Such PAN-based carbon nanofibers were then used as substrates to grow hierarchical carbon nanostructures. Toluene, pyridine and chlorobenzine were employed as carbon sources for the carbon nanostructures. With the Pd nanoparticles embedded in the carbonized PAN nanofibers acting as catalysts, molecules of toluene, pyridine or chlorobenzine were decomposed into carbon species which were dissolved into the Pd nanoparticles and consequently grew into straight carbon nanotubes, Y-shaped carbon nanotubes or carbon nano-ribbons on the carbon nanofiber substrates. X-ray diffraction analysis and transmission electron microscopy (TEM) were utilized to capture the mechanism of formation of Pd nanoparticles, regular carbon nanotubes, Y-shaped carbon nanotubes and carbon nano-ribbons. It was observed that the Y shaped carbon nanotubes and carbon nano-ribbons were formed on carbonized PAN nanofibers containing Pd-nanoparticle catalyst, and the carbon sources played a crucial role in the formation of different hierarchical carbon nanostructures. PMID- 21825713 TI - The fabrication of polymeric nanochannels by electrospinning. AB - Polymeric nanochannels have been fabricated using a cost-effective, fast, one step method involving the collision of nanosized jets during electrospinning. The nanochannels had a uniform U-shaped cross-section, with a height below 100 nm and lengths around 1 mm. It was explained that the strength of the electric field had an important effect on the formation of the nanochannels. An adhesion test on the nanochannels using the lateral force mode of an atomic force microscope showed that the nanochannels formed by the jet impingement adhered well to a surface. PMID- 21825714 TI - Fano-Rashba effect in quantum dots. AB - We consider the electronic transport through a Rashba quantum dot coupled to ferromagnetic leads. We show that the interference of localized electron states with resonant electron states leads to the appearance of the Fano-Rashba effect. This effect occurs due to the interference of bound levels of spin-polarized electrons with the continuum of electronic states with an opposite spin polarization. We investigate this Fano-Rashba effect as a function of the applied magnetic field and Rashba spin-orbit coupling. PMID- 21825715 TI - Gate-controlled charge transfer in Si:P double quantum dots. AB - We present low temperature charge sensing measurements of nanoscale phosphorus implanted double dots in silicon. The implanted phosphorus forms two 50 nm diameter islands with source and drain leads, which are separated from each other by undoped silicon tunnel barriers. Occupancy of the dots is controlled by surface gates and monitored using an aluminium single-electron transistor which is capacitively coupled to the dots. We observe a charge stability diagram consistent with the designed many-electron double-dot system and this agrees well with capacitance modelling of the structure. We discuss the significance of these results to the realization of smaller devices which may be used as charge or spin qubits. PMID- 21825716 TI - Fluorescence spectroscopy of electrochemically self-assembled ZnSe and Mn:ZnSe nanowires. AB - We report room temperature fluorescence spectroscopy (FL) studies of ZnSe and Mn doped ZnSe nanowires of different diameters (10, 25, 50 nm) produced by an electrochemical self-assembly technique. All samples exhibit increasing blue shift in the band edge fluorescence with decreasing wire diameter because of quantum confinement. The 10 nm ZnSe nanowires show four distinct emission peaks due to band-to-band recombination, exciton recombination, recombination via surface states and via band gap (trap) states. The exciton binding energy in these nanowires exhibits a giant increase (~10-fold) over the bulk value due to quantum confinement, since the effective wire radius (taking into account side depletion) is smaller than the exciton Bohr radius in bulk ZnSe. The 25 and 50 nm diameter wires show only a single FL peak due to band-to-band electron-hole recombination. In the case of Mn-doped ZnSe nanowires, the band edge luminescence in 10 nm samples is significantly quenched by Mn doping but not the exciton luminescence, which remains relatively unaffected. We observe additional features due to Mn(2+) ions. The spectra also reveal that the emission from Mn(2+) states increases in intensity and is progressively red-shifted with increasing Mn concentration. PMID- 21825717 TI - Monoclinic zirconium oxide nanostructures synthesized by a hydrothermal route. AB - Zirconium oxide (ZrO(2)) nanostructures were synthesized by a hydrothermal route. Surface morphology analysis depicts the formation of rice-grain-like and fiber like ZrO(2) nanostructures at different synthesis conditions. The structural analysis confirms that the as-synthesized ZrO(2) product is of pure monoclinic phase (m-ZrO(2)). The clear and equally spaced lattice fringes in high-resolution transmission electron microscopy (HRTEM) images and discrete spot pattern of selected area electron diffraction (SAED) confirm the high quality of the synthesized product. The product consists of monodispersed nanoparticles of uniform composition, high purity, and crystallinity. The Raman spectra are quantitatively analyzed and the observed peaks are attributed to various vibration modes of m-ZrO(2). PMID- 21825718 TI - Predicting the growth of two-dimensional nanostructures. AB - The ability to predict the morphology of crystals formed by chemical reactions is of fundamental importance for the shape-controlled synthesis of nanostructures. Based on the atomistic mechanism for crystal growth under different driving forces, we have developed morphology diagrams to predict regimes for the growth of two-dimensional crystals. By using controlled reactions for crystal growth in the absence of surfactants/capping agents, we demonstrate the validity of this approach for the formation of 2D structures of Au, Ag, Pt and Pd. PMID- 21825719 TI - Modelling the increase in anisotropic reaction rates in metal nanoparticle oxidation using carbon nanotubes as thermal conduits. AB - Nanostructured energetic materials are attracting attention for their faster reaction rates compared to materials with micron-scale particles. We numerically solve the coupled energy balances for a carbon nanotube with an annular coating of reactive metal, such that coupling to thermal transport in the nanotube accelerates reaction in the annulus. For the case of Zr metal, the nanotube increases the velocity of the reaction front in the direction of the nanotube length from 530 to 5100 mm s(-1). This offers a proof-of-concept for one dimensional anisotropic energetic materials, which could find new applications in inorganic synthesis and novel propellants. Nanotube conductivity as well as the relative sizes of the Zr annulus and the nanotube limit enhancement of the reaction velocity to a maximum of a factor of ~10. Interestingly, the interfacial heat conductance is not the most significant factor affecting the coupling, due to the large temperature differences (more than 1000 K) between the nanotube and the annulus at the reaction front and directional heat conduction in the nanotube. Although the enhancement is insufficient to change a Zr/nanotube composite from a deflagrating to a detonating material, using faster-reacting materials may enable nanotubes to effect this transition. PMID- 21825721 TI - Synthesis and nonlinear optical properties of nanometer-size silver-coated polydiacetylene composite vesicles. AB - Two kinds of nanometer-size silver-coated polydiacetylene (PDA) composite vesicles were prepared by simple and effective approaches. Silver nanoparticles were coated onto the outer and inner surface (I) or only on the outer surface of PDA vesicles (II), respectively. UV-vis spectra and transmission electron microscopy (TEM) were used to confirm the formation of PDA/Ag nanocomposite vesicles. Nonlinear optical (NLO) properties of these PDA/Ag nanocomposite vesicles had been measured by the Z-scan technique. The value of n(2) for pure PDA vesicles was 1.2 * 10(-14) cm(2) W(-1). However, for PDA/Ag nanocomposite vesicles (on the outer surface) it was 7.3 * 10(-14) cm(2) W(-1). Nearly seven times enhancement was observed as a result of local field enhancement under the surface plasmon resonance of silver nanoparticles at the interface. NLO properties of these PDA/Ag nanocomposite vesicles can be modulated by varying the size, shape and coverage of Ag nanoparticles and these PDA/Ag nanocomposite vesicles are expected to be good candidates for new optical and nonlinear devices. PMID- 21825720 TI - A molecular dynamics simulation study on trapping ions in a nanoscale Paul trap. AB - We found by molecular dynamics simulations that a low energy ion can be trapped effectively in a nanoscale Paul trap in both vacuum and aqueous environments when appropriate AC/DC electric fields are applied to the system. Using the negatively charged chlorine ion as an example, we show that the trapped ion oscillates around the center of the nanotrap with an amplitude dependent on the parameters of the system and applied voltages. Successful trapping of the ion within nanoseconds requires an electric bias of GHz frequency, in the range of hundreds of mV. The oscillations are damped in the aqueous environment, but polarization of water molecules requires the application of a higher voltage bias to reach improved stability of the trapping. Application of a supplemental DC driving field along the trap axis can effectively drive the ion off the trap center and out of the trap, opening up the possibility of studying DNA and other charged molecules using embedded probes while achieving a full control of their translocation and localization in the trap. PMID- 21825722 TI - An elastic shell model for characterizing single-walled carbon nanotubes. AB - This paper proposes a two-dimensional elastic shell model to characterize the deformation of single-walled carbon nanotubes using the in-plane rigidity, Poisson ratio, bending rigidity and off-plane torsion rigidity as independent elastic constants. It was found that the off-plane torsion rigidity of a single walled carbon nanotube is not zero due to the off-plane change in the pi-orbital electron density on both sides of the nanotube. It was concluded that a three dimensional elastic shell model of single-walled carbon nanotubes can be established with well-defined effective thickness. PMID- 21825723 TI - The role of an amorphous carbon layer on a multi-wall carbon nanotube attached atomic force microscope tip in making good electrical contact to a gold electrode. AB - Multi-wall carbon nanotube (MWNT) attached atomic force microscope (AFM) tips (MWNT tips) have good potential for use in AFM lithography. Good conducting MWNT tips are needed in such applications. However, characterizing the conductance of MWNT tips is nontrivial: making a good electrical contact between the MWNT and electrode is difficult. We observed that MWNT tips produced by hydrocarbon deposition attachment usually do not make good electrical contacts to gold electrodes because of the thin and rough amorphous carbon layer on the MWNT that was unintentionally deposited during the attachment. We found that good contacts can be made if a more amorphous carbon layer is deposited to form a thick and smooth amorphous carbon layer on MWNTs. Good contact was made either by transformation of the amorphous carbon layer into a conducting or peel-off layer, exposing the bare MWNT surface. MWNT tips with an exposed MWNT surface showed the well-known high-current-flowing capacity and the stepped-cutting behavior of bare MWNTs. The peeling-off behavior of a thick amorphous carbon layer may be utilized in producing bare-surfaced MWNT tips that have good conductance and therefore are useful for applications. PMID- 21825724 TI - Finite-size effect on magnetic properties in iron sulfide nanowire arrays. AB - We report the size effect on the magnetic properties in Fe(7)S(8) nanowire arrays. Samples with diameters in the range of 50-200 nm have been prepared by electrodeposition with AAO films. The Mossbauer measurement results show that four parameters (hyperfine fields, isomer shift, quadrupole splitting, full width at half-maximum) increased with decreasing the diameter of the nanowires. The magnetic properties were investigated. The hysteresis loop shape and the magnetization are dependent on the diameter of the nanowires. The thermomagnetic measurements on the as-synthesized nanowire samples and the corresponding bulk display a mixed-type curve and a Weiss-type curve, respectively. PMID- 21825725 TI - Slip-enhanced electrokinetic energy conversion in nanofluidic channels. AB - We investigate theoretically the influence of hydrodynamic slip at the surface of a nanofluidic channel on the efficiency with which electrokinetic phenomena can be used to convert hydrostatic energy to electrical power. Slip is introduced by applying the Navier boundary condition to the pressure-driven and the electro osmotic components of the fluid velocity. A strong enhancement in the efficiency is predicted for increasing slip length due to the resulting decrease in the fluidic impedance and increase in the streaming conductance. These effects are moderated by a decrease in the electrical impedance, which promotes dissipation. The maximum efficiency approaches 100% as the slip length diverges, and a potentially practical 40% efficiency is expected for a moderate 30 nm slip length in a 10 nm high channel. Recently reported slip lengths for carbon nanotube filters suggest that efficiencies above 70% and high power densities might be achieved in a graphitic system. PMID- 21825726 TI - Side-by-side comparison of Raman spectra of anchored and suspended carbon nanomaterials. AB - Raman spectra of ordered carbon nanomaterials are quite sensitive to surface perturbations, including trace residues, structural defects and residual stress. This is demonstrated by a series of experiments with carbon nanotubes and graphene. Their spectra change due to subtle changes in preparation and attachment to the substrate and to each other. Differences are most clearly seen by forming a material into an air bridge and probing it in the air gap and at the anchor points. A monolayer graphene sheet, shows a larger disorder band at the anchor points than in the air gap. However, a bundle or rope of parallel-aligned single-wall nanotubes shows a larger disorder band in the gap than at the anchor points. For the graphene sheet the substrate surface deforms the graphene, leading to increases in the disorder band. For the rope, the close proximity of the nanotubes to each other appears to produce a larger stress than the rope resting on the substrate. PMID- 21825727 TI - Synthesis and photocatalytic activity of WO(3) nanoparticles prepared by the arc discharge method in deionized water. AB - In this paper, we discuss the synthesis and characterization of tungsten trioxide nanoparticles prepared by the arc discharge method in deionized (DI) water. The size and morphology of WO(3) nanoparticles prepared using different arc currents (25, 35 and 45 A) were studied. Dynamic light scattering (DLS) and scanning electron microscopy (SEM) results indicate that at an arc current of 25 A, the size of the particles is about 30 nm, and this increases to 64 nm by increasing the arc current. This size increase caused a decrease of optical band gap from 2.9 to 2.6 eV. X-ray diffraction (XRD) and x-ray photoelectron spectroscopy (XPS) spectra demonstrate the formation of the WO(3) phase. Photodegradation of Rhodamine B shows that samples prepared at the lowest current have more photocatalytic activity due to having the smallest particle size and highest surface area. The results demonstrate the ability of the arc discharge method for direct formation of WO(3) nanoparticles in DI water medium. PMID- 21825728 TI - Dimethylformamide: an effective dispersant for making ceramic-carbon nanotube composites. AB - Carbon nanotube (CNT) and alumina dispersions were prepared separately in dimethylformamide (DMF) and ethanol by ultrasonication. The colloidal stability of the dispersions was monitored and a particle size analysis was performed to evaluate the size range of the agglomerates after different times. DMF was found to be a much more effective dispersant than ethanol for making stable, homogeneous CNT and composite dispersions. Alumina-CNT (4.65 vol%) nanocomposites were sintered in a spark plasma sintering (SPS) furnace. DMF dispersions produced homogeneously distributed and agglomerate-free CNT-alumina nanocomposites with higher electrical conductivity as compared to nanocomposites prepared using ethanol. PMID- 21825729 TI - Platinum nanoparticles on carbonaceous materials: the effect of support geometry on nanoparticle mobility, morphology, and melting. AB - Molecular dynamics simulations have been used to investigate the morphology and mobility of platinum nanoparticles of various sizes supported by carbon materials. The embedded-atom method was used to model Pt-Pt interactions, and the Lennard-Jones potential was used to model the Pt-C interactions. The C atoms in the supports were held fixed during the simulations. The supports considered were a single graphite sheet and three bundles of carbon nanotubes. Three sizes of Pt nanoparticles were considered: 130 atoms, 249 atoms, and 498 atoms (Pt(130), Pt(249), and Pt(498) respectively). It was found that for all three sizes, diffusion coefficients were approximately one order of magnitude higher for graphite-supported nanoparticles than for carbon nanotube-supported nanoparticles. In addition, increasing the size of the nanoparticle decreased its diffusion coefficient, with Pt(130) having the highest and Pt(498) the lowest diffusion coefficients. More interestingly, we found that for the Pt nanoparticles of all three sizes the diffusion coefficient increases as temperature increases, reaches a maximum at the melting temperature of the nanoparticle, and then decreases. The melting temperature was found to be strongly dependent on the particle size, but only slightly dependent on the features of the supports. While the size of the nanoparticle was seen to affect the particles' mobility, it did not significantly affect their structure. The nanoparticles supported by graphite have density profiles that indicate a highly ordered, fcc-like structure, while the particles supported by carbon nanotubes have a more disordered structure. An order parameter confirms that the nanoparticles' structure depends on the support morphology. PMID- 21825730 TI - Gold island films on indium tin oxide for localized surface plasmon sensing. AB - Mechanically, chemically and optically stable gold island films were prepared on indium tin oxide (ITO) substrates by direct thermal evaporation of thin gold films (2-6 nm) without the need for pre- or post-coating. The effect of mild thermal annealing (150 degrees C, 12 h) or short high temperature annealing (500 degrees C, 1 min) on the morphology of the gold nanostructures was investigated. ITO covered with 2 nm gold nanoislands and annealed at 500 degrees C for 1 min was investigated for its ability to detect the adsorption of biotinylated bovine serum albumin using local surface plasmon resonance (LSPR), and its subsequent molecular recognition of avidin. PMID- 21825731 TI - UV-screening chitosan nanocontainers: increasing the photostability of encapsulated materials and controlled release. AB - Methyl ether terminated poly(ethylene glycol)-4-methoxycinnamoylphthaloylchitosan (PCPLC), a UV absorptive polymer, and methyl ether terminated poly(ethylene glycol)-phthaloylchitosan (PPLC) were synthesized, characterized and self assembled into stable water-dispersible spherical nanoparticles. The encapsulation of a model compound, 2-ethylhexyl-4-methoxycinnamate (EHMC), was carried out to give particles with 67% (w/w) EHMC loading. The E to Z photoisomerization of EHMC encapsulated inside both particles was monitored and compared to non-encapsulated EHMC. Minimal E to Z photoisomerization was observed when EHMC was encapsulated in PCPLC particles prepared from a polymer with a maximum degree of 4-methoxycinnamoyl substitution. The results indicated that the grafted UVB absorptive chromophore, 4-methoxycinnamoyl moieties, situated at the shell of PCPLC nanoparticles acted as a UV-filtering barrier, protecting the encapsulated EHMC from the UVB radiation, thus minimizing its photoisomerization. In vitro experiments revealed the pH-dependent controlled release of EHMC from PCPLC and PPLC particles. Ex vivo experiments, using a Franz diffusion cell with baby mouse skin, indicated that neither PPLC nor PCPLC particles could penetrate the skin into the receptor medium after a 24 h topical application. When applied on the baby mouse skin, both EHMC-encapsulated PPLC and EHMC-encapsulated PCPLC showed comparable controlled releases of the EHMC. The released EHMC could transdermally penetrate the baby mouse skin. PMID- 21825732 TI - Alpha-bungarotoxin binding to target cell in a developing visual system by carboxylated nanodiamond. AB - Biological molecules conjugating with nanoparticles are valuable for applications including bio-imaging, bio-detection, and bio-sensing. Nanometer-sized diamond particles have excellent electronic and chemical properties for bio-conjugation. In this study, we manipulated the carboxyl group produced on the surface of nanodiamond (carboxylated nanodiamond, cND) for conjugating with alpha bungarotoxin (alpha-BTX), a neurotoxin derived from Bungarus multicinctus with specific blockade of alpha7-nicotinic acetylcholine receptor (alpha7-nAChR). The electrostatic binding of cND-alpha-BTX was mediated by the negative charge of the cND and the positive charge of the alpha-BTX in physiological pH conditions. Sodium dodecyl sulfate-polyacrylamide gel analysis and matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI/TOF-MS) spectra displayed that alpha-BTX proteins were conjugated with cND particles via non covalent bindings. The green fluorescence of the cND particles combining with the red fluorescence of tetramethylrhodamine-labeled alpha-BTX presented a yellow color at the same location, which indicated that alpha-BTX proteins were conjugated with cND particles. Xenopus laevis's oocytes expressed the human alpha7-nAChR proteins by microinjection with alpha7-nAChR mRNA. The cND-alpha-BTX complexes were bound to alpha7-nAChR locating on the cell membrane of oocytes and human lung A549 cancer cells analyzed by laser scanning confocal microscopy. The choline-evoked alpha7-nAChR-mediated inward currents of the oocytes were blocked by cND-alpha-BTX complexes in a concentration-dependent manner using two electrode voltage-clamp recording. Furthermore, the fluorescence intensity of cND alpha-BTX binding on A549 cells could be quantified by flow cytometry. These results indicate that cND-conjugated alpha-BTX still preserves its biological activity in blocking the function of alpha7-nAChR, and provide a visual system showing the binding of alpha-BTX to alpha7-nAChR. PMID- 21825733 TI - Auger quenching-based modulation of electroluminescence from ion-implanted silicon nanocrystals. AB - We describe high-speed control of light from silicon nanocrystals under electrical excitation. The nanocrystals are fabricated by the ion implantation of Si(+) in the 15 nm thick gate oxide of a field effect transistor at 6.5 keV. A characteristic read-peaked electroluminescence is obtained either by DC or AC gate excitation. However, AC gate excitation is found to have a frequency response that is limited by the radiative lifetimes of silicon nanocrystals, which makes impossible the direct modulation of light beyond 100 kb s(-1) rates. As a solution, we demonstrate that combined DC gate excitation along with an AC channel hot electron injection of electrons into the nanocrystals may be used to obtain a 100% deep modulation at rates of 200 Mb s(-1) and low modulating voltages. This approach may find applications in biological sensing integrated into CMOS, single-photon emitters or direct encoding of information into light from Si-nc doped with erbium systems, which exhibit net optical gain. In this respect, the main advantage compared to conventional electro-optical modulators based on plasma dispersion effects is the low power consumption (10(4) times smaller) and thus the inherent large scale of integration. A detailed electrical characterization is also given. An Si/SiO(2) barrier change from Phi(b) = 3.2 to 4.2 eV is found while the injection mechanism is changed from Fowler-Nordheim to channel hot electron, which is a clear signature of nanocrystal charging and subsequent electroluminescence quenching. PMID- 21825734 TI - Thermal stability of Ti/Mo and Ti/MoN nanostructures for barrier applications in Cu interconnects. AB - This work focuses on the barrier capabilities of sputter deposited Ti/Mo and Ti/MoN nanofilms against diffusion of Cu into Si substrates. The thermal stability of the corresponding bi-layer barrier structures is investigated after annealing Cu/barrier layer/Si samples at different temperatures in N(2) for 5 min. The drastic increase in sheet resistance of Cu and the probing of Cu(3)Si with x-ray diffraction after high temperature annealing indicate the failure of these barrier structures. The formation of Cu(3)Si at the barrier breakdown temperature is also confirmed by scanning electron microscopy and energy dispersive x-ray spectroscopy. Cu diffusion barrier performance analyses show that a Ti(5 nm)/MoN(5 nm) bi-layer nanostructure fails only after annealing at 800 degrees C; on the other hand, a Ti(5 nm)/Mo(5 nm) barrier stack is found to break down at 700 degrees C. PMID- 21825735 TI - Low cost fabrication of the large-area anti-reflection films from polymer by nanoimprint/hot-embossing technology. AB - In this paper, we present a low cost approach to produce large-area polymer sheets with sub-wavelength nanostructures. The fabricated polymer films would have great potentials to attach to optical or solar-cell-related consumer products when anti-reflection/anti-glaring is mandatory. We employed a special electron cyclotron resonance (ECR) plasma process to fabricate the SWSs with large area directly on silicon substrates. Homogeneously distributed nanotips on the full 4 inch silicon substrate were fabricated by using gas mixtures of silane, methane, argon and hydrogen. An Ni-Co metal mold with a hardness of 550 HV was produced through the replication of the Si mold by electroplating. Afterwards, the molding process was applied to manufacture the nanostructures in PMMA plates in large volume. The nanostructures in PMMA plates with aspect ratios of 4 and diameters of 150 nm were fabricated. The fabricated PMMA sheets could generate the gradient of the refractive indices, absorb the light and greatly reduce the reflectivity. Compared with the PMMA without SWSs, the reflectivity of PMMA with SWSs decreased dramatically from 4.25% to 0.5% at the wavelength of light from 400 to 800 nm. PMID- 21825737 TI - Synthesis of water-soluble CdSe quantum dots by ligand exchange with p sulfonatocalix(n)arene (n = 4, 6) as fluorescent probes for amino acids. AB - A simple, rapid ligand exchange route to prepare highly fluorescent, stable and water-soluble CdSe quantum dots (QDs) is reported by using p sulfonatocalix(n)arene (SFCA(n), n = 4 or 6) instead of original trioctylphosphine oxide (TOPO) ligands. The ligands were found to have a profound effect on the luminescence response of QDs to amino acids. The SFCA(4) coated CdSe QDs were sensitive to methionine. On the other hand, SFCA(6) coated CdSe QDs turned out to be sensitive to phenylalanine. To demonstrate the detection capability of these new probes, SFCA(n) (n = 4, 6) coated CdSe QDs were used to detect methionine and phenylalanine in physiological buffer solution. Under optimal conditions, the relative fluorescence intensities of the SFCA(n) coated QDs (n = 4, 6) increased linearly with increasing concentration of amino acids. Methionine and phenylalanine enhanced the luminescence of SFCA(n) coated QDs with a concentration dependence that was best described by a Langmuir-type equation. The possible mechanism is also discussed. PMID- 21825738 TI - Improving the NH(3) gas sensitivity of ZnO nanowire sensors by reducing the carrier concentration. AB - We report a method to improve the sensitivity of a zinc oxide (ZnO) nanowire gas sensor towards ammonia (NH(3)) without the use of catalyst nanoparticles on the nanowire surface. This improvement is achieved by lowering the nominal carrier concentration in the as-grown ZnO nanowires. The carrier concentration in the as grown ZnO nanowires can be tuned by treating these nanowires to either an oxidizing gas plasma or a reducing gas plasma, as observed from the measured current-voltage (I-V) characteristics response. We demonstrate that a ZnO nanowire sensor device that has been subjected to oxygen plasma treatment, thereby having a reduced carrier concentration, exhibits a sensitivity towards 0.75% NH(3) gas that is improved by approximately four times. The origin of this gas sensitivity improvement is discussed based on x-ray photoelectron spectroscopy analysis results of the plasma-treated ZnO nanowires. PMID- 21825736 TI - Controlled manipulation of carbon nanopillars and cantilevers by focused ion beam. AB - We explore a novel phenomenon of focused ion beam (FIB) induced bending of carbon nanopillars or cantilever structures. The bending occurs towards the ion beam during scanning. The explanation of this bending has been sought on the basis of a model which considers temperature rise and gradients caused by the impinging ion beam. The process is controllable and reversible, which makes it highly suitable for in situ manipulation to make desired 3D shapes by the piecewise bending of the nanopillars and cantilever structures during their fabrication using electron beam or FIB chemical vapor deposition (EB-CVD or FIB-CVD). Its usefulness in the fabrication of nanosize mechanical components has been demonstrated by making a branch structure from a single cantilever. PMID- 21825739 TI - Electrochemical fabrication of Sn nanowires on titania nanotube guide layers. AB - We describe a novel approach for the fabrication of tailored nanowires using a two-step electrochemical process. It is demonstrated that self-organized TiO(2) nanotubes can be used to activate and guide the electrochemical growth of Sn crystallites, leading to the formation of vertical features with a high aspect ratio. We show that the dimensions and the density of Sn crystallites depend on the electrodeposition parameters. PMID- 21825740 TI - Cluster synthesis of branched CdTe nanocrystals for use in light-emitting diodes. AB - Highly luminescent cadmium telluride (CdTe) nanocrystals were synthesized using Li(2)[Cd(4)(SPh)(10)] as a reactive Cd cluster compound at relatively low temperature, making it a safe precursor for the large scale synthesis of CdTe nanocrystals. Transmission electron microscopy (TEM) showed that the shape of the CdTe nanocrystals changes from nanorods to branched structures with increasing reaction time. The nanocrystals show high luminescent quantum yields up to 37% for CdTe branched nanostructures, and as high as 52% for CdTe/CdS core-shell heterostructures. CdTe/CdS nanocrystals were used to make light-emitting diodes in combination with organic layers for electron and hole injection. The devices show a maximum luminance efficiency of 0.35 cd A(-1). PMID- 21825741 TI - The synthesis and selective gas sensing characteristics of SnO(2)/alpha-Fe(2)O(3) hierarchical nanostructures. AB - SnO(2)/alpha-Fe(2)O(3) hierarchical nanostructures, in which the SnO(2) nanorods grow on the side surface of alpha-Fe(2)O(3) nanorods as multiple rows, were synthesized via a three-step process. The diameters and lengths of the SnO(2) nanorods are 6-15 nm and about 120 nm. The growth direction of SnO(2) nanorods is [001], significantly affected by that of alpha-Fe(2)O(3) nanorods. The hetero nanostructures exhibit very good selectivity to ethanol. The sensing characteristics are related to the special heterojunction structures, confirmed by high-resolution transmission electron microscopy observation. Therefore, a heterojunction barrier controlled gas sensing mechanism is realized. Our results demonstrate that the hetero-nanostructures are promising materials for fabricating sensors and other complex devices. PMID- 21825742 TI - Continuous-flow laser synthesis of large quantities of iron oxide nanowires in solution. AB - Large quantities of iron oxide nanowires are rapidly synthesized at room temperature by pulsed-laser (248 nm) ablation of iron powder under methanol. By introducing a stream of methanol, a continuous flow of nanoscale products is collected. Through control of the flow rate, and hence the residence time of the products within the growth vessel, their morphology can be controlled. At high collection rates a lamellate 'nanobelt' morphology is observed, whereas at low collection rates nanowires dominate. Chemical and structural characterization suggests that the as-synthesized products have the stoichiometry of the goethite [FeO(OH)] phase. Annealing at temperatures above 400 degrees C crystallizes the products as hematite (alpha-Fe(2)O(3)). PMID- 21825743 TI - In situ modifying of carbon tube-in-tube nanostructures with highly active Fe(2)O(3) nanoparticles. AB - A novel in situ method based on a liquid membrane templated self-assembly process is employed to modify carbon tube-in-tube nanostructures (TTCNTs) with Fe(2)O(3) nanoparticles. The as-obtained Fe(2)O(3) modified TTCNTs (Fe(2)O(3)/TTCNTs) nanocomposites are well constructed and the Fe(2)O(3) nanoparticles are well dispersed and decorated on the outer, inner and intramolecular surfaces of TTCNTs. In addition, the Fe(2)O(3)/TTCNTs nanocomposites are employed as catalysts for selective catalytic reduction (SCR) of NO with NH(3) and show high SCR catalytic activity, indicating that the novel multiple intramolecular channels and unique surface chemistry of the TTCNTs should play an important role in improving the properties of TTCNTs. PMID- 21825744 TI - The structure and properties of small Pd clusters. AB - The zero-temperature minimal energy structure of small free-standing Pd clusters (14<=N<=21, where N is the number of atoms in the cluster), their characteristics and their magnetic configurations are investigated. Results obtained using five different phenomenological many-body potentials (implemented in combination with a genetic algorithm search) are refined by means of various density functional theory (DFT) techniques. The agreement and differences between the results obtained with our procedure, using these five potentials, are displayed in detail. While phenomenological potentials yield values that approach the minimal energies of larger clusters, as compared with DFT results, they fail to predict the right symmetry group for some of the clusters with N>14. We find that the minimal energy configurations are not necessarily associated with high symmetry of the atomic arrangement. Actually, several cases of previously overlooked low symmetry structures turn out to have lower energies than more symmetric ones. PMID- 21825745 TI - The microstructure and electrical conductivity of mixed-valence TlIn(4)S(5)Cl quaternary compound micro- and nanowires. AB - Quaternary mixed-valence compound TlIn(4)S(5)Cl micro- and nanowires are prepared by partial substitution of chalcogen with halogen starting from a stoichiometric mixture of TlCl, In and S. Their electrical conductivity and gas sensitivity properties are investigated by using standard four-terminal systems. The specific nanowire resistivity is about 10(7) Omega cm and corresponds to the value of a typical undoped semiconductor in air. This resistivity is, however, extremely sensitive to NO(2) (sensitivity about 150) or NH(3), with a rapid response of about 2 s and recovery times. This phenomenon is supposed to be particularly important for future nanodevice applications. PMID- 21825746 TI - Efficient coating of transparent and conductive carbon nanotube thin films on plastic substrates. AB - Optically transparent and electrically conductive single-walled carbon nanotube (SWNT) thin films were fabricated at room temperature using a dip-coating technique. The film transparency and sheet resistance can be easily tailored by controlling the number of coatings. Aminopropyltriethoxysilane (APTS) was used as an adhesion promoter and, together with surfactant Triton X-100, greatly improved the SWNTs coating. Only five coats were required to obtain a sheet resistance of 2.05 [Formula: see text] and film transparency of 84 %T. The dip-coated film after post-deposition treatment with nitric acid has a sheet resistance as low as 130 [Formula: see text] at 69 %T. This technique is suitable for large-scale SWNT coating at room temperature and can be used on different types of substrates such as glass and plastics. This paper will discuss the role of the adhesion promoter and surfactant in the coating process. PMID- 21825747 TI - The two-photon excitation of SiO(2)-coated Y(2)O(3):Eu(3+) nanoparticles by a near-infrared femtosecond laser. AB - In order to improve the photoluminescence property of Eu(3+)-doped nanoparticles, Y(2)O(3):Eu(3+) nanoparticles were synthesized using the Pechini-type sol-gel method, then coated with SiO(2) shells by using the Stober method for different coating times. The SiO(2)-coated nanoparticles were characterized by x-ray diffraction (XRD), transmission electron microscopy (TEM), Fourier transform infrared (FT-IR) spectroscopy and Raman spectroscopy, and their photoluminescence spectra were recorded under 800 nm femtosecond laser excitation. The results indicate that a two-photon simultaneous absorption upconversion luminescence is obtained, and their upconversion luminescence intensities are further enhanced after the surfaces of the nanoparticles are coated with different thickness SiO(2) shells. Compared to the upconversion luminescence intensity of non-coated nanoparticles at 611 nm, the upconversion luminescence intensities of SiO(2) coated Y(2)O(3):Eu(3+) nanoparticles with coating times of 60, 90 and 120 min were enhanced by 3.30, 3.96 and 4.13 times, respectively. This can be attributed to the contributions of the increased amounts of Eu(3+) ions populated at the (5)D(0) level on the surfaces of the nanoparticles because the cooperative ligand fields between the Y(2)O(3) core and non-crystalline SiO(2) shell interfaces activate the 'dormant' Eu(3+) ions near or on the surfaces of the nanoparticles. From a Judd-Ofelt (J-O) theory analysis, the coated shell structures can improve the radiative quantum efficiencies of Eu(3+)-doped nanoparticles. It is therefore concluded that more intense red upconversion luminescence with high radiative quantum efficiencies can enable the SiO(2)-coated Y(2)O(3):Eu(3+) nanoparticles to have the great potential to be used as a fine resolution phosphor. PMID- 21825748 TI - TiO(2) nanorods/PMMA copolymer-based nanocomposites: highly homogeneous linear and nonlinear optical material. AB - Original nanocomposites have been obtained by direct incorporation of pre synthesized oleic acid capped TiO(2) nanorods into properly functionalized poly(methyl methacrylate) copolymers, carrying carboxylic acid groups on the repeating polymer unit. The presence of carboxylic groups on the alkyl chain of the host functionalized copolymer allows an highly homogeneous dispersion of the nanorods in the organic matrix. The prepared TiO(2)/PMMA-co-MA nanocomposites show high optical transparency in the visible region, even at high TiO(2) nanorod content, and tunable linear refractive index depending on the nanoparticle concentration. Finally measurements of nonlinear optical properties of TiO(2) polymer nanocomposites demonstrate a negligible two-photon absorption and a negative value of nonlinear refractive index, highlighting the potential of the nanocomposite for efficient optical devices operating in the visible region. PMID- 21825749 TI - The solid state reaction of Fe with the Si(111) vicinal surface: splitting of bunched steps. AB - The solid state reaction of deposited Fe (four monolayers, ML) with vicinal Si(111) substrate induced by subsequent thermal treatment has been studied using scanning tunnelling microscopy. At the lower range of annealing temperatures up to 400 degrees C the bunched steps of bare substrate are reproduced by the surface of the covering iron silicide layer. At 400 degrees C the onset of three dimensional growth of iron silicide islands is observed. In comparison to the samples covered with smaller amounts of Fe it appears at a lower annealing temperature. Above 500 degrees C the bunched steps split into lower ones but more densely distributed due to proceeding reactions between Fe-rich iron silicide and Si substrate. As a consequence, at 700 degrees C the well-developed three-dimensional nanocrystallites of iron silicide are randomly distributed on the Si surface. This observation is in contrast to the formation of a regular array of iron silicide crystallites upon deposition of 2 ML of Fe. PMID- 21825750 TI - First-principles study of Co-doped single-walled silicon nanotubes. AB - We performed spin-polarized density functional calculations to study the stable configurations, energetics and electronic structures of Co-doped single-walled silicon nanotubes (CoSi(2)NTs) with the stoichiometry of CoSi(2). We found that the incorporation of Co atoms into the wall of SiNTs not only effectively stabilizes the tubes but also tunes their electronic properties. The formation energies of the CoSi(2)NTs are much lower than those of pristine SiNTs, indicating the plausibility of these tubes. The electronic structures of the CoSi(2)NTs display the characters of metals. This provides a promising synthetic route to stable SiNTs which may find potential applications in building nanoscale devices. PMID- 21825751 TI - Structural, electronic and magnetic properties of manganese doping in the upper layer of bilayer graphene. AB - First-principles spin-polarized calculations have been conducted to investigate the structural, electronic and magnetic properties of 3d transition metal Mn doping into two typical sites in the upper layer of bilayer graphene with the AB Bernal structure. One of the doping sites is above the center of a carbon hexagon of the lower graphene layer (called the H site) and the other is directly on top of a carbon atom of the lower graphene layer (called the T site). We found that Mn doping enlarges the interlayer distance in bilayer graphene. Charge density distribution indicates that the region between the upper and lower graphene layer has apparent covalent-bonding characters due to the Mn doping. In the spin polarized band structure of H site doping, the pi and pi(*) bands separate from each other at the Dirac point both in majority spin and minority spin. In the band structure of T site doping, the Fermi level is located above the Dirac point and moves to the conduction bands in majority spin and minority spin, making the bilayer graphene n doped. A high spin polarization of 95% is achieved due to the H site doping. The local moment of Mn for H and T site doping is reduced to 1.76 MU(B) and 1.88 MU(B), respectively, which are smaller than the value (5 MU(B)) in the free state. PMID- 21825752 TI - Interactions between halloysite nanotubes and 2,5-bis(2-benzoxazolyl) thiophene and their effects on reinforcement of polypropylene/halloysite nanocomposites. AB - Many types of clay tend to absorb organics via electron transferring interactions between the clay and the organics. This may be utilized to design clay incorporated polymer composites with better interfacial properties. In the present paper, 2,5-bis(2-benzoxazolyl) thiophene (BBT), capable of donating electrons, is selected as the interfacial modifier for polypropylene (PP)/halloysite nanotube (HNTs) composites. The electron transfer between HNTs and BBT are confirmed. The mechanical properties and the unique morphology of the nanocomposites are examined. Formation of fibrils of BBT in the presence of HNTs is found in the nanocomposites. The chemical composition of the fibrils in the nanocomposites is found to be composed of largely BBT and a small amount of HNTs. The formation mechanism of BBT fibrils are elucidated to be the strong interactions between BBT and HNTs under melt shearing. The formation of the BBT fibrils leads to much higher crystallinity compared with previously reported PP nanocomposites. The nanocomposites with BBT show substantially increased tensile and flexural properties, which are attributed to the enhanced crystallinity of the nanocomposites. PMID- 21825753 TI - Nanodiamond particles forming photonic structures. AB - Colloid suspensions of irregularly shaped, highly charged detonation nanodiamond particles are found to have unexpected optical properties, similar to those of photonic crystals. This finding is all the more surprising since the particles used in this work are far more polydisperse than those typically forming photonic crystals. Intensely iridescent structures have been fabricated using the centrifugation of aqueous suspensions of nanodiamonds. PMID- 21825754 TI - Nanocrystalline silicon as the light emitting material of a field emission display device. AB - A nanocrystalline Si-based paste was successfully tested as the light emitting material in a field emission display test device that employed a film of carbon nanofibers as the electron source. Stable emission in the 550-850 nm range was obtained at 16 V um(-1). This relatively low field required for intense cathodoluminescence (CL) from the PSi paste may lead to longer term reliability of both the electron emitting and the light emitting materials, and to lower power consumption. Here we describe the synthesis, characterization, and analyses of the light emitting nanostructured Si paste and the electron emitting C nanofibers used for building the device, including x-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM), transmission electron microscopy (TEM), and Raman spectroscopy. The corresponding spectra and field emission curves are also shown and discussed. PMID- 21825755 TI - Electrical transport of bottom-up grown single-crystal Si(1-x)Ge(x) nanowire. AB - In this work, we fabricated an Si(1-x)Ge(x) nanowire (NW) metal-oxide semiconductor field-effect transistor (MOSFET) by using bottom-up grown single crystal Si(1-x)Ge(x) NWs integrated with HfO(2) gate dielectric, TaN/Ta gate electrode and Pd Schottky source/drain electrodes, and investigated the electrical transport properties of Si(1-x)Ge(x) NWs. It is found that both undoped and phosphorus-doped Si(1-x)Ge(x) NW MOSFETs exhibit p-MOS operation while enhanced performance of higher I(on)~100 nA and I(on)/I(off)~10(5) are achieved from phosphorus-doped Si(1-x)Ge(x) NWs, which can be attributed to the reduction of the effective Schottky barrier height (SBH). Further improvement in gate control with a subthreshold slope of 142 mV dec(-1) was obtained by reducing HfO(2) gate dielectric thickness. A comprehensive study on SBH between the Si(1 x)Ge(x) NW channel and Pd source/drain shows that a doped Si(1-x)Ge(x) NW has a lower effective SBH due to a thinner depletion width at the junction and the gate oxide thickness has negligible effect on effective SBH. PMID- 21825756 TI - An electron microscopy investigation of the structure of porous silicon by oxide replication. AB - The morphology of porous silicon is studied by scanning electron microscopy (SEM) by making an oxide replica of the pore structure. Highly branched n-type porous silicon samples were prepared and a replica was formed by oxidation of the pores followed by selective removal of the silicon substrate to expose the oxide pores. Scanning and transmission electron microscopy images confirmed many previously held assumptions about porous silicon formation, including the fractal structure and crystallographic propagation; they also provided a clearer understanding of the details of pore formation. The replica procedure also provides a platform for a more facile and comprehensive analysis of the porous silicon morphology. PMID- 21825757 TI - Equal intensity double plasmon resonance of bimetallic quasi-nanocomposites based on sandwich geometry. AB - We report a strategy to achieve a material showing equal intensity double plasmon resonance (EIDPR) based on sandwich geometry. We studied the interaction between localized plasmon resonances associated with different metal clusters (Au/Ag) on Teflon AF (TAF) in sandwich geometry. Engineering the EIDPR was done by tailoring the amount of Au/Ag and changing the TAF thickness. The samples were investigated by transmission electron microscopy (TEM) and UV-visible spectroscopy. Interestingly, and in agreement with the dipole-surface interaction, the critical barrier thickness for an optimum EIDPR was observed at 3.3 nm. The results clearly show a plasmon sequence effect and visualize the role of plasmon decay. PMID- 21825758 TI - The effect of residual stresses in the ZnO buffer layer on the density of a ZnO nanowire array. AB - Density control is a valuable concern in the research of ZnO nanowire arrays. In this study, unannealed and annealed ZnO thin films were used as substrates to fabricate ZnO nanowire arrays. In the unannealed thin film, an inhomogeneous distribution of the nanowire array was found: the density of nanowires decreases with the increase of distance to the edge. In the annealed thin film, the density of nanowire array becomes larger and more homogeneous. Moreover, nanowires are found in high density along microcracks. It is proposed that the residual stresses in the thin film and the density of the nanowire array are in inverse proportion, leading to the results mentioned above. The relationship between residual stresses and the density of nanowires will have potential applications in modifying the density of ZnO nanowire arrays. PMID- 21825759 TI - The fabrication of a flexible mold for high resolution soft ultraviolet nanoimprint lithography. AB - One key issue for all nanoimprint techniques is an appropriate method for the fabrication of desirable molds. We report on a novel flexible mold fabrication process-pressure-assisted molding (PAM)-for high resolution soft ultraviolet nanoimprint lithography (soft UV-NIL). In PAM, enhanced master filling is achieved by applying an external pressure during the mold fabrication process. Flexible molds, fabricated with PAM using different pressures in the range of 10 90 kPa, are compared to determine the role of pressures applied in the imprint performance. PMID- 21825760 TI - Growth behavior near the ultimate resolution of nanometer-scale focused electron beam-induced deposition. AB - An attempt has been made to reach the ultimate spatial resolution for electron beam-induced deposition (EBID) using W(CO)(6) as a precursor. The smallest dots that have been written have an average diameter of 0.72 nm at full width at half maximum (FWHM). A study of the nucleation stage revealed that the growth is different for each dot, despite identical growth conditions. The center of mass of each dot is not exactly on the position irradiated by the e-beam but on a random spot close to the irradiated spot. Also, the growth rate is not constant during deposition and the final deposited volume varies from dot to dot. The annular dark field signal was recorded during growth in the hope to find discrete steps in the signal which would be evidence of the one-by-one deposition of single molecules. Discrete steps were not observed, but by combining atomic force microscope measurements and a statistical analysis of the deposited volumes, it was possible to estimate the average volume of the units of which the deposits consist. It is concluded that the volume per unit is as small as 0.4 nm(3), less than twice the volume of a single W(CO)(6) molecule in the solid phase. PMID- 21825761 TI - The control of the growth orientations of electrodeposited single-crystal nanowire arrays: a case study for hexagonal CdS. AB - The controllable growth of highly aligned and ordered semiconductor nanowire arrays is crucial for their potential applications in nanodevices. In the present study, both the growth orientation and the microstructure of hexagonal CdS nanowire arrays electrodeposited in a porous alumina template with 40 nm diameter pores have been controlled by simply tuning the deposition current density. An extremely low current density of 0.05 mA cm(-2) is favorable for the growth of single-crystal CdS nanowires along the normal direction of the intrinsic low surface-energy (103) face. This can be understood well by a modified critical dimension model given in the present work. PMID- 21825762 TI - Ferroelectric hollow particles obtained by solid-state reaction. AB - Hollow particles of barium titanate were obtained by a two-step process combining colloidal chemistry and solid-state reaction. BaCO(3) crystals (size ~1 um) suspended in a peroxy-Ti(IV) aqueous solution were coated with an amorphous TiO(2) shell using a precipitation process. Calcination of the BaCO(3)@TiO(2) core-shell particles at 700 degrees C resulted in the formation of BaTiO(3) hollow particles (shell thickness of ~70 nm) which retain the morphology of the BaCO(3) crystals. Formation of the cavity occurs because out-diffusion of the core phase is much faster than in-diffusion of the shell material. X-ray diffraction (XRD) and Raman spectroscopy indicate that the hollow particles possess a tetragonal ferroelectric structure with axial ratio c/a = 1.005. Piezoresponse force microscopy has shown strong piezoactivity and 180 degrees ferroelectric domains. The process described provides a general route to fabricate hollow ferroelectric structures of several compounds. PMID- 21825763 TI - Mesosynthesis of ZnO-SiO(2) porous nanocomposites with low-defect ZnO nanometric domains. AB - Silica-based ZnO-MCM-41 mesoporous nanocomposites with high Zn content (5<=Si/Zn<=50) have been synthesized by a one-pot surfactant-assisted procedure from aqueous solution using a cationic surfactant (CTMABr = cetyltrimethylammonium bromide) as structure-directing agent, and starting from molecular atrane complexes as inorganic hydrolytic precursors. This preparative technique allows optimization of the dispersion of the ZnO nanodomains in the silica walls. The mesoporous nature of the final materials is confirmed by x-ray diffraction (XRD), transmission electron microscopy (TEM) and N(2) adsorption desorption isotherms. The ZnO-MCM-41 materials show unimodal pore size distributions without blocking of the pore system even for high Zn content. A careful optical spectroscopic study (using x-ray photoelectron spectroscopy (XPS), photoluminescence (PL) and UV-visible spectroscopy) of these materials shows that, irrespective of the Si/Zn ratio, the Zn atoms are organized in well dispersed, uniform low-defect ZnO nanodomains (radius about 1 nm) and are partially embedded within the silica walls. PMID- 21825764 TI - Fabrication of novel porous anodic alumina membranes by two-step hard anodization. AB - Porous anodic alumina (PAA) membranes with highly ordered hexagonal cells and a novel pore structure have been fabricated by two-step hard anodization in a H(2)SO(4)-Al(2)(SO(4))(3)-H(2)O system at 40 and 50 V, giving average cell diameters of 77 and 96 nm, respectively. There are several tiny pores embedded in each big shallow pore on the top of the membranes, and there is only one pore in one cell at their bottom. The cells on both sides of the membranes present almost the same periodic arrangement. In order to explore the formation of the novel pore structure, PAA membranes fabricated at different current densities (30-200 mA cm(-2)) are obtained by maintaining a constant voltage at 40 V. The experimental results show that the interpore distance is not only dependent on the anodization voltage, but is also influenced by the current density, which means that the pore structure of PAA membranes fabricated by hard anodization can be accurately designed and controlled by adjusting the anodization voltage and current density simultaneously. PMID- 21825765 TI - PbTiO(3) nanorod arrays grown by self-assembly of nanocrystals. AB - Arrays of ferroelectric lead titanate (PbTiO(3)) nanorods have been grown on a substrate by a novel template-free method. Hydrothermal treatment of an amorphous PbTiO(3) precursor in the presence of a surfactant and PbTiO(3) or SrTiO(3) substrates resulted in the growth of PbTiO(3) nanorod arrays aligned perpendicular to the substrate surface. Two steps in the growth mechanism were demonstrated: first an epitaxial layer was formed on the substrate; this was followed by self-assembly of nanocrystals forming a mesocrystal layer which matured into arrays of PbTiO(3) nanorods. PMID- 21825766 TI - Controllable synthesis of alpha- and beta-MnO(2): cationic effect on hydrothermal crystallization. AB - alpha- and beta-MnO(2) were controllably synthesized by hydrothermally treating amorphous MnO(2) obtained via a reaction between Mn(2+) and MnO(4)(-), and cationic effects on the hydrothermal crystallization of MnO(2) were investigated systematically. The crystallization is believed to proceed by a dissolution recrystallization mechanism; i.e. amorphous MnO(2) dissolves first under hydrothermal conditions, then condenses to recrystallize, and the polymorphs formed are significantly affected by added cations such as K(+), NH(4)(+) and H(+) in the hydrothermal systems. The experimental results showed that K(+)/NH(4)(+) were in competition with H(+) to form polymorphs of alpha- and beta MnO(2), i.e., higher relative K(+)/NH(4)(+) concentration favoured alpha-MnO(2), while higher relative H(+) concentration favoured beta-MnO(2). PMID- 21825767 TI - A simple route to synthesize size-controlled Ag(2)S core-shell nanocrystals, and their self-assembly. AB - Silver sulfide (Ag(2)S) nanocrystals were successfully synthesized by the thermal treatment of the single source precursors, silver dialkyldithiophosphates (Ag[S(2)P(OC(n)H(2n+1))(2)]), under mild reaction conditions. The size of Ag(2)S nanocrystals with regular shape can be controlled in the range of tens of nanometers by adjusting critical parameters, such as the carbon number of the substitute alkyl, the solvent and the reaction temperature. Electron diffraction and x-ray powder diffraction confirmed the orthorhombic phase of the Ag(2)S nanocrystals. The as-prepared Ag(2)S nanocrystals have an inorganic-organic core shell structure, in which Ag(2)S nanocrystals are the inorganic core and the organic modifiers, consisting of oleylamine and dialkyldithiophosphate, are the shell. The organic modifiers were anchored to the surface of Ag(2)S nanocores by their active groups of -NH(2) and -SPS- , respectively, and their direct-alkyl chains spread to the outside. So, these as-prepared Ag(2)S nanocrystals can self assemble to form orderly two-dimensional arrays easily, and they disperse in some non-polar solvents stably. PMID- 21825769 TI - Synphos modified Pt nanoclusters, their heterogenization by silica sol-gel entrapment, and catalytic activity in hydrogenolysis of bicyclo[2.2.2]oct-7-enes and hydrogenation of ethyl pyruvate. AB - Platinum (Pt) colloids modified by the chiral ligand synphos were prepared with the goal of obtaining a catalytic nanomaterial and were subsequently embedded in silica to form a heterogeneous catalyst. The systems were characterized by (31)P NMR, x-ray diffraction, molecular modeling and diffuse reflectance infrared Fourier transform spectroscopy (DRIFTs) measurements. These colloids, both as 'quasi-homogeneous catalysts' (or soluble heterogeneous catalysts) and embedded in silica (heterogeneous catalysts) were employed in the selective hydrogenolysis of highly sterically constrained bicyclo[2.2.2]oct-7-enes and hydrogenation of ethyl pyruvate. PMID- 21825768 TI - The effective modulus of super carbon nanotubes predicted by molecular structure mechanics. AB - A super carbon nanotube (ST) is a kind of hierarchical structure constructed from carbon nanotubes (named as CNT arm tubes). With the detailed construction of a Y junction considered, the effective mechanical properties of ST structures are studied by the molecular structure mechanics (MSM) method. The Young's modulus and shear modulus of STs are found to depend mainly on the aspect ratio of CNT arm tubes instead of the chirality of the ST. A scale law is adopted to express the relation between the effective modulus (Young's modulus or shear modulus) and the aspect ratio of the CNT arm tubes. The Poisson's ratio of the ST is affected by both the aspect ratio of the CNT arm tubes and the chirality of the ST. The deformation of the ST comes from both the bending and the stretching of the CNT arm tubes. The Y-junction acts as an reinforcement phase to make the bending and stretching couple together and induce large linearity in ST structures. PMID- 21825770 TI - Atomistic study of structures and elastic properties of single crystalline ZnO nanotubes. AB - The structural stability and Young's modulus of single crystalline ZnO nanotubes are investigated using atomistic simulations. Unlike the case for conventional layered nanotubes, the energetic stability of single crystalline ZnO nanotubes is related to the wall thickness. The potential energy of ZnO nanotubes with fixed outer and inner diameters decreases with increasing wall thickness, while the nanotubes with the same wall thickness are independent of the outer and inner diameters. The transformation of single crystalline ZnO nanotubes with a double layer from wurtzite phase to graphitic phase suggests the possibility of wall typed ZnO nanotubes. The size-dependent Young's modulus of ZnO nanotubes is also investigated. The wall thickness plays a significant role in the Young's modulus of single crystalline ZnO nanotubes, whereas the variation of outer and inner diameters slightly affects the Young's modulus of nanotubes with same wall thickness. PMID- 21825771 TI - Statistical analysis of the breaking processes of Ni nanowires. AB - We have performed a massive statistical analysis on the breaking behaviour of Ni nanowires using molecular dynamic simulations. Three stretching directions, five initial nanowire sizes and two temperatures have been studied. We have constructed minimum cross-section histograms and analysed for the first time the role played by monomers and dimers. The shape of such histograms and the absolute number of monomers and dimers strongly depend on the stretching direction and the initial size of the nanowire. In particular, the statistical behaviour of the breakage final stages of narrow nanowires strongly differs from the behaviour obtained for large nanowires. We have analysed the structure around monomers and dimers. Their most probable local configurations differ from those usually appearing in static electron transport calculations. Their non-local environments show disordered regions along the nanowire if the stretching direction is [100] or [110]. Additionally, we have found that, at room temperature, [100] and [110] stretching directions favour the appearance of non-crystalline staggered pentagonal structures. These pentagonal Ni nanowires are reported in this work for the first time. This set of results suggests that experimental Ni conducting histograms could show a strong dependence on the orientation and temperature. PMID- 21825772 TI - Thermochemical growth of Mn-doped CdS nanoparticles and study of luminescence evolution. AB - We report a new method of growing Mn-doped CdS (CdS:Mn) nanoparticles in an aqueous solution at boiling temperature. The idea is to use precursors that react only at high temperature, in order to gain crystalline luminescent nanoparticles. CdSO(4), Mn(NO(3))(2) and Na(2)S(2)O(3) were used as the precursors, and thioglycerol was employed as the capping agent and also the reaction catalyst. Na(2)S(2)O(3) is thermally sensitive and it releases S(2-) ions upon heating. The CdS:Mn nanoparticles obtained are about 4 nm in size and show both cubic and hexagonal crystalline phases with a ratio of 35% to 65%. The luminescence of nanoparticles contains a peak at 580 nm, which is related to Mn(2+) ions. Prolonged reaction time results in a decrease of the Mn luminescence peak to about 35% of the maximum value. We discuss the possible causes of the Mn peak reduction and attribute it to preferential dissolution of Mn ions into the solution due to shape reconfiguration of the nanoparticles. PMID- 21825773 TI - Stable field emission performance of SiC-nanowire-based cathodes. AB - In this paper we report the fabrication and testing of diode-type low-voltage field emission display (FED) devices with SiC-nanowire-based cathodes. The SiC nanowire FEDs (flat vacuum lamps) were characterized by low emission threshold fields (~2 V um(-1)), high current density and stable long-term performance. The analysis of field emission data evidenced that the Schottky effect would have a considerable influence on the field emission from nanowire-based samples, leading to the true values of the field enhancement factor being significantly lower than those derived from Fowler-Nordheim plots. PMID- 21825774 TI - C(60) reduces the flammability of polypropylene nanocomposites by in situ forming a gelled-ball network. AB - The thermal and flame retardancy properties of polypropylene/fullerene (PP/C(60)) nanocomposites were investigated by thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and cone calorimetry with the C(60) loading varied from 0.5 to 2% by weight. Dispersion of C(60) in the PP matrix was characterized by transmission electron microscopy (TEM) and optical microscopy (OM). TGA and DSC results showed that the presence of C(60) could remarkably enhance the thermal property and cone calorimeter measurements suggested that C(60) could to some extent reduce the flammability of PP, with a significant reduction in peak heat release rate and a much longer time to ignition. Furthermore, the larger the loading level of C(60), the better the flame retardancy property of PP/C(60) nanocomposites. The flame retardation mechanism and corresponding model were proposed with the help of rheological measurements, TEM and x-ray diffraction. C(60) reduced the flammability of PP by trapping free radicals in the gas phase and in situ forming a gelled-ball crosslink network to improve the flame retardancy of PP in the condensed phase. Finally, this suggested mechanism was supported by the results of advanced rheological extended systems (ARES), gel content, infrared spectrum, OM, and atomic force microscopy (AFM) measurements. PMID- 21825775 TI - Molecular-beam epitaxy-grown Si whisker structures: morphological, optical and electrical properties. AB - Scanning electron microscopy, spectroscopic ellipsometry, and current-voltage and current-temperature measurements were employed to characterize nanowhisker structures grown by molecular-beam epitaxy on Si(111) substrates. Small clusters of gold deposited on the Si surface were used as the seeds for nanowhisker growth. The diameter of grown nanowhiskers and their length ranged from 70 to 200 nm and from 580 to 890 nm, respectively. The whiskers were found to inherit the (111) orientation of the Si substrate. By means of spectroscopic ellipsometry in the range 1.5-4.77 eV, lateral optical inhomogeneity of the nanowhisker layer was revealed, with optical properties of the layer substantially differing from those of single-crystal Si. Electrical measurements point to the presence of a Schottky barrier with height 0.70 eV in the structure and to the presence of electrically active centers non-uniformly distributed over the nanowhisker length. PMID- 21825776 TI - Super-low friction and super-elastic hydrogenated carbon films originated from a unique fullerene-like nanostructure. AB - Hydrogenated carbon films were grown by a plasma-enhanced chemical vapor deposition (PECVD) technique using CH(4) and H(2) as feedstock at ambient temperature. The microstructure of the films was characterized by high resolution transmission electron microscopy (HRTEM). The images showed the presence of curved basal planes in fullerene-like arrangements. An apparent amorphous graphene structure with nm-sized packages of basal planes in a turbostratic feature was observed. The fabricated fullerene-like hydrogenated carbon films (FL C:H) possess superior mechanical properties, i.e. high hardness (19 GPa) and high elasticity (elastic recovery of 85%). More importantly, the films exhibit ultra low friction (MU = 0.009) under ambient conditions with 20% relative humidity. PMID- 21825777 TI - Application of photostable quantum dots for indirect immunofluorescent detection of specific bacterial serotypes on small marine animals. AB - An indirect immunofluorescence approach was developed using semiconductor quantum dot nanocrystals to label and detect a specific bacterial serotype of the bacterial human pathogen Vibrio parahaemolyticus, attached to small marine animals (i.e. benthic harpacticoid copepods), which are suspected pathogen carriers. This photostable labeling method using nanotechnology will potentially allow specific serotypes of other bacterial pathogens to be detected with high sensitivity in a range of systems, and can be easily applied for sensitive detection to other Vibrio species such as Vibrio cholerae. PMID- 21825778 TI - Fluorescent nanoscale detection of biotin-streptavidin interaction using near field scanning optical microscopy. AB - We describe a nanoscale strategy for detecting biotin-streptavidin binding using near-field scanning optical microscopy (NSOM) that exploits the fluorescence properties of single polydiacetylene (PDA) liposomes. NSOM is more useful to observe nanomaterials having optical properties with the help of topological information. We synthesized amine-terminated 10,12-pentacosadiynoic acid (PCDA) monomer (PCDA-NH(2)) and used this derivatized monomer to prepare PCDA liposomes. PCDA-NH(2) liposomes were immobilized on an aldehyde-functionalized glass surface followed by photopolymerization by using a 254 nm light source. To measure the biotin-streptavidin binding, we conjugated photoactivatable biotin to immobilized PCDA-NH(2) liposomes by UV irradiation (365 nm) and subsequently allowed them to interact with streptavidin. We analyzed the fluorescence using a fluorescence scanner and observed single liposomes using NSOM. The average height and NSOM signal observed in a single liposome after binding were ~31.3 to 8.5 +/- 0.5 nm and 0.37 to 0.16 +/- 0.6 kHz, respectively. This approach, which has the advantage of not requiring a fluorescent label, could prove highly beneficial for single molecule detection technology. PMID- 21825779 TI - Can silver nanoparticles be useful as potential biological labels? AB - Silver (Ag) nanoparticles have unique plasmon-resonant optical scattering properties that are finding use in nanomedical applications such as signal enhancers, optical sensors, and biomarkers. In this study, we examined the chemical and biological properties of Ag nanoparticles of similar sizes, but that differed primarily in their surface chemistry (hydrocarbon versus polysaccharide), in neuroblastoma cells for their potential use as biological labels. We observed strong optical labeling of the cells in a high illumination light microscopy system after 24 h of incubation due to the excitation of plasmon resonance by both types of Ag nanoparticle. Surface binding of both types of Ag nanoparticle to the plasma membrane of the cells was verified with scanning electron microscopy as well as the internalization and localization of the Ag nanoparticles into intracellular vacuoles in thin cell sections with transmission electron microscopy. However, the induction of reactive oxygen species (ROS), degradation of mitochondrial membrane integrity, disruption of the actin cytoskeleton, and reduction in proliferation after stimulation with nerve growth factor were found after incubation with Ag nanoparticles at concentrations of 25 ug ml(-1) or greater, with a more pronounced effect produced by the hydrocarbon based Ag nanoparticles in most cases. Therefore, the use of Ag nanoparticles as potential biological labels, even if the surface is chemically modified with a biocompatible material, should be approached with caution. PMID- 21825780 TI - Quantum dot-labeled aptamer nanoprobes specifically targeting glioma cells. AB - Two new techniques, aptamer-based specific recognition and quantum dot (QD)-based fluorescence labeling, are becoming increasingly important in biosensing. In this study, these two techniques have been coupled together to construct a new kind of fluorescent QD-labeled aptamer (QD-Apt) nanoprobe by conjugating GBI-10 aptamer to the QD surface. GBI-10 is a single-stranded DNA (ssDNA) aptamer for tenascin C, which distributes on the surface of glioma cells as a dominant extracellular matrix protein. The QD-Apt nanoprobe can recognize the tenascin-C on the human glioma cell surface, which will be helpful for the development of new convenient and sensitive in vitro diagnostic assays for glioma. The QD-Apt nanoprobe has particular features such as strong fluorescence, stability, monodispersity and uniformity. In addition, this probe preparation method is universal, so it is expected to provide a new type of stable nanoprobe for high-throughput and fast biosensing detection and bioimaging. New methods for real-time and dynamic tracking and imaging can be accordingly developed. PMID- 21825781 TI - Biomolecule detection using a silicon nanoribbon: accumulation mode versus inversion mode. AB - Silicon nanoribbons were fabricated using standard optical lithography from silicon on insulator material with top silicon layer thicknesses of 100, 60 and 45 nm. Electrically these work as Schottky-barrier field-effect transistors and, depending on the substrate voltage, electron or hole injection is possible. The current through the nanoribbon is extremely sensitive to charge changes at the oxidized top surface and can be used for biomolecule detection in a liquid. We show that for detection of streptavidin molecules the response is larger in the accumulation mode than in the inversion mode, although not leading to higher detection sensitivity due to increased noise. The effect is attributed to the location in depth of the conducting channel, which for holes is closer to the screened surface charges of the biomolecules. Furthermore, the response increases for decreasing silicon thickness in both the accumulation mode and the inversion mode. The results are verified qualitatively and quantitatively through a two dimensional simulation model on a cross section along the nanoribbon device. PMID- 21825783 TI - Enhanced 400-600 nm photoresponsivity of metal-oxide-semiconductor diodes with multi-stack germanium quantum dots. AB - Metal-oxide-semiconductor (MOS) diodes with zero-, one- or three-layer Ge quantum dots (QDs) embedded in the gate oxide are fabricated for visible to near ultraviolet photodetection. Ge dots are formed by thermally oxidizing one or three stacks of amorphous Si (a-Si)/polycrystalline-Si(0.87)Ge(0.13)/a-Si multi layers that are sandwiched by SiO(2) barriers. The current-voltage characteristics of Ge QD MOS diodes exhibit strong rectification in darkness and feature significant current enhancement in the inversion mode when illuminated. Increasing the number of Ge QD layers from zero through one to three in the gate oxide improves the responsivity from 4.64 through 482 to 812 mA W(-1) and enhances the corresponding quantum efficiency from 1.42 through 148 to 245%, respectively. The spectral response reveals a considerable blueshift in peak energies as the Ge dot size decreases from 9.1 to 5.1 nm, suggesting that the light absorption originates from the quantum confinement effect of Ge QDs. The temperature and bias dependences of the dark current indicate that the carrier transport mechanism involves percolation hopping. PMID- 21825782 TI - Discretely tunable single-mode lasers on GaSb using two-dimensional photonic crystal intracavity mirrors. AB - We report on single-mode emitting coupled cavity ridge waveguide lasers on the GaSb material system in the 2 um spectral range using two-dimensional (2D) photonic crystals (PhCs). Eight rows of 2D PhCs lateral to the ridge waveguides act as intermediate mirrors and are used to create two coupled cavities. This leads to preferential emission at one single longitudinal mode in the emission spectrum with side mode suppression ratios of 30-35 dB. Monolithic integration of high reflectivity 2D PhC back mirrors allows the realization of cavity lengths as short as 300 um with threshold currents as low as 18.5 mA while reaching output powers well above 18 mW. Under variation of driving current the lasers exhibit both discrete and continuous tuning behavior over a wide current range very well explicable by simulation of the sub-threshold spectra, rendering the devices especially interesting for multi-gas sensing by absorption spectroscopy. PMID- 21825784 TI - Fabrication of 20 nm half-pitch gratings by corrugation-directed self-assembly. AB - The evolution of the scaling of modern semiconductor devices is governed by the ability to create scalable high-resolution patterns on substrates. Since it is becoming increasingly difficult and expensive to extend to smaller dimensions using optical lithography, there is a great deal of interest in alternative patterning methods. The self-assembly of block copolymers in thin films, which provides periodic patterns of 10-50 nm length scales, has been recognized as a promising candidate for such patterning. To be practical, however, this approach must provide control over the orientation and lateral placement of the microdomains. We report here our discovery of the controlled alignment of the lamellar microdomains of a block copolymer containing hybrid material using topographic pre-patterns on substrates. We find that this hybrid material forms lamellae with a half-pitch of approximately 20 nm perpendicular to the lines of a surface corrugation. PMID- 21825785 TI - Spontaneous formation of highly ordered nanostructures: thermal instability and mode selection in surface-capped polymer films. AB - We demonstrate a controllable formation process of wave-like patterns in thermally unstable surface-capped polymer films on a rigid substrate. Self ordered wave-like structures over a large area can be created by applying a small lateral tension to the film, whereupon it becomes unstable. A clear mode selection process which includes creation, decay and interference between coexisting waves at different annealing conditions has been observed, which makes it possible to restrain the patterns which are formed finally. Our results provide a clear and new evidence of spinodal behaviour in such a film due to thermal instability. Furthermore, we show that the well-controlled patterns generated in such a process can be used to fabricate nanostructures for various applications. PMID- 21825786 TI - Thermochemical hole burning performance of TCNQ-based charge transfer complexes with different electrical conductivities. AB - Thermochemical hole burning (THB) memory is an ultrahigh density data storage technique based on the scanning tunneling microscope (STM). It utilizes the STM current to induce localized thermochemical decomposition of TCNQ-based charge transfer (CT) complexes and sequentially create nanometer-sized holes as information bits. The writing reliability and hole size depend on many factors, including the properties of the storage materials and the STM tip, and the tip sample distance and interaction. We have found here that for the high electrical conductivity CT complexes, the hole size (represented by volume) monotonically decreases with the tip displacement increasing in the direction of leaving the sample; but for low electrical conductivity samples, the hole size first increases and then decreases with the tip displacement increasing in the same direction. Subsequent experiments and analyses indicate that the surface deformation induced by the tip-sample interaction and the heat conduction of the metal tip account for such a unique phenomenon. PMID- 21825787 TI - Controlled fabrication of nanopores using a direct focused ion beam approach with back face particle detection. AB - We report a direct, ion drilling technique that enables the reproducible fabrication and placement of nanopores in membranes of different thickness. Using a 30 keV focused Ga ion beam column combined with an in situ, back face, multi channelplate particle detector, nanopores are sputtered in Si(3)N(4) and W/Si(3)N(4) to have diameters as small as 12 nm. Transmission electron microscopy shows that focused ion beam-drilled holes are near-conical with the diameter decreasing from entry to exit side. By monitoring the detector signal during ion exposure, the drilled hole width can be minimized such that the exit-side diameter is smaller than the full width at half-maximum of the nominally Gaussian shaped incident beam. Judicious choice of the beam defining aperture combined with back face particle detection allows for reproducible exit-side hole diameters between 18 and 100 nm. The nanopore direct drilling technique does not require potentially damaging broad area exposure to tailor hole sizes. Moreover, this technique successfully achieves breakthrough despite the effects of varying membrane thickness, redeposition, polycrystalline grain structure, and slight ion beam current fluctuations. PMID- 21825788 TI - Ion beam nanopatterning in graphite: characterization of single extended defects. AB - The morphology and the electronic structure of a single focused ion-beam-induced artificial extended defect is probed by several methods including micro-Raman spectroscopy, atomic force and scanning tunneling microscopies and Monte Carlo and/or semi-analytical simulation within standard codes. The efficiency of the artificial defect for deposited metallic cluster pinning is also investigated. We show a correlation between the ion dose, morphology, electronic structure and cluster trapping efficiency. At room temperature, cluster pinning is efficient when the displacement per atom is one or more. Well-ordered patterned cluster networks are considered for potential applications. PMID- 21825789 TI - The high contrast ratio and fast response time of a liquid crystal display lit by a carbon nanotube field emission backlight unit. AB - We report on the fabrication of a carbon nanotube field emission backlight unit (CNT-BLU) and its application for liquid crystal displays (LCD). The CNT-BLU was operated with locally controllable luminance and impulse-type scanning. The local luminance control, which is based on a very small block size of 1 cm(2), consisted of local dimming and local brightening. This resulted in the contrast ratio of the LCD-TV to be as high as 300 000:1. A fast response time of ~5.7 ms was also achieved from the LCD-TV lit by CNT-BLU, originating from the impulse type scanning. In addition, the CNT-BLU showed long-term emission stability and high luminance uniformity. PMID- 21825790 TI - Built-in surface electric field, piezoelectricity and photoelastic effect in GaN nanorods for nanophotonic devices. AB - Novel behaviors arising from the coupling between the built-in surface electric field, piezoelectricity, electron-hole pairs and external light beam were observed in GaN nanorods. An increase in the optical excitation density resulted in a blueshift in the photoluminescence spectra and a redshift in the frequency of the GaN A(1)(LO) phonon. The underlying mechanism was attributed to the screening of the built-in surface electric field by photoexcited carriers and, through the converse piezoelectric effect, a reduction in the internal strain. The existence of the built-in surface electric field in GaN nanorods was confirmed by scanning Kelvin probe microscopy. Our results firmly establish the existence of the photoelastic effect in GaN nanorods. In addition to underpinning the principle for applications in nanophotonic devices, this discovery also draws attention to the novel effects arising from the inherent large surface-to-volume ratio of nanostructures, which is possibly applicable to many other nanomaterials. PMID- 21825791 TI - Quantum model of space-charge-limited field emission in a nanogap. AB - This paper presents a modified Thomas-Fermi-approximated quantum model for space charge-limited field emission in a nanogap with metal electrodes, where the image charge potential (including anode screening), direct tunnelling, space-charge effects and exchange-correlation effects of the tunnelling current are treated in a one-dimensional quantum model. It is found that the traditional Fowler-Nordheim (FN) law (even with the classical model of anode screening) is no longer valid in a nanogap of less than 10 nm. The smooth transition of our proposed model to the traditional FN law extended to large gap spacing is demonstrated. Application of the model to estimate the emission area of an experimental I-V curve in a nanogap is discussed. PMID- 21825792 TI - Size-dependent magneto-optical effects in CdMnTe diluted magnetic quantum dots. AB - We report on the growth and high spatial resolution magneto-photoluminescence of CdMnTe quantum dots embedded in a ZnCdTe matrix with Mn content of about 3%. The giant Zeeman spitting of excitonic emission coming from individual quantum dots and magnetization fluctuations inside them are studied in magnetic fields up to 7 T. We have found that the description of these effects requires the inclusion of antiferromagnetic Mn-Mn interaction in the considerations. Moreover, the values of the Zeeman shift are strongly related to the size of the dot. In particular, the higher spectral position of the line is, i.e., the smaller the dot, the smaller the Zeeman splitting that is observed. This effect is quantitatively explained with model calculations made under the assumption of magnetic polaron formation in diluted magnetic quantum dots and the presence of ion-ion exchange interaction. PMID- 21825793 TI - Spin transfer torques in the nonlocal lateral spin valve. AB - We report a theoretical study on the spin and electron transport in the nonlocal lateral spin valve with a non-collinear magnetic configuration. The nonlocal magnetoresistance, defined as the voltage difference on the detection lead over the injected current, is derived analytically. The spin transfer torques on the detection lead are calculated. It is found that spin transfer torques are symmetrical for parallel and antiparallel magnetic configurations, in contrast to that in a conventional sandwiched spin valve. PMID- 21825794 TI - Coupling effects of refractive index discontinuity, spot size and spot location on the deflection sensitivity of optical-lever based atomic force microscopy. AB - Atomic force microscopy (AFM) plays an essential role in nanotechnology and nanoscience. The recent advances of AFM in bionanotechnology include phase imaging of living cells and detection of biomolecular interactions in liquid biological environments. Deflection sensitivity is a key factor in both imaging and force measurement, which is significantly affected by the coupling effects of the refractive index discontinuity between air, the glass window and the liquid medium, and the laser spot size and spot location. The effects of both the spot size and the spot location on the sensitivity are amplified by the refractive index discontinuity. The coupling effects may govern a transition of the deflection sensitivity from enhancement to degradation. It is also found that there is a critical value for the laser spot size, above which the deflection sensitivity is mainly determined by the refractive index of the liquid. Experimental results, in agreement with theoretical predication, elucidate the coupling effects. PMID- 21825795 TI - Label-free ultra-sensitive detection of atrazine based on nanomechanics. AB - The alarming increase in the amount of dangerous pesticides such as atrazine in agricultural fields and drinking water is driving the growth of new technologies to detect these toxins well below their threat level. The recent elucidation of microcantilever nanomechanical bending in response to chemical and biomolecular interactions has added another significant facet to biochemical engineering research and has fostered the development of a variety of signal detection paradigms, at both the microscale and the nanoscale. We report the label-free detection of highly specific atrazine antibody-antigen interactions at the nanometer scale on microcantilevers, with 1 ppt (past per trillion) sensitivity. The chemical interaction-induced deflection of the cantilever beam reflects the interplay between the strain energy increase of the cantilever and the free energy reduction of the reaction, providing a unique system for investigating the connection between the nanomechanics and the chemistry of antibody-antigen interaction at picomolar concentration with nanometer resolution. Cantilevers were functionalized with highly specific and site-directed anti-atrazine antibodies and exposed to target antigen over a wide range of concentration from 4.65 pM to 46.5 uM of varying sequence in static and flow conditions. Antibody antigen interaction of atrazine with the specific antibody resulted in net negative deflection of the cantilever. The results show that high specificity and site-directed antibody immobilization lead to ultra-high sensitivity detection of atrazine. The measurements provide results within minutes at the picomolar level, and exhibit high target specificity. This qualifies the technology as a rapid method to validate organic toxins and its progression. PMID- 21825796 TI - Controlled growth of vertically aligned ZnO nanowires with different crystal orientation of the ZnO seed layer. AB - A novel synthesis and growth method achieving vertically aligned zinc oxide (ZnO) nanowires on a silicon dioxide (SiO(2)) coated silicon (Si) substrate is demonstrated. The growth direction of the ZnO nanowires is determined by the crystal structure of the ZnO seed layer, which is formed by the oxidation of a DC sputtered Zn film. The [002] crystal direction of the seed layer is dominant under optimized thickness of the Zn film and thermal treatment. Vertically aligned ZnO nanowires on SiO(2) coated Si substrate are realized from the appropriately thick oxidized Zn seed layer by a vapor-solid growth mechanism by catalyst-free thermal chemical vapor deposition (CVD). These experimental results raise the possibility of using the nanowires as functional blocks for high density integration systems and/or photonic applications. PMID- 21825797 TI - Dye-sensitized solar cells based on thick highly ordered TiO(2) nanotubes produced by controlled anodic oxidation in non-aqueous electrolytic media. AB - Dye-sensitized solar cells (DSSCs) were prepared using TiO(2) nanotubes, grown by controlled Ti anodic oxidation in non-aqueous media. Smooth, vertically oriented TiO(2) nanotube arrays, presenting a high degree of self-organization and a length of 20 um, have been grown using ethylene glycol electrolyte containing HF. As-grown nanotubes exhibit an amorphous structure, which transforms to the anatase TiO(2) crystalline phase upon post-annealing in air at 450 degrees C. Atomic force microscopy (AFM) revealed the porous morphology together with high roughness and fractality of the surface. The annealed tubes were sensitized by the standard N719 ruthenium dye and the adsorption was characterized using resonance micro-Raman spectroscopy and adsorption-desorption measurements. The sensitized tubes were further used as active photoelectrodes after incorporation in sandwich-type DSSCs using both liquid and solidified electrolytes. The efficiencies obtained under air mass (AM) 1.5 conditions, using a back-side illumination geometry, were very promising: 0.85% using a composite polymer redox electrolyte, while the efficiency was further increased up to 1.65% using a liquid electrolyte. PMID- 21825798 TI - Synthesis of highly stable dihydrolipoic acid capped water-soluble CdTe nanocrystals. AB - To prevent the dissociation of organic ligands from the inorganic core and accordingly enhance colloidal stability, is the prerequisite for the further application of nanocrystals in different areas. Dihydrolipoic acid (DHLA) appears very promising for the stabilization and the further functionalization of CdTe nanocrystals because DHLA is characterized by a carboxylic acid group and two thiol functions, through which simultaneous anchorage onto a nanoparticle's surface is possible. For the first time, we synthesized highly luminescent CdTe nanocrystals (maximum quantum yield of 42%) in aqueous solution by the reaction of Cd(2+) and NaHTe using DHLA as capping reagent. The influence of various experimental variables, including reaction temperature, ligand-to-Cd ratio and pH value as well as Te-to-Cd ratio, on the growth rate and optical properties of the obtained CdTe nanocrystals have been systematically investigated. Furthermore, the stability of the dithiol DHLA capped CdTe nanocrystals was compared with the monothiol ligands thioglycolicacid (TGA) and mercaptopropionic acid (MPA) capped nanocrystals. Experimental results indicate that the DHLA capped nanoparticles show better chemical and thermal stability than those capped by TGA or MPA. The mechanism for the high-quality optical properties and the good stability of the resulting CdTe nanocrystals is also primarily elucidated. PMID- 21825799 TI - Pulsed laser dewetting of nickel catalyst for carbon nanofiber growth. AB - We present a pulsed laser dewetting technique that produces single nickel catalyst particles from lithographically patterned disks for subsequent carbon nanofiber growth through plasma enhanced chemical vapor deposition. Unlike the case for standard heat treated Ni catalyst disks, for which multiple nickel particles and consequently multiple carbon nanofibers (CNFs) are observed, single vertically aligned CNFs could be obtained from the laser dewetted catalyst. Different laser dewetting parameters were tested in this study, such as the laser energy density and the laser processing time measured by the total number of laser pulses. Various nickel disk radii and thicknesses were attempted and the resultant number of carbon nanofibers was found to be a function of the initial disk dimension and the number of laser pulses. PMID- 21825800 TI - Mapping the elastic properties of granular Au films by contact resonance atomic force microscopy. AB - Endowed with nanoscale spatial resolution, contact resonance atomic force microscopy (CR-AFM) provides extremely localized elastic property measurements. We advance here the applicability of CR-AFM on surfaces with nanosize features by considering the topography contribution to the CR-AFM signal. On nanosize granular Au films, the elastic modulus at the grain scale has been mapped out by considering a self-consistent deconvolution of the contact geometry effect in the CR-AFM image. Significant variation in the contact area over granular topography arises as the probe is either in single- or multiple-asperity contact with the surface. Consequently, in extracting the elastic modulus from CR-AFM measurements on granular surfaces we considered both the normal and lateral couplings established through multiple-asperity contacts between the tip and the surface. Thus, by appropriately considering the change in the contact mechanics during CR AFM imaging, variations in the elastic modulus have been revealed in the intergrain regions as well as across individual grains. PMID- 21825801 TI - Theoretical modelling of tip effects in the pushing manipulation of C(60) on the Si(001) surface. AB - We present the results of our theoretical studies on the repulsive (pushing) manipulation of a C(60) molecule on the Si(001) surface with several scanning tunnelling microscopy tips. We show that, for silicon tips, tip-C(60) bonds are formed even with tips that do not initially have dangling bonds, and this tip C(60) interaction drives the manipulation of the molecule. The details of the atomic structure of the tip and its position relative to the molecule do not have a significant effect on the mechanism and the sequence of adsorption configurations during the pushing manipulation of C(60) along the trough, where the trough itself provides a guiding effect. The pushing manipulation is thus a very robust process that occurs largely independently of the tip structure. On the other hand, the pushing manipulation across an Si-Si dimer row into the neighbouring trough proceeds in a more complex way, with tip deformation and detachment more likely to occur. We demonstrate the role of tip deformation and tip-molecule bond rearrangement in the continuous manipulation of the molecule. Finally, we calculate and analyse the forces acting on the tip during manipulation and identify characteristic patterns. PMID- 21825802 TI - Evolution of texture and atomic order in annealed sinter-free FePt nanoparticles. AB - Monodisperse FePt nanoparticles have been synthesized chemically. The spherically shaped as-made nanoparticles were 6.0 nm in size and they were single crystals. The average composition of these particles is determined as Fe(50)Pt(50). The nanoparticles did not show any sign of sintering after annealing at 800 degrees C for up to 120 min. The texture and order parameters of as-made and annealed FePt nanoparticles were determined from azimuthally integrated selected area electron diffraction patterns. The close to perfect [Formula: see text] axial texture in as-made particles degraded with increasing annealing time, in contrast to the order parameter, which showed a monotonic dependence on annealing time. With 60 min annealing, a 0.8 degree of chemical ordering has been achieved and the particles were sinter-free as observed from bright field images. PMID- 21825803 TI - Ultrasharp and high aspect ratio carbon nanotube atomic force microscopy probes for enhanced surface potential imaging. AB - The resolution of scanning surface potential microscopy (SSPM) is mainly limited by non-local electrostatic interactions due to the finite probe size. Here we present high resolution surface potential imaging with ultrasharp and high aspect ratio carbon nanotube (CNT) atomic force microscopy (AFM) probes fabricated via dielectrophoresis. Enhancement of surface potential contrast by several factors is reported for integrated circuit structures and purple membrane fragments for these CNT AFM probes as compared to conventional probes. In particular, ultrahigh lateral resolution (~2 nm) surface potential images of self-assembled bacteriorhodopsin proteins are reported at ambient conditions, with the implication of label-free protein detection by SSPM techniques. PMID- 21825804 TI - Silicon quantum dot/crystalline silicon solar cells. AB - Silicon (Si) quantum dot (QD) materials have been proposed for 'all-silicon' tandem solar cells. In this study, solar cells consisting of phosphorus-doped Si QDs in a SiO(2) matrix deposited on p-type crystalline Si substrates (c-Si) were fabricated. The Si QDs were formed by alternate deposition of SiO(2) and silicon rich SiO(x) with magnetron co-sputtering, followed by high-temperature annealing. Current tunnelling through the QD layer was observed from the solar cells with a dot spacing of 2 nm or less. To get the required current densities through the devices, the dot spacing in the SiO(2) matrix had to be 2 nm or less. The open circuit voltage was found to increase proportionally with reductions in QD size, which may relate to a bandgap widening effect in Si QDs or an improved heterojunction field allowing a greater split of the Fermi levels in the Si substrate. Successful fabrication of (n-type) Si QD/(p-type) c-Si photovoltaic devices is an encouraging step towards the realization of all-silicon tandem solar cells based on Si QD materials. PMID- 21825805 TI - End-functional silicone coupling agent modified PEO/P(VDF-HFP)/SiO(2) nanocomposite polymer electrolyte DSSC. AB - The end-functional silicone coupling agent (dodecyl-trimethoxysilane, DTMS for short) was used to modify the PEO/P(VDF-HFP)/SiO(2) nanocomposite polymer electrolyte (CPE) and the different amounts of DTMS modification effects were studied. The experiments showed the silicone coupling agent with hydrophobic alkyl chains (-C(12)H(25)) chemically engineered on the SiO(2) nanoparticles, and formed a Si-O-Si cross-linked network in the new nanocomposite polymer electrolyte. Proper content of DTMS modified CPE exhibited improved ionic conductivity and the connection with the photoanode and counter electrode. However, much higher content of the DTMS modification changed the conformation of the polymer network and reduced the ionic movement. Compared with the performance (3.84%) of the original DSSC, the DSSC with functional silicone coupling agent modified CPE (DTMS:SiO(2) = 2:1, mol ratio) exhibited improved J(sc) (7.94 mA cm( 2)), V(oc) (0.624 V) and optimal efficiency (5.2%) (measured at AM1.5, light intensity of 58.4 mW cm(-2)). The V(oc) of the silicone coupling agent modified polymer electrolyte DSSC is obviously improved, which is mainly due to that the hydrophobic alkyl chain end groups formed an insulating layer that retarded the electron recombination at the TiO(2) nanoporous photoanode/polymer electrolyte interface. The DTMS:SiO(2) = 2:1 modified CPE type DSSC exhibited a performance of 6.42% at a light intensity of 32.1 mW cm(-2) and 4.94% at 99.2 mW cm(-2). PMID- 21825806 TI - Electrophoretic deposition of ZnO nanoparticles, from micropatterns to substrate coverage. AB - We report on an electrophoretic deposition (EPD) method that is suited for the preparation of both ZnO thin films and micropatterns. By applying small DC voltages between a Cu electrode and a conductive Si substrate, submersed in a suspension of ZnO quantum dots, we can cover entire substrates with ZnO layers of a tuneable thickness ranging from a few monolayers to 200 nm. The deposition occurs selectively at the cathode, which indicates that the ZnO particles have a positive charge. Atomic force microscopy was used to study the influence of the deposition voltage, time, and the quantum dot concentration on the final layer thickness. By using lithographically patterned Si substrates, the same technique enables the formation of ZnO micropatterns of variable thickness with dimensions down to 5 um. This is done by depositing a ZnO layer on a Si substrate that is covered with a patterned, developed photoresist. After EPD, the resist is removed by submersing the substrate in the appropriate solvent without damaging the ZnO deposit. This illustrates the robustness of the layers obtained by EPD. PMID- 21825807 TI - A novel tip-induced local electrical decomposition method for thin GeO films nanostructuring. AB - Decomposition of germanium monoxide (GeO) films under the impact of an atomic force microscope (AFM) tip was observed for the first time. It is known that GeO is metastable in the solid phase and decomposes into Ge and GeO(2) under thermal annealing or radiation impact. AFM tip treatments allow us to carry out local decomposition. A novel tip-induced local electrical decomposition (TILED) method of metastable GeO films has been developed. Using TILED of 10 nm thin GeO film, Ge nanowires on silicon substrates were obtained. PMID- 21825808 TI - Fabrication and photoluminescence of hyperbranched silicon nanowire networks on silicon substrates by laser-induced forward transfer. AB - The structure and photoluminescent properties of films obtained by modified laser induced forward transfer of silicon are presented. Strong variations in structure with ambient gas composition are observed: in Ar, porous films of mutually agglomerated silicon nanoparticles are observed, while in air the films consist of a network of hyperbranched nanowires (SiHBNWs) whose diameter varies periodically along their length, and which are composed of crystalline silicon nanoparticles surrounded and interconnected by amorphous silicon oxide of varying stoichiometry. The mechanisms of formation of the structures are dwelt upon and explained in term of dynamics within the plume. For the SiHBNWs, the pioneering use of fluorescence imaging was employed to obtain evidence for the photoluminescence originating from the crystalline nanoparticles themselves, and origins of the emission bands are thus attributed to radiative recombination of excitons at the Si/SiO(2) interface accordingly. PMID- 21825809 TI - Transformation of InAs islands to quantum ring structures by metalorganic vapor phase epitaxy. AB - The transformation of InAs islands to quantum rings (QRs) by metalorganic vapor phase epitaxy is investigated. After covering the InAs islands with a thin GaAs partial capping layer and annealing under tertiarybutylarsine (TBAs) flow, ring shaped nanostructures with a density of 10(7)-10(9) cm(-2) are obtained at 500 600 degrees C. The effects of the growth temperature, annealing process and thickness of the partial capping layer are studied. Optimum values for the annealing time and the partial capping layer thickness were found to be 60-120 s and 0.5-2.0 nm, respectively. Low temperature photoluminescence (PL) emission peaks from islands and QRs grown at 500 degrees C are observed at 1.04 eV and 1.22 eV, respectively. The annealing temperature affected the QR evolution and the PL emission from the QRs due to the temperature dependence of the diffusion rate of indium atoms. PMID- 21825810 TI - Arrays of ultrasmall metal rings. AB - In this paper, we present a simple method to fabricate ultra-high-density hexagonal arrays of ferromagnetic nanorings having 13 nm outer diameter, 5 nm inner diameter and 5 nm thickness. Cobalt magnetic nanorings were fabricated using a self-assembled diblock copolymer template with an angular evaporation of metal followed by an ion-beam etching. Magnetic measurements and theoretical calculations suggest that, at low fields, only the single domain and vortex states are important for rings of this size. The measured magnetization as a function of applied field shows a hysteresis that is consistent. These ultrasmall ferromagnetic rings have potential use in magnetic memory devices due to the simplicity of the preparation coupled with the ultra-high-density and geometry controlled switching. This fabrication technique can be extended to other materials for applications in optics, sensing and nanoscale research. PMID- 21825811 TI - Room temperature Cl(2) sensing using thick nanoporous films of Sb-doped SnO(2). AB - Thick film resistive Cl(2) sensors were fabricated using SnO(2) doped with Sb. The nanocrystalline powders of Sb-doped SnO(2) synthesized by a sol-gel method were compressed into an 800 um thick pellet. The fabricated sensors were tested against gases like Cl(2), Br(2), HCl, NO, NO(2), CHCl(3), NH(3) and H(2). The highest response to Cl(2) was achieved in 0.1% Sb doping where an exposure to 3 ppm of Cl(2) gas led to a 500-fold increase in device resistance. The high sensitivity to Cl(2) is accompanied by minor interference due to other gases at room temperature. It was found that the SnO(2) doped with 0.1% Sb exhibited high response, selectivity (>100 in comparison to the gases described above) and short response time (~60 s) to Cl(2) at 3 ppm level at room temperature. PMID- 21825812 TI - Selective growth of silica nanowires using an Au catalyst for optical recognition of interleukin-10. AB - The vapor-liquid-solid (VLS) growth procedure has been extended for the selective growth of silica nanowires on SiO(2) layer by using Au as a catalyst. The nanowires were grown in an open tube furnace at 1100 degrees C for 60 min using Ar as a carrier gas. The average diameter of these bottom-up nucleated wires was found to be 200 nm. Transmission electron microscopy analysis indicates the amorphous nature of these nanoscale wires and suggests an Si-silica heterostructure. The localized silica nanowires have been used as an immunoassay template in the detection of interleukin-10 which is a lung cancer biomarker. Such a nanostructured platform offered a tenfold enhancement in the optical response, aiding the recognition of IL-10 in comparison to a bare silica substrate. The role of nanowires in the immunoassay was verified through the quenching behavior in the photoluminescence (PL) spectra. Two orders of reduction in PL intensity have been observed after completion of the immunoassay with significant quenching after executing every step of the protocol. The potential of this site-specific growth of silica nanowires on SiO(2) as a multi-modal biosensing platform has been discussed. PMID- 21825813 TI - A facile and green preparation of high-quality CdTe semiconductor nanocrystals at room temperature. AB - One chemical reagent, hydrazine hydrate, was discovered to accelerate the growth of semiconductor nanocrystals (cadmium telluride) instead of additional energy, which was applied to the synthesis of high-quality CdTe nanocrystals at room temperature and ambient conditions within several hours. Under this mild condition the mercapto stabilizers were not destroyed, and they guaranteed CdTe nanocrystal particle sizes with narrow and uniform distribution over the largest possible range. The CdTe nanocrystals (photoluminescence emission range of 530 660 nm) synthesized in this way had very good spectral properties; for instance, they showed high photoluminescence quantum yield of up to 60%. Furthermore, we have succeeded in detecting the living Borrelia burgdorferi of Lyme disease by its photoluminescence image using CdTe nanocrystals. PMID- 21825814 TI - Tailoring silver nanoparticle construction using dendrimer templated silica networks. AB - We have examined the role of the internal environment of dendrimer templated silica networks in tailoring the construction of silver nanoparticle assemblies. Silica networks from which 3,5-dihydroxybenzyl alcohol based dendrimer templates have been completely removed, slowly wet with an aqueous solution of silver acetate. The latter then reacts with internal silica silanol groups, leading to chemisorption of silver ions, followed by the growth of silver oxide nanoparticles. Silica network constructed using generation 4 dendrimer contains residual dendrimer template, and mixes with aqueous silver acetate solution easily. Upon chemisorption, silver ions get photolytically reduced to silver metal under a stabilizing dendrimer environment, leading to the formation of silver metal nanoparticles. PMID- 21825815 TI - Air-stable full-visible-spectrum emission from silicon nanocrystals synthesized by an all-gas-phase plasma approach. AB - A novel dual-plasma system has been developed to combine the synthesis of silicon nanocrystals (Si-NCs), the etching to controllably tailor the Si-NC size, and the surface functionalization of Si-NCs into one simple all-gas-phase process. Si-NCs are synthesized in SiH(4)-based plasma; they then travel through CF(4)-based plasma, where Si-NCs are etched and passivated by C and F. The resulting Si-NCs exhibit air-stable emission across the full visible spectrum. Structural and optical characterization indicates that the emission in the red-to-green range is based on the recombination of quantum-confined excitons in Si-NCs, while the blue emission originates from defect states. The quantum yields of stabilized photoluminescence from Si-NCs range from 16% at the red end to 1% at the blue end. PMID- 21825816 TI - Growth of hydroxyapatite on physiologically clotted fibrin capped gold nanoparticles. AB - The growth of hydroxyapatite (HAp) on physiologically clotted fibrin (PCF)-gold nanoparticles is presented for the first time by employing a wet precipitation method. Fourier transform infrared (FTIR) spectroscopy confirmed the characteristic functionalities of PCF and HAp in the PCF-Au-HAp nanocomposite. Scanning electron microscopy (SEM) images have shown cuboidal nanostructures having a size in the range of 70-300 nm of HAp, whereas 2-50 nm sized particles were visualized in high-resolution transmission electron microscopy (TEM). Energy dispersive x-ray (EDX) and x-ray diffraction (XRD) studies have confirmed the presence of HAp. These results show that gold nanoparticles with PCF acted as a matrix for the growth of HAp, and that PCF-Au-HAp nanocomposite is expected to have better osteoinductive properties. PMID- 21825817 TI - Biomimetic synthesis of oriented hydroxyapatite mediated by nonionic surfactants. AB - Highly oriented organization of hydroxyapatite (HAP) nanorods was achieved through a simple reflux method using mixtures of triblock copolymer pluronic P123 and tween-60 as the mediated agents. Raft-like organized complexes were prepared when the nanorods were only directed by the mixed surfactants. Bundles of nanorod like HAP crystals were obtained when urea was used as the cosurfactant. These HAP nanorods with a large amount of uniform 4 nm worm-like mesopores were arranged in parallel to each other along the c axis of HAP. The raft-like complexes might be mediated by the reverse lamellar micelles. And the added urea transformed the reverse lamellar micelles into hexagonal ones due to its association with the surfactant molecules by hydrogen bonds, resulting in the formation of bundles of nanorod-like HAP crystals. The regulation of the oriented HAP complexes in morphology extends the understanding of biomineralization and permits controllable design of biomimetic materials. In addition, the c-axis oriented raft-like HAP complex has great potential in selective bio-absorption and separation. PMID- 21825818 TI - Fabrication of silicon carbide nanowires/carbon nanotubes heterojunction arrays by high-flux Si ion implantation. AB - An array of silicon carbide nanowire (SiCNW)-carbon nanotube (CNT) heterojunctions was fabricated by high-flux Si ion implantation into a multi walled carbon nanotube (MWCNT) array with a metal vapor vacuum arc (MEVVA) ion source. Under Si irradiation, the top part of a CNT array was gradually transformed into an amorphous nanowire array with increasing Si dose while the bottom part still remained a CNT structure. X-ray photoelectron spectroscopy (XPS) analysis shows that the SiC compound was produced in the nanowire part even at the lower Si dose of 5 * 10(16) ions cm(-2), and the SiC amount increased with increasing the Si dose. Therefore, the fabrication of a SiCNW-CNT heterojunction array with the MEVVA technique has been successfully demonstrated. The corresponding formation mechanism of SiCNWs was proposed. PMID- 21825819 TI - An efficient fabrication of vertically aligned carbon nanotubes on flexible aluminum foils by catalyst-supported chemical vapor deposition. AB - An efficient and versatile growth of thin-layer carbon nanotubes on a flexible aluminum foil (for kitchen use) by catalyst-supported chemical vapor deposition is reported. The aluminum foil used in the present experiment is commercially available for kitchen use. The electron-beam vapor deposition and dip-coating have been used for preparing catalysts on the aluminum foil. Vertically aligned thin-layer CNTs with typical diameters of 2.5-6.0 nm and lengths up to 90 um are obtained when ethanol is used in combination with Fe and Co catalyst particles at a growth temperature of around 650 degrees C under an Ar/H(2) gas flow. Thermo gravimetric analyses together with HR-TEM observations indicate that the purity of the CNTs synthesized by the current technique is very high. PMID- 21825820 TI - Self-assembly of conductive Cu nanowires on Si(111)'5 * 5 '-Cu surface. AB - Upon room-temperature deposition onto a Cu/Si(111)'5 * 5' surface in ultra-high vacuum, Cu atoms migrate over extended distances to become trapped at the step edges, where they form Cu nanowires (NWs). The formed NWs are 20-80 nm wide, 1-3 nm high and characterized by a resistivity of ~8 uOmega cm. The surface conductance of the NW array is anisotropic, with the conductivity along the NWs being about three times greater than that in the perpendicular direction. Using a similar growth technique, not only the straight NWs but also other types of NW based structures (e.g. nanorings) can be fabricated. PMID- 21825821 TI - Room temperature ferromagnetism in CoO nanoparticles obtained from sonochemically synthesized precursors. AB - In this paper we report the magnetic properties of nanosized CoO particles, prepared from sonochemically synthesized precursors and characterized using x-ray diffraction (XRD), conventional transmission electron microscopy (TEM) and scanning tunneling electron microscopy combined with energy dispersive x-ray analysis (STEM-EDX) techniques. The nanoparticles were faceted and the sizes varied between 30 and 60 nm depending on the time of annealing. They were stable even in the absence of any organic coating on them. Magnetic measurements reveal the presence of ferromagnetic interactions at low temperatures in the CoO nanoparticles synthesized after 2 and 4 h of annealing of the sonochemically synthesized precursor under nitrogen. However, after 6 h of annealing, the nanoparticles show hysteresis not only at low temperatures (1.5 K) but also at higher temperatures (100 K and room temperature), indicating the presence of room temperature ferromagnetism. PMID- 21825822 TI - Mass production of ZnO nanotetrapods by a flowing gas phase reaction method. AB - We have developed a flowing gas phase reaction method for synthesizing ZnO nanotetrapods. The synthesis was carried out in a tube furnace under air pressure using air and nitrogen as reactive and carrying gases. The zinc precursor was provided by carbothermal reduction of ZnO powder. The source material transformation efficiency is higher than 90%. ZnO nanotetrapods were nucleated and grown in the gas phase via a vapor-solid mechanism. The reaction occurred at a temperature controlled to 1050-1200 degrees C and gas flow rate controlled to 0.7-2 L/min. The high flow rate suppressed the diffusion of growth precursors and productions towards the tube wall, and localized them into a gas phase pipe. The harvested ZnO nanotetrapods were carried by the flowing gas and collected outside of the furnace. The sizes of the nanotetrapods range from several hundred nanometers to more than 10 um with leg diameters of 30-200 nm. The flowing gas phase reaction method provides a relatively uniformity environment for nanotetrapod growth and simplifies the product collection procedure compared with other techniques. This technique is simple and inexpensive, which is promising for realizing continuous mass production of ZnO nanotetrapods on a factory scale. PMID- 21825823 TI - Highly porous CdO nanowires: preparation based on hydroxy- and carbonate containing cadmium compound precursor nanowires, gas sensing and optical properties. AB - Highly porous cadmium oxide (CdO) nanowires have been prepared by calcining the hydroxy- and carbonate-containing cadmium compound precursor nanowires. The large scale precursor nanowires were synthesized through a hydrothermal method. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) were employed to characterize and analyze the as-synthesized precursor nanowires as well as the calcined products. It was revealed that the wire-like morphology of the precursor was fundamentally retained during the process of calcination and the CdO nanowires obtained were polycrystalline with highly porous structures. In order to illustrate the formation mechanism of the porous structures, the morphology and composition evolutions of the precursor nanowires under different stages of the calcining process were further investigated via SEM, x-ray diffraction (XRD) and infrared (IR) absorbance spectroscopy. Gas sensing has been explored for the sensor device fabricated with highly porous CdO nanowires, which demonstrates that it has good response owing to its special structures and great selectivity to NO(x). Furthermore, the UV-visible and photoluminescence spectra of highly porous CdO nanowires have also been investigated. PMID- 21825824 TI - The growth of aligned carbon nanotubes on quartz substrate by spray pyrolysis of hexane. AB - Vertically aligned multiwall carbon nanotubes were grown by spray pyrolysis of hexane as the carbon source in the presence of ferrocene as catalyst precursor on a quartz substrate. In recent work we used optimal experimental parameters for the feeding method, reactor conditions, reaction temperature and time, concentration of catalyst and flow rate of feed and gas. The process parameters were chosen so as to obtain multiwall carbon nanotubes and aligned multiwall carbon nanotubes. The tubes are around 15-80 nm in diameter. The morphology and structure of the samples were characterized by x-ray diffraction, Raman spectroscopy, scanning electron microscopy, and transmission electron microscopy analyses. PMID- 21825825 TI - A facile and fast approach for the synthesis of doped nanoparticles using a microfluidic device. AB - The microfluidic approach emerges as a new and promising technology for the synthesis of nanomaterials. A microreactor allows a variety of reaction conditions to be quickly scanned without consuming large amounts of raw material. In this study, we investigated the synthesis of water soluble 1-thioglycerol capped Mn-doped ZnS nanocrystalline semiconductor nanoparticles (TG-capped ZnS:Mn) via a microfluidic approach. This is the first report for the successful doping of Mn in a ZnS semiconductor at room temperature as well as at 80 degrees C using a microreactor. Transmission electron microscopy and x-ray diffraction analysis show that the average particle size of Mn-doped ZnS nanoparticles is ~3.0 nm with a zinc-blende structure. Photoluminescence, x-ray photoelectron spectroscopy, atomic absorption spectroscopy and electron paramagnetic resonance studies were carried out to confirm that the Mn(2+) dopants are present in the ZnS nanoparticles. PMID- 21825826 TI - Engineering the magnetic structure of Fe clusters by Mn alloying. AB - We propose to tailor the magnetic structure of atomic clusters by suitable doping, which produces the nanometric equivalent to alloying. As a proof of principle, we perform a theoretical analysis of Fe(6-x)Mn(x) clusters (x = 0-5), which shows a modulation of the magnetic moment of the clusters as a function of Mn doping and, more importantly, a collinear to noncollinear transition at x = 4. PMID- 21825827 TI - Optoelectronic property modeling of carbon nanotubes grafted with gold nanoparticles. AB - A three-dimensional (3D) electrodynamic model is built using the finite difference time-domain (FDTD) method to investigate the optical response of carbon nanotubes grafted with gold nanoparticles. Theoretical characterizations suggest an anisotropic response, in line with previously observed absorption peaks of such systems in the optical range. An investigation of geometric and wavelength dependences is conducted, predicting the ability to tune the sub wavelength intensity enhancement for efficient localization and propagation. The support of electric field enhancement along the nanotube walls raises the possibility of utilizing such systems as plasmon generators and waveguides for optical signal propagation. PMID- 21825828 TI - Alignment of carbon nanotubes and reinforcing effects in nylon-6 polymer composite fibers. AB - Alignment of pristine carbon nanotubes (P-CNTs) and fluorinated carbon nanotubes (F-CNTs) in nylon-6 polymer composite fibers (PCFs) has been achieved using a single-screw extrusion method. CNTs have been used as filler reinforcements to enhance the mechanical and thermal properties of nylon-6 composite fibers. The composites were fabricated by dry mixing nylon-6 polymer powder with the CNTs as the first step, then followed by the melt extrusion process of fiber materials in a single-screw extruder. The extruded fibers were stretched to their maxima and stabilized using a godet set-up. Finally, fibers were wound on a Wayne filament winder machine and tested for their tensile and thermal properties. The tests have shown a remarkable change in mechanical and thermal properties of nylon-6 polymer fibers with the addition of 0.5 wt% F-CNTs and 1.0 wt% of P-CNTs. To draw a comparison between the improvements achieved, the same process has been repeated with neat nylon-6 polymer. As a result, tensile strength has been increased by 230% for PCFs made with 0.5% F-CNTs and 1% P-CNTs as additives. These fibers have been further characterized by DSC, Raman spectroscopy and SEM which confirm the alignment of CNTs and interfacial bonding to nylon-6 polymer matrix. PMID- 21825829 TI - Surface modification of nanoporous alumina membranes by plasma polymerization. AB - The deposition of plasma polymer coatings onto porous alumina (PA) membranes was investigated with the aim of adjusting the surface chemistry and the pore size of the membranes. PA membranes from commercial sources with a range of pore diameters (20, 100 and 200 nm) were used and modified by plasma polymerization using n-heptylamine (HA) monomer, which resulted in a chemically reactive polymer surface with amino groups. Heptylamine plasma polymer (HAPP) layers with a thickness less than the pore diameter do not span the pores but reduce their diameter. Accordingly, by adjusting the deposition time and thus the thickness of the plasma polymer coating, it is feasible to produce any desired pore diameter. The structural and chemical properties of modified membranes were studied by scanning electron microscopy (SEM), atomic force microscopy (AFM) and x-ray electron spectroscopy (XPS). The resultant PA membranes with specific surface chemistry and controlled pore size are applicable for molecular separation, cell culture, bioreactors, biosensing, drug delivery, and engineering complex composite membranes. PMID- 21825830 TI - Sonochemical coating of silver nanoparticles on textile fabrics (nylon, polyester and cotton) and their antibacterial activity. AB - Silver nanoparticles were synthesized and deposited on different types of fabrics using ultrasound irradiation. The structure of silver-fabric composites was studied by physico-chemical methods. The mechanism of the strong adhesion of silver nanoparticles to the fibers is discussed. The excellent antibacterial activity of the Ag-fabric composite against Escherichia coli (gram-negative) and Staphylococcus aureus (gram-positive) cultures was demonstrated. PMID- 21825831 TI - Photovoltaic properties of a ZnO nanorod array affected by ethanol and liquid crystalline porphyrin. AB - A vertically aligned array of ZnO nanorods, fabricated on conductive ITO substrate in aqueous solution, was characterized by scanning electron microscopy (SEM), x-ray diffraction (XRD), and UV-visible transmission spectroscopy. Surface photovoltage (SPV) techniques based on a lock-in amplifier and a Kelvin probe were both employed to study the photogenerated charges in the system. The effects of ethanol solvent and a liquid-crystalline porphyrin, [5-(para-dodecyloxy)phenyl 10,15,20-tri-phenyl] porphyrin (DPTPP), on the photovoltage enhancement in the ZnO nanorod array were studied via SPV comparison between different irradiation directions on the system. We demonstrate that the ethanol adsorption could induce the space charge region to expand towards the ZnO/ITO interface. In the absence of ethanol, the ZnO nanorod array with the DPTPP adsorption showed enhanced SPV with reduced attenuation rate of photogenerated charge carriers. We found that the separation of photogenerated charges could be further improved by coating the surface with DPTPP and ethanol together. Furthermore, the SPV spectra patterns of the composite system with opposite incident-light directions reveal that the DPTPP molecules adsorbed just at the surface of ZnO nanorods adopt a more monomeric alignment in contrast to the aggregative state in the DPTPP bulk. PMID- 21825832 TI - Nanostructures in high-performance (GeTe)(x)(AgSbTe(2))(100-x) thermoelectric materials. AB - The thermoelectric properties of (GeTe)(x)(AgSbTe(2))(100-x) compounds (x = 75, 80, 85 and 90; TAGS-x) have been studied as a function of temperature from 300 to 720 K. At 720 K the dimensionless figure of merit ZT reaches the state-of-the-art value of 1.53 for TAGS-75 and 1.50 for TAGS-80 and TAGS-85 samples, respectively. But the ZT value of the TAGS-90 sample is only 0.50 at 720 K due to the high carrier concentration. Utilizing high-resolution transmission electron microscope and selected area electron diffraction techniques, we identify a considerable number of nanoscale domains with typical size ~10 nm in the samples that show high ZT values. It is suggested that the presence of nanoscale domains, like the situation in PbTe-AgSbTe(2) compounds, should make a slight contribution to the low lattice thermal conductivity of TAGS compounds due to the enhanced mid frequency phonon scattering. PMID- 21825833 TI - ZnO nanotips and nanorods on carbon nanotube/Si substrates: anomalous p-type like optical properties of undoped ZnO nanotips. AB - ZnO nanotips and nanorods were grown on screen-printed multi-walled carbon nanotube (MWCNT) films via thermal chemical vapor deposition at relative low growth temperatures of 400 and 500 degrees C. Uniform formation of ZnO nanotips and nanorods occurred on MWCNT-printed Si substrates, but were rarely observed on bare Si substrates at the same growth temperatures. In photoluminescence (PL) measurements, it was found that ZnO nanorods exhibit typical intrinsic optical properties, while ZnO nanotips revealed p-type like luminescence behavior. Acceptor-related emission bands originating from neutral acceptor-bound exciton, free-to-acceptor and donor-acceptor pair transitions are clearly observed in temperature-dependent PL spectra of ZnO nanotips. PMID- 21825834 TI - Comparative study of codon substitution patterns in foot-and-mouth disease virus (serotype O). AB - We compared genetic variations in the VP1 gene of foot-and-mouth disease viruses (FMDVs) isolated since 2000 from various region of the world. We analyzed relative synonymous codon usage (RSCU) and phylogenetic relationship between geographical regions, and calculated the genetic substitution patterns between Korean isolate and those from other countries. We calculated the ratios of synonymously substituted codons (SSC) to all observed substitutions and developed a new analytical parameter, EMC (the ratio of exact matching codons within each synonymous substitution group) to investigate more detailed substitution patterns within each synonymous codon group. We observed that FMDVs showed distinct RSCU patterns according to phylogenetic relationships in the same serotype (serotype O). Moreover, while the SSC and EMC values of FMDVs decreased according to phylogenetic distance, G + C composition at the third codon position was strictly conserved. Although there was little variation among the SSC values of 18 amino acids, more dynamic differences were observed in EMC values. The EMC values of 4- and 6-fold degenerate amino acids showed significantly lower values while most 2 fold degenerate amino acids showed no significant difference. Our findings suggest that different EMC patterns among the 18 amino acids might be an important factor in determining the direction of evolution in FMDV. PMID- 21825835 TI - Mirrors for Haiti. PMID- 21825836 TI - Subclinical hyperthyroidism: current concepts and scintigraphic imaging. AB - Subclinical hyperthyroidism is defined as normal serum free thyroxine and a free triiodothyronine level, with a thyroid-stimulating hormone level suppressed below the normal range and is usually undetectable. Although patients with this diagnosis have no or few signs and symptoms of overt thyrotoxicosis, there is sufficient evidence that it is associated with a relatively higher risk of supraventricular arrhythmias as well as the acceleration or the development of osteoporosis. Consequently, the approach to the patient with subclinical hyperthyroidism is controversial, that is, therapeutic intervention versus watchful waiting. Regardless, it is imperative for the referring physician to identify the causative thyroid disorder. This is optimally accomplished by a functional study, namely scintigraphy. Recognition of the scan findings of the various causes of subclinical hyperthyroidism enables the imaging specialist to help in diagnosing the underlying condition causing thyroid-stimulating hormone suppression thereby facilitating the workup and management of this thyroid disorder. PMID- 21825837 TI - Role of PET/CT in gynecological tumors based on the revised FIGO staging classification. AB - FDG PET/CT imaging offers important information for the pre-, intra-, and postoperative management of gynecologic tumors. A review of FDG PET/CT imaging for the diagnosis of gynecologic tumors based on the revised International Federation of Gynecology and Obstetrics staging classification is presented. PMID- 21825838 TI - Cholecystocolic fistula of Crohn disease mimics colon adenocarcinoma invasion of gallbladder on F-18 FDG PET/CT. PMID- 21825839 TI - FDG PET/CT imaging of NUT midline carcinoma. PMID- 21825840 TI - Increased right ventricular glucose metabolism in patients with pulmonary arterial hypertension. AB - BACKGROUND AND AIMS: We aimed to assess the characteristics of glucose utilization in left and right ventricle (LV, RV) myocardium with F-18 fluorodeoxyglucose (FDG) on positron emission tomography in patients with pulmonary arterial hypertension (PAH), and to evaluate whether predominance of RV glucose metabolism as compared with that in LV relates to clinical, hemodynamic, echocardiographic, and neurohormonal parameters. METHODS: The study group comprised 23 patients with PAH and 16 healthy controls who underwent FDG positron emission tomography. The ratio of RV uptake (u) of FDG to those of LV was used as a marker for the glucose utilization by RV myocardium. Six-minute walking distance, plasma brain natriuretic peptide (BNP), planimetric echo measures of RV and LV areas, pulmonary arterial systolic pressure estimated by Doppler, Tei index, tricuspid annular excursion, and systolic tissue velocity (St) were used to assess the RV function. RESULTS: The patients with PAH had significantly higher FDG SUV ratios as compared with controls. The RV to LV FDGu ratio showed a high correlation with PAPs (r=0.87, P<0.05), BNP (r=0.63, P<0.05), and planimetric echo measures of RV to LV area ratio (r=0.61, P<0.05); a mild correlation with Tei index (r=0.47, P<0.05); and a high and inverse correlation with tricuspid annular excursion (r=-0.80, P<0.05), 6-minute walking distance (r= 0.74, P<0.05), and St (r=-0.68, P<0.05). CONCLUSIONS: Increased RV myocardium FDG accumulation indicates increased RV loading that correlates with prognostic markers in pulmonary hypertension including reduced exercise capacity, elevated BNP, and echo variables of tricuspid annular function. Moreover, identification of increased RV FDG accumulation predicts the presence but not the severity of elevated pulmonary systolic pressure. PMID- 21825841 TI - Early planar and early SPECT Tc-99m sestamibi imaging: can it replace the dual phase technique for the localization of parathyroid adenomas by omitting the delayed phase? AB - PURPOSE: To evaluate whether an early protocol (EP) (early planar and early SPECT) with Tc-99m sestamibi could demonstrate the delayed image of the established dual-phase scintigraphy unnecessary without any decrease in sensitivity for the localization of parathyroid adenomas. MATERIALS AND METHODS: A study was carried out in 80 consecutive patients with primary hyperparathyroidism (65 women; mean age, 61.8+/-14.2 years). Final diagnosis by surgery was possible in 79 patients and confirmed parathyroid adenoma in 76 patients, 1 hyperplasic gland in 1 patient, 2 hyperplasic glands in 1 patient, and differentiated thyroid carcinoma in another patient. Ten minutes after intravenous injection of 740 MBq (20 mCi) of Tc-99m sestamibi, a planar image followed by a SPECT and a 2 to 3 hours delayed planar image were acquired. Two sets of images were evaluated, one without (EP) and the other with the delayed image (dual-phase protocol [DPP]). An abnormality rating of 0 to 4 was given to each set and was compared with the final diagnosis. RESULTS: When any focal uptake, no matter the intensity, was considered positive, that is setting the threshold in the abnormality rating 1, 71 of the 76 adenomas were correctly localized by DPP and EP (sensitivity: 93.4%). CONCLUSIONS: The delayed planar image could be omitted without any loss in sensitivity for the localization of parathyroid adenomas, and therefore EP could replace DPP. PMID- 21825842 TI - Colonic FDG uptake pattern in subjects receiving oral contrast with no known or suspected colonic disease. AB - AIM: We assessed the pattern of metabolic activity in the colon of subjects who received oral contrast and had no known or suspected colonic disease. METHODS: Positron emission tomography/computed tomography (PET/CT) with [F-18] fluorodeoxyglucose was performed in 50 patients with cancer and no known or suspected colonic pathology. Studies with intense focal or segmental colonic activity (in comparison to liver reference activity), which are known to be predictive of colonic pathology were excluded. Retrospectively, colon was divided into cecum, ascending, transverse, descending, and rectosigmoid partitions, and the corresponding volumetric regions of interest were drawn on all relevant CT images. Partitioned colonic maximum standardized uptake values (SUVmax) were compared using Wilcoxon rank-sum test. Frequency of occurrence for the various colonic uptake rank orders was also tabulated. RESULTS: For colonic partitions, range and median SUVmax, respectively, were in decreasing order: rectosigmoid (1.5-9.9, 2.9), cecum (1.2-6.3, 2.6), ascending (0.7-4.0, 1.8), transverse (0.4 4.1, 1.2), and descending (0.6-3.1, 1.2). The SUVmax at different colonic partitions were significantly different from each other (P<0.001), except for the SUVmax between descending and transverse colonic segments (P=0.77). Combining the latter segments, the uptake rank order of "rectosigmoid>cecum>ascending" was demonstrated in 50% and "cecum>rectosigmoid>ascending" in 30% of subjects. CONCLUSIONS: Rectosigmoid and cecum tend to demonstrate higher metabolism than other colonic segments in the majority subjects who receive oral contrast during [F-18]-fluorodeoxyglucose positron emission tomography/CT and have no known or suspected colonic pathology. PMID- 21825843 TI - Iodine-123 metaiodobenzylguanidine cardiac imaging as a method to detect early sympathetic neuronal dysfunction in chagasic patients with normal or borderline electrocardiogram and preserved ventricular function. AB - PURPOSE: The indeterminate form of Chagas disease represents the most common chronic presentation. The aim of this study was to assess cardiovascular autonomic system function with I-123 metaiodobenzylguanidine (MIBG) scintigraphy in chagasic patients with normal or "borderline" electrocardiographic alterations and preserved left ventricular function evaluated by echocardiography. MATERIALS AND METHODS: A total of 40 chagasic patients and 19 control subjects were included in this study. Patients had normal echocardiogram and chest radiography; no arrhythmias or myocardial ischemia; and normal exercise performance for age, gender, and body mass index. I-123 MIBG scintigraphy was performed and the heart to-mediastinum (H/M) uptake was used as the primary predictor in the present analysis. The data analysis was performed by using Nonparametric Regression Trees and the Survival Agreement Plot. We included only patients with preserved right and left ventricular function assessed by echocardiographic methods. RESULTS: Variables analyzed in the regression tree were age, sex, 20 minutes and 3 hours H/M uptake after injection of I-123 MIBG, washout rate, and single photon emission computed tomography imaging. The 3 hours H/M ratio was the only significant variable (P<0.001) and for 95% of chagasic patients, this value was less than 2.19. CONCLUSIONS: This study presents evidence that cardiac autonomic sympathetic modulation may be affected in chagasic subjects with preserved ventricular function evaluated by echocardiography, especially in those with "borderline" electrocardiogram. PMID- 21825844 TI - Pulse wave as an alternate signal for data synchronization during gated myocardial perfusion SPECT imaging. AB - PURPOSE: Proper identification of the cardiac cycle is essential for gated SPECT myocardial perfusion imaging. We have developed an alternate method of ECG for gating, that is, using the peripheral pulse wave (PW) as the triggering signal for gated SPECT acquisition. The aim of this study is to compare the use of this method of gating with the standard ECG trigger. METHODS: We tested the PW triggering by comparing it with the ECG trigger. We evaluated 33 patients (25 males, 8 females), average age of 61 years (39-80) referred for stress myocardial perfusion imaging. Data from all patients were acquired twice and were processed by CEqual and QGS software. We compared the left ventricular ejection fraction (LVEF), end-diastolic and end-systolic volumes (EDV, ESV). Paired t test and Pearson correlation coefficient were used for comparison. RESULTS: The mean LVEF, EDV, and ESV calculated with the ECG trigger were 0.52, 120, and 64, respectively, those with the pulse-wave trigger were 0.48, 126, and 71, respectively. Mean paired difference for LVEF was -0.034 (P<0.001), for EDV 5.9 (P=0.012), and for ESV 7.9 (P<0.001). Pearson correlation coefficient for LVEF was 0.955, for EDV 0.987, and for ESV 0.991 (P<0.001 for all correlations). CONCLUSION: Triggering of gated-data acquisition by the PW is feasible. Quantitative parameters of cardiac function correlate highly with those obtained from the ECG trigger and the absolute differences are not clinically significant across a wide range of values. PMID- 21825845 TI - FDG uptake in lipomatous hypertrophy of the interatrial septum is not likely related to brown adipose tissue. AB - Lipomatous hypertrophy of the interatrial septum (LHIS) may be associated with arrhythmias or sudden death. Increased fluorine-18 fluorodeoxyglucose (FDG) uptake in LHIS is occasionally found on positron emission tomography, and has been attributed to metabolically active brown adipose tissue (BAT) contained within LHIS. We report a case of a patient suggesting that neither of the 2 currently known mechanisms of glucose uptake by BAT is responsible for FDG uptake in LHIS, unless a mechanism of BAT activation exists that has not been previously described. This study also suggests that FDG uptake is unlikely to be due to cardiomyocytes contained within LHIS. Inflammation is a potential mechanism, although further investigation is needed. PMID- 21825846 TI - Comparison of pinhole and high-resolution parallel-hole imaging for nodular thyroid disease. AB - INTRODUCTION AND OBJECTIVE: Pinhole has been the main standard collimator to be used for thyroid imaging. There has been a gradually increasing trend to replace pinhole with the use of high-resolution low-energy parallel-hole collimator with zoom in thyroid imaging. The objective of this study is to compare parallel-hole collimator acquisition of thyroid gland with that obtained by pinhole collimator to find the effect on the diagnostic information in nodular thyroid disease. MATERIAL AND METHODS: A total of 29 patients, 24 women and 5 men, aged 18 to 70 years who were routinely referred for thyroid imaging for the assessment of nodular disease were studied. Each patient was injected with 185 MBq (5 mCi) of Tc-99m sodium pertechnetate intravenously. After 20 minutes, acquisition using pinhole followed by parallel-hole collimators was obtained. For pinhole acquisition, a 3-mm insert was used, and 3 images were obtained in the anterior and anterior oblique projections. For parallel-hole acquisition, anterior view was obtained for 250 K. The collimator was placed as close as possible to the patient. The image quality, number, and definition of nodules were evaluated by 2 independent, qualified nuclear medicine physicians. Differences were resolved by consensus. RESULTS: There were 14 patients who had nodular patterns and 15 had no apparent nodules. There were 40 nodules of different sizes detected by pinhole imaging. Only 10 (25%) of these nodules were observed on parallel-hole images. CONCLUSION: Pinhole imaging must be used for thyroid imaging particularly in patients suspected of having nodular disease. PMID- 21825847 TI - Diagnosis of multiple endocrine neoplasia type 2A in patients with positive thyroid imaging by iodine-131 metaiodobenzylguanidine scintigraphy. AB - We retrospectively analyzed iodine-131 metaiodobenzylguanidine (I-131 MIBG) scintigraphy in 320 patients (male, 108 cases; female, 211 cases; average age, 45+/-15 years). All patients received thyroid block before examination between 2007 and 2010 in our department. Various degrees of radioactivity were found in the thyroid glands or thyroid region after bilateral thyroid surgery, in addition to bilateral or unilateral abnormal radioactivity in the adrenal glands in 3 patients. These cases were confirmed for medullary thyroid carcinoma and adrenal pheochromocytoma by pathology after surgical removal of the glands, and the diagnosis of multiple endocrine neoplasia type 2A was established from the patients' history and genetic examination. The possibility of medullary thyroid carcinoma should be considered on the finding of abnormal radioactivity in the thyroid or thyroid region by I-131 MIBG scintigraphy after excluding normal radioactivity in the thyroid. When significant abnormal radioactivity is seen in the adrenal gland on I-131 MIBG scintigraphy, the possibility of adrenal pheochromocytoma should be considered. Adrenal pheochromocytoma cannot be excluded when adrenal uptake is increased. The possibility of multiple endocrine neoplasia type 2A should be considered taking into account the history of these patients. PMID- 21825848 TI - Comparison of myocardial perfusion imaging using thallium-201 between a new cadmium-zinc-telluride cardiac camera and a conventional SPECT camera. AB - PURPOSE OF THE REPORT: Cadmium zinc telluride (CZT) solid-state detectors have been recently introduced in myocardial perfusion imaging. However, they had not been yet validated with thallium-201. This study compares the clinical performances of the CZT ultrafast camera GE DNM 530c with a conventional SPECT camera (CC) using thallium-201. MATERIALS AND METHODS: We prospectively studied with thallium-201 a total of 153 consecutive patients referred for myocardial perfusion imaging at exercise (3-4 mCi) then redistribution (with 1 mCi reinjection). Sequential acquisitions were performed first with a conventional dual-head tomographic Anger camera (CC) in 10 to 15 minutes and then with a CZT camera (CZT) in 5 minutes, in prone position. RESULTS: In all, 9 patients were excluded: 1 for mispositioning, 3 for camera failure, 3 for delayed acquisition after exercise, 1 for nonacceptance of redistribution, 1 for motion. Acquisition was more comfortable with CZT for all patients. Global counts rate was higher with CZT than with CC (3.6+/-0.57 KCts/s vs. 1.14+/-0.16). CZT has a 5-fold increased myocardial counts rate compared with CC (448+/-69 Kcts in 5 minutes vs. 209+/-40 Kcts in 12.5+/-1.8 minutes). Quality of CZT images was considered as better in 40%, equal in 56%, and worse in 4% of cases; we found less artifacts with CZT; diagnostic conclusions were the same in 140 of 144 cases (97%); discordances were 2 artifacts with CC and 2 small ischemia (less than 2 segments) missed by CZT. CONCLUSIONS: This new dedicated cardiac CZT camera allows with thallium-201 five minutes acquisitions with an increased image quality and a reliable diagnosis quality. PMID- 21825849 TI - Thyroid remnant estimation by Tc-99m-sestamibi scanning predicts the effectiveness of rhTSH-stimulated I-131 ablation in patients with differentiated thyroid carcinoma. AB - AIM: To evaluate the relationship between postsurgical cervical Tc-99m-sestamibi scan uptake and the rate of successful remnant ablation after recombinant human thyrotropin (rhTSH)-aided-I-131 ablation in patients with differentiated thyroid carcinoma (DTC). METHODS: In all, 154 DTC patients who underwent total thyroidectomy and rhTSH-aided remnant ablation with I-131 (3.7 GBq) were enrolled. Tc-99m-sestamibi scans were performed during continuing thyroid hormone administration in all cases. Thyroid ablation was assessed after 6 to 12 months by rhTSH-stimulated I-131-whole-body scan and thyroglobulin measurement. The rate of successful ablation, occurrence of radioiodine-induced thyroiditis, and length of hospitalization were correlated with the Tc-99m-sestamibi scintigraphy results. RESULTS: Tc-99m-sestamibi uptake was significantly lower in ablated versus nonablated patients (P<0.0001). A visually positive scan and a Tc-99m sestamibi uptake greater than 0.9% predicted a high-risk of unsuccessful ablation, prolonged hospitalization, and the occurrence of radioiodine-induced thyroiditis. CONCLUSIONS: Tc-99m-sestamibi scintigraphy is a simple and feasible tool to evaluate thyroid remnants and to predict radioiodine ablation results in patients with DTC. PMID- 21825850 TI - Tips for leaders, Part II: Leading a private practice physician group. AB - Leaders of private practice groups face many challenges. Establishing proper governance, having a good mission statement and business plan, having good participation by the members in administrative practice activities, and establishing proper channels of communication are some important steps. Once that is done, efficient decision making can be done regarding issues of finance, operations, keeping existing business, and finding new opportunities. Who is chosen to be the leader of such a group is less dependent on their field of specialization, but more dependent on their leadership skills. Nuclear medicine physicians interested in the future of their group and field should seek opportunities to learn leadership skills by experience and education. PMID- 21825851 TI - Bilateral tibial adamantinomas simulating stress fractures on scintigraphy. PMID- 21825852 TI - Three synchronous primary malignancies detected by F-18 FDG PET/CT: breast, rectal, and urothelial bladder carcinomas. PMID- 21825853 TI - F-18 FDG PET/CT in the diagnosis of a rare case of neurosarcoidosis in a patient with diabetes insipidus. PMID- 21825854 TI - Simultaneous uptake of I-131 and F-18 FDG by a renal metastasis of thyroid papillary cancer. PMID- 21825855 TI - Unusual presentations of metastatic prostate carcinoma as detected by anti-3 F-18 FACBC PET/CT. PMID- 21825856 TI - Tc-99m- and Ga-68-labeled somatostatin analogues in the evaluation of Hurthle cell thyroid cancer. PMID- 21825857 TI - False-positive findings in post-treatment iodine-131 whole-body scintigraphy in a nasolacrimal sac cyst, confirmed with SPECT/CT and MRI. PMID- 21825858 TI - Unsuspected thyroid metastases from renal cell cancer detected on in-111 octreotide with no uptake in primary renal cancer. PMID- 21825859 TI - Elevated MDP activity in the spleen due to fungal infection. PMID- 21825860 TI - Cortical hypometabolism in Morvan syndrome. PMID- 21825861 TI - A case of iodine-131 retention in the esophagus mimicking a mediastinal metastasis in a patient with follicular thyroid carcinoma after gastric volume reduction operation. PMID- 21825862 TI - Serendipitous diagnosis of hyperthyroidism on pulmonary perfusion scintigraphy. PMID- 21825863 TI - A PET-MRI case of corticocerebellar diaschisis after stroke. PMID- 21825864 TI - Poor FDG avidity in a case of metastatic pulmonary choriocarcinoma. PMID- 21825865 TI - False heart-to-mediastinum ratio of I-123 metaiodobenzylguanidine due to right ventricular attenuation. PMID- 21825866 TI - Intraoperative localization of recurrent medullary carcinoma of the thyroid using Tc-99m HYNIC-TATE and a surgical gamma probe. PMID- 21825867 TI - Current readings in nuclear medicine. PMID- 21825869 TI - Innate immune factors associated with HIV-1 transmission. AB - PURPOSE OF REVIEW: Relatively little is known with regards to the mechanisms of HIV-1 transmission across a mucosal surface and more specifically what effects host factors have on influencing infection and early viral dissemination. The purpose of this review is to summarize which factors of the innate immune response can influence mucosal transmission of HIV-1. RECENT FINDINGS: A large array of cell types reside at the mucosal surface ranging from Langerhans cells, dendritic cells, macrophages as well as CD4+ lymphocytes, all of which interact with the virus in a unique and different way and which can contribute to risk of HIV-1 transmission. Numerous factors present in bodily secretions as well as the carrier fluids of HIV-1 (breast milk, vaginal secretions, semen and intestinal mucus) can influence transmission and early virus replication. These range from cytokines, chemokines, small peptides, glycoproteins as well as an array of host intracellular molecules which can influence viral uncoating, reverse transcription as well as egress from the infected cell. SUMMARY: Better understanding the cellular mechanisms of HIV-1 transmission and how different host factor can influence infection will aide in the future development of vaccines, microbicides, and therapies. PMID- 21825870 TI - Natural killer cells, dendritic cells, and the alarmin high-mobility group box 1 protein: a dangerous trio in HIV-1 infection? AB - PURPOSE OF REVIEW: Natural killer (NK) cells promote antiviral immunity by producing proinflammatory cytokines and by lysing infected cells. In addition, NK cells can modulate dendritic cell functions. NK-dendritic cell crosstalk results in activation of both cell types, with dendritic cells promoting NK-cell activity and NK cells inducing further maturation of dendritic cells. Here we review the recent evidence suggesting that NK-dendritic cell crosstalk is disrupted during HIV-1 infection and we discuss the consequences on HIV persistence in dendritic cells. RECENT FINDINGS: NK cell-mediated dendritic cell editing is compromised during HIV-1 infection, and NK cells from viremic individuals show a decreased ability to kill immature dendritic cells. The defect is associated with impaired NKp30 function. Moreover, the resistance of HIV-1-infected dendritic cells to NK mediated lysis is associated with the upregulation of apoptosis inhibitors, thus protecting infected dendritic cells from TRAIL-dependent apoptosis. These inhibitors are upregulated by the high-mobility group box 1 protein (HMGB1), an alarmin produced at NK-dendritic cell synapse that is essential for NK-dependent dendritic cell maturation, but also promotes viral replication in infected dendritic cells. SUMMARY: HIV-1-induced impairment of NK-dendritic cell crosstalk may significantly alter both innate and adaptive immunity. It may also contribute to HIV persistence in dendritic cells through an HMGB1-dependent mechanism. PMID- 21825871 TI - Emerging role for complement in HIV infection. AB - PURPOSE OF REVIEW: New evidence is provided that the complement system is not only an effective component of the innate immunity, but is also involved in bridging innate and adaptive immune response to control retroviral infections. RECENT FINDINGS: The complement contributes to the control of retroviral replication by various strategies, such as complement-mediated lysis, triggering of B-cell responses by trapping the virus on follicular dendritic cells in the germinal center or enhancing of antigen presentation and thus the induction of virus-specific cytotoxic T lymphocytes. HIV has evolved mechanisms to escape from complement-meditated neutralization and counteracts these immune responses by escaping from lysis, using follicular dendritic cells as anchor to generate a latent viral reservoir and enhancing the infection of antigen-presenting cells. SUMMARY: This review will discuss the complex interactions of complement and complement receptors with retroviruses and review the escape mechanisms, which protect this virus family from complement-mediated destruction. PMID- 21825872 TI - Current world literature. PMID- 21825874 TI - Mental health services for people with intellectual disabilities. AB - PURPOSE OF REVIEW: This review summarizes recent research into psychiatric services for adults with intellectual disabilities, with a particular focus on inpatient care. RECENT FINDINGS: People with intellectual disability appear to be admitted with more severe problems and receive more interventions than those without intellectual disability when admitted to general psychiatric units. Qualitative research has shown poor standards of care on some general psychiatric inpatient units. Studies of supported generic inpatient units have reported successful outcomes, supported by qualitative studies of satisfaction. Length of stay for people with intellectual disability is not consistently longer on specialist than general psychiatric units. Delayed discharge and restrictive practices, however, still need addressing. The important components of community mental health services have been evaluated from the points of view of psychiatrists, patients and carers. Emergency provision of psychiatric assessment and care remains a problem in some centres. SUMMARY: There have been few randomized controlled trials in this field; however, uncontrolled comparisons and service evaluations suggest positive outcomes in specialist services. Qualitative work has made important contributions to understanding the patients' and carers' experiences. Further work should focus on the measurements of outcome and satisfaction. PMID- 21825875 TI - Fragile X syndrome: lifespan developmental implications for those without as well as with intellectual disability. AB - PURPOSE OF REVIEW: Advances in developmental neuropsychiatry and the mental health needs of people with intellectual disability are creating ever greater understanding of the critical associations between human genome variations and psychological functioning throughout lifespan and across the entire intellectual ability spectrum. This review highlights the recent developments and their clinical implications for people with fragile X syndrome. RECENT FINDINGS: There is substantial evidence for individuals of all ages and intellectual abilities being prone to psychological profiles determined not only by having a fragile X gene full mutation, but also by having premutations and intermediate alleles. The importance of these genetic contributors to mental life, if anything, increases with age. Premutation carriers are prone to neurodegenerative mid-life fragile X tremor-ataxia syndrome. Women with premutations experience premature ovarian insufficiency. Imbalances in the (gamma amino butyrie acid)-glutamate mediated postsynaptic cascade central neuronal pathways are a current focus of psychopharmacological enquiry, giving the hope of syndrome-specific medical treatments. SUMMARY: Findings from genetic, neurological, biochemical, psychological and pharmacological research are combining to revolutionize understanding of the pathogenesis of developmental and psychological disabilities affecting individuals with fragile X syndrome irrespective of age, intelligence level and gene mutation status. Results of syndrome-specific medication trials are awaited. PMID- 21825876 TI - Bibliography. Mental retardation and developmental disorders. Current world literature. PMID- 21825878 TI - Prevention of postoperative recurrence of Crohn's disease: does the type of surgery matter? PMID- 21825880 TI - Right colonic transposition technique for pelvic anastomosis. PMID- 21825883 TI - Predicting response to neoadjuvant treatment for rectal cancer: a step toward individualized medicine. PMID- 21825884 TI - Practice parameters for the management of hemorrhoids (revised 2010). PMID- 21825885 TI - Long-term efficacy and safety of sacral nerve stimulation for fecal incontinence. AB - BACKGROUND AND OBJECTIVE: Sacral nerve stimulation is effective in the treatment of urinary incontinence and is currently under Food and Drug Administration review in the United States for fecal incontinence. Previous reports have focused primarily on short-term results of sacral nerve stimulation for fecal incontinence. The present study reports the long-term effectiveness and safety of sacral nerve stimulation for fecal incontinence in a large prospective multicenter study. DESIGN AND METHODS: Patients with fecal incontinent episodes more than twice per week were offered participation in this multicentered prospective trial. Patients showing >= 50% improvement during test stimulation were offered chronic implantation of the InterStim Therapy system (Medtronic; Minneapolis, MN). The aims of the current report were to provide 3-year follow-up data on patients from that study who underwent sacral nerve stimulation and were monitored under the rigors of an Food and Drug Administration-approved investigational protocol. RESULTS: One hundred thirty-three patients underwent test stimulation with a 90% success rate, of whom 120 (110 females) with a mean age of 60.5 years and a mean duration of fecal incontinence of 7 years received chronic implantation. Mean length of follow-up was 3.1 (range, 0.2-6.1) years, with 83 patients completing all or part of the 3-year follow-up assessment. At 3 years follow-up, 86% of patients (P < .0001) reported >= 50% reduction in the number of incontinent episodes per week compared with baseline and the number of incontinent episodes per week decreased from a mean of 9.4 at baseline to 1.7. Perfect continence was achieved in 40% of subjects. The therapy also improved the fecal incontinence severity index. Sacral nerve stimulation had a positive impact on the quality of life, as evidenced by significant improvements in all 4 scales of the Fecal Incontinence Quality of Life instrument at 12, 24, and 36 months of follow-up. The most common device- or therapy-related adverse events through the mean 36 months of follow-up included implant site pain (28%), paresthesia (15%), change in the sensation of stimulation (12%), and infection (10%). There were no reported unanticipated adverse device effects associated with sacral nerve stimulation therapy. CONCLUSIONS: Sacral nerve stimulation using InterStim Therapy is a safe and effective treatment for patients with fecal incontinence. These data support long-term safety and effectiveness to 36 months. PMID- 21825886 TI - Utility and short-term outcomes of hand-assisted laparoscopic colorectal surgery: a single-institution experience in 1103 patients. AB - BACKGROUND: Despite its introduction in 1991, laparoscopic colectomy is performed in <10% of United States patients requiring colectomy. Laparoscopic colectomy is avoided principally because of its technical difficulty, steep learning curve, and increased operative times. Hand-assisted laparoscopic colectomy is an alternative technique that addresses these problems while preserving the short term benefits of laparoscopic colectomy. OBJECTIVE: To describe the utility and short-term outcomes, we evaluated 1103 patients who underwent hand-assisted laparoscopic colorectal resections over a 5-year period. DESIGN: This study was a retrospective analysis of prospectively collected data. SETTINGS: The setting was a single tertiary care institution. PATIENTS: A total of 1103 consecutive hand assisted laparoscopic colorectal resections from 2004 to 2009 were identified using a prospectively maintained database. MAIN OUTCOME MEASURES: Demographics, perioperative variables, and 30-day outcomes were reported. Data are presented as frequency (proportion) or median (interquartile range). RESULTS: A total of 1103 hand-assisted laparoscopic colorectal resections were documented. Median age of patients was 55 years; 47% were women, and median body mass index was 26.5 (range, 23-34) kg/m. Diagnoses included inflammatory bowel disease (35%), colorectal cancer (31%), diverticular disease (23%), and "other" (11%). Forty-two percent of patients had prior abdominal surgery. Segmental colectomies were performed in 533 (48%) patients, proctocolectomy with ileal pouch-anal anastomosis in 229 (21%), proctocolectomy with end ileostomy in 114 (10%), and "other" in 227 (21%). The conversion rate was 9%. Overall median operative time was 201 (range, 145-269) minutes, and the median postoperative length of stay was 5 (range, 4-7) days. Postoperative complications occurred in 27% and readmissions in 7%; mortality was 0.3%. LIMITATIONS: This was a single institutional retrospective study. CONCLUSIONS: Hand-assisted laparoscopic colorectal resection can be performed for numerous indications. It preserves nearly all the benefits of laparoscopic colectomy reported in the literature. With experience, it is associated with significantly reduced operative times. Wider adoption of hand assisted laparoscopic colorectal surgery would increase the number of patients benefiting from minimal access colorectal surgery. PMID- 21825887 TI - Adjuvant chemotherapy for stage III colon cancer: does timing matter? AB - BACKGROUND: Clinical trials commonly mandate that adjuvant chemotherapy for colon cancer should commence within 8 weeks (56 days) of surgery. OBJECTIVE: We investigated the consequences of the timing of adjuvant chemotherapy for stage III colon cancer. PATIENTS AND METHODS: This is a retrospective review of all patients with newly diagnosed stage III colon cancer who received adjuvant chemotherapy in 2 provincial centers in 1999 and 2000. The impact of time to adjuvant chemotherapy on overall survival and relapse-free survival was analyzed by the use of univariate and multivariate Cox modeling, adjusting for prognostic factors. RESULTS: Three hundred forty-five subjects were included. Median time to adjuvant chemotherapy was 50 days (range, 20-242 days); in 111 (32.2%) patients, it was beyond 56 days. On univariate analysis, time >56 days was nonsignificantly associated with a hazard ratio of death of 1.31 (P = .12). Similar results were seen for relapse-free survival. Planned exploratory analysis suggests that the commencement of adjuvant chemotherapy up to 10 weeks postsurgery still confers a benefit. CONCLUSIONS: Delaying adjuvant chemotherapy in stage III colon cancer beyond 8 to 10 weeks postsurgery appears to be associated with diminished benefit. PMID- 21825888 TI - Surgery and high-dose-rate intraoperative radiation therapy for recurrent squamous-cell carcinoma of the anal canal. AB - BACKGROUND: Locoregionally recurrent squamous-cell carcinoma of the anal canal is managed with salvage surgery. High-dose-rate intraoperative radiation therapy has been used in selected patients with this disease to reduce the risk of local recurrence. OBJECTIVE: The aim of this article is to present our institutional experience with this technique. DESIGN: Medical records of 14 patients with locoregionally recurrent squamous-cell carcinoma of the anal canal who underwent this technique between 1992 and 2007 were reviewed. SETTING: The study was conducted at an academic cancer center. PATIENTS: The median age was 45 years (range, 36-77), and 13 of the patients were women. All had prior radiation with or without chemotherapy. INTERVENTIONS: The surgical procedures included abdominoperineal resection with or without sacrectomy (n = 8), low anterior resection (n = 2), and pelvic exenteration (n = 4). The median radiation dose was 1500 cGy (range, 1500-1750). All cases of radiographic invasion of adjacent structures correctly predicted pathologic invasion. There was pathologic invasion into adjacent structures in 11 cases (79%), and adherence to the sacrum without invasion in 2 cases (14%). Surgical margins were positive (n = 6), close (<1 mm) (n = 3), and negative (n = 5). RESULTS: The median follow-up from our technique was 17 months (range, 5-145). Subsequent recurrence occurred in 11 cases, at a median of 8 months from treatment. Two-year actuarial control was 7.1%, and the overall survival was 21.4%. Acute toxicities included wound-healing complications (n = 6); gastrointestinal obstruction (n = 5); neurogenic bladder (n = 1); ureteral stricture (n = 3); and peripheral neuropathy (n = 2). LIMITATIONS: This is a small retrospective series in which the meaningful analysis of associations between clinical variables and outcomes was not possible. CONCLUSION: Salvage surgery with high-dose-rate intraoperative radiation therapy did not appear to be associated with a locoregional control or survival benefit in this series. The addition of high-dose-rate intraoperative radiation therapy to salvage surgery is insufficient to compensate for positive surgical margins. Preoperative imaging should be used to aid in patient selection to identify those patients in whom negative margins can be obtained and to aid in the determination of appropriate salvage surgery. PMID- 21825889 TI - Pretreatment CD133 and cyclooxygenase-2 expression as the predictive markers of the pathological effect of chemoradiotherapy in rectal cancer patients. AB - BACKGROUND: CD133 confers chemoradioresistance properties to cells and has recently been used to identify cancer-initiating cells. OBJECTIVE: We investigated whether the overexpression of CD133 and cyclooxygenase-2 can be used as predictive markers of tumor response to preoperative chemoradiotherapy in patients with rectal cancer. SETTING: The study was conducted at the National Defense Medical College Hospital in Japan. PATIENTS: We recruited 96 patients who underwent a single regimen of preoperative short-term chemoradiotherapy (20 Gy in 5 fractions with 400 mg/day Tegafur/Uracil for 1 week) and radical resection. DESIGN: This was a retrospective study. We obtained pretreatment biopsy specimens of these patients and immunostained these specimens with antibodies for CD133, cyclooxygenase-2, p53, p27, p21, and epidermal growth factor receptor. The resected primary tumor was evaluated according to 2 different tumor regression grading systems that were based on the degrees of fibrosis and cytological alterations. RESULTS: Positivity for CD133 or cyclooxygenase-2 expression was associated with chemoradioresistance, which was determined by the degree of fibrosis, in both univariate (P = .02 and P = .0003) and multivariate (P = .03 and P = .001) analyses. Univariate and multivariate analyses of the degree of cytological alterations also revealed a significant association between chemoradioresistance and the expression of CD133 (P = .005 and P = .003) and cyclooxygenase-2 (P = .005 and P = .03), whereas other markers failed to associate. LIMITATIONS: The information on patients' outcome was not available. CONCLUSIONS: Our study revealed the independent predictive values of CD133 and cyclooxygenase-2 expressions in histological tumor regression after preoperative chemoradiotherapy. PMID- 21825890 TI - Effectiveness of biofeedback therapy in the treatment of anterior resection syndrome after rectal cancer surgery. AB - BACKGROUND: Although anterior resection syndrome commonly occurs after anal sphincter-saving surgery, no standard treatment option is currently available. OBJECTIVE: The aim of the present study was to evaluate the clinical effectiveness of biofeedback in patients with anterior resection syndrome after sphincter-saving surgery for rectal cancer. DESIGN: This study was a retrospective review of data collected during the course of treatment. SETTINGS: Patients were treated at a teaching hospital (Asan Medical Center) in Seoul, Korea, from January 2003 through December 2008. PATIENTS: Patients who received biofeedback therapy for anterior resection syndrome after rectal cancer surgery were included. MAIN OUTCOME MEASURES: The Cleveland Clinic Florida fecal incontinence score, number of bowel movements per day, a visual analog scale for assessing patient satisfaction, and anorectal manometry were used to assess outcome of biofeedback treatment. RESULTS: : After biofeedback therapy, significant improvements were observed in fecal incontinence score (P < .001), number of bowel movements (P < .001), and anorectal manometry data (maximum resting pressure, P = .010; maximum squeeze pressure, P = .006; rectal capacity, P = .003). Compared with patients who started biofeedback treatment less than 18 months after surgery, those who started biofeedback at 18 months or longer after surgery showed greater improvements in fecal incontinence score (P = .032). Only patients with fecal incontinence as the primary symptom showed significant improvements in all variables, including fecal incontinence score, P < .001; defecation frequency, P < .001; and anorectal manometry (maximum resting pressure, P = .027; maximum squeeze pressure, P = .021; rectal capacity, P = .004). Patients who received radiation therapy in addition to surgery reported a significantly higher satisfaction score than those receiving surgery alone (P = .041). LIMITATIONS: This is a nonrandomized retrospective study. Anorectal manometry was not regularly performed in all patients. CONCLUSIONS: Biofeedback therapy produced significant clinical benefits for patients with severe fecal incontinence and may be an effective treatment for patients with anterior resection syndrome after surgery for rectal cancer. PMID- 21825891 TI - Bowel biofeedback treatment in patients with multiple sclerosis and bowel symptoms. AB - BACKGROUND: Bowel symptoms are common in patients with multiple sclerosis, but current treatment is empirical. OBJECTIVE: This study aimed to identify effect of biofeedback on bowel symptoms, mood, and anorectal physiology in patients with multiple sclerosis. DESIGN: This was a prospective observational study: the amount of change between pre- and posttreatment values of outcome measures was compared and analyzed. Responders were considered to be patients who demonstrated an improvement greater than or equal to the 25th percentile of the change in bowel score. Comparison between responders and nonresponders was performed. SETTINGS: This investigation was conducted at a neurogastroenterology clinic, tertiary referrals center. PATIENTS: Thirty-nine patients with multiple sclerosis and constipation and/or fecal incontinence were included in the study. INTERVENTION: Patients were given bowel biofeedback therapy. MAIN OUTCOME MEASURES: The primary outcome measures were the Wexner Constipation and Wexner Incontinence scores. The secondary outcome measures were hospital anxiety and depression scores and anorectal physiology parameters. RESULTS: Data are reported as median and interquartile ranges. After biofeedback there was significant improvement in Wexner Constipation (12 (5-19) pretreatment vs 8 (4-14) posttreatment, P = .001), Wexner Incontinence (12 (3-15) pretreatment vs 4 (2-10) posttreatment, P < .001) and hospital depression scores (7 (3-11) pretreatment vs 5 (3-10) posttreatment, P = .015). The 5-second endurance squeeze pressure was also improved (21 (11-54) mmHg pretreatment vs 43 (26-59) mmHg posttreatment, P = .001). Posttreatment change of Wexner Constipation was -2(-5/0), and of Wexner Incontinence was -3(-9/0) ("-" indicates improvement). Therefore, those patients who had a reduction of at least 5 points in the Wexner Constipation score and/or of at least 9 points in the Wexner Incontinence score were considered responders (18 patients, 46%). They showed a greater improvement of only 5-second endurance squeeze pressure (23.5 (7.5/32.75) mmHg responders vs 4 (-6/20) mmHg nonresponders, P = .008); no difference was observed in the comparison of baseline variables with nonresponders. Significant negative relationship existed between the change in the Wexner Constipation score (-2 (-5/0)) and the pretreatment Wexner Constipation score (12 (5/19), beta = -0.463, P < .001), and the change in the Wexner Incontinence score (-3 (-9/0)) with the pretreatment Wexner Incontinence score (12 (3/15), beta = -0.590, P < .001). So, the higher the initial bowel symptom score, the greater the improvement. LIMITATIONS: This study was limited by the lack of a control group. CONCLUSIONS: Biofeedback improves bowel symptoms, depression, and 5-second endurance squeeze pressure in patients with multiple sclerosis. PMID- 21825892 TI - Anal acoustic reflectometry: a new reproducible technique providing physiological assessment of anal sphincter function. AB - BACKGROUND: Anal acoustic reflectometry is a new technique of assessing anal sphincter function. Five new variables reflecting anal canal function are measured: the opening and closing pressure, the opening and closing elastance, and hysteresis. OBJECTIVE: This study aimed to compare the reproducibility of this new technique, in terms of test-retest and interrater reliability, with manometry, the current standard test of sphincter function. DESIGN: This is a comparative study of reproducibility between anal acoustic reflectometry and manometry. SETTINGS: This study was conducted at a university hospital (outpatient clinic and endoscopy unit). PATIENTS: Twenty-six (21 female) subjects were assessed with both anal acoustic reflectometry and manometry on 2 separate occasions (test-retest reliability) and 22 (16 female) subjects were assessed with both methods by 2 separate investigators (interrater reliability). MAIN OUTCOME MEASURES: Reproducibility was assessed according to the Bland-Altman method. RESULTS: All of the measured novel anal acoustic reflectometry parameters had acceptable mean differences and repeatability coefficients. Comparison of the 2 methods of sphincter assessment (anal acoustic reflectometry vs manometry) was made for measurements taken at rest and during voluntary contraction. There was no significant difference in terms of test-retest reliability between the manometry maximum resting pressure vs the reflectometry opening pressure (P = .57) or manometry maximum squeeze pressure vs the reflectometry squeeze opening pressure (P = .68). No significant difference between methods was found in interrater reliability during assessments at rest (P = .62) and voluntary contraction (P = .96). LIMITATIONS: Anal acoustic reflectometry is limited, as with all tests of anorectal function, in that the device is placed within the anal canal, causing stimulation of sensory and stretch receptors. CONCLUSIONS: Anal acoustic reflectometry has a reproducibility comparable to manometry in terms of both test-retest and interrater reliability. Anal acoustic reflectometry is a promising technique that allows an assessment of anal canal physiology that is not available with manometry. PMID- 21825893 TI - Evaluation of the role of the puborectal part of the levator ani muscle in anal incontinence: a prospective study of 78 female patients with anal incontinence. AB - BACKGROUND: Anal incontinence is most often linked with sphincter rupture and/or stretching the pudendal nerves. OBJECTIVE: The aim of our study was to investigate the involvement of the puborectal part of the levator ani muscle in anal incontinence. PATIENTS AND MAIN OUTCOME MEASURES: Seventy-eight female patients were studied by anorectal manometry, 3-dimensional ultrasound examination, and concentric needle electromyography of the external anal sphincter, puborectal muscle, and bulbocavernous muscles, completing with the evaluation of the pudendal nerve terminal motor latencies. Damage to the puborectal muscle was defined by an abnormal ultrasound and/or abnormal electromyography. RESULTS: Rupture of the anal sphincter apparatus and puborectal muscle was found in 23% and 3.8%. The EMG showed damage to the puborectal part in 39 cases: this was isolated in 4 cases and combined with external anal sphincter damage in 35 patients. Unilateral or bilateral increase in the terminal motor latencies of the pudendal nerves was found in 36% (28/78) of the patients. The frequency of peripheral neurogenic lesions varied from 36% to 90% according to the electromyographic tests used. There was no correlation between puborectal part damage and resting pressure, perception threshold, and maximum tolerable rectal volume. The mean Wexner index score was not increased by the existence of a defect involving the puborectal part found by echography or by damage to the puborectal part shown by the EMG. Investigating puborectal muscle lesions reduced the percentage of idiopathic anal incontinence to 2.5%. CONCLUSION: Our study confirms the feasibility and usefulness of combined electromyography and 3 dimensional ultrasound examination of the puborectal muscle in anal incontinence. PMID- 21825894 TI - Temporary sacral nerve stimulation alters rectal sensory function: a physiological study. AB - BACKGROUND: The indications for sacral nerve stimulation are increasing, but the mechanism remains poorly understood. OBJECTIVE: This study aimed to examine the effect of sacral nerve stimulation on rectal compliance and rectal sensory function. DESIGN: This was a prospective study. SETTINGS: This study took place at a university teaching hospital. PATIENTS: Twenty-three consecutive consenting patients (22 female; median age, 49 y) undergoing temporary sacral nerve stimulation for fecal incontinence were prospectively studied. Clinical response was assessed by the use of bowel diaries and Wexner scores. MAIN OUTCOME MEASURES: Anal manometry, rectal compliance, volume and pressure thresholds to rectal distension (barostat), and rectal Doppler mucosal blood flow were measured before and at the end of stimulation. RESULTS: Sixteen patients (70%) had a favorable clinical response. Median anal squeeze pressures increased with stimulation from 40 (range, 6-156) cmH2O to 64 (range, 16-243) cmH2O. Median rectal compliance did not significantly change with stimulation (prestimulation: 11.5 (range, 7.9-21.8) mL/mmHg, poststimulation: 12.4 (range, 6.2-22) mL/mmHg, P = .941). Rectal wall pressures associated with urge (baseline: 15.4 (range, 11 26.7) mmHg, poststimulation: 19 (range, 11.1-42.7) mmHg, P = .054) and maximal tolerated thresholds (baseline: 21.6 (8.5-31.9) mmHg, poststimulation: 27.1 (14.3 43.3) mmHg, P = .023) significantly increased after stimulation. Rectal Doppler mucosal blood flow did not significantly change with stimulation (baseline: 125.8 (69.9-346.8), poststimulation: 112.4 (50.2-404.1), P = .735). Changes in anal resting pressure and rectal wall pressures with stimulation were evident only in responders; however, changes in anal squeeze pressures were evident in both responders and nonresponders. LIMITATIONS: The study reports results following short-term stimulation in a small but homogenous group of patients. A larger long term study will follow. CONCLUSION: Temporary sacral nerve stimulation does not change rectal compliance, but is associated with significant changes to the pressure thresholds of rectal distension. This, together with the observation that outcome is not related to sphincter integrity, supports the hypothesis of an afferent-mediated mechanism of action. PMID- 21825895 TI - Accuracy of endoscopic ultrasound to assess tumor response after neoadjuvant treatment in rectal cancer: can we trust the findings? AB - BACKGROUND: The finding that some rectal cancers respond to neoadjuvant chemoradiation is broadening new surgical options for the treatment of some of these tumors that, until now, required a total mesorectal excision. Nevertheless, a fine match between clinical and pathological response is required when planning conservative surgical approaches. OBJECTIVE: This study aims to prospectively validate the use of endoscopic ultrasound as a predictor of clinical and pathological tumor response in patients with locally advanced rectal cancer. DESIGN: : This is an observational study of a cohort of patients undergoing chemoradiation followed by surgery. SETTINGS: This study was conducted at a tertiary medical center. PATIENTS: A total of 235 consecutive patients who underwent chemoradiation followed by surgery at a single institution during a 7 year period were included. MAIN OUTCOME MEASURES: All tumors were staged and restaged at 4 to 6 weeks after neoadjuvant treatment. Downsizing and downstaging were calculated between the initial and posttreatment measures and correlated to the pathological stage. The accuracy of endoscopic ultrasound to predict response was determined. RESULTS: Findings after chemoradiation showed T-downstaging in 54 patients (23%) and N-downstaging in 110 (47%). Overstaging occurred in 88 (37%) patients and was more commonly observed than understaging (21 patients; 9%). Related to the pathological report, endoscopic ultrasound correctly matched the T stage in 54% and the N stage in 75% of tumors. Sensitivity, specificity, and positive and negative predictive values to predict nodal involvement were 39%, 91%, 67%, and 76%. Accuracy was not influenced by such factors as age, distance of the tumor from the anal verge, or time to surgery. LIMITATIONS: This study was limited by the lack of comparison with other imaging methods. CONCLUSIONS: Endoscopic ultrasound allows prediction of involved lymph nodes in 75% of the cases; however, 1 in 5 patients are missclassified as uN0 after neoadjuvant treatment. In our point of view, this percentage is too high to rely only on this diagnostic modality to support a "wait and see" approach. PMID- 21825896 TI - Clinical features and risk factors for primary surgery in 205 patients with Crohn's disease: analysis of a South China cohort. AB - BACKGROUND: The frequency of Crohn's disease in China is increasing, but few reports are available on clinical features, phenotypes according to the Montreal classification, or risk factors for surgery in mainland China. OBJECTIVE: This study aimed to assess clinical presentation, phenotypes according to the Montreal classification, and potential risk factors for initial surgery in patients with Crohn's disease in southern China. DESIGN: This was an observational study designed as a retrospective analysis of a historical cohort. SETTINGS: The study was conducted at a tertiary referral hospital, Guangzhou, China. PATIENTS: Medical records of 212 consecutive patients with Crohn's disease were reviewed; data from 205 patients who met inclusion criteria were analyzed. MAIN OUTCOME MEASURES: The value of age, location, and behavior of disease according to the Montreal system, smoking behavior, and other clinical variables as potential risk factors in predicting the requirement for initial surgery was assessed by use of Cox regression analysis. RESULTS: A total of 205 patients were studied. Abdominal pain (181 patients, 88.3%) was the most common clinical presentation. At the time of diagnosis, age was between 17 and 40 years in 145 patients (70.7%). The Montreal classification of disease location was L3 (ileocolonic) in 114 patients (55.6%), disease behavior was classified as inflammatory in 133 patients (64.9%). During the course of their disease (median, 4 years; range, 1-21 years), 79 patients (38.5%) required bowel resection. Kaplan-Meier analysis showed that the overall cumulative rate of primary bowel surgery was 17.6% at 1 year after onset of symptoms, 20.3% at 2 years, 35.2% at 5 years, and 58.3% at 10 years. In our final Cox model, stricturing (HR, 3.67; 95% CI, 2.14-6.29; P < .001), penetrating behavior (HR, 4.60; 95% CI, 2.58-8.22; P < .001), and smoking habit (HR, 2.02; 95% CI, 1.15-3.53; P = .014) were significantly associated with an increased risk for bowel resection. LIMITATIONS: The study was limited by its retrospective nature. CONCLUSIONS: In Chinese patients with Crohn's disease, abdominal pain is the most common clinical presentation, and the most common phenotypes are age 17 to 40 years at diagnosis, ileocolonic disease location, and inflammatory disease behavior. More than one-third of patients require surgery at a median of 4 years after onset of symptoms. Stricturing, penetrating disease, and smoking are associated with an increased risk of requiring bowel resection. PMID- 21825897 TI - Effects of a tissue sealing-cutting device versus monopolar electrocautery on early pilonidal wound healing: a prospective randomized controlled trial. AB - BACKGROUND: Monopolar electrocauterization produces thermal effects on neighboring tissues, causing tissue damage. Recently, tissue sealing-cutting devices, which are easy to use and achieve simultaneous selective sealing and cutting with less production of heat, have been used. OBJECTIVE: The aim of this study was to investigate the effects of a tissue sealing-cutting device vs monopolar electrocautery on wound healing in the early postoperative period after pilonidal sinus surgery. DESIGN: This study was a prospective randomized clinical trial. SETTING: This study was conducted at Military Hospital, Eskisehir, Turkey. PATIENTS: In total, 128 patients with chronic pilonidal disease were randomly assigned into 2 clinically comparable groups between December 2009 and June 2010. INTERVENTION: Pilonidal sinus excision was performed with monopolar electrocautery in the control group (n = 64) and with a tissue sealing-cutting device in the study group (n = 64). Data regarding wound healing, demographic variables, history, physical examination findings, defect dimensions, and scores for a visual analog scale were recorded. MAIN OUTCOME MEASURES: The main outcomes measured were surgical site infection, early wound failure (dehiscence), and unhealed wound rate. RESULTS: : Wound infection and dehiscence rates were significantly lower (P = .01 and .02), but the duration of surgery was significantly longer (P < .01) in the tissue sealing-cutting group. The unhealed wound rate was 12.5% in the electrocautery group and 4.7% in the tissue sealing cutting group (P = .01). When the distance from the lowest margin to the anus was 5 cm or less, wound infection and dehiscence rates were lower in the tissue sealing-cutting group (P < .01 and .03). LIMITATIONS: We could not obtain data regarding the cost-effectiveness of the instruments. CONCLUSIONS: A tissue sealing-cutting device in pilonidal sinus surgery yields better wound healing than monopolar electrocautery. PMID- 21825898 TI - Circumferential excisional hemorrhoidectomy for extensive acute thrombosis: a 14 year experience. AB - BACKGROUND: Recurrence and/or complications after 3-quadrant hemorrhoidectomy or stapled hemorrhoidopexy still remain a challenging problem. This challenge is even greater for massive hemorrhoidal thrombosis leading to edema, ulceration, and/or gangrene. To address this challenge, we developed a further modification of the Whitehead procedure termed circumferential excisional hemorrhoidectomy. The proposed procedure allows access to a submucoanodermal/skin workspace that provides a "view from inside" the hemorrhoidal disease, and therefore facilitates the precise excision of even each hemorrhoidal vein while preserving the overlying normal tissues. OBJECTIVE: This study aimed to describe the circumferential excisional hemorrhoidectomy procedure and to demonstrate its results in patients presenting with total hemorrhoidal thrombosis. DESIGN, SETTINGS, PATIENTS: This prospective, descriptive study was conducted with 294 consecutive patients who underwent urgent circumferential excisional hemorrhoidectomy at our coloproctological center from January 1996 to June 2009. INTERVENTION: Circumferential excisional hemorrhoidectomy involves the stripping and excision of hemorrhoids from the submucoanodermal space with reconstruction of the anal canal by the use of an undermined irregular/zigzag-shaped mucoanodermal flap and accurately trimmed skin. MAIN OUTCOME MEASURES: The main outcome measures were the surgical outcomes and complications. RESULTS: The mean patient age was 41.7 for both sexes. There were 215 men and 79 women. The mean operative time was 26.4 (range, 17-43) minutes. In terms of postoperative complications, there were 39 (13.2%) urinary retentions, 1 (0.3%) fecal impaction, and 3 (1%) delayed complete wound epithelization. The mean hospital stay was 3.1 (range, 2-5) days, and the mean time off from work was 10 (range, 7 18) days. At the fifth week after surgery, digital rectal examination revealed easily dilated mild stricture in 26 (8.8%) patients. At a mean follow-up of 6.8 (range, 2-14) years, 271 (92.2%) accessible patients were actually symptom-free. LIMITATION: This study did not have a control group. CONCLUSION: Circumferential excisional hemorrhoidectomy is an anatomically safe surgical procedure with a low rate of complications and no recurrences, even after a long-term follow-up. PMID- 21825899 TI - Heterogeneity of KRAS status may explain the subset of discordant KRAS status between primary and metastatic colorectal cancer. AB - BACKGROUND: KRAS status is a useful predictive marker for anti-epidermal growth factor receptor antibody therapy. OBJECTIVE: This study aimed to examine the concordance rate of KRAS mutation status between corresponding primary and metastatic colorectal cancer lesions, and also among multiple metastatic tumors. Furthermore, we examined the heterogeneity of KRAS mutations with respect to discordant KRAS status between primary and metastatic tumors. DESIGN AND SETTINGS: This study was retrospective in design. PATIENTS: Forty-three patients with primary tumors and 113 metastatic tumors were studied. MAIN OUTCOME MEASURES: The KRAS mutational status was determined by the peptide nucleic acid clamp real-time polymerase chain reaction TaqMan assay. We also performed sequencing analysis to validate the KRAS mutational status. When KRAS status differed between primary and metastatic tumors, we examined the heterogeneity of KRAS status within individual primary tumors by microdissecting multiple samples in each patient. RESULTS: The frequency of KRAS mutations in primary tumors was 34.9%. A high concordance rate of KRAS (88.4-91.7%) mutations was observed between primary and metastatic tumors. All 5 cases (11.6%) with discordant KRAS status had heterogeneous KRAS status in primary tumors. However, in 10 concordant cases all microdissected areas showed an identical KRAS mutational status within each patient. The KRAS mutational statuses in all multiple liver and/or lung metastatic tumors were the same as those of the primary tumor. LIMITATIONS: We could not validate KRAS status in microdissected samples by the direct sequence method that was used in the present study, because the quantity of DNA was not sufficient to perform direct sequencing. CONCLUSION: KRAS status in a primary site may be used for selecting patients who would benefit from anti-epidermal growth factor receptor therapy. However, KRAS status can be heterogeneous within a primary tumor, and thus different parts of such tumors should be examined for KRAS status to correctly predict the KRAS status in metastatic lesions. PMID- 21825900 TI - Perineal and pelvic anatomy of extralevator abdominoperineal excision for rectal cancer: cadaveric dissection. AB - BACKGROUND: Circumferential margin positivity and tumor perforations are the main reasons for the poor oncological outcome following standard abdominoperineal excision for low rectal cancer. The extralevator abdominoperineal excision approach has been developed to avoid "coning down" or "surgical waisting"; however, surgical education in this area has been neglected. PURPOSE: This study aims to define correct surgical anatomical planes for extralevator abdominoperineal excision and show the differences in excision planes between standard and extralevator abdominoperineal excision. DESIGN AND SETTING: Macroscopic surgical dissections were performed in a clinical anatomy laboratory. The dissections were recorded as video clips. METHODS: In accordance with the surgical technique of extralevator abdominoperineal excision, abdominal and then perineal dissections were performed on 1 female and 5 male cadavers. Neurovascular, muscular, and fascial structures located in or near the excision field were carefully revealed. RESULTS: The surgical planes of extralevator abdominoperineal excision, which widen the tumor-free margins and prevent inadvertent bowel perforation, are described in this step-by-step anatomical dissection study. Within the surgical excision planes, sacral vessels and sympathetic chains form a neurovascular network at the level of the sacrococcygeal joint. Although pelvic autonomic plexuses were away from the lateral incision line, their branches extending to urogenital organs were very close to the anterolateral dissection line. Perineal dissection showed that the internal pudendal vessels and pudendal nerve were close to the lateral excision plane. The superficial transverse perineal muscle and perineal body were the most important landmarks to determine the anterior boundary of dissection. LIMITATIONS: The study focused on the perineal dissection of extralevator abdominoperineal excision. CONCLUSIONS: Successful extralevator abdominoperineal excision crucially depends on an accurate knowledge of surgical anatomical planes. PMID- 21825901 TI - Traumatic injury of the colon and rectum: the evidence vs dogma. AB - BACKGROUND: The treatment of traumatic injuries to the colon and rectum is often driven by dogma, despite the presence of evidence suggesting alternative methods of care. OBJECTIVE: This is an evidence-based review, in the format of a review article, to determine the ideal treatment of noniatrogenic traumatic injuries to the colon and rectum to improve the care provided to this group of patients. Recommendations and treatment algorithms were based on consensus conclusions of the data. DATA SOURCES: A search of MEDLINE, PubMed, and the Cochrane Database of Collected Reviews was performed from 1965 through December 2010. STUDY SELECTION: Authors independently reviewed selected abstracts to determine their scientific merit and relevance based on key-word combinations regarding colorectal trauma. A directed search of the embedded references from the primary articles was also performed in select circumstances. We then performed a complete evaluation of 108 articles and 3 additional abstracts. MAIN OUTCOME MEASURES: The main outcomes were morbidity, mortality, and colostomy rates. RESULTS: Evidence-based recommendations and algorithms are presented for the management of traumatic colorectal injuries. LIMITATIONS: Level I and II evidence was limited. CONCLUSIONS: Colorectal injuries remain a challenging clinical entity associated with significant morbidity. Familiarity with the different methods to approach and manage these injuries, including "damage control" tactics when necessary, will allow surgeons to minimize unnecessary complications and mortality. PMID- 21825902 TI - Canadian Association of General Surgeons, the American College of Surgeons, the Canadian Society of Colorectal Surgeons, and the American Society of Colon and Rectal Surgeons: evidence based reviews in surgery-colorectal surgery. PMID- 21825903 TI - Is there any additional psychological and/or physical job constraint associated with informal caregiving status? Findings from the GAZEL Cohort Study. PMID- 21825906 TI - Complications that can occur during pregnancy. PMID- 21825907 TI - The assessment of health literacy is a nursing priority. PMID- 21825908 TI - Neonatal healthcare: what does the future hold? PMID- 21825909 TI - Brown adipose tissue. PMID- 21825910 TI - The National Practitioner Data Bank: a primer for clinicians. PMID- 21825911 TI - Screening and diagnosing gestational diabetes mellitus revisited: implications from HAPO. AB - Screening and diagnosis of gestational diabetes has lacked uniform criteria both nationally and internationally. In addition, the relationship between the degree of hyperglycemia or glucose intolerance and the risk of maternal, fetal, and neonatal adverse outcomes has not been clearly established. The International Association of Diabetes and Pregnancy Study Groups (IADPSG) recently published their recommendation for diagnosing and classifying gestational hyperglycemia in pregnancy after evaluation of the results of the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) observational study. Their recommendations have recently been accepted by the American Diabetes Association and are currently under review by the American College of Obstetricians and Gynecologist (ACOG) in the United States. If accepted in the United States and internationally, the world would have consistent thresholds for evaluating hyperglycemia in pregnancy, which would not only include the diagnosis of gestational diabetes mellitus but also overt diabetes, which has not been encompassed by previously accepted definitions. PMID- 21825913 TI - Pulmonary complications in pregnancy: considerations for care. AB - Anatomic and physiologic changes of pregnancy predispose the mother to increased morbidity and mortality whereas increasing risks of a less than optimal outcome for the fetus. The frequency and significance of acute and chronic respiratory conditions in pregnant women have increased in recent years. Clinicians must have an understanding of cardiopulmonary physiology to promptly recognize and treat pregnant women with respiratory conditions ranging from asthma to adult respiratory distress syndrome. Hospitals must establish systems to assure timely assessment, multidisciplinary care, and possibly a plan for transfer to a higher level of care to provide highest quality care to the perinatal patient presenting with a severe respiratory condition to promote optimal outcomes for the woman and the fetus. PMID- 21825914 TI - Preeclampsia: pathophysiology and implications for care. AB - Nurses are increasingly encountering pregnant/postpartum women with hypertensive disorders of pregnancy, of which preeclampsia is one of the most common. The Joint Commission published a Sentinel Event Alert in 2010 on prevention of maternal death. This report notes that one of the 5 leading causes of pregnancy related mortality between 1991 and 1997 was "hypertensive disorder." Preeclampsia presents significant risk to the health of the mother and the fetus. Clearly, nurses must understand the pathophysiology, assessment, management, recurrence risk, and long-term implications of preeclampsia to participate fully in a management plan that promotes safe patient care. PMID- 21825915 TI - Acute volume resuscitation following obstetric hemorrhage. AB - Hemorrhage remains a leading cause of pregnancy-related morbidity and mortality. A rapid collaborative approach to management of the woman experiencing excessive blood loss is required to optimize outcomes. Successful treatment of the hemorrhaging pregnant woman is dependent on early recognition of bleeding and clinical manifestations of shock, treatment of the underlying cause of the hemorrhage, and simultaneous restoration of adequate circulating volume as well as blood component therapy. Early communication with providers, identified triggers for changes in patient condition, and drills/simulations with the multidisciplinary healthcare team are critical strategies for improving response and outcomes. PMID- 21825916 TI - Informing parents about the actual or impending death of their infant in a newborn intensive care unit. AB - Modern perinatal and neonatal care practices have increased survival of infants that in previous care eras would have perished. The majority of infants admitted to a newborn intensive care unit following delivery currently do well and are discharged home. Unfortunately for others, the ultimate outcome may be death. The death of a newborn infant is clearly a devastating loss to parents. How parents are informed of their infant's actual or impending death can either add to a grief reaction, or help support parents through their loss. The literature supports that most healthcare professionals frequently feel inept while discussing the death of a newborn with the baby's family. This article will present parents' descriptions of what helped or did not help when they were informed of their infant's inevitable death. It will also demonstrate how simulation may be effective in improving communication of bad or sad news to families in a manner that sustains them in the immediate present, as well as adds to their future well-being. PMID- 21825918 TI - Failure to rescue in neonatal care. AB - Failure to rescue (FTR) has been described as the end result of a series of events relating to the environment of care and nursing quality. Only recently has FTR as a process measure been applied to perinatal care settings. Nurses' continuous presence at the bedside puts them in a privileged position to recognize signs of clinical deterioration and to take action. Many factors contribute to nurses' ability to save lives when infants develop complications. Although such factors are often system-related, nurses may be held responsible if they do not act according to an acceptable standard of care. In the neonatal intensive care unit, FTR has not been applied or adopted as a measure of nursing quality. This article describes how FTR is relevant in the neonatal intensive care unit and outlines nursing and system actions that can be taken to rescue some of the hospital's most vulnerable patients. PMID- 21825917 TI - Hyperoxia in very preterm infants: a systematic review of the literature. AB - Supplemental oxygen plays a critical role in the management of infants born at the lower limit of viability, but not without the risk of complications resulting from high levels or prolonged exposure. Longitudinal studies of very premature infants, born at less than 28 weeks' gestation, establish a clear relationship between pulse oximetry saturation readings above 92%, or hyperoxia, and development of severe retinopathy of prematurity, chronic lung disease, and brain injury. Hyperoxia is neither natural nor random. It is an unintended consequence of intervention. A comprehensive review of the literature reveals a strong association between exposure to hyperoxia and subsequent expression of comorbidities. Owing to this knowledge, eradication of hyperoxia, and consequent reduction of sequelae, is a significant public health concern that deserves attention by the neonatal community. Although prospective, collaborative meta analyses will soon provide needed additional data to inform practice, existing compelling evidence supports urgent practice change to reduce exposure to hyperoxia in very preterm infants. PMID- 21825919 TI - Postnatal steroids for the treatment of bronchopulmonary dysplasia: a complex case presentation. AB - Postnatal steroids are a controversial intervention for the prevention and treatment of bronchopulmonary dysplasia in preterm infants. Studies demonstrating a potential for steroid-related adverse effects, including growth and neurodevelopmental impairment, have significantly changed clinical practice over the past decade. There are circumstances in which the potential benefits may outweigh the risks associated with postnatal steroids. This case presentation details the hospital course and treatment plan for an extremely low-birth-weight infant who remained ventilator dependent at the age of 3 weeks. Evidence-based research, American Academy of Pediatric recommendations, and collaboration with the family helped guide the plan of care. Following a short course of low-dose dexamethasone, the infant was successfully extubated. The case highlights the importance of using clinical judgment based on research and family preferences to benefit the patient. PMID- 21825921 TI - Learning to listen. PMID- 21825922 TI - Minimally invasive treatment for Neer IIb distal clavicle fractures with titanium cable. AB - BACKGROUND: Neer IIB distal clavicle fracture is associated with disruption of the coracoclavicular ligament and a variable degree of displacement. Surgical treatment using various implants such as intramedullary wires, screws, and plates has been described in the literature with satisfactory results. METHODS: We report our experience of minimally invasive treatment using titanium cable for type IIB clavicular fractures. A retrospective analysis was performed to evaluate the outcomes of patients with Neer IIB distal clavicle fractures that were treated with titanium cable between 2003 and 2008. Functional outcome was evaluated using the Karlsson's criteria. The mean follow-up was 32 months (range, 12-48 months). Twenty-nine patients met the inclusion criteria. RESULTS: All patients progressed to osseous union at a mean time of 12 weeks (range, 10-15 weeks). There was one metal work failure that did not affect functional recovery. According to Karlsson's criteria, radiographic representations (3 months after surgery) and postoperative shoulder functional recovery revealed an excellent and good rate in all cases. CONCLUSION: Minimally invasive surgery using titanium cable seems to be a good option for the treatment of Neer IIB distal clavicle fractures, with early functional recovery and no requirement for revision surgery. PMID- 21825923 TI - Fornix hemorrhage after mild head injury. PMID- 21825924 TI - Perforated Amyand's hernia with necrotizing fasciitis. PMID- 21825925 TI - Submucous traumatic rectal hematoma treated conservatively. PMID- 21825926 TI - Toxic megacolon with abdominal compartment syndrome. PMID- 21825927 TI - Hypertonic saline resuscitation of hemorrhagic shock does not decrease in vivo neutrophil interactions with endothelium in the blood-brain microcirculation. AB - BACKGROUND: Resuscitation of hemorrhagic shock with isotonic crystalloids has been shown to activate polymorphonuclear neutrophils (PMNs). Although hypertonic saline (HTS) can reduce PMN activation and interactions with endothelial cells (EC) in systemic microvascular beds, no data exist demonstrating that the same occurs in the unique blood-brain barrier microcirculation. We hypothesized that resuscitation of hemorrhagic shock with HTS would blunt brain in vivo PMN-EC interactions. METHODS: Wistar rats (250-350 g) underwent craniotomy and placement of a window for live intravital viewing of pial vessels. Twenty animals were bled to a mean arterial pressure of 30 mm Hg to 35 mm Hg for 1 hour and resuscitated with shed blood and either 5% HTS (6 mL/kg) or Ringer's lactate (RL) (2* shed blood volume). Circulating rhodamine-6G-labeled PMN in pial venules were captured by videomicroscopy at baseline (preshock), end of the shock period, after resuscitation, and every 15 minutes to 30 minutes for 2 hours. Hemodynamics and arterial gases were monitored. Off-line footage analysis allowed comparisons of PMN-EC interactions between groups. RESULTS: Animals in both groups developed significant metabolic acidosis (p < 0.01) after hemorrhage, but postresuscitation blood pressures were similar at all time points. Crystalloid resuscitation volumes were 10* greater in RL than HTS animals (p < 0.001). For all time points, we did not observe the expected reduction in PMN rolling and adhesion in HTS animals, instead noted trends of consistently lower interactions in RL counterparts. CONCLUSIONS: In contradistinction to studies evaluating the systemic microcirculation, HTS may activate PMN-EC crosstalk in the blood-brain microcirculation. Further studies are needed to analyze whether this effect is due to the unique nature of the blood-brain interface. PMID- 21825928 TI - Impact of enhanced mobilization of bone marrow derived cells to site of injury. AB - BACKGROUND: Bone marrow derived cells (BMDC) and mesenchymal stem cells (MSC) are necessary for healing of injured tissues. Intravenous granulocyte-colony stimulating factor (G-CSF) is known to induce mobilization of BMDC to peripheral blood and the tissue levels of the stromal cell derived factor-1 (SDF-1) to be key in their homing to sites of injury. We hypothesized that injection of SDF-1 to the site of injury and/or systemic administration of G-CSF increases homing of BMDC and improves healing of traumatic injury. We also postulated that increased homing of MSC alone to sites of injury would also improve tissue healing. METHODS: Male Sprague-Dawley rats were subjected to unilateral lung contusion (LC) and assigned to the following groups: LC + injection of SDF-1 (LC + SDF-1) in the contused lung, pretreatment with systemic G-CSF for 5 days followed by either LC alone (LC + G-CSF) or by LC + injection of SDF-1 (LC + SDF-1/G-CSF). Rats in the MSC group were subjected to LC followed by systemic injection of MSC (LC + MSC). Unmanipulated controls and LC + local injection of saline (LC + saline) served as controls. Lung injury was assessed on days 1 and 5 postinjury using a histologic Lung Injury Score. BMDC and MSC homing were assessed on day 1 by hematopoietic progenitor cell (CFU-GEMM, BFU-E, and CFU-E) colony growth and immunofluorescence tracking of tagged MSC in the injured lung, respectively. RESULTS: Both LC + SDF-1 and LC + G-CSF had increased hematopoietic progenitor cell colony growth in the injured lung, and their combination (LC + SDF-1/G-CSF) was additive when compared with LC + saline (18 +/- 3, 24 +/- 3, 32 +/- 3; 21 +/- 3, 36 +/- 10, 36 +/- 3; 31 +/- 4, 44 +/- 10, 53 +/- 5 vs. 6 +/- 2, 11 +/- 3, 17 +/- 4; *p < 0.05). Tagged MSC were tracked predominantly in the contused lung versus the non-contused lung (7 +/- 3 vs. 3 +/- 2, N degrees MSC/HPF; *p < 0.05). Lung Injury Score on day 5 after injury was significantly lower in the LC + SDF-1, LC + G-CSF, LC + SDF-1/G-CSF and LC + MSC groups versus LC + saline (1 +/- 0.6, 0.7 +/- 0.5, 1 +/- 0.9, 1.1 +/- 0.9 vs. 3.1 +/- 0.8; *p < 0.05). CONCLUSION: Local SDF-1 and/or systemic G-CSF can effectively increase BMDC homing to sites of traumatic injury in an additive way and improve wound healing. This process appears to be mediated predominantly through MSC. Additional investigations are needed to identify the optimal adjuncts to improve wound healing following severe traumatic injury. PMID- 21825929 TI - Lyophilized plasma with ascorbic acid decreases inflammation in hemorrhagic shock. AB - BACKGROUND: Delivery of a high ratio of plasma to packed red blood cells to patients who require massive transfusion is associated with improved survival. Hemorrhagic shock causes increased production of pro-inflammatory cytokines. These are associated with late morbidity and mortality. The use of fresh frozen plasma makes high ratio resuscitation logistically difficult and does not address dysfunctional inflammation. Lyophilized plasma (LP) is a stable powdered form of plasma that is both safe and easily reconstituted. Previous work demonstrated that LP reconstituted with ascorbic acid (AA) decreased inflammation. Whether the reduction of inflammation was associated with LP or the AA is unknown. METHODS: Thirty female swine were anesthetized and subjected to a multisystem combat relevant model consisting of femur fracture, controlled hemorrhage, and hypothermia. A standardized grade V liver injury was made and the animals were randomly assigned to receive LP reconstituted with AA, citric acid (CA), or hydrochloric acid (HCl). Blood was drawn at baseline and at 2 hours and 4 hours for interleukin (IL)-6, IL-8, and tumor necrosis factor-alpha serum concentrations measured by enzyme-linked immunosorbent assay. Lung tissue was harvested and processed for gene expression before euthanizing the animals. RESULTS: No differences were observed in mortality, baseline cytokine serum concentration, or gene expression. Enzyme-linked immunosorbent assay demonstrated that IL-6 concentration increased over time for all groups (p < 0.05), but less so at 2 hours in the AA group compared with CA and HCl. CONCLUSION: In this animal model of trauma, hemorrhage and resuscitation, AA decreases IL-6 expression relative to CA and HCl. These findings confirm previous work from our laboratory and suggest that AA is responsible for suppression of dysfunctional inflammation in this model. PMID- 21825930 TI - Early blood product and crystalloid volume resuscitation: risk association with multiple organ dysfunction after severe blunt traumatic injury. AB - BACKGROUND: Elements of volume resuscitation from hemorrhagic shock, such as amount of blood product and crystalloid administration, have been shown to be associated with multiple organ dysfunction (MOD). However, it is unknown whether these are causative factors or merely markers of an underlying requirement for large-volume resuscitation. We sought to further delineate the relevance of the major individual components of early volume resuscitation to onset of MOD after severe blunt traumatic injury. METHODS: We performed a secondary analysis of a large, multicenter prospective observational cohort of severely injured blunt trauma patients, the NIGMS Trauma Glue Grant, to assess the relevance of individual components of resuscitation administered in the first 12 hours of resuscitation including packed red blood cells (PRBC), fresh frozen plasma (FFP), and isotonic crystalloid, to the onset of MOD within the first 28 days after injury. Deaths within 48 hours of injury were excluded. We used a two tiered, exhaustive logistic regression model search technique to adjust for potential confounders from clinically relevant MOD covariates, including indicators of shock severity, injury severity, comorbidities, age, and gender. RESULTS: The study cohort consisted of 1,366 severely injured blunt trauma patients (median new Injury Severity Score = 34). Incidence of 28-day Marshall MOD was 19.6%. Transfusion of >=10 Units of PRBC in the first 12 hours (odds ratio, 2.06; 95% confidence interval 1.44-2.94), but not FFP (>=8 U) or large volume crystalloid administration (>=12 L), was independently associated with onset of 28-day Marshall MOD. PRBC:FFP ratio in the first 12 hours was not significantly associated with MOD. CONCLUSIONS: When controlling for all major components of acute volume resuscitation, massive-transfusion volumes of PRBC's within the first 12 hours of resuscitation are modestly associated with MOD, whereas FFP and large volume crystalloid administration are not independently associated with MOD. Previous reported associations of blood products and large-volume crystalloid with MOD may be reflecting overall resuscitation requirements and burden of injury rather than independent causation. PMID- 21825932 TI - Incidence of pulmonary fat embolism at autopsy: an undiagnosed epidemic. AB - BACKGROUND: To determine the incidence, time course, and severity of pulmonary fat embolism (PFE) and cerebral fat embolism (CFE) in trauma and nontrauma patients at the time of autopsy. METHODS: Prospectively, consecutive patients presenting for autopsy were evaluated for evidence pulmonary and brain fat embolism. The lung sections were obtained from the upper and lower lobe of the patients' lungs on the right and left and brain tissue. This tissue was prepared with osmium tetroxide for histologic evaluation. The number of fat droplets per high power field was counted for all sections. The autopsy reports and medical records were used to determine cause of death, time to death, injuries, if cardiopulmonary resuscitation (CPR) was attempted, sex, height, weight, and age. RESULTS: Fifty decedents were evaluated for PFE and CFE. The average age was 45.8 years +/- 17.4 years, average body mass index was 30.1 kg/cm2 +/- 7.0 kg/cm2, and 68% of the patients were men. The cause of death was determined to be trauma in 68% (34/50) of decedents, with 88% (30/34) blunt and 12% (4/34) penetrating. CPR was performed on 30% (15/50), and PFE was present in 76% (38/50) of all patients. Subjects with PFE had no difference with respect to sex, trauma, mechanism of injury, CPR, external contusions, fractures, head, spine, chest, abdominal, pelvic, and extremity injuries. However, subjects without PFE had significantly increased weight (109 +/- 29 kg vs. 86 +/- 18 kg; p = 0.023) but no difference in height or body mass index. PFE was present in 82% (28/34) of trauma patents and 63% (10/16) nontrauma patients. Eighty-eight percent of nontrauma patients and 86% of trauma patients who received CPR had PFE. Trauma patients with PFE showed no significant difference in any group. Eighty-eight percent of trauma patients died within 1 hour of injury, and 80% (24/30) of them had PFE at the time of autopsy. CFE was present only in one patient with a severe head and cervical spine injury. CONCLUSION: PFE is common in trauma patients. CPR is associated with a high incidence of PFE regardless of cause of death. PFE occurs acutely within the "golden hour" and should be considered in traumatically injured patients. Further studies are needed to evaluate the pathogenesis of PFE. PMID- 21825931 TI - HIV and hepatitis in an urban penetrating trauma population: unrecognized and untreated. AB - BACKGROUND: Despite limited prospective data, it is commonly believed that human immunodeficiency virus (HIV) and hepatitis infections are widespread in the penetrating trauma population, placing healthcare workers at risk for occupational exposure. Our primary study objective was to measure the prevalence of HIV (anti-HIV), hepatitis B (HB surface antigen [HBsAg]), and hepatitis C virus (anti-HCV) in our penetrating trauma population. METHODS: We prospectively analyzed penetrating trauma patients admitted to Temple University Hospital between August 2008 and February 2010. Patients (n = 341) were tested with an oral swab for anti-HIV and serum evaluated for HBsAg and anti-HCV. Positives were confirmed with western blot, neutralization immunoassay, and reverse transcription polymerase chain reaction, respectively. Demographics, risk factors, and clinical characteristics were analyzed. RESULTS: Of 341 patients, 4 patients (1.2%) tested positive for anti-HIV and 2 had a positive HBsAg (0.6%). Hepatitis C was the most prevalent measured infection as anti-HCV was detected in 26 (7.6%) patients. Overall, 32 (9.4%) patients were tested positive for anti HIV, HBsAg, or anti-HCV. Twenty-eight (75%) of these patients who tested positive were undiagnosed before study enrollment. When potential risk factors were analyzed, age (odds ratio, 1.07, p = 0.031) and intravenous drug use (odds ratio 14.4, p < 0.001) independently increased the likelihood of anti-HIV, HBsAg, or anti-HCV-positive markers. CONCLUSIONS: Greater than 9% of our penetrating trauma study population tested positive for anti-HIV, HBsAg, or anti-HCV although patients were infrequently aware of their seropositive status. As penetrating trauma victims frequently require expedient, invasive procedures, universal precautions are essential. The prevalence of undiagnosed HIV and hepatitis in penetrating trauma victims provides an important opportunity for education, screening, and earlier treatment of this high-risk population. PMID- 21825933 TI - The natural history of upper extremity deep venous thromboses in critically ill surgical and trauma patients: what is the role of anticoagulation? AB - BACKGROUND: The natural history and optimal treatment of upper extremity (UE) deep venous thromboses (DVT's) remains uncertain as does the clinical significance of catheter-associated (CA) UE DVT's. We sought to analyze predictors of UE DVT resolution and hypothesized that anticoagulation will be associated with quicker UE DVT clot resolution and that CA UE DVT's whose catheters are removed will resolve more often than non-CA UE DVT's. METHODS: All patients on the surgical intensive care unit service were prospectively followed from January 2008 to May 2010. A standardized DVT prevention protocol was used and screening bilateral UE and lower extremity duplex examinations were obtained within 48 hours of admission and then weekly. Computed tomography angiography for pulmonary embolism was obtained if clinically indicated. Patients with UE DVT were treated according to attending discretion. Data regarding patient demographics and UE DVT characteristics were recorded: DVT location, catheter association, occlusive status, treatment, and resolution. The primary outcome measure was UE DVT resolution before hospital discharge. Interval decrease in size on the subsequent duplex after UE DVT detection was also noted. UE DVTs without a follow-up duplex were excluded from the final analysis. Univariate and multivariate analyses were used to identify independent predictors of UE DVT resolution. RESULTS: There were 201 UE DVT's in 129 patients; 123 DVTs had a follow-up duplex and were included. Fifty-four percent of UEDVTs improved on the next duplex, 60% resolved before discharge, and 2% embolized. The internal jugular was the most common site (52%) and 72% were nonocclusive. Sixty-four percent were CAUEDVT's and line removal was associated with more frequent improvement on the next duplex (55% vs. 17%, p = 0.047, mid-P exact). Sixty-eight percent of UEDVTs were treated with some form of anticoagulation, but this was not associated with improved UE DVT resolution (61% vs. 60%). Independent predictors of clot resolution were location in the arm (odds ratio = 4.1 compared with the internal jugular, p = 0.031) and time from clot detection until final duplex (odds ratio =1.052 per day, p = 0.032). CONCLUSION: A majority of UE DVT's are CA, more than half resolve before discharge, and 2% embolize. Anticoagulation does not appear to affect outcomes, but line removal does result in a quicker decrease in clot size. PMID- 21825934 TI - A pilot study on the randomization of inferior vena cava filter placement for venous thromboembolism prophylaxis in high-risk trauma patients. AB - BACKGROUND: Placement of prophylactic inferior vena cava filters (pIVCFs) for the prevention of pulmonary embolism (PE) in high-risk trauma patients (HRTPs) are widely practiced despite the lack of Level I data supporting this use. We report the 2-year interim analysis of the Filters in Trauma pilot study. METHODS: This is a single institution, prospective randomized controlled pilot feasibility study in a Level I trauma center. HRTPs were identified for pIVCF placement by the Eastern Association for the Surgery of Trauma guidelines. From November 2008 to November 2010, HRTPs were enrolled and randomized to either pIVCF or no pIVCF. All patients received pharmacologic prophylaxis when safe. Primary outcomes included feasibility objectives and secondary outcomes were incidence of PE, deep vein thrombosis (DVT), and death. RESULTS: Thirty-four of 38 enrolled patients were eligible for analysis. The baseline sociodemographic characteristics were balanced between the both groups. Results of the feasibility objectives included: time from admission to enrollment (mean, 47.4 hours +/- 22.0 hours), time from enrollment to randomization (mean, 4.8 hours +/- 9.1 hours), time from randomization to IVCF placement (mean, 16.9 hours +/- 9.2 hours), adherence to weekly compression ultrasound within first month (IVCF group = 44.4%; non-IVCF group = 62.5%), and 1-month clinical follow-up (IVCF group = 83.3%; non-IVCF group = 100%). At 6-month follow-up, one PE in the nonfilter group and one DVT in the filter group had occurred. One non-PE-related death occurred in the filter group. Barriers to enrollment included inability to obtain informed consent due to patient refusal or no next of kin identified and delayed notification of eligibility status. CONCLUSION: Our pilot study demonstrates for the first time that a randomized controlled trial evaluating the efficacy of pIVCFs in trauma patients is feasible. This pilot data will be used to inform the design of a multicenter randomized controlled trial to determine the incidence of PE and DVT in HRTPs receiving pIVCFs versus no pIVCF. PMID- 21825935 TI - Short simulation training improves objective skills in established advanced practitioners managing emergencies on the ward and surgical intensive care unit. AB - BACKGROUND: Several studies evaluating simulation training in intensive care unit (ICU) physicians have demonstrated improvement in leadership and management skills. No study to date has evaluated whether such training is useful in established ICU advanced practitioners (APs). We hypothesized that human patient simulator-based training would improve surgical ICU APs' skills at managing medical crises. METHODS: After institutional review board approval, 12 APs completed 1/2 day of simulation training on the SimMan, Laerdal system. Each subject participated in five scenarios, first as team leader (pretraining scenario), then as observer for three scenarios, and finally, again as team leader (posttraining). Faculty teaching accompanied each scenario and preceded a debriefing session with video replay. Three experts scored emergency care skills (Airway-Breathing-Circulation [ABCs] sequence, recognition of shock, pneumothorax, etc.) and teamwork leadership/interpersonal skills. A multiple choice question examination and training effectiveness questionnaire were completed before and after training. Fellows underwent the same curriculum and served to validate the study. Pre- and postscores were compared using the Wilcoxon signed rank test with two-tailed significance of 0.05. RESULTS: Improvement was seen in participants' scores combining all parameters (73% +/- 13% vs. 80% +/- 11%, p = 0.018). AP leadership/interpersonal skills (+12%), multiple choice question examination (+4%), and training effectiveness questionnaire (+6%) scores improved significantly (p < 0.05). Fellows teamwork leadership/interpersonal skills scores were higher than APs (p < 0.001) but training brought AP scores to fellow levels. Interrater reliability was high (r = 0.77, 95% confidence interval 0.71-0.82; p < 0.001). CONCLUSIONS: Human patient simulator training in established surgical ICU APs improves leadership, teamwork, and self-confidence skills in managing medical emergencies. Such a validated curriculum may be useful as an AP continuing education resource. PMID- 21825936 TI - The relationship between annual hospital volume of trauma patients and in hospital mortality in New York State. AB - BACKGROUND: Several studies in the literature have examined the volume-outcome relationship for trauma, but the findings have been mixed, and the associated impact of the trauma center level has not been examined to date. The purposes of this study are to (1) determine whether there is a significant relationship between the annual volume of trauma inpatients treated in a trauma center (with "patients" defined in multiple ways) and short-term mortality of those patients, and (2) examine the impact on the volume-mortality relationship of being a Level I versus Level II trauma center. METHODS: Data from New York's Trauma Registry in 2003 to 2006 were used to examine the impact of total trauma patient volume and volume of patients with Injury Severity Score (ISS) of at least 16 on in-hospital mortality rates after adjusting for numerous risk factors that have been demonstrated to be associated with mortality. RESULTS: The adjusted odds of in hospital mortality patients in centers with a mean annual volume of less than 2,000 patients was significantly higher (adjusted odds ratio = 1.46, 95% confidence interval, 1.25-1.71) than the odds for patients in higher volume centers. The adjusted odds of mortality for patients in centers with an American College of Surgeons-recommended annual volume of less than 240 patients with an ISS of at least 16 was 1.41 times as high (95% confidence interval, 1.17-1.69) as the odds for patients in higher volume centers. However, for both volume cohorts analyzed, the variation in risk-adjusted in-hospital mortality rate was greater among centers within each volume subset than between these volume subsets. CONCLUSION: When considering the trauma system as a whole, higher total annual trauma center volume (2,000 or higher) and higher volume of patients with ISS >=16 (240 and higher) are significant predictors of lower in-hospital mortality. Although the American College of Surgeons-recommended 1,200 total volume is not a significant predictor, hospitals in New York with ISS >=16 volumes in excess of 240 also have total volumes in excess of 2,000. However, when considering individual trauma centers, high volume centers do not consistently perform better than low volume centers. Thus, despite the association between volume and mortality, we believe that the most accurate way to assess trauma center performance is through the use of an accurate, complete, comprehensive database for computing center-specific risk-adjusted mortality rates, rather than volume per se. PMID- 21825937 TI - A model to increase trauma reimbursement in the private practice environment. AB - BACKGROUND: Trauma physician reimbursement at many trauma centers is based on an academic or employed model. However, private practice is also used, especially at community-based trauma centers. Commercial insurance companies acknowledge that trauma care should be reimbursed at a higher rate than elective practice, but they often lack the ability to separate these lines of business. Federal law also prevents groups that are not integrated from shared negotiation. The objective of this study was to develop a model for private practice billing that provides increased reimbursement for trauma line of business. METHODS: The hospital created a trauma contracting organization. This organization contracted with the hospital and insurance companies to deliver trauma care. It obtained fee schedules for trauma care that were greater than for elective surgical care. It then contracted with trauma physicians to deliver trauma care using those fee schedules and its provider number. Data from 2009 were evaluated to determine the impact. RESULTS: Reimbursement rates were evaluated for multiple carriers and compared between the trauma contracting organization and the standard practice. Rate of reimbursement for self-pay patients and government carriers (Medicare, Medicaid, and Champus) were the same for both: 7% of charges for self-pay and 25% of charges for government carriers. Commercial carriers provided increased reimbursement for the trauma line of business, averaging 7% to 10% more return on charges. The annualized impact was over $300,000 more reimbursement on over $5,000,000 in charges. CONCLUSION: This model can provide a means to increase reimbursement for trauma care in a private practice environment. PMID- 21825938 TI - Canadian Cervical Spine rule compared with computed tomography: a prospective analysis. AB - BACKGROUND: The Canadian cervical spine rule (CCS) has been found to be an effective tool to determine the need for radiographic evaluation of the cervical spine (c-spine) incorporating both clinical findings and mechanism. Previously, it has been validated only through clinical follow-up or selective use of X-rays. The purpose of this study was to validate it using computed tomography (CT) as the gold standard to identify fractures. METHODS: Prospective evaluation was performed on 3,201 blunt trauma patients who were screened by CCS and were compared with a complete c-spine CT. CSS positive indicated at least one positive clinical or mechanism finding, whereas CT positive indicated presence of a fracture. RESULTS: There were 192 patients with c-spine fractures versus 3,009 without fracture on CT. The fracture group was older (42.7 +/- 19.0 years vs. 37.8 +/- 17.5 years, p = 0.0006), had a lower Glasgow Coma Scale score (13.8 +/- 4.2 vs. 14.4 +/- 4.3, p < 0.0001), and lower systolic blood pressure (133.3 +/- 23.8 mm Hg vs. 139.5 +/- 23.1 mm Hg, p = 0.0023). The sensitivity of CCS was 100% (192/192), specificity was 0.60% (18/3009), positive predictive value was 6.03% (192/3183), and negative predictive value was 100% (18/18). Logistic regression identified only 8 of the 19 factors included in the CCS to be independent predictors of c-spine fracture. CONCLUSIONS: CCS is very sensitive but not very specific to determine the need for radiographic evaluation after blunt trauma. Based on this study, the rule should be streamlined to improve specificity while maintaining sensitivity. PMID- 21825939 TI - Platelet transfusion: an unnecessary risk for mild traumatic brain injury patients on antiplatelet therapy. AB - INTRODUCTION: To determine whether there is a benefit to platelet transfusion in mild traumatic brain injury (MTBI) patients with intracranial hemorrhage (ICH), taking antiplatelet therapy before hospitalization. MATERIALS AND METHODS: The study design retrospectively reviewed patients admitted to a Level I trauma center during a 2-year period with an isolated MTBI (Glasgow Coma Scale score >=13, ICH seen on a head computed tomographic scan (head computed tomography [HCT]), and taking an antiplatelet agent before hospitalization. HCT's were categorized based on the Marshall Classification, Rotterdam Score, and ICH volume. Hospital records were reviewed noting neurologic, cardiac, respiratory events, and discharge Glasgow Outcome Scale. RESULTS: There were 1,101 patients with TBI hospitalized during the 2-year study period. Three hundred twenty-one of these patients had an MTBI with ICH at the time of admission, and from this group, 113 were taking an antiplatelet agent. Only 4 (1.2%) of the 321 patients suffered a neurologic decline. All were gradual in nature, and none required emergent intervention. An analysis of the 113 patients taking antiplatelet agents, comparing patients who were not given a platelet transfusion with those who received a platelet transfusion, found no significant difference in the rate of HCT progression, neurologic decline, or Glasgow Outcome Scale at hospital discharge between the two groups. There was a trend, which was not significant, toward more medical declines in patients who received a platelet transfusion. A further review, analyzing all 321 patients with ICH showed receiving a transfusion of any type (i.e., platelets, fresh frozen plasma, or blood) was a strong predictor of medical decline (p < 0.0001). The odds ratio of having a medical decline after transfusion was 5.8 (95% confidence interval, 1.2-28.2). CONCLUSIONS: Platelet transfusion did not improve short-term outcomes after MTBI. Further randomized controlled trials need to be done to truly assess if there is no benefit in platelet transfusion in patients taking antiplatelet agents suffering an MTBI. Because the overall outcome in MTBI patients is favorable, platelet transfusion in these patients may not be indicated. PMID- 21825940 TI - Brief episodes of intracranial hypertension and cerebral hypoperfusion are associated with poor functional outcome after severe traumatic brain injury. AB - BACKGROUND: Management strategies after severe traumatic brain injury (TBI) target prevention and treatment of intracranial hypertension (ICH) and cerebral hypoperfusion (CH). We have previously established that continuous automated recordings of vital signs (VS) are more highly correlated with outcome than manual end-hour recordings. One potential benefit of automated vital sign data capture is the ability to detect brief episodes of ICH and CH. The purpose of this study was to establish whether a relationship exists between brief episodes of ICH and CH and outcome after severe TBI. MATERIALS: Patients at the R Adams Cowley Shock Trauma Center were prospectively enrolled over a 2-year period. Inclusion criteria were as follows: age >14 years, admission within the first 6 hours after injury, Glasgow Coma Scale score <9 on admission, and placement of a clinically indicated ICP monitor. From high-resolution automated VS data recording system, we calculated the 5-minute means of intracranial pressure (ICP), cerebral perfusion pressure (CPP), and Brain Trauma Index (BTI = CPP/ICP). Patients were stratified by mortality and 6-month Extended Glasgow Outcome Score (GOSE). RESULTS: Sixty subjects were enrolled with a mean admission Glasgow Coma Scale score of 6.4 +/- 3.1, a mean Head Abbreviated Injury Severity Scale score of 4.2 +/- 0.7, and a mean Marshall CT score of 2.5 +/- 0.9. Significant differences in the mean number of brief episodes of CPP <50 and BTI <2 in patients with a GOSE 1-4 versus GOSE 5-8 (9.4 vs. 4.7, p = 0.02 and 9.3 vs. 4.9, p = 0.03) were found. There were significantly more mean brief episodes per day of ICP >30 (0.52 vs. 0.29, p = 0.02), CPP <50 (0.65 vs. 0.28, p < 0.001), CPP <60 (1.09 vs. 0.7, p = 0.03), BTI <2 (0.66 vs. 0.31, p = 0.002), and BTI <3 (1.1 vs. 0.64, p = 0.01) in those patients with GOSE 1-4. Number of brief episodes of CPP <50, CPP <60, BTI <2, and BTI <3 all demonstrated high predictive power for unfavorable functional outcome (area under the curve = 0.65-0.75, p < 0.05). CONCLUSIONS: This study demonstrates that the number of brief 5-minute episodes of ICH and CH is predictive of poor outcome after severe TBI. This finding has important implications for management paradigms which are currently targeted to treatment rather than prevention of ICH and CH. This study demonstrates that these brief episodes may play a significant role in outcome after severe TBI. PMID- 21825941 TI - Cost-utility analysis of levetiracetam and phenytoin for posttraumatic seizure prophylaxis. AB - BACKGROUND: The standard for early posttraumatic brain injury (TBI) seizure prophylaxis is phenytoin. Despite its effectiveness, some argue for the use of newer antiepileptics (e.g., levetiracetam) because phenytoin requires close monitoring to maintain its therapeutic window and is associated with rare cutaneous hypersensitivity reactions. The purpose of this study was to evaluate whether phenytoin or levetiracetam would be more cost-effective in preventing early post-TBI seizures and reducing their negative impact on TBI outcomes. METHODS: Cost-effectiveness analysis with the following base case assumptions: (1) phenytoin patients receive 1.0 g fosphenytoin load + 3 days of 100 mg three times a day (TID), have level drawn on day 3, "therapeutic" patients receive 100 mg TID on days 4 to 7, and "subtherapeutic" patients receive 200 mg TID on days 4 to 7; (2) levetiracetam patients receive 500 mg load + 7 days of 500 mg two times a day. Glasgow Outcome Scale (GOS) scores 4 to 5 represent good outcome, and GOS scores 2 to 3 represent poor outcome. Patients who develop early seizures: 40% good outcome, 50% poor outcome, and 10% death. Those who do not develop seizures: 75% good outcome, 20% poor outcome, and 5% death. Quality of life outcomes by GOS: good = 0.7, poor = 0.3, and death = 0.0. Severe adverse events and those impacting costs are rare for each agent. Assumptions were obtained through hospital query and exhaustive literature review. RESULTS: The cost of a 7-day course of fosphenytoin, phenytoin, and free phenytoin level was $37.50, whereas the cost of a 7-day course of levetiracetam was $480.00. Literature review noted phenytoin to be as effective as levetiracetam in preventing early post-TBI seizures (and more effective in subclinical seizures). Quality-adjusted life years (QALY) were 23.6 for phenytoin and 23.2 for levetiracetam. As a result, the cost/effectiveness ratios were $1.58/QALY for phenytoin and $20.72/QALY for levetiracetam. All sensitivity analyses favored phenytoin unless levetiracetam prevented 100% of seizures and cost <$400 for 7-day course. CONCLUSIONS: Phenytoin is more cost-effective than levetiracetam at all reasonable prices and at all clinically plausible reductions in post-TBI seizure potential. PMID- 21825942 TI - The mortality inflection point for age and acute cervical spinal cord injury. AB - BACKGROUND: Acute cervical spinal cord injury (cSCI) is associated with significant morbidity and mortality. Vertebral level and American Spinal Injury Association (ASIA) score influence both hospital course and ultimate outcome. While controlling for these variables, we describe the effect of age on cSCI related pneumonia and mortality. METHODS: All patients treated at our regional spinal cord injury center with an acute cSCI during a 5-year period (2005-2009) were reviewed retrospectively. Patient demographics, injury level, ASIA score, length of stay (LOS), radiologic, laboratory, and microbiology data were reviewed. Pneumonia was defined as an infiltrate on chest X-ray along with two of the following: leukocytosis, fever greater than 101 degrees F, or positive bronchial alveolar lavage cultures; all occurring within the same 24-hour period. RESULTS: There were 244 cSCI during the study period. In-hospital mortality was significantly higher for those older than 75 years (40.5% vs. 4.0%, p < 0.0001). Pneumonia rates were not significantly different between age groups. In all age groups, high ASIA scores (A and B) were associated with increased pneumonia (61.9% vs. 17.4%, p < 0.0001) and mortality (16.7% vs. 3.5%, p = 0.002). Similarly, patients with higher cervical injury levels (C4 and above) had a higher incidence of pneumonia (39.5% vs. 25.9%, p < 0.05) and a trend toward higher mortality. CONCLUSIONS: Age was associated with an increase in mortality among patients with an acute cSCI. Injury level and ASIA score contributed significantly to overall pneumonia rate and mortality at all ages; however, pneumonia did not correlate directly with mortality in this population. Other factors play a role in the mortality associated with geriatric spinal cord injured patients, including end-of-life decision making; these need to be investigated further in future studies. PMID- 21825943 TI - Safety and efficacy of heparin or enoxaparin prophylaxis in blunt trauma patients with a head abbreviated injury severity score >2. AB - BACKGROUND: Timing and type of chemoprophylaxis (CP) that should be used in patients with traumatic brain injury (TBI) remains unclear. We reviewed our institutions experience with low-molecular-weight heparin (LMWH) and unfractionated heparin (UFH) in TBI. METHODS: The charts of all TBI patients with a head abbreviated injury severity score >2 (HAIS) and an intensive care unit length of stay >48 hours admitted during a 42-month period between 2006 and 2009 were reviewed. CP was initiated after intracranial hemorrhage was considered stable. We reviewed all operative notes and radiologic reports in these patients to analyze the rate of significant intracranial hemorrhagic complications, deep venous thrombosis, or pulmonary embolus. RESULTS: A total of 386 patients with TBI were identified; 158 were treated with LMWH and 171 were treated with UFH. HAIS was significantly different between the LMWH (3.8 +/- 0.7) and UFH (4.1 +/- 0.7) groups; the time to initiation of CP was not. The UFH group had a significantly higher rate of deep venous thrombosis and pulmonary embolus. Progression of ICH that occurred after the initiation of CP was significantly higher in the UFH-treated patients (59%) when compared with those treated with LMWH (40%). Two patients in the UFH group required craniotomy after the initiation of CP. CONCLUSION: LMWH is an effective method of CP in patients with TBI, providing a lower rate of venous thromboembolic and hemorrhagic complications when compared with UFH. A large, prospective, randomized study would better evaluate the safety and efficacy of LMWH in patients suffering blunt traumatic brain injury. PMID- 21825944 TI - Laser Doppler imaging for early detection of hemorrhage. AB - BACKGROUND: Laser Doppler Imaging (LDI) is a noninvasive means to measure blood flow through the superficial skin capillary plexus using flux units. Our objective was to determine the ability of LDI of the skin to detect and quantify rapid, severe hemorrhage. METHODS: Five Yucatan mini-pigs (25-35 kg) underwent controlled hemorrhage of 25 mL/kg blood for 20 minutes. Median flux of a 10 cm * 10 cm area of the lower abdomen was measured at 2-minute intervals from initiation of hemorrhage to resuscitation with concurrent measurement of heart rate (HR), systolic blood pressure (SBP), and mean arterial pressure (MAP). RESULTS: Average time to a change of 5 U in flux following start of hemorrhage was 2.4 minutes. This was significantly faster than time to change in HR (19.2 minutes, p < 0.05) and showed a trend toward more rapid identification of hemorrhage relative to changes in SBP (3.2 minutes, p = 0.157) and MAP (3.6 minutes, p = 0.083). Flux changes occurred at smaller % total blood volume lost than HR (3.94% vs. 28.8%, p < 0.05) and trended toward smaller volume identification than SBP (4.88%, p = 0.180) and MAP (5.36%, p = 0.102). Average correlation (rho) of blood volume lost to flux was -0.974; HR, 0.346; SBP, 0.978; and MAP, -0.975. A change of 5 flux units was significantly more sensitive for hemorrhage than a change of 5 beats per minute in HR or 5 mm Hg in SBP or MAP (0.596 vs. 0.169, 0.438, and 0.287 respectively, all p < 0.05). CONCLUSION: LDI is a sensitive, specific, and early means to detect and quantify severe hemorrhage. PMID- 21825945 TI - Rapid thrombelastography delivers real-time results that predict transfusion within 1 hour of admission. AB - BACKGROUND: Recognition of trauma-induced coagulopathy by conventional coagulation testing (CCT) is limited by their slow results, incomplete characterization, and their poor predictive nature. Rapid thrombelastography (r TEG) delivers a more comprehensive assessment of the coagulation system but has not been prospectively validated in trauma patients. The purpose of this pilot study was to evaluate the timeliness of r-TEG results, their correlation with CCTs, and the ability of r-TEG to predict early blood transfusion. METHODS: Over a 5-month period, 583 consecutive major trauma activations were prospectively entered into a database, of which 272 met entry criteria. r-TEG and CCTs (prothrombin time, international normalized ratio, partial thromboplastin time, and platelet count) were obtained on all patients. Graphical results for r-TEG were displayed "real time" in the trauma bay. Spearman's correlation and regression models were used to compare r-TEG and CCTs. RESULTS: Early r-TEG values (activated clotting time [ACT], k-time, and r-value) were available within 5 minutes, late r-TEG values (maximal amplitude and alpha-angle) within 15 minutes, and CCTs within 48 minutes (p < 0.001). ACT, r-value, and k-time showed strong correlation with prothrombin time, international normalized ratio, and partial thromboplastin time (all r >0.70; p < 0.001), whereas maximal amplitude (r = -0.49) and alpha-angle (r = 0.40) correlated with platelet count (both p < 0.001). Linear regression demonstrated ACT predicted red blood cells (coef. 0.05; 95% confidence interval [CI], 0.04-0.06; p < 0.001), plasma (coef. 0.03; 95% CI, 0.02-0.04; p < 0.001), and platelet (coef. 0.06; 95% CI, 0.04-0.07; p < 0.001) transfusions within the first 2 hours of arrival. Controlling for all demographics and Emergency Department vitals, ACT >128 predicted massive transfusion (>=10 U) in the first 6 hours (odds ratio, 5.15; 95% CI, 1.36-19.49; p = 0.01). In addition, ACT <105 predicted patients who did not receive any transfusions in the first 24 hours (odds ratio, 2.80; CI, 1.02-7.07; p = 0.04). CONCLUSIONS: Graphical r-TEG results are available within minutes, correlate with conventional coagulation test that are not as rapidly available, and are predictive of early transfusions of packed red blood cells, plasma, and platelets. PMID- 21825946 TI - Does regionalization of acute care surgery decrease mortality? AB - BACKGROUND: During the initial development of an Emergency General Surgery (EGS) service, severity of illness (SOI) can be expected to be high and should decrease as the service matures. We hypothesize that a matured regional EGS service would show decreasing mortality and length of stay (LOS) over time. METHODS: We performed a retrospective study of a prospectively collected EGS registry data from 2004 to 2009. Patients were included if they had been discharged from the EGS service and were stratified by year of discharge. Systemic inflammatory response syndrome, sepsis, shock, peritonitis, perforation, and acute renal failure were used as markers of SOI. Patients were defined as high acuity if they had one or more of these SOI markers. Differences in mortality, LOS, intensive care unit admissions, SOI, charges, and distance were compared across and between years using nonparametric statistical tests (Fisher's exact, Wilcoxon rank-sum, and Kruskal-Wallis tests). RESULTS: A total of 3,439 patients met study criteria. The mean age was 47 years +/- 17.5 years. The majority of the patients were female (1,813, 47.3%). The overall LOS was 6.4 days +/- 9.4 days (median, 4 days). In all, 2,331 (67.8%) of the patients underwent operation. Over the course of the study period, the SOI indicators stabilized at between 13% and 17% of the patient population with at least one indicator. During that time period, mortality steadily decreased from 4.9% to 1.3% (p < 0.5). CONCLUSION: Despite consistently high SOI, a dedicated and matured EGS service demonstrated a decrease in mortality and LOS. PMID- 21825947 TI - Does late night hip surgery affect outcome? AB - BACKGROUND: There is a perception that after-hours hip surgery may result in increased complication rates. Surgeon fatigue, decreased availability of support staff, and other logistical factors may play an adverse role. However, there are little data supporting this perception in the hip fracture literature. We present a retrospective study comparing outcomes of hip fracture surgeries performed after hours versus regular daytime hours and outcomes before and after implementation of a dedicated orthopedic trauma room staffed by a fellowship trained traumatologist. METHODS: A retrospective study of 767 consecutive patients with intertrochanteric, subtrochanteric, or femoral neck fractures was performed for the years 2000 to 2006. Surgeries were stratified by time of incision into two groups: day (07:00 AM-05:59 PM) and night (06:00 PM-06:59 PM). Each group was further divided into a period before the implementation of a trauma room and the period after (August 2004). Records were examined for procedure length, intraoperative blood loss, complications (nonunion, implant failure, infection, deep vein thrombosis, pulmonary embolus, and refracture), reoperation, and mortality. RESULTS: Four hundred ninety-nine patients were included the day group and 268 in the night group. There were no differences in terms of age, ethnicity, American Society of Anesthesiologists status, total number of comorbidities, and fracture type between groups. There were significantly more females in the night group than the day group. Intertrochanteric fractures were 64% of all fractures, femoral neck fractures were 34%, and subtrochanteric fractures were 2%. Duration of surgery for Dynamic Hip System procedures was significantly longer in the night group and also before the trauma room became available. These differences in duration of surgery also correlate with blood loss differences between the groups. Intramedullary nails also took longer to do at night. Hemiarthroplasties demonstrated no significant differences. The 1-year and 2-year mortalities of hip fracture patients operated during daytime hours in a trauma room (13 and 15%, respectively) were significantly less than they were before the implementation of the trauma room (25 and 37%, respectively). When the effect of the trauma room was eliminated, there were no significant differences between overall daytime and nighttime mortalities at 1 month, 1 year, and 2 years. There were no significant differences in other complications noted between the different groups. CONCLUSIONS: We recommend that nighttime surgery should not be dismissed in hip fracture patients that would otherwise benefit from an early operation. However, there seems to be a decreasing trend in mortality when hip fractures are operated in a dedicated daytime trauma room staffed by a dedicated traumatologist. PMID- 21825948 TI - Independent predictors of mortality for necrotizing fasciitis: a retrospective analysis in a single institution. AB - BACKGROUND: Necrotizing fasciitis (NF), a life-threatening soft tissue infection, requires early diagnosis, prompt and repeated surgical intervention, and broad spectrum antibiotic therapy. The aim of this study was to identify the independent predictors of mortality among patients with NF in Taiwan. METHODS: We retrospectively reviewed the medical records of all patients who were admitted to Chi-Mei Medical Center, Tainan, Taiwan, with a diagnosis of NF. The definitive diagnosis was confirmed by the surgical findings, including (1) dishwater or foul smelling discharge, (2) presence of necrotic fascia or lack of fascial bleeding, and (3) lack of resistance of normally adherent muscular fascia to blunt dissection. To identify factors associated with mortality, variables including personal history and comorbidities, clinical symptoms and signs, laboratory data, and microbiological data were compared between survivors and nonsurvivors. RESULTS: From January 2003 to December 2009, 472 patients treated for NF were included in the study. The overall mortality was 12.1% (n = 57) and the 30-day mortality was 11.0% (n = 52). Multivariate analysis revealed eight independent predictors of mortality for NF including liver cirrhosis, soft tissue air, Aeromonas infection, age older than 60 years, band polymorphonuclear neutrophils >10%, activated partial thromboplastin time >60 s, bacteremia, and serum creatinine >2 mg/dL. CONCLUSION: We identified eight independent predictors of mortality that provided useful information on the severity of NF and guidance for treatment. Prospective studies are required to examine the fitness and sufficiency of these variables as effective predictors of NF mortality. PMID- 21825949 TI - Gender dimorphism in the gut: mucosal protection by estrogen stimulation of IgA transcytosis. AB - BACKGROUND: Laboratory studies demonstrate gender dimorphism following trauma/hemorrhagic shock (T/HS). These differences have been attributed to estrogen (E2) levels. Maintenance of gut barrier function by E2 following T/HS has been recently described. However, the mechanisms are not clear. The principle humoral defense mechanism of the gut is provided by secretory immunoglobulin IgA. It is transported across intestinal epithelial cells (IEC) by a specific transmembrane protein receptor (polyimmunoglobulin receptor, pIgR). Transport of IgA (transcytosis) may be influenced by a number of factors. We postulated that there may be differences in IgA transcytosis and IEC pIgR expression in response to sex hormones. We studied this in vitro. METHODS: Confluent HT-29 IEC monolayers were established in a two-chamber cell culture system. E2 or dihydrotestosterone (DHT) was added for 72 hours; then dimeric IgA (dIgA) was added to the basal chamber (4 degrees C, to obtain maximal pIgR binding of dIgA). Apical media were sampled at intervals and recovery of secretory immunoglobulin IgA quantitated by enzyme-linked immunosorbent assay. PIgR expression in HT-29 cells was quantitated as mean fluorescence intensity using flow cytometry. Monolayer integrity was confirmed by serial measurement of transepithelial electrical resistance. RESULTS: IgA transcytosis increased fourfold in 12-hour versus 3-hour culture periods in the control experiments. A similar finding was noted in the DHT experiments on IgA transcytosis. There were dramatic increases in IgA transcytosis across HT-29 cells exposed to E2.This was apparent at both 3- and 12-hour experimental time points and exhibited a dose-response effect. HT-29 cells cocultured with E2 increased pIgR expression in a time- and dose-dependent fashion. The greatest pIgR expression was noted following coculture of HT-29 cells with E2 for 6 days at the 1.0 MUmol/L E2 concentration. The integrity of HT 29 monolayers in both the E2 and DHT treatment groups at T = 0 and 72 hours was assessed and showed no significant differences versus control cells. CONCLUSION: IgA transcytosis was augmented by E2 in a dose-response fashion. This effect was due to augmented intracellular trafficking of IgA and later partly due to increased pIgR expression. The dose-related effects of E2 on IgA transport confirm the findings in animal studies that improved outcomes in females can be related to the estrus cycle. PMID- 21825950 TI - Treatment of traumatic flail chest with muscular sparing open reduction and internal fixation: description of a surgical technique. PMID- 21825951 TI - Eastern Association for the Surgery of Trauma: a review of the management of the open abdomen--part 2 "Management of the open abdomen". PMID- 21825952 TI - The dedicated orthopedic trauma operating room. AB - The development and implementation of a dedicated orthopedic trauma operating room (OTOR) that is used for the treatment of orthopedic trauma patients has changed and improved the practice of orthopedic trauma surgery. Advantages noted with OTOR implementation include improvements in morbidity and complication rates, enhancements in the professional and personal lifestyles of the on-call surgeon, and increased physician recruitment and retention in orthopedic traumatology. However, the inappropriate use of the OTOR, which can waste valuable resources and delay the treatment of emergent cases, must be monitored and avoided. PMID- 21825953 TI - Ruptured horseshoe kidney. PMID- 21825954 TI - Blunt trauma causing transection of a horseshoe kidney. PMID- 21825955 TI - S(CV)O2 is not a universal indicator of fluid responsiveness. PMID- 21825956 TI - A criticism of the trauma scan. PMID- 21825959 TI - Rhabdomyolysis associated with the use of a mislabeled "acai berry" dietary supplement. AB - INTRODUCTION: This case report describes a patient who developed rhabdomyolysis temporally associated with the use of a mislabeled acai berry dietary supplement. METHODS AND RESULTS: The authors describe a 22-year-old man presenting with rhabdomyolysis approximately 2 weeks after starting a weight-loss dietary supplement. His medical history was significant only for hypertension treated with amlodipine. The diagnosis of rhabdomyolysis was confirmed (creatine kinase, 84,000 IU/L, positive urine myoglobin) with other potential causes ruled out. The signs and symptoms of the patient gradually resolved and he was discharged on hospital day 5. Assessment using the Naranjo Adverse Drug Reaction Probability Scale yielded a score of 3, indicating a possible relationship between the supplement and rhabdomyolysis. Although the product was labeled and promoted as containing acai berry and additional ingredients, there was no acai berry found on analysis. CONCLUSION: Clinicians should be aware that all dietary supplements may vary in uniformity and contain unknown contaminants. PMID- 21825960 TI - Spondylodiskitis secondary to Streptococcus equi subspecies zooepidemicus. AB - Streptococcus equi subspecies zooepidemicus, traditionally classified under Group C Streptococci, is primarily a veterinary pathogen. Rarely, it may cause infections such as bacteremia, meningitis, endocarditis and pneumonia in humans. Musculoskeletal infections secondary to this pathogen are very uncommon. The authors present the first case of osteomyelitis due to S. zooepidemicus in a farmer who had close contact with a dead horse. The authors review all cases of osteoarticular infections secondary to this microbe, in addition to providing an overview of clinical manifestations, treatment and outcome of this infection. PMID- 21825961 TI - Clinical spectrum and outcome of Nocardia infection: experience of 15-year period from a single tertiary medical center. AB - INTRODUCTION: Nocardiosis, although very rare, is considered as an important opportunistic infection; however, recent literature is limited. This study describes all cases of nocardial infection treated in the authors' hospital to provide more information about clinical manifestations, species isolated, treatment and outcome of patients with nocardiosis. METHODS: A retrospective review of the clinical features and outcome of nocardial infections was conducted during a 15-year period (1996-2010) at Rambam Health Care Campus. RESULTS: The study included 53 patients with nocardial infection, 43 of them had underlying immunodeficiency. The most common clinical form was pulmonary nocardiosis with and without dissemination (60%), followed by skin and soft tissue infection (21%), bacteremia (11%) and pertonitis (5%). Resistance to trimethoprim/sulfamethoxazile was detected in 15% of isolates; to imipenem in 5% and to ciprofloxacin in 65%. Overall mortality was 25% (13/53), mainly observed in patients with pulmonary involvement (37.5%). CONCLUSIONS: Nocardiosis is a rare infection and mainly affects immunocompromised patients. Higher index of suspicion is needed for earlier diagnosis and treatment to improve prognosis. PMID- 21825962 TI - Spontaneous bacterial empyema in a noncirrhotic patient: an unusual scenario. AB - Spontaneous bacterial empyema (SBEM) is infection of a preexisting pleural effusion without evidence of pneumonia. It has been reported mostly in patients with hepatic hydrothorax. Only 1 case of SBEM in a noncirrhotic patient has been reported. We present an unusual case of bilateral SBEM from Streptococcus pneumoniae bacteremia in a noncirrhotic patient. A 52-year-old man presented with bilateral pleuritic chest pain and dyspnea for 2 days. His medical history included congestive heart failure, hemodialysis-dependent renal failure and known bilateral pleural effusions. No ascites or hepatosplenomegaly was noticed. Bilateral pleural effusions were again present on physical examination and confirmed by a chest computed tomography scan. Cardiac medical treatment and hemodialysis failed to improve his condition. Bilateral thoracentesis revealed purulent pleural fluid that was culture-positive for Streptococcus pneumonia as were blood cultures. There was no clinical or radiographic evidence of pneumonia. The detailed clinical course, treatment and highlighted points are described. PMID- 21825963 TI - Modulation of liver L-gamma-glutamyl-L-cysteinylglycine homeostasis by N-acetyl glucosamine-thiazolidine-4(R)-carboxylic acid in mice. AB - The properties of modulating liver L-gamma-glutamyl-L-cysteinylglycine (GSH) homeostasis by thiazolidine derivative N-acetyl-glucosamine-thiazolidine-4(R) carboxylic acid (GlcNAcCys) and the underlying mechanisms were investigated in L buthionine-[S,R]-sulfoximine (BSO)-induced mice liver GSH depletion model. The data show that BSO (6 mmol/kg body weight; intraperitoneally) significantly decreased liver total sulfhydryl and GSH concentrations when compared with control. When mice were treated with different doses of GlcNAcCys (200, 400, 900 mg/kg body weight; intraperitoneally, respectively), total sulfhydryl and GSH concentrations were significantly increased when measured 6 hours after treatment. The activities of GSH-associated enzymes were also measured. Liver glutathione S-transferase (GST) activities were significantly decreased by BSO compared with the control, and GlcNAcCys significantly increased GST activity. Moreover, reverse-transcriptase polymerase chain reaction data indicated that GlcNAcCys could significantly induce glutamylcysteine ligase catalytic subunit c mRNA transcription. The mRNA levels of transcription factors c-jun and c-fos were increased by BSO administration but were decreased back to normal after the administration of GlcNAcCys. In a conclusion, GlcNAcCys can modulate liver GSH homeostasis, which may be related to its ability to induce glutamylcysteine ligase catalytic subunit transcription. GlcNAcCys has potential hepatoprotective properties by increasing GSH content, increasing GST activity. PMID- 21825964 TI - Regression of the carotid intima media thickness by propylthiouracil therapy in Graves' hyperthyroidism. AB - INTRODUCTION: One of the cardiovascular effects of hyperthyroidism is increased carotid intima media thickness (CIMT). The aim of this study is to investigate the CIMT in patients with Graves' hyperthyroidism and the effect of propylthiouracil (PTU) therapy on CIMT. METHOD: Twenty-six patients with Graves' hyperthyroidism and 33 healthy controls were included in the study. CIMT was measured at the right and left external carotid arteries in every patient in both groups. CIMT was measured before and after the PTU therapy in patients with Graves' hyperthyroidism. RESULTS: There was a significant difference in CIMT between the group of Graves' hyperthyroid patients and the control group (0.72 versus 0.55 mm, P < 0.0001) at baseline. Twenty-five of 26 patients with Graves' disease were followed up for 18 months prospectively. Euthyroidism has been achieved in 21 patients. After 18 months of treatment, CIMT decreased significantly compared with the baseline values [0.84 (0.54-1.3) to 0.72 (0.50 1.2), change 0.12 mm, P < 0.001]. CONCLUSION: Graves' hyperthyroidism is associated with atherosclerosis as assessed by CIMT. Treatment of Graves' hyperthyroidism with PTU decreases the CIMT. PMID- 21825965 TI - Remove airway ultraflex stents by flexible bronchoscope. AB - INTRODUCTION: Despite removal of airway metallic stents by rigid bronchoscope was presented, there are few reports describing such removal by flexible bronchoscope. METHODS: 36 patients who had airway Ultraflex stents removed by flexible bronchoscope from 2002 to 2009 were reviewed. Factors contributing to removal method and complications during and after removal were analyzed by multinomial logistic regression. RESULTS: Among 36 patients with stent extraction; 17 stents (47.2%) were removed by a single procedure and 19 (52.8%) by multiple procedures. There was no mortality or severe morbidity during or after stent removal. There were 21 complications after stent removal, including retained stent pieces (n = 9), mucosal tear with bleeding (n = 5), and re obstruction requiring silicone stent placement (n = 7). Stent indwelling time >10 months (adjusted odds ratio: 9.5; 95% confidence interval: 7.9-11.1, P=0.01), obstructive granulation tissue formation before stent removal (adjusted odds ratio: 5.2; 95% confidence interval: 2.2-8.6, P=0.01), and stent fracture before removal (adjusted odds ratio: 3.5; 95% confidence interval: 1.8-15.4, P=0.04) were independent predictors of the need for multiple procedures for stent removal. Stent indwelling time >10 months (adjusted odds ratio: 4.2; 95% confidence interval: 2.1-8.9, P=0.01), obstructive granulation tissue formation before stent removal (adjusted odds ratio: 16.5; 95% confidence interval, 1.8 49.6, P=0.01), and multiple procedures required for removal (adjusted odds ratio: 6.9; 95% confidence interval, 1.1-43.5, P=0.04) were independent predictors of removal complications. CONCLUSIONS: A flexible bronchoscope can be used to remove stents in patients with central airway obstruction and stent-related complications. This procedure should be performed in centers with experienced multidisciplinary teams. PMID- 21825966 TI - Craniomaxillofacial reconstruction using allotransplantation and tissue engineering: challenges, opportunities, and potential synergy. AB - The face is composed of an intricate underlying bony/cartilaginous framework that supports muscle, secretory organs, and sophisticated skin/subcutaneous structures. These components are attached through numerous ligaments and interact dynamically with a vast neurovascular network. The most sophisticated autologous reconstructive techniques, utilizing composite free-tissue flaps, are often inadequate to restore extensive maxillofacial defects. Massive craniomaxillofacial (CMF) defects resulting from trauma, oncologic resection, or congenital deformity present a unique challenge to reconstructive surgeons. Therefore, recent advances in craniofacial surgery and immunotherapy spurred the innovation of composite tissue allotransplantation (CTA), which permits reconstruction with tissue composed of all necessary components. However, CMF allotransplantation carries with it side effects of lifelong immunosuppression. Furthermore, the donor skeletal framework may not provide an ideal match, resulting in less than ideal occlusion and soft-tissue anthropometrics. An alternative to transplantation, tissue engineering, has provided hope for regenerating missing tissue and avoiding the need for immunosuppression. Many tissue subtypes, including bone and cartilage, have been successfully created, with sparse reports of clinical application. Tissue-engineered composite tissue required for complete CMF reconstruction continues to elude development, with vascular supply and tissue interactions posing the largest remaining obstacles. We report herein the current status and limitations of CTA and tissue engineering. Furthermore, we describe for the first time our vision of hybridization of CTA and engineering, utilizing the strengths of each strategy. PMID- 21825967 TI - The use of multislice CT angiography preoperative study for supraclavicular artery island flap harvesting. AB - BACKGROUND: The vascular anatomy of the supraclavicular artery island (SAI) flap has been investigated using both cadaveric anatomic dissections and angiographic studies. Accurate preoperative evaluation and localization of its vascular pedicle confirms its location, course, anatomic variation, and improves flap success. The objective of this report is to demonstrate the utility of multislice computed tomography (CT) angiography for confirming the presence of the vascular pedicle of the SAI flap when planning head and neck reconstruction. METHODS: Patients were studied using 64-multislice CT angiography (CTA) to localize the supraclavicular artery, including its origin and destination. Axial images, multiplanar reconstructions, and 3D volume-rendered images were analyzed on a Philips workstation. Radiologic image findings and clinical experience will be described. RESULTS: SAI CT angiography was successfully performed in 15 patients (30 shoulders) ranging from ages 22 to 81 years. Accurate identification of the main vascular pedicle was achieved in 14/15 patients. Location, course, pedicle length, and anatomic variations were reported for 23 of 30 arteries. Mean vessel diameter was found to be 1.49 mm (range, 0.8-2.0 mm) on the right and 1.51 mm (range, 1.0-2.1 mm) on the left. The mean length of the artery was 38.3 mm on the right (range, 26.6-59.6 mm) and 38.4 mm on the left (range, 24.3-67.0 mm). In all patients, the supraclavicular artery originated off the transverse cervical artery-a branch of the thyrocervical trunk. Positioning of the patient's upper extremities at the side was helpful in the identification of the supraclavicular artery and its distribution. Contrast injection site should be contralateral to the side needed for the flap if sidedness is of importance, secondary to contrast bolus artifact. CONCLUSIONS: Preoperative evaluation of the SAI flap with multislice computed tomography angiography is feasible in patients. A radiologic study protocol has been developed which improves the ability to detect this vessel. This technique provides a noninvasive approach to the identification of the vascular anatomy and is easily standardized/reproducible. The identification of the vascular pedicle and its anatomy can be a benefit to the surgical team during preoperative design of the SAI flap; however, clinical experience confirming these radiologic findings will be needed to optimize surgical outcome. PMID- 21825968 TI - Subfascial directionality of perforators of the distal lower extremity: an anatomic study regarding selection of perforators for 180-degree propeller flaps. AB - BACKGROUND: The 180-degree propeller flaps allow closure of soft-tissue defects of the distal lower extremity. In addition to twist, the pedicle is often subject to additional kinking which increases proportionally to the angle at which the perforator pierces through the fascia. This study evaluates the directionality of the perforators at the fascial level to guide in the selection process of the best perforator. MATERIAL AND METHODS: Perforators were identified in the lower extremities of 16 fresh cadavers. The angle of fascial perforation was measured. Perforators were grouped according to source vessel and location. Results were analyzed statistically regarding angle of fascial perforation along the source vessel and region. RESULTS: A total of 324 perforators were identified. Distal perforators pierced the fascia at a significantly greater angle than in the proximal and middle segment of the peroneal and anterior tibial vessels (P < 0.005). Perforators originating from the posterior tibial artery pierced the fascia at less acute angles distally. When grouped according to the region of the perforators, no significant difference was found between perforators from all source vessels in the proximal region of the distal lower extremity. Even distally, perforators from the posterior tibial artery traveled almost perpendicular (P < 0.005). CONCLUSION: Perforators traveling in a near perpendicular manner are ideal to serve as a pedicle for 180-degree propeller flaps as solely the twist has to be distributed along the vessel. The posterior tibial artery was the source to perforators with the most constant, near perpendicular course, predisposing them for use in 180-degree propeller flaps. PMID- 21825969 TI - Acellular dermal matrix slings in tissue expander breast reconstruction: are there substantial benefits? AB - Acellular dermal matrix (ADM) slings in breast reconstruction are increasingly used but are not yet validated. This study compares immediate, expander-based breast reconstruction with and without the use of inferolateral ADM slings. There were 63 patients (106 breasts) in the ADM group and 42 patients (68 breasts) in the control group. Initial intraoperative fill volumes were significantly greater in the ADM group, median 69% full (250 mL) versus 50% full (180 mL; P < 0.001). However, the number of days to complete expansion between the 2 groups was similar. One less office visit was required to complete the fills in the ADM group (P < 0.01). Drains were removed 3 days later in the ADM group (P < 0.01). Overall complication rate was greater in the ADM group (18.9% vs. 7.4%, P < 0.05), with a slightly higher percentage of expanders requiring removal due to infection in the ADM group (5.7% vs. 4.4%, P = NS). This study suggests inferolateral ADM slings in expander-based breast reconstruction allow for significantly increased initial fill volumes and may offer an aesthetic advantage; however, its use is costly and increases complications. PMID- 21825970 TI - Creating patient and family education web sites: design and content of the home parenteral nutrition family caregivers web site. AB - When managing chronic illnesses, caregivers repeatedly seek online information about providing complex, long-term care but often neglect to find information about how to care for themselves. Poor health among caregivers is not only detrimental to their own well-being but may also result in harm to those for whom they care. For this reason, caregivers need access to information and activities about caring for themselves in addition to the information about managing home care they are already likely to seek. The HPN Family Caregivers Web site was developed to guide caregivers through the process of caring for themselves by establishing a caregiving routine, self-monitoring their mental and physical health, and practicing good sleep hygiene, while also managing the complexities of home care. While Web site information, activities, and algorithms for managing chronic illnesses need to be specific to each population, the content guiding caregivers to care for their own health is universal. PMID- 21825971 TI - Student nurses and the electronic medical record: a partnership of academia and healthcare. AB - The advent of the electronic medical record has brought a new challenge to nursing education. Although most nursing students are proficient in data entry and computer skills, they often do not comprehend how the information they enter becomes a vital component of interdisciplinary team communication. Furthermore, the electronic medical record becomes a repository for information that can be retrieved for the purpose of decision support. Developed by the Cleveland Clinic, the Deans' Roundtable, and University Hospitals of Cleveland, the Student Nurse Portal provides a means of assisting the student to understand how data entered into the computer transforms into information and knowledge, resulting in the wisdom that enables healthcare workers to provide optimal patient care. Current courses present the purpose of the electronic medical record and its roleas a powerful communication tool, but future courses will also help the student develop data entry and retrieval skills. Hosted on the Cleveland Clinic servers and available to students around-the-clock from any computer with Internet access, students have found the Student Nurse Portal to be a valuable tool in preparing for the use of the electronic medical record during their clinical experiences. PMID- 21825972 TI - Nurses' perceptions of how clinical information system implementation affects workflow and patient care. AB - There is a little evidence of the impact of clinical information system implementation on nurses' workflow and patient care to guide institutions across the nation as they implement electronic health records. This study compared changes in nurse's perceptions about patient care processes and workflow before and after a comprehensive clinical information system implementation at a rural referral hospital. The study used the Information Systems Expectations and Experiences survey, which consists of seven scales-provider-patient communication, interprovider communication, interorganizational communication, work-life changes, improved care, support and resources, and patient care processes. Survey responses were examined across three administrations-before and after training and after implementation. The survey responses decreased significantly for eight of the 47 survey items from the first administration to the second and for 37 items from the second administration to the third. Perceptions were more positive in nurses who had previous experience with electronic health records and less positive in nurses with more years of work experience. These findings point to the importance of setting realistic expectations, assessing user perceptions throughout the implementation process, designing training to meet the needs of the end user, and adapting training and implementation processes to support nurses who have concerns. PMID- 21825973 TI - Is there a link between the hospital-acquired injurious fall rates in US acute care hospitals and these institutions' implementation levels of computerized systems? AB - Medicare no longer reimburses acute care hospitals for the costs of additional care required due to hospital-acquired injuries. Consequently, this study explored the effective computerized systems to inform practice for better interventions to reduce fall risk. It provided a correlation between type of computerized system and hospital-acquired injurious fall rates at acute care hospitals in California, Florida, and New York. It used multiple publicly available data sets, with the hospital as the unit of analysis. Descriptive and Pearson correlation analyses were used. The analysis included 462 hospitals. Significant correlations could be categorized into two groups: (1) meaningful computerized systems that were associated with lower injurious fall rates: the decision support systems for drug allergy alerts, drug-drug interaction alerts, and drug-laboratory interaction alerts; and (2) computerized systems that were associated with higher injurious fall rates: the decision support system for drug drug interaction alerts and the computerized provider order entry system for radiology tests. Future research may include additional states, multiple years of data, and patient-level data to validate this study's findings. This effort may further inform policy makers and the public about effective clinical computerized systems provided to clinicians to improve their practice decisions and care outcomes. PMID- 21825974 TI - Mapping evidence-based guidelines to standardized nursing terminologies. AB - The purpose of this study was to explore how evidence-based practice recommendations for adults with depression were represented in two standardized nursing terminologies. A qualitative concept analysis was used to answer the research question. Concepts were extracted from the recommendations and matched to two standardized nursing terminologies through lexical and semantic concept mapping techniques. Study findings included variability in the lexical mapping to the standardized terminologies. The ability to map semantically was greater than lexical mapping, but the majority of these were partial matches. Findings also raised concerns about the potential for ambiguity of data retrieved when using standardized terminology. PMID- 21825975 TI - Nonconventional support of respiration. AB - PURPOSE OF REVIEW: Several alternative treatments have been proposed to decrease mortality of patients with acute respiratory distress syndrome (ARDS). We will discuss most recent trials and meta-analysis studies on nonconventional ventilatory and pharmacological treatments of ARDS patients. RECENT FINDINGS: Nonconventional ventilatory treatments such as prone positioning, high frequency oscillatory ventilation (HFOV), and extracorporeal membrane oxygenation (ECMO) aim to restore gas exchange while further decreasing ventilator induced lung injury. Though randomized trials failed to prove survival benefits with the use of prone positioning or HFOV, recent meta-analyses have shown, for both treatments, a decrease in mortality in the subpopulation of more severe ARDS patients. In a randomized controlled trial, referral of ARDS patients in a center with experience on ECMO was associated with an improved survival rate. Promising results come from new miniaturized extracorporeal techniques optimized for effective CO(2) removal from low blood flow. These techniques should allow early application of superprotective ventilator strategies. Pharmacological treatments such as neuromuscular blocking and intravenous beta2 agonist may be effective in specific times and subsets of patients. SUMMARY: Existing data suggest that some of the available nonconventional treatments may be effective in more severe ARDS patients. New techniques and drugs that should facilitate prevention or healing of lung injury are under investigation. PMID- 21825976 TI - Translational research: what does it mean, what has it delivered and what might it deliver? AB - PURPOSE OF REVIEW: In this article, we review recent developments in translational research in the fields of acute lung injury, acute kidney injury and sepsis with a focus on emerging biomarkers and outline future advances in the field. RECENT FINDINGS: There is currently a significant and unmet need for high quality translational research in critical care. The emergence of '-omics' technologies and sophisticated imaging techniques have resulted in a rapid growth of emerging biomarkers. Biomarkers would ideally provide early and reliable endpoints for proof of concept in clinical trials and inform clinical decision making through earlier and more precise diagnosis and risk stratification. SUMMARY: Despite significant investment in basic science and time-consuming clinical trials, the majority of pharmacological interventions developed for critical illness have yet to translate into measurable clinical benefit. Future validation and qualification of emerging biomarkers allied to advances in pharmacogenomic profiling have the potential to provide valuable clinical information while accurately phenotyping patients enrolled in future clinical trials. PMID- 21825977 TI - The possible roles of environmental factors and the aryl hydrocarbon receptor in the prevalence of thyroid diseases in Vietnam era veterans. AB - PURPOSE OF REVIEW: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) profoundly affects the immune system in experimental animals. TCDD was a contaminant in defoliants used in the Vietnam War, and is known to cause prolonged activation of the aryl hydrocarbon receptor (AhR) in humans. Chronic exposure to TCDD is associated with an increased prevalence of certain chronic diseases, lymphomas and leukemias. The AhR is a transcription factor that responds to cellular metabolites as well as to environmental substances. We review how TCDD and the AhR alter thyroid metabolism directly, and how recent experimental and clinical findings on TCDD and immunity are related to autoimmune thyroid diseases. RECENT FINDINGS: TCDD exaggerates the normal responses of the AhR to endogenous activators, affecting dendritic cells, regulatory T cells (T(reg)), T(helper)17 (T(h)17) and T(helper)22 (T(h)22) cells. A recent study on approximately 225 000 veterans of the Vietnam era found that those who served in Vietnam or were otherwise exposed to defoliants had a 2.5 fold to three-fold higher prevalence of the diagnosis of Graves' disease, compared to Veterans who served elsewhere. SUMMARY: The balance between T(reg), T(h)17 and T(h)22 cells is disrupted by TCDD, resembling what has been found clinically in Graves' disease and Hashimoto's thyroiditis, and in animal models of these diseases. By altering the immune balance in susceptible individuals, chronic TCDD exposure may influence the prevalence of autoimmune thyroid diseases. PMID- 21825978 TI - Thyroid hormone transport in developing brain. AB - PURPOSE OF REVIEW: To discuss the recent advances on thyroid hormone transport in the brain. A special attention is paid to the X-linked thyroid hormone cell transport (THCT) defect (also known as the Allan-Herndon-Dudley syndrome), caused by mutations of the specific thyroid hormone transporter MCT8 gene. RECENT FINDINGS: MCT8 is involved in thyroid hormone transport in the brain. MRI of patients with THCT defect showed myelination delays, probably related to impaired thyroid hormone action on oligodendrocytes. MCT8 is also expressed in the thyroid and has an important role in thyroid hormone secretion. The altered circulating concentrations of thyroid hormone in the patients are partly because of impaired secretion and altered peripheral metabolism. Increased deiodinase activity is important in the pathophysiology of the syndrome. High D1 activity in liver and kidney increases T4 and rT3 deiodination, and contributes to the increased serum T3. High D2 activity in the brain contributes to compensate the deficient T3 transport by increasing local T3 production. SUMMARY: Patients with suspected X linked leukoencephalopathy should be screened for MCT8 gene mutations. Research on the brain pathophysiology of the THCT defect should focus on the specific role of Mct8 on oligodendrocytes and myelination. PMID- 21825979 TI - The pathogenesis of essential thrombocythemia. AB - PURPOSE OF REVIEW: The identification of new mutations continues to further our understanding of the molecular pathogenesis of essential thrombocythemia and related disorders, and offers opportunities for improvements in diagnosis, risk stratification and disease classification. RECENT FINDINGS: Molecular lesions in essential thrombocythemia affect two distinct pathways: cytokine signaling and transcriptional regulation. Signaling pathway mutations show a high degree of phenotypic specificity, in contrast to alterations in transcriptional pathways in which the same mutations are seen in diverse myeloid malignancies. Signaling pathway mutations are directly implicated in driving the myeloproliferation which characterizes essential thrombocythemia, whereas the phenotypic consequences of transcriptional pathway mutations are yet to be elucidated. The expanding lexicon of genetic abnormalities has revealed a surprising degree of clonal heterogeneity in essential thrombocythemia, although the clinical significance of this clonal complexity is currently unclear. Potential clinical applications for mutation screening include streamlining of the diagnostic process, improved risk stratification, and molecular distinction of essential thrombocythemia from related disorders such as polycythemia vera and myelofibrosis. SUMMARY: The genetic lexicon of essential thrombocythemia remains incomplete. Given the current acceleration in sequencing technology, further insights into essential thrombocythemia pathogenesis are likely close at hand. PMID- 21825980 TI - Cytochrome P450-dependent eicosanoid production and crosstalk. AB - PURPOSE OF REVIEW: This review highlights recent advances in eicosanoid biology, especially linked to the cytochrome P450 (CYP)/soluble epoxide hydrolase (sEH) axis in vascular biology and disease. RECENT FINDINGS: Since the first reports that CYP-derived metabolites of arachidonic acid can elicit vascular smooth muscle hyperpolarization and relaxation, it has become clear that fatty acid epoxides and diols are important lipid signaling molecules. Targeting CYP epoxygenases in vivo is difficult as these enzymes are involved in the metabolism of many currently used clinical agents. However, targeting the sEH which metabolizes fatty acid epoxides to their corresponding diols is a highly effective way of manipulating levels of these lipid mediators in vivo. Indeed, sEH-/- mice are protected against the development of some forms of hypertension, and have altered adipocyte metabolism and insulin resistance, phenomena reproduced by selective sEH inhibitors. SUMMARY: Given that elevated epoxide levels have been linked with decreased blood pressure and inflammation in animal models, inhibitors of the sEH are currently being developed for the treatment of human hypertension and inflammation/atherosclerosis. This review focuses on outlining recent insights gained in the beneficial as well as the potentially adverse aspects of interfering with the CYP/sEH axis. PMID- 21825981 TI - Macrophage polarization in metabolic disorders: functions and regulation. AB - PURPOSE OF REVIEW: To discuss recent findings on the role and regulation of macrophage polarization in obesity and atherosclerosis. RECENT FINDINGS: Macrophages infiltrate the vascular wall during atherosclerosis and adipose tissue during obesity. At least two distinct subpopulations with different functions, the classically (M1) and the alternatively (M2) activated macrophages, have been found in these tissues. Reciprocal skewing of macrophage polarization between the M1 and M2 states is a process modulated by diet, humoral and transcription factors, such as the nuclear receptor peroxisome proliferator activated receptor gamma. SUMMARY: Recent literature highlights the importance not only of the number of infiltrated macrophages, but also their activation in the maintenance of the inflammation state. Identifying mechanisms and molecules able to modify the balance between M1 and M2 represents a promising field of research. PMID- 21825982 TI - Inflammation as a risk factor and target for therapy in chronic kidney disease. AB - PURPOSE OF REVIEW: Inflammation is a major driving force of the uremic phenotype. This review provides an update on inflammatory biomarkers in chronic kidney disease and possible therapeutic approaches targeting the uremic inflammatory milieu. RECENT FINDINGS: Single and longitudinal changes of C-reactive protein provide important outcome prediction. The uremic phenotype, which includes persistent inflammation, oxidative stress and protein energy wasting, has recently been shown to overshadow the traditional risk profile. As several small randomized controlled trials have shown that various nutritional, nonspecific immunomodulatory and targeted anticytokine interventions may have anti inflammatory potential, future randomized control trials are needed to explore whether interventions specifically targeting inflammation will improve the dismal prognosis in end-stage renal disease. SUMMARY: Because circulating inflammatory markers predict outcomes in patients with end-stage renal disease, inflammation may be a logical future therapeutic target for nutritional and pharmacological interventions. PMID- 21825983 TI - Consequences of a highly evolved distal nephron: current concepts in transport, regulation and molecular structure. PMID- 21825984 TI - Limb girdle muscular dystrophies: update on genetic diagnosis and therapeutic approaches. AB - PURPOSE OF REVIEW: This review is an up-to-date analysis of the genetic diagnosis and therapeutic strategies for limb girdle muscular dystrophies (LGMDs). RECENT FINDINGS: LGMDs are an example of both clinical and genetic heterogeneity. Clinically, by the description of non-LGMD phenotypes associated with LGMD genes and of LGMD phenotypes associated with originally non-LGMD disease genes; and genetically, by the description of new LGMD genes that further increase the diagnostic complexity. Moreover, new powerful approaches for DNA analysis, such as exome sequencing, promise to revolutionize the field of heterogeneous genetic diseases, also providing information about the true penetrance of LGMD mutations. The recent inputs on novel pathogenic mechanisms and pathways in LGMD will suggest novel therapeutic approaches and future clinical trials. In addition, therapeutic approaches of gene and cell delivery into animal models show promising results that will be translated into clinical trials. SUMMARY: The genetic diagnosis of LGMD from the present home-made algorithms will move toward high-throughput diagnostic strategies based on next-generation sequencing (NGS) technologies. As therapy, new powerful drug approaches based on recent pathogenetic findings will be pushed to clinical trials. In addition, novel more efficient and safer viral vectors for gene delivery will be proposed. PMID- 21825985 TI - Muscular dystrophies due to glycosylation defects: diagnosis and therapeutic strategies. AB - PURPOSE OF REVIEW: Dystroglycanopathies are a common group of diseases characterized by a reduction in alpha-dystroglycan glycosylation. This review discusses the recent novel discovery of additional dystroglycanopathy variants and progress in dystroglycanopathy animal models. RECENT FINDINGS: Several novel glycosyltransferase genes have been found to be responsible for a dystroglycanopathy phenotype, and in addition recessive mutations in DAG1 have been identified for the first time in a primary dystroglycanopathy. Studies in dystroglycanopathy mouse models have clarified some aspects of the structural defects observed in the central nervous system and in the eye, whereas a study in zebrafish implicates unfolded protein response in the pathogenesis of two of the secondary dystroglycanopathies. SUMMARY: Improved understanding of the molecular bases of dystroglycanopathies will lead to more precise diagnosis and genetic counseling; therapeutic strategies are being developed and tested in the preclinical models and it is hoped that these observations will pave the way to therapeutic interventions in humans. PMID- 21825986 TI - Motor neuron, nerve, and neuromuscular junction disease. AB - PURPOSE OF REVIEW: The aim is to review the most relevant findings published during the last year concerning clinical, genetic, pathogenic, and therapeutic advances in motor neuron disease, neuropathies, and neuromuscular junction disorders. RECENT FINDINGS: Studies on animal and cell models have improved the understanding of how mutated survival motor neuron protein in spinal muscular atrophy governs the pathogenetic processes. New phenotypes of SOD1 mutations have been described. Moreover, animal models enhanced the insight into the pathogenetic background of sporadic and familial amyotrophic lateral sclerosis. Novel treatment options for motor neuron disease have been described in humans and animal models. Considerable progress has been achieved also in elucidating the genetic background of many forms of inherited neuropathies and high clinical and genetic heterogeneity has been demonstrated. Mutations in MuSK and GFTP1 have been shown to cause new types of congenital myasthenic syndromes. A third type of autoantibodies (Lrp4) has been detected to cause myasthenia gravis. SUMMARY: Advances in the clinical and genetic characterization of motor neuron diseases, neuropathies, and neuromuscular transmission defects have important implications on the fundamental understanding, diagnosis, and management of these disorders. Identification of crucial steps of the pathogenetic process may provide the basis for the development of novel therapeutic strategies. PMID- 21825987 TI - Fabry disease. AB - PURPOSE OF REVIEW: This review discusses the literature on Fabry disease mainly in the domain of neurology with special attention to recent advancement. RECENT FINDINGS: Fabry neuropathy is known as a length-dependent peripheral neuropathy affecting mainly the small myelinated (Adelta) fibers and unmyelinated (C) fibers. Recently, concerning heterozygotes, it seems that they suffer from peripheral neuropathy at a higher rate than previously shown, significant multisystemic disease, and severely decreased quality of life. The existence of an atypical variant of Fabry disease with late-onset cerebrovascular disease (cerebrovascular variant) is now suggested, like the cardiac and renal variants of Fabry disease. Although enzyme replacement therapy (ERT) has been shown to have some positive effects on reduction of neuropathic pain, the improvement of detection threshold for thermal sensation and sweat function, the effect of ERT on the central nervous system has not been established. Gene replacement therapy, chemical chaperone therapy, and ERT using modified alpha-N acetylgalactosaminidase are in progress, and induced pluripotent stem cells were generated from mouse models of Fabry disease. SUMMARY: Heterozygotes should be carefully monitored for precise estimation and adequate therapy. Early initiation of ERT before irreversible organ failure is most important, and alternative therapeutic approaches are currently being explored. PMID- 21825988 TI - Update on adolescent condom use. AB - PURPOSE OF REVIEW: Pregnancy prevention efforts in the USA have largely focused on the use of hormonal contraceptive methods, relegating male condoms to discussions of 'dual-method' contraception or sexually transmitted infection prevention. With national attention and funding directed toward adolescent pregnancy prevention, a renewed focus on adolescent condom use, specifically addressing contraceptive benefits, is both timely and relevant. RECENT FINDINGS: Two recent developments in condom use research are essential to increasing consistent condom use. First, there is a necessary shift toward understanding the relationship dynamics of condom use. As a coital event level contraceptive, condom use requires negotiation and participation from both participants. Second, there is increased attention to the condom itself as a determinant of use. Improvements in condom design, feel, and lubrication have reduced differences in sexual pleasure with condom use and nonuse. SUMMARY: Promoting the initiation and maintenance of condom use across multiple partnered sexual encounters requires understanding of individual, dyadic, and condom attributes. PMID- 21825989 TI - Advances in PET imaging of brain tumors: a referring physician's perspective. AB - PURPOSE OF REVIEW: To highlight the most recent advances in PET imaging of brain tumors, aiming at expanding the referring physician's knowledge in the field, the sine qua non for translating PET into the practice of neuro-oncology. RECENT FINDINGS: The role of PET with amino acid tracers in the setting of brain lesions of unknown significance has been better defined, reducing the need for invasive procedures. The impact of PET-guided resection of high-grade glioma using 11C methionine (11C-MET) has been strongly documented. [18F]Fluoroethyl-L-tyrosine is currently available for glioma management; advances in targeting glial tumor biopsy and monitoring response to standard chemoradiation of malignant glioma have been remarkable. 2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-penta fluoropropyl)-acetamide is a rationally designed radiotracer with potential for imaging hypoxia in glioblastoma. New insights regarding the predictive value of 3 deoxy-3-[18F]fluorothymidine in outcome of recurrent malignant glioma treated with bevacizumab/irinotecan have been provided. First steps are being made toward apoptosis PET imaging for early assessment of radiotherapy response in brain metastases. SUMMARY: The use of 11C-MET and 18F-labeled PET tracers is getting a more precise position in the management of brain tumors. Advances hold promises in routine decision-making and in the design and conduct of clinical trials. PMID- 21825990 TI - Genetic causes of glioma: new leads in the labyrinth. AB - PURPOSE OF REVIEW: A small percentage of gliomas are caused by inheritance in cancer syndromes but there is also a general familial aggregation of glioma. Recently, low penetrant genes associated with glioma risk have been identified. RECENT FINDINGS: Seven independent chromosomal loci have robustly been associated with glioma risk: 5p15.33 (rs2736100, TERT), 8q24.21 (rs4295627, CCDC26), 9p21.3 (rs4977756, CDKN2A-CDKN2B), 20q13.33 (rs6010620, RTEL1), and 11q23.3 (rs498872, PHLDB1), and two loci at 7p11.2 (rs11979158 and rs2252586, EGFR). Several of these genes are obvious candidates in their role for chromosomal integrity and glioma progression. Moreover, all loci but the EGFR and CDKN2A genes display a pattern of association to certain glioma subtypes. SUMMARY: The causes of glioma have until recently been unknown for most cases, partly due to lack of statistically powered studies enabling subclassification of glioma subtypes. The novel chromosomal loci associated with different glioma subtypes have provided us with an additional understanding of causes of glioma. All low penetrant genes contribute with a modest increased risk and cannot by themselves be used for risk prediction. Nevertheless, they could provide a tool to understand the underlying biology of glioma progression and to be used in future studies of gene environment studies of specific glioma subtypes. PMID- 21825991 TI - Brown's syndrome. AB - PURPOSE OF REVIEW: To better understand the various causes of Brown's syndrome, provide a historical account of the progression of Brown's syndrome, and to bring attention to clinical characteristics specific to Brown's syndrome. RECENT FINDINGS: The inability to elevate an eye in adduction is a common problem with a number of possible causes usually pointing to cyclovertical muscle involvement. The specific cause can usually be determined by either the three-step test or forced ductions. Because Brown's syndrome does not involve a paretic cyclovertical muscle but rather a mechanical muscle limitation, forced ductions instead of the three-step test must be used to evaluate a patient of Brown's syndrome and is crucial in the diagnosis. SUMMARY: The recognition of true Brown's syndrome can be accomplished by clinical examination and confirming the diagnosis with a positive forced duction test. PMID- 21825992 TI - Compositional differences among commercially available botulinum toxin type A. AB - PURPOSE OF REVIEW: Since the advent of botulinum neurotoxin (BoNT) in the facial cosmetic field, it has become the leading nonsurgical cosmetic procedure in the USA, and several different formulations are currently in use. The aim of this study is to review the major 'players' in order to help the physician understand the clinically relevant dissimilarities between the products and by that promote treatment efficacy and patient satisfaction. RECENT FINDINGS: The different available formulations can be classified into two groups by the existence of absence of complexing proteins. Most of the influence that was previously attributed to these proteins has been found to be less relevant clinically, the immune response being the only remaining issue with supporting evidence in the literature. SUMMARY: Botulinum toxin type A is widely utilized in the cosmetic field, and it seems that all available and approved formulations are both well tolerated and effective in treating facial rhytids. The treating physician must be familiar with the differences between all the products, especially the fact that they are not interchangeable in respect to their recommended dosage. PMID- 21825993 TI - The genetics of anophthalmia and microphthalmia. AB - PURPOSE OF REVIEW: To summarize recent breakthroughs regarding the genes known to play a role in normal ocular development in humans and to elucidate the role mutations in these genes play in anophthalmia and microphthalmia. RECENT FINDINGS: The main themes discussed within this article are the various documented genetic advances in identifying the various causes of anophthalmia and microphthalmia. In addition, the complex interplay of these genes during critical embryonic development will be addressed. SUMMARY: The recent identification of many eye development genes has changed the ability to identify a cause of anophthalmia and microphthalmia in many individuals. Syndrome identification and the availability of genetic testing underscores the desirability of evaluation by a geneticist for all individuals with anophthalmia and microphthalmia in order to provide appropriate management, long-term guidance, and genetic counseling. PMID- 21825994 TI - What can we learn from the thalidomide experience: an ophthalmologic perspective. AB - PURPOSE OF REVIEW: The thalidomide tragedy of the early 1960s resulted in a great number of studies and reports involving many specialties of medicine. Because of the estimated large number of affected children (5000+) worldwide exposed to this potent teratogen, and the many informative cases in which the exposure time was known, a teratogenic timetable was constructed relating affected structures to the time of exposure. This demonstrated that thalidomide had a teratogenic effect between approximately 20 to 36 days after fertilization. RECENT FINDINGS: We found that Duane syndrome and its variants were prominent in individuals who were exposed to thalidomide early in the sensitive period (days 20 to 26+/-). Other anomalies associated with this early effect were aberrant tearing, facial nerve palsy, ear malformations, and autism. Structural eye malformations were less frequent in this early phase, appearing slightly later in the sensitive period. SUMMARY: This study summarizes the ophthalmologic findings from a number of studies and compares them with respect to the implications of time of exposure. Because the timing of anomalies such as external ear and limb malformations are well established in the thalidomide literature, correlation with associated eye anomalies gives insight into the approximate timing of the causative teratogen exposure. PMID- 21825995 TI - Genetic disorders of the vestibular system. AB - PURPOSE OF REVIEW: This review highlights the current body of literature related to the genetics of inherited vestibular disorders and provides a framework for the characterization of these disorders. We emphasize peripheral causes of vestibular dysfunction and highlight recent advances in the field, point out gaps in understanding, and focus on key areas for future investigation. RECENT FINDINGS: The discovery of a modifier gene that leads to a more severe Usher syndrome phenotype calls into question the assumption that Usher syndrome is universally a monogenic disorder. Despite the use of several investigational approaches, the genetic basis of Meniere's disease remains poorly understood. Evidence for a vestibular phenotype associated with DFNB1 suggests that mutations in other genes causally related to nonsyndromic hearing loss also may have an unrecognized vestibular phenotype. SUMMARY: Our understanding of the genetic basis for vestibular disorders is superficial. Significant challenges include defining the genetics of inherited isolated vestibular dysfunction and understanding the pathological basis of Meniere's disease. However, improved characterization of inherited vestibular dysfunction, coupled with advanced genetic techniques such as targeted genome capture and massively parallel sequencing, provides an opportunity to investigate these diseases at the genetic level. PMID- 21825996 TI - The physical basis of active mechanosensitivity by the hair-cell bundle. AB - PURPOSE OF REVIEW: Hearing starts with the deflection of the hair bundle that sits on top of each mechanosensory hair cell. Recent advances indicate that the hair bundle mechanically amplifies its inputs to participate in the active process that boosts the ear's technical specifications. This review integrates experimental and modeling studies to dissect the mechanisms of active mechanosensation by the hair-cell bundle. RECENT FINDINGS: The exquisite mechanosensitivity of the hair-cell bundle results from a precisely choreographed interplay between a structure of mechanically coupled stereocilia that ensures efficient transmission of sound-energy to the transduction machinery, Ca-driven adaptation that provides fast electromechanical feedback on hair-bundle movements, and a mechanical nonlinearity inherent to the transduction process that fosters autonomous hair-bundle oscillations. In cochlear outer hair cells, cooperation between active hair-bundle motility and somatic electromotility brings the cochlear partition to the brink of an oscillatory instability, at which general physical laws ensure optimal properties for auditory detection. SUMMARY: The study of active hair-bundle mechanics promotes a general principle for auditory detection that is based on the generic properties of self-sustained mechanical oscillators. This principle may guide future engineering design of cochlear implants. PMID- 21825997 TI - Preventing complications in pediatric cochlear implantation. AB - PURPOSE OF REVIEW: This review addresses four key areas of controversy in the prevention of common complications of pediatric cochlear implant surgery: reducing meningitis risk, managing acute otitis media (AOM) in the cochlear implant population, assessing the optimum age for implanting a child to take advantage of the critical periods of language acquisition, and managing the social risk in defining ethical issues still surrounding cochlear implant in children. RECENT FINDINGS: Improved surgical techniques and the replacement of Prenvar-7 with Prenvar-13 significantly reduce the risk of cochlear implant related meningitis. AOM within 2 months of cochlear implant placement requires aggressive management to reduce the risk of complication. Tympanostomy tubes do not increase the risk of otitis media or meningitis and should be used when appropriate according to accepted AOM standards. Although the controversy over cochlear implant and the dissolution of Deaf Culture is decreasing, the use of cochlear implant in children remains an area for open dialogue between groups to ensure children are treated appropriately. Discussions ought to be based on fact and scientific evidence. SUMMARY: Although cochlear implants remain the gold standard for hearing restoration in children with severe to profound hearing loss, several issues remain controversial and are in need of further scientific exploration. PMID- 21825998 TI - Cancer and systemic sclerosis: novel insights into pathogenesis and clinical implications. AB - PURPOSE OF REVIEW: Most epidemiologic studies have demonstrated an increased risk of cancer in scleroderma patients. Reasons for this risk increase have been poorly understood and often attributed to cytotoxic therapies or damage from scleroderma. Recognition that some patients have a close temporal relationship between cancer diagnosis and scleroderma clinical onset has focused attention on the possibility that scleroderma may be a paraneoplastic syndrome in a subset of patients. This review will discuss the latest epidemiologic data linking cancer and scleroderma and explore a model for the development of paraneoplastic scleroderma. RECENT FINDINGS: New investigations have demonstrated an association between RNA polymerase III autoantibodies and a close temporal relationship between cancer diagnosis and the development of clinical scleroderma. A unique nucleolar RNA polymerase III expression pattern has been identified in malignant tissue from these scleroderma patients suggesting that autoantigen expression in the cancer and the autoantibody response are associated. Similar data in inflammatory myositis have illustrated that disease-specific autoantigens may be expressed in cancers and damaged target tissues (muscle) undergoing regeneration. SUMMARY: These data suggest a model of paraneoplastic autoimmunity in which cross reactive immune responses may target autoantigens that are expressed in both cancers and diseased autoimmune target tissues. PMID- 21825999 TI - Antitumor effects of bisphosphonates: from the laboratory to the clinic. AB - PURPOSE OF REVIEW: The use of bisphosphonates has focused on their antibone resorptive effects but recent studies have shown that these drugs also possess a variety of antitumor effects in the laboratory that are now being observed in clinical trials. RECENT FINDINGS: It is becoming increasingly clear that bisphosphonates - especially the more potent nitrogen-containing bisphosphonates (N-BPs) and, in particular, zoledronic acid - show a multitude of antitumor effects in the laboratory. These drugs have been shown to induce apoptosis in a variety of cancer cells and enhance the antitumor effects of a variety of treatments including steroids, chemotherapeutic agents and hormonal therapies as well as many classes of new anticancer drugs. In addition, the agents inhibit vasculogenesis and angiogenesis. The N-BPs also show immunostimulatory effects that have been shown to have potent antitumor effects. They also block tumor cell adhesion making tumor cells more susceptible to the cytotoxic effects of chemotherapy as well as migration and invasion of tumor cells. Recent clinical trials have demonstrated their ability to not only reduce skeletal morbidity but also delay time to progression of the malignant disease in some but not all studies and improve overall survival in other trials. SUMMARY: Emerging laboratory and clinical data now support the important antitumor effects of N-BPs in both solid and hematological cancers. It will be important to determine whether the combination of these drugs with other agents with not only chemotherapy but newer agents may enhance these effects. PMID- 21826000 TI - Denosumab: benefits of RANK ligand inhibition in cancer patients. AB - PURPOSE OF REVIEW: RANK ligand (RANKL) plays a central role in the cancer-induced bone destruction that results from bone metastasis. The RANKL inhibitor denosumab was recently approved for the prevention of skeletal-related events (SREs) in patients with bone metastases from solid tumors. This review summarizes recent findings of the effects of RANKL inhibition and denosumab in the cancer setting. RECENT FINDINGS: Preclinical data show that RANKL inhibition in combination with antitumor therapies has additive effects on preventing skeletal tumor progression. Preclinical breast cancer models also suggest RANKL may be involved in primary tumorigenesis and establishment of metastases in bone and other tissues. Pivotal clinical trial data with denosumab in advanced cancer patients across tumor types showed it was superior (breast and prostate) or noninferior trending toward superior (solid tumors/multiple myeloma) to zoledronic acid, in reducing the risk of developing an SRE and demonstrated a favorable safety profile. Denosumab has also demonstrated efficacy in the treatment of giant cell tumor of bone. SUMMARY: Denosumab offers an important new treatment option for patients with solid tumors and bone metastases. The efficacy of RANKL inhibition with denosumab in other disease states in the cancer setting continues to be evaluated. PMID- 21826001 TI - Penile cancer: what's new? AB - PURPOSE OF REVIEW: This article reviews the epidemiology, diagnostic modalities and treatment of localized and advanced penile cancer, with special emphasis on most recent findings from the literature. RECENT FINDINGS: Penile cancer is a rare disease and its treatment suffers from a paucity of evidence in the literature. Risk factors include phimosis with poor hygiene, human papilloma virus infections, chronic balanitis xerotica obliterans and smoking, among others. Surgical treatment for local disease remains the best option, but organ preserving procedures provide good aesthetic and functional results with acceptable oncologic control. Regional disease, when present in the form of adenopathy, is best diagnosed with fine-needle aspiration, and treated with radical inguinal lymphadenectomy if resectable. Occult metastatic disease constitutes a challenge and is managed according to primary tumour risk factors. For nonresectable regional disease and metastases, neoadjuvant cisplatinum-based regimens are the best option, and provide a selection of patients who will be optimal candidates to consolidative surgical therapies. SUMMARY: Penile cancer at its various stages constitutes a therapeutic challenge. Management should be increasingly confined to high volumes centres of excellence, allowing for clinical trials, which will hopefully provide a better understanding of the disease and the best treatment approach. PMID- 21826002 TI - Long-term outcome of hypospadias surgery: current dilemmas. AB - PURPOSE OF REVIEW: To list the main questions and dilemmas raised by hypospadias management and its long-term evaluation. RECENT FINDINGS: Criteria of evaluation of hypospadias have changed in terms of anatomical description and biological screening. A better understanding of the causative and epidemiological aspects of the development anomalies of the genital tubercle has led to a more adjusted biological and surgical approach. The place of preoperative biological screening, preoperative hormonal stimulation and the choice of urethroplasty are the three main fields of discussion between hypospadiologists. Evaluation of outcome is the critical point as there are no current consensual protocols, and long-term results are often lacking as well as psychological evaluation. SUMMARY: Efforts are made to coordinate the management and evaluation of disorders of sex development (DSD) patients and more specifically hypospadias patients. National, European (EuroDSD) and international (consensus conferences) aim at finding common tracks to improve the quality of treatment and follow-up. PMID- 21826003 TI - Clinical measures of hearing aid directivity: assumption, accuracy, and reliability. AB - OBJECTIVES: A number of clinical measures of directivity, including the front-to back ratio (FBR) and front-to-side ratio (FSR), have been suggested to audiologists to monitor the functionality of hearing aids with directional microphones. These suggestions, however, are based on the assumption that directivity measured clinically changes monotonically when compared with changes measured using the directivity index (DI) and perceptual directional benefit. The objective of the present study was to empirically examine this assumption. In addition, the reliability of the clinical directivity measure was estimated to establish a referral threshold for defective directional microphone hearing aids. DESIGN: The directivity of the directional microphones of two behind-the-ear hearing aids was systematically degraded by plugging the microphone ports. The directivity was measured using four clinical measures: the FBR and FSR performed in the test chamber of a hearing aid analyzer and in sound field. Each measure was repeated four times in each directivity-degraded condition. The degraded directivity was also assessed using the DI measure in an anechoic chamber. The perceptual directional benefit in each directivity-degraded condition was obtained by testing 10 hearing-impaired adults in a sound field with diffuse noise using the Hearing in Noise Test (HINT). RESULTS: The results of the DI and HINT measures showed strong correlation between the two FSRs (test chamber and sound field), while the two FBRs showed no correlation. The directivity generated by the FBRs could remain unchanged even when the directional microphone had lost more than 50% of its directivity. The results further indicated that the measures performed in the sound field were more reliable than those performed in the test chamber. Based on the results of the reliability measures, a 30% change in directivity was suggested as the referral threshold signifying defective directional systems. CONCLUSIONS: Because the FSR predicts the DI and HINT measurements more accurately than does the FBR, it is suggested that clinicians use the FSR to monitor hearing aid directivity. By using the FSR measure and informed by the suggested referral threshold, clinicians would be able to correctly identify defective directional microphone hearing aids at an early stage, rather than at a point when the directivity has been diminished completely or even reversed. PMID- 21826004 TI - The influence of semantically related and unrelated text cues on the intelligibility of sentences in noise. AB - OBJECTIVES: In two experiments with different subject groups, we explored the relationship between semantic context and intelligibility by examining the influence of visually presented, semantically related, and unrelated three-word text cues on perception of spoken sentences in stationary noise across a range of speech-to-noise ratios (SNRs). In addition, in Experiment (Exp) 2, we explored the relationship between individual differences in cognitive factors and the effect of the cues on speech intelligibility. DESIGN: In Exp 1, cues had been generated by participants themselves in a previous test session (own) or by someone else (alien). These cues were either appropriate for that sentence (match) or for a different sentence (mismatch). A condition with nonword cues, generated by the experimenter, served as a control. Experimental sentences were presented at three SNRs (dB SNR) corresponding to the entirely correct repetition of 29%, 50%, or 71% of sentences (speech reception thresholds; SRTs). In Exp 2, semantically matching or mismatching cues and nonword cues were presented before sentences at SNRs corresponding to SRTs of 16% and 29%. The participants in Exp 2 also performed tests of verbal working memory capacity and the ability to read partially masked text. RESULTS: In Exp 1, matching cues improved perception relative to the nonword and mismatching cues, with largest benefits at the SNR corresponding to 29% performance in the SRT task. Mismatching cues did not impair speech perception relative to the nonword cue condition, and no difference in the effect of own and alien matching cues was observed. In Exp 2, matching cues improved speech perception as measured using both the percentage of correctly reported words and the percentage of entirely correctly reported sentences. Mismatching cues reduced the percentage of repeated words (but not the sentence based scores) compared with the nonword cue condition. Working memory capacity and ability to read partly masked sentences were positively associated with the number of sentences repeated entirely correctly in the mismatch condition at the 29% SNR. CONCLUSIONS: In difficult listening conditions, both relevant and irrelevant semantic context can influence speech perception in noise. High working memory capacity and good linguistic skills are associated with a greater ability to inhibit irrelevant context when uncued sentence intelligibility is around 29% correct. PMID- 21826005 TI - Hearing ability in working life and its relationship with sick leave and self reported work productivity. AB - OBJECTIVES: Reduced hearing ability has been shown to influence various aspects of daily life, such as communication, psychosocial functioning, and working life. The aim of this study is to examine the association between hearing ability in noise and both sick leave and self-reported work productivity. In addition, the relationship between hearing ability and perceived health-caused limitations at work is examined. METHODS: Data were collected at the baseline measurement of the Dutch "National Longitudinal Study on Hearing" and at each month during a subsequent period of 3 mo. Hearing ability was determined by means of the National Hearing Test, a speech-in-noise test over the Internet using digit triplets. The sample comprised 748 workers (385 with normal hearing ability and 363 with insufficient or poor hearing ability). RESULTS: Linear regression analyses revealed a significant adverse association between reduced hearing ability and self-reported absolute and differential productivity; for every dB signal-to-noise ratio (dB SNR) poorer hearing ability, self-rated absolute productivity for people experiencing little social support decreased by 0.054 points on a scale from 0 to 10 (b = -0.054; 95% confidence interval [CI] = -0.088 to -0.02). For people with less than three other chronic conditions, self-rated differential productivity also decreased significantly with decreasing hearing ability (no chronic conditions: b = -0.048 points/dB SNR on a scale from -10 to + 10, 95% CI = -0.094 to -0.001; one or two other chronic conditions: b = -0.035 points/dB SNR, 95% CI = -0.067 to -0.002). With adjustment for confounders, poorer hearing ability in noise furthermore significantly increased the odds for experiencing limitations (in the type or amount of work one could do) sometimes (odds ratio = 1.14; 95% CI = 1.07-1.21) and often to very often (odds ratio = 1.24; 95% CI = 1.05-1.45) in comparison with experiencing limitation seldom to never. A higher level of need for recovery among people with poorer hearing ability appeared to be one of the factors mediating the higher odds for sick leave of more than 5 days. CONCLUSION: Reduced hearing ability in noise was significantly associated with a lower self-reported absolute and differential productivity in specific cases. Also, poorer hearing increased the odds for experiencing health-caused limitations in the type or amount of work one can do. The significant relationship between hearing ability and sick leave, which was found when not adjusting for confounders, could partly be explained by a higher need for recovery among people with reduced hearing ability in noise. PMID- 21826006 TI - Postoperative nausea and vomiting: simple risk scoring does work. PMID- 21826007 TI - Gadolinium contrast agent associated stimulation of human fibroblast collagen production. AB - OBJECTIVES: Nephrogenic systemic fibrosis occurs in patients with poor renal function who receive gadolinium-based contrast agents (Gd-CAs). Several reports suggest that this is more likely to occur with the less stable forms of Gd chelates, suggesting a release of cytotoxic free Gd ions from these. There is evidence that Gd can stimulate human fibroblast proliferation but the evidence is less clear concerning the production of collagen by these cells. Our aim was to assess effects of Gd chelates on human skin cell activity and collagen production. MATERIALS AND METHODS: Keratinocytes and fibroblasts were cultured with 3 Gd chelates (Gd-EDTA, Omniscan [nonionic linear Gd-CA], and Dotarem [ionic macrocyclic Gd-CA]) for up to 7 days, and cell viability and collagen production were assessed using the colorimetric assays of MTT (3-(4, 5-dimethylthiazol-2-yl) 2, 5-diphenyltetrazolium bromide) and Sirius Red, respectively. The uptake of Gd by cultured fibroblasts was also undertaken using the techniques of inductively coupled plasma mass spectrometry and relaxometry. RESULTS: Our data show that Gd EDTA and Omniscan significantly stimulated both fibroblast and keratinocyte viability and fibroblast (but not keratinocyte) collagen production. In contrast, Dotarem had little, if any, effect on these cultured cells. The Omniscan-induced increase in fibroblast collagen was around 40% over 7 days-a similar increase to that seen for cell viability, suggesting that collagen production was secondary to an initial stimulatory effect on fibroblast viability. Studies of the uptake of Gd by the cultured fibroblasts showed that these took up Gd when cultured with Omniscan for 7 days, and our study also suggests that some of this Gd was in a free dissociated form. CONCLUSIONS: We conclude that these results support a simple nephrogenic systemic fibrosis causative role of low-stability nonionic linear Gd-CA inducing dermal collagen via the release of dissociated Gd which enters fibroblasts and stimulates their activity and associated collagen production. PMID- 21826008 TI - Imaging atherosclerotic plaques by cardiac computed tomography in vitro: impact of contrast type and acquisition protocol. AB - OBJECTIVE: Noninvasive contrast-enhanced coronary computed tomography (CT) angiography enables distinction between calcified and noncalcified atherosclerotic plaques. However, separation of noncalcified plaques into rupture prone lipid-rich and stable fibrous subtypes is challenging because CT density of the plaque, characterized by Hounsfield Units (HU), varies with intraluminal contrast density and acquisition protocol. This study aims at testing the influence of intraluminal contrast densities and kV-settings on coronary plaque density values in vitro. MATERIALS AND METHODS: We scanned 16 coronary arteries with 3 different contrast solutions (no contrast, 1:70, and 1:23 Iomeron, 350 mgI/mL) and 3 different kV-settings (80, 120, and 140 kV). The arteries were sectioned into 5-mm segments. Every segment was evaluated with CT and histopathology for suitability of analysis, presence, and subtype of plaque. RESULTS: Sixty-four segments were analyzed and classified with CT. Agreement between plaques classified with CT angiography in vitro and histopathology was poor-to-moderate, with no kappa-values above 0.21. The kV-settings affected the CT density in all plaque types. The CT density decreased 0.25 (0.07) HU, P=0.013 in noncalcified plaques, and 5.5 (0.7) HU, P<0.0001, in calcified plaques for every kV increase. CT densities in noncalcified plaques changed when the contrast concentration was changed. From no to high contrast concentration resulted in a 21.7 (8.3) HU increase, P=0.041, and from low to high contrast concentration resulted in a 21.5 (6) HU increase, P=0.011, causing several plaques to change in subtype from lipid-rich (low contrast concentration) to fibrotic (high contrast concentration). CONCLUSION: Agreement between CT angiography in vitro and histopathology for classification of coronary plaque subtype is poor to moderate. However, no specific combination seems superior to the most commonly used protocols for distinction between lipid-rich and fibrotic plaque subtypes in current clinical practice. PMID- 21826009 TI - Safety and efficacy of HIV hyperimmune globulin for prevention of mother-to-child HIV transmission in HIV-1-infected pregnant women and their infants in Kampala, Uganda (HIVIGLOB/NVP STUDY). AB - BACKGROUND: This phase III, randomized, clinical trial compared single-dose nevirapine (sdNVP) plus HIV hyperimmune globulin (HIVIGLOB) with sdNVP alone for preventing maternal-to-child transmission of HIV. Primary objectives were to determine rates of HIV infection among infants and to assess the safety of HIVIGLOB in combination with sdNVP in HIV-infected Ugandan pregnant women and their infants. METHODS: Mother-infant pairs were randomized to receive 200 mg of nevirapine to women in labor and 2 mg/kg NVP to newborns within 72 hours after birth (sdNVP arm) or to receive sdNVP plus a single intravenous 240-mL dose of HIVIGLOB given to women at 36- to 38-week gestation and a single intravenous 24 mL dose to newborns within 18 hours of birth (HIVIGLOB/sdNVP arm). Risk of HIV infection was determined using Kaplan-Meier and risk ratio estimates at birth, 2, 6, 14 weeks, 6, and 12 months of age. RESULTS: Intent-to-treat analysis included 198 HIVIGLOB/sdNVP and 294 sdNVP mother-infant pairs. At 6 months of age, the primary endpoint, there was no statistically significant difference in HIV transmission in the HIVIGLOB/sdNVP arm vs. the sdNVP arm [18.7% vs. 15.0%; risk ratio = 1.240 (95% confidence interval: 0.833 to 1.846); P = 0.290]. Similarly, the proportion of serious adverse events in the HIVIGLOB/sdNVP and sdNVP arms, respectively, for mothers (18.9% vs. 19.3%; P = 0.91) and infants (62.6% vs. 59.5%; P = 0.51) was not significantly different. CONCLUSIONS: Giving mother infant pairs an infusion of peripartum HIV hyperimmune globulin in addition to sdNVP for preventing maternal-to-child transmission was as safe as sdNVP alone but was no more effective than sdNVP alone in preventing HIV transmission. PMID- 21826010 TI - Barriers to antiretroviral initiation in HIV-1-discordant couples. AB - BACKGROUND: In Kenya and much of sub-Saharan Africa, nearly half of all couples affected by HIV are discordant. Antiretroviral therapy (ART) slows disease progression in HIV-1-infected individuals and reduces transmission to uninfected partners. We examined time to ART initiation and factors associated with delayed initiation in HIV-1-discordant couples in Nairobi. METHODS: HIV-1-discordant couples were enrolled and followed quarterly for up to 2 years. Clinical staff administered questionnaires and conducted viral loads and CD4 counts. Participants with a CD4 count meeting ART criteria were referred to a nearby US President's Emergency Plan for AIDS Relief-funded treatment center. Barriers to ART initiation among participants with a CD4 count eligible for ART were assessed by Cox regression. RESULTS: Of 439 HIV-1-infected participants (63.6% females and 36.4% males), 146 met CD4 count criteria for ART during follow-up. Median time from meeting CD4 criteria until ART initiation was 8.9 months, with 42.0% of eligible participants on ART by 6 months and 63.4% on ART by 1 year. The CD4 count at the time of eligibility was inversely associated with time to ART initiation (hazard ratio = 0.49, P < 0.001). Compared with homeowners, those paying higher rents started ART 48% more slowly (P = 0.062) and those paying lower rents started 71% more slowly (P = 0.002). CONCLUSIONS: Despite access to regular health care, referrals to treatment centers, and free access to ART, over one-third of participants with an eligible CD4 count had not started ART within 1 year. Factors of lower socioeconomic status may slow ART initiation, and targeted approaches are needed to avoid delays in treatment initiation. PMID- 21826012 TI - Increased HIV and primary and secondary syphilis diagnoses among young men- United States, 2004-2008. AB - OBJECTIVES: National data document increases in HIV and syphilis diagnoses in young black men who have sex with men (MSM), but trends could be driven by increases in a few large areas. We describe the extent to which metropolitan areas of varying population sizes have reported increases in HIV and syphilis diagnoses in young MSM. METHODS: We examined trends in HIV and primary and secondary syphilis case reports from 2004 to 2008 in metropolitan areas having more than 500,000 persons and at least 500 black men aged 13-24 years (n = 73). We examined differences by age at diagnosis, race/ethnicity, and area size. RESULTS: Comparing 2004/2005 with 2007/2008, HIV diagnoses increased in 85% (n = 62) of areas among black MSM aged 13-24 years; primary and secondary syphilis diagnoses in young black men increased in 70% of areas (n = 51). Areas had an average percentage increase of 68.7% (Interquartile range: 25.0-103.1) in HIV diagnoses among young black MSM and an average increase of 203.5% (interquartile range: 0.0-192.7) in primary and secondary syphilis. Across area size strata, the youngest group of black men had the highest average percentage increase in diagnoses of HIV and syphilis and the highest percentage of areas with increases in diagnoses. CONCLUSIONS: HIV and syphilis diagnoses increased among young black men in almost all areas, suggesting widespread increases across metropolitan areas of different sizes. Findings highlight the need for continued prevention efforts for young MSM, particularly young black MSM. PMID- 21826014 TI - Clinical outcomes of adolescents and young adults in adult HIV care. AB - We sought to describe virologic and clinical retention outcomes among a group of HIV-infected adolescents and young adults (AYA) newly established in an adult HIV clinic compared with matched HIV-infected adults. AYA demonstrated lower rates of HIV-1 virologic suppression and higher rates of HIV-1 viral rebound and loss to follow-up compared with adults. African American AYA had the lowest rates of virologic suppression and the highest rates of viral rebound. Adult providers should consider HIV-infected AYA, particularly African American HIV-infected AYA, to potentially be at high risk for poor clinical outcomes in adult care. PMID- 21826015 TI - The congruence of patient communication preferences and physician communication behavior in cardiac patients. AB - BACKGROUND: The purpose of this study was to examine the communication preferences of patients with chronic ischemic heart disease (CIHD) and matching between the preferences and physician communication behavior. Prior to this, psychometric testing was performed on a questionnaire on the perceived communication behavior of the physician (KOVA Questionnaire). METHODS: Patients with CIHD undergoing rehabilitation (N = 342) in Germany were questioned. At the beginning of rehabilitation, patients answered questions about their communication preferences (KOPRA Questionnaire), and at the end of rehabilitation, they answered questions regarding the perceived communication behavior of the physician. Preference-matching values were determined by combining the KOPRA and KOVA items. RESULTS: The KOVA Questionnaire psychometric properties proved to be good. Patients with CIHD indicated clear and open communication and patient participation were especially important. This was followed by emotionally supportive communication and, finally, communication about personal things. Overall, the behavior of physicians corresponded quite closely with the patients' communication preferences. However, preference matching was low (the physicians demonstrated too little of the desired behavior) regarding the open communication of bad news and explanation of treatments. There was relatively high fulfillment of expectations on the part of patients in terms of seeking information from the physician, the physician's explanation of the diagnosis, and regarding aspects of shared decision making. We observed no gender differences, but did identify age-group differences. CONCLUSIONS: The instruments developed (KOPRA and KOVA questionnaires) can be used for communication studies of patients with chronic conditions. However, some patient communication needs seem to require greater consideration from physicians. PMID- 21826016 TI - Cardiac rehabilitation wait times: effect on enrollment. AB - PURPOSE: Cardiac rehabilitation (CR) is a proven effective means for secondary prevention of coronary heart disease. Timely access to CR services is key to promoting patient participation and ensuring optimal patient outcomes. Despite wait time benchmarks having been established, research regarding how long patients wait to enter CR following referral receipt is limited. The aim of this study was to (a) describe wait times from CR referral to intake assessment and (b) examine the association of wait time to CR enrollment rates. METHODS: Wait time from date of CR referral to date of intake assessment was calculated in days for 599 participants referred to CR from 2006 to 2009 inclusive. A descriptive examination of sociodemographic and clinical characteristics was performed, followed by logistic regression analysis to assess the wait time by enrollment relationship. RESULTS: Median wait time from referral receipt to CR intake was 42.0 days. Wait time had a negative effect on CR enrollment, such that for every 1-day increment in wait time, patients were 1% less likely to enroll. CONCLUSIONS: The time that patients wait to enroll in CR may affect the number of patients who choose to attend, and longer wait times may mean fewer patients will benefit from CR participation. Programs should be encouraged to undertake quality improvement initiatives to ensure wait times are not negatively impacting patient enrollment and ultimately preventing patients from benefiting from CR participation. Further research is needed to establish evidence-based wait time benchmarks and interventions to promote timely access to CR services. PMID- 21826011 TI - Prevalence of hypovitaminosis D and factors associated with vitamin D deficiency and morbidity among HIV-infected patients enrolled in a large Italian cohort. AB - BACKGROUND: A high prevalence of hypovitaminosis D (hypD) in HIV-infected patients has been reported, but reasons are unclear. METHODS: The 25 hydroxy vitamin D (vitD) concentration was measured in a sample of HIV-positive patients from Italy enrolled in the Icona Foundation Study. The change in absolute levels of vitD pre/post combination antiretroviral treatment was modelled by linear regression controlling for confounders and seasonality. Factors associated with hypD were identified using logistic regression analysis, and survival analysis was employed to evaluate the prognostic value of vitD concentration to predict severe diseases (diabetes, cardiovascular, renal), AIDS, and death. RESULTS: We studied 810 patients contributing 1408 vitD measures. Median age was 36 years (range: 20-69). VitD insufficiency (30-75 nmol/L) and deficiency (<30 nmol/L) were found in 47% and 6% of the measures. Factors independently associated with vitD deficiency were African or Centre/South American nationality [odds ratio (OR): 4.16 vs. European, P = 0.04], the sample being collected in spring (OR: 11.27, P = 0.001) or in winter (OR: 4.22, P = 0.03) vs. summer, and a previous history of severe diseases (OR: 5.43, P = 0.03) or AIDS (OR: 2.44, P = 0.04). Over a median follow-up of 6.3 years, patients with vitD insufficiency were at higher risk of subsequent severe diseases than those with normal levels (relative hazard = 1.60, P = 0.05). CONCLUSIONS: Our analysis shows that despite the relatively young age of our HIV-infected population, the prevalence of hypD was high. Classic risk factors for hypD in the general population were confirmed in this setting. HypD seems to be moderately associated with the risk of severe disease, AIDS, and death. PMID- 21826013 TI - Natural killer cell activation distinguishes Mycobacterium tuberculosis-mediated immune reconstitution syndrome from chronic HIV and HIV/MTB coinfection. AB - BACKGROUND: With increased access to antiretroviral treatment (ART), immune reconstitution inflammatory syndrome (IRIS) in Mycobacterium tuberculosis (MTB) infected populations remains a clinical challenge. We studied a cross-sectional cohort of HIV-infected subjects in Johannesburg (South Africa) to help define the immune correlates that best distinguish IRIS from ongoing MTB cases. METHODS: We studied HIV+ subjects developing MTB-related unmasking tuberculosis-related immune reconstitution inflammatory syndrome (uTB-IRIS) after ART initiation; control groups were subjects with HIV and HIV/tuberculosis-coinfected subjects with comparable ART treatment. Testing was conducted with whole blood-based 4 color flow cytometry and plasma-based Luminex cytokine assessment. RESULTS: Natural killer cell activation, C-reactive protein, and interleukin 8 serum concentration were significantly higher in uTB-IRIS subjects compared with both control groups. In addition, all MTB-coinfected subjects, independent of clinical presentation, had higher neutrophils and T-cell activation, together with lower lymphocytes, CD4+ T-cell, and myeloid dendritic cell counts. Using conditional inference tree analysis, we show that elevated natural killer cell activation in combination with lymphocyte count characterizes the immunological profile of uTB IRIS. CONCLUSION: Our results support a role for innate immune effectors in the immunopathogenesis of unmasking MTB-related IRIS and identify new immune parameters defining this pathology. PMID- 21826017 TI - The development of a self-reported version of the chronic heart questionnaire. AB - PURPOSE: Health status is increasingly recognized as an important outcome for the management of chronic heart failure (CHF). The Chronic Heart Questionnaire (CHQ) is valid, reliable, and responsive but is interview led. The aim of this study was to develop a self-reported version (CHQ-SR) to aid practical application of the questionnaire. The validity, repeatability, and responsiveness were investigated. METHODS: Patients with CHF (n = 54) were recruited; 50 completed both CHQs-the self-reported (CHQ-SR) and the interview led (CHQ-IL)-within a 2 week period with the order of administration alternated. Patients (n = 43) completed the CHQ-SR twice within a 2-week period. Construct validity was assessed using the Medical Outcomes Short Form 36 (SF-36) questionnaire, and the responsiveness was assessed using a randomized controlled trial of exercise rehabilitation versus usual care. RESULTS: The CHQ-SR was comparable but not interchangeable with the CHQ-IL. There were no significant differences between the mean scores for each domain on 2 administrations of the CHQ-SR, except for a small improvement in the emotional function domain. There were moderate-to-high correlations between the domains of the CHQ-SR and relevant components of the SF 36. The CHQ-SR was as responsive as the CHQ-IL when applied to a randomized controlled trial of exercise rehabilitation versus usual care in patients with CHF. CONCLUSION: The CHQ-SR is comparable with the CHQ-IL and is repeatable. It has construct validity with other health status measures and is responsive. The advantage of not requiring interviewer time and associated cost provides for a practical administration of the questionnaire. PMID- 21826018 TI - Work adjustment in cardiovascular disease: job characteristics and social support. AB - PURPOSE: To better understand social influences on work recovery, we studied the association between work status, work adjustment (WA), job demands, and social support (employer, family, physician) for return to work in cardiac rehabilitation (CR) patients. METHODS: Multiple cross-sectional design with questionnaire data collected from patients (72% working; age = 57 +/- 10.7 years) either at program entry (n = 126) or 6 to 12 months (n = 88) of CR exposure. Work adjustment was assessed by utilizing a visual analogue scale (WA VAS). Perceived social support from the employer, family, and physician was assessed using 5 point Likert scales. Physical demands (PD) and psychological job demands, and job control, were assessed utilizing the Job Content Questionnaire. RESULTS: Working patients expressed higher levels of employer support (4.2 +/- 1.2 vs 3.6 +/- 1.4, P < .04) and lower PD (7.9 +/- 3.4 vs 10.5 +/- 4.0, P < .001) than those not working. Employer support was positively correlated with WA VAS (R = 0.34, P < .002). High PD were negatively correlated with WA VAS (R = -0.31, P < .002). Weaker relationships were observed between family support and physician support and the dependent measures. CONCLUSIONS: Findings suggest that CR patients view their employer as a significant source of social support for return to work. Efforts to foster support from employers are an important consideration for the functional rehabilitation of these workers. The nature of the supportive relationship requires further investigation to determine the salient aspects that impact on work adjustment. PMID- 21826019 TI - n-3 Polyunsaturated fatty acids for the prevention of postoperative atrial fibrillation: a meta-analysis of randomized controlled trials. AB - BACKGROUND: n-3 Polyunsaturated fatty acids (n-3 PUFAs) have been proposed as prophylactic therapy in the prevention of postoperative atrial fibrillation (POAF) in patients undergoing cardiac surgery. We conducted a meta-analysis of randomized controlled trials to better clarify this issue. METHODS: An electronic database search for randomized controlled trials on the effect of n-3 PUFAS on POAF was conducted, limited to English language publications until December 2010. For each study, data regarding the incidence of POAF were used to generate risk ratio (<1, favors n-3 PUFA; >1, favors placebo). Pooled summary effect estimate was calculated by means of a fixed or random effect according to heterogeneity. Meta-regression was used to investigate the effect of eicosapentaenoic acid (EPA)/docosahexaenoic acid (DHA) ratio and preoperative beta-blockers on the effect of n-3 PUFA on POAF. RESULTS: Three publications were included in the analysis, enrolling a total of 431 patients. Overall incidence of POAF ranged from 24 to 54%. Pooling data, n-3 PUFA did not show a significant effect on the risk of POAF [risk ratio 0.89; 95% confidence interval (CI) 0.55-1.44; P=0.63]. However, meta-regression analysis showed a trend toward a benefit from n-3 PUFA supplementation when the EPA/DHA ratio was 1:2 (Q model=7.4; p model=0.02) and when preoperative beta-blocker rate was lower (Q model=8.0; p model=0.01). CONCLUSION: In conclusion, the results of the present meta-analysis of randomized controlled trials suggest that preoperative n-3 PUFA therapy may not reduce POAF in patients undergoing cardiac surgery. However, several aspects may have influenced this negative result, which need to be investigated. PMID- 21826020 TI - Effects of hyperacute blood pressure and heart rate on stroke outcomes after intravenous tissue plasminogen activator. AB - BACKGROUND AND PURPOSE: The present study clarifies associations between stroke outcomes after intravenous tissue plasminogen activator (tPA) and blood pressure (BP) as well as heart rate (HR) profiles. METHODS: We assessed 125 patients with stroke who received tPA within 3 h of onset. We obtained baseline, mean, maximum, minimum, and coefficient of variation values for BP and HR during the initial 24 h. The primary outcome was independence at 3 months corresponding to a modified Rankin Scale score of 2 or less. The secondary outcomes were early neurological improvement at 24 h and intracerebral hemorrhage (ICH) within 36 h. RESULTS: Among the patients, 64 (51%) achieved independence, 66 (53%) early improvement, and 26 (21%) developed ICH. The 24-h time courses of SBP (P = 0.033), pulse pressure (PP, P = 0.007), and HR (P < 0.001) were lower among patients who reached independence than among those who did not. After multivariate adjustment, 24-h mean levels of SBP (odds ratio 0.69, 95% confidence interval 0.48-0.97, per 10-mmHg increase), PP (0.63, 0.41-0.94), and HR (0.59, 0.42-0.80, per 10-bpm increase) were inversely associated with independence, as were their maximum and minimum values. In particular, mean SBP values were inversely associated with independence at 8-16 and 16-24 h (0.73, 0.54-0.97 and 0.66, 0.47-0.91, respectively), but not at 0-8 h (0.79, 0.57-1.07). Baseline and maximum SBP were inversely associated with early improvement. Maximum and coefficient of variation of SBP were associated with ICH. CONCLUSION: Lower SBP, PP, and HR values during the initial 24 h after tPA, especially at 8 h thereafter, were associated with independence at 3 months. PMID- 21826021 TI - Obesity phenotype and cardiovascular changes. AB - OBJECTIVE: Healthy obese phenotype with favorable metabolic profiles is proposed. However, whether healthy obesity leads to target organ changes is controversial. We investigated the impact of a healthy obesity on cardiovascular structure and function. METHODS: A total of 2540 participants without known cardiovascular disease were enrolled. According to BMI and the metabolic syndrome (MetS) component, the participants were divided into six groups: healthy (none of five MetS components) normal weight (BMI <23 kg/m2), unhealthy (one or more of five MetS components) normal weight, healthy overweight (BMI 23-24.9 kg/m2), unhealthy overweight, healthy obesity (BMI >=25 kg/m2), and unhealthy obesity. The cardiovascular changes were assessed by echocardiography, tissue Doppler imaging (TDI), carotid ultrasonography, and pulse wave velocity (PWV). RESULTS: In a multivariate analysis after adjusting for age, sex, heart rate, high-sensitivity C-reactive protein, and medication for hypertension and diabetes mellitus, the unhealthy overweight and obese groups showed statistically significant changes in the left ventricular mass index, mitral E/A ratio, E/Ea ratio, TDI Ea velocity, common carotid artery intima-media thickness (CCA-IMT), and brachial-ankle PWV (P < 0.001), compared with the healthy normal weight individuals. In the healthy overweight and obese groups, CCA-IMT and brachial-ankle PWV values were similar, but left-ventricular mass index and TDI Ea velocity were significantly different (P < 0.001). CONCLUSION: Healthy obesity was associated with subtle changes in left ventricular structure and function. These data provide evidence that metabolically healthy phenotypes with excess weight may not be a benign condition. PMID- 21826022 TI - Cardiovascular manifestations of phaeochromocytoma. AB - Clinical expression of phaeochromocytoma may involve numerous cardiovascular manifestations, but usually presents as sustained or paroxysmal hypertension associated with other signs and symptoms of catecholamine excess. Most of the life-threatening cardiovascular manifestations of phaeochromocytoma, such as hypertensive emergencies, result from a rapid and massive release of catecholamines from the tumour. More rarely, patients with phaeochromocytoma present with low blood pressure or even shock that may then precede multisystem crisis. Sinus tachycardia, with palpitations as the presenting symptom, is the most prevalent abnormality of cardiac rhythm in phaeochromocytoma, but tumours can also be associated with more serious ventricular arrhythmias or conduction disturbances. Reversible dilated or hypertrophic cardiomyopathy are well established cardiac manifestations of phaeochromocytoma, with more recent attention to an increasing number of cases with Takotsubo cardiomyopathy. This review provides an update on the cause, clinical presentation and treatment of the cardiovascular manifestations of phaeochromocytoma. As the cardiovascular complications of phaeochromocytoma can be life-threatening, all patients who present with manifestations that even remotely suggest excessive catecholamine secretion should be screened for the disease. PMID- 21826023 TI - Aldosterone as a modulator of immunity: implications in the organ damage. AB - High plasmatic levels of aldosterone cause hypertension and contribute to progressive organ damage to the heart, vasculature, and kidneys. Recent studies have demonstrated a role for the immune system in these pathological processes. Aldosterone promotes an inflammatory state characterized by vascular infiltration of immune cells, reactive oxidative stress, and proinflammatory cytokine production. Further, cells of the adaptive immune system, such as T cells, seem to participate in the genesis of mineralocorticoid hormone-induced hypertension. In addition, the observation that aldosterone can promote CD4+ T-cell activation and Th17 polarization suggests that this hormone could contribute to the onset of autoimmunity. Here we discuss recent evidence supporting a significant involvement of the immune system, especially adaptive immunity, in the genesis of hypertension and organ damage induced by primary aldosteronism. In addition, possible new therapeutic approaches consisting of immunomodulator drugs to control exacerbated immune responses triggered by elevated aldosterone concentrations will be described. PMID- 21826024 TI - Relations between large artery structure and function and aldosterone. AB - Aldosterone influences independently the vascular environment in humans, acting through structural and functional modifications of the arterial wall as derived from mineralocorticoid receptors. In rats, aldosterone infusion increases arterial stiffness in the presence of high-sodium intake, together with development of extracellular matrix and inflammatory factors. A selective increase in systolic and pulse pressure ensues, causing predominant organ damage on the heart, kidney and large arteries. In humans at rest, but independently of mean arterial pressure, arterial stiffness and wave reflections are associated with a steeper increase in these parameters with age. This finding is observed mainly with the CC genotype and not the TT or the TC genotype of the aldosterone synthase gene polymorphism. Early identification of individuals presenting this genotype could be important to detect hypertension. PMID- 21826025 TI - Branch retinal vein occlusion during fingolimod treatment in a patient with multiple sclerosis. PMID- 21826026 TI - Preventing avoidable rehospitalizations by understanding the characteristics of "frequent fliers". AB - This project used chart review to evaluate 22 patients labeled as "frequent fliers," each with 4 to 8 readmissions over a 6-month period at a Michigan community hospital. The goal was to identify whether the 4 key elements identified by the Institute for Healthcare Improvement for reducing rehospitalization had been put into place for these patients. It found that a clear discharge plan was only documented for 15 (68%) of the 22 patients. Better coordinated care is warranted. PMID- 21826027 TI - Use of ultrasound guidance for peripheral intravenous placement in difficult-to access patients: advancing practice with evidence. AB - Placement of peripheral intravenous (PIV) lines in difficult-to-access patients can be daunting. Multiple unsuccessful peripheral sticks, numerous PIV restarts, and potentially excess use of peripherally inserted central catheters can result. The goals of this project were to decrease the number of peripherally inserted central catheter referrals and lower the number of PIV restarts by having clinical nurses employ ultrasound guidance when initiating deep PIVs. After 10 months of nurses using the ultrasound as needed to insert a PIV line, the number of total peripherally inserted central catheter referrals decreased by 20%. PMID- 21826028 TI - Preventing device-related pressure ulcers: using data to guide statewide change. AB - Data collected through Minnesota's mandatory statewide reporting system indicate that prevention of hospital-acquired pressure ulcers continues to be a challenge, particularly for patients who require the use of stabilization collars or other immobilizers, respiratory equipment, orthotics, and tubing. This article describes the process of identifying a pattern of device-related pressure ulcers through statewide pressure ulcer reports and developing a set of recommendations for prevention. PMID- 21826030 TI - Reported antiplatelet use influences long-term outcome independently in deep intracerebral hemorrhage. AB - BACKGROUND: Recent studies have focused on antiplatelet (AP) use in intracerebral hemorrhage (ICH) patients. Several outcome predictors have been debated, but influences on mortality and outcome still remain controversial, especially for different ICH locations. OBJECTIVE: To investigate the characteristics and functional outcome of ICH patients with reported regular AP use according to hemorrhage locations. METHODS: This retrospective analysis included 210 consecutive spontaneous ICH patients. Clinical data including the preadmission status, initial presentation, neuroradiological data, treatment, and outcome were evaluated. Analyses were calculated for AP use vs non-AP use according to hematoma locations, and multivariate models were calculated for hematoma expansion and unfavorable (modified Rankin Scale = 4-6) long-term functional outcome (at 1 year). RESULTS: For all AP users ICH volume was significantly larger, 27.7 mL (interquartile range 7.4-66.1) vs 16.8 mL (interquartile range 4.2-44.7); (P = .032). Analyses showed an increased mortality for AP users at 90 days and 1 year (P = .036; P = .008). Multivariately, for all ICH patients, prior AP use was independently associated with hematoma expansion (odds ratio [OR] 3.61; P = .026) and poorer functional outcome at 1 year (OR 3.82, P = .035). In deep ICH patients, AP use was an independent predictor of an unfavorable functional outcome at 1 year (OR 4.75, P = .048). CONCLUSION: Hematoma expansion and more frequent unfavorable long-term functional outcome were independently associated with prior AP use for all patients, and in deep ICH patients AP use was an independent predictor of an unfavorable long-term functional outcome. PMID- 21826031 TI - Hearing preservation using the middle fossa approach for the treatment of vestibular schwannoma. AB - BACKGROUND: The incidence of small vestibular schwannomas in patients with serviceable hearing is increasing because of the widespread use of MRI. The middle fossa approach provides the patient with an opportunity for tumor removal with hearing preservation. OBJECTIVE: To determine the rate of hearing preservation and facial nerve outcomes after removal of a vestibular schwannoma with the use of the middle fossa approach. METHODS: A retrospective case review at a tertiary, academic medical center was performed identifying patients from 1998 through 2008 that underwent removal of a vestibular schwannoma by the middle fossa approach. Preoperative and postoperative audiograms were compared to determine hearing preservation rates. In addition, facial nerve outcomes at last follow-up were recorded. RESULTS: Forty-six patients underwent a middle fossa craniotomy for the removal of a vestibular schwannoma. Of the 38 patients that had class A or class B hearing preoperatively, 24 (63.2%) retained class A or B hearing and 29 (76.3%) retained class A, B, or C hearing. When tumors were 10 mm or less in patients with class A or B preoperative hearing, 22 of 30 patients (73.3%) retained class A or B hearing. When the tumor size was greater than 10 mm in patients with class A or B preoperative hearing, 2 of 8 patients (25%) retained class A or B hearing. At most recent follow-up, 76.1% of patients had House-Brackmann grade I facial function, 13.0% had House-Brackmann grade II facial function, and 10.9% had House-Brackmann grade III facial function. CONCLUSION: Hearing preservation rates are excellent using the middle fossa approach, especially for smaller tumors. No patient experienced long-term facial nerve function worse than House-Brackmann grade III. PMID- 21826029 TI - Psychomotor vigilance testing of professional drivers in the occupational health clinic: a potential objective screen for daytime sleepiness. AB - OBJECTIVE: Psychomotor vigilance testing (PVT) rapidly assesses attention, reaction time (RT), and abnormal vigilance. Thus, PVT may be an adjunct to screening drivers for high-risk obstructive sleep apnea (OSA)/excess daytime sleepiness (EDS). METHODS: Commercial drivers and emergency responders undergoing occupational examinations took a 10-minute PVT and were instructed to achieve their fastest possible RTs. Participants with maximum RT >5 seconds or >= 2 "super lapses" (RT >= 1000 ms) were categorized as "microsleepers." RESULTS: Among 193 male participants, the 15 microsleepers (8%) were significantly more obese, but not different on age or Epworth Sleepiness Score. Time of day had no effect on RT. CONCLUSION: PVT is suitable to occupational clinics and can identify otherwise unrecognized, impaired vigilance. Further studies must validate the PVT abnormalities most predictive of OSA/EDS and vehicular crashes, compared to adiposity measures alone. PMID- 21826034 TI - What does EMTALA mean for you? PMID- 21826032 TI - Efficacy of reductive ventricular osmotherapy in a swine model of traumatic brain injury. AB - BACKGROUND: The presence of osmotic gradients in the development of cerebral edema and the effectiveness of osmotherapy are well recognized. A modification of ventriculostomy catheters described in this article provides a method of osmotherapy that is not currently available. The reductive ventricular osmotherapy (RVOT) catheter removes free water from ventricular cerebrospinal fluid (CSF) by incorporating hollow fibers that remove water vapor, thereby providing osmotherapy without increasing osmotic load. OBJECTIVE: To increase osmolarity in the ventricular CSF through use of RVOT in vivo. METHODS: Twelve Yorkshire swine with contusional injury were randomized to external ventricular drainage (EVD) or RVOT for 12 hours. MR imaging was obtained. Serum, CSF, and brain ultrafiltrate were analyzed. Histology was compared using Fluor-Jade B and hematoxylin and eosin (H & E) stains. RESULTS: With RVOT, CSF osmolality increased from 292 +/- 2.7 to 345 +/- 8.0 mOsmol/kg (mean +/- SE, P = 0.0006), and the apparent diffusion coefficient (ADC) in the injury region increased from 0.735 +/- 0.047 to 1.135 +/- .063 (P = 0.004) over 24 hours. With EVD controls, CSF osmolarity and ADC were not significantly changed. Histologically, all RVOT pigs showed no evidence of neuronal degeneration (Grade 1/4) compared to moderate degeneration (Grade 2.6 +/- .4/4) seen in EVD treated animals (P = 0.02). The difference in intracranial pressure (ICP) by area under the curve approached significance at P = .065 by Mann Whitney test. CONCLUSION: RVOT can increase CSF osmolarity in vivo after experimental traumatic brain injury (TBI). In anticipated clinical use, only a slight increase in CSF osmolarity may be required to reduce cerebral edema. PMID- 21826033 TI - Endoscopic image-guided transcervical odontoidectomy: outcomes of 15 patients with basilar invagination. AB - BACKGROUND: Ventral decompression with posterior stabilization is the preferred treatment for symptomatic irreducible basilar invagination. Endoscopic image guided transcervical odontoidectomy (ETO) may allow for decompression with limited morbidity. OBJECTIVE: To describe the perioperative outcomes of patients undergoing anterior decompression of basilar invagination with the use of ETO. METHODS: Fifteen patients who had a follow-up of at least 16 months were retrospectively reviewed. Intraoperatively, the vertebral body of C2 was removed and the odontoid was resected in a "top-down" manner using endoscopic visualization and frameless stereotactic navigation. Posterior instrumented stabilization was subsequently performed. RESULTS: The average (+/- standard deviation) age of the patients was 42.6 +/- 24.5 (range, 11-72) years. Postoperative complications occurred in 6 patients, including a urinary tract infection (n = 2), upper airway swelling (n = 2), dysphagia (n = 2), gastrostomy tube placement (n = 1), and an asymptomatic pseudomeningocele (n = 1). No patients required a tracheostomy, had bacterial meningitis, or developed a venous thromboembolic event; only 1 patient was intubated for more than 48 hours postoperatively. With a mean follow-up of 41.9 +/- 14.4 (range, 16-59) months, myelopathy improved in all patients and no patient experienced late neurological deterioration. The mean modified Japanese Orthopedic Association (JOA) score increased from 11.2 +/- 4.2 to 15.9 +/- 1.4 (P = .002). Patients with a diagnosis other than rheumatoid arthritis or who had a higher preoperative JOA score had a significantly better postoperative neurological recovery (P = .005). CONCLUSION: ETO may be a valid treatment for patients with symptomatic irreducible basilar invagination that avoids some of the morbidity of transoral surgery and leads to long-term improvement in myelopathy. PMID- 21826036 TI - Women & heart disease: symptoms and treatment guidelines. AB - Coronary heart disease is the leading cause of death for women. Many women and some NPs are not aware of women's risk of myocardial infarction (MI) or that women's MI symptoms often differ from men's. NPs need to educate women about their risk and follow practice guidelines. PMID- 21826037 TI - Celiac disease: helping patients live gluten-free. AB - Celiac disease affects approximately 1% of the U.S. population, and many cases go undiagnosed until later in life. A wide range of symptoms, illnesses, and disorders may accompany undiagnosed celiac disease. This article reviews screening, diagnosis, and treatment of celiac disease for the NP. PMID- 21826038 TI - Scientific evidence underlying the American College of Obstetricians and Gynecologists' practice bulletins. AB - OBJECTIVE: Clinical guidelines are an important source of guidance for clinicians. Few studies have examined the quality of scientific data underlying evidence-based guidelines. We examined the quality of evidence that underlies the recommendations made by the American College of Obstetricians and Gynecologists (the College). METHODS: The current practice bulletins of the College were examined. Each bulletin makes multiple recommendations. Each recommendation is categorized based on the quality and quantity of evidence that underlies the recommendation into one of three levels of evidence: A (good and consistent evidence), B (limited or inconsistent evidence), or C (consensus and opinion). We analyzed the distribution of levels of evidence for obstetrics and gynecology recommendations. RESULTS: A total of 84 practice bulletins that offered 717 individual recommendations were identified. Forty-eight (57.1%) of the guidelines were obstetric and 36 (42.9%) were gynecologic. When all recommendations were considered, 215 (30.0%) provided level A evidence, 270 (37.7%) level B, and 232 (32.3%) level C. Among obstetric recommendations, 93 (25.5%) were level A, 145 (39.7%) level B, and 117 (34.8%) level C. For the gynecologic recommendations, 122 (34.7%) were level A, 125 (35.5%) level B, and 105 (29.8%) level C. The gynecology recommendations were more likely to be of level A evidence than the obstetrics recommendations (P=.049). CONCLUSION: One third of the recommendations put forth by the College in its practice bulletins are based on good and consistent scientific evidence. PMID- 21826039 TI - Hospital volume, provider volume, and complications after childbirth in U.S. hospitals. AB - OBJECTIVE: To examine the relationship between both hospital and provider case volume and obstetric complication rates in U.S. hospitals. METHODS: This was a nationwide retrospective cohort study of women admitted to acute care U.S. hospitals for childbirth in 2007. We examined four categories of maternal complications (lacerations, hemorrhage, infections, and thromboses) and created a composite measure. We examined the relationship of hospital volume, provider volume, and odds of complications. RESULTS: We found no consistent relationship between hospital volume and rates of maternal complications. In contrast, we found that women cared for by providers in the lowest quartile of provider volume (fewer than seven deliveries per year) had a 50% higher odds of complications compared with women cared for by obstetricians in the highest quartile (odds ratio 1.5, 95% confidence interval, 1.3-1.7, P<.001). Each of the individual complications occurred more frequently among the lowest-volume providers compared with others. Models that adjusted for hospital characteristics and cesarean delivery rate had only modest effects. CONCLUSION: Individual providers with a low volume of deliveries have greater maternal complication rates than providers with a high volume. If volume is causally related to lower complication rates, strategies for improving care for women during childbirth may include selective referral to higher-volume providers or additional training for low-volume providers to ensure better outcomes. LEVEL OF EVIDENCE: III. PMID- 21826040 TI - Highlighting complications over successes in occurrence of sectoral choroidal occlusive vasculopathy. PMID- 21826041 TI - Mobile surgical skills education unit: a new concept in surgical training. AB - Basic surgical skills are an integral part of surgical training. Simulation-based surgical training offers an opportunity both to trainees and trainers to learn and teach surgical skills outside the operating room in a nonpatient, nonstressed environment. However, widespread adoption of simulation technology especially in medical education is prohibited by its inherent higher cost, limited space, and interruptions to clinical duties. Mobile skills laboratory has been proposed as a means to address some of these limitations. A new program is designed by the Royal College of Surgeons in Ireland (RCSI), in an approach to teach its postgraduate basic surgical trainees the necessary surgical skills, by making the use of mobile innovative simulation technology in their own hospital settings. In this article, authors describe the program and students response to the mobile surgical skills being delivered in the region of their training hospitals and by their own regional consultant trainers. PMID- 21826042 TI - Simulation of a patient with severe aortic stenosis undergoing emergency abdominal surgery. PMID- 21826043 TI - Good medicine benefits from ownership stake. PMID- 21826044 TI - 2008 New Jersey legislation for HIV testing of pregnant women and newborns. PMID- 21826045 TI - Increased access to medical care in New Jersey through telemedicine: increased risks to providers of healthcare without borders. PMID- 21826046 TI - No lines, no waiting: retail health clinics are here. PMID- 21826047 TI - Risk factors: how well do they explain disease etiology? PMID- 21826048 TI - Gamma knife stereotactic radiosurgery: review and update. PMID- 21826049 TI - Taking a timeout to address the changing face of healthcare. PMID- 21826050 TI - Communicating in a high-tech world. PMID- 21826051 TI - Hunterdon County Medication Access Partnership: applying a medication access model to the uninsured in New Jersey. PMID- 21826052 TI - Professor Roentgen and his ray: the evolution of technology in medicine. PMID- 21826053 TI - Corydaline inhibits multiple cytochrome P450 and UDP-glucuronosyltransferase enzyme activities in human liver microsomes. AB - Corydaline is a bioactive alkaloid with various antiacetylcholinesterase, antiallergic, and antinociceptive activities found in the medicinal herb Corydalis Tubers. The inhibitory potential of corydaline on the activities of seven major human cytochrome P450 and four UDP-glucuronosyltransferase enzymes in human liver microsomes was investigated using LC-tandem MS. Corydaline was found to inhibit CYP2C19-catalyzed S-mephenytoin-4'-hydroxylatoin and CYP2C9-catalyzed diclofenac 4-hydroxylation, with K(i) values of 1.7 and 7.0 mM, respectively. Corydaline also demonstrated moderate inhibition of UGT1A1-mediated 17b-estradiol 3-glucuronidation and UGT1A9-mediated propofol glucuronidation with K(i) values of 57.6 and 37.3 mM, respectively. In the presence of corydaline, CYP3A-mediated midazolam hydroxylation showed a decrease with increasing preincubation time in a dose-dependent manner with K(i) values of 30.0 mM. These in vitro results suggest that corydaline should be evaluated for potential pharmacokinetic drug interactions in vivo due to potent inhibition of CYP2C19 and CYP2C9. PMID- 21826055 TI - FHL2 expression in peritumoural fibroblasts correlates with lymphatic metastasis in sporadic but not in HNPCC-associated colon cancer. AB - Four and a half LIM domain protein-2 (FHL2) is a component of the focal adhesion structures and has been suggested to have an important role in cancer progression. This study analyses the role of FHL2 in peritumoural fibroblasts of sporadic and hereditary non-polyposis colorectal cancer (HNPCC). Tissue specimens of 48 sporadic and 49 hereditary colon cancers, respectively, were stained immunohistochemically for FHL2, transforming growth factor (TGF)-beta1 ligand and alpha-SMA. Myofibroblasts at the tumour invasion front co-expressed alpha-SMA and FHL2. Sporadic colon cancer but not HNPCC cases showed a correlation between TGF beta1 expression of the invading tumour cells and FHL2 staining of peritumoural myofibroblasts. Overexpression of FHL2 in peritumoural myofibroblasts correlated to lymphatic metastasis in sporadic colon cancer but not in HNPCC. In cultured mouse fibroblasts, TGF-beta1 treatment induced myofibroblast differentiation, stimulated FHL2 protein expression and elevated number of migratory cells in transwell motility assays, suggesting that FHL2 is regulated downstream of TGF beta. Physical contact of colon cancer cells and myofibroblasts via FHL2-positive focal adhesions was detected in human colon carcinoma tissue and in co-culture assays using sporadic as well as HNPCC-derived tumour cell lines. Our data provide strong evidence for an important role of FHL2 in the progression of colon cancers. Tumour-secreted TGF-beta1 stimulates FHL2 protein expression in peritumoural fibroblasts, probably facilitating the invasion of tumour glands into the surrounding tissue by enhanced myofibroblast migration and tight connection of fibroblasts to tumour cells via focal adhesions. These findings are absent in HNPCC-associated colon cancers in vivo and may contribute to a less invasive and more protruding tumour margin of microsatellite instable carcinomas. PMID- 21826054 TI - Nuclear receptor CAR (NR1I3) is essential for DDC-induced liver injury and oval cell proliferation in mouse liver. AB - The liver is endowed with the ability to regenerate hepatocytes in response to injury. When this regeneration ability is impaired during liver injury, oval cells, which are considered to be postnatal hepatic progenitors, proliferate and differentiate into hepatocytes. Here we have demonstrated that 3,5 diethoxycarbonyl-1,4-dihydrocollidine (DDC) activates the nuclear receptor constitutive active/androstane receptor (CAR), resulting in proliferation of oval cells in mouse liver. Activation of CAR by DDC was shown by hepatic nuclear CAR accumulation and cytochrome P450 (CYP)2B10 mRNA induction after feeding a 0.1% DDC-containing diet to Car(+/+) mice. After being fed the DDC diet, Car(+/+), but not Car(-/-) mice, developed severe liver injury and an A6 antibody-stained ductular reaction in an area around the portal tract. Oval cell proliferation was confirmed by laser capture microdissection and real-time PCR; mRNAs for the two oval cell markers epithelial cell adhesion molecule and TROP2 were specifically induced in the periportal region of DDC diet-fed Car(+/+), but not Car(-/-) mice. Although rates of both hepatocyte growth and death were initially enhanced only in DDC diet-fed Car(+/+) mice, growth was attenuated when oval cells proliferated, whereas death continued unabated. DDC-induced liver injury, which differs from other CAR activators such as phenobarbital, occurred in the periportal region where cells developed hypertrophy, accumulated porphyrin crystals and inflammation developed, all in association with the proliferation of oval cells. Thus, CAR provides an excellent experimental model for further investigations into its roles in liver regeneration, as well as the development of diseases such as hepatocellular carcinoma. PMID- 21826056 TI - Nodular fasciitis: a novel model of transient neoplasia induced by MYH9-USP6 gene fusion. AB - Nodular fasciitis (NF) is a relatively common mass-forming and self-limited subcutaneous pseudosarcomatous myofibroblastic proliferation of unknown pathogenesis. Due to its rapid growth and high mitotic activity, NF is often misdiagnosed as a sarcoma. While studying the USP6 biology in aneurysmal bone cyst and other mesenchymal tumors, we identified high expression levels of USP6 mRNA in two examples of NF. This finding led us to further examine the mechanisms underlying USP6 overexpression in these lesions. Upon subsequent investigation, genomic rearrangements of the USP6 locus were found in 92% (44 of 48) of NF. Rapid amplification of 5'-cDNA ends identified MYH9 as the translocation partner. RT-PCR and direct sequencing revealed the fusion of the MYH9 promoter region to the entire coding region of USP6. Control tumors and tissues were negative for this fusion. Xenografts of cells overexpressing USP6 in nude mice exhibited clinical and histological features similar to human NF. The identification of a sensitive and specific abnormality in NF holds the potential to be used diagnostically. Considering the self-limited nature of the lesion, NF may represent a model of 'transient neoplasia', as it is, to our knowledge, the first example of a self-limited human disease characterized by a recurrent somatic gene fusion event. PMID- 21826057 TI - Glutathione transferase kappa deficiency causes glomerular nephropathy without overt oxidative stress. AB - Glutathione transferase kappa (GSTK1-1) is a highly conserved, mitochondrial enzyme potentially involved in redox reactions. GSTK1-1-deficient mice were generated to further study the enzyme's biological role. Reduced and total glutathione levels in liver and kidney were unchanged by GSTK1-1 deficiency and NADPH quinone oxidoreductase 1 expression was not elevated indicating that there is no general underlying oxidative stress in Gstk1(-/-) mice. Electron microscopy of liver and kidney showed no changes in mitochondrial morphology with GSTK1-1 deficiency. The death of a number of Gstk1(-/-) males with urinary tract problems prompted close examination of the kidneys. Electron microscopy revealed glomerular basement membrane changes at 3 months, accompanied by detectable microalbuminuria in male mice (albumin:creatinine ratio of 2.66+/-0.83 vs 1.13+/ 0.20 mg/mmol for Gstk1(-/-) and wild-type (WT), respectively, P=0.001). This was followed by significant foot process effacement (40-55% vs 10% for Gstk1(-/-) and WT, respectively) at 6 months of age in all Gstk1(-/-) mice examined. Kidney tubules were ultrastructurally normal. Compared with human disease, the Gstk1(-/ ) kidneys show changes seen in glomerulopathies causing nephrotic syndrome. Gstk1(-/-) mice may offer insights into the early development of glomerular nephropathies. PMID- 21826058 TI - CCDC22: a novel candidate gene for syndromic X-linked intellectual disability. PMID- 21826059 TI - Don't give up on GWAS. PMID- 21826060 TI - A genome-wide linkage study of individuals with high scores on NEO personality traits. AB - The NEO-Five-Factor Inventory divides human personality traits into five dimensions: neuroticism, extraversion, openness, conscientiousness and agreeableness. In this study, we sought to identify regions harboring genes with large effects on the five NEO personality traits by performing genome-wide linkage analysis of individuals scoring in the extremes of these traits (>90th percentile). Affected-only linkage analysis was performed using an Illumina 6K linkage array in a family-based study, the Erasmus Rucphen Family study. We subsequently determined whether distinct, segregating haplotypes found with linkage analysis were associated with the trait of interest in the population. Finally, a dense single-nucleotide polymorphism genotyping array (Illumina 318K) was used to search for copy number variations (CNVs) in the associated regions. In the families with extreme phenotype scores, we found significant evidence of linkage for conscientiousness to 20p13 (rs1434789, log of odds (LOD)=5.86) and suggestive evidence of linkage (LOD >2.8) for neuroticism to 19q, 21q and 22q, extraversion to 1p, 1q, 9p and12q, openness to 12q and 19q, and agreeableness to 2p, 6q, 17q and 21q. Further analysis determined haplotypes in 21q22 for neuroticism (P-values = 0.009, 0.007), in 17q24 for agreeableness (marginal P value = 0.018) and in 20p13 for conscientiousness (marginal P-values = 0.058, 0.038) segregating in families with large contributions to the LOD scores. No evidence for CNVs in any of the associated regions was found. Our findings imply that there may be genes with relatively large effects involved in personality traits, which may be identified with next-generation sequencing techniques. PMID- 21826061 TI - Genome-wide association studies establish that human intelligence is highly heritable and polygenic. AB - General intelligence is an important human quantitative trait that accounts for much of the variation in diverse cognitive abilities. Individual differences in intelligence are strongly associated with many important life outcomes, including educational and occupational attainments, income, health and lifespan. Data from twin and family studies are consistent with a high heritability of intelligence, but this inference has been controversial. We conducted a genome-wide analysis of 3511 unrelated adults with data on 549,692 single nucleotide polymorphisms (SNPs) and detailed phenotypes on cognitive traits. We estimate that 40% of the variation in crystallized-type intelligence and 51% of the variation in fluid type intelligence between individuals is accounted for by linkage disequilibrium between genotyped common SNP markers and unknown causal variants. These estimates provide lower bounds for the narrow-sense heritability of the traits. We partitioned genetic variation on individual chromosomes and found that, on average, longer chromosomes explain more variation. Finally, using just SNP data we predicted ~1% of the variance of crystallized and fluid cognitive phenotypes in an independent sample (P=0.009 and 0.028, respectively). Our results unequivocally confirm that a substantial proportion of individual differences in human intelligence is due to genetic variation, and are consistent with many genes of small effects underlying the additive genetic influences on intelligence. PMID- 21826063 TI - Prognostic implications and molecular associations of NADH dehydrogenase subunit 4 (ND4) mutations in acute myeloid leukemia. AB - To study the prevalence and prognostic importance of mutations in NADH dehydrogenase subunit 4 (ND4), a mitochondrial encoded transmembrane component of the electron transport chain respiratory Complex I, 452 AML patients were examined for ND4 mutations by direct sequencing. The prognostic impact of ND4 mutations was evaluated in the context of other clinical prognostic markers and genetic risk factors. In all, 29 of 452 patients (6.4%) had either somatic (n=12) or germline (n=17) ND4 mutations predicted to affect translation. Somatic mutations were more likely to be heteroplasmic (P<0.001), to occur in predicted transmembrane domains (P<0.001) and were predicted to have damaging effects upon translation (P<0.001). Patients with somatically acquired ND4 mutations had significantly longer relapse-free survival (P=0.017) and overall survival (OS) (P=0.021) than ND4(wildtype) patients. Multivariate analysis also demonstrated a tendency for increased survival in patients with somatic ND4 mutations (RFS: hazard ratio (HR) 0.25, confidence interval (CI) 0.06-1.01, P=0.052; OS: HR 0.29, CI 0.74-1.20, P=0.089). Somatic ND4(mutated) patients had a higher prevalence of concomitant DNMT3A mutations (P=0.023) and a higher percentage of the NPM1/FLT3 ITD low-risk genotype (P=0.021). Germline affected cases showed higher BAALC (P=0.036) and MLL5 (P=0.051) expression levels. Further studies are warranted to validate the favorable prognostic influence of acquired ND4 mutations in AML. PMID- 21826062 TI - MRK003, a gamma-secretase inhibitor exhibits promising in vitro pre-clinical activity in multiple myeloma and non-Hodgkin's lymphoma. AB - Notch-stimulated signaling cascade results in transcriptional regulation of genes involved in cell fate decision, apoptosis and proliferation and has been implicated in various malignancies. Here, we investigated the impact of MRK003, an inhibitor of this pathway, on myeloma and lymphoma cells. We first studied the expression patterns of notch receptors and ligands on multiple myeloma (MM) and non-Hodgkin's lymphoma (NHL) cell lines. Next, we used a gamma-secretase inhibitor, MRK003 to test the importance of notch-stimulated pathways in MM and NHL disease biology. We observed expression of notch receptors and ligands on MM and NHL cell lines. MRK003 treatment induced caspase-dependent apoptosis and inhibited proliferation of MM and NHL cell lines and patient cells. Examination of signaling events after treatment showed time-dependent decrease in levels of the notch intracellular domain, Hes1 and c-Myc. MRK003 downregulated cyclin D1, Bcl-Xl and Xiap levels in NHL cells and p21, Bcl-2 and Bcl-Xl in MM cells. In addition, MRK003 caused an upregulation of pAkt, indicating crosstalk with the PI3K/Akt pathway. We evaluated MRK003 in combination with Akt1/2 kinase inhibitor and observed synergy in killing MM and NHL cell lines examined. PMID- 21826064 TI - Evo-devo: Hidden rewiring comes to light. PMID- 21826065 TI - Systems biology: Plant networks. PMID- 21826066 TI - IL-2 repositioned. PMID- 21826067 TI - B cells need their flip-flops. PMID- 21826068 TI - Pharmacotherapy: No link found between statins and risk of cancer. PMID- 21826069 TI - Antiplatelet therapy: Discontinuation of low-dose aspirin reverses its prophylactic effect. PMID- 21826070 TI - Interventional cardiology: Antithrombotic drug and stent choices in primary PCI. PMID- 21826072 TI - Cardiomyopathies: CMR sheds new light on the clinical profile of stress cardiomyopathy. PMID- 21826071 TI - Diagnosis and management of patients with white-coat and masked hypertension. AB - White-coat hypertension is characterized by an elevation in clinic blood pressure but normal home or ambulatory blood-pressure values, whereas patients with masked hypertension have normal clinic blood pressure and elevated ambulatory or home blood-pressure load. Both white-coat and masked hypertension are frequent clinical entities that need appropriate recognition and a close diagnostic follow up. White-coat and masked hypertension seem to be associated with organ damage and increased cardiovascular risk, although not invariably. In addition, patients with masked or white-coat hypertension have an increased risk of abnormalities affecting their glucose and lipid profiles. Therefore, the diagnosis of these conditions should be accurate and include the assessment of cardiovascular as well as of metabolic risk. Once diagnosed, first-line therapeutic interventions should be nonpharmacological and aim at lifestyle changes, but drug treatment can be indicated, particularly when the patient's cardiovascular risk profile is elevated or when target-organ damage is detected. PMID- 21826074 TI - Arrhythmias: Control rhythm rather than rate to delay permanent AF. PMID- 21826073 TI - Cost-effectiveness of oral antiplatelet agents--current and future perspectives. AB - Cardiovascular disease is both highly prevalent and exceedingly costly to treat. Several novel antiplatelet agents have been found to be effective in reducing the morbidity and mortality associated with cardiovascular disease. Understanding both the economic and the clinical implications of these novel therapies is particularly important. In this article, the results of published evaluations of the cost-effectiveness of oral antiplatelet strategies for use across a range of clinical conditions and treatment settings are reviewed. The results of these studies support the use of aspirin for primary prevention in high-risk patients and for secondary prevention in all patients with previous cardiovascular events. Although the optimal duration of dual antiplatelet therapy after an event remains uncertain, favorable cost-effectiveness estimates have been demonstrated for aspirin plus clopidogrel versus aspirin alone after a myocardial infarction or percutaneous coronary intervention. Moreover, prasugrel has been shown to be more cost-effective than clopidogrel for patients with an acute coronary syndrome and planned percutaneous coronary intervention. As novel antiplatelet agents emerge and existing agents are tested in different patient populations, the evaluation of the relative economic efficiency of these oral antiplatelet treatment strategies will continue to be instrumental to optimally inform clinical and health-policy decision-making. PMID- 21826077 TI - Transplantation: Should we match for HLA-DR in pediatric renal transplantation? PMID- 21826075 TI - The pharmacogenetics of antiplatelet agents: towards personalized therapy? AB - Considerable variability exists in how individual patients respond to oral antiplatelet therapy, specifically to aspirin and to P2Y(12)-receptor inhibitors such as clopidogrel. This variability translates to differences in clinical outcomes and might in part be as a result of common variation within genes that are involved in the absorption, metabolic activation, and biological activity of these medications. The field of pharmacogenetics has yielded several genetic loci that predict variation in patient response to antiplatelet therapies. The most robust data indicate an association between loss-of-function alleles of the CYP2C19 gene and adverse outcomes among high-risk patients treated with clopidogrel. However, several fundamental questions surrounding the information gained from genotyping and the efficacy of modifying therapy on the basis of testing remain unanswered. Routine genetic testing for platelet responsiveness cannot, therefore, be recommended for clinical decision-making. Ongoing and future clinical trials might provide evidence to support a change in practice towards pharmacogenetic-based selection of antiplatelet therapy. PMID- 21826078 TI - Nephrotic syndrome: A new specific test for idiopathic membranous nephropathy. PMID- 21826081 TI - Epidemiology: Revisiting family history. PMID- 21826080 TI - Management of hepatorenal syndrome in patients with cirrhosis. AB - Patients with liver cirrhosis develop progressive circulatory dysfunction, which induces activation of the renin-angiotensin-aldosterone system (RAAS), activation of the sympathetic nervous system and increased activity of antidiuretic hormone. Such activation results in renal fluid retention, ascites and dilutional hyponatremia. In patients with advanced cirrhosis, these processes culminate in renal vasoconstriction and type 2 hepatorenal syndrome (HRS), which is characterized by slowly progressive renal failure and refractory ascites. Type 1 HRS is characterized by acute renal failure and rapid deterioration in the function of other organs in the setting of a precipitating event. Prognosis for both types of HRS is notably poor and orthotopic liver transplantation is the only definitive treatment; however, various therapies that restore renal function can provide a bridge to transplantation. Vasoconstrictors plus albumin improve renal function in 40-60% of patients with type 1 HRS. Transjugular intrahepatic portosystemic shunt (TIPS) placement is also effective in type 1 HRS, but its applicability is low (as it is not suitable for all patients), and it increases the risk of encephalopathy. Albumin dialysis is a potentially effective treatment for type 1 HRS still under investigation. Patients with type 2 HRS are treated with repeated large-volume paracentesis or TIPS. PMID- 21826079 TI - Kidney aging--inevitable or preventable? AB - The aging process affects all organs, including the kidneys. As part of this process, progressive scarring and a measurable decline in renal function occur in most people over time. The improved understanding of the processes that can lead to and/or hasten scarring and loss of renal function over time parallels advances in our understanding of the aging process. Clinical factors, including hypertension, diabetes mellitus, obesity, abnormal lipid levels and vitamin D deficiency, have been associated with increasing renal sclerosis with age. In addition, tissue factors such as angiotensin II, advanced glycation end products, oxidative stress and Klotho are associated with renal aging. These associations and possible interventions, including the control of blood pressure, blood sugar, weight, diet and calorie restriction might make renal aging more preventable than inevitable. PMID- 21826082 TI - The changing therapeutic landscape of castration-resistant prostate cancer. AB - Castration-resistant prostate cancer (CRPC) has a poor prognosis and remains a significant therapeutic challenge. Before 2010, only docetaxel-based chemotherapy improved survival in patients with CRPC compared with mitoxantrone. Our improved understanding of the underlying biology of CRPC has heralded a new era in molecular anticancer drug development, with a myriad of novel anticancer drugs for CRPC entering the clinic. These include the novel taxane cabazitaxel, the vaccine sipuleucel-T, the CYP17 inhibitor abiraterone, the novel androgen receptor antagonist MDV-3100 and the radioisotope alpharadin. With these developments, the management of patients with CRPC is changing. In this Review, we discuss these promising therapies along with other novel agents that are demonstrating early signs of activity in CRPC. We propose a treatment pathway for patients with CRPC and consider strategies to optimize the use of these agents, including the incorporation of predictive and intermediate end point biomarkers, such as circulating tumor cells. PMID- 21826085 TI - DPP6 as a candidate gene for neuroleptic-induced tardive dyskinesia. AB - We implemented a two-step approach to detect potential predictor gene variants for neuroleptic-induced tardive dyskinesia (TD) in schizophrenic subjects. First, we screened associations by using a genome-wide (Illumina HumanHapCNV370) SNP array in 61 Japanese schizophrenia patients with treatment-resistant TD and 61 Japanese schizophrenia patients without TD. Next, we performed a replication analysis in 36 treatment-resistant TD and 138 non-TD subjects. An association of an SNP in the DPP6 (dipeptidyl peptidase-like protein-6) gene, rs6977820, the most promising association identified by the screen, was significant in the replication sample (allelic P=0.008 in the replication sample, allelic P=4.6 * 10(-6), odds ratio 2.32 in the combined sample). The SNP is located in intron-1 of the DPP6 gene and the risk allele was associated with decreased DPP6 gene expression in the human postmortem prefrontal cortex. Chronic administration of haloperidol increased Dpp6 expression in mouse brains. DPP6 is an auxiliary subunit of Kv4 and regulates the properties of Kv4, which regulates the activity of dopaminergic neurons. The findings of this study indicate that an altered response of Kv4/DPP6 to long-term neuroleptic administration is involved in neuroleptic-induced TD. PMID- 21826084 TI - The current landscape of locally advanced rectal cancer. AB - Postoperative adjuvant chemoradiotherapy was recommended as the standard treatment for patients with rectal cancer because it reduces local recurrence. This paradigm shifted with the use of neoadjuvant chemoradiotherapy, which not only reduces local recurrence but also improves sphincter preservation and surgical outcomes. However, the treatment of rectal carcinoma remains complicated. The accuracy of tumor staging can be compromised depending on the imaging modality used. The addition of modern chemotherapeutics and biologics to 5-fluorouracil as radiation sensitizers is questionable. Oxaliplatin as a radiation sensitizer has minimal effects on the pathologic complete response, but improves the radiographical response at the expense of an increased risk of toxicities. The role of biologics in addition to radiation therapy continues to be explored. Attention has focused on improving diagnostic imaging, radiation oncology, and surgical techniques, treatment regimens, and on exploring a role of molecular markers for patients with rectal cancers. We review the pivotal trials that have led to the current treatment paradigm for locally advanced rectal cancer and discuss novel methodologies that are being developed for the treatment of this prevalent malignancy. PMID- 21826083 TI - Cancer immunology--analysis of host and tumor factors for personalized medicine. AB - Immune cells in the tumor microenvironment have an important role in regulating tumor progression. Therefore, stimulating immune reactions to tumors can be an attractive therapeutic and prevention strategy. Cancer cells and host cells constantly interact with each other in the tumor microenvironment; thus, cancer immunology is an interdisciplinary area where integrated analysis of both host and tumor factors is needed. Cancer represents a heterogeneous group of diseases with different genetic and epigenetic alterations; therefore, molecular classification of cancer (for example lung, prostate and breast cancers) is an important component in clinical decision making. However, most studies on antitumor immunity and clinical outcome lack analysis of tumor molecular biomarkers. In this Review, we discuss colorectal cancer as a prototypical example of cancer. Common molecular classifiers of colon cancer include KRAS, BRAF and PIK3CA mutations, microsatellite instability, LINE-1 methylation, and CpG island methylator phenotype. Since tumor molecular features and immune reactions are inter-related, a comprehensive assessment of these factors is critical. Examining the effects of tumor-host interactions on clinical outcome and prognosis represents an evolving interdisciplinary field of molecular pathological epidemiology. Pathological immunity evaluation may provide information on prognosis and help identify patients who are more likely to benefit from immunotherapy. PMID- 21826086 TI - Background gene expression networks significantly enhance drug response prediction by transcriptional profiling. AB - A central goal of gene expression studies coupled with drug response screens is to identify predictive profiles that can be exploited to stratify patients. Numerous methods have been proposed towards this end, most of them focusing on novel statistical methods and model selection techniques that attempt to uncover groups of genes, whose expression profiles are directly and robustly correlated with drug response. However, biological systems process information through the crosstalk of multiple signaling networks, whose ultimate phenotypic consequences may only be determined by the combined input of relevant interacting systems. By restricting predictive signatures to direct gene-drug correlations, biologically meaningful interactions that may serve as superior predictors are ignored. Here we demonstrate that predictive signatures, which incorporate the interaction between background gene expression patterns and individual predictive probes, can provide superior models than those that directly relate gene expression levels to pharmacological response, and thus should be more widely utilized in pharmacogenetic studies. PMID- 21826089 TI - IBD: Trying to optimize a tool to measure disability in IBD. PMID- 21826087 TI - Nucleotide excision repair gene variants and association with survival in osteosarcoma patients treated with neoadjuvant chemotherapy. AB - The aim of this study was to investigate the role of common polymorphisms in the nucleotide excision repair pathway genes in the tumorigenesis of osteosarcoma and in the response to DNA damaging therapies, such as cisplatin-based neoadjuvant therapy. Excision repair cross-complementing (ERCC) group 2 (XPD; rs13181 and rs1799793), group 5 (XPG; rs17655) and group 1 (XPA; rs3212986 and rs11615) polymorphisms were analyzed in a group of 130 homogenously treated patients with high-grade osteosarcoma, for association with event-free survival (EFS), using the Kaplan-Meier plots and log-rank test. A positive association was observed between both XPD single-nucleotide polymorphisms and an increased EFS (hazards ratio (HR) = 0.34, 95% confidence interval (CI) 0.12-0.98 and HR = 0.19, 95% CI 0.05-0.77, respectively). We had also performed a case-control study for relative risk to develop osteosarcoma. Patients carrying at least one variant allele of XPD rs1799793 had a reduced risk of developing osteosarcoma, compared with wild type patients (odds ratio = 0.55, 95% CI 0.36-0.84). This study suggests that XPD rs1799793 could be a marker of osteosarcoma associated with features conferring either a better prognosis or a better outcome after platinum therapy, or both. PMID- 21826090 TI - Experimental arthritis: outcome of Btk blockade in mice. PMID- 21826091 TI - Connective tissue diseases: SAP-induced macrophage polarization: a potential therapeutic option for SLE? PMID- 21826088 TI - Alcoholic liver disease: pathogenesis and new targets for therapy. AB - Alcoholic liver disease (ALD) is a major cause of morbidity and mortality worldwide. The spectrum of disease ranges from fatty liver to hepatic inflammation, necrosis, progressive fibrosis and hepatocellular carcinoma. In developed countries, ALD is a major cause of end-stage liver disease that requires transplantation. The most effective therapy for ALD is alcohol abstinence. However, for patients with severe forms of ALD (that is, alcoholic hepatitis) and for those who do not achieve abstinence from alcohol, targeted therapies are urgently needed. The development of new drugs for ALD is hampered by the scarcity of studies and the drawbacks of existing animal models, which do not reflect all the features of the human disease. However, translational research using liver samples from patients with ALD has identified new potential therapeutic targets, such as CXC chemokines, osteopontin and tumor necrosis factor receptor superfamily member 12A. The pathogenetic roles of these targets, however, remain to be confirmed in animal models. This Review summarizes the epidemiology, natural history, risk factors and current knowledge of the pathogenetic mechanisms of ALD. In addition, this article provides a detailed description of the findings of these translational studies and of the animal models used to study ALD. PMID- 21826094 TI - Deep brain stimulation and neuropsychology: a step forward? PMID- 21826093 TI - Pharmacogenetics: implications for therapy in rheumatic diseases. AB - DMARDs not only improve the joint pain and swelling associated with rheumatoid arthritis (RA), but also slow down the joint damage associated with the disease. The efficacy of biologic therapies, introduced in the past decade for the treatment of RA, has been unequivocally established. Similarly, in addition to traditional drugs such as hydroxychloroquine, new biologic agents such as rituximab have been introduced for systemic lupus erythematosus in recent years. However, considerable variability occurs in the responses of patients to these therapies. Pharmacogenetics, the study of variations in genes encoding drug transporters, drug-metabolizing enzymes and drug targets, and their translation to differential responses to drugs, is a rapidly progressing field in rheumatology. Pharmacogenetic applications, particularly to the old vanguard DMARD, methotrexate, and the newer, more expensive biologic agents, might make personalized therapy in rheumatic diseases possible. The pharmacogenetics of commonly used DMARDs and of biologic therapies are described in this Review. PMID- 21826095 TI - A new approach to respiratory recovery after spinal cord injury? PMID- 21826096 TI - Othello syndrome-at the interface of neurology and psychiatry. PMID- 21826098 TI - PSA affects prostate cancer cell invasion in vitro and induces an osteoblastic phenotype in bone in vivo. AB - BACKGROUND: Patients with advanced prostate cancer frequently have a poor prognosis as a result of metastasis and present with high serum PSA levels. There is evidence suggesting that the serine protease activity of PSA could be involved in the invasion and metastasis of prostate cancer. In this study, we determined the effects of PSA and its precursor, pro-PSA, on invasion and the type of bone metastasis. METHODS: We stably transfected prostate adenocarcinoma cells, human DU-145 and rat MatLyLu, with either the full-length prepro-PSA sequence or pre PSA DNA, to generate subclones of cells that secrete pro-PSA or free PSA, respectively. Secretion of PSA was measured by western blot analysis and enzyme linked immunosorbent assay (ELISA). The invasive and migratory properties of the cells were determined using a basement membrane extract and were compared with corresponding empty vector control cells. Twelve days after injection of PSA secreting MatLyLu cells into the femora of nude mice, bone tumor burden and histomorphometry were determined using a stereological technique. RESULTS: The transfected cells secreted 0.15-2.23 ng PSA/10(6) cells/day. Pro-PSA-secreting subclones increased invasion and migration by 24-263%. Conversely, the PSA secreting subclones significantly reduced both invasion and migration by 59-70%. The divergent effects on invasion and migration observed in pro-PSA- and PSA secreting subclones indicate that different forms of PSA may have different functions. Intrafemoral injections with PSA-secreting MatLyLu cells resulted in an increase in osteoblastic parameters when compared with non-PSA-secreting subclones as measured by bone histomorphometry. Concomitantly, a decrease in osteoclasts and eroded surface was observed. CONCLUSIONS: Our in vitro data suggest that PSA, dependent on the predominant form secreted, may decrease or increase invasive properties of prostate cancer cells. The in vivo results indicate that PSA in the bone microenvironment may contribute to the osteoblastic phenotype of bone metastasis frequently observed in prostate cancer. PMID- 21826097 TI - Transcriptional and post-transcriptional regulation of Sprouty1, a receptor tyrosine kinase inhibitor in prostate cancer. AB - Sprouty1 (Spry1) is a negative regulator of fibroblast growth factor signaling with a potential tumor suppressor function in prostate cancer (PCa). Spry1 is downregulated in human PCa, and Spry1 expression can markedly inhibit PCa proliferation in vitro. We have reported DNA methylation as a mechanism for controlling Spry1 expression. However, promoter methylation does not seem to explain gene silencing in all PCa cases studied to suggest other mechanisms of gene inactivation, such as alterations in trans-acting factors and/or post transcriptional activity may be responsible for the decreased expression in those cases. Binding sites for Wilm's tumor (WT1) transcription factors EGR1, EGR3 and WTE are highly conserved between the mouse and human Spry1 promoter regions, suggesting an evolutionary conserved mechanism(s) involving WT1 and EGR in Spry1 regulation. Spry1 mRNA contains multiple microRNA (miRNA) binding sites in its 3'UTR region suggesting post-transcriptional control. We demonstrate that Spry1 is a target for miR-21-mediated gene silencing. miRNA-based therapeutic approaches to treat cancer are emerging. Spry1 is highly regulated by miRNAs and could potentially be an excellent candidate for such approaches. PMID- 21826099 TI - Nutrition: new guidelines on vitamin D-ficiency--clear or confusing? PMID- 21826101 TI - Genetics: AIP mutations in young patients with sporadic pituitary macroadenoma. PMID- 21826100 TI - Targeting gut microbiota in obesity: effects of prebiotics and probiotics. AB - At birth, the human colon is rapidly colonized by gut microbes. Owing to their vast number and their capacity to ferment nutrients and secrete bioactive compounds, these gastrointestinal microbes act as an environmental factor that affects the host's physiology and metabolism, particularly in the context of obesity and its related metabolic disorders. Experiments that compared germ-free and colonized mice or analyzed the influence of nutrients that qualitatively change the composition of the gut microbiota (namely prebiotics) showed that gut microbes induce a wide variety of host responses within the intestinal mucosa and thereby control the gut's barrier and endocrine functions. Gut microbes also influence the metabolism of cells in tissues outside of the intestines (in the liver and adipose tissue) and thereby modulate lipid and glucose homeostasis, as well as systemic inflammation, in the host. A number of studies describe characteristic differences between the composition and/or activity of the gut microbiota of lean individuals and those with obesity. Although these data are controversial, they suggest that specific phyla, classes or species of bacteria, or bacterial metabolic activities could be beneficial or detrimental to patients with obesity. The gut microbiota is, therefore, a potential nutritional and pharmacological target in the management of obesity and obesity-related disorders. PMID- 21826103 TI - Treatment and follow-up of low-risk patients with thyroid cancer. AB - The postoperative administration of radioiodine can be avoided in low-risk patients with undetectable TSH-stimulated serum thyroglobulin and no lymph-node metastases detected at surgery. Sensitive methods for serum thyroglobulin determination can be used to avoid TSH stimulation 9-12 months after surgery in low-risk patients who have an undetectable serum thyroglobulin on levothyroxine treatment; the role of these sensitive assays in the period immediately after surgery needs to be established by further studies. Finally, a low activity of radioiodine (1.1 GBq) should be administered selectively in low-risk patients receiving levothyroxine treatment following injections of recombinant human TSH. These modifications of current protocols will improve the quality of life of patients, potentially decrease morbidity and considerably reduce the cost of treatment and follow-up. PMID- 21826104 TI - Cardiovascular endocrinology: RAGE--a biomarker for CHD in T2DM? PMID- 21826102 TI - Radioiodine for remnant ablation and therapy of metastatic disease. AB - Radioiodine is considered an effective and low-risk therapy modality of advanced differentiated thyroid cancer. For patients without lymph-node or distant metastases and low stages of the primary tumor, debate is ongoing about the necessity of thyroid remnant tissue ablation in an adjuvant setting. On the basis of evidence from retrospective studies, and until results of ongoing controlled prospective randomized trials become available, (131)I ablation of remnant thyroid tissue in patients with primary tumors >1 cm is advisable. For thyroid remnant ablation, individual dosimetry is not obligatory. By contrast, the effectiveness of (131)I therapy of locally advanced and/or metastatic disease can be improved by individual dosimetry. For practical reasons, an approach delivering the maximal possible radiation dose to the tumor without exceeding a critical blood dose of approximately 2 Gy seems advantageous. The availability of recombinant human TSH (rhTSH) has improved the quality of life of patients and reduces the radiation exposure of healthy nonthyroid tissue compared with TSH stimulation through levothyroxine withdrawal. In patients with distant metastases, rhTSH stimulation is possible only in off-label use, from which especially elderly and frail patients may benefit, as they most severely suffer from hypothyroidism caused by thyroid hormone withdrawal. PMID- 21826105 TI - The MRE11 GAR motif regulates DNA double-strand break processing and ATR activation. AB - The MRE11/RAD50/NBS1 complex is the primary sensor rapidly recruited to DNA double-strand breaks (DSBs). MRE11 is known to be arginine methylated by PRMT1 within its glycine-arginine-rich (GAR) motif. In this study, we report a mouse knock-in allele of Mre11 that substitutes the arginines with lysines in the GAR motif and generates the MRE11(RK) protein devoid of methylated arginines. The Mre11(RK/RK) mice were hypersensitive to gamma-irradiation (IR) and the cells from these mice displayed cell cycle checkpoint defects and chromosome instability. Moreover, the Mre11(RK/RK) MEFs exhibited ATR/CHK1 signaling defects and impairment in the recruitment of RPA and RAD51 to the damaged sites. The M(RK)RN complex formed and localized to the sites of DNA damage and normally activated the ATM pathway in response to IR. The M(RK)RN complex exhibited exonuclease and DNA-binding defects in vitro responsible for the impaired DNA end resection and ATR activation observed in vivo in response to IR. Our findings provide genetic evidence for the critical role of the MRE11 GAR motif in DSB repair, and demonstrate a mechanistic link between post-translational modifications at the MRE11 GAR motif and DSB processing, as well as the ATR/CHK1 checkpoint signaling. PMID- 21826107 TI - Turning skin into dopamine neurons. PMID- 21826108 TI - Isolation and proteomic analysis of the SYP61 compartment reveal its role in exocytic trafficking in Arabidopsis. AB - The endomembrane system is a complex and dynamic intracellular trafficking network. It is very challenging to track individual vesicles and their cargos in real time; however, affinity purification allows vesicles to be isolated in their natural state so that their constituent proteins can be identified. Pioneering this approach in plants, we isolated the SYP61 trans-Golgi network compartment and carried out a comprehensive proteomic analysis of its contents with only minimal interference from other organelles. The proteome of SYP61 revealed the association of proteins of unknown function that have previously not been ascribed to this compartment. We identified a complete SYP61 SNARE complex, including regulatory proteins and validated the proteome data by showing that several of these proteins associated with SYP61 in planta. We further identified the SYP121-complex and cellulose synthases, suggesting that SYP61 plays a role in the exocytic trafficking and the transport of cell wall components to the plasma membrane. The presence of proteins of unknown function in the SYP61 proteome including ECHIDNA offers the opportunity to identify novel trafficking components and cargos. The affinity purification of plant vesicles in their natural state provides a basis for further analysis and dissection of complex endomembrane networks. The approach is widely applicable and can afford the study of several vesicle populations in plants, which can be compared with the SYP61 vesicle proteome. PMID- 21826109 TI - Generation of induced pluripotent stem cells from bovine embryonic fibroblast cells. PMID- 21826110 TI - Small molecule-based disruption of the Axin/beta-catenin protein complex regulates mesenchymal stem cell differentiation. AB - The Wnt/beta-catenin pathway plays important roles in the differentiation of multiple cell types, including mesenchymal stem cells. Using a cell-based chemical screening assay with a synthetic chemical library of 270 000 compounds, we identified the compound SKL2001 as a novel agonist of the Wnt/beta-catenin pathway and uncovered its molecular mechanism of action. SKL2001 upregulated beta catenin responsive transcription by increasing the intracellular beta-catenin protein level and inhibited the phosphorylation of beta-catenin at residues Ser33/37/Thr41 and Ser45, which would mark it for proteasomal degradation, without affecting CK1 and GSK-3beta enzyme activities. Biochemical analysis revealed that SKL2001 disrupted the Axin/beta-catenin interaction, which is a critical step for CK1- and GSK-3beta-mediated phosphorylation of beta-catenin at Ser33/37/Thr41 and Ser45. The treatment of mesenchymal stem cells with SKL2001 promoted osteoblastogenesis and suppressed adipocyte differentiation, both of which were accompanied by the activation of Wnt/beta-catenin pathway. Our findings provide a new strategy to regulate mesenchymal stem cell differentiation by modulation of the Wnt/beta-catenin pathway. PMID- 21826112 TI - Quantitative hepatitis B surface antigen levels in patients with chronic hepatitis B after 2 years of entecavir treatment. AB - OBJECTIVES: The role of quantitative hepatitis B surface antigen (HBsAg) levels in patients receiving oral antiviral therapy is controversial. We aimed to determine the HBsAg response in chronic hepatitis B patients treated with entecavir 0.5 mg daily for 2 years. METHODS: A total of 166 patients were included. Liver biochemistry, hepatitis B virus (HBV) serological markers, HBV DNA, and quantitative HBsAg levels were performed at baseline, year 1, and year 2 after commencing entecavir. Additional HBsAg levels were measured at 12 and 24 weeks in patients with available sera. RESULTS: In all, 68 patients were hepatitis B e-antigen (HBeAg) positive. Age, HBV DNA, and alanine aminotransferase (ALT) were significantly correlated with HBsAg levels at baseline (r=-0.429, 0.607, and 0.254, respectively, all P<0.05). The correlation with HBV DNA and ALT levels was reduced by entecavir treatment, and was lost after 2 years of treatment. There was an overall decline in HBsAg levels from baseline to year 1 to year 2 (3,377.4 vs. 2,316.5 vs. 1,903.0 IU/ml, respectively, P<0.001). However, at year 2, 102 patients (61%) had no significant changes (<0.5 log difference), 50 (30%) had significant decline (>=0.5 log decrease), whereas 14 (9%) had significant increase (>=0.5 log increase). Of the patients, 151 (91%) had undetectable HBV DNA; 25 (37%) underwent HBeAg seroconversion. Neither HBsAg at baseline nor early decline at weeks 12 or 24 was predictive of HBeAg seroconversion at 2 years. CONCLUSIONS: Despite HBV DNA suppression, the majority did not show significant decline in HBsAg levels. Early decline of HBsAg levels at 12/24 weeks was not associated with HBV DNA suppression or HBeAg seroconversion. PMID- 21826111 TI - Buried metaplasia after endoscopic ablation of Barrett's esophagus: a systematic review. AB - OBJECTIVES: Endoscopic ablation of Barrett's esophagus can bury metaplastic glands under a layer of neosquamous epithelium. To explore the frequency and importance of buried metaplasia, we have conducted a systematic review of reports on endoscopic ablation. METHODS: We performed computerized and manual searches for articles on the results of photodynamic therapy (PDT) and radiofrequency ablation (RFA) for Barrett's esophagus. We extracted information on the number of patients treated, biopsy protocol, biopsy depth, and frequency of buried metaplasia. RESULTS: We found 9 articles describing 34 patients with neoplasia appearing in buried metaplasia (31 after PDT). We found five articles describing a baseline prevalence of buried metaplasia (before ablation) ranging from 0% to 28%. In 22 reports on PDT for 953 patients, buried metaplasia was found in 135 (14.2%); in 18 reports on RFA for 1,004 patients, buried metaplasia was found in only 9 (0.9%). A major problem limiting the conclusions that can be drawn from these reports is that they do not describe specifically how frequently biopsy specimens contained sufficient subepithelial lamina propria to be informative for buried metaplasia. CONCLUSIONS: Endoscopic ablation can bury metaplastic glands with neoplastic potential but, even without ablation, buried metaplasia often is found in areas where Barrett's epithelium abuts squamous epithelium. Buried metaplasia is reported less frequently after RFA than after PDT. However, available reports do not provide crucial information on the adequacy of biopsy specimens and, therefore, the frequency and importance of buried metaplasia after endoscopic ablation remain unclear. PMID- 21826113 TI - Changes in depressive symptoms and impact on treatment course among hepatitis C patients undergoing interferon-alpha and ribavirin therapy: a prospective evaluation. AB - OBJECTIVES: Accounting for severity of depressive symptoms at baseline (pretreatment), this study describes (i) depressive symptom change over the course of antiviral treatment among patients with hepatitis C virus (HCV), and (ii) the relationship of such symptom change to treatment duration and response. METHODS: Depressive symptoms, measured with the Beck Depression Inventory (BDI), were examined prospectively among 129 HCV patients (95% male) who endorsed minimal (n=91), mild (n=28), or moderate depressive symptoms (n=10) prior to commencement of antiviral therapy. Assessments were obtained at baseline, 2 weeks, 4 weeks, and thereafter at 4-week intervals until treatment was discontinued or completed. RESULTS: The average depression score of the participants prior to commencing treatment was 7.4 (minimal depression). Depressive symptoms increased over the course of treatment, with average scores of 12.6 (mild depression) at the final assessment at the end of treatment. Patients with mild depressive symptoms at baseline demonstrated the greatest increase (M(increase)=12.7) and the greatest change (M(Delta)=5.8) in depressive symptoms from baseline to treatment completion. Patients who were minimally depressed at baseline completed the least amount of treatment (74%). Likewise, minimally depressed patients were less likely than mildly and moderately depressed patients to attain an antiviral treatment response. CONCLUSIONS: Depressive symptoms may worsen during antiviral therapy among patients with HCV. Notable changes in patients with subclinical depressive symptoms at baseline may be of significant concern, as the present work suggests that their depressive symptom changes are the most unstable. Thus, findings suggest that the degree of within treatment symptom change may be a more useful predictor (compared with baseline depression status) of ability to tolerate treatment. As the findings of the present study are preliminary, we urge further research and replication before drawing firm conclusions. PMID- 21826114 TI - Developing teachers' understanding of molecular biology: Building a foundation for students. AB - Molecular biology often uses participation in active research laboratories as a form of educational training. However, this approach to learning severely restricts access. As a way of addressing this need, the University of Hawaii launched a project to expand this model to include newly developed online training materials in addition to a hands-on laboratory experience. This paper further explores the process of material development and assessment plans. A pilot case study of a group of advanced biology teachers who embark on learning molecular biology over a four-month period through online training materials and working side-by-side with medical researchers in a laboratory is described. Teachers were positive in reporting about the many areas they gained instruction in although some feedback suggested that the initial online materials over emphasised abstract concepts and laboratory techniques and did not adequately connect to the active research problems or local context of most interest to teachers and students. The experiences of the teachers are shared in an effort to gain insight on how teachers perceive their participation in the study. PMID- 21826115 TI - Abnormal peripheral chemokine profile in Huntington's disease. AB - Huntington's disease (HD) is an inherited neurodegenerative disorder characterized by both neurological and systemic abnormalities. Immune activation is a well-established feature of the HD brain and we have previously demonstrated a widespread, progressive innate immune response detectable in plasma throughout the course of HD. In the present work we used multiplex ELISA to quantify levels of chemokines in plasma from controls and subjects at different stages of HD. We found an altered chemokine profile tracking with disease progression, with significant elevations of five chemokines (eotaxin-3, MIP-1beta, eotaxin, MCP-1 and MCP-4) while three (eotaxin-3, MIP-1beta and eotaxin) showed significant linear increases across advancing disease stages. We validated our results in a separate sample cohort including subjects at different stages of HD. Here we saw that chemokine levels (MCP-1 and eotaxin) correlated with clinical scores. We conclude that, like cytokines, chemokines may be linked to the pathogenesis of HD, and that immune molecules may be valuable in tracking and exploring the pathogenesis of HD. PMID- 21826116 TI - Assessing behavioural manifestations prior to clinical diagnosis of huntington disease: "anger and irritability" and "obsessions and compulsions". AB - The Functional Rating Scale Taskforce for pre-Huntington Disease (FuRST-pHD) is a multinational, multidisciplinary initiative with the goal of developing a data driven, comprehensive, psychometrically sound, rating scale for assessing symptoms and functional ability in prodromal and early Huntington disease (HD) gene expansion carriers. The process involves input from numerous sources to identify relevant symptom domains, including HD individuals, caregivers, and experts from a variety of fields, as well as knowledge gained from the analysis of data from ongoing large-scale studies in HD using existing clinical scales. This is an iterative process in which an ongoing series of field tests in prodromal (prHD) and early HD individuals provides the team with data on which to make decisions regarding which questions should undergo further development or testing and which should be excluded. We report here the development and assessment of the first iteration of interview questions aimed to assess "Anger and Irritability" and "Obsessions and Compulsions" in prHD individuals. PMID- 21826118 TI - Application of a water-soluble pyridyl disulfide amine linker for use in Cu-free click bioconjugation. AB - Described herein is the design and synthesis of a discrete heterobifunctional PEG based pyridyl disulfide/amine-containing linker that can be used in the Cu-free click preparation of bioconjugates. The title PEG-based pyridyl disulfide amine linker is a potentially useful reagent for preparing water-soluble disulfide linked cargos. It may be particularly valuable in expanding the field of Cu-free click-based bioconjugations to include reductively labile antibody, polymer, or nanoparticle-based drug conjugates. PMID- 21826119 TI - Dynamics of epileptiform activity in mouse hippocampal slices. AB - Increase of the extracellular K( + ) concentration mediates seizure-like synchronized activities in vitro and was proposed to be one of the main factors underlying epileptogenesis in some types of seizures in vivo. While underlying biophysical mechanisms clearly involve cell depolarization and overall increase in excitability, it remains unknown what qualitative changes of the spatio temporal network dynamics occur after extracellular K( + ) increase. In this study, we used multi-electrode recordings from mouse hippocampal slices to explore changes of the network activity during progressive increase of the extracellular K( + ) concentration. Our analysis revealed complex spatio-temporal evolution of epileptiform activity and demonstrated a sequence of state transitions from relatively simple network bursts into complex bursting, with multiple synchronized events within each burst. We describe these transitions as qualitative changes of the state attractors, constructed from experimental data, mediated by elevation of extracellular K( + ) concentration. PMID- 21826117 TI - Enhancing Cell therapies from the Outside In: Cell Surface Engineering Using Synthetic Nanomaterials. AB - Therapeutic treatments based on the injection of living cells are in clinical use and preclinical development for diseases ranging from cancer to cardiovascular disease to diabetes. To enhance the function of therapeutic cells, a variety of chemical and materials science strategies are being developed that engineer the surface of therapeutic cells with new molecules, artificial receptors, and multifunctional nanomaterials, synthetically endowing donor cells with new properties and functions. These approaches offer a powerful complement to traditional genetic engineering strategies for enhancing the function of living cells. PMID- 21826120 TI - Simethicone for the Preparation before Esophagogastroduodenoscopy. AB - Aim. The presence of air bubbles and foam in stomach and duodenum is a common problem during esophagogastroduodenoscopy (EGD). Methods. Candidates of elective EGD received 40 mg chewable tablet of simethicone (n = 90) or placebo (n = 83), with 30 mL water, 15-30 min before the EGD. Foam/air bubbles during endoscopy were assessed and graded on a 4-point scale, and patients' satisfaction with the endoscopy was scored from 0 to 10. Results. The amount of gastric but not duodenal foam/air bubbles was significantly lower in the simethicone group compared with the placebo group (P = 0.002). Duration of endoscopy was, on average, one minute shorter in the simethicone group compared with the placebo group (P < 0.001). Patients' satisfaction with the procedure was the same in the two groups. Conclusion. Administration of simethicone prior to EGD reduces the amount of gastric foam and bubbles and provides better visibility for evaluating the mucosa. It also decreases the duration of endoscopy. Further trials are required to find the final effect of the drug on diagnosis of pathological lesions. PMID- 21826121 TI - Prediction of RNA-binding proteins by voting systems. AB - It is important to identify which proteins can interact with RNA for the purpose of protein annotation, since interactions between RNA and proteins influence the structure of the ribosome and play important roles in gene expression. This paper tries to identify proteins that can interact with RNA using voting systems. Firstly through Weka, 34 learning algorithms are chosen for investigation. Then simple majority voting system (SMVS) is used for the prediction of RNA-binding proteins, achieving average ACC (overall prediction accuracy) value of 79.72% and MCC (Matthew's correlation coefficient) value of 59.77% for the independent testing dataset. Then mRMR (minimum redundancy maximum relevance) strategy is used, which is transferred into algorithm selection. In addition, the MCC value of each classifier is assigned to be the weight of the classifier's vote. As a result, best average MCC values are attained when 22 algorithms are selected and integrated through weighted votes, which are 64.70% for the independent testing dataset, and ACC value is 82.04% at this moment. PMID- 21826122 TI - Infantile Enuresis: Current State-of-the-Art Therapy and Future Trends. AB - Enuresis nocturna is a widespread problem among children, with up to 25% of all children possibly suffering from this condition. Several therapeutic modalities are currently available. This article reviews current state-of-the-art therapies, highlights current literature, and provides an update on recent developments within the field of enuresis nocturna. PMID- 21826123 TI - Postprostatectomy erectile dysfunction: the role of penile rehabilitation. AB - Radical prostatectomy has become the gold standard for the treatment of prostate cancer in patients who have a longer than 10-year life expectancy. Surgical treatment has led to severe quality-of-life issues in these patients, especially urinary incontinence and erectile dysfunction (ED). This article reviews the etiology and pathophysiology of postprostatectomy ED, and current management strategies for these patients. PMID- 21826124 TI - alpha-Fetoprotein-Producing Non-Germ Cell Tumors of the Urological System. AB - Elevated serum levels of alpha-fetoprotein (AFP), a fetal serum protein, occur mainly in the development of hepatocellular carcinoma (HCC) or germ cell tumors, mainly yolk sac tumor. Rarely, other tumors of the urological system produce AFP. This article reviews the AFP-producing non-germ cell tumors of the urological tract reported to date. These include different types of tumors of the adrenal glands, kidney, ureter, urinary bladder, and testis. It is important for pathologists, urologists, and oncologists to be aware of such cases as the diagnosis affects the management plan for the patient. PMID- 21826125 TI - Medical treatment of benign prostatic hyperplasia. AB - Medical therapy for the treatment of benign prostatic hyperplasia (BPH) became an accepted standard of care in the 1990s following the reports of randomized, double-blind, placebo-controlled studies showing that finasteride, a 5-alpha reductase inhibitor, and terazosin, an alpha-blocker, significantly improved lower urinary tract symptoms and increased peak urinary flow rates in men with BPH. This article reviews novel approaches to the pharmacological treatment of BPH. PMID- 21826126 TI - Demystifying the medical management of nephrolithiasis. AB - Nephrolithiasis is a common problem associated with significant costs to the health care system. Its prevalence continues to increase, particularly in women, which is attributed to changes in diet and lifestyle. The costs associated with the evaluation and management of nephrolithiasis in the United States has been estimated to be $1.83 billion, and, without any intervention, the risk of recurrence is high. This article reviews the management options for nephrolithiasis including a new formulation of potassium citrate, Urocit(r)-K 15 mEq, that allows for dosing flexibility which can lead to improved compliance and tolerability. PMID- 21826127 TI - Update on urologic pelvic pain syndromes: highlights from the 2010 international chronic pelvic pain symposium and workshop, august 29, 2010, kingston, ontario, Canada. PMID- 21826128 TI - New Insights in Pediatric Urology: Highlights From the American Academy of Pediatrics Section on Urology Meeting, October 2-4, 2010, San Francisco, CA. PMID- 21826129 TI - Appendiceal abscess revealed by right renal colic and hydronephrosis. AB - Reported is the case of a patient who had an appendiceal abscess revealed by right renal colic with fever and general fatigue. The abdominal computed tomography scan showed hydronephrosis and an appendiceal abscess surrounding and compressing the ureter. The appendix contained a stercolith and was perforated. PMID- 21826130 TI - Squamous cell carcinoma of the prostate. AB - Squamous cell carcinoma of the prostate is a rare tumor, making up 0.5% to 1% of all prostate carcinomas. It is typically described as an aggressive cancer, with a median postdiagnosis survival of 14 months. Presented here is a case of primary squamous cell carcinoma of the prostate, with a complicated presentation of metastatic disease. Due to the extent of the patient's disease, he was treated with palliative radiation therapy using a four-field technique (AP/PA and left and right lateral fields) with 18 mV photons prescribed to the 100% isodose line. The prescription dose was 4000 cGy in 16 fractions of 250 cGy per fraction. No definitive treatment of squamous cell carcinoma of the prostate exists but varying approaches including surgical intervention, chemotherapy, and radiation therapy have been implemented without durable response. However, multimodal treatments appear to be the most promising with longer durations of survival. PMID- 21826131 TI - Minimally invasive ablative therapies for the treatment of prostate cancer. PMID- 21826132 TI - Attributions and Attitudes of Mothers and Fathers in the Philippines. AB - OBJECTIVE.: This paper investigates the mean level and within-family similarities and differences in Filipino mothers' and fathers' attributions about success and failure in caregiving situations, and their progressive and authoritarian parenting attitudes. DESIGN.: Both mothers and fathers in 95 families in metropolitan Manila completed interviews. RESULTS.: Controlling for parents' age, education, and possible social desirability bias, there was a significant gender difference in modernity of attitudes, with mothers exhibiting higher levels of modernity than fathers. There was a strong correlation in mothers' and fathers' authoritarian attitudes and moderate correlations in modernity of attitudes. There were neither parent gender effects nor concordance in the attributions of mothers and fathers. CONCLUSIONS.: Cultural explanations are presented to account for the findings, specifically the sociocultural values that foster traditional attitudes favoring parental authority and child obedience, and the differences in gender and family roles of Filipino mothers and fathers. PMID- 21826133 TI - Biological and Spectral Studies of Newly Synthesized Triazole Schiff Bases and Their Si(IV), Sn(IV) Complexes. AB - The Schiff bases HL(1-3) have been prepared by the reaction of 5-bromothiophene-2 carboxaldehyde with 4-amino-5-mercapto-3-methyl/propyl/isopropyl-s-triazole, respectively. Organosilicon(IV) and organotin(IV) complexes of formulae (CH(3))(2)MCl(L(1-3)), (CH(3))(2)M(L(1-3))(2) were synthesized from the reaction of (CH(3))(2)MCl(2) and the Schiff bases in 1 : 1 and 1 : 2 molar ratio, where M = Si and Sn. The synthesized Schiff bases and their metal complexes have been characterized with the aid of various physicochemical techniques like elemental analyses, molar conductance, UV, IR, (1)H, (13)C, (29)Si, and (119)Sn NMR spectroscopy. Based on these studies, the trigonal bipyramidal and octahedral geometries have been proposed for these complexes. The ligands and their metal complexes have been screened in vitro against some bacteria and fungi. PMID- 21826134 TI - A framework of vertebra segmentation using the active shape model-based approach. AB - We propose a medical image segmentation approach based on the Active Shape Model theory. We apply this method for cervical vertebra detection. The main advantage of this approach is the application of a statistical model created after a training stage. Thus, the knowledge and interaction of the domain expert intervene in this approach. Our application allows the use of two different models, that is, a global one (with several vertebrae) and a local one (with a single vertebra). Two modes of segmentation are also proposed: manual and semiautomatic. For the manual mode, only two points are selected by the user on a given image. The first point needs to be close to the lower anterior corner of the last vertebra and the second near the upper anterior corner of the first vertebra. These two points are required to initialize the segmentation process. We propose to use the Harris corner detector combined with three successive filters to carry out the semiautomatic process. The results obtained on a large set of X-ray images are very promising. PMID- 21826135 TI - Image processing techniques for assessing contractility in isolated neonatal cardiac myocytes. AB - We describe a computational framework for the quantitative assessment of contractile responses of isolated neonatal cardiac myocytes. To the best of our knowledge, this is the first report on a practical and accessible method for the assessment of contractility in neonatal cardiocytes. The proposed methodology is comprised of digital video recording of the contracting cell, signal preparation, representation by polar Fourier descriptors, and contractility assessment. The different processing stages are variants of mathematically sound and computationally robust algorithms very well established in the scientific community. The described computational approach provides a comprehensive assessment of the neonatal cardiac myocyte contraction without the need of elaborate instrumentation. The versatility of the methodology allows it to be employed in determining myocyte contractility almost simultaneously with the acquisition of the Ca(2+) transient and other correlates of cell contraction. The proposed methodology can be utilized to evaluate changes in contractile behavior resulting from drug intervention, disease models, transgeneity, or other common applications of neonatal cardiocytes. PMID- 21826136 TI - Epidemiological survey on the prevalence of periodontitis and diabetes mellitus in Uyghur adults from rural Hotan area in Xinjiang. AB - BACKGROUND AND AIMS: This study was designed to explore the relationship between periodontitis and diabetes mellitus (DM) in Uygur adults from Xinjiang. METHODS AND RESULTS: Data were obtained using questionnaire and oral examination. Participants (48.87 +/- 13.72 yr) were categorized into periodontitis and non periodontitis groups in accordance with the chronic periodontitis diagnostic criteria. Based on gum inflammation, bleeding on probing, periodontal pocket depth and attachment loss, patients were further divided into mild, moderate and severe periodontitis groups. Among 962 subjects, 453 (47.1%) suffered from chronic periodontitis with a prevalence of type 2 DM and impaired fasting glucose of 9.5% and 11.4%, respectively. In the periodontitis group, the prevalence of type 2 DM was 75.6% compared with 22.4% in the non-periodontitis group. Likewise, the prevalence of impaired fasting glucose was 71.3% and 28.7% in periodontitis and non-periodontitis groups, respectively. The univariate logistic regression analysis revealed moderate and severe periodontitis as risk factors for DM (OR = 3.4, OR = 2.9). Multivariate logistic regression analysis showed that moderate periodontitis is independently associated with DM (OR = 4). CONCLUSIONS: Our data revealed that prevalence of DM is overtly higher in periodontitis patients than in individuals without periodontitis. Furthermore, moderate periodontitis is considered an independent risk factor for type 2 DM. PMID- 21826137 TI - The pain system in oesophageal disorders: mechanisms, clinical characteristics, and treatment. AB - Pain is common in gastroenterology. This review aims at giving an overview of pain mechanisms, clinical features, and treatment options in oesophageal disorders. The oesophagus has sensory receptors specific for different stimuli. Painful stimuli are encoded by nociceptors and communicated via afferent nerves to the central nervous system. The pain stimulus is further processed and modulated in specific pain centres in the brain, which may undergo plastic alterations. Hence, tissue inflammation and long-term exposure to pain can cause sensitisation and hypersensitivity. Oesophageal sensitivity can be evaluated ,for example, with the oesophageal multimodal probe. Treatment should target the cause of the patient's symptoms. In gastro-oesophageal reflux diseases, proton pump inhibitors are the primary treatment option, surgery being reserved for patients with severe disease resistant to drug therapy. Functional oesophageal disorders are treated with analgesics, antidepressants, and psychological therapy. Lifestyle changes are another option with less documentation. PMID- 21826138 TI - Reliability of Diagnostic Tests for Helicobacter pylori Infection. AB - Introduction. Helicobacter pylori (H. pylori) infection is very common worldwide. A reliable diagnosis is crucial for patients with H. pylori-related diseases. At followup, it is important to confirm that eradication therapy has been successful. There is no established gold standard for the diagnosis of H. pylori infection. Material and Methods. A sample of 304 volunteers from the general population was screened for H. pylori infection with serology, (13)C-urea breath test (UBT), rapid urease test (RUT) on fresh biopsy, culture from biopsy, and histological examination. Culture was used as gold standard. Results. The sensitivity was 0.99 for serology, 0.90 for UBT, 0.90 for RUT, and 0.90 for histological examination. Corresponding specificities were 0.82, 0.99, 0.98, and 0.97, respectively. The accuracy was 0.86 for serology, 0.96 for UBT, 0.95 for RUT, 0.93 for culture, and 0.95 for histology. There was a strong correlation between the results of UBT and the histological scores of H. pylori colonisation as well as between the results of UBT and the scores of RUT. Conclusion. There were only minor differences in accuracy between the three invasive tests for H. pylori infection in this population. RUT may be recommended as the first choice since a result is obtained within hours. The accuracy of UBT was comparable to the invasive tests, and it is recommended for situations when endoscopy is not needed. PMID- 21826140 TI - Patient safety climate: variation in perceptions by infection preventionists and quality directors. AB - Background. Healthcare-associated infections (HAIs) are an important patient safety issue, and safety climate is an important organizational factor. This study explores perceptions of infection preventionists (IPs) and quality directors (QDs) regarding two safety microclimates, Senior Management Engagement (SME) and Leadership on Patient Safety (LOPS), across California hospitals. Methods. This was an analysis of two cross-sectional surveys. We conducted Wilcoxon signed-rank test, univariate analyses, and a multivariate ordinary least square regression. Results. There were 322 eligible hospitals; 149 hospitals (46.3%) responded to both surveys. The IP response rate was 59%, and the QD response rate was 79.5%. We found IPs perceived SME more positively than did QDs (21.4 vs. 20.4, P < 0.01). No setting characteristics predicted variation in perceptions. Presence of an independent budget predicted more positive perceptions of microclimates across personnel types (P < 0.01). Conclusions. Differences in perceptions continue to exist between essential leaders in acute health care settings which could have critical effects on outcomes such as HAIs. Having an independent budget for the infection prevention and control department may enhance the overall safety climate and in turn patient care. PMID- 21826139 TI - Health-related quality of life after cystectomy and urinary diversion for bladder cancer. AB - With multiple options for urinary diversion after radical cystectomy for bladder cancer that have comparable cancer control and complication rates, health-related quality of life (HRQOL) has become an important consideration. This article reviews the methods for defining HRQOL, the challenges in measuring HRQOL in bladder cancer, and the literature comparing HRQOL after various methods of urinary diversion. Recent contributions include the validation of HRQOL instruments specific to bladder cancer and the publication of several prospective studies measuring HRQOL outcomes after cystectomy and urinary diversion. There is no convincing evidence from existing literature that any particular method of urinary diversion offers superior HRQOL outcomes. Rather, there is growing evidence that good HRQOL can be achieved with patient education and consideration of each patient's clinical and psychosocial situation. Future research should utilize the validated bladder cancer specific HRQOL instruments and perhaps explore the impact of preoperative counseling on postoperative HRQOL. PMID- 21826141 TI - Normal sweat secretion despite impaired growth hormone-insulin-like growth factor I axis in obese subjects. AB - Adults with GH deficiency are known to exhibit reduced sweating. Whether sweating capacity is impacted in obese subjects with impaired GH secretion have not previously been investigated. The main objective was to investigate sweat secretion rate and the GH-IGF-I axis in obese subjects before and after weight loss. Sixteen severely obese women (BMI, 40.6 +/- 1.1 kg/m(2)) were investigated before and after a diet-induced weight loss. Sixteen age-matched nonobese women served as controls. The obese subjects presented the characteristic decreased GH release, hyperinsulinaemia, increased FFA levels, and impaired insulin sensitivity, which all were normalised after diet-induced weight loss of 30 +/- 5 kg. Sweat secretion rates were similar comparing obese and nonobese subjects (78 +/- 10 versus 82 +/- 9 mg/30 minutes) and sweat secretion did not change after a diet-induced weight loss in obese subjects. We conclude that although obese subjects have markedly reduced GH release and impaired IGF-I levels, sweat secretion rate is found to be normal. PMID- 21826142 TI - Optimization of molecularly imprinted polymer method for rapid screening of 17beta-estradiol in water by fluorescence quenching. AB - A new method was optimized for rapid screening of 17beta-estradiol (E2) in water under 10 min. Molecularly imprinted polymer (MIP) particles (325 +/- 25 nm) were added in a water sample at pH 5.5 and 20 degrees C to form a suspension. Fluorescence emission from E2 nonspecifically bound onto the MIP particles was first quenched by large gold nanoparticles (43 +/- 5 nm). The Stern-Volmer plot was linear, with dynamic quenching constants (K(sv)) of 2.9 *10(4) M(-1). Fluorescence emission from E2 specifically bound inside the MIP particles was next quenched by small nitrite anions that easily penetrated the imprinted cavities. The Stern-Volmer plot became nonlinear, with K(sv) = 2.1 * 10(2) M(-1) and static quenching constant (V) below 1.0 M(-1). The difference between these two emission intensities varied as the initial E2 concentration in water, generating a Scatchard calibration curve with R(2) > 0.97 from 0.1 to 10 ppb. PMID- 21826143 TI - Biodegradable Polymers Induce CD54 on THP-1 Cells in Skin Sensitization Test. AB - Currently, nonanimal methods of skin sensitization testing for various chemicals, biodegradable polymers, and biomaterials are being developed in the hope of eliminating the use of animals. The human cell line activation test (h-CLAT) is a skin sensitization assessment that mimics the functions of dendritic cells (DCs). DCs are specialized antigen-presenting cells, and they interact with T cells and B cells to initiate immune responses. Phenotypic changes in DCs, such as the production of CD86 and CD54 and internalization of MHC class II molecules, have become focal points of the skin sensitization test. In this study, we used h-CLAT to assess the effects of biodegradable polymers. The results showed that several biodegradable polymers increased the expression of CD54, and the relative skin sensitizing abilities of biodegradable polymers were PLLG (75 : 25) < PLLC (40 : 60) < PLGA (50 : 50) < PCG (50 : 50). These results may contribute to the creation of new guidelines for the use of biodegradable polymers in scaffolds or allergenic hazards. PMID- 21826144 TI - Aspergillus fumigatus in Poultry. AB - Aspergillus fumigatus remains a major respiratory pathogen in birds. In poultry, infection by A. fumigatus may induce significant economic losses particularly in turkey production. A. fumigatus develops and sporulates easily in poor quality bedding or contaminated feedstuffs in indoor farm environments. Inadequate ventilation and dusty conditions increase the risk of bird exposure to aerosolized spores. Acute cases are seen in young animals following inhalation of spores, causing high morbidity and mortality. The chronic form affects older birds and looks more sporadic. The respiratory tract is the primary site of A. fumigatus development leading to severe respiratory distress and associated granulomatous airsacculitis and pneumonia. Treatments for infected poultry are nonexistent; therefore, prevention is the only way to protect poultry. Development of avian models of aspergillosis may improve our understanding of its pathogenesis, which remains poorly understood. PMID- 21826145 TI - B-cell depletion therapy in systemic sclerosis: experimental rationale and update on clinical evidence. AB - Systemic sclerosis (SSc) is a systemic rheumatic disease with poor prognosis since therapeutic options are limited. Recent evidence from animal models suggests that B-cells may be actively involved in the fibrotic process. B-cells from tight skin mice, an animal model of scleroderma, display a "hyperresponsive" phenotype; treatment with rituximab (RTX) significantly attenuates skin fibrosis in this animal model. In humans, B-cell infiltration is a prominent finding in most lung biopsies obtained from patients with SSc-associated interstitial lung disease. Several open label studies have assessed the clinical efficacy of RTX in SSc. In most patients skin fibrosis improved; lung function either improved or remained stable. Definite conclusions regarding the clinical efficacy of RTX in SSc cannot be drawn but further exploration with a multicenter, randomized study is warranted. PMID- 21826147 TI - Quantitative effects of repeated muscle vibrations on gait pattern in a 5-year old child with cerebral palsy. AB - Objective. To investigate quantitatively and objectively the effects of repeated muscle vibration (rMV) of triceps surae on the gait pattern in a 5-year-old patient with Cerebral Palsy with equinus foot deformity due to calf spasticity. Methods. The patient was assessed before and one month after the rMV treatment using Gait Analysis. Results. rMV had positive effects on the patient's gait pattern, as for spatio-temporal parameters (the stance duration and the step length increased their values after the treatment) and kinematics. The pelvic tilt reduced its anteversion and the hip reduced the high flexion evidenced at baseline; the knee and the ankle gained a more physiological pattern bilaterally. The Gillette Gait Index showed a significant reduction of its value bilaterally, representing a global improvement of the child's gait pattern. Conclusions. The rMV technique seems to be an effective option for the gait pattern improvement in CP, which can be used also in very young patient. Significant improvements were displayed in terms of kinematics at all lower limb joints, not only at the joint directly involved by the treatment (i.e., ankle and knee joints) but also at proximal joints (i.e., pelvis and hip joint). PMID- 21826148 TI - Octreotide-treated diabetes accompanied by endogenous hyperinsulinemic hypoglycemia and protein-losing gastroenteropathy. AB - Occurrence of hypoglycemia in diabetes patients is very rare. We report here a case of frequent hypoglycemic attacks caused by inappropriate endogenous hyperinsulinemia in a female patient with poorly controlled diabetes and protein losing gastroenteropathy. The blood glucose profiles of the patient were unstable. Results of the fasting test performed to investigate the cause of hypoglycemia suggested endogenous hyperinsulinism. Repeated selective arterial calcium injection tests suggested that hyperinsulinemia might be extrapancreatic in origin. However, efforts to detect a responsible lesion such as insulinoma were unsuccessful. Octreotide was used for the treatment of hypoglycemia and protein-losing gastroenteropathy. After treatment, although her leg edema caused by hypoalbuminemia persisted, hypoglycemia almost disappeared. PMID- 21826149 TI - Fetal cervical neuroblastoma: prenatal diagnosis. AB - Neuroblastoma is the most frequent extracranial solid tumor in childhood, but it is seldom diagnosed prenatally. It usually presented with adrenal masses. Presentation of other localization is extremely rare. We report a case of cervical neuroblastoma identified at 20 weeks of gestational age. This is the third case diagnosed antenatally on neck region in the literature. Additionally, it is the first case that extended to the brain. We also discussed the literature for cervical neuroblastoma detected prenatally. PMID- 21826146 TI - Effects of Glucosamine and Chondroitin Sulfate on Cartilage Metabolism in OA: Outlook on Other Nutrient Partners Especially Omega-3 Fatty Acids. AB - Osteoarthritis (OA) is a degenerative joint disease that is characterized by increasing loss of cartilage, remodeling of the periarticular bone, and inflammation of the synovial membrane. Besides the common OA therapy with nonsteroidal anti-inflammatory drugs (NSAIDs), the treatment with chondroprotectives, such as glucosamine sulfate, chondroitin sulfate, hyaluronic acid, collagen hydrolysate, or nutrients, such as antioxidants and omega-3 fatty acids is a promising therapeutic approach. Numerous clinical studies have demonstrated that the targeted administration of selected micronutrients leads to a more effective reduction of OA symptoms, with less adverse events. Their chondroprotective action can be explained by a dual mechanism: (1) as basic components of cartilage and synovial fluid, they stimulate the anabolic process of the cartilage metabolism; (2) their anti-inflammatory action can delay many inflammation-induced catabolic processes in the cartilage. These two mechanisms are able to slow the progression of cartilage destruction and may help to regenerate the joint structure, leading to reduced pain and increased mobility of the affected joint. PMID- 21826150 TI - The use of intravitreal ranibizumab for choroidal neovascularization associated with vogt-koyanagi-harada syndrome. AB - Purpose. To describe the use of intravitreal ranibizumab for choroidal neovascular membrane (CNVM) secondary to Vogt-Koyanagi-Harada (VKH) syndrome. Methods. Interventional case report. Results. A 50-year-old woman presented with conjunctival injection and bilateral eye pain. Vision was 20/400 and 20/80 in the right and left eyes, respectively. Bilateral iritis, vitritis, and choroidal thickening were evident. Exudative retinal detachment was present in the left eye. Corticosteroid treatment improved vision to 20/40 bilaterally. Methotrexate (MTX) was initiated and vision remained stable for 3 months. After a 5-month loss to follow-up, vision in the left eye decreased to finger counting (CF) and a parafoveal CNVM was identified. After 3 intravitreal ranibizumab injections, vision improved to 20/40. Twelve months later, despite inflammation control, vision decrease to CF due to recurrent CNVM. A fourth ranibizumab injection was given. Twenty months later, best-corrected vision was 20/400, and an inactive CNVM was present in the left eye. Conclusion. After initial CNVM regression and visual acuity improvement due to ranibizumab, the CNVM recurred and became refractory to treatment. Despite control of inflammation and neovascularization, VKH chronicity lead to permanent vision loss in our patient. A combinational treatment approach may be required in such patients. PMID- 21826151 TI - Spontaneously Healed Pathologic Fracture over a Critical-Size Calcaneal Cyst. AB - Simple bone cysts are nonsymptomatic lesions. They typically involve the medullary cavity, but they can also be found in nonlong bones such as the calcaneum. Their treatment remains controversial varying from observation and conservative healing to irritating injections or bone grafting. In the case of a pathologic fracture, surgical treatment seems most appropriate especially when the cyst is situated on a weight-bearing bone. We present herein the rare case of a spontaneously healed pathological fracture over a critical-size calcaneal cyst of a patient reluctant to undergo surgical treatment. An interpretation of the healing procedure as well as a review of the literature is presented. PMID- 21826152 TI - Establishment of a mesenchymal stem cell bank. AB - Adult stem cells have generated great amount of interest amongst the scientific community for their potential therapeutic applications for unmet medical needs. We have demonstrated the plasticity of mesenchymal stem cells isolated from the umbilical cord matrix. Their immunological profile makes it even more interesting. We have demonstrated that the umbilical cord is an inexhaustible source of mesenchymal stem cells. Being a very rich source, instead of discarding this tissue, we worked on banking these cells for regenerative medicine application for future use. The present paper gives a detailed account of our experience in the establishment of a mesenchymal stem cell bank at our facility. PMID- 21826153 TI - Molecular mechanisms and in vivo mouse models of skin aging associated with dermal matrix alterations. AB - Skin is the most superficial body organ and plays an important role in protecting the body from environmental damage and in forming social relations. With the increase of the aging population in our society, dermatological and cosmetic concerns of skin aging are rapidly increasing. Skin aging is a complex process combined with intrinsic and extrinsic factors. Intrinsic or chronological skin aging results from the passage of time and is influenced by genetic factors. Extrinsic skin aging is mainly determined by UV irradiation, also called photoaging. These two types of aging processes are superimposed on sun-exposed skin, and have a common feature of causing dermal matrix alterations that mostly contribute to the formation of wrinkles, laxity, and fragility of aged skin. The dermal matrix contains extracellular matrix proteins such as collagen, elastin, and proteoglycans that confer the strength and resiliency of skin. Skin aging associated with dermal matrix alterations and atrophy can be caused by cellular senescence of dermal cells like fibroblasts, and decreased synthesis and accelerated degradation of dermal matrix components, especially collagen fibers. Both intrinsic aging and photoaging exert influence during each step of dermal matrix alteration via different mechanisms. Mouse models of skin aging have been extensively developed to elucidate intrinsic aging and photoaging processes, to validate in vitro biochemical data, and to test the effects of pharmacological tools for retarding skin aging because they have the advantages of being genetically similar to humans and are easily available. PMID- 21826154 TI - Effects of selenium on colon carcinogenesis induced by azoxymethane and dextran sodium sulfate in mouse model with high-iron diet. AB - Selenium (Se) is known to prevent several cancers while the relationship between high iron and the risk of colorectal cancer is controversial. To investigate the effects of Se in colon carcinogenesis, we subjected three different levels of Se and high-iron diet to a mouse model of colon cancer in which animals were treated with three azoxymethane (AOM) injections followed by dextran sodium sulfate (DSS) administration. There were five experimental groups including vehicle group [normal-Fe (NFe, 45 ppm)+medium-Se (MSe, 0.1 ppm)], positive control group (AOM/DSS+NFe+MSe), AOM/DSS+high-Fe (HFe, 450 ppm)+low-Se (LSe, 0.02 ppm), AOM/DSS+HFe+MSe, and AOM/DSS+HFe+high-Se (HSe, 0.5 ppm). The animals were fed on the three different Se diets for 24 weeks. The incidence of colon tumor in the high-Se diet group (AOM/DSS+HFe+HSe) showed 19.4% lower than positive control group, 5.9% lower than AOM/DSS+HFe+MSe diet group, and 11.1% lower than AOM/DSS+HFe+LSe group. The tumor multiplicity was significantly higher in the low Se diet group (AOM/DSS+HFe+LSe) compare to all other AOM/DSS treated groups. In the high-Se diet group, the activity of hepatic GPx was comparable to that of positive control group, and significantly higher than those of low-Se or medium Se diet groups. Expression level of hepatic GPx-1 showed similar results. Hepatic malondialdehyde (MDA) level (indicator of oxidative stress) in the low-Se diet group showed the highest compared to the other groups, and it was significantly higher than positive control group. In the high-Se diet group the level of MDA in the liver was significantly lower than all other AOM/DSS treated groups. High-Se diet group showed significantly lower proliferative index than low-Se and medium Se groups. The apoptotic indices in low-Se group and medium-Se group were significantly lower than positive control group. However, apoptotic index of high Se diet group was significantly higher than all other AOM/DSS treated groups. These findings suggest that dietary Se supplement may have protective effect against colon cancer by decreasing proliferation, increasing apoptosis of tumor cells, and reducing oxidative stress in mice with high iron diet. PMID- 21826155 TI - The Apoptotic Effect of the Hexane Extract of Rheum undulatum L. in Oral Cancer Cells through the Down-regulation of Specificity Protein 1 and Survivin. AB - The hexane extract of Rheum undulatum L. (HERL) has been shown to have anti cancer activity in several cancers in vivo and in vitro. However, the anti-cancer activity of HERL and its molecular mechanism in human oral cancer cells has not been explored. Thus, the aim of this study was to elucidate the growth-inhibitory and apoptosis-inducing effects of HERL in HN22 and SCC15 oral cancer cell lines. This study shows that HERL inhibits oral cancer growth, decreases cell viability, and causes apoptotic cell death in HN22 and SCC15 cells, as characterized by morphological changes, nuclear condensation and fragmentation, the cleavage of PARP and the accumulation of cells in the sub-G(1) phase. The treatment of oral cancer cells with HERL also resulted in decreased expression of specificity protein (Sp1) and its downstream protein, survivin. Therefore, our results suggest that the regulation of Sp1 and survivin plays a critical role in HERL induced apoptosis in human oral cancer cells. PMID- 21826156 TI - Increased nephrotoxicity after combined administration of melamine and cyanuric Acid in rats. AB - Renal toxicity by melamine in combination with cyanuric acid (1:1) was investigated. Male rats were orally administered melamine plus cyanuric acid (5, 50 or 400 mg/kg each) for 3 days. In contrast to a negligible effect by melamine alone (50 mg/kg, a no-observed-adverse-effect-level: NOAEL), co-administration with cyanuric acid markedly increased the concentrations of blood urea nitrogen and creatinine, as well as kidney weight. A high dose (400 mg/kg) of melamine plus cyanuric acid induced more severe kidney toxicity. The increased blood parameters for kidney toxicity and organ weight lasted longer than 4 days. Combined treatment with melamine and cyanuric acid (50-400 mg/kg each) resulted in many gold-brown crystals and toxic lesions in renal tubules, which were not observed in animals treated with melamine alone (50 mg/kg). These results indicate that only a 3-day exposure to melamine in combination with cyanuric acid causes severe renal damage, even at a NOAEL for melamine found in a 13-week toxicity study. Therefore, it is suggested that the tolerable daily intake or regulatory/management levels of melamine need to be re-considered for cases of co exposure with cyanuric acid. PMID- 21826157 TI - Overexpression of Insulin Degrading Enzyme could Greatly Contribute to Insulin Down-regulation Induced by Short-Term Swimming Exercise. AB - Exercise training is highly correlated with the reduced glucose-stimulated insulin secretion (GSIS), although it enhanced insulin sensitivity, glucose uptake and glucose transporter expression to reduce severity of diabetic symptoms. This study investigated the impact of short-term swimming exercise on insulin regulation in the Goto-Kakizaki (GK) rat as a non-obese model of non insulin-dependent diabetes mellitus. Wistar (W/S) and GK rats were trained 2 hours daily with the swimming exercise for 4 weeks, and then the changes in the metabolism of insulin and glucose were assessed. Body weight was markedly decreased in the exercised GK rats compare to their non-exercised counterpart, while W/S rats did not show any exercise-related changes. Glucose concentration was not changed by exercise, although impaired glucose tolerance was improved in GK rats 120 min after glucose injection. However, insulin concentration was decreased by swimming exercise as in the decrease of GSIS after running exercise. To identify the other cause for exercise-induced insulin down-regulation, the changes in the levels of key factors involved in insulin production (C-peptide) and clearance (insulin-degrading enzyme; IDE) were measured in W/S and GK rats. The C-peptide level was maintained while IDE expression increased markedly. Therefore, these results showed that insulin down-regulation induced by short term swimming exercise likely attributes to enhanced insulin clearance via IDE over-expression than by altered insulin production. PMID- 21826158 TI - Determination of Oxyclozanide in Beef and Milk using High-Performance Liquid Chromatography System with UV Detector. AB - This study was developed and validated for the determination of oxyclozanide residue concentrations in beef and commercial milk, using high-performance liquid chromatography system. Oxyclozanide was successfully separated on a reverse phase column (Xbridge-C(18), 4.6*250 mm, 5 um) with a mobile phase composed of acetonitrile and 0.1% phosphoric acid (60:40, v/v%). This analytical procedure involved a deproteinization process using acetonitrile for beef and 2% formic acid in acetonitrile for commercial milk, dehydration by adding sodium sulfate to the liquid analytical sample, and a defatting process using n-hexane; after these steps, the extract was exposed to a stream of nitrogen dryness. The final extracted sample was dissolved in the mobile phase and filtered using a 0.45 um syringe filter. This method had good selectivity and recovery (70.70+/-7.90 110.79+/-14.95%) from the matrices. The LOQs ranged from 9.7 to 9.8 ug/kg for beef and commercial milk. The recoveries met the standards set by the CODEX guideline. PMID- 21826159 TI - Mapping of the Faded (fe) Gene to a Region between D10mit191 and D10mit44 on Mouse Chromosome 10. AB - The faded mouse is a coat color mutant that shows faded coat color and age related loss of pigmentation. This mutation is transmitted by an autosomal recessive gene with 100% penetrance. In the present study, we carried out linkage analysis of the faded (fe) gene using intra-specific backcross panels. Affected faded mice were carefully confirmed by their faded coat color at about 4 weeks of age. In the intra-specific backcross between faded and CBA mice (n=198), the fe gene was mapped to a region 2.1 cM distal to D10mit191. Therefore, the gene order was defined as follows: centromere-D10mit51 (12.4+/-2.4 cM)-D10mit191 (2.1+/-1.0 cM)-fe-D10mit44 (13.3+/-2.4 cM)-D10mit42 (14.4+/-2.5 cM). This linkage map of the fe locus will provide a good entry point to isolate the fe gene. Since the faded mouse has pigmentary abnormalities, this mutant may be a useful model for studies of pigmentary abnormalities in humans. PMID- 21826160 TI - Different antiulcer activities of pantoprazole in stress, alcohol and pylorus ligation-induced ulcer models. AB - Antiulcer effects of pantoprazole, a proton-pump inhibitor, on water-immersion restraint stress (WIRS)-, alcohol (ethanol)- and pylorus ligation-induced gastric ulcers were investigated in male rats. Rats were orally administered with pantoprazole 30 min prior to exposure to various types of ulcer inducers. In stress-induced ulcer model, rats were subjected to WIRS at 22C for 4 hours, and the degree of ulcer (in mm) was evaluated. In alcohol-induced ulcer model, rats were orally administered with pure (100%) ethanol (1 mL/kg), and the ulcer lesions were measured 1 hour after ethanol challenge. In pylorus ligation-induced ulcer model, rats were subjected to pylorus ligation, and the degree of erosions and ulcers was scored 17 hours after the operation. Pantoprazole attenuated the ulcer lesions induced by WIRS in a dose-dependent manner, exhibiting a median effective dose (ED(50)) value of 0.78 mg/kg. By comparison, pantoprazole was effective at relatively-high doses for the improvement of ethanol-induced ulcers, showing an ED(50) value of 20.5 mg/kg. Notably, pantoprazole was practically ineffective (ED(50)>50.0) in pylorus ligation model. Taken together, it was confirmed that pantoprazole showed inhibitory activity on gastric ulcers induced by stress and alcohol, but was ineffective on pylorus ligation-induced ulcer. Therefore, the results indicate that proton-pump inhibitors including pantoprazole might reveal highly-different effects according to the type of ulcer inducers, and that the prescription of antiulcer agents should be carefully selected. PMID- 21826161 TI - Chordoma in the tail of a ferret. AB - A chordoma is an uncommon tumor that originates from the remnants of the notochord and most commonly involves the cranial and caudal regions of the axial skeleton. Chordoma has been described in laboratory animals such as dogs, rats, minks, and ferrets. This report describes a case of a chordoma in the tail of a ferret. Grossly, a grayish-white, expansile, subcutaneous soft-tissue mass was observed in the tail. Histopathologically, the mass was a loosely placed, nodular, unencapsulated neoplasm within the dermis. In the mass, tumor lobules were intermingled with fibrous tissues. Fibrous tissues contained abundant extracellular basophilic material that was consistent with mucin. The tumor was composed of a close pack of adipocyte-like vacuolated cells (physaliferous cells). The cells were centrally or eccentrically located round nuclei and eosinophilic cytoplasm with large vacuoles. Immunohistologically, neoplastic cells were positive for vimentin and S-100 protein. Based on histopathologic findings and special staining characteristics, this case was diagnosed as chordoma. PMID- 21826162 TI - Cronobacter sakazakii Infection Induced Fatal Clinical Sequels Including Meningitis in Neonatal ICR Mice. AB - Cronobacter sakazakii (C. sakazakii), formerly Enterobacter sakazakii, is an emerging pathogen associated with the ingestion of contaminated reconstituted formula that causes serious illnesses such as bacteremia, septicemia, necrotizing enterocolitis, meningitis and death in low-birth-weight preterm neonatal infants. The objective of this study was to develop an animal model for human neonatal C. sakazakii infections. We acquired timed-pregnant ICR mice and allowed them to give birth naturally. On postnatal day 3.5, each pup was administered orally a total dose of approximately 10(7) CFU C. sakazakii strain 3439. Mice were observed twice daily for morbidity and mortality. At postnatal day 10.5, the remaining pups were euthanized, and brain, liver, and cecum were excised and analyzed for the presence of C. sakazakii. C. sakazakii was isolated from cecum and other tissues in inoculated mice. In the tissues of C. sakazakii infected mice, meningitis and gliosis were detected in brain. In this study, we confirmed the neonatal ICR mice may be used a very effective animal model for human neonatal C. sakazakii infections. PMID- 21826163 TI - Mural folliculitis and alopecia with cutaneous candidiasis in a beagle dog. AB - A one-year-old male Beagle dog showed dermatitis, alopecia and scales. Examination of the affected dog revealed generalized alopecia, patchy erythema, and superficial erosions with histological evidence of mural folliculitis. External tests for parasites in scraped skin samples were negative. However, fungal culture tests and polymerase chain reaction revealed the existence of Candida in the lesion. These results suggest that cutaneous candidiasis may induce mural folliculitis and alopecia in dogs. PMID- 21826164 TI - Neuroprotection of Alpinia katsumadai Seed Extract against Neuronal Damage in the Ischemic Gerbil Hippocampus is Linked to Altered Brain-Derived Neurotrophic Factor. AB - The extract of Alpinia katsumadai, a member of the family Zingiberaceae, shows anti-inflammatory effects and antioxidant activity. We observed the neuroprotective effects of the extract from Alpinia katsumadai seed (EAKS) against ischemic damage in gerbils administered oral EAKS (25, and 50 mg/kg) once a day for 7 days before transient cerebral ischemia. In the 50 mg/kg EAKS-treated ischemia group, about 67% of neurons in the hippocampal CA1 region (CA1) survived after ischemia/reperfusion (I/R) based on cresyl violet staining. We observed that EAKS treatment significantly maintained brain-derived neurotrophic factor (BDNF) immunoreactivity in the ischemic CA1 region after I/R. In addition, protein levels of BDNF in the 50 mg/kg EAKS-treated ischemia group were much higher than those in the vehicle-treated ischemia group after I/R. These findings indicate that repeated supplementation of EAKS protects neurons from ischemic damage, such that BDNF is distinctively maintained in ischemic areas. PMID- 21826165 TI - Focal Cerebral Ischemia Reduces Protein Phosphatase 2A Subunit B Expression in Brain Tissue and HT22 Cells. AB - Protein phosphatase 2A (PP2A) is a serine and threonine protein phosphatase that regulates cell cycle progression and apoptosis. PP2A is composed of various subunits. Among these subunits, subunit B plays an important role in the modulation of PP2A function in the brain. This study investigated PP2A subunit B expression levels after neuronal cell injury. Middle cerebral artery occlusions (MCAO) were surgically induced in adult male rats to induce focal cerebral ischemic injury, and brain tissues were collected 24 h after MCAO. A proteomic approach revealed reduction of PP2A subunit B protein spots in MCAO-operated animals in comparison to sham-operated animals. Western blot analysis confirmed that MCAO induces reductions in PP2A subunit B levels. Moreover, glutamate exposure induces neuronal cell death and leads to reductions of PP2A subunit B levels in a hippocampal-derived cell line. This study demonstrated the decrease of PP2A subunit B in ischemic neuronal cell injury. These results suggest that the decrease of PP2A subunit B after ischemic brain injury can mediate neuronal cell death. PMID- 21826167 TI - Epigallocatechin-3-gallate Regulates Inducible Nitric Oxide Synthase Expression in Human Umbilical Vein Endothelial Cells. AB - Inducible nitric oxide synthase (iNOS) is a main enzyme producing nitric oxide during inflammation and thus contributes to the initiation and development of inflammatory cardiovascular diseases such as atherosclerosis. Epigallocatechin-3 gallate (EGCG), the major catechin derived from green tea, has multiple beneficial effects for treating cardiovascular disease, but the effect of EGCG on the expression of vascular iNOS remains unknown. In this study, we investigated (i) whether EGCG inhibits the expression of vascular iNOS induced by angiotensin II in human umbilical vein endothelial cells and, if it does inhibit, (ii) mechanisms underlying the inhibition. Angiotensin II increased expression levels of vascular iNOS; EGCG counteracted this effect. EGCG increased the production of reactive oxygen species. Moreover, EGCG did not affect the production of reactive oxygen species induced by angiotensin II. These data suggest a novel mechanism whereby EGCG provides direct vascular benefits for treating inflammatory cardiovascular diseases. PMID- 21826168 TI - Difference in Resistance to Streptococcus pneumoniae Infection in Mice. AB - Streptococcus pneumoniae is a major pathogen that causes various diseases, including pneumonia and sepsis, as millions of people suffer from S. pneumoniae infection worldwide. To better understand the immune and inflammatory responses to S. pneumoniae, we produced murine models. To investigate the differences between intranasal and intratracheal infection, BALB/c mice were infected with S. pneumoniae D39 intranasally or intratracheally. Mice showed no significant differences in survival rates, body weight changes, and bacterial loads. To investigate resistance and susceptibility among mouse strains, BALB/c, C57BL/6J, tumor necrosis factor-alpha (TNF-alpha) knockout, and interleukin-10 (IL-10) knockout mice were infected with S. pneumoniae D39 via intranasal or intravenous routes. In this study, BALB/c and C57BL/6J mice were resistant, IL-10 knockout mice were intermediate, and TNF-alpha knokout mice were susceptible to S. pneumoniae infection. These data show that intranasal and intratracheal infection induced similar results after S. pneumoniae infection, and the genetic background of mice must be considered when studying S. pneumoniae infection in vivo. PMID- 21826166 TI - Animal models of periventricular leukomalacia. AB - Periventricular leukomalacia, specifically characterized as white matter injury, in neonates is strongly associated with the damage of pre-myelinating oligodendrocytes. Clinical data suggest that hypoxia-ischemia during delivery and intrauterine or neonatal infection-inflammation are important factors in the etiology of periventricular leukomalacia including cerebral palsy, a serious case exhibiting neurobehavioral deficits of periventricular leukomalacia. In order to explore the pathophysiological mechanisms of white matter injury and to better understand how infectious agents may affect the vulnerability of the immature brain to injury, novel animal models have been developed using hypoperfusion, microbes or bacterial products (lipopolysaccharide) and excitotoxins. Such efforts have developed rat models that produce predominantly white matter lesions by adopting combined hypoxia-ischemia technique on postnatal days 1-7, in which unilateral or bilateral carotid arteries of animals are occluded (ischemia) followed by 1-2 hour exposure to 6-8% oxygen environment (hypoxia). Furthermore, low doses of lipopolysaccharide that by themselves have no adverse-effects in 7 day-old rats, dramatically increase brain injury to hypoxic-ischemic challenge, implying that inflammation sensitizes the immature central nervous system. Therefore, among numerous models of periventricular leukomalacia, combination of hypoxia-ischemia-lipopolysaccharide might be one of the most-acceptable rodent models to induce extensive white matter injury and ensuing neurobehavioral deficits for the evaluation of candidate therapeutics. PMID- 21826170 TI - Isolation and Expression Profile of the Ca-Activated Chloride Channel-like Membrane Protein 6 Gene in Xenopus laevis. AB - To clone the first anion channel from Xenopus laevis (X. laevis), we isolated a calcium-activated chloride channel (CLCA)-like membrane protein 6 gene (CMP6) in X. laevis. As a first step in gene isolation, an expressed sequence tags database was screened to find the partial cDNA fragment. A putative partial cDNA sequence was obtained by comparison with rat CLCAs identified in our laboratory. First stranded cDNA was synthesized by reverse transcription polymerase-chain reaction (RT-PCR) using a specific primer designed for the target cDNA. Repeating the 5' and 3' rapid amplification of cDNA ends, full-length cDNA was constructed from the cDNA pool. The full-length CMP6 cDNA completed via 5'- and 3'-RACE was 2,940 bp long and had an open reading frame (ORF) of 940 amino acids. The predicted 940 polypeptides have four major transmembrane domains and showed about 50% identity with that of rat brain CLCAs in our previously published data. Semi quantification analysis revealed that CMP6 was most abundantly expressed in small intestine, colon and liver. However, all tissues except small intestine, colon and liver had undetectable levels. This result became more credible after we did real-time PCR quantification for the target gene. In view of all CLCA studies focused on human or murine channels, this finding suggests a hypothetical protein as an ion channel, an X. laevis CLCA. PMID- 21826169 TI - Gene alterations of ovarian cancer cells expressing estrogen receptors by estrogen and bisphenol a using microarray analysis. AB - Since endocrine disrupting chemicals (EDCs) may interfere with the endocrine system(s) of our body and have an estrogenicity, we evaluated the effect(s) of bisphenol A (BPA) on the transcriptional levels of altered genes in estrogen receptor (ER)-positive BG-1 ovarian cancer cells by microarray and real-time polymerase-chain reaction. In this study, treatment with 17beta-estradiol (E(2)) or BPA increased mRNA levels of E(2)-responsive genes related to apoptosis, cancer and cell cycle, signal transduction and nucleic acid binding etc. In parallel with their microarray data, the mRNA levels of some altered genes including RAB31_MEMBER RAS ONCOGENE FAMILY (U59877), CYCLIN D1 (X59798), CYCLIN DEPENDENT KINASE 4 (U37022), IGF-BINDING PROTEIN 4 (U20982), and ANTI-MULLERIAN HORMONE (NM_000479) were significantly induced by E(2) or BPA in this cell model. These results indicate that BPA in parallel with E(2) induced the transcriptional levels of E(2)-responsive genes in an estrogen receptor (ER)-positive BG-1 cells. In conclusion, these microarray and real-time polymerase-chain reaction results indicate that BPA, a potential weak estrogen, may have estrogenic effect by regulating E(2)-responsive genes in ER-positive BG-1 cells and BG-1 cells would be the best in vitro model to detect these estrogenic EDCs. PMID- 21826171 TI - Effects of Steaming Time and Frequency for Manufactured Red Liriope platyphylla on the Insulin Secretion Ability and Insulin Receptor Signaling Pathway. AB - In oriental medicine, Liriope platyphylla (LP) has long been regarded as a curative herb useful for the treatment of diabetes, asthma, and neurodegenerative disorders. The principal objective of this study was to assess the effects of steaming time and frequency for manufactured Red LP (RLP) on insulin secretion ability and insulin receptor signaling pathway. To achieve our goal, several types of LPs manufactured under different conditions were applied to INS cells and streptozotocin (STZ)-induced diabetic ICR mice, after which alterations in insulin concentrations were detected in the culture supernatants and sera. The optimal concentration for the investigation of insulin secretion ability was found to be 50 ug/mL of LP. At this concentration, maximum insulin secretion was observed in the INS cells treated with LP extract steamed for 3 h (3-SLP) with two repeated steps (3 h steaming and 24 h air-dried) carried out 9 times (9 SALP); no significant changes in viability were detected in any of the treated cells. Additionally, the expression and phosphorylation levels of most components in the insulin receptor signaling pathway were increased significantly in the majority of cells treated with steaming-processed LP as compared to the cells treated with LP prepared without steaming. With regard to glucose transporter (GLUT) expression, alterations of steaming time induced similar responses on the expression levels of GLUT-2 and GLUT-3. However, differences in steaming frequency were also shown to induce dose-dependent responses in the expression level of GLUT-2 only; no significant differences in GLUT-3 expression were detected under these conditions. Furthermore, these responses observed in vitro were similarly detected in STZ-induced diabetic mice. 24-SLP and 9-SALP treatment applied for 14 days induced the down-regulation of glucose concentration and upregulation of insulin concentration. Therefore, these results indicated that the steaming processed LP may contribute to the relief of diabetes symptoms and should be regarded as an excellent candidate for a diabetes treatment. PMID- 21826172 TI - Traumatic and Non-traumatic Osteonecrosis in the Femoral Head of a Rabbit Model. AB - Osteonecrosis of the femoral head is an idiopathic, debilitating and progressive disease. A number of traumatic or non-traumatic animal models have been reported for research on osteonecrosis. This study was performed to compare the efficacy of femoral head osteonecrosis in rabbits by traumatic and non-traumatic methods. Twenty-seven New Zealand White rabbits were divided into three experimental groups, nine heads each. Two groups were surgically induced into osteonecrosis; a steel cerclage wire was ligated tightly around the neck of the right femoral head (Group W), and the femoral neck was tied with a cerclage wire in the same way as in the W group, and burned by attachment of an electrode tip to the wire and then the wire was removed (Group B). The other group was induced into osteonecrosis with a single intra-muscular injection of 20 mg/kg methyl-prednisolone acetate single injection (Group M). In the control group, the left femoral head of animals in group W and B was used. After two weeks, rabbits were sacrificed and the femoral head and neck were collected. Osteonecrosis of the femoral head was evaluated by radiography, histology and immunohistology methods. Osteonecrosis lesions in the femoral head were identified in traumatic models of groups W and B. Cartilage degeneration in the superficial layer and TUNEL positive cells in the femoral head were detected more in Group B than in Group W. These findings revealed that short-term induced osteonecrosis of the femoral head was effectively achieved by cautery around the femoral neck. PMID- 21826173 TI - Granulocyte-derived cationic Peptide enhances homing and engraftment of bone marrow stem cells after transplantation. AB - Current strategies to accelerate hematopoietic reconstitution after transplantation include transplantation of greater numbers of hematopoietic stem/progenitor cells (HSPCs) or ex vivo expansion of harvested HSPCs before transplant. However, the number of cells available for transplantation is usually low, and strategies to expand HSPCs and maintain equivalent engraftment capability ex vivo are limited. We noted that activated granulocyte-derived cationic peptides positively primed responsiveness of HSPCs to a CXCL12 gradient. Accordingly, we noted that accelerated homing/engraftment of beta-defensin-2, a well-known antimicrobial cationic peptide, primed bone marrow nucleated cells (BMNCs) compared to normal BMNCs after transplantation into lethally irradiated recipients. We envision that small cationic peptides, which primarily possess antimicrobial functions and are harmless to mammalian cells, could be applied to prime HSPCs before transplantation. This novel approach would be particularly important in cord blood transplantation, where the number of HSPCs available for transplantation is usually limited. PMID- 21826174 TI - Sensitive and Specific Detection of Mycoplasma species by Consensus Polymerase Chain Reaction and Dot Blot Hybridization. AB - Mycoplasmas are highly fastidious bacteria, difficult to culture and slow growing. Many species of mycoplasmas are important pathogens that cause respiratory infection in laboratory animals and that are known to affect experimental results obtained with contaminated animals. The aim of the present study was to develop a sensitive and specific assay for the detection of mycoplasma species. To this end, we developed a polymerase chain reaction and dot blot hybridization assay (PCR/DBH) for detecting mycoplasma DNA and evaluated it for its sensitivity and specificity. Mycoplasma consensus primer pairs were used for the amplification of target DNA. When PCR product was visually detected, the limit of detection of the PCR test was 10(2) pg of mycoplasma purified DNA. For DBH, the amplified DNA was labeled by incorporation of digoxigenin (DIG). This DIG-labeled probe was capable of detecting 10(4) pg of purified mycoplasma DNA by DBH. PCR/DBH was more sensitive than PCR or DBH alone and was also very specific. Our PCR/DBH assay can be applied efficiently to confirm the presence of mycoplasma species on clinical samples and to differentiate between mycoplasma species infection and other bacterial infections. PMID- 21826175 TI - OCT4 Expression Enhances Features of Cancer Stem Cells in a Mouse Model of Breast Cancer. AB - The cancer stem cell (CSC) hypothesis proposes that CSCs are responsible for metastasis and disease recurrence. Therefore, targeting CSCs has the potential to significantly improve outcomes for cancer patients. The OCT4 transcription factor gene is a master gene that plays a key role in the self-renewal and pluripotency of stem cells. In this study, we introduced an OCT4 reporting vector into 4T1 mouse breast cancer cells and sorted OCT4 high and OCT4 low cell populations. We then determined whether OCT4 expression is associated with maintenance and expansion of CSCs. We found that OCT4(high) 4T1 cells have an increased ability to form tumorsphere and a high expression of stem cell markers such as Sca-1, CD133, CD34, and ALDH1, when compared with OCT4(low) 4T1 cells. In addition, OCT4(high) 4T1 cells have greater tumorigenic potential in vivo. These findings suggest that OCT4 expression may be a useful target for stem cell-specific cancer therapy. PMID- 21826176 TI - Detailed differentiation of calbindin d-28k-immunoreactive cells in the dentate gyrus in C57BL/6 mice at early postnatal stages. AB - The hippocampus makes new memories and is involved in mental cognition, and the hippocampal dentate gyrus (DG) is critical because neurogenesis, which occurs throughout life, occurs in the DG. We observed the differentiation of neuroblasts into mature neurons (granule cells) in the DG of C57BL/6 mice at various early postnatal (P) ages: P1, P7, P14, and P21 using doublecortin (DCX) immunohistochemistry (IHC) for neuroblasts and calbindin D-28k (CB) IHC for granule cells. DCX-positive cells decreased in the DG with age; however, CB(+) cells increased over time. At P1, DCX and CB double-labeled (DCX(+)CB(+)) cells were scattered throughout the DG. At P7, DCX(+)CB(+) cells (about 92% of CB(+) cells) were seen only in the granule cell layer (GCL) of the dorsal blade. At P14, DCX(+)CB(+) cells (about 66% of CB(+) cells) were found in the lower half of the GCL of both blades. In contrast, at P21, about 18% of CB(+) cells were DCX(+)CB(+) cells, and they were mainly located only in the subgranular zone of the DG. These results suggest that the developmental pattern of DCX(+)CB(+) cells changes with time in the early postnatal stages. PMID- 21826177 TI - Transcriptome analysis of the effects of gomisin a on the recovery of carbon tetrachloride-induced damage in rat liver. AB - Gomisin A possesses a hepatic function-facilitating property in liver-injured rats. Its preventive action on carbon tetrachloride-induced cholestasis is due to maintenance of the function of the bile acids-independent fraction. To investigate alterations in gene expression after gomisin A treatment on injured rat liver, DNA microarray analyses were performed on a Rat 44K 4-Plex Gene Expression platform with duplicated reactions after gomisin A treatment. We identified 255 up-regulated and 230 down-regulated genes due to the effects of gomisin A on recovery of carbon tetrachloride-induced rat liver damage. For functional characterization of these genes, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes biochemical pathways analyses were performed. Many up regulated or down-regulated genes were related to cell cycle or focal adhesion and cell death genes, respectively. Our microarray experiment indicated that the liver repair mechanism induced by gomisin A was strongly associated with increased gene expressions related to cell cycle and suppression of the gene expression related in cell death. PMID- 21826178 TI - Bone marrow-derived mesenchymal stem cells improve the functioning of neurotrophic factors in a mouse model of diabetic neuropathy. AB - Diabetic neuropathy is one of the most frequent and troublesome complications of diabetes. Although there has been a continuous increase in the incidence of diabetic neuropathy, treatments have yet to be found that effectively treat diabetic neuropathy. Neurotrophic factors are proteins that promote the survival of specific neuronal populations. They also play key roles in the regeneration of peripheral nervous system. Recent evidence from diabetic animal models and human diabetic subjects suggest that reduced availability of neurotrophic factors may contribute to the pathogenesis of diabetic neuropathy. One way to reverse this effect is to take advantage of the finding that bone marrow derived mesenchymal stem cells (BM-MSCs) promote peripheral nerve repair and the functioning of neurotrophic factors. Therefore, we speculated that treatment with BM-MSCs could be a viable therapeutic strategy for diabetic neuropathy. The present study was designed to examine the possible beneficial effect of BM-MSCs on functions of neurotrophic factors in diabetic neuropathy. To assess this possibility, we used an in vivo streptozotocin-induced diabetic neuropathy mouse model. Quantitative real-time polymerase-chain reacion showed that BM-MSCs significantly increase expression levels of neurotrophic factors. Also, BM-MSCs ameliorated nerve conduction velocity in streptozotocin-treated mice. These results may help to elucidate the mechanism by which BM-MSCs function as a cell therapy agent in diabetic neuropathy. PMID- 21826180 TI - Retraction. PMID- 21826179 TI - Spontaneous sertoli cell tumor with cryptorchism in a beagle dog. AB - A male one year-old beagle dog with unilateral cryptorchism was presented for investigation of reduced appetite. Abdominal sonography and radiography demonstrated abnormal enlargement of the left testicle in the abdominal cavity. Both the retroperitoneal cryptorchid testicle and the other contralateral testicle were removed surgically. The retroperitoneal cryptorchid testicle was an enlarged, firm and bulging sphere mass. The cut surface revealed a homogeneous white color. The contralateral testicle in the scrotum showed an almost normal appearance. Histopathologically, the retroperitoneal cryptorchid testicle was diagnosed as a Sertoli cell tumor. This report describes a case of Sertoli cell tumor with cryptorchism in a beagle dog. PMID- 21826182 TI - Novel 5, 6-Dihydropyrrolo[2,1-a]isoquinolines as Scaffolds for Synthesis of Lamellarin Analogues. AB - AS CORE SKELETONS OF LAMELLARINS: 5,6-Dihydropyrrolo[2,1-a]isoquinolines are one of the important alkaloids that exhibit significant biological activities, in this study, an efficient synthetic route was described for two novel compounds, 5,6-dihydropyrrolo[2,1-a]isoquinolines I and II. Compound I was synthesized from isovanillin with 28.3% overall yield by a six-step reaction while II from 2-(3, 4 dimethoxyphenyl) ethanamine was with 61.6% overall yield by a three-step reaction. And the structures of these two compounds were confirmed by means of IR spectrum, (1)H NMR, (13)C NMR, MS, HRMS, and melting point measurements. PMID- 21826181 TI - Cytokines: the future of intranasal vaccine adjuvants. AB - Due to its potential as an effective, needle-free route of immunization for use with subunit vaccines, nasal immunization continues to be evaluated as a route of immunization in both research and clinical studies. However, as with other vaccination routes, subunit vaccines often require the addition of adjuvants to induce potent immune responses. Unfortunately, many commonly used experimental vaccine adjuvants, such as cholera toxin and E. coli heat-labile toxin, are too toxic for use in humans. Because new adjuvants are needed, cytokines have been evaluated for their ability to provide effective adjuvant activity when delivered by the nasal route in both animal models and in limited human studies. It is the purpose of this paper to discuss the potential of cytokines as nasal vaccine adjuvants. PMID- 21826183 TI - Dieckol from Ecklonia cava Regulates Invasion of Human Fibrosarcoma Cells and Modulates MMP-2 and MMP-9 Expression via NF-kappaB Pathway. AB - The matrix metalloproteinase (MMP) family is involved in the breakdown of extracellular matrix in normal physiological processes, as well as in the disease processes such as arthritis and cancer metastasis. In the present study, dieckol was obtained with high yield from marine brown alga Ecklonia cava (EC), and its effect was assessed on the expression of MMP-2 and -9 and morphological changes in human fibrosarcoma cell line (HT1080). Dieckol inhibited the expression of MMP 2 and -9 in a dose-dependent manner and also suppressed the cell invasion and the cytomorphology in 3D culture system on HT1080 cells. Moreover, dieckol may influence nuclear factor kappa B (NF-kappaB) pathway without obvious influence on activator protein-1 (AP-1) pathway and tissue inhibitor of metalloproteinases (TIMPs). In conclusion, dieckol could significantly suppress MMP-2 and -9 expression and alter cytomorphology of HT1080 cell line via NF-kappaB pathway. PMID- 21826184 TI - Genome-based studies of marine microorganisms to maximize the diversity of natural products discovery for medical treatments. AB - Marine microorganisms are rich source for natural products which play important roles in pharmaceutical industry. Over the past decade, genome-based studies of marine microorganisms have unveiled the tremendous diversity of the producers of natural products and also contributed to the efficiency of harness the strain diversity and chemical diversity, as well as the genetic diversity of marine microorganisms for the rapid discovery and generation of new natural products. In the meantime, genomic information retrieved from marine symbiotic microorganisms can also be employed for the discovery of new medical molecules from yet unculturable microorganisms. In this paper, the recent progress in the genomic research of marine microorganisms is reviewed; new tools of genome mining as well as the advance in the activation of orphan pathways and metagenomic studies are summarized. Genome-based research of marine microorganisms will maximize the biodiscovery process and solve the problems of supply and sustainability of drug molecules for medical treatments. PMID- 21826185 TI - Biphasic effect of curcumin on morphine tolerance: a preliminary evidence from cytokine/chemokine protein array analysis. AB - The aim of this study was to evaluate the effect of curcumin on morphine tolerance and the corresponding cytokine/chemokine changes. Male ICR mice were made tolerant to morphine by daily subcutaneous injection for 7 days. Intraperitoneal injections of vehicle, low-dose or high-dose curcumin were administered 15 min after morphine injection, either acutely or chronically for 7 days to test the effect of curcumin on morphine-induced antinociception and development of morphine tolerance. On day 8, cumulative dose-response curves were generated and the 50% of maximal analgesic dose values were calculated and compared among groups. Corresponding set of mice were used for analyzing the cytokine responses by antibody-based cytokine protein array. Acute, high-dose curcumin enhanced morphine-induced antinociception. While morphine tolerance was attenuated by administration of low-dose curcumin following morphine injections for 7 days, it was aggravated by chronic high-dose curcumin following morphine injection, suggesting a biphasic effect of curcumin on morphine-induced tolerance. Of the 96 cytokine/chemokines analyzed by mouse cytokine protein array, 14 cytokines exhibited significant changes after the different 7-day treatments. Mechanisms for the modulatory effects of low-dose and high-dose curcumin on morphine tolerance were discussed. Even though curcumin itself is a neuroprotectant and low doses of the compound serve to attenuate morphine tolerance, high-doses of curcumin might cause neurotoxicity and aggravate morphine tolerance by inhibiting the expression of antiapoptotic cytokines and neuroprotective factors. Our results indicate that the effect of curcumin on morphine tolerance may be biphasic, and therefore curcumin should be used cautiously. PMID- 21826186 TI - Medical Student Attitudes toward Complementary, Alternative and Integrative Medicine. AB - While the use of complementary, alternative and integrative medicine (CAIM) is substantial, it continues to exist at the periphery of allopathic medicine. Understanding the attitudes of medical students toward CAIM will be useful in understanding future integration of CAIM and allopathic medicine. This study was conducted to develop and evaluate an instrument and assess medical students' attitudes toward CAIM. The Complementary, Alternative and Integrative Medicine Attitudes Questionnaire (CAIMAQ) was developed by a panel of experts in CAIM, allopathic medicine, medical education and survey development. A total of 1770 CAIMAQ surveys (51% of US medical schools participated) were obtained in a national sample of medical students in 2007. Factor analysis of the CAIMAQ revealed five distinct attitudinal domains: desirability of CAIM therapies, progressive patient/physician health care roles, mind-body-spirit connection, principles of allostasis and a holistic understanding of disease. The students held the most positive attitude for the "mind-body-spirit connection" and the least positive for the "desirability of CAIM therapies". This study provided initial support for the reliability of the CAIMAQ. The survey results indicated that in general students responded more positively to the principles of CAIM than to CAIM treatment. A higher quality of CAIM-related medical education and expanded research into CAIM therapies would facilitate appropriate integration of CAIM into medical curricula. The most significant limitation of this study is a low response rate, and further work is required to assess more representative populations in order to determine whether the relationships found in this study are generalizable. PMID- 21826187 TI - Myrrh inhibits LPS-induced inflammatory response and protects from cecal ligation and puncture-induced sepsis. AB - Myrrh has been used as an antibacterial and anti-inflammatory agent. However, effect of myrrh on peritoneal macrophages and clinically relevant models of septic shock, such as cecal ligation and puncture (CLP), is not well understood. Here, we investigated the inhibitory effect and mechanism(s) of myrrh on inflammatory responses. Myrrh inhibited LPS-induced productions of inflammatory mediators such as nitric oxide, prostaglandin E(2), and tumor necrosis factor alpha but not of interleukin (IL)-1beta and IL-6 in peritoneal macrophages. In addition, Myrrh inhibited LPS-induced activation of c-jun NH(2)-terminal kinase (JNK) but not of extracellular signal-regulated kinase (ERK), p38, and nuclear factor-kappaB. Administration of Myrrh reduced the CLP-induced mortality and bacterial counts and inhibited inflammatory mediators. Furthermore, administration of Myrrh attenuated CLP-induced liver damages, which were mainly evidenced by decreased infiltration of leukocytes and aspartate aminotransferase/alanine aminotransferase level. Taken together, these results provide the evidence for the anti-inflammatory and antibacterial potential of Myrrh in sepsis. PMID- 21826188 TI - Synergistic Apoptosis-Inducing Antileukemic Effects of Arsenic Trioxide and Mucuna macrocarpa Stem Extract in Human Leukemic Cells via a Reactive Oxygen Species-Dependent Mechanism. AB - The objective of this study was to examine the potential of enhancing the antileukemic activity of arsenic trioxide (ATO) by combining it with a folk remedy, crude methanolic extract of Mucuna macrocarpa (CMEMM). Human leukemia cells HL-60, Jurkat, and Molt-3 were treated with various doses of ATO, CMEMM, and combinations thereof for 24 and 48 h. Results indicated that the combination of 2.5 MUM ATO and 50 MUg/mL CMEMM synergistically inhibited cell proliferation in HL-60 and Jurkat cell lines. Apoptosis triggered by ATO/CMEMM treatment was confirmed by accumulation of cells in the sub-G(1) phase in cell cycle analyses, characteristic apoptotic nuclear fragmentation, and increased percentage of annexin V-positive apoptotic cells. Such combination treatments also led to elevation of reactive oxygen species (ROS). The antioxidants N-acetyl cysteine (NAC), butylated hydroxytoluene, and alpha-tocopherol prevented cells from ATO/CMEMM-induced apoptosis. The ATO/CMEMM-induced activation of caspase-3 and caspase-9 can be blocked by NAC. In summary, these results suggest that ATO/CMEMM combination treatment exerts synergistic apoptosis-inducing effects in human leukemic cells through a ROS-dependent mechanism and may provide a promising antileukemic approach in the future. PMID- 21826190 TI - Optical imaging of rheumatoid arthritis. AB - Optical Imaging (OI) for rheumatoid arthritis is a novel imaging modality. With the high number of people affected by this disease, especially in western countries, the availability of OI as an early diagnostic imaging method is clinically highly relevant. In this article we describe the current techniques of OI and discuss potential future applications of this promising technology. Overall, we demonstrate that OI is a fast, inexpensive, noninvasive, nonionizing and accurate imaging modality. Furthermore, OI is a clinically applicable tool allowing for the early detection of inflammation and potentially facilitating the monitoring of therapy. PMID- 21826189 TI - Regulation of p53 function by lysine methylation. AB - The reversible and dynamic methylation of proteins on lysine residues can greatly increase the signaling potential of the modified factor. In addition to histones, several other nuclear factors such as the tumor suppressor and transcription factor p53 undergo lysine methylation, suggesting that this modification may be a common mechanism for modulating protein-protein interactions and key cellular signaling pathways. This article focuses on how lysine methylation events on the C-terminal tail of p53 are generated, sensed and transduced to modulate p53 functions. PMID- 21826191 TI - Dipole source analysis of auditory P300 response in depressive and anxiety disorders. AB - This paper is to study auditory event-related potential P300 in patients with anxiety and depressive disorders using dipole source analysis. Auditory P300 using 2-stimulus oddball paradigm was collected from 35 patients with anxiety disorder, 32 patients with depressive disorder, and 30 healthy controls. P300 dipole sources and peak amplitude of dipole activities were analyzed. The source analysis resulted in a 4-dipole configuration, where temporal dipoles displayed greater P300 amplitude than that of frontal dipoles. In addition, a right-greater than-left hemispheric asymmetry of dipole magnitude was found in patients with anxiety disorder, whereas a left-greater-than-right hemispheric asymmetry of dipole magnitude was observed in depressed patients. Results indicated that the asymmetry was more prominent over the temporal dipole than that of frontal dipoles in patients. Patients with anxiety disorder may increase their efforts to enhance temporal dipole activity to compensate for a deficit in frontal cortex processing, while depressed patients show dominating reduction of right temporal activity. The opposite nature of results observed with hemispheric asymmetry in depressive and anxiety disorders could serve to be valuable information for psychiatric studies. PMID- 21826192 TI - Neural representations of the sense of self. AB - The brain constructs representations of what is sensed and thought about in the form of nerve impulses that propagate in circuits and network assemblies (Circuit Impulse Patterns, CIPs). CIP representations of which humans are consciously aware occur in the context of a sense of self. Thus, research on mechanisms of consciousness might benefit from a focus on how a conscious sense of self is represented in brain. Like all senses, the sense of self must be contained in patterns of nerve impulses. Unlike the traditional senses that are registered by impulse flow in relatively simple, pauci-synaptic projection pathways, the sense of self is a system- level phenomenon that may be generated by impulse patterns in widely distributed complex and interacting circuits. The problem for researchers then is to identify the CIPs that are unique to conscious experience. Also likely to be of great relevance to constructing the representation of self are the coherence shifts in activity timing relations among the circuits. Consider that an embodied sense of self is generated and contained as unique combinatorial temporal patterns across multiple neurons in each circuit that contributes to constructing the sense of self. As with other kinds of CIPs, those representing the sense of self can be learned from experience, stored in memory, modified by subsequent experiences, and expressed in the form of decisions, choices, and commands. These CIPs are proposed here to be the actual physical basis for conscious thought and the sense of self. When active in wakefulness or dream states, the CIP representations of self act as an agent of the brain, metaphorically as an avatar. Because the selfhood CIP patterns may only have to represent the self and not directly represent the inner and outer worlds of embodied brain, the self representation should have more degrees of freedom than subconscious mind and may therefore have some capacity for a free-will mind of its own. S everal lines of evidence for this theory are reviewed. Suggested new research includes identifying distinct combinatorially coded impulse patterns and their temporal coherence shifts in defined circuitry, such as neocortical microcolumns. This task might be facilitated by identifying the micro-topography of field-potential oscillatory coherences among various regions and between different frequencies associated with specific conscious mentation. Other approaches can include identifying the changes in discrete conscious operations produced by focal trans-cranial magnetic stimulation. PMID- 21826193 TI - Estimated HIV incidence in the United States, 2006-2009. AB - BACKGROUND: The estimated number of new HIV infections in the United States reflects the leading edge of the epidemic. Previously, CDC estimated HIV incidence in the United States in 2006 as 56,300 (95% CI: 48,200-64,500). We updated the 2006 estimate and calculated incidence for 2007-2009 using improved methodology. METHODOLOGY: We estimated incidence using incidence surveillance data from 16 states and 2 cities and a modification of our previously described stratified extrapolation method based on a sample survey approach with multiple imputation, stratification, and extrapolation to account for missing data and heterogeneity of HIV testing behavior among population groups. PRINCIPAL FINDINGS: Estimated HIV incidence among persons aged 13 years and older was 48,600 (95% CI: 42,400-54,700) in 2006, 56,000 (95% CI: 49,100-62,900) in 2007, 47,800 (95% CI: 41,800-53,800) in 2008 and 48,100 (95% CI: 42,200-54,000) in 2009. From 2006 to 2009 incidence did not change significantly overall or among specific race/ethnicity or risk groups. However, there was a 21% (95% CI:1.9% 39.8%; p = 0.017) increase in incidence for people aged 13-29 years, driven by a 34% (95% CI: 8.4%-60.4%) increase in young men who have sex with men (MSM). There was a 48% increase among young black/African American MSM (12.3%-83.0%; p<0.001). Among people aged 13-29, only MSM experienced significant increases in incidence, and among 13-29 year-old MSM, incidence increased significantly among young, black/African American MSM. In 2009, MSM accounted for 61% of new infections, heterosexual contact 27%, injection drug use (IDU) 9%, and MSM/IDU 3%. CONCLUSIONS/SIGNIFICANCE: Overall, HIV incidence in the United States was relatively stable 2006-2009; however, among young MSM, particularly black/African American MSM, incidence increased. HIV continues to be a major public health burden, disproportionately affecting several populations in the United States, especially MSM and racial and ethnic minorities. Expanded, improved, and targeted prevention is necessary to reduce HIV incidence. PMID- 21826195 TI - Measuring nepotism through shared last names: the case of Italian Academia. AB - Nepotistic practices are detrimental for academia. Here I show how disciplines with a high likelihood of nepotism can be detected using standard statistical techniques based on shared last names among professors. As an example, I analyze the set of all 61,340 Italian academics. I find that nepotism is prominent in Italy, with particular disciplinary sectors being detected as especially problematic. Out of 28 disciplines, 9 - accounting for more than half of Italian professors - display a significant paucity of last names. Moreover, in most disciplines a clear north-south trend emerges, with likelihood of nepotism increasing with latitude. Even accounting for the geographic clustering of last names, I find that for many disciplines the probability of name-sharing is boosted when professors work in the same institution or sub-discipline. Using these techniques policy makers can target cuts and funding in order to promote fair practices. PMID- 21826194 TI - Incidence of sarcoma histotypes and molecular subtypes in a prospective epidemiological study with central pathology review and molecular testing. AB - BACKGROUND: The exact overall incidence of sarcoma and sarcoma subtypes is not known. The objective of the present population-based study was to determine this incidence in a European region (Rhone-Alpes) of six million inhabitants, based on a central pathological review of the cases. METHODOLOGY/PRINCIPAL FINDINGS: From March 2005 to February 2007, pathology reports and tumor blocks were prospectively collected from the 158 pathologists of the Rhone-Alpes region. All diagnosed or suspected cases of sarcoma were collected, reviewed centrally, examined for molecular alterations and classified according to the 2002 World Health Organization classification. Of the 1287 patients screened during the study period, 748 met the criteria for inclusion in the study. The overall crude and world age-standardized incidence rates were respectively 6.2 and 4.8 per 100,000/year. Incidence rates for soft tissue, visceral and bone sarcomas were respectively 3.6, 2.0 and 0.6 per 100,000. The most frequent histological subtypes were gastrointestinal stromal tumor (18%; 1.1/100,000), unclassified sarcoma (16%; 1/100,000), liposarcoma (15%; 0.9/100,000) and leiomyosarcoma (11%; 0.7/100,000). CONCLUSIONS/SIGNIFICANCE: The observed incidence of sarcomas was higher than expected. This study is the first detailed investigation of the crude incidence of histological and molecular subtypes of sarcomas. PMID- 21826196 TI - Heart rate and risk of cancer death in healthy men. AB - BACKGROUND: Data from several previous studies examining heart-rate and cardiovascular risk have hinted at a possible relationship between heart-rate and non-cardiac mortality. We thus systematically examined the predictive value of heart-rate variables on the subsequent risk of death from cancer. METHODS: In the Paris Prospective Study I, 6101 asymptomatic French working men aged 42 to 53 years, free of clinically detectable cardiovascular disease and cancer, underwent a standardized graded exercise test between 1967 and 1972. Resting heart-rate, heart-rate increase during exercise, and decrease during recovery were measured. Change in resting heart-rate over 5 years was also available in 5139 men. Mortality including 758 cancer deaths was assessed over the 25 years of follow up. FINDINGS: There were strong, graded and significant relationships between all heart-rate parameters and subsequent cancer deaths. After adjustment for age and tobacco consumption and, compared with the lowest quartile, those with the highest quartile for resting heart-rate had a relative risk of 2.4 for cancer deaths (95% confidence interval: 1.9-2.9, p<0.0001) This was similar after adjustment for traditional cardiovascular risk factors and was observed for the commonest malignancies (respiratory and gastrointestinal). Similarly, significant relationships with cancer death were observed between poor heart rate increase during exercise, poor decrease during recovery and greater heart-rate increase over time (p<0.0001 for all). INTERPRETATION: Resting and exercise heart rate had consistent, graded and highly significant associations with subsequent cancer mortality in men. PMID- 21826197 TI - A gene optimization strategy that enhances production of fully functional P glycoprotein in Pichia pastoris. AB - BACKGROUND: Structural and biochemical studies of mammalian membrane proteins remain hampered by inefficient production of pure protein. We explored codon optimization based on highly expressed Pichia pastoris genes to enhance co translational folding and production of P-glycoprotein (Pgp), an ATP-dependent drug efflux pump involved in multidrug resistance of cancers. METHODOLOGY/PRINCIPAL FINDINGS: Codon-optimized "Opti-Pgp" and wild-type Pgp, identical in primary protein sequence, were rigorously analyzed for differences in function or solution structure. Yeast expression levels and yield of purified protein from P. pastoris (~130 mg per kg cells) were about three-fold higher for Opti-Pgp than for wild-type protein. Opti-Pgp conveyed full in vivo drug resistance against multiple anticancer and fungicidal drugs. ATP hydrolysis by purified Opti-Pgp was strongly stimulated ~15-fold by verapamil and inhibited by cyclosporine A with binding constants of 4.2+/-2.2 uM and 1.1+/-0.26 uM, indistinguishable from wild-type Pgp. Maximum turnover number was 2.1+/-0.28 umol/min/mg and was enhanced by 1.2-fold over wild-type Pgp, likely due to higher purity of Opti-Pgp preparations. Analysis of purified wild-type and Opti-Pgp by CD, DSC and limited proteolysis suggested similar secondary and ternary structure. Addition of lipid increased the thermal stability from T(m) ~40 degrees C to 49 degrees C, and the total unfolding enthalpy. The increase in folded state may account for the increase in drug-stimulated ATPase activity seen in presence of lipids. CONCLUSION: The significantly higher yields of protein in the native folded state, higher purity and improved function establish the value of our gene optimization approach, and provide a basis to improve production of other membrane proteins. PMID- 21826198 TI - The BMP antagonist follistatin-like 1 is required for skeletal and lung organogenesis. AB - Follistatin-like 1 (Fstl1) is a secreted protein of the BMP inhibitor class. During development, expression of Fstl1 is already found in cleavage stage embryos and becomes gradually restricted to mesenchymal elements of most organs during subsequent development. Knock down experiments in chicken and zebrafish demonstrated a role as a BMP antagonist in early development. To investigate the role of Fstl1 during mouse development, a conditional Fstl1 KO allele as well as a Fstl1-GFP reporter mouse were created. KO mice die at birth from respiratory distress and show multiple defects in lung development. Also, skeletal development is affected. Endochondral bone development, limb patterning as well as patterning of the axial skeleton are perturbed in the absence of Fstl1. Taken together, these observations show that Fstl1 is a crucial regulator in BMP signalling during mouse development. PMID- 21826200 TI - Modeling users' activity on twitter networks: validation of Dunbar's number. AB - Microblogging and mobile devices appear to augment human social capabilities, which raises the question whether they remove cognitive or biological constraints on human communication. In this paper we analyze a dataset of Twitter conversations collected across six months involving 1.7 million individuals and test the theoretical cognitive limit on the number of stable social relationships known as Dunbar's number. We find that the data are in agreement with Dunbar's result; users can entertain a maximum of 100-200 stable relationships. Thus, the 'economy of attention' is limited in the online world by cognitive and biological constraints as predicted by Dunbar's theory. We propose a simple model for users' behavior that includes finite priority queuing and time resources that reproduces the observed social behavior. PMID- 21826199 TI - Anti-inflammatory effect of fluvastatin on IL-8 production induced by Pseudomonas aeruginosa and Aspergillus fumigatus antigens in cystic fibrosis. AB - BACKGROUND: Early in life, patients with cystic fibrosis (CF) are infected with microorganisms including bacteria and fungi, particularly Pseudomonas aeruginosa and Aspergillus fumigatus. Since recent research has identified the anti inflammatory properties of statins (besides their lipid-lowering effects), we investigated the effect of fluvastatin on the production of the potent neutrophil chemoattractant chemokine, IL-8, in whole blood from CF patients, stimulated by Pseudomonas aeruginosa (LPS) and Aspergillus fumigatus (AFA) antigens. RESULTS: Whole blood from adult patients with CF and from healthy volunteers was collected at the Rennes University Hospital (France). Blood was pretreated for 1 h with fluvastatin (0-300 uM) and incubated for 24 h with LPS (10 ug/mL) and/or AFA (diluted 1/200). IL-8 protein levels, quantified by ELISA, were increased in a concentration-dependent manner when cells were stimulated by LPS or AFA. Fluvastatin strongly decreased the levels of IL-8, in a concentration-dependent manner, in whole blood from CF patients. However, its inhibitory effect was decreased or absent in whole blood from healthy subjects. Furthermore, the inhibition induced by fluvastatin in CF whole blood was reversed in the presence of intermediates within the cholesterol biosynthesis pathway, mevalonate, farnesyl pyprophosphate or geranylgeranyl pyrophosphate that activate small GTPases by isoprenylation. CONCLUSIONS: For the first time, the inhibitory effects of fluvastatin on CF systemic inflammation may reveal the important therapeutic potential of statins in pathological conditions associated with the over-production of pro-inflammatory cytokines and chemokines as observed during the manifestation of CF. The anti-inflammatory effect could be related to the modulation of the prenylation of signalling proteins. PMID- 21826201 TI - Unique CRF01_AE Gag CTL epitopes associated with lower HIV-viral load and delayed disease progression in a cohort of HIV-infected Thais. AB - Cytotoxic T Lymphocytes (CTLs) play a central role in controlling HIV replication. Although numerous CTL epitopes have been described, most are in subtype B or C infection. Little is known about CTL responses in CRF01_AE infection. Gag CTL responses were investigated in a cohort of 137 treatment-naive HIV-1 infected Thai patients with high CD4+ T cell counts, using gIFN Enzyme Linked Immunospot (ELISpot) assays with 15-mer overlapping peptides (OLPs) derived from locally dominant CRF01_AE Gag sequences. 44 OLPs were recognized in 112 (81.8%) individuals. Both the breadth and magnitude of the CTL response, particularly against the p24 region, positively correlated with CD4+ T cell count and inversely correlated with HIV viral load. The breadth of OLP response was also associated with slower progression to antiretroviral therapy initiation. Statistical analysis and single peptide ELISpot assay identified at least 17 significant associations between reactive OLP and HLA in 12 OLP regions; 6 OLP HLA associations (35.3%) were not compatible with previously reported CTL epitopes, suggesting that these contained new CTL Gag epitopes. A substantial proportion of CTL epitopes in CRF01_AE infection differ from subtype B or C. However, the pattern of protective CTL responses is similar; Gag CTL responses, particularly against p24, control viral replication and slow clinical progression. PMID- 21826202 TI - Asiatic acid inhibits pro-angiogenic effects of VEGF and human gliomas in endothelial cell culture models. AB - Malignant gliomas are one of the most devastating and incurable tumors. Sustained excessive angiogenesis by glioma cells is the major reason for their uncontrolled growth and resistance toward conventional therapies resulting in high mortality. Therefore, targeting angiogenesis should be a logical strategy to prevent or control glioma cell growth. Earlier studies have shown that Asiatic Acid (AsA), a pentacyclic triterpenoid, is effective against glioma and other cancer cells; however, its efficacy against angiogenesis remains unknown. In the present study, we examined the anti-angiogenic efficacy of AsA using human umbilical vein endothelial cells (HUVEC) and human brain microvascular endothelial cells (HBMEC). Our results showed that AsA (5-20 uM) inhibits HUVEC growth and induces apoptotic cell death by activating caspases (3 and 9) and modulating the expression of apoptosis regulators Bad, survivin and pAkt-ser473. Further, AsA showed a dose-dependent inhibition of HUVEC migration, invasion and capillary tube formation, and disintegrated preformed capillary network. AsA also inhibited the VEGF-stimulated growth and capillary tube formation by HUVEC and HBMEC. Next, we analyzed the angiogenic potential of conditioned media collected from human glioma LN18 and U87-MG cells treated with either DMSO (control conditioned media, CCM) or AsA 20 uM (AsA20 conditioned media, AsA20CM). CCM from glioma cells significantly enhanced the capillary tube formation in both HUVEC and HBMEC, while capillary tube formation in both endothelial cell lines was greatly compromised in the presence of AsA20CM. Consistent with these results, VEGF expression was lesser in AsA20CM compared to CCM, and indeed AsA strongly inhibited VEGF level (both cellular and secreted) in glioma cells. AsA also showed dose-dependent anti-angiogenic efficacy in Matrigel plug assay, and inhibited the glioma cells potential to attract HUVEC/HBMEC. Overall, the present study clearly showed the strong anti-angiogenic potential of AsA and suggests its usefulness against malignant gliomas. PMID- 21826204 TI - What people believe about how memory works: a representative survey of the U.S. population. AB - Incorrect beliefs about the properties of memory have broad implications: the media conflate normal forgetting and inadvertent memory distortion with intentional deceit, juries issue verdicts based on flawed intuitions about the accuracy and confidence of testimony, and students misunderstand the role of memory in learning. We conducted a large representative telephone survey of the U.S. population to assess common beliefs about the properties of memory. Substantial numbers of respondents agreed with propositions that conflict with expert consensus: Amnesia results in the inability to remember one's own identity (83% of respondents agreed), unexpected objects generally grab attention (78%), memory works like a video camera (63%), memory can be enhanced through hypnosis (55%), memory is permanent (48%), and the testimony of a single confident eyewitness should be enough to convict a criminal defendant (37%). This discrepancy between popular belief and scientific consensus has implications from the classroom to the courtroom. PMID- 21826203 TI - Genotype and ancestry modulate brain's DAT availability in healthy humans. AB - The dopamine transporter (DAT) is a principal regulator of dopaminergic neurotransmission and its gene (the SLC6A3) is a strong biological candidate gene for various behavioral- and neurological disorders. Intense investigation of the link between the SLC6A3 polymorphisms and behavioral phenotypes yielded inconsistent and even contradictory results. Reliance on objective brain phenotype measures, for example, those afforded by brain imaging, might critically improve detection of DAT genotype-phenotype association. Here, we tested the relationship between the DAT brain availability and the SLC6A3 genotypes using an aggregate sample of 95 healthy participants of several imaging studies. These studies employed positron emission tomography (PET) with [11C]cocaine wherein the DAT availability was estimated as Bmax/Kd; while the genotype values were obtained on two repeat polymorphisms--3-UTR- and intron 8- VNTRs. The main findings are the following: 1) both polymorphisms analyzed as single genetic markers and in combination (haplotype) modulate DAT density in midbrain; 2) ethnic background and age influence the strength of these associations; and 3) age-related changes in DAT availability differ in the 3-UTR and intron 8--genotype groups. PMID- 21826205 TI - Skin conductance response to the pain of others predicts later costly helping. AB - People show autonomic responses when they empathize with the suffering of another person. However, little is known about how these autonomic changes are related to prosocial behavior. We measured skin conductance responses (SCRs) and affect ratings in participants while either receiving painful stimulation themselves, or observing pain being inflicted on another person. In a later session, they could prevent the infliction of pain in the other by choosing to endure pain themselves. Our results show that the strength of empathy-related vicarious skin conductance responses predicts later costly helping. Moreover, the higher the match between SCR magnitudes during the observation of pain in others and SCR magnitude during self pain, the more likely a person is to engage in costly helping. We conclude that prosocial motivation is fostered by the strength of the vicarious autonomic response as well as its match with first-hand autonomic experience. PMID- 21826206 TI - Variability of sequence surrounding the Xist gene in rodents suggests taxon specific regulation of X chromosome inactivation. AB - One of the two X chromosomes in female mammalian cells is subject to inactivation (XCI) initiated by the Xist gene. In this study, we examined in rodents (voles and rat) the conservation of the microsatellite region DXPas34, the Tsix gene (antisense counterpart of Xist), and enhancer Xite that have been shown to flank Xist and regulate XCI in mouse. We have found that mouse regions of the Tsix gene major promoter and minisatellite repeat DXPas34 are conserved among rodents. We have also shown that in voles and rat the region homologous to the mouse Tsix major promoter, initiates antisense to Xist transcription and terminates around the Xist gene start site as is observed with mouse Tsix. A conservation of Tsix expression pattern in voles, rat and mice suggests a crucial role of the antisense transcription in regulation of Xist and XIC in rodents. Most surprisingly, we have found that voles lack the regions homologous to the regulatory element Xite, which is instead replaced with the Slc7a3 gene that is unassociated with the X-inactivation centre in any other eutherians studied. Furthermore, we have not identified any transcription that could have the same functions as murine Xite in voles. Overall, our data show that not all the functional elements surrounding Xist in mice are well conserved even within rodents, thereby suggesting that the regulation of XCI may be at least partially taxon-specific. PMID- 21826208 TI - Nicotinamide phosphoribosyltransferase/visfatin does not catalyze nicotinamide mononucleotide formation in blood plasma. AB - Nicotinamide (Nam) phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme in mammalian NAD synthesis, catalyzing nicotinamide mononucleotide (NMN) formation from Nam and 5-phosphoribosyl 1-pyrophosphate (PRPP). NAMPT has also been described as an adipocytokine visfatin with a variety of actions, although physiological significance of this protein remains unclear. It has been proposed that possible actions of visfatin are mediated through the extracellular formation of NMN. However, we did not detect NMN in mouse blood plasma, even with a highly specific and sensitive liquid chromatography/tandem mass spectrometry. Furthermore, there is no or little ATP, the activator of NAMPT, in extracellular spaces. We thus questioned whether visfatin catalyzes the in situ formation of NMN under such extracellular milieus. To address this question, we here determined K(m) values for the substrates Nam and PRPP in the NAMPT reaction without or with ATP using a recombinant human enzyme and found that 1 mM ATP dramatically decreases K(m) values for the substrates, in particular PRPP to its intracellular concentration. Consistent with the kinetic data, only when ATP is present at millimolar levels, NAMPT efficiently catalyzed the NMN formation at the intracellular concentrations of the substrates. Much lower concentrations of Nam and almost the absence of PRPP and ATP in the blood plasma suggest that NAMPT should not efficiently catalyze its reaction under the extracellular milieu. Indeed, NAMPT did not form NMN in the blood plasma. From these kinetic analyses of the enzyme and quantitative determination of its substrates, activator, and product, we conclude that visfatin does not participate in NMN formation under the extracellular milieus. Together with the absence of NMN in the blood plasma, our conclusion does not support the concept of "NAMPT-mediated systemic NAD biosynthesis." Our study would advance current understanding of visfatin physiology. PMID- 21826207 TI - B7 costimulation molecules encoded by replication-defective, vhs-deficient HSV-1 improve vaccine-induced protection against corneal disease. AB - Herpes simplex virus 1 (HSV-1) causes herpes stromal keratitis (HSK), a sight threatening disease of the cornea for which no vaccine exists. A replication defective, HSV-1 prototype vaccine bearing deletions in the genes encoding ICP8 and the virion host shutoff (vhs) protein reduces HSV-1 replication and disease in a mouse model of HSK. Here we demonstrate that combining deletion of ICP8 and vhs with virus-based expression of B7 costimulation molecules created a vaccine strain that enhanced T cell responses to HSV-1 compared with the ICP8-vhs- parental strain, and reduced the incidence of keratitis and acute infection of the nervous system after corneal challenge. Post-challenge T cell infiltration of the trigeminal ganglia and antigen-specific recall responses in local lymph nodes correlated with protection. Thus, B7 costimulation molecules expressed from the genome of a replication-defective, ICP8-vhs- virus enhance vaccine efficacy by further reducing HSK. PMID- 21826209 TI - Co-transplantation of olfactory ensheathing cells from mucosa and bulb origin enhances functional recovery after peripheral nerve lesion. AB - Olfactory ensheathing cells (OECs) represent an interesting candidate for cell therapy and could be obtained from olfactory mucosa (OM-OECs) or olfactory bulbs (OB-OECs). Recent reports suggest that, depending on their origin, OECs display different functional properties. We show here the complementary and additive effects of co-transplanting OM-OECs and OB-OECs after lesion of a peripheral nerve. For this, a selective motor denervation of the laryngeal muscles was performed by a section/anastomosis of the recurrent laryngeal nerve (RLN). Two months after surgery, recovery of the laryngeal movements and synkinesis phenonema were analyzed by videolaryngoscopy. To complete these assessments, measure of latency and potential duration were determined by electrophysiological recordings and myelinated nerve fiber profiles were defined based on toluidine blue staining. To explain some of the mechanisms involved, tracking of GFP positive OECs was performed. It appears that transplantation of OM-OECs or OB OECs displayed opposite abilities to improve functional recovery. Indeed, OM-OECs increased recuperation of laryngeal muscles activities without appropriate functional recovery. In contrast, OB-OECs induced some functional recovery by enhancing axonal regrowth. Importantly, co-transplantation of OM-OECs and OB-OECs supported a major functional recovery, with reduction of synkinesis phenomena. This study is the first which clearly demonstrates the complementary and additive properties of OECs obtained from olfactory mucosa and olfactory bulb to improve functional recovery after transplantation in a nerve lesion model. PMID- 21826210 TI - Metabolic deficiences revealed in the biotechnologically important model bacterium Escherichia coli BL21(DE3). AB - The Escherichia coli B strain BL21(DE3) has had a profound impact on biotechnology through its use in the production of recombinant proteins. Little is understood, however, regarding the physiology of this important E. coli strain. We show here that BL21(DE3) totally lacks activity of the four [NiFe] hydrogenases, the three molybdenum- and selenium-containing formate dehydrogenases and molybdenum-dependent nitrate reductase. Nevertheless, all of the structural genes necessary for the synthesis of the respective anaerobic metalloenzymes are present in the genome. However, the genes encoding the high affinity molybdate transport system and the molybdenum-responsive transcriptional regulator ModE are absent from the genome. Moreover, BL21(DE3) has a nonsense mutation in the gene encoding the global oxygen-responsive transcriptional regulator FNR. The activities of the two hydrogen-oxidizing hydrogenases, therefore, could be restored to BL21(DE3) by supplementing the growth medium with high concentrations of Ni2+ (Ni2+-transport is FNR-dependent) or by introducing a wild-type copy of the fnr gene. Only combined addition of plasmid-encoded fnr and high concentrations of MoO42- ions could restore hydrogen production to BL21(DE3); however, to only 25-30% of a K-12 wildtype. We could show that limited hydrogen production from the enzyme complex responsible for formate-dependent hydrogen evolution was due solely to reduced activity of the formate dehydrogenase (FDH-H), not the hydrogenase component. The activity of the FNR dependent formate dehydrogenase, FDH-N, could not be restored, even when the fnr gene and MoO42- were supplied; however, nitrate reductase activity could be recovered by combined addition of MoO42- and the fnr gene. This suggested that a further component specific for biosynthesis or activity of formate dehydrogenases H and N was missing. Re-introduction of the gene encoding ModE could only partially restore the activities of both enzymes. Taken together these results demonstrate that BL21(DE3) has major defects in anaerobic metabolism, metal ion transport and metalloprotein biosynthesis. PMID- 21826211 TI - Primary B-cell deficiencies reveal a link between human IL-17-producing CD4 T cell homeostasis and B-cell differentiation. AB - IL-17 is a pro-inflammatory cytokine implicated in autoimmune and inflammatory conditions. The development/survival of IL-17-producing CD4 T cells (Th17) share critical cues with B-cell differentiation and the circulating follicular T helper subset was recently shown to be enriched in Th17 cells able to help B-cell differentiation. We investigated a putative link between Th17-cell homeostasis and B cells by studying the Th17-cell compartment in primary B-cell immunodeficiencies. Common Variable Immunodeficiency Disorders (CVID), defined by defects in B-cell differentiation into plasma and memory B cells, are frequently associated with autoimmune and inflammatory manifestations but we found no relationship between these and Th17-cell frequency. In fact, CVID patients showed a decrease in Th17-cell frequency in parallel with the expansion of activated non differentiated B cells (CD21(low)CD38(low)). Moreover, Congenital Agammaglobulinemia patients, lacking B cells due to impaired early B-cell development, had a severe reduction of circulating Th17 cells. Finally, we found a direct correlation in healthy individuals between circulating Th17-cell frequency and both switched-memory B cells and serum BAFF levels, a crucial cytokine for B-cell survival. Overall, our data support a relationship between Th17-cell homeostasis and B-cell maturation, with implications for the understanding of the pathogenesis of inflammatory/autoimmune diseases and the physiology of B-cell depleting therapies. PMID- 21826212 TI - Juvenile greylag geese (Anser anser) discriminate between individual siblings. AB - Social species that maintain individualised relationships with certain others despite continuous changes in age, reproductive status and dominance rank between group members ought to be capable of individual recognition. Tests of "true" individual recognition, where an individual recognises unique features of another, are rare, however. Often kinship and/or familiarity suffice to explain dyadic interactions. The complex relationships within a greylag goose flock suggest that they should be able to recognise individuals irrespective of familiarity or kinship. We tested whether six-week-old hand-raised greylags can discriminate between two of their siblings. We developed a new experimental protocol, in which geese were trained to associate social siblings with geometrical symbols. Subsequently, focals were presented with two geometrical symbols in the presence of a sibling associated with one of the symbols. Significant choice of the geometrical symbol associated with the target present indicated that focals were able to distinguish between individual targets. Greylag goslings successfully learned this association-discrimination task, regardless of genetic relatedness or sex of the sibling targets. Social relationships within a goose flock thus may indeed be based on recognition of unique features of individual conspecifics. PMID- 21826213 TI - High glucose-mediated oxidative stress impairs cell migration. AB - Deficient wound healing in diabetic patients is very frequent, but the cellular and molecular causes are poorly defined. In this study, we evaluate the hypothesis that high glucose concentrations inhibit cell migration. Using CHO.K1 cells, NIH-3T3 fibroblasts, mouse embryonic fibroblasts and primary skin fibroblasts from control and diabetic rats cultured in 5 mM D-glucose (low glucose, LG), 25 mM D-glucose (high glucose, HG) or 25 mM L-glucose medium (osmotic control--OC), we analyzed the migration speed, protrusion stability, cell polarity, adhesion maturation and the activity of the small Rho GTPase Rac1. We also analyzed the effects of reactive oxygen species by incubating cells with the antioxidant N-Acetyl-Cysteine (NAC). We observed that HG conditions inhibited cell migration when compared to LG or OC. This inhibition resulted from impaired cell polarity, protrusion destabilization and inhibition of adhesion maturation. Conversely, Rac1 activity, which promotes protrusion and blocks adhesion maturation, was increased in HG conditions, thus providing a mechanistic basis for the HG phenotype. Most of the HG effects were partially or completely rescued by treatment with NAC. These findings demonstrate that HG impairs cell migration due to an increase in oxidative stress that causes polarity loss, deficient adhesion and protrusion. These alterations arise, in large part, from increased Rac1 activity and may contribute to the poor wound healing observed in diabetic patients. PMID- 21826214 TI - Climate change hastens the conservation urgency of an endangered ungulate. AB - Global climate change appears to be one of the main threats to biodiversity in the near future and is already affecting the distribution of many species. Currently threatened species are a special concern while the extent to which they are sensitive to climate change remains uncertain. Przewalski's gazelle (Procapra przewalskii) is classified as endangered and a conservation focus on the Qinghai Tibetan Plateau. Using measures of species range shift, we explored how the distribution of Przewalski's gazelle may be impacted by projected climate change based on a maximum entropy approach. We also evaluated the uncertainty in the projections of the risks arising from climate change. Modeling predicted the Przewalski's gazelle would be sensitive to future climate change. As the time horizon increased, the strength of effects from climate change increased. Even assuming unlimited dispersal capacity of gazelles, a moderate decrease to complete loss of range was projected by 2080 under different thresholds for transforming the probability prediction to presence/absence data. Current localities of gazelles will undergo a decrease in their occurrence probability. Projections of the impacts of climate change were significantly affected by thresholds and general circulation models. This study suggests climate change clearly poses a severe threat and increases the extinction risk to Przewalski's gazelle. Our findings 1) confirm that endangered endemic species is highly vulnerable to climate change and 2) highlight the fact that forecasting impacts of climate change needs an assessment of the uncertainty. It is extremely important that conservation strategies consider the predicted geographical shifts and be planned with full knowledge of the reliability of projected impacts of climate change. PMID- 21826215 TI - Lessons from history for designing and validating epidemiological surveillance in uncounted populations. AB - BACKGROUND: Due to scanty individual health data in low- and middle-income countries (LMICs), health planners often use imperfect data sources. Frequent national-level data are considered essential, even if their depth and quality are questionable. However, quality in-depth data from local sentinel populations may be better than scanty national data, if such local data can be considered as nationally representative. The difficulty is the lack of any theoretical or empirical basis for demonstrating that local data are representative where data on the wider population are unavailable. Thus these issues can only be explored empirically in a complete individual dataset at national and local levels, relating to a LMIC population profile. METHODS AND FINDINGS: Swedish national data for 1925 were used, characterised by relatively high mortality, a low proportion of older people and substantial mortality due to infectious causes. Demographic and socioeconomic characteristics of Sweden then and LMICs now are very similar. Rates of livebirths, stillbirths, infant and cause-specific mortality were calculated at national and county levels. Results for six million people in 24 counties showed that most counties had overall mortality rates within 10% of the national level. Other rates by county were mostly within 20% of national levels. Maternal mortality represented too rare an event to give stable results at the county level. CONCLUSIONS: After excluding obviously outlying counties (capital city, island, remote areas), any one of the remaining 80% closely reflected the national situation in terms of key demographic and mortality parameters, each county representing approximately 5% of the national population. We conclude that this scenario would probably translate directly to about 40 LMICs with populations under 10 million, and to individual states or provinces within about 40 larger LMICs. Unsubstantiated claims that local sub national population data are "unrepresentative" or "only local" should not therefore predominate over likely representativity. PMID- 21826216 TI - Caveolin-1 plays a crucial role in inhibiting neuronal differentiation of neural stem/progenitor cells via VEGF signaling-dependent pathway. AB - In the present study, we aim to elucidate the roles of caveolin-1(Cav-1), a 22 kDa protein in plasma membrane invaginations, in modulating neuronal differentiation of neural progenitor cells (NPCs). In the hippocampal dentate gyrus, we found that Cav-1 knockout mice revealed remarkably higher levels of vascular endothelial growth factor (VEGF) and the more abundant formation of newborn neurons than wild type mice. We then studied the potential mechanisms of Cav-1 in modulating VEGF signaling and neuronal differentiation in isolated cultured NPCs under normoxic and hypoxic conditions. Hypoxic embryonic rat NPCs were exposed to 1% O2 for 24 h and then switched to 21% O2 for 1, 3, 7 and 14 days whereas normoxic NPCs were continuously cultured with 21% O2. Compared with normoxic NPCs, hypoxic NPCs had down-regulated expression of Cav-1 and up regulated VEGF expression and p44/42MAPK phosphorylation, and enhanced neuronal differentiation. We further studied the roles of Cav-1 in inhibiting neuronal differentiation by using Cav-1 scaffolding domain peptide and Cav-1-specific small interfering RNA. In both normoxic and hypoxic NPCs, Cav-1 peptide markedly down-regulated the expressions of VEGF and flk1, decreased the phosphorylations of p44/42MAPK, Akt and Stat3, and inhibited neuronal differentiation, whereas the knockdown of Cav-1 promoted the expression of VEGF, phosphorylations of p44/42MAPK, Akt and Stat3, and stimulated neuronal differentiation. Moreover, the enhanced phosphorylations of p44/42MAPK, Akt and Stat3, and neuronal differentiation were abolished by co-treatment of VEGF inhibitor V1. These results provide strong evidence to prove that Cav-1 can inhibit neuronal differentiation via down-regulations of VEGF, p44/42MAPK, Akt and Stat3 signaling pathways, and that VEGF signaling is a crucial target of Cav-1. The hypoxia induced down-regulation of Cav-1 contributes to enhanced neuronal differentiation in NPCs. PMID- 21826217 TI - Fanconi anemia core complex gene promoters harbor conserved transcription regulatory elements. AB - The Fanconi anemia (FA) gene family is a recent addition to the complex network of proteins that respond to and repair certain types of DNA damage in the human genome. Since little is known about the regulation of this novel group of genes at the DNA level, we characterized the promoters of the eight genes (FANCA, B, C, E, F, G, L and M) that compose the FA core complex. The promoters of these genes show the characteristic attributes of housekeeping genes, such as a high GC content and CpG islands, a lack of TATA boxes and a low conservation. The promoters functioned in a monodirectional way and were, in their most active regions, comparable in strength to the SV40 promoter in our reporter plasmids. They were also marked by a distinctive transcriptional start site (TSS). In the 5' region of each promoter, we identified a region that was able to negatively regulate the promoter activity in HeLa and HEK 293 cells in isolation. The central and 3' regions of the promoter sequences harbor binding sites for several common and rare transcription factors, including STAT, SMAD, E2F, AP1 and YY1, which indicates that there may be cross-connections to several established regulatory pathways. Electrophoretic mobility shift assays and siRNA experiments confirmed the shared regulatory responses between the prominent members of the TGF-beta and JAK/STAT pathways and members of the FA core complex. Although the promoters are not well conserved, they share region and sequence specific regulatory motifs and transcription factor binding sites (TBFs), and we identified a bi-partite nature to these promoters. These results support a hypothesis based on the co-evolution of the FA core complex genes that was expanded to include their promoters. PMID- 21826219 TI - Asymmetric dispersal and colonization success of Amazonian plant-ants queens. AB - BACKGROUND: The dispersal ability of queens is central to understanding ant life history evolution, and plays a fundamental role in ant population and community dynamics, the maintenance of genetic diversity, and the spread of invasive ants. In tropical ecosystems, species from over 40 genera of ants establish colonies in the stems, hollow thorns, or leaf pouches of specialized plants. However, little is known about the relative dispersal ability of queens competing for access to the same host plants. METHODOLOGY/PRINCIPAL FINDINGS: We used empirical data and inverse modeling--a technique developed by plant ecologists to model seed dispersal--to quantify and compare the dispersal kernels of queens from three Amazonian ant species that compete for access to host-plants. We found that the modal colonization distance of queens varied 8-fold, with the generalist ant species (Crematogaster laevis) having a greater modal distance than two specialists (Pheidole minutula, Azteca sp.) that use the same host-plants. However, our results also suggest that queens of Azteca sp. have maximal distances that are four-sixteen times greater than those of its competitors. CONCLUSIONS/SIGNIFICANCE: We found large differences between ant species in both the modal and maximal distance ant queens disperse to find vacant seedlings used to found new colonies. These differences could result from interspecific differences in queen body size, and hence wing musculature, or because queens differ in their ability to identify potential host plants while in flight. Our results provide support for one of the necessary conditions underlying several of the hypothesized mechanisms promoting coexistence in tropical plant-ants. They also suggest that for some ant species limited dispersal capability could pose a significant barrier to the rescue of populations in isolated forest fragments. Finally, we demonstrate that inverse models parameterized with field data are an excellent means of quantifying the dispersal of ant queens. PMID- 21826218 TI - A novel acyl-CoA beta-transaminase characterized from a metagenome. AB - BACKGROUND: Bacteria are key components in all ecosystems. However, our knowledge of bacterial metabolism is based solely on the study of cultivated organisms which represent just a tiny fraction of microbial diversity. To access new enzymatic reactions and new or alternative pathways, we investigated bacterial metabolism through analyses of uncultivated bacterial consortia. METHODOLOGY/PRINCIPAL FINDINGS: We applied the gene context approach to assembled sequences of the metagenome of the anaerobic digester of a municipal wastewater treatment plant, and identified a new gene which may participate in an alternative pathway of lysine fermentation. CONCLUSIONS: We characterized a novel, unique aminotransferase that acts exclusively on Coenzyme A (CoA) esters, and proposed a variant route for lysine fermentation. Results suggest that most of the lysine fermenting organisms use this new pathway in the digester. Its presence in organisms representative of two distinct bacterial divisions indicate that it may also be present in other organisms. PMID- 21826221 TI - The effects of wildfire on mortality and resources for an arboreal marsupial: resilience to fire events but susceptibility to fire regime change. AB - BACKGROUND: Big environmental disturbances have big ecological effects, yet these are not always what we might expect. Understanding the proximate effects of major disturbances, such as severe wildfires, on individuals, populations and habitats will be essential for understanding how predicted future increases in the frequency of such disturbances will affect ecosystems. However, researchers rarely have access to data from immediately before and after such events. Here we report on the effects of a severe and extensive forest wildfire on mortality, reproductive output and availability of key shelter resources for an arboreal marsupial. We also investigated the behavioural response of individuals to changed shelter resource availability in the post-fire environment. METHODOLOGY/PRINCIPAL FINDINGS: We fitted proximity-logging radiotransmitters to mountain brushtail possums (Trichosurus cunninghami) before, during and after the 2009 wildfires in Victoria, Australia. Surprisingly, we detected no mortality associated with the fire, and despite a significant post-fire decrease in the proportion of females carrying pouch young in the burnt area, there was no short term post-fire population decline. The major consequence of this fire for mountain brushtail possums was the loss of over 80% of hollow-bearing trees. The types of trees preferred as shelter sites (highly decayed dead standing trees) were those most likely to collapse after fire. Individuals adapted to resource decline by being more flexible in resource selection after the fire, but not by increased resource sharing. CONCLUSIONS/SIGNIFICANCE: Despite short-term demographic resilience and behavioural adaptation following this fire, the major loss of decayed hollow trees suggests the increased frequency of stand-replacing wildfires predicted under climate change will pose major challenges for shelter resource availability for hollow-dependent fauna. Hollow-bearing trees are typically biological legacies of previous forest generations in post-fire regrowth forests but will cease to be recruited to future regrowth forests if the interval between severe fires becomes too rapid for hollow formation. PMID- 21826220 TI - Proteomic characterization of cellular and molecular processes that enable the Nanoarchaeum equitans--Ignicoccus hospitalis relationship. AB - Nanoarchaeum equitans, the only cultured representative of the Nanoarchaeota, is dependent on direct physical contact with its host, the hyperthermophile Ignicoccus hospitalis. The molecular mechanisms that enable this relationship are unknown. Using whole-cell proteomics, differences in the relative abundance of >75% of predicted protein-coding genes from both Archaea were measured to identify the specific response of I. hospitalis to the presence of N. equitans on its surface. A purified N. equitans sample was also analyzed for evidence of interspecies protein transfer. The depth of cellular proteome coverage achieved here is amongst the highest reported for any organism. Based on changes in the proteome under the specific conditions of this study, I. hospitalis reacts to N. equitans by curtailing genetic information processing (replication, transcription) in lieu of intensifying its energetic, protein processing and cellular membrane functions. We found no evidence of significant Ignicoccus biosynthetic enzymes being transported to N. equitans. These results suggest that, under laboratory conditions, N. equitans diverts some of its host's metabolism and cell cycle control to compensate for its own metabolic shortcomings, thus appearing to be entirely dependent on small, transferable metabolites and energetic precursors from I. hospitalis. PMID- 21826222 TI - Excessive food intake, obesity and inflammation process in Zucker fa/fa rat pancreatic islets. AB - Inappropriate food intake-related obesity and more importantly, visceral adiposity, are major risk factors for the onset of type 2 diabetes. Evidence is emerging that nutriment-induced beta-cell dysfunction could be related to indirect induction of a state of low grade inflammation. Our aim was to study whether hyperphagia associated obesity could promote an inflammatory response in pancreatic islets leading to beta-cell dysfunction. In the hyperphagic obese insulin resistant male Zucker rat, we measured the level of circulating pro inflammatory cytokines and estimated their production as well as the expression of their receptors in pancreatic tissue and beta-cells. Our main findings concern intra-islet pro-inflammatory cytokines from fa/fa rats: IL-1beta, IL-6 and TNFalpha expressions were increased; IL-1R1 was also over-expressed with a cellular redistribution also observed for IL-6R. To get insight into the mechanisms involved in phenotypic alterations, abArrays were used to determine the expression profile of proteins implicated in different membrane receptors signaling, apoptosis and cell cycle pathways. Despite JNK overexpression, cell viability was unaffected probably because of decreases in cleaved caspase3 as well as in SMAC/DIABLO and APP, involved in the induction and amplification of apoptosis. Concerning beta-cell proliferation, decreases in important cell cycle regulators (Cyclin D1, p35) and increased expression of SMAD4 probably contribute to counteract and restrain hyperplasia in fa/fa rat islets. Finally and probably as a result of IL-1beta and IL-1R1 increased expressions with sub-cellular redistribution of the receptor, islets from fa/fa rats were found more sensitive to both stimulating and inhibitory concentrations of the cytokine; this confers some physiopathological relevance to a possible autocrine regulation of beta-cell function by IL-1beta. These results support the hypothesis that pancreatic islets from prediabetic fa/fa rats undergo an inflammatory process. That the latter could contribute to beta-cell hyperactivity/proliferation and possibly lead to progressive beta-cell failure in these animals, deserves further investigations. PMID- 21826223 TI - Drosophila carrying pex3 or pex16 mutations are models of Zellweger syndrome that reflect its symptoms associated with the absence of peroxisomes. AB - The peroxisome biogenesis disorders (PBDs) are currently difficult-to-treat multiple-organ dysfunction disorders that result from the defective biogenesis of peroxisomes. Genes encoding Peroxins, which are required for peroxisome biogenesis or functions, are known causative genes of PBDs. The human peroxin genes PEX3 or PEX16 are required for peroxisomal membrane protein targeting, and their mutations cause Zellweger syndrome, a class of PBDs. Lack of understanding about the pathogenesis of Zellweger syndrome has hindered the development of effective treatments. Here, we developed potential Drosophila models for Zellweger syndrome, in which the Drosophila pex3 or pex16 gene was disrupted. As found in Zellweger syndrome patients, peroxisomes were not observed in the homozygous Drosophila pex3 mutant, which was larval lethal. However, the pex16 homozygote lacking its maternal contribution was viable and still maintained a small number of peroxisome-like granules, even though PEX16 is essential for the biosynthesis of peroxisomes in humans. These results suggest that the requirements for pex3 and pex16 in peroxisome biosynthesis in Drosophila are different, and the role of PEX16 orthologs may have diverged between mammals and Drosophila. The phenotypes of our Zellweger syndrome model flies, such as larval lethality in pex3, and reduced size, shortened longevity, locomotion defects, and abnormal lipid metabolisms in pex16, were reminiscent of symptoms of this disorder, although the Drosophila pex16 mutant does not recapitulate the infant death of Zellweger syndrome. Furthermore, pex16 mutants showed male-specific sterility that resulted from the arrest of spermatocyte maturation. pex16 expressed in somatic cyst cells but not germline cells had an essential role in the maturation of male germline cells, suggesting that peroxisome-dependent signals in somatic cyst cells could contribute to the progression of male germ cell maturation. These potential Drosophila models for Zellweger syndrome should contribute to our understanding of its pathology. PMID- 21826224 TI - Anthropogenic disturbance can determine the magnitude of opportunistic species responses on marine urban infrastructures. AB - BACKGROUND: Coastal landscapes are being transformed as a consequence of the increasing demand for infrastructures to sustain residential, commercial and tourist activities. Thus, intertidal and shallow marine habitats are largely being replaced by a variety of artificial substrata (e.g. breakwaters, seawalls, jetties). Understanding the ecological functioning of these artificial habitats is key to planning their design and management, in order to minimise their impacts and to improve their potential to contribute to marine biodiversity and ecosystem functioning. Nonetheless, little effort has been made to assess the role of human disturbances in shaping the structure of assemblages on marine artificial infrastructures. We tested the hypothesis that some negative impacts associated with the expansion of opportunistic and invasive species on urban infrastructures can be related to the severe human disturbances that are typical of these environments, such as those from maintenance and renovation works. METHODOLOGY/PRINCIPAL FINDINGS: Maintenance caused a marked decrease in the cover of dominant space occupiers, such as mussels and oysters, and a significant enhancement of opportunistic and invasive forms, such as biofilm and macroalgae. These effects were particularly pronounced on sheltered substrata compared to exposed substrata. Experimental application of the disturbance in winter reduced the magnitude of the impacts compared to application in spring or summer. We use these results to identify possible management strategies to inform the improvement of the ecological value of artificial marine infrastructures. CONCLUSIONS/SIGNIFICANCE: We demonstrate that some of the impacts of globally expanding marine urban infrastructures, such as those related to the spread of opportunistic, and invasive species could be mitigated through ecologically driven planning and management of long-term maintenance of these structures. Impact mitigation is a possible outcome of policies that consider the ecological features of built infrastructures and the fundamental value of controlling biodiversity in marine urban systems. PMID- 21826225 TI - Developmental localization and methylesterification of pectin epitopes during somatic embryogenesis of banana (Musa spp. AAA). AB - BACKGROUND: The plant cell walls play an important role in somatic embryogenesis and plant development. Pectins are major chemical components of primary cell walls while homogalacturonan (HG) is the most abundant pectin polysaccharide. Developmental regulation of HG methyl-esterification degree is important for cell adhesion, division and expansion, and in general for proper organ and plant development. METHODOLOGY/PRINCIPAL FINDINGS: Developmental localization of pectic homogalacturonan (HG) epitopes and the (1->4)-beta-D-galactan epitope of rhamnogalacturonan I (RG-I) and degree of pectin methyl-esterification (DM) were studied during somatic embryogenesis of banana (Musa spp. AAA). Histological analysis documented all major developmental stages including embryogenic cells (ECs), pre-globular, globular, pear-shaped and cotyledonary somatic embryos. Histochemical staining of extracellularly secreted pectins with ruthenium red showed the most intense staining at the surface of pre-globular, globular and pear-shaped somatic embryos. Biochemical analysis revealed developmental regulation of galacturonic acid content and DM in diverse embryogenic stages. Immunodots and immunolabeling on tissue sections revealed developmental regulation of highly methyl-esterified HG epitopes recognized by JIM7 and LM20 antibodies during somatic embryogenesis. Cell walls of pre-globular/globular and late-stage embryos contained both low methyl-esterified HG epitopes as well as partially and highly methyl-esterified ones. Extracellular matrix which covered surface of early developing embryos contained pectin epitopes recognized by 2F4, LM18, JIM5, JIM7 and LM5 antibodies. De-esterification of cell wall pectins by NaOH caused a decrease or an elimination of immunolabeling in the case of highly methyl-esterified HG epitopes. However, immunolabeling of some low methyl esterified epitopes appeared stronger after this base treatment. CONCLUSIONS/SIGNIFICANCE: These data suggest that both low- and highly-methyl esterified HG epitopes are developmentally regulated in diverse embryogenic stages during somatic embryogenesis. This study provides new information about pectin composition, HG methyl-esterification and developmental localization of pectin epitopes during somatic embryogenesis of banana. PMID- 21826227 TI - The notch and TGF-beta signaling pathways contribute to the aggressiveness of clear cell renal cell carcinoma. AB - BACKGROUND: Despite recent progress, therapy for metastatic clear cell renal cell carcinoma (CCRCC) is still inadequate. Dysregulated Notch signaling in CCRCC contributes to tumor growth, but the full spectrum of downstream processes regulated by Notch in this tumor form is unknown. METHODOLOGY/PRINCIPAL FINDINGS: We show that inhibition of endogenous Notch signaling modulates TGF-beta dependent gene regulation in CCRCC cells. Analysis of gene expression data representing 176 CCRCCs showed that elevated TGF-beta pathway activity correlated significantly with shortened disease specific survival (log-rank test, p = 0.006) and patients with metastatic disease showed a significantly elevated TGF-beta signaling activity (two-sided Student's t-test, p = 0.044). Inhibition of Notch signaling led to attenuation of both basal and TGF-beta1 induced TGF-beta signaling in CCRCC cells, including an extensive set of genes known to be involved in migration and invasion. Functional analyses revealed that Notch inhibition decreased the migratory and invasive capacity of CCRCC cells. CONCLUSION: An extensive cross-talk between the Notch and TGF-beta signaling cascades is present in CCRCC and the functional properties of these two pathways are associated with the aggressiveness of this disease. PMID- 21826226 TI - Functional dicer is necessary for appropriate specification of radial glia during early development of mouse telencephalon. AB - Early telencephalic development involves transformation of neuroepithelial stem cells into radial glia, which are themselves neuronal progenitors, around the time when the tissue begins to generate postmitotic neurons. To achieve this transformation, radial precursors express a specific combination of proteins. We investigate the hypothesis that micro RNAs regulate the ability of the early telencephalic progenitors to establish radial glia. We ablate functional Dicer, which is required for the generation of mature micro RNAs, by conditionally mutating the Dicer1 gene in the early embryonic telencephalon and analyse the molecular specification of radial glia as well as their progeny, namely postmitotic neurons and basal progenitors. Conditional mutation of Dicer1 from the telencephalon at around embryonic day 8 does not prevent morphological development of radial glia, but their expression of Nestin, Sox9, and ErbB2 is abnormally low. The population of basal progenitors, which are generated by the radial glia, is disorganised and expanded in Dicer1-/- dorsal telencephalon. While the proportion of cells expressing markers of postmitotic neurons is unchanged, their laminar organisation in the telencephalic wall is disrupted suggesting a defect in radial glial guided migration. We found that the laminar disruption could not be accounted for by a reduction of the population of Cajal Retzius neurons. Together, our data suggest novel roles for micro RNAs during early development of progenitor cells in the embryonic telencephalon. PMID- 21826228 TI - Towards a characterization of behavior-disease models. AB - The last decade saw the advent of increasingly realistic epidemic models that leverage on the availability of highly detailed census and human mobility data. Data-driven models aim at a granularity down to the level of households or single individuals. However, relatively little systematic work has been done to provide coupled behavior-disease models able to close the feedback loop between behavioral changes triggered in the population by an individual's perception of the disease spread and the actual disease spread itself. While models lacking this coupling can be extremely successful in mild epidemics, they obviously will be of limited use in situations where social disruption or behavioral alterations are induced in the population by knowledge of the disease. Here we propose a characterization of a set of prototypical mechanisms for self-initiated social distancing induced by local and non-local prevalence-based information available to individuals in the population. We characterize the effects of these mechanisms in the framework of a compartmental scheme that enlarges the basic SIR model by considering separate behavioral classes within the population. The transition of individuals in/out of behavioral classes is coupled with the spreading of the disease and provides a rich phase space with multiple epidemic peaks and tipping points. The class of models presented here can be used in the case of data-driven computational approaches to analyze scenarios of social adaptation and behavioral change. PMID- 21826229 TI - Host cytokine responses of pigeons infected with highly pathogenic Thai avian influenza viruses of subtype H5N1 isolated from wild birds. AB - Highly pathogenic avian influenza virus (HPAIV) of the H5N1 subtype has been reported to infect pigeons asymptomatically or induce mild symptoms. However, host immune responses of pigeons inoculated with HPAIVs have not been well documented. To assess host responses of pigeons against HPAIV infection, we compared lethality, viral distribution and mRNA expression of immune related genes of pigeons infected with two HPAIVs (A/Pigeon/Thailand/VSMU-7-NPT/2004; Pigeon04 and A/Tree sparrow/Ratchaburi/VSMU-16-RBR/2005; T.sparrow05) isolated from wild birds in Thailand. The survival experiment showed that 25% of pigeons died within 2 weeks after the inoculation of two HPAIVs or medium only, suggesting that these viruses did not cause lethal infection in pigeons. Pigeon04 replicated in the lungs more efficiently than T.sparrow05 and spread to multiple extrapulmonary organs such as the brain, spleen, liver, kidney and rectum on days 2, 5 and 9 post infection. No severe lesion was observed in the lungs infected with Pigeon04 as well as T.sparrow05 throughout the collection periods. Encephalitis was occasionally observed in Pigeon04- or T.sparrow05-infected brain, the severity, however was mostly mild. To analyze the expression of immune related genes in the infected pigeons, we established a quantitative real-time PCR analysis for 14 genes of pigeons. On day 2 post infection, Pigeon04 induced mRNA expression of Mx1, PKR and OAS to a greater extent than T.sparrow05 in the lungs, however their expressions were not up-regulated concomitantly on day 5 post infection when the peak viral replication was observed. Expressions of TLR3, IFNalpha, IL6, IL8 and CCL5 in the lungs following infection with the two HPAIVs were low. In sum, Pigeon04 exhibited efficient replication in the lungs compared to T.sparrow05, but did not induce excessive host cytokine expressions. Our study has provided the first insight into host immune responses of pigeons against HPAIV infection. PMID- 21826230 TI - Diagnosis of Alzheimer's disease based on disease-specific autoantibody profiles in human sera. AB - After decades of Alzheimer's disease (AD) research, the development of a definitive diagnostic test for this disease has remained elusive. The discovery of blood-borne biomarkers yielding an accurate and relatively non-invasive test has been a primary goal. Using human protein microarrays to characterize the differential expression of serum autoantibodies in AD and non-demented control (NDC) groups, we identified potential diagnostic biomarkers for AD. The differential significance of each biomarker was evaluated, resulting in the selection of only 10 autoantibody biomarkers that can effectively differentiate AD sera from NDC sera with a sensitivity of 96.0% and specificity of 92.5%. AD sera were also distinguishable from sera obtained from patients with Parkinson's disease and breast cancer with accuracies of 86% and 92%, respectively. Results demonstrate that serum autoantibodies can be used effectively as highly-specific and accurate biomarkers to diagnose AD throughout the course of the disease. PMID- 21826231 TI - A mismatch-based model for memory reconsolidation and extinction in attractor networks. AB - The processes of memory reconsolidation and extinction have received increasing attention in recent experimental research, as their potential clinical applications begin to be uncovered. A number of studies suggest that amnestic drugs injected after reexposure to a learning context can disrupt either of the two processes, depending on the behavioral protocol employed. Hypothesizing that reconsolidation represents updating of a memory trace in the hippocampus, while extinction represents formation of a new trace, we have built a neural network model in which either simple retrieval, reconsolidation or extinction of a stored attractor can occur upon contextual reexposure, depending on the similarity between the representations of the original learning and reexposure sessions. This is achieved by assuming that independent mechanisms mediate Hebbian-like synaptic strengthening and mismatch-driven labilization of synaptic changes, with protein synthesis inhibition preferentially affecting the former. Our framework provides a unified mechanistic explanation for experimental data showing (a) the effect of reexposure duration on the occurrence of reconsolidation or extinction and (b) the requirement of memory updating during reexposure to drive reconsolidation. PMID- 21826233 TI - Examining the evidence for chytridiomycosis in threatened amphibian species. AB - Extinction risks are increasing for amphibians due to rising threats and minimal conservation efforts. Nearly one quarter of all threatened/extinct amphibians in the IUCN Red List is purportedly at risk from the disease chytridiomycosis. However, a closer look at the data reveals that Batrachochytrium dendrobatidis (the causal agent) has been identified and confirmed to cause clinical disease in only 14% of these species. Primary literature surveys confirm these findings; ruling out major discrepancies between Red List assessments and real-time science. Despite widespread interest in chytridiomycosis, little progress has been made between assessment years to acquire evidence for the role of chytridiomycosis in species-specific amphibian declines. Instead, assessment teams invoke the precautionary principle when listing chytridiomycosis as a threat. Precaution is valuable when dealing with the world's most threatened taxa, however scientific research is needed to distinguish between real and predicted threats in order to better prioritize conservation efforts. Fast paced, cost effective, in situ research to confirm or rule out chytridiomycosis in species currently hypothesized to be threatened by the disease would be a step in the right direction. Ultimately, determining the manner in which amphibian conservation resources are utilized is a conversation for the greater conservation community that we hope to stimulate here. PMID- 21826234 TI - The economic value of environmental services on indigenous-held lands in Australia. AB - Australians could be willing to pay from $878m to $2b per year for Indigenous people to provide environmental services. This is up to 50 times the amount currently invested by government. This result was derived from a nationwide survey that included a choice experiment in which 70% of the 927 respondents were willing to contribute to a conservation fund that directly pays Indigenous people to carry out conservation activities. Of these the highest values were found for benefits that are likely to improve biodiversity outcomes, carbon emission reductions and improved recreational values. Of the activities that could be undertaken to provide the services, feral animal control attracted the highest level of support followed by coastal surveillance, weed control and fire management. Respondents' decisions to pay were not greatly influenced by the additional social benefits that can arise for Indigenous people spending time on country and providing the services, although there was approval for reduced welfare payments that might arise. PMID- 21826232 TI - Exposure to moderate air pollution during late pregnancy and cord blood cytokine secretion in healthy neonates. AB - BACKGROUND/OBJECTIVES: Ambient air pollution can alter cytokine concentrations as shown in vitro and following short-term exposure to high air pollution levels in vivo. Exposure to pollution during late pregnancy has been shown to affect fetal lymphocytic immunophenotypes. However, effects of prenatal exposure to moderate levels of air pollutants on cytokine regulation in cord blood of healthy infants are unknown. METHODS: In a birth cohort of 265 healthy term-born neonates, we assessed maternal exposure to particles with an aerodynamic diameter of 10 um or less (PM10), as well as to indoor air pollution during the last trimester, specifically the last 21, 14, 7, 3 and 1 days of pregnancy. As a proxy for traffic-related air pollution, we determined the distance of mothers' homes to major roads. We measured cytokine and chemokine levels (MCP-1, IL-6, IL-10, IL 1beta, TNF-alpha and GM-CSF) in cord blood serum using LUMINEX technology. Their association with pollution levels was assessed using regression analysis, adjusted for possible confounders. RESULTS: Mean (95%-CI) PM10 exposure for the last 7 days of pregnancy was 18.3 (10.3-38.4 ug/m3). PM10 exposure during the last 3 days of pregnancy was significantly associated with reduced IL-10 and during the last 3 months of pregnancy with increased IL-1beta levels in cord blood after adjustment for relevant confounders. Maternal smoking was associated with reduced IL-6 levels. For the other cytokines no association was found. CONCLUSIONS: Our results suggest that even naturally occurring prenatal exposure to moderate amounts of indoor and outdoor air pollution may lead to changes in cord blood cytokine levels in a population based cohort. PMID- 21826235 TI - Checkpoints in adenoviral production: cross-contamination and E1A. AB - Adenoviruses are widely used for overexpressing proteins in primary mammalian cells. Incorporation of the early viral gene, E1A, or viral cross-contamination can occur during amplification, and identification of these products is crucial as the transcription of unwanted genetic material can impact cell function and compromise data interpretation. Here we report methods for evaluation of contaminating adenovirus and E1 viral DNA. PMID- 21826236 TI - Warm water and cool nests are best. How global warming might influence hatchling green turtle swimming performance. AB - For sea turtles nesting on beaches surrounded by coral reefs, the most important element of hatchling recruitment is escaping predation by fish as they swim across the fringing reef, and as a consequence hatchlings that minimize their exposure to fish predation by minimizing the time spent crossing the fringing reef have a greater chance of surviving the reef crossing. One way to decrease the time required to cross the fringing reef is to maximize swimming speed. We found that both water temperature and nest temperature influence swimming performance of hatchling green turtles, but in opposite directions. Warm water increases swimming ability, with hatchling turtles swimming in warm water having a faster stroke rate, while an increase in nest temperature decreases swimming ability with hatchlings from warm nests producing less thrust per stroke. PMID- 21826237 TI - Quantifying the impact of deprivation on preterm births: a retrospective cohort study. AB - BACKGROUND: Social deprivation is associated with higher rates of preterm birth and subsequent infant mortality. Our objective was to identify risk factors for preterm birth in the UK's largest maternity unit, with a particular focus on social deprivation, and related factors. METHODOLOGY/PRINCIPAL FINDINGS: Retrospective cohort study of 39,873 women in Liverpool, UK, from 2002-2008. Singleton pregnancies were stratified into uncomplicated low risk pregnancies and a high risk group complicated by medical problems. Multiple logistic regression, and generalized additive models were used to explore the effect of covariates including area deprivation, smoking status, BMI, parity and ethnicity on the risk of preterm birth (34+0 weeks). In the low risk group, preterm birth rates increased with deprivation, reaching 1.6% (CI95 1.4 to 1.8) in the most deprived quintile; the unadjusted odds ratio comparing an individual in the most deprived quintile, to one in the least deprived quintile was 1.5 (CI95 1.2 to 1.9). Being underweight and smoking were both independently associated with preterm birth in the low risk group, and adjusting for these factors explained the association between deprivation and preterm birth. Preterm birth was five times more likely in the high risk group (RR 4.8 CI95 4.3 to 5.4), and there was no significant relationship with deprivation. CONCLUSIONS: Deprivation has significant impact on preterm birth rates in low risk women. The relationship between low socio economic status and preterm births appears to be related to low maternal weight and smoking in more deprived groups. PMID- 21826238 TI - Persistence of Escherichia coli O157:H7 and its mutants in soils. AB - The persistence of Shiga toxin-producing E. coli O157:H7 in the environment poses a serious threat to public health. However, the role of Shiga toxins and other virulence factors in the survival of E. coli O157:H7 is poorly defined. The aim of this study was to determine if the virulence factors, stx1, stx2, stx1-2, and eae in E. coli O157:H7 EDL933 play any significant role in the growth of this pathogen in rich media and in soils. Isogenic deletion mutants that were missing one of four virulence factors, stx1, stx2, stx1-2, and eae in E. coli O157:H7 EDL933 were constructed, and their growth in rich media and survival in soils with distinct texture and chemistry were characterized. The survival data were successfully analyzed using Double Weibull model, and the modeling parameters of the mutant strains were not significantly different from those of the wild type. The calculated T(d) (time needed to reach the detection limit, 100 CFU/g soil) for loamy sand, sandy loam, and silty clay was 32, 80, and 110 days, respectively. It was also found that T(d) was positively correlated with soil structure (e.g. clay content), and soil chemistry (e.g. total nitrogen, total carbon, and water extractable organic carbon). The results of this study showed that the possession of Shiga toxins and intimin in E. coli O157:H7 might not play any important role in its survival in soils. The double deletion mutant of E. coli O157:H7 (stx1-stx2-) may be a good substitute to use for the investigation of transport, fate, and survival of E. coli O157:H7 in the environment where the use of pathogenic strains are prohibited by law since the mutants showed the same characteristics in both culture media and environmental samples. PMID- 21826239 TI - Modulation of glucose transporter 1 (GLUT1) expression levels alters mouse mammary tumor cell growth in vitro and in vivo. AB - Tumor cells exhibit an altered metabolism characterized by elevated aerobic glycolysis and lactate secretion which is supported by an increase in glucose transport and consumption. We hypothesized that reducing or eliminating the expression of the most prominently expressed glucose transporter(s) would decrease the amount of glucose available to breast cancer cells thereby decreasing their metabolic capacity and proliferative potential.Of the 12 GLUT family glucose transporters expressed in mice, GLUT1 was the most abundantly expressed at the RNA level in the mouse mammary tumors from MMTV-c-ErbB2 mice and cell lines examined. Reducing GLUT1 expression in mouse mammary tumor cell lines using shRNA or Cre/Lox technology reduced glucose transport, glucose consumption, lactate secretion and lipid synthesis in vitro without altering the concentration of ATP, as well as reduced growth on plastic and in soft agar. The growth of tumor cells with reduced GLUT1 expression was impaired when transplanted into the mammary fat pad of athymic nude mice in vivo. Overexpression of GLUT1 in a cell line with low levels of endogenous GLUT1 increased glucose transport in vitro and enhanced growth in nude mice in vivo as compared to the control cells with very low levels of GLUT1.These studies demonstrate that GLUT1 is the major glucose transporter in mouse mammary carcinoma models overexpressing ErbB2 or PyVMT and that modulation of the level of GLUT1 has an effect upon the growth of mouse mammary tumor cell lines in vivo. PMID- 21826240 TI - Sexual phenotype differences in zic2 mRNA abundance in the preoptic area of a protogynous teleost, Thalassoma bifasciatum. AB - The highly conserved members of the zic family of zinc-finger transcription factors are primarily known for their roles in embryonic signaling pathways and regulation of cellular proliferation and differentiation. This study describes sexual phenotype differences in abundances of zic2 mRNA in the preoptic area of the hypothalamus, a region strongly implicated in sexual behavior and function, in an adult teleost, Thalassoma bifasciatum. The bluehead wrasse (Thalassoma bifasciatum) is a valuable model for studying neuroendocrine processes because it displays two discrete male phenotypes, initial phase (IP) males and territorial, terminal phase (TP) males, and undergoes socially-controlled protogynous sex change. Previously generated microarray-based comparisons suggested that zic2 was upregulated in the brains of terminal phase males relative to initial phase males. To further explore this difference, we cloned a 727 bp sequence for neural zic2 from field-collected animals. Riboprobe-based in situ hybridization was employed to localize zic2 signal in adult bluehead brains and assess the relative abundance of brain zic2 mRNA across sexual phenotypes. We found zic2 mRNA expression was extremely abundant in the granular cells of the cerebellum and widespread in other brain regions including in the thalamus, hypothalamus, habenula, torus semicircularis, torus longitudinalis, medial longitudinal fascicle and telencephalic areas. Quantitative autoradiography and phosphorimaging showed zic2 mRNA hybridization signal in the preoptic area of the hypothalamus was significantly higher in terminal phase males relative to both initial phase males and females, and silver grain analysis confirmed this relationship between phenotypes. No significant difference in abundance was found in zic2 signal across phenotypes in the habenula, a brain region not implicated in the control of sexual behavior, or cerebellum. PMID- 21826241 TI - Is CFTR-delF508 really absent from the apical membrane of the airway epithelium? AB - BACKGROUND: Understanding where mutant CFTR is localised in airway epithelia is essential in guiding the best therapeutic approach to correct the dysfunction of the CFTR protein. The widely held paradigm is that CF patients harbouring the commonest mutation, CFTR-delF508, trap CFTR within the endoplasmic reticulum and target it for degradation. However there are conflicting reports concerning expression and localisation of CFTR-delF508 in lung tissue. To attempt to resolve this fundamental issue we developed a novel approach to measure CFTR-delF508 in the lower airways of patients who have undergone lung transplantation for advanced CF. By sampling CF and non-CF epithelium simultaneously from the same individual, confounding factors of different airway microenvironments which may have influenced previous observations can be overcome. METHODS: Epithelia sampled by bronchial brushing above (CF) and below (non-CF) the bronchial anastomosis were stained for CFTR and the localisation and level of expression assessed (n = 12). RESULTS: There was no significant difference in the proportion of tall columnar cells showing CFTR immunostaining as a discrete band at the apical membrane in cells harbouring the CFTR-delF508 mutation compared to non-CF cells (p = 0.21, n = 12). However, the amount of CFTR expressed at the apical surface was reduced by ~50% in CF cells compared to non-CF cells (p = 0.04, n = 5). CONCLUSIONS: Our novel observation challenges the prevailing paradigm that CFTR is essentially absent from the apical membrane of respiratory cells harbouring the CFTR-delF508 mutation. Moreover, it raises the possibility that the new generation of CFTR potentiators may offer a realistic therapeutic option for CF patients. PMID- 21826242 TI - Evidence for a two-metal-ion mechanism in the cytidyltransferase KdsB, an enzyme involved in lipopolysaccharide biosynthesis. AB - Lipopolysaccharide (LPS) is located on the surface of Gram-negative bacteria and is responsible for maintaining outer membrane stability, which is a prerequisite for cell survival. Furthermore, it represents an important barrier against hostile environmental factors such as antimicrobial peptides and the complement cascade during Gram-negative infections. The sugar 3-deoxy-D-manno-oct-2-ulosonic acid (Kdo) is an integral part of LPS and plays a key role in LPS functionality. Prior to its incorporation into the LPS molecule, Kdo has to be activated by the CMP-Kdo synthetase (CKS). Based on the presence of a single Mg2+ ion in the active site, detailed models of the reaction mechanism of CKS have been developed previously. Recently, a two-metal-ion hypothesis suggested the involvement of two Mg2+ ions in Kdo activation. To further investigate the mechanistic aspects of Kdo activation, we kinetically characterized the CKS from the hyperthermophilic organism Aquifex aeolicus. In addition, we determined the crystal structure of this enzyme at a resolution of 2.10 A and provide evidence that two Mg2+ ions are part of the active site of the enzyme. PMID- 21826243 TI - Stability of yellow fever virus under recombinatory pressure as compared with chikungunya virus. AB - Recombination is a mechanism whereby positive sense single stranded RNA viruses exchange segments of genetic information. Recent phylogenetic analyses of naturally occurring recombinant flaviviruses have raised concerns regarding the potential for the emergence of virulent recombinants either post-vaccination or following co-infection with two distinct wild-type viruses. To characterize the conditions and sequences that favor RNA arthropod-borne virus recombination we constructed yellow fever virus (YFV) 17D recombinant crosses containing complementary deletions in the envelope protein coding sequence. These constructs were designed to strongly favor recombination, and the detection conditions were optimized to achieve high sensitivity recovery of putative recombinants. Full length recombinant YFV 17D virus was never detected under any of the experimental conditions examined, despite achieving estimated YFV replicon co-infection levels of ~2.4 x 106 in BHK-21 (vertebrate) cells and ~1.05 x 105 in C710 (arthropod) cells. Additionally YFV 17D superinfection resistance was observed in vertebrate and arthropod cells harboring a primary infection with wild-type YFV Asibi strain. Furthermore recombination potential was also evaluated using similarly designed chikungunya virus (CHIKV) replicons towards validation of this strategy for recombination detection. Non-homologus recombination was observed for CHIKV within the structural gene coding sequence resulting in an in-frame duplication of capsid and E3 gene. Based on these data, it is concluded that even in the unlikely event of a high level acute co-infection of two distinct YFV genomes in an arthropod or vertebrate host, the generation of viable flavivirus recombinants is extremely unlikely. PMID- 21826244 TI - TRAPPC4-ERK2 interaction activates ERK1/2, modulates its nuclear localization and regulates proliferation and apoptosis of colorectal cancer cells. AB - The trafficking protein particle complex 4 (TRAPPC4) is implicated in vesicle mediated transport, but its association with disease has rarely been reported. We explored its potential interaction with ERK2, part of the ERK1/2 complex in the Extracellular Signal-regulated Kinase/ Mitogen-activated Protein Kinase (ERK MAPK) pathway, by a yeast two-hybrid screen and confirmed by co immunoprecipitation (Co-IP) and glutathione S-transferase (GST) pull-down. Further investigation found that when TRAPPC4 was depleted, activated ERK1/2 specifically decreased in the nucleus, which was accompanied with cell growth suppression and apoptosis in colorectal cancer (CRC) cells. Overexpression of TRAPPC4 promoted cell viability and caused activated ERK1/2 to increase overall, but especially in the nucleus. TRAPPC4 was expressed more highly in the nucleus of CRC cells than in normal colonic epithelium or adenoma which corresponded with nuclear staining of pERK1/2. We demonstrate here that TRAPPC4 may regulate cell proliferation and apoptosis in CRC by interaction with ERK2 and subsequently phosphorylating ERK1/2 as well as modulating the subcellular location of pERK1/2 to activate the relevant signaling pathway. PMID- 21826245 TI - Low frequency vibrations disrupt left-right patterning in the Xenopus embryo. AB - The development of consistent left-right (LR) asymmetry across phyla is a fascinating question in biology. While many pharmacological and molecular approaches have been used to explore molecular mechanisms, it has proven difficult to exert precise temporal control over functional perturbations. Here, we took advantage of acoustical vibration to disrupt LR patterning in Xenopus embryos during tightly-circumscribed periods of development. Exposure to several low frequencies induced specific randomization of three internal organs (heterotaxia). Investigating one frequency (7 Hz), we found two discrete periods of sensitivity to vibration; during the first period, vibration affected the same LR pathway as nocodazole, while during the second period, vibration affected the integrity of the epithelial barrier; both are required for normal LR patterning. Our results indicate that low frequency vibrations disrupt two steps in the early LR pathway: the orientation of the LR axis with the other two axes, and the amplification/restriction of downstream LR signals to asymmetric organs. PMID- 21826246 TI - Differences in the properties and mirna expression profiles between side populations from hepatic cancer cells and normal liver cells. AB - AIMS: Because hepatic cancer stem cells (HCSCs) are believed to derive from the conversion of hepatic normal stem cells (HNSCs), the identification of the differences that distinguish HCSCs from HNSCs is important. METHODS: The HCC model was established in F344 rats by DEN induction. Using FACS analysis, side population cells from HCC (SP-HCCs) were isolated from the epithelial-like cells of HCC tissues, and the side population cells from normal liver (SP-NLCs) were isolated from syngeneic normal liver cells. The expression of stem cell markers was detected in both freshly isolated and amplified subpopulations. After induction with HGF, the differentiation of each subpopulation was analyzed by detection of early and late liver markers. In vivo, the biological characteristics of SP-HCCs and SP-NLCs were analyzed by repairing injured livers or forming tumors in nude mice. In addition, the expression of miRNAs was examined in both populations by miRNA array and QRT-PCR. RESULTS: SP-NLCs and SP HCCs were 4.30+/-0.011% and 2.100+/-0.010% of the whole population, respectively. Both SP-NLCs and SP-HCCs displayed greater expression of stem cell markers (CD133 and EpCAM) than NSP-NLCs and NSP-HCCs, respectively (P<0.01), both after fresh isolation and amplification. Upon HGF induction, SP-NLCs generated many ALB positive cells and few CK-7 positive cells, but NSP-NLCs could generate only ALB positive cells. In contrast, SP-HCCs gave rise to only AFP positive cells. As few as 5 * 105 SP-NLCs were capable of repairing liver injury, while the same number of NSP-NLCs could not repair the liver. Furthermore, only 1 * 104 SP-HCCs were necessary to initiate a tumor, while NSP-HCCs could not form a tumor. Compared to SP-NLCs, 68 up-regulated and 10 down-regulated miRNAs were present in SP-HCCs (P<0.01). CONCLUSION: Based on the decisive roles of some miRNAs in the genesis of HCSCs, miRNAs may contribute to the different characteristics that distinguish SP-HCCs from SP-NLCs. PMID- 21826247 TI - My hand or yours? Markedly different sensitivity to egocentric and allocentric views in the hand laterality task. AB - In the hand laterality task participants judge the handedness of visually presented stimuli--images of hands shown in a variety of postures and views--and indicate whether they perceive a right or left hand. The task engages kinaesthetic and sensorimotor processes and is considered a standard example of motor imagery. However, in this study we find that while motor imagery holds across egocentric views of the stimuli (where the hands are likely to be one's own), it does not appear to hold across allocentric views (where the hands are likely to be another person's). First, we find that psychophysical sensitivity, d', is clearly demarcated between egocentric and allocentric views, being high for the former and low for the latter. Secondly, using mixed effects methods to analyse the chronometric data, we find high positive correlation between response times across egocentric views, suggesting a common use of motor imagery across these views. Correlations are, however, considerably lower between egocentric and allocentric views, suggesting a switch from motor imagery across these perspectives. We relate these findings to research showing that the extrastriate body area discriminates egocentric ('self') and allocentric ('other') views of the human body and of body parts, including hands. PMID- 21826248 TI - Recombinant VP1, an Akt inhibitor, suppresses progression of hepatocellular carcinoma by inducing apoptosis and modulation of CCL2 production. AB - BACKGROUND: The application of viral elements in tumor therapy is one facet of cancer research. Recombinant capsid protein VP1 (rVP1) of foot-and-mouth disease virus has previously been demonstrated to induce apoptosis in cancer cell lines. Here, we aim to further investigate its apoptotic mechanism and possible anti metastatic effect in murine models of hepatocellular carcinoma (HCC), one of the most common human cancers worldwide. METHODOLOGY/PRINCIPAL FINDINGS: Treatment with rVP1 inhibited cell proliferation in two murine HCC cell lines, BNL and Hepa1-6, with IC50 values in the range of 0.1-0.2 uM. rVP1 also induced apoptosis in these cells, which was mediated by Akt deactivation and dissociation of Ku70 Bax, and resulted in conformational changes and mitochondrial translocation of Bax, leading to the activation of caspases-9, -3 and -7. Treatment with 0.025 uM rVP1, which did not affect the viability of normal hepatocytes, suppressed cell migration and invasion via attenuating CCL2 production. The production of CCL2 was modulated by Akt-dependent NF-kappaB activation that was decreased after rVP1 treatment. The in vivo antitumor effects of rVP1 were assessed in both subcutaneous and orthotopic mouse models of HCC in immune-competent BALB/c mice. Intratumoral delivery of rVP1 inhibited subcutaneous tumor growth as a result of increased apoptosis. Intravenous administration of rVP1 in an orthotopic HCC model suppressed tumor growth, inhibited intra-hepatic metastasis, and prolonged survival. Furthermore, a decrease in the serum level of CCL2 was observed in rVP1 treated mice. CONCLUSIONS/SIGNIFICANCE: The data presented herein suggest that, via inhibiting Akt phosphorylation, rVP1 suppresses the growth, migration, and invasion of murine HCC cells by inducing apoptosis and attenuating CCL2 production both in vitro and in vivo. Recombinant protein VP1 thus has the potential to be developed as a new therapeutic agent for HCC. PMID- 21826249 TI - A novel single-dose dengue subunit vaccine induces memory immune responses. AB - To protect against dengue viral infection, a novel lipidated dengue subunit vaccine was rationally designed to contain the consensus amino acid sequences derived from four serotypes of dengue viruses. We found that the lipidated consensus dengue virus envelope protein domain III (LcED III) is capable of activating antigen-presenting cells and enhancing cellular and humoral immune responses. A single-dose of LcED III immunization in mice without extra adjuvant formulation is sufficient to elicit neutralizing antibodies against all four serotypes of dengue viruses. In addition, strong memory responses were elicited in mice immunized with a single-dose of LcED III. Quick, anamnestic neutralizing antibody responses to a live dengue virus challenge were elicited at week 28 post immunization. These results demonstrate the promising possibility of a future successful tetravalent vaccine against dengue viral infections that utilizes one dose vaccination with LcED III. PMID- 21826250 TI - Growth dynamics of Australia's polar dinosaurs. AB - Analysis of bone microstructure in ornithopod and theropod dinosaurs from Victoria, Australia, documents ontogenetic changes, providing insight into the dinosaurs' successful habitation of Cretaceous Antarctic environments. Woven fibered bone tissue in the smallest specimens indicates rapid growth rates during early ontogeny. Later ontogeny is marked by parallel-fibered tissue, suggesting reduced growth rates approaching skeletal maturity. Bone microstructure similarities between the ornithopods and theropods, including the presence of LAGs in each group, suggest there is no osteohistologic evidence supporting the hypothesis that polar theropods hibernated seasonally. Results instead suggest high-latitude dinosaurs had growth trajectories similar to their lower-latitude relatives and thus, rapid early ontogenetic growth and the cyclical suspensions of growth inherent in the theropod and ornithopod lineages enabled them to successfully exploit polar regions. PMID- 21826251 TI - Holoclone forming cells from pancreatic cancer cells enrich tumor initiating cells and represent a novel model for study of cancer stem cells. AB - BACKGROUND: Pancreatic cancer is one of the direct causes of cancer-related death. High level of chemoresistance is one of the major obstacles of clinical treatment. In recent years, cancer stem cells have been widely identified and indicated as the origin of chemoresistance in multi-types of solid tumors. Increasing evidences suggest that cancer stem cells reside in the cells capable of forming holoclones continuously. However, in pancreatic cancer, holoclone forming cells have not been characterized yet. Therefore, the goal of our present study was to indentify the holoclone-forming pancreatic cancer stem cells and develop an in vitro continuous colony formation system, which will greatly facilitate the study of pancreatic cancer stem cells. METHODOLOGY/PRINCIPAL FINDINGS: Pancreatic cancer cell line BxPC3 was submitted to monoclonal cultivation to generate colonies. Based on the morphologies, colonies were classified and analyzed for their capacities of secondary colony formation, long term survival in vitro, tumor formation in vivo, and drug resistance. Flowcytometry and quantitative RT-PCR were performed to detect the expression level of cancer stem cells associated cell surface markers, regulatory genes and microRNAs in distinct types of colonies. Three types of colonies with distinct morphologies were identified and termed as holo-, mero-, and paraclones, in which only holoclones generated descendant colonies of all three types in further passages. Compared to mero- and paraclones, holoclones possessed higher capacities of long-term survival, tumor initiation, and chemoresistance. The preferential expression of cancer stem cells related marker (CXCR4), regulatory genes (BMI1, GLI1, and GLI2) and microRNAs (miR-214, miR-21, miR-221, miR-222 and miR-155) in holoclones were also highlighted. CONCLUSIONS/SIGNIFICANCE: Our results indicate that the pancreatic tumor-initiating cells with high level of chemoresistance were enriched in holoclones derived from BxPC3 cell line. Generation of holoclones can serve as a novel model for studying cancer stem cells, and attribute to developing new anti-cancer drugs. PMID- 21826253 TI - The Use of 3,5,4'-Tri-O-acetylresveratrol as a Potential Pro-drug for Resveratrol Protects Mice from gamma-Irradiation-Induced Death. AB - Currently, no drugs are available to protect humans from gamma-irradiation induced death. Because reactive oxygen species are produced upon exposure to gamma-irradiation and directly responsible for the resulting death, we hypothesized that antioxidants found in foodstuffs may provide a safe and potent means of antioxidant-dependent radioprotection. Here, we describe our studies investigating the radioprotective properties of resveratrol and 3,5,4'-tri-O acetylresveratrol. Each of these natural antioxidants was found to protect live cells after gamma-irradiation. In mice, the use of 3,5,4'-tri-O-acetylresveratrol with Cremophor EL was particularly effective, indicating that this natural antioxidant may be a leading candidate for radioprotective drug development. PMID- 21826252 TI - Biospecimen Reporting for Improved Study Quality. AB - Human biospecimens are subject to a number of different collection, processing, and storage factors that can significantly alter their molecular composition and consistency. These biospecimen preanalytical factors, in turn, influence experimental outcomes and the ability to reproduce scientific results. Currently, the extent and type of information specific to the biospecimen preanalytical conditions reported in scientific publications and regulatory submissions varies widely. To improve the quality of research utilizing human tissues, it is critical that information regarding the handling of biospecimens be reported in a thorough, accurate, and standardized manner. The Biospecimen Reporting for Improved Study Quality recommendations outlined herein are intended to apply to any study in which human biospecimens are used. The purpose of reporting these details is to supply others, from researchers to regulators, with more consistent and standardized information to better evaluate, interpret, compare, and reproduce the experimental results. The Biospecimen Reporting for Improved Study Quality guidelines are proposed as an important and timely resource tool to strengthen communication and publications around biospecimen-related research and help reassure patient contributors and the advocacy community that the contributions are valued and respected. PMID- 21826254 TI - Visual discomfort with stereo displays: Effects of viewing distance and direction of vergence-accommodation conflict. AB - Prolonged use of conventional stereo displays causes viewer discomfort and fatigue because of the vergence-accommodation conflict. We used a novel volumetric display to examine how viewing distance and the sign of the vergence accommodation conflict affect discomfort and fatigue. In the first experiment, we presented a fixed conflict at short, medium, and long viewing distances. We compared subjects' symptoms in that condition and one in which there was no conflict. We observed more discomfort and fatigue with a given vergence accommodation conflict at the longer distances. The second experiment compared symptoms when the conflict had one sign compared to when it had the opposite sign at short, medium, and long distances. We observed greater symptoms with uncrossed disparities at long distances and with crossed disparities at short distances. These findings help define comfortable viewing conditions for stereo displays. PMID- 21826255 TI - Predictors of fracture risk and bone mineral density in men with prostate cancer on androgen deprivation therapy. AB - Decrease of bone mineral density (BMD) and fracture risk is increased in men with prostate cancer receiving androgen deprivation therapy (ADT). We looked at possible predictors of decreased BMD and increased fracture risk in men with prostate cancer; most of whom were on ADT. In a retrospective study, we analyzed serum, BMD, and clinical risk factors used in the Fracture Risk Assessment (FRAX) tool and others in 78 men with prostate cancer with reported height loss. The subjects were divided in two groups: 22 men with and 56 without vertebral fractures. 17 of the 22 men with vertebral fractures on spine X-rays did not know they had a vertebral fracture. Of those 17 men, 9 had not previously qualified for treatment based on preradiograph FRAX score calculated with BMD, and 6 based on FRAX calculated without BMD. Performing spine films increased the predictive ability of FRAX for vertebral fracture. Vertebral fracture was better predicted by FRAX for other osteoporotic fractures than FRAX for hip fractures. The inclusion of BMD in FRAX calculations did not affect the predictive ability of FRAX. The PSA level showed a positive correlation with lumbar spine BMD and accounted for about 9% of spine BMD. PMID- 21826256 TI - Targeted treatment of differentiated and medullary thyroid cancer. AB - The incidence of thyroid cancer is increasing, with a concomitant increase in the number of patients with advanced and metastatic disease. Discoveries regarding the pathogenesis of thyroid cancer have led to the recent development of new therapeutic agents that are beginning to appear on the market. Many of these new agents are targeted kinase inhibitors primarily affecting oncogenic kinases (BRAF V600E, RET/PTC) or signaling kinases (VEGFR, PDGFR). Some of these agents report significant partial response rates, while others attain stabilization of disease as their best response. Their impact on survival is unclear. While these agents target similar pathways, a wide variety of differences exist regarding efficacy and side effect profile. Current expert opinion advises that these agents be used only in a specific subset of patients. PMID- 21826257 TI - Contribution of Alanine-76 and Serine Phosphorylation in alpha-Synuclein Membrane Association and Aggregation in Yeasts. AB - In Parkinson's disease (PD), misfolded and aggregated alpha-synuclein protein accumulates in degenerating midbrain dopaminergic neurons. The amino acid alanine 76 in alpha-synuclein and phosphorylation at serine-87 and serine-129 are thought to regulate its aggregation and toxicity. However, their exact contributions to alpha-synuclein membrane association are less clear. We found that alpha synuclein is indeed phosphorylated in fission yeast and budding yeast, the two models that we employed for assessing alpha-synuclein aggregation and membrane association properties, respectively. Surprisingly, blocking serine phosphorylation (S87A, S129A, and S87A/S129A) or mimicking it (S87D, S129D) altered alpha-synuclein aggregation in fission yeast. Either blocking or mimicking this phosphorylation increased endomembrane association in fission yeast, but only mimicking it decreased plasma membrane association in budding yeast. Polar substitution mutations of alanine-76 (A76E and A76R) decreased alpha synuclein membrane association in budding yeast and decreased aggregation in fission yeast. These yeast studies extend our understanding of serine phosphorylation and alanine-76 contributions to alpha-synuclein aggregation and are the first to detail their impact on alpha-synuclein's plasma membrane and endomembrane association. PMID- 21826259 TI - MicroRNAs and Alzheimer's Disease Mouse Models: Current Insights and Future Research Avenues. AB - Evidence from clinical trials as well as from studies performed in animal models suggest that both amyloid and tau pathologies function in concert with other factors to cause the severe neurodegeneration and dementia in Alzheimer's disease (AD) patients. Accumulating data in the literature suggest that microRNAs (miRNAs) could be such factors. These conserved, small nonprotein-coding RNAs are essential for neuronal function and survival and have been implicated in the regulation of key genes involved in genetic and sporadic AD. The study of miRNA changes in AD mouse models provides an appealing approach to address the cause consequence relationship between miRNA dysfunction and AD pathology in humans. Mouse models also provide attractive tools to validate miRNA targets in vivo and provide unique platforms to study the role of specific miRNA-dependent gene pathways in disease. Finally, mouse models may be exploited for miRNA diagnostics in the fight against AD. PMID- 21826260 TI - Hypertension, periodontal disease, and potassium intake in nonsmoking, nondrinker african women on no medication. AB - The purpose of this cross-sectional study was to investigate the association of periodontitis and/or tooth loss with hypertension by excluding the common confounders. Eighty-one Tanzanian women who were aged 46-58 years, nonsmokers, nonalcoholic drinkers, and on no medication underwent clinical examination. Multiple-regression analysis showed that the severity of periodontitis was significantly correlated with increased systolic blood pressure and diastolic blood pressure. Simple-regression analysis indicated that the severity of periodontitis was inversely correlated with 24-hour urinary excretion of potassium (r = -0.579, P = 0.0004) and also inversely with the frequency of intakes of green vegetables (r = -0.232, P = 0.031) and fruits (r = -0.217, P = 0.0043). Low-potassium intake in the diet mostly accompanied by low dietary fiber intake increases BP as well as periodontal inflammation. Potassium intake may be an important factor linking periodontitis and hypertension in middle-aged nonsmoking and nonalcoholic women on no medication, although chronic inflammation such as periodontitis may cause hypertension through a more direct mechanism. PMID- 21826258 TI - Animal models of calcific aortic valve disease. AB - Calcific aortic valve disease (CAVD), once thought to be a degenerative disease, is now recognized to be an active pathobiological process, with chronic inflammation emerging as a predominant, and possibly driving, factor. However, many details of the pathobiological mechanisms of CAVD remain to be described, and new approaches to treat CAVD need to be identified. Animal models are emerging as vital tools to this end, facilitated by the advent of new models and improved understanding of the utility of existing models. In this paper, we summarize and critically appraise current small and large animal models of CAVD, discuss the utility of animal models for priority CAVD research areas, and provide recommendations for future animal model studies of CAVD. PMID- 21826261 TI - Computational simulations to predict creatine kinase-associated factors: protein protein interaction studies of brain and muscle types of creatine kinases. AB - Creatine kinase (CK; EC 2.7.3.2) is related to several skin diseases such as psoriasis and dermatomyositis. CK is important in skin energy homeostasis because it catalyzes the reversible transfer of a phosphoryl group from MgATP to creatine. In this study, we predicted CK binding proteins via the use of bioinformatic tools such as protein-protein interaction (PPI) mappings and suggest the putative hub proteins for CK interactions. We obtained 123 proteins for brain type CK and 85 proteins for muscle type CK in the interaction networks. Among them, several hub proteins such as NFKB1, FHL2, MYOC, and ASB9 were predicted. Determination of the binding factors of CK can further promote our understanding of the roles of CK in physiological conditions. PMID- 21826262 TI - Matrix metalloproteinase-3 in myasthenia gravis compared to other neurological disorders and healthy controls. AB - MMP-3 is capable of degrading a variety of proteins, including agrin, which plays a critical role in neuromuscular signaling by controlling acetylcholine receptor clustering. High MMP-3 levels in a proportion of myasthenia gravis (MG) patients have been reported. A pathogenic role of MMP-3 in other neurological disorders has been suggested but not proven. We have therefore examined the levels of MMP-3 in 124 MG patients and compared them to 59 multiple sclerosis (MS) patients, 74 epilepsy patients, 33 acute stroke patients, and 90 healthy controls. 15.3% of the patients in the MG group were MMP-3-positive (defined as higher than cutoff value 48 ng/mL) with very high mean MMP-3 concentration (79.9 ng/mL), whereas the proportion of MMP-3 positive patients in the MS (3.4%), epilepsy (6.7%), stroke (0%), and the control group (4.4%) was significantly lower. Mean MMP-3 concentration in the total MG group (25.5 ng/mL) was significantly higher than in the MS (16.6 ng/mL) and stroke (11.7 ng/mL) groups, but did not differ significantly from the epilepsy (19.4 ng/mL) and the control group (23.4 ng/mL). MMP-3 may have a specific pathogenic effect in MG in addition to being associated with autoimmune diseases in general. PMID- 21826263 TI - Iron-Fortified Drinking Water Studies for the Prevention of Children's Anemia in Developing Countries. AB - Anemia and iron deficiency should receive special attention considering their high prevalence and serious consequences. For prevention, globally it is recommended to increase dietary iron intake, iron fortification of industrialized foods, and medical iron supplementation. Food fortification for the prevention of iron deficiency in developing countries should consider carriers locally available and consumed daily, requiring limited infrastructure and technology. Drinking water is the iron carrier we have been working for years for the prevention of iron deficiency and anemia in small children in Brazil. It was shown that studies with iron-fortified drinking water were proved to be effective on children's anemia prevention. Water is found everywhere, consumed daily by everyone may be easily fortified with simple technology, is low priced and was effective on the prevention of children's anemia. Fortification of drinking water with iron was locally implemented with the direct participation of the government and community. Government authorities, health personnel and population were part of the project and responsible for its community implementation. The mayor/municipality permitted and supported the proposal to supply it to children at their day-care centers. To keep the children drinking water iron fortified supply an officially authorized legislation was also approved. PMID- 21826265 TI - Relationship between Depressive Symptoms and Cardiovascular Disease Risk Factors in African American Individuals. AB - Objective. To examine the relationship between depressive symptoms and cardiovascular disease (CVD) risk factors in a group of African American individuals. Design. A nonrandom sample of 253 (age 43.7 +/- 11.6 years; 37% male) African American individuals was recruited by advertisements. Data were obtained by validated questionnaires, anthropometric, blood pressure, and blood sample measurements. Results. Regression analyses were performed to assess the relationship between depressive symptoms and CVD risk factors controlling for socioeconomic status indicators. These analyses demonstrated that those with higher levels of depressive symptoms had larger waist-to-hip ratios, higher percent body fat, higher triglycerides, and were more likely to be smokers. Conclusions. It has been well documented that higher levels of depressive symptoms are associated with higher CVD risk. However, this evidence is derived primarily from samples of predominantly Caucasian individuals. The present investigation demonstrates that depressive symptoms are related to CVD risk factors in African American individuals. PMID- 21826264 TI - Paliperidone ER in the Treatment of Borderline Personality Disorder: A Pilot Study of Efficacy and Tolerability. AB - Antipsychotics are recommended for the treatment of impulsive dyscontrol and cognitive perceptual symptoms of borderline personality disorder (BPD). Three reports supported the efficacy of oral risperidone on BPD psychopathology. Paliperidone ER is the metabolite of risperidone with a similar mechanism of action, and its osmotic release reduces plasmatic fluctuations and antidopaminergic effects. The aim of this study is to evaluate efficacy and safety of paliperidone ER in BPD patients. 18 outpatients with a DSM-IV-TR diagnosis of BPD were treated for 12 weeks with paliperidone ER (3-6 mg/day). They were assessed at baseline, week 4, and week 12, using the CGI-Severity item, the BPRS, the HDRS, the HARS, the SOFAS, the BPD Severity Index (BPDSI), and the Barratt Impulsiveness Scale (BIS-11). Adverse events were evaluated with the DOTES. Paliperidone ER was shown to be effective and well tolerated in reducing severity of global symptomatology and specific BPD symptoms, such as impulsive dyscontrol, anger, and cognitive-perceptual disturbances. Results need to be replicated in controlled trials. PMID- 21826266 TI - Exposure to community violence, psychopathology, and personality traits in Russian youth. AB - Previous research with the US inner-city youth demonstrated the hazardous effects of community violence exposure. It remains unclear, however, whether these findings are generalizable to other cultures and populations. Furthermore, the role of factors influencing the processing of traumatic events such as personality has not been investigated. Two groups of Russian adolescents (community youth (N = 546) and male delinquents (N = 352)) completed questionnaires assessing their exposure to community violence, conduct problems, internalizing psychopathology and personality. The study demonstrates that the relationships between exposure to violence and psychopathology are similar across different populations within the same culture (community youth and juvenile delinquents), suggesting similar mechanisms behind this phenomenon. The patterns of these relationships were also similar for boys and girls, suggesting similarities in the mechanisms across gender. Hence, the effects of community violence exposure are generalizable to other cultures outside the US. The associations between personality traits and specific types of behaviors also tend to be similar across different populations. Higher levels of novelty seeking were related to more severe problem behaviors and to higher levels of witnessing and victimization, whereas higher levels of harm avoidance were related to higher levels of depression and posttraumatic stress. PMID- 21826268 TI - Vascular and valvular calcification in chronic peritoneal dialysis patients. AB - Cardiovascular disease accounts over half of the total mortality in peritoneal dialysis (PD) patients. In addition, there is an increasing recognition of a high prevalence of vascular and valvular calcification that may contribute to the increased all-cause and cardiovascular mortality in the PD patients. Disturbed mineral metabolism in association with chronic kidney disease has been suggested as one of the major contributing factors to the increased vascular/valvular calcification in this population. In this paper, we provide an overview of the prevalence and importance of this complication in the PD patients. In addition, we review the contributing factors and some emerging mechanisms for this complication. Furthermore, we discuss some therapeutic strategies that may be useful in limiting the progression of vascular/valvular calcification in the PD population. PMID- 21826269 TI - Bioincompatible impact of different peritoneal dialysis fluid components and therapeutic interventions as tested in a rat peritoneal dialysis model. AB - Peritoneal dialysis (PD) is associated with functional and structural changes of the peritoneal membrane. In this paper, we describe the impact of different factors contributing to peritoneal incompatibility of PD fluid installation including presence of a catheter, volume loading, and the PD fluid components itself. These factors initiate recruitment and activation of peritoneal immune cells such as macrophages and mast cells, as well as activation of peritoneal cells as mesothelial cells in situ. We provide an overview of PD-associated changes as seen in our rat PD-exposure model. Since these changes are partly reversible, we finally discuss therapeutic strategies in the rat PD model with possible consequences of long-term PD in the relevant human setting. PMID- 21826267 TI - Autoimmunity in amyotrophic lateral sclerosis: past and present. AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting particularly motor neurons for which no cure or effective treatment is available. Although the cause of ALS remains unknown, accumulative evidence suggests an autoimmune mechanism of pathogenesis. In this paper, we will summarize the current research related to autoimmunity in the sporadic form of ALS and discuss the potential underlying pathogenic mechanisms and perspectives. Presented data supports the view that humoral immune responses against motor nerve terminals can initiate a series of physiological changes leading to alteration of calcium homeostasis. In turn, loss of calcium homeostasis may induce neuronal death through apoptotic signaling pathways. Additional approaches identifying specific molecular features of this hypothesis are required, which will hopefully allow us to develop techniques of early diagnosis and effective therapies. PMID- 21826270 TI - Inflammatory Mechanisms of Organ Crosstalk during Ischemic Acute Kidney Injury. AB - Acute kidney injury (AKI) is a common complication during inpatient hospitalization, and clinical outcomes remain poor despite advancements in renal replacement therapy. AKI in the setting of multiple organ failure (MOF) remains a formidable challenge to clinicians and incurs an unacceptably high mortality rate. Kidney ischemia-reperfusion injury (IRI) incites a proinflammatory cascade and releases cellular and soluble mediators with systemic implications for remote organ injury. Evidence from preclinical models cites mechanisms of organ crosstalk during ischemic AKI including the expression of cellular adhesion molecules, lymphocyte trafficking, release of proinflammatory cytokines and chemokines, and modification of the host innate and adaptive immune response systems. In this paper, the influence of kidney IRI on systemic inflammation and distant organ injury will be examined. Recent experimental data and evolving concepts of organ crosstalk during ischemic AKI will also be discussed in detail. PMID- 21826271 TI - Apple Procyanidins Suppress Amyloid beta-Protein Aggregation. AB - Procyanidins (PCs) are major components of the apple polyphenols (APs). We previously reported that treatment with PC extended the mean lifespan of Caenorhabditis elegans (Sunagawa et al., 2011). In order to estimate the neuroprotective effects of PC, we investigated the antiaggregative activity of PC on amyloid beta-protein (Abeta) aggregation, which is a pathological hallmark of Alzheimer's disease. We herein report that PC significantly suppressed Abeta42 aggregation and dissociated Abeta42 aggregates in a dose-dependent manner, indicating that PC is a potent suppressor of Abeta aggregation. Furthermore, PC significantly inhibited Abeta42 neurotoxicity and stimulated proliferation in PC 12 cells. These results suggested that the PC and AP acted as neuroprotective factors against toxic Abeta aggregates. PMID- 21826272 TI - Basal Cell Carcinoma in Type 2 Segmental Darier's Disease. AB - Background. Darier's disease (DD), also known as Keratosis Follicularis or Darier White disease, is a rare disorder of keratinization. DD can present as a generalized autosomal dominant condition as well as a localized or segmental postzygotic condition (Vazquez et al., 2002). Clinical features of DD include greasy, warty papules and plaques on seborrheic areas, dystrophic nails, palmo plantar pits, and papules on the dorsum of the hands and feet. Objective. We report a case of basal cell carcinoma developing in a patient with type 2 segmental DD. Conclusion. According to the current literature, Type 2 segmental disease is a rare presentation of Darier's disease with only 8 previous cases reported to date. In addition, nonmelanoma skin cancer (NMSC) arising from DD is rarely reported; however, there may be an association between DD and risk of carcinogenesis. PMID- 21826273 TI - Involvement of Physical Parameters in Medium Improvement for Tannase Production by Aspergillus niger FETL FT3 in Submerged Fermentation. AB - Aspergillus niger FETL FT3, a local extracellular tannase producer strain that was isolated from one of dumping sites of tannin-rich barks of Rhizophora apiculata in Perak, Malaysia. This fungus was cultivated in 250 mL Erlenmeyer flask under submerged fermentation system. Various physical parameters were studied in order to maximize the tannase production. Maximal yield of tannase production, that is, 2.81 U per mL was obtained on the fourth day of cultivation when the submerged fermentation was carried out using liquid Czapek-Dox medium containing (percent; weight per volume) 0.25% NaNO(3), 0.1% KH(2)PO(4), 0.05% MgSO(4) .7H(2)O, 0.05% KCl, and 1.0% tannic acid. The physical parameters used initial medium pH of 6.0, incubation temperature of 30 degrees C, agitation speed of 200 rpm and inoculums size of 6 * 10(6) spores/ ml. This research has showed that physical parameters were influenced the tannase production by the fungus with 156.4 percent increment. PMID- 21826274 TI - A profile of cases of gestational trophoblastic neoplasia at a large tertiary centre in dubai. AB - Objectives. To study (1) the prevalence of different types of gestational trophoblastic neoplasia (GTN) in the local and nonlocal population of women at Al Wasl Hospital, a tertiary level referral centre for northern Emirates, (2) the safety of cervical preparation before uterine evacuation, (3) the role of repeat uterine evacuation in curing these cases, and (4) the percentage of cases ultimately requiring chemotherapy. Material and Methods. Retrospective analysis of case records of 35 women with diagnosis of gestational trophoblastic neoplasia were managed in the Department of Obstetrics and Gynecology at Al Wasl Hospital, over a 2-year period between January 2007 to December 2008. Results. 35 cases of gestational trophoblastic neoplasia were seen in a 2-year period (January 2007 to December 2008) at Al Wasl Hospital, with 7000 deliveries per year, prevalence being 1 in 400 live births. 60% cases were local Arabs. Histopathology revealed complete mole in 13 cases, partial mole in 17 cases, hydropic degeneration of villi in 4 cases, and no identifiable tissue in 1 case. No cases of choriocarcinoma or placental site trophoblastic tumour were seen during the study period. 34% cases received cervical preparation with prostaglandins prior to surgical curettage. Complications were minor. 62% were cured by primary suction curettage, 12% after second (repeat) uterine evacuation, and 25% needed single drug chemotherapy. 8% cases defaulted after primary evacuation and were lost to followup. Conclusions. Prevalence of GTN in the local Arab population is similar to other Asian populations. The majority of cases are cured by simple suction uterine curettage. Cervical preparation with prostaglandins should be done in selected cases to avoid perforation during evacuation. Second (repeat) uterine evacuation can be curative in some cases with strict selection criteria and avoid the need for chemotherapy. Regional registry of cases is needed to estimate the true incidence of this disease. PMID- 21826275 TI - Carcinomas of Distal Fallopian Tube and Their Association with Tubal Intraepithelial Carcinoma: Do They Share a Common "Precursor" Lesion? Loss of Heterozygosity and Immunohistochemical Analysis Using PAX 2, WT-1, and P53 Markers. AB - As the role of distal fallopian tube as organ of serous carcinogenesis is emerging, additional literature on the role of tubal intraepithelial carcinoma (TIC) as a precursor lesion in a subset of primary peritoneal serous carcinomas (PPSC is emerging as well. TIC although fallopian tube in origin can be genetically related to ovarian/peritoneal carcinomas. The role of PAX2 in primary fallopian tube carcinomas (PFTC)/PPSC is yet to be defined. The aim of our study was to understand if the biologic properties of tumors arising in the distal fallopian tube that remain as PFTC are different when they seed on to the peritoneal surface (PPSC). A panel of 6 polymorphic microsatellite markers corresponding to p53, PAX2, and WT1 tumor suppressor genes were studied. Invasive carcinomas as well as TIC arising in the distal fallopian tube when remain as PFTC appears to exhibit different LOH patterns in comparison to PPSC. PAX 2 LOH patterns might represent a "hidden PAX 2 signature" analogous to p53 signatures. PAX 2 might be an emerging marker for detection of early serous carcinomas particularly in BRCA + women. PMID- 21826276 TI - The role of GABAergic inhibition in ocular dominance plasticity. AB - During the last decade, we have gained much insight into the mechanisms that open and close a sensitive period of plasticity in the visual cortex. This brings the hope that novel treatments can be developed for brain injuries requiring renewed plasticity potential and neurodevelopmental brain disorders caused by defective synaptic plasticity. One of the central mechanisms responsible for opening the sensitive period is the maturation of inhibitory innervation. Many molecular and cellular events have been identified that drive this developmental process, including signaling through BDNF and IGF-1, transcriptional control by OTX2, maturation of the extracellular matrix, and GABA-regulated inhibitory synapse formation. The mechanisms through which the development of inhibitory innervation triggers and potentially closes the sensitive period may involve plasticity of inhibitory inputs or permissive regulation of excitatory synapse plasticity. Here, we discuss the current state of knowledge in the field and open questions to be addressed. PMID- 21826278 TI - Diacylglycerol signaling underlies astrocytic ATP release. AB - Astrocytes have the ability to modulate neuronal excitability and synaptic transmission by the release of gliotransmitters. The importance of ATP released downstream of the activation of Gq-coupled receptors has been well established, but the mechanisms by which this release is regulated are unclear. The current work reveals that the elevation of diacylglycerol (DAG) in astrocytes induces vesicular ATP release. Unexpectedly, DAG-induced ATP release was found to be independent of PKC activation, but dependent upon activation of a C1 domain containing protein. Astrocytes express the C1 domain-containing protein Munc13-1, which has been implicated in neuronal transmitter release, and RNAi-targeted downregulation of Munc13-1 inhibits astrocytic ATP release. These studies demonstrate that elevations of DAG induce the exocytotic release of ATP in astrocytes, likely via a Munc13-1-dependent mechanism. PMID- 21826277 TI - Altered GABA signaling in early life epilepsies. AB - The incidence of seizures is particularly high in the early ages of life. The immaturity of inhibitory systems, such as GABA, during normal brain development and its further dysregulation under pathological conditions that predispose to seizures have been speculated to play a major role in facilitating seizures. Seizures can further impair or disrupt GABA(A) signaling by reshuffling the subunit composition of its receptors or causing aberrant reappearance of depolarizing or hyperpolarizing GABA(A) receptor currents. Such effects may not result in epileptogenesis as frequently as they do in adults. Given the central role of GABA(A) signaling in brain function and development, perturbation of its physiological role may interfere with neuronal morphology, differentiation, and connectivity, manifesting as cognitive or neurodevelopmental deficits. The current GABAergic antiepileptic drugs, while often effective for adults, are not always capable of stopping seizures and preventing their sequelae in neonates. Recent studies have explored the therapeutic potential of chloride cotransporter inhibitors, such as bumetanide, as adjunctive therapies of neonatal seizures. However, more needs to be known so as to develop therapies capable of stopping seizures while preserving the age- and sex-appropriate development of the brain. PMID- 21826279 TI - Molecular mechanisms underlying activity-dependent GABAergic synapse development and plasticity and its implications for neurodevelopmental disorders. AB - GABAergic interneurons are critical for the normal function and development of neural circuits, and their dysfunction is implicated in a large number of neurodevelopmental disorders. Experience and activity-dependent mechanisms play an important role in GABAergic circuit development, also recent studies involve a number of molecular players involved in the process. Emphasizing the molecular mechanisms of GABAergic synapse formation, in particular basket cell perisomatic synapses, this paper draws attention to the links between critical period plasticity, GABAergic synapse maturation, and the consequences of its dysfunction on the development of the nervous system. PMID- 21826281 TI - Phosphorylation of RNAPII: To P-TEFb or not to P-TEFb? AB - The C-terminal domain of RNA polymerase II undergoes a cycle of phosphorylation which allows it to temporally couple transcription with transcription-associated processes. The characterization of hitherto unrecognized metazoan elongation phase CTD kinase activities expands our understanding of this coupling. We discuss the circumstances that delayed the recognition of these kinase activities. PMID- 21826282 TI - Transcription of ncDNA: Many roads lead to local gene regulation. AB - Transcription of ncDNA occurs throughout eukaryotic genomes, generating a wide array of ncRNAs. One large class of ncRNAs includes those transcribed over the promoter regions of nearby protein coding genes. Recent studies, primarily focusing on individual genes have uncovered multiple mechanisms by which promoter associated transcriptional activity locally alters gene expression. PMID- 21826280 TI - Autism: a "critical period" disorder? AB - Cortical circuits in the brain are refined by experience during critical periods early in postnatal life. Critical periods are regulated by the balance of excitatory and inhibitory (E/I) neurotransmission in the brain during development. There is now increasing evidence of E/I imbalance in autism, a complex genetic neurodevelopmental disorder diagnosed by abnormal socialization, impaired communication, and repetitive behaviors or restricted interests. The underlying cause is still largely unknown and there is no fully effective treatment or cure. We propose that alteration of the expression and/or timing of critical period circuit refinement in primary sensory brain areas may significantly contribute to autistic phenotypes, including cognitive and behavioral impairments. Dissection of the cellular and molecular mechanisms governing well-established critical periods represents a powerful tool to identify new potential therapeutic targets to restore normal plasticity and function in affected neuronal circuits. PMID- 21826283 TI - Time-based patterning in development: The role of oscillating gene expression. AB - Oscillating gene expression is a mechanism of patterning during development in both plants and animals. In vertebrates, oscillating gene expression establishes the musculoskeletal precursors (somites), while in plant roots it establishes the position of future organs (lateral roots). Both mechanisms constitute a specialized type of biological clock that converts temporal information into precise spatial patterns. Similarities, differences, and their functionality in organisms that evolved independently are discussed. PMID- 21826284 TI - Ubiquitin and transcription: The SCF/Met4 pathway, a (protein-) complex issue. AB - Ubiquitylation has emerged as an omnipresent factor at all levels of transcriptional regulation. A recent study that describes the yeast transcriptional activator Met4 as a functional component of the very same ubiquitin ligase that regulates its own activity highlights the close relation between transcription and the ubiquitin proteasome system. PMID- 21826285 TI - The replication-transcription conflict. AB - In response to environmental and nutritional stimuli, a whole array of proteins remodel genome architecture, activate or transcribe genes, suppress genes, repair lesions and base-modifications, faithfully replicate and safely separate the parental and daughter genomes during cell division. Negotiating and resolving conflicts of genome trafficking is essential for genome stability. PMID- 21826286 TI - Distinct RNA degradation pathways and 3' extensions of yeast non-coding RNA species. AB - Non-coding transcripts originating from bidirectional promoters have been reported in a wide range of organisms. In yeast, these divergent transcripts can be subdivided into two classes. Some are designated Cryptic Unstable Transcripts (CUTs) because they are terminated by the Nrd1-Nab3-Sen1 pathway and then rapidly degraded by the nuclear exosome. This is the same processing pathway used by yeast snoRNAs. Whereas CUTs are only easily observed in cells lacking the Rrp6 or Rrp47 subunits of the nuclear exosome, Stable Uncharacterized Transcripts (SUTs) are present even in wild-type cells. Here we show that SUTs are partially susceptible to the nuclear exosome, but are primarily degraded by cytoplasmic 5' to 3' degradation and nonsense-mediated decay (NMD). Therefore, SUTs may be processed similarly to mRNAs. Surprisingly, both CUTs and SUTs were found to produce 3' extended species that were also subject to cytoplasmic degradation. The functions, if any, of these extended CUTs and SUTs are unknown, but their discovery suggests that yeasts generate transcripts reminiscent of long non coding RNAs found in higher eukaryotes. PMID- 21826287 TI - Using Force Sensors and Neural Models to Encode Tactile Stimuli as Spike-based Responses. AB - Tactile sensors will augment the next generation of prosthetic limbs. However, currently available sensors do not produce biologically-compatible output. This work seeks to illustrate that a force sensor combined with a bi-phasic, neural spiking algorithm, or spiking-sensor, can produce spiking patterns similar to that of the slowly adapting type I (SAI) mechanoreceptor. Experiments were conducted where first spike latency and inter-spike interval, in response to a rapidly delivered (100 ms) sustained displacement (1.1, 1.3, 1.5 mm for 5 s), were compared between the spiking-sensor and SAI recording. The results indicated that the predicted spike times were similar, in magnitude and increasing linear trend, to those observed with the SAI. Over the three displacements, average dynamic ISIs were 7.3, 4.2, 3.8 ms for the spiking-sensor and 6.2, 6.9, 4.1 ms for the SAI, while average static ISIs were 69.0, 45.2, 35.1 ms and 159.9, 69.6, 38.8 ms. The predicted first spike latencies (74.3, 73.9, 96.3 ms) lagged in comparison to those observed for the SAI (26.8, 31.7, 28.8 ms), which may be due to both the different applied force ramp-ups and the SAI's exquisite dynamic sensitivity range and rapid response time. PMID- 21826288 TI - A microgap impedance sensor for the determination of trace water in organic solvents. AB - A microgap impedance sensor with a 50 MUm gap was developed for the determination of trace water in organic solvents by coating poly(dimethyldiallylammonium chloride) (PDMDAAC) and ferricyanide/ferrocyanide composite materials on indium tin oxide (ITO). The electrochemical properties of the composite materials were investigated with cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). We observed that the impedance response of the sensor depended on the concentration of trace water in the organic solvents. Under optimized conditions, the linear range for the determination of trace water was 0 0.06% for chloroform (CHCl(3)), 0-0.10% for acetone (CH(3)COCH(3)), 0-0.12% for tetrahydrofuran (THF), and 0-0.10% for acetonitrile (CH(3)CN), and the detection limits were 0.65, 1.54, 0.61, and 1.72 ppm, respectively. The results obtained from the impedance sensors were comparable to those obtained using the traditional Karl Fischer method. PMID- 21826289 TI - An ultra-sensitive electrochemical sensor for ascorbic acid based on click chemistry. AB - A highly selective and sensitive electrochemical sensor for ascorbic acid (AA) assay has been prepared through Cu(I) catalyzed azide-alkyne cycloaddition reaction (CuAAC). The catalyst, Cu(I) species, is acquired from the reduction of Cu(II) by AA in situ. In the presence of Cu(I) catalyst, the azide modified Au electrode surface is shown to react quantitatively with terminal propargyl functionalized ferrocene forming 1,2,3-triazoles. The electrochemical response of propargyl-functionalized ferrocene modified Au electrode surface can be monitored using differential pulse voltammetry (DPV) technique. Under optimal conditions, it is found that the current intensity has a linear relationship with the logarithm of AA concentration in the range of 5.0 * 10(-12) to 1.0 * 10(-9) M. Furthermore, the proposed electrochemical sensor shows a good stability (RSD 4.2%), high selectivity and low detection limit for AA detection. In addition, it also demonstrates that the proposed sensor can be applied to detect AA in real urine samples with satisfactory results. PMID- 21826290 TI - Electronic structure and oxygen vacancies in PdO and ZnO: validation of DFT models. AB - PdO is one of the most important catalytic materials currently used in the industry. In redox catalytic reactions involving PdO, the bulk phase is an additional source of oxygen. This leads to strong transformations not only at the surface of PdO but also in the near sub-surface and bulk regions. The redox process is, therefore, governed not only by the extent of PdO d-band filling, but also depends on the material properties of the PdO crystal--the ease with which its structure can be deformed. Methane oxidation is of key industrial interest, and therein the rate of CH(4) conversion depends strongly on the reversible oxygen defects formation on the surface and in the bulk of the catalyst. The present study gives a first insight into these complex phenomena at the atomistic level. Comparison of different density functional theory (DFT) approaches and their capacity to reproduce experimental values of the heat of formation as well as the band gap of the PdO are discussed in detail. Results from DFT calculations for an oxygen vacancy creation in the bulk and on the surface of PdO are presented and compared at the level of accuracy of the implemented approaches with defect calculations for ZnO. Many different modeling approaches based on functionals and pseudopotentials (non-modified PP and empirically tuned) have been evaluated in their aptness to capture key PdO properties. It was shown that simulations with the PP-115 pseudopotential gave the closest possible agreement to the relevant PdO thermodynamic data and energy of oxygen vacancy formation. PMID- 21826291 TI - Cross-section energy dependence of the [C6H6-M]+ adduct formation between benzene molecules and alkali ions (M = Li, Na, K). AB - The association reactions of benzene molecules with alkali ions M(+) (Li(+), Na(+) and K(+)) under single collision conditions have been studied using a radiofrequency-guided-ion-beam apparatus and mass spectrometry characterization of the different adducts. Cross-section energy dependences for [M-C(6)H(6)](+) adduct formation have been measured at collision energies up to 1.20 eV in the center of mass frame. All excitation functions decrease when collision energy increases, showing the expected behaviour for barrierless reactions. From ab initio chemical structure calculations at the MP2(full) level, the formation of the adducts makes evident the alkali ion-benzene non-covalent chemical bond. The cross-section energy dependence and the role of radiative cooling rates and unimolecular decomposition on the stabilization of the energized collision complex are also discussed. PMID- 21826292 TI - Experimental investigation of droplet acceleration and collision in the gas phase in a microchannel. AB - We developed a novel microfluidic system, termed a micro-droplet collider, by utilizing the spatial-temporal localized liquid energy to realize chemical processes, which achieved rapid mixing between droplets having a large volume ratio by collision. In this paper, in order to clarify the characteristics of the micro-droplet collider, dynamics of droplet acceleration, stationary motion and collision in the gas phase in a microchannel were experimentally investigated with visualized images using a microscope equipped with a high-speed camera. The maximum velocity of 450 mm s(-1) and acceleration of 1500 m s(-2) of a 1.6 nL water droplet were achieved at an air pressure of 100 kPa. Measurement results of dynamic contact angles of droplets indicated that wettability of the surface played an important role in the stability of droplet acceleration and collision. We found that the bullet droplet penetrated into the target droplet at collision, which differed from bulk scale. The deformation of the droplet was strongly suppressed by the channel structure, thus stable collision and efficient utilization of the droplet energy were possible. These results are useful for estimating the localized energy, for improving the system in order to realize extreme performance, and for extending the applications of microfluidic devices. PMID- 21826293 TI - Particle separation in microfluidics using a switching ultrasonic field. AB - We present a new method for separation of micro-sized constituents with positive acoustic contrast factors in a microfluidic channel using ultrasound. The ultrasound field is switched between the first and third resonant modes of the fluid channel, and the suspended constituents are separated onto the side and center pressure nodal lines according to their sizes or acoustic contrast factors. Initial hydrodynamic focusing of the constituents within a region of the channel near to the side nodal line is a crucial step in this separation method. This new method is shown to provide a novel "parallel-stream" separation of two species of particles with good robustness. Prior numerical simulations provide essential information on this operating region and also the voltage cycle to be applied to the ultrasonic actuators for optimal separation. Experiments were conducted using a prototype of the design with polystyrene microspheres of different sizes to demonstrate the efficiency and robustness of the separation process. PMID- 21826294 TI - Inverse electron-demand 1,3-dipolar cycloaddition of nitrile oxide with common nitriles leading to 3-functionalized 1,2,4-oxadiazoles. AB - A carbamoyl-substituted nitrile oxide was generated upon treatment of easily available 2-methyl-4-nitro-3-isoxazolin-5(2H)-one with THF (not dried); the reaction proceeded efficiently even in the absence of any special reagents and reaction conditions. The nitrile oxide caused 1,3-dipolar cycloaddition with common aliphatic nitriles or electron-rich aromatic nitriles to afford 3 functionalized 1,2,4-oxadiazoles, which are expected to serve as precursors for the preparation of a variety of functional materials by the chemical transformation of the carbamoyl group. While conventional preparative methods for 1,2,4-oxadiazoles involve the cycloaddition of an electron-rich nitrile oxide with an electron-deficient nitrile or a nitrile activated by a Lewis acid, our method employs the complementary combination of an electron-rich nitrile and an electron-deficient nitrile oxide- the inverse electron-demand 1,3-cycloaddition. The DFT calculations using B3LYP 6-31G* supported the abovementioned inverse reactivity, and also suggested the presence of an accelerating effect by the carbamoyl group as a result of hydrogen bond formation with a dipolarophilic nitrile. PMID- 21826295 TI - Synthesis of alpha, beta-unsaturated gamma-amino esters with unprecedented high (E)-stereoselectivity and their conformational analysis in peptides. AB - Mild, efficient and racemization-free synthesis of N-protected alpha, beta unsaturated gamma-amino esters with unprecedented high E- stereoselectivity is described. This method is found to be compatible with Boc-, Fmoc- and other side chain protecting groups. The crystal conformations of the vinylogous gamma-amino esters in monomers and in homo- and mixed dipeptides are studied. Further, the vinylogous homo-dipeptide showed a beta-sheet conformation, while mixed alpha- and alpha,beta-unsaturated gamma-hybrid dipeptide adapted an irregular structure in single crystals. PMID- 21826296 TI - Domino alkylation/oxa-Michael of 1,3-cyclohexanediones: steering the C/O chemoselectivity to reach tetrahydrobenzofuranones. AB - An unprecedented domino synthesis of tetrahydrobenzofuran-4-ones is described implicating chemoselective alkylation of various 1,3-cyclohexanediones with bromocrotonate or crotonitrile followed by oxa-Michael cyclization. Further transformations of this core to reach molecular diversity are also presented. PMID- 21826298 TI - A gold nanorod based colorimetric probe for the rapid and selective detection of Cu2+ ions. AB - A gold nanorod (AuNR) based colorimetric probe was reported for the rapid and selective detection of Cu(2+) ions. The probe was fabricated by functionalizing cysteine (Cys) onto AuNR (Cys-AuNR) with an aspect ratio of 2.3. The strong coordination of Cu(2+) with cysteine resulted in a stable Cys-Cu-Cys complex, and induced the aggregation of the colloidal nanorods along with a rapid colour change from blue-green to dark gray. Potential factors affecting the performance of the probe for the detection of Cu(2+) were carefully optimized, including the pH value of the buffer media, the concentration of cysteine, and the kinetics for the coordination of Cu(2+) with Cys-AuNR. Under optimal conditions, the developed colorimetric method gave a linear range of 1-100 MUM for Cu(2+), and a detection limit (3s) of 0.34 MUM. Moreover, the developed method exhibited excellent selectivity for Cu(2+), and quantitative spike-recoveries from 90% to 107% in environmental water samples. The proposed colorimetric approach can in principle be used to detect other metal ions by functionalizing various specific ligands onto the AuNR that can selectively bind the other target metal ions. PMID- 21826299 TI - The rational synthesis of (10,3)-type MOFs based on tetranuclear [W(Mo)OS3Cu3]+ secondary building units. AB - The self-assembly reaction of the preformed clusters with two extended linear and trigonal rigid ligands as organic linkers afforded two 2D and 3D Mo(W)/Cu/S-based cluster polymers. They show unprecedented structure types in Mo(W)/S/Cu chemistry and exhibit strong third-order nonlinear optical properties. PMID- 21826300 TI - Poptube approach for ultrafast carbon nanotube growth. AB - Microwave irradiation can be used to heat conductive materials and metallocene precursors to initiate ultrafast CNT growth. It takes only 15-30 seconds to grow CNTs at room temperature in air, without the need for any inert gas protection and additional feed stock gases. PMID- 21826297 TI - Top-down mass spectrometry: recent developments, applications and perspectives. AB - Top-down mass spectrometry is an emerging approach for the analysis of intact proteins. The term was coined as a contrast with the better-established, bottom up strategy for analysis of peptide fragments derived from digestion, either enzymatically or chemically, of intact proteins. Although the term top-down originates from proteomics, it can also be applied to mass spectrometric analysis of intact large biomolecules that are constituents of protein assemblies or complexes. Traditionally, mass spectrometry has usually started with intact molecules, and in this regard, top-down approaches reflect the spirit of mass spectrometry. This article provides an overview of the methodologies in top-down mass spectrometry and then reviews applications covering protein posttranslational modifications, protein biophysics, DNAs/RNAs, and protein assemblies. Finally, challenges and future directions are discussed. PMID- 21826301 TI - Total synthesis of (-)-nakadomarin A. AB - A highly diastereoselective bifunctional organocatalyst controlled Michael addition, a nitro-Mannich/lactamization cascade, a furan N-acyliminium cyclisation, a sequential alkyne RCM/syn-reduction and an alkene RCM has allowed a 19 step, highly stereoselective synthesis of (-)-nakadomarin A. PMID- 21826302 TI - Supramolecular polymer for explosives sensing: role of H-bonding in enhancement of sensitivity in the solid state. AB - A pi-electron rich supramolecular polymer as an efficient fluorescent sensor for electron deficient nitroaromatic explosives has been synthesized, and the role of H-bonding in dramatic amplification of sensitivity/fluorescence quenching efficiency in the solid state has been established. PMID- 21826303 TI - In situ time-resolved XAFS study on the structural transformation and phase separation of Pt3Sn and PtSn alloy nanoparticles on carbon in the oxidation process. AB - The dynamic behavior and kinetics of the structural transformation of supported bimetallic nanoparticle catalysts with synergistic functions in the oxidation process are fundamental issues to understand their unique catalytic properties as well as to regulate the catalytic capability of alloy nanoparticles. The phase separation and structural transformation of Pt(3)Sn/C and PtSn/C catalysts during the oxidation process were characterized by in situ time-resolved energy dispersive XAFS (DXAFS) and quick XAFS (QXAFS) techniques, which are element selective spectroscopies, at the Pt L(III)-edge and the Sn K-edge. The time resolved XAFS techniques provided the kinetics of the change in structures and oxidation states of the bimetallic nanoparticles on carbon surfaces. The kinetic parameters and mechanisms for the oxidation of the Pt(3)Sn/C and PtSn/C catalysts were determined by time-resolved XAFS techniques. The oxidation of Pt to PtO in Pt(3)Sn/C proceeded via two successive processes, while the oxidation of Sn to SnO(2) in Pt(3)Sn/C proceeded as a one step process. The rate constant for the fast Pt oxidation, which was completed in 3 s at 573 K, was the same as that for the Sn oxidation, and the following slow Pt oxidation rate was one fifth of that for the first Pt oxidation process. The rate constant and activation energy for the Sn oxidation in PtSn/C were similar to those for the Sn oxidation in Pt(3)Sn/C. In the PtSn/C, however, it was hard for Pt oxidation to PtO to proceed at 573 K, where Pt oxidation was strongly affected by the quantity of Sn in the alloy nanoparticles due to swift segregation of SnO(2) nanoparticles/layers on the Pt nanoparticles. The mechanisms for the phase separation and structure transformation in the Pt(3)Sn/C and PtSn/C catalysts are also discussed on the basis of the structural kinetics of the catalysts themselves determined by the in situ time-resolved DXAFS and QXAFS. PMID- 21826304 TI - The effect of the position of methyl substituents on photophysical and photochemical properties of [Ru(x,x'-dmb)(CN)4]2- complexes: experimental confirmation of the theoretical predictions. AB - The molecular geometry, electronic structure and electronic spectra and the energy levels of the molecular orbitals responsible for the photophysical characteristics of a series of solvent tunable [Ru(x,x'-dmb)(CN)(4)](2-) complexes (where x,x'-dmb = x,x'-dimethyl-2,2'-bipyridine) were calculated by density-functional theory-based quantum chemical methods, with the purpose of proposing for experimental study the best candidate for sensitizing electron- and energy transfer processes or for light induced structural changes in the molecule. The methods applied include geometry optimization using the B3LYP functional combination and various basis sets, time-dependent density functional theory with the B3LYP and PBE0 functionals, with and without explicit inclusion of coordinated solvent H(2)O molecules and the conductor-like polarizable continuum model for solvation. The accuracy of the theoretical predictions was tested by experiments: the model compounds have been synthesized and characterized by various spectroscopic methods, such as (1)H-NMR, UV-Vis absorption and emission spectroscopy and by cyclic voltammetry. Excellent correlation was found between the theoretically calculated and the experimentally determined photophysical and photochemical characteristics. The electronic transition energies measured in water are superbly reproduced by TD-PBE0 and well by TD-B3LYP, but the performance of both functionals is worse if the solvent is acetonitrile. PMID- 21826305 TI - Illumination of the effect of the overlap of lone-pairs on indirect nuclear spin spin coupling constants. AB - The effect of electron lone-pairs on the Fermi-contact (FC) contribution to indirect nuclear spin-spin coupling constants is analyzed using new tools for their interpretation. In particular, visualization of spin-spin coupling pathways using the coupling deformation density (CDD) has been employed. Furthermore, the recently developed perturbation-stable localization procedure has been applied for decomposition of CDD and the calculated value of couplings into contributions from localized molecular orbitals (LMOs). Correlation between the overlap of densities of LMOs representing lone-pairs and the Fermi-contact contribution to spin-spin coupling constants has been demonstrated. A new way for analyzing spin spin couplings using the expansion of CDD as a linear combination of the products of molecular orbitals has been suggested. The considered examples include two- and three-bond phosphor-phosphor couplings. Significance of the obtained insight is not restricted to spin-spin couplings of nuclei possessing lone-pairs, as demonstrated in the example of vicinal hydrogen-hydrogen coupling in ethane. PMID- 21826306 TI - CVD graphene electrochemistry: the role of graphitic islands. AB - Graphitic islands are shown to dominate the electrochemical response at CVD grown graphene electrodes. PMID- 21826307 TI - Rapid dissolution of ZnO nanocrystals in acidic cancer microenvironment leading to preferential apoptosis. AB - The microenvironment of cancer plays a very critical role in the survival, proliferation and drug resistance of solid tumors. Here, we report an interesting, acidic cancer microenvironment-mediated dissolution-induced preferential toxicity of ZnO nanocrystals (NCs) against cancer cells while leaving primary cells unaffected. Irrespective of the size-scale (5 and 200 nm) and surface chemistry differences (silica, starch or polyethylene glycol coating), ZnO NCs exhibited multiple stress mechanisms against cancer cell lines (IC(50)~150 MUM) while normal human primary cells (human dermal fibroblast, lymphocytes, human umbilical vein endothelial cells) remain less affected. Flow cytometry and confocal microscopy studies revealed that ZnO NCs undergo rapid preferential dissolution in acidic (pH ~5-6) cancer microenvironment causing elevated ROS stress, mitochondrial superoxide formation, depolarization of mitochondrial membrane, and cell cycle arrest at S/G2 phase leading to apoptosis. In effect, by elucidating the unique toxicity mechanism of ZnO NCs, we show that ZnO NCs can destabilize cancer cells by utilizing its own hostile acidic microenvironment, which is otherwise critical for its survival. PMID- 21826308 TI - Enhanced photocatalytic H2-production activity of graphene-modified titania nanosheets. AB - Graphene-modified TiO(2) nanosheets with exposed (001) facets (graphene/TiO(2)) were prepared by microwave-hydrothermal treatment of graphene oxide (GO) and hydrothermally synthesized TiO(2) nanosheets with exposed (001) facets in an ethanol-water solvent. These nanocomposite samples showed high photocatalytic H(2)-production activity in aqueous solutions containing methanol, as sacrificial reagent, even without Pt co-catalyst. The optimal graphene content was found to be ~1.0 wt%, giving a H(2)-production rate of 736 MUmol h(-1) g(-1) with a quantum efficiency (QE) of 3.1%, which exceeded the rate observed on pure TiO(2) nanosheets by more than 41 times. This high photocatalytic H(2)-production activity is due to the deposition of TiO(2) nanosheets on graphene sheets, which act as an electron acceptor to efficiently separate the photogenerated charge carriers. The observed enhancement in the photocatalytic activity is due to the lower absolute potential of graphene/graphene(-) (-0.08 V vs. SHE, pH = 0) in comparison to the conduction band (-0.24 V) of anatase TiO(2), meanwhile the aforementioned absolute value is higher than the reduction potential of H(+) (0 V), which favors the electron transfer from the conduction band (CB) of TiO(2) to graphene sheets and the reduction of H(+), thus enhancing photocatalytic H(2) production activity. The proposed mechanism for the observed photocatalytic performance of TiO(2) nanosheets, modified with a small amount of graphene, was further confirmed by photoluminescence spectroscopy and transient photocurrent response. This work not only shows a possibility for the utilization of low cost graphene sheets as a substitute for noble metals (such as Pt) in the photocatalytic H(2)-production but also for the first time shows a significant enhancement in the H(2)-production activity by using metal-free carbon material as an effective co-catalyst. PMID- 21826309 TI - Optimization of the solid phase extraction method for determination of Cu(II) in natural waters by using response surface methodology. AB - A solid-phase extraction method was proposed for the preconcentration of Cu(II) in different samples in a mini-column packed with functionalized multi-walled carbon nanotubes (MWCNTs-COOH) as an effective sorbent, without using any complexing reagent, prior to its determination by flame atomic absorption spectrometry using response surface methodology. The experimental optimization step was performed by both a two-level full factorial design, with a center point, and a Box-Behnken design combined with response surface methodology. Three variables (pH, amount of Cu(II), and sample volume) were regarded as factors in the optimization. It was found that pH is the most significant factor affecting the preconcentration of Cu(II). The preconcentration factor was obtained as 100. The linear range was 1-5 mg L(-1) (R(2) = 0.999). Under the optimized experimental conditions, the detection limit (3s) of the proposed method followed by FAAS was found to be 0.27 MUg L(-1). The relative standard deviation for 10 replicate measurements of 50 and 100 MUg L(-1) Cu(II) was 2.39% and 0.98%, respectively. The response surface methodology was successfully applied to the determination of Cu(II) in water samples and mussel samples, and in a certified standard reference material (BCR-320R, Channel sediment). PMID- 21826310 TI - Preliminary study for simultaneous detection and quantification of androgenic anabolic steroids using ELISA and pattern recognition techniques. AB - A first step towards the multidetection, identification and quantification of anabolic androgenic steroids by enzyme-linked immunosorbent assay (ELISA) has been performed in this study. This proposal combines multiple competitive ELISA assays with different cross-reactivity profiles and multivariate data analysis techniques. Data have been analyzed by principal component analysis in conjunction with a novel K-nearest line classifier. This proposal allows simultaneous detection of up to four different steroids in the range of concentration from 0.1 to 316.2 nM with a total rate of 90.6% of correct detection, even in the presence of cross-reactivities. A methodology for concentration prediction is also presented with satisfactory results. PMID- 21826311 TI - An ultrasensitive peroxidase DNAzyme-associated aptasensor that utilizes a target triggered enzymatic signal amplification strategy. AB - By rationally employing enzymes for signal amplification, an ultrasensitive aptasensor was developed and successfully tested in a system designed to detect lysozyme with a detection limit of 0.1 fM. This detection limit is nearly three orders of magnitude lower than those of any previously reported DNAzyme-based aptasensors. PMID- 21826312 TI - The phase (trans)formation and physical state of a model drug in mesoscopic confinement. AB - Compounds embedded into mesoporous or even microporous matrices are interesting for many emerging applications, such as novel catalysts, sensors, batteries, hydrogen storage materials or modern drug delivery devices. We report on two unexpected phenomena regarding the structural and dynamic properties of a model drug substance (indomethacin) when confined in mesoscopic matrices. Firstly, we show that the confinement directs the crystallization of the drug into a stable polymorph that is not otherwise formed at all; its relative amount depends on the pore size. This phenomenon is also explained theoretically using a modified classical heterogeneous nucleation theory. Secondly, we demonstrate that--even at relatively low volume fractions--the confined drug forms a condensed phase in a way that obstructs the passage of the pore channels. This may have far-reaching consequences for understanding the mechanisms of drug release from porous matrices. PMID- 21826313 TI - Size-controlled deposition of Ag nanoparticles on alumina with the assistance of a photo-induced chromic reaction, and study of their catalytic properties. AB - This paper describes a promising method to synthesize supported metal catalysts based on a photochromic reaction. Highly dispersed Ag nanoparticles (NPs) with a mean diameter of ca. 10 nm stabilized by 3-mercaptopropionic acid (3-MPA) were prepared as a colloidal precursor solution. The zeta electric potential was found to be negatively charged in the region of pH higher than 5 due to the presence of dissociated carboxylate ions (-COO(-)), which led to electric repulsion between Ag NPs and kept the solution in a highly dispersed colloidal state. In the presence of photochromic molecules, trans-2-hydroxychalcone, the photo irradiation gradually decreased the electric charge on the nanoparticles owing to the formation of flavylium cations, which induced the assembly of Ag NPs. Such photo-induced assembly-dispersion control of Ag NPs enables size selective deposition on a catalyst support, which is controlled by varying the photo irradiation time. PMID- 21826314 TI - One-electron oxidized product of difluoroiron(III) porphyrin: is it iron(IV) porphyrin or iron(III) porphyrin pi-cation radical? AB - The electronic structure of [Fe(TMP)F(2)], which is formally a one-electron oxidation equivalent above [Fe(III)(TMP)F(2)](-), has been examined in solution by (1)H NMR, UV-Vis, and Mossbauer spectroscopy. In CD(2)Cl(2)-CD(3)OD solution at 193 K, the pyrrole-H and m-H signals appeared at 128.2 and 116.7 ppm, respectively. The UV-Vis spectrum showed broad absorption bands at 560-680 nm. The Mossbauer spectrum taken in frozen toluene-methanol solution exhibited a very broad single line from which the IS and QS values were determined by computer simulation to be 0.50 and 0.14 mm s(-1), respectively. On the basis of these results, it was concluded that the one-electron oxidized product of [Fe(TMP)F(2)](-) should be formulated as the iron(III) radical cation [Fe(III)(TMP)F(2)], not as iron(IV) porphyrin [Fe(IV)(TMP)F(2)] as previously suggested. PMID- 21826316 TI - Electrochemiluminescence detection of near single DNA molecules by using quantum dots-dendrimer nanocomposites for signal amplification. AB - An ultrasensitive electrochemiluminescent biosensor was developed for detection of near single DNA molecules with a linear range of 7 orders of magnitude by combining the specific recognition of a molecular beacon with signal amplification of quantum dots-dendrimer nanocomposites. PMID- 21826317 TI - Bifunctional single-crystalline rutile nanorod decorated heterostructural photoanodes for efficient dye-sensitized solar cells. AB - A novel heterostructural TiO(2) nanocomposite, which consists of single crystalline rutile TiO(2) nanorod decorated Degussa P25 nanoparticles, has been fabricated through a facile acidic hydrothermal method and successfully applied as the photoanodes for efficient dye-sensitized solar cells. The morphology, crystal structure, specific surface area and pore size distribution of the obtained nanocomposite were systematically investigated by X-ray diffraction (XRD), field-emission scanning electron microscope (FESEM), high resolution transmission electron microscope (HRTEM), selected-area electron diffraction patterns (SAED) and nitrogen adsorption-desorption measurements. Under standard illumination conditions (AM 1.5, 100 mW cm(-2)), devices with these hybrid anodes exhibited considerably enhanced photocurrent density and overall conversion efficiency in comparison with that of the commercial Degussa P25 electrodes, which can be partially attributed to the light scattering effect in the long wavelength region as evidenced from the incident photon-to-current conversion efficiency (IPCE) response and the diffuse reflectance spectroscopy. More importantly, devices employing these hybrid anodes have demonstrated extended electron lifetimes and larger electron diffusion coefficient as validated by the intensity-modulated photocurrent/photovoltage spectroscopy measurements, which can be mainly ascribed to the fast electron transport and collection superiority of the single-crystalline nanorods. PMID- 21826315 TI - VEGF internalization is not required for VEGFR-2 phosphorylation in bioengineered surfaces with covalently linked VEGF. AB - Vascular endothelial growth factor (VEGF) is known to activate proliferation, migration, and survival pathways in endothelial cells through phosphorylation of VEGF receptor-2 (VEGFR-2). VEGF has been incorporated into biomaterials through encapsulation, electrostatic sequestration, and covalent attachment, but the effect of these immobilization strategies on VEGF signaling has not been thoroughly investigated. Further, although growth factor internalization along with the receptor generally occurs in a physiological setting, whether this internalization is needed for receptor phosphorylation is not entirely clear. Here we show that VEGF covalently bound through a modified heparin molecule elicits an extended response of pVEGFR-2 in human umbilical vein endothelial cells (HUVECs) and that the covalent linkage reduces internalization of the growth factor during receptor endocytosis. Optical tweezer measurements show that the rupture force required to disrupt the heparin-VEGF-VEGFR-2 interaction increases from 3-8 pN to 6-12 pN when a covalent bond is introduced between VEGF and heparin. Importantly, by covalently binding VEGF to a heparin substrate, the stability (half-life) of VEGF is extended over three-fold. Here, mathematical models support the biological conclusions, further suggesting that VEGF internalization is significantly reduced when covalently bound, and indicating that VEGF is available for repeated phosphorylation events. PMID- 21826318 TI - The effects of organotin on female gastropods. AB - Female masculinisation (FM) in gastropods (imposex, intersex and ovo-testis) has been documented in > 260 species globally. Biomonitoring studies use FM to indirectly assess the presence of tributyltin (TBT), a once popular biocide in antifouling paint, which has since been regulated. Laboratory studies confirm that FM in gastropods can be induced not only by TBT, but other tin (Sn) compounds, Sn "cocktails", steroids, and other contaminants such as Aroclor 1260. Even though FM in gastropods in the field has been attributed to TBT from boating activity, there is evidence that imposex occurred prior to the advent use of TBT in the 1960s, and for some species imposex occurs naturally. There are roughly 42 species that do not elicit a FM response even if they are exposed to TBT under laboratory conditions, collected sympatrically with other species displaying FM, and/or have TBT in their tissues. A geographic analysis of field studies in four regions indicates that the bulk of studies were conducted in Europe > Asia and Oceania > North America > Latin America. More data are needed regarding FM in Africa, the Middle East, and Latin America since data regarding the masculinisation of female gastropods in these areas are lacking. The most studied gastropod species used in TBT biomonitoring studies is the dogwhelk, Nucella lapillus. This review summarizes the progression of the literature from 1962 to 2009 outlining how the terminology, science, and theories have evolved over time. PMID- 21826319 TI - Nanocomposite mesoporous ordered films for lab-on-chip intrinsic surface enhanced Raman scattering detection. AB - Mesoporous nanocomposite materials have been fabricated through integration of evaporation-induced self-assembly and deep X-ray lithography. Micropatterned films made using a mesoporous ordered silica matrix which contains silver nanoparticles have been obtained. The exposure of the mesoporous films to high energy X-rays, which are generated by a synchrotron source, produces several effects: the removal of the surfactant, the densification of the silica backbone and the formation of silver nanoparticles. This integrated process produces a nanocomposite material which has a 2D-hexagonal organized porosity and silver nanoparticles with a sharp size distribution around 5 nm. The patterned nanostructured films have been tested as a lab-on-chip device for intrinsic surface enhanced Raman scattering detection using a solution containing rhodamine 6G in ethanol and measuring Raman response as a function of laser power. PMID- 21826320 TI - Plasmon-induced modulation of the emission spectra of the fluorescent molecules near gold nanorods. AB - Both the excitation and emission processes of a fluorescent molecule positioned near a noble metal nanocrystal can interact strongly with the localized surface plasmon resonance of the metal nanocrystal. While the effects of this plasmon fluorophore interaction on the intensity, polarization, and direction of the fluorescence emission have been intensively investigated, the plasmonic effect on the emission spectrum has barely been explored. We show, on the single-particle level, that the localized surface plasmon resonance of Au nanorods can strongly alter the spectral profile of the emission from adjacent fluorescent molecules. The fluorescent molecules are embedded in a mesostructured silica shell that is uniformly coated on each Au nanorod. The longitudinal plasmon resonance wavelengths of the nanorods are deliberately shifted away from the intrinsic fluorescence emission peak wavelength by synthetically tuning the nanorod aspect ratio. The resultant emission spectra of the fluorescent molecules are found to be remarkably modulated. Besides the intrinsic fluorescence peak, a plasmon induced new peak emerges at the plasmon resonance wavelength. The intensity of this plasmon-induced fluorescence peak increases as the size of the Au nanorod is increased. This spectral modulation can be understood by depicting the decay process of the fluorophore with multiple vibrational energy levels. The plasmon with a specific resonance energy will enhance the transition rate between the energy levels that have the transition energy approximately equal to the plasmon energy. This plasmon-enhanced transition rate results in a modulated spectral profile of the fluorescence emission. PMID- 21826321 TI - Microwave absorption enhancement and electron microscopy characterization of BaTiO3 nano-torus. AB - Uniform BaTiO(3) nano-torus with either concave or epicenter holes were synthesized by a hydrothermal method. Experimental observations indicated that the BaTiO(3) nano-torus with an average diameter ranging from 50 to 100 nm was of tetragonal phases at room temperature. The morphology of the BaTiO(3) nano-torus depends on the shape of the original titanium dioxide precursor and reaction time. The microwave absorption properties of both the BaTiO(3) nano-torus and the BaTiO(3) solid nanoparticles were examined between 2-18 GHz microwave frequency bands. The maximum reflection loss of the BaTiO(3) nano-torus reached -28.38 dB at 11.36 GHz, compared to that of -12.87 dB at 16.32 GHz of the BaTiO(3) solid nanoparticles. The nearly 120% enhancement of the reflection loss in the range of 8-12 GHz was probably attributed to the hollow volume inside the BaTiO(3) nano torus which might contribute more dissipation and scattering effects of the microwave. Growth mechanisms of the BaTiO(3) nano-torus were also investigated by changing both the reaction time from 0.5 h to 48 h and the reactants concentration ratio between Ba(OH)(2).8H(2)O and titanium dioxide. Both an "in situ transformation" mechanism and a "dissolution-precipitation" growth mode were proposed. PMID- 21826322 TI - New synthetic route to substituted dihydroazulene photoswitches. AB - A new procedure for functionalization of the dihydroazulene photoswitch on its seven-membered ring was developed, which has allowed isolation of the first dihydroazulene with a phenyl substituent at position 5 from a mixture of regioisomers. Light-induced ring-opening to the corresponding vinylheptafulvene and the thermal back-reaction was studied in detail. PMID- 21826323 TI - Room temperature synthesis of upconversion fluorescent nanocrystals. AB - Synthesis of nanocrystals that exhibit strong upconversion (UC) luminescence upon infrared excitation has been challenging due to the stringent control needed over experimental variables. Herein, we report a method to synthesize nanocrystals demonstrating high UC at room temperature in aqueous solution on graphene. PMID- 21826324 TI - A novel core-shell molecularly imprinted polymer based on metal-organic frameworks as a matrix. AB - A novel core-shell molecularly imprinted polymer is firstly prepared by coating the MIP shell onto the surface of the metal-organic framework, which shows a homogeneous polymer film, cubic shape, thermal stability, and exhibits a higher specific surface area and a faster transfer-mass speed compared with that of the bulk MIP. PMID- 21826325 TI - Theory and simulation of organic solar cell model compounds: from atoms to excitons. AB - We approach the electronic properties of a simple model of organic solar cells, a binary mixture of alphaalpha'-oligothiophenes and buckminsterfullerene, from a theoretical and numerical perspective. Close-packed model geometries are generated using a Monte Carlo method, the electronic structure is described by a reparametrized semiempirical Pariser-Parr-Pople Hamiltonian. All electronic properties, such as optical absorption spectra, tightly-bound charge transfer states and exciton bands, arise from the same atomistic Hamiltonian using a configuration interaction method involving single excitations. The absorption spectra are dominated by intramolecular contributions, whereas in the optical gap low-lying charge transfer states are predicted. The efficiency of the solar cell crucially depends on the structure of the charge-transfer exciton bands and on the relaxation mechanism. We discuss how these findings may help improve the design of organic solar cells from an excitonic view. PMID- 21826326 TI - Adsorption and reaction of SO2 on clean and oxygen precovered Pd(100)--a combined HR-XPS and DF study. AB - We studied the adsorption and reactivity of SO(2) on clean and oxygen precovered Pd(100) with high resolution X-ray photoelectron spectroscopy and density functional calculations. Upon adsorption at 120 K two different SO(2) species were detected, which were identified as upright-standing and flat-lying molecules by comparing the calculated core level shifts. In agreement with the relative stabilities determined by the calculations the intensities of the photoelectron spectra indicate that the majority species are upright-standing SO(2). Upon heating the quantitative analysis of the data indicates desorption of SO(3) and formation of atomic sulfur. On the oxygen precovered surface small amounts of SO(3) are formed already upon SO(2) adsorption at low temperatures. Upon heating stepwise oxidation of SO(2) to SO(3) and, eventually, to SO(4) is found. Two different SO(4) species were detected, which are assigned to SO(4) bound in the proximity of or remote from oxygen adatoms, according to core level shift estimates. PMID- 21826327 TI - Flexible single-walled carbon nanotubes/polyaniline composite films and their enhanced thermoelectric properties. AB - Flexible single-walled carbon nanotubes/polyaniline (SWNT/PANi) composite films with enhanced thermoelectric properties were prepared via a simple method. Furthermore, these paper-like composite films show good flexibility, which makes them possible to be widely applied in various flexible energy converter devices. PMID- 21826328 TI - pH-reversed ionic current rectification displayed by conically shaped nanochannel without any modification. AB - Ion current through a nascent nanochannel with conically shaped geometry in PET (polyethylene terephthalate) membrane sandwiched between two same buffer solutions at pH <= 3 was routinely considered to exhibit no rectification and, if any, much weaker rectification than that for a nanochannel with a negative surface charge, since the surface charge on the membrane decreases to zero along with decreasing the pH value of the buffer solution down to the pK(a) of carboxylic acid. However, in this study, we discovered that in the buffer solution with low ionic strength at pH values below 3, the conically shaped nanochannels exhibited distinct ion current rectification, as expected for nanochannels with a positive surface charge, if voltages beyond +/-2V range were scanned. We reasoned that the current rectification engendered by the positive surface charge of a conical nanochannel was due to further protonation of the hydrogen bonded hydrogel layer or neutral carboxylic acid inside the nanochannel. Therefore, our results enrich the knowledge about nanochannel technology and indicate that a nanofluidic diode based on pH-reversed ion current rectification through a conical nanochannel can be achieved without any modification of the PET membrane. PMID- 21826329 TI - Effect of ester chemical structure and peptide bond conformation in fragmentation pathways of differently metal cationized cyclodepsipeptides. AB - Fragmentation behavior of two classes of cyclodepsipeptides, isariins and isaridins, obtained from the fungus Isaria, was investigated in the presence of different metal ions using multistage tandem mass spectrometry (MS(n)) with collision induced dissociation (CID) and validated by NMR spectroscopy. During MS(n) process, both protonated and metal-cationized isariins generated product ions belonging to the identical 'b-ion' series, exhibiting initial backbone cleavage explicitly at the beta-ester bond. Fragmentation behavior for the protonated and metal-cationized acyclic methyl ester derivative of isariins was very similar. On the contrary, isaridins during fragmentation produced ions belonging to the 'b' or/and the 'y' ion series depending on the nature of interacting metal ions, due to initial backbone cleavages at the alpha-ester linkage or/and at a specific amide linkage. Interestingly, independent of the nature of the interacting metal ions, the product ions formed from the acyclic methyl ester derivative of isaridins belonged only to the 'y-type'. Complementary NMR data showed that, while all metal ions were located around the beta-ester group of isariins, the metal ion interacting sites varied across the backbone for isaridins. Combined MS and NMR data suggest that the different behavior in sequence specific charge-driven fragmentation of isariins and isaridins is predetermined because of the constituent beta-hydroxy acid residue in isariins and the cis peptide bond in isaridins. PMID- 21826331 TI - Neocuproine-KOtBu promoted intramolecular cross coupling to approach fused rings. AB - Polycycles can be produced with different linkages (A, B = O, N, C, S) by constructing biaryl C-C bonds via neocuproine-KO(t)Bu promoted cross coupling between C-Xs and C-Hs. PMID- 21826330 TI - gamma-AApeptides bind to RNA by mimicking RNA-binding proteins. AB - The interactions between proteins and RNAs are of vital importance for many cellular processes, including transcription and processing of RNA, translation, and viral infections. Here we report an gamma-AApeptide that can mimic HIV-1 Tat protein and bind to TAR RNAs of HIV and BIV with nanomolar affinity, comparable to that of the RNA-binding fragment of Tat (amino acids 49-58). The interaction is resistant to the presence of a large excess of tRNA. With resistance to proteolytic hydrolysis and limitless potential for diversification, gamma AApeptides may emerge as a new class of peptidomimetics to modulate RNA-protein interactions. PMID- 21826345 TI - Coalescence-assisted generation of single nanoliter droplets with predefined composition. AB - We demonstrate the generation of highly accurate nanoliter droplets with a predefined composition. This composition control over a single droplet is achieved by merging two droplets with known concentrations and defined volumes. A forced coalescence is accomplished by synchronizing two piezoelectric-based active droplet generators. A microscope-mounted CCD camera is used to record, quantify and monitor the process to assure its high fidelity. The device is disposable, surfactant free, simple to operate and does not require microelectrode fabrication. It delivers a single on-demand droplet with adjustable high resolution mixing ratios up to 9 at a volume range of 1-10 nanoliters. The presented platform offers, for the first time, a means to perform droplet-based high-throughput screening in the nanoliter range. PMID- 21826346 TI - Multiple fluorescence DeltaCIE and DeltaRGB codes for sensing volatile organic compounds with a wide range of responses. AB - A highly luminescent compound, stilbene-2,4-dimethyl-6-(1,2,2,4-tetramethyl-1,2 dihydroquinolin-6-yl)-1,3,5-s-triazine (MQT), exhibits solvent polarity-induced emission enhancement. A fluorescent sensor array was fabricated with MQT and porous polymer substrates. The colorimetric changes of the array exposed to VOCs can be readily distinguished by the naked eye. Post-processing procedures proved the high selectivity of the array for VOCs. PMID- 21826347 TI - Multi-state multi-mode nuclear dynamics on three isomers of C6H4F2+ using parallelized TDDVR approach. AB - We have performed molecular dynamics on the three isomers of the difluorobenzene radical cation (C(6)H(4)F(2)(+)) after excitation from the ground state to a specific higher electronically excited state by using our recently implemented parallelized Time-Dependent Discrete Variable Representation (TDDVR) methodology. A five-state eleven-mode realistic model Hamiltonian for o-C(6)H(4)F(2)(+) and two separate five-state ten-mode Hamiltonians for m- and p-isomer of the same radical cation are considered, where those five electronic states are interconnected through several conical intersections in the vicinity of the Franck-Condon (FC) region and thus the dynamics for each case become complex. The photoelectron, mass analyzed threshold ionization spectra and population profiles obtained by using our TDDVR approach show reasonably good agreement with the results obtained by multiconfiguration time dependent Hartree (MCTDH) method. It is worthwhile to mention that the parallelized TDDVR algorithm reduces the computation time by more than an order of magnitude compared to its serial analog and, therefore, such approach appears to be a good compromise between accuracy and speed for a large molecular system. PMID- 21826348 TI - On the interpretation of transport properties of sodium cholate and sodium deoxycholate in binary and ternary aqueous mixtures. AB - Sodium cholate (NaC) and sodium deoxycholate (NaDC) in binary and ternary aqueous mixtures were investigated by means of surface tension, electron paramagnetic resonance spectroscopy (EPR), small angle neutron scattering (SANS) and mutual diffusion coefficient analysis. Concerning the NaC-H(2)O and NaDC-H(2)O binary mixtures, the surface tension, EPR and diffusion measurements confirmed the formation of micelles above a well detectable critical concentration. The SANS data indicated for both systems, the formation of ellipsoidal micelles whose major axis increased with concentration and minor axis remained constant. The data were interpreted under the assumption that aggregate growth occurred via hydrogen bonding of small aggregates along one preferential direction. For the NaC-NaDC-H(2)O ternary mixtures, the surface tension and EPR results were in good agreement with the Clint model prediction for the ideal mixed micellization. Based on this model, the SANS data enabled a complete description of the mixed aggregates in terms of dimensions, composition and concentration. In turn, this strategy allowed for a satisfactory interpretation of the main and cross-term diffusion coefficient trends, which are quite complex. PMID- 21826349 TI - Electron-capture induced dissociation of doubly charged dipeptides: on the neutral losses and N-Calpha bond cleavages. AB - Electron capture by doubly charged peptide cations leads to neutral losses in addition to N-C(alpha) bond cleavages that give c and z fragments. In this work we discuss the influence of amino acid sequence on hydrogen versus ammonia loss and the propensity for subsequent partial side-chain cleavage after ammonia loss to give w fragment ions. Experiments were done on two series of doubly protonated dipeptides, [XK+2H](2+) and [XR+2H](2+), where X is one of the twenty common amino acid residues, excluding aspartic acid (D), and K and R are lysine and arginine, respectively. While it was previously established that NH(3) is lost exclusively from the N-terminal ammonium group and not from side-chain ammonium groups, we find here that ammonia can be lost from guanidinium radicals as well. The ratio between H loss and NH(3) loss reveals some information on internal ionic hydrogen bonds and peptide conformation since proton sharing between the N terminal ammonium group and a basic side chain decreases the probability for NH(3) loss due to a lower recombination energy and as a result reduced capture probability. The abundance of w ions was found to correlate with the reaction energy for their formation; highest yield was found for CK and lowest for AK and HK. The survival rate of charge-reduced species was higher for XR than for XK, which is likely linked to the formation of long-lived C(alpha) radicals in the latter case. The probability for N-C(alpha) bond cleavage is smaller on average for XR than for XK which indicates that hydrogen transfer from the epsilon ammonium radical to the amide group triggers some of the cleavages, or is a result of the different distances between the amide group and the charges in XR and XK. Finally, our data support the previous concept that charge partitioning between c and z fragments can be explained by competition between the two fragments for the proton. PMID- 21826350 TI - Molecular dynamics of liquid acetone determined by depolarized Rayleigh and low frequency Raman scattering spectroscopy. AB - Slow to ultrafast dynamics of liquid acetone at variable temperature was investigated by depolarized Rayleigh and low-frequency Raman scattering spectroscopy, in the region 0-200 cm(-1). A detailed analysis was performed on the spectra and corresponding time responses, and a consistent view of the molecular dynamics of this dipolar solvent was obtained. The effects of temperature on the spectra were interpreted, and distinct dynamical processes identified. At very low frequencies, or long time scales, acetone dynamics is characterized by a slow diffusive reorientation obeying the Stokes-Einstein-Debye hydrodynamic theory only in the limit of subslip boundary conditions. An alternative model based on the microviscosity concept proved to be able to reproduce this correlation time and its temperature dependence. A comparative analysis of collective and single-molecule reorientational times, these latter estimated from intramolecular Raman spectra, led to an orientational correlation parameter g(2) of unity, which denotes a statistical disorder of molecular polarizability tensors. A fast local restructuring process is putatively responsible for an additional contribution at subpicosecond time scales often referred to as intermediate response in other molecular liquids. The high frequency portion of the dynamical susceptibility showed the signature of librational intermolecular motions, giving rise to an ultrafast decay of the time correlation function of polarizability anisotropy. The overall approach, which provided valuable information on dynamics, structure and molecular interactions of neat acetone, will be applied to acetone electrolytic solutions. PMID- 21826351 TI - Cross-coupling in flow. AB - Until recently, cross-coupling reactions have been exclusively performed in batch processes. With the advent of microfluidics, significant effort has been devoted to develop a wide variety of continuous-flow techniques to facilitate organic synthesis. In this critical review, we attempt to give an overview of the different continuous-flow methodologies that have been developed and utilized for cross-coupling reactions. In addition, we attempt to point out the advantages of continuous-flow when compared with their batch counterparts (246 references). PMID- 21826352 TI - Binding of metal ions by pyrimidine base pairs in DNA duplexes. AB - Pyrimidine base pairs in DNA duplexes selectively capture metal ions to form metal ion-mediated base pairs, which can be evaluated by thermal denaturation, isothermal titration calorimetry, and nuclear magnetic resonance spectroscopy. In this critical review, we discuss the metal ion binding of pyrimidine bases (thymine, cytosine, 4-thiothymine, 2-thiothymine, 5-fluorouracil) in DNA duplexes. Thymine-thymine (T-T) and cytosine-cytosine (C-C) base pairs selectively capture Hg(II) and Ag(I) ions, respectively, and the metallo-base pairs, T-Hg(II)-T and C-Ag(I)-C, are formed in DNA duplexes. The metal ion binding properties of the pyrimidine-pyrimidine pairs can be changed by small chemical modifications. The binding selectivity of a metal ion to a 5 fluorouracil-5-fluorouracil pair in a DNA duplex can be switched by changing the pH of the solution. Two silver ions bind to each thiopyrimidine-thiopyrimidine pair in the duplexes, and the duplexes are largely stabilized. Oligonucleotides containing these bases are commercially available and can readily be applied in many scientific fields (86 references). PMID- 21826353 TI - Charge-transfer complexes from decamethylferrocene and 1,4-quinone derivatives: neutral-ionic phase diagrams for metallocene complexes. AB - Charge-transfer (CT) complexes of ferrocenes with 1,4-quinone derivatives were investigated. Deca- and octamethylferrocene complexes with 1,4-naphthoquinone derivatives were prepared and structurally characterized; these were neutral 1:2 DA complexes with mixed-stack structures. The formation of complexes with 1,4 benzoquinones was examined by applying solvent-drop grinding. CT energies and phase transitions in these neutral and other ionic complexes were investigated. Their electronic states are discussed on the basis of the phase diagrams derived for mixed-stack ferrocene-based CT complexes, taking into account their dependence on the DA ratio, dimensionality, and intermolecular interactions. PMID- 21826354 TI - Gold(I) complexes of water-soluble diphos-type ligands: synthesis, anticancer activity, apoptosis and thioredoxin reductase inhibition. AB - Gold(I) complexes of imidazole and thiazole-based diphos type ligands were prepared and their potential as chemotherapeutics investigated. Depending on the ligands employed and the reaction conditions complexes [L(AuCl)(2)] and [L(2)Au]X (X = Cl, PF(6)) are obtained. The ligands used are diphosphanes with azoyl substituents R(2)P(CH(2))(2)PR(2) {R = 1-methylimidazol-2-yl (1), 1 methylbenzimidazol-2-yl (4), thiazol-2-yl (5) and benzthiazol-2-yl (6)} as well as the novel ligands RPhP(CH(2))(2)PRPh {R = 1-methylimidazol-2-yl (3)} and R(2)P(CH(2))(3)PR(2) {R = 1-methylimidazol-2-yl (2)}. The cytotoxic activity of the complexes was assessed against three human cancer cell lines and a rat hepatoma cell line and correlated to the lipophilicity of the compounds. The tetrahedral gold complexes [(3)(2)Au]PF(6) and [(5)(2)Au]PF(6) with intermediate lipophilicity (logD(7.4) = 0.21 and 0.25) showed significant cytotoxic activity in different cell lines. Both compounds induce apoptosis and inhibit the enzymes thioredoxin reductase and glutathione reductase. PMID- 21826355 TI - Phosphido pincer complexes of platinum: synthesis, structure and reactivity. AB - A series of platinum(II) complexes supported by the tridentate bis(phosphine)phosphido ligand bis(2-diisopropylphosphinophenyl)phosphide) [(i)Pr PPP] have been synthesized and characterized (1-4). X-Ray structural studies of [(i)Pr-PPP]PtCl (1) and [(i)Pr-PPP]PtCH(3) (3) complexes show meridional [(i)Pr PPP] ligands around approximately square-planar platinum centers. Structural data and NMR analysis highlight a strong trans influence for the phosphido phosphorous donor, comparable to that of the anionic aryl carbon of the classic PCP pincer complexes. A series of thermally stable [PPP]Pt(IV) compounds, including [PPP]Pt(CH(3))(2)X [X = I (5) and SbF(6) (6)], were also synthesized. The study of the binding affinity of SO(2) and NO to complex 1 has also been addressed. PMID- 21826356 TI - A facile method for the synthesis of copper modified amine-functionalized mesoporous zirconia and its catalytic evaluation in C-S coupling reaction. AB - A new copper modified amine functionalized zirconia has been synthesized by a co condensation method using zirconium butoxide and aminopropyltriethoxy-silane (APTES) in the presence of a cationic surfactant CTAB followed by impregnation of copper. Nitrogen adsorption-desorption, X-ray powder diffraction, Fourier transform infrared spectroscopy (FT-IR), (13)C nuclear magnetic resonance (NMR), scanning electron micrography (SEM), transmittance electron micrography (TEM), thermo gravimetric analysis-differential thermal analysis (TGA-DTA), X-ray photoelectron spectroscopy (XPS) and UV-vis DRS spectroscopic tools are used to characterize the materials. FT-IR and DRS results indicated the incorporation of Cu and amino groups on the surface of zirconia. This Cu-anchored mesoporous material acts as an efficient, reusable catalyst in the aryl-sulfur coupling reaction between aryl iodide and thiophenol for the synthesis of value added diarylsulfides. PMID- 21826357 TI - A comparison of rapid and conventional measures of indicator bacteria as predictors of waterborne protozoan pathogen presence and density. AB - E. coli and enterococci in recreational waters are monitored as indicators of fecal contamination, pathogen presence, and health risk. Quantitative polymerase chain reaction (qPCR) tests for fecal indicator bacteria can provide beach managers with same-day information about water quality, unlike culture methods which provide that information the following day. The abilities of qPCR measurements of indicator bacteria, as compared to culture measurements of indicator bacteria, as predictors of pathogen presence or density in surface waters are not well understood. The purpose of this study was to make such comparisons between water samples collected from Chicago area surface waters, including rivers, inland lakes, Lake Michigan, and the Chicago Area Waterways System, which is dominated by wastewater effluent. A total of 294 twenty-litre samples were collected and analyzed for Giardia and Cryptosporidium. qPCR and membrane filtration methods were used to quantify E. coli and enterococci. Correlation, logistic regression, and zero-inflated Poisson modeling were utilized to evaluate associations between indicators and parasites. qPCR and culture measures of the indicator bacteria were similar in their ability to predict parasite presence and density. Correlations between parasites and indicators were generally stronger at waters not dominated by effluent. Associations between indicator density and Giarida presence were observed more consistently than between indicator density and Cryptosporidium presence. Associations between enterococci and parasites were generally stronger than associations between E. coli and parasites. The use of qPCR monitoring in our setting would generate more timely results without compromising the ability to predict parasite presence or density. PMID- 21826358 TI - Monitoring fine and ultrafine particles in the atmosphere of a Southeast Chinese city. AB - There have been few studies on submicron particles in the atmosphere reported from developing countries. With rapid economic development, the size of the road vehicle fleet has increased dramatically in China. The increase in vehicle emissions has raised concerns about air quality, especially in the urban areas of this developing country. A model study was conducted in Hangzhou, a city in Southeast China, with the aim of characterizing the emission patterns of submicron particles <=1.0 micron from on-road vehicles and the impact of vehicle density and speed on the concentrations of submicron particles in the atmosphere. Results showed that the average ultrafine particle (UFP) number concentration was 45 805 particles cm(-3) and the average mass concentration of particulate matter 1.0 (PM1.0) was 217 MUg m(-3) during the survey period. Autoregressive Integrated Moving Average modelling results indicated that an increase of vehicle density and driving speed were positively correlated with the increase of UFP and PM1.0 concentrations (p < 0.05) in the atmosphere. Results from this study suggest that vehicle density and driving speed are significant predictors of submicron particle emissions. This study provides first hand information for future investigations on the submicron particle emissions in Hangzhou, a city with rapidly increasing vehicle numbers and for further investigations into a possible causal relationship between submicron particles and health effects on local residents. PMID- 21826359 TI - Cranberry phytochemicals inhibit glycation of human hemoglobin and serum albumin by scavenging reactive carbonyls. AB - Protein glycation caused by sugars and reactive carbonyls is a contributing factor to diabetic complications, aging, and other chronic diseases. The objective of this study was to investigate the inhibitory effects of cranberry phytochemicals on protein glycation. Cranberries, purified to yield sugar-free phytochemical powder, were fractionated into ethyl acetate and water fractions. Water fraction was further separated into water fraction I, II, and III on a Sephadex LH-20 column. Cranberry phytochemical powder and its fractions significantly inhibited the formation of glycated hemoglobin. The concentrations of cranberry phytochemicals required to inhibit 50% of albumin glycation (EC(50)) in albumin-glucose assay were lower than that of aminoguanidine except for water fraction I. Cranberry phytochemicals inhibited glycation of human serum albumin mediated by methylglyoxal, but the EC(50) were higher than that of aminoguanidine. Carbonyl scavenging assay showed that water fraction II scavenged 89.3% of methylglyoxal at 6 h of reaction. Fractions enriched with procyanidins showed higher antiglycation activities, suggesting procyanidins were the major active components. The hypothesis whether cranberry procyanidins scavenged reactive carbonyls by forming adducts was tested. Epicatechin was used as a model compound to react with methylglyoxal and glyoxal at pH 7.4. Five adducts were detected and their structures were tentatively identified using HPLC-ESI-MS/MS. PMID- 21826360 TI - A tunable 3D optofluidic waveguide dye laser via two centrifugal Dean flow streams. AB - This paper presents a tunable optofluidic waveguide dye laser utilizing two centrifugal Dean flows. The centrifugal Dean flow increases the light confinement of the dye laser by shaping a three-dimensional (3D) liquid waveguide from curved microchannels. The active medium with the laser dye is dissolved in the liquid core and pumped with an external pump laser to produce stimulated emission. The laser's Fabry-Perot microcavity is formed with a pair of aligned gold-coated fiber facets to amplify the fluorescent emission. The advantage of the 3D optofluidic waveguide dye laser is its higher efficiency, thus to obtain lasing at a reduced threshold (60%) with higher output energy. The demonstrated slope efficiency is at least 3-fold higher than its traditional two-dimensional equivalent. In addition, the laser output energy can be varied on demand by tuning the flow rates of the two flows. This technique provides a versatile platform for high potential applications microfluidic biosensor and bioanalysis. PMID- 21826361 TI - Classification of cell types using a microfluidic device for mechanical and electrical measurement on single cells. AB - This paper presents a microfluidic system for cell type classification using mechanical and electrical measurements on single cells. Cells are aspirated continuously through a constriction channel with cell elongations and impedance profiles measured simultaneously. The cell transit time through the constriction channel and the impedance amplitude ratio are quantified as cell's mechanical and electrical property indicators. The microfluidic device and measurement system were used to characterize osteoblasts (n=206) and osteocytes (n=217), revealing that osteoblasts, compared with osteocytes, have a larger cell elongation length (64.51 +/- 14.98 MUm vs. 39.78 +/- 7.16 MUm), a longer transit time (1.84 +/- 1.48 s vs. 0.94 +/- 1.07 s), and a higher impedance amplitude ratio (1.198 +/- 0.071 vs. 1.099 +/- 0.038). Pattern recognition using the neural network was applied to cell type classification, resulting in classification success rates of 69.8% (transit time alone), 85.3% (impedance amplitude ratio alone), and 93.7% (both transit time and impedance amplitude ratio as input to neural network) for osteoblasts and osteocytes. The system was also applied to test EMT6 (n=747) and EMT6/AR1.0 cells (n=770, EMT6 treated by doxorubicin) that have a comparable size distribution (cell elongation length: 51.47 +/- 11.33 MUm vs. 50.09 +/- 9.70 MUm). The effects of cell size on transit time and impedance amplitude ratio were investigated. Cell classification success rates were 51.3% (cell elongation alone), 57.5% (transit time alone), 59.6% (impedance amplitude ratio alone), and 70.2% (both transit time and impedance amplitude ratio). These preliminary results suggest that biomechanical and bioelectrical parameters, when used in combination, could provide a higher cell classification success rate than using electrical or mechanical parameter alone. PMID- 21826362 TI - Control of silver-polymer aggregation mechanism by primary particle spatial correlations in dynamic fractal-like geometry. AB - Silver nanocrystals have been prepared by reacting silver nitrate with ascorbic acid in aqueous solution containing a low concentration of a commercial polynaphthalene sulfonate polymer (Daxad 19). Various crystalline morphologies have been obtained simply by tuning the reaction temperature. We have investigated the nanoparticle formation mechanism at three different temperatures by in situ and time resolved small angle X-ray scattering measurements. By modeling the scattering intensity with interacting spherical particles in a fractal-like polymer-Ag matrix, we found signatures of nucleation, growth and assembly of primary particles of about 15-20 nm. We observed how the time evolution of both spatial correlations between primary particles and the dynamic fractal geometry of the polymer-Ag matrix could influence and determine both the aggregation mechanism and the morphology of forming nanostructures in solution. PMID- 21826363 TI - Applicability of photodynamic antimicrobial chemotherapy as an alternative to inactivate fish pathogenic bacteria in aquaculture systems. AB - Aquaculture activities are increasing worldwide, stimulated by the progressive reduction of natural fish stocks in the oceans. However, these activities also suffer heavy production and financial losses resulting from fish infections caused by microbial pathogens, including multidrug resistant bacteria. Therefore, strategies to control fish infections are urgently needed, in order to make aquaculture industry more sustainable. Antimicrobial photodynamic therapy (aPDT) has emerged as an alternative to treat diseases and prevent the development of antibiotic resistance by pathogenic bacteria. The aim of this work was to evaluate the applicability of aPDT to inactivate pathogenic fish bacteria. To reach this objective a cationic porphyrin Tri-Py(+)-Me-PF was tested against nine pathogenic bacteria isolated from a semi-intensive aquaculture system and against the cultivable bacteria of the aquaculture system. The ecological impact of aPDT in the aquatic environment was also tested on the natural bacterial community, using the overall bacterial community structure and the cultivable bacteria as indicators. Photodynamic inactivation of bacterial isolates and of cultivable bacteria was assessed counting the number of colonies. The impact of aPDT in the overall bacterial community structure of the aquaculture water was evaluated by denaturing gel gradient electrophoresis (DGGE). The results showed that, in the presence of Tri-Py(+)-Me-PF, the growth of bacterial isolates was inhibited, resulting in a decrease of ~7-8 log after 60-270 min of irradiation. Cultivable bacteria were also considerably affected, showing decreases up to the detection limit (~2 log decrease on cell survival), but the inactivation rate varied significantly with the sampling period. The DGGE fingerprint analyses revealed changes in the bacterial community structure caused by the combination of aPDT and light. The results indicate that aPDT can be regarded as a new approach to control fish infections in aquaculture systems, but it is clearly more difficult to inactivate the complex natural bacterial communities of aquaculture waters than pure cultures of bacteria isolated from aquaculture systems. Considering the use of aPDT to inactivate pathogenic microbial community of aquaculture systems the monitoring of microorganisms is needed in order to select the most effective conditions. PMID- 21826364 TI - A thiolate/disulfide ionic liquid electrolyte for organic dye-sensitized solar cells based on Pt-free counter electrodes. AB - The ionic liquid, 1-ethyl-3-methylimidazolium tetracyanoborate, was employed to prepare a thiolate/disulfide ionic liquid electrolyte with low viscosity for organic dye-sensitized solar cells (DSCs). CoS was introduced and showed better photovoltaic performance in DSCs than the ubiquitous platinized FTO CE. PMID- 21826365 TI - Strong anodic near-infrared electrochemiluminescence from CdTe quantum dots at low oxidation potentials. AB - Anodic near-infrared electrochemiluminescence (ECL) from CdTe quantum dots was achieved at low potential on a glass carbon electrode and a strategy for greatly enhanced band-gap ECL was presented. PMID- 21826366 TI - One-pot synthesis of imidazoles from aromatic nitriles with nickel catalysts. AB - Nickel(0) catalysts were used to produce substituted imidazoles in good to high yields using benzonitrile, p-substituted benzonitriles and 4-cyanopyridine as starting materials. PMID- 21826367 TI - Preparation of fibrous cellulose by enzymatic polymerization using cross-linked mutant endoglucanase II. AB - A cross-linked mutant endoglucanase II was prepared for enzymatic polymerization to cellulose. The cross-linked enzyme is composed of three mutant enzymes showing polymerization activity. A characteristic feature of the polymerization with this cross-linked enzyme is formation of cellulose fibrils in contrast to plate-like crystals obtained by using a free enzyme. PMID- 21826368 TI - A fluoro analogue of UDP-alpha-D-glucuronic acid is an inhibitor of UDP-alpha-D apiose/UDP-alpha-D-xylose synthase. AB - UDP-2F-glucuronic acid was synthesized and analyzed as a mechanistic probe to investigate the ring contraction step catalyzed by UDP-d-apiose/UDP-d-xylose synthase (AXS). PMID- 21826369 TI - A general and efficient approach to 2H-indazoles and 1H-pyrazoles through copper catalyzed intramolecular N-N bond formation under mild conditions. AB - A new efficient copper-catalyzed intramolecular amination reaction has been developed to readily synthesise a wide variety of multi-substituted 2H-indazole and 1H-pyrazole derivatives from easily accessible starting materials under mild conditions. A highly selective ligand for estrogen receptor beta was prepared in three steps by employing this method. PMID- 21826370 TI - Preparation of eta2-complexes of fullerenes by reduction. Crystal structure and optical properties of {Ni(dppp).(eta2-C70)}.(C6H4Cl2)0.5. AB - The new reduction method for preparation of eta(2)-complexes of fullerenes with nickel-1,3-bis(diphenylphosphino)propane has been developed in which Ni(dppp)Cl(2) and C(60)(C(70)) mixtures are reduced with sodium tetraphenylborate. Single crystals of the first eta(2)-complex of nickel with fullerene C(70): {Ni(dppp).(eta(2)-C(70))}.(C(6)H(4)Cl(2))(0.5) (1) (C(6)H(4)Cl(2) = o-dichlorobenzene) have been obtained as well as the previously described complex with fullerene C(60): {Ni(dppp).(eta(2)-C(60))}.(Solvent) (2). The crystal structure of 1 has been solved to show the coordination of nickel to the C-C bond of C(70) at the 6-6 ring junction of eta(2)-type to form Ni-C(C(70)) bonds of 1.929-1.941(2) A length, the shortest M-C bonds among those known for eta(2)-complexes of fullerenes C(60) and C(70). The length of the C-C bond to which Ni atom is coordinated (1.494(3) A) is noticeably longer than the average length of these bonds in C(70) (1.381(2) A). Optical spectra of 1 in the IR- and UV-visible ranges have been analyzed to show the splitting of some C(70) bands due to C(70) symmetry lowering. The complex has a red-brown color in solution and manifests three bands in the visible range at 379, 467 and 680 nm. The solution of 1 is air sensitive since air exposure restores the color and absorption bands of the starting C(70) at 383 and 474 nm. PMID- 21826371 TI - Multiple receptor-mediated functions of activated protein C. AB - The central effector protease of the protein C pathway, activated protein C (APC), interacts with the endothelial cell protein C receptor, with protease activated receptors (PAR), the apolipoprotein E2 receptor, and integrins to exert multiple effects on haemostasis and immune cell function. Such receptor interactions modify the activation of PC and determine the biological response to endogenous and therapeutically administered APC. This review summarizes the current knowledge about interactions of APC with cell surface-associated receptors, novel substrates such as histones and tissue factor pathway inhibitor, and their implications for the biologic function of APC in the control of coagulation and inflammation. PMID- 21826372 TI - Retroviral insertional mutagenesis can contribute to immortalization of mature T lymphocytes. AB - Several cases of T-cell leukemia caused by gammaretroviral insertional mutagenesis in children treated for x-linked severe combined immunodeficiency (SCID) by transplantation of autologous gene-modified stem cells were reported. In a comparative analysis, we recently showed that mature T cells, on the contrary, are highly resistant to transformation by gammaretroviral gene transfer. In the present study, we observed immortalization of a single T-cell clone in vitro after gammaretroviral transduction of the T-cell protooncogene LMO2. This clone was CD4/CD8 double-negative, but expressed a single rearranged T cell receptor. The clone was able to overgrow nonmanipulated competitor T-cell populations in vitro, but no tumor formation was observed after transplantation into Rag-1 deficient recipients. The retroviral integration site (RIS) was found to be near the IL2RA and IL15RA genes. As a consequence, both receptors were constitutively upregulated on the RNA and protein level and the immortalized cell clone was highly IL-2 dependent. Ectopic expression of both, the IL2RA chain and LMO2, induced long-term growth in cultured primary T cells. This study demonstrates that insertional mutagenesis can contribute to immortalization of mature T cells, although this is a rare event. Furthermore, the results show that signaling of the IL-2 receptor and the protooncogene LMO2 can act synergistically in maligniant transformation of mature T lymphocytes. PMID- 21826373 TI - let-7 microRNAs induce tamoxifen sensitivity by downregulation of estrogen receptor alpha signaling in breast cancer. AB - MicroRNAs (miRNAs) play an important regulatory role in breast tumorigenesis. Previously, we found that let-7 miRNAs were downregulated significantly in formalin-fixed paraffin-embedded (FFPE) breast cancer tissues. In this study, we further found that endogenous levels of let-7b and let-7i miRNAs are inversely correlated with levels of estrogen receptor (ER)-a36, a new variant of ER alpha66, in the FFPE tissue set. Bioinformatic analysis suggested that ER-alpha36 may be another target of let-7 miRNAs. To test this hypothesis, cotransfection of let-7 mimics or inhibitors together with full-length or a fragment of ER-alpha36 3'UTR luciferase construct was performed, and we found that let-7b and let-7i mimics suppressed the activity of reporter gene significantly, which was enhanced remarkably by let-7b and let-7i inhibitors. Both mRNA and protein expression of ER-alpha36 were inhibited by let-7 mimics and enhanced by let-7 inhibitors. Furthermore, ER-alpha36 mediated nongenomic MAPK and Akt pathways were weakened by let-7b and let-7i mimics in triple negative breast cancer cell line MDA-MB 231. The reverse correlation between let-7 miRNAs and ER-alpha36 also exists in Tamoxifen (Tam)-resistant MCF7 cell line. Transfection of let-7 mimics to Tam resistant MCF7 cells downregulated ER-alpha36 expression and enhanced the sensitivity of MCF7 cells to Tam in estrogen-free medium, which could be restored by overexpression of ER-alpha36 constructs without 3'UTR. Our results suggested a novel regulatory mechanism of let-7 miRNAs on ER-alpha36 mediated nongenomic estrogen signal pathways and Tam resistance. PMID- 21826375 TI - [Assets health model: are possible salutogenic policies?]. PMID- 21826376 TI - [Salutogenic model analysis in Spain: application in public health and implications for asset health model]. AB - This article seeks to provide an in depth review about one of the most revolutionary and influential methods used in understanding the variables and processes that explain human health. Based on a new vision in the analysis of the consequences of the Nazi Holocaust, a doctor-sociologist--Aaron Antonovsky- managed to influence medicine and behavioral science by facilitating the keys for the optimal development of public health today. Despite the fact that this theory began appearing in the 1970s in the 20th century, its real development and expansion have been seen in recent years. In fact, in Spain, there is little scientific literature that analyses the theoretic keys of the model in depth. This work seek to cover this gap; to achieve this objective, it first presents how the construct of salutogenesis arose, the social-cultural context that promoted it, as well as the importance public health acquires today. This is the aim of this work, which analyses the theoretical bases of the salutogenesis model, with specific emphasis on its background and precursors, as well as its inception, development and current expansion. PMID- 21826377 TI - [Social impact of abusive alcohol consumption in Spain: consumption, cost and policies]. AB - Although it has declined in recent decades, alcohol consumption in Spain is still high compared with other European countries. The consumption pattern shows a converging trend with Europe, with a decrease in consumption of wine and an increase in the consumption of beer. Likewise, mortality related to alcohol consumption has also declined in the last twenty years, but remains a major cause of death. The direct healthcare costs and indirect costs of diseases totally and partially attributable to alcohol consumption in 2007 was 2669.74 million. The effective tax regime in Spain gravel alcohol very little, so a substantial increase, in line with some European countries, could be an option to be considered for accelerating the reduction of the burden of morbidity and mortality associated with alcohol consumption. PMID- 21826378 TI - [Validation of scale to evaluate the relationship between family-work in family physicians]. AB - BACKGROUND: Studying the work-family relationships is important because it affects the personal and professional life. Women increases in medicine without redistribute domestic tasks and responsibilities. The purpose of this study was to create and validate a scale of work-family relations in women and men family physician (FP) in Andalusia. METHODS: Cross sectional and multicenter study. The study population were FP of urban primary care centres, sample=500FP (50% by sex). We studied: sex, age, postgraduate family medicine specialty, care burden (2 variables), and family burden (7 variables). We design, and included in self administered questionnaires, a scale of 13 questions on work-family relations. Bivariate analysis, exploratory factor and multiple regressions to test the convergent validity was performed. RESULTS: The response rate was 73.6%. We identified two dimensions, Overloading and Family Support Deficit (OFSD) (5 questions), and Work-Family Conflict (WFC) (6 questions), in both, female FP score higher than their peers. There are more family variables associated with both dimensions in female FP, it expresses differences in the complexity of the causes of OFSD and WFC by sex. CONCLUSION: The scale obtained is valid, reliable and gives two empirical dimensions of family-work relationships. PMID- 21826374 TI - Selective IgA deficiency in autoimmune diseases. AB - Selective immunoglobulin A deficiency (IgAD) is the most common primary immunodeficiency in Caucasians. It has previously been suggested to be associated with a variety of concomitant autoimmune diseases. In this review, we present data on the prevalence of IgAD in patients with Graves disease (GD), systemic lupus erythematosus (SLE), type 1 diabetes (T1D), celiac disease (CD), myasthenia gravis (MG) and rheumatoid arthritis (RA) on the basis of both our own recent large-scale screening results and literature data. Genetic factors are important for the development of both IgAD and various autoimmune disorders, including GD, SLE, T1D, CD, MG and RA, and a strong association with the major histocompatibility complex (MHC) region has been reported. In addition, non-MHC genes, such as interferon-induced helicase 1 (IFIH1) and c-type lectin domain family 16, member A (CLEC16A), are also associated with the development of IgAD and some of the above diseases. This indicates a possible common genetic background. In this review, we present suggestive evidence for a shared genetic predisposition between these disorders. PMID- 21826379 TI - [Validation of the underlying cause of death in medicolegal deaths]. AB - BACKGROUND: Deaths due to external causes require additional medical tests in order to determine the cause of death. If these results are not incorporated into the death register these causes may be misclassified. The objective of this study is to validate the underlying cause of death of the Mortality Register with information obtained from forensic sources in Barcelona between 2004 and 2006. METHODS: Cross-sectional design. The study population consisted of deceased residents in Barcelona with a medicolegal intervention between 2004 and 2006. The sources of information are the Mortality Registry and the forensic pathology file filled in by Institute of Legal Medicine of Catalonia (ILMC) (gold standard). The study variables are the cause of death, sex and age. Sensitivity and percentage of confirmation (PC) with 95% confidence intervals (95% CI) are calculated. RESULTS: The sensitivity of external causes is 59.7% (95% CI:56.5-62.9) and PC is 96.7% (95% CI:94.8-98.0). Traffic injuries, poisonings and suicides are under reported in the Mortality Register with a sensitivity lower than 45% and a PC higher than 80%. Symptoms, signs and ill-defined conditions are over-reported with a sensitivity of 89.2% (95% CI:83.4-93.4) and a PC of 28.0% (95% CI:24.2 32.1). There are no differences by sex and age. CONCLUSIONS: The validity of the external causes in the Mortality Register is low due to under-reporting and the high proportion of symptoms signs and ill-defined causes. According to the results, incorporating information from forensic sources to the Mortality Register increases the quality of mortality statistics. PMID- 21826380 TI - [Situation of environmental and food area disinfectants registered in Spain under directive 98/8/CE]. AB - BACKGROUND: Directive 98/8/EC harmonizes and regulates in the European market authorization and registration of biocides and establishes a period of 14 years for review of active substances. This study analyzes the most significant changes produced in the registry of biocides used as disinfectants registered since the publication of the Directive. METHOD: Information was obtained from the registry of biocides published in the website of the Ministry of Health, Social Policy and Equality in May 2010. We used an Excel data base for the dump and data processing. RESULTS: There are 1575 biocides with intended use as environmental and food area disinfectants registered in Spain (1137 formulas and 438 active ingredients). Formulas are composed of 56 active sustances which are being assessed for their inclusion in the Community list of authorized substances. 54% of the formulas are registered as both bactericide and fungicide, 79% are contact disinfectants, 42% of the formulas correspond to those composed of quaternary ammonium compounds and 67.9% are made with a single active substance. Regarding hazardous properties 45.3% are corrosive, 25.7% irritant, 9.8% harmful, 1.1% toxic , and 33.1% are dangerous to the environment. CONCLUSIONS: The Spanish registry of biocides has complied with the provisions of the Directive cancelling the registrations of the formulas containing substances not included in the list. Of all the substances which are under review in Europe, 58% of environmental disinfectants and 76.4% of food area disinfectants are authorized in Spain. PMID- 21826381 TI - [Exposure to lindane, other pesticides and organochlorines in the general population Barakaldo, Spain]. AB - BACKGROUND: A plant of lindane in Barakaldo produced discharges of hexachlorocyclohexane (HCH). Closed in 1987 leaving inside 4500Tm; the problem was not solved until 2002. A judicial process required an epidemiological assessment of the possible contamination The aim of this study is to measure the degree of impregnation of the POPs in the nearby population. METHODS: Cross sectional study conducted in 2008, 154 volunteers from three health centres in Barakaldo and 270 controls from Bilbao, Alonsotegi and Balmaseda. We measured serum levels of eight organochlorine pesticides, and seven polychlorinated biphenyls (PCBs). We used the chi2 test to study the association between categorical variables and t test of Student to compare geometric means. Confounding factors were adjusted using a linear regression model. RESULTS: There was a detectable compound average of 6.3 per person. PCBs 52 and 101, alpha -HCH, beta-endosulfan and heptachlor epoxide could not be quantified; PCB 28, gamma-HCH and p, p'-DDT were detected in 6.6, 0.9 and 8.05 % of subjects respectively and the beta-HCH, HCB, p, p'-DDE, and PCBs 118, 138, 153 and 180 in the 73.8, 87.3, 98.6, 59.2, 97.6, 98.6 y 98.6 % respectively. After adjusting for age, there were no higher levels of beta-HCH in Barakaldo than in controls, (beta = 0.02, SE = 0.07), or HCB, p, p'-DDE, PCB 118, PCB 138, PCB 153 and PCB 180. CONCLUSION: Six years after having solved the problem near to the factory and storage of HCH, there was no significantly higher levels of HCH, after adjustment for age. PMID- 21826382 TI - [Caesarean delivery in Andalusia, Spain: relationship with social, clinical and health services factors (2007-2009)]. AB - BACKGROUND: Increasing trend and geographical variations in the use of caesarean section suggest the influence of non-clinical factors. The objective was to describe the use of caesarean section in the Andalusian region in Spain by exploring the role of social, clinical, and health services variables. METHODS: A cross-sectional study was carried out using vital statistics. It involves all births occurred in Andalusia during the period of 2007-2009. The dependent variable was the use of caesarean section and the set of covariates were classified into three groups: those with a clinical meaning, those related to the health services organization, and those with a social significance. Multivariate logistic regressions were used. RESULTS: In the data set of 293,558 births, the prevalence of caesarean delivery was 24.8%. The multivariate analysis highlights the labour complications as the clinical variable with the highest odds ratio (OR=19.36). Regarding the health services variables, the odds of experiencing a caesarean delivery were 55% higher on weekdays than on weekends. Cadiz was the province with the highest OR for caesarean section (comparison between Cadiz and Almeria: OR=1,21) where the ratio between births in public and private hospitals was 3.7. The frequency of caesarean section was 34% higher in women with third level education than those with no education. CONCLUSIONS: Labour complication is the most influential variable for caesarean section. Caesarean birth rate is above the accepted standards for all social classes and increases with educational level. Inter-provincial differences reflect different patterns with regard to the use of private medicine. PMID- 21826383 TI - [Relationship between tobacco smoke and dental caries in school children at the Valencian Country]. AB - BACKGROUND: Recently, it has focused the role of exposure to environmental tobacco smoke in the etiology of dental caries, so we plan to evaluate the association between environmental tobacco smoke inhalation and caries experience in 10-15-years-old children. METHODS: A transversal descriptive study was designed. Carried out in the Primary Dentistry Unit. 9th Health Department. Valencian Country (Spain). 380 children random sample was selected (following the inclusion criteria). Each participant was clinically explored, then answered a self-administered opinion test about contact with tobacco smoke. MEASUREMENTS: DMF-T and df-t indexes and their components, plaque and gingival indexes, contact with tobacco smoke frequency (at home or not), own opinion about tobacco effects and present or future tobacco consumption. RESULTS: Children living with smokers at home showed a decayed teeth average of 1,9 +/- 2,34, while those not living with smokers had 1,03 +/- 1,46 ( p<0,001). df and DMF average indexes for children exposed and not exposed to tobacco smoke were 0,27 +/- 0,78 (df)and 1,62 +/- 2,21 (DMF) and 0,10 +/- 0,47 (df) and 0,92 +/- 1,40 (DMF) respectively (p=0,039 y p<0,001). CONCLUSIONS: In our study conditions, coexistence with environmental tobacco smoke is associated with a higher caries prevalence in both deciduous and permanent dentitions in 10-15-years-old children. PMID- 21826384 TI - [Changes in the distribution of hepatitis C virus (HCV) genotypes over the 1999 2010 period in northern Valladolid, Spain]. AB - BACKGROUND: A retrospective analysis was carried out in all specimens from subjects with chronic hepatitis C sent for testing to our laboratory in Hospital Universitario Rio Hortega (Valladolid, Spain) over the period 1999-2009. The reason for this study was to examine the suggestion of other authors on the spread of genotype 4 strains. The objective was to describe the distribution of VHC genotypes in our geographical area and compare it with other state-wide reports. METHODS: A total of 1074 patients were studied. Specimen preparation to isolate HCV RNA was carried out with the COBAS AmpliPrep system (Roche). Reverse transcription, amplification and reverse hybridization were performed with Qiagen and Siemens kits. RESULTS: The most frequent HCV genotype was 1 (69%), followed by 3 (19,6%) and 4 (8.2%). The most frequent HCV subtype was 1b (41.3%). Most infections with genotype 4 (58%) were found among HCV-HIV-coinfected patients. From our previous report in 2002 to date (end December 2010), both an increase in the prevalence of genotypes 4 (from 7.3 to 8.8%) and 1 and 1a (from 25.9 to 29.4%) and a decrease in the prevalence of genotype 1b (from 44% to 39,5%) has been observed over time. Patients with genotype 4 were, mostly, men and with HIV HCV coinfection. CONCLUSIONS: The prevalence of genotype 4 in our geographical environment was significantly different than the national average which leads to the conclusion that the spread of this genotype was much slower than suggested. PMID- 21826385 TI - Upper limb function in adults with Duchenne muscular dystrophy. AB - OBJECTIVE: To determine upper limb function and associated factors in adults with Duchenne muscular dystrophy. DESIGN: Cross-sectional study. SUBJECTS: A sample of 70 men with Duchenne muscular dystrophy (age range 20-43 years). METHODS: General motor function and, in particular, upper limb distal motor function, were assessed with the Motor Function Measure. Muscle strength and range of motion of the upper limb were evaluated using hand-held dynamo-metry, manual muscle-testing and goniometry. Associations were studied using Spearman's correlation coefficients and multiple linear regression analysis. RESULTS: General motor function was severely impaired. Wide variability was found in distal motor function, muscle strength and range of motion of the upper limb, especially in early adulthood. Muscle strength and range of motion explained 76% of the variance in upper limb distal motor function. CONCLUSION: This study illustrates a large variability in upper limb function in adult patients with Duchenne muscular dystrophy, and identifies muscle strength and range of motion as factors strongly associated with upper limb function. These results suggest that preserving muscle strength and range of motion in Duchenne patients might be relevant for a better outcome of distal motor function of the upper limb when adult. PMID- 21826387 TI - Commentary on "spasticity or reversible muscle hypertonia?". PMID- 21826386 TI - Changes in gait symmetry, gait velocity and self-reported function following total hip replacement. AB - OBJECTIVE: To investigate the magnitude of change at different time points in measures of gait symmetry, gait velocity and self-reported function following total hip replacement. DESIGN: Longitudinal with test occasions pre-surgery and 3, 6 and 12 months post-surgery. SUBJECTS: Thirty-four patients with hip osteoarthritis (mean age 63 years, standard deviation 11 years). METHODS: Subjects walked back and forth along a 7-m walkway at slow, preferred and fast speed. Anteroposterior, vertical and mediolateral trunk symmetry was assessed by accelerometry, while single support symmetry, step-length symmetry and gait velocity was simultaneously assessed by an electronic walkway. Self-reported function was assessed by Hip disability and Osteoarthritis Outcome Score. Gait symmetry data were normalized for gait velocity. Changes between test occasions were reported as effect size. RESULTS: All measures showed effect sizes > 0.30 from pre-operative to 12-months postoperative assessments, and improvements were significant (p < 0.05) in all measures, except mediolateral symmetry. In general, gait symmetry and gait velocity improved most 6 and 12 months postoperatively, while self-reported function improved most 3 months postoperatively. CONCLUSION: Early improvements were seen in self-reported function, suggesting immediate relief from stiffness and pain, while gait symmetry and velocity improved later postoperatively, suggesting that gait quality and performance require prolonged rehabilitation with postoperative guidance, muscular strengthening and motor relearning. PMID- 21826388 TI - Hand-held dynamometry: tester strength is paramount, even in frail populations. AB - OBJECTIVE: To determine test-retest and inter-rater reliability of hand-held dynamometry when used to measure knee--extensor strength in patients with advanced cancer. SUBJECTS: Adults with metastatic or locally advanced cancer recruited from palliative care services to a study of the risk factors for falls. METHODS: Consecutive recruits (n = 30) underwent repeat testing after an interval of 1 h, by the same researcher, to assess test-retest reliability. The subsequent 15 patients underwent retesting by a second researcher. The intra-class correlation coefficient and limits of agreement were calculated. RESULTS: The test-retest reliability difference between measurements increased with the magnitude of measurement, mean leg strength = 113 N (standard deviation 43.1), 95% ratio limits of agreement 0.81-1.5, intra-class correlation coefficient = 0.9. The inter-rater testing mean leg strength = 128.5 N (standard deviation 35.1), 95% limits of agreement = -57.24 to 36.06 N. Intra-class correlation coefficient = 0.83. CONCLUSION: Test-retesting and inter-rater testing yielded high intra-class correlation coefficients, but the limits of agreement were wide. In test-retesting, the difference between tests increased as the magnitude of measurement increased. It has been widely reported that hand-held dynamometry is reliable when used to measure knee-extensor strength in frail or elderly persons. However, our results show that, even in these populations, reliability may be compromised by inadequate tester strength. PMID- 21826389 TI - Towards a conceptual description of rehabilitation as a health strategy. AB - OBJECTIVE: A proposal for a conceptual description of rehabilitation was made in 2007 based on the International Classification of Functioning, Disability and Health. This conceptual description should foster the development of a common understanding of rehabilitation and its professions. The present paper aims to report on the development and current state of the discussions about this conceptual description and to provide the current version, which has been adopted by different European professional and scientific organizations. METHODS: First, the history of the development of the conceptual description of rehabilitation is reported. Secondly, suggestions for modifications or amendments are introduced, and the resulting phrases and terms are presented and discussed. DISCUSSION AND CONCLUSION: One major change to the conceptual description of rehabilitation is the explicit integration of the perspective of the disabled person. The relationship between person and provider is characterized as a partnership. However, it is argued that quality of life should not be introduced as a primary goal of rehabilitation. This conceptual description can foster a common understanding of the rehabilitation professions and provide a point of departure for clarifying the role of different professions and services within the broad field of rehabilitation. It can also serve to position rehabilitation as a major health strategy and to sharpen the perception of rehabilitation among external stakeholders. PMID- 21826390 TI - Commentary on "spasticity or reversible muscle hypertonia?". PMID- 21826391 TI - Optimization of SMN trans-splicing through the analysis of SMN introns. AB - Spinal muscular atrophy (SMA), a neurodegenerative disease, is the leading genetic cause of infantile death and is caused by the loss of survival motor neuron 1 (SMN1). Humans carry a duplicated copy gene, SMN2, which produces very low levels of functional protein due to an alternative splicing event. This splicing difference is the reason that SMN2 cannot prevent SMA development when SMN1 is deleted. SMN2 generates a transcript lacking exon 7 and consequently gives rise to an unstable truncated SMN protein that cannot protect from SMA. To increase full-length SMN protein, we utilize a strategy referred to as trans splicing. This strategy relies upon pre-mRNA splicing occurring between two separate molecules: (1) the endogenous target RNA and (2) the therapeutic RNA that provides the correct RNA sequence via a trans-splicing event. The initial trans-splicing RNA targeted intron 6 and replaced exon 7 with the SMN1 exon 7 in SMN2 pre-mRNA. To determine the most efficient intron for SMN trans-splicing event, a panel of trans-splicing RNA molecules was constructed. Each trans splicing RNA molecule targets a specific intron within the SMN2 pre-mRNA and based on the target intron, replaces the downstream exons including exon 7. These constructs were examined by RT-PCR, immunofluorescence, and Western blotting. We have identified intron 3 as the most efficient intron to support trans-splicing in cellular assays. The intron 3 trans-splicing construct targets intron 3 and replaces exons 4-7 and was distinguished based on its ability to produce the highest level of the trans-spliced RNA and full-length SMN protein in SMA patient fibroblasts. The efficiency of the intron 3 construct was further improved by addition of an antisense that blocks the 3' splice site at the intron 4/exon 5 junction. Most importantly, intracerebroventricular injection of the Int3 construct into SMNDelta7 mice elevated the SMN protein levels in the central nervous system. This research demonstrates an alternative platform to correct genetic defects, including SMN expression and examines the molecular basis for trans-splicing. PMID- 21826393 TI - Accessing community-based and long-term care services: challenges facing persons with frontotemporal dementia and their families. AB - There are several barriers to accessing services for persons with frontotemporal dementia (FTD), and few studies have examined service needs and satisfaction with services for family caregivers of persons with FTD. Persons with FTD and their families have reported consistent difficulties in their attempts to access care and support. These are: (1) difficulty obtaining a diagnosis; (2) financial concerns due to loss of employment, job-related income; (3) problems accessing social security disability insurance; and (4) lack of adequate community-based and long-term care services and resources. Successful care practices such as use of an interdisciplinary team and helpful care models such as person-centered care and the antecedent-behavior-consequence method are described. Further investigation and research are needed to understand best care strategies for persons with FTD. PMID- 21826392 TI - Inflammation-induced changes in the chemical coding pattern of colon-projecting neurons in the inferior mesenteric ganglia of the pig. AB - The present study examines the chemical coding of the inferior mesenteric ganglia after chemically induced colitis in the pig animal model. In all animals (n = 6), a median laparotomy was performed under anesthesia, and the Fast Blue retrograde tracer was injected into the descending colon wall. In experimental animals (n = 3), the thick descending colon were injected with formalin solution to induce inflammation. The animals were euthanized and the inferior mesenteric ganglion was harvested and processed for double-labeling immunofluorescence for calbindin D28k (CB) in combination with either tyrosine hydroxylase (TH), neuropeptide Y (NPY), somatostatin (SOM), vasoactive intestinal polypeptide (VIP), nitric oxide synthase (NOS), Leu-enkephalin (LENK), substance P (SP), vesicular acetylcholine transporter (VAChT), or galanin (GAL). Immunohistochemistry revealed significant changes in the chemical coding pattern of inferior mesenteric ganglion neurons. In control animals, Fast Blue-positive neurons were immunoreactive to TH, NPY, SOM, VIP, LENK, CB, and NOS. In the experimental group, TH, NPY, SOM, VIP, and LENK expressing neurons were reduced, whereas the number of neurons immunoreactive to CB, NOS, and GAL were increased. The increase of so-called neuroprotective neuropeptides suggests that the changes in the chemical coding of inferior mesenteric ganglion neurons reflect adaption under pathological conditions to promote their own survival. PMID- 21826394 TI - Right hemisphere recruitment during language processing in frontotemporal lobar degeneration and Alzheimer's disease. AB - Right hemisphere recruitment of areas homotopical to affected left-sided language areas has classically been described in aphasia following stroke or brain tumors. It may also be a clinically significant mechanism in frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD). In a pooled analysis of previous functional magnetic resonance imaging studies of a modified version of the Pyramids and Palm Trees test, we probed the language network in 19 patients with primary progressive aphasia (nine semantic (SV) and ten agrammatic variant; neuropathologically confirmed FTLD in three cases to date), 15 patients with AD (14 clinically probable and one neuropathologically definite AD to date), and 37 healthy controls. The upper and lower bank of the left posterior superior temporal sulcus (STS) was affected in AD and the left anterior temporal pole (ATP) in primary progressive aphasia (PPA; mainly driven by SV). In the right hemisphere, the posterior STS showed an activity increase in both patient groups compared with controls. In AD, this activity increase correlated positively with naming accuracy. Both in AD and in PPA, the connection strength between right STS and right ATP was decreased compared with controls and this correlated with naming and comprehension scores, respectively. Only in PPA did the right anterior temporal pole show an activity increase, which correlated negatively with comprehension. Right-hemispheric recruitment and disconnections within the right temporal lobe may affect the degree of aphasia in cortical neurodegenerative disease. PMID- 21826395 TI - Increased expression of DNA methyltransferase 1 and 3a in human temporal lobe epilepsy. AB - DNA methylation is a key epigenetic modification of DNA that is catalyzed by DNA methyltransferase (DNMT). Increasing evidence suggests that DNA methylation in neurons regulates synaptic plasticity as well as neuronal network activity. Here, we evaluated DNA methyltransferase 1 (Dnmt1) and Dnmt3a expression in brain tissues of epileptic patients to explore their possible role in epileptogenesis. Tissue samples from temporal neocortices of 25 patients with intractable temporal lobe epilepsy (TLE) and ten histologically normal temporal lobes from control patients were used to detect Dnmt1 and Dnmt3a expression through immunohistochemistry, immunofluorescence, and Western blotting analysis. We found that both Dnmt1 and Dnmt3a expression were principally expressed in the nucleus and the cytoplasm of NeuN-positive neurons, but not in GFAP-positive astrocytes. Levels of the two DNMT proteins were significantly increased in patients with TLE. Our study suggests that DNMT1 and DNMT3a may play a role in the pathogenesis of TLE. PMID- 21826396 TI - Expression of a secretory beta-glucosidase from Trichoderma reesei in Pichia pastoris and its characterization. AB - A beta-glucosidase gene (bglI) from Trichoderma reesei was cloned into the pPIC9 vector and integrated into the genome of Pichia pastoris GS115. Under the control of the methanol-inducible alcohol oxidase (AOX) promoter and using Saccharomyces cerevisiae secretory signal peptide (alpha-factor), the recombinant beta glucosidase was expressed and secreted into the culture medium. The maximum recombinant beta-glucosidase activity achieved was 60 U/ml, and beta-glucosidase expression reached 0.3 mg/ml. The recombinant 76 kDa beta-glucosidase was purified 1.8-fold with 26% yield and a specific activity of 197 U/mg. It was optimally active at 70 degrees C and pH 5.0. PMID- 21826397 TI - Synthesis of gamma-aminobutyric acid by expressing Lactobacillus brevis-derived glutamate decarboxylase in the Corynebacterium glutamicum strain ATCC 13032. AB - PURPOSE OF WORK: Purpose of this work is to synthesize gamma-aminobutyric acid by glutamate-producing species expressing Lactobacillus brevis-derived glutamate decarboxylase genes, i.e. recombinant Corynebacterium glutamicum strains, which directly convert endogenous L-glutamate precursor into gamma-aminobutyric acid (GABA) through single-step fermentation. To express exogenous glutamate decarboxylase (GAD) in an L-glutamate-producing strain, Lactobacillus brevis Lb85, which can produce GABA, was used. Two Lb85 GAD genes, gadB1 and gadB2, and the ancillary genes, gadC-gadB2 and gadR-gadC-gadB2, were cloned separately into pDXW-8 and transformed into C. glutamicum. All four recombinant strains produced GABA whereas the wild-type strain did not. GABA produced by the recombinant strains continually increased after 36 h of fermentation. Although the mRNA levels of LbgadB2 and LbgadC were similar among the corresponding recombinants, GABA production of pDXW-8/gadRCB2 at 72 h (2.15 g/l) was higher than that of pDXW 8/gadCB2 (1.25 g/l) and pDXW-8/gadB2 (0.88 g/l). Thus, by introducing Lbgad genes, C. glutamicum was genetically engineered to synthesize GABA using endogenous L-glutamate. PMID- 21826398 TI - Effects of temperature during soybean seed development on defense-related gene expression and fungal pathogen accumulation. AB - Soybean [Glycine max (L.) Merr] plants were exposed to three temperature regimens during seed development to investigate the effect of temperature on the expression of eight defense-related genes and the accumulation of two fungal pathogens in inoculated seeds. In seeds prior to inoculation, either a day/night warm (34/26 degrees C) or a cool temperature (22/18 degrees C) relative to normal (26/22 degrees C) resulted in altered patterns of gene expression including substantially lower expression of PR1, PR3 and PR10. After seed inoculation with Cercospora kikuchii, pathogen accumulation was lowest in seeds produced at 22/18 degrees C in which of all defense genes, MMP2 was uniquely most highly induced. For seeds inoculated with Diaporthe phaseolorum, pathogen accumulation was lowest in seeds produced at 34/26 degrees C in which of all defense genes, PR10 was uniquely most highly induced. Our detached seed assays clearly demonstrated that the temperature regimens we applied during seed development produced significant changes in seed defense-related gene expression both pre- and post inoculation and our findings support the hypothesis that global climate change may alter plant-pathogen interactions and thereby potentially crop productivity. PMID- 21826399 TI - Inducible protein expression in Drosophila Schneider 2 cells using the lac operator-repressor system. AB - Schneider line 2 cells, derived from Drosophila melanogaster, can be used as a highly versatile gene expression system. Two powerful promoters derived from the actin5C (Ac5) and metallothionein (Mtn) genes are available. The Mtn promoter can be used for the inducible expression of heterologous proteins unsuitable for constitutive expression. However, to circumvent using CuSO(4) or CdCl(2) as inducers of the Mtn promoter, we created a modified Ac5 promoter, Ac5LacO, in which two short lac operator sequences are embedded. Expression from the Ac5LacO promoter was regulated with co-expression of the lac repressor and IPTG. More than 25-fold induction of firefly luciferase expression was achieved in transient transfection experiments. Furthermore, we demonstrated that the lac operator repressor regulatory system functioned in chromosomally integrated cell lines. PMID- 21826400 TI - Malic acid production from thin stillage by Aspergillus species. AB - The ability of Aspergillus strains to utilize thin stillage to produce malic acid was compared. The highest malic acid was produced by Aspergillus niger ATCC 9142 at 17 g l(-1). Biomass production from thin stillage was similar with all strains but ATCC 10577 was the highest at 19 g l(-1). The highest malic acid yield (0.8 g g(-1)) was with A. niger ATCC 9142 and ATCC 10577 on the stillage. Thus, thin stillage has the potential to act as a substrate for the commercial production of food-grade malic acid by the A. niger strains. PMID- 21826401 TI - Ginsenoside F1 production from ginsenoside Rg1 by a purified beta-glucosidase from Fusarium moniliforme var. subglutinans. AB - Fusarium moniliforme var. subglutinans was selected from among 100 strains of fungi for producing ginsenoside F(1) from ginsenoside Rg(1). The enzyme responsible was purified as a single 85 kDa band with a specific activity of 136 U mg(-1). It hydrolysed glucose-linked ginsenosides Rb(1), Rd and Rg(1) but not for other monosaccharide-linked ginsenosides, Rb(2), Rc, R(1), and Re. Under the optimum conditions of pH 6.0, 50 degrees C, 30 U l(-1) of enzyme, and 5 mg Rg(1) ml(-1), 4 mg F(1) ml(-1) was produced after 4 h, with a molar yield of 100% and a productivity of 1 g l(-1) h(-1). This represents the highest productivity and conversion yield of F(1) yet reported. PMID- 21826402 TI - Micropropagation and hairy root culture of Ophiorrhiza alata Craib for camptothecin production. AB - An efficient system was developed for the in vitro micropropagation and hairy root culture of Ophiorrhiza alata Craib for camptothecin (CPT) production. Shoot multiplication on leaf and node explants from germinated seeds of O. alata was successful on half-strength Murashige and Skoog medium supplemented with varying amounts of kinetin and alpha-naphthaleneacetic acid. Node explants grown in vitro were successfully infected by Agrobacterium rhizogenes TISTR 1450 for the establishment of hairy root culture. The amount of CPT in various parts of O. alata was analyzed by HPLC. The accumulation of CPT in transformed hairy roots was twice that in soil-grown plants (785 +/- 52 and 388 +/- 32 MUg/g dry wt, respectively). In the presence of a polystyrene resin (Diaion HP-20) that absorbed CPT, the CPT content in the culture media increased sevenfold compared with controls (1,036 and 151 MUg per 250 ml medium, respectively). These results enable the feasible production of CPT of O. alata by means of a cell culture strategy. These measures can help safeguard the plant from extinction. PMID- 21826403 TI - The difficult mountain: enriched composition in adjective-noun phrases. AB - When readers need to go beyond the straightforward compositional meaning of a sentence (i.e., when enriched composition is required), costly additional processing is the norm. However, this conclusion is based entirely on research that has looked at enriched composition between two phrases or within the verb phrase (e.g., the verb and its complement in . . . started the book . . .) where there is a discrepancy between the semantic expectations of the verb and the semantics of the noun. We carried out an eye-tracking experiment investigating enriched composition within a single noun phrase, as in the difficult mountain. As compared with adjective-noun phrases that allow a straightforward compositional interpretation (the difficult exercise), the coerced phrases were more difficult to process. These results indicate that coercion effects can be found in the absence of a typing violation and within a single noun phrase. PMID- 21826404 TI - The effect of HIV protease inhibitors on amyloid-beta peptide degradation and synthesis in human cells and Alzheimer's disease animal model. AB - Combined antiretroviral therapy (ART) tremendously improved the lifespan and symptoms associated with AIDS-defining illness in affected individuals. However, chronic ART-treated patients frequently develop age-dependent complications, including dementia, diabetes, and hyperlipidemia: all risk factors of Alzheimer's disease. Importantly, the effect of ART compounds on amyloid generation and clearance has never been systematically examined. Nine prescribed HIV protease inhibitors were tested for their effect on amyloid-beta peptide (Abeta) clearance in primary cultured human monocyte-derived macrophages. Atazanavir, ritonavir, and saquinavir modestly inhibited of Abeta degradation, while lopinavir, nelfinavir, and ritonavir enhanced secretion of undigested Abeta after phagocytosis. Lopinavir, nelfinavir, ritonavir, and saquinavir inhibited endogenous Abeta40 production from primary cultured human cortical neurons, which were associated with reduction in Beta-site APP Converting Enzyme 1 (BACE1) and gamma-secretase enzyme activities. However, ART compounds showed little inhibition of purified BACE1 activity in vitro, suggesting the indirect effect of ART compounds on BACE1 activity in neurons. Finally, nefinavir or lopinavir/ritonavir (Kaletra) were orally administered for 30 days into APP SCID mice expressing a double mutant form of APP 695 (KM670/671NL + V717F) in homozygosity for the scid allele of Prkdc. There was no difference in beta amyloidosis by ART drug administration as determined by both immunohistochemistry and ELISA measurements although the therapeutic doses of the ART compounds was present in the brain. These data demonstrated that ART drugs can inhibit Abeta clearance in macrophages and Abeta production in neurons, but these effects did not significantly alter Abeta accumulation in the mouse brain. PMID- 21826406 TI - LOX-1: a new target for therapy for cardiovascular diseases. AB - There is much interest in the role of oxidant stress in an ever-increasing list of disease states. However, the precise mediator of oxidant stress and the stressor molecule/s have not been identified. Accordingly, trials of inhibitors of oxidant stress in animal models of disease states have met only limited success. The trials of traditional anti-oxidant vitamins have been largely unsuccessful in the treatment of a wide array of disease states in humans. Recent identification of LOX-1 in vascular endothelial cells and its activation by oxidant species have led to a marked improvement in our understanding of the pathology of several cardiovascular disease states. Here, we review the disease states where therapy targeted at LOX-1 inhibition might be helpful. PMID- 21826405 TI - Morphine, but not trauma, sensitizes to systemic Acinetobacter baumannii infection. AB - Acinetobacter baumannii is an important nosocomial pathogen in civilian intensive care units. Recently the incidence has increased in wounded military personnel. Morphine is documented in numerous animal studies to be immunosuppressive and to sensitize to infection. The hypotheses were tested that morphine, administered for analgesia in the battlefield, predisposes to Acinetobacter infection, and that the opioid may have an additive or synergistic effect with trauma. To test these hypotheses, an intraperitoneal infection model was established in mice using several Acinetobacter strains. Morphine administered for 48 h by implantation of a slow-release morphine pellet increased mortality compared to animals receiving a placebo pellet, an effect that was blocked by the mu-opioid receptor antagonist, naltrexone. Acinetobacter burdens in the blood, spleens, livers, and lungs of morphine-treated mice, were significantly higher than those in placebo-treated animals, confirming that mortality was due to potentiated growth of the bacteria. There were also elevated levels of pro-inflammatory cytokines in morphine-treated versus placebo-treated mice. Morphine caused a reduction in the total number of cells in the peritoneal cavity, a decrease in the percentage and total numbers of neutrophils, and a decrease in the total number of macrophages. Morphine treatment also suppressed levels of the neutrophil-inducing molecules, IL-17A and KC/CXCL1. However, IL-17A(-/-) mice given morphine were not sensitized to Acintobacter infection to a greater degree than similarly treated wild-type mice. Trauma alone did not sensitize to Acinetobacter infection, and there was no additive effect between morphine and trauma. These results support the hypothesis that morphine potentiates Acinetobacter infection. PMID- 21826407 TI - Tunnel position and graft orientation in failed anterior cruciate ligament reconstruction: a clinical and imaging analysis. AB - PURPOSE: It has been reported that technical error in positioning the graft tunnel is the most common problem in anterior cruciate ligament (ACL) reconstruction. The objective of this study was to quantitatively evaluate femoral and tibial tunnel positions and intra-articular graft orientation of primary ACL reconstruction in patients who had undergone revision ACL reconstruction. We postulated that this patient cohort had a nonanatomically positioned tunnel and graft orientation. METHODS: Twenty-six patients who had undergone a revision ACL were investigated. Clinical magnetic resonance (MR) images prior to revision were analysed. Three-dimensional models of bones and tunnels on the femur and tibia were created. Intra-articular graft orientation was measured in axial, sagittal and coronal planes. Graft positions were measured on the tibial plateau as a percentage from anterior to posterior and medial to lateral; graft positions on the femur were measured using the quadrant method. RESULTS: Sagittal elevation angle for failed ACL reconstruction graft (69.6 degrees +/- 13.4 degrees ) was significantly greater (p < 0.05) than that of the native anteromedial (AM) and posterolateral (PL) bundles of the ACL (AM 56.2 degrees +/- 6.1 degrees , PL 55.5 degrees +/- 8.1 degrees ). In the transverse plane, the deviation angle of the failed graft (37.3 degrees +/- 21.0 degrees ) was significantly greater than native ACL bundles. The tibial tunnel in this patient cohort was placed posteromedially and medially to the anatomical AM and PL bundles, respectively. The femoral tunnel was placed anteriorly to the anatomical AM and PL bundles. CONCLUSIONS: This study reveals that both the tibial and femoral tunnel positions and consequently the intra-articular graft orientation in this patient group with failed ACL reconstruction were nonanatomical when compared with native ACL values. The results can be used to improve tunnel placement in ACL reconstruction. PMID- 21826408 TI - Modular endoprosthetic replacement for failed internal fixation of the proximal femur following trauma. AB - PURPOSE: Although originally designed for reconstruction after primary malignant bone tumour resection, modular endoprosthetic replacement (EPR) can be used in salvage surgery for complex periprosthetic fracture and failed internal fixation. The purpose of this study was to assess the functional outcome following EPR for failed internal fixation of the proximal femur. METHODS: We assessed clinical and functional outcomes of using a modular tumour endoprosthesis to reconstruct the proximal femur following failed internal fixation in eight consecutive patients between 2001 and 2008. RESULTS: There were four men and four women, with a mean age of 67.5 (range 50-79) years and a mean follow-up of 16.5 (6-36) months. All patients had failed internal fixation for traumatic proximal femoral fractures- four 31.A2.3, two 31.A3.1, two 31.A3.3 using the Arbeitsgemeinshaft fur Osteosynthesefragen (AO) fracture classification. Mean time from the first attempted internal fixation to definitive EPR was 34 (6-102) months, and the median number of previous surgical procedures was two (1-11). Histology revealed infection (two cases), uninfected nonunion (five cases) and plasmocytoma (one case). The EPR was carried out as a one-stage procedure in six cases and a two stage procedure in two cases. Mean postoperative Harris Hip Score was 71.4 (range 64-85). There were no surgical complications. One patient died as a result of systemic complications of myeloma several years following EPR. CONCLUSIONS: EPR is an effective salvage procedure for failed fixation of traumatic proximal femoral fractures. Immediate weightbearing and a good functional outcome can be expected in this difficult group of patients. PMID- 21826409 TI - Leptomeningeal Metastasis from Appendiceal Adenocarcinoma: Case Report and Literature Review. PMID- 21826410 TI - CD117 (C-Kit)-Negative Jejunal Epithelioid Gastrointestinal Stromal Tumour (GIST) Presenting as Intussusception. PMID- 21826411 TI - Alpha-Fetoprotein-Producing Extrahepatic Tumor: Clinical and Histopathological Significance of a Case. AB - INTRODUCTION: The serum rise of alpha-fetoprotein (AFP) has been relationed to hepatic tumors. Other than these, such as gastric adenocarcinoma, can present with high levels of this glycoprotein. One rare kind of gastric adenocarcinoma, called hepatoid subtype, has two essential features: hepatoid differentiation in histology and high levels of AFP in serum. DISCUSSIONS: We report a Spanish female who consulted because of fatigue, anorexia, and weight loss. In laboratory data, she presented anemia and markedly elevation of AFP. On CT scan, a gastric mass resulted without hepatic dissemination, and subsequently, gastroduodenoscopy was performed for histological diagnosis. Then, an ulcerated mass was detected and sample was taken, resulting in poorly-differentiated adenocarcinoma of stomach with hepatoid tissue foci, with intense positivity for AFP immunohistochemical staining. This rare cancer has poor prognosis even with early gastrectomy and chemotherapy. PMID- 21826412 TI - Formation of novel CENP-A domains on tandem repetitive DNA and across chromosome breakpoints on human chromosome 8q21 neocentromeres. AB - Endogenous human centromeres form on megabase-sized arrays of tandemly repeated alpha satellite DNA. Human neocentromeres form epigenetically at ectopic sites devoid of alpha satellite DNA and permit analysis of centromeric DNA and chromatin organization. In this study, we present molecular cytogenetic and CENP A chromatin immunoprecipitation (ChIP) on CHIP analyses of two neocentromeres that have formed in chromosome band 8q21 each with a unique DNA and CENP-A chromatin configuration. The first neocentromere was found on a neodicentric chromosome 8 with an inactivated endogenous centromere, where the centromeric activity and CENP-A domain were repositioned to band 8q21 on a large tandemly repeated DNA. This is the first example of a neocentromere forming on repetitive DNA, as all other mapped neocentromeres have formed on single copy DNA. Quantitative fluorescent in situ hybridization (FISH) analysis showed a 60% reduction in the alpha satellite array size at the inactive centromere compared to the active centromere on the normal chromosome 8. This neodicentric chromosome may provide insight into centromere inactivation and the role of tandem DNA in centromere structure. The second neocentromere was found on a neocentric ring chromosome that contained the 8q21 tandemly repeated DNA, although the neocentromere was localized to a different genomic region. Interestingly, this neocentromere is composed of two distinct CENP-A domains in bands 8q21 and 8q24, which are brought into closer proximity on the ring chromosome. This neocentromere suggests that chromosomal rearrangement and DNA breakage may be involved in neocentromere formation. These novel examples provide insight into the formation and structure of human neocentromeres. PMID- 21826414 TI - Microbial population analysis of nutrient removal-related organisms in membrane bioreactors. AB - Membrane bioreactors (MBR) are an important and increasingly implemented wastewater treatment technology, which are operated at low food to microorganism ratios (F/M) and retain slow-growing organisms. Enhanced biological phosphorus removal (EBPR)-related organisms grow slower than ordinary heterotrophs, but have never been studied in detail in MBRs. This study presents a comprehensive analysis of the microorganisms involved in EBPR in pilot- and full-scale MBRs, using fluorescence in situ hybridization (FISH), as well as an overall assessment of other relevant microbial groups. The results showed that polyphosphate accumulating organisms (PAOs) were present at similar levels in all studied MBRs (10% +/- 6%), even those without a defined anaerobic zone. Glycogen accumulating organisms were also detected, although rarely. The FISH results correlated well with the observed P removal performance of each plant. The results from this study suggest that a defined anaerobic zone is not necessarily required for putative PAO growth in MBRs, since polyphosphate storage may provide a selective advantage in fulfilling cell maintenance requirements in substrate-limited conditions (low F/M). PMID- 21826413 TI - The template choice decision in meiosis: is the sister important? AB - Recombination between homologous chromosomes is crucial to ensure their proper segregation during meiosis. This is achieved by regulating the choice of recombination template. In mitotic cells, double-strand break repair with the sister chromatid appears to be preferred, whereas interhomolog recombination is favoured during meiosis. However, in the last year, several studies in yeast have shown the importance of the meiotic recombination between sister chromatids. Although this thinking seems to be new, evidences for sister chromatid exchange during meiosis were obtained more than 50 years ago in non-model organisms. In this mini-review, we comment briefly on the most recent advances in this hot topic and also describe observations which suggest the existence of inter-sister repair during meiotic recombination. For instance, the behaviour of mammalian XY bivalents and that of trivalents in heterozygotes for chromosomal rearrangements are cited as examples. The "rediscovering" of the requirement for the sister template, although it seems to occur at a low frequency, will probably prompt further investigations in organisms other than yeast to understand the complexity of the partner choice during meiosis. PMID- 21826415 TI - Imported malaria in Belgrade, Serbia, between 2001 and 2009. AB - Since 2000, travel of Serbian citizens to tropical areas has been slowly but steadily increasing. To determine the epidemiological and clinical characteristics of imported malaria in Serbia, we analyzed clinical history data of all travelers who presented at the Clinic for Infectious and Tropical Diseases in Belgrade after their return from tropical and subtropical areas between 2001 and 2009. The study series involved a total of 2981 travelers, and included both those with (847) and without (2134) health problems. Malaria was diagnosed in 102 cases (3.4% of all travelers; 12.0% of travelers with febrile episodes). Occurring at a rate of 6 to 16 cases per year, it was predominantly imported from Africa (92.2%), particularly from Equatorial Guinea (38.2%) and Nigeria (15.7%). The most frequent reason for travel was work/business. Patients were predominantly (87.3%) male, and the majority (66.7%) was between 40 and 59 years of age. A total of 15 (14.7%) patients took some form of anti-malarial chemoprophylaxis. The dominant causative species was Plasmodium falciparum (78), alone (70) or in mixed infection with P. vivax (5) and P. malariae (3). P. vivax, P. ovale and P. malariae as single agents were each identified in 11, 1 and 1 cases, respectively. Of the 11 cases in which the parasite was not detected, six appeared to be true submicroscopic cases. The clinical course of the disease was severe in 13 patients, all with falciparum malaria, of which three (2.9%) died. Rather than for all travelers, in Serbia screening for malaria should be mandatory in all travelers to endemic regions who present with fever irrespective of chemoprophylaxis history. Inadequate sensitivity of conventional diagnostic methods, illustrated by the cases of submicroscopic malaria, requires introduction of molecular diagnosis in routine practice. PMID- 21826417 TI - Iatrogenic death: A review of cases from 1990-2000 investigated at the Department of Forensic Medicine, Vienna. AB - Medical malpractice is a global problem which can have considerable financial and legal consequences for the community as well as personal consequences for those involved. Austria does not record any statistical and epidemiological data concerning medical malpractice cases. Data from 7,211 autopsy cases from the Department of Forensic Medicine in Vienna covering the period from 1990 to 2000 were analyzed. Fifty-five autopsy reports that were filed as suspected medical malpractice were recorded and analyzed. Thirty cases were classified as surgical incidents, 19 cases as negligence, and 6 cases as medication incidents. Out of a total of 40 cases from available court files, 36 cases were dropped, there were 2 acquittals and only two resulted in convictions. The number of instances of medical malpractice leading to iatrogenic deaths in Austria seems to be very low in comparison to other countries. The possibility that many cases go unnoticed needs to be taken into consideration. PMID- 21826416 TI - Current status of the clinical development and implementation of paediatric artemisinin combination therapies in Sub-Saharan Africa. AB - Timely treatment of infected children with artemisinin based combination therapies is an essential tool for the effective control and potential elimination of malaria. Until recently only tablet formulations have been available for the treatment of children leading to problems of swallowability, palatability and dosing. In consequence, paediatric drug formulations of artemisinin-based combination therapy (ACT) have been developed, showing a clinically significant improvement of tolerability in young children and of their implementation is an increasingly important public health issue. In this mini review, we focus on the recent development of paediatric ACTs and their use in practice. Paediatric ACTs are formulated as syrup, powder for suspension, dispersible tablets and granules. Overall, the use of paediatric formulation results in an improved management of clinical malaria in young children. To date, only two paediatric ACTs have been certified with WHO prequalification status as an internationally accepted quality standard. Many more paediatric ACTs are available and in use in sub-Saharan Africa despite a lack of publicly available evidence from stringent clinical development programs. The conduct of effectiveness studies to support the introduction of paediatric ACTs in official treatment recommendations is crucial in the global strategy of malaria elimination and quality assurance of available products is a public health priority. PMID- 21826418 TI - Massive gastric distension. PMID- 21826421 TI - A preconcentration procedure for the determination of cadmium in biological material after on-line cloud point extraction. AB - In this paper, a method involving on-line preconcentration with cloud point extraction for the determination of cadmium in biological samples is presented. The procedure is based on the sorption of micelles containing Cd(II) ions and the reagent 4-(5'-bromo-2'-thiazolylazo)orcinol (Br-TAO) in a minicolumn packed with polyester. The surfactant Triton X-114 was used in the formation of micelles. After sorption, the Cd(II) ions were desorbed from the minicolumn with acid eluent and determined by flame atomic absorption spectrometry. Parameters influencing the cloud point extraction were studied. The method showed a detection limit of 0.5 MUg l(-1) and an enhancement factor of 27. The accuracy was tested by determination of cadmium in certified reference materials (spinach leaves 1570a and tomato leaves 1573a) from the National Institute of Standards and Technology. PMID- 21826420 TI - Urban daily life routines and human exposure to environmental discomfort. AB - This study suggests a shift in focus from studying environmental discomfort in urban strategic stations, from which average results for the city or specific results for selected sites are deduced, and from measuring environmental conditions in fixed monitoring stations to a study in which we monitor, with mobile portable sensors, the exposure of people to environmental sources of discomfort while performing their daily life activities. Significant variations in sense of discomfort were measured in this study, and almost half of this variability was found to be explained while four independent environmental variables were considered: air quality (concentrations of CO), noise level, climatic variables (thermal load), and social loads. The study conducted in the city of Tel Aviv, which suffers from hot, humid summers and cool winters, and noise levels that reach the average levels of 85 dB, and relatively lower levels of exposure to the other potential stressors. These levels of combined exposures result in moderate levels of discomfort for young, healthy people once they experience the more stressing environments in the city. It is shown also that noise from other people is the most salient source of discomfort in Tel Aviv. Levels of discomfort accumulate during the working hours, either due to the impact of social loads or noise, but the subjects showed good coping abilities that enabled them to recover in late afternoons. It seems that thermal load does not have immediate impact, but rather cumulative ones, mainly during transitional seasons when subjects are less adaptive to extreme changes in weather. PMID- 21826422 TI - Removable, fully covered, self-expandable metal stents for the treatment of refractory benign esophagogastric anastomotic strictures. AB - The use of metal stents for malignant esophageal strictures for palliation is well accepted. However, utilization of metal stents for benign esophageal diseases has been controversial. Given the availability of removable, fully covered, self-expandable metal stents (RFCSEMSs), this study was undertaken to evaluate the effectiveness and safety of RFCSEMSs in patients with refractory benign esophagogastric anastomotic strictures. Twenty-four patients with RFCSEMSs were enrolled in this study. All patients had undergone endoscopic Savary Gilliard bougie dilatation five times or more but there was no significant improvement in symptoms. For all 24 patients, the symptom of dysphagia was alleviated significantly while the stent was in place and for a short time after stent removal, and dysphagia scores decreased from 3-4 to 0-1. After 12 months of follow-up, 18 patients were free from dysphagia but the other 6 patients still suffered obvious dysphagia. RFCSEMSs are still not perfect and can induce some complications. The treatment failure rate of restenting was remarkably high after the first failure. Given that effective methods for treating refractory stricture have not been found, RFCSEMSs could be considered for treating refractory benign esophagogastric anastomotic stricture. PMID- 21826423 TI - Synthesis of benzimidazoles containing pyrazole group and quantum chemistry calculation of their spectroscopic properties and electronic structure. AB - Five benzimidazole compounds containing pyrazole group were synthesized via one step reaction of o-phenylenediamine and 1-arylpyrazole-4-carbaldehyde in ethanol under mild conditions. The composition and structure of resultant benzimidazole compounds were analyzed by means of elemental analysis, mass spectrometry, (1)H nuclear magnetic resonance spectroscopy and X-ray single crystal diffraction. The ultraviolet-visible light spectra and fluorescent spectra of the products were measured. Their ground-state (S(0)) equilibrium geometries and vibrational frequencies were determined based on B3LYP method, and their first excited-state (S(1)) geometries were fully optimized based on 6-31G (d, p) basis set of TD B3LYP method. Besides, the spectroscopic properties of the products were computed based on cc-pVTZ basis set of TD-B3LYP method and compared with corresponding experimental data. It has been found that benzimidazole compounds containing pyrazole group can be readily synthesized in a high yield via one-step reaction of o-phenylenediamine and 1-arylpyrazole-4-carbaldehyde in ethanol solvent. The fluorescence properties of the five synthesized compounds are closely related to their molecular structure; and their computed fluorescence spectra well correspond to their experimental values. Moreover, they have stable structure and strong fluorescence, showing potential application in time-resolved fluoroimmunoassay and DNA probe. PMID- 21826424 TI - Thermal effect on Aequorea green fluorescent protein anionic and neutral chromophore forms fluorescence. AB - The emission behaviour of Aequorea green fluorescent protein (A-GFP) chromophore, in both neutral (N) and anionic (A) form, was studied in the temperature range from 20 degrees C to 75 degrees C and at pH = 7. Excitation wavelengths of 399 nm and 476 nm were applied to probe the N and A forms environment, respectively. Both forms exhibit distinct fluorescence patterns at high temperature values. The emission quenching rate, following a temperature increase, is higher for the chromophore N form as a result of the hydrogen bond network weakening. The chromophore anionic form emission maximum is red shifted, upon temperature increase, due to a charge transfer process occurring after A form excitation. PMID- 21826425 TI - A novel single fluorophore-labeled double-stranded oligonucleotide probe for fluorescence-enhanced nucleic acid detection based on the inherent quenching ability of deoxyguanosine bases and competitive strand-displacement reaction. AB - We develop a novel single fluorophore-labeled double-stranded oligonucleotide (OND) probe for rapid, nanostructure-free, fluorescence-enhanced nucleic acid detection for the first time. We further demonstrate such probe is able to well discriminate single-base mutation in nucleic acid. The design takes advantage of an inherent quenching ability of guanine bases. The short strand of the probe is designed with an end-labeled fluorophore that is placed adjacent to two guanines as the quencher located on the long opposite strand, resulting in great quenching of dye fluorescence. In the presence of a target complementary to the long strand of the probe, a competitive strand-displacement reaction occurs and the long strand forms a more stable duplex with the target, resulting in the two strands of the probe being separated from each other. As a consequence of this displacement, the fluorophore and the quencher are no longer in close proximity and dye fluorescence increases, signaling the presence of target. PMID- 21826426 TI - Procedures for controlling the size, structure and optical properties of CdS quantum dots during synthesis in aqueous solution. AB - We report an easy approach for the synthesis of CdS Quantum Dots (CdS QDs) with high luminescence and temporal stability through the reaction of Cd(2+) and S(2-) in the presence of mercaptoacetic acid (MAA) as a capping reagent in aqueous medium, under normal pressure and room temperature. The influence of several experimental variables, including temperature, pH, the Cd/S ratio and the Cd/MAA ratio, on the optical properties of the QDs obtained was studied systematically. The experimental results indicate that these variables play an important role in determining the size and state of the surface of the nanoparticles, and hence their luminescent properties and temporal stability. The general aspects of nanocrystal nucleation and growth in the synthesis of nanocrystals were studied. The best conditions for the synthesis of nanoparticles of high quality are also reported. The CdS nanocrystals obtained exhibited a narrow PL band, with reproducible room-temperature quantum yields. PMID- 21826427 TI - Solvent effect profiles of absorbance and fluorescence spectra of some indole based chalcones. AB - The photophysical properties of a series of 3-(1'H-Indol-3'-yl)-1-phenylprop-2-en 1-one and its derivatives (indole chalcones) were studied in different solvents. Solvent effects on the absorption and fluorescence spectra were quantified using Reichardt's and bulk solvent polarity parameters and were complemented by the results of the Kamlet-Taft treatment. The observed excited state dipole moment was found to be larger than the ground state dipole moment of these chalcones. The correlation of the solvatochromic Stokes-shifts with the microscopic solvent polarity parameter (E(T)(N)) was found to be superior to that obtained using bulk solvent polarity functions. PMID- 21826428 TI - Purine scaffold effect on fluorescence properties of purine-hydroxyquinolinone bisheterocycles. AB - The fluorescence properties of bisheterocyclic compounds that contain purine and the 3-hydroxyquinolin-4(1H)-one skeleton connected with an aliphatic spacer of a different length/structure (3HQP) were examined. It was found that the introducing of the spacer-purine scaffold led in the comparison to 3HQs themselves to (1) the possibility of the effectual excitation in the wider range of excitation wavelengths, moreover, some derivatives can be excited at relatively high wavelengths around 400 nm, (2) the lowering of the quantum yield and (3) the slight longer wavelength shift of the dual emission spectra. Tested organic solvents did not affect significantly the 3HQP fluorescence properties. The characters of emission spectra as well as the quantum yields of 3HQPs were notably influenced by the ratio of water and DMSO in their composed mixture applied as a solvent. With increasing water content in the mixture both I(1)/I(2) and the quantum yield decreased. PMID- 21826429 TI - Immunoisolation of pancreatic islet grafts with no recipient's immunosuppression: actual and future perspectives. AB - In spite of steady and remarkable progress, islet transplantation in patients with type 1 diabetes mellitus (T1DM) continues to face two major bottlenecks: inadequate availability of human pancreatic donors and necessity to totally immunosuppress the graft recipients lifelong. Microencapsulation of the islet grafts within highly biocompatible and selective permeable biomembranes could obviate use of the immunosuppressants, while potentially offering the opportunity to use a wide array of insulin-producing cells, in active development, including xenogeneic pig islets. Although macrodevices and microcapsules, which essentially differ by size/configuration, and both serve for immunoisolation devices, have been used for many years with initial human applications, new products on development in both areas might open new perspectives for more focused use in patients with T1DM. Physical-chemical properties and material engineering of these devices are critically reviewed to assess where we actually stand and where the future expansion of these technologies may go. PMID- 21826430 TI - Expression of lorelei-like genes in aposporous and sexual Paspalum notatum plants. AB - Gametophytic apomictic plants form non-reduced embryo sacs that generate clonal embryos by parthenogenesis, in the absence of both meiosis and egg-cell fertilization. Here we report the sequence and expression analysis of a lorelei like Paspalum notatum gene, n20gap-1, which encodes a GPI-anchored protein previously associated with apomixis in this species. Phylogeny trees showed that n20gap-1 was evolutionary related to the Arabidopsis thaliana lorelei genes At4g26466 and At5g56170. The lorelei At4g26466 disruption was shown to be detrimental to sperm cell release in arabidopsis. RFLP (Restriction Fragment Length Polymorphism) analysis revealed the occurrence of several homologous sequences in the Paspalum notatum genome, exhibiting polymorphisms genetically linked to apomixis. Real-time PCR showed that lorelei-family genes present a minor activity peak at pre-meiosis and a major one at anthesis. The apomictic genotype analyzed showed a significantly increased activity at pre-meiosis, post meiosis and anthesis with respect to a sexual genotype. In situ hybridization assays revealed expression in integuments, nucellus and the egg-cell apparatus. Several n20gap-1 alleles differing mainly at the 3' UTR sequence were identified. Allele-specific real-time PCR experiments showed that allele 28 was significantly induced in reproductive tissues of the apomictic genotype with respect to the sexual genotype at anthesis. Our results indicate that P. notatum lorelei-like genes are differentially expressed in representative sexual (Q4188) and apomictic (Q4117) genotypes, and might play a role in the final stages of the apomixis developmental cascade. However, the association of n20gap-1 expression with the trait should be confirmed in significant number of sexual and apomictic genotypes. PMID- 21826431 TI - Power spectral analysis of plethysmographic pulse waveform in pregnant women. AB - OBJECTIVE: To investigate the effect of pregnancy on the pulse wave of the mother. PATIENTS AND METHODS: Pulse waveforms recorded via a pulse oximeter from the left index finger of non-pregnant women and pregnant women in the three trimesters of pregnancy were Fourier transformed into power spectra. Spectral indices of the power spectra of pulse waveform were obtained and compared among non-pregnant women and pregnant women in the three trimesters of pregnancy. RESULTS: The power of harmonics of pulse wave decayed exponentially with respect to the order of harmonics. The exponent and initial value of exponential decay for the power of harmonics and the power of the 2nd harmonic were increased, whereas the total power of pulse and the powers of higher order harmonics were decreased during pregnancy. CONCLUSION: The power of harmonics of pulse wave can be described by an exponential decay function with respect to the order of harmonics in both non-pregnant and pregnant women. The effects of pregnancy on the pulse wave are the reduction in the total power of pulse and the power of higher order harmonics, and the increase in the power of lower order harmonics in the power spectrum of pulse wave. This effect of pregnancy on the pulse wave might be caused by the decrease in vascular resistance during pregnancy, the increase in workload on the heart due to increased demand of the growing fetus, and the aortocaval compression caused by the progressively enlarged gravid uterus and fetus. PMID- 21826432 TI - The glenoid in total shoulder arthroplasty. AB - Management of glenohumeral arthrosis with a total shoulder prosthesis is becoming increasingly common. However, failure of the glenoid component remains one of the most common causes for failure. Our understanding of this problem has evolved greatly since the first implants were placed in the 1970's. However glenoid failure remains a challenging problem to address and manage. This article reviews the current knowledge regarding the glenoid in total shoulder arthroplasty touching on anatomy, component design, implant fixation, causes of implant failure, management of glenoid failure and alternatives to glenoid replacement. PMID- 21826433 TI - The Rottinger approach for total hip arthroplasty: technique and review of the literature. AB - The surgical approach utilized in total hip arthroplasty has been identified as a factor that may affect surgical outcomes. There have been many different approaches and modifications used since the procedure was popularized by Sir John Charnley. The popular approaches today can be grouped by their relationship to the trochanter (anterior or posterior), patient position, leg position for dislocation/femoral preparation, and treatment of the abductors and short external rotators. The Rottinger approach is an anterior approach which utilizes the muscle interval between the tensor fascia lata and abductor musculature. The abductor attachments are preserved and the femur is prepared in extension, adduction, and external rotation. This approach has been shown in literature to be safe with some studies showing improved outcomes both in terms of reduced complications and better function than other standard approaches. PMID- 21826434 TI - Why do physicians prescribe antibiotics? PMID- 21826435 TI - Bilateral Bartonella henselae neuroretinitis with stellate maculopathy in a 6 year-old boy. AB - PURPOSE: Bartonella henselae, the cause of cat-scratch disease in humans, may lead to characteristic vision-threatening ocular findings, which importantly indicate diagnosis. METHODS: This is an observational case report of a 6-year-old boy who presented with bilateral stellate maculopathy and lymphadenopathy. RESULTS: After serologic verification of B. henselae infection, systemic azithromycin therapy initiated the full recovery of visual acuity and bilateral complete resolution of stellate exudates during the following months. CONCLUSION: Stellate maculopathy should always include the differential diagnosis of B. henselae infection. In this rare case of bilateral stellate maculopathy, we observed full recovery of function following systemic macrolide therapy. PMID- 21826436 TI - Clostridium difficile infection: monoclonal or polyclonal genesis? AB - Clostridium difficile is considered to be a leading cause of hospital-acquired diarrhea. C. difficile (CDI) infection shows a high rate of recurrence. There would have to be a predominantly monoclonal mechanism of CDI within individual patients in order for molecular epidemiologic tools such as polymerase chain reaction (PCR) ribotyping to be useful in outbreak investigation or differentiation between infection relapse versus re-infection. It was the aim of our study to determine whether CDI is of monoclonal or of polyclonal genesis. Between December 2009 and June 2010, 11 patients with nosocomial CDI were chosen arbitrarily. Five individual colonies of C. difficile were picked from each of the primary culture plates. Of 55 isolates gained, 47 were available for PCR ribotyping (eight isolates failed attempts to re-culture). Among these 47 isolates, eight different PCR ribotypes were identified. Only one of the 11 patients had a stool sample that yielded more than one ribotype (PCR ribotypes 438 and 232); this 67-year-old female cancer patient was already suffering from recurring diarrhea prior to the fatal episode of colitis which was subsequently investigated. We conclude that polyclonal infections may occasionally occur in patients with CDI. Our findings of predominantly monoclonal origin of CDI within patients suggest that molecular epidemiologic investigations can be used reliably for outbreak investigations or discrimination between relapse and re-infection. PMID- 21826437 TI - Food-borne tonsillopharyngitis outbreak in a hospital cafeteria. AB - OBJECTIVE: A food-borne tonsillopharyngitis outbreak was reported between 9th and 13th of February, 2008, in Soke State Hospital, Aydin, Turkey. METHODS: This descriptive cohort study was carried out immediately after the outbreak. In order to determine the probable origin, a questionnaire involving demographical features, clinical features, and possible risk factors was distributed to 403 persons. The participants of the questionnaire (n = 403) were divided into two groups: the study group (n = 252); those with any two of the following three complaints; sore throat, fever, and dizziness, and the control group (n = 151); those without these complaints. RESULTS: This investigation revealed that 252 people were affected by this outbreak. Group A beta-hemolytic streptococci were isolated from the throat cultures of 63 affected individuals (25%) and an employee working in the patisserie that made desserts served for lunch. Since the number of people who ate the milky dessert was statistically higher compared to the non-eaters, the milky dessert was thought to be the origin of the outbreak. CONCLUSIONS: We suggest that throat infections among employees working in food production may cause outbreaks of upper respiratory tract infections. PMID- 21826438 TI - Extended-spectrum beta-lactamase-producing Escherichia coli strains in the feces of carriers contribute substantially to urinary tract infections in these patients. AB - INTRODUCTION: The current increase in the incidence of urinary tract infections (UTIs) worldwide caused by extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli may be due to the high number of ESBL-producing Enterobacteriaceae carriers in the community. However, whether ESBL-producing bacteria can cause UTIs in carriers remains uncertain. MATERIALS AND METHODS: In this study, 21 fecal carriers of ESBL-producing Enterobacteriaceae were assessed for UTIs caused by ESBL-producing E. coli. Bacterial isolates obtained from patients' urine and stool specimens were phenotypically and genotypically examined. Clonal similarities of isolates were assessed by multilocus sequence typing (MLST) and random amplified polymorphic DNA (RAPD) fingerprinting. RESULTS: The study revealed that 9 of 21 carriers developed UTIs, and genetic analysis showed that 44% of the UTIs developed were caused by the same ESBL producing E. coli as that found in the feces of the patients. CONCLUSIONS: The ESBL-producing E. coli in carriers can cause UTIs. PMID- 21826439 TI - A phase 1 study of KOS-862 (Epothilone D) co-administered with carboplatin (Paraplatin(r)) in patients with advanced solid tumors. AB - PURPOSE: To determine the maximally tolerated dose (MTD) and pharmacokinetics of carboplatin plus KOS-862 (Epothilone D) a novel cytotoxic macrolide capable of causing mitotic arrest, in patients with advanced solid malignancies. EXPERIMENTAL DESIGN: Patients who have progressed on standard regimens were treated at four different levels of KOS-862(mg/m(2))/Carboplatin(AUC): 50/5,75/5, 75/6 and 100/6 in a "3 + 3" phase I study study design to determine MTD. Patients received KOS-862 on Days 1 and 8, and carboplatin on day 1, of 3-week cycles. Pharmacokinetics of KOS-862 and Carboplatin were studied. RESULTS: Twenty-seven patients enrolled in the study. At the top dose level, 2 out of the 9 patients experienced Dose Limiting Toxicity. (grade 3 peripheral motor neuropathy in both patients) Twenty-seven patients had sufficient plasma data points for pharmacokinetic analysis Both the parent drug, KOS-862, and the major inactive metabolite Seco-D KOS-862 (KOS-1965) were quantified in plasma. Kinetics of KOS 862 were the same as seen in monotherapy studies using the same route and time of administration. Two patients had tumor response after study treatment. Ten of 20 evaluable patients had stable disease after 2 cycles of study treatment. The MTD in the present study was KOS-862 100 mg/m(2) + carboplatin AUC = 6. CONCLUSIONS: The pharmacokinetics of KOS-862 were similar in this combination study to those seen in previous monotherapy studies using the same route and time of administration. We have described the MTD of this schedule. The neurotoxicity seen with this regimen should be considered prior to its administration in unselected populations. PMID- 21826440 TI - Synergistic effects of the combination of beta-ionone and sorafenib on metastasis of human hepatoma SK-Hep-1 cells. AB - The combination of anti-cancer drugs with nutritional factors is a potential strategy for improving the efficacy of chemotherapy, particularly for hepatocellular carcinoma because its conventional therapies are mostly ineffective. Using a highly invasive hepatoma SK-Hep-1 cell line, we investigated the possible synergistic anti-metastatic efficacy of a combination of sorafenib (SF), a multi-kinase inhibitor, and beta-ionone (BI), a precursor of carotenoids. We found that SF (1 MUM) in combination with BI (1 MUM) synergistically inhibited cell invasion and additively inhibited cell migration, especially at 48 h of incubation. Mechanistically, the combination of SF and BI was found to decrease the protein expression of focal adhesion kinase (FAK) and Rho, and to enhance the protein expression of tissue inhibitor matrix metalloproteinase (TIMP)-1 and TIMP 2. In addition, the combination of SF and BI inhibited the activity of matrix metalloproteinase (MMP)-2 and MMP-9 and decreased the phosphorylation of FAK and of Rac1 proteins. Importantly, SF enhanced the suppressing effect of BI (1-50 MUM) on the viability of SK-Hep-1 cells, but not on murine hepatic BNL CL.2 cells, indicating the selective cytotoxicity of this combination on tumor cells. The combination of SF and BI could be a potential therapeutic strategy against human hepatoma cells. PMID- 21826441 TI - Intelligence and temporal accuracy of behaviour: unique and shared associations with reaction time and motor timing. AB - Intelligence is associated with accuracy in a wide range of timing tasks. One source of such associations is likely to be individual differences in top-down control, e.g., sustained attention, that influence performance in both temporal tasks and other cognitively controlled behaviours. In addition, we have studied relations between intelligence and a simple rhythmic motor task, isochronous serial interval production (ISIP), and found a substantial component of that relation, which is independent of fluctuations in top-down control. The main purpose of the present study was to investigate whether such bottom-up mechanisms are involved also in the relation between intelligence and reaction time (RT) tasks. We thus investigated whether common variance between the ISIP and RT tasks underlies their respective associations with intelligence. Two hundred and twelve participants performed a simple RT task, a choice RT task and the ISIP task. Intelligence was assessed with the Raven SPM Plus. The analysed timing variables included mean and variability in the RT tasks and two variance components in the ISIP task. As predicted, RT and ISIP variables were associated with intelligence. The timing variables were positively intercorrelated, and a principal component analysis revealed a substantial first principal component that was strongly related to all timing variables, and positively correlated with intelligence. Furthermore, a commonality analysis demonstrated that the relations between intelligence and the timing variables involved a commonality between the timing variables as well as unique contributions from choice RT and ISIP. We discuss possible implications of these findings and argue that they support our main hypothesis, i.e., that relations between intelligence and RT tasks have a bottom up component. PMID- 21826442 TI - Estrogen synthesis in the hippocampus. AB - Estradiol plays essential roles in the modulation of synaptic plasticity and neuroprotection in males as well as in females, as has been shown particularly in the hippocampus. Although it has long been known that aromatase, the final enzyme in estrogen synthesis, is expressed in the hippocampus, a new paradigm emerged when it was shown that estradiol is actually synthesized de novo in this part of the brain. Increasing evidence indicates that hippocampus-derived estradiol plays a role in synaptic plasticity and neuroptrotection, rather than estradiol originating from the gonads. In recent years, a number of in vivo and in vitro studies have shown that hippocampus-derived estradiol substantially contributes to hippocampal function, in particular to structural synaptic plasticity. PMID- 21826443 TI - Development of astroglia heterogeneously expressing Pax2, vimentin and GFAP during the ontogeny of the optic pathway of the lizard (Gallotia galloti): an immunohistochemical and ultrastructural study. AB - The successful regrowth of retinal ganglion cell (RGC) axons after optic nerve (ON) axotomy in Gallotia galloti indicates a permissive role of the glial environment. We have characterised the astroglial lineage of the lizard optic pathway throughout its ontogeny (embryonic stage 30 [E30] to adults) by using electron microscopy and immunohistochemistry to detect the proliferation marker PCNA (proliferating cell nuclear antigen), the transcription factor Pax2 and the gliofilament proteins vimentin (Vim) and GFAP (glial fibrillary acidic protein). PCNA(+) cells were abundant until E39, with GFAP(+)/PCNA(+) astrocytes being observed between E37 and hatching. Proliferation diminished markedly afterwards, being undetectable in the adult optic pathway. Muller glia of the central retina expressed Pax2 from E37 and their endfeet accumulated Vim from E33 and GFAP from E37 onwards. Astrocytes were absent in the avascular lizard retina, whereas abundant Pax2(+) astrocytes were observed in the ON from E30. A major subpopulation of these astrocytes coexpressed Vim from E35 and also GFAP from E37 onwards; thus the majority of mature astrocytes coexpressed Pax2/Vim/GFAP. The astrocytes were ultrastructurally identified by their gliofilaments, microtubules, dense bodies, desmosomes and glycogen granules, which preferentially accumulated in cell processes. Astrocytes in the adult ON coexpressed both gliofilaments and presented desmosomes indicating a reinforcement of the ON structure; this is physiologically necessary for local adaptation to mechanical forces linked to eye movement. We suggest that astrocytes forming this structural scaffold facilitate the regrowth of RGCs after ON transection. PMID- 21826444 TI - Physical activity and depression in adolescents: cross-sectional findings from the ALSPAC cohort. AB - PURPOSE: Few studies have examined the association between physical activity (PA), measured objectively, and adolescent depressive symptoms. The aim of this study was to determine whether there is an association between objective measures of PA (total PA and time spent in moderate and vigorous PA (MVPA)) and adolescent depressive symptoms. METHODS: Data on 2,951 adolescents participating in ALSPAC were used. Depressive symptoms were measured using the self-report Mood and Feelings Questionnaire (MFQ) (short version). Measures of PA were based on accelerometry. The association between PA and MFQ scores was modelled using ordinal regression. RESULTS: Adolescents who were more physically active (total PA or minutes of MVPA) had a reduced odds of depressive symptoms [OR(adj) total PA (tertiles): medium 0.82 (95% CI: 0.69, 0.97); high 0.69 (95% CI: 0.57, 0.83)]; OR(adj) per 15 min MVPA: 0.92 (95% CI: 0.86, 0.98). In a multivariable model including both total PA and the percentage of time spent in MVPA, total PA was associated with depressive symptoms (OR(adj) total PA (tertiles): medium 0.82 (95% CI: 0.70, 0.98); high 0.70 (95% CI: 0.58, 0.85) but the percentage of time spent in MVPA was not independently associated with depressive symptoms [OR(adj) MVPA (tertiles) medium 1.05 (95% CI: 0.88, 1.24), high 0.91 (95% CI: 0.77, 1.09)]. CONCLUSIONS: The total amount of PA undertaken was associated with adolescent depressive symptoms, but the amount of time spent in MVPA, once total PA was accounted for, was not. If confirmed in longitudinal studies and randomised controlled trials, this would have important implications for public health messages. PMID- 21826445 TI - Brooding rumination and risk for depressive disorders in children of depressed mothers. AB - The goal of the current study was to examine the role of brooding rumination in children at risk for depression. We found that children of mothers with a history of major depression exhibited higher levels of brooding rumination than did children of mothers with no depression history. Examining potential mechanisms of this risk, we found no evidence for shared genetic influences (BDNF or 5-HTTLPR) or modeling of mothers' rumination. However, we did find that children with a history of prior depressive disorders exhibited higher current levels of brooding rumination than children with no depression history. Importantly, children's brooding predicted prospective onsets of new depressive episodes over a 20-month follow-up even when we statistically controlled for depressive symptom levels at the initial assessment, suggesting that the predictive effect of brooding rumination in children was not due simply to co-occurring depressive symptoms. PMID- 21826446 TI - Association of positive and negative parenting behavior with childhood ADHD: interactions with offspring monoamine oxidase A (MAO-A) genotype. AB - Relatively little is known about the potential interplay between genetic and environmental influences on attention-deficit/hyperactivity disorder (ADHD), including gene-environment interaction (G*E). There is evidence that parenting behavior interacts with offspring genotype in the development of externalizing problems, but studies have largely focused on explicit maltreatment rather than differentiated measures of parenting behavior, including positive and negative parenting. We tested the interactive effects of the 30-base pair variable number tandem repeat (VNTR) polymorphism of the monoamine oxidase A gene (MAO-A) with positive and negative parenting behavior on parent- and teacher ratings of inattention and hyperactivity symptoms among 150 6-9 year-old boys with and without ADHD. Negative parenting predicted parent and teacher ratings of inattention symptoms, but only among boys with high-activity MAO-A genotype. MAO A genotype did not moderate the association of positive parenting and parent- and teacher ratings of ADHD. We discuss the potential role of interactive exchanges between parenting behavior and child genotype in the development and persistence of ADHD and related behavior problems. PMID- 21826447 TI - 3D-QSAR based pharmacophore modeling and virtual screening for identification of novel pteridine reductase inhibitors. AB - Pteridine reductase is a promising target for development of novel therapeutic agents against Trypanosomatid parasites. A 3D-QSAR pharmacophore hypothesis has been generated for a series of L. major pteridine reductase inhibitors using Catalyst/HypoGen algorithm for identification of the chemical features that are responsible for the inhibitory activity. Four pharmacophore features, namely: two H-bond donors (D), one Hydrophobic aromatic (H) and one Ring aromatic (R) have been identified as key features involved in inhibitor-PTR1 interaction. These features are able to predict the activity of external test set of pteridine reductase inhibitors with a correlation coefficient (r) of 0.80. Based on the analysis of the best hypotheses, some potent Pteridine reductase inhibitors were screened out and predicted with anti-PTR1 activity. It turned out that the newly identified inhibitory molecules are at least 300 fold more potent than the current crop of existing inhibitors. Overall the current SAR study is an effort for elucidating quantitative structure-activity relationship for the PTR1 inhibitors. The results from the combined 3D-QSAR modeling and molecular docking approach have led to the prediction of new potent inhibitory scaffolds. PMID- 21826449 TI - The administration of food supplemented with cocoa powder during nutritional recovery reduces damage caused by oxidative stress in rat brain. AB - Malnutrition contributes to the development of oxidative damage in the central nervous system. The selective administration of nutrients tends to show positive results in individuals who have suffered from malnutrition. To determine the effect of the administration of cocoa powder on the peroxidation of lipids and glutathione level during the nutritional recovery in brain, rats of 21 days old were subjected to a protocol that resembles malnutrition (MN) by feeding them with 60% of the daily food consumption of the control group (WN) and later to nutritional recovery with regular rodent feed (RFR) or added with cocoa (10 g of cocoa powder/kg of regular rodent feed) (CCR). Animals fed with regular rodent food showed significant reduction in brain glutathione: RFR (84.18 +/- 6.38 ng/mg protein) vs. CCR (210.61 +/- 50.10 ng/mg protein) and WN (186.55 +/- 33.18 ng/mg protein), but with similar level to that of MN (92.12 +/- 15.60 ng/mg protein). On the contrary, lipid peroxidation in RFR-fed animals increased RFR (1.32 +/- 0.2 MUM malondialdehyde/g of tissue), CCR (0.86 +/- 0.07 MUM malondialdehyde/g of tissue), WN (0.89 +/- 0.09 MUM malondialdehyde/g of tissue), but their thiobarbituric acid reactive substances concentration is similar to that of MN group (1.50 +/- 0.2 MUM malondialdehyde/g of tissue). Consumption of cocoa powder as a source of antioxidants favors the restoration of the concentration of glutathione and reduces the damage caused by oxidative stress during nutritional recovery in rat brain. PMID- 21826450 TI - Ventriculoperitoneal shunt catheter protrusion through the anus: case report of an uncommon complication and literature review. Commentary. PMID- 21826452 TI - Uptake of different forms of antimony by wheat and rye seedlings. AB - PURPOSE: The objectives of the research were to study how antimony (Sb) chemical form present in the growth medium can affect Sb uptake by plants and estimate effects of Sb on wheat and rye seedlings, in particular, assess variations in concentrations of nutrients resulting from bioaccumulation of Sb. METHODS: Seedlings were (1) germinated in media spiked with Sb(III) or Sb(V) and then transferred to clean water, and (2) germinated in Sb-free medium and then grown in water enriched with Sb. Variations of Sb concentrations in the seedlings were studied, and effects of Sb bioaccumulation on plant development and concentrations of macro- and trace elements in the plants were assessed. RESULTS: Rye was capable of accumulating more Sb than wheat. This resulted in necrosis of the rye leaves. During germination in Sb-rich medium rye and wheat accumulated Sb differently. When the seedlings germinated in Sb-amended medium were then grown in clean water, Sb concentration in all plant parts decreased. Plant concentrations of Sb increased significantly when seedlings germinated in Sb-free medium were transferred to Sb-spiked water. However, with time saturation with Sb in the plants was observed. The bioaccumulation of Sb led to significant variations in concentrations of various elements in different plant parts. CONCLUSIONS: Wheat and rye seedlings were capable of identifying different Sb forms and demonstrated certain differences in the ability to uptake Sb and survive under high external Sb concentrations. An increase of Sb in the plants caused important variations in the concentrations of many essential nutrients. PMID- 21826451 TI - Homing of cancer cells to the bone. AB - A variety of tumor cells preferentially home to the bone. The homing of cancer cells to the bone represents a multi-step process that involves malignant progression of the tumor, invasion of the tumor through the extracellular matrix and the blood vessels and settling of the tumor cells in the bone. Gaining a greater understanding as to the mechanisms used by cancer cells in these processes will facilitate the design of drugs which could specifically target the homing process. In this review we will discuss the properties of tumor cells and the bone microenvironment which promote homing of a cancer cell to the bone. We will highlight the different steps and the molecular pathways involved when a cancer cell metastasize to the bone. Since bone is the major home for hematopoietic stem cells (HSCs), we will also highlight the similarities between the homing of cancer and HSC to the bone. Finally we will conclude with therapeutic and early detection strategies which can prevent homing of a cancer cell to the bone. PMID- 21826453 TI - Characterization of tannery effluent wastewater by proton-induced X-ray emission (PIXE) analysis to investigate their role in water pollution. AB - INTRODUCTION: Over the last few decades, the chromium-based tanning industry has shown rapid growth in Pakistan. However, the rules and regulations promulgated by the government are not strictly followed for processing the effluent discharge from the tanneries. Consequently, tannery effluents have become a great source of water pollution in surrounding areas. MATERIALS AND METHODS: In this case study, characterization of tannery effluent wastewater (TW), shallow groundwater (SW), and deep groundwater (DW) samples was carried out to determine the source of water pollution in the district of Kasur, Pakistan. RESULTS: The concentrations of calcium (Ca), chlorine (Cl), chromium (Cr), iron (Fe), potassium (K), Mg, sulfur (S), silicon (Si), and Sr in TW were significantly higher than SW and DW, which also exceeded the international limits. In addition, increased concentrations of major toxic elements (Cl, Cr, Fe, K, Ni, and Si) were also observed in SW, which were higher in comparison to DW. Strikingly, the concentrations of Cr and Si in various DW samples were also beyond World Health Organization (WHO) safe limit, which reinforced the trend that water pollution in the area is directly linked to the distance from the source (TW). The particle induced X-ray emission (PIXE) indices also suggested that TW is a main contributory source of water-based pollution in the area, which is imposing great threat to local inhabitants due to known hazardous and carcinogenic potential of these elements. CONCLUSION: Protecting the water resources will be a formidable challenge in the study area, which requires modernization of tannery industry, thereby improving the recovery and recycling of TW. Moreover, PIXE analysis presented here as a successful tool, could serve as landmark for the contemporary research in environmental toxicology. PMID- 21826455 TI - Organization of the cholinergic systems in the brain of two lungfishes, Protopterus dolloi and Neoceratodus forsteri. AB - Lungfishes (dipnoans) are currently considered the closest living relatives of tetrapods. The organization of the cholinergic systems in the brain has been carefully analyzed in most vertebrate groups, and major shared characteristics have been described, although traits particular to each vertebrate class have also been found. In the present study, we provide the first detailed information on the distribution of cholinergic cell bodies and fibers in the central nervous system in two representative species of lungfishes, the African lungfish (Protopterus dolloi) and the Australian lungfish (Neoceratodus forsteri), as revealed by immunohistochemistry against the enzyme choline acetyltransferase (ChAT). Distinct groups of ChAT immunoreactive (ChAT-ir) cells were observed in the basal telencephalon, habenula, isthmic nucleus, laterodorsal tegmental nucleus, cranial nerve motor nuclei, and the motor column of the spinal cord, and these groups seem to be highly conserved among vertebrates. In lungfishes, the presence of a cholinergic cell group in the thalamus and the absence of ChAT-ir cells in the tectum are variable traits, unique to this group and appearing several times during evolution. Other characters were observed exclusively in Neoceratodus, such as the presence of cholinergic cells in the suprachiasmatic nucleus, the pretectal region and the superior raphe nucleus. Cholinergic fibers were found in the medial pallium, basal telencephalon, thalamus and prethalamus, optic tectum and interpeduncular nucleus. Comparison of these results with those from other classes of vertebrates, including a segmental analysis to correlate cell populations, reveals that the cholinergic systems in lungfishes largely resemble those of amphibians and other tetrapods. PMID- 21826454 TI - High-intensity sprint fatigue does not alter constant-submaximal velocity running mechanics and spring-mass behavior. AB - We investigated the changes in constant velocity spring-mass behavior after high intensity sprint fatigue in order to better interpret the results recently reported after ultra-long distance (ULD) exercises. Our hypothesis was that after repeated sprints (RS), subjects may likely experience losses of force such as after ULD, but the necessity to modify their running pattern to attenuate the overall impact at each step (such as after ULD) may not be present. Eleven male subjects performed four sets of five 6-s sprints with 24-s recovery between sprints and 3 min between sets, on a sprint treadmill and on a bicycle ergometer. For each session, their running mechanics and spring-mass characteristics were measured at 10 and 20 km h(-1) on an instrumented treadmill before and after RS. Two-way (period and velocity) ANOVAs showed that high-intensity fatigue did not induce any change in the constant velocity running pattern at low or high velocity, after both running and cycling RS, despite significant decreases (P < 0.001) in maximal power (-27.1 +/- 8.2% after running RS and -15.4 +/- 11.5 % after cycling RS) and knee extensors maximal voluntary force (-18.8 +/- 6.7 % after running RS and -15.0 +/- 7.6 % after cycling RS). These results bring indirect support to the hypothesis put forward in recent ULD studies that the changes in running mechanics observed after ULD are likely not related to the decrease in strength capabilities, but rather to the necessity for subjects to adopt a protective running pattern. PMID- 21826456 TI - Nitrogen and water availability interact to affect leaf stoichiometry in a semi arid grassland. AB - The effects of global change factors on the stoichiometric composition of green and senesced plant tissues are critical determinants of ecosystem feedbacks to anthropogenic-driven global change. So far, little is known about species stoichiometric responses to these changes. We conducted a manipulative field experiment with nitrogen (N; 17.5 g m(-2) year(-1)) and water addition (180 mm per growing season) in a temperate steppe of northern China that is potentially highly vulnerable to global change. A unique and important outcome of our study is that water availability modulated plant nutritional and stoichiometric responses to increased N availability. N addition significantly reduced C:N ratios and increased N:P ratios but only under ambient water conditions. Under increased water supply, N addition had no effect on C:N ratios in green and senesced leaves and N:P ratios in senesced leaves, and significantly decreased C:P ratios in both green and senesced leaves and N:P ratios in green leaves. Stoichiometric ratios varied greatly among species. Our results suggest that N and water addition and species identity can affect stoichiometric ratios of both green and senesced tissues through direct and interactive means. Our findings highlight the importance of water availability in modulating stoichiometric responses of plants to potentially increased N availability in semi-arid grasslands. PMID- 21826457 TI - Novel approach to the microscopic inspection during laser cleaning treatments of artworks. AB - The present work focuses on the potential of 3D digital microscopy for assessing micro-morphological features during laser cleaning treatments of artworks. This application requires preliminary optimization studies aimed at defining operative irradiation parameters and practicable degree of cleaning, as well as in situ diagnostic assessments during the restoration work. To this goal, we developed and tested a dedicated 3D digital microscope by implementing the "shape-from focus" technique. The significant potential of this instrument, which provides textural and chromatic information, was proven for the phenomenological characterization of black crust removal from stones, earthy concretion from bronzes and dark varnish from easel paintings. Comparative measurements using 3D digital microscopy and contact microprofilometry were performed after laser cleaning tests of prepared samples, genuine archaeological bronze artefacts and a stone sculptural element from Florence's Dome. The results achieved demonstrate the effectiveness and reliability of the novel approach and the advantages it provides with respect to alternative techniques, which will allow the methods to be used in the wider restoration community. PMID- 21826458 TI - Discrimination of bacteria from Jamaican bauxite soils using laser-induced breakdown spectroscopy. AB - Soil bacteria are sensitive to ecological change and can be assessed to gauge anthropogenic influences and ecosystem health. In recent years, there has been a significant increase in the focus on new technologies that can be applied to the evaluation of soil quality. Laser-induced breakdown spectroscopy (LIBS) is a promising technique that has been used for the investigation and characterization of explosives, solids, liquids, gases, biological and environmental samples. In this study, bacteria from un-mined and a chronosequence of reclaimed bauxite soils were isolated on Luria-Bertani agar media. Polymerase chain reaction amplification of the bacterial 16S rDNA, sequencing, and phylogenetic analysis were applied to each isolated soil bacteria from the sample sites resulting in the identification and classification of the organisms. Femtosecond LIBS performed on the isolated bacteria showed atomic and ionic emission lines in the spectrum containing inorganic elements such as sodium (Na), magnesium (Mg), potassium (K), zinc (Zn), and calcium (Ca). Principal component analysis and partial least squares regression analysis were performed on the acquired bacterial spectra demonstrating that LIBS has the potential to differentiate and discriminate among bacteria in the un-mined and reclaimed chronosequence of bauxite soils. PMID- 21826459 TI - Retention indices in comprehensive two-dimensional gas chromatography. AB - The identification of compounds by using gas chromatography (GC) in samples with significant complexity comprising a range of isomeric species, where characterization is based on peak retention times and mass spectra, generates uncertainty for the analyst. This leads to identification errors. The most reliable way to confirm the identification of each compound is based on authentic standard co-injection, which in several cases is economically prohibitive, and often unachievable in the time available for analysis. Retention index procedures are important tools to minimize misidentification of compounds in conventional chromatography. The introduction of comprehensive two-dimensional GC (GC * GC) for analysis of complex samples was a decisive step to increase the analytical capacity of chromatographic techniques. For many samples, the chromatographic resolution increase leads to quantitative expansion in the number of peaks identified, compared with conventional GC analysis. Notwithstanding this improved resolution, limitations still persist in correct peak identification, which suggests the use of retention indices may assist in supporting component identification in this important technique. In this work, approaches to use of the retention index in GC * GC are discussed, based on an evaluation of the literature in this area. Interpretation of effective chain length data for fatty acid methyl esters in the first and second dimensions is presented. PMID- 21826460 TI - Effect of dietary iron deficiency and overload on the expression of ZIP metal-ion transporters in rat liver. AB - The mammalian ZIP (Zrt-, Irt-like Protein) family of transmembrane transport proteins consists of 14 members that share considerable homology. ZIP proteins have been shown to mediate the cellular uptake of the essential trace elements zinc, iron, and manganese. The aim of the present study was to determine the effect of dietary iron deficiency and overload on the expression of all 14 ZIP transporters in the liver, the main site of iron storage. Weanling male rats (n = 6/group) were fed iron-deficient (FeD), iron-adequate (FeA), or iron-overloaded (FeO) diets in two independent feeding studies. In study 1, diets were based on the TestDiet 5755 formulation and contained iron at 9 ppm (FeD), 215 ppm (FeA), and 27,974 ppm (3% FeO). In study 2, diets were based on the AIN-93G formulation and contained iron at 9 ppm Fe (FeD), 50 ppm Fe (FeA), or 18916 ppm (2% FeO). After 3 weeks, the FeD diets depleted liver non-heme iron stores and induced anemia, whereas FeO diets resulted in hepatic iron overload. Quantitative RT-PCR revealed that ZIP5 mRNA levels were 3- and 8-fold higher in 2% FeO and 3% FeO livers, respectively, compared with FeA controls. In both studies, a consistent downregulation of ZIP6, ZIP7, and ZIP10 was also observed in FeO liver relative to FeA controls. Studies in H4IIE hepatoma cells further documented that iron loading affects the expression of these ZIP transporters. Overall, our data suggest that ZIP5, ZIP6, ZIP7, and ZIP10 are regulated by iron, indicating that they may play a role in hepatic iron/metal homeostasis during iron deficiency and overload. PMID- 21826461 TI - Coping and emotional distress during acute hospitalization in older persons with earlier trauma: the case of Holocaust survivors. AB - BACKGROUND: Older persons with earlier trauma are often more vulnerable to stresses of old age. AIMS: To examine the levels of emotional distress in relation to cognitive appraisal of acute hospitalization and coping strategies in Holocaust survivors compared with an age- and education-matched group of elderly persons without Holocaust experience. METHODS: This is a cross-sectional study of 63 Holocaust survivors, 65 years and older, hospitalized for an acute illness, and 57 age-, education- and hospital unit-matched people without Holocaust experience. Participants completed appraisal and coping strategies (COPE) questionnaires, and the brief symptoms inventory (BSI-18). RESULTS: Holocaust survivors reported higher levels of emotional distress, appraised the hospitalization higher as a threat and lower as a challenge, and used more emotion-focused and less problem-focused or support-seeking coping strategies than the comparison group. Study variables explained 65% of the variance of emotional distress; significant predictors of emotional distress in the final regression model were not having a partner and more use of emotion-focused coping. The latter mediated the relation of group variable and challenge appraisal to emotional distress. CONCLUSIONS: Health professionals must be aware of the potential impact of the hospital environment on the survivors of Holocaust as well as survivors of other trauma. Being sensitive to their specific needs may reduce the negative impact of hospitalization. PMID- 21826462 TI - Function of MbtH homologs in nonribosomal peptide biosynthesis and applications in secondary metabolite discovery. AB - Mycobacterium tuberculosis encodes mycobactin, a peptide siderophore that is biosynthesized by a nonribosomal peptide synthetase (NRPS) mechanism. Within the mycobactin biosynthetic gene cluster is a gene that encodes a 71-amino-acid protein MbtH. Many other NRPS gene clusters harbor mbtH homologs, and recent genetic, biochemical, and structural studies have begun to shed light on the function(s) of these proteins. In some cases, MbtH-like proteins are required for biosynthesis of their cognate peptides, and non-cognate MbtH-like proteins have been shown to be partially complementary. Biochemical studies revealed that certain MbtH-like proteins participate in tight binding to NRPS proteins containing adenylation (A) domains where they stimulate adenylation reactions. Expression of MbtH-like proteins is important for a number of applications, including optimal production of native and genetically engineered secondary metabolites produced by mechanisms that employ NRPS enzymes. They also may serve as beacons to identify gifted actinomycetes and possibly other bacteria that encode multiple functional NRPS pathways for discovery of novel secondary metabolites by genome mining. PMID- 21826463 TI - Reproductive phenology of coastal plain Atlantic forest vegetation: comparisons from seashore to foothills. AB - The diversity of tropical forest plant phenology has called the attention of researchers for a long time. We continue investigating the factors that drive phenological diversity on a wide scale, but we are unaware of the variation of plant reproductive phenology at a fine spatial scale despite the high spatial variation in species composition and abundance in tropical rainforests. We addressed fine scale variability by investigating the reproductive phenology of three contiguous vegetations across the Atlantic rainforest coastal plain in Southeastern Brazil. We asked whether the vegetations differed in composition and abundance of species, the microenvironmental conditions and the reproductive phenology, and how their phenology is related to regional and local microenvironmental factors. The study was conducted from September 2007 to August 2009 at three contiguous sites: (1) seashore dominated by scrub vegetation, (2) intermediary covered by restinga forest and (3) foothills covered by restinga pre montane transitional forest. We conducted the microenvironmental, plant and phenological survey within 30 transects of 25 m * 4 m (10 per site). We detected significant differences in floristic, microenvironment and reproductive phenology among the three vegetations. The microenvironment determines the spatial diversity observed in the structure and composition of the flora, which in turn determines the distinctive flowering and fruiting peaks of each vegetation (phenological diversity). There was an exchange of species providing flowers and fruits across the vegetation complex. We conclude that plant reproductive patterns as described in most phenological studies (without concern about the microenvironmental variation) may conceal the fine scale temporal phenological diversity of highly diverse tropical vegetation. This phenological diversity should be taken into account when generating sensor-derived phenologies and when trying to understand tropical vegetation responses to environmental changes. PMID- 21826464 TI - Biometeorological and air quality assessment in an industrialized area of eastern Mediterranean: the Thriassion Plain, Greece. AB - Evidence that heat wave events are associated with poor air quality conditions and health hazards has become stronger in recent years. In this study, the impact of two heat wave episodes on human thermal discomfort and air quality is examined during summer 2007, in an industrial plain of eastern Mediterranean: the Thriassion Plain, Greece. For this purpose, two biometeorological indices Discomfort Index (DI) and Heat Load (HL)-as well as an air quality index-Air Quality Stress Index (AQSI)-were calculated using data from seven measuring sites. A land-use map was procured in order to examine the effect of different land cover types on human thermal comfort. The results indicated high level of thermal discomfort and increased air pollution levels, while a significant correlation between the DI and the AQSI was identified. PMID- 21826465 TI - US depiction of the appendix: role of abdominal wall thickness and appendiceal location. AB - The purpose of the present study was to correlate direct measurements of abdominal wall fat at the site of exam and appendiceal position with ultrasound (US) visualization of the appendix. The study took place at a large, urban pediatric teaching hospital. Demographic and imaging data of all patients who underwent both US and CT examinations within a 72-h period to evaluate for appendicitis were assessed. Two hundred eighteen patients met study criteria. Greater abdominal wall fat (p < 0.001) was observed in the subjects where the appendix was not visualized with ultrasound (17.04 mm, SD +/- 13.52) than in subjects where the appendix was visualized with ultrasound (11.75 mm, SD +/- 11.81) was significant. Using ROC curve analyses, there was no abdominal fat thickness cutoff threshold above which the appendix was significantly unlikely to be seen using US. Retrocecal location of the appendix was found to impair appendiceal visualization with US for both normal and inflamed appendices. Increased abdominal wall fat thickness was associated with decreased US appendiceal visualization rates, although there was no fat thickness value above which we could predict that the appendix would not be visualized with US. In patients with retrocecal appendices, the difference in visualization rates was significantly worse regardless of whether the appendix was normal or inflamed. PMID- 21826466 TI - Diffusion-weighted MR imaging of abdominopelvic abscesses. AB - This study was conducted to determine the incremental value of diffusion-weighted MR imaging (DW-MRI) over T2-weighted imaging diagnosing abdominopelvic abscesses and compare apparent diffusion coefficient (ADC) values of abscesses and non infected ascites. In this IRB-approved, HIPAA-compliant study, two radiologists retrospectively compared T2-weighted, T2-weighted + DW-MRI and T2-weighted + contrast enhanced MR images of 58 patients (29 with abscess, 29 with ascites) who underwent abdominal MRI for abscess detection. Confidence and sensitivity was compared using McNemar's test. ADC of abscesses and ascites was compared by t test, and a receiver operating characteristic (ROC) curve was constructed. Detection of abscesses and confidence improved significantly when T2-weighted images were combined with DW-MRI (sensitivity: observer 1-100%, observer 2-96.6%) or contrast enhanced images (sensitivity: both observers-100%) compared to T2 weighted images alone (sensitivity: observer 1-65.5%, observer 2-72.4%). All abscesses showed restricted diffusion. Mean ADC of abscesses (observer 1-1.17 +/- 0.42 * 10(-)3 mm2/s, observer 2-1.43 +/- 0.48 * 10(-3) mm2/s) was lower than ascites (observer 1-3.57 +/- 0.68 * 10(-3) mm2/s, observer 2-3.42 +/- 0.67 * 10( 3) mm2/s) (p < 0.01). ROC analysis showed perfect discrimination of abscess from ascites with threshold ADC of 2.0 * 10(-3) mm2/s (Az value 1.0). DW-MRI is a valuable adjunct to T2-weighted images diagnosing abdominopelvic abscesses. ADC measurements may have the potential to differentiate abdominal abscesses from ascites. PMID- 21826467 TI - Compendium of national guidelines for imaging of the pediatric patient. AB - BACKGROUND: Diagnostic imaging plays an integral role in diagnosing and managing many pediatric disorders, but there is growing concern in both the medical community and the general public about the long-term health effects of ionizing radiation in children, as well as utilization of imaging evaluation. These concerns, coupled with increasing pressure to reduce national health care spending, underscore the need for an assessment of readily available guidelines, especially evidence-based guidelines, for imaging in children. OBJECTIVE: To generate a list of national medical organization-endorsed guidelines with provisions for imaging the pediatric patient. MATERIALS AND METHODS: Several resources, including the National Guideline Clearinghouse (NGC) and the Web sites of major medical organizations, were searched for documents that contained specific recommendations for imaging in the pediatric population. RESULTS: A total of 155 guidelines from 40 medical organizations met inclusion criteria and are represented in our compendium. CONCLUSIONS: The compendium generated in this study can be used to direct clinical care, inform policy development and improve education of health care personnel. Additionally, the compendium can be used to identify areas of redundancy or deficiency, which may stimulate the reassessment of existing recommendations as well as the creation of new guidelines. PMID- 21826468 TI - The pituitary stalk transection syndrome: multifaceted presentation in adulthood. AB - The pituitary stalk transection syndrome was characterized after introducing the MRI scan in the evaluation of children with hypopituitarism. Its prevalence and natural history into adulthood have not been clearly established. We present 4 cases of stalk transection syndrome diagnosed by the adult endocrinologist that reflect its pleiotropic manifestations. In all cases, MRI showed pathognomonic findings with small anterior pituitary, diminutive or absent infundibulum and ectopic posterior pituitary at the median eminence. Clinical presentation occurred in childhood or the second decade of life. The hormonal deficits were variable in severity and onset, with adrenal insufficiency diagnosed in the second and forth decade in three patients, and absent in another. Growth hormone deficiency was diagnosed before age 10 in three cases and at age 20 in one case with normal spontaneous linear growth. Hypothyroidism had onset in the first or second decade of life and hypogonadism was diagnosed during work-up for lack of pubertal development in all cases. The pituitary stalk transection syndrome should be considered in patients who were previously thought to have idiopathic GH deficiency or multiple pituitary hormone deficiencies. Presence of MRI characteristics compatible with the pituitary stalk transection syndrome should prompt a full pituitary hormonal evaluation. Long-term follow-up by the adult endocrinologist is warranted as new hormone deficiencies might appear later in life. PMID- 21826469 TI - Heart failure associated with sunitinib: lessons learned from animal models. AB - Sunitinib is a highly potent, multitargeted anticancer agent. However, there is growing clinical evidence that sunitinib induces cardiac dysfunction. Disruption of multiple signaling pathways, which are important in the maintenance of adult cardiac function, is likely to result in cardiovascular toxicity. Basic and translational evidence implicates a potential role for specific growth factor signaling pathways. This review discusses the relevant translational data from animal models of heart failure, focusing on three key pathways that are inhibited by sunitinib: AMP-activated protein kinase (AMPK), platelet-derived growth factor receptors (PDGFRs), and the vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3. We hypothesize that disruption of these pathways by sunitinib results in cardiotoxicity, and present direct and indirect evidence to support the notion that sunitinib-induced cardiac dysfunction likely involves a variety of molecular mechanisms that are critical for cardiac homeostasis. PMID- 21826470 TI - Transconjunctival immunotherapy using cholera toxin B to treat experimental allergic conjunctivitis in a mouse model. AB - PURPOSE: We evaluated the use of immunological biomarkers in transconjunctival immunotherapy by using cholera toxin B for treating experimental allergic conjunctivitis in a mouse model. METHODS: Balb/c mice were sensitized using intraperitoneal injections of ovalbumin (OVA) and were then divided into two groups. The first group was treated by topical instillation of OVA after the instillation of combined OVA and cholera toxin B (CTB) solution B group). The second group was treated by topical instillation of OVA alone (allergy group). The control group consisted of nonsensitized mice undergoing topical OVA instillation only. The numbers of eosinophils and CD4-positive lymphocytes in the conjunctiva were determined histologically, and the observation of immunoglobulin A (IgA)-positive cells in the conjunctiva was performed by immunohistochemistry. Cytokine concentration in the conjunctiva was determined by the protein-array methods. Messenger RNA expression of T-cell-specific markers, such as T-bet, GATA 3, and Foxp3, in the conjunctiva was detected by reversed transcriptase polymerase chain reaction. RESULTS: The number of eosinophils and CD4-positive lymphocytes increased significantly in the allergy group compared with the control group (P < 0.001) but showed no difference between the CTB group and control group. Concentrations of interleukin 4 (IL-4) (P < 0.05), B-lymphocyte chemoattractant (P < 0.01), and thymus-expressed chemokine (P < 0.05) in the conjunctiva were significantly higher in the CTB group than in the other two groups. GATA-3 messenger RNA (mRNA) in the conjunctiva was expressed in the three groups, but T-bet and Foxp3 were not detected. CONCLUSION: Transconjunctival immunotherapy using CTB can be evaluated by histological examination of eosinophils and CD4-positive T cells, and a mucosal immunity-associated chemokine and a helper T-cell-17-associated chemokine as biomarkers. PMID- 21826471 TI - Nutritional status independently affects quality of life of patients with systemic immunoglobulin light-chain (AL) amyloidosis. AB - Nutritional status is an independent prognostic factor in immunoglobulin light chain amyloidosis (AL), but its influence on quality of life (QoL) is unknown. The aim of this cross-sectional study was to investigate the association between nutritional status and QoL in AL patients at diagnosis. One hundred and fifty consecutive patients with biopsy-proven AL were assessed for nutritional status by anthropometry [body mass index, unintentional weight loss (WL) in the previous 6 months and mid-arm muscle circumference (MAMC)], biochemistry (serum prealbumin), and semiquantitative food intake at referral. QoL was assessed by the Medical Outcomes Study 36-item Short Form General Health Survey. The composite physical component summary (PCS) and the mental component summary (MCS) for AL outpatients were 36.2 +/- 10.1 and 44.9 +/- 11.3, respectively (p < 0.001 for both vs the population norms of 50). In multivariate linear regression models adjusted for gender, age, Eastern Cooperative Oncology Group performance status, the number of organs involved, the severity of cardiac damage, C-reactive protein, energy intake, and WL, PCS was significantly lower for serum prealbumin <200 mg/L and MAMC <10th percentile (adjusted difference 3.8, 95% CI 0.18-7.5, p = 0.040 and 5.3, 95% CI 2.0-8.7, p = 0.002, respectively). MCS was decreased by 0.47 (95% CI 0.18-0.75, p = 0.002) for each kilogram of body weight lost in the previous 6 months. Nutritional status independently affects QoL in AL patients since diagnosis. Nutritional evaluation should be integral part of the clinical assessment of AL patients. Nutritional support intervention trials are warranted in such patients' population. PMID- 21826474 TI - High expression of survivin predicts poor prognosis in esophageal squamous cell carcinoma following radiotherapy. AB - Radiotherapy is one of the main treatments for esophageal squamous cell carcinoma, but there are still no biomarkers to differentiate patients who will benefit from radiation. Although treatment with a combination of radiotherapy with chemotherapy, and/or surgery improves the prognosis of patients, no biomarkers can distinguish between the responses obtained with the combined therapies. Therefore, in this study, we selected patients treated with radiotherapy alone to evaluate survivin as a predictor for radiotherapy. One hundred two biopsy samples collected by endoscopy were immunostained by survivin antibody. Positive staining for survivin was obtained in 60.8% tumor samples. Survivin expression, metastasis, and clinical stage correlated significantly with overall survival. In multivariate analysis, survivin was an independent prognostic factor for predicting overall survival of patients with esophageal cancer. Moreover, in esophageal cancer cell lines, overexpression of survivin reduced the percentage of cell death induced by radiation. Our data indicate that survivin could be a potential predictor to define those patients with esophageal squamous carcinoma who would benefit from radiotherapy. PMID- 21826472 TI - A high cholesterol diet given to apolipoprotein E-knockout mice has a differential effect on the various neurotrophin systems in the hippocampus. AB - Apolipoprotein E (apoE) is one of the major transporters of cholesterol in the body and is essential for maintaining various neural functions in the brain. Given that hypercholesterolemia is a risk factor in Alzheimer's disease (AD), it has been suggested that altered cholesterol metabolism may be involved in the development of the pathogenesis, including neural degeneration, commonly observed in AD patients. Neurotrophic factors and their receptors, which are known to regulate various neural functions, are also known to be altered in various neurodegenerative diseases. We therefore hypothesized that cholesterol metabolism may itself influence the neurotrophin system within the brain. We decided to investigate this possibility by modulating the amount of dietary cholesterol given to apoE-knockout (apoE-KO) and wild-type (WT) mice, and examining the mRNA expression of various neurotrophin ligands and receptors in their hippocampal formations. Groups of eight-week-old apoE-KO and WT mice were fed a diet containing either "high" (HCD) or "normal" (ND) levels of cholesterol for a period of 12 weeks. We found that high dietary cholesterol intake elevated BDNF mRNA expression in both apoE-KO and WT mice and TrkB mRNA expression in apoE-KO animals. On the other hand, NGF and TrkA mRNA levels remained unchanged irrespective of both diet and mouse type. These findings indicate that altered cholesterol metabolism induced by HCD ingestion combined with apoE deficiency can elicit a differential response in the various neurotrophin ligand/receptor systems in the mouse hippocampus. Whether such changes can lead to neural degeneration, and the mechanisms that may be involved in this, awaits further research. PMID- 21826475 TI - Effect of surface-enhanced laser desorption/ionization time-of-flight mass spectrometry on identifying biomarkers of laryngeal carcinoma. AB - The aim is to study the serum protein fingerprint of patients with laryngeal carcinoma (LC) and to screen for protein molecules closely related to LC during the onset and progression of the disease with surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS). Serum samples from 68 patients with LC and 117 non-cancer control samples (75 healthy volunteers and 42 Vocal fold polyps). Q10 protein chips and PBSII-C protein chips reader (Ciphergen Biosystems Inc.) were used. The protein fingerprint expression of all the Serum samples and the resulting profiles between cancer and non-cancer groups were analyzed with Biomarker Wizard system. A group of proteomic peaks were detected. Three differently expressed potential biomarkers were identified with the relative molecular weights of 5,915, 6,440 and 9,190 Da. Among the three peaks, the one with m/z 6,440 was down-regulated, and the other two peaks with m/z 5,915 and 9,190 were up-regulated in LC. This diagnostic model could distinguish LC patients from controls with a sensitivity of 92.1% and a specificity of 91.9%. Moreover, blind test data showed a sensitivity of 86.7% and a specificity of 89.1%. The data suggested that SELDI technology could be used to screen proteins with altered expression levels in the serum of LC patients. These protein peaks were considered as specific serum biomarkers of LC and have the potential value for further investigation. PMID- 21826476 TI - Improving participation rates for women of color in health research: the role of group cohesion. AB - Adherence to physical activity and dietary interventions is a common challenge. Interventions that use group cohesion strategies show promise for increasing adherence, but have not been tested among women of color. The purpose of this study was to determine whether dimensions of group cohesion mediate the association between intervention condition and attendance within a community physical activity program for women of color. African American and Hispanic or Latina women (N = 310) completed measurements at baseline and post-intervention and participated in a social cohesion intervention to improve physical activity and dietary habits. Women were assigned to a physical activity or fruit and vegetable intervention group. Social and task cohesion was measured using the Physical Activity Group Environment Questionnaire (PAGE-Q). Attendance was recorded at each of six intervention sessions. Women were generally middle-age (M age = 46.4 years, SD = 9.1) and obese (M BMI = 34.4 kg/m2, SD = 7.7). The estimate of the mediated effect was significant for all group cohesion constructs, indicating both task constructs-attraction to the group's task (SE = 0.096, CI: -0.599 to -0.221) and group integration around the task (SE = 0.060, CI: -0.092 to -0.328)-and social constructs-attraction to the group's social aspects (SE = 0.046, CI: -0.546 to -0.366) and group integration around social aspects (SE = 0.046, CI: -0.546 to -0.366)-significantly mediated the association between group assignment and attendance. Both task and social constructs are important to improve attendance in health promotion interventions for women of color. PMID- 21826477 TI - Thienopyridine-associated drug-drug interactions: pharmacologic mechanisms and clinical relevance. AB - The thienopyridines inhibit platelet activation and aggregation by directly inhibiting the platelet P2Y12 adenosine diphosphate receptor. The available thienopyridines are prodrugs and must be converted into active forms by the cytochrome P450 (CYP) enzyme system. An important portion of the variability in platelet response to clopidogrel is explained by the variability in plasma concentrations of the clopidogrel active metabolite. Several reports have thus progressively raised concerns about potential drug interactions as a result of inhibition or induction of CYP450 enzymes. Pharmacokinetics and pharmacodynamics studies have notably shown that concomitant use of clopidogrel and some proton pump inhibitors reduces the antiplatelet effect of clopidogrel. Several other drugs (metabolized through CYP3A4 such as statins or antifungals) similarly impact the pharmacologic response to clopidogrel. Conversely, agents that induce CYP activity increase clopidogrel responsiveness. However, the data supporting the clinical relevance of such pharmacological drug interactions have been controversial. This review will provide an overview of the mechanisms underlying thienopyridine-associated drug-drug interactions, and highlight the most recent developments in the field and propose guidance for the practitioner. PMID- 21826478 TI - The Heinz Nixdorf Recall study and its potential impact on the adoption of atherosclerosis imaging in European primary prevention guidelines. AB - Non-contrast-enhanced computed tomography (CT) imaging of the heart enables noninvasive quantification of coronary artery calcification (CAC), a surrogate marker of the atherosclerotic burden in the coronary artery tree. Multiple studies have underlined the ability of CAC score for individual risk stratification and, accordingly, the American Heart Association recommended cardiac CT for risk assessment in individuals with an intermediate risk of cardiovascular events as measured by Framingham Risk Score. However, limitations in transcribing risk stratification algorithms based on American cohort studies into European populations have been acknowledged in the past. Moreover, data on implications for reclassification into higher- or lower-risk groups based on CAC scores were lacking. The Heinz Nixdorf Recall (HNR) study is a population-based cohort study that investigated the ability of CAC scoring in risk prediction for major cardiovascular events above and beyond traditional cardiovascular risk factors. According to Heinz Nixdorf Recall findings, CAC can be used for reclassification, especially in those in the intermediate-risk group, to advise on lifestyle changes for the reclassified low-risk category, or to implement intensive treatments for the reclassified high-risk individuals. This article discusses the present findings of the Heinz Nixdorf Recall Study with respect to the current literature, risk stratification algorithms, and current European guidelines for risk prediction. PMID- 21826479 TI - Combination of myocardial perfusion imaging and coronary artery calcium scanning: potential synergies for improving risk assessment in subjects with suspected coronary artery disease. AB - For many years, the mainstay of noninvasive evaluation of patients suspected of ischemic cardiovascular disease (CVD) centered on the use of myocardial perfusion imaging (MPI). In recent years, the advent of newer modalities such as coronary artery calcium (CAC) scanning, coronary CT angiography, and MRI have broadened the means of assessing cardiac patients for this purpose. Moreover, the advent of these newer modalities has created potential synergies whereby combinations of tests may be clinically useful. In this review, we assess the potential synergies between MPI, whether assessed by single photon emission computed tomography (SPECT) or positron emission tomography (PET), and CAC scanning. Whereas MPI has long been used for diagnostic assessment and for risk stratification purposes, the emerging uses of CAC scanning now appear multifold: screening for CVD, triaging patients for diagnostic stress testing, improving risk stratification in patients following stress testing, and enhancing the direct management of patients' CVD risk following CAC scanning. Recent work suggests that CAC scanning may be emerging as the initial test of choice for most asymptomatic patients. The advent of hybrid SPECT-CT and PET-CT scanners may signify an important new opportunity for the combined use of these modalities in the higher-risk asymptomatic patient population. PMID- 21826480 TI - Circulating cytokine levels in acute pancreatitis-model of SIRS/CARS can help in the clinical assessment of disease severity. AB - The aim of our study was to evaluate the pro- and anti-inflammatory cytokine response during acute pancreatitis and its predictive value on severity of disease. A hospital-based prospective clinical study was conducted. Twenty patients with acute pancreatitis were enrolled during a 12-month period. Plasma concentrations of TNF-alpha, IL-1beta, IL-6, and IL-10 were determined at days 1, 2, 3, 6, and 9. The patient population was analyzed by type of acute pancreatitis. Severity was defined according to the Atlanta criteria for assessing severity of acute pancreatitis. Clinical variables were recorded to patients classified in one of two groups: severe acute pancreatitis (SAP group) and mild acute pancreatitis (MILD group). Patients with SAP had significantly higher average levels of IL-6 compared to the MILD group patients (539.2 pg/L vs. 23.4 pg/L, p < 0.0001). Also, the values of IL-10 were significantly higher in patients with SAP (242.4 pg/L vs. 8.1 pg/L, p = 0.003). The values of TNF-alpha were not significantly different in both groups. The value of IL-6 and IL-10 showed a positive correlation (r = 0.7964, p < 0.0001). Although a relatively small sample of patients was used, we can conclude that the determination of the value of IL-6 and IL-10 can help in the clinical assessment of disease severity. PMID- 21826481 TI - Effects of the brief viewing of emotional stimuli on understanding of insight solutions. AB - In the present study, we examined whether and how brief viewing of positive and negative images influences subsequent understanding of solutions to insight problems. For each trial, participants were first presented with an insight problem and then briefly viewed a task-irrelevant positive, negative, or neutral image (660 ms), which was followed by the solution to the problem. In our behavioral study (Study 1), participants were faster to report that they understood the solutions following positive images, and were slower to report it following negative images. A subsequent fMRI study (Study 2) revealed enhanced activity in the angular gyrus and medial prefrontal cortex (MPFC) while viewing solutions following positive, as compared with negative, images. In addition, greater activation of the angular gyrus was associated with more rapid understanding of the solutions. These results suggest that brief viewing of positive images enhances activity in the angular gyrus and MPFC, which results in facilitation of understanding solutions to insight problems. PMID- 21826483 TI - Microfluidic LIPS for serum antibody detection: demonstration of a rapid test for HSV-2 infection. AB - There is great interest in point-of-care antibody testing for the diagnosis of infectious and autoimmune diseases. As a first step in the development of self contained and miniaturized devices for highly quantitative antibody detection, we demonstrate the application of Luciferase Immunoprecipitation Systems (LIPS) technology in a microfluidic format. Protein A/G was immobilized on the walls of PDMS-glass microchannels of 500 nL volume. The assay proceeds with the simultaneous introduction of plasma and Renilla luciferase-tagged antigens. Following washing, coelenterazine substrate was added and bound antigen luciferase measured by chemiluminescence. Total assay time, including rinsing and detection, is under 10 min. Using these stable microfluidic devices, high diagnostic performance (100% sensitivity and 100% specificity) was achieved for the diagnosis of HSV-2 infection. Based on these findings, the LIPS microfluidic format should readily lend itself to automation and the transfer to portable instrumentation. PMID- 21826484 TI - Heritability and familiality of type 2 diabetes and related quantitative traits in the Botnia Study. AB - AIMS/HYPOTHESIS: To study the heritability and familiality of type 2 diabetes and related quantitative traits in families from the Botnia Study in Finland. METHODS: Heritability estimates for type 2 diabetes adjusted for sex, age and BMI are provided for different age groups of type 2 diabetes and for 34 clinical and metabolic traits in 5,810 individuals from 942 families using a variance component model (SOLAR). In addition, family means of these traits and their distribution across families are calculated. RESULTS: The strongest heritability for type 2 diabetes was seen in patients with age at onset 35-60 years (h (2) = 0.69). However, including patients with onset up to 75 years dropped the h (2) estimates to 0.31. Among quantitative traits, the highest h (2) estimates in all individuals and in non-diabetic individuals were seen for lean body mass (h (2) = 0.53-0.65), HDL-cholesterol (0.52-0.61) and suppression of NEFA during OGTT (0.63 0.76) followed by measures of insulin secretion (insulinogenic index [IG(30)] = 0.41-0.50) and insulin action (insulin sensitivity index [ISI] = 0.37-0.40). In contrast, physical activity showed rather low heritability (0.16-0.18), whereas smoking showed strong heritability (0.57-0.59). Family means of these traits differed two- to fivefold between families belonging to the lowest and highest quartile of the trait (p < 0.00001). CONCLUSIONS/INTERPRETATION: To detect stronger genetic effects in type 2 diabetes, it seems reasonable to restrict inclusion of patients to those with age at onset 35-60 years. Sequencing of families with extreme quantitative traits could be an important next step in the dissection of the genetics of type 2 diabetes. PMID- 21826485 TI - Type 2 diabetes: remission in just a week. PMID- 21826486 TI - Recovery and characterization of environmental variants of Shigella flexneri from surface water in Bangladesh. AB - Little is known about the distribution, survival, and transmission of Shigella in environmental surface waters. To gain more insight into the environmental biology of Shigella we isolated five bacterial strains serotyped as Shigella flexneri 2b from a freshwater lake in Bangladesh using a modified nutrient broth supplemented with nucleic acid bases. The biochemical properties of the isolates, including inability to ferment lactose and a negative lysine decarboxylase test, indicated common physiological characteristics with Shigella, but differed significantly from that of standard clinical strains. The isolates possessed the ipaH virulence gene and a megaplasmid, but lacked other Shigella-related virulence marker genes. Genetic fingerprinting and sequence analysis of housekeeping genes confirmed the strains as S. flexneri isolates. An apparent clonal origin of strains recovered with a one-year interval indicates a strong environmental selection pressure on Shigella for persistence in the freshwater environment. The lack of a complete set of virulence genes as well as uncommon biochemical properties suggest that these strains might represent a group of non-invasive and atypical environmental Shigella variants, with the potential for further elucidation of the survival mechanism, diversity, and emergence of virulent Shigella in tropical freshwater environments. PMID- 21826487 TI - Structural changes of Schistosoma mansoni adult worms recovered from C57BL/6 mice treated with radiation-attenuated vaccine and/or praziquantel against infection. AB - Although the current treatment of schistosomiasis relies largely on praziquantel (PZQ), it has not significantly reduced the overall number of disease cases, perhaps due to inevitable resistance to PZQ. Previous studies showed that radiation-attenuated vaccine gives protection levels for Schistosoma mansoni in host various species. In the present study, we evaluated the effect of various vaccination strategies in C57BL/6 mice, including single or multiple vaccination strategy, subcurative dose (20 mg/kg) of PZQ, and a combination of single vaccination with subcurative dose of PZQ. Groups of five mice were sacrificed postinfection in 42 days and schistosomes were collected by perfusion and examined by scanning electron microscopy. Treatment either with subcurative dose of PZQ or with a single vaccination of attenuated cercariae (500 per mouse), caused significant reduction in total worm burden, hepatic and intestinal ova counts 43.03%, 73.2%, 59.5% and 37.97%, 52.02%, 26.3%, respectively. Furthermore, tegumental changes were observed, including severe swelling, fusion of tegumental folds, vesicle formation, and loss or shortening of the spines on the tubercles. However, multiple vaccination strategy resulted in much higher reduction in total worm burden, hepatic and intestinal ova count. However, multiple vaccination strategy resulted in high reduction of worm burden, hepatic and intestinal ova counts 72.5%, 90.7%, 65.79%, respectively, and further causing swollen, disruption of tubercles teguments and erosion, extensive peeling, fusion of tegumental folds. Our findings suggest that multiple vaccination strategy is the most effective strategy to clear schistosomal infection, indicating its potential in guiding the design of appropriate therapeutic strategy against schistosomes. PMID- 21826488 TI - In vitro assessment of the chemotherapeutic action of a specific hydrogen peroxide, peracetic, acetic, and peroctanoic acid-based formulation against the free-living stages of Ichthyophthirius multifiliis (Ciliophora). AB - Traditionally, malachite green administrated as in-bath treatment was the most effective and common strategy used in freshwater aquaculture systems to control infections of the ciliate protozoan parasite Ichthyophthirius multifiliis Fouquet, 1876. After the ban of malachite green in the USA and Europe to be used in fish for human consumption, there has been extensive research destined to find efficacious replacements. Recently, peracetic acid-based compounds have demonstrated a strong cytotoxic effect in vitro and in vivo against I. multifiliis. In the present study, we tested the efficacy of a hydrogen peroxide, peracetic, acetic and peroctanoic acid-based formulation (HPPAPA) to eliminate the free-living stages of I. multifiliis (tomonts, cysts and theronts). The results obtained showed that the administration of low doses (8, 12 or 15 mg/l) of a specific HPPAPA-based product during a short window of exposure (60 min) kills nearly all free-living stages of I. multifiliis (theronts, tomonts and cysts) within the window of treatment (~100% mortality for all the stages; one way ANOVA, P <= 0.001). Of note, even the lowest concentration of HPPAPA tested (8 mg/l) was able to disrupt normal cyst development and therefore theront release. The demonstrated in vitro efficacy of the peracetic acid-based product tested on the present study suggests its great potential to control I. multifiliis infections in commercial aquacultural systems. PMID- 21826489 TI - Interaction between ciprofloxacin and chloroquine in mice infected with chloroquine resistant Plasmodium berghei: interaction between ciprofloxacin and chloroqune. AB - The increasing spread of chloroquine resistant malaria has intensified the search for new antimalarial treatment, especially drugs that can be used in combination. Ciprofloxacin (CFX) a fluoroquinolone commonly used to treat bacterial infections has been shown to possess significant antimalarial activity both in vitro and in vivo. Thus efforts in this study were devoted to evaluating the antimalarial activity of combination of chloroquine (CQ) with varying doses (10, 20, 40 80, 160 mg/kg body weight) of CFX in groups of 35 mice inoculated intraperitoneally with 10(7) chloroquine resistant strain Plasmodium berghei ANKA. Parasitological activity and survival of the animals were assessed over 21 days. Parasitemia in non-treated control mice peaked at 78% on day 9 and none survived by day 10. However, the combination of CQ with 160 mg/kg body weight of CFX resulted in a reduction in parasitemia between days 9 and 14 and this was significantly lower than that obtained with CQ alone or CQ combined with the lower doses of CFX (p < 0.05). In addition, the combination of CQ with 160 mg/kg CFX significantly reduced mortality in the infected animals (p = 0.0002) compared with the other treatment groups. The results from this study support the potential usefulness of CFX in combination with antimalarial drugs for the treatment of chloroquine resistant human malaria. PMID- 21826490 TI - The relevance of conditional dispersal for bacterial colony growth and biodegradation. AB - Bacterial degradation is an ecosystem service that offers a promising method for the remediation of contaminated soils. To assess the dynamics and efficiency of bacterial degradation, reliable microbial simulation models, along with the relevant processes, are required. We present an approach aimed at improving reliability by studying the relevance and implications of an important concept from theoretical ecology in the context of a bacterial system: conditional dispersal denoting that the dispersal strategy depends on environmental conditions. Different dispersal strategies, which either incorporate or neglect this concept, are implemented in a bacterial model and results are compared to data obtained from laboratory experiments with Pseudomonas putida colonies growing on glucose agar. Our results show that, with respect to the condition of resource uptake, the model's correspondence to experimental data is significantly higher for conditional than for unconditional bacterial dispersal. In particular, these results support the hypothesis that bacteria disperse less when resources are abundant. We also show that the dispersal strategy has a considerable impact on model predictions for bacterial degradation of resources: disregarding conditional bacterial dispersal can lead to overestimations when assessing the performance of this ecosystem service. PMID- 21826491 TI - Integrated evaluation of environmental parameters influencing Vibrio occurrence in the coastal Northern Adriatic Sea (Italy) facing the Venetian lagoon. AB - In the marine environment, the persistence and abundance of Vibrio are related to a number of environmental parameters. The influence of the different environmental variables in determining the Vibrio occurrence could be different in the specific geographic areas around the world. Moreover, oceanographic parameters are generally interdependent and should not be considered separately when their influence on bacterial presence and concentration is tested. In this study, an integrated approach was used to identify key parameters determining the abundance of Vibrio spp in marine samples from the Venetian Lagoon in Italy, which is an important area for fish farming and tourism. Multivariate techniques have been adopted to analyze the dataset: using PCA, it was shown that a relatively high proportion of the total variance in this area was mainly due to two independent variables, namely salinity and temperature. Using cluster analysis, it was possible to categorize different groups with homogeneous features as regards space ("stations") and time ("seasons") distribution, as well as to quantify the values of environmental variables and the Vibrio abundances in each category. Furthermore, integrating key environmental factors and bacterial concentration values, it was possible to identify levels of salinity and sea surface temperature which were optimal for Vibrio concentration in water, plankton, and sediment samples. The identification of key environmental variables conditioning Vibrio occurrence should facilitate ocean monitoring, making it possible to predict unexpected variations in marine microflora which determine possible public health risks in coastal areas. PMID- 21826493 TI - [Financing of inpatient orthopaedics and trauma surgery in the 2011 G-DRG System]. AB - BACKGROUND: The German DRG system forms the basis for billing inpatient hospital services. It includes not only the case groups (G-DRGs), but also copayments. This paper analyses and evaluates the relevant developments of the 2011 G-DRG system for orthopaedics and traumatology from the medical and classificatory perspective. METHODS: An analysis was performed of relevant diagnoses, medical procedures and G-DRGs in the 2010 and 2011 versions based on the publications of the German DRG Institute (InEK) and the German Institute of Medical Documentation and Information (DIMDI). RESULTS: A number of codes for surgical measures have been newly established or modified - above all in foot surgery, arthroscopic surgery and wound surgery. Here, the identification and the correct and performance-based mapping of complex and elaborate scenarios was again the focus of the restructuring of the G-DRG system. The G-DRG structure in orthopaedics and traumatology is changed, especially for polytraumata. CONCLUSION: The allocation of common cases with a standardized treatment pattern appears to be appropriate and the reimbursement adequate. For the less common and more complex cases the 2011 G-DRG system still shows need for further modification (e.g. polytraumata, joint replacement, spine surgery). The proper integration of the modified OPS classification for foot surgery to the appropriate G-DRGs will be essential to maintain the high quality of the reimbursement structure for the future. PMID- 21826492 TI - Transgenic Stra8-EYFP pigs: a model for developing male germ cell technologies. AB - The male germ line in mammals is composed of self-renewing cells, spermatogonia, the meiotic spermatocytes and spermiogenic spermatids. Identification of these cell stages in vitro has been problematic. Transgenic animals expressing a marker gene with a promoter specific to certain cell stages in the testis would be a useful approach to identifying these cells in a viable state. Towards this end, we have produced transgenic pigs expressing mitochondrial localized enhanced yellow fluorescent protein (EYFP-mito) under control of the germ cell specific Stimulated by Retinoic Acid 8 (Stra8) promoter. Stra8 has been shown to be expressed in pre-meiotic germ cells of mice. Twelve clones harboring the Stra8 EYFP-mito transgene were produced. Analysis by Western blot indicated that expression of the transgene was limited to testicular tissue in the transgenic pigs. Single cells and seminiferous tubules were cultured in vitro and subsequently examined with epifluorescent microscopy. Expression of EYFP was noted in cells cultured for up to 5 days. Both EYFP-mito and STRA8 antibodies were shown to bind and co-localize in seminiferous tubule cells in whole mounts and in histological sections. EYFP-mito in the transgenic pigs co-localized with the endogenous stem cell marker, NANOG. Expression of the Stra8-EYFP transgene in spermatogenic cells indicates that these pigs will be useful by providing labelled cells for use in such technologies such as germ cell transplantation and in vitro spermatogenic studies. PMID- 21826494 TI - [Trauma research net of the German Society for Orthopaedics and Trauma Surgery]. AB - A first meeting of the recently founded "Trauma Research Net" of the German Society for Orthopaedics and Trauma Surgery (DGOU e.V.) took place at the Reisensburg Castle, Gunzburg, from 24 to 26 February 2011. Numerous representatives of trauma-related Research Institutes and University Hospitals in Germany demonstrated their main research foci. There was also an open discussion of current problems in trauma research, especially the lack of junior researchers and nationwide collaborations as well as limited information about the research topics of individual research groups. The overall research efforts of the "Trauma Research Net" apparently focus on fracture, multiple injury and inflammation on an organ and cellular level. Furthermore, an up-to-date matrix of the existing methods has been generated which is now provided for the networker. The common middle-term goal of the "Trauma Research Net" is the inclusive, intensive scientific exchange as well as the generation and workup of common hypotheses using standard operating procedures. In the long term, the resulting clustered research activities are intended to address and resolve clinically relevant questions in the field of trauma research. PMID- 21826495 TI - [Comparison between the Austrian and German DRG systems in hand surgery]. AB - BACKGROUND: Diagnosis-Related Groups (DRG) are a patient classification system grouping related types of patients treated to the resources they consumed. In this analysis, we compared the Austrian and the German DRG systems. METHOD: The 15 most common hand surgical diagnoses and their corresponding operative treatment were transferred into the Austrian system. Thus, the length of stay and the reimbursement of both countries could be obtained and compared. RESULTS: The mean values and the median values of the upper and lower thresholds of length of stay as well as the average length of stay were all lower in Austria compared to Germany. Reimbursement in Germany was higher in 13 of 19 cases. Total proceeds amounted to 1.67 million in the German and 1.70 million in the Austrian health care system. Considering the purchasing power applying consumer prize parities, the difference of reimbursement between the countries rose to 130,000 which equals a difference of almost 8%. CONCLUSION: Reimbursement of the top 15 diagnoses in hand surgery in Austria is 8% higher than in Germany. Except for one case, mean values as well as upper and lower thresholds of length of stay are considerably shorter in Austria. Comparison of international data to refine a national compensation system is advocated. PMID- 21826496 TI - [Osteomyelitis of the costae caused by salmonella]. AB - Salmonella enterica serotype Enteritidis was detected in a 34-year-old, previously healthy patient who suffered from osteomyelitis of the costae. Radical surgical debridement and antibiotic therapy were able to stop the infection. An abdominal flap and a thoracic flap were used to cover the soft tissue defect. PMID- 21826497 TI - A comparison of anterior cervical discectomy and corpectomy in patients with multilevel cervical spondylotic myelopathy. AB - BACKGROUND: The optimal surgical approach for multilevel cervical spondylotic myelopathy (CSM) has not been defined, and the relative merits of multilevel anterior cervical discectomy and fusion (ACDF) and anterior cervical corpectomy (2-level or skip 1-level corpectomy) and fusion (ACCF) remain controversial. However, few comparative studies have been conducted on these two surgical approaches. METHODS: This study retrospectively reviewed the case histories of 120 patients that underwent surgical treatment for 3- or 4-level CSM from July 2003 to June 2008. One hundred and twenty patients (81 male and 39 female) of mean age 58.3+/-9.8 years (37-78) were included. The study compared perioperative parameters (blood loss, operation times), complications [surgery-related complications (CSF, hoarseness, epidural hematoma, C5-palsy, dysphagia), instrumentation and graft related complications (dislodgement, subsidence)], clinical parameters [Japanese Orthopedic Association (JOA) scores, Neck Dysfunciton Index (NDI) scores], and radiologic parameters (segmental lordosis, fusion rate). RESULTS: At a minimum of 2-year follow-up, both ACDF and ACCF groups demonstrated a significant increase in the JOA scores (preoperatively 9.25+/-1.9 and 8.86+/-1.9, postoperatively 13.86+/-1.6 and 13.27+/-1.8, respectively), segmental lordosis (preoperatively 9.79+/-3.4 and 9.54+/-3.0, postoperatively 17.75+/-2.6 and 14.49+/-2.5, respectively) and NDI scores (preoperatively 12.56+/-3.0 and 12.21+/-3.4, postoperatively 3.44+/-1.7 and 5.68+/-2.6, respectively). Six patients (2 dislodgement, 4 subsidence) in ACCF group had instrumentation and graft related-complications and they had no obvious neurological symptoms without a second operation. Blood loss (102.81+/-51.3 and 149.05+/-74, respectively, P=0.000), NDI scores (P=0.000), and instrumentation and graft related-complications (P=0.032) were significantly lower in the ACDF group, whereas operation time (138.07+/-30.9 and 125.08+/-26.4, respectively, P=0.021) and segmental lordosis (P=0.000) were significantly greater in the ACDF group. Other parameters were not significantly different in the two groups. CONCLUSIONS: Surgical managements of 3- or 4-level CSM by ACDF or ACCF showed no significant differences in terms of achieved clinical symptom improvements, with the exception of better postoperative NDI scores in ACDF. In addition, ACDF is better than ACCF in terms of blood loss, lordotic curvature improvement and instrumentation and graft related-complication rates, with the exception of operation times. PMID- 21826498 TI - Abnormal anthropometric measurements and growth pattern in male adolescent idiopathic scoliosis. AB - PURPOSE: The progression of adolescent idiopathic scoliosis is closely correlated with longitudinal growth during puberty. A decreased incidence of curve progression has been found in male patients with adolescent idiopathic scoliosis compared with female patients with the condition. This finding implies that there might be a sexual dimorphism in the pubertal growth patterns of adolescent idiopathic scoliosis patients. Abnormal pubertal growth in female adolescent idiopathic scoliosis patients has been well characterized; however, the pubertal growth patterns of male adolescent idiopathic scoliosis patients have not been reported. We conducted a cross-sectional study of anthropometric measurements to compare the growth patterns of male patients with adolescent idiopathic scoliosis with those of healthy boys during puberty and explore the difference in the pubertal growth patterns of female and male patients with adolescent idiopathic scoliosis. METHODS: A total of 688 subjects were involved in the study, including 332 male adolescent idiopathic scoliosis patients and 356 age-matched healthy boys. The subjects were categorized according to their chronological ages. Their body weights, heights and arm spans were obtained using standard methods; the corrected body heights of the adolescent idiopathic scoliosis boys were determined using Bjour's equation. The inter-group differences in the anthropometric parameters were analyzed. Multivariate regression analysis was carried out in the adolescent idiopathic scoliosis patients to identify the anthropometric parameters that influence curve severity. RESULTS: The corrected standing heights and arm spans of male adolescent idiopathic scoliosis patients were similar to those of the matched controls during puberty. However, the body weights of the adolescent idiopathic scoliosis patients who were more than 14 years old were significantly less than those of the control group. The body mass index of the adolescent idiopathic scoliosis patients between the ages of 15 and 17 were also significantly less than those of the control subjects. Moreover, a significantly higher incidence of underweight was found in adolescent idiopathic scoliosis patients (8.6%) than in the controls (3.4%). Upon multivariate regression analysis, body weight and chronological age were identified as independent predictors of curve magnitude in male adolescent idiopathic scoliosis patients. The male adolescent idiopathic scoliosis patients with variable curve patterns exhibited no significant differences in their anthropometric parameters. CONCLUSIONS: The results showed abnormal pubertal growth in the male adolescent idiopathic scoliosis patients compared with their age- and gender-matched normal controls. Despite similar longitudinal growth, the male patients with adolescent idiopathic scoliosis exhibited significantly lower body weights and a higher incidence of underweight during the later stage of puberty compared with their normal controls. These abnormalities in the pubertal growth of male patients were different from those observed in female patients with adolescent idiopathic scoliosis. Body weight could be an important parameter for further longitudinal studies on the prognostication of curve progression in adolescent idiopathic scoliosis. PMID- 21826499 TI - [Mesenchymal stem cells and their interaction with biomaterials: potential applications in tissue engineering]. AB - INTRODUCTION: Mesenchymal stem cells (MSC) are an important cell type for regenerative medicine and tissue engineering. They are involved in tissue regeneration by means of: (a) differentiation into specialised mesodermal cells and (b) their biosynthetic activity that is both immunomodulatory and trophic. In recent studies we analysed MSC in contact with different biomaterials to identify suitable combinations for tissue engineering. METHODS: A biomaterial test platform was established to analyse cell adhesion, viability, proliferation, cytotoxicity according to ISO 10993-5, apoptosis and differentiation to adipocytes and osteoblasts on a variety of polymers (degradable biopolymers, degradable synthetic polymers, non-degradable synthetic polymers, shape memory polymers, and ceramics). RESULTS: Using this platform, biomaterials which support MSC growth by maintaining their stem cell characteristics and support the differentiation of MSC towards mature osteoblasts were identified. Furthermore, we showed that MSC possess fibrinolytic capacities and perform extracellular matrix remodelling. CONCLUSION: The data support the theory that MSC are involved in tissue regeneration both via their differentiation capacity and their trophic characteristics. We identified different MSC/biomaterial combinations which are suitable for stem cell-based bone tissue engineering. PMID- 21826500 TI - Understanding the need of health care providers for teleconsultation and technological attributes in relation to the acceptance of teleconsultation in Malaysia: a mixed methods study. AB - The aim of this study was to explore the importance of service need along with perceived technology attributes in potentially influence the acceptance of teleconsultation. The study was conducted based on the concurrent triangulation design involving qualitative and quantitative study methods. These entailed interviews with key informants and questionnaires survey of health care providers who practiced in the participating hospitals in Malaysia. Thematic analysis involving iterative coding was conducted on qualitative data. Scale reliability test and hypothesis testing procedures were performed on quantitative data. Subsequently, both data were merged, compared and interpreted. In particular, this study utilized a qualitative priority such that a superior emphasis was placed on the qualitative method to demonstrate an overall understanding. Based on the responses of 20 key informants, there was a significant need for teleconsultation as a tool to extend health services to patients under constrained resources and critical conditions. Apparently, the latest attributes of teleconsultation technology have generally met users' expectation but rather perceived as supportive facets in encouraging the usage. Concurrently, based on the survey engaging 72 health care providers, teleconsultation acceptance was statistically proven to be strongly associated with service need and not originated exclusively from the technological attributes. Additionally, the results of this study can be used to promote teleconsultation as an effective means in delivering better health services. Thus, the categories emerged from this study may be further revised and examined for explaining the acceptance of teleconsultation technology in other relevant contexts. PMID- 21826501 TI - Manual refinement system for graph-based segmentation results in the medical domain. AB - The basic principle of graph-based approaches for image segmentation is to interpret an image as a graph, where the nodes of the graph represent 2D pixels or 3D voxels of the image. The weighted edges of the graph are obtained by intensity differences in the image. Once the graph is constructed, the minimal cost closed set on the graph can be computed via a polynomial time s-t cut, dividing the graph into two parts: the object and the background. However, no segmentation method provides perfect results, so additional manual editing is required, especially in the sensitive field of medical image processing. In this study, we present a manual refinement method that takes advantage of the basic design of graph-based image segmentation algorithms. Our approach restricts a graph-cut by using additional user-defined seed points to set up fixed nodes in the graph. The advantage is that manual edits can be integrated intuitively and quickly into the segmentation result of a graph-based approach. The method can be applied to both 2D and 3D objects that have to be segmented. Experimental results for synthetic and real images are presented to demonstrate the feasibility of our approach. PMID- 21826502 TI - The grotesque female in Malaysian poems: shaping the migrant's psyche. AB - The works of Malaysian poet, Wong Phui Nam's Against the Wilderness (vii) China bride and Variations on a Birthday Theme (iv) Kali, illustrate a bride and a mother in terrifying images. Wong's stylistic form of representing the female body through startling images of inversion and degradation evoke feelings of unease. The suspension between the known and the unknown causes a bewildering reality verging on madness. Interpreted through the lens of the carnivalesque, specifically, the grotesque body, festive language and parody, I attempt to reconstruct the psyche of the Chinese migrant which underpins these poems. The migrant who arrived in Malaya during the colonial era in the early nineteenth century faced political and social struggles in adapting to a new land. In the poems, the migrant juxtaposes his position to a female and uses the female body as a site of contention to intensify the torment of the psyche and to reflect the despair of the Chinese in Malaysia. PMID- 21826504 TI - Trauma and truth: representations of madness in Chinese literature. AB - With only a few exceptions, the literary theme of madness has long been a domain of Western cultural studies. Much of Western writing represents madness as an inquiry into the deepest recesses of the mind, while the comparatively scarce Chinese tradition is generally defined by madness as a voice of social truth. This paper looks at five works of twentieth-century Chinese fiction that draw on socio-somatic aspects of madness to reflect upon social truths, suggesting that the inner voice of subjectivity is perhaps not the only true voice of the self. PMID- 21826505 TI - The other self: psychopathology and literature. AB - The figure of the "double" or the other self is an important topic in the history of literature. Many centuries before Jean Paul Richter coined the term, "doppelganger," at the beginning of the Romantic Movement in the year 1796, it is possible to find the figure of the double in myths and legends. The issue of the double emphaszses the contradictory character of the human being and invokes a sinister dimension of the psychological world, what has been called in German as "umheimlich." However, does multiciplicity always involve pathology? Related to this figure in literary history, a new perspective from clinical psychology called "dialogical self" defines the self as a multi-voice reality. Along the same line, postmodernist psychology considers the self a discursive construction. From these perspectives, the "self" is situated a long way away from the classical essential conception of the self. In this paper, we review briefly some important landmarks of the figure of the double in the literature, and we compare the coincidences of the "double" experiencies described in literature with the experiences of our patients. Finally, we discuss how this literary tradition can help us to understand new psychological perspectives. PMID- 21826506 TI - Cryoablation of atrial fibrillation. AB - Atrial fibrillation (AF) is a significant burden to the public health. AF is associated with increased morbidity and mortality, including an increased risk of heart failure, stroke, cognitive impairment, and diminished quality of life. Catheter ablation is an effective therapy for recurrent, symptomatic, drug refractory AF. To date, radiofrequency ablation has been the most common catheter based method of pulmonary vein isolation; however, there is increasing interest in cryoablation. Emerging evidence from both observational and randomized studies suggests that cryoablation of AF is a reasonable alternative to radiofrequency ablation, with comparable safety and efficacy. The goal of this narrative review will be to trace the development of cryoablation for AF, summarize the available evidence base for both the safety and efficacy of the procedure, and finally to discuss the relative advantages and disadvantages of cryoablation versus radiofrequency ablation. PMID- 21826507 TI - Utility of a novel pacing guidewire in pre-implantation testing at different left ventricular sites in cardiac resynchronization therapy procedures. AB - PURPOSE: This study aimed to evaluate the utility of a novel pacing guidewire in pre-implantation testing of different left ventricular (LV) sites during cardiac resynchronization therapy (CRT) procedures. METHODS: Ten consecutive patients (8 male, mean age 65.8 +/- 4.9) undergoing CRT procedures were studied. Pacing threshold and R-wave sensing measured by the guidewire and LV lead at different LV sites were compared. RESULTS: Thirty sites (6 apical, 13 middle, and 11 basal; 15 lateral and 15 anterior) were tested. There was significant correlation between pacing threshold (r = 0.878, p < 0.0001), and R-wave sensing (r = 0.896, p < 0.0001) obtained by guidewire and those obtained by LV lead. Separating into lateral and anterior sites, significant correlation was also found in pacing threshold (lateral r = 0.658, p = 0.008; anterior r = 0.886, p < 0.0001) and R wave sensing (lateral r = 0.887, p < 0.0001; anterior 0.865, p < 0.0001). For basal and middle sites, significant correlation was found in pacing threshold (basal r = 0.890, p < 0.0001; middle r = 0.878, p < 0.0001), and R-wave sensing (basal r = 0.930, p < 0.0001; middle r = 0.823, p < 0.001). No and borderline correlation was found in pacing threshold (r = 0.548, p = 0.26) and R-wave sensing (r = 0.835, p = 0.039), respectively, for apical sites. Concordance rate for the presence of phrenic nerve stimulation at high pacing output was 87%. CONCLUSION: The accuracy of the novel pacing guidewire in pre-implantation testing in CRT procedures is site-dependent. There was good correlation with LV lead in the measurement of pacing threshold and R-wave sensing at basal and middle sites, but not apical sites. Presence of phrenic nerve stimulation can be predicted by guidewire testing with high accuracy. PMID- 21826508 TI - Distributions of heavy metals in the sediments of South Korean harbors. AB - Bottom sediments of harbors in the South Korea have been long suspected for metal contamination due to ship-based and urban-based activities for the past several decades. A number of areas have been suspected to impair ecosystem services to the local residents and drawn complaints from main stakeholders. Twelve contamination suspected harbors were subject to evaluate the level of contamination of Cr, Ni, Cu, Zn, As, Cd, Pb and Hg. The level of sediment contamination for each metal was evaluated comparing the relative enrichment of a given metal to pollution-insensitive aluminum. Regional background concentration of a given metal was also determined based on its down core measurement and sediment texture. Ecological risk posed by the presence of heavy metals was evaluated using the sediment quality guidelines (SQGs) developed by United States National Ocean and Atmosphere Administration (US NOAA) as benchmarks for evaluating sediment chemistry to aquatic organisms. Cu, Zn, Cd, Pb and Hg in the surface sediment were found to be higher than a factor of 1.5 than background sediments, and the overall metal contaminations of surface sediment can be regarded as medium-high- to high-priority sites in the sense of SQGs. PMID- 21826509 TI - Environmental geochemistry studies in the area of Idrija mercury mine, Slovenia. AB - Five centuries of mining and processing of mercury ore in the Idrija area have resulted in widespread contamination of different environmental compartments. Environmental impacts on a regional and local scale, caused by atmospheric emissions from the Idrija ore roasting plant, were established in the investigations of mercury spatial distribution in soil and attic dust in 160 km(2) area. Very high values were determined in the Idrijca River valley, and they decrease exponentially with the distance from Idrija. Mercury concentrations in attic dust are higher than in surrounding soils and the attic dust/soil ratio changes with distance. Measurements of mercury in the air confirmed widespread dispersion of mercury and showed highly elevated mercury concentrations around roasting plant and mine ventilation shaft. Beside, systematic monitoring of mercury contents in the stream sediments has demonstrated that huge amounts of mercury are stored in areas where ancient overbank sediments were deposited, and there was no decrease in mercury concentration in active sediments during the last 15 years. Recently, interesting and extremely polluted locations of historical small-scale roasting sites in the Idrija surroundings were discovered. Ongoing geochemical study aims to determine the extreme pollution and significance of these sites for wider contamination of soils and aquatic systems. Presented studies have shown that Hg mining in Idrija caused intense pollution of local and regional environment including the aquatic systems in the Gulf of Trieste, which is seen as the final sink of a major part of the Hg stored in soils and river sediments in the Idrija area. PMID- 21826510 TI - Stabilization of the As-contaminated soil from the metal mining areas in Korea. AB - The stabilization efficiencies of arsenic (As) in contaminated soil were evaluated using various additives such as limestone, steel mill slag, granular ferric hydroxide (GFH), and mine sludge collected from an acid mine drainage treatment system. The soil samples were collected from the Chungyang area, where abandoned Au-Ag mines are located. Toxicity characteristic leaching procedure, synthetic precipitation leaching procedure, sequential extraction analysis, aqua regia digestion, cation exchange capacity, loss on ignition, and particle size distribution were conducted to assess the physical and chemical characteristics of highly arsenic-contaminated soils. The total concentrations of arsenic in the Chungyang area soil ranged up to 145 mg/kg. After the stabilization tests, the removal percentages of dissolved As(III) and As(V) were found to differ from the additives employed. Approximately 80 and 40% of the As(V) and As(III), respectively, were removed with the use of steel mill slag. The addition of limestone had a lesser effect on the removal of arsenic from solution. However, more than 99% of arsenic was removed from solution within 24 h when using GFH and mine sludge, with similar results observed when the contaminated soils were stabilized using GFH and mine sludge. These results suggested that GFH and mine sludge may play a significant role on the arsenic stabilization. Moreover, this result showed that mine sludge can be used as a suitable additive for the stabilization of arsenic. PMID- 21826511 TI - Use of metal-reducing bacteria for bioremediation of soil contaminated with mixed organic and inorganic pollutants. AB - Mixed contamination by organic and inorganic compounds in soil is a serious problem for remediation. Most laboratory studies and field-scale trials focused on individual contaminant in the past. For concurrent bioremediation by biodegradation and bioleaching processes, we tested metal-reducing microorganism, Geobacter metallireducens. In order to prove the feasibility of the coupled process, multiple-contaminated soil was prepared. Mineralogical analyses have shown the existence of labile forms of As(V) as amorphous and/or weakly sorbed phases in the secondary Fe oxides. In the biotic experiment using G. metallireducens, biodegradation of toluene and bioleaching of As by bacteria were observed simultaneously. Bacteria accelerated the degradation rate of toluene with reductive dissolution of Fe and co-dissolution of As. Although there have been many studies showing each individual process, we have shown here that the idea of concurrent microbial reaction is feasible. However, for the practical use as a remediation technology, more details and multilateral evaluations are required in future studies. PMID- 21826513 TI - Investigation of As, Mn and Fe fixation inside the aquifer during groundwater exploitation in the experimental system imitated natural conditions. AB - Water-dissolved oxygen was supplied into anaerobic aquifer , which oxidized Fe(II), Mn(II) and trivalent arsenic and changed them into undissolved solid matter through hydrolysis, precipitation, co-precipitation and adsorption processes. The experiment was carried out on the column imitated a bore core of anaerobic aquifer with water phase containing Fe(II), Mn(II), As(III) concentration of 45.12 mg/L, 14.52 mg/L, 219.4 MUg/L, respectively and other ions similarly composition in groundwater. After 6 days of air supply, concentration of iron reduced to 0.38 mg/L, manganese to 0.4 mg/L, arsenic to 9.8 MUg/L (equivalent 99.16% of iron, 97.25% of manganese and 95.53% of arsenic fixed), and for other ions, the concentration changed almost according to general principles. Ion phosphate and silicate strongly influenced on arsenic removal but supported iron and manganese precipitation from water phase. Based on the experimental results, new model of groundwater exploitation was proposed. PMID- 21826514 TI - Narratives: an essential tool for evaluating living kidney donations. AB - Norway's living kidney donation-rate is among the highest in the world (36 per million). According to questionnaire-results, donors enjoy better than average health, presumably due to the strict medical criteria for being allowed to donate and life long medical follow up. However, in recent years international studies have cast doubt on the predominantly positive picture of donors and recipients, particularly regarding psychological aspects of transplantation surgery and donor evalutation. Findings in this study derive from anthropological fieldwork lasting 36 months at three university hospitals in the Oslo-basin. 18 end stage kidney disease patients and their potential donors were recruited opportunistically and interviewed (separately) in three or more semi-structured conversations during the evaluation process and after transplantation. 3 cases are discussed in detail. Notes were transcribed and analysed according to narrative theory. Focus was to explore the content of donors' and recipients' pre- and post transplantation narratives and to examine whether these accounts warrant a need for more comprehensive psychological assessment than is current practice in Norway. Donor- and recipient-narratives are well suited as a tool to improve living kidney donation-decisions. The material indicates a need to offer psychological care to LKD-partners, before and after transplantation. PMID- 21826515 TI - Acute left ventricular failure in a patient with hydroxychloroquine-induced cardiomyopathy. AB - We present the case of a 75-year-old woman with a medical history of rheumatoid arthritis treated with hydroxychloroquine, who was admitted with acute left-sided heart failure due to a hydroxychloroquine-induced cardiomyopathy as supported by endomyocardial biopsy. PMID- 21826516 TI - Ewing's sarcoma as second malignancy following a short latency in unilateral retinoblastoma. AB - Second malignancies, mostly in the form of bone sarcomas, are known to occur in hereditary retinoblastomas, which usually present with bilateral disease. Only 2 cases of Ewing's sarcoma have been reported in the literature following sporadic unilateral retinoblastoma. A 5-year-old boy presented to our hospital with Ewing's sarcoma of the right humerus (proven by biopsy and immunohistochemistry) following successful treatment of retinoblastoma of the left eye with enucleation and chemotherapy 2 years previously. He was treated with 2 cycles of chemotherapy followed by radiation therapy. At 15 months follow-up, the tumor had reduced in size and the child had a good functional outcome. The cumulative risk of second malignancies in retinoblastoma survivors is 32%. Ninety-eight percent of second malignancies occur in patients with bilateral retinoblastoma. Germ line mutations have been considered in sporadic tumors occurring bilaterally and multifocal unilateral sporadic tumors. Bone and soft tissue sarcomas are the most common second malignancies. Radiation therapy increases the risk of developing a second malignancy in the irradiated field. Unilateral retinoblastomas, which comprise the majority of retinoblastomas, are not immune from the development of second malignancies. Close follow-up of all retinoblastomas--even in the early period- can improve the outcome by facilitating the early detection and aggressive treatment of second malignancies. PMID- 21826517 TI - Structural elements of the C-terminal domain of subunit E (E133-222) from the Saccharomyces cerevisiae V1V0 ATPase determined by solution NMR spectroscopy. AB - Subunit E of the vacuolar ATPase (V-ATPase) contains an N-terminal extended alpha helix (Rishikesan et al. J Bioenerg Biomembr 43:187-193, 2011) and a globular C terminal part that is predicted to consist of a mixture of alpha-helices and beta sheets (Gruber et al. Biochem Biophys Res Comm 298:383-391, 2002). Here we describe the production, purification and 2D structure of the C-terminal segment E133-222 of subunit E from Saccharamyces cerevisiae V-ATPase in solution based on the secondary structure calculation from NMR spectroscopy studies. E133-222 consists of four beta-strands, formed by the amino acids from K136-V139, E170 V173, G186-V189, D195-E198 and two alpha-helices, composed of the residues from R144-A164 and T202-I218. The sheets and helices are arranged as beta1:alpha1:beta2:beta3:beta4:alpha2, which are connected by flexible loop regions. These new structural details of subunit E are discussed in the light of the structural arrangements of this subunit inside the V1- and V1V0 ATPase. PMID- 21826518 TI - Evaluation of the influence of intermolecular electron-nucleus couplings and intrinsic metal binding sites on the measurement of 15N longitudinal paramagnetic relaxation enhancements in proteins by solid-state NMR. AB - Magic-angle spinning solid-state NMR measurements of (15)N longitudinal paramagnetic relaxation enhancements (PREs) in (13)C,(15)N-labeled proteins modified with Cu(2+)-chelating tags can yield multiple long-range electron nucleus distance restraints up to ~20 A (Nadaud et al. in J Am Chem Soc 131:8108 8120, 2009). Using the EDTA-Cu(2+) K28C mutant of B1 immunoglobulin binding domain of protein G (GB1) as a model, we investigate the effects on such measurements of intermolecular electron-nucleus couplings and intrinsic metal binding sites, both of which may potentially complicate the interpretation of PRE data in terms of the intramolecular protein fold. To quantitatively assess the influence of intermolecular (15)N-Cu(2+) interactions we have determined a nearly complete set of longitudinal (15)N PREs for a series of microcrystalline samples containing ~10, 15 and 25 mol percent of the (13)C,(15)N-labeled EDTA-Cu(2+) tagged protein diluted in a matrix of diamagnetic natural abundance GB1. The residual intermolecular interactions were found to be minor on the whole and account for only a fraction of the relatively small but systematic deviations observed between the experimental (15)N PREs and corresponding values calculated using protein structural models for residues furthest removed from the EDTA Cu(2+) tag. This suggests that these deviations are also caused in part by other factors not related to the protein structure, such as the presence in the protein of intrinsic secondary sites capable of binding Cu(2+) ions. To probe this issue we performed a Cu(2+) titration study for K28C-EDTA GB1 monitored by 2D (15)N (1)H solution-state NMR, which revealed that while for Cu(2+):protein molar ratios of <= 1.0 Cu(2+) binds primarily to the high-affinity EDTA tag, as anticipated, at even slightly super-stoichiometric ratios the Cu(2+) ions can also associate with side-chains of aspartate and glutamate residues. This in turn is expected to lead to enhanced PREs for residues located in the vicinity of the secondary Cu(2+) binding sites, and indeed many of these residues were ones found to display the elevated longitudinal (15)N PREs in the solid phase. PMID- 21826519 TI - Cryogenic temperature effects and resolution upon slow cooling of protein preparations in solid state NMR. AB - X-ray crystallography using synchrotron radiation and the technique of dynamic nuclear polarization (DNP) in nuclear magnetic resonance (NMR) require samples to be kept at temperatures below 100 K. Protein dynamics are poorly understood below the freezing point of water and down to liquid nitrogen temperatures. Therefore, we investigate the alpha-spectrin SH3 domain by magic angle spinning (MAS) solid state NMR (ssNMR) at various temperatures while cooling slowly. Cooling down to 95 K, the NMR-signals of SH3 first broaden and at lower temperatures they separate into several peaks. The coalescence temperature differs depending on the individual residue. The broadening is shown to be inhomogeneous by hole-burning experiments. The coalescence behavior of 26 resolved signals (of 62) was compared to water proximity and crystal structure Debye-Waller factors (B-factors). Close proximity to the solvent and large B-factors (i.e. mobility) lead, generally, to a higher coalescence temperature. We interpret a high coalescence temperature as indicative of a large number of magnetically inequivalent populations at cryogenic temperature. PMID- 21826520 TI - Narrowing the conformational space sampled by two-domain proteins with paramagnetic probes in both domains. AB - Calmodulin is a two-domain protein which in solution can adopt a variety of conformations upon reorientation of its domains. The maximum occurrence (MO) of a set of calmodulin conformations that are representative of the overall conformational space possibly sampled by the protein, has been calculated from the paramagnetism-based restraints. These restraints were measured after inclusion of a lanthanide binding tag in the C-terminal domain to supplement the data obtained by substitution of three paramagnetic lanthanide ions to the calcium ion in the second calcium binding loop of the N-terminal domain. The analysis shows that the availability of paramagnetic restraints arising from metal ions placed on both domains, reduces the MO of the conformations to different extents, thereby helping to identify those conformations that can be mostly sampled by the protein. PMID- 21826521 TI - Lean processes for optimizing OR capacity utilization: prospective analysis before and after implementation of value stream mapping (VSM). AB - BACKGROUND: The decision to optimize the processes in the operating tract was based on two factors: competition among clinics and a desire to optimize the use of available resources. The aim of the project was to improve operating room (OR) capacity utilization by reduction of change and throughput time per patient. SETTING: The study was conducted at Centre Hospitalier Emil Mayrisch Clinic for specialized care (n = 618 beds) Luxembourg (South). METHOD: A prospective analysis was performed before and after the implementation of optimized processes. Value stream analysis and design (value stream mapping, VSM) were used as tools. VSM depicts patient throughput and the corresponding information flows. Furthermore it is used to identify process waste (e.g. time, human resources, materials, etc.). For this purpose, change times per patient (extubation of patient 1 until intubation of patient 2) and throughput times (inward transfer until outward transfer) were measured. VSM, change and throughput times for 48 patient flows (VSM A(1), actual state = initial situation) served as the starting point. Interdisciplinary development of an optimized VSM (VSM-O) was evaluated. Prospective analysis of 42 patients (VSM-A(2)) without and 75 patients (VSM-O) with an optimized process in place were conducted. RESULTS: The prospective analysis resulted in a mean change time of (mean +/- SEM) VSM-A(2) 1,507 +/- 100 s versus VSM-O 933 +/- 66 s (p < 0.001). The mean throughput time VSM-A(2) (mean +/- SEM) was 151 min (+/-8) versus VSM-O 120 min (+/-10) (p < 0.05). This corresponds to a 23% decrease in waiting time per patient in total. CONCLUSION: Efficient OR capacity utilization and the optimized use of human resources allowed an additional 1820 interventions to be carried out per year without any increase in human resources. In addition, perioperative patient monitoring was increased up to 100%. PMID- 21826522 TI - Left main coronary artery atresia: the role of computed tomographic coronary angiography. PMID- 21826524 TI - Cerebellar hypoplasia and brainstem thinning associated with severe white matter and basal ganglia abnormalities in a child with an mtDNA deletion. AB - Cerebellar and brainstem hypoplasia may occur in different conditions, including those disorders designated as pontocerebellar hypoplasia (PCH). In particular, when PCH is combined with severe supratentorial white matter involvement and cerebral atrophy, mutations in the mitochondrial arginyl-tRNA synthethase (RARS2) gene causing PCH6 are possible. We describe a patient with a lethal mitochondrial encephalomyopathy due to a mtDNA deletion and no alterations in RARS2, whose magnetic resonance (MR) findings mimicked PCH6. A thorough diagnostic work-up for mitochondrial disorders should be carried out when facing with a PCH-like and severe white matter and basal ganglia involvement on brain MR imaging in children, even if clinical and laboratory mitochondrial "stigmata" are scant or nonspecific. PMID- 21826523 TI - Molecular mechanisms underlying cardiac antihypertrophic and antifibrotic effects of natriuretic peptides. AB - Natriuretic peptides (NPs) exert well-characterized protective effects on the cardiovascular system, such as vasorelaxation, natri- and diuresis, increase of endothelial permeability, and inhibition of renin-angiotensin-aldosterone system. It has been reported that they also possess antihypertrophic and antifibrotic properties and contribute actively to cardiac remodeling. As a consequence, they are involved in several aspects of cardiovascular diseases. Antihypertrophic and antifibrotic actions of NPs appear to be mediated by specific signaling pathways within a more complex cellular network. Elucidation of the molecular mechanisms underlying the effects of NPs on cardiac remodeling represents an important research objective in order to gain more insights on the complex network leading to cardiac hypertrophy, ventricular dysfunction, and transition to heart failure, and in the attempt to develop novel therapeutic agents. The aim of the present article is to review well-characterized molecular mechanisms underlying the antihypertrophic and antifibrotic effects of NPs in the heart that appear to be mainly mediated by guanylyl cyclase type A receptor. In particular, we discuss the calcineurin/NFAT, the sodium exchanger NHE-1, and the TGFbeta1/Smad signaling pathways. The role of guanylyl cyclase type B receptor, along with the emerging functional significance of natriuretic peptide receptor type C as mediators of CNP antihypertrophic and antifibrotic actions in the heart are also considered. PMID- 21826525 TI - Expression of monocarboxylate transporter (MCT) 1 and MCT4 in overloaded mice plantaris muscle. AB - A number of studies have shown that changes in muscle contractile activity regulate the expression of monocarboxylate transporters (MCTs) in the skeletal muscle. The aim of this study was to investigate the effect of functional overload on MCT1 and MCT4 protein expression. Plantaris muscles were functionally overloaded for 15 days by ablation of the synergistic muscles. MCT1 and MCT4 mRNA abundance increased by 160-161% (p < 0.01) and 265-325% (p < 0.05), respectively, after 1-3 days of functional overload. MCT1 and MCT4 protein expression increased by 92 and 61%, respectively, after 12 days of functional overload (p < 0.05). AMP activated protein kinase (AMPK) phosphorylation status [phospho-AMPK (Thr172)/total AMPK] was significantly elevated after 3-9 days of functional overload. Plasma testosterone concentration was elevated after 12 days of functional overload, while blood lactate concentration was not altered. Thus, the current study demonstrated that heavy mechanical loading induces increase in MCT1 and MCT4 protein expression in the muscles with increase in AMPK phosphorylation status and plasma testosterone concentration. PMID- 21826526 TI - Effect of uremia on semen quality and reproductive function in humans. AB - In this study, we sought to evaluate the effect of uremia on semen quality and reproductive function in humans. For this purpose, 53 end-stage uremic patients were randomly selected. The semen samples were produced by masturbation. Fertility index (FI) was calculated according to the following formula: sperm density (*10(6)/ml) * sperm motility (%) * normal sperm morphology rate (% per 10,000). The semen samples of uremic patients were compared with those of fertile and infertile males. The results show that three patients failed to produce semen. There were no sperm found in four semen samples. The sperm motility, survival rate, sperm density, and normal sperm morphology rate of the remaining 46 patients were found to be significantly lower than those of controls. The uremic patients had the FI of 0.68(2.08) which was obviously lower than that of fertile 7.7(13.51) and infertile 4.13(5.77) males. It was, therefore, concluded that uremia caused a significant decline in sperm quality and reproductive function which resulted in consequential infertility in humans. PMID- 21826528 TI - ApoB siRNA-induced liver steatosis is resistant to clearance by the loss of fatty acid transport protein 5 (Fatp5). AB - The association between hypercholesterolemia and elevated serum apolipoprotein B (APOB) has generated interest in APOB as a therapeutic target for patients at risk of developing cardiovascular disease. In the clinic, mipomersen, an antisense oligonucleotide (ASO) APOB inhibitor, was associated with a trend toward increased hepatic triglycerides, and liver steatosis remains a concern. We found that siRNA-mediated knockdown of ApoB led to elevated hepatic triglycerides and liver steatosis in mice engineered to exhibit a human-like lipid profile. Many genes required for fatty acid synthesis were reduced, suggesting that the observed elevation in hepatic triglycerides is maintained by the cell through fatty acid uptake as opposed to fatty acid synthesis. Fatty acid transport protein 5 (Fatp5/Slc27a5) is required for long chain fatty acid (LCFA) uptake and bile acid reconjugation by the liver. Fatp5 knockout mice exhibited lower levels of hepatic triglycerides due to decreased fatty acid uptake, and shRNA-mediated knockdown of Fatp5 protected mice from diet-induced liver steatosis. Here, we evaluated if siRNA-mediated knockdown of Fatp5 was sufficient to alleviate ApoB knockdown-induced steatosis. We determined that, although Fatp5 siRNA treatment was sufficient to increase the proportion of unconjugated bile acids 100-fold, consistent with FATP5's role in bile acid reconjugation, Fatp5 knockdown failed to influence the degree, zonal distribution, or composition of the hepatic triglycerides that accumulated following ApoB siRNA treatment. PMID- 21826527 TI - SWOG S0215: a phase II study of docetaxel and vinorelbine plus filgrastim with weekly trastuzumab for HER2-positive, stage IV breast cancer. AB - SWOG trial S0102 showed significant activity of the combination of docetaxel and vinorelbine in HER2-negative metastatic breast cancer (MBC). For HER2-positive patients, additional benefit may occur with the addition of trastuzumab due to its synergy with docetaxel and vinorelbine. Patients with HER2-positive MBC, but without prior chemotherapy for MBC or adjuvant taxane, were eligible. Docetaxel (60 mg/m2) was given intravenously on Day 1, vinorelbine (27.5 mg/m2) intravenously on Days 8 and 15, and filgrastim (5 ug/kg) on Days 2-21 of a 21-day cycle. In addition, patients received weekly infusions of trastuzumab (2 mg/kg) after an initial bolus of 4 mg/kg. The primary outcome was 1 year overall survival (OS), with secondary outcomes of progression-free survival (PFS), response rate, and toxicity. Due to slow accrual (February 2003-December 2006), enrollment was stopped after 76 of 90 planned patients. There have been 32 deaths and 51 progressions among the 74 eligible patients who received treatment. The estimated 1 year OS was 93% (95% CI 84-97%) with a median of 48 months. One-year PFS was 70% (95% CI 58-79%) with a median of 20 months. Response rate for measurable disease was 84%. No deaths were attributed to treatment. Grade 4 toxicities were reported for 19% with neutropenia the most common (15%). The most common grade 3 toxicities (33%) were leucopenia (14%) and fatigue (10%). The combination of trastuzumab, docetaxel, and vinorelbine is effective as first-line chemotherapy in HER2-positive MBC with minimal toxicity. One-year survival estimates are among the highest reported in this population. PMID- 21826529 TI - The Banishing Obesity and Diabetes in Youth (BODY) Project: description and feasibility of a program to halt obesity-associated disease among urban high school students. AB - Type 2 diabetes (T2DM) and cardiovascular disease (CVD) are rising dramatically in adolescents in parallel with excess weight. The Banishing Obesity and Diabetes in Youth (BODY) Project, is a school-based intervention that medically screens overweight and obese high school students, provides personalized feedback, and connects to appropriate healthcare. Body mass index (BMI) was determined for 1,526 students in one New York City public high school with a school-based health center (SBHC). Overweight and obese students (n = 640) were invited to complete a medical evaluation that included a survey, blood pressure and blood tests. 328/640 (51%) eligible students returned signed parental consent and participated. All participants received a personalized report detailing their results along with specific recommendations on how to improve their health. Parents of participants with results outside healthy ranges (82%; 270/328) were called and mailed referral letters to connect with healthcare services. Project staff reached by telephone 74% (199/270) of those families and 29% (58/199) stated that the report led them to make arrangements to see a healthcare provider. Most students (83%; 273/328) were registered at the SBHC, and we shared their medical results with them so they could follow-up with the students. The BODY Project is a feasible program for urban schools with a SBHC. This may allow effective prevention of T2DM, and CVD from dyslipidemia and hypertension. PMID- 21826530 TI - Pharyngeal airway in children with sleep-disordered breathing in relation to head posture. AB - PURPOSE: The aim of this study was to compare the pharyngeal airway size in different cranio-cervical postures in children with sleep-disordered breathing (SDB) and asymptomatic control children. We tested the hypothesis that the site of the most constricted pharyngeal airway in SDB children is not affected by head posture. METHODS: The study group comprised 29 children (14 boys, 15 girls, mean age 7.3 +/- 1.37 years, range 4.8-9.8 years) with SDB. A control group of 29 age- and gender-matched healthy children was recruited. The pharyngeal airway of the children was imaged with a low-field 0.23-T open-configuration magnetic resonance imaging scanner in three different head postures: neutral, extension, and flexion. Inter-group differences in pharyngeal variables were analyzed using two sided paired t test and intra-group differences using Bonferroni and Sidak correlations for multiple comparisons. RESULTS: Nasopharyngeal airway was not affected by head posture. Head extension had no significant effect on the most constricted retropalatal airway in the SDB group, but it increased the hypopharyngeal airway (P = 0.000) significantly when compared to neutral head posture. The hypopharyngeal airway increased more in the SDB group than in the asymptomatic children (P = 0.031). The retropalatal oropharynx was on the whole significantly narrower in the SDB children compared with the controls in all head postures (neutral P = 0.000, extended P = 0.001, flexed P = 0.000). CONCLUSIONS: Head posture is an important factor in maintaining airway patency. We suggest that the effectiveness of neuromuscular compensation may be compromised in constricted retropalatal airways. Instead, the hypopharyngeal airway is enlarged suggesting possible neuromuscular compensation for oropharyngeal narrowing in children with SDB. PMID- 21826531 TI - Interferon-gamma induced adipose tissue inflammation is linked to endothelial dysfunction in type 2 diabetic mice. AB - Interferon-gamma (IFNgamma) has previously been associated with immuno-mediated inflammation in diet-induced obesity and type 1 diabetes. This study sought to define the role of IFNgamma-induced adipose tissue inflammation in endothelial dysfunction in type 2 diabetes. We examined mesenteric adipose tissue (MAT) inflammation, and endothelial function of small mesenteric artery (SMA) in control mice (m Lepr(db)), diabetic mice (Lepr(db)), m Lepr(db) treated with IFNgamma, and Lepr(db) treated with anti-IFNgamma or anti-monocyte chemoattractant protein-1 (anti-MCP-1). mRNA and protein expression of IFNgamma and MCP-1 were increased in MAT of Lepr(db), accompanied by increased T lymphocyte and macrophage infiltration. Anti-IFNgamma reduced MAT inflammatory cell infiltration and inflammatory cytokine expression in Lepr(db), while IFNgamma treatment showed the opposite effects in m Lepr(db). Acetylcholine (ACh) induced vasorelaxation of SMA was impaired in Lepr(db) versus m Lepr(db), but sodium nitroprusside (SNP)-induced vasorelaxation was comparable. Both anti IFNgamma and anti-MCP-1 improved endothelial function of Lepr(db), while IFNgamma treatment impaired endothelial function of m Lepr(db). Superoxide production was higher in both MAT and SMA of Lepr(db) mice, and anti-IFNgamma reduced MAT and SMA superoxide production. Macrophage accumulation in the adventitia of SMA, and mRNA expression of MCP-1 in SMA were increased in Lepr(db) and IFNgamma-treated m Lepr(db), but reduced in anti-IFNgamma treated Lepr(db). These findings suggest IFNgamma has a key role in the regulation of visceral adipose tissue inflammatory response and endothelial dysfunction in type 2 diabetes. PMID- 21826532 TI - Combination of narrow band imaging (NBI) and autofluorescence imaging (AFI) videobronchoscopy in endoscopic assessment of lung cancer extension. AB - Both narrow band imaging (NBI) and autofluorescence imaging (AFI) are new techniques for the assessment of lung cancer. The major aim of this study was to investigate whether the combination of these two techniques improve sensitivity and specificity in the assessment of lung cancer extension. The study prospectively evaluated 118 patients with suspected lung cancer. All of the patients were examined using EVIS LUCERA SPECTRUM videobronchoscopy system. The narrow band imaging preceded autofluorescence imaging examination. In every patient, at least 1 but no more than 4 biopsies were taken from places visualized as pathologic, surrounding primary tumor, and at least 1 biopsy from places that appeared visually normal. Sensitivity, specificity, positive, and negative predictive value for autofluorescence imaging in the assessment of tumor extension were 89.2, 77.8, 87, and 81%, respectively. Sensitivity, specificity, positive, and negative predictive value for narrow band imaging were 90.4, 82.4, 91.8, and 79.7%, respectively. Corresponding values for combination of techniques were 93.7, 86.9, 94.5, and 85.1%. Combination of techniques significantly improves sensitivity (P = 0.034) with borderline effect on specificity (P = 0.056) of autofluorescence imaging. There was no significant improvement for sensitivity and specificity of NBI alone. The combination of techniques shows significantly better sensitivity and specificity in the assessment of lung cancer extension when compared to white light videobronchoscopy alone, but improvement is not so convincing when compared to the each technique alone. PMID- 21826534 TI - The frequency following response (FFR) may reflect pitch-bearing information but is not a direct representation of pitch. AB - The frequency following response (FFR), a scalp-recorded measure of phase-locked brainstem activity, is often assumed to reflect the pitch of sounds as perceived by humans. In two experiments, we investigated the characteristics of the FFR evoked by complex tones. FFR waveforms to alternating-polarity stimuli were averaged for each polarity and added, to enhance envelope, or subtracted, to enhance temporal fine structure information. In experiment 1, frequency-shifted complex tones, with all harmonics shifted by the same amount in Hertz, were presented diotically. Only the autocorrelation functions (ACFs) of the subtraction-FFR waveforms showed a peak at a delay shifted in the direction of the expected pitch shifts. This expected pitch shift was also present in the ACFs of the output of an auditory nerve model. In experiment 2, the components of a harmonic complex with harmonic numbers 2, 3, and 4 were presented either to the same ear ("mono") or the third harmonic was presented contralaterally to the ear receiving the even harmonics ("dichotic"). In the latter case, a pitch corresponding to the missing fundamental was still perceived. Monaural control conditions presenting only the even harmonics ("2 + 4") or only the third harmonic ("3") were also tested. Both the subtraction and the addition waveforms showed that (1) the FFR magnitude spectra for "dichotic" were similar to the sum of the spectra for the two monaural control conditions and lacked peaks at the fundamental frequency and other distortion products visible for "mono" and (2) ACFs for "dichotic" were similar to those for "2 + 4" and dissimilar to those for "mono." The results indicate that the neural responses reflected in the FFR preserve monaural temporal information that may be important for pitch, but provide no evidence for any additional processing over and above that already present in the auditory periphery, and do not directly represent the pitch of dichotic stimuli. PMID- 21826533 TI - Regulation of major histocompatibility complex class I molecule expression on cancer cells by amyloid precursor-like protein 2. AB - The three members of the amyloid precursor protein family in mammals [amyloid precursor protein, amyloid precursor-like protein 1, and amyloid precursor-like protein 2 (APLP2)] have been implicated in a large array of intracellular processes, which include development, transcription, apoptosis, metabolism, and the cell cycle. A series of studies by our laboratories has demonstrated that APLP2 is highly expressed by many cancer cell lines (with the highest expression in pancreatic cancer cell lines) and that it facilitates major histocompatibility complex (MHC) class I molecule endocytosis. This review focuses on this recently revealed function of APLP2 relevant to tumor immunology: that it acts as a novel regulator of MHC class I molecule surface expression. PMID- 21826535 TI - A five-gene model predicts clinical outcome in ER+/PR+, early-stage breast cancers treated with adjuvant tamoxifen. AB - Primary breast carcinomas expressing both estrogen and progesterone receptors are most likely to respond to tamoxifen therapy, especially in patients with early stage lesions. However, certain patients exhibit clinicopathologic features suggesting good prognosis relapse within 10 years, justifying a search for biomarkers identifying patients at risk for recurrence. Nine candidate genes associated with estrogen signaling were selected from microarray studies and combined with those for conventional biomarkers (ESR1, PGR, ERBB2). Expression of this 12-gene subset was analyzed by RT-qPCR in frozen tissue specimens from 60 early-stage, estrogen receptor (ER)+/progestin receptor (PR)+ breast cancers from patients treated with adjuvant tamoxifen. A multivariate model was created by Cox regression using a training data set and applied to an independent validation set. A five-gene model was developed from the training set (n = 36) that exhibited significant correlations with both relapse-free and overall survival. Applying this model to Kaplan-Meier regression, patients were separated into low risk (100% relapse-free at 150 months) and high-risk (60% relapse-free at 150 months) groups (P = 0.03). When this model was applied to the validation set (n = 24), similar risk stratification was achieved for both relapse-free and overall survival (P = 0.01 and 0.04, respectively). We developed a five-gene model composed of PgR, BCL2, ERBB4 JM-a, RERG, and CD34 that identified early-stage, ER+/PR+ breast cancers in patients treated with tamoxifen that relapsed, although they exhibited clinicopathologic features suggesting good prognosis. Within this multivariate model, increased expression of PgR, ERBB4 JM-a, RERG, and CD34 was associated with increased survival, while increased expression of BCL2 was associated with decreased survival. PMID- 21826536 TI - Relating engagement to outcomes in prevention: the case of a parenting program for couples. AB - Analyses of program engagement can provide critical insight into how program involvement leads to outcomes. This study examines the relation between participant engagement and program outcomes in Family Foundations (FF), a universal preventive intervention designed to help couples manage the transition to parenthood by improving coparenting relationship quality. Previous intent-to treat outcome analyses from a randomized trial indicate FF improves parental adjustment, interparental relationships, and parenting. Analyses for the current study use the same sample, and yield statistically reliable relations between participant engagement and interparental relationships but not parental adjustment or parenting. Discussion considers implications for FF and the difficulties researchers face when examining the relation between engagement and outcomes in preventive interventions. PMID- 21826537 TI - A rationale for mTOR inhibitors as chemoprevention agents in Peutz-Jeghers syndrome. AB - Peutz-Jeghers patients frequently develop clinically significant complications, namely hemorrhage and bowel obstruction, from small intestinal hamartomatous polyps that frequently require surgery. In addition, many PJS patients develop epithelial malignancies in a variety of organs. The vast majority of PJS is due to germline alterations in the STK11 gene that encodes a protein that modulates PI3-kinase signaling, a key regulator of cell survival and growth. One of the major downstream mediators of PI3-kinase signaling is mTOR, the mammalian target of rapamycin. Several drugs that inhibit the PI3-kinase signal transduction pathway are in development and one, RAD001 (everolimus), an mTOR inhibitor, was recently approved for the treatment of renal cell carcinoma. Effective chemoprevention of intestinal polyps would be a first step in simplifying and improving the management of PJS patients. We present here, the rationale for the first human PJS chemoprevention trial using an mTOR inhibitor. PMID- 21826538 TI - Influence of orthognathic surgery on periodontal tissues: short-term results. AB - OBJECTIVE: The present prospective study aimed at evaluating the influence of orthognathic surgery on mucogingival tissues and the subgingival microflora. PATIENTS AND METHODS: Fifteen consecutively-treated patients with a mean age of 24.9+/-7.7 years were included in this study. The surgical interventions comprised the Le Fort I osteotomy of the maxilla and/or sagittal split osteotomy of the mandible. The following periodontal and microbial parameters were measured preoperatively (T(0)) as well as 1 week (T(1)) and 6 weeks (T(2)) postoperatively: pocket probing depth (PPD), gingival recession (GR), clinical attachment level (CAL), bleeding on probing (BOP), plaque index (PI), and changes in the subgingival microflora. Periodontal parameters were calculated for all sites as well as for buccal and oral sites separately. For statistical analysis, the general linear model and paired t test were applied (level of significance: p<0.05). RESULTS: PPD readings increased significantly on oral tooth sites when T(0) values were compared to T(1) (p=0.009) and T(2 )values (p=0.042). GR increased significantly on buccal sites from 0.10+/-0.16 mm at baseline to 0.21+/ 0.23 mm at T(1) (p=0.013) and 0.31+/-0.31 mm at T(2) (p=0.001). Furthermore, we noted significant changes in the CAL (oral sites) and PI (buccal and oral sites). We observed no significant differences in BOP and periodontopathogenetic bacteria. CONCLUSION: Orthognathic surgery has a statistically significant effect on the development of gingival recessions. However, this effect may not necessarily clinically impair the esthetic appearance. PMID- 21826539 TI - The topography of displaced canines: a 3D-CT study. AB - AIM: This study investigated the development of a three-dimensional (3D) coordinate system for radiologic volumetric data, allowing the analysis of the tooth axis of displaced teeth in relation to the occlusal, frontal, and sagittal reference planes. PATIENTS AND METHODS: The data basis consisted of multislice computed tomography (MSCT) data of 37 patients with displaced upper canines. A total of 20 patients displayed unilateral displacement and 17 patients bilateral displacement (n = 54). The non-displaced canines of the opposite side served as the reference group (n = 20), together with MSCT data of 6 patients with non displaced canines (n = 12). Three reference planes were constructed in the VoXim(r)5.6 program using landmarks (apex point and tip of the canine, incision point of the lower jaw, mesiobuccal tip of the lower left and right first molar, A-point). The tooth axis of the canines was analyzed in relation to these planes. RESULTS: The angle to the frontal plane was only slightly smaller in non displaced canines (mean: 17.53 degrees ) than in palatally displaced canines (mean: 19.62 degrees ), which however exhibited a considerably greater range (0.40-38.00 degrees ). In contrast, the mean angle in buccally displaced canines was 32.79 degrees . Both the differences between the reference group and buccally displaced canines and those between the palatally and buccally displaced canines were statistically significant. The angles for buccal (55.16 degrees ) and palatal (56.63 degrees ) displacement relative to the occlusal plane were significantly smaller than for the non-displaced teeth (70.95 degrees ). However, the range of palatal displacement was high (27.3-80.6 degrees ). The inclination towards the sagittal plane was slight for non-displaced canines (mean 6.07 degrees ) and for buccally displaced canines (mean 8.25 degrees ). The mean angle of palatally displaced canines was significantly larger (23.28 degrees ) than that in the other groups, with a much greater range (6.70-50.80 degrees ). CONCLUSION: The 3D coordinate system developed in this study allows the exact measurement of tooth position relative to three spatial planes, thus, enabling tooth position to be objectively determined. PMID- 21826540 TI - What are risk factors for local recurrence of deep high-grade soft-tissue sarcomas? AB - BACKGROUND: Patients with local recurrence of soft-tissue sarcomas have a poor overall survival. High-grade, soft-tissue sarcomas in deep locations may have a poorer prognosis regarding local recurrence than low-grade sarcomas or those located superficially. Although previous reports evaluated tumors at various depths, it is unclear what factors influence recurrence of deep, high-grade sarcomas. QUESTIONS/PURPOSES: We therefore determined whether possible risk factors (tumor size, location, histologic subtype, unplanned excision, local recurrence at presentation, metastasis at diagnosis, surgical procedure, surgical margin, and adjuvant treatments) influenced local recurrence of deep, high-grade, soft-tissue sarcomas. PATIENTS AND METHODS: We retrospectively reviewed 433 patients with deep, high-grade, soft-tissue sarcomas surgically treated between 1985 and 2005. For each patient, we reviewed tumor size, location, histologic subtype, unplanned excision, local recurrence at presentation, metastasis at diagnosis, surgical procedure, surgical margin, and adjuvant treatments and determined the effect of each prognostic variable on local recurrence. The minimum followup was 1 month (median, 51 months; range, 1-305 months). RESULTS: Forty-seven patients had local recurrence at a median of 10.7 months. Local recurrence at presentation, metastasis at diagnosis, and positive margins independently predicted local recurrence. No other factors independently predicted local recurrence. CONCLUSIONS: Unplanned excisions did not increase the rate of local recurrence of deep, high-grade, soft-tissue sarcomas if treated appropriately. Aggressiveness of tumor represented by metastasis or local recurrence at presentation may be a risk for local recurrence. LEVEL OF EVIDENCE: Level II, prognostic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 21826541 TI - [Internet therapy for ICD-patients]. AB - Implantable cardioverter-defibrillators (ICD) are increasingly used for the prevention of potentially lethal cardiac arrhythmias due to their confirmed superior medical efficiency. Nevertheless, ICD-patients often suffer from psychosocial problems, e.g., anxiety and depression. These issues are rarely addressed in routine medical follow-up care. Due to the limited mobility of many ICD-patients, Internet-based care may be ideal for delivering psychosocial care to patients in their homes. Our pilot study and case studies illustrate prospects and challenges of this approach. We developed icd-forum.de, a 6-week internet based prevention program that provides a platform for information, a virtual self help group, and a professionally moderated chat room in order to help decrease anxiety and to improve quality of life. A critical evaluation in the context of other published studies on the subject allows recommendations for the implementation of future internet-based psychosocial programs for ICD-patients to be deduced. It is the authors' opinion that such programs offer advantages specifically for heart failure patients and they recommend their broader use. Prior to this, conclusive evaluation studies are needed. PMID- 21826542 TI - Endovascular treatment of basilar artery trunk aneurysms. AB - BACKGROUND: There has been little reported on the endovascular experience of basilar artery (BA) trunk aneurysms due to its low incidence. The purpose of this study is to report the results of endovascular treatment (EVT) of BA trunk aneurysms. METHODS: Between 2004 and 2008, eight BA trunk aneurysms were treated by EVT. Five patients presented with subarachnoid hemorrhage, one had intracranial mass effect, and in two of the patients the aneurysms were found incidentally. Four lesions were saccular aneurysms, three of them were found with BA fenestration. Three lesions were dissecting aneurysms and one was a giant fusiform aneurysm. The mean follow-up period of clinical outcome was 17.1 months (range, 6-32 months). Angiographic follow-up data was obtained in six patients for period of a mean of 15.6 months (range, 6-25 months). RESULTS: Four patients with saccular aneurysms were treated by stent-assisted coil embolization except for one patient that was treated without a stent. Three patients with dissecting aneurysms were treated by a single stent placement. One of these dissecting aneurysms rebled in 4 days after stent placement and was secured by BA occlusion. One giant fusiform aneurysm was treated by bilateral vertebral artery (VA) occlusion after balloon test occlusion. Six patients (75.0%) had excellent or good clinical outcomes, one patient whose aneurysm rebled became vegetative, and one patient with bilateral VA occlusion died. Follow-up angiograms showed that four lesions had complete occlusion and two had neck remnant. CONCLUSIONS: The endovascular catheterization of these lesions tends to be relatively simple compared to more complex neurosurgical approaches. EVT, especially using a stent, could be a valuable therapeutic method in treating BA trunk aneurysms. PMID- 21826543 TI - Juvenile psammomatoid ossifying fibroma of the orbit and paranasal sinuses. A case report. AB - Juvenile psammomatoid ossifying fibroma (JPOF) is an uncommon benign fibro osseous lesion predominantly arising in the paranasal sinuses and orbits of children and young adults. We report a case of JPOF involving the paranasal sinuses and orbit in a 15-year-old boy that presented due to progressive proptosis and downward displacement of the left eye. The lesion, first described as fibrous dysplasia (FD), was totally removed surgically, and then proved to be a JPOF, by histopathology. We discuss its differential diagnosis with other fibro osseous lesions, histopathological features, and treatment options. PMID- 21826545 TI - Hepatic hydatid: PAIR, drain or resect? AB - STUDY BACKGROUND: Hydatid disease of the liver is endemic in India and is a common health problem. Although various treatment options have been described ranging from pharmacotherapy to radiological interventions and surgical procedures (both conservative and radical), the best treatment option in an individual case continues to be debated. METHODS: We did a retrospective analysis of patients with hydatid disease of the liver who were managed at our centre between January 2000 and December 2009. All cysts were classified as per the Gharbi's classification. The various treatment options used to treat hydatid cysts of the liver included percutaneous aspiration, injection and reaspiration (PAIR) or PAIR with drainage (PAIR-D) and surgery (both conservative and radical). The immediate and long-term outcomes following such management were analysed. RESULTS: During the study period, 128 patients with hydatid cyst of the liver were managed with PAIR/PAIR-D (n = 52), radical/excisional surgery (n = 61) and conservative surgery (n = 33). In ten patients, the PAIR procedure was abandoned due to either bile or pultaceous material aspirated after the initial puncture and these patients subsequently underwent surgical management. The PAIR was unsuccessful in eight of the 42 patients in whom it was attempted and these subsequently underwent surgery. The mean intraoperative blood loss and the duration of surgery were comparable in patients who underwent either conservative or radical surgery (p = 0.35 and 0.19, respectively). Postoperative bile leaks and cavity abscesses were significantly higher in patients who underwent conservative surgery (p = 0.032 and p = 0.001, respectively). Five patients (one following a radical operation and four following a conservative surgery, p = 0.05) developed recurrence in a mean follow-up period of 28 months and these were managed medically. CONCLUSION: Several treatment options are available for the management of hydatid disease of the liver and the treatment modality chosen should be tailored to the individual patient. While percutaneous drainage (with PAIR/PAIR-D) is reserved for more favourable cases of type I and II cysts, the others are best managed surgically. Complete excision (cystopericstectomy or resection) of the hydatid cyst is the preferred approach and 61 of the 94 patients who were managed surgically were suitable for it. Although excisional surgery minimizes the risk of long-term recurrence and cavity-related complications, it may be hazardous in cysts located close to major biliovascular channels. In these cases (considering that it is benign disease), a drainage operation is preferable. Both conservative and radical surgery can be safely performed laparoscopically. PMID- 21826544 TI - Clinical outcomes and prognostic factors of cancer patients with pyogenic liver abscess. AB - PURPOSE: Pyogenic liver abscess (PLA) of cancer patients often has a poor prognosis, but corresponding prognostic factors are less investigated. This study aimed to identify predictors of mortality in cancer patients with PLA. PATIENTS AND METHODS: Medical records of 85 consecutive cancer patients (46 with hepatobiliary pancreatic cancer, 14 with gastrointestinal cancer, and 25 with non digestive system cancer) having PLA who were admitted to two university hospitals were retrospectively reviewed. The predictors of mortality were determined using Cox regression model. RESULTS: The overall case fatality rate was 33%. In multivariate analysis, the greater Acute Physiology and Chronic Health Evaluation II score (P = 0.028), multiloculated abscess (P = 0.025), and polymicrobial infection (P = 0.003) were associated with mortality. In subgroup analysis of the 25 patients with multiloculated abscess undergoing percutaneous catheter drainage as primary treatment, the case fatality rates of patients with a solitary smaller abscess (size < 5 cm), those with a solitary larger abscess (size > 5 cm), and those with larger multiple abscesses were 0%, 36%, and 85%, respectively (P = 0.002; using chi (2) for trend). CONCLUSIONS: The advanced disease stage, multiloculated abscess, and polymicrobial infection posed a greater mortality risk in cancer patients with PLA. Moreover, an early surgical approach should be considered for cancer patients having large, multiloculated complex PLAs. PMID- 21826546 TI - Ischemic preconditioning-like effect of polyunsaturated fatty acid-rich diet on hepatic ischemia/reperfusion injury. AB - AIM: The aim of this study was to investigate a possible preconditioning effect of oral diet enriched with polyunsaturated fatty acids (PUFAs) on liver ischemia/reperfusion (I/R) injuries. METHODS: Wistar male rats were fed a standard diet or polyunsaturated fatty acid-rich diet (PRD) enriched with (GII) or without (GIII) omega-3 PUFA. Rats were submitted to partial liver ischemia during 1 h and evaluated in pre- and post-I/R conditions. In pre-I/R condition, livers were collected for determination of fatty acid composition, liver mitochondrial function, malondialdehyde (MDA) content, and histological analysis. Four hours after liver reperfusion serum activities of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), serum levels of tumor necrosis factor alpha, interleukin-6, interleukin-10, and prostaglandin-E2, liver mitochondrial function, MDA content, and histology were evaluated. RESULTS: In the pre-I/R condition, GII and GIII groups had an increase on PUFA content and exhibited slight increased macrosteatosis and microsteatosis in the liver. After 4 h of reperfusion, PRD-fed rats showed a marked decrease on steatosis, diminished necrosis, an increase in MDA formation, and mitochondrial uncoupling. We also observed a marked decrease in plasma levels of cytokines and ALT and AST activities in post-I/R condition in PRD groups. CONCLUSION: In this experimental model in the rat, PRD has a preconditioning effect protecting the liver from I/R injury and should be object of future clinical studies. PMID- 21826547 TI - Zinc and copper serum levels of morbidly obese patients before and after biliopancreatic diversion: 4 years of follow-up. AB - BACKGROUND: Zinc and copper are two essential trace elements. However, few studies have been conducted specifically to investigate these deficiencies in patients who underwent bariatric surgery. The aim of our work was to describe the influence of biliopancreatic diversion (BPD) on serum copper and zinc levels during 4 years. METHODS: We have analyzed a consecutive series of 65 patients who have been followed-up for 4 years after undergoing open BPD. RESULTS: The final (4 years) initial excess weight percent loss was 63.5%. A significant improvement of BMI, weight, waist circumference, and fat mass was detected. The preoperative average zinc (42.2 +/- 53.2 MUg/dl) and copper (61.3 +/- 58.6 MUg/dl) levels are under the lower limit of the normal values. These data show a deficient micronutrient status in morbidly obese patients, 73.8% of patients had low basal zinc values and 67.8% low basal copper values. Values of both micronutrients at different times (6 months, 1, 2, 3, and 4 years) were lower than basal value. CONCLUSION: BPD is an effective method of sustainable weight loss. Otherwise, a high prevalence of zinc and copper basal deficiencies in morbidly obese seeking bariatric surgery was detected. These deficiencies of copper and zinc increased during the 4 years of follow-up after BDP. PMID- 21826548 TI - Phytobezoar as a cause of intestinal obstruction. AB - INTRODUCTION: A small bowel phytobezoar is a rare cause of intestinal obstruction, whose most common cause is adhesion. CASE REPORT: This is a case report in which the etiology of small bowel obstruction was identified due to intussusception via computed tomography scan, and upon exploration, was found to be due to a small bowel phytobezoar. PMID- 21826549 TI - Management and outcomes of primary coloduodenal fistulas. AB - PURPOSE: Primary coloduodenal fistula (CDF) is a rare entity. We review our experience with the management and outcomes of CDF. METHODS: This is a retrospective review from 1975 to 2005 of patients with primary CDF. Patients were followed through clinic visits and mail correspondence with a mean (+/-SE) follow-up of 56 +/- 14 months. RESULTS: Twenty-two patients were diagnosed at a mean age of 54 +/- 3 years with primary CDF: benign (n = 14) or malignant (n = 8). Benign CDF were due to Crohn's disease (n = 9) or peptic ulcer disease (n = 5); malignant CDF was primarily due to colon cancer (n = 7) plus 1 patient with lymphoma. Indications for operative intervention included intractable symptoms (n = 15), gastrointestinal bleeding (n = 14), and to rule out malignancy (n = 8). Complete resection of malignant CDF with negative margins was achieved in half of patients after en bloc resection. Palliative bypass was performed in those patients with unresectable disease. Thirteen patients with benign CDF had resection of the fistula-2 of these patients required a duodenal bypass. There were no perioperative deaths, and the morbidity rate was 38%. Median survival for patients with malignant CDF was 20 months (range 1-150 months). Two patients with malignant CDF had >5-year survival. All patients with benign CDF who underwent fistula resection had resolution of fistula-related symptoms with one recurrence. CONCLUSION: Benign CDF is amenable to operative therapy with resolution of symptoms and a low recurrence rate. Complete resection of malignant CDF can impart survival benefit. PMID- 21826550 TI - Analysis of risk factors for delayed gastric emptying (DGE) after 387 pancreaticoduodenectomies with usage of 70 stapled reconstructions. AB - BACKGROUND: Delayed gastric emptying (DGE) is one of the most troublesome complications after pancreaticoduodenectomy (PD). METHODS: Between 2004 and 2009, 387 patients underwent PD and of these, 302 patients (78%) underwent pylorus preserving PD. The stapled reconstruction of duodeno- or gastrojejunostomy was introduced in 2006, and 70 patients (18%) underwent stapled Roux-en-Y reconstruction. Postoperative DGE was defined based on the International Study Group on Pancreatic Surgery classification, and grade B or C DGE was considered to be clinically relevant. Risk factors for DGE were evaluated using univariate and multivariate analyses. RESULTS: Four patients died in the hospital (1.0%). Postoperative DGE was found in 70 patients (18%). DGE was less frequently seen in stapled reconstruction than in hand-sewn reconstruction (7.2% vs. 21%, P < 0.001), and in single-layer anastomosis than in double-layer anastomosis (12% vs. 24%, P = 0.02). The multivariate logistic regression analysis revealed that the independent risk factors for DGE were postoperative pancreatic fistula (risk ratio [RR] 2.4, P = 0.002), hand-sewn reconstruction (RR 2.9, P = 0.03) and male (RR 2.2, P = 0.02). CONCLUSION: The method of alimentary reconstruction affected the occurrence of DGE. The incidence of DGE was less in stapled reconstruction than in hand-sewn reconstruction. PMID- 21826551 TI - Transfer of associative grouping to novel perceptual contexts in infancy. AB - Learning can be highly adaptive if associations learned in one context are generalized to novel contexts. We examined the development of such generalization in infancy in the context of grouping. In Experiment 1, 3- to 4-month-olds and 6- to 7-month-olds were habituated to shapes grouped via the organizational principle of common region and were tested with familiar and novel pairs as determined by the principle of proximity. Older infants generalized from common region to proximity, but younger infants did not. Younger infants failed to generalize when the task was easier (Experiment 2), and their failure was not due to inability to group via proximity (Experiment 3). However, in Experiment 4, even younger infants generalized grouping on the basis of connectedness to proximity. Thus, the ability to transfer learned associations of shapes to novel contexts is evident early in life, although it continues to undergo quantitative change during infancy. Moreover, the operation of this generalization mechanism may be induced by means of bootstrapping onto functional organizational principles, which is consistent with a developmental framework in which core processes scaffold learning. PMID- 21826552 TI - Multidimensional processing of dynamic sounds: more than meets the ear. AB - Strong cross-modal interactions exist between visual and auditory processing. The relative contributions of perceptual versus decision-related processes to such interactions are only beginning to be understood. We used methodological and statistical approaches to control for potential decision-related contributions such as response interference, decisional criterion shift, and strategy selection. Participants were presented with rising-, falling-, and constant amplitude sounds and were asked to detect change (increase or decrease) in sound amplitude while ignoring an irrelevant visual cue of a disk that grew, shrank, or stayed constant in size. Across two experiments, testing context was manipulated by varying the grouping of visual cues during testing, and cross-modal congruency showed independent perceptual and decision-related effects. Whereas a change in testing context greatly affected criterion shifts, cross-modal effects on perceptual sensitivity remained relatively consistent. In general, participants were more sensitive to increases in sound amplitude and less sensitive to sounds paired with dynamic visual cues. As compared with incongruent visual cues, congruent cues enhanced detection of amplitude decreases, but not increases. These findings suggest that the relative contributions of perceptual and decisional processing and the impacts of these processes on cross-modal interactions can vary significantly depending on asymmetries in within-modal processing, as well as consistencies in cross-modal dynamics. PMID- 21826553 TI - Enhancement of perceptual representations by endogenous attention biases competition in response selection. AB - Perception and response selection are core processes in the generation of overt behavior. Selective attention is known to facilitate behavioral performance by altering perceptual processes. It remains unclear, however, whether selective attention can aid the resolution of response conflict, and if so, at what stage of processing this takes place. In two experiments, an endogenous cuing task was combined with a flanker task to assess the interaction of selective attention with response selection. The results of Experiment 1 show that cuing reduces the flanker-congruency effect when the cue and flanker are presented in close temporal proximity to each other. The results of Experiment 2 demonstrate that pre- but not post-cuing the target reduced the congruency effect, showing that selective attention can affect performance, but is ineffective once stimulus processing has proceeded to response selection. Our results provide evidence that selective attention can aid the resolution of response conflict by altering early perceptual processing stages. PMID- 21826554 TI - Developing an extended genomic engineering approach based on recombineering to knock-in heterologous genes to Escherichia coli genome. AB - Most existing genomic engineering protocols for manipulation of Escherichia coli are primarily focused on chromosomal gene knockout. In this study, a simple but systematic chromosomal gene knock-in method was proposed based on a previously developed protocol using bacteriophage lambda (lambda Red) and flippase-flippase recognition targets (FLP-FRT) recombinations. For demonstration purposes, DNA operons containing heterologous genes (i.e., pac encoding E. coli penicillin acylase and palB2 encoding Pseudozyma antarctica lipase B mutant) engineered with regulatory elements, such as strong/inducible promoters (i.e., P( trc ) and P( araB )), operators, and ribosomal binding sites, were integrated into the E. coli genome at designated locations (i.e., lacZYA, dbpA, and lacI-mhpR loci) either as a gene replacement or gene insertion using various antibiotic selection markers (i.e., kanamycin and chloramphenicol) under various genetic backgrounds (i.e., HB101 and DH5alpha). The expression of the inserted foreign genes was subjected to regulation using appropriate inducers [isopropyl beta-D: -1 thiogalactopyranoside (IPTG) and arabinose] at tunable concentrations. The developed approach not only enables more extensive genomic engineering of E. coli, but also paves an effective way to "tailor" plasmid-free E. coli strains with desired genotypes suitable for various biotechnological applications, such as biomanufacturing and metabolic engineering. PMID- 21826556 TI - The aged-related increase in xanthine oxidase expression and activity in several tissues from mice is not shown in long-lived animals. AB - Xanthine oxidase (XO) is an important source of oxidant production and plays an essential role in several oxidative stress-related diseases. Aging is associated with a progressive deregulation of homeostasis as a result of a chronic oxidative stress situation. In the present work the age-related changes in XO expression and activity, as well as the activities of superoxide dismutase and catalase have been investigated in liver, kidney and thymus from four different age groups of mice, including long-lived animals. Furthermore, we have evaluated the contribution of the XO to the oxidative stress-associated with aging, in comparison to another enzymatic key source of oxidant generation, the NADPH oxidase, in peritoneal leukocytes from old mice. In all the tissues analyzed, the old mice showed higher activity and expression of XO, and decreased or unchanged superoxide dismutase and catalase activities as compared with adult mice. Moreover, the inhibition of reactive oxygen species with allopurinol or apocynin in peritoneal leukocytes from old mice, suggest that both XO and NADPH oxidase contribute to the generation of superoxide anion, whereas the XO may have a special relevance in the production of hydrogen peroxyde. Finally, long-lived animals showed a well-preserved redox state, in terms of antioxidant defenses and oxidant compounds in tissues and immune cells, which may be related to the ability of these subjects to reach a very advanced age in healthy condition. These results confirm that XO plays an important role in the age-related oxidative stress in tissues and immune cells. PMID- 21826555 TI - VSDMIP 1.5: an automated structure- and ligand-based virtual screening platform with a PyMOL graphical user interface. AB - A graphical user interface (GUI) for our previously published virtual screening (VS) and data management platform VSDMIP (Gil-Redondo et al. J Comput Aided Mol Design, 23:171-184, 2009) that has been developed as a plugin for the popular molecular visualization program PyMOL is presented. In addition, a ligand-based VS module (LBVS) has been implemented that complements the already existing structure-based VS (SBVS) module and can be used in those cases where the receptor's 3D structure is not known or for pre-filtering purposes. This updated version of VSDMIP is placed in the context of similar available software and its LBVS and SBVS capabilities are tested here on a reduced set of the Directory of Useful Decoys database. Comparison of results from both approaches confirms the trend found in previous studies that LBVS outperforms SBVS. We also show that by combining LBVS and SBVS, and using a cluster of ~100 modern processors, it is possible to perform complete VS studies of several million molecules in less than a month. As the main processes in VSDMIP are 100% scalable, more powerful processors and larger clusters would notably decrease this time span. The plugin is distributed under an academic license upon request from the authors. PMID- 21826557 TI - Soul whisperers. AB - Personal recollections are offered in reflection upon the tragedy of 9/11. The outreach efforts of the Blanton-Peale Institute in conjunction with the Health Care Chaplaincy of New York and the Red Cross are recalled by CEO Emeritus, Kathryn Madden. A brief clinical study describes the responses of a young man who was one of only a few persons to make it out of the North Tower from above the 85th floor. Blanton-Peale's Benefit Honorees Brian Clark, Lauren and Greg Manning are named as survivors of the tragedy. Their courage enables the rest of us to still dream of hope. PMID- 21826558 TI - Cutaneous head and neck squamous cell carcinoma with regional metastases: the prognostic importance of soft tissue metastases and extranodal spread. AB - BACKGROUND: Extranodal spread (ENS) is an established adverse prognostic factor in metastatic cutaneous squamous cell carcinoma (cSCC); however, the clinical significance of soft tissue metastases (STM) is unknown. The aim of this study was to evaluate the prognosis of patients with STM from head and neck cSCC, and to compare this with that of node metastases with and without ENS. METHODS: Patients with cSCC metastatic to the parotid and/or neck treated by primary surgical resection between 1987 and 2007 were included. Metastatic nodes >3 cm in size were an exclusion criterion. A Cox proportional hazard model was used to determine the effect of STM adjusting for other relevant prognostic factors. RESULTS: The population included 164 patients with a median follow-up of 26 months. There were 8 distant and 37 regional recurrences. There were 22 were cancer-specific deaths, and 29 patients died. STM was a significant predictor of reduced overall (hazard ratio 3.3; 95% confidence interval 1.6-6.4; P = 0.001) and disease-free survival (hazard ratio 2.4; 95% confidence interval 1.4-4.1; P = 0.001) when compared to patients with node disease with or without ENS. After adjusting for covariates, STM and number of involved nodes were significant independent predictors of overall and disease-free survival. CONCLUSIONS: In metastatic cSCC of the head and neck, the presence of STM is an independent predictor of reduced survival and is associated with a greater adverse effect than ENS alone. PMID- 21826560 TI - Laparoscopic abdominoperineal resection with open posterior cylindrical excision and primary transpelvic VRAM flap. AB - BACKGROUND: In our own experience over the last 15 years, the primary transpelvic vertical rectus abdominis myocutaneous (VRAM) flap is a reliable tool to prevent perineal wound complications after cylindrical excision in radical anorectal tumor surgery. To minimize the operative trauma in such patients, we performed a laparoscopic abdominoperineal resection combined with an open posterior cylindrical excision and a primary transpelvic vertical rectus abdominis myocutaneous (VRAM) flap via a minimal supraumbilical incision, which is described here for the first time. METHODS: A 49-year-old patient with recurrent anal cancer received radiochemotherapy with curative intention and underwent laparoscopic abdominoperineal rectal excision with posterior cylindrical excision combined with a primary transpelvic vertical rectus abdominis myocutaneous (VRAM) flap. The rectal stump was clipped and pulled through the pelvis together with the VRAM flap, which was then placed into the sacral defect. RESULTS: We found that the combined operative technical approaches with laparoscopy and minimal incisions for flap harvest and cylindrical excision were technically feasible, and no mesh was needed to close the small-sized laparotomies. We achieved complete tumor removal and flap perfusion, and healing was uneventful. The patient showed no relapse at 3 years postoperative. CONCLUSIONS: Our report of the operative technique shows that the combination of minimally invasive methods together with transpelvic VRAM flap transposition is technically feasible, can be performed with operative efficiency, and may become a valuable tool to minimize perioperative complications in advanced colorectal tumor surgery. PMID- 21826562 TI - Purchasing piety? Coresidence of married children with their older parents in Japan. AB - We investigated the conditions under which married children live with their older parents in Japan. We focused on how needs and resources in each generation are associated with whether married couples live with their parents in parent-headed and child-headed households, and we also investigated difference in power relations between older and younger generations and between children and their spouses. We analyzed a nationally representative sample of older parents (n = 3,853) and their married children (n = 8,601) from the 1999 Nihon University Japanese Longitudinal Study of Aging (NUJLSOA). Mutinomial regression revealed that married children with relatively affluent parents tended to live with them in parent-headed households and that married children with parents who are in relatively poor health or who are widowed tended to live with them in child headed households. We also found that less-educated married children tended to live in the households of their higher-income parents, suggesting that parents may be "purchasing" traditional arrangements with less-affluent children. In addition, children with an educational advantage over their spouses were more likely to have parents living with them in child-headed coresident households. We conclude that traditional multigenerational coresidence has become a commodity negotiated within families based on relative resources and needs within and across generations. PMID- 21826561 TI - Pediatric intracranial ependymoma: the roles of surgery, radiation and chemotherapy. AB - Management of pediatric intracranial ependymomas poses a major challenge, and optimal treatment remains controversial. We sought to investigate the roles of surgery, radiation, and chemotherapy in a historical cohort. Thirty-nine children, age 21 or younger, with non-metastatic intracranial ependymomas were treated from 1972 to 2008. Median age was 8 years (range 0.2-19.1). Twenty-one patients (54%) underwent GTRs, and 18 (45%) underwent STRs. Twenty-six patients (67%) received upfront adjuvant RT (67%), and 14 (44%) received adjuvant chemotherapy. Twenty-four patients had disease recurrence and 12 died. Only one patient recurred after 5 years. Median PFS was 2.7 years and median OS was 20 years. Fifteen year PFS and OS were 30 and 67%. Adjuvant RT was associated with improved PFS (P = 0.045), and remained significant after adjusting for EOR (P = 0.04). Greater EOR trended towards prolonged survival, but did not reach statistical significance (P = 0.156). Of the patients that underwent GTR, the median PFS was 38 months for those treated with adjuvant RT versus 30 months for those that were not treated with RT. Of the patients that had STR, the median PFS for those treated with RT was 26.3 months versus 6.9 months for those were not treated with RT. In conclusion, for localized intracranial pediatric ependymomas, adjuvant RT is associated with improved PFS, even after adjusting for EOR. Our findings suggest the benefit of RT even in the presence of GTR. Future prospective studies with larger sample number are needed to validate our findings. PMID- 21826563 TI - Frequency characteristics of contralateral sound suppression of 40-Hz auditory steady-state response. AB - Sound presented to the contralateral ear suppresses the amplitude of the 40-Hz auditory steady-state response (ASSR). The frequency characteristics of this suppression of the 40-Hz ASSR for amplitude modulated (AM) tones at 1,000 Hz (79 dB SPL) were examined in 12 healthy volunteers (10 males and 2 females, mean age 32.3 years) using contralateral AM tones (500, 1,000, 2,000, and 4,000 Hz) and 1/3 octave-band noise (500, 1,000, 2,000, and 4,000 Hz). The 40-Hz ASSR at 1,000 Hz was suppressed by a relatively wide frequency range of contralateral sound than expected from the known characteristics of psychophysical central masking by contralateral sound: the greatest suppression was obtained with 500- and 1,000-Hz sounds, but considerable suppression was also obtained with 2,000- and 4,000-Hz sounds. Substantial differences in the suppression pattern were not observed between two types of contra-suppressors; i.e., AM tones and 1/3 octave-band noise. Therefore, any sound presented to the contralateral ear, regardless of the frequency, can suppress the 40-Hz ASSR. Moreover, the different frequency characteristics of the contralateral sound effects between the psychophysical central masking and the 40-Hz ASSR would support the idea that the 40-Hz ASSR has an additive role in the processing of auditory signals to simple threshold judgment. Investigation of the type of psychophysical measurement using the AM signal showing similar suppression patterns by the presentation of contralateral sound would be helpful to reveal the functional relevance of ASSRs. PMID- 21826564 TI - Flexible memory networks. AB - Networks of neurons in some brain areas are flexible enough to encode new memories quickly. Using a standard firing rate model of recurrent networks, we develop a theory of flexible memory networks. Our main results characterize networks having the maximal number of flexible memory patterns, given a constraint graph on the network's connectivity matrix. Modulo a mild topological condition, we find a close connection between maximally flexible networks and rank 1 matrices. The topological condition is H (1)(X;Z)=0, where X is the clique complex associated to the network's constraint graph; this condition is generically satisfied for large random networks that are not overly sparse. In order to prove our main results, we develop some matrix-theoretic tools and present them in a self-contained section independent of the neuroscience context. PMID- 21826565 TI - [Benefit of dynamic MRI for assessment of pelvic floor reconstruction with polypropylene meshes]. PMID- 21826566 TI - [Postoperative findings in the spinal column]. AB - Postoperative imaging after spinal surgery is usually performed to document the correct positioning of implants or to rule out complications if patients still suffer from pain after surgery. Depending on the question various imaging modalities can be used all of which have benefits and limitations. Conventional X ray is used for the documentation of the correct positioning of spinal implants, stability (olisthesis) and during follow-up to rule out fractures or instability of the implants, whereas soft tissue changes cannot be completely assessed. Besides these indications, imaging is usually performed because of ongoing symptoms (pain for the most part) of the patients. Soft tissue changes including persistent or recurrent herniated disc tissue, hematoma or infection can best be depicted using magnetic resonance imaging (MRI) which should be performed within the immediate postoperative period to be able to distinguish physiological development of scar tissue from inflammatory changes in the area of the surgical approach. Often imaging alone cannot differentiate between these and imaging can therefore only be considered as an adjunct. Computed tomography is the modality of choice for the evaluation of bony structures and an adjunct of new therapies such as image-guided application of cement for kyphoplasty or vertebroplasty. PMID- 21826567 TI - [Inflammatory diseases of the spinal column and the myelon]. AB - Inflammatory diseases of the spine and the spinal cord (myelon) can be caused by a wide range of pathological conditions. Except for degenerative inflammatory diseases of the spine, infectious and autoimmune disorders are relatively rare. The latter can also be a significant source of pain and disability, especially if these hard to diagnose conditions go untreated. In cases of advanced disease some entities, such as spondylodiscitis or rheumatoid arthritis can cause severe neurological impairment especially by progressive intraspinal spread. Inflammation of the myelon cannot be depicted with conventional radiographs in general and by computed tomography only occasionally. In these cases magnetic resonance imaging is the method of choice to detect early abnormalities of the myelon and to provide detailed information for the differential diagnosis. PMID- 21826568 TI - [PPI vs fundoplication in the treatment of gastroesophageal reflux disease : results of the Cochrane meta-analysis and the LOTUS study]. PMID- 21826571 TI - Hard impact: journal impact factor and JMT. PMID- 21826569 TI - [Liposuction]. AB - Liposuction is one of the most commonly performed procedures in aesthetic surgery. The primary aim is body contouring and not weight reduction. The vast amount of available methods for suctioning subcutaneous fat allows an optimal individual treatment plan, keeping in mind the correct indications. Although liposuction is often offered as a minor and harmless surgery, it is a complex procedure. A thorough training of the surgeon and in-depth knowledge about possible complications is essential. In addition to aesthetic indications liposuction is also a valuable tool in reconstructive surgery. For optimal patient selection the skin elasticity has to be considered during the preoperative assessment. Besides pure volume reduction through liposuction, the regenerative possibilities of adipose tissue are of great interest for basic research and clinical applications. Lipofilling or autologous fat transfer is used for a wide variety of aesthetic and reconstructive procedures. Of special interest is the regenerative and reconstructive potential of adipose-derived stem cells (ADSC). PMID- 21826570 TI - Aqueous-methanolic extract of sweet flag (Acorus calamus) possesses cardiac depressant and endothelial-derived hyperpolarizing factor-mediated coronary vasodilator effects. AB - This investigation was aimed to probe the pharmacological base of medicinal use of Acorus calamus in ischemic heart diseases. Effect on heart parameters was studied in isolated rabbit heart while coronary vasodilator effect was studied in isolated bovine coronary arterial rings, suspended in tissue baths filled with Krebs solution, maintained at 37 degrees C, aerated with carbogen and responses were measured on PowerLab data acquisition system. In Langendorrf's perfused rabbit heart, the crude extract of Acorus calamus (Ac.Cr) at 0.01-10 mg/mL partially suppressed force of ventricular contractions (FVC), heart rate (HR) and coronary flow (CF). The ethylacetate fraction completely suppressed FVC, partially suppressed HR and CF, while the nHexane fraction exhibited similar effect on FVC and HR but increased CF, similar to methacholine and arachidonic acid. In bovine coronary arterial preparations, Ac.Cr caused inhibition of U46619 (20 nM)-precontractions, which was blocked in presence of increasing concentration of K(+) (4.8-20 mM), tetraethylammonium (1 MUM) and SKF525A (10 MUM), similar to arachidonic acid and methacholine, indicating K(+) channels activation and possible involvement of endothelial-derived hyperpolarizing factor (EDHF). Activity-directed fractionation revealed that EDHF-mediated activity is concentrated in the nHexane fraction. When tested against high K(+), the ethylacetate fraction was found more potent than parent crude extract and nHexane fraction. These data indicate that Ac.Cr mediates coronary vasodilator effect primarily through EDHF, responsible for the increase in CF, while the cardiac depressant effects may be due to the presence of additional cardiac depressant constituent(s), thus provides possible mechanistic basis to its medicinal use in ischemic heart diseases. PMID- 21826572 TI - Development of a performance verification test for USP apparatus 4. AB - PURPOSE: To evaluate salicylic acid tablets as a candidate reference material in a Performance Verification Test (PVT) when a USP performance test for dissolution (General Chapter <711>) relies on USP Apparatus 4 (flow-through cell). METHODS: We developed a dissolution procedure relying on Apparatus 4 and salicylic acid tablets. Thereafter, a designed experiment was conducted to identify operational variables that significantly affect salicylic acid dissolution in this apparatus. RESULTS: Four variables (size of glass beads, cell temperature, flow rate, level of deaeration) and one combination effect (deaeration/bead size) were significant for mean percent dissolved. Two variables (tablet orientation, level of deaeration) were significant for standard deviation results, but these effects were less pronounced than those for mean percent dissolved results. Three variables (analyst, tester manufacturer, amount of glass beads) had no statistically significant effects on either the mean or standard deviation of the responses. CONCLUSIONS: The proposed PVT is capable of probing effects of changes in several critical operational parameters of Apparatus 4. Salicylic acid tablets were shown to be a suitable reference material for the PVT. The PVT using salicylic acid tablets satisfies important aspects of a PVT. PMID- 21826574 TI - Thrombin injection failure with subsequent successful stent-graft placement for the treatment of an extracranial internal carotid pseudoaneurysm in a 5-year-old child. AB - Internal carotid artery pseudoaneurysm is a rare life-threatening condition that may develop in different clinical situations. We report the case of an extracranial internal carotid artery pseudoaneurysm secondary to a throat infection in a pediatric patient that was initially treated with percutaneous thrombin injection under ultrasound guidance. However, recanalization occurred at 48 h, and definitive treatment was then performed by endovascular stent-graft placement. We briefly review the clinical characteristics of this uncommon clinical condition as well as the treatment options. PMID- 21826575 TI - Placement of endovascular stent across the branching arteries: long-term serial evaluation of stent-tissue responses overlying the arterial orifices in an experimental study. AB - PURPOSE: This study was designed to investigate the effects of stenting across the branching arteries on the patency and stent-tissue responses over the branching arterial orifices. METHODS: Thirteen dogs were observed after placing aortic stents across the celiac arteries (CA), superior mesenteric arteries (SMA), and renal arteries (RA). The animals were grouped according to stent types: large-cell group (n = 6) and small-cell group (n = 7). Angiography was performed to evaluate the branching artery patency at 2, 6, and 12 months after stent insertion, and the stent-tissue responses covering the orifices were evaluated on histopathologic examination. RESULTS: All branching arteries were patent on follow-up angiography; however, three patterns of stent-tissue responses over the orifices were observed: neointimal layering, bridging septa, and papillary hyperplasia. Although neointimal layering and bridging septa were evenly observed, severe papillary hyperplasia was more frequent at SMA and CA than RA. Four RA showed less than 50% ostial patency, and localized infarct was observed in six kidneys (24%). The ostial patency tended to decrease with small cell stent during the follow-up period. CONCLUSIONS: Various stent-tissue responses over the branching artery orifices are induced by the aortic stent covering the branching arteries and may not be easily detected by conventional angiography. Subclinical renal infarct also may occur despite patent renal angiography. PMID- 21826577 TI - Effectiveness of pre-counseling genetic education workshops at a large urban community health center serving low-income Chinese American women. AB - Chinese American pregnant women and women of childbearing age face economic, cultural and linguistic barriers in accessing mainstream health care services. The Charles B. Wang Community Health Center developed a culturally and linguistically competent genetic education workshop for high-risk Chinese American prenatal patients. Patients referred for genetic counseling for thalassemia, abnormal triple screen results, and/or advanced maternal age were recruited to participate in the workshop. The workshop provided basic "genetic 101" education, focusing on topics that were directly relevant to the patients' reasons for referral. The effectiveness of the workshop was measured using a quasi-experimental design with pre-post surveys administered to intervention and control group participants. The evaluation also included a genetic counselor assessment and a pilot study of genetic counseling appointment length. Overall, workshop participants showed significant increases in knowledge, positive attitude and self-efficacy regarding genetic services as compared to their control group counterparts. The pilot appointment length study data revealed that the workshop reduced the length of the genetic counseling appointment time by 40%. These positive findings suggest that it would be worthwhile to replicate the genetic education workshop at other health agencies serving Chinese-speaking populations and that further evaluation research should be conducted. PMID- 21826576 TI - A randomized trial comparing the effect of two phone-based interventions on colorectal cancer screening adherence. AB - BACKGROUND: Early-stage diagnosis of colorectal cancer is associated with high survival rates; screening prevalence, however, remains suboptimal. PURPOSE: This study seeks to test the hypothesis that participants receiving telephone-based tailored education or motivational interviewing had higher colorectal cancer screening completion rates compared to usual care. METHODS: Primary care patients not adherent with colorectal cancer screening and with no personal or family history of cancer (n = 515) were assigned by block randomization to control (n = 169), tailored education (n = 168), or motivational interview (n = 178). The response rate was 70%; attrition was 24%. RESULTS: Highest screening occurred in the tailored education group (23.8%, p < .02); participants had 2.2 times the odds of completing a post-intervention colorectal cancer screening than did the control group (AOR = 2.2, CI = 1.2-4.0). Motivational interviewing was not associated with significant increase in post-intervention screening. CONCLUSIONS: Tailored education showed promise as a feasible strategy to increase colorectal cancer screening. PMID- 21826573 TI - Antiviral RNAi: translating science towards therapeutic success. AB - Viruses continuously evolve to contend with an ever-changing environment that involves transmission between hosts and sometimes species, immune responses, and in some cases therapeutic interventions. Given the high mutation rate of viruses relative to the timescales of host evolution and drug development, novel drug classes that are readily screened and translated to the clinic are needed. RNA interference (RNAi)-a natural mechanism for specific degradation of target RNAs that is conserved from plants to invertebrates and vertebrates-can potentially be harnessed to yield therapies with extensive specificity, ease of design, and broad application. In this review, we discuss basic mechanisms of action and therapeutic applications of RNAi, including design considerations and areas for future development in the field. PMID- 21826578 TI - At-risk marriages after compulsory premarital testing and counseling for beta thalassemia and sickle cell disease in Saudi Arabia, 2005-2006. AB - Results from a screening program for sickle cell disease and beta-thalassemia suggest about 90% of couples in Saudi Arabia at risk of having affected children still decide to marry. This study determined the rate of at-risk marriages and identified several factors that may prevent at risk couples from marrying. The marriage status of 934 at-risk couples was determined from original screening program records in the Ministry of Health. Of 934 couples, 824 married (88.2%) and 110 (11.8%) did not. A case-controlled study was conducted on 104 couples who did not marry (cases) and 478 couples who did marry (controls) in order to assess relationships between various cultural and social factors and marriage decisions. In the case-controled study, 28.8% of couples (30/104) who did not marry (cases) knew their disease or carrier status before screening compared to 18% (86/478) of those who married (controls). Reasons couples gave for proceeding with marriage included: wedding plans could not be canceled, and fear of social stigma. Couples who did not marry reported being influenced by prior knowledge of their disease or carrier status and whether they or family members were affected. Approximately half of the cases and controls (n = 270, 46.4%) thought it best to undergo screening before proceeding with the engagement and wedding plans. Most couples received no advice to participate in genetic counseling services. Marriage decisions for the small number who received genetic counseling (n = 168, 27.6%) did not differ significantly from those that received no counseling. Recommendations are made for improving the effectiveness of this screening program. PMID- 21826579 TI - Influence of genetic risk information on parental role identity in adolescent girls and young women from families with fragile X syndrome. AB - Using a multi-group cross-sectional design, we explored self-concept related to parental role salience and enactment in 53 young women (14 to 24 years) with knowledge they were either carriers, non-carriers, or could be a carrier of fragile X syndrome (FXS). Parental role salience included the participants' desire "to be a mother" and the importance they placed on this role. Enactment focused on the participants' views regarding ways to become a mother (reproductive options), parenting a child affected by FXS, and the development of partner relationships (marriage). Participants completed the FXS Adolescent Interview and the FX-Visual Analog Scale. Participants' knowledge of their genetic risk status appears to have influenced both salience and enactment of the parental role, and the effect varied based on carrier status. For many, knowledge of genetic risk appears to have led to reappraisal, redefinition, and re engagement with the goal of becoming a parent. This process was prominent in those who were carriers and less so in those who were at-risk, and it did not typically occur in those who were non-carriers. Findings offer valuable insight into the impact of genetic risk information on developing perceptions of the parental role and offer new directions for genetic counseling with adolescents and young women with a family history of FXS. PMID- 21826580 TI - The challenge of imaging-guided therapeutic management. PMID- 21826581 TI - Summary of evidence on immediate statins therapy following aneurysmal subarachnoid hemorrhage. AB - Statins were shown to have neuroprotective effects, with reduced vasospasm and delayed ischemic deficits in statin-treated patients after aneurysmal subarachnoid hemorrhage in two small, randomized, controlled clinical trials published in 2005. This review consolidated data from available published studies evaluating statin treatment for subarachnoid hemorrhage. A literature search was conducted to identify original research studies published through October 2010 testing immediate treatment with a statin in statin-naive patients following aneurysmal SAH. Six randomized controlled clinical trials and four observational studies were identified. Despite inconsistent results among studies, a meta analysis of randomized controlled data showed a significant reduction in delayed ischemic deficits with statins. Effect on vasospasm was more difficult to determine, due to differences in definitions used among studies. Interpretations from observational studies were limited by the use of relatively small sample sizes, historical controls, and treatment variability. PMID- 21826582 TI - Laparoscopic sleeve gastrectomy with an extensive posterior mobilization: technique and preliminary results. AB - BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) is becoming increasingly popular as a stand-alone procedure for the treatment of morbidly obese patients. A direct posterior approach to the angle of His was developed at our department to improve visualization of the difficult dissection of the short gastric vessels and to facilitate proper mobilization of the stomach around the left crus enabling safe realization of a tight sleeve. The technique and its preliminary results are described. METHODS: LSG by posterior approach was performed in a consecutive series of 445 (110 male/335 female, age 18-63 years, mean body mass index 46 kg/m(2) (range 35-76)) patients between 2007 and 2010. RESULTS: Weight loss defined as mean percent excess weight loss (%EWL) was 71% (+/-26%) at 1 year, 69% (+/-25%) at 2 years, and 55% (+/-27%) at 3 years. Sixteen patients (4%) developed postoperative intra-abdominal hematoma, 8 patients (2%) anastomotic leakage, and 6 patients intra-abdominal abscess (1%), requiring reoperation in 20 patients (4%). Five patients (1%) had pulmonary embolism. Thirty-day mortality rate was 0.2%. CONCLUSIONS: LSG by the posterior approach is a safe and effective procedure, enabling a tight sleeve formation leading to satisfactory %EWL results. Since long-term results of LSG are unknown, further studies are needed to define the exact place of the LSG as a stand-alone bariatric procedure. PMID- 21826583 TI - Is the environment near home and school associated with physical activity and adiposity of urban preschool children? AB - Preventing sedentary behavior and adiposity in childhood has become a public health priority. We examined urban social and built environment characteristics as correlates of physical activity and anthropometry among 428 preschool children from low-income families in New York City. We measured the children's height, weight, skinfold thicknesses, physical activity by accelerometer, and covariates. We geocoded home and Head Start center addresses and estimated the following for an area within 0.5 km of those two locations using a detailed geographic database: neighborhood composition, walkability, crime and traffic safety, and aesthetic characteristics. Generalized estimating equations were used to examine the associations of area characteristics with physical activity or adiposity, adjusted for characteristics of the child, mother, and home. Participants were 2 5 years old, 53% female, 83% Hispanic, and 43% either overweight or obese. Of the walkability indicators, land use mix was associated with physical activity (26 more activity counts/minute per standard deviation increase in mixed land use, p = 0.015) and subway stop density was associated with adiposity (1.2 mm smaller sums of skinfold thicknesses sum per standard deviation increase in subway stop density, p = 0.001). The pedestrian-auto injury rate, an indicator of traffic safety problems, was associated with physical activity and adiposity (16 fewer activity counts/minute, p = 0.033, and 1.0 mm greater skinfold thickness per standard deviation increase in pedestrian-auto injuries, p = 0.018). Children living in areas with more street trees were more physically active and those living in areas with more park access had smaller skinfolds. However, many of the tested associations were not statistically significant and some trends were not in the hypothesized direction. Efforts to enhance walkability, safety, and green spaces in the local environment may be relevant to physical activity and adiposity, and therefore to the health of preschool-aged children from low-income families. PMID- 21826584 TI - The role of subway travel in an influenza epidemic: a New York City simulation. AB - The interactions of people using public transportation in large metropolitan areas may help spread an influenza epidemic. An agent-based model computer simulation of New York City's (NYC's) five boroughs was developed that incorporated subway ridership into a Susceptible-Exposed-Infected-Recovered disease model framework. The model contains a total of 7,847,465 virtual people. Each person resides in one of the five boroughs of NYC and has a set of socio demographic characteristics and daily behaviors that include age, sex, employment status, income, occupation, and household location and membership. The model simulates the interactions of subway riders with their workplaces, schools, households, and community activities. It was calibrated using historical data from the 1957-1958 influenza pandemics and from NYC travel surveys. The surveys were necessary to enable inclusion of subway riders into the model. The model results estimate that if influenza did occur in NYC with the characteristics of the 1957-1958 pandemic, 4% of transmissions would occur on the subway. This suggests that interventions targeted at subway riders would be relatively ineffective in containing the epidemic. A number of hypothetical examples demonstrate this feature. This information could prove useful to public health officials planning responses to epidemics. PMID- 21826586 TI - Social organization of a stable natal group of captive Guyanese squirrel monkeys (Saimiri sciureus sciureus). AB - Socioecological models suggest competition for food, foraging efficiency, predation, infanticide risk, and the costs of dispersal regulate primate social structure and organization. Wild populations of squirrel monkeys (Saimiri spp.) appear to conform to the predictions of the predation/competition socioecological model (Sterck et al. in Behav Ecol Sociobiol 41:291-309, 1997) and the dispersal/foraging efficiency model (Isbell in Kinship and behavior in primates. Oxford University, New York, pp 71-108, 2004). However, squirrel monkeys in captivity are reported to maintain patterns of social behavior observed in their wild conspecifics despite different food distribution, predation risk, and dispersal options. This behavioral similarity suggests squirrel monkeys' social behavior has limited flexibility to respond to environmental changes. In this study, we experimentally evaluated the flexibility of social behavior within a captive group of S. sciureus. First, we determined whether dominance and affiliative relationships observed under normal laboratory conditions (with abundant, widely distributed, food; no dispersal option; and no predators) better matched published reports of relationships among wild conspecifics or the predictions of the predation/competition model. Second, we made preferred food items defensible to determine whether dominance interactions would become more frequent and linear, as predicted by the model. The model correctly predicted rates of dominance behavior in both conditions and a linear hierarchy in the defensible food condition but did not predict the consistent affiliative relationships and linear dominance hierarchy observed in normal lab conditions. Although hierarchies were linear and male dominant, manipulating food distribution changed the dominant individual within each sex. Our findings suggest interaction rates adapt more rapidly than social structure to environmental changes in Saimiri and recommend caution in interpreting tests of socioecological models. PMID- 21826585 TI - Engaging pediatricians in developmental screening: the effectiveness of academic detailing. AB - Use of formal developmental screening tools in the pediatric medical home improves early identification of children with developmental delays and disorders, including Autism Spectrum Disorders. A pilot study evaluated the impact of an academic detailing module in which trainers visited 43 pediatric primary care practices to provide education about implementing developmental screening tools in well-child services. Attendees responded to a post presentation survey stating that they planned to implement screening in their practices. Medicaid billing data showed an increase in the state's overall rate of screening. An audit of medical charts in five practices that received the training and five that did not showed higher screening rates in practices that received the training as well as higher rates after the training than before. These pilot study results indicate the potential of academic detailing as an effective strategy for improving rates of developmental screening. PMID- 21826587 TI - Epidemiological survey of rifampicin resistance in clinic isolates of Brucella melitensis obtained from all regions of Turkey. AB - The aim of the present study was to assess the antimicrobial susceptibility of Brucella melitensis isolates to rifampicin (RIF) depending on time and regional differences. A total of 94 human Brucella isolates collected in an 8-year period from the beginning of 2002 to the end of 2009 throughout Turkey were investigated. The isolates were identified at species and biovar levels by conventional methods, and minimum inhibitory concentrations (MIC) of RIF was determined by using the E test method. All isolates were identified as B. melitensis (93 isolates, biovar 3; 1, biovar 1), and MIC(50) and MIC(90) values of RIF were 1 and 1.5 MUg/ml, respectively (MIC range, 0.25-1.5 MUg/ml). All isolates were sensitive to RIF except 2 isolates, which had intermediate susceptibility to RIF. These findings indicated that B. melitensis biovar 3 may be the most frequently agent responsible for human brucellosis in Turkey. None of the isolates in our region was resistant to RIF. PMID- 21826588 TI - Pandemic H1N1 influenza A viral infection complicated by atypical hemolytic uremic syndrome and diffuse alveolar hemorrhage. AB - We report here on a case of a 27-year-old man with atypical hemolytic uremic syndrome and diffuse alveolar hemorrhage associated with influenza A H1N1 infection. Treatment with oseltamivir, plasma exchange and hemodiafiltration for the hemolytic uremic syndrome and meticulous supportive care with steroid pulse therapy for the pulmonary alveolar hemorrhage was successful in this case. We discuss the relationship between hemolytic uremic syndrome and influenza A and the underlying immunologic factors that should be tested in a patient with atypical hemolytic uremic syndrome. We also discuss using steroid therapy for patients with H1N1-related diffuse alveolar hemorrhage. PMID- 21826589 TI - Cloning and characterization of a novel oligoalginate lyase from a newly isolated bacterium Sphingomonas sp. MJ-3. AB - A bacterium possessing alginate-degrading activity was isolated from marine brown seaweed soup liquefied by salted and fermented anchovy. The isolated strain was designated as Sphingomonas sp. MJ-3 based on the analyses of 16S ribosomal DNA sequences, 16S-23S internal transcribed spacer region sequences, biochemical characteristics, and cellular fatty acid composition. A novel alginate lyase gene was cloned from genomic DNA library and then expressed in Escherichia coli. When the deduced amino acid sequence was compared with the sequences on the databases, interestingly, the cloned gene product was predicted to consist of AlgL (alginate lyase L)-like and heparinase-like protein domain. The MJ-3 alginate lyase gene shared below 27.0% sequence identity with exolytic alginate lyase of Sphingomonas sp. A1. The optimal pH and temperature for the recombinant MJ-3 alginate lyase were 6.5 and 50 degrees C, respectively. The final degradation products of alginate oligosaccharides were analyzed by electrospray ionization mass spectrometry and proved to be alginate monosaccharides. Based on the results, the recombinant alginate lyase from Sphingomonas sp. MJ-3 is regarded as an oligoalginate lyase that can degrade oligoalginate and alginate into alginate monosaccharides. PMID- 21826591 TI - Moxibustion for managing type 2 diabetes mellitus: a systematic review. AB - OBJECTIVE: Moxibustion is currently used for treating diabetes mellitus (DM) as a non-drug intervention in East Asian countries. This systematic review aims to evaluate the effectiveness of moxibustion for managing the symptoms of type 2 DM patients. METHODS: We searched MEDLINE, AMED, EMBASE, CINAHL, The Cochrane Library, six Korean databases, and four Chinese databases. Risk of bias was used for evaluating the quality of the included studies. RESULTS: A total of 5 studies met the inclusion criteria for this review. All of the included studies had high risks of bias. One randomized clinical trial (RCT) compared the effectiveness of one-time moxibustion use with oral administration of glibenclimide and showed the significant effects of moxibustion on glycemic control. Another RCT tested the effectiveness of moxibustion plus conventional treatment, and the moxibustion group reported significant improvement in fasting and postprandial blood glucose levels compared with the conventional treatment group. Two RCTs compared the effectiveness of moxibustion versus acupuncture or moxibustion plus acupuncture, and the combined treatment showed the most favorable effects on the control of blood glucose, urine glucose, and glycocylated hemoglobin A(1c) (HbA(1c)). One uncontrolled observational study showed favorable effects of moxibustion on the response rate. CONCLUSIONS: It is difficult to conclude that moxibustion is an effective intervention for the control of type 2 DM due to the scarcity of trials and the low methodological quality of included studies. Further rigorous RCTs may be necessary to evaluate the effectiveness of moxibustion for type 2 DM. PMID- 21826590 TI - Mechanism of action of natural products used in the treatment of diabetes mellitus. AB - Diabetes mellitus (DM) is a metabolic disorder caused by insufficient or inefficient insulin secretary response and it is characterized by increased blood glucose levels (hyperglycemia). DM is a heterogonous group of syndromes. Glucose is the main energy source for the body, and in the case of DM, management of glucose becomes irregular. There are three key defects in the onset of hyperglycemia in DM, namely increased hepatic glucose production, diminished insulin secretion, and impaired insulin action. Conventional drugs treat diabetes by improving insulin sensitivity, increasing insulin production and/or decreasing the amount of glucose in blood. This article provides a comprehensive review of the mode of action of most popular hypoglycemic herbs, such as ginseng, bitter melon, fenugreek, banaba, Gymnema sylvestre and Coptis chinensis. The herbs act by increasing insulin secretion, enhancing glucose uptake by adipose and skeletal muscle tissues, inhibiting intestinal glucose absorption and inhibiting hepatic glucose production. Although evidence from animals and humans consistently supports the therapeutic effect of these phytomedicines, multicenter large-scale clinical trials have not been conducted to evaluate the safety and efficacy of these herbal medicines and their interaction with conventional drugs when administered simultaneously. PMID- 21826592 TI - Research on the correlation between platelet gelsolin and blood-stasis syndrome of coronary heart disease. AB - OBJECTIVE: To study the distribution of gelsolin in human platelet and plasma, and the association with blood-stasis syndrome (BSS) of coronary heart disease (CHD). METHODS: Sixty patients with CHD (30 in BSS group and 30 in non-BSS group) and 30 healthy subjects (control group) were included in this study. The classification of the syndrome was based on clinical symptoms and signs. Gelsolin concentration in platelet rich plasma (PRP), platelet poor plasma (PPP), filamentous actin (F-actin) and group-specific component globulin (Gc-globulin) of PPP were determined by enzyme-linked immunosorbent assay (ELISA). The fluorescence intensity of CD62p and cytoplasmic calcium ([Ca(2+)](i)) in human platelets of patients and healthy persons was measured with flow cytometry. RESULTS: Compared with the control group, gelsolin in PRP of the BSS group increased significantly (P<0.01), while that in PPP of the BSS and non-BSS groups decreased markedly (P<0.05), the CD62p, [Ca(2+)](i) of platelet, F-actin, and Gc globulin of the BSS and non-BSS groups increased significantly (P<0.01). Compared with the non-BSS group, the gelsolin concentration in PRP of BSS group increased significantly (P<0.01), the [Ca(2+)](i) of platelet of the BSS group increased markedly (P<0.01), while the F-actin and Gc-globulin of the BSS group had no statistical defference (P>0.05). CONCLUSIONS: Gelsolin concentration in PRP was increased and accompanied by the elevated [Ca(2+)](i) of platelet in CHD with BSS, while gelsolin in PPP were lowered markedly. We speculate that plasma gelsolin may clear F-actin from circulation, thus resulting in depletion of plasma gelsolin significantly. This, in addition to the increased calcium influx of platelets, may lead to the gelsolin abnormal expression on platelets during the process of BSS in CHD. Therefore, platelet gelsolin may serve as a new potential biomarker and a therapeutic target of BSS in CHD. PMID- 21826593 TI - Yiqi zhuyu decoction combined with FOLFOX-4 as first-line therapy in metastatic colorectal cancer. AB - OBJECTIVE: To evaluate the efficacy and safety of yiqi zhuyu decoction (YZD) combined with oxaliplatin plus 5-flurouracil/leucovorin (FOLFOX-4) in the patients with metastatic colorectal cancer (MCRC). METHODS: A total of 120 patients with MCRC were randomly divided into the experimental group (FOLFOX-4 plus YZD, 60 cases) and the control group (FOLFOX-4 plus placebo, 60 cases), according to the sequence of hospitalization from January 2005 to December 2007. The treatment was supposed to be continued until disease progression (PD) or for 48 weeks (i.e., up to 24 cycles of FOLFOX-4). Response rate (RR), progression free survival (PFS), overall survival (OS) and adverse events (AEs) were observed. RESULTS: RR was 41.5% in the experimental group and 34.0% in the control group [odds ratio (OR): 1.18, 95% CI: 0.77 to 1.82, P=0.432]. Median PFS were 9.0 months and 8.0 months, respectively [hazard ratio (HR): 0.78, 95% CI: 0.53 to 1.15, P=0.215]. Median OS were 21.0 months and 18.0 months (HR: 0.65, 95% CI: 0.43 to 0.99, P=0.043) and grade 3/4 AEs were 56.6% and 76.7% (OR: 0.61, 95% CI: 0.18 to 0.87, P=0.020), respectively. CONCLUSIONS: YZD combined with FOLFOX-4 chemotherapy significantly improved OS in this first-line trial in the patients with MCRC and significantly decreased grade 3/4 AEs. However, RR was not improved, and PFS did not reach statistical significance by the addition of YZD. The treatment of YZD combined with FOLFOX-4 may be necessary in order to optimize efficacy and safety. PMID- 21826594 TI - Correlation analysis for the attack of respiratory diseases and meteorological factors. AB - OBJECTIVE: To investigate the relationship between respiratory diseases onset and the meteorological factors in the same period and in a specific environment. METHODS METHODS: By using the data of daily incidence of respiratory diseases obtained from Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine from January 1, 1998 to December 31, 2007, and the data of 16 items of meteorological factors (such as the average, maximum, and minimum temperatures, etc., including meteorological factors derived) obtained from the Beijing Municipal Meteorological Observatory, mathematical statistical methods were applied to achieve the non-linear correlation analysis, or the correlation test, between the incidence of respiratory diseases and the time-related meteorological factors. RESULTS: The simple correlation coefficients of the relationship between the incidence of respiratory diseases and 9 meteorological elements, including the average values of temperature, maximum temperature, minimum temperature, degree of comfort, precipitation, vapor pressure, low cloud cover, change of vapor pressure, and change of wind speed, were all greater than 0.8286, in which one of the relationship between the incidence of respiratory diseases and the maximum temperature is as high as 0.9670. Statistical tests showed R>Ralpha=0.05 and F>Falpha=0.05. CONCLUSIONS: The incidence of respiratory diseases was closely correlated to meteorological factors, such as air temperature, vapor pressure, precipitation, wind speed, etc. To a certain extent, this conclusion confirmed the scientificity and objectivity of the theory of five evolutive phases and six climatic factors (Wu Yun Liu Qi ) in Huang Di Nei Jing (The Yellow Emperor's Canon of Internal Medicine). PMID- 21826595 TI - Proliferation-inhibiting and apoptosis-inducing effects of ursolic acid and oleanolic acid on multi-drug resistance cancer cells in vitro. AB - OBJECTIVE: To investigate the proliferation-inhibiting and apoptosis-inducing effects of ursolic acid (UA) and oleanolic acid (OA) on multi-drug resistance (MDR) cancer cells in vitro. METHODS: UA and OA in different concentrations (0 100 MUmol/L) were added separately to cultures of different cancer cell lines, including the human colon cancer cell lines SW480 and SW620, human acute myelocytic leukemia cancer cell lines HL60 and HL60/ADR, human chronic myelogenous leukemia cell lines K562 and K562/ADR, and the human breast cancer cell lines MCF-7 and MCF-7/ADR. Effects of UA and OA on cell proliferation were detected by 3-(4,5-dimethyl-2-thiazole)-2-5-biphenly-tetrazole bromide (MTT) method and effects on cell apoptosis were tested by flow cytometry (FCM) and Western blot at 24, 48, and 72 h after treatment. RESULTS: Both UA and OA showed significant inhibition on parent and MDR cell lines in a time- and concentration dependent manner; the drug-resistant multiple of them on K562 and K562/ADR as well as on HL60 and HL60/ADR was 1; the effects of UA were better than those of OA in inhibiting cell growth of solid colonic cancer and breast cancer. After SW480 cells were treated by UA at the concentrations of 0-40 MUmol/L for 48 h, FCM showed that annexin V (AV) positive cells and hypodiploid peak ratio increased along with the increase in the drug's concentrations; and Western blot found that expressions of Bcl-2, Bcl-xL and survivin decreased in a concentration dependent manner. CONCLUSIONS: Both UA and OA have antitumor effects on cancer cells with MDR, and the optimal effect is shown by UA on colonic cancer cells. Also, UA shows cell apoptosis-inducing effect on SW480, possibly by way of down regulating the expressions of apoptosis antagonistic proteins, Bcl-2, Bcl-xL, and survivin. PMID- 21826596 TI - Effects of Panax notoginoside on the nephropathy in rats with type 1 diabetes mellitus. AB - OBJECTIVE: To explore the effects and underlying mechanisms of Panax notoginoside (PNS) on the nephropathy in rats with type 1 diabetes. METHODS: A murine model of diabetic nephropathy was set up by an intravenous injection of streptozotocin (STZ). Wistar rats were randomly divided into 5 groups: the control group, the diabetic group (DM), the group treated with low-dosage PNS (PNS-L), the group treated with high-dosage PNS (PNS-H) and the group treated with catopril. Rats in the PNS-L and PNS-H groups were given different dosages of PNS while rats in the catopril group were given catopril through gastrogavage every day for the next four consecutive weeks. Serum creatinine (Cr) levels, endogenous creatinine clearance rate (CCr), and 24-h urinary microalbumin (UAlb) were examined and calculated. Meanwhile, immunohistochemistry was applied to determine the expression of vascular endothelial growth factor (VEGF) and bone morphogenetic protein-7 (BMP-7) in the kidney tissue. RESULTS: The levels of Cr, Ccr, and UAlb were all elevated significantly in the DM group (P<0.01). The expression of VEGF protein was increased but BMP-7 protein was decreased in the kidney tissue (P<0.01). However, the above items decreased in the PNS-L, PNS-H and catopril groups compared with the DM group (P<0.05, P<0.01). In the PNS-L, PNS-H and catopril groups, the expression of VEGF protein was decreased but BMP-7 protein was increased in the kidney tissue (P<0.05, P<0.01). CONCLUSION: PNS shows protective effects on the kidney in type 1 diabetic rats at the early stage. The protective mechanism might be closely related to its role of inhibiting the expression of VEGF protein and enhancing the expression of BMP-7 protein in the kidney. PMID- 21826597 TI - Protective effect of total alkaloids of Sophora alopecuroides on dextran sulfate sodium-induced chronic colitis. AB - OBJECTIVE: To investigate the effect of total alkaloids of Sophora alopecuroides (TASA) on dextran sulfate sodium (DSS)-induced colitis in mice. METHODS: Chronic experimental colitis was induced by administration of 4 cycles of 4% DSS. Fifty mice were randomly distributed into 4 groups (normal, DSS, DSS/high-dose TASA, and DSS/low-dose TASA groups) by a random number table with body weight stratification. Mice in the normal group (n=11) and DSS-induced colitis control group (n=15) received control treatment of 20 mL/kg distilled water; DSS plus TASA high- and low-dose groups (n=12 each) were treated with TASA solution (20 mL/kg) at the doses of 60 mg/kg and 30 mg/kg, respectively. The severity of colitis was assessed on the basis of clinical signs, colon length, and histology scores. Moreover, secretory immunoglobulin A (sIgA) and haptoglobin (HP) were analyzed by enzyme linked immunosorbent assay; intercellular adhesion molecule 1 (ICAM-1) and macrophage-migration inhibitory factor (MIF) gene expressions were analyzed by quantitative reverse transcriptase realtime polymerase chain reaction (qRT-PCR) using SYBA green I; and nuclear factor kappa B (NF-kappa B) expression and activation and p65 interaction with the promoter of ICAM-1 gene were assessed by Western blotting and chromatin immunoprecipitation assay. RESULTS: TASA administration significantly attenuated the damage and substantially reduced HP elevation and maintained the level of cecum sIgA. TASA inhibited the ICAM-1 gene expression and had no effect on MIF gene expression. Also, TASA was able to reduce phospho-I kappa B alpha (p-I kappa B alpha) protein expression; however, it had no effect on the activation of I kappa B kinase alpha (IKK alpha) and inhibitor of NF-kappa B alpha (I kappa B alpha). Moreover, TASA inhibited the p65 recruitment to the ICAM-1 gene promoter. CONCLUSIONS: TASA had a protective effect on DSS-induced colitis. Such effect may be associated with its inhibition of NF-kappa B activation and blockade of NF-kappa B-regulated transcription activation of proinflammatory mediator gene. PMID- 21826598 TI - Effects of Salivae Miltiorrhizae Liguspyragine Hydrochloride and Glucose Injection on the levels of main platelet thrombin receptors in chronic haemodialysis patients. AB - OBJECTIVE: To investigate the effects of Salvia Miltiorrhiza Liguspyragine Hydrochloride and Glucose Injection (, SLGI) on the expression of platelet membrane receptors proteinase-activated receptor-1 (PAR1) and proteinase activated receptor-4 (PAR4) in end-stage renal disease (ESRD) patients on chronic haemodialysis (HD). METHODS: Eighty-six ESRD patients on HD (treated group) were treated with SLGI, 7 days as one therapeutic course, for two successive courses. The previous therapies were unchanged. Flow cytometry was used to assess the expression of platelet PAR1 and PAR4 in the patients, and turbidity method was used to determine the platelet maximum aggregation rate (MAR). Meanwhile, renal function was measured. The final data were compared with those before treatment and with those in the normal control group (54 healthy subjects). RESULTS: Compared with the normal control group, the expressions of PAR1 and PAR4 and platelet MAR in ESRD patients on HD was significantly higher before treatment (P=0.001, P=0.006, and P=0.008); after treatment with SLGI, the above indices in patients were remarkably decreased (P=0.036 and P=0.046), except PAR4 (P=0.067), but still higher than those in the normal control group, however, it was not statistically significant. CONCLUSIONS: (1) The overexpression of PAR1 and PAR4 might lead to increased platelet aggregation and this could be one of the reasons for the thrombotic events in ESRD patients on HD. (2) SLGI was able to down regulate the expression of PAR1 in ESRD patients on HD, improve platelet function, and regulate platelet activation. PMID- 21826599 TI - Principles of ethics review on traditional medicine and the practice of institute review board in China. AB - As one of the significant parts of medical science research in China, the research on Chinese medicine (CM) reflects the essence of healthcare tradition in the country both theoretically and clinically, and embodies the values of Chinese culture. Therefore, in the practice of ethics review on CM research protocols, besides abiding by the contemporary prevalent international principles and guidelines on bioethics, which emphasizes the scientific and bioethical value of the study, we should also stress the CM theoretical background and relevant clinical experience in the framework of Chinese culture and values. In this paper, we went over the traits of CM clinical research and the experience from the practice of ethics review by the institution review board for bioethics, and then attempted to summarize the key points for the bioethics review to CM researches in China, so as to serve as reference for the bioethics review to traditional and alternative medicine researches. PMID- 21826600 TI - Delaying vascular aging with Chinese medicine: implications from an overview of the p53 and miR-34s family. AB - p53 is an important target for studying vascular aging. However, as people gradually learned more about the miR-34s and the relationship between miR-34s and p53, new research idea emerged. This paper tries to elaborate the feature of p53, microRNA and miR-34s in-depth, analyze the regulatory action of miR-34s on p53, and offer some new prevention and treatment prospects about vascular aging in Chinese medicine. PMID- 21826601 TI - Tongue as the window to the heart. PMID- 21826602 TI - EPR in protein science : intrinsically disordered proteins. AB - Intrinsically disordered proteins (IDPs) form a unique protein category characterized by the absence of a well-defined structure and by remarkable conformational flexibility. Electron Paramagnetic Resonance (EPR) spectroscopy combined with site-directed spin labeling (SDSL) is amongst the most suitable methods to unravel their structure and dynamics. This review summarizes the tremendous methodological developments in the area of SDSL EPR and its applications in protein research. Recent results on the intrinsically disordered Parkinson's disease protein alpha-synuclein illustrate that the method has gained increasing attention in IDP research. SDSL EPR has now reached a level where broad application in this rapidly advancing field is feasible. PMID- 21826603 TI - DNA-based soft phases. AB - This chapter reviews the state-of-the-art in the study of molecular or colloidal systems whose mutual interactions are mediated by DNA molecules. In the last decade, the robust current knowledge of DNA interactions has enabled an impressive growth of self-assembled DNA-based structures that depend crucially on the properties of DNA-DNA interactions. In many cases, structures are built on design by exploiting the programmable selectivity of DNA interactions and the modularity of their strength. The study of DNA-based materials is definitely an emerging field in condensed matter physics, nanotechnology, and material science. This chapter will consider both systems that are entirely constructed by DNA and hybrid systems in which latex or metal colloidal particles are coated by DNA strands. We will confine our discussion to systems in which DNA-mediated interactions promote the formation of "phases," that is structures extending on length scales much larger than the building blocks. Their self-assembly typically involves a large number of interacting particles and often features hierarchical stages of structuring. Because of the possibility of fine-tuning the geometry and strength of the DNA-mediated interactions, these systems are characterized by a wide variety of patterns of self-assembly, ranging from amorphous, to liquid crystalline, to crystalline in one, two, or three dimensions. PMID- 21826604 TI - Single molecule logical devices. AB - After almost 40 years of development, molecular electronics has given birth to many exciting ideas that range from molecular wires to molecular qubit-based quantum computers. This chapter reviews our efforts to answer a simple question: how smart can a single molecule be? In our case a molecule able to perform a simple Boolean function is a child prodigy. Following the Aviram and Ratner approach, these molecules are inserted between several conducting electrodes. The electronic conduction of the resulting molecular junction is extremely sensitive to the chemical nature of the molecule. Therefore designing this latter correctly allows the implementation of a given function inside the molecular junction. Throughout the chapter different approaches are reviewed, from hybrid devices to quantum molecular logic gates. We particularly stress that one can implement an entire logic circuit in a single molecule, using either classical-like intramolecular connections, or a deformation of the molecular orbitals induced by a conformational change of the molecule. These approaches are radically different from the hybrid-device approach, where several molecules are connected together to build the circuit. PMID- 21826605 TI - Liquid crystalline crown ethers. AB - In this chapter, a comprehensive review over the entire reserarch on liquid crystalline crown ethers since their discovery will be given. Monomeric and polymeric molecules containing crown ethers as well as aza crown ethers, thia crown ethers and crown ethers with several different heteroatoms will be presented. Liquid crystallinity is, in most cases, caused by the substituents attached to the crown ethers. The respective macrocycle can be surrounded by multiple substituents or attachment can take place terminally or laterally. Within the substituents, a variety of geometries, such as rods, discs or tapers have been reported, resulting in different types of mesophases. The effects of complexation will be discussed in detail as complexation has a varying influence on the properties, ranging from the induction or stabilization of a mesophase to the destabilization or even the complete loss of the mesophase, depending on the crown, the salt or the counterion of the salt. For selected examples, the synthesis of the materials will be discussed. Possible applications in sensor or membrane technology as well as in chromatography will be shown. PMID- 21826607 TI - Beyond BRAF in melanoma. AB - Recent progress in the analysis of genetic alterations in melanoma has identified recurrent mutations that result in the activation of critical signaling pathways promoting growth and survival of tumors cells. Alterations in the RAS-RAF-MAP kinase and PI3-kinase signaling pathways are commonly altered in melanoma. Mutations in BRAF, NRAS, KIT, and GNAQ occur in a mutually exclusive pattern and lead to MAP-kinase activation. Loss of PTEN function, primarily by deletion, is the most common known genetic alteration in the PI3-kinase cascade, and is commonly associated with BRAF mutations (Curtin et al., N Engl J Med 353:2135 2147, 2005; Tsao et al., Cancer Res 60:1800-1804, 2000, J Investig Dermatol 122:337-341, 2004). The growth advantage conveyed by the constitutive activation of these pathways leads to positive selection of cells that have acquired the mutations and in many instances leads to critical dependency of the cancer cells on their activation. This creates opportunities for therapeutic interventions targeted at signaling components within these pathways that are amenable for pharmacological inhibition. This concept follows the paradigm established by the landmark discovery that inhibition of the fusion kinase BCR-ABL can be used to treat chronic myelogenous leukemia (Druker et al., N Engl J Med 344:1031-037, 2001). The review will focus primarily on kinases involved in signaling that are currently being evaluated for therapeutic intervention in melanoma. PMID- 21826608 TI - Silicate-mediated alleviation of Pb toxicity in banana grown in Pb-contaminated soil. AB - Silicate (Si) can enhance plant resistance or tolerance to the toxicity of heavy metals. However, it remains unclear whether Si can ameliorate lead (Pb) toxicity in banana (Musa xparadisiaca) roots. In this study, treatment with 800 mg kg(-1) Pb decreased both the shoot and root weight of banana seedlings. The amendment of 800 mg kg(-1) Si (sodium metasilicate, Na(2)SiO(3).9H(2)O) to the Pb-contaminated soil enhanced banana biomass at two growth stages significantly. The amendment of 800 mg kg(-1) Si significantly increased soil pH and decreased exchangeable Pb, thus reducing soil Pb availability, while Si addition of 100 mg kg(-1) did not influence soil pH. Results from Pb fractionation analysis indicated that more Pb were in the form of carbonate and residual-bound fractions in the Si-amended Pb contaminated soils. The ratio of Pb-bound carbonate to the total Pb tended to increase with increasing growth stages. Treatment with 100 mg kg(-1) Si had smaller effects on Pb forms in the Si-amended soils than that of 800 mg kg(-1) Si. Pb treatment decreased the xylem sap greatly, but the addition of Si at both levels increased xylem sap and reduced Pb concentration in xylem sap significantly in the Si-amended Pb treatments. The addition of Si increased the activities of POD, SOD, and CAT in banana roots by 14.2% to 72.1% in the Si amended Pb treatments. The results suggested that Si-enhanced tolerance to Pb toxicity in banana seedlings was associated with Pb immobilization in the soils, the decrease of Pb transport from roots to shoots, and Si-mediated detoxification of Pb in the plants. PMID- 21826609 TI - Assessing the tolerance of castor bean to Cd and Pb for phytoremediation purposes. AB - This study evaluated Cd and Pb accumulation by castor bean (Ricinus communis cv. Guarany) plants grown in nutrient solution, aiming to assess the plant's ability and tolerance to grow in Cd- and Pb-contaminated solutions for phytoremediation purposes. The plants were grown in individual pots containing Hoagland and Arnon's nutrient solution with increasing concentrations of Cd and Pb. The production of root and shoot dry matter and their contents of Cd, Pb, Ca, Mg, Cu, Fe, Mn, and Zn were evaluated in order to calculate the translocation and bioaccumulation factors, as well as toxicity of Cd and Pb. Cadmium caused severe symptoms of phytotoxicity in the plant's root and shoot, but no adverse effect was observed for Pb. Castor bean is an appropriate plant to be used as indicator plant for Cd and tolerante for Pb in contaminated solution and it can be potentially used for phytoremediation of contaminated areas. PMID- 21826606 TI - Elastomeric polypeptides. AB - Elastomeric polypeptides are very interesting biopolymers and are characterized by rubber-like elasticity, large extensibility before rupture, reversible deformation without loss of energy, and high resilience upon stretching. Their useful properties have motivated their use in a wide variety of materials and biological applications. This chapter focuses on elastin and resilin - two elastomeric biopolymers - and the recombinant polypeptides derived from them (elastin-like polypeptides and resilin-like polypeptides). This chapter also discusses the applications of these recombinant polypeptides in the fields of purification, drug delivery, and tissue engineering. PMID- 21826611 TI - Sodium selenite-induced apoptosis mediated by ROS attack in human osteosarcoma U2OS cells. AB - Sodium selenite (Na(2)SeO(3), SSE) is an inorganic Se compound that is widely used in cancer chemoprevention studies. SSE has been shown to have anti proliferative effects on several types of human cancer cells, but its effect on osteosarcoma cells has thus far not been reported. In this study, the cytotoxic effect of SSE on osteosarcoma cells U2OS was investigated in vitro and found to be higher than on comparable non-cancer cell lines 293 and L6. Treatment with SSE decreased cell growth in a dose- and time-dependent manner and altered cellular morphology. SSE also inhibited cell viability by inducing apoptosis, as evidenced by the formation of apoptotic bodies, generation of reactive oxygen species (ROS), and accumulation of cells during the advanced phase of apoptosis. SSE induced apoptosis correlated with the activation of CASP 3, downregulation of BCL 2, and upregulation of P53 and PTEN in U2OS cells. These results indicated that SSE induces apoptosis in U2OS cells mainly through an ROS-mediated caspase pathway. This is the first report to show a possible mechanism of the anti proliferative effect of SSE for the prevention of osteosarcoma in cell culture models. PMID- 21826610 TI - Investigation of the effects of phosphate fertilizer application on the heavy metal content in agricultural soils with different cultivation patterns. AB - The use of phosphate fertilizers is essential in agriculture, because they supply farmland with nutrients for growing plants. However, heavy metals might be included as impurities in natural materials and minerals, so heavy metals can also be present in phosphate fertilizers or other chemical fertilizers. The aim of this work was to assess the heavy metal content and contamination status of agricultural soils in the Hamadan province of Iran used for the cultivation of different crops, including cucumber, potatoes, and sugar beet. Surface soil samples were collected and analyzed to determine the total concentration of specific elements (As, Cd, Cr, Cu, Fe, Mn, Ni, Pb, and Zn), before the pollution index was calculated for each element. Soils used for the cultivation of the three types of crop were not contaminated with As, Cr, Cu, Pb, or Zn. However, the pollution indices for Cd were 1.1, 4.4, and 3.8 in cucumber, potato, and sugar beet fields, respectively, which indicated moderate, high, and high levels of contamination, respectively. Soils from potato and sugar beet fields were heavily contaminated with Cd, which may have resulted from long-term overuse of phosphate fertilizers. PMID- 21826612 TI - Surgery for MSK tumors: 1971-2011. AB - Since 1971 surgical management of musculoskeletal tumors has changed dramatically. In 1971 less than one-fourth of patients with a malignant tumor had limb salvage surgery, the remainder having an amputation. Amputations were also sometimes done for recurrent benign tumors. Since then amputation has become unusual for malignant disease and is virtually never done for benign tumors. The changes have been made possible because of advances in anesthesiology, surgery, radiology, medical oncology, and radiation oncology. PMID- 21826613 TI - High-resolution MR imaging of talar osteochondral lesions with new classification. AB - PURPOSE: Retrospective review of high-resolution MR imaging features of talar dome osteochondral lesions and development of new classification system based on these features. MATERIAL AND METHODS: Over the past 7 years, 70 osteochondral lesions of the talar dome from 70 patients (49 males, 21 females, mean age 42 years, range 15-62 years) underwent high-resolution MR imaging with a microscopy coil at 1.5 T. Sixty-one (87%) of 70 lesions were located on the medial central aspect and ten (13%) lesions were located on the lateral central aspect of the talar dome. Features evaluated included cartilage fracture, osteochondral junction separation, subchondral bone collapse, bone:bone separation, and marrow change. Based on these findings, a new five-part grading system was developed. Signal-to-noise characteristics of microscopy coil imaging at 1.5 T were compared to dedicated ankle coil imaging at 3 T. RESULTS: Microscopy coil imaging at 1.5 T yielded 20% better signal-to-noise characteristics than ankle coil imaging at 3 T. High-resolution MR revealed that osteochondral junction separation, due to focal collapse of the subchondral bone, was a common feature, being present in 28 (45%) of 61 medial central osteochondral lesions. Reparative cartilage hypertrophy and bone:bone separation in the absence of cartilage fracture were also common findings. Complete osteochondral separation was uncommon. A new five part grading system incorporating features revealed by high-resolution MR imaging was developed. CONCLUSIONS: High-resolution MRI reveals clinically pertinent features of talar osteochondral lesions, which should help comprehension of symptomatology and enhance clinical decision-making. These features were incorporated in a new MR-based grading system. Whenever possible, symptomatic talar osteochondral lesions should be assessed by high-resolution MR imaging. PMID- 21826614 TI - Limitations of radiographs in evaluating non-displaced osteochondral lesions of the talus. AB - OBJECTIVE: To evaluate what limitations, if any, radiographs have in detecting and characterizing the morphology of non-displaced OCLTs (size, cystic change, fragmentation, and avascular necrosis [AVN]). MATERIALS AND METHODS: Thirty-three OCLTs in 32 patients were reviewed in consensus by a board-certified, fellowship trained musculoskeletal radiologist and orthopedic surgeon, on radiographs and MRI examinations performed within 15 days of one another. Location, dimensions, and characteristics of the OCLT (fragmentation, bone marrow edema, cystic change, and necrosis) were documented on the radiographs and MRI examinations. RESULTS: There was an average of 7.5 days (range: 1-15 days) between the MRIs and radiographs. Eighteen (55%) medial and 15 (45%) lateral OCLTs were found; none was displaced. OCLTs were categorized into three groups: Group 1-initially diagnosed with radiographs (4/33; 12%), Group 2-diagnosed with radiographs only after MRI correlation (20/33; 61%), and Group 3-not identifiable on radiographs despite MRI correlation (9/33; 27%). The dimensions of all of the lesions in Groups 1 and 2 were underestimated on radiographs. Only 1 of the 4 (25%) lesions in Group 1 and 1 of the 20 (5%) lesions in Group 2 could be measured in the anteroposterior (AP) dimension (using a lateral radiograph). The most common radiographic appearance of non-displaced OCLTs was an "ill-defined" lucency at the talar dome (20/33; 61%). Across all three groups, fragmentation, cystic change, and AVN were radiographically apparent in 3/10 (30%), 4/19 (21%), and 1/6 (17%) cases respectively. CONCLUSION: Compared with MRI, radiographs are limited in their evaluation of the size (particularly the AP dimension) and characteristics (fragmentation, cystic change, and AVN) of non-displaced OCLTs. The most common appearance of non-displaced OCLTs is an "ill-defined" lucency at the talar dome. When this appearance is also considered, the estimated retrospective sensitivity of radiographs improves considerably. PMID- 21826615 TI - Chronic middle foot pain in a patient with a swollen leg: diagnosis and discussion. PMID- 21826617 TI - Abstracts of the 47th Annual Meeting of the European Association for the Study of Diabetes. September 16, 2011. Lisbon, Portugal. PMID- 21826616 TI - Idiopathic carpal tarsal osteolysis (ICTO) with additional elbow involvement. PMID- 21826619 TI - [Classical trauma of the elderly or injury of senior citizens?]. PMID- 21826620 TI - [Ankle fractures in the elderly]. AB - There has been a significant increase in the incidence and severity of ankle fractures in the elderly population in the last few decades. Classification and diagnostic procedures in the elderly are not different from standards in younger patients. We provide an overview of the characteristic features of treatment of ankle fractures in the elderly. An algorithm for therapy of ankle fractures in the elderly is presented. PMID- 21826621 TI - [Severe traumatic brain injury]. AB - Traumatic brain injury is a leading cause of morbidity and mortality, especially under 45 years of age. The primary brain injury occurs at the moment of trauma and is defined by the direct damage to tissue. In contrast, secondary brain injury develops over time and is accessible to therapeutic interventions. Patients with severe traumatic brain injury have to be transferred to a specialized trauma centre in order to perform appropriate diagnostic and therapeutic procedures. These include surgical management of lesions (e.g. haematoma evacuation) as well as specific neurointensive care. Neurointensive care medicine principles such as treatment of increased intracranial pressure and advanced invasive neuromonitoring of brain tissue have to be followed. PMID- 21826622 TI - Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: 7-year follow-up of a rare clinicopathologic syndrome. AB - BACKGROUND: Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare clinical pathological syndrome. There have been only 49 cases of DIPNECH reported in the literature so far. We report a case of a 69-year-old nonsmoking man with a 7-year follow-up. METHODS: The initial CT scan from December 2003 showed persistent nonspecific bilateral reticulonodular infiltrates. In January 2004, the patient underwent a video-assisted thoracoscopic wedge resection of his right lower lobe for further diagnostic workup. Pathology of the resected wedge of the right lower lobe revealed a diffuse idiopathic pulmonary cell hyperplasia (DIPNECH) highlighted by staining for the neuroendocrine typical carcinoid markers, such as marker CD 56. RESULTS: All the performed CT scans over a 7-year period showed no progression of the bilateral pulmonary lesion. The bilateral pulmonary nodules were stable in terms of size, number and form. The yearly control with chest CT scans will be continued. CONCLUSIONS: The neuroendocrine cell hyperplasia is confined to the airway mucosa without penetration through the basement membrane and appears in a diffuse pattern, generally in close association with obliterative bronchiolar fibrosis. DIPNECH is characterized by a mixed obstructive and/or restrictive ventilation pattern with bilateral reticulonodular infiltrates and a predilection for middle-aged women. Little is known about the clinical course and treatment for DIPNECH. PMID- 21826623 TI - Griseofulvin/carrier blends: application of partial least squares (PLS) regression analysis for estimating the factors affecting the dissolution efficiency. AB - The main aim of the present study was to estimate the carrier characteristics affecting the dissolution efficiency of griseofulvin (Gris) containing blends (BLs) using partial least squares (PLS) regression analysis. These systems were prepared at three different drug/carrier weight ratios (1/5, 1/10, and 1/20) by the solvent evaporation method, a well-established method for preparing solid dispersions (SDs). The carriers used were structurally different including polymers, a polyol, acids, bases and sugars. The BLs were characterised at the solid-state by spectroscopic (Fourier transform infrared spectroscopy), thermoanalytical (differential scanning calorimetry) and X-ray diffraction studies and their dissolution behaviours were quantified in terms of dissolution efficiencies (log DE/DE(Gris)). The correlation between the selected descriptors, including parameters for size, lipophilicity, cohesive energy density, and hydrogen bonding capacity and log DE/DE(Gris) (i.e., DE and DE(Gris) are the dissolution efficiencies of the BLs and the pure drug, respectively) was established by PLS regression analysis. Thus two models characterised by satisfactory coefficient of determination were derived. The generated equations point out that aqueous solubility, density, lipophilic/hydrophilic character, dispersive/polar forces and hydrogen bonding acceptor/donor ability of the carrier are important features for dissolution efficiency enhancement. Finally, it could be concluded that the correlations developed may be used to predict at a semiquantitative level the dissolution behaviour of BLs of other essentially neutral drugs possessing hydrogen bonding acceptor groups only. PMID- 21826624 TI - [Aquired Horner syndrome in the case of a baby]. PMID- 21826625 TI - [Theory and practice of Pavlov Sleep Therapy in the GDR]. AB - The following study describes theoretical foundations and practical application of Pavlov Sleep Therapy within the GDR in the 1950s and earlier 1960s. Implementing the sleeping treatment as a psychiatric therapy examplifies how the ideological guideline to integrate Pavlov's teachings was converted into medical practice in the GDR. One of the protagonists of this approach was Dietfried Muller-Hegemann in Leipzig. Although being successful with some diseases such as fatigue, its practical application ceased after several cases of death that were brought in connection with the sleep treatment. Indirectly this discontinuation of Pavlov Sleep Therapy also terminated Muller-Hegemann's academic career. PMID- 21826626 TI - ["Treated and promoted or detained and left behind" - intensive psychiatric care of residents of a psychiatric hostel over seven years]. AB - OBJECTIVE: In this observational study indicators for the quality of psychiatric care in a psychiatric hostel will be examined for all residents over a period of 7 years. METHODS: Data has been collected at an annual basis. Relationships among variables have been analysed by means of random effects regression analyses for longitudinal data. RESULTS: GAF score increases slightly. Number of psychopharmacological drugs and neuroleptics as well as inpatient costs remains stable. Psychiatric treatment costs are negatively related to the functional level, residents' age and the duration of stay in the residential facility. Even under control of several variables, variance of total costs was found to be mainly explained by the costs of inpatient and psychopharmacological treatment. DISCUSSION: Increase of the general functional level indicates a positive development of autonomy. Changes and the influence factors of psychopharmacological treatment may indicate a need-oriented drug therapy. Some findings may indicate an institutionalisation process and an increasing of medical conditions in chronically mentally ill people. PMID- 21826627 TI - [Community care for former forensic patients in the local mental health care system--evaluation of the basic documentation in two regions]. AB - OBJECTIVE: This study analyzes, to which extent clients formerly detained in forensic psychiatric units can be integrated into the community and what kind of assistance they need. METHODS: Analysis of basic documentation in community mental health care in 2 regions. RESULTS: Integration into the community is feasible. Former forensic patients are more likely to show aggressive behaviour than clients without forensic history. These aggressive acts nevertheless can be handled. Aggressive acts decrease with the duration of integration. Crisis interventions are not more frequent in patients with forensic history. CONCLUSIONS: Integration of patients who are "difficult to place" into a community can be accomplished by community based services with obligation to provide assistance. PMID- 21826628 TI - The Cooperative Italian FLIN Study Group: prevalence and clinico-pathological features of colorectal laterally spreading tumors. AB - BACKGROUND AND STUDY AIMS: Laterally spreading tumors (LSTs) are increasingly recognized as important precursors of colorectal carcinoma. The clinical behavior of these large nonpolypoid lesions is still uncertain. The aim of the present study was to assess prevalence and clinico-pathological features of LSTs in a large Italian cohort of patients. METHODS: The study was a subgroup analysis of a large database of patients undergoing total colonoscopy. The database originated from a multicenter cross-sectional observational study involving 80 centers throughout Italy. RESULTS: Data from 27,400 total colonoscopies were analyzed. Precancerous lesions were detected in 5609 patients. Of these, LSTs were identified in 254 patients (4.5%; 95% confidence interval [CI] 3.5-6.2). Granular type LSTs (G-LSTs) accounted for 83% of the cases (211/254). LSTs were predominant in the proximal colon (154, 60.6%). A total 231 lesions were endoscopically removed, with histology being available for 242. Neoplasia was confirmed in 225 lesions (93.4%) (143 low grade adenoma, 76 high grade adenoma, and six submucosal cancer). The six cases of submucosally invasive carcinoma were diagnosed in five G-LST and one nongranular LST (NG-LST). The risk of containing advanced histology was not increased in G-LST compared with NG-LST (odds ratio [OR] 1.55, 95%CI 0.73-3.27); it was significantly higher in lesions with large nodules (OR 3.09, 95%CI 1.05-9.04; P = 0.041) or depressed surface (OR 4.27, 95%CI 1.24-14.61; P = 0.021). CONCLUSIONS: LSTs represent approximately 5% of all precancerous colorectal lesions in the Italian population and are prevalent in the proximal colon. These lesions are no more likely to harbor advanced histology than similar-sized polypoid lesions. Large nodularity or depressed surface are risk factors for advanced histology. PMID- 21826629 TI - Recurrent disease following endoscopic ablation of Barrett's high-grade dysplasia with spray cryotherapy. AB - BACKGROUND AND AIMS: Recurrent disease after endoscopic ablation of Barrett's esophagus should be detected early to prevent malignant progression. We assessed the incidence and patterns of disease recurrence in patients after liquid nitrogen spray cryotherapy ablation of Barrett's esophagus with high grade dysplasia (HGD), including the area below the neosquamocolumnar junction (NSCJ). PATIENTS AND METHODS: This is a single-center, retrospective study of prospectively collected data on consecutive cases of endoscopic ablation with liquid nitrogen spray cryotherapy for Barrett's HGD. Post-treatment surveillance biopsies were obtained of suspicious lesions and in 4 quadrants every 1 cm in the treated esophagus and just below the NSCJ. Primary outcome measures were location and histology of recurrent disease. RESULTS: 36 patients (median age 62 years, 92% men) were enrolled, and 11 (30%) developed recurrent disease in a median of 6.5 months; three developed a second recurrence. Ten recurrences (71%) were identified below the NSCJ in 9 patients, including HGD (4), low grade dysplasia (LGD) (2), and intestinal metaplasia (4). Six recurrences were identified in the treated esophagus in five patients, including intramucosal cancer (1), HGD (1), and intestinal metaplasia (4). Two patients had recurrent disease involving both locations. Ultimately 33 patients (92%) achieved a complete response. Diagnosis in the remaining three was LGD (1) and intestinal metaplasia (2). CONCLUSION: Most patients with recurrent intestinal metaplasia with or without dysplasia after ablation achieve a complete response. Recurrent disease commonly involves the area just below the NSCJ. Surveillance endoscopies should include this area to accurately identify patients with disease recurrence. PMID- 21826630 TI - [Treasure hunt--a retrospect on Ernst-August Dolle's prospective research]. PMID- 21826631 TI - [Dyadic assessment and dyadic data analysis]. PMID- 21826632 TI - Postural strategies employed by orangutans (Pongo abelii) during feeding in the terminal branch niche. AB - Obtaining food in an arboreal habitat is complex due to the irregular and flexible nature of the supports available. As the largest predominantly arboreal primate, orangutans are expected to have developed particular postural strategies to enable them to feed successfully. In particular, they need to be able to cope within the terminal branch niche (TBN) as this is where the smallest, most compliant supports are, and also where the majority of the fruit and leaves are situated. We recorded feeding posture, along with a number of ecological and behavioral variables from different age-sex classes to enable analysis of the interactions between these and the compliance of the supports (as estimated from stiffness score). Suspensory postures with a pronograde orientation were used on the most compliant supports for all age-sex classes and appeared to play a particular role in facilitating safe use of the TBN by distributing body weight and using limbs for balance across multiple supports. This contradicts the idea that orthograde suspension evolved in response to the demands of feeding in the TBN. Adult males appear to use the same postures and feeding zones as the other age-sex classes, but appear to use stiffer supports where possible due to their larger body mass. Feeding method differed between the age-sex classes in relation to support stiffness, with larger adult males taking fewer risks due to their larger size, compared to infants and juveniles. PMID- 21826633 TI - Regionalized autosomal STR profiles among Armenian groups suggest disparate genetic influences. AB - The archeology and ethnology of Armenia suggest that this region has acted as a crossroads for human migrations from Europe and the Middle East since at least the Neolithic. Near continual foreign influx has, in turn, led to the supposition that the gene pools of geographically separated Armenian populations may have diverged as differing historical influences potentially left distinct genetic traces in the various regions of the Armenian plateau. In this study, we seek to address whether any evidence for such genetic regional partitioning in Armenians exists by analyzing, for the first time, 15 autosomal short tandem repeat (STR) loci in 404 Armenians from four geographically well-characterized collections (Ararat Valley, Gardman, Sasun, and Lake Van) that represent distinct communities from across Historical Armenia. In addition, to determine whether genetic differences among these four Armenian populations are the result of differential affinities to populations of known historical influence in Armenia, we utilize 27 biogeographically targeted reference populations for phylogenetic and admixture analyses. From these examinations, we find that while close genetic affiliations exist between the two easternmost Armenian groups analyzed, Ararat Valley and Gardman, the remaining two populations display substantial distinctions. In particular, Sasun is distinguished by evidence for genetic contributions from Turkey, while a stronger Balkan component is detected in Lake Van, potentially suggestive of remnant genetic influences from ancient Greek and Phrygian populations in this region. PMID- 21826634 TI - Energetic consequences of seasonal breeding in female Japanese macaques (Macaca fuscata). AB - Japanese macaques inhabit a relatively cold environment and females of this species could have developed strategies of energy economy to face the sometimes harsh seasonal conditions of temperate climates, as well as reproductive costs, and thus regulate their energy balance. Here, we explore the relationship between nutritional status, body composition, seasonality, and reproductive status using isotope-labeled water, anthropometric measurements, and leptin assays from 14 captive female Japanese macaques. Our results indicated that body mass provided the best predictor of fat-free mass and fat mass. These females varied in estimated percent body fat between 8 and 25% (18% on average at the beginning of the mating season and 13% during the birth season). Higher body mass and body fat content were observed at the beginning of the mating season, which supports the hypothesis that individual females need to attain a sufficient physical condition to cover energy costs associated with mating activity, and to survive under severe ecological conditions in winter with high thermoregulatory costs. We found a relationship between conception rates and energetic condition or body fat, with females that conceived during one mating season being fatter after the end of their previous mating season. Together, these results suggest that, even in captive settings with constant food availability, seasonal breeding entails relatively high energy costs, and that females with higher energy status could invest more in reproductive activities and could afford to reproduce more rapidly. PMID- 21826635 TI - Male lineages in South American native groups: evidence of M19 traveling south. AB - With this study, we aimed to determine the different male ancestral components of two Native American communities from Argentina, namely Toba and Colla. The analysis of 27 Y-chromosome SNPs allowed us to identify seven different haplogroups in both samples. Chromosomes carrying the M3 mutation, which typically defines the Native American haplogroup Q1a3a, were seen most frequently in the Toba community (90%). Conversely, Q1a3a was represented in 34% of the Colla Y-chromosomes, whereas haplogroup R1b1, the main representative of western European populations, exhibited the highest frequency in this population (41%). Different M3 sublineages in the Toba community could be identified by observing point mutations at both DYS385 and M19 loci. A microvariant at DYS385, named 16.1, has been characterized, which helps to further subdivide Q1a3a. It is the first time the M19 mutated allele is described in a population from Argentina. This finding supports the old age of the lineages carrying the M19 mutation, but it contradicts the previous hypothesis that the M19 mutated allele is confined to only two Equatorial-Tucano population groups from the north region of South America. The detection of M19 further south than previously thought allows questioning of the hypothesis that this lineage serves as an example of isolation after colonization. This observation also affirms the strong genetic drift to which Native Americans have been subjected. Moreover, our study illustrates a heterogeneous contribution of Europeans to these populations and supports previous studies showing that most Native American groups were subjected to European admixture that primarily involved immigrant men. PMID- 21826636 TI - Impact of intrasexual selection on sexual dimorphism and testes size in the Mexican howler monkeys Alouatta palliata and A. pigra. AB - One of the goals of physical anthropology and primatology is to understand how primate social systems influence the evolution of sexually selected traits. Howler monkeys provide a good model for studying sexual selection due to differences in social systems between related species. Here, we examine data from the sister howler monkey species Alouatta palliata and A. pigra inhabiting southeastern Mexico and northern Guatemala. We use a resampling approach to analyze differences in sexual dimorphism of body and canine size. In addition, we compare testes size as a way of gauging the intensity of sperm competition in both species. Morphometric data were collected from wild-caught individuals, including body mass and length, and dental data were obtained from casts from wild individuals and from museum specimens. Although A. pigra individuals are larger than their A. palliata counterparts, we find that both species exhibit similar levels of sexual dimorphism for all of the variables considered. Testicular volume results indicate that A. palliata male testes are on average twice as large as those of A. pigra males, suggesting more intense sperm competition in the former species. Our study shows that A. pigra is not highly sexually dimorphic as was once thought, and testes size differences suggest the need for a clearer understanding of howler monkey social systems. PMID- 21826637 TI - Status and health in Roman Dorset: the effect of status on risk of mortality in post-conquest populations. AB - The Roman conquest of Britain was previously shown to have negatively impacted health, particularly for children, older adults, and men. We build upon this previous research by investigating the effect that status had on risks of mortality within the Roman Britain populations of Dorset. This study incorporates a sample of 291 individuals excavated from several cemeteries in the county of Dorset dating between the first to early fifth centuries AD. To assess the effect of status on risks of mortality, burial type was used as a proxy for status and modeled as a covariate affecting the Siler and Gompertz-Makeham models of mortality. The results of these analyses indicate that high-status individuals, particularly children, had a lower mortality risk compared to lower-status groups; and for those buried in urban cemeteries, higher-status individuals of all age-groups had a lower mortality risk. As with our previous study (Redfern and DeWitte: Am J Phys Anthropol 144 (2011) 269-285), we found that male mortality risk was higher than females, which we consider to reflect underlying sex-differences in immunity and disease response. PMID- 21826638 TI - mtDNA diversity in Azara's owl monkeys (Aotus azarai azarai) of the Argentinean Chaco. AB - Owl monkeys (Aotus spp.) inhabit much of South America yet represent an enigmatic evolutionary branch among primates. While morphological, cytogenetic, and immunological evidence suggest that owl monkey populations have undergone isolation and diversification since their emergence in the New World, problems with adjacent species ranges, and sample provenance have complicated efforts to characterize genetic variation within the genus. As a result, the phylogeographic history of owl monkey species and subspecies remains unclear, and the extent of genetic diversity at the population level is unknown. To explore these issues, we analyzed mitochondrial DNA (mt DNA) variation in a population of wild Azara's owl monkeys (Aotus azarai azarai) living in the Gran Chaco region of Argentina. We sequenced the complete mitochondrial genome from one individual (16,585 base pairs (bp)) and analyzed 1,099 bp of the hypervariable control region (CR) and 696 bp of the cytochrome oxidase II (COII) gene in 117 others. In addition, we sequenced the mitochondrial genome (16,472 bp) of one Nancy Ma's owl monkey (A. nancymaae). Based on the whole mtDNA and COII data, we observed an ancient phylogeographic discontinuity among Aotus species living north, south, and west of the Amazon River that began more than eight million years ago. Our population analyses identified three major CR lineages and detected a high level of haplotypic diversity within A. a. azarai. These data point to a recent expansion of Azara's owl monkeys into the Argentinean Chaco. Overall, we provide a detailed view of owl monkey mtDNA variation at genus, species, and population levels. PMID- 21826639 TI - Technical note: the midline and endocranial volume of the Taung endocast. AB - The Taung endocast is one of the best-preserved and most important known in paleoanthropology. Although the endocast is undistorted and preserves distinctive landmarks, Taung has proved a difficult endocast, because it is only about 60% complete. To reconstruct Taung it is necessary to first use the available anatomical landmarks to define the midline of the endocast. It is only with a proper description of the midline that it is possible to reconstruct the endocast and obtain an accurate measurement of Taung's endocranial volume. Holloway (Science 168 (1970) 966-968) determined a conservative estimate for Taung of 404 ml. More recently this estimate has been revised downward by Falk and Clarke (Am J Phys Anthropol 134 (2007) 529-534) to 382 ml, giving Taung the smallest endocast for A. africanus. Certain challenges exist with the reconstruction of any endocast, particularly a hemi-endocast such as Taung. A virtual reconstruction of Taung must assume perfect symmetry, a feature called into question here in Taung's most recent reconstruction by Falk and Clarke (2007). Holloway's (1970) reconstruction of Taung provides a guidepost for a conservative approach to endocast reconstructions, and the most reliable measurement of Taung's true endocranial volume. PMID- 21826640 TI - The mechanical significance of morphological variation in the macaque mandibular symphysis during mastication. AB - Catarrhine symphyseal morphology displays considerable variation. Although this has been related to dentition, phylogeny, sexual dimorphism, and facial orientation, most emphasis has been given to the functional significance of the symphysis to mechanical loading during mastication. The current state of knowledge regarding the mechanical significance of the symphysis is based on a combination of in vivo experimental and comparative studies on Macaca fascicularis. These approaches have provided considerable insight into the stereotypical patterns of loading in the symphyseal region during chewing and hypotheses related to the associated symphyseal morphologies. Finite element analysis (FEA) was used to assess how in silico manipulation translates into the mechanical loading hypotheses previously proposed experimentally. In particular, this study tests the form-function relationship of the symphysis of an adult M. fascicularis mandible during lateral transverse bending and dorsoventral shear of the mandibular symphysis, and a series of modified hypothetical morphologies including absence/presence of tori and variation in the inclination and depth of the symphysis. FEA results of this study support previous findings that stresses associated with lateral transverse bending and dorsoventral shear of the mandibular symphysis can be minimized via an increased labio-lingual thickness in the superior transverse torus, an oblique symphyseal inclination, and/or an increased symphyseal depth. The finding that reduction of strains related to lateral transverse bending and dorsoventral shear can be achieved through a number of different morphologies contributes to our understanding of the influence of morphological and/or developmental constraints, such as dental development, on symphyseal form. PMID- 21826643 TI - Nicotine dependence phenotype, time to first cigarette, and risk of head and neck cancer. AB - BACKGROUND: A behavioral phenotype that characterizes nicotine dependence, the time to first cigarette after waking, is hypothesized to increase the risk of head and neck cancer. METHODS: A case-control study of histologically confirmed head and neck cancer was conducted that included 1055 cases and 795 controls with a history of cigarette smoking. RESULTS: The pack-years-adjusted odds ratio was 1.42 (95% confidence interval [95% CI], 1.02-1.99) for an interval of 31 minutes to 60 minutes to first cigarette after waking and 1.59 (95% CI, 1.19-2.11) for an interval of 1 minute to 30 minutes. The risk estimates were similar when smoking was modeled as total years, smoking status (current vs former), number of cigarettes smoked per day, years since quitting, and excess odds ratio. Findings were consistent for cancers of the floor of the mouth, palate, and pharynx. CONCLUSIONS: Time to first cigarette is an indicator of increased nicotine dependence, smoke uptake, and risk of head and neck cancer. This high-risk group of individuals would benefit from targeted smoking interventions. PMID- 21826644 TI - Nicotine dependence phenotype and lung cancer risk. AB - BACKGROUND: A behavioral phenotype that characterizes nicotine dependence, the time to first cigarette after waking, is hypothesized to increase the risk of lung cancer. METHODS: A case-control study of histologically confirmed lung cancer was conducted. The current analysis included 4775 lung cancer cases and 2835 controls who were regular cigarette smokers. RESULTS: Compared with subjects who smoked their first cigarette > 60 minutes after waking, the pack-years adjusted odds ratio was 1.31 (95% confidence interval [95% CI], 1.11-1.54) for subjects who smoked 31 minutes to 60 minutes after waking and 1.79 (95% CI, 1.56 2.07) for subjects who smoked within 30 minutes of waking. The risk estimates were similar when smoking was modeled as total years, smoking status (current vs former), number of cigarettes smoked per day, years since quitting, and excess odds ratio. The findings were consistent for all histologic types of lung cancer. CONCLUSIONS: The findings of the current study indicate that a specific nicotine dependence phenotype that is associated with the amount of smoke uptake per cigarette is independently associated with lung cancer risk. These findings may help to identify high-risk individuals who would benefit from targeted interventions. PMID- 21826645 TI - Detection of mitochondrial deoxyribonucleic acid alterations in urine from urothelial cell carcinoma patients. AB - Our study aims at understanding the timing and nature of mitochondrial deoxyribonucleic acid (mtDNA) alterations in urothelial cell carcinoma (UCC) and their detection in urine sediments. The entire 16.5 kb mitochondrial genome was sequenced in matched normal lymphocytes, tumor and urine sediments from 31 UCC patients and compared to different clinical stages and histological grades. The mtDNA content index was examined in all the specimens. Sixty-five percent (20/31) of the patients harbored at least 1 somatic mtDNA mutation. A total of 25 somatic mtDNA mutations were detected, which were more frequent in the respiratory complex coding regions (Complex I, III, IV and V) of the mtDNA and significantly affected respiratory Complex III compared to the other complexes (p = 0.021 0.039). Compared to Stage Ta, mtDNA mutation was higher in Stage T1 and significantly higher in Stage T2 (p = 0.01) patients. MtDNA mutation was also significantly higher (p = 0.04) in Stage T2 compared to Stage T1 patients. Ninety percent (18/20) of the patients harboring mtDNA mutation in the tumor also had mutation in their urine sediments. Eighty percent (20/25) of the tumor-associated mtDNA mutations was detectable in the urine sediments. Compared to the normal lymphocytes, the mtDNA content increased significantly in the tumor (p = 0.0013) and corresponding urine sediments (p = 0.0025) in 19/25 (76%) patients analyzed. Our results indicate that mtDNA alterations occur frequently in progressive stages of UCC patients and are readily detectable in the urine sediments. MtDNA mutations appear to provide a promising tool for developing early detection and monitoring strategies for UCC patients. PMID- 21826646 TI - The antitumor effect of a novel angiogenesis inhibitor (an octahydronaphthalene derivative) targeting both VEGF receptor and NF-kappaB pathway. AB - Development of a novel type of angiogenesis inhibitor will be essential for further improvement of therapeutics against cancer patients. We examined whether an octahydronaphthalene derivative, AMF-26, which was screened as an inhibitor of intercellular adhesion molecule-1 (ICAM-1) production stimulated by inflammatory stimuli in vascular endothelial cells, could block angiogenesis in response to vascular endothelial growth factor (VEGF) and/or inflammatory cytokines. Low dose AMF-26 effectively inhibited the tumor necrosis factor-alpha (TNF-alpha)- or the interleukin-1beta (IL-1beta)-induced production of ICAM-1 in human umbilical vascular endothelial cells (HUVECs). We found that the TNF-alpha-induced phosphorylation of nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor, alpha (IkappaBalpha) and nuclear translocation of p65 were impaired by AMF-26 in both endothelial cells and cancer cells. AMF-26 was found to inhibit the phosphorylation of VEGF receptor 1 (VEGFR1), VEGFR2 and the downstream signaling molecules Akt, extracellular signal-regulated kinase (ERK)1/2 stimulated by VEGF in HUVECs. Therefore, the VEGF-induced proliferation, migration and tube formation of vascular endothelial cells was highly susceptible to inhibition by AMF-26. Oral administration of AMF-26 significantly blocked VEGF or IL-1beta-induced angiogenesis in the mouse cornea, and also tumor angiogenesis and growth. Together, our results indicate that AMF-26 inhibits angiogenesis through suppression of both VEGFR1/2 and nuclear factor-kappaB (NF kappaB) signaling pathways when stimulated by VEGF or inflammatory cytokines. AMF 26 could be a promising novel candidate drug for cancer treatments. PMID- 21826647 TI - Differential action of small molecule HER kinase inhibitors on receptor heterodimerization: therapeutic implications. AB - Deregulation of ErbB/HER receptor tyrosine kinases has been linked to several types of cancer. The mechanism of activation of these receptors includes establishment of receptor dimers. Here, we have analyzed the action of different small molecule HER tyrosine kinase inhibitors (TKIs) on HER receptor dimerization. Breast cancer cell lines were treated with distinct TKIs and the formation of HER2-HER3 dimers was analyzed by coimmunoprecipitation and western blot or by Forster resonance energy transfer assays. Antibody-dependent cellular cytotoxicity was analyzed by measuring the release of lactate dehydrogenase and cell viability. Lapatinib and neratinib interfered with ligand-induced dimerization of HER receptors; while pelitinib, gefitinib, canertinib or erlotinib did not. Moreover, lapatinib and neratinib were able to disrupt previously formed receptor dimers. Structural analyses allowed the elucidation of the mechanism by which some TKIs prevent the formation of HER receptor dimers, while others do not. Experiments aimed at defining the functional importance of dimerization indicated that TKIs that impeded dimerization prevented down regulation of HER2 receptors, and favored the action of trastuzumab. We postulate that TKIs that prevent dimerization and down-regulation of HER2 may augment the antitumoral action of trastuzumab, and this mechanism of action should be considered in the treatment of HER2 positive tumors which combine TKIs with antireceptor antibodies. PMID- 21826648 TI - Host-derived osteopontin maintains an acute inflammatory response to suppress early progression of extrinsic cancer cells. AB - The matricellular protein osteopontin (OPN), expressed in various cancer types and elevated in the blood of cancer patients, is thought to have different functions when derived from host versus cancer cells. To assess the effect of host-derived OPN on growth of cancers of epithelial origin, we established a line of cutaneous squamous cell carcinoma (SCC) cells, named ONSC, which lacks the OPN gene and develops SCC in syngeneic wild-type (WT) and OPN-null mice. At 8 and/or 10 week after subcutaneous injection of ONSC cells in mice, however, there was a lower tumor incidence in WT mice, suggesting that host-derived OPN is associated with suppression of early growth of extrinsic cancer cells. Histological, immunohistochemical, biochemical and hematological analyses were performed on the tumor microenvironment and blood from tumor-bearing mice during the first week after implantation. Host-derived OPN suppression of extrinsic ONSC cell progression is likely mediated through elicitation of an early innate inflammatory response, through its function as a chemoattractant and/or by enhancing survival of inflammatory cells. Further, consistent with a previous report, the serum levels of host-derived OPN, which are elevated during the early phase of tumor growth in mice implanted with ONSC, appear to reflect an anti tumor progression effect. PMID- 21826649 TI - Beneficial effects of fenofibrate in retinal pigment epithelium by the modulation of stress and survival signaling under diabetic conditions. AB - In this study, we found an imbalance between stress-mediated and survival signaling and elevated apoptotic markers in retinal pigment epithelium (RPE) from diabetic patients. Since fenofibric acid (FA) treatment reduces the progression of diabetic retinopathy (DR), we investigated the effect of hyperglycemia and hypoxia, two components of the diabetic milieu, on stress, apoptosis, and survival pathways in ARPE-19 cells (immortalized human RPE cell line) and whether FA is able to prevent the deleterious effects induced by these conditions. ARPE 19 cells cultured in high-glucose (HG) medium or under hypoxia (1% oxygen) induced phosphorylation of the stress-activated kinases JNK and p38 MAPK. This effect was increased by the combination of both conditions. Likewise, hyperglycemia and hypoxia triggered the phosphorylation of the endoplasmic reticulum (ER) stress markers PERK and eIF2alpha and the induction of the pro apoptotic transcription factor CHOP. Under these experimental conditions, reactive oxygen species (ROS) were elevated and the integrity of tight junctions was disrupted. Conversely, ARPE-19 cells treated with FA were protected against these deleterious effects induced by hyperglycemia and hypoxia. FA increased insulin-like growth factor I receptor (IGF-IR)-mediated survival signaling in cells cultured under hyperglycemia and hypoxia, thereby suppressing caspase-3 activation and down-regulation of BclxL. Moreover, FA increased LC3-II, an autophagy marker. In conclusion, our results demonstrated that FA elicits a dual protective effect in RPE by down-regulation of stress-mediated signaling and induction of autophagy and survival pathways. These molecular mechanisms could be involved in the beneficial effects of fenofibrate reported in clinical trials. PMID- 21826650 TI - Proliferation of rat small hepatocytes requires follistatin expression. AB - Small hepatocytes (SHs) are a subpopulation of hepatocytes that have high growth potential in culture and can differentiate into mature hepatocytes (MHs). The activin (Act)/follistatin (Fst) system critically contributes to homeostasis of cell growth in the normal liver. ActA and ActB consist of two disulfide-linked Inhibin (Inh)beta subunits, InhbetaA and InhbetaB, respectively. Fst binds to Act and blocks its bioactivity. In the present study we carried out the experiments to clarify how Fst regulates the proliferation of SHs. The gene expression was analyzed using DNA microarray analysis, reverse transcription-polymerase chain reaction (RT-PCR) and real-time PCR, and protein expression was examined by western blots, immunocytochemistry, and enzyme-linked immunosorbent assay. RT-PCR showed that Fst expression was high in SHs and low in MHs. Although the ActA expression was opposite to that of Fst, ActB expression was high in SHs and low in MHs and increased with time in culture. Fst protein was detected in the cytoplasm of SHs and secreted into the culture medium. ActB protein was also secreted into the medium. Although the exogenous administration of ActA and ActB apparently suppressed the proliferation of SHs, apoptosis of SHs was not induced by treatment with ActA or ActB. On the other hand, Fst treatment did not affect the colony formation of SHs but prevented the inhibitory effect of ActA. Neutralization by the anti-Fst antibody resulted in the suppression of DNA synthesis in SHs, and small hairpin RNA against Fst suppressed the expansion of SH colonies. In conclusion, Fst expression is necessary for the proliferation of SHs. PMID- 21826651 TI - Growth inhibition of human hepatocellular carcinoma cells by overexpression of G protein-coupled receptor kinase 2. AB - Hepatocellular carcinoma (HCC) is one of the deadliest forms of human liver cancer and does not respond well to conventional therapies. Novel effective treatments are urgently in need. G-protein-coupled kinase 2 (GRK2) is unique serine/threonine kinase that involves in many signaling pathways and regulates various essential cellular processes. Altered levels of GRK2 have been linked with several human diseases including cancer. In this study, we investigated a novel approach for HCC treatment by inducing overexpression of GRK2 in human HCC cells. We found that overexpression of GRK2 through recombinant adenovirus transduction inhibits the growth of human HCC cells. BrdU incorporation assay showed that the growth inhibition caused by elevated GRK2 level was due to reduced cell proliferation but not apoptosis. To examine the anti-proliferative function of increased GRK2 level, we performed cell cycle analysis using propidium iodide staining. We found that the proliferation suppression was associated with G2/M phase cell cycle arrest by the wild-type GRK2 but not its kinase-dead K220R mutant. Furthermore, increased levels of wild-type GRK2 induced upregulation of phosphor-Ser(15) p53 and cyclin B1 in a dose-dependent manner. Our data indicate that the anti-proliferative function of elevated GRK2 is associated with delayed cell cycle progression and is GRK2 kinase activity dependent. Enforced expression of GRK2 in human HCC by molecular delivery may offer a potential therapeutic approach for the treatment of human liver cancer. PMID- 21826652 TI - PTHrP(1-34)-mediated repression of the PHEX gene in osteoblastic cells involves the transcriptional repressor E4BP4. AB - PHosphate-regulating gene with homology to Endopeptidase on the X chromosome (PHEX) has been identified as the gene mutated in X-linked hypophosphatemia (XLH) syndrome, the most prevalent form of rickets in humans. The predominant expression of PHEX in bones and teeth, and the defective mineralization of these tissues in XLH patients indicate that PHEX is an important regulator of mineralization. Parathyroid hormone (PTH) and PTH-related protein (PTHrP) are known to regulate the expression of numerous genes in osteoblastic cells through activation of the protein kinase A pathway, including repression of PHEX. PTH also activates the transcriptional repressor E4BP4 through the same pathway, suggesting that PTH or PTHrP-mediated repression of PHEX expression could involve E4BP4. To evaluate this possibility, we treated UMR-106 osteoblastic cells with PTHrP(1-34), and used RT-PCR and immunoblotting to analyze PHEX and E4BP4 expression. E4BP4 mRNA and protein levels were rapidly increased in cells treated with PTHrP(1-34), with a concomitant decrease in PHEX expression. This downregulation of PHEX could be reproduced by overexpression of E4BP4. Moreover, PTHrP(1-34)-mediated PHEX repression was blocked when cells were transfected with a siRNA targeting E4BP4 mRNA. Finally, DNA pull-down and luciferase assays showed that two E4BP4 response elements located in PHEX promoter were functional. These results underline the important role of E4BP4 in osteoblastic cells and further define the repression mechanism of PHEX gene by PTHrP(1-34). PMID- 21826653 TI - 3,5,3'triiodo-L-thyronine induces SREBP-1 expression by non-genomic actions in human HEP G2 cells. AB - Liver is an important target for thyroid hormone actions. T(3) exerts its effects by two mechanisms: (i) Genomic actions consisting of T(3) link to nuclear receptors that bind responsive elements in the promoter of target genes, (ii) non genomic actions including integrin alphavb3 receptor-mediated MAPK/ERK and PI3K/Akt/mTOR-C1 activation. SREBP-1a, SREBP-1c, and SREBP-2 are transcription factors involved in the regulation of lipogenic genes. We show in Hep G2 cells that T(3) determined a dose- and time-dependent increase in the level of the precursor form of SREBP-1 without affecting SREBP-1 mRNA abundance. T(3) also induced phosphorylation of ERK1/2, Akt and of mTOR-C1 target S6K-P70, and the cytosol-to-membrane translocation of PKC-alpha. Modulation of SREBP-1 protein level by T(3) was dependent on MAPK/ERK, PI3K/Akt/mTOR-C1 pathway activation since the MEK inhibitor PD98059 or the PI3K inhibitor LY294002 abolished the stimulatory effect of T(3) . Conversely, the effect of T(3) on SREBP-1 level was enhanced by using rapamycin, mTOR-C1 inhibitor. These data suggest a negative control of mTOR-C1 target S6K-P70 on PI3K/Akt pathway. The effect of T(3) on SREBP-1 content increased also by using PKC inhibitors. These inhibitors increased the action of T(3) on Akt phosphorylation suggesting that conventional PKCs may work as negative regulators of the T(3) -dependent SREBP-1 increase. T(3) effects were partially abrogated by tetrac, an inhibitor of the T(3) alphavbeta3 receptor interaction and partially evoked by T(3) analog T(3) agarose. These findings support a model in which T(3) activates intracellular signaling pathways which may be involved in the increment of SREBP-1 level through an IRES-mediated translation mechanism. PMID- 21826654 TI - Shear stress regulates expression of death-associated protein kinase in suppressing TNFalpha-induced endothelial apoptosis. AB - Death associated protein kinase (DAPK) is a positive regulator in tumor necrosis factor alpha (TNFalpha)-induced apoptotic pathway, and DAPK expression is lost in cancer cells. In the vasculature, misdirected apoptosis in endothelial cells leads to pathological conditions such as inflammation and physiological shear stress is protective against apoptosis. Using bovine aortic endothelial cells, we found that DAPK expression increased, while the auto-inhibitory phosphorylation of serine 308 decreased with shear stress at 12 dynes/cm(2) for 6 h. Quantitative RT-PCR revealed a corresponding increase in DAPK mRNA [P < 0.01]. We found that after 18-h TNFalpha induction, shearing cells for another 6 h significantly reduced apoptosis based on TUNEL staining [P < 0.05], although cell necrosis was not affected. Under the same conditions, we observed significantly decreased overall DAPK, as well as phospho-serine 308 DAPK [P < 0.05] compared to TNFalpha treatment alone. Caspase-3 and -7 activities downstream of DAPK were also attenuated. Shearing cells alone resulted in enhanced apoptosis, likely due to increased DAPK activity. Our findings were further supported by DAPK siRNA, which yielded contrary results. We present conclusive evidence for the first time that shear stress of up to 6 h up-regulates DAPK expression and activation. However, in the presence of apoptotic stimuli such as TNFalpha, shear stress caused decrease in DAPK activity. In fact, long-term shear stress of 24 h significantly reduced overall DAPK expression. Our findings strongly support a novel role for DAPK in mediating effects of shear stress in suppressing cytokine-activated apoptosis. PMID- 21826655 TI - Diverse effects of type II collagen on osteogenic and adipogenic differentiation of mesenchymal stem cells. AB - Type II collagen is known to modulate chondrogenesis of mesenchymal stem cells (MSCs). In this study, MSCs from human bone marrow aspirates were used to study the modulating effects of type II collagen on MSC differentiation during the early stages of osteogenesis and adipogenesis. With osteogenic induction, MSCs cultured on the type II collagen-coated surface showed an enhanced calcium deposition level with increasing mRNA expressions of RUNX2, osteocalcin, and alkaline phosphatase. A synthetic integrin binding peptide, which specifically interacts with the I-domain of alpha(1)beta(1)/alpha(2)beta(1) integrins significantly blocks the mineralization-enhancing effect of type II collagen. MSCs attached on the type II collagen-coated plates exhibited expanded cell morphology with increasing spreading area, and the pretreatment of cells with integrin alpha(1)beta(1) or alpha(2)beta(1)-blocking antibody reduced the effect. The phosphorylation levels of FAK, ERK, and JNK significantly increased in the MSCs that attached on the type II collagen-coated plates. On the contrary, the mineralization-enhancing effect of type II collagen was diminished by JNK and MEK inhibitors. Furthermore, type II collagen blocked the adipogenic differentiation of MSCs, and this effect is rescued by JNK and MEK inhibitors. In conclusion, type II collagen facilitates osteogenesis and suppresses adipogenesis during early stage MSC differentiation. Such effects are integrin binding-mediated and conducted through FAK-JNK and/or FAK-ERK signaling cascades. These results inspire a novel strategy encompassing type II collagen in bone tissue engineering. PMID- 21826656 TI - STAT5 isoforms regulate colorectal cancer cell apoptosis via reduction of mitochondrial membrane potential and generation of reactive oxygen species. AB - Although the two isoforms of signal transducer and activator of transcription 5 (STAT5) protein, STAT5a and STAT5b, have 94% sequence identity, they are encoded by different genes. Previous studies have been unable to define clearly the roles of the STAT5 genes in colorectal cancer (CRC). To investigate the role of STAT5 isoforms in CRC oncogenesis, immunohistochemical staining was performed. Colorectal adenocarcinomas showed higher expression of STAT5a/5b than normal colonic mucosa (P < 0.05), and STAT5b expression was significantly higher than that of STAT5a in colorectal adenocarcinoma tissue (P < 0.05). Furthermore, STAT5b expression was significantly associated with TNM stage. To delineate the roles of STAT5a/5b in CRC carcinogenesis, we studied CRC cells depleted of each isoform by treating the cells with small interfering RNA. Both STAT5a and STAT5b were found to be involved in cell growth, cell cycle progression, and apoptosis of CRC cells, and exerted their effects via the regulation of downstream targets of the STAT genes. However, STAT5b influenced CRC cell apoptosis more than STAT5a (P < 0.05), reducing mitochondrial membrane potential and generating reactive oxygen species. In conclusion, both isoforms of STAT5 are involved in the growth and cell cycle progression of CRC cells, STAT5b could play a more important role than STAT5a in the clinicopathological characteristics of CRC and CRC cell apoptosis. PMID- 21826657 TI - CREB coactivator CRTC2/TORC2 and its regulator calcineurin crucially mediate follicle-stimulating hormone and transforming growth factor beta1 upregulation of steroidogenesis. AB - In vitro and in vivo studies implicate that follicle-stimulating hormone (FSH) and transforming growth factor beta1 (TGFbeta1) play crucial physiological roles in regulating ovarian granulosa cell function essential to fertility control in females. FSH induces cAMP and calcium signaling, thereby activating transcription factor CREB to upregulate steroidogenic gene expression, and TGFbeta1 greatly enhances FSH-stimulated steroidogenesis. A CREB coactivator CRTC2/TORC2 was identified to function as a cAMP and calcium-sensitive coincidence sensor. This led us to explore the role of CRTC2 and its regulator calcineurin in FSH and TGFbeta1-stimulated steroidogenesis. Primary culture of granulosa cells from gonadotropin-primed immature rats was used. Immunoblotting analysis shows that FSH rapidly and transiently induced dephosphorylation/activation of CRTC2, and FSH + TGFbeta1 additionally induced late-phase CRTC2 dephosphorylation. Immunofluorescence analysis further confirms FSH +/- TGFbeta1 promoted CRTC2 nuclear translocation. Using selective inhibitors, we demonstrate that FSH activated CRTC2 in a PKA- and calcineurin-dependent manner, and TGFbeta1 acting through its type I receptor (TGFbetaRI)-modulated FSH action in a calcineurin mediated and PKA-independent fashion. Next, we investigated the involvement of calcineurin and CRTC2 in FSH and TGFbeta1-stimulated steroidogenesis. Calcineurin and TGFbetaRI inhibitor dramatically reduced the FSH +/- TGFbeta1-increased progesterone synthesis and protein levels of StAR, P450scc, and 3beta-HSD enzyme. Furthermore, chromatin-immunoprecipitation and immunoprecipitation analyses demonstrate that FSH +/- TGFbeta1 differentially increased CRTC2, CREB, and CBP binding to these steroidogenic genes, and CREB nuclear association with CRTC2 and CBP. In all, this study reveals for the first time that CRTC2 and calcineurin are critical signaling mediators in FSH and TGFbeta1-stimulated steroidogenesis in ovarian granulosa cells. PMID- 21826658 TI - Sequential IL-23 and IL-17 and increased Mmp8 and Mmp14 expression characterize the progression of an experimental model of periodontal disease in type 1 diabetes. AB - Molecular mechanisms responsible for periodontal disease (PD) and its worsening in type 1 Diabetes Mellitus (DM1) remain unknown. Cytokine profile and expression levels of collagenases, Mmp14, and tissue inhibitors were determined, as were the numbers of neutrophils and macrophages in combined streptozotocin-induced DM1 and ligature-induced PD models. Increased IL-23 (80-fold) and Mmp8 expression (25 fold) was found in DM1. Ligature resulted in an IL-1beta/IL-6 profile, increased expression of Mmp8, Mmp13, and Mmp14 (but not Mmp1), and transient expression of Timp1 and Reck in non-diabetics. PD in DM1 involved IL-1beta (but not IL-6) and IL-23/IL-17, reduced IL-6 and IL-10, sustained Mmp8 and Mmp14, increased Mmp13 and reduced Reck expression in association with 20-fold higher counts of neutrophils and macrophages. IL-23 and Mmp8 expression are hallmarks of DM1. In association with the IL-1/IL-6 (Th1) response in PD, one found a secondary IL-17 (Th17) pathway in non-diabetic rats. Low IL-6/TNF-alpha suggest that the Th1 response was compromised in DM1, while IL-17 indicates a prevalence of the Th17 pathway, resulting in high neutrophil recruitment. Mmp8, Mmp13, and Mmp14 expression seems important in the tissue destruction during PD in DM1. PD associated IL-1/IL-6 (Th1), IL-10, and Reck expression are associated with the acute-to-chronic inflammation transition, which is lost in DM1. In conclusion, IL 23/IL-17 are associated with the PD progression in DM1. PMID- 21826659 TI - Neuropeptide F immunoreactive clock neurons modify evening locomotor activity and free-running period in Drosophila melanogaster. AB - Different subsets of Drosophila melanogaster's clock neurons are characterized by their specific functions in daily locomotor rhythms and the differences in their neurotransmitter composition. We investigated the function of the neuropeptide F (NPF) immunoreactive clock neurons in the rhythmic locomotor behavior of adult flies. We newly identified the fifth s-LN(v) and a subset of the l-LN(v)s as NPF positive in addition to the three LN(d)s that have been described previously. We then selectively ablated different subsets of NPF-expressing neurons using npfGal4-targeted expression of the cell death gene head involution defective (hid) in combination with cryGal80 and pdfGal80. By analyzing daily locomotor rhythms in these flies, we show that the NPF-positive clock neurons--especially the fifth s-LN(v) and the LN(d)s--are involved in both the control of the free running period in constant darkness (DD) and the phasing and amplitude of the evening activity in light-dark (LD) cycles. Furthermore, we show that the simultaneous ablation of NPF and pigment dispersing factor (PDF)-immunoreactive neurons has additive effects in LD, resulting in an evening peak phase that is even more advanced in comparison to PDF-ablated flies. We also found that this more advanced evening peak is additionally reduced in amplitude. To putatively assign the observed phenotypes to the action of NPF, we knocked it down in conjunction with PDF using RNA-interference (RNAi) and further suggest a possible role for NPF in the control of the flies' evening activity. PMID- 21826660 TI - Toward a single-cell-based analysis of neuropeptide expression in Periplaneta americana antennal lobe neurons. AB - A multitude of potential neurotransmitters and neuromodulators, including peptides, have been detected in the antennal lobe (AL), the first synaptic relay of the central olfactory pathway in the insect brain. However, the functional role of neuropeptides in this system has yet to be revealed. An important prerequisite to understanding the role of neuropeptides is to match the functionally different cell types in the AL with their peptide profiles by using electrophysiological recordings combined with immunocytochemical studies and/or single-cell mass spectrometry. The olfactory system of Periplaneta americana is particularly well suited to accomplish this goal because several physiologically distinct neuron types can be unequivocally identified. With the aim to analyze the neuropeptide inventory of the P. americana AL, this study is an essential step in this direction. First, we systematically analyzed different parts of the AL by matrix-assisted laser desorption/ionization time of flight (MALDI-TOF) mass spectrometry to obtain the complete set of neuropeptides present. Altogether, 56 ion signals could be assigned to products of 10 neuropeptide genes (allatostatins A, B, C, SIFamide, allatotropin, FMRFamide-related peptides [myosuppressin, short neuropeptides F, extended FMRFamides], crustacean cardioactive peptide, tachykinin-related peptides). In a second step, a combination of immunocytochemistry and mass spectrometric profiling of defined AL compartments was used to reveal the spatial distribution of neuropeptide-containing cells. Finally, we demonstrated the feasibility of MALDI-TOF mass spectrometric profiling of single AL neurons, which is an important precondition for combining electrophysiology with peptide profiling at the single-cell level. PMID- 21826662 TI - ON ganglion cells are intrinsically photosensitive in the tiger salamander retina. AB - Intrinsically photosensitive retinal ganglion cells (ipRGCs) have been well characterized in mammalian systems, both morphologically and electrophysiologically. They show slow, sustained responses to bright light in the absence of photoreceptor-based input, mediated by the photopigment melanopsin. Only one mammalian melanopsin gene is expressed in a small fraction of the retinal ganglion cell population, but there are two genes for melanopsin among nonmammalian vertebrates that are widely expressed in a variety of retinal and extraretinal cell types, along with other photosensitive pigments. The current study provides an electrophysiological study of ipRGCs in the larval tiger salamander (Ambystoma tigrinum), a nonmammalian vertebrate with a well characterized retina. The results show that the ipRGC population is equivalent to the ON ganglion cell population in the tiger salamander retina. This sheds light on the evolutionary trajectory and functional significance of intrinsic photosensitivity through the vertebrate lineage and also affects our understanding of ON cell activity and development. We have characterized the nature of the intrinsic responses of the ON cell population, compared intrinsic and synaptically based receptive fields, and quantified the spectrum of the intrinsic activity. A wider action spectrum of intrinsic photosensitivity was obtained than would be expected for a single opsin photopigment, suggesting the expression of multiple photopigments in the salamander ipRGC. J. Comp. Neurol., 2012. (c) 2011 Wiley Periodials, Inc. PMID- 21826661 TI - Structural organization of the presynaptic density at identified synapses in the locust central nervous system. AB - In a synaptic active zone, vesicles aggregate around a densely staining structure called the presynaptic density. We focus on its three-dimensional architecture and a major molecular component in the locust. We used electron tomography to study the presynaptic density in synapses made in the brain by identified second order neuron of the ocelli. Here, vesicles close to the active zone are organized in two rows on either side of the presynaptic density, a level of organization not previously reported in insect central synapses. The row of vesicles that is closest to the density's base includes vesicles docked with the presynaptic membrane and thus presumably ready for release, whereas the outer row of vesicles does not include any that are docked. We show that a locust ortholog of the Drosophila protein Bruchpilot is localized to the presynaptic density, both in the ocellar pathway and compound eye visual neurons. An antibody recognizing the C-terminus of the Bruchpilot ortholog selectively labels filamentous extensions of the presynaptic density that reach out toward vesicles. Previous studies on Bruchpilot have focused on its role in neuromuscular junctions in Drosophila, and our study shows it is also a major functional component of presynaptic densities in the central nervous system of an evolutionarily distant insect. Our study thus reveals Bruchpilot executes similar functions in synapses that can sustain transmission of small graded potentials as well as those relaying large, spike evoked signals. PMID- 21826663 TI - Parallel feedback pathways in visual cortex of cats revealed through a modified rabies virus. AB - The visual cortex of cats is highly evolved. Analogously to the brains of primates, large numbers of visual areas are arranged hierarchically and can be parsed into separate dorsal and ventral streams for object recognition and visuospatial representation. Within early primate visual areas, V1 and V2, and to a lesser extent V3, the two streams are relatively segregated and relayed in parallel to higher order cortex, although there is some evidence suggesting an alignment of V2 and V3 to one stream over the other. For cats, there is no evidence of anatomical segregation in areas 18 and 19, the analogs to V2 and V3. However, previous work was only qualitative in nature. Here we re-examined the feedback connectivity patterns of areas 18/19 in quantitative detail. To accomplish this, we used a genetically modified rabies virus that acts as a retrograde tracer and fills neurons with fluorescent protein. After injections into area 19, many more neurons were labeled in putative ventral stream area 21a than in putative dorsal stream region posterolateral suprasylvian complex of areas (PLS), and the dendrites of neurons in 21a were significantly more complex. Conversely, area 18 injections labeled more neurons in PLS, and these were more complex than neurons in 21a. We infer from our results that area 19 in cat is more aligned to the ventral stream and area 18 to the dorsal stream. Based on the success of our approach, we suggest that this method could be applied to resolve similar issues related to primate V3. PMID- 21826664 TI - Variability and asymmetry of the sulcal contours defining Broca's area homologue in the chimpanzee brain. AB - There has been recent motivation to search for neuroanatomical asymmetries in nonhuman primates in order to provide comparative information on how the human brain is structurally organized to support specific cognitive capabilities, such as language functions. We took the opportunity to study Broca's area homologue in a novel sample of 80 preserved postmortem chimpanzee (Pan troglodytes) cerebral hemispheres. Consistent with the only prior study documenting the morphology of Broca's area homologue in the chimpanzee (Sherwood et al. [2003] Anat Rec 271:276 285), we report great interindividual variation in the structure and connections of the sulci investigated, most notably a left-sided bias in the bifurcation of the inferior precentral sulcus, an anatomical feature that occurs much more frequently in chimpanzees relative to humans. Consistent with our recent neuroimaging report (Keller et al. [2009b] J Neurosci 29:14607-14616), no population-based interhemispheric asymmetries of sulcal length existed that could be considered markers of the size of Broca's area homologue. With strict anatomical guidelines, we report that the diagonal sulcus was present in 25% left and 20% right chimpanzee hemispheres studied, which is substantially less that the general prevalence in humans. Through the presentation of schematic drawings, photographs, morphological recordings and sulcal length metrics, our data illustrate the interindividual variability of Broca's area homologue in the chimpanzee and support the notion of no macroscopic asymmetry of this important homologous language brain region in one of the closest evolutionary ancestor to modern humans. PMID- 21826665 TI - Neutrophils promote motility of cancer cells via a hyaluronan-mediated TLR4/PI3K activation loop. AB - Inflammation is a component of tumour progression mechanisms. Neutrophils are a common inflammatory infiltrate in many tumours, but their regulation and functions in neoplasia are not understood. We recently demonstrated that pro inflammatory IL-17-producing cells recruited blood neutrophils into the peritumoural stroma of hepatocellular carcinoma by epithelium-derived CXC chemokines. Here we show that a substantial population of neutrophils accumulates in the peritumoural stroma of hepatocellular, cervical, colorectal, and gastric carcinomas, and that this correlates with metastases in hepatocellular and gastric carcinomas. Exposure of neutrophils to culture supernatants from several types of solid tumour cells (TSN) resulted in sustained survival and pro tumourigenic effects of cells. Kinetic experiments reveal that, shortly after exposure to TSN, neutrophils began to provoke activation and then produced significant inflammatory cytokines and expressed more anti-apoptotic Mcl-1 but less pro-apoptotic Bax. These long-lived neutrophils effectively enhanced the cancer cell motility via a contact-dependent mechanism; this effect, together with early activation and subsequent longevity of TSN-exposed neutrophils, could be reversed by blocking the activation of PI3K/Akt signalling in neutrophils. Moreover, we found that hyaluronan (HA) fragments constitute a common factor produced by various tumours that mimics the effect of TSN to induce long-lived neutrophils and subsequent malignant cell migration. The effects of TSN were inhibited by function blocking interactions between HA and its receptor TLR4 on neutrophils, suggesting that this is a key signalling pathway involved. These results indicate that HA derived from malignant cells educates neutrophils to adopt an activated phenotype, and in that way stimulates the metastasis of malignant cells, which represents a positive regulatory loop between tumours and their stroma during neoplastic progression. PMID- 21826666 TI - Increased midkine expression correlates with desmoid tumour recurrence: a potential biomarker and therapeutic target. AB - Desmoid tumours (DTs) are soft tissue monoclonal neoplasms exhibiting a unique phenotype, consisting of aggressive local invasiveness without metastatic capacity. While DTs can infrequently occur as part of familial adenomatosis polyposis, most cases arise sporadically. Sporadic DTs harbour a high prevalence of CTNNB1 mutations and hence increased beta-catenin signalling. However, beta catenin downstream transcriptional targets and other molecular deregulations operative in DT inception and progression are currently not well defined, contributing to the lack of sensitive molecular prognosticators and efficacious targeted therapeutic strategies. We compared the gene expression profiles of 14 sporadic DTs to those of five corresponding normal tissues and six solitary fibrous tumour specimens. A DT expression signature consisting of 636 up- and 119 down-regulated genes highly enriched for extracellular matrix, cell adhesion and wound healing-related proteins was generated. Furthermore, 98 (15%) of the over expressed genes were demonstrated to contain a TCF/LEF consensus binding site in their promoters, possibly heralding direct beta-catenin downstream targets relevant to DT. The protein products of three of the up-regulated DT genes: ADAM12, MMP2 and midkine, were found to be commonly expressed in a large cohort of human DT samples assembled on a tissue microarray. Interestingly, enhanced midkine expression significantly correlated with a higher propensity and decreased time for primary DT recurrence (log-rank p = 0.0025). Finally, midkine was found to enhance the migration and invasion of primary DT cell cultures. Taken together, these studies provide insights into potential DT molecular aberrations and novel beta-catenin transcriptional targets. Further studies to confirm the utility of midkine as a clinical DT molecular prognosticator and a potential therapeutic target are therefore warranted. Raw gene array data can be found at: http://smd.stanford.edu/ PMID- 21826667 TI - CTGF/CCN-2 over-expression can directly induce features of skeletal muscle dystrophy. AB - Muscular dystrophies are diseases characterized by muscle weakness together with cycles of degeneration and regeneration of muscle fibres, resulting in a progressive decrease of muscle mass, diminished muscle force generation and an increase in fibrosis. Fibrotic disorders are the endpoint of many chronic diseases in different tissues, where accumulation of the extracellular matrix (ECM) occurs. Connective tissue growth factor CTGF/CCN2, which is over-expressed in muscular dystrophies, plays a major role in many progressive scarring conditions. To test the hypothesis that CTGF might not only contribute conversion of already damaged muscle into scar tissue, but that it could by itself also directly contribute to skeletal muscle deterioration, we evaluated the effect of CTGF over-expression in tibialis anterior muscle of wild-type mice, using an adenovirus containing the CTGF mouse sequence (Ad-mCTGF). CTGF over-expression induced extensive skeletal muscle damage, which was followed by a massive regeneration of the damaged muscle, as evidenced by increased embryonic myosin and fibres with centrally located nuclei. It also induced strong fibrosis with increased levels of fibronectin, collagen, decorin and alpha-smooth muscle actin (alpha-SMA). Moreover, CTGF over-expression caused a decrease of the specific isometric contractile force. Strikingly, when CTGF over-expression stopped, the entire phenotype proved to be reversible, in parallel with normalization of CTGF levels. Thus, CTGF not merely acts downstream of muscle injury but also contributes directly to the deterioration of skeletal muscle phenotype and function. Moreover, normalization of expression levels led to spontaneous reversal of the CTGF-induced phenotype and to full recovery of muscle structure. These observations underscore the importance of CTGF in the pathophysiology of muscular dystrophies and suggest that targeting CTGF might have significant potential in the development of novel therapies for Duchenne muscular dystrophy and related diseases. PMID- 21826668 TI - Reduced expression of MUTYH with suppressive activity against mutations caused by 8-hydroxyguanine is a novel predictor of a poor prognosis in human gastric cancer. AB - The MUTYH gene encodes a DNA glycosylase that can initiate the excision repair of adenine mispaired with 8-hydroxyguanine (8OHG) and is responsible for a susceptibility to multiple colorectal adenomas and carcinomas. To determine whether the MUTYH gene is involved in gastric carcinogenesis, we first examined the expression level of MUTYH in gastric cancer. The reduced expression of MUTYH mRNA transcript was detected in both gastric cancer cell lines and primary gastric cancers using qRT-PCR analysis. Immunohistochemical analysis also showed a significant reduction in MUTYH protein expression in gastric cancer, compared with non-cancerous gastric epithelium (immunohistochemical score, 175.5 +/- 43.0 versus 281.5 +/- 24.8; p < 0.0001). Among the gastric cancers, the MUTYH expression level was significantly associated with the histopathology (p < 0.0001) and the pT stage (p < 0.001). The outcome of patients with gastric cancer exhibiting low MUTYH expression was significantly worse than the outcome of patients with gastric cancer exhibiting high MUTYH expression (p = 0.0007, log rank test) and a multivariate analysis revealed that reduced MUTYH expression was an independent predictor of a poor survival outcome among the gastric cancer patients (hazard ratio, 1.865; 95% confidence interval, 1.028-3.529; p = 0.0401). We next compared the functional effects of MUTYH on gastric cancer cells, based on their MUTYH expression levels. MUTYH-over-expressing stable clones of the gastric cancer cell line AGS showed: (a) higher DNA cleavage activity towards adenine:8OHG mispair-containing substrates; (b) higher suppressive activity against mutations caused by 8OHG in a supF forward mutation assay; and (c) higher suppressive activity for cellular proliferation than empty vector-transfected AGS clones. These results suggested that MUTYH is a suppressor of mutations caused by 8OHG in gastric cells and that its reduced expression is associated with a poor prognosis in gastric cancer. PMID- 21826670 TI - How dense, how intense? Role of tumour-infiltrating lymphocytes across colorectal cancer stages. Re: Nosho et al. Tumour-infiltrating T-cell subsets, molecular changes in colorectal cancer, and prognosis: cohort study and literature review. J Pathol 2010; 222: 350-366. PMID- 21826669 TI - Identification of Endothelin-1 and NR4A2 as CD133-regulated genes in colon cancer cells. AB - Several in vitro assays have been proposed to identify cancer stem cells (CSCs), including immunophenotyping, sphere assay and side population (SP) assay. CD133 antigen has been proposed as a CSC marker in colon cancer (CC). However, no functional data are available to date and conflicting results have been reported regarding its role as true CSC marker. Here we set out to identify a molecular signature associated with potential CSC. CD133(+) cells isolated from the CaCo-2 CC cell line were analysed by microarray molecular profiling compared to CD133(-) counterparts. Various differentially expressed genes were identified and the most relevant transcripts found to be over-expressed in CD133(+) cells were evaluated by quantitative RT-PCR in the CD133(+) fractions isolated from several CC cell lines. In the attempt to find a correlation between putative CSCs, isolated by means of CD133 immunophenotyping and the SP approach, we demonstrated a significant enrichment of CD133(+) cells within the SP fraction of CC cells, and comparison of the gene expression profiles revealed that Endothelin-1 (END-1) and nuclear receptor subfamily 4, group A, member 2 (NR4A2) transcripts are highly expressed in both CD133(+) and SP fractions of CC cells. Moreover, depletion of CD133 by siRNA induced a significant attenuation of END-1 and NR4A2 expression levels in CaCo-2 cells, while expression of all three molecules decreased during sodium butyrate-induced differentiation. In conclusion, we have identified a molecular signature associated with potential CSCs and showed for the first time the existence of a functional relationship between CD133, END-1 and NR4A2 expression in colon cancer cells. PMID- 21826671 TI - Local therapy and survival in breast cancer with distant metastases. AB - This review article presents an evaluation of the effects of local therapy on survival of breast cancer patients with distant metastases along with a discussion of their relevance. Primary and recurrent breast cancers with distant metastases are systemic diseases with poor prognosis. However, several retrospective studies have demonstrated that surgical removal of the primary breast tumor has a favorable impact on the prognosis of stage IV breast cancer patients. Similarly, it has been reported that surgical resection of metastatic lesions in the lung as well as the liver yields unexpectedly promising results. The interaction of local treatment and systemic therapy may be important, because surgery and radiotherapy are only local treatments. However, it remains uncertain whether these encouraging findings are due to the surgical procedure itself or preoperative patient selection. Only a randomized prospective study can definitively show whether local treatment can prevent death from stage IV disease or recurrent breast cancer with distant metastases. Until data from prospective studies are available, clinicians must weigh retrospective experiences and clinical judgment in deciding whether to offer surgery or radiotherapy to these patients. PMID- 21826672 TI - Surgical resection for bulky or recurrent axillary metastatic melanoma. AB - INTRODUCTION: Metastatic melanoma has few FDA approved treatments, and aggressive surgical resection has to be considered for management of bulky axillary metastases. We hypothesized that axillary resection in this setting is well tolerated and improves symptoms in the majority of patients. METHODS: We reviewed a prospectively collected database and identified 47 stage IIIC and IV patients with axillary nodal disease greater than 5 cm (68%), recurrent disease (36%), or disease adherent to axillary neurovascular structures (45%). Paresthesias, pain, and bleeding were present in 40% of patients, and were stable or improved after surgery in 75%. Most patients were asymptomatic prior to resection, and underwent resection for prevention of potential symptoms. RESULTS: Most patients underwent outpatient surgery. Postoperative complications included lymphedema (34%), range of motion limitation (23%), wound infection (17%), and neuropathic pain (17%). Among symptomatic patients, average time to progression was 3 months, compared to 9.5 months in asymptomatic patients (P = 0.08). Five-year survival was lower (16%) in symptomatic patients than in asymptomatic patients (35%, P = 0.001). DISCUSSION: Surgery for bulky axillary melanoma metastases is well tolerated, and should be considered in the management of Stage III or IV melanoma. Resection prior to symptoms may improve quality of life and is associated with longer survival. PMID- 21826673 TI - Allelic loss of susceptibility loci and the occurrence of BRAF and RAS mutations in patients with familial non-medullary thyroid cancer. AB - OBJECTIVES: Approximately 5% of non-medullary thyroid cancer (NMTC) diagnoses are made against a background of familial predisposition and, in such instances, the disease is termed familial non-medullary thyroid cancer (FNMTC). To date, neither genetic alterations causing FNMTC nor genes predisposing to the condition have been described. The objective of the present study was to evaluate loss of heterozygosity (LOH) at the four known susceptibility loci (fPTC/PRN, NMTC1, MNG1, and TCO1) and to compare the mutation rates of RAS/RAF genes in patients with FNMTC and sporadic NMTC. METHODS: Fourteen FNMTCs in patients from seven families were analyzed in terms of involvement of the four susceptibility loci, and 63 thyroid cancer tumors [FNMTC (29) and NMTC (34)] were evaluated for the occurrence of mutations in BRAF, and H-, N-, and K-RAS, using polymerase chain reaction, single-strand conformation polymorphism (PCR-SSCP) analysis, and direct sequencing. RESULTS: Only five (35.7%) tumors showed loss of LOH at the three susceptibility loci (NMTC1, MNG1, or TCO1). These allelic losses did not show a specific pattern. Four (13.8%) FNMTCs and one (2.9%) NMTC had H-RAS (codon 12) mutations. Further, mutation of BRAF V600E was observed in 12 (41.4%) FNMTCs and 29 (85.3%) NMTCs. CONCLUSION: Four known susceptibility loci are infrequently involved in FNMTC. Although further studies are needed, the present findings additionally suggest that somatic activation of oncogenes via BRAF and RAS mutation plays a role in FNMTC tumorigenesis. PMID- 21826674 TI - Multidisciplinary head and neck cancer clinic and adherence with speech pathology. AB - OBJECTIVES: To determine the effect of referral patterns on compliance with speech-language pathology (SLP) treatment of voice and swallowing difficulties in patients with head and neck cancer (HNCA). STUDY DESIGN: Retrospective cohort study. METHODS: Patients with newly diagnosed oropharyngeal HNCA referred for pretreatment SLP evaluation comprised the study population. Compliance was measured by participation in SLP therapy during and after head and neck treatment, as well as by the number of missed and completed visits. Outcomes were compared between patients who were initially evaluated through the multidisciplinary clinic and those evaluated outside of the multidisciplinary clinic format. RESULTS: The final study sample included 118 individuals with oropharyngeal tumors. All patients were treated with primary radiotherapy with or without chemotherapy. Patients evaluated initially through the multidisciplinary clinic had more SLP visits than those who did not participate in the multidisciplinary clinic (mean = 1.8 vs. 0.2, P <.0001). Participation in SLP treatment was significantly greater for patients >= 60 years of age (odds ratio [OR] = 2.4, P =.032) and for patients who participated in the multidisciplinary clinic (OR = 19.3, P <.0001). Tumor stage, sex, race, marital status, and insurance status were not associated with patient compliance. Multivariate analysis revealed that participation in a multidisciplinary clinic was the only significant variable associated with SLP treatment compliance (OR = 12.9, P <.0001), after controlling for all other variables. CONCLUSIONS: Patients evaluated in a multidisciplinary clinic are more likely to comply with SLP treatment recommendations. PMID- 21826675 TI - Congenital choristomas of the oral cavity in children. AB - OBJECTIVES/HYPOTHESIS: To review our institutional experience with oral cavity choristomas in children. STUDY DESIGN: Retrospective case series and medical record review. METHODS: Medical records including clinic notes, operative reports, radiologic studies, and pathology specimens were reviewed. All imaging studies and pathology material were reviewed by a head and neck radiologist and pediatric pathologist, respectively. RESULTS: Sixteen patients (10 males and 6 females) with congenital oral cavity choristomas were identified. Mean age at diagnosis was 1.8 months. Location of the lesions included tongue (n = 9) and floor of mouth (n = 7). Preoperative imaging included magnetic resonance imaging (n = 6), computed tomography (n = 5), plain radiography (n = 1), and no imaging (n = 4). Radiographically, the lesions were consistently lobular with well defined margins, but other imaging features often mimicked other masses that can arise in the tongue and floor of mouth. Symptoms were present in five of 16 patients and included difficulty feeding, swelling with upper respiratory infection, and partial airway obstruction. Complete surgical excision was performed in 15 of 16 patients; mean age at the time of surgery was 12.7 months. One patient underwent marsupialization. No complications were noted perioperatively. No recurrences of choristoma were seen. On histologic examination, the predominant component was cystic with cyst linings of respiratory epithelium (n = 5), gastric (foveolar) epithelium (n = 1), or both (n = 10). CONCLUSIONS: This study supports surgical excision as an effective intervention for children with oral cavity choristomas. Because the etiology of these cysts is unknown and diagnostic terminology is widely variable, we propose a more descriptive diagnosis based on the histology (i.e., lingual choristoma [or lingual developmental cyst] with respiratory epithelium or lingual choristoma [or lingual developmental cyst] with gastric epithelium). PMID- 21826676 TI - Importance of considering testosterone-cortisol interactions in predicting human aggression and dominance. AB - A novel "field" study recently published in Aggressive Behavior found that individual differences in baseline testosterone concentrations were positively correlated with endorsement of political aggression and that baseline cortisol concentrations were negatively correlated with self-reported aggression among Palestinian boys living in Gaza. Here, we discuss recent evidence indicating that testosterone and cortisol interact to predict competitive, aggressive, and dominant behaviors and urge researchers collecting both hormones to perform and report analyses that formally test for such interaction effects. PMID- 21826677 TI - In vitro identification of the human cytochrome p450 enzymes involved in the oxidative metabolism of loxapine. AB - In vitro studies were conducted to identify the hepatic cytochrome P450 (CYP) enzymes responsible for the oxidative metabolism of loxapine to 8 hydroxyloxapine, 7-hydroxyloxapine, N-desmethylloxapine (amoxapine) and loxapine N-oxide. These studies included use of cDNA-expressed enzymes, correlation analysis with 12 phenotyped human liver microsomal samples, and use of selective inhibitors of cytochrome P450s. The resultant data indicated that loxapine was mainly metabolized by human liver microsomes to (i) 8-hydroxyloxapine by CYP1A2, (ii) 7-hydroxyloxapine by CYP2D6, (iii) N-desmethyloxapine by CYP3A4 and (iv) loxapine N-oxide by CYP3A4. The involvement of flavin-containing monooxygenase (FMO) in the formation of loxapine N-oxide was also observed. PMID- 21826678 TI - Looking for differences in copy number between blood and brain in sporadic amyotrophic lateral sclerosis. AB - INTRODUCTION: Most analyses of blood DNA in sporadic neuromuscular disorders have been inconclusive. This may be because some genetic variants occur only in brain tissue. We therefore looked for copy number variants (CNVs) in both blood and brain in patients with sporadic amyotrophic lateral sclerosis (SALS). METHODS: Genome-wide CNVs were compared in blood and brain from 32 SALS patients and from 26 normal (control) brains, using Affymetrix 6.0 arrays. RESULTS: There were 410 CNVs present in brain but not blood (somatic CNVs) in 94% of the patients (median 8 CNVs per patient). Twenty-four of the somatic CNVs were rare, were not found in control brains, and overlapped with genes. CONCLUSIONS: Brain-specific CNVs may be common and appear to be present in a proportion of patients with SALS. The more detailed copy number analysis that is becoming available with massively parallel sequencing may uncover brain-specific CNVs that underlie some cases of SALS. PMID- 21826679 TI - Regional body composition and functional impairment in patients with myotonic dystrophy. AB - INTRODUCTION: In this study we determined regional body composition in myotonic dystrophy (DM1) and able-bodied controls and evaluated the relationship between fat and lean tissue mass and functional impairment in DM1 patients. METHODS: Dual energy X-ray absorptiometry (DEXA) was used to obtain regional measurements of fat-free mass index (FFMI) and fat mass index (FMI) in 48 DM1 and anthropometrically matched control pairs. RESULTS: DM1 patients had lower regional FFMI and higher FMI than controls (P < 0.01-0.001). In DM1 patients, total FMI increased significantly with increased muscular disability rating, decreased motor function measurement, and with both decreasing vital capacity and total lung capacity. Hypertriglyceridemia correlated with increasing FMI. CONCLUSIONS: Regional FFMI is decreased in DM1, whereas FMI is underestimated by body mass index and is negatively correlated with patients' functional capacity. DEXA may provide valuable supporting evidence in the management of DM1. PMID- 21826680 TI - Utility of ultrasound-guided surface electrode placement in lateral femoral cutaneous nerve conduction studies. AB - INTRODUCTION: Meralgia paresthetica is a common clinical complaint for which some patients ultimately undergo surgical treatment. The lateral femoral cutaneous nerve (LFCN) has been difficult to reliably test electrophysiologically, likely due to anatomic variability and lack of responses in asymptomatic obese subjects. METHODS: We compared a novel ultrasound-guided antidromic sensory nerve conduction study (NCS) with a technique described previously in a population of normal subjects, of whom 50% had body mass indices within the obese range (>27.5). RESULTS: Responses were obtained in at least 92% of subjects using either technique, and 92% of normal subjects had <60% interside variability using the ultrasound-guided technique. CONCLUSIONS: LFCN sensory nerve action potentials can be obtained in the vast majority of normal subjects, even in an obese population and can provide a useful sensory NCS for evaluation of mid lumbar radiculopathy, plexopathy, or meralgia paresthetica. PMID- 21826681 TI - Effect of botulinum neurotoxin treatment in the lateral spread monitoring of microvascular decompression for hemifacial spasm. AB - INTRODUCTION: Botulinum neurotoxin (BtNtx) treatment for hemifacial spasm (HFS) prior to microvascular decompression (MVD) is hypothesized to be a factor in the variability of intraoperative neurophysiological monitoring (IONM) during this procedure. METHODS: We analyzed 282 MVDs performed at the University of Pittsburgh Medical Center between January 1, 2000 and December 31, 2007. We retrospectively compared the lateral spread response (LSR) in the mentalis muscle when stimulus-triggered electromyography (EMG) was elicited from the facial nerve. Previous BtNtx treatment was the grouping factor. RESULTS: Baseline LSR amplitudes during MVD (prior BtNtx: mean = 341.47 MUV; no BtNtx: mean = 241.81 MUV) were significantly different between groups (df = 1,281; t = -2.463; P = 0.014). Comparisons of latency and current threshold at baseline, as well as HFS disappearance or LSR persistence after the procedure, did not achieve statistical significance. CONCLUSIONS: HFS patients treated with BtNtx prior to MVD demonstrated higher LSR baseline amplitudes during IONM. This could be related to muscle poly-reinnervation after recovery from repeated BtNtx use. PMID- 21826683 TI - Evaluation of spinal and bulbar muscular atrophy by the clustering index method. AB - INTRODUCTION: A reliable electrophysiological marker for clinical trials is increasingly needed in spinal and bulbar muscular atrophy (SBMA). We previously developed a quantitative analysis method for surface electromyography (SEMG), the clustering index (CI) method. Our purpose was to test the utility of the CI method for evaluating lower motor neuron involvement in SBMA patients. METHODS: Subjects included 29 SBMA patients and 27 healthy controls. The recording electrode was placed over the abductor digiti minimi (ADM) muscle with a proximal reference. The Z-score, based on the CI method, was compared with compound muscle action potential (CMAP) amplitude and motor unit number estimation (MUNE), with regard to sensitivity. RESULTS: The Z-scores of the CI method, CMAP amplitude, and MUNE were abnormal in 100%, 72%, and 93% of the patients, respectively. Interrater reliability of the CI method was sufficiently high. CONCLUSION: The CI method is promising as a non-invasive electrophysiological marker in SBMA. PMID- 21826684 TI - Reliability of thermal quantitative sensory testing of the hand in a cohort of young, healthy adults. AB - INTRODUCTION: The reliability of thermal quantitative sensory testing (QST) has yet to be fully established. In this study we investigated intra- and interrater reliability of thermal QST in a blinded manner. METHODS: Two investigators recorded thermal detection and pain thresholds on the hand of 22 volunteers, twice on two occasions. Results were analyzed using descriptive statistics, intraclass correlation coefficients (ICCs), and coefficients of variation (CVs). RESULTS: Mean intraindividual differences were small for all measures except cold pain thresholds. ICC values for intra- and interrater reliability were: cold detection, 0.27-0.55; warm detection, 0.33-0.69; and heat pain, 0.39-0.86. Cold pain yielded high ICC values (0.87-0.94), but also high CV (84.9-90.2%). CONCLUSIONS: In young, healthy adults, thermal detection and heat pain thresholds of the hand demonstrated good reliability for group comparisons and individual analyses. Cold pain threshold measures may be suitable for group comparisons, but a large variance in the data limits individual analyses. PMID- 21826682 TI - Association of common variants in the human eyes shut ortholog (EYS) with statin induced myopathy: evidence for additional functions of EYS. AB - INTRODUCTION: Of the nearly 38 million people in the USA who receive statin therapy, 0.1-0.5% experience severe or life-threatening myopathic side effects. METHODS: We performed a genome-wide association study (GWAS) in a group of patients with severe statin myopathy versus a statin-tolerant group to identify genetic susceptibility loci. RESULTS: Replication studies in independent groups of severe statin myopathy (n = 190) and statin-tolerant controls (n = 130) resulted in the identification of three single-nucleotide polymorphisms (SNPs), rs9342288, rs1337512, and rs3857532, in the eyes shut homolog (EYS) on chromosome 6 suggestive of an association with risk for severe statin myopathy (P = 0.0003 0.0008). Analysis of EYS cDNA demonstrated that EYS gene products are complex and expressed with relative abundance in the spinal cord as well as in the retina. CONCLUSION: Structural similarities of these EYS gene products to members of the Notch signaling pathway and to agrin suggest a possible functional role in the maintenance and regeneration of the structural integrity of skeletal muscle. PMID- 21826686 TI - Safety assessment of ultra-wideband antennas for microwave breast imaging. AB - This article deals with the safety assessment of several ultra-wideband (UWB) antenna designs for use in prototype microwave breast imaging systems. First, the performances of the antennas are validated by comparison of measured and simulated data collected for a simple test case. An efficient approach to estimating the specific energy absorption (SA) is introduced and validated. Next, SA produced by the UWB antennas inside more realistic breast models is computed. In particular, the power levels and pulse repetition periods adopted for the SA evaluation follow the measurement protocol employed by a tissue sensing adaptive radar (TSAR) prototype system. Results indicate that the SA for the antennas examined is below limits prescribed in standards for exposure of the general population; however, the difficulties inherent in applying such standards to UWB exposures are discussed. The results also suggest that effective tools for the rapid evaluation of new sensors have been developed. PMID- 21826685 TI - Regulation of the calpain and ubiquitin-proteasome systems in a canine model of muscular dystrophy. AB - INTRODUCTION: Previous studies have tested the hypothesis that calpain and/or proteasome inhibition is beneficial in Duchenne muscular dystrophy, based largely on evidence that calpain and proteasome activities are enhanced in the mdx mouse. METHODS: mRNA expression of ubiquitin-proteasome and calpain system components were determined using real-time polymerase chain reaction in skeletal muscle and heart in the golden retriever muscular dystrophy model. Similarly, calpain 1 and 2 and proteasome activities were determined using fluorometric activity assays. RESULTS: We found that less than half of the muscles tested had increases in proteasome activity, and only half had increased calpain activity. In addition, transcriptional regulation of the ubiquitin-proteasome system was most pronounced in the heart, where numerous components were significantly decreased. CONCLUSION: This study illustrates the diversity of expression and activities of the ubiquitin-proteasome and calpain systems, which may lead to unexpected consequences in response to pharmacological inhibition. PMID- 21826689 TI - Pilot study for the characterization of pharmacogenetically relevant CYP2D6, CYP2C19 and ABCB1 gene polymorphisms in the Hungarian population. AB - Polymorphisms of CYP450 metabolizer enzymes and transport proteins play crucial roles in the inter-individual variability of drug efficiency. The aim of our study was to predict the frequency of functional variants of CYP2D6, CYP2C19 and ABCB1 genes in the Hungarian population. One hundred twelve unrelated healthy subjects donated DNA sample in the study. ABCB1 C3435T and G2677T/A single nucleotide polymorphisms (SNPs) were determined by LightCycler polymerase chain reaction. Because only limited amount of data is available on the rare allelic variants of CYP2D6 in the European populations, our study applied an expanded set of CYP2D6 and CYP2C19 alleles by using AmpliChip test. Our results show that the CYP2D6 phenotypes were 1.9% ultra-rapid metabolizer, 6.5% intermediate metabolizer (IM), 8.3% poor metabolizer (PM) and 83.3% extensive metabolizer (EM), and the CYP2C19 phenotypes were 1.8% PM, 31.2% IM and 67% EM. The prevalence of the commonly observed CYP2D6 and CYP2C19 alleles in our study corresponds with that of other European populations. Nevertheless, our study confirms that extending the CYP2D6 allele set with loss-of-function variants such as CYP2D6*7, *9, *41 is worth considering. Frequency of the wild type ABCB1 3435C was 42.8% whereas the prevelance of 2677 G was 50.4%. Although frequency data of G2677T/A SNP in the European area are limited, some discrepancies with other studies were found. PMID- 21826690 TI - A mechanism of mechanotransduction at the cell-cell interface: emergence of alpha catenin as the center of a force-balancing mechanism for morphogenesis in multicellular organisms. PMID- 21826691 TI - Running on empty: does mitochondrial DNA mutation limit replicative lifespan in yeast?: Mutations that increase the division rate of cells lacking mitochondrial DNA also extend replicative lifespan in Saccharomyces cerevisiae. AB - Mitochondrial DNA (mtDNA) mutations escalate with increasing age in higher organisms. However, it has so far been difficult to experimentally determine whether mtDNA mutation merely correlates with age or directly limits lifespan. A recent study shows that budding yeast can also lose functional mtDNA late in life. Interestingly, independent studies of replicative lifespan (RLS) and of mtDNA-deficient cells show that the same mutations can increase both RLS and the division rate of yeast lacking the mitochondrial genome. These exciting, parallel findings imply a potential causal relationship between mtDNA mutation and replicative senescence. Furthermore, these results suggest more efficient methods for discovering genes that determine lifespan. PMID- 21826692 TI - Counting citations in texts rather than reference lists to improve the accuracy of assessing scientific contribution: citation frequency of individual articles in other papers more fairly measures their scientific contribution than mere presence in reference lists. PMID- 21826693 TI - Seasonal variation in the patient diagnosis of primary biliary cirrhosis: further evidence for an environmental component to etiology. AB - The etiology of primary biliary cirrhosis (PBC) is far from clear. Both genetic and environmental factors are likely to be involved. We have previously reported evidence of space-time clustering, suggesting that a transient environmental agent may be involved in etiology. To further examine whether a seasonally varying environmental agent may contribute to the etiology of PBC, we have analyzed seasonal variation with respect to month of diagnosis using population based data from northeast England over a defined period (1987-2003). Date of diagnosis was defined as the earliest date at which the patient was found to have fulfilled any two of three diagnostic criteria (i.e., antimitochondrial antibody positive titer >=1 in 40, cholestatic liver blood tests, diagnostic or compatible liver histology). Monthly expected (E) numbers of cases were calculated under an assumption of a uniform distribution throughout the year. Observed counts (O) were compared with the expected numbers. The chi-squared heterogeneity test was used to test for overall nonuniform variation and also for individual months. Poisson regression analysis was used to fit a sinusoidal (i.e., harmonic) model to the data, using month of diagnosis as a covariate in the model. There was a marked peak for diagnoses in the month of June (O = 115, E = 84.7, O/E = 1.36; P = 0.001). Furthermore, there was evidence of a sinusoidal pattern with a June peak (P = 0.012). CONCLUSION: These highly novel results provide further evidence for the involvement of a seasonally varying environmental agent in the etiology of PBC. PMID- 21826694 TI - An essential role for monocyte chemoattractant protein-1 in alcoholic liver injury: regulation of proinflammatory cytokines and hepatic steatosis in mice. AB - The importance of chemokines in alcoholic liver injury has been implicated. The role of the chemokine, monocyte chemoattractant protein-1 (MCP-1), elevated in patients with alcoholic liver disease is not yet understood. Here, we evaluated the pathophysiological significance of MCP-1 and its receptor, chemokine (C-C motif) receptor 2 (CCR2), in alcoholic liver injury. The Leiber-DeCarli diet containing alcohol or isocaloric control diets were fed to wild-type (WT) and MCP 1-deficient knockout (KO) mice for 6 weeks. In vivo and in vitro assays were performed to study the role of MCP-1 in alcoholic liver injury. MCP-1 was increased in Kupffer cells (KCs) as well as hepatocytes of alcohol-fed mice. Alcohol feeding increased serum alanine aminotransferase in WT and CCR2KO, but not MCP-1KO, mice. Alcohol-induced liver steatosis and triglyceride were attenuated in alcohol-fed MCP-1KO, but high in CCR2KO mice, compared to WT, whereas serum endotoxin was high in alcohol-fed WT and MCP-1KO mice. Expression of liver proinflammatory cytokines tumor necrosis factor alpha, interleukin (IL) 1beta, IL-6, KC/IL-8, intercellular adhesion molecule 1, and cluster of differentiation 68 was induced in alcohol-fed WT, but inhibited in MCP-1KO, mice independent of nuclear factor kappa light-chain enhancer of activated B cell activation in KCs. Oxidative stress, but not cytochrome P450 2E1, was prevented in chronic alcohol-fed MCP-1KO mice, compared to WT. Increased expression of peroxisome proliferator-activated receptor (PPAR)alpha and PPARgamma was accompanied by nuclear translocation, DNA binding, and induction of fatty acid metabolism genes acyl coenzyme A oxidase and carnitine palmitoyltransferase 1A in livers of alcohol-fed MCP-1KO mice, compared to WT controls. In vitro assays uncovered an inhibitory effect of recombinant MCP-1 on PPARalpha messenger RNA and peroxisome proliferator response element binding in hepatocytes independent of CCR2. CONCLUSION: Deficiency of MCP-1 protects mice against alcoholic liver injury, independent of CCR2, by inhibition of proinflammatory cytokines and induction of genes related to fatty acid oxidation, linking chemokines to hepatic lipid metabolism. PMID- 21826695 TI - Protease profiling of liver fibrosis reveals the ADAM metallopeptidase with thrombospondin type 1 motif, 1 as a central activator of transforming growth factor beta. AB - During chronic liver disease, tissue remodeling leads to dramatic changes and accumulation of matrix components. Matrix metalloproteases and their inhibitors have been involved in the regulation of matrix degradation. However, the role of other proteases remains incompletely defined. We undertook a gene-expression screen of human liver fibrosis samples using a dedicated gene array selected for relevance to protease activities, identifying the ADAMTS1 (A Disintegrin And Metalloproteinase [ADAM] with thrombospondin type 1 motif, 1) gene as an important node of the protease network. Up-regulation of ADAMTS1 in fibrosis was found to be associated with hepatic stellate cell (HSC) activation. ADAMTS1 is synthesized as 110-kDa latent forms and is processed by HSCs to accumulate as 87 kDa mature forms in fibrotic tissues. Structural evidence has suggested that the thrombospondin motif-containing domain from ADAMTS1 may be involved in interactions with, and activation of, the major fibrogenic cytokine, transforming growth factor beta (TGF-beta). Indeed, we observed direct interactions between ADAMTS1 and latency-associated peptide-TGF-beta (LAP-TGF-beta). ADAMTS1 induces TGF-beta activation through the interaction of the ADAMTS1 KTFR peptide with the LAP-TGF-beta LKSL peptide. Down-regulation of ADAMTS1 in HSCs decreases the release of TGF-beta competent for transcriptional activation, and KTFR competitor peptides directed against ADAMTS1 block the HSC-mediated release of active TGF beta. Using a mouse liver fibrosis model, we show that carbon tetrachloride treatment induces ADAMTS1 expression in parallel to that of type I collagen. Importantly, concurrent injection of the KTFR peptide prevents liver damage. CONCLUSION: Our results indicate that up-regulation of ADAMTS1 in HSCs constitutes a new mechanism for control of TGF-beta activation in chronic liver disease. PMID- 21826696 TI - Diagnostic concordance of the interview and questionnaire versions of the eating disorder examination. AB - OBJECTIVE: The diagnostic concordance of the interview (EDE) and questionnaire (EDE-Q) versions of the Eating Disorder Examination was examined. METHOD: Two hundred seventeen patients seeking eating disorder treatment completed the EDE and EDE-Q before beginning treatment. Diagnostic algorithms were generated for the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision (DSM-IV-TR) and proposed Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria using data first from the EDE and then from the EDE-Q; thus, each participant received four diagnoses. RESULTS: The sensitivity of the EDE-Q for individual diagnoses ranged from 27.8% to 84.3% (DSM-IV-TR) and from 36.8% to 80.8% (DSM-5). The specificity of the EDE-Q for individual diagnoses ranged from 71.1% to 98.5% (DSM-IV-TR) and from 77.3% to 98.0% (DSM-5). The overall diagnostic concordance was moderate (kappa = .57-.60). DISCUSSION: The proposed DSM-5 criteria improved the diagnostic concordance of the two instruments and reduced the prevalence of Eating Disorder Not Otherwise Specified (EDNOS). However, concordance improvement was modest and both instruments still diagnosed most respondents with EDNOS. PMID- 21826697 TI - Expressing findings from meta-analyses of continuous outcomes in terms of risks. AB - Meta-analyses of clinical trials with continuous outcome data typically report the effect of an intervention as either a mean difference or a standardized mean difference. These results can be difficult to interpret, and re-expressing the effect size in terms of risk may facilitate understanding and applicability. We describe three methods for obtaining risks in such situations. Two of these methods involve direct transformation of a standardized mean difference to an odds ratio. The third entails estimation of risks in the two groups for a specific cut point. We extend this third approach to a completed meta-analysis by expressing the finding in the format of a single 'meta-study'. We compare the methods in two examples of meta-analyses and in a series of simulation studies that examine their properties in individual studies and in meta-analyses. These simulations show that the methods for expressing meta-analysis results from continuous outcomes are sensitive to underlying distributions, sample sizes and cut points but are remarkably robust to the presence of heterogeneity across studies. We offer suggestions of situations in which the various methods may safely be applied. In particular, if the underlying distribution is approximately normal, then estimation of risks for a specific cut point may be used for large sample sizes; direct transformations may be preferable otherwise. However, if the standard deviations in the two groups are notably different, then none of the methods have good properties. Furthermore, absolute risks are safely estimated after direct transformation only if they are in the region of 20% to 80%. PMID- 21826698 TI - Testing the evolution process of prostate-specific antigen in early stage prostate cancer: what is the proper underlying model? AB - This paper empirically tests a model of stochastic evolutions of prostate specific antigen (PSA), a trigger for intervention in an early stage prostate cancer surveillance program. It conducts hypothesis testing of the Geometric Browning Motion model based on its attributes of independent increments and linearity of the variance in the increment length versus a wide range of stochastic and deterministic alternatives. These alternatives include the currently accepted deterministic growth model. The paper reports strong empirical evidence in favour of the Geometric Browning Motion model. A model that best describes PSA evolution is a prerequisite to the establishment of decision-making criteria for abandoning active surveillance (i.e. a strategy that involves close monitoring) in early stage prostate cancer. Thus, establishing empirically the type of PSA process is a first step toward the identification of more accurate triggers for abandoning active surveillance and starting treatment while the chances of curing the disease are still high. PMID- 21826699 TI - Neuroprotection by rosiglitazone in transient focal cerebral ischemia might not be mediated by glutamate transporter-1. AB - Glutamate transport represents a key mechanism for maintaining low level of glutamate in the extracellular milieu to restrict the excitotoxic action of glutamate released during ischemia/reperfusion (I/R) injury. Recently, it has been reported that glutamate transporter-1 (GLT-1) is a novel target for peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist, which shows neuroprotection following oxygen glucose deprivation (OGD) in neuronal-astrocytic cocultures. Hence, the present study was undertaken to investigate the role of rosiglitazone in neuroprotection mediated by GLT-1 following focal cerebral I/R injury in rat. We found that rosiglitazone (2 mg/kg i.p) administered pre- or post-I/R injury significantly improved behavioral outcome and decreased cerebral infarct volume. However, no significant changes were observed in GLT-1 mRNA and protein expression in rosiglitazone-treated rats following 1 hr of ischemia/24 hr of reperfusion (1/24 hr I/R) injury. Interestingly, bioinformatics analysis also does not reveal any PPAR response element on the GLT-1/EAAT2 promoter region. Further rosiglitazone neither increased [(3) H]glutamate uptake in glia-enriched preparations nor caused any change in glutamine synthetase activity. On the other hand, there was a significant (P < 0.05) downregulation in tumor necrosis factor alpha and interleukin-1beta gene expression, which were more pronounced in the posttreatment group. The posttreatment with rosiglitazone also significantly reduced the increase in prostaglandin E2 level in the ischemic brain. Therefore, the present findings suggest that the neuroprotective effect of rosiglitazone does not seem to be mediated by modulation of GLT-1 protein expression/activity in a focal cerebral ischemia model. However, the results do provide increasing evidence that the neuroprotective effect may be mediated by its antiinflammatory action. PMID- 21826700 TI - Regulation of P-glycoprotein by human immunodeficiency virus-1 in primary cultures of human fetal astrocytes. AB - P-glycoprotein (P-gp), a drug efflux pump, is known to alter the bioavailability of antiretroviral drugs at several sites, including the brain. We have previously shown that human immunodeficiency virus-1 (HIV-1) glycoprotein 120 (gp120) induces proinflammatory cytokine secretion and decreases P-gp functional expression in rat astrocytes, a cellular reservoir of HIV-1. However, whether P gp is regulated in a similar way in human astrocytes is unknown. This study investigates the regulation of P-gp in an in vitro model of gp120-triggered human fetal astrocytes (HFAs). In this system, elevated levels of interleukin-6 (IL-6), IL-1beta, and tumor necrosis factor-alpha were detected in culture supernatants. Pretreatment with CCR5 neutralizing antibody attenuated cytokine secretion, suggesting that gp120-CCR5 interaction mediated cytokine production. Treatment with gp120 (R5-tropic) resulted in reduced P-gp expression (64%) and function as determined by increased (1.6-fold) cellular accumulation of [(3) H]digoxin, a P gp substrate. Exposure to R5 or R5/X4-tropic viral isolates led to a downregulation in P-gp expression (75% or 90%, respectively), and treatment with IL-6 also showed lower P-gp expression (50%). Moreover, IL-6 neutralizing antibody blocked gp120-mediated P-gp downregulation, suggesting that IL-6 is a key modulator of P-gp. Gp120- or IL-6-mediated downregulation of P-gp was attenuated by SN50 (a nuclear factor-kappaB [NF-kappaB] inhibitor), suggesting involvement of NF-kappaB signaling in P-gp regulation. Our results suggest that, similarly to the case with rodent astrocytes, pathophysiological stressors associated with brain HIV-1 infection have a downregulatory effect on P-gp functional expression in human astrocytes, which may ultimately result in altered antiretroviral drug accumulation within brain parenchyma. PMID- 21826702 TI - Sirt1 overexpression in neurons promotes neurite outgrowth and cell survival through inhibition of the mTOR signaling. AB - The mammalian nicotinamide-adenine dinucleotide (NAD)-dependent deacetylase Sirt1 impacts different processes involved in the maintenance of brain integrity and in the pathogenic pathways associated with several neurodegenerative disorders, including Alzheimer's disease. Here we used human Sirt1 transgenic mice to demonstrate that neuron-specific Sirt1 overexpression promoted neurite outgrowth and improved cell viability under normal and nutrient-limiting conditions in primary culture systems and that Sirt1-overexpressing neurons exhibited higher tolerance to cell death or degeneration induced by amyloid-beta1-42 oligomers. Coincidentally, we found that enhanced Sirt1 expression in neurons downregulated the mammalian target of rapamycin (mTOR) protein levels and its phosphorylation without changes in its mRNA levels, which was accompanied by concomitant inhibition of the mTOR downstream signaling activity as revealed by decreased p70S6 kinase (p70S6K) phosphorylation at Thr389. Consistently with this, using a Sirt1 siRNA transfection approach, we observed that reduction of endogenous mouse Sirt1 led to increased levels of mTOR and phosphorylation of itself and p70S6K as well as impaired cell survival and neurite outgrowth in wild-type mouse primary neurons, corroborating a suppressing effect of mTOR by Sirt1. Correspondingly, the mTOR inhibitor rapamycin markedly improved neuronal cell survival in response to nutrient deprivation and significantly enhanced neurite outgrowth in wild-type mouse neurons. The protective effect of rapamycin was extended to neurons even with Sirt1 siRNA knockdown that displayed developmental abnormalities compared with siRNA control-treated cells. Collectively, our findings suggest that Sirt1 may act to promote growth and survival of neurons in the central nervous system via its negative modulation of mTOR signaling. PMID- 21826701 TI - The new indirubin derivative inhibitors of glycogen synthase kinase-3, 6-BIDECO and 6-BIMYEO, prevent tau phosphorylation and apoptosis induced by the inhibition of protein phosphatase-2A by okadaic acid in cultured neurons. AB - Alterations in glycogen synthase kinase-3beta (GSK3beta) and protein phosphatase 2A (PP2A) have been proposed to be involved in the abnormal tau phosphorylation and aggregation linked to Alzheimer's disease (AD). Interconnections between GSK3beta and PP2A signaling pathways are well established. Targeting tau kinases was proposed to represent a therapeutic strategy for AD. However, which tau kinases should be blocked and to what extent, keeping in mind that kinases have physiological roles? Because most kinase inhibitors are relatively specific and many of them interfere with the cell cycle, it is necessary to develop more specific tau kinase inhibitors devoid of cell toxicity. Here, we used the PP2A inhibition by okadaic acid (OKA) in primary cultured cortical neurons as an in vitro model of increased tau phosphorylation and apoptosis. We tested the effects of two newly characterized indirubin derivative inhibitors of GSK3, 6-BIDECO (6 bromoindirubin-3'-[O-(N,N-diethylcarbamyl)-oxime] and 6-BIMYEO (6-bromoindirubin 3'-[O-(2-morpholin-1-ylethyl)-oxime] hydrochloride) on OKA-induced tau phosphorylation and neuronal apoptosis. Both compounds exhibit higher selectivity toward GSK3 compared with other tau kinases (for 6-BIDECO, IC50 is 0.03 MUM for GSK3, >10 MUM for CDK1, and 10 MUM for CDK5; for 6-BIMYEO, IC50 is 0.11 MUM for GSK3, 1.8 MUM for CDK1, and 0.9 MUM for CDK5). We show that 6-BIDECO and 6-BIMYEO used at micromolar concentrations are not neurotoxic and potently reversed tau phosphorylation and apoptosis induced by OKA. The neuroprotection by these compounds should be further validated in animal models of AD. PMID- 21826703 TI - Use of monocyte/endothelial cell co-cultures (in vitro) and a subcutaneous implant mouse model (in vivo) to evaluate a degradable polar hydrophobic ionic polyurethane. AB - Potential benefits of co-culturing monocytes (MC) with vascular smooth muscle cells have been reported on for tissue engineering applications with a degradable, polar, hydrophobic, and ionic polyurethane (D-PHI). Since the interaction of MC and endothelial cells (EC) within the blood vessel endothelium is also a process of wound repair it was of interest to investigate their function when cultured on the synthetic D-PHI materials, prior to considering the materials' use in vascular engineering. The co-culture (MC/EC) in vitro studies were carried out on films in 96 well plates and porous scaffold disks were prepared for implant studies in an in vivo subcutaneous mouse model. After 7 days in culture, the MC/EC condition was equal to EC growth but had lower esterase activity (a measure of degradative potential), no pro-inflammatory TNF-alpha and a relatively high anti-inflammatory IL-10 release while the ECs maintained their functional marker CD31. After explantation of the porous scaffolds, a live/dead stain showed that the cells infiltrating the scaffolds were viable and histological stains (May-Grunwald, Trichrome) demonstrated tissue in growth and extracellular matrix synthesis. Lysates from the implant scaffolds analyzed with a cytokine antibody array showed decreased pro-inflammatory cytokines (IL-6, TNF alpha, GM-CSF), increased anti-inflammatory cytokines (IL-10, IL-13, TNF-RI), and increased chemotactic cytokines (MCP-1, MCP-5, RANTES). The low foreign body response elicited by D-PHI when implanted in vivo supported the in vitro studies (EC and MC co-culture), demonstrating that D-PHI promoted EC growth along with an anti-inflammatory MC, further demonstrating its potential as a tissue engineering scaffold for vascular applications. PMID- 21826704 TI - Reduction of myoblast differentiation following multiple population doublings in mouse C2 C12 cells: a model to investigate ageing? AB - Ageing skeletal muscle displays declines in size, strength, and functional capacity. Given the acknowledged role that the systemic environment plays in reduced regeneration (Conboy et al. [2005] Nature 433: 760-764), the role of resident satellite cells (termed myoblasts upon activation) is relatively dismissed, where, multiple cellular divisions in-vivo throughout the lifespan could also impact on muscular deterioration. Using a model of multiple population doublings (MPD) in-vitro thus provided a system in which to investigate the direct impact of extensive cell duplications on muscle cell behavior. C(2) C(12) mouse skeletal myoblasts (CON) were used fresh or following 58 population doublings (MPD). As a result of multiple divisions, reduced morphological and biochemical (creatine kinase, CK) differentiation were observed. Furthermore, MPD cells had significantly increased cells in the S and decreased cells in the G1 phases of the cell cycle versus CON, following serum withdrawal. These results suggest continued cycling rather than G1 exit and thus reduced differentiation (myotube atrophy) occurs in MPD muscle cells. These changes were underpinned by significant reductions in transcript expression of: IGF-I and myogenic regulatory factors (myoD and myogenin) together with elevated IGFBP5. Signaling studies showed that decreased differentiation in MPD was associated with decreased phosphorylation of Akt, and with later increased phosphorylation of JNK1/2. Chemical inhibition of JNK1/2 (SP600125) in MPD cells increased IGF-I expression (non-significantly), however, did not enhance differentiation. This study provides a potential model and molecular mechanisms for deterioration in differentiation capacity in skeletal muscle cells as a consequence of multiple population doublings that would potentially contribute to the ageing process. PMID- 21826705 TI - ERalpha17p, an ERalpha P295 -T311 fragment, modifies the migration of breast cancer cells, through actin cytoskeleton rearrangements. AB - Recently, our knowledge on estrogen receptor alpha (ERalpha) functions and fate has progressed: ERalpha enters in repeated transcription-modulating cycles (nucleus/cytoplasm/membrane trafficking processes and proteasomal degradation) that are governed by specific protein-protein interactions. Receptor fragments, especially those resulting from the proteolysis of its ligand binding domain, as well as corresponding synthetic peptides, have been studied with respect to their estrogenic/antiestrogenic potency. A peptide, corresponding to the human ERalpha P(295) -T(311) sequence (ERalpha17p) has been shown to alter breast cancer cell fate, triggering proliferation, or apoptosis. The aim of this work was to explore the effect of ERalpha17p on breast cancer cell migration and actin cytoskeleton dynamics and further analyze the mechanism of its membrane action. We show that ERalpha17p increases (MCF-7 and SK-BR-3 cells) or decreases (T47D and MDA-MB-231 cells) migration of breast cancer cells, in an ERalpha-independent manner, by mechanism(s) depending on Rho/ROCK and PI3K/Akt signaling pathways. Moreover, the peptide enhances the association of both estrogens and androgens to membranes and modifies cell migration, induced by E(2) -BSA. Additionally, initial evidence of a possible agonistic action of the peptide on GPR30 is also provided. ERalpha17p can be considered as a cell migration-modulator and could therefore constitute a therapeutic challenge, even in anti-estrogen-resistant tumors. PMID- 21826706 TI - Molecular basis underlying the biological effects elicited by extremely low frequency magnetic field (ELF-MF) on neuroblastoma cells. AB - Extremely low-frequency magnetic fields (ELF-MFs) may affect human health because of the possible associations with leukemia but also with cancer, cardiovascular, and neurological disorders. In the present work, human SH-SY5Y neuroblastoma cells were exposed to a 50 Hz, 1 mT sinusoidal ELF-MF at three different times, that is, 5 days (T5), 10 days (T10), and 15 days (T15) and then the effects of ELF-MF on proteome expression and biological behavior were investigated. Through comparative analysis between treated and control samples, we analyzed the proteome changes induced by ELF-MF exposure. Nine new proteins resolved in sample after a 15-day treatment were involved in a cellular defense mechanism and/or in cellular organization and proliferation such as peroxiredoxin isoenzymes (2, 3, and 6), 3-mercaptopyruvate sulfurtransferase, actin cytoplasmatic 2, t-complex protein subunit beta, ropporin-1A, and profilin-2 and spindlin-1. Our results indicated that ELF-MFs exposure altered the proliferative status and other important cell biology-related parameters, such as cell growth pattern, and cytoskeletal organization. These findings support our hypothesis that ELF radiation could trigger a shift toward a more invasive phenotype. PMID- 21826707 TI - Signal transduction pathways mediating the effect of adrenomedullin on osteoblast survival. AB - Adrenomedullin (ADM) plays an important role in the regulation of osteoblastic cells through both a proliferative and an anti-apoptotic effects. The present study investigated mechanisms involved in the effect of ADM on survival. We report that ADM can act in osteoblasts both through a non-transcriptional action, by phosphorylation of different kinases and components, and through a transcriptional effect by activation of CREB. So, we observed by Western blot analysis, modifications in the downstream targets of ERK, the pro-apoptotic protein Bad, which is inactivated by increase in Ser155 phosphorylation, and the transcription factor CREB, which is activated by phosphorylation at Ser133. CREB activation was confirmed by a CRE-dependent gene transcription assay and an immunocytochemical study. This increase in CREB phosphorylation could lead to its enhanced transcriptional activity, as indicated by the induced expression of the proliferation marker, PCNA. Moreover, ADM could also activate the tyrosine kinase Src and the PI3-Kinase, both of which are implicated in survival. The use of specific pharmacological inhibitors allowed to establish that ADM could activate a signaling cascade involving Src, MEK, ERK, p90RSK, and that the effect of ADM, in particular on the CREB protein, greatly depends on the regulatory control of interfering signaling pathways. Moreover, as Wnt signaling plays an important role in the control of osteoblast apoptosis, we explored a major component of this pathway, protein GSK3beta. ADM-induced inactivation of GSK3beta by phosphorylation at Ser9, highly suggests that ADM could also exert its survival effect in osteoblast via components of the Wnt pathway. PMID- 21826708 TI - Ailanthoidol suppresses lipopolysaccharide-stimulated inflammatory reactions in RAW264.7 cells and endotoxin shock in mice. AB - The biological properties of ailanthoidol, a neolignan from Zanthoxylum ailanthoides or Salvia miltiorrhiza Bunge, which is used in Chinese traditional herbal medicine, have not been evaluated. Here, we report that ailanthoidol inhibits inflammatory reactions in macrophages and protects mice from endotoxin shock. Our in vitro experiments showed that ailanthoidol suppressed the generation of nitric oxide (NO) and prostaglandin E(2) , as well as the expression of inducible NO synthase (iNOS) and cyclooxygenase (COX)-2 induced by lipopolysaccharide (LPS) in RAW264.7 cells. Similarly, ailanthoidol inhibited the production of inflammatory cytokines induced by LPS in RAW264.7 cells, including interleukin (IL)-1beta and IL-6. In an animal model, ailanthoidol protected BALB/c mice from LPS-induced endotoxin shock, possibly through inhibition of the production of inflammatory cytokines and NO. Collectively, ailanthoidol inhibited the production of inflammatory mediators and may be a potential target for treatment of various inflammatory diseases. PMID- 21826709 TI - Transduction of peptides and proteins into live cells by cell penetrating peptides. AB - Internalization of peptides and proteins into live cells is an essential prerequisite for studies on intracellular signal pathways, for treatment of certain microbial diseases and for signal transduction therapy, especially for cancer treatment. Cell penetrating peptides (CPPs) facilitate the transport of cargo-proteins through the cell membrane into live cells. CPPs which allow formation of non-covalent complexes with the cargo are used primarily in this study due to the relatively easy handling procedure. Efficiency of the protein uptake is estimated qualitatively by fluorescence microscopy and quantitatively by SDS-PAGE. Using the CPP cocktail JBS-Proteoducin, the intracellular concentrations of a secondary antibody and bovine serum albumin can reach the micromolar range. Internalization of antibodies allows mediation of intracellular pathways including knock down of signal transduction. The high specificity and affinity of antibodies makes them potentially more powerful than siRNA. Thus, CPPs represent a significant new possibility to study signal transduction processes in competition or in comparison to the commonly used other techniques. To estimate the highest attainable intracellular concentrations of cargo proteins, the CPPs are tested for cytotoxicity. Cell viability and membrane integrity relative to concentration of CPPs are investigated. Viability as estimated by the reductive activity of mitochondria (MTT-test) is more sensitive to higher concentrations of CPPs versus membrane integrity, as measured by the release of dead cell protease. Distinct differences in uptake efficiency and cytotoxic effects are found using six different CPPs and six different adhesion and suspension cell lines. PMID- 21826710 TI - D-galactose induces necroptotic cell death in neuroblastoma cell lines. AB - D-Galactose (D-gal) can induce oxidative stress in non-cancer cells and result in cell damage by disturbing glucose metabolism. However, the effect of D-gal on cancer cells is yet to be explored. In this study, we investigated the toxicity of D-gal to malignant cells specifically neuroblastoma cells. As the results, high concentrations of D-gal had significant toxicity to cancer cells, whereas the same concentrations of glucose had no; the viability loss via D-gal treatment was prominent to malignant cells (Neuro2a, SH-SY5Y, PC-3, and HepG2) comparing to non-malignant cells (NIH3T3 and LO(2)). Differing from the apoptosis induced by H(2) O(2), D-gal damaged cells showed the characters of necrotic cell death, such as trypan blue-tangible and early phase LDH leakage. Further experiments displayed that the toxic effect of D-gal can be alleviated by necroptosis inhibitor Necrostatin (Nec-1) and autophagy inhibitor 3-methyladenine (3-MA) but not by caspase inhibitor z-VAD-fmk. D-Gal treatment can transcriptionally up regulate the genes relevant to necroptosis (Bmf, Bnip3) and autophagy (Atg5, TIGAR) but not the genes related to apoptosis (Caspase3, Bax, and p53). D-Gal did not activate Caspase-3, but prompted puncta-like GFP-LC3 distribution, an indicator for activated autophagy. The involvement of aldose reductase (AR) mediated polyol pathway was proved because the inhibitor of AR can attenuate the toxicity of D-gal and D-gal treatment elevates the expression of AR. This study demonstrates for the first time that D-gal can induce non-apoptotic but necroptotic cell death in neuroblastoma cells and provides a new clue for developing the strategy against apoptosis-resistant cancers. PMID- 21826711 TI - SIRT1 and SIRT5 activity expression and behavioral responses to calorie restriction. AB - To investigate the effects of calorie restriction (CR) on behavioral performance and expression of SIRT1 and SIRT5 in rat cerebral tissues. Beginning at 18 months of age, 60 rats were randomly divided into a CR group (n = 30) and a group that remained fed ad libitum (AL; n = 30). CR rats were restricted to a diet of 60% of their daily food consumption. After 6 months of CR, CR rats displayed a maximum 50% reduction in escape latency (AL 20 +/- 0.3 s vs. CR 10 +/- 0.2 s) and a 3.2 s decrease in time and distance to target when evaluated in Morris water maze tests. The levels of SIRT1 and SIRT5 protein in cerebral tissues of CR rats were elevated compared to AL rats (P < 0.05). CR retarded declines in cognitive ability and enhanced the expression of both SIRT1 and SIRT5 proteins in the cerebral tissue of CR rats compared with AL rats. PMID- 21826712 TI - Proteome profile changes in SH-SY5y neuronal cells after treatment with neurotrophic factors. AB - Artemin, one of glial cell line-derived neurotrophic factors (GDNFs) supports sensory neuron. Although a role of artemin and GDNF as neurite outgrowth regulators in early neuron development has been suggested, the immediate effects of artemin and GDNF on neuronal cells have not been elucidated. Here, we investigated artemin and GDNF actions on the neuronal cell proteome. To identify immediate-early protein changes by artemin and GDNF in neuronal cells, we used a differential proteomics approach in SH-SY5y human neuronal cells treated with artemin or GDNF for 1 h. Eleven proteins that changed after both artemin and GDNF treatment were identified using two-dimensional gel electrophoresis and matrix assisted laser desorption ionization time-of-flight tandem mass spectroscopy. The calcium ion-binding chaperone calreticulin and calcium/calmodulin-binding nuclear matrix protein matrin 3 showed common quantitative differences after both artemin and GDNF treatment. Cytoskeletal proteins also showed quantitative profile differences, which are functionally relevant to cytoskeletal rearrangement leading to the neurite elongation in neurons. These protein changes were detected in neuronal cells without accompanying changes in mRNA levels. These results suggest that immediate changes induced by artemin and GDNF are related to cytoskeletal protein level changes without transcriptional regulation. PMID- 21826713 TI - Is on-demand sacral neuromodulation in patients with OAB syndrome a feasible therapy regime? AB - INTRODUCTION: Sacral neuromodulation (SNM) of the lower urinary tract has proven to be safe and effective in patients with complaints of OAB syndrome who are not responding to conservative therapy. After 5 years of treatment the implanted system is still effective in 56-71% of patients. The loss of effect could be caused by adaptation of the nerve system to prolonged stimulation of the sacral nerves. MATERIALS AND METHODS: We set up a pilot intervention study. After a run in period of 2 weeks patients were randomized into two groups: one group with on demand neuromodulation (intervention group) and one group with continuous neuromodulation (control group). Patients in the intervention group were instructed to switch their INS off by default and to switch it on again when they felt recurrent symptoms, patients in the control group were asked to use their system as normally. RESULTS: After 2 weeks 10 out of 16 subjects reported a comparable symptom score during on-demand use of their neuromodulation system. Patients appreciated the comfort of being self-determent in the need for therapy. CONCLUSIONS: Possible benefits for patients could be: more autonomy, longer battery life of the implanted INS, decreasing the chance of adaptation by the nervous system. PMID- 21826714 TI - Prevalence, risk factors, and impact on health related quality of life of overactive bladder in China. AB - AIMS: To evaluate the prevalence, associated risk factors and the impact on health related quality of life (HRQoL) of overactive bladder (OAB) among men and women aged >=18 years in China, using the 2002 International Continence Society (ICS) definition. METHODS: The population-based, cross-sectional field survey was conducted between June 2009 and February 2010 in China using questionnaires regarding demographics, the prevalence and the HRQoL. A stratified random sample of men and women aged >=18 years residing in China who were representative of the general populations was selected for demographic questionnaires first. The individuals meeting the diagnostic criteria of OAB (urgency occurring once a week or more) were further interviewed through King's health questionnaire (KHQ) to estimate the impact of OAB on HRQoL. Data were stratified by city, age cohort, and gender. RESULTS: A total of 21,513 individuals were contacted to participate in the survey, and 14,844 individuals (7,614 men, 7,230 women) with complete data were included in this study. The prevalence of OAB was 6.0%, OAB(dry) 4.2%, and OAB(wet) 1.8%. The prevalence varied slightly among six geographical regions of China. Nocturia was the most common OAB symptom besides urgency. Advanced age, higher BMI, lower education level, manual worker, alcohol consumption, and married were associated risk factors for OAB in men. Advanced age, lower education level, manual worker, alcohol consumption, married, menopause, more parities and vaginal delivery were potential risk factors for OAB in women. The symptoms of OAB had a detrimental effect on HRQoL, especially on Coping Measures, Sleep/Energy, General Health Perceptions, and Severity of Urinary Problems. CONCLUSIONS: The prevalence of OAB in China is lower than that of most previous reports. Many known risk factors are associated with OAB. The symptoms of OAB have a detrimental effect on HRQoL. Efforts need to be made to improve public and professional education about the problems of OAB and decrease the unnecessary burden of this condition. PMID- 21826716 TI - Prevalence of self-reported double incontinence in the urban population of a Brazilian city. AB - AIMS: To determine the prevalence, and sociodemographic and clinical factors associated with combined fecal and urinary incontinence in adults living in Pouso Alegre, Minas Gerais, Brazil. METHODS: This epidemiological study was approved by the Research Ethics Committee of the University of Sao Paulo School of Nursing. The participants were selected using a stratified cluster sampling design. The final sample consisted of 519 individuals, randomly selected, aged >=18 years, living in 341 households in the urban area. Prevalence was adjusted for age and gender. RESULTS: The total prevalence of double incontinence was 3.0% (men 1.0%; women 5.0%). The results of the final logistic regression model showed that changes in the habit of going out (odds ratio = 62.2; P < 0.001), duration of incontinence (odds ratio = 39.2; P < 0.001), female gender (odds ratio = 21.6; P < 0.001), and widowhood (odds ratio = 19.4; P < 0.001) were associated with the presence of double incontinence. CONCLUSION: The study allowed a better understanding of the epidemiology of double incontinence and may contribute to the development of public policies and programs for primary and secondary prevention and treatment of double incontinence, at least at the municipal level. PMID- 21826715 TI - Evaluation of drug efflux transporter liabilities of darifenacin in cell culture models of the blood-brain and blood-ocular barriers. AB - AIMS: The objective of the present study was to evaluate drug efflux transporter interactions of darifenacin and examine the impact of such transporter interactions on darifenacin permeability in an in vitro model of the blood-brain barrier (BBB) and blood-ocular barrier (BOB). METHODS: Cell membranes expressing human P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP), and breast cancer resistance protein (BCRP) were examined for ATPase activity following darifenacin exposure (0-10 uM). Primary cultured bovine brain microvessel endothelial cells (BBMEC) and P-gp transfected Manin-Darby canine kidney epithelial cells (MDCKMDR1) were used to examine darifenacin permeability and drug efflux transporter responses. RESULTS: Concentration-dependent increases in ATPase activity was observed in P-gp membranes following darifenacin exposure. Both MRP and BCRP membrane preparations were unresponsive to darifenacin. Studies in both BBMEC and MDCKMDR1 monolayers confirmed a P-gp interaction for darifenacin and significantly greater efflux (basolateral to apical) permeability for darifenacin that was reduced by the P-gp inhibitor, elacridar. CONCLUSIONS: Darifenacin is a substrate for the P-gp drug efflux transporter present in both BBB and BOB. The P-gp drug efflux transporter liabilities of darifenacin may limit its penetration into brain and ocular tissue thereby reducing side effect potential. PMID- 21826718 TI - Botulinum toxin outcomes for idiopathic overactive bladder stratified by indication: lack of anticholinergic efficacy versus intolerability. AB - AIMS: To determine if the outcomes of intradetrusor botulinum toxin A (BTX-A) injections for the management of refractory overactive bladder (OAB) symptoms are different if performed due to lack of anticholinergic efficacy versus medication intolerability. METHODS: Retrospective chart review was performed on all patients undergoing intradetrusor BTX-A (BOTOX(r), Allergan Inc., Irvine, CA) injections from 2004 to 2010 for the management of refractory idiopathic OAB with or without urge incontinence. All patients failed anticholinergic medications due to either lack of efficacy or intolerable side effects. Patient outcomes following BTX-A injections (150-200 units) were compared based on the primary reason for discontinuing anticholinergic medications (lack of efficacy vs. intolerability). Successful BTX-A injections were defined as those producing symptomatic OAB improvement warranting future repeat injections upon return of symptoms. RESULTS: A total of 85 patients were included in the study. Overall, 58/85 (68%) reported symptomatic improvement following BTX-A injections. Successful outcomes were reported in 34/57 (60%) patients treated secondary to lack of anticholinergic efficacy versus 24/28 (86%) due to intolerable side effects (P = 0.02). CONCLUSIONS: BTX-A injections are more successful in patients with anticholinergic intolerability as compared to patients with poor medication efficacy (86% vs. 60%, P = 0.02). PMID- 21826717 TI - Increased serum nerve growth factor levels in patients with overactive bladder syndrome refractory to antimuscarinic therapy. AB - OBJECTIVE: To investigate the serum nerve growth factor (NGF) and urinary NGF levels in patients with overactive bladder syndrome (OAB) refractory to antimuscarinic therapy. MATERIALS AND METHODS: Thirty-four patients with OAB (17 OAB-dry and 17 OAB-wet) and 31 normal subjects were enrolled. The patients were diagnosed to have OAB based on symptoms of urgency with/without urgency incontinence and 3-day voiding diary. All OAB patients had been treated with previous antimuscarinic therapy for at least 3 months but had failed. Serum and urine were collected at baseline and after solifenacin treatment for 3 months. The serum NGF and urinary NGF levels were compared between OAB-dry and OAB-wet and between baseline and after solifenacin treatment. RESULTS: Serum NGF levels were significantly elevated in OAB (median and interquartile range, 7.367 pg/ml, 0-57.66) compared to the controls (0.0728 pg/ml, 0-0.234, P < 0.001). Urinary NGF/Cr levels were significantly elevated in patients with OAB (0.685 pg/mg, 0.08 1.94) compared to the controls (0.005 pg/mg, 0-0.0275, P < 0.001). Serum NGF levels were significantly correlated with urinary NGF (P = 0.002) and NGF/Cr levels (P < 0.001) in OAB patients. There was no significant difference of serum NGF levels between OAB-dry and OAB-wet. The serum and urinary NGF levels remained unchanged (P = 0.504 and 0.414, respectively) in OAB patients after solifenacin therapy. The serum NGF levels were highly correlated between baseline and after solifenacin treatment (R(2) = 0.83, P < 0.001). CONCLUSIONS: Increased serum and urinary NGF levels in patients with OAB refractory to antimuscarinic treatment suggest these bladder disorders might be caused by chronic inflammation. PMID- 21826719 TI - Pelvic floor muscle and transversus abdominis activation in abdominal hypopressive technique through surface electromyography. AB - AIMS: The abdominal hypopressive technique (AHT) is performed mainly via transversus abdominis (TrA) activation and has been indicated for pelvic floor muscle (PFM) disorders. In some European countries, this technique has become widely used. This study aimed to investigate PFM and TrA activation during the AHT through surface electromyography. METHODS: Thirty-four nulliparous physical therapists in good general health were asked to participate in the trial. To ascertain a correct PFM contraction, each of the participants was assessed by inspection and digital palpation. Ability to contract the TrA was assessed by surface electromyography and AHT training was given before analysis. TrA and PFM activity was recorded using surface electromyography. RESULTS: The mean age of the volunteers was 28.1 (+/-6.0) years and the mean body mass index was 23.7 (+/ 3.3) kg/m(2) . More than half of the volunteers were physically active (61.3%) and regularly performed PFM training (52.9%) but not TrA exercises (58.8%). Although the AHT activates the PFM when compared to resting tone (P < 0.001), this method is significantly less effective than PFM alone (P < 0.001). Additionally, the combination of the two techniques (AHT + PFM) was similarly effective as isolated PFM contraction (P = 0.586). Although the AHT activated the TrA significantly more than did PFM alone (P = 0.002), the addition of PFM contraction to the AHT significantly increased the amount of TrA activation (P < 0.001). CONCLUSIONS: Based on our results, the AHT is less effective than PFM contraction alone, and adding PFM contraction to AHT also improves the TrA contraction. PMID- 21826720 TI - A comparative analysis of pediatric uroflowmetry curves. AB - AIMS: This study was conducted to try to objectify assessment of pediatric uroflowmetry curves. MATERIALS AND METHODS: Nine professionals in pediatric incontinence care judged 480 pediatric uroflows. On a 1-5 scale, where 1 = anomalous and 5 = normal, uroflows were assessed on four items: staccato, interrupted, flow time and obstruction. Eighty uroflows were re-evaluated for intra-observer agreement. After staccato and interrupted flow had been defined more sharply, another 100 uroflows were analyzed. Cohen's Kappa test for nominally classified data was applied to assess agreement. Kappa value of <0.20 denoted poor agreement, 0.21-0.40 fair, 0.41-0.60 moderate, 0.61-0.80 substantial and 0.81-1.0 perfect or almost perfect agreement. A second analysis was done using a 3 point scale, anomalous, intermediate and normal. RESULTS: For interobserver agreement, Kappas were 0.45 for staccato flow, 0.67 for interrupted, 0.59 for flow time, and 0.66 for obstruction. For intra-observer agreement, Kappas were 0.47 for staccato, 0.65 for interrupted, 0.55 for flow time, and 0.65 for obstruction. On a three-point scale, anomalous, intermediate, and normal, interobserver agreement was equal to 0.80 or above. In the second 100 uroflows, the interobserver agreement Kappas were 0.44 for staccato, 0.95 for interrupted, 0.71 for flow time and 0.73 for obstruction. CONCLUSION: Moderate to substantial agreement on uroflowmetry curves can be reached, except for staccato. Agreement increases if staccato and interrupted flows are defined more sharply. Staccato is defined as three or more peaks and troughs of more than the square root of maximal flow without touching 0, whereas interrupted flow needs at least one 0 passage. In a normal, uninterrupted uroflow, flow time is under 15 sec. PMID- 21826721 TI - The effect of intravesical acetylsalicylic acid instillation on tissue prostaglandin levels after partial bladder outlet obstruction in rabbits. AB - AIMS: To examine whether obstruction changes the expression of prostaglandins (PGs) in bladder, intravesical low-dose aspirin could be used as a new route of drug administration, this way of administration influences PGs' expression, and contractile function of the bladder is protected after treatment. METHODS: Eighteen rabbits were divided into three groups. Sham-operated group (group 1) included 6 rabbits. Twelve rabbits were partially obstructed for 70 days. Six of these 12 rabbits not receiving any treatment constituted obstructed group (group 2). The remaining six rabbits received 2 mg/kg/day aspirin (group 3). One rabbit in each group was evaluated on 1st, 7th, 14th, 28th, 42nd, and 70th days following obstructive surgery. After scarification, the percentage of collagenous area and concentrations of PGE2 and PGF2-alpha were measured. Contractile responses to field stimulation (EFS), carbachol, and potassium chloride (KCl) were determined. RESULTS: Wet tissue PGE2 and PGF2-alpha levels were higher in obstructed group than the other groups. Aspirin decreased the percentage of collagenous area in group 3 compared to the group 2, but this difference was not statistically significant. The strips from aspirin groups resulted in better contractile response to cholinergic stimulation with KCl, but this difference was not statistically significant between the obstructed and aspirin groups. Similarly, carbachol did not elicit significantly greater concentration-dependent contraction in strips from obstructed group compared to those from aspirin groups. Maximum responses to EFS were not significant in aspirin group compared to those from obstructed group. CONCLUSIONS: Intravesical aspirin may have protective effect on partially obstructed bladder. PMID- 21826723 TI - Lost to follow-up in high level evidence-based studies related to the surgical management of lower urinary tract symptoms secondary to benign prostatic enlargement: does it matter? AB - AIMS: A contemporary review of the literature on benign prostatic hyperplasia (BPH) for lost to follow-up (LTF) rate was performed to evaluate the significance of LTF in the surgical management of lower urinary tract symptoms (LUTS) secondary to benign prostatic enlargement (BPE). METHODS: Randomized clinical trials (RCT level I) on the surgical treatment of LUTS secondary to BPE, with at least 12-month follow-up, from 1/1995 to 10/2010 were searched on PUBMED. Data reviewed included types of study, number of participating centers or hospitals, sample size calculation, surgical techniques, power calculation, estimated dropout rate, duration of follow-up, rate and reasons for LTF. RESULTS: Forty eight RCT articles were identified. Eleven articles gave details on sample size calculation, and 13 explained their LTF rate after reaching LTF patients by mail or telephone. Percentages of LTF patients were 12% (492/4202) at 12 months in 39 articles, 21% (398/1891) at 24 months in 16 articles, 33% (485/1479) at 36 months in 11 articles, 41% (283/694) at 48 months in 6 articles, and 56% (409/729) at >=60 months in 6 articles. Fifteen articles reported no missing data, mostly because of small sample size or short follow-up. Only 7 articles defined LTF patients as treatment failure and reported outcomes accordingly. CONCLUSIONS: The increase in LTF rate over time compromises the strength of the conclusions from the leftover patient population. Only 15% of RCTs adhered to the CONSORT statement by considering their LTF patients as treatment failures. PMID- 21826722 TI - Strain-dependent urethral response. AB - AIMS: The Sprague-Dawley (SD) rat, an out-bred, all-purpose strain, has served well for lower urinary tract research. However, to test new cellular therapies for conditions such as stress urinary incontinence, an in-bred rat strain with immune tolerance, such as the Lewis rat, may be more useful. The objective of this study was to reveal any differences in lower urinary tract continence mechanisms between the Lewis and SD rat. METHODS: The contribution of (1) the striated and smooth muscle to the mechanical and functional properties of the urethra in vitro, and (2) the striated sphincter to leak point pressure (LPP) and reflex continence mechanisms in vivo were assessed in normal (control) Lewis and SD rats and in a model of stress urinary incontinence produced by bilateral pudendal nerve transection. RESULTS: Control, Lewis rats had significantly lower LPP, significantly less fast-twitch skeletal muscle and relied less on the striated sphincter for continence than control, SD rats, as indicated by the failure of neuromuscular blockade with alpha-bungarotoxin to reduce LPP. Nerve transection significantly decreased LPP in the SD rat, but not in the Lewis rat. Although the Lewis urethra contained more smooth muscle than the SD rat, it was less active in vitro as indicated by a low urethral baseline pressure and lack of response to phenylephrine. CONCLUSIONS: We have observed distinct differences in functional and mechanical properties of the SD and Lewis urethra and have shown that the Lewis rat may not be suitable as a chronic model of SUI via nerve transection. PMID- 21826724 TI - Reducing bias in pelvic floor disorders research: using directed acyclic graphs as an aid. AB - AIMS: The aim of most pelvic floor disorders (PFD) research is to obtain an unbiased effect estimate and to make causal inferences. New developments in epidemiologic research, including the use of causal directed acyclic graphs (DAGs), have shown that traditional analytical strategies for research can be inadequate, leading to unintended consequences such as introducing additional bias. Although DAGs have been proven to be useful in other medical fields, their use has been limited in PFD research. The aim of this paper is to introduce DAGs and then demonstrate their application in PFD research. This paper will also illustrate how relying purely on statistical techniques can lead to pitfalls in reducing bias in research studies. METHODS/RESULTS: DAGs are a graphical epidemiologic tool that provide a method to select for potential confounders and minimize bias in the design and analysis of research studies. We start by providing an introduction to DAGs. We then describe six scenarios in PFD research in which DAGs can be helpful: (1) identifying appropriate confounding variables for adjustment; (2) identifying potential over-adjustment when conditioning on a mediator; (3) identifying unintended confounding due to inappropriate adjustment; (4) identifying unintended selection bias due to inappropriate adjustment; (5) planning analyses in cross-sectional studies; and (6) using DAGs as a framework to help plan data collection and analyses in PFD research. CONCLUSIONS: We demonstrate how the application of DAGs as an aid to PFD research can help to decrease bias and discuss the insights and implications for study design and analytical approaches. PMID- 21826725 TI - Systemic administration of fluorogold for anatomical pre-labeling of autonomic and motor neurons in the rat spinal cord compromises urodynamic recordings in acute but not long-term studies. AB - AIMS: The use of anatomical tracer injections into peripheral tissues for retrograde labeling of spinal cord neurons may compromise physiological experiments in combined functional and morphological studies. METHODS: We investigated whether a systemic injection of a retrogradely transported tracer, fluorogold (FG), may provide an alternative to direct injections into end organs for combined anatomical and physiological studies of the lower urinary tract. Urodynamic studies including cystometrogram recordings and external urethral sphincter electromyography were used as functional outcome measures. RESULTS: Pre labeling of spinal cord neurons by intraperitoneal (i.p.) administration of FG resulted in a transient decrease in voiding efficiency, increase in resting pressure as well as increase in bladder size and weight at 5-7 days after the tracer administration. In contrast, there were no urodynamic or end-organ effects detected at 6-8 weeks after the i.p. injection of FG. CONCLUSIONS: We suggest that pre-labeling of spinal autonomic and motor neurons using i.p. administration of FG may be a useful tool when combining anatomical and functional outcome measures in long-term but not acute studies. PMID- 21826726 TI - Short-term effects of systematized behavioral modification program for nocturia: a prospective study. AB - AIMS: This study is to investigate whether a repetitive education program for behavioral modification is necessary for the patients with nocturnal polyuria (NPU). MATERIALS AND METHODS: A prospective single-arm study was carried out and 82 patients with NPU were analyzed. We developed a 30-min systematized behavioral modification program (SBMP), which consisted of (1) watching videos about normal physiology of storing and emptying function of urine, (2) regulation of fluid intake, (3) explanation by giving specific examples, and (4) discussion with a specialized nurse practitioner. Patients received reinforcement SBMP if they still had NPU after the first SBMP. RESULTS: Mean age was 66 +/- 8.3 years. Sixty three males (77%) and 19 females (23%) were included. The results of all questionnaires showed significant improvement of nocturia after the first SBMP. Nocturnal voids, quality of life scores, nocturia index, and nocturnal bladder capacity index were significantly improved and the decrease of nocturnal urine volume was borderline significant. No additional significant improvement was demonstrated after the second SBMP. Overall, 62 patients (78.5%) were satisfied with the first SBMP and 6 patients (7.6%) became satisfied after reinforcement SBMP. Eleven patients (13.9%) were eventually dissatisfied with SBMP. CONCLUSIONS: A single SBMP was sufficient for treating most of the patients with NPU and reinforcement SBMP was effective in some patients. Moving from two to one rises at night may significantly reduce bother and this may explain quality of life improvements rather than any decrease in amount voided. PMID- 21826727 TI - Patient reported incontinence after radical prostatectomy is more common than expected and not associated with the nerve sparing technique: results from the Center for Prostate Disease Research (CPDR) database. AB - AIMS: The reported incidence of urinary incontinence (UI) after radical prostatectomy (RP) ranges from 2.5 to 87%. We reviewed data from the Center for Prostate Disease Research (CPDR) to determine the incidence of patient reported UI after RP (postRPUI) and establish risk factors for postRPUI. METHODS: We obtained IRB approval to query the CPDR database on all patients undergoing RP between 1990 and 2007. We assessed patient age, nerve sparing status, blood loss, margin status, stage, and patient self-reported incontinence status as entered into the database. Patients were counted as having UI only if the database showed patient reported UI in every follow-up encounter. Patients were counted as permanently dry if at any time in the follow-up they answered that they had no UI. RESULTS: Four thousand three hundred seventy four patients underwent RP without radiation therapy or hormonal ablation between 1990 and 2007. Complete data were available for 1,616 (37%) and 1,459 (90.3%) reported UI more than 1 year after RP with a median follow-up of 50.7 months. Older age is an independent risk factor for UI (OR = 1.021, P <= 0.0003). Nerve sparing, blood loss, stage of cancer, and margin status were not predictive for UI. CONCLUSIONS: Our data indicate that patient reported post-RPUI is higher than expected but is not related to the nerve sparing technique, stage of cancer nor blood loss at the time of surgery. PMID- 21826728 TI - Overactive bladder in Taiwanese women: re-analysis of epidemiological database of community from 1999 to 2001. AB - AIMS: To update our previous computerized epidemiological data according to the new taxonomy, we re-evaluated and re-analyzed the data using the current definitions of lower urinary tract symptoms (LUTS) which were approved and published by the ICS in 2002 and 2010 according to patient perception. Further, we divided overactive bladder (OAB) symptoms into OAB dry and OAB wet to assess their prevalence percentages by using the current definitions. METHODS: OAB syndrome in our computerized database was re-defined as having the following storage symptoms present, that is, frequency, urgency, nocturia, urgency incontinence, or stress urinary incontinence (SUI). The prevalence of OAB syndrome was determined with a different taxonomy for those five storage symptoms either singly or in combination. OAB symptoms which were probably associated with mixed incontinence were either ignored or excluded. RESULTS: The prevalence of OAB syndrome varied from 34.76% to 28.33% to 20.95% using different classifications of the above five storage symptoms. The prevalence of OAB wet symptoms increased with advancing age and this finding was consistent with three different definitions. CONCLUSIONS: The prevalence of OAB using the current definition is slightly higher than the result found in our previous published data using a defective classification system of OAB symptoms. The effects of mixed symptoms and probable misclassification cannot be overlooked because many women with OAB (with or without urgency incontinence) might also have SUI. PMID- 21826729 TI - Hybrid prospective and retrospective head motion correction to mitigate cross calibration errors. AB - Utilization of external motion tracking devices is an emerging technology in head motion correction for MRI. However, cross-calibration between the reference frames of the external tracking device and the MRI scanner can be tedious and remains a challenge in practical applications. In this study, we present two hybrid methods, both of which combine prospective, optical-based motion correction with retrospective entropy-based autofocusing to remove residual motion artifacts. Our results revealed that in the presence of cross-calibration errors between the optical tracking device and the MR scanner, application of retrospective correction on prospectively corrected data significantly improves image quality. As a result of this hybrid prospective and retrospective motion correction approach, the requirement for a high-quality calibration scan can be significantly relaxed, even to the extent that it is possible to perform external prospective motion tracking without any prior cross-calibration step if a crude approximation of cross-calibration matrix exists. Moreover, the motion tracking system, which is used to reduce the dimensionality of the autofocusing problem, benefits the retrospective approach at the same time. PMID- 21826731 TI - Analysis and correction of background velocity offsets in phase-contrast flow measurements using magnetic field monitoring. AB - The value of phase-contrast magnetic resonance imaging for quantifying tissue motion and blood flow has been long recognized. However, the sensitivity of the method to system imperfections can lead to inaccuracies limiting its clinical acceptance. A key source of error relates to eddy current-induced phase fluctuations, which can offset the measured object velocity significantly. A higher-order dynamic field camera was used to study the spatiotemporal evolution of background phases in cine phase-contrast measurements. It is demonstrated that eddy current-induced offsets in phase-difference data are present up to the second spatial order. Oscillatory temporal behaviors of offsets in the kHz range suggest mechanical resonances of the MR system to be non-negligible in phase contrast imaging. By careful selection of the echo time, their impact can be significantly reduced. When applying field monitoring data for correcting eddy current and mechanically induced velocity offsets, errors decrease to less than 0.5% of the maximum velocity for various sequence settings proving the robustness of the correction approach. In vivo feasibility is demonstrated for aortic and pulmonary flow measurements in five healthy subjects. Using field monitoring data, mean error in stroke volume was reduced from 10% to below 3%. PMID- 21826730 TI - On multiple alternating steady states induced by periodic spin phase perturbation waveforms. AB - Direct measurement of neural currents by means of MRI can potentially open a high temporal resolution (10-100 ms) window applicable for monitoring dynamics of neuronal activity without loss of the high spatial resolution afforded by MRI. Previously, we have shown that the alternating balanced steady state imaging affords high sensitivity to weak periodic currents owing to its amplification of periodic spin phase perturbations. This technique, however, requires precise synchronization of such perturbations to the radiofrequency pulses. Herein, we extend alternating balanced steady state imaging to multiple balanced alternating steady states for estimation of neural current waveforms. Simulations and phantom experiments show that the off-resonance profile of the multiple alternating steady state signal carries information about the frequency content of driving waveforms. In addition, the method is less sensitive than alternating balanced steady state to precise waveform timing relative to radiofrequency pulses. Thus, multiple alternating steady state technique is potentially applicable to MR imaging of the waveforms of periodic neuronal activity. PMID- 21826732 TI - Quantitative assessment of the effects of high-permittivity pads in 7 Tesla MRI of the brain. AB - The use of high-permittivity materials has been shown to be an effective method for increasing transmit and receive sensitivity in areas of low-signal intensity in the brain at high field. Results in this article show that the use of these materials does not increase the intercoil coupling for a phased array receive coil, does not have any detrimental effects on the B(0) homogeneity within the brain, and does not affect the specific absorption rate distribution within the head. Areas of the brain close to the pads exhibit significant increases (>100%) in transmit field efficiency, but areas further away show a less pronounced (~10%) decrease due to the homogenization of the transmit field and the loss introduced by the dielectric pads. PMID- 21826733 TI - Developing country health systems and the governance of international HIV/AIDS funding. AB - Donor country initiatives for the prevention and mitigation of HIV/AIDS are not a matter of simple burden sharing. Instead, they have brought in their wake many of the complexities and unforeseen effects that have long been associated with more general overseas development assistance. In the case of funding directed toward HIV/AIDS, these effects are by no means either secondary or easily calculable. It is widely acknowledged that there is no consensus framework on how these impacts may be defined, no framework/toolkit for the evaluation of impacts and no longitudinally significant data that could provide the substance for those evaluations. The subject of this study focuses not on the health outcomes of funding but on how donor-recipient relations could be better deliberated, negotiated and coordinated. We argue that effective leadership and governance of developing country health systems for HIV/AIDS work requires a reconfiguration of how donor-recipient relations are conceived and contracted, and for this purpose, we propose an adaptation of the Organisation for Economic Co-operation and Development Paris Declaration principles of aid effectiveness. PMID- 21826734 TI - The pathophysiology of early-stage chronic kidney disease-mineral bone disorder (CKD-MBD) and response to phosphate binders in the rat. AB - Chronic kidney disease-mineral bone disorder (CKD-MBD) is a systemic disorder that describes the complex bone and mineral abnormalities that occur in CKD. To understand the pathophysiology of CKD-MBD and determine whether the early use of phosphate binders would alter this physiology, we used a naturally occurring, slowly progressive model of CKD-MBD, the Cy/+ rat. Male Cy/+ rats were compared with their normal littermates at 20 weeks of age after 1 week of no phosphate binder, calcium carbonate, or sevelamer carbonate. The Cy/+ rat had renal function that was 50% of that of normal littermates, elevated parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23), decreased 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] levels, but normal calcium and phosphorus levels. There was a significant positive correlation of blood FGF23 and phosphorus levels and blood FGF23 and urine phosphorus levels. There was an inverse correlation between FGF23 and calcium levels. mRNA from the kidney demonstrated 50% reduction in klotho and Npt2a expression but no difference in CYP27B1. In the intestine, CKD animals had reduced active phosphate absorption in the jejunum using modified Ussing chambers and a reduction in Npt2b expression throughout the small intestine compared with normal littermates. In bone, mRNA expression of FGF23 was reduced (driven by lowering with phosphate binders), and TRAP expression was increased in CKD. By histology, there was increased osteoclast activity and number, and there were reductions in some measures of femoral neck mechanical strength. One week of phosphate binders reduced intestinal phosphate flux, serum phosphorus levels, and urinary phosphate excretion. These results demonstrate marked abnormalities in kidney, intestine, and bone in early CKD-MBD. While phosphate binders were effective in lowering urine phosphorus, they had little effect on end organs after 1 week of administration. PMID- 21826735 TI - The transcriptome of fracture healing defines mechanisms of coordination of skeletal and vascular development during endochondral bone formation. AB - Fractures initiate one round of endochondral bone formation in which callus cells differentiate in a synchronous manner that temporally phenocopies the spatial variation of endochondral development of a growth plate. During fracture healing C57BL/6J (B6) mice initiate chondrogenesis earlier and develop more cartilage than bone, whereas C3H/HeJ (C3H) mice initiate osteogenesis earlier and develop more bone than cartilage. Comparison of the transcriptomes of fracture healing in these strains of mice identified the genes that showed differences in timing and quantitative expression and encode for the variations in endochondral bone development of the two mouse strains. The complement of strain-dependent differences in gene expression was specifically associated with ontologies related to both skeletal and vascular formation. Moreover, the differences in gene expression associated with vascular tissue formation during fracture healing were correlated with the underlying differences in development and function of the cardiovascular systems of these two strains of mice. Significant differences in gene expression associated with bone morphogenetic protein/transforming growth factor beta (BMP/TGF-beta) signal-transduction pathways were identified between the two strains, and a network of differentially expressed genes specific to the MAP kinase cascade was further defined as a subset of the genes of the BMP/TGF beta pathways. Other signal-transduction pathways that showed significant strain specific differences in gene expression included the RXR/PPAR and G protein related pathways. These data identify how bone and vascular regeneration are coordinated through expression of common sets of transcription and morphogenetic factors and suggest that there is heritable linkage between vascular and skeletal tissue development during postnatal regeneration. PMID- 21826737 TI - The prevalence and clinical-demographic correlates of diabetes mellitus in chronic schizophrenic patients receiving clozapine. AB - OBJECTIVE: To examine the prevalence and correlates of diabetes in a large sample of Chinese patients with schizophrenia on long-term clozapine treatment, because this population previously has received little systematic study. METHODS: Two hundred and six inpatients meeting Diagnostic and Statistical Manual of Mental Disorders, 4th Edition schizophrenia criteria were recruited in a cross-sectional naturalistic study, and compared with 615 healthy control subjects matched for age, sex, education, and body mass index (BMI). The patient's psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS). Diagnoses of diabetes were established through review of medical records and fasting blood glucose testing, or an oral glucose tolerance test. RESULTS: Diabetes mellitus was more common in patients than in the normal controls (22.3% vs 6.2%) (odds ratio = 4.37, confidence interval (CI) 2.76-6.92, p < 0.001). The prevalence of diabetes increased with age across five age-groups as compared with normal controls (X(2) = 18.0, df = 4, p = 0.001). The PANSS total score and sub-scores showed no differences between the diabetic and non-diabetic groups. Logistic regression in the patients revealed significant associations between diabetes and a family history of diabetes (p < 0.001), age (p < 0.01), and BMI (p < 0.05). CONCLUSION: Long-term clozapine treatment was associated with an increased and clinically important risk of diabetes mellitus in Chinese chronic schizophrenic patients, which is consistent with previous reports in Western populations. PMID- 21826736 TI - Mutations in SERPINF1 cause osteogenesis imperfecta type VI. AB - Osteogenesis imperfecta (OI) is a spectrum of genetic disorders characterized by bone fragility. It is caused by dominant mutations affecting the synthesis and/or structure of type I procollagen or by recessively inherited mutations in genes responsible for the posttranslational processing/trafficking of type I procollagen. Recessive OI type VI is unique among OI types in that it is characterized by an increased amount of unmineralized osteoid, thereby suggesting a distinct disease mechanism. In a large consanguineous family with OI type VI, we performed homozygosity mapping and next-generation sequencing of the candidate gene region to isolate and identify the causative gene. We describe loss of function mutations in serpin peptidase inhibitor, clade F, member 1 (SERPINF1) in two affected members of this family and in an additional unrelated patient with OI type VI. SERPINF1 encodes pigment epithelium-derived factor. Hence, loss of pigment epithelium-derived factor function constitutes a novel mechanism for OI and shows its involvement in bone mineralization. PMID- 21826739 TI - Restless legs syndrome in older people: a community-based study on its prevalence and association with major depressive disorder in older Korean adults. AB - OBJECTIVE: The prevalence of restless legs syndrome (RLS) and its relationship with the demographic variables in an older Korean population were examined. METHODS: A face-to-face household survey was conducted in five different regions of Korea from June 2008 to August 2008. Among a total of 3074 individuals who were aged more than 65, 1990 participants were interviewed, and the response rate was 64.7%. The diagnosis of RLS was made using an RLS questionnaire. The medical review of systems was assessed by a self-report questionnaire containing 15 items. Depression was diagnosed with the diagnostic section of depressive disorder of the Korean version of the Composite International Diagnostic Interview (CIDI) and the short form of the Geriatric Depression Scale (GDS). RESULTS: The prevalence of RLS in the older Korean population was 9.5% (men, 7.1%; women, 11.3%). RLS had a significant association with anemia (odds ratio (OR), 1.66; 95% confidence interval (CI), 1.29-2.12; P < 0.001) and renal diseases (OR, 2.57; 95% CI, 1.95-3.38; P < 0.001). RLS seemed to have a significant relationship with depression by using the CIDI (adjusted OR 2.01; 95% CI, 1.45-2.79. P < 0.001) and GDS (adjusted OR, 1.62; 95% CI, 1.34-1.94; P < 0.001). CONCLUSIONS: Restless legs syndrome might be a risk factor for major depressive disorder in older Koreans. Future investigations should focus on the causality and mechanism underlying the relationship between RLS and major depressive disorder. PMID- 21826738 TI - QTc prolongation: is clozapine safe? Study of 82 cases before and after clozapine treatment. AB - OBJECTIVE: The most feared cardiological consequence of clozapine is sudden cardiac death. A potential marker of it is QTc interval (QTc) prolongation. This study aimed to determine the prevalence of QTc prolongation in patients before and after 18 weeks of clozapine treatment and to detect predictors of QTc prolongation. METHODS: Patients undergoing treatment with clozapine who had been given an electrocardiogram prior to the treatment and had their electrocardiogram, serum clozapine and norclozapine levels taken on the 18th week were selected. Exclusion criteria were thioridazine, pimozide, diuretics or beta blocker treatment, electrolytic alteration, heart diseases and substance misuse diagnosis. Prolonged QTc was defined as >450 ms in men and >470 ms in women. RESULTS: No significant differences were detected in prevalence of prolonged QTc or mean QTc before and after 18 weeks of clozapine treatment (p = 0.15, p = 0.32, respectively). Age, heart rate at 18th week and QTc prior to clozapine treatment had significant effects on QTc at follow-up. Prolonged QTc during previous treatment and heart rate >95 beats/min at 18 weeks were found to be predictors of QTc prolongation. CONCLUSION: No significant differences were detected in prevalence of QTc prolongation or mean QTc among patients before and after 18 weeks on clozapine. PMID- 21826740 TI - Monitoring humans for somatic mutation in the endogenous PIG-a gene using red blood cells. AB - The endogenous X-linked PIG-A gene is involved in the synthesis of glycosyl phosphatidyl inositol (GPI) anchors that tether specific protein markers to the exterior of mammalian cell cytoplasmic membranes. Earlier studies in rodent models indicate that Pig-a mutant red blood cells (RBCs) can be induced in animals treated with genotoxic agents, and that flow cytometry can be used to identify rare RBCs deficient in the GPI-anchored protein, CD59, as a marker of Pig-a gene mutation. We investigated if a similar approach could be used for detecting gene mutation in humans. We first determined the frequency of spontaneous CD59-deficient RBCs (presumed PIG-A mutants) in 97 self-identified healthy volunteers. For most subjects, the frequency of CD59-deficient RBCs was low (average of 5.1 +/- 4.9 * 10(-6) ; median of 3.8 * 10(-6) and mutant frequency less than 8 * 10(-6) for 75% of subjects), with a statistically significant difference in median mutant frequencies between males and females. PIG-A RBC mutant frequency displayed poor correlation with the age and no correlation with the smoking status of the subjects. Also, two individuals had markedly increased CD59-deficient RBC frequencies of ~300 * 10(-6) and ~100 * 10( 6) . We then monitored PIG-A mutation in 10 newly diagnosed cancer patients undergoing chemotherapy with known genotoxic drugs. The frequency of CD59 deficient RBCs in the blood of the patients was measured before the start of chemotherapy and three times over a period of ~6 months while on/after chemotherapy. Responses were generally weak, most observations being less than the median mutant frequency for both males and females; the greatest response was an approximate three-fold increase in the frequency of CD59-deficient RBCs in one patient treated with a combination of cisplatin and etoposide. These results suggest that the RBC PIG-A assay can be adopted to measuring somatic cell mutation in humans. Further research is necessary to determine the assay's sensitivity in detecting mutations induced by genotoxic agents acting via different mechanisms. PMID- 21826741 TI - Trimethoprim-sulfamethoxazole increase micronuclei formation in peripheral blood from weanling well-nourished and malnourished rats. AB - The combination of trimethoprim and sulfamethoxazole (TMP-SMX) is a widely used drug. In spite of this, there are few reports on its genotoxicity, and the results are controversial. Severe malnutrition is a complex condition that increases the susceptibility to infections. Consequently, drugs are extensively used in malnutrition cases. Experimental animal models have been widely used to study the effects of malnutrition. Neonatal rats were experimentally malnourished (UN) during lactation. The UN rats weighed 51.1% less than the well-nourished (WN) controls and had lower concentrations of serum protein and blood lipids. The micronucleus (MN) assay is useful for detecting chromosome damage induced by nutritional deficiencies. In vivo rodent MN assays have been widely used to screen genotoxic agents. In this study, we have evaluated the frequency of spontaneous and TMP-SMX-induced micronuclei in the peripheral blood of weanling (21 days of age) rats using a flow cytometric analysis technique. The spontaneous frequency of micronucleated reticulocytes (MN-RETs) was 2.7 times greater in the UN rats than in the WN rats. In rats that were not treated with TMP-SMX, the percentage of reticulocytes was significantly lower (41.1%) in the UN rats than the WN controls. A therapeutic dose of TMP-SMX (80 mg/kg (TMP), 400 mg/kg (SMX) for 48 hr) increased MN-RETs in the WN and in the UN rats. The data demonstrate the genotoxic effect of this drug. The results indicate that severe protein calorie restriction and drug treatment enhance DNA damage in rat peripheral blood reticulocytes, potentially increasing the risk of negative effects on health. PMID- 21826744 TI - Polarizing organic photovoltaics. PMID- 21826742 TI - Multiple cellular and molecular mechanisms are involved in human Abeta clearance by transplanted adult astrocytes. AB - Astrocytes and microglia are able to degrade potentially neurotoxic beta-amyloid (Abeta) deposits typical for Alzheimer's disease (AD) pathology. Contrary to microglia, astrocytes degrade human Abeta from tissue sections in vitro without any additional stimulation, but it has remained unclear whether transplanted astrocytes are able to clear deposited human Abeta in vivo. We transplanted adult mouse astrocytes into the hippocampi of transgenic mice mimicking AD and observed their fate, effects on microglial responses, and Abeta clearance. After 2-months follow-up time, we discovered a significant reduction in Abeta burden compared with AD mice infused with PBS only. The remaining Abeta deposits were fragmented and most of the Abeta immunoreactivity was seen within the transplanted astrocytes. Concomitant to Abeta reduction, both CD68 and CD45 immunoreactivities were significantly upregulated but phagocytic microglia were often surrounding and engulfing Abeta burdened, TUNEL-positive astrocytes rather than co-localizing with Abeta alone. Astrocytes are known to degrade Abeta also by secreting proteases involved in Abeta catabolism. To study the contribution of neprilysin (NEP), angiotensin-converting enzyme-1 (ACE-1), and endothelin-converting enzyme 2 (ECE-2) in human Abeta clearance, we utilized an ex vivo assay to demonstrate that adult astrocytes respond to human Abeta by upregulating NEP expression. Further, incubation of adult astrocytes with known inhibitors of NEP, ACE-1, or ECE-2 significantly inhibited the removal of human Abeta from the tissue suggesting an important role for these proteases in Abeta clearance by adult astrocytes ex vivo. PMID- 21826745 TI - Charge-shifting click capsules with dual-responsive cargo release mechanisms. PMID- 21826746 TI - Dimensional reduction: a design tool for new radiation detection materials. PMID- 21826747 TI - Highly conformable conducting polymer electrodes for in vivo recordings. PMID- 21826748 TI - High-speed carbon nanotube actuators based on an oxidation/reduction reaction. AB - Actuators with a high-speed response under a high-frequency (more than 100 Hz) applied square-wave voltage of +/-2 V have been developed with an electrode composed of millimeter-long single-walled carbon nanotubes synthesized by the "supergrowth method" (SG-SWNTs) and ionic liquids (ILs). Detailed studies concerning induced electric current and transferred charge in the electrode as well as cyclic voltammetric studies of the electrode revealed that the high-speed response originates from the electric current generated by an oxidation/reduction (redox) reaction in addition to electric double-layer charging. The contribution of the redox reactions of SG-SWNTs to the actuation is sensitive to the presence of supporting polymers, the thickness of the electrolyte, and the amplitude of the applied voltage. PMID- 21826749 TI - The route to a feasible hydrogen-storage material: MOFs versus ammonia borane. AB - The replacement of fossil fuels is one of the greatest challenges that chemistry and material sciences will have to face in the near future. While hydrogen seems to be the most likely candidate for this, a material able to store the hydrogen itself is sorely needed. Intense research in the past decade has narrowed down the field of possible concepts to two materials: ammonia borane with chemically bound hydrogen atoms and metal-organic frameworks with physisorbed hydrogen molecules. Herein we want to give an overview of the strengths and weaknesses of each concept, discuss the challenges that need to be overcome, and try to compare the future capabilities of these two materials. PMID- 21826750 TI - Substrate-mediated phase separation of two porphyrin derivatives on Cu(111). PMID- 21826751 TI - Violet-to-blue tunable emission of aryl-substituted dispirofluorene indenofluorene isomers by conformationally-controllable intramolecular excimer formation. AB - Two series of DiSpiroFluorene-IndenoFluorene (DSF-IF) positional isomers, namely dispiro[2,7-diarylfluorene-9',6,9'',12-indeno[1,2-b]fluorenes], (1,2-b)-DSF-IFs 1 and dispiro[2,7-diarylfluorene-9',6,9'',12-indeno[2,1-a]fluorenes], (2,1-a)-DSF IFs 2 have been synthesized. These violet-to-blue fluorescent emitters possess a 3pi-2spiro architecture, which combines via two spiro links two different indenofluorene cores, that is, (1,2-b)-IF or (2,1-a)-IF and 2,7-substituted diaryl-fluorene units. Due to their different geometric profiles, the two families of positional isomers present drastically different properties. The marked difference observed between the properties of (1,2-b)-DSF-IF (1) and (2,1 a)-DSF-IF (2) is discussed in terms of intramolecular pi-pi interactions occurring in (2,1-a)-DSF-IF (2) leading to conformationally-controllable intramolecular excimer formation. Indeed, the original geometry of the (2,1-a) DSF-IF (2) family, with face-to-face "aryl-fluorene-aryl" moieties, leads to remarkable excimer emission through intramolecular pi-pi interactions in the excited state. Furthermore, the emission wavelengths can be gradually modulated by the control of the steric hindrance between the adjacent substituted phenyl rings. Thus, through a comparative and detailed study of the (1)H NMR, electrochemical and photophysical properties of DSF-IFs 1 and 2, we have evidenced the intramolecular pi-pi interactions occurring between the two "aryl fluorene-aryl" moieties in the ground state and in the excited state. These properties have been finally correlated to the spectacular conformational change modeled by density functional theory (DFT) calculations. Indeed, the two "aryl fluorene-aryl" moieties switch from a staggered conformation in the ground state to an eclipsed conformation in the first excited state. PMID- 21826752 TI - Can a metal-metal bond hop in the fullerene cage? PMID- 21826753 TI - Xenon-nitrogen chemistry: gas-phase generation and theoretical investigation of the xenon-difluoronitrenium ion F2N-Xe+. AB - The xenon-difluoronitrenium ion F(2)N-Xe(+) , a novel xenon-nitrogen species, was obtained in the gas phase by the nucleophilic displacement of HF from protonated NF(3) by Xe. According to Moller-Plesset (MP2) and CCSD(T) theoretical calculations, the enthalpy and Gibbs energy changes (DeltaH and DeltaG) of this process are predicted to be -3 kcal mol(-1) . The conceivable alternative formation of the inserted isomers FN-XeF(+) is instead endothermic by approximately 40-60 kcal mol(-1) and is not attainable under the employed ion trap mass spectrometric conditions. F(2)N-Xe(+) is theoretically characterized as a weak electrostatic complex between NF(2)(+) and Xe, with a Xe-N bond length of 2.4-2.5 A, and a dissociation enthalpy and free energy into its constituting fragments of 15 and 8 kcal mol(-1), respectively. F(2)N-Xe(+) is more fragile than the xenon-nitrenium ions (FO(2)S)(2)NXe(+), F(5)SN(H)Xe(+), and F(5)TeN(H)Xe(+) observed in the condensed phase, but it is still stable enough to be observed in the gas phase. Other otherwise elusive xenon-nitrogen species could be obtained under these experimental conditions. PMID- 21826754 TI - Integration of protein motions with molecular networks reveals different mechanisms for permanent and transient interactions. AB - The integration of molecular networks with other types of data, such as changing levels of gene expression or protein-structural features, can provide richer information about interactions than the simple node-and-edge representations commonly used in the network community. For example, the mapping of 3D-structural data onto networks enables classification of proteins into singlish- or multi interface hubs (depending on whether they have >2 interfaces). Similarly, interactions can be classified as permanent or transient, depending on whether their interface is used by only one or by multiple partners. Here, we incorporate an additional dimension into molecular networks: dynamic conformational changes. We parse the entire PDB structural databank for alternate conformations of proteins and map these onto the protein interaction network, to compile a first version of the Dynamic Structural Interaction Network (DynaSIN). We make this network available as a readily downloadable resource file, and we then use it to address a variety of downstream questions. In particular, we show that multi interface hubs display a greater degree of conformational change than do singlish interface ones; thus, they show more plasticity which perhaps enables them to utilize more interfaces for interactions. We also find that transient associations involve smaller conformational changes than permanent ones. Although this may appear counterintuitive, it is understandable in the following framework: as proteins involved in transient interactions shuttle between interchangeable associations, they interact with domains that are similar to each other and so do not require drastic structural changes for their activity. We provide evidence for this hypothesis through showing that interfaces involved in transient interactions bind fewer classes of domains than those in a control set. PMID- 21826755 TI - Pre-existing soft modes of motion uniquely defined by native contact topology facilitate ligand binding to proteins. AB - Modeling protein flexibility constitutes a major challenge in accurate prediction of protein-ligand and protein-protein interactions in docking simulations. The lack of a reliable method for predicting the conformational changes relevant to substrate binding prevents the productive application of computational docking to proteins that undergo large structural rearrangements. Here, we examine how coarse-grained normal mode analysis has been advantageously applied to modeling protein flexibility associated with ligand binding. First, we highlight recent studies that have shown that there is a close agreement between the large-scale collective motions of proteins predicted by elastic network models and the structural changes experimentally observed upon ligand binding. Then, we discuss studies that have exploited the predicted soft modes in docking simulations. Two general strategies are noted: pregeneration of conformational ensembles that are then utilized as input for standard fixed-backbone docking and protein structure deformation along normal modes concurrent to docking. These studies show that the structural changes apparently "induced" upon ligand binding occur selectively along the soft modes accessible to the protein prior to ligand binding. They further suggest that proteins offer suitable means of accommodating/facilitating the recognition and binding of their ligand, presumably acquired by evolutionary selection of the suitable three-dimensional structure. PMID- 21826756 TI - Ultrasound-guided fine needle aspiration diagnosis of supraglottic laryngeal cancer. AB - BACKGROUND: Although intraoperative laryngoscopic examination and biopsy of patients who present with locally advanced supraglottic carcinomas remains the standard of care, there are occasions when a more expedited biopsy can be helpful. METHODS AND RESULTS: We describe a quick diagnostic technique of ultrasound-guided fine needle aspiration of endolaryngeal advanced supraglottic carcinomas, which can be performed in the clinic without any preparation. Ultrasound scanning is performed through the thyrohyoid membrane. The tumor is visualized as an irregular hypoechoic mass. While continuing to visualize the mass, a 21-gange needle attached to a syringe is passed through the contralateral thyrohyoid membrane into the mass. Suction is applied, and the aspirate is sent for cytologic study. CONCLUSIONS: When formal intraoperative laryngoscopy and biopsy is not feasible or timely, ultrasound-guided fine-needle aspiration biopsy enables a rapid diagnosis and eliminates the cost, side effects, and risks of a direct laryngoscopy. PMID- 21826757 TI - Decreased frontostriatal microstructural organization in attention deficit/hyperactivity disorder. AB - Frontostriatal brain areas have been implicated in the neurobiology of attention deficit/hyperactivity disorder (ADHD), but little work has directly addressed the white matter connections between these regions. The present study investigates the microstructural organization and myelination of frontostriatal white matter in children with ADHD and controls. Diffusion tensor imaging and magnetization transfer imaging scans were acquired in 30 children with ADHD and 34 controls. A study specific volume of interest (VOI) of frontostriatal white matter was created using a tractography based statistical group map. Fractional anisotropy (FA, indexing microstructural organization) and magnetization transfer ratio (MTR, indexing macromolecular content, myelin in particular) were computed for the frontostriatal VOI and for total cerebral white matter. Exploratory analyses were conducted investigating the effect of stimulant use on these measures. Frontostriatal FA but not MTR was decreased in ADHD compared with controls. There were no differences in FA or MTR for total cerebral white matter. Frontostriatal FA correlated negatively with teacher-rated attention problems in controls but not children with ADHD. The duration of stimulant use did not affect the main results. Changes in frontostriatal connectivity in ADHD appear to be related to changes in microstructural organization rather than myelination per se. A correlation with attention problems for controls suggests that frontostriatal organization is relevant to ADHD-related behaviors. PMID- 21826758 TI - Event-related potential activity in the basal ganglia differentiates rewards from nonrewards: temporospatial principal components analysis and source localization of the feedback negativity: commentary. AB - Foti et al. propose that a reward-related brain potential component recorded from scalp EEG is generated by deep brain basal ganglia structures. Previous work, cited in their original article, provides only speculative and theoretical support for this interpretation. Based on empirical and anatomical evidence, we argue that this scalp-recorded ERP component is highly unlikely to be generated by the basal ganglia. PMID- 21826759 TI - Representation of perceived sound valence in the human brain. AB - Perceived emotional valence of sensory stimuli influences their processing in various cortical and subcortical structures. Recent evidence suggests that negative and positive valences are processed separately, not along a single linear continuum. Here, we examined how brain is activated when subjects are listening to auditory stimuli varying parametrically in perceived valence (very unpleasant-neutral-very pleasant). Seventeen healthy volunteers were scanned in 3 Tesla while listening to International Affective Digital Sounds (IADS-2) in a block design paradigm. We found a strong quadratic U-shaped relationship between valence and blood oxygen level dependent (BOLD) signal strength in the medial prefrontal cortex, auditory cortex, and amygdala. Signals were the weakest for neutral stimuli and increased progressively for more unpleasant or pleasant stimuli. The results strengthen the view that valence is a crucial factor in neural processing of emotions. An alternative explanation is salience, which increases with both negative and positive valences. PMID- 21826760 TI - Functional MRI assessment of orofacial articulators: neural correlates of lip, jaw, larynx, and tongue movements. AB - Compared with complex coordinated orofacial actions, few neuroimaging studies have attempted to determine the shared and distinct neural substrates of supralaryngeal and laryngeal articulatory movements when performed independently. To determine cortical and subcortical regions associated with supralaryngeal motor control, participants produced lip, tongue and jaw movements while undergoing functional magnetic resonance imaging (fMRI). For laryngeal motor activity, participants produced the steady-state/i/vowel. A sparse temporal sampling acquisition method was used to minimize movement-related artifacts. Three main findings were observed. First, the four tasks activated a set of largely overlapping, common brain areas: the sensorimotor and premotor cortices, the right inferior frontal gyrus, the supplementary motor area, the left parietal operculum and the adjacent inferior parietal lobule, the basal ganglia and the cerebellum. Second, differences between tasks were restricted to the bilateral auditory cortices and to the left ventrolateral sensorimotor cortex, with greater signal intensity for vowel vocalization. Finally, a dorso-ventral somatotopic organization of lip, jaw, vocalic/laryngeal, and tongue movements was observed within the primary motor and somatosensory cortices using individual region-of interest (ROI) analyses. These results provide evidence for a core neural network involved in laryngeal and supralaryngeal motor control and further refine the sensorimotor somatotopic organization of orofacial articulators. PMID- 21826761 TI - Response inhibition and reward anticipation in medication-naive adults with attention-deficit/hyperactivity disorder: a within-subject case-control neuroimaging study. AB - BACKGROUND: Previous research suggests that ADHD patients are characterized by both reduced activity in the inferior frontal gyrus (IFG) during response inhibition tasks (such as the Go-NoGo task), and reduced activity in the ventral striatum during reward anticipation tasks (such as the Monetary-Incentive-Delay [MID] task). However, no prior research has applied either of these paradigms in medication-naive adults with ADHD, nor have these been implemented in an intrasubject manner. METHODS: The sample consisted of 19 medication-naive adults with ADHD and 19 control subjects. Main group analyses were based on individually defined regions of interest: the IFG and the VStr for the Go-NoGo and the MID task respectively. In addition, we analyzed the correlation between the two measures, as well as between these measures and the clinical symptoms of ADHD. RESULTS: We observed reduced bilateral VStr activity in adults with ADHD during reward anticipation. No differences were detected in IFG activation on the Go NoGo paradigm. Correlation analyses suggest that the two tasks are independent at a neural level, but are related behaviorally in terms of the variability of the performance reaction time. Activity in the bilateral VStr but not in the IFG was associated negatively with symptoms of hyperactivity/impulsivity. CONCLUSIONS: Results underline the implication of the reward system in ADHD adult pathophysiology and suggest that frontal abnormalities during response inhibition performance may not be such a pivotal aspect of the phenotype in adulthood. In addition, our findings point toward response variability as a core feature of the disorder. PMID- 21826762 TI - Effects of rapid eye movement sleep deprivation on fear extinction recall and prediction error signaling. AB - In a temporal difference learning approach of classical conditioning, a theoretical error signal shifts from outcome deliverance to the onset of the conditioned stimulus. Omission of an expected outcome results in a negative prediction error signal, which is the initial step towards successful extinction and may therefore be relevant for fear extinction recall. As studies in rodents have observed a bidirectional relationship between fear extinction and rapid eye movement (REM) sleep, we aimed to test the hypothesis that REM sleep deprivation impairs recall of fear extinction through prediction error signaling in humans. In a three-day design with polysomnographically controlled REM sleep deprivation, 18 young, healthy subjects performed a fear conditioning, extinction and recall of extinction task with visual stimuli, and mild electrical shocks during combined functional magnetic resonance imaging (fMRI) and skin conductance response (SCR) measurements. Compared to the control group, the REM sleep deprivation group had increased SCR scores to a previously extinguished stimulus at early recall of extinction trials, which was associated with an altered fMRI time-course in the left middle temporal gyrus. Post-hoc contrasts corrected for measures of NREM sleep variability also revealed between-group differences primarily in the temporal lobe. Our results demonstrate altered prediction error signaling during recall of fear extinction after REM sleep deprivation, which may further our understanding of anxiety disorders in which disturbed sleep and impaired fear extinction learning coincide. Moreover, our findings are indicative of REM sleep related plasticity in regions that also show an increase in activity during REM sleep. PMID- 21826763 TI - Dissociable neural correlates of contour completion and contour representation in illusory contour perception. AB - Object recognition occurs even when environmental information is incomplete. Illusory contours (ICs), in which a contour is perceived though the contour edges are incomplete, have been extensively studied as an example of such a visual completion phenomenon. Despite the neural activity in response to ICs in visual cortical areas from low (V1 and V2) to high (LOC: the lateral occipital cortex) levels, the details of the neural processing underlying IC perception are largely not clarified. For example, how do the visual areas function in IC perception and how do they interact to archive the coherent contour perception? IC perception involves the process of completing the local discrete contour edges (contour completion) and the process of representing the global completed contour information (contour representation). Here, functional magnetic resonance imaging was used to dissociate contour completion and contour representation by varying each in opposite directions. The results show that the neural activity was stronger to stimuli with more contour completion than to stimuli with more contour representation in V1 and V2, which was the reverse of that in the LOC. When inspecting the neural activity change across the visual pathway, the activation remained high for the stimuli with more contour completion and increased for the stimuli with more contour representation. These results suggest distinct neural correlates of contour completion and contour representation, and the possible collaboration between the two processes during IC perception, indicating a neural connection between the discrete retinal input and the coherent visual percept. PMID- 21826764 TI - Internalizing and externalizing behaviour problems in childhood contribute to the development of anorexia and bulimia nervosa-a study comparing sister pairs. AB - OBJECTIVE: We wanted to clarify whether there is any clinically relevant behavioural psychopathology in patients before onset of an eating disorder (ED) compared with their healthy sisters and if there are differences in behavioural problems between the ED subtypes anorexia nervosa-restricting type (AN-R) and EDs with bulimic behaviour. METHOD: Behavioural psychopathology was examined by parental report using the Child Behaviour Checklist retrospectively in 83 sister pairs discordant for an ED (37 with AN-R and 46 with bulimic EDs) by means of conditional logistic regression. RESULTS: Participants who later developed an ED had significantly higher internalizing and externalizing behavioural abnormality scores before onset of the ED than their unaffected sisters. Conditional logistic regression revealed significantly higher internalizing behaviour scores in AN-R and significantly higher internalizing and externalizing scores in the bulimic disorders. DISCUSSION: Internalizing problems (anxiety, depression and somatization) preceded the development of AN, whereas both internalizing and externalizing behaviour problems (aggressive and delinquent behaviour) preceded bulimic disorders. PMID- 21826765 TI - Efficacy of infliximab rescue therapy in patients with chronic refractory pouchitis: a multicenter study. AB - BACKGROUND: Despite medical therapy, 30% of patients with ulcerative colitis (UC) need to undergo surgery. Around 50% of patients with proctocolectomy with ileal pouch-anal anastomosis (IPAA) develop complications of the pouch. Clinical evidence for the use of infliximab (IFX) in refractory pouchitis is limited. The aim of this study was to report efficacy of IFX in these patients. METHODS: A retrospective, multicenter study was designed. Patients older than 18 years with chronic refractory pouchitis treated with IFX (5 mg/kg) were included. Short-term IFX efficacy was evaluated at week 8 and mid-term efficacy at weeks 26 and 52. Complete response was defined as cessation of diarrhea and urgency and partial response as marked clinical improvement but persisting symptoms. The modified Pouchitis Disease Activity Index (mPDAI) without endoscopy was calculated when available. RESULTS: Thirty-three consecutive UC patients with chronic refractory pouchitis were included (18 male, mean age 45 years, range 21-67). At week 8, 21% patients achieved complete response and 63% showed partial clinical response. At weeks 26 and 52, 33% and 27% achieved complete response and 33% and 18% showed partial clinical response, respectively. Thirteen patients (39%) withdrew treatment (four for lack of efficacy, four for loss of response and five for adverse events). None of the potential factors analyzed had an influence on response to IFX. CONCLUSIONS: IFX was effective in the short- and mid-term in patients with chronic refractory pouchitis. However, medication had to be discontinued in a high number of patients. PMID- 21826767 TI - Severe CMV-related pneumonia complicated by the hemophagocytic lymphohistiocytic (HLH) syndrome in quiescent Crohn's colitis: harmful cure? PMID- 21826766 TI - Statins are associated with reduced use of steroids in inflammatory bowel disease: a retrospective cohort study. AB - BACKGROUND: Statin medications have antiinflammatory effects. We sought to determine whether statin use in persons with inflammatory bowel disease (IBD) was associated with reduced rates of steroid use or other markers of disease activity. METHODS: We performed a retrospective cohort study using administrative data. Statin users with IBD were compared to statin-unexposed IBD subjects. The primary outcome was an oral steroid prescription; secondary outcomes included anti-tumor necrosis factor (TNF) initiation, hospitalization, or abdominal surgery. Cox proportional hazard models were used to estimate hazard ratios (HRs) adjusted for potential confounders. RESULTS: The study cohort included 1986 statin-exposed and 9871 unexposed subjects. Statin use was associated with an 18% reduction in the rate of steroid initiation (HR 0.82, 95% confidence interval [CI] 0.71, 0.94). A statistically significant result was seen with atorvastatin only (HR 0.76, 95% CI 0.60, 0.96). Statins were associated with a reduced rate of steroids in ulcerative colitis (HR 0.75, 95% CI 0.62, 0.91), but not in Crohn's disease (HR 0.91, 95% CI 0.74, 1.12). Statin use was associated with reduced hazard of anti-TNF use (HR 0.72, 95% CI 0.46, 1.11), abdominal surgery (HR 0.80, 95% CI 0.63, 1.02), and hospitalization (HR 0.88, 95% CI 0.74, 1.05), but these results did not reach statistical significance. CONCLUSIONS: In this large retrospective cohort study, statin use among persons with IBD was associated with reduced use of oral steroids, particularly for ulcerative colitis. Prospective clinical trials are needed to confirm whether adjuvant treatment of IBD with statin drugs may spare immunosuppressant therapy or ameliorate flares. PMID- 21826768 TI - Differences of small intestinal bacteria populations in adults and children with/without celiac disease: effect of age, gluten diet, and disease. AB - BACKGROUND: Scientific evidence has revealed microecological changes in the intestinal tract of celiac infants. The objective of this work is the study of bacterial differences in the upper small intestine in both adults (healthy, untreated celiac disease [CD], and CD treated with a gluten-free diet) and children (healthy and untreated CD). METHODS: Intestinal bacterial communities were identified by 16S rRNA gene sequencing of DNA extracted from duodenal biopsies. RESULTS: Analysis of the sequences from adults and children showed that this niche was colonized by bacteria affiliated mainly with three phyla: Firmicutes, Proteobacteria, and Bacteroidetes. In total, 89 different genera were identified in adults and 46 in children. Bacterial richness was significantly lower in the children than in the adults. A global principal component analysis of the bacterial communities of both healthy and untreated CD patient groups (including both children and adults) revealed a strong effect of age in principal component 1--clustering all adults and children separately--and a possible effect of the disease in adults with untreated patients clustering separately. CONCLUSIONS: There are bacterial differences in the upper small intestine between untreated children CD patients and untreated CD adults due to age. There are bacterial differences in the upper small bacteria microbiota between treated and untreated CD adults due to treatment with a gluten-free diet. PMID- 21826769 TI - Claisen rearrangement of graphite oxide: a route to covalently functionalized graphenes. PMID- 21826770 TI - pH-Tunable calcium phosphate covered mesoporous silica nanocontainers for intracellular controlled release of guest drugs. PMID- 21826771 TI - Layered-carbon-stabilized iron oxide nanostructures as oxidation catalysts. PMID- 21826772 TI - A simple recipe for sophisticated cocktails: organocatalytic one-pot reactions- concept, nomenclature, and future perspectives. AB - Asymmetric organocatalysis has been successfully incorporated in many multistep one-pot sequences to provide simple access to structurally complex target molecules in a highly stereoselective fashion. The key feature behind this success is the ability of organocatalyzed reactions to proceed efficiently in the presence of large amounts of spectator reagents. Additionally, owing to their organic nature and substoichiometric presence, organocatalysts are also expected to become innocent bystanders in subsequent transformations. In this Minireview, an easy-to-use classification and nomenclatural system that is capable of systematically and informatively describing each one-pot reaction is introduced, and selected important contributions within the field of organocatalytic one-pot reactions are reviewed according to this new system. Finally, future developments and perspectives in the field are discussed. PMID- 21826773 TI - Actuation of asymmetric cyclopropanation catalysts: reversible single-crystal to single-crystal reduction of metal-organic frameworks. PMID- 21826776 TI - Effect of PIP2 on bilayer structure and phase behavior of DOPC: an X-ray scattering study. AB - Phosphatidylinositol 4,5-bis-phosphate (PIP(2)) is an important lipid in regulation of several cellular processes, particularly membrane fusion. We use X ray diffraction from solid-supported multilamellar 1,2-dioleoyl-sn-glycero-3 phosphocholine (DOPC)/PIP(2) samples to study changes in bilayer structure and the lyotropic phase behavior induced by physiologically relevant concentrations of PIP(2) . Electron-density profiles reconstructed from X-ray reflectivity measurements indicate that PIP(2) strongly affects structural parameters such as lipid head-group width, bilayer thickness, and lamellar repeat spacing of DOPC bilayer stacks. In addition, at lower degrees of hydration, a few molar per cent of PIP(2) facilitates stalk-phase formation and also leads to formation of a hexagonal phase, which is not observed in pure DOPC. These results indicate that the role of PIP(2) in membrane fusion could be, in part, due to its effect on the properties of the lipid bilayer matrix. Furthermore, coexistence of two lamellar phases with different lattice constants is observed in single-component PIP(2) samples. PMID- 21826775 TI - Papain-catalyzed peptide bond formation: enzyme-specific activation with guanidinophenyl esters. AB - The substrate mimetics approach is a versatile method for small-scale enzymatic peptide-bond synthesis in aqueous systems. The protease-recognized amino acid side chain is incorporated in an ester leaving group, the substrate mimetic. This shift of the specific moiety enables the acceptance of amino acids and peptide sequences that are normally not recognized by the enzyme. The guanidinophenyl group (OGp), a known substrate mimetic for the serine proteases trypsin and chymotrypsin, has now been applied for the first time in combination with papain, a cheap and commercially available cysteine protease. To provide insight in the binding mode of various Z-X(AA)-OGp esters, computational docking studies were performed. The results strongly point at enzyme-specific activation of the OGp esters in papain through a novel mode of action, rather than their functioning as mimetics. Furthermore, the scope of a model dipeptide synthesis was investigated with respect to both the amino acid donor and the nucleophile. Molecular dynamics simulations were carried out to prioritize 22 natural and unnatural amino acid donors for synthesis. Experimental results correlate well with the predicted ranking and show that nearly all amino acids are accepted by papain. PMID- 21826778 TI - Density gradient ultracentrifugation on carbon nanotubes according to structural integrity as a foundation for an absolute purity evaluation. PMID- 21826777 TI - Carbogenic nanodots: photoluminescence and room-temperature ferromagnetism. AB - Herein, blue fluorescent carbogenic nanodots (CNDs) with room-temperature ferromagnetism were synthesized by thermal decomposition of organic precursors at different temperatures. Photoluminescence (PL) studies show excitation-wavelength dependent emission properties and PL excitation (PLE) studies confirm the triplet ground state of carbene at the zigzag edge as the fluorescent center. Room temperature magnetic studies reveal the ferromagnetic nature of CNDs and temperature-dependent studies show the presence of an antiferromagnetic phase along with a ferromagnetic phase below 50 K. EPR studies reveal the presence of conduction electrons and localized spins with different g factors. Localized spins at zigzag edges are the origin of the unconventional magnetic behavior, whereas exchange coupling between conduction and localized spins are responsible for long-range magnetic ordering. PMID- 21826779 TI - A remembrance: James B. Nachman 1948-2011. PMID- 21826780 TI - Immature platelet count: a simple parameter for distinguishing thrombocytopenia in pediatric acute lymphocytic leukemia from immune thrombocytopenia. AB - BACKGROUND: Platelet counts below normal values define thrombocytopenia. However, platelet counts alone do not reveal the underlying pathomechanism. New blood cell counters provide additional information on platelet size and volume, and enable the distinction of sub-populations. In this preliminary study, we evaluate whether one of these markers can be used for diagnosis of isolated thrombocytopenia in children. PROCEDURE: We provide normal values for mean platelet volume (MPV), platelet distribution width (PDW), plateletcrit (PCT), platelet large cell ratio (P-LCR), platelet mean-frequent volume (P-MFV), relative immature platelet fraction (IPF%), and absolute IPF (IPF#) for 100 healthy children and analyzed 87 children with thrombocytopenia. RESULTS: In children with platelet production defects, IPF% was low, while in acute immune thrombocytopenia (ITP), IPF% was markedly increased (median 25.2%, P < 0.01), representing accelerated platelet turnover. Interestingly, children diagnosed with acute lymphocytic leukemia (ALL) also had elevated IPF% (median 10%, P < 0.01), suggesting that thrombopoiesis is stimulated despite virtual absence of bone marrow progenitors. Low IPF# was only found in patients with acute ITP. CONCLUSIONS: IPF% is a marker for thrombocytopenia due to defective platelet production while IPF#, representing the immature platelet count, might become a practical parameter to distinguish acute ITP from thrombocytopenia in children with newly diagnosed ALL (P < 0.01). PMID- 21826781 TI - The diagnostic utility of routine chest radiography in the evaluation of the initial fever in patients undergoing hematopoietic stem cell. AB - BACKGROUND: A routine chest radiograph is often performed to evaluate initial fever in patients undergoing hematopoietic stem cell transplantation (HSCT) given the signs and symptoms of infectious pulmonary pathology may be subtle or absent. Studies in patients receiving conventional chemotherapy have shown that chest radiographs do not appear to be helpful in the evaluation of asymptomatic patients with febrile neutropenia. We performed a retrospective review of pediatric stem cell transplant recipients to determine if chest radiographs are useful in the evaluation of initial fever. PROCEDURE: We retrospectively identified 81 consecutive pediatric hematopoietic stem transplant recipients who had a chest radiograph performed as a routine part of the evaluation of initial fever during stem cell transplantation. RESULTS: Seventy-six (94%) of the chest radiographs performed had no evidence of pulmonary infiltrate. Of the five children with positive radiographs, three had symptomatic respiratory infection and two (40%) were asymptomatic. One asymptomatic patient had a history of pulmonary infection with persistent stable infiltrates prior to transplantation. This patient did not have any evidence of pneumonia during the transplant. The second asymptomatic patient had subsequent resolution of the infiltrate with antibiotic administration. None of the patients had a change made in the empiric antibiotic regimen based upon the results of the chest film. CONCLUSIONS: Routine radiographs are not useful in the evaluation of asymptomatic children at the time of an initial febrile event while undergoing HSCT. PMID- 21826782 TI - Stroke With Transfusions Changing to Hydroxyurea (SWiTCH): a phase III randomized clinical trial for treatment of children with sickle cell anemia, stroke, and iron overload. AB - BACKGROUND: Stroke occurs in 5-10% of children with sickle cell anemia (SCA) and has a high (>50%) risk of recurrence without therapy. Chronic monthly erythrocyte transfusions effectively prevent recurrent stroke, but their long-term use is limited by serious side effects, including iron overload. An alternative to transfusion for secondary stroke prevention in SCA is needed, especially one that also improves the management of iron overload. METHODS: Stroke With Transfusions Changing to Hydroxyurea (SWiTCH) is an NHLBI-sponsored Phase III multicenter randomized controlled clinical trial for children with SCA, stroke, and iron overload (NCT00122980). The primary goal of SWiTCH is to compare 30 months of alternative therapy (hydroxyurea and phlebotomy) with standard therapy (transfusions and chelation) for the prevention of secondary stroke and reduction of transfusional iron overload. DISCUSSION: SWiTCH has several distinctive study features including novel methodological and design components: (1) composite primary endpoint including both stroke recurrence rate and iron burden; (2) non inferiority design with an "acceptable" increased stroke risk; (3) transfusion goals based on current academic community practices; (4) special oversight for the enrollment and randomization process; (5) overlap treatment period within the alternative treatment arm; (6) masking of the overall trial Principal Investigator to treatment results; (7) inclusive independent stroke adjudication process for all suspected new neurological events; and (8) periodic therapeutic phlebotomy program to alleviate iron overload. CONCLUSION: Investigation of alternative treatments in SWiTCH could lead to changes in the management of cerebrovascular disease for selected patients with SCA, stroke, and iron overload. PMID- 21826783 TI - Does surgery have a role in the treatment of local relapses of non-metastatic rhabdomyosarcoma? AB - PURPOSE: Patients with non-metastatic rhabdomyosarcoma (RMS) have a cure rate of 50-90%, but up to one-third of them experience mostly a local recurrence. Second line treatment is not standardized as for newly diagnosed tumors. We evaluated the role of surgery on local relapses in a series of patients with RMS. METHODS: This retrospective analysis involves 70 patients enrolled in two consecutives Italian Studies, RMS88 and RMS96, who presented local recurrence. After relapse, 40/70 underwent a surgical excision (Surgery Group, SG), that was demolitive in 10/40; 24/40 had radiotherapy, 16/40 did not receive radiotherapy or data are not known. Thirty patients out of 70 did not receive any surgical treatment (No Surgery Group, NSG), and 20/30 received radiotherapy. RESULTS: Overall survival (OS) after local relapse was 41.6% (mean follow-up 59 months, range 1-226). OS of SG patients was 54% versus 24.7% of the NSG patients (P = 0.0117). Furthermore, OS among the SG was 61.4% with and 41.8% without radiotherapy, and 37.1% with and 0% without radiotherapy among the NSG (P < 0.0001). One patient developed a second local relapse after excision without radiotherapy for the first one, and was cured with further treatment. Demolitive surgery did not improve survival compared to conservative surgery (40% vs. 58.4%, P = 0.1462). CONCLUSION: The treatment of recurrent RMS represents a challenge. In our experience, patients with local relapse had a poor prognosis. SG patients had a better outcome than NSG patients and those treated with resection plus radiotherapy had the best outcome; patients who did not receive any local treatment had an unfavorable outcome. PMID- 21826784 TI - Impact of PET-CT on involved field radiotherapy design for pediatric Hodgkin lymphoma. AB - PURPOSE: To determine how the incorporation of PET-CT changes radiotherapy treatment in pediatric Hodgkin lymphoma. PROCEDURE: Fifty-three Hodgkin lymphoma patients with a median age of 14 years (6-21 years) underwent multiagent chemotherapy followed by involved field radiotherapy (IFRT) to initial sites of disease. All patients had conventional staging which included CT scan of the neck, chest, abdomen and pelvis, bone marrow biopsy +/- MRI, Gallium scan and bone scan. All had an initial 18-F-fluoro-deoxy-D-glucose (FDG) PET-CT. When there was discordance between conventional staging and PET-CT staging, true sites of disease were determined either by biopsy or response to multiagent chemotherapy. RESULTS: In 19 of 53 (35.8%) patients, there was discordance between conventional staging and PET-CT findings. The most common location for the 23 sites of discordance were the spleen in 6 (26.1%), neck in 3 (13%), inguinal nodes in 3 (13%) and mediastinum in 3 (13%). A change in stage occurred in 5 (9.4%) as a result of PET-CT imaging. A change in IFRT fields occurred in 9 (17%); eight were more extensive while one was less extensive. For PET-CT, the specificity, sensitivity, positive predictive value and accuracy were 99.5%, 96.3%, 97.9%, and 98.9%. CONCLUSION: Incorporation of PET-CT information was found to influence IFRT design in 17% of patients, with most having more extensive radiotherapy fields. PMID- 21826785 TI - Second malignant neoplasms following chemoreduction with carboplatin, etoposide, and vincristine in 245 patients with intraocular retinoblastoma. AB - BACKGROUND: To evaluate the occurrence of second malignant neoplasms (SMN) following chemoreduction (CRD) with carboplatin, vincristine, and etoposide (CEV) as frontline therapy in patients with retinoblastoma (RB). PRODECURE: We conducted a two-institution retrospective chart review of 245 patients with intraocular RB treated with six cycles of vincristine, carboplatin, and etoposide for treatment of intraocular retinoblastoma. Cumulative incidence of SMN was calculated with adjustment for the competing risk of death. RESULTS: There were 187 patients with germline retinoblastoma and 58 with non-germline disease. External beam radiotherapy was subsequently utilized in 46 (24%) of germline cases and six (10%) of non-germline cases. Mean follow-up of germline and non germline patients was 80 and 70 months, respectively. Seven subsequent cancers were found in six patients for an overall incidence of 3% at a mean of 11 years. For germline cases, following CEV alone (n = 156), SMN were found in 4% following the RB diagnosis. We found no SMN in patients with non-germline RB. One patient developed pineoblastoma. SMN included osteosarcoma (n = 3), rhabdomyosarcoma (n = 1), orbital and conjunctival melanoma (n = 1), low-grade glioma (n = 1), and acute promyeloctic leukemia (n = 1). Five of the six patients with a second malignancy survive at mean of 46 months (range 15-71 months). CONCLUSIONS: At a mean of 11 years, 4% of children with germline RB treated with CEV as frontline therapy developed SMN's. No SMN was found in non-germline patients. Concerns regarding CEV-induced second cancers should not deter clinicians from using life and vision preserving therapy in patients with retinoblastoma. PMID- 21826786 TI - Levels of biological organization and the origin of novelty. AB - The concept of novelty in evolutionary biology pertains to multiple tiers of biological organization from behavioral and morphological changes to changes at the molecular level. Identifying novel features requires assessments of similarity (homology and homoplasy) of relationships (phylogenetic history) and of shared developmental and genetic pathways or networks. After a brief discussion of how novelty is used in recent literature, we discuss whether the evolutionary approach to homology and homoplasy initially formulated by Lankester in the 19th century informs our understanding of novelty today. We then discuss six examples of morphological features described in the recent literature as novelties, and assess the basis upon which they are regarded as novel. The six are: origin of the turtle shell, transition from fish fins to tetrapod limbs, origination of the neural crest and neural crest cells, cement glands in frogs and casquettes in fish, whale bone-eating tubeworms, and the digestion of plant proteins by nematodes. The article concludes with a discussion of means of acquiring novel genetic information that can account for novelty recognized at higher levels. These are co-options of existing genetic circuitry, gene duplication followed by neofunctionalization, gene rearrangements through mobile genetic elements, and lateral gene transfer. We conclude that on the molecular level only the latter category provides novel genetic information, in that there is no homologous precursor. However, novel phenotypes can be generated through both neofunctionalization and gene rearrangements. Therefore, assigning phenotypic or genotypic "novelty" is contingent on the level of biological organization addressed. PMID- 21826787 TI - Effects of environmental perturbations during postnatal development on the phenotypic integration of the skull. AB - Integration and modularity are fundamental determinants of how natural selection effects evolutionary change in complex multivariate traits. Interest in the study of the specific developmental basis of integration through experimental approaches is fairly recent and it has mainly focused on its genetic determinants. In this study, we present evidence that postnatal environmental perturbations can modify the covariance structure by influencing the variance of some developmental processes relative to the variances of other processes that contribute to such structure. We analyzed the effects of the reduction of nutrient supply in different ontogenetic stages (i.e. before and after weaning, and from birth to adulthood) in Rattus norvegicus. Our results show that this environmental perturbation alters the phenotypic variation/covariation structure of the principal modules of the skull (base, vault, and face). The covariance matrices of different treatment groups exhibit low correlations and are significantly different, indicating that the treatments influence covariance structure. Postnatal nutrient restriction also increases the variance of somatic growth. This increased variance drives an increase in overall integration of cranial morphology through the correlated allometric effects of size variation. The extent of this increase in integration depends on the time and duration of the nutritional restriction. These results support the conclusion that environmental perturbations can influence integration and thus covariance structure via developmental plasticity. PMID- 21826788 TI - Expression of a Musashi-like gene in sexual and asexual development of the colonial chordate Botryllus schlosseri and phylogenetic analysis of the protein group. AB - Tunicates are the unique chordates to possess species reproducing sexually and asexually. Among them, the colonial ascidian Botryllus schlosseri is a reference model for the study of similarities and differences in these two developmental pathways. We here illustrate the characterization and expression pattern during both pathways of a transcript for a gene orthologous to Dazap1. Dazap1 genes encode for RNA-binding proteins and fall into the Musashi-like (Msi-like) group. Our phylogenetic analysis shows that these are related to other RNA-binding proteins (Tardbp and several heterogeneous nuclear ribonucleoproteins types) that share the same modular domain structure of conserved tandem RNA Recognition Motifs (RRMs). We also classify the whole group as derived from a single ancient duplication of the RRM. Our results also show that Dazap1 is expressed with discrete spatiotemporal pattern during embryogenesis and blastogenesis of B. schlosseri. It is never expressed in wholly differentiated tissues, but it is located in all bud tissues and in different spatiotemporally defined territories of embryos and larva. These expression patterns could indicate different roles in the two processes, but an intriguing relationship appears if aspects of cell division dynamics are taken into account, suggesting that it is related to the proliferative phases in all tissues, and raising a similarity with known Dazap1 orthologs in other metazoans. PMID- 21826790 TI - Optimisation of a solid-phase microextraction method for the analysis of nicotine in hair. AB - A headspace solid-phase microextraction method (HS-SPME) followed by gas chromatography with mass spectrometric detection (GC/MS) has been developed for the determination of low concentrations of nicotine in hair. Parameters affecting the SPME procedure including type of fiber coating, extraction mode, extraction temperature and time, desorption time, stirring, and salt addition have been evaluated and optimised. The method provided good linearity (r(2)>=0.9980) over the concentration range tested (0.2-20 ng/mg) and low detection limit (0.02 ng/mg). Precision expressed as relative standard deviation was <10%. The average accuracy was 95%. The proposed method was used to determine hair nicotine levels in 100 children in order to assess exposure to environmental tobacco smoke (ETS). The described HS-SPME procedure is fast, simple, sensitive, and solvent-free and is therefore suitable for studies involving ETS exposure assessment. PMID- 21826789 TI - Retinoic acid modulates chondrogenesis in the developing mouse cranial base. AB - The retinoic acid (RA) signaling pathway is known to play important roles during craniofacial development and skeletogenesis. However, the specific mechanism involving RA in cranial base development has not yet been clearly described. This study investigated how RA modulates endochondral bone development of the cranial base by monitoring the RA receptor RARgamma, BMP4, and markers of proliferation, programmed cell death, chondrogenesis, and osteogenesis. We first examined the dynamic morphological and molecular changes in the sphenooccipital synchondrosis forming region in the mouse embryo cranial bases at E12-E16. In vitro organ cultures employing beads soaked in RA and retinoid-signaling inhibitor citral were compared. In the RA study, the sphenooccipital synchondrosis showed reduced cartilage matrix and lower BMP4 expression while hypertrophic chondrocytes were replaced with proliferating chondrocytes. Retardation of chondrocyte hypertrophy was exhibited in citral-treated specimens, while BMP4 expression was slightly increased and programmed cell death was induced within the sphenooccipital synchondrosis. Our results demonstrate that RA modulates chondrocytes to proliferate, differentiate, or undergo programmed cell death during endochondral bone formation in the developing cranial base. PMID- 21826791 TI - Ultra-performance liquid chromatography coupled to mass spectrometry as a sensitive and powerful technology for metabolomic studies. AB - Metabolomics is the comprehensive assessment of endogenous metabolites of a biological system. These large-scale analyses of metabolites are intimately bound to advancements in ultra-performance liquid chromatography-electrospray (UPLC) technologies and have emerged in parallel with the development of novel mass analyzers and hyphenated techniques. Recently, the combination of UPLC with MS covers a number of polar metabolites, thus enlarging the number of detected analytes in the widely used separation sciences. This technology has rapidly been accepted by the analytical community and is being gradually applied to various fields such as metabolomics and traditional Chinese medicine (TCM). Given the power of the technology, metabolomics has become increasingly popular in drug development, molecular medicine, traditional medicine and other biotechnology fields, since it profiles directly the phenotype and changes thereof in contrast to other "-omics" technologies. Hyphenated UPLC/MS technique is becoming a useful tool in the study of body fluids, represents a promising hyphenated microseparation platform in metabolomics and has a strong potential to contribute to disease diagnosis. This review describes the applications of UPLC/MS in metabolomic research, and comparison role of HPLC/MS, NMR and GC/MS, highlights its advantages and limitations with certain characteristic examples in the life and TCM sciences. PMID- 21826792 TI - Detection of nonfluorescent molecules using differential interference contrast thermal lens microscope for extended nanochannel chromatography. AB - An ultrasensitive absorbance detector, the differential interference contrast thermal lens microscope (DIC-TLM), was employed for a chromatography system using silica nanochannel. Recently, separation of ultrasmall volume sample has been strongly required for single-cell biological and chemical analysis. Previously, we have developed a chromatography system using nanochannels of ~100 nm scale (extended nanochannels) fabricated on a silica substrate. The extended nanochromatography realized highly efficient separation of samples <1 fL without packing materials. However, its detection method was limited to fluorescence method due to the small volume, and a new detector based on absorbance has been required. On the contrary, we have also developed DIC-TLM, a photothermal spectrometer based on absorption and thermal relaxation of sample for determination of concentration of nonfluorescent molecules in extended nanochannel. In this paper, we combined the extended nanochromatography and the DIC-TLM for separation and detection of nonfluorescent dyes. Particularly, basic performances of the DIC-TLM including quantitative performance and sensitivity were deliberated for injected samples of ~fL volume. PMID- 21826794 TI - Alliance for biomedical research in Europe. PMID- 21826793 TI - Regulation of innate immune signalling pathways by the tripartite motif (TRIM) family proteins. AB - The innate immune system recognizes microbial components through pattern recognition receptors (PRRs), including membrane-bound Toll-like receptors and cytosolic receptors such as RIG-I-like receptors and deoxyribonucleic acid (DNA) sensors. These PRRs trigger distinct signal transduction pathways that culminate in induction of an array of cytokines and other mediators required for host defense. The tripartite motif (TRIM) family is a diverse family of RING finger domain-containing proteins, which are involved in a variety of cellular functions. Importantly, recent studies have shown that they are also involved in the regulation of innate immune responses through the modulation of PRR signalling pathways. PMID- 21826795 TI - Bis[3,5-bis(benzylidene)-4-oxo-1-piperidinyl]amides: a novel class of potent cytotoxins. AB - The principal objective of this study was the examination of the theory of cytotoxic synergism. In this exploratory study, we tested the hypothesis that doubling the number of sites available for thiol alkylation in a series of candidate cytotoxins increases potency more than two-fold. This concept was verified in one-third of our comparisons using human Molt 4/C8 and CEM T lymphocytes and murine L1210 cells. In addition, the significant potencies of various members of our compound series justified further studies. Molecular modeling revealed that relative locations of the amidic groups correlate with cytotoxicity. A potent cytotoxic compound, 1,2-bis(3,5-dibenzylidene-4-oxo piperidin-1-yl)ethane-1,2-dione (1a) inhibited the growth of a large number of human tumor cell lines and displayed greater toxicity toward certain non-adherent cells than toward adherent neoplasms or fibroblasts. The mode of action of 1a includes induction of apoptosis and necrosis. PMID- 21826796 TI - Synthesis and antiproliferative activity of some ellipticine-like 11H pyrido[a]carbazole derivatives. AB - Some modified 11H-pyrido[a]carbazoles (11H-PyC) and their corresponding tetrahydro derivatives (11H-THPyC) were prepared. A common multistep pathway characterized by conventional reactions, including a Fischer-indole-type synthesis, yielded the tetracyclic compounds. To improve cytotoxicity, 11H-PyC and 11H-THPyC derivatives were endowed with a diethylaminoethyl side chain. The antiproliferative activity was assessed in three human tumor cell lines, and a number of derivatives showed a cytotoxic effect in agreement with their capacity to form a molecular intercalative complex with DNA and to interfere with the relaxation activity of DNA topoisomerase II. In contrast, three derivatives that exhibited significant antiproliferative efficacy, showed no inhibition of topoisomerase II, thus suggesting an unexpected and novel mode of action for these ellipticine-like compounds independent of topoisomerase II activity. PMID- 21826797 TI - Raman spectroscopy: a potential tool for early objective diagnosis of neoplasia in the oesophagus. AB - There is a profound clinical need for a diagnostic tool that will enable clinicians to identify early neoplastic change in the oesophagus. Raman Spectroscopy (RS) has demonstrated the potential to provide non-invasive, rapid, objective diagnosis of endoscopically invisible precancerous oesophageal dysplasia in vitro. RS analyses biological material to identify highly specific biochemical information that can be used to influence clinical care. Raman spectroscopic mapping could provide automated assessment of tissue biopsies to aid histopathological diagnosis in vitro. Furthermore, the recent development of fibre-optic Raman probes has enabled endoscopic assessment of oesophageal mucosa in vivo. Accurate identification of dysplasia will enable targeted endoscopic resection of early lesions preventing the development of oesophageal cancer. This review summarises the development of Raman systems for use as laboratory based analytical adjuncts and endoscopic diagnostic tools in the distal oesophagus. PMID- 21826798 TI - Reformer and membrane modules for methane conversion: experimental assessment and perspectives of an innovative architecture. AB - An innovative concept for steam methane reforming (SMR), based on reformer and membrane modules (RMMs), has been developed and tested to investigate its performance, in terms of feed conversion, on an industrial scale. A major benefit of the proposed RMM configuration is a shift of the chemical equilibrium of SMR reactions, achieved by removing the hydrogen produced at high temperature through the integration of highly selective palladium-based membranes, which enhances the yield of product. In this manner the process can operate at temperatures as low as 600-650 degrees C, compared to the 850-880 degrees C range used in conventional plants, and allows for the use of a low-temperature heat source. This Full Paper discusses experimental data on feed conversion at different operating parameters, gathered during 1000 h of testing, and processes these data to optimize the overall architecture, defining the maximum achievable feed conversion. An overall conversion of 59% is achieved with two-step reactions at a reforming temperature of 620 degrees C. A conversion as high as 90% can be obtained with a three-step architecture at 650 degrees C by properly extending the design parameters within reasonable limits. PMID- 21826799 TI - Reduction reactions in green solvents: water, supercritical carbon dioxide, and ionic liquids. PMID- 21826800 TI - Microwave-assisted partial hydrogenation of citral by using ionic liquid-coated porous glass catalysts. AB - The microwave-assisted hydrogenation of citral (3,7-dimethylocta-2,6-dienal) to citronellal with molecular hydrogen as the reducing agent was investigated. Several polar and non-polar solvents were screened and imidazolium-based ionic liquids were applied as modifiers for the palladium-containing porous glass catalysts (Pd/TP). The best results were obtained with N-ethyl-N' methylimidazolium dicyanamide, N-ethyl-N'-methylimidazolium acetate, or N-ethyl N'-methylimidazolium trifluoroacetate, which were used to prepare supported catalysts with an ionic liquid layer (SCILL) on Pd/TP by wet-impregnation. The influence of pressure and temperature when using these ionic liquid-containing catalysts, as well as their long-term stabilities, were examined. Working with microwave-assisted heating, high yields of citronellal were achieved under mild conditions within short reaction times. Catalyst characterization was carried out by means of BET measurements, X-ray photoelectron spectroscopy (XPS) and thermo gravimetric analyses. The influences of the ionic liquid layer were derived from experiments carried out before and after the reactions. PMID- 21826802 TI - [Improvement requires good data]. PMID- 21826803 TI - Vision and cognitive neuroscience. Fang Fang. PMID- 21826804 TI - Boom time for neuroscience in China. PMID- 21826805 TI - Donors continue to hold back support from Global Fund. PMID- 21826801 TI - A systems biology approach to synovial joint lubrication in health, injury, and disease. AB - The synovial joint contains synovial fluid (SF) within a cavity bounded by articular cartilage and synovium. SF is a viscous fluid that has lubrication, metabolic, and regulatory functions within synovial joints. SF contains lubricant molecules, including proteoglycan-4 and hyaluronan. SF is an ultrafiltrate of plasma with secreted contributions from cell populations lining and within the synovial joint space, including chondrocytes and synoviocytes. Maintenance of normal SF lubricant composition and function are important for joint homeostasis. In osteoarthritis, rheumatoid arthritis, and joint injury, changes in lubricant composition and function accompany alterations in the cytokine and growth factor environment and increased fluid and molecular transport through joint tissues. Thus, understanding the synovial joint lubrication system requires a multifaceted study of the various parts of the synovial joint and their interactions. Systems biology approaches at multiple scales are being used to describe the molecular, cellular, and tissue components and their interactions that comprise the functioning synovial joint. Analyses of the transcriptome and proteome of SF, cartilage, and synovium suggest that particular molecules and pathways play important roles in joint homeostasis and disease. Such information may be integrated with physicochemical tissue descriptions to construct integrative models of the synovial joint that ultimately may explain maintenance of health, recovery from injury, or development and progression of arthritis. PMID- 21826806 TI - USA homes in on prescription drug abuse. PMID- 21826807 TI - The Lancet Technology: August, 2011. PMID- 21826809 TI - Retraction. A comparison of nefopam and clonidine for the prevention of postanaesthetic shivering: a comparative, double-blind and placebo-controlled dose-ranging study. PMID- 21826808 TI - Galen and his patients. PMID- 21826810 TI - Retraction. Prevention of propofol-induced injection pain by remifentanil: a placebo-controlled comparison with lidocaine. PMID- 21826812 TI - Retraction. Acute phase response to nitroprusside-induced controlled hypotension in patients undergoing radical prostatectomy. PMID- 21826811 TI - Retraction. Effects of postoperative sedation with propofol and midazolam on pancreatic function assessed by pancreatitis-associated protein. PMID- 21826813 TI - Retraction. Nefopam and clonidine in the prevention of postanaesthetic shivering. PMID- 21826814 TI - Strabismus-related prejudice in 5-6-year-old children. PMID- 21826816 TI - Anaphylaxis to patent blue dye--the benefit and the risk. PMID- 21826817 TI - Emergency surgery following trancutaneous aortic valve insertion. PMID- 21826818 TI - Successful airway management in a patient with Goldenhar syndrome using preoperative three-dimensional computed tomography. PMID- 21826819 TI - Ventilation failure as a result of internal battery leakage in an Ulco Ev500 ventilator. PMID- 21826820 TI - [Genetic principles of food related problems--introduction: unexpected reactions on food]. PMID- 21826821 TI - Accentuate the positive. PMID- 21826822 TI - How the mosquito (man) liberated Cuba. PMID- 21826823 TI - Contagion and culture: a view from Victorian studies. PMID- 21826824 TI - Immunology and microbiology devices; reclassification of the herpes simplex virus serological assay device. Final rule. AB - The Food and Drug Administration (FDA) is amending the special controls for the herpes simplex virus (HSV) serological assay device type, which is classified as class II (special controls). These device types are devices that consist of antigens and antisera used in various serological tests to identify antibodies to herpes simplex virus in serum, and the devices that consist of herpes simplex virus antisera conjugated with a fluorescent dye (immunofluorescent assays) used to identify herpes simplex virus directly from clinical specimens or tissue culture isolates derived from clinical specimens. PMID- 21826825 TI - Canine locomotion. PMID- 21826826 TI - Surgical perspectives on inflammatory bowel disease. PMID- 21826827 TI - Image of the Month: Traumatic tricuspid regurgitation. PMID- 21826828 TI - [The barber surgeons of the city of Valencia in the fifteenth century through the book of criminal justice]. PMID- 21826829 TI - Mycobacterium spp. in naturally infected game meat and organs. PMID- 21826830 TI - William Horner Andrews (1887-1953)- first professor of physiology at Onderstepoort. AB - W H Andrews qualified as a veterinarian in London in 1908 and was recruited soon after, in 1909, by Sir Arnold Theiler to join the staff of the newly established veterinary laboratory at Onderstepoort. After initial studies on the treatment of trypanosomosis and on snake venoms he was deployed by Theiler in 1911 to start research on lamsiekte (botulism)at a field station on the farm Kaffraria near Christiana, where he met and married his wife Doris. After a stint as Captain in the SA Veterinary Corps during World War I he succeeded D T Mitchell as head of the Allerton Laboratory in 1918, where he excelled in research on toxic plants, inter alia identifying Matricaria nigellaefolia as the cause of staggers in cattle. When the Faculty of Veterinary Science was established in 1920 he was appointed as the first Professor of Physiology. After the graduation of the first class in 1924, and due to health problems, he returned to the UK, first to the Royal Veterinary College and then to the Weybridge Veterinary Laboratories of which he became Director in 1927. After his retirement in 1947 he returned to South Africa as a guest worker at Onderstepoort where he again became involved in teaching physiology when Prof. Quin unexpectedly died in 1950. Andrews died in Pretoria in 1953 and was buried in the Rebecca Street Cemetery. PMID- 21826831 TI - Origin and history to date of the World Association for the Advancement of Veterinary Parasitology (WAAVP) African Foundation. AB - The origin of the World Association for the Advancement of Veterinary Parasitology (WAAVP) African Foundation is described. The 16th WAAVP Conference held in South Africa in 1997 generated a surplus of ZAR 430 460 (US$ 70 116). This was invested and a foundation established to manage the fund with the intention of using it to the mutual advantage of the WAAVP and African veterinary parasitologists. To date, more than 110 scholarship applications have been screened, and 51 full and partial scholarships awarded to young African veterinary parasitologists to attend subsequent biennial WAAVP Conferences. This investment has grown into a very successful endowment currently valued at US$ 206 553. This article is written in response to many queries across the globe about the origin of this fund and how it has been invested, managed, sustained and utilised. PMID- 21826832 TI - Comparative evaluation of halothane anaesthesia in medetomidine-butorphanol and midazolam-butorphanol premedicated water buffaloes (Bubalus bubalis). AB - Six clinically healthy male water buffaloes (Bubalus bubalis) 2-3 years of age and weighing 290-325 kg were used for 2 different treatments (H1 and H2). The animals of group H1 were premedicated with medetomidine (2.5 g/kg,i.v.) and butorphanol (0.05 mg/kg, i.v.), while in group H2 midazolam (0.25 mg/kg) and butorphanol (0.05 mg/kg) were used intravenously. Induction of anaesthesia was achieved by 5% thiopental sodium in H1 (3.85 +/- 0.63 mg/kg) and H2 (6.96 +/- 0.45 mg/kg) groups. The anaesthesia was maintained with halothane in 100 % oxygen through a large animal anaesthetic machine. Better analgesia and sedation with a significantly lower dose of thiopental for induction and significantly higher values of sternal recumbency time and standing time were recorded in group H1 than in group H2, whereas no significant (P > 0.05) difference for the halothane concentration was observed between groups H1 and H2. Significant decrease in heart rate was observed in group H1 whereas it significantly increased in group H2. In both groups, RR decreased during the preanaesthetic period, which increased significantly (P < 0.01) after halothane administration. In both groups a significant (P < 0.01) fallin RT was recorded from 20 min to the end of observation period. A significant (P < 0.05) fall in MAP was observed in group H1 from 15 min until the end, while in group H2 MAP increased nonsignificantly (P > 0.05) after premedication and a significant (P < 0.05) occurredafter thiopental administration. In both groups a significant (P < 0.01) increase in CVP and a significant (P < 0.01) decrease in SpO2 were observed after premedication which persisted up to 120 min. ECG changes included significant (P < 0.01) decrease and increase in QRS amplitudes in groups H1 and H2 respectively, a significant (P < 0.05) increase in PR interval was recorded at 15 min in group H1, a significant (P < 0.05) decrease in PR interval in group H2, a significant (P < 0.05) decrease in T wave amplitude in group H1, and a significant (P < 0.01) increase in duration of T wave in group H1 . It is concluded that both combinations can be used safely in buffaloes for surgery of 2 h duration but better sedation, analgesia and muscular relaxation and more dose sparing effect on anaesthetics and shorter recovery times were observed in group H1. PMID- 21826833 TI - Evaluation of the effects of long-term storage of bovine ear notch samples on the ability of 2 diagnostic assays to identify calves persistently infected with bovine viral diarrhoea virus. AB - Research aimed at optimising diagnostic laboratory procedures is central to the development of effective bovine viral diarrhoea virus (BVDV) control programmes. BVDV is a single-stranded RNA virus that crosses the placenta to infect foetuses, resulting in reproductive losses due to foetal death or persistently infected calves that die early in life. Persistently infected animals are widely accepted to be the primary reservoir of BVDV and the largest source of infection. This poses important challenges to overall animal/herd health and can cause major losses to the cattle industry. Long-term storage of bovine ear notch samples from calves persistently infected with BVDV may adversely affect the ability of diagnostic assays to detect the virus efficiently. In order to test this hypothesis, ear notch samples from 7 animals were divided into 2 groups. One set was subjected to prompt formalin fixation and the other set stored either as fresh samples without preservatives at -2 degrees C, or soaked overnight in phosphate buffered saline followed by freezing of the supernatant fluid at -2 degrees C. Frozen ear notches and ear notch supernatant yielded positive results with an antigen-capture, enzyme linked immunosorbent assay (AC-ELISA) for the duration of the study (6 months) and optical density (OD) values remained significantly within range. There was no significant difference between storing fresh ear notch samples or PBS at -2 degrees C. However, positive immunohistochemistry (IHC) staining on formalin fixed ear notches started to fade between Day 17 and Day 29 when stored at room temperature. It was concluded that fresh ear notches could safely be stored at -2 degrees C for a period of 6 months prior to testing for BVD viral antigens. PMID- 21826834 TI - Vulture rescue and rehabilitation in South Africa: an urban perspective. AB - South Africa is home to 9 vulture species, of which 7 are endangered. While the cause of the population declines remains largely speculative, a vast amount of effort has been dedicated towards the protection of populations by ensuring sustainable and safe food sources for the various colonies. Limited focus was placed in the past on efforts related to the rescue and/or rehabilitation (R&R) of injured birds and the release of these birds back into the wild. This paper provides an overview of the causes, the impact and success of 3 organisations involved in R&R efforts of vultures in the Magaliesberg mountain range and surrounding areas over a period of 10 years. Study material included 162 Cape griffon (CGV) and 38 African white-backed (AWBV) vultures. Datasets include the number, sex and age of birds received, the reason the vultures were brought in for R&R, surgical interventions performed and outcomes of rescue efforts. The CGV dominated the rehabilitation attempts. Results further show that a large number of apparently healthy birds were presented for veterinary treatment. The R&R data clearly indicate that the major cause of injuries was birds colliding with overhead pylons, as a high number of soft tissue and skeletal injuries were observed. The study also shows that successful releases of rescued birds are possible. It is concluded that urbanisation has had a major negative impact on vultures around the Magaliesberg mountain range. PMID- 21826835 TI - A serological survey for infectious bursal disease virus antibodies in free-range village chickens in northern Tanzania. AB - A study of infectious bursal disease (IBD) or 'Gumboro disease' seroprevalence rates in healthy, non-vaccinated indigenous scavenging chickens in northern Tanzania was conducted in November and December 2009 on 362 chickens raised in a traditional management system. Individual bird and flock-level information was collected using a semi-structured questionnaire, and serum samples were screened for IBD virus (IBDV) antibodies using the enzyme-linked immunosorbent assay (ELISA). The study revealed high rates of IBDV antibodies, yielding an overall seropositive rate of 58.8 % and with at least one positive bird detected in 82.8 % (74/90) of flocks. Univariate logistic regression analysis revealed that seropositivity to IBDV varied significantly (chi2 = 16.1, P < 0.001) between the study sites. The flock seroprevalence was found to vary from 37.5 % to 91 % between districts and from 75 % to 90 % between regions. The results of this study showed that IBD is an endemic and widely distributed disease in northern Tanzania. PMID- 21826836 TI - Piroplasm parasites of white rhinoceroses (Ceratotherium simum) in the Kruger National Park, and their relation to anaemia. AB - As part of a larger survey to map the geographical distribution of Babesia and Theileria parasites in the southern African rhinoceros population, white rhinoceroses were sampled during routine immobilisations in the Kruger National Park. Polymerase chain reaction (PCR) and reverse line blot (RLB) hybridisation assays were used to screen for the presence of piroplasms and complete blood counts were used to assess associated changes in clinical parameters. Of the 195 rhinoceroses sampled, 71 (36.4 %) tested positive for the presence of Theileria bicornis, with no significant change in the haematological parameters measured, while 18 (9.2 %) tested positive for Theileria equi. None of the rhinoceroses sampled tested positive for Babesia bicornis, a parasite associated with mortalities in black rhinoceroses. PMID- 21826837 TI - Serial plasma glucose changes in dogs suffering from severe dog bite wounds. AB - The objective of this study was to describe the changes in plasma glucose concentration in 20 severely injured dogs suffering from dog bite wounds over a period of 72 hours from the initiation of trauma. Historical, signalment, clinical and haematological factors were investigated for their possible effect on plasma glucose concentration. Haematology was repeated every 24 hours and plasma glucose concentrations were measured at 8-hourly intervals post-trauma. On admission, 1 dog was hypoglycaemic, 8 were normoglycaemic and 11 were hyperglycaemic. No dogs showed hypoglycaemia at any other stage during the study period. The median blood glucose concentrations at each of the 10 collection points, excluding the 56-hour and 64-hour collection points, were in the hyperglycaemic range (5.8- 6.2 mmol/l). Puppies and thin dogs had significantly higher median plasma glucose concentrations than adult and fat dogs respectively (P < 0.05 for both). Fifteen dogs survived the 72-hour study period. Overall 13 dogs (81.3 %) made a full recovery after treatment. Three of 4 dogs that presented in a collapsed state died, whereas all dogs admitted as merely depressed or alert survived (P = 0.004). The high incidence of hyperglycaemia can possibly be explained by the "diabetes of injury" phenomenon. However, hyperglycaemia in this group of dogs was marginal and potential benefits of insulin therapy are unlikely to outweigh the risk of adverse effects such as hypoglycaemia. PMID- 21826838 TI - The effect of unrestricted milk feeding on the growth and health of Jersey calves. AB - This study was conducted to determine the effect of feeding high milk volumes on the growth rate, health and cross-sucking behaviour in group-fed Jersey calves. Three-day-old heifers (n = 120) in a seasonal calving dairy herd were randomly assigned to one of 6 treatment groups. Three groups received high milk volumes (HMV), consisting of ad libitum milk or milk replacer feeding twice a day, while 3 groups received restricted milk volumes (RMV), consisting of 2 l twice daily, during the pre-weaning period. After a pre-weaning period during which feeding was reduced to once daily, all calves were weaned at 42 days and monitored until 60 days of age. Adjusting for birth mass, birth date, dam parity and sire, average daily mass gain (ADG), both pre-weaning (days 0-42) and overall (days 0 60), was higher in HMV than in RMV calves (P < 0.001). After weaning, growth rates showed no differences and at 60 days of age the HMV calves maintained a 6.74 kg advantage in mean body mass (P < 0.001). The mean intake of dry starter feed was higher in RMV than in HMV calves. Overall feed conversion rate of HMV calves was 9.6 % better than RMV calves. However, the variable cost per kg mass gain was 12 % higher for HMV calves. In the RMV groups 75 % of calves showed cross-sucking behaviour pre-weaning and 18 % post-weaning, whereas in HMV calves the proportions were 2 % and 7 %, respectively. There was no significant effect of milk volume on the incidence of diarrhoea. We conclude that the feeding of high volumes of milk to Jersey calves has a positive effect on growth rate, without compromising health or reducing solid feed intake after weaning. However, the higher cost of such a feeding system may limit its implementation. PMID- 21826839 TI - Uterine adenocarcinoma with transcoelomic metastases in breeder hens (Gallus domesticus). AB - Hens involved in a Newcastle disease study were euthanased at regular intervals according to a designed protocol. Of these, 7.14 % (n = 42) of the 82-week-old specific pathogen-free breeder hens were found to have well-delineated firm white to yellowish nodules of varying sizes in the abdominal cavity. Histologically, the nodules were identified as an adenocarcinoma originating in the uterus. Transcoelomic spread was evidenced by the presence of similar neoplastic cells embedded in the serosa and outer longitudinal muscle layer of the intestines as well as the liver. PMID- 21826840 TI - Seroprevalence of Brucella abortus and B. canis in household dogs in southwestern Nigeria: a preliminary report. AB - A preliminary serological study of 366 household dogs in Lagos and Ibadan, southwestern Nigeria, was carried out to determine antibodies due to exposure to Brucella abortus and B. canis, using the rose bengal test (RBT) and the rapid slide agglutination (RSA) test, respectively. Results showed that 5.46 % (20/366) and 0.27 % (1/366) of the dogs screened were seropositive to B. abortus and B. canis, respectively. Of all dogs, 36 had a history of being fed foetuses from cows and 11 (30.6 %) of these tested positive in the RBT. Our findings, although based on a limited sample size and a dearth of clinical details, revealed that dogs in Nigeria may be infected with Brucella spp. given the wide range of risk factors. Further studies are recommended to elucidate the epidemiology of brucellosis in dogs and its possible zoonotic consequences in the country. PMID- 21826841 TI - Putting the health in Healthcare Executive. We must serve as role models by living healthier lifestyles. PMID- 21826842 TI - Reducing variations in care: standardization yields improved. PMID- 21826844 TI - Lessons from masters of healthcare leadership. PMID- 21826843 TI - Well-balanced partnerships: achieving physician-hospital alignment. PMID- 21826845 TI - Examining the code. ACHE's Code of Ethics highlights challenges faced by healthcare leaders. PMID- 21826846 TI - Ask the right questions. PMID- 21826847 TI - Building a culture of trust. PMID- 21826848 TI - Aligning hospital and physician leadership strategies. PMID- 21826849 TI - Transitioning to "perfected" informed consent. Mutual understanding calls for shared decision making. PMID- 21826850 TI - Transforming physician-nurse communication. Deteriorating relationships must be reversed for the benefit of patients, staff and the organization. PMID- 21826851 TI - Healthier hospitals initiative. Improving sustainability and safety in healthcare. PMID- 21826852 TI - Value-Based Purchasing Program. Part II. Payments will be based on performance. PMID- 21826853 TI - Never stop networking. Connecting regularly ensures a valuable resource. PMID- 21826854 TI - The tipping point for clinical integration. No turning back now. PMID- 21826855 TI - Leaders' role in patient experience. Hospital leadership must drive efforts to better meet patients' needs. PMID- 21826856 TI - Empowering staff with communication. Addressing conflict and silence contributes to a safer culture. PMID- 21826857 TI - Preventing and addressing workplace abuse: inappropriate and disruptive behavior. PMID- 21826858 TI - Considering the value of older, experienced healthcare executives. PMID- 21826859 TI - An unprecedented attack. PMID- 21826860 TI - College vows to press for further changes to NHS reform bill. PMID- 21826861 TI - Pensions talks in jeopardy after minister's pre-emptive speech. PMID- 21826862 TI - NMC urges registrants to raise concerns about colleagues. PMID- 21826863 TI - Manual checks for deterioration helps trust cut cardiac arrests. PMID- 21826864 TI - Intense lobbying pays off as NHS reforms are watered down. PMID- 21826865 TI - A special relationship. AB - Nurse specialists can make a world of difference to patients with rare diseases, who otherwise can struggle to get an accurate diagnosis and appropriate treatment. PMID- 21826866 TI - Present at the end. AB - Having time to sit with a dying patient would be every nurse's ideal, but in reality that is often not possible. One trust has found a different method of support. PMID- 21826867 TI - In the same vein. AB - A link between chronic cerebrospinal venous insufficiency and multiple sclerosis has not been proved, but patients are clamouring for treatment nonetheless. PMID- 21826868 TI - Calling time on cancer. AB - Ignorance of bowel cancer symptoms prevent people taking action. One charity's nurses are informing and supporting patients. PMID- 21826869 TI - Improving care planning in oncology nursing practice. AB - This article describes a practice development project undertaken in an acute oncology unit in a large teaching hospital in Scotland. The project was designed to address care planning practice in the unit by introducing a pilot intravenous access care plan. The article discusses the review and audit process of the care plans previously used in the unit. The findings are discussed and areas for improvement and recommendations for future practice are outlined. PMID- 21826870 TI - Nursing metrics: measuring quality in patient care. AB - Nursing metrics have been used increasingly in UK health services over the past two years to measure and improve nursing performance and to aid commissioners in linking funding to quality. This article provides an introduction to nursing metrics, including some of the nurse-sensitive indicators and the background to their development. It also provides examples of how metrics are used in practice to improve the care and experience of patients. PMID- 21826871 TI - Stem cell transplantation. PMID- 21826872 TI - Antibiotics: mode of action and mechanisms of resistance. AB - Antibiotic therapy has revolutionised medical care and has many benefits for patients with or at risk of infections. However, the development of antibiotic resistance now limits the effectiveness of these agents, which is a serious public health concern. This article examines these issues and offers guidance on prescribing strategies and resources for nurse prescribers. PMID- 21826873 TI - Benefits of mobile working for community nurse prescribers. AB - This article examines the professional considerations that motivate the adoption of mobile working by nurse prescribers in England. The article presents some of the findings of an ongoing Transforming Community Services Programme pilot study of mobile working in the community by the Department of Health. The benefits and challenges associated with mobile technology are discussed in addition to the importance of clinical leadership and engagement. PMID- 21826874 TI - Community perspective. PMID- 21826875 TI - New nursing role mired in controversy. PMID- 21826876 TI - Stand up to abuse. PMID- 21826877 TI - Is microsurgical technique really necessary in inguinal or sub-inguinal surgical treatment of varicocele? AB - The ideal method for treatment of varicocele is still controversial. The techniques of inguinal and sub-inguinal ligation, although less invasive than "high" abdominal ligations (Palomo, Ivanissevich), have been less popular than the former ones. Up to now most authors have considered as mandatory microsurgical techniques for the ligation of spermatic veins at inguinal or sub inguinal level, or at least instruments of optical magnification in order to preserve testicular arterial supply of the spermatic and cremasteric artery at groin and to prevent testicular atrophia or gonadic ischemia. The aim of this study was to assess clinical outcomes of open surgical technique of varicocele repair compared to results derived from microsurgical series. A retrospective study included 45 patients of mean age 31 years (range 18-39) that underwent open surgical technique of inguinal ligation of spermatic veins in the period 2004 2009; clinical results of this series were compared with those obtained in five relevant studies derived from systematic review of the literature on microsurgical techniques. The pre-operatory evaluation in our series included a physical examination, a minimum of two semen analysis and scrotal color Doppler ultrasound. Post-operative pain, complication rates, days of hospitalization and time to return to work were considered as main outcomes. All patients were evaluated at 1 week, at 3 and 6 months after the operation by means of a physical examination, scrotal Doppler ultrasound and sperm analysis. Most patients (39/45) presented no pain in the first week, 6/45 mild to moderate pain (mean VAS score 2). None of the patients reported pain in the weeks thereafter The hospitalization (1.8 +/- 0.7 days) and the time for return to work (7.2 +/- 3.2 days) were not significantly different in microsurgical and open groups. During follow-up no complications like hydrocele or testicular atrophy were observed. Doppler ultrasound carried out 3 and 6 months after surgery, pointed out no reflux in testicular veins in 41/45 cases while in 4/45 it showed a persistence of reflux grade I, less than the grade before the treatment. Comparing pre-and post-operatory sperm analysis allowed us to observe a significant improvement either in spermatozoa concentration (22 +/- 4 40_+/- 6 millions/ml, p < 0.01), either in motility (33 +/- 4% and 48 +/- 4%, p < 0.05), without significant changes in morphology. No significant differences were recorded comparing these data with those coming from microsurgical series. Our study reported positive clinical outcomes using the technique of sub-inguinal surgical ligature of varicocele without using microsurgical techniques or instruments of optical magnification. The operative time, complication and relapse rates, Doppler flow parameters and semen parameters were not significantly different from those reported in the literature of microsurgical techniques, with the advantage of such a simple surgical technique combined with cost savings and patient's comfort. PMID- 21826878 TI - Blood donors: an ideal population to study the PSA value and the incidence of prostate cancer in healthy population. AB - Population screening for prostatic carcinoma (CP) is a debated topic, and its real utility is still unknown. Nowadays only surveys on little groups or clinical randomized studies are recommended. In this study the male population of blood donors of our hospital aged between 45 and 65 years underwent a complete evaluation for CP. The objectives of the study were: (a) early diagnosis of CEP (b) exclusion of carriers of neoplastic pathology from blood donations (theoretic risk of transmission of neoplastic cells in immunodepressed patients); (c) evaluation of the feasibility of a model to be exported to other Transfusion Centres if successful with an high adhesion rate to the screening. A total of 1387 PSA dosages were obtained on 605 patients. In the 45 to 49 years group PSA value ranged from 0.26 to 2.86 ng/mL (mean and median value were 0.85 and 0.68 respectively), in the 50-59 years group PSA range was 0.6 to 7.96 (mean and median value 1.21 and 0.87 respectively) and in the 60 to 69 years group PSA ranged from 0.7 to 293.67 (mean and median 3.6 and 1.29 respectively). A total of 32 biopsies for high PSA values and/or for suspect digital rectal finding were performed allowing diagnosis of prostate adenocarcinoma in 15 subjects (2.4%). Out of them, 14 underwent radical prostatectomy (9 pT2 - 5 pT3), and one was placed on hormonal therapy PMID- 21826879 TI - Residual prostatic tumour in the surgical bed following radical prostatectomy in organ-confined prostate cancer: possible prognostic significance. AB - INTRODUCTION AND OBJECTIVES: The aim of our study was to verify the impact of benign and malignant residual glandular tissue on surgical bed after radical prostatectomy, in terms of both biochemical and clinical disease progression, in a group of patients with pathologically organ-confined cancer of the prostate (PCa). MATERIAL AND METHODS: Files from 70 consecutive patients who undergone radical retropubic prostatectomy (RRP) for organ-confined PCa were retrospectively evaluated. During each intervention, after prostate removal, biopsies of the surgical bed were obtained from the following sites: urethral/periapical section margin, basal, left and right postero-lateral and under/retrotrigonal regions. No patient was been previously treated with either radiation or hormone therapy. We evaluated the relationship between the presence of either benign or malignant prostatic cells at surgical bed biopsies and the following parameters: postoperative serum PSA levels, definitive Gleason score, tumour staging, margin status. RESULTS: In all cases pathological stage was pT2NOMO, an immediate postoperative PSA zeroing occurred and surgical margins were negative. Surgical bed biopsies after prostate removal were positive for malignant cells in 5/70 cases (7.1%) and for benign prostatic cells in 16/70 patients (22.9%). Overall a biochemical disease progression was observed in 13/70 cases (18.6%): 1 case with surgical bed biopsies positive for cancer; 3 cases with biopsies positive for benign prostatic tissue; 9 patients with biopsies negative for prostatic tissue residuals. In this latter group 2 cases of disease progression were observed. Stratifying patients according to biopsy features, we did not find any significant difference between groups concerning preoperative PSA (p = 0.319), prostate weight (p = 0.158), pathological staging (p = 0.371), Gleason score (p = 0.457), follow-up (p = 0.144), biochemical progression rates (p = 0.553). At logistic regression model the only statistically significant association was between disease progression and preoperative PSA (p = 0.026). Stratifying patients with no malignant biopsies in two subgroups (presence and absence of residual benign prostate tissue) no statistically significant differences were detected in terms of disease relapse (p = 0.158). CONCLUSIONS: In patients with pathologically organ-confined PCa, minimal neoplastic tissue residuals might not significantly affect medium-long-term prognosis: 80% of patients with positive biopsy showed undetectable serum PSA levels after a median follow-up over 5 years. In contrast, surgical margins positive for benign prostatic glands was not significantly related to a possible disease relapse/progression. PMID- 21826880 TI - High energy microwave thermotherapy for symptomatic benign prostatic enlargment: predictive parameters of long term outcome. AB - OBJECTIVES: High-energy transurethral microwave thermotherapy (HE-TUMT) has become one of the most preferred minimally invasive procedure for the treatment of benign prostatic enlargement (BPE). In this study we report the long term results in a subset of patients treated with the 30-minute high energy protocol. PATIENTS AND METHODS: A total of 135 patients were treated with TUMT Prostasoft 3.5. The International Prostate Symptom Score (IPSS), Madsen Symptom Score (MSS), Quality of Life (QoL) score, peak urinary flow rate (Qmax) and post-voiding residual urine volume (PVR) were assessed at baseline and at 12, 24, 36, 48 and 60 months after treatment. RESULTS: The mean follow-up period was 46.1 months. The mean IPSS at baseline was 17.8 and decreased to 5.6 at 60 months (p < 0.001). The MSS decreased from 12.6 at baseline to 4.3 at 5 years (p < 0.0001). The QoL score improved from 4.1 to 2.2 at 5 years (p < 0.001). The mean Qmax value at baseline was 9.4 ml/sec and it improved to 15.7 ml/sec at 60 months (p = 0.001), whereas PVR decreased from 97 to 24 ml at 5 years (p = 0.001). Retreatment was required for 47 patients (34.8%). Univariate and multivariate analysis showed that the only baseline parameters able to predict the long-term efficacy were a IPSS <18 and a Qm, > 10 ml/sec (p = 0.04). CONCLUSIONS: These data shows a high response rate obtained with 30-minute TUMT protocol and a durability of response up to 5 years after treatment, making this procedure a safe and effective alternative to TURP in selected patients. PMID- 21826882 TI - Giant scrotal lymphedema as unique onset sign of muscle-invasive bladder cancer. The risk of a misdiagnosis. AB - A 78-year-old male presented complaining voiding low urinary tract symptoms associated to genital weightiness over the past few years. Grossly the lesion was only interesting the scrotum, for an about 7.5 kg mass. The scrotum was minimally tender, with an intact skin bereft of erythema or inflammation, lower limb lymphedema, inguinal/crural lymphadenopathy. Despite repeated urinary cytologies were negative, an abdominal CT and urethrocystoscopy confirmed a muscle-invasive transitional cell carcinoma affecting the bladder. The surgical strategy included a direct excision of the giant scrotum with local tissue reconstruction and a radical cystectomy with ileal conduit. This is the first time it's noted a giant scrotal lymphedema as the unique onset sign of a muscle invasive transitional cell carcinoma of the bladder otherwise clinically silent. In this clinical setting, a differential diagnosis has always to be carried out, as bladder cancer is a life-threatening disease requiring an aggressive approach. PMID- 21826881 TI - Comparative randomized study on the efficaciousness of treatment of BOO due to BPH in patients with prostate up to 100 gr by endoscopic gyrus prostate resection versus open prostatectomy. Preliminary data. AB - OBJECTIVES: With the advent of medical management and minimally techniques for benign prostate hypeplasia (BPH), invasive surgical procedures such open prostatectomy (OPSU) have become less common, although selected patients may still benefit from open prostatectomy. Aim of this study was to evaluate efficacy and safety of Bipolar TURP (Gyrus electro surgical system) versus standard open prostatectomy in patients with lower urinary tract symptoms (LUTS) due to bladder outlet obstruction (BOO) with markedly enlarged glands refractory to medical therapy. METHODS: From January 2003 to January 2004, 140 patients affected by mild-severe LUTS, secondary to BOO from BPH, refractory to medical therapy, with markedly enlarged glands, were randomized in two groups (1:1), and subjected to open prostatectomy (OPSU) carried out with traditional method (Bracci Thechnique) versus transurethral resection of the prostate (TURP) utilizing the bipolar methodology. Preoperative work-up included IPSS, IIEF-5 and Qol questionnaires. All patients were submitted to uroflowmetry, transrectal ultrasound (TRUS), measurament of postvoidal residual urine and PSA determination. IPSS, IIEF-5 and Qol, uroflowmetry, TRUS, measurement of post-voidal residual urine, PSA determination and number of reoperations were evaluated at 1, 3, 6, 12, 18, 24, 30 and 36 months. Operative time, resected tissue weight and perioperative complications were also registered. Total post-operative catheter time, total postoperative hospital stay, haemoglobin loss were recorded in the 2 groups. RESULTS: Comparative data on IPSS symptom score, IIEF-5 and Qol, PSA, peak urinary flow rates and post-void residual urine volume in the 2 groups were similar but showed a significative improvement with respect to baseline value. Postoperative haemoglobin levels, postoperative catheterization, hospital stay and 3-yr overall surgical re-treatment-free rate were significantly better in the Bipolar group. CONCLUSIONS: In the treatment of LUTS due to bladder outlet obstruction (BOO) with markedly enlarged glands refractory to medical therapy, Bipolar TURP has a comparable outcome to open prostatectomy at short and medium term according to both subjective and objective outcome measures. PMID- 21826883 TI - Ureterectomy and ureteral reimplatation for low-grade transitional cell carcinoma: is the laparoscopic approach feasible and effective? AB - As it is well known, the gold-standard to treat ureteric and pelvi-caliceal transitional cell carcinoma (TCC) is nephroureterectomy. Nevertheless, in particular circumstances, such as solitary kidney, a more conservative treatment is needed. Conservative treatment has been reported for low-grade TCC, also. In this paper we discuss the laparoscopic approach to low-grade ureteric TCC in patients with otherwise normal urinary tract. After reporting a case of a patient treated with this approach, we deal with some technical aspect of the surgical procedure and with the pre-operative and post-operative management of the patient. PMID- 21826885 TI - Benign intrascrotal lesion: fibrous pseudotumor of testis. AB - Fibrous pseudotumors of the tunica vaginalis, epididymis, and spermatic cord are uncommon benign paratesticular masses. We report the case of a 27-year-old man who presented with grossly abnormal testicular examination. Scrotal Doppler ultrasound scan showed normal testicles bilaterally and solid, round, multiple 15 40 mm hypoechoic lesions adjacent to the right testis. Tumoral markers were within normal limits. Uncomplicated right radical orchiectomy was performed. After a follow-up of 12 months, no relapse occurred. We discuss about rare benign paratesticular masses identified as fibrous pseudotumors. PMID- 21826884 TI - Rupture of superficial dorsal vein of penis. AB - Penile fracture is a remarkable but under reported urologic injury. Coitus and penile manipulations are common predisposing factors. Rupture of the superficial vein of penis is an uncommon situation that makes differential diagnosis with other penile lesions. The diagnosis in such cases is mostly after exploration. We report the cases of 34 and 49-year-old male patients with a painless hematoma after intercourse. Conservative or surgery intervention are the alternative mode of treatment. PMID- 21826886 TI - Emphysematous pyelonephritis in decompensated diabetes: a case report and review of the literature. AB - Emphysematous pyelonephritis is a rare and severe renal parenchyma necrotizing infection visible just in diabetic patients which results in gas presence- probably produced through the glucose fermentation process--in the collecting system, renal parenchyma and perirenal tissue. We present a case of a not known diabetic female patient with emphysematous pyelonephritis of the left kidney and emphysematous pyelitis of the controlateral kidney. PMID- 21826887 TI - Caring for bladder dysfunctions in patients with Parkinson's disease. AB - Parkinson's disease and parkinson-like syndromes are frequently associated with disautonomic disorders, particularly urinary symptoms, with various degrees of severity. Urinary symptoms can represent the debut of an extrapiramidal syndrome and in most cases are urgency and incontinence due to detrusor hyperreflexia. Urodynamic studies allow to understand the causes of urinary symptoms, and thus makes possible a rational nursing and therapeutic approach. PMID- 21826888 TI - [Cloning and expression of metalloprotease gene from Schistosoma japonicum and its immunoprotective efficiency]. AB - OBJECTIVE: To clone and express a metalloprotease gene of Schistosoma japonicum, purify the expressed protein, and investigate the induced immune response in mice and its localization in the parasite. METHODS: Specific primers were designed according to the EST sequence and used for amplification of the encoding sequence from the S. japonicum cDNA clone containing S. japonicum metalloprotease. The gene was subcloned into pET-28a plasmid and expressed, and the recombinant protein was purified with HisoTag affinity chromatography. Western blotting was used to analyze the immunogenicity. Eighteen C57BC/6 mice were divided into two groups. Mice in group A were immunized each with 25 microg purified recombinant SjB04 at every 2 weeks for 3 times. Mice in group B received only adjuvant as control. Each mouse was challenged by (40 +/- 2) cercariae at the third week after the last immunization. Fecal samples were collected for 6 days from 37th days after challenge. Eggs per gram feces and rate of egg reduction were calculated. S. japonicum adult worms were collected from infected mice, and used for preparing frozen sections and indirect immunofluorescence staining with specific polyclone antibody to S. japonicum metalloprotease. RESULTS: The metalloprotease gene SjB04 was cloned, sequenced and expressed. The immuno fluorescence localization showed that SjBO4 protein distributed mainly in the intestinal epithelium of the adult worm. The recombinant protein was specifically recognized by the S. japonicum-infected rabbit sera, showing that the expressed product possessed antigenicity. Mice immunized with the recombinant protein revealed a reduction in number of adult worms, eggs in feces by 27.1% and 57.8%, respectively. CONCLUSION: The recombinant protein of S. japonicum metalloprotease has been obtained with Mr 36,500. The protein locates in the intestinal epithelium of adult worm. Immunization with the SjB04 protein induces significant reduction of fecal eggs. PMID- 21826889 TI - [Preliminary function study on Mago nashi gene of Schistosoma japonicum]. AB - OBJECTIVE: To study the function of Mago nashi gene in reproductive system of Schistosoma japonicum. METHODS: dsRNA products of SjMago nashi gene and control gene (lacZ) were generated by in vitro transcription. SjMago nashi dsRNA and control (lacZ) dsRNA were electroporated into mechanically transformed schistosomula. Aliquots of parasites (1000) were harvested at day 1, 3, and 5 after electroporation, respectively. Total RNA and proteins were isolated simultaneously using TRIzol reagent. Levels of SjMago nashi mRNA and protein were determined by RT-PCR and Western blotting analysis, respectively. About 1000 dsRNA-electroporated schistosomula were injected into each BALB/c female mouse. Six weeks later the worms were collected, fixed, stained, clarified, dehydrated and mounted. The male and female reproductive organs were observed and measured under the confocal laser scanning microscope. RESULTS: At day 1, 3 and 5 post electroporation, 22%, 69%, and 80% reduction in Mago nashi mRNA levels were detected respectively in SjMago nashi dsRNA-electroporated schistosomula (experiment group) compared to parasites treated with control dsRNA (control group); and schistosomula of experiment group exhibited 12%, 39%, and 56% decreased in Mago nashi protein expression levels in comparison to the control group, respectively. In experiment group there were many spermatozoa in testicular lobes and no changes were observed in ovary and vitelline gland. Compared to control group, adult worms in experiment group were smaller in the body width, the width and length of testicles and ovaries (P < 0.05). CONCLUSION: Mago nashi dsRNA can specifically inhibit the expression of target gene and protein. SjMago nashi gene is a reproduction-related gene. PMID- 21826890 TI - [Inhibitory effect of paeoniflorin on the collagen production by fibroblasts through IL-13/STAT6 signaling pathway]. AB - OBJECTIVE: To observe the effects of paeoniflorin on 3T3 fibroblast activation, proliferation and collagen production through IL-13/STAT6 signaling pathway. METHODS: 3T3 cell strain was cultured with serum-free medium for 12 h, then stimulated by paeoniflorin (200, 400, 600, 800, and 1000 mg/L) or rIL-13 (6.25, 12.5, 50, 100, and 200 microg/L) for another 24 h. At the same time the blank control group for paeoniflorin or rIL-13 was observed. 3T3 cell proliferation was assayed by Cell Counting Kit-8 (CCK-8), and an appropriate concentration (100 microg/L) of rIL-13 was chosen according to the result of cell proliferation. Subsequently, 3T3 cell cultured with serum-free medium for 12 h was stimulated by 100 microg/L rIL-13 for 12 h, and then was treated with different concentrations of paeoniflorin (200, 400, 600, 800, and 1000 mg/L) for another 24 h. Untreated 3T3 cell served as blank control Cell proliferation was measured by CCK-8. Hydroxyproline content in cell supernatant was determined by alkaline lysis method. IL-13Ralpha1, alpha-SMA and STAT6 protein expression were detected by Western blotting. Col-I, Col-III, IL-13Ralpha1 and STAT6 mRNA expression were analyzed by RT-PCR. RESULTS: Paeoniflorin inhibited 3T3 cell proliferation in a concentration-dependent manner (r = -0.980, P < 0.01), and there was a statistically significant difference among all groups (F = 198.599, P < 0.01). rIL-13 caused a remarkably concentration-dependent increase in proliferation of 3T3 cells (r = 0.538, P < 0.05). Paeoniflorin (200, 400, 600, 800, and 1000 mg/L) inhibited proliferation of 3T3 cell stimulated by rIL-13 in a concentration dependent manner (1.780 +/- 0.177, 1.636 +/- 0.073, 0.965 +/- 0.066, 0.623 +/- 0.037, 0337 +/- 0.022, r = -0.971, P < 0.01), and among all groups there existed a significant difference (F = 198.537, P < 0.01). Moreover, paeoniflorin also suppressed secretion of hydroxyproline from 3T3 cell stimulated by rIL-13 in a concentration-dependent manner (3.030 +/- 0.094, 2.976 +/- 0.047, 2.814 +/- 0.047, 2.652 +/- 0.124, 2.408 +/- 0.124, r = -0.916, P < 0.01) with a statistical significance among all groups (F = 13.642, P < 0.01). Further investigations showed that paeoniflorin decreased both protein expression of alpha-SMA, IL 13Ralpha1, and STAT6, and mRNA expression of Col-I, Col-III, IL-13Ralpha1, and STAT6 in 3T3 cell stimulated by rIL-13. CONCLUSION: Paeoniflorin inhibits activation, proliferation of fibroblasts and production of collagen from fibroblasts through IL-13/STAT6 signaling pathway, which might be one of mechanisms of anti-hepatic fibrosis of paeoniflorin in schistosomiasis japonica. PMID- 21826891 TI - [Sequence analysis of 16S rDNA gene of endosymbiont of Acanthamoeba sp. CB/S1 isolated from soil]. AB - The endosymbiont of Acanthamoeba sp. CB/SI was identified by orcein-carmine staining and 16S rDNA sequence analysis. The endosymbiont bacteria were rod shaped and darkly stained, and irregularly localized within the cytoplasm. The length of the 16S rDNA was 1534 bp and its DNA sequence was closely related to those of Candidatus Amoebophilus asiaticus and Acanthamoeba sp. KA/E21 with 98% homology. Phylogenetic analysis showed that the endosymbiont of CB/SI, the endosymbiont of KA/E21, Candidatus Amoebophilus asiaticus, the endosymbiont of Ixodes scapularis, and the endosymbiont of Encarsia pergandiella constitute a monophyletic lineage in phylogenetic tree. PMID- 21826892 TI - [Ageing down-modulates the immune responses to Schistosoma japonicum infection in mice]. AB - OBJECTIVE: To investigate the effect of ageing on the immune responses against Schistosoma japonicum infection in mice. METHODS: Female BALB/c mice were divided into young group (2 months) and old group (18 months), each composed of 8 mice. Each mouse was percutaneously infected with 40 +/- 1 S. japonicum cercariae. At 6 weeks post-infection, the mice were sacrificed, and the spleens were removed and single-cell suspensions of splenocytes were prepared. Worms were perfused from hepatic portal system and counted. The number of eggs in the liver was determined after KOH digestion. Mean single-egg granulomas sizes were determined in stained histological sections. Splenocyte proliferation responses were analyzed by MTT colorimetry. Level of interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) in the splenocyte culture supernatants was determined by ELISA. RESULTS: The worm burden and egg per gram of liver in old mice [19.75 +/- 1.95, (1.59 +/- 1.05) x 10(4)] were significantly lower than that of young mice [26.00 +/- 2.42, (208 +/- 0.87) x 10(4)] (P < 0.05). The mean volume of single-egg granulomas of the livers in old mice [(30.13 +/- 10.97) x 10(3) mm3] was significantly lower than that of the young mice [(47.02 +/- 24.13) x l0(3) mm3] (P < 0.05). RESULTS: of T cell proliferation showed that the splenocytes had poorer immune reactivity to ConA in old mice (SI: 1.08 +/- 0.12) than that in young mice (SI: 131 +/- 0.14) (P < 0.05). Levels of IFN-gamma and IL-4 in the splenocyte culture supernatants [(24.05 +/- 6.24), (4.15 +/- 0.68) pg/ml] from old mice were lower than that of young mice [(34.25 +/- 869), (7125 +/- 0.83) pg/ml](P < 0.05). CONCLUSION: Ageing down-modulates the immune responses and the poorer immune reactivity might decrease pathological alterations in mice infected with Schistosoma japonicum. PMID- 21826893 TI - [Histology of the alimentary canal in mature larva of Simulium (Wilhelmia) xingyiense chen and zhang (Diptera: Simuliidae)]. AB - The histology of alimentary canal of Simulium (Wilhelmia) xingyiense mature larva (with gill spots) was investigated by using paraffin serial section. The alimentary canal is composed of foregut, midgut and hindgut. The foregut includes pharynx, esophagus and proventriculus. The up-inside of buccal cavity invaginates to form the labral gland with irregular shape. Ossified cibarium exist in anterior pharynx. Canular proventriculus forms by the invagination of esophagus. The midgut begins with four big gastric caeca, and divides into three regions according to the epithelium cell shape. The hindgut consists of pylorus, ileum and rectal. The structure of the ileum is different from rectal. Four malpighian tubules diverge from the boundary between midgut and hindgut. The structure of silk duct is special PMID- 21826894 TI - [Effect of ginsenoside Rg3 on hepatic fibrosis in murine schistosomiasis japonica]. AB - OBJECTIVE: To investigate the therapeutic efficacy of ginsenoside Rg3 on hepatic fibrosis in murine schistosomiasis japonica. METHODS: 54 ICR-strain male mice were divided into 4 groups named as normal control group (A), infected control group (B), praziquantel+Rg3 treated group (C) and praziquantel treated group (D). There were 12 mice in each group, but 18 in group A. Mice in groups B, C, and D were infected with 20 +/- 2 cercariae of Schistosoma japonicum. At ten weeks post infection, 10 mice of group A and 12 mice of group B were weighed and sacrificed. Specimens from left hepatic lobes were taken and fixed in 10% formaldehyde solution. Mice in groups C and D were treated intragastrically with praziquantel at a single dose of 300 mg/kg. At the second day after praziquantel treatment, each mouse in group C was given 3 mg/(kg x d) ginsenoside Rg3 for 8 weeks. The rest mice were sacrificed on 8 weeks after treatment, and liver tissue samples from left hepatic lobes were prepared. The histological changes and collagen fiber deposition in the liver tissue sections were observed with hematoxylin eosin staining and van gieson staining. Liver fibrosis was graded according to semi-quantitative scoring system (SSS) method. RESULTS: In group B, many eggs deposited in the hepatic lobules and portal areas, and eosinophilic abscesses and pseudo-tubercles developed in the liver, especially common in portal areas. There were many fibre hyperplasia and deposit inside abbacy and liver flocculus. Pipestem fibrosis formed around the portal areas, and some cord-like fibres extended into hepatic lobules, and formed in the fibrous septa. After 8-week treatment with ginsenoside Rg3, in group C, the livers were initially enlarged, firm and dust-color; and the degree of hepatomegaly varied from mild to marked; but the degree of fibre hyperplasia and inflammatory infiltration were mitigated compared with that of group B. Mean percentage of collagen area in group C [(2.32 +/- 0.99)%] was lower than that of groups B [(11.08 +/- 4.43)%] and D [(11.19 +/- 4.91)%] (P < 0.05). The SSS scores of hepatic fibrosis in group C (2.83 +/- 1.09) was lower than that of groups B (7.42 +/- 1.16) and D (8.08 +/- 1.76) (P < 0.05). CONCLUSION: Ginsenoside Rg3 shows anti-hepatofibrosis effects in murine schistosomiasis japonica after praziquantel treatment. PMID- 21826895 TI - [Echinococcus granulosus recombinant antigen B induced IDO expression in mouse bone marrow-derived dendritic cells in vitro]. AB - OBJECTIVE: To observe the expression of indoleamine 2,3-dioxygenase (IDO) in mouse bone marrow-derived dendritic cells (DCs) after adding Echinococcus granulosus recombinant antigen B (rAgB) in vitro. METHODS: CD11c+ DCs generated from bone marrow precursor cells of C57BL/6 mice and cultured in the presence of recombinant mouse GM-CSF (rmGM-CSF). The morphology of DCs was observed by inverted microscope and scanning electronic microscope. The level of I-A/I-E, CD40, CD80, and CD86 on DCs were determined by flow cytometry. T cell proliferation induced by DCs were evaluated by using mixed lymphocyte reaction (MLR) assay. At day 6 post culture, the immature DCs were collected, and part of the immature DCs stimulated with lipopolysaccharide (LPS) for 24 h were examined by flow cytometry. Immature DCs were divided into 3 groups: negative control group, positive control group (rmIFN-gamma, 1000 U/ml) and rAgB group. Immature DCs of positive control group and rAgB group were induced with 1000 U/ml rmIFN gamma and 15 microg/ml rAgB, respectively. IDO expression in DCs was examined 24 h after induction using immunohistochemical method and Western blotting. RESULTS: More than 80% CD11c+ DCs were harvested. The typical DCs were observed under inverted microscope and scanning electronic microscope. The level of CD40, CD80, and IA/IE (MHC II) in mature DCs group was significantly higher than that of immature DCs group (P < 0.05). In MLR, mitomycin-treated DCs can stimulate T lymphocytes proliferation activity. There were significantly differences in IDO expression in the negative control group [(4.544 +/- 1.752)%], positive control group [(20.464 +/- 4.452)%] and rAgB group [(11.148 +/- 1.966)%] (P < 0.05). Western blotting result indicated that the ratio of IDO/GAPDH in rAgB group (0.573 +/- 0.129) was significantly higher than that of negative group (0.229 +/- 0.085) (P < 0.05), and there were no significant difference in the ratio of IDO/GAPDH between IFN-gamma group (0.794 +/- 0.114) and rAgB group (P > 0.05). CONCLUSION: rAgB can induce IDO expression in bone marrow-derived dendritic cells in vitro. PMID- 21826897 TI - [Immunogenicity of the recombinant plasmid of Leishmania donovani amastigote gene]. AB - OBJECTIVE: To investigate the immunogenicity of recombinant plasmid pcDNA3.1 amastigote with Leishmania donovani amastigote gene. METHODS: Eighteen female BALB/c mice were randomly divided into experimental group and control group. Mice in experimental group and control group were intramuscularly injected with 50 microg recombinant plasmid pcDNA3.1-amastigote and blank plasmid vector pcDNA3.1(+), respectively, and then received equivalent dose of plamid after 2 weeks. On days 7, 14, and 21 after the second immunization, serum samples were collected from 3 mice each group. The mice were then sacrificed, spleens were removed and splenocytes were collected. Serum antibody level was determined by indirect ELISA. Splenocyte proliferation responses and cytotoxicity of spleen derived lymphocytes were analyzed by MTT colorimetry after stimulation with ConA. Level of IFN-gamma, IL-2 and IL-4 in the splenocyte culture supernatants was determined by double antibody sandwich ELISA. RESULTS: On days 7, 14, and 21 after the second immunization, specific IgG antibody (more than 1:640) was found in experimental group, but not in the control (P < 0.01); stimulation index (SI) of spleen cells in experimental group (428 +/- 0.51, 5.01-0.60, and 4.39 +/- 0.50) was higher than that of control group (P < 0.01); the level of IFN-gamma [(42.06 +/- 4.26), (66.02 +/- 6.02), and (58.29 +/- 3.75) pg/ml] and IL-2 [(38.21 +/- 5.11), (64.79 +/- 8.67), and (52.69 +/- 7.15) pg/ml] in splenocyte culture supernatants of experimental group was higher than that of control group (P < 0.01); IL-4 was not found in the two groups; cytotoxicity of spleen-derived lymphocytes in experimental group [(42.20 +/- 5.96)%, (63.66 +/- 5.44)%, and (52.24 +/- 4.56)%] was stronger than that of control (P < 0.01). CONCLUSION: The recombinant plasmid pcDNA3.1-amastigote can induce specific humoral and Th1 type cellular immune responses in mice. PMID- 21826898 TI - [Three imported cases of trichinosis]. PMID- 21826896 TI - [Effect of oral administration of tribendimidine at different dosages against Trichinella spiralis encapsulated larvae in mice]. AB - OBJECTIVE: To observe the efficacy of oral administration of tribendimidine (TBD) at different dosages against Trichinella spiralis encapsulated larvae in murine striated muscle. METHODS: A total of 88 BALB/c mice were divided equally into 11 groups. Each mouse was infected orally with 50 T spiralis encapsulated larvae. At day 29 after infection, TBD was each orally administered to mice of the 11 groups with doses of 0 (control group), 50, 100, 150, 200, 250, 300, 350, 400, 450, and 500 mg/(kg x d), respectively. All mice were administered once a day and lasted for 6d, and untoward drug reactions for mice were observed. Mice were sacrificed at the 7th day after administration of TBD, the encapsulated larvae in diaphragmatic muscle, jugomaxillary muscle, pectoral muscle and gastrocnemius muscle were examined by pellet method, and the total, survival and dead worms were counted. The therapeutic effect was estimated on the basis of average quantity of encapsulated larvae per gram muscle. RESULTS: During the administration period, no untoward reaction were observed in mice of 50-300 mg/(kg x d) groups. Mice in 350 and 400 mg/(kg x d) groups showed body hair dishevelment, emaciation and food-intake decrease, death rates were 25% and 50%, respectively. All mice in 450 and 500 mg/(kg x d) groups died on day 4 and 5 after TBD administration, respectively. In control group, the highest total burden (per gram) was found in diaphragmatic muscle, followed by jugomaxillary muscle, gastrocnemius muscles and pectoral muscles. TBD at dose of 50 mg/(kg x d) was unable to kill encapsulated larvae. In the rest groups, with the increase of drug dose, the total worm burden and the number of survival worms showed a decreasing trend in four kinds of muscles, and were significantly lower than that of the control group (P < 0.05 or P < 0.01). In 300 mg/(kg x d) group the number of survival worms in diaphragmatic muscle, jugomaxillary muscle, pectoral muscle and gastrocnemius muscle [8.6 +/- 1.7, 2.8 +/- 0.7, 3.9 +/- 0.8, and 0, respectively] were significantly lower than that of the control group [3648.1 +/- 989.2, 1266.4 +/- 812.3, 701.9 +/- 196.4, and 711.6 +/- 34.6] (P < 0.01). All encapsulated larvae in the four kinds of muscle died in 350 and 400 mg/(kg x d) groups. With the increase of TBD dosage, the mortality of encapsulated larvae increased in the muscles, reached up to 98.6%--100% in 300 m (kg x d) group (P < 0.01), and 100% in 350 and 400 mg/(kg x d) groups (P < .01). CONCLUSION: Oral tribendimidine administered at 50 mg/(kg x d) to mice for 6 d is unable to reduce worm burden in muscle. Tribendimidine 300 mg/(kg x d) effectively kill encapsulated larvae and is a suitable dose against encapsulated larva stage. However, tribendimidine at doses of 350 mg/(kg x d) and above for 6d is toxic to mice and even causing death. PMID- 21826899 TI - [Effect of 6 MeV radiotherapy on secondary Echinococcus multilocularis infection in rats]. AB - OBJECTIVE: To explore the effect of 6-MeV X-ray radiotherapy on secondary Echinococcus multilocularis infection in rats. METHODS: Female SD rats were used to develop a secondary infection model, and then randomly divided into experimental group and control group (5/group). Rats in experimental group received two irradiations at 7-day intervals with the same dose (20 Gy) which applied with 6-MeV ray. The rats in control group did not receive any treatment. At one month after the second irradiation, the pathomorphological changes of E. multilocularis cysts were observed. RESULTS: Cysts in experimental group showed different degrees of damage, including that the laminated layer and germinal layer became swollen and separated from each other, brood capsules and protoscoleces were rare. The structure of cysts was normal in control group, laminated layer and germinal layer were clear, and there were many protoscoleces in the brood capsule. CONCLUSION: 6 MeV radiotherapy can inhibit the growth of E. multilocularis. PMID- 21826900 TI - [Extraction of agglutinin from Oncomelania hupensis and its haemagglutination activity]. AB - OBJECTIVE: To explore the extraction methods of agglutinin from Oncomelania hupensis snail and study its haemagglutination activity. METHODS: Protein obtained by ammonium sulfate fractionation precipitation with 20%-100% saturation of ammonium sulfate. Its haemagglutination activity was determined by rabbit erythrocytes. The precipitation which could agglutinate rabbit erythrocytes was diluted with 2.5 mg/ml D-galactose, D-fructose, D-glucose, saccharose, maltose and lactose, respectively, and then their haemagglutination activity was tested. Snail agglutinin were incubated at different temperatures (25-90 degrees C) and assayed for agglutinating activity. The effect of pH on the haemagglutination activity was determined by using the PBS buffer at different pH values (3.0 10.0). RESULTS: Oncomelania snail agglutinin exhibited high haemagglutination activity in 20%-40% saturated ammonium sulfate pellet. Lactose and galactose could inhibit the haemagglutination activity of snail agglutinin. The agglutinin showed maximum activity at pH 7.0. In temperature range of 30-70 degrees C, the haemagglutination activity decreased with increasing temperature, and all activity lost beyond 80 degrees C. CONCLUSION: Galactose/lactose specific agglutinin exists in Oncomelania snail, its haemagglutination activity is affected by pH and temperature. PMID- 21826901 TI - [A case of Thelazia callipaeda infection]. PMID- 21826902 TI - [An investigation on malaria vectors in western part of China-Myanmar border]. AB - OBJECTIVE: To reveal the distribution and composition of malaria-transmitting vectors on the western part of China-Myanmar border. METHODS: An entomological survey of malaria vectors was carried out in six villages of Yingjiang County and Xidong County on China-Myanmar border between August and September, 2008. Mosquitoes in human dwellings and cattle sheds were collected by overnight trapping with ovitrap light. The mosquitoes were firstly identified morphologically, and then Anopheles minimus A and C, An. aconitus, and An. jeyporiensis were identified by using multiplex PCR. Some mosquitoes were selected to extract the total genomic DNA, and detect sporozoites by nested PCR. RESULTS: A total of 4571 mosquitoes were captured with 54.32% (2483/4571) of anopheline mosquitoes. There was significant difference in Anopheles species composition in human dwellings and cattle sheda The main species in human dwellings were An. kochi, An. minimus, and An. sinensis, while the principal species in cattle sheds consist of An. kochi (223), An. annularis (184), An. vagus (131), and An jeyporiensis (129). Furthermore, the composition in human dwellings of villages with and without cattle was significantly different. An. minimus (260) and An. kochi (49) werethe most important species in villages with cattle, whereas An. kochi (481) and An. sinensis (124) were the key species in villages without cattle. A total of 1075 mosquitoes were examined for sporozoites and 9 mosquitoes were found to be infected. Only three species, Le. An. minimus (7/408), An aconiaus (1/125) and An. pseudowillmori (1/101) were infected with malaria parasite. All sporozoites were identified as Plasmodium falcipoarum by sequencing, the target fragment was 204 bp. CONCLUSION: The species composition of mosquitoes is complex in the study sites on the western part of China-Myanmar border, and An. minimus is the major malaria vector. Additionally, An. aconitus and An.pseudowillmori are also confirmed as potential malaria vector in this area. PMID- 21826903 TI - [Progress on regulation of gene expression in Giardia lamblia]. AB - Giardia lamblia is an important human pathogen that causes diarrhea and malnutrition. As a late-branching eukaryote, G. lamblia may have special mechanisms for regulating gene expression which differ from other eukaryotes. In this paper, the mechanisms that governing regulation of G. lamblia gene expression, such as promoters, transcription factors, transcriptional regulation, translation initiation and epigenetic mechanisms are summarized. PMID- 21826905 TI - [One case of plerocercoidosis]. PMID- 21826904 TI - [Research progress on anti-tumor mechanism of Trichinella spiralis]. AB - Trichinella spiralis has restrain effect on tumors. Different amount of T. spiralis can emerge different tumor inhibition effect T. spiralis infection can reduce tumor growth to various extents in mice bearing tumor cells at different times post infection. Each developmental stage of T. spiralis in the host may have anti-tumor effect T. spiralis may play anti-tumor roles by stimulating cell mediated immune response, and/or possessing tumor-associated antigen and anti tumor active substances of the parasite. PMID- 21826907 TI - [Progress on transgenic mosquitoes]. AB - The genetically modified mosquitoes have been developed aiming to control mosquito-borne diseases by either reducing population sizes or replacing existing populations with vectors unable to transmit the disease. introduces some progress on the generation of transgenic mosquitoes and their fitness in wild population. This paper PMID- 21826906 TI - [Insect odorant receptors and their olfactory signal transduction pathway]. AB - Protection against insect bites is one of the main strategies in prevention and control of the vector-borne diseases. However, due to the obvious shortcomings of traditional control methods, it is necessary to develop new control measures. Most insects rely on their olfactory systems for host and mate location. Interfering with insect olfactory systems is becoming a hot research area in the control of vector-borne diseases. As odorant receptors play a major role in perception of odorant molecules by insect olfactory system, this paper summarizes the recent progress on insect odorant receptors and their olfactory signal transduction. PMID- 21826908 TI - [Preliminary analysis of chigger mite community on Eothenomys miletus in 19 counties of Yunnan province]. AB - Eothenomys miletus were captured in 19 counties of Yunnan Province. The distribution of species-abundance and the species-plots relationship between E. miletus and chigger mites were analyzed by using ecological statistic method. There were totally 40,052 chigger mites collected from the body surface of 1741 E. miletus. 111 species of chigger mites were identified. The species-abundance distribution showed that with the increase of mite individuals, the number of chigger mite species gradually decreased. Most mite species were rare ones. Species-plot relation indicated that with the number of mouse plots (samples of E. miletus) increasing, the number of chigger mite species increased. E. miletus collected quantity up to date still could not reflect the exact species richness of chigger mite. PMID- 21826909 TI - [Infection status of wild freshwater fish with Metacercariae of Clonorchis sinensis in west Liaoning]. AB - A total of 1131 wild freshwater fishes were collected from Nver River, Gou River and Liao River in the west region of Liaoning Province, and examined for metacercariae by direct compression and artificial digestion (pepsin-HCl) method. All the 6 species fishes were infected by Clonorchis sinensis. The highest prevalence (82.8%, 216/261) were found in Pseudorasbora parva and the lowest (1.5%, 2/137) in Phoxinus lagowskii. The highest intensity of infection (2390 per fish) was in Perccottus glehnidybowski and the lowest (30 per fish) in Phoxinus lagorwskii. PMID- 21826911 TI - [Medicines: the 12 months that changed everything]. PMID- 21826910 TI - [Investigation on life quality of patients with chronic lymphatic filariasis in Yuhang district of Hangzhou]. AB - Data were collected from chronic lymphatic filariasis patients and the public in Yuhang District of Hangzhou. Health status was assessed by using EuroQol (EQ)-5D. A total of 600 questionnaires were sent and 550 (91.7%) returned (276 chronic lymphatic filariasis patients and 274 members of the public). The EQ-SD index score for patients with chronic lymphatic filariasis (0.770 +/- 0.128) were lower than the general public (0.872 +/- 0.073). In contrast to the public (6.6%, 5.8%, 12.0%, 20.4%, and 10.6%), patients reported more problems with their mobility (43.8%), self-care (22.5%), daily activities (44.9%), anxiety/depression (47.8%), and pain/discomfort (29.0%) (P < 0.01). Strength of association were 6.67, 3.86, 3.74, 2.73, and 2.34, respectively. These results indicated that chronic lymphatic filariasis shows an impact on patients' health-related quality of life. It particularly causes great problems in the dimensions of mobility, self-care, and daily activities. PMID- 21826912 TI - [The natural carers aged between 60 to 80 years]. PMID- 21826914 TI - [Hereditary angioedema]. PMID- 21826913 TI - [Serous submylohyoid cellulitis of dental origin]. PMID- 21826916 TI - [Hydatid cyst]. PMID- 21826915 TI - [Dengue: an emerging infection in travelers]. AB - Dengue is a common, mosquito borne, travel-related, viral infection in the tropical traveler caused by an arbovirus. This virus has 4 different serotypes and is responsible for approximately 50 to 100 million cases per year. Its incidence and geographic distribution are clearly increasing lately. Although occurring in tropical endemic areas, sporadic and autochthonous cases have been recently reported in temperate countries including France. The tropical influenza like clinical presentation is not very specific except for rash. Diagnosis is facilitated by the existence of thrombocytopenia and the early detection of NS1 antigen using rapid test. Hemorragic forms with or without shock syndrome are rare in travelers and represent the severe manifestations especially in children. Their pathophysiology remains controversial. Management is essentially symptomatic. Aspirine should be avoided because of bleeding risk. Beyond individual (travel) or collective (endemic zone) vector control measures, the development of a quadrivalent vaccine seems about to succeed. PMID- 21826917 TI - [The impact of COPD, major, can be limited]. PMID- 21826918 TI - [Epidemiology of chronic obstructive pulmonary disease]. AB - COPD is responsible of morbidity, mortality and health costs. Projection in 2020 is State of COPD as the 3rd cause of global mortality (6th in 1990); 5th issue of years lost early death or disability (disability-adjusted life years, DALYs) [12th in 1990].Active smoking remains the main risk factor, but other factors are better known as professional factors, infections, the role of air pollution. The prevalence of COPD varies by country, age and sex. This condition is also associated with significant Comorbidities. Major challenge for the next few years is based on the prevention of smoking and the early detection of the disease in general population early. PMID- 21826919 TI - [Occupational risk factors of COPD]. PMID- 21826920 TI - [Treatment of COPD]. AB - COPD treatment begins with smoking cessation and influenza and pneumococcal vaccines. Bronchodilators are indicated when dyspnea on exertion is reported (usually, FEV1 < 80% predicted). On-demand short-acting agents are chosen when dyspnea is intermittent, daily long-acting agents are administered once dyspnea occurs in daily life activities. In all cases, anticholinergics and beta2 agonists can be associated when one class is not sufficiently effective. In patients with FEV1 < 50% predicted (budesonide-formoterol) or 60% predicted (fluticasone-salmeterol), repeated exacerbations and symptoms despite maintenance bronchodilators, fixed associations are indicated. When a handicap persists on pharmacological treatment, respiratory rehabilitation centered on education and exercise training has to be proposed. Care for COPD has to integrate treatment of comorbidities such as cardio-vascular diseases, anxiety-depression, malnutrition, muscle dysfunction, osteoporosis, anemia ... Ongoing research aims at identifying new therapeutic targets, focusing on inflammation, remodeling, protease antiprotease balance, oxidative stress, lung regeneration/repair and mucus production. PMID- 21826921 TI - [From COPD to chronic respiratory failure]. AB - Chronic obstructive pulmonary disease (COPD) is characterized by chronic airflow obstruction, leading to an airflow limitation that is not fully reversible, with extrapulmonary effects or comorbidities that may contribute to the severity of the disease. The most important cause is tobacco smoking that is associated with an abnormal inflammatory pulmonary and systemic response. Chronic airflow obstruction is defined by postbronchodilator FEV1/FVC ratio < 0.7. A spirometric classification of the COPD severity is recommended into four stages. COPD has a variable natural history. Usually, COPD is a progressive disease with an increase in airways obstruction. Airflow limitation leads to hyperinflation, the most important cause of dyspnea in COPD patients. Assessment of the prognosis is based on the severity of the spirometric abnormality (FEV1) and includes other factors such as body mass index (BMI), dyspnea and exercise impairment. The underlying disease process in COPD leads to gas exchange abnormalities, chronic respiratory insufficiency and pulmonary hypertension. The more frequent causes of death are respiratory insufficiency, cardiovascular comorbidities and lung cancer. PMID- 21826922 TI - [Classification of COPD and prognostic factors]. PMID- 21826923 TI - [What are the mechanisms of obstruction in COPD?]. PMID- 21826924 TI - [Disproportionate pulmonary hypertension in COPD]. PMID- 21826925 TI - [What are the mechanisms of breathlessness in COPD?]. PMID- 21826926 TI - [When to consider COPD and how to assess it?]. AB - Detected in 30% of COPD patients and underdiagnosed, COPD must be systematically investigated in all about 40 years-old smokers, without waiting for clinical symptoms, late and inconstant. The diagnosis is made with spirometry. Search for a status of "frequent exacerbations", co-morbidities (including cardio-vascular disease), evaluation of dyspnea intensity with a scale (MRC), assessment of disease impact on daily life, allow to identify risk groups and to target the therapeutic management overall. Pulmonary rehabilitation, in addition to medication, improves dyspnea, and decreases the impact of COPD on daily life. PMID- 21826927 TI - [Comorbidities in patients with chronic obstructive pulmonary disease]. AB - Subjects with chronic obstructive pulmonary disease (COPD) are often affected by other chronic diseases (called comorbidities). It is only recently that the impact of comorbidities on symptoms and on natural history of COPD has been recognized. Comorbidities may be responsible for increased dyspnea, reduction in exercise capacity and in physical activity. The presence of comorbidities is associated with increased mortality and with increased costs related to healthcare utilization. COPD is underdiagnosed in patients suffering from other chronic diseases (e.g., cardiovascular disease). These findings should lead to the development of therapeutic strategies taking into account comorbidities in patients with COPD. It is also suggested that early diagnosis and treatment of COPD in subjects suffering from other chronic diseases may result in improved patient care. PMID- 21826928 TI - [Acute exacerbation of chronic obstructive pulmonary disease]. AB - Exacerbation of COPD is a common problem, which causes a considerable burden to the patient and the healthcare system. Management of exacerbations is broadly based on clinical features and severity. Initial clinical evaluation is crucial to define the patients requiring hospital admissions and those that could be managed as outpatients. Medical treatment should follow updated recommendations including rest, inhaled or nebulized short-acting bronchodilators (B2-agonists and anticholinergic agents), and in most severe patients steroids unless there are contraindications and antibiotics. Hospitalized patients should receive titrated oxygen therapy, and DVT prevention. Unless contra indicated, noninvasive ventilation should be the first line ventilatory support for COPD with acute hypercapnic respiratory failure. Future exacerbations should be avoided by respiratory specialists' management. PMID- 21826929 TI - [Hospitalization in patients with exacerbating COPD]. PMID- 21826931 TI - [Lung transplantation in COPD]. PMID- 21826930 TI - [Management of chronic obstructive pulmonary disease]. AB - Long-term oxygen therapy (LTOT) is indicated in stage-IV COPD. It increases survival when used 24h/24, ideally, and at least 15h/24. There is no indication for prescribing nocturnal oxygen therapy without de LTOT. Ambulatory oxygen therapy is indicated in patients with COPD who benefit from LTOT in case of significant exercise-induced desaturation. In that regard, recent technologies allow to provide patients with small-size, stand-alone and portable oxygen units. Non-invasive ventilation (NIV) is a type of mechanical ventilation administered through a mouthpiece, a nasal mask or a facial mask. It should not be confused with continuous positive airway pressure (CPAP), indicated in the treatment of obstructive sleep apnea, which does not improve alveolar ventilation in hypercapnic patients. In patients with COPD, long-term NIV does not provide any benefits in terms of survival instead, it improves arterial gasometry, clinical symptoms, quality of life and the frequency of severe exacerbations. PMID- 21826932 TI - [Instrumental treatments of emphysema]. PMID- 21826933 TI - [Pulmonary rehabilitation in COPD]. PMID- 21826934 TI - [Balance disorders in the elderly]. PMID- 21826935 TI - [Practitioners facing balance disorders in older subjects]. AB - As life expectancy keeps increasing, balance disorders in older patients represent a major medical and public health issue, mostly because they are the most important risk factor for repeated falls. The inevitable deterioration of the physiological mechanisms which control balance explains their important prevalence and their often multifactor nature. A multidisciplinary approach should thus be adopted. However, during physical examination, practitioners can and must identify the general causes (polymedication, metabolic or cardiovascular diseases, etc.), take certain simple environmental actions and, most importantly, look for risk factors for falls. Falls are indeed the first complication of balance disorders and represent a frequent cause of mortality, loss of independence and high institutionalization and, as such, have serious socioeconomic consequences. Any balance disorder in older subjects thus requires in-depth examination and quick medical management. PMID- 21826936 TI - [Geriatric investigation in front of a balance disorders in the older elderly]. PMID- 21826937 TI - [ENT investigation in front of a balance disorders in the elderly]. PMID- 21826938 TI - [Neurological investigation in front of a balance disorders in the elderly]. PMID- 21826939 TI - [Radiological investigation in front of a balance disorders in the elderly]. PMID- 21826940 TI - [Ophthalmic survey in front of a balance disorders in the elderly]. PMID- 21826941 TI - [Orthopedic investigation in front of a balance disorders in the elderly]. PMID- 21826943 TI - [MEDLINE research. What are the Medline display setting used for?]. PMID- 21826942 TI - [Rehabilitation of balance disorders for elderly]. AB - The problems encountered by elderly in balancing themselves, possibly causing instability, perception troubles, and even falls, are the consequence of physiopathological causes. Their comprehension by the way of a thorough clinical survey gives a lead to the rehabilitation based on precise objectives. The subsequent programme of exercises presents the significant features of modularity, clarity of objectives and a progress led by the evolution of the symptoms. This personalized undertaking may include a correction of the musculosqueletics troubles, a sensorial resetting, a development of postural stabilization capabilities independent of the internal or external circumstances, a self-balancing capability independent of the current cognitive condition, a restoration of self-confidence, a physical resetting and an adaptation of the living place. The transposition of the exercises in ecological situation, the virtual reality of which is getting closer and closer, remains a priority in order to achieve the best results. PMID- 21826944 TI - [Medical education in France: data from students and government]. PMID- 21826945 TI - [Current issues of prevention of occupational accidents and diseases]. PMID- 21826946 TI - [Type 1 diabetes of the child]. PMID- 21826947 TI - [Contraception]. PMID- 21826948 TI - [Bronchopulmonary infections in child]. PMID- 21826949 TI - [Cutaneous ectoparasitosis]. PMID- 21826950 TI - [Medical recollections. Open a King's body: why and how? The case of Henry IV]. PMID- 21826951 TI - [Breast cancer]. PMID- 21826952 TI - [Recommendations from the Royal Academy of Medicine on the screening of breast cancer]. PMID- 21826953 TI - [Breast cancer in Belgium: why are we the first in Europe?]. AB - Breast cancer incidence in Belgium is on the top of European countries, with 9.697 new cases in 2008 and 106/100.000 women/year. The explanation of this high incidence in our country is probably the accumulation of risk factors (many of them are linked to lifestyle), and the impact of screening and registration of cases. The relative impact of each of theses factors is less clear because we don't have powerful statistical studies. Belgium is slightly above the European mean for breast cancer mortality, with 19,4/100.000 women/year and an all stages 15-year survival of 75%. Breast cancers are responsible for around 3% of all cause mortality in Belgian women. This article discusses the causes of this high Belgian incidence and of current decrease of incidence in western countries, and reviews known and less known risk factors of breast cancers, with a special focus on menopause hormonal treatments. PMID- 21826954 TI - [Obesity, insulin resistance and type 2 diabetes: risk factors for breast cancer]. AB - Obesity and type 2 diabetes are two risk factors of breast cancer, especially after menopause. Underlying mechanisms are multiple and include hyperinsulinism due to insulin resistance (insulin, as insulin-like-growth factor -IGF-, is a growth factor), hyperleptinaemia associated with hypoadiponectinaemia, and high levels of estrogens resulting from aromatization of androgens in adipose tissue. In presence of type 2 diabetes associated with obesity, hyperglycaemia might provide energy substrate promoting tumour growth. These data have therapeutic implications with expected favourable effects of weight loss, resulting in a reduction of fat mass and insulin resistance, and the promising results recently reported with metformin contrasting with the negative effects of exogenous administration of high doses of insulin. PMID- 21826955 TI - [Primary and secondary prevention for women at high risk for breast cancer]. AB - Many factors determine a woman's risk of breast cancer; some genetic are related to family history, others are based on personal factors such reproductive and medical history. A high-risk woman must benefit of a specific screening regimen including breast examination, mammography, ultrasonography and contrast material enhanced magnetic resonance. But she can also benefit of chemo prevention or/and risk-reducing surgery such bilateral prophylactic salpingo-oophorectomy and bilateral prophylactic mastectomy. PMID- 21826956 TI - [Bilateral prophylactic mastectomy for women at very high risk for breast cancer: beyond the technique]. AB - Bilateral prophylactic mastectomy is the most efficient risk management strategy for women at very high risk for breast cancer. Different methods can be used. The implementation of such a strategy must respond to the request of a well informed patient. PMID- 21826957 TI - [Breast cancer: the interest of pathological classification]. AB - The breast pathology includes a large array of entities for which macroscopic and microscopic analysis remains fundamental. Tissue and cell morphology allows in most cases the distinction between benign or malignant tumours and therefore provides the clinicians with essential information for the therapeutic strategy. In the Pathology laboratory, immunohistochemistry and molecular biology have improved the specificity of the diagnosis and have introduced new prognostic and predictive markers for tumour management. The last edition of the WHO classification, released in 2003, distinguishes 21 varieties of invasive carcinoma and 2 categories of intraepithelial neoplasia based on the morphology and immunohistochemical profile. Other diseases can affect the breast, although much less frequently, such as Paget's disease of the nipple, phyllode tumours, sarcomas, lymphomas... These diseases will not be reviewed here. PMID- 21826958 TI - [Cytological sampling techniques in breast pathology]. AB - Mammary cytology is part of the breast cancer test. Its accuracy depends on both the sample quality and the cyto-pathologist's competence. Extracting cells in a liquid environment allows obtaining smears in less hemorrhagic thin layers, containing more cells and with less interference with the fixation artefact. This technique keeps materiel for further immunocytochemistry and cell biology studies if needed. It will be especially useful in automated analysis. PMID- 21826959 TI - [Mammary Paget's disease]. AB - Mammary Paget's disease is an intraepithelial carcinoma present on the nipple and its areola. The tumor typically develops in middle aged women. It is frequently associated or contiguous to an underlying galactophoric adenocarcinoma. The histopathologic and immunopathologic aspects are typical and linked to the presence of Paget's cells. Early diagnosis is required searching for a possible underlying carcinoma. The surgical treatment is directed by the characteristics of the deep mammary carcinoma. PMID- 21826960 TI - [Behind the scenes of breast cancer]. AB - A 55 year-old women presented with lesions simulating cysts of the scalp. The dermatopathological examination revealed a metastasis of a breast adenocarcinoma. At the diagnosis disclosure, the patient recognized having concealed for 7 years a neoplastic wound replacing one of her breasts. About this case report, we report the astonishing clinical diversity of skin metastases of breast adenocarcinomas. PMID- 21826961 TI - [Invasion and metastatic dissemination in breast cancer: mechanisms]. AB - Metastases formation is a complex process involving genetic and epigenetic modifications leading to several molecular pathway dysfunctions and alterations in the production and fonction of a panel of molecular mediators. Recent studies have shed light on the importance of multiple interactions occuring between tumor cells and host cells involved in the elaboration of a microenvironment permissive for tumor cell survival and growth. These tumor-host interactions are decisive, not only in the primary tumor, but also in secondary sites colonized by tumor cells. Cancer appears more and more as a sytemic disease in which tumor cell is one of the pawn in the game. System of defense are rapidly overwhelmed and tumor cells hijack host cells to promote their dissemination that likely occurs at earlier stages than initially anticipated. In the present review, we describe the novel concepts of metastases formation based on recent transcriptomic analyses and new insights acquired on the tumor microenvironment in the primary tumor and in secondary foci. PMID- 21826962 TI - [Circulating tumor cells: detection, characterization and clinical impact]. AB - The metastatic process generates circulating tumor cells (CTCs) and disseminated tumor cells (DTCs) in bone marrow and other organs which can remain as occult metastases. Various methods and systems have been developed to allow the isolation and identification of those cells but major technical limitations still exist. Research on CTCs is a nevertheless tremendously growing field of cancer research because of their potential clinical applications. CTCs indeed convey predictive information for the development of metastasis and recurrence, and prognostic information regarding patient survival. CTCs enumeration could also be used to monitor the effectiveness of adjuvant treatments. Moreover, enhancing our basic understanding of the metastatic process, CTCs, and DTCs in particular, are thought to contain subpopulations of cells with stem cells properties that would be responsible for relapses. PMID- 21826963 TI - [Single cervical metastasis of breast cancer]. AB - We report a rare case of single cervical metastasis of breast cancer. Bone metastases are the most frequent in breast cancer. Early diagnosis combined with the new therapeutic advances have considerably improved the quality of life and increased the survival. Imaging plays a great role in the diagnosis, particularly scintigraphy and radiography, but sometimes also CT and MRI. The treatment is currently not standardized and it combines hormone therapy, chemotherapy, radiotherapy, and/or surgery. PMID- 21826965 TI - [Imaging bone metastases in breast cancer]. AB - Breast cancer is the most common female malignancy and bone is the most common site of distant metastases. Early detection and accurate assessment of bone involvement is needed to optimize treatment and therefore reduce or delay skeletal-related events. We discuss the different bone imaging modalities with emphasis on nuclear medicine techniques. Currently, whole body bone scintigraphy (BS) is recommended in selected patients at high risk of bone metastases (BM). New hybrid cameras combining 3-D scintigraphic images and computed tomography (SPECT/CT) improve diagnostic accuracy of BS. The 2-deoxy-2-[18F]fluoro-D-glucose (FDG) positron emission tomography (PET) seems to exhibit higher specificity and accuracy to detect BM in breast cancer. FDG PET/CT could be a useful tool for monitoring the effectiveness of treatment of breast cancer BM. Recent whole-body magnetic resonance imaging (MRI) techniques could become an additional tool to assess bone involvement from breast cancer. No consensus has been yet established regarding the best modality for diagnosing breast cancer BM and for assessing its response to treatment. The best approach is probably the combination of the different imaging modalities knowing the strengths and weaknesses of each technique. PMID- 21826964 TI - [Heterogeneity of bone metastases in a patient with breast cancer: case report illustrating the potential of combining various imaging techniques]. AB - Morphological appearance of bone metastases in breast cancer can be classified into three groups: osteolytic, sclerotic and mixed types. 18F-NaF PET/CT is considered to be superior to bone scintigraphy (BS) for the detection of bone metastases. 18F-NaF PET shows a higher uptake in both lytic and sclerotic bone metastases with a higher contrast and spatial resolution than BS. 18F-FDG PET is generally considered to be superior to BS for detection of lytic bone metastases. However, BS and 18F-NaF PET/CT are more sensitive for sclerotic lesions, as a decreased 18F-FDG uptake in this subtype of lesion has been reported. In conclusion, as various types of bone metastases may coexist in a single patient, the combination of both 18F-FDG and 18F-fluoride PET/CT studies is likely to provide the most comprehensive assessment of metastatic spread to the skeleton. PMID- 21826966 TI - [Breast cancer and brain metastases]. AB - The cerebral metastases are frequent in the evolution of breast cancer and convey a poor prognosis. The frequency depends on the histology of the cancer and on the expression of oestrogen and progesterone receptors as well as of HER2 antigen. The treatment is currently based on surgery and the different modalities of radiotherapy used alone or in association. Indeed, chemotherapy agents available for the treatment of breast cancer do not cross the hematoencephalic barrier and are thus ineffective. However, some encouraging results have been recently reported with the therapies targeting HER2. PMID- 21826967 TI - [Late relapse of breast cancer after adjuvant chemotherapy]. AB - Late relapses (> 10 years) of breast cancer are mainly observed in ER positive tumors. The yearly relapse rate is still 0.5 % after 10 years. These relapses occurred even if adjuvant chemotherapy was given. Consequently, a better knowledge of the metastatic process is warranted in order to define better treatment options. We will discuss here a case of hormonosensitive breast cancer relapsing 20 years after the initial treatment. We will discuss the most recent data concerning late relapses. New hypotheses concerning disseminated tumoral cells and circulating cells will be reported. We will also review data about stem cells, tumor initiating cells and dormancy state. PMID- 21826969 TI - [Psychosocial aspects of breast cancer]. AB - In occidental countries, breast cancer is the most frequent cancer in women. In the last 30 years, the therapeutical progresses have improved the prognosis and the survival rate. However, despite this hope of recovering, women continue to face the fear of death and vulnerability. Moreover, treatments can induce cognitive, emotional and behavioral reactions in patients but also in their relatives. Therefore, the treatments are associated with physical and psychosocial dysfunctioning influencing quality of life. PMID- 21826968 TI - [The role of multidisciplinary tumor board discussions in treatment decisions]. AB - The diagnosis and treatment of cancer is complex. Multidisciplinary tumor board discussions optimise the care of patients suffering from cancer. The most promising and rational treatment is chosen taking into account the opinion from all participants. Quality of life is important if only a palliative approach can be offered. The final decision concerning the treatment will be taken by the patient because he/she has the right to refuse the best treatment for personal reasons. PMID- 21826970 TI - [Radiotherapy in breast cancer: current standards of treatment, prediction of local recurrence and open questions]. AB - Adjuvant radiotherapy after surgery is a ("well-established standard" in routine clinical practice for breast cancer. Nevertheless, a variety of questions still remain unanswered. We intend to illustrate the overall importance of radiotherapy in breast cancer and highlight some unresolved questions by quoting presentations recently made at ASTRO-2010. More and more emphasis is put on the idea of an individual approach. Predicting the individual local recurrence risk is the search for the "Holy Grail". Methods such as nomograms and genomic profiling are currently tested but need to be validated before their widespread clinical application. PMID- 21826971 TI - [Surgical treatment of breast cancer]. AB - Surgical treatment of breast cancer has significantly evolved over the last years. Quality of life and cosmetic outcomes became an important part of breast cancer management. Indications for different types of breast and axillary techniques are reviewed in this article. We also consider a frequent but not widely known complication of breast surgery: axillary cording. PMID- 21826972 TI - [Management and follow-up of a consecutive series of 411 surgically treated breast cancer patients]. AB - This study reports a consecutive serie of 427 breast neoplasms (411 patients) diagnosed and treated in our department between 1994 and 2004. Patients' records were prospectively collected including personnal medical history and the major elements of the diagnostic and the therapeutic protocol applied. 12 patients (3%) had to be excluded due to incomplete follow-up data. With a median follow-up of 8 years, a 4.5% loco-regional relapse rate is noted while 11% of patients recurred at distant sites and 9% died of their disease progression. These statistics are comparable to those published by prominant breast cancer centers. Amongst the 16% of deaths (67/411 Pts), 54% are due to breast cancer progression. The results are discussed with the aim to upgrade the diagnostic and the therapeutic protocols offered to our patients. PMID- 21826973 TI - [Sentinel lymph node biopsy and axillary reverse mapping: a tailoring axillary staging in breast cancer]. AB - The status of the axillary lymph nodes is one of the most important prognostic factors in women with early stage breast cancer. Histologic examination of removed lymph nodes is the most accurate method for assessing spread of disease to these nodes. Axillary lymph node dissection (ALND) remains the standard approach for women who have clinically palpable axillary nodes. The benefits of ALND include its impact on disease control (axillary recurrence and survival), its prognostic value, and its role in treatment selection. However, the anatomic disruption caused by ALND may result in lymphedema, nerve injury, and shoulder dysfunction, which compromise functionality and quality of life. For patients who have clinically negative axillary lymph nodes, sentinel lymph node (SLN) biopsy offers a less morbid method to determine if there are positive nodes, in which case axillary node dissection would be necessary. Patients who are SLN-positive should undergo complete ALND. Axillary reverse mapping (ARM) is a recent improvement of ALND which, like the biopsy of the GS, would reduce morbidity. PMID- 21826974 TI - [Breast oncoplastic surgery]. AB - Oncoplastic surgery combines large lumpectomy and defect remodeling by different plastic surgery methods. These procedures improve the cosmetic result after partial mastectomy and widens the possibilities for conservative treatment. Different techniques are used from simple glandular remodeling to more difficult techniques for breast plasties with or without simultaneous controlateral symetrisation procedure. The surgical option depends especially on the ratio between the volume of the tumor and the volume of the breast and the position of the tumor. This more effective conservative treatment facilitates also postoperative radiotherapy, reduces the sequellae and the psychological impact of breast cancer treatment. PMID- 21826975 TI - [Microsurgical breast reconstruction: for whom and how?]. AB - Breast reconstruction is now an integral part of breast cancer treatment. There are several different procedures that make use of flaps or prostheses, or a combination of the two. Which of these procedures is indicated depends on the sequelae of the initial treatment and the patient's wishes and morphology. However, the constraints caused by the prosthetic material and the now regular use of microsurgical techniques have greatly favoured the purely autologous options. The different surgical techniques and their respective advantages and disadvantages will be described, before considering the timing of the various stages of the procedure. We will also give a summary of our experience with free flaps. PMID- 21826976 TI - [Immediate breast reconstruction and postoperative radiotherapy: an overview]. AB - Breast reconstruction is nowadays integral part of the treatment of breast cancer. When it is proposed as an immediate reconstruction, the plastic surgeon has to deal with several constraints. The coverage of the patients that must benefit from a mastectomy is complicated by additional treatments of radiotherapy. We propose, in this work, a multidisciplinary splitting of the patients into specific subgroups. An immediate reconstruction will be proposed to certain patients considering the adjuvant radiotherapy. The choices of orientation are complex and a scarce literature on this subject does not allow us to guide in a systematic way all the patients. More studies, with a prospective design, are necessary to guide the patients wishing an immediate reconstruction associated with a radiotherapy after mastectomy. PMID- 21826977 TI - [Autologous fat grafting in the breast: oncological implications]. AB - Autologous fat grafting for breast is increasing dramatically. This fat injection needs accurate technical conditions, and shows very good and long-lasting clinical results. Nevertheless, in breast conservative treatment sequellae, fat injection could lead to difficulties in breast imaging, but also there is some concerns about the potential oncologic risks of these procedures. PMID- 21826978 TI - [Hormone therapy for breast cancer]. AB - Following Beatson's publications in 1896, various modalities of endocrine therapy applied to breast cancer have been developed. Endocrine treatment has greatly contributed to the improvement of the disease's prognosis. Tamoxifen has established itself as a first choice adjuvant therapy for patients with tumors expressing hormone receptors. Over the last decade, third generation aromatase inhibitors have demonstrated their efficacy amongst menopausal patients, alone or in combination with tamoxifen. Efficacy of these medications is dependent on patient's compliance. This article proposes a synthesis of the main knowledges available in the field of breast cancer endocrine therapy. PMID- 21826979 TI - [Systemic chemotherapy and breast cancer]. AB - Breast cancer mortality is decreasing, partly due to better adjuvant treatments with new drugs and new schedules. In Belgium, the overall survival is 76%. Chemotherapy is still an important treatment option. We need to better select patients who really will benefit from treatment in order to decrease toxicity and improve long term outcome.Targeting the specific population is now a priority. Prognostic and predictive factors will enable us to better define the sub population of patients most benefiting from treatment. We will also discuss the knowledge of systemic treatment. When we have to decide wether chemotherapy is indicated, we need to well balance the treatment risks and benefits because gain in survival is important but reducing short and long term toxicity is also a challenge. PMID- 21826981 TI - [Management of estrogen deficiency after breast cancer]. AB - The prevention and the treatment of oestrogen deficiency induced by breast cancer treatments are crucial in the management of patients. The impacts of this deficiency must not be neglected: quality of life impairments inducing eventually premature withdrawal of hormonotherapies, and excess of bone and cardio-vascular morbidities and mortalities, especially in good prognosis young women. Management strategies of short and long term effects of this deficiency are reviewed and discussed here. PMID- 21826980 TI - [Targeted therapies in breast cancer]. AB - The better understanding of the biology of breast cancer has allowed the identification of new targets for anticancer therapy. Trastuzumab, a monoclonal antibody binding the HER2 receptor, is used since several years in the treatment of HER2 overexpressing breast cancer, including in the adjuvant setting. Lapatinib, a tyrosine kinase inhibitor, was introduced more recently into the clinic. New treatment options under evaluation in HER2 overexpressing breast cancer include combinations of anti-HER2 treatments, drugs targeting the downstream signaling pathway and new anti-HER2 agents such as pertuzumab and T DM1. This article also reviews other targeted treatments of interest in the field of breast cancer including antiangiogenic agents and drugs targeting the PI3K-AKT mTOR pathway. PMID- 21826983 TI - [Breast cancer in young women]. AB - The outcome of very young patients with early breast cancer is worser compared to older patients with a similar clinical presentation. The triple negative, luminal B, HER2+ subtypes are more frequent in this population. Adequate local treatment (breast-conserving surgery or total mastectomy) must be discussed with the patient. The role of radiotherapy is very important in these patients with high risk of local recurrence. The progress in adjuvant treatment of very young patients requires studies of tailored treatments. PMID- 21826982 TI - [Molecular and genetic aspects of triple negative breast cancer and therapeutic implications]. AB - Triple negative breast cancers are defined by the lack of expression of estrogen, progesterone and HER2 receptors. They represent an heterogeneous population with poor prognosis. The treatment of these tumors is a challenge because there is no known specific target. A huge number of studies try to better characterise these tumors at the molecular level with the aim to identify new therapeutic targets. The finding of new specific biomarkers like intracellular and extracellular microRNAs is also an important field of research. This article reviews some recent data in this field and the research on different pathways for the development of new therapies. PMID- 21826984 TI - [Breast cancer in the elderly patient]. AB - There is no standard of care for breast cancer treatment in the elderly patient. Given the heterogeneity of this population, the treatment of both localized and metastatic disease, requires to take into account not only the characteristics of this cancer but also factors related to the patient such as co-morbidities, life expectancy and the social environment. PMID- 21826985 TI - [Establishment of pancreatic ductal cell lines with stably silencing of MyD88 mediated by lentivirus]. AB - OBJECTIVE: To design and construct a lentiviral vector containing shRNA against rat myeloid differentiation protein 88 gene (MyD88), and to establish rat pancreatic ductal cell line with stable knockdown of MyD88 expression. METHODS: Constructed two plasmid expression vectors coding shRNA against MyD88 and converted them into lentiviral particles using three-plamid package system, named as Lenti-sh MyD88-1 and LentishMyD88-2. Rat pancreatic ductal cell, ARIP were divided into untreated group, Lenti-Non Target group, LentishMyD88-1 and LentishMyD88-2 treated groups, and transduced with corresponding lentiviral particles. The GFP positive cells were selected by fluorescence-activated cell sorting and puromycin, the MyD88 gene silencing efficiency was detected by real time RT-PCR. RESULTS: After the transduction, we observed highly efficient transduction (reach to 100%) of lentivirus in ARIP cells by fluorescent microscopy and FACS. Quantitative RT-PCR showed that Lenti-shMyD88-1 reduced MyD88 mRNA expression by about 82.73% +/- 1.203% in ARIP cells, and LentishMyD88 2, reduced 75.56% +/- 1.176% as compared with that of the untreated cells (P < 0.05). CONCLUSION: The results demonstrated that lentivector containing the short hairpin RNA expression cassette specifically targeting MyD88 (pLVshMyD88-1,-2) were successfully constructed, which could stably knock down the MyD88 expression in ARIP cells. This study finally provided a new and stable cell model for the study of MyD88's function in acute pancreatitis. PMID- 21826986 TI - [The OmpA-like protein Loa22 from Leptospira interrogans serovar lai induces apoptosis in A549 via Ca2+ signal pathway]. AB - OBJECTIVE: To study the effect of Loa22 mature peptide on the apoptosis of A549 to explore the mechanism of pulmonary impairment in severe forms of leptospirosis. METHODS: Loa22 mature peptide (100 microg/mL) was administered to culture with human lung adenocarcinoma cell line (A549). After 24 hours, the apoptosis, the concentration of calcium of the cells were evaluated. The F-actin cytoskeleton structure was observed and calmdulin (CaM) mRNA expression was also detected. At the same time, after the pretreatment of A549 with PLC specific inhibitor U73122, adding an appropriate amount of mature peptide of Loa22 to act on the cells for a period of time, then detection same index. RESULTS: Loa22 mature peptide could induce the increase of intracellular Ca2+ concentration ([Ca2+]i), CaM expression in mRNA level, the activity of LDH, and cytoskeleton rearrangement of F-actin. But after blocking the signal pathway of PLC, Loa22 mature peptide reduced the increase degree of [Ca2+]i, apoptosis rate, the expression of CaM mRNA, the activity of LDH compared with the unblocked group. CONCLUSION: These data suggest that Loa22 mature peptide involves in the pathological processes of L. interrogans invasion and increase apoptosis in A549 by increase of [Ca2+]i through signaling pathway of PLC. PMID- 21826987 TI - [Effect of heat shock protein 90 inhibitor 17-dimethylamino ethylaminogeldanamycin on TNfalpha-mediated apoptosis and TNF-induced NF-kappaB activation]. AB - OBJECTIVE: To investigate the effect of heat shock protein 90 (HSP90) inhibitor 17-dimethylaminoethylaminogeldanamycin (17DMAG) on tumor necrosis factor alpha (TNFalpha) mediated apopotosis in cancer cells and the underlying molecular mechanisms. METHODS: Cell death treated with different concentration of 17DMAG and TNFalpha was detected based on the release of lactate dehydrogenase (LDH) using a cytotoxicity detection kit. For morphological study of cell death, cells were stained with 50 microg/mL of acridine orange and 50 microg/mL of ethidium bromide and observed and photographed under a fluorescence microscope. Activation of apoptosis and NF-kappaB pathway were evaluated on the change of caspase-8, caspase-3, poly (ADP-ribose) polymerase (PARP), receptor-interaction protein (RIP), IkappaB kinase beta (IKKbeta) and inhibitor of IkappaB (IkappaBalpha) by Western blot. RESULTS: 17DMAG sensitized cervical cancer cells HeLa and ovarian cancer cells SKOV3 to TNFalpha-induced cell death in a dose-dependent manner, which was accompanied with degradation of RIP and Ikappakappabeta, and consequent blockage of TNFalpha-induced NFkappaB activation. 17DMAG and TNFalpha cotreated cells showed typical apoptotic morphologies and enhancing of activation of caspases. CONCLUSION: 17DMAG sensitizes cancer cells to TNFalpha-mediated apoptosis through blockage of TNF-induced NF-kappaB activation, and disabling this survival signal with 17DMAG followed by TNF treatment could be an effective new therapeutic strategy for improving the anti-cancer value of TNFalpha. PMID- 21826988 TI - [Antitumor effect by combination of shRNA interfering plasmid targeting PKM2 with recombinant endostatin]. AB - OBJECTIVE: To investigate the enhancement effect of the combination of shRNA interfering plasmid targeting PKM2 with recombinant Endostatin in the treatment of lung cancer. METHODS: Twenty five BABL/nu/nu mice bearing A549 lung cancer were divided into 5 groups (NS control, psh-Control, psh-PKM2 treated group, Endostar treated group, psh-PKM2+Endostar treated group) and treated with shRNA interfering plasmid targeting PKM2 and recombinant Endostatin respectively or in combination. The expression of PKM2 in A549 detected with immunofluorescent assay. The interference effect of psh-PKM2 was determined by Western blot. The tumor volume, microvessel density (MVD), apoptosis index (AI) and side effects were observed. RESULTS: The combination treatment of RNA interfering plasmid targeting PKM2 with recombinant Endostatin inhibited tumor growth obviously (P < 0.05); The combination group revealed a decreased MVD and an increased AI (P < 0.05). CONCLUSION: The combination of shRNA interfering plasmid targeting PKM2 with recombinant Endostatin might enhance anti-tumor effect by increasing the apoptosis of the cancer cell. PMID- 21826989 TI - [Therapeutic effects of survivinT34A mutants on pulmonary metastases of melanoma B16 in mice]. AB - OBJECTIVE: To study the antitumor effects and mechanism of cationic liposome mediated SurvivinT34A mutants in mice with pulmonary metastases of melanoma B16. METHODS: The pulmonary metastases model of B16, a mouse melanoma cell line, was established by the injection of B16 cell suspension via tail vein of C57BL/6 mouse. 3 days later, 18 tumor-bearing mice were randomly divided into 3 groups, which were intravenously administrated with normal saline (100 microL), vector (5 microg DNA, 100 microL) and recombinant plasmid SurvivinT34A mutants (5 microg DNA, 100 microL) every other day for five doses, respectively. After 28 days, the mice were sacrificed, the lung tissue was weighted, and the number of metastasis foci on lung surface was counted and measured. Then, pathological change of lung tissue was studied with HE stainning. The number of apoptotic cells in tumor tissues was assessed by TUNEL assay. RESULTS: Compared with the control, mice treated with mSurvivnT34A had an intact structure of lung, with significant reduction in the number of metastasis foci on lung surface (P < 0.05), and high level of apoptosis in tumor tissue (P < 0. 05). CONCLUSION: Recombinant plasmid SurvivinT34A mutants (pORF9-mSurvivinT34A) may inhibit the formation of pulmonary metastases of melanoma. PMID- 21826990 TI - [Construction and expression of recombinant human serum albumin-EPO fusion protein]. AB - OBJECTIVE To construct the recombinant plasmid pCI-HLE encoding human serum album EPO (HSA-EPO) fusion protein and to express it in CHO cell. METHODS: The cDNA encoding human serum album and EPO were amplified by PCR, and then spliced with the synsitic DNA fragment encoding GS (GGGGS), by overlap PCR extension to form LEPO. After BamH I digestion, the HSA and LEPO was ligated to generate the fusion HSA-EPO gene and was then cloned into the expression vector pCI-neo to generate the recombinant plasmid pCI-HLE. The plasmid pCI-HLE was transfected into CHO cell by liposome protocol. Then, the recombinant cells were screened by G418 and identified by PCR and Western blot. Expression of fusion protein was evaluated by Enzyme Linked Immunosorbent Assay (ELISA). RESULTS: Restrictive enzymes digestion and DNA sequencing revealed that HSA-EPO fusion gene was cloned into expression vector pCI-neo successfully. PCR and Western blot analysis confirmed that the fusion gene was integrated in the genome of CHO cells and expressed successfully. The HSA-EPO production varied from 86 Iu/(mL x 10(6) x 72 h) to 637 IU/(mLx 10(6) x 72 h). CONCLUSION: The results confirmed that HSA-EPO fusion gene can be expressed in the CHO cells, with EPO immunogenicity, which could serve as foundation for the development of long-lasting recombinant HSA-EPO protein. PMID- 21826991 TI - [Effects of dimethyloxalyl glycine on hypoxic-ischemic brain damage in newborn rats]. AB - OBJECTIVE: To investigate the effects of dimethyloxalyl glycine on hypoxic ischemic brain damage in newborn rats. METHODS: Forty eight postnatal day 10 SD rats were divided into 3 groups, including sham surgery group, hypoxic-ischemic group and DMOG treated group. The brain tissues were collected at 4, 8, 24 and 72 hours after the hypoxic-ischemic treatment. The expressions of hypoxia inducible factor-1alpha (HIF-1alfa) protein and anti apoptoticprotein cleaved caspase 3 (CC3) were detected by immunohistochemistry. The apoptotic cells were detected by TUNEL staining. RESULTS: The expression level of HIF-1alpha was significantly higher in DMOG treated group than in hypoxic-ischemic group. While the expression level of CC3 was lower and the number of tunel positive cells was fewer in DMOG treated group than that in hypoxic-ischemic group. CONCLUSION: Dimethyloxalyl glycine may play a neuro-protective role in hypoxic-ischemic brain damage in newborn rats by stabilizing HIF-1alpha. PMID- 21826992 TI - [Effect of combination of taxol and celecoxib on reversing multidrug resistance human breast cancer cells (MCF-7/ Taxol) and explore its underlying mechanism]. AB - OBJECTIVE: To investigate the reversal effect of Celecoxib and Taxol on multidrug resistance (MDR) human breast cancer cells (MCF-7/Taxol) and its underlying mechanism. METHODS: After establishing the resistance cell lines of human breast cancer on Taxol (MCF-7/Taxol), the effects of the drugs on the toxicity of MCF 7/Taxol cells and the reversal effect of Celecoxib on MDR were determined by CCK 8 assay. The cells were divided into seven groups (A: MCF-7; B: MCF-7/Taxol; C: MCF-7/Taxol + 0.03 microg/mL Taxol; D: MCF-7/ Taxol + 0 .03 microg/mL Taxol + 3 microg/mL Celecoxib; E: MCF-7/Taxol + 0.03 microg/mL Taxol-6 /g/mL Celecoxib; F: MCF-7/Taxol + 3 microg/mL Celecoxib; G: MCF-7/Taxol + 6 microg/mL Celecoxib). The mRNA levels of MDR1 and BCRP in these treated cells were also determined by reverse transcription-polymerase chain reaction (RT-PCR), the protein levels of P gp and BCRP in these treated cells were also determined by Western blot method. RESULTS: Compared with the Taxol control, the cytotoxicity effects was obviously increased by combination of Taxol and Celecoxib (P < 0.05). Compared with the vehicle control, Taxol up-regulated mRNA and protein levels of P-gp, whereas Celecoxib down-regulated mRNA and protein levels of P-gp and BCRP (P < 0.05). CONCLUSION: Celecoxib has reversal effect on MDR in MCF-7/Taxol cells, it's possible mechanism might be related to reduce the protein expression of COX-2, the inhibition of P-gp, BCRP mRNA and protein overexpression. PMID- 21826993 TI - [Diagnosis of chronic schistosomiasis japonicum with the recombinant Sj26GST-Sj32 fusion protein by ELISA]. AB - OBJECTIVE: To study the feasibility of rSj26GST-Sj32-IgG-ELISA for diagnosis of chronic schistosomiasis japonicum. METHODS: The Escherichia coli BL21 (DE3) with recombinant plasmid pET32alphaSj26GST-Sj32 were induced with isopropy-beta-D thiogalactopyranosid (IPTG), and the expression product was analyzed by SDS-PAGE and purified by Ni-NTA kits. Schistosoma japonicum (Sj) adult worm antigen(SjAWA) was produced by routine method. The IgG antibodies were detected with the sera of chronic schistosomiasis japonicum by ELISA using recombinant Sj26GST-Sj32 (rSj26GST-Sj32) fusion protein and SjAWA, while the controls included the sera of patients with clonorchiasis, paragonimiasis westermani, alveolar echinococcosis, cystic echinococcosis, hepatitis B, pulmonary tuberculosis and healthy people. RESULTS: The sensitivity and specificity of rSj26GST-Sj32 fusion protein were 95.00% (38/40) and 97.67% (42/43) respectively, they were 92.50% (37/40) and 97.67% (42/43) respectively in SjAWA groups. There were no difference in sensitivity and specificity between rSj26GST-Sj32 and SjAWA (P > 0.05). There were different cross reactions in clonorchiasis sinensis and paragonimiasis westermani between the two methods. The cross reaction with SjAWA was 20.00% (2/10) in patients with alveolar echinococcosis, but no cross reaction with rSj26GST-Sj32 (P > 0.05). CONCLUSION: rSj26-Sj32-IgG-ELISA probably could be applied to immunodiagnosis for chronic schistosomiasis japonicum. PMID- 21826994 TI - [Effects of the LIPE C-60G polymorphism on changes of plasma lipids and glucose induced by a high-carbohydrate diet in healthy youth]. AB - OBJECTIVE: To investigate the interaction of the C-60G polymorphism of hormone sensitive lipase gene (LIPE) with a high carbohydrate (high-CHO) diet on plasma lipids and glucose in a young and healthy Chinese Han population. METHODS: 27 males and 29 females were given a washout diets of 31% fat, 54% carbohydrate and 15% protein for 7 days, followed by the high-CHO diet of 15% fat, 70% carbohydrate and 15% protein for 6 days, without total energy restriction. Plasma lipid profiles, glucose, insulin, homeostasis model assessment for insulin resistance (HOMA-IR) and body mass index (BMI) at baseline, before and after the high-CHO diets as well as the LIPE C-60G polymorphism were analyzed. RESULTS: The females with the CC genotype had significantly higher levels of high-density lipoprotein cholesterol (HDL-C) (P < 0.01, P < 0.05) and apolipoprotein A-I (apo A-I ) (P < 0.01, P < 0.01) than the males with the same genotype both before and after the high-CHO diet. After the high-CHO diet, only the females with the CC genotype had significantly higher levels of total cholesterol (TC) (P < 0.01) and low-density lipoprotein cholesterol (LDL-C) (P < 0.05) than their male counterparts. Compared with those before the high-CHO diet, the males with the CC genotype had significantly lower levels of BMI (P < 0.05), TC (P < 0.01) and LDL C (P < 0.01), but significantly higher levels of HDL-C (P < 0.01) and apo A-I (P < 0.05) after the high-CHO diet. The males with the CG genotype experienced significant decreases of BMI (P < 0.05) and TC (P < 0.01). The females with the CC genotype experienced significant decreases of TC (P < 0.01) and LDL-C (P < 0.01) but significant increases of triglyceride (TG) (P < 0.01) and insulin (P < 0.05). The females with the CG genotype experienced a significant decrease of TC (P < 0.05) but a significant increase of TG (P < 0.05). CONCLUSION: LIPE C-60G variation can inhibit the decrease of LDL-C and the increases of HDL-C and apo A I in young healthy males induced by the high-CHO diet, and can inhibit the decrease of LDL-C and the increase of insulin in young healthy females induced by the same diet. PMID- 21826995 TI - [Multiplex PCR and genetic polymorphism of STR loci D4S1627, D14S1426, D1S1649]. AB - OBJECTIVE: To prepare the allelic ladder materials of three STR loci includes D1S1649, D4S1627, D14S1426, and construct a synchronous detection method by multiplex amplification of the three loci. METHODS: Multiplex PCR method, PAGE (polyacrylamide gel electrophoresis) and silver staining were applied to detect 120 unrelated Chinese Han population from Chengdu whose allele and gene frequency distributing of these three loci. The electrophoretic bands of the multiplex PCR of these three loci were clear, no overlap of each alleles were observed, and the results were the same with single-locus test results. The results of the multiplex PCR demonstrated that the genotype of these three STR loci in Chengdu Han population in the genotype distribution met with Hardy-Weinberg equilibrium. 6 alleles (10-15) were detected in D4S1627, 9 alleles(5, 6, 8-14, without 7) were detected in D14S1426, 6 alleles (7-12) were detected in D1S1649. CONCLUSION: The results suggested that the multiplex PCR system of these three loci is of practical value in genetic research and forensic identification. PMID- 21826996 TI - [Differential expression of colon cancer microRNA in microarry study]. AB - OBJECTIVE: To investigate the miRNA expression difference between colon cancer and normal colonic mucosa. METHODS: Twelve (12) pairs of colorectal cancer tissue and normal colonic mucosa were collected, total RNA was extracted and purified. After fluorescent tags being added, hybridization was carried out on miRNA microarray chip (Affymetrix company). SAM analysis was performed to find out the significant expression difference, then the difference was verified by RT-PCR, finally target gene analysis software was utilized to predict the miRNA function. RESULTS: The up-regulated miRNAs in colon cancer included has-miR-182, has-miR 17, hasmiR-106a, has-miR-93, has-miR-200c, has-miR-92a, has-let-7a, has-miR-20a (FDR value < 5%), while the downregulated miRNAs were has-miR-l195, has-miR-143, has-miR-145 (FDR value < 5%). CONCLUSION: There is significant difference of miRNA expression between colon caner and normal colonic mucosa. PMID- 21826997 TI - [Effects of oxidative stress on MuRF1 expression in skeletal muscle of diabetic rats]. AB - OBJECTIVE: To determine whether muscle-specific RING finger protein 1 (MuRF1) expression induced by oxidative stress lead to muscle wasting in diabetes rats. METHODS: The diabetes rat model was established by high-carbohydrate, high-fat diet and injection of streptozotocin. The expression of MuRF1 in gastrocnemius was detected by immunohistochemistry and real time PCR. The level of lipid peroxidation, SOD and fiber size of gastrocnemius was also detected. Further more, C2C12 myotubes were cultured with different concentration of H2O2 (0, 0.01, 0.05, 0.10 and 0.20 mmol/L), the level of MuRF1 protein was detected by western blot. RESULTS: Compared with the control group, the diabetes rats showed higher level of thiobarbituric acid reactive substances (TBARS) and MuRF1 mRNA and lower fiber size in gastrocnemius (P < 0.01). The oxidative stress induced by H2O2 (0.05, 0.10 and 0.20 mmol/L) upregulated the expression of MuRF1 (P < 0.01) in C2C12 myotube cells. CONCLUSION: Our results indicated that diabetes modulated the expression of MuRF1 leading to muscle wasting, and the mechanism might be involved with oxidative stress. PMID- 21826998 TI - [Developing a risk appraisal model for gestational diabetes mellitus]. AB - OBJECTIVE: To identify risk factors associated with gestational diabetes mellitus (GDM) and establish a risk appraisal model for GDM. METHODS: A case-control study of 156 women with GDM and 362 pregnant women without GDM was undertaken. Non conditional logistic regression analysis was performed to identify risk factors associated with GDM and establish a prediction model. The diagnostic efficiency of this model was estimated by receiver operator characteristic curve (ROC) and Hosmer-lemeshow goodness-of-fit. RESULTS: Age, high blood pressure, history of poor pregnant outcome, obesity before pregnancy, excessive consumption of fruits, history of DM of immediate family members and taste preference were identified as risk factors of GDM. High consumption of white meat was identified as a protective factor. When the threshold value was set at 3.6, maximum sensitivity (73.7%) and specificity (68.5%) was obtained. The area under curve (AUC) of ROC was 0.79, with Hosmer-lemeshow P = 0.97. CONCLUSION: The developed model has high diagnostic efficiency, which provides a good instrument for screening women with high-risk GDM. PMID- 21827000 TI - [Inhibition effect and mechanism of artemisnin on surgically induced endometriosis]. AB - OBJECTIVE: To evaluate the inhibitory effect of artemisnin on surgically induced endometriosis in rat model and the possible mechanism related to cellular apoptosis and microvascular angiogenesis. METHODS: Surgically induced endometriosis model was established with female rats, and then the rats were divided into four groups: high dose artemisinin [300 mg/(kg x d)), low dose artemisinin [150 mg/(kg x d)], danazol [160 mg/(kg x d)] and solvent control group After daily administration of the above agents for 4 weeks, the rats were sacrificed, then the implant size of ectopic endometrium was measured and appotosis index (AI), Bcl-2 and MVD in ectopic endometrium were evaluated with S P immunohistochemistry. RESULTS: Compared with solvent control, both artemisinin (high and low quality) and danazol decrease the size of implants significantly (P < 0.05), and there was no significant difference among the three treatment groups. AI of the three treatment groups increased significantly, while Bcl-2 and MVD decreased significantly (P < 0.05). AI of both artemisinin groups were significantly higher than that of danazol group, but Bcl-2 level was lower. CONCLUSION: Artemisnin inhibits surgically induced endometriosis in rats, and the possible mechanism may be related to stimulatation of cellular apoptosis and inhibition of angiogenesis. PMID- 21826999 TI - [Study of the function and mechanism of interleukin cytokines in acute pancreatitis rats]. AB - OBJECTIVE: To explore the molecular mechanism of interleukin cytokines IL-6, IL 17, IL-23, IL-23R in the onset of acute pancreatitis in rats pancreatitis models. METHODS: Thirty six SD rats were randomized into 3 groups: control group, model group, and intervention group (n = 12). The rats in model group and intervention group were induced by intraperitoneal injection of 1-arginine, and those in intervention group were treated by tail intravenous administration of drugs at the same time. Then the rats were sacrified at 3rd, 6th, and 12th h. after the modeling. The levels of IL-6 ,IL-17, IL-23, IL-23R in blood, pancreas, lung and kidney were checked by ELISA. RESULTS: The IL-6 levels of serum, pancreas, lung and kidney in AP Model group were obviously higher than those in the control group and intervention group. This trend increased with time. Similarly, the levels of IL-17 and IL-23 in AP group were obviously higher than those in the control group and intervention group. Compared with the control and intervention group, AP group showed higher IL-23R levels in serum, pancreas, but lower IL-23R levels in lung and kidney. CONCLUSION: IL-23 is a mediator involved in the formation of IL-17 and IL-6, they all can promote acute pancreatitis. PMID- 21827002 TI - [Detecting anti-cyclic citrullinated peptide antibody in patients with connective tissue diseases]. AB - OBJECTIVE: To determine the clinical significance of anti-cyclic citrullinated peptide antibody (anti CCP) in mixed connective tissue diseases (MCTD). METHODS: Enzyme linked immunosorbent assay was performed to detect anti-CCP in 57 patients with MCTD, 78 with rheumatoid arthritis (RA), 64 with systemic lupus erythematosus (SLE), 56 with polymyositis/dermatomyositis (PM/DM), 53 with Sjogren syndrome (SS) and with 33 systemic sclerosis (SSc). The association between anti-CCP and clinical features of MCTD was analysed. RESULTS: Anti-CCP was detected in 87.5% RA cases, 15.8% MCTD cases, 57.1% MCTD with RA cases, 14.1% SLE cases, 15.2% PM/DM cases, 18.9% SS cases and 9.1% SSc cases. Patients with RA (or MCTD with RA) were more likely to be anti-CCP positive than those without RA (P < 0.05). The MCTD patients with positive anti-CCP had higher prevalence of RA and SS related manifestations than those MCTD patients with negative anti-CCP (P < 0.05). The MCTD patients with RA had higher prevalence of RA-related symptoms, diffuse sclerosis and positive anti-CCP than those MCTD patients without RA (P < 0.01). Significant deviation of disease spectrum was found in the MCTD patients with RA compared with the anti-CCP positive MCTD patients without RA. CONCLUSION: High titer of anti-CCP in combination with RA, SLE and SSc manifestations in MCTD patients can be an indicator of erosive arthritis. PMID- 21827001 TI - [Prognostic value of plasma N-terminal pro-B-type natriuretic peptide in patients with severe sepsis and septic shock]. AB - OBJECTIVE: To evaluate the prognostic value of plasma N-Terminal Pro-B-type Natriuretic Peptide (NT-proBNP) in severe sepsis and septic shock. METHODS: The blood samples were collect in 72 patients with severe sepsis and septic shock staying in intensive care unit (ICU) at consecutive days. The levels of plasma NT proBNP, lactate at the 1, 2, 3, 5, 7 day, as well as the levels of CK-MBmass, cTnT and procalcitonin at the 1, 3, 7 day were measured. All the patients were subjected to the calculation of APACHE (acute physiology and chronic ealth evaluation) II scores and SOFA (sequential organ failure assessment) scores,and the clinical outcome, ICU mortality, hospital mortality, ICU time, hospital time, 28-day mortality were collected. The prognostic value of plasma NT-proBNP was analyzed. RESULTS: Plasma NT-proBNP levels were markedly increased in the patients in our study. The level of NT-proBNP in nonsurvivors at 28 days was higher than that of survivors, and the peak level was emerged on the second day after admission. In multivariate logistic regression analyses, NT-proBNP level at day 3 after inclusion and APACHE II Score were independent predictors of hospital mortality, and only APACHE II Score is the independent predictor for 28-day mortality. CONCLUSION: Plasma NT-proBNP level shows obvious increase in patients with severe sepsis and septic shock. NT-proBNP on day 3 in ICU is an independent prognostic marker of hospital mortality in severe sepsis and septic shock. PMID- 21827003 TI - [Non-invasive assessment of renal oxygenation with BOLD MRI in patients with type 2 diabetes]. AB - OBJECTIVE: To evaluate renal oxygenation in patients with type 2 diabetes using blood oxygenation level-dependent magnetic resonance imaging (BOLD MRI). METHODS: The R2* values of cortex and medulla as well as cortical thickness were measured in 25 patients with type 2 diabetes and 30 normal controls. The associations between R2* values and clinical parameters were analyzed. RESULTS: The medulla R2* value of the patients with diabetes was significantly higher than that of the normal controls. No significant difference in cortical thickness was found between the patients with diabetes and the normal controls. The medulla R2* value increased with eGFR in the patients with diabetes. CONCLUSION: BOLD MRI is a non invasive and efficient method to assess the oxygenation in different regions of kidney. Abnormality of kidney in diabetic patients can be detected earlier by BOLD MRI than traditional imaging. PMID- 21827004 TI - [Whole-liver perfusion scans with 64-slice spiral CT in patients with liver cirrhosis]. AB - OBJECTIVE: To test the value of whole-liver perfusion in demonstrating liver angiography and assessing the degree of liver cirrhosis. METHODS: Forty patients with confirmed liver cirrhosis (patient group) and twenty patients without any liver abnormalities (control group) were prospectively enrolled in this study. All patients underwent whole-liver perfusion CT scans. The time density curve (TDC), hepatic arterial perfusion (HAP), hepatic portal perfusion (HPP) and total liver perfusion (TLP) were measured using a special software for the whole-liver perfusion. The CTA imaging of hepatic vessels was obtained by reconstructing the single scanning images. The peak values and time to reach peak values of abdominal aorta and portal veins and the hepatic perfusion parameters were measured. The collateral vessels were observed. RESULTS: Delay in the time to reach peak values and reduced peak values of the abdominal aorta and portal veins in patients with live cirrhosis were observed compared to the controls (P < 0.05). The HAP value in Child A was higher than those in Child B, C and the controls (P < 0.05). The HPP and TLP values decreased gradually in Child A, B and C, all with significance compared to the controls (P < 0.05). The HPI values in Child C was higher than those in other groups (P < 0.05). Reconstructed CTA images showed that different collateral vessels were developed at the end-stage of chronic liver cirrhosis due to severe portal hypertension. The parameters of HPP and TLP in the group with more collateral vessels development were greater than those in other groups (P < 0.05). CONCLUSION: The whole-liver perfusion is valuable in evaluation the severity of liver cirrhosis. The CT angiography can precisely illustrate the hepatic vascular anatomy of liver and the collateral vessels. PMID- 21827005 TI - [Non-contrast-enhanced MR angiography for selective visualization of the hepatic vein]. AB - OBJECTIVE: To evaluate the diagnostic performance of non-contrast-enhanced MR angiography (NCE-MRA) in the preoperative assessment of hepatic vein. MATERIALS AND METHODS: Contrast-enhanced MR angiography (CE-MRA)and NCE-MRA were performed on ten patients with hepatic cirrhosis and twelve potential living liver donors with the same 1. 5T MR scanner. The anatomic angiographic images were reconstructed and reviewed by two radiologists independently. The quality of the images of hepatic vein vessels was rated with a four point scale. RESULTS: After consensus reading, 19 NCE-MRA images (86.4%) and 20 CE-MRA images (90.9%) scored more than 3 point, respectively. The segmental branch vessels were visualized on MR angiography in the majority of cases. Both NCE-MRA and CE-MRA correctly characterized 20 out of 22 hepatic veins without false positive reporting. The NCE-MRA reported two false negative cases. There were no statistically significant differences between NCE-MRA and CE-MRA for the characterization of hepatic vasculature (P > 0.05). High consistency was achieved between the two reviewers, with Kappa values over 0.75. CONCLUSION: NCE-MRA is a non-invasive and effective method for the comprehensive assessment of hepatic vein. PMID- 21827006 TI - [Impact of patient motion on myocardial perfusion imaging with double-head SPECT and assessment of motion correction]. AB - OBJECTIVE: To investigate the impact of patient motion on myocardial perfusion imaging with double-head Single Photon Emission Computed Tomography (SPECT) and assess the effect of motion correction. METHODS: Twenty (20) patients were included in the study. Acquisitions were performed for all patients under the situations with or without body motion respectively. Images were reconstructed without or with motion correction software separately. The extent of perfusion defects was assessed by QPS (Quantitative Perfusion SPECT) with a 20 -segment, 5 point scoring system. RESULTS: The extent of artifacts and perfusion defects was related to the extent (r = 0.58, P < 0.01) and frequency (r = 0.811, P < 0.01) of patient motion. The image quality was improved in 18 of 20 patients (900%) significantly after motion correction (P < 0.05). Only 2.2% (7/318) of segments that were previously considered normal (score = 0 or 1) changed to abnormal (score = 2-4) after motion correction, whereas 35.3% (29/82) of abnormal segments were reclassified as normal after motion correction. CONCLUSION: Motion correction is necessary in myocardial perfusion imaging reconstruction if the range of patient motion is out of one pixel or the motion frequency is more than one time. But the correction is not helpful when the extent of body motion exceeds 3 pixel or the motion frequency is over one time. PMID- 21827007 TI - [Study on resting-state default mode network in patients with posttraumatic stress disorder after the earthquake]. AB - OBJECTIVE: To explore the pathogenesis of posttraumatic stress disorder (PTSD) by studying default mode network during the resting state in patients with PTSD after homologous traumatic experience. METHODS: Seventeen PTSD patients and 20 matched normal controls received the examnation of resting-state fMRI scanning. Left and right posterior cingulate cortex was regarded as seed region respectively, and the functional connectivity about whole brain was assessed by using resting-state functional connectivity analysis. RESULTS: Compared with control group, the patients with PTSD showed that the brain area with decreased functional connectivity included left superior frontal gyrus and right fusiform gyrus, while the brain area with increased functional connectivity included right precuneus, right superior temporal gyrus and right middle temporal gyrus. CONCLUSION: The brain default mode network of PTSD patients is abnormal in resting state. These abnormalities might be the neuropathological mechanisms of PTSD. PMID- 21827008 TI - [Changes in the prevalence of obesity and abdominal obesity in middle-aged Chengdu residents during 1992 and 2007]. AB - OBJECTIVE: To analyze the changes in the prevalence of obesity and abdominal obesity in the middle-aged Chengdu residents during 1992 and 2007. METHODS: In 1992, a cohort of 1365 Chengdu residents were selected using a combination of nonrandom cluster sampling and intra-cluster random sampling stratified by age and gender for cardiovascular disease risk factor surveys. In 2007, 1061 of the selected residents completed a second survey. We analyzed the changes in the prevalence of obesity and abdominal obesity in the middle-aged residents using BMI and waist circumference as indicators. RESULTS: From 1992 to 2007, the BMI, waist circumference, prevalence of obesity and abdominal obesity of this cohort of respondents increased significantly (P < 0.05). The 2007 survey found significant higher BMI, waist circumference, and prevalence of obesity and abdominal obesity in the residents of 50-64 years old than those with the same age in 1992 (P < 0.05). The female respondents had consistently greater standardized prevalence of obesity and abdominal obesity than their male counterparts except for the abdominal obesity in the 2007 survey. CONCLUSION: Both prevalence of obesity and abdominal obesity are increasing in Chengdu residents, even after adjustment of age. PMID- 21827009 TI - [Cognitive-behavior of HIV-positive women of fertility age regarding AIDS in three counties of Henan Province]. AB - OBJECTIVE: To investigate the demographic characteristics of HIV-positive women of fertility age in Henan province and their knowledge and behavior in relation to AIDS. METHODS: A questionnaire survey was administered to 686 HIV-positive women of fertility age through face to face interview. The demographic characteristics of the respondents and their association with AIDS-related knowledge and behavior were analysed. RESULTS: Over 90% of respondents had good knowledge about AIDS. Statistically significant differences existed in the knowledge of AIDS and the use of condom among those with different age, education and income (P < 0.05). Age (OR < 1) and annual income (OR > 1) were identified as risk factors of failing to use condoms in regression analysis. CONCLUSION: Interventions need to be strengthened for HIV-positive women of fertility age, in particular for those who are young and have high incomes. PMID- 21827010 TI - [Health status of rural elderly with migrant children and associated factors]. AB - OBJECTIVE: To determine the influence of children migration on the health of rural elderly in Sichuan province, and to provide reference for the subsequent research and health policy making. METHODS: Data used in the analysis were extracted from the expanded database for Western China collected in the Fourth National Health Survey in Sichuan province. The prevalence of acute illness in two weeks and the prevalence of chronic illness in the rural elderly were analysed and compared between those with different demographic characteristics and those with and without migrant children using a bivariate multi-level regression model. RESULTS: The prevalence of acute illness in two weeks and the prevalence of chronic illness in the rural elderly with migrant children were 44.0% and 44.5% respectively, significantly higher than the average level of elderly population in western rural China. No significant differences in the prevalence of two-week acute illness and the prevalence of chronic illness were observed in spite of the differences in the rank orders of diseases between whose with and without migrant children. Gender, children migration and living arrangements had a significant influence on the prevalence of acute illness in two weeks and the prevalence of chronic illness of the rural elderly. The influence of children migration differed between those who shared houses with other children and those who did not (alone or with spouse/grandchildren). CONCLUSION: Rural elderly with migrant children have poorer health than those without migrant children, especially those who live alone or with spouses and grandchildren only. The elderly with migrant children bear a greater burden of spinal disk disease perhaps because of their heavier physical workload. Greater attention needs to be paid to the health of the rural elderly with migrant children. PMID- 21827012 TI - [The establishment of craniopharyngioma cell line]. AB - OBJECTIVE: To establish the craniopharyngioma cell line with primary culture which might provide experiment background and evidence for future eternal tumor cell line establishment. METHODS: Thirty six surgical specimens were collected from patients with craniopharyngiomas definited by iconography and pathology examinations in West China Hospital, Sichuan University, including twenty one adamantine epitheliomas and fifteen squamous papillary tumors. The tumor cell was treated through primary cukture, purification, passage, freezing, resuscitation, and identified by keratin 7 staining through SP method. The growth curve and double time were detected through trypan blue dye cell count and MTT assay. The growth of the tumor cells treated with growth hormone (GH) and Tamoxifen was also observed. RESULTS: Thirty six primary cultures were done, 29 of which were successful and subculture was achieved in 80.6% of all primary cultures. These cell lines were from squamous epithelium by keratin 7 antibody identification, with three days of double time. Proloferative effect of GH was most prevalent at 100 ng/mL, while tamoxifen suppressed cell growth. CONCLUSION: The finite craniopharyngioma cell lines were obtained through primary culture. PMID- 21827011 TI - [Adherent culture of CD133+ cells in glioblastomas and expression of ADLH1]. AB - OBJECTIVE: To investigate the influence of adherent culture on the acquisition of CD133+ cells in glioblastomas and the expressions of acetaldehyde dehydrogenase 1 (ALDH1) in the undifferentiated and differentiated cells. METHODS: Adherent culture was performed with immunomagnetic bead technique in 7 glioblastoma samples to gain CD133+ cells. The cell differentiation was induced via serum medium culture. Immunocytochemistry staining was used to detect the expressions of ALDH1 and Sox2 in the undifferentiated and differentiated cells. RESULTS: CD133+ cells were obtained in 6 samples and typical tumor spheres were observed. Positive expressions of ALDH1 and Sox2 were detected in the undifferentiated cells and co-localization was found. No expressions of those two markers in the differentiated cells were observed. CONCLUSION: CD133+ cells can be efficiently obtained via adherent culture method. ALDH1 expression appears only in the undifferentiated cells, which can be a new marker for glioma stem cells. PMID- 21827014 TI - Treatment of oral infections prior to heart valve surgery does not improve long term survival. AB - The objective was to evaluate the importance of preoperative elimination of oral infections and oral health for survival after heart valve surgery In a group of patients (n=149; treatment group, GP group), oral health was examined and dental treatment was performed 3-6 months prior to heart valve surgery. In a second group (n=103; control group, SP group), oral health was examined postoperatively, but patients did not receive dental treatment prior to surgery. Sixteen years after heart valve surgery was performed, morbidity endpoint data were obtained. Differences in survival between the two groups and the influence of differences in oral health were analyzed. Fewer patients survived in the study group (37%) compared with the control group (45%). Mean survival was 122.9 months in the GP group compared with 143.3 months in the SP group, including time to death and those alive at the endpoint (p=0.018). A positive relationship was found between the number of teeth and survival, with RR = 0.98 (95% CI 0962-0.996 (p=0.016)).The deaths from heart valve disease were 18% in the GP group and 7% in the SP group (chi2=3.65, df=1, p=0.56). At the long-term follow-up,the results of the present study show,that it was not possible to demonstrate that dental treatment before heart valve surgery improved survival. Therefore, the need for extensive dental treatment prior to heart valve surgery may be reconsidered. PMID- 21827013 TI - [The CD133 polyclonal antibody generation and cancer stem cells identification]. AB - OBJECTIVE: To generate the cancer stem cells (CSCs) specific protein CD133 polyclonal antibody for the study of the biological characteristics of CSCs in tumor tissues and CSCs screening for the mouse model. METHODS: The extracellular peptide of the human CD133 was injected into rabbits to generate polyclonal antibody which was used for glioblastoma(GBM) Western blot and immunohistochemistry. RESULTS: The CD133 antiserum we made could detect both overexpressed myc-CD133 and endogenous CD133 efficiently by Western blot. Immunohistochemistry indicated that the CD133 polyclonal antibody can label CSCs in GBM sections. CONCLUSION: High efficient and specific CD133 antibody was generated successfully and could be used to label CSCs in tumor sections and screen CSCs for the mouse model. PMID- 21827015 TI - Aetiology of severe demarcated enamel opacities--an evaluation based on prospective medical and social data from 17,000 children. AB - During the 1970s dentists reported an increasing prevalence of a "new" type of enamel disturbance.The disturbance was very specific, with areas of demarcated hypomineralised enamel, and was mostly found in permanent first molars and incisors. Several studies have tried to reveal the aetiology behind the enamel disturbance but sofar no clear factors correlated have been found. The aim of the present study was to evaluate aetiological factors to severe demarcated opacities (SDO) in first permanent molars in a large cohort of children enrolled in the "All Babies in Southeast Sweden" (ABIS) project. ABIS is a prospective study of all children in five Swedish counties born between Oct 1, 1997 and Oct 1, 1999, in all about 17,000 children.They have been followed from birth with recording of a large number of factors on nutrition, diseases, medication, infections, social situation etc. With help from 89 Public Dental Service clinics in the same area preliminary examinations of the children, born between Oct 1,1997 and Oct 1,1999, reported 595 children with severe demarcated opacities (SDO) in first molars.These children and a randomly selected age matched group of 1,200 children were further invited to be examined by specialists in paediatric dentistry. At these examinations 224 severe cases were identified as well as 253 children completely without enamel disturbances among children registered in ABIS.These two groups were analysed according to any correlation between SDO and variables in the ABIS databank. The analyses showed no association between SDO and pre-, peri-, and neonatal data. However, we found a positive association between SDO and breastfeeding for more than 6 months (OR 1.9; 95% CI 1.1-3.2), late introduction of gruel (OR 1.9; 95% CI 1.1-2.9), and late introduction of infant formula (OR 1.8; 95% CI 1.2-2.9). A combination of these three variables increased the risk to develop SDO by more than five times (OR 5.1; 95% CI 1.6 15.7). No significant associations were found to other environmental, developmental, or medical factors. We conclude that nutritional conditions during first 6 months of life may influence the risk to develop severe demarcated opacities in first permanent molars. PMID- 21827016 TI - A history of frequent dental care reduces the risk of tooth loss but not periodontitis in older subjects. AB - OBJECTIVES: Information on the significance of dental care in older adults is limited. We hypothesized that regular dental visits has an effect on the number of remaining teeth and periodontal conditions in older subjects. MATERIALS AND METHODS: 1020 randomly selected individuals age 60 - 96 from the Swedish National Study on Aging and Care Blekinge received a comprehensive oral health examination. RESULTS: Dentate women and men had, on average 18.4 teeth (SD +7.6,) and 18.9 teeth (SD + 7.5) respectively (NS). In the youngest group (60 and 66 years old) with less than one dental visit per year, 37% had >20 teeth, compared with 73% among those with at least annual visits. Among the old-old, comparable figures were 1.8 % and 37% respectively. Across age groups, bleeding on probing was 23 %.When adjusting for age, and number of teeth GLM univariate analysis failed to demonstrate an effect of dental visit frequency on alveolar bone loss (p = 0.18), the number of periapical lesions (p = 0.65), or the number of endodontically treated teeth ( p = 0.41). Frequent dental visitors had more teeth than infrequent visitors (p = 0.001). CONCLUSIONS: Tooth loss and alveolar bone loss severity increase with age. Individuals with regular dental visits retained more teeth but the frequency of dental visits had no impact on plaque deposits, gingival inflammation, or alveolar bone levels. PMID- 21827018 TI - Self perceived oral health, oral treatment need and the use of oral health care of the adult population in Skane, Sweden. AB - The aim was to describe how the adult population in Skane, Sweden, perceived their oral health, dental status, oral treatment need and use of oral health care. A questionnaire was sent to a randomly selected sample of 10 000 persons in Skane, Sweden. The individuals were between 20 and 89 years old and registered as residents of the region during 2006. After excluding those no longer living in the region, 9 690 individuals remained. The response rate to the questionnaire was 63%, of which 57% were women and 43% men.A majority was satisfied with their teeth and with their teeth's appearance, 65% and 62% respectively. Of the respondents, 35% considered their dental health to be better than others in their age group. Symptoms associated with periodontitis were experienced by 40%. 7% were missing more than ten teeth while 7% had no dental fillings. 30% rated their need of dental treatment as high and most expected their treatment need to increase in the future. Most of the respondents, 60%, received their oral care at a private practice, whereas 13% did not see a dentist regularly for check-ups. More women than men perceived a high dental treatment need, 32% compared to 28%. CONCLUSIONS: A majority of the adult population in Skane have a positive attitude towards their oral health. Most individuals had lost few teeth and removable dentures were uncommon.A third rated their dental treatment need as high and most expected their treatment need to increase in the future.. PMID- 21827017 TI - Changes in tooth mortality between 1990 and 2002 among adults in Vasterbotten County, Sweden: influence of socioeconomic factors, general health, smoking, and dental care habits on tooth mortality. AB - The objectives of the study were to analyse changes in tooth mortality among adults in Vasterbotten County, Sweden, between 1990 and 2002 and determine whether socioeconomic factors, general health, smoking, and dental care habits influenced tooth mortality. The study was based on samples drawn from the adult population in Vasterbotten County in 1990 and 2002. The studied age groups were 35-, 50-, and 65-year-olds. In 2002 75-year-olds were included. The surveys comprised a clinical examination and a questionnaire.The latter focused on oro facial symptoms, socioeconomic factors, general health, smoking, and dental care habits. Complete data were obtained from 715 individuals in 1990 and from 768 individuals in 2002.Variables used to depict tooth mortality were edentulousness, occlusal supporting zones (Eichner index), and number of teeth. The prevalence of edentulousness in Vasterbotten County decreased from 12.7% in 1990 to 3.7% in 2002 (P < 0.001). The mean number of teeth increased in all age groups between 1990 and 2002, and so did the number of individuals with tooth contact in all occlusal supporting zones and no gaps between teeth. Low educational level, weak economic status, smoking, and irregular visits to the dental clinic were all significantly related to increased tooth mortality. Between 1990 and 2002 tooth mortality decreased significantly in the adult population of Vasterbotten County, Sweden. Cross-sectional analysis identified socioeconomic factors, smoking, and irregular use of dental care services as being related to tooth mortality in both 1990 and 2002. PMID- 21827019 TI - [An opinion of preventive oral health care]. PMID- 21827020 TI - [Detection of potentially malignant and malignant lesions of oral cavity using autofluorescence visualization device]. AB - Light-based oral cancer screening aids have been developed in identifying potentially malignant and malignant lesions of oral cavity at their earliest stage. The VELscope system is a simple hand-held device that facilitates the direct visualization of oral-cavity fluorescence for the detection of precancerous and cancerous lesions. Some published reports have shown that this system can assist in the detection of precancerous and cancerous lesions, but there is no evidence that it can distinguish between them. We studied whether objective discrimination criteria can be set for this system when observing oral mucosal lesions. We examined 74 cases with biopsy-confirmed oral mucosal lesions; 37 squamous cell carcinoma lesions, 14 moderate to severe epithelial dysplasia lesions, 13 mild epithelial dysplasia lesions and 10 lichen planus lesions. Lesions were examined macroscopically under the conventional overhead light, and then, examined by this device. Each examination was recorded with a digital camera. We contrasted findings with histopathological manifestation, and calculated the attenuation score. It is found that several conditions and sites, such as keratinization and the degree of inflammatory cell infiltration, were associated with detection sensitivity using this device. Based on the attenuation scores, a significant difference was seen between squamous cell carcinoma and epithelial dysplasia. It is suggested that this device might be a valuable adjunct in the early detection of potentially malignant and malignant lesions of the oral cavity. PMID- 21827021 TI - Remember our older Australians--and nurses in aged care. PMID- 21827022 TI - Labour Day: celebrating the past, committing to the future. PMID- 21827023 TI - Picking up the pieces. PMID- 21827024 TI - $2.2 Billion for mental health federal budget 2011-2012. PMID- 21827025 TI - English language test registration win. PMID- 21827026 TI - QNU membership ensures your legal interests are independently represented. PMID- 21827027 TI - Heavy workloads do not reduce your professional responsibilities. PMID- 21827028 TI - Having your say on change. PMID- 21827029 TI - Starting a new job in the private sector? Know your entitlements! PMID- 21827030 TI - National health reform edging closer. PMID- 21827031 TI - Complaints about harmonisation hint at anti-union campaign. PMID- 21827033 TI - Where are we on climate change? PMID- 21827032 TI - Birthing on country. PMID- 21827034 TI - Nurses and midwives--shaping a better future. PMID- 21827035 TI - Dr. Ronald L. Rhea, President. President's address to the Texas Dental Association House of Delegates, May 5, 2011. PMID- 21827036 TI - Dr. Jerry S. Long, ADA 15th District Trustee. Trustee's Address to the Texas Dental Association House of Delegates, May 7, 2011. PMID- 21827037 TI - Dr. J. Preston Coleman, President-Elect. Incoming President's address to the Texas Dental Association House of Delegates, May 8, 2011. PMID- 21827038 TI - Latex and non-latex orthodontic elastic force loss due to cyclic temperature. AB - The purpose of this study was to compare the force loss of 1/4 inch (6.35mm) 3.5oz (99g) medium latex elastics from Ormco Corp. to non-latex elastics from ClassOne Orthodontics and Phoenix after being cycled between different temperatures. Elastics were stretched to 1.57 inches (40mm) on jigs and cycled in water baths for 4 minutes at 5 degrees C and 37 degrees C, 21 degrees C and 37 degrees C, 5 degrees C and 50 degrees C, 37 degrees C and 50 degrees C, and a control group was held at 3 degrees 7 degrees C. The force produced by new elastics and elastics after incubation was measured using a Mini 44 Instron. RESULTS: All elastics experienced increased force loss that correlated with increased temperatures with the exception of Ormco latex elastics. The latex elastics had the greatest force loss upon cycling between 5 degrees C and 50 degrees C while the non-latex elastics had the greatest force loss while cycling between 37 degrees C and 50 degrees C. All elastics were strongest when cycled between 5 degrees C and 37 degrees C. CONCLUSION: This study suggests that hot liquids reduce the force of latex and non-latex elastics even when cycled between hot temperatures for brief periods of time. PMID- 21827039 TI - Adhesive dentistry and endodontics: materials, clinical strategies, and procedures for restoration of access cavities: a review. AB - The complexity of restorative dentistry has increased greatly in recent years, with the myriad of products used in "adhesive dentistry." So too has the "simple" matter of restoring access cavities after completion of endodontic treatment. This review discusses current methods of "bonding" to tooth structure, ceramic materials, and metals, with emphasis on those aspects that are important to endodontics. Specific materials, procedures and major decision making elements are discussed, as well as how to avoid problems in compatibility between endodontic and restorative materials. PMID- 21827040 TI - Papillary tip melanosis (pigmented fungiform lingual papillae). PMID- 21827041 TI - Value for your profession. Strategies for improving patient understanding and compliance. PMID- 21827042 TI - Synthesis and anticonvulsant evaluation of some novel (thio)semicarbazone derivatives of arylalkylimidazole. AB - A number of novel 2-(1H-imidazole-1-yl)-1-aryl-substituted ethane-1-one N substituted phenyl(thio)semicarbazones (1-14) were synthesized to test for their anticonvulsant activity against the two seizure models, maximal electroshock (MES) and subcutaneous pentylenetetrazol (scPTZ). Title compounds were prepared by the reaction of appropriate (thio)semicarbazides with ketones. Neurotoxicity was screened by the rotarod test. The structure of compounds was confirmed by elemental analysis results and the spectroscopic techniques such as IR, 1H-NMR, 13C-NMR, ESI-MS and HRMS. As a result of activity studies, when the thiosemicarbazone compounds were compared at different doses, 2-(1H-imidazole-1 yl)-1-(2-naphthyl)ethane-1-one N-(3-chlorophenyl)thiosemicarbazone (3) and 2-(1H imidazole-1-yl)-1-(2-biphenyl)ethane-1-one N-(4-fluorophenyl) thiosemicarbazone (12) were found selective and highly active compounds against MES-induced seizures after 0.5 h and 4 h, respectively. Beside this, 2-(1H-imidazole-1-yl)-1 (1-biphenyl)ethane-1-one N-(4-methylphenyl)thiosemicarbazone (14) was the most active compound in the scPTZ-induced seizure test after 4 h. The 2,4 dichlorophenyl (9) and 2-fluorophenyl (10) substituted biphenyl derivatives of thiosemicarbazone compounds showed neurotoxicity at higher doses. PMID- 21827043 TI - Plasma levels of clozapine and norclozapine in Mexican schizophrenia patients. AB - The aim of the present study was to determine the prescribing practice for clozapine (CAS 5786-21-0) as well as the plasma levels of clozapine and its main metabolite norclozapine (CAS 6104-71-8) in Mexican patients. A prospective study was performed in 69 in and out psychotic patients taking clozapine. Blood samples were taken at steady state. Plasma concentrations of clozapine and norclozapine were determined by HPLC. The results showed that the mean daily dose administered was 250 mg/d. Plasma levels showed a large interindividual variability. Mean plasma levels were 411.3 +/- 328.12 ng/mL, for clozapine and 172.0 +/- 129.9 ng/mL for norclozapine. When data were compared with those reported in other populations, it was found that although the dose was lower than that reported in Caucasians, the plasma levels were similar. As a result, the predictive models for the estimation of clozapine concentration in Caucasians were not appropriate for application in Mexican patients. The findings suggest ethnic differences in the ratio dose/plasma levels of clozapine in Mexican patients. Further studies are required to expand the observations. PMID- 21827044 TI - Simultaneous determination of L-arginine, asymmetric dimethylarginine, and symmetric dimethylarginine in the plasma of rodents with LC-MS/MS. AB - Nitric oxide (NO) is synthesized from L-arginine (Arg) by NO synthase (NOS), and asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) are endogenous inhibitors of NO formation. Normal distribution values of Arg, ADMA, and SDMA are required to evaluate the effects of cardiovascular drugs on blood vessels, but insufficient normal reference values from rat and mouse plasma exist for new drug development and screening. To determine the means and variations in the basal endogenous materials concentration, Arg, ADMA, and SDMA in blank rat (n = 24) and mouse (n = 37) plasma samples were quantified using LC-MS/MS equipped with an electrospray ionization interface to generate positive mode ions. Accuracy and precision were within 90.42-110.91%, and 0.88-13.84%, respectively, for analyses of Arg, ADMA, and SDMA. The average plasma concentrations of Arg, ADMA, and SDMA were 175.38 +/- 13.87 microM, 0.79 +/- 0.20 microM, and 0.84 +/- 0.20 microM, respectively, in rats and 70.81 +/- 19.38 microM, 0.66 +/- 0.21 microM, and 0.42 +/- 0.10 microM, respectively, in mice. These results will provide a basis on which to evaluate cardiovascular drug effects on ARG, ADMA, and SDMA levels in new drug development. PMID- 21827045 TI - Simultaneous determination of liensinine, isoliensinine and neferine from seed embryo of Nelumbo nucifera Gaertn. in rat plasma by a rapid HPLC method and its application to a pharmacokinetic study. AB - A rapid and specific HPLC method has been developed and validated for the simultaneous determination of liensinine (CAS 2586-96-1), isoliensinine (CAS 6817 41-0) and neferine (CAS 2292-16-2) in rat plasma. The sample was prepared by a liquid-liquid extraction with diethyl ether and the recovery was above 80% from the plasma for the three compounds. Chromatographic separation was achieved with a Hypersil BDS C18 column (4.0 mm x 250 mm, particle size 5 microm). A mobile phase consisting of methanol: 0.2 M KH2PO4:0.2 M NaOH:triethylamine (71:17:12:0.002, v/v/v/v, pH 9.2-9.3) was slowly delivered at 0.8 ml/min in isocratic mode with a detection wavelength of 282 nm. The linearity of calibration curves were good (r > 0.999) in the concentration range of 0.031-2.00 microg/ ml. The lower limit of quantification can reach 0.03 microg/ml for the three compounds. The intra-day and inter-day variations estimated with QC samples were less than 8% for the three tested concentration levels. This developed method was applied in the plasma pharmacokinetic study of total bisbenzylisoquinoline alkaloids (TAL) of the lotus flower (Lian Zi Xin) following a single oral and intravenous administration of TAL in rats. PMID- 21827046 TI - Study on bioavailability difference between clopidogrel bisulfate form I and form II using liquid chromatography/tandem mass spectrometry. AB - The bioavailability of clopidogrel bisulfate (CAS 135046-48-9) form I was compared with that of clopidogrel bisulfate form II in 12 male Sprague-Dawley rats. The rats, randomly divided into two groups, received a single oral dose of 8 mg/kg clopidogrel (CP) bisulfate form I and form II, respectively, under fasting condition. The plasma concentrations of CP and its inactive carboxylic acid metabolite (CAS 144457-28-3, IM) were simultaneously determined by a sensitive, specific LC-MS/MS method. The pharmacokinetic parameters included C(max), T(max), t1/2, AUC(0-t), AUC(0-infinity). The AUC(0-infinity) of CP was 13.78 +/- 0.67 and 11.46 +/- 1.98 ng/ mL x h for CP form I and form II, respectively. The AUC(0-infinity) of IM was 33.08 +/- 5.76 and 21.67 +/- 8.95 microg/mL x h for CP form I and form II, respectively. The maximum plasma concentration (C(max)) of CP was 3.81 +/- 0.54 ng/mL for CP form I and 3.18 +/- 0.31 ng/mL for CP form II, the C(max) of IM was 3.42 +/- 0.41 and 2.08 +/- 0.68 microg/ mL for the CP form I and form II, respectively. There was an obvious difference between form I and form II for C(max) and the area under the plasma concentration time curve for both CP and IM after a t-test. This study shows that CP form I has better bioavailability in rats than CP form II. PMID- 21827047 TI - Synthesis and in vitro antiplasmodial activity of quinoline-ferrocene esters. AB - New 4-aminoquinoline-derived esters containing the redox-active ferrocene group brought in by either ferrocenyformic or 4-ferrocenylbutanoic acids were synthesized and tested in vitro for their antiplasmodial activity. The results revealed that only esters derived from ferrocenylformic acid were active against both chloroquine (CQ)-resistant Dd2 and CQ-sensitive D10 strains of Plasmodium falciparum. However, none of these showed higher actvity than CQ against the sensitive strain. Ester 16, which possesses a butyl branch in the structure, was the most active of all. With an IC50 of 0.13 mM on the resistant strain, this ester possessed 2.5-fold higher activity than CQ (IC50 = 0.34 mM). All tested esters showed good selectivity towards P. falciparum with indexes higher than 60. PMID- 21827049 TI - This painful curve. PMID- 21827048 TI - Synthesis of some Mannich bases with dimethylamine and their hydrazones and evaluation of their cytotoxicity against Jurkat cells. AB - 1-Aryl-3-dimethylamino-1-propanone hydrochlorides type mono Mannich bases, D series, and corresponding hydrazone derivatives, K series, were synthesized and their cytotoxicity was tested against Jurkat cells (transformed human T lymphocytes). The aryl part was changed as phenyl in D1 and K1, 4-methylphenyl in D2 and K2, 4-methoxyphenyl in D3 and K3, 4-hydroxyphenyl in D4 and K4, 4 chlorophenyl in D5 and K5, 3-methoxyphenyl in D6 and K6, 4-fluorophenyl in D7 and K7, 4-bromophenyl in D8 and K8, 3-hydroxyphenyl in D9 and K9, and 2 acetylthiophene in D10 and K10. Of the compounds synthesized, K2, K3, K5, K6, K7, K8, K9, and K10 are reported for the first time. Cytotoxic activities of the D and K series were compared with each other to see alterations in bioactivity depending on the chemical structures in Jurkat cells. Cytotoxicities of the compounds synthesized were also compared with the reference compound, 5 fluorouracil (CAS 148-82-3). Mono Mannich bases, D1 (3.60 times), D2 (4.45 times), D3 (2.46 times), D4 (3.52 times), D5 (5.18 times), D6 (3.20 times), D7 (3.23 times), D8 (3.95 times), D9 (3.36 times) and D10 (3.99 times) had 2.46-5.18 times higher cytotoxic potency than the reference compound 5-fluorouracil against Jurkat cells, while hydrazones K1 (4.92 times), K2 (4.65 times), K3 (6.04 times), K4 (6.34 times), K5 (4.67 times), K6 (5.12 times), K7 (5.39 times), K8 (8.31 times), K9 (4.65 times) and K10 (8.65 times) had 4.65-8.65 times higher cytotoxic potency than the reference compound 5-fluorouracil against the same cell line. On the other hand, hydrazone compounds K1 (1.37 times), K3 (2.46 times), K4 (1.80 times), K6 (1.60 times), K7 (1.67 times), K8 (2.11 times), K9 (1.38 times), and K10 (2.17 times) had 1.37-2.46 times higher cytotoxic potency than their corresponding mono Mannich bases. The results of this study suggest that hydrazones were better compounds compared with the corresponding mono Mannich bases in terms of cytotoxicity, and they may serve as model compounds to develop new cytotoxic agents for further studies. PMID- 21827050 TI - Variations in dental and alveolar arch dimensions among different malocclusion groups in a sample of untreated patients. AB - This study compares the different transverse relationships of the upper and lower arches in the 4 different malocclusion groups and describes the origin of these transverse discrepancies. Knowledge of dental and alveolar arch dimensions will help the clinician in diagnosis and treatment planning of patients with different malocclusions. PMID- 21827051 TI - A comparative analysis of adhesive resin removal methods. AB - The objective was to determine which bracket adhesive removal method was the most effective. Four different techniques were investigated: adhesive removing pliers, 12-fluted carbide, white stone, and Sof-Lex discs. Scanning electron microscopy was used for microanalysis and photographing. Sof-Lex discs was the best removal method, similar to the negative control. PMID- 21827052 TI - The effects of miniscrew with Class III traction in growing patients with maxillary deficiency. AB - The aim of this study was to compare the effects of face mask and miniscrew combined with Class III traction on Class III malocclusion maxillary deficiency in growing patients. 10 patients were treated with facemask and 10 other patients were treated by means of miniscrew and Class III traction. Pre- and post treatment cephalometric data were analyzed and compared between the two groups. Both groups were successfully treated; however, IMPA increased in miniscrew group while it decreased in facemask group. PMID- 21827053 TI - Study of the effect of different surface treatments and surface roughness of veneered crowns on shear bond strength of ceramic brackets. AB - The orthodontist is often faced with the problem of bonding brackets to ceramic restorations. The purpose of this study was to find the most reliable method for bonding ceramic brackets onto ceramic crowns. PMID- 21827054 TI - Correction of bilateral second molar scissors-bite during retention phase. AB - A clear removable appliance can be an effective method to correct bilateral second molar scissors-bite during the retention phase. In certain cases of bilateral second molar scissors-bite where the patient refuses to wear conventional fixed appliances, Serial Aligner could be an effective alternative option. PMID- 21827055 TI - Transforce lingual appliances pre-adjusted invisible appliances simplify treatment. AB - Transforce lingual appliances are designed to be used in conjunction with conventional fixed appliances. Lingual arch development is normally followed by bonded fixed appliances to detail the occlusion. Alternatively Transforce appliance treatment is an efficient method of preparing complex malocclusions prior to a finishing stage with invisible appliances. This approach is ideal for adult treatment, using light continuous forces for arch development with appliances that are comfortable to wear. Sagittal and Transverse appliances are designed for arch development in a range of sizes for contracted arches. They can be used to treat all classes of malocclusion and are pre-adjusted fixed/removable devices for non-compliance treatment. Force modules with nickel titanium coil springs enclosed in a tube deliver a gentle, biocompatible continuous force with a long range of action. They are excellent for mixed dentition and ideal for adult arch development. There are multiple sizes for upper and lower arch development and a sizing chart may be placed over a study model for correct selection, eliminating the need for laboratory work. PMID- 21827056 TI - The Simplicity System: the innovation of concept and technique. AB - The Simplicity System is a custom comprehensive orthodontic system for treating 80+% of all orthodontic cases seen. It uses indirect bonding, and specific diagnostic criteria, to incorporate the Diagnostic Goals and the Treatment Goals into the Bonding Phase. This is accomplished by creating a Positioner type setup model, which has been manufactured to incorporate the finished arch form (created from diagnostic criteria) into the initial indirect bonding trays for correct bracket placement. Light wire forces are the engine that moves the teeth, and the teeth are guided into their final treatment position by the Roth Bracket prescription, mesial stops at the first molars that give the starting wire the correct arch length needed and a wire size that fills the slot from the start of treatment. For molar anchorage and lateral development, when needed, the incorporation of lingual arches upper and lower are placed at the start of treatment. The entire treatment is designed to be accomplished using only two treatment wires. Most non-extraction cases finish treatment in 12 to 16 months. PMID- 21827057 TI - 10 reasons to thank your patients. PMID- 21827058 TI - Infant secondhand smoke exposure in Louisiana, 1998-2004: trend and high risk population. AB - PURPOSES: To evaluate the trend of infant secondhand smoke exposure (ISHSE) at home from 1998 to 2004 and define high risk infants exposed to secondhand smoke. METHODS AND SUBJECTS: 1998-2004 Louisiana Pregnancy Risk Assessment Monitoring System data were used. Logistic regression was applied to determine the trend of ISHSE and define variables associated with ISHSE. RESULTS: Adjusted annual percent increase of odds of ISHSE was 9.0% (p = .0020) among blacks. Adjusted annual percent decrease of odds of ISHSE was 5.0% (p = .0084) among whites. Adjusted odds of ISHSE was higher among women with characteristics as follows: currently smoked, age < 20 years, < high school education, unmarried, never breastfed their infants, had term delivery or deliveries paid for by Medicaid. CONCLUSIONS: Prevalence of ISHSE increased in blacks and decreased in whites between 1998 and 2004. Smoking status, maternal age, education, marital status, delivery payment source, delivery status, and breastfeeding status were associated with ISHSE. PMID- 21827059 TI - A case report of intraoperative endoscopic ultrasound during robotic assisted Heller myotomy for severe esophageal achalasia. AB - Esophageal achalasia is the best described primary esophageal motility disorder. Endoscopic ultrasound (EUS) is considered a useful adjunct for grading and establishing the prognosis of these patients. Recent experience using Da Vinci robotic assisted myotomy has demonstrated that this is a safe and effective approach of treatment. The benefit of magnification and three dimensional imaging helps prevent esophageal perforation and identify residual circular muscle fibers. This paper reports the relative efficacy and safety of intraoperative ultrasound during robotic assisted myotomy in a patient with severe achalasia. Intraoperative esophageal endoscopic ultrasound is a safe technique that may improve the success rate of surgery by confirming the adequacy of myotomy, thereby decreasing the likelihood of recurrent symptoms. PMID- 21827060 TI - An infant with recurrent maculopapular rashes, anemia, lymphadenopathy, and hepatosplenomegaly. PMID- 21827061 TI - Restoration of medical oncology services at LSU Interim Public Hospital in New Orleans after Hurricane Katrina: a two-year experience of LSUHSC. AB - BACKGROUND: Oncology services at Charity Hospital were discontinued following Hurricane Katrina in August 2005. Medical oncology and chemotherapy services resumed at the Louisiana State University Interim Public Hospital in 2007. Demographic, clinical, and displacement data of the re-established patient cohort were reviewed. METHODS: Patients evaluated in the Louisiana State University Health Sciences Center (LSUHSC) Oncology Clinics from September 1, 2007, to August 31, 2009, were identified and data collected included time from diagnosis of malignancy to initial oncology evaluation, insurance status, percentage displaced for six months or more due to Hurricane Katrina, ethnicity, referrals for radiation oncology, and the number of outpatient clinical encounters (OCE). RESULTS: 464 patients were evaluated in the study time period. Sixty-five percent of the patients had new cancer diagnoses and 35% re-established cancer care in the Charity System and a substantial proportion were either unfunded or had Medicaid coverage. Thirty-four percent were confirmed to be displaced from New Orleans for greater than six months and the majority of patients were black. The majority of new cancer diagnoses were breast, lung, and colon cancer. Human immunodeficiency virus (HIV) positive patients made up 7.5% of the patient cohort. There was a 70% decline in patient volumes following Hurricane Katrina. CONCLUSIONS: Oncology services for a minority-based, underinsured patient population were severely impacted by Hurricane Katrina. Following the storm, persistent systemwide resource limitations led to suboptimal timeliness of medical oncology evaluations. Health care systems serving underinsured patients require a disaster plan to minimize interruption of oncology care. Our experience illustrates the need for resources to ensure rapid re-establishment of care for economically disadvantaged patients following natural disasters. PMID- 21827062 TI - Bronchobiliary fistula: a case report. AB - Bronchobiliary fistula was first described by Peacock in 1850 and is a rare clinical finding. Bronchobiliary fistula is usually a result of hydatid cyst disease or a congenital abnormality. Hepatic intervention is the most common cause in American adults. Other reports have described bronchobiliary fistula, but the number of cases is relatively small, and little consensus on treatment exists. This report describes a patient presenting with bronchobiliary fistula after hepatic resection for metastatic colon cancer; the fistula was treated by thoracic surgical intervention. PMID- 21827064 TI - White Coat Ceremony: keynote address for the Department of Medicine LSUHSC 2010. PMID- 21827063 TI - Paracardiac mediastinal mass. PMID- 21827065 TI - Significance of a new systolic murmur in a patient with an acute myocardial infarct. PMID- 21827066 TI - ECG of the month. Chest pain in a 56-year-old man. Normal sinus rhythm. PMID- 21827067 TI - Radiology case of the month. Progressive loss of knee extension post anterior cruciate ligament reconstruction. Localized anterior arthrofibrosis. PMID- 21827068 TI - Clinical case of the month. A 20-year-old man with cough of two months duration. PMID- 21827069 TI - What are my rights when a health plan audits my claims? PMID- 21827070 TI - High flying performance incentives. PMID- 21827071 TI - The British debate assisted suicide. PMID- 21827072 TI - What's next? PMID- 21827073 TI - Part time physician employment on the rise. PMID- 21827074 TI - A conversation with MDCH head Olga Dazzo. PMID- 21827075 TI - Keynoter sees national trends in medical home movement. Interview by Mark Holoweiko. PMID- 21827076 TI - Qualifying for meaningful use may not be as hard as physicians think. PMID- 21827077 TI - When investing, diversification is a virtue. PMID- 21827078 TI - Dangerous choices: how our neighbors are dealing with life-changing health decisions. PMID- 21827079 TI - Equipoise. PMID- 21827080 TI - Whistleblowing hits record high. PMID- 21827081 TI - Specialist roles suffer most in training cuts. PMID- 21827082 TI - Fraud unit "targets" black staff. PMID- 21827083 TI - "We need to understand that the right to care is a privilege". PMID- 21827084 TI - "Why does the glass always have to be half empty for nurses"? PMID- 21827085 TI - "Depression after stroke may be missed--nurses can spot it". PMID- 21827086 TI - Air embolus. PMID- 21827087 TI - Nutritional support: how to reduce the risk of harm. PMID- 21827088 TI - Does non-medical prescribing make a difference to patients? AB - This article examines the literature on non-medical prescribing to establish its impact on UK healthcare. It discusses how better access to medication through non medical prescribing can improve patient safety and patient-centred care, and how nurse prescribing can help ensure quality of care in the NHS during the current financial crisis. PMID- 21827089 TI - The effectiveness of nurse prescribing in acute care. AB - BACKGROUND: The role of nurse prescriber has been recognised in the community since the 1990s but it was only in 2002 that it was extended to acute care. At the time of the study, little was known about the impact and effectiveness of nurse prescribing in the acute setting. AIM: To evaluate the implementation of nurse prescribing roles at an acute trust in England. METHOD: A mixed-methods, single-case study was carried out in 2005-06. Semi-structured interviews were conducted with 18 hospital staff, two doctors and two nurses undertaking 52 patient-prescriber consultations involving 47 patients were observed, and 74 patients were surveyed using a questionnaire. RESULTS: Nurse prescribing was found to benefit patients through improvements in service delivery and better use of staff skills. No differences were found between the ways in which doctors and nurses performed prescribing roles but there was between the medicine-related satisfaction ratings of patients seen by a nurse compared with those seen by a doctor. CONCLUSION: Nurses and doctors provided equivalent care. Nurse prescribers were crucial to the success of the initiative because of their enthusiasm, motivation, drive to succeed and a shared vision supporting prescribing roles. PMID- 21827090 TI - Common mental health disorders. PMID- 21827091 TI - Mental health and long-term conditions 2: Managing depression. AB - This second article in a two-part series on mental health and long-term conditions discusses the complex area of comorbid physical health and mental health problems. It focuses on depression--one of the most common mental illnesses--examining its prevalence and symptoms in people with long-term conditions, and how it can affect the ability to self-manage them. It also examines how nurses can support clients who experience depression as part of their long-term condition. PMID- 21827092 TI - Change of life. PMID- 21827094 TI - The state of the unions. PMID- 21827093 TI - Making the most of your meetings. PMID- 21827095 TI - I can't believe they said that about me!--Surviving union turmoil. PMID- 21827096 TI - Shipping prisoners to Australia and population health-responding to health care reform. PMID- 21827097 TI - Changing the "Peter Principled" culture of health care systems. AB - The 40-year-old "Peter Principle" still reminds us of the stagnant nature of organizational culture within many health care systems. Consider a prescription to help instill a culture of innovation. PMID- 21827098 TI - Creating a diabetes chronic disease management program that works. PMID- 21827099 TI - Integrating behavioral screening and intervention into general health care. PMID- 21827100 TI - A path to world-class service for medical organizations. PMID- 21827101 TI - Effective ways to decrease costs of labor in a cardiac catheterization lab. PMID- 21827102 TI - Reasons to hire recovered physicians. PMID- 21827103 TI - The role of project managers who assist physician leaders at Mayo Clinic. PMID- 21827104 TI - Health care leadership and the dyad model. PMID- 21827105 TI - Clinician adoption of technology. PMID- 21827106 TI - Technology jobs for physician leaders. PMID- 21827107 TI - A proven approach to physician engagement. PMID- 21827108 TI - Four important roles of a manager. PMID- 21827110 TI - Stand and deliver. PMID- 21827109 TI - Physician employment is here to stay. PMID- 21827111 TI - A dearth of new meds. PMID- 21827112 TI - Mental illness in a dish. PMID- 21827113 TI - A skill better than Rudolph's. PMID- 21827114 TI - Parsing the Twitterverse. PMID- 21827115 TI - Anatomy of an outbreak. PMID- 21827116 TI - E. coli on the march. PMID- 21827117 TI - Going viral. PMID- 21827118 TI - Mouth wide open. PMID- 21827119 TI - The mind-reading salmon. PMID- 21827120 TI - Cryogenic cooking. PMID- 21827121 TI - How do tumors grow? PMID- 21827122 TI - The perils of copy protection. PMID- 21827123 TI - Does the multiverse really exist? PMID- 21827124 TI - The evolution of grandparents. PMID- 21827125 TI - How to build a better learner. PMID- 21827126 TI - The false promise of biofuels. PMID- 21827127 TI - Treasure in the trees. PMID- 21827128 TI - A breath of fresh air. PMID- 21827129 TI - How New York beat crime. PMID- 21827131 TI - Guardian of the pharoahs. Interview by Jeffrey Bartholet. PMID- 21827130 TI - Why math works. PMID- 21827132 TI - Globaloney. PMID- 21827133 TI - Bombarded. PMID- 21827134 TI - Structures of the dimeric and monomeric chromanones, gonytolides A-C, isolated from the fungus Gonytrichum sp. and their promoting activities of innate immune responses. AB - Innate immunity is the front line of self-defense against microbial infection. After searching for natural substances that regulate innate immunity using an ex vivo Drosophila culture system, we identified a novel dimeric chromanone, gonytolide A, as an innate immune promoter from the fungus Gonytrichum sp. along with gonytolides B and C. Gonytolide A also increased TNF-alpha-stimulated production of IL-8 in human umbilical vein endothelial cells. PMID- 21827135 TI - Phytochemical, antioxidant, and antiproliferative properties of seed oil and flour extracts of Maryland-grown tobacco cultivars. AB - To determine the possible alternative use of tobacco, the seeds representing seven Maryland tobacco cultivars were investigated for their phytochemical, antioxidant, and antiproliferative properties. Tobacco seed oils were extracted by the Soxhlet method, and analyzed for their yield, density, refractive index, fatty acid profiles, and tocopherol profile. The defatted flours were extracted in 50% acetone and 80% ethanol. The tobacco seed oil and flour extracts were analyzed for total phenolic contents (TPC) and scavenging capacities against peroxyl, hydroxyl and 2,2-diphenyl-1-picryhydrazyl (DPPH) radicals. The fatty acid compositions of phospholipids and the protein content of the flours were also analyzed. In addition, oil and flour extracts of varieties MD609 and MD609LA were evaluated for their antiproliferative effects on HT-29 human colon cancer cells. All of the tested extracts significantly inhibited HT-29 cell proliferation except that from MD609 oil. The data from this study suggest the potential alternative use of tobacco seeds in developing natural antioxidants and antiproliferative agents for improving human health. PMID- 21827136 TI - A new half-condensed Schiff base compound: highly selective and sensitive pH responsive fluorescent sensor. AB - A new probe, 3-[(3-benzyloxypyridin-2-ylimino)methyl]-2-hydroxy-5 methylbenzaldehyde (1-H) behaves as a highly selective fluorescent pH sensor in a Britton-Robinson buffer at 25 degrees C. The pH titrations show a 250-fold increase in fluorescence intensity within the pH range of 4.2 to 8.3 with a pK(a) value of 6.63 which is valuable for studying many of the biological organelles. PMID- 21827137 TI - Tandem reactions of 1,2,4-oxadiazoles with allylamines. AB - A reaction of 3-chloro-1,2,4-oxadiazoles with allylamine and diallylamine has been investigated. 3,3a,4,5-Tetrahydroisoxazolo[3,4-d]pyrimidines are produced through a tandem ANRORC/[3 + 2]cycloaddition pathway consisting of the addition of allylamine to the 1,2,4-oxadiazole, followed by ring opening, nitrone formation, and finally cycloaddition. 3-N-Allylamino-1,2,4-oxadiazoles were also obtained as minor products through a classical SNAr. Conversely, a reaction with diallylamine produces 3-N,N-diallylamino-1,2,4-oxadiazole and imidazoline through tandem SNAr/aziridination and nucleophilic ring opening. PMID- 21827138 TI - Influence of foliar fertilization with P and K on chemical constituents of grape cv. 'Cardinal'. AB - The foliar fertilization has been used as an important agrotechnical measure to avoid deficiencies and to improve quality. During the two consecutive years, a study has been performed on Vitis vinifera L. (cv. 'Cardinal') to examine whether a grape berry quality has been affected by the foliar application of PK fertilizer. A liquid mineral fertilizer containing 15% P2O5, 20% K2O with 0.1% B, 0.1% Mn and 0.01% Mo (% w/w) has been sprayed three times at rate of 8 L ha(-1) every 14-15 days starting at about 15 days before veraison. The sugars, organic acids and flavonoids (anthocyanins, flavonols and flavan-3-ols) have been analyzed by the high performance liquid chromatography in the grape berries. The foliar fertilization of grapevine can accelerate the accumulation of sugars and anthocyanins, whereas climatic factors and yearly fluctuations influence the content of sugars, organic acids, and phenolic compounds in general. The effect of fertilizer spraying on flavonols and flavan-3-ols has not been found. PMID- 21827139 TI - Synthesis of large polycyclic aromatic hydrocarbons from bis(biaryl)acetylenes: large planar PAHs with low pi-sextets. AB - A new synthesis of large PAHs with low Clar sextets was developed. This synthesis involves initial bis(biaryl)acetylene 1, which undergoes initial ICl aromatization and a subsequent Mizoroki-Heck coupling reaction to give dibenzochrysene derivative 3 that can be transformed into planar PAHs 4 using DDQ oxidation. PMID- 21827141 TI - An efficient difluorohydroxylation of indoles using selectfluor as a fluorinating reagent. AB - An efficient difluorohydroxylation of substituted indoles leading to 3,3 difluoroindolin-2-ols with good yields by using Selectfluor as the electrophilic fluorinating reagent has been developed. In this methodology, the indole rings were difluorinated highly regioselectively at the C3 carbon site. This protocol is practically convenient, easily handled under mild conditions, and provides an efficient way to produce the unique difluorinated indolin-2-ol structure. When alcohols were used as the nucleophiles instead of H(2)O, the corresponding products were obtained in moderate yields. Based on the experimental observations, a plausible mechanism is proposed. PMID- 21827140 TI - The catalytic asymmetric 1,3-dipolar cycloaddition of ynones with azomethine ylides. AB - The first catalytic asymmetric 1,3-dipolar cycloaddition of electron-deficient carbon-carbon triple bonds with azomethine ylides has been established. This reaction provides an unprecedented approach to access novel 2,5-dihydropyrrole derivatives with potential bioactivities in perfect enantioselectivities of up to >99% ee. PMID- 21827142 TI - Asymmetric synthesis of 3,4-diaminochroman-2-ones promoted by guanidine and bisguanidium salt. AB - A highly enantioselective synthesis of 3,4-diaminochroman-2-ones has been realized via the domino reaction of o-hydroxy aromatic aldimines and azlactones. Notably, a cis-product was obtained as the major product by the use of guanidine 2a whereas a trans-product was the major product with bisguanidium salt 3*HBAr(F)(4). In two cases, various substituted 3,4-dihydrocoumarins were obtained with high yields (up to 99%) as well as excellent enantioselectivities (up to 99% ee) and diastereoselectivities (up to >99:1 cis:trans and 98:2 trans:cis, respectively) under mild reaction conditions. PMID- 21827143 TI - Design and characterization of stabilized derivatives of human CD4D12 and CD4D1. AB - CD4 is present on the surface of T-lymphocytes and is the primary cellular receptor for HIV-1. CD4 consists of a cytoplasmic tail, one transmembrane region, and four extracellular domains, D1-D4. A construct consisting of the first two domains of CD4 (CD4D12) is folded and binds gp120 with similar affinity as soluble 4-domain CD4 (sCD4). However, the first domain alone (CD4D1) was previously shown to be largely unfolded and had 3-fold weaker affinity for gp120 when compared to sCD4 [Sharma, D.; et al. (2005) Biochemistry 44, 16192-16202]. We now report the design and characterization of three single-site mutants of CD4D12 (G6A, L51I, and V86L) and one multisite mutant of CD4D1 (G6A/L51I/L5K/F98T). G6A, L51I, and V86L are cavity-filling mutations while L5K and F98T are surface mutations which were introduced to minimize the aggregation of CD4D1 upon removal of the second domain. Two mutations, G6A and V86L in CD4D12 increased the stability and yield of the protein relative to the wild-type protein. The mutant CD4D1 (CD4D1a) with the 4 mutations was folded and more stable compared to the original CD4D1, but both bound gp120 with comparable affinity. In in vitro neutralization assays, both CD4D1a and G6A-CD4D12 were able to neutralize diverse HIV-1 viruses with similar IC(50)s as 4-domain CD4. These stabilized derivatives of human CD4 can be useful starting points for the design of other more complex viral entry inhibitors. PMID- 21827145 TI - Construction of polyoxometalate-based inorganic-organic compounds using silver(I) double helicates as secondary building blocks. AB - Two polyoxometalate-based silver(I) compounds including a three-dimensional porous crystalline array and a double-helicate bisupporting cluster were achieved using metal-organic helicates and Keggin [PMo(12)O(40)](3-) as secondary building blocks. PMID- 21827146 TI - Conformationally restricted calix[8]arenes substituted at all methylene bridges. AB - Reaction under S(N)1 conditions of the octabromocalix[8]arene derivative 2d with alcohols proceeds in nonstereoselective fashion, but all-cis octaryl derivatives are the single major products in the reaction with arenes. The incorporation of aryl substituents at the bridges rigidifies the calix[8]arene skeleton. PMID- 21827147 TI - Synthesis, crystal structures, photophysical properties, and bioimaging of living cells of bis-beta-diketonate phenothiazine ligands and its cyclic dinuclear complexes. AB - Two bis-beta-diketones, RCOCH(2)CO-EPTZ-COCH(2)COR (EPTZ = 10-ethylphenothiazine; R = C(6)H(5) for H(2)L(1) and CF(3) for H(2)L(2)) and their cyclic dinuclear Zn(II), Cd(II), Ni(II), Mn(II), Cu(II), Co(II) complexes have been synthesized and fully characterized. Their crystal structures were determined by single crystal X-ray diffraction analysis. Their photophysical properties have been further investigated both experimentally and theoretically. The results revealed that significant enhancement of two-photon absorption cross section values were obtained for the cyclic dinuclear Zn(II) and Cd(II) complexes compared with their free ligands. Additionally, confocal microscopy and two-photon microscopy fluorescent imaging of MCF-7 cells labeled with two ligands and Zn(II) complexes reveal their potential applications as a biological fluorescent probe. PMID- 21827148 TI - Silver-mediated trifluoromethoxylation of aryl stannanes and arylboronic acids. AB - A silver-mediated cross-coupling of trifluoromethoxide with aryl stannanes and arylboronic acids to give aryl trifluoromethyl ethers is reported. This is the first report of a transition-metal-mediated C(aryl)-OCF(3) bond formation. PMID- 21827149 TI - Charge photoinjection in intercalated and covalently bound [Re(CO)3(dppz)(py)]+ DNA constructs monitored by time-resolved visible and infrared spectroscopy. AB - The complex [Re(CO)(3)(dppz)(py'-OR)](+) (dppz = dipyrido[3,2-a:2',3' c]phenazine; py'-OR = 4-functionalized pyridine) offers IR sensitivity and can oxidize DNA directly from the excited state, making it a promising probe for the study of DNA-mediated charge transport (CT). The behavior of several covalent and noncovalent Re-DNA constructs was monitored by time-resolved IR (TRIR) and UV/visible spectroscopies, as well as biochemical methods, confirming the long range oxidation of DNA by the excited complex. Optical excitation of the complex leads to population of MLCT and at least two distinct intraligand states. Experimental observations that are consistent with charge injection from these excited states include similarity between long-time TRIR spectra and the reduced state spectrum observed by spectroelectrochemistry, the appearance of a guanine radical signal in TRIR spectra, and the eventual formation of permanent guanine oxidation products. The majority of reactivity occurs on the ultrafast time scale, although processes dependent on slower conformational motions of DNA, such as the accumulation of oxidative damage at guanine, are also observed. The ability to measure events on such disparate time scales, its superior selectivity in comparison to other spectroscopic techniques, and the ability to simultaneously monitor carbonyl ligand and DNA IR absorption bands make TRIR a valuable tool for the study of CT in DNA. PMID- 21827150 TI - Analysis of the antioxidant capacities of flavonoids under different spectrophotometric assays using cyclic voltammetry and density functional theory. AB - Flavonoids often show inconsistent antioxidant activities (AAs) depending on the assay used. The electrochemical properties of 14 flavonoid standards in cyclic voltammetry [area under anodic wave (Q) and oxidant peak potentials (Epa)] and the structural parameters [bond dissociation enthalpy (BDE) and ionization potential (IP)] were investigated. They were compared with the results of four spectrophotometric assays, namely, diphenyl-1-picrylhydrazyl (DPPH), Folin Ciocalteu reagent (FCR), ferric reducing ability of plasma (FRAP), Trolox equivalent antioxidant capacity (TEAC), to analyze the chemical reasons for the varying AAs of flavonoids under different assays. Using the cyclic voltammetry method, the AAs of the flavonoids in the DPPH, FCR, and FRAP assays were mainly determined by the ease of charge transferring in the first oxidation step. Meanwhile, the results of TEAC assays were primarily influenced by the amount of charge transfer in the multiple oxidation steps (MOS) of flavonoids. In the theoretical calculation, the BDE values of the selected flavonoids had considerably higher correlations with the results of the DPPH assay (r2=0.89) compared with the other three assays, which indicates that the oxidant-scavenging reaction of the tested flavonoids in the DPPH assay is closer to a hydrogen atom transfer mechanism. Neither the IP values nor BDE values had satisfactory correlation with the AAs of the flavonoids in the TEAC assay (r2=0.57, r2=0.54, respectively), Therefore, complex reaction mechanisms underlie this method and appropriate structural descriptors for reflecting the AAs of flavonoids based on MOS (e.g., TEAC values) need further investigation. PMID- 21827151 TI - Optical rotation calculated with time-dependent density functional theory: the OR45 benchmark. AB - Time-dependent density functional theory (TDDFT) computations are performed for 42 organic molecules and three transition metal complexes, with experimental molar optical rotations ranging from 2 to 2 * 10(4) deg cm(2) dmol(-1). The performances of the global hybrid functionals B3LYP, PBE0, and BHLYP, and of the range-separated functionals CAM-B3LYP and LC-PBE0 (the latter being fully long range corrected), are investigated. The performance of different basis sets is studied. When compared to liquid-phase experimental data, the range-separated functionals do, on average, not perform better than B3LYP and PBE0. Median relative deviations between calculations and experiment range from 25 to 29%. A basis set recently proposed for optical rotation calculations (LPol-ds) on average does not give improved results compared to aug-cc-pVDZ in TDDFT calculations with B3LYP. Individual cases are discussed in some detail, among them norbornenone for which the LC-PBE0 functional produced an optical rotation that is close to available data from coupled-cluster calculations, but significantly smaller in magnitude than the liquid-phase experimental value. Range-separated functionals and BHLYP perform well for helicenes and helicene derivatives. Metal complexes pose a challenge to first-principles calculations of optical rotation. PMID- 21827152 TI - Comparing the temperature dependence of photosynthetic electron transfer in Chloroflexus aurantiacus and Rhodobactor sphaeroides reaction centers. AB - The process of electron transfer from the special pair, P, to the primary electron donor, H(A), in quinone-depleted reaction centers (RCs) of Chloroflexus (Cf.) aurantiacus has been investigated over the temperature range from 10 to 295 K using time-resolved pump-probe spectroscopic techniques. The kinetics of the electron transfer reaction, P* -> P(+)H(A)(-), was found to be nonexponential, and the degree of nonexponentiality increased strongly as temperature decreased. The temperature-dependent behavior of electron transfer in Cf. aurantiacus RCs was compared with that of the purple bacterium Rhodobacter (Rb.) sphaeroides . Distinct transitions were found in the temperature-dependent kinetics of both Cf. aurantiacus and Rb. sphaeroides RCs, at around 220 and 160 K, respectively. Structural differences between these two RCs, which may be associated with those differences, are discussed. It is suggested that weaker protein-cofactor hydrogen bonding, stronger electrostatic interactions at the protein surface, and larger solvent interactions likely contribute to the higher transition temperature in Cf. aurantiacus RCs temperature-dependent kinetics compared with that of Rb. sphaeroides RCs. The reaction-diffusion model provides an accurate description for the room-temperature electron transfer kinetics in Cf. aurantiacus RCs with no free parameters, using coupling and reorganization energy values previously determined for Rb. sphaeroides , along with an experimental measure of protein conformational diffusion dynamics and an experimental literature value of the free energy gap between P* and P(+)H(A)(-). PMID- 21827153 TI - Nitroalkene fatty acids mediate activation of Nrf2/ARE-dependent and PPARgamma dependent transcription by distinct signaling pathways and with significantly different potencies. AB - Naturally occurring nitroalkene fatty acids (NAs) derived from oleic (NO(2)-OA) and linoleic (NO(2)-LA) acids mediate a variety of cellular responses. We examined the signaling pathways involved in NA activation of Nrf2/ARE-dependent versus PPARgamma/PPRE-dependent transcription in human MCF7 breast cancer cells. Additionally, we compared the relative potencies of NO(2)-OA and NO(2)-LA in activating these two transcriptional programs. Here it is demonstrated that, in addition to the direct adduct formation of NA with the Nrf2 inhibitory protein, Keap1, shown by others, NA activation of Nrf2/ARE-mediated transcription results from increased nuclear Nrf2 levels and depends upon activation of the PI3K/AKT and PKC, but not ERK and JNK MAPK, signaling pathways. Examination of the relationship between NA stimulation of the Nrf2/ARE versus PPARgamma/PPRE transcriptional programs revealed concentration-dependent activation of distinct signaling pathways that were readily distinguished by selective attenuation of Nrf2/ARE-dependent, but not PPARgamma-dependent, transcription by inhibitors of PI3K and PKC. Moreover, measurable, statistically significant activation of PPARgamma/PPRE-dependent transcription occurred at nanomolar concentrations of NAs-the 12-NO(2) isomer of NO(2)-LA showing the most potent activity-whereas significant activation of Nrf2/ARE-dependent transcription occurred at much higher NA concentrations (>=3 MUM) with the NO(2)-OA isomers the most potent. These findings have implications for the physiological roles of NAs, suggesting that, at concentrations likely to be encountered in vivo, their direct activation of PPARgamma transcription will dominate over their electrophilic activation of Nrf2 antioxidant/protective responses. PMID- 21827154 TI - First principle simulation of the temperature dependent magnetic circular dichroism of a trinuclear copper complex in the presence of zero field splitting. AB - We present a test of a recently developed density functional theory (DFT) based methodology for the calculation of magnetic circular dichroism (MCD) spectra in the presence of zero-field splitting (ZFS). The absorption and MCD spectra of the trinuclear copper complex MU(3)O ([Cu(3)(L)(MU(3)-O)](4+)), which models the native intermediate produced in the catalytic cycle of the multicopper oxidases, have been simulated from first principle within the framework of adiabatic time dependent density functional theory. The effects of the ZFS of the quartet (4)A(2) ground state on the theoretical MCD spectrum of MU(3)O have been analyzed. The simulated spectra are consistent with the experimental ones. The theoretical assignments of the MCD spectra are based on direct simulation as well as a detailed analysis of the molecular orbitals in MU(3)O. Some of the assignments differ from those given in previous studies. The ZFS effects in the presence of a strong external magnetic field (7 T) prove negligible. The change of the sign of the ZFS changes systematically the intensity of the MCD bands of the z-polarized excitations. The effect of the ZFS on the x,y-polarized excitations is not uniform. PMID- 21827155 TI - Influence of the chemical structure of water-soluble cryptophanes on their overall chiroptical and binding properties. AB - The synthesis and the chiroptical properties of the two enantiomers of the hexacarboxylic acid cryptophane-A derivative, 1, are described in this article. The chiroptical and binding properties of 1 toward achiral and chiral guests have been investigated in water under basic conditions by polarimetry, electronic circular dichroism (ECD), vibrational circular dichroism (VCD), and (1)H NMR spectroscopy. These experiments reveal that the (1)H NMR spectra of 1 are very sensitive to the nature of the guest trapped in its cavity whereas ECD and VCD spectra remain unchanged. We also show that the two enantiomers of 1 are able to distinguish between the two enantiomers of a series of small chiral epoxides. The enantiodiscrimination increases with the size of the chiral guest whereas the corresponding binding constants decrease. In contrast to what was observed for other water-soluble cryptophanes, the molecular recognition process is found independent of the nature of the counterions surrounding host 1, shedding light on the importance of the chemical structure of cryptophanes on their binding and chiroptical properties. PMID- 21827156 TI - Colloidal dynamics near a particle-covered surface. AB - How the diffusive dynamics of colloidal spheres changes in the vicinity of a particle-coated surface is of importance for industrial challenges such as fouling and sedimentation as well as for fundamental studies into confinement effects. We addressed this question by studying colloidal dynamics in a partially coated surface layer, using video microscopy. Particle mean squared displacement (MSD) functions were measured as a function of a (local) effective volume fraction (EVF), which was varied by making use of gravity settling. Comparison of MSDs at the bare and coated surfaces for EVF of 0.2-0.4 revealed that at the latter surface the motion amplitudes are strongly reduced, accompanied by a sharp transition from diffusive to nearly caged motion. This clearly indicates that the surface-attached particles cannot be taken into account via volume fraction and that their immobility has a distinct effect. For EVF > 0.45, the caging becomes dominated by the suspended particles, making the dynamics at the bare and coated surfaces similar. PMID- 21827157 TI - Palladium-catalyzed Minisci reaction with simple alcohols. AB - A palladium-catalyzed coupling of N-heterocycles with simple alcohols was achieved. The reaction is initiated by peroxide and does not require the use of stoichiometric acid for activation of the heterocycle. PMID- 21827158 TI - Novel size and surface oxide effects in silicon nanowires as lithium battery anodes. AB - With its high specific capacity, silicon is a promising anode material for high energy lithium-ion batteries, but volume expansion and fracture during lithium reaction have prevented implementation. Si nanostructures have shown resistance to fracture during cycling, but the critical effects of nanostructure size and native surface oxide on volume expansion and cycling performance are not understood. Here, we use an ex situ transmission electron microscopy technique to observe the same Si nanowires before and after lithiation and have discovered the impacts of size and surface oxide on volume expansion. For nanowires with native SiO(2), the surface oxide can suppress the volume expansion during lithiation for nanowires with diameters <~50 nm. Finite element modeling shows that the oxide layer can induce compressive hydrostatic stress that could act to limit the extent of lithiation. The understanding developed herein of how volume expansion and extent of lithiation can depend on nanomaterial structure is important for the improvement of Si-based anodes. PMID- 21827159 TI - Building a bridge between coordination compounds and clusters: bonding analysis of the icosahedral molecules [M(ER)12] (M = Cr, Mo, W; E = Zn, Cd, Hg). AB - The bonding situation of the icosahedral compounds [M(EH)(12)] (M = Cr, Mo, W; E = Zn, Cd, Hg), which are model systems for the isolated species [Mo(ZnCp*)(3)(ZnMe)(9)] possessing the coordination number 12 at the central atom M, have been analyzed with a variety of charge and energy decomposition methods (AIM, EDA-NOCV, WBI, MO). The results give a coherent picture of the electronic structure and the nature of the interatomic interactions. The compounds [M(EH)(12)] are transition metal complexes that possess 12 M-EH radial bond paths (AIM) that can be described as 6 three-center two-electron bonds (MO). The radial M-EH bonds come from the electron sharing interactions mainly between the singly occupied valence s and d AOs of the central atom M and the singly occupied EH valence orbitals (MO, EDA-NOCV). The orbital interactions provide ~42% of the total attraction, while the electrostatic attraction contributes ~58% to the metal-ligand bonding (EDA-NOCV). There is a weak peripheral E-E bonding in [M(EH)(12)] that explains the unusually high coordination number (MO). The peripheral bonding leads for some compounds [M(EH)(12)] to the emergence of E-E bond paths, while in others it does not (AIM). The relative strength of the radial and peripheral bonding in [Al(13)](-) and [Pt@Pb(12)](2-) is clearly different from the situation in [M(EH)(12)], which supports the assignments of the former species as cluster compounds or inclusion compounds (MO, WBI). The bonding situation in [WAu(12)] is similar to that in [M(EH)(12)]. PMID- 21827160 TI - Graphene transistors via in situ voltage-induced reduction of graphene-oxide under ambient conditions. AB - Here, we describe a simple approach to fabricate graphene-based field-effect transistors (FETs), starting from aqueous solutions of graphene-oxide (GO), processed entirely under ambient conditions. The process relies on the site selective reduction of GO sheets deposited in between or on the surface of micro/nanoelectrodes. The same electrodes are first used for voltage-induced electrochemical GO reduction, and then as the source and drain contacts of FETs, allowing for the straightforward production and characterization of ambipolar graphene devices. With the use of nanoelectrodes, we could reduce different selected areas belonging to one single sheet as well. PMID- 21827161 TI - Near-infrared absorbing boron-dibenzopyrromethenes that serve as light-harvesting sensitizers for polymeric solar cells. AB - Hexylthiophene-conjugated boron-dibenzopyrromethenes with benzo[1,3,2]oxazaborinine rings, 1, that absorb near-infrared light with relatively high molecular extinction coefficients have been synthesized. The incorporation of 3-hexylthiophene-conjugated dye 1a at a blend ratio of 5 wt % into a polymeric solar cell based on a P3HT/indene-C(70) bisadduct (IC(70)BA) bulk heterojunction structure improved power conversion efficiency from 3.7 to 4.3%. The present work suggests that well-defined near-infrared absorbing BODIPY analogues can potentially be used as photosensitizers in polymeric solar cells. PMID- 21827163 TI - Molecular dynamics study of polysaccharides in binary solvent mixtures of an ionic liquid and water. AB - Some ionic liquids (ILs) have great promise as effective solvents for biomass pretreatment, and there are several that have been reported that can dissolve large amounts of cellulose. The solubilized cellulose can then be recovered by addition of antisolvents, such as water or ethanol, and this regeneration process plays an important role in the subsequent enzymatic saccharification reactions and in the recovery of the ionic liquid. To date, little is known about the fundamental intermolecular interactions that drive the dissolution and subsequent regeneration of cellulose in complex mixtures of ionic liquids, water, and cellulose. To investigate these interactions, in this work, molecular dynamics (MD) simulations were carried out to study binary and ternary mixtures of the ionic liquid 1-ethyl-3-methylimidazolium acetate ([C2mim][OAc]) with water and a cellulose oligomer. Simulations of a cellulose oligomer dissolved in three concentrations of binary mixtures of [C2mim][OAc] and water were used to represent the ternary system in the dissolution phase (high [C2mim][OAc] concentration) and present during the initial phase of the regeneration step (intermediate and low [C2mim][OAc] concentrations). The MD analysis of the structure and dynamics that exist in these binary and ternary mixtures provides information on the key intermolecular interactions between cellulose and [C2mim][OAc] that lead to dissolution of cellulose and the key intermolecular interactions in the intermediate states of cellulose precipitation as a function of water content in the cellulose/IL/water system. The analysis of this intermediate state provides new insight into the molecular driving forces present in this ternary system. PMID- 21827166 TI - High compliance randomized controlled field trial of solar disinfection of drinking water and its impact on childhood diarrhea in rural Cambodia. AB - Recent solar disinfection (SODIS) studies in Bolivia and South Africa have reported compliance rates below 35% resulting in no overall statistically significant benefit associated with disease rates. In this study, we report the results of a 1 year randomized controlled trial investigating the effect of SODIS of drinking water on the incidence of dysentery and nondysentery diarrhea among children of age 6 months to 5 years living in rural communities in Cambodia. We compared 426 children in 375 households using SODIS with 502 children in 407 households with no intervention. Study compliance was greater than 90% with only 5% of children having less than 10 months of follow-up and 2.3% having less than 6 months. Adjusted for water source type, children in the SODIS group had a reduced incidence of dysentery, with an incidence rate ratio (IRR) of 0.50 (95% CI 0.27-0.93, p = 0.029). SODIS also had a protective effect against nondysentery diarrhea, with an IRR of 0.37 (95% CI 0.29-0.48, p < 0.001). This study suggests strongly that SODIS is an effective and culturally acceptable point-of-use water treatment method in the culture of rural Cambodia and may be of benefit among similar communities in neighboring South East Asian countries. PMID- 21827164 TI - Mechanism of ribonuclease A endocytosis: analogies to cell-penetrating peptides. AB - Pancreatic-type ribonucleases can exert toxic activity by catalyzing the degradation of cellular RNA. Their ability to enter cells is essential for their cytotoxicity. Here, we determine the mechanism by which bovine pancreatic ribonuclease (RNase A) enters human cells. Inhibiting clathrin-dependent endocytosis with dynasore or chlorpromazine decreases RNase A-uptake by ~70%. Limited colocalization between RNase A and transferrin indicates that RNase A is not routed through recycling endosomes. Instead, vesicular staining of RNase A overlaps substantially with that of nona-arginine and the cationic peptide corresponding to residues 47-57 of the HIV-1 TAT protein. At low concentrations (<5 MUM), internalization of RNase A and these cell-penetrating peptides (CPPs) is inhibited by chlorpromazine as well as the macropinocytosis inhibitors cytochalasin D and 5-(N-ethyl-N-isopropyl)amiloride to a similar extent, indicative of common endocytic mechanism. At high concentrations, CPPs adopt a nonendocytic mechanism of cellular entry that is not shared by RNase A. Collectively, these data suggest that RNase A is internalized via a multipathway mechanism that involves both clathrin-coated vesicles and macropinosomes. The parallel between the uptake of RNase A and CPPs validates reference to RNase A as a "cell-penetrating protein". PMID- 21827168 TI - Pathways of cluster growth and kinetic slowing down in a model of short-range attractive colloids. AB - We present the results of an extensive 3D Brownian dynamics simulation of the self-assembly of colloidal particles for a short-range attractive model that is quenched below its metastable critical point. In particular, results are obtained in the small-volume-fraction, low-temperature region in which we find so-called sticky beads that diffuse around the system, without reaching a final large cluster on the timescale of our simulation. For larger volume fractions in this low-temperature regime, a gel forms as the result of kinetically slowed down spinodal decomposition, as shown earlier for other short-range attractive models (Foffi, G.; De Michele, C.; Sciortino, F.; Tartaglia, P. Phys. Rev. Lett. 2005, 94, 078301. Zaccarelli, E. J. Phys.: Condens. Matter 2007, 19, 323101). We also show that for quenches below the critical point but above the intersection of the binodal with the glass line, two-step crystallization takes place. For sufficiently small volume fractions, the first step is the nucleation of dense fluid drops, followed by the second step of crystallization within these drops, as first proposed for a model of protein crystallization for quenches just above the metastable critical point (ten Wolde, P. R.; Frenkel, D. Science 1997, 277, 1975). For larger values of the volume fraction, the initial step is spinodal decomposition that leads to the formation of an interconnected network of low- and high-density fluids. The second step is crystallization that takes place within the dense fluid phase. PMID- 21827167 TI - Competitive selection from single domain antibody libraries allows isolation of high-affinity antihapten antibodies that are not favored in the llama immune response. AB - Single-domain antibodies (sdAbs) found in camelids lack a light chain, and their antigen-binding site sits completely in the heavy-chain variable domain (VHH). Their simplicity, thermostability, and ease in expression have made VHHs highly attractive. Although this has been successfully exploited for macromolecular antigens, their application to the detection of small molecules is still limited to a very few reports, mostly describing low-affinity VHHs. Using triclocarban (TCC) as a model hapten, we found that conventional antibodies, IgG1 fraction, reacted with free TCC with a higher relative affinity (IC(50) 51.0 ng/mL) than did the sdAbs (IgG2 and IgG3, 497 and 370 ng/mL, respectively). A VHH library was prepared, and by elution of phage with limiting concentrations of TCC and competitive selection of binders, we were able to isolate high-affinity clones, K(D) 0.98-1.37 nM (SPR), which allowed development of a competitive assay for TCC with an IC(50) = 3.5 ng/mL (11 nM). This represents a 100-fold improvement with regard to the performance of the sdAb serum fraction, and it is 100-fold better than the IC(50) attained with other antihapten VHHs reported thus far. Despite the modest overall antihapten sdAbs response in llamas, a small subpopulation of high-affinity VHHs is generated that can be isolated by careful design of the selection process. PMID- 21827169 TI - Development of a far-red to near-infrared fluorescence probe for calcium ion and its application to multicolor neuronal imaging. AB - To improve optical imaging of Ca(2+) and to make available a distinct color window for multicolor imaging, we designed and synthesized CaSiR-1, a far-red to near-infrared fluorescence probe for Ca(2+), using Si-rhodamine (SiR) as the fluorophore and the well-known Ca(2+) chelator BAPTA. This wavelength region is advantageous, affording higher tissue penetration, lower background autofluorescence, and lower phototoxicity in comparison with the UV to visible range. CaSiR-1 has a high fluorescence off/on ratio of over 1000. We demonstrate its usefulness for multicolor fluorescence imaging of action potentials (visualized as increases in intracellular Ca(2+)) in brain slices loaded with sulforhodamine 101 (red color; specific for astrocytes) that were prepared from transgenic mice in which some neurons expressed green fluorescent protein. PMID- 21827170 TI - Effect of ionic size on the structure of cylindrical electric double layers: a systematic study by Monte Carlo simulations and density functional theory. AB - The effect of ionic size on the diffuse layer characteristics of a cylindrical electric double layer is studied using density functional theory and Monte Carlo simulations for the restricted primitive model and solvent primitive model. The double layer is comprised of an infinitely long, rigid, impenetrable charged cylinder also referred to as the polyion, located at the center of a cylindrical cell containing the electrolyte, which is composed of charged hard spheres and the solvent molecules as neutral hard spheres (in the case of the solvent primitive model). The diameters of all the hard spheres are taken to be the same. The theory is based on a partially perturbative scheme, where perturbation is used to approximate the ionic interactions and the hard sphere contribution is treated within the weighted density approach. The Monte Carlo simulations are performed in the canonical ensemble. The zeta potential profiles as a function of the polyion surface charge density are presented for cylindrical double layers at different ionic concentrations, ionic valences, and different hard sphere (ionic and the solvent) diameters of 2, 3, and 4 A. The theory agrees quite well with the simulation results for a wide range of system parametric conditions and is capable of showing the maximum and minimum in the zeta potential value for systems having divalent counterions. The steric effects due to the presence of solvent molecules play a major role in characterizing the zeta potential and the ionic density profiles. A noticeable change in the concavity of the zeta potential plots with increasing particle size at very low concentrations of monovalent electrolytes is suggestive of the occurrence of infinite differential capacitance for such systems. PMID- 21827171 TI - Chemo- and regioselectivity-tunable Pd-catalyzed allylic alkylation of imines. AB - alpha-Carbanions of cyclic and acyclic imines have been successfully applied as nucleophiles in the Pd-catalyzed allylic alkylation reaction. Tuning of chemo- and regioselectivity has been realized by using t-BuOK/THF and LDA/toluene to give branched and linear products, respectively, with high regio- and diastereoselectivities. A plausible mechanism is proposed on the basis of the experimental results and DFT calculations. PMID- 21827172 TI - GSH-mediated S-transarylation of a quinone glyceraldehyde-3-phosphate dehydrogenase conjugate. AB - Many cellular proteins with reactive thiols form covalent bonds with electrophiles, thereby modifying their structures and activities. Here, we describe the recovery of a glycolytic protein, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), from such an electrophilic attack by 1,2-napthoquinone (1,2-NQ). GAPDH readily formed a covalent bond with 1,2-NQ through Cys152 at a low concentration (0.2 MUM) in a cell-free system, but when human epithelial A549 cells were exposed to this quinone at 20 MUM, only minimal binding was observed although extensive binding to numerous other cellular proteins occurred. Depletion of cellular glutathione (GSH) with buthionine sulfoximine (BSO) resulted in some covalent modification of cellular GAPDH by 1,2-NQ and a significant reduction of GAPDH activity in the cells. Incubation of native, but not boiled, human GAPDH that had been modified by 1,2-NQ with GSH resulted in a concentration-dependent removal of 1,2-NQ from the GAPDH conjugate, accompanied by partial recovery of lost catalytic activity and formation of a 1,2-NQ-GSH adduct (1,2-NQ-SG). While GAPDH is recognized as a multifunctional protein, our results show that GAPDH also has a unique ability to recover from electrophilic modification by 1,2-NQ through a GSH-dependent S-transarylation reaction. PMID- 21827173 TI - A robust, air-stable, reusable ruthenium catalyst for dehydrogenation of ammonia borane. AB - We describe an efficient homogeneous ruthenium catalyst for the dehydrogenation of ammonia borane (AB). This catalyst liberates more than 2 equiv of H(2) and up to 4.6 system wt % H(2) from concentrated AB suspensions under air. Importantly, this catalyst is robust, delivering several cycles of dehydrogenation at high [AB] without loss of catalytic activity, even with exposure to air and water. PMID- 21827175 TI - Versatile flow-injection amperometric ion detector based on an interface between two immiscible electrolyte solutions: numerical and experimental characterization. AB - The present paper describes a flexible thin layer electrochemical flow cell for ultrasensitive amperometric detection at a supported interface between immiscible electrolyte solutions. Nanomolar detection limits were demonstrated using the cell design, and 3D finite element simulations allowed a detailed characterization of the flow cell. The cell design employed in the present work allowed the sensing oil membrane and the aqueous reference electrode to be placed in close contact, thereby minimizing cell resistance. The adjustable cell volume means that the same cell design can be used for different application with different requirement for detection limits and dynamic range. A disposable membrane was employed which reduces the need for surface cleaning and prevents sample carryover between different applications. For the lowest cell volumes the detection chamber approaches a thin layer electrochemical flow cell detector with a large surface to volume ratio. PMID- 21827174 TI - High-affinity DNA targeting using readily accessible mimics of N2'-functionalized 2'-amino-alpha-L-LNA. AB - N2'-Pyrene-functionalized 2'-amino-alpha-L-LNAs (locked nucleic acids) display extraordinary affinity toward complementary DNA targets due to favorable preorganization of the pyrene moieties for hybridization-induced intercalation. Unfortunately, the synthesis of these monomers is challenging (~20 steps, <3% overall yield), which has precluded full characterization of DNA-targeting applications based on these materials. Access to more readily accessible functional mimics would be highly desirable. Here we describe short synthetic routes to a series of O2'-intercalator-functionalized uridine and N2' intercalator-functionalized 2'-N-methyl-2'-aminouridine monomers and demonstrate, via thermal denaturation, UV-vis absorption and fluorescence spectroscopy experiments, that several of them mimic the DNA-hybridization properties of N2' pyrene-functionalized 2'-amino-alpha-L-LNAs. For example, oligodeoxyribonucleotides (ONs) modified with 2'-O-(coronen-1-yl)methyluridine monomer Z, 2'-O-(pyren-1-yl)methyluridine monomer Y, or 2'-N-(pyren-1-ylmethyl) 2'-N-methylaminouridine monomer Q display prominent increases in thermal affinity toward complementary DNA relative to reference strands (average DeltaT(m)/mod up to +12 degrees C), pronounced DNA-selectivity, and higher target specificity than 2'-amino-alpha-L-LNA benchmark probes. In contrast, ONs modified with 2'-O (2-napthyl)uridine monomer W, 2'-O-(pyren-1-yl)uridine monomer X or 2'-N-(pyren-1 ylcarbonyl)-2'-N-methylaminouridine monomer S display very low affinity toward DNA targets. This demonstrates that even conservative alterations in linker chemistry, linker length, and surface area of the appended intercalators have marked impact on DNA-hybridization characteristics. Straightforward access to high-affinity building blocks such as Q, Y, and Z is likely to accelerate their use in DNA-targeting applications within nucleic acid based diagnostics, therapeutics, and material science. PMID- 21827176 TI - Electronic structure similarities in Pb(x)Sb(y)(-) and Sn(x)Bi(y)(-) clusters. AB - The geometric and electronic structure of Pb(x)Sb(y)(-) and Sn(x)Bi(y)(-) clusters are investigated by photoelectron spectroscopy and theoretical methods. It is found that PbSb(2)(-) and SnBi(2)(-) have similar spectroscopic patterns, reflecting correlations in electronic nature that are a result of their isoelectronic character and common geometries. Analogous findings are presented for Pb(2)Sb(2)(-) and Sn(2)Bi(2)(-). Further, we investigate the effect of altering the total valence count, and separately the geometry, on spectroscopic patterns. We conclude that these heavy p-block elements are interchangeable and that the electronic structure correspondence can be preserved regardless of elemental composition. This represents an extension of the traditional concepts of periodicity, where elements of similar valence configuration are grouped into columns. Instead, elements from different columns may be combined to yield similarities in chemistry, given the overall valence count is preserved. PMID- 21827177 TI - Integrated all-diamond ultramicroelectrode arrays: optimization of faradaic and capacitive currents. AB - Integrated all-diamond ultramicroelectrode arrays (UMEAs) were fabricated using standard photolithography processes. The array consisted of typically 45 ultramicroelectrodes with a diameter of 10 MUm and with a center-to-center spacing of 60 MUm. The quasi-reference and counter electrodes were made from conductive diamond and were integrated on a 5 * 5 mm(2) chip. On the UMEA, a high ratio of faradaic current to capacitive current was achieved on heavily boron doped and hydrogen-terminated diamond surfaces at slow scan rates and in high concentration of supporting electrolyte. A sensitive and reproducible detection of dopamine was achieved on hydrogen-terminated diamond UMEA at slow scan rates. The detection limit of dopamine in the presence of ascorbic acid was 1.0 nM, which is 50-100 times lower than that obtained on the macrosized boron-doped diamond electrodes. This array is promising for sensitive and reproducible detection of analytes in solutions with low detection limits. PMID- 21827178 TI - Determination of the depth of localized radioactive contamination by 137Cs and 60Co in sand with principal component analysis. AB - A method to determine the depth of buried localized radioactive contamination nonintrusively and nondestructively using principal component analysis is described. The gamma-ray spectra from two radionuclides, cesium-137 and cobalt 60, have been analyzed to derive the two principal components that change most significantly as a result of varying the depth of the sources in a bespoke sand filled phantom. The relationship between depth (d) and the angle (theta) between the first two principal component coefficients has been derived for both cases, viz. d(Phi) = x + y log(e) Phi where x and y are constants dependent on the shielding material and the gamma-ray energy spectrum of the radioactivity in question, and phi is a function of theta. The technique enables the depth of a localized radioactive source to be determined nonintrusively in the range 5 to 50 mm with an accuracy of +/-1 mm. PMID- 21827179 TI - Work function of vanadium dioxide thin films across the metal-insulator transition and the role of surface nonstoichiometry. AB - Vanadium dioxide (VO(2)) undergoes a sharp metal-insulator transition (MIT) in the vicinity of room temperature and there is great interest in exploiting this effect in novel electronic and photonic devices. We have measured the work function of vanadium dioxide thin films across the phase transition using variable temperature Kelvin force microscopy (KFM). The work function is estimated to be ~5.15 eV in the insulating phase and increases by ~0.15 eV across the MIT. We further show that the work function change upon the phase transition is highly sensitive to near-surface stoichiometry studied by X-ray photoelectron spectroscopy. This change in work function is distinct from bulk resistance versus temperature trends commonly used to evaluate synthesis protocols for such vanadium oxide films and optimize stoichiometry. The results are pertinent to understanding fundamental electronic properties of vanadium oxide as well as charge injection phenomena in solid-state devices incorporating complex oxides containing multivalence cations. PMID- 21827180 TI - Synthesis and properties of oxo-carboxylato- and dioxo-bridged diosmium complexes of tris(2-pyridylmethyl)amine. AB - A series of oxo-bridged diosmium complexes with tpa ligand (tpa = tris(2 pyridylmethyl)amine) are synthesized. The hydrolytic reaction of the mononuclear osmium complex [Os(III)Cl(2)(tpa)]PF(6) in aqueous solution containing a sodium carboxylate yields a MU-oxo-MU-carboxylato-diosmium(III) complex, [Os(III)(2)(MU O)(MU-RCOO)(tpa)(2)](PF(6))(3) (R = C(3)H(7) (1), CH(3) (2), or C(6)H(5) (3)). One-electron oxidation of 1 with (NH(4))(2)Ce(IV)(NO(3))(6) gives a mixed-valent [Os(III)Os(IV)(MU-O)(MU-C(3)H(7)COO)(tpa)(2)](PF(6))(4) complex (4). A mixed valent di-MU-oxo-diosmium complex, [Os(III)Os(IV)(MU-O)(2)(tpa)(2)](PF(6))(3) (5), is also synthesized from 1 in an aerobic alkaline solution (pH 13.5). All the complexes exhibit strong absorption bands in a visible-near-infrared region based on interactions of the osmium dpi and oxygen ppi orbitals of the Os-O-Os moiety. The X-ray crystallographic analysis of 1, 3, and 4 shows that the osmium centers take a pseudo-octahedral geometry in the MU-oxo-MU-carboxylato-diosmium core. The mixed-valent osmium(III)osmium(IV) complex 4 has a shorter osmium-oxo bond and a larger osmium-oxo-osmium angle as compared with those of the diosmium(III) complex 1 having the same bridging carboxylate. Crystal structure of 5 reveals that the two osmium ions are bridged by two oxo groups to give an Os(2)(MU-O)(2) core with the significantly short osmium-osmium distance (2.51784(7) A), which is indicative of a direct osmium-osmium bond formation with the bond order of 1.5 (sigma(2)pi(2)delta(2)delta*(2)pi*(1) configuration). In the electrochemical studies, the MU-oxo-MU-carboxylato-diosmium(III) complexes exhibit two reversible Os(III)Os(III)/Os(III)Os(IV) and Os(III)Os(IV)/Os(IV)Os(IV) oxidation couples and one irreversible redox wave for the Os(III)Os(III)/Os(II)Os(III) couple in CH(3)CN. The irreversible reductive process becomes reversible in CH(3)CN/H(2)O (1:1 Britton-Robinson buffer; pH 5 11), where the {1H(+)/2e(-)} transfer process is indicated by the plot of the redox potentials against the pH values of the solution of 1. Thus, the MU-oxo-MU butyrato-diosmium(III) center undergoes proton-coupled electron transfer to yield a MU-hydroxo-MU-butyrato-diosmisum(II) species. The di(MU-oxo) complex 5 exhibits one reversible Os(III)Os(IV)/Os(IV)Os(IV) oxidation process and one reversible Os(III)Os(IV)/Os(III)Os(III) reduction process in CH(3)CN. The comproportionation constants K(com) of the Os(III)Os(IV) states for the present diosmium complexes are on the order of 10(19). The values are significantly larger when compared with those of similar oxo-bridged dimetal complexes of ruthenium and rhenium. PMID- 21827182 TI - Pentafluorophenylhalocarbenes. AB - Pentafluorophenylchlorocarbene and pentafluorophenylfluorocarbene are highly reactive species and effective carriers of fluorine labels via addition to alkenes and insertion into C-H bonds. PMID- 21827181 TI - Multicomponent macrocyclization reactions (MCMRs) employing highly reactive acyl ketene and nitrile oxide intermediates. AB - An efficient synthesis of spiro-fused macrolactams by a multicomponent macrocyclization reaction (MCMR) is reported. The use of highly reactive, transient intermediates in this MCMR permits short reaction times, even at high dilution. The methods employed for this MCMR were first developed as a four component strategy for the synthesis of beta-ketoamide isoxazolines and a new macrocyclization reaction is reported. PMID- 21827183 TI - Sesterterpenes from the tropical sponge Coscinoderma sp. AB - Eight new sesterterpenes (2, 5, and 10-15), including structurally related pentaprenyl hydroquinones (2 and 5), and seven known ones of the same structural classes were isolated from the sponge Coscinoderma sp., collected from Chuuk Island, Micronesia. On the basis of the results of combined spectroscopic analyses, the new compounds were determined to be derivatives of the halisulfates and suvanine. These compounds exhibited moderate cytotoxicity against the K562 cell line and inhibitory activities against isocitrate lyase, sortase A, and Na+/K+-ATPase; significant structure-activity relationships were evident. PMID- 21827184 TI - Mechanism of ultrasound scission of a silver-carbene coordination polymer. AB - Scission of a supramolecular polymer-metal complex can be carried out using collapsing cavitation bubbles created by ultrasound. Although the most plausible scission mechanism of the coordinative bonds is through mechanical force, the influence of radicals and high hot-spot temperatures on scission has to be considered. A silver(I)-N-heterocyclic carbene complex was exposed to 20 kHz ultrasound in argon, nitrogen, methane, and isobutane saturated toluene. Scission percentages were almost equal under argon, nitrogen, and methane. Radical production differs by a factor of 10 under these gases, indicating that radical production is not a significant contributor to the scission process. A model to describe the displacement of the bubble wall, strain rates, and temperature in the gas shows that critical strain rates for coil-to-stretch transition, needed for scission, are achieved at reactor temperatures of 298 K, an acoustic pressure of 1.2 * 10(5) Pa, and an acoustic frequency of 20 kHz. Lower scission percentages were measured under isobutane, which also shows lower strain rates in model simulations. The activation of the polymer-metal complexes in toluene under the influence of ultrasound occurs through mechanical force. PMID- 21827185 TI - Unusual scaling in the rheology of branched wormlike micelles formed by cetyltrimethylammonium bromide and sodium oleate. AB - Natural fatty acids such as sodium oleate form highly viscous supramolecular complexes with long-chain cationic surfactants through cooperative self-assembly. Here we report the rheological behavior of linear and branched wormlike micelles formed in mixtures of cetyltrimethylammonium bromide (CTAB) and sodium oleate (NaOL). Addition of sodium oleate induces an increase in the axial ratio of the mixed micelles. At a constant mole fraction of the mixture, an increase in total surfactant concentration leads to a transition from linear to branched micelles. Both linear and branched micelles impart viscoelastic behavior to the fluid, and the low-frequency data can be approximated to the Maxwell model. Scaling of the rheological parameters of CTAB-NaOL catanionic mixtures, as a function of concentration, employing dynamic rheological measurements has been determined and compared with the predictions of existing scaling laws. The structural transition from linear micelles to the branched micelles in the CTAB-NaOL micellar system greatly influences the scaling behavior of shear modulus. The scaling exponent is lower for the branched micelles compared to linear micelles, analogous to those of linear and branched polymer melts. The structural evolution is probed by light scattering and small-angle neutron scattering measurements as well. PMID- 21827186 TI - Quantifying remediation effectiveness under variable external forcing using contaminant rating curves. AB - Remediation efforts are typically assessed through before-and-after comparisons of contaminant concentrations or loads. These comparisons can be misleading when external drivers, such as weather conditions, differ between the pre- and postremediation monitoring periods. Here, we show that remediation effectiveness may be better assessed by comparing pre- and postremediation contaminant rating curves, which permit "all else equal" comparisons of pre- and postremediation contaminant concentrations and loads under at any specified external forcing. We illustrate this approach with a remediation case study at an abandoned mercury mine in Northern California. Measured mercury loads in the stream draining the mine site were a factor of 1000 smaller after the remediation than before, superficially suggesting that the cleanup was 99.9% effective, but rainstorms were weaker and less frequent during the postremediation monitoring period. Our analysis shows that this difference in weather conditions alone reduced mercury loads at our site by a factor of 73-85, with a further factor of 12.6-14.5 being attributable to the remediation itself, implying that the cleanup was 92-93% (rather than 99.9%) effective. Our results illustrate the need to account for external confounding drivers when assessing remediation efforts, particularly in systems with highly episodic forcing. PMID- 21827187 TI - High-pressure hydrothermal crystal growth and multiferroic properties of a perovskite YMnO3. AB - Orthorhombic perovskites RMnO(3) are representative of spin-driven ferroelectrics. When the radius of the rare-earth ion R is smaller than that of Dy, for instance in YMnO(3), the orthorhombic phase becomes metastable at ambient pressure, which impedes the crystal growth; thus, the detailed magnetic and multiferroic properties of the metastable phase have not been characterized. In this work, we successfully obtained single crystals of orthorhombic YMnO(3) using quasi-hydrothermal conditions under a high pressure of 5.5 GPa. Magnetic and dielectric measurements under magnetic fields revealed that the magnetic ground state is the commensurate E-type antiferromagnetic, while a cycloidal spin phase likely coexists in the intermediate temperature range, which enhances the magnetoelectric response to external fields. PMID- 21827188 TI - Spectral signature of 2-[4-(dimethylamino)styryl]-1-methylquinolinium iodide: a case of negative solvatochromism in water. AB - Photophysics of the 2-[4-(dimethylamino) styryl]-1-methylquinolinium iodide (DASQMI) molecule has been studied in different solvents by steady-state and time resolved emission spectroscopy and also with quantum chemical calculations. The probe molecule exhibits a strong solvent-polarity-dependent characteristic. The low-energy fluorescence band of DASQMI shows an anomalous 40 nm blue shift in water from that in dimethyl sulfoxide (DMSO); though in deuterium oxide the normal trend of red shift was observed. A marked increase in intensity of this band at 77 K and an increase in lifetime in viscous solvent point clearly to the intramolecular charge-transfer (ICT) character of the low-energy band. From the temperature-dependent emission and emission spectra in mixed solvents, the negative solvatochromism of DASQMI has been established, which means that the ICT state moves toward ground state with polarity and hydrogen-bond ability and beyond a critical dielectric constant coupled with protic nature of the solvent ground state gets further stabilized to show anomalous blue shift. In ethanol, below a critical temperature, 253 K, a blue shift starts due to greater solvent molecular polarization. A third long-lifetime component with dominant 75% amplitude was observed only in aqueous solution and may be due to the cis-isomer of hydrophobic DASQMI, a stable form in the excited state predicted from polarizable continuum model (PCM) calculations in water with 6-31G+(d,p) as basis set. PMID- 21827189 TI - Role of the pyridine nitrogen in pyridoxal 5'-phosphate catalysis: activity of three classes of PLP enzymes reconstituted with deazapyridoxal 5'-phosphate. AB - Pyridoxal 5'-phosphate (PLP; vitamin B(6))-catalyzed reactions have been well studied, both on enzymes and in solution, due to the variety of important reactions this cofactor catalyzes in nitrogen metabolism. Three functional groups are central to PLP catalysis: the C4' aldehyde, the O3' phenol, and the N1 pyridine nitrogen. In the literature, the pyridine nitrogen has traditionally been assumed to be protonated in enzyme active sites, with the protonated pyridine ring providing resonance stabilization of carbanionic intermediates. This assumption is certainly correct for some PLP enzymes, but the structures of other active sites are incompatible with protonation of N1, and, consequently, these enzymes are expected to use PLP in the N1-unprotonated form. For example, aspartate aminotransferase protonates the pyridine nitrogen for catalysis of transamination, while both alanine racemase and O-acetylserine sulfhydrylase are expected to maintain N1 in the unprotonated, formally neutral state for catalysis of racemization and beta-elimination. Herein, kinetic results for these three enzymes reconstituted with 1-deazapyridoxal 5'-phosphate, an isosteric analogue of PLP lacking the pyridine nitrogen, are compared to those for the PLP enzyme forms. They demonstrate that the pyridine nitrogen is vital to the 1,3 prototropic shift central to transamination, but not to reactions catalyzed by alanine racemase or O-acetylserine sulfhydrylase. Not all PLP enzymes require the electrophilicity of a protonated pyridine ring to enable formation of carbanionic intermediates. It is proposed that modulation of cofactor electrophilicity plays a central role in controlling reaction specificity in PLP enzymes. PMID- 21827190 TI - Self-sorting under solvent-free conditions: one-pot synthesis of a hetero[3]rotaxane. AB - The one-pot synthesis of a hetero[3]rotaxane, assembled from five different molecular components under solvent-free conditions, through "self-sorting" of the bead and stopper units during the threading and stoppering processes, is reported. PMID- 21827191 TI - CuCl/bipyridine-catalyzed addition reactions of arylboroxines with aldehydes, alpha,beta-unsaturated ketones, and N-tosyl aldimines. AB - CuCl/bipyridine-catalyzed addition reactions of arylboroxines with aldehydes and alpha,beta-unsaturated ketones at elevated temperatures were described. By using the microwave energy, CuCl/bipyridine-catalyzed addition reactions of arylboroxines with aldimines were also realized. PMID- 21827192 TI - Self-assembling zeolite crystals into uniformly oriented layers. AB - We report important progress made in the synthesis of oriented functional layers of nanochannel materials by using coordination chemistry as a tool. Zeolite L (ZL) crystals have been arranged into oriented layers through the coordinative interactions between a functional organic linker (L) and metal cations used for connecting the different parts. As organic linker we used a terpyridyl ligand bearing a urea group and a reactive siloxane part. Two strategies that lead to monolayers with different properties are described. The first consists of reacting the siloxane group of ligand L with OH groups of the substrate (S), and selectively reacting the siloxane group of L with OH groups located at the base of the ZL crystals. Next, metal cations M(n+), for example, Zn(2+) or Cu(2+), are coordinated to the terpy group on the modified substrate. To this the modified ZL is added and coordinatively bound by the terpy(Mn(n+))terpy interaction, leading to oriented ZL layers. The second method consists of reacting substrate S and ligand L in the presence of a metal cation. A layer with reactive siloxane groups is formed on S to which the ZL crystals are bound by the reaction of the hydroxyl groups of their base. Zn(2+), Cu(2+), and lanthanide ions Eu(3+) and Tb(3+)have been tested successfully, all of them leading to high-quality ZL monolayers with open channels, accessible for accepting guests, oriented perpendicularly with respect to the surface of S. PMID- 21827193 TI - Studies on the synthesis of apoptolidin: synthesis of a C1-C27 fragment of apoptolidin D. AB - Synthesis of a C(1)-C(27) fragment, a key intermediate in the synthesis of apoptolidin D, is reported. The synthesis involves a combination of Heck coupling and Horner-Wadsworth-Emmons reaction for the C(1)-C(7) trienoate portion and an efficient Suzuki cross-coupling protocol for the C(10)-C(13) diene portion. PMID- 21827194 TI - Formation of heterodimer nanocrystals: UO2/In2O3 and FePt/In2O3. AB - This Article reports a mechanistic study on the formation of colloidal UO(2)/In(2)O(3) and FePt/In(2)O(3) heterodimer nanocrystals. These dimer nanocrystals were synthesized via the growth of In(2)O(3) as the epitaxial material onto the seed nanocrystals of UO(2) or FePt. The resulting dimer nanocrystals were characterized using X-ray powder diffraction (XRD), energy dispersion spectroscopy, transmission electron microscopy (TEM), scanning transmission electron microscopy, and high-resolution TEM (HRTEM). The results from XRD and HRTEM clearly show that lattice strains exist in both of these dimer nanocrystals. Interestingly, the lattice of In(2)O(3) expands in UO(2)/In(2)O(3) dimers, whereas FePt/In(2)O(3) dimers exhibit compressed In(2)O(3) lattices. Using HRTEM and nanocrystal structure simulations, we have identified the crystallographic orientation of the attachment of the two segments in these two types of dimers. An unconventional Miller index was introduced to describe the crystallographic orientation of these heterodimer nanocrystals. On the basis of the results herein as well as those from other researchers, we propose an empirical law for the determination of the crystallographic attachment orientation in heterodimers: instead of growth on the facet of the seed nanocrystals where lattice mismatch is minimized, the growth of an epitaxial material often chooses the crystal facets where the first atomic monolayer of this material has the strongest affinity for the seed nanocrystals. PMID- 21827195 TI - Chemical approaches to understand the language of histone modifications. AB - Genomic DNA in the eukaryotic cell nucleus is present in the form of chromatin. Histones are the principal protein component of chromatin, and their post translational modifications play important roles in regulating the structure and function of chromatin and thereby in determining cell development and disease. An understanding of how histone modifications translate into downstream cellular events is important from both developmental and therapeutic perspectives. However, biochemical studies of histone modifications require access to quantities of homogenously modified histones that cannot be easily isolated from natural sources or generated by enzymatic methods. In the past decade, chemical synthesis has proven to be a powerful tool in translating the language of histone modifications by providing access to uniformly modified histones and by the development of stable analogues of thermodynamically labile modifications. This Review highlights the various synthetic and semisynthetic strategies that have enabled biochemical and biophysical characterization of site-specifically modified histones. PMID- 21827197 TI - Solar cells using quantum funnels. AB - Colloidal quantum dots offer broad tuning of semiconductor bandstructure via the quantum size effect. Devices involving a sequence of layers comprised of quantum dots selected to have different diameters, and therefore bandgaps, offer the possibility of funneling energy toward an acceptor. Here we report a quantum funnel that efficiently conveys photoelectrons from their point of generation toward an intended electron acceptor. Using this concept we build a solar cell that benefits from enhanced fill factor as a result of this quantum funnel. This concept addresses limitations on transport in soft condensed matter systems and leverages their advantages in large-area optoelectronic devices and systems. PMID- 21827196 TI - Determination of equilibrium constants for the reaction between acetone and HO2 using infrared kinetic spectroscopy. AB - The reaction between the hydroperoxy radical, HO(2), and acetone may play an important role in acetone removal and the budget of HO(x) radicals in the upper troposphere. We measured the equilibrium constants of this reaction over the temperature range of 215-272 K at an overall pressure of 100 Torr using a flow tube apparatus and laser flash photolysis to produce HO(2). The HO(2) concentration was monitored as a function of time by near-IR diode laser wavelength modulation spectroscopy. The resulting [HO(2)] decay curves in the presence of acetone are characterized by an immediate decrease in initial [HO(2)] followed by subsequent decay. These curves are interpreted as a rapid (<100 MUs) equilibrium reaction between acetone and the HO(2) radical that occurs on time scales faster than the time resolution of the apparatus, followed by subsequent reactions. This separation of time scales between the initial equilibrium and ensuing reactions enabled the determination of the equilibrium constant with values ranging from 4.0 * 10(-16) to 7.7 * 10(-18) cm(3) molecule(-1) for T = 215 272 K. Thermodynamic parameters for the reaction determined from a second-law fit of our van't Hoff plot were Delta(r)H degrees (245) = -35.4 +/- 2.0 kJ mol(-1) and Delta(r)S degrees (245) = -88.2 +/- 8.5 J mol(-1) K(-1). Recent ab initio calculations predict that the reaction proceeds through a prereactive hydrogen bonded molecular complex (HO(2)-acetone) with subsequent isomerization to a hydroxy-peroxy radical, 2-hydroxyisopropylperoxy (2-HIPP). The calculations differ greatly in the energetics of the complex and the peroxy radical, as well as the transition state for isomerization, leading to significant differences in their predictions of the extent of this reaction at tropospheric temperatures. The current results are consistent with equilibrium formation of the hydrogen bonded molecular complex on a short time scale (100 MUs). Formation of the hydrogen-bonded complex will have a negligible impact on the atmosphere. However, the complex could subsequently isomerize to form the 2-HIPP radical on longer time scales. Further experimental studies are needed to assess the ultimate impact of the reaction of HO(2) and acetone on the atmosphere. PMID- 21827198 TI - Ultrafast dynamics of epicocconone, a second generation fluorescent protein stain. AB - Femtosecond upconversion experiment has been carried out for epicocconone and its butylamine adduct in acetonitrile and tert-butanol. An ultrafast component is found to dominate the decay of fluorescence of epicocconone in acetonitrile solution. Upon reacting with butylamine, a model for the epicocconone-protein adduct, this ultrafast component remains almost unaffected but an additional rise time occurs, indicating the formation of a highly emissive species from the locally excited state. This phenomenon is central to the extraordinary applications of epicocconone in biotechnology. The magnitude of the rise time of the butylamine adduct is similar to that of the longer component of the decay of epicocconone in acetonitrile, suggesting that the dynamics of epicocconone and its butylamine adduct are similar. The ultrafast component is slowed upon increasing the viscosity of the solvent. This results in a marked increase in quantum yield and suggests that it corresponds to rapid bond isomerization, leading to a nonradiative decay. Surprisingly, in water/sucrose mixtures, the ultrafast component remains unaffected but there is still an increase in quantum yield, suggesting that there are at least two nonradiative pathways, one involving bond isomerization and another involving proton transfer. The correct interpretation of these data will allow the design of second generation protein stains based on the epicocconone scaffold with increased quantum yields and photostability. PMID- 21827199 TI - Amphiphilic co-networks with moisture-induced surface segregation for high performance nonfouling coatings. AB - Herein we report the design of a photocurable amphiphilic co-network consisting of perfluoropolyether and poly(ethylene glycol) segments that display outstanding nonfouling characteristics with respect to spores of green fouling alga Ulva when cured under high humidity conditions. The analysis of contact angle hysteresis revealed that the poly(ethylene glycol) density at the surface was enhanced when cured under high humidity. The nonfouling behavior of nonbiocidal surfaces against marine fouling is rare because such surfaces usually reduce the adhesion of organisms rather than inhibit colonization. We propose that the resultant surface segregation of these materials induced by high humidity may be a promising strategy for achieving nonfouling materials, and such an approach is more important than simply concentrating poly(ethylene glycol) moieties at an interface because the low surface energy has been maintained in our work. PMID- 21827201 TI - Supramolecular hybrid of gold nanoparticles and semiconducting single-walled carbon nanotubes wrapped by a porphyrin-fluorene copolymer. AB - We describe the design, synthesis, and characterization of a supramolecular hybrid of gold nanometals and semiconducting single-walled carbon nanotubes (SWNTs) wrapped by a porphyrin-fluorene copolymer (1), as well as fabrication of a thin-film transistor (TFT) device using the hybrid. Photoluminescence mapping revealed that the copolymer selectively dissolved SWNTs with chirality indices of (8,6), (8,7), (9,7), (7,6), and (7,5); dissolution of (8,6), and (8,7) SWNTs was especially efficient. The solubilized SWNTs were connected to gold nanoparticles (AuNPs) via a coordination bond to prepare a supramolecular hybrid composed of AuNPs/copolymer 1-wrapped SWNTs, which were studied by atomic force and scanning and transmission electron microscopies. A fabricated TFT device using the semiconducting SWNTs/copolymer 1 shows evident p-type transport with an On/Off ratio of ~10(5). The transport properties of the TFT changed after coordination of the AuNPs with the SWNTs/copolymer 1. PMID- 21827200 TI - Vibrational and valence photoelectron spectroscopies, matrix photochemistry, and conformational studies of ClC(O)SSCl. AB - ClC(O)SSCl was prepared by an improved method by the reaction of [(CH(3))(2)CHOC(S)](2)S with SO(2)Cl(2) in hexane. The photoelectron spectra in the gas phase present four distinct regions, corresponding to ionizations from electrons formally located at the S, O, and Cl atoms and at the C?O bond. The vibrational IR and Raman spectra of the liquid were interpreted in terms of the most stable syn-gauche conformer (the O?C double bond syn with respect to the S-S single bond and the C-S single bond gauche with respect to the S-Cl single bond) in equilibrium with the less stable anti-gauche form, both occurring in two enantiomeric forms. The randomization process between the conformers was induced by broad-band UV-visible irradiation in matrix conditions, and several photoproducts were identified by FTIR spectroscopy. The experimental results were complemented by theoretical calculations. PMID- 21827202 TI - The ammonia-hydrogen system under pressure. AB - Binary mixtures of hydrogen and ammonia were compressed in diamond anvil cells to 15 GPa at room temperature over a range of compositions. The phase behavior was characterized using optical microscopy, Raman spectroscopy, and synchrotron X-ray diffraction. Below 1.2 GPa we observed two-phase coexistence between liquid ammonia and fluid hydrogen phases with limited solubility of hydrogen within the ammonia-rich phase. Complete immiscibility was observed subsequent to the freezing of ammonia phase III at 1.2 GPa, although hydrogen may become metastably trapped within the disordered face-centered-cubic lattice upon rapid solidification. For all compositions studied, the phase III to phase IV transition of ammonia occurred at ~3.8 GPa and hydrogen solidified at ~5.5 GPa, transition pressures equivalent to those observed for the pure components. A P-x phase diagram for the NH(3)-H(2) system is proposed on the basis of these observations with implications for planetary ices, molecular compound formation, and possible hydrogen storage materials. PMID- 21827203 TI - First-principles study of one- and two-photon absorption of the H-bonding complexes from monomeric red fluorescent proteins with large Stokes shifts. AB - LSSmKate1 and LSSmKate2 are monomeric red fluorescent proteins (RFPs) with large Stokes shifts (LSS). The hydrogen-bonding (H-bonding) network within LSSmKate1 or LSSmKate2, which is composed of a chromophore and some surrounding amino acid residues, supports their special spectral properties. In this work, we propose H bonding complex models to simulate the H-bonding network of LSSmKate1 and LSSmKate2 and employ the time-dependent density functional theory combining with the sum-overstates method to calculate their one- and two-photon absorption characters. We discuss the influence of the hydrogen bond on the one- and two photon absorption properties of these H-bonding complexes through intermolecular hyperconjugation of the hydrogen-bond form. PMID- 21827205 TI - In situ recording of particle network formation in liquids by ion conductivity measurements. AB - The formation of fractal silica networks from a colloidal initial state was followed in situ by ion conductivity measurements. The underlying effect is a high interfacial lithium ion conductivity arising when silica particles are brought into contact with Li salt-containing liquid electrolytes. The experimental results were modeled using Monte Carlo simulations and tested using confocal fluorescence laser microscopy and zeta-potential measurements. PMID- 21827204 TI - Impact of lignin structure and cell wall reticulation on maize cell wall degradability. AB - In this study, eight maize recombinant inbred lines were selected to assess both the impact of lignin structure and the impact of cell wall reticulation by p hydroxycinnamic acids on cell wall degradability independently of the main "lignin content" factor. These recombinant lines and their parents were analyzed for in vitro degradability, cell wall residue content, esterified and etherified p-hydroxycinnamic acid content, and lignin content and structure. Lignin structure and esterified p-coumaric acid content showed significantly high correlation with in vitro degradability (r=-0.82 and r=-0.72, respectively). A multiple regression analysis showed that more than 80% of cell wall degradability variations within these 10 lines (eight recombinant inbred lines and their two parents) were explained by a regression model including two main explanatory factors: lignin content and estimated proportion of syringyl lignin units esterified by p-coumaric acid. This study revealed new biochemical parameters of interest to improve cell wall degradability and promote lignocellulose valorization. PMID- 21827206 TI - Chiral phosphoric acid-catalyzed enantioselective three-component Povarov reaction using enecarbamates as dienophiles: highly diastereo- and enantioselective synthesis of substituted 4-aminotetrahydroquinolines. AB - A chiral phosphoric acid (5)-catalyzed three-component Povarov reaction of aldehydes 2, anilines 3, and enecarbamates 4 afforded cis-4-amino-2-aryl(alkyl) 1,2,3,4-tetrahydroquinolines 1 in high yields with excellent diastereoselectivities (>95%) and almost complete enantioselectivities (up to >99% ee). The reaction was applicable to a wide range of anilines bearing electron-donating (OMe) and electron-withdrawing groups (e.g., Cl, CF(3), NO(2)) and allowed, for the first time, aliphatic aldehydes to be employed in the enantioselective Povarov reaction. With beta-substituted acyclic enecarbamates, 2,3,4-trisubstituted 1,2,3,4-tetrahydroquinolines with three contiguous stereogenic centers were produced in excellent diastereo- and enantioselectivities (87 to >99% ee). A detailed study of the active catalytic species allowed us to reduce the catalyst loading from 10% to 0.5% with no deterioration of enantiomeric excess. In addition, mechanistic studies allowed us to conclude unequivocally that the Povarov reaction involving enecarbamate as dienophile proceeded via a stepwise mechanism. The key role of the free NH function of the enecarbamate in the success of this transformation was demonstrated. NMR experiments indicating the catalyst-substrate interaction as well as a linear correlation between catalyst and product ee's were also documented. PMID- 21827208 TI - Vapor-liquid coexistence curves for methanol and methane using dispersion corrected density functional theory. AB - First principles Monte Carlo simulations in the Gibbs and isobaric-isothermal ensembles were performed to map the vapor-liquid coexistence curves of methanol and methane described by Kohn-Sham density functional theory using the Becke-Lee Yang-Parr (BLYP) exchange and correlation functionals with the Grimme correction term for dispersive (D2) interactions. The simulations indicate that the BLYP-D2 description with the TZV2P basis set underpredicts the saturated vapor densities and overpredicts the saturated liquid densities and critical and boiling temperatures for both compounds. Although the deviations are quite large, these results present a significant improvement over the BLYP functional without the correction term, which misses the experimental results by a larger extent in the opposite direction. Simulations at one temperature indicate that use of the larger QZV3P basis set may lead to improved saturated vapor densities, but not to significant changes in the liquid density. PMID- 21827207 TI - Intermolecular alignment in Y145Stop human prion protein amyloid fibrils probed by solid-state NMR spectroscopy. AB - The Y145Stop mutant of human prion protein, huPrP23-144, has been linked to PrP cerebral amyloid angiopathy, an inherited amyloid disease, and also serves as a valuable in vitro model for investigating the molecular basis of amyloid strains. Prior studies of huPrP23-144 amyloid by magic-angle-spinning (MAS) solid-state NMR spectroscopy revealed a compact beta-rich amyloid core region near the C terminus and an unstructured N-terminal domain. Here, with the focus on understanding the higher-order architecture of huPrP23-144 fibrils, we probed the intermolecular alignment of beta-strands within the amyloid core using MAS NMR techniques and fibrils formed from equimolar mixtures of (15)N-labeled protein and (13)C-huPrP23-144 prepared with [1,3-(13)C(2)] or [2-(13)C]glycerol. Numerous intermolecular correlations involving backbone atoms observed in 2D (15)N-(13)C spectra unequivocally suggest an overall parallel in-register alignment of the beta-sheet core. Additional experiments that report on intermolecular (15)N (13)CO and (15)N-(13)Calpha dipolar couplings yielded an estimated strand spacing that is within ~10% of the distances of 4.7-4.8 A typical for parallel beta sheets. PMID- 21827209 TI - Total synthesis of dermostatin A. AB - The concise total synthesis of dermostatin A is described. Highlights include a two-directional application of the asymmetric acetate aldol method developed in our lab, a novel diastereotopic-group-selective acetal isomerization for terminus differentiation, and a selective cross-metathesis reaction between a terminal olefin and a trienal. A study of the scope and viability of similar cross metathesis reactions is also described. The synthesis is convergent and utilizes fragments of roughly equal complexity. PMID- 21827211 TI - Identification and functional characterization of 14-3-3 in TLR2 signaling. AB - The Interleukin-1/Toll-like receptor signaling pathway is a crucial signaling pathway within the innate immune system and the use of mass spectrometric techniques became valuable to investigate signal transduction pathways. To date only a few reports exist that focus on the mass spectrometric identification of novel signaling intermediates within the TLR signal transduction pathway. Here we used this approach systematically to identify new interaction partners of the TLR signaling pathway and subsequently characterized them functionally. We identified 14-3-3 theta as a new member of the TLR signaling complex. With genetic complementation assays, we demonstrate that 14-3-3 negatively regulates TLR2 dependent NF-kappaB activity and amplifies the TLR4-dependent activation of the transcription factor. While 14-3-3 has no effect on TLR-induced apoptosis in innate immune cells, it controls the release of the inflammatory, IRF3-dependent cytokines like RANTES and IP-10 after stimulation with LPS. Most strikingly, 14-3 3 controls the production of proinflammatory cytokines like IL-6, IL-8, and TNFalpha in a different manner. Our results identify 14-3-3 theta as a new and important regulatory protein in the TLR signaling suppressing the MyD88-dependent pathway. PMID- 21827210 TI - Leading neuroblastoma cells to die by multiple premeditated attacks from a multifunctionalized nanoconstruct. AB - To conquer complex and devastating diseases such as cancer, more coordinated and combined attack strategies are needed. We suggest that these can be beautifully achieved by using nanoconstruct design. We present an example showing that neuroblastoma cells are selectively killed by a nanoconstruct that specifically targets neuroblastoma cells, pushes cells to the vulnerable phase of the cell cycle, and greatly enhances radiation-induced cell death. The success of this multipronged attack approach launched by cell-embedded nanoconstructs demonstrates the power and flexibility of nanotechnology in treating cancer, a difficult task for a small molecule. PMID- 21827213 TI - Nanofabrication yields. Hybridization and click-fixation of polycyclic DNA nanoassemblies. AB - We demonstrate the stepwise assembly of a fully addressable polycyclic DNA hexagon nanonetwork for the preparation of a four-ring system, one of the biggest networks yet constructed from tripodal building blocks. We find that the yield exhibits a distinct upper level <100%, a fundamental problem of thermodynamic DNA assembly that appears to have been overlooked in the DNA nanotechnology literature. A simplistic model based on a single step-yield parameter y can quantitatively describe the total yield of DNA assemblies in one-pot reactions as Y = y(duplex)(n), with n the number of hybridization steps. Experimental errors introducing deviations from perfect stoichiometry and the thermodynamics of hybridization equilibria contribute to decreasing the value of y(duplex) (on average y = 0.96 for our 10 base pair hybridization). For the four-ring system (n = 31), the total yield is thus less than 30%, which is clearly unsatisfactory if bigger nanoconstructs of this class are to be designed. Therefore, we introduced site-specific click chemistry for making and purifying robust building blocks for future modular constructs of larger assemblies. Although the present yield of this robust module was only about 10%, it demonstrates a first step toward a general fabrication approach. Interestingly, we find that the click yields follow quantitatively a binomial distribution, the predictability of which indicates the usefulness of preparing pools of pure and robust building blocks in this way. The binomial behavior indicates that there is no interference between the six simultaneous click reactions but that step-yield limiting factors such as topological constraints and Cu(I) catalyst concentration are local and independent. PMID- 21827215 TI - The pregnane X receptor agonist St John's Wort has no effects on the pharmacokinetics and pharmacodynamics of repaglinide. AB - BACKGROUND AND OBJECTIVES: St John's wort (SJW; Hypericum perforatum) has been one of the most commonly used herbal remedies for mood disorders. This study aimed to investigate the effect of SJW, a pregnane X receptor (PXR) agonist, on the pharmacokinetics and pharmacodynamics of repaglinide, a widely consumed glucose-lowering drug. METHODS: In a two-phase, randomized, crossover study with a 4-week washout period between phases, 15 healthy subjects with specific solute carrier organic anion transporter family member 1B1 (SLCO1B1) genotypes were given pretreatment with SJW 325 mg or placebo three times daily for 14 days, and a single dose of repaglinide 1 mg was administered followed by 75 g glucose at 15 minutes after repaglinide administration. RESULTS: In all subjects, SJW had no effect on the total area under the plasma concentration-time curve from time zero to infinity (AUC(infinity)), the peak plasma concentration (C(max)) or the elimination half-life (t(½)) of repaglinide. In addition, SJW had no significant effect on the blood glucose-lowering and insulin-elevating effects of repaglinide. CONCLUSION: Consumption of SJW for 14 days had no clinically significant effect on the pharmacokinetics and pharmacodynamics of repaglinide. PMID- 21827216 TI - Development of a physiologically based model for oseltamivir and simulation of pharmacokinetics in neonates and infants. AB - BACKGROUND: Physiologically based pharmacokinetic (PBPK) modelling can assist in the development of drug therapies and regimens suitable for challenging patient populations such as very young children. This study describes a strategy employing PBPK models to investigate the intravenous use of the neuraminidase inhibitor oseltamivir in infants and neonates with influenza. METHODS: Models of marmoset monkeys and humans were constructed for oseltamivir and its active metabolite oseltamivir carboxylate (OC). These models incorporated physicochemical properties and in vitro metabolism data into mechanistic representations of pharmacokinetic processes. Modelled processes included absorption, whole-body distribution, renal clearance, metabolic conversion of the pro-drug, permeability-limited hepatic disposition of OC and age dependencies for all of these processes. Models were refined after comparison of simulations in monkeys with plasma and liver concentrations measured in adult and newborn marmosets after intravenous and oral dosing. Then simulations with a human model were compared with clinical data taken from intravenous and oral studies in healthy adults and oral studies in infants and neonates. Finally, exposures after intravenous dosing in neonates were predicted. RESULTS: Good simulations in adult marmosets could be obtained after model optimizations for pro-drug conversion, hepatic disposition of OC and renal clearance. After adjustment for age dependencies, including reductions in liver enzyme expression and renal function, the model simulations matched the trend for increased exposures in newborn marmosets compared with those in adults. For adult humans, simulated and observed data after both intravenous and oral dosing showed good agreement and although the data are currently limited, simulations in 1-year-olds and neonates are in reasonable agreement with published results for oral doses. Simulated intravenous infusion plasma profiles in neonates deliver therapeutic concentrations of OC that closely mimic the oral profiles, with 3-fold higher exposures of oseltamivir than those observed with the same oral dose. CONCLUSIONS: This work exemplifies the utility of PBPK models in predicting pharmacokinetics in the very young. Simulations showed agreement with a wide range of observational data, indicating that the processes determining the age-dependent pharmacokinetics of oseltamivir are well described. PMID- 21827218 TI - Rural youth and violence: a gender perspective. AB - INTRODUCTION: The public health system must consider violence as an all too common reality in modern life. Violence can contribute to long-lasting negative consequences for individuals and communities. Research on violence has primarily focused on urban environments. Research examining youth violence within rural communities is limited. This is particularly the case for the links between gender and violence in small rural settings. The purpose of this study was to examine rural violence from a gender perspective by examining four variables: meaning, causes, consequences and solutions. METHODS: A survey was completed in Central Alberta, Canada with 178 students from grades 6 to 12. The schools' geographic locations represented two distinct economic settings: one natural resources and the other agriculture. The mean age of the participants was 16 years with 60% of the youth female and 40% male. The survey instrument was composed of demographic questions and 70 questions that focused on violence. RESULTS: Violence was a concern for all youth, but there were gender differences. Females viewed the meaning of violence as having the intent to harm others and causes contributing to violence included television, movies, video games and the internet. Females were more concerned than males about the emotional consequences of violence. For solutions, females were more accepting of intrusive means to control violence such as increased security and stricter school rules, and involving non-peer helpers such as teachers and community based agencies as a means to help combat violence. CONCLUSIONS: The results of this study indicate that violence exists among rural youth and causes a great deal of concern. In particular, the study underscores the fact that there are potential gender differences in relation to causes, meaning, impact and solutions to violence. All the youth believed that violence in their lives needs to be addressed and want to develop anti-violence strategies. Females in particular see the development of such programs including youth themselves and community partners. PMID- 21827214 TI - Clinical pharmacokinetics of tyrosine kinase inhibitors: focus on pyrimidines, pyridines and pyrroles. AB - Pyrimidine (imatinib, dasatinib, nilotinib and pazopanib), pyridine (sorafenib) and pyrrole (sunitinib) tyrosine kinase inhibitors (TKIs) are multi-targeted TKIs with high activity towards several families of receptor and non-receptor tyrosine kinases involved in angiogenesis, tumour growth and metastatic progression of cancer. These orally administered TKIs have quite diverse characteristics with regard to absorption from the gastrointestinal tract. Absolute bioavailability in humans has been investigated only for imatinib (almost 100%) and pazopanib (14 39%; n = 3). On the basis of human radioactivity data, dasatinib is considered to be well absorbed after oral administration (19% and 0.1% of the total radioactivity were excreted as unchanged dasatinib in the faeces and urine, respectively). Quite low absolute bioavailability under fasted conditions is assumed for nilotinib (31%), sorafenib (50%) and sunitinib (50%). Imatinib, dasatinib and sunitinib exhibit dose-proportional increases in their area under the plasma concentration-time curve values over their therapeutic dose ranges. Less than dose-proportional increases were observed for nilotinib at doses >=400 mg/day and for sorafenib and pazopanib at doses >=800 mg/day. At steady state, the accumulation ratios are 1.5-2.5 (unchanged imatinib), 2.0 (nilotinib once daily dosing), 3.4 (nilotinib twice-daily dosing), 1.2-4.5 (pazopanib), 5.7-6.4 (sorafenib) and 3.0-4.5 (sunitinib). Concomitant intake of a high-fat meal does not alter exposure to imatinib, dasatinib and sunitinib but leads to considerably increased bioavailability of nilotinib and pazopanib and decreased bioavailability of sorafenib. With the exception of pazopanib, the TKIs described here have large apparent volumes of distribution, exceeding the volume of body water by at least 4-fold. Very low penetration into the central nervous system in humans has been reported for imatinib and dasatinib, but there are currently no published human data for nilotinib, pazopanib, sorafenib or sunitinib. All TKIs that have been described are more than 90% bound to the plasma proteins: alpha(1) acid glycoprotein and/or albumin. They are metabolized primarily via cytochrome P450 (CYP) 3A4, the only exception being sorafenib, for which uridine diphosphate glucuronosyltransferase 1A9 is the other main enzyme involved. Active metabolites of imatinib and sunitinib contribute to their antitumour activity. Although some patient demographics have been identified as significant co-factors that partly explain interindividual variability in exposure to TKIs, these findings have not been regarded as sufficient to recommend age-, sex-, bodyweight- or ethnicity specific dose adjustment. Systemic exposure to imatinib, sorafenib and pazopanib increases in patients with hepatic impairment, and reduction of the initial therapeutic dose is recommended in this subpopulation. The starting dose of imatinib should also be reduced in renally impaired subjects. Because the solubility of dasatinib is pH dependent, co-administration of histamine H(2) receptor antagonists and proton pump inhibitors with dasatinib should be avoided. With the exception of sorafenib, systemic exposure to TKIs is significantly decreased/increased by co-administration of potent CYP3A4 inducers/inhibitors, and so it is strongly recommended that the TKI dose is adjusted or that such co administration is avoided. Caution is also recommended for co-administration of CYP3A4 substrates with TKIs, especially for those with a narrow therapeutic index. However, current recommendations with regard to dose adjustment of TKIs need to be validated in clinical studies. Further investigations are needed to explain the large interindividual variability in the pharmacokinetics of these drugs and to assess theclinical relevance of their interaction potential and inhibitory effects on metabolizing enzymes and transporters. PMID- 21827219 TI - Patient perspectives on health, health needs, and health care services in a rural Irish community: a qualitative study. AB - INTRODUCTION: There is evidence that living in a rural environment confers certain health advantages in terms of health and wellbeing. However, there is limited knowledge of patients' perspectives on determinants of health in rural areas. The aim of the present study was to explore determinants of health, health needs, and healthcare services in a rural community in the west of Ireland. METHODS: Semi-structured interviews were carried out on a purposeful sample of 12 participants who presented to a community medical centre during a designated 14 day period in May 2010. The often interwoven conceptual themes identified during analysis of the data included 'community', 'environment', 'familiarity', 'accessibility', and 'expectations'. RESULTS: The advantages of living in a rural environment included the strong sense of community, the benefits of the natural environment, familiarity, and a general sense of satisfaction in life. Issues of geographical inaccessibility and availability of affordable food were highlighted as disadvantages. In addition, hesitation was expressed about confiding mental health issues to medical professionals. CONCLUSIONS: The rural environment and sense of community with its associated strong social networks were identified as key determinants of good mental and physical health. However, the inaccessibility to mental health care and reluctance to seek help for mental health issues remain a significant problem in rural areas. In considering priorities for health, greater effort and resources are required to increase public awareness and change attitudes to mental health issues. PMID- 21827222 TI - Comparison of premolar cuspal deflection in bulk or in incremental composite restoration methods. AB - OBJECTIVES: This study examined the cuspal deflection of maxillary premolars when either a bulk filling or incremental filling technique was employed using a range of composites with different elastic moduli. METHODS: Four brands of composite materials, Heliomolar (HM, Ivoclar Vivadent, Schaan, Liechtenstein), Heliomolar HB (HH, Ivoclar Vivadent, Schaan, Liechtenstein), Filtec Supreme XT (FS, 3M Dental Product, St Paul, MN, USA), and Renew (RN, Bisco Inc, Schaumburg, IL, USA), as well as three filling techniques, bulk filling, two-layer incremental filling, and three-layer incremental filling methods, were used. One hundred twenty caries-free human premolars were collected and divided into four groups according to the filling material used. Each of these four groups was then subdivided into three groups according to filling method. In group 1, a bulk filling of 0.15 g of each resin was inserted and light-cured with LED light from the occlusal, mesial, and distal surfaces for 60 seconds each. Group 2 was given two horizontal increments, 0.08 g and 0.07 g, with each increment light-cured from the occlusal, mesial, and distal surfaces for 30 seconds each. In group 3, three horizontal increments of 0.05 g were used, each of which was light-cured from the occlusal, mesial, and distal surfaces for 20 seconds each. The cuspal deflection was measured using a customized cuspal deflection measuring machine for 10 minutes after initiating light polymerization. The elastic modulus of each composite resin material was measured using a three-point bending test. Two-way analysis of variance (ANOVA) with a Dunnet test was used to examine the effect of the two variables (curing methods, materials) on the amount of cuspal deflection at the 95% confidence level. In each material, groups 1, 2 and 3 were compared using one-way ANOVA and a Dunnet test at the 95% confidence level. The elastic moduli of HM, HH, FS, and RN were compared using one-way ANOVA and a Tukey test at the 95% confidence level. The relationship between the amount of cuspal deflection in each group and the elastic modulus of the composite was analyzed using a Pearson correlation test. RESULTS: The amount of cuspal deflection in HH was larger than in the other materials (HM, FS, and RN; p<0.05). There was no significant difference between HM, FS, and RN. The amount of cuspal deflection was greatest in group 1, followed in order by groups 2 and 3 (p<0.05). The amount of cuspal deflection was in the following order: group 1>=2>=3 in HM, and 1>2, 3 in HH, FS, and RN. The elastic modulus was HH>RN>FS>HM (p<0.05). There was a positive correlation between the cuspal deflection and the elastic modulus of the composite. CONCLUSIONS: The incremental filling techniques reduced the amount of cuspal deflection in all composite groups with different elastic moduli. The amount of cuspal deflection showed a positive correlation with the elastic modulus of the composite. PMID- 21827223 TI - Histologic response and tenascin and fibronectin expression after pulp capping in pig primary teeth with mineral trioxide aggregate or calcium hydroxide. AB - This study evaluated the histological response and the expression of tenascin (TN) and fibronectin (FN) after pulp capping with mineral trioxide aggregate (MTA) or calcium hydroxide (CH). Class V cavities and pulp exposure were performed in 40 primary pig teeth. The pulps were capped with either MTA or CH, and the cavities were sealed with resin-modified glass ionomer cement. CH was used as a control. Seven and 70 days posttreatment, the animals were sacrificed and teeth were prepared for histological evaluation. TN and FN were detected by immunostaining. A severe inflammatory response was observed after 7 days in the CH group (p<0.043), while in the MTA group, a mild response was observed. Similar reparative dentin deposition was observed after 70 days for both groups (p<0.005). The expression of FN and TN was similar for both groups in the two periods evaluated. TN and FN were expressed during pulp reparative events, independently of the capping material. PMID- 21827225 TI - In vitro evaluation of surface roughness and microhardness of restorative materials submitted to erosive challenges. AB - The aim of this study was to evaluate the effect of different acidic solutions on the microhardness and surface roughness of restorative materials. The 120 specimens of restorative materials (Fuji II LC, Vitremer, Supreme XT, and Supreme XT + Biscover LV) were randomly divided into three groups according to the immersion media: hydrochloric acid, soft drink, or distilled water. Over a period of five weeks, the groups were immersed in the solutions, which were changed weekly. Data were tested using analysis of variance and the Fisher protected least significant difference test (p<0.05). The results showed that the glass ionomer materials showed the highest surface roughness values (Fuji II LC: 0.111 +/- 0.014 MUm before and 0.139 +/- 0.016 MUm after immersion; Vitremer: 0.177 +/- 0.012 MUm before and 0.084 +/- 0.012 MUm after immersion), whereas the lowest values were found for the resin sealed with Biscover LV before (0.047 +/- 0.011 MUm) and after exposure in distilled water (0.043 +/- 0.007 MUm), soft drink (0.040 +/- 0.005 MUm), and hydrochloric acid (0.045 +/- 0.005 MUm). The Supreme XT showed the highest microhardness values before (44.96 +/- 2.51 KHN) and after the aging process (41.26 +/- 1.22 KHN in water, 35.96 +/- 0.81 KHN in soft drink, and 34.74 +/- 0.97 KHN in HCl), with significant differences from the other materials (p<0.0001). The lowest microhardness values were found for glass ionomer materials. The solutions used in this study decreased the microhardness of all studied materials, whereas the sealed surface suffered minor changes in microhardness and surface roughness after exposure to acidic solutions. PMID- 21827224 TI - Effect of tooth bleaching on bond strength of enamel-dentin cavities restored with silorane- and dimethacrylate-based materials. AB - The aim of this study was to evaluate the influence of tooth bleaching on the push-out bond strength of a composite resin based on dimethacrylates and silorane to cavities that involve both enamel and dentin. A total of 80 bovine incisors were sectioned on the buccal surface to obtain specimens (10 * 10 mm) presenting enamel and dentin (1-mm thick each substrate). The specimens were randomly distributed into eight groups (n=10), according to the bleaching protocol (1- none; 2--10% carbamide peroxide [CP] for 21 days, six hours each day; 3--three applications of 35% hydrogen peroxide [HP] in 15-minute sessions, one session every seven days for three weeks; 4--10% CP for 18 days, six hours each day + three applications of 35% HP in 15-minute sessions, one session every seven days for three weeks) and the restorative system applied (Adper Single Bond 2 + Filtek Supreme; Filtek Silorane adhesive and composite resin). After treatment, cavities were made (1.2-mm diameter on dentin; 1.5-mm diameter on enamel) with a diamond bur. At 24 hours after restoration, a push-out bond strength test was performed at a crosshead speed of 0.5 mm/min. The bleaching treatments did not significantly affect the bond strengths of either restorative system to enamel dentin. Regardless of the bleaching treatment, the dimethacrylate-based resin system exhibited significantly higher bond strengths to enamel-dentin than did the silorane-based system. PMID- 21827226 TI - Authentication analysis of cod liver oil from beef fat using fatty acid composition and FTIR spectra. AB - This study aimed to authenticate cod liver oil (CLO) from beef fat (BF) by determining the level of BF as a fat adulterant in CLO. Two instrumental techniques, namely GC-FID for fatty acid analysis and Fourier transform infrared (FTIR) spectroscopy, were exploited for such authentication. The decreased level of some fatty acids, especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), could be used as an indicative means to detect the adulteration of CLO with BF. In addition, FTIR spectroscopy combined with partial least-squares (PLS) at frequency regions of 1200-1000 cm(-1) was successfully developed for the quantification of BF in CLO. Using the PLS model, the errors obtained in calibration and prediction samples were 0.55% and 0.82% v/v, respectively. PMID- 21827221 TI - Maternal plasma concentrations of angiogenic/anti-angiogenic factors are of prognostic value in patients presenting to the obstetrical triage area with the suspicion of preeclampsia. AB - OBJECTIVE: To determine whether maternal plasma concentrations of placental growth factor (PlGF), soluble endoglin (sEng), soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) and -2 could identify patients at risk for developing preeclampsia (PE) requiring preterm delivery. STUDY DESIGN: Patients presenting with the diagnosis "rule out PE" to the obstetrical triage area of our hospital at <37 weeks of gestation (n = 87) were included in this study. Delivery outcomes were used to classify patients into four groups: I) patients without PE or those with gestational hypertension (GHTN) or chronic hypertension (CHTN) who subsequently developed PE at term (n = 19); II): mild PE who delivered at term (n = 15); III): mild disease (mild PE, GHTN, CHTN) who subsequently developed severe PE requiring preterm delivery (n = 26); and IV): diagnosis of severe PE (n = 27). Plasma concentrations of PlGF, sEng, sVEGFR-1 and -2 were determined at the time of presentation by ELISA. Reference ranges for analytes were constructed by quantile regression in our laboratory (n = 180; 1046 samples). Comparisons among groups were performed using multiples of the median (MoM) and parametric statistics after log transformation. Receiver operating characteristic curves, logistic regression and survival analysis were employed for analysis. RESULTS: The mean MoM plasma concentration of PlGF/sVEGFR-1, PlGF/sEng, PlGF, sVEGFR-1 and -2, and sEng in Group III was significantly different from Group II (all p < 0.05). A plasma concentration of PlGF/sVEGFR-1 <= 0.05 MoM or PlGF/sEng <=0.07 MoM had the highest likelihood ratio of a positive test (8.3, 95% CI 2.8-25 and 8.6, 95% CI 2.9-25, respectively), while that of PlGF <=0.396 MoM had the lowest likelihood ratio of a negative test (0.08, 95% CI 0.03-0.25). The association between low plasma concentrations of PlGF/sVEGFR-1 (<=0.05 MoM) as well as that of PlGF/sEng (<=0.07 MoM) and the development of severe PE remained significant after adjusting for gestational age at presentation, average systolic and diastolic blood pressure, and a history of chronic hypertension [adjusted odds ratio (OR) = 27 (95% CI 6.4-109) and adjusted OR 30 (95% CI 6.9-126), respectively]. Among patients who presented <34 weeks gestation (n = 59), a plasma concentration of PlGF/sVEGFR-1 < 0.033 MoM identified patients who delivered within 2 weeks because of PE with a sensitivity of 93% (25/27) and a specificity of 78% (25/32). This cut-off was associated with a shorter interval to-delivery due to PE [hazard ratio = 6 (95% CI 2.5-14.6)]. CONCLUSIONS: Plasma concentrations of angiogenic/anti-angiogenic factors are of prognostic value in the obstetrical triage area. These observations support the value of these biomarkers in the clinical setting for the identification of the patient at risk for disease progression requiring preterm delivery. PMID- 21827227 TI - Determination of tadalafil and N-desmethylsibutramine in health and dietary supplements using ultra-performance liquid chromatography (UPLC) coupled with quadrupole-time-of-flight mass spectrometry (Q-TOF MS). AB - The adulteration of dietary supplements with drugs is potentially dangerous for human health. In this study, a method was used to test simultaneously for the presence of three synthetic PDE-5 inhibitors (sildenafil, vardenafil and tadalafil), and sibutramine and its two major metabolites (N-desmethylsibutramine and N-didesmethylsibutramine) using ultra-performance liquid chromatography (UPLC) coupled with quadrupole-time-of-flight mass spectrometry (Q-TOF MS) in dietary supplements. This approach with UPLC/Q-TOF MS uses the high accurate mass of six compounds for identification and has a short run time. The recovery was from 87% to 113%; precision was less than 12.8%. The limit of detection and limit of quantification were from 0.4 to 2.0 ug kg(-1) and from 1.3 to 6.0 ug kg(-1), respectively. This method allows easy and fast analysis and detection of diverse adulterants. PMID- 21827229 TI - Astrocytes and microglia: responses to neuropathological conditions. AB - Activated astrocytes and microglia, hallmark of neurodegenerative diseases release different factors like array of pro and anti-inflammatory cytokines, free radicals, anti-oxidants, and neurotrophic factors during neurodegeneration which further contribute to neuronal death as well as in survival mechanisms. Astrocytes act as double-edged sword exerting both detrimental and neuroprotective effects while microglial cells are attributed more in neurodegenerative mechanisms. The dual and insufficient knowledge about the precise role of glia in neurodegeneration showed the need for further investigations and thorough review of the function of glia in neurodegeneration. In this review, we consolidate and categorize the glia-released factors which contribute in degenerative and protective mechanisms during neuropathological conditions. PMID- 21827231 TI - Effect of sodium bicarbonate air abrasive polishing on attrition and surface micromorphology of ceramic and stainless steel brackets. AB - OBJECTIVES: To evaluate the frictional resistance of ceramic and metal brackets using rectangular stainless steel orthodontic wires before and after using sodium bicarbonate air abrasive polishing and to evaluate the surface micromorphology of these brackets by means of scanning electron microscopy. MATERIALS AND METHODS: Two commercial brands of metal brackets and two commercial brands of ceramic brackets were evaluated. The specimens were divided into eight groups (n = 10) according to brackets and the application or not of sodium bicarbonate airborne particle abrasion for 10 seconds. A device adapted to a universal testing machine was used to simulate the movement of retraction in sliding mechanics, measuring the traction force needed to slide 10 mm of the wire over the test specimen brackets. The test speed was 5 mm/min. The data were analyzed by two-way analysis of variance (ANOVA) and Tukey test. RESULTS: There was higher frictional resistance after airborne particle abrasion irrespective of the type of bracket (P < .05). One of the ceramic brackets showed higher frictional resistance before and after airborne application than the other metal and ceramic brackets. The micromorphologic analysis showed that airborne particle abrasion caused alterations on the metal bracket surfaces. CONCLUSIONS: It may be concluded that it is not recommended to apply airborne particle abrasion on the slots of ceramic or metal brackets. PMID- 21827232 TI - Effects of bonding materials on the mechanical properties of enamel around orthodontic brackets. AB - OBJECTIVE: To determine if the enamel around orthodontic brackets is significantly altered after demineralization followed by application of adhesives with and without fluoride-releasing ability. MATERIALS AND METHODS: One hundred eight noncarious human premolars were divided into six groups of 18 each and exposed to a demineralization solution. Stainless steel brackets were bonded using two conventional composite resin etch-and-rinse systems, three self-etching primer (SEP) composite resin systems, and one resin-modified glass ionomer cement (RMGIC) system. One conventional and one SEP composite resin adhesive did not have fluoride-releasing ability, which was claimed for the other four adhesives. The elastic modulus and hardness of the enamel were determined with a nanoindenter at 10 equidistant depths ranging from 1-46 um and at four regions: control (not exposed) enamel surface, under the adhesive, and at 50 um and 100 um from the bracket edges. Using the Kruskal-Wallis and Mann-Whitney U-tests (P < .0125 for statistical significance), these properties were compared at different regions. RESULTS: The same behavior was observed for values of elastic modulus and hardness. Significant differences were found within approximately 21 um of the enamel surface for etching with 35% phosphoric acid or priming with SEP, but only minimal changes occurred for the SEP adhesive. Increases in near-surface elastic modulus and hardness of enamel were found with the SEP adhesive and RMGIC with fluoride-releasing ability. CONCLUSIONS: Clinical use of the fluoride releasing adhesives investigated may prevent demineralization of enamel around brackets during orthodontic treatment. PMID- 21827233 TI - Microbiologic changes in subgingival plaque before and during the early period of orthodontic treatment. AB - OBJECTIVE: To evaluate changes in subgingival microbiota before and during the leveling and alignment orthodontic stage using the polymerase chain reaction (PCR) method. MATERIALS AND METHODS: Thirty orthodontic patients (17 females and 13 males; aged 16.7 +/- 6.5 y) were included in this study. Subgingival microbial samples were taken from the disto-buccal gingival crevice of the left upper central incisors, the left lower central incisors, the mesio-buccal gingival crevice of the left upper first molars, and the left lower first molars, at four different times: at baseline, before placement of orthodontic appliances (T1), and 1 week (T2), 3 months (T3), and 6 months after placement of orthodontic appliances (T4). DNA was extracted from the samples, and the 16S rRNA-based PCR detection method was used to determine the prevalence of Aggregatibacter actinomycetemcomitans, Tannerella forsythia, Campylobactor rectus, Eikenella corrodens, Porphyromonas gingivalis, Prevotella intermedia, Prevotella nigrescens, and Treponema denticola, which are considered as putative periodontopathogens. RESULTS: The frequency of T forsythia, C rectus, and P nigrescens significantly increased after placement of orthodontic appliances. For the other species, the frequency tended to increase but no statistically significant difference was noted. The frequency of the change, representing microorganisms not existing at T1 but newly developing at T2, T3, and T4, was higher at the molars than at the incisors. CONCLUSION: The placement of orthodontic appliances affects the subgingival microbial composition even during the early period of orthodontic treatment, increasing the prevalence of periodontopathogens, especially in the molar region. PMID- 21827234 TI - Caries risk profile using the Cariogram in governmental and private orthodontic patients at de-bonding. AB - OBJECTIVES: To analyze various caries-related factors in orthodontic patients at de-bonding, and to test the null hypothesis that there is no difference in caries risk between governmental and private orthodontic patients immediately after orthodontic treatment. MATERIALS AND METHODS: A cross-sectional examination was carried out on 89 orthodontic patients aged 13-29 years, mean age 21.5 years. They were divided into two groups based on the center of treatment, governmental group (G) (n = 45) and private group (P) (n = 44). The investigation comprised a questionnaire, plaque scoring, caries examination, bitewing radiographs, salivary secretion rate, buffering capacity, and cariogenic microorganisms. Data were entered into the Cariogram PC program to illustrate caries risk profiles. RESULTS: Findings revealed that "the chance of avoiding new cavities," according to the Cariogram, was high in the P-group and low in the G group (61% and 28%, respectively) (P < .001). Decayed, missing, and filled surfaces (DMFS), plaque index, mutans streptococcus and lactobacillus counts, and salivary buffer capacity were significantly higher in the G-group compared with the P-group (P < .05). The total number of caries lesions at de-bonding in the G group was more than two times higher than that in the P-group (150 vs 68) (P < .001). CONCLUSIONS: The "chance to avoid new cavities" in orthodontic patients at de-bonding was less in the governmental group compared with the private group, as illustrated by the Cariogram. The governmental group also had significantly less favorable values than the private group for most of the caries-related factors. PMID- 21827235 TI - Effect of coating on properties of esthetic orthodontic nickel-titanium wires. AB - OBJECTIVE: To determine the effect of coating on the properties of two esthetic orthodontic nickel-titanium wires. MATERIALS AND METHODS: Woowa (polymer coating; Dany Harvest) and BioForce High Aesthetic Archwire (metal coating; Dentsply GAC) with cross-section dimensions of 0.016 * 0.022 inches were selected. Noncoated posterior regions of the anterior-coated Woowa and uncoated Sentalloy were used for comparison. Nominal coating compositions were determined by x-ray fluorescence (JSX-3200, JOEL). Cross-sectioned and external surfaces were observed with a scanning electron microscope (SEM; SSX-550, Shimadzu) and an atomic force microscope (SPM-9500J2, Shimadzu). A three-point bending test (12-mm span) was carried out using a universal testing machine (EZ Test, Shimadzu). Hardness and elastic modulus of external and cross-sectioned surfaces were obtained by nanoindentation (ENT-1100a, Elionix; n = 10). RESULTS: Coatings on Woowa and BioForce High Aesthetic Archwire contained 41% silver and 14% gold, respectively. The coating thickness on Woowa was approximately 10 um, and the coating thickness on BioForce High Aesthetic Archwire was much smaller. The surfaces of both coated wires were rougher than the noncoated wires. Woowa showed a higher mean unloading force than the noncoated Woowa, although BioForce High Aesthetic Archwire showed a lower mean unloading force than Sentalloy. While cross-sectional surfaces of all wires had similar hardness and elastic modulus, values for the external surface of Woowa were smaller than for the other wires. CONCLUSIONS: The coating processes for Woowa and BioForce High Aesthetic Archwire influence bending behavior and surface morphology. PMID- 21827237 TI - Development and validation of an indirect competitive enzyme-linked immunosorbent assay for monitoring quinoxaline-2-carboxylic acid in the edible tissues of animals. AB - The feed drug additive carbadox is a suspected carcinogen and mutagen. To monitor effectively residues of carbadox in the edible tissues of food-producing animals, an indirect competitive enzyme-linked immunosorbent assay (ic-ELISA) to detect quinoxaline-2-carboxylic acid, the marker residue of carbadox, was developed. Several haptens were synthesised and conjugated to the carrier protein. Nine female New Zealand white rabbits were immunised with the immunising conjugates to produce polyclonal antibodies according to the designed schemes of immunisation. The highly specific antibody that was very sensitive to N-butylquinoxaline-2 carboxamide with an IC(50) value of 7.75 ug l(-1) was selected for the development of an ic-ELISA. The standard curves based on the N-butylquinoxaline-2 carboxamide matrix calibration ranged from 0.2 to 51.2 ug l(-1). The decision limit and detection capability of the ic-ELISA were 0.60 and 0.83 ug kg(-1) for liver and 0.68 and 0.79 ug kg(-1) for muscle of swine, respectively. The recoveries were 57-108% with coefficients of variation of less than 20% when the quinoxaline-2-carboxylic acid was spiked into liver and muscle with the concentrations of 1.0-20.0 ug kg(-1). Excellent correlations between the results of the ic-ELISA and an HPLC method (r = 0.9956 - 0.9969) were observed for incurred tissues. These results suggest that the ic-ELISA is a sensitive, accurate and low-cost method that would be a useful tool for screening residues of carbadox in the edible tissues of food-producing animals. PMID- 21827243 TI - Long-term effects of brief dynamic psychotherapy. AB - The author addresses the use of transference interpretations in brief dynamic psychotherapy, length of treatment needed for limited characterological changes, and selection criteria for this treatment modality. Prior research has suggested that (a) frequent use of transference interpretations should be avoided in brief dynamic psychotherapy, (b) patients with personality disorders or a history of low-quality interpersonal relationships need more than 30-35 sessions to achieve stable dynamic changes, and (c) quality of interpersonal relationships is the best pretreatment predictor of long-term changes. This study examines specific effects of the moderate use of transference interpretations. Possible mediators of long-term effects (i.e., insight or identification with the therapist) are also tested. The author's experiences regarding the interface between research and clinical practice are discussed. PMID- 21827236 TI - Root resorption diagnosed with cone beam computed tomography after 6 months of orthodontic treatment with fixed appliance and the relation to risk factors. AB - OBJECTIVES: To investigate root resorption after 6 months of active orthodontic treatment and its relation to possible risk factors. MATERIALS AND METHODS: Ninety-seven patients (10-18 years) with a Class I malocclusion and crowding treated with fixed appliance and premolar extractions were examined with cone beam computed tomography before and after 6 months of active treatment. The exposure covered all teeth from first molar to first molar in both jaws. The Malmgren index was used to evaluate the degree of root resorption. Irregular root contour (score 1) was seen in most teeth already before active treatment, and therefore resorptions were registered only as score 2 (<2 mm, minor resorption) or higher. RESULTS: Minor root resorption was noted in 10% of the patients and severe root resorption, >2 mm (score 3) was found in four patients. Root resorption was more frequently seen in the upper jaw, especially the incisors. There was no statistically significant correlation of root resorption with any of the selected risk factors. CONCLUSIONS: After 6 months of treatment, clinically significant resorption was diagnosed in 4% of the patients, ie, in 96% of the patients the radiographic examination did not reveal any significant information. The selected risk factors did not have any impact on the amount of resorption after 6 months of active treatment. PMID- 21827244 TI - Treatment selection in private practice psychodynamic psychotherapy: a naturalistic prospective longditudinal study. AB - In this naturalistic prospective longitudinal study, the authors evaluated the treatment selection decisions of 24 psychotherapists in private practice over a 12-month period. A comparison of the treatment selection criteria for patients who were accepted for treatment and for those who were not yielded 3 results: (a) Motivation was the outstanding factor determining whether a patient was accepted for treatment; (b) selection of short-term or long-term psychotherapy depended on the therapists' emotional response to the patient; and (c) psychiatric diagnosis and symptom severity contributed relatively little to treatment selection. These findings suggest that treatment selection in private practice psychodynamic psychotherapy is based on specific aspects of the therapist-patient relationship rather than on patient characteristics related to symptom severity or psychiatric diagnosis. PMID- 21827245 TI - Antidepressant medication and the assimilation of problematic experiences in psychotherapy. AB - The authors assessed whether the psychotherapeutic process is enhanced by the addition of antidepressant medication. Mildly to moderately depressed patients received client-centered therapy with or without medication. Patients were assessed for symptoms of depression and the ability to assimilate problematic experiences successfully. Ratings of improvement on Stiles's Scale for the Assimilation of Problematic Experiences rose significantly in both treatment conditions. There was no significant effect of the addition of antidepressant medication on the psychotherapeutic process. However, patients without medication tended to reach higher stages of assimilation (e.g., problem clarification and insight). Psychotherapy alone seems as effective in reducing depression as that with the addition of pharmacotherapy and may be superior in supporting the psychotherapeutic process in the longer term. The question remains as to the nature of the conditions in which one may achieve additive effects of psychotherapy and medication. PMID- 21827246 TI - Efficacy of a one-session virtual reality exposure treatment for fear of flying. AB - The authors examined the efficacy of a 1-session virtual reality (VR) exposure treatment and sought to determine whether VR exposure is the active treatment component. Forty-five patients with fear of flying were randomly assigned to (a) cognitive treatment plus VR exposure with motion simulation, (b) cognitive treatment plus VR exposure without motion simulation, or (c) cognitive treatment alone. Fear of flying was assessed before, immediately after, and 6 months after treatment. Posttreatment and 6-month follow-up assessments revealed reduced fear of flying only in the VR exposure groups. VR exposure with or without motion simulation yielded comparable treatment outcomes. Dismantling of treatment components indicated that exposure to visual and acoustic stimuli is the main active component of VR exposure therapy. Motion simulation as part of VR exposure does not seem to further enhance treatment effects. PMID- 21827247 TI - Assessing problematic States in patients' narratives: the grid of problematic States. AB - The authors present the theoretical background, development, and validation of a new psychotherapy process rating tool: Grid of Problematic States (GPS). The GPS is based on Horowitz's states of mind theory, which describes recurrent patterns of experience and behavior. Meaningful changes in the observed states indicate therapeutic change. The GPS is designed for use with transcripts from psychotherapy sessions and focuses on narrative episodes within the patient dialogue. The GPS was applied to a completely transcribed cognitive psychotherapy with a patient diagnosed as mild major depressive. The authors demonstrated that the GPS could reliably assess disorganization and the development of stable construct clusters of thought themes, emotions, and somatic sensations. The interpretation of results is consistent with the patient's clinical assessment. PMID- 21827248 TI - Impact of the turning-against-self defense mechanism on the process and outcome of inpatient psychotherapy. AB - The authors examined the relation between specific defense mechanisms and treatment process and outcome in psychodynamic psychotherapy. Three measures, Questionnaire for Conflict Coping Strategies, Questionnaire on the Experience of the Inpatient Therapeutic Process, and Symptom Checklist-90-R, were given to 65 inpatients of a psychosomatic clinic, predominantly with depressive or eating disorders. Turning against self was the most frequently used defense mechanism in the patient group. A high level of turning against self that could be reduced significantly during treatment was associated with good adaptation to treatment setting and positive treatment outcome defined by symptom distress reduction. Assessment of defense mechanisms and their interaction with therapeutic factors in the therapy setting can be useful to better understand the treatment process and the subsequent development of specific interventions to enhance treatment outcome. PMID- 21827249 TI - Respective contributions of therapist and client adult attachment orientations to the development of the early working alliance: a preliminary growth modeling study. AB - The authors investigated the temporal relationship between client and therapist attachment orientations and early working alliance. Attachment was measured by self-report after the 1st session of therapy. The working alliance ratings were completed after the 1st, 4th, and 7th therapy sessions. Hierarchical linear modeling results indicated that anxiously attached therapists had a significant positive effect on the client working alliances after the 1st session but significant negative effects over time. No other therapist or client attachment variables or related interactions had a significant effect on client working alliance ratings. Results also indicated that time was a significant positive predictor of client working alliance ratings. PMID- 21827250 TI - Link among therapist and parent relationship, working alliance, and therapy outcome. AB - On the basis of interpersonal and intergenerational family theories, this study examined (a) the association between therapists' reported relationship with their parents and clients' report of the working alliance at 3 points in the therapy process (i.e., after the 3rd, 7th, and final sessions); (b) the association between clients' report of the working alliance at 3 points in the therapy process and outcome, and (c) the association between therapists' reported relationships with parents and outcome. With 20 therapist-client dyads, results indicated that the therapist-parent relationship, measured by the Personal Authority in the Family System Questionnaire, predicted working alliance at the 3rd, middle, and final sessions of therapy. Additionally, working alliance predicted outcome. Of particular note, the results indicated that both healthy (i.e., intimacy and individuation) and less healthy (i.e., fusion and triangulation) therapist-parent relationship patterns contributed to the client's perception of a positive working alliance. PMID- 21827251 TI - Multiculturalism and the therapeutic process. PMID- 21827252 TI - Concept mapping of therapeutic common factors. AB - The cognitive structure used by 16 American Board of Professional Psychology certified psychologists and 5 experienced psychotherapy researchers to delineate common factors of psychotherapy was examined using multidimensional scaling and cluster analysis. The results indicate that 2 dimensions-hot (feeling) versus cool (thinking) processing and therapeutic activity-and 3 clusters-bond, information, and role-are used in conceptualizing common factors. Results are discussed with respect to research and conceptualization of common factors. PMID- 21827253 TI - Increase in coherence in action control as a feature of successful psychotherapies: a sequential analytical examination of the therapist-patient interaction. AB - The authors investigated the hypothesis that utterances of patients and therapists concerning action control theory (Kuhl, 1985) would converge in successful therapies. This study focused on the motivational content of patient and therapist statements from 128 therapy sessions of 32 different therapies. Using sequential analysis, the authors analyzed the starting and final therapy phases, different therapeutic conditions, and outcome. Generally, successful therapies had more action-oriented successions of utterances. In successful therapies, patients adhered less to their preferred action control style and moved closer to the motivational attitude of their psychotherapists. Independent of therapy success, more coherent action control sequences were found in therapies focusing on clarification than in those focusing on behavioral change. An increase of coherent action control sequences, either action or state oriented, promoted a successful course of therapy. PMID- 21827254 TI - Professional possible selves, anxiety, and seniority as determinants of professional satisfaction of psychotherapists. AB - The authors addressed 3 major issues regarding psychotherapists' professional satisfaction: What are the determinants of psychotherapists' professional satisfaction and the role of possible selves? How are hopes and fears about the future associated with professional satisfaction? How are these effects revealed by 2 methods of measuring possible selves? Possible selves refer to individuals' images of their future in terms of what they hope to become and what they are afraid of becoming. It was assumed that individuals who are more concerned about their future will display a higher level of both hopes and fears and that hopes concerning one's professional future quite often involve fears expressed in more positive terms. Accordingly, it was hypothesized that higher professional satisfaction would be negatively correlated with anxiety and both hopes and fears regarding professional future and that this professional satisfaction will be positively associated with seniority. The data tended to support these hypotheses. The findings were discussed in terms of the role of seniority and hopes and fears about the future in the development of psychotherapists' professional satisfaction. PMID- 21827255 TI - Empowerment events in process-experiential psychotherapy of depression: an exploratory qualitative analysis. AB - The goal of this study was to analyze different types of empowering therapy events. Twelve significantly empowering therapy events, involving 9 depressed clients undergoing individual process-experiential psychotherapy, were selected from a larger collection of significant events (Elliott et al., 1990) using client ratings of feeling powerful/hopeful/active. The data consisted of transcripts of client-identified significant events along with parts of client and therapist Brief Structured Recall interviews. The events were first sorted into broad domains and then into types. Finally, general and variant themes across domains were tracked. We found 5 types of empowerment events: poignant, emergent, decisional, empowerment, and accomplishment. A description is provided for each event type across domains: client processes, therapist processes and interaction, and therapeutic impact. Different therapeutic processes were present in a variety of empowerment types. However, some therapist interventions contributed to several types of empowerment, among them communication of empathic understanding, empathic affirmation of client growth-promoting aspects, and 2 chair work. PMID- 21827256 TI - Do interpersonal behavior and emotional experience change in the course of successful long-term psychoanalytic therapies? AB - The way in which patients behave toward others is considered to be a correlate of mental health and thus of successful psychotherapy. Until now, research regarding the extent to which this assumption is justified has produced contradictory findings. On the basis of 2 definitions of normal interpersonal behavior (Benjamin, 1993; Crits-Christoph, Demorest, Muenz, & Baranackie, 1994), the authors studied 10 patients undergoing psychoanalytic therapy to determine whether changes in their descriptions of interpersonal relationships were associated with a decrease in self-reported symptoms and interpersonal problems during the first 2 years of treatment. Using a hierarchical linear model, the authors identified moderate to high correlations in the expected direction: The patients' affiliative behavior toward their objects as well as the average valence and variability of their affective experience increased when therapy was successful. In contrast, patients' descriptions of their objects' behavior did not change in a systematic manner. PMID- 21827257 TI - The therapist experience of being the target of hostile versus suspected unasserted client anger: factors associated with resolution. AB - The authors qualitatively studied 13 therapists' recollections of 12 hostile and 13 suspected-unasserted client anger events. The trigger for all anger events was a disliked therapist action or inaction. Therapists had more difficulty with hostile than suspected-unasserted client anger. Factors associated with resolution of hostile anger events were a lack of problematic client behaviors, therapists turning negative feelings outward, a goal of connecting with clients, therapists exploring the anger with clients and explaining their behaviors, and therapists conceptualizing the anger as being due to problems in the therapeutic relationship rather than to client personality problems. Factors associated with resolution in suspected-unasserted anger events were a good therapeutic relationship and therapists trying to help clients gain insight and explore the anger. Implications are given for practice and research. PMID- 21827258 TI - Patient factors predicting dropout from supportive-expressive psychotherapy for patients with personality disorders. AB - In this prospective study of psychiatric outpatients with personality disorders, the authors examined patient factors that predicted dropout from supportive expressive (SE) psychotherapy. Eighty patients were randomized to 40 sessions of time-limited SE psychotherapy. The dropout rate was 35%; 50% of dropouts terminated psychotherapy before Session 7, and 10% were nonengagers. A model including age, type of Axis II cluster, total amount of interpersonal distress, and degree of focus on 1 particular type of interpersonal problem predicted 71% of the completers and 50% of the dropouts. The prediction model was more accurate for men than women. The findings regarding age and type of Axis II cluster are consistent with those of prior studies. The findings for total amount of interpersonal distress and degree of focus on 1 particular type of interpersonal problem are in accordance with key concepts in interpersonal theory and research. Thus, patients' manner of relating to others is associated with dropout. Researchers are encouraged to examine the association between interpersonal factors and dropout in greater depth. PMID- 21827259 TI - Bibliometric analysis of psychotherapy research: performance assessment and position in the journal landscape. AB - The authors provide an overview of advanced bibliometric methods for (a) an objective and transparent assessment of journal performance and (b) positioning of a journal in relation to other journals. These methods are applied to Psychotherapy Research, an international journal within the field of clinical psychology. In the first analysis, the authors focus on journal performance in an international comparative perspective (i.e., the performance of the journal in relation to all other journals in the same field of science) and introduce a novel type of journal impact factor. In the second analysis, the authors position the journal on the basis of total citation relations among all relevant journals, including those outside the specific field of science to which the journal belongs. A multitude of interdisciplinary relations between the journal under investigation and many other journals is revealed. The investigators discuss briefly the potential of such a "journal citation mapping" for unraveling interdisciplinary developments and "interfaces" between different fields of science. PMID- 21827260 TI - Psychotherapy relationships that work: therapist contributions and responsiveness to patients. PMID- 21827261 TI - Integration in psychotherapy: models and methods. PMID- 21827262 TI - Clinical management of sex addiction. PMID- 21827264 TI - Combining multiple biomarkers for cardiovascular risk assessment: more is usually better - up to a point. PMID- 21827267 TI - Bioanalysis young investigator: Narahara Chari Dingari. PMID- 21827268 TI - The status of trace elements analysis in biological systems. PMID- 21827269 TI - Aspects of bioanalytical method validation for the quantitative determination of trace elements. AB - Bioanalytical methods are used to quantitatively determine the concentration of drugs, biotransformation products or other specified substances in biological matrices and are often used to provide critical data to pharmacokinetic or bioequivalence studies in support of regulatory submissions. In order to ensure that bioanalytical methods are capable of generating reliable, reproducible data that meet or exceed current regulatory guidance, they are subjected to a rigorous method validation process. At present, regulatory guidance does not necessarily account for nuances specific to trace element determinations. This paper is intended to provide the reader with guidance related to trace element bioanalytical method validation from the authors' perspective for two prevalent and powerful instrumental techniques: inductively coupled plasma-optical emission spectrometry and inductively coupled plasma-MS. PMID- 21827270 TI - A simple HPLC method for the simultaneous determination of venlafaxine and its major metabolite O-desmethylvenlafaxine in human serum. AB - Venlafaxine is a very popular antidepressant in Greece. There is an increasing rate of self-poisoning cases with this drug presenting at the emergency departments around the country. We have developed a simple HPLC method with ultraviolet detection for the simultaneous determination of venlafaxine and its major metabolite, O-desmethylvenlafaxine, in human serum following solid-phase extraction. The developed method was validated in terms of sensitivity, linearity, accuracy, precision, stability and selectivity both for therapeutic and toxic serum ranges, and was applied to human serum samples. The method currently developed and validated is simple, does not require expensive instrumentation and can therefore be easily applied in the clinical toxicology setting for the diagnosis and management of acute venlafaxine intoxication. PMID- 21827272 TI - A practical approach to reduce interference due to in-source collision-induced dissociation of acylglucuronides in LC-MS/MS. AB - BACKGROUND: In LC-MS/MS, glucuronide conjugated metabolites may convert back to the parent drug due to in-source collision-induced dissociation (CID). RESULTS: During the bioanalysis of naproxen, it was noticed that naproxen acylglucuronide exhibited intense in-source CID to the naproxen [M+H](+) ion under positive ESI. However, no in-source CID of the acylglucuronide to the naproxen [M+NH(4)](+) adduct was observed. Furthermore, absolutely no in-source CID was detected under negative ESI. This phenomenon was not only observed for naproxen acylglucuronide but for eight other acylglucuronides compounds. CONCLUSION: We have shown that monitoring the parent drug [M-H](-) or [M+NH(4)](+) whenever possible could be an easy approach used by bioanalytical scientists to minimize the impact of in source CID of acylglucuronides to the parent drug. PMID- 21827271 TI - Development of methods to monitor ionization modification from dosing vehicles and phospholipids in study samples. AB - Two approaches to monitor the matrix effect on ionization in study samples were described. One approach is the addition of multiple reaction monitoring transitions to the bioanalytical methods to monitor the presence of known ionization modification-causing components of the matrix, for example, m/z 184 >125 (or m/z 184->184) and m/z 133->89 may be used for phospholipids and polyethylene oxide containing surfactants, respectively. This approach requires no additional equipment and can be readily adapted for most method. The approach detects only the intended interfering compounds and provides little quantitative indication if the matrix effect is within the tolerable range (+/-15%). The other approach requires the addition of an infusion pump and identifies an appropriate surrogate of the analyte to be infused for the determination of modification on the ionization of the analyte. The second approach detects interferences in the sample regardless of the sources (i.e., dosing vehicle components, co administrated drugs, their metabolites, phospholipids, plasticizers and endogenous components introduced due to disease stage). PMID- 21827273 TI - Monitoring free drug concentrations: challenges. AB - Measurement of drug concentrations in biological samples is of utmost importance in many research areas. The information about the amount of drug in a biological sample can be given as either total concentration, which ignores the interaction of the drug with the sample matrix, or as free concentration, which shows the portion of molecules able to diffuse through membranes and exert biological activity. Although the historical trend has been towards determining total concentrations, measurement of free concentrations is becoming more important since it correlates better with pharmacological and toxicological effects. This review will discuss the most popular experimental approaches for monitoring free drug concentrations, based on the type of sample to be investigated and the kind of information to be collected. It is shown that the current challenges in measuring free concentrations are: convenience, accuracy, precision, wide applicability, availability of accurate and precise reference methods, ruggedness, and standardized sample conditions. PMID- 21827274 TI - Advances in metabolite identification. AB - One of the central challenges to metabolomics is metabolite identification. Regardless of whether one uses so-called 'targeted' or 'untargeted' metabolomics, eventually all paths lead to the requirement of identifying (and quantifying) certain key metabolites. Indeed, without metabolite identification, the results of any metabolomic analysis are biologically and chemically uninterpretable. Given the chemical diversity of most metabolomes and the character of most metabolomic data, metabolite identification is intrinsically difficult. Consequently a great deal of effort in metabolomics over the past decade has been focused on making metabolite identification better, faster and cheaper. This review describes some of the newly emerging techniques or technologies in metabolomics that are making metabolite identification easier and more robust. In particular, it focuses on advances in metabolite identification that have occurred over the past 2 to 3 years concerning the technologies, methodologies and software as applied to NMR, MS and separation science. The strengths and limitations of some of these approaches are discussed along with some of the important trends in metabolite identification. PMID- 21827276 TI - Blood lead levels and cumulative blood lead index (CBLI) as predictors of late neurodevelopment in lead poisoned children. AB - OBJECTIVE: To find the best lead exposure assessment marker for children. METHODS: We recruited 11 children, calculated a cumulative blood lead index (CBLI) for the children, measured their concurrent BLL, assessed their development, and measured their bone lead level. RESULTS: Nine of 11 children had clinically significant neurodevelopment problems. CBLI and current blood lead level, but not the peak lead level, were significantly or marginally negatively associated with the full-scale IQ score. CONCLUSION: Lead exposure at younger age significantly impacts a child's later neurodevelopment. CBLI may be a better predictor of neurodevelopment than are current or peak blood lead levels. PMID- 21827277 TI - HIV type 1 gag genetic diversity among antenatal clinic attendees in North Rift Valley, Kenya. AB - HIV genetic recombination and high mutation rate increase diversity allowing it to escape from host immune response or antiretroviral drugs. This diversity has enabled specific viral subtypes to be predominant in specific regions. To determine HIV-1 subtypes among seropositive antenatal clinic attendees in Kenya's North Rift Valley, a cross-sectional study was carried out on 116 HIV-1-positive blood samples. Proviral DNA was extracted from peripheral blood mononuclear cells by DNAzol lysis and ethanol precipitation. Polymerase chain reactions using specific primers for HIV-1 gag and population sequencing on resulting amplicons were carried out. Phylogenetic analysis revealed that 81 (70%) were subtype A1, 13 (11%) subtype D, 8 (7%) subtype C, 3 (3%) subtype A2, 1 (1%) subtype G, and 10 showed possible recombinants: 5 (4%) subtype A1D, 4 (3%) subtype A1C, and 1 (1%) subtype A2C. These data support the need to establish circulating subtypes for better evaluation of effective HIV diagnostic and treatment options in Kenya. PMID- 21827278 TI - Monoclonal antibody-based candidate therapeutics against HIV type 1. AB - Treatment of HIV-1 infection has been highly successful with small molecule drugs. However, resistance still develops. In addition, long-term use can lead to toxicity with unpredictable effects on health. Finally, current drugs do not lead to HIV-1 eradication. The presence of the virus leads to chronic inflammation, which can result in increased morbidity and mortality after prolonged periods of infection. Monoclonal antibodies (mAbs) have been highly successful during the past two decades for therapy of many diseases, primarily cancers and immune disorders. They are relatively safe, especially human mAbs that have evolved in humans at high concentrations to fight diseases and long-term use may not lead to toxicities. Several broadly neutralizing mAbs (bnmAbs) against HIV-1 can protect animals but are not effective when used for therapy of an established infection. We have hypothesized that HIV-1 has evolved strategies to effectively escape neutralization by full-size antibodies in natural infections but not by smaller antibody fragments. Therefore, a promising direction of research is to discover and exploit antibody fragments as potential candidate therapeutics against HIV-1. Here we review several bnmAbs and engineered antibody domains (eAds), their in vitro and in vivo antiviral efficacy, mechanisms used by HIV-1 to escape them, and strategies that could be effective to develop more powerful mAb-based HIV-1 therapeutics. PMID- 21827280 TI - A customized self-assembling peptide hydrogel for dental pulp tissue engineering. AB - Root canal therapy is common practice in dentistry. During this procedure, the inflamed or necrotic dental pulp is removed and replaced with a synthetic material. However, recent research provides evidence that engineering of dental pulp and dentin is possible by using biologically driven approaches. As tissue engineering strategies hold the promise to soon supersede conventional root canal treatment, there is a need for customized scaffolds for stem cell delivery or recruitment. We hypothesize that the incorporation of dental pulp-derived stem cells with bioactive factors into such a scaffold can promote cell proliferation, differentiation, and angiogenesis. In this study, we used a cell adhesive, enzyme cleavable hydrogel made from self-assembling peptide nanofibers to encapsulate dental pulp stem cells. The growth factors (GFs) fibroblast growth factor basic, transforming growth factor beta1, and vascular endothelial growth factor were incorporated into the hydrogel via heparin binding. Release profiles were established, and the influence of GFs on cell morphology and proliferation was assessed to confirm their bioactivity after binding and subsequent release. Cell morphology and spreading in three-dimensional cultures were visualized by using cell tracker and histologic stains. Subcutaneous transplantation of the hydrogel within dentin cylinders into immunocompromised mice led to the formation of a vascularized soft connective tissue similar to dental pulp. These data support the use of this novel biomaterial as a highly promising candidate for future treatment concepts in regenerative endodontics. PMID- 21827281 TI - The tissue-engineered auricle: past, present, and future. AB - The reconstruction, repair, and regeneration of the external auricular framework continue to be one of the greatest challenges in the field of tissue engineering. To replace like with like, we should emulate the native structure and composition of auricular cartilage by combining a suitable chondrogenic cell source with an appropriate scaffold under optimal in vitro and in vivo conditions. Due to the fact that a suitable and reliable substitute for auricular cartilage has yet to be engineered, hand-carved autologous costal cartilage grafts and ear-shaped porous polyethylene implants are the current treatment modalities for auricular reconstruction. However, over the last decade, significant advances have been made in the field of regenerative medicine and tissue engineering. A variety of scaffolds and innovative approaches have been investigated as alternatives to using autologous carved costal cartilage or porous polyethylene implants. A review of recent developments and the current state of the art and science is presented, focusing on scaffolds, cell sources, seeding densities, and mechanical characteristics of tissue-engineered auricular cartilage. PMID- 21827279 TI - Heme oxygenase-1 inhibits myoblast differentiation by targeting myomirs. AB - AIMS: Heme oxygenase-1 (HMOX1) is a cytoprotective enzyme degrading heme to biliverdin, iron ions, and carbon monoxide, whose expression is induced in response to oxidative stress. Its overexpression has been suggested as a strategy improving survival of transplanted muscle precursors. RESULTS: Here we demonstrated that HMOX1 inhibits differentiation of myoblasts and modulates miRNA processing: downregulates Lin28 and DGCR8, lowers the total pool of cellular miRNAs, and specifically blocks induction of myomirs. Genetic or pharmacological activation of HMOX1 in C2C12 cells reduces the abundance of miR-1, miR-133a, miR 133b, and miR-206, which is accompanied by augmented production of SDF-1 and miR 146a, decreased expression of MyoD, myogenin, and myosin, and disturbed formation of myotubes. Similar relationships between HMOX1 and myomirs were demonstrated in murine primary satellite cells isolated from skeletal muscles of HMOX1(+/+), HMOX1(+/-), and HMOX1(-/-) mice or in human rhabdomyosarcoma cell lines. Inhibition of myogenic development is independent of antioxidative properties of HMOX1. Instead it is mediated by CO-dependent inhibition of c/EBPdelta binding to myoD promoter, can be imitated by SDF-1, and partially reversed by enforced expression of miR-133b and miR-206. Control C2C12 myoblasts injected to gastrocnemius muscles of NOD-SCID mice contribute to formation of muscle fibers. In contrast, HMOX1 overexpressing C2C12 myoblasts form fast growing, hyperplastic tumors, infiltrating the surrounding tissues, and disseminating to the lungs. INNOVATION: We evidenced for the first time that HMOX1 inhibits differentiation of myoblasts, affects the miRNA processing enzymes, and modulates the miRNA transcriptome. CONCLUSION: HMOX1 improves the survival of myoblasts, but concurrently through regulation of myomirs, may act similarly to oncogenes, increasing the risk of hyperplastic growth of myogenic precursors. PMID- 21827282 TI - Essential oil composition of Foeniculum vulgare Mill. fruits from pharmacies in different countries. AB - Variations in the essential oil composition of Foeniculum vulgare Mill. commercial fruits obtained from retail pharmacies in Estonia, Norway, Austria and Moldova and from a spice shop in Turkey were determined using capillary GC techniques. The essential oil content of all the samples was 5-51 mL kg(-1) and between 22 and 51 mL kg(-1) in fennel fruits bought from pharmacies. A total of 34 compounds were identified. The major component was trans-anethole (34.8 82.0%); the other principal compounds in oils were fenchone (1.6-22.8%), estragole (2.4-17.0%), limonene (0.8-16.5%), and cis-anethole (0.1-8.6%). The yield of essential oil (5.0 mL kg(-1)) and content of trans-anethole was very low (34.8%) in the Turkish spice sample. Maximum yield of essential oil was found in fennel from Norway and Austria (50.7 and 50.5 mL kg(-1), respectively); these samples were rich in fenchone (21.2% and 22.8%), but contained less trans anethole (64.6-63.7) than samples from Estonia and Moldova (82.0% and 80.9%). The typical samples of sweet fennel (bought from Estonia and Moldova) and bitter fennel (from Norway and Austria) were found to conform completely or partially to EP standards, although fennel type was always not marked on the packages. PMID- 21827283 TI - Composition and in vitro antibacterial activity of essential oils from four Satureja species growing in Iran. AB - The composition and in vitro antibacterial activity of essential oils from four Satureja species (S. bachtiarica, S. khuzistanica, S. mutica and S. rechingeri) growing in Iran were determined. According to the results of GC-FID and GC-MS analysis, all oil samples were principally composed of phenolic constituents (carvacrol and/or thymol) with the percentages ranging from 41.2% (S. bachtiarica) to 77.7% (S. rechingeri). Determining antibacterial activities by the disc diffusion method against two Gram-positive and two Gram-negative bacteria revealed the maximum activity against Bacillus cereus with a range of minimum inhibitory concentration values from 0.25 to 1 mg mL(-1) and minimum bactericidal concentration values from 0.5 to 1 mg mL(-1). The oils of S. khuzistanica and S. rechingeri appeared to be more active in general than those of other species. In conclusion, the essential oils of studied Satureja species have the potential to be considered as alternatives for synthetic food preservatives. PMID- 21827284 TI - A new triterpenoid saponin from the roots of Phytolacca acinosa. AB - A new triterpenoid saponin, named esculentoside T (1), together with five known compounds (2-5), was isolated from the roots of Phytolacca acinosa. The structures of these compounds were elucidated on the basis of spectral data. PMID- 21827285 TI - Isolation and chromatographic analysis of bioactive triterpenoids from the bark extract of Cariniana domestica (Mart) Miers. AB - The Lecythidaceae family is composed of 25 genera and 400 species that occur in the form of trees with a pantropical distribution. The genera Cariniana belongs to the family Lecythidaceae, and there are few reports considering these species. In this work, fractionation of the dichloromethane fraction obtained from the aqueous extract of the stem bark of Cariniana domestica (Mart) Miers, popularly known as Jequitiba-roxo, led to the isolation of two mixtures of triterpenoids: lupeol and beta-amyrin and beta-sitosterol and stigmasterol. The structures of the isolated compounds were elucidated by spectroscopic (NMR) and chromatographic (GC-MS) techniques as well as literature data comparisons. beta-Sitosterol, stigmasterol, lupeol and beta-amyrin were quantified in dichloromethane fraction by high-performance liquid chromatography (HPLC/DAD). The dichloromethane fraction was also investigated for antioxidant and antifungal activities. The isolated compounds and their biological activities are reported for the first time for the species C. domestica. PMID- 21827286 TI - ModuleSearch: finding functional modules in a protein-protein interaction network. AB - Many biological processes are performed by a group of proteins rather than by individual proteins. Proteins involved in the same biological process often form a densely connected sub-graph in a protein-protein interaction network. Therefore, finding a dense sub-graph provides useful information to predict the function or protein complex of uncharacterised proteins in the sub-graph. We developed a heuristic algorithm that finds functional modules in a protein protein interaction network and visualises the modules. The algorithm has been implemented in a platform-independent, standalone program called ModuleSearch. In an interaction network of yeast proteins, ModuleSearch found 366 overlapping modules. Of the modules, 71% have a function shared by more than half the proteins in the module and 58% have a function shared by all proteins in the module. Comparison of ModuleSearch with other programs shows that ModuleSearch finds more sub-graphs than most other programs, yet a higher proportion of the sub-graphs correspond to known functional modules. ModuleSearch and sample data are freely available to academics at http://bclab.inha.ac.kr/ModuleSearch. PMID- 21827288 TI - Coping with adverse drug events in patients with heart failure: Exploring the role of medication beliefs and perceptions. AB - This study describes coping strategies that patients with heart failure (HF) use to manage adverse drug events (ADEs). The included coping strategies were social support seeking, information seeking, non-adherence and taking alleviating medication. The role of beliefs about medication and ADE perceptions in explaining these coping strategies was assessed using the Self-Regulation Model. We performed a cross-sectional study including 250 HF patients who experienced an ADE. Patients completed validated questionnaires assessing their coping strategies, ADE perceptions and medication beliefs. Social support (60%) and information seeking (32%) were the most commonly used strategies to cope with ADEs. Non-adherence was reported by 7% of the patients. Multivariate linear regression analysis showed that demographics, clinical factors and medication beliefs explained only a small amount of the variance in coping strategies, whereas ADE perceptions explained a substantial amount of variance. Path analysis showed that patients' perceptions about the timeline, consequences and controllability of ADEs by the health care provider were directly related to their coping behaviour. The effect of patients' medication beliefs on their coping strategies was consistent with mediation through their ADE perceptions. Our results support the value of the Self-Regulation Model in understanding patients' coping behaviour with regard to ADEs. PMID- 21827287 TI - Identification and molecular characterization of new simian T cell lymphotropic viruses in nonhuman primates bushmeat from the Democratic Republic of Congo. AB - Four types of human T cell lymphotropic viruses (HTLV) have been described (HTLV 1 to HTLV-4) with three of them having closely related simian virus analogues named STLV-1, -2, and -3. To assess the risk of cross-species transmissions of STLVs from nonhuman primates to humans in the Democratic Republic of Congo, a total of 330 samples, derived from primate bushmeat, were collected at remote forest sites where people rely on bushmeat for subsistence. STLV prevalences and genetic diversity were estimated by PCR and sequence analysis of tax-rex and LTR fragments. Overall, 7.9% of nonhuman primate bushmeat is infected with STLVs. We documented new STLV-1 and STLV-3 variants in six out of the seven species tested and showed for the first time STLV infection in C. mona wolfi, C. ascanius whitesidei, L. aterrimus aterrimus, C. angolensis, and P. tholloni. Our results provide increasing evidence that the diversity and geographic distribution of PTLVs are much greater than previously thought. PMID- 21827289 TI - Comparative study of composition and biological activities of SDE prepared essential oils from flowers and fruits of two Hypericum species from central Iran. AB - Essential oil (EO) compositions of flowers and fruits of Hypericum perforatum L. and Hypericum scabrum L. growing wild in Kashan, central Iran, were determined by simultaneous steam distillation-solvent extraction method and analysed using GC MS technique. Analysis revealed 28 identified compounds for H. perforatum, with two main components being alpha-pinene (25.36%) and alpha-amorphene (12.12%). Thirty-five compounds were identified in H. scabrum L. representing 98.60% of the oil with alpha-pinene (70.21%) and p-mentha-1,5-dien-8-ol (2.89%) as main components. Some new compounds were found in significant quantities which were not found in other chemotypes. The antioxidant activities of the EOs evaluated for the first time in this study using beta-carotene bleaching and DPPH assays seemed to be attributed directly to alpha-pinene contents in them. Antibacterial activities of both mentioned EOs were higher than that of their main constituent, alpha-pinene, against Staphylococcus aureus and Escherichia coli. PMID- 21827290 TI - Analysis of peripheral T cells and the CC chemokine receptor (CCR5) delta32 polymorphism in prostate cancer patients treated with carboxymethyl-glucan (CM G). AB - beta-Glucan, derived from Saccharomyces cerevisiae, is a biological response modifier which affects the innate and adaptive immune responses. The CCR5 chemokine receptor is crucial for immune cell responses. In this study, the effects of the carboxymethylated form of beta-glucan (CM-G) on the lymphocyte population of CCR5 genotype patients with prostate cancer (PCa), undergoing androgen deprivation therapy (ADT) was assessed. The CCR5 genotype and lymphocyte population was investigated by cytometry flow in 30 Brazilian patients with advanced PCa who were treated with CM-G for 28 days. The analysis of the CCR5 chemokine receptor revealed that the wild-type genotype Wt/Wt was present in 80% of patients, while the heterozygotic genotype Wt/delta32 was present in 20% of patients. After CM-G administration, a significant increase in CD3(+), CD4(+) and CD8(+) T lymphocytes was observed in patients who displayed the wild-type genotype for the CCR5 chemokine receptor. No association was found between patient's age or length of ADT and increase in T lymphocyte cells. The results demonstrated the ability of CM-G to stimulate CD4(+) and CD8(+) T cells in the peripheral blood of patients carrying a wild-type CCR5 genotype, suggesting an interaction between immunomodulation by CM-G and the CCR5 receptor. PMID- 21827291 TI - Self-regulation versus habit: the influence of self-schema on fruit and vegetable consumption. AB - The aim of this study is to examine the determinants of fruit and vegetable (F&V) consumption with the application of the Theory of Planned Behaviour (TPB) and the additional variables of self-schema, habit and self-regulation. While it has been shown that those with a healthy-eater self-schema are more likely to carry out their healthy dietary intentions, the underlying processes that influence this relationship have received limited empirical attention. Recent findings on dietary behaviour suggest that self-regulatory ability and habit strength may have dissimilar effects on the intention-behaviour relationship within schematics and non-schematics. Self-report questionnaires regarding F&V consumption cognitions and two tests of self-regulation were administered to 209 university students. One week later, participants completed questionnaires on their behaviour. The TPB significantly predicted intentions and prospective behaviour. Self-schema did not moderate the relationship between intention and behaviour. However, within healthy-eater schematics, those with high intention and high self regulatory ability were more likely to consume F&V, while within non-schematics, those with low intention and high habit strength were more likely to consume F&V. The findings support the use of the TPB in predicting F&V consumption and the validity of the self-schema distinction. Implications for designing interventions are discussed. PMID- 21827292 TI - A study on multiple drowning syndromes. AB - Non-intentional drowning incidents remain a leading cause of mortality in Turkey as well as all over the world. A following related secondary syndrome is composed of those who drown during altruistic attempts to rescue a drowning person. Such 'rescuers' who attempt to rescue a drowning person, may themselves drown, resulting in a tragic multiple death. This study covers the year 2009, and necessary data was found by using internet search engines to identify cases in which a potential rescue attempt resulted with the rescuer's fatal drowning. Thirty-one 'rescuers' and 20 primary drowning victims (PDV) drowned in 28 incidents in which 80% of drowned primary victims (DPV) were children, and 48.4% of the 'rescuers' were children. In 48.4% of the 'rescuers' succeeded in rescuing the PDV's life. Out of them, 38.7% of the 'rescuers' and PDVs were friends/colleagues. The aim of this study is to define and examine multiple drowning syndromes (MDSs) and to suggest preventative measures. An increased awareness of such risks as promotion of swimming and rescue skills could help reducing the MDSs. PMID- 21827293 TI - A qualitative approach to the intangible cost of road traffic injuries. AB - The consequences of fatal and non-fatal road traffic injuries (RTI) at the personal and household levels were analysed using qualitative interviews of 12 injured and of 12 relatives of people who died for this reason. Collisions change physical and mental health both of the injured and of their relatives. This leads to changes in daily activities and even to the redefinition of future life. RTI also changes the way people see and act in life, becoming an experience that teaches them. Survivors commonly transmit a road safety message afterwards. Changes in family life were evident (in extreme cases family's composition also changed), affecting intra-familial relationships. Associated unexpected and unplanned expenditures and loss of income have consequences in the short, medium and long term that unbalance household's economies and immerse people into a constant stress. Individuals and family's future plans are occasionally condition to whether they have or not debts. Household dependence in economic terms was sometimes observed, as well as uncertainty about future life and household's sustainability. Sometimes, households change and adapt their life to what they now are able to afford, having important repercussions in vital spheres. PMID- 21827294 TI - The neural correlates of Fitts's law in action observation: an fMRI study. AB - Previous neuroimaging studies support the assumption of a strong link between perception and action, demonstrating that the motor system is involved when others' actions are observed. One question that is still open to debate is which aspects of observed actions engage the motor system. The present study tested whether motor activation corresponds to the difficulty of the observed action, using Fitts's law. This law postulates that the difficulty of any movement (ID) is a function of the distance to the target (A) and the target width (W). In an observation task, the ID of the observed action was manipulated orthogonally to W (by using five different As). The results revealed activity in the primary motor cortex, the supplementary motor area, and the basal ganglia in response to increasing ID levels, but not in response to different levels of A or W. Thus, activation in the motor system during action observation is not driven by perceptual parameters but by the motor difficulty of the observed action. PMID- 21827295 TI - Genetic variation of myeloperoxidase gene contributes to preeclampsia: a preliminary association study in Turkish population. AB - OBJECTIVE: To examine MPO gene polymorphisms of women with preeclampsia in Turkish population. METHODS: Sixty-one preeclamptic and 61 normotensive women without history of preeclampsia in earlier pregnancies were enrolled in this prospective controlled study. MPO mutations were characterized by PCR-RFLP method. RESULTS: We demonstrated a significant difference in patients with preeclampsia in terms of genotype frequency. Heterozygous carriers of -463A among preeclamptic pregnancies were significantly frequent, whereas rare A/A homozygotes failed to differ from controls. CONCLUSION: The -463G/A polymorphism of leukocyte MPO could be an intriguing susceptibility factor that modulates an individual's risk of preeclampsia in Turkish population. PMID- 21827296 TI - Inhibition of mitochondrial respiration and rapid depletion of mitochondrial glutathione by beta-phenethyl isothiocyanate: mechanisms for anti-leukemia activity. AB - AIMS: beta-Phenethyl isothiocyanate (PEITC) is a natural product with potent anticancer activity against human leukemia cells including drug-resistant primary leukemia cells from patients. This study aimed at investigating the key mechanisms that contribute to the potent anti-leukemia activity of PEITC and at evaluating its therapeutic potential. RESULTS: Our study showed that PEITC caused a rapid depletion of mitochondrial glutathione (GSH) and a significant elevation of reactive oxygen species (ROS) and nitric oxide, and induced a disruption of the mitochondrial electron transport complex I manifested by an early degradation of NADH dehydrogenase Fe-S protein-3 and a significant suppression of mitochondrial respiration. Using biochemical and pharmacological approaches, we further showed that inhibition of mitochondrial respiration alone by rotenone caused only a moderate cytotoxicity in leukemia cells, whereas a combination of respiratory inhibition and an ROS-generating agent exhibited a synergistic effect against leukemia and lymphoma cells. INNOVATION AND CONCLUSION: Although PEITC is a reactive compound and might have multiple mechanisms of action, we showed that a rapid depletion of GSH and inhibition of mitochondrial respiration are two important early events that induced synergistic cytotoxicity in leukemia cells. These findings not only suggest that PEITC is a promising compound for potential use in leukemia treatment, but also provide a basis for developing new therapeutic strategies to effectively kill leukemia cells by using a novel combination to modulate ROS and inhibit mitochondrial respiration. PMID- 21827297 TI - Is there a role for isofurans and neuroprostanes in pre-eclampsia and normal pregnancy? AB - Pre-eclampsia is a complex disorder of pregnancy that adversely affects the mother and baby. Arachidonic acid and docosahexaenoic acid are essential for fetal development and can undergo free radical oxidation to F(2)-isoprostanes (F(2)-IsoPs) and isofurans (IsoFs); and F(4)-neuroprostanes (F(4)-NeuroPs), respectively. These metabolites may be relevant to pre-eclampsia and fetal development. We examined IsoFs, F(4)-NeuroPs, and F(2)-IsoPs in maternal plasma and cord blood plasma of 23 women with pre-eclampsia and 21 normal pregnancies. Women with pre-eclampsia had significantly elevated maternal IsoFs and F(4) NeuroPs, but not F(2)-IsoPs. Cord blood F(4)-NeuroPs were elevated among neonates of women with pre-eclampsia. In women with pre-eclampsia, birth weight was predicted by gestation at delivery. The latter was also true in normal pregnancy, but birth weight was negatively related to maternal F(2)-IsoPs, IsoFs, and F(4) NeuroPs. We have shown that in women with pre-eclampsia, IsoFs and F(4)-NeuroPs are elevated, and cord blood F(4)-NeuroPs are increased. The inverse relationship between maternal F(2)-IsoPs, IsoFs, and F(4)-NeuroPs and birth weight may be relevant as predictors of low birth weight in normal pregnancy. Future studies should examine whether these markers in maternal blood at early stages of pregnancy relate to subsequent maternal, fetal, and neonatal complications. PMID- 21827299 TI - Women and men with intellectual disabilities who sell or trade sex: voices from the professionals. AB - The phenomenon of women and men with intellectual disabilities (ID) selling or exchanging sexual services is poorly understood. In this study, the authors explored the knowledge and perceptions of this phenomenon shared by professionals working in the field. Focus group discussions demonstrated broad familiarity with the phenomenon. Different motives and contributing factors were identified for the behavior, blurring the boundary line between free choice and exploitation. Two distinct discourses emerged from the interviews based on the assumed "rationality" of the sex transaction and its rewards: Those with ID who traded sexual favors were presented as either conscious and autonomous agents or unaware and exploited victims. PMID- 21827298 TI - Clinical and economic burden of depression/anxiety in chronic obstructive pulmonary disease patients within a managed care population. AB - BACKGROUND: Anxiety and depression are common co-morbidities that can complicate the course of chronic obstructive pulmonary disease (COPD). The purpose of this study was to evaluate their impact on healthcare utilization and costs in a managed care COPD population. METHODS: Administrative claims data were used to conduct a retrospective cohort study of COPD patients >= 40 years of age, including those with co-morbid COPD-Depression (including anxiety). COPD Depression patients were matched to COPD patients without depression (COPD-Only cohort) using propensity scores. Conditional logistic regression models assessed the 1-year risk of COPD exacerbations (i.e., emergency room [ER] visit/inpatient hospitalization) between cohorts. Differences in annual all-cause and COPD related utilization/costs, along with 2-year costs, were also compared between the cohorts. RESULTS: There were 3,761 patients per cohort. Patients in the COPD Depression cohort were 77% more likely to have a COPD-related hospitalization (odds ratio [OR] = 1.77, P < 0.001), 48% more likely to have an ER visit (OR = 1.48, P < 0.001), and 60% more likely to have hospitalization/ER visit (OR = 1.60, P < 0.001) compared to the COPD-Only cohort. Average annual all-cause medical cost per patient was $23,759 for COPD-Depression vs $17,765 for COPD-Only (P < 0.001) and total (medical plus pharmacy) cost was $28,961 vs $22,512 (P < 0.001), respectively; corresponding average annual COPD-related medical cost was $2,040 vs $1,392 (P < 0.001) and total cost was $3,185 vs $2,680 (P < 0.001). Similar trends were observed over the 2-year period. CONCLUSIONS: In the COPD population, patients with depression/anxiety have significantly higher risk of COPD exacerbations and annual all-cause and COPD-related costs than patients without these co-morbidities. These findings may have therapeutic implications and seem worthy of further exploration. PMID- 21827300 TI - Student perceptions of progress in a postsecondary residential program for adults with learning disabilities. AB - In recent years, residential postsecondary schools have been created to help adults who have completed high school, but need more assistance to make the transition to college or a career. The purpose of this study is to understand the subjective experiences of students at one such facility. Using qualitative methodology, 16 adult students were interviewed to identify areas in which they have made progress toward their goal of living independently. Students acknowledged gains in the areas of social and emotional growth, employment training, academic achievement, and independent living skill development. The results suggest that a residential postsecondary intervention is beneficial for adults with learning disabilities. PMID- 21827301 TI - Interpersonal violence against people with disabilities: understanding the problem from a rural context. AB - Interpersonal violence against people with disabilities is a significant social problem. Little attention has focused on the rural context and the relevance for understanding violence. Given the dearth of literature exploring interpersonal violence, disability, and rurality, a review of rural-focused literature on domestic violence, sexual violence, and elder abuse was conducted to identify themes that could provide insight into this problem for people with disabilities. Themes include geographic isolation, traditional cultural values and norms, lack of anonymity, lack of resources, and poor response of systems. Implications for understanding interpersonal violence against rural people with disabilities and for social work practice are discussed. PMID- 21827302 TI - The fabric of engagement: the engagement and personality of managers and professionals in human and developmental disability services. AB - Employee engagement is a complex and dynamic process that reflects each individual's unique, personal relationship with work. Engaged employees have a clear and defining connection to the organization's mission and purpose, and employee engagement is reflected in behaviors that meet or exceed expectations of service in the workplace. The purpose of this study was to explore relationships between personality and engagement among professionals and managers providing services to people with developmental disabilities. In particular, the authors investigated relationships between the 5-factor model of personality (FFM) and William Kahn's model of employee engagement encompassing physical, emotional, and cognitive components. PMID- 21827303 TI - Evidence-based practice knowledge and utilization among social workers. AB - In this study the researchers examined the knowledge, skills, and use of Evidence Based Practice in a sample of social workers from different practice settings. Using an electronic survey, data were collected from a group of social work practitioners (N = 200). Participants in their 30s and 40s demonstrated the most knowledge and use of Evidence-Based Practice. In addition, a high percentage of social workers reported to be knowledgeable about social work research databases; a smaller percentage actually used online resources in their practice. Through this study the researchers add to what is currently known about social workers' perceptions, knowledge, and use of Evidence-Based Practice. PMID- 21827304 TI - Quality of abstracts in the context of a systematic review on parenting of children with chronic health conditions and disabilities. AB - In this study the authors address the quality of abstracts reviewed during a systematic review. Their objective was to describe the proportion of abstracts that could not be coded and to explore factors associated with that outcome. Using an exploratory design, a database of titles uploaded for analysis was examined for clarity, type and year of publication, and abstract format. Of the 1851 references examined, 481 (26%) were coded as unclear. The inter-rater reliability Kappa score was 0.777. These abstracts were more likely to have been published prior to 2002 and did not use a structured format. Abstracts are an important tool in the systematic review process. Structured abstracts can reduce the time and costs associated with conducting a systematic review. PMID- 21827305 TI - Intervention fidelity in psychosocial oncology. AB - Intervention fidelity refers to strategies that practitioners and researchers use to monitor, enhance, or evaluate the accuracy and consistency of the delivery of an intervention to ensure that it is implemented according to how it was planned. The purpose of the authors in this article was to evaluate intervention fidelity in the psychosocial oncology intervention effectiveness research. Twenty-eight studies located in a previous systematic review on psychosocial oncology intervention effectiveness comprised the sample for this research. A treatment fidelity checklist was applied to each study independently by each author (MP & PB). Percent agreement between raters ranged from 68% to 100% (M = 89%). Overall, the mean proportion of adherence was 0.57 (SD 0.12), which may be considered to be moderate fidelity. Critical examination and applicability of the checklist in examining and assessing intervention fidelity were highlighted and discussed. Overall, intervention fidelity was adequately addressed in the psychosocial oncology intervention effectiveness research, and integrity was confirmed in the majority of studies reviewed. Suggestions for future psychosocial oncology effectiveness research were made. PMID- 21827306 TI - Low effect sizes of evidence-based programs in school settings. AB - School practitioners working from an evidence-based practice framework are expected to implement interventions that are effective with students. In the current study, the authors explore the feasibility of that expectation in light of the availability of critical effect size information necessary for making informed intervention decisions. Effect sizes for 51 school-based programs endorsed as effective by authoritative sources were reviewed. Effect size analyses reveal that the programs were not, on average, highly effective. Difficulties finding effect size information and programs with high effect sizes are discussed. Recent advances in evidence-based programs and suggestions for increasing the feasibility of evidence-based programs in schools are offered. PMID- 21827307 TI - Evidence-based practice with families of chronically ill children: a critical literature review. AB - A chronically ill child is financially, emotionally, and physically demanding on the family system. Although researchers have identified a plethora of risks, stressors, and needs of the families with a chronically ill child, there is a scarceness of evidence-based interventions in the existing literature. The purpose of the authors in this study was to critically analyze current treatment and identify the gaps in the available research. Findings revealed that there is a lack of support for empirically tested interventions that can help parents, siblings, and families of chronically ill children. The issues raised within this literature review bring attention to the need for shifts in research from exploratory to evidence based in order to successfully achieve more effective care. PMID- 21827308 TI - The effects of ethnocultural empathy on level of stereotyping toward college athletes. AB - In the current study the author examined whether ethnocultural empathy affects people's beliefs and expectations regarding athletes, hypothesizing that (1) individuals demonstrating a high level of ethnocultural empathy would be less likely to endorse stereotypes toward athletes, (2) females would be less likely to stereotype toward athletes than would males, (3) athletes would be less likely to stereotype toward athletes than would non-athletes, and (4) behavioral science majors would be less likely to stereotype toward athletes than would non behavioral science majors. As predicted, participants high on ethnocultural empathy were less likely to stereotype towards athletes, females were less likely to stereotype toward athletes than were males, and behavioral science majors were less likely to stereotype toward athletes than were non-behavioral science majors. However, contrary to the hypotheses, athletes were more likely to stereotype toward their own in-group than were non-athletes. PMID- 21827309 TI - Analysis of suspected suicides using poison center data. AB - Although there has been extensive research into the epidemiology and prevention of suicide, there continues to be a paucity of research on non-fatal suicides, in particular persons not treated in hospitals following a suicide attempt. In this study, we analyzed call data from the Illinois Poison Center from 2002 to 2007, which primarily comprises of non-fatal hospitalized and non-hospitalized attempts. We analyzed 43,057 calls by persons suspected of attempting suicide. The three most common groups of substances used were analgesics, antidepressants, and sedative/hypnotics/antipsychotics. The Poisson regression model showed significant declines in calls for suspected suicides during periods of holidays and vacations, and was more pronounced among youths. This study provides a current and detailed description of substances used primarily in non-fatal suicide attempts. PMID- 21827310 TI - Offering support to suicidal individuals in an online support group. AB - The objective of this study was to reveal response strategies to suicidal messages and to examine the relationships between the messages and types of responses in an online support group moderated by volunteers within an interpersonal perspective of the Action Theory. This theory posits that individuals actively impact their social environment, which in turn shapes their development and mental health. In the study, 120 interactions were analyzed to identify characteristics of the message and strategies of response. The analysis yielded 8 strategies employed by the volunteers in response to the suicidal messages. Hypothesized relationships between those strategies and characteristics of suicidal messages were found. The results suggest that online support groups enable suicidal individuals to generate an environment that provides emotional support, and offer alternatives to the suicidal view. PMID- 21827312 TI - Deliberate self-harm/poisoning, suicide trends. The link to increased alcohol consumption in Sri Lanka. AB - Sri Lanka has witnessed a fall in suicide rates in the period 1991 to 2010, however the incidence of self-harm remains high. Over the same period alcohol consumption has increased for both alcohol that is purchased legally and distilled privately. This paper investigates a number of secondary data sets from such bodies as the Department of Police, Registrar General's Office for Statistics, Ministry of Health and Nutrition, National Poisons Information Center and Lanka Library Forum to shed light on the link between suicide/self-harm and rising alcohol consumption. The authors conclude that there is a strong association between alcohol consumption and suicide/poisoning/deliberate self harm in Sri Lanka and propose a number of research priorities. PMID- 21827311 TI - Risk for suicidal ideation among the offspring of bipolar parents: results from the Bipolar Offspring Study (BIOS). AB - The objective of the study was to examine rates and identify risk factors for suicidal ideation among offspring of parents with bipolar disorder. Subjects included 388 offspring of parents with bipolar disorder and 250 offspring of matched community controls enrolled in the Pittsburgh Bipolar Offspring Study (BIOS). Offspring of bipolar probands displayed greater rates of lifetime suicidal ideation than offspring of controls (33% versus 20%). Factors most strongly associated with lifetime suicidal ideation in offspring of bipolar parents included offspring mood disorder, hostility, recent sexual abuse, and family conflict. Offspring of parents with bipolar disorder are at elevated risk for suicidal ideation as compared with offspring of controls. Suicide risk assessment in this population should attend to specific risk factors identified. PMID- 21827313 TI - Suicide by self-burning in Iraqi Kurdistan: description and risk factors. AB - This study aims to provide evidence for the problem of suicide by self-burning in Iraqi Kurdistan. Data were collected prospectively from all patients admitted to the burn center in the province of Sulaymaniyah and cases of self-burning were compared with cases of accidental burns. There were 197 cases with an annual incidence rate of 8.4 per 100,000 per year and female to male risk ratio of 13.1. Independent risk factors for self-burning were female sex (odds ratio 13.75, 95% CI 6.91-27.36, P < 0.001); young age of 11 to 18 years (OR 3.92, 95% CI 2.20-7.0, P < 0.001); poor education (OR 2.50, 95% CI 1.15-5.45, P = 0.02); spring season (OR 2.39, 95% CI 1.3-4.41, P = 0.005); and small family size (OR 2.72, 95% CI 1.44-5.15, P = 0.002). Suicide by self-burning is common in Iraqi Kurdistan especially among women. Urgent action is required to provide a better understanding of the situation, and identify partners, capacities, and opportunities for action. PMID- 21827314 TI - A psychometric study of the Suicide Ideation Scale. AB - An exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) were conducted on the Suicide Ideation Scale (SIS) with a large military clinical sample (total N = 3,072). The EFA identified a two-factor solution with the first factor (Resolved Plans/Preparation) accounting for 17.3% of the variance and the second (Suicidal Desire) accounting 15.1% of the variance. This 2-factor solution demonstrated a good fit to the data in the CFA. SIS construct validity and internal reliability data are also reported. The results of this study provide additional psychometric data for the SIS that support use of the measure in clinical work and research. Implications for theories related to suicide assessment and clinical practice are discussed. PMID- 21827315 TI - Training mental healthcare providers to reduce at-risk patients' access to lethal means of suicide: evaluation of the CALM Project. AB - The objective of this study was to evaluate the "CALM" (Counseling on Access to Lethal Means) training, in which community-based mental health care providers were trained to work with at-risk clients and their families to assess and reduce access to lethal means of suicide, including firearms. In 2006, CALM trainers conducted workshops in 7 community-based mental health care centers in New Hampshire towns. Participants completed a post-test immediately after the workshop and a follow-up questionnaire approximately 6 weeks later. At follow-up, 65% reported that they had counseled clients' parents about access to lethal means (n = 111). Findings also indicate that the workshop influenced participants' attitudes, beliefs, and skills regarding conducting lethal means counseling. PMID- 21827316 TI - Differences between youth with a single suicide attempt and repeaters regarding their and their parents history of psychiatric illness. AB - The objective of this study was to determine predictors of repeated suicide attempts in young people, focusing on psychiatric illness. A longitudinal population-based register study of all adolescents born in Denmark between 1984 and 2006 was conducted. Greater numbers of hospitalizations, psychiatric diagnoses, and psychopharmacological medications prescribed to youth before and after the index attempt were risk factors for repeated suicide attempts. Parental diagnoses and drug prescriptions following a child's first suicide attempt moderated the risk of repeated attempts. Psychiatric illness is a strong predictor of repeated suicide attempts in young people, and those with co-morbid diagnoses are at increased risk of repeated suicide attempts. Treatment of psychiatric illness in the parents after their child's first suicide attempt is a potential protective factor. PMID- 21827317 TI - Trends in explicit portrayal of suicidal behavior in popular U.S. movies, 1950 2006. AB - Trends in suicidal behavior portrayal in movies may reflect greater societal acceptance of suicide with potential adverse effects on adolescents. To assess the potential for such adverse effects, explicit portrayals of suicidal behavior and the ratings of films were coded in top-grossing U.S. movies from 1950-2006 (N = 855). Suicidal behavior portrayal in films increased linearly from 1950 to 2006. From 1968-1984, movies rated R by the Motion Picture Association of America had 5 times more highly explicit suicide behavior portrayals than did G/PG films. After the adoption of the PG-13 category in 1985, PG-13 and R films were indistinguishable on this measure. The results indicate the need for further study of the effects of suicidal behavior portrayals on adolescent movie audiences. PMID- 21827318 TI - Prevention of hypoglycemia by using low glucose suspend function in sensor augmented pump therapy. AB - BACKGROUND: Severe hypoglycemic episodes are a barrier for achieving optimal glycemic control. Sensor-augmented pump (SAP) therapy with insulin in combination with a novel mechanism of automatic insulin shutoff (low glucose suspend [LGS]) can be used to prevent and reduce hypoglycemia. In a prospective study, we investigated the effect of the LGS algorithm on the frequency of hypoglycemia in children and adolescents with type 1 diabetes under real-life conditions. METHODS: Twenty-one patients with type 1 diabetes (10.8+/-3.8 years old, duration of diabetes 5.9+/-3.0 years, pump therapy for 3.7+/-1.7 years, glycated hemoglobin level 7.8+/-1.1%) from three pediatric centers used the Paradigm((r)) Veo(TM) system (Medtronic Minimed, Northridge, CA) during two subseqent time periods: SAP without LGS for 2 weeks and then SAP with LGS enabled for 6 weeks. The primary objective was to assess the frequency of hypoglycemic episodes when using the LGS feature with an insulin delivery shutoff of a maximum of 2 h at a sensor glucose level below 70 mg/dL (3.9 mmol/L). RESULTS: In total, 1,298 LGS alerts occurred (853 shorter than 5 min). Forty-two percent of LGS activations (>5 min) lasted less than 30 min, whereas 24% had a duration of 2 h. The number of hypoglycemic excursions (average/day) was reduced during SAP+LGS (<70 mg/L, 1.27+/-0.75 vs. 0.95+/-0.49, P=0.010; <=40 mg/dL, 0.28+/-0.18 vs. 0.13+/-0.14, P=0.005) as was the time spent in hypoglycemia (average minutes/day, 101+/-68 vs. 58+/-33, P=0.002) without significant difference in the mean glucose level (145+/ 23 vs. 148+/-19 mg/dL). No episodes of severe hyperglycemia or diabetic ketoacidosis were observed following LGS activation. CONCLUSIONS: The present investigation provides evidence that SAP with LGS reduces the frequency of hypoglycemia without compromising safety. PMID- 21827319 TI - Coefficient of variation for hemoglobin A1c results that are traceable to national glycohemoglobin standardization program must be distinguished from coefficient of variation for results traceable to International Federation of Clinical Chemistry and Laboratory Medicine. PMID- 21827320 TI - Are meals at full-service and fast-food restaurants "normal" or "inferior"? AB - Whereas some studies show statistically significant linear associations between consumption at full-service restaurants and consumer incomes, studies of fast food restaurants fail to find statistically significant linear associations. In this study, nationally representative data were drawn from the 1994-1996 Continuing Survey of Food Intakes by Individuals and the accompanying Diet and Health Knowledge Survey. The sample contained 4972 individuals who were 21 years of age or older. Dependent variables measured number of restaurant visits on 2 nonconsecutive days. Income was total annual household income. Control variables reflected sociodemographic, economic, lifestyle, and attitudinal variables. To capture possible curvilinear relationships between income and food consumption, we analyzed frequency distributions, regressions on full samples including income squared, and we divided samples into above- and below-average income groups. Zero inflated negative binomial regressions accounted for excessive zeros within dependent variables. We found that fast-food restaurants were "normal goods" for below-average income, but "inferior goods" for above-average income, whereas full service restaurants were "normal" for virtually all income levels. Earlier studies were flawed because they only tested for linear associations. Our results have implications for the poverty and obesity debate. PMID- 21827321 TI - Systems vaccinomics: the road ahead for vaccinology. PMID- 21827322 TI - In vitro manipulation of mammalian preimplantation embryos can alter transcript abundance of histone variants and associated factors. AB - Manipulation of mammalian embryos and gametes in vitro reduces viability. Specific causes for these reductions are still largely undetermined. Accumulating evidence suggests that survival rates and developmental competency may be reduced following disruptions in the epigenetic regulation of gene expression. Chromatin based epigenetics can regulate the transcriptome through the establishment of different transcriptionally permissive and repressive chromatin environments. Recently, support has been gathering for the hypothesis that the in vitro embryo displays reduced viability due to abnormal remodelling of the paternal chromatin, which is hypothesized to result in global transcriptional repression. In this study, we have used quantitative real-time PCR to document the effect of in vitro culture on the transcription of genes that code for proteins that are directly involved in the establishment of chromatin environments. We compare in vitro embryos to embryos generated through parthenogenetic activation to determine how the absence of paternal chromatin remodeling affects transcriptional activity. Through these studies, we show that the expression of many genes encoding for histone proteins and other modifiers involved in chromatin-based epigenetic regulation are perturbed by in vitro culture. In addition, we show that the expression of many candidate genes was reduced in in vitro embryos but not in parthenogenetic embryos. These results support the hypothesis that events linked to remodeling of paternal chromatin may influence transcriptional activity in the in vitro embryo and that chromatin-based reprogramming events in developing embryos are dynamically responsive to prevailing conditions. PMID- 21827323 TI - JAK-1 rs2780895 C-related genotype and allele but not JAK-1 rs10789166, rs4916008, rs2780885, rs17127114, and rs3806277 are associated with higher susceptibility to asthma. AB - BACKGROUND: Asthma, one major respiratory consequence, might be caused by a complex interaction between multiple candidate genes and environmental factors. Herein, we aimed to investigate whether Janus kinase (JAK)-1 gene polymorphisms are associated with asthma susceptibility. MATERIALS AND METHODS: Patients were divided into two groups: (1) asthma (n=117) and (2) nonasthma (n=60). The JAK-1 polymorphisms (rs2780895, rs10789166, rs4916008, rs2780885, rs17127114, and rs3806277) were amplified by polymerase chain reaction and detected by electrophoresis after restriction enzyme (HpyCH4IV, Tsp45I, HpaII, XmnI, MspI, and HpaII) digestions. Genotypes, allelic frequencies, and association of haplotypes in both groups were compared. RESULTS: JAK-1 rs2780895 gene polymorphism is associated with susceptibility to asthma. Distributions of JAK-1 rs2780895*CC/CT/TT and C/T allele in both groups are: (1) 80/4/16% and 82/18%; (2) 48/45/7% and 71/29%. Other 5 JAK-1 SNPs (rs10789166, rs4916008, rs2780885, rs17127114, and rs3806277) are not associated with asthma susceptibilities. Distributions of JAK-1 rs10789166*AA/AG/GG, rs4916008*CC/CT/TT, rs2780885*CC/CT/TT, rs17127114*AA/AG/GG, rs3806277*AA/AG/GG in both groups are: (1) 50/40/10%, 42/49/9%, 50/40/10%, 9/37/54%, 8/35/57%; (2) 43/50/7%, 40/50/10%, 50/43/7%, 7/48/45%, 6/42/52%. Haplotype analyses for JAK-1 gene polymorphisms (rs2780895-rs10789166-rs4916008-rs2780885-rs17127114-rs3806277) revealed that JAK 1 haplotypes are not associated with asthma susceptibilities. CONCLUSIONS: JAK-1 rs2780895 C-related genotype and allele are associated with higher susceptibility to asthma. JAK-1 rs10789166, rs4916008, rs2780885, rs17127114, and rs3806277 single-nucleotide polymorphisms are not associated with asthma development. Some JAK-related genetic variations might be associated with asthma pathogenesis, which deserve further surveys. PMID- 21827326 TI - Public anxiety and information seeking following the H1N1 outbreak: blogs, newspaper articles, and Wikipedia visits. AB - Web-based methodologies may provide a new and unique insight into public response to an infectious disease outbreak. This naturalistic study investigates the effectiveness of new web-based methodologies in assessing anxiety and information seeking in response to the 2009 H1N1 outbreak by examining language use in weblogs ("blogs"), newspaper articles, and web-based information seeking. Language use in blogs and newspaper articles was assessed using Linguistic Inquiry and Word Count, and information seeking was examined using the number of daily visits to H1N1-relevant Wikipedia articles. The results show that blogs mentioning "swine flu" used significantly higher levels of anxiety, health, and death words and lower levels of positive emotion words than control blogs. Change in language use on blogs was strongly related to change in language use in newspaper coverage for the same day. Both the measure of anxiety in blogs mentioning "swine flu" and the number of Wikipedia visits followed similar trajectories, peaking shortly after the announcement of H1N1 and then declining rapidly. Anxiety measured in blogs preceded information seeking on Wikipedia. These results show that the public reaction to H1N1 was rapid and short-lived. This research suggests that analysis of web behavior can provide a source of naturalistic data on the level and changing pattern of public anxiety and information seeking following the outbreak of a public health emergency. PMID- 21827327 TI - In vitro metabolic interactions between black cohosh (Cimicifuga racemosa) and tamoxifen via inhibition of cytochromes P450 2D6 and 3A4. AB - Women who experience hot flashes as a side effect of tamoxifen (TAM) therapy often try botanical remedies such as black cohosh to alleviate these symptoms. Since pharmacological activity of TAM is dependent on the metabolic conversion into active metabolites by the action of cytochromes P450 2D6 (CYP2D6) and 3A4, the objective of this study was to evaluate whether black cohosh extracts can inhibit formation of active TAM metabolites and possibly reduce its clinical efficacy. At 50 MUg/mL, a 75% ethanolic extract of black cohosh inhibited formation of 4-hydroxy- TAM by 66.3%, N-desmethyl TAM by 74.6% and alpha-hydroxy TAM by 80.3%. In addition, using midazolam and dextromethorphan as probe substrates, this extract inhibited CYP3A4 and CYP2D6 with IC(50) values of 16.5 and 50.1 MUg/mL, respectively. Eight triterpene glycosides were identified as competitive CYP3A4 inhibitors with IC(50) values ranging from 2.3-5.1 uM, while the alkaloids protopine and allocryptopine were identified as competitive CYP2D6 inhibitors with K(i) values of 78 and 122 nM, respectively. The results of this study suggests that co-administration of black cohosh with TAM might interfere with the clinical efficacy of this drug. However, additional clinical studies are needed to determine the clinical significance of these in vitro results. PMID- 21827325 TI - Nonmalignant diseases and treatments associated with primary ovarian failure: an expanded role for fertility preservation. AB - Cancer treatments can be detrimental to fertility; recent literature has focused on the efforts of fertility preservation for this patient population. It should be recognized, however, that several nonmalignant medical conditions and therapeutic interventions could be similarly hazardous to fertility. Some of these nonmalignant diseases and their treatments that can adversely impact the reproductive axis are gastrointestinal diseases, rheumatologic disorders, nonmalignant hematologic conditions, neurologic disorders, renal disorders, gynecologic conditions, and metabolic diseases. Their negative effects on reproductive function are only now being appreciated and include impaired ovarian function, endocrine function, or sexual function and inability to carry a pregnancy to term. Complications and comorbidities associated with certain diseases may limit the success of established fertility preservation options. Recent advances in fertility preservation techniques may provide these patients with new options for childbearing. Here, we review several fertility-threatening conditions and treatments, describe current established and experimental fertility preservation options, and present three initiatives that may help minimize the adverse reproductive effects of these medical conditions and treatments by raising awareness of the issues and options: (1) increase awareness among practitioners about the reproductive consequences of specific diseases and treatments, (2) facilitate referral of patients to fertility-sparing or restorative programs, and (3) provide patient education about the risk of infertility at the time of diagnosis before initiation of treatment. PMID- 21827328 TI - Sugar composition of the moss Rhodobryum ontariense (Kindb.) Kindb. AB - Although the second biggest terrestrial group of plants, bryophytes remain poorly known chemically compared to the angiosperms. In this article, the sugars of the moss Rhodobryum ontariense, an unstudied representative of the medicinally known genus, are reported. The chemical analysis revealed the usual plant sugar sucrose, and a new sugar, fructooligosaccharide 1-kestose, which is reported first not only for the genus Rhodobryum, but also for mosses. The trisaccharides have been scantily reported in bryophytes hitherto. This gives more significance to this study for further investigation of its role in the moss species. The health-promoting effect of 1-kestose is also briefly discussed. PMID- 21827329 TI - Essential oil composition and antiradical activity of the oil of Iraq plants. AB - This study examined the antiradical activity and chemical composition of essential oils of some plants grown in Mosul, Iraq. The essential oils of myrtle and parsley seed contained alpha-pinene (36.08% and 22.89%, respectively) as main constituents. Trans-Anethole was the major compound found in fennel and aniseed oils (66.98% and 93.51%, respectively). The dominant constituent of celery seed oil was limonene (76.63%). Diallyl disulphide was identified as the major component in garlic oil (36.51%). Antiradical activity was higher in garlic oil (76.63%) and lower in myrtle oil (39.23%). The results may suggest that some essential oils from Iraq possess compounds with antiradical activity, and these oils can be used as natural antioxidants in food applications. PMID- 21827331 TI - Me against we: in-group transgression, collective shame, and in-group-directed hostility. AB - People can experience great distress when a group to which they belong (in-group) is perceived to have committed an immoral act. We hypothesised that people would direct hostility toward a transgressing in-group whose actions threaten their self-image and evoke collective shame. Consistent with this theorising, three studies found that reminders of in-group transgression provoked several expressions of in-group-directed hostility, including in-group-directed hostile emotion (Studies 1 and 2), in-group-directed derogation (Study 2), and in-group directed punishment (Study 3). Across studies, collective shame-but not the related group-based emotion collective guilt-mediated the relationship between in group transgression and in-group-directed hostility. Implications for group-based emotion, social identity, and group behaviour are discussed. PMID- 21827332 TI - In the beginning: role of autonomy support on the motivation, mental health and intentions of participants entering an exercise referral scheme. AB - Self-determination theory (Deci & Ryan, 2000, Intrinsic motivation and self determination in human behaviour. New York: Plenum Publishing) highlights the impact autonomy supportive environments can have on exercise motivation and positive health outcomes. Yet little is known about whether differential effects occur as a function of which significant other is providing this support. Further, no research has examined the relationship between motivation and the social environment with participants' mental health and intentions to be physically active before entering an exercise intervention. Study participants were 347 British adults who were about to start an exercise referral scheme. Regression analyses revealed that the effects of autonomy support on mental health and physical activity intentions differed as a function of who provided the support (offspring, partner or physician), with the offspring having the weakest effects. A structural model was supported, indicating that autonomy support and more autonomous regulations led to more positive mental health outcomes and stronger intentions to be physically active. Knowledge of the social environmental and personal motivation of those about to commence an exercise programme can provide important insights for professionals supporting such efforts. PMID- 21827334 TI - A new alkaloid and a new diterpene from Cleome paradoxa B.Br. (Cleomaceae). AB - A new alkaloid, paradoxonine, and its enol tautomer, paradoxenoline, in addition to a new cembranoid diterpene, paradoxenoic acid, were isolated from the chloroformic fraction of the methanolic extract of Cleome paradoxa B.Br. The structures of the isolated compounds were established based on their spectral data, including MS, (1)HNMR, (13)CNMR, COSY, HMBC and HMQC. This is the first report on the isolation of alkaloids from the family Cleomaceae. PMID- 21827333 TI - Identification of essential oil components of Marrubium thessalum Boiss. & Heldr., growing wild in Greece. AB - The essential oil of the Greek endemic species Marrubium thessalum Boiss. & Heldr. (Lamiaceae) was obtained by the hydrodistillation of its aerial parts during the flowering stage. The composition of the oil was analysed by GC and GC MS. Thirty compounds were identified. The oil was devoid of monoterpenes, while sesquiterpenes constituted the major fraction. The main components of the oil were caryophyllene oxide (21.7%), beta-caryophyllene (17.6%), germacrene D (15.3%), beta-bisabolene (12.6%) and trans-beta-farnesene (8.1%). PMID- 21827335 TI - Optimising settlement assays of pediveligers and plantigrades of Mytilus galloprovincialis. AB - The mussel Mytilus galloprovincialis is a common aquaculture species, and also a major fouling organism that has negative economic impacts. There are no standard assay conditions for this important species and therefore, this study quantified the effect of key factors on the settlement of pediveligers and plantigrades. Density dependent settlement did not occur for either pediveligers or plantigrades. Settlement increased in drop assays in a 12 h light:12 h dark cycle, while bottom shade had no effect of any magnitude. In addition, settlement was significantly enhanced by storing pediveligers for between 4 and 24 days at 4 degrees C. Overall, these data provide the template to optimise and standardise static laboratory settlement assays for mussels in order to develop materials that either enhance settlement for the aquaculture industry, or deter settlement for antifouling applications. Furthermore, simple mechanisms such as storage at 4 degrees C can enhance settlement beyond current methods used in aquaculture hatcheries. PMID- 21827336 TI - The antifouling potentiality of galactosamine characterized from Vibrio vulnificus exopolysaccharide. AB - To gain a better insight into biofilm composition, the exopolysaccharide (EPS) of the Gram-negative bacterium Vibrio vulnificus was studied. Monosaccharide composition analysis of the wild-type and mutant V. vulnificus EPS carried out with Bio-liquid chromatography revealed the presence of D-glucosamine, D galactose, D-glucose and D-xylose in both strains. D-galactosamine was found only in the mutant that formed less biofilm compared to its wild-type. The influence of galactosamine on biofilm formation was then studied by adding this substance gradually to six different Gram-negative/positive bacteria associated with various autoinducers. Four bacterial species known to use the autoinducer type-2 signaling system produced less biofilm in the presence of galactosamine. No significant inhibition of biofilm formation was observed in bacteria that produce autoinducer type-1 signal molecules. Galactosamine was also immobilized on polymeric nanofibers to determine its re-usability for the study of biofilm inhibition. The immobilized galactosamine retained >65% of its initial antifouling activity after 10 repeated uses. The results of this study suggest the antifouling role of galactosamine for bacteria that produce AI-2. PMID- 21827337 TI - Inhibition of hepatitis B virus and human immunodeficiency virus (HIV-1) replication by Warscewiczia coccinea (Vahl) Kl. (Rubiaceae) ethanol extract. AB - The primary objective of this study was to search for natural products capable of inhibiting hepatitis B virus (HBV) replication. The research design, methods and procedures included testing hydro-alcoholic extracts (n = 66) of 31 species from the Venezuelan Amazonian rain forest on the cell line HepG2 2.2.15, which constitutively produces HBV. The main outcomes and results were as follows: the species Euterpe precatoria, Jacaranda copaia, Jacaranda obtusifolia, Senna silvestris, Warscewiczia coccinea and Vochysia glaberrima exerted some degree of inhibition on HBV replication. The leaves of W. coccinea showed a significant antiviral activity: 80% inhibition with 100 ug mL-1 of extract. This extract also exerted inhibition on covalently closed circular deoxyribonucleic acid (cccDNA) production and on HIV-1 replication in MT4 cells (more than 90% inhibition with 50 ug mL-1 of extract). Initial fractionation using organic solvents of increasing polarity and water showed that the ethanol fraction was responsible for most of the antiviral inhibitory activities of both the viruses. It was concluded that Warscewiczia coccinea extract showed inhibition of HBV and HIV-1 replication. Bioassay-guided purification of this fraction may allow the isolation of an antiviral compound with inhibitory activity against both viruses. PMID- 21827338 TI - Characteristics of unintentional carbon monoxide poisoning in Northwest Iran- Tabriz. AB - The study describes the epidemiology and characteristics of unintentional carbon monoxide (CO) poisoning in Northwest Iran between 2007 and 2009 using multiple data sources including records of the main provider of emergency medical transportation, death certificate reports of the Legal Medicine Organization and through household surveys. A total of 1005 people were diagnosed with non-fatal CO poisoning. Ninety deaths were confirmed due to CO exposure. The ratio of unintentional CO-related poisoning cases in relation to all poisonings was 17.6%. Non-fatal CO poisoning was higher in females and adults aged 25-44 year olds, whereas the death rate was highest for those over 64 years. Domestic gas appliances were involved in 98% of non-fatal incidents and in all fatal poisonings, with gas water heaters (59.2%) and free-standing heaters (25.3%) being the most common causes of CO exposure. The main mechanisms of poisoning were faulty installations and defective devices. The main locations of incidents were the bathroom (48%) and living room (32%). Only 19% of the households reported that they were aware of the hazards of CO exposure before the incident, and no household reported having a CO detector at the time of the poisoning. The results suggest that interventions should be targeted at home environments and focus on at-risk groups such as women and elderly people. Setting stricter standards and environmental legislations and promotion of public awareness against the dangers of CO exposure are important considerations for overcoming this public health problem. PMID- 21827339 TI - A phase II study of rituximab combined with pirarubicin-cyclophosphamide, vincristine and prednisolone regimen as first-line therapy for patients with indolent B-cell lymphoma. AB - The anthracycline drug pirarubicin (tetrahydropyranyl-adriamycin [THP]) apparently has been reported to show fewer cardiotoxic effects than doxorubicin. We have previously described the effectiveness of the R-THP-COP regimen comprising rituximab, cyclophosphamide, pirarubicin, vincristine and prednisolone in patients with diffuse large B-cell lymphoma. We conducted a phase II study to determine the effectiveness of a regimen incorporating rituximab (R-THP-COP) for patients with previously untreated advanced-stage indolent CD20-positive B-cell lymphoma according to the Working Formulation and World Health Organization classification. Four to six courses of the regimen were administered every 3 weeks in 50 patients. The complete remission rate was 57%, while the 3-year overall survival rate was 92%. Regimen-related death was not observed. The R-THP COP regimen appears very effective for patients with previously untreated advanced-stage indolent CD20-positive B-cell lymphoma. The present results indicate the need for randomized trials of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone) and R-THP-COP among patients with CD20 positive indolent lymphoma. PMID- 21827340 TI - Three cases of hairy cell leukemia in coal miners. PMID- 21827341 TI - Magnetic resonance signal intensity measurements in the diagnosis of fetal central nervous system anomalies. AB - OBJECTIVES: To evaluate the possible role of Magnetic Resonance (MR) signal intensity measurements in diagnosing Central Nervous System (CNS) anomalies antenatally. METHODS: MR images of 110 fetal brains between 18 and 38 weeks were studied. Nine were excluded due to destroyed brain. 50 had CNS anomalies. 51 had normal CNS and were used as controls. Regions of interest (ROI) cursors were placed in Vitreous, cerebellar vermis, thalamus, frontal white matter, corona radiata, periventricular region and grey matter. The lateral ventricle diameters were also obtained. Signal intensity ratio (SIR) was calculated by the signal intensity of each of the above regions to that of the vitreous. SIR in controls were compared with fetuses having: (1) Hydrocephalus. (2) Arnold Chiari type-2 Malformation (ACM-2) (3) Non-progressive ventriculomegaly (4) Miscellaneous CNS anomalies. The correlation of the normalcy or abnormalcy of the brain was based on Clinical/Physical examination in 51, Ultrasound in 20, MRI in 2 and autopsy in 28. RESULTS: In hydrocephalus and ACM-2, the SIR of vermis and periventricular region were higher than controls whereas in non-progressive ventriculomegaly and miscellaneous CNS anomalies there was no significant difference. CONCLUSION: Signal intensity measurements are useful to differentiate physiological and non progressive ventriculomegaly from hydrocephalus and ACM-2. PMID- 21827342 TI - Noting a landmark achievement: Mental Health First Aid training reaches 1% of Australian adults. PMID- 21827343 TI - Psychiatric drug prescribing in elderly Australians: time for action. PMID- 21827344 TI - Low-risk pregnancy at 41 weeks: when should we induce labor? AB - OBJECTIVE: To study the perinatal outcome according to whether labor was induced or not, when a low-risk pregnancy reached 41 weeks of gestation. METHODS: A quasi experimental study of 11492 low-risk singleton pregnancies was designed. A total of 1,721 patients (15.0%) women met the study criteria, were informed about the risks and benefits and gave their informed consent, of whom 629 (36.5%) were planned for induction soon after the 41 weeks (287-289 days). RESULTS: An intention-to-treat analysis was performed. The proportion of small-for gestational age babies was lower in the early-induced labor cohort (10.5% versus 15%; p = 0.008). This cohort showed an increased hospital stay (4.54 versus 3.80 days; p < 0.001), and a higher rate of requiring delivery by caesarean section (31.1% versus 19.8%;p < 0.001), including the need for caesarean section for failed induction (21.8% versus 11%;p < 0.001). Three stillbirths occurred in the group followed expectantly, whereas no stillbirths were seen in the early induction group. CONCLUSIONS: Induction of labor for prolonged pregnancy in low risk patients soon after the 41 weeks, reduces the proportion of small-for gestational age babies, but increases the mean hospital stay as well as the need for delivery by caesarean section, including that for failed induction. PMID- 21827345 TI - Targeted intervention to improve monitoring of antipsychotic-induced weight gain and metabolic disturbance in first episode psychosis. AB - OBJECTIVE: International guidelines recommend monitoring for weight gain and metabolic disturbance in patients prescribed second generation antipsychotics. We aimed to investigate whether a targeted intervention could improve levels of monitoring in a first episode psychosis clinic. METHOD: A pre-intervention audit of both metabolic screening rates and specific monitoring of weight and metabolic indices following the initiation of antipsychotic medication was performed in our first episode psychosis clinic. This was repeated 18 months later, following an intervention that included a number of targeted improvement strategies based on an analysis of barriers and enablers to performing monitoring within the clinic. The intervention included provision of monitoring equipment, interactive educational events, reminders and prompts and embedding processes for monitoring within team structure. RESULTS: There were significant improvements in both the screening of metabolic indices and the monitoring of indices following initiation of antipsychotic medications. There were also improvements in the number of active interventions offered to clients by clinicians. However, the level of guideline concordant monitoring remains low within our service. CONCLUSIONS: A comprehensive programme of implementation strategies can improve both screening and monitoring of the metabolic side-effects of antipsychotic medications. Further focused strategies are necessary to continue to improve monitoring to guideline concordant levels. PMID- 21827346 TI - Risk factors for self-harm in children and adolescents admitted to a mental health inpatient unit. AB - OBJECTIVE: The aim of this study was to identify risk factors for self-harm for children and adolescents in a mental health inpatient unit. METHODS: A retrospective file audit of patient files over three years (2006-2009) was conducted to determine risk factors associated with self-harm in children and adolescents admitted to a mental health unit. A checklist of potential factors was based on risk factors found in a review of the literature including demographic information, diagnosis, home situation, environmental stressors, childhood trauma and previous mental health care. The study compared those who self-harmed with a control group who did not self-harm. RESULTS: There were 150 patients who self-harmed (mean age 14 years) and 56 patients who did not self harm with a mean age of 13 years. Several factors were identified that increased the likelihood of self-harm, including a diagnosis of depression, female gender, increasing age, being Australian-born, living with a step parent, not having received previous mental health care, having a history of trauma, and having other stressors including problems within the family. CONCLUSIONS: While increasing age, female gender, a history of trauma and a diagnosis of depression are well known as risk factors for self-harm, this study confirms that family factors, in particular living with a step parent, significantly add to the risk. Child and adolescent services should be aware of the increased risk of self-harm in young people with mental health problems who live in blended families. Treatment approaches need to involve parents as well as the child or young person. PMID- 21827347 TI - Personality disorder comorbidity and outcome: comparison of three age groups. AB - BACKGROUND: Personality disorder comorbidity has been extensively studied in young adult populations, to a lesser extent in elderly populations, and not at all in an Australian population. This study examines PD comorbidity over the life span 18-100. AIM: The object of this study was to examine the interactions of comorbid personality disorder and age on outcome of Axis I disorders. METHOD: A total of 238 consecutive consenting eligible psychiatric inpatients were assessed on admission, prior to discharge, and after 6 and 12 months as regards symptoms, function, well-being, relapse and readmission rates and social supports. Outcomes were compared for young (18-40 years old), middle-aged (41-64) and old (65+) patients. RESULTS: Patients improved over time symptomatically and functionally. Across all age groups patients with comorbid personality disorder had worse outcomes than those without, but improved though never to the same extent. Personality disorder was associated with increased rates of relapse and readmission in the whole sample and in the older group, but not increased length of stay. Severity of personality disorder was associated with poorer outcome. CONCLUSION: Personality disorder adversely affects outcomes, particularly for younger (and older) patients with psychiatric disorders independently of diagnosis and other factors. PMID- 21827348 TI - Solid fibrous tumor of the liver: a case in pregnancy. AB - BACKGROUND: Solid fibrous tumor (SFT) is a rare neoplasm, preferentially involving the pleura, rarely the liver. CASE: A primigravida between 13-15 weeks gestation developed nausea, vomiting, and abdominal pain. Imaging revealed a large, complex septated mass filling the abdomen and pelvis. At surgery a firm, lobular mass involved in the inferior aspect of the right liver lobe. Open cholecystectomy and hepatic segmentectomy were performed; confirmatory immunohistochemical staining was positive for SFT. CONCLUSION: A rapidly growing abdominopelvic mass during pregnancy may be a SFT. The diagnosis and perioperative management of SFT presents multiple challenges to the obstetrician. PMID- 21827349 TI - Longitudinal patterns of social functioning and conversion to psychosis in subjects at ultra-high risk. AB - OBJECTIVE: Impaired social functioning is one of the defining features of patients with schizophrenia and subjects at ultra-high risk (UHR) for psychosis. This prospective study aimed to investigate the course of social dysfunction in UHR subjects and to examine its relationship with later conversion to psychosis. The effect of pharmacotherapy on the course of social dysfunction was also examined. METHOD: A total of 57 UHR subjects and 58 healthy controls participated in this study. The Social Functioning Scale (SFS) was used to assess social functioning of UHR subjects at baseline and at the 1 year follow up. The changes in social functioning of UHR subjects have been examined to compare the social functioning of those who later converted to psychosis ('converters') with those who did not ('non-converters'). The effect of pharmacotherapy on longitudinal change in social functioning was also evaluated. RESULTS: Subjects at UHR for psychosis showed more impaired social functioning at baseline than did healthy controls. Moreover, the course of social dysfunction of the converter and non converter groups differed during the 1 year follow up period. The converters showed decreases in SFS average (F (1,32) = 7.85, p = 0.009) and interpersonal behaviour (F (1,32) = 10.43, p = 0.003) scores over time, whereas the non converters showed increased scores. Additionally, we found that pharmacological treatment was associated with increased prosocial activities score (F (1,32) = 4.66, p = 0.038). CONCLUSIONS: We found that the social functioning of converters was impaired before the onset of the psychosis and further declined during the at risk phase. A series of social functioning indices in the longitudinal course may be helpful in predicting conversion to psychosis in subjects at UHR. Appropriate pharmacotherapy can offer clinical benefits by improving social functioning in UHR individuals. PMID- 21827350 TI - Sexual behaviour research using the survey method: a critique of the literature over the last six years. AB - OBJECTIVES: The survey method is often used to identify trends in sexual behaviour and attitudes. In order for research conclusions to be valid, however, data gathered from surveys must be unambiguous. For the current paper we reviewed survey research of sexual behaviour published in recent years. Our objective was to identify common methodological issues and provide recommendations for how to address them. METHOD: We examined 62 articles, published in four prominent sexual health journals over the past six years. We evaluated each article based on how adequately its authors addressed four recurring methodological issues: ambiguous terminology, heterosexual bias, procedures that compromise honesty in responses, and survey language/literacy considerations. RESULTS: The review revealed some recurring issues: 47% of the studies failed to address the question of sexual orientation, sexual behaviour terminology was explicitly defined in only 32% of questionnaires, fewer than 5% of surveys clarified whether the sexual encounters in question were consensual, and 21% of the articles contained no mention of anonymity or confidentiality for participants. DISCUSSION: These results reveal common issues with survey data that compromise the validity of findings. In order to have confidence in research conclusions and recommendations, it is important that these issues be addressed. PMID- 21827351 TI - Ananas comosus: is the unripe fruit juice an abortifacient in pregnant Wistar rats? AB - OBJECTIVE: The juice of unripe pineapple (Ananas comosus) was investigated for abortifacient activity in pregnant Wistar rats. METHOD: Animals in Groups A, B, C and D received orally 0.5 ml of distilled water, 250, 500 and 1000 mg/kg body weight of the juice, respectively, once daily from day 7 until day 14 of pregnancy. RESULTS: The juice contained tannins, cardenolides, dienolides, cardiac glycoside and flavonoids. The number and weights of live fetuses, number of implantation sites, corpora lutea, computed percent implantation index, resorption index, pre- and post-implantation losses were not significantly (p > 0.05) altered. Neither fetal death, nor provoked vaginal bleeding was observed in the pregnant rats. The maternal weight increased in all the experimental animals with that of the control augmenting least. The 250 and 500 mg/kg body weight dosages increased (p < 0.05) the serum concentrations of progesterone and oestrogen in the pregnant rats. CONCLUSION: The fruit juice of Ananas comosus does not exhibit abortifacient activity in pregnant Wistar rats. PMID- 21827352 TI - Management of placenta accreta: a survey of Maternal-Fetal Medicine practitioners. AB - OBJECTIVE: To describe the management strategies for placenta accreta used by Maternal-Fetal Medicine practitioners. METHODS: We conducted a 36-question online survey of members of the Society for Maternal-Fetal Medicine regarding management of placenta accreta, and tabulated the results. RESULTS: We had 508 respondents. Most respondents have been in practice for >20 years (30%), at a university affiliated institution (58.1%). In the previous 2 years, 44.6% of respondents operated on 1-3 cases of placenta accreta, with 3% having operated on greater than 10 cases. Magnetic resonance imaging (MRI) is used as a diagnostic adjunct when the suspicion for accreta is both low (43.1%) and high (68%). In asymptomatic patients with high suspicion for accreta, 15.4% of practitioners hospitalize patients antenatally, 34.5% administer corticosteroids, and 46.8% perform amniocentesis for fetal lung maturity prior to delivery, which they schedule most commonly at 36 weeks (48.4%). Equipment requested prior to delivery includes intravascular balloon catheters (35%) and ureteral stents or catheters (26.2%). With high suspicion for accreta intraoperatively, the majority proceed with hysterectomy, but 14.9% report conservative management. CONCLUSION: Survey respondents employ diverse approaches in the management of patients with placenta accreta. Further study may lead to consensus strategies to improve outcome in this high-risk obstetric condition. PMID- 21827353 TI - Persistent pulmonary hypertension of the newborn in twin-twin transfusion syndrome following fetoscopic laser surgery. AB - OBJECTIVE: We investigated persistent pulmonary hypertension of the newborn (PPHN) among monochorionic-diamniotic (MD) twins. METHODS: A retrospective cohort study examined MD twins from 195 deliveries and 373 live-born neonates at our center. RESULTS: PPHN occurred in three cases (3/373: 0.8%), all of which were recipients of twin-twin transfusion syndrome (TTTS), after fetoscopic laser surgery (FLS) (3/117: 2.6%). Although the clinical course of the three cases differed, all cardiothoracic area ratios exceeded 40%, and other cardiac parameters also worsened after FLS. CONCLUSIONS: The occurrence of PPHN in TTTS recipients should be noted, particularly when fetal cardiac function declines following FLS. PMID- 21827354 TI - Negotiating control: patients' experiences of unsuccessful weight-loss surgery. AB - Interviews were carried out with 10 men and women who had undergone weight-loss surgery (WLS) up to 10 years ago and felt that it had failed. Seven had had a further successful procedure. Data were analysed using Interpretative Phenomenological Analysis. Weight regain following surgery was explained in terms of either the mechanics of the operation or with participants describing ways to 'cheat' as food continued to be used for emotional regulation. Everyone spoke of how surgery neglected their mind. Following the second successful surgery, participants described changes in both their eating behaviour and cognitions emphasising how their mind had been brought 'in gear' through the investment of two invasive procedures. Transcending all accounts was the mind/body relationship and the issue of control with attributions for both failed and successful surgery shifting from the self to the surgical mechanism as the participants negotiated the pathway between self-blame and responsibility and utilised conflicting frameworks in which the mind and body were either divided or united. Whereas failed surgery is characterised by a battle for control, successful surgery involves handing control over to their restricted stomachs or considering WLS as a tool to be worked with. PMID- 21827356 TI - Nonhalogenated solvent-based solvent evaporation process useful in preparation of PLGA microspheres. AB - The objective of this study was to develop an isopropyl formate-based evaporation process useful in producing poly-D,L-lactide-co-glycolide microspheres. Surprisingly, the evaporating tendency of isopropyl formate was comparable to that of methylene chloride and far better than that of ethyl acetate. After optimization of the isopropyl formate-based process, progesterone was encapsulated into microspheres. Under our conditions, its encapsulation efficiency ranged from 75.1% to 92.6%. Even though all microspheres took spherical geometry, their external and internal morphologies were greatly influenced by progesterone payloads. A GC analysis demonstrated that residual isopropyl formate in various microspheres was 1.8% to 4.0%. Interestingly, progesterone underwent polymorphic transition during the microencapsulation process - the beta form was present in microspheres with lower progesterone payloads, whereas the alpha form predominated over the beta one at higher progesterone loads. In terms of human safety and environmental toxicity, isopropyl formate might have an edge over halogenated organic solvents for solvent evaporation. PMID- 21827355 TI - Plasma YKL-40 in relation to the degree of coronary artery disease in patients with stable ischemic heart disease. AB - BACKGROUND: YKL-40 is a glycoprotein secreted by macrophages and neutrophils in tissues with inflammation. Plasma YKL-40 is increased in patients with coronary artery disease (CAD) and associated with cardiovascular and all-cause mortality. Furthermore, plasma YKL-40 seems related to the number of diseased main vessels in patients with stable CAD. The aim was to further study the relation between YKL-40 and stenosis degree, stenosis type and actual ischemia in stable CAD patients. METHODS: Plasma YKL-40 and hsCRP levels were determined from 206 consecutive patients with stable angina pectoris admitted for coronary angiography. Plasma YKL-40 in 245 healthy subjects was used for comparison. In addition to one to three vessel stenosis scores, two new scores for evaluating coronary angiographies were established for discriminating between focal and diffuse CAD and the extent of myocardial ischemia. RESULTS: YKL-40 levels in CAD patients (median: 52 MUg/L and quartiles: 37-85 MUg/L) were significantly increased (p < 0.001) compared to the healthy controls. In univariate analyses plasma YKL-40 was significantly associated with ischemic myocardium score, age, hypertension, peripheral vascular disease and serum creatinine levels. In multivariate analyses YKL-40 was related to hsCRP, peripheral artery disease, hypertension, and statin treatment. CONCLUSIONS: Plasma YKL-40 was increased in patients with CAD compared to controls. YKL-40 was related to the ischemic myocardium, but not to degree of CAD using different scoring systems. Therefore, YKL-40 is not related to the extent of CAD, but to some other pathophysiological mechanisms of importance for the prognosis. PMID- 21827357 TI - Effect of prolonged gelling time on the intrinsic properties of barium alginate microcapsules and its biocompatibility. AB - Pericapsular fibrotic overgrowth (PFO) may be attributed to an immune response against microcapsules themselves or to antigen shedding through microcapsule pores from encapsulated islet tissue. Modification of microcapsules aimed at reducing pore size should prevent PFO and improve graft survival. This study investigated the effect of increased gelling time (20 vs. 2 min) in barium chloride on intrinsic properties of alginate microcapsules and tested their biocompatibility in vivo. Prolonged gelling time affected neither permeability nor size of the microcapsules. However, prolonged gelling time for 20 min produced brittle microcapsules compared to 2 min during compression test. Encapsulation of human islets in both types of microcapsules affected neither islet viability nor function. The presence of PFO when transplanted into a large animal model such as baboon and its absence in small animal models such as rodents suggest that the host immune response towards alginate microcapsules is species rather than alginate specific. PMID- 21827358 TI - Application of the combined use of ultrasonic homogenization and electro-spraying in the formation of nano carrier systems. AB - Chitosan-coated nano-liposomes containing etofenprox were prepared by ultrasonic homogenization (UH) and a combined use of UH and electro-spraying. The physicochemical properties of the resulting samples were examined and compared. The two methods yielded similar values and tendencies, except for encapsulation efficiency that differed by an average of 15%. In the coating process, as the chitosan concentration increased (0.1-0.5%, w/v) and the degree of deacetylation increased (chitosans A, B and C), the surface charge of the nano carrier likewise increased and carrier size distribution was altered. The encapsulation efficiency as measured by gas chromatography decreased slightly with the increasing chitosan concentration (0.1-0.5%, w/v). The results indicate that diverse preparation conditions could affect the physicochemical properties of the resulting nano carrier systems. PMID- 21827359 TI - Microencapsulation of Lactobacillus plantarum (mtcc 5422) by spray-freeze-drying method and evaluation of survival in simulated gastrointestinal conditions. AB - Spray-drying (SD) and freeze-drying (FD) are widely used methods for microencapsulation of heat-sensitive materials like probiotics for long-term preservation and transport. Spray-freeze-drying (SFD) is relatively a new technique that involves spraying a solution into a cold medium and removal of solvent (water) by conventional vacuum FD method. In this study, the SFD microencapsulated Lactobacillus plantarum powder (1:1 and 1:1.5 core-to-wall ratios of whey protein) is compared with the microencapsulated powders produced by FD and SD methods. The SFD and FD processed microencapsulated powder show 20% higher cell viability than the SD samples. In simulated gastrointestinal conditions, the SFD and FD cells show up to 4 h better tolerance than SD samples and unencapsulated cells in acidic and pepsin condition. The morphology of SFD samples shows particles almost in spherical shape with numerous fine pores, which in turn results in good rehydration behaviour of the powdered product. PMID- 21827360 TI - Preparation and evaluation of PLGA microparticles as carrier for the pulmonary delivery of rhIL-2 : I. Effects of some formulation parameters on microparticle characteristics. AB - In this study, recombinant human interleukin-2 (rhIL-2) containing poly(lactic-co glycolic acid) (PLGA) microparticles were prepared for pulmonary administration by modified w/o/w double emulsion solvent extraction method and the effects of various formulation parameters on the physicochemical properties of the microparticles were investigated. Microparticles in suitable size for pulmonary administration (4.02 um) were obtained by increasing dichloromethane volume used in the organic phase. Also, a very high encapsulation efficiency (99.22%) value could be reached in these microparticles. In the sodium dodecyl sulphate polyacrylamide gel electrophoresis analysis, rhIL-2 extracted from microparticles having a similar band with native rhIL-2 showed that the protein was not affected by the encapsulation process. The release curves of microparticles exhibited a biphasic fashion, characterized by a fast release phase at initial 1 day, followed by a slower one on the remaining days. Bioactivity investigations using T cells show that rhIL-2 encapsulated in PLGA microparticles retain their biological activity. PMID- 21827361 TI - Prevention and management of asparaginase/pegasparaginase-associated toxicities in adults and older adolescents: recommendations of an expert panel. AB - The rapidly increasing use of pegasparaginase (pegASNase) in adults, after a half century of use of asparaginase (ASNase) in children, has prompted a need for guidelines in the management and prevention of toxicities of asparagine depletion in adults. Accordingly, an initial set of recommendations are provided herein. Major advantages of pegASNase are its 2-3-week duration of action, in contrast to less than 3 days with native ASNase, and the flexibility of intravenous or intramuscular administration of pegASNase and associated patient and physician convenience. The most frequent toxicities of both types of ASNase are hepatic and pancreatic, with pancreatitis being the most serious. Other toxicities are hypersensitivity reactions, thrombosis, nausea/vomiting, and fatigue. Whether or not the replacement of one dose of pegASNase for 6-9 doses of native ASNase can be achieved in adults with similar efficacy and acceptable toxicities to those achieved in children remains to be established. PMID- 21827362 TI - Preterm birth aetiology 2004-2008. Maternal factors associated with three phenotypes: spontaneous preterm labour, preterm pre-labour rupture of membranes and medically indicated preterm birth. AB - OBJECTIVES: To (1) investigate the current distribution of PTB phenotypes; (2) identify factors associated with spontaneous preterm labour (SPTL), PPROM, and indicated PTB; (3) investigate the relationship of gestational age (ga) with each PTB phenotype. METHODS: Retrospective review of all live, singleton births 23(+0) to 36(+6) weeks ga at an obstetric referral centre 2004-2008. RESULTS: A total of 4,522 PTBs were included (SPTL 31.7%, PPROM 27.4%, indicated 40.8%). PTB phenotype distribution differed between ga groups (<27 weeks: SPTL 45%, PPROM 32%, indicated 23%; 27-33 weeks: SPTL 30%, PPROM 32%, indicated 39%; 34-36 weeks: SPTL 32%, PPROM 24%, indicated 44%, p < 0.001). Between 34-36 weeks', demographic factors were significantly different between PTB phenotypes (age >=35: SPTL 13.8%, PPROM 15.4%, indicated 21.6%; Caucasian ethnicity: SPTL 61.6%, PPROM 69.0%, indicated 70.2%; Assisted Reproductive Technology (ART): SPTL 2.8%, PPROM 1.9%, indicated 9.3%; all p < 0.001). Between 27-33 weeks' PTB phenotype was associated with smoking (SPTL 24.9%, PPROM 29.3%, indicated 20.2%; p = 0.002) and ART (SPTL 2.3%, PPROM 1.6%, indicated 5.0%; p = 0.002). Demographic factors were not associated with PTB phenotype at 23-26 weeks. CONCLUSIONS: The increase in PTB rates may be explained by medical indications at late preterm gestations, primarily in older, Caucasian women requiring fertility assistance. Interventions to reduce the rate of PTB need to be targeted to this high-risk population. PMID- 21827363 TI - Definition of peptide inhibitors from a synthetic peptide library by targeting gelatinase B/matrix metalloproteinase-9 (MMP-9) and TNF-alpha converting enzyme (TACE/ADAM-17). AB - Gelatinase B/matrix metalloproteinase-9 (MMP-9) is a regulatory and effector metalloproteinase in inflammation. TNF-alpha is an important proinflammatory cytokine and is released by the action of a Zn(2+)-containing converting enzyme (TACE/ADAM-17). Both metallo-enzymes play important roles during the development of shock syndromes. Combinatorial chemical synthesis and subsequent library deconvolution were previously used to define a peptide inhibitor (Regasepin1) acting, almost to the same degree, on neutrophil collagenase/MMP-8 and MMP-9 in vitro, and protecting mice against lethal endotoxinemia in vivo. We have now extended this approach by incorporating D-form amino acids and residues preferred by TACE. A new peptide library was designed and synthesized, and by deconvolution new peptide inhibitors were defined. These included a TACE-specific inhibitor, an MMP-9- specific inhibitor, and inhibitors for both enzymes. PMID- 21827364 TI - Evaluation of the inhibition of mushroom tyrosinase and cellular tyrosinase activities of oxyresveratrol: comparison with mulberroside A. AB - The inhibitory effects of oxyresveratrol, the aglycone of mulberroside A, on mushroom and cellular tyrosinase activities and melanin synthesis were evaluated. Mulberroside A and oxyresveratrol showed inhibitory activity against mushroom tyrosinase, with oxyresveratrol demonstrating a greater inhibitory effect than that of mulberroside A. Oxyresveratrol and mulberroside A strongly inhibited melanin production in Streptomyces bikiniensis and exhibited dose-dependent inhibition of tyrosinase activity and inhibition of melanin synthesis in B16F10 melanoma cells. However, the compounds exhibited nearly similar inhibitory effects on the activity of cellular tyrosinase and melanin synthesis in murine melanocytes. The inhibition of melanin synthesis by mulberroside A and oxyresveratrol was involved in suppressing the expression level of melanogenic enzymes, tyrosinase, tyrosinase-related protein-1 (TRP-1), and tyrosinase-related protein-2 (TRP-2). These results indicate that the inhibition rate of mushroom tyrosinase might not provide an accurate estimate of the inhibition rate of melanin synthesis in melanocytes. PMID- 21827365 TI - Inhibition of Lck: evidence for a novel natural Src family kinase inhibitor. AB - Src family kinase (SFK) is a family of protein tyrosine kinases that play important roles in the development of various cancers. Here, we showed that a naturally occurring inhibitory factor of SFK can be extracted from the rat brain. This inhibitor strongly suppressed the activity of SFKs including Lck and Fyn. It did not inhibit other protein tyrosine kinases including Wee1 or serine/threonine kinases Mst2, Cdk5/p25, Cdk5/p35, and Cdk2/cyclin A. The inhibitor was not an ATPase, a phosphatase that dephosphorylates substrates of the SFK reaction, or a protease that degrades SFKs. Activity of mutant Lck with C-terminal tyrosine substituted with phenylalanine was also suppressed by the inhibitor to a similar extent of wild-type Lck, indicating that the inhibitor was not CSK. Gel filtration chromatography indicated that the molecular size of the prevalent form of this inhibitor was approximately 44 kDa. PMID- 21827366 TI - Inhibitory alkaloids from Dictamnus dasycarpus root barks on lipopolysaccharide induced nitric oxide production in BV2 cells. AB - The methanolic extract of Dictamnus dasycarpus root barks afforded one new glycosidic quinoline alkaloid, 3-[1beta-hydroxy-2-(beta-D-glucopyranosyloxy) ethyl)-4-methoxy-2(1H)-quinolinone (1), together with nine known compounds, preskimmianine (2), 8-methoxy-N-methylflindersine (3), dictamine (4), gamma fagarine (5), halopine (6), skimmianine (7), dictangustine-A (8), iso-gamma fagarine (9), isomaculosidine (10). The isolated alkaloids significantly inhibited nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated BV2 cells. Among them, compounds 3 and 7 showed the most potent inhibitory activities on LPS-induced NO production. PMID- 21827367 TI - Effects of cysteinyl-leukotriene receptors' antagonism by montelukast on lung mechanics and olfactory system histology in healthy mice. AB - CONTEXT: At variance with steroid administration, the possible effects of leukotrienes inhibition on basal respiratory mechanics and olfactory system function are still unclear. OBJECTIVE: To investigate if interference with the leukotrienes activity may influence basal lung mechanics in healthy mammals, as well as the olfactory system. MATERIALS AND METHODS: We measured lung mechanics by the end-inflation occlusion method in control and in montelukast i.p. treated anaesthetised healthy mice (10 mg/kg/die for a week). A study of olfactory system histology was also conducted. RESULTS: Elastance and resistive properties of the lung were not affected by montelukast, while a significant increment of lung hysteresis was observed. The analysis of olfactory system histology revealed no significant effects of montelukast compared to controls. DISCUSSION AND CONCLUSIONS: Leukotrienes' antagonism does not affect respiratory mechanics in basal conditions, except for a hysteresis increment, which might counteract the increase in expiratory flow in asthmatic subjects assuming montelukast. PMID- 21827368 TI - Maternal cardiac risks in pre-eclamptic patients. AB - OBJECTIVE: To investigate the relationship between pre-eclampsia (PE) and maternal cardiac risk factors. MATERIAL-METHODS: A total of 41 pregnant women were included in this study. Patient groups consisted of 25 PE patients and 16 normal pregnant women as a control group. We measured the serum total cholesterol, high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), homocystein, apoprotein A1, apoprotein B100, lipoprotein (a), high sensitivity C reactive protein (hsCRP), cystatin C levels as cardiac risk factors. Serum low density lipoprotein (LDL) and very low density lipoprotein (VLDL) cholesterol levels were calculated using Friedwald equation. RESULTS: The levels of TG, LDL C, homocysteine, apoprotein B100 and cystatine C were higher in the PE patients than those in the control group (p < 0.05). HDL-C and apolipoprotein's AI levels were lower than those of normotensive pregnants (p < 0.05). HsCRP levels were also higher in the patient group but the difference was not statistically significant. CONCLUSION: PE is an important and as yet, incompletely understood disorder of pregnancy. Our study showed that the blood levels for some cardiac risk factors were increased in women with PE, which may contribute to its multisystem pathology. Consideration should be given to monitoring women with PE for these cardiac risk factors in pre-eclamptic women both during pregnancy, as well as later in life. PMID- 21827370 TI - Trichosanthes dioica root possesses stimulant laxative activity in mice. AB - Trichosanthes dioica Roxb. (Cucurbitaceae), named 'pointed gourd' in English, is a dioecious climber grown in India. This study was aimed at evaluating the laxative activity of the aqueous extract of T. dioica root (TDA) in Swiss albino mice. The laxative activity of TDA (100 and 200 mg kg(-1) body weight per os) was evaluated by assessing the excretory bowel activities in naive (non-constipated) and in drug (loperamide)-induced constipation in mice. Further, the gastrointestinal transit was measured in both naive and in constipated mice. Castor oil (0.5 mL/mouse per os) was used as the reference. TDA significantly and dose-dependently increased all the excretory bowel activities and gastrointestinal transit in both naive and constipated mice. TDA at 200 mg kg(-1) body weight was found to be the most active, causing diarrhoea in mice. Thus, T. dioica root demonstrated stimulant laxative activity in Swiss mice, validating its traditional usage in India. PMID- 21827369 TI - Placental ischemia and changes in umbilical and uteroplacental arterial and venous hemodynamics. AB - OBJECTIVE: To relate Doppler velocimetry findings in fetoplacental and uteroplacental circulation to placental histomorphology. MATERIAL AND METHODS: In 14 uncomplicated and 31 high-risk pregnancies Doppler velocimetry was performed in umbilical artery and vein, and in maternal uterine veins and arteries during the second half of gestation. Histopathology of the placentas was examined, especially for signs of ischemia and inflammation. RESULTS: All fetuses in uncomplicated pregnancies had normal flow velocity waveforms in umbilical artery; in the high-risk group, 18 fetuses had abnormal flow (increased PI or absent/reverse end-diastolic flow). The latter group had more often high ischemic score and infarctions in the placenta than found in pregnancies with normal umbilical artery flow (p < 0.001 and p = 0.02, respectively). Similarly, the abnormal uterine artery flow pattern (uterine artery score 3-4) occurred more often with high ischemic score and placenta infarctions (p < 0.001 and p < 0.001, respectively). No significant associations were found between the uterine venous flow type and placental ischemia. CONCLUSION: Placental ischemic morphological changes were associated with Doppler ultrasound signs of increased resistance to arterial blood flow, both on the fetal and maternal sides of the placenta. No significant relation to the uterine venous flow velocities was found. PMID- 21827371 TI - The effects of attentional training on physiological stress recovery after induced social threat. AB - Social stress has been related to both physiological and psychological responses. The recovery of stress is influenced by the way environmental information is processed, i.e., what information is attended to and how it is interpreted. The present study investigated the effect of attention modification training on physiological stress recovery following induced stress. A group of applicants preparing for a job interview were randomly allocated to an attention training condition versus a control condition. Afterwards, they were asked to give an artificial job interview to a real life jury while being videotaped. Participants in both conditions showed decreased heart rate variability during the job interview, which indicates an overall physiological stress response. However, during a 30-minute follow-up period after the training, indices of heart rate variability showed improved stress recovery only in the attention training condition. Attentional training is proposed as a promising strategy to prevent enduring stress reactions. PMID- 21827372 TI - Transient state-dependent fluctuations in anxiety measured using STAI, POMS, PANAS or VAS: a comparative review. AB - Several psychometric instruments can be used to measure state-dependent variations in anxiety, including the State-Trait Anxiety Inventory (STAI), the Profile of Mood States (POMS), the Positive and Negative Affect Schedule (PANAS) and the Visual Analog Scales (VAS). Each of these instruments rests on specific theoretical assumptions about the construct of state anxiety, and has been widely used for this purpose in different research domains. However, it remains difficult to determine what may be the specificities of these four instruments, when the goal is to measure transient state-dependent variations in anxiety. In this work, we provide a systematic and comparative literature review of studies which have explored rapid fluctuations (i.e., test-retest intervals not exceeding 24 hours) in state anxiety by means of these specific instruments. Almost 200 studies were eventually included in our review. This comparative review confirms that, despite some disparities and specificities, each of these four instruments provides a reliable measure to capture rapid state-dependent variations in anxiety, although they have been used in non-overlapping research domains or experimental contexts. PMID- 21827374 TI - Phase II study of cenersen, an antisense inhibitor of p53, in combination with fludarabine, cyclophosphamide and rituximab for high-risk chronic lymphocytic leukemia. AB - Patients with chronic lymphocytic leukemia (CLL) with deletion or mutation of TP53 have exceedingly poor clinical outcomes. Cenersen, an oligonucleotide targeting TP53, has been shown to abrogate the activity of TP53 gain-of-function mutants and to increase sensitivity of lymphoma cells to cytotoxic chemotherapy in vitro. We combined cenersen with fludarabine, cyclophosphamide and rituximab (FCR) as treatment for patients with high-risk CLL. The purpose of this phase II study was to determine the overall response rate, response duration and toxicity of cenersen administered in combination with FCR. Twenty patients with relapsed or high-risk CLL were evaluated. Nineteen patients were previously treated. The complete response rate was 18%; the overall response rate was 53%. Median progression-free and overall survival was 5.3 and 10.6 months, respectively. The most common serious adverse events were neutropenia and thrombocytopenia. In this single arm phase II study, cenersen combined with FCR yielded clinical responses with acceptable toxicity in patients with high-risk CLL. PMID- 21827375 TI - Pro12Ala PPAR gamma2 gene polymorphism in PCOS women: the role of compounds regulating satiety. AB - Five to ten percent of women of reproductive age suffer from polycystic ovary syndrome (PCOS). Leptin, NPY, galanin, cholecystokinin (CCK) are involved in the regulation of eating behavior. PPARgamma are receptors that are probably involved in hyperandrogenism. This study was designed to assess associations between the Pro12Ala PPARgamma2 gene polymorphism and satiety factors in PCOS. Fifty-four PCOS women and 51 healthy women were studied. Leptin, NPY, galanin, CCK levels, and genetic studies to detect Pro12Ala PPARgamma2 gene polymorphism were assessed. The leptin levels in the PCOS women carrying Pro12Ala genotype were higher than in those with Pro12Pro and Ala12Ala. The PCOS women had higher leptin and NPY levels and lower galanin levels. Obese PCOS patients had lower CCK levels. CONCLUSIONS: In the PCOS women, a single Ala allele may have a protective role as far as hyperleptinemia is concerned. The PCOS women may reveal a disrupted central leptin/NPY feedback loop with some shifts in food intake. PMID- 21827376 TI - Allergens in household dust and serological indicators of atopy and sensitization in Detroit children with history-based evidence of asthma. AB - BACKGROUND: Home exposure to allergens is an important factor in the development of sensitization and subsequent exacerbations of allergic asthma. We investigated linkages among allergen exposure, immunological measurements, and asthma by examining (1) reservoir dust allergen levels in homes, (2) associations between presence of allergens in homes and sensitization status of resident children, and (3) associations between asthma status and total IgE, atopy (by Phadiatop), and positive allergen-specific tests. METHODS: The study protocol was approved by Institutional Review Boards (IRBs) of the University of North Carolina Chapel Hill; Westat, Inc.; and the US Environmental Protection Agency Human Research Protocol Office. Data were collected from questionnaires, serum analyses, and household vacuum dust. Children (n = 205) were predominately African American (AA) (85.4%) and 51.6% were asthmatic. Sera from 185 children and home dust samples (n = 141) were analyzed for total and specific IgE antibodies to allergens from cat and dog dander, cockroach, dust mites, mice, rats, and molds. RESULTS: Sixty percent of the homes had detectable levels of three or more dust allergens. The proportions of children with positive allergen-specific IgE tests were dust mite (32%), dog (28%), cat (23%), cockroach (18%), mouse (5%), rat (4%), and molds (24-36%). Children testing positive to a single allergen also had positive responses to other allergens. Those children with positive serum tests for cat, dog, and dust mite lived in homes with detectable levels of cat (51%), dog (90%), and dust mite (Der f 1) (92%) allergens. Correlations between children's specific IgE levels and dust levels were linearly related for dog (p < .04), but not for cat (p = .12) or dust mite (Der f 1) (p = .21). Odds ratios (95% CI) for the associations between asthma and serum-specific IgE were over 1.0 for cat, dog, dust mite (Der f 1), cockroach, and four types of molds. House dust allergen exposure levels, however, exhibited no differences between asthmatic and non-asthmatic homes. CONCLUSIONS: Both the co-occurrence of multiple allergens in dust and the high frequency of multiple allergen sensitizations indicate that a broad-based intervention aimed at reducing multiple allergens (pets, pests, and molds) would be more successful than any approach that aimed at reducing one type of allergen. PMID- 21827377 TI - The effects of sleep quality and duration in late pregnancy on labor and fetal outcome. AB - BACKGROUND: Sleep disturbance is common during pregnancy. The aim of this study was to assess the effects of sleep duration and its quality on labor and fetal outcome. METHOD: In a cross sectional study, primigravida women with singleton pregnancy (gestational age > 37 weeks) were recruited. Women with hypertension, diabetes mellitus, or those who needed emergency cesarean section were excluded. Data regarding the type and length of delivery, the quality of sleep as well as the neonates' weight and Apgar scores were recorded. RESULTS: Totally, 457 participants were recruited. There was a significant correlation between the sleep duration and length of delivery stages. In most participants with more than 8 hours sleep, the first stage of delivery lasted between 6 and 10 hours. They had normal vaginal delivery with induction, and their neonates' Apgar score was > 9 (p = 0.029, p = 0.018, and p = 0.001, respectively). Most mothers with refreshing sleep had normal vaginal delivery with induction, their neonates weighted >= 2500 g and with Apgar score > 9 (p = 0.010, p < 0.001, and p = 0.005 respectively). CONCLUSION: Sleep duration and quality of sleep can affect the type of delivery, length of labor stages, as well as neonates' Apgar score and birth weight. Such predictors of labor and fetal outcome should be assessed during prenatal evaluations. PMID- 21827378 TI - Oral subchronic immunotoxicity study of ethyl tertiary butyl ether in the rat. AB - The potential for immunotoxicological effects of ethyl tertiary butyl ether (ETBE, CAS RN 637-92-3) was studied in young adult female Crl:CD(SD) rats following subchronic oral exposures. Rats were exposed by gavage once daily for 28 consecutive days to 0, 250, 500, or 1000 mg ETBE/kg body weight (BW)/day; a concurrent positive control group received four intraperitoneal injections of at 50 mg cyclophosphamide monohydrate (CPS)/kg/day on study Days 24-27. Immunotoxicity was evaluated using a splenic antibody-forming cell (AFC) assay to assess T-cell-dependent antibody responses in rats sensitized with sheep red blood cells (SRBC). All rats survived to the scheduled necropsy. There were no effects on clinical observations, body weights, feed or water consumption, or macroscopic pathology findings in the ETBE-treated rats. No ETBE-related effects were observed on absolute or relative (to final body weight) spleen or thymus weights, spleen cellularity, or on the specific (AFC/10(6) spleen cells) or total activity (AFC/spleen) of splenic IgM AFC to the T-cell-dependent antigen SRBC. CPS produced expected effects consistent with its known immunosuppressive properties and validated the appropriateness of the AFC assay. Based on the results of this study, ETBE did not suppress the humoral component of the immune system in female rats. The no-observed-effect level for immunotoxicity was the highest dosage tested at 1000 mg/kg/day. PMID- 21827379 TI - Coexistence of adenomyosis in women operated for benign gynecological diseases. AB - BACKGROUND: To compare demographic, clinical and histopathological characteristics of women diagnosed with adenomyosis (AG) after hysterectomy to those of women diagnosed with leiomyoma (LG) and to investigate the predisposing factors for AG. METHODS: This study was carried out on 204 patients who underwent gynecologic surgery for various indications except for gynecologic malignancy between January 2005 and December 2009 and whose histopathological analysis of hysterectomy/myomectomy specimen revealed either AG or LG. Women with AG and those with LG were compared with respect to age, parity, menstrual pattern, history of induced abortion, history of prior uterine surgery, smoking, dysmenorrhea, dyspareunia, chronic pelvic pain and coexisting endometrial and ovarian pathologies. RESULTS: The mean age of our patients was 51 +/- 8 years (range 28-85), 40% of them were postmenopausal, and 64% had a history of uterine surgery. The mean age (p = 0.014), gravida (p = 0.018), parity (p = 0.017) and previous endometrial sampling (p < 0.01) were significantly higher in AG. Main symptoms were abnormal uterine bleeding (39%), dysmenorrhea (63%) and nonmenstrual pelvic pain (62%). Age (p = 0.01), menometrorrhagia (p = 0.02) and endometrial sampling (p < 0.01) were the significant covariants in binary logistic regression for AG. CONCLUSION: AG is an enigmatic disease frequently causing gynecologic complaints and endomyometrial junction deterioration during endometrial sampling may be a trigger point for developing AG. PMID- 21827380 TI - Recent patents related to phosphorylation signaling pathway on cancer. AB - Phosphorylation and dephosphorylation play an important role in the regulation of growth factor and cytokine signal transduction to modulate cell proliferation, differentiation, survival, and apoptosis. In some cellular systems, the information suggests that EGFR, somatostatin receptors, SHP-1, Akt and PI3K can regulate carcinogenesis implied process through regulated the activity of NF kappaB. Current patents related to signaling pathway that includes somatostatin receptors, phosphotyrosine phosphatases, tyrosine kinases, AKT/PKB and PI3K are focusing in diagnosis, prognosis and treatment. Many recent patented techniques include inhibition, antagonism or alternative therapeutic methods. Furthermore, it is necessary to deepen understanding of the molecular mechanisms involved in cancer to develop other alternative therapies focusing not only on new inhibitors. PMID- 21827381 TI - Biobanks between common good and private interest: the example of umbilical cord blood private biobanks. AB - Storage of human biological samples and personal data associated with them is organised in Biobanks. In spite of expectation given by biobanks in medicine, their management involved some ethical questions, for example, the need for policies to regulate economic interests, potential commercial use of data (including patents), private sector financing, ownership of samples and benefit sharing. In the context of contributing to the general public interest, we can consider the act of giving biological material to biobanks as a donation, in which the donation constitutes part of a generalised form of reciprocity in which the act of donation contributes to society's common good. Starting from this perspective, we move into a different situation represented by the biobanking of umbilical cord blood for personal use. We used the example of the private biobanking of umbilical cords to demonstrate the restrictive utility of the collection and preservation of cord blood for personal use in private biobanks, in the context of society's common good. In summary, a system based on solidarity seems to be able to guarantee necessary levels of supply for the donation of biological material to biobanks. PMID- 21827382 TI - The Vpr gene polymorphism of human immunodeficiency virus type 1 in China and its clinical significance. AB - Recent studies have explored that mutated Human immunodeficiency virus type 1(HIV 1) Vpr genes likely influence clinical manifestations of HIV infected patients. However, the relationship between the mutation sites on HIV Vpr gene and subsequent function changes is still not clear. In this study we investigated such relationship in analyzing the Vpr genes of HIV-1 viruses isolated from 208 HIV-1 infected patients from different regions in China. Reverse transcription polymerase chain reaction (RT-PCR) and nested PCR were used to amplify HIV-1 Vpr gene extracted from plasma of 208 HIV-1 infected patients and 153 isolates displayed the target gene sequences. Biological analysis software analyzed the deduced amino acid sequence, and identified the characteristics of the polymorphism of HIV-1 Vpr gene and its clinical significance. Results show the sequence subtypes as follows: CRF01-AE is 51.63%, subtype C is 24.84%, ubtype B is 17.65%, CRF03-AB is 3.92% and CRF08-BC is 1.31%. This paper revealed for the first time the HIV-1 Vpr gene polymorphism in HIV-1 positive individuals in China.: the subtype CRF01-AE is the main Vpr gene subtype in this region. The mutations in the C-terminal were more obvious than those observed in the N terminal. It was also discovered that in the 77th position, 84.3% of the 153 amino acid sequences were glutamine (Q), which differ from overseas reports. Our data showed that the mutations 63, 70, 85, 86, 89 and 94 of the Vpr gene were possibly correlated with the clinical manifestations of the HIV-1 infected individuals. PMID- 21827383 TI - Gender differences in liver fibrosis and hepatitis C virus-related parameters in patients coinfected with human immunodeficiency virus. AB - OBJECTIVES: To evaluate gender differences in liver fibrosis and hepatitis C virus-related parameters in patients coinfected with human immunodeficiency virus. METHODS: Transversal study of 782 patients who underwent a complete clinical and laboratory evaluation. Fibrosis was measured by transient elastometry (TE) and by commonly used laboratory-derived fibrosis indexes. RESULTS: Men were older, had higher rates of alcohol abuse, higher HCV viral load and liver tests, lower platelet values, poorer CDC clinical stages, longer duration of HCV infection, shorter time on successful antiretroviral therapy (ART) and had appreciably more advanced fibrosis than women. Multivariate analysis revealed that male gender (P < 0.0001), longer time since HCV acquisition (P < 0.0001), alcohol abuse (P < 0.0001), HCV genotype 3 (P=0.01), shorter time on successful ART (P=0.005) and worse CDC clinical stages (P=0.03) were independently associated with significant or higher stages of fibrosis. Male gender was also independently predictive of advanced or higher stages of fibrosis (P=0.06) or cirrhosis (P=0.02). In patients with no alcohol abuse, men had worse fibrosis parameters than women (P < 0.01 for each), but these differences decreased in patients with alcohol abuse and became non-significant. CONCLUSIONS: HIV-HCV-coinfected women have more favorable HCV virological and clinical profile than men and, particularly, lower degrees of fibrosis. Alcohol abuse seemed to result more deleterious in women than in men. The reportedly poorer outcomes of liver disease in HIV-HCV-coinfected patients, as compared with their HCV monoinfected counterparts, could be ameliorated by addressing these cofactors, some of them preventable or treatable. PMID- 21827384 TI - Accuracy of ultrasound imaging technique for assessing lipoatrophy in HIV infected subjects. AB - OBJECTIVE: To compare the accuracy of ultrasound imaging technique to that of clinical diagnosis in evaluating subcutaneous fat changes in HIV-infected subjects. METHODS: HIV-uninfected control subjects (Group A), HIV-infected subjects with clinically assessed lipoatrophy (Group B), and HIV-infected subjects without clinical lipoatrophy (Group C) underwent ultrasound measurements of subcutaneous fat thickness at facial, brachial and thigh regions. ROC curve analyses were used to estimate ultrasound prediction accuracy and cut-off values of subcutaneous fat thickness. RESULTS: 228 subjects were enrolled: 78 in Group A, 73 in Group B, and 77 in Group C. Facial lipoatrophy: ROC curve analysis identified optimal cut-off value of 13.3 mm [sensitivity, 96.0%; specificity, 76.9% AUC 0.92], 5.0 mm [sensitivity, 71.4%; specificity, 92.3%; AUC 0.90] and 11.2 mm [sensitivity, 95.8%; specificity, 89.7%; AUC 0.97] for females and 12.05 mm [sensitivity, 51.2%; specificity, 87.2%; AUC 0.74], 4.1 mm [sensitivity, 76.2%; specificity, 89.7%; AUC 0.85] and 4.35 mm [sensitivity, 60.0%; specificity, 89.7%; AUC 0.82] for males in assessing facial, brachial and crural lipoatrophy respectively. Using this cut-off values, 12/25 (48%) females and 17/49 (34.7%) males, 12/28 (42.9%) females and 23/49 (46.9%) males, 19/28 (67.9%) females and 12/49 (24.5%) males in Group C would be classified as "sub-clinical" facial, brachial and crural lipoatrophy respectively. CONCLUSIONS: The results of our study show that in the assessment of subtle subcutaneous fat changes ultrasound is more accurate than clinical evaluation and confirm the usefulness of ultrasound imaging technique in identifying lipoatrophy at an early stage. PMID- 21827385 TI - Lipodystrophy, insulin resistance, and adiponectin concentration in HIV-infected children and adolescents. AB - Alterations of fat distribution and insulin resistance are associated with increased risk of metabolic derangements and cardiovascular disease. HIV-infected adult patients on antiretroviral treatment often show lipodystrophy, insulin resistance and hypoadiponectinemia, but data in children are controversial. We investigated serum adiponectin concentration in a cohort of HIV-infected youths, and we assessed the relationships with lipodystrophy and insulin resistance. We studied 36 HIV-infected patients (aged 5.0 - 19.4 years), and 171 healthy subjects (aged 4.9 - 17.9 years) for adiponectin measurements. All patients underwent body composition assessment by dual-energy x-ray absorptiometry, and an oral glucose tolerance test to determine the fasting insulin concentration, the insulin area under the curve (AUC), and the HOMA index. Adiponectin serum concentration was measured by an immunoenzymatic assay. Sixteen patients had central fat accumulation, 6 had peripheral lipoatrophy, 5 had a mixed phenotype, and the remaining 9 were non-lipodystrophic. Fasting insulin, insulin AUC, and HOMA index were significantly higher in patients with central fat adiposity and mixed phenotype than in the other two groups. The patients of the former two groups had adiponectin concentration much lower than healthy controls, and patients with peripheral lipoatrophy or normal phenotype had normal concentration. Low adiponectin concentration is associated to central fat and mixed lipohypertrophy, and to signs of insulin resistance in HIV-infected youths. Strict monitoring of metabolic and cardiovascular evolution should be performed in these patients. PMID- 21827386 TI - Women's desire for children in an HIV population: a clinical pilot study in Burkina Faso. AB - INTRODUCTION: Today, thanks to the HAART, HIV has become a chronic disease. In most cases, HIV positive women are of reproductive age and at present, the vertical transmission rate is around 0.1% for women with an undetectable viral load. So, it is normal that the question of seropositive women's desire to have children is on the table. METHODS: In this experimental study, 50 HIV seropositive and 44 seronegative women were interviewed about their desire to have children. Some of the questions asked were: "How many children did you want to have before you got married/at 15 years of age if you aren't married?" "How many children would you like to have today, considering your present situation?". In case of a difference between "before" and "now", we asked them: "What are the reasons for this difference?". This study was performed in Burkina Faso. RESULTS: The positive women tend to desire more children "before" and fewer children "now" than negative women (OR: 1.33; C.I. 95%: 0.86-2; p= 0.19 vs OR: 0.78; C.I. 95%: 0.51-1.21; p= 0.27). 62% of HIV positive women mention multiple reasons directly linked to their seropositivity to explain the difference between "before" and "now". 70% of HIV positive women still want to have children. We have noted that the positive women who still want children are more likely to be younger (p < 0.05 by Two-Sample T tests), in a relationship (p < 0.01 by Chi-Square Test) and to have been diagnosed earlier than the positive women who don't want any children (p=0.01 by Wilcoxon Rank Sum Test). CONCLUSION: Even if the results of this pilot study are preliminary, they show that HIV positive and negative women have a relatively similar desire for children, even though seropositive women seem to want fewer children than their uninfected counterparts. Most of the reasons which reduce HIV positive women's desire to have children are directly linked to HIV. This is why getting these women informed about materno-fetal transmission risks and existing treatments is really important to give them the opportunity to make a conscious choice. PMID- 21827387 TI - Anticoagulants in cirrhotic patients: controversies and certainties in PVT management. AB - Portal vein thrombosis (PVT) is a relatively common event in patients with advanced-stage liver cirrhosis, even in patients with a compensated disease. Because of the protean clinical manifestation of PVT, ranging from massive variceal bleeding and mesenteric infarction to the complete absence of any symptom, it is mandatory to provide an early diagnosis and a prompt management. However, even if various treatments have been tested in clinical studies, most of them can be suitable only for a limited number of patients and anticoagulants are recognized as the gold standard, even if the debate about their use in PVT management in cirrhotic patients is still opened. In particular, "old" and "new" generations of anticoagulants have always been used carefully and, sometimes, with skepticism or diffidence in cirrhotic patients. In this review, we report the rationale of anticoagulants use in PVT cirrhotic patients management, analyzing the most accepted controversies and certainties, with a particular attention to their possible role as preemptive therapy. PMID- 21827388 TI - Emerging targeted therapies in metastatic renal cell carcinoma. AB - Insights into renal cell carcinoma (RCC) biology have greatly expanded the treatment armamentarium for metastatic RCC (mRCC). Since 2005, six targeted agents have been approved by the US Food and Drug Administration (FDA) for the management of mRCC, and many new targeted therapies are in development. A number of novel VEGF Inhibitors/Multi-Tyrosine Kinase Inhibitors are currently in various stages of development. New targeted agents with novel mechanisms of action are also being studied, including Histone Deacetylase Inhibitors, Angiopoietin/TIE-2 inhibitors, Carbonic anhydrase IX inhibitors, vaccines, and others. In addition to combining currently available immunologic therapies with emerging agents, researchers are also developing novel immunologic therapies to treat mRCC, including those that block Cytotoxic T-Lymphocyte Antigen 4 (CTLA4). Several trials evaluating combinations and sequential therapy of targeted agents have been published, and several others are underway. Trials of special mRCC populations, including poor-risk disease, non-clear cell RCC (NCC-RCC), and papillary type RCC are further refining the use of targeted treatments. As new targeted agents emerge and therapies with novel mechanisms of action are developed, the treatments options available for metastatic RCC are expected to increase. New therapies will likely have fewer detrimental side effects and better efficacy, leading to better quality of life for patients. PMID- 21827389 TI - Clonidine: clinical pharmacology and therapeutic use in pain management. AB - Pain is an unpleasant sensory perception warning of actual or impending tissue damage. Pain serves a vital physiological role, however, severe and uncontrolled pain in the peri-operative setting can adversely affect outcome from surgery and lead to chronic pain. Multiple neurochemical and receptor processes are involved in pain perception but the role of pro-inflammatory cytokines and adrenergic pathways has only recently been recognised. Clonidine is an agonist at the alpha2 adrenergic receptor that has been in clinical use for over 40 years. Clonidine was recognised at an early stage as having analgesic properties however its systemic use was frequently limited by side-effects. Recent advances in anaesthetic practice, allowing more targeted drug delivery and a better understanding of the basic physiology of pain have led to a re-evaluation of the role of clonidine in pain management. Experimental and clinical studies have identified a diverse action of clonidine in modifying not only the adrenergic component to pain perception but also an important effect on modifying the neurohumoral response to tissue injury. This has implications for the management of a diverse range of pain problems and potentially offers a method of preventing the transition from acute to chronic pain. Clonidine is likely to play an increasing role in clinical practice in anaesthetics and pain management. PMID- 21827390 TI - Immunotherapy of kidney cancer. AB - Renal cell carcinoma (RCC) accounts for 4% of all new cancer cases in males and 3% in females in the US. Compared to other solid tumors, it does not respond to traditional management modalities, such as chemotherapy and radiation therapy. However, it appears to be an immune-responsive tumor and several immunotherapeutic strategies have been investigated in the management of RCC with variable degrees of success. Active immunotherapy refers mainly to the use of vaccines, while adoptive (passive) immunotherapy includes the use of autologous immune cells, allogeneic immune cells (stem cell transplantation, donor lymphocyte infusion), as well as antibody delivery. Cytokine delivery with IL-2 has resulted in long-term disease-free survival in a small proportion of patients with metastatic disease. The continuous understanding of the mechanisms that underlie the immune complex networks has led to the identification of key molecules that play a major role in the immune response process. A panel of immuno-modulatory compounds that target such molecules has been tested in the preclinical and clinical setting. At the post-genomic era, the development of novel biomarkers can contribute to more accurate patient selection, resulting in higher responses and less toxicity of immunotherapeutic approaches. PMID- 21827391 TI - Immunotherapy and targeted therapy combinations in renal cancer. AB - In recent years an improved understanding of renal cell carcinoma (RCC) tumor biology has translated into major advancements in the treatment of patients with metastatic RCC. These novel therapies include inhibitors of the vascular endothelial growth factor (VEGF) pathway, and inhibitors of the mammalian target of rapamycin (mTor) pathway. In contrast to the results seen with molecularly targeted therapies, the administration of high-dose bolus IL-2 (HD IL-2) can produce durable responses in a small percentage of patients. While the substantial toxicity and limited efficacy that is associated with HD IL-2 limits its application, novel immunotherapies may be able to produce durable benefit with less toxicity. Once the standard of care, the role of low-dose single-agent cytokines is now limited in patients with RCC. However, combinations of cytokines with targeted therapy may have merit. The advent of targeted therapy in RCC does not eliminate the potential utility of immunotherapy but rather requires a rational refinement of this approach through improvements in patient selection and combination therapy that may increase the cure rate for patients with this disease. PMID- 21827392 TI - Toxicities of targeted agents in advanced renal cell carcinoma. AB - The targeted therapies available to treat metastatic kidney cancer include vascular endothelial growth factor (VEGF) inhibitors, bevacizumab, sorafenib, sunitinib, pazopanib, and the mTor inhibitors temsirolimus and everolimus. These agents have significantly improved patient outcomes but are associated with toxicities. The most common toxicities seen with the VEGF inhibitors are hypertension, fatigue, and hand- foot syndrome. The mTor inhibitors exhibit a different toxicity profile which includes hyperglycemia and hypertriglyceridemia. Recognition and understanding the mechanism of the toxicities is crucial for optimal patient management. PMID- 21827394 TI - VEGF inhibitors in metastatic renal cell carcinoma: current therapies and future perspective. AB - Metastatic renal cell carcinoma (RCC) is predominantly refractory to treatment with traditional cytotoxic chemotherapies, and until recently management options were limited to immunotherapy, palliative care, or phase I trials. The past five years have witnessed a major change in the treatment of advanced RCC with the introduction of targeted therapies that derive their efficacy through affecting angiogenesis. The main class of agents involves drugs that target the vascular endothelial growth factor (VEGF). Several VEGF inhibitors are now approved for the treatment of metastatic RCC. The field is expanding rapidly with goals including 1) developing novel more potent and better tolerated agents and 2) defining the role of combination and sequential anti-VEGF regimens. PMID- 21827393 TI - Adjuvant and neoadjuvant therapy in renal cell carcinoma. AB - Nephrectomy continues to be the cornerstone of treatment for localized renal cell carcinoma (RCC). Despite undergoing nephrectomy, recurrence of disease remains a concern in many patients, and different medical therapies are being investigated as means to decrease this risk. The use of the traditional immunotherapy options has not provided benefit as adjuvant treatment in this disease state. Recently, the treatment of metastatic RCC has experienced key advances with the introduction of targeted agents against the vascular endothelial growth factor (VEGF) molecule and related pathways as well as inhibitors of the mammalian target of rapamycin (mTOR), in addition to improvements in surgical technique. Additionally, there are questions about the optimal timing of systemic therapy in the context of high risk non-metastatic disease. There is optimism that locally advanced RCC might benefit from adjuvant or neoadjuvant treatment with these therapies. Ongoing clinical trials are addressing the role of targeted agents in this disease state. PMID- 21827396 TI - Tau protein in Alzheimer's disease. PMID- 21827395 TI - Therapeutic rationale for mTOR inhibition in advanced renal cell carcinoma. AB - Inhibitors of the mammalian target of rapamycin (mTOR) have entered the landscape of treatment for advanced RCC. Their development has been based on their unique biology and their potential to simultaneously inhibit both tumor cell proliferation and angiogenesis. Despite the solid biologic rationale for their development, existing clinical data is somewhat mixed. Although Temsirolimus is capable of improving overall survival it does so only in a minority of selected mRCC patients and its effects on tumor burden reduction and PFS are minimal. Similarly the activity and clinical utility of Everolimus in the refractory setting is questionable. First, because it is unknown if mTOR becomes the major driver or cancer growth after developing progressive disease on a VEGF inhibitor and secondly because existing sequential VEGF data in same setting appears to be the same if not a bit more robust to that reported with Everolimus. Combination of mTOR and VEGF inhibitors has been disappointing due to the excessive toxicities encountered in early trials without a noticeable difference in efficacy. Efforts are now placed in a series of novel compounds capable of inhibiting mTOR and the upstream signaling pathway of PI3K/AKT. PMID- 21827397 TI - Site-specific integration by the adeno-associated virus rep protein. AB - Inserting genetic information at precise locations into the human genome has been the goal of gene transfer technology for almost two decades. The spectacular progress of mammalian genetics has led to the development of technology for genome editing and homologous recombination in human somatic cells that is finally approaching efficiency compatible with clinical application. Site specific integration, or the insertion of genes at known locations by enzymes with target recognition capacity, has progressed slowly but steadily in recent years, and could very well be the basis of the next generation of gene transfer technology. This review focuses on the use of Rep, the replicase/integrase of the adeno-associated virus (AAV), to insert genes at the natural AAV integration site on human chromosome 19. This region (AAVS1) has characteristics that make it an ideal target for somatic transgenesis. PMID- 21827398 TI - Inhibitors of phosphoinositol 3 kinase and NFkappaB for the treatment of chronic obstructive pulmonary disease. AB - Chronic Obstructive Pulmonary Disease (COPD) is a preventable and treatable disease characterized mainly by pulmonary airflow limitation that is not fully reversible. New different pharmacological approaches to decrease inflammation of the airways and consequently disease progression and increase airway obstruction reversibility have been developed. In the present article, we review the new patents on phosphoinositide 3 kinase and NFkappab inhibitors for future therapies. PMID- 21827399 TI - Dietary flavonoids: molecular mechanisms of action as anti- inflammatory agents. AB - Flavonoids are a large group of polyphenolic compounds, which are ubiquitously expressed in plants. They are grouped according to their chemical structure and function into flavonols, flavones, flavan-3-ols, anthocyanins, flavanones and isoflavones. Many of flavonoids are found in fruits, vegetables and beverages. Flavonoids have been demonstrated to have advantageous effects on human health because their anti-allergic, anti-inflammatory, anti-platelet aggregation, anti tumor and anti-oxidant behavior. This report reviews the current knowledge on the molecular mechanisms of action of flavonoids as anti-inflammatory agents and also discusses the relevant patents. PMID- 21827400 TI - APO2L/TRAIL: new insights in the treatment of autoimmune disorders. AB - Apo2 Ligand/TNF Related Apoptosis-Inducing Ligand (Apo2L/TRAIL) is a cytokine that belongs to the TNF superfamilily that was described as capable of inducing apoptosis on tumor cells through activation of the extrinsic pathway in a Fas independent manner. Besides this function, Apo2L/TRAIL, like other members of the TNF superfamily, has been shown to exert important functions in the immune system. Depending on their status of activation, Apo2L/TRAIL can be expressed by various cells of the immune system such as natural killer cells, T cells, dendritic cells and macrophages and has been implicated in distinct immunoeffector, immunoregulatory functions. Whit respect to pathological conditions, the Apo2L/TRAIL signaling pathway plays an important role in the response to infections, in immune surveillance against tumors, and in autoimmune disorders. Moreover, its implication in suppression of autoimmunity suggests that Apo2L/TRAIL has potential as therapeutic agent not only in cancer but also in autoimmune diseases. In fact, Apo2L/TRAIL-based therapies have been shown effective in various animal models of autoimmune disease. This review summarizes the current knowledge on the biology of Apo2L/TRAIL and its role in the immune system. Finally, patent applications, mainly related with the use of Apo2L/TRAIL as therapeutic agent in several autoimmune diseases, are also summarized. PMID- 21827401 TI - Bringing drugs into the injured brain and keeping them there. AB - The delivery of pharmacological compounds to the injured brain is a huge challenge, which may predispose to drug failure and resistance. Besides the limited passage of drugs across the blood-brain barrier, which is a physical obstacle for the majority of pharmacological compounds, brain capillary cells express ATP-binding cassette (ABC) transporters on their surface, which actively remove drugs from the brain against concentration gradients. Eliminating a large number of pharmacological compounds and endogenous substrates from the brain tissue, ABC transporters play a major role for the maintenance of brain homeostasis and detoxification. The present issue summarizes current knowledge on ABC transporters in the injured brain, outlining how these efflux systems are regulated under pathological conditions, how they impede the brain accumulation of drugs and how they might contribute to the pathogenesis of neurological diseases once they become dysfunctional. This issue analyzes the validity of the concept of multidrug resistance, evaluating how ABC transporters may be modified in order to enable the development of more efficacious pharmacological treatments. PMID- 21827402 TI - ATP-binding cassette transporters at the blood-brain barrier in ischaemic stroke. AB - Ischaemic stroke is one of the most common diseases world-wide. Recent studies provide new insights into the role of ATP-binding cassette (ABC) transporters in brain ischaemia. Expressional and functional transporter changes that have been observed at the brain capillary endothelium during ischaemia impede the access of pharmacological compounds into the brain tissue. The current review summarizes the most important findings and discusses the role of hypoxia, inflammation, oxidative stress and lipids as factors regulating ABC transporters at the blood brain barrier. A better understanding of biodistribution processes at the blood brain barrier is urgently needed, so that the accumulation of drugs in the brain can be improved, enabling a successful translation of pharmacological treatments in ischaemic stroke. PMID- 21827404 TI - The clinical impact of ABCB1 polymorphisms on the treatment of psychiatric diseases. AB - Polymorphisms in the drug transporter gene ABCB1 account for differences in the clinically efficacy of the most drugs, most likely by influencing their access to the brain. The majority proportion of depressed patients, given a regular dose, do not respond properly or experience severe side effects. One explanation may be the polymorphisms in the drug transporter gene ABCB1, which account for differences in the clinical efficacy of antidepressants, neuroleptics or mood stabilizers most likely by influencing their access to the brain. If patients are treated with a substrate of P-gp, functionally relevant genetic variants in the ABCB1 transporter could influence intracerebral drug concentrations and, thereby, clinical response. The review shows recently investigated clinical impact of ABCB1 variants including the three most important SNPs rs1045642, rs2032582, and rs2032583. In the paper, with respect not to go beyond the scope of this review, we will focus on these three SNPs. The final goal of pharmacogenetics is to help clinicians to choose the best treatment for each individual patient. >From the evidence reviewed in this publication, it is likely that combination of metabolizing and drug target polymorphisms will produce the best prediction for the selection of the optimal dose and optimal drug as a function of the individual' s genetic profile. PMID- 21827405 TI - ATP-binding cassette transporters in inflammatory brain disease. AB - Owing to therapeutic progress, the role of ABC-transporters in infectious and autoimmune inflammatory CNS-diseases has recently gained considerable attention. In HIV-encephalitis and HIV-associated neurocognitive disorders, ABC-transporters are discussed to contribute to limited CNS-penetration and -retention of antiviral agents. In multiple sclerosis and its animal model experimental autoimmune encephalomyelitis, ABC-transporters may be involved in pathogenesis and treatment response alike. A prospective pharmacogenetic study is currently underway to examine the predictive role of genetic variations in ABC-transporters for treatment response and adverse events to mitoxantrone, a therapeutic agent used in aggressive MS. These approaches may aid in individualized treatment with this cytostatic anthracenedione, addressing its narrow therapeutic index with potentially fatal side effects. Finally, understanding regulation and function of ABC-transporters under inflammatory conditions may also optimize ABC-transporter related treatment strategies in other neurological diseases (e.g. neurodegenerative, and neurovascular) where neuroinflammatory mechanisms have gained considerable attention as important contributors to pathogenesis. PMID- 21827403 TI - Breast cancer resistance protein and P-glycoprotein in brain cancer: two gatekeepers team up. AB - Brain cancer is a devastating disease. Despite extensive research, treatment of brain tumors has been largely ineffective and the diagnosis of brain cancer remains uniformly fatal. Failure of brain cancer treatment may be in part due to limitations in drug delivery, influenced by the ABC drug efflux transporters P-gp and BCRP at the blood-brain and blood-tumor barriers, in brain tumor cells, as well as in brain tumor stem-like cells. P-gp and BCRP limit various anti-cancer drugs from entering the brain and tumor tissues, thus rendering chemotherapy ineffective. To overcome this obstacle, two strategies - targeting transporter regulation and direct transporter inhibition - have been proposed. In this review, we focus on these strategies. We first introduce the latest findings on signaling pathways that could potentially be targeted to down-regulate P-gp and BCRP expression and/or transport activity. We then highlight in detail the new paradigm of P-gp and BCRP working as a "cooperative team of gatekeepers" at the blood-brain barrier, discuss its ramifications for brain cancer therapy, and summarize the latest findings on dual P-gp/BCRP inhibitors. Finally, we provide a brief summary with conclusions and outline the perspectives for future research endeavors in this field. PMID- 21827406 TI - The role of the ATP-binding cassette transporter P-glycoprotein in the transport of beta-amyloid across the blood-brain barrier. AB - The blood-brain barrier (BBB) protects the brain against endogenous and exogenous compounds and plays an important part in the maintenance of the microenvironment of the brain. In particular, the importance of brain-to-blood transport of brain derived metabolites across the BBB has gained increasing attention as a potential mechanism in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease, which is characterized by the aberrant polymerization and accumulation of specific misfolded proteins, particularly beta-amyloid (Abeta). There is growing evidence that the ABC transport protein P-glycoprotein (P-gp), a major component of the BBB, mediates the efflux of Abeta from the brain. In this review, we discuss the possible role of P-gp in Alzheimer's disease and other neurodegenerative disorders, and consider how a fuller understanding of this function might promote the development of more effective treatment strategies. PMID- 21827407 TI - The ABC of the blood-brain barrier - regulation of drug efflux pumps. AB - According to the World Health Organization Central nervous system disorders are the major medical challenge of the 21st Century, yet treatments for many CNS disorders are either inadequate or absent. One reason is the existence of the blood-brain barrier, which strictly limits the access of substances to the brain. A key element of the barrier function is the expression of ABC export proteins in the luminal membrane of brain microvessel endothelial cells. Understanding the signaling cascades and the response to endogenous and exogenous stimuli, which lead to altered expression or function of the transporters as well as subsequent modulation of the transporters, may offer novel strategies to overcome the barrier and to improve drug delivery to the brain. This review gives a short overview about structure of the key elements of the blood-brain barrier with emphasis on ABC transporters. An insight into regulation of function and expression of these transport proteins is given and the involvement of these transporters in CNS diseases is discussed. PMID- 21827408 TI - Do ATP-binding cassette transporters cause pharmacoresistance in epilepsy? Problems and approaches in determining which antiepileptic drugs are affected. AB - Resistance to multiple antiepileptic drugs (AEDs) is a common problem in epilepsy, affecting at least 30% of patients. One prominent hypothesis to explain this resistance suggests an inadequate penetration or excess efflux of AEDs across the blood - brain barrier (BBB) as a result of overexpressed efflux transporters such as P-glycoprotein (Pgp), the encoded product of the multidrug resistance- 1 (MDR1, ABCB1) gene. Pgp and MDR1 are markedly increased in epileptogenic brain tissue of patients with AED-resistant partial epilepsy and following seizures in rodent models of partial epilepsy. In rodent models, AED resistant rats exhibit higher Pgp levels than responsive animals; increased Pgp expression is associated with lower brain levels of AEDs; and, most importantly, co-administration of Pgp inhibitors reverses AED resistance. Thus, it is reasonable to conclude that Pgp plays a significant role in mediating resistance to AEDs in rodent models of epilepsy - however, whether this phenomenon extends to at least some human refractory epilepsy remains unclear, particularly because it is still a matter of debate which AEDs, if any, are transported by human Pgp. The difficulty in determining which AEDs are substrates of human Pgp is mainly a consequence of the fact that AEDs are highly permeable compounds, which are not easily identified as Pgp substrates in in vitro models of the BBB, such as monolayer (Transwell((r))) efflux assays. By using a modified assay (concentration equilibrium transport assay; CETA), which minimizes the influence of high transcellular permeability, two groups have recently demonstrated that several major AEDs are transported by human Pgp. Importantly, it was demonstrated in these studies that Pgp-mediated transport highly depends on the AED concentration and may not be identified if concentrations below or above the therapeutic range are used. In addition to the efflux transporters, seizure induced alterations in BBB integrity and activity of drug metabolizing enzymes (CYPs) affect the brain uptake of AEDs. For translating these findings to the clinical arena, in vivo imaging studies using positron emission tomography (PET) with (11)C-labelled AEDs in epileptic patients are under way. PMID- 21827409 TI - Getting to know the cast - cellular interactions and signaling at the neurovascular unit. AB - The neurovascular unit (NVU), consisting of endothelial cells, basement membrane, pericytes, astrocytes and microglial cells, couples local neuronal function to local cerebral blood flow and regulates transport of blood-borne molecules across the blood-brain barrier (BBB). The building blocks and the phenotype of the NVU are well-established but the intercellular signaling between the different components remains elusive. A better understanding of the cellular interactions and signaling within the NVU is critical for the development of efficient therapeutics for the treatment of a variety of brain diseases, such as brain cancer, stroke, neuroinflammation and neurodegeneration. This review gives an overview about the current in vivo knowledge of the NVU and the communication between its different cellular constituents. We also discuss the usefulness of various model organisms for studies of the brain vasculature. PMID- 21827410 TI - In vitro modeling of the blood-brain barrier: simplicity versus complexity. AB - Proper understanding of blood-brain barrier (BBB) regulation is crucial to reduce/prevent its disruption during injury. Since high brain complexity makes interpretation of in vivo data challenging BBB studies are frequently performed using simplified in vitro models. Although such models represent an important and frequently employed alternative for investigation of BBB function and alterations, our ability to translate in vitro findings to in vivo situation remains sub-optimal. Consequently, despite the fact that our knowledge of the cellular and molecular mechanisms underlying BBB physiology and pathophysiology is constantly increasing, our ability to modulate barrier function remains virtually non-existent. Classical in vitro model systems have provided a wealth of knowledge until now, but it is now evident that newer in vitro models that are more representative of the in vivo situation are needed to further our understanding of barrier physiology. This paper will provide an overview of the BBB cellular components and the most frequently used in vitro BBB model systems. I will discuss their advantages and disadvantages, as well as highlight recently developed models that more closely mimic the BBB in vivo. PMID- 21827411 TI - Opioid transport by ATP-binding cassette transporters at the blood-brain barrier: implications for neuropsychopharmacology. AB - Some of the ATP-binding cassette (ABC) transporters like P-glycoprotein (P-gp; ABCB1, MDR1), BCRP (ABCG2) and MRPs (ABCCs) that are present at the blood-brain barrier (BBB) influence the brain pharmacokinetics (PK) of their substrates by restricting their uptake or enhancing their clearance from the brain into the blood, which has consequences for their CNS pharmacodynamics (PD). Opioid drugs have been invaluable tools for understanding the PK-PD relationships of these ABC transporters. The effects of morphine, methadone and loperamide on the CNS are modulated by P-gp. This review examines the ways in which other opioid drugs and some of their active metabolites interact with ABC transporters and suggests new mechanisms that may be involved in the variability of the response of the CNS to these drugs like carrier-mediated system belonging to the solute carrier (SLC) superfamily. Exposure to opioids may also alter the expression of ABC transporters. P-gp can be overproduced during morphine treatment, suggesting that the drug has a direct or, more likely, an indirect action. Variations in cerebral neurotransmitters during exposure to opioids and the release of cytokines during pain could be new endogenous stimuli affecting transporter synthesis. This review concludes with an analysis of the pharmacotherapeutic and clinical impacts of the interactions between ABC transporters and opioids. PMID- 21827412 TI - Designing new drugs for high grade gliomas. PMID- 21827413 TI - Targeting ErbB receptors in high-grade glioma. AB - High-grade gliomas, including glioblastoma, are among the most malignant and treatment-refractory human neoplasms. The tumors show high levels of resistance to conventional therapies (i.e. surgery, irradiation, and chemotherapy), and despite treatment advances patient outcome remains poor. New therapeutic options are needed. An especially interesting idea is the rational development of new therapies targeting molecules in cancer specific signaling pathways, thereby ideally increasing treatment efficacy and minimizing toxicity. Clearly, rational design requires thorough understanding of the molecular pathogenesis and resistance mechanisms. One highly promising approach is the targeted inhibition of ErbB growth factor receptors, which are recognized as key signaling pathways in many types of human tumors, including high-grade glioma. The ErbB receptor family of tyrosine kinases comprises four members: epidermal growth factor receptor (EGFR/ErbB1/HER1), ErbB2 (HER2/neu), ErbB3 (HER3) and ErbB4 (HER4). Physiologically, signaling is induced by ligand initiated receptor homo- or heterodimerization, activating intracellular downstream signaling pathways and leading to increased cell proliferation, anti-apoptosis and migration. A truncated, constitutively activated mutant EGFR (EGFRvIII) is associated with poor survival in GBM. Thus, to date anti-ErbB approaches are mainly focused on EGFR. The two major classes of anti-ErbB therapeutics are monoclonal antibodies (e.g. cetuximab, panitumumab) and small molecule Tyrosine kinase inhibitors (TKI, e.g. gefitinib, erlotinib, lapatinib). Some compounds entered clinical trials already, but clinical efficacy needs to be enhanced. Here we review current therapeutic advances targeting ErbB receptors in high-grade gliomas, and give a concise overview on current understanding of ErbB biology in gliomas, paving the way to novel rational therapeutic development. PMID- 21827415 TI - The role of integrins in glioma biology and anti-glioma therapies. AB - The tumor environment is critical for tumor maintenance and progression. Integrins are a large family of cell surface receptors mediating the interaction of tumor cells with their microenvironment and play important roles in glioma biology, including migration, invasion, angiogenesis and tumor stem cell anchorage. Here, we review preclinical and clinical data on integrin inhibition in malignant gliomas. Various pharmacological approaches to the modulation of integrin signaling have been explored including antibodies and peptide-based agents. Cilengitide, a cyclic RGD-mimetic peptide of alphavbeta3 and alphavbeta5 integrins is in advanced clinical development in glioblastoma. Cilengitide had only limited activity as a single agent in glioblastoma, but, when added to standard radiochemotherapy, appeared to prolong progression-free and overall survival in patients with newly diagnosed glioblastomas and methylation of the promoter of the O6 methylguanine methyltransferase (MGMT) gene. MGMT gene promoter methylation in turn predicts benefit from alkylating chemotherapy. A phase III randomized clinical trial in conjunction with standard radiochemotherapy in newly diagnosed glioblastoma patients with MGMT gene promoter methylation has recently completed accrual (EORTC 26071-22072). A companion trial explores a dose-escalated regimen of cilengitide added to radiotherapy plus temozolomide in patients without MGMT gene promoter methylation. Promising results in these trials would probably result in a broader interest in integrins as targets for glioma therapy and hopefully the development of a broader panel of anti-integrin agents. PMID- 21827416 TI - Targeting the AKT pathway in glioblastoma. AB - Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults. The treatment options for patients diagnosed with GBM are limited and the current median survival is 14-16 months following diagnosis. Genetic mutations have been identified that act as drivers of GBM growth and these should be considered as a basis for identifying novel therapeutic strategies. AKT is a downstream serine/threonine kinase in the RTK/PTEN/PI3K pathway and large scale genomic analysis of GBM has demonstrated that this pathway is mutated in the majority of GBMs. This RTK/PTEN/PI3K pathway leads to activated AKT and phospho-AKT levels are elevated in the majority of GBM tumor samples and cell lines, which studies show help glioma cells grow uncontrolled, evade apoptosis, and enhance tumor invasion. AKT represents a nodal point in this pathway which allows for amplification of growth signals, thereby making inhibition of AKT an attractive target for GBM therapy. Many different classes of AKT inhibitors exist, however, few have been tested sufficiently to demonstrate in vivo efficacy. This article will summarize the key components of the Akt pathway with special attention to gliomas, the genetic alterations driving this pathway in gliomas, and the studies evaluating inhibitors of this pathway. Inhibitors of the Akt pathway represent a potential treatment option against GBM and additional research efforts are required to fully explore and develop this possible treatment strategy. PMID- 21827417 TI - Collateral damage control in cancer therapy: defining the stem identity in gliomas. AB - The discovery of discrete functional components in cancer systems advocates a paradigm shift in therapeutic design towards the targeted destruction of critical cellular constituents that fuel tumorigenic potential. In astrocytomas, malignant growth can be propagated and sustained by glioma stem cells (GSCs) endowed with highly efficient clonogenic and tumor initiation capacities. Given their disproportionate oncogenic contribution, GSCs are often considered the optimal targets for curative treatment because their eradication may subvert the refractory nature of GBMs. However, the close affinity of GSCs and normal neural stem cells (NSCs) is a cautionary note for off-target effects of GSC-based therapies. In fact, many parallels can be drawn between GSC and NSC functions, which ostensibly rely on a communal collection of stem cell-promoting transcription factors (TFs). Only through rigorous scrutiny of nuances in the stemness program of GSCs and NSCs may we clarify the pathogenic mechanisms of stemness factors and reveal processes exploited by cancer cells to co-opt stem cell traits. Importantly, discerning the specific requirements for GSC and NSC maintenance may be an essential requisite when assessing molecular targets for discriminatory targeting of GSCs with minimal sequelae. PMID- 21827418 TI - Bioenergetics pathways and therapeutic resistance in gliomas: emerging role of mitochondria. AB - Cancer metabolism has gained considerable interest, since significant studies have indicated a close relationship between the activation of various oncogenes and alterations of cellular metabolism. Furthermore, several lines of evidence have shown that metabolic imaging can significantly impact malignant glioma patient management and monitoring of tumor response to therapy. In this context, mitochondria play a central role in cellular energy production, apoptosis and free radical generation. Mitochondrial malfunctions have been associated with development of many cancers, including brain tumors. Glioblastoma multiforme (GBM) is the most common primary intracranial neoplasm and its almost uniform lethality is exemplified by a median survival of 12-15 months. Current management consists of a combination of surgery, radiotherapy and chemotherapy. Despite aggressive treatment approaches, recurrence occurs in 90% of GBM patients. One cause of this poor outcome is development of a multidrug-resistance (MDR) phenotype. We and others have described in detail the bioenergetic pathways central to glioma growth and progression. One of the most striking observations is that glioma cells which rely on glycolytic metabolism readily adapt to bioenergetic stress by engaging their mitochondrial pathway in order to survive and grow. This suggests that mitochondrial function plays a critical role in the biology of gliomas. Still, the role that mitochondrial function has in development of chemoresistance in malignant brain tumors is largely unknown. Our goal in this review is to describe the current knowledge on the role of mitochondria function in the development of chemoresistance in glioma. Particular emphasis will be on ABC transporters. We will discuss the significance of these research areas in the context of development of more effective, targeted therapeutic modalities and diagnostic strategies for malignant glioma patients. PMID- 21827414 TI - Glioma stem cell maintenance: the role of the microenvironment. AB - Glioblastomas are highly lethal cancers for which conventional therapies provide only palliation. The cellular heterogeneity of glioblastomas is manifest in genetic and epigenetic variation with both stochastic and hierarchical models informing cellular phenotypes. At the apex of the hierarchy is a self-renewing, tumorigenic, cancer stem cell (CSC). The significance of CSCs is underscored by their resistance to cytotoxic therapies, invasive potential, and promotion of angiogenesis. Thus, targeting CSCs may offer therapeutic benefit and sensitize tumors to conventional treatment, demanding elucidation of CSC regulation. Attention has been paid to intrinsic cellular systems in CSCs, but recognition of extrinsic factors is evolving. Glioma stem cells (GSCs) are enriched in functional niches--prominently the perivascular space and hypoxic regions. These niches provide instructive cues to maintain GSCs and induce cellular plasticity towards a stem-like phenotype. GSC-maintaining niches may therefore offer novel therapeutic targets but also signal additional complexity with perhaps different pools of GSCs governed by different molecular mechanisms that must be targeted for tumor control. PMID- 21827419 TI - Preclinical development of novel anti-glioma drugs targeting the endoplasmic reticulum stress response. AB - The endoplasmic reticulum (ER) stress response represents a cellular "yin-yang" process, where low to moderate activity is cell protective and supports chemoresistance (yang), but where more severe conditions will aggravate these mechanisms to the point where they abandon their protective efforts and instead turn on a cell death program (yin). Because tumor cells frequently experience chronic stress conditions (due to hypoxia, hypoglycemia, acidification, etc.), the protective yang components of their ER stress response are continuously engaged and thus less able to neutralize additional insults taxing the ER stress response. This tumor-specific situation may provide therapeutic opportunities for pharmacologic intervention, where further aggravation of ER stress would lead to the activation of pro-apoptotic yin components and result in tumor cell death. This review will describe the yin-yang principle of ER stress, and will present pharmacologic agents and combination strategies aimed at exploiting the ER stress response for improved therapeutic outcomes, particularly in the setting of difficult to treat tumor types such as glioblastoma. PMID- 21827420 TI - New perspectives in glioma immunotherapy. AB - Glioblastoma (GBM) is a deadly tumor, which in spite of surgery and radio/chemotherapy frequently undergoes relapses related to the infiltration of the normal parenchyma and to resistance to cytotoxic and radiation therapy. Immunotherapy may represent a promising approach, which may complement existing therapies with the aim of eliminating residual tumor cells, through their selective targeting by immune effector cells or antibodies. This goal can be achieved through different approaches, based either on the induction of an immune response of the host, or by the injection of in vitro generated effector cells or monoclonal antibodies. Recent advances in the immunobiology of GBM and of its stem cell compartment will help in the development of more effective immunotherapy protocols. To this aim, the identification of antigens and receptors involved in GBM/immune cell interactions and of GBM immune escape mechanisms will provide new targets and tools. In this review we will discuss active immunotherapy approaches, including molecular-defined, GBM cell-based and dendritic-cell based vaccines. In addition, cytokines such as interferons and several interleukins can be used to enhance the immune response, both as recombinant molecules and by gene transfer technologies. Monoclonal antibodies or other ligands specific for GBM- or neovasculature-associated targets are now available in different genetically modified formats and can be used as such or for the targeted delivery of active compounds. Finally the in vitro activation and expansion of specific or innate immunity effector cells endowed with anti-GBM properties may provide an additional weapon for adoptive imunotherapy approaches. PMID- 21827422 TI - Lacticin 3147--biosynthesis, molecular analysis, immunity, bioengineering and applications. AB - The continuing problem of the emergence of multidrug resistance in pathogens has resulted in renewed efforts to identify novel antimicrobials that could be used in clinical settings. Lantibiotics are bacterially produced gene encoded antimicrobial peptides which have been the focus of extensive investigation in recent years because of their broad spectrum of activity. Lantibiotics (lanthionine-containing antibiotics), which have traditionally been regarded as antimicrobials for use in food or veterinary medicine, may provide at least part of the solution to these problems. Lacticin 3147 is a two peptide lantibiotic (consisting of the peptides Ltnalpha and Ltnbeta) which is active at low concentrations against many pathogens. It has been the subject of extensive research, which has generated significant insights into the mechanisms of lacticin 3147 biosynthesis, immunity, structure function relationships and the consequences of molecular bioengineering. The merits of employing lacticin 3147 to control spoilage microbes as well as its potential in the elimination of food, human and veterinary pathogens have also been highlighted. Here we review the knowledge which has been gained with respect to lacticin 3147 since its discovery in 1995. PMID- 21827423 TI - Molecular determinants of enzyme cold adaptation: comparative structural and computational studies of cold- and warm-adapted enzymes. AB - The identification of molecular mechanisms underlying enzyme cold adaptation is a hot-topic both for fundamental research and industrial applications. In the present contribution, we review the last decades of structural computational investigations on cold-adapted enzymes in comparison to their warm-adapted counterparts. Comparative sequence and structural studies allow the definition of a multitude of adaptation strategies. Different enzymes carried out diverse mechanisms to adapt to low temperatures, so that a general theory for enzyme cold adaptation cannot be formulated. However, some common features can be traced in dynamic and flexibility properties of these enzymes, as well as in their intra- and inter-molecular interaction networks. Interestingly, the current data suggest that a family-centered point of view is necessary in the comparative analyses of cold- and warm-adapted enzymes. In fact, enzymes belonging to the same family or superfamily, thus sharing at least the three-dimensional fold and common features of the functional sites, have evolved similar structural and dynamic patterns to overcome the detrimental effects of low temperatures. PMID- 21827425 TI - Global and threshold-free Transcriptional Regulatory Networks reconstruction through integrating ChIP-Chip and expression data. AB - Inferring transcriptional regulatory networks from high-throughput biological data is a major challenge to bioinformatics today. To address this challenge, we developed TReNGO (Transcriptional Regulatory Networks reconstruction based on Global Optimization), a global and threshold-free algorithm with simulated annealing for inferring regulatory networks by the integration of ChIP-chip and expression data. Superior to existing methods, TReNGO was expected to find the optimal structure of transcriptional regulatory networks without any arbitrary thresholds or predetermined number of transcriptional modules (TMs). TReNGO was applied to both synthetic data and real yeast data in the rapamycin response. In these applications, we demonstrated an improved functional coherence of TMs and TF (transcription factor)- target predictions by TReNGO when compared to GRAM, COGRIM or to analyzing ChIP-chip data alone. We also demonstrated the ability of TReNGO to discover unexpected biological processes that TFs may be involved in and to also identify interesting novel combinations of TFs. PMID- 21827424 TI - Computational analysis of phosphoproteomics: progresses and perspectives. AB - Phosphorylation is one of the most essential post-translational modifications (PTMs) of proteins, regulates a variety of cellular signaling pathways, and at least partially determines the biological diversity. Recent progresses in phosphoproteomics have identified more than 100,000 phosphorylation sites, while this number will easily exceed one million in the next decade. In this regard, how to extract useful information from flood of phosphoproteomics data has emerged as a great challenge. In this review, we summarized the leading edges on computational analysis of phosphoproteomics, including discovery of phosphorylation motifs from phosphoproteomics data, systematic modeling of phosphorylation network, analysis of genetic variation that influences phosphorylation, and phosphorylation evolution. Based on existed knowledge, we also raised several perspectives for further studies. We believe that integration of experimental and computational analyses will propel the phosphoproteomics research into a new phase. PMID- 21827426 TI - Systematic annotation and bioinformatics analyses of large-scale Oryza sativa proteome. AB - Much has been now recognized on the rice (Oryza sativa L.) proteomics by using the powerful experimental tool two-dimensional polyacrylamide gel electrophoresis (2D-PAGE). 2D-PAGE can be utilized for monitoring global changes of quantitative protein expression in specific tissues under various conditions. However, systematic annotations of the protein spots generated by 2D-PAGE are still limited for rice. In this study, a new approach for Oryza sativa proteome annotation based on the 2D-gel maps was developed. Based on the publicly available 2D-PAGE data of rice, 11,201 gel spots were annotated accounting for 87.2% of the total spots on the gel maps. Gel spot alignments were performed for the annotated gel maps belonging to 23 rice tissues or organelles. In summary, 253 alignments between 23 tissues or organelles were performed, and 26,207 co expressed proteins were identified using our analytical strategy. Large-scale bi cluster analysis of 23 tissues/organelles proteomes of rice was carried out to detect novel functional proteins. Function and pathway analysis identified a number of common gene products with great potential in regulating specific physiological and biochemical events within various rice tissues/organelles. It also suggested that the tissue- or organelle-specific proteins might be responsible for the functional divergence of these tissues or organelles. Taken together, this study provides us new strategies and informative resources for rice proteome research based on 2D-PAGE data. PMID- 21827427 TI - In silico Protein-Protein Interaction prediction with sequence alignment and classifier stacking. AB - Protein-Protein Interaction (PPI) prediction is a well known problem in Bioinformatics, for which a large number of techniques have been proposed in the past. However, prediction results have not been sufficiently satisfactory for guiding biologists in web-lab experiments. One reason is that not all useful information, such as pairwise protein interaction information based on sequence alignment, has been integrated together in PPI prediction. Alignment is a basic concept to measure sequence similarity in Proteomics that has been used in a number of applications ranging from protein recognition to protein subcellular localization. In this article, we propose a novel integrated approach to predicting PPI based on sequence alignment by jointly using a k-Nearest Neighbor classifier (SA-kNN) and a Support Vector Machine (SVM). SVM is a machine learning technique used in a wide range of Bioinformatics applications, thanks to the ability to alleviate the overfitting problems. We demonstrate that in our approach the two methods, SA-kNN and SVM, are complementary, which are combined in an ensemble to overcome their respective limitations. While the SVM is trained on Amino Acid (AA) compositions and protein signatures mined from literature, the SA-kNN makes use of the similarity of two protein pairs through alignment. Experimentally, our technique leads to a significant gain in accuracy, precision and sensitivity measures at ~5%, 16% and 10% respectively. PMID- 21827428 TI - Identification of plant protein kinases in response to abiotic and biotic stresses using SuperSAGE. AB - Plants are sessile organisms subjected to many environmental adversities. For their survival they must sense and respond to biotic and abiotic stresses efficiently. During this process, protein kinases are essential in the perception of environmental stimuli, triggering signaling cascades. Kinases are among the largest and most important gene families for biotechnological purposes, bringing many challenges to the bioinformaticians due to the combination of conserved domains besides diversified regions. Cowpea [Vigna unguiculata (L.) Walp.] is an important legume that is adapted to different agroclimatic conditions, including drought, humidity and a range of temperatures. For this crop, the association of the SuperSAGE method with high-throughput sequencing technology would generate reliable transcriptome profiles with millions of tags counted and statistically analyzed. An approach evaluating biotic and abiotic stresses was carried out generating over 13 million cowpea SuperSAGE tags available from leaves/roots of plants under abiotic (mechanical injury and salinity) or biotic (CABMV, Cowpea aphid born mosaic virus) stresses. The annotation and identification of tags linked by BlastN to previously well described ESTs, allowed the posterior identification of kinases. The annotation efficiency depended on the database used, with the KEGG figuring as a good source for annotated ESTs especially when complemented by an independent Gene Ontology categorization, as well as the Gene Index using selected species. The use of different approaches allowed the identification of 1,350 kinase candidates considering biotic libraries and 2,268 regarding abiotic libraries, based on a combination of both, adequate descriptions and GO terms. Additional searches in kinase specific databases allowed the identification of a relatively low number of additional kinases, uncovering the lack of kinase databases for non-model organisms, especially plants. Concerning the kinase families, a total of 713 potential kinases were classified into 13 families of the CMGC and STE groups. Concerning the differentially expressed kinases, 169 of the 713 potential kinases were identified (p < 0.05), 100 up- and 69 down-regulated when comparing distinct libraries, allowing the generation of a comprehensive panel of the differentially expressed kinases under biotic and abiotic stresses in a non-model plant as cowpea. PMID- 21827429 TI - A closer look at "social" boundary genes reveals knowledge to gene expression profiles. AB - As social network analysis is gaining popularity in modeling real world problems, the task of applying the social network model concepts and notions to biological data is still one of the most attractive research problems to be addressed. According, our work described in this paper focuses on a particular set of genes that reside on the community boundaries in gene co-expression networks. Stemmed from community mining problem in social networks, peripheries of communities (i.e., boundaries) can be used to aid certain biological analysis. The proposed method consists of three parts: 1) Finding communities of gene co-expression networks through clustering. 2) Analyzing stability of community structures by Monte Carlo method. 3) Designing of dynamic adoption of boundaries using geometric convexity. We validated our findings using breast cancer gene expression data from various studies. Our approach contributes to the new branch of applying social network mechanisms in biological data analysis, leading to new data mining strategies implied by witnessing social behaviors in gene expression analysis. PMID- 21827432 TI - Antiviral treatment of cytomegalovirus infection. AB - Cytomegalovirus (CMV) is an opportunistic pathogen associated with significant morbidity and mortality in immunocompromised hosts. Antiviral agents specifically targeting CMV were initially developed during the human immunodeficiency virus (HIV) epidemic to treat end-organ disease in patients with acquired immunodeficiency syndrome (AIDS). There are currently four antiviral drugs licensed for the treatment of CMV infections: ganciclovir (GCV), valganciclovir (VGCV), foscarnet (FOS), and cidofovir (CDV). The role of these agents has evolved from the treatment of disease to include prevention of CMV infection and disease, primarily in solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) recipients. The potential use of these drugs is being explored for the treatment of congenital CMV infection, another CMV-associated disease with significant morbidity. The availability of antiviral therapy has provided major advances in the treatment and prevention of CMV infection and has resulted in dramatically improved outcomes for immunocompromised hosts. At the same time, the clinical utility of most of these agents is limited by poor oral bioavailability, associated toxicities, and the potential for development of resistance with extended use. Novel therapeutic agents are needed to address these limitations. In this article, currently available anti-CMV agents will be described. An overview of the clinical syndromes caused by CMV will be provided, with specific reference to the role of antiviral agents in treating and preventing these infections. Antiviral resistance in CMV will be reviewed and novel therapeutic agents that may address resistance will be briefly discussed. PMID- 21827431 TI - The genetic basis of human cytomegalovirus resistance and current trends in antiviral resistance analysis. AB - Infections due to resistant human cytomegalovirus (CMV) are an emerging problem, particularly in immunocompromised hosts. When managing such patients, clinicians should be aware of the possibility of developing CMV antiviral resistance, especially while on prolonged therapy or if severe immunosuppression is present. CMV resistance to current antiviral agents is mediated by alterations in either the UL97 kinase or DNA polymerase, encoded by the UL97 and UL54 genes, respectively. UL97 mutations are capable of conferring resistance to ganciclovir, while UL54 mutations can impart resistance to ganciclovir, cidofovir, and foscarnet. If treatment failure is suspected to be due to antiviral resistance, CMV resistance analysis should be obtained. Phenotypic resistance assays performed on clinical isolates measure antiviral susceptibilities directly, but are laborious and time-consuming. Therefore, genotypic resistance analysis has become the more common means of diagnosing CMV resistance. Mutations in UL97 or UL54 may be clinically associated with resistance, but their effect on antiviral susceptibility must be confirmed by marker transfer techniques such as recombinant phenotyping. PMID- 21827435 TI - Cytomegalovirus infection in pediatric immunocompromised hosts. AB - Disease caused by cytomegalovirus (CMV) infection can clinically manifest in a variety of ways in the immunodeficient host and lead to significant morbidity and mortality. Infections can be primary, occur as a result of reactivation of latent virus, or infection with a new strain of CMV. Cell-mediated immunity is the main defense against CMV disease. This component of the immune system is frequently affected in children who are born prematurely, have undergone solid organ transplantation or hematopoietic stem cell transplantation, or have infection with human immunodeficiency virus. Accordingly, these children are at increased risk for severe disease due to CMV. In addition, CMV itself alters cell-mediated immunity and may predispose hosts to other bacterial, fungal, or viral infections as well as predispose to graft rejection. The importance of CMV in these special populations of children, emphasizing epidemiology, risk factors, and preventive strategies, is reviewed. PMID- 21827436 TI - Congenital cytomegalovirus infection: an overview. AB - Cytomegalovirus (CMV) remains the most common cause of congenitally-acquired infection in the United States and is a leading infectious cause of sensorineural hearing loss, cognitive delay, and permanent neurologic sequelae. Although most cases of congenital CMV infection are asymptomatic, significant morbidity and mortality exist for symptomatic infants and may also occur in asymptomatic ones. Diagnosis remains relatively straightforward, but treatment options are limited and associated with some toxicity. Efforts at prevention via vaccination, screening, and improved epidemiology deserve high priority to limit the impact of this common infection. PMID- 21827437 TI - Overview of congenital infections: the prominence of cytomegalovirus. AB - Congenital infections are those that are acquired transplacentally by the fetus from an infected mother. They constitute a major public health burden, affecting millions of infants and children worldwide. Despite significant advances in medical diagnostics, the majority of newborns with congenital infections are not recognized, since many of these infections may not cause clinically - apparent disease in the newborn period. Nonetheless, these infections - whether they are apparent or silent - have the potential to adversely impact the neurodevelopmental outcomes of these vulnerable children. PMID- 21827433 TI - Overview of the diagnosis of cytomegalovirus infection. AB - Cytomegalovirus (CMV) is recognized as the most common congenital viral infection in humans and an important cause of morbidity and mortality in immunocompromised hosts. This recognition of the clinical importance of invasive CMV disease in the setting of immunodeficiency and in children with congenital CMV infection has led to the development of new diagnostic procedures for the rapid identification of CMV. Diagnosis of acute maternal CMV infection by the presence of immunoglobulin (Ig)M and low-avidity IgG requires confirmation of fetal infection, which is typically performed using polymerase chain reaction (PCR) assays for CMV on amniotic fluid. Viral culture of the urine and saliva obtained within the first two weeks of life continues to be the gold standard for diagnosis of congenitally infected infants. PCR assays of dried blood spots from newborns have been shown to lack sufficient sensitivity for the identification of most neonates with congenital CMV infection for universal screening purposes. However, saliva PCR assays are currently being assessed as a useful screening method for congenital CMV infection. In the immunocompromised host, newer rapid diagnostic assays, such as phosphoprotein 65 antigenemia and CMV real-time PCR of blood or plasma have allowed for preemptive treatment, reducing morbidity and mortality. However, lack of standardized real-time PCR protocols hinders the comparison of data from different centers and the development of uniform guidelines for the management of invasive CMV infections in immunocompromised individuals. PMID- 21827438 TI - Editorial: cytomegalovirus infection in the fetus, infant, child, and adolescent: an overview of virus genetics and pathogenesis, disease burden, prevention, diagnosis, treatment, antiviral resistance, and drug targets. PMID- 21827439 TI - Is a pre-anaesthetic information form really useful? AB - BACKGROUND: All patients should be fully informed about the risks and benefits of anaesthetic procedures before giving a written consent. Moreover, the satisfaction level may vary in proportion to the information given. We aimed to determine, in a single-blind randomized-controlled study, whether an information form given before the pre-anaesthetic consultation could improve perceived information, information gain and satisfaction level. METHODS: Two hundred patients ASA 1-3 scheduled for an elective orthopaedic surgery were randomized into two groups: a group that received an information form before the pre anaesthetic consultation (IF group) and a control group (no information form). A standardized questionnaire was submitted after the pre-anaesthetic consultation and after the operation. This 17-item questionnaire explored perceived information (five items), information gain (three items) and satisfaction level (nine items). The items of each topic were pooled and compared between groups. RESULTS: One hundred and eighty-five patients (92.5%) completed the study. The IF group had better perceived information (IF group 73% vs. control group 63%, P=0.002), higher information gain (IF group 75% vs. control group 62%, P=0.001) and a higher satisfaction level (IF group 95% vs. control group 92%, P=0.048). CONCLUSIONS: Our study suggests that an information form given before the pre anaesthetic consultation enhances perceived information, information gain and satisfaction level. PMID- 21827434 TI - Congenital cytomegalovirus infection: molecular mechanisms mediating viral pathogenesis. AB - Human cytomegalovirus (CMV) is responsible for approximately 40,000 congenital infections in the United States each year. Congenital CMV disease frequently produces serious neurodevelopmental disability, as well as vision impairment and sensorineural hearing loss. Development of a CMV vaccine is therefore considered to be a major public health priority. The mechanisms by which CMV injures the fetus are complex and likely include a combination of direct fetal injury induced by pathologic virally-encoded gene products, an inability of the maternal immune response to control infection, and the direct impact of infection on placental function. CMV encodes gene products that function, both at the RNA and the protein level, to interfere with many cellular processes. These include gene products that modify the cell cycle; interfere with apoptosis; induce an inflammatory response; mediate vascular injury; induce site-specific breakage of chromosomes; promote oncogenesis; dysregulate cellular proliferation; and facilitate evasion of host immune responses. This minireview summarizes current concepts regarding these aspects of the molecular virology of CMV and the potential pathogenic impact of viral gene expression on the developing fetus. Areas for potential development of novel therapeutic intervention are suggested for improving the outcome of this disabling congenital infection. PMID- 21827440 TI - Propofol 2 mg/kg is superior to propofol 1 mg/kg for tracheal intubation in children during sevoflurane induction. AB - BACKGROUND: Propofol has been used to facilitate tracheal intubation within a short time of sevoflurane induction without a muscle relaxant in children. We compared as the primary outcome the incidence of excellent intubating conditions after 8% sevoflurane and propofol 1 or 2 mg/kg. METHODS: One hundred and four patients (2-7 years) were randomly assigned to receive propofol 1 mg/kg in group SP1 (n=53) or propofol 2 mg/kg in group SP2 (n=51) after inhalation induction using sevoflurane 8% in oxygen. Forty-five seconds after propofol and controlled ventilation, intubating conditions were assessed using a four-point scoring system based on ease of laryngoscopy, vocal cords position, coughing, jaw relaxation and limb movement. Heart rate and systolic blood pressure were measured as baseline, after sevoflurane induction, propofol, intubation and at 2 and 5 min following intubation. RESULTS: Three patients in group SP1 were excluded from analysis. Time from sevoflurane induction to intubation (248.9+/ 71.3 s in group SP1 vs. 230.9+/-61.3 s in group SP2) and endtidal sevoflurane before intubation (5.6+/-1.6% in group SP1 vs. 5.2+/-1.5% in group SP2) did not differ between the two groups. The incidence of excellent intubating conditions was significantly higher in group SP2 compared with group SP1 [47/51 (92%) vs. 28/50 (56%)]. The incidence of acceptable intubating conditions was significantly higher in group SP2 compared with group SP1 [48/51 (94%) vs. 35/50 (70%)]. No hemodynamic difference was noted at any time point between the two groups. CONCLUSION: Propofol 2 mg/kg during 8% sevoflurane induction resulted in a higher proportion of excellent intubating conditions compared with propofol 1 mg/kg. PMID- 21827441 TI - The effects of intraoperative infusion of dexmedetomidine on early renal function after percutaneous nephrolithotomy. AB - BACKGROUND: Percutaneous nephrolithotomy (PCNL) may interfere with renal function because of continuous fluid irrigation and compression. The aim of this study was to evaluate the effects of an intraoperative infusion of dexmedetomidine on renal function in patients undergoing PCNL. METHODS: This study included 40 patients between the ages of 18 and 65 years who underwent PCNL. After induction of anesthesia, we administered 100 ml of normal saline to the patients in the control group (n=20) and 1 mcg/kg dexmedetomidine in 100 ml of normal saline to the patients in the dexmedetomidine group (n=20) over 10 min. Throughout the surgery, 1 mcg/kg/h dexmedetomidine and 1 ml/kg/h normal saline infusions were given to the dexmedetomidine and control groups, respectively. Renal function, electrolytes, serum levels of neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C were analyzed after induction and post-operatively at 2, 8 and 24 h. Renin levels and blood gas analyses were performed after induction and before extubation. RESULTS: No statistically significant differences were found between the two groups with regard to renal function, creatinine clearance (CrCl), NGAL, cystatin C and serum electrolyte levels at 0, 2, 8 and 24 h post-operatively. End surgery renin levels in the dexmedetomidine group were significantly lower than the baseline levels in the control group. CONCLUSION: In PCNL, an intraoperative infusion of dexmedetomidine was not found to have beneficial effects on CrCl, NGAL or cystatin C levels early after the procedure; however, it reduced renin levels. PMID- 21827442 TI - Ultrasound-guided block of the axillary nerve: a volunteer study of a new method. AB - BACKGROUND: Interscalene brachial plexus block (IBPB) is the gold standard for perioperative pain management in shoulder surgery. However, a more distal technique would be desirable to avoid the side effects and potential serious complications of IBPB. Therefore, the aim of the present study was to develop and describe a new method to perform an ultrasound-guided specific axillary nerve block. METHODS: After initial investigations, 12 healthy volunteers were included. We performed an in-line ultrasound-guided specific axillary nerve block by injecting 8 ml local anesthetic (lidocaine 20 mg/ml) after placing the tip of a nerve stimulation needle cranial to the posterior circumflex humeral artery in the neurovascular space bordered by the teres minor muscle, the deltoid muscle, the triceps muscle and the shaft of the humerus. Needle placement was aided by simultaneous nerve stimulation. We assessed sensory (pinprick and cold stimulation) and motor (active resistive force) block of the axillary nerve before, 15, 30, 60, 90 and 120 min after performing the block and every 30 min until termination of the block. RESULTS: All 12 volunteers demonstrated sensory block of the axillary nerve and 10 volunteers demonstrated complete motor block. Even though it was difficult to directly visualize the axillary nerve, the block was easy to perform with easily recognizable ultrasonographic landmarks. Block duration was approximately 120 min. CONCLUSIONS: We describe a new ultrasound guided technique to specifically block the axillary nerve. The potential clinical role of this new block remains to be determined. PMID- 21827443 TI - Humidity affects the performance of von Frey monofilaments. AB - BACKGROUND: Assessment of tactile and nociceptive thresholds of the skin with calibrated polyamide monofilaments is an established testing method both in animal and in human research. It is known that changes in relative humidity may affect the physical properties of the monofilaments. As this effect has only been studied in very small diameter monofilaments, used in neonatal research, we therefore studied complete sets of polyamide monofilaments. METHODS: The effects were studied in a controlled climate chamber during six incremental changes in relative humidity from 20% to 79% (22-24 degrees C). Following 24 h of equilibration at each humidity level, calibration with a precision scale was performed. RESULTS: A highly significant linear correlation between the natural logarithm (In) of the bending force and the von Frey number was observed at all humidity levels (r(2)>0.99, P<0.0001). An inverse linear relationship between relative humidity and In of the bending force for each monofilament was found (r(2)=0.95, P<0.0001). One percent increase in relative humidity corresponded to a 1-4% relative decrease in numerical bending force, depending on the diameter of the monofilament. A significant linear relationship was observed between the coefficient of variation and the relative humidity (r(2)=0.87, P<0.001). CONCLUSIONS: The data indicate that the hygroscopic properties of polyamide monofilaments must be taken into account for their reliable use in quantitative sensory testing. PMID- 21827445 TI - Age-associated differences in the inhibition of mitochondrial permeability transition pore opening by cyclosporine A. AB - BACKGROUND: Inhibiting mitochondrial permeability transition pore (mPTP) opening is a key protection of the myocardium from ischemia/reperfusion (I/R) injury. Here, we investigated age-associated differences in the ability of cyclosporine A (CsA) to protect the heart and to modulate mPTP opening during I/R injury in vivo and its opening induced by reactive oxygen species (ROS) in vitro. METHODS: Fischer 344 male rats were assigned from their respective age groups, young or old groups, to (1) I/R or (2) I/R+CsA. All animals were subjected to 30 min of ischemia following 120 min of reperfusion to determine myocardial infarct size in vivo. To measure mPTP opening in vivo, left ventricular tissues were collected 10 min after reperfusion and nicotinamide adenine dinucleotide (NAD(+)) levels were measured. In parallel experiments, rat ventricular myocytes were prepared from young and old hearts, loaded with tetramethylrhodamine ethylester and then subjected to oxidative stress in the presence or absence of CsA, and the mPTP opening time was measured using laser scanning confocal microscopy. RESULTS: CsA reduced myocardial infarct size in young I/R rats. Whereas CsA failed to significantly affect myocardial infarct size in old I/R rats, NAD(+) levels were better preserved in young CsA-treated rats, but this relative improvement was not observed in old rats. CsA also significantly prolonged the time necessary to induce mPTP opening in young cardiomyocytes, but not in cardiomyocytes isolated from the old rats. CONCLUSIONS: mPTP regulation is dysfunctional in the aged myocardium and this could account for loss of cardioprotection with aging. PMID- 21827444 TI - Serum zinc in critically ill adult patients with acute respiratory failure. AB - BACKGROUND AND AIMS: Zinc deficiency leads to susceptibility to infections and may affect pulmonary epithelial cell integrity. Low zinc levels have also been associated with a degree of organ failure and decreased survival in critically ill children. Accordingly, the purpose of the study was to assess serum zinc in adult patients with acute respiratory failure, its association with ventilatory support time, intensive care unit (ICU) length of stay (LOS), organ dysfunction and 30-day mortality. METHODS: We included consecutive patients with acute respiratory failure during an eight-week prospective, observational multicentre study (the FINNALI-study). Acute respiratory failure was defined as a need for either non-invasive or invasive positive pressure ventilation for >6 h regardless of the underlying cause or risk factors. After informed consent, a sample for zinc measurement was drawn at 6 h after the start of treatment and analysed from 551 of these patients. RESULTS: Low serum zinc was frequent (95.8%) at the onset acute respiratory failure. The median interquartile range [IQR] was 4.7 [3.0-6.9] MUmol/l. The median [IQR] serum zinc levels in non-infectious, sepsis and septic shock patients were 5.0 [3.1-7.1], 5.1 [3.5-7.3] and 3.8 [2.6-5.9] MUmol/l, respectively, P<0.01. Baseline zinc levels were not associated with ventilatory support time (P=0.98) or ICU LOS (P=0.053). The area under curve in receiver operating characteristics analysis for serum zinc regarding 30-day mortality was 0.55 (95% CI 0.49-0.60). CONCLUSIONS: Serum zinc on initiation of ventilation had no predictive value for 30-day mortality, ventilatory support time or intensive care unit LOS. PMID- 21827446 TI - Does propofol induction in patients on olanzapine increase the susceptibility to dystonic reactions? PMID- 21827447 TI - Bootstrap methods for comparing independent regression slopes. AB - In this study, we explore the effects of non-normality and heteroscedasticity when testing the hypothesis that the regression lines associated with multiple independent groups have the same slopes. The conventional approach involving the F-test and the t-test (F/t approach) is examined. In addition, we introduce two robust methods which allow simultaneous testing of regression slopes. Our results suggest that the F/t approach is extremely sensitive to violations of assumptions and tends to yield misleading conclusions. The new robust alternatives are recommended for general use. PMID- 21827448 TI - Interaction of innovative small molecule drugs used for cancer therapy with drug transporters. AB - Multiple new small molecules such as tyrosine kinase, mammalian target of rapamycin (mTOR) and proteasome inhibitors have been approved in the last decade and are a considerable progress for cancer therapy. Drug transporters are important determinants of drug concentrations in the systemic circulation. Moreover, expression of drug transporters in blood-tissue barriers (e.g. blood brain barrier) can limit access of small molecules to the tumour (e.g. brain tumour). Finally, transporter expression and (up)regulation in the tumour itself is known to affect local drug concentrations in the tumour tissue contributing to multidrug resistance observed for multiple anticancer agents. This review summarizes the current knowledge on: (i) small molecules as substrates of uptake and efflux transporters; (ii) the impact of transporter deficiency in knockout mouse models on plasma and tissue concentrations; (iii) small molecules as inhibitors of uptake and efflux transporters with possible consequences for drug drug interactions and the reversal of multidrug resistance; and (iv) on clinical studies investigating the association of polymorphisms in genes encoding drug transporters with pharmacokinetics, outcome and toxicity during treatment with the small molecules. PMID- 21827449 TI - Genistein aglycone, a soy-derived isoflavone, improves skin changes induced by ovariectomy in rats. AB - BACKGROUND AND PURPOSE: Ovariectomy accelerates age-related skin changes as adequate oestrogen levels are required to control structural integrity and functional capacity of skin. Genistein, a soy-derived isoflavone, has been tested in anti-ageing cosmetic preparations with interesting results on skin elasticity, photoaging and skin cancer prevention. We investigated the effects of genistein aglycone and compared them with systemic raloxifene hydrochloride and 17-alpha ethinyloestradiol on skin changes in aged, ovariectomized (OVX) rats. EXPERIMENTAL APPROACH: Six months after ovariectomy, rats were randomly allocated to different groups and treated, daily, with genistein aglycone (1 and 10mg.kg( 1) s.c.), raloxifene hydrochloride (0.05 and 0.5mg.kg(-1) s.c.) or 17-alpha ethinyloestradiol (0.003 and 0.03mg.kg(-1) s.c.) for 12 weeks. Controls were untreated OVX and sham OVX rats. At the end of the treatment period, a skin biopsy was carried out and skin samples were assessed for molecular, histological and functional changes. KEY RESULTS: Skin samples of untreated OVX rats showed a decrease in TGF-beta1, VEGF, MMP-2, MMP-9, tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 compared with sham OVX rats. All the treatments significantly restored this depressed molecular profile revealed in OVX rats. Genistein aglycone, 1mg.kg(-1) , also significantly increased the thickness of collagen and breaking strength of skin in the OVX rats. CONCLUSIONS AND IMPLICATIONS: Relatively long-term, systemic treatment with genistein aglycone shows comparable efficacy to oestrogen in reversing some molecular, histological and functional changes of the skin associated with ovariectomy in aged rats. This suggests that genistein aglycone might be an effective alternative therapy for the management of age-related skin changes in postmenopausal women. PMID- 21827452 TI - Investigation of cool and hot executive function in ODD/CD independently of ADHD. AB - BACKGROUND: Children with oppositional defiant disorder/conduct disorder (ODD/CD) have shown deficits in 'cool' abstract-cognitive, and 'hot' reward-related executive function (EF) tasks. However, it is currently unclear to what extent ODD/CD is associated with neuropsychological deficits, independently of attention deficit hyperactivity disorder (ADHD). METHODS: Fifty-nine adolescents with a history of early-onset oppositional problems, 28 with pure ODD/CD symptoms and 31 with ADHD with or without ODD/CD, and 34 healthy controls were administered a task battery measuring motor response inhibition, sustained attention, cognitive flexibility and reward-related decision-making. Findings were analysed using dimensional and group analyses. RESULTS: In group analyses both groups with and without ADHD were impaired in EF measures. Dimensional analyses, however, showed that ODD/CD but not ADHD was related to hot EF based on increased risky decision making in the Iowa Gambling Task. ODD/CD was also independently related to aspects of cool EF independently of ADHD, namely slower speeds of inhibitory responding and increased intra-subject variability. CONCLUSIONS: These findings show EF deficits associated with ODD/CD independently of ADHD, and implicate reward-related abnormalities in theories of antisocial behaviour development. PMID- 21827450 TI - Corticosteroid-induced gene expression in allergen-challenged asthmatic subjects taking inhaled budesonide. AB - BACKGROUND AND PURPOSE: Inhaled corticosteroids (ICS) are the cornerstone of asthma pharmacotherapy and, acting via the glucocorticoid receptor (GR), reduce inflammatory gene expression. While this is often attributed to a direct inhibitory effect of the GR on inflammatory gene transcription, corticosteroids also induce the expression of anti-inflammatory genes in vitro. As there are no data to support this effect in asthmatic subjects taking ICS, we have assessed whether ICS induce anti-inflammatory gene expression in subjects with atopic asthma. EXPERIMENTAL APPROACH: Bronchial biopsies from allergen-challenged atopic asthmatic subjects taking inhaled budesonide or placebo were subjected to gene expression analysis using real-time reverse transcriptase-PCR for the corticosteroid-inducible genes (official gene symbols with aliases in parentheses): TSC22D3 [glucocorticoid-induced leucine zipper (GILZ)], dual specificity phosphatase-1 (MAPK phosphatase-1), both anti-inflammatory effectors, and FKBP5 [FK506-binding protein 51 (FKBP51)], a regulator of GR function. Cultured pulmonary epithelial and smooth muscle cells were also treated with corticosteroids before gene expression analysis. KEY RESULTS: Compared with placebo, GILZ and FKBP51 mRNA expression was significantly elevated in budesonide treated subjects. Budesonide also increased GILZ expression in human epithelial and smooth muscle cells in culture. Immunostaining of bronchial biopsies revealed GILZ expression in the airways epithelium and smooth muscle of asthmatic subjects. CONCLUSIONS AND IMPLICATIONS: Expression of the corticosteroid-induced genes, GILZ and FKBP51, is up-regulated in the airways of allergen-challenged asthmatic subjects taking inhaled budesonide. Consequently, the biological effects of corticosteroid-induced genes should be considered when assessing the actions of ICS. Treatment modalities that increase or decrease GR-dependent transcription may correspondingly affect corticosteroid efficacy. PMID- 21827453 TI - Latent evidence detection using a combination of near infrared and high dynamic range photography: an example using bloodstains. AB - In this paper, we use bloodstains to illustrate an approach for identifying latent evidence on dark cloth using near infrared (NIR) photography combined with high dynamic range (HDR) photography techniques. NIR photography alone has been used to capture latent evidence that cannot be seen in normal ambient light. HDR techniques combine multiple bracketed photographs of the same image to increase the dynamic range of the photograph which can provide greater contrast. Using NIR photography alone, we were able to detect a bloodstain up to a 1/16 dilution, an improvement over previous studies. Combining NIR photography with the HDR process resulted in a noticeable increase in visibility up to 1/16 dilution when compared to NIR photographs alone. At 1/32 dilution, we were able to detect bloodstains that were not visible using NIR alone. NIR is a useful tool for imaging latent evidence, and combining NIR with HDR consistently provides better results over NIR alone. PMID- 21827451 TI - Cannabidiol, a non-psychotropic component of cannabis, attenuates vomiting and nausea-like behaviour via indirect agonism of 5-HT(1A) somatodendritic autoreceptors in the dorsal raphe nucleus. AB - BACKGROUND AND PURPOSE: To evaluate the hypothesis that activation of somatodendritic 5-HT(1A) autoreceptors in the dorsal raphe nucleus (DRN) produces the anti-emetic/anti-nausea effects of cannabidiol (CBD), a primary non psychoactive cannabinoid found in cannabis. EXPERIMENTAL APPROACH: The potential of systemic and intra-DRN administration of 5-HT(1A) receptor antagonists, WAY100135 or WAY100635, to prevent the anti-emetic effect of CBD in shrews (Suncus murinus) and the anti-nausea-like effects of CBD (conditioned gaping) in rats were evaluated. Also, the ability of intra-DRN administration of CBD to produce anti-nausea-like effects (and reversal by systemic WAY100635) was assessed. In vitro studies evaluated the potential of CBD to directly target 5 HT(1A) receptors and to modify the ability of the 5-HT(1A) agonist, 8-OH-DPAT, to stimulate [(35) S]GTPgammaS binding in rat brainstem membranes. KEY RESULTS: CBD suppressed nicotine-, lithium chloride (LiCl)- and cisplatin (20 mg.kg(-1) , but not 40 mg.kg(-1) )-induced vomiting in the S. murinus and LiCl-induced conditioned gaping in rats. Anti-emetic and anti-nausea-like effects of CBD were suppressed by WAY100135 and the latter by WAY100635. When administered to the DRN: (i) WAY100635 reversed anti-nausea-like effects of systemic CBD, and (ii) CBD suppressed nausea-like effects, an effect that was reversed by systemic WAY100635. CBD also displayed significant potency (in a bell-shaped dose-response curve) at enhancing the ability of 8-OH-DPAT to stimulate [(35) S]GTPgammaS binding to rat brainstem membranes in vitro. Systemically administered CBD and 8 OH-DPAT synergistically suppressed LiCl-induced conditioned gaping. CONCLUSIONS AND IMPLICATIONS: These results suggest that CBD produced its anti-emetic/anti nausea effects by indirect activation of the somatodendritic 5-HT(1A) autoreceptors in the DRN. LINKED ARTICLES: This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7. PMID- 21827454 TI - Theory and the scientific basis for forensic anthropology. AB - Forensic anthropology has long been criticized for its lack of a strong theoretical and scientific foundation. This paper addresses this problem by examining the role of theory in forensic anthropology at different hierarchical levels (high-level, middle-range, and low-level) and the relevance of various theoretical concepts (taphonomic, agency, behavioral archaeology, nonlinear systems, and methodological theories) to the interpretation of forensic contexts. Application of these theories to a case study involving the search for the WWII Goettge Patrol illustrates the explanatory power these theories offer to the interpretation of forensic events as the end product of an often complex set of environmental constraints and behavioral interactions and choices. It also emphasizes the importance of case studies in theory building and hypothesis testing. A theoretical foundation does indeed currently exist in forensic anthropology; however, a recognition and broader implementation of anthropological (archaeological) theory is warranted and will further define forensic anthropology as a scientific endeavor. PMID- 21827455 TI - New optimized DNA extraction protocol for fingerprints deposited on a special self-adhesive security seal and other latent samples used for human identification. AB - Obtaining complete short tandem repeat (STR) profiles from fingerprints containing minimal amounts of DNA, using standard extraction techniques, can be difficult. The aim of this study was to evaluate a new kit, Fingerprint DNA Finder (FDF Kit), recently launched for the extraction of DNA and STR profiling from fingerprints placed on a special device known as Self-Adhesive Security Seal Sticker((r)) and other latent fingerprints on forensic evidentiary material like metallic guns. The DNA extraction system is based on a reversal of the silica principle, and all the potential inhibiting substances are retained on the surface of a special adsorbent, while nucleic acids are not bound and remain in solution dramatically improving DNA recovery. DNA yield was quite variable among the samples tested, rendering in most of the cases (>90%) complete STR profiles, free of PCR inhibitors, and devoid of artifacts. Even samples with DNA amount below 100 pg could be successfully analyzed. PMID- 21827456 TI - Availability of target odor compounds from seized ecstasy tablets for canine detection. AB - The aim of this study was to compare seized samples of 3,4-methylenedioxy-N methylamphetamine (MDMA) pills, used to train law enforcement detection canine teams, to determine what differences exist in the chemical makeup and headspace odor and their effect on detectability. MDMA solutions were analyzed by liquid chromatography-mass spectrometry. Analysis of these samples showed a wide variance of MDMA (8-25%). Headspace SPME-GC/MS analysis showed that several compounds such as 3,4-methylenedioxyphenylacetone and 1-(3,4 methylenedioxyphenyl)-2-propanol are common among these MDMA samples regardless of starting compound and synthesis procedure. However, differences, such as the level of the various methylenedioxy starting compounds, were shown to affect the overall outcome of canine detection, indicating the need for more than one MDMA training aid. Combinations of compounds such as the primary odor piperonal in conjunction with a secondary compound such as MDP-2-OH or isosafrole are recommended to maximize detection of different illicit MDMA samples. PMID- 21827457 TI - Suicide behind bars: trends, inconsistencies, and practical implications. AB - The results of two comprehensive approaches are compared: the nationwide surveys of suicides in U.S. jails by Hayes and the international meta-analyses of suicides in jails and prisons by Fazel et al. Factors are classified as demographic, situational, clinical, and methodical. More than 50% of U.S. jail suicide victims were men, white, unmarried, under 28 years of age, charged with minor or drug-related offenses, and intoxicated with drugs or alcohol. Suicides significantly occurred in isolation. Suicide victims in the international study were significantly (p < 0.001) men, white, married, pretrial, and charged with or convicted of violent offenses. Psychiatric diagnosis, alcohol abuse, taking psychotropic medication, and suicidal ideation were also positively correlated in the international study, but suicide victims were distributed more evenly over age-groups. Results of other studies illustrate the near universality of some findings. Three theories of suicide are briefly discussed. PMID- 21827458 TI - Validating TrueAllele(r) DNA mixture interpretation. AB - DNA mixtures with two or more contributors are a prevalent form of biological evidence. Mixture interpretation is complicated by the possibility of different genotype combinations that can explain the short tandem repeat (STR) data. Current human review simplifies this interpretation by applying thresholds to qualitatively treat STR data peaks as all-or-none events and assigning allele pairs equal likelihood. Computer review, however, can work instead with all the quantitative data to preserve more identification information. The present study examined the extent to which quantitative computer interpretation could elicit more identification information than human review from the same adjudicated two person mixture data. The base 10 logarithm of a DNA match statistic is a standard information measure that permits such a comparison. On eight mixtures having two unknown contributors, we found that quantitative computer interpretation gave an average information increase of 6.24 log units (min = 2.32, max = 10.49) over qualitative human review. On eight other mixtures with a known victim reference and one unknown contributor, quantitative interpretation averaged a 4.67 log factor increase (min = 1.00, max = 11.31) over qualitative review. This study provides a general treatment of DNA interpretation methods (including mixtures) that encompasses both quantitative and qualitative review. Validation methods are introduced that can assess the efficacy and reproducibility of any DNA interpretation method. An in-depth case example highlights 10 reasons (at 10 different loci) why quantitative probability modeling preserves more identification information than qualitative threshold methods. The results validate TrueAllele((r)) DNA mixture interpretation and establish a significant information improvement over human review. PMID- 21827459 TI - Age estimation by measurements of developing teeth: accuracy of Cameriere's method on a Brazilian sample. AB - Developing teeth are commonly the criteria used for age estimation in children and young adults. The method developed by Cameriere et al. (Int J Legal Med 2006;120:49-52) is based on measures of teeth with open apex, and application of a formula, to estimate chronological age of children. The present study evaluated a sample of panoramic radiographs from Brazilian children from 5 to 15 years of age, to evaluate the accuracy of the method proposed by Cameriere et al. The results has proven the system reliable for age estimation, with a median residual error of -0.014 years between chronological and estimated ages (p = 0.603). There was a slight tendency to overestimate the ages of 5-10 years and underestimate the ages of 11-15 years. PMID- 21827460 TI - In the eye of the beholder: sex and race estimation using the human orbital aperture. AB - From the works of Broca and Krogman to modern-day Jantz and Buikstra, the orbit has been used for both quantitative and qualitative sex and race estimation. This study evaluates the practical value of these estimations. Orbital height and breadth were measured to determine the orbital index and assess differences between men and women or black people and white people in the Hamann-Todd Collection. Replicability of these measures was also examined. Finally, a geometric morphometric study was performed to assess shape differences using the entire margin. Significant differences were found in both the index and the geomorphometric study; however, further investigation revealed that the differences were of little practical use. The measurement differences were found to be smaller than intra-observer error, while the geometric morphometric analysis demonstrated that minimal percentage of variation in shape was attributable to group differences. Thus, these techniques should not be used to estimate sex or race. PMID- 21827461 TI - How useful is basal renal tubular epithelial cell vacuolization as a marker for significant hyperglycemia at autopsy? AB - Basal vacuolization of renal tubular epithelial cells (so-called Armanni-Ebstein phenomenon) has been attributed to hyperglycemia causing accumulation of cytoplasmic glycogen. Review of 34 autopsy cases with significant hyperglycemia (vitreous glucose >= 15 mmol/L/270 mg/dL) was undertaken to determine whether there was any significant association between the degree of hyperglycemia and the severity of this morphological change (graded as 0, 1+, 2+, and 3+). No association was demonstrated. Review of the subgroup of 14 cases with terminal hyperglycemia without ketoacidosis was then undertaken to assess the effect of hyperglycemia in isolation on renal tubular epithelial cells. Vitreous glucose levels in these 14 cases ranged from 17 to 49.7 mmol/L (306-894.6 mg/dL) with a mean of 26.25 mmol/L (472.5 mg/dL) and beta-hydroxybutyrate levels ranged from 0.02 to 2.55 mmol/L (0.36-45.9 mg/dL) with a mean 0.79 mmol/L (14.22 mg/dL). Not one of the latter cases displayed basal vacuolization. No relationship between basal vacuolization of renal tubular epithelial cells at autopsy and terminal hyperglycemia could, therefore, be demonstrated. PMID- 21827462 TI - Advantage of affinity histochemistry combined with histology to investigate death causes: indications from sample cases. AB - Mast cell histochemistry has been proposed in addition to classic histological methods to estimate the course of traumatic events before and after death. We have addressed the utility of this approach on nine victims of different types of trauma. Sections of wounded skin were stained with hematoxylin and eosin and with fluorescent avidin to tag mast cells. Mast cell numbers were evaluated by both direct and digitalized counts. Intact skin was used as control. The results on mast cells implemented the findings upon hematoxylin and eosin stain and helped to put the wounds and death in chronological sequence. Digitalized morphometry allowed to reduce intra- and inter-observer variation. We conclude that combined histological and histochemical analyses can be of practical use in forensic pathology, that a preliminary setting of the reference values is needed for each laboratory, and that image analysis can be of help for the quantification of the results. PMID- 21827463 TI - Comparisons of familial DNA database searching strategies. AB - The current familial searching strategies are generally based on either Identity By-State (IBS) (i.e., number of shared alleles) or likelihood ratio (i.e., kinship index [KI]) assessments. In this study, the expected IBS match probabilities given relationships and the logic of the likelihood ratio method were addressed. Further, the false-positive and false-negative rates of the strategies were compared analytically or by simulations using Caucasian population data of the 13 CODIS Short Tandem Repeat (STR). IBS >= 15, IBS >= 16, KI >= 1000, or KI >= 10,000 were found to be good thresholds for balancing false positive and false-negative rates. IBS >= 17 and/or KI >= 1,000,000 can exclude the majority of candidate profiles in the database, either related or not, and may be an initial screening option if a small candidate list is desired. Polices combining both IBS and KI can provide higher accuracy. Typing additional STRs can provide better searching performance, and lineage markers can be extremely useful for reducing false rates. PMID- 21827464 TI - Remote spectroscopic identification of bloodstains. AB - Blood detection and identification at crime scenes are crucial for harvesting forensic evidence. Unfortunately, most tests for the identification of blood are destructive and time consuming. We present a fast and nondestructive identification test for blood, using noncontact reflectance spectroscopy. We fitted reflectance spectra of 40 bloodstains and 35 nonbloodstains deposited on white cotton with spectroscopic features of the main compounds of blood. Each bloodstain was measured 30 times to account for aging effects. The outcome of the blood measurements was compared with the reflectance of blood-mimicking stains and various body fluids. We found that discrimination between blood and nonblood deposited on white cotton is possible with a specificity of 100% and a sensitivity of 98%. In conclusion, a goodness of fit between the sample's reflectance and the blood component fit may allow identification of blood at crime scenes by remote spectroscopy. PMID- 21827465 TI - Investigation into the merits of infrared imaging in the investigation of tattoos postmortem. AB - Infrared imaging has a history of use in the forensic examination of artwork and documents and is investigated here for its wider use in the detection of tattoos on the human body postmortem. Infrared photographic and reflectographic techniques were tested on 18 living individuals, displaying a total of 30 tattoos. It was observed that neither age, sex, age of the tattoo, nor, most significantly, skin color affected the ability to image the tattoos using infrared imaging techniques. Second, a piglet carcass was tattooed and the impact of the decomposition process on the visibility of the tattoos assessed. Changes were recorded for 17 days and decomposition included partial mummification and skin discoloration. Crucially, the discoloration was recorded as greatly affecting the image quality using conventional photography, but was insignificant to the infrared recording of these tattoos. It was concluded that infrared reflectography was beneficial in the investigation into tattoos postmortem. PMID- 21827466 TI - Rapid presumptive "fingerprinting" of body fluids and materials by ATR FT-IR spectroscopy. AB - Human body fluids and materials were evaluated using attenuated total reflectance Fourier transform infrared spectroscopy. Purified proteins, cosmetics, and foodstuffs were also assayed with the method. The results of this study show that the sampled fluids and materials vary in the fingerprint region and locations of the amide I peaks because of the secondary structure of the composite proteins although the C = O stretch is always present. The distinct 1016 cm(-1) peak serves as a signature for semen. The lipid-containing materials (e.g., fingerprints, earwax, tears, and skin) can also be easily separated from the aqueous materials because of the strong CH(3) asymmetric stretch of the former. Blood-saliva and blood-urine mixtures were also successfully differentiated using combinations of peaks. Crime scene investigators employing rapid, portable, or handheld infrared spectroscopic instruments may be able to reduce their need for invasive, destructive, and consumptive presumptive test reagents in evaluating trace evidence. PMID- 21827467 TI - Comparison of the analytical capabilities of the BAC Datamaster and Datamaster DMT forensic breath testing devices. AB - The State of Michigan uses the Datamaster as an evidential breath testing device. The newest version, the DMT, will replace current instruments in the field as they are retired from service. The Michigan State Police conducted comparison studies to test the analytical properties of the new instrument and to evaluate its response to conditions commonly cited in court defenses. The effects of mouth alcohol, objects in the mouth, and radiofrequency interference on paired samples from drinking subjects were assessed on the DMT. The effects of sample duration and chemical interferents were assessed on both instruments, using drinking subjects and wet-bath simulators, respectively. Our testing shows that Datamaster and DMT results are essentially identical; the DMT gave accurate readings as compared with measurements made using simulators containing standard ethanol solutions and that the DMT did not give falsely elevated breath alcohol results from any of the influences tested. PMID- 21827468 TI - Motor vehicle accident fatalities trends, Puerto Rico 2000-2007. AB - Motor vehicle accident fatalities (MVAF) are an important cause of death that affects millions of people worldwide. Using the Puerto Rico Institute of Forensic Science database, this study accessed the mortality trends of MVAF in Puerto Rico from 2000 to 2007. Descriptive statistics, age-adjusted mortality rates, geographical analysis, and annual percentage change were calculated. An annual mean of 559 MVAF occurred during the study period. The overall MVAF mortality rate declined from 2000 to 2007 (16.6 and 12.4 per 100,000 population, respectively)-mortality rates annually decreased 3%. Most MVAF (80.2%) occurred in men, showing a risk four times higher than women (23.6 and 5.4 deaths per 100,000 populations, respectively). Drivers aged 20-24 years and pedestrians older than 75 years had the highest risk of death. This study emphasizes the need of public health efforts to focus on the prevention of MVAF in the most affected groups. PMID- 21827469 TI - To be used or not to be used, that is the question: legal use of forensic and clinical information collected in a self-referral sexual assault centre. AB - This study explores how the police select cases for using information from a self referral Sexual Assault Centre (SAC). The study is retrospective and descriptive: a 2-year series from a Scandinavian SAC and corresponding police files. The police had access to 163 SAC cases, requested 84% of available forensic medical documentation, and had 50% of the trace samples analyzed. The two main predictors of police utilization of forensic evidence were cases the police classified as rape and complaints filed during January to August. Extrinsic DNA was found in 27/60 trace evidence analyses, 21 matching a suspect. For one-third of the suspects who denied sexual acts, the forensic evidence contradicted their denial. Nonuse forfeited this possibility in several cases, and relevant information on injuries was lost. Our results indicate that available medical information is not fully utilized for legal purposes. Main barriers are police classification of cases and insufficient economic funding. PMID- 21827470 TI - Sexual assault centres and police reporting--an important arena for medical/legal interaction. AB - This study explores the usefulness of forensic medical examination (FME) irrespective of police request and police-reporting practices at a self-referral Sexual Assault Centre (SAC). The study is retrospective, descriptive: a 2-year series of cases from a Scandinavian SAC and corresponding police files. Among 354 SAC cases, 180 were reported to the police, comprising 103 of 197 total rapes registered in this police district. Of 278 complainants presenting in time for FME, 55% reported to the police. FME was performed in 238 cases, 142 of these registered by the police. In 24% of the latter, examination preceded reporting by >= 2 days. Thus, substantial amounts of SAC casework remain unavailable to the police owing to nonreporting. However, performing FME regardless of reporting considerably increases the amount of information available to the police in late reported cases. Although several factors predict reporting, the predictive power is insufficient for performing FME selectively. PMID- 21827471 TI - Validation of thin layer chromatography with AccuTOF-DARTTM detection for forensic drug analysis. AB - Thin layer chromatography (TLC) is a technique that is commonly employed in the forensic drug analysis of pharmaceutical preparations. Detection is typically accomplished using various visualization spray reagents. Conventional gas chromatography-mass spectrometry (GC-MS) analysis is typically performed to confirm the TLC results. Depending on the drugs tested and the instrument conditions required, this confirmation can take up to an hour to complete. Direct analysis in real time (DARTTM) is an ionization source, coupled to an accurate mass time-of-flight mass spectrometer that has the capability to ionize materials under ambient conditions. To streamline analysis, the combination of TLC with DARTTM detection is proposed to screen and subsequently identify drug compounds, all from the same TLC plate. DARTTM confirmations of TLC analyses take <10 min to complete and compare favorably to GC-MS in sensitivity and selectivity. This study validates the use of TLC-DART in the forensic identification of the components of several pharmaceutical preparations. PMID- 21827472 TI - Prevalence and effects of violence against women in a rural community in Minia governorate, Egypt. AB - This study was carried out to investigate prevalence and the characteristics of domestic violence (DV) against women in a rural area in Minia governorate, Egypt, as well as its physical and psychological consequences. Seven hundred and seventy two women were interviewed. Sociodemographic data were collected; the WHO questionnaire was used to identify the abuse; the Structured Clinical Interview for DSM IIIR (SCID) to detect psychiatric disorders. Abused females constituted 57.4% of the total sample. There were significant relationships between DV and low education, low income, higher number of children, and husband's education. Psychiatric disorders occurred in 18% of the sample. There were statistically significant relationships between psychological and physical abuse of women and the occurrence of psychiatric disorders. In conclusion, DV against women was related to various negative health outcomes, and it is recommended to be given its real importance in both Forensic Medicine Council and in psychiatric assessment. PMID- 21827473 TI - Toxicological findings in cases of sexual assault in the Netherlands. AB - Reports on cases of alleged drug-facilitated sexual assault (DFSA) have increased since the mid-1990s. The aim of this study was to identify the extent and types of drugs found in cases of alleged sexual assault (DFSA) in the Netherlands. In total, 135 cases of alleged DFSA were identified. Most of the victims were women (94%), and the mean age of the victims was 25 years. Blood and urine samples were tested for the presence of alcohol, drugs (drugs of abuse and prescription drugs), or both. In 27% of the cases, no alcohol and/or drugs were found. With increasing time delay, more cases were found to be negative. Alcohol is the most commonly found drug followed by nonopiate analgesics, illicit drugs, and benzodiazepines. In some cases, the absence of alcohol and drugs may represent false-negative results owing to the time delay between alleged sexual assault and sampling. PMID- 21827474 TI - Death certification of "suicide by cop". AB - Death certification of "suicide by cop" is controversial among some medical examiners and coroners. We present five such deaths that were certified as suicides and discuss the medico-legal issues involved with these certifications. To certify such a death as a suicide, certain criteria should be met. Suicide by cop is a circumstance that involves competing intentional acts that may result in dichotomous determinations of the manner of death. Despite the absence of direct self-infliction, there is overwhelming evidence that these five individuals intended to end their own lives. Their use of an unusual method to accomplish this goal may inappropriately result in a reflexive certification of homicide. All of the decedents possessed weapons or a facsimile of a weapon. We present five instances of suicide by cop and contend that these types of deaths are best certified as suicides. PMID- 21827475 TI - Fatal acute intracranial injury, subdural hematoma, and retinal hemorrhages caused by stairway fall. AB - We describe an infant with an acute subdural hematoma, a fatal head injury, and severe hemorrhagic retinopathy caused by a stairway fall. His cerebral and ocular findings are considered diagnostic of abusive head trauma by many authors. Our literature search of serious injuries or fatalities from stairway or low-height falls involving young children yielded 19 articles of primary data. These articles are discrepant, making the classification of a young child's death following a reported short fall problematic. This case report contradicts the prevalent belief of many physicians dealing with suspected child abuse that low height falls by young children are without exception benign occurrences and cannot cause fatal intracranial injuries and severe retinal hemorrhages. The irreparable harm to a caregiver facing an erroneous allegation of child abuse requires physicians to thoroughly investigate and correctly classify pediatric accidental head injuries. PMID- 21827476 TI - Specific micro-RNA signatures for the detection of saliva and blood in forensic body-fluid identification. AB - Micro-RNAs (miRNAs) are a class of small noncoding RNA (ncRNA) molecules with a length of 18-24 nucleotides which play an essential regulative role for many cellular processes. Evidence suggests that the miRNome is a more precise and meaningful representation of a cell type and condition than the mRNA transcriptome. To identify miRNAs that are suitable for forensic body-fluid identification, a global screening by microarray analysis of c. 800 miRNAs of forensic blood and saliva samples was performed, and by bioinformatic processing, three differentially expressed candidate miRNAs for saliva and blood each were selected. The six candidates were then validated and confirmed via quantitative PCR. Herein, we present miRNA assays consisting of three differentially expressed miRNAs for the identification of blood (miR-126, miR-150, miR-451) and saliva (miR-200c, miR-203, miR-205), respectively. We conclude that miRNA extraction from forensic samples is possible and support a "proof of concept" that body fluid identification by miRNA analysis may become a potent forensic technique. PMID- 21827477 TI - Retrospective evaluation of attention deficit hyperactivity disorder with the Wender Utah Rating Scale in a sample of Spanish prison inmates. AB - The aim of this study is to determine the prevalence of childhood history of attention deficit hyperactivity disorder (ADHD) in a sample of prison inmates. This is a descriptive, cross-sectional study, which consisted of a sample of 100 inmates from penitentiary centers in Madrid. The instruments used were the Wender Utah Rating Scale (WURS), the International Personality Disorder Examination, and a questionnaire of demographic, penitentiary, and toxicological data. For statistical analysis, the SPSS program was used with confidence interval estimation of 95%. The mean score of the WURS was 65.7 points. Fifty percent of the sample surpassed the cut-off point of 32 for the 25 best discriminative items in the Spanish validated version. A significant association was found between a childhood history of ADHD and antisocial and borderline personality disorders. The disorder was also found to be associated with autoaggressive behavior, more probability to be sanctioned in prison, and have a history of substance dependence. PMID- 21827478 TI - Femoral artery pseudoaneurysm and sudden death. AB - Pseudoaneurysm formation may be a late complication of vascular grafting. A case of sudden death in an 83-year-old woman with a previous aortobifemoral bypass graft is reported that was due to spontaneous hemorrhage from a pseudoaneurysm of the graft site that had eroded through the overlying skin and subcutaneous tissues. Pseudoaneuryms do not have to be of a particularly large size for rupture to occur. Social isolation and age-related cognitive impairment may delay treatment in older individuals resulting in a lethal outcome. The elderly are also more vulnerable to serious morbidity and death under these circumstances owing to significant underlying cardiovascular and respiratory disease and/or anticoagulant medication. Rarer conditions that may cause pseudoaneurysms include tumors and vasculidites. The possibility of an infectious contribution to the pseudoaneurysm should be considered and microbiological sampling undertaken. PMID- 21827479 TI - Autoerotic death: incidence and age of victims--a population-based study. AB - Review of the Australian National Coronial Information System and the Swedish National Forensic Database was undertaken over a 7-year period from 2001 to 2007 for all cases where death had been attributed to autoerotic death or sexual asphyxia. In Australia, there were 44 cases (M:F = 42:2) with the majority of victims aged >30 years (77%)-a yearly national rate of approximately 0.3/million. In Sweden, there were nine cases (M:F = 9:0) with the majority of cases aged <30 years (55%)-a yearly national rate of approximately 0.14/million. The usual male predominance was present in both populations, although the Australian victims were older than is usually reported. Lethal sexual asphyxia is uncommon in both the Australian and Swedish populations, with a lower rate than has been cited for North America. Whether this is because of different kinds of paraphilic activities in different populations or of differences in methods of central data collection is uncertain. PMID- 21827480 TI - Littre hernia--a rare cause of unexpected death in the elderly. AB - A rare case of sudden and unexpected death is reported in an 87-year-old woman who was found dead at her home. At autopsy, the most striking finding was of a right-sided direct inguinal hernia containing a 20 mm infarcted Meckel diverticulum, with proximal small intestinal obstruction. Significant stenosing atherosclerosis was present in all three major epicardial coronary arteries, but with no histological evidence of acute or chronic ischemic myocardial damage. Death was attributed to small intestinal obstruction due to direct inguinal herniation (and infarction) of a Meckel diverticulum (a Littre hernia), complicating ischemic heart disease. Although Littre hernias are not a reported cause of sudden death in the elderly, congenital gastrointestinal anomalies may rarely play a significant role in terminal episodes well beyond childhood years. The autopsy assessment of sudden death at any age involves detailed examination of the entire length of the intestinal tract. PMID- 21827481 TI - Freeze substitution in 3 hours or less. AB - Freeze substitution is a process for low temperature dehydration and fixation of rapidly frozen cells that usually takes days to complete. New methods for freeze substitution have been developed that require only basic laboratory tools: a platform shaker, liquid nitrogen, a metal block with holes for cryotubes and an insulated container such as an ice bucket. With this equipment, excellent freeze substitution results can be obtained in as little as 90 min for cells of small volume such as bacteria and tissue culture cells. For cells of greater volume or that have significant diffusion barriers such as cuticles or thick cell walls, one can extend the time to 3 h or more with dry ice. The 3-h method works well for all manner of specimens, including plants and Caenorhabditis elegans as well as smaller samples. Here, we present the basics of the techniques and some results from Nicotiana leaves, C. elegans adult worms, Escherichia coli and baby hamster kidney tissue culture cells. PMID- 21827482 TI - A proposed dissection procedure for vertebral arteries in forensic pathology. AB - Vertebral artery removing constitutes a significant forensic pathology challenge. Dissection techniques during head-neck autopsy are based on anterior approach, a difficult method, which is unable to assess the transverse part of the artery. This work presents an original and simple method for dissecting vertebral arteries by a posterior approach, opening the vertebroarterial canal through the spinal canal without any special equipment. Once the spinal cord is removed, the transversarium foramens are opened by an internal cut at the pedicle and an external cut at the transverse process. This enables us to visualize vertebral arteries in its entirety. The method improves both the examination of the upper extracranial segment of the vertebral artery and the neuropathological study when arterial injury is suspected. Applying this method routinely is both feasible and useful in suspected cases of vertebral artery trauma and could contribute to assess more precisely the actual incidence of this injury. PMID- 21827483 TI - A study on the depression levels of children who are brought to the forensic DNA laboratory for paternity testing. AB - This study aims to identify the depression levels of children who were brought to the forensic DNA laboratory for paternity testing. A total of 35 such children were enrolled in the study. Data were gathered using the parent interview form, general information form for children, and the "Child Depression Scale" as it had been tested for validity and reliability in the 6-17 year age group in the country. Data were analyzed using one-way analysis of variance and Scheffe test. The results showed that the age of children who were brought in for paternity testing created a meaningful difference in their depression scores (p < 0.01) while gender did not. In addition, c. 63% of the children in this study did not know why they were in the laboratory, which also caused a meaningful difference in depression scores (p < 0.01). PMID- 21827484 TI - Pharmaceutical applications of cyclodextrins: effects on drug permeation through biological membranes. AB - OBJECTIVES: Cyclodextrins are useful solubilizing excipients that have gained currency in the formulator's armamentarium based on their ability to temporarily camouflage undesirable physicochemical properties. In this context cyclodextrins can increase oral bioavailability, stabilize compounds to chemical and enzymatic degradation and can affect permeability through biological membranes under certain circumstances. This latter property is examined herein as a function of the published literature as well as work completed in our laboratories. KEY FINDINGS: Cyclodextrins can increase the uptake of drugs through biological barriers if the limiting barrier component is the unstirred water layer (UWL) that exists between the membrane and bulk water. This means that cyclodextrins are most useful when they interact with lipophiles in systems where such an UWL is present and contributes significantly to the barrier properties of the membrane. Furthermore, these principles are used to direct the optimal formulation of drugs in cyclodextrins. A second related critical success factor in the formulation of cyclodextrin-based drug product is an understanding of the kinetics and thermodynamics of complexation and the need to optimize the cyclodextrin amount and drug-to-cyclodextrin ratios. Drug formulations, especially those targeting compartments associated with limited dissolution (i.e. the eye, subcutaneous space, etc.), should be carefully designed such that the thermodynamic activity of the drug in the formulation is optimal meaning that there is sufficient cyclodextrin to solubilize the drug but not more than that. Increasing the cyclodextrin concentration decreases the formulation 'push' and may reduce the bioavailability of the system. CONCLUSIONS: A mechanism-based understanding of cyclodextrin complexation is essential for the appropriate formulation of contemporary drug candidates. PMID- 21827485 TI - Determination of trace amounts of beta tegafur in commercial alpha tegafur by powder X-ray diffractometric analysis. AB - OBJECTIVES: The main objective of this work was to develop a suitable analytical technique for determining trace amounts of the thermodynamically stable solid form in bulk samples of metastable form, to a sensitivity of 0.005%-1.0%. Tegafur (5-fluoro-1-(tetrahydro-2-furyl)-uracil) alpha and beta crystalline forms were used as a model for this problem. METHODS: The trace content of the thermodynamically stable beta polymorphic form in tegafur samples was increased by promoting phase transition from the bulk of thermodynamically metastable alpha form to beta form, and achieving sufficient beta form content for a quantitative powder X-ray diffractometry (PXRD) analysis. The phase transition was stimulated by adding water to the samples and then grinding in controlled conditions (temperature, time, grinding speed). A calibration line was constructed using the least squares method. KEY FINDINGS: By using a solvent that does not form hydrates with the analysed polymorphs, it was possible to promote the phase transformation from metastable form to the thermodynamically stable form. After sample preparation, the thermodynamically stable solid form content in the analysed mixture had increased proportionally to the initial weight fraction (0.005%-1.0%) of the stable form seed crystals in the samples, and the coefficient of proportionality was 43.0+/-0.9, with a standard deviation S(n) =1.5%. CONCLUSIONS: A simple, sensitive, semi-quantitative analytical method was developed for the low-level determination of the thermodynamically stable polymorphic form in mixtures of thermodynamically stable and metastable polymorphs. PMID- 21827486 TI - Mechanisms of burst release from pH-responsive polymeric microparticles. AB - OBJECTIVES: Microencapsulation of drugs into preformed polymers is commonly achieved through solvent evaporation techniques or spray drying. We compared these encapsulation methods in terms of controlled drug release properties of prepared microparticles and investigated the underlying mechanisms responsible for the 'burst release' effect. METHODS: Using two different pH-responsive polymers with a dissolution threshold of pH 6 (Eudragit L100 and AQOAT AS-MG), hydrocortisone, a model hydrophobic drug, was incorporated into microparticles below and above its solubility within the polymer matrix. KEY FINDINGS: Although, spray drying was an attractive approach due to rapid particle production and relatively low solvent waste, the oil-in-oil microencapsulation method was superior in terms of controlled drug release properties from the microparticles. Slow solvent evaporation during the oil-in-oil emulsification process allowed adequate time for drug and polymer redistribution in the microparticles and reduced uncontrolled drug burst release. Electron microscopy showed that this slower manufacturing procedure generated nonporous particles whereas thermal analysis and X-ray diffractometry showed that drug loading above the solubility limit of the drug in the polymer generated excess crystalline drug on the surface of the particles. Raman spectral mapping illustrated that drug was homogeneously distributed as a solid solution in the particles when loaded below saturation in the polymer with consequently minimal burst release. CONCLUSIONS: Both the manufacturing method (which influenced particle porosity and density) and drug:polymer compatibility and loading (which affected drug form and distribution) were responsible for burst release seen from our particles. PMID- 21827487 TI - Light effect on the stability of beta-lapachone in solution: pathways and kinetics of degradation. AB - OBJECTIVES: The purpose of this work was to study the chemical stability of the new antitumoral beta-lapachone (betaLAP) to determine the degradation pathway/s of the molecule and the degradation kinetics in addition to identifying several degradation products. METHOD: Samples of betaLAP in solution were stored under conditions of darkness and illumination at 40 degrees C at which the pseudo-first order rate constants for the betaLAP degradation were determined. Furthermore, drug degraded solutions were concentrated and purified using Sephadex LH-20 and preparative thin-layer chromatography and degradation products were identified by nuclear magnetic resonance spectroscopy. KEY FINDINGS: The results revealed that betaLAP shows two different degradation routes: hydrolysis in the dark and photolysis under the light. The betaLAP exposure to light accelerated the drug degradation about 140 fold, compared with the samples stored in the absence of light. The hydrolysis produced hydroxylapachol as the main degradation product. The photolysis yielded phthalic acid, 6-hydroxy-3methylene-3H-isobenzofuran-1-one and a benzomacrolactone together with a complex mixture of other phthalate derivatives such as 2-(2-carboxy-acetyl)-benzoic acid. CONCLUSIONS: This study provides useful information for the development of betaLAP dosage forms, their storage, manipulation and quality control. PMID- 21827488 TI - Pharmacokinetics of caffeine in plasma and saliva, and the influence of caffeine abstinence on CYP1A2 metrics. AB - OBJECTIVES: To investigate the utility of metrics of CYP1A2 activity using caffeine as a probe, and saliva and plasma sampling with or without a 24-h caffeine abstinence. METHODS: This was a cross-over pharmacokinetic study in 30 healthy male subjects who received a single oral 100mg caffeine dose after 24-h caffeine abstinence or after maintaining their regular caffeine intake (no caffeine abstinence). Serial blood and saliva samples were collected simultaneously over 24h. Caffeine and paraxanthine concentrations were measured using a validated HPLC assay. KEY FINDINGS: There was a strong correlation between the paraxanthine/caffeine AUC(0-24) ratio (reference metric) and the paraxanthine/caffeine concentration (C(t) ) ratio at 4h (C(4) ) in both saliva and plasma (r>=0.75). The paraxanthine/caffeine AUC(0-24) ratio in plasma and saliva did not differ between the 24-h caffeine abstinence and the no abstinence period (P>0.05). The optimal paraxanthine/caffeine C(t) that correlated with the plasma paraxanthine/caffeine AUC(0-24) ratio in the 24-h abstinence period was 2 and 4h (r=0.88) in plasma, and 4 and 6h in saliva (r=0.70), while it was the saliva 4h time-point in the no abstinence period (r=0.78). CONCLUSIONS: The saliva paraxanthine/caffeine concentration ratio at 4h was a suitable metric to assess CYP1A2 activity after oral administration of caffeine without the need for 24-h caffeine abstinence. PMID- 21827489 TI - Similar potency of catechin and its enantiomers in alleviating 1-methyl-4 phenylpyridinium ion cytotoxicity in SH-SY5Y cells. AB - OBJECTIVES: Previously, the flavonoid (+/-)-catechin was shown to exert potent neuroprotective action in the mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine induced Parkinson's disease model. The purpose of this study was to investigate whether the different enantiomers of catechin ((+)-catechin, (-)-catechin and (+/ )-catechin, a 50:50 mixture of (+)-catechin and (-)-catechin) could protect SH SY5Y cells against 1-methyl-4-phenylpyridinium ion (MPP(+) ) toxicity by decreasing the generation of oxygen free radicals. The inhibitive effect of (+/-) catechin on JNK/c-Jun activation was investigated. METHODS: The effects of (+) catechin, (-)-catechin or (+/-)-catechin in protecting against MPP(+) toxicity were evaluated and compared in SH-SY5Y cells by testing the release of lactate dehydrogenase. The generation of reactive oxygen species (ROS) was measured by immunochemistry and the phosphorylation level of JNK/c-Jun was determined by Western blotting. KEY FINDINGS: In SH-SY5Y cells, (+)-catechin, (-)-catechin or (+/-)-catechin reduced apoptosis induced by MPP(+) and decreased ROS generation caused by MPP(+) . Different enantiomers of catechin showed protective effects at similar potency. Moreover (+/-)-catechin decreased JNK/c-Jun phosphorylation which was increased by MPP(+). CONCLUSIONS: Catechin and its two enantiomers could protect SH-SY5Y cells against MPP(+) cytotoxicity at a similar potency. Antioxidative stress and inhibition of the JNK/c-Jun signalling pathway might have been involved in the neuroprotective mechanisms of catechin against MPP(+) cytotoxicity in SH-SY5Y cells. PMID- 21827490 TI - Characterization of a unique dihydropyrimidinone, ethyl 4-(4'-heptanoyloxyphenyl) 6-methyl-3,4-dihydropyrimidin-2-one-5-carboxylate, as an effective antithrombotic agent in a rat experimental model. AB - OBJECTIVES: To evaluate the potential of a novel dihydropyrimidinone, ethyl 4-(4' heptanoyloxyphenyl)-6-methyl-3,4-dihydropyrimidin-2-one-5-carboxylate (H-DHPM), as a calcium channel blocker, endowed with the ability to inhibit platelet aggregation effectively. METHODS: In-vitro and in-vivo studies were conducted for the determination of antiplatelet activity using adenosine diphosphate (ADP), collagen or thrombin as inducers. Calcium channel blocking activity and nitric oxide synthase (NOS) activity were monitored. Lipopolysaccharide (LPS)-mediated prothrombotic conditions were developed in rats to study the efficacy of H-DHPM to suitably modulate the inflammatory mediators such as inducible NOS (iNOS) and tissue factor. The cGMP level and endothelial NOS (eNOS) expression were checked in aortic homogenate of LPS-challenged rats pretreated with H-DHPM. The effect of H-DHPM on FeCl(3) -induced thrombus formation in rats was examined. KEY FINDINGS: The concentrations of H-DHPM required to give 50% inhibition (IC50) of in-vitro platelet aggregation induced by ADP, collagen or thrombin were 98.2+/-2.1, 74.5+/ 2.3 and 180.7+/-3.4um, respectively. H-DHPM at a dose of 52.0+/-0.02mg/kg (133umol/kg) was found to optimally inhibit ADP-induced platelet aggregation in vivo. The level of nitric oxide was found to be up to 9+/-0.08-fold in H-DHPM treated platelets in-vitro and 8.2+/-0.05-fold in H-DHPM-pretreated rat platelets in-vivo compared with control. OH-DHPM, the parent compound was found to be ineffective both in-vitro and in-vivo. H-DHPM-pretreated rats were able to resist significantly the prothrombotic changes caused by LPS by blunting the expression of iNOS, tissue factor and diminishing the increased level of cGMP to normal. H DHPM enhanced the eNOS expression in aorta of rats treated with LPS. H-DHPM displayed synergy with antiplatelet activity of aspirin even at lower doses. H DHPM was found to inhibit the LPS-induced platelet aggregation in younger as well as older rats. H-DHPM exhibited the ability to markedly decrease FeCl(3) -induced thrombus formation in rats. CONCLUSIONS: H-DHPM has the attributes of a promising potent antiplatelet candidate molecule that should attract further study. H-DHPM displayed antiplatelet activity both in vivo and in vitro, which was due partially by lowering the intraplatelet calcium concentration. PMID- 21827491 TI - Inhibitory effects of sertraline in rat isolated perfused kidneys and in isolated ring preparations of rat arteries. AB - OBJECTIVES: Sertraline is often prescribed to patients suffering with end stage renal disease, but its action on kidney has not been investigated. We aimed to investigate the pharmacological action of sertraline on rat kidney with emphasis on the underlying mechanisms involved in the vascular actions of the drug. METHODS: The effects of sertraline were evaluated in rat isolated perfused kidneys and on ring preparations of mesenteric or segmental rat renal artery. KEY FINDINGS: In kidneys, sertraline prevented the effects of phenylephrine on perfusion pressure, glomerular filtration rate, urinary flow and renal vascular resistance. In mesenteric rings sertraline inhibited phenylephrine-induced contractions with potency 30-times lower than verapamil. Sertraline reversed sustained contractions induced by phenylephrine or 60mm K(+) within a similar concentration range. In segmental isolated rings, sertraline also reversed contractions induced by phenylephrine or 60mm K(+) with the same concentration range, but with higher potency compared with mesenteric preparations. Under Ca(2+) -free conditions, sertraline did not change the intracellularly-mediated phasic contractions induced by phenylephrine or caffeine. Sertraline was ineffective against contractions induced by extracellular Ca(2+) restoration after thapsigargin treatment and Ca(2+) store depletion with phenylephrine. Conversely, sertraline decreased the contractions induced by Ca(2+) addition in tissues under high K(+) solution or phenylephrine plus verapamil. CONCLUSIONS: In rat isolated kidneys and in rat ring preparations of mesenteric or renal vessels, sertraline had antispasmodic effects that appeared to be caused by a direct action on vascular smooth muscle cells. Its actions were ineffective against Ca(2+) -releasing intracellular pathways, but appeared to interfere with sarcolemmal Ca(2+) influx with reduced permeability of both receptor- and voltage gated Ca(2+) channels. PMID- 21827492 TI - Mildronate treatment alters gamma-butyrobetaine and l-carnitine concentrations in healthy volunteers. AB - OBJECTIVES: In this study, we aimed to investigate the effects of long-term administration of the cardioprotective drug mildronate on the concentrations of l carnitine and gamma-butyrobetaine in healthy volunteers. METHODS: Mildronate was administered perorally, at a dosage of 500mg, twice daily. Plasma and urine samples were collected weekly. Daily meat consumption within an average, non vegetarian diet was monitored. l-Carnitine, gamma-butyrobetaine and mildronate concentrations were measured using the UPLC/MS/MS method. KEY FINDINGS: After 4 weeks, the average concentrations of l-carnitine in plasma significantly decreased by 18%. The plasma concentrations of gamma-butyrobetaine increased about two-fold, and this effect was statistically significant in both the male and female groups. In urine samples, a significant increase in l-carnitine and gamma-butyrobetaine levels was observed, which provides evidence for increased excretion of both substances during the mildronate treatment. At the end of the treatment period, the plasma concentration of mildronate was 20um on average. There were no significant differences between the effects observed in female and male volunteers. Meat consumption partially reduced the l-carnitine-lowering effects induced by mildronate. CONCLUSIONS: Long-term administration of mildronate significantly lowers l-carnitine plasma concentrations in non vegetarian, healthy volunteers. PMID- 21827493 TI - Antiproliferative and anti-invasive effects of inorganic and organic arsenic compounds on human and murine melanoma cells in vitro. AB - OBJECTIVES: For patients with advanced melanoma, no treatment options are available at present that provide either sufficient response rates or a significant prolongation of overall survival. The present study examines the effects of two inorganic and six organic arsenic compounds on cell proliferation and cell invasion of melanoma cells in vitro. METHODS: The effects of arsenic compounds on proliferation of human melanoma A375 cells and murine melanoma B16F10 cells were examined by MTT assay and 5-bromo-2'-deoxyuridine (BrdU) incorporation assay, and the effects of the compounds on cell invasion were examined by the Boyden chamber invasion assay. The amounts of active matrix metalloproteinase (MMP)-2 and pro-MMP-2 in the culture supernatant of A375 cells were determined by an MMP-2 activity assay system. KEY FINDINGS: Arsenate and arsenic trioxide (As(2) O(3) ) inhibited the proliferation of A375 and B16F10 cells significantly at concentration ranges of 0.1-20ug/ml (P<0.001), while the organic compounds arsenobetaine, arsenocholine, dimethylarsinic acid, methylarsonic acid, tetramethylarsonium and trimethylarsine oxide did not show any inhibitory effects even at 20ug/ml. Cell invasion of A375 and B16F10 cells through a layer of collagen IV was significantly inhibited by 0.1-20 ug/ml of arsenate or As(2) O(3) (P<0.05), while the organic compounds did not inhibit cell invasion. Arsenate or As(2) O(3) at 0.2-10ug/ml significantly inhibited the amount of active MMP-2 and pro-MMP-2 secreted into the A375 cell culture supernatant (P<0.05). CONCLUSIONS: Our findings show that the inorganic arsenic compounds arsenate and As(2) O(3) inhibit cell proliferation and prevent the invasive properties of melanoma cells, possibly by decreasing MMP-2 production from the cells. PMID- 21827494 TI - Myrrh mediates haem oxygenase-1 expression to suppress the lipopolysaccharide induced inflammatory response in RAW264.7 macrophages. AB - OBJECTIVES: To elucidate a novel anti-inflammatory mechanism of myrrh against lipopolysaccharide (LPS)-induced inflammation. METHODS: RAW264.7 macrophages were cultured in DMEM and then cells were treated with LPS or LPS plus a myrrh methanol extract (MME) for 24h. The culture medium was collected for determination of nitric oxide (NO), prostaglandin (PG)E(2) , interleukin (IL) 1beta, and tumour necrosis factor (TNF)-alpha, and cells were harvested by lysis buffer for Western blot analysis. KEY FINDINGS: Our data showed that treatment with the MME (1~100ug/ml) did not cause cytotoxicity or activate haem oxygenase-1 (HO-1) protein synthesis in RAW264.7 macrophages. Furthermore, the MME inhibited LPS-stimulated NO, PGE(2) , IL-1beta and TNF-alpha release and inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 protein expression. Zn(II) protoporphyrin IX, a specific inhibitor of HO-1, blocked the inhibition of iNOS and COX-2 expression by the MME. CONCLUSIONS: These results suggest that among mechanisms of the anti-inflammatory response, the MME inhibited the production of NO, PGE(2) , IL-1beta and TNF-alpha by downregulating iNOS and COX-2 gene expression in macrophages and worked through the action of HO-1. PMID- 21827495 TI - Boldo prevents UV light and nitric oxide-mediated plasmid DNA damage and reduces the expression of Hsp70 protein in melanoma cancer cells. AB - OBJECTIVES: This study was designed to investigate the potential protective effect of a methanolic extract of Peumus boldus leaves on UV light and nitric oxide (NO)-mediated DNA damage. In addition, we investigated the growth inhibitory activity of this natural product against human melanoma cells (M14). METHODS: Boldine, catechin, quercetin and rutin were identified using a HPLC method. The extract was incubated with plasmid DNA and, before irradiating the samples with UV-R, H(2) O(2) was added. For analysis of DNA single-strand breaks induced by NO, the experiments were performed by incubating the extract with Angeli's salt. In the study on M14 cell line, cell viability was measured using MTT assay. Release of lactate dehydrogenase, a marker of membrane breakdown, was also measured. For the detection of apoptosis, the evaluation of DNA fragmentation (COMET assay) and caspase-3 activity assay were employed. The expression of heat shock protein 70 (Hsp70) was detected by Western blot analysis. Generation of reactive oxygen species was measured by using a fluorescent probe. KEY FINDINGS: The extract (demonstrating the synergistic effect of the constituents boldine and flavonoids), showed a protective effect on plasmid DNA and selectively inhibited the growth of melanoma cells. But a novel finding was that apoptosis evoked by this natural product in M14 cells, appears to be mediated, at least in part, via the inhibition of Hsp70 expression, which may be correlated with a modulation of redox-sensitive mechanisms. CONCLUSIONS: These results confirm the promising biological properties of Peumus boldus and encourage in-vivo investigations into its potential anti-cancer activity. PMID- 21827496 TI - Gastroprotective activity of methanol extract and marrubiin obtained from leaves of Marrubium vulgare L. (Lamiaceae). AB - OBJECTIVES: The purpose of this study was to assess the gastroprotective properties of the methanol extract and the diterpene marrubiin obtained from the leaves of M. vulgare. METHODS: Assays were performed using different protocols in mice. Studies focusing on mechanisms of gastroprotection were also undertaken. KEY FINDINGS: In the model of ethanol-induced ulcers, we observed a significant reduction in all the parameters analysed; the curative ratios obtained were 49.31+/-0.57, 74.31+/-0.91 and 79.86+/-0.59 for the groups treated with 50 and 100mg/kg of extract of M. vulgare and omeprazole (30mg/kg), respectively. For indomethacin-induced ulcers, the percentages of ulcer inhibition were 50.32+/ 5.60, 66.24+/-4.30, 82.17+/-04.09 and 67.52+/-4.38, for the groups treated with 25, 50 and 100mg/kg M. vulgare and positive control (cimetidine), respectively. In both models, the marrubiin (25mg/kg) produced a significant reduction in all the parameters when compared with the control group (P<0.01). There was also a significant increase in pH and mucus production in the groups treated with M. vulgare extract and marubiin. The results also demonstrated that the gastroprotection induced by the extract and marubiin is related to the activity of nitric oxide and endogenous sulfhydryls, which are important gastroprotective factors. CONCLUSIONS: The results of this study show that the extract of M. vulgare and marrubiin displays antiulcer activity and that this effect can be partly attributed to the isolated diterpene. PMID- 21827497 TI - Effects of Ginkgo biloba extract on the pharmacokinetics and pharmacodynamics of tolbutamide in protein-restricted rats. AB - OBJECTIVES: Effects of repeated administration of Ginkgo biloba extract on pharmacokinetics and pharmacodynamics of tolbutamide were examined in rats fed a low-protein diet. METHODS: Rats were given a low (7% casein) or control (20% casein) protein diet for 21 days and administered Ginkgo biloba extract (100mg/kg per day) for the last 5 days. Tolbutamide was co-administered on the last day. Blood glucose and plasma tolbutamide concentrations were determined over the subsequent 12h and the activity of hepatic cytochrome P450s were determined at 12h after dosing. KEY FINDINGS: There were significant decreases in body weight, the ratio of liver to body weight, and plasma albumin concentrations in rats on the low-protein diet compared with controls. The hypoglycaemic effect of tolbutamide was significantly greater and the concentration of the drug in plasma was higher in the former group. The repeated administration of Ginkgo biloba extract had little influence on the hypoglycaemic effect of tolbutamide, but tended to decrease the drug concentration in plasma of control rats, while it reduced significantly the hypoglycaemic action and plasma concentration of tolbutamide in the protein-restricted rats. CONCLUSIONS: The effects of Ginkgo biloba extract on the pharmacokinetics and pharmacodynamics of tolbutamide were significantly enhanced in rats on the low-protein diet. PMID- 21827498 TI - Honokiol attenuates vascular contraction through the inhibition of the RhoA/Rho kinase signalling pathway in rat aortic rings. AB - OBJECTIVES: Honokiol is a small-molecule polyphenol isolated from the species Magnolia obovata. We hypothesized that honokiol attenuated vascular contractions through the inhibition of the RhoA/Rho-kinase signalling pathway. METHODS: Rat aortic rings were denuded of endothelium, mounted in organ baths, and subjected to contraction or relaxation. Phosphorylation of 20kDa myosin light chains (MLC(20) ), myosin phosphatase targeting subunit 1 (MYPT1) and protein kinase C (PKC)-potentiated inhibitory protein for heterotrimeric myosin light chain phosphatase (MLCP) of 17kDa (CPI17) were examined by immunoblot. We also measured the amount of guanosine triphosphate RhoA as a marker for RhoA activation. KEY FINDINGS: Pretreatment with honokiol dose-dependently inhibited the concentration response curves in response to sodium fluoride (NaF) or thromboxane A(2) agonist U46619. Honokiol decreased the phosphorylation levels of MLC(20) , MYPT1(Thr855) and CPI17(Thr38) as well as the activation of RhoA induced by 8.0mm NaF or 30nm U46619. CONCLUSIONS: These results demonstrated that honokiol attenuated vascular contraction through the inhibition of the RhoA/Rho-kinase signalling pathway. PMID- 21827499 TI - A dual porosity model of nutrient uptake by root hairs. AB - * The importance of root hairs in the uptake of sparingly soluble nutrients is understood qualitatively, but not quantitatively, and this limits efforts to breed plants tolerant of nutrient-deficient soils. * Here, we develop a mathematical model of nutrient uptake by root hairs allowing for hair geometry and the details of nutrient transport through soil, including diffusion within and between soil particles. We give illustrative results for phosphate uptake. * Compared with conventional 'single porosity' models, this 'dual porosity' model predicts greater root uptake because more nutrient is available by slow release from within soil particles. Also the effect of soil moisture is less important with the dual porosity model because the effective volume available for diffusion in the soil is larger, and the predicted effects of hair length and density are different. * Consistent with experimental observations, with the dual porosity model, increases in hair length give greater increases in uptake than increases in hair density per unit main root length. The effect of hair density is less in dry soil because the minimum concentration in solution for net influx is reached more rapidly. The effect of hair length is much less sensitive to soil moisture. PMID- 21827500 TI - Thermal effectiveness of different IR radiators employed in rheumatoid hand therapy as assessed by thermovisual examination. AB - We conducted a thermovisual comparison of mean hand surface temperature changes upon local heating with two different IR sources. Sixty-six patients with rheumatoid arthritis (47 women and 19 men; average age, 56.1 +/- 8.6 years) were subjected to topical heat therapy for one hand with either the standard IR radiator (SIR) or the water filter IRA (wIRA). The surface temperature of the dorsal side of both hands was measured, and thermal images were taken before and up to 2 h after treatment. At 1 min after treatment, SIR application increased the surface skin temperature of the heated hand from 31.5 +/- 1.9 to 35.0 +/- 1.9 degrees C (P<0.05), while wIRA increased it from 32.1 +/- 1.6 to 34.2 +/- 1.1 degrees C (P<0.05). Constant decline in temperature was observed immediately after treatment, with the temperatures reaching baseline in about 30 and 120 min after wIRA and SIR treatment, respectively. Similar temperature changes were observed in the heated hands for wIRA and SIR, except at 1 min after treatment. Changes in the untreated hands indicated contralateral reaction. The temperature of the warmed hand showed a correlation to the body mass index. PMID- 21827501 TI - Application of implicit attitude measures to the blood donation context. AB - BACKGROUND: Past blood donation research has relied on explicit (self-report) measures to understand blood donation motivations, but has not yet considered the inherent implicit or automatic processing involved in decision-making. This study addresses this limitation by introducing and validating two novel implicit measures of blood donation attitudes. STUDY DESIGN AND METHODS: Healthy young adults (n = 253) performed both image and word versions of a Single Target Implicit Association Test (ST-IAT) and then completed self-report measures of blood donation attitudes, blood and needle fears, social desirability, and donation intention. RESULTS: These results affirmed the validity of the blood donation ST-IATs in at least three ways. First, as expected, nondonors demonstrated more negative implicit donation attitudes than donors. Second, the implicit measures were significantly related in expected directions with explicit measures of donation attitudes as well as blood and needle fears. Finally, implicit donation attitudes were significantly related to donation intention, and the Image ST-IAT (but not the Word ST-IAT) significantly enhanced prediction of donation intention over and above needle fears and marginally enhanced prediction over and above blood fears. CONCLUSION: Image and word versions of the blood donation ST-IAT offer a valid method of assessing underlying automatic attitudes toward blood donation. PMID- 21827502 TI - Evaluating pathogen reduction of Trypanosoma cruzi with riboflavin and ultraviolet light for whole blood. AB - BACKGROUND: Trypanosoma cruzi, the protozoan parasitic agent of Chagas disease, can be transmitted by blood transfusion. In 2007, most US blood banks started screening blood donations for T. cruzi, but the cost and perceived need of the test have been the subject of ongoing discussion. In this study, we evaluated the ability of the Mirasol System (CaridianBCT), which uses riboflavin (RB) and ultraviolet light to inactivate pathogens, to reduce the levels of infectious T. cruzi in whole blood (WB). STUDY DESIGN AND METHODS: WB units were inoculated with 4, 40, 400, and 4000 trypomastigotes/mL. After addition of RB and illumination at various energy levels, the samples were tested for the presence of live parasites by hemoculture. RESULTS: All preillumination samples exhibited T. cruzi growth in hemoculture, while postillumination samples from units containing 4 and 40 trypomastigotes/mL showed no signs of viable parasites after 16 weeks of culture. In contrast, at both 400 and 4000 parasites/mL, two of the three units were positive for viable parasites. CONCLUSIONS: The total log reduction observed for T. cruzi was 3.5 log or greater, but less than 4.5 log. This level of reduction is likely to be orders of magnitude higher than what would be expected in a tainted blood donation, indicating that the Mirasol System could be effective at preventing transfusion of the causative agent of Chagas disease. PMID- 21827503 TI - Hematopoietic stem cells from poor and good mobilizers are qualitatively equivalent. AB - BACKGROUND: Marrow damage from chemo- and radiation therapies has been suggested to affect quality and quantity of hematopoietic stem cell (HSC) products. We tested the hypothesis that CD34+ cells (HSCs) from low mobilizers are qualitatively inferior to HSCs from high mobilizers. STUDY DESIGN AND METHODS: HSC quality was defined by proportion of primitive HSC subsets (CD34+CD38-, CD34+HLA-DR-, and CD34+ in G0 stage of cell cycle), the proportion of HSCs that express CXCR4 and CD26 homing proteins, and days to neutrophil and platelet (PLT) engraftments after transplant. HSC content and CD34 subsets analyses were performed using flow cytometry following the ISHAGE protocol. We evaluated the HSC quantity and quality of 139 autologous filgrastim-mobilized HSC products. Patients were categorized into low, moderate, and high mobilizers if their total HSC collection was less than 3 * 10(6), 3 * 10(6) or more and less than 5 * 10(6), and 5 * 10(6)/kg or more, respectively. RESULTS: The median number of primitive CD34 subsets increases with increasing HSC numbers and this association was significant (p = 0.001). However, when the ratios of the primitive CD34 subsets to total HSC counts were compared among the mobilization groups, the ratios were not significantly different. Coexpression of neither CD26 nor CXCR4 with CD34 antigen correlated with HSC mobilization. Evaluation of days to neutrophil engraftment among the mobilization groups did not show a significant difference (p = 0.1). However, days to PLT engraftment among the mobilization groups was significantly different (p = 0.05). CONCLUSION: The quality of HSCs from low mobilizers was comparable to HSCs from high mobilizers. PMID- 21827504 TI - Riboflavin and ultraviolet light treatment potentiates vasodilator-stimulated phosphoprotein Ser-239 phosphorylation in platelet concentrates during storage. AB - BACKGROUND: Pathogen reduction technologies (PRTs) were developed to improve the safety of platelet concentrates (PCs) for transfusion purposes; however, several studies report a negative impact on the in vitro and in vivo platelet (PLT) quality. Therefore, analyses of the underlying molecular processes triggered by PRT treatments are necessary to understand their effects on PLT function. STUDY DESIGN AND METHODS: In two separate two-arm studies PCs prepared in plasma for storage either by the leukoreduced buffy coat (BC-PCs) or by the leukoreduced apheresis (AP-PCs) method were treated with or without riboflavin and ultraviolet (UV) light (Mirasol; 6.24 J/mL; 265-375 nm). Samples were drawn after treatment and after 1, 4, and 6 days of storage with subsequent analyses performed using in vitro measurements for PLT quality monitoring. Semiquantitative proteomic studies identified proteins that changed in band intensities in response to treatment or storage. Protein validation and subsequent biochemical studies were carried out by immunoblot analyses. RESULTS: The proteomic results identified changes mainly of proteins associated with the structure and regulation of the cytoskeleton. Focusing on the vasodilator-stimulated phosphoprotein (VASP) in AP-PCs revealed a storage-dependent, but treatment-independent, delocalization and a strong treatment-dependent phosphorylation at Ser-239 that was also present, but to a much lesser degree in BC-PCs. This modification correlated exponentially with PLT activation as determined by P-selectin expression. CONCLUSION: Treatment of PCs with Mirasol leads to the amplification of VASP Ser-239 phosphorylation, which is linked to actin dynamics and regulation of integrin alpha(IIb) beta(3) activation. This change offers one explanation for Mirasol's impact on PLT in vitro quality measures. The Ser-239 phosphorylation level of VASP might be a useful protein marker for riboflavin and UV light-mediated PLT compromise. PMID- 21827505 TI - Molecular blood typing augments serologic testing and allows for enhanced matching of red blood cells for transfusion in patients with sickle cell disease. AB - BACKGROUND: Sickle cell disease (SCD) patients have dissimilar red blood cell (RBC) phenotypes compared to the primarily Caucasian blood donor base due, in part, to underlying complex Rh and silenced Duffy expression. Gene array-based technology offers high-throughput antigen typing of blood donors and can identify patients with altered genotypes. The purpose of the study was to ascertain if RBC components drawn from predominantly Caucasian donors could provide highly antigen matched products for molecularly typed SCD patients. STUDY DESIGN AND METHODS: SCD patients were genotyped by a molecular array (HEA Beadchip, BioArray Solutions). The extended antigen phenotype (C, c, E, e, K, k, Jk(a) , Jk(b) , Fy(a) , Fy(b) , S, s) was used to query the inventory using different matching algorithms; the resulting number of products was recorded. RESULTS: A mean of 96.2 RBC products was available for each patient at basic-level, 34 at mid-level, and 16.3 at high-level stringency. The number of negative antigens correlated negatively with the number of available products. The Duffy silencing mutation in the promoter region (67T>C) (GATA) was found in 96.5% of patients. Allowing Fy(b+) products for patients with GATA increased the number of available products by up to 180%, although it does not ensure prevention of Duffy antibodies in all patients. CONCLUSIONS: This feasibility study provides evidence that centers with primarily Caucasian donors may be able to provide highly antigen-matched products. Knowledge of the GATA status expands the inventory of antigen-matched products. Further work is needed to determine the most clinically appropriate match level for SCD patients. PMID- 21827506 TI - Relative distribution of West Nile virus RNA in blood compartments: implications for blood donor nucleic acid amplification technology screening. AB - BACKGROUND: Despite implementation of targeted individual-donor nucleic acid test (NAT) screening of blood donors for West Nile virus (WNV), three "breakthrough" WNV transfusion transmission cases were reported (2004-2008), suggesting that current plasma-based assays are unable to detect all WNV-infectious donations. A 2007 report found that 19 of 20 red blood cell components from WNV-infected donors contained 1 log higher viral load than plasma components. This study's aim was to further establish the value of screening whole blood relative to plasma for WNV RNA by generating differential viral loads on paired samples derived from blood screening tubes. STUDY DESIGN AND METHODS: WNV RNA-positive donors identified by routine NAT screening were enrolled and quantitative viral data were generated using cross-sectional (index-donation) and longitudinal (follow up) specimens. A real-time reverse transcription-polymerase chain reaction viral load assay was used on both study sample sets and replicate qualitative NAT screening assays were also used on the longitudinal study samples. RESULTS: For the cross-sectional study, seronegative index donations (n = 29) had WNV RNA concentrations fourfold higher in plasma than in whole blood, whereas for seropositive donations (n = 13), the WNV RNA concentrations were 10-fold higher in whole blood than in plasma. All 10 longitudinal study participants were seropositive throughout the follow-up study; whole blood viral load was consistently greater than plasma viral load (mean difference, 343 copies; p < 0.001) up to 200 days after index. CONCLUSION: The improved sensitivity of WNV NAT using whole blood instead of plasma was confirmed, but appears to be limited to better detection in seropositive stages. However, the implication of these findings for blood screening requires further study to establish the infectivity of persistent whole blood viremia. PMID- 21827507 TI - Acute exacerbation of subclinical pulmonary fibrosis after red blood cell transfusion: a case report. AB - BACKGROUND: Red blood cell (RBC) transfusion is associated with lung injury in susceptible hosts, although many cases do not meet criteria for transfusion related acute lung injury. Patients with underlying pulmonary fibrosis can exhibit precipitous deteriorations in respiratory status of unknown etiology defined as acute exacerbations due to superimposed lung injury syndrome. It is unclear whether RBC transfusion is associated with acute exacerbation of underlying pulmonary fibrosis. CASE REPORT: We describe a patient who underwent an uneventful elective left total hip replacement but developed anemia postoperatively. Twenty-four hours after transfusion of her fifth nonleukoreduced AS-5 RBC unit, she developed new bilateral airspace infiltrates associated with progressive hypoxemia. These RBC units were 35 to 38 days old. Despite supportive care and diuresis, the patient remained profoundly hypoxemic with infiltrates that progressed to fibrosis. RESULTS: The patient had mild subclinical lower-lobe predominant interstitial pulmonary fibrosis but developed diffuse bilateral ground glass opacities with areas of consolidation 24 hours after receiving her last RBC unit. Transbronchial biopsy of the right lower lobe showed active organizing pneumonia and underlying interstitial fibrosis, supporting the clinical diagnosis of acute exacerbation of pulmonary fibrosis. The bronchoalveolar lavage showed progressive bloody effluent, consistent with diffuse alveolar hemorrhage, a marker of lung injury. There was no evidence of viral inclusions, fungal elements, pneumocystis, or bacterial organisms. CONCLUSION: Transfusion of multiple units of aged RBCs was temporally associated with an acute exacerbation and rapid progression of underlying subclinical pulmonary fibrosis. PMID- 21827508 TI - Hemolysis of red blood cells during processing and storage. AB - BACKGROUND: During processing and storage, red blood cells (RBCs) undergo changes and cell injury resulting in hemolysis. Mostly, the separation of whole blood in top-and-bottom quadruple bag systems with break openings takes less than 4 minutes. However, longer separation times are not uncommon. The aims were to investigate whether hemolysis is increased in RBCs with longer separation time (RBCs(>6 min)) compared to regular RBCs (RBCs(reg)), to measure hemolysis increase during storage and to study whether frequency of hemolytic donations is donor dependent. STUDY DESIGN AND METHODS: RBCs(>6 min) (n = 172) and 172 matched controls were tested for hemolysis on Days 1 and 21 RBC units from each group were stored at 4 +/- 2 degrees C and tested again after 5 weeks. Donor dependency was retrospectively investigated for 100 hemolytic RBC units. RESULTS: RBCs(>6 min) exhibited a higher mean hemolysis rate than RBCs(reg) (0.058% vs. 0.033%). Four RBC units were hemolytic (>0.8%), all RBCs(>6 min) (2.36%). During storage, hemolysis in both groups increased with 0.24%. Hemolysis frequency did not seem to be donor dependent. CONCLUSIONS: Increased separation time is a useful screening tool for potentially increased hemolysis rate in RBCs. Hemolysis rate increased during storage equally in both groups. Hemolysis frequency appears donor independent. PMID- 21827509 TI - Allergic contact dermatitis caused by tetracaine contained in otic drops. PMID- 21827510 TI - Two cases of airborne allergic contact dermatitis caused by methylisothiazolinone in paint. PMID- 21827511 TI - Multiple contact allergies to benzophenones. PMID- 21827512 TI - Acute bullous irritant contact dermatitis caused by EMLA(r) cream. PMID- 21827513 TI - Allergic contact dermatitis caused by methylphenidate. PMID- 21827514 TI - Spatial distribution of seroprevalence for Anaplasma phagocytophilum, Borrelia burgdorferi, Ehrlichia canis, and Dirofilaria immitis in dogs in Washington, Oregon, and California. AB - BACKGROUND: In the US little spatially defined information regarding exposure to most vector-borne pathogens in dogs is available for the states of California (CA), Oregon (OR), and Washington (WA). OBJECTIVES: The purpose of the present study was to evaluate the spatial distribution of seroprevalence for 4 vector borne pathogens, Anaplasma phagocytophilum, Borrelia burgdorferi, Ehrlichia canis, and Dirofilaria immitis, across the 3 western coastal states of the contiguous United States that extend from the northern Mexican to the southern Canadian border. METHODS: A convenience sample, targeting blood from 20 pet dogs per county across CA, OR, and WA, was evaluated using a canine point-of-care ELISA kit. Geographic coordinates of home zip code were displayed using a geographic information system. A total of 2431 dogs from CA, OR, and WA were tested. RESULTS: The overall seroprevalence was highest for A. phagocytophilum (2.4%), followed by B. burgdorferi (1.2%), and E. canis (0.7%). The prevalence of infection with D. immitis was 0.7%. At the individual dog level, there was a significant association between seropositivity to B. burgdorferi and A. phagocytophilum (odds ratio=18.7, 95% confidence interval=6.8-47.1). For most positive results, prevalence tended to decrease with increasing latitude; thus, the highest rates of seropositivity occurred in CA, followed by OR, and then WA; one exception was seropositivity for B. burgdorferi, which was higher in WA (0.38%) than in OR (0.15%), but considerably lower than in CA (2.00%). In WA, dogs that tested positive for A. phagocytophilum, E. canis, and B. burgdorferi were in the southern Puget Sound area. For D. immitis, none of the dogs in WA was positive. CONCLUSIONS: Seropositivity for vector-borne pathogens is broadly but patchily distributed in dogs in CA, OR, and WA. PMID- 21827515 TI - Hematology, leukocyte cytochemical analysis, plasma biochemistry, and plasma electrophoresis of wild-caught and captive-bred Gila monsters (Heloderma suspectum). AB - BACKGROUND: The Gila monster (Heloderma suspectum), one of several venomous lizard species in the world, is found within the United States and Mexico and is recognized as an iconic symbol of the American Southwest. Thus, Gila monsters are of growing interest in the captive reptile trade and within zoological and educational institutions. OBJECTIVES: The aims of this study were to determine results for CBCs, describe cytochemical reactions in WBCs, and obtain plasma biochemical and protein electrophoresis results from wild-caught and captive-bred H. suspectum. METHODS: Ventral tail vein blood samples were obtained from 16 captive (14 wild-caught and 2 captive-bred) Gila monsters. CBCs, RBC morphometric analysis, plasma biochemical analysis, and protein electrophoresis were performed. Leukocytes were stained for peroxidase, Sudan black B (SBB), chloroacetate esterase, napthyl butyrate esterase, and leukocyte alkaline phosphatase, and blood smears were examined for the presence of hemoparasites. RESULTS: The median (range) PCV was 37% (22-50%) and WBC count was 4.6 * 10(3) /MUL (3.3-6.4 * 10(3) /MUL) with approximately 50% heterophils and fewer lymphocytes, basophils, azurophils, and monocytes in decreasing order. Cytochemical reactions were unique among reptiles with strong staining for peroxidase and SBB in monocytes/azurophils. Biochemical results were similar to those of earlier reports with slight increases in uric acid and urea concentrations. Plasma electrophoretic results indicated that albumin was approximately equal to the combined globulin fractions. CONCLUSIONS: Results of blood analysis in healthy wild-caught and captive-bred H. suspectum may be useful for monitoring health status in this species. PMID- 21827516 TI - Clinicopathologic abnormalities associated with snake envenomation in domestic animals. AB - Envenomation of domestic animals by snakes occurs frequently in certain geographic areas. However, reports describing clinical signs, clinicopathologic abnormalities, therapeutic approaches, and outcomes are sparse. This review summarizes various snake families, venom types associated with harmful snakes, and the significant hematologic, hemostatic, and biochemical abnormalities associated with envenomation. Hematologic abnormalities include RBC membrane abnormalities, hemolysis, hemoconcentration, leukogram changes, and platelet abnormalities, specifically thrombocytopenia. Coagulopathies associated with snake envenomation are well described in human medicine, and many studies have demonstrated properties of venoms that lead to both procoagulation and anticoagulation. As expected, similar abnormalities have been described in domestic animals. Biochemical abnormalities are associated with the effects of venom on tissues such as liver, skeletal and cardiac muscle, vascular endothelium, and kidney as well as effects on protein components and cholesterol. This comprehensive review of clinicopathologic abnormalities associated with envenomation and their relationships to characterized venom constituents should be useful both in the diagnosis and management of envenomation and should serve as a foundation for future research in this field. PMID- 21827517 TI - Tick toxicosis in a dog bitten by Ornithodoros brasiliensis. AB - Ticks are hematophagous parasites of people and animals and are a public health hazard in several countries. They are vectors of infectious diseases; in addition, the bite of some ticks, mainly from the Ornithodoros genus, may lead to local lesions and systemic illness, referred to as tick toxicosis. In this report, we describe a dog bitten by Ornithodoros brasiliensis, popularly known as the mouro tick. The main clinical findings were disseminated skin rash, pruritus, mucosal hyperemia, lethargy, and fever. Laboratory abnormalities 48 hours after the bites occurred included mild nonregenerative anemia, eosinophilia, basophilia, increased serum creatine kinase activity, increased serum C-reactive protein concentration, and prolonged coagulation times. Tick-borne pathogens were not detected by PCR analysis or serologic testing, supporting the diagnosis of a noninfectious syndrome due to tick bite, compatible with tick toxicosis. PMID- 21827518 TI - Evaluation of a point-of-care test for canine C-reactive protein. AB - BACKGROUND: In veterinary medicine, there is increasing interest in measuring C reactive protein (CRP) as a tool for diagnosis and monitoring of inflammatory diseases. Reported CRP concentrations for healthy dogs have ranged from 0 to 8.9 mg/L. OBJECTIVES: The aims of this study were to evaluate a canine-specific point of-care (POC) lateral flow immunoassay for qualitative CRP measurement in healthy and diseased dogs and to compare results with those obtained by a quantitative ELISA. METHODS: Blood samples from 73 client-owned dogs were available for testing: 16 healthy dogs and 57 dogs with a variety of infectious, inflammatory, or neoplastic diseases. CRP was measured in heparinized whole blood samples and serum with the TECO medical Dog CRP-visual POC test. A red line develops in the POC device if CRP is >= 5 mg/L, and results are scored as negative or positive. An ELISA validated previously for canine serum was used as the reference method. RESULTS: For all dogs, serum CRP concentrations measured by the ELISA ranged from 0.1 to >= 350 mg/L (median = 38 mg/L). Percentages of the CRP POC test results that agreed with the ELISA results were 98.6% for whole blood and 97.3% for serum samples. For serum samples, sensitivity of the POC test was 96.4% and specificity was 81.3%. For whole blood, sensitivity was 94.7% and specificity was 93.8%. CONCLUSIONS: The POC test had very good agreement with the ELISA test and had high sensitivity and specificity; therefore, it can be used as a qualitative test to screen for increases in CRP concentrations. PMID- 21827519 TI - Waldenstrom's macroglobulinemia in a dog with a bleeding diathesis. AB - An 11-year-old female spayed Whippet dog was referred to the Veterinary Hospital of the National Veterinary School of Lyon with a 3-month history of chronic bleeding, cutaneous masses suggestive of hematomas, and hemorrhagic diarrhea. Laboratory abnormalities included leukopenia with neutropenia and lymphopenia, rouleaux formation, marked hyperproteinemia with hyperglobulinemia and normoalbuminemia, hypercalcemia, markedly increased serum urea concentration, mildly increased creatinine concentration, and proteinuria. Hemostatic screening tests showed marked prolongation of thrombin time, increased concentrations of fibrin(ogen) degradation products and D-dimers, and slightly prolonged activated partial thromboplastin time. Serum and urine protein electrophoresis revealed a monoclonal peak identified as IgM by immunoelectrophoresis and an M-spike, respectively. Cytologic evaluation of bone marrow revealed a hypocellular sample with lymphoplasmacytic cells comprising approximately 50% of all nucleated cells. These findings were consistent with a diagnosis of Waldenstrom's macroglobulinemia with secondary bleeding diathesis. Treatment with prednisone and chlorambucil was initiated, and the dog had a good response. PMID- 21827520 TI - Neutrophilic myeloperoxidase index and mean light absorbance in neonatal septic and nonseptic foals. AB - BACKGROUND: Two neutrophilic indices reported by the ADVIA 120 Hematology Analyzer, neutrophilic myeloperoxidase index (MPXI), and mean light absorbance (neutrophil X mean [NXM]) have been proposed as indicators of systemic inflammatory disease in horses and of neutrophil activation in coronary ischemic syndromes in people. OBJECTIVE: The aim of this study was to evaluate NXM and MPXI in healthy, sick nonseptic, and sick septic foals to determine whether conditions likely associated with neutrophil activation result in decreases in these variables. METHODS: In this retrospective study, CBC data from 61 neonatal foals presented to the Equine Teaching Hospital of Barcelona were evaluated for correlations between MPXI, NXM, percentage of large unstained cells, neutrophil count, and percentage of band neutrophils. Results obtained in septic (n=32), sick nonseptic (n=22), and healthy foals (n=7) were compared. In addition, results recorded in septic/neutropenic (n=12), septic/non-neutropenic (n=20), nonseptic/neutropenic (n=8), nonseptic/non-neutropenic (n=14), and healthy foals (n=7) were also compared. RESULTS: A weak negative correlation was found between MPXI and neutrophil count and between NXM and percentage of band neutrophils. Septic/neutropenic foals had significantly higher MPXI values (median 17.9, minimum-maximum 4.7-42.5) than did septic/non-neutropenic (1.5, -24.4 to 22.3), nonseptic/neutropenic (6.6, 0.6-17.9), and nonseptic/non-neutropenic foals (8.8, 10.1 to 16.8) but did not differ significantly from controls (12.8, -8.5 to 20.4). CONCLUSIONS: Significant differences in NXM or MPXI were not found when disease groups were compared with controls; however, septic/neutropenic foals had significantly higher median MPXI than other groups of sick foals. Further prospective studies are needed to clarify if this finding is related to decreased neutrophil function or activation in septic/neutropenic foals. PMID- 21827521 TI - Age- and gender-specific prevalence of carotid atherosclerosis and its association with metabolic syndrome in Hangzhou, China. AB - OBJECTIVE: Because of rapid alterations in lifestyle and the incidence of metabolic syndrome (MetS), the prevalence of carotid atherosclerosis (CA) and carotid plaque (CP) may increase in China. We aimed to evaluate the prevalence of CA and CP as well as its relation to MetS in an East Chinese population. METHODS: The study included 6142 subjects who underwent general health screening including carotid ultrasonography in 2009. Diagnoses of MetS were made according to the revised Adult Treatment Panel III criteria. RESULTS: The prevalence of CA and CP increased gradually with age. These conditions were more prevalent in men than in women (CA: 22.1%vs 12.0%, P < 0.001; CP: 12.6%vs 7.2%, P < 0.001). Multivariate logistic regression analysis showed that male gender, age, blood pressure, fasting blood glucose (FBG) and low-density lipoprotein cholesterol were risk factors for CA and CP, while high-density lipoprotein cholesterol was protective for CA. Age >= 50 years has the largest impact on CA and CP, followed by elevated blood pressure and elevated blood glucose. Individuals with MetS had a higher prevalence of CA (27.7%vs 20.0% in men, 24.0%vs 10.3% in women; P < 0.001 in both) and CP (16.6%vs 11.2% in men, P < 0.001; 11.8%vs 6.5% in women, P < 0.005) than those without MetS. The prevalence and odds ratios of CA and CP aggregated with an increasing number of MetS components, even in individuals exhibiting only one component. CONCLUSIONS: These results indicate that CA and CP have become a major public health problem in China. MetS and its components were associated with an increased prevalence of CA and CP. PMID- 21827522 TI - The effectiveness of cognitive-behavioural therapy for temporomandibular disorders: a systematic review. AB - Cognitive-behavioural therapy (CBT) and its effects on temporomandibular disorders (TMD) have been examined in several studies. We are trying to combine results of these studies and to explore the effectiveness. MEDLINE, EMBASE, Cochrane Central Register of Controlled Trial, Pubmed and the Chinese Biomedical Literature Data were searched to collect randomised and semi-randomised controlled trials (RCTs), comparing CBT with any control group receiving other dental treatments. Two authors independently retrieved, extracted and assessed the quality of included studies. The search strategy resulted in 323 studies, of which five met the inclusion criteria, including three RCTs and two semi-RCTs. The quality of the included studies was diverse. Meta-analysis was not performed owing to five studies involving different comparison groups and follow-up periods. The effect of CBT on patients with TMD is inconsistent among the studies, so no firm conclusion could be drawn in this systematic review. There is insufficient evidence to make firm recommendations for the use of CBT over other intervention for the treatment of TMD. Further high-quality RCTs are clearly needed for this theme. PMID- 21827523 TI - Composite vertical bite reconstructions in eroded dentitions after 5.5 years: a case series. AB - In the following case series, we report on six cases of erosive worn dentitions (75 posterior teeth), which have been reconstructed using a template-based technique with direct composite resin restorations and already examined after 3 years in service. In all patients either one or both tooth arches were completely restored using direct resin composite restorations. A wax-up-based template was used to avoid freehand build-up techniques and to ensure optimal anatomy and function. All patients were re-assessed after a mean service time of 5.5 years (mean 67 +/- 4 months) using United States Public Health Service criteria. The overall quality of the restorations was good with predominantly 'alpha' and 'bravo' scores, respectively. However, the restorations showed some deterioration with respect to marginal quality, marginal discoloration, surface texture and anatomy as compared to the 3-year investigation. The marginal impairments could be resolved by polishing. It is concluded that this non-invasive technique provides a possible treatment option at least for the displayed observation period of 5.5 years. PMID- 21827524 TI - Response shift in oral health-related quality of life measurement in patients with partial edentulism. AB - The purposes of this study were to determine whether a response shift was observable after partial denture treatment and to identify the predictors that influenced the response shift magnitude and direction. A total of 173 consecutive patients with no more than eight missing teeth who received implant-supported, fixed or removable partial dentures at Okayama University Dental Hospital were asked to complete a full-version Oral Health-Related Quality of Life (OHRQoL) questionnaire before (pre-test) and after treatment (post-test). Additionally, a short form (then-test) consisting of seven questions selected from the full version had its reliability verified and was utilised to retrospectively assess the pre-treatment OHRQoL status. The difference between the summary scores of the then-test and the pre-test determined the response shift magnitude and direction. The then-test mean score (22.9 +/- 6.6) was significantly lower (worse OHRQoL) than that of the pre-test (26.4 +/- 5.2). The response shift effect size was of moderate magnitude and negative direction (d = -0.78). A multiple regression analysis showed that age (younger patients) (P < 0.01), number of replaced teeth (fewer) (P < 0.01) and pre-test scores (lower) (P < 0.01) were the significant predictors for response shift. In conclusion, a response shift phenomenon with negative and moderate effect size was observed after partial denture treatment. The significant predictor variables were young age, fewer numbers of replaced teeth and lower pre-test scores. PMID- 21827525 TI - Developing abbreviated OHIP versions for use with TMD patients. AB - The aim of this study was to evaluate the psychometric characteristics of three versions of the Dutch Oral Health Impact Profile (OHIP-NL), for clinical use with temporomandibular disorder (TMD) patients. To that end, two abbreviated OHIP versions (OHIP-NL14 and OHIP-NL5) were developed by respectively selecting 14 and five items from the officially translated and culturally adapted original 49-item OHIP-NL questionnaire. A total of 245 consecutive patients, referred by their dentist to the TMD clinic of the Academic Centre for Dentistry Amsterdam (77% women; mean age +/- s.d. = 41.0 +/- 14.9 years), completed the Research Diagnostic Criteria for TMD (RDC/TMD) axis II questionnaire and the OHIP-NL. Reliability and validity of all three OHIP versions were compared, and their associations with four psychological axis II variables, indicating the level of impairment of patients with TMD, were examined. According to guidelines for clinical application, internal consistency scores were sufficient for OHIP-NL and OHIP-NL14, but insufficient for OHIP-NL5. Test-retest reliability (n = 64) was excellent for OHIP-NL and OHIP-NL14 and fair to good for OHIP-NL5. For all three versions, there was evidence for score validity: associations between OHIP summary scores on the one hand and validation variables and other RDC/TMD axis II variables on the other hand met the expectations and were statistically significant (P < 0.001). In conclusion, the OHIP-NL and OHIP-NL14 both performed comparatively well and better than the OHIP-NL5. When the length of the questionnaire (i.e. the time needed for its completion) is an issue, the OHIP-14 would therefore be the preferred version. PMID- 21827526 TI - Internationally adopted children in Finland: parental evaluations of symptoms of reactive attachment disorder and learning difficulties - FINADO study. AB - OBJECTIVE: This study investigated the association between psychological symptoms, such as features of reactive attachment disorder (RAD), and learning difficulties among international adoptees in Finland. METHODS: The data for this study came from the FINnish ADOption (FINADO) study covering all internationally adopted children in Finland (n= 1450), with a response rate of 55.7%. The subsample consisted of 395 adopted children aged 9-15 (51.6% girls, 48.4% boys). Learning difficulties were evaluated by a screening questionnaire 'Five To Fifteen' and symptoms of RAD by FINADO RAD scale. RESULTS: The parents estimated that one-third (33.4%) of the internationally adopted children had some, and 12.7% had severe learning difficulties, i.e. three and six times more than in normal population, respectively. RAD symptoms at the time of adoption were associated with learning difficulties at school age (OR 4.57, 95% CI 2.57-8.13). CONCLUSIONS: Learning difficulties are common among internationally adopted children in Finland and symptoms of RAD are associated with a child's learning difficulties. PMID- 21827527 TI - Impact of early weight loss on growth of Caesarean delivered babies: how long does it last? AB - BACKGROUND: We hypothesized that Caesarean delivered babies might experience excessive weight loss during neonatal period. AIM: To investigate amount of weight loss among Caesarean delivered babies with exclusive breastfeeding and to identify role of relative weight change (RWC) in early postnatal period on the growth of infants in subsequent months. METHODS: We studied healthy infants born >=36 completed weeks, by Caesarean section between September 2008 and August 2009, with Apgar scores >7. Weight measurements were performed at birth, at 24 h postpartum and at days 2, 4, 7, 14, 30 and monthly up to 6 months. Predictive roles of RWC at each assessment on detecting excessive weight loss and poor weight gain in 1st month, as well as bodyweight z scores in subsequent months were assessed. RESULTS: We studied 160 infants (88 female, 72 male) with a mean gestational age of 38.01 +/- 1 weeks and birthweight of 3239 +/- 421 g. Overall, 22.5% of infants lost >10% of birthweight; 11.9% at day 2, 16.9% at day 4 and 6.6% at day 7. Degree of weight loss was not related with parity, gestational age, birthweight or type of anaesthesia. Predictive values of RWCs in detecting poor weight gain in 0-30 days were: 2nd day; limit =-9.4%, specificity = 91.5%, 4th day; limit =-10.2%, specificity = 89.4%, 7th day; limit =-6.3%, specificity = 85%, sensitivity = 78%, 14th day; limit =+0.8%, specificity = 91.5%, sensitivity = 83.3%. Adjusting for birthweight z scores, RWC at 14th day had a significant influence on 1st and 2nd month bodyweight z scores. Bodyweight z scores were significantly correlated with the z scores of bodyweight in 1-5 months but not with that of 6 months. CONCLUSION: Incidence of excessive weight loss is very high among Caesarean delivered babies. RWC at earlier measurements proves satisfactory in predicting poor infant growth. Management strategies based on identifying infants at risk could prevent excessive weight loss and improve future growth of those infants. PMID- 21827528 TI - A pilot study of scoliosis assessment using radiation free surface topography in children with GMFCS IV and V cerebral palsy. AB - BACKGROUND: Prevalence of scoliosis in cerebral palsy (CP) parallels the extent of neurological impairment and causes significant morbidity. Monitoring is important but requires regular radiological investigation. Surface topography provides a non-radiological approach to scoliosis monitoring. AIM: To evaluate validity, reproducibility and feasibility of Quantec((r)) scans to monitor scoliosis in children with severe CP. METHODS: Twenty non-ambulant children with CP, Gross Motor Function Classification System (GMFCS) grade IV/V had clinical, radiological and Quantec spinal assessment. The children were supported during scans using a seating system specifically designed for this study. Validity was assessed by comparing Quantec (Q) angle with gold standard (Cobb angle), reproducibility analysed using Bland-Altman plots and feasibility assessed using a questionnaire. RESULTS: Prevalence of scoliosis on radiological examination was 65%. Of these children, 85% had curves with Cobb angle less than 28 degrees . Quantec scanning was feasible with appropriate postural support. Mean (and standard deviation) for differences between Cobb and Quantec (Q) angle were 0.02 degrees (6.2 degrees ) and for Quantec inter-observer variability were 0.5 degrees (5.8 degrees ). CONCLUSIONS: Quantec scanning was feasible, reproducible and had good validity when compared with Cobb angle in a supportive seating system. To consolidate these findings a further study needs to be undertaken with larger number of children with Cobb angles between 25 degrees and 45 degrees . PMID- 21827529 TI - Personal and environmental pathways to participation in young children with and without mild motor disabilities. AB - OBJECTIVE: Participation in everyday activities has a positive influence upon health and well-being and is considered as an outcome measure. According to recent models child participation is the product of the dynamic interaction between health states and both individual and environmental factors. Children with mild developmental disabilities often present decreased participation in everyday activities. The purpose of this study was to explore the extent to which individual and environmental factors explain the participation of young children, with and without mild motor disabilities. METHODS: The study population included 58 kindergarten children together with their parents (29 children with mild motor disabilities who were referred to occupational therapy and 29 children without motor disabilities). Both groups of children were matched for: age; gender; age of parents; and socio-economic status (SES). We assessed participation using the Child Participation Questionnaire (intensity, diversity, independence, child enjoyment and parental satisfaction) and we assessed children's self-efficacy and motor abilities for individual factors. Parental self-efficacy and SES were collected by questionnaires. RESULTS: Participation diversity (number of activities) was predicted by child and mother self-efficacy and by SES. Child independence and enjoyment as well as parental satisfaction were predicted by child motor ability but mainly by maternal self-efficacy. Results suggest that the total explained variance is more than double when the environmental variables (parental self-efficacy and SES) are inserted to the participation model. CONCLUSIONS: Maternal self-efficacy and SES serve as facilitators to increased participation and well-being of children with mild motor disabilities. PMID- 21827530 TI - Health promotion: the way forward for diabetic control. PMID- 21827531 TI - Effectiveness of a brief intervention for managing hazardous drinking problems of inpatients in Taiwan. AB - AIMS: This paper is a report of a randomized control trial undertaken to evaluate the efficacy of the Brief Intervention for Alcohol Use in Taiwanese inpatients with hazardous drinking patterns. BACKGROUND: The Brief Intervention for Alcohol Use has been found to be as effective as medical and psychological treatments for individuals with alcohol use disorders in western countries. However, few studies have examined brief alcohol interventions for a Chinese population. METHODS: Patients from the medical and surgical wards of a medical centre in northern Taiwan were enrolled if they had an Alcohol Use Disorders Identification Test score >8. Participants were randomly assigned to the experimental group (n = 47), which received the Brief Intervention, and the control group (n = 48), which received no special psychosocial intervention except routine nursing care. Data were collected from February 2005 to March 2006 on hospitalized participants' demographic characteristics and alcohol use. Scores on the Alcohol Use Disorders Identification Test were re-assessed over the telephone 6 months later by a trained assistant blinded to the treatment group. RESULTS: The experimental group had a significantly higher mean improved Alcohol Use Disorders Identification Test score and better outcomes in all three dimensions of the test than the control group. CONCLUSIONS: The Brief Intervention for Alcohol Use is recommended for use in clinical settings to help Taiwanese inpatients with hazardous drinking patterns to improve their drinking problems. PMID- 21827532 TI - How many mechanisms are needed to analyze speech? A connectionist simulation of structural rule learning in artificial language acquisition. AB - Some empirical evidence in the artificial language acquisition literature has been taken to suggest that statistical learning mechanisms are insufficient for extracting structural information from an artificial language. According to the more than one mechanism (MOM) hypothesis, at least two mechanisms are required in order to acquire language from speech: (a) a statistical mechanism for speech segmentation; and (b) an additional rule-following mechanism in order to induce grammatical regularities. In this article, we present a set of neural network studies demonstrating that a single statistical mechanism can mimic the apparent discovery of structural regularities, beyond the segmentation of speech. We argue that our results undermine one argument for the MOM hypothesis. PMID- 21827534 TI - Aortic root abscess complicated by fistulization in a young patient with bicuspid aortic valve. AB - Aortic root abscess is a relatively common complication of aortic valve endocarditis. However, aortic root abscess and formation of a fistula from the aortic root to the right ventricular outflow tract in the setting of a native bicuspid aortic valve (BAV) is a rare event. We present consecutive echocardiographic images of unruptured periaortic abscess and fistulization of it to the right ventricle in 24 hours, in a patient with BAV and fever of unexplained origin. PMID- 21827535 TI - Left ventricular twisting as determinant of diastolic function: a speckle tracking study in patients with cardiac hypertrophy. AB - PURPOSE: Left ventricular hypertrophy (LVH) can develop in response to training with morphological changes in the heart and to pathological increase in afterload such as in essential hypertension. Deformation analysis using two-dimensional (2D) strain echocardiography can detect early systolic function abnormalities in patients with LVH. The aim of this study was to characterize left ventricular twisting (LVT) modifications, in professional athletes, compared with control subjects and with patients with hypertensive cardiopathy. METHODS: Seventy-six patients were enrolled: 37 professional athletes with cardiac hypertrophy (group A), 22 patients with early hypertensive cardiopathy (group B) cross-matched for LV mass index, and 17 healthy controls (group C), with no evidence of cardiac hypertrophy. All patients had no concomitant cardiac disease. All patients were investigated at rest using transthoracic echocardiography. LVT was obtained with speckle tracking analysis, using dedicated software. RESULTS: LVT was reduced in group A compared to group B and C (group A: 8.0 degrees +/- 2.4 degrees ; group C: 10.3 degrees +/- 2.3 degrees ; group B: 16.0 degrees +/- 4.2 degrees ; P < 0.01). In overall population, LVT showed a significant correlation with transmitral flow pattern (r =-0.58, P < 0.01) and with age (r =-0.57, P < 0.01). LVT showed the best predictive value to diagnose diastolic dysfunction (AUC: 0.86, P < 0.0001). CONCLUSIONS: 2D strain can identify specific patterns of myocardial deformation in professional athletes, controls, and patients with early hypertensive cardiopathy. In our study LVT showed a parallel trend with modifications of diastolic function and could represent a promising tool to differentiate functional cardiac hypertrophy from hypertensive cardiac hypertrophy. PMID- 21827536 TI - Quantitative measurement of circumferential carotid arterial strain by two dimensional speckle tracking imaging in healthy subjects. AB - BACKGROUND: Two-dimensional speckle tracking imaging (2DS) enables quantitative measurement of left ventricular strain. However, application of 2DS for measurement of circumferential carotid arterial strain (CAS) is not fully elucidated. We investigated the feasibility and reproducibility of measuring CAS by 2DS and determinants of CAS in healthy subjects. METHODS: Fifty-one healthy subjects (20 men and 31 women) with a mean age of 29 +/- 11 years were enrolled. Ultrasound examination of bilateral common carotid arteries (CCAs) was performed and short axial views were recorded. The mean intima-media thickness (IMT) of bilateral CCAs was measured using semiautomated edge-detection software. Bilateral peak CAS at systole and time to peak CAS in each region were measured by 2DS. Stiffness parameter beta of bilateral CCAs was measured and bilateral cardio-ankle vascular index (CAVI) was recorded. Intraobserver and interobserver variabilities for mean CAS were calculated in 15 subjects. RESULTS: Of the 612 regions, 577 (94%) had adequate waveforms for measurement of CAS. The mean value of CAS was 6.7 +/- 2.1%. Required time for CAS analysis was 128 +/- 12 seconds per subject. Multiple regression analysis identified age (P < 0.001) and pulse pressure (P < 0.05) as independent significant determinants of mean CAS. Corrected CAS, which was calculated as mean CAS/pulse pressure, correlated with age, mean IMT, and stiffness parameter beta and systolic pressure (P < 0.001), age (P < 0.01), and stiffness parameter beta (P = 0.02) were identified as independent significant determinants of corrected CAS. Coefficient of variance (CV) of intraobserver and interobserver variabilities for mean CAS were 8.8% and 5.9%, respectively. CONCLUSIONS: 2DS in the CCAs is simply and quickly performed with high feasibility and excellent reproducibility. In healthy subjects, age and pulse pressure are the most important determinants of mean CAS. PMID- 21827533 TI - Learning foreign sounds in an alien world: videogame training improves non-native speech categorization. AB - Although speech categories are defined by multiple acoustic dimensions, some are perceptually weighted more than others and there are residual effects of native language weightings in non-native speech perception. Recent research on nonlinguistic sound category learning suggests that the distribution characteristics of experienced sounds influence perceptual cue weights: Increasing variability across a dimension leads listeners to rely upon it less in subsequent category learning (Holt & Lotto, 2006). The present experiment investigated the implications of this among native Japanese learning English /r/ /l/ categories. Training was accomplished using a videogame paradigm that emphasizes associations among sound categories, visual information, and players' responses to videogame characters rather than overt categorization or explicit feedback. Subjects who played the game for 2.5h across 5 days exhibited improvements in /r/-/l/ perception on par with 2-4 weeks of explicit categorization training in previous research and exhibited a shift toward more native-like perceptual cue weights. PMID- 21827537 TI - The challenge of integrated echocardiographic approach in percutaneous closure of paravalvular leak. AB - Paravalvular leak after prosthetic mitral valve surgery may lead to symptomatic mitral regurgitation and hemolytic anemia requiring reoperation. Percutaneous closure of paravalvular leaks is a relatively recent technique still considered a challenging procedure burdened by possible complications, to be offered only to poor redo surgical candidate patients. Multimodality imaging is advocated to plan and guide the procedure, to minimize the risk of complications. We report on a case of dehisced prosthetic mitral valve in which transthoracic real time three dimensional echocardiography was used to locate the dehiscence area and characterize mitral paraprosthesis leak, whereas intracardiac echocardiography was used to guide and monitor the percutaneous closure procedure. PMID- 21827538 TI - The dilated coronary sinus: utility of coronary sinus cross-sectional area and eccentricity index in differentiating right atrial pressure overload from persistent left superior vena cava. AB - BACKGROUND: Pulmonary hypertension and right atrial pressure overload (RAPO) cause dilation of the coronary sinus (CS). Persistent connection of the left superior vena cava (LSVC) to the CS is another cause of CS dilation. The purpose of this study was to evaluate the usefulness of coronary sinus cross-sectional area (CSA) and eccentricity index (EI) in differentiating persistent LSVC from right heart overload and RAPO in patients with dilated CS. METHODS: We identified 15 patients with a dilated CS by echocardiography. Offline analysis was used to measure CS-CSA and CS-EI at end-diastole in the parasternal long axis plane. EI was defined as B/A, where A is the widest diameter and major axis of the CS, and B is the diameter of the minor axis (perpendicular to and bisecting A at its midpoint). Persistent LSVC was confirmed by either computed tomography or injection of agitated saline in the left antecubital vein. RESULTS: CS-CSA was significantly larger in PLSVC group than in group with RAPO. Also, CS-EI was lower in PLSVC than in RAPO group (P = 0.0003). EI was the most sensitive and specific discriminator between patients with persistent LSVC vs. RAPO. CS-EI was <0.8 in all PLSVC patients and >0.8 in all RAPO patients (sensitivity and specificity = 100%). CONCLUSION: Patients with persistent LSVC have a significantly higher CS-CSA than those with elevated RA pressure. When dilated CS is present, a CS-EI <0.8 is 100% sensitive and specific for persistent LSVC. Thus, the CS-EI can be used in cases of dilated CS to diagnose the presence of persistent LSVC with a very high degree of certainty, and can help differentiate this congenital anomaly from RAPO. PMID- 21827539 TI - Reversible systolic anterior motion of the mitral valve and left ventricular outflow tract obstruction in association with Takotsubo syndrome. PMID- 21827540 TI - Effect of food intake on commonly used pulsed Doppler and tissue Doppler measurements. AB - OBJECTIVE: This study evaluates the effect of food intake on commonly used pulsed Doppler and tissue Doppler measurements. METHODS: Twenty-three healthy subjects aged 25.6 +/- 4.5 years were investigated. A wide selection of pulsed Doppler and tissue Doppler variables were measured before a standardized meal as well as and 30 and 110 minutes afterwards. RESULTS: The following variables increased significantly (P < 0.05) 30 minutes after food intake: left ventricular stroke volume, left ventricular cardiac output, left ventricular outflow velocity-time integral, peak of early diastolic (E) and late diastolic (A) mitral flow velocities, pulmonary vein peak velocities in systole (S) and in diastole (D), S/D, pulsed tissue Doppler peak systolic velocities, and late diastolic velocities. Deceleration time of E-wave decreased significantly (P < 0.05). The change in measured variables between fasting and 30 minutes after the food intake ranged from 7% to 28%. There were no significant (P > 0.05) changes in E/A, early diastolic tissue Doppler velocities (e'), and E/e'. Most, but not all variables returned to baseline values 110 minutes after food intake. CONCLUSIONS: This study shows that food intake affects several echocardiographic variables used to routinely assess diastolic function and hemodynamics. Further studies are warranted in older healthy subjects and in patients with various cardiac diseases to determine whether the findings are reproducible in such populations. PMID- 21827541 TI - Cumulative impact of cardiovascular risk factors on regional left ventricular function and reserve: progressive long-axis dysfunction with compensatory radial changes. AB - BACKGROUND: The risk factors that contribute to atherosclerosis also predict clinical heart failure, but it is unclear how they affect myocardial function. Aims were to assess if major cardiovascular risk factors cause subclinical myocardial dysfunction in asymptomatic subjects. METHODS: We measured regional left ventricular (LV) function at rest and during dobutamine stress echocardiography in 246 subjects (54 +/- 12 years, 54% men) analyzed in five groups according to the presence of six risk factors (diabetes, hypertension, obesity, dyslipidemia, smoking, and family history; age was similar in the five groups). LV longitudinal function was assessed from the mean velocities of four basal segments, and radial function from the velocities of the basal posterior wall. RESULTS: Risk factors did not affect LV ejection fraction, but longitudinal systolic velocity decreased progressively with the number of risk factors, at rest (6.8 +/- 1.3 vs. 6.2 +/- 1.6 vs. 5.8 +/- 1.5 vs. 5.4 +/- 1.3 vs. 5.3 +/- 1.3 cm/sec, for the five groups, respectively) and at peak stress (14.3 +/- 3.3 vs. 12.9 +/- 3.2 vs. 11.8 +/- 3.4 vs. 11.3 +/- 2.6 vs. 11.1 +/- 2.3 cm/sec) (both P < 0.0001). Radial systolic velocity increased according to the number of risk factors (P < 0.01). By multivariate regression, determinants of reduced longitudinal systolic velocity at rest were body mass index, diastolic blood pressure, age, and fasting plasma glucose (r = 0.57, r(2) = 0.32, P < 0.0001). CONCLUSION: Asymptomatic subjects have impaired LV long-axis function at rest and during stress, according to their number of major cardiovascular risk factors. Global LV systolic function is maintained by compensatory increases in radial function. These changes provide new targets for preclinical diagnosis and for monitoring responses to preventive strategies. PMID- 21827542 TI - Normotensive male offspring of essential hypertensive parents show early changes in left ventricular geometry independent of blood pressure. AB - For the purpose of detecting early left ventricle (LV) abnormalities in normotensive offspring of hypertensive parents (EH+), 23 normotensive sedentary male EH+ (age 25 +/- 3 years) and 20 matched offspring of normotensive families (EH-), underwent: clinic bloop pressure (BP) measurement, 24-hour ambulatory BP monitoring (ABPM), frequency-domain parameters of autonomic heart rate control and conventional and Doppler tissue echocardiographic (DTE) study of both ventricles, including relative wall thickness (RWT) as an index of LV remodeling. EH+ subjects had slightly higher office systolic and diastolic (P < 0.05), average 24-hour systolic (P < 0.001), diastolic (P < 0.01), and mean BP (P < 0.05). No between-group differences were detected for heart rate variability, LV mass and systolic and diastolic function in both ventricles. RWT was greater in EH+ (0.38 +/- 0.05 vs. 0.34 +/- 0.03 SD; P < 0.01), which was significantly related, at the univariate analysis, to the condition of EH+ (P < 0.004) and to the clinic and ambulatory BP parameters as well (P = 0.06-0.01). However, at the stepwise multiple regression analysis, with RWT used as the dependent variable, only the condition of EH+ was independently associated with RWT (P < 0.008), whereas BP did not. RWT, according to receiver operating characteristic curves analysis, predicted the condition of EH+ (cutoff point 0.369, specificity 90%, sensitivity 65%). Our data suggest that an higher RWT, as an index towards LV concentric remodeling, is the earliest change in LV geometry in EH+ subjects, independent of any slight elevation in BP. Thus, RWT measurement may be a quite specific tool to detect early LV alterations due to the condition of EH+. PMID- 21827543 TI - Role of patent foramen ovale in migraine etiology and treatment: a review. AB - An increased prevalence between patent formen ovale (PFOs) and migraine exists but there is conflicting data regarding causal relationship between these two conditions. It is controversial whether cardiac screening and intervention like PFO closure provides any benefit in this population and so this area still remains under intense investigation. The management of migraine lies at the intersection between the practice of primary care physicians, neurologists, and cardiologists. There is no consensus as to what is the best practice for the evaluation of these patients with difficult to control migraine given the millions of dollars spent on physician visits and pharmacotherapy. This review seeks to summarize the current literature on this association and studies that have investigated PFO closure in this population. PMID- 21827544 TI - Incremental value of live/real time three-dimensional transesophageal echocardiography over the two-dimensional technique in the assessment of sinus of valsalva aneurysm rupture. AB - We present an adult patient with rupture of the right sinus of Valsalva aneurysm in whom the two-dimensional transesophageal echocardiogram failed to show the rupture. On the other hand, live/real time three-dimensional transesophageal echocardiography clearly delineated the site of rupture into the pericardium and mediastinum. PMID- 21827545 TI - Missed diagnosis of limited ascending aortic dissection by multiple imaging modalities leading to fatal cardiac tamponade and aortic rupture. AB - Modern diagnostic imaging modalities for ascending aortic dissection include transesophageal echocardiography (TEE), computed tomography angiography (CTA), and magnetic imaging resonance (MRI). All have extremely high sensitivity and specificity for detection of an intimal flap to diagnose ascending aortic dissection. We present a case of fatal cardiac tamponade caused by a limited aortic dissection not detected by multiple imaging modalities. This may represent a class of aortic dissection variant that cannot be detected by conventional testing. A high index of suspicion should be maintained in the appropriate clinical setting and should prompt serial imaging and even consideration for preemptive surgical exploration. PMID- 21827546 TI - The assessment of left ventricular systolic asynchrony in patients with primary hyperparathyroidism. AB - OBJECTIVES: Primary hyperparathyroidism (PHP) is associated with a variety of cardiovascular disturbances such as left ventricular (LV) hypertrophy, diastolic cardiac dysfunction, and hypertension. LV asynchrony is defined as the loss of the simultaneous peak contraction of corresponding cardiac segments. The objective of this study was to assess systolic asynchrony in patients with overt hyperparthyroidism. METHODS: Asynchrony was evaluated in 22 patients with PHP and 24 controls. All the patients and controls were subjected to a tissue synchronization imaging (TSI). The time to regional peak systolic tissue velocity (Ts) in LV by the six-basal-six-midsegmental model was measured on ejection phase TSI images and four TSI parameters of systolic asynchrony were computed. RESULTS: All TSI parameters of LV asynchrony increased in patients with PHP patients compared to the controls: the standard deviation (SD) of the 12 LV segments Ts (37.3+/-20.6 vs. 21.5+/-11.1, P=0.01); the maximal difference in Ts between any 2 of the 12 LV segments (111.2+/-59.8 vs. 70.2+/-32.1, P=0.01); the SD of the 6 basal LV segments (42.9+/-36.4 vs. 18.5+/-13, P=0.003); and the maximal difference in Ts between any 2 of the 6 basal LV segments (89.6+/-50.5 vs. 48+/ 31.1, P=0.003). CONCLUSION: Patients with PHP show an evidence of LV asynchrony by TSI. Asynchrony may contribute to the harmful cardiovascular effects of PHP. PMID- 21827547 TI - Hypertrophic cardiomyopathy is associated with abnormal echocardiographic aortic elastic properties and arteriograph-derived pulse-wave velocity. AB - OBJECTIVE: Hypertrophic cardiomyopathy (HCM) is a genetic cardiac disease and defined by the presence of unexplained left ventricular hypertrophy (LVH). Vascular alterations are frequently associated with HCM including microvascular and/or peripherial endothelial dysfunction. This study was designed to evaluate echocardiographic ascending aortic elastic properties and arteriograph-derived pulse-wave velocity (PWV) and augmentation index (Aix) in HCM. METHODS: This study comprised 38 patients with typical features of HCM. Their results were compared to 20 hypertensive patients with LVH and 23 controls. Systolic and diastolic ascending aortic diameters were recorded in M-mode at a level of 3 cm above the aortic valve from a parasternal long-axis view. The following echocardiographic aortic elastic properties were measured from aortic data and forearm blood pressure values: aortic strain, distensibility, and stiffness index. Arteriograph-derived PWV and AIx were also measured. RESULTS: Aortic stiffness index (18.4 +/- 17.6 vs. 6.88 +/- 3.63, P < 0.05), PWV (9.44 +/- 4.08 vs. 7.97 +/- 1.20 m/sec, P < 0.05) and Aix (-24.9 +/- 32.6 vs. -41.4 +/- 24.3, P < 0.05) were increased, while aortic strain (0.061 +/- 0.053 vs. 0.100 +/- 0.059, P < 0.05) and aortic distensibility (1.94 +/- 1.68 cm(2) /dynes 10(-6) vs. 3.08 +/- 1.77 cm(2) /dynes 10(-6) , P < 0.05) were decreased in HCM patients compared to controls. Aortic elastic properties of hypertensive patients with LVH showed similar alterations to HCM patients. CONCLUSIONS: Abnormal echocardiographic aortic elastic properties and arteriograph-derived PWV and Aix could be demonstrated in HCM patients compared to matched controls. PMID- 21827548 TI - Echo features of posteromedial papillary muscle rupture without papillary muscle prolapse into the left atrium. PMID- 21827549 TI - Echocardiographic epicardial fat thickness is associated with carotid intima media thickness in patients with metabolic syndrome. AB - BACKGROUND: Carotid intima-media thickness (CIMT) is a potential indicator of subclinical atherosclerosis in patients with metabolic syndrome (MetS). Epicardial fat thickness (EFT) is suggested as a new cardiometabolic risk factor. We investigated the association between EFT and CIMT in patients with MetS. METHODS: Forty patients with MetS were compared with 40 age- and sex-matched subjects without MetS in terms of echocardiographic EFT, CIMT, anthropometric measurements, and metabolic profile in this cross-sectional study. RESULTS: The waist circumference, total and LDL-cholesterol, fasting glucose, triglycerides, systolics and diastolic blood pressure levels, hs-CRP, and homeostasis model assessment index for insulin resistance (HOMA-IR) were significantly increased in patients with MetS. The EFT and CIMT were also increased significantly in patients with MetS compared to controls (7.2 +/- 2 mm vs. 5.7 +/- 1.9 mm; P = 0.001, 0.74 +/- 0.1 mm vs. 0.59 +/- 0.1 mm; P < 0.01, respectively). Echocardiographic EFT was the only independent predictor of CIMT in the multivariate analysis (standardized beta coefficient = 0.74, P < 0.001). CONCLUSION: EFT is associated with increased CIMT in patients with MetS. PMID- 21827550 TI - Proposed new diagnostic criteria for gestational diabetes--a pause for thought? AB - New criteria for the diagnosis of gestational diabetes promulgated by the International Association of Diabetes and Pregnancy Study Groups (IADSPG) have been adopted by a number of groups, including the American Diabetes Association. These criteria will increase two- to three-fold the number of women diagnosed with gestational diabetes and have enormous resource implications. The recommendations are derived from observations made in the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study, which demonstrated continuous relationships between maternal glucose tolerance and two clinically relevant outcomes of pregnancy (caesarean section rate and neonatal hypoglycaemia) and two surrogate measures (birth weight and cord C-peptide). The recent randomized intervention studies in mild gestational diabetes indicate that the major effects of detecting and treating mild gestational diabetes are a reduction in mean birthweight of 100-140 g, and a reduction in the incidence of shoulder dystocia. However, the women included in these studies were identified using different diagnostic criteria, and it cannot be assumed that women diagnosed by the less stringent IADSPG criteria will have the same benefit. Moreover, as the majority of cases of macrosomia and shoulder dystocia occur in women with normal glucose tolerance, the real impact of diagnosing many more 'cases' of gestational diabetes is likely to be minimal. The concentration on mild degrees of hyperglycaemia may well be misplaced, as most of the outcomes usually attributed to gestational diabetes are more strongly associated with maternal obesity and weight gain in pregnancy. The new testing procedure (with diagnosis based on a single blood glucose measurement) will inevitably be imprecise. Given the many reservations about the new criteria an urgent but dispassionate debate is required on the risks, costs and benefits of their introduction. PMID- 21827551 TI - Measuring maternal stress and perceived support in 25 Italian NICUs. AB - AIMS: To determine the validity and reliability of the Parental Stressor Scale: Neonatal Intensive Care Unit (PSS: NICU) and the Nurse Parental Support Tool (NPST) for use with Italian parents; to investigate to which extent demographic variables and/or situational factors affect NICU-related maternal stress. METHODS: Mothers (N = 156) of very preterm (VPT) infants from 25 Italian NICUs completed a socio-demographic form, the PSS: NICU and the NPST at discharge. Psychometric properties of both tools were evaluated. RESULTS: High internal consistency and split-half reliability were found for both measures. The multi dimensional structure of the PSS:NICU was confirmed. Alteration in parental role emerged as the greatest source of NICU-related stress. Length of stay in NICU and familiar socio-economic status explained partial variance in the PSS: NICU scores. NPST score mitigates the stress because of the infant's appearance and behaviour, but not that related to the parental role alteration. CONCLUSIONS: PSS: NICU and NPST demonstrated adequate psychometric properties in a large sample of Italian mothers. The need for a psychologically informed support to NICU mothers is suggested. PMID- 21827554 TI - Mother-young relationships in sheep: a model for a multidisciplinary approach of the study of attachment in mammals. AB - The onset of maternal responsiveness and the development of mother-young attachment in sheep are under the combined influence of hormonal and sensory stimulations. In the mother, the prepartum rise in oestrogen and vaginocervical stimulation caused by expulsion of the foetus act on the main olfactory system and on hypothalamic regions. This induces maternal care through the central release of oxytocin, modulated by opiates and corticotrophin-releasing hormone. In parallel, activation of the main olfactory network enables the learning of individual lamb odour and maternal attachment. In the neonate, the first suckling episodes and the concomitant activation of the cholecystokinin, opioids and oxytocin systems facilitate the development of a preference for the mother. Gastrointestinal signals activate the brain stem, the hypothalamus and the amygdala. Within 72 h of parturition, the mother-young attachment shifts from proximal to distal recognition based on visual and auditory cues after which vocal cues become more salient. Although olfaction remains a key element in the display of selective maternal nursing, maternal attachment relies on a multisensory mental image of the lamb. These findings support the view that sheep are amongst the most appropriate animal models for the study of maternal and filial attachment in mammals. PMID- 21827555 TI - The clinical presentation and surgical treatment of verrucous dermatitis lesions in a draught horse. AB - Verrucous pastern dermatitis is a progressive inflammatory skin disease commonly involving the palmar or plantar aspects of the pasterns of horses. There are no reports of successful surgical treatment for multifocal circumscribed verrucous masses in the chronic stages of verrucous pastern dermatitis. A combination of sharp dissection and electrocautery was used to resect numerous multifocal circumscribed verrucous masses from the distal hindlimb of an 11-year-old gelding draught horse. There was no evidence of significant regrowth or complications at a 24 month postoperative examination. PMID- 21827556 TI - Periodic leg movements during sleep in narcoleptic patients with or without restless legs syndrome. AB - We compared periodic and non-periodic leg movements during sleep and polysomnography in patients with narcolepsy with cataplexy (NC) with or without restless legs syndrome (RLS) with matched idiopathic RLS (iRLS) and control subjects. We enrolled 100 patients with NC: 17 having RLS were compared with 34 sex- and age-matched patients without RLS and with 17 normal controls and 17 iRLS subjects. Periodic leg movements were highest in iRLS and lowest in controls, with those in NC with RLS very close to iRLS, but higher than those in NC without RLS. The periodicity indexes showed the highest value in iRLS followed by NC with or without RLS and, finally, by controls. The inter-leg movement intervals peaked between 10 and 50 s in NC with RLS and in iRLS, the former did not display the nocturnal gradual decrease of periodic leg movements typical of iRLS. Periodic leg movements during sleep and polysomnography displayed specific features in RLS and NC, respectively, with NC with RLS showing an intermediate pattern. Even if RLS is only detected by targeted interview in NC, its frequency and impact on night-time sleep architecture and continuity suggest that this condition should be routinely searched for in NC. PMID- 21827557 TI - Framework Convention on Tobacco Control (FCTC) Article 14 guidelines: a new era for tobacco dependence treatment. PMID- 21827558 TI - Seroma is an expected consequence and not a complication of MammoSite brachytherapy. AB - Seroma has long been listed as a complication of MammoSite brachytherapy. Palpable abnormalities are clinically apparent months after treatment and a vast majority of patients demonstrate seroma formation in radiologic studies. We embarked on this study to evaluate the actual sonographic incidence and eventual sonographic resolution, possible contributing factors, cosmesis, pain, and local control associated with seroma formation after MammoSite partial breast irradiation (PBI). We investigated 160 patients who underwent MammoSite PBI from 2002 to 2006 of whom 100 patients had serial sonographic information. Clinical and tumor variables, infection, pain, and cosmesis were investigated. Dosimetric data including volume of balloon, dose at balloon surface, and at skin were analyzed. After a median follow-up of 36 months, the incidence of sonographically confirmed post-radiation seroma was 78% within the first 1 year following radiation and steadily decreased with time. The average size of a seroma cavity was 2.3 cm (range 0.6-6 cm) with a decline to an average of 1.4 cm after 1 year, with complete resolution in 65% of patients at 2 years. No statistically significant correlation was found between patient characteristics, tumor variables, and volumetric or dosimetric data for seroma formation. Excellent/good cosmetic scores were achieved in 94% of women with and 92% without seroma. Local control was equivalent between patients with and without seroma. Consecutive sonographic imaging reveals a high rate of seroma formation after MammoSite PBI, with resolution in 65% of patients by 2 years without intervention. Seroma formation does not prevent an excellent cosmetic result or alter local control. PMID- 21827559 TI - Sarcoidosis mimicking metastatic breast cancer. PMID- 21827560 TI - A case of fat necrosis acquiring worrisome features. PMID- 21827561 TI - Thrombus presents as palpable breast mass. PMID- 21827562 TI - Bilateral mastectomy for refractory galactorrhea. PMID- 21827563 TI - Breast cancer with ipsilateral supraclavicular metastases. PMID- 21827564 TI - Knowledge towards breast cancer among Malaysian university students. PMID- 21827565 TI - Cytochrome P450 polymorphisms and their relationship with premature ovarian failure in premenopausal women with breast cancer receiving doxorubicin and cyclophosphamide. PMID- 21827566 TI - Patient perception of choice in decision-making for early stage breast cancer: does race and socioeconomic status matter? PMID- 21827568 TI - Non-bacterial thrombotic endocarditis with systemic embolic events caused by adenomyosis. AB - Non-bacterial thrombotic endocarditis is caused by a hypercoagulable state that is sometimes related to malignancy and this type of endocarditis associated with benign tumors has not yet been reported. In this study we report the first case of non-bacterial thrombotic endocarditis caused by adenomyosis, which is a benign gynecological condition. PMID- 21827567 TI - Survival of inflammatory breast cancer patients compared to non-inflammatory breast cancer patients in Egypt. PMID- 21827569 TI - Drug utilization pattern in pregnant women in rural areas, India: cross-sectional observational study. AB - AIM: The aim of this study was to evaluate the drug-utilization trend of pregnant women in rural areas of central India. MATERIALS AND METHODS: This was a prospective, observational study using a questionnaire, face-to-face interview and a prescription audit. RESULTS: The majority of the subjects were primigravida (51.4%), from the lower socioeconomic group (71.3%) and with poor formal education. Although the drugs prescribed for them per prescription (2.66) were within rational limits, there was scope for improvement in generic (21%) and essential drugs (18%), antibiotics (9.6%) and injections (10.97%). CONCLUSIONS: Morbidity and mortality during the antenatal period occur due to different factors. Regular drug-utilization studies following the guidelines of the World Health Organization and information, education and communication factors related to drug use by pregnant women can be improved. PMID- 21827570 TI - Levels of soluble endothelial selectin in umbilical cord serum are influenced by gestational age and histological chorioamnionitis, but not by pre-eclampsia. AB - AIMS: The aim of this study was to examine the factors that influence soluble endothelial selectin (sE-selectin) levels in umbilical cord serum. MATERIALS AND METHODS: sE-selectin levels in umbilical cord serum were measured in 144 patients using enzyme-linked immunosorbent assay. We examined the association of sE selectin levels with gestational age, pre-eclampsia (PE), histological chorioamnionitis (HCAM), preterm premature rupture of membranes, magnesium sulfate use, birthweight, and placental weight. RESULTS: A significant positive correlation was observed between sE-selectin levels and gestational age in the patients who had neither PE nor HCAM (r = 0.559, P < 0.0001). This statistically positive correlation persisted in patients with PE without HCAM (n = 25, r = 0.644, P < 0.001), but not in patients with HCAM without PE (n = 58, r = 0.102, P = 0.448). In matched gestational age analysis, sE-selectin levels were increased in the presence of HCAM (P = 0.0006), but were not influenced by the presence of PE (P = 0.127), preterm premature rupture of membranes (P = 0.352) or magnesium sulfate use (P = 0.337). CONCLUSION: sE-selectin levels in umbilical cord serum were positively correlated with gestational weeks. sE-selectin levels in umbilical cord serum were higher in mothers with HCAM but not with PE, when compared with gestational-age-matched controls. PMID- 21827571 TI - Fibroblast growth factor receptor 4 Gly388 Arg polymorphism is not associated with pre-eclampsia in Turkish women. AB - AIM: The aim of this study was to assess the association between human fibroblast growth factor receptor 4 (FGFR4) Gly(388) Arg polymorphism and pre-eclampsia (PE) by carrying out a case-control study in Turkish women. MATERIALS AND METHODS: In the present study 159 PE patients and 161 controls were included. DNA was extracted from peripheral blood leukocyte and FGFR4 Gly(388) Arg polymorphism was investigated using polymerase chain reaction-restriction fragment length polymorphism methods. RESULTS: For Gly388Arg polymorphism of FGFR4 we found no significant association between controls and PE patients. The frequencies of GlyGly, GlyArg and ArgArg genotypes were 56.6%, 36.4% and 7% for the study group and 50.3%, 44.7% and 5% for the control group, respectively. The risk of women with the GlyArg (odds ratio = 0.7, 95% confidence interval: 0.45-1.14) and ArgArg (odds ratio = 1.2, 95% confidence interval: 0.47-3.22) genotypes for PE did not differ significantly from that of GlyGly genotype carriers. CONCLUSION: As we could not find any association between genetic variability in Gly(388) Arg of FGFR4 and PE, this specific polymorphism of FGFR4 can be eliminated as a risk factor for PE at least for Turkish women. PMID- 21827572 TI - Effect of pre-amniocentesis counseling on maternal pain and anxiety. AB - AIM: The aim of this study was to evaluate the levels of anticipated and perceived pain and anxiety in expectant mothers at the times of pre-counseling, post-counseling, and post-amniocentesis and to investigate the effect of pre amniocentesis counseling on the level of pain and anxiety. MATERIALS AND METHODS: This prospective study was carried out on 240 women with singleton pregnancies at mid-trimester. The maternal pain and anxiety levels associated with the procedure were evaluated using the visual analogue scale. Perceived pain and anxiety were assessed before and after counseling the pregnant woman about amniocentesis, and after amniocentesis. RESULTS: Median anticipated pain levels before (pain 1) and after pre-procedure counseling (pain 2) were 5 and 4, respectively. The actual pain after the procedure (pain 3) was 3. Median levels of anxiety felt by the patients before (anxiety 1) and after pre-procedure counseling (anxiety 2) were 6 and 3, respectively, while the median anxiety after the procedure (anxiety 3) was 5. For the pain and anxiety measurements, the results for each of the comparison times were significantly different from the results for the other two comparison times (P < 0.001). CONCLUSION: Adequate pre-amniocentesis counseling effectively reduces the actual level of pain and anxiety felt by the mother undergoing mid trimester amniocentesis. PMID- 21827573 TI - Alpha-fetoprotein producing ovarian clear cell carcinoma with a neometaplasia to hepatoid carcinoma arising from endometriosis: a case report. AB - We present a rare case of alpha-fetoprotein (AFP) producing ovarian clear cell carcinoma. This is the first report of a clear cell ovarian carcinoma with hepatoid carcinoma arising from endometriosis. A 54-year-old menopausal woman had a primary ovarian carcinoma of International Federation of Gynecology and Obstetrics stage IIIc. Serum level of AFP was 4195 ng/mL. Histological examination revealed clear cell adenocarcinoma arising from endometriosis with hepatoid carcinoma. Metastatic liver and lymph node tumors were found after 25 months from the first surgery. However, the patient's serum AFP was within normal limits. The recurrent and metastatic tumors disappeared in response to combined liposomal doxorubicin and carboplatin chemotherapy. She has had a disease-free survival of 4 years. In conclusion, the patient had a clear cell ovarian carcinoma with hepatoid carcinoma arising clearly from endometriosis. The recurrent tumors did not show a component of hepatoid carcinoma. Therefore, it is possible to expect better survival with good sensitivity to chemotherapy. PMID- 21827574 TI - Successful management of pregnancy and delivery in a woman with multiple coronary stenoses of unknown cause. AB - We describe the case of a 30-year-old primiparous woman who had multiple coronary stenoses of unknown cause, and discuss causes and risks in pregnancy in a patient with coronary stenoses and the management and outcome. At 13 years of age, the patient was diagnosed as having multiple coronary stenoses and percutaneous transluminal coronary angioplasty was performed. At the age of 30, coronary arteriography demonstrated multiple severe stenoses. Her previous physician had permitted her to become pregnant. At 32 weeks' gestation, due to uncontrollable uterine contractions, magnesium sulfate was administered. At 37 weeks' gestation, a cesarean section was performed because of breech presentation, and she delivered a healthy female infant. During cesarean section, oxytocin was given at a slower rate. There has been no recurrence of cardiac events during and after pregnancy. Multiple coronary stenoses during pregnancy need a multidisciplinary approach. PMID- 21827575 TI - Prevalence and risk factors of lower genital tract infections among women in Beijing, China. AB - AIM: The aim of our study was to estimate the prevalence and risk factors of common female lower genital tract infections (LGTIs) among married women in Beijing. MATERIAL & METHODS: A community-based, cross-sectional survey was conducted among married women aged 25-54years. All subjects were interviewed, followed by gynecological examination and laboratory tests. RESULTS: A total of 6339 women were enrolled. The prevalence of LGTIs was 11.4%, including 8.7% bacterial vaginosis, 1.0% trichomoniasis and 1.7% candidiasis. Three factors were associated with the increased likelihood of LGTIs: age of 30-49years (odds ratio (OR), 1.39; 95% confidence interval (CI), 1.046-1.840), a high number of sexual partners (OR, 1.47; 95% CI, 0.911-2.173), and failure to use a condom (OR, 1.72; 95% CI, 1.434-2.065). Bacterial vaginosis was significantly associated with the incidence of cervical intraepithelial neoplasia and high-risk human papillomavirus infection. CONCLUSIONS: Improving women's living standards and knowledge regarding reproductive health issues can help decrease the incidence of LGTIs and cervical intraepithelial neoplasia. PMID- 21827576 TI - Immunohistochemical distribution of toll-like receptor 4 in preterm human fetal membrane. AB - AIM: Toll-like receptor 4 (TLR-4) is the major receptor used for recognition of specific gram negative bacteria by the host immune system. The role of TLR-4 has been revealed in preterm parturition. This study aims to demonstrate the immunohistochemical expression of TLR-4 with regard to histological layers and anatomical regions of the human fetal membranes. MATERIAL AND METHODS: Fetal membranes were obtained from the uterine fundus and low segment. Immunohistochemical staining for TLR-4 and hematoxylin and eosin stain were performed. RESULTS: The chorion expressed significantly higher levels of TLR-4 than the amnion (P=0.001). There was no difference in the expression of TLR-4 between the uterine fundus and the uterine low segment (P=0.942). There was no significant difference in TLR-4 expression according to the presence of histological chorioamnionitis (P=0.444). TLR-4 expression decreased significantly with the progression of gestation (P=0.002). CONCLUSIONS: The level of expression of TLR-4 did not differ according to anatomic location, but did differ according to the histological layer of the human fetal membranes and gestational age. These results suggest that TLR-4 may be involved in preterm parturition. PMID- 21827577 TI - Balloon tamponade during cesarean section is useful for severe post-partum hemorrhage due to placenta previa. AB - AIM: Severe post-partum hemorrhage during cesarean section due to placenta previa is still one of the leading causes of maternal mortality. The aim of this study was to evaluate the efficiency of intrauterine tamponade with a Sengstaken Blakemore tube (SB-tube) for the treatment of severe post-partum hemorrhage in cases of placenta previa. MATERIAL AND METHODS: Data were collected from our departmental clinical records on all patients who underwent caesarian section due to placenta previa between 2007 and 2009. RESULTS: During the period analyzed, 37 patients underwent caesarian section due to placenta previa/low-lying placenta. Four (11%) underwent hysterectomy due to placenta accreta and 33 (89%) were treated conservatively. Of the 33 patients with conserved uterus, 10 (28%) patients required a SB-tube during the cesarean section because of continuous post-partum hemorrhage despite appropriate medical treatment. The median bleeding during the operation was 2030+/-860mL in the patients who used SB-tube. None of them presented severe complications related to these procedures or required any further invasive surgery. CONCLUSION: Intrauterine balloon-tamponade could successfully control severe hemorrhage from a lower uterine segment of a patient with placenta previa. This technique is simple to use, scarcely invasive, and available at a low cost to all maternity wards, and should be considered as one of the first management options to reduce the risk of undesirable hysterectomy. PMID- 21827578 TI - Body mass index and survival in patients with epithelial ovarian cancer. AB - AIM: There is controversy regarding the effect of obesity on the treatment and survival of ovarian cancer. This study examined the impact of obesity on the treatment and survival outcomes of epithelial ovarian cancer. METHODS: The medical records of patients undergoing surgery for epithelial ovarian cancer (EOC) between January 2000 and February 2010 were reviewed. Patient demographics, surgical outcomes, clinicopathological factors and survival were evaluated and compared according to the body mass index (BMI). The Asian BMI criteria for Koreans were used. RESULTS: Of a total of 486 patients identified, 31 (6.4%) were underweight (BMI<18.5), 224 (46.1%) were normal (18.5<=BMI<23), 179 (36.8%) were overweight (23<=BMI<27.5) and 52 (10.3%) were obese (27.5>=BMI). All surgical outcome parameters except for wound problems failed to show a significant association with BMI. Similarly, there were no differences in the stage, recurrence rate, pathological features or chemotherapy characteristics, including platinum resistance rates, between the BMI groups. However, overweight and obese patients were significantly older than the underweight and normal body weight patients (P<0.01). A history of cardiovascular disease and diabetes mellitus were more common in these overweight and obese patients (P<0.01 for both). There were no differences in progression free survival (P>0.05) or overall survival (P>0.05) according to the BMI. No difference in progression free survival (P>0.05) or overall survival (P>0.05) could be found, even in the subcohort of stages III and IV. CONCLUSION: Obesity itself does not affect the surgical and clinicopathological outcomes or even survival in EOC patients. PMID- 21827579 TI - Comparison of success rates of 'transvaginal aspiration and tetracycline sclerotherapy' versus 'only aspiration' in the management of non-neoplastic ovarian cysts. AB - AIM: To investigate the value of tetracycline sclerotherapy for management of recurrent or persisting non-neoplastic ovarian cysts in comparison to the aspiration without sclerotherapy. MATERIAL AND METHODS: Ninety-six patients with proven non-neoplastic ovarian cysts were randomized into two groups. Group 1 patients underwent cyst aspiration together with tetracycline sclerotherapy (n=48). Group 2 patients underwent only cyst aspiration without tetracycline sclerotherapy (n=48). Then, all patients were followed up monthly with ultrasonography for 12months. The procedure was considered to have failed if the recurring cyst, detected by ultrasound, was 4cm in size or greater. RESULTS: There were no differences between the two groups regarding demographic data, initial cyst volume and tumor markers. Recurrence rates within 12months were 14.6% in group 1 and 50% in group 2 (P<0.001). CONCLUSION: Based on the recurrence rates, we suggest transvaginal aspiration together with tetracycline sclerotherapy rather than only simple transvaginal aspiration in the management of non-neoplastic ovarian cysts. PMID- 21827580 TI - Exploiting the antioxidant potential of a common vitamin: could vitamin C prevent postmenopausal osteoporosis? AB - AIM: Oxidative stress is thought to play a central role in the pathophysiology of various conditions affecting women's health, including cancer, preeclampsia and osteoporosis. On the back of animal experimentation, we sought to establish whether the oral administration of vitamin C at high doses to postmenopausal women would achieve the plasma antioxidant activity that could prevent osteoporosis. METHODS: In our pilot study, we administered vitamin C at a dose of 10 grams daily to eight healthy postmenopausal women over a period of four weeks and measured their serum levels of vitamin C and crosslaps (markers of bone turnover) at baseline and then on a weekly basis. RESULTS: We found an initial rise in the plasma levels of vitamin C, but these rapidly fell over four weeks and could not be sustained despite continued therapy, presumably due to limited absorption and possibly even augmented excretion. We found no discernable change in the serum levels of crosslaps in association with the consumption of high doses of vitamin C. CONCLUSION: Although vitamin C has antioxidant properties, when given orally, even at a high dose, the serum levels required for it to exhibit antioxidant activity cannot be attained. This approach holds no potential for the use of vitamin C in the prevention of osteoporosis, although other routes of administration could overcome this. PMID- 21827581 TI - Downregulation of GRIM-19 promotes growth and migration of human glioma cells. AB - It has become increasingly clear that there are notable parallels between normal development and tumorigenesis. Glioma is a classic model that links between tumorigenesis and development. We evaluated the expression of GRIM-19, a novel gene essential for normal development, in various grades of gliomas and several human glioma cell lines. We showed that GRIM-19 mRNA and protein expression were markedly lower in gliomas than in control brain tissues and negatively correlated with the malignancy of gliomas. Downregulation of GRIM-19 in glioma cells significantly enhanced cell proliferation and migration, whereas overexpression of GRIM-19 showed the opposite effects. We also showed that the activation of signal transducer and activator of transcription 3 (STAT3) and the expression of many STAT3-dependent genes were regulated by the expression of GRIM-19. In addition, GRIM-19 exerted its role probably through the non-STAT3 signaling pathway. Collectively, our data suggest that most gliomas expressed GRIM-19 at low levels, which may play a major role in tumorigenesis in the brain. PMID- 21827582 TI - Involvement of retrotransposition of long interspersed nucleotide element-1 in skin tumorigenesis induced by 7,12-dimethylbenz[a]anthracene and 12-O tetradecanoylphorbol-13-acetate. AB - Tumor development induced by 7,12-dimethylbenz[a]anthracene (DMBA) plus 12-O tetradecanoylphorbol-13-acetate (TPA) is a well-characterized model of multistep carcinogenesis. DMBA mutates the Ha-ras gene, whereas TPA promotes the growth of transformed cells by activating cellular signaling molecules. It remains to be clarified how repeated TPA treatment endows transformed cells with autonomous cell growth. Long interspersed nucleotide element-1 (L1) is an endogenous retroelement, and 80-100 copies of L1 function as autonomous mobile elements. Although the L1 retrotransposition (RTP) has been found in various human tumors, implying the possible mobility of L1 during carcinogenesis, little is known about how L1-RTP arises in tumor cells, owing to a lack of experimental models. To dissect the mechanism of L1-RTP during carcinogenesis, we established a line of transgenic mice carrying human L1 and enhanced green fluorescent protein (hL1 EGFP mice) and subjected them to DMBA/TPA-induced skin tumorigenesis. Of 15 skin tumors examined, 13 were positive for L1-RTP; L1-RTP was not detected in normal skin tissues adjacent to the tumors. Moreover, nine L1-RTP-positive tumors were positive for activated Ha-ras, and immunohistochemical analysis revealed cells positive for both L1-RTP and phosphorylated Stat3, a marker of tumor cells. Additional in vivo experiments suggested that L1-RTP occurred during tumor promotion by TPA. This is the first report on the involvement of L1-RTP in chemical carcinogenesis. We propose hL1-EGFP mice as a versatile system for investigating the mode of L1-RTP in tumor development and discuss the possible role of L1-RTP in tumorigenesis. PMID- 21827583 TI - Development of pharyngo-esophageal physiology during swallowing in the preterm infant. AB - BACKGROUND: Poor feeding is a common cause of prolonged hospitalization of preterm infants. Pharyngeal and upper esophageal sphincter (UES) function of preterm infants has been technically difficult to assess and is therefore poorly characterized. The aim of this study was to assess the development of pharyngeal motility, UES function, and their coordination during nutritive swallowing in preterm infants. METHODS: Development of swallowing was assessed in 18 preterm infants. High resolution manometry was performed at first oral feeding attempt (31-32 week) and then weekly for 4 weeks. Pharyngeal and UES pressure changes were characterized in 980 swallows. KEY RESULTS: During swallowing, we observed an age-related increase in peak pharyngeal pressure at the laryngeal inlet (1 cm above UES) but an age-related decrease in the time required for the UES to fully relax to nadir. Analysis of the timing of proximal pharyngeal contractile peak and UES nadir showed that the UES was not fully relaxed when bolus propulsive forces were at their peak in the youngest infants. CONCLUSIONS & INFERENCES: Results show developmental changes in infant swallow physiology that can be clearly linked to the effectiveness of nutritive swallowing. Most preterm infants demonstrated poor pharyngeal pressures at the laryngeal inlet coupled with poor coordination of pharyngeal propulsion with UES relaxation. These pressure patterns were less efficient than those demonstrated by older infants who were more adept at feeding. These observations may explain why infants under 34 weeks are physiologically unable to feed effectively and experience frequent choking and fatigue during feeding. PMID- 21827584 TI - Development and evaluation of a multiplex real-time PCR assay for the detection and differentiation of Moraxella bovis, Moraxella bovoculi and Moraxella ovis in pure culture isolates and lacrimal swabs collected from conventionally raised cattle. AB - AIM: To develop a multiplex real-time PCR assay for the detection and differentiation of Moraxella bovis (M. bovis), M. bovoculi and M. ovis. METHODS AND RESULTS: The multiplex real-time PCR assay was validated on three reference strains, 57 pure culture isolates and 45 lacrimal swab samples. All reference strains were identified correctly with no cross-reactions between species. Sequencing of 53 of the 57 culture isolates confirmed the results obtained with the multiplex real-time PCR, and the assay had 96.5% (55/57) concordance with a Moraxella spp. multiplex conventional PCR assay on the isolates. Among the lacrimal swab samples, the concordance between the multiplex real-time PCR and culture was 86.7% (39/45) for M. bovoculi and 75.6% (34/45) for M. bovis. CONCLUSIONS: The multiplex real-time PCR assay is specific and sensitive and can be used directly on lacrimal swab samples. SIGNIFICANCE AND IMPACT OF STUDY: The lack of a rapid, specific and sensitive detection method is a barrier for determining the roles of M. bovis, M. bovoculi and M. ovis in infectious bovine keratoconjunctivitis cases, and the developed PCR assay will contribute to improved understanding of the epidemiology and pathogenesis of these three Moraxella species. PMID- 21827585 TI - Evaluation of process-oriented supervision of student nurses: a Swedish case study. AB - The value of supervision that is provided to student nurses during their education is high. The aim of this study was to evaluate the organizational changes in an educational program for Swedish student nurses, focusing on the content and quality of process-oriented supervision. The research question was: Do the organizational changes pertaining to the student nurses' supervision (its reduced frequency and mandatory nature) influence its content and quality and, if so, in which ways? The data were collected by focus group discussions and were analyzed by a qualitative content analysis. Three themes emerged: difficulties with the new organization, the content and learning outcomes of supervision, and the nurse supervisors' intentions. Supervision is recommended in order to achieve the goal of nursing education and to ensure that student nurses gain an understanding of their experiences, thus equipping them with the professional skills and competence that are required to meet patients' needs. PMID- 21827586 TI - The impact of rapid evolution on population dynamics in the wild: experimental test of eco-evolutionary dynamics. AB - Rapid evolution challenges the assumption that evolution is too slow to impact short-term ecological dynamics. This insight motivates the study of 'Eco Evolutionary Dynamics' or how evolution and ecological processes reciprocally interact on short time scales. We tested how rapid evolution impacts concurrent population dynamics using an aphid (Myzus persicae) and an undomesticated host (Hirschfeldia incana) in replicated wild populations. We manipulated evolvability by creating non-evolving (single clone) and potentially evolving (two-clone) aphid populations that contained genetic variation in intrinsic growth rate. We observed significant evolution in two-clone populations whether or not they were exposed to predators and competitors. Evolving populations grew up to 42% faster and attained up to 67% higher density, compared with non-evolving control populations but only in treatments exposed to competitors and predators. Increased density also correlates with relative fitness of competing clones suggesting a full eco-evolutionary dynamic cycle defined as reciprocal interactions between evolution and density. PMID- 21827587 TI - Output performance: cardiac output by pulse contour analysis. PMID- 21827588 TI - The use of intravenous lipid emulsion as an antidote in veterinary toxicology. AB - OBJECTIVE: To review the use of IV lipid emulsion (ILE) for the treatment of toxicities related to fat-soluble agents; evaluate current human and veterinary literature; and to provide proposed guidelines for the use of this emerging therapy in veterinary medicine and toxicology. DATA SOURCES: Human and veterinary medical literature. HUMAN DATA SYNTHESIS: Human data are composed mostly of case reports describing the response to treatment with ILE as variant from mild improvement to complete resolution of clinical signs, which is suspected to be due to the variability of lipid solubility of the drugs. The use of ILE therapy has been advocated as an antidote in cases of local anesthetic and other lipophilic drug toxicoses, particularly in the face of cardiopulmonary arrest and unsuccessful cardiopulmonary cerebral resuscitation. VETERINARY DATA SYNTHESIS: The use of ILE therapy in veterinary medicine has recently been advocated by animal poison control centers for toxicoses associated with fat-soluble agents, but there are only few clinical reports documenting successful use of this therapy. Evidence for the use of ILE in both human and veterinary medicine is composed primarily from experimental animal data. CONCLUSIONS: The use of ILE appears to be a safe therapy for the poisoned animal patient, but is warranted only with certain toxicoses. Adverse events associated with ILE in veterinary medicine are rare and anecdotal. Standard resuscitation protocols should be exhausted before considering this therapy and the potential side effects should be evaluated before administration of ILE as a potential antidote in cases of lipophilic drug toxicoses. Further research is waranted. PMID- 21827589 TI - Assessment of cardiac output measurement in dogs by transpulmonary pulse contour analysis. AB - OBJECTIVE: To determine if metatarsal artery pressure (COmet) is comparable to femoral artery pressure (COfem) as the input for transpulmonary pulse contour analysis (PiCCO) in anesthetized dogs, using the lithium dilution method (LiDCO) as a standard for cardiac output (CO) measurement. DESIGN: Prospective randomized study. SETTING: University research laboratory. ANIMALS: Ten healthy purpose-bred mixed breed dogs were anesthetized and instrumented to measure direct blood pressure, heart rate, arterial blood gases, and CO. INTERVENTIONS: The CO was measured using LiDCO and PiCCO techniques. Animals had their right femoral and left distal metatarsal artery catheterized for proximal (COfem) and distal (COmet) PiCCO analysis, respectively. Measurements were obtained from each animal during low, normal, and high CO states by changing amount of inhalant anesthetics and heart rate. Measurements were converted to CO indexed to body weigh (CI(BW) =CO/kg) for statistical analysis. Agreement was determined using Bland and Altman analysis and concordance correlation coefficients. MEASUREMENTS AND MAIN RESULTS: Thirty paired measurements were taken. The LiDCO CI(BW) (+/- SD) was 68.7 +/- 30.3, 176.0 +/- 53.0, and 211.1 +/- 76.5 mL/kg/min during low, normal, and high CO states, respectively. There was a significant effect of CI(BW) state on bias and relative bias with COmet (P<0.001 and P=0.003, respectively). Bias of the COmet method (+/- SD) was -116.6 (70.5), 20.1(76.4), and 91.3 (92.0) mL/kg/min at low, normal, and high CI(BW), respectively. Bias of the COfem (+/- SD) was -20.3 (19.0), 8.6 (70.9), and -2.9 (83.0) mL/kg/min at low, normal, and high CI(BW) , respectively. The mean relative bias for COfem was -6.7 +/- 44% (limits of agreements: -81.2 to 67.9%). CONCLUSION: Compared with lithium dilution, the pulse contour analysis provides a good estimation of CO, but requires femoral artery catheterization in anesthetized dogs. PMID- 21827590 TI - Comparison of cardiac output determined by arterial pulse pressure waveform analysis method (FloTrac/Vigileo) versus lithium dilution method in anesthetized dogs. AB - OBJECTIVE: To compare the determination of cardiac output (CO) via arterial pulse pressure waveform analysis (FloTrac/Vigileo) versus lithium dilution method. DESIGN: Prospective study. SETTING: University teaching hospital. ANIMALS: Six adult dogs. INTERVENTIONS: Dogs were instrumented for CO determinations using lithium dilution (LiDCO) and FloTrac/Vigileo methods. Direct blood pressure, heart rate, arterial blood gases, and end-tidal isoflurane (ETIso) and CO(2) concentrations were measured throughout the study while CO was manipulated with different depth of anesthesia and rapid administration of isotonic crystalloids at 60 mL/kg/h. MEASUREMENTS AND MAIN RESULTS: Baseline CO measurements were obtained at 1.3% ETIso and were lowered by 3% ETIso. Measurements were obtained in duplicate or triplicate with LiDCO and averaged for comparison with corresponding values measured continuously with the FloTrac/Vigileo method. For 30 comparisons between methods, a mean bias of -100 mL/kg/min and 95% limits of agreement between -311 and +112 mL/kg/min (212 mL/kg/min) was determined. The mean (mL/kg/min) of the differences of LiDCO-Vigileo=62.0402+-0.8383 * Vigileo, and the correlation coefficient (r) between the 2 methods 0.70 for all CO determinations. The repeatability coefficients for the individual LiDCO and FloTrac/Vigileo methods were 187 and 400 mL/kg/min, respectively. Mean LiDCO and FloTrac/Vigileo values from all measurements were 145 +/- 68 mL/kg/min (range, 64 354) and 244 +/- 144 mL/kg/min (range, 89-624), respectively. The overall mean relative error was 48 +/- 14%. CONCLUSION: The FloTrac/Vigileo overestimated CO values compared with LiDCO and the relative error was high, which makes this method unreliable for use in dogs. PMID- 21827591 TI - A randomized multicenter trial of Crotalidae polyvalent immune F(ab) antivenom for the treatment of rattlesnake envenomation in dogs. AB - OBJECTIVE: To determine clinical efficacy of the Crotalidae polyvalent immune F(ab) (ovine) antivenom (OPCA) against progressive crotalid envenomation in the dog as reflected in stabilization or improvement of snakebite severity scores (SSS). Additionally, due to the potential decreased half-life of the F(ab) antibodies in dogs we compared SSS between dogs receiving 2 different dosing regimes. DESIGN: Prospective, clinical trial. SETTING: Five veterinary emergency and critical care facilities. ANIMALS: One hundred and fifteen client-owned Crotalid (rattlesnake) snake bitten dogs in whom worsening of the envenomation syndrome was observed before OPCA treatment. INTERVENTIONS: In a multicenter randomized clinical trial a single dose (1 vial) of OPCA alone was compared with 2 doses (1/2 vial each) administered 6 hours apart. Standard supportive care was provided in all cases. MEASUREMENTS AND MAIN RESULTS: Data were available for 115 patients, 9 of which were fatalities. All patients' clinical condition was documented with a standardized SSS system accounting for each major body system. Each fatality received maximum severity scores of 20. The mean severity score of the 115 patients decreased from 4.19 to 3.29 points and there was no difference between the 2 treatment groups. The mean severity score of the 107 patients without fatalities decreased from 4.16 to 2.15. Antivenin-related acute reactions occurred in 6 dogs (6%), and no serum sickness occurred within the 95 cases contacted at the 2-week posttreatment follow-up. CONCLUSIONS: In the first randomized trial in dogs of antivenin in the United States, OPCA effectively stabilized or terminated venom effects. There were no statistical differences detected between treatment groups within the study time frame. PMID- 21827592 TI - Examination of hemostatic parameters to detect hypercoagulability in dogs with severe protein-losing nephropathy. AB - OBJECTIVE: To identify hemostatic abnormalities in dogs with protein-losing nephropathies (PLN) that represent risk factors for pathologic thrombosis. DESIGN: Cross-sectional observational study of client-owned dogs with PLN, nonprotein losing renal failure (RF), and systemic illness (SI) exclusive of primary renal disease. SETTING: Urban University Referral Center. ANIMALS: A total of 29 dogs (n=11 PLN, n=7 RF, n=11 SI) were enrolled between January 2001 and July 2002. Samples were also collected from 20 clinically normal dogs to serve as hemostasis assay controls. INTERVENTIONS: None. HEMOSTASIS TESTING: Citrate anticoagulated blood was collected for point-of-care testing with a viscoelastic monitor (thromboelastograph [TEG]) and citrate plasma was prepared for coagulation screening tests and specific assay of the following hemostatic proteins: antiplasmin, antithrombin, D-dimer, Factor VIII, fibrinogen, plasminogen, protein C, and von Willebrand factor. RESULTS: Dogs with PLN and RF demonstrated TEG abnormalities consistent with hypercoagulability (eg, short clotting time, high clot amplitude) and both groups had significantly lower antithrombin than the SI group. The PLN dogs had significantly higher protein C than either the RF or SI group. Hyperfibrinogenemia was a consistent finding among all 3 disease groups, and the coagulation index a measure of hypercoagulability derived from TEG parameters, directly correlated with fibrinogen values of all study dogs. CONCLUSIONS: Hemostatic abnormalities consistent with systemic hypercoagulability are common in dogs with RF and PLN, however, no prothrombotic factors unique to PLN were identified in our study. The thrombotic tendency of PLN may therefore involve parameters we did not directly assess such as platelet reactivity, fibrinolysis, perturbations in blood flow, and/or endothelial dysfunction. High protein C is a novel finding in PLN dogs of unknown clinical relevance. PMID- 21827593 TI - Refractometric total plasma protein measurement as a cage-side indicator of hypoalbuminemia and hypoproteinemia in hospitalized dogs. AB - OBJECTIVE: To assess the relationship between total plasma protein (TPP) as measured by refractometry and serum hypoalbuminemia and hypoproteinemia in hospitalized dogs. DESIGN: Retrospective, observational study conducted over 6 month period between March and August 2008. SETTING: University teaching hospital. ANIMALS: Four hundred and three hospitalized dogs in an ICU. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: TPP, serum albumin, total protein, glucose, urea, cholesterol was measured from dogs enrolled in study. TPP was evaluated as a predictor for hypoalbuminemia defined both as albumin <25 g/L (<2.5 g/dL) and albumin <20 g/L (<2.0 g/dL), and serum hypoproteinemia, defined as serum total protein <40 g/L (<4.0 g/dL), using logistic regression. Impact of glucose, urea, cholesterol, and total bilirubin on refractometric readings were also assessed. TPP predicted hypoalbuminemia at albumin concentrations of <25 g/L (<2.5 g/dL) and <20 g/L (<2.0 g/dL) (P<0.001). A TPP<60 g/L (<6.0 g/dL) predicted albumin <25 g/L (<2.5 g/dL) with 73% sensitivity and 86% specificity. A TPP<58 g/L (<5.8 g/dL) predicted a serum albumin <20 g/L (<2.0 g/dL) with 70% sensitivity and 80% specificity. For dogs with known risk factors where specificity optimization may be appropriate, refractometer TPP<50 g/L (<5.0 g/dL) and <48 g/L (<4.8 g/dL) predicted hypoalbuminemia at each level with >95% specificity, although sensitivity was poor. Refractometer TPP<58 g/L (<5.8 g/dL) predicted serum total protein of <40 g/L (<40 g/dL) with sensitivity of 82% and specificity of 84%. Hypercholesterolemia and hyperglycemia significantly affected TPP readings; an increase in serum glucose by 10 mmol/L (180 mg/dL) was associated with an average independent increase in refractometer TPP of 2.27 g/L (0.23 g/dL) (P<0.001, 95% confidence interval=1.08-3.47) and an increase in serum cholesterol of 1 mmol/L (38.6 mg/dL) was associated with an average independent increase in refractometer TPP of 1.36 g/L (0.14 g/dL) (P<0.001, 95% confidence interval=1.12-1.59). CONCLUSION: Suboptimal sensitivity limits the use of refractometric TPP for prediction of hypoalbuminemia in the context of patient screening; a high proportion of false negatives may result. However, identification of a refractometric TPP<58 g/L is strongly indicative of both serum hypoalbuminemia and hypoproteinemia, with high specificity, and warrants further investigation. Refractometric readings may be falsely increased in patients with hyperglycemia or hypercholesterolemia. PMID- 21827594 TI - Treatment of accidental ethanol intoxication with hemodialysis in a dog. AB - OBJECTIVE: To describe the successful treatment of accidental ethanol intoxication with hemodialysis in a dog. CASE SUMMARY: A 1.5-year-old female intact mixed breed dog was presented in a comatose state believed to be due to ethanol intoxication. The initial 9 hours of supportive care treatment were complicated by multiple seizures and hypothermia, and resulted in only minimal improvement in the dog's level of consciousness. Hemodialysis was implemented and resulted in rapid clinical recovery, corresponding to a rapid decline in serum ethanol concentration. NEW OR UNIQUE INFORMATION PROVIDED: To the authors' knowledge, this is the first reported case of using hemodialysis to treat accidental ethanol intoxication in a dog. The patient's initial serum ethanol concentration was higher than those previously reported for cases of accidental ethanol intoxication in dogs, and the serum ethanol concentration was shown to rapidly decline during hemodialysis. Treatment with hemodialysis for severe ethanol intoxication was effective in this case and may be able to decrease morbidity and mortality in some cases. PMID- 21827595 TI - Gastrointestinal tract perforations caused by ingestion of multiple magnets in a dog. AB - OBJECTIVE: To describe a case of gastrointestinal tract perforation, septic peritonitis and coagulopathy caused by ingestion of multiple magnets in a dog. CASE SUMMARY: An 8-month-old castrated male Rottweiler, weighing 30.5 kg was presented for evaluation of vomiting and weakness. Abdominal radiography and abdominal ultrasonographic examination identified a metallic foreign object within the gastric lumen, presence of free peritoneal gas, and peritoneal effusion. Septic peritonitis was diagnosed by abdominal fluid analysis. Exploratory celiotomy revealed the presence of an omental abscess, and gastric and colonic perforations. Four magnetic foreign objects were found within the lumen of the perforated stomach. Surgical management including removal of the magnets, abscess debridement and excision, perforation repair, and abdominal drainage combined with intensive medical therapy resulted in complete recovery of this dog. NEW OR UNIQUE INFORMATION PROVIDED: This report describes in detail the case management of a dog that developed both gastric and colonic perforations and severe morbidity secondary to ingesting multiple magnets. PMID- 21827596 TI - Extravasation injury associated with parenteral nutrition in a cat with presumptive gastrinomas. AB - OBJECTIVE: To describe the pathologic consequences of parenteral nutrition (PN) extravasation into the mediastinum of a cat. CASE SUMMARY: An 8-year-old domestic short hair cat with persistent vomiting and anorexia was initiated on PN for nutritional support. PN was being administered at a rate of 12.9 mL/h when inadvertent jugular catheter migration resulted in thrombophlebitis and cellulitis and 40-80 mL of PN extravasated into the SC and mediastinal tissues. The cat was euthanized 36 hours after the extravasation of PN due to poor prognosis related to the gastric complications associated with a presumed primary gastrinoma. Grossly there was excessive mediastinal lymphatic drainage and pronounced edema in the cervical SC and mediastinal tissue. Histopathologic examination of the PN-extravasated area revealed a severe mixed inflammatory reaction, represented by a severe neutrophilic and mild histiocytic infiltrate with lymphoplasmacytic perivascular cuffing. No bacterial agents were observed or cultured from this area. UNIQUE INFORMATION PROVIDED: This is the first case report of a foreign body-type reaction due to extravasation of PN (extravasation injury) in a cat. Extravasation of PN is not without pathologic consequence, and can result in a severe inflammatory reaction in affected tissues. PMID- 21827597 TI - Corneal ulceration in a dog following exposure to the defensive spray of a walkingstick insect (Anisomorpha spp.). AB - OBJECTIVE: To describe a case of corneal ulceration in a dog resulting from ocular exposure to the defensive spray of a walkingstick insect (Anisomorpha spp.). CASE SUMMARY: A 4-year-old, male Chihuahua in southeastern Louisiana presented to an emergency veterinary hospital approximately 20 hours after it was witnessed to have come in close proximity to a walkingstick insect. Within seconds of approaching the insect, the dog yelped, jumped backwards and developed lacrimation, blepharospasm, and periocular swelling of the left eye. Upon presentation, the dog was found to have blepharospasms and miosis of the left eye. Fluorescein stain was applied to the affected eye and diffuse corneal uptake of stain was noted. A diffuse superficial corneal ulceration was diagnosed and treated supportively with ocular flushing, topical antibiotics, ocular lubrication, and a 1% solution of ocular atropine, as well as systemic nonsteroidal anti-inflammatory agents. Clinical signs resolved 10 days after injury. NEW OR UNIQUE INFORMATION PROVIDED: While most species of walkingstick insects are considered harmless, certain species in the southeastern United States have the ability to spray defensive venom at their predators. Upon ocular exposure to the venom, the victim may experience intense pain followed by blurred vision, conjunctivitis, keratitis, and corneal ulceration. To date, there is only 1 previous reported case of ocular exposure to walkingstick venom in a dog although both children and animals may be at higher risk for ocular exposure due to their curious nature and proximity in size to the insect. Superficial corneal and conjunctival damage can occur following direct exposure to the defensive chemical spray of the Northern and Southern Twostriped walkingstick insects found in the southeastern United States and may be considered a differential diagnosis in cases involving diffuse corneal ulceration. PMID- 21827598 TI - Colonic, ureteral, and vascular injuries secondary to stick impalement in a dog. AB - OBJECTIVE: To report the surgical repair, case management, and outcome of a dog with sepsis and severe intraabdominal trauma secondary to a penetrating stick injury. CASE OR SERIES SUMMARY: A 1.5-year-old, spayed female, mixed-breed dog was presented to the emergency service after incurring a small laceration on the medial aspect of the left pelvic limb while running in the woods. The wound was surgically explored and a primary closure achieved. The patient was discharged the same day with oral antimicrobial therapy. The following morning the dog was represented to the emergency service for acute vomiting. Abdominal radiographs were performed and demonstrated loss of serosal detail and pneumoperitoneum. An emergency celiotomy was performed and revealed distal colonic perforation, left ureteral laceration, and lacerations of the left common iliac vein. Ureteronephrectomy, as well as primary closure of the distal colonic perforation and left common iliac vein lacerations, were performed. The patient recovered and was ultimately discharged from the hospital 5 days later. Follow-up 1 year later revealed no significant physical exam or biochemical abnormalities. NEW OR UNIQUE INFORMATION PROVIDED: A seemingly benign penetrating stick injury initially deemed to be superficial in nature was later demonstrated to have resulted in sepsis following severe intraabdominal trauma that included lacerations of the distal colon, left ureter, and left common iliac vein in a dog. Successful surgical management and intensive care led to a full recovery without any residual impairment noted a year later. PMID- 21827606 TI - A proposed ternary complex model of prothrombinase with prothrombin: protein protein docking and molecular dynamics simulations. PMID- 21827607 TI - A novel automated microchip flow-chamber system to quantitatively evaluate thrombus formation and antithrombotic agents under blood flow conditions. AB - BACKGROUND AND AIMS: In the present study, we describe a newly developed microchip-based analytical system to evaluate white thrombus formation (WTF). Efficacies of various antithrombotic agents were compared under different flow conditions. METHODS: Whole blood containing corn trypsin inhibitor was perfused over a microchip coated with collagen and tissue thromboplastin at the lower and higher shear rates of 240 and 600 s(-1) , and WTF process inside the microchip was quantified by monitoring a flow pressure. Parameters of T(10) (time to 10 kPa), T(10-80) (time from 10 to 80 kPa) and OT (occlusion time; time to 80 kPa) were used to evaluate the onset and the growth rate of WTF, and the capillary occlusion, respectively. RESULTS: After perfusion was started, white thrombus composed of activated platelets and fibrin was formed on the coated surface. Thrombus gradually increased in size and eventually occluded the capillary. Among anticoagulants, heparin (0.5-1.0 U mL(-1)) potently prolonged T(10) at both shear rates, whereas low molecular weight heparin (1.0-2.0 IU mL(-1)) inhibited the growth of WTF at the lower shear rate. Among antiplatelet agents, abciximab (1-2 MUg mL(-1)) significantly reduced the size and number of thrombi, which was additively enhanced in the presence of heparin (0.5 U mL(-1) ). OS-1 (specific GPIbalpha-antagonist) prevented the complete capillary occlusion. CONCLUSION: The novel monitoring system of WTF may be useful in preclinical and clinical evaluations of different types of antithrombotic strategies, and their effects in combination. PMID- 21827608 TI - Impact of cytomegalovirus disease in D+/R- kidney transplant patients receiving 6 months low-dose valganciclovir prophylaxis. AB - Late-onset cytomegalovirus (CMV) disease remains common in CMV serology naive kidney transplant patients of CMV serology positive organs (D+/R-) despite the use of antiviral prophylaxis. We studied clinical efficacy of 6-month low-dose valganciclovir (VGCV) prophylaxis, risk factors for late-onset CMV disease and its impact on kidney transplant outcomes. Between October 2005 and December 2009, 166 consecutive D+/R- kidney alone and simultaneous pancreas and kidney transplant patients received VGCV 450 mg daily for 6 months after transplantation. After a median follow-up of 3.2 years, 30 cases of CMV disease occurred within the first 2 years after transplantation with a cumulative incidence of 11.5 and 18.1% at 1 and 2 years, respectively. The use of an induction agent with rabbit antithymocyte globulin and older donor age were factors associated with the risk of late-onset CMV disease (AHR 2.91, 95% CI 1.18 7.20, p = 0.021 and AHR 1.03, 95% CI 1.01-1.06, p = 0.016, respectively). Late onset CMV disease was associated with increased risk for death-uncensored graft loss (AHR 2.95, 95% CI 1.15-7.61, p = 0.025). In conclusion, late-onset CMV disease continues to negatively impact kidney transplant outcome despite 6-month low-dose VGCV prophylaxis. Investigations focusing on novel preventive approaches should be emphasized. PMID- 21827609 TI - Association of cytomegalovirus infection and disease with death and graft loss after liver transplant in high-risk recipients. AB - In the era of effective antiviral chemoprophylaxis, cytomegalovirus (CMV) disease has been inconsistently associated with increased mortality in liver transplant (LT) recipients. A retrospective study evaluating the association of CMV infection and disease occurring within 1 year of transplant with the endpoints of death or the combined endpoint of graft loss or death was undertaken in a cohort of 227 CMV donor seropositive, recipient seronegative first LT recipients. Associations were evaluated using Cox proportional hazards regression models. CMV infection and disease occurred in 91 (40%) and 43 (19%) patients, respectively. Forty-eight (21%) died while 58 (26%) sustained graft loss or death. In multivariable analysis, CMV infection was associated with an increased risk of death (RR: 2.24, p = 0.008) and graft loss or death (RR: 2.85, p < 0.001). CMV disease was also associated with an increased risk of death (RR: 2.73, p = 0.003) and graft loss or death (RR: 3.04, p = 0.001). CMV infection and disease occurring within the first year after LT in high-risk recipients is associated with increased risk of death and of graft loss or death. Investigation of strategies to further reduce the risk of CMV infection and disease in high-risk LT recipients is warranted. PMID- 21827611 TI - The impact of MELD/PELD revisions on the mortality of liver-intestine transplantation candidates. AB - Patients listed for liver-intestine transplantation suffer higher waiting list mortality than those listed for liver-only, thus leading to policy revisions seeking to close the gap. We sought to determine the impact of key model for end stage liver disease (MELD)/pediatric end-stage liver disease (PELD) policy modifications on the waiting list mortality of adult and pediatric liver intestine candidates as compared to liver-only candidates. Analysis of UNOS data separated into adult and pediatric categories and based on time periods of policy implementation revealed higher mortality in liver-intestine candidates over all time periods studied (p < 0.001 pediatric and adult). After implementation of a revision to augment their MELD scores based on a sliding scale, adult liver intestine candidates with calculated MELD > 15 no longer suffered higher mortality although this change did not completely eliminate the mortality disparity for candidates with MELD < 15 (p < 0.01). The waiting list mortality of pediatric liver-intestine candidates dropped significantly after a revision that gave them 23 additional MELD/PELD points (p < 0.01) although the mortality disparity with pediatric liver-only candidates was not eliminated. Following this revision, mortality in pediatric liver-only and liver-intestine Status 1 candidates was similar, however more liver-intestine candidates were listed as Status 1B. This data demonstrates that a mortality disparity remains for liver intestine candidates compared with candidates listed for liver-only. PMID- 21827610 TI - CD154 blockade abrogates allospecific responses and enhances CD4(+) regulatory T cells in mouse orthotopic lung transplant. AB - Acute cellular rejection (ACR) is a common and important clinical complication following lung transplantation. While there is a clinical need for the development of novel therapies to prevent ACR, the regulation of allospecific effector T-cells in this process remains incompletely understood. Using the MHC mismatched mouse orthotopic lung transplant model, we investigated the short-term role of anti-CD154 mAb therapy alone on allograft pathology and alloimmune T-cell effector responses. Untreated C57BL/6 recipients of BALB/c left lung allografts had high-grade rejection and diminished CD4(+) : CD8(+) graft ratios, marked by predominantly CD8(+) >CD4(+) IFN-gamma(+) allospecific effector responses at day 10, compared to isograft controls. Anti-CD154 mAb therapy strikingly abrogated both CD8(+) and CD4(+) alloeffector responses and significantly increased lung allograft CD4(+) : CD8(+) ratios. Examination of graft CD4(+) T-cells revealed significantly increased frequencies of CD4(+) CD25(+) Foxp3(+) regulatory T-cells in the lung allografts of anti-CD154-treated mice and was associated with significant attenuation of ACR compared to untreated controls. Together, these data show that CD154/CD40 costimulation blockade alone is sufficient to abrogate allospecific effector T-cell responses and significantly shifts the lung allograft toward an environment predominated by CD4(+) T regulatory cells in association with an attenuation of ACR. PMID- 21827612 TI - Virologic and immunologic monitoring of cytomegalovirus to guide preemptive therapy in solid-organ transplantation. AB - Control of human cytomegalovirus (HCMV) infection during the posttransplant period was investigated in 134 solid-organ transplant recipients by monitoring in parallel virologic and immunologic parameters for at least 1 year of follow-up. Virologic monitoring was achieved by determining HCMV DNAemia with real-time PCR, using the threshold of 300 000 DNA copies/mL blood as a cutoff for starting preemptive therapy. Immunologic monitoring included measurement of HCMV-specific CD4+ and CD8+ T cells by cytokine flow cytometry, using HCMV-infected dendritic cells as a stimulus. HCMV infection was diagnosed in 110 (82%) and required treatment in 49 (36%) patients. At 12 months after transplantation 'protective' immunity (>=0.4 CD4+ and CD8+ HCMV-specific T cells/MUL blood) was achieved in 115/129 (89%) patients. During the entire study period, 122 patients reconstituting HCMV-specific CD4+ and CD8+ T-cell immunity at 60 days posttransplant onward were able to control HCMV infection, except for one patient who developed HCMV disease because of a rejection episode. Patients reconstituting HCMV-specific CD8+ only did not control HCMV infection. In conclusion, the presence of both HCMV-specific CD4+ and CD8+ T cells >= 0.4/MUL blood appears to be protective against HCMV disease. This result does not apply to patients undergoing antirejection treatment, or reconstituting HCMV-specific CD8+ T cells only. PMID- 21827613 TI - Comparison of transcriptional and blood cell-phenotypic markers between operationally tolerant liver and kidney recipients. AB - A proportion of transplant recipients can spontaneously accept their grafts in the absence of immunosuppression (operational tolerance). Previous studies identified blood transcriptional and cell-phenotypic markers characteristic of either liver or kidney tolerant recipients. However, the small number of patients analyzed and the use of different transcriptional platforms hampered data interpretation. In this study we directly compared samples from kidney and liver tolerant recipients in order to identify potential similarities in immune-related parameters. Liver and kidney tolerant recipients differed in blood expression and B-cell immunophenotypic patterns and no significant overlaps were detectable between them. Whereas some recipients coincided in specific NK-related transcripts, this observation was not reproducible in all cohorts analyzed. Our results reveal that certain immune features, but not others, are consistently present across all cohorts of operationally tolerant recipients. This provides a set of reproducible biomarkers that should be explored in future large-scale immunomonitoring trials. PMID- 21827614 TI - Development of donor yield models. AB - Increasing donor yield, or the number of organs transplanted per donor, has been a focus of the transplant community in recent years. However, an exclusive focus on observed yield, unadjusted for the donor characteristics, ignores important differences between donors and donor case mixes in donation service areas (DSAs). We analyzed deceased donor registry data from the Organ Procurement and Transplantation Network/Scientific Registry of Transplant Recipients from January 2006 to December 2009 (N = 32 116 donors). Overall yields and kidney yields were modeled using ordinal logistic regression, and logistic regression was used to model heart, lung, pancreas and liver yields. Donor characteristics, including demographics, historical information and positive serology were related to overall and organ-specific yield. This study shows the potential value of the yield models as evaluation metrics and as tools that can inform DSA-wide practices in donor management and can improve organ utilization. PMID- 21827615 TI - Proliferation of CD8-positive T cells in blood vessels of rat renal allografts. AB - It is still disputed in which anatomical compartments of allograft recipients T cells proliferate. After experimental renal transplantation, host monocytes and lymphocytes accumulate in the lumina of graft blood vessels. In this study, we test the hypothesis that T lymphocytes proliferate in the vascular bed of the graft. Kidneys were transplanted in the Dark Agouti to Lewis rat strain combination, an established experimental model for acute rejection. Isogeneic transplantation was performed as a control. Cells in the S-phase of mitosis were detected in situ three days posttransplantation by pulse-labeling with BrdU and by immunohistochemical detection of the proliferating cell nuclear antigen (PCNA). More than 20% of all T-cells in the lumina of allograft blood vessels incorporated BrdU and approximately 30% of them expressed PCNA. In the blood vessels of isografts as well as in other organs of allograft recipients, only few BrdU(+) cells were detected. A majority of the BrdU(+) cells in graft blood vessels expressed CD8. In conclusion, we demonstrate that CD8(+) T lymphocytes proliferate in the lumina of the blood vessels of renal allografts during the onset of acute rejection. PMID- 21827616 TI - Autoantibodies specific for the phospholipase A2 receptor in recurrent and De Novo membranous nephropathy. AB - Recent findings in idiopathic membranous nephropathy (MN) suggest that in most patients, the disease is because of anti-phospholipase A(2) receptor (PLA(2) R1) autoantibodies. Our aim was to analyze the prevalence and significance of anti PLA(2) R1 antibodies in recurrent and de novo MN after transplantation. We assessed circulating PLA(2) R1 autoantibodies by a direct immunofluorescence assay based on human embryonic kidney cells transfected with a PLA(2) R1 cDNA, and the presence of PLA(2) R1 antigen in immune deposits. We showed that PLA(2) R1 was involved in 5 of 10 patients with recurrent MN, but in none of the 9 patients with de novo MN. We also showed a marked heterogeneity in the kinetics and titers of anti-PLA(2) R1, which may relate to different pathogenic potential. We provide evidence that some patients with PLA(2) R1-related idiopathic MN and anti-PLA(2) R1 antibodies at the time of transplantation will not develop recurrence. Because PLA(2) R1 autoantibody was not always associated with recurrence, its predictive value should be carefully analyzed in prospective studies. PMID- 21827617 TI - Association of surgeon with surgical site infection after liver transplantation. AB - Surgical site infection (SSI) after liver transplantation has been associated with increased risk of allograft loss and death. Identification of modifiable risk factors for these infections is imperative. To our knowledge, intraoperative practices associated with transplant surgeons have not been assessed as a risk factor. A retrospective cohort study of risk factors for SSI after 1036 first liver transplantations completed by seven surgeons at a single center between 2003 and 2008 was undertaken. Cox proportional hazards models were used to evaluate the association between surgeons and SSIs. SSIs were identified in 166 of 1036 patients (16%). Single variable analysis showed strong evidence of an association between surgeon and SSI (p = 0.0007); the estimated cumulative incidence of SSI ranged from 7% to 24%. This result was consistent in multivariable analysis adjusting for potentially confounding variables (p = 0.002). The occurrence of organ-space or deep SSI varied significantly among surgeons in both single variable analysis (p = 0.005) and multivariable analysis (p = 0.006). These findings provide evidence that differences in the surgical practices of individual surgeons are associated with risk for SSI after liver transplantation. Identification of specific surgical practices associated with risk of SSI is warranted. PMID- 21827618 TI - Early ultrastructural changes in renal allografts: correlation with antibody mediated rejection and transplant glomerulopathy. AB - Transplant glomerulopathy (TG) is associated with antibody-mediated renal allograft rejection (AMR) and reduced graft survival. Histologically, TG is typically seen >1 year posttransplantation. However, ultrastructural changes including glomerular endothelial swelling, subendothelial widening and early glomerular basement membrane duplication are associated with development of TG but appear much earlier. We examined the specificity of these changes for AMR, and whether these are inevitably associated with development of TG. Of 98 for cause renal allograft biopsies carried out within 3 months of transplantation with available serologic data, 17 showed C4d-positive AMR and 16 had histologic changes of AMR and donor-specific antibodies (DSA), but no C4d. All three ultrastructural changes were seen in 11 of 17 biopsies with C4d-positive AMR, 8 of 16 with histologic changes of AMR and DSA but no C4d, and 0 of 65 without histologic changes of AMR and/or DSA (p < 0.0001 for both of the former groups vs. the latter). Twenty patients with positive DSA (18 with histologic changes of AMR and 11 C4d-positive) had >=1 follow-up biopsy; eight developed overt TG 3.5 30 months posttransplantation. Among the 18 patients with DSA and histologic changes of AMR, 11 C4d-positive and 7 C4d-negative, treatment for AMR after the early biopsy significantly reduced subsequent development of overt TG. PMID- 21827619 TI - Accommodation: how you see it, how you don't. PMID- 21827620 TI - Chronic kidney disease after liver transplantation for acute liver failure is not associated with perioperative renal dysfunction. AB - Renal dysfunction of acute liver failure (ALF) may have distinct pathophysiological mechanisms to hepatorenal syndrome of cirrhosis. Yet, the impact of perioperative renal function on posttransplant renal outcomes in ALF patients specifically has not been established. The aims of this study were (1) to describe the incidence and risk factors for chronic renal dysfunction following liver transplantation for ALF and (2) to compare renal outcomes with age-sex-matched patients transplanted for chronic liver disease. This was a single-center study of 101 patients transplanted for ALF. Fifty-three-and-a-half percent had pretransplant acute kidney injury and 64.9% required perioperative renal replacement therapy. After transplantation the 5-year cumulative incidence of chronic kidney disease (eGFR <60 mL/min/1.73 m2) was 41.5%. There was no association between perioperative acute kidney injury (p = 0.288) or renal replacement therapy (p = 0.134) and chronic kidney disease. Instead, the independent predictors of chronic kidney disease were older age (p = 0.019), female gender (p = 0.049), hypertension (p = 0.031), cyclosporine (p = 0.027) and nonacetaminophen-induced ALF (p = 0.039). Despite marked differences in the perioperative clinical condition and survival of patients transplanted for ALF and chronic liver disease, renal outcomes were the same. In conclusion, in patients transplanted for ALF the severity of perioperative renal injury does not predict posttransplant chronic renal dysfunction. PMID- 21827621 TI - The use of drug-eluting stents in the management of transplant renal artery stenosis. AB - Transplant renal artery stenosis (TRAS) is a common occurrence following kidney transplantation with an incidence rate ranging from 6% to 23%. A single-center retrospective study was conducted to examine the use of drug-eluting stents (DES) in eligible patients with hemodynamically significant TRAS. Between March 2008 and January 2011, 12 patients were diagnosed with TRAS with reference vessel diameter measuring <5 mm and underwent endovascular intervention (EVI) with DES placement. TRAS was detected within the first year posttransplantation in a majority of these patients (83%) and manifested as hypertension (100%), allograft dysfunction (100%) and edema (58%). Procedural success rate was 100%. Patients were followed for a mean period of 16 +/- 10 months. Blood pressure improved from a mean of 156/82 to 138/73 mmHg at the end of the follow-up period. In 11/12 patients, serum creatinine improved from 3.1 +/- 1.3 mg/dL to 2.3 +/- 0.5 mg/dL at the end of the follow-up period. TRAS of early onset is readily amenable to EVI with stent placement resulting in improvement in blood pressure control and allograft function. PMID- 21827622 TI - Managing risk in developing transplant immunosuppressive agents: the new regulatory environment. AB - Recent adverse experience with a number of medications after their approval, including rofecoxib, erythropoietin and rosiglitazone, has led to an increased focus on safety in drug development in the postmarketing setting. The result was implementation of new measures to address perceived deficits in the system for drug approval and postmarketing safety. The resulting legislation introduced risk evaluation and mitigation strategies (REMS) and postmarketing requirements (PMRs). Although these initiatives have the potential to improve patient outcomes, many healthcare practitioners are not yet familiar with REMS or PMRs or may have misconceptions regarding their goals and limitations. REMS is a program to manage known or potential serious risks associated with pharmaceutical products and is designed to ensure that the benefits of using a particular product outweigh the risks. Although the concepts underlying REMS and PMRs are not novel, the FDA now has legal authority to enforce such measures as part of the drug approval process. This article outlines the objectives and limitations of REMS and PMRs, with a focus on how these regulatory measures may impact the clinical specialty of transplantation. The article also briefly describes efforts to address aspects of drug safety less amenable to management through REMS and PMRs. PMID- 21827623 TI - New partners for tolerogenic dendritic cells. PMID- 21827624 TI - Robotic-assisted laparoscopic partial nephrectomy for a 7-cm mass in a renal allograft. AB - Treatment options for a suspicious renal mass in a renal allograft include radical nephrectomy or nephron-sparing surgery (NSS). To our knowledge robotic assisted laparoscopic partial nephrectomy (RPN) as treatment for a renal mass in a transplant kidney has not been previously reported. We report the case of RPN for a 7-cm renal mass in a transplanted kidney. A 35-year-old female with reflux nephropathy received a living-related donor kidney transplant in 1986. At 24 years after transplantation she had a 7-cm Bosniak III cystic mass of the allograft detected on computerized tomography (CT) scan. Preoperative creatinine was 2.2 mg/dL with an estimated glomerular filtration rate (eGFR) of 25 mL/min/1.73 m(2) . RPN was performed with bulldog clamping of the renal vessels, the graft was left in situ and immunosuppression was maintained postoperatively. Tumor diameter was 7.3 cm with a nephrometry score of 10a. Warm ischemia time (WIT) was 26.5 min. Estimated blood loss was 100 mL. There was no change between pre- and postoperative eGFR. There were no operative complications. Histology was papillary renal cell carcinoma type 1, nuclear grade 2. Margins were negative. RPN is a technically feasible treatment option for a suspicious renal mass in renal allografts. PMID- 21827625 TI - Substrate-induced conformational changes in Plasmodium falciparum guanosine monophosphate synthetase. AB - GMP synthetase is a glutamine amidotransferase that incorporates ammonia derived from glutamine into the nucleotide xanthosine 5'-monophosphate (XMP) to form guanosine 5'-monophosphate (GMP). Functional coordination of domains in glutamine amidotransferases leads to upregulation of glutamine hydrolysis in the presence of acceptor substrates and is a common feature in this class of enzymes. We have shown earlier that binding of substrates to the acceptor domain of Plasmodium falciparum GMP synthetase (PfGMPS) leads to enhancement in both glutaminase activity and rate of glutaminase inactivation, by the irreversible inhibitors acivicin and diazo-oxonorleucine [Bhat JY et al. (2008) Biochem J409, 263-273], a process that must be driven by conformational alterations. In this paper, through the combined use of biochemical assays, optical spectroscopy and mass spectrometry, we demonstrate that PfGMPS undergoes conformational transitions upon binding of substrates to the acceptor domain. Limited proteolysis and hydrogen-deuterium exchange in conjunction with mass spectrometry unveil region specific conformational changes in the ATP + XMP bound state of PfGMPS. Decreased accessibility of R294 and K428 residues to trypsin in the ATP pyrophosphatase domain and reduced deuterium incorporation in the 143-155 region, pertaining to the glutaminase domain, suggest that in PfGMPS ligand-induced conformational changes are not only local but also transmitted over a long range across the domains. Overall, these results provide a detailed understanding of the substrate induced changes in PfGMPS that could be essential for the overall catalytic process. PMID- 21827627 TI - Compression strapping: the development of a novel compression technique to enhance compression therapy and healing for 'hard-to-heal' leg ulcers. AB - Non healing wounds of the lower limb continue to be a significant issue for both practitioners and patients. Failure of gold-standard management demands a creative response. This article describes the development of a novel and intuitive strapping technique overlying the compression bandage that appears to have an influence in healing complex lower limb ulcers. A retrospective audit of 17 patients with 25 ulcers allows further analysis and discussion. The strapping technique uses cohesive inelastic compression bandaging; narrow strips of bandages are layered in a fan distribution over the ulcer and oedema. This approach seems to offer an intuitive response to these complex wounds, allowing management to be tailored to the site of the ulcer and oedema. Tolerance for this less bulky compression therapy regime is excellent, thereby aiding healing and reducing all costs associated with non healing leg ulcers. PMID- 21827626 TI - Letter: microbiological and clinical mismanagement of non healing diabetic leg ulcers? PMID- 21827628 TI - Patient's pain feedback using negative pressure wound therapy with foam and gauze. AB - Wounds can be caused by different mechanisms and have a significant morbidity and mortality. Negative pressure wound therapy (NPWT) is one of the most successful treatment modalities for wound healing. We have been using both foam and gauze based NPWT. During application of NPWT, we noticed that the patient's pain was of varying intensity depending on the filler used. The aim of our work was to compare the level of pain and feedback before, during the treatment and at the dressing change after treatment with NPWT with two different fillers. For this study, we compared a pool of 13 gauze-treated patients with a pool of 18 foam treated patients regarding the level of pain and feedback before, during the treatment and at the dressing change after treatment with NPWT. They were all post-traumatic patients with loss of tissue up to the muscular band. The patients were asked to respond to a questionnaire interviewed by the same physician to assess the level of pain using VNS (verbal numerical scale). We observed similar difference of means before and during the treatment with NPWT with gauze and foam. Regarding the pain at the dressing change, the mean of the scores for the foam was 6.5 while for the gauze was 4.15. In this case, we noticed the most significant difference between means from the scores given: 2.35 which was a statistically significant difference between the two groups (P = 0.046). The finding of this study confirms less pain at the dressing change after treatment with gauze-based NPWT. In our opinion, this finding is related to the more adhesive property of the foam probably because of the ingrowth of the granulation tissue in the micropores present on the foam. Considering this statement, we recommend the foam for neuropathic and paraplegic patients and the gauze for patients with bone and tendon exposition wounds, patients that do not tolerate NPWT with foam and low compliant patient particularly paediatric and old-age patients. We remind that the performance of this study was not sponsored by any company. PMID- 21827629 TI - Pressure ulcer prevention in Australia: the role of the nurse practitioner in changing practice and saving lives. AB - This paper reports on a successful nurse practitioner-led Pressure Ulcer Prevention Program (PUPP), established with members from nursing, allied health and senior management, within a regional area health service in Australia. The aims of PUPP were to quantify the prevalence of pressure ulcers within the health organisation, evaluate the policy compliances, identify cost effectiveness by implementing appropriate pressure redistributing surfaces and raise awareness of pressure ulcer prevention amongst all levels of clinical staff. The strategies include annual point prevalence study across 41 facilities, mattress replacement and online education program. The prevalence survey data were collected by skin inspection and chart audits by the trained surveyors. Since this quality improvement program commenced in 2008, it has demonstrated a reduction in pressure ulcer prevalence by 16.4%, increased pressure ulcer risk assessment by 7.9% and use of appropriate pressure-relieving devices by 46.5%, which led to cost saving of AUD 500 000. This paper highlights the patient and organisation benefits that management and clinicians can accomplish through a systemic collaborative approach, in particular with strong support from the Area Executive Team of the health organisation. PMID- 21827630 TI - Management of Marjolin's ulcer in a chronic pressure sore secondary to paraplegia: a radical surgical solution. AB - Marjolin's ulcer refers to malignant degeneration in a chronic wound. Although originally described in an area of burns scar, many other chronic wounds such as osteomyelitis sinus tracts, venous stasis ulcers and chronic pressure sores have the potential to undergo malignant transformation. We present an interesting case of malignant degeneration in a male paraplegic patient with chronic sacral and ischial pressure sores. By discussing our radical surgical solution to this problem, we aim to highlight the importance of prompt diagnosis. PMID- 21827631 TI - Non-healing leg ulcers in a patient with dystrophic calcification and crest syndrome: a challenging clinical case. AB - The management of non-healing leg ulcers in patients with CREST syndrome and subdermal calcification is rarely reported in medical literature. Only one similar case was found in the literature (1). Dealing with such patients can be a challenge for wound specialists. In this article, we discuss the clinical progress of an interesting case of extensive non-healing leg ulcers in a CREST patient with dystrophic calcification. The combination of systemic physiological deficits and immune compromise, along with the local physical abnormalities associated with the wound pose a complex multifactorial aetiological mix. There is no conclusive data on the optimal management of these wounds in CREST patients. It seems that ablation of the calcific deposits may offer some hope. PMID- 21827632 TI - Characterization of d-boroAla as a novel broad-spectrum antibacterial agent targeting d-Ala-d-Ala ligase. AB - d-boroAla was previously characterized as an inhibitor of bacterial alanine racemase and d-Ala-d-Ala ligase enzymes (Biochemistry, 28, 1989, 3541). In this study, d-boroAla was identified and characterized as an antibacterial agent. d boroAla has activity against both Gram-positive and Gram-negative organisms, with minimal inhibitory concentrations down to 8 MUg / mL. A structure-function study on the alkyl side chain (NH(2) -CHR-B(OR')(2) ) revealed that d-boroAla is the most effective agent in a series including boroGly, d-boroHomoAla, and d-boroVal. l-boroAla was much less active, and N-acetylation completely abolished activity. An LC-MS / MS assay was used to demonstrate that d-boroAla exerts its antibacterial activity by inhibition of d-Ala-d-Ala ligase. d-boroAla is bactericidal at 1* minimal inhibitory concentration against Staphylococcus aureus and Bacillus subtilis, which each encode one copy of d-Ala-d-Ala ligase, and at 4* minimal inhibitory concentration against Escherichia coli and Salmonella enterica serovar Typhimurium, which each encode two copies of d-Ala-d-Ala ligase. d-boroAla demonstrated a frequency of resistance of 8 * 10(-8) at 4* minimal inhibitory concentration in S. aureus. These results demonstrate that d-boroAla has promising antibacterial activity and could serve as the lead agent in a new class of d-Ala-d-Ala ligase targeted antibacterial agents. This study also demonstrates d-boroAla as a possible probe for d-Ala-d-Ala ligase function. PMID- 21827633 TI - 1-[(2-arylthiazol-4-yl)methyl]azoles as a new class of anticonvulsants: design, synthesis, in vivo screening, and in silico drug-like properties. AB - A series of novel thiazole incorporated (arylalkyl)azoles were synthesized and screened for their anticonvulsant properties using maximal electroshock and pentylenetetrazole models in mice. Among target compounds, 1-[(2-(4 chlorophenyl)thiazol-4-yl)methyl]-1H-imidazole (compound 4b), 1-[(2-phenylthiazol 4-yl)methyl]-1H-1,2,4-tria-zole (8a), and its 4-chlorophenyl analog (compound 8b) were able to display noticeable anticonvulsant activity in both pentylenetetrazole and maximal electroshock tests with percentage protection range of 33-100%. A computational study was carried out for prediction of pharmacokinetics properties and drug-likeness. The structure-activity relationship and in silico drug relevant properties (molecular weight, topological polar surface area, clog P, hydrogen bond donors, hydrogen bond acceptors, and log BB) confirmed that the compounds were within the range set by Lipinski's rule-of-five, and possessing favorable physicochemical properties for acting as CNS-drugs, making them potentially promising agents for epilepsy therapy. PMID- 21827634 TI - Antifungal agents. Part 3: synthesis and antifungal activities of 3-acylindole analogs against phytopathogenic fungi in vitro. AB - To find more potent antifungal compounds, twenty 3-acylindole analogs were synthesized and bio-evaluated for their antifungal activities against seven phytopathogenic fungi. Structure-activity relationships investigations revealed that 4- or 6-methyl and 3-acetyl or propionyl groups were the important structural properties of 3-acylindoles for the activities. Especially 4-methyl-3 propionylindole, 12, displayed the more potent activities than hymexazol, a commercially available agricultural fungicide, and might be considered as a new promising lead candidate for further design and synthesis of agricultural fungicides. PMID- 21827635 TI - Infusion with the antioxidant N-acetylcysteine attenuates early adaptive responses to exercise in human skeletal muscle. AB - AIM: Production of reactive oxygen species (ROS) in skeletal muscle is markedly increased during exercise and may be essential for exercise adaptation. We, therefore, investigated the effects of infusion with the antioxidant N acetylcysteine (NAC) on exercise-induced activation of signalling pathways and genes involved in exercise adaptation in human skeletal muscle. METHODS: Subjects completed two exercise tests, 7 days apart, with saline (control, CON) or NAC infusion before and during exercise. Exercise tests comprised of cycling at 71% VO(2peak) for 45 min, and then 92% VO(2peak) to fatigue, with vastus lateralis biopsies at pre-infusion, after 45-min cycling and at fatigue. RESULTS: Analysis was conducted on the mitogen-activated protein kinase signalling pathways, demonstrating that NAC infusion blocked the exercise-induced increase in JNK phosphorylation, but not ERK1/2, or p38 MAPK. Nuclear factor-kappaB p65 phosphorylation was unaffected by exercise; however, it was reduced in NAC at fatigue by 14% (P < 0.05) compared with pre-infusion. Analysis of exercise and/or ROS-sensitive genes demonstrated that exercise-induced mRNA expression is ROS dependent of MnSOD, but not PGC-1alpha, interleukin-6, monocyte chemotactic protein-1, or heat-shock protein 70. CONCLUSION: These results suggest that inhibition of ROS attenuates some skeletal muscle cell signalling pathways and gene expression involved in adaptations to exercise. PMID- 21827636 TI - The regulation of blood perfusion in the renal cortex and medulla by reactive oxygen species and nitric oxide in the anaesthetised rat. AB - AIMS: The regulation of blood flow through the renal medulla is important in determining blood pressure, and its dysregulation in pathophysiological states, such as oxidative stress, may contribute to the development of hypertension. This investigation examined the hypothesis that reactive oxygen species has both direct and indirect actions, via scavenging NO, to determine the degree of blood perfusion through the renal medulla. METHODS: Groups of male Wistar rats received a renal interstitial infusion of either tempol, a superoxide dismutase (SOD) mimetic, or tempol plus catalase (tem + cat), or diethyldithio-carbamic acid (DETC) a SOD inhibitor, or L-NAME alone or L-NAME followed by DETC. RESULTS: Medullary blood perfusion (MBP) increased by 16 +/- 1% (P < 0.05) following the renal infusion of tempol and by 35 +/- 4%% (P < 0.05) when tem + cat was infused. Cortical blood perfusion (CBP) was unchanged during the administration of tempol and tem + cat. The renal interstitial infusion of DETC reduced CBP by 13 +/- 2%, (P < 0.05) and MBP by 22 +/- 3% (P < 0.05). Infusion of L-NAME to block NOS did not change CBP but decreased MBP by 12 +/- 4%, which was (P < 0.05) less than the reduction obtained with DETC. Administration of DETC in the presence of L-NAME reduced CBP and MBP by 17 and 14%, respectively, the latter response being approximately half that obtained when only DETC was infused. CONCLUSIONS: These findings demonstrated that both reactive oxygen species and NO determined the level of MBP. The findings support the hypothesis that reactive oxygen species can act both indirectly, via scavenging of NO, and directly via H(2)O(2) to modulate blood perfusion in the medulla. PMID- 21827637 TI - Opioid MU-receptors in the rostral medullary raphe modulate hypoxia-induced hyperpnea in unanesthetized rats. AB - AIM: It has been suggested that the medullary raphe (MR) plays a key role in the physiological responses to hypoxia. As opioid MU-receptors have been found in the MR, we studied the putative role of opioid MU-receptors in the rostral MR (rMR) region on ventilation in normal and 7% hypoxic conditions. METHODS: We measured pulmonary ventilation (VE) and the body temperatures (Tb) of male Wistar rats before and after the selective opioid MU-receptor antagonist CTAP (D-Phe-Cys-Tyr D-Trp-Arg-Thr-Pen-Thr-NH2, cyclic, 0.1 MUg per 0.1 MUL) was microinjected into the rMR during normoxia or after 60 min of hypoxia. RESULTS: The animals treated with intra-rMR CTAP exhibited an attenuation of the ventilatory response to hypoxia (430 +/- 86 mL kg(-1) min(-1)) compared with the control group (790 +/- 82 mL kg(-1) min(-1) ) (P < 0.05). No differences in the Tb were observed between groups during hypoxia. CONCLUSION: These data suggest that opioids acting on MU receptors in the rMR exert an excitatory modulation of hyperventilation induced by hypoxia. PMID- 21827638 TI - Obesity augments the age-induced increase in mitochondrial capacity for H2O2 release in Zucker fatty rats. AB - AIM: Mitochondrial dysfunction has been suggested to play a significant role in obesity and insulin resistance. The aim of the present study was to investigate if changes in obesity and insulin resistance were related to similar changes in mitochondrial capacity for hydrogen peroxide release in Zucker diabetic fatty rats and their lean littermates. METHODS: Thirty-four rats were used in this study. Rats were either lean or obese Zucker rats killed at 5-6 (young) or 12-14 (adults) weeks of age. Mitochondria were isolated from soleus muscles; respiration and release of hydrogen peroxide were determined and related to citrate synthase activity to determine intrinsic mitochondrial function. Mitochondrial-specific super-oxide dismuthase (MnSOD) protein content was determined in isolated mitochondria and muscle homogenate. Catalase protein content was determined in muscle homogenate. RESULTS: Young lean and obese rats had a higher mitochondrial respiration when using palmitoyl-l-carnitine as substrate compared with adult lean and obese rats. The obese strain had higher mitochondrial hydrogen peroxide release but only in the adult animals. In both lean and obese animals, increased age was associated with increased mitochondrial hydrogen peroxide release. MnSOD tended to be higher in the obese strain in the isolated mitochondria. Regardless of age, catalase protein content was significantly lower in the obese rats. CONCLUSIONS: This study shows that the augmented increase in obesity and insulin resistance seen in Zucker diabetic fatty rats is associated with increased capacity for mitochondrial hydrogen peroxide release. PMID- 21827639 TI - Interplay of endothelial and inducible nitric oxide synthases modulates the vascular response to ischaemia-reperfusion in the rabbit lung. AB - AIM: Lung ischaemia-reperfusion induces nitric oxide synthesis and reactive nitrogen species, decreasing nitric oxide bioavailability. We hypothesized that in the ventilated lung, this process begins during ischaemia and intensifies with reperfusion, contributing to ischaemia-reperfusion-induced pulmonary vasoconstriction. The aim was to determine whether ischaemia-reperfusion alters inducible and endothelial nitric oxide synthase expression/activity, reactive nitrogen species generation, and nitric oxide bioavailability, potentially affecting pulmonary perfusion. METHODS: Ischaemia-reperfusion was induced for various times in anesthetized rabbits with ventilated lungs by reversibly occluding the right pulmonary artery and initiating reperfusion. Nitric oxide synthase activity/expression and phosphorylation, reactive nitrogen species generation and total nitrate/nitrite were determined in lung tissue. RESULTS: Inducible nitric oxide synthase expression and activity, and reactive nitrogen species formation coincided with increased pulmonary vascular resistance during reperfusion and increased with ischaemia duration, further increasing after 2-h reperfusion. Total nitrate/nitrite also increased with ischaemia but decreased after 2-h reperfusion. Pre-treatment with an inducible nitric oxide synthase inhibitor (1400W; Cayman Chemical Company, Ann Arbor, MI, USA) attenuated inducible nitric oxide synthase activity, reactive nitrogen species generation and pulmonary vascular resistance, but did not affect total nitrate/nitrite. Endothelial nitric oxide synthase expression was unchanged by ischaemia reperfusion; however, its phosphorylation on serine 1177 and dephosphorylation on threonine 495 was uncoupled, suggesting decreased endothelial nitric oxide synthase activity. 1400W prevented uncoupling of endothelial nitric oxide synthase phosphorylation, maintaining its activity during reperfusion. CONCLUSION: Ischaemia-reperfusion up-regulates inducible nitric oxide synthesis and/activity, which coincides with reduced endothelial nitric oxide synthase activity as suggested by its uncoupling and may contribute to ischaemia reperfusion-induced pulmonary vasoconstriction. PMID- 21827640 TI - GONe: software for estimating effective population size in species with generational overlap. AB - GONe is a user-friendly, Windows-based program for estimating effective size (N(e) ) in populations with overlapping generations. It uses the Jorde-Ryman modification to the temporal method to account for age structure in populations. This method requires estimates of age-specific survival and birth rate and allele frequencies measured in two or more consecutive cohorts. Allele frequencies are acquired by reading in genotypic data from files formatted for either GENEPOP or TEMPOFS. For each interval between consecutive cohorts, N(e) is estimated at each locus and over all loci. Furthermore, N(e) estimates are output for three different genetic drift estimators (F(s) , F(c) and F(k) ). Confidence intervals are derived from a chi-square distribution with degrees of freedom equal to the number of independent alleles. GONe has been validated over a wide range of N(e) values, and for scenarios where survival and birth rates differ between sexes, sex ratios are unequal and reproductive variances differ. GONe is freely available for download at https://bcrc.bio.umass.edu/pedigreesoftware/. PMID- 21827641 TI - The fundamental building blocks of red human hair pheomelanin are isoquinoline containing dimers. PMID- 21827642 TI - Virus load in pigs affected with different clinical forms of classical swine fever. AB - Classical swine fever (CSF) is an endemic disease in India, but the real magnitude of the problem is not known as only outbreaks of acute CSF are reported and many cases of chronic and clinically inapparent forms of the disease, which manifest a confusing clinical picture, remain undiagnosed. The real status of classical swine fever virus (CSFV) infection can only be known by testing pigs with highly specific and sensitive diagnostic assays. To obtain the baseline prevalence of CSFV infection among pigs in an endemic region where no vaccination was being performed, a real-time PCR assay was used to detect viral genetic material in tissue samples collected from a slaughterhouse in the northern state of Uttar Pradesh in India. In total, 1120 slaughtered pigs were examined for the presence of CSF suggestive pathological lesions and tissues from suspected cases were tested for the presence of CSFV antigen and nucleic acids by indirect immuno peroxidase test and real-time PCR, respectively. Based on the detection of viral genetic material in the tonsils, the prevalence of CSFV infection among slaughtered pigs was found to be 7.67%. Pigs detected positive for viral genome by quantitative real-time PCR assay when categorized into different forms of CSF, depending upon the pathological lesions observed, the viral load in the tonsils of some of the pigs with chronic or clinically inapparent form of the disease was similar to that detected in pigs with acute CSF. The results of the study suggested that the risk posed by pigs with chronic disease or those infected but showing no clinical disease may be relatively higher as they can transmit the virus to new susceptible hosts over a longer period of time. PMID- 21827644 TI - Performance evaluation on an air-cooled heat exchanger for alumina nanofluid under laminar flow. AB - This study analyzes the characteristics of alumina (Al2O3)/water nanofluid to determine the feasibility of its application in an air-cooled heat exchanger for heat dissipation for PEMFC or electronic chip cooling. The experimental sample was Al2O3/water nanofluid produced by the direct synthesis method at three different concentrations (0.5, 1.0, and 1.5 wt.%). The experiments in this study measured the thermal conductivity and viscosity of nanofluid with weight fractions and sample temperatures (20-60 degrees C), and then used the nanofluid in an actual air-cooled heat exchanger to assess its heat exchange capacity and pressure drop under laminar flow. Experimental results show that the nanofluid has a higher heat exchange capacity than water, and a higher concentration of nanoparticles provides an even better ratio of the heat exchange. The maximum enhanced ratio of heat exchange and pressure drop for all the experimental parameters in this study was about 39% and 5.6%, respectively. In addition to nanoparticle concentration, the temperature and mass flow rates of the working fluid can affect the enhanced ratio of heat exchange and pressure drop of nanofluid. The cross-section aspect ratio of tube in the heat exchanger is another important factor to be taken into consideration. PMID- 21827643 TI - Adeno-associated virus type 2 infection activates caspase dependent and independent apoptosis in multiple breast cancer lines but not in normal mammary epithelial cells. AB - BACKGROUND: In normal cells proliferation and apoptosis are tightly regulated, whereas in tumor cells the balance is shifted in favor of increased proliferation and reduced apoptosis. Anticancer agents mediate tumor cell death via targeting multiple pathways of programmed cell death. We have reported that the non pathogenic, tumor suppressive Adeno-Associated Virus Type 2 (AAV2) induces apoptosis in Human Papillomavirus (HPV) positive cervical cancer cells, but not in normal keratinocytes. In the current study, we examined the potential of AAV2 to inhibit proliferation of MCF-7 and MDA-MB-468 (both weakly invasive), as well as MDA-MB-231 (highly invasive) human breast cancer derived cell lines. As controls, we used normal human mammary epithelial cells (nHMECs) isolated from tissue biopsies of patients undergoing breast reduction surgery. RESULTS: AAV2 infected MCF-7 line underwent caspase-independent, and MDA-MB-468 and MDA-MB-231 cell lines underwent caspase-dependent apoptosis. Death of MDA-MB-468 cells was marked by caspase-9 activation, whereas death of MDA-MB-231 cells was marked by activation of both caspase-8 and caspase-9, and resembled a mixture of apoptotic and necrotic cell death. Cellular demise was correlated with the ability of AAV2 to productively infect and differentially express AAV2 non-structural proteins: Rep78, Rep68 and Rep40, dependent on the cell line. Cell death in the MCF-7 and MDA-MB-231 lines coincided with increased S phase entry, whereas the MDA-MB-468 cells increasingly entered into G2. AAV2 infection led to decreased cell viability which correlated with increased expression of proliferation markers c Myc and Ki-67. In contrast, nHMECs that were infected with AAV2 failed to establish productive infection or undergo apoptosis. CONCLUSION: AAV2 regulated enrichment of cell cycle check-point functions in G1/S, S and G2 phases could create a favorable environment for Rep protein expression. Inherent Rep associated endonuclease activity and AAV2 genomic hair-pin ends have the potential to induce a cellular DNA damage response, which could act in tandem with c-Myc regulated/sensitized apoptosis induction. In contrast, failure of AAV2 to productively infect nHMECs could be clinically advantageous. Identifying the molecular mechanisms of AAV2 targeted cell cycle regulation of death inducing signals could be harnessed for developing novel therapeutics for weakly invasive as well as aggressive breast cancer types. PMID- 21827646 TI - High prevalence of myositis in a southeastern United States pediatric systemic lupus erythematosus cohort. AB - Inflammatory myositis is reported in 4-16% of adult systemic lupus erythematosus (SLE) patients. The aim of this study was to determine the prevalence of myositis in a cohort of pediatric SLE patients in the southeastern United States. A retrospective chart review was performed of 55 SLE patients evaluated by Pediatric Rheumatologists in Alabama since January 1, 2008. Patients were defined as having myositis if they satisfied one of the following categories: 1) Proximal muscle weakness on exam with lower extremity muscle edema on MRI; 2) Proximal muscle weakness with elevation in CK, AST, aldolase, or LDH muscle enzymes; or 3) Patient reported weakness or muscle pain and an elevated CK. Inflammatory myositis was present as a feature of SLE in 31% (n = 17) with a 95% confidence interval of 19-45%, statistically different from the reported rates of 4-16% (p < 0.0001). Myositis was positively associated with the presence of anti ribonucleoprotein antibodies (p = 0.009). Negative associations with myositis were the presence of anti-double stranded DNA antibodies (p = 0.02) and hematologic disorders (p = 0.02). Thus, in the state of Alabama, pediatric SLE myositis is present at a statistically higher rate than previously published values of adult SLE myositis, possibly reflecting geographic (genetic or environmental) and/or age-of-onset related influence(s). PMID- 21827645 TI - Air pollution and general practitioner access and utilization: a population based study in Sarnia, 'Chemical Valley,' Ontario. AB - BACKGROUND: Health impacts of poor environmental quality have been identified in studies around the world and in Canada. While many of the studies have identified associations between air pollution and mortality or morbidity, few have focused on the role of health care as a potential moderator of impacts. This study assessed the determinants of health care access and utilization in the context of ambient air pollution in Sarnia, Ontario, Canada. METHODS: Residents of Sarnia participated in a Community Health Study administered by phone, while several ambient air pollutants including nitrogen dioxide (NO2), sulphur dioxide (SO2) and the volatile organic compounds benzene, toluene, ethylbenzene, mp- and o xylene (BTEX) were monitored across the city. Land Use Regression models were used to estimate individual exposures to the measured pollutants and logistic regression models were utilized to assess the relative influence of environmental, socioeconomic and health related covariates on general practitioner access and utilization outcomes. RESULTS: The results show that general practitioner use increased with levels of exposure to nitrogen dioxide (NO2- Odds Ratio [OR]: 1.16, p < 0.05) and sulphur dioxide (SO2- OR: 1.61, p < 0.05). Low household income was a stronger predictor of having no family doctor in areas exposed to high concentrations of NO2 and SO2. Respondents without regular care living in high pollution areas were also more likely to report travelling or waiting for care in excess of 20 minutes (OR: 3.28, p < 0.05) than their low exposure counterparts (OR: 1.11, p > 0.05). CONCLUSIONS: This study provides evidence for inequitable health care access and utilization in Sarnia, with particular relevance to its situation as a sentinel high exposure environment. Levels of exposure to pollution appears to influence utilization of health care services, but poor access to primary health care services additionally burden certain groups in Sarnia, Ontario, Canada. PMID- 21827647 TI - Polymorphisms in melatonin synthesis pathways: possible influences on depression. AB - BACKGROUND: It has been reported that rs4446909, a single nucleotide polymorphism (SNP) in the promoter of acetylserotonin methyltransferase (ASMT), influences the expression of the ASMT enzyme. The common G allele is associated with lower ASMT activity, and therefore, diminishes conversion of N-acetylserotonin to melatonin. The G allele was associated with recurrent depressive disorder in a Polish group. ASMT might also affect bipolar relapse, given evidence that N-acetylserotonin might stimulate TRKB receptors, and TRKB may influence mood relapse in bipolar disorder. Additionally, arylalkylamine N-acetyltransferase (AANAT) polymorphisms have been reported associated with depression, perhaps through their influence upon N-acetylserotonin or melatonin synthesis. RESULTS: To replicate and further explore these ideas, rs4446909 was genotyped in four research groups, as part of a panel of 610 SNPs surveyed by an Illumina Golden Gate assay. In 768 cases with delayed sleep phase disorder or matched controls, rs4446909 was indeed associated with the depressive symptoms on a self-report scale (P = 0.01, R2 = 0.007). However, there was no significant association of rs4446909 with self-reported depression in a sleep clinic patient group or with two groups of elderly men and women from multicenter studies, nor was the response to lithium treatment associated with rs4446909 in bipolar patients. No associations of two AANAT SNPs with depression were found. CONCLUSIONS: The evidence did not support a strong influence of rs4446909 upon mood, but the partial replication may be consistent with a modest effect. It is possible that larger or younger subject groups with improved phenotype ascertainment might demonstrate more persuasive replication. PMID- 21827649 TI - Decreased catalytic function with altered sumoylation of DNA topoisomerase I in the nuclei of scleroderma fibroblasts. AB - INTRODUCTION: Sumoylation is involved in nucleolus-nucleoplasm transport of DNA topoisomerase I (topo I), which may associate with changes of cellular and topo I functions. Skin fibroblasts of patients with systemic sclerosis (SSc) exhibit profibrotic cellular changes. The aims of this study were to examine the catalytic function and sumoylation of topo I in the nuclei of SSc fibroblasts, a major cell type involved in the fibrotic process. METHODS: Eleven pairs of fibroblast strains obtained from nonlesional skin biopsies of SSc patients and age/sex/ethnicity-matched normal controls were examined for catalytic function of nuclear topo I. Immunoprecipitation (IP)-Western blots were used to examine sumoylation of fibroblast topo I. Real-time quantitative RT-PCR was used to measure transcript levels of SUMO1 and COL1A2 in the fibroblasts. RESULTS: Topo I in nuclear extracts of SSc fibroblasts generally showed a significantly lower efficiency than that of normal fibroblasts in relaxing equivalent amounts of supercoiled DNA. Increased sumoylation of topo I was clearly observed in 7 of 11 SSc fibroblast strains. Inhibition of SUMO1 with SUMO1 siRNA improved the catalytic efficiency of topo I in the SSc fibroblasts. In contrast, sumoylation of recombinant topo I proteins reduced their catalytic function. CONCLUSIONS: The catalytic function of topo I was decreased in SSc fibroblasts, to which increased sumoylation of topo I may contribute. PMID- 21827648 TI - The effect of regular walks on various health aspects in older people with dementia: protocol of a randomized-controlled trial. AB - BACKGROUND: Physical activity has proven to be beneficial for physical functioning, cognition, depression, anxiety, rest-activity rhythm, quality of life (QoL), activities of daily living (ADL) and pain in older people. The aim of this study is to investigate the effect of walking regularly on physical functioning, the progressive cognitive decline, level of depression, anxiety, rest-activity rhythm, QoL, ADL and pain in older people with dementia. METHODS/DESIGN: This study is a longitudinal randomized controlled, single blind study. Ambulatory older people with dementia, who are regular visitors of daily care or living in a home for the elderly or nursing home in the Netherlands, will be randomly allocated to the experimental or control condition. Participants of the experimental group make supervised walks of 30 minutes a day, 5 days a week, as part of their daily nursing care. Participants of the control group will come together three times a week for tea or other sedentary activities to control for possible positive effects of social interaction. All dependent variables will be assessed at baseline and after 6 weeks, and 3, 6, 9, 12 and 18 months of intervention. The dependent variables include neuropsychological tests to assess cognition, physical tests to determine physical functioning, questionnaires to assess ADL, QoL, level of depression and anxiety, actigraphy to assess rest activity rhythm and pain scales to determine pain levels. Potential moderating variables at baseline are: socio-demographic characteristics, body mass index, subtype of dementia, apolipoprotein E (ApoE) genotype, medication use and comorbidities. DISCUSSION: This study evaluates the effect of regular walking as a treatment for older people with dementia. The strength of this study is that 1) it has a longitudinal design with multiple repeated measurements, 2) we assess many different health aspects, 3) the intervention is not performed by research staff, but by nursing staff which enables it to become a routine in usual care. Possible limitations of the study are that 1) only active minded institutions are willing to participate creating a selection bias, 2) the drop-out rate will be high in this population, 3) not all participants will be able to perform/understand all tests. TRIAL REGISTRATION: NTR1482. PMID- 21827650 TI - Hypoxia-mimetic agents inhibit proliferation and alter the morphology of human umbilical cord-derived mesenchymal stem cells. AB - BACKGROUND: The therapeutic efficacy of human mesenchymal stem cells (hMSCs) for the treatment of hypoxic-ischemic diseases is closely related to level of hypoxia in the damaged tissues. To elucidate the potential therapeutic applications and limitations of hMSCs derived from human umbilical cords, the effects of hypoxia on the morphology and proliferation of hMSCs were analyzed. RESULTS: After treatment with DFO and CoCl2, hMSCs were elongated, and adjacent cells were no longer in close contact. In addition, vacuole-like structures were observed within the cytoplasm; the rough endoplasmic reticulum expanded, and expanded ridges were observed in mitochondria. In addition, DFO and CoCl2 treatments for 48 h significantly inhibited hMSCs proliferation in a concentration-dependent manner (P < 0.05). This treatment also increased the number of cells in G0/G1 phase and decreased those in G2/S/M phase. CONCLUSIONS: The hypoxia-mimetic agents, DFO and CoCl2, alter umbilical cord-derived hMSCs morphology and inhibit their proliferation through influencing the cell cycle. PMID- 21827651 TI - Development of a classification scheme for disease-related enzyme information. AB - BACKGROUND: BRENDA (BRaunschweig ENzyme DAtabase, http://www.brenda-enzymes.org) is a major resource for enzyme related information. First and foremost, it provides data which are manually curated from the primary literature. DRENDA (Disease RElated ENzyme information DAtabase) complements BRENDA with a focus on the automatic search and categorization of enzyme and disease related information from title and abstracts of primary publications. In a two-step procedure DRENDA makes use of text mining and machine learning methods. RESULTS: Currently enzyme and disease related references are biannually updated as part of the standard BRENDA update. 910,897 relations of EC-numbers and diseases were extracted from titles or abstracts and are included in the second release in 2010. The enzyme and disease entity recognition has been successfully enhanced by a further relation classification via machine learning. The classification step has been evaluated by a 5-fold cross validation and achieves an F1 score between 0.802 +/- 0.032 and 0.738 +/- 0.033 depending on the categories and pre-processing procedures. In the eventual DRENDA content every category reaches a classification specificity of at least 96.7% and a precision that ranges from 86 98% in the highest confidence level, and 64-83% for the smallest confidence level associated with higher recall. CONCLUSIONS: The DRENDA processing chain analyses PubMed, locates references with disease-related information on enzymes and categorises their focus according to the categories causal interaction, therapeutic application, diagnostic usage and ongoing research. The categorisation gives an impression on the focus of the located references. Thus, the relation categorisation can facilitate orientation within the rapidly growing number of references with impact on diseases and enzymes. The DRENDA information is available as additional information in BRENDA. PMID- 21827652 TI - Decay in chest compression quality due to fatigue is rare during prolonged advanced life support in a manikin model. AB - BACKGROUND: The aim of this study was to measure chest compression decay during simulated advanced life support (ALS) in a cardiac arrest manikin model. METHODS: 19 paramedic teams, each consisting of three paramedics, performed ALS for 12 minutes with the same paramedic providing all chest compressions. The patient was a resuscitation manikin found in ventricular fibrillation (VF). The first shock terminated the VF and the patient remained in pulseless electrical activity (PEA) throughout the scenario. Average chest compression depth and rate was measured each minute for 12 minutes and divided into three groups based on chest compression quality; good (compression depth >= 40 mm, compression rate 100 120/minute for each minute of CPR), bad (initial compression depth < 40 mm, initial compression rate < 100 or > 120/minute) or decay (change from good to bad during the 12 minutes). Changes in no-flow ratio (NFR, defined as the time without chest compressions divided by the total time of the ALS scenario) over time was also measured. RESULTS: Based on compression depth, 5 (26%), 9 (47%) and 5 (26%) were good, bad and with decay, respectively. Only one paramedic experienced decay within the first two minutes. Based on compression rate, 6 (32%), 6 (32%) and 7 (37%) were good, bad and with decay, respectively. NFR was 22% in both the 1-3 and 4-6 minute periods, respectively, but decreased to 14% in the 7-9 minute period (P = 0.002) and to 10% in the 10-12 minute period (P < 0.001). CONCLUSIONS: In this simulated cardiac arrest manikin study, only half of the providers achieved guideline recommended compression depth during prolonged ALS. Large inter-individual differences in chest compression quality were already present from the initiation of CPR. Chest compression decay and thereby fatigue within the first two minutes was rare. PMID- 21827653 TI - Anemia and iron homeostasis in a cohort of HIV-infected patients in Indonesia. AB - BACKGROUND: Anemia is a common clinical finding in HIV-infected patients and iron deficiency or redistribution may contribute to the development of low hemoglobin levels. Iron overload is associated with a poor prognosis in HIV and Hepatitis C virus infections. Iron redistribution may be caused by inflammation but possibly also by hepatitis C co-infection. We examined the prevalence of anemia and its relation to mortality in a cohort of HIV patients in a setting where injecting drug use (IDU) is a main mode of HIV transmission, and measured serum ferritin and sTfR, in relation to anemia, inflammation, stage of HIV disease, ART and HCV infection. METHODS: Patient characteristics, ART history and iron parameters were recorded from adult HIV patients presenting between September 2007 and August 2009 in the referral hospital for West Java, Indonesia. Kaplan-Meier estimates and Cox's regression were used to assess factors affecting survival. Logistic regression was used to identity parameters associated with high ferritin concentrations. RESULTS: Anemia was found in 49.6% of 611 ART-naive patients, with mild (Hb 10.5 -12.99 g/dL for men; and 10.5-11.99 g/dL for women) anemia in 62.0%, and moderate to severe anemia (Hb < 10.5 g/dL) in 38.0%. Anemia remained an independent factor associated with death, also after adjustment for CD4 count and ART (p = 0.008). Seroprevalence of HCV did not differ in patients with (56.9%) or without anemia (59.6%). Serum ferritin concentrations were elevated, especially in patients with anemia (p = 0.07) and/or low CD4 counts (p < 0.001), and were not related to hsCRP or HCV infection. Soluble TfR concentrations were low and not related to Hb, CD4, hsCRP or ART. CONCLUSION: HIV-associated anemia is common among HIV-infected patients in Indonesia and strongly related to mortality. High ferritin with low sTfR levels suggest that iron redistribution and low erythropoietic activity, rather than iron deficiency, contribute to anemia. Serum ferritin and sTfR should be used cautiously to assess iron status in patients with advanced HIV infection. PMID- 21827654 TI - Effectiveness of a family-centered method for the early identification of social emotional and behavioral problems in children: a quasi experimental study. AB - BACKGROUND: Social-emotional and behavioral problems are common in childhood. Early identification of these is important as it can lead to interventions which may improve the child's prognosis. In Dutch Preventive Child Healthcare (PCH), a new family-centered method has been implemented to identify these problems in early childhood. Its main features are consideration of the child's developmental context and empowerment of parents to enhance the developmental context. METHODS/DESIGN: In a quasi-experimental study, embedded in routine PCH in the Netherlands, regions in which the family-centered method has been implemented (intervention condition) will be compared to "care as usual" regions (control condition). These regions are comparable in regard to socio-demographic characteristics. From more than 3,500 newborn babies, 18-month follow-up data on social-emotional and behavioral development will be obtained. PCH professionals will assess development during each routine well-child visit; participating parents will fill in standardized questionnaires.Primary outcomes in the study are the proportion of social-emotional and behavioral problems identified by PCH professionals in children aged 2-14 and 18 months in both conditions, and the proportion of agreement between the assessment of PCH professionals and parents. In addition, the added value of the family-centered approach will be assessed by comparing PCH findings with standardized questionnaires. The secondary outcomes are the degree to which the needs of parents are met and the degree to which they are willing to disclose concerns. DISCUSSION: The family-centered method seems promising for early identification of social-emotional and behavioral problems. The results of this study will contribute to evidence-based public health. TRIAL REGISTRATION: NTR2681. PMID- 21827655 TI - A radiographic analysis of tooth morphology following the use of a novel cyclical force device in orthodontics. AB - BACKGROUND: The purpose was to determine whether or not a novel device used in conjunction with orthodontic treatment produced root resorption shown on 3D images generated from a new cone beam computerized tomography. METHODS: Subjects were actively recruited and those who received braces for the first time were invited to participate. Patients were assigned to receive a functioning device and used the devices for 20 min daily for a six month study period. CBCT images were taken of the dentition at the start of treatment and at the end of the study period. RESULTS: 14 subjects out of a possible 17 subjects completed using the device during the study period. The mean age of the subjects was 20.3 years. Measurements of all teeth present were made from the mesial buccal roots of the first molar on one side of the dental arch to the mesial buccal roots of the first molar on the opposing side of the same arch. These measurements were recorded as linear lengths in mm. A paired t-test was used to determine if significant differences occurred for root lengths at the end of treatment compared to the start of treatment for each of the individual tooth groups. No statistical differences were noted for root length changes above 0.5 mm and 1 mm. CONCLUSIONS: No statistically significant findings were noted for root length change at the end of treatment compared to the start of treatment when using this novel robotic device. No significant differences were noted between roots of anterior and posterior teeth. No clinically significant changes between root lengths were noted above 0.5 mm. PMID- 21827656 TI - Randomization techniques for assessing the significance of gene periodicity results. AB - BACKGROUND: Modern high-throughput measurement technologies such as DNA microarrays and next generation sequencers produce extensive datasets. With large datasets the emphasis has been moving from traditional statistical tests to new data mining methods that are capable of detecting complex patterns, such as clusters, regulatory networks, or time series periodicity. Study of periodic gene expression is an interesting research question that also is a good example of challenges involved in the analysis of high-throughput data in general. Unlike for classical statistical tests, the distribution of test statistic for data mining methods cannot be derived analytically. RESULTS: We describe the randomization based approach to significance testing, and show how it can be applied to detect periodically expressed genes. We present four randomization methods, three of which have previously been used for gene cycle data. We propose a new method for testing significance of periodicity in gene expression short time series data, such as from gene cycle and circadian clock studies. We argue that the underlying assumptions behind existing significance testing approaches are problematic and some of them unrealistic. We analyze the theoretical properties of the existing and proposed methods, showing how our method can be robustly used to detect genes with exceptionally high periodicity. We also demonstrate the large differences in the number of significant results depending on the chosen randomization methods and parameters of the testing framework.By reanalyzing gene cycle data from various sources, we show how previous estimates on the number of gene cycle controlled genes are not supported by the data. Our randomization approach combined with widely adopted Benjamini-Hochberg multiple testing method yields better predictive power and produces more accurate null distributions than previous methods. CONCLUSIONS: Existing methods for testing significance of periodic gene expression patterns are simplistic and optimistic. Our testing framework allows strict levels of statistical significance with more realistic underlying assumptions, without losing predictive power. As DNA microarrays have now become mainstream and new high-throughput methods are rapidly being adopted, we argue that not only there will be need for data mining methods capable of coping with immense datasets, but there will also be need for solid methods for significance testing. PMID- 21827657 TI - Both male and female identity influence variation in male signalling effort. AB - BACKGROUND: Male sexual displays play an important role in sexual selection by affecting reproductive success. However, for such displays to be useful for female mate choice, courtship should vary more among than within individual males. In this regard, a potentially important source of within male variation is adjustment of male courtship effort in response to female traits. Accordingly, we set out to dissect sources of variation in male courtship effort in a fish, the desert goby (Chlamydogobius eremius). We did so by designing an experiment that allowed simultaneous estimation of within and between male variation in courtship, while also assessing the importance of the males and females as sources of courtship variation. RESULTS: Although males adjusted their courtship depending on the identity of the female (a potentially important source of within male variation), among-male differences were considerably greater. In addition, male courtship effort towards a pair of females was highly repeatable over a short time frame. CONCLUSION: Despite the plasticity in male courtship effort, courtship displays had the potential to reliably convey information about the male to mate-searching females. Our experiment therefore underscores the importance of addressing the different sources contributing to variation in the expression of sexually-selected traits. PMID- 21827658 TI - A high sensitivity assay is more accurate than a classical assay for the measurement of plasma CRP levels in endometriosis. AB - BACKGROUND: Endometriosis is associated with chronic subclinical inflammation. C reactive protein (CRP), a marker of inflammation, could serve as a biomarker of endometriosis. We tested the hypothesis that a high sensitivity CRP assay (hsCRP) is more accurate than a classical CRP assay in the detection of subclinical inflammation in plasma of women with endometriosis. METHODS: CRP levels were measured by hsCRP and classical CRP assays in plasma of 204 women with endometriosis and 91 women without endometriosis. Both assays were compared with respect to their value for the diagnosis of endometriosis. RESULTS: The number of plasma samples with detectable CRP was significantly higher (100%) using the hsCRP assay when compared to the classical CRP assay (42.7%) (p < 0.0001). Significantly increased CRP plasma levels were found in women with endometriosis when compared with controls when the hsCRP assay was used in samples obtained during the luteal phase (p = 0.008). The highest discriminative ability for the diagnosis of endometriosis was also obtained using the hsCRP assay during the luteal phase, especially for moderate -severe endometriosis. At a cut-off level of hsCRP > 0.71 mg/L, moderate-severe stages were diagnosed with 80.7% sensitivity and 63.9% specificity during the luteal phase. Using a similar cut off value for CRP analyzed by the classical method, moderate-severe endometriosis was diagnosed with lower sensitivity (67.7%, p = 0.06) and comparable specificity (63.9%). CONCLUSIONS: The hsCRP assay was superior to the classical CRP assay for the detection of low CRP levels and for revealing subclinical inflammation in plasma of women with endometriosis. PMID- 21827659 TI - Transcriptional responses to glucose in Saccharomyces cerevisiae strains lacking a functional protein kinase A. AB - BACKGROUND: The pattern of gene transcripts in the yeast Saccharomyces cerevisiae is strongly affected by the presence of glucose. An increased activity of protein kinase A (PKA), triggered by a rise in the intracellular concentration of cAMP, can account for many of the effects of glucose on transcription. In S. cerevisiae three genes, TPK1, TPK2, and TPK3, encode catalytic subunits of PKA. The lack of viability of tpk1 tpk2 tpk3 triple mutants may be suppressed by mutations such as yak1 or msn2/msn4. To investigate the requirement for PKA in glucose control of gene expression, we have compared the effects of glucose on global transcription in a wild-type strain and in two strains devoid of PKA activity, tpk1 tpk2 tpk3 yak1 and tpk1 tpk2 tpk3 msn2 msn4. RESULTS: We have identified different classes of genes that can be induced -or repressed- by glucose in the absence of PKA. Representative examples are genes required for glucose utilization and genes involved in the metabolism of other carbon sources, respectively. Among the genes responding to glucose in strains devoid of PKA some are also controlled by a redundant signalling pathway involving PKA activation, while others are not affected when PKA is activated through an increase in cAMP concentration. On the other hand, among genes that do not respond to glucose in the absence of PKA, some give a full response to increased cAMP levels, even in the absence of glucose, while others appear to require the cooperation of different signalling pathways. We show also that, for a number of genes controlled by glucose through a PKA-dependent pathway, the changes in mRNA levels are transient. We found that, in cells grown in gluconeogenic conditions, expression of a small number of genes, mainly connected with the response to stress, is reduced in the strains lacking PKA. CONCLUSIONS: In S. cerevisiae, the transcriptional responses to glucose are triggered by a variety of pathways, alone or in combination, in which PKA is often involved. Redundant signalling pathways confer a greater robustness to the response to glucose, while cooperative pathways provide a greater flexibility. PMID- 21827660 TI - Combinations of newly confirmed Glioma-Associated loci link regions on chromosomes 1 and 9 to increased disease risk. AB - BACKGROUND: Glioblastoma multiforme (GBM) tends to occur between the ages of 45 and 70. This relatively early onset and its poor prognosis make the impact of GBM on public health far greater than would be suggested by its relatively low frequency. Tissue and blood samples have now been collected for a number of populations, and predisposing alleles have been sought by several different genome-wide association (GWA) studies. The Cancer Genome Atlas (TCGA) at NIH has also collected a considerable amount of data. Because of the low concordance between the results obtained using different populations, only 14 predisposing single nucleotide polymorphism (SNP) candidates in five genomic regions have been replicated in two or more studies. The purpose of this paper is to present an improved approach to biomarker identification. METHODS: Association analysis was performed with control of population stratifications using the EIGENSTRAT package, under the null hypothesis of "no association between GBM and control SNP genotypes," based on an additive inheritance model. Genes that are strongly correlated with identified SNPs were determined by linkage disequilibrium (LD) or expression quantitative trait locus (eQTL) analysis. A new approach that combines meta-analysis and pathway enrichment analysis identified additional genes. RESULTS: (i) A meta-analysis of SNP data from TCGA and the Adult Glioma Study identifies 12 predisposing SNP candidates, seven of which are reported for the first time. These SNPs fall in five genomic regions (5p15.33, 9p21.3, 1p21.2, 3q26.2 and 7p15.3), three of which have not been previously reported. (ii) 25 genes are strongly correlated with these 12 SNPs, eight of which are known to be cancer-associated. (iii) The relative risk for GBM is highest for risk allele combinations on chromosomes 1 and 9. (iv) A combined meta-analysis/pathway analysis identified an additional four genes. All of these have been identified as cancer-related, but have not been previously associated with glioma. (v) Some SNPs that do not occur reproducibly across populations are in reproducible (invariant) pathways, suggesting that they affect the same biological process, and that population discordance can be partially resolved by evaluating processes rather than genes. CONCLUSION: We have uncovered 29 glioma-associated gene candidates; 12 of them known to be cancer related (p = 1. 4 * 10-6), providing additional statistical support for the relevance of the new candidates. This additional information on risk loci is potentially important for identifying Caucasian individuals at risk for glioma, and for assessing relative risk. PMID- 21827661 TI - Prevalence of aac(6')-Ib-cr plasmid-mediated and chromosome-encoded fluoroquinolone resistance in Enterobacteriaceae in Italy. AB - The spread of aac(6')-Ib-cr plasmid-mediated quinolone resistance determinants was evaluated in 197 enterobacterial isolates recovered in an Italian teaching hospital. The aac(6')-Ib-cr gene was found exclusively in Escherichia coli strains. The gene was located on a plasmid which presented additional ESBL genes. Most of the clinical strains were clonally related and displayed three point mutations at the topoisomerase level which conferred high resistance to fluoroquinolones. PMID- 21827662 TI - EBM in primary care: a qualitative multicenter study in Spain. AB - BACKGROUND: Evidence based medicine (EBM) has made a substantial impact on primary care in Spain over the last few years. However, little research has been done into family physicians (FPs)' attitudes related to EBM. The present study investigates FPs' perceptions of EBM in the primary care context. METHODS: This study used qualitative methodology. Information was obtained from 8 focus groups composed of 67 FPs from 47 health centers in 4 autonomous regions in Spain. Intentional sampling considered participants' previous education in EBM, and their experience as tutors in family medicine or working groups' members of the Spanish Society of Family Practice. Sociological discourse analysis was used with the support of the MAXqda software. Results were validated by means of triangulation among researchers and contrast with participants. RESULTS: Findings were grouped into three main areas: 1) The tug-of-war between the "science" of EBM and "experience" in the search for good clinical practice in primary care; 2) The development of EBM sensemaking as a reaction to contextual factors and interests; 3) The paradox of doubt and trust in the new EBM experts.The meaning of EBM was dynamically constructed within the primary care context. FPs did not consider good clinical practice was limited to the vision of science that EBM represents. Its use appeared to be conditioned by several factors that transcended the common concept of barriers. Along with concerns about its objectivity, participants showed a tendency to see EBM as the use of simplified guidelines developed by EBM experts. CONCLUSIONS: The identification of science with EBM and its recognition as a useful but insufficient tool for the good clinical practice requires rethinking new meanings of evidence within the primary care reality. Beyond the barriers related to accessing and putting into practice the EBM, its reactive use can determine FPs' questions and EBM development in a direction not always centred on patients' needs. The questioning of experts' authority as a pillar of EBM could be challenged by the emergence of new kinds of EBM texts and experts to believe in. PMID- 21827663 TI - TLR4 mutation reduces microglial activation, increases Abeta deposits and exacerbates cognitive deficits in a mouse model of Alzheimer's disease. AB - BACKGROUND: Amyloid plaques, a pathological hallmark of Alzheimer's disease (AD), are accompanied by activated microglia. The role of activated microglia in the pathogenesis of AD remains controversial: either clearing Abeta deposits by phagocytosis or releasing proinflammatory cytokines and cytotoxic substances. Microglia can be activated via toll-like receptors (TLRs), a class of pattern recognition receptors in the innate immune system. We previously demonstrated that an AD mouse model homozygous for a loss-of-function mutation of TLR4 had increases in Abeta deposits and buffer-soluble Abeta in the brain as compared with a TLR4 wild-type AD mouse model at 14-16 months of age. However, it is unknown if TLR4 signaling is involved in initiation of Abeta deposition as well as activation and recruitment of microglia at the early stage of AD. Here, we investigated the role of TLR4 signaling and microglial activation in early stages using 5-month-old AD mouse models when Abeta deposits start. METHODS: Microglial activation and amyloid deposition in the brain were determined by immunohistochemistry in the AD models. Levels of cerebral soluble Abeta were determined by ELISA. mRNA levels of cytokines and chemokines in the brain and Abeta-stimulated monocytes were quantified by real-time PCR. Cognitive functions were assessed by the Morris water maze. RESULTS: While no difference was found in cerebral Abeta load between AD mouse models at 5 months with and without TLR4 mutation, microglial activation in a TLR4 mutant AD model (TLR4M Tg) was less than that in a TLR4 wild-type AD model (TLR4W Tg). At 9 months, TLR4M Tg mice had increased Abeta deposition and soluble Abeta42 in the brain, which were associated with decrements in cognitive functions and expression levels of IL 1beta, CCL3, and CCL4 in the hippocampus compared to TLR4W Tg mice. TLR4 mutation diminished Abeta-induced IL-1beta, CCL3, and CCL4 expression in monocytes. CONCLUSION: This is the first demonstration of TLR4-dependent activation of microglia at the early stage of beta-amyloidosis. Our results indicate that TLR4 is not involved in the initiation of Abeta deposition and that, as Abeta deposits start, microglia are activated via TLR4 signaling to reduce Abeta deposits and preserve cognitive functions from Abeta-mediated neurotoxicity. PMID- 21827664 TI - Antihypertensive and antioxidant effects of dietary black sesame meal in pre hypertensive humans. AB - BACKGROUND: It has been known that hypertension is an independent risk factor for cardiovascular disease (CVD). CVD is the major cause of morbidity and mortality in developed and developing countries. Elevation of blood pressure (BP) increases the adverse effect for cardiovascular outcomes. Prevention of increased BP plays a crucial role in a reduction of those outcomes, leading to a decrease in mortality. Therefore, the purpose of this study was to investigate the effects of dietary black sesame meal on BP and oxidative stress in individuals with prehypertension. METHODS: Twenty-two women and eight men (aged 49.8 +/- 6.6 years) with prehypertension were randomly divided into two groups, 15 subjects per group. They ingested 2.52 g black sesame meal capsules or placebo capsules each day for 4 weeks. Blood samples were obtained after overnight fasting for measurement of plasma lipid, malondialdehyde (MDA) and vitamin E levels. Anthropometry, body composition and BP were measured before and after 4-week administration of black sesame meal or a placebo. RESULTS: The results showed that 4-week administration of black sesame meal significantly decreased systolic BP (129.3 +/- 6.8 vs. 121.0 +/- 9.0 mmHg, P < 0.05) and MDA level (1.8 +/- 0.6 vs. 1.2 +/- 0.6 MUmol/L, P < 0.05), and increased vitamin E level (29.4 +/- 6.0 vs. 38.2 +/- 7.8 MUmol/L, P < 0.01). In the black sesame meal group, the change in SBP tended to be positively related to the change in MDA (R = 0.50, P = 0.05), while the change in DBP was negatively related to the change in vitamin E (R = 0.55, P < 0.05). There were no correlations between changes in BP and oxidative stress in the control group. CONCLUSIONS: These results suggest the possible antihypertensive effects of black sesame meal on improving antioxidant status and decreasing oxidant stress. These data may imply a beneficial effect of black sesame meal on prevention of CVD. PMID- 21827666 TI - A statistical model that predicts the length from the left subclavian artery to the celiac axis; towards accurate intra aortic balloon sizing. AB - BACKGROUND: Ideally the length of the Intraaortic balloon membrane (22-27.5 cm) should match to the distance from the left subclavian artery (LSA) to the celiac axis (CA), (LSA - CA). By being able to estimate this distance, better guidance regarding IABP sizing could be recommended. METHODS: Internal aortic lengths and demographic values were collected from a series of 40 cadavers during autopsy. External somatometric measurements were also obtained.There were 23 males and 17 females. The mean age was 73.1+/-13.11 years, weight 56.75+/-12.51 kg and the height 166+/-9.81 cm. RESULTS: Multiple regression analysis revealed the following predictor variables (R2 > 0.70) for estimating the length from LSA to CA: height (standardized coefficient (SRC) = 0.37, p = 0.004), age (SRC = 0.35, p < 0.001), sex (SRC = 0.21, p = 0.088) and the distance from the jugular notch to trans-pyloric plane (SRC = 0.61, p < 0.001). RECOMMENDATIONS: If LSA-CA < 21.9 cm use 34 cc IABP & if LSA-CA > 26.3 cm use 50 cc IABP. However if LSA-CA = 21.9- 26.3 cm use 40 cc, but be aware that it could be "aortic length-balloon membrane length" mismatching. CONCLUSIONS: Routinely, IABP size selection is being dictated by the patient's height. Inevitably, this leads to pitfalls. We reported a mathematical model of accurate intraaortic balloon sizing, which is easy to be applied and has a high predictive value. PMID- 21827665 TI - Effects of bacteriophage traits on plaque formation. AB - BACKGROUND: The appearance of plaques on a bacterial lawn is one of the enduring imageries in modern day biology. The seeming simplicity of a plaque has invited many hypotheses and models in trying to describe and explain the details of its formation. However, until now, there has been no systematic experimental exploration on how different bacteriophage (phage) traits may influence the formation of a plaque. In this study, we constructed a series of isogenic lambda phages that differ in their adsorption rate, lysis timing, or morphology so that we can determine the effects if these changes on three plaque properties: size, progeny productivity, and phage concentration within plaques. RESULTS: We found that the adsorption rate has a diminishing, but negative impact on all three plaque measurements. Interestingly, there exists a concave relationship between the lysis time and plaque size, resulting in an apparent optimal lysis time that maximizes the plaque size. Although suggestive in appearance, we did not detect a significant effect of lysis time on plaque productivity. Nonetheless, the combined effects of plaque size and productivity resulted in an apparent convex relationship between the lysis time and phage concentration within plaques. Lastly, we found that virion morphology also affected plaque size. We compared our results to the available models on plaque size and productivity. For the models in their current forms, a few of them can capture the qualitative aspects of our results, but not consistently in both plaque properties. CONCLUSIONS: By using a collection of isogenic phage strains, we were able to investigate the effects of individual phage traits on plaque size, plaque productivity, and average phage concentration in a plaque while holding all other traits constant. The controlled nature of our study allowed us to test several model predictions on plaque size and plaque productivity. It seems that a more realistic theoretical approach to plaque formation is needed in order to capture the complex interaction between phage and its bacterium host in a spatially restricted environment. PMID- 21827667 TI - Exposure to anti-malarial drugs and monitoring of adverse drug reactions using toll-free mobile phone calls in private retail sector in Sagamu, Nigeria: implications for pharmacovigilance. AB - BACKGROUND: Adverse drug reactions (ADRs) contribute to ill-health or life threatening outcomes of therapy during management of infectious diseases. The exposure to anti-malarial and use of mobile phone technology to report ADRs following drug exposures were investigated in Sagamu--a peri-urban community in Southwest Nigeria. METHODS: Purchase of medicines was actively monitored for 28 days in three Community Pharmacies (CP) and four Patent and Proprietary Medicine Stores (PPMS) in the community. Information on experience of ADRs was obtained by telephone from 100 volunteers who purchased anti-malarials during the 28-day period. RESULTS AND DISCUSSION: A total of 12,093 purchases were recorded during the period. Antibiotics, analgesics, vitamins and anti-malarials were the most frequently purchased medicines. A total of 1,500 complete courses of anti malarials were purchased (12.4% of total purchases); of this number, purchases of sulphadoxine-pyrimethamine (SP) and chloroquine (CQ) were highest (39.3 and 25.2% respectively). Other anti-malarials purchased were artesunate monotherapy (AS)- 16.1%, artemether-lumefantrine (AL) 10.0%, amodiaquine (AQ)--6.6%, quinine (QNN)- 1.9%, halofantrine (HF)--0.2% and proguanil (PR)--0.2%. CQ was the cheapest (USD 0.3) and halofantrine the most expensive (USD 7.7). AL was 15.6 times ($4.68) more expensive than CQ. The response to mobile phone monitoring of ADRs was 57% in the first 24 hours (day 1) after purchase and decreased to 33% by day 4. Participants in this monitoring exercise were mostly with low level of education (54%). CONCLUSION: The findings from this study indicate that ineffective anti malaria medicines including monotherapies remain widely available and are frequently purchased in the study area. Cost may be a factor in the continued use of ineffective monotherapies. Availability of a toll-free telephone line may facilitate pharmacovigilance and follow up of response to medicines in a resource poor setting. PMID- 21827668 TI - Respiratory syncytial virus infection is associated with an altered innate immunity and a heightened pro-inflammatory response in the lungs of preterm lambs. AB - INTRODUCTION: Factors explaining the greater susceptibility of preterm infants to severe lower respiratory infections with respiratory syncytial virus (RSV) remain poorly understood. Fetal/newborn lambs are increasingly appreciated as a model to study key elements of RSV infection in newborn infants due to similarities in lung alveolar development, immune response, and susceptibility to RSV. Previously, our laboratory demonstrated that preterm lambs had elevated viral antigen and developed more severe lesions compared to full-term lambs at seven days post-infection. Here, we compared the pathogenesis and immunological response to RSV infection in lungs of preterm and full-term lambs. METHODS: Lambs were delivered preterm by Caesarian section or full-term by natural birth, then inoculated with bovine RSV (bRSV) via the intratracheal route. Seven days post infection, lungs were collected for evaluation of cytokine production, histopathology and cellular infiltration. RESULTS: Compared to full-term lambs, lungs of preterm lambs had a heightened pro-inflammatory response after infection, with significantly increased MCP-1, MIP-1alpha, IFN-gamma, TNF-alpha and PD-L1 mRNA. RSV infection in the preterm lung was characterized by increased epithelial thickening and periodic acid-Schiff staining, indicative of glycogen retention. Nitric oxide levels were decreased in lungs of infected preterm lambs compared to full-term lambs, indicating alternative macrophage activation. Although infection induced significant neutrophil recruitment into the lungs of preterm lambs, neutrophils produced less myeloperoxidase than those of full-term lambs, suggesting decreased functional activation. CONCLUSIONS: Taken together, our data suggest that increased RSV load and inadequate immune response may contribute to the enhanced disease severity observed in the lungs of preterm lambs. PMID- 21827669 TI - The thyroid function of Graves' disease patients is aggravated by depressive personality during antithyroid drug treatment. AB - BACKGROUND: We previously reported that depressive personality (the scores of hypochondriasis, depression and psychasthenia determined by the Minnesota Multiphasic Personality Inventory (MMPI)) and daily hassles of Graves' disease (GD) patients treated long trem with antithyroid drug (ATD) were significantly higher in a relapsed group than in a remitted group, even in the euthyroid state. The present study aims to examine the relationship among depressive personality, emotional stresses, thyroid function and the prognosis of hyperthyroidism in newly diagnosed GD patients. METHODS: Sixty-four untreated GD patients responded to the MMPI for personality traits, the Natsume's Stress Inventory for major life events, and the Hayashi's Daily Life Stress Inventory for daily life stresses before and during ATD treatment. RESULTS: In the untreated thyrotoxic state, depressive personality (T-scores of hypochondriasis, depression or psychasthenia greater than 60 points in MMPI) were found for 44 patients (69%). For 15 (23%) of these patients, the scores decreased to the normal range after treatment. However, depressive personality persisted after treatment in the remaining 29 patients (46%). Normal scores before treatment were found for 20 patients (31%), and the scores were persistently normal for 15 patients (23%). The remaining 5 patients (8%) had higher depressive personality after treatment. Such depressive personality was not associated with the severity of hyperthyroidism. Serum TSH receptor antibody activity at three years after treatment was significantly (p = 0.0351) greater in the depression group than in the non- depression group. The remission rate at four years after treatment was significantly (p = 0.0305) lower in the depression group than in the non- depression group (22% vs 52%). CONCLUSION: The data indicate that in GD patients treated with ATD, depressive personality during treatment reflects the effect of emotional stress more than that of thyrotoxicosis and that it aggravates hyperthyroidism. Psychosomatic therapeutic approaches including antipsychiatric drugs and/or psychotherapy appears to be useful for improving the prognosis of hyperthyroidism. PMID- 21827670 TI - Probabilistic modeling and analysis of the effects of extra-cellular matrix density on the sizes, shapes, and locations of integrin clusters in adherent cells. AB - BACKGROUND: Regulation of integrin binding to the specific complementary sites on extra-cellular matrix (ECM) proteins plays a major role in cell adhesion and migration. In addition to regulating single integrin-ligand bonds by affinity modulation, cells regulate their adhesiveness by forming integrin clusters. Although it is clear that cells exhibit different adhesion and migration behaviors on surfaces coated with different concentrations of ECM proteins, it is not clear if this response is mediated by changes in the availability of integrin binding sites or by differential intracellular signaling that may affect integrin binding and clustering. RESULTS: To quantify how the concentration of ECM affects integrin clustering, we seeded cells expressing the integrin alphaIIbbeta3 on different concentrations of the complementary ECM protein fibrinogen (Fg) and measured the resulting integrin cluster properties. We observed heterogeneity in the properties of integrin clusters, and to characterize this population heterogeneity we use a probabilistic modeling approach to quantify changes to the distributions of integrin cluster size, shape, and location. CONCLUSIONS: Our results indicate that in response to increasing ECM density cells form smaller integrin clusters that are less elongated and closer to the cell periphery. These results suggest that cells can sense the availability of ECM binding sites and consequently regulate integrin clustering as a function of ECM density. PMID- 21827671 TI - A retrospective analysis of clinicopathological and prognostic characteristics of ovarian tumors in the State of Espirito Santo, Brazil. AB - BACKGROUND: Ovarian cancer is sixth most common cancer among women and the leading cause of death in women with gynecological malignancies. Despite the great impact ovarian cancer has on women's health and its great impact in public economy, Brazil still lacks valuable information concerning epidemiological aspects of this disease METHODS: We've compiled clinical data of all ovarian tumors registered at the two public hospitals of reference (1997 - 2007), such as: patients' age at diagnosis, tumor histological type, tumor stage, chemotherapy regimens, chemotherapy responsiveness, disease-free survival, and overall survival. RESULTS: Women's mean age at diagnosis was 54.67 +/- 13.84 for ovarian cancer, 46.15 +/- 11.15 for borderline tumors, and 42.01 +/- 15.06 for adenomas. Among epithelial ovarian cancer cases, 30.1% were of serous, 13.7% were of mucinous, and 13.7% were of endometrioid type; exceptionally serous carcinoma was diagnosed in women younger than 30 years old. Endometrioid cancer had lower disease-free survival than others (p < 0.05). Cases were predominantly diagnosed as poor prognosis disease (FIGO III and IV, 56.2%). Regarding responsiveness to platinum-based therapy, 17.1% of patients were resistant, whereas 24.6%, susceptible. From these, we found equally responsiveness to platinum alone or its association with paclitaxel or cyclophosphamide. DISCUSSION: Our data agreed with other studies regarding mean patients' age at diagnosis, histological type frequency, FIGO stages distribution, and chemotherapy regimens. However, the histological type distribution, with equal contribution of mucinous and endometrioid types seems to be a unique characteristic of the studied highly miscegenated population. CONCLUSION: We have enlighten the profile of the studied ovarian cancer population, which might enable the development of more efficient political strategies to control this malignancy that is the fifth leading cause of cancer-related deaths among women. PMID- 21827672 TI - Serous papillary adenocarcinoma possibly related to the presence of primitive oocyte-like cells in the adult ovarian surface epithelium: a case report. AB - INTRODUCTION: The presence of oocytes in the ovarian surface epithelium has already been confirmed in the fetal ovaries. We report the presence of SSEA-4, SOX-2, VASA and ZP2-positive primitive oocyte-like cells in the adult ovarian surface epithelium of a patient with serous papillary adenocarcinoma. CASE PRESENTATION: Ovarian tissue was surgically retrieved from a 67-year old patient. Histological analysis revealed serous papillary adenocarcinoma. A proportion of ovarian cortex sections was deparaffinized and immunohistochemically stained for the expression of markers of pluripotency SSEA-4 and SOX-2 and oocyte-specific markers VASA and ZP2. The analysis confirmed the presence of round, SSEA-4, SOX 2, VASA and ZP2-positive primitive oocyte-like cells in the ovarian surface epithelium. These cells were possibly related to the necrotic malignant tissue. CONCLUSION: Primitive oocyte-like cells present in the adult ovarian surface epithelium persisting probably from the fetal period of life or developed from putative stem cells are a pathological condition which is not observed in healthy adult ovaries, and might be related to serous papillary adenocarcinoma manifestation in the adult ovarian surface epithelium. This observation needs attention to be further investigated. PMID- 21827673 TI - Towards targeted screening for acute HIV infections in British Columbia. AB - BACKGROUND: Our objective was to describe the characteristics of acute and established HIV infections diagnosed in the Canadian province of British Columbia. Province-wide HIV testing and surveillance data were analyzed to inform recommendations for targeted use of screening algorithms to detect acute HIV infections. METHODS: Acute HIV infection was defined as a confirmed reactive HIV p24 antigen test (or HIV nucleic acid test), a non-reactive or reactive HIV EIA screening test and a non-reactive or indeterminate Western Blot. Characteristics of unique individuals were identified from the British Columbia HIV/AIDS Surveillance System. Primary drug resistance and HIV subtypes were identified by analyzing HIV pol sequences from residual sera from newly infected individuals. RESULTS: From February 2006 to October 2008, 61 individuals met the acute HIV infection case definition, representing 6.2% of the 987 newly diagnosed HIV infections during the analysis period. Acute HIV infection cases were more likely to be men who have sex with men (crude OR 1.71; 95% CI 1.01-2.89], to have had a documented previous negative HIV test result (crude OR 2.89; 95% CI 1.52-5.51), and to have reported a reason for testing due to suspected seroconversion symptoms (crude OR 5.16; 95% CI 2.88-9.23). HIV subtypes and rates of transmitted drug resistance across all classes of drugs were similar in persons with both acute and established HIV infections. CONCLUSIONS: Targeted screening to detect acute HIV infection is a logical public health response to the HIV epidemic. Our findings suggest that acute HIV infection screening strategies, in our setting, are helpful for early diagnosis in men who have sex with men, in persons with seroconversion symptoms and in previously negative repeat testers. PMID- 21827674 TI - CGB and GNRH1 expression analysis as a method of tumor cells metastatic spread detection in patients with gynecological malignances. AB - BACKGROUND: Metastasis is a common feature of many advanced stage cancers and metastatic spread is thought to be responsible for cancer progression. Most cancer cells are localized in the primary tumor and only a small population of circulating tumor cells (CTC) has metastatic potential. CTC amount reflects the aggressiveness of tumors, therefore their detection can be used to determine the prognosis and treatment of cancer patients.The aim of this study was to evaluate human chorionic gonadotropin beta subunit (CGB) and gonadoliberin type 1 (GNRH1) expression as markers of tumor cells circulating in peripheral blood of gynecological cancer patients, indicating the metastatic spread of tumor. METHODS: CGB and GNRH1 expression level in tumor tissue and blood of cancer patients was assessed by real-time RT-PCR. The data was analyzed using the Mann Whitney U and Spearman tests. In order to distinguish populations with homogeneous genes' expression the maximal likelihood method for one- and multiplied normal distribution was used. RESULT: Real time RT-PCR results revealed CGB and GNRH1 genes activity in both tumor tissue and blood of gynecological cancers patients. While the expression of both genes characterized all examined tumor tissues, in case of blood analysis, the transcripts of GNRH1 were found in all cancer patients while CGB were present in 93% of patients. CGB and GNRH1 activity was detected also in control group, which consisted of tissue lacking cancerous changes and blood of healthy volunteers. The log-transformation of raw data fitted to multiplied normal distribution model showed that CGB and GNRH1 expression is heterogeneous and more than one population can be distinguished within defined groups.Based on CGB gene activity a critical value indicating the presence of cancer cells in studied blood was distinguished. In case of GNRH1 this value was not established since the results of the gene expression in blood of cancer patients and healthy volunteers were overlapping. However one subpopulation consists of cancer patient with much higher GNRH1 expression than in control group was found. CONCLUSIONS: Assessment of CGB and GNRH1 expression level in cancer patients' blood may be useful for indicating metastatic spread of tumor cells. PMID- 21827675 TI - Engineered artificial antigen presenting cells facilitate direct and efficient expansion of tumor infiltrating lymphocytes. AB - BACKGROUND: Development of a standardized platform for the rapid expansion of tumor-infiltrating lymphocytes (TILs) with anti-tumor function from patients with limited TIL numbers or tumor tissues challenges their clinical application. METHODS: To facilitate adoptive immunotherapy, we applied genetically-engineered K562 cell-based artificial antigen presenting cells (aAPCs) for the direct and rapid expansion of TILs isolated from primary cancer specimens. RESULTS: TILs outgrown in IL-2 undergo rapid, CD28-independent expansion in response to aAPC stimulation that requires provision of exogenous IL-2 cytokine support. aAPCs induce numerical expansion of TILs that is statistically similar to an established rapid expansion method at a 100-fold lower feeder cell to TIL ratio, and greater than those achievable using anti-CD3/CD28 activation beads or extended IL-2 culture. aAPC-expanded TILs undergo numerical expansion of tumor antigen-specific cells, remain amenable to secondary aAPC-based expansion, and have low CD4/CD8 ratios and FOXP3+ CD4+ cell frequencies. TILs can also be expanded directly from fresh enzyme-digested tumor specimens when pulsed with aAPCs. These "young" TILs are tumor-reactive, positively skewed in CD8+ lymphocyte composition, CD28 and CD27 expression, and contain fewer FOXP3+ T cells compared to parallel IL-2 cultures. CONCLUSION: Genetically-enhanced aAPCs represent a standardized, "off-the-shelf" platform for the direct ex vivo expansion of TILs of suitable number, phenotype and function for use in adoptive immunotherapy. PMID- 21827676 TI - Neoadjuvant chemoradiation compared to neoadjuvant radiation alone and surgery alone for Stage II and III soft tissue sarcoma of the extremities. AB - BACKGROUND: Neoadjuvant chemoradiation (NCR) prior to resection of extremity soft tissue sarcoma (STS) has been studied, but data are limited. We present outcomes with NCR using a variety of chemotherapy regimens compared to neoadjuvant radiation without chemotherapy (NR) and surgery alone (SA). METHODS: We conducted a retrospective chart review of 112 cases. RESULTS: Treatments included SA (36 patients), NCR (39 patients), and NR (37 patients). NCR did not improve the rate of margin-negative resections over SA or NR. Loco-regional relapse-free survival, distant metastases-free survival, and overall survival (OS) were not different among the treatment groups. Patients with relapsed disease (OR 11.6; p = 0.01), and tumor size greater than 5 cm (OR 9.4; p = 0.01) were more likely to have a loco-regional recurrence on logistic regression analysis. Significantly increased OS was found among NCR-treated patients with tumors greater than 5 cm compared to SA (3 year OS 69 vs. 40%; p = 0.03). Wound complication rates were higher after NCR compared to SA (50 vs. 11%; p = 0.003) but not compared to NR (p = 0.36). Wet desquamation was the most common adverse event of NCR. CONCLUSIONS: NCR and NR are acceptable strategies for patients with STS. NCR is well-tolerated, but not clearly superior to NR. PMID- 21827677 TI - Coenzyme Q10 levels are low and may be associated with the inflammatory cascade in septic shock. AB - INTRODUCTION: Mitochondrial dysfunction is associated with increased mortality in septic shock. Coenzyme Q10 (CoQ10) is a key cofactor in the mitochondrial respiratory chain, but whether CoQ10 is depleted in septic shock remains unknown. Moreover, statin therapy may decrease CoQ10 levels, but whether this occurs acutely remains unknown. We measured CoQ10 levels in septic shock patients enrolled in a randomized trial of simvastatin versus placebo. METHODS: We conducted a post hoc analysis of a prospective, randomized trial of simvastatin versus placebo in patients with septic shock (ClinicalTrials.gov ID: NCT00676897). Adult patients with suspected or confirmed infection and the need for vasopressor support were included in the initial trial. For the current analysis, blood specimens were analyzed for plasma CoQ10 and low-density lipoprotein (LDL) levels. The relationship between CoQ10 levels and inflammatory and vascular endothelial biomarkers was assessed using either the Pearson or Spearman correlation coefficient. RESULTS: We analyzed 28 samples from 14 patients. CoQ10 levels were low, with a median of 0.49 (interquartile range 0.26 to 0.62) compared to levels in healthy control patients (CoQ10 = 0.95 MUmol/L +/- 0.29; P < 0.0001). Statin therapy had no effect on plasma CoQ10 levels over time (P = 0.13). There was a statistically significant relationship between plasma CoQ10 levels and levels of vascular cell adhesion molecule (VCAM) (r2 = 0.2; P = 0.008), TNF-alpha (r2 = 0.28; P = 0.004), IL-8 (r2 = 0.21; P = 0.015), IL-10 (r2 = 0.18; P = 0.025), E-selectin (r2 = 0.17; P = -0.03), IL-1ra (r2 = 0.21; P = 0.014), IL-6 (r2 = 0.17; P = 0.029) and IL-2 (r2 = 0.23; P = 0.009). After adjusting for LDL levels, there was a statistically significant inverse relationship between plasma CoQ10 levels and levels of VCAM (r2 = 0.24; P = 0.01) (Figure 3) and IL-10 (r2 = 0.24; P = 0.02). CONCLUSIONS: CoQ10 levels are significantly lower in septic shock patients than in healthy controls. CoQ10 is negatively associated with vascular endothelial markers and inflammatory molecules, though this association diminishes after adjusting for LDL levels. PMID- 21827678 TI - Malignant melanoma arising from a perianal fistula and harbouring a BRAF gene mutation: a case report. AB - BACKGROUND: Melanoma of the anal region is a very uncommon disease, accounting for only 0.2-0.3% of all melanoma cases. Mutations of the BRAF gene are usually absent in melanomas occurring in this region as well as in other sun-protected regions. The development of a tumour in a longstanding perianal fistula is also extremely rare. More frequent is the case of a tumour presenting as a fistula, that is, the fistula being a consequence of the cancerous process, although we have found only two cases of fistula-generating melanomas reported in the literature. CASE PRESENTATION: Here we report the case of a 38-year-old male who presented with a perianal fistula of four years of evolution. Histopathological examination of the fistulous tract confirmed the presence of malignant melanoma. Due to the small size and the central location of the melanoma inside the fistulous tract, we believe the melanoma reported here developed in the epithelium of the fistula once the latter was already formed. Resected sentinel lymph nodes were negative and the patient, after going through a wide local excision, remains disease-free nine years after diagnosis. DNA obtained from melanoma tissue was analysed by automated direct sequencing and the V600E (T1799A) mutation was detected in exon 15 of the BRAF gene. CONCLUSION: Since fistulae experience persistent inflammation, the fact that this melanoma harbours a BRAF mutation strengthens the view that oxidative stress caused by inflammatory processes plays an important role in the genesis of BRAF gene mutations. PMID- 21827679 TI - Lobular neoplasia: frequency and association with other breast lesions. AB - BACKGROUND: Using new molecular biology techniques, recent studies have implicated a common evolutionary pathway between lobular neoplasia, lobular carcinomas, and columnar cell lesions. Our aims were to assess the frequency of lobular neoplasia in a series of breast biopsies that were performed and examined in the same institution and to analyze the association between subtypes of lobular neoplasia and benign and malignant breast lesions. METHODS: Cases were selected after reviewing archived pathological reports in the Breast Pathology Laboratory, School of Medicine of Federal University of Minas Gerais (1999-2008). Cases of lobular neoplasia were reviewed and classified as atypical lobular hyperplasia, ductal involvement by cells of atypical lobular hyperplasia, lobular carcinoma in situ, and pleomorphic lobular carcinoma in situ. Coexistence of lobular neoplasia with other breast lesions, including columnar cell lesions, invasive ductal carcinoma and invasive lobular carcinoma, was evaluated. The association between lobular neoplasia and breast lesions was analyzed by Fisher's exact test and chi-square test for linear trend. RESULTS: We analyzed 5650 breast specimens, selecting 135 breast specimens (2.4%) that had a diagnosis of lobular neoplasia, corresponding to 106 patients. Hematoxylin and eosin-stained slides were available for 84 cases, 5 of which were excluded because they contained only "indeterminate" in situ lesions. Of the 79 remaining cases, columnar cell lesions were present in 78.5%, primarily with columnar cell changes without atypia (67.7%). Invasive carcinoma was present in 45.6% of cases of lobular neoplasia--a similar frequency (47.2%) as invasive ductal carcinoma and invasive lobular carcinoma. We noted a significant linear trend (p < 0.03) of a higher frequency of invasive carcinomas that were concomitant with lobular carcinoma in situ compared with atypical lobular hyperplasia. Invasive lobular carcinomas were associated with lobular carcinoma in situ in 33% of cases, compared with 2.8% of atypical lobular hyperplasia cases. CONCLUSIONS: Our findings confirm a frequent association between lobular neoplasia and columnar cell lesions, the majority of which lacked atypia. We also observed a greater frequency of invasive carcinoma, more commonly invasive lobular carcinoma, associated with more developed forms of lobular neoplasia (lobular carcinoma in situ). PMID- 21827682 TI - Description of evandromyia spelunca, a new phlebotomine species of the cortelezzii complex, from a cave in Minas Gerais State, Brazil (Diptera: Psychodidae: Phlebotominae). AB - BACKGROUND: The cave fauna of the Brazil is poorly documented, and among the insects those live or frequent caves and their adjacent environments phlebotomine sand flies call for special attention because several species are vectors of pathogens among vertebrates hosts. A new species of sand fly from Minas Gerais is described based in females and males collected in a cave of the municipality of Lassance. RESULTS: The morphological characters of the new species permit to include in the Evandromyia genus, cortelezzii complex. This complex consists of three species: Evandromyia corumbaensis (Galati, Nunes, Oshiro & Rego, 1989), Evandromyia cortelezzii (Brethes, 1923) and Evandromyia sallesi (Galvao & Coutinho, 1940). CONCLUSIONS: The new species can be separate from the others of the cortelezzii complex through morphological characters of the male terminalia and female spermathecae. PMID- 21827680 TI - Molecular evolution of the LNX gene family. AB - BACKGROUND: LNX (Ligand of Numb Protein-X) proteins typically contain an amino terminal RING domain adjacent to either two or four PDZ domains - a domain architecture that is unique to the LNX family. LNX proteins function as E3 ubiquitin ligases and their domain organisation suggests that their ubiquitin ligase activity may be targeted to specific substrates or subcellular locations by PDZ domain-mediated interactions. Indeed, numerous interaction partners for LNX proteins have been identified, but the in vivo functions of most family members remain largely unclear. RESULTS: To gain insights into their function we examined the phylogenetic origins and evolution of the LNX gene family. We find that a LNX1/LNX2-like gene arose in an early metazoan lineage by gene duplication and fusion events that combined a RING domain with four PDZ domains. These PDZ domains are closely related to the four carboxy-terminal domains from multiple PDZ domain containing protein-1 (MUPP1). Duplication of the LNX1/LNX2-like gene and subsequent loss of PDZ domains appears to have generated a gene encoding a LNX3/LNX4-like protein, with just two PDZ domains. This protein has novel carboxy terminal sequences that include a potential modular LNX3 homology domain. The two ancestral LNX genes are present in some, but not all, invertebrate lineages. They were, however, maintained in the vertebrate lineage, with further duplication events giving rise to five LNX family members in most mammals. In addition, we identify novel interactions of LNX1 and LNX2 with three known MUPP1 ligands using yeast two-hybrid asssays. This demonstrates conservation of binding specificity between LNX and MUPP1 PDZ domains. CONCLUSIONS: The LNX gene family has an early metazoan origin with a LNX1/LNX2-like protein likely giving rise to a LNX3/LNX4 like protein through the loss of PDZ domains. The absence of LNX orthologs in some lineages indicates that LNX proteins are not essential in invertebrates. In contrast, the maintenance of both ancestral LNX genes in the vertebrate lineage suggests the acquisition of essential vertebrate specific functions. The revelation that the LNX PDZ domains are phylogenetically related to domains in MUPP1, and have common binding specificities, suggests that LNX and MUPP1 may have similarities in their cellular functions. PMID- 21827681 TI - Rhodococcus equi venous catheter infection: a case report and review of the literature. AB - INTRODUCTION: Rhodococcus equi is an animal pathogen that was initially isolated from horses and is being increasingly reported as a cause of infection in humans with impaired cellular immunity. However, this pathogen is underestimated as a challenging antagonist and is frequently considered to be a mere contaminant despite the potential for life-threatening infections. Most case reports have occurred in immunocompromised patients who have received organ transplants (for example kidney, heart, bone marrow) or those with human immunodeficiency virus infection. Infections often manifest as pulmonary involvement or soft tissue abscesses. Bacteremia related to R. equi infections of tunneled central venous catheters has rarely been described. CASE PRESENTATION: We report the case of a 63-year-old non-transplant recipient, non-HIV infected Caucasian woman with endometrial carcinoma who developed recurrent bloodstream infections and septic shock due to R. equi and ultimately required the removal of her port catheter, a subcutaneous implantable central venous catheter. We also review the medical literature related to human infections with R. equi. CONCLUSION: R. equi should be considered a serious pathogen, not a contaminant, particularly in an immunocompromised patient who presents with a central venous catheter-related bloodstream infection. Counseling patients with central venous catheters who participate in activities involving exposure to domesticated animals is recommended. PMID- 21827683 TI - Preparation and characterization of superhydrophobic surfaces based on hexamethyldisilazane-modified nanoporous alumina. AB - Superhydrophobic nanoporous anodic aluminum oxide (alumina) surfaces were prepared using treatment with vapor-phase hexamethyldisilazane (HMDS). Nanoporous alumina substrates were first made using a two-step anodization process. Subsequently, a repeated modification procedure was employed for efficient incorporation of the terminal methyl groups of HMDS to the alumina surface. Morphology of the surfaces was characterized by scanning electron microscopy, showing hexagonally ordered circular nanopores with approximately 250 nm in diameter and 300 nm of interpore distances. Fourier transform infrared spectroscopy-attenuated total reflectance analysis showed the presence of chemically bound methyl groups on the HMDS-modified nanoporous alumina surfaces. Wetting properties of these surfaces were characterized by measurements of the water contact angle which was found to reach 153.2 +/- 2 degrees . The contact angle values on HMDS-modified nanoporous alumina surfaces were found to be significantly larger than the average water contact angle of 82.9 +/- 3 degrees on smooth thin film alumina surfaces that underwent the same HMDS modification steps. The difference between the two cases was explained by the Cassie-Baxter theory of rough surface wetting. PMID- 21827684 TI - Buyer beware? Does the information provided with herbal products available over the counter enable safe use? AB - BACKGROUND: Herbal products obtained over the counter are commonly used in Europe, North America and Australia. Although there is concern about a lack of information provided to consumers to allow the safe use of these products, there has been no published research to confirm these fears. In this study, we evaluated written information provided with commonly used herbal products in the UK in advance of a European Union Directive issued in April 2011 that tightened regulations for some herbal products, including requirements to provide safety information. METHODS: Five commonly used herbal products were purchased from pharmacies, health food shops and supermarkets: St John's wort, Asian ginseng, echinacea, garlic and ginkgo. Written information provided with the products (on the package or on a leaflet contained in the package) was evaluated for inclusion of each of the key safety messages included in the monographs of the US National Center for Complementary and Alternative Medicine. Specifically, we looked for information on precautions (such as Asian ginseng not being suitable for people with diabetes), interactions with conventional medicines (such as St John's wort with the contraceptive pill and warfarin) and side effects (such as ginkgo and allergic reactions). RESULTS: Our analysis showed that, overall, 51 (75%) of 68 products contained none of the key safety messages. This included 4 of 12 St John's wort products, 12 of 12 ginkgo products, 6 of 7 Asian ginseng products, 20 of 21 garlic products and 9 of 13 echinacea products. The two products purchased that are registered under the new European Union regulations (for St John's wort) contained at least 85% of the safety messages. CONCLUSIONS: Most of the herbal medicine products studied did not provide key safety information which consumers need for their safe use. The new European Union legislation should ensure that St John's wort and echinacea products will include the previously missing information in due course. The legislation does not apply to existing stock. Depending on therapeutic claims made by manufacturers, garlic, ginkgo and Asian ginseng products may not be covered by the legislation and can continue to be bought without the safety information. Also, consumers will still be able to buy products over the internet from locations outside European Union jurisdiction. Potential purchasers need to know, in both the short term and the long term, how to purchase herbal products which provide the information they need for the safe use of these products. PMID- 21827685 TI - Infective endocarditis with Lactococcus garvieae in Japan: a case report. AB - INTRODUCTION: Lactococcus garvieae is a well-recognized fish pathogen, and it is considered a rare pathogen with low virulence in human infection. We describe the 11th case of L. garvieae infective endocarditis reported in the literature, and the first reported case in Japan. CASE PRESENTATION: We report a case of a 55 year-old Japanese woman who had native valve endocarditis with L. garvieae. The case was complicated by renal infarction, cerebral infarction, and mycotic aneurysms. After anti-microbial treatment, she was discharged from the hospital and is now well while being monitored in the out-patient clinic. CONCLUSION: We encountered a case of L. garvieae endocarditis that occurred in a native valve of a healthy woman. The 16S ribosomal RNA gene sequencing was useful for the identification of this pathogen. Although infective endocarditis with L. garvieae is uncommon, it is possible to treat high virulence clinically. PMID- 21827686 TI - A 64-year old man presenting with carotid artery occlusion and corticobasal syndrome: a case report. AB - INTRODUCTION: Magnetic resonance imaging of the brain in patients with corticobasal degeneration typically shows focal or asymmetric atrophy, usually maximal in the frontoparietal cortex. Many patients who are diagnosed with corticobasal degeneration using current diagnostic criteria do not have classical corticobasal degeneration pathology. Our case is remarkable for the fact that the symptoms and the characteristic magnetic resonance imaging appearance were typical for corticobasal degeneration. However, we were quite convinced that the clinical picture had a vascular etiology. Only a few cases have been reported where the presumed cause for the corticobasal syndrome was multiple brain infarctions bilaterally. CASE PRESENTATION: A 64-year-old Caucasian man visited a neurologist because of profound asymmetric sensory and motor disturbances. A magnetic resonance imaging scan of his brain revealed occlusion of his internal carotid artery on the left side with multiple vascular lesions in his left hemisphere and notable atrophy of mainly the left parietal and frontal cortex. CONCLUSION: We describe a patient with corticobasal syndrome caused by multiple infarctions, probably caused by emboli of the carotid stenosis. This patient illustrates the fact that the word 'syndrome' should be preferred above 'degeneration' in the name of this disease. PMID- 21827687 TI - Extraparenchymal neurocysticercosis in the United States: a case report. AB - INTRODUCTION: Neurocysticercosis is endemic in the developing world, but is becoming more common in the United States due to immigration. CASE PRESENTATION: A 26-year-old Caucasian man presented with headache, nausea and vomiting and was found to have hydrocephalus and meningitis. Brain imaging and immunological studies were suggestive of neurocysticercosis. Endoscopic removal of the cyst resulted in resolution of symptoms. This case represents a combination of two rare presentations of extraparenchymal neurocysticercosis; intraventricular neurocysticercosis and subarachnoid neurocysticercosis. CONCLUSION: Although neurocysticercosis is pleomorphic in its presentation, extraparenchymal neurocysticercosis may be challenging to diagnose and treat. Clinicians should be aware of this condition given increasing incidence in the United States. PMID- 21827688 TI - In vitro activation and enzyme kinetic analysis of recombinant midgut serine proteases from the Dengue vector mosquito Aedes aegypti. AB - BACKGROUND: The major Dengue virus vector Aedes aegypti requires nutrients obtained from blood meal proteins to complete the gonotrophic cycle. Although bioinformatic analyses of Ae. aegypti midgut serine proteases have provided evolutionary insights, very little is known about the biochemical activity of these digestive enzymes. RESULTS: We used peptide specific antibodies to show that midgut serine proteases are expressed as zymogen precursors, which are cleaved to the mature form after blood feeding. Since midgut protein levels are insufficient to purify active proteases directly from blood fed mosquitoes, we engineered recombinant proteins encoding a heterologous enterokinase cleavage site to permit generation of the bona fide mature form of four midgut serine proteases (AaET, AaLT, AaSPVI, AaSPVII) for enzyme kinetic analysis. Cleavage of the chromogenic trypsin substrate BApNA showed that AaET has a catalytic efficiency (k(cat)/K(M)) that is ~30 times higher than bovine trypsin, and ~2-3 times higher than AaSPVI and AaSPVII, however, AaLT does not cleave BApNA. To measure the enzyme activities of the mosquito midgut proteases using natural substrates, we developed a quantitative cleavage assay based on cleavage of albumin and hemoglobin proteins. These studies revealed that the recombinant AaLT enzyme was indeed catalytically active, and cleaved albumin and hemoglobin with equivalent efficiency to that of AaET, AaSPVI, and AaSPVII. Structural modeling of the AaLT and AaSPVI mature forms indicated that AaLT is most similar to serine collagenases, whereas AaSPVI appears to be a classic trypsin. CONCLUSIONS: These data show that in vitro activation of recombinant serine proteases containing a heterologous enterokinase cleavage site can be used to investigate enzyme kinetics and substrate cleavage properties of biologically important mosquito proteases. PMID- 21827689 TI - Pre-validation methods for developing a patient reported outcome instrument. AB - BACKGROUND: Measures that reflect patients' assessment of their health are of increasing importance as outcome measures in randomised controlled trials. The methodological approach used in the pre-validation development of new instruments (item generation, item reduction and question formatting) should be robust and transparent. The totality of the content of existing PRO instruments for a specific condition provides a valuable resource (pool of items) that can be utilised to develop new instruments. Such 'top down' approaches are common, but the explicit pre-validation methods are often poorly reported. This paper presents a systematic and generalisable 5-step pre-validation PRO instrument methodology. METHODS: The method is illustrated using the example of the Aberdeen Glaucoma Questionnaire (AGQ). The five steps are: 1) Generation of a pool of items; 2) Item de-duplication (three phases); 3) Item reduction (two phases); 4) Assessment of the remaining items' content coverage against a pre-existing theoretical framework appropriate to the objectives of the instrument and the target population (e.g. ICF); and 5) qualitative exploration of the target populations' views of the new instrument and the items it contains. RESULTS: The AGQ 'item pool' contained 725 items. Three de-duplication phases resulted in reduction of 91, 225 and 48 items respectively. The item reduction phases discarded 70 items and 208 items respectively. The draft AGQ contained 83 items with good content coverage. The qualitative exploration ('think aloud' study) resulted in removal of a further 15 items and refinement to the wording of others. The resultant draft AGQ contained 68 items. CONCLUSIONS: This study presents a novel methodology for developing a PRO instrument, based on three sources: literature reporting what is important to patient; theoretically coherent framework; and patients' experience of completing the instrument. By systematically accounting for all items dropped after the item generation phase, our method ensures that the AGQ is developed in a transparent, replicable manner and is fit for validation. We recommend this method to enhance the likelihood that new PRO instruments will be appropriate to the research context in which they are used, acceptable to research participants and likely to generate valid data. PMID- 21827690 TI - Molecular evolution of a chordate specific family of G protein-coupled receptors. AB - BACKGROUND: Chordate evolution is a history of innovations that is marked by physical and behavioral specializations, which led to the development of a variety of forms from a single ancestral group. Among other important characteristics, vertebrates obtained a well developed brain, anterior sensory structures, a closed circulatory system and gills or lungs as blood oxygenation systems. The duplication of pre-existing genes had profound evolutionary implications for the developmental complexity in vertebrates, since mutations modifying the function of a duplicated protein can lead to novel functions, improving the evolutionary success. RESULTS: We analyzed here the evolution of the GPRC5 family of G protein-coupled receptors by comprehensive similarity searches and found that the receptors are only present in chordates and that the size of the receptor family expanded, likely due to genome duplication events in the early history of vertebrate evolution. We propose that a single GPRC5 receptor coding gene originated in a stem chordate ancestor and gave rise by duplication events to a gene family comprising three receptor types (GPRC5A-C) in vertebrates, and a fourth homologue present only in mammals (GPRC5D). Additional duplications of GPRC5B and GPRC5C sequences occurred in teleost fishes. The finding that the expression patterns of the receptors are evolutionarily conserved indicates an important biological function of these receptors. Moreover, we found that expression of GPRC5B is regulated by vitamin A in vivo, confirming previous findings that linked receptor expression to retinoic acid levels in tumor cell lines and strengthening the link between the receptor expression and the development of a complex nervous system in chordates, known to be dependent on retinoic acid signaling. CONCLUSIONS: GPRC5 receptors, a class of G protein-coupled receptors with unique sequence characteristics, may represent a molecular novelty that helped non-chordates to become chordates. PMID- 21827691 TI - ELISA measurement of specific non-antigen-bound antibodies to Abeta1-42 monomer and soluble oligomers in sera from Alzheimer's disease, mild cognitively impaired, and noncognitively impaired subjects. AB - BACKGROUND: The literature contains conflicting results regarding the status of serum anti-Abeta antibody concentrations in Alzheimer's disease (AD). Reduced levels of these antibodies have been suggested to contribute to the development of this disorder. The conflicting results may be due to polyvalent antibodies, antibody "masking" due to Abeta binding, methodological differences, and/or small sample sizes. The objectives of this pilot study were to compare serum anti-Abeta antibody concentrations between AD, mild cognitive impairment (MCI), and elderly noncognitively impaired (NCI) subjects while addressing these issues, and to perform power analyses to determine appropriate group sizes for future studies employing this approach. METHODS: Serum antibodies to Abeta1-42 monomer and soluble oligomers in AD, MCI, and NCI subjects (10/group) were measured by ELISA, subtracting polyvalent antibody binding and dissociating antibody-antigen complexes. Differences in mean antibody levels were assessed for significance with repeated measures ANOVA using restricted maximum likelihood estimation, using Tukey-Kramer tests and confidence intervals for multiple comparisons. Spearman's rank correlation was used to determine associations between anti monomer and anti-oligomer antibody concentrations. Estimated sample sizes required to detect effects of various sizes were calculated. RESULTS: There were no significant differences between groups for mean anti-Abeta antibody levels, although these tended to be higher in AD than NCI specimens. Estimated group sizes of 328 and 150 for anti-Abeta monomer and oligomer antibodies, respectively, would have been required for 80% power for significance at 0.05 for a 25% increase in the AD mean relative to the NCI mean. Serum antibody concentrations to Abeta monomer and oligomers were strongly associated (correlations: 0.798 for undissociated sera, 0.564 for dissociated sera). Antibody-antigen dissociation significantly increased anti-Abeta monomer but not anti-Abeta oligomer antibody levels. CONCLUSIONS: The findings in this pilot study are consistent with relatively similar concentrations of specific, non antigen-bound antibodies to Abeta1-42 monomer and soluble oligomers in AD, MCI, and NCI sera. The differences between groups for these antibodies would have required approximate group sizes of 328 and 150, respectively, for a high probability for statistical significance. These findings do not support the hypothesis that reduced levels of anti-Abeta antibodies might contribute to AD's pathogenesis. PMID- 21827692 TI - Genome-wide algorithm for detecting CNV associations with diseases. AB - BACKGROUND: SNP genotyping arrays have been developed to characterize single nucleotide polymorphisms (SNPs) and DNA copy number variations (CNVs). Nonparametric and model-based statistical algorithms have been developed to detect CNVs from SNP data using the marker intensities. However, these algorithms lack specificity to detect small CNVs owing to the high false positive rate when calling CNVs based on the intensity values. Therefore, the resulting association tests lack power even if the CNVs affecting disease risk are common. An alternative procedure called PennCNV uses information from both the marker intensities as well as the genotypes and therefore has increased sensitivity. RESULTS: By using the hidden Markov model (HMM) implemented in PennCNV to derive the probabilities of different copy number states which we subsequently used in a logistic regression model, we developed a new genome-wide algorithm to detect CNV associations with diseases. We compared this new method with association test applied to the most probable copy number state for each individual that is provided by PennCNV after it performs an initial HMM analysis followed by application of the Viterbi algorithm, which removes information about copy number probabilities. In one of our simulation studies, we showed that for large CNVs (number of SNPs >= 10), the association tests based on PennCNV calls gave more significant results, but the new algorithm retained high power. For small CNVs (number of SNPs <10), the logistic algorithm provided smaller average p-values (e.g., p = 7.54e - 17 when relative risk RR = 3.0) in all the scenarios and could capture signals that PennCNV did not (e.g., p = 0.020 when RR = 3.0). From a second set of simulations, we showed that the new algorithm is more powerful in detecting disease associations with small CNVs (number of SNPs ranging from 3 to 5) under different penetrance models (e.g., when RR = 3.0, for relatively weak signals, power = 0.8030 comparing to 0.2879 obtained from the association tests based on PennCNV calls). The new method was implemented in software GWCNV. It is freely available at http://gwcnv.sourceforge.net, distributed under a GPL license. CONCLUSIONS: We conclude that the new algorithm is more sensitive and can be more powerful in detecting CNV associations with diseases than the existing HMM algorithm, especially when the CNV association signal is weak and a limited number of SNPs are located in the CNV. PMID- 21827693 TI - Risk factors of post renal transplant anaemia among Sudanese patients, a study in three renal transplant centres. AB - BACKGROUND: There is a relative lack of recent information about late post kidney transplantation anaemia (PTA), especially in the developing countries; data are scarce about the prevalence and risk factors of PTA. Sudan was a leading country in Africa and Arab world in kidney transplantation. The first kidney transplantation in Sudan was in 1973. METHODS: This is a cross-sectional hospital analytic study enrolling all kidney transplanted recipients following in the transplant referral clinics at Ahmed Gassim, Selma and Ibn Sina Hospitals, Khartoum/Sudan, in the period from 1/8/2010 to 1/9/2010, clinical and laboratory data were obtained from 114 patients, anaemia was defined as Hb levels of < 13 g/dl for male patients and < 12 g/dl for female patients, exclusion criteria were pregnancy, below 18 years old patients, multiple organ transplantation, and patients with less than one year from the transplantation. RESULTS: The study showed that 39.5% of the patients were anaemic. Univariate analysis showed that late PTA is significantly associated with not using Erythropoietin (EPO) in the pre-transplant period (p = < 0.001), history of rejection (p = 0.003), longer time from transplantation (p = 0.015), and eGFR (p < 0.0001). Multivariate analysis showed that eGFR (p = < 0.001) and not use of EPO in the pre transplant period (p < 0.001) are strong predictors of PTA. The use of Angiotensin converting enzyme inhibitors/Angiotensin receptors blockers (ACEI/ARB), immunosuppressive treatments, presence or absence of co-morbidities, donor type and donor age are not significantly associated with late PTA. CONCLUSION: The study concluded that late PTA is common and under recognized. Risk factors for late PTA include renal dysfunction, history of rejection, longer duration of transplantation and not using EPO in the pre-transplant period. Renal dysfunction and not using EPO in the pre-transplant period are major predictors of late PTA. PMID- 21827694 TI - Use of a radiopaque localizer grid to reduce radiation exposure. AB - BACKGROUND: Minimally invasive spine surgery requires placement of the skin incision at an ideal location in the patient's back by the surgeon. However, numerous fluoroscopic x-ray images are sometimes required to find the site of entry, thereby exposing patients and Operating Room personnel to additional radiation. To minimize this exposure, a radiopaque localizer grid was devised to increase planning efficiency and reduce radiation exposure. RESULTS: The radiopaque localizer grid was utilized to plan the point of entry for minimally invasive spine surgery. Use of the grid allowed the surgeon to accurately pinpoint the ideal entry point for the procedure with just one or two fluoroscopic X-ray images. CONCLUSIONS: The reusable localizer grid is a simple and practical device that may be utilized to more efficiently plan an entry site on the skin, thus reducing radiation exposure. This device or a modified version may be utilized for any procedure involving the spine. PMID- 21827695 TI - Inhibition of telomerase activity preferentially targets aldehyde dehydrogenase positive cancer stem-like cells in lung cancer. AB - BACKGROUND: Mortality rates for advanced lung cancer have not declined for decades, even with the implementation of novel chemotherapeutic regimens or the use of tyrosine kinase inhibitors. Cancer Stem Cells (CSCs) are thought to be responsible for resistance to chemo/radiotherapy. Therefore, targeting CSCs with novel compounds may be an effective approach to reduce lung tumor growth and metastasis. We have isolated and characterized CSCs from non-small cell lung cancer (NSCLC) cell lines and measured their telomerase activity, telomere length, and sensitivity to the novel telomerase inhibitor MST312. RESULTS: The aldehyde dehydrogenase (ALDH) positive lung cancer cell fraction is enriched in markers of stemness and endowed with stem cell properties. ALDH+ CSCs display longer telomeres than the non-CSC population. Interestingly, MST312 has a strong antiproliferative effect on lung CSCs and induces p21, p27 and apoptosis in the whole tumor population. MST312 acts through activation of the ATM/pH2AX DNA damage pathway (short-term effect) and through decrease in telomere length (long term effect). Administration of this telomerase inhibitor (40 mg/kg) in the H460 xenograft model results in significant tumor shrinkage (70% reduction, compared to controls). Combination therapy consisting of irradiation (10Gy) plus administration of MST312 did not improve the therapeutic efficacy of the telomerase inhibitor alone. Treatment with MST312 reduces significantly the number of ALDH+ CSCs and their telomeric length in vivo. CONCLUSIONS: We conclude that antitelomeric therapy using MST312 mainly targets lung CSCs and may represent a novel approach for effective treatment of lung cancer. PMID- 21827696 TI - Study protocol: optimization of complex palliative care at home via telemedicine. A cluster randomized controlled trial. AB - BACKGROUND: Due to the growing number of elderly with advanced chronic conditions, healthcare services will come under increasing pressure. Teleconsultation is an innovative approach to deliver quality of care for palliative patients at home. Quantitative studies assessing the effect of teleconsultation on clinical outcomes are scarce. The aim of this present study is to investigate the effectiveness of teleconsultation in complex palliative homecare. METHODS/DESIGN: During a 2-year recruitment period, GPs are invited to participate in this cluster randomized controlled trial. When a GP refers an eligible patient for the study, the GP is randomized to the intervention group or the control group. Patients in the intervention group have a weekly teleconsultation with a nurse practitioner and/or a physician of the palliative consultation team. The nurse practitioner, in cooperation with the palliative care specialist of the palliative consultation team, advises the GP on treatment policy of the patient. The primary outcome of patient symptom burden is assessed at baseline and weekly using the Edmonton Symptom Assessment Scale (ESAS) and at baseline and every four weeks using the Hospital Anxiety and Depression Scale (HADS). Secondary outcomes are self-perceived burden from informal care (EDIZ), patient experienced continuity of medical care (NCQ), patient and caregiver satisfaction with the teleconsultation (PSQ), the experienced problems and needs in palliative care (PNPC-sv) and the number of hospital admissions. DISCUSSION: This is one of the first randomized controlled trials in palliative telecare. Our data will verify whether telemedicine positively affects palliative homecare. TRIAL REGISTRATION: The Netherlands National Trial Register NTR2817. PMID- 21827697 TI - Expanding the clinical spectrum associated with defects in CNTNAP2 and NRXN1. AB - BACKGROUND: Heterozygous copy-number and missense variants in CNTNAP2 and NRXN1 have repeatedly been associated with a wide spectrum of neuropsychiatric disorders such as developmental language and autism spectrum disorders, epilepsy and schizophrenia. Recently, homozygous or compound heterozygous defects in either gene were reported as causative for severe intellectual disability. METHODS: 99 patients with severe intellectual disability and resemblance to Pitt Hopkins syndrome and/or suspected recessive inheritance were screened for mutations in CNTNAP2 and NRXN1. Molecular karyotyping was performed in 45 patients. In 8 further patients with variable intellectual disability and heterozygous deletions in either CNTNAP2 or NRXN1, the remaining allele was sequenced. RESULTS: By molecular karyotyping and mutational screening of CNTNAP2 and NRXN1 in a group of severely intellectually disabled patients we identified a heterozygous deletion in NRXN1 in one patient and heterozygous splice-site, frameshift and stop mutations in CNTNAP2 in four patients, respectively. Neither in these patients nor in eight further patients with heterozygous deletions within NRXN1 or CNTNAP2 we could identify a defect on the second allele. One deletion in NRXN1 and one deletion in CNTNAP2 occurred de novo, in another family the deletion was also identified in the mother who had learning difficulties, and in all other tested families one parent was shown to be healthy carrier of the respective deletion or mutation. CONCLUSIONS: We report on patients with heterozygous defects in CNTNAP2 or NRXN1 associated with severe intellectual disability, which has only been reported for recessive defects before. These results expand the spectrum of phenotypic severity in patients with heterozygous defects in either gene. The large variability between severely affected patients and mildly affected or asymptomatic carrier parents might suggest the presence of a second hit, not necessarily located in the same gene. PMID- 21827698 TI - Willingness to work in rural areas and the role of intrinsic versus extrinsic professional motivations - a survey of medical students in Ghana. AB - BACKGROUND: Retaining health workers in rural areas is challenging for a number of reasons, ranging from personal preferences to difficult work conditions and low remuneration. This paper assesses the influence of intrinsic and extrinsic motivation on willingness to accept postings to deprived areas among medical students in Ghana. METHODS: A computer-based survey involving 302 fourth year medical students was conducted from May-August 2009. Logistic regression was used to assess the association between students' willingness to accept rural postings and their professional motivations, rural exposure and family parental professional and educational status (PPES). RESULTS: Over 85% of students were born in urban areas and 57% came from affluent backgrounds. Nearly two-thirds of students reported strong intrinsic motivation to study medicine. After controlling for demographic characteristics and rural exposure, motivational factors did not influence willingness to practice in rural areas. High family PPES was consistently associated with lower willingness to work in rural areas. CONCLUSIONS: Although most Ghanaian medical students are motivated to study medicine by the desire to help others, this does not translate into willingness to work in rural areas. Efforts should be made to build on intrinsic motivation during medical training and in designing rural postings, as well as favour lower PPES students for admission. PMID- 21827700 TI - Meningeal carcinomatosis diagnosed during stroke evaluation in the emergency department. AB - A 70-year-old female presented to the emergency department with a 3-day history of intermittent dysphasia and right facial droop. Computed tomography (CT) and magnetic resonance imaging (MRI) were obtained, and the patient was found to have meningeal carcinomatosis, also known as leptomeningeal metastases. Meningeal carcinomatosis is a rare metastatic complication of some solid tumors and hematopoietic neoplasms, and has a median survival rate of 2.4 months. The role of the emergency physician is to appropriately diagnose this condition, treat emergent side effects, provide symptomatic relief, and ensure multi-disciplinary management. PMID- 21827699 TI - Early evolution of the biotin-dependent carboxylase family. AB - BACKGROUND: Biotin-dependent carboxylases are a diverse family of carboxylating enzymes widespread in the three domains of life, and thus thought to be very ancient. This family includes enzymes that carboxylate acetyl-CoA, propionyl-CoA, methylcrotonyl-CoA, geranyl-CoA, acyl-CoA, pyruvate and urea. They share a common catalytic mechanism involving a biotin carboxylase domain, which fixes a CO2 molecule on a biotin carboxyl carrier peptide, and a carboxyl transferase domain, which transfers the CO2 moiety to the specific substrate of each enzyme. Despite this overall similarity, biotin-dependent carboxylases from the three domains of life carrying their reaction on different substrates adopt very diverse protein domain arrangements. This has made difficult the resolution of their evolutionary history up to now. RESULTS: Taking advantage of the availability of a large amount of genomic data, we have carried out phylogenomic analyses to get new insights on the ancient evolution of the biotin-dependent carboxylases. This allowed us to infer the set of enzymes present in the last common ancestor of each domain of life and in the last common ancestor of all living organisms (the cenancestor). Our results suggest that the last common archaeal ancestor had two biotin-dependent carboxylases, whereas the last common bacterial ancestor had three. One of these biotin-dependent carboxylases ancestral to Bacteria most likely belonged to a large family, the CoA-bearing-substrate carboxylases, that we define here according to protein domain composition and phylogenetic analysis. Eukaryotes most likely acquired their biotin-dependent carboxylases through the mitochondrial and plastid endosymbioses as well as from other unknown bacterial donors. Finally, phylogenetic analyses support previous suggestions about the existence of an ancient bifunctional biotin-protein ligase bound to a regulatory transcription factor. CONCLUSIONS: The most parsimonious scenario for the early evolution of the biotin-dependent carboxylases, supported by the study of protein domain composition and phylogenomic analyses, entails that the cenancestor possessed two different carboxylases able to carry out the specific carboxylation of pyruvate and the non-specific carboxylation of several CoA-bearing substrates, respectively. These enzymes may have been able to participate in very diverse metabolic pathways in the cenancestor, such as in ancestral versions of fatty acid biosynthesis, anaplerosis, gluconeogenesis and the autotrophic fixation of CO2. PMID- 21827701 TI - Iron and zinc content of selected foods in the diet of schoolchildren in Kumi district, east of Uganda: a cross-sectional study. AB - BACKGROUND: Iron and zinc are essential micronutrients for humans and deficiency of the two elements is widespread in the world with the highest prevalence in less developed countries. There are few data on dietary intake of iron and zinc in Uganda, and no food composition table is available. There is hardly any widely published literature that clearly documents the quality of Ugandan children's diet. Thus information of both food intake and the concentration of these trace elements in local food ingredients are needed in order to assess daily intake. METHODS: The present study focused on the iron and zinc content in selected foods and intake of the micronutrients iron and zinc among schoolchildren in Kumi District, Uganda. Over a period of 4 weeks single 24-hour dietary recall interviews were carried out on a convenience sample of 178 schoolchildren (9-15 years old). Data from the dietary recalls was used when selecting foods for chemical analysis. RESULTS: Results from this study showed that the iron concentrations varied, and were high in some cereals and vegetables. The zinc concentrations in foods generally corresponded with results from other African countries (Mali and Kenya). Data from the 24-hour dietary recall showed that the daily Recommended Nutrient Intake (RNI) was met for iron but not for zinc. CONCLUSIONS: The schoolchildren of Kumi district had a predominantly vegetable based diet. Foods of animal origin were consumed occasionally. The iron content in the selected foods was high and variable, and higher than in similar ingredients from Kenya and Mali, while the zinc concentrations were generally in accordance with reported values. The total daily zinc (mg) intake does not meet the daily RNI. The iron intake is adequate according to RNI, but due to iron contamination and reduced bioavailability, RNI may not be met in a vegetable based diet. More studies are needed to investigate possible sources of contamination. PMID- 21827702 TI - Expanding the molecular toolbox for Lactococcus lactis: construction of an inducible thioredoxin gene fusion expression system. AB - BACKGROUND: The development of the Nisin Inducible Controlled Expression (NICE) system in the food-grade bacterium Lactococcus lactis subsp. cremoris represents a cornerstone in the use of Gram-positive bacterial expression systems for biotechnological purposes. However, proteins that are subjected to such over expression in L. lactis may suffer from improper folding, inclusion body formation and/or protein degradation, thereby significantly reducing the yield of soluble target protein. Although such drawbacks are not specific to L. lactis, no molecular tools have been developed to prevent or circumvent these recurrent problems of protein expression in L. lactis. RESULTS: Mimicking thioredoxin gene fusion systems available for E. coli, two nisin-inducible expression vectors were constructed to over-produce various proteins in L. lactis as thioredoxin fusion proteins. In this study, we demonstrate that our novel L. lactis fusion partner expression vectors allow high-level expression of soluble heterologous proteins Tuc2009 ORF40, Bbr_0140 and Tuc2009 BppU/BppL that were previously insoluble or not expressed using existing L. lactis expression vectors. Over-expressed proteins were subsequently purified by Ni-TED affinity chromatography. Intact heterologous proteins were detected by immunoblotting analyses. We also show that the thioredoxin moiety of the purified fusion protein was specifically and efficiently cleaved off by enterokinase treatment. CONCLUSIONS: This study is the first description of a thioredoxin gene fusion expression system, purposely developed to circumvent problems associated with protein over-expression in L. lactis. It was shown to prevent protein insolubility and degradation, allowing sufficient production of soluble proteins for further structural and functional characterization. PMID- 21827703 TI - Validation of the Comprehensive Feeding Practices Questionnaire with parents of 10-to-12-year-olds. AB - BACKGROUND: There is a lack of validated instruments for quantifying feeding behavior among parents of older children and adolescents. The Comprehensive Feeding Practices Questionnaire (CFPQ) is a self-report measure to assess multiple parental feeding practices. The CFPQ is originally designed for use with parents of children ranging in age from about 2 to 8 years. It is previously validated with American and French parents of children within this age range. The aim of the present study was to adapt and test the validity of this measure with parents of older children (10-to-12-year-olds) in a Norwegian setting. METHODS: A sample of 963 parents of 10-to-12-year-olds completed a Norwegian, slightly adapted version of the CFPQ. Scale analyses were performed to test the validity of the instrument in our sample. RESULTS: Although a few problematic items and scales were revealed, scale analyses showed that the psychometric properties of the slightly adapted, Norwegian version of the CFPQ were surprisingly similar to those of the original CFPQ. CONCLUSIONS: Our results indicated that the CFPQ, with some small modifications, is a valid tool for measuring multiple parental feeding practices with parents of 10-to 12-year-olds. PMID- 21827704 TI - Randomized, double-blind, placebo-controlled clinical trial of sublingual immunotherapy in natural rubber latex allergic patients. AB - BACKGROUND: Natural rubber latex allergy is a common and unsolved health problem. Since the avoidance of exposure is very difficult, immunotherapy is strongly recommended, but before its use in patients, it is essential to prove the efficacy and safety of extracts.The aim of the present randomised, double-blind, placebo-controlled clinical trial was to assess the efficacy and tolerability of latex sublingual immunotherapy in adult patients undergoing permanent latex avoidance. METHODS: Twenty-eight adult latex-allergic patients (5 males and 23 females), with mean age of 39 years (range 24-57) were randomized to receive a commercial latex-sublingual immunotherapy or placebo during one year, followed by another year of open, active therapy. The following outcomes were measured at baseline and at the end of first and second year of follow-up: skin prick test, gloves-use score, conjunctival challenge test, total and specific IgE, basophil activation test, and adverse reactions monitoring. RESULTS: No significant difference in any of the efficacy in vivo variables was observed between active and placebo groups at the end of the placebo-controlled phase, nor when each group was compared with their baseline values at the end of the two year-study. An improvement in the average percentage of basophils activated was observed. During the induction phase, 4 reactions in the active group and 5 in the placebo group were recorded. During the maintenance phase, two patients dropped out due to pruritus and to acute dermatitis respectively. CONCLUSION: Further studies are needed to evaluate latex-sublingual immunotherapy, since efficacy could not be demonstrated in adult patients with avoidance of the allergen. TRIAL REGISTRATION NUMBER: ACTRN12611000543987. PMID- 21827705 TI - Classifying short genomic fragments from novel lineages using composition and homology. AB - BACKGROUND: The assignment of taxonomic attributions to DNA fragments recovered directly from the environment is a vital step in metagenomic data analysis. Assignments can be made using rank-specific classifiers, which assign reads to taxonomic labels from a predetermined level such as named species or strain, or rank-flexible classifiers, which choose an appropriate taxonomic rank for each sequence in a data set. The choice of rank typically depends on the optimal model for a given sequence and on the breadth of taxonomic groups seen in a set of close-to-optimal models. Homology-based (e.g., LCA) and composition-based (e.g., PhyloPythia, TACOA) rank-flexible classifiers have been proposed, but there is at present no hybrid approach that utilizes both homology and composition. RESULTS: We first develop a hybrid, rank-specific classifier based on BLAST and Naive Bayes (NB) that has comparable accuracy and a faster running time than the current best approach, PhymmBL. By substituting LCA for BLAST or allowing the inclusion of suboptimal NB models, we obtain a rank-flexible classifier. This hybrid classifier outperforms established rank-flexible approaches on simulated metagenomic fragments of length 200 bp to 1000 bp and is able to assign taxonomic attributions to a subset of sequences with few misclassifications. We then demonstrate the performance of different classifiers on an enhanced biological phosphorous removal metagenome, illustrating the advantages of rank-flexible classifiers when representative genomes are absent from the set of reference genomes. Application to a glacier ice metagenome demonstrates that similar taxonomic profiles are obtained across a set of classifiers which are increasingly conservative in their classification. CONCLUSIONS: Our NB-based classification scheme is faster than the current best composition-based algorithm, Phymm, while providing equally accurate predictions. The rank-flexible variant of NB, which we term epsilon-NB, is complementary to LCA and can be combined with it to yield conservative prediction sets of very high confidence. The simple parameterization of LCA and epsilon-NB allows for tuning of the balance between more predictions and increased precision, allowing the user to account for the sensitivity of downstream analyses to misclassified or unclassified sequences. PMID- 21827706 TI - Randomized trials of artemisinin-piperaquine, dihydroartemisinin-piperaquine phosphate and artemether-lumefantrine for the treatment of multi-drug resistant falciparum malaria in Cambodia-Thailand border area. AB - BACKGROUND: Drug resistance of falciparum malaria is a global problem. Sulphadoxine/pyrimethamine-resistant and mefloquine-resistant strains of falciparum malaria have spread in Southeast Asia at lightning speed in 1980s 1990s, and the Cambodia-Thailand border is one of the malaria epidemic areas with the most severe forms of multi-drug resistant falciparum malaria. METHODS: Artemisinin-piperaquine (AP), dihydroartemisinin-piperaquine phosphate (DHP) and artemether-lumefantrine (AL) were used to treat 110, 55 and 55 uncomplicated malaria patients, respectively. The total dosage for adults is 1,750 mg (four tablets, twice over 24 hours) of AP, 2,880 mg (eight tablets, four times over two days) of DHP, and 3,360 mg (24 tablets, six times over three days) of AL. The 28 day cure rate, parasite clearance time, fever clearance time, and drug tolerance of patients to the three drugs were compared. All of the above methods were consistent with the current national guidelines. RESULTS: The mean parasite clearance time was similar in all three groups (66.7 +/- 21.9 hrs, 65.6 +/- 27.3 hrs, 65.3 +/- 22.5 hrs in AP, DHP and AL groups, respectively), and there was no remarkable difference between them; the fever clearance time was also similar (31.6 +/- 17.7 hrs, 34.6 +/- 21.8 hrs and 36.9 +/- 15.4 hrs, respectively). After following up for 28-days, the cure rate was 95.1%(97/102), 98.2%(54/55) and 82.4%(42/51); and the recrudescence cases was 4.9%(5/102), 1.8%(1/55) and 17.6%(9/51), respectively. Therefore, the statistical data showed that 28-day cure rate in AP and DHP groups was superior to AL group obviously.The patients had good tolerance to all the three drugs, and some side effects (anoxia, nausea, vomiting, headache and dizziness) could be found in every group and they were self-limited; patients in control groups also had good tolerance to DHP and AL, there was no remarkable difference in the three groups. CONCLUSIONS: AP, DHP and AL all remained efficacious treatments for the treatment of falciparum malaria in Cambodia-Thailand border area. However, in this particular setting, the AP regimen turned out to be favourable in terms of efficacy and effectiveness, simplicity of administration, cost and compliance. TRIAL REGISTRATION: The trial was registered at Chinese Clinical Trial Register under identifier 2005L01041. PMID- 21827707 TI - The CpG island methylator phenotype may confer a survival benefit in patients with stage II or III colorectal carcinomas receiving fluoropyrimidine-based adjuvant chemotherapy. AB - BACKGROUND: Colorectal carcinoma (CRC) with CpG island methylator phenotype (CIMP) is recognized as a distinct subgroup of CRC, and CIMP status affects prognosis and response to chemotherapy. Identification of CIMP status in CRC is important for proper patient management. In Eastern countries, however, the clinicopathologic and molecular characteristics and prognosis of CRCs with CIMP are still unclear. METHODS: A total of 245 patients who underwent their first surgical resection for sporadic CRC were enrolled and CIMP status of the CRCs was determined using the quantitative MethyLight assay. The clinicopathologic and molecular characteristics were reviewed and compared according to CIMP status. In addition, the three-year recurrence-free survival (RFS) of 124 patients with stage II or stage III CRC was analyzed in order to assess the effectiveness of fluoropyrimidine-based adjuvant chemotherapy with respect to CIMP status. RESULTS: CIMP-high CRCs were identified in 34 cases (13.9%), and were significantly associated with proximal tumor location, poorly differentiated carcinoma, mucinous histology, and high frequencies of BRAF mutation, MGMT methylation, and MSI-high compared to CIMP-low/negative carcinomas. For patients with stage II or III CIMP-low/negative CRCs, no significant difference was found in RFS between those undergoing surgery alone and those receiving surgery with fluoropyrimidine-based adjuvant chemotherapy. However, for patients with CIMP high CRCs, patients undergoing surgery with fluoropyrimidine-based adjuvant chemotherapy (n = 17; three-year RFS: 100%) showed significantly better RFS than patients treated with surgery alone (n = 7; three-year RFS: 71.4%) (P = 0.022). CONCLUSIONS: Our results suggest that selected patients with CIMP-high CRC may benefit from fluoropyrimidine-based adjuvant chemotherapy with longer RFS. Further large scale-studies are required to confirm our results. PMID- 21827708 TI - Identification, analysis, and linkage mapping of expressed sequence tags from the Australian sheep blowfly. AB - BACKGROUND: The Australian sheep blowfly Lucilia cuprina (Wiedemann) (Diptera: Calliphoridae) is a destructive pest of the sheep, a model organism for insecticide resistance research, and a valuable tool for medical and forensic professionals. However, genomic information on L. cuprina is still sparse. RESULTS: We report here the construction of an embryonic and 2 larval cDNA libraries for L. cuprina. A total of 29,816 expressed sequence tags (ESTs) were obtained and assembled into 7,464 unique clusters. The sequence collection captures a great diversity of genes, including those related to insecticide resistance (e.g., 12 cytochrome P450s, 2 glutathione S transferases, and 6 esterases). Compared to Drosophila melanogaster, codon preference is different in 13 of the 18 amino acids encoded by redundant codons, reflecting the lower overall GC content in L. cuprina. In addition, we demonstrated that the ESTs could be converted into informative gene markers by capitalizing on the known gene structures in the model organism D. melanogaster. We successfully assigned 41 genes to their respective chromosomes in L. cuprina. The relative locations of these loci revealed high but incomplete chromosomal synteny between L. cuprina and D. melanogaster. CONCLUSIONS: Our results represent the first major transcriptomic undertaking in L. cuprina. These new genetic resources could be useful for the blowfly and insect research community. PMID- 21827710 TI - Seaweed intake and blood pressure levels in healthy pre-school Japanese children. AB - BACKGROUND: Few studies have examined whether dietary factors might affect blood pressure in children. We purposed to investigate whether seaweed intake is associated with blood pressure level among Japanese preschool children. METHODS: The design of the study was cross-sectional and it was conducted in autumn 2006. Subjects were healthy preschoolers aged 3-6 years in Aichi, Japan. Blood pressure and pulse were measured once by an automated sphygmomanometer, which uses oscillometric methods. Dietary data, including seaweed intake, were assessed using 3-day dietary records covering 2 consecutive weekdays and 1 weekend day. Of a total of 533 children, 459 (86.1 percent) agreed to be enrolled in our study. Finally, blood pressure measurement, complete dietary records and parent-reported height and weight were obtained for 223 boys and 194 girls. RESULTS: When we examined Spearman's correlation coefficients, seaweed intake was significantly negatively related to systolic blood pressure in girls (P = 0.008). In the one way analysis of covariance for blood pressure and pulse after adjustments for age and BMI, the boys with the lowest, middle and highest tertiles of seaweed intake had diastolic blood pressure readings of 62.8, 59.3 and 59.6 mmHg, respectively (P = 0.11, trend P = 0.038). Girls with higher seaweed intake had significantly lower systolic blood pressure readings (102.4, 99.2 and 96.9 mmHg for girls with the lowest, middle and highest tertiles of seaweed intake, respectively; P = 0.037, trend P = 0.030). CONCLUSION: Our study showed that seaweed intake was negatively related to diastolic blood pressure in boys and to systolic blood pressure in girls. This suggests that seaweed might have beneficial effects on blood pressure among children. PMID- 21827709 TI - Activation of protease activated receptor 1 increases the excitability of the dentate granule neurons of hippocampus. AB - Protease activated receptor-1 (PAR1) is expressed in multiple cell types in the CNS, with the most prominent expression in glial cells. PAR1 activation enhances excitatory synaptic transmission secondary to the release of glutamate from astrocytes following activation of astrocytically-expressed PAR1. In addition, PAR1 activation exacerbates neuronal damage in multiple in vivo models of brain injury in a manner that is dependent on NMDA receptors. In the hippocampal formation, PAR1 mRNA appears to be expressed by a subset of neurons, including granule cells in the dentate gyrus. In this study we investigate the role of PAR activation in controlling neuronal excitability of dentate granule cells. We confirm that PAR1 protein is expressed in neurons of the dentate cell body layer as well as in astrocytes throughout the dentate. Activation of PAR1 receptors by the selective peptide agonist TFLLR increased the intracellular Ca2+ concentration in a subset of acutely dissociated dentate neurons as well as non neuronal cells. Bath application of TFLLR in acute hippocampal slices depolarized the dentate gyrus, including the hilar region in wild type but not in the PAR1-/- mice. PAR1 activation increased the frequency of action potential generation in a subset of dentate granule neurons; cells in which PAR1 activation triggered action potentials showed a significant depolarization. The activation of PAR1 by thrombin increased the amplitude of NMDA receptor-mediated component of EPSPs. These data suggest that activation of PAR1 during normal function or pathological conditions, such as during ischemia or hemorrhage, can increase the excitability of dentate granule cells. PMID- 21827711 TI - Patients' perceptions of safety and quality of maternity clinical handover. AB - BACKGROUND: Maternity clinical handover serves to address the gaps in knowledge existing when transitions between individuals or groups of clinicians occur throughout the antenatal, intra-partum and postnatal period. There are limited published studies on maternity handover and a paucity of information about patients' perceptions of the same. This paper reports postnatal patients' perceptions of how maternity handover contributes to the quality and safety of maternity care. METHODS: This paper reports on a mixed-methods study consisting of qualitative interviews and quantitative medical record analysis. Thirty English-speaking postnatal patients who gave birth at an Australian tertiary maternity hospital participated in a semi-structured interview prior to discharge from hospital. Interview data were coded thematically using the constant comparative method and managed via NVivo software; this data set was supplemented by medical record data analysed using STATA. RESULTS: Almost half of the women were aware of a handover process. Clinician awareness of patient information was seen as evidence that handover had taken place and was seen as representing positive aspects of teamwork, care and communication by participants, all important factors in the perception of quality health care. Collaborative cross checking, including the use of cognitive artefacts such as hand held antenatal records and patient-authored birth plans, and the involvement of patients and their support people in handover were behaviours described by participants to be protective mechanisms that enhanced quality and safety of care. These human factors also facilitated team situational awareness (TSA), shared decision making and patient motivation in labour. CONCLUSIONS: This study illustrates that many patients are aware of handover processes. For some patients, evidence of handover, through clinician awareness of information, represented positive aspects of teamwork, care and communication. Cross-checking and cognitive artefacts were observed to support handover. Patient-authored birth plans were described by some to enhance the quality and safety of the handover by providing a 'voice' to the patient in this process. This was a novel and potentially important perspective. Future research involving patients and their support people in supporting and evaluating handover should be considered. PMID- 21827712 TI - Prognostic factors related to sequelae in childhood bacterial meningitis: data from a Greek meningitis registry. AB - BACKGROUND: Bacterial meningitis (BM) is a life-threatening disease, often related with serious complications and sequelae. Infants and children who survive bacterial meningitis often suffer neurological and other sequelae. METHODS: A total of 2,477 patients aged 1 month to 14 years old hospitalized in a Children's Hospital in Greece diagnosed with acute bacterial meningitis were collected through a Meningitis Registry, from 1974 to 2005. Clinical, laboratory and other parameters (sex, age, pathogen, duration of symptoms before and after admission) were evaluated through univariate and multivariate analysis with regard to sequelae. Analysis of acute complications were also studied but not included in the final model. RESULTS: The rate of acute complications (arthritis and/or subdural effusion) was estimated at 6.8% (152 out of 2,251 patients, 95%CI 5.8 7.9) while the rate of sequelae (severe hearing loss, ventriculitis, hydrocephalus or seizure disorder) among survivors was estimated at 3.3% (73 out of 2,207 patients, 95%CI 2.6-4.2). Risk factors on admission associated with sequelae included seizures, absence of hemorrhagic rash, low CSF glucose, high CSF protein and the etiology of meningitis. A combination of significant prognostic factors including presence of seizures, low CSF glucose, high CSF protein, positive blood culture and absence of petechiae on admission presented an absolute risk of sequelae of 41.7% (95%CI 15.2-72.3). CONCLUSIONS: A combination of prognostic factors of sequelae in childhood BM may be of value in selecting patients for more intensive therapy and in identifying possible candidates for new treatment strategies. PMID- 21827714 TI - Identification of candidate genes linking systemic inflammation to atherosclerosis; results of a human in vivo LPS infusion study. AB - BACKGROUND: It is widely accepted that atherosclerosis and inflammation are intimately linked. Monocytes play a key role in both of these processes and we hypothesized that activation of inflammatory pathways in monocytes would lead to, among others, proatherogenic changes in the monocyte transcriptome. Such differentially expressed genes in circulating monocytes would be strong candidates for further investigation in disease association studies. METHODS: Endotoxin, lipopolysaccharide (LPS), or saline control was infused in healthy volunteers. Monocyte RNA was isolated, processed and hybridized to Hver 2.1.1 spotted cDNA microarrays. Differential expression of key genes was confirmed by RT-PCR and results were compared to in vitro data obtained by our group to identify candidate genes. RESULTS: All subjects who received LPS experienced the anticipated clinical response indicating successful stimulation. One hour after LPS infusion, 11 genes were identified as being differentially expressed; 1 down regulated and 10 up regulated. Four hours after LPS infusion, 28 genes were identified as being differentially expressed; 3 being down regulated and 25 up regulated. No genes were significantly differentially expressed following saline infusion. Comparison with results obtained in in vitro experiments lead to the identification of 6 strong candidate genes (BATF, BID, C3aR1, IL1RN, SEC61B and SLC43A3) CONCLUSION: In vivo endotoxin exposure of healthy individuals resulted in the identification of several candidate genes through which systemic inflammation links to atherosclerosis. PMID- 21827713 TI - Comparative effect of olmesartan and candesartan on lipid metabolism and renal function in patients with hypertension: a retrospective observational study. AB - BACKGROUND: Angiotensin II receptor blockers (ARBs), including olmesartan and candesartan, are widely used antihypertensive agents. Many clinical studies have demonstrated that ARBs have organ-protecting effects, e.g., cardioprotection, vasculoprotection and renoprotection. However, the effect of prolonged olmesartan monotherapy on lipid metabolism in patients with hypertension is less well studied. We performed a retrospective observational study to compare the effects of olmesartan with those of candesartan, focusing on lipid metabolism and renal function. METHODS: We used data from the Clinical Data Warehouse of Nihon University School of Medicine obtained between Nov 1, 2004 and Feb 28, 2011, to identify cohorts of new olmesartan users (n = 168) and candesartan users (n = 266). We used propensity-score weighting to adjust for differences in all covariates (age, sex, comorbid diseases, previous drugs) between olmesartan and candesartan users, and compared serum chemical data including serum triglyceride (TG), LDL-cholesterol (LDL-C), total cholesterol (TC), potassium, creatinine and urea nitrogen. The mean exposure of olmesartan and candesartan users was 126.1 and 122.8 days, respectively. RESULTS: After adjustment, there were no statistically significant differences in all covariates between olmesartan and candesartan users. The mean age was 60.7 and 61.0 years, and 33.4% and 33.7% of olmesartan and candesartan users were women, respectively. There were no statistically significant differences in mean values for all laboratory tests between baseline and during the exposure period in both olmesartan and candesartan users. In olmesartan users, the reduction of serum TG level was significant in comparison with that in candesartan users. Other parameters of lipid profile and renal function showed no statistically significant difference in the change from baseline to during the exposure period between olmesartan and candesartan users. CONCLUSIONS: In this study, we observed a more beneficial effect on lipid metabolism, a reduction of serum TG, with olmesartan monotherapy than with candesartan monotherapy. However, there were no clinically significant changes in the levels of all test parameters between baseline and during the exposure period with both drugs. These results suggest that the influence of olmesartan or candesartan monotherapy on lipid metabolism and renal function is small, and that they can be safely used in patients with hypertension. PMID- 21827715 TI - Comparison of human glomerulus proteomic profiles obtained from low quantities of samples by different mass spectrometry with the comprehensive database. AB - BACKGROUND: We have previously constructed an in-depth human glomerulus proteome database from a large amount of sample for understanding renal disease pathogenesis and aiding the biomarker exploration. However, it is usually a challenge for clinical research to get enough tissues for large-scale proteomic characterization. Therefore, in this study, we focused on high-confidence proteomics analysis on small amounts of human glomeruli comparable to those obtained from biopsies using different mass spectrometers and compared these results to the comprehensive database. RESULTS: One microgram of human glomerular protein digest was analyzed each on five LC- combined mass spectrometers (LIT TOF, LTQ-Orbitrap, Q-TOF, LIT and MALDI-TOF/TOF) yielding 139, 185, 94, 255 and 108 proteins respectively identified with strict criteria to ensure high confidence (> 99%) and low false discovery rate (FDR) (< 1%). An integrated profile of 332 distinct glomerular proteins was subsequently generated without discerned bias due to protein physicochemical properties (pI and MW), of which around 60% were detected commonly by more than two LC-MS/MS platforms. Comparative analysis with the comprehensive database demonstrated 14 proteins uniquely identified in this study and more than 70% of identified proteins in small datasets were concentrated to the top abundant 500 in the comprehensive database which consists of 2775 non-redundant proteins. CONCLUSION: This study showed representative human glomerulus proteomic profiles obtained from biopsies through analysis of comparable amounts of samples by different mass spectrometry. Our results implicated that high abundant proteins are more likely to be reproducibly identified in multiple mass spectrometers runs and different mass spectrometers. Furthermore, many podocyte essential proteins such as nephrin, podocin, podocalyxin and synaptopodin were also identified from the small samples in this study. Bioinformatic enrichment analysis results extended our understanding of the major glomerular proteins about their subcellular distributions and functions. The present study indicated that the proteins localized in certain cellular compartments, such as actin cytoskeleton, mitochondrial matrix, cell surface, basolateral plasma membrane, contractile fiber, proteinaceous extracellular matrix and adherens junction, represent high abundant glomerular proteins and these subcellular structures are also highly significantly over-represented in the glomerulus compared to the whole human background. PMID- 21827716 TI - Prepregnancy obesity and the risk of gestational diabetes mellitus. AB - BACKGROUND: Prepregnancy obesity is associated with increased risk for adverse pregnancy outcome such as gestational diabetes mellitus (GDM), gestational hypertension, preeclampsia, fetal macrosomia and the need for cesarean delivery. The objectives of this study assessed whether Thai women classified as obese according to WHO's recommended body mass index (BMI) for Asians were at risk for developing gestational diabetes mellitus (GDM) and other complications such as preeclampsia, gestational hypertension and fetal macrosomia. METHODS: Two hundred and forty women participated in this study and followed prospectively until delivery. Half of the women (n = 120) were obese (BMI >= 27.5 kg/m2) and the other half (n = 120) had normal weight (BMI > 18.5-23 kg/m2). Maternal demographic data, obstetric and neonatal outcomes from both groups were compared to each other. Relative risk and 95% confidence interval (CI) were calculated. RESULTS: Compared to normal weight women, obese Thai women were not at increased risk for gestational diabetes mellitus (RR = 0.9 [95% CI 0.6-1.4]). Relative risk of preeclampsia and fetal macrosomia in obese women were 0.7 [95% CI 0.2-3.3] and 1.4 [95% CI 0.5-4.3], respectively. Relative risk of gestational hypertension in obese women was 12 [95% CI 1.6-90.8]. CONCLUSION: When WHO's classification of obesity was used for Asian populations, prepregnancy obesity without metabolic problems did not increase the risk for GDM, preeclampsia and fetal macrosomia in Thai women. But, prepregnancy obesity continued to increase the risk for developing gestational hypertension. PMID- 21827717 TI - Dicer and miRNA in relation to clinicopathological variables in colorectal cancer patients. AB - BACKGROUND: Dicer is aberrantly expressed in several types of cancers. Applying real-time PCR, we detected the expression of Dicer mRNA in normal mucosa (n = 162), primary colorectal cancer (CRC) (n = 162) and liver metastasis (n = 37), and analysed the relationship between Dicer expression and clinicopathological features. We also correlated the expression of Dicer mRNA to the miRNA expression of miR-141, miR-200a, miR-200b, mir-200c and miR-429 in liver metastases. METHODS: RT-PCR and qPCR were used to analyse the Dicer expression in normal mucosa, primary tumour and liver metastasis by using the High Capacity cDNA Reverse Transcription Kit and TaqManTM(r) Gene Expression assays for Dicer and GAPDH. RT-PCR and qPCR were used to detect miRNA expression in liver metastases by utilizing TaqMan(r) MicroRNA Reverse Transcription Kit and TaqMan(r) miRNA Assays. Statistical analyses were performed with STATISTICA. RESULTS: Dicer expression in rectal cancer (3.146 +/- 0.953) was higher than in colon cancer (2.703 +/- 1.204, P = 0.018). Furthermore the Dicer expression was increased in primary tumours (3.146 +/- 0.952) in comparison to that in normal mucosa from rectal cancer patients (2.816 +/- 1.009, P = 0.034) but this is not evident in colon cancer patients. Dicer expression in liver metastases was decreased in comparison to that of either normal mucosa or primary tumour in both colon and rectal cancers (P < 0.05). Patients with a high Dicer expression in normal mucosa had a worse prognosis compared to those with a low Dicer expression, independently of gender, age, tumour site, stage and differentiation (P < 0.001, RR 3.682, 95% CI 1.749 - 7.750). In liver metastases, Dicer was positively related to miR-141 (R = 0.419, P = 0.015). CONCLUSION: Dicer is up-regulated in the early development of rectal cancers. An increased expression of Dicer mRNA in normal mucosa from CRC patients is significantly related to poor survival independently of gender, age, tumour site, stage and differentiation. PMID- 21827718 TI - IPNV with high and low virulence: host immune responses and viral mutations during infection. AB - BACKGROUND: Infectious pancreatic necrosis virus (IPNV) is an aquatic member of the Birnaviridae family that causes widespread disease in salmonids. IPNV is represented by multiple strains with markedly different virulence. Comparison of isolates reveals hyper variable regions (HVR), which are presumably associated with pathogenicity. However little is known about the rates and modes of sequence divergence and molecular mechanisms that determine virulence. Also how the host response may influence IPNV virulence is poorly described. METHODS: In this study we compared two field isolates of IPNV (NFH-Ar and NFH-El). The sequence changes, replication and mortality were assessed following experimental challenge of Atlantic salmon. Gene expression analyses with qPCR and microarray were applied to examine the immune responses in head kidney. RESULTS: Significant differences in mortality were observed between the two isolates, and viral load in the pancreas at 13 days post infection (d p.i.) was more than 4 orders of magnitude greater for NFH-Ar in comparison with NFH-El. Sequence comparison of five viral genes from the IPNV isolates revealed different mutation rates and Ka/Ks ratios. A strong tendency towards non-synonymous mutations was found in the HRV of VP2 and in VP3. All mutations in VP5 produced precocious stop codons. Prior to the challenge, NFH-Ar and NFH-El possessed high and low virulence motifs in VP2, respectively. Nucleotide substitutions were noticed already during passage of viruses in CHSE-214 cells and their accumulation continued in the challenged fish. The sequence changes were notably directed towards low virulence. Co ordinated activation of anti-viral genes with diverse functions (IFN-a1 and c, sensors - Rig-I, MDA-5, TLR8 and 9, signal transducers - Srk2, MyD88, effectors - Mx, galectin 9, galectin binding protein, antigen presentation - b2 microglobulin) was observed at 13 d p.i. (NFH-Ar) and 29 d p.i. (both isolates). CONCLUSIONS: Mortality and expression levels of the immune genes were directly related to the rate of viral replication, which was in turn associated with sequences of viral genes. Rapid changes in the viral genome that dramatically reduced virus proliferation might indicate a higher susceptibility to protective mechanism employed by the host. Disease outbreak and mortality depend on a delicate balance between host defence, regulation of signalling cascades and virus genomic properties. PMID- 21827719 TI - Neurological abnormalities and neurocognitive functions in healthy elder people: a structural equation modeling analysis. AB - BACKGROUND/AIMS: Neurological abnormalities have been reported in normal aging population. However, most of them were limited to extrapyramidal signs and soft signs such as motor coordination and sensory integration have received much less attention. Very little is known about the relationship between neurological soft signs and neurocognitive function in healthy elder people. The current study aimed to examine the underlying relationships between neurological soft signs and neurocognition in a group of healthy elderly. METHODS: One hundred and eighty healthy elderly participated in the current study. Neurological soft signs were evaluated with the subscales of Cambridge Neurological Inventory. A set of neurocognitive tests was also administered to all the participants. Structural equation modeling was adopted to examine the underlying relationship between neurological soft signs and neurocognition. RESULTS: No significant differences were found between the male and female elder people in neurocognitive function performances and neurological soft signs. The model fitted well in the elderly and indicated the moderate associations between neurological soft signs and neurocognition, specifically verbal memory, visual memory and working memory. CONCLUSIONS: The neurological soft signs are more or less statistically equivalent to capture the similar information done by conventional neurocognitive function tests in the elderly. The implication of these findings may serve as a potential neurological marker for the early detection of pathological aging diseases or related mental status such as mild cognitive impairment and Alzheimer's disease. PMID- 21827720 TI - Improved prenatal detection of chromosomal anomalies. AB - INTRODUCTION: Prenatal screening for karyotype anomalies takes place in most European countries. In Denmark, the screening method was changed in 2005. The aim of this study was to study the trends in prevalence and prenatal detection rates of chromosome anomalies and Down syndrome (DS) over a 22-year period. MATERIAL AND METHODS: The study was based on data collected from the EUROCAT registry of congenital anomalies for Funen County. The registry includes information about live births, foetal deaths with a gestational age > 20 weeks and terminations of pregnancy after prenatal diagnosis of foetal anomaly (TOPFA). The study includes all foetuses/infants diagnosed with a chromosome anomaly born between 1986 and 2007 of a mother residing in Funen County. RESULTS: A total of 431 foetuses/infants had a chromosome anomaly corresponding to an overall prevalence of 35.6 chromosome anomalies per 10,000 births. This figure remained constant during the study period. Two hundred and three cases were live births (47% of total), 26 foetal deaths (6%) and 202 TOPFAs (47%). The prenatal detection rate for chromosome anomalies increased from 27% in the 1980s to 71% in the new millennium (p < 0.001). There were 235 cases with DS (55% of total cases), which yields an overall prevalence of 19 DS cases per 10,000 births. CONCLUSION: The prevalence of all chromosomal anomalies and DS did not change over time. The prenatal DS detection rate more than doubled from 1986-1989 to 2000-2007. The number of TOPFAs increased, which is consistent with a decrease in the number of live births with DS as well as in all chromosomal anomalies. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 21827721 TI - A medical admission unit reduces duration of hospital stay and number of readmissions. AB - INTRODUCTION: Political initiatives promoting a more efficient emergency admission process have triggered a reorganisation of the Danish health system with a view to creating fewer and larger admission units counting more experienced physicians. At our hospital, a medical admission unit (MAU) was established. We present the effect of this on the length of hospital stay, mortality rates and the number of readmissions for the last year with the previous structure and the first year of the new MAU structure. MATERIAL AND METHODS: We retrospectively extracted data from the hospital databases on two periods: one year before and the first year after establishment of the MAU. RESULTS: After establishment of the MAU, the overall average length of hospital stay was reduced from 4.1 to 3.8 days (p < 0.01). No increase in mortality either in-house or within 30 days after discharge was seen. A substantial reduction (26%) in the overall number of readmissions within 30 days after discharge was observed. CONCLUSION: The establishment of the MAU improved efficacy at the hospital owing to reduction in the length of hospital stay and the number of readmissions. As judged from mortality rates and indicated by readmission rates, neither the quality of treatment nor patient safety was compromised in a setup, where patients with suspected cardiac diseases are admitted along with patients suspected to suffer from other internal medical diseases. The dynamics between multidisciplinary physicians and nurses seems to improve when they are working close to each other in a setting where team spirit evolves. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 21827722 TI - Collaborative assessment and management of suicidality method shows effect. AB - INTRODUCTION: Previous studies confirm the effect of collaborative assessment and management of suicidality (CAMS) in an experimental setup, but there is a need to test CAMS with regard to its effectiveness and feasibility in a real-life clinical context. The purpose of this study was to investigate CAMS in a Danish population in such a context. MATERIAL AND METHODS: In the present descriptive study, CAMS treatment was administered to a total of 42 patients referred during 1 August 2008 to 30 September 2009 to The Centre of Excellence in Suicide Prevention due to suicidal thoughts or a suicide attempt. Qualitative and quantitative data were obtained before and after CAMS treatment. Five major suicidal markers were regularly assessed. The patients' experiences of the importance of the treatment were studied as endpoints. RESULTS: A total of 81% of the patients completed treatment and 68% hereof completed the final evaluation. 74% from this group judged the sessions to be the main factor in the elimination of their suicidality. A significant decrease was observed in the five suicidal markers recorded for the 42 patients included. One patient attempted suicide and another patient committed suicide. CONCLUSION: CAMS was assessed to be effective and useful in a real-life clinical context. Further studies in larger patient populations are needed as are studies to determine whether the CAMS method may be applied with equal effect to all patient groups. FUNDING: not relevant. TRIAL REGISTRATION: Danish Data Protection Agency. PMID- 21827723 TI - Glycaemic control in diabetic patients during hospital admission is not optimal. AB - INTRODUCTION: The aim of this pilot study was to evaluate glycaemic control in diabetic patients admitted to hospital. MATERIAL AND METHODS: Patients were prospectively identified at 11 consecutive Wednesdays in one medical and one surgery department and information from the previous three days of admission was collected, including: bedside p-glucose readings, scheduled and supplemental insulin treatment. RESULTS: In total, 111 observation days were included from 37 diabetic patients (27 medical and ten surgical). P-glucose was measured on average four and 2.5 times daily at the medical and the surgery department, respectively. The median p-glucose level was 8.6 mmol/l (range 4.0-22), with no obvious difference between the two departments and no trend towards improvement observed. Approximately one third of the patients had median p-glucose values > 10 mmol/l. 7% of the patients at the medical and none at the surgery department had a p-glucose < 3 mmol/l. Supplemental insulin was prescribed to the majority of patients at the medical department and to 30% at the surgery department with a median p-glucose threshold of 12 and 14 mmol/l at the two departments, respectively. Supplemental insulin was not given despite being indicated in 37% of the elevated glucose episodes. Increments in scheduled insulin dose were rarely observed despite being indicated. CONCLUSION: Despite acceptable median p glucose levels, hyperglycaemia was frequent. The number of glucose readings was low and clinical inertia was observed, both with regard to intensification the scheduled insulin and with regard to administration of supplemental insulin. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 21827724 TI - Drug-related death in Denmark in 2007. AB - INTRODUCTION: We investigated fatal poisonings among drug addicts in 2007. The cause of death, abuse pattern and geographic differences are presented. MATERIAL AND METHODS: All drug-related deaths examined at the three forensic medicine institutes in Denmark in 2007 were evaluated. RESULTS: The number of drug-related deaths in 2007 was 226. Methadone deaths had increased since 1997 while heroin/morphine deaths decreased. In earlier studies, very few deaths from central stimulants like cocaine and amphetamines occurred (1-1.5%), but in 2007 6% of the deaths were caused by these drugs. Multiple drug use was common. Heroin/morphine, cocaine, amphetamine, cannabis, methadone, benzodiazepines and alcohol were included in the poly-drug use. CONCLUSION: This investigation shows stabilization in the number of fatal poisonings in drug addicts. Geographic differences were observed. Methadone was the most frequent cause of fatal poisoning and there was a continuous decrease in heroin/morphine deaths. Fatal deaths from cocaine and amphetamine have increased considerably. Multiple drug use was common. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 21827725 TI - Cardiovascular morbidity and mortality in diabetes mellitus: prediction and prognosis. PMID- 21827726 TI - On the use of abciximab in percutaneous coronary intervention. PMID- 21827727 TI - Uncertainties in target definition for radiotherapy of peripheral lung tumours. PMID- 21827728 TI - The Danish longitudinal study of alcoholism 1978-2008. A clinical high-risk study. PMID- 21827729 TI - Demostration of multivessel coronary dissection with multislice computed tomography. PMID- 21827730 TI - Telaprevir with peginterferon and ribavirin for treatment-naive patients chronically infected with HCV of genotype 1 in Japan. AB - BACKGROUND & AIMS: To evaluate the efficacy and safety of telaprevir in combination with peginterferon-alpha2b (PEG-IFN) and ribavirin (RBV) in patients with chronic hepatitis C. METHODS: In a multi-center randomized clinical trial in Japan, on patients infected with HCV of genotype 1, 126 patients were assigned to telaprevir for 12 weeks along with PEG-IFN and RBV for 24 weeks (Group A), while 63 to PEG-IFN and RBV for 48 weeks (Group B). RESULTS: HCV RNA disappeared more swiftly in patients in Group A than B, and the frequency of patients without detectable HCV RNA at week 4 (rapid virological response (RVR)) was higher in Group A than B (84.0% vs. 4.8%, p <0.0001). Grade 3 and 4 skin disorders, including Stevens-Johnson syndrome and drug rashes with eosinophilia and systemic symptoms, as well as Grade 3 anemia (<8.0 g/dl), occurred more frequently in Group A than B (skin disorders, 11.9% vs. 4.8%; anemia, 11.1% vs. 0.0%). The total RBV dose was smaller in Group A than B (47.0% vs. 77.7% of the target, p <0.0001). Despite these drawbacks, sustained virological response (SVR) was achieved more frequently in Group A than B (73.0% vs. 49.2%, p=0.0020). CONCLUSIONS: Although the triple therapy with telaprevir-based regimen for 24 weeks resulted in more adverse events and less total RBV dose than PEG-IFN and RBV for 48 weeks, it was able to achieve higher SVR within shorter duration by carefully monitoring adverse events and modifying the RBV dose as required. PMID- 21827731 TI - SRC-3 is required for CAR-regulated hepatocyte proliferation and drug metabolism. AB - BACKGROUND & AIMS: Nuclear receptors such as pregnane X receptor and constitutive androstane receptor (CAR) are important regulators of drug-metabolizing systems such as P450 enzymes and modulate xenobiotic metabolism as well as hepatocellular proliferation. Binding of CAR to NR response elements alone is not sufficient to activate gene expression. Here, we investigate the role of steroid receptor co activator (SRC) family members in CAR-mediated hepatocyte proliferation and drug metabolism. METHODS: The role of SRCs in CAR activation was assessed in cell based transfection assays and protein-protein interaction assays. The in vivo role of SRCs in CAR-mediated hepatocyte proliferation and drug metabolism was examined by using mice deficient in SRCs. RESULTS: SRC-3 displayed the highest co activating activity to CAR compared with SRC-1 and SRC-2 in a cell-based reporter assay. Knockout of SRC-3 in mice attenuated hepatic hyperplasia induced by a CAR agonist 1,4-bis-[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP), which was associated with a reduced expression of c-Myc and Foxm-1. In contrast, knockout of SRC-1 or SRC-2 in mice did not affect TCPOBOP-induced hepatic hyperplasia. SRC 3-deficient mice were hypersensitive to zoxazolamine-induced paralysis, but were resistant to acetaminophen hepatotoxicity induced by TCPOBOP, whereas mutant mice deficient in SRC-1 or SRC-2 exhibited severe acetaminophen hepatotoxicity similar to wild-type controls. Accordingly, deficiency in SRC-3, but not SRC-1 or SRC-2, resulted in a reduced CAR-mediated expression of drug metabolism-related genes in the liver. CONCLUSIONS: Our study demonstrates that SRC-3 is the predominant transcriptional co-activator among the three SRC family members for CAR activation to promote hepatocyte proliferation and drug metabolism. PMID- 21827732 TI - Ligand-dependent corepressor acts as a novel corepressor of thyroid hormone receptor and represses hepatic lipogenesis in mice. AB - BACKGROUND & AIMS: Transcriptional co-regulators assist nuclear receptors to control the transcription and maintain the metabolic homeostasis. Ligand dependent corepressor (LCOR) was reported to function as a transcriptional corepressor in vitro. We found LCOR expression decreased in fatty livers of leptin-deficient (ob/ob) mice, diet-induced obese mice, as well as patients, suggesting LCOR may play a role in lipid homeostasis. We sought to investigate the physiological role of LCOR in vivo and elucidate the underlining molecular mechanisms. METHODS: The effect of LCOR on hepatic lipid accumulation and thyroid hormone receptor (TR) mediated expression of lipogenic genes was studied in vitro and in vivo. RESULTS: Ectopic expression of LCOR via intravenous infection with LCOR adenovirus decreased the hepatic triglyceride level in wild type, ob/ob, and diet-induced obese mice. Interestingly, overexpression of LCOR repressed the thyroid hormone induced expression of lipogenic genes and non-lipogenic genes, and ameliorated hepatic steatosis in obese mice, suggesting that LCOR might regulate lipogenesis as a novel TR corepressor. Furthermore, our study revealed that LCOR could interact with TRbeta1 in the presence of the ligand, which resulted in competitive binding and reduced recruitment of steroid receptor coactivator-1/3 (SRC-1/3) to the promoter region of TR target genes. CONCLUSIONS: Our data suggest that LCOR is likely to suppress TRbeta1-mediated hepatic lipogenesis by decreasing binding and recruitment of SRCs to TRbeta1. Our study reveals the physiological function of hepatic LCOR in lipid metabolism and the mechanism by which LCOR regulates lipogenesis. Hepatic LCOR may be a potential target for treating hepatic steatosis. PMID- 21827733 TI - Assessment of portal hypertension by transient elastography in patients with compensated cirrhosis and potentially resectable liver tumors. AB - BACKGROUND & AIMS: Patients with cirrhosis and small hepatocellular carcinoma with normal bilirubin and hepatic venous pressure gradient (HVPG) <10 mm Hg have >70% 5-year survival after hepatic resection. On the contrary, patients with HVPG >=10 mm Hg (clinically significant portal hypertension, CSPH) frequently develop decompensation following surgery, with around 50% 5-year survival. Liver stiffness (LS) evaluation by transient elastography might non-invasively identify CSPH. We investigated the usefulness of LS predicting CSPH in patients with compensated cirrhosis and potentially resectable liver tumors. METHODS: Ninety seven consecutive Child-Pugh A patients with potentially resectable liver tumors referred for HVPG measurement were prospectively evaluated. In fasting conditions LS was measured before the hemodynamic study. RESULTS: HVPG could be measured in all patients, whereas LS could not be measured in 18 (18.5%) obese patients. In the 79 patients with valid LS, 32 (40.5%) had CSPH; mean HVPG was 8.8+/-4.7 mm Hg. Mean LS was 18.4+/-12.3 kPa. LS showed a moderate correlation with HVPG (r=0.552; p<0.001). LS<13.6 kPa had high sensitivity (91%) but low specificity (57%) excluding CSPH. Conversely, LS>21 kPa had low sensitivity (53%) and high specificity (91%) predicting CSPH. 35% of patients had LS between 13.6 and 21 kPa ("grey zone"). CONCLUSIONS: These data suggest that in real-life scenarios half of patients with potentially resectable liver nodules can be non-invasively classified as having or not CSPH by LS. However, in the remaining half, LS is either not applicable or inaccurate. In this last population HVPG is still a non replaceable method to detect CSPH. PMID- 21827734 TI - Nucleotide change of codon 182 in the surface gene of hepatitis B virus genotype C leading to truncated surface protein is associated with progression of liver diseases. AB - BACKGROUND & AIMS: Hepatitis B virus (HBV) genotype C infection is associated with progression of hepatocellular carcinoma (HCC). Specific mutations of the HBV surface (S) gene have been reported to contribute to the development of HCC. In this study, novel nucleotide changes (sW182*) that result in a premature stop at codon 182 in the S gene of genotype C are investigated with regards to the development of HCC. METHODS: A multi-probe real time PCR that enables rapid and reliable detection of sW182* was developed and applied to 292 DNA samples from Korean patients with diverse chronic liver diseases. RESULTS: sW182* was detected in a total of 73 patients out of the 275 with positive amplification (26.5%). Its prevalence was significantly higher in patients with progressive forms of the disease (HCC and liver cirrhosis) than in patients with less severe forms of the disease (chronic hepatitis and carrier) [31.8% (56/176 patients) vs. 17.2% (17/99 patients); p=0.010]. In addition, an in vitro study using cell lines stable expressing the S protein with sW182* also strongly supported its relationship with HCC. CONCLUSIONS: In the present study, we demonstrate that the sW182* of HBV could provide an important contribution to the progression of liver diseases, through molecular epidemiologic and in vitro studies. PMID- 21827735 TI - Sensitive fluorogenic substrate for alkaline phosphatase. AB - Alkaline phosphatase serves both as a model enzyme for studies on the mechanism and kinetics of phosphomonoesterases and as a reporter in enzyme-linked immunosorbent assays (ELISAs) and other biochemical methods. The tight binding of the enzyme to its inorganic phosphate product leads to strong inhibition of catalysis and confounds measurements of alkaline phosphatase activity. We have developed an alkaline phosphatase substrate in which the fluorescence of rhodamine is triggered on P-O bond cleavage in a process mediated by a "trimethyl lock." Although this substrate requires a nonenzymatic second step to manifest fluorescence, we demonstrated that the enzymatic first step limits the rate of fluorogenesis. The substrate enables the catalytic activity of alkaline phosphatase to be measured with high sensitivity and accuracy. Its attributes are ideal for enzymatic assays of alkaline phosphatase for both basic research and biotechnological applications. PMID- 21827736 TI - Transmembrane helix-helix interactions are modulated by the sequence context and by lipid bilayer properties. AB - Folding of polytopic transmembrane proteins involves interactions of individual transmembrane helices, and multiple TM helix-helix interactions need to be controlled and aligned to result in the final TM protein structure. While defined interaction motifs, such as the GxxxG motif, might be critically involved in transmembrane helix-helix interactions, the sequence context as well as lipid bilayer properties significantly modulate the strength of a sequence specific transmembrane helix-helix interaction. Structures of 11 transmembrane helix dimers have been described today, and the influence of the sequence context as well as of the detergent and lipid environment on a sequence specific dimerization is discussed in light of the available structural information. This article is part of a Special Issue entitled: Protein Folding in Membranes. PMID- 21827737 TI - Plasmalemmal vesicle associated protein (PV1) modulates SV40 virus infectivity in CV-1 cells. AB - Plasmalemmal vesicle associated protein (Plvap/PV1) is a structural protein required for the formation of the stomatal diaphragms of caveolae. Caveolae are plasma membrane invaginations that were implicated in SV40 virus entry in primate cells. Here we show that de novo Plvap/PV1 expression in CV-1 green monkey epithelial cells significantly reduces the ability of SV40 virus to establish productive infection, when cells are incubated with low concentrations of the virus. However, in presence of high viral titers PV1 has no effect on SV40 virus infectivity. Mechanistically, PV1 expression does not reduce the cell surface expression of known SV40 receptors such as GM1 ganglioside and MHC class I proteins. Furthermore, PV1 does not reduce the binding of virus-like particles made by SV40 VP1 protein to the CV-1 cell surface and does not impact their internalization when cells are incubated with either high or low VLP concentrations. These results suggest that PV1 protein is able to block SV40 infectivity at low but not at high viral concentration either by interfering with the infective internalization pathway at the cell surface or at a post internalization step. PMID- 21827738 TI - Impedance measurement: a new method to detect ligand-biased receptor signaling. AB - Ligand-biased receptor signaling has been proposed for several G-protein coupled receptors including the niacin receptor GPR109A. Coupling to the G(i/o) pathway has been shown to be responsible for the well described triglyceride lowering effect of nicotinic acid in mice, while activation of the beta-arrestin pathway has been suggested to be responsible for its peripheral vasodilatory effect that causes cutaneous flushing. Several ligands have been described to selectively induce triglyceride lowering without inducing flushing. Cellular impedance has been demonstrated to determine G-protein coupled receptors activation in a G protein specific manner. Agonists, which induce triglyceride lowering, but not flushing show a profile in cellular impedance that is distinct from the one induced by niacin and those compounds that induce triglyceride lowering as well as flushing. The strength of the signal correlates with the activation of beta arrestin. PMID- 21827740 TI - Melatonin and structural analogues do not possess antioxidant properties on Fe(2+)-initiated peroxidation of sonicated liposomes made of retinal lipids. AB - Melatonin and its structural analogues display antioxidant activity in vivo but their activity in model membranes is not very well known. In this study, we have investigated the antioxidant capacity of melatonin and structural analogues on Fe(2+)-initiated peroxidation of sonicated liposomes made of retinal lipids. The indoleamines were evaluated against butylated hydroxitoluene (BHT) which was chosen as a reference standard because of its high antioxidant capacity. After the addition of Fe(2+) as initiator of lipid peroxidation, quick production of conjugated dienes was observed. With addition of increasing concentrations of BHT the start of the reaction was delayed and initial reaction rates were lower. However, this reduction was not proportional to the increase in concentration. The start of the reaction and initial reaction rates were not modified in the presence of melatonin and its structural analogues. The formation of TBARS started immediately after the addition of Fe(2+). The increase in the concentration of BHT avoided the emergence of TBARS. Changes were not observed in the presence of melatonin or structural analogues. Retinal lipids showed a high content of docosahexaenoic (22: 6 (Delta4,7,10,13,16,19) acid, characteristic of this tissue. A little bit of that fatty acid was lost when sonicated liposomes were prepared with these retinal lipids. The polyunsaturated fatty acids (PUFAs) diminished significantly after incubation of liposomes with Fe(2+) during 1h. BHT preserved PUFAs whereas melatonin and its related indoleamines did not. These data reinforce the hypothesis that melatonin and structural analogues do not possess antioxidant properties per se in this liposomal model system. PMID- 21827741 TI - Parameters affecting the accuracy of the MALDI-TOF MS determination of the phosphatidylcholine/lysophosphatidylcholine (PC/LPC) ratio as potential marker of spermatozoa quality. AB - Matrix-assisted laser desorption and ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) is increasingly used to characterize (phospho)lipids. However, quantitative MALDI data are often questioned because ion suppression may occur if mixtures are analyzed. Therefore, relative (but no absolute) data are normally derived from the MALDI mass spectra of lipid mixtures. We are particularly interested in the phosphatidylcholine/lysophosphatidylcholine (PC/LPC) ratio because it seems to represent a suitable measure of the inflammatory activity. In this study, different parameters affecting the achievable accuracy of the MALDI TOF MS determination of the PC/LPC ratio are compared. It will be shown that particularly the applied laser fluence as well as the used solvents influence the accuracies. Using artificial lipid mixtures it will be demonstrated that the PC/LPC ratio can be determined with an accuracy of about +/-10% making the MALDI assay comparable to established methods. Finally, it will be shown that the optimized conditions are also useful to determine the PC/LPC ratios in human seminal plasma. PMID- 21827739 TI - Green tea catechin, epigallocatechin-3-gallate (EGCG): mechanisms, perspectives and clinical applications. AB - An expanding body of preclinical evidence suggests EGCG, the major catechin found in green tea (Camellia sinensis), has the potential to impact a variety of human diseases. Apparently, EGCG functions as a powerful antioxidant, preventing oxidative damage in healthy cells, but also as an antiangiogenic and antitumor agent and as a modulator of tumor cell response to chemotherapy. Much of the cancer chemopreventive properties of green tea are mediated by EGCG that induces apoptosis and promotes cell growth arrest by altering the expression of cell cycle regulatory proteins, activating killer caspases, and suppressing oncogenic transcription factors and pluripotency maintain factors. In vitro studies have demonstrated that EGCG blocks carcinogenesis by affecting a wide array of signal transduction pathways including JAK/STAT, MAPK, PI3K/AKT, Wnt and Notch. EGCG stimulates telomere fragmentation through inhibiting telomerase activity. Various clinical studies have revealed that treatment by EGCG inhibits tumor incidence and multiplicity in different organ sites such as liver, stomach, skin, lung, mammary gland and colon. Recent work demonstrated that EGCG reduced DNMTs, proteases, and DHFR activities, which would affect transcription of TSGs and protein synthesis. EGCG has great potential in cancer prevention because of its safety, low cost and bioavailability. In this review, we discuss its cancer preventive properties and its mechanism of action at numerous points regulating cancer cell growth, survival, angiogenesis and metastasis. Therefore, non-toxic natural agent could be useful either alone or in combination with conventional therapeutics for the prevention of tumor progression and/or treatment of human malignancies. PMID- 21827742 TI - Genotyping for CYP2C9 and VKORC1 alleles by a novel point of care assay with HyBeacon(r) probes. AB - BACKGROUND: Coumarin anticoagulants such as warfarin are used to treat and prevent thromboembolic events in patients. The required dosage is difficult to predict and the risk of over or under anticoagulation are dependent on several environmental and clinical factors, such as concurrent medication, diet, age and genotype for polymorphisms in two genes CYP2C9 and VKORC1. METHODS: A novel fluorescent PCR genotyping assay using HyBeacon(r) probes, was developed to enable clinical staff to genotype the CYP2C9*2 and CYP2C9*3 alleles and the VKORC1 G-1639A polymorphism directly from unextracted blood samples. A prototype PCR instrument, Genie 1, suitable for point of care use was developed to carry out the assays. The panel of tests was validated by analysing blood samples from 156 individuals and comparing genotypes with data obtained using DNA samples from the same individuals. The accuracy of genotypes obtained with the Genie 1 was compared against results from well validated real time PCR and PCR-restriction fragment length polymorphism analysis. RESULTS: Identical results were obtained for the newly developed HyBeacon(r) method and the validation method in all cases except for one where no result was obtained for the VKORC1 polymorphism on the Genie instrument. The samples used for validation represented all six possible *2 and *3 allele-related CYP2C9 genotypes and all three VKORC1 G-1639A genotypes. CONCLUSIONS: We observed excellent accuracy for the newly developed method which can determine genotype in less than 2 h. PMID- 21827743 TI - The F-box protein Fbw7 is required for cerebellar development. AB - The F-box protein Fbw7 (also known as Fbxw7, hCdc4 and Sel-10) functions as a substrate recognition component of a SCF-type E3 ubiquitin ligase. SCF(Fbw7) facilitates polyubiquitination and subsequent degradation of various proteins such as Notch, cyclin E, c-Myc and c-Jun. Fbw7 is highly expressed in the nervous system and controls neural stem cell differentiation and apoptosis via Notch and c-Jun during embryonic development (Hoeck et al., 2010). Fbw7 deletion in the neural lineage is perinatal lethal and thus prohibits studying the role of Fbw7 in the adult nervous system. fbw7 mRNA is highly expressed in the postnatal brain and to gain insights into the function of Fbw7 in postnatal neurogenesis we analysed Fbw7 function in the cerebellum. We generated conditional Fbw7-knockout mice (fbw7(?Cb)) by inactivating Fbw7 specifically in the cerebellar anlage. This resulted in decreased cerebellar size, reduced Purkinje cell number and defects in axonal arborisation. Moreover, Fbw7-deficient cerebella showed supranumeral fissures and aberrant progenitor cell migration. Protein levels of the Fbw7 substrates Notch1 and N-terminally phosphorylated c-Jun were upregulated in fbw7(?Cb) mice. Concomitant deletion of c-Jun, and also the junAA knock-in mutation which specifically abrogates c-Jun N-terminal phosphorylation, rescued Purkinje cell numbers and arborisation in the fbw7(?Cb) background. Taken together these data demonstrate that Fbw7 is essential during cerebellar development, and identify N-terminally phosphorylated c-Jun as an important substrate of SCF(Fbw7) during neurogenesis. PMID- 21827744 TI - Patterns of cell lineage, movement, and migration from germ layer specification to gastrulation in the amphipod crustacean Parhyale hawaiensis. AB - The acquisition of specific cell fates throughout embryonic development is one of the core problems in developmental and evolutionary biology. In the amphipod Parhyale hawaiensis all three germ layers and the germ line are determined by the eight-cell stage. Despite this early fate determination, multiple cell types can be replaced following ablation of their founder cells, showing that this embryo also has significant regulative properties. Here we present a cellular-level resolution lineage analysis for P. hawaiensis embryos between fertilization and gastrulation, including analysis of cleavage patterns, division times, and clonal behaviors. We compare these cellular behaviors in wild type embryos with those in embryos where specific founder cells have been ablated, or where zygotic transcription has been inhibited. We observe that when germ line, endoderm or mesoderm founder cells are ablated, the remaining cells do not alter their cleavage or migration behaviors before the onset of gastrulation. In the absence of zygotic transcription, ingression movements proceed normally, but epibolic movements are disrupted. This indicates that the embryo's regulative response to germ layer founder loss, in the form of altered cell behavior, is realized in the ~32h between gastrulation and early germ band elongation, and is likely to require zygotic reprogramming rather than alternative deployment of maternally supplied determinants. Combining these data with the observations of previous studies, we propose a framework to elucidate the molecular mechanisms that regulate the determinative and regulative properties of the P. hawaiensis embryo. PMID- 21827745 TI - The core planar cell polarity gene prickle interacts with flamingo to promote sensory axon advance in the Drosophila embryo. AB - The atypical cadherin Drosophila protein Flamingo and its vertebrate homologues play widespread roles in the regulation of both dendrite and axon growth. However, little is understood about the molecular mechanisms that underpin these functions. Whereas flamingo interacts with a well-defined group of genes in regulating planar cell polarity, previous studies have uncovered little evidence that the other core planar cell polarity genes are involved in regulation of neurite growth. We present data in this study showing that the planar cell polarity gene prickle interacts with flamingo in regulating sensory axon advance at a key choice point - the transition between the peripheral nervous system and the central nervous system. The cytoplasmic tail of the Flamingo protein is not required for this interaction. Overexpression of another core planar cell polarity gene dishevelled produces a similar phenotype to prickle mutants, suggesting that this gene may also play a role in regulation of sensory axon advance. PMID- 21827746 TI - Cks85A and Skp2 interact to maintain diploidy and promote growth in Drosophila. AB - The Cks or Suc1 proteins are highly conserved small proteins that play remarkably diverse roles in the cell cycle. All Cks homologues have the ability to associate with Cyclin dependent kinases (Cdks) and in many cases this interaction has been shown to be important for function. Here we characterize the null and RNAi knockdown phenotype of the Drosophila Cks1 (Cks85A) gene. Cks85A is essential for viability in Drosophila. Cks85A null animals have reduced overall growth and this correlates with reduced ploidy and impaired DNA replication in endoreplicating cells. Interestingly, Cks85A is also required for the maintenance of diploidy in mitotically cycling cells. The requirement for Cks85A in growth is similar to that of the mammalian Cks1, which was found to interact with the SCF(Skp2) ubiquitin ligase. We identified the Drosophila Skp2 gene and generated null alleles. Comparison of these mutants to null mutants for Cks85A reveals a remarkably similar dual requirement in growth and in maintenance of diploidy. We find that Cks85A interacts directly with the SCF(Skp2) ubiquitin ligase and genetic evidence indicates that this is its major molecular function. The closely related Cks30A cannot interact with the SCF(Skp2) and cannot functionally compensate for loss of Cks85A. We also find that the critical growth promoting and diploidy maintaining functions of Cks85A and Skp2 are independent of known SCF(Skp2) substrates, p27 and Cdt1, indicating that other critical substrates remain to be identified. PMID- 21827748 TI - Mechanism of potentiation by tea epigallocatechin of contraction in porcine coronary artery: the role of protein kinase Cdelta-mediated CPI-17 phosphorylation. AB - The effects of green tea catechins, (+)- and (-)-catechins (C), (-)-epicatechin (EC), (-)-epicatechin gallate (ECG), (-)-epigallocatechin (EGC), and (-) epigallocatechin gallate (EGCG), on vascular contractility were investigated in porcine coronary artery. At the concentration of 200 MUM, only EGC, but not other catechins, potentiated high K(+)-induced contraction in a concentration-dependent manner, although EGC by itself did not produce contraction. The potentiator effect of EGC was still observed in endothelium-denuded preparations. Moreover, EGC increased the translocation of protein kinase Cdelta (PKCdelta) from the cytosol to the plasma membrane and increased phosphorylations of 17-kDa PKC potentiated protein phosphatase inhibitor protein (CPI-17) and myosin light chain (MLC(20)). These effects of EGC were inhibited by the PKCdelta inhibitor rottlerin, but not by the conventional PKC inhibitor Go6976. These results suggest that EGC activates PKCdelta, leading to the phosphorylation of CPI-17, which in turn inhibits myosin light chain phosphatase and increases MLC(20) phosphorylation. The series of events would increase Ca(2+) sensitivity of contractile elements, thereby augmenting high K(+)-induced vascular contraction. PMID- 21827747 TI - KR33426, [2-(2,5-dichlorophenyl)-5-methyloxazol-4yl]carbonylguanidine, is a novel compound to be effective on mouse systemic lupus erythematosus. AB - B cell-activating factor (BAFF) is a key regulator of B lymphocyte development. Signals from BAFF are transmitted through binding to a specific BAFF receptor (BAFF-R). Here, we established screening method to find a specific inhibitor for the interference of BAFF-BAFF-R interactions. We screened oxazole-4 carbonylguanidine derivatives and selected KR33426, [2-(2,5-dichlorophenyl)-5 methyloxazol-4yl]carbonylguanidine, as a candidate to interfere BAFF-BAFF-R interactions. KR33426 inhibited BAFF-mediated anti-apoptotic effect on splenocytes as judged by hypodiploid cell formation. KR33426 also increased the degradation of procaspase-3 that was inhibited by BAFF protein. In addition, we examined whether KR33426 was effective on the treatment of systemic lupus erythematosus-like symptom in MRL(lpr/lpr) mouse. When 5 or 10mg/kg KR33426 was intraperitoneally administered to MRL(lpr/lpr) mice for 4 weeks, histopathological changes were ameliorated in the narrowed space between renal glomerulus and glomerulus capsule. KR33426 reduced B220(+) B cell population and B cell mitogen, lipopolysaccharide-stimulated lymphocyte proliferation in splenocytes. KR33426 attenuated an increase in CD43(-)IgM(+) immature pro-B and a decrease in CD21(+) IgM(+) T2-B and IgD(+) IgM(-)recirculating-B cells on B cell development. Data show that KR33426 inhibits BAFF-BAFF-R interactions and it is effective on the treatment of systemic lupus erythematosus-like symptom in MRL(lpr/lpr) mice. Thus, it suggests that KR33426 is a novel candidate to develop anti-autoimmune therapeutics by the interference of BAFF-BAFF-R interactions, specifically. PMID- 21827749 TI - Leishmania amazonensis: characterization of an ecto-3'-nucleotidase activity and its possible role in virulence. AB - Ecto-3'-nucleotidase/nuclease (3'NT/NU) is a membrane-bound enzyme that plays a key role in the nutrition of Leishmania sp. protozoan parasites. This enzyme generates nucleosides via hydrolyzes of 3'mononucleotides and nucleic acids, which enter the cell by specific transporters. In this work, we identify and characterize Leishmania amazonensis ecto-3'-nucleotidase activity (La3' nucleotidase), report ammonium tetrathiomolybdate (TTM) as a novel La3' nucleotidase inhibitor and approach the possible involvement of ecto-3' nucleotidase in cellular adhesion. La3'-nucleotidase presented characteristics similar to those reported for the class I single-strand nuclease family; a molecular weight of approximately 40 kDa and optimum activity in an alkaline pH range were observed. Although it is conserved among the genus, La3'-nucleotidase displays different kinetic properties; it can be inhibited by vanadate, molybdate and Cu(2+) ions. Interestingly, ecto-3'-nucleotidase activity is 60-fold higher than that of ecto-5'-nucleotidase in L. amazonensis. Additionally, ecto-3' nucleotidase activity is two-fold higher in virulent L. amazonensis cells than in avirulent ones. Notably, macrophage-parasite attachment/invasion was increased by 400% in the presence of adenosine 3'-monophosphate (3'AMP); however, this effect was reverted by TTM treatment. We believe that La3'-nucleotidase may play a significant role in the generation of adenosine, which may contribute to mammalian host immune response impairment and establishment of infection. PMID- 21827750 TI - Regulatory T-cells in systemic lupus erythematosus and rheumatoid arthritis. AB - Regulatory T-cells (Tregs) are the guardians of peripheral tolerance acting to prevent autoimmune diseases such as systemic lupus erythomatosus (SLE) and rheumatoid arthritis (RA). Defects in Tregs have been reported in these two diseases despite significant differences in their clinical phenotype and pathogenesis. In both diseases the potency of Treg fails to keep pace with the activation of effector cells and are unable to resist the ensuing inflammation. This review will discuss the phenotypic, numeric, and functional abnormalities in Tregs and their role in patients and murine models of SLE and RA. PMID- 21827752 TI - A yeast two hybrid screen identifies SPATA4 as a TRAPP interactor. AB - The TRAPP vesicle-tethering complex consists of more than 10 distinct polypeptides and is involved in protein transport. Using the C2 subunit as bait we identified SPATA4, a spermatocyte-specific protein of unknown function, as an interacting partner in a yeast two hybrid screen. Further studies indicate SPATA4 interacts with the C2 portion of the TRAPP complex. SPATA4 fractionates with both cytosolic and nuclear fractions suggesting it may have several distinct functions. SPATA4 is one of only three human proteins that contain a DUF1042 domain and we show that C2 does not interact with another one of the DUF1042 domain-containing proteins. Our results suggest a role for SPATA4 in membrane traffic and a specialized function for TRAPP in spermatocytes. PMID- 21827753 TI - Unraveling the enigmatic complexities of BRMS1-mediated metastasis suppression. AB - Expression of BRMS1 causes dramatic suppression of metastasis in multiple in vivo model systems. As we gain further insight into the biochemical mechanisms of BRMS1, we appreciate the importance of both molecular and cellular context for functional metastasis suppression. BRMS1 associates with large chromatin remodeling complexes including SIN3:HDAC which are powerful epigenetic regulators of gene expression. Additionally, BRMS1 inhibits the activity of NFkappaB, a well known transcription factor that plays significant roles in tumor progression. Moreover, BRMS1 coordinately regulates the expression of metastasis-associated microRNA known as metastamir. How these biochemical mechanisms and biological pathways are linked, either directly or indirectly, and the influence of molecular and cellular context, are critical considerations for the discovery of novel therapeutic targets for the most deadly aspect of tumor progression metastasis. PMID- 21827754 TI - Molecular machines encoded by bacterially-derived multi-domain gene fusions that potentially synthesize, N-methylate and transfer long chain polyamines in diatoms. AB - Silica glass formation in diatoms requires the biosynthesis of unusual, very long chain polyamines (LCPA) composed of iterated aminopropyl units. Diatoms processively synthesize LCPA, N-methylate the amine groups and transfer concatenated, N-dimethylated aminopropyl groups to silaffin proteins. Here I show that diatom genomes possess signal peptide-containing gene fusions of bacterially derived polyamine biosynthetic enzymes S-adenosylmethionine decarboxylase (AdoMetDC) and an aminopropyltransferase, sometimes fused to a eukaryotic histone N-methyltransferase domain, that potentially synthesize and N-methylate LCPA. Fusions of similar, alternatively configured domains but with a catalytically dead AdoMetDC and in one case a Tudor domain, may N-dimethylate and transfer multiple aminopropyl unit polyamines onto silaffin proteins. PMID- 21827751 TI - CD44 and HCELL: preventing hematogenous metastasis at step 1. AB - Despite great strides in our knowledge of the genetic and epigenetic changes underlying malignancy, we have limited information on the molecular basis of metastasis. Over 90% of cancer deaths are caused by spread of tumor cells from a primary site to distant organs and tissues, highlighting the pressing need to define the molecular effectors of cancer metastasis. Mounting evidence suggests that circulating tumor cells (CTCs) home to specific tissues by hijacking the normal leukocyte trafficking mechanisms. Cancer cells characteristically express CD44, and there is increasing evidence that hematopoietic cell E-/L-selectin ligand (HCELL), a sialofucosylated glycoform of CD44, serves as the major selectin ligand on cancer cells, allowing interaction of tumor cells with endothelium, leukocytes, and platelets. Here, we review the structural biology of CD44 and of HCELL, and present current data on the function of these molecules in mediating organ-specific homing/metastasis of CTCs. PMID- 21827755 TI - Regulation of chaperone gene expression by heat shock transcription factor in Saccharomyces cerevisiae: importance in normal cell growth, stress resistance, and longevity. AB - Heat shock transcription factor (HSF), a key regulator in the expression of heat shock protein (HSP) chaperones, is involved in the maintenance of protein homeostasis. However, the impact of HSF-mediated transcription of each HSP gene on this process is not fully understood. We show that Saccharomyces cerevisiae cells containing mutations in the HSF-binding sequences of chromosomal HSP90 promoters exhibit various phenotypes, including slow growth, proteotoxic stress sensitivity, and reduced chronological lifespan. Similar phenotypes were observed when HSF-binding sequences in five mitochondrial HSP promoters were mutated. Therefore, HSF-regulated changes in expression of these chaperone genes are necessary to maintain cell viability under various growth conditions. PMID- 21827756 TI - RNF20-RNF40: A ubiquitin-driven link between gene expression and the DNA damage response. AB - The DNA damage response (DDR) is emerging as a vast signaling network that temporarily modulates numerous aspects of cellular metabolism in the face of DNA lesions, especially critical ones such as the double strand break (DSB). The DDR involves extensive dynamics of protein post-translational modifications, most notably phosphorylation and ubiquitylation. The DSB response is mobilized primarily by the ATM protein kinase, which phosphorylates a plethora of key players in its various branches. It is based on a core of proteins dedicated to the damage response, and a cadre of proteins borrowed temporarily from other cellular processes to help meet the challenge. A recently identified novel component of the DDR pathway - histone H2B monoubiquitylation - exemplifies this principle. In mammalian cells, H2B monoubiquitylation is driven primarily by an E3 ubiquitin ligase composed of the two RING finger proteins RNF20 and RNF40. Generation of monoubiquitylated histone H2B (H2Bub) has been known to be coupled to gene transcription, presumably modulating chromatin decondensation at transcribed regions. New evidence indicates that the regulatory function of H2Bub on gene expression can selectively enhance or suppress the expression of distinct subsets of genes through a mechanism involving the hPAF1 complex and the TFIIS protein. This delicate regulatory process specifically affects genes that control cell growth and genome stability, and places RNF20 and RNF40 in the realm of tumor suppressor proteins. In parallel, it was found that following DSB induction, the H2B monoubiquitylation module is recruited to damage sites where it induces local H2Bub, which in turn is required for timely recruitment of DSB repair protein and, subsequently, timely DSB repair. This pathway represents a crossroads of the DDR and chromatin organization, and is a typical example of how the DDR calls to action functional modules that in unprovoked cells regulate other processes. PMID- 21827757 TI - MicroRNA-451 regulates p38 MAPK signaling by targeting of Ywhaz and suppresses the mesangial hypertrophy in early diabetic nephropathy. AB - Diabetic nephropathy (DN) is a major diabetic complication. However, the initiating molecular events triggering DN are unknown. In this study we focused on microRNA-451 (miR-451), which is downregulated during early DN. We found that miR-451 negatively regulated the expression of Ywhaz through Ywhaz 3'UTR and that Ywhaz was required for the miR-451-mediated downregulation of p38 MAPK signalling. Moreover, over-expression of miR-451 inhibits glomerular mesangial cell proliferation in vitro and in vivo. These findings suggest that the growth inhibitory effect of miR-451 may be explained in part by miR-451-induced suppression of Ywhaz and p38 MAPK signalling, providing evidence for the potential role of miR-451 in early DN. PMID- 21827758 TI - How Salmonella oxidises H(2) under aerobic conditions. AB - Salmonella enterica serovar Typhimurium is a Gram negative bacterial pathogen and a common cause of food-borne illness. Molecular hydrogen has been shown to be a key respiratory electron donor during infection and H(2) oxidation can be catalysed by three genetically-distinct [NiFe] hydrogenases. Of these, hydrogenases-1 (Hyd-1) and Hyd-2 have well-characterised homologues in Escherichia coli. The third, designated Hyd-5 here, is peculiar to Salmonella and is expressed under aerobic conditions. In this work, Salmonella was genetically modified to enable the isolation and characterisation of Hyd-5. Electrochemical analysis established that Hyd-5 is a H(2)-oxidising enzyme that functions in very low levels of H(2) and sustains this activity in high levels of O(2). In addition, electron paramagnetic resonance spectroscopy of the Hyd-5 isoenzyme reveals a complex paramagnetic FeS signal at high potentials which is comparable to that observed for other O(2)-tolerant respiratory [NiFe] hydrogenases. Taken altogether, Hyd-5 can be classified as an O(2)-tolerant hydrogenase that confers upon Salmonella the ability to use H(2) as an electron donor in aerobic respiration. PMID- 21827759 TI - Molt-inhibiting hormone from Chinese mitten crab (Eriocheir sinensis): Cloning, tissue expression and effects of recombinant peptide on ecdysteroid secretion of YOs. AB - Molt-inhibiting hormone (MIH), a member of the crustacean hyperglycemic hormone (CHH) family, inhibits the synthesis of ecdysteroid in Y-organ (YO) and plays a significant role in the regulation of molting and growth of crustaceans. A complete cDNA sequence encoding MIH (Ers-MIH, GenBank Accession No.: DQ341280) was cloned from eyestalk of Chinese mitten crab (Eriocheir sinensis) by 5' and 3' RACEs and PCR cloning. The full-length cDNA consists of 1457 bp with a 330 bp open reading frame, encoding 110 amino acids, containing a 75 amino acid mature peptide. The deduced amino acid sequence contains a typical CHH domain. Transcripts of Ers-MIH mRNA were detected in eyestalk by Northern blotting. The production of purified recombinant Ers-MIH (rErs-MIH) expressed in Escherichia coli was 0.3g/L. The LC-ESI-MS analysis showed that two peptide fragments of the recombinant protein were identical to the deduced amino acid sequence of Ers-MIH. By in vitro assay on E. sinensis YOs, a cGMP mediated suppression of rErs-MIH on ecdysteroidogenesis could be observed. Accumulation of cGMP in YOs showed a concentration-dependent manner within 0.01-1 nmol/mL of rErs-MIH; ecdysteroid secretion was inhibited significantly at the range of 0.01-100 nmol/mL rErs-MIH; furthermore, a significant inhibition effect on ecdysteroid releasing was shown when cGMP analog (8-Br-cGMP) concentration rose up to 100 nmol/mL. This study would facilitate to investigate the roles of MIH in molt cycle regulation. PMID- 21827760 TI - Molecular cloning, molecular evolution and gene expression of cDNAs encoding thyrotropin-releasing hormone receptor subtypes in a teleost, the sockeye salmon (Oncorhynchus nerka). AB - Molecular cloning of thyrotropin-releasing hormone receptors (TRHR) was performed in a teleost, the sockeye salmon (Oncorhynchus nerka). Four different TRHR cDNAs were cloned and named TRHR1, TRHR2a, TRHR2b and TRHR3 based on their similarity to known TRHR subtypes in vertebrates. Important residues for TRH binding were conserved in deduced amino acid sequences of the three TRHR subtypes except for the TRHR2b. Seven transmembrane domains were predicted for TRHR1, TRHR2a and TRHR3 proteins but only five for TRHR2b which appears to be truncated. In silico database analysis identified putative TRHR sequences including invertebrate TRHR and reptilian, avian and mammalian TRHR3. Phylogenetic analyses predicted the molecular evolution of TRHR in vertebrates: from the common ancestral TRHR (i.e. invertebrate TRHR), the TRHR2 subtype diverged first and then TRHR1 and TRHR3 diverged. Reverse transcription-polymerase chain reaction analyses revealed TRHR1 transcripts in the brain (hypothalamus), retina, pituitary gland and large intestine; TRHR2a in the brain (telencephalon and hypothalamus); and TRHR3 in the brain (olfactory bulbs) and retina. PMID- 21827761 TI - Age-related differences in baseline and stress-induced corticosterone in Florida scrub-jays. AB - In physiological studies of free-living species, it is essential to consider the context of the life history stage at which an individual was observed in order to link measures of physiology with ecological parameters. One such measure that is important to consider is the age of an individual. We tested whether baseline or stress-induced corticosterone levels vary with age in free-living Florida scrub jays (Aphelocoma coerulescens) during the pre-breeding period. Corticosterone (CORT), the primary avian stress hormone, is released in response to stressful stimuli, and stimulates gluconeogenesis; however, it also serves as a chemical messenger that can influence other physiological processes, reproduction, and behavior. We monitored both baseline CORT levels longitudinally throughout a five year period and stress-induced CORT responses over a shorter two-year period. We predicted that older jays would have lower baseline CORT levels and a dampened stress response compared to younger birds, as has been shown in other avian species. We found no significant differences in baseline CORT levels with age. We found a decrease in total corticosterone responses to a stressor with age, however, the oldest birds in the population showed greater total corticosterone responses to a stressor. These results may be a product of age-related changes in physiological processes related to the stress response or a result of selection acting on the population, resulting in only the most responsive individuals surviving to old age. PMID- 21827762 TI - Distribution of pepsinogen- and ghrelin-producing cells in the digestive tract of Japanese eel (Anguilla japonica) during metamorphosis and the adult stage. AB - Pepsinogen is the precursor form of the gastric-specific digestive enzyme, pepsin. Ghrelin is a representative gastric hormone with multiple functions in vertebrates, including the regulation of growth hormone release, stimulation of food intake and gastrointestinal motility function. We investigated chronological changes in the distribution of pepsinogen-expressing cells by in situ hybridization and ghrelin-immunoreactive cells by immunohistochemistry in the Japanese eel (Anguilla japonica) during metamorphosis from the leptocephalus sage to the elver stage. The ghrelin-producing cells first appeared in the gastric cecum and pyloric portion of the stomach in the late phase of metamorphosing leptocephali, whereas the pepsinogen-producing cells were first detected in the early phase of the glass-eel stage. These suggest that endocrine cells differentiated earlier than exocrine cells in the eel stomach. Accompanying eel development, the distribution of ghrelin-producing cells spread to the esophagus and other regions of the stomach, but not to the intestine. These results may be related to the changes in dietary habits during metamorphosis in the Japanese eel. PMID- 21827763 TI - Characterisation and expression of beta1-, beta2- and beta3-adrenergic receptors in the fathead minnow (Pimephales promelas). AB - Complimentary DNAs for three beta-adrenergic receptors (betaARs) were isolated and characterised in the fathead minnow. The encoded proteins of 402 (beta(1)AR), 397 (beta(2)AR) and 434 (beta(3)AR) amino acids were homologous to other vertebrate betaARs, and displayed the characteristic seven transmembrane helices of G Protein-coupled receptors. Motifs and amino acids shown to be important for ligand binding were conserved in the fathead minnow receptors. Quantitative RT PCR revealed the expression of all receptors to be highest in the heart and lowest in the ovary. However, the beta(1)AR was the predominant subtype in the heart (70%), and beta(3)AR the predominant subtype in the ovary (53%). In the brain, beta(1)AR expression was about 200-fold higher than that of beta(2)- and beta(3)AR, whereas in the liver, beta(2)AR expression was about 20-fold and 100 fold higher than beta(3)- and beta(1)AR expression, respectively. Receptor gene expression was modulated by exposure to propranolol (0.001-1mg/L) for 21 days, but not in a consistent, concentration-related manner. These results show that the fathead minnow has a beta-adrenergic receptor repertoire similar to that of mammals, with the molecular signatures required for ligand binding. An exogenous ligand, the beta-blocker propranolol, is able to alter the expression profile of these receptors, although the functional relevance of such changes remains to be determined. Characterisation of the molecular targets for beta-blockers in fish will aid informed environmental risk assessments of these drugs, which are known to be present in the aquatic environment. PMID- 21827764 TI - Vasotocin induces final oocyte maturation and ovulation through the production of a maturation-inducing steroid in the catfish Heteropneustes fossilis. AB - The study reports for the first time vasotocin (VT) induction of final oocyte maturation and ovulation through the production of the maturation-inducing steroid 17, 20beta-dihydroxy-4-pregnen-3-one (MIS, 17, 20beta-DP). Post vitellogenic follicles of the catfish Heteropneustes fossilis were incubated with different concentrations of VT (1, 10, 100 and 1000 nM) for different time periods. Germinal vesicle breakdown [GVBD, as a marker of final oocyte maturation (FOM)] and ovulation were scored. In another series of experiments, the follicles were incubated with VT alone or in combination with VT receptor (V(1) and V(2)) antagonists, and GVBD and ovulation were increased with progesterone, 17-hydroxy 4-pregnene-3, 20-dione (17-P) and 17, 20beta-DP levels. VT stimulated both GVBD and ovulation in a concentration and time-dependent manner, and the responses were inhibited to varying degrees in groups incubated with the VT receptor antagonists. The V(1) antagonist inhibited the responses by 2- to 3-fold and more than the V(2) antagonist, and the combination was more potent than the separate incubation. Progestins increased time-dependently in the VT groups and the fold increase was greater for the MIS. The VT-induced steroid stimulation was significantly inhibited to near the control levels in co-incubations with both V(1) and V(2) receptor antagonists, in the order 17, 20beta-DP > 17-P > P(4). The inhibition by the V(1) receptor antagonist was greater than that with the V(2) blocker, and followed the same order of inhibition described above. The results suggest that VT induces FOM and ovulation mainly through the V(1) receptors. PMID- 21827765 TI - The phenotype and function of naturally existing regulatory dendritic cells in nematode-infected mice. AB - Immunosuppression associated with chronic helminth infections has been documented in many studies and regulatory T (Treg) cells have been shown to mediate the nematode-induced immunosuppression, but the role of dendritic cells (DCs) in the induction of Treg cell response and immunosuppression has not yet been fully determined. We analysed the response and function of DCs in mesenteric lymph node (MLNs) of mice infected with a gastrointestinal nematode, Heligmosomoides polygyrus, and observed a substantial expansion of DCs in MLNs following the infection. The CD11c(+) DCs in MLNs of infected mice showed reduced expression of co-stimulatory molecules CD40, CD86 and MHC-II, and production of inflammatory cytokines IL-12 and IL-6. Analysis of MLN DC subsets defined by CD11c and CD45RB expression showed that the CD11c(low)CD45RB(mid) subset increased rapidly following H. polygyrus infection and the CD11c(mid)CD45RB(high) subset expanded from the third week after infection. In the co-culture of sorted DC subsets with ovalbumin-(OVA-)specific T cell receptor (TCR) transgenic CD4(+) T cells, CD11c(low)CD45RB(mid) DCs induced a low proliferation response and a high level of IL-10 production in CD4(+) T cells, whereas CD11c(mid)CD45RB(high) DCs induced more IFN-gamma and IL-4 producing CD4(+) T cells. Intracellular staining revealed that CD11c(low)CD45RB(mid) DCs promoted CD4(+) Foxp3(+) differentiations. These results indicate that nematode infections selectively induce expansion of the CD11c(low)CD45RB(mid) regulatory DC subset that promotes development of Foxp3(+) and IL-10 producing Treg cells. The Treg cell responses and immunoregulatory cytokines induced by this regulatory DC subset in turn play an important role in mediation of the nematode-induced immunosuppression. PMID- 21827766 TI - 4000 holes. PMID- 21827767 TI - Crystal structure of alpha-galactosidase from Lactobacillus acidophilus NCFM: insight into tetramer formation and substrate binding. AB - Lactobacillus acidophilus NCFM is a probiotic bacterium known for its beneficial effects on human health. The importance of alpha-galactosidases (alpha-Gals) for growth of probiotic organisms on oligosaccharides of the raffinose family present in many foods is increasingly recognized. Here, the crystal structure of alpha Gal from L. acidophilus NCFM (LaMel36A) of glycoside hydrolase (GH) family 36 (GH36) is determined by single-wavelength anomalous dispersion. In addition, a 1.58-A-resolution crystallographic complex with alpha-d-galactose at substrate binding subsite -1 was determined. LaMel36A has a large N-terminal twisted beta sandwich domain, connected by a long alpha-helix to the catalytic (beta/alpha)(8) barrel domain, and a C-terminal beta-sheet domain. Four identical monomers form a tightly packed tetramer where three monomers contribute to the structural integrity of the active site in each monomer. Structural comparison of LaMel36A with the monomeric Thermotoga maritima alpha-Gal (TmGal36A) reveals that O2 of alpha-d-galactose in LaMel36A interacts with a backbone nitrogen in a glycine rich loop of the catalytic domain, whereas the corresponding atom in TmGal36A is from a tryptophan side chain belonging to the N-terminal domain. Thus, two distinctly different structural motifs participate in substrate recognition. The tetrameric LaMel36A furthermore has a much deeper active site than the monomeric TmGal36A, which possibly modulates substrate specificity. Sequence analysis of GH36, inspired by the observed structural differences, results in four distinct subgroups having clearly different active-site sequence motifs. This novel subdivision incorporates functional and architectural features and may aid further biochemical and structural analyses within GH36. PMID- 21827769 TI - BacPP: bacterial promoter prediction--a tool for accurate sigma-factor specific assignment in enterobacteria. AB - Promoter sequences are well known to play a central role in gene expression. Their recognition and assignment in silico has not consolidated into a general bioinformatics method yet. Most previously available algorithms employ and are limited to sigma70-dependent promoter sequences. This paper presents a new tool named BacPP, designed to recognize and predict Escherichia coli promoter sequences from background with specific accuracy for each sigma factor (respectively, sigma24, 86.9%; sigma28, 92.8%; sigma32, 91.5%; sigma38, 89.3%, sigma54, 97.0%; and sigma70, 83.6%). BacPP is hence outstanding in recognition and assignment of sequences according to sigma factor and provide circumstantial information about upstream gene sequences. This bioinformatic tool was developed by weighing rules extracted from neural networks trained with promoter sequences known to respond to a specific sigma factor. Furthermore, when challenged with promoter sequences belonging to other enterobacteria BacPP maintained 76% accuracy overall. PMID- 21827768 TI - Increased hydrophobicity and decreased backbone flexibility explain the lower solubility of a cataract-linked mutant of gammaD-crystallin. AB - A number of point mutations in gammaD-crystallin are associated with human cataract. The Pro23-to-Thr (P23T) mutation is perhaps the most common, is geographically widespread, and presents itself in a variety of phenotypes. It is therefore important to understand the molecular basis of lens opacity due to this mutation. In our earlier studies, we noted that P23T shows retrograde and sharply lowered solubility, most likely due to the emergence of hydrophobic patches involved in protein aggregation. Binding of 4,4'-dianilino-1,1'-binaphthyl-5,5' disulfonate (Bis-ANS) dye (a probe commonly used for detecting surface hydrophobicity) competed with aggregation, suggesting that the residues involved in Bis-ANS binding are also involved in protein aggregation. Here, using NMR spectroscopy in conjunction with Bis-ANS binding, we identify three residues (Y16, D21, and Y50) in P23T that are involved in binding the dye. Furthermore, using (15)N NMR relaxation experiments, we show that, in the mutant protein, backbone fluctuations are restricted to the picosecond-to-nanosecond and microsecond timescales relative to the wild type. Our present studies specify the residues involved in these two pivotal characteristics of the mutant protein, namely increased surface hydrophobicity and restricted mobility of the protein backbone, which can explain the nucleation and further propagation of protein aggregates. Thus, we have now identified the residues in the P23T mutant that give rise to novel hydrophobic surfaces, as well as those regions of the protein backbone where fluctuations in different timescales are restricted, providing a comprehensive understanding of how lens opacity could result from this mutation. PMID- 21827770 TI - A generalization of substitution evolution models of nucleotides to genetic motifs. AB - We generalize here the classical stochastic substitution models of nucleotides to genetic motifs of any size. This generalized model gives the analytical occurrence probabilities of genetic motifs as a function of a substitution matrix containing up to three formal parameters (substitution rates) per motif site and of an initial occurrence probability vector of genetic motifs. The evolution direction can be direct (past-present) or inverse (present-past). This extension has been made due to the identification of a Kronecker relation between the nucleotide substitution matrices and the motif substitution matrices. The evolution models for motifs of size 4 (tetranucleotides) and 5 (pentanucleotides) are now included in the SEGM (Stochastic Evolution of Genetic Motifs) web server. PMID- 21827771 TI - A spatial scan statistic for multiple clusters. AB - Spatial scan statistics are commonly used for geographical disease surveillance and cluster detection. While there are multiple clusters coexisting in the study area, they become difficult to detect because of clusters' shadowing effect to each other. The recently proposed sequential method showed its better power for detecting the second weaker cluster, but did not improve the ability of detecting the first stronger cluster which is more important than the second one. We propose a new extension of the spatial scan statistic which could be used to detect multiple clusters. Through constructing two or more clusters in the alternative hypothesis, our proposed method accounts for other coexisting clusters in the detecting and evaluating process. The performance of the proposed method is compared to the sequential method through an intensive simulation study, in which our proposed method shows better power in terms of both rejecting the null hypothesis and accurately detecting the coexisting clusters. In the real study of hand-foot-mouth disease data in Pingdu city, a true cluster town is successfully detected by our proposed method, which cannot be evaluated to be statistically significant by the standard method due to another cluster's shadowing effect. PMID- 21827772 TI - Non-thermal effects of 2.45 GHz microwaves on spindle assembly, mitotic cells and viability of Chinese hamster V-79 cells. AB - The production of mitotic spindle disturbances and activation of the apoptosis pathway in V79 Chinese hamster cells by continuous 2.45 GHz microwaves exposure were studied, in order to investigate possible non-thermal cell damage. We demonstrated that microwave (MW) exposure at the water resonance frequency was able to induce alteration of the mitotic apparatus and apoptosis as a function of the applied power densities (5 and 10mW/cm(2)), together with a moderate reduction in the rate of cell division. After an exposure time of 15 min the proportion of aberrant spindles and of apoptotic cells was significantly increased, while the mitotic index decreased as well, as compared to the untreated V79 cells. Additionally, in order to understand if the observed effects were due to RF exposure per se or to a thermal effect, V79 cells were also treated in thermostatic bath mimicking the same temperature increase recorded during microwave emission. The effect of temperature on the correct assembly of mitotic spindles was negligible up to 41 degrees C, while apoptosis was induced only when the medium temperature achieved 40 degrees C, thus exceeding the maximum value registered during MW exposure. We hypothesise that short-time MW exposures at the water resonance frequency cause, in V79 cells, reversible alterations of the mitotic spindle, this representing, in turn, a pro-apoptotic signal for the cell line. PMID- 21827773 TI - Potent protection of gallic acid against DNA oxidation: results of human and animal experiments. AB - Gallic acid (3,4,5-trihydroxybenzoic acid, GA) is a constituent of plant derived foods, beverages and herbal remedies. We investigated its DNA protective properties in a placebo controlled human intervention trial in single cell gel electrophoresis experiments. Supplementation of drinking water with GA (12.8 mg/person/d) for three days led to a significant reduction of DNA migration attributable to oxidised pyrimidines (endonuclease III sensitive sites) and oxidised purines (formamidopyrimidine glycosylase sensitive sites) in lymphocytes of healthy individuals by 75% and 64% respectively. Also DNA damage caused by treatment of the cells with reactive oxygen species (ROS) was reduced after GA consumption (by 41%). These effects were paralleled by an increase of the activities of antioxidant enzymes (superoxide dismutase, glutathione peroxidase and glutathion-S-transferase-pi) and a decrease of intracellular ROS concentrations in lymphocytes, while no alterations of the total antioxidant capacity (TAC), of malondialdehyde levels in serum and of the urinary excretion of isoprostanes were found. Experiments with rats showed that GA reduces oxidatively damaged DNA in lymphocytes, liver, colon and lungs and protects these organs against gamma-irradiation-induced strand breaks and formation of oxidatively damaged DNA-bases. Furthermore, the number of radiation-induced preneoplastic hepatic foci was decreased by 43% after oral administration of the phenolic. Since we did not find alterations of the TAC in plasma and lipid peroxidation of cell membranes but intracellular effects it is likely that the antioxidant properties of GA seen in vivo are not due to direct scavenging of radicals but rather to indirect mechanisms (e.g. protection against ROS via activation of transcription factors). As the amount of GA used in the intervention trial is similar to the daily intake in Middle Europe (18 mg/person/day), our findings indicate that it may contribute to prevention of formation of oxidatively damaged DNA in humans. PMID- 21827774 TI - Micronuclei levels in mothers and their newborns from regions with different types of air pollution. AB - The aim of this study was to analyze genetic damage in human lymphocytes measured using automated image analysis of micronuclei (MN) in a group of 178 mothers and their newborns from two locations in the Czech Republic. The concentrations of benzo[a]pyrene (B[a]P), particulate matter of aerodynamic diameter <2.5 MUm (PM2.5) and benzene were measured by stationary monitoring in the winter season of 2008/2009 in the capital city of Prague and in Ceske Budejovice, a regional city in a rural area. The 3-month mean concentration of B[a]P before delivery was lower in Prague in comparison with Ceske Budejovice: 1.9 +/- 0.5ng/m3 vs. 3.2 +/- 0.2ng/m3 (p<0.001). The opposite trend was found for PM2.5 and benzene: 27.0 +/- 2.5MUg/m3 and 2.5 +/- 0.5MUg/m3 vs. 24.5 +/- 0.7MUg/m3 and 2.1 +/- 0.8MUg/m3 (p<0.001) for Prague vs. Ceske Budejovice, respectively. The average age of the mothers was 31 years (range, 18-49 years). The frequencies of MN per 1000 binucleated cells were 8.35 +/- 3.06 vs. 6.47 +/- 2.35 (p<0.001) for mothers from Prague and Ceske Budejovice, respectively, and 2.17 +/- 1.32 vs. 3.82 +/- 2.43 (p<0.001) for newborns from Prague and Ceske Budejovice, respectively. Other factors, including vitamin intake, exposure to tobacco smoke, body mass index (BMI) before pregnancy, the education level of the mothers and the impact of the mothers' and fathers' ages were analyzed in our study. The results suggest that the different sensitivity of the study groups to various mixtures of carcinogenic pollutants could be affected by significant differences in lifestyle factors. Possible higher genetic damage was analyzed in newborns of smoking mothers, and the birth weight of this group was 7.4% lower (p<0.05) in comparison with the newborns of nonsmoking mothers. No impact of the age of the mothers or fathers on MN frequency in the newborns was observed. PMID- 21827776 TI - When word identification fails: ERP correlates of recognition without identification and of word identification failure. AB - Recognition without identification (RWI) refers to people's ability to discriminate studied from unstudied items when the items themselves fail to be identified, as when people fail to identify words from fragments. We sought to identify the ERP correlates of word fragment RWI in an effort to better understand its underlying mechanisms; in so doing, we also examined the ERP correlates of word identification failure vs. success. We found the ERP correlate of the RWI effect to be the N300; greater negativity was shown for unidentified fragments of studied words than for unidentified fragments of unstudied words between 300-325 ms post test fragment onset. We further separated the ERPs according to whether subjects showed the behavioral RWI effect or not; the N300 effect emerged only among those subjects who showed the behavioral effect, suggesting that the N300 is related to the behavioral effect itself. With regard to the ERP correlates of word identification failure vs. success, we found very early indicators of later word identification success vs. failure (starting at 125 ms) that were independent of priming. These early effects may be preconscious markers of downstream word identification success vs. failure. We also found a later persistent negativity associated with successfully identified words that we propose to be associated with executive function and possibly the successful suppression of irrelevant words that might initially come to mind when attempting to complete a unique word fragment; word fragment identification failure may sometimes be due to a failure to suppress irrelevant or incorrect words. PMID- 21827777 TI - Alterations of sucrose preference after Roux-en-Y gastric bypass. AB - Roux-en-Y gastric bypass (gastric bypass) patients reportedly have changes in perception and consumption of sweet-tasting foods. This study aimed to further investigate alterations in sweet food intake in rats and sucrose detection in humans after gastric bypass. Wistar rats were randomized to gastric bypass or sham-operations and preference for sucrose (sweet), sodium chloride (salty), citric acid (sour) and quinine hydrochloride (bitter) was assessed with standard two-bottle intake tests (vs. water). Intestinal T1R2 and T1R3 expression and plasma levels of glucagon-like-peptide 1 (GLP-1) and peptide YY (PYY) were measured. Furthermore, obese patients and normal weight controls were tested for sucrose taste detection thresholds pre- and postoperatively. Visual analogue scales measuring hedonic perception were used to determine the sucrose concentration considered by patients and controls as "just about right" pre- and postoperatively. Gastric bypass reduced the sucrose intake relative to water in rats (p<0.001). Preoperative sucrose exposure reduced this effect. Preference or aversion for compounds representative of other taste qualities in naive rats remained unaffected. Intestinal T1R2 and T1R3 expression was significantly decreased in the alimentary limb while plasma levels of GLP-1 and PYY were elevated after bypass in rats (p=0.01). Bypass patients showed increased taste sensitivity to low sucrose concentrations compared with controls (p<0.05), but both groups considered the same sucrose concentration as "just about right" postoperatively. In conclusion, gastric bypass reduces sucrose intake relative to water in sucrose-naive rats, but preoperative sucrose experience attenuates this effect. Changes in sucrose taste detection do not predict hedonic taste ratings of sucrose in bypass patients which remain unchanged. Thus, factors other than the unconditional affective value of the taste may also play a role in determining food preferences after gastric bypass. PMID- 21827778 TI - Nocturnal hyperthermia induced by social stress in male tree shrews: relation to low testosterone and effects of age. AB - Stress is known to elevate core body temperature (CBT). We recorded CBT in a diurnal animal, the male tree shrew, during a one-week control period and a one week period of social stress using a telemetric system. During the stress period, when animals were confronted with a dominant male for about 1h daily, CBT was increased throughout the day. We analyzed CBT during the night when animals were left undisturbed and displayed no locomotor activity. To determine whether nocturnal hyperthermia may be related to stress-induced changes in hormonal status, we measured testosterone, noradrenalin and cortisol in the animals' morning urine. The daily social stress increased the mean nocturnal temperature by 0.37 degrees C. Urinary testosterone was reduced during the stress period, and there was a significant negative correlation between testosterone and the area under the curve (AUC) of the nocturnal CBT. This means that stress-induced hyperthermia was strongest in the animals with the lowest testosterone concentrations. As expected, urinary noradrenalin was elevated during the stress week but a positive correlation with the AUC data was only found for animals younger than 12 months. Cortisol was also increased during the stress week but there were no correlations with nocturnal hyperthermia. However, the stress induced increases in noradrenalin and cortisol correlated with each other. Furthermore, there were no correlations between the stress-induced increase in nocturnal CBT and body weight reduction or locomotor activity during the light phase. Interestingly, the extent of nocturnal hyperthermia depended on the animals' ages: In animals younger than 12 months, stress increased the AUC by 48%, in animals aged between 12 and 24 months, stress increased the AUC by 36%, and older animals showed only a 7% increase. However, testosterone was not significantly reduced in the older animals. The present data reveal an interrelation between the extent of stress-induced nocturnal hyperthermia, the animals' gonadal hormone status and their ages. The negative correlation between hyperthermia and testosterone indicates that this hormone in particular plays an important role in the regulation of body temperature in male tree shrews. PMID- 21827779 TI - Hypoxia stimulates the production of the angiogenesis inhibitor 2 methoxyestradiol by swine granulosa cells. AB - We previously demonstrated the presence of 2-methoxyestradiol (2-ME) in swine follicular fluid. Present study was aimed first of all to investigate if swine granulosa cell produce 2-ME; in addition, we tried to assess a potential effect of hypoxia in modulating 2-ME output. Finally, we explored the effect of 2-ME in an angiogenesis bioassay set up in our lab. Our data show that cultured granulosa cells are able to produce 2-ME; interestingly, the secretion of the hormone appeared to be stimulated by hypoxia. Angiogenesis bioassay points out that 2-ME displays an inhibitory effect on neovascularisation. Therefore our data suggest that 2-ME could be a local effector in determining the fine tuning responsible for follicle angiogenesis. These data deserve special attention since the ovary is a valuable experimental model in angiogenesis research. PMID- 21827775 TI - Towards a glutamate hypothesis of depression: an emerging frontier of neuropsychopharmacology for mood disorders. AB - Half a century after the first formulation of the monoamine hypothesis, compelling evidence implies that long-term changes in an array of brain areas and circuits mediating complex cognitive-emotional behaviors represent the biological underpinnings of mood/anxiety disorders. A large number of clinical studies suggest that pathophysiology is associated with dysfunction of the predominant glutamatergic system, malfunction in the mechanisms regulating clearance and metabolism of glutamate, and cytoarchitectural/morphological maladaptive changes in a number of brain areas mediating cognitive-emotional behaviors. Concurrently, a wealth of data from animal models have shown that different types of environmental stress enhance glutamate release/transmission in limbic/cortical areas and exert powerful structural effects, inducing dendritic remodeling, reduction of synapses and possibly volumetric reductions resembling those observed in depressed patients. Because a vast majority of neurons and synapses in these areas and circuits use glutamate as neurotransmitter, it would be limiting to maintain that glutamate is in some way 'involved' in mood/anxiety disorders; rather it should be recognized that the glutamatergic system is a primary mediator of psychiatric pathology and, potentially, also a final common pathway for the therapeutic action of antidepressant agents. A paradigm shift from a monoamine hypothesis of depression to a neuroplasticity hypothesis focused on glutamate may represent a substantial advancement in the working hypothesis that drives research for new drugs and therapies. Importantly, despite the availability of multiple classes of drugs with monoamine-based mechanisms of action, there remains a large percentage of patients who fail to achieve a sustained remission of depressive symptoms. The unmet need for improved pharmacotherapies for treatment-resistant depression means there is a large space for the development of new compounds with novel mechanisms of action such as glutamate transmission and related pathways. This article is part of a Special Issue entitled 'Anxiety and Depression'. PMID- 21827780 TI - Study of the effect of thiols on the vasodilatory potency of S-nitrosothiols by using a modified aortic ring assay. AB - Both low-molecular-mass thiols (LMM-SH) and protein thiols (P-SH) can modulate the biological activity of S-nitrosothiols (RSNO) via S-transnitrosation reactions. It has been difficult to evaluate the entity of this effect in blood circulation by in vitro assays with isolated aorta rings so far, because media rich in proteins cannot be used due to the foaming as a consequence of the needed gas bubbling. We have modified the original apparatus for organ bioassay in order to minimize foaming and to increase analytical performance. By using this modified bioassay we investigated the vasodilatory potency of various endogenous RSNOs in the presence of physiologically relevant concentrations of albumin and LMM-SH. Our results show that the sulfhydryl group of the cysteine moiety of albumin and LMM-SH has a dramatic effect on the vasodilatory potency of RSNO. Considering the equilibrium constants for S-transnitrosation reactions and the concentration of P-SH and LMM-SH we measured in healthy humans (aged 18-85 years), we infer that the age-dependency of hematic levels of LMM-SH may have a considerable impact in RSNO-mediated vasodilation. S-Nitrosoproteins such as S nitrosoalbumin may constitute a relatively silent and constant amount of circulating RSNO. On the other hand, LMM-SH may mediate and control the biological actions of S-nitrosoproteins via S-transnitrosation reactions, by forming more potent nitric oxide-releasing LMM-S-nitrosothiols. Lifestyle habits, status of health and individual age are proven factors that, in turn, may influence the concentration of these compounds. These aspects should be taken into consideration when testing the vasodilatory effects of RSNO in pre-clinical studies. PMID- 21827781 TI - Non-response bias in a web-based health behaviour survey of New Zealand tertiary students. AB - OBJECTIVE: There has been little investigation of non-response bias in web-based health surveys. We hypothesised that non-respondents have a higher prevalence of risk behaviours than respondents. METHOD: In 2005, random samples of students aged 17-25 years from 12 New Zealand tertiary institutions (n=7130) were invited to complete a web-based health behaviour survey, with three e-mail reminders. Early respondents (before 2nd reminder) were compared with late respondents (after 2nd reminder). Late respondents served as a proxy for non-respondents. RESULTS: 2607 students (37%) responded early, 676 (9%) responded late, and 3847 (54%) did not respond. There were differences between early and late respondents in high school binge drinking (38% vs 47%, p=0.002) and non-compliance with physical activity guidelines (12% vs 18%, p=0.004). Differences in overweight/obesity (26% vs 31%, p=0.058), smoking (18% vs 22%, p=0.091) and non compliance with dietary guidelines (76% vs 77%, p=0.651) were non-significant but point estimates were in the expected direction. Estimated bias in prevalence of risk behaviours was an absolute difference of 1-4% and a relative difference of 0 21%. CONCLUSION: Respondents whose participation was hardest to elicit reported more risk behaviour. Assuming non-respondents' behaviour is similar or more extreme than that of late respondents, prevalence will have been substantially underestimated. PMID- 21827782 TI - Rheological and structural characterisation of film-forming solutions and biodegradable edible film made from kefiran as affected by various plasticizer types. AB - The rheological properties of kefiran film-forming solutions, as well as the structural characterisation of the resulting films, were investigated as a function of various plasticizer types. The behaviours of the storage (G') and loss (G") moduli as a function of frequency were typical of gel-like material, with the G' higher than the G". Kefiran-based films, which may find application as edible films, were prepared by a casting and solvent-evaporation method. Possible interaction between the adjacent chains in the kefiran polymer and various plasticizers was proven by Fourier-transform infrared spectroscopy (FT IR). The crystallinity of plasticized kefiran film was also analysed using X-ray diffraction (XRD); this revealed an amorphous-crystalline structure. These results were explained by the film's microstructure, which was analysed by atomic force microscopy (AFM) and scanning electron microscopy (SEM). The present study has helped determine possible interactions of kefiran, plasticizer and water molecules in determining film properties. PMID- 21827783 TI - Molecular cloning, characterization and expression analysis of two novel Tolls (LvToll2 and LvToll3) and three putative Spatzle-like Toll ligands (LvSpz1-3) from Litopenaeus vannamei. AB - Toll-like receptor-mediated NF-kappaB pathways are essential for inducing immune related-gene expression in the defense against bacterial, fungal and viral infections in insects and mammals. Although a Toll receptor (LvToll1) was cloned in Litopenaeus vannamei, relatively little is known about other types of Toll like receptors and their endogenous cytokine-like ligand, Spatzle. Here, we report two novel Toll-like receptors (LvToll2 and LvToll3) and three Spatzle-like proteins (LvSpz1-3) from L. vannamei. LvToll2 has 1009 residues with an extracellular domain containing 18 leucine-rich repeats (LRRs) and a cytoplasmic Toll/interleukin-1 receptor (TIR) domain of 139 residues. LvToll3 is 1244 residues long with an extracellular domain containing 23 LRRs and a cytoplasmic TIR domain of 138 residues. The Spatzle-like proteins LvSpz1, LvSpz2 and LvSpz3 are 237, 245 and 275 residues in length, respectively, and all of them have a putative C-terminal cystine-knot domain. In Drosophila Schneider 2 (S2) cells, LvToll1 and LvToll3 were localized to the membrane and cytoplasm, and LvToll2 was confined to the cytoplasm. In Drosophila S2 cells, LvToll2 could significantly activate the promoters of NF-kappaB-pathway-controlled antimicrobial peptide genes, whereas LvToll1 and LvToll3 had no effect on them. LvSpz1 exerted some degree of inhibition on the promoter activities of Drosophila Attacin A and L. vannamei Penaeidin4. LvSpz3 also inhibited the Drosophila Attacin A promoter, but LvSpz2 could only slightly activate it. LvToll1, LvToll2 and LvToll3 were constitutive expressed in various tissues, while LvSpz1, LvSpz2 and LvSpz3 exhibited tissue-specific expression in the epithelium, eyestalk, intestine, gill and muscle. In the gill, after Vibrio alginolyticus challenge, LvToll1 was upregulated, but LvToll2 and LvToll3 showed no obvious changes. LvSpz1 and LvSpz3 were also strongly induced by V. alginolyticus challenge, but LvSpz2 only showed a slight downregulation. In the gill, after white spot syndrome virus (WSSV) challenge, LvToll1, LvToll2, LvToll3, LvSpz1 and LvSpz3 were upregulated, but LvSpz2 showed no obvious change, except for a slight downregulation at 12h post injection of WSSV. These findings might be valuable in understanding the innate immune signal pathways of shrimp and enabling future studies on the host-pathogen interactions in V. alginolyticus and WSSV infections. PMID- 21827784 TI - Constructions of expression vectors of polyhydroxybutyrate-co-hydroxyvalerate (PHBV) and transient expression of transgenes in immature oil palm embryos. AB - Polyhydroxybutyrate-co-hydroxyvalerate (PHBV) is a polyhydroxyalkanoate (PHA) bioplastic group with thermoplastic properties is thus high in quality and can be degradable. PHBV can be produced by bacteria, but the process is not economically competitive with polymers produced from petrochemicals. To overcome this problem, research on transgenic plants has been carried out as one of the solutions to produce PHBV in economically sound alternative manner. Four different genes encoded with the enzymes necessary to catalyze PHBV are bktB, phaB, phaC and tdcB. All the genes came with modified CaMV 35S promoters (except for the tdcB gene, which was promoted by the native CaMV 35S promoter), nos terminator sequences and plastid sequences in order to target the genes into the plastids. Subcloning resulted in the generation of two different orientations of the tdcB, pLMIN (left) and pRMIN (right), both 17.557 and 19.967 kb in sizes. Both plasmids were transformed in immature embryos (IE) of oil palm via Agrobacterium tumefaciens. Assays of GUS were performed on one-week-old calli and 90% of the calli turned completely blue. This preliminary test showed positive results of integration. Six-months-old calli were harvested and RNA of the calli were isolated. RT-PCR was used to confirm the transient expression of PHBV transgenes in the calli. The bands were 258, 260, 315 and 200 bp in size for bktB, phaB, phaC and tdcB transgenes respectively. The data obtained showed that the bktB, phaB, phaC and tdcB genes were successfully integrated and expressed in the oil palm genome. PMID- 21827785 TI - Neural bases of childhood speech disorders: lateralization and plasticity for speech functions during development. AB - Current models of speech production in adults emphasize the crucial role played by the left perisylvian cortex, primary and pre-motor cortices, the basal ganglia, and the cerebellum for normal speech production. Whether similar brain behaviour relationships and leftward cortical dominance are found in childhood remains unclear. Here we reviewed recent evidence linking motor speech disorders (apraxia of speech and dysarthria) and brain abnormalities in children and adolescents with developmental, progressive, or childhood-acquired conditions. We found no evidence that unilateral damage can result in apraxia of speech, or that left hemisphere lesions are more likely to result in dysarthria than lesion to the right. The few studies reporting on childhood apraxia of speech converged towards morphological, structural, metabolic or epileptic anomalies affecting the basal ganglia, perisylvian and rolandic cortices bilaterally. Persistent dysarthria, similarly, was commonly reported in individuals with syndromes and conditions affecting these same structures bilaterally. In conclusion, for the first time we provide evidence that longterm and severe childhood speech disorders result predominantly from bilateral disruption of the neural networks involved in speech production. PMID- 21827786 TI - Cognitive mechanisms of auditory verbal hallucinations in psychotic and non psychotic groups. AB - The continuum model of psychosis has been extremely influential. It assumes that psychotic symptoms, such as auditory verbal hallucinations (AVH), are not limited to patients with psychosis but also occur in healthy, non-clinical individuals - suggesting similar mechanisms of origin. Recent debate surrounding this model has highlighted certain differences, as well as similarities, in the phenomenology of AVH in clinical and non-clinical populations. These findings imply that there may, in fact, be only partial overlap of the mechanism(s) involved in generating AVH in these groups. We review evidence of continuity or similarity, and dissimilarity, in cognitive, and related neural processes, underlying AVH in clinical and non-clinical samples. The results reveal some shared (intrusive cognitions, inhibitory deficits) and some distinct (aspects of source memory and cerebral lateralization) mechanisms in these groups. The evidence, therefore, supports both continuous and categorical models of positive psychotic symptoms. The review considers potential risks of uncritical acceptance of the continuum model and highlights some important methodological issues for future research. PMID- 21827787 TI - Neuronal apoptosis in the striatum of rats treated with 3-nitropropionic acid is not triggered by cell-cycle re-entry. AB - Although terminally differentiated neurons lack the capacity to undergo cell division, they retain the capacity to reactivate the cell cycle. This reactivation, however, has been linked to the degeneration of neurons in many experimental models of neurodegenerative disease and in post-mortem brains of affected patients. Expression of markers of the G1 phase and apoptotic neurons has been detected in the striatal lesion of rats treated with 3-nitropropionic acid (3-NPA). Here we examined whether neuronal apoptosis induced by 3-NPA was mediated by the reactivation of the cell cycle. To this end, we studied whether TUNEL-positive neurons expressed the G1-phase markers cyclin-dependent kinase 4 (CDK4) and cyclin D (CyD). In addition, we also evaluated the neuronal expression of pRb and Ki67 antigens, both of which are involved in the regulation of cell cycle progression. In 3-NPA-treated rats, CDK4 and CyD were not detected in TUNEL positive neurons, but they were expressed in neurons in the core of the lesion, which were assumed to be in a more advanced stage of degeneration, since they had weaker NeuN staining and lacked Hoechst staining. In addition, injured neurons in the striatal lesion of 3-NPA-treated rats had lost the constitutive expression of pRb and Ki67 that we had detected in control animals. Taken together, these results indicate that neuronal apoptosis in the striatal lesion of 3-NPA-treated rats was not triggered by cell-cycle re-entry, and we conclude that expression of G1 markers may be considered an aberrant survival response, with no relation to the mechanisms of apoptosis. PMID- 21827788 TI - Brain activity during stepping: a novel MRI-compatible device. AB - Little is known about the impact of supraspinal centers on the control of human locomotion. Analyzing brain activity can help to clarify their impact and to improve the effects of locomotor training. A fMRI-compatible pneumatic robotic device is presented that can generate freely programmable, highly repetitive periodic active and passive leg movements comprised by hip, knee, and ankle joint displacements. Forces of up to 400N can be applied to each foot while the subject is lying in a supine position. Magnetic interference of the device with the magnetic field of the scanner is measurable, but does not affect the image quality as obtained by a usual image analysis procedure. In a first experiment, brain activity of one healthy subject was acquired during nine different gait like movement conditions. Brain activity in the somatosensory and motor function related areas increased more when the subject actively moved the legs than when the legs were passively moved by the device. In almost all conditions, mean head motion could be limited to 2mm within the duration of one fMRI scan by a specifically developed head and trunk fixation system. Based on these results, it is concluded that our device will significantly contribute to a better understanding of human locomotor control and related therapeutic effects in spinal cord injured and stroke patients, and thereby, to improve training approaches. PMID- 21827789 TI - Adeno-associated viral vector-mediated gene transduction in mesencephalic slice culture. AB - Adeno-associated viral (AAV) vector is a non-pathogenic vehicle that is suitable for the delivery of foreign genes into non-dividing neuronal cells. This vector has been utilized for in vivo neurological research and in clinical trials of gene therapy for neurodegenerative disorders. Viral vector-mediated gene delivery has the limitation that progressive changes in cellular phenotype cannot be monitored in living animals. To visualize living neurons transduced with foreign genes in vitro, we used cultured mesencephalic tissue harboring living dopaminergic (DA) neurons and examined cellular tropism of serotype-1 and serotype-2 AAV vectors in a culture system. The viability of DA neurons was evaluated using transgenic mice carrying enhanced green fluorescent protein under the control of the rat tyrosine hydroxylase (TH) promoter, which enables the visualization of living DA cells in the substantia nigra. Apoptosis of a subset of neuronal cells was noted within one day of culture. After 7 days, the serotype 1 AAV vector had successfully delivered the foreign gene into neurons and astrocytes, and serotype-2 AAV vector was able to transduce TH-positive DA neurons efficiently. Our method should be useful for in vitro investigations of pathological changes in DA neurons following transduction with foreign genes. PMID- 21827790 TI - Validation of an IgM antibody capture ELISA based on a recombinant nucleoprotein for identification of domestic ruminants infected with Rift Valley fever virus. AB - The presence of competent vectors in some countries currently free of Rift Valley fever (RVF) and global changes in climate, travel and trade have increased the risk of RVF spreading to new regions and have emphasised the need for accurate and reliable diagnostic tools for early diagnosis during RVF outbreaks. Highly sensitive viral detection systems like PCR have a limited use during outbreaks because of the short duration of viraemia, whereas antibodies like specific IgM which are serological indicators of acute infection, can be detected for up to 50 days after infection. Using the highly conserved and immunogenic recombinant nucleoprotein of RVF virus in an IgM capture ELISA, the risk of laboratory infection associated with traditional serological methods is avoided. The use of pre-coated/pre-blocked ELISA plates and the conjugation of the recombinant nucleoprotein with horseradish peroxidase simplified and shortened the assay procedure. Results showed the assay to be highly reproducible with a lower detection limit equal to that of a commercial competition ELISA. By receiver operating characteristic (ROC) curve analysis the area under curve (AUC) index was determined as 1.0 and the diagnostic sensitivity and specificity at a PP cut off value of 4.1 as 100% and 99.78% respectively. The results of this study demonstrated that the IgM capture ELISA is a safe, reliable and highly accurate diagnostic tool which can be used on its own or in parallel with other methods for the early diagnosis of RVF virus infection and also for monitoring of immune responses in vaccinated domestic ruminants. PMID- 21827791 TI - Secretory expression of all 16 subtypes of the hemagglutinin 1 protein of influenza A virus in insect cells. AB - Influenza viruses are known for their ability to change their antigenic structure and create new viral strains. Hemagglutinin (HA), for which 16 subtypes have been identified, is a major antigenic determinant essential for the pathogenesis of influenza A viruses. To predict and monitor future epidemics, it is critical to produce various HA subtype antigens conveniently and rapidly. A simple, effective, and economic method to generate subunit HA1 of all 16 HA subtypes as recombinant proteins (rHA1) is reported. rHA1 proteins are expressed in insect cells as secretory proteins after integration into a baculovirus expression vector containing a 6*His tag element and the signal peptide of the GP67 protein, a membrane glycoprotein identified in Autographa californica nuclear polyhedrosis virus. The proteins can be purified to >=90% purity using a single Ni(2+) chelating affinity chromatography step, yielding a recovery rate of about 50%. The rHA1 proteins elicit high titer antibodies in mice and show high specificity in Western blots. This study paves the way for subtype specific detection methods and for future studies of the immune relationships among the subtypes of influenza A virus HA proteins. PMID- 21827793 TI - Activity of cholinergic neurons in the laterodorsal tegmental nucleus during emission of 22kHz vocalization in rats. AB - It has been postulated that the ascending cholinergic tegmental system is responsible for the initiation of the aversive emotional state with a concomitant alarm vocalization in the rat. It is assumed that the activity of cholinergic neurons of the laterodorsal tegmental nucleus (LDT) will cause release of acetylcholine in the target areas and will initiate the emission of 22kHz vocalizations. The goal of the present study was to test the hypothesis that the cholinergic neurons of the LDT increase their activity during emission of 22kHz alarm calls. Vocalizations were induced by an air puff or by intrahypothalamic preoptic injection of carbachol. The activity of the LDT cholinergic neurons was studied by a double histochemical labelling for choline acetyltransferase, as a marker of cholinergic somata, and for c-Fos protein, as a marker of cells with heighten metabolic activity. Both air puff stimulation and intracerebral carbachol induced comparable 22kHz alarm vocalizations. The activity of neurons in the LDT was significantly higher during prolonged emission of 22kHz alarm calls induced by air puff or injection of carbachol than in the non-vocalizing or low-vocalizing controls. There were approximately two times more of all c-Fos labelled cells in the LDT of vocalizing animals and 2.5 times more active cholinergic neurons during prolonged 22kHz vocalization than in the control conditions without vocalization. However, the active cholinergic neurons constituted only a small proportion of all active LDT cells (2.3%). At the same time, there were no significant increases in the number of c-Fos-labelled cells in the neighbouring pedunculopontine nucleus (PPT). These findings lead to the conclusion that the neurons of the LDT, including cholinergic neurons, but not those of the PPT, significantly increased their activity during prolonged emission of alarm vocalizations, as evidenced by the c-Fos immunoreactivity. PMID- 21827792 TI - Damage to the lateral prefrontal cortex impairs familiarity but not recollection. AB - Frontal lobe lesions impair recognition memory but it is unclear whether the deficits arise from impaired recollection, impaired familiarity, or both. In the current study, recognition memory for verbal materials was examined in patients with damage to the left or right lateral prefrontal cortex. Words were incidentally encoded under semantic or phonological orienting conditions, and recognition memory was tested using a 6-point confidence procedure. Receiver operating characteristics (ROCs) were examined in order to measure the contributions of recollection and familiarity to recognition memory. In both encoding conditions, lateral prefrontal cortex damage led to a deficit in familiarity but not recollection. Similar deficits were observed in left and right hemisphere patients. The results indicate that the lateral prefrontal cortex plays a critical role in the monitoring or decision processes required for accurate familiarity-based recognition responses. PMID- 21827795 TI - Variation in the NMDA receptor 2B subunit gene GRIN2B is associated with differential language lateralization. AB - Variations in the N-methyl-d-aspartate receptor 2B subunit gene (GRIN2B) have been associated with schizophrenia, a psychiatric disorder associated with reduced left-hemispheric language dominance. Here, we investigated, whether different polymorphisms in GRIN2B influence language lateralization and handedness in healthy individuals. In a cohort of 424 genetically unrelated participants we found significant association between the synonymous GRIN2B variation rs1806201 and language lateralization assessed using the dichotic listening task. Individuals carrying the heterozygous CT genotype exhibited more pronounced left-hemispheric language dominance as compared to both homozygous CC and TT individuals. Such an association was not identified for handedness. These findings suggest that variation in NMDA-receptors contributes to the interindividual variability of language lateralization. PMID- 21827794 TI - The context preexposure facilitation effect in mice: a dose-response analysis of pretraining scopolamine administration. AB - The context preexposure facilitation effect (CPFE) is an elaboration of contextual fear conditioning and refers to enhanced contextual conditioning resulting from preexposure to the context prior to a separate, brief context shock episode. A version of the CPFE developed by Rudy and colleagues in rats has demonstrated greater sensitivity to pre-training hippocampal insult relative to standard contextual fear conditioning preparations. Our aim was to adapt the Rudy CPFE procedures to mice. In Experiment 1 we compared performance of young adult male C57BL6/J mice on two versions of the CPFE. One version - not previously used in mice - adapted methods established by Rudy and colleagues, and the other CPFE task replicated procedures previously established in this mouse strain by Gould and colleagues. In Experiment 2 we compared the effects of pre-training intraperitoneal administration of moderate levels of scopolamine or methylscopolamine on contextual conditioning between mice trained using the Rudy CPFE method and a separate group trained using standard contextual fear procedures. Scopolamine is a muscarinic cholinergic receptor antagonist that impairs hippocampal function. Robust freezing to the conditioning context was observed in mice trained using the Rudy CPFE method (Experiment 1), and greater scopolamine-induced impairments in contextual freezing were observed using this CPFE method relative to mice trained using standard contextual fear procedures (Experiment 2). These findings support use of the Rudy CPFE task as a behavioral assay for hippocampal function in mice. PMID- 21827796 TI - Comparison of molecular and McMaster microscopy techniques to confirm the presence of naturally acquired strongylid nematode infections in sheep. AB - Patent strongylid nematode infections were identified using McMaster worm egg counts (WEC) and PCR assays (ITS-2 nuclear ribosomal DNA) to screen genomic DNA extracted directly from lamb faecal samples. Lambs from four different farms in southern Western Australia were sampled rectally on two separate occasions, with McMaster WECs and PCRs conducted on a total of 858 samples. Negative controls (n=96) (WEC <50 eggs per gram [epg]) and positive controls (n=96) (faecal samples spiked with a 100 MUL suspension of third-stage larvae (L(3)) containing approximately equal proportions of Teladorsagia circumcincta, Trichostrongylus colubriformis, Haemonchus contortus, Oesophagostomum spp. and Chabertia ovina) were generated. All control samples amplified in accordance with positive controls. High levels of agreement (Kappa values >= 0.93) were identified between the two diagnostic tests. PCRs detected an additional 2.0% of samples as strongylid-positive but there was no significant difference in the number of strongylid-positive samples identified using PCR or McMaster WEC. PMID- 21827797 TI - Directed evolution of a thermostable l-aminoacylase biocatalyst. AB - Enzymes from extreme environments possess highly desirable traits of activity and stability for application under process conditions. One such example is l aminoacylase (E.C. 3.5.1.14) from Thermococcus litoralis (TliACY), which catalyzes the enantioselective amide hydrolysis of N-protected l-amino acids, useful for resolving racemic mixtures in the preparation of chiral intermediates. Variants of this enzyme with improved activity and altered substrate preference are highly desirable. We have created a structural homology model of the enzyme and applied various two different directed evolution strategies to identify improved variants. Mutants P237S and F251Y were 2.4-fold more active towards N benzoyl valine relative to the wild type at 65 degrees C. F251 mutations to basic residues resulted in 4.5-11-fold shifts in the substrate preference towards N benzoyl phenylalanine relative to N-benzoyl valine. The substrate preference of wild type decreases with increasingly branched and sterically hindered substrates. However, the mutant S100T/M106K disrupted this simple trend by selectively improving the substrate preference for N-benzoyl valine, with a >30 fold shift in the ratio of k(cat) values for N-benzoyl valine and N-benzoyl phenylalanine. Mutations that favoured N-benzoyl-phenylalanine appeared at the active site entrance, whereas those improving activity towards N-benzoyl-valine occurred in the hinge region loops linking the dimerization and zinc-binding domains in each monomer. These observations support a previously proposed substrate induced conformational transition between open and closed forms of aminoacylases. PMID- 21827798 TI - Generation of recombinant metapneumovirus nucleocapsid protein as nucleocapsid like particles and development of virus-specific monoclonal antibodies. AB - Human metapneumovirus (hMPV) is a member of the Pneumovirinea subfamily within the Paramyxoviridea family. Since its discovery in 2001, hMPV has been isolated in several continents, which suggests its prevalence worldwide. hMPV resembles human respiratory syncytial virus with regard to disease symptoms and its ability to infect and cause disease in young infants as well as individuals of all ages. The aim of the current study was to construct an efficient high-level yeast expression system for the generation of hMPV nucleocapsid (N) protein and to develop monoclonal antibodies (MAbs) suitable for hMPV detection. The genome of hMPV was isolated from oral fluid of an infected patient by using specific primers and reverse transcriptase polymerase chain reaction (RT-PCR). DNA sequence corresponding to the N protein gene was inserted into yeast expression vector under inducible GAL7 promoter. SDS-PAGE analysis of crude lysates of yeast Saccharomyces cerevisiae harbouring recombinant plasmid revealed the presence of a protein band of approximately 43 kDa corresponding to the molecular weight of hMPV N protein. Electron microscopy analysis of purified N protein revealed nucleocapsid-like structures with typical herring-bone morphology: rods of 20 nm diameter with repeated serration along the edges and central core of 5 nm. Recombinant hMPV N protein was reactive with human serum specimens collected from patients with confirmed hMPV infection. After immunization of mice with recombinant hMPV N protein, a panel of MAbs was generated. The specificity of newly generated MAbs was proven by immunofluorescence analysis of hMPV-infected cells. Epitope mapping using truncated variants of hMPV N revealed localization of linear MAb epitopes at the N-terminus of hMPV N protein, between amino acid residues 1 and 90. The MAbs directed against conformational epitopes did not recognize hMPV N protein variants containing either N- or C-terminal truncations. The reactivity of recombinant hMPV N protein with hMPV-positive serum specimens and the ability of MAbs to recognize virus-infected cells confirms the antigenic similarity between yeast-expressed hMPV N protein and native viral nucleocapsids. In conclusion, recombinant hMPV N protein and hMPV-specific MAbs provide new diagnostic reagents for hMPV infection. PMID- 21827799 TI - Phylogenetic analysis of VP1, VP2, and VP3 gene segments of genotype G5 group A rotavirus strains circulating in Brazil between 1986 and 2005. AB - Genotype G5 group A rotavirus (RV-A), which is common in pigs and also detected in horses and cattle, circulated as endemic genotype in the 1980s and early 1990s in Brazil. After 1996, G5 RV-A has been replaced by G9 RV-A, becoming only sporadically detected. Recently, G5 has been reported in children with severe diarrhea in Argentina, Cameroon, Paraguay, People's Republic of China, and Vietnam, suggesting that, although uncommon in humans, it has a worldwide distribution. In a previous study, Brazilian G5 RV-A VP7 gene analysis demonstrated the existence of three main lineages: I, II, and III; all Brazilian strains and three porcine strains from Thailand grouped inside Lineage I. The VP8(*) subunit of VP4 gene showed that all P[8] strains fell into three major genetic lineages: P[8]-1; P[8]-2; and P[8]-3. Partial sequencing and phylogenetic analysis of VP1, VP2 and VP3 genes of P[8]G5 human RV-A strains were determined from 28 Brazilian strains collected from 1986 to 2005. The VP1-VP3 partial sequences analysis showed that the Brazilian strains have high amino acid identity with the human RV-A prototype IAL28 and other Wa-like genogroup strains. It was also shown that G5 RV-A Brazilian VP1-VP3 and VP7 sequences have a similar pattern of gouping: The study strains and the G5 prototype strain IAL-28 grouped together, while other prototypes, like OSU grouped separately. These results suggest that the core protein genes (VP1-VP3) of the G5 RV-A Brazilian strains might have originated from porcine and human strains. Phylogenetic analyses of VP7, VP4, VP1, VP2, and VP3 genes of P[8]G5 strains revealed a conserved genomic constellation (G5-P[8]-R1-C1-M1) with sequence similarity to Wa-like strains: IAL28, Wa, BE00048, CK00032, CK00033, DC4772 and DC1898, suggesting that despite the differences in genotypes (i.e., G5, G1 and G3) these viruses are genetically similar. The results presented here are fundamental to understand the epidemiology and evolution of genotype G5 RV-A and demonstrate the importance of continuous monitoring and molecular characterization of RV-A strains circulating in human and animal populations. PMID- 21827800 TI - Inkjet printing as a novel medicine formulation technique. AB - We demonstrate the viability of using an ink-jet printer to produce a formulation capable of controlling the release of a drug. This is shown for the drug felodipine, an antihypertensive, with polyvinyl pirrolidone (PVP) as an excipient. As felodipine is a poorly water soluble drug, its molecular dispersion in a soluble polymer (ie. PVP) is a commonly used approach to improve bioavailability. Various ratios of felodipine and PVP in an ethanol-DMSO mixture (95/5) were dispensed in picoliter quantities using a piezoelectric 'ink-jet' head onto a hydrophobic substrate. The resultant formulation spots were characterized using atomic force microscopy, localized nano-thermal analysis, ATR IR and imaging confocal Raman spectroscopy. Intimate mixing of the felodipine and PVP within the micro-dots was observed. ATR-IR confirmed the known molecular level interaction of felodipine and PVP through hydrogen bonding. Nanothermal analysis indicated a single glass transition point, indicative of an intimate polymer drug mixture, which is lowered as the drug concentration increases. Confocal Raman microscopy mapping on single micro-scale droplets allowed the visualization of the drug distribution in the spots as well as facilitating characterization of the release of the drug. The drug release can be altered through control of the drug loading. As inkjet printing is an inherently scalable technology, this proof of principal work with single deposited micro-spot formulations demonstrates the potential of this approach to print practical dosage forms (e.g. as an array of many thousands of spots with different release profiles). This, for example, raises the possibility in the future of producing dosage forms at points of care with one or more drugs which have been formulated for the needs of individual patients. PMID- 21827801 TI - LyP-1-conjugated PEGylated liposomes: a carrier system for targeted therapy of lymphatic metastatic tumor. AB - The application of liposomes in targeted therapy of lymphatic metastatic tumors has been hampered by the low uptake rate of liposome by metastatic lymph nodes. In this report, LyP-1, a peptide that can specifically bind tumor cells, tumor lymphatics and tumor-associated macrophages, was conjugated to liposomes for targeting and treating lymphatic metastatic tumors. Firstly, LyP-1-conjugated PEGylated liposomes loaded with fluorescein or doxorubicin (DOX) were prepared and showed satisfactory vesicle size and size distribution. The in vitro cellular uptake and in vivo near-infrared fluorescence imaging results showed that LyP-1 modification increased liposome uptake by tumor cells and metastatic lymph nodes, but did not increase uptake by normal lymph nodes. The immunofluorescence analysis evidenced that LyP-1-conjugated liposomes were distributed adjacent to tumor lymphatics and tumor-associated macrophages in metastatic lymph nodes. The pharmacodynamic study suggested that compared with unmodified liposomes, LyP-1 conjugated DOX-loaded liposomes exhibited enhanced inhibition effect on tumor cells in vitro and lymphatic metastatic tumors in vivo. Pathological examination showed that liposomal DOX caused reduced tissue damage to injection site compared with DOX solution. In summary, LyP-1-conjugated PEGylated liposomes could be targeted to metastatic lymph nodes based on their specific binding to tumor cells, tumor lymphatics and tumor-associated macrophages. They are a safe and effective drug delivery system of antineoplastic agents for targeted therapy of lymphatic metastatic tumors. PMID- 21827802 TI - Gut-associated lymphoid tissues for the development of oral vaccines. AB - Oral vaccine has been considered to be a prospective vaccine against many pathogens especially invading across gastrointestinal tracts. One key element of oral vaccine is targeting efficient delivery of antigen to gut-associated lymphoid tissue (GALT), the inductive site in the intestine where antigen specific immune responses are initiated. Various chemical and biological antigen delivery systems have been developed and some are in clinical trials. In this review, we describe the immunological features of GALT and the current status of antigen delivery system candidates for successful oral vaccine. PMID- 21827803 TI - Polymorphisms of ERCC1 C118T/C8092A and MDR1 C3435T predict outcome of platinum based chemotherapies in advanced non-small cell lung cancer: a meta-analysis. AB - BACKGROUND AND AIMS: With great progress made in individualized chemotherapy, pharmacogenetics is gradually put on the agenda. We performed this meta-analysis to compare outcome to platinum-based chemotherapies in advanced non-small cell lung cancer (NSCLC) with different ERCC1 C118T/C8092A and MDR1 C3435T polymorphisms. METHODS: Relevant studies were identified according to search strategy in this meta-analysis. Inclusion criteria were patients with advanced NSCLC who were receiving platinum-based chemotherapies. We evaluated the relationship between single nucleotide polymorphisms (SNP) and outcome of platinum-based chemotherapies. RevMan and STATA package were used for the comprehensive quantitative analyses. RESULTS: Twenty studies were included in the meta-analysis. There was no significant association between SNPs and objective response or overall survival of platinum-based chemotherapies with CC vs. CT/TT: ERCC1 C118T (OR 1.21, 95% CI 0.81-1.82 for objective response; HR 1.09, 95% CI 0.79-1.51 for overall survival); ERCC1 C8092A SNP (OR 0.84, 95% CI 0.59-1.18; HR 1.26, 95% CI 0.68-2.36) and MDR1 C3435T SNP (HR 1.11, 95% CI 0.78-1.56). Ethnic stratification provided the same results. We found a significant difference for MDR1 C3435T (OR 2.22, 95% CI 1.46-3.37; OR 2.63, 95% CI 1.56-4.45 for Asians; OR 1.61, 95% CI 0.79-3.28 for Caucasians). CONCLUSIONS: We found no evidence to support the use of ERCC1 C118T/C8092A polymorphisms as prognostic predictors of platinum-based chemotherapies in NSCLC. For the MDR1 C3435T SNP, a significant association with objective response was detected for CC genotype in overall and Asian populations stratified. Multiple and large-scale studies with ethnic stratification are required for the correlation between biomarkers and tumor prognosis. PMID- 21827804 TI - Effect of the E-selectin gene polymorphism (S149R) on platelet activation and adverse events after coronary artery surgery. AB - BACKGROUND AND AIMS: A common single nucleotide polymorphism in the E-selectin (SELE) gene S149R results in the loss of E-selectin ligand binding specificity. The 149R allele has been associated with severe cardiovascular diseases. We hypothesized that S149R may regulate platelet activation after stimuli associated with perioperative procedures in patients undergoing isolated coronary artery bypass grafting (CABG). Associations between the S149R polymorphism and an increased risk of perioperative acute thrombotic events with regards to a platelet count and activity were analyzed. METHODS: In elective CABG patients (n = 152) we analyzed associations between S149R polymorphism and an increased risk of perioperative acute thrombotic events with regard to platelet count and activity. The S149R SELE gene polymorphism was determined by real-time polymerase chain reaction. Platelet count and activation marker (beta-thromboglobulin betaTG) were evaluated. RESULTS: Prevalence of the S149R genotypes was as follows: 81.8% (n = 121) of homozygotes (149SS), 15.5% (n = 23) of heterozygotes and 2.7% (n = 4) of homozygotes (149RR). The 149R allele carriers had significantly higher postoperative betaTG levels than the homozygotes (97 [79 120] vs. 76 [66-91] IU/mL, p = 0.03). Sixteen patients had adverse events: myocardial infarction (n = 14), stroke (n = 1) and fatal pulmonary embolism (n = 1). Twelve patients were carriers of the 149R allele. Relative risk (RR) of postoperative adverse events in the 149R allele carriers was 2.03 with 95% CI (1.05-3.03). CONCLUSIONS: Postoperative platelet activation is related to the S149R polymorphism, which enhances the risk of adverse events after CABG. PMID- 21827806 TI - Cellular uptake of transportan 10 and its analogs in live cells: Selectivity and structure-activity relationship studies. AB - Transportan 10 (TP10) is an amphipathic cell-penetrating peptide with high translocation ability. In order to obtain more details of structure-activity relationship of TP10, we evaluated the effects of structure and charge on its translocation ability. Our results demonstrated that disrupting the helical structure or Arg substitution could remarkably decrease the cellular uptake of TP10. However, increasing the number of positive charge was an effective strategy to enhance translocation ability of TP10. Furthermore, the molecular dynamics simulation supported the results derived from experiments, suggesting that higher membrane disturbance leads to higher cellular uptake of peptides. In addition, our study also demonstrated TP10 and its analogs preferentially entered cancer cells rather than normal cells. The uptake selectivity toward cancer cells makes TP10 and its analogs as potent CPPs for drug delivery. PMID- 21827805 TI - Localization and enzymatic activity profiles of the proteases responsible for tachykinin-directed oocyte growth in the protochordate, Ciona intestinalis. AB - We previously substantiated that Ci-TK, a tachykinin of the protochordate, Ciona intestinalis (Ci), triggered oocyte growth from the vitellogenic stage (stage II) to the post-vitellogenic stage (stage III) via up-regulation of the gene expression and enzymatic activity of the proteases: cathepsin D, carboxypeptidase B1, and chymotrypsin. In the present study, we have elucidated the localization, gene expression and activation profile of these proteases. In situ hybridization showed that the Ci-cathepsin D mRNA was present exclusively in test cells of the stage II oocytes, whereas the Ci-carboxypeptidase B1 and Ci-chymotrypsin mRNAs were detected in follicular cells of the stage II and stage III oocytes. Double immunostaining demonstrated that the immunoreactivity of Ci-cathepsin D was largely colocalized with that of the receptor of Ci-TK, Ci-TK-R, in test cells of the stage II oocytes. Ci-cathepsin D gene expression was detected at 2h after treatment with Ci-TK, and elevated for up to 5h, and then slightly decreased. Gene expression of Ci-carboxypeptidase B1 and Ci-chymotrypsin was observed at 5h after treatment with Ci-TK, and then decreased. The enzymatic activities of Ci cathepsin D, Ci-carboxypeptidase B1, and Ci-chymotrypsin showed similar alterations with 1-h lags. These gene expression and protease activity profiles verified that Ci-cathepsin D is initially activated, which is followed by the activation of Ci-carboxypeptidase B1 and Ci-chymotrypsin. Collectively, the present data suggest that Ci-TK directly induces Ci-cahtepsin D in test cells expressing Ci-TK receptor, leading to the secondary activation of Ci-chymotrypsin and Ci-carboxypeptidase B1 in the follicle in the tachykininergic oocyte growth pathway. PMID- 21827807 TI - Discovery and development of a synthetic peptide derived from lactoferrin for clinical use. AB - There is an urgent need to develop new antimicrobial drugs especially for combating the rise of infections caused by multi-resistant pathogens such as MRSA and VRSA. The problem of antibiotic resistant micro-organisms is expected to increase disproportionally and controlling of infections is becoming difficult because of the rapid spread of those micro-organisms. Primary therapy with classical antibiotics is becoming more ineffective. Combinational therapy of antibiotics with antimicrobial peptides (AMP's) has been suggested as an alternative approach to improve treatment outcome. Their unique mechanism of action and safety profile makes AMP's appealing candidates for simultaneous or sequential use in different cases of infections. In this review, for antimicrobial treatment the application of synthetic antimicrobial peptide hLF(1 11), derived from the first 11 amino acids of human lactoferrin is evaluated in both pre-clinical and clinical settings. Present information indicates that this derivate from lactoferrin is well tolerated in pre-clinical tests and clinical trials and thus hLF(1-11) is an interesting candidate for further exploration in various clinical indications of obscure infections, including meningitis. Another approach of using AMP's is their use in prevention of infections e.g. as coating for dental or bone implants or in biosensing applications or useful as infection specific radiopharmaceutical. PMID- 21827808 TI - Circulating kisspeptin levels exhibit sexual dimorphism in adults, are increased in obese prepubertal girls and do not suffer modifications in girls with idiopathic central precocious puberty. AB - The system KISS1-KISS1R is one of the main regulators of the hypothalamic pituitary-gonadal axis and constitutes a link between metabolism and reproduction through its interaction with leptin. The aim of this study was to clarify the possible utility of kisspeptin as a pubertal marker and/or the possible influence of nutritional status in kisspeptin levels. To this end, we have studied kisspeptin plasma levels throughout sexual development and in prepubertal obese girls and girls affected by idiopathic central precocious puberty (CPP). Plasma kisspeptin concentrations were analyzed by RIA. An increase in kisspeptin levels was observed in adult females compared to healthy prepubertal and pubertal girls (p<0.001) and to adult males (p<0.001). Additionally, kisspeptin was increased in prepubertal obese girls compared to healthy prepubertal girls (p<0.01) and girls with idiopathic CPP (p<0.05). As revealed by the regression analysis, in prepubertal healthy and obese girls and girls with idiopathic CCP, the parameters that influenced kisspeptin levels were BMI (R(2)=0.10, p<0.05) and leptin levels (R(2)=0.14, p<0.01). In conclusion, kisspeptin levels do not seem to be a good pubertal marker. The results obtained in prepubertal and idiopathic CCP girls point to a relationship between leptin, BMI and kisspeptin at least in this group, and suggest a possible role for adipose tissue in the modulation kisspeptin synthesis. PMID- 21827809 TI - The effect of Ginkgo biloba extract on 3-nitropropionic acid-induced neurotoxicity in rats. AB - 3-Nitropropionic acid (3-NP), an irreversible inhibitor of succinate dehydrogenase enzyme (SDH), induces neurodegeneration similar to that observed in Huntington's disease (HD). Reduction of prepulse inhibition (PPI) of acoustic startle response, locomotor hypoactivity, bilateral striatal lesions as well as brain oxidative stress are major features of HD. The present study was designed to investigate neuroprotective effect of Ginkgo biloba extract (EGb 761) on 3-NP induced neurobehavioral changes and striatal lesions. Rats administered 3-NP (20mg/kg, s.c.) for five consecutive days exhibited PPI deficits and locomotor hypoactivity whereas, pretreatment of animals with EGb 761 (100mg/kg, i.p. for 15 days) ahead of and during the induction of HD by 3-NP (20mg/kg for 5 days starting at day 8) ameliorated 3-NP-induced neurobehavioral deficits. Administration of 3-NP increased the level of striatal malondialdehyde (MDA). This effect was prevented in animals pre-treated with EGb 761. Changes in the level of apoptotic regulatory gene expressions, following 3-NP treatment, were demonstrated as both an up-regulation and a down-regulation of the expression levels of striatal Bax and Bcl-xl genes, respectively. In addition, an up regulation of the expression level of striatal glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was also observed. Pre-treatment with EGb 761 caused a down regulation in striatal GAPDH and Bax together with an up-regulation of striatal Bcl-xl expression level as compared to the 3-NP treated group. Histochemical examination of striatal tissue showed that EGb 761 significantly prevented 3-NP induced inhibition of SDH activity. Histopathological examination further affirmed the neuroprotective effect of EGb 761 against 3-NP toxicity. Taken together, these results suggest that EGb 761 has a neuroprotective role in the current HD paradigm, which may be related to improvement of energy metabolism, antioxidant properties and antiapoptotic effects. PMID- 21827810 TI - Dendritic cells expressing BTLA induces CD8+ T cell tolerance and attenuates the severity of diabetes. AB - Numerous evidence demonstrate Type 1 diabetes (T1D) is due to a loss of immune tolerance to islet antigens, and CD8(+) T cells play an important role in the development of T1D in NOD mice. The novel coinhibitory receptor BTLA may have a regulatory role in maintaining peripheral tolerance, however, its role in autoimmune diabetes is unknown. To explore whether the generation of tolerance aiming at BTLA will help therapeutic intervention in T1D, the NOD mice were treated with genetically modified dendritic cells (DCs) expressing BTLA. The results demonstrated that transfer of modified DCs significantly induced CD8(+) T cell tolerance and attenuated the severity of diabetes. The findings suggest that genetically modified DC therapies enhancing the BTLA negative cosignal may prove valuable in treating T1D and other autoimmune diseases. PMID- 21827811 TI - An experimental outer membrane vesicle vaccine from N. meningitidis serogroup B strains that induces serum bactericidal activity to multiple serogroups. AB - A trivalent native outer membrane vesicle vaccine that has potential to provide broad based protection against Neisseria meningitidis serogroup B strains has been developed. Preliminary immunogenicity studies in mice showed that the vaccine was capable of inducing an effective broad based bactericidal antibody response against N. meningitidis serogroup B strains. These findings in mice have been repeated with a cGMP trivalent NOMV vaccine and extended to show that the bactericidal antibody response induced by the vaccine in mice is effective against strains belonging to serogroups C, Y, W135, X, and NadA-expressing serogroup A strains. Taken together these results suggest that this experimental vaccine may provide protection against both serogroup B and non-serogroup B N. meningitidis strains. PMID- 21827812 TI - College students' perceptions of H1N1 flu risk and attitudes toward vaccination. AB - College students are highly susceptible to the H1N1 virus, yet previous studies suggest that college students perceive themselves at low risk for the flu. We surveyed 514 undergraduates to assess their perceptions of H1N1 flu risk and opinions about flu vaccines. A third of respondents stated that they were not at risk of getting the H1N1 flu because they were young. Responses indicated a distrust of the safety and effectiveness of influenza vaccinations; only 15.8% of participants planned on receiving H1N1 vaccination. Top reasons for refusing the H1N1 vaccine included questioning vaccine safety and effectiveness, and concerns about potential serious and/or benign side effects. Top reasons for H1N1 vaccination acceptance included receiving a doctor recommendation for the vaccine, having previously gotten a seasonal vaccine, and being at high-risk for influenza. Our findings suggest that college students are inaccurate in assessing their risk level and are unlikely to seek vaccinations. PMID- 21827813 TI - RSV 2010: Recent advances in research on respiratory syncytial virus and other pneumoviruses. AB - Respiratory syncytial virus (RSV) and human metapneumovirus (HMPV) are important causes of acute respiratory tract disease in infants, immunocompromised patients and the elderly. The Seventh International RSV symposium was held in Rotterdam, the Netherlands, from December 2-5, 2010. This symposium is the flagship event for leading investigators engaged in RSV and HMPV research around the world. The objective of the symposium was to provide a forum to review recent advances in research on RSV, HMPV and other pneumoviruses. More than 200 young and established investigators attended the meeting. Over a hundred papers were presented in 55 oral presentations and six poster sessions, providing all participants the opportunity to share and to discuss their work. The Chanock lecture, instituted in 2003 to acknowledge important contributors to RSV research, was presented by Peter Collins. As a preface to his lecture, he presented an in memoriam of the late Dr. Robert M. Chanock, who played a key role in the characterization of RSV as a human pathogen. The current report presents highlights of the meeting, covering topics from basic virology, pathogenesis and immunology to clinical studies, therapeutics and vaccine development. PMID- 21827814 TI - Special section: Universal influenza vaccination of children: food for thought. PMID- 21827815 TI - Serious adverse events following receipt of trivalent inactivated influenza vaccine in Korea, 2003-2010. AB - BACKGROUND: Vaccination is very important for the control and prevention of influenza, yet no vaccine is perfectly safe. Little is known, however, about influenza vaccination-associated serious adverse events following immunization (AEFI). This study aimed to identify background information on influenza vaccination-related serious AEFI in Korea. METHODS: Retrospective review of data from Korea National Vaccine Injury Compensation Program from 2003 to 2010. RESULTS: Distribution of approximately 75 million doses of influenza vaccine by end of 2010 gave rise to 42 potentially serious AEFI. In all, nine Guillain-Barre syndrome, eighteen other neurologic events, eight local events, and seven miscellaneous events were included. 62% of these events were identified to have unlike causal association with the vaccine. The reporting rate of serious AEFI ranged from 0.006 to 0.07 cases per 100,000 distributed doses of the vaccine. CONCLUSION: GBS was the most common influenza vaccination-related serious AEFI. Enhancing post-vaccination GBS surveillance may increase public confidence in future routine and pandemic influenza vaccination. PMID- 21827816 TI - Combined effects of curcumin and piperine in ameliorating benzo(a)pyrene induced DNA damage. AB - The present study was planned to investigate the antigenotoxic effects of curcumin and piperine separately and in combination against benzo(a)pyrene (BaP) induced DNA damage in lungs and livers of mice. Male Swiss albino mice received curcumin (100 mg kg(-1) body weight) and piperine (20 mg kg(-1) body weight) separately as well as in combination orally in corn oil for 7 days as pretreatments and subsequently, 2h after, BaP was administered orally in corn oil (125 mg kg(-1) body weight). A single dose of BaP to normal mice increased the level of 8-oxo-2'-deoxyguanosine (8-oxo-dG) content and % DNA in the comet tail in the lungs and liver. Pretreatments of curcumin and curcumin plus piperine before administration of single dose of BaP significantly decreased the levels of 8-oxo-dG content and % DNA in the comet tail in both the tissues. Moreover, the genoprotective potential of curcumin plus piperine was significantly higher as compared to curcumin alone against BaP induced DNA damage. PMID- 21827817 TI - Rapid induction of colonic adenocarcinoma in mice exposed to benzo[a]pyrene and dextran sulfate sodium. AB - Previously, we reported that the mutation frequency was markedly increased in the colon after the oral treatment of mice with an environmental mutagen/carcinogen, benzo[a]pyrene (BP); however this was not followed by tumor development. The reasons for this are as yet unresolved. The purpose of the present study is to explore the mechanisms why a high frequency of mutations induced by BP in the colon is not associated with subsequent tumor development. We show in this study that oral administration of BP to CD2F(1) mice at 125 mg/kg/day for 5 days can lead to adenocarcinomas in the mouse colon both at Weeks 4 (5/8 mice) and 11 (100% of mice), but only in the presence of inflammation induced by 4% dextran sulfate sodium (DSS) in the drinking water for up to 2 weeks. These data indicate that, in this DSS model, BP induced mutagenic events lead to tumors in the mouse colon, a tissue which is not a BP target organ. DSS-induced inflammation in a tissue primed with mutagenic risk is a key to the induction of tumors in this model. This study provides a novel, rapid and useful colon carcinogenesis model (BP/DSS model). PMID- 21827818 TI - Hypermethylation of estrogen receptor promoter region in adult testis of rats exposed neonatally to bisphenol A. AB - BACKGROUND: Bisphenol A (BPA) is an estrogenic endocrine disruptor commonly used in manufacture of polycarbonate plastics and epoxy resins. Due to its ubiquitous presence in the environment, health concerns are increasing. Earlier studies from our group have shown that neonatal exposure of male rats to BPA affected spermatogenesis leading to impairment in fertility during adulthood. Further we also observed an altered gene expression of ERalpha and ERbeta in adult testis upon BPA exposure. Based on these results, we hypothesized that apart from endocrine action, BPA might mediate perturbations in expression of ERs via epigenetic mechanism. OBJECTIVES: The present study was undertaken to determine the effect of exposure of neonatal male rats to BPA on DNA methylation profile of estrogen receptor promoter region and on DNA methylation machinery. METHODS: In order to test this hypothesis, neonatal male rats were subcutaneously injected with 2.4MUg of BPA/day for the first five days of life, i.e., on postnatal days (PND) 1-5, while control group received vehicle (sesame oil). Animals were sacrificed during adulthood (PND-125) and testes were dissected out for analysis. Methylation pattern of promoter region of ERalpha and ERbeta was analyzed in the testis by bisulfite sequencing and expression levels of DNA methyltransferases by quantitative RT-PCR and Western blotting respectively. RESULTS: Bisulfite sequencing revealed significant hypermethylation of ERalpha promoter to varying extents from 40% to 60%, and ERbeta promoter region with varying extent from 20% to 65%. Approximately 2-fold increase in Dnmt3a and Dnmt3b expression at transcript and protein level was also observed. CONCLUSION: The experimental evidence demonstrated that the neonatal exposure of rats to BPA led to aberrant DNA methylation in testis, indicating methylation mediated epigenetic changes as one of the possible mechanisms of BPA induced adverse effects on spermatogenesis and fertility. PMID- 21827819 TI - Prosthetic rehabilitation and treatment outcome of partially edentulous patients with severe tooth wear: 3-years results. AB - OBJECTIVES: The purpose of this study was to report on the management and treatment outcomes of partially edentulous elderly patients with severe tooth wear. METHODS: Partially edentulous patients with severe tooth wear who underwent the same protocols for full prosthodontic rehabilitation were eligible for this observational study. Their clinical diagnoses were based on a complete oral examination, photos, functional and cast analysis, general health conditions and behavioural aspects, such as acidic diets and bruxism. A 6-month preliminary phase with splints and provisional prostheses was maintained prior to the final fabrication of fixed and removable prostheses. All patients completed a follow-up period of >=3years. The outcomes were technical and biological complications with the prosthesis (wear or fracture of anchorage, abutment, prosthesis core or veneering, and implants, plaque index, caries, endodontic and periodontal lesions, tooth fractures and periimplantitis) and oral health-related quality of life (using the oral health impact profile questionnaire, German version of OHIP G-14). RESULTS: Data from 42 patients (33 men, 9 women) with a mean age of 62+/ 8years were available. The probability that a first, second or third technical complication occurred was 49%, 38% and 21%, respectively. About 50% of the patients remained without any complication. The average OHIP-value was 5+/-7, which represents high oral health-related quality of life. No statistically significant correlations between the OHIP values and the type of prostheses or the occurrence of complications were observed. CONCLUSIONS: From multiple perspectives, the rehabilitation of partially edentulous patients with severe tooth wear is a complex task, and more information regarding treatment protocols, prosthetic indications and treatment outcome is needed. PMID- 21827820 TI - Mitochondrial dysfunction in ALS. AB - In the present article, we review the many facets of mitochondrial dysfunction in amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease due to loss of upper motor neurons in cerebral cortex and lower motor neurons in brainstem and spinal cord. Accumulating evidence from recent studies suggests that the many, interconnected facets of mitochondrial dysfunction may play a more significant role in the etiopathogenesis of this disorder than previously thought. This notion stems from our expanding knowledge of the complex physiology of mitochondria and of alteration of their properties that might confer an intrinsic susceptibility to long-lived, post-mitotic motor neurons to energy deficit, calcium mishandling and oxidative stress. The wealth of evidence implicating mitochondrial dysfunction as a major event in the pathology of ALS has prompted new studies aimed to the development of new mitochondria-targeted therapies. However, it is now clear that drugs targeting more than one aspect of mitochondrial dysfunction are needed to fight this devastating disease. PMID- 21827821 TI - State and trait variance in salivary alpha-amylase: a behavioral genetic study. AB - This is the first behavior genetic study of salivary alpha-amylase (sAA), focusing on genetic and environmental influences on stability and change in sAA during baseline and exposure to infant crying. The sample consisted of 184 adult twin pairs. Although there was significant variation between individuals in basal levels of sAA and in responsivity to infant crying, strong stability in sAA concentrations across conditions was found. Similar genetic mechanisms influenced sAA at baseline and in response to cry sounds (explained variance: 51-62%), accounting for part of the stability in sAA. Unique environmental factors explained the remaining variance in sAA, some of them only emerging in response to the cry sounds, explaining individual differences in the pattern of reactivity. These findings confirm that sAA is sensitive to the effects of potentially stressful stimuli (state variance) and at the same time demonstrate its relative robustness and stability across time and conditions (trait variance). PMID- 21827823 TI - Mutations in inhibin and activin genes associated with human disease. AB - Inhibins and activins are members of the transforming growth factor (TGFbeta) superfamily, that includes the TGFbetas, inhibins and activins, bone morphogenetic proteins (BMPs) and growth and differentiation factors (GDFs). The family members are expressed throughout the human body, and are involved in the regulation of a range of important functions. The precise regulation of the TGFbeta pathways is critical, and mutations of individual molecules or even minor alterations of signalling will have a significant affect on function, that may lead to development of disease or predisposition to the development of disease. The inhibins and activins regulate aspects of the male and female reproductive system, therefore, it is not surprising that most of the diseases associated with abnormalities of the inhibin and activin genes are focused on reproductive disorders and reproductive cancers. In this review, I highlight the role of genetic variants in the development of conditions such as premature ovarian failure, pre-eclampsia, and various reproductive cancers. Given the recent advances in human genetic research, such as genome wide association studies and next generation sequencing, it is likely that inhibins and activins will be shown to play more important roles in a range of human genetic diseases in the future. PMID- 21827824 TI - Modulation of AT-1R/MAPK cascade by an olmesartan treatment attenuates diabetic nephropathy in streptozotocin-induced diabetic mice. AB - There is increasing evidence that angiotensin (Ang)-II plays an unprecedented role in diabetic complications. It could also be an important therapeutic target for ameliorating various diseases, especially diabetic nephropathy (DN). We therefore studied the beneficial effects of olmesartan, an Ang-II type 1 receptor (AT-1R) blocker in streptozotocin (150 mg/kg, BW)-induced diabetic kidney disease in mice. The diabetic kidney mice displayed upregulated protein expression levels of AT-1R, AT-2R, ERK-1/2, p-p38 MAPK, p-MAPKAPK-2, ET-1, p-JNK, p-c-Jun, TGF beta1, and gp91-phox, and all of these effects were expectedly downregulated by an olmesartan treatment. Also, immunohistochemical analysis, and Azan-Mallory and HE staining were performed to examine the expression of collagen-III and fibronectin, renal fibrosis, and hypertrophy, respectively. Furthermore, olmesartan treatment significantly abrogated the downregulation of ACE-2 and Ang (1-7) mas R protein expression in diabetic kidney mice. Considering all these findings together, the AT-1R/MAPK pathway might be a potential therapeutic target in diabetes kidney disease, and olmesartan treatment could have beneficial effects on DN by modulating the AT-1R/MAPK pathway. PMID- 21827822 TI - The paracrinology of tubal ectopic pregnancy. AB - As part of successful human reproduction, the Fallopian tube must provide a suitable environment for pre-implantation development of the embryo and for efficient transport of the embryo to the uterus for implantation. These functions are coordinated by paracrine interactions between tubal epithelial, smooth muscle and immune cells and the cells of the developing embryo. Alterations in these signals can lead to a tubal microenvironment encouraging of embryo implantation and to dysregulated tubal motility, ultimately resulting in inappropriate and early implantation of the embryo in the Fallopian tube. Here, we highlight novel and emerging concepts in tubal physiology and pathobiology, such as the induction of a receptive phenotype within the Fallopian tube, leading to ectopic implantation. Chlamydia trachomatis infection is a risk factor for tubal ectopic pregnancy. Activation of toll-like receptor 2 (TLR-2) in the Fallopian tube epithelium, by C. trachomatis has recently been demonstrated, leading to the dysregulation of factors involved in implantation and smooth muscle contractility, such as prokineticins (PROK), activin A and interleukin 1 (IL-1). The Fallopian tube has also recently been shown to harbour a unique population of immune cells, compared to the endometrium. In addition, the complement of immune cells in the Fallopian tube has been reported to be altered in Fallopian tube from women with ectopic pregnancy. There are increasing data suggesting that vascularisation of the Fallopian tube, by the embryo during ectopic pregnancy, differs from that initiated in the uterus during normal pregnancy. This too, is likely the result of paracrine signals between the embryo and the tubal microenvironment. PMID- 21827825 TI - Gastrulation in rabbit blastocysts depends on insulin and insulin-like-growth factor 1. AB - Insulin and insulin-like-growth-factor 1 (IGF1) are components of the uterine secretions. As potent growth factors they influence early embryo development. The underlying molecular mechanisms are largely unknown. Here we report on the effects of insulin and IGF1 on early gastrulation in rabbit blastocysts. We have studied blastocysts grown in vivo in metabolically healthy rabbits, in rabbits with type 1 diabetes and in vitro in the presence or absence of insulin or IGF1. Embryonic disc morphology and expression of Brachyury, Wnt3a and Wnt4 were analysed by qPCR and IHC. Pre-gastrulated blastocysts (stage 0/1) cultured with insulin or IGF1 showed a significantly higher capacity to form the posterior mesoderm and primitive streak (stage 2 and 3) than blastocysts cultured without growth factors. In gastrulating blastocysts the levels of the mesoderm-specific transcription factor Brachyury and the Wnt signalling molecules Wnt3a and Wnt4 showed a stage-specific expression pattern with Brachyury transcripts increasing from stage 0/1 to 3. Wnt4 protein was found spread over the whole embryoblast. Insulin induced Wnt3a, Wnt4 and Brachyury expression in a temporal- and stage specific pattern. Only blastocysts cultured with insulin reached the Wnt3a, Wnt4 and Brachyury expression levels of stage 2 in vivo blastocysts, indicating that insulin is required for Wnt3a, Wnt4 and Brachyury expression during gastrulation. Insulin-induced Wnt3a and Wnt4 expression preceded Brachyury. Wnt3a-induced expression could be depleted by MEK1 inhibition (PD98059). Involvement of insulin in embryonic Wnt3a expression was further shown in vivo with Wnt3a expression being notably down regulated in stage 2 blastocysts from rabbits with type 1 diabetes. Blastocysts grown in diabetic rabbits are retarded in development, a finding which supports our current results that insulin is highly likely required for early mesoderm formation in rabbit blastocysts by inducing a distinct spatiotemporal expression profile of Wnt3a, Wnt4 and Brachyury. PMID- 21827826 TI - Depot-specific and hypercaloric diet-induced effects on the osteoblast and adipocyte differentiation potential of adipose-derived stromal cells. AB - Adipose-derived stromal cells (ADSCs) can be differentiated in vitro into several mesenchyme-derived cell types. We had previously described depot-specific differences in the adipocyte differentiation of ADSCs, and consequently we hypothesized that there may also be depot-specific differences in osteoblast differentiation of ADSCs. For this study, the osteoblast differentiation potential of rat subcutaneous ADSCs (scADSCs) and perirenal visceral ADSCs (pvADSCs) was compared. Osteoblast differentiation media (OM) induced markers of the osteoblastic phenotype in scADSCs, but not in pvADSCs. ADSCs harvested from rats with diet-induced visceral obesity (DIO) exhibited reduced osteoinduction, compared to lean controls, but adipocyte differentiation was not affected. Expression of the pro-osteogenic transcription factor Msx2 was significantly higher in naive scADSCs from lean and DIO rats than in pvADSCs. Our findings indicate that ADSCs from different anatomical sites are uniquely pre-programmed in vivo in a depot-specific manner, and that diet-induced metabolic disturbances translate into reduced osteoblast differentiation of ADSCs. PMID- 21827827 TI - Developing brain as an endocrine organ: secretion of dopamine. AB - This study was aimed to test our hypothesis that the developing brain operates as an endocrine organ before the establishment of the blood-brain barrier (BBB), in rats up to the first postnatal week. Dopamine (DA) was selected as a marker of the brain endocrine activity. The hypothesis was supported by the observations in rats of: (i) the physiological concentration of DA in peripheral blood of fetuses and neonates, before the BBB establishment, and its drop by prepubertal period, after the BBB development; (ii) a drop of the DA concentration in the brain for 54% and in blood for 74% on the 3rd postnatal day after the intraventricular administration of 50 MUg of alpha-methyl-p-tyrosine, an inhibitor of DA synthesis, with no changes in the DA metabolism in peripheral DA-producing organs. Thus, the developing brain is a principal source of circulating DA which is capable of providing an endocrine regulation of peripheral organs and the brain. PMID- 21827828 TI - Interaction between mineralocorticoid receptor and epidermal growth factor receptor signaling. AB - The mineralocorticoid receptor (MR) is a steroid receptor that physiologically regulates water and electrolyte homeostasis but that can also induce pathophysiological effects in the renocardiovascular system. Classically, the MR acts as a transcription factor at glucocorticoid response elements but additional protein-protein interactions with other signaling cascades have been described. Of these, the crosstalk with EGFR signaling is especially interesting because various vasoactive substances like angiotensin II and endothelin-1 also mediate their pathophysiological effects via the EGFR. Recently, the MR has been shown to interact nongenomically (via transactivation) and genomically with the epidermal growth factor receptor (via altered expression). These interactions seem to contribute to physiological (e.g. salt homeostasis) as well as pathophysiological (e.g. vascular function) MR effects. The current knowledge on the mechanisms of interaction and on the possible cellular and systemic physiological as well as pathophysiological relevance is reviewed in this article. PMID- 21827829 TI - Involvement of glutamate NMDA and AMPA receptors, glial cells and IL-1beta in the spinal hyperalgesia evoked by the chemokine CCL2 in mice. AB - We study here the involvement of excitatory amino acid receptors, glial cell activation and IL-1beta release in the spinal hyperalgesia evoked by the chemokine CCL2 (MCP-1). Three hours after the intrathecal administration of CCL2 (1-100ng), mice exhibit dose-dependent thermal hyperalgesia, that was inhibited by the coadministration of the antagonist of chemokine receptor type 2 (CCR2) RS504393 (0.3-3MUg). To assess the involvement of excitatory amino acid receptor sensitisation, CCL2 was coadministered with CPP (0.3-3ng) and NBQX (25-250ng), antagonists of NMDA and AMPA receptors, respectively. Both drugs blocked CCL2 evoked hyperalgesia, strongly suggesting that CCL2 evokes in vivo NMDA and AMPA receptor sensitisation, as previously described in electrophysiological studies. Furthermore, this rapid induction of CCL2-mediated hyperalgesia was blocked by the previous acute administration of the microglial inhibitor minocyclin (4.9MUg) or the astroglial inhibitor l-aminoadipate (1.6MUg). Since IL-1beta can be released by activated glial cells we tested whether this cytokine could be underlying the spinal sensitisation induced by CCL2. The administration of the type I IL-1 receptor antagonist, IL-1ra (3-30MUg), partially prevented CCL2 evoked hyperalgesia. Finally, to elucidate if IL-1beta could produce NMDA and AMPA receptor sensitisation by itself, we performed experiments in which this cytokine was i.t. administered. Thermal hyperalgesia induced by IL-1beta (30pg) was completely prevented by the coadministration of CPP (3ng) but unaffected by NBQX (250ng). Globally, our results suggest that spinal CCL2 induces thermal hyperalgesia by sensitising NMDA and AMPA receptors in a process that involves glial activation and IL-1beta release. PMID- 21827830 TI - Understanding the subliminal affective priming effect of facial stimuli: an ERP study. AB - The subliminal affective priming was studied by recording event-related potential (ERP) to ambiguous neutral faces preceded by 20ms positive or negative prime faces. Behavioral results showed that positive and negative prime faces led to valance-consistent biases in affective judgments of ambiguous neutral faces. ERP data showed that subliminal primes differentially influenced N100, N300 and vertex positive potential (VPP), with larger amplitudes in negative priming trials. These results support the conclusion that the early perceptual analysis of targets, as well as evaluation and selection of targets, is affected by subliminal affective information. PMID- 21827831 TI - A 5-HT(2C) receptor antagonist potentiates a low dose amphetamine-induced conditioned place preference. AB - This study was designed to determine whether a 5-HT(2C) receptor antagonist could induce a conditioned place preference indicative of reward and/or abuse potential. Here, we present the first evidence that a selective 5-HT(2C) receptor antagonist, 6-chloro-5-ethoxy-N-(pyridin-2-yl)indoline-1-carboxamide hydrochloride (CEPC), can potentiate a low dose (0.5 mg/kg) amphetamine-induced positive conditioned place preference (CPP). CEPC did not produce any CPP given alone at doses of either 2.0 or 4.0 mg/kg, whereas low dose amphetamine alone produced only a slight, but statistically nonsignificant, place preference. These studies suggest that 5-HT(2C) receptor antagonists can indirectly potentiate the rewarding effects of amphetamine, and perhaps other psychostimulants. If the results can be translated to man, putative 5-HT(2C) receptor antagonist treatments for anxiety or depression may enhance or potentiate the rewarding effects of drugs of abuse such as amphetamine, which release dopamine. PMID- 21827832 TI - The impact of emotion valence on brain processing of behavioral inhibitory control: spatiotemporal dynamics. AB - Emotion is known to interact with behavioral inhibitory control (BIC), an ability critical for adaptive living. Nevertheless, how emotion valence influences this control, and the spatiotemporal dynamics underlying this influence, remain undetermined. For this purpose, the present study recorded event-related potentials (ERPs) for a standard stimulus which required no BIC, and for deviant stimuli that required controlling habitual responses during pleasant, neutral and unpleasant blocks. Behavioral results showed prolonged reaction times (RTs) and diminished accuracy rates for deviant than for standard stimuli, irrespective of the emotionality of deviants. Moreover, there were significant main effects of stimulus type, and significant stimulus and emotion interaction effects on the averaged amplitudes of the 200-300ms and 300-500ms intervals. Through analyzing the deviant-standard difference ERPs that index BIC directly, we found larger N2 and smaller P3 amplitudes during the unpleasant block than during the neutral block. The pleasant block, in contrast, showed a trend of more pronounced P3 amplitudes than the neutral block. Thus, by synchronizing BIC with emotion induction, we found distinct impact of pleasant and unpleasant emotions on behavioral inhibitory processing, not only in early monitoring of response conflicts but also in the late stage of response inhibition. PMID- 21827833 TI - Semantic fluency and executive functions as candidate endophenotypes for the early diagnosis of schizophrenia in Han Chinese. AB - Neurocognitive deficits are recognized as core features of schizophrenia. The aim of this study was to compare the cognitive performance of antipsychotic, drug naive patients with first-episode schizophrenia (FES patients) to their healthy siblings and to healthy controls from the Han Chinese population for exploring potential endophenotypes for the early detection of schizophrenia. A battery of cognitive assessment tools was used to measure seven cognitive domains in matched groups consisting of 56 subjects each. Cognitive tests included the grooved pegboard test (GPT), the category fluency test (CFT), the trail making test A (TMT-A), the Wechsler memory scale-III spatial span test (WMS-III SST), the Hopkins verbal learning test-revised (HVLT-R), the brief visuospatial memory test revised (BVMT-R), the paced auditory serial addition test (PASAT), and the Wisconsin card sorting test-64 cards version (WCST-64). The performances of FEP patients were inferior to normal controls on all neuropsychological tests, while siblings were lower than healthy controls in many of the same tasks. Patients' performances were lower than siblings' on all tests except for the CFT, the WMS III SST backward test, and four subtests of the WCST-64. Our data suggest that FEP patients exhibited pronounced impairment of fine motor skills, speed of processing, attention, verbal memory, visual memory, and executive function, while siblings exhibited deficits intermediate between those of schizophrenic patients and the control group. Semantic fluency function and executive function may be potential endophenotypes for the early diagnosis of schizophrenia. PMID- 21827834 TI - Cannabinoids and emotionality: a neuroanatomical perspective. AB - The endocannabinoid system has recently emerged as a promising therapeutic target for the treatment of stress-related emotional disorders. A growing literature base has collectively demonstrated that facilitation of endocannabinoid signaling promotes antidepressant- and anxiolytic-like responses in preclinical animal models, while disruption of this system profoundly affects emotion, cognition, and neuroendocrine functioning. Although these findings are encouraging, the role of endocannabinoid signaling within discrete corticolimbic brain structures is considerably complex. Consequently, researchers have recently shifted focus to examining the effects of local cannabinoid manipulations on emotion from a neuroanatomical standpoint. This review provides an overview of the site-specific effects of cannabinergic compounds in preclinical tests of emotionality, as well as the alterations in endocannabinoid signaling observed in animal models of depression. Broadly speaking, these studies indicate that CB(1) receptors in the medial prefrontal cortex and ventral hippocampus appear to be responsible for the antidepressant- and anxiolytic-like phenotype elicited by systemic CB(1) receptor agonists, which parallels biochemical studies showing that endocannabinoids are downregulated in these two regions following exposure to chronic stress. Conversely, CB(1) receptor activation within distinct amygdalar nuclei yields opposing effects on emotional behavior, such that local stimulation of CB(1) receptors in the basolateral amygdala and central amygdala promoting anxiogenesis and anxiolysis, respectively. Moreover, a series of elegant studies has revealed that cannabinoid transmission in the basolateral amygdala strongly modulates the acquisition and processing of associative fear memory via interactions with the medial prefrontal cortex. Given the crucial role of this corticolimbic network in regulating emotional behavior, it is palpable that alterations in endocannabinoid signaling within any of these structures could have profound implications for the pathophysiological development of affective illnesses. Accordingly, local pharmacological augmentation of endocannabinoid signaling within discrete corticolimbic subregions may serve as a promising therapeutic strategy for the treatment of these debilitating disorders. PMID- 21827835 TI - MicroRNA let-7e regulates the expression of caspase-3 during apoptosis of PC12 cells following anoxia/reoxygenation injury. AB - This study aimed to investigate the role and mechanism of action of microRNA (miR) let-7e in PC12 cells undergoing apoptosis following anoxia/reoxygenation (A/R) injury. The putative binding site of let-7e in the 3' UTR of caspase-3 (Casp3) mRNA was analyzed using the miRanda algorithm. Precursor let-7e (pre miRNA), let-7e miR and anti-let-7e oligonucleotides were transfected into PC12 cells, which were then subjected to A/R injury. The levels of Casp3 mRNA and let 7e miRNA, the total protein levels of Casp3, Casp8 and Casp9 and levels of cellular apoptosis were measured. It was found that let-7e expression in PC12 cells was decreased, whereas the expression of Casp3 was significantly increased after A/R injury. The transfection of pre-miRNA or let-7e miR into PC12 cells decreased Casp3 expression levels and cellular apoptosis following A/R injury, while co-transfection of anti-let-7e strikingly alleviated the effects of let-7e miR. These results indicate that let-7e may protect PC12 cells against apoptosis following A/R injury by negatively regulating the expression of Casp3. PMID- 21827836 TI - Phonological-dependent territorial responses in yellowhammers (Emberiza citrinella). AB - In songbirds, males sing to attract potential mate and to defend their territory. Information about the sender such as its sex, its motivational state, its strength or identity can be encoded through subtle modifications in songs. In this study, we investigated whether territorial responses of yellowhammer males may be affected by modifications of song syntax and phonology. Yellowhammer song is mainly composed of three elements among which the last one is a long and low frequency note that is supposed to be the main component used by males to assess their potential rival. We carried out field experiments and played back either fully natural songs or partly natural and partly artificial songs to test this hypothesis. We identified that phonology rather than syntax modifications altered territorial responses. Our results also suggest that the phonology of the first song element plays a critical role in driving territorial responses. PMID- 21827837 TI - Isolation of genomic DNA suitable for community analysis from mature trees adapted to arid environment. AB - Isolation of intact and pure genomic DNA (gDNA) is essential for many molecular biology applications. It is difficult to isolate pure DNA from mature trees of hot and dry desert regions because of the accumulation of high level of polysaccharides, phenolic compounds, tannins etc. We hereby report the standardized protocol for the isolation and purification of gDNA from seven ecologically and medically important tree species of Combretaceae viz. Anogeissus (Anogeissus sericea var. nummularia, Anogeissus pendula, and Anogeissus latifolia) and Terminalia (Terminalia arjuna, Terminalia bellirica, Terminalia catappa and Terminalia chebula). This method involves (i) washing the sample twice with Triton buffer (2%) then (ii) isolation of gDNA by modified-CTAB (cetyl trimethyl ammonium bromide) method employing a high concentration (4%) of PVP (Polyvinylpyrrolidone) and 50mM ascorbic acid, and (iii) purification of this CTAB-isolated gDNA by spin-column. gDNA isolated by modified CTAB or spin-column alone were not found suitable for PCR amplification. The Triton washing step is also critical. The quality of DNA was determined by the A(260)/A(280) absorbance ratio. gDNA was also observed for its intactness by running on 0.8% agarose gel. The suitability of extracted DNA for PCR was tested by amplification with RAPD primers, which was successful. Further, rbcLa (barcoding gene) was amplified and sequenced to check the quality of extracted gDNA for its downstream applications. PMID- 21827838 TI - The complete mitochondrial genome of Macrobrachium nipponense. AB - The complete mitochondrial (mt) genome sequence plays an important role in the accurate determination of phylogenetic relationships among metazoans. Herein, we determined the complete mt genome sequence, structure and organization of Macrobrachium nipponense (M. nipponense) (GenBank ID: NC_015073.1) and compared it to that of Macrobrachium lanchesteri (M. lanchesteri) and Macrobrachium rosenbergii (M. rosenbergii). The 15,806 base pair (bp) M. nipponense mt genome, which is comprised of 37 genes, including 13 protein-coding genes (PCGs), 22 transfer RNAs (tRNAs) and 2 ribosomal RNAs (rRNAs), is slightly larger than that of M. lanchesteri (15,694bp, GenBank ID: NC_012217.1) and M. rosenbergii (15,772bp, GenBank ID: NC_006880.1). The M. nipponense genome contains a high AT content (66.0%), which is a common feature among metazoan mt genomes. Compared with M. lanchesteri and M. rosenbergii, we found a peculiar non-coding region of 950bp with a microsatellite-like (TA)(6) element and many hairpin structures. The 13 PCGs are comprised of a total of 3707 codons, excluding incomplete termination codons, and the most frequently used amino acid is Leu (16.0%). The predicted start codons in the M. nipponense mt genome include ATG, ATC and ATA. Seven PCGs use TAA as a stop codon, whereas two use TAG, three use T and only one uses TA. Twenty-three of the genes are encoded on the L strand, and ND1, ND4, ND5, ND4L, 12S rRNA, 16S rRNA, tRNA(His), tRNA(Pro), tRNA(Phe), tRNA(Val), tRNA(Gln), tRNA(Cys), tRNA(Tyr) and a tRNA(Leu) are encoded on the H strand. The two rRNAs of M. nipponense and M. rosenbergii are encoded on the H strand, whereas the M. lanchesteri rRNAs are encoded on the L stand. PMID- 21827839 TI - A simple and effective SuperBuffer for DNA agarose electrophoresis. AB - In the paper, we describe a unique effective electrophoresis buffer for DNA agarose electrophoresis, called SuperBuffer. Using this buffer, electrophoresis could be performed within 10 min at voltages as high as 25V/cm. In addition, DNA fragments of different lengths could be isolated clearly even at lower agarose gel concentrations and the DNA recovery efficiency was higher than that of the TAE/TBE running buffers. The SuperBuffer still retained its electrophoretic effect even after several uses. PMID- 21827840 TI - Computational analysis of the transcriptional regulation of the adenine nucleotide translocator isoform 4 gene and its role in spermatozoid glycolytic metabolism. AB - Computational phylogenetic analysis coupled to promoter sequence alignment was used to understand mechanisms of transcriptional regulation and to identify potentially coregulated genes. Our strategy was validated on the human ANT4 gene which encodes the fourth isoform of the mitochondrial adenine nucleotide translocator specifically expressed during spermatogenesis. The movement of sperm flagella is driven mainly by ATP generated by glycolytic pathways, and the specific induction of the mitochondrial ANT4 protein presented an interesting puzzle. We analysed the sequences of the promoters, introns and exons of 30 mammalian ANT4 genes and constructed regulatory models. The whole human genome and promoter database were screened for genes that were potentially regulated by the generated models. 80% of the identified co-regulated genes encoded proteins with specific roles in spermatogenesis and with functions linked to male reproduction. Our in silico study enabled us to precise the specific role of the ANT4 isoform in spermatozoid bioenergetics. PMID- 21827842 TI - Pharmaceutical cocrystals: an overview. AB - Pharmaceutical cocrystals are emerging as a new class of solid drugs with improved physicochemical properties, which has attracted increased interests from both industrial and academic researchers. In this paper a brief and systematic overview of pharmaceutical cocrystals is provided, with particular focus on cocrystal design strategies, formation methods, physicochemical property studies, characterisation techniques, and recent theoretical developments in cocrystal screening and mechanisms of cocrystal formations. Examples of pharmaceutical cocrystals are also summarised in this paper. PMID- 21827843 TI - Cell penetrating peptide-mediated systemic siRNA delivery to the liver. AB - The cell-penetrating peptide (CPP) is one of the most attractive tools for efficiently delivering biomolecules to a target organelle. Here, we describe the use of octaarginine (R8)-modified lipid nanoparticles for the efficient and targeted in vivo delivery of siRNA to the liver. In this study, SR-BI (a scavenger receptor class B, member 1) was targeted by this nanoparticle. Our results demonstrate that R8-modified lipid nanoparticles can be used for the efficient and targeted delivery of liver siRNA to induce the specific knock-down of an endogenous gene with minimum liver toxicity and immune response, and that this CPP based technology holds considerable promise for further in vivo biological applications of siRNA. PMID- 21827841 TI - Identification of a possible role for atrial natriuretic peptide in MDMA-induced hyperthermia. AB - MDMA (3,4-methylenedioxymethamphetamine) induces thermogenesis in a mitochondrial uncoupling protein 3-dependent manner. There is evidence that this hyperthermia is mediated in part by the lipolytic release of free fatty acids, that subsequently activate uncoupling protein 3 in skeletal muscle mitochondria. We hypothesize that atrial natriuretic peptide (ANP), a strong lipolytic mediator, may contribute to the induction and maintenance of MDMA-induced thermogenesis. The specific aims of this study were to (1) determine if ANP is released following MDMA administration, and (2) use the ANP receptor antagonist, Anantin, to ascertain the role of ANP in MDMA-induced hyperthermia. ANP levels were measured in plasma at baseline, 10, 20, 30 and 60 min following MDMA (40 mg/kg, sc) administration in 16 male Sprague-Dawley rats. A robust increase in ANP was seen within 10 min of MDMA administration. ANP levels returned to baseline at 20 min and then gradually rose over the 60 min monitoring period. The administration of Anantin (40 mg, ip), 15 min before and after MDMA, significantly attenuated the MDMA-induced hyperthermia. We conclude that ANP signaling contributes to the hyperthermia induced by MDMA. PMID- 21827844 TI - Lipid nanoparticles for brain targeting I. Formulation optimization. AB - The aim of this study was to optimize the formulation of lipid nanoparticles (NPs), intended for brain targeting, with the aid of a computer generated experimental design. The high pressure homogenization technique, selected for this purpose, was suitable to formulate the 3 investigated lipids (i.e., Softisan((r)) 142, SOFT; Compritol((r)) 888 ATO, COMP; cetyl palmitate, CP) into nanometre-length particles, while the computer generated experimental design helped to individuate the best preparation conditions with a small number of experimental assay. Even though all the 3 optimized formulations were suitable for intravenous infusion, CP NPs showed the smallest particle size and the appropriate thermal behaviour to be used as carriers in brain targeting applications. PMID- 21827845 TI - Two variants located in the upstream enhancer region of human UCP1 gene affect gene expression and are correlated with human longevity. AB - The brown fat specific UnCoupling Protein 1 (UCP1) is involved in thermogenesis, a process by which energy is dissipated as heat in response to cold stress and excess of caloric intake. Thermogenesis has potential implications for body mass control and cellular fat metabolism. In fact, in humans, the variability of the UCP1 gene is associated with obesity, fat gain and metabolism. Since regulation of metabolism is one of the key-pathways in lifespan extension, we tested the possible effects of UCP1 variability on survival. Two polymorphisms (A-3826G and C-3740A), falling in the upstream promoter region of UCP1, were analyzed in a sample of 910 subjects from southern Italy (475 women and 435 men; age range 40 109). By analyzing haplotype specific survival functions we found that the A-C haplotype favors survival in the elderly. Consistently, transfection experiments showed that the luciferase activity of the construct containing the A-C haplotype was significantly higher than that containing the G-A haplotype. Interestingly, the different UCP1 haplotypes responded differently to hormonal stimuli. The results we present suggest a correlation between the activity of UCP1 and human survival, indicating once again the intricacy of mechanisms involved in energy production, storage and consumption as the key to understanding human aging and longevity. PMID- 21827846 TI - Perspective on the use of humic acids from biomass as natural surfactants for industrial applications. AB - In the context of renewable vs. non-renewable sources of chemical compounds, the development of natural surfactants as a substitute for synthetic surfactants in technological applications is an important issue. In addition, as synthetic surfactants can persist in the environment causing toxic effects, the use of natural products presents a possibility to minimize impact on the environment. Nowadays, a promising new approach in surfactant-based technologies, consists of the use of humic acids (HAs) extracted directly from biomass that exhibit amphiphilic properties, and can be conveniently used as environmentally friendly surfactants. The raw material from which HAs are extracted and their macromolecular composition affect surfactant properties. Therefore fundamental data from more strictly qualitative aspects, needs to be investigated. This review highlights surfactant ability and chemical properties of HA substances coming from renewable sources in comparison to synthetic surfactants, and points out the capacity for HAs to be used effectively in this field of application. PMID- 21827847 TI - Telomerase reverse transcriptase: a novel neuroprotective mechanism involved in neonatal hypoxic-ischemic brain injury. AB - Hypoxic-ischemic (HI) brain injury is one of the most severe diseases in the neonatal central nervous system (CNS). The pathological mechanisms of HI brain injury, including cellular apoptosis, excitotoxicity, oxidative stress, etc., are complicated and not well known. Cellular processes such as angiogenesis, neuronal survival and neurogenesis have been proven to be closely associated with brain repair following HI injury. Telomerase reverse transcriptase (TERT), a component of telomerase, plays a primary role in maintaining telomere length. In addition, recent studies have demonstrated that TERT can protect neurons from apoptosis and excitotoxicity, and promote angiogenesis, neurogenesis and neuronal survival. However, there are few reports on the roles of TERT in neonatal HI brain injury and the mechanisms involved are unclear. It is reported that TERT is activated and plays a protective role in adult brains with ischemia and recently we have shown that TERT was induced and may act protectively in a neonatal rat model of HI brain injury. Therefore, it is quite possible that TERT plays an important role in neuroprotection in developing brains following HI injury by inhibiting apoptosis and excitotoxicity, and promoting angiogenesis, neuronal survival and neurogenesis. These very novel mechanisms could lead to more effective neuroprotective strategies against hypoxic-ischemic brain injury in neonates. PMID- 21827848 TI - Catalase rs769214 SNP in elderly malnutrition and during renutrition: is glucagon to blame? AB - Impaired glucose tolerance is common during aging. The transcription factor PAX6 is involved in glucose homeostasis. Computational promoter sequence analysis of the catalase gene highlighted a putative PAX6 binding site on the rs769214 polymorphism A allele. Creation of this binding site has been suggested to explain renutrition inefficiency in malnourished elderly patients. Our aim was to evaluate the link between the rs769214 polymorphism of the catalase gene and glucose homeostasis in malnourished elderly patients at inclusion and during renutrition. Thirty-three malnourished elderly Caucasian inpatients were recruited. Nutritional and inflammatory statuses were assessed and a multiplex adipokine analysis was conducted at inclusion and discharge from the Geriatric Nutritional Care Unit at Charles-Foix Hospital (Ivry-sur-Seine, France). Serum glucagon, PAI-1, and TNF-alpha levels were significantly lower in the A-allele carriers at inclusion. During renutrition, A-allele carriers exhibited increased serum glucagon, PAI-1, and TNF-alpha variation. After renutrition, levels of these parameters were similar for A-allele carriers and G-allele carriers. A logistic ordinal multivariate regression analysis linked only variation of glucagon to rs769214 SNP. These results support a role for catalase SNP in the efficiency of renutrition in malnourished elderly patients via the modulation of glucagon secretion, probably involving PAX6. PMID- 21827849 TI - Acute toluene exposure alters expression of genes in the central nervous system associated with synaptic structure and function. AB - Toluene is a volatile organic compound (VOC) and a ubiquitous air pollutant of interest to EPA regulatory programs. Whereas its acute functional effects are well described, several modes of action in the CNS have been proposed. Therefore, we sought to identify potential pathways mediating direct or indirect effects of VOCs by investigating the genomic response of the rat CNS to acutely-inhaled toluene. Adult male Long-Evans rats inhaled clean air or 1000 ppm toluene vapor for 6 h. Specific brain regions were collected from the rats either immediately after 6 h of treatment or 18 h after removal from the exposure chambers (n=6/group/time). Total mRNA was extracted from the striatum and hybridized to Rat 230A Affymetrix arrays. Statistical analyses showed 226 and 3352 transcripts altered in the toluene-exposed groups relative to controls at the 6 h time point and after the 18 h recovery period, respectively. Relative to controls, toluene exposure was associated with induction or repression of genes in pathways associated with synaptic plasticity, including long-term depression, GABA receptor signaling and mitochondrial function. In each of these pathways, responses were characterized by changes in a small number of transcripts following the 6 h toluene inhalation and with substantial increases in numbers of changed transcripts at 18 h recovery following termination of exposure. This report provides the first global genomic evidence that CNS pathways affected by toluene are strongly associated with neurological processes participating in synaptic transmission and plasticity. PMID- 21827850 TI - Bone, joint and tooth development in mucopolysaccharidoses: relevance to therapeutic options. AB - The mucopolysaccharidoses (MPS) are prominent among the lysosomal storage diseases. The intra-lysosomal accumulation of glycosaminoglycans (GAGs) in this group of diseases, which are caused by several different enzyme deficiencies, induces a cascade of responses that affect cellular functions and maintenance of the extra-cellular matrix. Against the background of normal tissue-specific processes, this review summarizes and discusses the histological and biochemical abnormalities reported in the bones, joints, teeth and extracellular matrix of MPS patients and animal models. With an eye to the possibilities and limitations of reversing the pathological changes in the various tissues, we address therapeutic challenges, and present a model in which the cascade of pathologic events is depicted in terms of primary and secondary events. PMID- 21827851 TI - Melt extruded helical waxy matrices as a new sustained drug delivery system. AB - The aim of this research was to prepare helical and cylindrical extrudates by melt extrusion and to evaluate their potential as sustained release dosage form. The systems contained theophylline as water-soluble model drug and microcrystalline wax as thermoplastic binder. The temperature suitable to ensure a successful extrusion process of formulations containing the wax in three different percentages was found to be below the melting point of the excipient. After the production of the extrudates in three different helical shapes (having 2, 3 and 4 blades) and a classical cylindrical shape, the systems were studied by means of X-ray powder diffraction and differential scanning calorimetry to check possible variations of the solid state of the drug during the thermal process. The morphology and chemical composition of the surface of the extrudates were examined by Scanning Electron Microscopy/Energy Dispersive X-ray Microanalysis to evaluate the presence of the drug on the surface of the extrudates and to monitor changes on the aspect of the waxy matrix during dissolution. Then, the different systems were analysed from the in vitro dissolution point of view to study the influence of the shape and of the composition on the drug release. An in vivo pilot study on the best performing system (helix with 3 blades) was carried out on five healthy volunteers and monitoring the intestinal transit by X-ray images. The resulting plasma profiles were analysed by means of a suitable pharmacokinetic analysis. Finally, an ad hoc mathematical model was developed to perform an accurate description of the in vitro release and in vivo performance of the 3-blades helical system. PMID- 21827852 TI - Design of prolonged release tablets using new solid acrylic excipients for direct compression. AB - The design of new excipients that extend the release of drugs from tablets over prolonged periods is essential in reaching enhanced therapeutic performances. In this sense, the objective of this study was to develop new excipients, based on acrylic monomers (ethyl acrylate, methyl methacrylate, and butyl methacrylate) for use in direct compression (DC). The polymeric excipients were prepared by suspension and emulsion polymerization reactions and were characterized by FTIR to confirm the polymerization reaction. For the success of direct compression, excipients must present good flow and compactability properties. Therefore, excipients were submitted to analysis of morphology (SEM), particle size and size distribution by laser diffraction, and powder density (bulk density and tapped density). The Carr index, Hausner ratio, flow ratio, and cotangent of the angle alpha were determined. Thereafter, the polymeric excipients were used to prepare inert matrices by DC using propranolol hydrochloride (PHCl) as a model drug. The tablets were evaluated for average weight, breaking force, and friability tests. The release profiles were determined, and the dissolution kinetics was studied. The results indicated that matrices prepared from excipients obtained by suspension polymerization (NWCB and PECB) presented a release of PHCl for a period exceeding 12h, most likely due to the higher micromeritic properties. The results suggested that the increase in the percentage of polymers, as well as in the compression time, resulted in a higher hardness of the matrix with a reduced rate release of the PHCl. Finally, in vitro preliminary tests showed that the polymeric excipients produced were non-toxic for the gingival fibroblasts. PMID- 21827853 TI - Co-processed MCC-Eudragit(r) E excipients for extrusion-spheronization. AB - This study investigates the extrusion-spheronization performance of some mixtures of co-processed microcrystalline cellulose and Eudragit(r) E (as excipients) and sorbitol (as soluble filler-disintegrant). Attention is focused on the dissolution rate of low water solubility drugs (hydrochlorothiazide is used as a model drug) from pellets prepared with these mixtures. All pellet formulations studied presented adequate morphological, flow and mechanical properties. The pellets prepared with co-processed MCC-Eudragit(r) E and sorbitol show a drug dissolution rate dependent on the content of Eudragit(r) E in the co-processed excipient and on the proportion of sorbitol incorporated. Furthermore, the pellets made with co-processed MCC-Eudragit(r) E incorporating the higher proportion of sorbitol (50%) show a very high dissolution rate of hydrochlorothiazide (HCT) and undergo rapid disintegration in the dissolution medium. PMID- 21827854 TI - Different modalities of NaCl osmogen in biodegradable microspheres for bone deposition of risedronate sodium by alveolar targeting. AB - Risedronate sodium was formulated into polylactide-co-glycolic acid microspheres for pulmonary delivery using the w/o/w double emulsion technique. Sodium chloride was used as osmogen in either the internal or external aqueous phase to surface engineer the particles to achieve favorable properties. The prepared microspheres were characterized for the surface morphology, entrapment efficiency, in vitro release behavior, particle size, surface area, aerodynamic as well as powder flow properties. Furthermore, the safety of the drug and the selected formula were assessed by MTT viability test performed on Calu-3 cell line as well as histopathological lung tissue examination. A novel in vivo approach based on the radiolabeling of risedronate sodium with I(125) was developed in order to assess its deposition in the bones of male albino rats. The majority of the prepared microspheres exhibited high entrapment efficiency, sustained release profile up to 15 days, suitable geometric and aerodynamic particle sizes as well as good flow properties. The safety of the drug and the selected formula were proven by the high cell viability percentage of Calu-3 cells as well as the normal lung histology after intra-tracheal administration. The in vivo study showed high bone deposition for risedronate sodium following the pulmonary route, suggesting that it could be utilized as an alternative route of administration for delivery of bisphosphonates. PMID- 21827856 TI - Impact of estradiol structural modifications (18-methyl and/or 17-hydroxy inversion of configuration) on the in vitro and in vivo estrogenic activity. AB - It is well recognized that the majority of breast cancers are initially hormone dependent and that 17beta-estradiol (17beta-E2) plays a crucial role in their development and progression. For this reason, using a compound able to block a specific enzyme involved in the last steps of the biosynthesis of 17beta-E2 remains a rational way to treat estrogen-dependent diseases such as breast cancer. The present study describes the biological in vitro and in vivo evaluation of a structural modification (inversion of C18-methyl group at position 13 from beta to alpha face) of 17beta-E2 (1) and 17alpha-estradiol (17alpha-E2; 2). The two epimers 18-epi-17beta-E2 (3) and 18-epi-17alpha-E2 (4) were obtained in two chemical steps by inversion of the C18-methyl of estrone using 1,2-phenylendiamine in refluxing acetic acid and reduction of ketone at position C17 with LiAlH(4). The new E2 isomers were tested on estrogen-sensitive cell lines (MCF-7 and T-47D), on estrogen-sensitive tissues (uterus and vagina of mice) and on estrogen receptor (ER) to determine their estrogenic potency relatively to natural estrogen 17beta-E2 (1). The results show that 18-epi-17beta E2 (3) possesses the lower affinity for ER (RBA = 1.2%), the lower estrogenicity on estrogen-sensitive cells (1000 folds less estrogenic than 17beta-E2 in MCF-7) and no uterotrophic (estrogenic) activity when tested on mice. In fact, we observed the following order of estrogenicity: 18-epi-17beta-E2 (3)<18-epi 17alpha-E2 (4) << 17alpha-E2 (2)17beta-E2 (1). These results suggest that the inversion of C18-methyl of natural 17beta-E2 scaffold could be a useful strategy to decrease the estrogenicity of E2 derivatives used as enzyme inhibitors in the context of a treatment of estrogen-dependent diseases. PMID- 21827855 TI - Estrogenic environmental chemicals and drugs: mechanisms for effects on the developing male urogenital system. AB - Development and differentiation of the prostate from the fetal urogenital sinus (UGS) is dependent on androgen action via androgen receptors (AR) in the UGS mesenchyme. Estrogens are not required for prostate differentiation but do act to modulate androgen action. In mice exposure to exogenous estrogen during development results in permanent effects on adult prostate size and function, which is mediated through mesenchymal estrogen receptor (ER) alpha. For many years estrogens were thought to inhibit prostate growth because estrogenic drugs studied were administered at very high concentrations that interfered with normal prostate development. There is now extensive evidence that exposure to estrogen at very low concentrations during the early stages of prostate differentiation can stimulate fetal/neonatal prostate growth and lead to prostate disease in adulthood. Bisphenol A (BPA) is an environmental endocrine disrupting chemical that binds to both ER receptor subtypes as well as to AR. Interest in BPA has increased because of its prevalence in the environment and its detection in over 90% of people in the USA. In tissue culture of fetal mouse UGS mesenchymal cells, BPA and estradiol stimulated changes in the expression of several genes. We discuss here the potential involvement of estrogen in regulating signaling pathways affecting cellular functions relevant to steroid hormone signaling and metabolism and to inter- and intra-cellular communications that promote cell growth. The findings presented here provide additional evidence that BPA and the estrogenic drug ethinylestradiol disrupt prostate development in male mice at administered doses relevant to human exposures. PMID- 21827857 TI - Impaired social interactions and motor learning skills in tuberous sclerosis complex model mice expressing a dominant/negative form of tuberin. AB - Tuberous sclerosis complex (TSC) is a genetic disorder characterized by the development of hamartomas in multiple organs. Neurological manifestation includes cortical dysplasia, epilepsy, and cognitive deficits such as mental impairment and autism. We measured the impact of TSC2-GAP mutations on cognitive processes and behavior in, DeltaRG transgenic mice that express a dominant/negative TSC2 that binds to TSC1, but has mutations affecting its GAP domain and its rabaptin-5 binding motif, resulting in inactivation of the TSC1/2 complex. We performed a behavioral characterization of the DeltaRG transgenic mice and found that they display mild, but significant impairments in social behavior and rotarod motor learning. These findings suggest that the DeltaRG transgenic mice recapitulate some behavioral abnormalities observed in human TSC patients. PMID- 21827858 TI - Davunetide (NAP) as a preventative treatment for central nervous system complications in a diabetes rat model. AB - AIMS: Central nervous system complications including cognitive impairment are an early manifestation of diabetes mellitus, also evident in animal models. NAP (generic name, davunetide), a neuroprotective peptide was tested here for its ability to prevent diabetes-related brain pathologies in the streptozotocin injected diabetes rat model. METHODS: Diabetes was induced by an intraperitoneal streptozotocin injection (55 mg/kg). Intranasal NAP or vehicle was administered daily starting on the day following streptozotocin injection. Cognitive assessment was performed 12 weeks after diabetes induction, using the Morris water maze paradigm. Brain structural integrity was assessed on the 15th week of diabetes by magnetic resonance T2 scan. Characterization of cellular populations, apoptosis and synaptic density was performed 16 weeks after diabetes induction, using immunohistochemical markers and quantified in the prefrontal cortex, the cerebral cortex and the hippocampus of both hemispheres. RESULTS: Impaired spatial memory of the diabetic rats was observed in the water maze by attenuated learning curve and worsened performance in the probe memory test. NAP treatment significantly improved both measurements. T2 magnetic resonance imaging revealed atrophy in the prefrontal cortex of the diabetes rat group, which was prevented by NAP treatment. Immunohistochemical analysis showed that NAP treatment protected against major loss of the synaptic marker synaptophysin and astrocytic apoptosis, resulting from streptozotocin treatment. CONCLUSIONS: Our results show for the first time protective effects for NAP (davuentide) in a diabetes rat model at the behavioral and structural levels against one of the most severe complications of diabetes. PMID- 21827859 TI - Fear-relevant outcomes modulate the neural correlates of probabilistic classification learning. AB - Although much work has implicated the contributions of frontostriatal and medial temporal lobe (MTL) systems during probabilistic classification learning, the impact of emotion on these learning circuits is unknown. We used a modified version of the weather prediction task in which two participant groups were scanned with identical neutral cue cards probabilistically linked to either emotional (snake/spider) or neutral (mushroom/flower) outcomes. Owing to the differences in visual information shown as outcomes, analyses were restricted to the cue phase of the trials. Learning rates did not differ between the two groups, although the Emotional group was more likely to use complex strategies and to respond more slowly during initial learning. The Emotional group had reduced frontostriatal and MTL activation relative to the Neutral group, especially for participants who scored higher on snake/spider phobia questionnaires. Accurate performance was more tied to medial prefrontal activity in the Emotional group early in training, and to MTL activity in the Neutral group later in training. Trial-by-trial fluctuations in functional connectivity between the caudate and MTL were also reduced in the Emotional group compared to the Neutral group. Across groups, reaction time indexed a switch in learning systems, with faster trials mediated by the caudate and slower trials mediated by the MTL and frontal lobe. The extent to which the caudate was activated early in training predicted later performance improvements. These results reveal insights into how emotional outcomes modulate procedural learning systems, and the dynamics of MTL-striatal engagement across training trials. PMID- 21827860 TI - Relationship between aberrant brain connectivity and clinical features in Angelman Syndrome: a new method using tract based spatial statistics of DTI color coded orientation maps. AB - AIM: In order to relate brain structural abnormalities to clinical features of Angelman Syndrome (AS), we determined the locations of abnormal regional white matter architecture in AS children using a sensitive and objective whole brain approach to analyze diffusion tensor imaging (DTI) color-coded orientation maps. METHODS: Using tract based spatial statistics (TBSS) of DTI color-coded orientation maps, the fraction of fibers oriented in the anteroposterior (AP), mediolateral (ML) and superioinferior (SI) directions were determined in whole brain white matter of 7 children with AS (mean age: 70+/-25.78 months, 5 males) and 7 children with typical development (TD, mean age: 79.8+/-17.25 months, 4 males). TBSS of FA map was also performed for comparison. RESULTS: Children with AS had a significantly lower AP component than the TD group in 9 clusters (3 bilateral and 3 unilateral). Bilateral clusters were located in inferior fronto occipital fasciculus, anterior thalamic radiation and arcuate fasciculus regions. Unilateral clusters involved left brainstem, left cingulum and right uncinate regions. Similarly, children with AS had significantly lower ML component than the TD group in 4 clusters (2 in corpus callosum and 2 unilateral clusters). Unilateral clusters were located in the left cingulum and left anterior thalamic radiation regions. SI component was lower in children with AS in two clusters compared to TD (corticospinal tract and corpus callosum). FA map clusters mostly corresponded with component clusters. INTERPRETATION: Children with AS have a global impairment of white matter integrity including AP, ML and SI components in whole brain suggesting a potential underlying error with axon guidance mechanisms during brain development possibly due to loss of UBE3A gene expression. Some of this aberrant connectivity can be related to the clinical features of AS. PMID- 21827862 TI - Molecular phylogenetic analysis of tropical freshwater mussels (Mollusca: Bivalvia: Unionoida) resolves the position of Coelatura and supports a monophyletic Unionidae. AB - In previous molecular phylogenetic analyses of the freshwater mussel family Unionidae (Bivalvia: Unionoida), the Afrotropical genus Coelatura had been recovered in various positions, generally indicating a paraphyletic Unionidae. However that result was typically poorly supported and in conflict with morphology-based analyses. We set out to test the phylogenetic position of Coelatura by sampling tropical lineages omitted from previous studies. Forty-one partial 28S nuclear rDNA and partial COI mtDNA sequences (1130 total aligned nucleotides) were analyzed separately and in combination under both maximum parsimony and likelihood, as well as Bayesian inference. There was significant phylogenetic incongruence between the character sets (partition homogeneity test, p<0.01), but a novel heuristic for comparing bootstrap values among character sets analyzed separately and in combination illustrated that the observed conflict was due to homoplasy rather than separate gene histories. Phylogenetic analyses robustly supported a monophyletic Unionidae, with Coelatura recovered as part of a well-supported Africa-India clade (=Parreysiinae). The implications of this result are discussed in the context of Afrotropical freshwater mussel evolution and the classification of the family Unionidae. PMID- 21827861 TI - Cortical thickness correlates with impulsiveness in healthy adults. AB - BACKGROUND: Impulsiveness is a central domain of human personality and of relevance for the development of substance use and certain psychiatric disorders. This study investigates whether there are overlapping as well as distinct structural cerebral correlates of attentional, motor and nonplanning impulsiveness in healthy adults. METHODS: High-resolution magnetic resonance scans were acquired in 32 healthy adults to model the gray-white and gray cerebrospinal fluid borders for each individual cortex and to compute the distance of these surfaces as a measure of cortical thickness (CT). Associations between CT and the dimensions of impulsiveness (Barratt-Impulsiveness-Scale 11, BIS) were identified in entire cortex analyses. RESULTS: We observed a significant negative correlation between left middle frontal gyrus (MFG) CT and the attention BIS score (FDR p<.05), motor, nonplanning and total BIS score (each p<0.001 uncorrected). In addition, CT of the orbitofrontal (OFC) and superior frontal gyrus (SFG) were inversely correlated (p<0.001 uncorrected) with BIS total and motor score. Among other negative associations only one positive correlation (right inferior temporal with nonplanning score, p<0.001 uncorrected) was found. CONCLUSIONS: The MFG is crucial for top-down control, executive and attentional processes. The MFG together with the OFC and SFG appears to be part of brain structures, which have previously been shown to mediate behavioral inhibition, well-planned action and attention, which are core facets of impulsiveness as measured with the Barratt-Impulsiveness-Scale. PMID- 21827863 TI - A double antigen bridging immunogenicity ELISA for the detection of antibodies to polyethylene glycol polymers. AB - INTRODUCTION: Polyethylene glycol (PEG) polymers attached to biotherapeutic molecules enhance in vivo delivery and stability of these large molecular weight drugs. However, these polymers may by themselves be immunogenic and elicit antibodies that can reduce the efficacy of the drug and contribute to potential patient morbidity. A double antigen bridging ELISA immunogenicity assay for the detection of anti-drug antibodies (ADAs) specific to PEG polymers of various sizes has been developed. METHODS: Hapten-labeled conjugate of 40kDa PEG polymer was synthesized and used in a double antigen bridging ELISA. The hapten-labeled PEG is incubated with the patient sample, then this mixture is added to a 96-well microplate precoated with 40kDa PEG, allowing PEG-specific ADA to form a bridge complex with the PEG conjugate and the PEG coated on the microplate. After incubation, the reaction mixture is removed and replaced by horseradish peroxidase (HRP)-labeled anti-hapten antibody. After sufficient incubation, the plate is washed and substrate reagent is added. Enzyme color development, directly proportional to ADA, is stopped after 20min with 2N sulfuric acid and the absorbance in each well is measured at 450/630nm. Dose response, drug tolerance, matrix effects, reproducibility, specificity/free drug depletion experiments and screening cut-point determination of 350 naive normal human sera were performed. RESULTS: Using an anti-PEG mouse monoclonal IgM as a positive control, a reproducible dose response curve was demonstrated for the PEG Immunogenicity ELISA. Pre-existing PEG-specific antibodies which were proven to be highly specific to the PEG polymer structure were found in 15 human serum samples in a total population of 350 naive donors. The assay exhibited no significant matrix effects and was shown to be highly reproducible. DISCUSSION: A double antigen bridging immunogenicity assay for the detection of antibodies to PEG in the typical polymer size ranges used in biotherapeutics has been successfully developed in ELISA format. The antibodies detected in positive samples displayed a diverse spectrum of specificities for different PEG polymer lengths and linking functional groups. The discovery of 15 confirmed positive samples among 350 naive patient samples calls into focus the need for testing PEG specific immunogenicity of PEGylated biotherapeutics. PMID- 21827864 TI - Computed tomography detects changes in contrast agent diffusion after collagen cross-linking typical to natural aging of articular cartilage. AB - OBJECTIVE: The effect of threose-induced collagen cross-linking on the mechanical and diffusive properties of cartilage was investigated in vitro. In particular, we investigated the potential of Contrast Enhanced Computed Tomography (CECT) to detect changes in articular cartilage after increased collagen cross-linking, which is an age-related phenomenon. METHODS: Osteochondral plugs (O=6.0 mm, n=28) were prepared from intact bovine patellae (n=7). Two of the four adjacent samples, prepared from each patella, were treated with threose to increase the collagen cross-linking, while the other two specimen served as paired controls. One sample pair was mechanically tested and then mechanically injured using a material testing device. Contrast agent [ioxaglate (HexabrixTM)] diffusion was imaged in the other specimen pair for 25 h using CECT. Water fraction, collagen and proteoglycan content, collagen network architecture and the amount of cross links [hydroxylysyl pyridinoline (HP), lysyl pyridinoline (LP) and pentosidine (Pent)] of the samples were also determined. RESULTS: Cartilage collagen cross linking, both Pent and LP, were significantly (P<0.001) increased due to threose treatment. CECT could detect the increased cross-links as the contrast agent penetration and the diffusion flux were significantly (P<0.05) lower in the threose treated than in untreated samples. The equilibrium modulus (+164%, P<0.05) and strain dependent dynamic modulus (+47%, P<0.05) were both significantly greater in the threose treated samples than in reference samples, but there was no association between the initial dynamic modulus and the threose treatment. The water fraction, proteoglycan and collagen contents, as well as collagen architecture, were not significantly altered by the threose treatment. CONCLUSIONS: To conclude, the CECT technique was found to be sensitive at detecting changes in cartilage tissue due to increased collagen cross-linking. This is important since increased cross-linking has been proposed to be related to the increased injury susceptibility of tissue. PMID- 21827865 TI - The effect of Quercus castaneifolia extract on pathogenic enteric bacteria. AB - The family of Enterobacteriaceae is a major group of gram negative bacteria, some of these microorganisms are pathogen and could cause disease mainly gastroenteritis. Recently, due to drug resistant nature of these bacteria specially in developing countries treatment of the patient considered as important investigate. Quercus castaneifolia is a native plant of Yasuj province in Iran, which the people who living in this area consume the fruit of this plant for treatment of enteric disease. Hence, the present study was conducted to evaluate the effect of fruit of Q. castaneifolia extract on pathogenic enteric bacteria viz., E. coli, Salmonella typhimurium, Shigella dysenteriae and Yersinia enterocolitica. Antimicrobial susceptibility and minimal inhibitory concentration (MIC) of the extracts were assessed by gel diffusion method and modification of E test respectively. All the experiments were performed in triplicate and the statistical analysis was carried out on the results. The results obtained from this study indicated that alcoholic extract was shown antimicrobial effect on the microorganisms tested. In addition, S. dysentriae was more sensitive with zone of inhibition 18 mm and MIC value was 2.5 * 10(-4) whereas, E. coli was less sensitive with zone of inhibition 12 mm and MIC value 1 * 10(-2). Salmonella typhimurium and Yersinia enterocolitica showed relatively intermediate susceptibility to the extract with zone of inhibition of 14 mm and MIC value 5 * 10(-3). Overall, Q. castaneifolia may be considered for treatment of the patients suffering from enteric disease. PMID- 21827866 TI - Synapsin regulation of vesicle organization and functional pools. AB - Synaptic vesicles are organized in clusters, and synapsin maintains vesicle organization and abundance in nerve terminals. At the functional level, vesicles can be subdivided into three pools: the releasable pool, the recycling pool, and the reserve pool, and synapsin mediates transitions between these pools. Synapsin directs vesicles into the reserve pool, and synapsin II isoform has a primary role in this function. In addition, synapsin actively delivers vesicles to active zones. Finally, synapsin I isoform mediates coupling release events to action potentials at the latest stages of exocytosis. Thus, synapsin is involved in multiple stages of the vesicle cycle, including vesicle clustering, maintaining the reserve pool, vesicle delivery to active zones, and synchronizing release events. These processes are regulated via a dynamic synapsin phosphorylation/dephosphorylation cycle which involves multiple phosphorylation sites and several pathways. Different synapsin isoforms have unique and non redundant roles in the multifaceted synapsin function. PMID- 21827868 TI - Glutamatergic neurotransmission in the synapsin I and II double knock-out mouse. AB - The synaptic vesicle-associated synapsin proteins may participate in synaptic transmission, but their exact functional role(s) here remain(s) uncertain. We here briefly describe the important characteristics of the synapsin proteins, and review recent studies on transgenic mice devoid of the gene products encoded by the synapsin I and II genes, where both neurochemical, cell biological and electrophysiological methods have been employed. We present evidence for synapsin effects on both neurotransmitter synthesis and homeostasis, as well as on synaptic vesicle development and functions. Moreover, we describe physiological analyses of excitatory glutamatergic hippocampal synapses where a novel synapsin dependent delayed response enhancement (DRE) phase occurs, and demonstrate the postnatal developmental patterns of both frequency facilitations and DRE responses. Finally, we report synapsin I and II effects in distinct excitatory glutamatergic synapses in the hippocampus, and indicate that synapsin-dependent modulations of synaptic function may use distinct presynaptic response patterns in order to induce different classes of presynaptic plasticity. PMID- 21827869 TI - Increased H2 production in the cyanobacterium Synechocystis sp. strain PCC 6803 by redirecting the electron supply via genetic engineering of the nitrate assimilation pathway. AB - The unicellular cyanobacterium Synechocystis sp. strain PCC 6803 contains a single bidirectional NiFe-Hox-hydrogenase, which evolves hydrogen under certain environmental conditions. The nitrate assimilation pathway is a potential competing pathway that may reduce the electron flow to the hydrogenase and thereby limit hydrogen production. To improve H(2) production, the nitrate assimilation pathway was disrupted by genetic engineering to redirect the electron flow towards the Hox-hydrogenase. Mutant strains disrupted in either nitrate reductase (DeltanarB) or nitrite reductase (DeltanirA) or both nitrate reductase and nitrite reductase (DeltanarB:DeltanirA) were constructed and tested for their ability to produce hydrogen. H(2) production and Hox-hydrogenase activities in all the mutant strains were higher than those in wild-type. Highest H(2) production was observed in the DeltanarB:DeltanirA strain. Small changes were observed for Hox-hydrogenase enzyme activities and only minor changes in transcript levels of hoxH and hoxY were not correlated with H(2) production. The results suggest that the high rate of H(2) production observed in the DeltanarB:DeltanirA strain of the cyanobacterium Synechocystis sp. strain PCC 6803 is the result of redirecting the electron supply from the nitrate assimilation pathway, through genetic engineering, towards the Hox-hydrogenase. PMID- 21827870 TI - Prevent the cause, not just the symptoms. AB - If people stay healthy, less health care treatments need to be paid. Alternatively, health care treatments are uneconomical and unethical when they only remove signs and symptoms and leave the primary cause neglected and unchanged to cause future harm. Neglected preventable causes continue to cause massive health-related financial loss in the US. Monitoring imbalances of omega-3 and omega-6 hormone precursors in individuals can increase awareness and motivation for making efforts to prevent this pervasive diet-related cause of dysfunction, disease and financial loss. We now have low-cost tools for individuals to monitor their balance of omega-3 and omega-6 hormone precursors and to identify and choose foods that will maintain a desired balance and a desired quality of life. PMID- 21827867 TI - Synapsin III: role in neuronal plasticity and disease. AB - Synapsin III was discovered in 1998, more than two decades after the first two synapsins (synapsins I and II) were identified. Although the biology of synapsin III is not as well understood as synapsins I and II, this gene is emerging as an important factor in the regulation of the early stages of neurodevelopment and dopaminergic neurotransmission, and in certain neuropsychiatric illnesses. Molecular genetic and clinical studies of synapsin III have determined that its neurodevelopmental effects are exerted at the levels of neurogenesis and axonogenesis. In vitro voltammetry studies have shown that synapsin III can control dopamine release in the striatum. Since dopaminergic dysfunction is implicated in many neuropsychiatric conditions, one may anticipate that polymorphisms in synapsin III can exert pervasive effects, especially since it is localized to extrasynaptic sites. Indeed, mutations in this gene have been identified in individuals diagnosed with schizophrenia, bipolar disorder and multiple sclerosis. These and other findings indicate that the roles of synapsin III differ significantly from those of synapsins I and II. Here, we focus on the unique roles of the newest synapsin, and where relevant, compare and contrast these with the actions of synapsins I and II. PMID- 21827872 TI - The invaders: phylogeography of dengue and chikungunya viruses Aedes vectors, on the South West islands of the Indian Ocean. AB - Aedes albopictus and Aedes aegypti are the two main worldwide arbovirus vectors that have experienced invasion phases. Aedes aegypti is a pantropical species that spread centuries ago whereas Ae. albopictus started the main wave of invasion in the 1980s. Both species have been at various times on the different islands in Southwestern Indian Ocean (SWIO). This area provides an opportunity to examine the extent to which mosquitoes colonization patterns are influenced by different introductory events likely linked with human settlement and migration between the islands. To explore this hypothesis, we propose a CO1-based phylogeny using a large sampling of fresh Ae. albopictus, Ae. aegypti, and Ae. mascarensis, and 50-year-old dry specimens originating from different Indian Ocean islands. Our data allow us to hypothesize the existence of at least two waves of invasion for Ae. albopictus in the islands of SWIO. The first one most likely occurred several centuries ago with establishments in Madagascar, Mauritius and Reunion Island. The other one that appears to currently still on-going, reached almost all the islands of SWIO during the 1990s or later. The low genetic diversity found between the ancient invasive strain and the contemporary one, indicates with great certainty that Ae. albopictus is not indigenous to the islands of SWIO. Recently, in Madagascar, an invasive lineage of Ae. albopictus has expanded all over the island while Ae. aegypti populations have declined in urban areas. Three clusters of Aedes aegypti have been observed, two fitting with the wild form Ae. aegypti formosus and the other one fitting with the more domestic form Ae. ae. aegypti. Sequence of Ae. mascarensis, endemic to Mauritius suggest that this species might belong to Ae. aegypti species and on this basis we propose to classify it as a sub species or form of Ae. aegypti species. Given the increase of human population flux on these islands, the occurrence of these vectors and their ability to spread quickly are of high importance of arbovirus transmission and the epidemicity of the associated diseases in these islands. PMID- 21827871 TI - Recombinant Wolbachia heat shock protein 60 (HSP60) mediated immune responses in patients with lymphatic filariasis. AB - Wolbachia, an endosymbiont present in filarial nematodes, have been implicated in a variety of roles, including the worm development and survival. Elucidation of the role of Wolbachia in filarial nematode biology and pathogenesis has become the focus of many studies and its contribution to parasite survival or immune response is still unclear. Recombinant Wolbachia HSP60 decreases T cell activation and lymphoproliferation in filarial infected people compared to endemic controls as observed by the assessment of T cell activation markers and cytokine responses in the peripheral blood mononuclear cells. Reduced T cell activation may be linked to T regulatory cell activity since it is associated with increased expression of CTLA4 and CD25 on CD4(+) T cells in filarial infected group upon stimulation with recombinant Wolbachia HSP60. In addition, elevated interleukin-10 and TGF-beta cytokines corroborate the reduced CD4(+) T cell activation and interferon-gamma observed upon recombinant Wolbachia HSP60 stimulation in filarial patients. Hence, these findings indicate that Wolbachia HSP60 may also contribute to the immune modulation seen in filarial patients. PMID- 21827874 TI - Surface modification with polyethylene glycol-corn trypsin inhibitor conjugate to inhibit the contact factor pathway on blood-contacting surfaces. AB - Blood contacting surfaces bind plasma proteins and trigger coagulation by activating factor XII (FXII). The objective of this work was to develop blood contacting surfaces having the dual properties of protein resistance and inhibition of coagulation. Gold was used as a model substrate because it is amenable to facile modification using gold-thiol chemistry and to detailed surface characterization. The gold was modified with both polyethylene glycol (PEG) and corn trypsin inhibitor (CTI), a potent and specific inhibitor of activated FXII (FXIIa). Two methods of surface modification were developed; sequential and direct. In the sequential method PEG was first chemisorbed on gold; CTI was then attached to the PEG. In the direct method a conjugate of PEG and CTI was first prepared; the conjugate was then immobilized on gold. The surfaces were characterized by water contact angle and XPS. Biointeractions with the modified surfaces were assessed by measuring fibrinogen adsorption from buffer and plasma and by immunoblot analysis of eluted proteins after plasma exposure. Inhibition of FXIIa, autoactivation of FXII, and clotting times of plasma in contact with the surfaces were also measured. Both the sequential and direct surfaces showed reduced protein adsorption, increased FXIIa inhibition and longer clotting times compared with controls. Although the CTI density was lower on surfaces prepared using the sequential method, surfaces so prepared exhibited greater CTI activity than those generated by the direct method. It is concluded that the activity of immobilized PEG-CTI depends on the method of attachment and that immobilized CTI may be useful in rendering biomaterials more blood compatible. PMID- 21827873 TI - Partial molecular characterisation of New World non-human primate lymphocryptoviruses. AB - The description of numerous viruses belonging to the Lymphocryptovirus genus from different Old and New World non-human primate species during the past 10 years has led to developing and supporting co-speciational evolution hypotheses for these viruses and their hosts. Among the different primate species tested, only a few were from the New World. This study attempted to achieve a better understanding of the evolutionary processes within the Platyrrhini branch. Molecular screening of 253 blood DNA samples from 20 New World non-human primate species from Central and South America was carried out using polymerase chain reaction amplification with degenerate consensus primers targeting highly conserved amino acid motifs of the herpesvirus DNA polymerase gene. In addition to the 33 samples from which we have already described three lymphocryptoviruses, amplification products were detected in 17 other samples originating from 11 species (13 sub-species). BLAST searches, pairwise nucleotide and amino acid sequence comparisons, and phylogenetic analyses confirm that they all belong to the Lymphocryptovirus genus. Fourteen distinct Lymphocryptovirus sequences were detected, of which nine have never been reported. Phylogenetic analyses showed that, as expected, the New World virus lineage formed a sister clade to that of the Old World viruses. The parallel determination of the host taxa has demonstrated a good correlation between the distinct monophyletic clades of viruses and the infected primates at the sub-family level. In addition, these results further suggest the existence of two distinct groups within the Cebidae for Saimirinae and Cebinae primates. Nevertheless, based on the current genetic data, this study fell short of achieving a tree that was completely resolved within the lineage of Platyrrhini viruses. Further studies will be needed to better assess the evolutionary relationships between these viruses. PMID- 21827875 TI - In search of representative models of human bone-forming cells for cytocompatibility studies. AB - Osteosarcoma-derived cells have been routinely used for studying osteoblastic functions, but it remains unclear to what extent they mimic the behavior of primary osteoblasts in the study of cells and materials interactions. This study reports comparatively on the responses of three human osteosarcoma cell lines, MG 63, Saos-2 and U-2 OS, and human primary osteoblasts cultured on Ti6Al4V surfaces or exposed to Ti particles. Phenotypic characterization of the cell lines revealed that Saos-2 cells and primary osteoblasts displayed similar expression patterns of Cbfa1, SP7 and osteocalcin. Unlike primary cells, the cell lines expressed markers of undifferentiated cells, had high proliferative rates and poor fibronectin matrix assembly. None of the three cell lines faithfully reproduced the adhesive behavior of primary osteoblasts when cultured on Ti6Al4V surfaces or exposed to Ti particles. Differences in cell growth between the cell lines and primary osteoblasts cultured on Ti6Al4V surfaces were also observed. Ti particles inhibited the growth of Saos-2 cells and primary osteoblasts to a similar extent, while no such effect was observed in U-2 OS and MG-63 cells. Saos 2 cells reproduced the alkaline phosphatase (ALP) activity profile of primary osteoblasts cultured on metallic surfaces or exposed to particles. Altogether, these results show that none of the osteoblast-like cells studied perfectly mimic the behavior of human osteoblast cells (hOB) on Ti6Al4V surfaces or exposed to Ti particles. Saos-2 cells reproduce some of the hOB responses such as the profile of enzymatic ALP activity when cultured on the surfaces or treated with particles as well as cell growth inhibition when exposed to Ti particles. Although in vitro cytocompatibility studies involve the evaluation of multiple parameters, Saos-2 cells may be used as representative of human osteoblasts when these standard tests are evaluated. PMID- 21827876 TI - Broad spectrum antimicrobial activity of functionalized polyanilines. AB - The antimicrobial properties of conductive functionalized polyanilines (fPANI) were investigated by exploring their interaction with bacterial cells. In sharp contrast to polyaniline (PANI), lower concentrations of fPANI were needed to strongly inhibit the growth of wild-type Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus, as well as several antibiotic-resistant clinical pathogens. To gain an insight into how fPANI have an impact on cellular physiology we used a whole genome expression study in the model E. coli MG1655 strain exposed to a representative fPANI. The expression levels of 218 (~5.1%) genes changed significantly. Moreover, we found that certain oxidative damage responsive genes were strongly induced, while genes potentially involved in energy metabolism and transport and in forming bacterial cell walls and stress resistant cellular communities (biofilms) were repressed. Taken together, our results appear to indicate that the antimicrobial effects of fPANI, in part at least, might stem from their ability to target the operations of multiple and diverse cellular processes, and suggest that fPANI could be useful ingredients for biomaterials used in the development of food packaging and medical devices. PMID- 21827877 TI - Parkinson's disease. PMID- 21827878 TI - Inherited ataxias. PMID- 21827879 TI - The cerebellum - structure and connections. PMID- 21827880 TI - Physiology of clinical dysfunction of the cerebellum. AB - Experimental and theoretical research into cerebellar function has begun to converge toward understanding the cerebellum as a "controller" in the engineering sense. The purpose of a controller is to convert high-level intent commands and information describing the current state of a system into low-level control signals suitable for maintaining or changing system behavior. The cerebellar subsystem appears to play this role for parts of the body and other parts of the brain. As with engineering controllers, fundamental functions include stabilization at a fixed posture or state, adjustment of movement or transition amplitude, facilitation of movement/transition speed and crispness of launch and braking, improvement of resistance to disturbances, coordination of control across multiple degrees of freedom, and assistance with estimation and/or prediction of current and future system states. As with adaptive engineering controllers, the cerebellar subsystem also readily tunes itself over time. At a more detailed level, many of the specific actions of cerebellar circuits can be understood in terms of proportional (P), integrator-like (I), and differentiator like (D) signal processing which are fundamental components of many engineering control systems. This chapter presents an integrated, mechanistic view of ataxia, tremor, and several cerebellar oculomotor signs in terms of PID control and the neural centers that appear to subserve these functions. It also suggests the manner in which impairments in motor learning, perception, and cognition that are associated with cerebellar dysfunction may be viewed from a similar perspective. PMID- 21827881 TI - Oculomotor aspects of the hereditary cerebellar ataxias. PMID- 21827882 TI - Magnetic resonance and nuclear medicine imaging in ataxias. AB - Imaging techniques including computed tomography (CT), magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT), and positron emission tomography (PET) have been widely applied to the investigation of patients with acute or chronic ataxias. Fundamentally, CT has a role in the emergency evaluation of the patient with acute ataxia to ascertain brainstem or cerebellar hemorrhage and to exclude a mass lesion in the posterior cranial fossa. Conventional MRI is the most frequently performed imaging investigation in patients with ataxia. It can support the diagnosis of acute cerebellitis and Wernicke encephalopathy by revealing T2 signal changes with a typical distribution. In patients with inherited or sporadic chronic ataxia it reveals three fundamental patterns of atrophy of the brainstem, cerebellum, and spinal cord which match the gross neuropathological descriptions. These are represented by olivopontocerebellar atrophy (OPCA), cortical cerebellar atrophy (CCA), and spinal atrophy (SA). A substantial correspondence exists among these patterns of atrophy shown by MRI and the etiological classification of inherited or acquired chronic ataxias. This, along with demonstration of T2 signal changes characteristic of some diseases, makes conventional MRI potentially useful for the diagnostic work-up of the single patient, especially in the case of a sporadic disease. Non-conventional MR techniques including diffusion MR, spectroscopy, and functional MR have been used in patients with acute or chronic ataxia, but their exact role in the evaluation of the single patient is not established yet. They are currently investigated as potential tools to monitor progression of neurodegeneration in chronic ataxia and to serve as "surrogate markers" in clinical trials. Several radiotracers have been utilized in combination with SPECT and PET in patients with ataxia. Perfusion SPECT can reveal cerebellar blood flow abnormalities early in the course of cerebellitis. It has also been utilized to investigate perfusion of the brain in several inherited or sporadic chronic ataxic diseases, contributing to improved understanding of the pathophysiology of these conditions. Recently, perfusion SPECT has been tested as a "surrogate marker" to verify the effects of newly developed therapies in patients with a variety of chronic ataxias. Whole-body FDG PET is recommended in patients with suspected paraneoplastic cerebellar degeneration to detect the primary malignancy. Brain FDG-PET has provided important information on the pathophysiology of several acquired and inherited conditions. PET and SPECT with radiotracers able to assess the nigrostriatal system or the density of D2 dopamine receptors in the striatum are increasingly used in patients with adult-onset sporadic ataxia for the differential diagnosis between multiple system atrophy in which overt striatal abnormalities are found and idiopathic late-onset cerebellar ataxia in which no abnormality is detected. PMID- 21827883 TI - Neuropathology of degenerative ataxias. PMID- 21827884 TI - Approach to ataxic diseases. PMID- 21827885 TI - Acquired ataxias, infectious and para-infectious. PMID- 21827886 TI - Ataxia in patients with brain infarcts and hemorrhages. AB - Gait and limb incoordination and ataxia are most often found in patients with brainstem and cerebellar infarcts and hemorrhages. Lesions involving the thalamus and the deep portions of the cerebral hemispheres also may cause ataxia accompanied by weakness and sensory symptoms. Patients who have lesions in the lateral medulla and inferior cerebellum often topple, lean, or veer when attempting to sit, stand, or walk. They list to the side or abruptly veer when walking. The affected limbs are often hypotonic. In pontine lesions, ataxia is accompanied by weakness and pyramidal tract signs as part of an ataxic hemiparesis syndrome. In lesions affecting the superior cerebellum and the brachium conjunctivum, limb dysmetria and overshoot and dysarthria predominate and gait ataxia is absent or slight and transient. Infarcts affecting the thalamus can cause gait instability and astasia with ataxia. Lateral thalamic lesions are characterized by hemisensory symptoms, extrapyramidal limb postures and dysfunction, and gait ataxia. Lesions that affect the posterior limb of the internal capsule and its afferent and efferent projections may also cause an ataxic hemiparesis syndrome, often with accompanying hemisensory abnormalities. PMID- 21827887 TI - Ataxia resulting from posterior fossa tumors of childhood and other mass lesions. AB - Ataxia is a common presenting symptom and sequela of treatment in children with posterior fossa tumors, and is the most common focal neurological deficit in the majority of tumor types. Owing to the diversity of histologies among pediatric posterior fossa tumors and the concomitant diversity in tumor biology and prognosis, distinctive management strategies are required for each tumor type. In addition, age-related factors influence the ease of diagnosis and difficulty of management for patients with these tumors. In most modern centers, children with such tumors are treated in cooperative group studies, which are designed to increase the percentage of children who achieve long-term survival as well as their functional outcome. PMID- 21827888 TI - Nutritional cerebellar degeneration, with comments on its relationship to Wernicke disease and alcoholism. AB - Nutritional cerebellar degeneration occurs in alcoholism and other states that predispose to malnutrition, such as gastric bypass surgery. Gait ataxia is the principal clinical manifestation. Ataxia of the lower limbs is not uncommon, but upper extremity ataxia and nystagmus are rare. Atrophy of the anterior superior vermis is the primary pathological manifestation in established disease. Typically, the onset is subacute. This cerebellar disease is part of the spectrum of the Wernicke-Korsakoff syndrome, i.e. the cerebellar manifestation of Wernicke disease. It may occur with other lesions of Wernicke disease or in isolation. Rarely, with florid disease, lesions may be hemorrhagic. Active disease should be treated with thiamine in the same way that one treats Wernicke disease. Clinicopathologic correlation in this disease has provided the best evidence that the anterior superior vermis is important in coordinating bipedal locomotion. PMID- 21827889 TI - Immune-mediated acquired ataxias. AB - The cerebellum, and in particular the Purkinje cells within it, appear to be a frequent immunological target in the context of some systemic diseases. This is perhaps more often the case with the cerebellum by comparison to other structures within the central nervous system. This observation may relate to the fact that the cerebellum is one of the largest, oldest, and most structurally conserved structures in the vertebrate nervous system and/or that Purkinje cells possess good and multiple antigenic targets. Immune-mediated ataxias include paraneoplastic cerebellar degeneration and post-infective cerebellitis, but these will be discussed elsewhere. This chapter covers in detail the epidemiology, clinical characteristics, pathophysiology, and treatment of some other examples of immune-mediated ataxias, including gluten ataxia and ataxia associated with anti-GAD antibodies. There is particular emphasis on gluten ataxia as this is one of the commonest immune-mediated cerebellar ataxias and one of the few ataxias that are potentially treatable. The chapter also introduces the concept of primary autoimmune cerebellar ataxia as a form of organ-specific autoimmune disease for the first time. The pathophysiology leading to cerebellar damage, loss of Purkinje cells, and the development of ataxia remains speculative, but existing clues are discussed in detail. PMID- 21827890 TI - Toxic agents causing cerebellar ataxias. AB - The cerebellum is particularly vulnerable to intoxication and poisoning, especially so the cerebellar cortex and Purkinje neurons. In humans, the most common cause of a toxic lesion to the cerebellar circuitry is alcohol related, but the cerebellum is also a main target of drug exposure (such as anticonvulsants, antineoplastics, lithium salts, calcineurin inhibitors), drug abuse and addiction (such as cocaine, heroin, phencyclidine), and environmental toxins (such as mercury, lead, manganese, toluene/benzene derivatives). Although data for the prevalence and incidence of cerebellar lesions related to intoxication and poisoning are still unknown in many cases, clinicians should keep in mind the list of agents that may cause cerebellar deficits, since toxin induced cerebellar ataxias are not rare in daily practice. Moreover, the patient's status may require immediate therapies when the intoxication is life threatening. PMID- 21827891 TI - Paraneoplastic cerebellar degeneration. AB - One of the most dramatic and devastating examples of a remote effect of cancer is paraneoplastic cerebellar degeneration (PCD). There is convincing evidence that this disorder is caused by autoimmunity directed against cerebellar targets. Typically, the neurological presentation antedates the diagnosis of malignancy, and the cancer, when found, tends to be localized and responsive to treatment. Diagnosis depends on clinical suspicion, serology for paraneoplastic antibodies, and a focused search for cancer. Neuronal autoantibody tests facilitate the diagnosis and help direct the search for malignancy. Unfortunately, even with prompt diagnosis, current treatment strategies meet with limited success. Optimum management includes early diagnosis, treatment of cancer to remission, immunosuppression, symptomatic therapies, and compassionate support. PMID- 21827892 TI - Epidemiology and population genetics of degenerative ataxias. PMID- 21827893 TI - Sporadic adult-onset ataxia of unknown etiology. AB - Sporadic adult-onset ataxia of unknown etiology (SAOA) denotes the non-hereditary degenerative adult-onset ataxia disorders that are distinct from multiple system atrophy (MSA). Rather than being a defined disease entity, SAOA has to be regarded as a group of disorders of unknown etiology that are defined by a common clinical syndrome and the exclusion of known disease causes. Epidemiological studies have revealed prevalence rates ranging from 2.2 to 8.4 per 100000, which are higher than those of hereditary ataxias. Clinically, SAOA is characterized by a slowly progressive cerebellar syndrome starting around the age of 50 years. About one-third of SAOA patients have either polyneuropathy or pyramidal tract involvement accompanying cerebellar ataxia. Cognitive impairment is not the rule, and, if present, is only mild. More than half of SAOA patients have signs of mild autonomic dysfunction that do not meet the criteria of severe autonomic failure required for a diagnosis of MSA. Neuropathological and imaging studies show an isolated cerebellar cortical degeneration with no or only mild brainstem involvement. There is no established therapy for SAOA. PMID- 21827894 TI - Overview of autosomal recessive ataxias. PMID- 21827895 TI - Friedreich ataxia. PMID- 21827896 TI - Ataxia with vitamin E deficiency and abetalipoproteinemia. PMID- 21827897 TI - Ataxia-telangiectasia. PMID- 21827898 TI - Autosomal recessive cerebellar ataxias with oculomotor apraxia. PMID- 21827899 TI - Other autosomal recessive and childhood ataxias. AB - The label of "early-onset cerebellar ataxia with retained tendon reflexes" (EOCA) has been created to differentiate it from Friedreich ataxia (FRDA) patients with preserved knee jerks and absence of cardiomyopathy, optic atrophy, and diabetes mellitus. However, EOCA is a heterogeneous syndrome and several FRDA patients present with an EOCA-like phenotype. Cerebellar ataxia with hypogonadism is another heterogeneous syndrome for which no locus has been mapped yet. Two peculiar ataxic syndromes have been identified in genetically isolated populations: autosomal recessive ataxia of Charlevoix-Saguenay (ARSACS) in Quebec and infantile-onset spinocerebellar ataxia (IOSCA) in Finland. Both conditions present usually within the second year of life. ARSACS is characterized by marked spasticity and IOSCA by a complex phenotype which includes, besides ataxia, epilepsy, optic atrophy, ophthalmoplegia, hearing loss, and areflexia. The responsible genes are SACS, encoding sacsin, a protein which may act as a chaperone, and C10orf2, encoding Twinkle, a mitochondrial DNA-specific helicase. Marinesco-Sjogren syndrome, clinically characterized by cerebellar ataxia, cataracts, myopathy, and mental retardation, is genetically heterogeneous. One gene, SIL1, encodes a nucleotide exchange factor for the heat-shock protein 70 chaperone HSPA5. Five conditions account for most cases of progressive myoclonic ataxia: Unverricht-Lundborg disease, Lafora disease, myoclonic epilepsy with ragged-red fibers, neuronal ceroid lipofuscinoses, and sialidoses. PMID- 21827900 TI - Ataxia in mitochondrial disorders. AB - Mitochondria are subcellular organelles whose major function is to generate energy by coupling through oxidation of nutrient substrates with ATP synthesis, via ADP phosphorylation. This process, known as oxidative phosphorylation, is carried out by the mitochondrial respiratory chain, a pathway consisting of five multi-subunit complexes, four of which take contribution from genes located in two separate compartments, the nuclear chromosomes, and a genome found in mitochondria themselves, mitochondrial DNA (mtDNA). Defects affecting either genome give rise to mitochondrial dysfunction, causing disease that often affects the brain and in particular the cerebellum. Mitochondrial disorders can give rise to pure cerebellar, spinocerebellar, or sensory ataxia, usually as part of a multisystem (and multisymptom) disorder. In this chapter we divide the diseases into those caused by mtDNA defects and those due to mutations involving nuclear genes. With more than 100 mutations in mtDNA and new nuclear genes being described all the time, we have focused on the commonest disorders and used these as examples of the different types of mitochondrial ataxia. PMID- 21827901 TI - Fragile X-associated tremor/ataxia syndrome. AB - Fragile X-associated tremor/ataxia syndrome (FXTAS) is an under-recognized disorder that is a significant cause of late-adult-onset ataxia. The etiology is expansion of a trinucleotide repeat to the premutation range (55-200 CGG repeats) in the fragile X mental retardation 1 (FMR1) gene. Expansion to >200 CGGs causes fragile X syndrome, the most common heritable cause of cognitive impairment and autism. Core features of FXTAS include progressive action tremor and gait ataxia; with frequent, more variable features of cognitive decline, especially executive dysfunction, parkinsonism, neuropathy, and autonomic dysfunction. MR imaging shows generalized atrophy and frequently abnormal signal in the middle cerebellar peduncles. Autopsy reveals intranuclear inclusions in neurons and astrocytes and dystrophic white matter. FXTAS is likely due to an RNA toxic gain-of-function of the expanded-repeat mRNA. The disorder typically affects male premutation carriers over age 50, and, less often, females. Females also are at increased risk for primary ovarian insufficiency, chronic muscle pain, and thyroid disease. Treatment targets specific symptoms, but progression of disability is relentless. Although the contribution of FXTAS to the morbidity and mortality of the aging population requires further study, the disorder is likely the most common single gene form of tremor and ataxia in the older adult population. PMID- 21827902 TI - Overview of autosomal dominant ataxias. PMID- 21827903 TI - Spinocerebellar ataxia type 1. AB - Spinocerebellar ataxia type 1 (SCA1) is one out of nine polyglutamine diseases, a group of late-onset neurodegenerative diseases present only in humans. SCA1, the first autosomal dominant cerebellar ataxia (ADCA) to be genetically characterized, is caused by the expansion of a CAG triplet repeat located in the N-terminal coding region of the disease-causing gene ATX1 located on chromosome 6p23: the mutation results in the production of a mutant protein, dubbed ataxin 1, with a longer-than-normal polyglutamine stretch. The predominant effect of the mutation is thought to be a toxic gain-of-function of the aberrant protein, and longer expansions are associated with earlier onset and more severe disease in subsequent generations. The most common presentation of SCA1 is dominant ataxia 'plus', characterized by cerebellar dysfunctions variably associated with slow saccades, ophthalmoplegia, pyramidal and extrapyramidal features, mild to moderate dementia, amyotrophy, and peripheral neuropathy. Its diagnostic pathological feature is olivopontocerebellar atrophy and degeneration predominantly affects the Purkinje cells and the dentate nuclei of the cerebellum. Pathogenesis is mainly attributed to the toxic effect of mutant ataxin-1, which localizes into the nucleus and, through restricted and aberrant protein-protein interactions, causes putative dysfunctional gene transcription in target cells which leads to late-onset cell dysfunction and death. PMID- 21827904 TI - Spinocerebellar ataxia type 2. PMID- 21827906 TI - Spinocerebellar ataxia type 5. AB - In 1994, Ranum and colleagues identified a ten-generation American kindred with a relatively mild autosomal dominant form of spinocerebellar ataxia (Ranum et al., 1994). The mutation was mapped to the centromeric region of chromosome 11, and the disorder designated SCA5 (Ranum et al., 1994). Using a multifaceted mapping approach, Ikeda et al. (2006) discovered that beta-III spectrin (SPTBN2) mutations cause spinocerebellar ataxia type 5 (SCA5) in the American kindred and two additional independently reported SCA5 families. The American and French families have separate in-frame deletions of 39 and 15 bp, respectively, in the third of 17 spectrin repeat motifs. A third mutation, found in a German family, is located in the second calponin homology domain, a region known to bind actin and Arp1. Consistent with Purkinje cell degeneration in SCA5, beta-III spectrin is highly expressed in cerebellar Purkinje cells. TIRF microscopy performed on cell lines transiently transfected with mutant or wild-type spectrin shows that mutant beta-III spectrin fails to stabilize the glutamate transporter EAAT4 at the plasma membrane. Additionally, marked differences in EAAT4 and GluRdelta2 were found by protein blot and cell fractionation in SCA5 autopsy tissue. This review summarizes data showing that beta-III spectrin mutations are a novel cause of neurodegenerative disease, which may affect the stabilization or trafficking of membrane proteins. PMID- 21827907 TI - Spinocerebellar ataxia type 6. AB - The autosomal dominant spinocerebellar ataxias (SCA) are a genetically heterogeneous group of neurodegenerative disorders characterized by progressive motor incoordination, in some cases with ataxia alone and in others in association with additional progressive neurological deficits. Spinocerebellar ataxia type 6 (SCA6) is the prototype of a pure cerebellar ataxia, associated with a severe form of progressive ataxia and cerebellar dysfunction. SCA6, originally classified as such by Zhuchenko et al. (1997), is caused by a CAG repeat expansion in the CACNA1A gene which encodes the alpha1A subunit of the P/Q type voltage-gated calcium channel. SCA6 is one of ten polyglutamine-encoding CAG nucleotide repeat expansion disorders comprising other neurodegenerative disorders such as Huntington's disease. The present review describes clinical, genetic, and pathological manifestations associated with this illness. Currently, there is no treatment for this neurodegenerative disease. Successful therapeutic strategies must target a valid pathological mechanism; thus, understanding the underlying mechanisms of disease is crucial to finding a proper treatment. Hence, this chapter will discuss as well the molecular mechanisms possibly associated with SCA6 pathology and their implication for the development of future treatment. PMID- 21827905 TI - Machado-Joseph disease/spinocerebellar ataxia type 3. AB - Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), may be the most common dominantly inherited ataxia in the world. Here I will review historical, clinical, neuropathological, genetic, and pathogenic features of MJD, and finish with a brief discussion of present, and possible future, treatment for this currently incurable disorder. Like many other dominantly inherited ataxias, MJD/SCA3 shows remarkable clinical heterogeneity, reflecting the underlying genetic defect: an unstable CAG trinucleotide repeat that varies in size among affected persons. This pathogenic repeat in MJD/SCA3 encodes an expanded tract of the amino acid glutamine in the disease protein, which is known as ataxin-3. MJD/SCA3 is one of nine identified polyglutamine neurodegenerative diseases which share features of pathogenesis centered on protein misfolding and accumulation. The specific properties of MJD/SCA3 and its disease protein are discussed in light of what is known about the entire class of polyglutamine diseases. PMID- 21827909 TI - Clinical and genetic features of spinocerebellar ataxia type 8. PMID- 21827908 TI - Spinocerebellar ataxia type 7. AB - Spinocerebellar ataxia type 7 (SCA7) is associated with progressive blindness, dominant transmission, and marked anticipation. SCA7 represents one of the polyglutamine expansion diseases with increase of CAG repeats. The gene maps to chromosome 3p12-p21.1. Normal values of CAG repeats range from 4 to 18. The SCA7 gene encodes a protein of largely unknown function, called ataxin-7. SCA7 is reported in many countries and ethnic groups. Its phenotypic expression depends on the number of expanded repeats. The infantile phenotype is very severe, with more than 100 repeats. The classic type has 50 to 55 repeats and is characterized by a combination of visual and ataxic disturbances lasting for 20-40 years.When the number of CAG repeats is between 36 and 43, the evolution is much slower, with few or no retinal abnormalities. A CAG repeat number from 18 to 35 is asymptomatic but predisposes to the development of the disorder when expanding to the pathological range through transmission. The diagnosis is made by molecular genetics. The neuropathology of the disorder includes atrophy of the spinocerebellar pathways, pyramidal tracts, and motor nuclei in the brainstem and spinal cord, a cone-rod sytrophy of the retina, and ataxin-7 immunoreactive neuronal intranuclear inclusions. The neuropathological features vary as a function of the number of CAG repeats. Present research deals mainly with the study of ataxin-7 in transfected neural cells and transgenic mouse models. PMID- 21827910 TI - Spinocerebellar ataxia type 10. PMID- 21827911 TI - Spinocerebellar ataxia type 11. PMID- 21827912 TI - Spinocerebellar ataxia type 12. AB - SCA12 is a late-onset, autosomal dominant, slowly progressive disorder. Action tremor is the usual presenting sign. Subsequent development of ataxia and hyperreflexia suggests spinocerebellar ataxia. In the index SCA12 kindred, which resides in North America and is of German ancestry, parkinsonism, anxiety, depression, and cognitive dysfunction are not uncommon. SCA12 is linked to a CAG repeat expansion mutation in exon 7 of PPP2R2B, a gene that encodes Bbeta, a regulatory subunit of protein phosphatase 2A (PP2A). CAG repeats number 7-28 in normal individuals and 55-78 in SCA12 patients. The mechanism by which this mutation leads to SCA12 has not been determined. The CAG expansion in PPP2R2B has promoter function in vitro. CAG length correlates with increased Bbeta expression. There is no evidence that this CAG expansion results in polyglutamine production. In addition to the North. American SCA12 kindred, multiple SCA12 families have been found in Northern India that are not related to the index SCA12 kindred. SCA12 has been reported, rarely, in Singapore and China. Action tremor, anxiety, and depression in SCA12 have responded to usual treatments for these disorders. SCA12 may be considered in patients who present with action tremor and later develop signs of cerebellar and cortical dysfunction. PMID- 21827913 TI - Spinocerebellar ataxia 13 and 25. AB - Spinocerebellar ataxia (SCA) types 13 and 25 are two genetic entities among the autosomal dominant cerebellar ataxias, initially mapped in two French families to chromosomes 19q and 2p, respectively. The SCA13 locus was confirmed by the identification of a second kindred of Filipino ancestry. SCA13 patients have cerebellar ataxia of adult onset, or of early onset when associated with mental impairment. SCA25 patients present with cerebellar ataxia with sensory neuropathy and frequent gastrointestinal features. While the gene responsible for SCA25 is still unknown, missense mutations affecting the potassium channel KCNC3 function have been identified. PMID- 21827914 TI - Spinocerebellar ataxia type 14. AB - SCA14 is an autosomal dominant hereditary cerebellar ataxia that usually has an onset in early to mid adult life, with slow progression and normal lifespan. Although generally an uncomplicated cerebellar ataxia with gait imbalance, dysarthria, and nystagmus, there is occasionally sensory loss, hyperactive tendon reflexes, cognitive decline, or myoclonus. Brain MRI shows cerebellar atrophy. A single autopsy has shown loss of cerebellar Purkinje cells. The disease is caused by mutations in the protein kinase C gamma (PKCgamma, PRKCG) gene with a hotspot for mutations in exon 4. Genetic testing for SCA14 is clinically available. PMID- 21827915 TI - Spinocerebellar ataxia type 15. AB - Spinocerebellar ataxia type 15 (SCA15), first described in 2001, is a slowly progressive, relatively pure dominantly inherited ataxia. Six pedigrees have been reported to date, in Anglo-Celtic and Japanese populations. Other than notably slow progression, its main distinguishing characteristic is tremor, often affecting the head, which is seen in about half of affecteds and which may be the presenting feature. Neuroradiology shows cerebellar atrophy, particularly affecting the anterior and dorsal vermis. SCA15 is due to various deletions of the inositol 1,4,5-triphosphate receptor 1 gene (ITPR1) on the distal short arm of chromosome 3. The potential of point mutations in ITPR1 to cause SCA15 is not yet confirmed. "SCA16" has now been shown to be due to an ITPR1 mutation, and has now been subsumed into SCA15. PMID- 21827916 TI - Spinocerebellar ataxia type 20. AB - Spinocerebellar ataxia type 20 (SCA20), first reported in 2004, is a slowly progressive dominantly inherited disorder so far reported in a single Anglo Celtic family from Australia. It is characterized by dentate calcification from an early stage of the illness. Dysarthria without ataxia is the first symptom in the majority - an unusual feature amongst the SCAs. In addition to ataxia, examination often reveals spasmodic dysphonia and palatal tremor, but the syndrome is otherwise fairly pure. The responsible genetic abnormality has been tentatively identified as a 260-kb duplication in the pericentric region of chromosome 11, but confirmation will necessarily await description of further families. PMID- 21827917 TI - Spinocerebellar ataxia type 28. AB - We have recently mapped the spinocerebellar ataxia type 28 (SCA28) locus on chromosome 18p11.22 in a four-generation Italian family. The clinical phenotype in affected individuals of this family was characterized by juvenile onset, slowly progressive gait and limb ataxia, dysarthria, hyperreflexia at lower limbs, nystagmus, and ophthalmoparesis. The mean age at onset was 19.5 years, and no evidence of anticipation between generations was observed. The disease locus on chromosome 18p11.22-q11.2 was found to span a region of 7.9 Mb of genomic DNA. Direct sequencing of candidate genes within the critical interval led to the identification of a heterozygous point mutation in one of them. The mutation was located in a highly conserved domain with proposed functional properties in the protein product of the SCA28 gene, and segregated with the disease phenotype in all affected members of this family. Further genetic screening in 105 patients with autosomal dominant spinocerebellar ataxia negative for mutations in known SCA genes allowed the identification of a distinct missense mutation in a second Italian family. Both mutations are associated with amino acid changes in evolutionarily conserved residues of the alleged SCA28 gene, and indicate SCA28 as the sixth recognized SCA genotype caused by point mutations. PMID- 21827918 TI - Other spinocerebellar ataxias. PMID- 21827919 TI - Dentatorubral-pallidoluysian atrophy. AB - Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare autosomal dominant neurodegenerative disorder clinically characterized by various combinations of cerebellar ataxia, choreoathetosis, myoclonus, epilepsy, dementia, and psychiatric symptoms. The most striking clinical features of DRPLA are the considerable heterogeneity in clinical presentation, depending on the age of onset, and the prominent genetic anticipation. DRPLA is caused by unstable expansion of CAG repeats coding for polyglutamine stretches located in exon 5 of the DRPLA gene. DRPLA is characterized by prominent anticipation, with paternal transmission resulting in more prominent anticipation than does maternal transmission, which is now understood based on the intergenerational stability of the CAG repeats. DRPLA protein (also called atrophin-1) is localized in the nucleus and functions as a transcription co-regulator. Recent immunohistochemical studies on autopsied tissues of patients with DRPLA have demonstrated that diffuse accumulation of mutant DRPLA protein (atrophin-1) in the neuronal nuclei, rather than the formation of neuronal intranuclear inclusions (NIIs), is the predominant pathologic condition and involves a wide range of central nervous system regions far beyond the systems previously reported to be affected. Thus, age-dependent and CAG repeat-dependent intranuclear accumulation of mutant DRPLA leading to nuclear dysfunctions are suggested to be the essential pathophysiologic mechanisms in DRPLA. PMID- 21827920 TI - Episodic ataxias 1 and 2. AB - The episodic ataxias are autosomal dominant disorders usually beginning in the first two decades of life. Episodic ataxia type 1 (EA1) is characterized by brief episodes of ataxia, typically lasting seconds, and interictal myokymia, while episodic ataxia type 2 (EA2) is manifested by longer episodes of ataxia (hours) with interictal nystagmus. The EA1 gene (KCNA1) codes for the six transmembrane segments (S1 to S6) of the Kv1.1 potassium channel subunit and the EA2 gene (CACNA1A) encodes for the Ca(v)2.1 subunit of the P/Q calcium channel complex. EA1 mutations are always missense while most EA2 mutations disrupt the reading frame. Studies of the biophysical properties of the mutant Kv1.1 and Ca(v)2.1 channels in Xenopus oocytes and mammalian cell lines demonstrate clear physiologic consequences of the genetic mutations although no consistent pattern for genotype-phenotype correlation has emerged. Genetic testing for EA1 and EA2 is available, but since no single mutation is prominent for either KCNA1 or CACNA1A, all of the coding regions of the genes need to be screened for mutations. Acetazolamide can be dramatic in controlling episodes of ataxia with EA2 but is typically less beneficial with EA1. PMID- 21827921 TI - Ataxias related to sensory neuropathies. PMID- 21827922 TI - Frontal lobe ataxia. AB - The precise anatomy and physiology of human walking remains poorly understood. The frontal lobes appear crucial, and, on the basis of clinical observation, contribute to the control of truncal motion, postural responses, and the maintenance of equilibrium and locomotion. The rich repertoire of frontal gait disorders gives some indication of this complexity. Variable combinations of disequilibrium with a wide stance base, increased body sway and falls, loss of control of truncal motion, locomotor disability with gait ignition failure, start hesitation, shuffling, and freezing are encountered in diseases of the frontal lobes. Furthermore, the pattern of gait may change as the frontal disease progresses. The slowness of walking, lack of heel-shin or upper limb ataxia, dysarthria or nystagmus distinguishes the wide stance base from cerebellar gait ataxia. A lively facial expression, normal voluntary movements of the upper limbs, upper motor neuron signs, and the absence of a rest tremor distinguish the hypokinetic elements from Parkinson's disease. Poor truncal mobility, impaired postural responses, and falls after the slightest perturbation eventually make walking impossible even though simple leg movements may still be possible while seated or lying. One or more of these features usually predominates in the initial presentation of a frontal gait syndrome. Accordingly, there is considerable variation in the manner of presentation and evolution of frontal gait disorders. The gait syndrome is accompanied by frontal motor and cognitive changes, which may be subtle or overshadowed by the gait disorder. This complexity of clinical presentation accounts for the plethora of descriptions from "frontal ataxia" to "gait apraxia". As suggested in the original descriptions of frontal ataxia, the spectrum of gait disturbance is likely to be due to damage to frontal cortex and its connections with subcortical structures including the basal ganglia, cerebellum, and the brainstem. PMID- 21827923 TI - Balance and gait problems in the elderly. AB - Gait and balance problems are common with advancing age. Disorders of balance and gait are particularly important in the elderly because they compromise independence and contribute to the risk of falls and injury. Although they are considered as separate clinical entities, balance and gait disturbance are often intertwined. Here, we discuss the principal anatomical and physiologic mechanisms responsible for balance and gait. We also review the different types of fall patterns commonly seen in subjects and a classification scheme for various gait disorders. Furthermore, we consider the relationship between balance and gait disorders and subcortical vascular disease. Potential interventions and therapies in those individuals with balance and gait disorders are also discussed. PMID- 21827924 TI - Treatment and management issues in ataxic diseases. PMID- 21827925 TI - The potential of stem cells for 21st century neuroscience. PMID- 21827926 TI - Prediction of acute traumatic coagulopathy and massive transfusion - Is this the best we can do? PMID- 21827927 TI - [Repositories and business skills: why?]. PMID- 21827930 TI - A single exposure to voluntary ethanol self-administration produces adaptations in ethanol consumption and accumbal dopamine signaling. AB - In well-trained animals, accumbal dopamine release is stimulated during operant ethanol self-administration, but the time course of development of this dopaminergic response, particularly during the acquisition of ethanol drinking behavior, remains unknown. To examine this, we trained male Long-Evans rats to self-administer 10% ethanol plus 10% sucrose, using a protocol in which the concentration of ethanol was kept constant throughout the study. The animals were required to press the lever four times to gain continuous access to the drinking solution for 20 minutes, and microdialysis was performed on either the first or second day of 10% ethanol plus 10% sucrose self-administration or 10% sucrose as controls. Ethanol and dopamine were both analyzed in the dialysates. All groups (day 1 and 2 ethanol and their corresponding sucrose controls) showed an increase in accumbal dopamine during the transfer from the home cage into the operant chamber. Our main finding was an increase in dopamine in the nucleus accumbens core-shell border during the first 5 minutes of consumption on the second day but not on the first day of ethanol self-administration. Our results suggest that a single exposure to a 10% ethanol plus 10% sucrose drinking solution may be sufficient to learn the association between ethanol cues and its reinforcing properties. Furthermore, we speculate that the dopamine response during ethanol consumption likely reflects the reward-prediction role of the mesolimbic dopamine system. PMID- 21827929 TI - Ethanol drinking reduces extracellular dopamine levels in the posterior ventral tegmental area of nondependent alcohol-preferring rats. AB - Moderate ethanol exposure produces neuroadaptive changes in the mesocorticolimbic dopamine (DA) system in nondependent rats and increases measures of DA neuronal activity in vitro and in vivo. Moreover, moderate ethanol drinking and moderate systemic exposure elevates extracellular DA levels in mesocorticolimbic projection regions. However, the neuroadaptive changes subsequent to moderate ethanol drinking on basal DA levels have not been investigated in the ventral tegmental area (VTA). In the present study, adult female alcohol-preferring (P) rats were divided into alcohol-naive, alcohol-drinking, and alcohol-deprived groups. The alcohol-drinking group had continuous access to water and ethanol (15%, vol/vol) for 8 weeks. The alcohol-deprived group had 6 weeks of access followed by 2 weeks of ethanol deprivation, 2 weeks of ethanol re-exposure, followed again by 2 weeks of deprivation. The deprived rats demonstrated a robust alcohol deprivation effect (ADE) on ethanol reinstatement. The alcohol-naive group had continuous access to water only. In the last week of the drinking protocol, all rats were implanted with unilateral microdialysis probes aimed at the posterior VTA and no-net-flux microdialysis was conducted to quantify extracellular DA levels and DA clearance. Results yielded significantly lower basal extracellular DA concentrations in the posterior VTA of the alcohol drinking group compared with the alcohol-naive and alcohol-deprived groups (3.8+/ 0.3nM vs. 5.0+/-0.5nM [P<.02] and 4.8+/-0.4nM, [P<.05], respectively). Extraction fractions were significantly (P<.0002) different between the alcohol-drinking and alcohol-naive groups (72+/-2% vs. 46+/-4%, respectively) and not significantly different (P=.051) between alcohol-deprived and alcohol-naive groups (61+/-6% for the alcohol-deprived group). The data indicate that reductions in basal DA levels within the posterior VTA occur after moderate chronic ethanol intake in nondependent P rats. This reduction may result, in part, from increased DA uptake and may be important for the maintenance of ethanol drinking. These adaptations normalize with ethanol deprivation and may not contribute to the ADE. PMID- 21827928 TI - Alcohol abuse and Streptococcus pneumoniae infections: consideration of virulence factors and impaired immune responses. AB - Alcohol is the most frequently abused substance in the world. Both acute and chronic alcohol consumption have diverse and well-documented effects on the human immune system, leading to increased susceptibility to infections like bacterial pneumonia. Streptococcus pneumoniae is the most common bacterial etiology of community-acquired pneumonia worldwide. The frequency and severity of pneumococcal infections in individuals with a history of alcohol abuse is much higher than the general population. Despite this obvious epidemiological relevance, very few experimental studies have focused on the interaction of pneumococci with the immune system of a host acutely or chronically exposed to alcohol. Understanding these host-pathogen interactions is imperative for designing effective prophylactic and therapeutic interventions for such populations. Recent advances in pneumococcal research have greatly improved our understanding of pneumococcal pathogenesis and virulence mechanisms. Additionally, a large body of data is available on the effect of alcohol on the physiology of the lungs and the innate and adaptive immune system of the host. The purpose of this review is to integrate the available knowledge in these diverse areas of for a better understanding of the how the compromised immune system derived from alcohol exposure responds to pneumococcal infections. PMID- 21827931 TI - Patient consensus on mode of use of nettle sting for musculoskeletal pain. AB - BACKGROUND: Many patients with musculoskeletal pain prefer topical treatments because they consider them safer than oral drugs. There is a long history of topical use of nettle sting for pain, but no standard method of application. Our objective was to develop a consensus of the experiences of nettle sting users. METHODS: A consensus study was conducted using the expert panel method. Media articles resulted in 16 responses and nine users attended a meeting. Participants first responded to questions on how they chose the leaf and how they applied the nettle sting; then discussed their individual responses; and finally responded once more to the same questions. Consensus was defined as 70% agreement. Participants' consensus was developed from the responses and discussions, and modified in response to repeated feedback and to comments of seven other nettle users. RESULTS: Consensus was present initially on three questions: 'Important to feel a good strong sting', 'Immediately sting the area again' and 'Sting once a day'. Opinions on the method and site of application, and format of a course of treatment varied. This range of advice was incorporated into a treatment consensus document acceptable to all users in the study. CONCLUSIONS: The users' consensus document for the use of nettle sting for musculoskeletal pain is published for anyone who wishes to use this self-care approach to treating their pain. The user's consensus document represents an essential step in undertaking further research into the effectiveness of nettle sting as a treatment for musculoskeletal pain. PMID- 21827932 TI - A multicenter, randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of a far infrared-emitting sericite belt in patients with primary dysmenorrhea. AB - OBJECTIVE: To determine the efficacy and safety of a sericite which emits far infrared rays in the management of primary dysmenorrhea. DESIGN: A multicenter randomized double-blind placebo-controlled trial. SETTING: One hundred four patients with primary dysmenorrhea were randomized to wear a sericite or placebo belt during sleep for 3 menstrual cycles, and followed for 2 menstrual cycles. Hot packs were used to heat the ceramics and ensure slight pain relief in both groups. MAIN OUTCOME MEASURES: The main outcome measures were the severity of dysmenorrhea assessed by a 10-point visual analog scale (VAS) and the number of patients who took analgesics at each menstrual cycle. Safety was evaluated by physical examination and self-reporting of adverse events. RESULTS: The baseline VAS scores were 7.27+/-0.19 in the experimental group and 7.38+/-0.19 in the control group. The severity of dysmenorrhea gradually decreased during the treatment period in both groups, with major improvements observed in the third treatment cycle (4.96+/-0.30 in the experimental group and 5.69+/-0.30 in the control group, p=0.087). During the follow-up period, the decreased VAS score was maintained in the experimental group, whereas the VAS score gradually returned to baseline in the control group, which resulted in significant difference between the groups (5.08+/-0.31 vs. 6.47+/-0.31 at cycle 5, difference -1.39 [95% CI, 2.25 to -0.53], p=0.0017). The number of patients who took analgesics decreased in both groups, but the differences were not statistically significant. No serious adverse events related to wearing the sericite belt occurred. CONCLUSIONS: Our data suggest that a far infrared-emitting sericite belt with a hot pack might be used as an effective and safe non-pharmacologic treatment option for women with primary dysmenorrhea, with a prolonged effect after treatment. PMID- 21827933 TI - Effects of progressive relaxation on anxiety and quality of life in female students: a non-randomized controlled trial. AB - OBJECTIVES: This study conducted to assess the effects of relaxation techniques on anxiety and the quality of life of female dormitory students. DESIGN AND SETTING: A non-randomized controlled trial was conducted in 4 female dormitories of Tehran University of medical sciences. INTERVENTIONS: The students of four dorms were randomly allocated to the experimental and control groups. The Spielberger inventory and a modified version of WHO quality of life questionnaire were administered to both groups. Then the experimental group was taught to do the relaxation techniques for two months. A post-test conducted on both groups after two months. RESULTS: Significant differences were noticed between anxiety and quality of life of the two groups after the intervention. The overall quality of life score was significantly higher in experimental group after the two months of relaxation exercises. CONCLUSIONS: relaxation techniques can be effective for improving the students' anxiety that in turn will improve their quality of life especially in the examination periods. PMID- 21827934 TI - A spirituality teaching program for depression: qualitative findings on cognitive and emotional change. AB - OBJECTIVES: This study was conducted with participants from a trial evaluating an 8-week spirituality teaching program to treat unipolar major depression. The objectives of this study were to understand the nature of the observed mood following participation in the spirituality based intervention. DESIGN: This study used the methods of a naturalistic inquiry. SETTING: A total of 15 interviewees were purposefully sampled from the trial population. INTERVENTION: The intervention consisted of audio CDs for home-based use that delivered lectures and stories about spirituality, suggested behavioural applications and included relaxation practices. MAIN OUTCOME MEASURES: In-depth, semi-structured interviews were conducted with each participant 6 months post program completion. Interviews were audio recorded and transcribed verbatim. The data were coded for patterns of substantive core meaning in terms of the participants' subjective and behavioural experiences of the program materials. RESULTS: Participants described an expanded spiritual awareness, characterized by a sense of connection with self, others, the world and universal energy. The primary influences participants reported occurred as a result of practicing forgiveness, compassion, gratitude and acceptance in their daily lives and included reduced negative thinking patterns, being less judgmental, reduced ego-centricity, and improved self esteem. Concurrent with these shifts, participants experienced an improved mood characterized by reduced anxiety and/or depression, mental clarity, calmness and improved relationships. CONCLUSION: Findings suggest that the spirituality teaching program impacts depression by expanding spiritual beliefs and shifting perspectives of life situations, oneself and others. Spiritual teachings and practices could be an innovative and valuable adjunct intervention to treat depression. PMID- 21827935 TI - Use of complementary and alternative medicine among USA adults with functional limitations: for treatment or general use? AB - OBJECTIVES: This study compared the use of complementary and alternative medicine (CAM) to treat health conditions with CAM use for general wellness or disease prevention among USA adults with and without functional limitations. DESIGN: This was a cross-sectional survey. METHODS: Data were obtained from the 2007 U.S. National Health Interview Survey (n=20,710). RESULTS: Overall use of CAM treatment was higher among adults with functional limitations than among those without (61.4% versus 41.8%; p<0.001). Adults with functional limitations were more likely to use 3 of 4 CAM groupings: biologically based therapies (BBT) (47.9% versus 29.5%, p<0.001), manipulative and body-based therapies (73.7% versus 54.1%, p<0.001), and mind-body therapies (MBT) (39.3% versus 17.4%, p<0.001). Use of alternative medical systems for treatment was highly prevalent among adults (86.9% versus 80.0%, p=0.06), regardless of functional status. Adults with functional limitations were as likely to use CAM to treat the condition underlying their functioning difficulty (48.7%) as they were to treat other conditions (51.3%). Massage therapy was used most often to treat conditions that limited functional ability (53.4%). Older age was a predictor of the use of BBT for treatment, whereas younger age was a predictor of the use of MBT. CONCLUSIONS: The prevalence of CAM use for treatment of conditions is high. Public health strategies are needed to promote disclosure of CAM use to health care providers, promote increased screening for CAM use by health care providers, and promote health care interactions that facilitate communication about CAM safety and efficacy. PMID- 21827936 TI - Complementary medicines (herbal and nutritional products) in the treatment of Attention Deficit Hyperactivity Disorder (ADHD): a systematic review of the evidence. AB - OVERVIEW: Complementary and Alternative Medicines (CAMs) are frequently given to children and adolescents for reputed benefits in the treatment of hyperkinetic and concentration disorders such as Attention Deficit Hyperactivity Disorder (ADHD). In such vulnerable populations high quality evidence is required to support such claims. AIMS: The aim of the paper is to assess the current evidence of herbal and nutritional interventions for ADHD using a systematic search of clinical trials meeting an acceptable standard of evidence. METHODS: PubMed, PsycINFO, Cochrane Library and CINAHL were searched up to May 26th, 2011 for randomised, controlled clinical trials using CAM products as interventions to treat ADHD. A quality analysis using a purpose-designed scale, and an estimation of effect sizes (Cohen's d) where data were available, were also calculated. RESULTS: The review revealed that 16 studies met inclusion criteria, with predominant evidentiary support found for zinc, iron, Pinus marinus (French maritime pine bark), and a Chinese herbal formula (Ningdong); and mixed (mainly inconclusive) evidence for omega-3, and l-acetyl carnitine. Current data suggest that Ginkgo biloba (ginkgo), and Hypercium perforatum (St. John's wort) are ineffective in treating ADHD. CONCLUSION: The research suggests only some CAMs may be beneficial in ADHD, thus clinicians need to be aware of the current evidence. Promising candidates for future research include Bacopa monniera (brahmi) and Piper methysticum (kava), providing potential efficacy in improving attentional and hyperkinetic disorders via a combination of cognitive enhancing and sedative effects. PMID- 21827937 TI - The molecular basis of nutritional intervention in multiple sclerosis: a narrative review. AB - It is commonly accepted that nutrition is one of the possible environmental factors involved in the pathogenesis of multiple sclerosis (MS), but its role as complementary MS treatment is unclear and largely disregarded. At present, MS therapy is not associated to a particular diet, probably due to lack of information on the effects of nutrition on the disease. To overcome the distrust of the usefulness of dietary control in MS and to encourage nutritional interventions in the course of the disease, it is necessary to assess the nature and the role of bioactive dietary molecules and their targets, and establish how a dietary control can influence cell metabolism and improve the wellness of MS patients. The aim of this review is to provide a rationale for a nutritional intervention in MS by evaluating at the molecular level the effects of dietary molecules on the inflammatory and autoimmune processes involved in the disease. Present data reveal that healthy dietary molecules have a pleiotropic role and are able to change cell metabolism from anabolism to catabolism and down-regulate inflammation by interacting with enzymes, nuclear receptors and transcriptional factors. The control of gut dysbiosis and the combination of hypo-caloric, low fat diets with specific vitamins, oligoelements and dietary integrators, including fish oil and polyphenols, may slow-down the progression of the disease and ameliorate the wellness of MS patients. PMID- 21827938 TI - Mechanistic insight from chaos: how RecA mediates DNA strand exchange. AB - Cleverly designed single-molecule FRET experiments reported in this issue of Structure by Ragunathan et al. coax RecA to reveal some of its secrets. Observing individual events identifies intermediate steps and provides clues for how to drive strand exchange forward. PMID- 21827939 TI - Nipped in the bud: how the AMSH MIT domain helps deubiquitinate lysosome-bound cargo. AB - Recruitment of the K63-linkage specific deubiquitinating enzyme AMSH is an important step in ESCRT-dependent membrane protein sorting. In this issue of Structure, Solomons et al. now reveal an extraordinarily high affinity complex between the "MIM4" region of one ESCRT-III subunit, CHMP3, and the MIT domain of AMSH. PMID- 21827940 TI - Bacterial, fungal, and algal lectins: combatants in tug of war against HIV. AB - High-resolution X-ray crystallography and NMR studies by Koharudin and Gronenborn in this issue provide new information on the mode of N-glycan recognition by a cyanobacterial agglutinin, with anti-HIV activity pointing to the pentamannosyl core as a novel target for therapeutic intervention. PMID- 21827941 TI - Insights into [FeFe]-hydrogenase structure, mechanism, and maturation. AB - Hydrogenases are metalloenzymes that are key to energy metabolism in a variety of microbial communities. Divided into three classes based on their metal content, the [Fe]-, [FeFe]-, and [NiFe]-hydrogenases are evolutionarily unrelated but share similar nonprotein ligand assemblies at their active site metal centers that are not observed elsewhere in biology. These nonprotein ligands are critical in tuning enzyme reactivity, and their synthesis and incorporation into the active site clusters require a number of specific maturation enzymes. The wealth of structural information on different classes and different states of hydrogenase enzymes, biosynthetic intermediates, and maturation enzymes has contributed significantly to understanding the biochemistry of hydrogen metabolism. This review highlights the unique structural features of hydrogenases and emphasizes the recent biochemical and structural work that has created a clearer picture of the [FeFe]-hydrogenase maturation pathway. PMID- 21827942 TI - Preparation of distinct ubiquitin chain reagents of high purity and yield. AB - The complexity of protein ubiquitination signals derives largely from the variety of polyubiquitin linkage types that can modify a target protein, each imparting distinct functional consequences. Free ubiquitin chains of uniform linkages and length are important tools in understanding how ubiquitin-binding proteins specifically recognize these different polyubiquitin modifications. While some free ubiquitin chain species are commercially available, mutational analyses and labeling schemes are limited to select, marketed stocks. Furthermore, the multimilligram quantities of material required for detailed biophysical and/or structural studies often makes these reagents cost prohibitive. To address these limitations, we have optimized known methods for the synthesis and purification of linear, K11-, K48-, and K63-linked ubiquitin dimers, trimers, and tetramers on a preparative scale. The high purity and relatively high yield of these proteins readily enables material-intensive experiments and provides flexibility for engineering specialized ubiquitin chain reagents, such as fluorescently labeled chains of discrete lengths. PMID- 21827944 TI - Crystal structure of full-length Apaf-1: how the death signal is relayed in the mitochondrial pathway of apoptosis. AB - The apoptotic protease-activating factor 1 (Apaf-1) relays the death signal in the mitochondrial pathway of apoptosis. Apaf-1 oligomerizes on binding of mitochondrially released cytochrome c into the heptameric apoptosome complex to ignite the downstream cascade of caspases. Here, we present the 3.0 A crystal structure of full-length murine Apaf-1 in the absence of cytochrome c. The structure shows how the mammalian death switch is kept in its "off" position. By comparing the off state with a recent cryo-electron microscopy derived model of Apaf-1 in its apoptosomal conformation, we depict the molecular events that transform Apaf-1 from autoinhibited monomer to a building block of the caspase activating apoptosome. Moreover, we have solved the crystal structure of the R265S mutant of full-length murine Apaf-1 in the absence of cytochrome c to 3.55 A resolution and we show that proper function of Apaf-1 relies on R265 in the vicinity of the bound nucleotide. PMID- 21827943 TI - Real-time observation of strand exchange reaction with high spatiotemporal resolution. AB - RecA binds to single-stranded (ss) DNA to form a helical filament that catalyzes strand exchange with a homologous double-stranded (ds) DNA. The study of strand exchange in ensemble assays is limited by the diffusion limited homology search process, which masks the subsequent strand exchange reaction. We developed a single-molecule fluorescence assay with a few base-pair and millisecond resolution that can separate initial docking from the subsequent propagation of joint molecule formation. Our data suggest that propagation occurs in 3 bp increments with destabilization of the incoming dsDNA and concomitant pairing with the reference ssDNA. Unexpectedly, we discovered the formation of a dynamic complex between RecA and the displaced DNA that remains bound transiently after joint molecule formation. This finding could have important implications for the irreversibility of strand exchange. Our model for strand exchange links structural models of RecA to its catalytic function. PMID- 21827946 TI - The structural basis for the function of two anti-VEGF receptor 2 antibodies. AB - The anti-VEGF receptor 2 antibody IMC-1121B is a promising antiangiogenic drug being tested for treatment of breast and gastric cancer. We have determined the structure of the 1121B Fab fragment in complex with domain 3 of VEGFR2, as well as the structure of a different neutralizing anti-VEGFR2 antibody, 6.64, also in complex with VEGFR2 domain 3. The two Fab fragments bind at opposite ends of VEGFR2 domain 3; 1121B directly blocks VEGF binding, whereas 6.64 may prevent receptor dimerization by perturbing the domain 3:domain 4 interface. Mutagenesis reveals that residues essential for VEGF, 1121B, and 6.64 binding are nonoverlapping among the three contact patches. PMID- 21827945 TI - The holo-apoptosome: activation of procaspase-9 and interactions with caspase-3. AB - Activation of procaspase-9 on the apoptosome is a pivotal step in the intrinsic cell death pathway. We now provide further evidence that caspase recruitment domains of pc-9 and Apaf-1 form a CARD-CARD disk that is flexibly tethered to the apoptosome. In addition, a 3D reconstruction of the pc-9 apoptosome was calculated without symmetry restraints. In this structure, p20 and p10 catalytic domains of a single pc-9 interact with nucleotide binding domains of adjacent Apaf-1 subunits. Together, disk assembly and pc-9 binding create an asymmetric proteolysis machine. We also show that CARD-p20 and p20-p10 linkers play important roles in pc-9 activation. Based on the data, we propose a proximity induced association model for pc-9 activation on the apoptosome. We also show that pc-9 and caspase-3 have overlapping binding sites on the central hub. These binding sites may play a role in pc-3 activation and could allow the formation of hybrid apoptosomes with pc-9 and caspase-3 proteolytic activities. PMID- 21827948 TI - Dynamics of the phosphoinositide 3-kinase p110delta interaction with p85alpha and membranes reveals aspects of regulation distinct from p110alpha. AB - Phosphoinositide 3-kinase delta is upregulated in lymphocytic leukemias. Because the p85-regulatory subunit binds to any class IA subunit, it was assumed there is a single universal p85-mediated regulatory mechanism; however, we find isozyme specific inhibition by p85alpha. Using deuterium exchange mass spectrometry (DXMS), we mapped regulatory interactions of p110delta with p85alpha. Both nSH2 and cSH2 domains of p85alpha contribute to full inhibition of p110delta, the nSH2 by contacting the helical domain and the cSH2 via the C terminus of p110delta. The cSH2 inhibits p110beta and p110delta, but not p110alpha, implying that p110alpha is uniquely poised for oncogenic mutations. Binding RTK phosphopeptides disengages the SH2 domains, resulting in exposure of the catalytic subunit. We find that phosphopeptides greatly increase the affinity of the heterodimer for PIP2-containing membranes measured by FRET. DXMS identified regions decreasing exposure at membranes and also regions gaining exposure, indicating loosening of interactions within the heterodimer at membranes. PMID- 21827947 TI - Status of GPCR modeling and docking as reflected by community-wide GPCR Dock 2010 assessment. AB - The community-wide GPCR Dock assessment is conducted to evaluate the status of molecular modeling and ligand docking for human G protein-coupled receptors. The present round of the assessment was based on the recent structures of dopamine D3 and CXCR4 chemokine receptors bound to small molecule antagonists and CXCR4 with a synthetic cyclopeptide. Thirty-five groups submitted their receptor-ligand complex structure predictions prior to the release of the crystallographic coordinates. With closely related homology modeling templates, as for dopamine D3 receptor, and with incorporation of biochemical and QSAR data, modern computational techniques predicted complex details with accuracy approaching experimental. In contrast, CXCR4 complexes that had less-characterized interactions and only distant homology to the known GPCR structures still remained very challenging. The assessment results provide guidance for modeling and crystallographic communities in method development and target selection for further expansion of the structural coverage of the GPCR universe. PMID- 21827949 TI - Oligomeric structure of the chemokine CCL5/RANTES from NMR, MS, and SAXS data. AB - CCL5 (RANTES) is a proinflammatory chemokine known to activate leukocytes through its receptor, CCR5. Although the monomeric form of CCL5 is sufficient to cause cell migration in vitro, CCL5's propensity for aggregation is essential for migration in vivo, T cell activation and apoptosis, and HIV entry into cells. However, there is currently no structural information on CCL5 oligomers larger than the canonical CC chemokine dimer. In this study the solution structure of a CCL5 oligomer was investigated using an integrated approach, including NMR residual dipolar couplings to determine allowed relative orientations of the component monomers, SAXS to restrict overall shape, and hydroxyl radical footprinting and NMR cross-saturation experiments to identify interface residues. The resulting model of the CCL5 oligomer provides a basis for explaining the disaggregating effect of E66 and E26 mutations and suggests mechanisms by which glycosaminoglycan binding may promote oligomer formation and facilitate cell migration in vivo. PMID- 21827950 TI - Structural basis for ESCRT-III CHMP3 recruitment of AMSH. AB - Endosomal sorting complexes required for transport (ESCRT) recognize ubiquitinated cargo and catalyze diverse budding processes including multivesicular body biogenesis, enveloped virus egress, and cytokinesis. We present the crystal structure of an N-terminal fragment of the deubiquitinating enzyme AMSH (AMSHDeltaC) in complex with the C-terminal region of ESCRT-III CHMP3 (CHMP3DeltaN). AMSHDeltaC folds into an elongated 90 A long helical assembly that includes an unusual MIT domain. CHMP3DeltaN is unstructured in solution and helical in complex with AMSHDeltaC, revealing a novel MIT domain interacting motif (MIM) that does not overlap with the CHMP1-AMSH binding site. ITC and SPR measurements demonstrate an unusual high-affinity MIM-MIT interaction. Structural analysis suggests a regulatory role for the N-terminal helical segment of AMSHDeltaC and its destabilization leads to a loss of function during HIV-1 budding. Our results indicate a tight coupling of ESCRT-III CHMP3 and AMSH functions and provide insight into the regulation of ESCRT-III. PMID- 21827951 TI - Structural basis for the Trembler-J phenotype of Charcot-Marie-Tooth disease. AB - Mutations in peripheral myelin protein 22 (PMP22) can result in the common peripheral neuropathy Charcot-Marie-Tooth disease (CMTD). The Leu16Pro mutation in PMP22 results in misassembly of the protein, which causes the Trembler-J (TrJ) disease phenotype. Here we elucidate the structural defects present in a partially folded state of TrJ PMP22 that are decisive in promoting CMTD-causing misfolding. In this state, transmembrane helices 2-4 (TM2-4) form a molten globular bundle, while transmembrane helix 1 (TM1) is dissociated from this bundle. The TrJ mutation was seen to profoundly disrupt the TM1 helix, resulting in increased backbone dynamics and changes in the tertiary interactions of TM1 with the PMP22 TM2-4 core in the folded state. Consequently, TM1 undergoes enhanced dissociation from the other transmembrane segments in TrJ PMP22, becoming available for recognition and sequestration by protein-folding quality control, which leads to loss of function and toxic accumulation of aggregates that result in CMTD. PMID- 21827952 TI - Structural basis of the anti-HIV activity of the cyanobacterial Oscillatoria Agardhii agglutinin. AB - The cyanobacterial Oscillatory Agardhii agglutinin (OAA) is a recently discovered HIV-inactivating lectin that interacts with high-mannose sugars. Nuclear magnetic resonance (NMR) binding studies between OAA and alpha3,alpha6-mannopentaose (Manalpha(1-3)[Manalpha(1-3)[Manalpha(1-6)]Manalpha(1-6)]Man), the branched core unit of Man-9, revealed two binding sites at opposite ends of the protein, exhibiting essentially identical affinities. Atomic details of the specific protein-sugar contacts in the recognition loops of OAA were delineated in the high-resolution crystal structures of free and glycan-complexed protein. No major changes in the overall protein structure are induced by carbohydrate binding, with essentially identical apo- and sugar-bound conformations in binding site 1. A single peptide bond flip at W77-G78 is seen in binding site 2. Our combined NMR and crystallographic results provide structural insights into the mechanism by which OAA specifically recognizes the branched Man-9 core, distinctly different from the recognition of the D1 and D3 arms at the nonreducing end of high-mannose carbohydrates by other antiviral lectins. PMID- 21827953 TI - Improving protein structure prediction using multiple sequence-based contact predictions. AB - Although residue-residue contact maps dictate the topology of proteins, sequence based ab initio contact predictions have been found little use in actual structure prediction due to the low accuracy. We developed a composite set of nine SVM-based contact predictors that are used in I-TASSER simulation in combination with sparse template contact restraints. When testing the strategy on 273 nonhomologous targets, remarkable improvements of I-TASSER models were observed for both easy and hard targets, with p value by Student's t test<0.00001 and 0.001, respectively. In several cases, template modeling score increases by >30%, which essentially converts "nonfoldable" targets into "foldable" ones. In CASP9, I-TASSER employed ab initio contact predictions, and generated models for 26 FM targets with a GDT-score 16% and 44% higher than the second and third best servers from other groups, respectively. These findings demonstrate a new avenue to improve the accuracy of protein structure prediction especially for free modeling targets. PMID- 21827955 TI - Retraction notice to: Structure of the parathyroid hormone receptor C terminus bound to the G-protein dimer Gbeta1gamma2. PMID- 21827954 TI - Flexible architecture of IP3R1 by Cryo-EM. AB - Inositol 1,4,5-trisphosphate receptors (IP3Rs) play a fundamental role in generating Ca2+ signals that trigger many cellular processes in virtually all eukaryotic cells. Thus far, the three-dimensional (3D) structure of these channels has remained extremely controversial. Here, we report a subnanometer resolution electron cryomicroscopy (cryo-EM) structure of a fully functional type 1 IP3R from cerebellum in the closed state. The transmembrane region reveals a twisted bundle of four alpha helices, one from each subunit, that form a funnel shaped structure around the 4-fold symmetry axis, strikingly similar to the ion conduction pore of K+ channels. The lumenal face of IP3R1 has prominent densities that surround the pore entrance and similar to the highly structured turrets of Kir channels. 3D statistical analysis of the cryo-EM density map identifies high variance in the cytoplasmic region. This structural variation could be attributed to genuine structural flexibility of IP3R1. PMID- 21827956 TI - Malignant hyperthermia in the oral and maxillofacial surgery patient: an update. AB - Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle that presents as a hypermetabolic response to potent volatile anesthetic gases, such as halothane, sevoflurane, desflurane, the depolarizing muscle relaxant succinylcholine, and, rarely in humans, to stresses, such as vigorous exercise and heat. The syndrome is likely to be fatal if untreated. Early recognition of the signs of MH provides the clinical diagnostic clues. Diagnostic testing relies on assessing the in vitro contracture response of biopsied muscle to halothane, caffeine, and other drugs. Dantrolene sodium is a specific antagonist of the pathophysiologic changes of MH and should be available wherever general anesthesia is administered. The prevention and treatment of acute episodes of this disorder is of paramount importance to the oral and maxillofacial surgeon. The management of such patients in the oral and maxillofacial surgery setting and the recent advances in the field of MH are presented. PMID- 21827958 TI - Integrating images in dental manufacturing technology: the prosthetic value chain. PMID- 21827957 TI - Antiviral effects of blackberry extract against herpes simplex virus type 1. AB - OBJECTIVE: The aim of this study was to evaluate antiviral properties of blackberry extract against herpes simplex virus type 1 (HSV-1) in vitro. STUDY DESIGN: HSV-infected oral epithelial (OKF6) cells and cell-free virus suspensions were treated with blackberry extract (2.24-1,400 MUg/mL), and virus yield and infectivity were quantified by direct plaque assay. RESULTS: Blackberry extract >=56 MUg/mL inhibited HSV-1 replication in oral epithelial cells by >99% (P < .005). Concentrations >=280 MUg/mL were antiviral when the extract was added after virus adsorption and entry. Exposure of cell-free virus to >=280 MUg/mL blackberry extract for 15 minutes at room temperature was virucidal (P = .0002). The virucidal effects were not due to pH changes at concentrations up to 1,500 MUg/mL. CONCLUSIONS: Blackberry extract inhibited the early stages of HSV-1 replication and had potent virucidal activity. These properties suggest that this natural fruit extract could provide advantage as a topical prophylactic/therapeutic agent for HSV infections. PMID- 21827959 TI - Initial evaluation of linear and spatially oriented planar images from a new dental panoramic system based on tomosynthesis. AB - OBJECTIVE: The purpose of this study was to describe a newly developed dental panoramic system based on the tomosynthesis method and to validate the accuracy of linear and spatially oriented planar images. STUDY DESIGN: An original robotic mechanism incorporating a new high-speed cadmium-telluride (CdTe) semiconductor detector was fabricated to acquire panoramic images (raw data). The shift-and-add tomosynthesis method was applied to facilitate changes in the depth of the panoramic imaging layer. Using the texture mapping method, planar and spatially oriented images were reconstructed along a custom curved imaging plane. Using a custom phantom and dry skulls, the accuracy of selected linear measurements was evaluated. RESULTS: Preliminary measurements demonstrated acceptable linear accuracy in reconstructed panoramic images with variations <5%. CONCLUSIONS: This preliminary investigation demonstrates that dental panoramic images acquired by a novel robotic mechanism and CdTe detector using a tomosynthesis method provides planar and spatially oriented images with an image quality that may be acceptable for dental practice. PMID- 21827960 TI - A comparative analysis of periapical radiography and cone-beam computerized tomography for the evaluation of endodontic obturation length. AB - OBJECTIVE: The aim of this study was to determine the consistency and inconsistency between the periapical radiography (PR) and cone-beam computerized tomography (CBCT) in evaluating the length of root canal obturations (RCOs) in vivo. STUDY DESIGN: Thirty-six maxillary and mandibular first and second molars yielding 109 obturated root canals with available PR and CBCT images were analyzed. The inclusion criterion was that the RCO extended 0-2 mm short of the radiographic apex on PR images. Teeth having root canal calcification, apical resorption, or poor quality PR/CBCT images were excluded. Agreement and disagreement between the 2 imaging modalities for obturation length were analyzed using the chi(2) test. RESULTS: A total of 30.3% of the RCOs evaluated by PR as having adequate length were diagnosed by CBCT to have inadequate length. Among these, 13.8% were overextended and 16.5% underextended as diagnosed by CBCT. When the distance from the filling tip to the radiographic apex was 0.5 to 1 mm on the PR image, the discordance rate was the lowest (11.1%) in all evaluated distance groups, significantly lower than with distances of 0-0.5 mm and 1.5-2 mm (P < .01). When RCOs were diagnosed as terminating at the facial/lingual side, overextension was the main evaluation result by CBCT in the disagreement evaluation with PR and significantly more frequent than those at the mesial/distal/central side (P < .01). CONCLUSIONS: CBCT evaluated 30.3% of the RCOs with radiographically adequate length as inadequate. When the RCOs radiographically terminated 0.5-1 mm short of the apex, the evaluation rated adequate for obturation length was comparatively reliable. PMID- 21827962 TI - Mercury and trace metal partitioning and fluxes in suburban Southwest Ohio watersheds. AB - Many natural watersheds are increasingly affected by changes in land use associated with suburban sprawl and such alterations may influence concentrations, partitioning, and fluxes of toxic trace metals in fluvial ecosystems. We investigated the cycling of mercury (Hg), monomethylmercury, cadmium, copper, lead, nickel, and zinc in three watersheds at the urban fringe of Dayton, Ohio, over a 13-month period. Metal concentrations were related positively to discharge in each stream, with each metal having a high affinity for suspended particles and Hg also having a noticeable association with dissolved organic carbon. Although not observed for the other metals, levels of Hg in river water varied seasonally and among streams. Yields of Hg from two of the catchments were comparable to that predicted for runoff of atmospherically deposited Hg (~25% of wet atmospheric flux), whereas the third watershed had a significantly greater annual flux associated with greater particle-specific and filtered water Hg concentrations, presumably from a point source. Fluxes of metals other than Hg were similar among each watershed and suggestive of a ubiquitous source, which could be either atmospheric deposition or weathering. Results of this study indicate that, with the exception of Hg being increased in one watershed, processes affecting metal partitioning and loadings are similar among southwest Ohio streams and comparable to other North American rivers that are equally or less impacted by urban development. Relative differences in land use, catchment area, and presence or absence of waste water treatment facilities had little or no detectable effect on most trace metal concentrations and fluxes. This suggests that suburban encroachment on agricultural and undeveloped lands has either similarly or not substantially impacted trace metal cycling in streams at the urban fringe of Dayton and, by extension, other comparable metropolitan areas. PMID- 21827963 TI - Realistic retrospective dose assessments to members of the public around Spanish nuclear facilities. AB - In the frame of an epidemiological study carried out in the influence areas around the Spanish nuclear facilities (ISCIII-CSN, 2009. Epidemiological Study of The Possible Effect of Ionizing Radiations Deriving from The Operation of Spanish Nuclear Fuel Cycle Facilities on The Health of The Population Living in Their Vicinity. Final report December 2009. Ministerio de Ciencia e Innovacion, Instituto de Salud Carlos III, Consejo de Seguridad Nuclear. Madrid. Available from: http://www.csn.es/images/stories/actualidad_datos/especiales/epidemiologico/epide iological_study.pdf), annual effective doses to public have been assessed by the Spanish Nuclear Safety Council (CSN) for over 45 years using a retrospective realistic-dose methodology. These values are compared with data from natural radiation exposure. For the affected population, natural radiation effective doses are in average 2300 times higher than effective doses due to the operation of nuclear installations (nuclear power stations and fuel cycle facilities). When considering the impact on the whole Spanish population, effective doses attributable to nuclear facilities represent in average 3.5*10(-5)mSv/y, in contrast to 1.6mSv/y from natural radiation or 1.3mSv/y from medical exposures. PMID- 21827961 TI - A new mechanism for pillar formation during tumor-induced intussusceptive angiogenesis: inverse sprouting. AB - One of the hallmarks of intussusceptive angiogenesis is the development of intraluminal connective tissue pillars. The exact mechanism of pillar formation has not yet been elucidated. By using electron and confocal microscopy, we observed intraluminal nascent pillars that contain a collagen bundle covered by endothelial cells (ECs) in the vasculature of experimental tumors. We proposed a new mechanism for the development of these pillars. First, intraluminal endothelial bridges are formed. Second, localized dissolution of the basement membrane occurs and a bridging EC attaches to a collagen bundle in the underlying connective tissue. A pulling force is then exerted by the actin cytoskeleton of the ECs via specific attachment points, which contain vinculin, to the collagen bundle, resulting in suction and subsequent transport of the collagen bundle into and through the vessel lumen. Third, the pillar matures through the immigration of connective tissue cells and the deposition of new collagenous connective tissue. The proposed simple mechanism generates a connection between the processes of endothelial bridging and intussusceptive angiogenesis and identifies the source of the force behind pillar formation. Moreover, it ensures the rapid formation of pillars from pre-existing building blocks and the maintenance of EC polarity. To describe it, we coined the term inverse sprouting. PMID- 21827964 TI - Cardiovascular risk factor profiles of recent immigrants vs long-term residents of Ontario: a multi-ethnic study. AB - BACKGROUND: There is growing evidence that cardiovascular risk profiles differ markedly across Canada's 4 major ethnic groups, namely White, South Asian, Chinese, and Black; however, the impact of long-term Canadian residency on cardiovascular risk within and across these ethnic groups is unknown. METHODS: Using pooled data from Statistics Canada's National Population and Canadian Community Health Surveys (1996-2007), we compared the age- and sex-standardized prevalence of cardiovascular risk factors and diseases between recent immigrants (< 15 years in Canada) and long-term residents (immigrants who lived in Canada for >= 15 years or people born in Canada) among White, South Asian, Chinese, and Black ethnic groups living in Ontario. We also calculated ethnic-specific attributable fraction (AF), defined as the proportion of risk that can be attributed to long-term Canadian residency. RESULTS: For all ethnic groups, cardiovascular risk factor profiles (ie, the percentage of people with >= 2 major cardiovascular risk factors, ie, smoking, obesity, diabetes, and hypertension) were worse among those with longer duration of residency in Canada. The greatest change in recent immigrants vs long-term residents was observed in the Chinese group (2.2% vs 5.2%; AF 0.47) followed by the White (6.5% vs 10.3%; AF 0.36), Black (9.2% vs 12.1%; AF 0.17), and South Asian (7.7% vs 8.2%; AF 0.03) groups. The prevalence of cardiovascular disease did not differ significantly between recent immigrants and long-term residents, irrespective of ethnic group. CONCLUSIONS: Our results suggest that cardiovascular disease prevention strategies must consider not only ethnicity, but also the level of acculturation within each ethnic group. PMID- 21827965 TI - Neuromagnetic oscillations and hemodynamic correlates of P50 suppression in schizophrenia. AB - Behavioral and electrophysiological data indicate compromised stimulus suppression in schizophrenia. The physiological basis of this effect and its contributions to the etiology of the disease are poorly understood. We examined neural and metabolic measures of P50 suppression in 12 patients with schizophrenia and controls. First, whole-head magnetoencephalography (MEG) assessed amplitudes of left- and right-hemispheric evoked responses and induced oscillations. Secondly, functional magnetic resonance imaging (fMRI) measured the hemodynamic responses to pairs of beeps with a short interval (500ms) as compared with those with a long interval (1500ms). The suppression of alpha power (8-13Hz) time-locked to the stimuli was negatively correlated with the suppression of evoked components and the hemodynamic measures. Remarkably, the suppression of alpha power was reduced in the patients already prior to stimulus onset. Conceivably, alpha oscillations play a central role in stimulus adaptation of neuronal networks and reflect an active mechanism for sensory suppression. The reduced stimulus suppression in schizophrenia seems to be in part due to impaired generation of alpha oscillations in the auditory cortex, resulting in higher metabolic demand as detected by fMRI. Delayed recovery of alpha rhythm may reflect an impaired gating function and contribute to sensory and cognitive deficits in schizophrenia. PMID- 21827966 TI - Measurement of soluble perforin, a marker of CD8+ T lymphocyte activation in epithelial lining fluid. AB - BACKGROUND: CD8(+) T lymphocytes in the peripheral airways have been suggested to be involved in the pathogenesis of COPD. However, the significance of CD8(+) T lymphocyte activation in COPD is not well understood. A biomarker of CD8(+) T lymphocyte activation in patients with COPD is required. METHODS: Thirty COPD patients and twenty-one healthy controls (eleven ex-smokers and ten who had never smoked or were light ex-smokers) were included in this study. We separately obtained epithelial lining fluid (ELF) from central and peripheral airways using a bronchoscopic microsampling technique. Levels of perforin in ELF were measured and we examined correlations between its values and patients characteristics including pulmonary function. RESULTS: Perforin levels in both the central and peripheral airways in COPD patients were significantly higher than those in the healthy control groups. In the healthy control groups, there was no significant difference in perforin levels between central and peripheral airways. However, in COPD patients, perforin levels in peripheral airways were significantly higher than those in central airways. Perforin levels in peripheral airways were significantly correlated with FEV(1) (percent predicted), FEV(1)/FVC, and DLco (percent predicted) in COPD patients. CONCLUSION: The microsampling technique is safe and useful for separately obtaining ELF from central and peripheral airways. Levels of perforin in ELF from peripheral airways were significantly increased and correlated with the degree of pulmonary dysfunction. Perforin might reflect inflammation involving CD8(+) T-lymphocytes. This novel biomarker might enable better understanding of the pathogenesis of COPD. PMID- 21827967 TI - A Bacillus anthracis strain deleted for six proteases serves as an effective host for production of recombinant proteins. AB - Bacillus anthracis produces a number of extracellular proteases that impact the integrity and yield of other proteins in the B. anthracis secretome. In this study we show that anthrolysin O (ALO) and the three anthrax toxin proteins, protective antigen (PA), lethal factor (LF), and edema factor (EF), produced from the B. anthracis Ames 35 strain (pXO1+, pXO2-), are completely degraded at the onset of stationary phase due to the action of proteases. An improved Cre-loxP gene knockout system was used to sequentially delete the genes encoding six proteases (InhA1, InhA2, camelysin, TasA, NprB, and MmpZ). The role of each protease in degradation of the B. anthracis toxin components and ALO was demonstrated. Levels of the anthrax toxin components and ALO in the supernatant of the sporulation defective, pXO1+ A35HMS mutant strain deleted for the six proteases were significantly increased and remained stable over 24 h. A pXO1-free variant of this six-protease mutant strain, designated BH460, provides an improved host strain for the preparation of recombinant proteins. As an example, BH460 was used to produce recombinant EF, which previously has been difficult to obtain from B. anthracis. The EF protein produced from BH460 had the highest in vivo potency of any EF previously purified from B. anthracis or Escherichia coli hosts. BH460 is recommended as an effective host strain for recombinant protein production, typically yielding greater than 10mg pure protein per liter of culture. PMID- 21827968 TI - Adjuvant radiotherapy and health-related quality of life of patients at intermediate risk of recurrence following primary surgery for oral squamous cell carcinoma. AB - Controversy surrounds who should receive adjuvant radiotherapy in patients with intermediate risk of recurrence of oral squamous cell carcinoma following primary surgery. The aim of this study was to compare health-related quality of life (HRQOL) outcomes of those who received adjuvant radiotherapy to those who did not in patients at intermediate-risk of recurrence. A total of 765 oral cancer patients were treated at the Regional Maxillofacial Unit, Liverpool from 1995 to 2007. After excluding 124 patients (87 primary radiotherapy, 23 died within 90 days, 14 had insufficient information for determining risk group status), 169 were low-risk, 271 intermediate-risk and 201 were high-risk. In the intermediate risk group, 33% had adjuvant radiotherapy. Allowing for attrition, more than 70% had University of Washington quality of life data (UW-QOL). Cumulative survival was similar in those with and without adjuvant radiotherapy in a subset of patients at intermediate risk. There was little difference in overall HRQOL scores and in the socio-emotional subscale scores of the UW-QOL. However, there was a significant difference in physical subscale scores and the issue most affected was saliva. These findings support better stratification of risk in the intermediate group, and the plausibility of withholding radiotherapy without compromising survival. This can have dramatic positive benefits on patient physical outcomes, in particular saliva. Where adjuvant radiotherapy is necessary, it is appropriate to minimise adverse effects through measures such as intensity-modulated radiation therapy. PMID- 21827969 TI - Proof of concept study to assess fetal gene expression in amniotic fluid by nanoarray PCR. AB - Microarray analysis of cell-free RNA in amniotic fluid (AF) supernatant has revealed differential fetal gene expression as a function of gestational age and karyotype. Once informative genes are identified, research moves to a more focused platform such as quantitative reverse transcriptase-PCR. Standardized NanoArray PCR (SNAP) is a recently developed gene profiling technology that enables the measurement of transcripts from samples containing reduced quantities or degraded nucleic acids. We used a previously developed SNAP gene panel as proof of concept to determine whether fetal functional gene expression could be ascertained from AF supernatant. RNA was extracted and converted to cDNA from 19 AF supernatant samples of euploid fetuses between 15 to 20 weeks of gestation, and transcript abundance of 21 genes was measured. Statistically significant differences in expression, as a function of advancing gestational age, were observed for 5 of 21 genes. ANXA5, GUSB, and PPIA showed decreasing gene expression over time, whereas CASC3 and ZNF264 showed increasing gene expression over time. Statistically significantly increased expression of MTOR and STAT2 was seen in female compared with male fetuses. This study demonstrates the feasibility of focused fetal gene expression analysis using SNAP technology. In the future, this technique could be optimized to examine specific genes instrumental in fetal organ system function, which could be a useful addition to prenatal care. PMID- 21827970 TI - Transcutaneous electrical nerve stimulation at different frequencies on heart rate variability in healthy subjects. AB - Sympathetic and parasympathetic nervous system imbalance has been strongly associated to sudden cardiac death. Among the non-pharmacological treatment, transcutaneous electrical nerve stimulation (TENS) represents a possible therapeutic intervention to reduce sympathetic excitation and improve the sympatho-vagal balance in different clinical conditions. We aimed to verify acute effects of high and low transcutaneous electrical nerve stimulation (TENS) frequencies by the evaluation of heart rate variability. Seven healthy volunteers received an application of low frequency (10-Hz) and high frequency (100-Hz) TENS. After 10-Hz, there was decrease of LF normalized units (n.u.) component (32.7+/-5.9 vs 18.3+/-3.4, p<0.002) and increase of HF n.u. (60.9+/-4.3 vs 72.6+/ 8.9, p<0.016). In contrast, after 100-Hz there was increase of LF n.u. (31.5+/ 16.1 vs 41.6+/-12.2, p<0.019) and reduction of HF n.u. (63.9+/-15.3 vs 53.7+/ 12.3, p<0.031). In conclusion, TENS modulates sympathetic and parasympathetic activity in a frequency dependent manner. PMID- 21827971 TI - Real-time closed-loop control of cognitive load in neurological patients during robot-assisted gait training. AB - Cognitively challenging training sessions during robot-assisted gait training after stroke were shown to be key requirements for the success of rehabilitation. Despite a broad variability of cognitive impairments amongst the stroke population, current rehabilitation environments do not adapt to the cognitive capabilities of the patient, as cognitive load cannot be objectively assessed in real-time. We provided healthy subjects and stroke patients with a virtual task during robot-assisted gait training, which allowed modulating cognitive load by adapting the difficulty level of the task. We quantified the cognitive load of stroke patients by using psychophysiological measurements and performance data. In open-loop experiments with healthy subjects and stroke patients, we obtained training data for a linear, adaptive classifier that estimated the current cognitive load of patients in real-time. We verified our classification results via questionnaires and obtained 88% correct classification in healthy subjects and 75% in patients. Using the pre-trained, adaptive classifier, we closed the cognitive control loop around healthy subjects and stroke patients by automatically adapting the difficulty level of the virtual task in real-time such that patients were neither cognitively overloaded nor under-challenged. PMID- 21827972 TI - Image similarity and tissue overlaps as surrogates for image registration accuracy: widely used but unreliable. AB - The accuracy of nonrigid image registrations is commonly approximated using surrogate measures such as tissue label overlap scores, image similarity, image difference, or transformation inverse consistency error. This paper provides experimental evidence that these measures, even when used in combination, cannot distinguish accurate from inaccurate registrations. To this end, we introduce a "registration" algorithm that generates highly inaccurate image transformations, yet performs extremely well in terms of the surrogate measures. Of the tested criteria, only overlap scores of localized anatomical regions reliably distinguish reasonable from inaccurate registrations, whereas image similarity and tissue overlap do not. We conclude that tissue overlap and image similarity, whether used alone or together, do not provide valid evidence for accurate registrations and should thus not be reported or accepted as such. PMID- 21827973 TI - On the bandwidth of the plenoptic function. AB - The plenoptic function (POF) provides a powerful conceptual tool for describing a number of problems in image/video processing, vision, and graphics. For example, image-based rendering is shown as sampling and interpolation of the POF. In such applications, it is important to characterize the bandwidth of the POF. We study a simple but representative model of the scene where band-limited signals (e.g., texture images) are "painted" on smooth surfaces (e.g., of objects or walls). We show that, in general, the POF is not band limited unless the surfaces are flat. We then derive simple rules to estimate the essential bandwidth of the POF for this model. Our analysis reveals that, in addition to the maximum and minimum depths and the maximum frequency of painted signals, the bandwidth of the POF also depends on the maximum surface slope. With a unifying formalism based on multidimensional signal processing, we can verify several key results in POF processing, such as induced filtering in space and depth-corrected interpolation, and quantify the necessary sampling rates. PMID- 21827974 TI - Enhanced models for expertise retrieval using community-aware strategies. AB - Expertise retrieval, whose task is to suggest people with relevant expertise on the topic of interest, has received increasing interest in recent years. One of the issues is that previous algorithms mainly consider the documents associated with the experts while ignoring the community information that is affiliated with the documents and the experts. Motivated by the observation that communities could provide valuable insight and distinctive information, we investigate and develop two community-aware strategies to enhance expertise retrieval. We first propose a new smoothing method using the community context for statistical language modeling, which is employed to identify the most relevant documents so as to boost the performance of expertise retrieval in the document-based model. Furthermore, we propose a query-sensitive AuthorRank to model the authors' authorities based on the community coauthorship networks and develop an adaptive ranking refinement method to enhance expertise retrieval. Experimental results demonstrate the effectiveness and robustness of both community-aware strategies. Moreover, the improvements made in the enhanced models are significant and consistent. PMID- 21827975 TI - Multisensor data fusion in an integrated tracking system for endoscopic surgery. AB - Surgical planning and navigation systems are vital for minimally invasive endoscopic surgeries but it is challenging to track the position and orientation of intrabody surgical instruments in these procedures. In order to address this problem, we propose a tracking system including multiple-sensor integration and data fusion. The proposed tracking approach is free of the constraints of line-of sight, less subject to environmental distortion, and with higher update rate. By incorporating electromagnetic and inertial sensors, the system yields continuous 6-DOF information. Based on a system dynamic model and estimation theories, a new multisensor fusion algorithm, cascade orientation and position-estimation algorithm, is proposed for the integrated tracking device. The experimental results show that the proposed algorithms achieve accurate orientation and position tracking with robustness. PMID- 21827976 TI - Development and evaluation of multilead wavelet-based ECG delineation algorithms for embedded wireless sensor nodes. AB - This work is devoted to the evaluation of multilead digital wavelet transform (DWT)-based electrocardiogram (ECG) wave delineation algorithms, which were optimized and ported to a commercial wearable sensor platform. More specifically, we investigate the use of root-mean squared (RMS)-based multilead followed by a single-lead online delineation algorithm, which is based on a state-of-the-art offline single-lead delineator. The algorithmic transformations and software optimizations necessary to enable embedded ECG delineation notwithstanding the limited processing and storage resources of the target platform are described, and the performance of the resulting implementations are analyzed in terms of delineation accuracy, execution time, and memory usage. Interestingly, RMS-based multilead delineation is shown to perform equivalently to the best single-lead delineation for the 2-lead QT database (QTDB), within a fraction of a sample duration of the Common Standards for Electrocardiography (CSE) committee tolerances. Finally, a comprehensive evaluation of the energy consumption entailed by the considered algorithms is proposed, which allows very relevant insights into the dominant energy-draining functionalities and which suggests suitable design guidelines for long-lasting wearable ECG monitoring systems. PMID- 21827977 TI - Long-term urban particulate air pollution, traffic noise, and arterial blood pressure. AB - BACKGROUND: Recent studies have shown an association of short-term exposure to fine particulate matter (PM) with transient increases in blood pressure (BP), but it is unclear whether long-term exposure has an effect on arterial BP and hypertension. OBJECTIVES: We investigated the cross-sectional association of residential long-term PM exposure with arterial BP and hypertension, taking short term variations of PM and long-term road traffic noise exposure into account. METHODS: We used baseline data (2000-2003) on 4,291 participants, 45-75 years of age, from the Heinz Nixdorf Recall Study, a population-based prospective cohort in Germany. Urban background exposure to PM with aerodynamic diameter <= 2.5 MUm (PM(2.5)) and <= 10 MUm (PM(10)) was assessed with a dispersion and chemistry transport model. We used generalized additive models, adjusting for short-term PM, meteorology, traffic proximity, and individual risk factors. RESULTS: An interquartile increase in PM2.5 (2.4 MUg/m(3)) was associated with estimated increases in mean systolic and diastolic BP of 1.4 mmHg [95% confidence interval (CI): 0.5, 2.3] and 0.9 mmHg (95% CI: 0.4, 1.4), respectively. The observed relationship was independent of long-term exposure to road traffic noise and robust to the inclusion of many potential confounders. Residential proximity to high traffic and traffic noise exposure showed a tendency toward higher BP and an elevated prevalence of hypertension. CONCLUSIONS: We found an association of long term exposure to PM with increased arterial BP in a population-based sample. This finding supports our hypothesis that long-term PM exposure may promote atherosclerosis, with air-pollution-induced increases in BP being one possible biological pathway. PMID- 21827978 TI - The impact of temperature on mortality in Tianjin, China: a case-crossover design with a distributed lag nonlinear model. AB - BACKGROUND: Although interest in assessing the impacts of temperature on mortality has increased, few studies have used a case-crossover design to examine nonlinear and distributed lag effects of temperature on mortality. Additionally, little evidence is available on the temperature-mortality relationship in China or on what temperature measure is the best predictor of mortality. OBJECTIVES: Our objectives were to use a distributed lag nonlinear model (DLNM) as a part of case-crossover design to examine the nonlinear and distributed lag effects of temperature on mortality in Tianjin, China and to explore which temperature measure is the best predictor of mortality. METHODS: We applied the DLNM to a case-crossover design to assess the nonlinear and delayed effects of temperatures (maximum, mean, and minimum) on deaths (nonaccidental, cardiopulmonary, cardiovascular, and respiratory). RESULTS: A U-shaped relationship was found consistently between temperature and mortality. Cold effects (i.e., significantly increased mortality associated with low temperatures) were delayed by 3 days and persisted for 10 days. Hot effects (i.e., significantly increased mortality associated with high temperatures) were acute and lasted for 3 days and were followed by mortality displacement for nonaccidental, cardiopulmonary, and cardiovascular deaths. Mean temperature was a better predictor of mortality (based on model fit) than maximum or minimum temperature. CONCLUSIONS: In Tianjin, extreme cold and hot temperatures increased the risk of mortality. The effects of cold last longer than the effects of heat. Combining the DLNM and the case-crossover design allows the case-crossover design to flexibly estimate the nonlinear and delayed effects of temperature (or air pollution) while controlling for season. PMID- 21827979 TI - Lower prevalence of antibiotic-resistant Enterococci on U.S. conventional poultry farms that transitioned to organic practices. AB - BACKGROUND: In U.S. conventional poultry production, antimicrobials are used for therapeutic, prophylactic, and nontherapeutic purposes. Researchers have shown that this can select for antibiotic-resistant commensal and pathogenic bacteria on poultry farms and in poultry-derived products. However, no U.S. studies have investigated on-farm changes in resistance as conventional poultry farms transition to organic practices and cease using antibiotics. OBJECTIVE: We investigated the prevalence of antibiotic-resistant Enterococcus on U.S. conventional poultry farms that transitioned to organic practices. METHODS: Poultry litter, feed, and water samples were collected from 10 conventional and 10 newly organic poultry houses in 2008 and tested for Enterococcus. Enterococcus (n = 259) was identified using the Vitek(r) 2 Compact System and tested for susceptibility to 17 antimicrobials using the SensititreTM microbroth dilution system. Data were analyzed using SAS software (version 9.2), and statistical associations were derived based on generalized linear mixed models. RESULTS: Litter, feed, and water samples were Enterococcus positive. The percentages of resistant Enterococcus faecalis and resistant Enterococcus faecium were significantly lower (p < 0.05) among isolates from newly organic versus conventional poultry houses for two (erythromycin and tylosin) and five (ciprofloxacin, gentamicin, nitrofurantoin, penicillin, and tetracycline) antimicrobials, respectively. Forty-two percent of E. faecalis isolates from conventional poultry houses were multidrug resistant (MDR; resistant to three or more antimicrobial classes), compared with 10% of isolates from newly organic poultry houses (p = 0.02); 84% of E. faecium isolates from conventional poultry houses were MDR, compared with 17% of isolates from newly organic poultry houses (p < 0.001). CONCLUSIONS: Our findings suggest that the voluntary removal of antibiotics from large-scale U.S. poultry farms that transition to organic practices is associated with a lower prevalence of antibiotic-resistant and MDR Enterococcus. PMID- 21827980 TI - [IMiDs in hematology]. AB - IMiDs belong to a new pharmalogical class, whose principal therapeutic agents are the thalidomide and the lenalidomide. They have immunomodulatory and antiangiogenic properties, as well as a direct effect on tumor cells. Thalidomide and lenalidomide were first approved for multiple myeloma, and in 5q myelodysplastic syndrome for lenalidomide. Several studies have shown the efficacy of these drugs in others hematologic malignancies. A third component has been developed, the pomalidomide, which may be more effective in certain indications. Here we present an overview of IMiDs in hematology, including mechanisms of action and known significant side effects. PMID- 21827981 TI - [Histone deacetylase inhibitors in the treatment of hematological malignancies]. AB - Histone deacetylases inhibitors (HDACi) represent a new epigenetic targeting therapy class, which is widely investigated in fundamental research and clinical trials. They are able to restore and increase tumor suppressor genes expression and to play an anti-tumoral activity through numerous targets, which are distributed all over the main differentiation, proliferation and survival cellular pathways. Their use in hematology led to vorinostat (SAHA) and romidepsin approval by FDA for the treatment of refractory cutaneous T-cell lymphomas. Preclinical and preliminary clinical results show a promising antineoplasic activity in most hematologic malignancies. This review will focus on the HDACi recent developments and current investigations, highlighted by recent communications. PMID- 21827982 TI - [m-TOR inhibitors: biology and use in the treatment of haematological diseases]. AB - Mammalian target of rapamycyin (mTOR) is a downstream serine/threonine kinase of the PI3K/AKT pathway that integrates signals from the microenvironment such as cytokines, growth factors, and nutriments to regulate multiple cellular processes, including mRNA translation, autophagy, metabolism, growth and survival. mTOR operates in two distinct multi-protein complexes: mTORC1 and mTORC2; sharing mTOR kinase as a common catalytic subunit, mTORC1 controls cell growth and mTORC2 modulates cell survival and drug resistance. mTOR signalling pathway has been found to be deregulated in many haematological malignancies, and has been designed as an attractive anti-tumor target. Thereby, mTOR inhibition with rapamycin (sirolimus) or its derivates (rapalogs) represents promising treatments, either alone or in combination with strategies to target other pathways that may overcome resistance. At present time, numerous clinical trials with mTOR inhibitors are ongoing for treatment of haematological diseases with modest or promising results. The aim of this review is to present the rationale for using mTOR inhibitors in haematology, first via biological explanations and secondly, by focusing on each haematological malignancies with new perspective of treatment. PMID- 21827983 TI - [Adventures at the Anatolian Journal of Cardiology]. PMID- 21827985 TI - Incidental finding on coronary multidetector CT angiography; a quadricuspid aortic valve. PMID- 21827986 TI - Challenging electrocardiography. PMID- 21827987 TI - Venous spasm during pacemaker implantation. PMID- 21827988 TI - [Kissing thrombi on the mitral prosthetic valve and in the left atrial appendix]. PMID- 21827989 TI - A giant broccoli-like thrombus secondary to patent foramen ovale. PMID- 21827990 TI - RF ablation of WPW syndrome using Ensite Array balloon mapping and Hansen-Sensei robotic cool-path catheter. PMID- 21827991 TI - Nuclear leakage and hypertension: is there any relationship? PMID- 21827992 TI - Complete cure with medical treatment of prosthetic mitral valve endocarditis, which is initially diagnosed as mitral valve thrombus. PMID- 21827993 TI - Microorganisms and valve tissue/ demonstration of Chlamydophila pneumoniae, Mycoplasma pneumoniae, Cytomegalovirus, and Epstein-Barr virus in atherosclerotic coronary arteries, nonrheumatic calcific aortic and rheumatic stenotic mitral valves by polymerase chain reaction. PMID- 21827994 TI - [An inferior myocardial infarction due to single dose paracetamol use]. PMID- 21827995 TI - Moxifloxacin-dependent Torsades de Pointes. PMID- 21827996 TI - A rare cause of atrial fibrillation: a European hornet sting. PMID- 21827997 TI - The effects of penetration and dose on in vivo imaging. PMID- 21827998 TI - Percutaneous mitral valvuloplasty: the debate is there. PMID- 21828002 TI - Ascending pharyngeal-vertebral anastomosis demonstrated by computed tomography angiography of the ascending pharyngeal artery: a case report. AB - Ascending pharyngeal-vertebral anastomosis has been identified by angiography of the carotid artery in several cases. We present a case of ascending pharyngeal vertebral anastomosis that was found incidentally in computed tomography angiography of the ascending pharyngeal artery. Images revealed that the anastomosis formed through the hypoglossal branch of the neuromeningeal trunk. The anastomosis seemed to be associated with hypoplasia of the right vertebral artery. Interventional radiologists should be aware of this dangerous anastomotic route of the APA to the VA. Discovery of hypoplasia of the major intracranial arteries before intra-arterial chemotherapy or embolization in head and neck area may avoid subsequent complications. PMID- 21828003 TI - Accuracy of CT angiography in the assessment of the circle of Willis: comparison of volume-rendered images and digital subtraction angiography. AB - BACKGROUND: Computed tomography angiography (CTA) is increasingly used for non invasive imaging of the cerebrovascular diseases. PURPOSE: To evaluate the accuracy of CTA in the assessment of the variation of the segment calibers of the circle of Willis. MATERIAL AND METHODS: One hundred and 17 patients with acute SAH (51 men and 66 women, mean age 50.9 years) who underwent CTA using a 16 detector-row CT scanner and DSA were evaluated retrospectively. The CTA and DSA studies were performed within 24 h after the onset of symptoms and within 24 h of each other. A total of 819 arterial segments (A-comA, right and left A1 segment, right and left P-com A, and right and left P1 segment) of the circle of Willis were determined to be aplastic (grade 1), hypoplastic (grade 2), or normal-sized (grade 3) by blinded observers evaluating CTA volume-rendered images. The CTA results were then compared with findings on the corresponding DSA images (reference standard). RESULTS: The overall agreement between CTA and DSA was 92.4%. We had 62 (7.6%) cases of disagreement (58 cases of under-estimation and four cases of over-estimation by CTA) between tow modalities. The sensitivity and specificity of CTA in the detection of aplastic and normal-sized segments were more than 90%. In contrast, subgroup analysis of the hypoplastic segments showed a sensitivity of 52.6% and a specificity of 98.2%. CONCLUSION: CTA is highly accurate in the assessment of anatomical variations of the circle of Willis; however, its sensitivity is limited in depicting hypoplastic segments. PMID- 21828004 TI - Systemic augmentation of alphaB-crystallin provides therapeutic benefit twelve hours post-stroke onset via immune modulation. AB - Tissue plasminogen activator is the only treatment option for stroke victims; however, it has to be administered within 4.5 h after symptom onset, making its use very limited. This report describes a unique target for effective treatment of stroke, even 12 h after onset, by the administration of alphaB-crystallin (Cryab), an endogenous immunomodulatory neuroprotectant. In Cryab(-/-) mice, there was increased lesion size and diminished neurologic function after stroke compared with wild-type mice. Increased plasma Cryab was detected after experimental stroke in mice and after stroke in human patients. Administration of Cryab even 12 h after experimental stroke reduced both stroke volume and inflammatory cytokines associated with stroke pathology. Cryab is an endogenous anti-inflammatory and neuroprotectant molecule produced after stroke, whose beneficial properties can be augmented when administered therapeutically after stroke. PMID- 21828005 TI - Cooperative transcription factor associations discovered using regulatory variation. AB - Regulation of gene expression at the transcriptional level is achieved by complex interactions of transcription factors operating at their target genes. Dissecting the specific combination of factors that bind each target is a significant challenge. Here, we describe in detail the Allele Binding Cooperativity test, which uses variation in transcription factor binding among individuals to discover combinations of factors and their targets. We developed the ALPHABIT (a large-scale process to hunt for allele binding interacting transcription factors) pipeline, which includes statistical analysis of binding sites followed by experimental validation, and demonstrate that this method predicts transcription factors that associate with NFkappaB. Our method successfully identifies factors that have been known to work with NFkappaB (E2A, STAT1, IRF2), but whose global coassociation and sites of cooperative action were not known. In addition, we identify a unique coassociation (EBF1) that had not been reported previously. We present a general approach for discovering combinatorial models of regulation and advance our understanding of the genetic basis of variation in transcription factor binding. PMID- 21828007 TI - Accessing the transport properties of graphene and its multilayers at high carrier density. AB - We present a comparative study of high carrier density transport in mono-, bi-, and trilayer graphene using electric double-layer transistors to continuously tune the carrier density up to values exceeding 10(14) cm(-2). Whereas in monolayer the conductivity saturates, in bi- and trilayer filling of the higher energy bands is observed to cause a nonmonotonic behavior of the conductivity and a large increase in the quantum capacitance. These systematic trends not only show how the intrinsic high-density transport properties of graphene can be accessed by field effect, but also demonstrate the robustness of ion-gated graphene, which is crucial for possible future applications. PMID- 21828006 TI - Structure of the protein core of the glypican Dally-like and localization of a region important for hedgehog signaling. AB - Glypicans are heparan sulfate proteoglycans that modulate the signaling of multiple growth factors active during animal development, and loss of glypican function is associated with widespread developmental abnormalities. Glypicans consist of a conserved, approximately 45-kDa N-terminal protein core region followed by a stalk region that is tethered to the cell membrane by a glycosyl phosphatidylinositol anchor. The stalk regions are predicted to be random coil but contain a variable number of attachment sites for heparan sulfate chains. Both the N-terminal protein core and the heparan sulfate attachments are important for glypican function. We report here the 2.4-A crystal structure of the N-terminal protein core region of the Drosophila glypican Dally-like (Dlp). This structure reveals an elongated, alpha-helical fold for glypican core regions that does not appear homologous to any known structure. The Dlp core protein is required for normal responsiveness to Hedgehog (Hh) signals, and we identify a localized region on the Dlp surface important for mediating its function in Hh signaling. Purified Dlp protein core does not, however, interact appreciably with either Hh or an Hh:Ihog complex. PMID- 21828008 TI - Flavobacterium chilense sp. nov. and Flavobacterium araucananum sp. nov., isolated from farmed salmonid fish. AB - Three Gram-staining-negative non-endospore-forming strains were isolated from farmed fish in Chile: one (LM-09-Fp(T)) from a rainbow trout (Oncorhynchus mykiss) and the others (LM-19-Fp(T) and LM-20-Fp) from two Atlantic salmon (Salmo salar). Phylogenetic analyses based on 16S rRNA gene sequences indicated that all three isolates belonged to the genus Flavobacterium. In these analyses, strain LM 09-Fp(T) appeared most closely related to the type strains of Flavobacterium chungangense (98.5 % sequence similarity), Flavobacterium glaciei (98.2 %), Flavobacterium aquidurense (97.6 %), Flavobacterium saccharophilum (97.6 %) and Flavobacterium hercynium (97.6 %). The 16S rRNA gene sequences of strains LM-19 Fp(T) and LM-20-Fp were found to be identical and most similar to the corresponding sequences of the type strains of Flavobacterium aquidurense (98.6 %), Flavobacterium frigidimaris (98.5 %), Flavobacterium hercynium (97.9 %), Flavobacterium saccharophilum (97.7 %) and Flavobacterium pectinovorum (97.7 %). For each of the three novel strains, menaquinone (MK-6) was the predominant respiratory quinone and the major compounds in the polar lipid profile were phosphatidylethanolamine, an unidentified aminolipid, phosphatidylserine and two or three unknown lipids. The fatty acid profile of each strain, which comprised major amounts of iso-C(15:0), C(15:0) and summed feature 3 (C(16:1)omega7c and/or iso-C(15:0) 2-OH) as well as smaller amounts of various hydroxylated fatty acids (e.g. iso-C(16:0) 3-OH, iso-C(17:0) 3-OH, C(16:0) 3-OH and C(15:0) 3-OH), indicated that each belonged to the genus Flavobacterium. Based on their physiological and biochemical characteristics and the results of DNA-DNA hybridizations, which showed relatively low levels of relatedness between the novel strains and the most closely related Flavobacterium species, strain LM-09 Fp(T) ( = LMG 26360(T) = CCM 7940(T)) represents a novel species within the genus Flavobacterium, for which the name Flavobacterium chilense sp. nov. is proposed, and strains LM-19-Fp(T) ( = LMG 26359(T) = CCM 7939(T)) and LM-20-Fp ( = LMG 26331) represent a second novel species within the same genus, for which the name Flavobacterium araucananum sp. nov. is proposed. PMID- 21828009 TI - Nonomuraea jiangxiensis sp. nov., isolated from acidic soil. AB - An actinomycete, designated FXJ1.102(T), was isolated from acidic soil collected in Jiangxi Province, south-east China. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain FXJ1.102(T) belonged to the genus Nonomuraea and was most closely related to Nonomuraea candida HMC10(T), Nonomuraea turkmeniaca DSM 43926(T), Nonomuraea antimicrobica YIM 61105(T) and 'Nonomuraea aegyptia' S136 (98.9, 98.3, 97.9 and 97.5 % 16S rRNA gene sequence similarities, respectively). The morphological characteristics were typical of the genus Nonomuraea. The chemotaxonomic properties, such as cell-wall chemotype IIIB, phospholipid type IV, MK-9(H(4)) as the major menaquinone and iso-C(16:0) (22.2 %) as the major fatty acid, supported the assignment of the strain to the genus Nonomuraea. DNA-DNA relatedness and physiological tests allowed genotypic and phenotypic differentiation of strain FXJ1.102(T) from its closest phylogenetic relatives. The isolate therefore represents a novel species, for which the name Nonomuraea jiangxiensis sp. nov. is proposed. The type strain is FXJ1.102(T) ( = CGMCC 4.6533(T) = NBRC 106679(T)). PMID- 21828010 TI - Marininema mesophilum gen. nov., sp. nov., a thermoactinomycete isolated from deep sea sediment, and emended description of the family Thermoactinomycetaceae. AB - A novel filamentous bacterium, strain SCSIO 10219(T), was isolated from a sediment sample collected from the South China Sea (113 degrees 3.752' E 18 degrees 1.722' N) at a depth of 2105 m. Growth was observed at 25-35 degrees C (optimum 30 degrees C) and pH 5.0-8.0 (optimum pH 6.0-7.0). The organism formed yellow-white colonies with radial wrinkles. Aerial mycelium was not produced on any of the growth media tested. Phenotypic characterization and 16S rRNA gene sequence analysis indicated that strain SCSIO 10219(T) belongs to the family Thermoactinomycetaceae. The strain contained ll-diaminopimelic acid in the cell wall. The predominant menaquinone was MK-7. The phospholipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylmethylethanolamine, phosphatidylethanolamine and five unknown phospholipids. Major fatty acids were anteiso-C(15:0) and iso-C(15:0). The DNA G+C content was 46.5 mol%. On the basis of chemotaxonomic properties and phylogenetic analysis based on 16S rRNA gene sequence data, it is proposed that this strain represents a novel species in a new genus, Marininema mesophilum gen. nov., sp. nov., in the family Thermoactinomycetaceae. The type strain of the type species is SCSIO 10219(T) ( = CCTCC AA 2011006(T) = DSM 45610(T)). In addition, we propose that the description of the family Thermoactinomycetaceae should be further emended based on the present study. PMID- 21828011 TI - Defluviitoga tunisiensis gen. nov., sp. nov., a thermophilic bacterium isolated from a mesothermic and anaerobic whey digester. AB - Strain SulfLac1(T), a thermophilic, anaerobic and slightly halophilic, rod-shaped bacterium with a sheath-like outer structure (toga), was isolated from a whey digester in Tunisia. The strain's non-motile cells measured 3-30*1 um and appeared singly, in pairs or as long chains. The novel strain reduced thiosulfate and elemental sulfur, but not sulfate or sulfite, into sulfide. It grew at 37-65 degrees C (optimum 55 degrees C), at pH 6.5-7.9 (optimum pH 6.9) and with 0.2-3 % (w/v) NaCl (optimum 0.5 %). The G+C content of the strain's genomic DNA was 33.6 mol%. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain SulfLac1(T) was most closely related to Petrotoga mobilis (91.4 % sequence similarity). Based on phenotypic, phylogenetic and chemotaxonomic evidence, strain SulfLac1(T) represents a novel species of a new genus within the order Thermotogales, for which the name Defluviitoga tunisiensis gen. nov., sp. nov. is proposed. The type strain of the type species is SulfLac1(T) ( = DSM 23805(T) = JCM 17210(T)). PMID- 21828012 TI - Pelosinus defluvii sp. nov., isolated from chlorinated solvent-contaminated groundwater, emended description of the genus Pelosinus and transfer of Sporotalea propionica to Pelosinus propionicus comb. nov. AB - Two anaerobic bacterial strains, designated SHI-1(T) and SHI-2, were isolated from chlorinated solvent-contaminated groundwater. They were found to be identical in phenotypic properties and shared high (98.5-99.8 %) pairwise 16S rRNA gene sequence similarity. Multiple 16S rRNA genes were found to be present in the isolates as well as Pelosinus fermentans DSM 17108(T) and Sporotalea propionica DSM 13327(T). Strains SHI-1(T) and SHI-2 could be differentiated from their closest phylogenetic relatives, P. fermentans DSM 17108(T) and S. propionica DSM 13327(T), on the basis of their phenotypic and phylogenetic properties. The isolates were Gram-negative, spore-forming, motile rods with peritrichous flagella. Growth occurred at 10-42 degrees C and pH 5.5-8.5. Fermentative growth was observed on Casamino acids, fructose, fumarate, glucose, glycerol, pyruvate and yeast extract. The major organic acids produced from glucose and glycerol fermentation were propionate and acetate. The major organic acids produced from fermentation of fumarate were propionate, acetate and succinate. The major cellular fatty acids were summed feature 4 (consisting of C(15:1)omega8c and/or C(15:2)), summed feature 8 (consisting of C(17:1)omega8c and/or C(17:2)) and C(14:0) dimethyl aldehyde. The polar lipids comprised aminophospholipids, including phosphatidylethanolamine and phosphatidylserine, and an unknown phospholipid. The genomic DNA G+C content was 39.2 mol%. We propose that strains SHI-1(T) and SHI-2 are assigned to a novel species of the genus Pelosinus, with the name Pelosinus defluvii sp. nov. (type strain SHI-1(T) = NRRL Y-59407(T) = LMG 25549(T)). The description of the genus Pelosinus is emended. We also propose the transfer of S. propionica to the genus Pelosinus as Pelosinus propionicus comb. nov. (type strain TmPN3(T) = DSM 13327(T) = ATCC BAA 626(T)), on the basis of phylogenetic, chemotaxonomic and phenotypic properties. PMID- 21828013 TI - Citeromyces hawaiiensis sp. nov., an ascosporic yeast associated with Myoporum sandwicense. AB - Citeromyces hawaiiensis sp. nov. (NRRL Y-11581(T) = CBS 12303(T), type strain) is described from 12 strains isolated from flux of the sandalwood (Myoporum sandwicense) and adjacent soil in Hawaii, USA. Analyses of gene sequences from the D1/D2 domains of nuclear large subunit rRNA, internal transcribed spacer (ITS), mitochondrial small-subunit rRNA and translation elongation factor-1alpha each separated the proposed novel species from Citeromyces matritensis and Citeromyces siamensis, the other known species of the genus Citeromyces. The three species are morphologically similar but they can be separated by growth reactions in standard assimilation tests. An additional strain of Citeromyces siamensis (NRRL Y-11788), a species previously known only from Thailand, was obtained from spoiled condensed milk in Ohio, USA. PMID- 21828014 TI - Fusibacter tunisiensis sp. nov., isolated from an anaerobic reactor used to treat olive-mill wastewater. AB - Strain BELH1(T), a novel mesophilic, anaerobic, halotolerant, rod-shaped bacterium, was isolated from a Tunisian wastewater digester. The cells of the strain are motile, measure 0.5*2-5 um, and occur singly or in pairs. The strain reduced thiosulfate and elemental sulfur (but not sulfate or sulfite) into sulfide. It grew at 15-40 degrees C (optimum 30 degrees C), pH 5.8-8.4 (optimum 7) and with 0-10 % (w/v) NaCl (optimum 3.0 %). The genomic DNA G+C content of strain BELH1(T) was 38.2 mol% and the strain's predominant cellular fatty acids were C(14:0), a summed feature that contained iso-C(17:1) and/or anteiso-C(17:1) B, and C(16:0). Phylogenetic analysis based on 16S rRNA gene sequences indicated that the novel strain was most closely related to Fusibacter paucivorans (94.8 % sequence similarity). Based on phenotypic, phylogenetic and taxonomic characteristics, strain BELH1(T) represents a novel species of the genus Fusibacter, for which the name Fusibacter tunisiensis sp. nov. is proposed. The type strain is BELH1(T) ( = DSM 24436(T) = JCM 17481(T)). PMID- 21828015 TI - Erythrobacter pelagi sp. nov., a member of the family Erythrobacteraceae isolated from the Red Sea. AB - A novel Gram-negative, aerobic, catalase- and oxidase-positive, non-sporulating, non-motile, rod-shaped bacterium, designated strain UST081027-248(T), was isolated from seawater of the Red Sea. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain UST081027-248(T) fell within the genus Erythrobacter. Levels of 16S rRNA gene sequence similarity between the novel strain and the type strains of Erythrobacter species ranged from 95.3 % (with Erythrobacter gangjinensis) to 98.2 % (with Erythrobacter citreus). However, levels of DNA-DNA relatedness between strain UST081027-248(T) and the type strains of closely related species were below 70 %. Optimal growth of the isolate occurred in the presence of 2.0 % NaCl, at pH 8.0-9.0 and at 28-36 degrees C. The isolate did not produce bacteriochlorophyll a. The predominant cellular fatty acids were C(17:1)omega6c, summed feature 8 (C(18:1)omega6c and/or C(18:1)omega7c) and C(15:0) 2-OH. The genomic DNA G+C content of strain UST081027 248(T) was 60.4 mol%. Phenotypic properties and phylogenetic distinctiveness clearly indicated that strain UST081027-248(T) represents a novel species of the genus Erythrobacter, for which the name Erythrobacter pelagi sp. nov. is proposed. The type strain is UST081027-248(T) ( = JCM 17468(T) = NRRL 59511(T)). PMID- 21828016 TI - Cellulophaga geojensis sp. nov., a member of the family Flavobacteriaceae isolated from marine sand. AB - A Gram-stain-negative, aerobic, non-flagellated, non-spore-forming, motile (by gliding) bacterial strain, designated M-M6(T), was isolated from marine sand of Geoje island, Korea. Strain M-M6(T) grew optimally at 25 degrees C, at pH 7.0 8.0 and in the presence of 2 % (w/v) NaCl. Phylogenetic analyses based on 16S rRNA gene sequences revealed that strain M-M6(T) fell within the clade comprising Cellulophaga species, forming a coherent cluster with Cellulophaga lytica ATCC 23178(T) and Cellulophaga fucicola NN015860(T), with which it shared 16S rRNA gene sequence similarities of 98.1 and 98.2 %, respectively. Sequence similarities between strain M-M6(T) and the type strains of other recognized Cellulophaga species were in the range 92.4-93.8 %. Strain M-M6(T) contained MK-6 as the predominant menaquinone and iso-C(15:0), iso-C(15:1) G, iso-C(17:0) 3-OH, and C(16:1)omega7c and/or iso-C(15:0) 2-OH as the major fatty acids. The major polar lipids detected in strain M-M6(T) and the type strains of C. lytica and C. fucicola were two unidentified lipids, one unidentified aminolipid and one unidentified aminophospholipid. The DNA G+C content of strain M-M6(T) was 35.4 mol%. Levels of DNA-DNA relatedness between strain M-M6(T) and C. lytica JCM 8516(T) and C. fucicola JCM 21778(T) were 33 and 35 %, respectively. Differential phenotypic properties and phylogenetic and genetic distinctiveness distinguished strain M-M6(T) from all recognized Cellulophaga species. On the basis of the data presented, strain M-M6(T) is considered to represent a novel species of the genus Cellulophaga, for which the name Cellulophaga geojensis sp. nov. is proposed. The type strain is M-M6(T) ( = KCTC 23498(T) = CCUG 60801(T)). PMID- 21828017 TI - Celeribacter baekdonensis sp. nov., isolated from seawater, and emended description of the genus Celeribacter Ivanova et al. 2010. AB - A Gram-stain-negative, non-motile, ovoid or rod-shaped bacterial strain, designated L-6(T), was isolated from seawater of Baekdo harbour of the East Sea in Korea and its taxonomic position was investigated by using a polyphasic study. Strain L-6(T) grew optimally at 30 degrees C, at pH 7.5-8.0 and in the presence of 2 % (w/v) NaCl. In the neighbour-joining phylogenetic tree based on 16S rRNA gene sequences, strain L-6(T) formed a cluster with the type strain of Celeribacter neptunius at a bootstrap resampling value of 100 %. Strain L-6(T) exhibited 16S rRNA gene sequence similarity values of 97.7 % to C. neptunius H 14(T) and of less than 96.2 % to the type strains of other species used in the phylogenetic analysis. The G+C content of the chromosomal DNA of strain L-6(T) was 60.9 mol%. The predominant ubiquinone found in strain L-6(T) and C. neptunius CIP 109922(T) was ubiquinone-10 (Q-10). The predominant fatty acid of strain L 6(T) and C. neptunius CIP 109922(T) was C(18:1)omega7c. The major polar lipids of strain L-6(T) were phosphatidylglycerol, one unidentified aminolipid and one unidentified lipid. The mean level of DNA-DNA relatedness between strain L-6(T) and C. neptunius CIP 109922(T) was 17 %. Differential phenotypic properties, together with phylogenetic and genetic distinctiveness, demonstrated that strain L-6(T) is distinguishable from C. neptunius. On the basis of the data presented, strain L-6(T) is considered to represent a novel species of the genus Celeribacter, for which the name Celeribacter baekdonensis sp. nov. is proposed. The type strain is L-6(T) ( = KCTC 23497(T) = CCUG 60799(T)). PMID- 21828018 TI - Cryptococcus cyanovorans sp. nov., a basidiomycetous yeast isolated from cyanide contaminated soil. AB - Eighteen yeast strains were isolated and identified from cyanide-contaminated soil in South Africa. According to sequence-based analyses using the D1/D2 region of the large ribosomal subunit and ITS region, three of these strains were found to be identical and represent a novel species. Phylogenetic analysis based on the combined dataset of the D1/D2 and ITS regions revealed a grouping with Cryptococcus curvatus, representing a defined clade (Curvatus) in the order Trichosporonales. The three strains were demarcated from Cryptococcus curvatus by standard physiological tests such as assimilation of lactose, xylitol, 5-keto-D gluconate, succinate and citrate as well as growth on media containing 10 % (w/v) NaCl and 5 % (w/v) glucose. In addition, it was established that these strains could utilize up to 10 mM NaCN as sole carbon source on solid media and as sole nitrogen source in liquid media. On the basis of these findings, it is suggested that the three strains represent a novel species for which the name Cryptococcus cyanovorans sp. nov. is given (type strain CBS 11948(T) = NRRL Y-48730(T)). PMID- 21828019 TI - Mycoplasma neophronis sp. nov., isolated from the upper respiratory tract of Canarian Egyptian vultures (Neophron percnopterus majorensis). AB - Six strains with the typical characteristics of mycoplasmas were isolated from the tracheae of six Canarian Egyptian vultures (Neophron percnopterus majorensis). The results of biochemical, serological and molecular genetic studies showed that the isolates were nearly identical and that they could be considered as representing a novel species of the genus Mycoplasma. Colonies possessed the typical fried-egg appearance and electron micrographs revealed a pleomorphic cellular morphology with the lack of a cell wall. The isolates hydrolysed arginine and required sterol for growth but did not ferment glucose or hydrolyse urea. We propose that the isolates be assigned to a novel species,Mycoplasma neophronis sp. nov. The type strain is G.A.(T) ( = DSM 24097(T) = ATCC BAA-2157(T)). The antiserum of strain G.A.(T) has been deposited in the Mollicutes collection at Purdue University (Indiana, USA). PMID- 21828020 TI - Paenibacillus chartarius sp. nov., isolated from a paper mill. AB - The taxonomy of strain CCUG 55240(T), a Gram-staining-positive, aerobic, endospore-forming bacterium that was isolated from a paper mill, was investigated using a polyphasic approach. In phylogenetic analysis based on 16S rRNA gene sequences, the novel strain was grouped with established members of the genus Paenibacillus and appeared most closely related to the type strains of Paenibacillus chinjuensis (93.7 % sequence similarity), P. elgii (93.7 %) and P. chitinolyticus (93.6 %). The levels of 16S rRNA gene sequence similarity with other species of the genus Paenibacillus, including the type species of the genus, Paenibacillus polymyxa, were all <93.5 %. The fatty acid profile of strain CCUG 55240(T), which showed a predominance of iso- and anteiso-branched fatty acids, supported the allocation of the strain to the genus Paenibacillus. Unusually high amounts of some iso-branched fatty acids, especially iso-C(15:0) and iso-C(16:0), allowed differentiation of strain CCUG 55240(T) from the most closely related species of the genus Paenibacillus. The diagnostic diamino acid found in the cell-wall peptidoglycan was meso-diaminopimelic acid. The predominant menaquinone was MK-7. The major polar lipids were phosphatidylethanolamine, diphosphatidylglycerol, phosphatidylglycerol, an unknown glycolipid, an unknown aminophosphoglycolipid and an unknown phospholipid. Spermidine was the major polyamine. The results of some physiological and biochemical tests also allowed the phenotypic differentiation of strain CCUG 55240(T) from the most closely related recognized species. On the basis of the phylogenetic, phenotypic and molecular evidence, strain CCUG 55240(T) represents a novel species of the genus Paenibacillus, for which the name Paenibacillus chartarius sp. nov. is proposed. The type strain of the novel species is CCUG 55240(T) ( = CCM 7759(T)). PMID- 21828021 TI - Burkholderia zhejiangensis sp. nov., a methyl-parathion-degrading bacterium isolated from a wastewater-treatment system. AB - The taxonomic status of a methyl-parathion-degrading strain, OP-1(T), isolated from a wastewater-treatment system in China, was determined using a polyphasic approach. The rod-shaped cells were Gram-staining-negative, non-spore-forming and non-motile. Phylogenetic analysis based on 16S rRNA gene sequences indicated that the novel strain belonged to the genus Burkholderia, as it appeared closely related to Burkholderia glathei ATCC 29195(T) (97.4 % sequence similarity), Burkholderia sordidicola KCTC 12081(T) (96.5 %) and Burkholderia bryophila LMG 23644(T) (96.3 %). The major cellular fatty acids, C(16:0), C(17:0) cyclo and C(18:1)omega7c, were also similar to those found in established members of the genus Burkholderia. The genomic DNA G+C content of strain OP-1(T) was 59.4 mol%. The level of DNA-DNA relatedness between the novel strain and the closest recognized species, Burkholderia glathei ATCC 29195(T), was only 30 %. Based on the phenotypic, genotypic and phylogenetic evidence, strain OP-1(T) represents a novel species of the genus Burkholderia, for which the name Burkholderia zhejiangensis sp. nov. is proposed. The type strain is OP-1(T) ( = CCTCC AB 2010354(T) = KCTC 23300(T)). PMID- 21828022 TI - Halovenus aranensis gen. nov., sp. nov., an extremely halophilic archaeon from Aran-Bidgol salt lake. AB - A novel red-pigmented halophilic archaeon, strain EB27(T), was isolated from Aran Bidgol salt lake, a hypersaline playa in Iran. Cells of strain EB27(T) were non motile and pleomorphic (rods to triangular or disc-shaped). Strain EB27(T) required at least 2.5 M NaCl and 0.1 M MgCl(2) for growth. Optimal growth was achieved at 4 M NaCl and 0.5 M MgCl(2). The optimum pH and temperature for growth were pH 7.5 and 40 degrees C; it was able to grow at pH 6.0-8.0 and 25-50 degrees C. 16S rRNA gene sequence analysis showed that strain EB27(T) is a member of the family Halobacteriaceae; however, levels of 16S rRNA gene sequence similarity were as low as 90.0, 89.3 and 89.1 % to the most closely related haloarchaeal taxa, namely Halalkalicoccus tibetensis DS12(T), Halosimplex carlsbadense 2-9-1(T) and Halorhabdus utahensis AX-2(T), respectively. The DNA G+C content of strain EB27(T) was 61 mol%. Strain EB27(T) contained phosphatidylglycerol and phosphatidylglycerol phosphate methyl ester, common phospholipids found in haloarchaea, together with two minor phospholipids. The only quinone present was MK-8(II-H(2)). Physiological, biochemical and phylogenetic differences between strain EB27(T) and recognized genera of extremely halophilic archaea suggest that this strain represents a novel species in a new genus within the family Halobacteriaceae, for which the name Halovenus aranensis gen. nov., sp. nov. is proposed. The type strain of Halovenus aranensis, the type species of the new genus, is strain EB27(T) ( = IBRC-M 10015(T) = CGMCC 1.11001(T)). PMID- 21828023 TI - Sphingomicrobium lutaoense gen. nov., sp. nov., isolated from a coastal hot spring. AB - A yellowish pigmented, Gram-negative, rod-shaped, non-spore-forming bacterium (strain CC-TBT-3(T)), was isolated on marine agar 2216 from a coastal hot spring of Green Island (Lutao), located off Taituang, Taiwan. 16S rRNA gene sequence analysis of strain CC-TBT-3(T) showed a relatively low similarity (<95.5 %) to representatives of the genera Novosphingobium, Sphingosinicella and Sphingomonas of the Sphingomonadaceae, with the most related strain being the type strain of Novosphingobium soli. In addition to the relatively low 16S rRNA gene sequence similarity to members of established species, the isolate also showed some unique chemotaxonomic features, including the presence of some glycolipids with unusual chromatographic behaviour. The major components of the polar lipid profile were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, sphingoglycolipid and three unidentified glycolipids. The major respiratory quinone was ubiquinone Q-10. The polyamine pattern was characterized by the triamine sym-homospermidine as a major component. Although the predominant fatty acids were C(18:1)omega7c and summed feature 3 (C(16:1)omega7c and/or iso-C(15:0) 2-OH), the isolate did not show the typical hydroxyl fatty acids, such as C(14:0) 2-OH, C(15:0) 2-OH and C(16:0) 2-OH, found in members of the genera Novosphingobium, Sphingomonas and Sphingosinicella, but showed instead high amounts of C(18:1) 2-OH (12.0 %). The DNA G+C content of strain CC-TBT-3(T) was 63.4 mol%. 16S rRNA gene sequence, chemotaxonomic and physiological analyses revealed that strain CC-TBT-3(T) represents a novel species in a new genus in the family Sphingomonadaceae for which the name Sphingomicrobium lutaoense gen. nov., sp. nov. is proposed; the type strain is of the type species S. lutoaense, CC-TBT 3(T) ( = DSM 24194(T) = CCM 7794(T)). PMID- 21828024 TI - WHO guidelines for the programmatic management of drug-resistant tuberculosis: 2011 update. AB - The production of guidelines for the management of drug-resistant tuberculosis (TB) fits the mandate of the World Health Organization (WHO) to support countries in the reinforcement of patient care. WHO commissioned external reviews to summarise evidence on priority questions regarding case-finding, treatment regimens for multidrug-resistant TB (MDR-TB), monitoring the response to MDR-TB treatment, and models of care. A multidisciplinary expert panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to develop recommendations. The recommendations support the wider use of rapid drug susceptibility testing for isoniazid and rifampicin or rifampicin alone using molecular techniques. Monitoring by sputum culture is important for early detection of failure during treatment. Regimens lasting >= 20 months and containing pyrazinamide, a fluoroquinolone, a second-line injectable drug, ethionamide (or prothionamide), and either cycloserine or p-aminosalicylic acid are recommended. The guidelines promote the early use of antiretroviral agents for TB patients with HIV on second-line drug regimens. Systems that primarily employ ambulatory models of care are recommended over others based mainly on hospitalisation. Scientific and medical associations should promote the recommendations among practitioners and public health decision makers involved in MDR-TB care. Controlled trials are needed to improve the quality of existing evidence, particularly on the optimal composition and duration of MDR-TB treatment regimens. PMID- 21828026 TI - New tools in pulmonary rehabilitation. AB - In patients with more severe chronic obstructive pulmonary disease (COPD), the benefits of rehabilitation might not be clear and, therefore, new treatment options have been developed to increase the benefits of rehabilitation. This review provides an overview of new approaches being developed as an addition to exercise training. In turn, the benefits of adding ventilatory support, oxygen, anabolics or neuromuscular stimulation to a rehabilitation programme will be discussed. While positive benefits for a number of these approaches have been found, many questions remain unsolved. Therefore, at present, we cannot recommend these new tools as part of the routine management of patients with COPD who start a rehabilitation programme. PMID- 21828025 TI - Bosentan inhibits cigarette smoke-induced endothelin receptor expression in pulmonary arteries. AB - The endothelin (ET) system contributes to lung vascular tension and remodelling in smokers and chronic obstructive pulmonary disease (COPD) patients. This study examined the effect of cigarette smoke (CS) on ET receptor A (ET(A)) and B (ET(B)) expression in human pulmonary artery smooth muscle cells (HPASMCs) and human small intrapulmonary arteries, as well as their functional consequences. CS extract (CSE) increased ET(A) and ET(B) expression in HPASMCs and small intrapulmonary arteries, which was attenuated by bosentan, the ET(A) antagonist BQ123 and the ET(B) antagonist BQ788, and by blocking ET-1 with a monoclonal antibody against ET-1, suggesting a feed-forward mechanism mediated by ET-1 release. ET receptor (ETR) antagonism attenuated the CSE-induced HPASMC proliferation. Furthermore, CSE exposure increased the acute ET-1-induced small intrapulmonary artery contraction, which was attenuated by bosentan, BQ123 and BQ788. Pulmonary arteries from smokers and COPD patients showed a higher expression of ET(A) and ET(B) than those of nonsmoker patients. These results show a novel mechanism by which ETR blockade attenuates CS-induced ETR overexpression and, subsequently, small intrapulmonary artery tension. These data may be of potential value to explain therapeutic effects of bosentan in some forms of disproportionate pulmonary hypertension in COPD patients. PMID- 21828028 TI - NiO and Co3O4 nanoparticles induce lung DTH-like responses and alveolar lipoproteinosis. AB - Lung exposure to metal oxide nanoparticles (NPs) comprising soluble metal haptens may produce T-helper cell type 1 (Th1)- and Th17-associated delayed-type hypersensitivity (DTH) responses and pulmonary alveolar proteinosis (PAP). In order to study this, haptenic metal oxide NPs (NiO, Co(3)O(4), Cr(2)O(3) and CuO) were instilled into the lungs of female Wistar rats, and the immunoinflammatory responses were assessed at 24 h and 4 weeks post-instillation. Primary culture of alveolar macrophages from Wistar rats was used to evaluate the effect of the NPs on the ability to clear surfactant. NiO NPs induced chronic interstitial inflammation and pro-inflammatory Th1 and Th17 immune responses characterised by increases in the cytokines monocyte chemotactic protein (MCP)-1/CCL2, interleukin (IL)-12 p40, interferon-gamma and IL-17A, whilst similar pathological responses induced by Co(3)O(4) NPs were associated with increases in MCP-1/CCL2 and IL-12 p40. However, neither Cr(2)O(3) nor CuO NPs elicited immunoinflammatory reactions. PAP was induced by both NiO and Co(3)O(4) NPs during the chronic phase. PAP was associated with over-production of surfactant by proliferation of type II cells and impaired clearance of surfactant by macrophages. These findings have implications for the risk management of occupational NP exposure and provide evidence that haptenic metal oxide NPs can induce chronic progressive lung immune responses via a DTH-like mechanism. PMID- 21828027 TI - Clara cells drive eosinophil accumulation in allergic asthma. AB - Development of allergic asthma is a complex process involving immune, neuronal and tissue cells. In the lung, Clara cells represent a major part of the "immunomodulatory barrier" of the airway epithelium. To understand the contribution of these cells to the inflammatory outcome of asthma, disease development was assessed using an adjuvant-free ovalbumin model. Mice were sensitised with subcutaneous injections of 10 MUg endotoxin-free ovalbumin in conjunction with naphthalene-induced Clara cell depletion. Clara epithelial cell depletion in the lung strongly reduced eosinophil influx, which correlated with decreased eotaxin levels and, moreover, diminished the T-helper cell type 2 inflammatory response, including interleukin (IL)-4, IL-5 and IL-13. In contrast, airway hyperresponsiveness was increased. Further investigation revealed Clara cells as the principal source of eotaxin in the lung. These findings are the first to show that Clara airway epithelial cells substantially contribute to the infiltration of eotaxin-responsive CCR3+ immune cells and augment the allergic immune response in the lung. The present study identifies Clara cells as a potential therapeutic target in inflammatory lung diseases such as allergic asthma. PMID- 21828029 TI - Surgical implications of the new IASLC/ATS/ERS adenocarcinoma classification. AB - A new adenocarcinoma classification was recently introduced by a joint working group of the International Association for the Study of Lung Cancer (IASLC), American Thoracic Society (ATS) and European Respiratory Society (ERS). A distinction is made between pre-invasive lesions, and minimally invasive and invasive adenocarcinoma. The confusing term "bronchioloalveolar carcinoma" is not used any more and new subcategories include adenocarcinoma in situ and minimally invasive adenocarcinoma. Due to a renewed interest in screen-detected nodules and early-stage lung cancers of <2 cm, this classification also has profound implications for thoracic surgeons. In this article, surgical topics are discussed: the role of a minimally invasive approach, especially video-assisted thoracic surgery, limited resection for early-stage lung cancer, the extent of lymph node dissection, the accuracy of intraoperative frozen section analysis, management of multiple lung nodules and prognostic factors in operated patients. Specific key issues are presented based on the current evidence and areas of surgical uncertainty are defined providing a basis for further studies. Thoracic surgeons will play a major role in the application and global introduction of this new adenocarcinoma classification. The remaining controversies regarding the precise diagnosis and management of early-stage lesions will have to be resolved by multidisciplinary and international collaboration. PMID- 21828030 TI - The impact and cost-effectiveness of strategies to detect drug-resistant tuberculosis. AB - Drug-resistant tuberculosis (TB) is a serious emerging problem in many low resource countries. TB control programmes are uncertain of which drug susceptibility tests (DSTs) to use and when to test patients. We predicted the potential cost-effectiveness of different DST strategies, in settings with varying prevalence of drug resistance. Using decision analysis, we assessed the cost-effectiveness of conventional and rapid DSTs for previously diagnosed smear positive TB cases. Five different time-points were considered for administering DSTs. Different initial drug resistance and HIV scenarios were also considered. All DST scenarios in the wide range of settings considered were found to be cost effective. The strategy of performing a rapid DST that detects any form of isoniazid (INH) and rifampicin (RIF) resistance for all patients before the initiation of treatment was predicted to be the most cost-effective strategy. In a setting with moderate drug resistance, the cost per disability-adjusted life year gained was as low as US$744. Our findings support the roll-out of rapid drug susceptibility testing at the moment of diagnosis to detect any form of INH and RIF resistance in all countries with moderate or greater burdens of drug resistant TB. PMID- 21828031 TI - Dexamethasone in patients with acute lung injury from acute monocytic leukaemia. AB - The use of steroids is not required in myeloid malignancies and remains controversial in patients with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). We sought to evaluate dexamethasone in patients with ALI/ARDS caused by acute monocytic leukaemia (AML FAB-M5) via either leukostasis or leukaemic infiltration. Dexamethasone (10 mg every 6 h until neutropenia) was added to chemotherapy and intensive care unit (ICU) management in 20 consecutive patients between 2005 and 2008, whose data were compared with those from 20 historical controls (1994-2002). ICU mortality was the primary criterion. We also compared respiratory deterioration rates, need for ventilation and nosocomial infections. 17 (85%) patients had hyperleukocytosis, 19 (95%) had leukaemic masses, and all 20 had severe pancytopenia. All patients presented with respiratory symptoms and pulmonary infiltrates prior to AML FAB-M5 diagnosis. Compared with historical controls, dexamethasone-treated patients had a significantly lower ICU mortality rate (20% versus 50%; p = 0.04) and a trend for less respiratory deterioration (50% versus 80%; p = 0.07). There were no significant increases in the rates of infections with dexamethasone. In conclusion, in patients with ALI/ARDS related to AML FAB-M5, adding dexamethasone to conventional chemotherapy seemed effective and safe. These results warrant a controlled trial of dexamethasone versus placebo in AML FAB-M5 patients with noninfectious pulmonary infiltrates. PMID- 21828032 TI - Surfactant protein C G100S mutation causes familial pulmonary fibrosis in Japanese kindred. AB - Several mutations in the surfactant protein C (SP-C) gene (SFTPC) have been reported as causing familial pulmonary fibrosis (FPF). However, the genetic background and clinical features of FPF are still not fully understood. We identified one Japanese kindred, in which at least six individuals over three generations were diagnosed with pulmonary fibrosis. We examined the patients radiologically and histopathologically and sequenced their SFTPC and ABCA3 genes. We also established a cell line stably expressing the mutant gene. All the patients had similar radiological and histopathological characteristics. Their histopathological pattern was that of usual interstitial pneumonia, showing numerous fibroblastic foci even in areas without abnormal radiological findings on chest high-resolution computed tomography. No child had respiratory symptoms in the kindred. Sequencing of SFTPC showed a novel heterozygous mutation, c.298G>A (G100S), in the BRICHOS domain of proSP-C, which co-segregated with the disease. However, in the ABCA3 gene, no mutation was found. In vitro expression of the mutant gene revealed that several endoplasmic reticulum stress-related proteins were strongly expressed. The mutation increases endoplasmic reticulum stress and induces apoptotic cell death compared with wild-type SP-C in alveolar type II cells, supporting the significance of this mutation in the pathogenesis of pulmonary fibrosis. PMID- 21828033 TI - Initial management of pneumonia and sepsis: factors associated with improved outcome. AB - Processes of care and adherence to guidelines have been associated with improved survival in community-acquired pneumonia (CAP). In sepsis, bundles of processes of care have also increased survival. We aimed to audit compliance with guideline recommended processes of care and its impact on outcome in hospitalised CAP patients with sepsis. We prospectively studied 4,137 patients hospitalised with CAP in 13 hospitals. The processes of care evaluated were adherence to antibiotic prescription guidelines, first dose within 6 h and oxygen assessment. Outcome measures were mortality and length of stay (LOS). Oxygen assessment was measured in 3,745 (90.5%) patients; 3,024 (73.1%) patients received antibiotics according to guidelines and 3,053 (73.8%) received antibiotics within 6 h. In CAP patients with sepsis, the strongest independent factor for survival was antibiotic adherence (OR 0.4). In severe sepsis, only compliance to antibiotic adherence plus first dose within 6 h was associated with lower mortality (OR 0.60), adjusted for fine prognostic scale and hospital. Antibiotic adherence was related to shorter hospital stay. In sepsis, antibiotic adherence is the strongest protective factor of care associated with survival and LOS. In severe sepsis, combined antibiotic adherence and first dose within 6 h may reduce mortality. PMID- 21828034 TI - Interleukin-17A induces glucocorticoid insensitivity in human bronchial epithelial cells. AB - A subset of asthma patients suffer from glucocorticoid (GC) insensitivity. T helper cell type 17 cells have an emerging role in GC insensitivity, although the mechanisms are still poorly understood. We investigated whether interleukin (IL) 17A induces GC insensitivity in airway epithelium by studying its effects on responsiveness of tumour necrosis factor (TNF)-alpha-induced IL-8 production to budesonide in human bronchial epithelial 16HBE cells. We unravelled the underlying mechanism by the use of specific pathway inhibitors, reporter and overexpression constructs and a histone deacetylase (HDAC) activity assay. We demonstrated that IL-17A-induced IL-8 production is normally sensitive to GCs, while IL-17A pre-treatment significantly reduced the sensitivity of TNF-alpha induced IL-8 production to budesonide. IL-17A activated the p38, extracellular signal-related kinase (ERK) and phosphoinositide-3-kinase (PI3K) pathways, and the latter appeared to be involved in IL-17A-induced GC insensitivity. Furthermore, IL-17A reduced HDAC activity, and overexpression of HDAC2 reversed IL-17A-induced GC insensitivity. In contrast, IL-17A did not affect budesonide induced transcriptional activity of the GC receptor, suggesting that IL-17A does not impair the actions of the ligated GC receptor. In conclusion, we have shown for the first time that IL-17A induces GC insensitivity in airway epithelium, which is probably mediated by PI3K activation and subsequent reduction of HDAC2 activity. Thus, blockade of IL-17A or downstream signalling molecule PI3K may offer new strategies for therapeutic intervention in GC-insensitive asthma. PMID- 21828035 TI - Resistin-like molecule-beta is a human airway remodelling mediator. AB - Though implicated in vascular remodelling, a role for the resistin-like molecule (RELM)-beta in human airway remodelling remains unexplored. We hypothesised that RELM-beta expression is increased in the airways of asthmatics and regulates airways epithelial cell function. Expression of RELM-beta in the bronchial mucosa and its concentrations in bronchoalveolar lavage (BAL) fluid from asthmatics and controls were measured by immunohistochemistry and ELISA, respectively. Proliferation assays, Western blotting, ELISA and real-time PCR were employed to detect effects of RELM-beta on airways epithelial cells. RELM-beta expression was increased in the bronchial mucosa and BAL fluid of asthmatics compared with controls. In the asthmatics, the numbers of mucosal RELM-beta+ cells correlated inversely with forced expiratory volume in 1 s (r=-0.531, p=0.016), while the numbers of epithelial RELM-beta+ cells correlated positively with those of mucin (MUC)5AC+ cells. In vitro, interleukin-13 enhanced RELM-beta expression by primary human airways epithelial cells, while RELM-beta itself acted on these cells to induce proliferation, expression of MUC5AC, extracellular signal regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) phosphatidylinositol 3-kinase (PI3K)/Akt phosphorylation and elevated expression of transforming growth factor-beta2, epidermal growth factor and vascular endothelial growth factor. RELM-beta has the potential to contribute to airway remodelling in diseases such as asthma by acting on epithelial cells to increase proliferation, mucin and growth factor production, at least partly via ERK/MAPK PI3K/Akt signalling pathways. PMID- 21828037 TI - Primary lung adenocarcinoma: characteristics by smoking habit and sex. AB - The incidence of adenocarcinoma is increasing, particularly among females. We sought to assess the role of tobacco consumption in clinical presentation according to sex. In this retrospective study, 848 patients diagnosed between 1997 and 2006 at Grenoble University Hospital (Grenoble, France) were stratified into four groups according to smoking habits. Differences between sexes and two contrasting female profiles emerged. Female current smokers were younger than female never-smokers (median 51 versus 69 yrs; p < 0.001), more often had surgery (62.7% versus 39%; p = 0.01) and had a median (95% CI) estimated survival of 26.2 (18.1-49.2) versus 15.1 (12.8-22.2) months (p = 0.002). Both groups had similar survival when taking treatment into account. Among males, smoking did not influence presentation. Male current smokers were older than female current smokers (median 59 yrs; p < 0.001) and fewer had surgery (48.8%; p = 0.015), although the percentage of stage IIIb-IV disease was similar (53% and 46%; nonsignificant) and they had a poorer estimated survival of 14.3 (13.0-18.5) months (p = 0.0024). Males smoked more than females (median 41 versus 30 pack yrs; p < 0.001). Quitting smoking delayed age at diagnosis by 11 yrs for females (p = 0.0035) and 8 yrs for males (p < 0.001). Our results support the hypothesis that carcinogenesis differs between males and females, and between female smokers and never-smokers. PMID- 21828036 TI - Mometasone furoate/formoterol reduces asthma deteriorations and improves lung function. AB - This study evaluated the effect of mometasone furoate (MF)/formoterol (F) versus its monocomponents, each administered via metered-dose inhaler, on asthma deteriorations and lung function. This 26-week, multicentre, double-blind, placebo-controlled study included subjects aged >=12 yrs with not well-controlled asthma on low-dose inhaled corticosteroids. After a 2-3-week open-label run-in (MF 100 MUg b.i.d.), 746 subjects were randomised to receive placebo, F 10 MUg, MF 100 MUg or MF/F 100/10 MUg b.i.d. Co-primary end-points were time to first asthma deterioration (MF/F versus F to assess effect of MF) and change in forced expiratory volume in 1 s (FEV(1)) area under the curve of serial spirometry measurements over the 12-h period following the morning dose (AUC(0-12h)) (baseline to week 12; MF/F versus MF to assess effect of F). The therapeutic effect of MF in the combination was demonstrated by a reduction in asthma deterioration incidence with MF/F versus F and a delayed time to first asthma deterioration (p<0.001). Asthma deterioration incidence was also reduced with MF/F versus MF (p=0.006). The therapeutic effect of F in the combination was demonstrated by MF/F versus MF in FEV(1) AUC(0-12h) change (4.00 versus 2.53 L.h, respectively; p=0.001). MF/F treatment also resulted in a marked improvement in health-related quality of life. MF/F 100/10 MUg b.i.d. treatment showed greater clinical efficacy than its individual components or placebo; both components contributed to the efficacy of MF/F. PMID- 21828038 TI - Dietary isothiocyanate-induced apoptosis via thiol modification of DNA topoisomerase IIalpha. AB - Studies in animal models have indicated that dietary isothiocyanates (ITCs) exhibit cancer preventive activities through carcinogen detoxification-dependent and -independent mechanisms. The carcinogen detoxification-independent mechanism of cancer prevention by ITCs has been attributed at least in part to their ability to induce apoptosis of transformed (initiated) cells (e.g. through suppression of IkappaB kinase and nuclear factor kappaB as well as other proposed mechanisms). In the current studies we show that ITC-induced apoptosis of oncogene-transformed cells involves thiol modification of DNA topoisomerase II (Top2) based on the following observations. 1) siRNA-mediated knockdown of Top2alpha in both SV40-transformed MEFs and Ras-transformed human mammary epithelial MCF-10A cells resulted in reduced ITC sensitivity. 2) ITCs, like some anticancer drugs and cancer-preventive dietary components, were shown to induce reversible Top2alpha cleavage complexes in vitro. 3) ITC-induced Top2alpha cleavage complexes were abolished by co-incubation with excess glutathione. In addition, proteomic analysis revealed that several cysteine residues on human Top2alpha were covalently modified by benzyl-ITC, suggesting that ITC-induced Top2alpha cleavage complexes may involve cysteine modification. Interestingly, consistent with the thiol modification mechanism for Top2alpha cleavage complex induction, the thiol-reactive selenocysteine, but not the non-thiol-reactive selenomethionine, was shown to induce Top2alpha cleavage complexes. In the aggregate, our results suggest that thiol modification of Top2alpha may contribute to apoptosis induction in transformed cells by ITCs. PMID- 21828039 TI - Mfc1 is a novel forespore membrane copper transporter in meiotic and sporulating cells. AB - To gain insight in the molecular basis of copper homeostasis during meiosis, we have used DNA microarrays to analyze meiotic gene expression in the model yeast Schizosaccharomyces pombe. Profiling data identified a novel meiosis-specific gene, termed mfc1(+), that encodes a putative major facilitator superfamily-type transporter. Although Mfc1 does not exhibit any significant sequence homology with the copper permease Ctr4, it contains four putative copper-binding motifs that are typically found in members of the copper transporter family of copper transporters. Similarly to the ctr4(+) gene, the transcription of mfc1(+) was induced by low concentrations of copper. However, its temporal expression profile during meiosis was distinct to ctr4(+). Whereas Ctr4 was observed at the plasma membrane shortly after induction of meiosis, Mfc1 appeared later in precursor vesicles and, subsequently, at the forespore membrane of ascospores. Using the fluorescent copper-binding tracker Coppersensor-1 (CS1), labile cellular copper was primarily detected in the forespores in an mfc1(+)/mfc1(+) strain, whereas an mfc1Delta/mfc1Delta mutant exhibited an intracellular dispersed punctate distribution of labile copper ions. In addition, the copper amine oxidase Cao1, which localized primarily in the forespores of asci, was fully active in mfc1(+)/mfc1(+) cells, but its activity was drastically reduced in an mfc1Delta/mfc1Delta strain. Furthermore, our data showed that meiotic cells that express the mfc1(+) gene have a distinct developmental advantage over mfc1Delta/mfc1Delta mutant cells when copper is limiting. Taken together, the data reveal that Mfc1 serves to transport copper for accurate and timely meiotic differentiation under copper-limiting conditions. PMID- 21828040 TI - mda-9/Syntenin protein positively regulates the activation of Akt protein by facilitating integrin-linked kinase adaptor function during adhesion to type I collagen. AB - The integrin-linked kinase (ILK)-PINCH1-alpha-parvin (IPP) complex functions as a signaling platform for integrins that modulates various cellular processes. ILK functions as a central adaptor for the assembly of IPP complex. We report here that mda-9/syntenin, a positive regulator of cancer metastasis, regulates the activation of Akt (also known as protein kinase B) by facilitating ILK adaptor function during adhesion to type I collagen (COL-I) in human breast cancer cells. COL-I stimulation induced the phosphorylation and plasma membrane translocation of Akt. Inhibition of mda-9/syntenin or expression of mutant ILK (E359K) significantly blocked the translocation of both ILK and Akt to the plasma membrane. mda-9/syntenin associated with ILK, and this association was increased at the plasma membrane by COL-I stimulation. Knockdown of mda-9/syntenin impaired COL-I-induced association of ILK with Akt and plasma membrane targeting of ILK Akt complex. These results demonstrated that mda-9/syntenin regulates the activation of Akt by controlling the plasma membrane targeting of Akt via a mechanism that facilitates the association of Akt with ILK at the plasma membrane during adhesion to COL-I. On a striking note, inhibition of mda-9/syntenin impaired COL-I-induced plasma membrane translocation of the IPP complex and assembly of integrin beta1-IPP signaling complexes. Thus, our study defines the role of mda-9/syntenin in ILK adaptor function and describes a new mechanism of mda-9/syntenin for regulation of cell migration. PMID- 21828041 TI - Osteoblastic gamma-aminobutyric acid, type B receptors negatively regulate osteoblastogenesis toward disturbance of osteoclastogenesis mediated by receptor activator of nuclear factor kappaB ligand in mouse bone. AB - The prevailing view is that signaling machineries for the neurotransmitter GABA are also expressed by cells outside the CNS. In cultured murine calvarial osteoblasts, mRNA was constitutively expressed for both subunits 1 and 2 of metabotropic GABA(B) receptor (GABA(B)R), along with inhibition by the GABA(B)R agonist baclofen of cAMP formation, alkaline phosphatase (ALP) activity, and Ca(2+) accumulation. Moreover, baclofen significantly inhibited the transactivation of receptor activator of nuclear factor-kappaB ligand (RANKL) gene in a manner sensitive to a GABA(B)R antagonist, in addition to decreasing mRNA expression of bone morphogenetic protein-2 (BMP2), osteocalcin, and osterix. In osteoblastic MC3T3-E1 cells stably transfected with GABA(B)R1 subunit, significant reductions were seen in ALP activity and Ca(2+) accumulation, as well as mRNA expression of osteocalcin, osteopontin, and osterix. In cultured calvarial osteoblasts from GABA(B)R1-null mice exhibiting low bone mineral density in tibia and femur, by contrast, both ALP activity and Ca(2+) accumulation were significantly increased together with promoted expression of both mRNA and proteins for BMP2 and osterix. No significant change was seen in the number of multinucleated cells stained for tartrate-resistant acid phosphatase during the culture of osteoclasts prepared from GABA(B)R1-null mice, whereas a significant increase was seen in the number of tartrate-resistant acid phosphatase-positive multinucleated cells in co-culture of osteoclasts with osteoblasts isolated from GABA(B)R1-null mice. These results suggest that GABA(B)R is predominantly expressed by osteoblasts to negatively regulate osteoblastogenesis through down-regulation of BMP2 expression toward disturbance of osteoclastogenesis after down-regulation of RANKL expression in mouse bone. PMID- 21828042 TI - Involvement of human natural killer-1 (HNK-1) sulfotransferase in the biosynthesis of the GlcUA(3-O-sulfate)-Gal-Gal-Xyl tetrasaccharide found in alpha thrombomodulin from human urine. AB - Thrombomodulin (TM) is an integral membrane glycoprotein, which occurs as both a chondroitin sulfate (CS) proteoglycan (PG) form (beta-TM) and a non-PG form without a CS chain (alpha-TM) and hence is a part-time PG. An alpha-TM preparation isolated from human urine contained the glycosaminoglycan linkage region tetrasaccharide GlcUAbeta1-3Galbeta1-3Galbeta1-4xylose, and the nonreducing terminal GlcUA residue is 3-O-sulfated. Because the human natural killer-1 sulfotransferase (HNK-1ST) transfers a sulfate group from 3' phosphoadenosine 5'-phosphosulfate to the C-3 position of the nonreducing terminal GlcUA residue in the HNK-1 antigen precursor trisaccharide, GlcUAbeta1 3Galbeta1-4GlcNAc, the sulfotransferase activity toward the linkage region was investigated. In fact, the activity of HNK-1ST toward the linkage region was much higher than that toward the glucuronylneolactotetraosylceramide, the precursor of the HNK-1 epitope. HNK-1ST may be responsible for regulating the sorting of alpha and beta-TM. Furthermore, HNK-1ST also transferred a sulfate group from 3' phosphoadenosine 5'-phosphosulfate to the C-3 position of the nonreducing terminal GlcUA residue of a chondroitin chain. Intriguingly, the HNK-1 antibody recognized CS chains and the linkage region if they contained GlcUA(3-O-sulfate), suggesting that HNK-1ST not only synthesizes the HNK-1 epitope but may also be involved in the generation of part-time PGs. PMID- 21828043 TI - Osteoblast-specific transcription factor Osterix (Osx) is an upstream regulator of Satb2 during bone formation. AB - Osterix (Osx) is an osteoblast-specific transcription factor essential for osteoblast differentiation and bone formation. Osx knock-out mice lack bone completely. Satb2 is critical for osteoblast differentiation as a special AT-rich binding transcription factor. It is not known how Satb2 is transcriptionally regulated during bone formation. In this study, quantitative real-time RT-PCR results demonstrated that Satb2 was down-regulated in Osx-null calvaria. In stable C2C12 mesenchymal cells using the tetracycline (Tet)-Off system, overexpression of Osx stimulated Satb2 expression. Moreover, inhibition of Osx by siRNA led to repression of Satb2 expression in osteoblasts. These results suggest that Osx controls Satb2 expression. Transient transfection assay showed that Osx activated 1kb Satb2 promoter reporter activity in a dose-dependent manner. To define the region of Satb2 promoter responsive to Osx activation, a series of deletion mutants of Satb2 constructs were made, and the minimal region was narrowed down to the proximal 130 bp of the Satb2 promoter. Further point mutation studies found that two GC-rich region mutations disrupted the Satb2 130bp promoter activation by Osx, suggesting that these GC-rich binding sites were responsible for Satb2 activation by Osx. Gel shift assay showed that Osx bound to the Satb2 promoter sequence directly. ChIP assays indicated that endogenous Osx associated with the native Satb2 promoter in osteoblasts. Importantly, Satb2 siRNA significantly inhibited Osx-induced osteoblast marker gene expressions. Taken together, our findings indicate that Osx is an upstream regulator of Satb2 during bone formation. This reveals a new additional link of the transcriptional regulation mechanism that Osx controls bone formation. PMID- 21828044 TI - Contractile forces contribute to increased glycosylphosphatidylinositol-anchored receptor CD24-facilitated cancer cell invasion. AB - The malignancy of a tumor depends on the capability of cancer cells to metastasize. The process of metastasis involves cell invasion through connective tissue and transmigration through endothelial monolayers. The expression of the glycosylphosphatidylinositol-anchored receptor CD24 is increased in several tumor types and is consistently associated with increased metastasis formation in patients. Furthermore, the localization of beta1-integrins in lipid rafts depends on CD24. Cell invasion is a fundamental biomechanical process and usually requires cell adhesion to the extracellular matrix (ECM) mainly through beta1 heterodimeric integrin receptors. Here, we studied the invasion of A125 human lung cancer cells with different CD24 expression levels in three-dimensional ECMs. We hypothesized that CD24 expression increases cancer cell invasion through increased contractile forces. To analyze this, A125 cells (CD24 negative) were stably transfected with CD24 and sorted for high and low CD24 expression. The invasiveness of the CD24(high) and CD24(low) transfectants was determined in three-dimensional ECMs. The percentage of invasive cells and their invasion depth was increased in CD24(high) cells compared with CD24(low) cells. Knockdown of CD24 and of the beta1-integrin subunit in CD24(high) cells decreased their invasiveness, indicating that the increased invasiveness is CD24- and beta1 integrin subunit-dependent. Fourier transform traction microscopy revealed that the CD24(high) cells generated 5-fold higher contractile forces compared with CD24(low) cells. To analyze whether contractile forces are essential for CD24 facilitated cell invasion, we performed invasion assays in the presence of myosin light chain kinase inhibitor ML-7 as well as Rho kinase inhibitor Y27632. Cell invasiveness was reduced after addition of ML-7 and Y27632 in CD24(high) cells but not in CD24(neg) cells. Moreover, after addition of lysophosphatidic acid or calyculin A, an increase in pre-stress in CD24(neg) cells was observed, which enhanced cellular invasiveness. In addition, inhibition of the Src kinase or STAT3 strongly reduced the invasiveness of CD24(high) cells, slightly reduced that of CD24(low) cells, and did not alter the invasiveness of CD24(neg) cells. Taken together, these results suggest that CD24 enhances cell invasion through increased generation or transmission of contractile forces. PMID- 21828045 TI - Gelsolin and non-muscle myosin IIA interact to mediate calcium-regulated collagen phagocytosis. AB - The formation of adhesion complexes is the rate-limiting step for collagen phagocytosis by fibroblasts, but the role of Ca(2+) and the potential interactions of actin-binding proteins in regulating collagen phagocytosis are not well defined. We found that the binding of collagen beads to fibroblasts was temporally and spatially associated with actin assembly at nascent phagosomes, which was absent in gelsolin null cells. Analysis of tryptic digests isolated from gelsolin immunoprecipitates indicated that non-muscle (NM) myosin IIA may bind to gelsolin. Immunostaining and immunoprecipitation showed that gelsolin and NM myosin IIA associated at collagen adhesion sites. Gelsolin and NM myosin IIA were both required for collagen binding and internalization. Collagen binding to cells initiated a prolonged increase of [Ca(2+)](i), which was absent in cells null for gelsolin or NM myosin IIA. Collagen bead-induced increases of [Ca(2+)](i) were associated with phosphorylation of the myosin light chain, which was dependent on gelsolin. NM myosin IIA filament assembly, which was dependent on myosin light chain phosphorylation and increased [Ca(2+)](i), also required gelsolin. Ionomycin-induced increases of [Ca(2+)](i) overcame the block of myosin filament assembly in gelsolin null cells. We conclude that gelsolin and NM myosin IIA interact at collagen adhesion sites to enable NM myosin IIA filament assembly and localized, Ca(2+)-dependent remodeling of actin at the nascent phagosome and that these steps are required for collagen phagocytosis. PMID- 21828046 TI - Proteolipidic composition of exosomes changes during reticulocyte maturation. AB - During the orchestrated process leading to mature erythrocytes, reticulocytes must synthesize large amounts of hemoglobin, while eliminating numerous cellular components. Exosomes are small secreted vesicles that play an important role in this process of specific elimination. To understand the mechanisms of proteolipidic sorting leading to their biogenesis, we have explored changes in the composition of exosomes released by reticulocytes during their differentiation, in parallel to their physical properties. By combining proteomic and lipidomic approaches, we found dramatic alterations in the composition of the exosomes retrieved over the course of a 7-day in vitro differentiation protocol. Our data support a previously proposed model, whereby in reticulocytes the biogenesis of exosomes involves several distinct mechanisms for the preferential recruitment of particular proteins and lipids and suggest that the respective prominence of those pathways changes over the course of the differentiation process. PMID- 21828047 TI - Reduced expression of adipose triglyceride lipase enhances tumor necrosis factor alpha-induced intercellular adhesion molecule-1 expression in human aortic endothelial cells via protein kinase C-dependent activation of nuclear factor kappaB. AB - We examined the effects of adipose triglyceride lipase (ATGL) on the initiation of atherosclerosis. ATGL was recently identified as a rate-limiting triglyceride (TG) lipase. Mutations in the human ATGL gene are associated with neutral lipid storage disease with myopathy, a rare genetic disease characterized by excessive accumulation of TG in multiple tissues. The cardiac phenotype, known as triglyceride deposit cardiomyovasculopathy, shows massive TG accumulation in both coronary atherosclerotic lesions and the myocardium. Recent reports show that myocardial triglyceride content is significantly higher in patients with prediabetes or diabetes and that ATGL expression is decreased in the obese insulin-resistant state. Therefore, we investigated the effect of decreased ATGL activity on the development of atherosclerosis using human aortic endothelial cells. We found that ATGL knockdown enhanced monocyte adhesion via increased expression of TNFalpha-induced intercellular adhesion molecule-1 (ICAM-1). Next, we determined the pathways (MAPK, PKC, or NFkappaB) involved in ICAM-1 up regulation induced by ATGL knockdown. Both phosphorylation of PKC and degradation of IkappaBalpha were increased in ATGL knockdown human aortic endothelial cells. In addition, intracellular diacylglycerol levels and free fatty acid uptake via CD36 were significantly increased in these cells. Inhibition of the PKC pathway using calphostin C and GF109203X suppressed TNFalpha-induced ICAM-1 expression. In conclusion, we showed that ATGL knockdown increased monocyte adhesion to the endothelium through enhanced TNFalpha-induced ICAM-1 expression via activation of NFkappaB and PKC. These results suggest that reduced ATGL expression may influence the atherogenic process in neutral lipid storage diseases and in the insulin-resistant state. PMID- 21828048 TI - Genome-wide structural analysis reveals novel membrane binding properties of AP180 N-terminal homology (ANTH) domains. AB - An increasing number of cytosolic proteins are shown to interact with membrane lipids during diverse cellular processes, but computational prediction of these proteins and their membrane binding behaviors remains challenging. Here, we introduce a new combinatorial computation protocol for systematic and robust functional prediction of membrane-binding proteins through high throughput homology modeling and in-depth calculation of biophysical properties. The approach was applied to the genomic scale identification of the AP180 N-terminal homology (ANTH) domain, one of the modular lipid binding domains, and prediction of their membrane binding properties. Our analysis yielded comprehensive coverage of the ANTH domain family and allowed classification and functional annotation of proteins based on the differences in local structural and biophysical features. Our analysis also identified a group of plant ANTH domains with unique structural features that may confer novel functionalities. Experimental characterization of a representative member of this subfamily confirmed its unique membrane binding mechanism and unprecedented membrane deforming activity. Collectively, these studies suggest that our new computational approach can be applied to genome-wide functional prediction of other lipid binding domains. PMID- 21828049 TI - Shedding of the Mer tyrosine kinase receptor is mediated by ADAM17 protein through a pathway involving reactive oxygen species, protein kinase Cdelta, and p38 mitogen-activated protein kinase (MAPK). AB - Mer tyrosine kinase (MerTK) is an integral membrane protein that is preferentially expressed by phagocytic cells, where it promotes efferocytosis and inhibits inflammatory signaling. Proteolytic cleavage of MerTK at an unidentified site leads to shedding of its soluble ectodomain (soluble MER; sMER), which can inhibit thrombosis in mice and efferocytosis in vitro. Herein, we show that MerTK is cleaved at proline 485 in murine macrophages. Site-directed deletion of 6 amino acids spanning proline 485 rendered MerTK resistant to proteolysis and suppression of efferocytosis by cleavage-inducing stimuli. LPS is a known inducer of MerTK cleavage, and the intracellular signaling pathways required for this action are unknown. LPS/TLR4-mediated generation of sMER required disintegrin and metalloproteinase ADAM17 and was independent of Myd88, instead requiring TRIF adaptor signaling. LPS-induced cleavage was suppressed by deficiency of NADPH oxidase 2 (Nox2) and PKCdelta. The addition of the antioxidant N-acetyl cysteine inhibited PKCdelta, and silencing of PKCdelta inhibited MAPK p38, which was also required. In a mouse model of endotoxemia, we discovered that LPS induced plasma sMER, and this was suppressed by Adam17 deficiency. Thus, a TRIF-mediated pattern recognition receptor signaling cascade requires NADPH oxidase to activate PKCdelta and then p38, culminating in ADAM17-mediated proteolysis of MerTK. These findings link innate pattern recognition receptor signaling to proteolytic inactivation of MerTK and generation of sMER and uncover targets to test how MerTK cleavage affects efferocytosis efficiency and inflammation resolution in vivo. PMID- 21828050 TI - Ubiquitin ligase activity of Cul3-KLHL7 protein is attenuated by autosomal dominant retinitis pigmentosa causative mutation. AB - Substrate-specific protein degradation mediated by the ubiquitin proteasome system (UPS) is crucial for the proper function of the cell. Proteins are specifically recognized and ubiquitinated by the ubiquitin ligases (E3s) and are then degraded by the proteasome. BTB proteins act as the substrate recognition subunit that recruits their cognate substrates to the Cullin 3-based multisubunit E3s. Recently, it was reported that missense mutations in KLHL7, a BTB-Kelch protein, are related to autosomal dominant retinitis pigmentosa (adRP). However, the involvement of KLHL7 in the UPS and the outcome of the adRP causative mutations were unknown. In this study, we show that KLHL7 forms a dimer, assembles with Cul3 through its BTB and BACK domains, and exerts E3 activity. Lys 48-linked but not Lys-63-linked polyubiquitin chain co-localized with KLHL7, which increased upon proteasome inhibition suggesting that KLHL7 mediates protein degradation via UPS. An adRP-causative missense mutation in the BACK domain of KLHL7 attenuated only the Cul3 interaction but not dimerization. Nevertheless, the incorporation of the mutant as a heterodimer in the Cul3-KLHL7 complex diminished the E3 ligase activity. Together, our results suggest that KLHL7 constitutes a Cul3-based E3 and that the disease-causing mutation inhibits ligase activity in a dominant negative manner, which may lead to the inappropriate accumulation of the substrates targeted for proteasomal degradation. PMID- 21828052 TI - Characterization of the dimerization interface of membrane type 4 (MT4)-matrix metalloproteinase. AB - MT4-MMP (MMP17) belongs to a unique subset of membrane type-matrix metalloproteinases that are anchored to the cell surface via a glycosylphosphatidylinositol moiety. However, little is known about its biochemical properties. Here, we report that MT4-MMP is displayed on the cell surface as a mixed population of monomeric, dimeric, and oligomeric forms. Sucrose gradient fractionation demonstrated that these forms of MT4-MMP are all present in lipid rafts. Mutational and computational analyses revealed that Cys(564), which is present within the stem region, mediates MT4-MMP homodimerization by forming a disulfide bond. Substitution of Cys(564) results in a more rapid MT4-MMP turnover, when compared with the wild-type enzyme, consistent with a role for dimerization in protein stability. Expression of MT4 MMP in Madin-Darby canine kidney cells enhanced cell migration and invasion of Matrigel, a process that requires catalytic activity. However, a serine substitution at Cys(564) did not reduce MT4-MMP-stimulated cell invasion of Matrigel suggesting that homodimerization is not required for this process. Deglycosylation studies showed that MT4-MMP is modified by N-glycosylation. Moreover, inhibition of N-glycosylation by tunicamycin diminished the extent of MT4-MMP dimerization suggesting that N-glycans may confer stability to the dimeric form. Taken together, the data presented here provide a new insight into the characteristics of MT4-MMP and highlight the common and distinct properties of the glycosylphosphatidylinositol-anchored membrane type-matrix metalloproteinases. PMID- 21828051 TI - Pericellular versican regulates the fibroblast-myofibroblast transition: a role for ADAMTS5 protease-mediated proteolysis. AB - The cell and its glycosaminoglycan-rich pericellular matrix (PCM) comprise a functional unit. Because modification of PCM influences cell behavior, we investigated molecular mechanisms that regulate PCM volume and composition. In fibroblasts and other cells, aggregates of hyaluronan and versican are found in the PCM. Dermal fibroblasts from Adamts5(-/-) mice, which lack a versican degrading protease, ADAMTS5, had reduced versican proteolysis, increased PCM, altered cell shape, enhanced alpha-smooth muscle actin (SMA) expression and increased contractility within three-dimensional collagen gels. The myofibroblast like phenotype was associated with activation of TGFbeta signaling. We tested the hypothesis that fibroblast-myofibroblast transition in Adamts5(-/-) cells resulted from versican accumulation in PCM. First, we noted that versican overexpression in human dermal fibroblasts led to increased SMA expression, enhanced contractility, and increased Smad2 phosphorylation. In contrast, dermal fibroblasts from Vcan haploinsufficient (Vcan(hdf/+)) mice had reduced contractility relative to wild type fibroblasts. Using a genetic approach to directly test if myofibroblast transition in Adamts5(-/-) cells resulted from increased PCM versican content, we generated Adamts5(-/-);Vcan(hdf/+) mice and isolated their dermal fibroblasts for comparison with dermal fibroblasts from Adamts5(-/-) mice. In Adamts5(-/-) fibroblasts, Vcan haploinsufficiency or exogenous ADAMTS5 restored normal fibroblast contractility. These findings demonstrate that altering PCM versican content through proteolytic activity of ADAMTS5 profoundly influenced the dermal fibroblast phenotype and may regulate a phenotypic continuum between the fibroblast and its alter ego, the myofibroblast. We propose that a physiological function of ADAMTS5 in dermal fibroblasts is to maintain optimal versican content and PCM volume by continually trimming versican in hyaluronan-versican aggregates. PMID- 21828053 TI - Role of key aromatic residues in the ligand-binding domain of alpha7 nicotinic receptors in the agonist action of beta-amyloid. AB - Soluble beta-amyloid (Abeta) resides in certain regions of the brain at or near picomolar concentration, rising in level during the prodromic stage of Alzheimer disease. Recently, we identified the homomeric alpha7 nicotinic acetylcholine receptor (alpha7-nAChR) as one possible functional target for picomolar Abeta. This study was aimed at addressing which residues in alpha7-nAChRs potentially interact with Abeta to regulate the presynaptic function of this receptor. Site directed mutagenesis was carried out to study the key aromatic residues in the mouse alpha7-nAChR agonist-binding pocket. Mutations of tyrosine188 resulted in a decrease in activation of presynaptic alpha7-nAChRs by ACh and Abeta but with no change in response to nicotine, indicating the critical role of Tyr-188 in presynaptic regulation by Abeta. Coimmunoprecipitation additionally revealed direct binding of Abeta to alpha7-nAChRs and to the Tyr-188 mutant receptor. In contrast, mutations of Tyr-195 in alpha7-nAChR led to decreased activation by nicotine without apparent effects on ACh- or Abeta-induced responses. Agonist induced responses of Tyr-93 mutant alpha7-nAChRs indicated possible interactions of nicotine and Abeta with its hydroxyl group, but there was no change in presynaptic responses after mutation of Trp-149. All of the mutants were shown to be expressed on the plasma membrane using cell surface labeling. Together, these results directly demonstrate an essential role for the aromatic residue Tyr-188 as a key component in the agonist binding domain for the activation of alpha7 nAChRs by Abeta. PMID- 21828054 TI - ATP potentiates competitive inhibition of guanylyl cyclase A and B by the staurosporine analog, Go6976: reciprocal regulation of ATP and GTP binding. AB - Natriuretic peptides and ATP activate and Go6976 inhibits guanylyl cyclase (GC)-A and GC-B. Here, the mechanism of inhibition was determined. Go6976 progressively increased the Michaelis-Menten constant and decreased the Hill coefficient without reducing the maximal velocity of GC-A and GC-B. In the presence of 1 mm ATP, the K(i) was 1 MUm for both enzymes. Inhibition of GC-B was minimal in the absence of ATP, and 1 mm ATP increased the inhibition 4-fold. In a reciprocal manner, 10 MUm Go6976 increased the potency of ATP for GC-B 4-fold. In contrast to a recent study (Duda, T., Yadav, P., and Sharma, R. K. (2010) FEBS J. 277, 2550-2553), neither staurosporine nor Go6976 activated GC-A or GC-B. This is the first study to show that Go6976 reduces GTP binding and the first demonstration of a competitive inhibitor of a receptor guanylyl cyclase. We conclude that Go6976 reduces GTP binding to the catalytic site of GC-A and GC-B and that ATP increases the magnitude of the inhibition. PMID- 21828056 TI - Structural and enzymatic insights into caspase-2 protein substrate recognition and catalysis. AB - Caspase-2, the most evolutionarily conserved member in the human caspase family, may play important roles in stress-induced apoptosis, cell cycle regulation, and tumor suppression. In biochemical assays, caspase-2 uniquely prefers a pentapeptide (such as VDVAD) rather than a tetrapeptide, as required for efficient cleavage by other caspases. We investigated the molecular basis for pentapeptide specificity using peptide analog inhibitors and substrates that vary at the P5 position. We determined the crystal structures of apo caspase-2, caspase-2 in complex with peptide inhibitors VDVAD-CHO, ADVAD-CHO, and DVAD-CHO, and a T380A mutant of caspase-2 in complex with VDVAD-CHO. Two residues, Thr-380 and Tyr-420, are identified to be critical for the P5 residue recognition; mutation of the two residues reduces the catalytic efficiency by about 4- and 40 fold, respectively. The structures also provide a series of snapshots of caspase 2 in different catalytic states, shedding light on the mechanism of capase-2 activation, substrate binding, and catalysis. By comparing the apo and inhibited caspase-2 structures, we propose that the disruption of a non-conserved salt bridge between Glu-217 and the invariant Arg-378 is important for the activation of caspase-2. These findings broaden our understanding of caspase-2 substrate specificity and catalysis. PMID- 21828055 TI - Novel C-terminal motif within Sec7 domain of guanine nucleotide exchange factors regulates ADP-ribosylation factor (ARF) binding and activation. AB - ADP-ribosylation factors (ARFs) and their activating guanine nucleotide exchange factors (GEFs) play key roles in membrane traffic and signaling. All ARF GEFs share a ~200-residue Sec7 domain (Sec7d) that alone catalyzes the GDP to GTP exchange that activates ARF. We determined the crystal structure of human BIG2 Sec7d. A C-terminal loop immediately following helix J (loop>J) was predicted to form contacts with helix H and the switch I region of the cognate ARF, suggesting that loop>J may participate in the catalytic reaction. Indeed, we identified multiple alanine substitutions within loop>J of the full length and/or Sec7d of two large brefeldin A-sensitive GEFs (GBF1 and BIG2) and one small brefeldin A resistant GEF (ARNO) that abrogated binding of ARF and a single alanine substitution that allowed ARF binding but inhibited GDP to GTP exchange. Loop>J sequences are highly conserved, suggesting that loop>J plays a crucial role in the catalytic activity of all ARF GEFs. Using GEF mutants unable to bind ARF, we showed that GEFs associate with membranes independently of ARF and catalyze ARF activation in vivo only when membrane-associated. Our structural, cell biological, and biochemical findings identify loop>J as a key regulatory motif essential for ARF binding and GDP to GTP exchange by GEFs and provide evidence for the requirement of membrane association during GEF activity. PMID- 21828057 TI - Transient depletion of p53 followed by transduction of c-Myc and K-Ras converts ovarian stem-like cells into tumor-initiating cells. AB - Although the existence of tumor-initiating cells (T-ICs) in several types of human cancer has been documented, the contribution of somatic stem cells to the development of T-ICs has remained unclear. Here, we show that normal mouse ovary contains epithelial cell adhesion molecule (EpCAM)-expressing stem-like cells that possess the ability to differentiate into cytokeratin 8 (CK8)-expressing epithelial progeny cells. Furthermore, RNA interference-mediated transient depletion of the tumor suppressor p53 followed by retrovirus-mediated transfer of c-Myc and K-Ras oncogenes in EpCAM-expressing ovarian stem-like cells resulted in the generation of ovarian T-ICs. The established ovarian T-ICs gave rise to hierarchically organized lethal tumors in vivo and were able to undergo peritoneal metastasis. Finally, subsequent RNA interference-mediated knockdown of p53 in tumor cells triggered the expansion of EpCAM-expressing stem-like tumor cells and induced further tumor growth. These data reveal a role for p53 in the development and expansion of ovarian stem-like tumor cells and subsequent malignant progression. PMID- 21828059 TI - Overexpression of Fn14 promotes androgen-independent prostate cancer progression through MMP-9 and correlates with poor treatment outcome. AB - Fibroblast growth factor-inducible 14 (Fn14), a transmembrane receptor binding to the multifunctional cytokine tumor necrosis factor-like weak inducer of apoptosis (TWEAK), is known to modulate many cellular activities including cancer progression. Here, we demonstrated the significant role of Fn14 in invasion, migration and proliferation of androgen-independent prostate cancer (AIPC) cells. Fn14 and its ligand TWEAK were highly expressed in two AIPC cell lines, DU 145 and PC-3, whereas expression was weak in androgen-sensitive LNCaP cells. Fn14 knockdown using small-interfering RNAs attenuated migration, invasion and proliferation and enhanced apoptosis in the AIPC cell lines. Both forced overexpression of Fn14 by stable Fn14 complementary DNA transfection to PC-3 cells (PC-3/Fn14) and ligand activation by recombinant TWEAK in PC-3 cells enhanced invasion. Fn14 was shown to modulate expression of matrix metalloproteinase (MMP)-9, and MMP-9 mediated the invasive potential influenced by Fn14 in PC-3 cells. In vivo, subcutaneous xenografts of PC-3/Fn14 grew significantly faster than xenograft of PC-3/Mock, and the invasive capacity in PC 3/Fn14 was found to be higher than that of PC-3/Mock as evaluated in an invasion model of the diaphragm. Furthermore, the messenger RNA expressions of MMP-9 in PC 3/Fn14 xenografts were significantly higher than those in PC-3/Mock xenografts. Clinically, high expression of Fn14 was significantly associated with higher prostate-specific antigen recurrence rate in patients who underwent radical prostatectomy. In conclusion, the overexpression of Fn14 may contribute to multiple malignant cellular phenotypes associated with prostate cancer (PCa) progression, in part via MMP-9. TWEAK-Fn14 signaling may be a novel therapeutic target of PCa. PMID- 21828058 TI - Decreased microRNA-214 levels in breast cancer cells coincides with increased cell proliferation, invasion and accumulation of the Polycomb Ezh2 methyltransferase. AB - MicroRNAs (miRNAs) are small non-coding RNAs, which regulate gene expression by inhibiting translation or promoting degradation of specific target messenger RNAs (mRNAs). Alteration of the levels of a number of miRNAs is common in solid and hematological tumors. We have shown previously that miR-214 regulates Ezh2 in skeletal muscle and embryonic stem cells. The current study was aimed at examining the role of miR-214 in breast cancer where miR-214 levels are reduced but whether this phenomenon bears a functional relevance is unknown. MiR-214 expression was inversely correlated with Ezh2 mRNA and protein levels in breast cancer cell lines and at least one copy of the miR-214 alleles was found to be deleted in 24% (6/25) of primary breast tumors. Experimental increase of miR-214 in breast cancer cell lines correlated with reduction of Ezh2 protein levels, a known marker of invasion and aggressive breast cancer behavior. Supporting a direct targeting mechanism, miR-214 decreased luciferase activity from a construct containing the Ezh2 3' untranslated region. Expression of miR-214 specifically reduced cell proliferation of breast cancer cells and inhibited the invasive potential of a highly metastatic breast cancer cell line. These findings indicate that reduced miR-214 levels may contribute to breast tumorigenesis by allowing abnormally elevated Ezh2 accumulation and subsequent unchecked cell proliferation and invasion. PMID- 21828060 TI - Selective changes of retroelement expression in human prostate cancer. AB - Retroelements constitute a large part of the human genome. These sequences are mostly silenced in normal cells, but genome-wide DNA hypomethylation in cancers might lead to their re-expression. Whether this re-expression really occurs in human cancers is largely unkown. We therefore investigated expression and DNA methylation of several classes of retroelements in human prostate cancer tissues and cell lines by quantitative reverse transcription-polymerase chain reaction and pyrosequencing, respectively. The most striking finding was strong and generalized increased expression of the HERV-K_22q11.23 provirus in cancers, including de novo expression of a spliced accessory Np9 transcript in some tumors. In parallel, DNA methylation in the long terminal repeat (LTR) decreased. Conversely, HERVK17 expression was significantly diminished in cancer tissues, but this decrease was unrelated to LTR methylation. Expression of both proviruses was restricted to androgen-responsive prostate cancer cell lines and LTRs sequences containing steroid hormone-responsive elements bound the androgen receptor and conferred androgen responsiveness to reporter constructs. Expression of LINE-1 5'-untranslated region (UTR) and 3'-UTR sequences in prostate cancers rather decreased, despite significant hypomethylation of the internal LINE-1 promoter. Increased expression of the young AluYa5 and AluYb8 families was restricted to individual tumors. Our findings demonstrate a surprising specificity of changes in expression and DNA methylation of retroelements in prostate cancer. In particular, LINE-1 hypomethylation does not lead to generalized overexpression, but specific human endogenous retrovirus-K proviruses display conspicuous changes in their expression hinting at significant functions during prostate carcinogenesis. PMID- 21828061 TI - Common variants in RYR1 are associated with left ventricular hypertrophy assessed by electrocardiogram. AB - AIMS: To identify the genetic risk factors that influence the development of electrocardiographic (ECG) left ventricular hypertrophy (LVH), a major risk factor for cardiovascular (CV) morbidity and mortality. METHODS AND RESULTS: We performed a genomewide association study (GWAS) of ECG-LVH, in which the community-based Korea Association REsource (KARE) study (8432 controls and 398 cases) was analysed by Affymetrix SNP array 5.0. The GWAS results were validated in hospital-based samples (597 controls and 207 cases). Fourteen single nucleotide polymorphisms (SNPs) in eight genetic loci (5q35.1, 6p22.3-22.1, 8q24.2, 11p15, 11q21-22.1, 14q12, 17q11.2, and 19q13.1) were associated with ECG LVH in the original GWAS study (P < 1 * 10(-5)). Of these SNPs, 12 were genotyped in the hospital sample. There was consistent association with the 19q13.1 region which contains RYR1 gene. The most significant SNP in the region was rs10500279, which had genomewide significance in the combined GWAS/replication sample [odds ratio = 1.58 (confidence interval: 1.35-1.85), P = 1.0 * 10(-8)]. Mutations in RYR1, which encodes a major Ca(2+) channel in the skeletal muscle, have been reported to correlate with CV diseases. CONCLUSION: We performed the first GWAS for ECG-LVH, implicating the skeletal muscle Ca(2+) channel protein RYR1 as a genetic risk factor. These results might increase our understanding of the development of ECG-LVH. PMID- 21828064 TI - Trends in residential exposure to electromagnetic fields from 2006 to 2009. AB - After measuring extremely low frequency electric and magnetic fields (ELF-EFs, ELF-MFs) and radio frequency electromagnetic fields (RF-EMFs) in 2006, a follow up investigation was done in 2009. Overall, 130 measurements in bedrooms at identical and 83 at changed locations within the same or a neighbouring building were performed. The median of ELF-EFs decreased from 25.15 to 17.35 V m(-1) from 2006 to 2009. The median of all-night ELF-MFs from power supply decreased from 16.86 to 12.76 nT, whereas the arithmetic mean was almost unchanged (+0.1%). No difference in the medians of all-night ELF-MFs of railway current was observed. RF-EMFs increased from 41.35 to 59.56 uW m(-2). Increases primarily occurred in the frequency ranges of Global System for Mobile 900 MHz, Universal Mobile Telecommunications System and Wireless Local Area Network. Television changeover from analogue to digital resulted in a reduction within the Ultra-high Frequency band from 0.47 to 0.35 uW m(-2). The base stations of the recently established terrestrial trunked radio system caused a median of 0.05 uW m(-2). PMID- 21828062 TI - Cardiac imaging: does radiation matter? AB - The use of ionizing radiation in cardiovascular imaging has generated considerable discussion. Radiation should not be considered in isolation, but rather in the context of a careful examination of the benefits, risks, and costs of cardiovascular imaging. Such consideration requires an understanding of some fundamental aspects of the biology, physics, epidemiology, and terminology germane to radiation, as well as principles of radiological protection. This paper offers a concise, contemporary perspective on these areas by addressing pertinent questions relating to radiation and its application to cardiac imaging. PMID- 21828065 TI - The use of a novel nitinol guidewire to facilitate transseptal puncture and left atrial catheterization for catheter ablation procedures. AB - AIMS: An increasing number of transseptal punctures (TSPs) are performed worldwide for atrial ablations. Transseptal punctures can be complex and can be associated with potentially life threatening complications. The purpose of the study was to evaluate the safety and efficacy of a novel transseptal guidewire (TSGW) designed to facilitate TSPs. METHODS AND RESULTS: Transseptal punctures were performed using a SafeSept TSGW passed through a standard TSP apparatus. Transseptal punctures were performed by standard technique with additional use of a TSGW allowing probing of the interatrial septum without needle exposure and penetration of the fossa into the left atrium (LA). Transseptal puncture using the TSGW was performed in 210 patients. Left atrial access was achieved successfully in 205 of 210 patients (97.6%) and in 96.3% of patients undergoing repeat TSP. Left atrial access was achieved with the first pass in 81.2% (mean 1.4 +/- 0.9 passes, range 1-6) using the TSGW. No serious complications were attributable to the use of the TSGW, even in cases of failed TSP. CONCLUSIONS: The TSGW is associated with a high success rate for TSP and may be a useful alternative to transoesophageal or intracardiac echocardiogram-guided TSP. PMID- 21828066 TI - Continuity of insurance coverage and ambulatory care-sensitive hospitalizations/ED visits: evidence from the children's health insurance program. AB - OBJECTIVE: To assess the effects of continuity of insurance coverage on treatment of ambulatory-care sensitive conditions (ACSC). STUDY POPULATION: 42,382 children enrolled in ALL Kids (Alabama Children's Health Insurance Program) for 3 or more years. METHODS: We model annual hospitalizations and ED visits for six ACSCs identified by the AHRQ - bacterial pneumonia, dehydration, perforated appendix, urinary tract infection, gastroenteritis, and severe ear, nose and throat infection. RESULTS: In unadjusted models, we find lower risk of ACSC hospitalizations and ED visits in the second and third years of continuous enrollment. Risk of hospitalization in year 3 was significantly lower for pneumonia (OR 0.608, 95% CI: 0.421-0.878) and gastroenteritis (OR 0.549, 95% CI: 0.404-0.746). These beneficial effects of duration of coverage disappear after controlling for age, year and other enrollee characteristics. CONCLUSIONS: Hospitalizations and ED visits for ACSCs are rare and do not decrease with additional years of coverage. PMID- 21828067 TI - Wristbands as aids to reduce misidentification: an ethnographically guided task analysis. AB - OBJECTIVE: Wristbands are recommended in the UK as a means of verifying patient identity but have been little studied. We aimed to document how wristbands are used in practice. DESIGN: and participants Task analysis of wristband application and use, drawing on qualitative analysis of workplace observation of, and interviews with, clinical and non-clinical staff. SETTING: Two acute district general hospitals in northern England. RESULTS: Our findings indicate high levels of awareness amongst clinical staff of local and national policies on wristband use, but some ambiguity about the details therein. In contrast, non-clinical staff such as ward clerks and porters were less aware of policy, although their actions also expose patients to risks resulting from misidentification. Of seven subtasks identified by the task analysis of wristband application and use, three appeared to offer particular opportunity for error. Making the decision to apply, especially in emergency patients, is important because delay in application can delay correct identification. Advance preparation of wristbands for elective admission without the patient being present can risk erroneous data or misapplication. Lastly, utilization of wristbands to verify patient identity was greater in some clinical circumstances (blood transfusion and medication administration) than in others (before transferring patients around the hospital and during handovers of care). CONCLUSIONS: Wristbands for patient identification are not being used to their full potential. Attention to detail in application and use, especially during handover and transfer, and an appreciation of the role played by 'non-clinical' staff, may offer further gains in patient safety. PMID- 21828068 TI - Phylogenetic utility of the nuclear genes AGAMOUS 1 and PHYTOCHROME B in palms (Arecaceae): an example within Bactridinae. AB - BACKGROUND AND AIMS: Molecular phylogenetic studies of palms (Arecaceae) have not yet provided a fully resolved phylogeny of the family. There is a need to increase the current set of markers to resolve difficult groups such as the Neotropical subtribe Bactridinae (Arecoideae: Cocoseae). We propose the use of two single-copy nuclear genes as valuable tools for palm phylogenetics. METHODS: New primers were developed for the amplification of the AGAMOUS 1 (AG1) and PHYTOCHROME B (PHYB) genes. For the AGAMOUS gene, the paralogue 1 of Elaeis guineensis (EgAG1) was targeted. The region amplified contained coding sequences between the MIKC K and C MADS-box domains. For the PHYB gene, exon 1 (partial sequence) was first amplified in palm species using published degenerate primers for Poaceae, and then specific palm primers were designed. The two gene portions were sequenced in 22 species of palms representing all genera of Bactridinae, with emphasis on Astrocaryum and Hexopetion, the status of the latter genus still being debated. KEY RESULTS: The new primers designed allow consistent amplification and high-quality sequencing within the palm family. The two loci studied produced more variability than chloroplast loci and equally or less variability than PRK, RPBII and ITS nuclear markers. The phylogenetic structure obtained with AG1 and PHYB genes provides new insights into intergeneric relationships within the Bactridinae and the intrageneric structure of Astrocaryum. The Hexopetion clade was recovered as monophyletic with both markers and was weakly supported as sister to Astrocaryum sensu stricto in the combined analysis. The rare Astrocaryum minus formed a species complex with Astrocaryum gynacanthum. Moreover, both AG1 and PHYB contain a microsatellite that could have further uses in species delimitation and population genetics. CONCLUSIONS: AG1 and PHYB provide additional phylogenetic information within the palm family, and should prove useful in combination with other genes to improve the resolution of palm phylogenies. PMID- 21828069 TI - Predicting babies' risk of obesity. PMID- 21828070 TI - Electro-acupuncture at 'Neiguan' (PC6) attenuates liver injury in endotoxaemic rats. AB - BACKGROUND: Intravenous injection of lipopolysaccharide (LPS) stimulates macrophages to release proinflammatory cytokines and nitric oxide (NO). This results in hypotension, vascular hyporeactivity and multiple organ failure (eg, liver injury) in rats. In rats with endotoxin shock, electro-acupuncture (EA) of 'Neiguan' (PC6) retrieved blood pressure and reduced plasma concentrations of NO. The authors evaluated whether EA at PC6 could alleviate the development of liver injury and dysfunction in endotoxic rats. METHODS: A total of 28 male adult Wistar rats were included in this study. Rats received intravenous LPS (10 mg/kg for 4 h) or saline for 4 h followed by EA at PC6 acupuncture point. RESULTS: Elevated biochemical parameters of liver injury and marked infiltration of neutrophils into liver tissues caused by LPS were significantly attenuated by EA. However, hypotension, tachycardia and raised production of plasma NO were not suppressed by EA at PC6. CONCLUSIONS: These results indicate that EA at PC6 should be further investigated as a possible adjuvant therapy for endotoxin induced liver dysfunction. Its mechanism of action needs further investigation. PMID- 21828072 TI - Mitochondrial redox signalling by p66Shc mediates ALS-like disease through Rac1 inactivation. AB - Increased oxidative stress and mitochondrial damage are among the mechanisms whereby mutant SOD1 (mutSOD1) associated with familial forms of amyotrophic lateral sclerosis (ALS) induces motoneuronal death. The 66 kDa isoform of the growth factor adapter Shc (p66Shc) is known to be central in the control of mitochondria-dependent oxidative balance. Here we report that expression of mutSOD1s induces the activation of p66Shc in neuronal cells and that the overexpression of inactive p66Shc mutants protects cells from mutSOD1-induced mitochondrial damage. Most importantly, deletion of p66Shc ameliorates mitochondrial function, delays onset, improves motor performance and prolongs survival in transgenic mice modelling ALS. We also show that p66Shc activation by mutSOD1 causes a strong decrease in the activity of the small GTPase Rac1 through a redox-sensitive regulation. Our results provide new insight into the potential mechanisms of mutSOD1-mediated mitochondrial dysfunction. PMID- 21828071 TI - Characterization of STAT6 target genes in human B cells and lung epithelial cells. AB - Using ChIP Seq, we identified 556 and 467 putative STAT6 target sites in the Burkitt's lymphoma cell line Ramos and in the normal lung epithelial cell line BEAS2B, respectively. We also examined the positions and expression of transcriptional start sites (TSSs) in these cells using our TSS Seq method. We observed that 44 and 132 genes in Ramos and BEAS2B, respectively, had STAT6 binding sites in proximal regions of their previously reported TSSs that were up regulated at the transcriptional level. In addition, 406 and 109 of the STAT6 target sites in Ramos and BEAS2B, respectively, were located in proximal regions of previously uncharacterized TSSs. The target genes identified in Ramos and BEAS2B cells in this study and in Th2 cells in previous studies rarely overlapped and differed in their identity. Interestingly, ChIP Seq analyses of histone modifications and RNA polymerase II revealed that chromatin formed an active structure in regions surrounding the STAT6 binding sites; this event also frequently occurred in different cell types, although neither STAT6 binding nor TSS induction was observed. The rough landscape of STAT6-responsive sites was found to be shaped by chromatin structure, but distinct cellular responses were mainly mediated by distinct sets of transcription factors. PMID- 21828073 TI - Induced pluripotent stem cells (iPSCs) and neurological disease modeling: progress and promises. AB - The systematic generation of neurons from patients with neurological disorders can provide important insights into disease pathology, progression and mechanism. This review will discuss recent progress in modeling neurodegenerative and neurodevelopmental diseases using induced pluripotent stem cells (iPSCs) and highlight some of the current challenges in the field. Combined with other technologies previously used to study brain disease, iPSC modeling has the promise to influence modern medicine on several fronts: early diagnosis, drug development and effective treatment. PMID- 21828074 TI - 'Progress' renders detrimental an ancient mitochondrial DNA genetic variant. AB - A human mitochondrial DNA (mtDNA) transition, m.1555A>G, in the 12S rRNA gene causes non-syndromic hearing loss. However, this pathological mutation is the wild-type allele in orangutan mtDNA. Here we rule out different genetic factors as the reason for its fixation in orangutans and show that aminoglycosides negatively affect the oxidative phosphorylation function by decreasing the synthesis of mtDNA-encoded proteins and the amount and activity of respiratory complex IV. These drugs also diminish the growth rate of orangutan cells. The m.1555G nucleotide is also the wild-type allele in other mammal species and they might be at risk of suffering a mitochondrial disorder if treated with aminoglycosides. Therefore, pharmacogenomic approaches should be used to confirm this possibility. These observations are important for human health. Due to the fact that old age and high frequency are criteria widely used in mitochondrial medicine to rule out a genetic change as being a pathological mutation, our results prevent against simplistic genetic approaches that do not consider the potential effect of environmental conditions. Hence, these results suggest that some ancient and highly frequent human population polymorphisms, such as those defining mtDNA haplogroups, in mitochondrial rRNA genes can be deleterious in association with new environmental conditions. Therefore, as the discovery of ribosomal antibiotics has allowed to fight infectious diseases and this breakthrough can be considered an important scientific advance or 'progress', our results suggest that 'progress' can also have a negative counterpart and render detrimental many of these mtDNA genotypes. PMID- 21828075 TI - Direct-to-consumer personalized genomic testing. AB - Over the past 18 months, there have been notable developments in the direct-to consumer (DTC) genomic testing arena, in particular with regard to issues surrounding governmental regulation in the USA. While commentaries continue to proliferate on this topic, actual empirical research remains relatively scant. In terms of DTC genomic testing for disease susceptibility, most of the research has centered on uptake, perceptions and attitudes toward testing among health care professionals and consumers. Only a few available studies have examined actual behavioral response among consumers, and we are not aware of any studies that have examined response to DTC genetic testing for ancestry or for drug response. We propose that further research in this area is desperately needed, despite challenges in designing appropriate studies given the rapid pace at which the field is evolving. Ultimately, DTC genomic testing for common markers and conditions is only a precursor to the eventual cost-effectiveness and wide availability of whole genome sequencing of individuals, although it remains unclear whether DTC genomic information will still be attainable. Either way, however, current knowledge needs to be extended and enhanced with respect to the delivery, impact and use of increasingly accurate and comprehensive individualized genomic data. PMID- 21828076 TI - A comprehensive functional analysis of PTEN mutations: implications in tumor- and autism-related syndromes. AB - The PTEN (phosphatase and tensin homolog) phosphatase is unique in mammals in terms of its tumor suppressor activity, exerted by dephosphorylation of the lipid second messenger PIP(3) (phosphatidylinositol 3,4,5-trisphosphate), which activates the phosphoinositide 3-kinase/Akt/mTOR (mammalian target of rapamycin) oncogenic pathway. Loss-of-function mutations in the PTEN gene are frequent in human cancer and in the germline of patients with PTEN hamartoma tumor-related syndromes (PHTSs). In addition, PTEN is mutated in patients with autism spectrum disorders (ASDs), although no functional information on these mutations is available. Here, we report a comprehensive in vivo functional analysis of human PTEN using a heterologous yeast reconstitution system. Ala-scanning mutagenesis at the catalytic loops of PTEN outlined the critical role of residues within the P-catalytic loop for PIP(3) phosphatase activity in vivo. PTEN mutations that mimic the P-catalytic loop of mammalian PTEN-like proteins (TPTE, TPIP, tensins and auxilins) affected PTEN function variably, whereas tumor- or PHTS-associated mutations targeting the PTEN P-loop produced complete loss of function. Conversely, Ala-substitutions, as well as tumor-related mutations at the WPD- and TI-catalytic loops, displayed partial activity in many cases. Interestingly, a tumor-related D92N mutation was partially active, supporting the notion that the PTEN Asp92 residue might not function as the catalytic general acid. The analysis of a panel of ASD-associated hereditary PTEN mutations revealed that most of them did not substantially abrogate PTEN activity in vivo, whereas most of PHTS associated mutations did. Our findings reveal distinctive functional patterns among PTEN mutations found in tumors and in the germline of PHTS and ASD patients, which could be relevant for therapy. PMID- 21828078 TI - Maternal separation and gastrointestinal transit time in neonate rats. AB - Gastrointestinal transit times (GItts) were compared in separate litters of 10- and 15-day-old Sprague Dawley rats using barium sulphate. By tracking the leading front of the bolus on radiographs, the gastrocaecal transit times in pups were estimated. To measure the total GItt, the duration from orogastric gavage until an observable defecation of barium sulphate was recorded. The gastrocaecal times for 10-day-old pups maintained with their dam (n = 5) ranged from 4-5 h and those removed from the dam ranged from 2.5-5 h. For 15-day-old pups with their dam (n = 6) and without dam (n = 5), gastrocaecal times ranged from 4-6 h and 3.5-5 h, respectively. Ten-day-old pups that remained with the dam had a GItt of 13.8 +/- 0.9 h and those kept in the absence of the dam had a time of 9.3 +/- 0.7 h. This decrease (P < 0.05) in GItt in the absence of the dam was age-dependent in 10-day old pups, and was not observed (P > 0.05) in 15-day-old pups. The results provide a basis, for the design of future studies involving neonate rat metabolism, to include maternal presence. PMID- 21828077 TI - LRRK2 protein levels are determined by kinase function and are crucial for kidney and lung homeostasis in mice. AB - Mutations in leucine-rich repeat kinase 2 (LRRK2) cause late-onset Parkinson's disease (PD), but the underlying pathophysiological mechanisms and the normal function of this large multidomain protein remain speculative. To address the role of this protein in vivo, we generated three different LRRK2 mutant mouse lines. Mice completely lacking the LRRK2 protein (knock-out, KO) showed an early onset (age 6 weeks) marked increase in number and size of secondary lysosomes in kidney proximal tubule cells and lamellar bodies in lung type II cells. Mice expressing a LRRK2 kinase-dead (KD) mutant from the endogenous locus displayed similar early-onset pathophysiological changes in kidney but not lung. KD mutants had dramatically reduced full-length LRRK2 protein levels in the kidney and this genetic effect was mimicked pharmacologically in wild-type mice treated with a LRRK2-selective kinase inhibitor. Knock-in (KI) mice expressing the G2019S PD associated mutation that increases LRRK2 kinase activity showed none of the LRRK2 protein level and histopathological changes observed in KD and KO mice. The autophagy marker LC3 remained unchanged but kidney mTOR and TCS2 protein levels decreased in KD and increased in KO and KI mice. Unexpectedly, KO and KI mice suffered from diastolic hypertension opposed to normal blood pressure in KD mice. Our findings demonstrate a role for LRRK2 in kidney and lung physiology and further show that LRRK2 kinase function affects LRRK2 protein steady-state levels thereby altering putative scaffold/GTPase activity. These novel aspects of peripheral LRRK2 biology critically impact ongoing attempts to develop LRRK2 selective kinase inhibitors as therapeutics for PD. PMID- 21828079 TI - Rodent laparoscopy: refinement for rodent drug studies and model development, and monitoring of neoplastic, inflammatory and metabolic diseases. AB - The refinement of surgical techniques represents a key opportunity to improve the welfare of laboratory rodents, while meeting legal and ethical obligations. Current methods used for monitoring intra-abdominal disease progression in rodents usually involve euthanasia at various time-points for end of study, one time individual tissue collections. Most rodent organ tumour models are developed by the introduction of tumour cells via laparotomy or via ultrasound-guided indirect visualization. Ischaemic rodent models are often generated using laparotomies. This approach requires a high number of rodents, and in some instances introduces high degrees of morbidity and mortality, thereby increasing study variability and expense. Most importantly, most laparotomies do not promote the highest level of rodent welfare. Recent improvements in laparoscopic equipment and techniques have enabled the adaptation of laparoscopy for rodent procedures. Laparoscopy, which is considered the gold standard for many human abdominal procedures, allows for serial biopsy collections from the same animal, results in decreased pain and tissue trauma as well as quicker postsurgical recovery, and preserves immune function in comparison to the same procedures performed by laparotomy. Laparoscopy improves rodent welfare, decreases inter animal variability, thereby reducing the number of required animals, allows for the replacement of larger species, decreases expense and improves data yield. This review article compares rodent laparotomy and laparoscopic surgical methods, and describes the utilization of laparoscopy for the development of cancer models and assessment of disease progression to improve data collection and animal welfare. In addition, currently available rodent laparoscopic equipment and instrumentation are presented. PMID- 21828080 TI - How the worm got its pharynx: phylogeny, classification and Bayesian assessment of character evolution in Acoela. AB - Acoela are marine microscopic worms currently thought to be the sister taxon of all other bilaterians. Acoels have long been used as models in evolutionary scenarios, and generalized conclusions about acoel and bilaterian ancestral features are frequently drawn from studies of single acoel species. There is no extensive phylogenetic study of Acoela and the taxonomy of the 380 species is chaotic. Here we use two nuclear ribosomal genes and one mitochondrial gene in combination with 37 morphological characters in an analysis of 126 acoel terminals (about one-third of the described species) to estimate the phylogeny and character evolution of Acoela. We present an estimate of posterior probabilities for ancestral character states at 31 control nodes in the phylogeny. The overall reconstruction signal based on the shape of the posterior distribution of character states was computed for all morphological characters and control nodes to assess how well these were reconstructed. The body-wall musculature appears more clearly reconstructed than the reproductive organs. Posterior similarity to the root was calculated by averaging the divergence between the posterior distributions at the nodes and the root over all morphological characters. Diopisthoporidae is the sister group to all other acoels and has the highest posterior similarity to the root. Convolutidae, including several "model" acoels, is most divergent. Finally, we present a phylogenetic classification of Acoela down to the family level where six previous family level taxa are synonymized. PMID- 21828081 TI - Guided tree topology proposals for Bayesian phylogenetic inference. AB - Increasingly, large data sets pose a challenge for computationally intensive phylogenetic methods such as Bayesian Markov chain Monte Carlo (MCMC). Here, we investigate the performance of common MCMC proposal distributions in terms of median and variance of run time to convergence on 11 data sets. We introduce two new Metropolized Gibbs Samplers for moving through "tree space." MCMC simulation using these new proposals shows faster average run time and dramatically improved predictability in performance, with a 20-fold reduction in the variance of the time to estimate the posterior distribution to a given accuracy. We also introduce conditional clade probabilities and demonstrate that they provide a superior means of approximating tree topology posterior probabilities from samples recorded during MCMC. PMID- 21828083 TI - Taxonomic structure of the fossil record is shaped by sampling bias. AB - Understanding biases that affect how species are partitioned into higher taxa is critical for much of paleobiology, as higher taxa are commonly used to estimate species diversity through time. We test the validity of using higher taxa as a proxy for species diversity for the first time by examining one of the best fossil records we have, that of deep-sea microfossils. Using a new, taxonomically standardized, data set of coccolithophorid species and genera recorded from 143 deep-sea drilling sites in the North Atlantic, Caribbean, and Mediterranean, we show that there is a two-stepped change in the ratio of species to genera over the last 150 myr. This change is highly unexpected and correlates strongly with changes in both the number of deep-sea sites yielding coccolithophorids that have been studied and with the number of taxonomists who have published on those sections. The same pattern is present in both structurally complex heterococcoliths and the simpler nannoliths, suggesting that increasing complexity is not the driving factor. As a stepped species-to-genus ratio exists even after subsampling to standardize either the numbers of sites or numbers of papers, both factors must be contributing substantially to the observed pattern. Although some limited biological signature from major extinction events can be recognized from changes in the species-to-genus ratio, the numbers of sites and the numbers of taxonomists combined explain some 82% of the observed variation over long periods of geological time. Such a strong correlation argues against using raw species-to-genus ratios to infer biological processes without taking sampling into account and suggests that higher taxa cannot be taken as unbiased proxies for species diversity. PMID- 21828084 TI - Analysis of ratios in multivariate morphometry. AB - The analysis of ratios of body measurements is deeply ingrained in the taxonomic literature. Whether for plants or animals, certain ratios are commonly indicated in identification keys, diagnoses, and descriptions. They often provide the only means for separation of cryptic species that mostly lack distinguishing qualitative characters. Additionally, they provide an obvious way to study differences in body proportions, as ratios reflect geometric shape differences. However, when it comes to multivariate analysis of body measurements, for instance, with linear discriminant analysis (LDA) or principal component analysis (PCA), interpretation using body ratios is difficult. Both techniques are commonly applied for separating similar taxa or for exploring the structure of variation, respectively, and require standardized raw or log-transformed variables as input. Here, we develop statistical procedures for the analysis of body ratios in a consistent multivariate statistical framework. In particular, we present algorithms adapted to LDA and PCA that allow the interpretation of numerical results in terms of body proportions. We first introduce a method called the "LDA ratio extractor," which reveals the best ratios for separation of two or more groups with the help of discriminant analysis. We also provide measures for deciding how much of the total differences between individuals or groups of individuals is due to size and how much is due to shape. The second method, a graphical tool called the "PCA ratio spectrum," aims at the interpretation of principal components in terms of body ratios. Based on a similar idea, the "allometry ratio spectrum" is developed which can be used for studying the allometric behavior of ratios. Because size can be defined in different ways, we discuss several concepts of size. Central to this discussion is Jolicoeur's multivariate generalization of the allometry equation, a concept that was derived only with a heuristic argument. Here we present a statistical derivation of the allometric size vector using the method of least squares. The application of the above methods is extensively demonstrated using published data sets from parasitic wasps and rock crabs. PMID- 21828082 TI - Phylogenetic and coalescent strategies of species delimitation in snubnose darters (Percidae: Etheostoma). AB - The rapid accumulation of multilocus data sets has led to dramatic advances in methodologies for estimating evolutionary relationships among closely related species, but relatively less advancement has been made in methods for discriminating between competing species delimitation hypotheses. Multilocus data sets provide an advantage in testing species delimitation scenarios because they offer a direct test of species monophyly and aid in the biological interpretation of such phenomena as allele-sharing and deep coalescent events. Most species tree estimation methods that are designed to analyze multilocus data sets require the a priori assignment of individuals to species categories and therefore do not provide a strategy to directly test competing species delimitation scenarios. An approach was recently proposed that utilizes a coalescent-based species tree estimation method to inform species delimitation decisions by comparing likelihood scores that measure the fit of gene trees within a given species tree. We use a multilocus nuclear and mitochondrial DNA sequence data set to both reexamine a recently proposed species delimitation scenario in the Etheostoma simoterum species complex and test the utility of species tree estimation methods in testing species delimitation hypotheses. Descriptions of species in the E. simoterum species complex of snubnose darters, a group of six teleost freshwater fish species, are based largely on male nuptial coloration. Most of the putative species are nonmonophyletic at every examined locus. Using a novel combination of Bayesian-estimated gene tree topologies, Bayesian phylogenetic species tree inferences, coalescent simulations, and examination of phenotypic variation, we assess the occurrence of shared alleles among species, and we propose that results from our analyses support a three-species rather than a six-species delimitation scenario in the E. simoterum complex. We found that comparing likelihood scores from the species tree estimation approach used across many potential delimitation scenarios resulted in a systematic bias toward over splitting in the E. simoterum complex and failed to support a species delimitation scenario that was consistent with geography, phenotype, or any previous species delimitation hypothesis. Despite common expectations, we demonstrate that application of molecular approaches to species delimitation can result in the recognition of fewer, instead of a larger number of species. In addition, our analyses highlight the importance of phenotypic character information in providing an independent assessment of alternative species delimitation hypotheses in the E. simoterum species complex. PMID- 21828085 TI - NetDS: a Cytoscape plugin to analyze the robustness of dynamics and feedforward/feedback loop structures of biological networks. AB - SUMMARY: NetDS is a novel Cytoscape plugin that conveniently simulates dynamics related to robustness, and examines structural properties with respect to feedforward/feedback loops. It can evaluate how robustly a network sustains a stable state against mutations by employing a Boolean network model. In addition, the plugin can examine all feedforward/feedback loops appearing in a network and determine whether or not a pair of loops is coupled. Random networks can also be generated to evaluate whether or not an interesting finding in real biological networks is significantly random. AVAILABILITY: NetDS is freely available for non commercial purposes at http://netds.sourceforge.net/. CONTACT: kwonyk@ulsan.ac.kr SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 21828086 TI - Exome sequencing-based copy-number variation and loss of heterozygosity detection: ExomeCNV. AB - MOTIVATION: The ability to detect copy-number variation (CNV) and loss of heterozygosity (LOH) from exome sequencing data extends the utility of this powerful approach that has mainly been used for point or small insertion/deletion detection. RESULTS: We present ExomeCNV, a statistical method to detect CNV and LOH using depth-of-coverage and B-allele frequencies, from mapped short sequence reads, and we assess both the method's power and the effects of confounding variables. We apply our method to a cancer exome resequencing dataset. As expected, accuracy and resolution are dependent on depth-of-coverage and capture probe design. AVAILABILITY: CRAN package 'ExomeCNV'. CONTACT: fsathira@fas.harvard.edu; snelson@ucla.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 21828087 TI - OrganismTagger: detection, normalization and grounding of organism entities in biomedical documents. AB - MOTIVATION: Semantic tagging of organism mentions in full-text articles is an important part of literature mining and semantic enrichment solutions. Tagged organism mentions also play a pivotal role in disambiguating other entities in a text, such as proteins. A high-precision organism tagging system must be able to detect the numerous forms of organism mentions, including common names as well as the traditional taxonomic groups: genus, species and strains. In addition, such a system must resolve abbreviations and acronyms, assign the scientific name and if possible link the detected mention to the NCBI Taxonomy database for further semantic queries and literature navigation. RESULTS: We present the OrganismTagger, a hybrid rule-based/machine learning system to extract organism mentions from the literature. It includes tools for automatically generating lexical and ontological resources from a copy of the NCBI Taxonomy database, thereby facilitating system updates by end users. Its novel ontology-based resources can also be reused in other semantic mining and linked data tasks. Each detected organism mention is normalized to a canonical name through the resolution of acronyms and abbreviations and subsequently grounded with an NCBI Taxonomy database ID. In particular, our system combines a novel machine-learning approach with rule-based and lexical methods for detecting strain mentions in documents. On our manually annotated OT corpus, the OrganismTagger achieves a precision of 95%, a recall of 94% and a grounding accuracy of 97.5%. On the manually annotated corpus of Linnaeus-100, the results show a precision of 99%, recall of 97% and grounding accuracy of 97.4%. AVAILABILITY: The OrganismTagger, including supporting tools, resources, training data and manual annotations, as well as end user and developer documentation, is freely available under an open source license at http://www.semanticsoftware.info/organism-tagger. CONTACT: witte@semanticsoftware.info. PMID- 21828088 TI - A molecular design that stabilizes active state in bacterial allosteric L-lactate dehydrogenases. AB - l-Lactate dehydrogenase (l-LDH) of Lactobacillus casei (LCLDH) is a typical bacterial allosteric l-LDH that requires fructose 1,6-bisphosphate (FBP) for its enzyme activity. A mutant LCLDH was designed to introduce an inter-subunit salt bridge network at the Q-axis subunit interface, mimicking Lactobacillus pentosus non-allosteric l-LDH (LPLDH). The mutant LCLDH exhibited high catalytic activity with hyperbolic pyruvate saturation curves independently of FBP, and virtually the equivalent K(m) and V(m) values at pH 5.0 to those of the fully activated wild-type enzyme with FBP, although the K(m) value was slightly improved with FBP or Mn(2+) at pH 7.0. The mutant enzyme exhibited a markedly higher apparent denaturating temperature (T(1/2)) than the wild-type enzyme in the presence of FBP, but showed an even lower T(1/2) without FBP, where it exhibited higher activation enthalpy of inactivation (DeltaH(?)). This result is consistent with the fact that the active state is more unstable than the inactive state in allosteric equilibrium of LCLDH. The LPLDH-like network appears to be conserved in many bacterial non-allosteric l-LDHs and dimeric l-malate dehydrogenases, and thus to be a key for the functional divergence of bacterial l-LDHs during evolution. PMID- 21828089 TI - Notch signaling: simplicity in design, versatility in function. AB - Notch signaling is evolutionarily conserved and operates in many cell types and at various stages during development. Notch signaling must therefore be able to generate appropriate signaling outputs in a variety of cellular contexts. This need for versatility in Notch signaling is in apparent contrast to the simple molecular design of the core pathway. Here, we review recent studies in nematodes, Drosophila and vertebrate systems that begin to shed light on how versatility in Notch signaling output is generated, how signal strength is modulated, and how cross-talk between the Notch pathway and other intracellular signaling systems, such as the Wnt, hypoxia and BMP pathways, contributes to signaling diversity. PMID- 21828090 TI - The evolution of nervous system patterning: insights from sea urchin development. AB - Recent studies of the sea urchin embryo have elucidated the mechanisms that localize and pattern its nervous system. These studies have revealed the presence of two overlapping regions of neurogenic potential at the beginning of embryogenesis, each of which becomes progressively restricted by separate, yet linked, signals, including Wnt and subsequently Nodal and BMP. These signals act to specify and localize the embryonic neural fields - the anterior neuroectoderm and the more posterior ciliary band neuroectoderm - during development. Here, we review these conserved nervous system patterning signals and consider how the relationships between them might have changed during deuterostome evolution. PMID- 21828091 TI - Satellite cells, connective tissue fibroblasts and their interactions are crucial for muscle regeneration. AB - Muscle regeneration requires the coordinated interaction of multiple cell types. Satellite cells have been implicated as the primary stem cell responsible for regenerating muscle, yet the necessity of these cells for regeneration has not been tested. Connective tissue fibroblasts also are likely to play a role in regeneration, as connective tissue fibrosis is a hallmark of regenerating muscle. However, the lack of molecular markers for these fibroblasts has precluded an investigation of their role. Using Tcf4, a newly identified fibroblast marker, and Pax7, a satellite cell marker, we found that after injury satellite cells and fibroblasts rapidly proliferate in close proximity to one another. To test the role of satellite cells and fibroblasts in muscle regeneration in vivo, we created Pax7(CreERT2) and Tcf4(CreERT2) mice and crossed these to R26R(DTA) mice to genetically ablate satellite cells and fibroblasts. Ablation of satellite cells resulted in a complete loss of regenerated muscle, as well as misregulation of fibroblasts and a dramatic increase in connective tissue. Ablation of fibroblasts altered the dynamics of satellite cells, leading to premature satellite cell differentiation, depletion of the early pool of satellite cells, and smaller regenerated myofibers. Thus, we provide direct, genetic evidence that satellite cells are required for muscle regeneration and also identify resident fibroblasts as a novel and vital component of the niche regulating satellite cell expansion during regeneration. Furthermore, we demonstrate that reciprocal interactions between fibroblasts and satellite cells contribute significantly to efficient, effective muscle regeneration. PMID- 21828092 TI - An absolute requirement for Pax7-positive satellite cells in acute injury-induced skeletal muscle regeneration. AB - Skeletal muscle tissue provides mechanical force for locomotion of all vertebrate animals. It is prone to damage from acute physical trauma and physiological stress. To cope with this, it possesses a tremendous capacity for rapid and effective repair that is widely held to be accomplished by the satellite cells lying between the muscle fiber plasmalemma and the basement membrane. Cell transplantation and lineage-tracing studies have demonstrated that Pax7 expressing (Pax7(+)) satellite cells can repair damaged muscle tissue repeatedly after several bouts of acute injury. These findings provided evidence that Pax7(+) cells are muscle stem cells. However, stem cells from a variety of other origins are also reported to contribute to myofibers upon engraftment into muscles, questioning whether satellite cells are the only stem cell source for muscle regeneration. Here, we have engineered genetic ablation of Pax7(+) cells to test whether there is any significant contribution to muscle regeneration after acute injury from cells other than this source. We find that such elimination of Pax7(+) cells completely blocks regenerative myogenesis either following injury to the tibialis anterior (TA) muscle or after transplantation of extensor digitorum longus (EDL) muscles into nude mice. As Pax7 is specifically expressed in satellite cells, we conclude that they are essential for acute injury-induced muscle regeneration. It remains to be established whether there is any significant role for stem cells of other origins. The implications of our results for muscle stem cell-based therapy are discussed. PMID- 21828093 TI - Pax7-expressing satellite cells are indispensable for adult skeletal muscle regeneration. AB - Distinct cell populations with regenerative capacity have been reported to contribute to myofibres after skeletal muscle injury, including non-satellite cells as well as myogenic satellite cells. However, the relative contribution of these distinct cell types to skeletal muscle repair and homeostasis and the identity of adult muscle stem cells remain unknown. We generated a model for the conditional depletion of satellite cells by expressing a human diphtheria toxin receptor under control of the murine Pax7 locus. Intramuscular injection of diphtheria toxin during muscle homeostasis, or combined with muscle injury caused by myotoxins or exercise, led to a marked loss of muscle tissue and failure to regenerate skeletal muscle. Moreover, the muscle tissue became infiltrated by inflammatory cells and adipocytes. This localised loss of satellite cells was not compensated for endogenously by other cell types, but muscle regeneration was rescued after transplantation of adult Pax7(+) satellite cells alone. These findings indicate that other cell types with regenerative potential depend on the presence of the satellite cell population, and these observations have important implications for myopathic conditions and stem cell-based therapeutic approaches. PMID- 21828095 TI - A LIM-homeobox gene is required for differentiation of Wnt-expressing cells at the posterior end of the planarian body. AB - Planarians have high regenerative ability, which is dependent on pluripotent adult somatic stem cells called neoblasts. Recently, canonical Wnt/beta-catenin signaling was shown to be required for posterior specification, and Hedgehog signaling was shown to control anterior-posterior polarity via activation of the Djwnt1/P-1 gene at the posterior end of planarians. Thus, various signaling molecules play an important role in planarian stem cell regulation. However, the molecular mechanisms directly involved in stem cell differentiation have remained unclear. Here, we demonstrate that one of the planarian LIM-homeobox genes, Djislet, is required for the differentiation of Djwnt1/P-1-expressing cells from stem cells at the posterior end. RNA interference (RNAi)-treated planarians of Djislet [Djislet(RNAi)] show a tail-less phenotype. Thus, we speculated that Djislet might be involved in activation of the Wnt signaling pathway in the posterior blastema. When we carefully examined the expression pattern of Djwnt1/P 1 by quantitative real-time PCR during posterior regeneration, we found two phases of Djwnt1/P-1 expression: the first phase was detected in the differentiated cells in the old tissue in the early stage of regeneration and then a second phase was observed in the cells derived from stem cells in the posterior blastema. Interestingly, Djislet is expressed in stem cell-derived DjPiwiA- and Djwnt1/P-1-expressing cells, and Djislet(RNAi) only perturbed the second phase. Thus, we propose that Djislet might act to trigger the differentiation of cells expressing Djwnt1/P-1 from stem cells. PMID- 21828094 TI - Effective fiber hypertrophy in satellite cell-depleted skeletal muscle. AB - An important unresolved question in skeletal muscle plasticity is whether satellite cells are necessary for muscle fiber hypertrophy. To address this issue, a novel mouse strain (Pax7-DTA) was created which enabled the conditional ablation of >90% of satellite cells in mature skeletal muscle following tamoxifen administration. To test the hypothesis that satellite cells are necessary for skeletal muscle hypertrophy, the plantaris muscle of adult Pax7-DTA mice was subjected to mechanical overload by surgical removal of the synergist muscle. Following two weeks of overload, satellite cell-depleted muscle showed the same increases in muscle mass (approximately twofold) and fiber cross-sectional area with hypertrophy as observed in the vehicle-treated group. The typical increase in myonuclei with hypertrophy was absent in satellite cell-depleted fibers, resulting in expansion of the myonuclear domain. Consistent with lack of nuclear addition to enlarged fibers, long-term BrdU labeling showed a significant reduction in the number of BrdU-positive myonuclei in satellite cell-depleted muscle compared with vehicle-treated muscle. Single fiber functional analyses showed no difference in specific force, Ca(2+) sensitivity, rate of cross-bridge cycling and cooperativity between hypertrophied fibers from vehicle and tamoxifen treated groups. Although a small component of the hypertrophic response, both fiber hyperplasia and regeneration were significantly blunted following satellite cell depletion, indicating a distinct requirement for satellite cells during these processes. These results provide convincing evidence that skeletal muscle fibers are capable of mounting a robust hypertrophic response to mechanical overload that is not dependent on satellite cells. PMID- 21828097 TI - The maintenance and regeneration of the planarian excretory system are regulated by EGFR signaling. AB - The maintenance of organs and their regeneration in case of injury are crucial to the survival of all animals. High rates of tissue turnover and nearly unlimited regenerative capabilities make planarian flatworms an ideal system with which to investigate these important processes, yet little is known about the cell biology and anatomy of their organs. Here we focus on the planarian excretory system, which consists of internal protonephridial tubules. We find that these assemble into complex branching patterns with a stereotyped succession of cell types along their length. Organ regeneration is likely to originate from a precursor structure arising in the blastema, which undergoes extensive branching morphogenesis. In an RNAi screen of signaling molecules, we identified an EGF receptor (Smed-EGFR-5) as a crucial regulator of branching morphogenesis and maintenance. Overall, our characterization of the planarian protonephridial system establishes a new paradigm for regenerative organogenesis and provides a platform for exploring its functional and evolutionary homologies with vertebrate excretory systems. PMID- 21828096 TI - VEGF signalling controls GnRH neuron survival via NRP1 independently of KDR and blood vessels. AB - Gonadotropin-releasing hormone (GnRH) neurons are neuroendocrine cells that are born in the nasal placode during embryonic development and migrate through the nose and forebrain to the hypothalamus, where they regulate reproduction. Many molecular pathways that guide their migration have been identified, but little is known about the factors that control the survival of the migrating GnRH neurons as they negotiate different environments. We previously reported that the class 3 semaphorin SEMA3A signals through its neuropilin receptors, NRP1 and NRP2, to organise the axons that guide migrating GnRH neurons from their birthplace into the brain. By combining analysis of genetically altered mice with in vitro models, we show here that the alternative neuropilin ligand VEGF164 promotes the survival of migrating GnRH neurons by co-activating the ERK and AKT signalling pathways through NRP1. We also demonstrate that survival signalling relies on neuronal, but not endothelial, NRP1 expression and that it occurs independently of KDR, the main VEGF receptor in blood vessels. Therefore, VEGF164 provides survival signals directly to developing GnRH neurons, independently of its role in blood vessels. Finally, we show that the VEGF164-mediated neuronal survival and SEMA3A-mediated axon guidance cooperate to ensure that migrating GnRH neurons reach the brain. Thus, the loss of both neuropilin ligands leads to an almost complete failure to establish the GnRH neuron system. PMID- 21828098 TI - Integrins are necessary for the development and maintenance of the glial layers in the Drosophila peripheral nerve. AB - Peripheral nerve development involves multiple classes of glia that cooperate to form overlapping glial layers paired with the deposition of a surrounding extracellular matrix (ECM). The formation of this tubular structure protects the ensheathed axons from physical and pathogenic damage and from changes in the ionic environment. Integrins, a major family of ECM receptors, play a number of roles in the development of myelinating Schwann cells, one class of glia ensheathing the peripheral nerves of vertebrates. However, the identity and the role of the integrin complexes utilized by the other classes of peripheral nerve glia have not been determined in any animal. Here, we show that, in the peripheral nerves of Drosophila melanogaster, two integrin complexes (alphaPS2betaPS and alphaPS3betaPS) are expressed in the different glial layers and form adhesion complexes with integrin-linked kinase and Talin. Knockdown of the common beta subunit (betaPS) using inducible RNAi in all glial cells results in lethality and glial defects. Analysis of integrin complex function in specific glial layers showed that loss of betaPS in the outermost layer (the perineurial glia) results in a failure to wrap the nerve, a phenotype similar to that of Matrix metalloproteinase 2-mediated degradation of the ECM. Knockdown of betaPS integrin in the innermost wrapping glia causes a loss of glial processes around axons. Together, our data suggest that integrins are employed in different glial layers to mediate the development and maintenance of the protective glial sheath in Drosophila peripheral nerves. PMID- 21828099 TI - Ancestral functions of Delta/Notch signaling in the formation of body and leg segments in the cricket Gryllus bimaculatus. AB - Delta/Notch signaling controls a wide spectrum of developmental processes, including body and leg segmentation in arthropods. The various functions of Delta/Notch signaling vary among species. For instance, in Cupiennius spiders, Delta/Notch signaling is essential for body and leg segmentation, whereas in Drosophila fruit flies it is involved in leg segmentation but not body segmentation. Therefore, to gain further insight into the functional evolution of Delta/Notch signaling in arthropod body and leg segmentation, we analyzed the function of the Delta (Gb'Delta) and Notch (Gb'Notch) genes in the hemimetabolous, intermediate-germ cricket Gryllus bimaculatus. We found that Gb'Delta and Gb'Notch were expressed in developing legs, and that RNAi silencing of Gb'Notch resulted in a marked reduction in leg length with a loss of joints. Our results suggest that the role of Notch signaling in leg segmentation is conserved in hemimetabolous insects. Furthermore, we found that Gb'Delta was expressed transiently in the posterior growth zone of the germband and in segmental stripes earlier than the appearance of wingless segmental stripes, whereas Gb'Notch was uniformly expressed in early germbands. RNAi knockdown of Gb'Delta or Gb'Notch expression resulted in malformation in body segments and a loss of posterior segments, the latter probably due to a defect in posterior growth. Therefore, in the cricket, Delta/Notch signaling might be required for proper morphogenesis of body segments and posterior elongation, but not for specification of segment boundaries. PMID- 21828100 TI - The THO complex is required for nucleolar integrity in Drosophila spermatocytes. AB - The THO complex is a conserved multisubunit protein complex that functions in the formation of export-competent messenger ribonucleoprotein (mRNP). Although the complex has been studied extensively at the single-cell level, its exact role at the multicellular organism level has been poorly understood. Here, we isolated a novel Drosophila male sterile mutant, garmcho (garm). Positional cloning indicated that garm encodes a subunit of the Drosophila THO complex, THOC5. Flies lacking THOC5 showed a meiotic arrest phenotype with severe nucleolar disruption in primary spermatocytes. A functional GFP-tagged fusion protein, THOC5-GFP, revealed a unique pattern of THOC5 localization near the nucleolus. The nucleolar distribution of a testis-specific TATA binding protein (TBP)-associated factor (tTAF), SA, which is required for the expression of genes responsible for sperm differentiation, was severely disrupted in mutant testes lacking THOC5. But THOC5 appeared to be largely dispensable for the expression and nuclear export of either tTAF target mRNAs or tTAF-independent mRNAs. Taken together, our study suggests that the Drosophila THO complex is necessary for proper spermatogenesis by contribution to the establishment or maintenance of nucleolar integrity rather than by nuclear mRNA export in spermatocytes. PMID- 21828102 TI - Membrane transport, sensing and signaling in plant adaptation to environmental stress. AB - Plants are generally well adapted to a wide range of environmental conditions. Even though they have notably prospered in our planet, stressful conditions such as salinity, drought and cold or heat, which are increasingly being observed worldwide in the context of the ongoing climate changes, limit their growth and productivity. Behind the remarkable ability of plants to cope with these stresses and still thrive, sophisticated and efficient mechanisms to re-establish and maintain ion and cellular homeostasis are involved. Among the plant arsenal to maintain homeostasis are efficient stress sensing and signaling mechanisms, plant cell detoxification systems, compatible solute and osmoprotectant accumulation and a vital rearrangement of solute transport and compartmentation. The key role of solute transport systems and signaling proteins in cellular homeostasis is addressed in the present work. The full understanding of the plant cell complex defense mechanisms under stress may allow for the engineering of more tolerant plants or the optimization of cultivation practices to improve yield and productivity, which is crucial at the present time as food resources are progressively scarce. PMID- 21828101 TI - Motoneurons are essential for vascular pathfinding. AB - The neural and vascular systems share common guidance cues that have direct and independent signaling effects on nerves and endothelial cells. Here, we show that zebrafish Netrin 1a directs Dcc-mediated axon guidance of motoneurons and that this neural guidance function is essential for lymphangiogenesis. Specifically, Netrin 1a secreted by the muscle pioneers at the horizontal myoseptum (HMS) is required for the sprouting of dcc-expressing rostral primary motoneuron (RoP) axons and neighboring axons along the HMS, adjacent to the future trajectory of the parachordal chain (PAC). These axons are required for the formation of the PAC and, subsequently, the thoracic duct. The failure to form the PAC in netrin 1a or dcc morphants is phenocopied by laser ablation of motoneurons and is rescued both by cellular transplants and overexpression of dcc mRNA. These results provide a definitive example of the requirement of axons in endothelial guidance leading to the parallel patterning of nerves and vessels in vivo. PMID- 21828104 TI - A heme oxygenase isoform is essential for aerobic growth in the cyanobacterium Synechocystis sp. PCC 6803: modes of differential operation of two isoforms/enzymes to adapt to low oxygen environments in cyanobacteria. AB - Heme oxygenase (HO) catalyzes the oxygen-dependent cleavage of heme to produce biliverdin IXalpha in phycobilin biosynthesis. In the genome of the cyanobacterium Synechocystis sp. PCC 6803 there are two genes, ho1 (sll1184) and ho2 (sll1875), encoding HO isoforms. Reverse transcription-PCR indicated that ho1 is constitutively expressed, and ho2 is induced under micro-oxic conditions. A mutant lacking ho1 (Deltaho1) failed to grow under aerobic conditions while it did grow at a significantly slower rate than the wild type under anaerobic (micro oxic) conditions. When micro-oxically grown Deltaho1 was incubated under aerobic conditions, the cells underwent chlorosis with a significant decrease in phycocyanin accompanied by anomalous accumulation of protoporphyrin IX. These results suggested that HO1 is essential for aerobic growth as the sole HO and is dispensable under micro-oxic conditions. A mutant lacking ho2 (Deltaho2) grew under both aerobic and micro-oxic conditions like the wild type at low light intensity (50 MUmol(photon) m-2 s-1). At higher light intensity (120 MUmol(photon) m-2 s-1) the Deltaho2 mutant showed significant growth retardation under micro-oxic conditions. It is suggested that HO2 operates as a dominant HO under high light and micro-oxic environments and acts as an accessory HO at low light intensity. Constitutive expression of HO2 in a neutral site of the chromosome restored aerobic growth of Deltaho1, suggesting that HO2 has an activity high enough to substitute for HO1 under aerobic conditions. The differential operation of two isoforms/enzymes in cyanobacterial tetrapyrrole biosynthesis to adapt to low oxygen environments is discussed, including three other reactions. PMID- 21828103 TI - Regulation of NAD(P)H dehydrogenase-dependent cyclic electron transport around PSI by NaHSO3 at low concentrations in tobacco chloroplasts. AB - Although bisulfite at low concentrations (L-NaHSO3) has been found to increase the cyclic electron transport around PSI (CET), its regulative mechanism remains unknown. In this work, the role of L-NaHSO3 (0.1-500 MUM) in NAD(P)H dehydrogenase-dependent CET (the NDH pathway) was investigated. After treatment of tobacco leaves with L-NaHSO3, the NDH pathway, as reflected by a transient post-illumination increase in Chl fluorescence, the dark reduction of P700+ after far-red light and the amount of NDH, was increased after the light-dark-light transition, but was slightly lowered under continuous light. Meanwhile, the linear electron transport (LET) was accelerated by L-NaHSO3 under both the light regimes. Experiments in thylakoids further demonstrated that both LET, monitored by light-dependent oxygen uptake, and CET, as determined from the NADPH-dependent oxygen uptake and dark reduction of P700+, were enhanced by L-NaHSO3 and the enhancements were abolished by superoxide dismutase. Furthermore, L-NaHSO3 induced CET was partially impaired in thylakoids of the DeltandhCKJ mutant, while L-NaHSO3-induced LET was not affected. Based on these results, we propose that the photooxidation of L-NaHSO3 initiated by superoxide anions in PSI regulates NDH pathway to maintain efficient photosynthesis. PMID- 21828105 TI - Achievements and challenges in understanding plant abiotic stress responses and tolerance. AB - Intensive research over the last decade has gradually unraveled the mechanisms that underlie how plants react to environmental adversity. Genes involved in many of the essential steps of the stress response have been identified and characterized. In particular, the recent discovery of ABA receptors, progress in understanding the transcriptional and post-transcriptional regulation of stress responsive gene expression, and studies on hormone interactions under stress have facilitated addressing the molecular basis of how plant cells respond to abiotic stress. Here, we summarize recent research progress on these issues, especially focusing on progress related to the essential and classically important signaling pathways and genes. Despite this wealth of achievements, many challenges remain not only for the further elucidation of stress response mechanisms but also for evaluation of the natural genetic variations and associating them with specific gene functions. Finally, the proper application of this knowledge to benefit humans and agriculture is another important issue that lies ahead. Collaborative wisdom and efforts are needed to confront these challenges. PMID- 21828107 TI - Single-port video-assisted thoracoscopic left upper lobectomy. AB - Video-assisted thoracic surgery (VATS) anatomic lobectomy for lung cancer was initially described in 1993. Since then, many thoracic surgery departments have progressively adopted this technique, although the approach description may vary greatly among them. Most of surgeons use three incisions but the lobectomy can be performed by only one port, especially when it is performed by surgeons experienced in double-port technique. Lower lobes are the easiest cases to perform. To the best of our knowledge this is the first report of a single-port upper lobectomy with no rib spreading. PMID- 21828106 TI - RSOsPR10 expression in response to environmental stresses is regulated antagonistically by jasmonate/ethylene and salicylic acid signaling pathways in rice roots. AB - Plant roots play important roles not only in the absorption of water and nutrients, but also in stress tolerance. Previously, we identified RSOsPR10 as a root-specific pathogenesis-related (PR) protein induced by drought and salt treatments in rice. Transcripts and proteins of RSOsPR10 were strongly induced by jasmonate (JA) and the ethylene (ET) precursor 1-aminocyclopropane-1-carboxylic acid (ACC), while salicylic acid (SA) almost completely suppressed these inductions. Immunohistochemical analyses showed that RSOsPR10 strongly accumulated in cortex cells surrounding the vascular system of roots, and this accumulation was also suppressed when SA was applied simultaneously with stress or hormone treatments. In the JA-deficient mutant hebiba, RSOsPR10 expression was up-regulated by NaCl, wounding, drought and exogenous application of JA. This suggested the involvement of a signal transduction pathway that integrates JA and ET signals in plant defense responses. Expression of OsERF1, a transcription factor in the JA/ET pathway, was induced earlier than that of RSOsPR10 after salt, JA and ACC treatments. Simultaneous SA treatment strongly inhibited the induction of RSOsPR10 expression and, to a lesser extent, induction of OsERF1 expression. These results suggest that JA/ET and SA pathways function in the stress-responsive induction of RSOsPR10, and that OsERF1 may be one of the transcriptional factors in the JA/ET pathway. PMID- 21828108 TI - Learning what works in surgical cryoablation of atrial fibrillation: results of different application techniques and benefits of prospective follow-up. AB - Atrial fibrillation (AF) in cardiac surgical patients is detrimental in the long perspective. Concomitant surgical ablation of AF is recommended in guidelines and performed in most centers. The article describes the experiences in a single institution with concomitant surgical argon-based cryoablation in 115 patients using three different application techniques (epicardial left atrium, endocardial left atrium, biatrial cryo-maze) and a structured local follow-up to one year postoperatively. Results showed cryoablation to be safe with few complications related to the ablation procedure and few thromboembolic events. In this study, a complete biatrial lesion set according to the classic Cox-maze III (CM III) lesion pattern yielded a higher success rate than left atrial procedures. At 12 months, patients in sinus or pacing rhythm, free of AF without antiarrhythmic drugs, were 27/39 (69%), 24/32 (74%) and 36/44 (82%) in the EpiLA, EndoLA and cryo-maze groups, respectively. A consistent prospective follow-up is essential not only for research purposes but also for assessing the local results of AF surgery in everyday practice. It may direct and develop the surgical ablation program, guide individual postoperative arrhythmia management and is needed to increase overall quality of surgical AF ablation. PMID- 21828109 TI - Mechanical versus chemical pleurodesis for management of primary spontaneous pneumothorax evaluated with thoracic echography. AB - The current study is designed to compare the effectiveness of brushing the pleura vs. instillation of minocycline for the management of primary spontaneous pneumothorax, and to assess the sensitivity of echography in defining areas of defects. Blebectomy and pleurodesis were carried out thoracoscopically on 84 patients. In group A (42 patients), abrasions were induced using a sponge on a long ring forceps. Group B (42 patients) received intrapleural instillation of minocycline. Echography was carried out two weeks after discharge and then repeated two weeks later. Follow-up ranged between 28 and 39 months. Two patients were excluded from group A for incomplete follow-up. In group A, five patients (12%) showed areas of free mobility of the lung on first echography. At the second examination, three (7% of the total) showed the same areas of mobility; one patient developed an attack of localized pneumothorax after 32 and another after 45 weeks. Each had three adjacent areas of free mobility. In group B, two patients each showed one area of free mobility on the first and second examinations but no recurrence during follow-up. The two groups had comparable chest drainage, postoperative hospital stay and complication rates. The patients in group B demonstrated a trend towards a decreased rate of prolonged air leaks (2% vs. 5%; P=0.100). Thus, pleurodesis by instillation of minocycline as a part of thoracoscopy is more effective than brushing the pleura. Thoracic echography is a highly sensitive method for assessing the effectiveness of pleurodesis. PMID- 21828110 TI - Cohort profile: the northern Swedish cohort. PMID- 21828111 TI - Parenting behavior, child functioning, and health behaviors in preadolescents with type 1 diabetes. AB - OBJECTIVE: To examine the association of critical parenting behaviors with preadolescent reported depressive symptoms, self-efficacy, and self-care behaviors in youth with type 1 diabetes (T1D). METHOD: A total of 84 youth with T1D, ages 9-11 years, completed the Diabetes Family Behavior Checklist, Child Depression Inventory, Self-Efficacy for Diabetes scale, and Self-Care Inventory during a baseline assessment for a randomized controlled trial of an intervention to promote adherence. RESULTS: Preadolescents who reported more critical parenting behaviors reported more depressive symptoms and lower self-efficacy. The relationship between critical parenting and self-efficacy was partially mediated by depressive symptoms. In a second model, depressive symptoms were associated with lower self-efficacy and fewer self-care behaviors. The relationship between depressive symptoms and self-care was fully mediated by self efficacy. CONCLUSIONS: Critical parenting behaviors are associated with preadolescents' psychological well-being, which has implications for self-care. Clinical implications include decreasing critical parenting behaviors and monitoring preadolescents with T1D for depressive symptoms. PMID- 21828112 TI - Neural circuitry underlying affective response to peer feedback in adolescence. AB - Peer feedback affects adolescents' behaviors, cognitions and emotions. We examined neural circuitry underlying adolescents' emotional response to peer feedback using a functional neuroimaging paradigm whereby, 36 adolescents (aged 9 17 years) believed they would interact with unknown peers postscan. Neural activity was expected to vary based on adolescents' perceptions of peers and feedback type. Ventrolateral prefrontal cortex (vlPFC) activity was found when adolescents indicated how they felt following feedback (acceptance or rejection) from peers of low vs high interest. Greater activation in both cortical (e.g. superior temporal gyrus, insula, anterior cingulate) and subcortical (e.g. striatum, thalamus) regions emerged in response to acceptance vs rejection feedback. Response to acceptance also varied by age and gender in similar regions (e.g. superior temporal gyrus, fusiform, insula), with greater age-related increases in activation to acceptance vs rejection for females than males. Affective response to rejection vs acceptance did not yield significantly greater neural activity in any region. vlPFC response suggests cognitive flexibility in reappraising initial perceptions of peers following feedback. Striatal response suggests that acceptance is a potent social reward for adolescents, an interpretation supported by more positive self-reported affective response to acceptance than rejection from high- but not low-interest peers. PMID- 21828113 TI - 11C-NS14492 as a novel PET radioligand for imaging cerebral alpha7 nicotinic acetylcholine receptors: in vivo evaluation and drug occupancy measurements. AB - Small-molecule alpha(7) nicotinic acetylcholine receptor (alpha(7)nAChR) agonists are currently validated for use as treatment for cognitive disturbances in schizophrenia and in Alzheimer disease. A suitable radiolabeled alpha(7)nAChR PET tracer would be important for in vivo quantification of alpha(7)nAChR binding in humans and to measure alpha(7)nAChR occupancy of alpha(7)nAChR drug candidates. Here, we present the radiosynthesis and in vivo evaluation of (11)C-NS14492 as a selective alpha(7)nAChR PET radioligand. METHODS: The high-affinity alpha(7)nAChR selective partial agonist NS14492 was radiolabeled by methylation of its desmethyl precursor using (11)C-methyl triflate. Female Danish Landrace pigs were studied at baseline and after intravenous administration of blocking doses of either the alpha(7)nAChR partial agonist SSR180711 or the unlabeled NS14492. (11)C-NS14492 was given as an intravenous bolus injection, and the pigs were scanned for 90 min both at baseline and in the blocked conditions. Arterial blood was collected during the scanning, plasma was counted, and parent compound fraction was determined with radio-high-performance liquid chromatography. PET data were quantified with a graphical analysis with arterial input; (11)C-NS14492 regional distribution volumes were calculated, and alpha(7)nAChR occupancy was determined using an occupancy plot. RESULTS: (11)C-NS14492 had a high uptake in the pig brain, with the highest binding in the cerebral cortex and thalamus in accordance with alpha(7)nAChR distribution. Pretreatment with NS14492 and SSR180711 consistently decreased distribution volumes of (11)C-NS14492 in all examined regions, in a dose-dependent manner, supporting the finding that the radioligand binds selectively to alpha(7)nAChR in vivo. CONCLUSION: We report here that (11)C-NS14492 is the first, to our knowledge, PET radioligand for alpha(7)nAChR showing a dose-dependent decline in cerebral binding after receptor blockade. This compound is considered a promising PET tracer for in vivo measurements of alpha(7)nAChR binding in the human brain. PMID- 21828114 TI - Radioimmunotherapy confers long-term survival to lymphoma patients with acceptable toxicity: registry analysis by the International Radioimmunotherapy Network. AB - The Radioimmunotherapy Network (RIT-N) is a Web-based, international registry collecting long-term observational data about radioimmunotherapy-treated patients with malignant lymphoma outside randomized clinical studies. The RIT-N collects unbiased data on treatment indications, disease stages, patients' conditions, lymphoma subtypes, and hematologic side effects of radioimmunotherapy treatment. METHODS: RIT-N is located at the University of Gottingen, Germany, and collected data from 14 countries. Data were entered by investigators into a Web-based central database managed by an independent clinical research organization. RESULTS: Patients (1,075) were enrolled from December 2006 until November 2009, and 467 patients with an observation time of at least 12 mo were included in the following analysis. Diagnoses were as follows: 58% follicular lymphoma and 42% other B-cell lymphomas. The mean overall survival was 28 mo for follicular lymphoma and 26 mo for other lymphoma subtypes. Hematotoxicity was mild for hemoglobin (World Health Organization grade II), with a median nadir of 10 g/dL, but severe (World Health Organization grade III) for platelets and leukocytes, with a median nadir of 7,000/MUL and 2.2/MUL, respectively. CONCLUSION: Clinical usage of radioimmunotherapy differs from the labeled indications and can be assessed by this registry, enabling analyses of outcome and toxicity data beyond clinical trials. This analysis proves that radioimmunotherapy in follicular lymphoma and other lymphoma subtypes is a safe and efficient treatment option. PMID- 21828115 TI - MRI-based attenuation correction for whole-body PET/MRI: quantitative evaluation of segmentation- and atlas-based methods. AB - PET/MRI is an emerging dual-modality imaging technology that requires new approaches to PET attenuation correction (AC). We assessed 2 algorithms for whole body MRI-based AC (MRAC): a basic MR image segmentation algorithm and a method based on atlas registration and pattern recognition (AT&PR). METHODS: Eleven patients each underwent a whole-body PET/CT study and a separate multibed whole body MRI study. The MR image segmentation algorithm uses a combination of image thresholds, Dixon fat-water segmentation, and component analysis to detect the lungs. MR images are segmented into 5 tissue classes (not including bone), and each class is assigned a default linear attenuation value. The AT&PR algorithm uses a database of previously aligned pairs of MRI/CT image volumes. For each patient, these pairs are registered to the patient MRI volume, and machine learning techniques are used to predict attenuation values on a continuous scale. MRAC methods are compared via the quantitative analysis of AC PET images using volumes of interest in normal organs and on lesions. We assume the PET/CT values after CT-based AC to be the reference standard. RESULTS: In regions of normal physiologic uptake, the average error of the mean standardized uptake value was 14.1% +/- 10.2% and 7.7% +/- 8.4% for the segmentation and the AT&PR methods, respectively. Lesion-based errors were 7.5% +/- 7.9% for the segmentation method and 5.7% +/- 4.7% for the AT&PR method. CONCLUSION: The MRAC method using AT&PR provided better overall PET quantification accuracy than the basic MR image segmentation approach. This better quantification was due to the significantly reduced volume of errors made regarding volumes of interest within or near bones and the slightly reduced volume of errors made regarding areas outside the lungs. PMID- 21828116 TI - An OHSS-Free Clinic by segmentation of IVF treatment. AB - Published data indicate a significant increase in ovarian hyperstimulation syndrome globally. The occurrence of approximately three maternal deaths per 100,000 stimulated women has been reported, and extrapolation of these figures to a global situation would give an impressive number. The syndrome can be erased by applying ovarian stimulation using the combination of GnRH antagonist with GnRH agonist to trigger ovulation. In this case, the strategy is to freeze all of the oocytes or embryos for later use. PMID- 21828117 TI - The use of morphokinetics as a predictor of embryo implantation. AB - BACKGROUND: Time-lapse observation presents an opportunity for optimizing embryo selection based on morphological grading as well as providing novel kinetic parameters, which may further improve accurate selection of viable embryos. The objective of this retrospective study was to identify the morphokinetic parameters specific to embryos that were capable of implanting. In order to compare a large number of embryos, with minimal variation in culture conditions, we have used an automatic embryo monitoring system. METHODS: Using a tri-gas IVF incubator with a built-in camera designed to automatically acquire images at defined time points, we have simultaneously monitored up to 72 individual embryos without removing the embryos from the controlled environment. Images were acquired every 15 min in five different focal planes for at least 64 h for each embryo. We have monitored the development of transferred embryos from 285 couples undergoing their first ICSI cycle. The total number of transferred embryos was 522, of which 247 either failed to implant or fully implanted, with full implantation meaning that all transferred embryos in a treatment implanted. RESULTS: A detailed retrospective analysis of cleavage times, blastomere size and multinucleation was made for the 247 transferred embryos with either failed or full implantation. We found that several parameters were significantly correlated with subsequent implantation (e.g. time of first and subsequent cleavages as well as the time between cleavages). The most predictive parameters were: (i) time of division to 5 cells, t5 (48.8-56.6 h after ICSI); (ii) time between division to 3 cells and subsequent division to 4 cells, s2 (<= 0.76 h) and (iii) duration of cell cycle two, i.e. time between division to 2 cells and division to 3 cells, cc2 (<= 11.9 h). We also observed aberrant behavior such as multinucleation at the 4 cell stage, uneven blastomere size at the 2 cell stage and abrupt cell division to three or more cells, which appeared to largely preclude implantation. CONCLUSIONS: The image acquisition and time-lapse analysis system makes it possible to determine exact timing of embryo cleavages in a clinical setting. We propose a multivariable model based on our findings to classify embryos according to their probability of implantation. The efficacy of this classification will be evaluated in a prospective randomized study that ultimately will determine if implantation rates can be improved by time-lapse analysis. PMID- 21828118 TI - Prognostic relevance of RUNX1 mutations in T-cell acute lymphoblastic leukemia. AB - The runt-related transcription factor 1, RUNX1, is crucial in the development of myeloid and lymphoid cell lineages and has been reported to be mutated in myeloid malignancies in approximately 30% of cases. In this study, the mutational status of RUNX1 was investigated in 128 acute lymphoblastic leukemia patients. We detected a mutation rate of 18.3% (13 of 71) in patients with T-cell acute lymphoblastic leukemia, 3.8% (2 of 52) in patients with B-cell acute lymphoblastic leukemia and no mutation (0 of 5) in patients with natural killer cell leukemia, respectively. In T-cell acute lymphoblastic leukemia patients, RUNX1 mutations were significantly associated with higher age (P=0.017) and lower white blood cell count (P=0.038). Moreover, an inferior outcome was observed in the subgroup of early T-cell acute lymphoblastic leukemia patients carrying RUNX1 mutations for overall survival (P=0.043). In conclusion, RUNX1 mutations are an important novel biomarker for a comprehensive characterization of T-cell acute lymphoblastic leukemia with poor prognostic impact and have implications for use also in monitoring disease. PMID- 21828119 TI - Isolated erythrocytosis: study of 67 patients and identification of three novel germ-line mutations in the prolyl hydroxylase domain protein 2 (PHD2) gene. AB - The oxygen sensing pathway modulates erythropoietin expression. In normal cells, intracellular oxygen tensions are directly sensed by prolyl hydroxylase domain (PHD)-containing proteins. PHD2 isozyme has a key role in tagging hypoxia inducible factor (HIF)-alpha subunits for polyubiquitination and proteasomal degradation. Erythrocytosis-associated PHD2 mutations reduce hydroxylation of HIF alpha. The investigation of 67 patients with isolated erythrocytosis, either sporadic or familial, allowed the identification of three novel mutations in the catalytic domain of the PHD2 protein. All new mutations are germ-line, heterozygous and missense, and code for a predicted full length mutant PHD2 protein. Identification of the disease-causing genes will be of critical importance for a better classification of familial and acquired erythrocytosis, offering additional insight into the erythropoietin regulating oxygen sensing pathway. PMID- 21828121 TI - CNR2 functional variant (Q63R) influences childhood immune thrombocytopenic purpura. AB - Immune thrombocytopenic purpura is an acquired autoimmune disorder that is the most common cause of thrombocytopenia in children. The endocannabinoid system is involved in immune regulation. We evaluated a common missense variant (CAA/CGG; Q63R) of the gene encoding the cannabinoid receptor type 2 (GeneID 1269) in 190 children with immune thrombocytopenic purpura and 600 healthy controls. The allelic frequencies and genotype distribution of the polymorphism in the patients were significant compared to control samples (P=0.006 and P=0.0001, respectively). Interestingly, when acute and chronic immune thrombocytopenic purpura patients were analyzed separately with respect to controls, a significant overrepresentation of the RR genotype and of the R allele was observed only for the chronic form (P=0.00021 and P=0.011, respectively). The relative odds ratio suggested the risk of developing chronic form was more than double in immune thrombocytopenic purpura children homozygous for the variant (odds ratio=2.349, 95% CI: 1.544-3.573; P<0.001). PMID- 21828120 TI - Management of fertility in patients treated for Hodgkin's lymphoma. AB - The risk of developing premature ovarian failure and azoospermia is a major concern in long-term survivors treated for Hodgkin's lymphoma. Alkylating chemotherapy containing procarbazine and/or cyclophosphamide causes prolonged azoospermia in 90-100% of men and premature ovarian failure in 5-25% of women under the age of 30. The risk of infertility increases with the cumulative dose of alkylating agents and the risk is high after salvage therapy including conditioning and autologous or allogeneic transplantation. The doxorubicin bleomycin-vinblastine-dacarbazine regimen is associated with a lower risk of gonadal damage; the rate of infertility is less than 10%. The risk of premature ovarian failure is limited after the doxorubicin-bleomycin-vinblastine dacarbazine regimen. However, age is an important factor; women over 30 years of age are at a much higher risk of ovarian failure. Semen cryopreservation should be routinely offered, especially before initial treatment with bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisolone or salvage therapy with high-dose chemotherapy and autologous transplantation. For women with a stable partner, in vitro fertilization for embryo cryopreservation is a routine procedure but can only be offered to a small number of patients and requires a delay in treatment initiation for at least four weeks. Cryopreservation of mature or immature oocytes remains experimental. Ovarian tissue cryopreservation is promising but has so far resulted in only a small number of pregnancies and births. This method, usually involving the removal of an entire ovary, is only proposed before treatment leading to a high risk of infertility. Analogs of LHRH were investigated in order to preserve fertility in women but are not recommended in the absence of studies demonstrating their effectiveness. The risk of secondary infertility should be discussed with patients from the time of the diagnosis and requires multidisciplinary collaboration between hematologists and Assisted Reproductive Techniques (ART) teams. PMID- 21828123 TI - Durable complete molecular remission of chronic myeloid leukemia following dasatinib cessation, despite adverse disease features. AB - Patients with chronic myeloid leukemia, treated with imatinib, who have a durable complete molecular response, might remain in complete molecular response after stopping treatment. Previous reports of patients stopping treatment in complete molecular response have included only patients with a good response to imatinib. We describe 3 patients with stable complete molecular response on dasatinib treatment following imatinib failure. Two of the 3 patients remain in complete molecular response more than 12 months after stopping dasatinib. In these 2 patients we used highly sensitive patient-specific BCR-ABL1 DNA PCR to show that the leukemic clone remains detectable, as we have previously shown in imatinib treated patients. Dasatinib-associated immunological phenomena, such as the emergence of clonal T-cell populations, were observed both in one patient who relapsed and in one patient in remission. Our results suggest that the characteristics of complete molecular response on dasatinib treatment may be similar to that achieved with imatinib, at least in patients with adverse disease features. PMID- 21828122 TI - N-cadherin-mediated interaction with multiple myeloma cells inhibits osteoblast differentiation. AB - BACKGROUND: Multiple myeloma is a hematologic malignancy characterized by a clonal expansion of malignant plasma cells in the bone marrow, which is accompanied by the development of osteolytic lesions and/or diffuse osteopenia. The intricate bi-directional interaction with the bone marrow microenvironment plays a critical role in sustaining the growth and survival of myeloma cells during tumor progression. Identification and functional analysis of the (adhesion) molecules involved in this interaction will provide important insights into the pathogenesis of multiple myeloma. DESIGN AND METHODS: Multiple myeloma cell lines and patients' samples were analyzed for expression of the adhesion molecule N-cadherin by immunoblotting, flow cytometry, immunofluorescence microscopy, immunohistochemistry and expression microarray. In addition, by means of blocking antibodies and inducible RNA interference we studied the functional consequence of N-cadherin expression for the myeloma cells, by analysis of adhesion, migration and growth, and for the bone marrow microenvironment, by analysis of osteogenic differentiation. RESULTS: The malignant plasma cells in approximately half of the multiple myeloma patients, belonging to specific genetic subgroups, aberrantly expressed the homophilic adhesion molecule N-cad herin. N-cadherin-mediated cell-substrate or homotypic cell-cell adhesion did not contribute to myeloma cell growth in vitro. However, N-cadherin directly mediated the bone marrow localization/retention of myeloma cells in vivo, and facilitated a close interaction between myeloma cells and N-cadherin-positive osteoblasts. Furthermore, this N-cadherin-mediated interaction contributed to the ability of myeloma cells to inhibit osteoblastogenesis. CONCLUSIONS: Taken together, our data show that myeloma cells frequently display aberrant expression of N-cadherin and that N-cadherin mediates the interaction of myeloma cells with the bone marrow microenvironment, in particular the osteoblasts. This N-cadherin-mediated interaction inhibits osteoblast differentiation and may play an important role in the pathogenesis of myeloma bone disease. PMID- 21828124 TI - High VLA-4 expression is associated with adverse outcome and distinct gene expression changes in childhood B-cell precursor acute lymphoblastic leukemia at first relapse. AB - BACKGROUND: Resistance to therapy and subsequent relapse remain major challenges in the clinical management of relapsed childhood acute lymphoblastic leukemia. As the bone marrow environment plays an important role in survival and chemotherapy resistance of leukemia cells by activating different signaling pathways, such as the VLA-4 and PI3K/Akt pathways, we studied the prognostic and biological impact of VLA-4 expression in leukemia cells from children with relapsed B-cell precursor acute lymphoblastic leukemia and its influence on the sensitivity of the leukemia cells to drugs. DESIGN AND METHODS: VLA-4 expression was quantified by real-time polymerase chain reaction in leukemia cells from 56 patients with relapsed acute lymphoblastic leukemia enrolled in the ALL-REZ BFM 2002 trial of the Berlin-Frankfurt-Munster study group. Gene expression changes related to VLA 4 expression were investigated by microarray-based mRNA profiling. The effect of VLA-4 signaling on proliferation and drug resistance was studied in co-cultures of leukemia and stromal cells. RESULTS: High expression of VLA-4 at first relapse was associated with adverse prognostic factors, poor molecular response to therapy and significantly worse probabilities of event-free and overall survival. VLA-4 expression was an independent prognostic parameter. Comparing gene expression profiles of leukemia cells with high versus low VLA-4 expression, we identified 27 differentially expressed genes primarily involved in the PI3K/Akt, ephrin and Rho GTPase pathways. Blocking of VLA-4 signaling in combination with cytarabine treatment abolished the growth supportive effect of stromal cells. CONCLUSIONS: Our results show that high VLA-4 expression is a marker of poor prognosis and a potential therapeutic target in children with relapsed acute lymphoblastic leukemia and confirm that cellular interactions and biological effects related to VLA-4 play a decisive role in the survival of leukemia cells and response to therapy. (ClinicalTrials.gov identifier: NCT00114348). PMID- 21828125 TI - Low expression of MN1 associates with better treatment response in older patients with de novo cytogenetically normal acute myeloid leukemia. AB - Low MN1 expression bestows favorable prognosis in younger adults with cytogenetically normal acute myeloid leukemia (CN-AML), but its prognostic significance in older patients is unknown. We analyzed pretherapy MN1 expression in 140 older (>= 60 years) de novo CN-AML patients treated on cytarabine/daunorubicin-based protocols. Low MN1 expressers had higher complete remission (CR) rates (P = .001), and longer overall survival (P = .03) and event free survival (EFS; P = .004). In multivariable models, low MN1 expression was associated with better CR rates and EFS. The impact of MN1 expression on overall survival and EFS was predominantly in patients 70 years of age or older, with low MN1 expressers with mutated NPM1 having the best outcome. The impact of MN1 expression was also observed in the Intermediate-I, but not the Favorable group of the European LeukemiaNet classification, where low MN1 expressers had CR rates and EFS similar to those of Favorable group patients. MN1 expresser-status associated gene- and microRNA-expression signatures revealed underexpression of drug resistance and adverse outcome predictors, and overexpression of HOX genes and HOX-gene-embedded microRNAs in low MN1 expressers. We conclude that low MN1 expression confers better prognosis in older CN-AML patients and may refine the European LeukemiaNet classification. Biologic features associated with MN1 expression may help identify new treatment targets. PMID- 21828126 TI - A randomized trial comparing standard versus high-dose daunorubicin induction in patients with acute myeloid leukemia. AB - We conducted a phase 3 randomized trial comparing 2 different doses of daunorubicin as induction chemotherapy in young adults (60 years of age or younger) with acute myeloid leukemia (AML). Of 383 patients who were analyzed, 189 received standard-dose daunorubicin (SD-DN, 45 mg/m2 per day times 3 days) and 194 received high-dose daunorubicin (HD-DN, 90 mg/m2 per day times 3 days) in addition to cytarabine (200 mg/m2 per day times 7 days) to induce complete remission (CR). The CR rates were 72.0% in the SD-DN arm and 82.5% in the HD-DN arm (P = .014). At a median follow-up of 52.6 months, overall (OS) and event-free (EFS) survival were higher in the HD-DN arm than in the SD-DN arm (OS, 46.8% vs 34.6%, P = .030; EFS, 40.8% vs 28.4%, P = .030). Differences in CR rate and both OS and EFS remained significant after adjusting for other variables (CR, hazard ratio [HR], 1.802, P = .024; OS, HR, 0.739, P = .032; EFS, HR, 0.774, P = .048). The survival benefits of HD-DN therapy were evident principally in patients with intermediate-risk cytogenetic features. The toxicity profiles were similar in the 2 arms. In conclusion, HD-DN improved both the CR rate and survival duration compared with SD-DN in young adults with AML. This study is registered at www.clinicaltrials.gov as #NCT00474006. PMID- 21828127 TI - Functional human regulatory T cells fail to control autoimmune inflammation due to PKB/c-akt hyperactivation in effector cells. AB - During the last decade research has focused on the application of FOXP3(+) regulatory T cells (Tregs) in the treatment of autoimmune disease. However, thorough functional characterization of these cells in patients with chronic autoimmune disease, especially at the site of inflammation, is still missing. Here we studied Treg function in patients with juvenile idiopathic arthritis (JIA) and observed that Tregs from the peripheral blood as well as the inflamed joints are fully functional. Nevertheless, Treg-mediated suppression of cell proliferation and cytokine production by effector cells from the site of inflammation was severely impaired, because of resistance to suppression. This resistance to suppression was not caused by a memory phenotype of effector T cells or activation status of antigen presenting cells. Instead, activation of protein kinase B (PKB)/c-akt was enhanced in inflammatory effector cells, at least partially in response to TNFalpha and IL-6, and inhibition of this kinase restored responsiveness to suppression. We are the first to show that PKB/c-akt hyperactivation causes resistance of effector cells to suppression in human autoimmune disease. Furthermore, these findings suggest that for a Treg enhancing strategy to be successful in the treatment of autoimmune inflammation, resistance because of PKB/c-akt hyperactivation should be targeted as well. PMID- 21828129 TI - Extracellular matrix structure and nano-mechanics determine megakaryocyte function. AB - Cell interactions with matrices via specific receptors control many functions, with chemistry, physics, and membrane elasticity as fundamental elements of the processes involved. Little is known about how biochemical and biophysical processes integrate to generate force and, ultimately, to regulate hemopoiesis into the bone marrow-matrix environment. To address this hypothesis, in this work we focus on the regulation of MK development by type I collagen. By atomic force microscopy analysis, we demonstrate that the tensile strength of fibrils in type I collagen structure is a fundamental requirement to regulate cytoskeleton contractility of human MKs through the activation of integrin-alpha2beta1 dependent Rho-ROCK pathway and MLC-2 phosphorylation. Most importantly, this mechanism seemed to mediate MK migration, fibronectin assembly, and platelet formation. On the contrary, a decrease in mechanical tension caused by N acetylation of lysine side chains in type I collagen completely reverted these processes by preventing fibrillogenesis. PMID- 21828128 TI - Cell-intrinsic role for IFN-alpha-STAT1 signals in regulating murine Peyer patch plasmacytoid dendritic cells and conditioning an inflammatory response. AB - Plasmacytoid dendritic cells (pDCs) reside in bone marrrow and lymphoid organs in homeostatic conditions and typically secrete abundant quantities of type I interferons (IFNs) on Toll-like receptor triggering. Recently, a pDC population was identified within Peyer patches (PPs) of the gut that is distinguished by its lack of IFN production; however, the relationship of PP pDCs to pDCs in other organs has been unclear. We report that PP pDCs are derived from common DC progenitors and accumulate in response to Fms-like tyrosine kinase 3 ligand, yet appear divergent in transcription factor profile and surface marker phenotype, including reduced E2-2 and CCR9 expression. Type I IFN signaling via STAT1 has a cell-autonomous role in accrual of PP pDCs in vivo. Moreover, IFN-alpha enhances pDC generation from DC progenitors by a STAT1-dependent mechanism. pDCs that have been developed in the presence of IFN-alpha resemble PP pDCs, produce inflammatory cytokines, stimulate Th17 cell generation, and fail to secrete IFN alpha on Toll-like receptor engagement. These results indicate that IFN-alpha influences the development and function of pDCs by inducing emergence of an inflammatory (Th17-inducing) antigen-presenting subset, and simultaneously regulating accumulation of pDCs in the intestinal microenvironment. PMID- 21828130 TI - Dominant-negative C/ebpalpha and polycomb group protein Bmi1 extend short-lived hematopoietic stem/progenitor cell life span and induce lethal dyserythropoiesis. AB - The primitive hematopoietic stem/progenitor cells (HSPCs) during embryonic hematopoiesis are thought to be short-lived (SL) with limited self-renewal potential. The fate and consequence of these short-lived HSPCs, once reprogrammed into "long-lived" in a living animal body, remain unknown. Here we show that targeted expression of a dominant-negative C/ebpalpha (C/ebpalphaDN) in the primitive SL-HSPCs during zebrafish embryogenesis extends their life span, allowing them to survive to later developmental stage to colonize the definitive hematopoietic sites, where they undergo a proliferative expansion followed by erythropoietic dysplasia and embryonic lethality because of circulation congestion. Mechanistically, C/ebpalphaDN binds to a conserved C/EBP-binding motif in the promoter region of bmi1 gene, associated with a specific induction of bmi1 transcription in the transgenic embryos expressing C/ebpalphaDN. Targeted expression of Bmi1 in the SL-HSPCs recapitulates nearly all aberrant phenotypes induced by C/ebpalphaDN, whereas knockdown of bmi1 largely rescues these abnormalities. The results indicate that Bmi1 acts immediately downstream of C/ebpalphaDN to regulate the survival and self-renewal of HSPCs and contribute to the erythropoietic dysplasia. PMID- 21828132 TI - Bone marrow-derived CMPs and GMPs represent highly functional proangiogenic cells: implications for ischemic cardiovascular disease. AB - Clinical studies using bone marrow-derived proangiogenic cells (PACs) have demonstrated modest improvements of function and/or perfusion of ischemic myocardium or skeletal muscle. Because the identities of these PACs and their functional ability to promote neovascularization remain poorly understood, it is possible that a subset of robust PACs exists but is obscured by the heterogeneous nature of this cell population. Herein, we found that common myeloid progenitors (CMPs) and granulocyte-macrophage progenitors (GMPs) preferentially differentiate into PACs compared with megakaryocyte-erythrocyte progenitors, hematopoietic stem cells, and common lymphoid progenitors. In vivo hindlimb ischemia studies and Matrigel plug assays verified the enhanced neovascularization properties uniquely associated with PACs derived from CMPs and GMPs. Taken together, these observations identify CMPs and GMPs as key bone marrow progenitors for optimal PAC function in vitro and in vivo and provide a foundation for novel therapeutic approaches to modulate angiogenesis. PMID- 21828131 TI - TGF-beta1 signaling and Kruppel-like factor 10 regulate bone marrow-derived proangiogenic cell differentiation, function, and neovascularization. AB - Emerging evidence demonstrates that proangiogenic cells (PACs) originate from the BM and are capable of being recruited to sites of ischemic injury where they contribute to neovascularization. We previously determined that among hematopoietic progenitor stem cells, common myeloid progenitors (CMPs) and granulocyte-macrophage progenitor cells (GMPs) differentiate into PACs and possess robust angiogenic activity under ischemic conditions. Herein, we report that a TGF-beta1-responsive Kruppel- like factor, KLF10, is strongly expressed in PACs derived from CMPs and GMPs, ~ 60-fold higher than in progenitors lacking PAC markers. KLF10(-/-) mice present with marked defects in PAC differentiation, function, TGF-beta responsiveness, and impaired blood flow recovery after hindlimb ischemia, an effect rescued by wild-type PACs, but not KLF10(-/-) PACs. Overexpression studies revealed that KLF10 could rescue PAC formation from TGF beta1(+/-) CMPs and GMPs. Mechanistically, KLF10 targets the VEGFR2 promoter in PACs which may underlie the observed effects. These findings may be clinically relevant because KLF10 expression was also found to be significantly reduced in PACs from patients with peripheral artery disease. Collectively, these observations identify TGF-beta1 signaling and KLF10 as key regulators of functional PACs derived from CMPs and GMPs and may provide a therapeutic target during cardiovascular ischemic states. PMID- 21828133 TI - Role of ZBP-89 in human globin gene regulation and erythroid differentiation. AB - The molecular mechanisms underlying erythroid-specific gene regulation remain incompletely understood. Closely spaced binding sites for GATA, NF-E2/maf, and CACCC interacting transcription factors play functionally important roles in globin and other erythroid-specific gene expression. We and others recently identified the CACCC-binding transcription factor ZBP-89 as a novel GATA-1 and NF E2/mafK interacting partner. Here, we examined the role of ZBP-89 in human globin gene regulation and erythroid maturation using a primary CD34(+) cell ex vivo differentiation system. We show that ZBP-89 protein levels rise dramatically during human erythroid differentiation and that ZBP-89 occupies key cis regulatory elements within the globin and other erythroid gene loci. ZBP-89 binding correlates strongly with RNA Pol II occupancy, active histone marks, and high-level gene expression. ZBP-89 physically associates with the histone acetyltransferases p300 and Gcn5/Trrap, and occupies common sites with Gcn5 within the human globin loci. Lentiviral short hairpin RNAs knockdown of ZBP-89 results in reduced Gcn5 occupancy, decreased acetylated histone 3 levels, lower globin and erythroid-specific gene expression, and impaired erythroid maturation. Addition of the histone deacetylase inhibitor valproic acid partially reverses the reduced globin gene expression. These findings reveal an activating role for ZBP-89 in human globin gene regulation and erythroid differentiation. PMID- 21828134 TI - Molecular predictors of response to decitabine in advanced chronic myelomonocytic leukemia: a phase 2 trial. AB - Hydroxyurea is the standard therapy of chronic myelomonocytic leukemia (CMML) presenting with advanced myeloproliferative and/or myelodysplastic features. Response to hypomethylating agents has been reported in heterogeneous series of CMML. We conducted a phase 2 trial of decitabine (DAC) in 39 patients with advanced CMML defined according to a previous trial. Median number of DAC cycles was 10 (range, 1-24). Overall response rate was 38% with 4 complete responses (10%), 8 marrow responses (21%), and 3 stable diseases with hematologic improvement (8%). Eighteen patients (46%) demonstrated stable disease without hematologic improvement, and 6 (15%) progressed to acute leukemia. With a median follow-up of 23 months, overall survival was 48% at 2 years. Mutations in ASXL1, TET2, AML1, NRAS, KRAS, CBL, FLT3, and janus kinase 2 (JAK2) genes, and hypermethylation of the promoter of the tumor suppressor gene TIF1gamma, did not predict response or survival on DAC therapy. Lower CJUN and CMYB gene expression levels independently predicted improved overall survival. This trial confirmed DAC efficacy in approximately 40% of CMML patients with advanced myeloproliferative or myelodysplastic features and suggested that CJUN and CMYB expression could be potential biomarkers in this setting. This trial is registered at EudraCT (eudract.ema.europa.eu) as #2008-000470-21 and www.clinicaltrials.gov as #NCT01098084. PMID- 21828135 TI - Mutational spectrum analysis of chronic myelomonocytic leukemia includes genes associated with epigenetic regulation: UTX, EZH2, and DNMT3A. AB - Chronic myelomonocytic leukemia (CMML), a myelodysplastic/myeloproliferative neoplasm, is characterized by monocytic proliferation, dysplasia, and progression to acute myeloid leukemia. CMML has been associated with somatic mutations in diverse recently identified genes. We analyzed 72 well-characterized patients with CMML (N = 52) and CMML-derived acute myeloid leukemia (N = 20) for recurrent chromosomal abnormalities with the use of routine cytogenetics and single nucleotide polymorphism arrays along with comprehensive mutational screening. Cytogenetic aberrations were present in 46% of cases, whereas single nucleotide polymorphism array increased the diagnostic yield to 60%. At least 1 mutation was found in 86% of all cases; novel UTX, DNMT3A, and EZH2 mutations were found in 8%, 10%, and 5.5% of patients, respectively. TET2 mutations were present in 49%, ASXL1 in 43%, CBL in 14%, IDH1/2 in 4%, KRAS in 7%, NRAS in 4%, and JAK2 V617F in 1% of patients. Various mutant genotype combinations were observed, indicating molecular heterogeneity in CMML. Our results suggest that molecular defects affecting distinct pathways can lead to similar clinical phenotypes. PMID- 21828136 TI - Cell of origin strongly influences genetic selection in a mouse model of T-ALL. AB - Identifying the normal cell from which a tumor originates is crucial to understanding the etiology of that cancer. However, retrospective identification of the cell of origin in cancer is challenging because of the accumulation of genetic and epigenetic changes in tumor cells. The biologic state of the cell of origin likely influences the genetic events that drive transformation. We directly tested this hypothesis by performing a Sleeping Beauty transposon mutagenesis screen in which common insertion sites were identified in tumors that were produced by mutagenesis of cells at varying time points throughout the T lineage. Mutation and gene expression data derived from these tumors were then compared with data obtained from a panel of 84 human T-cell acute lymphoblastic leukemia samples, including copy number alterations and gene expression profiles. This revealed that altering the cell of origin produces tumors that model distinct subtypes of human T-cell acute lymphoblastic leukemia, suggesting that even subtle changes in the cell of origin dramatically affect genetic selection in tumors. These findings have broad implications for the genetic analysis of human cancers as well as the production of mouse models of cancer. PMID- 21828137 TI - DNA methyltransferase 1 and DNA methylation patterning contribute to germinal center B-cell differentiation. AB - The phenotype of germinal center (GC) B cells includes the unique ability to tolerate rapid proliferation and the mutagenic actions of activation induced cytosine deaminase (AICDA). Given the importance of epigenetic patterning in determining cellular phenotypes, we examined DNA methylation and the role of DNA methyltransferases in the formation of GCs. DNA methylation profiling revealed a marked shift in DNA methylation patterning in GC B cells versus resting/naive B cells. This shift included significant differential methylation of 235 genes, with concordant inverse changes in gene expression affecting most notably genes of the NFkB and MAP kinase signaling pathways. GC B cells were predominantly hypomethylated compared with naive B cells and AICDA binding sites were highly overrepresented among hypomethylated loci. GC B cells also exhibited greater DNA methylation heterogeneity than naive B cells. Among DNA methyltransferases (DNMTs), only DNMT1 was significantly up-regulated in GC B cells. Dnmt1 hypomorphic mice displayed deficient GC formation and treatment of mice with the DNA methyltransferase inhibitor decitabine resulted in failure to form GCs after immune stimulation. Notably, the GC B cells of Dnmt1 hypomorphic animals showed evidence of increased DNA damage, suggesting dual roles for DNMT1 in DNA methylation and double strand DNA break repair. PMID- 21828138 TI - Extranodal dissemination of non-Hodgkin lymphoma requires CD47 and is inhibited by anti-CD47 antibody therapy. AB - Non-Hodgkin lymphoma (NHL) presents as both localized and disseminated disease with spread to secondary sites carrying a worse prognosis. Although pathways driving NHL dissemination have been identified, there are few therapies capable of inhibiting them. Here, we report a novel role for the immunomodulatory protein CD47 in NHL dissemination, and we demonstrate that therapeutic targeting of CD47 can prevent such spread. We developed 2 in vivo lymphoma metastasis models using Raji cells, a human NHL cell line, and primary cells from a lymphoma patient. CD47 expression was required for Raji cell dissemination to the liver in mouse xenotransplants. Targeting of CD47 with a blocking antibody inhibited Raji cell dissemination to major organs, including the central nervous system, and inhibited hematogenous dissemination of primary lymphoma cells. We hypothesized that anti-CD47 antibody-mediated elimination of circulating tumor cells occurred through phagocytosis, a previously described mechanism for blocking anti-CD47 antibodies. As predicted, inhibition of dissemination by anti-CD47 antibodies was dependent on blockade of phagocyte SIRPalpha and required macrophage effector cells. These results demonstrate that CD47 is required for NHL dissemination, which can be therapeutically targeted with a blocking anti-CD47 antibody. Ultimately, these findings are potentially applicable to the dissemination and metastasis of other solid tumors. PMID- 21828140 TI - Outcome of AL amyloidosis after high-dose melphalan and autologous stem cell transplantation: long-term results in a series of 421 patients. AB - Previous studies have suggested that, in patients with AL amyloidosis treated with high-dose melphalan and autologous stem-cell transplantation (HDM/SCT), the greatest benefit is seen in those patients achieving a hematologic complete response (CR). We analyzed a series of 421 consecutive patients treated with HDM/SCT at a single referral center and compared outcomes for patients with and without CR. Treatment-related mortality was 11.4% overall (5.6% in the last 5 years). By intention-to-treat analysis, the CR rate was 34% and the median event free survival (EFS) and overall survival (OS) were 2.6 and 6.3 years, respectively. Eighty-one patients died within the first year after HDM/SCT and were not evaluable for hematologic and organ response. Of 340 evaluable patients, 43% achieved CR and 78% of them experienced an organ response. For CR patients, median EFS and OS were 8.3 and 13.2 years, respectively. Among the 195 patients who did not obtain CR, 52% achieved an organ response, and their median EFS and OS were 2 and 5.9 years, respectively. Thus, treatment of selected AL patients with HDM/SCT resulted in a high organ response rate and long OS, even for those patients who did not achieve CR. PMID- 21828139 TI - How I treat hemophagocytic lymphohistiocytosis. AB - Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of pathologic immune activation, occurring as either a familial disorder or a sporadic condition, in association with a variety of triggers. This immune dysregulatory disorder is prominently associated with cytopenias and a unique combination of clinical signs and symptoms of extreme inflammation. Prompt initiation of immunochemotherapy is essential for survival, but timely diagnosis may be challenging because of the rarity of HLH, its variable presentation, and the time required to perform diagnostic testing. Therapy is complicated by dynamic clinical course, high risk of treatment-related morbidity, and disease recurrence. Here, we review the clinical manifestations and patterns of HLH and describe our approach to the diagnosis and therapy for this elusive and potentially lethal condition. PMID- 21828141 TI - Phase 2 study of rituximab in newly diagnosed stage IA nodular lymphocyte predominant Hodgkin lymphoma: a report from the German Hodgkin Study Group. AB - Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) accounts for ~ 5% of Hodgkin lymphoma cases. The disease is characterized by a strong CD20 expression on the malignant cells and a more indolent clinical course compared with classic HL. Anti-CD20 antibody treatment has shown clinical activity in relapsed NLPHL. In this phase 2 trial, we investigated rituximab in newly diagnosed stage IA NLPHL patients. Four weekly applications at 375 mg/m(2) were given. Among the 28 evaluable patients, overall response rate was 100%, 24 patients (85.7%) achieved complete remission, and 4 (14.3%) achieved partial remission. At a median follow up of 43 months, overall survival was 100%; progression-free survival at 12, 24, and 36 months was 96.4%, 85.3%, and 81.4%, respectively. No grade 3 or 4 toxicity was observed. Although treatment results with rituximab appear inferior compared with radiotherapy and combined-modality approaches in early-stage patients, investigation of anti-CD20 antibody-based combinations in NLPHL is warranted. This study was registered at www.clinicaltrials.gov as #NCT00346684. PMID- 21828142 TI - A phase 1 study of imatinib for corticosteroid-dependent/refractory chronic graft versus-host disease: response does not correlate with anti-PDGFRA antibodies. AB - Stimulatory antiplatelet derived growth factor receptor alpha (PDGFRA) antibodies have been associated with extensive chronic graft-versus-host disease (cGVHD). We performed a phase 1 dose escalation trial of imatinib in corticosteroid dependent/refractory cGVHD to assess the safety of imatinib and test the hypothesis that abrogation of PDGFRA signaling can ameliorate the manifestations of cGVHD. Fifteen patients were enrolled. Mean follow-up time was 56.6 weeks (range, 18-82.4 weeks). Imatinib 400 mg daily was associated with more frequent moderate to life-threatening adverse events than 200 mg daily. The main adverse events were nausea, edema, confusion, diarrhea, liver function test elevation, fatigue, and myalgia. The overall response rate was 40% (6 of 15). The treatment failure rate was 40% (6 of 15). Twenty percent (3 of 15) of subjects had stable disease. Of 4 subjects with phospho-PDGFRA and phospho-PDGFRB immunohistochemistry studies before and after treatment, inhibition of phosphorylation was observed in 3 but correlated with response in one. Anti PDGFRA antibodies were observed in 7 of 11 evaluable subjects but correlated with clinical activity in 4. We conclude that cGVHD responds to imatinib through multiple pathways that may include PDGFRA signal transduction. This study is registered at www.clinicaltrials.gov as #NCT00760981. PMID- 21828143 TI - TET2 mutation is an unfavorable prognostic factor in acute myeloid leukemia patients with intermediate-risk cytogenetics. AB - The studies concerning clinical implications of TET2 mutation in patients with primary acute myeloid leukemia (AML) are scarce. We analyzed TET2 mutation in 486 adult patients with primary AML. TET2 mutation occurred in 13.2% of our patients and was closely associated with older age, higher white blood cell and blast counts, lower platelet numbers, normal karyotype, intermediate-risk cytogenetics, isolated trisomy 8, NPM1 mutation, and ASXL1 mutation but mutually exclusive with IDH mutation. TET2 mutation is an unfavorable prognostic factor in patients with intermediate-risk cytogenetics, and its negative impact was further enhanced when the mutation was combined with FLT3-ITD, NPM1-wild, or unfavorable genotypes (other than NPM1(+)/FLT3-ITD(-) or CEBPA(+)). A scoring system integrating TET2 mutation with FLT3-ITD, NPM1, and CEBPA mutations could well separate AML patients with intermediate-risk cytogenetics into 4 groups with different prognoses (P < .0001). Sequential analysis revealed that TET2 mutation detected at diagnosis was frequently lost at relapse; rarely, the mutation was acquired at relapse in those without TET2 mutation at diagnosis. In conclusion, TET2 mutation is associated with poor prognosis in AML patients with intermediate-risk cytogenetics, especially when it is combined with other adverse molecular markers. TET2 mutation appeared to be unstable during disease evolution. PMID- 21828144 TI - Procoagulant activity induced by vascular injury determines contribution of elevated factor VIII to thrombosis and thrombus stability in mice. AB - Studies have correlated elevated plasma factor VIII (FVIII) with thrombosis; however, it is unclear whether elevated FVIII is a proinflammatory biomarker, causative agent, or both. We raised FVIII levels in mice and measured the time to vessel occlusion (TTO) after ferric chloride-induced injury. Compared with control (saline-infused) mice, elevated FVIII had no effect after longer (3 minute) carotid artery injury, but it shortened the TTO after shorter (2-minute) injury (P < .008). After injury, circulating thrombin-antithrombin (TAT) complexes were lower after short versus long injury (P < .04), suggesting short treatment produced less coagulation activation. TAT levels in FVIII-infused mice were higher than in controls after short, but not longer, injury. Accordingly, elevated FVIII had no effect on in vitro thrombin generation or platelet aggregation triggered by high tissue factor, but it increased thrombin generation rate and peak (2.4- and 1.5-fold, respectively), and it accelerated platelet aggregation (up to 1.6-fold) when initiated by low tissue factor. Compared with control mice, elevated FVIII stabilized thrombi (fewer emboli) after short injury, but it had no effect after longer injury. TTO and emboli correlated with TATs. These results demonstrate dependence of FVIII activity on extent of vascular injury. We propose elevated plasma FVIII is an etiologic, prothrombotic agent after moderate but not extensive vascular damage. PMID- 21828145 TI - Factor XIIa regulates the structure of the fibrin clot independently of thrombin generation through direct interaction with fibrin. AB - Recent data indicate an important contribution of coagulation factor (F)XII to in vivo thrombus formation. Because fibrin structure plays a key role in clot stability and thrombosis, we hypothesized that FXII(a) interacts with fibrin(ogen) and thereby regulates clot structure and function. In plasma and purified system, we observed a dose-dependent increase in fibrin fiber density and decrease in turbidity, reflecting a denser structure, and a nonlinear increase in clot stiffness with FXIIa. In plasma, this increase was partly independent of thrombin generation, as shown in clots made in prothrombin deficient plasma initiated with snake venom enzyme and in clots made from plasma deficient in FXII and prothrombin. Purified FXII and alpha-FXIIa, but not beta FXIIa, bound to purified fibrinogen and fibrin with nanomolar affinity. Immunostaining of human carotid artery thrombi showed that FXII colocalized with areas of dense fibrin deposition, providing evidence for the in vivo modulation of fibrin structure by FXIIa. These data demonstrate that FXIIa modulates fibrin clot structure independently of thrombin generation through direct binding of the N-terminus of FXIIa to fibrin(ogen). Modification of fibrin structure by FXIIa represents a novel physiologic role for the contact pathway that may contribute to the pathophysiology of thrombosis. PMID- 21828146 TI - Fluoroscopy as a surrogate for lung tumour motion. AB - OBJECTIVES: The aim of this article was to test a simple approach of using pixel density values from fluoroscopy images to enable gated radiotherapy. METHODS: Anterior and lateral (LAT) from images were acquired from 18 patients referred for radical radiotherapy for non-small cell lung cancer for a period of 30-45 s. The amplitude of movement and the number of breathing cycles were determined in the right-left (RL) and superoinferior (SI) directions on the anterior images and the anteroposterior (AP) and SI directions on the lateral images. The breathing pattern was created by analysing the variation in a summation of pixel values within a defined area. The greatest and lowest 30% of pixel values were set as the duty cycle to represent inhale and exhale amplitude-based gating. RESULTS: A median of eight breathing cycles was captured for each patient with a duration of 2.2-11.8 s per cycle. The mean (range) motion was 4.7 mm (2.4-5.8 mm), 7.2 mm (2.3-17.6 mm), 6.2 mm (1.9-13.8 mm) and 4.8 mm (2.4-11.3 mm) in the RL, SI (AP), SI (LAT) and AP directions, respectively. A total of 10/14 anterior videos and 7/11 LAT videos had correlations between motion and breathing of >0.6. Margins of 5.5 mm, 6.8 mm and 6.6 mm in the RL, SI and AP directions, respectively, were determined to gate in exhale. The benefit of gating was greater when motion was >5 mm. CONCLUSION: The simple approach of using pixel density values from fluoroscopy images to distinguish inhale from exhale and enable gating was successfully applied in all patients. This technique may potentially provide an accurate surrogate for tumour position. PMID- 21828147 TI - Calcifying cystic odontogenic tumour: CT imaging. AB - OBJECTIVES: Calcifying cystic odontogenic tumour (CCOT) is a rare disorder of the jaw. A comparison between conventional radiographs and CT images in CCOTs has not been reported. The purposes of this study were to analyse conventional radiographs and CT images of CCOTs, establish CT images of CCOTs and assess the utility of CT in the diagnosis of CCOTs. METHODS: Nine patients with a histopathologically confirmed CCOT who had both conventional radiographs and CT images were enrolled. RESULTS: CT was superior to conventional radiographs in detecting buccolingual expansion, odontomas and radio-opaque bodies. CONCLUSION: The characteristic CT appearances of CCOT were that radio-opaque bodies were typically located in the periphery of the lesion and the shape of radio-opaque bodies was linear and/or spotted. CT was useful in diagnosing a CCOT. PMID- 21828148 TI - Acute colonic pseudo-obstruction complicating chemotherapy in paediatric oncohaematological patients: clinical and imaging features. AB - OBJECTIVE: Although acute colonic pseudo-obstruction (ACPO) complicating chemotherapy is still a controversial entity, it is one with which radiologists should be familiar. We describe the imaging features of ACPO in children following chemotherapy for treatment of a haematological malignancy. METHODS: We retrospectively reviewed the imaging features of eight children (age 3-14 years) with chemotherapy-related ACPO, all of whom had undergone plain radiography and CT examinations. The diagnosis of ACPO was based on both clinical features and imaging findings. RESULTS: Abnormalities noted on plain radiography included faecal gaseous distension of the transverse colon (4/8), faecal gaseous distension of the ascending colon (3/8), gaseous distended transverse colon (3/8) and gaseous small bowel loops (6/8). As seen on CT scans, findings of faecal fluid distended the ascending and transverse colon (5/8), faecal gas distended the transverse and ascending colon (3/8), and small bowel dilatation (5/8) and pneumatosis intestinalis (2/8) were noted. Seven of the eight patients had colonic dilatation from the caecum to the transverse colon with the transition zone near the splenic flexure. CONCLUSION: In children presenting with abdominal pain and constipation following chemotherapy, imaging features of progressive colonic dilatation seen on radiography and dilatation from the caecum to the transverse colon with the transition zone near the splenic flexure, as noted on CT, are suggestive of ACPO. CT is more successful than plain radiography for evaluating this finding, particularly in colonic segments filled primarily with fluid, but CT should not be necessary for making the diagnosis as plain radiographs and clinical evaluation should be adequate. PMID- 21828149 TI - Prediction of microvascular invasion of hepatocellular carcinoma by pre-operative CT imaging. AB - OBJECTIVE: The aim of this study was to diagnose microvascular invasion in patients with solitary hepatocellular carcinoma (HCC) from pre-operative CT imaging. METHODS: 102 patients with solitary HCC who underwent curative hepatectomy were retrospectively included in our study. The pre-operative 3-phase CT imaging and laboratory data for the 102 patients were reviewed. Tumour size, tumour margin, peritumoral enhancement and alpha-fetoprotein level were assessed. Surgical pathology was reviewed; tumour differentiation, liver fibrosis score and microvascular invasion were recorded. RESULTS: The histopathological results revealed that 50 HCCs were positive and the other 52 were negative for microvascular invasion. Univariate analysis revealed that tumour size (p = 0.036), higher Edmondson-Steiner grade (p = 0.047) and non-smooth tumour margin (p < 0.001) showed statistically significant associations with microvascular invasion. Multivariate logistic regression analysis showed that non-smooth tumour margin had a statistically significant association with microvascular invasion only (p < 0.001). The sensitivity, specificity, positive predictive value and negative predictive value of the non-smooth tumour margin in the prediction of microvascular invasion were 66%, 86.5%, 82.5% and 72.6%, respectively. CONCLUSION: Non-smooth tumour margin in pre-operative CT had a statistically significant association with microvascular invasion. More aggressive treatment should be considered in HCC patients with suspected positive microvascular invasion. PMID- 21828150 TI - Comparison of fully automated and semi-automated biopsy needles for lung biopsy under CT fluoroscopic guidance. AB - OBJECTIVE: The aim of this study was to compare two different automated biopsy needles, a fully automated biopsy needle (Monopty; Bard, Covington, GA) and a semi-automated biopsy needle (Temno; Bauer Medical, Clearwater, FL), for lung biopsy. METHODS: 50 consecutive percutaneous lung biopsies using the Monopty needle between June 2006 and January 2007 and 66 consecutive lung biopsies for 1 nodule in each session using the Temno needle between February 2007 and August 2008 were performed under CT fluoroscopic guidance followed by histopathological evaluation. RESULTS: In 42/50 lung biopsies performed with the Monopty needle and 54/66 lung biopsies performed with the Temno needle, the final diagnosis was confirmed by independent surgical pathological findings or clinical follow-up. Sufficient samples for histopathological evaluation were obtained in all 50 (100%) biopsies using the Monopty needle and in 55 (83.3%) of the 66 biopsies using the Temno needle (p<0.01). Accurate diagnosis was achieved in 41 (97.6%) of 42 biopsies using the Monopty needle and in 45 (83.3%) of 54 biopsies using the Temno needle (p=0.04). Biopsy-induced complications were pneumothorax, haemoptysis and haemothorax in 44.0%, 10.0% and 6.0% of biopsies, respectively, using the Monopty needle and in 48.3%, 8.3% and 3.3%, respectively, using the Temno needle. CONCLUSION: There is a possibility that a fully automated biopsy needle such as the Monopty is more useful for CT scan-guided lung biopsy than semi-automated biopsy needles. PMID- 21828152 TI - Reproducibility of cornea measurements in anterior segment OCT images of normal eyes and eyes with bullous keratopathy analyzed with the Zhongshan Assessment Program. AB - PURPOSE: To determine the interobserver and intraobserver measurement reproducibility of cornea parameters of both normal eyes and eyes with bullous keratopathy (BK) obtained with the Zhongshan Assessment Program (ZAP) on anterior segment optical coherence tomography (AS-OCT) images. METHODS: A comparative study was carried out on 24 healthy volunteers and 25 subjects with BK. AS-OCT images were independently analyzed by two examiners. Parameters examined: anterior chamber depth (ACD), central corneal thickness (CCT), posterior corneal curvature (PCC), and posterior corneal arc length (PCAL). Interobserver and intraobserver reproducibility of these parameters was calculated in terms of limits of agreement (mean of differences +/- 1.96SD of differences). RESULTS: In the normal group, both horizontal and vertical ACD were successfully measured in 23 of 24 (96%) images. The mean bias for two measurements by two different observers ranged from 0.003 to 0.117 mm for ACD, PCC, and PCAL measurements and from 0.013 to 2.25 MUm for CCT measurements, and there were no differences between the two observers (P > 0.05). Mean bias for two measurements by the same grader ranged from 0.005 to 0.327 mm for ACD, PCC, and PCAL measurements and 1.46 to 2.53 MUm for CCT measurements. There was no difference between the two observations (P > 0.05). Similar results were found in the BK group. CONCLUSIONS: There was high inter- and intraobserver reproducibility for normal and pathologic corneas using the ZAP software. The ZAP software may serve as a new investigatory tool for accurately evaluating the anterior segment and corneal parameters for corneal procedures. PMID- 21828151 TI - Age-related impairment in choroidal blood flow compensation for arterial blood pressure fluctuation in pigeons. AB - PURPOSE: Choroidal vessels compensate for changes in systemic blood pressure (BP) so that choroidal blood flow (ChBF) remains stable over a BP range of approximately 40 mm Hg above and below basal. Because of the presumed importance of ChBF regulation for maintenance of retinal health, we investigated if ChBF compensation for BP fluctuation in pigeons fails with age. METHODS: Transcleral laser Doppler flowmetry was used to measure ChBF during spontaneous BP fluctuation in anesthetized pigeons ranging in age from 0.5 to 17 years (pigeons can live approximately 20 years in captivity). RESULTS: ChBF in <8-year-old pigeons remained near 100% of basal ChBF at BPs ranging 40 mm Hg above and below basal BP (95 mm Hg). Baroregulation failed below approximately 50 mm Hg BP. In >=8-year-old pigeons, ChBF compensation was absent at >90 mm Hg BP, with ChBF linearly following BP. Over the 60 to 90 mm Hg range, ChBF in >=8-year-old pigeons was maintained at 60-70% of young basal ChBF. Below approximately 55 mm Hg, baroregulation again followed BP linearly. CONCLUSIONS: Age-related ChBF baroregulatory impairment occurs in pigeons, with ChBF linear with above-basal BP, and ChBF failing to adequately maintain ChBF during below-basal BP. Defective autonomic sympathetic and parasympathetic neurogenic control, or defective myogenic control, may cause these baroregulatory defects. In either case, overperfusion during high BP may cause oxidative injury to the outer retina, whereas underperfusion during low BP may result in deficient nutrient supply and waste removal, with both abnormalities contributing to age-related retinal pathology and vision loss. PMID- 21828155 TI - Treatment of severe keratoconjunctivitis sicca by parotid duct transposition after tympanic neurectomy in rabbits. AB - PURPOSE: To investigate the feasibility of parotid duct transposition after tympanic neurectomy to treat severe keratoconjunctivitis sicca (KCS) in rabbits. METHODS: Thirty rabbits were divided into three groups in experiment 1. One eye was operated on, and the contralateral eye served as the control. In the KCS group, the lacrimal gland, harderian gland, and nictitating membrane were removed. In the group with parotid duct transposition (DT), the parotid duct was transposed into the lower conjunctival fornix. In the group with parotid duct transposition after tympanic neurectomy (DTTN), the tympanic nerve was resected in addition to parotid duct transposition. Schirmer test was performed and density of corneal staining was determined monthly after surgery, and goblet cell density was measured at postoperative month 3. In experiment 2, the tympanic nerve was resected on one side in 12 rabbits. Both sides of the parotid gland were resected for histopathology at intervals of 2 months to 1 year after surgery. RESULTS: Tear secretion from operated eyes at rest increased significantly after surgery in the treatment groups compared with the KCS group. Tear secretion from operated eyes after chewing was significantly lower in the DTTN than in the DT group. The corneal staining scores were higher in the operated than in the control eyes of the three groups, without significant difference among the operated eyes. Parotid gland atrophy on the operated side occurred at postoperative month 4 and recovered to normal 1 year after surgery. CONCLUSIONS: Parotid duct transposition after tympanic neurectomy could effectively reduce gustatory epiphora but may be insufficient to promote ocular surface health. PMID- 21828153 TI - Lamina-specific anatomic magnetic resonance imaging of the human retina. AB - PURPOSE: Magnetic resonance imaging (MRI) of the human retina faces two major challenges: eye movement and hardware limitation that could preclude human retinal MRI with adequate spatiotemporal resolution. This study investigated eye fixation stability and high-resolution anatomic MRI of the human retina on a 3 Tesla (T) MRI scanner. Comparison was made with optical coherence tomography (OCT) on the same subjects. METHODS: Eye-fixation stability of protocols used in MRI was evaluated on four normal volunteers using an eye tracker. High-resolution MRI (100 * 200 * 2000 MUm) protocol was developed on a 3-T scanner. Subjects were instructed to maintain stable eye fixation on a target with cued blinks every 8 seconds during MRI. OCT imaging of the retina was performed. Retinal layer thicknesses measured with MRI and OCT were analyzed for matching regions of the same eyes close to the optic nerve head. RESULTS: The temporal SDs of the horizontal and vertical displacements were 78 +/- 51 and 130 +/- 51 MUm (+/-SD, n = 4), respectively. MRI detected three layers within the human retina, consistent with MRI findings in rodent, feline, and baboon retinas. The hyperintense layer 1 closest to the vitreous likely consisted of nerve fiber, ganglion cell, and inner nuclear layer; the hypointense layer 2, the outer nuclear layer and the inner and outer segments; and the hyperintense layer 3, the choroid. The MRI retina/choroid thickness was 711 +/- 37 MUm, 19% (P < 0.05) thicker than OCT thickness (579 +/- 34 MUm). CONCLUSIONS: This study reports high-resolution MRI of lamina-specific structures in the human retina. These initial results are encouraging. Further improvement in spatiotemporal resolution is warranted. PMID- 21828154 TI - Genotype-dependent sensitivity of uveal melanoma cell lines to inhibition of B Raf, MEK, and Akt kinases: rationale for personalized therapy. AB - PURPOSE: Inhibitors of B-Raf and MEK kinases hold promise for the management of cutaneous melanomas harboring BRAF mutations. BRAF mutations are rare in uveal melanomas (UMs), but somatic mutations in the G protein alpha subunits Galphaq and Galpha11 (encoded by GNAQ and GNA11, respectively) occur in a mutually exclusive pattern in ~80% of UMs. The impact of B-Raf and MEK inhibitors on Galpha-mutant UMs remains unknown. METHODS: The impact of the B-Raf inhibitor PLX4720, the MEK inhibitor AZD6244, and the Akt inhibitor MK2206 on UM cell lines was assessed with the use of cell viability, proliferation, and apoptosis assays and immunoblot analysis. RESULTS: BRAF-mutant UM cells were sensitive to both PLX4720 and AZD6244, undergoing cell cycle arrest but not apoptosis. UM cells with a Galpha-protein mutation (GNAQ or GNA11) were mildly sensitive to AZD6244 but completely resistant to PLX4720. In fact, PLX4720 paradoxically increased ERK phosphorylation in Galpha-mutant UM cells. The combination of AZD6244 with PLX4720 had synergistic anticancer activity in BRAF-mutant cells but not in Galpha-mutant cells. The Akt inhibitor MK2206 sensitized BRAF-mutant cells to both PLX4720 and AZD6244 and sensitized Galpha-mutant cells to AZD6244 but did not overcome the resistance of the Galpha-mutant cells to PLX4720. CONCLUSIONS: The response of UM cells to inhibition of B-Raf, MEK, and Akt depends on their genotype. Future use of such targeted therapies in clinical trials of UM patients will require careful design and patient selection based on genotype to provide personalized and effective therapy. PMID- 21828156 TI - The effects of Mozart's music on the performance of glaucoma patients on automated perimetry. AB - PURPOSE: The purpose of this study was to examine the impact of the Mozart effect on the reliability of the Humphrey visual field (HVF; Carl Zeiss Meditec, Dublin, CA) test in subjects with glaucoma. A previous study showed improved reliability in normal subjects undergoing HVF testing. METHODS: One hundred sixty subjects with glaucoma were randomized to three groups: control, headphones, or music for 10 minutes before HVF testing. The headphone group was provided noise cancellation headphones but no music. The music group listened to Mozart's Sonata for Two Pianos in D Major. After treatment, subjects took an HVF test in both eyes. The reliability of the test was then compared between the groups and also to prior HVF results with regard to fixation losses, false positives, and false negatives. RESULTS: The rate of fixation losses did not differ significantly between the three groups (P = 0.30 right eye, P = 0.24 left eye). There were also no significant differences in the rate of false positives (P = 0.82 right eye, P = 0.18 left eye) or false negatives (P = 0.91 right eye, P = 0.97 left eye). The reliability of the subject's HVF result was also compared with past field results. No improvements were seen in fixation losses (P = 0.94 right eye, P = 0.17 left eye), false positives (P = 0.85 right eye, P = 0.38 left eye), and false negatives (P = 0.13 right eye, P = 0.50 left eye). CONCLUSIONS: The rate of fixation losses, false positives, and false negatives did not improve in subjects with glaucoma after they listened to Mozart's music. The Mozart effect did not enhance the reliability of the visual field test to a statistically significant degree (ClinicalTrials.gov number, NCT01027039). PMID- 21828157 TI - Choroidal blood flow response to isometric exercise in glaucoma patients and patients with ocular hypertension. AB - PURPOSE: To analyze submacular choroidal blood flow (ChBF) response to isometric exercise in untreated patients with glaucoma and ocular hypertension. METHODS: ChBF was examined by means of confocal laser Doppler flowmetry during 5 minutes of baseline, during 90 seconds of isometric exercise with a Martin's vigorimeter and during 15 minutes of recovery. Values from one randomly chosen eye of 45 healthy subjects, the eye with more advanced damage in 45 primary open-angle glaucoma (POAG) patients, and the eye with higher native intraocular pressure in 45 patients with ocular hypertension (OHT) were acquired, and parameters of ChBF as well as blood pressure response were analyzed. RESULTS: Healthy eyes demonstrated higher ChBF at baseline than did the eyes in both the other groups (5126 +/- 1487, 4186 +/- 1011, and 4437 +/- 1372 arbitrary units, ANOVA P = 0.003). Both mean and diastolic arterial blood pressures at baseline were lower in POAG patients than in those with OHT and healthy controls (P < 0.03); however, the response of mean blood pressure to isometric exercise was comparable across groups (P = 0.79). The ChBF response to exercise was stronger in the POAG group (ANOVA P = 0.02), it was twice as high as in the controls (+8.1% +/- 8.0% vs. +3.7% +/- 6.7%; P = 0.007) and borderline higher than in the OHT patients (+5.0% +/- 8.0%; P = 0.051). CONCLUSIONS: Baseline ChBF was lower in both the POAG and the OHT patients, compared with that in the controls. The stronger increase in ChBF in POAG patients in the face of an exercise-induced blood pressure increase indicates less active regulatory capacity in glaucoma patients. PMID- 21828158 TI - The high-mobility group box-1 nuclear factor mediates retinal injury after ischemia reperfusion. AB - PURPOSE: High-mobility group protein B1 (Hmgb1) is released from necrotic cells and induces an inflammatory response. Although Hmgb1 has been implicated in ischemia/reperfusion (IR) injury of the brain, its role in IR injury of the retina remains unclear. Here, the authors provide evidence that Hmgb1 contributes to retinal damage after IR. METHODS: Retinal IR injury was induced by unilateral elevation of intraocular pressure and the level of Hmgb1 in vitreous humor was analyzed 24 hours after reperfusion. To test the functional significance of Hmgb1 release, ischemic or normal retinas were treated with the neutralizing anti-Hmgb1 antibody or recombinant Hmgb1 protein respectively. To elucidate in which cell type Hmgb1 exerts its effect, primary retinal ganglion cell (RGC) cultures and glia RGC cocultures were treated with Hmgb1. To clarify the downstream signaling pathways involved in Hmgb1-induced effects in the ischemic retina, receptor for advanced glycation end products (Rage)-deficient mice (RageKO) were used. RESULTS: Hmgb1 is accumulated in the vitreous humor 24 hours after IR. Inhibition of Hmgb1 activity with neutralizing antibody significantly decreased retinal damage after IR, whereas treatment of retinas or retinal cells with Hmgb1 induced a loss of RGCs. The analysis of RageKO versus wild-type mice showed significantly reduced expression of proinflammatory genes 24 hours after reperfusion and significantly increased survival of ganglion cell layer neurons 7 days after IR injury. CONCLUSIONS: These results suggest that an increased level of Hmgb1 and signaling via the Rage contribute to neurotoxicity after retinal IR injury. PMID- 21828159 TI - Social support and health in patients with systemic lupus erythematosus: a literature review. AB - In the last decades, with the improvement of life expectancies for systemic lupus erythematosus (SLE) patients, the relationship between social support and health in this population has received a considerable amount of attention in behavioural medicine and health psychology. This paper is the first to review research studies which specifically investigated perceived social support in relation to SLE patients' health outcomes (quality of life, disease activity and damage). Starting with a descriptive approach to social support perceived by patients with SLE, the research evidence on the impact of social support on health is presented. These studies demonstrate that the consideration of social support is critical in predicting disease activity, damage and quality of life (both physical and psychological components) although the precise ways in which social support contributes to health are not yet completely understood. Discussing the results, the authors offer some suggestions which could guide further research in this field. Finally, clinical and non-clinical implications of the findings are discussed. PMID- 21828160 TI - Mycophenolate mofetil as a maintenance therapy for lupus-related diffuse alveolar hemorrhage: a case report. AB - Diffuse alveolar hemorrhage (DAH) is a life-threatening complication of systemic lupus erythematosus (SLE). Cases complicated with DAH often have active SLE with multi-organ involvement, especially lupus nephritis. We describe a rare case of DAH as the first presenting manifestation of SLE in the absence of lupus nephritis. Remission was induced by IV methylprednisolone, IV cyclophosphamide, and plasmapheresis. Further cycles of cyclophosphamide were prevented by recurrent infections. Maintenance of remission was successfully achieved with oral mycophenolate mofetil 1 g twice daily, with a good control of SLE and without further DAH episodes. PMID- 21828161 TI - Novel techniques in the use of bivalirudin for cardiopulmonary bypass anticoagulation in a child with heparin-induced thrombocytopenia. AB - Heparin-induced thrombocytopenia (HIT) occurs in both the pediatric and adult populations after exposure to heparin. Bivalirudin has been used as an alternative to heparin for adults undergoing cardiac surgery and cardiopulmonary bypass, but has only been used minimally in children for this purpose. We report the successful use of bivalirudin for anticoagulation during cardiopulmonary bypass in a small child with HIT, using novel techniques not previously described. PMID- 21828162 TI - Children's participation in decision-making: balancing protection with shared decision-making using a situational perspective. AB - Children's participation in decision-making in the health care setting is complex because parents and health professionals tend to take a protective stance towards children to act in their best interest. Children prefer to be protected in some situations and to share decision-making in others. Adults in the health care setting need to consider children as individuals, rather than as a homogenous group, and take into account that a child's competence and preferences will depend on the circumstances in every situation. This article argues for a situational perspective of children's participation to act in the child's best interest and to balance protection with shared decision-making, according to children's rights and desires. PMID- 21828163 TI - Special needs require special attention: a pilot project implementing the paediatric pain profile for children with profound neurological impairment in an in-patient setting following surgery. AB - There is a lack of knowledge regarding the implementation of pain assessment tools for children with profound neurological impairment (PNI) in in-patient settings. This article describes a pilot project to evaluate the Paediatric Pain Profile (PPP) for children with PNI undergoing surgery. Five families of children 5 to 16 years of age with a primary diagnosis of cerebral palsy and admitted for surgical procedures were interviewed. Nineteen nurses completed questionnaires and children's pain management documentation was audited. The project identified issues in three areas of pain management: implementation process, individualised pain management and partnership. The PPP required pre-admission assessment and parental involvement, and was considered time-consuming by nurses. Individualised pain assessment and intervention was difficult to achieve, as was shared assessment and documentation among parents and nurses. Despite initial resistance to change, with greater use there was growing appreciation of the value of components of the PPP. Further exploration of the PPP tool in practice is required before its use can be widely recommended for children with PNI in in patient settings. Future studies are required to determine which of the available pain assessment tools has the greatest accuracy and utility for assessment of post-operative pain in children with PNI. PMID- 21828164 TI - Birth outcomes among booked and unbooked women at a secondary health facility in southwest Nigeria: implications for strengthening perinatal health services. AB - A case-controlled analytic study involving 406 singleton unbooked and 396 singleton booked births was conducted. Unbooked births constituted 16.6% of all births during the study. Booked births were half as likely to preterm than unbooked births (43, 10.9% vs 81, 20.0%; p<0.001). Unbooked births were seven times more likely to be stillbirth than booked births (80, 17.7% vs 13, 3.3%; p< 0.001). Booked births were a third as likely to have a low birth weight as unbooked births (36, 9.1% vs 104, 25.6%; p< 0.001). Unbooked births had a significantly lower mean birth weight of 2.95 +/- 0.53 kg than 3.08 +/- 0.45 kg of booked births (p< 0.001). Unbooked births had a significantly lower mean Apgar score at 1 minute and 5 minutes than booked births (6.64 +/- 1.42 vs 7.08 +/- 1.12 and 9.16 +/- 1.40 vs 9.64 +/- 1.00; p< 0.001) respectively. Unbooked births are common and their birth outcomes may result in high morbidity and disability, thereby contributing to the high child mortality in developing countries. Strengthening perinatal health services through professional skilled care at birth and providing quality services for all unbooked births may lead to improved birth outcomes. PMID- 21828165 TI - Uncovering pain in critically ill non-verbal children: nurses' clinical experiences in the paediatric intensive care unit. AB - Critically ill paediatric patients are frequently exposed to pain that is required to be assessed and treated effectively. The most reliable resource for assessing pain is the child itself, but children in the paediatric intensive care unit (PICU) are commonly unable to communicate their needs, requiring professional caregivers to uncover and interpret pain. However, nurses and paediatricians do not have sufficient knowledge of how critical illness affects childrens' signs of pain. The aim of this study was to illuminate clinical experiences of pain in the PICU; describing nurses' perceptions of expressions of pain in non-verbal, critically ill 2-6 year old children. The participants were 17 experienced PICU nurses. Data were analysed according to the phenomenographic method and three qualitatively different main categories, gained from clinical experience, emerged: changes in the measurable parameters; perceived muscular tension; and, altered behaviour. Furthermore, contrasting the categories revealed two diverse perspectives to focus pain: measure-oriented and patient-oriented. Subtle expressions of pain were recognised when focus was patient-oriented. These findings support the necessity of actively looking for pain deriving from various perspectives and considering diverse caring needs when doing so. Acknowledging pain makes pain visible. PMID- 21828166 TI - Impact of a nurse-led clinic for chronic constipation in children. AB - The impact of a nurse-led constipation clinic was assessed by evaluating the first 50 patients, aged 1.5 to 10 years, using a questionnaire before initial clinic visit and at the third clinic visit, three to four months later. Patients had been constipated for at least six months. The nurses explained the physiology of constipation, the rationale for laxative treatment and the need to comply with treatment. Good toileting behaviour was encouraged. This resulted in an increase in defaecation frequency and stool softness, whereas soiling and pain on defaecation decreased. There was no significant change in the amount of laxatives taken, although it was suspected that compliance improved. Parental understanding of constipation and its management increased. Overall, the control of constipation in children improved markedly through attendance at a nurse-led clinic. PMID- 21828167 TI - Experiences of community health nurses regarding father participation in child health care. AB - Traditionally child health care (CHC) has been an arena where mothers and nurses meet, but in recent years fathers are entering CHC with increasing frequency. The aim of this study was to describe nurses' experiences of fathers' participation in CHC. Nine Swedish nurses working in CHC were interviewed and asked to give a description of their experiences from meetings with fathers in CHC. Phenomenology according to Giorgi was used for the analysis and the essence of the findings was that father participation was seen from the perspective of mother participation and was constantly compared to mother participation in CHC. The essence is explicated in the following themes: participation through activities; equal participation although diverse; influence of structures in society; and strengthening participation. Clinical implications include the need for creating a separate identity in CHC for fathers and more communication directed at fathers. PMID- 21828168 TI - Polyunsaturated fatty acids, cognition and literacy in children with ADHD with and without learning difficulties. AB - Suboptimal omega-3 polyunsaturated fatty acid (n-3 PUFA) levels may contribute to attention deficit hyperactivity disorder (ADHD) and related developmental problems. Associations between n-3 and omega-6 (n-6) PUFA levels in red blood cells (erythrocytes) and learning and behaviour were investigated in 75 children aged 7-12 with ADHD. Children provided blood samples and underwent cognitive assessments. Parents completed questionnaires and Conners' Rating Scales. Controlling for covariates, higher n-3 PUFA predicted lower anxiety/shyness (beta = -.27), higher docosahexaenoic acid (DHA) better word reading (beta = .22), and higher n-6 PUFA poorer reading (beta = -.34), vocabulary (beta = .-.26), spelling (beta = -.30) and attention (beta = -.30). Thirty-six per cent of the sample with learning difficulties had lower DHA than those without (M = 3.26 +/- 0.54 vs M = 3.68 +/- 0.76, p = .02). This study is the first to compare erythrocyte PUFAs (a measure of PUFA status) in children who have ADHD with and without learning difficulties, and supports emerging indications that the former may be more likely responders to n-3 PUFAs. PMID- 21828169 TI - Welcome back? Frequent attenders to a pediatric primary care center. AB - This study examines frequent attenders of a pediatric primary care clinic at a large urban children's hospital--who they are and their reasons for frequent attendance to the clinic. The literature suggests that some visits by frequent attenders may not be medically necessary, and these additional appointments may impair others' access to medical care within the same system. The key to eliminating excessive primary care visits is to determine if it is a problem in the primary care practice (quantify the problem), explore the reasons for the visits (from the patients' perspective), and then provide educational interventions that address the various causes for the extra visits and encourage the use of available resources, either ancillary services in the practice itself or resources and agencies available in the community (e.g. social service, legal aid). PMID- 21828170 TI - Weight loss surgery for morbidly obese adolescents: a review. AB - Obesity is common among adolescents resulting in substantial comorbidities and reduced life expectancy. Conservative treatments normally fail to ensure significant and sustained weight loss and suitable adolescents should be offered weight loss surgery. Laparoscopic Adjustable Gastric Banding and Roux-en-Y Gastric Bypass are commonly used in adolescents. Complications in RYGB tend to be more severe, but the procedure leads to more immediate results. LAGB complications are often device-related and less severe. Dietary adherence, eating behaviour and unrealistic patient expectations often cause problems. Significant and sustained weight loss of 50-70 per cent of excess weight is achievable, comorbidities and psychological problems improve. Meticulous patient selection and preparation and good post-operative care are vital for successful weight loss surgery. Weight loss surgery is safe, effective and economically viable with nurses playing a vital role at all stages of its application. PMID- 21828171 TI - Convergence at the surface; divergence beneath: cross-agency working within a small-scale, schools-based project. AB - In the UK school system social remits - requiring schools to work towards improved social as well as educational outcomes for children - have become significant over the last decade. This study focuses upon the inter-professional issues in the running of one small-scale intervention involving parents and their babies based in schools in an urban setting in the UK. The programme, run over the school year 2007/08, provided a professional framework in which parents from the local community surrounding a school brought their babies into classroom settings to talk about aspects of baby care and development. This professional framework included classroom teachers, one senior cross-school education manager, family health visitors and one senior children's health nurse. Despite agreement about the benefits of the programme there were also clear differences of priority. This paper describes the different perceptions that each of these two sets of professionals - from health and from education - had of the programme, and highlights some critical perspectives that tended to come more from health professionals. It also maps out potential solutions which draw upon recent literature that is similarly focused upon inter-professional and inter-agency service delivery. In so doing it offers valuable insights to professionals working in inter-agency collaborations in schools. PMID- 21828172 TI - Sensible use of observational clinical data. AB - Observational data sets offer many potential advantages for medical research including their low cost, large size and generalisability. Because they are collected for clinical care and health care operations purposes, observational data sets have some limitations that must be considered in order to perform useful analyses. Sensible use of observational data sets can yield valuable insights, particularly when clinical trials are impractical. PMID- 21828173 TI - Percutaneous transluminal angioplasty: association between depressive symptoms and diminished health status benefits. AB - Depressive symptoms are known to compromise health status in cardiac disease, but this relationship has not been described in peripheral artery disease (PAD). Depressive symptoms (PHQ-9) and disease-specific health status (Peripheral Artery Questionnaire, PAQ) were assessed in 242 PAD patients undergoing percutaneous transluminal angioplasty (PTA) at baseline and 1 year. Patients were classified by baseline and follow-up depression status (moderate-severe depressive symptoms = PHQ >= 10). Changes were categorized as no depression/improvement of depression versus persistent/worsened depression. At baseline, 20% of patients were depressed; at 1 year, 17% of patients experienced persistent/worsened depression. Although this group improved on most PAQ subscales, they improved to a significantly lesser degree than those without depressive symptoms or those who improved by 1 year (p-values < 0.05). Baseline depressive symptoms (B(per 5-point increment) = -11.9, 95% CI -15.3, -8.5, p < 0.0001) and changes in depression were independently associated with a decrease in 1-year health status (B(per 5 point increment) = -11.7, 95% CI -14.3, -9.2, p < 0.0001). In conclusion, depressive symptoms are associated with less improvement in health status 1 year after undergoing a peripheral endovascular revascularization (PER) as compared with those having no depression or whose depressive symptoms improve. Efforts to improve depression detection and treatment among patients with PAD may improve the health status outcomes of these patients. PMID- 21828175 TI - Fighting psychiatric stigma in the classroom: the impact of an educational intervention on secondary school students' attitudes to schizophrenia. AB - BACKGROUND: Adolescents constitute an appealing target group for fighting stigma and discrimination surrounding mental illness, since it is during this developmental period that adult attitudes about mental illness are formed and consolidated. AIM: The aim of the present study was twofold, to explore adolescents' beliefs and attitudes to schizophrenia and to evaluate the effectiveness of an anti-stigma intervention in altering them. METHODS: A total of 616 high school students participated in the study, divided into a control condition and an anti-stigma intervention group. Data were collected at three time points: before the intervention, upon its completion and at a 12-month follow-up. RESULTS: Baseline measurements indicated that students espoused certain stereotypical beliefs about patients with schizophrenia and were reluctant to interact with them on some occasions. Upon completion of the intervention, positive changes were recorded in students' beliefs, attitudes and desired social distance; however, only the changes in beliefs and attitudes were maintained after one year. CONCLUSION: For anti-stigma interventions to be effective, they should be continuously delivered to students throughout the school years and allow for an interaction between students and patients. Health promotion programmes might be an appropriate context for incorporating such interventions. PMID- 21828174 TI - Arterial elasticity in American Indian and Caucasian children, adolescents, and young adults. AB - We compared arterial elasticity in American Indian and Caucasian children, adolescents, and young adults, and we assessed whether demographic, body composition, and ambulatory activity measures were predictive of arterial elasticity within each group. Fifty-one American Indians and 66 Caucasians between the ages of 8 and 30 years were assessed on large artery elasticity index, small artery elasticity index, body fat percentage, and daily ambulatory activity during 7 consecutive days. American Indians had a higher percentage of body fat than Caucasians (p = 0.002), whereas daily ambulatory activity measures were similar (p > 0.05). American Indians had a 16% lower large artery elasticity index (p = 0.007) and a 19% lower small artery elasticity index (p < 0.001) than Caucasians. The regression model for large artery elasticity index included average cadence (p = 0.001), fat-free mass (p < 0.001), age component (Caucasian only) (p < 0.001), and sex (p = 0.025). The regression model for small artery elasticity index included fat-free mass (p < 0.001), maximum cadence for 30 continuous minutes (p = 0.009), race (p = 0.005), and average cadence (p = 0.049). Between 8 and 30 years of age, elasticity means for the large and small arteries is lower in American Indians than in Caucasians. A smaller difference was observed in children, with a trend to a much larger difference in young adults. Furthermore, greater fat-free mass and higher daily ambulatory cadence are associated with higher arterial elasticity in both American Indians and Caucasians. PMID- 21828176 TI - Norepinephrine causes a biphasic change in mammalian pinealocye membrane potential: role of alpha1B-adrenoreceptors, phospholipase C, and Ca2+. AB - Perforated patch clamp recording was used to study the control of membrane potential (V(m)) and spontaneous electrical activity in the rat pinealocyte by norepinephrine. Norepinephrine did not alter spiking frequency. However, it was found to act through alpha(1B)-adrenoreceptors in a concentration-dependent manner (0.1-10 MUM) to produce a biphasic change in V(m). The initial response was a hyperpolarization (~13 mV from a resting potential of -46 mV) due to a transient (~5 sec) outward K(+) current (~50 pA). This current appears to be triggered by Ca(2+) released from intracellular stores, based on the observation that it was also seen in cells bathed in Ca(2+)-deficient medium. In addition, pharmacological studies indicate that this current was dependent on phospholipase C (PLC) activation and was in part mediated by bicuculline methiodide and apamin sensitive Ca(2+)-controlled K(+) channels. The initial transient hyperpolarization was followed by a sustained depolarization (~4 mV) due to an inward current (~10 pA). This response was dependent on PLC-dependent activation of Na(+)/Ca(2+) influx but did not involve nifedipine-sensitive voltage-gated Ca(2+) channels. Together, these results indicate for the first time that activation of alpha(1B)-adrenoreceptors initiates a PLC-dependent biphasic change in pinealocyte V(m) characterized by an initial transient hyperpolarization mediated by a mixture of Ca(2+)-activated K(+) channels followed by a sustained depolarization mediated by a Ca(2+)-conducting nonselective cation channel. These observations indicate that both continuous elevation of intracellular Ca(2+) and sustained depolarization at approximately -40 mV are associated with and are likely to be required for activation of the pinealocyte. PMID- 21828177 TI - IL-1beta stimulates activin betaA mRNA expression in human skin fibroblasts through the MAPK pathways, the nuclear factor-kappaB pathway, and prostaglandin E2. AB - During mouse skin wound healing, mRNAs encoding IL-1, activins, and TGF-betas significantly increased. To elucidate involvement of IL-1 in the regulation of activins and related factors in the wounded skin, human foreskin fibroblasts were stimulated with IL-1beta, and levels of mRNAs encoding activins, TGF-betas, and follistatin family proteins were examined by quantitative real-time PCR. IL-1beta increased activin betaA (INHBA) and follistatin (FST) mRNA expression within 6 h. A p38 MAPK inhibitor, SB202190, a MAPK/ERK kinase inhibitor, U0126, and an nuclear factor kappaB pathway inhibitor, SC-514, significantly suppressed the IL 1beta-stimulated INHBA and FST mRNA expression. A prostaglandin-endoperoxide synthase inhibitor indomethacin, a potent inhibitor of prostaglandin E(2) (PGE(2)) synthesis, also significantly suppressed the IL-1beta-stimulated INHBA but not FST mRNA expression. Furthermore, stimulation of fibroblasts with PGE(2) significantly increased INHBA mRNA. The PGE(2)-induced INHBA mRNA expression was significantly suppressed by U0126 and a protein kinase C inhibitor, Go 6983. Although IL-1beta stimulated FST mRNA in an acute phase, long-term exposure of fibroblasts to IL-1beta revealed time-dependent stimulatory and inhibitory effects of IL-1beta on FST mRNA expression. On the other hand, coculture with keratinocytes significantly increased INHBA mRNA expression in dermal equivalents. In summary, the present study indicates that the p38 MAPK, the MAPK/ERK kinase, the nuclear factor kappaB pathway, and PGE(2) mediate the effects of IL-1beta on INHBA mRNA expression. Furthermore, it is indicated that keratinocyte-derived factor of factors stimulate INHBA mRNA expression during wound healing. PMID- 21828179 TI - Oleic acid modulates metabolic substrate channeling during glucose-stimulated insulin secretion via NAD(P)H oxidase. AB - Positive acute effects of fatty acids (FA) on glucose-stimulated insulin secretion (GSIS) and reactive oxygen species (ROS) formation have been reported. However, those studies mainly focused on palmitic acid actions, and reports on oleic acid (OA) are scarce. In this study, the effect of physiological OA levels on beta-cell function and the mechanisms involved were investigated. Analyses of insulin secretion, FA and glucose oxidation, and ROS formation showed that, at high glucose concentration, OA treatment increases GSIS in parallel with increased ROS content. At high glucose, OA oxidation was increased, accompanied by a suppression of glucose oxidation. Using approaches for protein knockdown of FA receptor G protein-coupled receptor 40 (GPR40) and of p47(PHOX), a reduced nicotinamide adenine dinucleotide phosphate [NAD(P)H] oxidase component, we observed that GPR40 does not mediate OA effects on ROS formation and GSIS. However, in p47(PHOX) knockdown islets, OA-induced ROS formation and the inhibitory effect of OA on glucose metabolism was abolished. Similar results were obtained by pharmacological inhibition of protein kinase C, a known activator of NAD(P)H oxidase. Thus, ROS derived from OA metabolism via NAD(P)H oxidase are an inhibitor of glucose oxidation. Put together, these results indicate that OA acts as a modulator of glucose oxidation via ROS derived from its own metabolism in beta-cells. PMID- 21828178 TI - A rapid release of corticosteroid-binding globulin from the liver restrains the glucocorticoid hormone response to acute stress. AB - A strict control of glucocorticoid hormone responses to stress is essential for health. In blood, glucocorticoid hormones are for the largest part bound to corticosteroid-binding globulin (CBG), and just a minor fraction of hormone is free. Only free glucocorticoid hormone is able to exert biological effects, but little is known about its regulation during stress. We found, using a dual-probe in vivo microdialysis method, that in rats, the forced-swim stress-induced rise in free corticosterone (its major glucocorticoid hormone) is strikingly similar in the blood and in target compartments such as the subcutaneous tissue and the brain. However, in all compartments, the free corticosterone response was delayed by 20-30 min as compared with the total corticosterone response in the blood. We discovered that CBG is the key player in this delay. Swim stress evoked a fast (within 5 min) and profound rise in CBG protein and binding capacity in the blood through a release of the protein from the liver. Thus, the increase in circulating CBG levels after stress restrains the rise in free corticosterone concentrations for approximately 20 min in the face of mounting total hormone levels in the circulation. The stress-induced increase in CBG seems to be specific for moderate and strong stressors. Both restraint stress and forced swimming caused an increase in circulating CBG, whereas its levels were not affected by mild novelty stress. Our data uncover a new, highly dynamic role for CBG in the regulation of glucocorticoid hormone physiology after acute stress. PMID- 21828180 TI - Melanocortin 4 receptor activation protects against testicular ischemia reperfusion injury by triggering the cholinergic antiinflammatory pathway. AB - Melanocortins (MC) trigger a vagus nerve-mediated cholinergic-antiinflammatory pathway projecting to the testis. We tested whether pharmacological activation of brain MC receptors might protect the testis from the damage induced by ischemia reperfusion. Adult male rats were subjected to 1-h testicular ischemia, followed by 24-h reperfusion [testicular ischemia-reperfusion (TI/R)]. Before TI/R, groups of animals were subjected to bilateral cervical vagotomy, or pretreated with the nicotinic acetylcholine receptor antagonist chlorisondamine or the selective MC(4) receptor antagonist HS024. Immediately after reperfusion, rats were ip treated with saline or the MC analog [Nle(4),D-Phe(7)]alpha-melanocyte stimulating hormone (NDP-alpha-MSH) (340 MUg/kg). We evaluated testicular IL-6 and TNF-alpha by Western blot analysis and organ damage by light microscopy. Some experimental groups were prepared for neural efferent activity recording along the vagus nerve starting 30 min after treatment with NDP-alpha-MSH or saline, and for a 30-min period. Additional groups of TI/R rats were treated for 30 d with saline, NDP-alpha-MSH, chlorisondamine plus NDP-alpha-MSH, or HS024 plus NDP alpha-MSH to evaluate spermatogenesis, organ damage, and the apoptosis machinery. After a 24-h reperfusion, in TI/R saline-treated rats, there was an increase in IL-6 and TNF-alpha expression and a marked damage in both testes. NDP-alpha-MSH inhibited IL-6 and TNF-alpha expression, decreased histological damage, and increased neural efferent activity. Furthermore, NDP-alpha-MSH administration for 30 d greatly improved spermatogenesis, reduced organ damage, and inhibited apoptosis. All positive NDP-alpha-MSH effects were abrogated by vagotomy, chlorisondamine, or HS024. Our data suggest that selective MC(4) receptor agonists might be therapeutic candidates for the management of testicular torsion. PMID- 21828181 TI - Nutrient responsive nesfatin-1 regulates energy balance and induces glucose stimulated insulin secretion in rats. AB - Nesfatin-1 is a recently discovered anorexigen, and we first reported nesfatin like immunoreactivity in the pancreatic beta-cells. The aim of this study was to characterize the effects of nesfatin-1 on whole-body energy homeostasis, insulin secretion, and glycemia. The in vivo effects of continuous peripheral delivery of nesfatin-1 using osmotic minipumps on food intake and substrate partitioning were examined in ad libitum-fed male Fischer 344 rats. The effects of nesfatin-1 on glucose-stimulated insulin secretion (GSIS) were examined in isolated pancreatic islets. L6 skeletal muscle cells and isolated rat adipocytes were used to assess the effects of nesfatin-1 on basal and insulin-mediated glucose uptake as well as on major steps of insulin signaling in these cells. Nesfatin-1 reduced cumulative food intake and increased spontaneous physical activity, whole-body fat oxidation, and carnitine palmitoyltransferase I mRNA expression in brown adipose tissue but did not affect uncoupling protein 1 mRNA in the brown adipose tissue. Nesfatin-1 significantly enhanced GSIS in vivo during an oral glucose tolerance test and improved insulin sensitivity. Although insulin-stimulated glucose uptake in L6 muscle cells was inhibited by nesfatin-1 pretreatment, basal and insulin induced glucose uptake in adipocytes from nesfatin-1-treated rats was significantly increased. In agreement with our in vivo results, nesfatin-1 enhanced GSIS from isolated pancreatic islets at both normal (5.6 mM) and high (16.7 mM), but not at low (2 mM), glucose concentrations. Furthermore, nesfatin 1/nucleobindin 2 release from rat pancreatic islets was stimulated by glucose. Collectively, our data indicate that glucose-responsive nesfatin-1 regulates insulin secretion, glucose homeostasis, and whole-body energy balance in rats. PMID- 21828182 TI - Visualizing microtubule-dependent vasopressin type 2 receptor trafficking using a new high-affinity fluorescent vasopressin ligand. AB - The vasopressin receptor type 2 (V2R) is the major target of vasopressin (VP) in renal epithelial cells. Although it is known that VP induces V2R internalization, accumulation in the perinuclear area, and degradation, the V2R intracellular trafficking pathways remain elusive. We visualized this process by developing a new fluorescent VP analog tagged by tetramethylrhodamine (TMR)-[Lys-(PEG)(2)-Suc TMR(8)]VP or (VP(TMR)). This ligand is fully functional as revealed by its high binding affinity toward V2R [(K(d)) =157 +/- 52 nM] and ability to increase intracellular cAMP 32-fold. VP(TMR) induced V2R internalization in LLC-PK1 cells expressing either a FLAG-tagged receptor (FLAG-V2R) or V2R C-terminally tagged with green fluorescent protein (GFP) (V2R-GFP). After internalization, VP(TMR) and V2R-GFP colocalized in the perinuclear area, suggesting that the hormone and receptor traffic along the same pathway. VP(TMR) and V2R colocalized initially with the early endosome markers EEA1 and Rab5, and later with the recycling and late endosome markers Rab11 and Rab25. Epifluorescence microscopy of LLC-PK1 cells expressing GFP-tagged microtubules (MT) showed that VP(TMR)-containing vesicles travel along the MT network, and even remain attached to MT during the metaphase and anaphase of mitosis. Colchicine, a MT-depolymerizing agent, abolished perinuclear accumulation of VP(TMR), and Western blot analysis showed that VP-induced V2R-GFP degradation is markedly retarded, but not abolished, by colchicine (10 MUM). We conclude that the new VP(TMR) ligand is suitable for dissecting V2R and VP internalization and trafficking in cells, and that V2R trafficking and down-regulation is an MT-dependent mechanism. PMID- 21828184 TI - Progesterone and Nestorone facilitate axon remyelination: a role for progesterone receptors. AB - Enhancing the endogenous capacity of myelin repair is a major therapeutic challenge in demyelinating diseases such as multiple sclerosis. We found that progesterone and the synthetic 19-norprogesterone derivative 16-methylene-17alpha acetoxy-19-norpregn-4-ene-3,20-dione (Nestorone) promote the remyelination of axons by oligodendrocytes after lysolecithin-induced demyelination in organotypic cultures of cerebellar slices taken from postnatal rats or mice. The intracellular progesterone receptors (PR) mediate the proremyelinating actions of Nestorone, because they are not observed in slices from PR knockout mice. Notably, Nestorone was less efficient in heterozygous mice, expressing reduced levels of PR, suggesting PR haploinsufficiency in myelin repair. Using mice expressing the enhanced green fluorescent protein (EGFP) under the control of the proteolipid gene promoter, we showed that both progesterone and Nestorone strongly increased the reappearance of cells of the oligodendroglial lineage in the demyelinated slices. In contrast to Nestorone, the pregnane derivative medroxyprogesterone acetate had no effect. The increase in oligodendroglial cells by Nestorone resulted from enhanced NG2(+) and Olig2(+) oligodendrocyte progenitor cell (OPC) recruitment. In cocultures of lysolecithin-demyelinated cerebellar slices from wild-type mice apposed to brain stem slices of proteolipid gene promoter-EGFP mice, Nestorone stimulated the migration of OPC towards demyelinated axons. In this coculture paradigm, Nestorone indeed markedly increased the number of EGFP(+) cells migrating into the demyelinated cerebellar slices. Our results show that Nestorone stimulates the recruitment and maturation of OPC, two steps which are limiting for efficient myelin repair. They may thus open new perspectives for the use of progestins, which selectively target PR, to promote the endogenous regeneration of myelin. PMID- 21828183 TI - The thyroid hormone-inactivating type III deiodinase is expressed in mouse and human beta-cells and its targeted inactivation impairs insulin secretion. AB - Deiodinases are selenoproteins that activate or inactivate thyroid hormone. During vertebrate development, these pathways control thyroid hormone action in a cell-specific fashion explaining how systemic thyroid hormone can affect local control of tissue embryogenesis. Here we investigated the role of the thyroid hormone-inactivating deiodinase (D3) in pancreatic islet function and glucose homeostasis. D3 expression was determined by real-time PCR, immunofluorescence, and enzyme activity. Embryonic and adult wild-type mice and Mice with targeted disruption of Dio3 gene (D3KO) as well as human fetal pancreas and adult islets were studied. Insulin secretion was evaluated in adult mouse isolated islets. We found Dio3 gene expression and protein highly expressed in embryonic and adult pancreatic islets, predominantly in beta-cells in both humans and mice. However, mRNA levels were barely detectable for both the thyroid hormone-activating deiodinases types 1 and 2. D3KO animals were found to be glucose intolerant due to in vitro and in vivo impaired glucose-stimulated insulin secretion, without changes in peripheral sensitivity to insulin. D3KO neonatal (postnatal day 0) and adult pancreas exhibited reduced total islet area due to reduced beta-cell mass, insulin content, and impaired expression of key beta-cells genes. D3 expression in perinatal pancreatic beta-cells prevents untimely exposure to thyroid hormone, the absence of which leads to impaired beta-cell function and subsequently insulin secretion and glucose homeostasis. An analogous role is likely in humans, given the similar D3 expression pattern. PMID- 21828185 TI - The P2Y(6) receptor stimulates bone resorption by osteoclasts. AB - Accumulating evidence indicates that extracellular nucleotides, signaling through P2 receptors, play a significant role in bone remodeling. Osteoclasts (the bone resorbing cell) and osteoblasts (the bone-forming cell) display expression of the G protein-coupled P2Y(6) receptor, but the role of this receptor in modulating cell function is unclear. Here, we demonstrate that extracellular UDP, acting via P2Y(6) receptors, stimulates the formation of osteoclasts from precursor cells, while also enhancing the resorptive activity of mature osteoclasts. Furthermore, osteoclasts derived from P2Y(6) receptor-deficient (P2Y(6)R(-/-)) animals displayed defective function in vitro. Using dual energy x-ray absorptiometry scanning and microcomputed tomographic analysis we showed that P2Y(6)R(-/-) mice have increased bone mineral content, cortical bone volume, and cortical thickness in the long bones and spine, whereas trabecular bone parameters were unaffected. Histomorphometric analysis showed the perimeter of the bone occupied by osteoclasts on the endocortical and trabecular surfaces was decreased in P2Y(6)R( /-) mice. Taken together these results show the P2Y(6) receptor may play an important role in the regulation of bone cell function in vivo. PMID- 21828186 TI - Metastatic ovarian and primary peritoneal cancer: assessing chemotherapy response with diffusion-weighted MR imaging--value of histogram analysis of apparent diffusion coefficients. AB - PURPOSE: To prospectively evaluate apparent diffusion coefficient (ADC) histograms in the prediction of chemotherapy response in patients with metastatic ovarian or primary peritoneal cancer. MATERIALS AND METHODS: Research ethics committee approval and patient written informed consent were obtained. Diffusion weighted (DW) magnetic resonance (MR) imaging was performed through the abdomen and pelvis before and after one and three cycles of chemotherapy in 42 women (mean age, 63.0 years +/- 11.4 [standard deviation]) with newly diagnosed or recurrent disease. Reproducibility and intra- and interobserver agreement of ADC calculations were assessed. Per-patient weighted ADC histograms were generated at each time point from pixel ADCs from five or fewer target lesions. Mean ADC, percentiles (10th, 25th, 50th, 75th, 90th), skew, kurtosis, and their change were analyzed according to histologic grade, primary versus recurrent disease status, and response, determined with integrated biochemical and morphologic criteria, with a linear mixed model. Areas under receiver operating characteristic curve (AUCs) for combinations of parameters were calculated with linear discriminant analysis. RESULTS: Coefficients of variation for repeat measurements and for within and between observers were 4.8%, 11.4%, and 13.7%, respectively. Grade and disease status did not significantly affect histogram parameters. Pretreatment ADCs were not predictive of response. In responders, all ADCs increased after the first and third cycle (P < .001), while skew and kurtosis decreased after the third (P < .001 and P = .006, respectively); however, in nonresponders, no parameter changed significantly. Percentage change of the 25th percentile performed best in identifying response (AUC = 0.82 and 0.83 after first and third cycle, respectively), whereas combination of parameters did not improve accuracy. CONCLUSION: An early increase of ADCs and later decrease of skew and kurtosis characterize chemotherapy response. Quantitative DW MR imaging can aid in early monitoring of treatment efficacy in patients with advanced ovarian cancer. PMID- 21828187 TI - The secretory flow of pancreatic juice in the main pancreatic duct: visualization by means of MRCP with spatially selective inversion-recovery pulse. AB - PURPOSE: To assess the feasibility of visualizing noninvasively the physiologic flow of pancreatic juice by using serial magnetic resonance cholangiopancreatography (MRCP) with a spatially selective inversion-recovery (IR) pulse in volunteers and patients with pancreatic disease. MATERIALS AND METHODS: The study was approved by the institutional review board, and informed consent was obtained. Twelve healthy volunteers and three patients with acute pancreatitis were included. MRCP with a spatially selective IR pulse was repeatedly performed every 15 seconds during a total of 10 minutes (total of 40 images). MRCP images were evaluated for the presence, frequency, and magnitude of pancreatic juice inflow within the tagged area. The two groups were compared by using the Mann-Whitney test. RESULTS: Pancreatic juice inflow was observed in all healthy volunteers and in two of three patients with acute pancreatitis. The pancreatic fluid inflow was observed 25-37 times (median, 32 times; mean, 31.4 times; range, 25-37 times) in a series of 40 images in 12 healthy volunteers, while it was seen 0-11 times (median, 2 times; mean, 4.3 times; range, 0-11 times) in a series of 40 images in the three patients with acute pancreatitis (P = .009). No regularity in the timing of the pancreatic fluid inflow was noted. The distance that the pancreatic fluid moved in the pancreatic duct within the tagged area was significantly longer in healthy volunteers (median grade, 2.46; mean grade, 2.41; range, 1.6-3.3) than in patients with acute pancreatitis (median grade, 0.05; mean grade, 0.13; range, 0-0.35) (P = .009). CONCLUSION: The physiologic flow of the pancreatic juice can be visualized noninvasively with serial MRCP by using a spatially selective IR pulse. PMID- 21828188 TI - Timing of cardiovascular MR imaging after acute myocardial infarction: effect on estimates of infarct characteristics and prediction of late ventricular remodeling. AB - PURPOSE: To define the evolution of infarct characteristics with cardiovascular magnetic resonance (MR) imaging and to assess which of the cardiovascular MR data acquired at day 2 or at 1 week after acute myocardial infarction (AMI), is the stronger predictor of infarct size and left ventricular (LV) function measured at 3 months. MATERIALS AND METHODS: The study protocol was reviewed and approved by the local research ethics committee, and written informed consent was obtained. Forty-eight patients with reperfused AMI underwent cine, T2-weighted, and late gadolinium enhancement cardiovascular MR imaging at days 2, 7, 30, and 90 after index presentation. Continuous data between times were compared by using paired t tests or one-way analysis of variance. Multiple linear regression analyses were used to predict linear end points. RESULTS: Infarct size and extent of myocardial edema decreased significantly between day 2 and 1 week: Mean scar as a percentage of LV mass and standard deviation (SD), respectively, were 27.2 and 13.9 versus 21.6 and 14.1 (P < .001), and myocardial edema as a percentage of LV mass and SD, respectively, were 37.9 and 15.2 versus 32.3 and 14.3 (P = .003). These changes were accompanied by a significant improvement in LV ejection fraction (LVEF): Mean percentage of LVEF and SD, respectively, were 41.7 and 9.6 versus 44.6 and 10.1 (P < .001). When comparing data acquired at day 2 and 1 week, only cardiovascular MR data acquired at 1 week were independent predictors of LVEF and infarct size at 3 months. CONCLUSION: LVEF, infarct size, and extent of myocardial edema changed significantly during the 1st week after AMI. Overall, cardiovascular MR measurements acquired after 1 week have greater predictive value for infarct size and LV function at 3 months than data acquired at day 2. PMID- 21828190 TI - MR imaging and outcome of term neonates with perinatal asphyxia: value of diffusion-weighted MR imaging and 1H MR spectroscopy. AB - PURPOSE: To compare the association between neurodevelopmental outcome in neonates with hypoxic-ischemic encephalopathy following perinatal asphyxia and (a) apparent diffusion coefficients (ADCs) in the thalamus and basal ganglia at diffusion-weighted (DW) magnetic resonance (MR) imaging and (b) hydrogen 1 (1H) MR spectroscopic measurements in the basal ganglia. MATERIALS AND METHODS: This retrospective study was approved by the local ethics committee, and the requirement to obtain informed consent was waived. Eighty-one term neonates with perinatal asphyxia underwent conventional and DW cranial MR imaging (median age, 4 days; age range, 1-14 days); 51 neonates also underwent 1H MR spectroscopy. Neurodevelopment was assessed from 18 to 46 months. Patients with favorable and adverse outcomes were compared. Receiver operating characteristics analysis was performed in all patients, and uni- and multivariate logistic regression analyses were performed in 44 patients examined within 7 days of birth by using MR imaging scores, ADCs in the basal ganglia and thalamus, and 1H MR spectroscopic measurements in the basal ganglia. RESULTS: An adverse outcome was seen in 28 of all 81 neonates (20 died, seven developed cerebral palsy, and one had severe mental retardation) and 22 of the 44 neonates examined within 7 days of birth with both ADC and 1H MR spectroscopy. Poor outcome was associated with (a) lower ADCs in the basal ganglia (P < .001) and thalamus (P = .001) of neonates examined within 7 days of birth and (b) a higher lactate (Lac)-N-acetylaspartate (NAA) ratio in the basal ganglia (P < .001). Multivariate analysis showed that MR imaging score combined with Lac/NAA ratios or ADCs in the basal ganglia within the 1st week of life had a better association with outcome than did MR imaging alone (P = .006, area under the receiver operating characteristic curve [AUC] = 0.85 with Lac/NAA ratio; P < .0001, AUC = 0.93 with ADCs in basal ganglia). CONCLUSION: The combination of MR imaging score with ADCs or Lac/NAA ratios in the basal ganglia has a better association with outcome of asphyxiated term neonates than does MR imaging alone. PMID- 21828189 TI - Discrimination of benign and malignant breast lesions by using shutter-speed dynamic contrast-enhanced MR imaging. AB - PURPOSE: To assess the accuracy of the shutter-speed approach compared with standard approach dynamic contrast material-enhanced magnetic resonance (MR) imaging pharmacokinetic analysis for breast cancer diagnosis. MATERIALS AND METHODS: This study was approved by the institutional review board and was HIPAA compliant. Informed consent was obtained from 89 high-risk women (age range, 28 83 years) who had 92 suspicious lesions with negative findings at mammography (but visible at MR imaging). Each underwent a research dynamic contrast-enhanced MR imaging examination just prior to a clinical MR imaging-guided interventional procedure. Tumor region of interest (ROI) averaged and (for some) pixel-by-pixel dynamic contrast-enhanced time-course data, together with mean arterial input function, were subjected to serial standard and shutter-speed approach analyses to extract pharmacokinetic parameters, including rate constant for passive contrast reagent transfer between plasma and interstitium (K(trans)) and interstitial space volume fraction, or v(e). Pathologic findings were used as reference standards. Diagnostic accuracy was assessed with receiver operating characteristic analyses. RESULTS: The pathologic analyses revealed 20 malignant and 72 benign lesions. Positive predictive value of the institutional clinical breast MR imaging protocol was 22%. At 100% sensitivity, ROI-averaged shutter speed approach K(trans) had significantly (P = .008) higher diagnostic specificity than standard approach K(trans): 86.1% versus 77.8%. The difference in the ROI-averaged K(trans) parameter value, or DeltaK(trans) (= K(trans) [shutter-speed approach] - K(trans) [standard approach]), had even higher specificity (88.9%). Combined use of ROI analysis and pixel-by-pixel mapping of DeltaK(trans) achieved 98.6% specificity at 100% sensitivity. CONCLUSION: The use of the shutter-speed dynamic contrast-enhanced MR imaging method has the potential to improve breast cancer diagnostic accuracy and reduce putatively unnecessary biopsy procedures that yield benign pathologic findings. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.11102413/ /DC1. PMID- 21828191 TI - Extrapulmonary malignancies detected at lung cancer screening. AB - PURPOSE: To retrospectively assess the detection rate, histologic characteristics, and clinical stage of screening-detected extrapulmonary malignancies in a population at high risk for lung cancer. MATERIALS AND METHODS: In this institutional review board-approved study, 5201 asymptomatic heavy smokers aged 50 years or older underwent annual low-dose computed tomography (CT) for 5 consecutive years. The 5-year cumulative effective dose was 5 mSv. Subjects with at least one "potentially significant extrapulmonary incidental finding" (PS IF) were extracted from the study database. An extrapulmonary finding was classified as potentially significant if it required further diagnostic and/or clinical evaluation. In retrospect all clinically relevant information, including findings from diagnostic work-up and final diagnosis of the PS-IF, was collected. On the basis of the information collected, only histologically proved screening detected extrapulmonary malignancies were eventually included in this study. The percentages of volunteers with extrapulmonary malignancies were calculated, along with 95% confidence intervals (CIs), on the basis of a binomial distribution. RESULTS: After 5 years of CT screening, 27 unsuspected extrapulmonary malignancies were diagnosed, representing 0.5% (27 of 5201 subjects; 95% CI: 0.34%, 0.75%) of volunteers enrolled and 6.2% (27 of 436 findings; 95% CI: 4.12%, 8.88%) of PS-IFs. Eight malignancies were diagnosed at the 1st year of screening, nine at the 2nd year, four at the 3rd year, two at the 4th year, and four at the 5th year. Twelve of the 27 extrapulmonary tumors (44%) were renal carcinomas (n = 7) or lymphomas (n = 5). Twenty-four of the 27 subjects with a malignancy were alive at the most recent follow-up. CONCLUSION: A considerable number of unsuspected extrapulmonary malignancies can be detected in lung cancer screening trials. A careful evaluation of extrapulmonary structures, with particular attention to the kidneys and lymph nodes, is recommended. PMID- 21828192 TI - Coronary artery stenoses: accuracy of 64-detector row CT angiography in segments with mild, moderate, or severe calcification--a subanalysis of the CORE-64 trial. AB - PURPOSE: To evaluate the influence of cross-sectional arc calcification on the diagnostic accuracy of computed tomography (CT) angiography compared with conventional coronary angiography for the detection of obstructive coronary artery disease (CAD). MATERIALS AND METHODS: Institutional Review Board approval and written informed consent were obtained from all centers and participants for this HIPAA-compliant study. Overall, 4511 segments from 371 symptomatic patients (279 men, 92 women; median age, 61 years [interquartile range, 53-67 years]) with clinical suspicion of CAD from the CORE-64 multicenter study were included in the analysis. Two independent blinded observers evaluated the percentage of diameter stenosis and the circumferential extent of calcium (arc calcium). The accuracy of quantitative multidetector CT angiography to depict substantial (>= 50%) stenoses was assessed by using quantitative coronary angiography (QCA). Cross-sectional arc calcium was rated on a segment level as follows: noncalcified or mild (< 90 degrees ), moderate (90 degrees -180 degrees ), or severe (> 180 degrees ) calcification. Univariable and multivariable logistic regression, receiver operation characteristic curve, and clustering methods were used for statistical analyses. RESULTS: A total of 1099 segments had mild calcification, 503 had moderate calcification, 338 had severe calcification, and 2571 segments were noncalcified. Calcified segments were highly associated (P < .001) with disagreement between CTA and QCA in multivariable analysis after controlling for sex, age, heart rate, and image quality. The prevalence of CAD was 5.4% in noncalcified segments, 15.0% in mildly calcified segments, 27.0% in moderately calcified segments, and 43.0% in severely calcified segments. A significant difference was found in area under the receiver operating characteristic curves (noncalcified: 0.86, mildly calcified: 0.85, moderately calcified: 0.82, severely calcified: 0.81; P < .05). CONCLUSION: In a symptomatic patient population, segment-based coronary artery calcification significantly decreased agreement between multidetector CT angiography and QCA to detect a coronary stenosis of at least 50%. PMID- 21828194 TI - The pharmacological profile of brain liver intestine Na+ channel: inhibition by diarylamidines and activation by fenamates. AB - The brain liver intestine Na(+) channel (BLINaC) is a member of the degenerin/epithelial Na(+) channel gene family of unknown function. Elucidation of the physiological function of BLINaC would benefit greatly from pharmacological tools that specifically affect BLINaC activity. Guided by the close molecular relation of BLINaC to acid-sensing ion channels, we discovered in this study that rat BLINaC (rBLINaC) and mouse BLINaC are inhibited by micromolar concentrations of diarylamidines and nafamostat, similar to acid-sensing ion channels. Inhibition was voltage-dependent, suggesting pore block as the mechanism of inhibition. Furthermore, we identified the fenamate flufenamic acid and related compounds as agonists of rBLINaC. Application of millimolar concentrations of flufenamic acid to rBLINaC induced a robust, Na(+)-selective current, which was blocked partially by amiloride. The identification of an artificial agonist of rBLINaC supports the hypothesis that rBLINaC is opened by an unknown physiological ligand. Inhibition by diarylamidines and activation by fenamates define a unique pharmacological profile for BLINaC, which will be useful to unravel the physiological function of this ion channel. PMID- 21828195 TI - Escalation to natalizumab or switching among immunomodulators in relapsing multiple sclerosis. AB - OBJECTIVE: To evaluate whether an escalation approach was more effective in suppressing clinical and magnetic resonance imaging (MRI) activity than switching among immunomodulators in relapsing-remitting multiple sclerosis (RRMS) patients. METHODS: In this post-marketing, prospective, observational study in two Italian multiple sclerosis (MS) centres, a total of 285 RRMS patients who failed a first line treatment with interferon beta (IFNbeta) or glatiramer acetate (GA) were considered. Patients were subdivided according to the strategy adopted after the failure (defined as the occurrence of >=2 relapses or 1 relapse with residual disability): the switching (SWI) group, i.e. those switched among different IFNbeta formulations, or from IFNbeta to GA and vice versa; and the escalating (ESC) group, i.e. those escalated to natalizumab. Proportions of patients free from different types of disease activity (relapses, sustained disability progression, new active lesions on MRI, or a combination of them) were calculated at 12 and 24 months. Since patients were not randomized to treatment group, propensity score (PS)-adjusted Cox regression models were built to control for several potential confounders. RESULTS: At 12 months there were no differences between the two groups in proportions of patients free from relapse, disability progression, MRI activity, and combined activity. After 24 months we observed greater proportions of patients in the ESC than SWI group free from relapse (p < 0.0001), disability progression (p = 0.0045), MRI activity (p = 0.0003), and combined activity (p < 0.0001). PS-adjusted models confirmed these findings, with hazard ratios ranging from 0.38 to 0.56 favours the ESC group. CONCLUSION: We suggest that an escalation to natalizumab is more effective than switching among immunomodulators in RRMS patients who failed a first-line treatment. PMID- 21828196 TI - Factor structure of Guy's Neurological Disability Scale in a sample of Dutch patients with multiple sclerosis. AB - BACKGROUND: Guy's Neurological Disability Scale (GNDS) is designed to assess disability (i.e. activity limitations) in patients with multiple sclerosis. It contains 12 functional domains, each indicating a level of disability. Four domain scores and a total score can be calculated. OBJECTIVE: The aim of this study was to evaluate the structural validity of the GNDS in a Dutch population who were definitely diagnosed as having multiple sclerosis. METHODS: Data of 974 patients were available. The structural validity of the GNDS was evaluated by confirmatory item factor analysis (CIFA). Two first-order models and two bifactor models were investigated. RESULTS: The best fitted model was a bifactor model with a general factor underlying all items, and 10 items loading on 3 group factors. Cronbach's alpha on the general factor (0.78) and on the group factor spinal-plus (0.74) were satisfying. Cronbach's alpha on the group factors mental (0.56) and bulbar (0.48) were low. Reliability based on CIFA was 0.85. CONCLUSION: Results showed a clear factor structure of the GNDS. It justifies the use of the total score of the GNDS. In addition, three sub-scale scores could be used. PMID- 21828198 TI - H1N1 vaccination does not increase risk of relapse in multiple sclerosis: a self controlled case-series study. PMID- 21828197 TI - Genetic variations within the OPA1 gene are not associated with neuromyelitis optica. AB - Neuromyelitis optica (NMO) is an idiopathic demyelinating disease which predominantly affects the optic nerve and spinal cord. Multiplex NMO pedigrees have been reported but the genetic risk factors conferring this increased familial susceptibility have not yet been determined. OPA1 mutations have recently been identified in families with progressive visual failure and spastic paraparesis, raising the possibility that OPA1 genetic variants could contribute to the aetiology of NMO. We therefore screened for OPA1 in 32 patients with NMO. No pathogenic mutations were found, and none of the 13 single-nucleotide polymorphisms identified were associated with an increased risk of developing NMO. PMID- 21828199 TI - Cortical oscillopsia without nystagmus, an isolated symptom of neuromyelitis optica spectrum disorder with anti-aquaporin 4 antibody. AB - Neuromyelitis optica (NMO), mainly affecting optic nerve and spinal cord, can also manifest diverse ocular symptoms due to brain abnormalities. We present a cortical oscillopsia without nystagmus or head tremor in a patient with neuromyelitis optica spectrum disorder (NMOSD) with anti-aquaporin 4 antibody. This rare ocular manifestation, which is easily underestimated owing to absence of the typical nystagmus, can be an initial manifestation of NMOSD. PMID- 21828200 TI - Functional magnetic resonance imaging correlates of cognitive performance in patients with a clinically isolated syndrome suggestive of multiple sclerosis at presentation: an activation and connectivity study. AB - BACKGROUND/OBJECTIVE: To assess whether abnormalities on functional magnetic resonance imaging (fMRI) are related to cognitive function in patients at presentation with clinically isolated syndrome (CIS) suggestive of multiple sclerosis. METHODS: Eighteen patients with CIS and 15 healthy controls (HCs) performed an adapted fMRI version of the Paced Auditory Serial Addition Test (PASAT). According to their PASAT performance, CIS patients were divided into two groups: 10 with a low PASAT performance (<1 SD from the mean value of HCs) were considered 'cognitive impairment' (CI); eight patients were defined as 'cognitively preserved' (CP). Between-group differences in the patterns of brain activations and effective connectivity were assessed. RESULTS: During PASAT, compared to HCs, CIS patients showed increased activations of the bilateral inferior parietal lobe (IPL), bilateral precuneus, bilateral middle frontal gyrus (MFG), left anterior cingulate cortex (ACC), left claustrum, right thalamus and right caudate nucleus. When CIS patients were analyzed, the CI group had a more significant activation of the bilateral IPL than HCs and CP patients. Compared to CP patients, they also had more significant recruitment of the right superior parietal lobe, right cerebellum, left MFG and left ACC. The analysis of effective connectivity showed stronger connections between several regions of the right hemisphere involved in working memory function in CI patients versus CP and HC. CONCLUSIONS: During performance of the PASAT, CIS patients show abnormalities in the patterns of cortical recruitment and connectivity related to the level of their cognitive impairment. PMID- 21828201 TI - Maximally tolerated versus minimally effective dose: the case of rituximab in multiple sclerosis. PMID- 21828202 TI - Antibodies against aquaporin-4 in neuromyelitis optica: distinction between recurrent and monophasic patients. AB - The detection of antibodies against aquaporin-4 (AQP4) has improved the diagnosis of neuromyelitis optica (NMO). We evaluated a recently established cell-based anti-AQP4 assay in 273 patients with inflammatory CNS demyelination. The assay had a specificity of 99% and a sensitivity of 56% to detect all NMO patients and of 74% to detect the recurrent NMO patients, similar to the initial studies reported. AQP4 antibodies were absent in monophasic NMO patients, while samples in recurrent cases remained positive during follow-up. We conclude that the pathogenesis of monophasic NMO may be different from that of relapsing NMO. PMID- 21828204 TI - "Irrelevant" WHO outpaced by younger rivals. PMID- 21828203 TI - Waking up to darkness. PMID- 21828205 TI - Bahraini authorities force Medecins Sans Frontieres to leave the country. PMID- 21828208 TI - Correcting refractive error in low income countries. PMID- 21828207 TI - Self correction of refractive error among young people in rural China: results of cross sectional investigation. AB - OBJECTIVE: To compare outcomes between adjustable spectacles and conventional methods for refraction in young people. DESIGN: Cross sectional study. SETTING: Rural southern China. PARTICIPANTS: 648 young people aged 12-18 (mean 14.9 (SD 0.98)), with uncorrected visual acuity <= 6/12 in either eye. INTERVENTIONS: All participants underwent self refraction without cycloplegia (paralysis of near focusing ability with topical eye drops), automated refraction without cycloplegia, and subjective refraction by an ophthalmologist with cycloplegia. MAIN OUTCOME MEASURES: Uncorrected and corrected vision, improvement of vision (lines on a chart), and refractive error. RESULTS: Among the participants, 59% (384) were girls, 44% (288) wore spectacles, and 61% (393/648) had 2.00 dioptres or more of myopia in the right eye. All completed self refraction. The proportion with visual acuity >= 6/7.5 in the better eye was 5.2% (95% confidence interval 3.6% to 6.9%) for uncorrected vision, 30.2% (25.7% to 34.8%) for currently worn spectacles, 96.9% (95.5% to 98.3%) for self refraction, 98.4% (97.4% to 99.5%) for automated refraction, and 99.1% (98.3% to 99.9%) for subjective refraction (P = 0.033 for self refraction v automated refraction, P = 0.001 for self refraction v subjective refraction). Improvements over uncorrected vision in the better eye with self refraction and subjective refraction were within one line on the eye chart in 98% of participants. In logistic regression models, failure to achieve maximum recorded visual acuity of 6/7.5 in right eyes with self refraction was associated with greater absolute value of myopia/hyperopia (P<0.001), greater astigmatism (P = 0.001), and not having previously worn spectacles (P = 0.002), but not age or sex. Significant inaccuracies in power (>= 1.00 dioptre) were less common in right eyes with self refraction than with automated refraction (5% v 11%, P<0.001). CONCLUSIONS: Though visual acuity was slightly worse with self refraction than automated or subjective refraction, acuity was excellent in nearly all these young people with inadequately corrected refractive error at baseline. Inaccurate power was less common with self refraction than automated refraction. Self refraction could decrease the requirement for scarce trained personnel, expensive devices, and cycloplegia in children's vision programmes in rural China. PMID- 21828209 TI - Maternal mortality in the UK and the need for obstetric physicians. PMID- 21828212 TI - After the nuclear incident, Fukushima has now been hit by floods. PMID- 21828214 TI - The rust genus Frommeella revisited: a later synonym of Phragmidium after all. AB - Frommeella (Phragmidiaceae, Pucciniales, Basidiomycota), which currently includes two species and is typified by F. tormentillae, causes rust on members of tribe Potentilleae (Rosaceae). The genus has been distinguished from Phragmidium on the basis of having only one germ pore per teliospore cell rather than two or three and by aecial characters. Phylogenetic analyses of both currently accepted Frommeella spp. with nLSU rDNA data suggest that Frommeella was derived from within a clade representing Phragmidium. Thus Frommeella should be considered to be a later generic synonym of Phragmidium. Analyses also indicate that Frommeella tormentillae on Potentilla species includes two taxa recognized herein as Phragmidium potentillae-canadensis and P. tormentillae. Frommeella mexicana on Potentilla spp. formerly classified in Duchesnea, is distinct from but sister to the other two species. Based on data regarding type specimens that were presented in a study by McCain and Hennen, the new combination Phragmidium mexicanum is proposed as the correct name for this species. Necessary studies of original material were made, and Phragmidium potentillae-canadensis is lectotpyified and epitypified. Although considered and expanded here, further examination of species boundaries and host ranges of the fungi formerly classified in Frommeella is warranted. PMID- 21828215 TI - Ascosphaera subglobosa, a new spore cyst fungus from North America associated with the solitary bee Megachile rotundata. AB - Ascosphaera subglobosa (Eurotiomycetes: Onygenales) is newly described from the pollen provisions and nesting material of the solitary leaf-cutting bee Megachile rotundata in Canada and the western United States. This new species, related to A. atra and A. duoformis, is distinguished from other Ascosphaera species by its globose to subglobose ascospores, evanescent spore balls and unique nuclear ribosomal DNA sequences (ITS and LSU). PMID- 21828216 TI - Alogomyces tanneri gen. et sp. nov., a chytrid in Lobulomycetales from horse manure. AB - The order Lobulomycetales contains chytrids from soil, freshwater and marine habitats; environmental DNA sampling has indicated that representatives of this order might be found in deep ocean localities. We describe Alogomyces tanneri as the first lobulomycetalean chytrid isolated from horse manure; A. tanneri is also the first species in the order to possess a rumposome in its zoospore. This species widens the range of habitats, ultrastructural variation and thallus morphology for Lobulomycetales. PMID- 21828217 TI - Cryptolepiota, a new sequestrate genus in the Agaricaceae with evidence for adaptive radiation in western North America. AB - Phylogenetic analyses based on nLSU and ITS sequence data indicate that the sequestrate genus Gigasperma is polyphyletic. Gigasperma cryptica, which is known only from New Zealand, has affinities with the Cortinariaceae whereas G. americanum and two additional undescribed taxa from western North America are derived from Lepiota within the Agaricaceae. The three North American taxa appear to be recently evolved and are closely related. They occur in similar environments and form a well supported clade indicating that adaptive radiation has occurred within this group of fungi. An independent genus with sequestrate fructifications, Cryptolepiota is proposed to accommodate the three species in this clade. Cryptolepiota microspora and C. mengei are described as new, and G. americanum is transferred to Cryptolepiota. Gigasperma cryptica is illustrated and compared with the species of Cryptolepiota. PMID- 21828218 TI - Type 1 interferon induction of natural killer cell gamma interferon production for defense during lymphocytic choriomeningitis virus infection. AB - Natural killer (NK) cells are equipped to innately produce the cytokine gamma interferon (IFN-gamma) in part because they basally express high levels of the signal transducer and activator of transcription 4 (STAT4). Type 1 interferons (IFNs) have the potential to activate STAT4 and promote IFN-gamma expression, but concurrent induction of elevated STAT1 negatively regulates access to the pathway. As a consequence, it has been difficult to detect type 1 IFN stimulation of NK cell IFN-gamma during viral infections in the presence of STAT1 and to understand the evolutionary advantage for maintaining the pathway. The studies reported here evaluated NK cell responses following infections with lymphocytic choriomeningitis virus (LCMV) in the compartment handling the earliest events after infection, the peritoneal cavity. The production of type 1 IFNs, both IFN alpha and IFN-beta, was shown to be early and of short duration, peaking at 30 h after challenge. NK cell IFN-gamma expression was detected with overlapping kinetics and required activating signals delivered through type 1 IFN receptors and STAT4. It took place under conditions of high STAT4 levels but preceded elevated STAT1 expression in NK cells. The IFN-gamma response reduced viral burdens. Interestingly, increases in STAT1 were delayed in NK cells compared to other peritoneal exudate cell (PEC) populations. Taken together, the studies demonstrate a novel mechanism for stimulating IFN-gamma production and elucidate a biological role for type 1 IFN access to STAT4 in NK cells. IMPORTANCE: Pathways regulating the complex and sometimes paradoxical effects of cytokines are poorly understood. Accumulating evidence indicates that the biological consequences of type 1 interferon (IFN) exposure are shaped by modifying the concentrations of particular STATs to change access to the different signaling molecules. The results of the experiments presented conclusively demonstrate that NK cell IFN-gamma can be induced through type 1 IFN and STAT4 at the first site of infection during a period with high STAT4 but prior to induction of elevated STAT1 in the cells. The response mediates a role in viral defense. Thus, a very early pathway to and source of IFN-gamma in evolving immune responses to infections are identified by this work. The information obtained helps resolve long-standing controversies and advances the understanding of mechanisms regulating key type 1 IFN functions, in different cells and compartments and at different times of infection, for accessing biologically important functions. PMID- 21828219 TI - Nonlytic exocytosis of Cryptococcus neoformans from macrophages occurs in vivo and is influenced by phagosomal pH. AB - A unique aspect of the interaction of the fungus Cryptococcus neoformans with macrophages is the phenomenon of nonlytic exocytosis, also referred to as "vomocytosis" or phagosome extrusion/expulsion, which involves the escape of fungal cells from the phagocyte with the survival of both cell types. This phenomenon has been observed only in vitro using subjective and time-consuming microscopic techniques. In spite of recent advances in our knowledge about its mechanisms, a major question still remaining is whether this phenomenon also occurs in vivo. In this study, we describe a novel flow cytometric method that resulted in a substantial gain in throughput for studying phagocytosis and nonlytic exocytosis in vitro and used it to explore the occurrence of this phenomenon in a mouse model of infection. Furthermore, we tested the hypothesis that host cell phagosomal pH affected nonlytic exocytosis. The addition of the weak bases ammonium chloride and chloroquine resulted in a significant increase of nonlytic exocytosis events, whereas the vacuolar ATPase inhibitor bafilomycin A1 had the opposite effect. Although all three agents are known to neutralize phagosomal acidity, their disparate effects suggest that phagosomal pH is an important and complex variable in this process. Our experiments established that nonlytic exocytosis occurred in vivo with a frequency that is possibly much higher than that observed in vitro. These results in turn suggest that nonlytic exocytosis has a potential role in the pathogenesis of cryptococcosis. IMPORTANCE: Cryptococcus neoformans causes disease in people with immune deficiencies such as AIDS. Upon infection, C. neoformans cells are ingested by macrophage immune cells, which provide a niche for survival and replication. After ingestion, macrophages can expel the fungi without causing harm to either cell type, a process named nonlytic exocytosis. To dissect this phenomenon, we evaluated its dependence on the pH inside the macrophage and addressed its occurrence during infection of mice. We developed new techniques using flow cytometry to measure C. neoformans internalization by and nonlytic exocytosis from macrophages. Neutralizing the phagosome acidity changed the rate of nonlytic exocytosis: activity increased with the weak bases chloroquine and ammonium chloride, whereas the vacuolar ATPase inhibitor bafilomycin A1 caused it to decrease. Experiments in mice suggested that nonlytic exocytosis occurred during infection with C. neoformans. These results shed new light on the interaction between C. neoformans and host macrophages. PMID- 21828221 TI - Permanent pacemaker implantation following isolated aortic valve replacement in a large cohort of elderly patients with severe aortic stenosis. AB - OBJECTIVES: To assess the incidence of conduction disturbances leading to permanent pacemaker implantation (PPI) following isolated aortic valve replacement (AVR) in a large cohort of elderly patients with severe symptomatic aortic stenosis, and to determine the predictive factors and prognostic value of PPI following AVR in such patients. METHODS: A total of 780 consecutive elderly patients (age 77 +/- 4 years, logistic EuroSCORE 10.4 +/- 8.5%, STS score 3.5 +/- 1.5%) with severe aortic stenosis and no previous pacemaker were analysed. MAIN OUTCOME MEASURES: The incidence, clinical indications, timing and predictive factors of PPI within 30 days after AVR and their prognostic value were evaluated. RESULTS: Baseline ECG showed the presence of conduction abnormalities in 37.1% of the patients. Twenty-five patients (3.2%) needed PPI during the index hospitalisation due to the occurrence of complete atrioventricular block (2.6%) or severe bradycardia (0.6%). The presence of preprocedural left bundle branch block (OR 4.65, 95% CI 1.62 to 13.36, p = 0.004) or right bundle branch block (OR 4.21, 95% CI 1.47 to 12.03, p = 0.007) predicted the need for PPI after AVR. The need for PPI was associated with a longer hospital stay (p<0.0001). Thirty-day mortality rates were similar between patients with and without PPI (4% vs 3.2%, p = 0.56). Survival rate at 5-year follow-up was 75%, with no differences between patients with and without PPI (p = 0.12). CONCLUSIONS: The need for PPI following isolated AVR in elderly patients with severe symptomatic aortic stenosis was low. Pre-existing bundle branch block predicted the need for PPI. PPI determined a longer hospital stay, but had no effect on acute and long-term mortality. PMID- 21828220 TI - Dynamics of Cryptococcus neoformans-macrophage interactions reveal that fungal background influences outcome during cryptococcal meningoencephalitis in humans. AB - Cryptococcosis is a multifaceted fungal infection with variable clinical presentation and outcome. As in many infectious diseases, this variability is commonly assigned to host factors. To investigate whether the diversity of Cryptococcus neoformans clinical (ClinCn) isolates influences the interaction with host cells and the clinical outcome, we developed and validated new quantitative assays using flow cytometry and J774 macrophages. The phenotype of ClinCn-macrophage interactions was determined for 54 ClinCn isolates recovered from cerebrospinal fluids (CSF) from 54 unrelated patients, based on phagocytic index (PI) and 2-h and 48-h intracellular proliferation indexes (IPH2 and IPH48, respectively). Their phenotypes were highly variable. Isolates harboring low PI/low IPH2 and high PI/high IPH2 values were associated with nonsterilization of CSF at week 2 and death at month 3, respectively. A subset of 9 ClinCn isolates with different phenotypes exhibited variable virulence in mice and displayed intramacrophagic expression levels of the LAC1, APP1, VAD1, IPC1, PLB1, and COX1 genes that were highly variable among the isolates and correlated with IPH48. Variation in the expression of virulence factors is thus shown here to depend on not only experimental conditions but also fungal background. These results suggest that, in addition to host factors, the patient's outcome can be related to fungal determinants. Deciphering the molecular events involved in C. neoformans fate inside host cells is crucial for our understanding of cryptococcosis pathogenesis. IMPORTANCE: Cryptococcus neoformans is a life threatening human fungal pathogen that is responsible for an estimated 1 million cases of meningitis/year, predominantly in HIV-infected patients. The diversity of infecting isolates is well established, as is the importance of the host factors. Interaction with macrophages is a major step in cryptococcosis pathogenesis. How the diversity of clinical isolates influences macrophages' interactions and impacts cryptococcosis outcome in humans remains to be elucidated. Using new assays, we uncovered how yeast-macrophage interactions were highly variable among clinical isolates and found an association between specific behaviors and cryptococcosis outcome. In addition, gene expression of some virulence factors and intracellular proliferation were correlated. While many studies have established that virulence factors can be differentially expressed as a function of experimental conditions, our study demonstrates that, under the same experimental conditions, clinical isolates behaved differently, a diversity that could participate in the variable outcome of infection in humans. PMID- 21828222 TI - Neurological picture. Occipitocervical malformation with atlas duplication. PMID- 21828223 TI - Smokeless tobacco (snus) and risk of heart failure: results from two Swedish cohorts. AB - BACKGROUND: Oral moist snuff (snus) is discussed as a safer alternative to smoking, and its use is increasing. Based on its documented effect on blood pressure, we hypothesized that use of snus increases the risk of heart failure. DESIGN: Two independent Swedish prospective cohorts; the Uppsala Longitudinal Study of Adult Men (ULSAM), a community-based sample of 1076 elderly men, and the Construction Workers Cohort (CWC), a sample of 118,425 never-smoking male construction workers. METHODS: Cox proportional hazards models were used to investigate possible associations of snus use with risk of a first hospitalization for heart failure. RESULTS: In ULSAM, 95 men were hospitalized for heart failure, during a median follow up of 8.9 years. In a model adjusted for established risk factors including past and present smoking exposure, current snus use was associated with a higher risk of heart failure [hazard ratio (HR) 2.08, 95% confidence interval (CI) 1.03-4.22] relative to non-use. Snus use was particularly associated with risk of non-ischaemic heart failure (HR 2.55, 95% CI 1.12-5.82). In CWC, 545 men were hospitalized for heart failure, during a median follow up of 18 years. In multivariable-adjusted models, current snus use was moderately associated with a higher risk of heart failure (HR 1.28, 95% CI 1.00 1.64) and non-ischaemic heart failure (HR 1.28, 95% CI 0.97-1.68) relative to never tobacco use. CONCLUSION: Data from two independent cohorts suggest that use of snus may be associated with a higher risk of heart failure. PMID- 21828224 TI - Review of health information technology usability study methodologies. AB - Usability factors are a major obstacle to health information technology (IT) adoption. The purpose of this paper is to review and categorize health IT usability study methods and to provide practical guidance on health IT usability evaluation. 2025 references were initially retrieved from the Medline database from 2003 to 2009 that evaluated health IT used by clinicians. Titles and abstracts were first reviewed for inclusion. Full-text articles were then examined to identify final eligibility studies. 629 studies were categorized into the five stages of an integrated usability specification and evaluation framework that was based on a usability model and the system development life cycle (SDLC) associated stages of evaluation. Theoretical and methodological aspects of 319 studies were extracted in greater detail and studies that focused on system validation (SDLC stage 2) were not assessed further. The number of studies by stage was: stage 1, task-based or user-task interaction, n=42; stage 2, system task interaction, n=310; stage 3, user-task-system interaction, n=69; stage 4, user-task-system-environment interaction, n=54; and stage 5, user-task-system environment interaction in routine use, n=199. The studies applied a variety of quantitative and qualitative approaches. Methodological issues included lack of theoretical framework/model, lack of details regarding qualitative study approaches, single evaluation focus, environmental factors not evaluated in the early stages, and guideline adherence as the primary outcome for decision support system evaluations. Based on the findings, a three-level stratified view of health IT usability evaluation is proposed and methodological guidance is offered based upon the type of interaction that is of primary interest in the evaluation. PMID- 21828226 TI - Opt-out organ donation without presumptions. AB - This paper defends an 'opt-out' scheme for organ procurement, by distinguishing this system from 'presumed consent' (which the author regards as an erroneous justification of it). It, first, stresses the moral importance of increasing the supply of organs and argues that making donation easier need not conflict with altruism. It then goes on to explore one way that donation can be increased, namely by adopting an opt-out system, in which cadaveric organs are used unless the deceased (or their family) registered an objection. Such policies are often labelled 'presumed consent', but it is argued that critics are right to be sceptical of this idea-consent is shown to be an action, rather than a mental attitude, and thus not something that can be presumed. Either someone has consented or they have not, whatever their attitude to the use of their organs. Thankfully, an opt-out scheme need not rest on the presumption of consent. Actual consent can be given implicitly, by one's actions, so it is argued that the failure to register an objection (given certain background conditions) should itself be taken as sign of consent. Therefore, it is permissible to use the organs of someone who did not opt out, because they have-by their silence actually consented. PMID- 21828225 TI - A partnership model for implementing electronic health records in resource limited primary care settings: experiences from two nurse-managed health centers. AB - OBJECTIVE: To present a partnership-based and community-oriented approach designed to ease provider anxiety and facilitate the implementation of electronic health records (EHR) in resource-limited primary care settings. MATERIALS AND METHODS: The approach, referred to as partnership model, was developed and iteratively refined through the research team's previous work on implementing health information technology (HIT) in over 30 safety net practices. This paper uses two case studies to illustrate how the model was applied to help two nurse managed health centers (NMHC), a particularly vulnerable primary care setting, implement EHR and get prepared to meet the meaningful use criteria. RESULTS: The strong focus of the model on continuous quality improvement led to eventual implementation success at both sites, despite difficulties encountered during the initial stages of the project. DISCUSSION: There has been a lack of research, particularly in resource-limited primary care settings, on strategies for abating provider anxiety and preparing them to manage complex changes associated with EHR uptake. The partnership model described in this paper may provide useful insights into the work shepherded by HIT regional extension centers dedicated to supporting resource-limited communities disproportionally affected by EHR adoption barriers. CONCLUSION: NMHC, similar to other primary care settings, are often poorly resourced, understaffed, and lack the necessary expertise to deploy EHR and integrate its use into their day-to-day practice. This study demonstrates that implementation of EHR, a prerequisite to meaningful use, can be successfully achieved in this setting, and partnership efforts extending far beyond the initial software deployment stage may be the key. PMID- 21828227 TI - A new and accurate way to identify elite athletes. AB - A simple thought experiment and web search tools are brought to bear on conventional notions of disability. A Nobel Prize winner weighs in. PMID- 21828228 TI - On triparenting. Is having three committed parents better than having only two? AB - Although research indicates that single parenting is not by itself worse for children than their being brought up by both their parents, there are reasons why it is better for children to have more than one committed parent. If having two committed parents is better, everything else being equal, than having just one, I argue that it might be even better for children to have three committed parents. There might, in addition, be further reasons why allowing triparenting would benefit children and adults, at least in some cases. Whether or not triparenting is on the whole preferable to bi- or monoparenting, it does have certain advantages (as well as shortcomings) which, at the very least, warrant its inclusion in debates over the sorts of family structures we should allow in our societies, and how many people should be accepted in them. This paper has the modest aim of scratching the surface of this wider topic by challenging the necessity of the max-two-parents framework. PMID- 21828229 TI - The reciprocal relationships between changes in adolescent perceived prevalence of smoking in movies and progression of smoking status. AB - BACKGROUND: Smoking in movies is associated with adolescent smoking worldwide. To date, studies of the association mostly are restricted to the exposure to smoking images viewed by 9-15-year-olds. The association among older adolescents is rarely examined. In addition, the reciprocal effect of smoking behaviour on subsequent reported exposure to smoking in movies has not been reported. METHODS: Data were from the Minnesota Adolescent Community Cohort Study collected every 6 months from 2000 to 2007 when participants were between the ages of 12 and 18 (n=4745). We estimated the prospective effect of the perceived prevalence of smoking in movies (four levels, from never to most of the time) on smoking stage (SS) measured 6 months later (six stages, from never-smoker to established smoker) and the reciprocal prospective association between the two factors. Estimates were adjusted for demographic factors. RESULTS: The perceived prevalence of smoking in movies measured between ages 13½ and 15½ consistently predicted subsequent SS. The association was inconsistent after the age of 15½. SS did not consistently predict subsequent perception of the prevalence of smoking in movies. CONCLUSIONS: Perceived exposure to movie smoking primarily influenced teenagers' smoking behaviour at younger ages. If future studies confirm this finding, developing and evaluating interventions to improve young teenagers' resistance to these images may complement policies to reduce smoking in movies to reduce prevalence of adolescent smoking. PMID- 21828230 TI - Tobacco expenditures and its implications for household resource allocation in Cambodia. AB - OBJECTIVES: To assess the determinants of smoking behaviour and to estimate the impact of tobacco consumption on the consumption of other commodities by Cambodian households. METHODS: To assess the determinants of smoking in Cambodia, the authors used a logistic regression model that estimated the probability of an individual smoking, given a set of socioeconomic and demographic characteristics. A Seemingly Unrelated Regression method was used to assess the impact of tobacco consumption on the consumption of other commodities. The nationally representative 2004 Cambodia Socio-Economic Survey, collected by the National Institute of Statistics of the Ministry of Planning in Cambodia, was used for the analysis. RESULTS: Smoking in Cambodia is influenced by a variety of factors such as gender, marital status, age, ethnicity, literacy, health status and perceptions about the health consequences of tobacco use. The authors found that spending on tobacco crowds out expenditures on education and clothing at the national level and expenditures on food for low- and middle-income households. CONCLUSIONS: The first analysis of the study showed that increased education is associated with lower daily smoking, and the second analysis revealed that expenditures on tobacco crowds out expenditures on education. Combining these two results points to a vicious circle where low education means higher likelihood of smoking, which in turn results in lower spending on education. Such budget allocation clearly has negative intergenerational consequences. PMID- 21828231 TI - Fluticasone furoate demonstrates efficacy in patients with asthma symptomatic on medium doses of inhaled corticosteroid therapy: an 8-week, randomised, placebo controlled trial. AB - BACKGROUND: Fluticasone furoate (FF) is a novel inhaled corticosteroid with 24 h activity. FF is being developed as a once-daily treatment in combination with the long-acting beta(2) agonist vilanterol trifenatate for asthma and chronic obstructive pulmonary disease. OBJECTIVES: To determine the optimal dose(s) of FF for treating patients with asthma. METHODS: An 8-week multicentre, randomised, double-blind study. 627 patients with persistent moderate-to-severe asthma, symptomatic on medium-dose inhaled corticosteroid therapy, were randomised to placebo, FF 200, 400, 600 or 800 MUg (once daily in the evening using a novel dry powder inhaler), or fluticasone propionate 500 MUg twice daily (via DiskusTM/AccuhalerTM). The primary efficacy measure was mean change from baseline in pre-dose evening forced expiratory volume in one second (FEV(1)). Other endpoints included morning and evening peak expiratory flow, and rescue/symptom free 24 h periods. RESULTS: Each dose was significantly superior to placebo for the primary endpoint (p<0.001) with efficacy at least similar to that reported with fluticasone propionate. There was no dose-response relationship across the FF doses studied. Peak expiratory flow improved in all groups (p<0.001 vs placebo), and there were significant treatment effects on rescue/symptom-free 24 h periods with all active treatments. FF was generally well tolerated. The incidence of oral candidiasis was higher with FF 800 MUg than placebo; pharmacokinetic and 24 h urinary cortisol analyses confirmed a higher systemic exposure of FF at this highest dose level. CONCLUSIONS: FF doses <800 MUg have a favourable therapeutic index. The absence of an efficacy dose response suggests that 200 MUg is an appropriate dose in patients with moderate persistent asthma. CLINICALTRIALS.GOV IDENTIFIER: NCT00603746. PMID- 21828232 TI - Prognostic significance of cytoplasmic p27 expression in human melanoma. AB - BACKGROUND: The cyclin-dependent kinase inhibitor p27 plays important roles in cell proliferation, cell motility, and apoptosis. Interestingly, the nuclear and cytoplasmic p27 exert opposite biological functions. In this study, we investigated the prognostic impact of subcellular p27 expression. METHODS: We constructed melanoma tissue microarrays in a large series of melanoma patients, including 29 normal nevi, 52 dysplastic nevi, 270 primary melanomas, and 148 metastatic melanomas. The expression level of subcellular p27 in different stages of melanocytic lesions and its prognostic significance were evaluated. RESULTS: Compared with dysplastic nevi, nuclear p27 expression was remarkably reduced in primary melanomas and further reduced in metastatic melanoma (P < 0.001 for both), whereas cytoplasmic p27 expression is significantly increased from dysplastic nevi to primary melanomas (P = 0.032) and further increased in melanoma metastases (P = 0.037). Although loss of nuclear p27 expression is correlated with a worse 5-year survival of primary melanoma patients in Kaplan Meier analysis (P = 0.046), it is not a prognostic factor by multivariate Cox regression analysis. On the contrary, Kaplan-Meier analysis showed that gain of cytoplasmic p27 was associated with a poor 5-year survival of metastatic melanoma patients (P < 0.001). Multivariate Cox regression analysis revealed that positive cytoplasmic p27 expression is an independent prognostic factor to predict metastatic melanoma patient outcome. CONCLUSION: Cytoplasmic p27 may serve as a promising prognostic marker for metastatic melanoma. IMPACT: Because there is no reliable prognostic marker for metastatic melanoma, our finding may have important clinical implications using cytoplasmic p27 as a prognostic biomarker for advanced melanoma. PMID- 21828233 TI - Identification of adipophilin as a potential plasma biomarker for colorectal cancer using label-free quantitative mass spectrometry and protein microarray. AB - BACKGROUND: The aim of this study was to identify a new plasma biomarker for use in early detection of colorectal cancer. METHODS: Using the combination of hollow fiber membrane (HFM)-based low-molecular weight protein enrichment and two dimensional image converted analysis of liquid chromatography and mass spectrometry (2DICAL), we compared the plasma proteome of 22 colorectal cancer patients with those of 21 healthy controls. An identified biomarker candidate was then validated in two larger cohorts [validation-1 (n = 210) and validation-2 (n = 113)] using a high-density reverse-phase protein microarray. RESULTS: From a total of 53,009 mass peaks, we identified 103 with an area under curve (AUC) value of 0.80 or higher that could distinguish cancer patients from healthy controls. A peak that increased in colorectal cancer patients, with an AUC of 0.81 and P value of 0.0004 (Mann-Whitney U test), was identified as a product of the PLIN2 gene [also known as perilipin-2, adipose differentiation-related protein (ADRP), or adipophilin]. An increase in plasma adipophilin was consistently observed in colorectal cancer patients, including those with stage I or stage II disease (P < 0.0001, Welch's t test). Immunohistochemical analysis revealed that adipophilin is expressed primarily in the basal sides of colorectal cancer cells forming polarized tubular structures, and that it is absent from adjacent normal intestinal mucosae. CONCLUSIONS: Adipophilin is a plasma biomarker potentially useful for the detection of early-stage colorectal cancer. IMPACT: The combination of HFM and 2DICAL enables the comprehensive analysis of plasma proteins and is ideal for use in all biomarker discovery studies. PMID- 21828234 TI - Common genetic variants in the vitamin D pathway including genome-wide associated variants are not associated with breast cancer risk among Chinese women. AB - BACKGROUND: Previous studies evaluating the association of vitamin D-related genetic variants with breast cancer risk have produced inconsistent results. METHODS: We evaluated the association between breast cancer risk and 559 single nucleotide polymorphisms (SNP) in 12 vitamin D-related genes, including 6 genes associated with circulating 25-hydroxyvitamin D [25(OH)D] level identified by recent genome-wide association studies (GWAS), using directly observed and imputed GWAS genotyping data from 2,919 breast cancer cases and 2,323 controls recruited in the Shanghai Breast Cancer Study. RESULTS: Of the SNPs studied, only rs12570116 in the ACADSB gene, rs4760658 in the VDR gene and rs6091822, rs8124792, and rs6097809 in the CYP24A1 gene, and rs10902845 in C10orf88 had a nominal association with breast cancer risk (P < 0.05 for all). None of these associations persisted after adjustment for multiple comparisons. The most extensively studied SNPs including rs10735810, also known as rs2228570 (Fok1, VDR), rs1544410 (Bsm1, VDR), and rs2296241 (CYP24A1), were not associated with breast cancer risk. GWAS-identified genetic variants that were associated with 25(OH)D were also not related to breast cancer risk. CONCLUSIONS: Our data suggest that genetic polymorphisms in vitamin D-related genes do not play a major role in breast cancer risk in Chinese women. IMPACT: Although our study confirms previously documented breast cancer risk factor associations, our null results suggest that common genetic variants in vitamin D genes and loci associated with control of vitamin D levels are not risk factors for breast cancer in Chinese women. Our data contribute to filling the gap in this field of research. PMID- 21828236 TI - Circulating markers of interstitial lung disease and subsequent risk of lung cancer. AB - BACKGROUND: Inflammation and pulmonary diseases, including interstitial lung diseases, are associated with increased lung cancer risk. Circulating levels of surfactant protein-D (SP-D) and Krebs von Lungren-6 (KL-6) are elevated in interstitial lung disease patients and may be useful markers of processes contributing to lung cancer. METHODS: We conducted a nested case-control study, including 532 lung cancer cases, 582 matched controls, and 150 additional controls with chest X-ray (CXR) evidence of pulmonary scarring, in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Serum SP-D and KL-6 levels were measured using enzyme immunoassay. Logistic regression was used to estimate the associations of SP-D and KL-6 with lung cancer and CXR scarring. RESULTS: Cases had higher levels than controls for SP-D (median 118.7 vs. 105.4 ng/mL, P = 0.008) and KL-6 (372.0 vs. 325.8 MUg/mL, P = 0.001). Lung cancer risk increased with SP-D (P(trend) = 0.0003) and KL-6 levels (P(trend) = 0.005). Compared with the lowest quartile, lung cancer risk was elevated among those with the highest quartiles of SP-D (OR = 1.87, 95% CI: 1.32-2.64) or KL-6 (OR = 1.58, 95% CI: 1.11 2.25). Among controls, participants with CXR scarring were more likely than those without scarring to have elevated levels of SP-D (quartile 4 vs. quartile 1: OR = 1.67, 95% CI: 1.04-2.70, P(trend) = 0.05) but not of KL-6 (OR = 1.04, 95% CI: 0.64-1.68, P(trend) = 0.99). CONCLUSION: Circulating levels of SP-D and KL-6 are associated with subsequent lung cancer risk. IMPACT: Our findings support a potential role for interstitial lung disease in lung cancer etiology or early detection, but additional research is needed. PMID- 21828238 TI - Overcoming antiangiogenic resistance. AB - The success of drugs targeting angiogenesis is tempered by the transient duration of disease control and modest survival improvement. The very hypoxic stress produced by successful therapy may lead to upregulation of multiple pathways that promote angiogenesis and invasive behavior. Overcoming this evasive resistance may further improve outcome. PMID- 21828237 TI - Does print size matter for reading? A review of findings from vision science and typography. AB - The size and shape of printed symbols determine the legibility of text. In this paper, we focus on print size because of its crucial role in understanding reading performance and its significance in the history and contemporary practice of typography. We present evidence supporting the hypothesis that the distribution of print sizes in historical and contemporary publications falls within the psychophysically defined range of fluent print size--the range over which text can be read at maximum speed. The fluent range extends over a factor of 10 in angular print size (x-height) from approximately 0.2 degrees to 2 degrees . Assuming a standard reading distance of 40 cm (16 inches), the corresponding physical x-heights are 1.4 mm (4 points) and 14 mm (40 points). We provide new data on the distributions of print sizes in published books and newspapers and in typefounders' specimens, and consider factors influencing these distributions. We discuss theoretical concepts from vision science concerning visual size coding that help inform our understanding of historical and modern typographical practices. While economic, social, technological, and artistic factors influence type design and selection, we conclude that properties of human visual processing play a dominant role in constraining the distribution of print sizes in common use. PMID- 21828239 TI - Prognostic model for survival in patients with metastatic renal cell carcinoma: results from the international kidney cancer working group. AB - PURPOSE: To develop a single validated model for survival in metastatic renal cell carcinoma (mRCC) using a comprehensive international database. EXPERIMENTAL DESIGN: A comprehensive database of 3,748 patients including previously reported clinical prognostic factors was established by pooling patient-level data from clinical trials. Following quality control and standardization, descriptive statistics were generated. Univariate analyses were conducted using proportional hazards models. Multivariable analysis using a log-logistic model stratified by center and multivariable fractional polynomials was conducted to identify independent predictors of survival. Missing data were handled using multiple imputation methods. Three risk groups were formed using the 25th and 75th percentiles of the resulting prognostic index. The model was validated using an independent data set of 645 patients treated with tyrosine kinase inhibitor (TKI) therapy. RESULTS: Median survival in the favorable, intermediate and poor risk groups was 26.9 months, 11.5 months, and 4.2 months, respectively. Factors contributing to the prognostic index included treatment, performance status, number of metastatic sites, time from diagnosis to treatment, and pretreatment hemoglobin, white blood count, lactate dehydrogenase, alkaline phosphatase, and serum calcium. The model showed good concordance when tested among patients treated with TKI therapy (C statistic = 0.741, 95% CI: 0.714-0.768). CONCLUSIONS: Nine clinical factors can be used to model survival in mRCC and form distinct prognostic groups. The model shows utility among patients treated in the TKI era. PMID- 21828240 TI - B-Myb, cancer, senescence, and microRNAs. AB - The transcription factor B-Myb plays a critical role in regulating gene expression and is implicated in controlling carcinogenesis and cellular senescence. Transcription of the B-Myb gene is regulated by retinoblastoma proteins acting directly on the B-Myb promoter. Recently, we found that microRNAs also control the abundance of B-Myb mRNA during senescence, adding another level of complexity to B-Myb regulation. This review focuses on the importance of B-Myb in cancer and senescence, with an emphasis on the regulation of B-Myb expression and activity. PMID- 21828241 TI - Long noncoding RNA, polycomb, and the ghosts haunting INK4b-ARF-INK4a expression. AB - Polycomb group proteins (PcG) function as transcriptional repressors of gene expression. The important role of PcG in mediating repression of the INK4b-ARF INK4a locus, by directly binding to the long noncoding RNA (lncRNA) transcript antisense noncoding RNA in the INK4 locus (ANRIL), was recently shown. INK4b-ARF INK4a encodes 3 tumor-suppressor proteins, p15(INK4b), p14(ARF), and p16(INK4a), and its transcription is a key requirement for replicative or oncogene-induced senescence and constitutes an important barrier for tumor growth. ANRIL gene is transcribed in the antisense orientation of the INK4b-ARF-INK4a gene cluster, and different single-nucleotide polymorphisms are associated with increased susceptibility to several diseases. Although lncRNA-mediated regulation of INK4b ARF-INK4a gene is not restricted to ANRIL, both polycomb repressive complex-1 (PRC1) and -2 (PRC2) interact with ANRIL to form heterochromatin surrounding the INK4b-ARF-INK4a locus, leading to its repression. This mechanism would provide an increased advantage for bypassing senescence, sustaining the requirements for the proliferation of stem and/or progenitor cell populations or inappropriately leading to oncogenesis through the aberrant saturation of the INK4b-ARF-INK4a locus by PcG complexes. In this review, we summarize recent findings on the underlying epigenetic mechanisms that link PcG function with ANRIL, which impose gene silencing to control cellular homeostasis as well as cancer development. PMID- 21828242 TI - Visual cues for person-centered communication. AB - Nursing home communication is frequently limited and task-focused and fails to affirm resident personhood. We tested the feasibility and effects of automated digital displays of resident photographs to remind staff (N = 11) of resident (n = 6) personhood. Historical photographs were displayed in digital photo frames mounted in each resident's room. To evaluate the intervention's effects, staff resident conversations were audio-recorded prior to displaying the frames and repeated 2 weeks and 3 months later. Conversations were transcribed and statements were topic coded (task-focused vs. interpersonal). Staff person centered talk increased from 11% to 32% (z = 2.37, p = .02) after the intervention and task-talk decreased from 64% to 40%. Resident interpersonal topics increased from 20% to 37%. Staff statements increased from 29 at baseline, to 37 postintervention, and 41 at 3-month follow-up and resident engagement and reminiscence also increased. Effects were reduced after 3 months. Automated photo displays are an easily implemented, low-cost intervention to promote person centered communication. PMID- 21828243 TI - Educational outcomes associated with providing a comprehensive guidelines program about nursing care of preterm neonates receiving total parenteral nutrition. AB - Poor understanding or practice of Total Parenteral Nutrition (TPN) causes devastating complications. Therefore, good Neonatal Intensive Care Unit (NICU) nursing care for preterm neonates and close monitoring of complications is essential for successful TPN therapy. The study was conducted in NICU at Ain Shams University Hospital in Cairo, Egypt, using a quasi-experimental research design with prepost intervention assessments. Data was collected using a self administered questionnaire sheet and an observation checklist (prepost format) and developed a comprehensive guidelines program about nursing care of TPN of preterm neonates. Results revealed that the program had a significant positive impact on nurses' knowledge and practice outcomes. PMID- 21828244 TI - Transcriptomic response of murine liver to severe injury and hemorrhagic shock: a dual-platform microarray analysis. AB - Trauma-hemorrhagic shock (HS/T) is a complex process that elicits numerous molecular pathways. We hypothesized that a dual-platform microarray analysis of the liver, an organ that integrates immunology and metabolism, would reveal key pathways engaged following HS/T. C57BL/6 mice were divided into five groups (n = 4/group), anesthetized, and surgically treated to simulate a time course and trauma severity model: 1) nonmanipulated animals, 2) minor trauma, 3) 1.5 h of hemorrhagic shock and severe trauma (HS/T), 4) 1.5 h HS/T followed by 1 h resuscitation (HS/T+1.0R), 5) 1.5 h HS/T followed by 4.5 h resuscitation (HS/T+4.5R). Liver RNA was hybridized to CodeLink and Affymetrix mouse whole genome microarray chips. Common genes with a cross-platform correlation >0.6 (2,353 genes in total) were clustered using k-means clustering, and clusters were analyzed using Ingenuity Pathways Analysis. Genes involved in the stress response and immunoregulation were upregulated early and remained upregulated throughout the course of the experiment. Genes involved in cell death and inflammatory pathways were upregulated in a linear fashion with elapsed time and in severe injury compared with minor trauma. Three of the six clusters contained genes involved in metabolic function; these were downregulated with elapsed time. Transcripts involved in amino acid metabolism as well as signaling pathways associated with glucocorticoid receptors, IL-6, IL-10, and the acute phase response were elevated in a severity-dependent manner. This is the first study to examine the postinjury response using dual-platform microarray analysis, revealing responses that may enable novel therapies or diagnostics. PMID- 21828245 TI - Transcriptome profiling and sequencing of differentiated human hematopoietic stem cells reveal lineage-specific expression and alternative splicing of genes. AB - Hematopoietic differentiation is strictly regulated by complex network of transcription factors that are controlled by ligands binding to cell surface receptors. Disruptions of the intricate sequences of transcriptional activation and suppression of multiple genes cause hematological diseases, such as leukemias, myelodysplastic syndromes, or myeloproliferative syndromes. From a clinical standpoint, deciphering the pattern of gene expression during hematopoiesis may help unravel disease-specific mechanisms in hematopoietic malignancies. Herein, we describe a human in vitro hematopoietic model system where lineage-specific differentiation of CD34(+) cells was accomplished using specific cytokines. Microarray and RNAseq-based whole transcriptome and exome analysis was performed on the differentiated erythropoietic, granulopoietic, and megakaryopoietic cells to delineate changes in expression of whole transcripts and exons. Analysis on the Human 1.0 ST exon arrays indicated differential expression of 172 genes (P < 0.0000001) and significant alternate splicing of 86 genes during differentiation. Pathway analysis identified these genes to be involved in Rac/RhoA signaling, Wnt/B-catenin signaling and alanine/aspartate metabolism. Comparison of the microarray data to next generation RNAseq analysis during erythroid differentiation demonstrated a high degree of correlation in gene (R = 0.72) and exon (R = 0.62) expression. Our data provide a molecular portrait of events that regulate differentiation of hematopoietic cells. Knowledge of molecular processes by which the cells acquire their cell-specific fate would be beneficial in developing cell-based therapies for human diseases. PMID- 21828246 TI - Androgen receptor polyglutamine repeat length affects receptor activity and C2C12 cell development. AB - Testosterone (T) has an anabolic effect on skeletal muscle and is believed to exert its local effects via the androgen receptor (AR). The AR harbors a polymorphic stretch of glutamine repeats demonstrated to inversely affect receptor transcriptional activity in prostate and kidney cells. The effects of AR glutamine repeat length on skeletal muscle are unknown. In this study we examined the effect of AR CAG repeat length on AR function in C2C12 cells. AR expression vectors harboring 14, 24, and 33 CAG repeats were used to assess AR transcriptional activity. C2C12 cell proliferation, differentiation, gene expression, myotube formation, and myonuclear fusion index were assessed. Transcriptional activity increased with increasing repeat length and in response to testosterone (AR14 = 3.91 +/- 0.26, AR24 = 25.21 +/- 1.72, AR33 = 36.08 +/- 3.22 relative light units; P < 0.001). Ligand activation was increased for AR33 (2.10 +/- 0.04) compared with AR14 (1.54 +/- 0.09) and AR24 (1.57 +/- 0.05, P < 0.001). AR mRNA expression was elevated in each stably transfected line. AR33 cell proliferation (20,512.3 +/- 1,024.0) was decreased vs. AR14 (27,604.17 +/- 1,425.3; P < 0.001) after 72 h. Decreased CK activity in AR14 cells (54.9 +/- 2.9 units/MUg protein) in comparison to AR33 (70.8 +/- 8.1) (P < 0.05) was noted. The myonuclear fusion index was lower for AR14 (15.21 +/- 3.24%) and AR33 (9.97 +/- 3.14%) in comparison to WT (35.07 +/- 5.60%, P < 0.001). AR14 and AR33 cells also displayed atypical myotube morphology. RT-PCR revealed genotype differences in myostatin and myogenin expression. We conclude that AR polyglutamine repeat length is directly associated with transcriptional activity and alters the growth and development of C2C12 cells. This polymorphism may contribute to the heritability of muscle mass in humans. PMID- 21828247 TI - Intrauterine growth restriction affects hippocampal dual specificity phosphatase 5 gene expression and epigenetic characteristics. AB - Intrauterine growth retardation (IUGR) predisposes humans toward hippocampal morbidities, such as impaired learning and memory. Hippocampal dual specificity phosphatase 5 (DUSP5) may be involved in these morbidities because DUSP5 regulates extracellular signal-regulated kinase phosphorylation (Erk). In the rat, IUGR causes postnatal changes in hippocampal gene expression and epigenetic characteristics. However, the impact of IUGR upon hippocampal DUSP5 expression and epigenetic characteristics is not known. We therefore hypothesized that IUGR affects hippocampal 1) DUSP5 expression, DNA CpG methylation, and histone code, and 2) erk1/2 phosphorylation in a well-characterized rat model of IUGR. We found that IUGR significantly decreased DUSP5 expression in the day of life (DOL) 0 and 21 male rat, while decreasing only DUSP5 protein levels in the DOL21 female rat. Fluorescent in situ hybridization and immunohistochemistry analyses localized the changes in DUSP5 mRNA and protein, many of which occurred in the dentate gyrus. IUGR also caused sex-specific differences in DNA CpG methylation and histone code in two sites of the hippocampal DUSP5 gene, a 5'-flanking specificity protein-1 (SP1) site and exon 2. Finally, when IUGR decreased DUSP5 protein levels, Erk phosphorylation increased. We conclude that IUGR affects hippocampal DUSP5 expression and epigenetic characteristics in a sex-specific manner. PMID- 21828249 TI - Tissue and circulating expression of IL-1 family members following heat stroke. AB - Interleukin-1 (IL-1) is thought to have a significant role in the pathophysiology of heat stroke (HS), although little is known regarding the actions or expression patterns of the IL-1 family. This study tested the hypotheses that following HS IL-1 family gene expression is dynamic, while loss of IL-1 signaling enhances recovery. IL-1 family expression was determined in plasma, spleen, and liver from C57BL/6J mice (n=24 control, n=20 HS) at maximum core temperature (Tc,Max), hypothermia, and 24 h post-HS (24 h). Soluble IL-1 receptor subtype I (sIL-1RI) protein expression peaked at 24 h (14,659.01+/-2,016.28 pg/ml, P<0.05), while sIL 1RII peaked at hypothermia (19,099.30+/-1,177.07 pg/ml). IL-1alpha gene expression in the spleen (ninefold) and liver (fourfold) along with IL-1RI (threefold spleen and fivefold liver) were maximal at hypothermia. Spleen IL 1beta gene expression peaked at Tc,Max (fourfold) but at hypothermia (fourfold) in liver. Gene expression of the IL-1 family member IL-18 peaked (2.5-fold) at Tc,Max but was similar at all other time points. Subsequent studies revealed that despite accruing a greater heating area (298+/-16 vs. 247+/-13 degrees C.min, P<0.05), IL-1RI knockout (KO) mice (n=14) showed an attenuated hypothermia depth (28.5+/-0.2 vs. 27.3+/-0.5 degrees C, P<0.05) and duration (675+/-82 vs. 1,283+/ 390 min, P<0.05) with a higher 24 h Tc (36.9 vs. 34.1 degrees C, P<0.05) compared with C57BL/6J mice (n=8). The current results demonstrate that following HS IL-1 family gene expression is altered and IL-1RI KO mice display Tc responses consistent with a more rapid recovery. PMID- 21828248 TI - Candidate genes for panhypopituitarism identified by gene expression profiling. AB - Mutations in the transcription factors PROP1 and PIT1 (POU1F1) lead to pituitary hormone deficiency and hypopituitarism in mice and humans. The dysmorphology of developing Prop1 mutant pituitaries readily distinguishes them from those of Pit1 mutants and normal mice. This and other features suggest that Prop1 controls the expression of genes besides Pit1 that are important for pituitary cell migration, survival, and differentiation. To identify genes involved in these processes we used microarray analysis of gene expression to compare pituitary RNA from newborn Prop1 and Pit1 mutants and wild-type littermates. Significant differences in gene expression were noted between each mutant and their normal littermates, as well as between Prop1 and Pit1 mutants. Otx2, a gene critical for normal eye and pituitary development in humans and mice, exhibited elevated expression specifically in Prop1 mutant pituitaries. We report the spatial and temporal regulation of Otx2 in normal mice and Prop1 mutants, and the results suggest Otx2 could influence pituitary development by affecting signaling from the ventral diencephalon and regulation of gene expression in Rathke's pouch. The discovery that Otx2 expression is affected by Prop1 deficiency provides support for our hypothesis that identifying molecular differences in mutants will contribute to understanding the molecular mechanisms that control pituitary organogenesis and lead to human pituitary disease. PMID- 21828250 TI - An Arabidopsis prenylated Rab acceptor 1 isoform, AtPRA1.B6, displays differential inhibitory effects on anterograde trafficking of proteins at the endoplasmic reticulum. AB - Prenylated Rab acceptors (PRAs), members of the Ypt-interacting protein family of small membrane proteins, are thought to aid the targeting of prenylated Rabs to their respective endomembrane compartments. In plants, the Arabidopsis (Arabidopsis thaliana) PRA1 family contains 19 members that display varying degrees of sequence homology to animal PRA1 and localize to the endoplasmic reticulum (ER) and/or endosomes. However, the exact role of these proteins remains to be fully characterized. In this study, the effect of AtPRA1.B6, a member of the AtPRA1 family, on the anterograde trafficking of proteins targeted to various endomembrane compartments was investigated. High levels of AtPRA1.B6 resulted in differential inhibition of coat protein complex II vesicle-mediated anterograde trafficking. The trafficking of the vacuolar proteins sporamin:GFP (for green fluorescent protein) and AALP:GFP, the secretory protein invertase:GFP, and the plasma membrane proteins PMP:GFP and H+-ATPase:GFP was inhibited in a dose-dependent manner, while the trafficking of the Golgi localized proteins ST:GFP and KAM1(DeltaC):mRFP was not affected. Conversely, in RNA interference plants displaying lower levels of AtPRA1.B6 transcripts, the trafficking efficiency of sporamin:GFP and AALP:GFP to the vacuole was increased. Localization and N-glycan pattern analyses of cargo proteins revealed that AtPRA1.B6-mediated inhibition of anterograde trafficking occurs at the ER. In addition, AtPRA1.B6 levels were controlled by cellular processes, including 26S proteasome-mediated proteolysis. Based on these results, we propose that AtPRA1.B6 is a negative regulator of coat protein complex II vesicle-mediated anterograde trafficking for a subset of proteins at the ER. PMID- 21828252 TI - Bioavailability of the glucuronide and sulfate conjugates of genistein and daidzein in breast cancer resistance protein 1 knockout mice. AB - The dietary polyphenols genistein and daidzein are potent effectors of biological processes. The plasma profile of both isoflavones is governed by the presence of phase II conjugates, mainly glucuronides and sulfates. Breast cancer resistance protein (ABCG2/BCRP) interacts with genistein and daidzein, which are among the natural substrates of the transporter and competitively inhibit ABCG2-mediated drug efflux. ABCG2/BCRP can also transport glucuronide and sulfate conjugates. In this study, we analyzed the plasma levels of aglycones and derived conjugated metabolites, glucuronides, and sulfates, after intragastric administration of these isoflavones to wild-type and Bcrp1(-/-) knockout mice. The results show that overall plasmatic profile is mainly governed by sulfate and glucuronide derivatives, the concentration of which was significantly increased (7- to 10 fold) in Bcrp1(-/-) mice. The total AUC h nM (0-180 min), as the sum of aglycones, glucuronides, and sulfates, was 901 +/- 207 in wild-type mice versus 4988 +/- 508 in Bcrp1(-/-) mice after genistein administration (50 mg/kg b.wt.); 584.3 +/- 90 in wild-type mice versus 4012 +/- 612 in Bcrp1(-/-) after daidzein administration (50 mg/kg); and 926 +/- 140 in wild-type mice versus 5174 +/- 696 in Bcrp1(-/-) after genistein+daidzein administration (25 + 25 mg/kg). Therefore, our results indicate a direct and conclusive Bcrp1 efflux action on phase II metabolites of these isoflavones in vivo and suggest a possible novel concept for ABCG2/BCRP as part of metabolism-driven efflux transport of these conjugates. PMID- 21828251 TI - miR393 and secondary siRNAs regulate expression of the TIR1/AFB2 auxin receptor clade and auxin-related development of Arabidopsis leaves. AB - The phytohormone auxin is a key regulator of plant growth and development that exerts its functions through F-box receptors. Arabidopsis (Arabidopsis thaliana) has four partially redundant of these receptors that comprise the TRANSPORT INHIBITOR RESPONSE1/AUXIN SIGNALING F-BOX1 auxin receptor (TAAR) clade. Recent studies have shown that the microRNA miR393 regulates the expression of different sets of TAAR genes following pathogen infection or nitrate treatment. Here we report that miR393 helps regulate auxin-related development of leaves. We found that AtMIR393B is the predominant source for miR393 in all aerial organs and that miR393 down-regulates all four TAAR genes by guiding the cleavage of their mRNAs. A mutant unable to produce miR393 shows developmental abnormalities of leaves and cotyledons reminiscent of enhanced auxin perception by TAARs. Interestingly, miR393 initiates the biogenesis of secondary siRNAs from the transcripts of at least two of the four TAAR genes. Our results indicate that these siRNAs, which we call siTAARs, help regulate the expression of TAAR genes as well as several unrelated genes by guiding the cleavage of their mRNAs. Thus, miR393 and possibly siTAARs regulate auxin perception and certain auxin-related aspects of leaf development. PMID- 21828255 TI - Supplementation with nitrate and nitrite salts in exercise: a word of caution. PMID- 21828253 TI - Commentaries on Viewpoint: Expending our physical activity (measurement) budget wisely. PMID- 21828256 TI - Reply to Lundberg, Larsen, and Weitzberg. PMID- 21828257 TI - Reply to Lundberg, Larsen, and Weitzberg. PMID- 21828258 TI - The opposite of dilution acidosis occurs during physical exercise. PMID- 21828260 TI - Anacardic acid (6-pentadecylsalicylic acid) inhibits tumor angiogenesis by targeting Src/FAK/Rho GTPases signaling pathway. AB - Anacardic acid (6-pentadecylsalicylic acid), a natural inhibitor of histone acetyltransferase from Amphipterygium adstringens, has been shown to have anti inflammatory, anticancer, antioxidative, and antimicrobial functions. However, whether this salicylic acid could block angiogenesis has not been elucidated to date. Here, we postulate that anacardic acid affects multiple steps of tumor angiogenesis to contribute to tumor inhibition. In this study, we found that vascular endothelial growth factor (VEGF)-induced cell proliferation, migration, and adhesion and capillary-like structure formation of primary cultured human umbilical vascular endothelial cells (HUVECs) could all be significantly suppressed by anacardic acid in vitro, without detectable cellular toxicity. Furthermore, anacardic acid effectively inhibited vascular development in chick embryo chorioallantoic membrane ex vivo (n = 10) and VEGF-triggered corneal neovascularization in vivo (n = 10). A mechanistic study revealed that anacardic acid blocked activities of Src and FAK kinases in concentration- and time dependent manners in HUVECs, resulting in activation of RhoA-GTPase and inactivation of Rac1- and Cdc42-GTPases. Of note, when anacardic acid (2 mg/kg per day) was subcutaneously administrated to mice bearing human prostate tumor xenografts (n = 6-7), the volume and weight of solid tumors were significantly retarded. Src, Ki-67, and CD31 immunohistochemical staining further revealed that Src protein expression, tumor cell proliferation, and microvessel density could be remarkably suppressed by anacardic acid. Taken together, our findings demonstrate for the first time that anacardic acid functions as a potent tumor angiogenesis inhibitor by targeting the Src/FAK/Rho GTPase signaling pathway, leading to significant suppression of prostate tumor growth. PMID- 21828261 TI - Characterization of a novel potassium-competitive acid blocker of the gastric H,K ATPase, 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N methylmethanamine monofumarate (TAK-438). AB - Inhibition of the gastric H,K-ATPase by the potassium-competitive acid blocker (P CAB) 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N methylmethanamine (TAK-438), is strictly K(+)-competitive with a K(i) of 10 nM at pH 7. In contrast to previous P-CABs, this structure has a point positive charge (pK(a) 9.06) allowing for greater accumulation in parietal cells compared with previous P-CABs [e.g., (8-benzyloxy-2-methyl-imidazo(1,2-a)pyridin-3 yl)acetonitrile (SCH28080), pK(a) 5.6]. The dissociation rate of the compound from the isolated ATPase is slower than other P-CABs, with the t(1/2) being 7.5 h in 20 mM KCl at pH 7. The stoichiometry of binding of TAK-438 to the H,K-ATPase is 2.2 nmol/mg in the presence of Mg-ATP, vanadate, or MgP(i). However, TAK-438 also binds enzyme at 1.3 nmol/mg in the absence of Mg(2+). Modeling of the H,K ATPase to the homologous Na,K-ATPase predicts a close approach and hydrogen bonding between the positively charged N-methylamino group and the negatively charged Glu795 in the K(+)-binding site in contrast to the planar diffuse positive charge of previous P-CABs. This probably accounts for the slow dissociation and high affinity. The model also predicts hydrogen bonding between the hydroxyl of Tyr799 and the oxygens of the sulfonyl group of TAK-438. A Tyr799Phe mutation resulted in a 3-fold increase of the dissociation rate, showing that this hydrogen bonding also contributes to the slow dissociation rate. Hence, this K(+)-competitive inhibitor of the gastric H,K-ATPase should provide longer-lasting inhibition of gastric acid secretion compared with previous drugs of this class. PMID- 21828263 TI - Dissecting the activation of thienopyridines by cytochromes P450 using a pharmacodynamic assay in vitro. AB - The thienopyridine antiplatelet drugs, such as ticlopidine, clopidogrel, and prasugrel, require activation by cytochromes P450 in vivo to effectively block platelet aggregation. The study of the metabolic activation of these compounds has been hampered by the lability and reactivity of the ring-opened active metabolite (AM) and by the numerous metabolites that can be formed in such a transformation. We have developed a novel method whereby platelets are incubated with the cytochrome P450 and the thienopyridine of interest for various amounts of time, and the effects on ADP-driven platelet aggregation are directly examined. In this way, the platelet is used as a biosensor for detection of the AM. Using this method, cytochromes P450 capable of converting clopidogrel, prasugrel, and 2-oxo-clopidogrel to metabolites that inhibit ADP-induced platelet aggregation were identified as well as which cytochromes P450 were capable of catalyzing partial reactions (e.g., conversion of 2-oxo-clopidogrel to the AM). These studies show that, in vitro, CYP3A4/5, 2C19, and 2B6 are individually capable of converting clopidogrel and prasugrel to the AM and that the cytochrome P450 preference for these two thienopyridines is very similar. PMID- 21828262 TI - Regulation of estrogen sulfotransferase expression by confluence of MCF10A breast epithelial cells: role of the aryl hydrocarbon receptor. AB - Estrogen sulfotransferase (SULT1E1) catalyzes the sulfonation of estrogens, which limits estrogen mitogenicity. We recently reported that SULT1E1 expression is low in preconfluent MCF10A human breast epithelial cells but increases when the cells become confluent. Pulse-chase labeling experiments with 5-bromouridine demonstrated that the confluence-mediated increase in SULT1E1 expression was due to increased mRNA synthesis. Because aryl hydrocarbon receptor (AhR) activation has been shown to suppress SULT1E1 expression and loss of cell-cell contact has been shown to activate the AhR in other cell types, we tested whether the confluence-associated changes in SULT1E1 expression were mediated by the AhR. Relative to confluent MCF10A cells, preconfluent cells had higher levels of CYP1A1 mRNA and greater activation of an AhR-responsive luciferase reporter, demonstrating that the AhR was active in the preconfluent cells. AhR and aryl hydrocarbon receptor nuclear translocator mRNA and protein levels were also higher in preconfluent than in confluent cultures. Treatment of preconfluent cells with the AhR antagonist, 3'-methoxy-4'-nitroflavone (MNF), or AhR knockdown significantly increased SULT1E1 expression. MCF10A cells stably transfected with a luciferase reporter containing ~7 kilobases of the SULT1E1 5'-flanking region showed both MNF- and confluence-inducible luciferase expression. Preconfluent cells transiently transfected with the reporter showed both MNF treatment- and AhR knockdown-mediated luciferase induction, but mutation of a computationally predicted dioxin response element (DRE) at nucleotide (nt) -3476 did not attenuate these effects. These results demonstrate that SULT1E1 expression in MCF10A cells is transcriptionally regulated by confluence through a suppressive action of the AhR, which is not mediated through a DRE at nt -3476. PMID- 21828264 TI - Blood-brain barrier (BBB) pharmacoproteomics: reconstruction of in vivo brain distribution of 11 P-glycoprotein substrates based on the BBB transporter protein concentration, in vitro intrinsic transport activity, and unbound fraction in plasma and brain in mice. AB - The purpose of this study was to examine whether in vivo drug distribution to the brain can be reconstructed by integrating P-glycoprotein (P-gp)/mdr1a expression levels, P-gp in vitro activity, and drug unbound fractions in mouse plasma and brain. For 11 P-gp substrates, in vitro P-gp transport activities were determined by measuring transcellular transport across monolayers of mouse P-gp-transfected LLC-PK1 (L-mdr1a) and parental cells. P-gp expression amounts were determined by quantitative targeted absolute proteomics. Unbound drug fractions in plasma and brain were obtained from the literature and by measuring brain slice uptake, respectively. Brain-to-plasma concentration ratios (K(p brain)) and its ratios between wild-type and mdr1a/1b(-/-) mice (K(p brain) ratio) were obtained from the literature or determined by intravenous constant infusion. Unbound brain-to plasma concentration ratios (K(p,uu,brain)) were estimated from K(p brain) and unbound fractions. Based on pharmacokinetic theory, K(p brain) ratios were reconstructed from in vitro P-gp transport activities and P-gp expression amounts in L-mdr1a cells and mouse brain capillaries. All reconstructed K(p brain) ratios were within a 1.6-fold range of observed values. K(p brain) then was reconstructed from the reconstructed K(p brain) ratios and unbound fractions. K(p,uu,brain) was reconstructed as the reciprocal of the reconstructed K(p brain) ratios. For quinidine, loperamide, risperidone, indinavir, dexamethasone, paclitaxel, verapamil, loratadine, and diazepam, the reconstructed K(p brain) and K(p,uu,brain) agreed with observed and estimated in vivo values within a 3-fold range, respectively. Thus, brain distributions of P-gp substrates can be reconstructed from P-gp expression levels, in vitro activity, and drug unbound fractions. PMID- 21828265 TI - Return to youth with Sox17. AB - Maturation of hematopoietic stem cells (HSCs) from fetal to adult state and differentiation to progenitors are thought to follow a one-way street. In this issue of Genes & Development, He and colleagues (pp. 1613-1627) show that overexpression of Sox17 can convert adult multipotential progenitors to self renewing HSCs that possess fetal properties. These findings challenge the irreversibility of hematopoietic development, and open up new perspectives to understand the different forms of HSC self-renewal at distinct stages of ontogeny and during transformation. PMID- 21828266 TI - A snRNP's ordered path to maturity. AB - The U5 snRNP (small ribonucleoprotein) contains several functionally crucial splicing factors that form an extensive interaction network both in the snRNP and within the spliceosome. In this issue of Genes & Development, Weber and colleagues (pp. 1601-1612) shed light on the dynamic assembly of this critical spliceosomal component and elucidate the molecular interactions underlying the ordered addition of Brr2, a pivotal spliceosomal helicase, to the U5 snRNP. PMID- 21828268 TI - Polycomb eviction as a new distant enhancer function. AB - Remote distal enhancers may be located tens or thousands of kilobases away from their promoters. How they control gene expression is still poorly understood. Here, we analyze the influence of a remote enhancer on the balance between repression (Polycomb-PcG) and activation (Trithorax-TrxG) of a developmentally regulated gene associated with a CpG island. We reveal its essential, nonredundant role in clearing the PcG complex and H3K27me3 from the CpG island. In the absence of the enhancer, the H3K27me3 demethylase (JMJD3) is not recruited to the CpG island. We propose a new role of long-range regulatory elements in removing repressive PcG complexes. PMID- 21828267 TI - Mechanism of CRL4(Cdt2), a PCNA-dependent E3 ubiquitin ligase. AB - Eukaryotic cell cycle transitions are driven by E3 ubiquitin ligases that catalyze the ubiquitylation and destruction of specific protein targets. For example, the anaphase-promoting complex/cyclosome (APC/C) promotes the exit from mitosis via destruction of securin and mitotic cyclins, whereas CRL1(Skp2) allows entry into S phase by targeting the destruction of the cyclin-dependent kinase (CDK) inhibitor p27. Recently, an E3 ubiquitin ligase called CRL4(Cdt2) has been characterized, which couples proteolysis to DNA synthesis via an unusual mechanism that involves display of substrate degrons on the DNA polymerase processivity factor PCNA. Through its destruction of Cdt1, p21, and Set8, CRL4(Cdt2) has emerged as a master regulator that prevents rereplication in S phase. In addition, it also targets other factors such as E2F and DNA polymerase eta. In this review, we discuss our current understanding of the molecular mechanism of substrate recognition by CRL4(Cdt2) and how this E3 ligase helps to maintain genome integrity. PMID- 21828269 TI - 'Inc-miRs': functional intron-interrupted miRNA genes. AB - The discovery of microRNAs (miRNAs) lin-4 and let-7 as temporal regulators in Caenorhabditis elegans led to broader searches for novel miRNAs and their biological roles. Unlike protein-coding genes and some long noncoding RNAs, canonical metazoan miRNAs are not known to contain introns within their genomic precursor sequences. Because the short length of miRNAs complicates a statistically definitive assignment of split genes in RNA sequencing data sets, we took an experimental approach toward testing the compatibility of splicing and functional miRNA biogenesis. To definitively evaluate the possibility that miRNAs could derive from interrupted genes, we constructed intron-interrupted variants of C. elegans lin-4 and assayed for their miRNA-encoding capability and biological activity in the developing organism. Our studies indicate that (1) intron-containing miRNAs (inc-miRs) can be efficiently spliced and processed to produce miRNAs with normal termini, and (2) these miRNAs can be functional in full rescue of developmental phenotypes in null mutants lacking endogenous lin-4. This study provides the first evidence to support the ability of intron interrupted miRNA precursors to produce functional regulators and identifies an additional modality available for metazoan miRNA production. PMID- 21828270 TI - Tsc1 mutant neural stem/progenitor cells exhibit migration deficits and give rise to subependymal lesions in the lateral ventricle. AB - Subependymal nodules (SENs) and subependymal giant cell astrocytomas (SEGAs) are common brain lesions found in patients with tuberous sclerosis complex (TSC). These brain lesions present a mixed glioneuronal phenotype and have been hypothesized to originate from neural stem cells. However, this hypothesis has not been tested empirically. Here, we report that loss of Tsc1 in mouse subventricular zone (SVZ) neural stem/progenitor cells (NSPCs) results in formation of SEN- and SEGA-like structural abnormalities in the lateral ventricle, the consequence of abnormal migration of NSPCs following Tsc1 loss. PMID- 21828271 TI - Sox17 expression confers self-renewal potential and fetal stem cell characteristics upon adult hematopoietic progenitors. AB - A key question concerns the mechanisms that determine temporal identity in stem cells. Fetal hematopoietic stem cells (HSCs) differ from adult HSCs in terms of gene expression profile, surface marker expression, differentiation, and self renewal capacity. We previously showed that the transcription factor SOX17 is expressed by fetal, but not adult, HSCs and is required for the maintenance of fetal and neonatal, but not adult, HSCs. In the current study, we show that ectopic expression of Sox17 in adult HSCs and transiently reconstituting multipotent progenitors was sufficient to confer increased self-renewal potential and the expression of fetal HSC genes, including fetal HSC surface markers. Sox17 expression enabled transiently reconstituting adult progenitors to give long-term multilineage reconstitution that resembled fetal hematopoiesis, including increased erythropoiesis, increased myelopoiesis, and decreased lymphopoiesis. Long-term ectopic expression of Sox17 eventually led to leukemogenesis. These data demonstrate that SOX17 is sufficient to confer fetal HSC characteristics to adult hematopoietic progenitors and is therefore a key determinant of fetal HSC identity. PMID- 21828272 TI - An integrated approach to dissecting oncogene addiction implicates a Myb coordinated self-renewal program as essential for leukemia maintenance. AB - Although human cancers have complex genotypes and are genomically unstable, they often remain dependent on the continued presence of single-driver mutations-a phenomenon dubbed "oncogene addiction." Such dependencies have been demonstrated in mouse models, where conditional expression systems have revealed that oncogenes able to initiate cancer are often required for tumor maintenance and progression, thus validating the pathways they control as therapeutic targets. Here, we implement an integrative approach that combines genetically defined mouse models, transcriptional profiling, and a novel inducible RNAi platform to characterize cellular programs that underlie addiction to MLL-AF9-a fusion oncoprotein involved in aggressive forms of acute myeloid leukemia (AML). We show that MLL-AF9 contributes to leukemia maintenance by enforcing a Myb-coordinated program of aberrant self-renewal involving genes linked to leukemia stem cell potential and poor prognosis in human AML. Accordingly, partial and transient Myb suppression precisely phenocopies MLL-AF9 withdrawal and eradicates aggressive AML in vivo without preventing normal myelopoiesis, indicating that strategies to inhibit Myb-dependent aberrant self-renewal programs hold promise as effective and cancer-specific therapeutics. Together, our results identify Myb as a critical mediator of oncogene addiction in AML, delineate relevant Myb target genes that are amenable to pharmacologic inhibition, and establish a general approach for dissecting oncogene addiction in vivo. PMID- 21828273 TI - Sustained activation of the HER1-ERK1/2-RSK signaling pathway controls myoepithelial cell fate in human mammary tissue. AB - Human mammary glands arise from multipotent progenitor cells, which likely respond both to cell-autonomous and to extrinsic cues. However, the identity of these cues and how they might act remain unclear. We analyzed HER1 ligand effects on mammary morphogenesis using a three-dimensional organoid model generated from human breast tissue that recapitulates both qualitatively and quantitatively the normal ductal network in situ. Strikingly, different HER1 ligands generate distinct patterns of cell fate. Epidermal growth factor (EGF) causes a massive expansion of the myoepithelial lineage. Amphiregulin, in contrast, enables normal ductal development. These differences cannot be ascribed to preferential apoptosis or proliferation of differentiated cell populations, but are dependent on HER1 signal intensity. Inhibition of the extracellular signal-regulated kinase 1/2 (ERK1/2) effector RSK prevents the EGF-induced myoepithelial expansion. Notably, mouse mammary organoids are much less responsive to HER1 ligands. Little is known about the myoepithelial lineage or about growth factor effects on mammary progenitor differentiation, and our studies provide an important window into human mammary development that reveals unexpected differences from the mouse model. PMID- 21828274 TI - HEB and E2A function as SMAD/FOXH1 cofactors. AB - Nodal signaling, mediated through SMAD transcription factors, is necessary for pluripotency maintenance and endoderm commitment. We identified a new motif, termed SMAD complex-associated (SCA), that is bound by SMAD2/3/4 and FOXH1 in human embryonic stem cells (hESCs) and derived endoderm. We demonstrate that two basic helix-loop-helix (bHLH) proteins-HEB and E2A-bind the SCA motif at regions overlapping SMAD2/3 and FOXH1. Furthermore, we show that HEB and E2A associate with SMAD2/3 and FOXH1, suggesting they form a complex at critical target regions. This association is biologically important, as E2A is critical for mesendoderm specification, gastrulation, and Nodal signal transduction in Xenopus tropicalis embryos. Taken together, E proteins are novel Nodal signaling cofactors that associate with SMAD2/3 and FOXH1 and are necessary for mesendoderm differentiation. PMID- 21828275 TI - Expression of innate and adaptive immune mediators in human corneal tissue infected with Aspergillus or fusarium. AB - BACKGROUND: Filamentous fungi of the genera Aspergillus and Fusarium are major causes of corneal ulcers in the United States and in the developing world and result in significant visual impairment and blindness. METHODS: RNA was extracted from 110 patients with corneal ulcers in southern India within 1 week of infection with either Fusarium solani or Aspergillus flavus, and gene expression was determined by quantitative polymerase chain reaction. Posttransplant corneas from later stage disease (>2 weeks after infection) were also examined. RESULTS: Expression of Dectin-1, Toll-like receptor 2 (TLR2), TLR4, TLR9, and NOD-like receptor protein (NLRP)3 messenger RNA was elevated >1000-fold compared with uninfected donor corneas, whereas Dectin-2 was constitutively expressed in uninfected corneas. Furthermore, interleukin 1beta (IL-1beta) expression was elevated >1000-fold, whereas IL-1alpha expression was not increased. Expression of IL-8, IL-17, and tumor necrosis factor alpha was also elevated. CD3(+)and CD4(+) T cells were detected in infected posttransplant corneas. Expression of IL 17 and interferon gamma was elevated but not that of IL-4. There were no significant differences in the host response between Aspergillus- and Fusarium infected corneas at any time point. CONCLUSIONS: There is a common innate and adaptive immune response to these filamentous fungi, which includes the generation of T-helper 1 and T-helper 17 cells. PMID- 21828277 TI - Is life law-like? AB - Genes are generally assumed to be primary biological causes of biological phenotypes and their evolution. In just over a century, a research agenda that has built on Mendel's experiments and on Darwin's theory of natural selection as a law of nature has had unprecedented scientific success in isolating and characterizing many aspects of genetic causation. We revel in these successes, and yet the story is not quite so simple. The complex cooperative nature of genetic architecture and its evolution include teasingly tractable components, but much remains elusive. The proliferation of data generated in our "omics" age raises the question of whether we even have (or need) a unified theory or "law" of life, or even clear standards of inference by which to answer the question. If not, this not only has implications for the widely promulgated belief that we will soon be able to predict phenotypes like disease risk from genes, but also speaks to the limitations in the underlying science itself. Much of life seems to be characterized by ad hoc, ephemeral, contextual probabilism without proper underlying distributions. To the extent that this is true, causal effects are not asymptotically predictable, and new ways of understanding life may be required. PMID- 21828279 TI - Fixation when N and s vary: classic approaches give elegant new results. PMID- 21828278 TI - Genome engineering with zinc-finger nucleases. AB - Zinc-finger nucleases (ZFNs) are targetable DNA cleavage reagents that have been adopted as gene-targeting tools. ZFN-induced double-strand breaks are subject to cellular DNA repair processes that lead to both targeted mutagenesis and targeted gene replacement at remarkably high frequencies. This article briefly reviews the history of ZFN development and summarizes applications that have been made to genome editing in many different organisms and situations. Considerable progress has been made in methods for deriving zinc-finger sets for new genomic targets, but approaches to design and selection are still being perfected. An issue that needs more attention is the extent to which available mechanisms of double-strand break repair limit the scope and utility of ZFN-initiated events. The bright prospects for future applications of ZFNs, including human gene therapy, are discussed. PMID- 21828280 TI - Genome evolution and meiotic maps by massively parallel DNA sequencing: spotted gar, an outgroup for the teleost genome duplication. AB - Genomic resources for hundreds of species of evolutionary, agricultural, economic, and medical importance are unavailable due to the expense of well assembled genome sequences and difficulties with multigenerational studies. Teleost fish provide many models for human disease but possess anciently duplicated genomes that sometimes obfuscate connectivity. Genomic information representing a fish lineage that diverged before the teleost genome duplication (TGD) would provide an outgroup for exploring the mechanisms of evolution after whole-genome duplication. We exploited massively parallel DNA sequencing to develop meiotic maps with thrift and speed by genotyping F(1) offspring of a single female and a single male spotted gar (Lepisosteus oculatus) collected directly from nature utilizing only polymorphisms existing in these two wild individuals. Using Stacks, software that automates the calling of genotypes from polymorphisms assayed by Illumina sequencing, we constructed a map containing 8406 markers. RNA-seq on two map-cross larvae provided a reference transcriptome that identified nearly 1000 mapped protein-coding markers and allowed genome-wide analysis of conserved synteny. Results showed that the gar lineage diverged from teleosts before the TGD and its genome is organized more similarly to that of humans than teleosts. Thus, spotted gar provides a critical link between medical models in teleost fish, to which gar is biologically similar, and humans, to which gar is genomically similar. Application of our F(1) dense mapping strategy to species with no prior genome information promises to facilitate comparative genomics and provide a scaffold for ordering the numerous contigs arising from next generation genome sequencing. PMID- 21828282 TI - The additive effects of ischemic postconditioning and cyclosporine-A on nitric oxide activity and functions of diabetic myocardium injured by ischemia/reperfusion. AB - BACKGROUND: The interaction of diabetes with cardioprotection by postconditioning in ischemia/reperfusion injury remains unclear. The aim of this study was to investigate the concomitant effects of ischemic postconditioning (IPostC) and cyclosporine-A (CsA) on nitric oxide (NO) content and parameters of cardiac function of the diabetic myocardium injured by ischemia/reperfusion. METHODS: Diabetes was induced by single injection of streptozotocin (50 mg/kg; intraperitoneally [ip]) in Wistar rats (250-320 g) and the diabetic period was 8 weeks. The hearts (n = 96) were removed quickly, mounted on Langendorff apparatus, and then subjected to 30-minute regional ischemia followed by 45 minute reperfusion. Ischemic postconditioning was induced by 3 cycles of 30 second reperfusion/ischemia at the onset of reperfusion. Myocardial function was measured throughout the experiment, and infarct size (IS) was identified by triphenyltetrazolium chloride (TTC) staining. Total amounts of NO metabolites were determined using Griess method and enzyme-linked immunosorbent assay (ELISA) reader. RESULTS: Administration of either IPostC or CsA alone in nondiabetic animals significantly improved myocardial function and reduced the ISs (28% +/- 1.9% or 23% +/- 2.0% vs 41% +/- 2.9% of the risk zone [RZ], respectively; P < .01), but they had no effect on diabetic hearts (35% +/- 1.8% or 32% +/- 2.1% vs 39% +/- 3.1%, respectively). In addition, myocardial NO level was significantly increased by IPostC only in nondiabetic animals (P < .01). However, after administration of CsA (5 minutes before and 10 minutes after the onset of reperfusion) in postconditioned animals, the cardioprotective and NO-enhancing effects of IPostC were restored in diabetic rats (IS: 21% +/- 1.1% vs 39% +/- 3.1%), similar to those in nondiabetic controls (19% +/- 1.3% vs 41% +/- 2.9%; P < .01). CONCLUSION: The present study indicated that IPostC or CsA failed to affect NO levels and failed to protect the diabetic myocardium against ischemia/reperfusion injury. Moreover, concomitant administration of CsA and IPostC at reperfusion can increase NO content and protect the diabetic myocardium. PMID- 21828281 TI - All preconditioning-related G protein-coupled receptors can be demonstrated in the rabbit cardiomyocyte. AB - G protein-coupled receptors for adenosine (A(1), A(3), A(2A), and A(2B)), bradykinin (B(1)) and opioids (delta) are all involved in the mechanism of ischemic preconditioning. Although the heart is comprised of many tissue types, it has been assumed that preconditioning's protective signaling occurs in the cardiomyocyte. We critically tested that hypothesis by testing for the presence of each of these receptors in isolated adult rabbit ventricular myocytes that had been transfected with cyclic nucleotide-gated (CNG) ion channels. Because subsarcolemmal cyclic adenosine monophosphate (cAMP) opens the CNG channels, we could monitor cAMP levels within a single cardiomyocyte by measuring channel current with a patch pipette. The presence of a receptor would be confirmed if we could alter cAMP in the cell with a selective agonist to the receptor being studied. Superfusion with the beta-adrenergic G(s)-coupled receptor agonist isoproterenol (50 nmol/L) transiently increased cAMP levels and, therefore, channel current. Pretreatment with selective agonists to A(1) or A(3) adenosine receptors (ARs) that are G(i)-coupled markedly attenuated the response to isoproterenol, indicating inhibition of adenylyl cyclase by increased G(i) activity. Agonists to bradykinin or delta-opioid receptors also attenuated isoproterenol's response. A(2A)AR and A(2B)AR are G(s)-coupled. The A(2A)AR selective agonist CGS21680 increased current through CNG channels but only in the presence of phosphodiesterase (PDE) inhibitors, indicating low surface receptor activity and high intracellular PDE activity. As we previously reported, BAY 60 6583, an A(2B)AR-selective agonist which mimics preconditioning's protection in rabbit heart, neither increased nor decreased membrane current in transfected cardiomyocytes, suggesting the absence or a markedly limited number of A(2B)AR in the sarcolemma. However, reverse transcription polymerase chain reaction (RT-PCR) of purified cardiomyocytes yielded an A(2B)AR band, implying that rabbit cardiomyocytes do indeed express A(2B)AR. These data reveal that all receptors reported to be involved in ischemic preconditioning do exist on or within the cardiomyocyte. PMID- 21828283 TI - Terminalia arjuna enhances baroreflex sensitivity and myocardial function in isoproterenol-induced chronic heart failure rats. AB - Chronic heart failure (CHF) is characterized by left ventricular (LV) dysfunction along with impaired autonomic control functions. Herbal drugs are increasingly being used in the treatment of cardiovascular disorders. The present study was designed to examine the protective effect of Terminalia arjuna (T arjuna) bark extract on LV and baroreflex function in CHF and to elucidate the possible mechanistic clues in its cardioprotective action. The baroreflex was evaluated by measuring the changes in heart rate (HR) with changes in arterial blood pressure induced by bolus injections of phenylephrine (vasoconstrictor) and sodium nitroprusside (vasodilator). T arjuna bark extract and fluvastatin were tested/administered therapeutically and prophylactically in isoproterenol-induced rat model of CHF. Fifteen days after isoproterenol administration, rats exhibited cardiac dysfunction, hypertrophy, and LV remodeling along with reduced baroreflex sensitivity. Prophylactic and therapeutic treatment with T arjuna improved cardiac functions and baroreflex sensitivity. It also attenuated hypertrophy and fibrosis of the LV. Fluvastatin treatment exerted a similar protective effect against myocardial remodeling and heart failure. Further, T arjuna and fluvastatin significantly reduced oxidative stress and inflammatory cytokine level in CHF rats. In conclusion, T arjuna exerts beneficial effect on LV functions, myocardial remodeling, and autonomic control in CHF possibly through maintaining endogenous antioxidant enzyme activities, inhibiting lipid peroxidation and cytokine levels. PMID- 21828284 TI - Medical therapy for calcific aortic stenosis. AB - Severe aortic stenosis due to calcification of the aortic valve is the most common indication for aortic valve replacement in the United States and Europe. The standard therapy for symptomatic patients with severe aortic stenosis is replacement of the valve. Some of the risk factors and pathophysiologic mechanisms in atherosclerosis play an important role in the development of calcific aortic stenosis. In the last few years, there have been an increased number of publications regarding the use of medications in order to delay the progression of aortic stenosis. These medications include statins, angiotensin converting enzyme inhibitors, and biphosphanates. This article describes and summarizes some of the medical approaches that have emerged to alter the progression of aortic stenosis. Currently, only statins have been evaluated in randomized, placebo-control trials. Furthermore, statins have not proven to alter the progression of aortic stenosis. Ongoing randomized controlled trials with the use of angiotensin-converting enzyme inhibitors, statins, and biphosphonates will determine the use of these medications to delay the progression of aortic stenosis. PMID- 21828285 TI - Proteomic profiling of adipose tissue from Zmpste24-/- mice, a model of lipodystrophy and premature aging, reveals major changes in mitochondrial function and vimentin processing. AB - Lipodystrophy is a major disease involving severe alterations of adipose tissue distribution and metabolism. Mutations in genes encoding the nuclear envelope protein lamin A or its processing enzyme, the metalloproteinase Zmpste24, cause diverse human progeroid syndromes that are commonly characterized by a selective loss of adipose tissue. Similarly to humans, mice deficient in Zmpste24 accumulate prelamin A and display phenotypic features of accelerated aging, including lipodystrophy. Herein, we report the proteome and phosphoproteome of adipose tissue as well as serum metabolome in lipodystrophy by using Zmpste24(-/ ) mice as experimental model. We show that Zmpste24 deficiency enhanced lipolysis, fatty acid biogenesis and beta-oxidation as well as decreased fatty acid re-esterification, thus pointing to an increased partitioning of fatty acid toward beta-oxidation and away from storage that likely underlies the observed size reduction of Zmpste24-null adipocytes. Besides the mitochondrial proteins related to lipid metabolism, other protein networks related to mitochondrial function, including those involved in tricarboxylic acid cycle and oxidative phosphorylation, were up-regulated in Zmpste24(-/-) mice. These results, together with the observation of an increased mitochondrial response to oxidative stress, support the relationship between defective prelamin A processing and mitochondrial dysfunction and highlight the relevance of oxidative damage in lipoatrophy and aging. We also show that absence of Zmpste24 profoundly alters the processing of the cytoskeletal protein vimentin and identify a novel protein dysregulated in lipodystrophy, High-Mobility Group Box-1 Protein. Finally, we found several lipid derivates with important roles in energy balance, such as Lysophosphatidylcholine or 2-arachidonoylglycerol, to be dysregulated in Zmpste24(-/-) serum. Together, our findings in Zmpste24(-/-) mice may be useful to unveil the mechanisms underlying adipose tissue dysfunction and its overall contribution to body homeostasis in progeria and other lipodystrophy syndromes as well as to develop novel strategies to prevent or ameliorate these diseases. PMID- 21828286 TI - Direct evidence of phosphorylated neuronal intermediate filament proteins in neurofibrillary tangles (NFTs): phosphoproteomics of Alzheimer's NFTs. AB - Alzheimer's disease (AD) is a neurodegenerative disorder characterized by brain pathology of intracellular neurofibrillary tangles (NFTs) and extracellular amyloid plaques. NFTs contain aberrantly hyperphosphorylated Tau as paired helical filaments (PHFs). Although NFs have been shown immunohistologically to be part of NFTs, there has been debate that the identity of NF proteins in NFTs is due to the cross-reactivity of phosphorylated NF antibodies with phospho-Tau. Here, we provide direct evidence on the identity of NFs in NFTs by immunochemical and mass spectrometric analysis. We have purified sarkosyl-insoluble NFTs and performed liquid chromatography/tandem mass spectrometry of NFT tryptic digests. The phosphoproteomics of NFTs clearly identified NF-M phosphopeptides SPVPKS*PVEEAK, corresponding to Ser685, and KAES*PVKEEAVAEVVTITK, corresponding to Ser736, and an NF-H phosphopeptide, EPDDAKAKEPS*KP, corresponding to Ser942. Western blotting of purified tangles with SMI31 showed a 150-kDa band corresponding to phospho-NF-M, while RT97 antibodies detected phospho-NF-H. The proteomics analysis also identified an NF-L peptide (ALYEQEIR, EAEEEKKVEGAGEEQAAAK) and another intermediate filament protein, vimentin (FADLSEAANR). Mass spectrometry revealed Tau phosphopeptides corresponding to Thr231, Ser235, Thr181, Ser184, Ser185, Thr212, Thr217, Ser396, and Ser403. And finally, phosphopeptides corresponding to MAP1B (corresponding to Ser1270, Ser1274, and Ser1779) and MAP2 (corresponding to Thr350, Ser1702, and Ser1706) were identified. In corresponding matched control preparations of PHF/NFTs, none of these phosphorylated neuronal cytoskeletal proteins were found. These studies independently demonstrate that NF proteins are an integral part of NFTs in AD brains. PMID- 21828287 TI - Role of ubiquitylation and USP8-dependent deubiquitylation in the endocytosis and lysosomal targeting of plasma membrane KCa3.1. AB - We recently demonstrated that plasma membrane KCa3.1 is rapidly endocytosed and targeted for lysosomal degradation via a Rab7- and ESCRT-dependent pathway. Herein, we assess the role of ubiquitylation in this process. Using a biotin ligase acceptor peptide (BLAP)-tagged KCa3.1, in combination with tandem ubiquitin binding entities (TUBEs), we demonstrate that KCa3.1 is polyubiquitylated following endocytosis. Hypertonic sucrose inhibited KCa3.1 endocytosis and resulted in a significant decrease in channel ubiquitylation. Inhibition of the ubiquitin-activating enzyme (E1) with UBEI-41 resulted in reduced KCa3.1 ubiquitylation and internalization. The general deubiquitylase (DUB) inhibitor, PR-619 attenuated KCa3.1 degradation, indicative of deubiquitylation being required for lysosomal delivery. Using the DUB Chip, a protein microarray containing 35 DUBs, we demonstrate a time-dependent association between KCa3.1 and USP8 following endocytosis, which was confirmed by coimmunoprecipitation. Further, overexpression of wild-type USP8 accelerates channel deubiquitylation, while either a catalytically inactive mutant USP8 or siRNA-mediated knockdown of USP8 enhanced accumulation of ubiquitylated KCa3.1, thereby inhibiting channel degradation. In summary, by combining BLAP-tagged KCa3.1 with TUBEs and DUB Chip methodologies, we demonstrate that polyubiquitylation mediates the targeting of membrane KCa3.1 to the lysosomes and also that USP8 regulates the rate of KCa3.1 degradation by deubiquitylating KCa3.1 prior to lysosomal delivery. PMID- 21828288 TI - Effects of the circadian rhythm gene period 1 (per1) on psychosocial stress induced alcohol drinking. AB - OBJECTIVE: Circadian and stress-response systems mediate environmental changes that affect alcohol drinking. Psychosocial stress is an environmental risk factor for alcohol abuse. Circadian rhythm gene period 1 (Per1) is targeted by stress hormones and is transcriptionally activated in corticotropin releasing factor expressing cells. The authors hypothesized that Per1 is involved in integrating stress response and circadian rhythmicity and explored its relevance to alcohol drinking. METHOD: In mice, the effects of stress on ethanol intake in mPer1 mutant and wild-type mice were assessed. In humans, single nucleotide polymorphisms (SNPs) in hPer1 were tested for association with alcohol drinking behavior in 273 adolescents and an adult case-control sample of 1,006 alcohol dependent patients and 1,178 comparison subjects. In vitro experiments were conducted to measure genotype-specific expression and transcription factor binding to hPer1. RESULTS: The mPer1-mutant mice showed enhanced alcohol consumption in response to social defeat stress relative to their wild-type littermates. An association with the frequency of heavy drinking in adolescents with the hPer1 promoter SNP rs3027172 and with psychosocial adversity was found. There was significant interaction between the rs3027172 genotype and psychosocial adversity on this drinking measure. In a confirmatory analysis, association of hPer1 rs3027172 with alcohol dependence was shown. Cortisol-induced transcriptional activation of hPer1 was reduced in human B-lymphoblastoid cells carrying the risk genotype of rs3027172. Binding affinity of the transcription factor Snail1 to the risk allele of the hPer1 SNP rs3027172 was also reduced. CONCLUSIONS: The findings indicate that the hPer1 gene regulates alcohol drinking behavior during stressful conditions and provide evidence for underlying neurobiological mechanisms. PMID- 21828290 TI - Plastid uridine salvage activity is required for photoassimilate allocation and partitioning in Arabidopsis. AB - Nucleotides are synthesized from de novo and salvage pathways. To characterize the uridine salvage pathway, two genes, UKL1 and UKL2, that tentatively encode uridine kinase (UK) and uracil phosphoribosyltransferase (UPRT) bifunctional enzymes were studied in Arabidopsis thaliana. T-DNA insertions in UKL1 and UKL2 reduced transcript expression and increased plant tolerance to toxic analogs 5 fluorouridine and 5-fluorouracil. Enzyme activity assays using purified recombinant proteins indicated that UKL1 and UKL2 have UK but not UPRT activity. Subcellular localization using a C-terminal enhanced yellow fluorescent protein fusion indicated that UKL1 and UKL2 localize to plastids. The ukl2 mutant shows reduced transient leaf starch during the day. External application of orotate rescued this phenotype in ukl2, indicating pyrimidine pools are limiting for starch synthesis in ukl2. Intermediates for lignin synthesis were upregulated, and there was increased lignin and reduced cellulose content in the ukl2 mutant. Levels of ATP, ADP, ADP-glucose, UTP, UDP, and UDP-glucose were altered in a light-dependent manner. Seed composition of the ukl1 and ukl2 mutants included lower oil and higher protein compared with the wild type. Unlike single gene mutants, the ukl1 ukl2 double mutant has severe developmental defects and reduced biomass accumulation, indicating these enzymes catalyze redundant reactions. These findings point to crucial roles played by uridine salvage for photoassimilate allocation and partitioning. PMID- 21828291 TI - The evolution of photorespiratory glycolate oxidase activity. PMID- 21828289 TI - RopGEF7 regulates PLETHORA-dependent maintenance of the root stem cell niche in Arabidopsis. AB - The root stem cell niche defines the area that specifies and maintains the stem cells and is essential for the maintenance of root growth. Here, we characterize and examine the functional role of a quiescent center (QC)-expressed RAC/ROP GTPase activator, RopGEF7, in Arabidopsis thaliana. We show that RopGEF7 interacts with At RAC1 and overexpression of a C-terminally truncated constitutively active RopGEF7 (RopGEF7DeltaC) activates RAC/ROP GTPases. Knockdown of RopGEF7 by RNA interference causes defects in embryo patterning and maintenance of the QC and leads to postembryonic loss of root stem cell population. Gene expression studies indicate that RopGEF7 is required for root meristem maintenance as it regulates the expression of PLETHORA1 (PLT1) and PLT2, which are key transcription factors that mediate the patterning of the root stem cell niche. Genetic analyses show that RopGEF7 interacts with PLT genes to regulate QC maintenance. Moreover, RopGEF7 is induced transcriptionally by auxin while its function is required for the expression of the auxin efflux protein PIN1 and maintenance of normal auxin maxima in embryos and seedling roots. These results suggest that RopGEF7 may integrate auxin-derived positional information in a feed-forward mechanism, regulating PLT transcription factors and thereby controlling the maintenance of root stem cell niches. PMID- 21828293 TI - Substance use and dependence education in predoctoral dental curricula: results of a survey of U.S. and Canadian dental schools. AB - The purpose of this study was to obtain information about education in substance use and dependence that appears in the predoctoral curricula of U.S. and Canadian dental schools. Sixty-eight deans were sent a twenty-item survey requesting information about when in the curriculum these subjects were taught, what instructional methods were used, and whether behavior change instruction was included to address these issues in clinical interactions. The survey had an 81 percent response rate. The topics of alcohol use and dependence, tobacco use and dependence, and prescription drug misuse and abuse were reported in over 90 percent (N=55) of responding schools' predoctoral curricula. The topic of other substance use and dependence was reported in only 72.7 percent (N=40) of these schools. The primary instructional method reported was the use of lecture. Less frequently used methods included small-group instruction, instruction in school based clinic, community-based extramural settings, and independent study. As future health professionals, dental students are an important source for patients concerning substance use, abuse, and treatment. Our investigation confirmed that alcohol, tobacco, and prescription drug abuse is addressed widely in predoctoral dental curricula, but other substance use and dependence are less frequently addressed. PMID- 21828294 TI - Dental students and intimate partner violence: measuring knowledge and experience to institute curricular change. AB - Our study documents the shortage of intimate partner violence (IPV) content exposure within one dental school curriculum, with an eye toward utilizing this information to revise an existing comprehensive family violence curriculum that will be fully integrated into required university coursework to improve competence and help overcome knowledge gaps. IPV is defined by the Centers for Disease Control and Prevention as physical and sexual violence, threats of physical and sexual violence, or psychological/emotional abuse including coercive tactics that adults or adolescents use against current or former intimate partners. We report on the results of a four-part (background, IPV knowledge, opinions, and personal experience), sixty-seven-item validated survey instrument used to measure knowledge, attitudes, beliefs, and self-reported behaviors among dental students preparing to become health care professionals working in the field. Survey responses from the nearly 80 percent of fourth-year dental students who completed the survey were examined within the context of students' actual IPV knowledge, as well as opinions and attitudes that could directly or indirectly influence patients. Our findings indicate that a sizeable number of students received no IPV training prior to or during dental school, leading to perceptions that they lack knowledge about IPV and are not well prepared to address IPV with patients. A notable percentage of students (20 percent) also reported personal experience with IPV. PMID- 21828295 TI - Dental students' attitudes toward underserved populations across four years of dental school. AB - The objective of this study was to assess dental students' attitudes toward underserved populations across their four years of dental school. Students at the Herman Ostrow School of Dentistry of the University of Southern California were invited to take part in the study. Participating students completed a questionnaire on their attitudes toward the underserved at three time points: 1) during orientation week; 2) at the end of their second year after taking part in some community dental programs; and 3) at the end of their fourth year after they had completed all their mandatory and volunteer rotations in community dental programs. Students' attitudes were measured in four categories: societal expectations, dentist/student responsibility, personal efficacy, and access to care. First-year students scored 85 out of a maximum of 115 on the questionnaire. Female students scored higher than male students (P=0.006). Age, debt, and past history of volunteer work were not related to first-year students' total attitude scores; however, students with a history of volunteer experience scored higher on the dentist/student responsibility category (P=0.04). Students' attitude scores declined across the four years of dental school (P=0.001). The same patterns were evident for all categories except societal expectations. The decline was not related to age, gender, debt, or volunteer work experience. Follow-up studies are needed to help explain the factors that may be related to this decline. PMID- 21828292 TI - Cyanobacterial lactate oxidases serve as essential partners in N2 fixation and evolved into photorespiratory glycolate oxidases in plants. AB - Glycolate oxidase (GOX) is an essential enzyme involved in photorespiratory metabolism in plants. In cyanobacteria and green algae, the corresponding reaction is catalyzed by glycolate dehydrogenases (GlcD). The genomes of N(2) fixing cyanobacteria, such as Nostoc PCC 7120 and green algae, appear to harbor genes for both GlcD and GOX proteins. The GOX-like proteins from Nostoc (No-LOX) and from Chlamydomonas reinhardtii showed high L-lactate oxidase (LOX) and low GOX activities, whereas glycolate was the preferred substrate of the phylogenetically related At-GOX2 from Arabidopsis thaliana. Changing the active site of No-LOX to that of At-GOX2 by site-specific mutagenesis reversed the LOX/GOX activity ratio of No-LOX. Despite its low GOX activity, No-LOX overexpression decreased the accumulation of toxic glycolate in a cyanobacterial photorespiratory mutant and restored its ability to grow in air. A LOX-deficient Nostoc mutant grew normally in nitrate-containing medium but died under N(2) fixing conditions. Cultivation under low oxygen rescued this lethal phenotype, indicating that N(2) fixation was more sensitive to O(2) in the Deltalox Nostoc mutant than in the wild type. We propose that LOX primarily serves as an O(2) scavenging enzyme to protect nitrogenase in extant N(2)-fixing cyanobacteria, whereas in plants it has evolved into GOX, responsible for glycolate oxidation during photorespiration. PMID- 21828296 TI - Dental hygienists' perceptions of barriers to graduate education. AB - To advance the profession of dental hygiene, graduate education is necessary to support growth in research, education, administration, and practice in the discipline and to sustain credibility in a climate in which other health professions require entry-level master's and doctoral degrees. The purpose of this study was to explore what dental hygienists perceive as barriers to pursuing a graduate degree. A survey was developed based on the literature and other national surveys. Data were collected from 160 respondents to the survey: 50 percent held an entry-level baccalaureate degree in dental hygiene, while the rest held an entry-level associate degree (48 percent) or certificate (2 percent) in dental hygiene. All respondents had completed a bachelor's degree. The top five barriers these respondents identified in pursuing graduate education were as follows: 1) cost of graduate education, 2) family responsibilities are too great, 3) concerns about personal funding to pay for graduate education, 4) finding time for graduate school while working, and 5) fear of thesis research. Dental hygiene is one of the few health professions that still have entry-level degrees at the associate and baccalaureate levels. The profession needs to reduce such barriers to enable dental hygienists to pursue graduate education and thus ensure an adequate supply of future leaders, educators, and researchers. PMID- 21828298 TI - Assessing the demand and preferred format of a student leadership development program at Pacific. AB - Dental students are future leaders of health care and the dental profession. The purpose of this study was to assess the interest in leadership development programs at the University of the Pacific Arthur A. Dugoni School of Dentistry and compare the results with similar studies. In April 2010, two surveys were administered. Of the 462 students enrolled, 58 percent completed the survey. Of the eighty-one faculty members and administrators who attended the Spring Faculty Development Day, 85 percent completed the survey. This study confirmed claims that students find it most effective to learn leadership from mentors. Over 80 percent of the student respondents indicated that faculty mentorship would be the most beneficial aspect of a leadership development program. Sixty-two percent of the faculty respondents said they would serve as mentors. Following mentorship, small-group discussion (74 percent), public speaking (56 percent), dental society member mentorship (40 percent), panel discussions (39 percent), community outreach (39 percent), and capstone project (13 percent) followed in popularity. This study established a foundation to develop a pilot for the Dugoni Practical Leadership Initiative at Pacific based on the preferences of the participants in this survey. With more data and longitudinal studies, we will assess how these programs translate to leadership in dental school and after graduation. PMID- 21828297 TI - Development of a sustainable community-based dental education program. AB - Increasing the use of community-based programs is an important trend in improving dental education to meet the needs of students and the public. To support this trend, understanding the history of programs that have established successful models for community-based education is valuable for the creation and development of new programs. The community-based education model of the University of Michigan School of Dentistry (UMSOD) offers a useful guide for understanding the essential steps and challenges involved in developing a successful program. Initial steps in program development were as follows: raising funds, selecting an outreach clinical model, and recruiting clinics to become partners. As the program developed, the challenges of creating a sustainable financial model with the highest educational value required the inclusion of new clinical settings and the creation of a unique revenue-sharing model. Since the beginning of the community-based program at UMSOD in 2000, the number of community partners has increased to twenty-seven clinics, and students have treated thousands of patients in need. Fourth-year students now spend a minimum of ten weeks in community-based clinical education. The community-based program at UMSOD demonstrates the value of service-based education and offers a sustainable model for the development of future programs. PMID- 21828300 TI - Student self-assessment in dental hygiene education: a cornerstone of critical thinking and problem-solving. AB - Self-assessment is an integral component of learning and developing decision making and critical thinking skills in the practice of dental hygiene. Dental hygienists must think critically and develop problem-solving strategies during their formal education to ensure lifelong quality and ongoing development of their personal knowledge and skill as related to providing comprehensive, evidence-based patient care. The primary focus of this qualitative investigation was to obtain undergraduate dental hygiene students' perceptions of and experiences with self-assessment. The sample consisted of an intact undergraduate dental hygiene class of seventeen students in their final semester of a two-year, entry-level dental hygiene program at a community college in the southeast United States. Data for this research were obtained from three sources: 1) a program designed self-assessment survey assignment, 2) in-depth interviews with four second-year dental hygiene students, and 3) program-designed clinical competence evaluation forms. Inductive data analysis revealed that the majority of students perceived that they had no prior experience with self-assessment in any prerequisite coursework and thus felt unprepared for its use in the dental hygiene program. As they matriculated in the program, students began to see the advantages of self-assessment in clinical practice. Programmatic orientation to self-assessment may therefore be beneficial due to the varying backgrounds of students entering dental hygiene programs. PMID- 21828299 TI - Advantages of the dental practice-based research network initiative and its role in dental education. AB - Practice-based research networks (PBRNs) provide a novel venue in which providers can increase their knowledge base and improve delivery of care through participation in clinical studies. This article describes some aspects of our experience with a National Institute of Dental and Craniofacial Research supported PBRN and discusses the role it can play in dental education. PBRNs create a structured pathway for providers to advance their professional development by participating in the process of collecting data through clinical research. This process allows practitioners to contribute to the goals of evidence-based dentistry by helping to provide a foundation of evidence on which to base clinical decisions as opposed to relying on anecdotal evidence. PBRNs strengthen the professional knowledge base by applying the principles of good clinical practice, creating a resource for future dental faculty, training practitioners on best practices, and increasing the responsibility, accountability, and scope of care. PBRNs can be the future pivotal instruments of change in dental education, the use of electronic health record systems, diagnostic codes, and the role of comparative effectiveness research, which can create an unprecedented opportunity for the dental profession to advance and be integrated into the health care system. PMID- 21828301 TI - Use of questioning during lectures in a dental hygiene didactic course. AB - The purposes of this quasi-experimental, one-group crossover study were to determine the effect of questioning during dental hygiene lectures on low-level and high-level learning and to evaluate student perceptions of questioning. Twenty-three dental hygiene students participated in two control lectures using traditional lecturing methods. The students served as their own controls by next participating in two experimental lectures with questions asked throughout the lecture at both low and high cognitive levels. Student performance was measured with an examination containing low- and high-level questions. The interaction between the group and the level of questions was analyzed using ANOVA, and no statistically significant difference was found. Based on a Likert scale (1 to 6), average ratings for student perceptions were as follows: enjoyment of use, 4.5; understanding the lecture material, 4.74; and questioning effectiveness, 4.35. Student perceptions of questioning were positive; however, this strategy was found to be no more effective than the traditional lecture in promoting retention of information. PMID- 21828302 TI - Does teaching method affect students' perceptions regarding communication patterns in pediatric dentistry? A comparison of lecture and video methods. AB - The purpose of this study was to determine whether dental students' perceptions regarding six communication patterns for use in pediatric dentistry differed depending on whether they were taught by lecturing or by video-based teaching. Prior to the introduction of interpersonal skills in a clinical course in pediatric dentistry, four consecutive cohorts of students (n=107) in a German dental school were divided equally into two groups. Group one (n=57) was taught by video sequences and group two (n=50) by conventional lecture. Six communication patterns were presented: involvement of the child's toy(s), speaking in positive phrases, mentioning a personal aspect, recalling positive behavior of the patient, addressing fear verbally, and complimenting the patient. Immediately after the presentation, students were asked by means of a questionnaire about their assessment of and intentions regarding the clinical application of the communication patterns presented. After completion of the course, they were asked about the communication patterns that had been used. There were significant differences for three communication patterns in favor of video-based teaching (p<0.05); there were no significant differences regarding the intention for clinical application and the actual clinical application. In this study, students perceived differences between video-based teaching and lecturing regarding ease of use, but they did not seem to benefit from one method over the other regarding clinical application. PMID- 21828303 TI - Comparing student-generated learning needs with faculty objectives in PBL cases in dental education. AB - The purpose of this study was to compare learning need reports generated by students during their investigation of a problem-based learning (PBL) case with the faculty-identified learning objectives established for it. Four PBL cases facilitated by four group tutors were selected for comparison. The student generated learning needs were collected for each and were compared to the faculty specified learning outcomes. The results were analyzed by individual case and compared among the four student groups. Over 96 percent of the faculty-specified objectives across all four cases and across all four groups of students were covered by the student-generated learning need reports. Only one of the four cases demonstrated a statistically significant difference between small groups with regard to percent coverage of the stated case objectives. Our data agree with previous research findings. Although there was some variability in the learning objectives investigated by student small groups studying the same case, the faculty-specified case objectives were included in the student-generated learning needs. First-trimester dental students were capable of generating learning needs that produced an excellent match with the faculty objectives for the cases studied. PMID- 21828304 TI - Foreign-trained dentists' perceived knowledge and skills after graduation from a structured two-year program. AB - In this survey study, graduates of the University of Western Ontario program for foreign-trained dentists from 1999 to 2009 were asked for their perceptions of their knowledge and skill in fourteen clinical topic areas before they were admitted to the program and after graduation. Their ratings were made on a ten point visual analog scale divided into three aptitude domains: competent, proficient, and master/expert. Definitions of each domain were provided. The majority of the respondents felt that their knowledge level improved at least one aptitude level in only four of the fourteen (29 percent) topic areas but that their skill level had increased at least one aptitude level in nine (64 percent) topic areas. Of note, clinical topics with content reflective of North American dental practice such as oral medicine and treatment planning, ethics, regulated dentistry, record keeping, and informed consent were the topic areas in which most respondents reported an improvement in both their knowledge and skill. It is suggested that programs evaluating or providing gap training for internationally trained dentists consider mandatory inclusion of these topics. PMID- 21828305 TI - Psychological stress among dental students at the University of Jordan. AB - The purpose of this study was to investigate the level of psychological stress as well as the perceived sources of stress among undergraduate dental students at the University of Jordan. The top perceived stressors were compared with those of a previous study that examined the perceived sources of stress among undergraduate dental students at the University of Jordan in the year 2000. Psychological stress was assessed using the General Health Questionnaire (GHQ 12). Perceived sources of stress were evaluated using the Dental Environment Stress questionnaire. In the study, 520 students completed the questionnaires, for a response rate of 74 percent. These students showed a high level of psychological stress, with 70 percent at the cutoff point of a score of more than 3 for the GHQ-12. Women had a higher level of stress than men: 73 percent scored more than 3 on the GHQ-12 vs. 63 percent for men, which was statistically significant at p=0.05. The top perceived sources of stress from the year 2000 were mostly unaltered in our study, despite a substantial increase in the number of students as well as changes in the curriculum. Further research is needed into methods to minimize stress on dental students. PMID- 21828306 TI - Treating patients with HIV and Hepatitis B and C infections: Croatian dental students' knowledge, attitudes, and risk perceptions. AB - Dentists and dental students can be exposed to the human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) during routine work. The aims of this study were to assess a group of dental students' knowledge about HIV, HBV, and HCV infections; assess their attitudes and risk perceptions about the treatment of patients with HIV, HBV, and HCV; and identify factors associated with their knowledge and willingness to treat these patients. An anonymous survey was administered to 534 predoctoral students at the School of Dental Medicine, University of Zagreb, Croatia. The response rate was 71.9 percent. Students' knowledge increased with each year of study. Senior students (in their third, fourth, and fifth years) had more professional attitudes and were significantly more positive about dentists' professional obligation to treat patients who are HIV-positive than were junior students (in their first and second years; p=0.0002). Senior students also expressed significantly more willingness to treat intravenous drug users and patients with hepatitis (p=0.016 and p=0.033, respectively). Female students were significantly more convinced than male students that routine dental treatment carried a significant risk of HIV and hepatitis infection (p=0.025). These students' knowledge negatively correlated with the lack of willingness to treat intravenous drug users and patients with hepatitis, and they expressed their willingness to receive further theoretical and practical education on this topic. PMID- 21828307 TI - Turkish dental students' and dentists' ability to assess gingival health status with DAAGS software. AB - The aim of this study was to compare the ability of final-year Turkish dental students and dentists to assess the level of gingival health status by using the Development of Ability to Assess Gingival Status (DAAGS) computer program. Forty eight students in their final year of dental education and 240 dentists participated in DAAGS tests in which they judged twenty-four photos. The participants were organized into one group of students and five groups of dentists: those who graduated in the last five years, in the last six to ten years, in the last eleven to fifteen years, in the last sixteen to twenty years, and twenty and/or more years ago. A gold standard of each photo was shown to participants after they completed test 1; then, test 2 was conducted immediately. Participants were asked to evaluate the DAAGS by written survey. There were significant differences between the parameters of two tests for all groups. Significance levels differed for each group and both tests considering correct answers, reproducibility, irrelevant answers, and overall ability. The findings from this study indicated that the DAAGS software is easier for more recently graduated dentists to use. PMID- 21828308 TI - Implementing accountable care organizations: ten potential mistakes and how to learn from them. PMID- 21828309 TI - Caring for patients with limited health literacy: a 76-year-old man with multiple medical problems. AB - Health literacy is the degree to which individuals have the capacity to obtain, process, and understand health information, skills, and services needed to make informed health decisions and take informed actions. Narratives from Mr J, a 76 year-old man with multiple medical problems and limited health literacy, and his physician exhibit some of the difficulties experienced by patients with limited health literacy. Clinicians can help patients with limited health literacy by removing unneeded complexity in their treatment regimens and in the health care system and by using teach-back methods to assess and improve understanding. Rather than a selective screening approach for limited health literacy, a patient based universal precaution approach for confirming patient comprehension of critical self-care activities helps ensure that all patients have their health literacy needs identified. PMID- 21828310 TI - Equality-in-quality in the era of the affordable care act. PMID- 21828311 TI - Insurance expansion and health literacy. PMID- 21828313 TI - The cover. Young woman with ibis. PMID- 21828314 TI - A piece of my mind. A great case. PMID- 21828315 TI - European drug agency under fire: critics charge that trial data are too inaccessible. PMID- 21828312 TI - Stimulating cardiac muscle by light: cardiac optogenetics by cell delivery. AB - BACKGROUND: After the recent cloning of light-sensitive ion channels and their expression in mammalian cells, a new field, optogenetics, emerged in neuroscience, allowing for precise perturbations of neural circuits by light. However, functionality of optogenetic tools has not been fully explored outside neuroscience, and a nonviral, nonembryogenesis-based strategy for optogenetics has not been shown before. METHODS AND RESULTS: We demonstrate the utility of optogenetics to cardiac muscle by a tandem cell unit (TCU) strategy, in which nonexcitable cells carry exogenous light-sensitive ion channels, and, when electrically coupled to cardiomyocytes, produce optically excitable heart tissue. A stable channelrhodopsin2 (ChR2)-expressing cell line was developed, characterized, and used as a cell delivery system. The TCU strategy was validated in vitro in cell pairs with adult canine myocytes (for a wide range of coupling strengths) and in cardiac syncytium with neonatal rat cardiomyocytes. For the first time, we combined optical excitation and optical imaging to capture light triggered muscle contractions and high-resolution propagation maps of light triggered electric waves, found to be quantitatively indistinguishable from electrically triggered waves. CONCLUSIONS: Our results demonstrate feasibility to control excitation and contraction in cardiac muscle by light, using the TCU approach. Optical pacing in this case uses less energy, offers superior spatiotemporal control and remote access and can serve not only as an elegant tool in arrhythmia research but may form the basis for a new generation of light driven cardiac pacemakers and muscle actuators. The TCU strategy is extendable to (nonviral) stem cell therapy and is directly relevant to in vivo applications. PMID- 21828316 TI - Performance measures for cardiology focus on improving patient outcomes. PMID- 21828317 TI - Effort launched to adapt HIV/AIDS drugs for children. PMID- 21828318 TI - Exercise interventions and glycemic control in patients with diabetes. PMID- 21828319 TI - Exercise interventions and glycemic control in patients with diabetes. PMID- 21828320 TI - Exercise interventions and glycemic control in patients with diabetes. PMID- 21828321 TI - Whole-genome sequencing and acute promyelocytic leukemia. PMID- 21828322 TI - Biomarkers for detecting and risk-stratifying chronic kidney disease. PMID- 21828323 TI - Biomarkers for detecting and risk-stratifying chronic kidney disease. PMID- 21828324 TI - Sleep-disordered breathing, hypoxia, and risk of mild cognitive impairment and dementia in older women. AB - CONTEXT: Sleep-disordered breathing (characterized by recurrent arousals from sleep and intermittent hypoxemia) is common among older adults. Cross-sectional studies have linked sleep-disordered breathing to poor cognition; however, it remains unclear whether sleep-disordered breathing precedes cognitive impairment in older adults. OBJECTIVES: To determine the prospective relationship between sleep-disordered breathing and cognitive impairment and to investigate potential mechanisms of this association. DESIGN, SETTING, AND PARTICIPANTS: Prospective sleep and cognition study of 298 women without dementia (mean [SD] age: 82.3 [3.2] years) who had overnight polysomnography measured between January 2002 and April 2004 in a substudy of the Study of Osteoporotic Fractures. Sleep-disordered breathing was defined as an apnea-hypopnea index of 15 or more events per hour of sleep. Multivariate logistic regression was used to determine the independent association of sleep-disordered breathing with risk of mild cognitive impairment or dementia, adjusting for age, race, body mass index, education level, smoking status, presence of diabetes, presence of hypertension, medication use (antidepressants, benzodiazepines, or nonbenzodiazepine anxiolytics), and baseline cognitive scores. Measures of hypoxia, sleep fragmentation, and sleep duration were investigated as underlying mechanisms for this relationship. MAIN OUTCOME MEASURES: Adjudicated cognitive status (normal, dementia, or mild cognitive impairment) based on data collected between November 2006 and September 2008. RESULTS: Compared with the 193 women without sleep-disordered breathing, the 105 women (35.2%) with sleep-disordered breathing were more likely to develop mild cognitive impairment or dementia (31.1% [n = 60] vs 44.8% [n = 47]; adjusted odds ratio [AOR], 1.85; 95% confidence interval [CI], 1.11-3.08). Elevated oxygen desaturation index (>=15 events/hour) and high percentage of sleep time (>7%) in apnea or hypopnea (both measures of disordered breathing) were associated with risk of developing mild cognitive impairment or dementia (AOR, 1.71 [95% CI, 1.04 2.83] and AOR, 2.04 [95% CI, 1.10-3.78], respectively). Measures of sleep fragmentation (arousal index and wake after sleep onset) or sleep duration (total sleep time) were not associated with risk of cognitive impairment. CONCLUSION: Among older women, those with sleep-disordered breathing compared with those without sleep-disordered breathing had an increased risk of developing cognitive impairment. PMID- 21828325 TI - Association of race and age with survival among patients undergoing dialysis. AB - CONTEXT: Many studies have reported that black individuals undergoing dialysis survive longer than those who are white. This observation is paradoxical given racial disparities in access to and quality of care, and is inconsistent with observed lower survival among black patients with chronic kidney disease. We hypothesized that age and the competing risk of transplantation modify survival differences by race. OBJECTIVE: To estimate death among dialysis patients by race, accounting for age as an effect modifier and kidney transplantation as a competing risk. DESIGN, SETTING, AND PARTICIPANTS: An observational cohort study of 1,330,007 incident end-stage renal disease patients as captured in the United States Renal Data System between January 1, 1995, and September 28, 2009 (median potential follow-up time, 6.7 years; range, 1 day-14.8 years). Multivariate age stratified Cox proportional hazards and competing risk models were constructed to examine death in patients who receive dialysis. MAIN OUTCOME MEASURES: Death in black vs white patients who receive dialysis. RESULTS: Similar to previous studies, black patients undergoing dialysis had a lower death rate compared with white patients (232,361 deaths [57.1% mortality] vs 585,792 deaths [63.5% mortality], respectively; adjusted hazard ratio [aHR], 0.84; 95% confidence interval [CI], 0.83-0.84; P <.001). However, when stratifying by age and treating kidney transplantation as a competing risk, black patients had significantly higher mortality than their white counterparts at ages 18 to 30 years (27.6% mortality vs 14.2%; aHR, 1.93; 95% CI, 1.84-2.03), 31 to 40 years (37.4% mortality vs 26.8%; aHR, 1.46; 95% CI, 1.41-1.50), and 41 to 50 years (44.8% mortality vs 38.0%; aHR, 1.12; 95% CI, 1.10-1.14; P <.001 for interaction terms between race and each aforementioned age category), as opposed to patients aged 51 to 60 years (51.5% vs 50.9%; aHR, 0.93; 95% CI, 0.92-0.94), 61 to 70 years (64.9% vs 67.2%; aHR, 0.87; 95% CI, 0.86-0.88), 71 to 80 years (76.1% vs 79.7%; aHR, 0.85; 95% CI, 0.84-0.86), and older than 80 years (82.4% vs 83.6%; aHR, 0.87; 95% CI, 0.85-0.88). CONCLUSIONS: Overall, among dialysis patients in the United States, there was a lower risk of death for black patients compared with their white counterparts. However, the commonly cited survival advantage for black dialysis patients applies only to older adults, and those younger than 50 years have a higher risk of death. PMID- 21828327 TI - Update: An 86-year-old woman with cardiac cachexia contemplating the end of her life: review of hospice care. PMID- 21828328 TI - The individual mandate and patient-centered care. PMID- 21828326 TI - Noninvasive fetal sex determination using cell-free fetal DNA: a systematic review and meta-analysis. AB - CONTEXT: Noninvasive prenatal determination of fetal sex using cell-free fetal DNA provides an alternative to invasive techniques for some heritable disorders. In some countries this testing has transitioned to clinical care, despite the absence of a formal assessment of performance. OBJECTIVE: To document overall test performance of noninvasive fetal sex determination using cell-free fetal DNA and to identify variables that affect performance. DATA SOURCES: Systematic review and meta-analysis with search of PubMed (January 1, 1997-April 17, 2011) to identify English-language human studies reporting primary data. References from review articles were also searched. STUDY SELECTION AND DATA EXTRACTION: Abstracts were read independently to identify studies reporting primary data suitable for analysis. Covariates included publication year, sample type, DNA amplification methodology, Y chromosome sequence, and gestational age. Data were independently extracted by 2 reviewers. RESULTS: From 57 selected studies, 80 data sets (representing 3524 male-bearing pregnancies and 3017 female-bearing pregnancies) were analyzed. Overall performance of the test to detect Y chromosome sequences had the following characteristics: sensitivity, 95.4% (95% confidence interval [CI], 94.7%-96.1%) and specificity, 98.6% (95% CI, 98.1% 99.0%); diagnostic odds ratio (OR), 885; positive predictive value, 98.8%; negative predictive value, 94.8%; area under curve (AUC), 0.993 (95% CI, 0.989 0.995), with significant interstudy heterogeneity. DNA methodology and gestational age had the largest effects on test performance. Methodology test characteristics were AUC, 0.988 (95% CI, 0.979-0.993) for polymerase chain reaction (PCR) and AUC, 0.996 (95% CI, 0.993-0.998) for real-time quantitative PCR (RTQ-PCR) (P = .02). Gestational age test characteristics were AUC, 0.989 (95% CI, 0.965-0.998) (<7 weeks); AUC, 0.994 (95% CI, 0.987-0.997) (7-12 weeks); AUC, 0.992 (95% CI, 0.983-0.996) (13-20 weeks); and AUC, 0.998 (95% CI, 0.990 0.999) (>20 weeks) (P = .02 for comparison of diagnostic ORs across age ranges). RTQ-PCR (sensitivity, 96.0%; specificity, 99.0%) outperformed conventional PCR (sensitivity, 94.0%; specificity, 97.3%). Testing after 20 weeks (sensitivity, 99.0%; specificity, 99.6%) outperformed testing prior to 7 weeks (sensitivity, 74.5%; specificity, 99.1%), testing at 7 through 12 weeks (sensitivity, 94.8%; specificity, 98.9%), and 13 through 20 weeks (sensitivity, 95.5%; specificity, 99.1%). CONCLUSIONS: Despite interstudy variability, performance was high using maternal blood. Sensitivity and specificity for detection of Y chromosome sequences was greatest using RTQ-PCR after 20 weeks' gestation. Tests using urine and tests performed before 7 weeks' gestation were unreliable. PMID- 21828329 TI - The role of physicians in controlling medical care costs and reducing waste. PMID- 21828330 TI - Genomic technology applied to pharmacological traits. PMID- 21828331 TI - Sleep-disordered breathing and cognitive decline in older adults. PMID- 21828332 TI - JAMA patient page. Systemic lupus erythematosus. PMID- 21828333 TI - Reciprocal transcriptional regulation of metabolic and signaling pathways correlates with disease severity in heart failure. AB - BACKGROUND: Systolic heart failure (HF) is a complex systemic syndrome that can result from a wide variety of clinical conditions and gene mutations. Despite phenotypic similarities, characterized by ventricular dilatation and reduced contractility, the extent of common and divergent gene expression between different forms of HF remains a matter of intense debate. METHODS AND RESULTS: Using a meta-analysis of 28 experimental (mouse, rat, dog) and human HF microarray studies, we demonstrate that gene expression changes are characterized by a coordinated and reciprocal regulation of major metabolic and signaling pathways. In response to a wide variety of stressors in animal models of HF, including ischemia, pressure overload, tachypacing, chronic isoproterenol infusion, Chagas disease, and transgenic mouse models, major metabolic pathways are invariably downregulated, whereas cell signaling pathways are upregulated. In contrast to this uniform transcriptional pattern that recapitulates a fetal gene expression program in experimental animal models of HF, human HF microarray studies displayed a greater heterogeneity, with some studies even showing upregulation of metabolic and downregulation of signaling pathways in end-stage human hearts. These discrepant results between animal and human studies are due to a number of factors, prominently cardiac disease and variable exposure to cold cardioplegic solution in nonfailing human samples, which can downregulate transcripts involved in oxidative phosphorylation (OXPHOS), thus mimicking gene expression patterns observed in failing samples. Additionally, beta-blockers and ACE inhibitor use in end-stage human HF was associated with higher levels of myocardial OXPHOS transcripts, thus partially reversing the fetal gene expression pattern. In human failing samples, downregulation of metabolism was associated with hemodynamic markers of disease severity. CONCLUSIONS: Irrespective of the etiology, gene expression in failing myocardium is characterized by downregulation of metabolic transcripts and concomitant upregulation of cell signaling pathways. Gene expression changes along this metabolic-signaling axis in mammalian myocardium are a consistent feature in the heterogeneous transcriptional response observed in phenotypically similar models of HF. PMID- 21828334 TI - Chronic reduction of insulin receptors in the ventromedial hypothalamus produces glucose intolerance and islet dysfunction in the absence of weight gain. AB - Insulin is believed to regulate glucose homeostasis mainly via direct effects on the liver, muscle, and adipose tissues. The contribution of insulin's central nervous system effects to disorders of glucose metabolism has received less attention. To evaluate whether postnatal reduction of insulin receptors (IRs) within the ventromedial hypothalamus (VMH), a brain region critical for glucose sensing, contributes to disorders of peripheral glucose metabolism, we microinjected a lentiviral vector expressing an antisense sequence to knockdown IRs or a control lentiviral vector into the VMH of nonobese nondiabetic rats. After 3-4 mo, we assessed 1) glucose tolerance, 2) hepatic insulin sensitivity, and 3) insulin and glucagon secretion, using the glucose clamp technique. Knockdown of IRs locally in the VMH caused glucose intolerance without altering body weight. Increments of plasma insulin during a euglycemic clamp study failed to suppress endogenous glucose production and produced a paradoxical rise in plasma glucagon in the VMH-IR knockdown rats. Unexpectedly, these animals also displayed a 40% reduction (P < 0.05) in insulin secretion in response to an identical hyperglycemic stimulus (~220 mg/dl). Our data demonstrate that chronic suppression of VMH-IR gene expression is sufficient to impair glucose metabolism as well as alpha-cell and beta-cell function in nondiabetic, nonobese rats. These data suggest that insulin resistance within the VMH may be a significant contributor to the development of type 2 diabetes. PMID- 21828335 TI - Circadian intervention of obesity development via resting-stage feeding manipulation or oxytocin treatment. AB - The obesity pandemic can be viewed as a result of an imbalanced reaction to changing environmental factors. Recent research has linked circadian arrhythmicity to obesity and related diseases; however, the underlying mechanisms are still unclear. In this study, we found that high-fat diet (HFD) feeding strikingly promoted daytime rather than nighttime caloric intake in mice, leading to feeding circadian arrhythmicity. Using scheduled feeding with a defined amount of daily HFD intake, we found that an increase in the ratio of daytime to nighttime feeding promoted weight gain, whereas a decrease of this ratio rebalanced energy expenditure to counteract obesity. In identifying the underlying mechanism, we found that hypothalamic release of anorexigenic neuropeptide oxytocin displayed a diurnal rhythm of daytime rise and nighttime decline, which negatively correlated with the diurnal feeding activities of normal chow-fed mice. In contrast, chronic HFD feeding abrogated oxytocin diurnal rhythmicity, primarily by suppressing daytime oxytocin rise. Using pharmacological experiments with hypothalamic injection of oxytocin or oxytocin antagonist, we showed that daytime manipulation of oxytocin can change feeding circadian patterns to reprogram energy expenditure, leading to attenuation or induction of obesity independently of 24-h caloric intake. Also importantly, we found that peripheral injection of oxytocin activated hypothalamic oxytocin neurons to release oxytocin, and exerted metabolic effects similar to central oxytocin injection, thus offering a practical clinical avenue to use oxytocin in obesity control. In conclusion, resting-stage oxytocin release and feeding activity represent a critical circadian mechanism and therapeutic target for obesity. PMID- 21828337 TI - Motilin beyond gut motility: a novel role in the regulation of adipose tissue metabolism. PMID- 21828336 TI - Proteomic identification of secreted proteins from human skeletal muscle cells and expression in response to strength training. AB - Regular physical activity protects against several types of diseases. This may involve altered secretion of signaling proteins from skeletal muscle. Our aim was to identify the most abundantly secreted proteins in cultures of human skeletal muscle cells and to monitor their expression in muscles of strength-training individuals. A total of 236 proteins were detected by proteome analysis in medium conditioned by cultured human myotubes, which was narrowed down to identification of 18 classically secreted proteins expressed in skeletal muscle, using the SignalP 3.0 and Human Genome Expression Profile databases together with a published mRNA-based reconstruction of the human skeletal muscle secretome. For 17 of the secreted proteins, expression was confirmed at the mRNA level in cultured human myotubes as well as in biopsies of human skeletal muscles. RT-PCR analyses showed that 15 of the secreted muscle proteins had significantly enhanced mRNA expression in m. vastus lateralis and/or m. trapezius after 11 wk of strength training among healthy volunteers. For example, secreted protein acidic and rich in cysteine, a secretory protein in the membrane fraction of skeletal muscle fibers, was increased 3- and 10-fold in m. vastus lateralis and m. trapezius, respectively. Identification of proteins secreted by skeletal muscle cells in vitro facilitated the discovery of novel responses in skeletal muscles of strength-training individuals. PMID- 21828338 TI - Cool-1/betaPIX functions as a guanine nucleotide exchange factor in the cycling of Cdc42 to regulate insulin secretion. AB - Second-phase insulin release requires the sustained mobilization of insulin granules from internal storage pools to the cell surface for fusion with the plasma membrane. However, the detailed mechanisms underlying this process remain largely unknown. GTP-loading of the small GTPase Cdc42 is the first glucose specific activation step in the process, although how glucose triggers Cdc42 activation is entirely unknown. In a directed candidate screen for guanine nucleotide exchange factors (GEFs), which directly activate small GTPases, Cool 1/betaPix was identified in pancreatic islet beta cells. In support of its role as the beta cell Cdc42 GEF, betaPix coimmunoprecipitated with Cdc42 in human islets and MIN6 beta cells in a glucose-dependent manner, peaking just prior to Cdc42 activation. Furthermore, RNAi-mediated betaPix reduction by 50% corresponded to full ablation of glucose-induced Cdc42 activation and significant attenuation of basal and glucose-stimulated insulin secretion. Of the two Cdc42 guanine nucleotide dissociation inhibitor (GDI) proteins identified in beta cells, betaPix competed selectively with caveolin-1 (Cav-1) but not RhoGDI in coimmunoprecipitation and GST-Cdc42-GDP interaction assays. However, a phospho deficient Cav-1-Y14F mutant failed to compete with betaPix; Cav-1(Tyr14) is an established phosphorylation site for Src kinase. Taken together, these data support a new model, wherein glucose stimulates Cav-1 and induces its dissociation from Cdc42, possibly via Src kinase activation to phosphorylate Cav 1(Tyr14), to promote Cdc42-betaPix binding and Cdc42 activation, and to trigger downstream signaling and ultimately sustain insulin release. PMID- 21828339 TI - Potentiation of the early-phase insulin response by a prior meal contributes to the second-meal phenomenon in type 2 diabetes. AB - Improved glucose tolerance following a sequential meal is known as the second meal phenomenon. We aimed to investigate its extent and underlying mechanisms in patients with type 2 diabetes. Metabolic responses after lunch in 12 diabetic patients were compared on two separate days: one with (Day BL) and another without (Day FL) breakfast. The responses of hormones were calculated by the incremental area under the curve (iAUC) values for 180 min after each meal. Indexes of early-phase insulin secretion were assessed, and beta-cell function was estimated by mathematical modeling. [iAUC(glucose(180-360 min))] was significantly lower on Day BL than on Day FL (181 +/- 43 vs. 472 +/- 29 mmol.liter(-1).min, P = 0.0005). The magnitude of the The second-meal phenomenon [iAUC(glucose(180-360 min)) on Day BL/Day FL] was 35 +/- 9%. The peak levels of insulin and C-peptide were attained 45 min earlier after the second meal than after the first meal. iAUC(glucose(180-360 min)) correlated negatively with iAUC(insulin(180-210 min)) (r = -0.443, P = 0.0300), insulinogenic index (r = 0.769, P < 0.0001), acute C-peptide response (r = -0.596, P = 0.0021), and potentiation factor [i.e., potentiation effect on insulin secretion] ratio (180 360)/(0-20) (r = -0.559, P = 0.0045), while correlated positively with free fatty acid level before lunch (r = 0.679, P = 0.0003). The second-meal phenomenon was evident in patients with type 2 diabetes. Potentiation of the early-phase insulin response by a prior meal contributes to this phenomenon in type 2 diabetes. PMID- 21828340 TI - Cardiac proteasome activity in muscle ring finger-1 null mice at rest and following synthetic glucocorticoid treatment. AB - Muscle ring finger-1 (MuRF1) is a muscle-specific E3 ubiquitin ligase that has been implicated in the regulation of cardiac mass through its control of the ubiquitin proteasome system. While it has been suggested that MuRF1 is required for cardiac atrophy, a resting cardiac phenotype has not been reported in mice with a null deletion [knockout (KO)] of MuRF1. Here, we report that MuRF1 KO mice have significantly larger hearts than age-matched wild-type (WT) littermates at >= 6 mo of age and that loss of cardiac mass can occur in the absence of MuRF1. The objective of this study was to determine whether changes in proteasome activity were responsible for the cardiac phenotypes observed in MuRF1 KO mice. Cardiac function, architecture, and proteasome activity were analyzed at rest and following 28 days of dexamethasone (Dex) treatment in 6-mo-old WT and MuRF1 KO mice. Echocardiography demonstrated normal cardiac function in the enlarged hearts in MURF1 KO mice. At rest, heart mass and cardiomyocyte diameter were significantly greater in MuRF1 KO than in WT mice. The increase in cardiac size in MuRF1 KO mice was related to a decrease in proteasome activity and an increase in Akt signaling relative to WT mice. Dex treatment induced a significant loss of cardiac mass in MuRF1 KO, but not WT, mice. Furthermore, Dex treatment resulted in an increase in proteasome activity in KO, but a decrease in WT, mice. In contrast, Akt/mammalian target of rapamycin signaling decreased in MuRF1 KO mice and increased in WT mice in response to Dex treatment. These findings demonstrate that MuRF1 plays an important role in regulating cardiac size through alterations in protein turnover and that MuRF1 is not required to induce cardiac atrophy. PMID- 21828341 TI - Recruited vs. nonrecruited molecular signatures of brown, "brite," and white adipose tissues. AB - Mainly from cell culture studies, a series of genes that have been suggested to be characteristic of different types of adipocytes have been identified. Here we have examined gene expression patterns in nine defined adipose depots: interscapular BAT, cervical BAT, axillary BAT, mediastinic BAT, cardiac WAT, inguinal WAT, retroperitoneal WAT, mesenteric WAT, and epididymal WAT. We found that each depot displayed a distinct gene expression fingerprint but that three major types of depots were identifiable: the brown, the brite, and the white. Although differences in gene expression pattern were generally quantitative, some gene markers showed, even in vivo, remarkable depot specificities: Zic1 for the classical BAT depots, Hoxc9 for the brite depots, Hoxc8 for the brite and white in contrast to the brown, and Tcf21 for the white depots. The effect of physiologically induced recruitment of thermogenic function (cold acclimation) on the expression pattern of the genes was quantified; in general, the depot pattern dominated over the recruitment effects. The significance of the gene expression patterns for classifying the depots and for understanding the developmental background of the depots is discussed, as are the possible regulatory functions of the genes. PMID- 21828342 TI - Out-of-theatre tracheal intubation: prospective multicentre study of clinical practice and adverse events. AB - BACKGROUND: Tracheal intubation is commonly performed outside the operating theatre and is associated with higher risk than intubation in theatre. Recent guidelines and publications including the 4th National Audit Project of the Royal College of Anaesthetists have sought to improve the safety of out-of-theatre intubations. METHODS: We performed a prospective observational study examining all tracheal intubations occurring outside the operating theatre in nine hospitals over a 1 month period. Data were collected on speciality and grade of intubator, presence of essential safety equipment and monitoring, and adverse events. RESULTS: One hundred and sixty-four out-of-theatre intubations were identified (excluding those where intubation occurred as part of the management of cardiac arrest). The most common indication for intubation was respiratory failure [74 cases (45%)]. Doctors with at least 6 month's experience in anaesthesia performed 136 intubations (83%); consultants were present for 68 cases (41%), and overall a second intubator was present for 94 procedures (57%). Propofol was the most common induction agent [124 cases (76%)] and 157 patients (96%) received neuromuscular blocking agents. An airway rescue device was available in 139 cases (87%). Capnography was not used in 52 cases (32%). Sixty four patients suffered at least one adverse event (39%) around the time of tracheal intubation. CONCLUSIONS: Out-of-theatre intubation frequently occurs in the absence of essential safety equipment, despite the existing guidelines. The associated adverse event rate is high. PMID- 21828343 TI - Occurrence of and risk factors for electroencephalogram burst suppression during propofol-remifentanil anaesthesia. AB - BACKGROUND: Suppression ratio (SR) derived from bispectral index (BIS) monitoring is correlated to EEG burst suppression. It may occur during deep anaesthesia, but also in the case of metabolic or haemodynamic brain injury. The goal of the study was to describe the occurrence of SR and to determine factors associated with SR during propofol-remifentanil general anaesthesia maintenance. METHODS: We conducted a post hoc analysis of BIS recordings in consecutive patients included in two multi-centre trials, undergoing non-cardiac surgery using a dual closed loop BIS controller allowing automated propofol-remifentanil administration. The percentage of time spent with a BIS value between 40 and 60 (T(BIS 40-60)) was measured. Two groups of patients were defined: the SR group, including patients with at least one episode of SR value >10% lasting more than 1 min, and the control group. Factors associated with SR were analysed using a stepwise multivariate analysis. RESULTS: A total of 1494 patients [age=57 (17) yr; T(BIS 40-60)=76 (17%)] were analysed and 131 (8.7%) patients constituted the SR group. The main independent factors associated with SR were advanced age [odds ratio (95% confidence interval)=4.80 (1.85-12.43) (P=0.027), 10.59 (3.76-29.81) (P<0.0001), for categories of age 60-80 and >80 yr, respectively], history of coronary artery disease (CAD) [2.53 (1.47-4.37) (P=0.001)] and male gender [1.57 (1.03-2.40) (P=0.03)]. CONCLUSIONS: The occurrence of SR during BIS-controlled propofol and remifentanil anaesthesia is mainly observed in elderly male patients or in patients with a history of CAD. The mechanisms underlying SR and the potential consequences for the patient's postoperative outcome remain unsolved. PMID- 21828344 TI - Are quality improvements in the get with the guidelines: stroke program related to better care or better data documentation? AB - BACKGROUND- Increased compliance with performance measures could reflect better care or better data documentation. We examined trends in the documentation of eligibility criteria, treatment contraindications, and missing data in the Get With The Guidelines-Stroke program to quantify their contribution to increased performance measure compliance. METHODS AND RESULTS- Data on 569 883 ischemic stroke admissions to 1028 GWTG-Stroke hospitals between April 2003 and September 2009 were obtained. Seven measures were examined: intravenous recombinant tissue plasminogen activator therapy, early antithrombotics, deep vein thrombosis prophylaxis, anticoagulants for atrial fibrillation/flutter, discharge antithrombotics, lipid therapy, and smoking cessation. Within each target population, the proportion of subjects treated, not treated, not treated because of contraindications, or with missing data were generated by calendar year. There were minimal changes in the size of the target populations for 6 of the measures; however, the size of the deep vein thrombosis prophylaxis population was reduced ~5% in 2008 because of a format change to the data collection form. All measures showed significant increases in the proportion of eligible subjects treated across the study period. These increases occurred without major shifts in contraindications or missing data, with the exception of anticoagulation for atrial fibrillation/flutter where the increase occurred in conjunction with a decline in contraindications. Similar findings were seen when the data were examined by the duration of hospital participation in the program. CONCLUSIONS- These findings suggest that the majority of performance improvement in the Get With The Guidelines-Stroke program represent an increase in the number of patients with stroke treated and not changes to the underlying target populations or documentation of contraindications or missing data. PMID- 21828345 TI - IgA1 immune complexes from pediatric patients with IgA nephropathy activate cultured human mesangial cells. AB - BACKGROUND: Circulating immune complexes (CIC) containing galactose (Gal) deficient IgA1 from adults with IgA nephropathy (IgAN) induce proliferation of cultured mesangial cells, but activities of CIC from pediatric patients with the disease have not been studied. METHODS: CIC of different sizes were isolated from sera of pediatric and adult IgAN patients and their effects on cultured human mesangial cells (MC) were assessed by measuring cellular proliferation, expression of IL-6 and IL-8 and laminin and phosphotyrosine signaling. RESULTS: Large CIC from pediatric IgAN patients (>800 kDa) containing Gal-deficient IgA1 stimulated cellular proliferation, whereas in some patients, smaller CIC were inhibitory. Addition of stimulatory and inhibitory CIC to MC differentially altered phosphorylation patterns of three major tyrosine-phosphorylated proteins of molecular mass 37, 60 and 115 kDa. The stimulatory CIC transiently increased tyrosine-phosphorylation of the 37-kDa protein and decreased phosphorylation of the other two proteins, whereas the inhibitory CIC increased phosphorylation of all three proteins. Furthermore, we investigated the influence of IgA1-containing CIC from sera of children with IgAN with clinically active disease (i.e., abnormal urinalysis and/or serum creatinine concentration) or inactive disease (i.e., normal urinalysis and serum creatinine concentration) on the expression of IL-6 and IL-8 genes by mesangial cells. Real-time reverse transcription polymerase chain reaction results showed that the CIC from a patient with active disease stimulated MC to express the two cytokine genes at higher levels than did the CIC from a patient with inactive disease. Moreover, stimulatory CIC increased production of the extracellular matrix protein laminin. CONCLUSION: These data indicate that sera of pediatric IgAN patients contain biologically active CIC with Gal-deficient IgA1. PMID- 21828346 TI - Boceprevir: a protease inhibitor for the treatment of chronic hepatitis C. AB - OBJECTIVE: To review the pharmacology, pharmacokinetics, safety, and efficacy of boceprevir, a novel oral hepatitis C virus (HCV) nonstructural 3 (NS3) protease inhibitor for the treatment of chronic HCV infection, specifically, genotype 1. DATA SOURCES: A literature search was conducted through MEDLINE and EMBASE (1966 May 2011) using the terms boceprevir and SCH 503034. Data from the package insert, abstracts obtained from conferences, and unpublished Phase 2-3 clinical trials, obtained through clinicaltrials.gov, were also reviewed. STUDY SELECTION AND DATA EXTRACTION: All English-language articles identified from the data sources were evaluated. References from selected articles were used to identify other pertinent citations. Article selection focused on pharmacology, clinical trials, safety analyses, and resistance. Preference was given to human data. DATA SYNTHESIS: Boceprevir is an oral protease inhibitor that binds to the NS3 protein of HCV, ultimately inhibiting viral intracellular replication. Boceprevir displays linear pharmacokinetics and is rapidly absorbed upon oral administration. In clinical studies of treatment-naive and treatment-experienced patients, boceprevir, in combination with standard of care (pegylated interferon [Peg-IFN]-alpha-2b with or without ribavirin) achieved greater sustained viral response (SVR) rates compared to standard of care. Safety analyses showed an increased incidence of adverse effects when boceprevir was used with Peg-IFN alpha-2b and ribavirin. The most common adverse events reported include fatigue, headache, nausea, dysguesia, and anemia; the incidence of the latter 2 adverse effects may be increased if boceprevir is added to standard therapy. Additional Phase 2 and 3 studies are currently enrolling participants. CONCLUSIONS: Boceprevir should be used in combination with Peg-IFN-alpha-2b and ribavirin in the treatment of chronic HCV genotype 1 infection. The improved response rates achieved with that combination will make boceprevir a viable option compared with other developing and approved NS3 protease inhibitors for treatment-naive and treatment-experienced nonresponders/relapsers. Additional data are needed to clarify the potential for resistance and drug interactions. PMID- 21828347 TI - Current therapeutic uses, pharmacology, and clinical considerations of neuromuscular blocking agents for critically ill adults. AB - OBJECTIVE: To summarize literature describing use of neuromuscular blocking agents (NMBAs) for common critical care indications and provide a review of NMBA pharmacology, pharmacokinetics, dosing, drug interactions, monitoring, complications, and reversal. DATA SOURCES: Searches of MEDLINE (1975-May 2011), EMBASE (1980-May 2011), and Cumulative Index to Nursing and Allied Health Literature (1981-May 2011) were conducted to identify observational and interventional studies evaluating the efficacy or safety of NMBAs for management of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), status asthmaticus, elevated intracranial pressure (ICP), and therapeutic hypothermia. STUDY SELECTION AND DATA EXTRACTION: We excluded case reports, animal- or laboratory-based studies, trials describing NMBA use during rapid sequence intubation or in the operating room, and studies published in languages other than English or French. DATA SYNTHESIS: Clinical applications of NMBAs in intensive care include, but are not limited to, immobilizing patients for procedural interventions, decreasing oxygen consumption, facilitating mechanical ventilation, reducing intracranial pressure, preventing shivering, and management of tetanus. Recent data on ARDS demonstrated that early application of NMBAs improved adjusted 90-day survival for patients with severe lung injury. These results may lead to increased use of these drugs. While emerging data support the use of cisatracurium in select patients with ALI/ARDS, current literature does not support the use of one NMBA over another for other critical care indications. Cisatracurium may be kinetically preferred for patients with organ dysfunction. Close monitoring with peripheral nerve stimulation is recommended with sustained use of NMBAs to avoid drug accumulation and minimize the risk for adverse drug events. Reversal of paralysis is achieved by discontinuing therapy or, rarely, the use of anticholinesterases. CONCLUSIONS: NMBAs are high-alert medications used to manage critically ill patients. New data are available regarding the use of these agents for treatment of ALI/ARDS and status asthmaticus, management of elevated ICP, and provision of therapeutic hypothermia after cardiac arrest. To improve outcomes and promote patient safety, intensive care unit team members should have a thorough knowledge of this class of medications. PMID- 21828348 TI - Implicitly perceived vocal attractiveness modulates prefrontal cortex activity. AB - Social interactions involve more than "just" language. As important is a more primitive nonlinguistic mode of communication acting in parallel with linguistic processes and driving our decisions to a much higher degree than is generally suspected. Amongst the "honest signals" that influence our behavior is perceived vocal attractiveness. Not only does vocal attractiveness reflect important biological characteristics of the speaker, it also influences our social perceptions according to the "what sounds beautiful is good" phenomenon. Despite the widespread influence of vocal attractiveness on social interactions revealed by behavioral studies, its neural underpinnings are yet unknown. We measured brain activity while participants listened to a series of vocal sounds ("ah") and performed an unrelated task. We found that voice-sensitive auditory and inferior frontal regions were strongly correlated with implicitly perceived vocal attractiveness. While the involvement of auditory areas reflected the processing of acoustic contributors to vocal attractiveness ("distance to mean" and spectrotemporal regularity), activity in inferior prefrontal regions (traditionally involved in speech processes) reflected the overall perceived attractiveness of the voices despite their lack of linguistic content. These results suggest the strong influence of hidden nonlinguistic aspects of communication signals on cerebral activity and provide an objective measure of this influence. PMID- 21828349 TI - Finding levels of abstraction in speech production: evidence from sound production impairment. AB - A widely held view in linguistics and psycholinguistics is that there are distinct levels of processing for context-independent and context-specific representations of sound structure. Recently, this view has been disputed, in part because of the absence of clear evidence that there are abstract mental representations of discrete sound-structure units. Here, we present novel evidence that separate context-independent and context-specific representations of sound structure are supported by distinct brain mechanisms that can be selectively impaired in individuals with acquired brain deficits. Acoustic data from /s/-deletion errors of 2 aphasic speakers suggest both a phonological level of processing at which sound representations (e.g., /p/) do not specify context specific detail (e.g., aspirated or unaspirated) and a distinct level at which context-specific information is represented. These data help constrain accounts of sound-structure processing in word production and crucially support the claim that context-independent linguistic information affects language production. PMID- 21828350 TI - Common-fate grouping as feature selection. AB - The visual system groups elements within the visual field that are physically separated yet similar to each other. Although grouping processes have been intensely studied for a century, the mechanisms of grouping remain elusive. We propose that a primary mechanism for grouping by common fate is attentional selection of a direction of motion. A unique prediction follows from this account: that the visual system must be limited to forming only a single common fate group at a time, and that attempts to find a particular common-fate group among other groups, or among nongroups, should therefore be highly inefficient. We show that this is true in searches for vertically oriented groups of moving dots among horizontally oriented groups (Experiment 1) and in searches for motion linked groups among nonlinked objects (Experiment 2). Feature selection may limit the visual system to the construction of only one common-fate group at a time, and thus the experience of simultaneous grouping may be an illusion. PMID- 21828351 TI - Underestimating nearby nature: affective forecasting errors obscure the happy path to sustainability. AB - Modern lifestyles disconnect people from nature, and this may have adverse consequences for the well-being of both humans and the environment. In two experiments, we found that although outdoor walks in nearby nature made participants much happier than indoor walks did, participants made affective forecasting errors, such that they systematically underestimated nature's hedonic benefit. The pleasant moods experienced on outdoor nature walks facilitated a subjective sense of connection with nature, a construct strongly linked with concern for the environment and environmentally sustainable behavior. To the extent that affective forecasts determine choices, our findings suggest that people fail to maximize their time in nearby nature and thus miss opportunities to increase their happiness and relatedness to nature. Our findings suggest a happy path to sustainability, whereby contact with nature fosters individual happiness and environmentally responsible behavior. PMID- 21828352 TI - Used tire recycling to produce granulates: evaluation of occupational exposure to chemical agents. AB - Exposure was assessed in four facilities where used tires are turned into rubber granulates. Particulate exposure levels were measured using filter samples and gravimetric analysis. In parallel, volatile organic compounds (VOCs) screening was carried out using samples taken on activated carbon supports, followed by an analysis using a gas chromatograph coupled to a spectrometric detector. The exposure level medians are between 0.58 and 3.95 mg m(-3). Clogging of the textile fiber separation systems can lead to worker exposure; in this case, the measured concentrations can reach 41 mg m(-3). However, in contrast to the data in the literature, VOC levels >1 p.p.m. were not detected. The particulate mixtures deposited on the installation surfaces are complex; some of the chemical agents are toxic to humans. The results of this study indicate significant exposure to complex mixtures of rubber dust. Optimizing exhaust ventilation systems inside the shredders, with a cyclone for example, is essential for reducing the exposure of workers in this rapidly developing sector. PMID- 21828353 TI - Effects of glial cell line-derived neurotrophic factor on dental pulp cells. AB - This study investigated the effects of glial cell line-derived neurotrophic factor (GDNF) on dental pulp cells (DPCs). Cultures of DPCs expressed GDNF as well as its receptors, GFRalpha1 and RET. Addition of recombinant GDNF to cultures in serum-containing medium did not significantly affect DPC growth; however, GDNF dose-dependently increased viable cell number under serum-free culture conditions. Live/dead, lactate dehydrogenase (LDH), and caspases-3/-7 assays demonstrated that cell death occurred under serum-free conditions, and that GDNF significantly reduced the number of dead cells by inhibiting apoptotic cell death. GDNF also stimulated cell proliferation in serum-free conditions, as assessed by the BrdU incorporation assay. The effect of GDNF was abolished in the presence of inhibitors to GFRalpha1 and RET suggesting receptor-mediated events. This study also demonstrated that GDNF counteracted TNFalpha-induced DPC cytotoxicity, suggesting that GDNF may be cytoprotective under disease conditions. In conclusion, our findings indicate that GDNF promotes cell survival and proliferation of DPCs and suggest that GDNF may play a multifunctional role in the regulation of dental pulp homeostasis. PMID- 21828354 TI - Chymotrypsin C (caldecrin) is associated with enamel development. AB - Two main proteases cleave enamel extracellular matrix proteins during amelogenesis. Matrix metalloprotease-20 (Mmp20) is the predominant enzyme expressed during the secretory stage, while kallikrein-related peptidase-4 (Klk4) is predominantly expressed during maturation. Mutations to both Mmp20 and Klk4 result in abnormal enamel phenotypes. During a recent whole-genome microarray analysis of rat incisor enamel organ cells derived from the secretory and maturation stages of amelogenesis, the serine protease chymotrypsin C (caldecrin, Ctrc) was identified as significantly up-regulated (> 11-fold) during enamel maturation. Prior reports indicate that Ctrc expression is pancreas-specific, albeit low levels were also noted in brain. We here report on the expression of Ctrc in the enamel organ. Quantitative PCR (qPCR) and Western blot analysis were used to confirm the expression of Ctrc in the developing enamel organ. The expression profile of Ctrc is similar to that of Klk4, increasing markedly during the maturation stage relative to the secretory stage, although levels of Ctrc mRNA are lower than for Klk4. The discovery of a new serine protease possibly involved in enamel development has important implications for our understanding of the factors that regulate enamel biomineralization. PMID- 21828355 TI - Mode of birth delivery affects oral microbiota in infants. AB - Establishment of the microbiota of the gut has been shown to differ between infants delivered by Caesarian section (C-section) and those delivered vaginally. The aim of the present study was to compare the oral microbiota in infants delivered by these different routes. The oral biofilm was assayed by the Human Oral Microbe Identification Microarray (HOMIM) in healthy three-month-old infants, 38 infants born by C-section, and 25 infants delivered vaginally. Among over 300 bacterial taxa targeted by the HOMIM microarray, Slackia exigua was detected only in infants delivered by C-section. Further, significantly more bacterial taxa were detected in the infants delivered vaginally (79 species/species clusters) compared with infants delivered by C-section (54 species/species clusters). Multivariate modeling revealed a strong model that separated the microbiota of C-section and vaginally delivered infants into two distinct colonization patterns. In conclusion, our study indicated differences in the oral microbiota in infants due to mode of delivery, with vaginally delivered infants having a higher number of taxa detected by the HOMIM microarray. PMID- 21828356 TI - Nanofibrous scaffolds for dental and craniofacial applications. AB - Tissue-engineering solutions often harness biomimetic materials to support cells for functional tissue regeneration. Three-dimensional scaffolds can create a multi-scale environment capable of facilitating cell adhesion, proliferation, and differentiation. One such multi-scale scaffold incorporates nanofibrous features to mimic the extracellular matrix along with a porous network for the regeneration of a variety of tissues. This review will discuss nanofibrous scaffold synthesis/fabrication, biological effects of nanofibers, their tissue- engineering applications in bone, cartilage, enamel, dentin, and periodontium, patient-specific scaffolds, and incorporated growth factor delivery systems. Nanofibrous scaffolds cannot only further the field of craniofacial regeneration but also advance technology for tissue-engineered replacements in many physiological systems. PMID- 21828357 TI - Effects of maxillary molar intrusion with zygomatic anchorage on the stomatognathic system in anterior open bite patients. AB - The aim of this study was to evaluate the effects of intrusion of the maxillary posterior teeth with zygomatic anchorage on the dentofacial system, on electromyographic (EMG) activity of the masticatory muscles, and on vibration of the temporomandibular joint. The study sample consisted of 19 subjects (13 females, 6 males) with a mean age of 17.7 years. Lateral cephalometric and posteroanterior (PA) radiographs, EMG, and electrovibratographic (EVG) records were obtained before (T0) and after (T1) intrusion. Paired t- and Wilcoxon signed ranks tests were used for statistical evaluation. Maxillary molar intrusion of 3.37 +/- 1.21 mm was obtained with a force of 400 g in an average period of 6.84 +/- 1.64 months. At T1, all measurements showed that facial growth direction, ANB angle, convexity, and overjet were decreased (P < 0.05). SNB angle, facial depth, and overbite were significantly increased (P < 0.05). Upper lip-E plane distance was increased (P < 0.05). Evaluation of the PA radiographs showed that the right and left molar reference angles were unchanged. EMG and EVG analysis showed that the stomatognathic system at T0 was maintained at T1. Intrusion of the maxillary posterior teeth with zygomatic anchorage is an effective treatment alternative for anterior open bite correction. PMID- 21828358 TI - The 5-year-olds' Index: determining the optimal format for rating dental arch relationships in unilateral cleft lip and palate. AB - The aim of this investigation was to determine the optimal format for presenting the 5-year-olds' Index reference models for the assessment of dental arch relationships in unilateral cleft lip and palate (UCLP). The 5-year-olds' Index reference models were presented in four different formats: plaster models, coloured acrylic models, and two digital formats, which included three dimensional digital models (3D), and black and white photographs. These formats were used to rate 45 plaster models of patients born with UCLP by a total of seven examiners comprising experienced and inexperienced examiners. Scoring was undertaken 1 week apart for each format with the patient models reassigned on each occasion to reduce the effect of memory bias. For intra-examiner agreement, the patient models were scored 3 weeks later under similar conditions by the same examiners. The reliability of using the different formats was determined using the plaster reference models as the 'gold' standard for comparison. Analysis of the results using weighted kappa (k) statistics showed the magnitude of agreement for all the formats of the 5-year-olds' Index were good to very good between examiners. The more experienced examiners were consistently more reliable in their scoring using the different formats. This study clearly demonstrated that 3D digital models of the 5-year-olds' Index could prove to be a promising alternative to physical models of the 5-year-olds' Index. PMID- 21828360 TI - Drug and alcohol use in college students with and without ADHD. AB - OBJECTIVE: This study examines differences in reported levels of drug and alcohol use between college students with and without ADHD. METHOD: The Michigan Alcohol Screening Test (MAST) and several self-report and interview questions, developed by Barkley, were used to examine the drug and alcohol use of college students with and without ADHD. RESULTS: Between-group differences were found on the MAST and in the endorsement of marijuana use. Subtype differences were also found on the MAST. Several factors, including medication treatment status, ethnicity, class standing, and gender were found to be differentially related to problematic drinking behaviors. CONCLUSIONS: Difficulties in self-regulation may put college students with ADHD at a higher risk of problematic drinking and the subsequent risk for alcohol-use disorders than their peers. Possible explanations for results are discussed in terms of theory, prevention efforts, and future research. PMID- 21828359 TI - Bioavailability, intracellular mobilization of nickel, and HIF-1alpha activation in human lung epithelial cells exposed to metallic nickel and nickel oxide nanoparticles. AB - Micron-sized particles of poorly soluble nickel compounds, but not metallic nickel, are established human and rodent carcinogens. In contrast, little is known about the toxic effects of a growing number of Ni-containing materials in the nano-sized range. Here, we performed physicochemical characterization of NiO and metallic Ni nanoparticles and examined their metal ion bioavailability and toxicological properties in human lung epithelial cells. Cellular uptake of metallic Ni and NiO nanoparticles, but not metallic Ni microparticles, was associated with the release of Ni(II) ions after 24-48 h as determined by Newport Green fluorescence. Similar to soluble NiCl2, NiO nanoparticles induced stabilization and nuclear translocation of hypoxia-inducible factor 1alpha (HIF 1alpha) transcription factor followed by upregulation of its target NRDG1 (Cap43). In contrast to no response to metallic Ni microparticles, nickel nanoparticles caused a rapid and prolonged activation of the HIF-1alpha pathway that was stronger than that induced by soluble Ni(II). Soluble NiCl2 and NiO nanoparticles were equally toxic to H460 human lung epithelial cells and primary human bronchial epithelial cells; metallic Ni nanoparticles showed lower toxicity and Ni microparticles were nontoxic. Cytotoxicity induced by all forms of Ni occurred concomitant with activation of an apoptotic response, as determined by dose- and time-dependent cleavage of caspases and poly (ADP-ribose) polymerase. Our results show that metallic Ni nanoparticles, in contrast to micron-sized Ni particles, activate a toxicity pathway characteristic of carcinogenic Ni compounds. Moderate cytotoxicity and sustained activation of the HIF-1alpha pathway by metallic Ni nanoparticles could promote cell transformation and tumor progression. PMID- 21828361 TI - Trastuzumab-related cardiotoxicity in the elderly: a role for cardiovascular risk factors. AB - BACKGROUND: Elderly breast cancer patients are usually excluded from clinical trials. Nevertheless, with the increasing use of trastuzumab, there is a need to address trastuzumab-related cardiotoxicity in this population. PATIENTS AND METHODS: Records for patients >= 70 years treated with trastuzumab since 2005 were reviewed. New York Heart Association classification was used to document symptomatic cardiotoxicity. Asymptomatic cardiotoxicity was defined as an absolute drop >= 10% with a final left ventricular ejection fraction < 50% or an absolute drop > 20%. RESULTS: Forty-five patients, median age 75.9 years (range 70-92), were identified. Three of 24 (12.5%) early breast cancer patients and 5 of 21 (23.8%) with advanced disease experienced asymptomatic cardiotoxicity. Four of 45 patients (8.9%), all with advanced breast cancer, developed symptomatic congestive heart failure. All but one of them recovered in a median time of 5 weeks (range 3-21). Patients with trastuzumab-related cardiotoxicity presented more often with cardiovascular risk factors, such as history of cardiac disease (33% versus 9.1%, P = 0.017) and diabetes (33.3% versus 6.1%, P = 0.010), compared with those without. CONCLUSIONS: Elderly breast cancer patients with a history of cardiac disease and/or diabetes treated with trastuzumab have an increased incidence of cardiotoxicity. Continuous cardiac monitoring is especially advised in this population. PMID- 21828362 TI - Functional and radiographic outcomes of juvenile osteochondritis dissecans of the knee treated with extra-articular retrograde drilling. AB - BACKGROUND: Osteochondritis dissecans (OCD) lesions of the medial femoral condyle in the adolescent population can cause significant impairment and restriction in physical activity. Studies have established the efficacy of transarticular antegrade drilling for juvenile OCD lesions of the knee, although concerns of consequences from drilling through the articular cartilage remain. Alternatively, retrograde extra-articular drilling avoids drilling the cartilage while ensuring adequate channels for revascularization and healing. PURPOSE: The authors present the results of 31 skeletally immature patients who underwent retrograde drilling of OCD lesions of the knee with an average follow-up of 4 years. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: The procedure consisted of a standard arthroscopic evaluation of the knee and subsequent percutaneous retrograde drilling obliquely through the condylar epiphysis starting distal to the physis and ending in the center-center of the OCD lesion. Outcome measures included radiographic signs of healing, Lysholm scoring and the Tegner activity scale to measure performance and activity restriction, and visual analog scale (VAS) pain scores. RESULTS: Average follow-up for the 31 patients was 4 years (range, 1.5-7 years). Sixteen of the 34 lesions were grade I or II based on radiographic findings with signs and symptoms greater than 6 months. The remaining 18 were grade III secondary to a sclerotic rim surrounding the defect. Overall, improvement in Lysholm scores (70 to 95; standard deviation [SD] +/- 14.95), Tegner scores (4 to 7; SD +/- 2.31), and VAS pain scores (6.9 to 1.3; SD +/- 2.16) were found to be statistically significant. Radiographs showed stable or improved lesions in all cases. CONCLUSION: Retrograde extra-articular drilling provided clinical and radiographic improvement in most juveniles with OCD lesions who failed nonoperative management. This method serves to decompress the lesion and allow revascularization without disrupting the articular cartilage surface in stable OCD lesions. PMID- 21828363 TI - Intramuscular transplantation of muscle-derived stem cells accelerates skeletal muscle healing after contusion injury via enhancement of angiogenesis. AB - BACKGROUND: Muscle contusions are common muscle injuries. Although these injuries are capable of healing, incomplete functional recovery often occurs. Muscle derived stem cells (MDSCs) are likely derived from blood vessel cells and have a multilineage differentiation potential. PURPOSE: The aims of this study are (1) to find optimal timing of MDSC transplantation to enhance muscle healing by stimulating muscle regeneration and preventing scar tissue (fibrosis) formation after skeletal muscle contusion injury, and (2) to investigate the role of angiogenesis in the muscle-healing process after MDSC transplantation. STUDY DESIGN: Controlled laboratory study. METHODS: Muscle-derived stem cells were injected directly into injured tibialis anterior muscles of mice at various time points (1, 4, and 7 days) after the muscle contusion injury. Muscle regeneration, angiogenesis, and fibrosis formation were evaluated by histology and real-time polymerase chain reaction analysis, and functional recovery was measured by physiologic testing. RESULTS: Transplantation of MDSCs at 4 days after injury significantly promoted angiogenesis, which was induced by high levels of vascular endothelial growth factor expression at week 1, and significantly increased muscle regeneration and muscle strength by week 2, when compared with the other groups. A decrease in fibrosis formation was observed at week 4, when compared with the other groups, after the transplantation of MDSCs at 4 and 7 days after injury. CONCLUSION: Intramuscular injection of MDSCs at 4 days after injury improved and accelerated skeletal muscle healing by increasing angiogenesis and decreasing scar tissue formation. CLINICAL RELEVANCE: These findings could contribute to the development of biologic treatments to aid in muscle healing after muscle injury. PMID- 21828364 TI - Single-legged hop tests as predictors of self-reported knee function in nonoperatively treated individuals with anterior cruciate ligament injury. AB - BACKGROUND: Previous studies have found significant predictors for functional outcome after anterior cruciate ligament (ACL) reconstruction; however, studies examining predictors for functional outcome in nonoperatively treated individuals are lacking. HYPOTHESIS: Single-legged hop tests predict self-reported knee function (International Knee Documentation Committee [IKDC] 2000) in nonoperatively treated ACL-injured individuals 1 year after baseline testing. STUDY DESIGN: Cohort study (prognosis); Level of evidence, 2. METHODS: Ninety-one nonoperatively treated patients with an ACL injury were tested using 4 single legged hop tests on average 74 +/- 30 days after injury in a prospective cohort study. Eighty-one patients (89%) completed the IKDC 2000 1 year later. Patients with an IKDC 2000 score equal to or higher than the age- and gender-specific 15th percentile score from previously published data on an uninjured population were classified as having self-reported function within normal ranges. Logistic regression analyses were performed to identify predictors of self-reported knee function. The area under the curve (AUC) from receiver operating characteristic curves was used as a measure of discriminative accuracy. Optimal limb symmetry index (LSI) cutoff for the best single-legged hop test was defined as the LSI with the highest product of sensitivity and specificity. RESULTS: Single hop for distance symmetry indexes predicted self-reported knee function at the 1-year follow-up (P = .036). Combinations of any 2 hop tests (AUC = 0.64-0.71) did not give a higher discriminative accuracy than the single hop alone (AUC = 0.71). A cutoff of 88% (LSI) for the single hop revealed a sensitivity of 71.4% and a specificity of 71.7%. CONCLUSION: The single hop for distance (LSI) significantly predicted self-reported knee function after 1 year in nonoperatively treated ACL injured patients. Combinations of 2 single-legged hop tests did not lead to higher discriminative accuracy than the single hop alone. PMID- 21828365 TI - Longitudinal tear of the medial meniscus posterior horn in the anterior cruciate ligament-deficient knee significantly influences anterior stability. AB - BACKGROUND: Longitudinal tears of the medial meniscus posterior horn (MMPH) are commonly associated with a chronic anterior cruciate ligament (ACL) deficiency. Many studies have demonstrated the importance of the medial meniscus in terms of limiting the amount of anterior-posterior tibial translation in response to anterior tibial loads in ACL-deficient knees. HYPOTHESIS: An MMPH tear in an ACL deficient knee increases the anterior-posterior tibial translation and rotatory instability. In addition, MMPH repair will restore the tibial translation to the level before the tear. STUDY DESIGN: Controlled laboratory study. METHODS: Ten human cadaveric knees were tested sequentially using a custom testing system under 5 conditions: intact, ACL deficient, ACL deficient with an MMPH peripheral longitudinal tear, ACL deficient with an MMPH repair, and ACL deficient with a total medial meniscectomy. The knee kinematics were measured at 0 degrees , 15 degrees , 30 degrees , 60 degrees , and 90 degrees of flexion in response to a 134-N anterior and 200-N axial compressive tibial load. The rotatory kinematics were also measured at 15 degrees and 30 degrees of flexion in a combined rotatory load of 5 N.m of internal tibial torque and 10 N.m of valgus torque. RESULTS: Medial meniscus posterior horn longitudinal tears in ACL-deficient knees resulted in a significant increase in anterior-posterior tibial translation at all flexion angles except 90 degrees (P < .05). An MMPH repair in an ACL deficient knee showed a significant decrease in anterior-posterior tibial translation at all flexion angles except 60 degrees compared with the ACL deficient/MMPH tear state (P < .05). The total anterior-posterior translation of the ACL-deficient/MMPH repaired knee was not significantly increased compared with the ACL (only)-deficient knee but was increased compared with the ACL-intact knee (P > .05). A total medial meniscectomy in an ACL-deficient knee did not increase the anterior-posterior tibial translation significantly compared with MMPH tears in ACL-deficient knees at all flexion angles (P > .05). In a combined rotatory load, tibial rotation after MMPH tears or a total medial meniscectomy in an ACL-deficient knee were not affected significantly at all flexion angles. CONCLUSION: This study shows that an MMPH longitudinal tear in an ACL-deficient knee alters the knee kinematics, particularly the anterior-posterior tibial translation. MMPH repair significantly improved anterior-posterior tibial translation in ACL-deficient knees. CLINICAL RELEVANCE: These findings may help improve the treatment of patients with ACL and MMPH longitudinal tear by suggesting that the medial meniscal repairs should be performed for greater longevity when combined with an ACL reconstruction. PMID- 21828366 TI - Cocultures of adult and juvenile chondrocytes compared with adult and juvenile chondral fragments: in vitro matrix production. AB - BACKGROUND: The use of allogenic juvenile chondrocytes or autologous chondral fragments has shown promising laboratory results for the repair of chondral lesions. HYPOTHESIS: Juvenile chondrocytes would not affect matrix production when mixed with adult chondrocytes or cartilage fragments. STUDY DESIGN: Controlled laboratory study. METHODS: Cartilage sources consisted of 3 adult and 3 juvenile (human) donors. In part 1, per each donor, juvenile chondrocytes were mixed with adult chondrocytes in 5 different proportions: 100%, 50%, 25%, 12.5%, and 0%. Three-dimensional cultures in low-melt agarose were performed. At 6 weeks, biochemical and histologic analyses were performed. In part 2, isolated adult, isolated juvenile, and mixed 3-dimensional cultures (1:1) were performed with chondral fragments (<1 mm), both with low-melt agarose and a hyaluronic acid scaffold. At 2 and 6 weeks, cultures were evaluated with biochemical and histologic analyses. RESULTS: Part 1: Biochemical and histologic analyses showed that isolated juvenile cultures performed significantly better than mixed and isolated adult cultures. No significant differences were noted between mixed cultures (1:1) and isolated adult cultures. Part 2: Biochemical and histologic results at 6 weeks showed that mixed cartilage fragment cultures performed better than isolated adult cultures in terms of proteoglycans/DNA ratio (P = .014), percentage of safranin O-positive cells (P = .012), Bern score (P = .001), and collagen type II. No statistically significant difference was noted between juvenile and mixed cultures. CONCLUSION: Extracellular matrix production of juvenile chondrocytes is inhibited by adult chondrocytes. The addition of juvenile cartilage fragments to adult fragments improves matrix production, with a positive interaction between the 2 sources. CLINICAL RELEVANCE: Even if the underlying mechanisms are still unknown, this study describes the behavior of juvenile/adult cocultures using both chondrocytes and cartilage fragments, with potential for new research and clinical applications. PMID- 21828367 TI - Group versus individual administration affects baseline neurocognitive test performance. AB - BACKGROUND: Computer-based tests are widely used for the purpose of documenting baseline neurocognitive function, and athletes are often tested in groups. At present, there is limited research on the effects of administering these tests in a group versus individual setting. HYPOTHESIS: Athletes assessed with neurocognitive tests in groups would show decreased performance compared with those assessed individually. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: High school athletes completed preseason baseline neurocognitive tests either in groups in their school or individually in a private neuropsychological clinic (with no significant between-group differences in sex, history of concussion, and attention deficit disorder/learning disability). All athletes completed the ImPACT (Immediate Post-Concussion Assessment and Cognitive Testing) test battery on 1 occasion, which yielded scores in the area of verbal memory, visual memory, motor processing speed, reaction time, and symptom scores. RESULTS: Athletes in the group setting scored significantly lower on verbal memory (mean 83.4 vs 86.5; P = .003), visual memory (mean 71.6 vs 76.7; P = .0001), motor processing speed (mean 35.6 vs 38.4; P = .0001), and reaction time (mean 0.61 vs 0.57; P = .001), but not symptom scores (mean 6.1 vs 4.4; P = .11), and exhibited a greater rate of invalid baselines. Similar results were obtained after excluding athletes with attention deficit disorder/learning disability and/or a history of concussion. CONCLUSION: Administering baseline neurocognitive testing to athletes in a group setting may introduce extraneous error, negatively affecting test performance. PMID- 21828368 TI - Methods for characterizing differences in longitudinal glomerular filtration rate changes between children with glomerular chronic kidney disease and those with nonglomerular chronic kidney disease. AB - The rate of decline of glomerular filtration rate (GFR) in children with chronic kidney disease (CKD) can vary, even among those with similar diagnoses. Classic regression methods applied to the log-transformed GFR (i.e., lognormal) quantify only rigid shifts in a given outcome. The generalized gamma distribution offers an alternative approach for characterizing the heterogeneity of effect of an exposure on a positive, continuous outcome. Using directly measured GFR longitudinally assessed between 2005 and 2010 in 529 children enrolled in the Chronic Kidney Disease in Children Study, the authors characterized the effect of glomerular CKD versus nonglomerular CKD diagnoses on the outcome, measured as the annualized GFR ratio. Relative percentiles were used to characterize the heterogeneity of effect of CKD diagnosis across the distribution of the outcome. The rigid shift assumed by the classic mixed models failed to capture the fact that the greatest difference between the glomerular and nonglomerular diagnosis' annualized GFR ratios was in children who exhibited the fastest GFR declines. Although this difference was enhanced in children with an initial GFR level of 45 mL/minute/1.73 m(2) or less, the effect of diagnosis on outcome was not significantly modified by level. Generalized gamma models captured heterogeneity of effect more richly and provided a better fit to the data than did conventional lognormal models. PMID- 21828369 TI - Asthma and caries: a systematic review and meta-analysis. AB - There is inconclusive evidence suggesting a possible association of asthma with increased risk of caries. The authors conducted a systematic review and meta analysis to synthesize the evidence on the relation between asthma and caries. They performed an Ovid Medline (US National Library of Medicine) database search of literature published from 1950 through May 2010 using the Medical Subject Headings "asthma" and "caries." Summary effect estimates were calculated with fixed- and random-effects models, and determinants of heterogeneity were studied in meta-regression analysis. The meta-analysis was based on 11 articles providing estimates of the effect of asthma on primary dentition and 14 articles on permanent dentition. Summary effect estimates for the relation between asthma and caries from the random-effects models were 2.73 (95% confidence interval: 1.61, 4.64) and 2.04 (95% confidence interval: 1.44, 2.89), respectively. Factors identified as determinants of heterogeneity were geographic region for primary dentition and publication year, sample size, asthma definition, and information on the use of asthma medication for permanent dentition. Evidence from this analysis suggests that asthma doubles the risk of caries in both primary and permanent dentition. Publication bias diagnostics and simulation suggested possible overestimation of the summary odds ratio for permanent dentition but not for primary dentition. Physicians and dentists should recommend preventive measures against caries for persons with asthma. PMID- 21828370 TI - Silicosis mortality with respiratory tuberculosis in the United States, 1968 2006. AB - The presence of tuberculosis (TB) in patients with silicosis increases mortality risk. To characterize silicosis-respiratory TB comortality in the United States, the authors used 1968-2006 National Center for Health Statistics multiple cause of-death data for decedents aged >=25 years. The authors calculated proportionate mortality ratios (PMRs) using available information on decedents' industries and occupations reported from 26 states from 1985 through 1999. Among 16,648 silicosis deaths, 2,278 (13.7%) had respiratory TB listed on the death certificate. Of silicosis-respiratory TB deaths, 1,666 decedents (73.1%) were aged >=65 years, 2,255 (99.0%) were male, and 1,893 (83.1%) were white. Silicosis respiratory TB deaths declined 99.5% during the study period (P < 0.001 for time related trend), from 239.8 per year during 1968-1972 to 1.2 per year during 2002 2006, with no reported deaths in 2006. Silicosis-respiratory TB deaths reported from Pennsylvania (n = 525; 1.29 per million population), Ohio (n = 258; 0.81 per million), and West Virginia (n = 146; 2.35 per million) accounted for 40.8% of all such deaths in the United States. The highest PMR for silicosis-respiratory TB death was associated with the "miscellaneous nonmetallic mineral and stone products" industry (PMR = 73.7, 95% confidence interval: 33.8, 139.8). In the United States, 2006 marked the first year since 1968 with no silicosis respiratory TB deaths. The substantial decline in silicosis-respiratory TB comortality probably reflects prevention and control measures for both diseases. PMID- 21828371 TI - Body size in early life and adult levels of insulin-like growth factor 1 and insulin-like growth factor binding protein 3. AB - Body size in early life has been associated with breast cancer risk. This may be partly mediated through the insulin-like growth factor (IGF) pathway. The authors assessed whether birth weight, body fatness at ages 5 and 10 years, and body mass index (BMI; weight (kg)/height (m)(2)) at age 18 years were associated with plasma concentrations of insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 3 in 6,520 women aged 32-70 years at blood draw from the Nurses' Health Study (1990-2006) and Nurses' Health Study II (1997 2005). Birth weight, body fatness in childhood, and BMI at age 18 years were inversely associated with adult IGF-1 levels. For example, IGF-1 levels were 11.9% lower in women who reported being heaviest at age 10 years than in those who were leanest at age 10 (P-trend < 0.0001). Further, women who reported their birth weight as >=10 pounds (>=4.5 kg) (vs. <5.5 pounds (<2.5 kg)) had 7.9% lower IGF-1 levels (P-trend = 0.002). Women whose BMI at age 18 years was >=30 (vs. <20) had 14.1% lower IGF-1 levels (P-trend < 0.0001). Similar inverse associations were observed for insulin-like growth factor binding protein 3. These observations did not vary by adult BMI or menopausal status at blood draw. These findings suggest that altered IGF-1 levels in adulthood may be a mechanism through which early-life body size influences subsequent breast cancer risk. PMID- 21828372 TI - On information coded in gene-environment independence in case-control studies. AB - For analysis of case-control genetic association studies, it has recently been shown that gene-environment independence in the population can be leveraged to increase efficiency for estimating gene-environment interaction effects in comparison with the standard prospective analysis. However, for the special case in which data on the binary phenotype and genetic and environmental risk factors can be summarized in a 2 * 2 * 2 table, the authors show here that there is no efficiency gain for estimating interaction effects, nor is there an efficiency gain for estimating the genetic and environmental main effects. This contrasts with the well-known result assuming that rare phenotype prevalence and gene environment independence in the control population for the same data can lead to efficiency gain. This discrepancy is counterintuitive, since the 2 likelihoods are also approximately equal when the phenotype is rare. An explanation for the paradox based on a theoretical analysis is provided. Implications of these results for data analyses are also examined, and practical guidance on analyzing such case-control studies is offered. PMID- 21828375 TI - Comparing diagnostic delay in cancer: a cross-sectional study in three European countries with primary care-led health care systems. AB - BACKGROUND: The principal aim of this study was to determine the feasibility of a large-scale comparative study, between the UK, the Netherlands and Sweden, to investigate whether delays in the diagnostic pathway of cancer might explain differences in cancer survival between countries. METHODS: Following a planning meeting to agree the format of a data collection instrument, data on delays in the cancer diagnostic pathway were abstracted from primary care-held medical records. Data were collected on 50 cases each (total of 150) from practices in each of Grampian, Northeast Scotland; Maastricht, the Netherlands and Skane, Sweden. Data were entered into SPSS 18.0 for analysis. RESULTS: Data on delays in the cancer diagnostic pathway were readily available from primary care-held case records. However, data on demographic variables, cancer stage at diagnosis and treatment were less well recorded. There was no significant difference between countries in the way in which cases were referred from primary to secondary care. There was no significant difference between countries in the time delay between a patient presenting in primary care and being referred to secondary care. Median delay between referral and first appointment in secondary care [19 (8.0-47.5) days] was significantly longer in Scotland that in Sweden [1.0 (0-31.5) days] and the Netherlands [5.5 (0-31.5) days] (P < 0.001). Secondary care delay (between first appointment in secondary care and diagnosis) in Scotland [22.5 (0-39.5) days] was also significantly longer than in Sweden [14.0 (4.5-31.5) days] and the Netherlands [3.5 (0-16.5) days] (P = 0.003). Finally, overall delay in Scotland [53.5 (30.3-96.3) days] was also significantly longer than in Sweden [32.0 (14.0 71.0) days] and the Netherlands [22.0 (7.0-60.3) days] (P = 0.003). CONCLUSIONS: A large-scale study comparing cancer delays in European countries and based on primary care-held records is feasible but would require supplementary sources of data in order to maximize information on demographic variables, the cancer stage at diagnosis and treatment details. Such a large-scale study is timely and desirable since our findings suggest systematic differences in the way cancer is managed in the three countries. PMID- 21828374 TI - Effects of inversions on within- and between-species recombination and divergence. AB - Chromosomal inversions disrupt recombination in heterozygotes by both reducing crossing-over within inverted regions and increasing it elsewhere in the genome. The reduction of recombination in inverted regions facilitates the maintenance of hybridizing species, as outlined by various models of chromosomal speciation. We present a comprehensive comparison of the effects of inversions on recombination rates and on nucleotide divergence. Within an inversion differentiating Drosophila pseudoobscura and Drosophila persimilis, we detected one double recombinant among 9,739 progeny from F(1) hybrids screened, consistent with published double-crossover frequencies observed within species. Despite similar rates of exchange within and between species, we found no sequence-based evidence of ongoing gene exchange between species within this inversion, but significant exchange was inferred within species. We also observed greater differentiation at regions near inversion breakpoints between species versus within species. Moreover, we observed strong "interchromosomal effect" (higher recombination in inversion heterozygotes between species) with up to 9-fold higher recombination rates along collinear segments of chromosome two in hybrids. Further, we observed that regions most susceptible to changes in recombination rates corresponded to regions with lower recombination rates in homokaryotypes. Finally, we showed that interspecies nucleotide divergence is lower in regions with greater increases in recombination rate, potentially resulting from greater interspecies exchange. Overall, we have identified several similarities and differences between inversions segregating within versus between species in their effects on recombination and divergence. We conclude that these differences are most likely due to lower frequency of heterokaryotypes and to fitness consequences from the accumulation of various incompatibilities between species. Additionally, we have identified possible effects of inversions on interspecies gene exchange that had not been considered previously. PMID- 21828373 TI - Organization and molecular evolution of CENP-A--associated satellite DNA families in a basal primate genome. AB - Centromeric regions in many complex eukaryotic species contain highly repetitive satellite DNAs. Despite the diversity of centromeric DNA sequences among species, the functional centromeres in all species studied to date are marked by CENP-A, a centromere-specific histone H3 variant. Although it is well established that families of multimeric higher-order alpha satellite are conserved at the centromeres of human and great ape chromosomes and that diverged monomeric alpha satellite is found in old and new world monkey genomes, little is known about the organization, function, and evolution of centromeric sequences in more distant primates, including lemurs. Aye-Aye (Daubentonia madagascariensis) is a basal primate and is located at a key position in the evolutionary tree to study centromeric satellite transitions in primate genomes. Using the approach of chromatin immunoprecipitation with antibodies directed to CENP-A, we have identified two satellite families, Daubentonia madagascariensis Aye-Aye 1 (DMA1) and Daubentonia madagascariensis Aye-Aye 2 (DMA2), related to each other but unrelated in sequence to alpha satellite or any other previously described primate or mammalian satellite DNA families. Here, we describe the initial genomic and phylogenetic organization of DMA1 and DMA2 and present evidence of higher-order repeats in Aye-Aye centromeric domains, providing an opportunity to study the emergence of chromosome-specific modes of satellite DNA evolution in primate genomes. PMID- 21828376 TI - Role of medical history and medication use in the aetiology of upper aerodigestive tract cancers in Europe: the ARCAGE study. AB - BACKGROUND: The study aimed to investigate the role of medical history (skin warts, Candida albicans, herpetic lesions, heartburn, regurgitation) and medication use (for heartburn; for regurgitation; aspirin) in the aetiology of upper aerodigestive tract (UADT) cancer. METHODS: A multicentre (10 European countries) case-control study [Alcohol-Related CAncers and GEnetic susceptibility (ARCAGE) project]. RESULTS: There were 1779 cases of UADT cancer and 1993 controls. History of warts or C. albicans infection was associated with a reduced risk [odds ratio (OR) 0.80, 95% confidence interval (CI) 0.68-0.94 and OR 0.73, 95% CI 0.60-0.89, respectively] but there was no association with herpetic lesions, heartburn, regurgitation or medication for related symptoms. Regurgitation was associated with an increased risk for cancer of the oesophagus (OR 1.47, 95% CI 0.98-2.21). Regular aspirin use was not associated with risk of UADT cancer overall but was associated with a reduced risk for cancer of oesophagus (OR 0.51, 95% CI 0.28-0.96), hypopharynx (OR 0.53, 95% CI 0.28-1.02) and larynx (OR 0.74, 95% CI 0.54-1.01). CONCLUSIONS: A history of some infections appears to be a marker for decreased risk of UADT cancer. The role of medical history and medication use varied by UADT subsites with aspirin use associated with a decreased risk of oesophageal cancer and suggestive of a decreased risk of hypopharyngeal and laryngeal cancers. PMID- 21828377 TI - Phase I study of the effects of renal impairment on the pharmacokinetics and safety of satraplatin in patients with refractory solid tumors. AB - BACKGROUND: Satraplatin is an oral platinum analog with demonstrated activity in a range of malignancies. The current study was designed to evaluate the effect of varying degrees of renal impairment on the safety and pharmacokinetics (PKs) of satraplatin. PATIENTS AND METHODS: Patients with advanced solid tumors, refractory to standard therapies, were eligible. The study included four cohorts of patients with varying levels of renal function, and eight patients per cohort: Group 1 (G1) = normal renal function; G2 = mild renal impairment [creatinine clearance (CrCl) 50-80 ml/min]; G3 = moderate impairment (CrCl 30 to <50 ml/min); G4 = severe impairment (CrCl <30 ml/min). Satraplatin was administered orally at 80 mg/m(2)/day on days 1-5 every 35 days. RESULTS: A total of 32 patients were enrolled, 8 patients in each renal function group. Each group tolerated the dose of 80 mg/m(2)/day on days 1-5 every 35 days without the need for dose deescalation. The most common adverse events were fatigue (63%), nausea (56%), diarrhea (53%), anorexia (47%), constipation (38%), vomiting (28%), anemia, dyspnea, and thrombocytopenia (25%). There were no dose-limiting toxic effects in any study group. There was increased exposure to plasma platinum and plasma ultrafiltrate platinum in patients with moderate to severe renal impairment. CONCLUSIONS: Satraplatin PKs was altered in patients with renal impairment. However, a corresponding increase in satraplatin-related toxic effects was not observed. PMID- 21828379 TI - Validation of the short form-36 health survey supported with isokinetic strength testing after sport knee injury. AB - CONTEXT: Valid patient-based outcome instruments are necessary for comprehensive patient care that focuses on all aspects of health, from impairments to participation restrictions. OBJECTIVE: To validate the Slovenian translation of Medical Outcome Survey (MOS) Short Form Health Survey (SF-36) and to assess relations among various knee measurements, activity tested with Oxford Knee Score (OKS) and health-related quality of life as estimated with SF-36 domains. DESIGN: Descriptive validation study. SETTING: Isokinetic laboratory in outpatient rehabilitation unit. PARTICIPANTS: 101 subjects after unilateral sport knee injury. INTERVENTIONS: All subjects completed the SF-36 and OKS, and isokinetic knee-muscle strength output at 60 degrees /s was determined in 78 participants. Within a 3-d period, 43 subjects completed the SF-36 and OKS questionnaires again. MAIN OUTCOME MEASURES: Reliability testing included internal consistency and test-retest reliability. Correlations between SF-36 subscales and OKS were calculated to assess construct validity, and correlation between SF-36 subscales and muscle strength was calculated to assess concurrent validity. RESULTS: Chronbach alpha was above .78 for all SF-36 subscales. ICCs ranged from .80 to .93. The correlation between OKS and the physical-functioning subscale, showing convergent construct validity, was higher (r = .83, P < .01) than between OKS and mental health (r = .50, P < .01), showing divergent construct validity. Knee extensor weakness negatively correlated with physical-functioning (r = -.59, P < .01) and social-functioning (r = -.43, P < .01) subscales. CONCLUSIONS: The Slovenian translation of the SF-36 is a reliable and valuable tool. The relationships between knee-muscle strength and activity and between knee-muscle strength and SF-36 subscales in patients after sport knee injury were established. PMID- 21828378 TI - Cediranib in combination with mFOLFOX6 in Japanese patients with metastatic colorectal cancer: results from the randomised phase II part of a phase I/II study. AB - BACKGROUND: Colorectal cancer (CRC) is the second most common malignancy in Japan. Treatment with inhibitors of the vascular endothelial growth factor (VEGF) signalling pathway has proven benefit in metastatic CRC. Cediranib is an oral highly potent VEGF signalling inhibitor that inhibits all three VEGF receptors. PATIENTS AND METHODS: In this phase II, double-blind, placebo-controlled study, 172 patients with metastatic CRC were randomised to receive once-daily cediranib (20 or 30 mg) or placebo, each combined with modified FOLFOX6 (mFOLFOX6). The primary objective was comparison of progression-free survival (PFS). RESULTS: The comparison of cediranib 20 mg versus placebo met the primary objective of PFS prolongation [hazard ratio = 0.70 (95% confidence interval 0.44-1.11), P = 0.167], which met the protocol-defined criterion of P < 0.2. Median PFS was 10.2 versus 8.3 months, respectively. The PFS comparison for cediranib 30 mg versus placebo did not meet the criterion. The most common adverse events (AEs) in the cediranib-containing groups were diarrhoea and hypertension. CONCLUSIONS: Cediranib 20 mg plus mFOLFOX6 met the predefined criteria in terms of improved PFS compared with placebo plus mFOLFOX6. Cediranib 20 mg was generally well tolerated and the AE profile was consistent with previous studies. PMID- 21828380 TI - The effect of gender on foot anthropometrics in older people. AB - CONTEXT: Some questions remain regarding the anthropometric differences between the feet of young men and women, but the gap is much greater when dealing with older adults. No studies were found concerning these differences in an exclusively older adult population, which makes it difficult to manufacture shoes based on the specific anthropometric measurements of the older adult population and according to gender differences. OBJECTIVE: To identify differences between the anthropometric foot variables of older men and women. DESIGN: Cross sectional. PARTICIPANTS: 154 older women (69.0 +/- 6.8 y) and 131 older men (69.0 +/- 6.5 y). MAIN OUTCOME MEASURES: The foot evaluations comprised the variables of width, perimeter, height, length, 1st and 5th metatarsophalangeal angles, the Arch Index (AI), and the Foot Posture Index (FPI). A data analysis was performed using t test and a post hoc power analysis. RESULTS: Women showed significantly higher values for the width and perimeter of the toes, width of the metatarsal heads, and width of the heel and presented significantly lower values for the height of the dorsal foot after normalization of the data to foot length. The 1st and 5th metatarsophalangeal angles were smaller in the men. There were no differences between men and women with respect to AI and FPI. CONCLUSIONS: Overall, the current study shows evidence of differences between some of the anthropometric foot variables of older men and women that must be taken into account for the manufacture of shoes for older adults. PMID- 21828381 TI - Hip- and trunk-muscle activation patterns during perturbed gait. AB - CONTEXT: Selected muscles in the kinetic chain may help explain the body's ability to avert injury during unexpected perturbation. OBJECTIVE: To determine the activation of the ipsilateral rectus femoris (RF), gluteus maximus (MA), gluteus medius (ME), and contralateral external obliques (EO) during normal and perturbed gait. DESIGN: Single-factor, repeated measures. SETTING: University research laboratory. PARTICIPANTS: 32 physically active, college-age subjects. INTERVENTION: Subjects walked a total of 20 trials the length of a 6.1-m custom runway capable of releasing either side into 30 degrees of unexpected inversion. During 5 trials, the platform released into inversion. MAIN OUTCOME MEASURES: Average, peak, and time to peak EMG were analyzed across the 4 muscles, and comparisons were made between the walking trials and perturbed trials. RESULTS: Significantly higher average and peak muscle activity were noted for the perturbed condition for RF, MA, and EO. Time to peak muscle activity was faster during the perturbed condition for the EO. CONCLUSION: Rapid contractions of selected postural muscles in the kinetic chain help explain the body's reaction to unexpected perturbation. PMID- 21828382 TI - Effects of a single-task versus a dual-task paradigm on cognition and balance in healthy subjects. AB - CONTEXT: Recent evidence has revealed deficiencies in the ability to divide attention after concussion. OBJECTIVE: To examine the effects of a single vs a dual task on cognition and balance in healthy subjects and to examine reliability of 2 dual-task paradigms while examining the overall feasibility of the tasks. DESIGN: Pretest-posttest experimental design. SETTING: Sports medicine research laboratory. PATIENTS: 30 healthy, recreationally active college students. INTERVENTION: Subjects performed balance and cognitive tasks under the single- and dual-task conditions during 2 test sessions 14 d apart. MAIN OUTCOME MEASURES: The procedural reaction-time (PRT) test of the Automated Neuropsychological Assessment Metrics (eyes-closed tasks) and an adapted Procedural Auditory Task (PAT; eyes-open tasks) were used to assess cognition. The NeuroCom Sensory Organization Test (SOT) and the Balance Error Scoring System (BESS) were used to assess balance performance. Five 2-way, within-subject ANOVAs and a paired-samples t test were used to analyze the data. ICCs were used to assess reliability across 2 test sessions. RESULTS: On the SOT, performance significantly improved between test sessions (F1,29 = 35.695, P < .001) and from the single to the dual task (F1,29 = 9.604, P = .004). On the PRT, performance significantly improved between test sessions (F1,29 = 57.252, P < .001) and from the single to the dual task (F1,29 = 7.673, P = .010). No differences were seen on the BESS and the PAT. Reliability across test sessions ranged from moderate to poor for outcome measure. CONCLUSIONS: The BESS appears to be a more reliable and functional tool in dual-task conditions as a result of its increased reliability and clinical applicability. In addition, the BESS is more readily available to clinicians than the SOT. PMID- 21828383 TI - The effects of anthropometric scaling parameters on normalized muscle strength in uninjured baseball pitchers. AB - CONTEXT: Muscle force must be normalized for between-subjects comparisons of strength to be valid. The most effective method for normalizing muscle strength has not, however, been systematically evaluated. OBJECTIVE: To evaluate the effects of normalizing muscle strength using a spectrum of anthropometric parameters. DESIGN: Cross-sectional. SETTING: Laboratory. PARTICIPANTS: 50 uninjured high-school-age baseball pitchers. INTERVENTIONS: Shoulder-rotation strength was tested at 0 degrees and 90 degrees abduction with a handheld dynamometer. Muscle force was normalized to parameters including subject height, weight, height * weight, body-mass index (BMI), forearm length, and forearm length * height. OUTCOME MEASURES: Statistical analysis included evaluating the coefficient of variation, skewness, and kurtosis of the nonnormalized and normalized muscle force. The most effective normalization method was determined based on the scaling factor that yielded the lowest variability for the data set and promoted the most normal distribution of the data set. RESULTS: Using body weight to scale muscle force was the most effective anthropometric parameter for normalizing strength values based on the group of statistical measures of variability. BMI, height * weight, and forearm length * weight as scaling factors also yielded less variable values for muscle strength compared with nonnormalized strength, but less consistently than body weight. Height and forearm length were least effective in reducing the variability of the data set relative to nonnormalized muscle force. CONCLUSION: This study provides objective support for scaling muscle strength to subject body weight. This approach to normalizing muscle strength uses methods readily accessible to clinicians and researchers and may facilitate the identification of differences in strength between individuals with diverse physical characteristics. PMID- 21828384 TI - Difference in response latency of the peroneus longus between the dominant and nondominant legs. AB - CONTEXT: The latency of the peroneus longus in response to an inversion perturbation is a key component in the prevention of lateral ankle sprains. In addition, the dominant ankle is sprained more frequently than the nondominant ankle, but the cause of this has not been examined. OBJECTIVE: To investigate the combination of these 2 research-supported statements, the purpose of this study was to use an inversion perturbation that replicates the mechanism of a lateral ankle sprain to determine whether there is a difference in the latency of the peroneus longus between the dominant and nondominant legs. DESIGN: Repeated measures single-group design. SETTING: University laboratory. PARTICIPANTS: 15 physically active healthy volunteers with no previous history of an ankle sprain or lower extremity surgery or fracture. INTERVENTIONS: Outer sole with fulcrum was used to cause 25 degrees of inversion at the subtalar joint on landing from a 27-cm step-down task. Participants performed 10 trials on both the dominant and nondominant leg. MAIN OUTCOME MEASURES: 2 latency measures of the peroneus longus of both the dominant and nondominant leg, calculated as the amount of time from the moment of touchdown of the fulcrum until muscle activity exceeded 5 and 10 SD above baseline muscle activity. RESULTS: The latency of the peroneus longus of the nondominant leg was significantly shorter when using both 5 SD (F1,14= 9.34, P = .009, d = .895) and 10 SD (F1,14= 18.56, P = .001, d = .920) above baseline muscle activity. CONCLUSIONS: This difference in latency may be a result of the different demands placed on the dominant and nondominant legs during activity and may predispose the dominant ankle to a greater number of ankle sprains than the nondominant ankle. PMID- 21828385 TI - Measurement of ankle dorsiflexion: a comparison of active and passive techniques in multiple positions. AB - CONTEXT: Limited ankle DF (DF) range of motion (ROM) resulting from restricted gastrocnemius and soleus mobility is associated with a variety of lower extremity pathologies. Several techniques are used clinically to measure ankle DF. OBJECTIVES: To evaluate the reliability and minimal detectable change of DF ROM measurement, determine whether there is a difference in measured DF between techniques, and quantify the electromyographic (EMG) activity of the soleus and tibialis anterior muscles associated with the techniques. DESIGN: Repeated measures. SETTING: Controlled laboratory setting. PARTICIPANTS: 39 healthy subjects, age 22-33. MAIN OUTCOME MEASURES: DF measurements using 5 different techniques including active and passive DF with the knee extended and flexed to 90 degrees and a modified lunge. EMG activity of the soleus and anterior tibialis muscles. RESULTS: Intrarater reliability values (ICC3,1) ranged from .68 to .89. Interrater reliability (ICC2,1) ranged from .55 to .82. ICCs were the greatest with the modified lunge. The minimal detectable change (MDC95) ranged from 6 degrees to 8 degrees among the different techniques. A significant difference in DF ROM was found between all methods. Measurements taken with active DF were greater than the same measures taken passively. The lunge position resulted in greater DF ROM than both active and passive techniques. EMG activity of the soleus was greater with active DF and the lunge than with passive DF. CONCLUSIONS: The modified lunge, which demonstrated excellent intrarater and interrater reliability, may best represent maximal DF. Active end-range DF was significantly greater than passive end-range DF when measured at either 0 degrees or 90 degrees knee flexion. Greater active DF was not explained by inhibition of the soleus. Finally, using the modified lunge, a difference between 2 measurements over time of 6 degrees or more suggests that a meaningful change has occurred. PMID- 21828386 TI - Cardiorespiratory responses during underwater and land treadmill exercise in college athletes. AB - CONTEXT: Underwater treadmill (UTM) exercise is being used with increased frequency for rehabilitation of injured athletes, yet there has been little research conducted on this modality. OBJECTIVE: To determine the cardiorespiratory responses of UTM vs land treadmill (LTM) exercise, particularly with respect to the relationship between heart rate (HR) and oxygen consumption (VO2). DESIGN AND SETTING: This quantitative original research took place in sports medicine and athletic training facilities at Wake Forest University. PARTICIPANTS: 11 Wake Forest University student athletes (20.8 +/- 0.6 y, 6 women and 5 men). INTERVENTION: All participants completed the UTM and LTM exercise testing protocols in random order. After 5 min of standing rest, both UTM and LTM protocols had 4 stages of increasing belt speed (2.3, 4.9, 7.3, and 9.6 km/h) followed by 3 exercise stages at 9.6 km/h with increasing water-jet resistance (30%, 40%, and 50% of jet capacity) or inclines (1%, 2%, and 4% grade). MAIN OUTCOME MEASURES: A Cosmed K4b2 device with Polar monitor was used to collect HR, ventilation (Ve), tidal volume (TV), breathing frequency (Bf), and VO2 every minute. Ratings of perceived exertion (RPE) were also obtained each minute. RESULTS: There was no significant difference between UTM and LTM for VO2 at rest or during any stage of exercise except stage 3. Furthermore, there were no significant differences between UTM and LTM for HR, Ve, Bf, and RPE on any exercise stage. Linear regression of HR vs VO2, across all stages of exercise, indicates a similar relationship in these variables during UTM (r = .94, y = .269x - 10.86) and LTM (r = .95, y = .291x - 12.98). CONCLUSIONS: These data indicate that UTM and LTM exercise elicits similar cardiorespiratory responses and that HR can be used to guide appropriate exercise intensity for college athletes during UTM. PMID- 21828387 TI - Comparison of the effects of ice and 3.5% menthol gel on blood flow and muscle strength of the lower arm. AB - CONTEXT: Soft-tissue injuries are commonly treated with ice or menthol gels. Few studies have compared the effects of these treatments on blood flow and muscle strength. OBJECTIVE: To compare blood flow and muscle strength in the forearm after an application of ice or menthol gel or no treatment. DESIGN: Repeated measures design in which blood-flow and muscle-strength data were collected from subjects under 3 treatment conditions. SETTING: Exercise physiology laboratory. PARTICIPANTS: 17 healthy adults with no impediment to the blood flow or strength in their right arm, recruited through word of mouth. INTERVENTION: Three separate treatment conditions were randomly applied topically to the right forearm: no treatment, 0.5 kg of ice, or 3.5 mL of 3.5% menthol gel. To avoid injury ice was only applied for 20 min. MAIN OUTCOME MEASURES: At each data-collection session blood flow (mL/min) of the right radial artery was determined at baseline before any treatment and then at 5, 10, 15, and 20 min after treatment using Doppler ultrasound. Muscle strength was assessed as maximum isokinetic flexion and extension of the wrist at 30 degrees /s 20, 25, and 30 min after treatment. RESULTS: The menthol gel reduced (-42%, P < .05) blood flow in the radial artery 5 min after application but not at 10, 15, or 20 min after application. Ice reduced (-48%, P < .05) blood flow in the radial artery only after 20 min of application. After 15 min of the control condition blood flow increased (83%, P < .05) from baseline measures. After the removal of ice, wrist-extension strength did not increase per repeated strength assessment as it did during the control condition (9-11%, P < .05) and menthol-gel intervention (8%, P < .05). CONCLUSIONS: Menthol has a fast-acting, short-lived effect of reducing blood flow. Ice reduces blood flow after a prolonged duration. Muscle strength appears to be inhibited after ice application. PMID- 21828388 TI - Reliability of isokinetic assessment of shoulder-rotator strength: a systematic review of the effect of position. AB - CONTEXT: Isokinetic assessment of shoulder internal-(IR) and external-rotator (ER) strength is commonly used with many different postures (sitting, standing, or supine) and shoulder positions (frontal or scapular plane with 45 degrees or 90 degrees of abduction). OBJECTIVE: To conduct a systematic review to determine the influence of position on the intersession reliability of the assessment of IR and ER isokinetic strength, to identify the most reliable position, and to determine which isokinetic variable appears to be most stable in intersession reliability. EVIDENCE ACQUISITION: A systematic literature search through MEDLINE and Pascal Biomed databases was performed in October 2009. Criteria for inclusion were that studies be written in English or French, describe the isokinetic evaluation methods, and describe statistical analysis. EVIDENCE SYNTHESIS: Sixteen studies meeting the inclusion criteria were included. Variable reliability of ER and IR peak torque (PT) were generally reported for all assessment positions; intraclass correlation coefficients were .44-.98 in the seated position with 45 degrees of shoulder abduction, .09-.77 in the seated position with 90 degrees of shoulder abduction, .86-.99 (coefficient of variation: 7.5-29.8%) in the supine position with 90 degrees of shoulder abduction, .82-.84 in the supine position with 45 degrees of shoulder abduction, and .75-.94 in standing. The ER:IR ratio reliability was low for all positions. CONCLUSIONS: The seated position with 45 degrees of shoulder abduction in the scapular plane seemed the most reliable for IR and ER strength assessment. The standing position or a shoulder posture with 90 degrees of shoulder abduction or in the frontal plane must be used with caution given the low reliability for peak torque. Good reliability of ER and IR PT was generally reported, but ER:IR ratio reliability was low. PMID- 21828389 TI - History of ankle sprain as a risk factor of future lateral ankle sprain in athletes. AB - Despite the attention and focus lateral ankle sprains receive in athletic training practice and research, they remain the most common injury in many sports. Whereas the functional limitations and time loss from lateral ankle sprains are apparent, consistently reducing their incidence is less certain. One important step in preventing lateral ankle sprains is identifying their risk factors. Although previous literature summaries suggest that specific risk factors are inconclusive in predicting lateral ankle sprains, recent literature investigating the predictors of ankle sprains should be included as evidence. Determining the primary risk factors for lateral ankle sprains may lead to good prevention programs, which in turn may decrease time lost because of injury. PMID- 21828390 TI - Transcatheter aortic valve implantation (TAVI) outcome according to standardized endpoint definitions by the Valve Academic Research Consortium (VARC). AB - BACKGROUND: Transcatheter aortic valve implantation (TAVI) has become an accepted treatment option for severe aortic stenosis (AS) in high-risk individuals. Yet, current results are difficult to compare given the lack of standardized definitions. METHODS AND RESULTS: TAVI was performed in 130 high-risk individuals. The Edwards SAPIEN (n = 50) and the Medtronic CoreValve (n = 80) prostheses were implanted by transfemoral (75%) or transapical (25%) access. Outcomes at 30 days and 1 year are reported according to the newly established Valve Academic Research Consortium (VARC) criteria. Median follow-up was 235 days (range, 44-490 days). Thirty-day device success was high (91.5%). Combined safety endpoint at 30 days was 20.8%, with an all-cause mortality of 11.5%. Major vascular complications (11.5%), life-threatening or disabling bleeding (8.5%), and acute kidney injury (6.2%) were further major adverse events. At 1-year follow-up, valve performance was accurate in 94.7% of patients. However, prosthetic-valve associated complications, such as new left bundle branch block (20.0%) or permanent pacemaker implantation (34.7%), were common; cumulative prosthetic-valve associated complications were significantly more frequent in patients treated with a Medtronic CoreValve prosthesis (p = 0.0012). Overall 1 year survival was 80%, with the VARC combined efficacy endpoint (composite of survival, freedom from therapy failure, and accurate valve performance) met in 70.2%. In particular, at 1 year, 68.5% of the patients were living independently at home. CONCLUSION: The newly established VARC standardized definitions are useful for TAVI outcome reporting. PMID- 21828391 TI - Transcatheter aortic valve implantation: comparing apples to apples. PMID- 21828392 TI - Routine invasive versus ischemia-guided strategy in patients with acute inferior ST-elevation myocardial infarction who received fibrinolytic therapy: a prospective randomized controlled pilot trial. AB - AIMS: We sought to compare a routine invasive strategy of early coronary angiography and intended revascularization, with an ischemia-guided strategy in patients with acute inferior ST-elevation myocardial infarction (STEMI) who received fibrinolytic therapy. METHODS: We enrolled 60 consecutive patients with acute inferior STEMI who received fibrinolytic therapy within 6 hours. Patients were randomly assigned to either a routine invasive strategy in which coronary angiography was performed within 48 hours with intended revascularization if eligible (Group A), or an ischemia-guided strategy in which catheterization was based on the presence of myocardial ischemia and viability as demonstrated by stress myocardial perfusion imaging (Group B). Patients were prospectively followed up for 6 months. The primary endpoint was a composite of cardiac death, recurrent myocardial infarction, recurrent ischemia or stroke at 6-month follow up. Total costs per patient were calculated over 6 months. RESULTS: The mean age of the whole series was 52 +/- 9.8 years (15% females). The primary endpoint occurred more frequently in group A as compared to group B, however, the difference did not meet statistical significance (36.7% versus 23.3%, respectively, p > 0.05). The mean cost per patient at 6-month follow-up was significantly higher in Group A as compared to that in Group B ($4953.5 +/- 3108.5 versus $2764.6 +/- 2636.7, respectively, p < 0.01). CONCLUSIONS: In patients presenting with inferior STEMI who received fibrinolytic therapy, a routine invasive strategy with early coronary angiography and intended revascularization, achieved a clinical outcome similar to an ischemia-guided strategy; yet, at a significantly higher cost. PMID- 21828393 TI - High incidence of inaccurate stent placement in the treatment of coronary aorto ostial disease. AB - OBJECTIVES: The purpose of this study was to evaluate the incidence of inaccurate stent positioning in the treatment of coronary aorto-ostial lesions. BACKGROUND: The percutaneous treatment of aorto-ostial disease is challenging, with a paucity of data describing the incidence of stent mispositioning. METHODS: We retrospectively reviewed the accuracy of stent positioning in 100 consecutive coronary aorto-ostial lesions. Using careful angiographic review, each stent placement was classified as "missed" (> 1 mm distal or proximal to the angiographically determined ostium) or "accurately" positioned. RESULTS: The true ostium was missed during stent placement in 54% of cases. In 52% of the misses, the stent was placed too proximally. This proximal miss was associated with an inability to coaxially re-engage the treated vessel in 93% of the cases. The stent was placed too distally in 48% of missed cases, resulting in a placement of one or more additional overlapping stents in 38% of those cases. Clinical follow up (mean, 24.5 +/- 12.9 months) was obtained in 98% of cases. Angiographic follow up prompted by recurrent chest pain or ischemia was performed in 45/100 cases. There was a three-fold increase in restenosis and target lesion revascularization (TLR) among the cohort of patients with stent misplacement (26% and 23%, respectively) compared to those with accurate stent placement (9% and 6%, respectively; p = 0.02 for both restenosis and TLR). CONCLUSIONS: Angiographically-guided stenting for coronary aorto-ostial disease leads to a high incidence of proximal and distal stent misplacement. Stent mispositioning is associated with significantly higher restenosis and clinically driven TLR compared to patients with accurate stent placement. PMID- 21828394 TI - What is the price for perfection for precise aorto-ostial stent placement? PMID- 21828395 TI - Long-term clinical outcome in STEMI patients treated with primary PCI and drug eluting or bare-metal stents: insights from a high-volume single-center registry. AB - OBJECTIVE: Use of drug-eluting stents (DES) in patients with ST-elevation myocardial infarction (STEMI) during routine primary percutaneous coronary intervention (pPCI) is controversial. METHODS: From January 2004 to July 2008, a total of 2,155 STEMI patients were treated with pPCI [DES or bare-metal stent (BMS)] at a single high-volume invasive center. We present 4-year outcomes in this observational registry study. RESULTS: A total of 1,725 were treated with DES and 430 with BMS. Patients treated with DES were younger and had more complex angiographic characteristics compared to BMS patients. Patients treated with DES had lower adjusted risk of target lesion revascularization (TLR) [hazard ratio (HR) = 0.68; 95% confidence interval (CI): 0.40-0.98; p = 0.04], but had a trend toward increased risk of definite stent thrombosis (HR = 1.96; 95% CI: 0.83-4.61; p = 0.12). No difference was found when evaluating all-cause mortality and non fatal myocardial infarction. CONCLUSIONS: In this study, we set out to evaluate the independent impact of DES or BMS treatment on long-term clinical outcomes in STEMI patients treated with pPCI in a real-life setting. DES use was associated with a reduced risk of TLR, but a trend toward increased risk of stent thrombosis was found. However, this safety issue did not translate into an increased risk of death or overall non-fatal myocardial infarction for DES patients. PMID- 21828396 TI - Drug-eluting or bare-metal stents in ST-elevation myocardial infarction: a growing dilemma or closer to an answer? PMID- 21828397 TI - Comparison of six-year clinical outcome of sirolimus- and paclitaxel-eluting stents to bare-metal stents in patients with ST-segment elevation myocardial infarction: an analysis of the RESEARCH (rapamycin-eluting stent evaluated at Rotterdam cardiology hospital) and T-SEARCH (taxus stent evaluated at Rotterdam cardiology hospital) registries. AB - BACKGROUND: Short- and long-term data showed that drug-eluting stents (DES) significantly decreased target vessel revascularization (TVR) and major adverse cardiac event (MACE) rates compared to bare-metal stents (BMS). However, conflicting long-term data remain for patients with ST-segment elevation myocardial infarction (STEMI). OBJECTIVE: Our aim was to assess the 6-year clinical outcome of all patients undergoing primary percutaneous coronary intervention (PPCI) for a de novo lesion with exclusive use of BMS, sirolimus eluting stents (SES) and paclitaxel-eluting stents (PES). METHODS: Three PPCI cohorts (BMS = 80; SES = 92; PES = 162) were systematically followed for the occurrence of MACE. RESULTS: Very late stent thrombosis was more common after the implantation of SES as compared to PES or BMS (7.6%, 0.6%, and 0.0%, respectively; p = 0.001). Kaplan-Meier estimates indicate no statistically significant difference for mortality between the three stent types at 6 years (BMS = 25%; SES = 15%; PES = 21%; Log-rank p = 0.2). After adjustment for differences in baseline characteristics, mortality, mortality/myocardial infarction (MI), and MACE rates were significantly lower for SES compared to BMS, but not for PES (aHR = 0.41, 95% CI: 0.17-0.98; aHR = 0.44, 95% CI: 0.21-0.96; aHR = 0.35, 95% CI: 0.17-0.72, respectively). No differences were observed between the three stent types for TVR rates. CONCLUSION: Neither SES nor PES improved safety or efficacy as compared to BMS in a STEMI population at 6 years. After adjusting, the usage of SES resulted in a significant decrease in mortality, mortality/MI and MACE rates as compared to BMS, in contrast to the usage of PES. SES and PES have a similar effectiveness and safety profile, although very late stent thrombosis was more common with SES. PMID- 21828398 TI - Long-term benefit using DES in STEMI patients. PMID- 21828399 TI - Percutaneous closure of aortocaval fistula using the amplatzer muscular VSD occluder. AB - Aortocaval fistula is an uncommon but often fatal complication of abdominal aortic aneurysm. Both open and endovascular repair of aortic aneurysm with aortocaval fistulae have been previously reported. We present the case of a patient with persistent aortocaval fistula after endovascular stent graft repair, which is closed using an Amplatzer muscular VSD occluder. Further studies using the Amplatzer muscular VSD occluder for closure of aortocaval fistulae are warranted. PMID- 21828400 TI - Pulseless right groin... bounding distal pulses. PMID- 21828401 TI - Aberrant anatomy: you see what you look for and you look for what you know. PMID- 21828402 TI - Post-transcoronary ethanol septal ablation (TESA) infective endocarditis complicated by a ventricular septal defect. AB - A 52-year-old man was referred to the cardiology outpatient service with exertional angina and shortness of breath due to hypertrophic obstructive cardiomyopathy. He underwent transcoronary ethanol septal ablation (TESA) with successful procedural outcome. The patient returned to hospital with a 3-week history of intermittent fever and a positive blood culture showing Staphylococcus aureus, sensitive to flucloxacillin. Transoesophageal echocardiography on admission demonstrated vegetation on interventricular septum and a repeated scan 10 days later demonstrated Doppler flow across the interventricular septum, confirming the presence of a small ventricular septal defect. This patient was successfully managed with 6 weeks of intravenous antibiotics and remained well at 1-year follow-up. PMID- 21828403 TI - Potential contribution of open-cell stent design to balloon entrapment and review of techniques to recover. AB - Balloon entrapment during coronary angioplasty is a rare but potentially disastrous complication of percutaneous coronary intervention (PCI), described during both angioplasty alone, as well as with stents. This report describes the case of an entrapped stent-balloon within an extremely calcified proximal left anterior descending artery (LAD) lesion, and reviews techniques and strategies that can be applied in similar situations. In this case, we suspect the open-cell design of the specific stent used, combined with the high radial force of the calcified lesion, led to a "pincer effect," and entanglement of the balloon material within the stent scaffolding. After exhaustion of all percutaneous options to retrieve the balloon, the patient was ultimately taken for urgent cardiac surgery for extraction of the balloon and vein patch of the LAD. PMID- 21828404 TI - Successful repair of a type 2 endoleak with coiling of inferior mesenteric artery. AB - BACKGROUND: One of the most common complications of endovascular aneurysm repair (EVAR) is type 2 endoleak. We describe a patient who presented with a recurrent endoleak despite initial intervention and was successfully treated with coil embolization of the inferior mesenteric artery (IMA). CASE REPORT: A 63-year-old Caucasian male was found to have a 7.5 cm abdominal aortic aneurysm (AAA) during a routine ultrasound of the kidneys. The patient successfully underwent EVAR with exclusion of the aneurysm sac. A computed tomographic (CT) scan was performed 30 days after the procedure, and showed presence of a large type 1a endoleak with slight enlargement of the sac. The endoleak was successfully repaired with 2 extension cuffs which resulted in resolution of the endoleak. A few months later, another CT scan was performed that showed a type 2 endoleak without enlargement of the sac; however, there was no reduction in the size of the sac. Multiplanar reconstruction was used and a small branch connecting the superior mesenteric artery (SMA) to the inferior mesenteric artery (IMA) through the marginal artery was found. A selective angiogram of the SMA was performed that showed filling of the aneurysm sac. A microcatheter was advanced through the SMA and marginal artery into the IMA. The IMA was occluded with coil embolization, resulting in resolution of the endoleak. CONCLUSION: Our case describes a patient who initially underwent treatment for type 1a endoleak and subsequently developed type 2 endoleak that was successfully treated with coil embolization of the IMA. PMID- 21828405 TI - Endovascular treatment of infrarenal aortic stenosis: importance of multimodality imaging. AB - We sought to describe the evolution in imaging and interventional options for endovascular treatment of significant infrarenal aortic stenosis. Balloon angioplasty and stent implantation for infrarenal aortic stenosis has generally required large-sized arterial access sheaths in the past, and was typically guided by visual size assessment. Computerized tomography angiography enables accurate preprocedural assessment of severity and extent of aortic atherosclerosis, degree of calcification, and luminal dimensions at both stenosis and reference sites, and visualizes possible aneurysm. Intraprocedural pressure gradient measurements evaluate the hemodynamic response to revascularization. On the other hand, intravascular ultrasound can further verify accuracy of equipment sizing. Small-profile stents and balloons can be used via small-sized sheaths, thereby rendering the procedure possible in patients with extensive peripheral arterial disease or small iliofemoral arteries. Improved non-invasive and intravascular imaging can guide with great accuracy infrarenal aortic stenosis procedures and may enable the use of reduced-size access sheaths and devices in fragile patients with vasculopathies. PMID- 21828406 TI - Primary malignant pericardial mesothelioma presenting as effusive-constrictive pericarditis. AB - Effusive-constrictive pericarditis is a clinical hemodynamic syndrome characterized by constriction of the heart by the visceral pericardium in the presence of a tense pericardial effusion. The hallmark of effusive-constrictive pericarditis is the persistence of elevated right atrial pressures and ventricular interdependence after relief of the elevated intrapericardial pressures. The present report discusses the unique case of a 46-year-old white female who presented with dyspnea on exertion and chest tightness in the setting of an effusive-constrictive pericarditis. The patient was subsequently diagnosed with primary malignant pericardial mesothelioma, an extremely rare neoplasm with a very poor prognosis. PMID- 21828407 TI - A case of combined percutaneous transfemoral mitral valvuloplasty and aortic valve implantation. AB - We present the case of an 83-year-old man who was admitted with New York Heart Association class III dyspnea and paroxysmal nocturnal dyspnea. Because of high surgical risk, a percutaneous treatment of both mitral and aortic valvulopathies was planned. This case reports the feasibility of a totally percutaneous approach in combined rheumatic mitral and aortic valve disease for patients with prohibitive surgical risk. PMID- 21828408 TI - Hypotension during carotid artery stenting with severe aortic stenosis: the intra aortic balloon pump option. AB - This case highlights the importance of intra-aortic balloon pump (IABP) during carotid artery stenting (CAS) in patients with severe aortic stenosis. We report the case of a patient with severe carotid artery disease and aortic stenosis who first underwent CAS using IABP and subsequently underwent aortic valve replacement. We conclude that IABP could be helpful in the staged treatment of patients with concomitant severe carotid artery disease and aortic valve disease. PMID- 21828409 TI - Pharmacomechanic approach for restoration of flow in occluded ectatic right coronary artery with huge thrombus burden. AB - Advancements in both pharmacological and mechanical approaches have taken place to deal with thrombus-containing lesions in the coronary tree. We describe a case wherein a totally occluded large ectatic right coronary artery with a large thrombus burden was successfully revascularized by a combined pharmacological mechanical approach, resulting in complete disappearance of the thrombi without distal embolization. PMID- 21828411 TI - Positive ion chemistry of SiH4/GeF4 gaseous mixtures studied by ion trap mass spectrometry and ab initio calculations. AB - The positive ion chemistry occurring in SiH(4)/GeF(4) gaseous mixtures was investigated by ion trap mass spectrometry and ab initio theoretical calculations. The GeF(3)(+) cation, the only fragment obtained from ionized GeF(4), was unreactive towards SiH(4). All the primary ions SiH(n)(+) (n = 0-3) react instead with GeF(4) so to form SiF(+) or SiH(2)F(+). The latter species reacts in turn with SiH(4) and GeF(4) so to form SiH(3)(+) and SiHF(2)(+), respectively. The potential energy profiles conceivably involved in these reactions were investigated by ab initio calculations performed at the MP2 and coupled cluster (CCSD(T)) level of theory. PMID- 21828410 TI - Very late bare-metal stent thrombosis, rare but stormy! AB - Recurrent in-stent thrombosis is rarely reported, with catastrophic clinical consequences of either acute coronary syndrome or death. We present a case of recurrent in-stent thrombosis with its outcome and a concise literature review. PMID- 21828412 TI - Study of metal ion labeling of the conformational and charge states of lysozyme by ion mobility mass spectrometry. AB - The efficiency of Zn(2+), Cu(2+), Ni(2+), Co(2+), Fe(2+) or Mn(2+) labeling of the conformational and charge states of lysozyme was studied in H(2)O solvent at pH 2.5-6.8. Labeling of lysozyme was conducted with 50 M, 100 M and 500 M excess of the metal ion, resulting in the number of metal ions attached to lysozyme increasing two-fold over this range. At pH 6.2-6.8, Zn(2+), Cu(2+), Ni(2+), Co(2+) and Mn(2+) labeled the highly folded 7+ conformer and the 8+ and 9+ partially unfolded conformers of lysozyme with the same number of metal ion tags, with only Fe(2+) exhibiting no labeling. Lysozyme conserved its charge after metal ion labeling which shows at each charge state the divalent metal ion is replacing two protons. As the pH is lowered to 4.7-5.0 and 2.5-2.9, the labeling of lysozyme by Zn(2+), Cu(2+), Ni(2+), Co(2+) or Mn(2+) decreased in efficiency due to increased competition from protons for the aspartate and glutamate binding sites. The metal ions preferentially labeled the highly folded 7+ and partially unfolded 8+ conformers, but labeling decreased as the charge of lysozyme increased. In contrast to the other metal ions, Fe(2+) exhibited labeling of lysozyme only at the lowest pH of 2.8. At higher pH, the oxidation of Fe(2+) and formation of hydroxy-bridged complexes probably make the Fe(2+) unreactive towards lysozyme. PMID- 21828413 TI - Rapid detection and identification of impurities in ten 2-naphthalenamines using an atmospheric pressure solids analysis probe in conjunction with ion mobility mass spectrometry. AB - The atmospheric pressure solids analysis probe (ASAP), in conjunction with ion mobility time-of-flight mass spectrometry (IM-ToF-MS), has been applied to the impurity profiling study of ten 2-naphthalenamines. The impurity profiles achieved by ASAP-IM-MS were compared with those obtained by liquid chromatography electrospray ionisation-mass spectrometry (LC-ESI-MS). All the impurities at the level of 0.1 area % and above, except for one, detected by LC-ESI-MS, were also found by ASAP-IMS analyses. In addition, one non-polar compound was detected by ASAP-IM-MS alone. The IM-MS plot of ion drift time versus m/z values offered sufficient separation between the impurities with different m/z. Therefore, instead of LC as a separation tool, IM-MS is able to provide fingerprint profiling for the ten samples analysed. The time of each analysis has been reduced from 25 min by LC-MS to less than 3 min by ASAP-IM-MS. When collision energy was applied for the selected precursor ion in the transfer T-wave, a clean MS/MS spectrum was obtained for structural elucidation of unknown impurities. The hyphenation of ASAP and IM-MS techniques represents a highly efficient approach for rapid detection and identification of impurities generated in complex reactions involved in pharmaceutical development. PMID- 21828414 TI - Electron ionization mass spectral study of oxo- and thio derivatives of minor tobacco alkaloids. AB - The electron-ionization mass spectra (EI-MS) of oxo- and thio-derivatives of minor tobacco alkaloids and structurally similar piperidine alkaloids, i.e. thiocotinine (1), 2'-oxo-N-methylanabasine (2), 2'-thio-N- methylanabasine (3), 2'-oxoanabasamine (4) and 2'-thioanabasamine (5) are discussed and general fragmentation routes of their molecular cations are proposed. Comparison of the data obtained for 1 with the EI-MS data of metameric metabolites of nicotine: 3' hydroxycotinine, (A) and 5'-hydroxycotinine, (B) allows a differentiation between these metamers. The data will be useful for the identification of metabolites of alkaloids of these types in biological matrices. PMID- 21828415 TI - Urinary peptides as a diagnostic tool for renal failure detected by matrix assisted laser desorption/ionisation mass spectrometry: an evaluation of their clinical significance. AB - The development of new analytical methodologies related to the proteome for the evaluation of renal physiology and pathology is surely of wide interest for physicians, giving them new tools for monitoring complications associated with diabetes, such as end-stage renal disease. In the present study, the clinical significance of the urinary abundance of two peptides, SGSVIDQSRVLNLGPITR (the uromodulin precursor, m/z 1912) and IGPHypGPHypGLMGPP [present in the collagen alpha-5(IV) chain precursor, m/z 1219], detected by matrix- assisted laser desorption/ionisation mass spectrometry (MALDI/MS) in microalbuminuric or nephropathic diabetic patients and in non-diabetic nephropathic patients was evaluated. A progressive increase in the abundance of the ion at m/z 1219 and a decrease in the abundance of the ion at m/z 1912 have been found in diabetic microalbuminuric, diabetic-nephropathic and nephropathic patients. Linear correlations are present between serum creatinine values and the abundances of the ions at m/z 1219 (positive correlation, r=0.3645, P<0.0001) and at m/z 1912 (negative correlation, r=-0.3053, P<0.0005). Correlations between the MALDI data and the estimated glomerular filtration rate were also found, while relationships with urinary albumin excretion were found only in sub-sets of patients. Analysis of receiver operating characteristic curves showed a sensitivity up to 96% and a specificity of up to 84% for the two ionic species, or their ratio, for distinguishing diabetic patients with different degrees of nephropathy from healthy subjects, proving that the urinary abundance of the two peptides at m/z 1219 and m/z 1912, determined with MALDI/MS, may be considered as a possible diagnostic tool for the determination of progression toward renal failure, also with the aim of monitoring kidney function, in diabetic patients. PMID- 21828416 TI - Pre-electrospray ionisation manifold methylation and post-electrospray ionisation manifold cleavage/ion cluster formation observed during electrospray ionisation of chloramphenicol in solutions of methanol and acetonitrile for liquid chromatography-mass spectrometry employing a commercial quadrupole ion trap mass analyser. AB - We have observed unusual mass spectra of chloramphenicol (CAP) in solutions of methanol or acetonitrile showing intense ions at m/z 297, m/z 311, m/z 325 and m/z 339. The observed ions were different from those which are traditionally observed in the full scan ESI mass spectra of CAP with ions of m/z 321, m/z 323 and m/z 325. We have evidence to show that this process starts with offline methylation of CAP in solutions of methanol or acetonitrile to give m/z 339. Investigations using nuclear magnetic resonance (NMR) spectroscopy showed that there is a methylene group somewhere within the CAP molecule but not attached to any of the carbon atoms when the CAP is dissolved in methanol or acetonitrile before infusion into the mass spectrometer. The possible locations of attachment were speculated to be the electronegative atoms apart from the chlorine atoms due to valence considerations. The methylene group is attached to the nitrogen atom and forms a bond as observed in the MS/MS spectra of m/z 297, m/z 311, m/z 325 and m/z 339 which give m/z 183 as the base peak in all cases. Further experiments showed that there is cleavage of the methylated CAP molecule followed by cluster ion formation involving addition of methylene groups to the CAP fragment with m/z 183 to produce ions of m/z including m/z 297, m/z 311, m/z 325 and m/z 339. This process occurs in the mass spectrometer in the region housing the tube lens and is triggered when the ions are accelerated through this region by application of a negative tube lens offset voltage. This region affords collision of the charged droplets with a collision gas in this case nitrogen to strip the droplets of their solvent molecules. Experiments to follow the intensities of m/z 183, m/z 311, m/z 321, m/z 323, m/z 325 and m/z 339 as the tube lens offset voltage was varied were done in which the intensities of m/z 311, m/z 325 and m/z 339 were observed to be at their peak when the tube lens offset voltage was set at -40 V. When the tube lens offset voltage is swung to +40 V, thus decelerating the ions through the capillary skimmer region via the tube lens, the traditionally observed spectra with m/z 321, m/z 323 and m/z 325 were observed. PMID- 21828417 TI - Identification of indole alkaloids in Nauclea officinalis using high-performance liquid chromatography coupled with ion trap and time-of-flight mass spectrometry. AB - Indole alkaloids from Nauclea officinalis (Pierra ex Pitard) Merr are prospective agents for inflammation- related diseases. To speed up the process of discovering such bioactive compounds from natural origins, a mass spectrometry-based method was developed to screen N. officinalis for the presence of indole alkaloids. First, representative alkaloids were purified from herbs and analyzed using an ion trap (IT) mass spectrometer. Multi-stage mass spectra (MS(n))were utilized to establish the characteristic fragmentation pathways of indole alkaloids. It was shown that their fragmentation behaviors were correlated with the degree of unsaturation on ring-D of such alkaloids: if there is a double bond between C-3 and C-14, no fragments of ring cleavage are observed; otherwise, a fragment ion after reverse Diels-Alder cleavage of ring-D is observed as the base peak in their tandem mass spectrometry data. Then, herbal extracts of N. officinalis were analyzed using a combination of high- performance liquid chromatography (HPLC)/IT and HPLC/time-of-flight (ToF) systems. The structures of suspected alkaloids were deduced based on the accurate mass information from ToF and MS(n) from IT. Finally, a total of 10 indole and one indolizidine alkaloids were identified or tentatively characterized in extracts of N. officinalis. This work has demonstrated that the combination of MS(n) and ToF-MS can be used for rapid identification of monoterpenoid indole alkaloids in N. officinalis. PMID- 21828418 TI - Letter: Electrospray ionization mass spectral characteristics and fragmentation mechanisms of triterpenoids in Fomes officinalis. AB - The electrospray ionization tandem mass spectrometric characteristics and fragmentation mechanisms of 12 triterpenoid compounds from Fomes officinalis (F. officinalis) and their analogs were investigated. The compounds could be classified into three types depending on their chemical structures. All of the compounds gave [M-H](-) and [2M-H](-) ions by electrospray negative ionization mode. In addition, the members of three isomeric groups of the analogs with the same elemental composition can be distinguished by tandem mass spectra of protonated molecules and of significant fragmention. The above fragmentations were reported for the first time and were implemented for the analysis of triterpenoids in F. officinalis. PMID- 21828419 TI - Electron ionization and electrospray mass spectra of diaryl-substituted enaminoketones and their thio analogs. AB - Electron ionization (EI) and positive electrospray ionization (ESI) mass spectra of selected diaryl enaminoketones and enaminothiones have been studied. In the EI mass spectra of both classes of compound, molecular ion peaks are accompanied by the peaks corresponding to the [M-H](+) ions. The formation of these ions can be rationalized by a cyclization reaction resulting in the formation of the respective isoxazolium and isothiazolium cations. Under positive ESI conditions, in the spectra recorded for the enaminoketones peaks corresponding to the [M+H](+), [M+Na](+) and [2M+Na](+) ions appeared, while in the spectra recorded for the enaminothiones, peaks corresponding to the [M-H](+) ions were dominant. These ions are most likely formed by oxidation of the neutral enaminothione molecules on the surface of the positively charged stainless steel capillary in the ESI ion source (anodic oxidation). PMID- 21828420 TI - Differentiation of diasteromeric alpha-sulfanyl-beta-amino acid derivatives by electrospray ionization tandem mass spectrometry. AB - A set of diastereomeric alpha-sulfanyl-beta-amino acid derivatives, which are important building blocks for pharmaceuticals with potent biological activity, are studied by electrospray ionization tandem mass spectrometry. The collision induced dissociation (CID) spectra of [M+H](+), [M+NH(4)](+), [M+Na](+) and [M+Li](+) of the diastereomers were studied, among them the CID of [M+Na](+) and [M+Li](+) showed consistent differences in the relative abundance of characteristic ions that enabled distinction of the anti isomers from syn isomers. The decomposition pathways for the diagnostic ions were arrived at based on high-resolution mass spectrometry data, multiple mass spectrometry data, deuterium labeling experiments and the mass shift in accordance with the substituents located at different places. Loss of (R(1)-C(6)H(4)-CH=NH) and (Cat NH-SO(2)R(2)) from [M+Cat](+), where Cat=Na and Li, and the product ions as a results of McLafferty rearrangement involving either >S=O or >C=O group were found to be diagnostic. The McLafferty rearrangement product ions involving >S=O group were more abundant in syn isomers while those involving >C=O group were more abundant in anti isomer. The selectivity observed in the decomposition of [M+Li](+) ions was found to be similar to that of [M+Na](+) ions, but in few cases the differences are marginal in the decomposition [M+Li](+) ions. PMID- 21828421 TI - Delapril and manidipine measurements by liquid chromatography-tandem mass spectrometry in a pharmaceutical formulation. AB - A simple, specific, fast and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous analysis of delapril (DEL) and manidipine (MAN) from their combination formulation was developed and validated using fesoterodine as the internal standard (IS). The LC-MS/MS method was carried out on a Luna C8 column (50 * 3.0 mm i.d., 3 um) with a mobile phase consisting of methanol and 10 mmol L(-1) ammonium acetate (90 : 0, v/v), run at a flow rate of 0.25 mL min(-1). The mass spectrometry method was performed employing positive electrospray ionization operating in multiple reaction monitoring mode, monitoring the transitions of m/z 453.1 -> 234.1 for DEL, m/z 611.1 -> 167.0 for MAN and m/z 412.2 -> 223.0 for IS. The total analysis time was 3 min and the method was linear in the concentration range of 6-1080 ng mL(-1) and 2-360 ng mL(-1) for DEL and MAN, respectively. Parameters investigated for the method validation, such as the specificity, linearity, precision, accuracy and robustness, gave results within the acceptable range. Moreover, the proposed method was successfully applied for the simultaneous determination of DEL and MAN and the results were compared to validated liquid chromatography and capillary electrophoresis methods showing non-significant differences (P = 0.9). PMID- 21828422 TI - Specific heat anomalies for [Formula: see text] in superconducting single crystal doped BaFe(2)As(2): comparison of different flux growth methods. AB - One way to address the nature of the superconductivity in the new iron pnictides is to measure the low temperature specific heat in the superconducting state, where the temperature, field, and angular dependences of the specific heat each give important information. We report on an initial study of the specific heat down to 0.4 K in single crystals of Ba(0.6)K(0.4)Fe(2)As(2), T(c) = 32 K, prepared via Sn-flux and In-flux methods and compare to literature data for samples prepared using the self-flux method. We also report on the specific heat in zero and 1 T applied magnetic fields of Ba(Fe(0.926)Co(0.074))(2)As(2), T(c) = 22 K, prepared via the In-flux method. All samples show upturns in the specific heat divided by temperature below 2 K, with the upturn in the Sn-flux sample starting already at 4 K. These upturns, which are strongly dependent on the preparation method, impede determination of the intrinsic properties. PMID- 21828423 TI - Superconductivity in CVD diamond films. AB - A beautiful jewel of diamond is insulator. However, boron doping can induce semiconductive, metallic and superconducting properties in diamond. When the boron concentration is tuned over 3 * 10(20) cm(-3), diamonds enter the metallic region and show superconductivity at low temperatures. The metal-insulator transition and superconductivity are analyzed using ARPES, XAS, NMR, IXS, transport and magnetic measurements and so on. This review elucidates the physical properties and mechanism of diamond superconductor as a special superconductivity that occurs in semiconductors. PMID- 21828424 TI - Spin-Hall effect and spin-Coulomb drag in doped semiconductors. AB - In this review, we describe in detail two important spin-transport phenomena: the extrinsic spin-Hall effect (coming from spin-orbit interactions between electrons and impurities) and the spin-Coulomb drag. The interplay of these two phenomena is analyzed. In particular, we discuss the influence of scattering between electrons with opposite spins on the spin current and the spin accumulation produced by the spin-Hall effect. Future challenges and open questions are briefly discussed. PMID- 21828425 TI - Upper critical magnetic fields in superconductor/ferromagnet hybrids. AB - We measured parallel upper critical magnetic fields in Nb/PdNi and Nb/CuNi bilayers and Nb/PdNi/Nb and Nb/CuNi/Nb trilayers. In the bilayers case the measurements reveal a dependence of the reduced two-dimensional-three-dimensional crossover temperature, t(cr) = T(cr)/T(c), on the different values of the superconductor (S)/ferromagnet (F) interface transparencies. In the case of the trilayers we observe that the reduced crossover temperature as a function of the ferromagnetic layer thickness, d(F), reaches a value equal to one only when the pi-phase occurs in these systems. Also in this case the influence of the interface transparency on the observed results is discussed. PMID- 21828426 TI - Change of the effective dimensionality of an Nb/CuNi bilayer in an external magnetic field. AB - A dimensional crossover of superconducting fluctuations in an external magnetic field, applied parallel to the layers, has been found for superconductor/ferromagnet bilayers of Nb/Cu(41)Ni(59). By lowering the temperature, a reduction of the superconducting nuclei size occurs. As soon as the size of the nuclei becomes smaller than the thickness of the superconducting bilayer structure, the dimensionality changes. The temperature dependence of the fluctuation conductivity exhibits a 2D behaviour in zero and weak magnetic fields in the vicinity of the critical temperature, switching to a 3D behaviour in a strong magnetic field at low temperatures. PMID- 21828427 TI - Is the nature of itinerant ferromagnetism playing a role in the competition between spin polarization and singlet pair correlations? AB - We consider the competition between spin singlet pairing and itinerant ferromagnetism whose magnetization is yielded by a relative shift of the bands with opposite spin polarization or by asymmetric spin-dependent bandwidths. Within the framework of the exact solution of an extended version of the reduced BCS model, the structure of the coexisting state is shown to have general features that are not related to the character of the ferromagnetism. The role of different types of ferromagnet is then investigated for the proximity effect in a system made of a bilayer junction with a spin singlet superconductor interfaced with a ferromagnet in the clean limit. We show that the qualitative behaviour of the proximity effect does not depend on the nature of the ferromagnetism. Differences emerge at the borderline with the half-metallic regime. For the spin dependent bandwidth type of ferromagnetism the pairing amplitude exhibits an oscillating behaviour until the density of the minority spin carrier becomes almost zero. The crossover from an oscillating to an exponentially damped profile occurs away from the half-metallic limit when a spin exchange type ferromagnet is considered. PMID- 21828428 TI - Rocking ratchets in nanostructured superconducting-magnetic hybrids. AB - Two rectification mechanisms in vortex lattice dynamics in Nb films have been studied. These two effects are based on ratchet effects, that is, an ac driving force induces a net dc vortex flow. In our case, an input ac current applied to the Nb films, grown on top of arrays of Ni nanotriangles, yields an output dc voltage. These two rectification effects occur when the vortex lattice moves in periodic asymmetric potentials. These pinning potentials are induced by the array of Ni triangles. In one configuration (longitudinal effect) the driven force is applied perpendicular to the triangle reflection symmetry axis; in the second one (transverse effect) the input current is injected parallel to the triangle reflection symmetry axis. In the framework of the rocking ratchet mechanism, the appropriate Langevin equation allows us to model the experimental data, taking into account the vortex-vortex interaction. PMID- 21828429 TI - Structural, electrical and magnetic characterization of artificial ferromagnetic/superconducting (La(0.7)Ca(0.3)MnO(3)/YBa(2)Cu(3)O(7-x)) heterostructures. AB - The fabrication and characterization of superconducting and ferromagnetic heterostructures is an open field due to the fundamental interest in the physics of the coexistence of these two competing orders and their possible applications in the spintronics industry. In this paper we present structural, electrical and magnetic characterization for the single La(0.7)Ca(0.3)MnO(3) (LCMO) thin layer, La(0.7)Ca(0.3)MnO(3)/YBa(2)Cu(3)O(7-x) (LCMO/YBCO) bilayers and the LCMO/YBCO/LCMO trilayers. In particular, we show a detailed magnetic characterization of the LCMO thin films by means of low temperature magnetic force microscopy. We discuss the different dynamics of the magnetic domains observed, depending on the substrate induced strain and on the film thickness. PMID- 21828430 TI - Superconducting-magnetic heterostructures: a method of decreasing AC losses and improving critical current density in multifilamentary conductors. AB - Magnetic materials can help to improve the performance of practical superconductors on the macroscale/microscale as magnetic diverters and also on the nanoscale as effective pinning centres. It has been established by numerical modelling that magnetic shielding of the filaments reduces AC losses in self field conditions due to decoupling of the filaments and, at the same time, it increases the critical current of the composite. This effect is especially beneficial for coated conductors, in which the anisotropic properties of the superconductor are amplified by the conductor architecture. However, ferromagnetic coatings are often chemically incompatible with YBa(2)Cu(3)O(7) and (Pb,Bi)(2)Sr(2)Ca(2)Cu(3)O(9) conductors, and buffer layers have to be used. In contrast, in MgB(2) conductors an iron matrix may remain in direct contact with the superconducting core. The application of superconducting-magnetic heterostructures requires consideration of the thermal and electromagnetic stability of the superconducting materials used. On one hand, magnetic materials reduce the critical current gradient across the individual filaments but, on the other hand, they often reduce the thermal conductivity between the superconducting core and the cryogen, which may cause destruction of the conductor in the event of thermal instability. A possible nanoscale method of improving the critical current density of superconducting conductors is the introduction of sub-micron magnetic pinning centres. However, the volumetric density and chemical compatibility of magnetic inclusions has to be controlled to avoid suppression of the superconducting properties. PMID- 21828431 TI - Magnetic field and temperature dependence of the critical vortex velocity in type II superconducting films. AB - We study the vortex dynamics in the instability regime induced by high dissipative states well above the critical current in Nb superconducting strips. The magnetic field and temperature behavior of the critical vortex velocity corresponding to the observed dynamic instability is ascribed to intrinsic non equilibrium phenomena. The Larkin-Ovchinnikov (LO) theory of electronic instability in high velocity vortex motion has been applied to interpret the temperature dependence of the critical vortex velocity. The magnetic field dependence of the vortex critical velocity shows new features in the low-field regime not predicted by LO. PMID- 21828432 TI - Nonlinear effects at high flux-flow electric fields. AB - Ohm's law with the linear relation between resistive voltage and electric current is strictly valid only in the limit of infinitesimally small voltages. On the other hand, at finite electric voltages nonlinearities in the electric resistance can develop due to the energy picked up by the charge carriers in the electric field. This can lead to important effects both in the case of semiconductors and of superconductors, where the energy rise of the charge carriers or the quasiparticles can become relatively large. In this paper we limit our discussion to the flux-flow voltage in the mixed state of a type-II superconductor. At sufficiently low temperatures the energy dependence of the quasiparticle density of states and, hence, of the quasiparticle scattering rate can cause distinct nonlinear effects in the flux-flow resistance. The recent advances in thin-film sample preparation provided new opportunities for observing nonlinear effects of the latter kind. PMID- 21828433 TI - Strong antiferromagnetic correlation effects on the momentum distribution function of the Hubbard model. AB - Strong antiferromagnetic correlations can radically change the behavior of an otherwise paramagnetic system, inducing anomalous effects in the single particle properties and driving the behavior of spin-spin response functions. In order to investigate such physics, we have studied the momentum distribution function of the two-dimensional Hubbard model at low doping, low temperatures and high values of the on-site Coulomb repulsion. The interpretation of the results has greatly benefited from the parallel analysis of the filling, temperature and interaction dependences of the spin-spin correlation function, the antiferromagnetic correlation length and the pole of the spin-spin propagator. On reducing doping or temperature and on increasing the interaction strength, the correlations become stronger and stronger and the Fermi surface develops hole and electron pockets and shows a dual nature (small-large). PMID- 21828434 TI - Effect of chemical composition on superconductivity and magnetism in layered ruthenocuprates. AB - The ruthenium-based layered cuprates RuSr(2)GdCu(2)O(8) (RuGd1212) can be considered naturally occurring magnetic and superconducting multilayer systems. We have concentrated on the preparation of RuGd1212-type compounds with nominally stoichiometric composition under ambient pressure conditions. For small rare earth ions R = Gd, Eu (and Sm), single phase compounds are obtained with the typical ordered layered structure and no significant changes of physical properties. With large rare earth ions (R = Nd, Pr), multiphase samples are obtained. In these cases, no ordered layered structure was observed. The effect of substituting Sr(2+) with the smaller Ca(2+) and larger Ba(2+) is examined. A different number and different types of phases in equilibrium are found with different alkaline earths (A = Ca, Sr, Ba) at the nominal RuA(2)NdCu(2)O(8) composition. The variation in the mismatch of the A/Nd size does not lead to the formation of an ordered layered RuA(2)NdCu(2)O(8) compound. Chemical transport in an open system was used to vary the Ru content in the RuGd1212 samples during the annealing step. With an increase of the Ru mass transport to the sample, the composition can be driven beyond the limit of the homogeneity range. Systematic changes in the phase composition of the resulting sample were observed. The magnetic and superconducting transition temperatures vary in a systematic way and are attributed to a variation of the Ru content in the RuR1212 phase. PMID- 21828435 TI - Structure, morphology and composition of natural junctions of Sr(2)RuO(4) Sr(3)Ru(2)O(7) eutectic crystals. AB - A detailed study of morphological, compositional and structural aspects of Sr(2)RuO(4)-Sr(3)Ru(2)O(7) eutectic crystals is reported. The stoichiometry of the phases that compose the crystals and how they are arranged in the crystals are studied. Understanding the behavior at the Sr(2)RuO(4)-Sr(3)Ru(2)O(7) interface represents a necessary prerequisite for the analysis of the experimental results on the transport properties recently reported in the literature. PMID- 21828436 TI - NMR and spin relaxation in systems with magnetic nanoparticles: effects of size and molecular motion. AB - To better understand the specifics of nuclear magnetic resonance and spin relaxation in systems with magnetic nanoparticles and test the limits of the outer sphere model for the diffusion-related relaxation, iron oxide nanoparticle suspensions are studied in dependence on the particle concentration and size (5 40 nm). The model is modified to account for aggregation of the particles into clusters with an enlarged effective radius. For liquid suspensions containing small particles or clusters, both the longitudinal and transverse spin relaxation rates, T(1)(-1) and T(2)(-1), correspond well to the theory, which predicts passing of T(1)(-1) through a maximum and monotonic increase in T(2)(-1) with increasing particle size. For the largest particle sizes, as well as in the case of strong aggregation, the relaxation rates are significantly lower than theoretical predictions. An abrupt change in both the relaxation rates is observed in a narrow temperature range around the melting point of paraffin wax doped with magnetic nanoparticles. The applicability of fast-motion and fast diffusion approximations is discussed for large effective sizes and limiting molecular motion cases. PMID- 21828437 TI - On the origin of the differences in the Cu K-edge XANES of isostructural and isoelectronic compounds. AB - Cu K-edge x-ray absorption near-edge structure (XANES) spectra of trigonal (3R) CuScO(2) and CuLaO(2) and of hexagonal (2H) CuScO(2) were investigated experimentally and theoretically, in order to study differences between spectra of isostructural and isoelectronic compounds. Significant differences were found in the Cu K-edge XANES of 3R CuScO(2) and 3R CuLaO(2); these differences can be understood by considering the calculated polarization dependence of the XANES spectra and the differences between the phaseshifts of Sc and La. Spectra of the 3R and 2H polytypes of CuScO(2) differ only weakly and the difference originates from the long-range order. The pre-edge peak around 8980 eV is generated by the same mechanism as the pre-edge peak in Cu(2)O, i.e. involving scattering by the Cu atoms in the plane which is perpendicular to the O-Cu-O axis. PMID- 21828438 TI - Spectroscopy and crystal-field analysis of KY(3)F(10):Ho(3+). AB - A laser excitation and infrared absorption study of the single C(4v) symmetry centre in KY(3)F(10):Ho(3+) is presented. Comparatively weak upconversion fluorescence is observed and can be attributed to an energy-transfer excitation mechanism proposed previously. Fifty one crystal-field energy levels for seven Ho(3+) multiplets ((5)I(8), (5)I(7), (5)I(6), (5)F(5), (5)S(2), (5)F(4) and (5)F(3)) have been deduced. A crystal-field analysis has been performed, with excellent agreement found between experimental and calculated energy levels. PMID- 21828439 TI - First-principles study of crystalline and amorphous Ge(2)Sb(2)Te(5) and the effects of stoichiometric defects. AB - Based on ab initio molecular dynamics simulations, we investigated the structural, electronic and vibrational properties of cubic and amorphous Ge(2)Sb(2)Te(5) (GST) phase change material, focusing in particular on the effects of defects in stoichiometry on the electronic properties. It turned out Ge/Sb deficiencies (excess) in the cubic phase induce a shift of the Fermi level inside the valence (conduction) bands. In contrast, the amorphous network is flexible enough to accommodate defects in stoichiometry, keeping the Fermi level pinned at the center of the bandgap (at zero temperature). Changes in the structural and electronic properties induced by the use of hybrid functionals (HSE03, PBE0) instead of gradient corrected functionals (PBE) are addressed as well. Analysis of vibrational spectra and Debye-Waller factors of cubic and amorphous GST is also presented. PMID- 21828440 TI - Superconducting pairing symmetry and energy gaps of the two-orbital t-t'-J-J' model: comparisons with the ARPES experiments in iron pnictides. AB - Motivated by the discovery of the iron-based superconductors, we present the theoretical results on the superconducting phase diagram, the temperature dependent Fermi surface structures in normal state and the angle-resolved photoemission spectroscopy (ARPES) character of quasiparticles of the two-orbital t-t'-J-J' model. In the reasonable physical parameter region of LaFeAsO(1-x)F(x), we find the superconducting phase is stable, and the pairing symmetry is weakly anisotropic and nodeless d(x(2)-etay(2))+S(x(2)y(2))-wave, qualitatively in agreement with the ARPES experiments in iron pnictide superconductors. Nevertheless, the two ratios of the energy gaps to T(c) deviate from the ARPES data, suggesting that a more elaborate theoretical model is needed. PMID- 21828441 TI - Density of states for dilute nitride systems: calculation of lifetime broadening. AB - We present calculations for the band structure of bulk and confined quantum well and quantum wire GaInNAs structures. To treat this non-randomly alloyed material system we follow previous approaches in using an Anderson impurity model where the nitrogen localized states interact with the GaInAs conduction band states. We solve this model using Matsubara Green's functions and the associated self energies which produce a complex band structure where both the real and imaginary components depend on the concentration of nitrogen. In particular this approach gives a definite nitrogen dependent lifetime broadening and is different from previous work in that no artificial input parameters are used. The density of states of the conduction band, derived from these functions, is strongly altered by interaction with the nitrogen states. The density of states is required for further optical and transport investigations involving this system. PMID- 21828442 TI - Near-surface nanoscale InAs Hall cross sensitivity to localized magnetic and electric fields. AB - We have measured the room temperature response of nanoscale semiconductor Hall crosses to local applied magnetic fields under various local electric gate conditions using scanning probe microscopy. Near-surface quantum wells of AlSb/InAs/AlSb, located just 5 nm from the heterostructure surface, allow very high sensitivity to localized electric and magnetic fields applied near the device surfaces. The Hall crosses have critical dimensions of 400 and 100 nm, while the mean free path of the carriers is about 160 nm; hence the devices nominally span the transition from diffusive to quasi-ballistic transport. With certain small gate voltages (V(g)) the devices of both sizes are strongly responsive to the local magnetic field at the center of the cross, and the results are well described using finite element modeling. At high V(g), the response to local magnetic fields is greatly distorted by strong electric fields applied near the cross corners. However we observe no change in behavior with the size of the device. PMID- 21828443 TI - Numerical studies of nonlocal electrostatic effects on the sub-nanoscale. AB - We study nonlocal electrostatics in inhomogeneous dielectric environments on the sub-nanometer scale using a recently introduced polarization energy functional. This functional is able to generate a wavevector-dependent dielectric function epsilon(q) that reflects local correlations in the medium's polarization. Its longitudinal component either decays continuously from its macroscopic continuum value to one at large q, or additionally exhibits two poles with a negative band at intermediate wavevectors (overscreening), which is characteristic of polar fluids such as water. We show that the functional reproduces known nonlocal electrostatic effects: the pair potential between point charges or Born ions in water at distances less than 5 A is strongly modified, and the Born solvation energy is found to either decrease or increase relative to its local electrostatics value, depending on which approximation is chosen for epsilon(q). We then apply the functional to geometries that can no longer be treated analytically, such as a molecular pore of finite length. In such an anisotropic dielectric background transverse correlations in the polarization field no longer vanish and can contribute to substantial modifications of the dielectric barrier for ion translocation in the regime of intermediate pore diameters of 6-10 A. PMID- 21828444 TI - Temperature dependence of the dielectric permittivity of CaF(2), BaF(2) and Al(2)O(3): application to the prediction of a temperature-dependent van der Waals surface interaction exerted onto a neighbouring Cs(8P(3/2)) atom. AB - The temperature behaviour in the range 22-500 degrees C of the dielectric permittivity in the infrared range is investigated for CaF(2), BaF(2) and Al(2)O(3) through reflectivity measurements. The dielectric permittivity is retrieved by fitting reflectivity spectra with a model taking into account multiphonon contributions. The results extrapolated from the measurements are applied to predict a temperature-dependent atom-surface van der Waals interaction. We specifically consider as the atom of interest Cs(8P(3/2)), the most relevant virtual couplings of which fall in the range of thermal radiation and are located in the vicinity of the reststrahlen band of fluoride materials. PMID- 21828445 TI - Fluorination of perovskite-related phases of composition SrFe(1-x)Sn(x)O(3 delta). AB - Perovskite-related compounds of composition SrFe(1-x)Sn(x)O(3-delta) (x = 0.31, 0.54) have been prepared. X-ray powder diffraction shows that the materials adopt orthorhombic unit cells. The lattice parameters increase with the incorporation of increasing amounts of tin, which is shown by x-ray absorption near edge structure investigation to be present as Sn(4+). (57)Fe Mossbauer spectroscopy indicates that iron in these phases is present as Fe(5+) and Fe(3+) and that the materials adopt the compositions SrFe(0.69)Sn(0.31)O(2.94) and SrFe(0.46)Sn(0.54)O(2.88). We propose that the disproportionation of Fe(4+) in SrFeO(3-delta) to Fe(5+) and Fe(3+) in SrFe(1-x)Sn(x)O(3-delta) is driven by the reduction of local lattice strain. The materials have been fluorinated by reaction with poly(vinylidene fluoride) to give products of composition SrFe(0.69)Sn(0.31)O(2.31)F(0.69) and SrFe(0.46)Sn(0.54)O(2.54)F(0.46). The increased iron to oxygen or fluorine distances as revealed by the extended x-ray absorption fine structure are associated with the reduction of Fe(5+) to Fe(3+) as evidenced by (57)Fe Mossbauer spectroscopy. The (57)Fe Mossbauer spectra recorded from the fluorinated materials at low temperature show the coexistence of magnetic sextet and non-magnetic doublet components corresponding to networks of Fe(3+) coupled through oxide ions. The Sn(4+) ions disrupt the coupling and the size of the networks. The magnetic susceptibility measurements and Mossbauer spectra recorded between 4.2 and 300 K are used to model the magnetic properties of these materials, with the larger networks appearing to possess random spin orientations consistent with spin glass-type materials. PMID- 21828446 TI - Stress-assisted large magnetic-field-induced strain in single-variant Co-Ni-Ga ferromagnetic shape memory alloy. AB - The magnetic anisotropy and the magnetic-field-induced strain (MFIS) in a single variant Co(47.5)Ni(22.5)Ga(30.0) ferromagnetic shape memory alloy (FSMA) have been investigated. From the magnetization curves for the single crystal, the hard c-axis was confirmed, and the uniaxial magnetic anisotropy constant K(u) at 300 K was evaluated to be -1.07 * 10(6) erg cm(-3) for the single-variant Co(47.5)Ni(22.5)Ga(30.0) martensite phase. The magnitude of compressive shear stress for the variant rearrangement was estimated to be 6.0-7.5 MPa from the stress-strain curves. An assisted stress tau(assist) of 6.0 MPa was applied before applying a magnetic field, and then a magnetic stress tau(mag) of 0.3 MPa was added. As a result, a large MFIS of about 7.6 % was obtained at room temperature in the martensite phase of the single-variant Co(47.5)Ni(22.5)Ga(30.0). PMID- 21828447 TI - Continuous and discrete modeling of the decay of two-dimensional nanostructures. AB - In this work we review some recent research on the surface diffusion-mediated decay of two-dimensional nanostructures. These results include both a continuous, vectorial model and a discrete kinetic Monte Carlo approach. Predictions from the standard linear continuous theory of surface-diffusion-driven interface decay are contrasted with simulational results both from kinetic and morphological points of view. In particular, we focused our attention on high-aspect-ratio nanostructures, where strong deviations from linear theory take place, including nonexponential amplitude decay and the emergence of several interesting nanostructures such as overhangs developing, nanoislands and nanovoids formation, loss of convexity, nanostructures-pinch off and nanostructures-break off, etc. PMID- 21828448 TI - Detection of charge distributions in insulator surfaces. AB - Charge distribution in insulators has received considerable attention but still poses great scientific challenges, largely due to a current lack of firm knowledge about the nature and speciation of charges. Recent studies using analytical microscopies have shown that insulators contain domains with excess fixed ions forming various kinds of potential distribution patterns, which are also imaged by potential mapping using scanning electric probe microscopy. Results from the authors' laboratory show that solid insulators are seldom electroneutral, as opposed to a widespread current assumption. Excess charges can derive from a host of charging mechanisms: excess local ion concentration, radiochemical and tribochemical reactions added to the partition of hydroxonium and hydronium ions derived from atmospheric water. The last factor has been largely overlooked in the literature, but recent experimental evidence suggests that it plays a decisive role in insulator charging. Progress along this line is expected to help solve problems related to unwanted electrostatic discharges, while creating new possibilities for energy storage and handling as well as new electrostatic devices. PMID- 21828449 TI - Diffusion of adatoms and small clusters on magnesium oxide surfaces. AB - The diffusion of isolated adatoms and small clusters is reviewed for transition and noble metals adsorbed on the (001) surface of magnesium oxide. While isolated adatoms diffuse by hopping among adsorption sites, small clusters such as dimers, trimers and tetramers already display a variety of diffusion mechanisms, from cluster hopping to rotation, sliding, leapfrog, walking, concertina, flipping, twisting, rolling and rocking. Since most of the available results are computational, the review is mostly related to theoretical work. Connection to experiments is discussed where possible, mostly by dealing with the consequences that adatom and small cluster mobility may have on the growth of larger aggregates on the MgO(001) surface. PMID- 21828450 TI - Relating chaos to deterministic diffusion of a molecule adsorbed on a surface. AB - Chaotic internal degrees of freedom of a molecule can act as noise and affect the diffusion of the molecule on a substrate. A separation of timescales between the fast internal dynamics and the slow motion of the centre of mass on the substrate makes it possible to directly link chaos to diffusion. We discuss the conditions under which this is possible, and show that in simple atomistic models with pair wise harmonic potentials, strong chaos can arise through the geometry. Using molecular dynamics simulations, we demonstrate that a realistic model of benzene is indeed chaotic, and that the internal chaos affects the diffusion on a graphite substrate. PMID- 21828451 TI - Dynamics of electron distributions probed by helium scattering. AB - Helium atom scattering (HAS) is the most important tool for surface science investigations. The analysis of helium scattering off a solid surface allows for a detailed analysis of its structural and dynamical properties. In this work we show how the dynamics of electron distributions at a metal surface can be investigated by HAS in the adiabatic approximation. First we examine the anticorrugating effect, namely the property of the He-surface potential of those metal systems in which the classical turning points of He beams are farther away from the surface layer at the bridge than at top sites. Anticorrugation for the system He/Cu(111) is examined in detail by a density functional theory (DFT) calculation and compared with the corrugating behaviour of He/Al(111). To explain such an effect the charge polarization of the system is crucial. Second we consider theoretically a surprising restricted diffusion result in the normal direction for Na adatoms on Cu(001) at coverages larger than 0.04 ML, obtained by measurements with spin polarized (3)He beams. From DFT calculations for this system a model for the description of the He-surface interaction based on the effective medium theory, which accounts for the observed phenomenon, is discussed. We show that the surface charge distribution probed by HAS is altered by the local concentration of the diffusing adatoms which is fluctuating with time and producing variations in the apparent height of the adatom measured by HAS. Our calculations demonstrate that such electronic dynamical rearrangements can be probed by the (3)He spin echo technique, which could be extended to other studies of surface electronic properties. PMID- 21828452 TI - Linewidths in bound state resonances for helium scattering from Si(111)-(1 * 1)H. AB - Helium-3 spin-echo measurements of resonant scattering from the Si(111)-(1 * 1)H surface, in the energy range 4-14 meV, are presented. The measurements have high energy resolution yet they reveal bound state resonance features with uniformly broad linewidths. We show that exact quantum mechanical calculations of the elastic scattering, using the existing potential for the helium/Si(111)-(1 * 1)H interaction, cannot reproduce the linewidths seen in the experiment. Further calculations rule out inelastic and other mechanisms that might give rise to losses from the elastic scattering channels. We show that corrugation in the attractive part of the atom-surface potential is the most likely origin of the experimental lineshapes. PMID- 21828454 TI - Comparative vibrational study on alkali coadsorption with CO and O on Ni(111) and Cu(111). AB - High-resolution electron energy loss spectroscopy was used to investigate alkali (Na, K) coadsorption with CO and O on Cu(111) and Ni(111). Measurements provided new insights in these systems. A CO-induced weakening of the alkali-substrate bond was revealed on both substrates. The effect is more pronounced for the Na+CO/Ni(111) system. Submonolayers of alkalis were found to promote the preferential population of the subsurface site for O/Cu(111) but not for O/Ni(111). PMID- 21828453 TI - Growth dynamics of L-cysteine SAMs on single-crystal gold surfaces: a metastable deexcitation spectroscopy study. AB - We report on a metastable deexcitation spectroscopy investigation of the growth of L-cysteine layers deposited under UHV conditions on well-defined Au(110)- (1 * 2) and Au(111) surfaces. The interaction of He(*) with molecular orbitals gave rise to well-defined UPS-like Penning spectra which provided information on the SAM assembly dynamics and adsorption configurations. Penning spectra have been interpreted through comparison with molecular orbital DFT calculations of the free molecule and have been compared with XPS results of previous works. Regarding adsorption of first-layer molecules at room temperature (RT), two different growth regimes were observed. On Au(110), the absence of spectral features related to orbitals associated with SH groups indicated the formation of a compact SAM of thiolate molecules. On Au(111), the data demonstrated the simultaneous presence, since the early stages of growth, of strongly and weakly bound molecules, the latter showing intact SH groups. The different growth mode was tentatively assigned to the added rows of the reconstructed Au(110) surface which behave as extended defects effectively promoting the formation of the S-Au bond. The growth of the second molecular layer was instead observed to proceed similarly for both substrates. Second-layer molecules preferably adopt an adsorption configuration in which the SH group protrudes into the vacuum side. PMID- 21828455 TI - Dissipative effects in the dynamics of N(2) on tungsten surfaces. AB - The role of electron-hole pair excitations in the dynamics of N(2) on W(100) and W(110) is evaluated using a theoretical model that accounts for the six dimensionality of the problem in the whole calculation. The six-dimensional potential energy surface is determined in each case from an extensive grid of energies calculated with density functional theory. Dissipative effects due to electron-hole pair excitations are introduced in the classical dynamics equations through a friction force. Corresponding electron friction coefficients are calculated for each atom in the molecule with density functional theory in a local density approximation. Our results show that electronic friction plays a very minor role in the dissociative dynamics of N(2) in both tungsten faces. A similar conclusion is reached when we calculate the energy lost by the reflecting molecules. PMID- 21828456 TI - Theoretical investigation of the anticorrugation effects on the tribological properties of the Xe/Cu interface. AB - We present a molecular dynamics study of the slip time and static friction for a slab of Xe deposited on a slab of Cu. To put in evidence the role played by the phonon field of the two blocks, we compare results obtained with a substrate formed by fixed atoms with one formed by mobile atoms. In the last case the scattering between Xe and Cu mobile atoms is inelastic and there is an exchange of momentum and energy between the two blocks which produces disorder in the interface plane. This disorder favors a decrease of the static friction and a consequent increase of the slip time. We describe the interaction between Xe and Cu with a phenomenological multi-ion potential which gives rise to an anticorrugation of the charge distribution and reproduces very well the ab initio density functional calculations. Our model potential is a linear superposition of a corrugating potential and an anticorrugating one. For this reason we can study the static friction by passing from an anticorrugated to a fully corrugated system. We also investigate the slip time and we compare our results with recent experimental data measured with the quartz crystal microbalance technique. PMID- 21828457 TI - Weak molecular chemisorption of N(2)/Pt(111). AB - The ordering in a higher-order-commensurate monolayer solid of Pt(111)- (3 * 3)-4 N(2), which has coexisting physisorbed and weakly chemisorbed N(2) species, is analyzed with model calculations. Density functional theory calculations are also used to evaluate properties of chemisorbed N(2) in a (2 * 2) unit cell on Pt(111). The relation of these results to the orientational ordering of N(2) on other metal surfaces is discussed. PMID- 21828458 TI - Ozonolysis of diamond. AB - The oxidation of diamond is attracting increasing interest, in the light of efforts to modulate its electronic properties for device applications. Ozone is a promising candidate oxidant species, allowing low temperature processing compared with molecular dioxygen. Here, we present first-principles molecular dynamics simulations for the dissociative adsorption of ozone on the {001} surface of diamond, carried out at the level of density functional theory. We find that ozone readily oxidizes the surface, with two distinct modes of reaction: partial dissociation results in deposition of a single oxygen adatom in an alkoxide-like structure that rapidly converts to an epoxide-like configuration; complete dissociation results in two adatoms located in ketone-like structures, with a third occupying an alkoxide geometry, expected to revert to the epoxide in due course. We describe not only the structural changes during the reactions, but also the variations in electron and spin densities that reveal the bonding rearrangements. PMID- 21828459 TI - Thermal stability of two-dimensional gold nanocrystal superlattices. AB - The thermal stability of highly ordered two-dimensional superlattices consisting of dodecanethiol-ligated Au nanoparticles has been investigated using in situ grazing incidence small-angle x-ray scattering in air and in vacuum. In the lower temperature region (<70 degrees C), annealing in air results in a minimal change of superlattice structure, whereas annealing in vacuum leads to a considerable lattice contraction and a decrease in long-range order. At higher temperatures (>100 degrees C), ligand desorption causes nanocrystals to sinter locally, destroying quasi-long-range order. The sintering process is significantly enhanced in vacuum compared to the case in air due to the increased desorption rate of thiol ligands under low pressure. PMID- 21828460 TI - Colloidal silver nanoparticle gradient layer prepared by drying between two walls of different wettability. AB - A one-dimensional silver (Ag) nanoparticle gradient layer is prepared from an aqueous colloidal solution upon a polystyrene (PS) coated silicon (Si) substrate. For preparation two walls of different wettability are used. The 40 nm PS-layer exhibits a locally constant film thickness due to the strong roughness correlation with the underlying Si-substrate and is less wettable as compared to the glass plate placed above. The Ag nanoparticles have a triangular prism-like shape. The structural characterization of the obtained complex gradient formed by drying is performed with microbeam grazing incidence small-angle x-ray scattering based on compound refractive lenses. Due to the adsorption from aqueous solution in the selective geometry a double gradient type structure defined by two areas with characteristic lateral lengths and a cross-over regime between both is observed. PMID- 21828461 TI - Self-assembly of highly fluorescent semiconductor nanorods into large scale smectic liquid crystal structures by coffee stain evaporation dynamics. AB - We deposit droplets of nanorods dispersed in solvents on substrate surfaces and let the solvent evaporate. We find that strong contact line pinning leads to dense nanorod deposition inside coffee stain fringes, where we observe large scale lateral ordering of the nanorods with the long axis of the rods oriented parallel to the contact line. We observe birefringence of these coffee stain fringes by polarized microscopy and we find the direction of the extraordinary refractive index parallel to the long axis of the nanorods. PMID- 21828462 TI - Massively ordered microstructures composed of magnetic nanoparticles. AB - Magnetic gamma-Fe(2)O(3) nanoparticle toluene solution was placed in a restricted, axially symmetric geometry composed of a spherical lens on a Si substrate (i.e., sphere-on-Si geometry), forming a capillary-held solution. The solvent evaporation led to the self-assembly of gamma- Fe(2)O(3) nanoparticles into hundreds of spatially well-ordered, gradient concentric 'coffee rings'. The rings were two nanoparticle layers high with a monolayer of nanoparticle thin film formed in between. The ring width ranged from submicron to a few microns. The center-to-center distance between adjacent rings was on the order of a few microns. The size and packing of gamma- Fe(2)O(3) nanoparticles, both within individual microscopic rings and in between, were dependent upon the preparation of the gamma-Fe(2)O(3) nanoparticle toluene solution. PMID- 21828463 TI - Self-assembled patterns from evaporating layered fluids. AB - We studied the formation of tree-like patterns of polymer aggregates and rings of nanoparticles during evaporation from a fluid film. We utilize phase separation between two immiscible fluids to generate a double-layer film which dries up in a sequential manner. Both fluid layers may contain a solute, polymer aggregates or nanoparticles. During evaporation of the top layer, instabilities may occur and direct a self-assembly process of the solute which may be further affected by an instability of the bottom layer at a later stage. We present two cases where, after evaporation of the top fluid layer, the solute was adsorbed on the surface of the bottom fluid layer. In comparison to dewetting of a single fluid layer on a solid substrate, the advantage of our double-layer approach lies in the deposition of the solute on the surface of the bottom fluid layer. The relatively high mobility of the solute on such a fluid surface favors the formation of ordered patterns, driven by an instability of the bottom layer. PMID- 21828464 TI - Modelling approaches to the dewetting of evaporating thin films of nanoparticle suspensions. AB - We review recent experiments on dewetting thin films of evaporating colloidal nanoparticle suspensions (nanofluids) and discuss several theoretical approaches to describe the ongoing processes including coupled transport and phase changes. These approaches range from microscopic discrete stochastic theories to mesoscopic continuous deterministic descriptions. In particular, we describe (i) a microscopic kinetic Monte Carlo model, (ii) a dynamical density functional theory and (iii) a hydrodynamic thin film model. Models (i) and (ii) are employed to discuss the formation of polygonal networks, spinodal and branched structures resulting from the dewetting of an ultrathin 'postcursor film' that remains behind a mesoscopic dewetting front. We highlight, in particular, the presence of a transverse instability in the evaporative dewetting front, which results in highly branched fingering structures. The subtle interplay of decomposition in the film and contact line motion is discussed. Finally, we discuss a simple thin film model (iii) of the hydrodynamics on the mesoscale. We employ coupled evolution equations for the film thickness profile and mean particle concentration. The model is used to discuss the self-pinning and depinning of a contact line related to the 'coffee-stain' effect. In the course of the review we discuss the advantages and limitations of the different theories, as well as possible future developments and extensions. PMID- 21828465 TI - The growth of an ordered Mn layer on the Si(111)- 1 * 1-Ho surface. AB - The growth of ordered Mn layers on room temperature and liquid nitrogen cooled Si(111)- 1 * 1-Ho surfaces has been studied using scanning tunnelling microscopy. We have shown for 4 ML (monolayers) of Mn grown on a cooled Si(111)- 1 * 1-Ho surface that an ordered Mn layer is produced without any, or with only limited, silicide formation. This surface exhibits a [Formula: see text] low energy electron diffraction pattern. Significant variations in Mn island sizes have also been seen on the Si(111)-1 * 1-Ho and Si(111)-7 * 7 surfaces for Mn deposited at room temperature and at -180 degrees C. PMID- 21828466 TI - Equilibrium properties of simple metal thin films in the self-compressed stabilized jellium model. AB - In this work, we have applied the self-compressed stabilized jellium model to predict the equilibrium properties of isolated thin Al, Na and Cs slabs. To make a direct correspondence to atomic slabs, we have considered only those L values that correspond to n-layered atomic slabs with 2<=n<=20, for surface indices (100), (110), and (111). The calculations are based on the density functional theory and self-consistent solution of the Kohn-Sham equations in the local density approximation. Our results show that firstly, the quantum size effects are significant for slabs with sizes smaller than or near to the Fermi wavelength of the valence electrons lambda(F), and secondly, some slabs expand while others contract with respect to the bulk spacings. Based on the results, we propose a criterion for realization of significant quantum size effects that lead to expansion of some thin slabs. For more justification of the criterion, we have tested it on Li slabs for 2<=n<=6. We have compared our Al results with those obtained from using all-electron or pseudo-potential first-principles calculations. This comparison shows excellent agreements for Al(100) work functions, and qualitatively good agreements for the other work functions and surface energies. These agreements justify the way we have used the self compressed stabilized jellium model for the correct description of the properties of simple metal slab systems. On the other hand, our results for the work functions and surface energies of large- n slabs are in good agreement with those obtained from applying the stabilized jellium model for semi-infinite systems. In addition, we have performed the slab calculations in the presence of surface corrugation for selected Al slabs and have shown that the results are worsened. PMID- 21828467 TI - Adsorbate reactivity and thermal mobility from simple modeling of high-resolution core-level spectra: application to O/Al(111). AB - A high-resolution core-level spectroscopy investigation of the adsorption of oxygen on Al(111) at variable oxygen exposure demonstrates a low surface reactivity for an intensively cleaned surface. The threshold for oxide formation is as high as ~200 L (langmuirs), at which point the coverage of the chemisorbed oxygen exceeds half a monolayer. A simple model is presented, using which it is possible to deduce the oxygen coverage from the core-level spectra and determine the initial sticking probability. For our data a value of 0.018 +/- 0.004 is obtained. The changes in core-level spectra following low-temperature annealing of low-coverage O/Al(111) reflect the formation of gradually larger islands of oxygen atoms (Ostwald ripening). The island formation is consistent with a random walk model from which the diffusion barrier can be deduced to be in the range of 0.80-0.90 eV. PMID- 21828468 TI - Magnetic ordering in Fe/Co sandwiches on Cu(100). AB - We investigate magnetic correlations and local magnetic moments at finite temperatures of some Fe and Co multilayers on Cu(100) substrates, such as Co(m)Fe(n)Co(m)/Cu(100) and Fe(m)Co(n)Fe(m)/Cu(100). We use an ab initio mean field theory of magnetic fluctuations for layered materials based on the first principles local spin-density functional theory implemented through the screened Korringa-Kohn-Rostoker method. We find that the presence of Fe layers in the neighbourhood of a Co layer always leads to a reduction in the magnetic moment of the Co atoms, whereas that of the Fe atoms is enhanced. Of particular interest is the lack of local moment formation on the single fcc-Co layer sandwiched between two fcc-Fe layers. However, a Co layer completely immersed in a Cu environment remains ferromagnetic. The Curie temperature of the Co(m)Fe(n)Co(m)/Cu(100) system oscillates as the Fe layer thickness is increased whereas that of the Fe(m)Co(n)Fe(m)/Cu(100) system increases almost monotonically with Co layer thickness. PMID- 21828469 TI - A scanning tunneling microscopy study of a new superstructure around defects created by tip-sample interaction on 2H- NbSe(2). AB - A low temperature scanning tunneling microscope (LT-STM) was used to investigate a new superstructure on the cleaved surface of a 2H- NbSe(2) single crystal after introduction of structural defects through bias voltage pulses during tunneling at 4.2 K. A charge density wave (CDW) with a [Formula: see text] reconstruction was observed in the vicinity of the defects and the well-known 3 * 3 CDW was observed far from these defects. Multiple layers inside the defects were also exposed and showed the new modulation of the CDW on all of the Se layers. This indicates a local 2H to 1T phase transition for the NbSe(2) crystal structure. Two other interesting observations are also included: a disordered CDW-like phase of the [Formula: see text] structure near the atomic steps and an anomalous distortion in the underlying atomic lattice revealed by STM images. A local heating mechanism is proposed to explain the creation of these novel structures. PMID- 21828470 TI - Acoustic and elastic properties of Sn(2)P(2)S(6) crystals. AB - We present the results concerned with acoustic and elastic properties of Sn(2)P(2)S(6) crystals. The complete matrices of elastic stiffness and compliance coefficients are determined in both the crystallographic coordinate system and the system associated with eigenvectors of the elastic stiffness tensor. The acoustic slowness surfaces are constructed and the propagation and polarization directions of the slowest acoustic waves promising for acousto-optic interactions are determined on this basis. The acoustic obliquity angle and the deviation of polarization of the acoustic waves from purely transverse or longitudinal states are quantitatively analysed. PMID- 21828471 TI - Interplay of inequivalent atomic positions in resonant x-ray diffraction of Fe(3)BO(6). AB - 'Forbidden' Bragg reflections of iron orthoborate Fe(3)BO(6) were studied theoretically and experimentally in the vicinity of the iron K edge. Their energy spectra are explained as resulting from the interference of x-rays scattered from two inequivalent crystallographic sites occupied by iron ions. This particular structure property gives rise to complex azimuthal dependences of the reflection intensities in the pre-edge region as they result from the interplay of site specific dipole-quadrupole and quadrupole-quadrupole resonant scattering. Also evidenced is an anisotropic character of the absorption spectrum. Self-absorption correction to the diffraction data, as well as possible contributions of thermal vibrations and magnetic order, are discussed. Particular care is given to extracting clean spectra from the data, and it is demonstrated that excellent results can be obtained even from measurements that appear corrupted by several effects such as poor crystal quality and multiple scattering. PMID- 21828472 TI - Time-dependent quantum transport behavior through T-shaped double quantum dots. AB - The time-dependent current flowing through a T-shaped double quantum dot is theoretically studied via nonequilibrium Green's function methods. Quantum coherent ringing or beats can appear in the transient current after a bias voltage is turned on or off, and their periods can be tuned by the pulse bias or the interdot coupling strength. In the weak interdot coupling case no quantum beat is observed and only quantum ringing appears in the current, the frequency of which depends on the pulse bias. In the strong interdot coupling case, quantum beats appear in the current and their frequency depends on the interdot coupling strength. Quantum beats are suppressed greatly by the large energy difference between the two quantum dots. In addition, quantum ringing and beats tend to disappear with increasing temperature. PMID- 21828473 TI - Electronic structure of C(84) film studied by photoemission measurement and first principles calculation. AB - We have measured the photoemission spectra of a C(84) film (isomer mixture) with synchrotron radiation. The valence band exhibits abundant spectral features from the Fermi level to ~18 eV binding energy. The relative intensity between the lowest binding energy feature (labeled as A) and the next lowest binding energy feature (labeled as B) oscillates distinctly within the experimental photon energy region from 21.0 to 63.0 eV. The energy levels and density of states (DOS) are calculated for the D(2d)(23)- C(84) and four D(2) symmetric (D(2)(1), D(2)(5), D(2)(21) and D(2)(22)) C(84) isomers to help us to understand the electronic structure. The experimental features and the theoretical DOS peaks have one-to-one correspondence. The number of electrons occupying the states of feature A is 12 or 13.3, depending on the different kinds of isomer mixtures. The electron occupation of feature B is 18.67 e. With the spherical symmetric approximation, features A and B can be characterized with angular momenta of 6 and 5, respectively. The angular momentum difference is the reason for the photoelectron intensity oscillations. PMID- 21828474 TI - Electromigration and potentiometry measurements of single-crystalline Ag nanowires under UHV conditions. AB - We report on in situ electromigration and potentiometry measurements on single crystalline Ag nanowires under ultra-high vacuum (UHV) conditions, using a four probe scanning tunnelling microscope (STM). The Ag nanowires are grown in place by self-organization on a 4 degrees vicinal Si(001) surface. Two of the four available STM tips are used to contact the nanowire. The positioning of the tips is controlled by a scanning electron microscope (SEM). Potentiometry measurements on an Ag nanowire were carried out using a third tip to determine the resistance per length. During electromigration measurements current densities of up to 1 * 10(8) A cm(-2) could be achieved. We use artificially created notches in the wire to initiate electromigration and to control the location of the electromigration process. At the position of the notch, electromigration sets in and is observed quasi-continuously by the SEM. PMID- 21828475 TI - Orbital orderings and optical conductivity of SrRuO(3) and CaRuO(3): first principles studies. AB - The Jahn-Teller (JT) distortion induced orbital order and optical conductivity in SrRuO(3) and CaRuO(3) are investigated by first-principles calculations. The total energy and optical conductivity of all the spin ordering states of SrRuO(3) and CaRuO(3) are calculated in the LDA+U scheme with U(eff) = 2.5 eV. The down spin t(2g) of Ru show antiferromagnetic-like orbital order in the a-b plane. We observe a d-d transition peak at an energy of about 1.0 eV in the calculated optical conductivity and analyze the reason for it not being observed in previous experiments. PMID- 21828476 TI - Superconductivity and magnetism in K-doped EuFe(2)As(2). AB - Superconductivity is found in 50% K-doped EuFe(2)As(2) samples below 33 K. Our results from electrical resistivity, magnetic susceptibility and (57)Fe and (151)Eu Mossbauer spectroscopy provide clear evidence that the ordering of the Fe moments observed at 190 K in undoped EuFe(2)As(2) is completely suppressed in our 50% K-doped sample; thus there is no coexistence of the Fe magnetic order and the superconducting state. However, short range ordering of the Eu moments coexists with the superconducting state below 15 K. A bump in the susceptibility well below T(c) as well as the broadening of the Fe Mossbauer line below 27 K evidence an interplay between the Eu magnetism and the superconducting state. PMID- 21828477 TI - Atomistic modeling of amorphous silicon carbide: an approximate first-principles study in constrained solution space. AB - Localized basis ab initio molecular dynamics simulation within the density functional framework has been used to generate realistic configurations of amorphous silicon carbide (a-SiC). Our approach consists of constructing a set of smart initial configurations that conform to essential geometrical and structural aspects of the materials obtained from experimental data, which is subsequently driven via a first-principles force field to obtain the best solution in a reduced solution space. A combination of a priori information (primarily structural and topological) along with the ab initio optimization of the total energy makes it possible to model a large system size (1000 atoms) without compromising the quantum mechanical accuracy of the force field to describe the complex bonding chemistry of Si and C. The structural, electronic and vibrational properties of the models have been studied and compared to existing theoretical models and available data from experiments. We demonstrate that the approach is capable of producing large, realistic configurations of a-SiC from first principles simulation that display its excellent structural and electronic properties. Our study reveals the presence of predominant short range order in the material originating from heteronuclear Si-C bonds with a coordination defect concentration as small as 5% and a chemical disorder parameter of about 8%. PMID- 21828478 TI - The magnetic contribution to the specific heat of Pb(1-x)Gd(x)Te. AB - The temperature dependence of the magnetic specific heat of the semimagnetic semiconductor Pb(1-x)Gd(x)Te for x = 0.033 and 0.054, over the temperature range from 0.5 to 10 K, in magnetic fields up to 2 T, has been measured and analyzed theoretically. The maxima of the magnetic specific heat in nonzero magnetic fields are shifted to lower temperatures in comparison with theoretical predictions based on the simple cluster model. We propose a mechanism which explains these shifts. According to our model, they are caused by strong hybridization of the 5d shell of gadolinium with band states of the crystal. PMID- 21828479 TI - Persistent photoinduced magnetization and oxygen non-stoichiometry in La(0.9)Ca(0.1)MnO(3) films. AB - The influence of thermal annealings on La(0.9)Ca(0.1)MnO(3) (LCMO) films in oxygen and in vacuum with low hole doping is investigated in the phase separation region where competition between AFM and FM phases is high. Measurements by x-ray diffractometry, atomic force microscopy and magnetometry reveal changes in the lattice parameters and magnetic properties of the films, depending on the oxygen content. All films show magnetic cluster glass properties with similar freezing temperatures of around 45 K. Clearly the highest increase of the magnetization is observed in the films annealed in vacuum. We attribute this effect to trapping of unpaired electrons at oxygen vacancies where they can form rigid self-trapped magnetic polarons in potential wells of local moments. As a result long-range spin distortions with local ferromagnetic order may be realized. In conformity with these results, photoinduced persistent magnetization showing different mechanisms of generation, depending on the method of thermal annealing, is observed. PMID- 21828480 TI - Re-examination of half-metallic ferromagnetism for doped LaMnO(3) in a quasiparticle self-consistent GW method. AB - We apply the quasiparticle self-consistent GW (QSGW) method to a cubic virtual crystal alloy La(1-x)Ba(x)MnO(3) as a theoretical representative for colossal magnetoresistive perovskite manganites. The QSGW predicts it as a fully polarized half-metallic ferromagnet for a wide range of x and lattice constant. Calculated density of states and dielectric functions are consistent with experiments. In contrast, the energies of the calculated spin wave are very low in comparison with experiments. This is affected neither by rhombohedral deformation nor the intrinsic deficiency in the QSGW method. Thus we end up with a conjecture that phonons related to the Jahn-Teller distortion should hybridize with spin waves more strongly than people thought until now. PMID- 21828481 TI - Is the Verwey transition in Fe(3)O(4) magnetite driven by a Peierls distortion? AB - In this viewpoint article we analyse recent crucial structural, optical and transport experiments on Fe(3)O(4) magnetite across the Verwey transition at T(V)~120-125 K. We find that all the relevant experimental data are consistent with a model of a Peierls distortion in the cubic spinel lattice, and likewise, some of them evidence against the original and still distributed hypothesis of the long range charge ordering origin of the Verwey transition. An estimated Peierls transition temperature (T(P)) is comparable with T(V). The Peierls model provides new insight into the electronic properties of magnetite. Application of the Peierls model to some other systems is briefly discussed also. PMID- 21828482 TI - Domain boundary formation in helical multishell gold nanowires. AB - Helical multishell gold nanowires are studied theoretically for the formation mechanism of the helical domain boundary. Nanowires with a wire length of more than 10 nm are relaxed by quantum mechanical molecular dynamics simulation with a tight-binding form Hamiltonian. In the results, non-helical nanowires are transformed into helical ones with the formation of atom pair defects at the domain boundary, where the defective atom pair is moved from an inner shell. Analysis of local electronic structure shows a competitive feature of the energy gain of reconstruction on the wire surface and the energy loss of the defect formation. A simple energy scaling theory gives a general explanation of domain boundary formation. PMID- 21828483 TI - First-principles study of the magnetization of oxygen-depleted In(2)O(3)(001) surfaces. AB - The origin of the magnetism in some oxide-based diluted magnetic semiconductors is still a puzzle. In this work, significantly ferromagnetic states of the oxygen depleted In(2)O(3)(001) surfaces are investigated on the basis of first principles density functional calculations. Our results show that the perfect oxygen-depleted surfaces are nonmagnetic; however, the surface states become ferromagnetic with the appearance of vacancies on the most outward In sites. The origin of the surface state magnetization can be explained using the Stoner model, and the exchange coupling between surfaces In s-p hybridization orbitals implies a ferromagnetic ground state. Our investigation gives a reasonable explanation for the source of the magnetism in oxygen-depleted In(2)O(3) nanostructures observed in previous experiments. PMID- 21828484 TI - Quantum dynamics of two-spin-qubit systems. AB - The aim of this topical review is a systematic and concise presentation of the results of a series of theoretical works on the quantum dynamics of two-spin qubit systems towards the elaboration of a physical mechanism of the quantum information transfer between two spin-qubits. For this purpose the main attention is paid to exactly solvable models of two-spin-qubit systems, since the analytical expressions of the elements of their reduced density matrices explicitly exhibit the mutual dependence of the quantum information encoded into the spin-qubits. The treatment of their decoherence due to the interaction with the environment is performed in the Markovian approximation. Rate equations for axially symmetric systems of two coupled spin-qubits non-interacting, as well as interacting, with the environment are exactly solved. It is shown how the solutions of rate equations demonstrate the physical mechanism of the quantum information exchange between the spin-qubits. This mechanism holds also in all two-spin-qubit systems whose rate equations can be solved only by means of numerical calculations. Exact solutions of rate equations for two uncoupled spin qubits interacting with two separate environments reveal an interesting physical phenomenon in the time evolution of the qubit-qubit entanglement generated by their interaction with the environments: the entanglement sudden death and revival. A two-spin-qubit system with an asymptotically decoherence free subspace was also explicitly constructed. The presented calculations and reasonings can be extended for application to the study of spin-qubit chains or networks. PMID- 21828485 TI - Elastic properties of NaXH(4) (X = B, Al). AB - Elastic properties of NaXH(4) (X = B, Al) have been studied by first-principles calculations using a projected augmented plane-wave approach. The calculated elastic constants compare favorably with experimental values. Our calculations show that the theoretically calculated elastic constants and bulk moduli have small values compared with those of typical metals and intermetallic compounds, which indicates that NaXH(4) (X = B, Al) are highly compressible. Comparison of bulk moduli B of different complex hydrides shows a correlation between B and the decomposition temperatures. Also, we calculated the elastic anisotropies and the Debye temperatures from the elastic constants. PMID- 21828486 TI - Ab initio lattice dynamics of MnO. AB - Vibrational dynamics of the MnO lattice has been studied using density functional theory combined with the direct method. Considerations have been limited to the harmonic approximation. Ab initio calculated Hellmann-Feynman forces were used to obtain density of states and the dispersion relations of phonons in the MnO crystal. Corrections for the local Coulomb interactions were applied. The Hubbard energies were varied from 1 to 7.9 eV. Increased Hubbard terms give a significant increase in the on-site force constants of cations, while the force constants on anions are affected indirectly. The density of phonon states and the dispersion curves are shifted to higher frequencies with the increasing Hubbard energies. The on-site Coulomb interactions influence mainly the optical phonon vibrations. The higher Hubbard terms lower the mean-squared vibrations of both cations and anions. The lattice contribution to the heat capacity experiences small changes upon variation of Coulomb repulsion. Results of the calculations are compared to the existing experimental data. PMID- 21828487 TI - Molecular dynamics simulation of the phase transition between calcite and CaCO(3) II. AB - Molecular dynamics (MD) simulation of calcium carbonate at high pressure was performed to understand the phase transition between calcite [Formula: see text] and CaCO(3)-II (P 2(1)/c). In the 300-800 K temperature range, the transition of calcite to CaCO(3)-II was reproduced at a pressure of around 8 GPa. This transition is of first order and reversible in the MD calculations except for runs at 300 K where a small hysteresis exists. The slope of the dP/dT curve at the phase boundary between calcite and CaCO(3)-II is negative at 300 K and turns positive at around 600 K, which was confirmed by analyzing the enthalpy change. Just below the transition pressure, the P 2(1)/c structure appears and its orientation switches among three positions with time, resulting in the maintenance of the [Formula: see text] structure as a whole. The P 2(1)/c structure resembles the structure of CaCO(3)-II on an increase of temperature. It can be suggested that the existence of the P 2(1)/c structure and the switching of its orientation just below the transition pressure are responsible for the change of the slope of the dP/dT curve at the boundary from negative to positive on an increase of temperature, because the switching increases entropy and results in an expansion of the stability field of calcite. PMID- 21828488 TI - Properties of the moving Holstein large polaron in one-dimensional molecular crystals. AB - The features of the moving large polaron are investigated within Holstein's molecular crystal model. The necessity to account for the phonon dispersion is emphasized and its impact on polaron properties is examined in detail. It was found that the large polaron dynamics is described by the nonlocal nonlinear Schrodinger equation. The character of its solutions is determined by the degree of nonlocality, which is specified by the polaron velocity and group velocity of the lattice modes. An analytic solution for the polaron wavefunction is obtained in the weakly nonlocal limit. It was found that the polaron velocity and phonon dispersion have a significant impact on the parameters and dynamics of large polarons. The polaron amplitude and effective mass increase while its spatial extent decreases with a rise in the degree of nonlocality. The criterion for the stability of large polaron is formulated in terms of the values of the degree of nonlocality, the magnitude of the basic energy parameters of the system and the polaron velocity. It turns out that the large polaron velocity cannot exceed a relatively small limiting value. A similar limitation on large polaron velocity has not been found in previous studies. The consequences of these results on polaron dynamics in realistic conditions are discussed. PMID- 21828489 TI - Lattice dynamics and Raman scattering by phonons of GaAs/AlAs(001) superlattices. AB - The lattice dynamics of (GaAs)(n)/(AlAs)(n)(001) superlattices (SLs), n = 1,2, with perfect and disordered (non-perfect) interfaces is studied in detail. The SLs with disordered interfaces are approached by primitive cells, much larger in volume than that of the perfect SL primitive cell. The dynamical matrices of the SLs have been constructed from a combination of the dynamical matrices corresponding to the bulk crystalline constituents, while the interionic forces are calculated by using a ten-parameter valence overlap shell model (VOSM). Furthermore, we calculate the Raman spectra, for both perfect and disordered superlattices by using an eight-parameter bond polarizability model (BPM). Our theoretical results are in very good agreement with the available experimental spectra. Finally, our results clearly demonstrate that intermixing of Ga and Al cations, even to a very small extent, can induce Raman activity, which although not expected in the spectra of perfect superlattices, is actually observed experimentally. PMID- 21828490 TI - A theoretical study of intrinsic point defects and defect clusters in magnesium aluminate spinel. AB - Point and small cluster defects in magnesium aluminate spinel have been studied from a first principles viewpoint. Typical point defects that occur during collision cascade simulations are cation anti-site defects, which have a small formation energy and are very stable, O and Mg split interstitials and vacancies. Isolated Al interstitials were found to be energetically unfavourable but could occur as part of a split Mg-Al pair or as a three atom-three vacancy Al 'ring' defect, previously observed in collision cascades using empirical potentials. The structure and energetics of the defects were investigated using density functional theory (DFT) and the results compared to simulations using empirical fixed charge potentials. Each point defect was studied in a variety of supercell sizes in order to ensure convergence. It was found that empirical potential simulations significantly overestimate formation energies, but that the type and relative stability of the defects are well predicted by the empirical potentials both for point defects and small defect clusters. PMID- 21828491 TI - A density functional study of the high-pressure chemistry of MSiN(2)(M = Be, Mg, Ca): prediction of high-pressure phases and examination of pressure-induced decomposition. AB - Normal pressure modifications and tentative high-pressure phases of the nitridosilicates MSiN(2) with M = Be, Mg, or Ca have been thoroughly studied by density functional methods. At ambient pressure, BeSiN(2) and MgSiN(2) exhibit an ordered wurtzite variant derived from idealized filled beta-cristobalite by a C1 type distortion. At ambient pressure, the structure of CaSiN(2) can also be derived from idealized filled beta-cristobalite by a different type of distortion (D1-type). Energy-volume calculations for all three compounds reveal transition into an NaCl superstructure under pressure, affording sixfold coordination for Si. At 76 GPa BeSiN(2) forms an LiFeO(2)-type structure, corresponding to the stable ambient-pressure modification of LiFeO(2), while MgSiN(2) and CaSiN(2) adopt an LiFeO(2)-type structure, corresponding to a metastable modification (24 and 60 GPa, respectively). For both BeSiN(2) and CaSiN(2) intermediate phases appear (for BeSiN(2) a chalcopyrite-type structure and for CaSiN(2) a CaGeN(2) type structure). These two tetragonal intermediate structures are closely related, differing mainly in their c/a ratio. As a consequence, chalcopyrite-type structures exhibit tetrahedral coordination for both cations (M and Si), whereas in CaGeN(2)-type structures one cation is tetrahedrally (Si) and one bisdisphenoidally (M) coordinated. Both structure types, chalcopyrite and CaGeN(2), can also be derived from idealized filled beta-cristobalite through a B1-type distortion. The group-subgroup relation of the BeSiN(2)/MgSiN(2), the CaSiN(2), the chalcopyrite, the CaGeN(2) and the idealized filled beta cristobalite structure is discussed and the displacive phase transformation pathways are illustrated. The zero-pressure bulk moduli were calculated for all phases and have been found to be comparable to compounds such as alpha- Si(3)N(4), CaIrO(3) and Al(4)C(3). Furthermore, the thermodynamic stability of BeSiN(2), MgSiN(2) and CaSiN(2) against phase agglomerates of the binary nitrides M(3)N(2) and Si(3)N(4) under pressure are examined. PMID- 21828492 TI - High-pressure phases and transitions of the layered alkaline earth nitridosilicates SrSiN(2) and BaSiN(2). AB - We investigate the high-pressure phase diagram of SrSiN(2) and BaSiN(2) with density-functional calculation. Searching a manifold of possible candidate structures, we propose new structural modifications of SrSiN(2) and BaSiN(2) attainable in high-pressure experiments. The monoclinic ground state of SrSiN(2) transforms at 3 GPa into an orthorhombic BaSiN(2) type. At 14 GPa a CaSiN(2)-type structure becomes the most stable configuration of SrSiN(2). A hitherto unknown Pbcm modification is adopted at 85 GPa and, finally, at 131 GPa a LiFeO(2)-type structure. The higher homologue BaSiN(2) transforms to a CaSiN(2) type at 41 GPa and further to a Pbcm modification at 105 GPa. Both systems follow the pressure coordination rule: the coordination environment of Si increases from tetrahedral through trigonal bipyramidal to octahedral. Some high-pressure phases are related in structure through simple group-subgroup mechanisms, indicating displacive phase transformations with low activation barriers. PMID- 21828493 TI - Energy levels and emission parameters of the Dy(3+) ion doped into the YPO(4) host lattice. AB - Single crystals of Dy(3+)-doped YPO(4) have been grown from Pb(2)P(2)O(7) flux and investigated by optical spectroscopy techniques. The energy level scheme of the active ion has been deduced from the low temperature spectra and reproduced by means of a crystal-field calculation. The room temperature absorption spectra have been analysed in the framework of the Judd-Ofelt approach, and the results of this analysis have been applied in a discussion concerning the spectral composition of the visible luminescence. PMID- 21828494 TI - Bulk and surface sp half-metallic ferromagnetism in alkali metal pnictides with rocksalt structure: a first-principles calculation. AB - Recently, sp half-metallic ferromagnetism in alkali metal/alkaline earth pnictides (I/II-V) with zinc blende structure was predicted by first-principles calculations (Sieberer et al 2006 Phys. Rev. B 73 024404). To search for half metallic ferromagnets with a more stable structure in alkali metal pnictides MX (M = Li, Na, K; X = N, P, As), we apply here first-principles all-electron and pseudopotential-method-based density functional theory to investigate the electronic and magnetic properties of these compounds with rocksalt structure. Five rocksalt compounds are found to be half-metallic ferromagnets with a magnetic moment of 2.00 MU(B)/f.u., and they are more stable energetically than the ones with zinc blende structure, which makes them more promising candidates for the possible growth of half-metallic films or ultrathin films on suitable semiconductor substrates. Furthermore, we show that both lithium- and nitrogen terminated (111) surfaces of rocksalt lithium nitride retain the bulk half metallic characteristic, and the surface atomic magnetic moments are enhanced compared to the bulk values. PMID- 21828495 TI - Transport properties and the large anisotropic magnetoresistance of Cu(x)NbS(2) single crystals. AB - The transport properties of Cu(x)NbS(2) (x = 0.09, 0.44 and 0.55) single crystals were systematically studied. The in-plane and out-of-plane resistivities decrease with increasing Cu content, and a transition with hysteresis shows up for the crystals with x = 0.44 and 0.55. The thermopower and Hall coefficient of Cu(x)NbS(2) show opposite signs, indicating that there are two kinds of carriers in this system. The angular dependences of the in-plane magnetoresistance (MR(ab) = (rho(ab)(H)-rho(ab)(0))/rho(ab)(0) * 100%) at different temperatures were also studied. The single crystals with x = 0.44 and 0.55 show a strong anisotropic MR(ab). For the x = 0.55 sample, MR(ab) reaches 80% with a magnetic field of 14 T applied along the c-axis, while MR(ab) is less than 5% for the magnetic field applied within the ab-plane. These results can be well understood in the light of the anisotropic Fermi surface in the multiband system. PMID- 21828496 TI - Ab initio molecular-dynamics simulation of liquid As(x)Te(1-x) alloys. AB - Ab initio molecular-dynamics simulations have been used to investigate the structure and dynamics properties of the liquid alloy As(x)Te(1-x) at 800 K and at the five compositions x = 0.2, 0.3, 0.4, 0.5 and 0.6. We present results for the static structure factors, diffusion coefficients and frequency spectra, in addition to the electronic density of states. Both the results for the structural and dynamic properties are in relatively good agreement with the experimental data available. The results also indicate that the increase in the number of As atoms reduces the metallic character of the sample in close connection with a corresponding disruption of the Te chain structure. PMID- 21828497 TI - Lorentz shear modulus of fractional quantum Hall states. AB - We show that the Lorentz shear modulus of macroscopically homogeneous electronic states in the lowest Landau level is proportional to the bulk modulus of an equivalent system of interacting classical particles in the thermodynamic limit. Making use of this correspondence, we calculate the Lorentz shear modulus of Laughlin's fractional quantum Hall states at filling factor nu = 1/m (m an odd integer) and find that it is equal to [Formula: see text], where n is the density of particles and the sign depends on the direction of magnetic field. PMID- 21828498 TI - Comparative study of the pressure effects on the magnetic penetration depth in electron- and hole-doped cuprate superconductors. AB - The effect of pressure on the magnetic penetration depth lambda was tested for the hole-doped superconductor YBa(2)Cu(3)O(7-delta) and in the electron-doped one Sr(0.9)La(0.1)CuO(2) by means of magnetization measurements. Whereas a large change of lambda was found in YBa(2)Cu(3)O(7-delta), confirming the non-adiabatic character of the electron-phonon coupling in hole-doped superconductors, the same quantity is not affected by pressure in electron-doped Sr(0.9)La(0.1)CuO(2), suggesting a close similarity of the latter to conventional adiabatic Bardeen Cooper-Schrieffer superconductors. The present results imply a remarkable difference between the electronic properties of hole-doped cuprates and electron doped Sr(0.9)La(0.1)CuO(2), giving a strong contribution to the long debated asymmetric consequences of hole and electron doping in cuprate superconductors. PMID- 21828499 TI - Spin-polarized transport through an Aharonov-Bohm interferometer embedded with a quantum dot molecule. AB - We propose an Aharonov-Bohm interferometer with a quantum dot molecule embedded in one arm and study the spin-dependent transport due to the interplay of the Fano and Rashba effects. It is found that the Fano resonances of the molecular states exhibit opposite directions of asymmetric tails with one being from peak to dip and the other from dip to peak. The Rashba spin-orbit interaction induces a spin-dependent phase, making the two Fano dips overlap for one spin component of conductance and the two Fano peaks overlap for the other spin component. Both the direction and magnitude of the spin polarization of the conductance are easily controlled and manipulated through the Rashba parameter and interdot coupling strength. In addition, spin accumulations with opposite signs can be generated in the two quantum dots. PMID- 21828500 TI - High pressure study of the zinc phosphide semiconductor compound in two different phases. AB - Electronic and structural properties of the zinc phosphide semiconductor compound are calculated at hydrostatic pressure using the full-potential all-electron linearized augmented plane wave plus local orbital (FP-LAPW+lo) method in both cubic and tetragonal phases. The exchange-correlation potential is treated by the generalized gradient approximation within the scheme of Perdew, Burke and Ernzerhof, GGA96 (1996 Phys. Rev. Lett. 77 3865). Also, the Engel and Vosko GGA formalism, EV-GGA (Engel and Vosko 1993 Phys. Rev. B 47 13164), is used to improve the band-gap results. Internal parameters are optimized by relaxing the atomic positions in the force directions using the Hellman-Feynman approach. The lattice constants, internal parameters, bulk modulus, cohesive energy and band structures have been calculated and compared to the available experimental and theoretical results. The structural calculations predict that the stable phase is tetragonal. The effects of hydrostatic pressure on the behavior of band parameters such as band-gap, valence bandwidths and internal gaps (the energy gap between different parts of the valence bands) are studied using both GGA96 and EV GGA. PMID- 21828501 TI - Ordered structures of exciton condensed phases in the presence of an inhomogeneous potential. AB - A theory of the separation of a system of indirect excitons into a condensed and a gaseous phase with the formation of regular patterns of alternating phases in inhomogeneous external fields is developed. The model of spinodal decomposition of phase transitions, generalized for systems of unstable particles, is used. The theory is applied to the study of the non-uniform distribution of the exciton density in a double quantum well under a slot cut in a metallic electrode. It is shown that in a certain range of exciton generation rates a chain of light emitting islands periodically localized along the slot is developed. With increasing width of the slot, the chain splits into two parallel chains shifted by a half period with respect to each other. By creating a biased external potential along the slot, the periodical pattern could be forced to move along the slot. The effect of the motion of the islands should manifest itself as time oscillations of the intensity of the light emitted from a fixed point. PMID- 21828502 TI - Negative pressure induced ferroelectric phase transition in rutile TiO(2). AB - First-principles pseudopotential calculations by means of the local density approximation (LDA) within density-functional theory (DFT) are carried out to investigate the negative pressure induced ferroelectric phase transition in rutile TiO(2) in the range of -25 to 25 GPa. The softening behavior of the A(2u)(TO) modes at the Gamma point following the decreasing pressure leads to a ferroelectric phase transition from P4(2)/mnm (rutile) space group to P42nm (ferro) space group. The calculated pressure dependence of the phonon frequencies, A(1)(TO), E(TO), and B(2) modes of the ferro TiO(2) relative to A(2u)(TO), E(u)(TO), and B(1u) modes of rutile TiO(2), indicates that the phase transition occurs at around -10 GPa, consistent with the total energy results. The dramatic increase of the c-axial dielectric tensor in the vicinity of the phase transition indicates it to be a typical ferroelectric phase transition. The character of the phase transition is generally identified in terms of the calculated order parameters, displaying a second order. PMID- 21828503 TI - A study of pressure and chemical substitution effects on the magnetocaloric properties of the ferromagnetic compound UGa(2). AB - We report on pressure effects on the magnetic and magnetocaloric properties of the compound UGa(2). Using a mean field approximation, we were able to calculate the isothermal entropy change and the adiabatic temperature change. Neither the applied pressure nor the chemical substitution experiments within the ranges studied revealed a remarkable improvement on the magnetocaloric effect (MCE) except for the Al substitutions. Nevertheless, we found that mechanical pressure and chemical pressure are equivalent in terms of the Curie temperature shift when Al, Ge and Si are substituted for Ga, but a different behavior is found when Ni, Fe and Co are used. Our results also show that a composite to operate between 80 and 120 K can be obtained using different concentrations of U(Ga,Ni)(2). PMID- 21828504 TI - The role of magnetoelastic strain on orbital control and transport properties in an LaTiO(3)-CoFe(2)O(4) heterostructure. AB - Epitaxial heterostructures of CoFe(2)O(4)/LaTiO(3)/LaAlO(3) have been successfully prepared by using the pulsed laser deposition technique. The magnetoresistance (MR) of the samples is negative and linear with field at H>=2 T, exhibiting no dependence on field directions. Nevertheless, when H<2 T, the MR is negative in a field parallel to the sample plane, but positive in that along the film normal. This novel observed anisotropic MR is explained in terms of the magnetic anisotropy in the ferrimagnetic layer, as well as the magnetoelastic coupling between the two. In fields of different directions, the top CoFe(2)O(4) layer contracts or expands in the sample plane due to the significant magnetostriction effect, changing its resistance accordingly and exerting compressive or tensile strains on the bottom LaTiO(3) layer. Apparently the orbital status and the one-electron bandwidth in the LaTiO(3) layer are altered, which leads to a change in resistance. PMID- 21828505 TI - Magnetic ground states of CaRu(1-x)Mn(x)O(3)(0.2 <= x <= 0.9): a magnetic Compton scattering study. AB - The magnetism of CaRu(1-x)Mn(x)O(3)(0.2<=x<=0.9) was studied by the magnetic Compton scattering experiment. The result of the spin-polarized electron momentum density distributions (magnetic Compton profiles) and the absolute value of spin moment indicate that Mn doping introduces magnetic moments on Ru ions, and the Ru and Mn spin moments were antiferromagnetically coupled. Moreover the spin moment of Ru ions increased proportionally in the x range. These results were explained by a mixed valence model and inhomogeneous magnetic structure, where the inhomogeneous magnetic ground state in CaRu(1-x)Mn(x)O(3) would be formed by a ferrimagnetic network from the Mn(3.5+) and Ru(4.5+) clusters in the paramagnetic matrix CaRuO(3) for x<0.5 and in the antiferromagnetic matrix CaMnO(3) for x>0.5. PMID- 21828506 TI - Liquid water and ices: understanding the structure and physical properties. AB - A review of the structure and some properties of condensed phases of water is given. Since the discovery of the polymorphism of crystalline ice (beginning of the twentieth century), 15 ice modifications have been found and their structures have been determined. If we do not take into consideration proton ordering or disordering, nine distinct crystalline ice modifications in which water molecules retain their individuality are known. In the tenth, ice X, there are no H(2)O molecules. It contains ions (or atoms) of oxygen and hydrogen. The structure of all these modifications is described and information about their fields of stability and about the transition between them is given. It is emphasized that there are ice modifications which are metastable at any temperature and pressure (ices Ic, IV and XII), and many modifications can exist as metastable phases beyond their fields of stability. The ability of water to exist in metastable states is one of its remarkable properties. Several amorphous ice modifications (all of them are metastable) are known. Brief information about their properties and transitions between them is given. At the end of the 1960s the conception of the water structure as a three-dimensional hydrogen-bonded network was conclusively formed. Discovery of the polymorphism of amorphous ices awakened interest in the heterogeneity of the water network. Structural and dynamical heterogeneity of liquid water is discussed in detail. Computer simulation showed that the diffusion coefficient of water molecules in dense regions of the network is lower than in the loose regions, while an increase of density of the entire network gives rise to an increase of diffusion coefficient. This finding contradicts the conceptions associated with the primitive two-state models and can be explained from pressure dependences of melting temperature and of homogeneous nucleation temperature. A brief discussion of the picture of molecular motions in liquid water based on experiment and on computer simulation is given. This picture is still very incomplete. The most fascinating idea that was put forward during the last 20 years was the second critical point conjecture. It is still not clear whether this conjecture corresponds to reality. PMID- 21828507 TI - Optical properties of lead borate glasses containing Dy(3+) ions. AB - Optical properties of lead borate glasses containing Dy(3+) ions were examined using absorption and luminescence measurements and theoretical calculations based on the Judd-Ofelt framework and the Inokuti-Hirayama model. The luminescence spectra show two characteristic bands at 480 and 573 nm, which are due to (4)F(9/2)-(6)H(15/2) (blue) and (4)F(9/2)-(6)H(13/2) (yellow) transitions of trivalent Dy(3+) ions. The yellow/blue luminescence and its decay were analyzed as a function of activator concentration. PMID- 21828508 TI - Colloidal glass transition in unentangled polymer nanocomposite melts. AB - The linear and non-linear rheology of a high volume fraction particle filled unentangled polymer melt is measured. The particles in the polymer melt behave like hard spheres as the particle volume fraction is raised. At high volume fractions, the suspension develops a plateau elastic modulus. Over the frequency range of the elastic modulus plateau, the viscous modulus develops a minimum and a maximum. The frequencies of the two local extrema initially have critical power law scaling, suggesting the approach of a singular glass transition. At higher volume fractions in excess of the glass transition, the viscous modulus continues to show a well defined minimum and a well defined maximum. The non-linear moduli show a single perturbative yield point beyond which the suspension softens. The yielding behavior of the nanocomposite is shown to be sensitive to the strain frequency and the proximity of the strain frequency to the maximum frequency for the linear viscous modulus from linear rheology which characterizes thermal relaxation of glassy particle clusters in the zero strain limit. The linear and non-linear measurements are compared against a recently developed mechanical theory for colloidal glasses. PMID- 21828509 TI - The shear modulus of metastable amorphous solids with strong central and bond bending interactions. AB - We derive expressions for the shear modulus of deeply quenched, glassy solids, in terms of a Cauchy-Born free energy expansion around a rigid (quenched) reference state, following the approach due to Alexander (1998 Phys. Rep. 296 65). Continuum-limit explicit expressions of the shear modulus are derived starting from the microscopic Hamiltonians of central and bond-bending interactions. The applicability of the expressions to dense covalent glasses as well as colloidal glasses involving strongly attractive or adhesive bonds is discussed. PMID- 21828510 TI - Influence of AlN, TiN and SiC reduction on the structural environment of lead in waste cathode-ray tubes glass: an x-ray absorption spectroscopy study. AB - This paper reports an x-ray absorption spectroscopy (XAS) analysis of the local structure around lead contained in foam glasses prepared with waste funnel cathode-ray tube glasses (CRT) and three reducing agents AlN, TiN and SiC. The XAS data were collected at the Pb-L(III) edge to measure the influence of the reducing agent concentration on the unreduced lead content present in the glass. XANES spectra have been demonstrated to be a linear combination of both pure metallic lead and funnel glass spectra, with a significant modification of the funnel spectra for the highest contents of reducing agent. We have shown that the average coordination number of lead decreases in the case of TiN and SiC but remains constant in the case of AlN. The coordination number was found to be more affected for TiN than for SiC. Nevertheless, Pb-O bond lengths were determined to be constant close to 2.23 A whatever the reducing agent and its content. PMID- 21828511 TI - Trapping and motion of polarons in weakly disordered DNA molecules. AB - Polaron effects for charge migration in DNA molecules have been previously considered within the Peyrard-Bishop-Holstein model. When a uniform electric field is applied, the polaron moves asymptotically at a constant velocity, provided dissipative effects are taken into account, and then current flows through DNA. Disorder originating from interactions with a random environment of solute molecules and ions surrounding the DNA molecule could prevent charge migration due to the localization of the carrier wavefunction. We studied numerically the Peyrard-Bishop-Holstein model when the disordered DNA molecule is subjected to a uniform electric field. We found the threshold value of the electric field to observe polaron motion when disorder is present. We also calculated the fluctuations of the electric current and found that they provide valuable information about the polaron dynamics. PMID- 21828512 TI - Origin of broad NIR photoluminescence in bismuthate glass and Bi-doped glasses at room temperature. AB - Bi-doped glasses with broadband photoluminescence in the near-infrared (NIR) spectral range are presently receiving significant consideration for potential applications in telecommunications, widely tunable fiber lasers and spectral converters. However, the origin of NIR emission remains disputed. Here, we report on NIR absorption and emission properties of bismuthate glass and their dependence on the melting temperature. Results clarify that NIR emission occurs from the same centers as it does in Bi-doped glasses. The dependence of absorption and NIR emission of bismuthate glasses on the melting temperature is interpreted as thermal dissociation of Bi(2)O(3) into elementary Bi. Darkening of bismuthate glass melted at 1300 degrees C is due to the agglomeration of Bi atoms. The presence of Bi nanoparticles is confirmed by transmission electron microscopy, high-resolution energy dispersive x-ray spectroscopy and element distribution mapping. By adding antimony oxide as an oxidation agent to the glass, NIR emission centers can be eliminated and Bi(3+) is formed. By comparing with atomic spectral data, absorption bands at ~320 , ~500 , 700 , 800 and 1000 nm observed in Bi-doped glasses are assigned to Bi(0) transitions [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text] and [Formula: see text], respectively, and broadband NIR emission is assigned to the transition [Formula: see text]. PMID- 21828513 TI - Dynamics and energy landscape in a tetrahedral network glass-former: direct comparison with models of fragile liquids. AB - We report molecular dynamics simulations for a new model of tetrahedral network glass-former, based on short-range spherical potentials. Despite the simplicity of the forcefield employed, our model reproduces some essential physical properties of silica, an archetypal network-forming material. Structural and dynamical properties, including dynamic heterogeneities and the nature of local rearrangements, are investigated in detail and a direct comparison with models of close-packed, fragile glass-formers is performed. The outcome of this comparison is rationalized in terms of the properties of the potential energy surface, focusing on the unstable modes of the stationary points. Our results indicate that the weak degree of dynamic heterogeneity observed in network glass-formers may be attributed to an excess of localized unstable modes, associated with elementary dynamical events such as bond breaking and reformation. In contrast, the more fragile Lennard-Jones mixtures are characterized by a larger fraction of extended unstable modes, which lead to a more cooperative and heterogeneous dynamics. PMID- 21828514 TI - Electrostatic properties of maghemite (gamma- Fe(2)O(3)) nanocrystalline quantum dots determined by electrophoretic deposition. AB - We applied a DC electric field between two flat electrodes to attract thermally charged maghemite (gamma-Fe(2)O(3)) nanocrystalline quantum dots dissolved in hexane to form smooth, robust, large area and apparently identical films of equal thickness on both electrodes. Visible microscopy, scanning electron microscopy, atomic force microscopy and profilometry showed that the electrophoretically deposited dot films were very smooth with an rms roughness of ~10 nm for ~0.2 um thick films. The films were of high quality. They did not re-dissolve in hexane (as do those formed by dry casting), which is a good solvent for these dots, or in common cleaning solvents such as water, alcohols and acetone. The deposition on both electrodes implies there are both positively and negatively thermally charged dots, unlike conventional electrophoretic deposition. We used simple thermodynamics to explain the results of electrophoretic deposition macroscopically. To connect the macroscopic nature of the deposition to the microscopic nature of the dots we performed electrophoretic mobility measurements of the dots and the results seem to complement the thermodynamic treatment. PMID- 21828515 TI - Relationships between composition and properties of (Cr/Ti)SiN and (Cr/Ti)CN alloys: an ab initio study. AB - It has previously been noted that different fcc metal nitrides exhibit different superior properties, including the high hardness of TiN and the excellent corrosion and oxidation resistance of CrN. Si and C have been added into such metal nitrides in order to tailor their functional properties. Contrary to the intensively studied TiSiN and TiCN nanocomposite and solid solution systems, much less is known about the complex relationships between the composition and the properties of CrSiN and CrCN. In fact, there is a qualitative difference between cubic spin-unpolarized materials such as TiN, and spin-polarized materials such as CrN which may exhibit a cubic/orthorhombic structural transformation. In the present work, we report ab initio calculations of the properties of (Cr/Ti)SiN and (Cr/Ti)CN systems of various compositions. We specifically predict the lattice constant, bulk modulus, elastic tensor, shear modulus, Young's modulus, Poisson's ratio, magnetization, electronic structure and preference towards the cubic/orthorhombic structural transformation. Knowledge of the modeled relationships allows one to tailor the material characteristics of various ternary metal nitrides for different technological applications. PMID- 21828516 TI - The Friedel sum rule at Fano resonances. AB - If a mesoscopic system is non-chaotic or non-ergodic then the thermodynamic and transport properties do not depend on the impurity averaged density of states. We show that the partial density of states as well as the density of states of a given system with a given impurity configuration can be determined exactly from the asymptotic wavefunction (or scattering matrix) at the resonances. The asymptotic wavefunction can be determined experimentally without any knowledge about the quantum mechanical potential (including electron-electron interaction) or wavefunction in the interior of the system. Some counterintuitive relations derived here allow this. PMID- 21828517 TI - Mechanical properties of graphene nanoribbons. AB - Herein, we investigate the structural, electronic and mechanical properties of zigzag graphene nanoribbons in the presence of stress by applying density functional theory within the GGA-PBE (generalized gradient approximation-Perdew Burke-Ernzerhof) approximation. The uniaxial stress is applied along the periodic direction, allowing a unitary deformation in the range of +/- 0.02%. The mechanical properties show a linear response within that range while a nonlinear dependence is found for higher strain. The most relevant results indicate that Young's modulus is considerable higher than those determined for graphene and carbon nanotubes. The geometrical reconstruction of the C-C bonds at the edges hardens the nanostructure. The features of the electronic structure are not sensitive to strain in this linear elastic regime, suggesting the potential for using carbon nanostructures in nano-electronic devices in the near future. PMID- 21828518 TI - The influence of nanoscale phase separation and devitrification on the electrical transport properties of amorphous Cu-Nb alloy thin films. AB - The formation of amorphous phases in immiscible alloys with a large positive enthalpy of mixing is thermodynamically unfavorable. Co-sputter deposited Cu-Nb films exhibit a nanoscale phase separation into Cu-rich and Nb-rich amorphous regions. They show relatively high room temperature resistivity, a negative temperature coefficient of resistance (TCR), and an incomplete superconducting transition with onset at 3.7 K. Annealing the nanophase-separated amorphous films at 200 degrees C results in the nucleation of fcc Cu-rich nanocrystals within an Nb-rich amorphous matrix. This film exhibits multiple resistance steps, eventually showing a sharp drop with (T(C))(onset) = 3.7 K. Annealing at 350 degrees C leads to complete devitrification via the formation of large bcc Nb rich grains encapsulating the existing fcc Cu nanocrystals. These films show low room temperature resistivity, positive TCR, and a sharp superconducting transition with onset at 5.2 K. The electrical transport and superconducting behavior appear to be consistent with a two-stage crystallization process. PMID- 21828519 TI - The mechanical behaviors of polytetrafluorethylene/Al/W energetic composites. AB - The tensile and impact properties of polytetrafluorethylene (PTFE)/Al/W reactive energetic composites were investigated using a universal materials testing machine and an improved pendulum impact tester at room temperature. Samples of four types, all containing W, of differing composition and particle size were prepared by cold pressing and sintering. With increasing W content in the PTFE/Al/W samples, the mass loss during sintering and the density of the materials obtained increased. The addition of microlevel W led to the tensile strength decreasing from 25.3 to 19.8 MPa, while the elongation changed little, but substituting nanolevel W for 5 wt% Al yields a maximal strength of 31.4 MPa. The failure behavior of PTFE/Al/W includes deformation, fracture, disorganization and reaction, in four steps. The addition of 30 wt% of coarse W particles improved the impact strength of the material, but the reactive activity increased and the perfectability of the reaction decreased. PMID- 21828520 TI - Anomalous shift of magnetic diffuse scattering studied by neutron diffraction. AB - Neutron diffraction results, in the vicinity of the magnetic phase transition of USb and MnF(2), are reported. The thermal evolution of the magnetic diffuse signal and nuclear Bragg reflections demonstrate that the centre of gravity of the magnetic signals does not lie at the predicted position as calculated from nuclear reflections. This phenomenon, called the q-shift, was first found using resonance x-ray scattering (RXS). The present results show that, (i) the effect is not an artefact of RXS and is also found with neutrons (ii) that the effect arises from the bulk of the sample and is not restricted to the near surface layer (~2000 A) associated with the RXS probe in actinide systems, (iii) the effect is not restricted to actinide compounds. PMID- 21828521 TI - The synthesis under controlled oxygen partial pressure and the characterization of a layered perovskite system Sr(2)V(1-x)Mo(x)O(4). AB - We have successfully synthesized Sr(2)V(1-x)Mo(x)O(4) from x = 0.3 to 1.0 by an improved process. The layered compound Sr(2)VO(4) is an antiferromagnetic insulator with S = 1/2, while the isostructural Sr(2)MoO(4) is a Pauli paramagnetic metal. The solid solution Sr(2)V(1-x)Mo(x)O(4) of these materials is expected to show a metal-insulator transition. In this paper we report the synthetic process and the results of the magnetic susceptibility and the electrical resistivity. The selection of the starting materials and the adjustment of O(2) partial pressure of less than 10(-12) atm were indispensable for the synthesis. The reducing conditions during the sintering had been determined rationally, according to thermodynamical analysis. Kondo-like behavior in both resistivity and magnetic susceptibility were observed in a limited range of V-containing samples. PMID- 21828522 TI - Investigation of molybdenum and caesium behaviour in urania by ab initio calculations. AB - A theoretical study of molybdenum and caesium solution in uranium dioxide is carried out. Calculations are performed using the density functional theory with the projector-augmented-wave method as implemented in the Vienna ab initio simulation package (VASP). Correlation effects are taken into account within the DFT+U approach. Molybdenum is preferentially inserted in uranium-oxygen divacancies for understoichiometric urania and uranium vacancies for overstoichiometric urania. The favourable sites for caesium solution are the Schottky defect for understoichiometric urania and U vacancies and U-O divacancies for overstoichiometric urania. Using the stability of many binary and ternary compounds in comparison to soluted atoms, we show that caesium and molybdenum are insoluble in uranium dioxide whatever the stoichiometric regime. PMID- 21828523 TI - The soft optic mode in ferroelastic Rb(4)LiH(3)(SO(4))(4). AB - Raman scattering measurements were performed on the ferroelastic compound Rb(4)LiH(3)(SO(4))(4) to determine the nature of the structural transition observed at T(c) = 134 K. A double-grating spectrometer was used to obtain the Raman active B modes of Rb(4)LiH(3)(SO(4))(4). Back-scattering measurements, as a function of temperature, reveal that the 31 cm(-1) mode shows softening consistent with that of an order parameter. As a result, our investigation indicates that the structural transition in Rb(4)LiH(3)(SO(4))(4) should be cataloged as a pseudo-proper ferroelastic transition rather than a proper ferroelastic one. PMID- 21828524 TI - Chiral Swiss rolls show a negative refractive index. AB - Chiral Swiss rolls, consisting of a metal/dielectric laminate tape helically wound on an insulating mandrel, have been developed to form the basis of a highly chiral metamaterial. We have fabricated these elements using a custom-built machine, and have characterized them. We find that the permeability, permittivity, and chirality are all resonant in the region of 80 MHz. The chirality is so strong that it can be directly measured by observing the magnetic response to an applied electric field, and is larger than either the permeability or the permittivity. We have estimated the refractive indices from these data, and find both strong circular dichroism and a wide frequency range where the refractive index is negative. PMID- 21828525 TI - Longitudinal elliptically polarized electromagnetic waves in off-diagonal magnetoelectric split-ring composites. AB - We study the propagation of plane electromagnetic waves through different systems consisting of arrays of split rings of different orientations. Many extraordinary EM phenomena were discovered in such systems, contributed by the off-diagonal magnetoelectric susceptibilities. We find a mode such that the electric field becomes elliptically polarized with a component in the longitudinal direction (i.e. parallel to the wavevector). Even though the group velocity [Formula: see text] and the wavevector k are parallel, in the presence of damping, the Poynting vector does not just get 'broadened', but can possess a component perpendicular to the wavevector. The speed of light can be real even when the product epsilonMU is negative. Other novel properties are explored. PMID- 21828526 TI - Transport and strong-correlation phenomena in carbon nanotube quantum dots in a magnetic field. AB - Transport through carbon nanotube (CNT) quantum dots (QDs) in a magnetic field is discussed. The evolution of the system from the ultraviolet to the infrared is analyzed; the strongly correlated (SC) states arising in the infrared are investigated. Experimental consequences of the physics are presented-the SC states arising at various fillings are shown to be drastically different, with distinct signatures in the conductance and, in particular, the noise. Besides CNT QDs, our results are also relevant to double-QD systems. PMID- 21828527 TI - Electron optics with magnetic vector potential barriers in graphene. AB - An analysis of electron transport in graphene in the presence of various arrangements of delta-function like magnetic barriers is presented. The motion through one such barrier gives an unusual non-specular refraction leading to asymmetric transmission. The symmetry is restored by putting two such barriers in opposite directions side by side. Periodic arrangements of such barriers can be used as Bragg reflectors whose reflectivity has been calculated using a transfer matrix formalism. Such Bragg reflectors can be used to make resonant cavities. We also analyze the associated band structure for the case of infinite periodic structures. PMID- 21828528 TI - Simulating functional magnetic materials on supercomputers. AB - The recent passing of the petaflop per second landmark by the Roadrunner project at the Los Alamos National Laboratory marks a preliminary peak of an impressive world-wide development in the high-performance scientific computing sector. Also, purely academic state-of-the-art supercomputers such as the IBM Blue Gene/P at Forschungszentrum Julich allow us nowadays to investigate large systems of the order of 10(3) spin polarized transition metal atoms by means of density functional theory. Three applications will be presented where large-scale ab initio calculations contribute to the understanding of key properties emerging from a close interrelation between structure and magnetism. The first two examples discuss the size dependent evolution of equilibrium structural motifs in elementary iron and binary Fe-Pt and Co-Pt transition metal nanoparticles, which are currently discussed as promising candidates for ultra-high-density magnetic data storage media. However, the preference for multiply twinned morphologies at smaller cluster sizes counteracts the formation of a single-crystalline L1(0) phase, which alone provides the required hard magnetic properties. The third application is concerned with the magnetic shape memory effect in the Ni-Mn-Ga Heusler alloy, which is a technologically relevant candidate for magnetomechanical actuators and sensors. In this material strains of up to 10% can be induced by external magnetic fields due to the field induced shifting of martensitic twin boundaries, requiring an extremely high mobility of the martensitic twin boundaries, but also the selection of the appropriate martensitic structure from the rich phase diagram. PMID- 21828529 TI - Coalescence phenomena in 1D silver nanostructures. AB - Different coalescence processes on 1D silver nanostructures synthesized by a PVP assisted reaction in ethylene glycol at 160 degrees C were studied experimentally and theoretically. Analysis by TEM and HRTEM shows different defects found on the body of these materials, suggesting that they were induced by previous coalescence processes in the synthesis stage. TEM observations showed that irradiation with the electron beam eliminates the boundaries formed near the edges of the structures, suggesting that this process can be carried out by the application of other means of energy (i.e. thermal). These results were also confirmed by theoretical calculations by Monte Carlo simulations using a Sutton Chen potential. A theoretical study by molecular dynamics simulation of the different coalescence processes on 1D silver nanostructures is presented, showing a surface energy driven sequence followed to form the final coalesced structure. Calculations were made at 1000-1300 K, which is near the melting temperature of silver (1234 K). Based on these results, it is proposed that 1D nanostructures can grow through a secondary mechanism based on coalescence, without losing their dimensionality. PMID- 21828530 TI - Thermodynamic approach to the description of dislocation mobility in quasicrystals. AB - Dislocation mobility in quasicrystals is calculated using basic thermodynamic and hydrodynamic equations. The dependence of the dislocation mobility on viscosity, vacancies and phasons is given. It is shown that the phasonic defects make the major contribution to the inverse mobility of the free segments of dislocations. PMID- 21828531 TI - Thermodynamic theory of epitaxial alloys: first-principles mixed-basis cluster expansion of (In, Ga)N alloy film. AB - Epitaxial growth of semiconductor alloys onto a fixed substrate has become the method of choice to make high quality crystals. In the coherent epitaxial growth, the lattice mismatch between the alloy film and the substrate induces a particular form of strain, adding a strain energy term into the free energy of the alloy system. Such epitaxial strain energy can alter the thermodynamics of the alloy, leading to a different phase diagram and different atomic microstructures. In this paper, we present a general-purpose mixed-basis cluster expansion method to describe the thermodynamics of an epitaxial alloy, where the formation energy of a structure is expressed in terms of pair and many-body interactions. With a finite number of first-principles calculation inputs, our method can predict the energies of various atomic structures with an accuracy comparable to that of first-principles calculations themselves. Epitaxial (In, Ga)N zinc-blende alloy grown on GaN(001) substrate is taken as an example to demonstrate the details of the method. Two (210) superlattice structures, (InN)(2)/(GaN)(2) (at x = 0.50) and (InN)(4)/(GaN)(1) (at x = 0.80), are identified as the ground state structures, in contrast to the phase-separation behavior of the bulk alloy. PMID- 21828532 TI - The minority spin surface bands of CoS(2)(001). AB - Angle-resolved photoemission was used to study the surface electronic band structure of high quality single crystals of ferromagnetic CoS(2) (below 120 K). Strongly dispersing Co t(2g) bands are identified along the ?100? [Formula: see text] direction, the [Formula: see text]-[Formula: see text] line of the surface Brillouin zone, in agreement with model calculations. The calculated surface band structure includes corrections for the previously determined surface structure of CoS(2)(001) and is in general agreement with the experimental photoemission spectra in the region of the Fermi level. There is evidence of the existence of several minority spin surface states, falling into a gap of the projected minority spin bulk CoS(2)(001) band structure. PMID- 21828533 TI - The Fulde-Ferrell-Larkin-Ovchinnikov phase in the presence of pair hopping interaction. AB - The recent experimental support for the presence of the Fulde-Ferrell-Larkin Ovchinnikov (FFLO) phase in CeCoIn(5) directed attention towards the mechanisms responsible for this type of superconductivity. We investigate the FFLO state in a model where on-site/inter-site pairing coexists with the repulsive pair hopping interaction. The latter interaction is interesting in that it leads to pairing with non-zero momentum of the Cooper pairs even in the absence of the external magnetic field (the so-called eta pairing). It turns out that, depending on the strength of the pair hopping interaction, the magnetic field can induce one of two types of the FFLO phase with different spatial modulations of the order parameter. It is argued that the properties of the FFLO phase may give information about the magnitude of the pair hopping interaction. We also show that eta pairing and d-wave superconductivity may coexist in the FFLO state. It holds true also for superconductors which, in the absence of magnetic field, are of pure d-wave type. PMID- 21828534 TI - Interference effects on vibration-mediated tunneling through interacting degenerate molecular states. AB - We study the combined effects of quantum electronic interference and Coulomb interaction on electron transport through near-degenerate molecular states with strong electron-vibration interaction. It is found that quantum electronic interference strongly affects the current and its noise properties. In particular, destructive interference induces pronounced negative differential conductances (NDCs) accompanying the vibrational excited states, and such NDC characters are not related to asymmetric tunnel coupling and are robust to the damping of a thermal bath. In a certain transport regime, the non-equilibrium vibration distribution even shows a peculiar sub-Poissonian behavior, which is enhanced by quantum electronic interference. PMID- 21828535 TI - Absence of localization in a disordered one-dimensional ring threaded by an Aharonov-Bohm flux. AB - Absence of localization is demonstrated analytically to leading order in weak disorder in a one-dimensional Anderson model of a ring threaded by an Aharonov Bohm (AB) flux. The result follows from adapting an earlier perturbation treatment of disorder in a superconducting ring subjected to an imaginary vector potential proportional to a depinning field for flux lines bound to random columnar defects parallel to the axis of the ring. The absence of localization in the ring threaded by an AB flux for sufficiently weak disorder is compatible with large free-electron-type persistent current obtained in recent studies of the above model. PMID- 21828536 TI - X-ray absorption near-edge structure of GaN with high Mn concentration grown on SiC. AB - By means of x-ray absorption near-edge structure (XANES) several Ga(1-x)Mn(x)N (0.03=0.2 in CaRu(1-x)Mn(x)O(3). For the sample with x = 0.4, the Curie temperature of ~160 K is obtained from the Arrott plot and the ratio of effective moment and saturation moment P(eff)/M(0) is estimated to be ~4.8. We further found that the magnetization is significantly suppressed with decreasing temperature T below ~90 K. In the neutron diffraction experiment at T = 15 K, we observed the evolution of a magnetic Bragg peak originating from the G-type antiferromagnetic order as well as the ferromagnetic one. This strongly suggests that both ferromagnetic and antiferromagnetic states are coexistent with each other at low temperatures. In the M(T)(0)(2) against T(2) plot (here, M(T)(0) is a spontaneous magnetization estimated from the Arrott plot), M(T)(0)(2) linearly increases with decreasing T(2) in the ferromagnetic region between ~90 and 160 K. The ferromagnetic properties of the CaRu(1-x)Mn(x)O(3) system (x<=0.5) are well explained in terms of spin fluctuation theory based on the itinerant electron model rather than the localized spin model. PMID- 21828542 TI - Magnetic properties of the field-induced ferromagnetic state in MnSi. AB - We present results of dc magnetization measurements focusing on the magnetic properties of the field-induced ferromagnetic state in MnSi. The temperature dependence of saturation magnetization in this ferromagnetic state exhibits the signatures of both spin wave excitations and itinerant electron ferromagnetism. The Arrott plots obtained from the isothermal field dependence of magnetization, however, are found to be distinctly nonlinear and hence cannot be explained within a simple framework of itinerant electron magnetism. PMID- 21828543 TI - Magnetic behavior of nanocrystalline ErCo(2). AB - We have investigated the magnetic behavior of the nanocrystalline form of a well known Laves phase compound, ErCo(2)-the bulk form of which has been known to undergo an interesting first-order ferrimagnetic ordering near 32 K-synthesized by high-energy ball-milling. It is found that, in these nanocrystallites, Co exhibits ferromagnetic order at room temperature, as inferred from the magnetization data. However, the magnetic transition temperature for the Er sub lattice remains essentially unaffected suggesting the (Er)4f-Co(3d) coupling is weak on Er magnetism. The net magnetic moment as measured at high fields, for example at 120 kOe, is significantly reduced with respect to that for the bulk in the ferrimagnetically ordered state and possible reasons are outlined for this. We have also compared the magnetocaloric behavior for the bulk and for nanoparticles. PMID- 21828544 TI - Study of magnetic anisotropy and magnetization reversal using the quadratic magnetooptical effect in epitaxial Co(x)Mn(y)Ge(z)(111) films. AB - Magnetic anisotropy, magnetization reversal and the magnetooptic Kerr effect in Co(x)Mn(y)Ge(z) have been studied over a range of compositions between 0 and 50 at.% of Ge and between 1 and 3 in the Co to Mn atomic ratio, including the Heusler alloy Co(2)MnGe. A strong quadratic magnetooptic Kerr effect has been observed within a narrow region of composition centered around the Co to Mn atomic ratio of 2, which has been used to probe and quantify the magnetic anisotropy and magnetization reversal of the system. The anisotropy is sixfold with a weak uniaxial component, and it exhibits sensitive dependence on composition, especially on the atomic ratio between Co and Mn. The magnetization reversal process is consistent with the single-domain Stoner-Wohlfarth model. PMID- 21828545 TI - First principles studies of multiferroic materials. AB - Multiferroics, materials where spontaneous long-range magnetic and dipolar orders coexist, represent an attractive class of compounds, which combine rich and fascinating fundamental physics with a technologically appealing potential for applications in the general area of spintronics. Ab initio calculations have significantly contributed to recent progress in this area, by elucidating different mechanisms for multiferroicity and providing essential information on various compounds where these effects are manifestly at play. In particular, here we present examples of density-functional theory investigations for two main classes of materials: (a) multiferroics where ferroelectricity is driven by hybridization or purely structural effects, with BiFeO(3) as the prototype material, and (b) multiferroics where ferroelectricity is driven by correlation effects and is strongly linked to electronic degrees of freedom such as spin-, charge-, or orbital-ordering, with rare-earth manganites as prototypes. As for the first class of multiferroics, first principles calculations are shown to provide an accurate qualitative and quantitative description of the physics in BiFeO(3), ranging from the prediction of large ferroelectric polarization and weak ferromagnetism, over the effect of epitaxial strain, to the identification of possible scenarios for coupling between ferroelectric and magnetic order. For the second class of multiferroics, ab initio calculations have shown that, in those cases where spin-ordering breaks inversion symmetry (e.g. in antiferromagnetic E-type HoMnO(3)), the magnetically induced ferroelectric polarization can be as large as a few uC cm(-2). The examples presented point the way to several possible avenues for future research: on the technological side, first principles simulations can contribute to a rational materials design, aimed at identifying spintronic materials that exhibit ferromagnetism and ferroelectricity at or above room temperature. On the fundamental side, ab initio approaches can be used to explore new mechanisms for ferroelectricity by exploiting electronic correlations that are at play in transition metal oxides, and by suggesting ways to maximize the strength of these effects as well as the corresponding ordering temperatures. PMID- 21828546 TI - The influence of tube length, radius and chirality on the buckling behavior of single-walled carbon nanotubes filled with copper atoms. AB - The buckling behavior of single-walled carbon nanotubes completely filled with copper atoms under uniaxial compression is investigated using molecular dynamics simulations and compared with that modeled by continuum mechanics. The effects of geometrical characteristics, i.e. tube length, radius and chirality, on buckling deformations are explored separately. Results show that the behavior of encapsulated tubes is more complicated than that of empty ones due to the accommodation of the internal metal atoms. There are both similarities and differences between the results obtained by the molecular dynamics method and continuum mechanics. For a group of completely filled (10, 10) tubes with different length, the dependence of the critical strain on the tube length can be roughly divided into four different linear stages and is accompanied by a transition of the buckling mode from local to global. It is the competition between the evolution of the structure of metal atoms and the variation of the tube length that determines the critical strain. There exists a rather wide range of tube radii within which the critical strain has a weak dependence on tube radius, which differs from the observation for empty tubes. As compared with a zigzag tube of the same length and radius, an armchair tube has a lower critical strain but can be easily strengthened with the incorporation of internal metal atoms. PMID- 21828547 TI - Nonlinear dc transport in graphene. AB - Considering electron-impurity, electron-acoustic-phonon and electron-optical phonon scatterings, the nonlinear steady-state transport properties of graphene are studied theoretically by means of the balance equation approach. We find that the conductivity as a function of electric field strength, E, exhibits strongly nonlinear behavior for E larger than a critical value, E(c)~0.1 kV cm(-1). With the increase of E from zero, the conductivity first decreases slowly and then it falls rapidly when E>E(c). The dependence of electron temperature on E is also demonstrated. PMID- 21828548 TI - Validity of the single-particle approach for electron transport in quantum wires assisted by surface acoustic waves. AB - We study by means of time-dependent numerical simulations the quantum entanglement stemming from the Coulomb interaction between two electrons trapped in the minima of the piezoelectric potential generated by surface acoustic waves. We find that for particles captured in low-energy bound states the quantum correlations turn out to be negligible, thus validating a single-particle approach to the dynamics of such systems. At long times, for high-energy electrons, a substantial entanglement appears, which is an indicator of a mostly correlated dynamics. PMID- 21828549 TI - The formation, structure and physical properties of M(2)Pd(14+x)B(5-y) compounds, with M = La, Ce, Pr, Nd, Sm, Eu, Gd, Lu and Th. AB - Novel ternary compounds, M(2)Pd(14+x)B(5-y) (M = La, Ce, Pr, Nd, Sm, Eu, Gd, Lu, Th; x~0.9, y~0.1), have been synthesized by arc melting. The crystal structures of Nd(2)Pd(14+x)B(5-y) and Th(2)Pd(14+x)B(5-y) were determined from x-ray single crystal data and both are closely related to the structure type of Sc(4)Ni(29)B(10). All compounds were characterized by Rietveld analyses and found to be isotypic with the Nd(2)Pd(14+x)B(5-y) type. Measurements of the temperature dependent susceptibility and specific heat as well as the temperature and field dependent resistivity were employed to derive basic information on bulk properties of these compounds. The electrical resistivity of M(2)Pd(14+x)B(5-y), in general, is characterized by small RRR (residual resistance ratio) values originating from defects inherent to the crystal structure. Whereas the compounds based on Ce, Nd, Sm and Gd exhibit magnetic order, those based on Pr and Eu seem to be non-magnetic, at least down to 400 mK. While the non-magnetic ground state of the Pr based compound is a consequence of crystalline electric field effects in the context of the non-Kramers ion Pr, the lack of magnetic order in the case of the Eu based compound results from an intermediate valence state of the Eu ion. PMID- 21828550 TI - Calculation of the vibrational properties of LiMgAs. AB - We have studied the vibrational properties of the filled tetrahedral semiconductor LiMgAs and its binary analog AlAs by using the plane-wave pseudopotential method within density functional theory. The calculated lattice constants for the studied compounds are in good agreement with previous theoretical and experimental results. The phonon dispersion curves and phonon density of states are calculated by using density functional perturbation theory. The sound speeds in different directions are quantitatively similar in LiMgAs and AlAs. The assignment of the zone center modes to the relative motion of the atoms shows that the lower optic modes are due to the Mg-As pair vibrations, while for the upper ones the Li-Mg pair dominates, which is attributed to the smaller Mg atom mass. The longitudinal interatomic force constant of Mg-As is about 66% higher than that of Li-As, showing the relatively high covalency of the former bond. PMID- 21828551 TI - A comprehensive survey of M(2)AX phase elastic properties. AB - M(2)AX phases are a family of nanolaminate, ternary alloys that are composed of slabs of transition metal carbide or nitride (M(2)X) separated by single atomic layers of a main group element. In this combination, they manifest many of the beneficial properties of both ceramic and metallic compounds, making them attractive for many technological applications. We report here the results of a large scale computational survey of the elastic properties of all 240 elemental combinations using first-principles density functional theory calculations. We found correlations revealing the governing role of the A element and its interaction with the M element on the c axis compressibility and shearability of the material. The role of the X element is relatively minor, with the strongest effect seen in the in-plane constants C(11) and C(12). We identify several elemental compositions with extremal properties such as W(2)SnC, which has by far the lowest value of C(44), suggesting potential applications as a high temperature dry lubricant. PMID- 21828552 TI - Electronic and magnetic structure for the spin-gapped system CuTe(2)O(5). AB - The results of the calculation of the electronic and magnetic properties for the spin-gapped material CuTe(2)O(5) are presented. The direct computation of exchange constants J in the framework of the LDA+U shows that the largest exchange coupling in CuTe(2)O(5) is found between fourth nearest neighbors, as was argued by Das et al (2008 Phys. Rev. 77 224437), and that this compound should be considered as the two-dimensional coupled dimer system. PMID- 21828553 TI - First-principles study of ionic oxygen mobility of Sr-containing LaAlO(3) perovskite. AB - The fundamental phenomena underlying the electrical conduction properties of Sr containing LaAlO(3) perovskites are studied through DFT simulations. The most energetically favourable substitution sites for Sr in the LaAlO(3) lattice and the energetic barriers for oxygen diffusion were calculated. Ab initio molecular dynamics was used to investigate the onset of oxygen transport. Experimental characterization of this material has suggested the existence of undercoordinated Al atoms upon substitution of La with Sr. Our results confirm the existence of four- (Al(IV)) and fivefold (Al(V))-coordinated Al at the expense of the amount of sixfold-coordinated ones (Al(VI)), and explain the appearance of a small peak at 66 ppm in the (27)Al NMR spectrum. PMID- 21828554 TI - Influence of pressure on the magnetic ordering of CeNiSnH and CeNiSnH(1.8) hydrides. AB - The magnetic properties of the antiferromagnet CeNiSnH and of the ferromagnet CeNiSnH(1.8) on hydrostatic pressure (0<=P<=10.8 bar) have been determined using a miniature piston-cylinder CuBe pressure cell. With increasing P, the Neel temperature of CeNiSnH increases weakly from 4.77 to 5.01 K whereas the Curie temperature of CeNiSnH(1.8) decreases rapidly from 7.16 to 5.30 K. Similar pressure dependence is also observed in the critical field of the metamagnetic transition of CeNiSnH and in the coercive field of CeNiSnH(1.8). Electronic structure calculations for these hydrides within the density functional theory show agreement with the experimental findings. Detailed examination of the chemical bonding features point to the conclusion that the antibonding Ce-Ni states below the Fermi level for CeNiSnH(1.8) could be responsible for the decrease of its Curie temperature under applied pressure. PMID- 21828555 TI - A functional renormalization group approach to the Anderson impurity model. AB - We develop a functional renormalization group approach which describes the low energy single-particle properties of the Anderson impurity model up to intermediate on-site interactions [Formula: see text], where Delta is the hybridization in the wide-band limit. Our method is based on a generalization of a method proposed by Schutz et al (2005 Phys. Rev. B 72 035107), using two independent Hubbard-Stratonovich fields associated with transverse and longitudinal spin fluctuations. Although we do not reproduce the exponentially small Kondo scale in the limit [Formula: see text], the spin fluctuations included in our approach remove the unphysical Stoner instability predicted by mean field theory for U>piDelta. We discuss different decoupling schemes and show that a decoupling which manifestly respects the spin-rotational invariance of the problem gives rise to the lowest quasiparticle weight. To obtain a closed flow equation for the fermionic self-energy we also propose a new scheme of truncation of the functional renormalization group flow equations using Dyson-Schwinger equations to express bosonic vertex functions in terms of fermionic ones. PMID- 21828556 TI - The metal-insulator transition in Fe(1.01-x)Cu(x)Se. AB - Iron selenide, Fe(1.01)Se, the layered parent compound of the recently discovered superconducting arsenide family, has previously been shown to be non-magnetic and superconducting with a critical temperature of 8 K. Here we show that copper can be substituted at the iron site in Fe(1.01)Se up to a solubility limit of 20-30%, after which a first-order transition to the three-dimensional CuFeSe(2) structure type is observed. As little as 1.5% copper is sufficient to suppress the superconductivity, and 4% drives the system through a metal-insulator transition. A local magnetic moment is introduced, which maximizes near 12% doping, where a spin-glass transition near 15 K is observed. PMID- 21828557 TI - Neutron diffraction investigation of the magnetic structure and magnetoelastic effects in NdMnO(3). AB - We investigated the evolution of the magnetic structure and magnetoelastic effects of NdMnO(3) by neutron powder diffraction. We confirmed the A-type antiferromagnetic (AF) structure of NdMnO(3) below T(N)~82 K with magnetic moments parallel to the b axis of the orthorhombic crystal structure (space group Pbnm). We found that the magnetic moments of Nd order below about T(N)(Nd)~20 K in a ferromagnetic structure with moments parallel to the c axis. At the same temperature the magnetic moments of Mn develop a ferromagnetic component parallel to the c axis. We found strong magnetoelastic effects associated with the AF transition at T(N)~82 K. The effect is very prominent for the b lattice parameter. All three lattice parameters and therefore the unit cell volume contracts at T(N)~82 K. We treated quantitatively the magnetoelastic effect of the b lattice parameter and found that the extra change in the lattice parameter Deltab due to the magnetoelastic effect is proportional to the magnetic moment of the Mn ion. We also determined the critical exponent of the AF phase transition to be beta = 0.296 +/- 0.008. PMID- 21828558 TI - Magnetic and structural properties of Lu(2)(Fe, Mn)(17)H(y) hydrides. AB - The Lu(2)Fe(17-x)Mn(x)H(y), x = 0-2, y = 0-3, hydrides with the Th(2)Ni(17)-type crystal structure were prepared and their structural and magnetic parameters were studied. The lattice parameters measured at room temperature increase smoothly with H content. The magnetic measurements indicate that the Lu(2)Fe(17)H(y) hydrides (with y up to 1.77) are antiferromagnets at high temperatures and ferromagnets at low temperatures. The Lu(2)Fe(16.5)Mn(0.5) compound also has a high temperature antiferromagnetic state, but its hydrides are ferromagnets only. The Lu(2)Fe(17-x)Mn(x)H(y) hydrides, with x = 0.7 and 2, are ferromagnets with T(c) monotonically increasing with H content. The saturation magnetization measured for Lu(2)Fe(17-x)Mn(x)H(y), (x = 0,0.5,0.7,2 and 0